PMID- 21298175 TI - Density, viscosity and electrical conductivity of protic alkanolammonium ionic liquids. AB - Ionic liquids are molten salts with melting temperatures below the boiling point of water, and their qualification for applications in potential industrial processes does depend on their fundamental physical properties such as density, viscosity and electrical conductivity. This study aims to investigate the structure-property relationship of 15 ILs that are primarily composed of alkanolammonium cations and organic acid anions. The influence of both the nature and number of alkanol substituents on the cation and the nature of the anion on the densities, viscosities and electrical conductivities at ambient and elevated temperatures are discussed. Walden rule plots are used to estimate the ionic nature of these ionic liquids, and comparison with other studies reveals that most of the investigated ionic liquids show Walden rule values similar to many non-protic ionic liquids containing imidazolium, pyrrolidinium, tetraalkylammonium, or tetraalkylphosphonium cations. Comparison of literature data reveals major disagreements in the reported properties for the investigated ionic liquids. A detailed analysis of the reported experimental procedures suggests that inappropriate drying methods can account for some of the discrepancies. Furthermore, an example for the improved presentation of experimental data in scientific literature is presented. PMID- 21298176 TI - C-H functionalization logic in total synthesis. AB - In this critical review, the strategic and economic benefits of C-H functionalization logic will be analyzed through the critical lens of total synthesis. In order to illustrate the dramatically simplifying effects this type of logic can potentially have on synthetic planning, we take the reader through a series of case studies in which it has already been successfully applied. In the first section, a chronological look at key historical syntheses will be examined, leading into modern day examples. In the second section, our own experience with applying and executing synthesis with a C-H functionalization "mindset" will be discussed (114 references). PMID- 21298177 TI - Enantioselective ecotoxicity of the herbicide dichlorprop and complexes formed with chitosan in two fresh water green algae. AB - To reduce the leaching potential, to prevent groundwater contamination and to maintain the efficacy of a pesticide, natural polysaccharides have received increasing attention due to their biocompatibility and useful biological reactivity for controlled release formulations (CRFs) of pesticides. In this paper, the toxicities of the chiral herbicide dichlorprop (DCPP) and its complexes with chitosan molecules (DCPP-CS) and chitosan nanoparticles (DCPP-NP) to two different green algae were determined and compared. The inhibition rates of DCPP, DCPP-CS and DCPP-NP were determined at 24, 48, 72, 96, 120, 144, 168 h, and the results show that (S)-DCPP was more toxic to Chlorella vulgaris than (R) DCPP, while the (R)-DCPP was more toxic to Scenedesmus obliquus than (S)-DCPP. The study also found that the chiral selectivity of DCPP to Chlorella vulgaris and Scenedesmus obliquus could be changed when DCPP was complexed with chitosan molecules (CS) or chitosan nanoparticles (NP). For Chlorella vulgaris, the order of inhibition was (R)-DCPP-CS > (S)-DCPP-CS and (R)-DCPP-NP > (S)-DCPP-NP; for Scenedesmus obliquus, the order was (S)-DCPP-CS > (R)-DCPP-CS and (S)-DCPP-NP > (R)-DCPP-NP. This phenomenon suggests that the enantioselective behaviors of chiral compounds might shift when interactions with other chiral receptors coexist in different biological environments. Additionally, chitosan molecules and chitosan nanoparticles also showed different toxicities, which could be ascribed to the difference in the physicochemical properties between CS and NP or the differences in the cell walls of the two fresh water green algae. PMID- 21298178 TI - Recombinant Escherichia coli GMP reductase: kinetic, catalytic and chemical mechanisms, and thermodynamics of enzyme-ligand binary complex formation. AB - Guanosine monophosphate (GMP) reductase catalyzes the reductive deamination of GMP to inosine monophosphate (IMP). GMP reductase plays an important role in the conversion of nucleoside and nucleotide derivatives of guanine to adenine nucleotides. In addition, as a member of the purine salvage pathway, it also participates in the reutilization of free intracellular bases. Here we present cloning, expression and purification of Escherichia coli guaC-encoded GMP reductase to determine its kinetic mechanism, as well as chemical and thermodynamic features of this reaction. Initial velocity studies and isothermal titration calorimetry demonstrated that GMP reductase follows an ordered bi-bi kinetic mechanism, in which GMP binds first to the enzyme followed by NADPH binding, and NADP(+) dissociates first followed by IMP release. The isothermal titration calorimetry also showed that GMP and IMP binding are thermodynamically favorable processes. The pH-rate profiles showed groups with apparent pK values of 6.6 and 9.6 involved in catalysis, and pK values of 7.1 and 8.6 important to GMP binding, and a pK value of 6.2 important for NADPH binding. Primary deuterium kinetic isotope effects demonstrated that hydride transfer contributes to the rate-limiting step, whereas solvent kinetic isotope effects arise from a single protonic site that plays a modest role in catalysis. Multiple isotope effects suggest that protonation and hydride transfer steps take place in the same transition state, lending support to a concerted mechanism. Pre-steady-state kinetic data suggest that product release does not contribute to the rate limiting step of the reaction catalyzed by E. coli GMP reductase. PMID- 21298179 TI - Sugar-bearing tetraphenylethylene: novel fluorescent probe for studies of carbohydrate-protein interaction based on aggregation-induced emission. AB - Neutral sugar-bearing tetraphenylethenes (TPE) are designed and prepared as "turn on" luminescent sensors for lectins and glycosidases based on aggregation-induced emission. Through aggregation derived from carbohydrate-lectin binding, multivalent mannosyl-bearing TPE shows a good selectivity and sensitivity to Con A by switching on the fluorescence of water-soluble tetraphenylethylene-based glyco-conjugates in aqueous solution. Meanwhile, cellobiosyl-bearing TPE can be used to investigate enzymatic hydrolysis based on emission enhancing by glycosidase-induced aggregation. PMID- 21298180 TI - Total synthesis of C19 lipid diols containing a 2,5-disubstituted-3-oxygenated tetrahydrofuran. AB - The total synthesis of the C(19) lipid diols 5 and 6, the enantiomers of the anthelmintic marine natural products 1 and 3, is described. Key steps in the divergent syntheses include a syn selective epoxidation of a homoallylic alcohol, a one-pot alkoxypalladation-carbonylation-lactonisation reaction sequence and a DMEAD promoted Mitsunobu inversion. PMID- 21298181 TI - An environmentally friendly Mukaiyama aldol reaction catalyzed by a strong Bronsted acid in solvent-free conditions. AB - o-Benzenedisulfonimide, a new strong bench-stable Bronsted acid, has been shown to efficiently catalyze the Mukaiyama aldol reaction of aldehydes or dimethyl acetals with silyl enol ethers under mild solvent-free reaction conditions. PMID- 21298182 TI - 7-Deazapurine biosynthesis: NMR study of toyocamycin biosynthesis in Streptomyces rimosus using 2-13C-7-15N-adenine. AB - Although 7-deazapurines are well known and feature in the hypermodified RNA base queuosine, and in a range of nucleoside antibiotics such as toyocamycin, a mechanistic understanding of their biosynthesis is a longstanding problem. In particular, the obligatory loss of the N-7 nitrogen atom is puzzling, and in order to address this mechanistic conundrum a novel doubly labeled purine, [2 (13)C, 7-(15)N]-adenine, has been prepared and used as a biosynthetic precursor to toyocamycin in Streptomyces rimosus. NMR spectroscopy and mass spectrometry clearly showed incorporation of (13)C but loss of (15)N in the toyocamycin produced. PMID- 21298183 TI - Photooxidation of 1,5-dihydroxynaphthalene with iridium complexes as singlet oxygen sensitizers. AB - Photooxidation reactions of 1,5-dihydroxynaphthalene (DHN) have been carried out in the presence of cyclometalated neutral and cationic iridium (Ir) complexes 1-6 as singlet oxygen ((1)O(2)) sensitizers in order to investigate the (1)O(2) generation quantum yield and photosensitizing durability of the complexes. The reactions allowed a successful kinetic study to provide the pseudo-first-order rate constants and the initial rates of DHN consumption, which in turn led to the (1)O(2) generation quantum yields. The results revealed that cationic Ir complexes [Ir(ppy)(2)(phen)(+) (4) and Ir(ppy)(2)(bpy)(+) (5), where ppy = 2 phenylpyridine, phen = 1,10-phenanthroline, bpy = 2,2'-bipyridyl] have high (1)O(2) generation quantum yields (Phi(Delta) = 0.93, 0.97). On the other hand, neutral complexes with lower oxidation potentials were considered to have a more efficient charge-transfer (CT) interaction with molecular oxygen, which decreased the efficiency of singlet oxygen formation. Additionally, a steric factor of the ligands was reflected in (1)O(2) generation quantum yield. High yields of the oxidized product for the photoreactions using the cationic complexes indicated their excellent photosensitizing durability, originating from the high photochemical stability upon irradiation. PMID- 21298184 TI - Fullerol in human lens and retinal pigment epithelial cells: time domain fluorescence spectroscopy and imaging. AB - Fullerol is a fullerene derivative that is extensively hydroxylated [nano C(60)(OH)(24)] and this makes it water-soluble. These fullerene derivatives have shown promise as drug carriers that bypass ocular barriers but fullerols are also potentially phototoxic to human lens and retinal tissues. Fluorescence imaging is a powerful and non-invasive means of probing nanoparticles in biological systems. However, fullerol nanoparticles have a very low level of fluorescence and have not as yet been imaged in vitro and in vivo. Using specialized measurements including time-correlated single photon counting (TCSPC), fullerol fluorescence was determined in aqueous solutions and detected in both human lens and retinal pigment epithelial cells. Time-resolved fluorescence of fullerol (5-200 MUM) was characterized in aqueous environment, where the fluorescence decay is best fitted with three lifetimes (3 ns, 0.7-0.9 ns and 0.2 ns). Time-resolved microspectrofluorimetry and time-gated fluorescence imaging were performed on both human lens and retinal pigment epithelial cells incubated with increasing fullerol doses (5-500 MUM and 5-50 MUM, respectively). Upon increasing concentration, we observe some shortening of the lifetimes, a reduction in the relative amplitude of the shortest-living component and a corresponding increase in the weight of the intermediate-living species. Time-gated imaging of fullerol fluorescence provided information on its intracellular distribution that correlates with progressive cell damage. Therefore time-gated imaging may potentially be used as a means to investigate fullerol distribution and toxicity in the human lens and retina in vivo. PMID- 21298185 TI - Control of metal-directed self-assembly by metal-amine interactions. AB - The complexation of a tweezers ligand with zinc perchlorate in the absence and presence of amines in methanol solution was explored. L(2)Zn(2)(ClO(4))(4) was a thermodynamic product of the reaction in the absence of an amine. The complex was shown to interact with aliphatic amines resulting in the formation of a Zn N(amine) bond. If metal-ligand complexation was carried out in the presence of an amine the formation of a trinuclear zinc complex L(3)Zn(3)(6+) was observed. Moreover the transformation of complex L(2)Zn(2)(4+) to L(3)Zn(3)(6+) occurred, when the former was subjected to an amine in the amount, which is sufficient to coordinate more than one amino group on each zinc atom. Complexes ligand-zinc amine were shown to be kinetically stable, and the method of their preparation was crucial to the purity of the final complexes. L(3)Zn(3)(6+) was favored under kinetic control: reagent concentration 10(-5)M, slow addition of zinc perchlorate to the mixture of an amine and the ligand. Under thermodynamic control (fast mixing of reagents, concentration 10(-2)-10(-3) M) formation of a mixture of complexes was observed. All pure complexes and their mixtures were characterized using UV-Vis, ROESY, PFGSE NMR and ESI-MS techniques. On the basis of DFT calculations the mechanism of influence of an amine on self-assembly was suggested. PMID- 21298186 TI - A study on the coordinative versatility of new N,S-donor macrocyclic ligands: XAFS, and Cu2+ complexation thermodynamics in solution. AB - We investigated, both in the solid state and in aqueous solution, the coordination environment and stability behavior of four macrocyclic ligands (three N(2)S(2) and one N(3)S(2)) and of the corresponding Cu(II) complexes. The structural characterization in the solid state of the copper derivatives was performed by X-Ray Absorption Spectroscopy. Copper is found to be 4-fold coordinated with a CuN(2)S(2) environment with different Cu-S distances depending on the size of the macrocyclic ring. The EXAFS technique has indicated that nitrogen and sulfur atoms are more preferable to oxygen atoms as donor systems, without the evidence of coordination of the carboxylic moieties to copper in the first shell. The joint EXAFS and XANES study of the copper(II) complex with the N(3)S(2) ligand confirms the 4-fold coordination with an additional, long Cu-N interaction. The Cu(2+) complexation constants for one ligand were determined in aqueous solution. The results indicate that the species [CuL], although isolated in the solid state, is not the most abundant at the pH of blood serum. Instead, at pH 7.4 the protonated [Cu(HL)](+) species was found to be the most relevant. The behaviour of the copper complexes in the presence of the strong copper chelating bioagent human serum albumin was also examined in order to gain information on the stability of these compounds in biological fluids. PMID- 21298187 TI - Supramolecular hydrogels based on short peptides linked with conformational switch. AB - Short peptides appropriately linked with an azobenzene conformational switch were found to be motif and pH dependant supramolecular hydrogelators. The hydrogelation properties of the short peptides linked with the conformational switch were studied in detail with respect to dependence on amino acid residue, pH and salt effect. The presence of amino acids with aromatic side chains such as Phe and Tyr was found to be favorable for the short peptides to gel water at an appropriate pH range. Cationic amino acid residues such as Arg and Lys in the short peptides were found to be unfavorable for hydrogelation. pH and salt effect were also found to be important factors for the hydrogelation properties of the short peptides. A series of short peptides with bioactive sequences were linked with the conformational switch and their hydrogelation properties were investigated. Photoresponsive supramolecular hydrogels were realized based on the E-/Z- transition of the conformational switch upon light irradiation. Proper combination of amino acid residues in the short peptides resulted in smart supramolecular hydrogels with responses to multiple stimuli. PMID- 21298188 TI - Pd nanoparticles on a porous ionic copolymer: a highly active and recyclable catalyst for Suzuki-Miyaura reaction under air in water. AB - A porous copolymer of an IL with divinylbenzene was prepared and applied as a support for Pd nanoparticles. The supported Pd nanocatalyst was found to be extremely active for Suzuki-Miyaura reaction of aryl bromides and chlorides with phenylboronic acid even with 10 ppm Pd loading under air in water. PMID- 21298189 TI - Insight into the chiral induction in supramolecular stacks through preferential chiral solvation. AB - Preferred handedness in the supramolecular chirality of self-assembled achiral oligo(p-phenylenevinylene) (OPV) derivatives is induced by chiral solvents and spectroscopic probing provides insight into the mechanistic aspects of this chiral induction through chiral solvation. PMID- 21298190 TI - Novel C3-symmetric n-type tris(aroyleneimidazole) and its analogs: synthesis, physical properties and self-assembly. AB - Novel n-type C(3)-symmetric materials are synthesized and shown to have desirable bandgap, broad absorption and high thermal stability, thus pose as viable candidates for organic photovoltaics. The strong intermolecular interactions among the extended pi-surfaces beget the self-assembly of nanofibers. PMID- 21298191 TI - Highly selective one-pot synthesis of H-bonded pentagon-shaped circular aromatic pentamers. AB - One-pot, multi-molecular macrocyclization allows the highly selective preparation of pentagon-shaped circular aromatic pentamers mediated by an inward-pointing continuous hydrogen-bonding network. PMID- 21298192 TI - Crown ethers at the aqueous solution-air interface: 1. Assignments and surface spectroscopy. AB - The surface of aqueous solutions of 4-Nitro Benzo-15-Crown-5 (NB15C5) and Benzo 15-Crown-5 (B15C5) has been studied using the surface sensitive technique vibrational sum frequency spectroscopy (VSFS). The NO, CN, COC and CH vibrational modes of these compounds at the air-water interface as well as OH vibrational modes of the surface water hydrating this compound have been targeted in order to obtain molecular information about arrangement and conformation of the adsorbed crown ether molecules at the air-water interface. The CH(2) vibrational modes of crown ethers have been identified and found to be split due to interaction with ether oxygen. The spectra provide evidence for the existence of a protonated crown complex moiety at the surface leading to the appearance of strongly ordered water species. The interfacial water species are influenced by the resulting charged interface and by the strong Zundel polarizability due to tunneling of the proton species between equivalent sites within the crown ring. PMID- 21298193 TI - A new chiral, poly-imidazole N8-ligand and the related di- and tri-copper(II) complexes: synthesis, theoretical modelling, spectroscopic properties, and biomimetic stereoselective oxidations. AB - The new poly-imidazole N(8) ligand (S)-2-piperazinemethanamine-1,4-bis[2-((N-(1 acetoxy-3-(1-methyl-1H-imidazol-4-yl))-2-(S)-propyl)-(N-(1-methyl-1H-imidazol-2 ylmethyl)))ethyl]-N-(phenylmethyl)-N-(acetoxy), also named (S)-Pz-(C2-(HisIm))(2) (L), containing three chiral (S) centers, was obtained by a multi-step synthesis and used to prepare dinuclear [Cu(2)(L)](4+) and trinuclear [Cu(3)(L)](6+) copper(II) complexes. Low-temperature EPR experiments performed on [Cu(2)(L)](4+) demonstrated that the two S = 1/2 centers behaved as independent paramagnetic units, while the EPR spectra used to study the trinuclear copper complex, [Cu(3)(L)](6+), were consistent with a weakly coupled three-spin 1/2 system. Theoretical models for the two complexes were obtained by DFT/RI-BP86/TZVP geometry optimization, where the structural and electronic characteristics nicely supported the EPR experimental findings. In addition, the theoretical analysis unveiled that the conformational flexibility encoded in both [Cu(2)(L)](4+) and [Cu(3)(L)](6+) arises not only from the presence of several sigma-bonds and the bulky residues attached to the (S)-Pz-(C2-(HisIm))(2) ligand scaffold, but also from the poor coordination ability of the tertiary amino groups located in the ligand side-chains containing the imidazole units towards the copper(II) ions. Both the dinuclear and trinuclear complexes are efficient catalysts in the stereoselective oxidation of several catechols and flavonoid compounds, yielding the corresponding quinones. The structural features of the substrate-catalyst adduct intermediates were assessed by searching the conformational space of the molecule through MMFF94/Monte Carlo (MMFF94/MC) methods. The conformational flexibility of the bound ligand in the complexes proves to be beneficial for substrate binding and recognition. For the dinuclear complex, chiral recognition of the optically active substrates derives from weak electrostatic interactions between bound substrates and folded regions of the ligand scaffold. For the trinuclear complex, in the case of L/D-Dopa, the chiral recognition has a remarkable stereoselectivity index of 75%, the highest so far reported for this type of reaction. Here the dominant contribution to stereoselectivity arises from the direct interaction between a donor group (the Dopa carboxylate) far from the substrate reaction site (the catechol ring) with the additional (third) copper center not involved in the oxidative catalysis. On the other hand, in the case of bulky substrates, such as L/D-catechin, the observed poor substrate recognition is associated with much weaker interactions between the chiral regions of the complex and the chiral part of the substrate. PMID- 21298194 TI - Hydrothermal synthesis, structure, and luminescent properties of selected Zn(II)/Cd(II) coordination polymers constructed from 3,5-bis(x-pyridyl)-1,2,4 triazole (x = 3, 4). AB - Utilizing 3,5-bis(x-pyridyl)-1,2,4-triazole (x-Hpytz, x = 3; x = 4) as multidentate ligands, six novel coordination polymers with Zn(II) or Cd(II) metal ions were prepared: [Zn(3-pytz)(0.5)(OH)(0.5)Cl](n) (1, 1D ladder), {[Zn(3 Hpytz)(H(2)O)(4)] [Zn(3-Hpytz)(H(2)O)(3).SO(4)]SO(4).5H(2)O}(n) (2.5H(2)O, 1D chain), [Cd(3-Hpytz)(SO(4))](n) (3, 3D framework), {[Cd(3 Hyptz)SO(4).3H(2)O].2H(2)O}(n) (4.2H(2)O, 1D chain), [Zn(4-pytz)Cl](n) (5, 3D framework) and [Zn(2)(4-pytz)(SO(4))(OH)](n) (6, 3D framework). All compounds were obtained from hydrothermal reactions, with the exception of compound 4 which was obtained by solvent diffusion at room temperature. All compounds were characterized by FTIR, elemental analysis and TGA analysis and their structures were determined by X-ray diffraction. All compounds exhibited substantial thermal stability and showed photofluorescent properties that resulted from ligand pi-pi* transition. PMID- 21298195 TI - Structural and magnetic studies of Schiff base complexes of nickel(II) nitrite: change in crystalline state, ligand rearrangement and a very rare MU-nitrito 1kappaO:2kappaN:3kappaO' bridging mode. AB - Four new nickel(II) complexes, [Ni(2)L(2)(NO(2))(2)].CH(2)Cl(2).C(2)H(5)OH, 2H(2)O (1), [Ni(2)L(2)(DMF)(2)(MU-NO(2))]ClO(4).DMF (2a), [Ni(2)L(2)(DMF)(2)(MU NO(2))]ClO(4) (2b) and [Ni(3)L'(2)(MU(3)-NO(2))(2)(CH(2)Cl(2))](n).1.5H(2)O (3) where HL = 2-[(3-amino-propylimino)-methyl]-phenol, H(2)L(') = 2-({3-[(2-hydroxy benzylidene)-amino]-propylimino}-methyl)-phenol and DMF = N,N-dimethylformamide, have been synthesized starting with the precursor complex [NiL(2)].2H(2)O, nickel(ii) perchlorate and sodium nitrite and characterized structurally and magnetically. The structural analyses reveal that in all the complexes, Ni(II) ions possess a distorted octahedral geometry. Complex 1 is a dinuclear di-MU(2) phenoxo bridged species in which nitrite ion acts as chelating co-ligand. Complexes 2a and 2b also consist of dinuclear entities, but in these two compounds a cis-(MU-nitrito-1kappaO:2kappaN) bridge is present in addition to the di-MU(2)-phenoxo bridge. The molecular structures of 2a and 2b are equivalent; they differ only in that 2a contains an additional solvated DMF molecule. Complex 3 is formed by ligand rearrangement and is a one-dimensional polymer in which double phenoxo as well as MU-nitrito-1kappaO:2kappaN bridged trinuclear units are linked through a very rare MU(3)-nitrito-1kappaO:2kappaN:3kappaO' bridge. Analysis of variable-temperature magnetic susceptibility data indicates that there is a global weak antiferromagnetic interaction between the nickel(ii) ions in four complexes, with exchange parameters J of -5.26, -11.45, -10.66 and -5.99 cm(-1) for 1, 2a, 2b and 3, respectively. PMID- 21298196 TI - 2,3-Bis(1-methylimidazol-2-yl)quinoxaline (bmiq), a new ligand with decoupled electron transfer and metal coordination sites: the very different redox behaviour of isoelectronic complexes with [PtCl2] and [AuCl2]+. AB - The new, potentially ambidentate heterocyclic ligand 2,3-bis(1-methylimidazol-2 yl)quinoxaline (bmiq) was obtained from 2,3-bis(1-methylimidazol-2-yl)glyoxal and 1,2-diaminobenzene. Its coordination to PtCl(2) and to the isoelectronic [AuCl(2)](+) in [AuCl(2)(bmiq)](AuCl(4)) occurs via the imine N donors of the imidazolyl groups, leading to the formation of seven-membered chelate rings with boat conformation. According to the spectroelectrochemistry (UV-vis-NIR, EPR), the reversible electron addition to the [PtCl(2)(bmiq)] and the free ligand takes place in the (non-coordinated) quinoxaline part of the molecule, similarly as for related complexes of dipyrido[3,2-a:2',3'-c]phenazines (dppz), 2,3-bis(2 pyridyl)quinoxalines (bpq) and 2,3-bis(dialkylphosphino)quinoxalines (QuinoxP). DFT calculations confirm the experimental results (structures, spectroscopy) and also point to the coordination potential of the quinoxaline N atoms. The electron addition to [AuCl(2)(bmiq)](+) takes place not at the ligand but at the metal site, according to experimental and DFT results. PMID- 21298197 TI - Trialkyl imido niobium and tantalum compounds: synthesis, structural study and migratory insertion reactions. AB - Trialkyl imido niobium and tantalum complexes [MR(3)(NtBu)] (M = Nb, R = Me 2, CH(2)CMe(3)3, CH(2)CMe(2)Ph 4, CH(2)SiMe(3)5; M = Ta, R = Me 6, CH(2)CMe(2)Ph 7, CH(2)SiMe(3)8) have been prepared by treatment of solutions containing [MCl(3)(NtBu)py(2)] (M = Nb 1a, Ta 1b) with three equivalents of magnesium reagent. By an unexpected hydrolysis reaction of the tris-trimethylsilylmethyl imido tantalum compound 8a, a MU-oxo derivative [(Me(3)SiCH(2)O)(Me(3)SiCH(2))(3)Ta(MU-O)Ta(CH(2)SiMe(3))(2)(NtBu)] (8a) was formed and its structure was studied by X-ray diffraction methods. Reactions of trialkyl imido compounds with two equivalents of isocyanide 2,6-Me(2)C(6)H(3)NC result in the migration of two alkyl groups, leading to the formation of a series of alkyl imido bisiminoacyl derivatives [MR(NtBu){C(R)NAr}(2)] (Ar = 2,6 Me(2)C(6)H(3); M = Nb, R = Me 9, CH(2)CMe(3)10, CH(2)CMe(2)Ph 11, CH(2)SiMe(3)12, CH(2)Ph 13; M = Ta, R = CH(2)CMe(3)14, CH(2)CMe(2)Ph 15, CH(2)SiMe(3)16). All compounds were studied by IR and NMR ((1)H, (13)C and (15)N) spectroscopy. PMID- 21298198 TI - Maternal mortality. PMID- 21298199 TI - The vascular endothelium masks the persistent inhibition of rat thoracic arterial tone induced by S-nitrosoglutathione. AB - AIM: In endothelium-denuded arteries, the nitric oxide (NO) donor S nitrosoglutathione (GSNO) induced a persistent hypo-reactivity to vasoconstrictors, and low-molecular weight thiols such as N-acetyl cysteine (NAC) produced a relaxant effect. These effects were attributed to the formation of vascular NO stores. In arteries with a functional endothelium, such long-lasting effects on arterial tone have not been well characterised. In this study, we proposed to examine the possibility of storing exogenous NO when the vascular endothelium is still able to produce its own NO. METHODS: For this purpose, changes in isometric tension of isolated arteries were assessed in organ chambers, and nitrosothiol formation was characterised by confocal microscopy. RESULTS: In rat aortic rings with endothelium pre-exposed to GSNO, the contractile response to norepinephrine (NE) was not attenuated in comparison with control rings, but NAC induced a relaxant effect. However, an attenuation of the response to NE was observed in GSNO-exposed, intact aortic rings after inhibition of NO synthase by N(omega)-nitro-L-arginine methylester (L-AME) or in GSNO denuded rings. The relaxing effects of NAC were due to the mobilisation of NO from nitrosothiols after nitrosylation of protein SH residues. Moreover, the hypo reactivity to NE and the relaxant effect of NAC were abolished by 1H-[1,2,4] oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), an inhibitor of soluble guanylyl cyclase, and partially by the K+-sensitive channel inhibitor tetra-ethyl-ammonium (TEA). CONCLUSION: These data show that endothelium-derived NO masked the persistent effect of GSNO in rat thoracic aorta. However, the ability of GSNO to form releasable NO stores without altering the vascular tone can be particularly useful in preventing endothelial dysfunction in which NO formation decreases. PMID- 21298200 TI - The variability of baroreflex sensitivity in juvenile, spontaneously hypertensive rats. AB - In this study the baroreflex sensitivity of conscious, juvenile, spontaneously hypertensive rats (SHRs) was compared. The study population consisted of 19 eight week-old male SHRs. The baroreflex sensitivity was quantified as the derivative of the variation in heart rate (HR) and the variation of mean arterial pressure (baroreflex sensitivity = DeltaHR/DeltaMAP). MAP was manipulated with sodium nitroprusside (SNP) and phenylephrine (PHE), administered via an inserted cannula in the right femoral vein. The SHRs were divided into four groups: (1) low bradycardic baroreflex (LB) where the baroreflex gain (BG) was between 0 and -1 bpm/mmHg with PHE; (2) high bradycardic baroreflex (HB), where the BG was < -1 bpm/mmHg with PHE; (3) low tachycardic baroreflex (LT) where the BG was between 0 and 3 bpm/mmHg with SNP; (4) high tachycardic baroreflex (HT) where the BG was > 3 bpm/mmHg with SNP. We noted that 36.8% of the rats presented with an increased bradycardic reflex, while 27.8% demonstrated an attenuated tachycardic reflex. No significant alterations were noted regarding the basal MAP and HR. There were significant differences in the baroreflex sensitivity between SHRs in the same laboratory. One should be careful when interpreting studies employing the SHR as a research model. PMID- 21298201 TI - Smoking and vascular dysfunction in Africans and Caucasians from South Africa. AB - BACKGROUND: Smoking is an important modifiable risk factor for cardiovascular disease, with limited research having been done in Africans. We aimed to determine the association between smoking and measurements of vascular function in Africans and Caucasians. METHODS: We determined anthropometric and cardiovascular variables, serum cotinine and C-reactive protein (CRP) in African and Caucasian participants from South Africa (n = 630). RESULTS: Africans had significantly lower body mass index (BMI), higher blood pressure and lower socio economic status (SES) than Caucasians. Only African smokers showed increased arterial stiffness and a significant correlation between smoking and arterial stiffness. African smokers had increased and Caucasian smokers decreased high density lipoprotein cholesterol (HDL-C) than the non-smokers. After adjusting for confounders, smoking showed few correlations, mainly with heart rate and CRP. In Africans, smoking also correlated positively with HDL-C, with the opposite result in Caucasians. CONCLUSION: African smokers had significantly increased arterial stiffness, which was not found in Caucasian smokers. Africans generally demonstrated more associations between smoking and cardiovascular dysfunction than Caucasians. PMID- 21298202 TI - Obesity-associated genetic variants in young Asian Indians with the metabolic syndrome and myocardial infarction. AB - OBJECTIVE: Associations between obesity-related polymorphisms and the metabolic syndrome in 485 young ( <= 45 Years) Asian Indian patients with acute myocardial infarction (AMI), and 300 matched controls were assessed. METHODS: Genetic variants included the adiponectin 45T->G and 276G->T, LEPR K109R and Q223R, MC4R associated C->T and FTO A->T polymorphisms. RESULTS: The metabolic syndrome, as defined by NCEP ATP III and IDF criteria, was diagnosed in 61 and 60% of patients, respectively. No relationship was found between the obesity-associated polymorphisms and the metabolic syndrome, or between AMI patients and controls. The MC4R-associated TT genotype occurred more frequently in patients with lower triglyceride levels (p = 0.024), while the adiponectin 45 TT genotype occurred more commonly in patients with normal fasting glucose levels (p = 0.004). The LEPR Q223R TT genotype was associated with low high-density lipoprotein (HDL) cholesterol levels (p = 0.003). CONCLUSION: The metabolic syndrome occurs commonly in young Asian Indian patients with AMI. No relationship was found between any obesity-associated polymorphism and the metabolic syndrome. Particular genotypes may exert protective or disadvantageous effects on individual components of the metabolic syndrome. PMID- 21298203 TI - Maternal deaths associated with hypertension in South Africa: lessons to learn from the Saving Mothers report, 2005-2007. AB - From 2005-2007, there were 622 deaths associated with hypertensive disorders of pregnancy. Eclampsia was the major cause of death (n = 344; 55.3%). There were 173 (28.3%) deaths due to pre-eclampsia, and 38 (6.1%) associated with chronic hypertension. Cerebral complications were the final cause of death in 283 (45.5%), while cardiac failure and respiratory failure were the final causes in 142 (22.8%) and 158 (25.4%), respectively. Major problems were identified in all areas of assessment. Non-attendance for antenatal care (n = 106; 19.4%) and delay in seeking help (n = 106; 19.4%) were major patient-related factors. Communication problems (n = 63; 10.8%) and lack of facilities (n = 50; 8.5%) were health administration issues. Health worker-avoidable factors included problem recognition, delay in referral and management at an inappropriate level of healthcare. Compared to the previous report of 2002-2004, there was a reduction in deaths due to hypertension. PMID- 21298204 TI - Coronary artery ectasia in a patient with myocardial infarction. AB - We report on a case of triple-vessel coronary artery ectasia (CAE) in a young patient. This patient presented with anterior wall myocardial infarction (MI) with post-infarct angina. His coronary angiogram revealed coronary artery ectasia involving the left anterior descending, circumflex and right coronary arteries. PMID- 21298205 TI - Re: The grapefruit: an old wine in a new glass? Metabolic and cardiovascular perspectives. PMID- 21298206 TI - Cardiac abnormalities in Anderson-Fabry disease and Fabry's cardiomyopathy. AB - Fabry's disease is an X-linked lysosomal storage disease most often associated with renal dysfunction and death due to renal failure in patients' fourth and fifth decades of life. However, cardiac manifestations including arrhythmias, angina and heart failure are common and probably underrecognized. Furthermore, Fabry's disease is now recognised as also affecting female carriers, who manifest signs later than males. A variant of Fabry's has been identified that only affects cardiac tissue, which presents as an unexplained hypertrophy of the left ventricle in middle-aged patients, possibly with women more affected than men. Given that epidemiological studies report a prevalence of Fabry's cardiomyopathy among middle-aged patients with cardiac hypertrophy to be anywhere from one to 12%, it is reasonable to screen these patients for alpha-galactosidase A deficiency. Although mortality data is lacking from randomised, controlled trials of galactosidase replacement therapy, there are some reports of improvement in cardiac endpoints. Therefore patients with known Fabry's disease should be screened early for cardiac involvement, as treatment benefit may not be seen once cardiac fibrosis has developed. PMID- 21298207 TI - Improving hypertension control in patients at cardiovascular risk: the case for telmisartan-based therapy. PMID- 21298208 TI - Boehringer Ingelheim and Eli Lilly and Company announce strategic alliance to bring new diabetes treatments to patients worldwide. PMID- 21298209 TI - South African experts comment on FDA approval of dabigatran in atrial fibrillation. PMID- 21298210 TI - ASCOT analysis with atorvastatin shows limits of CRP as indicator of cardiovascular risk. PMID- 21298211 TI - Chronic heart failure treatment benefits from pro-BNP-directed therapy. PMID- 21298212 TI - Fenofibrate profiled as the fibrate with additional new data, supporting its use with statins in the European Medicines Agency recommendations. PMID- 21298213 TI - Functional evaluation of GJB2 variants in nonsyndromic hearing loss. AB - Mutations in the gap junction beta2 (GJB2) gene, encoding the connexin26 (CX26) protein, are the most common cause of non-syndromic hearing loss (HL) in many populations. In the East Asian population, two variants, p.V27I (c.79G>A) and p.E114G (c.341G>A), are considered benign polymorphisms since these variants have been identified in both HL patients and normal hearing controls. However, some studies have postulated that homozygotes carrying both p.V27I and p.E114G variants could cause HL. To elucidate possible roles of these variants, we used in vitro approaches to directly assess the pathogenicity of four haplotypes generated by the two polymorphisms: VE (wild type), I*E (p.V27I variant only), VG* (p.E114G variant only), I*G* (both variants). In biochemical coupling assays, the gap junctions (GJs) composed of VG* and I*G* types displayed defective channel activities compared with those of VE wild types or I*E types, which showed normal channel activities. Interestingly, the defect in hemichannel activity was a bit less severe in I*G* type than VG* type, suggesting that I* variant (p.V27I) may compensate for the deleterious effect of G* variant (p.E114G) in hemichannel activities. Our population studies using 412 Korean individuals showed that I*G* type was detected at around 20% in both HL patients and normal controls, suggesting that I*G* type may not be a pathogenic polymorphism. In contrast, VG* type was very rare (3/824) and detected only in HL patients, suggesting that VG* homozygotes (VG*/VG*) or compound heterozygotes carrying VG* type with other mutations may cause HL. PMID- 21298215 TI - Uncertainty-weighted time averaging of mercury vapour concentrations in ambient air: application to measurements in the United kingdom. AB - Uncertainty-weighted time averaging of total gaseous mercury concentrations in ambient air, with associated robust uncertainties, has been performed for concentrations measured by the U.K. Heavy Metals Monitoring Network between 2007 and 2009. The results have been compared with averages produced using standard time-averaging methods with a view to investigating the properties of the new method and whether it represents an improvement over current practice. PMID- 21298216 TI - Impact of the project P.A.T.H.S. In the junior secondary school years: individual growth curve analyses. AB - The Tier 1 Program of the Project P.A.T.H.S. (Positive Adolescent Training through Holistic Social Programs) is a positive youth development program implemented in school settings utilizing a curricular-based approach. In the third year of the Full Implementation Phase, 19 experimental schools (n = 3,006 students) and 24 control schools (n = 3,727 students) participated in a randomized group trial. Analyses based on linear mixed models via SPSS showed that participants in the experimental schools displayed better positive youth development than did participants in the control schools based on different indicators derived from the Chinese Positive Youth Development Scale, including positive self-identity, prosocial behavior, and general positive youth development attributes. Differences between experimental and control participants were also found when students who joined the Tier 1 Program and perceived the program to be beneficial were employed as participants of the experimental schools. The present findings strongly suggest that the Project P.A.T.H.S. is making an important positive impact for junior secondary school students in Hong Kong. PMID- 21298217 TI - Mees' lines. AB - There are different nail manifestations of systemic diseases. This case represents Mees' lines. In the current report, this phenomenon was caused by chemotherapy agents used for treatment of leukemia. It was caused by medication insult to the nail matrix. Nonblanching and impalpable nail bands, migration with the nail growth, and thumb involvement differentiate Mees' from Beau's and Muehrcke's lines. PMID- 21298214 TI - HDAC inhibition and graft versus host disease. AB - Histone deacetylase (HDAC) inhibitors are currently used clinically as anticancer drugs. Recent data have demonstrated that some of these drugs have potent antiinflammatory or immunomodulatory effects at noncytotoxic doses. The immunomodulatory effects have shown potential for therapeutic benefit after allogeneic bone marrow transplantation in several experimental models of graft versus host disease (GVHD). These effects, at least in part, result from the ability of HDAC inhibitors (HDACi) to suppress the function of host antigen presenting cells such as dendritic cells (DC). HDACi reduce the dendritic cell (DC) responses, in part, by enhancing the expression of indoleamine 2,3 dioxygenase (IDO) in a signal transducer and activator of transcription-3 (STAT 3) dependent manner. They also alter the function of other immune cells such as T regulatory cells and natural killer (NK) cells, which also play important roles in the biology of GVHD. Based on these observations, a clinical trial has been launched to evaluate the impact of HDAC inhibitors on clinical GVHD. The experimental, mechanistic studies along with the brief preliminary observations from the ongoing clinical trial are discussed in this review. PMID- 21298218 TI - Penile carcinoma: risk factors and molecular alterations. AB - Penile carcinoma is a rare, male cancer. Although the incidence of penile carcinoma is very low in Western countries, in some countries, the incidence is significantly greater, with penile carcinoma accounting for <=10% of all male malignancies. Greater insight has been gained in recent years as to its pathogenesis, the risk factors associated with its development, and the clinical and histological precursor lesions related to this disease. In this review, risk and conditions factors for penile carcinoma, molecular alterations in this type of cancer, histological types, and prognostic factors will be discussed in order to further our understanding of the biology and behavior of this cancer. PMID- 21298219 TI - Role of re-resection in non-muscle-invasive bladder cancer. AB - Restaging, or second transurethral resection (TUR), is essential to successful management of high-risk, non-muscle-invasive bladder cancer. Here we review the relevant literature documenting the role of restaging TUR. Cohort and randomized studies show that restaging TUR detects more tumors than initial TUR, improves clinical staging, and reduces the frequency of early tumor recurrences. Our conclusions show thatrestaging TUR improves the outcomes of high-risk,non-muscle invasive bladder neoplasms. PMID- 21298220 TI - Prepuce: phimosis, paraphimosis, and circumcision. AB - Phimosis is a condition in which the prepuce cannot be retracted over the glans penis. Actually, physiologic phimosis is common in male patients up to 3 years of age, but often extends into older age groups. Balanoposthitisis a common inflammation occurring in 4-11% of uncircumcised boys. Circumcision is generally undertaken for three reasons: first, as an item of religious practice, typically neonatally although occasionally transpubertally, as a rite of passage; second, as a prophylactic measure against future ailments for the reduction in the risk of penile cancer, urinary tract infection, and sexually transmitted infection; and third, for immediate medical indication. Balanitisxeroticaobliterans is an infiltrative skin condition that causes a pathological phimosis and has been considered to be the only absolute indication for circumcision. Various kinds of effective alternatives to circumcision have been described, including manual retraction therapy, topical steroid therapy, and several variations of preputioplasty. All of these treatments have the ability to retract the foreskin as their goal and do not involve the removal of the entire foreskin. Paraphimosis is a condition in which the foreskin is left retracted. When manipulation is not effective, a dorsal slit should be done, which is usually followed by circumcision. PMID- 21298221 TI - A novel tool for high-throughput screening of granulocyte-specific antibodies using the automated flow cytometric granulocyte immunofluorescence test (Flow GIFT). AB - Transfusion-related acute lung injury (TRALI) is a severe complication related with blood transfusion. TRALI has usually been associated with antibodies against leukocytes. The flow cytometric granulocyte immunofluorescence test (Flow-GIFT) has been introduced for routine use when investigating patients and healthy blood donors. Here we describe a novel tool in the automation of the Flow-GIFT that enables a rapid screening of blood donations. We analyzed 440 sera from healthy female blood donors for the presence of granulocyte antibodies. As positive controls, 12 sera with known antibodies against anti-HNA-1a, -b, -2a; and -3a were additionally investigated. Whole-blood samples from HNA-typed donors were collected and the test cells isolated using cell sedimentation in a Ficoll density gradient. Subsequently, leukocytes were incubated with the respective serum and binding of antibodies was detected using FITC-conjugated antihuman antibody. 7-AAD was used to exclude dead cells. Pipetting steps were automated using the Biomek NXp Multichannel Automation Workstation. All samples were prepared in the 96-deep well plates and analyzed by flow cytometry. The standard granulocyte immunofluorescence test (GIFT) and granulocyte agglutination test (GAT) were also performed as reference methods. Sixteen sera were positive in the automated Flow-GIFT, while five of these sera were negative in the standard GIFT (anti-HNA 3a, n = 3; anti-HNA-1b, n = 1) and GAT (anti-HNA-2a, n = 1). The automated Flow-GIFT was able to detect all granulocyte antibodies, which could be only detected in GIFT in combination with GAT. In serial dilution tests, the automated Flow-GIFT detected the antibodies at higher dilutions than the reference methods GIFT and GAT. The Flow-GIFT proved to be feasible for automation. This novel high-throughput system allows an effective antigranulocyte antibody detection in a large donor population in order to prevent TRALI due to transfusion of blood products. PMID- 21298222 TI - Minimal residual disease diagnostics and chimerism in the post-transplant period in acute myeloid leukemia. AB - In acute myeloid leukemia (AML), the selection of poor-risk patients for allogeneic hematopoietic stem cell transplantation (HSCT) is associated with rather high post-transplant relapse rates. As immunotherapeutic intervention is considered to be more effective before the cytomorphologic manifestation of relapse, post-transplant monitoring gains increasing attention in stem cell recipients with a previous diagnosis of AML. Different methods for detection of chimerism (e.g., microsatellite analysis or quantitative real-time PCR) are available to quantify the ratio of donor and recipient cells in the post transplant period. Various studies demonstrated the potential use of mixed chimerism kinetics to predict relapse of the AML. CD34+-specific chimerism is associated with a higher specificity of chimerism analysis. Nevertheless, a decrease of donor cells can have other causes as well. Therefore, efforts continue to introduce minimal residual disease (MRD) monitoring based on molecular mutations in the post-transplant period. The NPM1 (nucleophosmin) mutations can be monitored by sensitive quantitative real-time PCR in subsets of stem cell recipients with AML, but for approximately 20% of patients, suitable molecular mutations for post-transplant MRD monitoring are not available so far. This emphasizes the need for an expansion of the panel of MRD markers in the transplant setting. PMID- 21298223 TI - Anti-inflammatory and immunosuppressive effects of the A2A adenosine receptor. AB - The production of adenosine represents a critical endogenous mechanism for regulating immune and inflammatory responses during conditions of stress, injury, or infection. Adenosine exerts predominantly protective effects through activation of four 7-transmembrane receptor subtypes termed A1, A2A, A2B, and A3, of which the A2A adenosine receptor (A2AAR) is recognised as a major mediator of anti-inflammatory responses. The A2AAR is widely expressed on cells of the immune system and numerous in vitro studies have identified its role in suppressing key stages of the inflammatory process, including leukocyte recruitment, phagocytosis, cytokine production, and immune cell proliferation. The majority of actions produced by A2AAR activation appear to be mediated by cAMP, but downstream events have not yet been well characterised. In this article, we review the current evidence for the anti-inflammatory effects of the A2AAR in different cell types and discuss possible molecular mechanisms mediating these effects, including the potential for generalised suppression of inflammatory gene expression through inhibition of the NF-kB and JAK/STAT proinflammatory signalling pathways. We also evaluate findings from in vivo studies investigating the role of the A2AAR in different tissues in animal models of inflammatory disease and briefly discuss the potential for development of selective A2AAR agonists for use in the clinic to treat specific inflammatory conditions. PMID- 21298224 TI - The transcribed-ultraconserved regions: a novel class of long noncoding RNAs involved in cancer susceptibility. AB - During recent years, novel approaches and new technologies have revealed a startling level of complexity of higher eukaryotes' transcriptome. A large proportion of the transcriptional output is represented by protein noncoding RNAs (ncRNAs) that arise from the "dark matter" of the genome. Focus on such sequences has revealed numerous RNA subtypes with several functions in RNA processing and gene expression regulation, and deep sequencing studies imply that many remain to be discovered. This review gives a picture of the state of the art of a novel class of long ncRNA known as transcribed-ultraconserved regions (T-UCRs). Most recent studies show that they are significantly altered in adult chronic lymphocytic leukemias, carcinomas, and pediatric neuroblastomas, leading to the hypothesis that UCRs may play a role in tumorigenesis and promising innovative future T-UCR-based therapeutic approaches. PMID- 21298225 TI - 1st place, PREMUS best paper competition: workplace and individual factors in wrist tendinosis among blue-collar workers--the San Francisco study. AB - OBJECTIVE: Workplace studies have linked hand/wrist tendinosis to forceful and repetitive hand exertions, but the associations are not consistent. We report findings from a prospective study of right wrist tendinosis among blue-collar workers. METHODS: Workers (N=413) at four industries were followed for 28 months with questionnaires and physical examinations every 4 months to identify incident cases of right wrist tendinosis. Exposure assessment of force and repetition were based on field measurements and video analysis to determine repetition rate and the percent time (% time) in heavy pinch (>1 kg-force) or power grip (>4 kg force). All exposure variables were measured at the level of the individual and task. For workers responsible for >1 task, a time-weighted average exposure was calculated based on task hours per week. A proportional hazards model was used to assess the relationship between exposures and incidence of wrist tendinosis. RESULTS: During the 481 person-years of follow-up, there were 26 incident cases of right wrist tendinosis [incidence rate (IR) 5.40 cases per 100 person-years]. Adjusting for age, gender, and repetition, wrist tendinosis was associated with % time spent in heavy pinch [hazard ratio (HR) 5.01, 95% CI 1.27-19.79). Composite exposure measure American Conference of Industrial Hygienists Threshold Limit Value (ACGIH-TLV) for hand activity level (HR 3.95, 95% CI 1.52-10.26) was also associated with the outcome for the medium-exposure group using video-based total repetition rate. CONCLUSIONS: The workplace factors predicting wrist tendinosis were time-weighted average values of % time spent in heavy pinch and the ACGIH TLV for Hand Activity Level. The % time spent in power grip was not a significant predictor, nor were any measures of repetition. An exposure-response relationship was observed for the % time spent in heavy pinch. These findings may improve programs for preventing occupational wrist tendinosis. PMID- 21298226 TI - Hypokalaemic paralysis secondary to distal renal tubular acidosis as the presenting symptom of systemic lupus erythematosus. AB - We report hypokalaemic quadriparesis presenting in a 43-year-old woman. Evaluation revealed hypokalaemic quadriparesis secondary to underlying distal renal tubular acidosis, also known as type 1 RTA. Four years after the diagnosis of RTA, the patient developed joint pain, and investigation revealed systemic lupus erythematosus with lupus nephritis. RTA is one of the very rare presentations of systemic lupus erythematosus. Thus, tubular dysfunction should be carefully assessed in patients with systemic lupus erythematosus. Similarly, patients with RTA should be evaluated for underlying lupus. Our patient was successfully treated with mycophenolate mofetil and steroids. PMID- 21298227 TI - Use of Ankaferd Blood Stopper for controlling actively bleeding fundal varices. AB - Variceal bleeding is one of the most important and life-threatening complications of portal hypertension. Although less common than oesophageal varices that have a lower frequency of bleeding, gastric varices tend to result in more severe and mortal bleeding. The Ankaferd Blood Stopper (ABS) has been used with varying success in recent years for the management of bleeding from skin lesions or after dental surgery, and in other clinical conditions in which conventional haemostatic measures have proved to be deficient. In serious bleeding gastric fundal varices, ABS can also act as a bridge in the absence or unavailability of definitive therapies. PMID- 21298228 TI - Case of acute akathisia from intravenous metoclopramide. AB - Intravenous (IV) metoclopramide is a frequently prescribed medication in the emergency department (ED). Extrapyramidal side effects like tardive dyskinesia are known to develop with chronic use of metoclopramide, while acute akathisia is a lesser known side effect following IV administration. Akathisia is characterised by a sensation of restlessness and distress, as well as constant, non-purposeful limb movement. It can present as a diagnostic challenge, cause distress and hinder the management of the primary condition of the patient in the ED. However, akathisia can be readily reversible, with a successful patient outcome if promptly diagnosed. We report a case of acute akathisia in a young female patient after IV bolus metoclopramide was administered to treat her gastroenteritis in our ED. We highlight the diagnostic process, the difficulties in the management of the primary condition resulting from her akathisia and its successful management using IV diphenhydramine and midazolam. PMID- 21298229 TI - Multiple cardiac anomalies in an elderly man with Klinefelter's syndrome. AB - We report a case of an elderly man with Klinefelter's syndrome and multiple cardiac defects, including partial anomalous pulmonary venous connection, atrial septal defect and pulmonary arterial hypertension. To the best of our knowledge, partial anomalous pulmonary venous connection in association with Klinefelter's syndrome has never been described in the literature. This anomalous pulmonary connection was a serendipitous discovery following the malpositioning of a peripherally inserted central catheter. PMID- 21298230 TI - Gastric volvulus with diaphragmatic hernia presenting with unexplained weight loss: a delayed diagnosis. AB - Gastric volvulus (GV) is a rare condition that presents with epigastric pain, retching and at times, vomiting. There are two types of GV: organoaxial and mesenteroaxial. We report the case of a 49-year-old woman with chronic mesenteroaxial volvulus with left-sided diaphragmatic defect. She presented with significant weight loss over a period of two years, with nonspecific symptoms of heartburn, occasional mild epigastric pain and anorexia. The patient was diagnosed with barium meal and contrast-enhanced computed tomography imaging. She was treated with open repair of diaphragmatic defect and anterior gastropexy. She was asymptomatic and had gained weight at the six-month follow-up. PMID- 21298231 TI - Rare mechanical complication of myocardial infarction: isolated right ventricle free wall rupture. AB - Rupture of the left ventricular free wall is a dramatic complication of acute myocardial infarction (MI) and occurs in about ten percent of patients with fatal acute MI. However, there are limited reports about right ventricular free wall rupture due to MI. In this case report, a patient with isolated right ventricular rupture following MI that was visualised with real-time transthoracic echocardiography is discussed for the first time in the literature. PMID- 21298232 TI - Emil von Behring (1854-1917): Medicine's first Nobel laureate. PMID- 21298233 TI - ECG ST segment elevation in patients with chest pain. AB - We discussed three cases of ST elevation myocardial infarction with ST elevation in the inferoposterior territory and anterior territory, and more uncommonly, concomitant ST elevations in the anterior and inferior electrocardiography (ECG) leads. Correct interpretation of the ECG is crucial in recognising this cardiac emergency, which often necessitates urgent coronary revascularisation. In addition, ECG aids localisation of the infarct-related artery and adds prognostic value. PMID- 21298234 TI - Anal canal malignancies: a review in an Asian population. AB - INTRODUCTION: Anal canal malignancies are rare tumours of the gastrointestinal tract that represent less than five percent of anorectal malignancies. METHODS: We retrospectively reviewed patients with anal canal malignancies who were treated from April 1989 to December 2008. Patients were identified from a prospective database and records were analysed for age, gender, presenting symptoms, duration of symptoms, mode of diagnosis, histological subtypes, stage of disease, treatment received, duration of follow-up, recurrence rates and survival. RESULTS: A total of 61 patients were treated for anal canal malignancies, comprising 2.1 percent of all anorectal malignancies treated during the same period. There were 31 male and 30 female patients, with a median age at diagnosis of 61 (range 38-83) years. The commonest presenting symptoms were per rectal bleeding (69.4 percent) and pain (33.9 percent). The commonest histology was adenocarcinoma (50.8 percent) and squamous cell carcinoma (SCC) (40.3 percent). Patients underwent either surgery, radiotherapy, chemoradiation or a combination of modalities. The median duration of follow-up was 28 (range 1-120) months. Five patients developed recurrences after a median of 23 (range 2-36) months. The five-year overall survival and disease-free survival was 65.5 percent and 63.7 percent, respectively, with SCC showing a trend toward a better prognosis. CONCLUSION: Anal canal tumours are a rare clinical entity. They are usually present in the elderly with per rectal bleeding. They are usually treated using a multimodality approach, after the accurate establishment of histological diagnosis, which can yield reasonable survival rates. PMID- 21298235 TI - Axial translaminar screw placement using three-dimensional fluoroscopy-based navigation. AB - INTRODUCTION: To circumvent the risk to the vertebral artery with C2 pars or pedicle screws, C2 laminar screws were considered as a method for rigid fixation of the axis. Although considered to be a relatively safe method, ventral spinal canal violations have been reported. Three-dimensional (3D) fluoroscopy-based image guidance may enhance the accuracy and safety of the technique. There is only one previous report in the literature on its use in the placement of C2 laminar screws. The purpose of this study was to assess the accuracy of C2 translaminar screws inserted using 3D fluoroscopy-based navigation. METHODS: Data from a single centre was gathered retrospectively and then analysed. 3D fluoroscopy-based navigation was used to insert five translaminar screws in four patients (two male, two female). Their mean age was 45.3 years and the average follow-up period was 13.8 months. The accuracy of screw placement and fusion was ascertained using postoperative computed tomography imaging. RESULTS: There were no complications in this series. No breach in the dorsal or ventral laminar wall was noted for any of the translaminar screws inserted. The average time required to set up the navigation platform and screen was 18 minutes. Successful fusion was observed in all four patients at six months follow-up. CONCLUSIONS: Although considered a relatively safe technique, laminar cortical violations have been reported with C2 translaminar screws. 3D fluoroscopy-based image guidance can greatly enhance the accuracy of C2 translaminar screw insertion, as this technology provides real-time images during screw insertion and permits accurate screw sizing. PMID- 21298236 TI - Single-dose periarticular steroid infiltration for pain management in total knee arthroplasty: a prospective, double-blind, randomised controlled trial. AB - INTRODUCTION: Post total knee replacement pain control using parenteral opioids results in significant side effects like nausea and vomiting. Periarticular injections are used to control pain without these side effects. This study aimed to evaluate the safety and efficacy of periarticular steroid injection in patients undergoing total knee arthroplasty, as well as assess the patient's functional outcomes over a period of two years. METHODS: A total of 100 patients who underwent total knee arthroplasty were randomised into two groups. The treatment group received periarticular infiltration with triamcinolone acetonide, bupivacaine and epinephrine. The control group received only bupivacaine and epinephrine. The postoperative analgesic regime was standardised for all patients. The immediate postoperative outcomes evaluated included pain score, morphine consumption, time to ambulation, straight leg raise, range of motion and duration of hospital stay. Longer-term outcomes were assessed at 1, 3, 6 and 24 months using the SF-36 questionnaire and Oxford Knee Score. RESULTS: Patients in the treatment group had significantly lower pain scores, reduced morphine consumption and earlier discharge. They also had better range of knee motion and were able to regain muscular strength earlier. There was no increase in major complications such as infection or tendon rupture in the treatment group. There was no difference between the groups with regard to the medium-term outcomes of up to two years. CONCLUSION: This modality of pain control is safe and efficacious for post total knee replacement pain control. PMID- 21298237 TI - Foreign bodies in the urinary bladder and their management: a Pakistani experience. AB - INTRODUCTION: This was a retrospective study conducted to assess the nature, presentation, mode of insertion, diagnosis and management of foreign bodies in the urinary bladder. METHODS: Between January 1998 and December 2007, 20 patients with foreign bodies in their urinary bladder were treated at our centre. The records of these patients were reviewed and analysed for their symptoms, mode of insertion, diagnosis, management and complications. RESULTS: A total of 20 foreign bodies were recovered from the urinary bladders during the study period. These included JJ stents with calculi, intrauterine contraceptive devices with stones, a rubber stick, ribbon gauze, encrusted pieces of Foley catheter, proline thread with calculus, a suture needle, broken cold knives, the ceramic beak of a paediatric resectoscope, a knotted suprapubic tube, a hair clip, a nail, an electrical wire and a hairpin. The common presenting features were dysuria and haematuria. The diagnosis was established radiologically in most of the cases. The circumstances of insertion were variable; iatrogenic in 16 (80.0 percent) cases, sexual stimulation in two (10.0 percent), accidental insertion by a child in one (5.0 percent) and physical torture in one (5.0 percent). 17 (85.0 percent) foreign bodies were recovered endoscopically, and cystolithotomy was required in three (15.0 percent) patients. CONCLUSION: The instances of foreign bodies in the urinary bladder are uncommon. A diagnosis is usually made radiologically. Iatrogenic foreign bodies were found to be the most frequent type of insertion encountered. Endoscopic retrieval is usually successful, with minimal morbidity. PMID- 21298238 TI - Coping styles and lifestyle factors among hypertensive and non-hypertensive subjects. AB - INTRODUCTION: The objective of this study was to investigate the relationship between hypertensive patients and their coping style and associated lifestyle factors. METHODS: A total of 502 participants attending nine outpatient clinics completed the validated Bahasa Malaysia version of the Coping Inventory for Stressful Situations and sociodemographic questionnaires. The height, weight, pulse rate and blood pressure of all the participants were measured using standardised methods. RESULTS: A total of 264 (52.6 percent) participants were hypertensive, while 238 (47.4 percent) were not. Participants with a high task oriented score showed a significantly lower risk of hypertension compared to those with a low score (odds ratio [OR] 0.546; 95 percent confidence interval [CI] 0.371-0.804). Those with a high emotion-oriented coping score were associated with an increased risk of hypertension (OR 1.691; 95 percent CI 1.107 2.582). Hypertension was also significantly associated with a higher mean body mass index, positive family history of hypertension, history of diabetes mellitus and hypercholesterolaemia. In multiple logistic regression analysis with hypertension status as the dependent variable, a high emotion-oriented coping score, a low task-oriented coping score, age, body mass index, positive family history of hypertension and history of diabetes mellitus remain significant factors in the final model. CONCLUSION: These results indicated a significant relationship between hypertension and coping styles and lifestyle factors. They underscored the importance of further study as well as the development and implementation of intervention measures to improve coping skills among hypertensive patients, which may be incorporated into the management of hypertension. PMID- 21298239 TI - Coactivation of the shoulder and arm muscles during closed kinetic chain exercises on an unstable surface. AB - INTRODUCTION: The purpose of this study was to compare the electromyography index of muscle coactivation of the following muscle pairs: posterior deltoid and pectoralis major (PD/PM); triceps brachii and biceps brachii (TB/BB); and serratus anterior and upper trapezius (SA/UT) during three different closed kinetic chain exercises (wall-press, bench-press and push-up) on an unstable surface at the maximal load. METHODS: A total of 20 healthy sedentary men participated in the study. Integral linear values were obtained from three sustained contractions of six seconds each for the three proposed exercises. Mean coactivation index values were compared using the mixed-effects linear model, with a five percent significance level. RESULTS: Electromyography indexes of muscle coactivation showed significant differences for the PD/PM and TB/BB muscle pairs. No differences were found between exercises for the SA/UT muscle pair. CONCLUSION: Our results seem to differ from those of previous studies, which reported that the similarity in exercises performed is responsible for the comparable muscle activation levels. PMID- 21298240 TI - Pneumatic ureterolithotripsy in paediatric and adolescent patients: a ten-year experience at the Hospital Universiti Sains Malaysia. AB - INTRODUCTION: Two to three percent of stone disease cases occur in the paediatric age group. It is common in some parts of the world, such as in Turkey, India and Thailand. More than 50 percent of stones in children are still managed through open surgery. Ureteroscopic intervention for children remains a challenging treatment option. However, in contemporary urology practice, this mode of intervention is becoming more common. In this retrospective study, we reviewed our experiences with ureteroscopy and pneumatic lithotripsy in the paediatric and adolescent age group. METHODS: A total of 13 patients at or below the age of 18 years underwent 17 retrograde semirigid ureteroscopy between 1998 and 2008. Their median age was 14 (range 3-18) years. The technique of ureterolithotripsy used for this age group was similar to that used among adults. The ureteric orifice and intramural part of the ureter were not dilated in all the patients. A double J stent was inserted into all the patients. RESULTS: The mean stone size was 7.9 (range 5-13) mm. The stone was in the distal ureter in eight patients, in the mid ureter in seven patients and at the ureterovesical junction in another two patients. The overall stone-free rate after one ureterolithotripsy procedure was 84.6%. We failed to clear the stones in two patients at the first sitting. CONCLUSION: Semi-rigid ureteroscopy and pneumatic ureterolithotripsy are safe and effective procedures that can be performed without ureteric dilation in experienced hands. PMID- 21298241 TI - New clinical sign of cervical myelopathy: Wazir hand myelopathy sign. AB - INTRODUCTION: Cervical spondylotic myelopathy (CSM) represents a spectrum of pathologies with progressive compression of the spinal cord. The clinical signs and symptoms play a key role in diagnosis. The characteristic hand myelopathy signs are of significant clinical importance. The aim of this descriptive study was to report a relatively easy to elicit new hand myelopathy sign. The basis for this is finger and wrist flexor disinhibition, which is used for the spinal specificity of cord compression at or above the C5/6 level. METHODS: The new clinical test was conducted in 68 patients with a mean age of 62 (range 54-68) years. The patients were divided into two groups according to their level of stenosis. Group 1 (n is 58) patients had stenosis at or above the C5/6 level, while Group 2 (n is 10) patients had stenosis at or below the C6/7 level. All these patients were clinically evaluated and their level of stenosis was confirmed using magnetic resonance imaging. RESULTS: The Wazir sign was observed and well reproducible in 54 (93%) patients (Group 1); the myelopathy signs of three patients were positive (Hoffman's sign, finger escape and ten-second test). In Group 2, the Wazir sign was not reproducible, but the myelopathy signs were also positive in three patients. CONCLUSION: The Wazir hand myelopathy sign was found to be consistently present in our patients, in addition to the other hand myelopathy signs. PMID- 21298242 TI - Clinics in diagnostic imaging (133). Retained placenta from an intra-abdominal pregnancy. AB - A 29-year-old Indonesian woman presented with abdominal pain seven months after an intra-abdominal pregnancy. Ultrasonography revealed a cystic mass in the pelvis and magnetic resonance imaging showed an umbilical stump within it, indicating a retained placenta. This was removed surgically, and on histology, an infarcted placenta was confirmed. PMID- 21298243 TI - Impact of a newly introduced medical officer night-float on-call system in a medical department in Singapore. PMID- 21298245 TI - Retraction. Sleep-disordered breathing in patients with Parkinson's disease. PMID- 21298244 TI - Can minimally invasive percutaneous plate osteosynthesis be a viable answer in such situations? PMID- 21298249 TI - [Molecular diagnostics of lung cancer for treatment stratification]. AB - Lung tumors continue to be the most frequent cause of cancer-related death in Western industrialized countries. The development of new chemotherapeutic substances that are directed specifically against oncogenic pathomechanisms of non-small cell lung cancer represents a promising therapeutic approach. Meanwhile treatment measures are being employed for pulmonary adenocarcinomas that target the epidermal growth factor receptor and transforming EML4-ALK fusion protein. However, these therapies benefit almost exclusively those patients who have never smoked and manifest relatively rare subtypes of adenocarcinomas. In contrast, targeted therapeutic options for squamous cell carcinomas of the lung frequently found in smokers are still limited, although amplifications of the fibroblast growth factor receptor 1 have recently been identified as possible therapeutic targets in this patient population. This contribution provides an overview of the underlying pathomechanisms and molecular diagnostics needed for treatment stratification. PMID- 21298250 TI - Multi residue analysis of pesticides in wheat and khat collected from different regions of Ethiopia. AB - The present study investigated the presence and level of pesticide residues in wheat and khat samples collected from various localities of Ethiopia. The khat samples from Galemso and Aseno had p,p'-DDT concentrations ranged from 141.2 to 973.0 MUg/Kg and 194.3-999.0 MUg/Kg, respectively. Diazinon was detected in all the khat samples from BadaBuna (173.9-686.9 MUg/Kg) but not in any of the samples from Galemso and Aseno. Diazinon was detected in all the wheat samples obtained from both Arsi and Bale (125.8 and 125.6 MUg/Kg, respectively) and aldrin levels in these samples were below the quantification limit. Khat may be a contributing factor in the pathological diseases found among khat users. PMID- 21298251 TI - Fast cleanup system combined with a dioxin-responsive element-driven luciferase bioassay for analysis of polychlorinated dibenzo-p-dioxins/furans in sediments and soils. AB - A green technique was designed for assessing toxic equivalence (TEQ) levels of polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs) in sediments and soil from dioxin-contaminated areas. This technique combines a fast cleanup system with a dioxin-responsive-element (DRE)-driven luciferase bioassay. Samples from sediment (n = 10) and soil (n = 11) were analyzed with the technique; levels of PCDD/Fs ranged from 75.1 to 2,670 ng DRE-driven luciferase activity (DL)-TEQ/kg dry weight (d.w.). Significant correlations were found between DL-TEQs (by the bioassay) and PCDD/F WHO-TEQs (by HRGC/HRMS). DL-TEQs is significantly correlated with WHO-TEQs of 2,3,7,8-TCDD and 1,2,3,7,8-PeCDD using a multiple stepwise linear regression model (adjusted R(2) = 0.962, p < 0.001). PMID- 21298252 TI - Analysis of the herbicide bispyribac-sodium in rice by solid phase extraction and high performance liquid chromatography. AB - Bispyribac-sodium is a commonly used herbicide. An analytical method employing HPLC with a diode array detector was developed to determine bispyribac-sodium residues in rice. The liquid-liquid partition and anion exchange solid phase procedures that were developed provide effective extraction and cleanup methods for analysis feasibility. Recoveries ranged from 83.98 to 98.51% with a relative standard deviation of 0.56-6.36% and sensitivity of 0.01 mg/kg. Bispyribac-sodium residues in rice were further confirmed by LC-MS. The proposed method was successfully applied to the analysis of bispyribac-sodium residues from a rice field in Jiangxi Province that had been treated using bispyribac-sodium. PMID- 21298253 TI - Residue dynamic of pyrimorph on tomatoes, cucumbers and soil under greenhouse trails. AB - A modified QuEChERS method for analysis of pyrimorph residue in tomatoes, cucumbers and soil was developed and validated. Residue dynamics and final residues in greenhouse vegetables and soil were studied. At fortification levels of 0.05, 0.1 and 1 mg kg(-1) in tomatoes, cucumbers and soil, the method got recoveries ranged from 86.1% to 99.3% with relative standard deviations of 1.0% 7.7%, in agreement with directives for method validation in residue analysis. The limit of determination in tomatoes, cucumbers and soil was 0.05 mg kg(-1). The proposed method was successfully employed for the determination of pyrimorph residue levels and dissipation rates in vegetables and soil. At six experimental sites, pyrimorph residues in tomatoes and cucumbers showed relatively fast dissipation rates, with half-lives of 5.8-7.7 days and 5.7-7.1 days respectively. Half-lives of pyrimorph in soil were 8.5-11.0 days. The final residues of pyrimorph in tomatoes ranged from 0.19 to 3.66 mg kg(-1), 0.18 to 4.35 mg kg(-1) in cucumbers and 0.22 to 16.5 mg kg(-1) in soil with pre-harvest interval of 3-7 days. 5 mg kg(-1) was proposed as the MRL of pyrimorph in tomatoes and cucumbers. PMID- 21298254 TI - Development and validation of a new method for the radiologic measurement of the tibial slope. AB - PURPOSE: The posterior tibial slope has a huge influence on the kinematics of the knee. In several orthopedic interventions such as high tibial osteotomy and unicondylar or bicondylar knee replacement changing, the tibial slope can result in altered knee mechanics. Therefore, an exact preoperative measurement of the posterior tibial slope is mandatory. Several methods are used on conventional radiographs and CT scans, but until now there is no standard validated method. The aim of this study was to compare several methods and imaging techniques to measure the posterior tibial slope and to establish a standard and reliable measurement method by radiography. METHODS: Fourteen knees (seven cadavers) were scanned by a 64-slice CT, a 3T-MRI, and true lateral radiographs were performed. The anatomical references (TPAA = tibial proximal anatomical axis; ATC = anterior tibial cortex; PTC = posterior tibial cortex) and the new computed reference (MPA = mean of PTA and ATC) were compared by short as well as long radiographs, CT scan and MRI. The influence of a malrotation in radiographs of the knees was also analyzed. RESULTS: CT scan and MRI are suitable for the measurement of the medial and lateral posterior tibial slopes, the results of the radiographs varied depending on the method used. The new method (MPA) showed the best correlation to the CT scan (r = 0.997), even on short radiographs (10 cm distal the joint line). CONCLUSION: The measurement of the posterior tibial slope on a short lateral radiograph using the MPA is a reliable method and should be established as a standard. LEVEL OF EVIDENCE: Diagnostic study, Level II. PMID- 21298255 TI - Effects of additional gracilis tendon harvest on muscle torque, motor coordination, and knee laxity in ACL reconstruction. AB - PURPOSE: To evaluate muscle torque, lower extremity coordination, and knee laxity after ACL reconstruction comparing patients operated on with semitendinosus graft (ST) and patients with combined semitendinosus and gracilis (STGR) grafts. METHODS: Forty-six subjects who underwent ST (n = 23) or STGR harvest (n = 23) ACL reconstruction participated in this study. Quadriceps and hamstring torque were recorded using an isokinetic dynamometer. The anterior tibial translation was measured using the Kneelax 3 Arthrometer. The eccentric and concentric motor coordination was tested by multi-joint lower-limb tracking-trajectory test. All measurements were taken 12 months after surgery. Side-to-side differences were determined for all subjects. RESULTS: Side-to-side differences in extensor peak torque at 180 degrees /s and 60 degrees /s did not differ between semitendinosus (ST) and semitendinosus + gracilis (STGR) groups (n.s.). However, side-to-side differences in flexor peak torque were significantly higher at 60 degrees /s for the STGR group than the ST group (P = 0.002). Side-to-side differences in eccentric and concentric parts of tracking-trajectory test and anterior tibial translation did not differ between the STGR and the ST groups (n.s.). CONCLUSION: The outcomes of this study suggested that additional harvest of gracilis did not influence lower extremity motor control, quadriceps muscle torque, and anterior tibial translation; however, it affected knee flexion isokinetic torque negatively at low angular velocity. This finding could be important for functional activity or sports with high demands on hamstring muscle strength. It is recommended that gracilis muscle should be preserved as possible during ACL reconstruction. LEVEL OF EVIDENCE: Prospective comparative study, Level II. PMID- 21298256 TI - Unload it: the key to the treatment of knee osteoarthritis. AB - Osteoarthritis (OA) of the knee is a major public health problem whose prevalence is expected to grow dramatically commensurate with the aging of the population and increasing rates of obesity. Unfortunately, little progress has been made therapeutically to avert this epidemic. We hypothesize that the lack of effective interventions is due, in large part, to an overemphasis on pharmacotherapy and direct chondral repair. Instead, we propose that research and development efforts be aimed at addressing the aberrant biomechanics that are the primary driver in the progression of knee OA. In particular, technologies that "unload" the joint may reverse the structural damage, which is the cardinal feature of this disease. Re-establishing a favorable local mechanical environment may not only delay the requirement for an invasive joint reconstruction procedure but obviate the need entirely. PMID- 21298257 TI - Modulation of a thermoregulated type VI secretion system by AHL-dependent quorum sensing in Yersinia pseudotuberculosis. AB - The type VI secretion system (T6SS) is a novel secretion system found in many Gram-negative bacterial pathogens, which appears to be tightly regulated by different regulatory mechanisms. In the present study, we identified 4 T6SS clusters in Yersinia pseudotuberculosis and demonstrated that they were differentially thermoregulated. Among them, T6SS4 was preferentially expressed at 26 degrees C, and its expression was growth phase dependent and subject to quorum sensing regulation. Both YpsI and YtbI AHL synthases contributed to the positive regulation of T6SS4, whereas YpsI synthase played the major role as T6SS4 expression was reduced strongly in the ypsI mutant strain but weakly in the ytbI mutant strain. Moreover, we provided evidence that exogenous addition of different synthetic AHLs complemented T6SS4 expression in different efficiencies in an ypsIytbI double mutant strain, suggesting C6-HSL had an antagonistic effect on T6SS4 expression. This is the first study demonstrating that the expression of T6SS is precisely regulated by temperature, growth phase, and AHL-dependent quorum sensing systems in Y. pseudotuberculosis. PMID- 21298258 TI - Determination of growth hormone releasing peptides (GHRP) and their major metabolites in human urine for doping controls by means of liquid chromatography mass spectrometry. AB - A family of small peptides has reached the focus of doping controls representing a comparably new strategy for cheating sportsmen. These growth hormone releasing peptides (GHRP) are orally active and induce an increased production of endogenous growth hormone (GH). While the established test for exogenous GH fails, the misuse of these prohibited substances remains unrecognized. The present study provides data for the efficient extraction of a variety of known drug candidates (GHRP-1, GHRP-2, GHRP-4, GHRP-5, GHRP-6, alexamorelin, ipamorelin, and hexarelin) from human urine with subsequent mass spectrometric detection after liquid chromatographic separation. The used method potentially enables the retrospective evaluation of the acquired data for unknown metabolites by means of a non-targeted approach with high-resolution/high-accuracy full-scan mass spectrometry with additional higher collision energy dissociation experiments. This is of great importance due to the currently unknown metabolism of most of the targets and, thus, the method is focused on the intact peptidic drugs. Only the already characterised major metabolite of GHRP-2 (D-Ala-D-2 naphthylAla-L-Ala, as well as its stable isotope-labelled analogue) was synthesised and implemented in the detection assay. Method validation for qualitative purpose was performed with respect to specificity, precision (<20%), intermediate precision (<20%), recovery (47-95%), limit of detection (0.2-1 ng/mL), linearity, ion suppression and stability. Two stable isotope-labelled internal standards were used (deuterium-labelled GHRP-4 and GHRP-2 metabolite). The proof-of-principle was obtained by the analysis of excretion study urine samples obtained from a single oral administration of 10 mg of GHRP-2. Here, the known metabolite was detectable over 20 h after administration while the intact drug was not observed. PMID- 21298259 TI - Identification and quantification of flavonoids and ellagic acid derivatives in therapeutically important Drosera species by LC-DAD, LC-NMR, NMR, and LC-MS. AB - Droserae herba is a drug commonly used for treatment of convulsive or whooping cough since the seventeenth century. Because of the contribution of flavonoids and ellagic acid derivatives to the therapeutic activity of Droserae herba, an LC DAD method has been developed for quantification of these analytes in four Drosera species used in medicine (Drosera anglica, D. intermedia, D. madagascariensis, and D. rotundifolia). During elaboration of the method 13 compounds, including three substances not previously described for Drosera species, were detected and unambiguously identified by means of extensive LC-MS and LC-NMR experiments and by off-line heteronuclear 2D NMR after targeted isolation. The most prominent component of D. rotundifolia and D. anglica, 2"-O galloylhyperoside, with myricetin-3-O-beta-glucopyranoside and kaempferol-3-O-(2" O-galloyl)-beta-galactopyranoside, were identified for the very first time in this genus. The LC-DAD method for quantification was thoroughly validated, and enables, for the first time, separation and precise analysis of these analytes in Droserae herba. Simple sample preparation and use of a narrow-bore column guarantee low cost and simplicity of the suggested system, which is excellently suited to quality control of the drug or herbal medicinal products containing this drug. PMID- 21298260 TI - Transformations of polycyclic musks AHTN and HHCB upon disinfection with hypochlorite: two new chlorinated disinfection by-products (CDBP) of AHTN and a possible source for HHCB-lactone. AB - In this work, the behavior of the polycyclic musks 6-acetyl-1,1,2,4,4,7 hexamethyltetraline (AHTN) and 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8 hexamethylcyclopenta-gamma-2-benzopyran (HHCB) was investigated upon disinfection by using sodium hypochlorite as disinfectant in a model disinfection basin in order to find new disinfection by-products (DBP). In the case of AHTN, the carboxylic acid 3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (AHTN-COOH) was generated by a haloform reaction, being the origin for two new chlorinated DBPs. In the case of HHCB, disinfection via hypochlorite led to the HHCB-lactone. All reaction products and intermediates were synthesized and isolated. The relevant degradation mechanisms are discussed in detail. PMID- 21298261 TI - Psychotropic drug use in community-dwelling elderly people-characteristics of persistent and incident users. AB - PURPOSE: The aim of this prospective cohort study was to analyze psychotropic drug use in community-dwelling elderly people over a 3-year period and characterize those individuals most susceptible to persistent and incident use. METHODS: Data on demographics, health status, cognition, functional capacity and drug use were gathered by interviews at baseline (2004) and in three follow-ups (2005-2007) in a population-based sample of 700 community-dwelling people aged >=75 years. Characteristics associated with persistent and incident use were identified using Cox proportional-hazards regression. RESULTS: At baseline, 38% (n = 269) of the participants used psychotropic drugs. Of these, 60% (n = 162) reported use in all three follow-ups, whereas 22% (n = 59) discontinued use. Among the baseline users of antipsychotics (n = 40), antidepressants (n = 83) and benzodiazepines (n = 219), respectively, 43, 51 and 55% reported use in all three follow-ups. The characteristics associated with persistent use of psychotropic drugs included concomitant use of psychotropic drugs, regular use of psychotropic drugs, increasing age and good self-rated health. Among the baseline nonusers of psychotropic drugs (n = 431), 20% (n = 88) initiated use during the follow-up. Incident use of psychotropic drugs was associated with increasing Geriatric Depression Scale scores, a Mini-Mental State Examination score <=24, number of visits to physician >= 6, moderate/poor self-rated health and moderate/poor life satisfaction. CONCLUSIONS: Psychotropic drugs, benzodiazepines in particular, are frequently used for extended periods in community-dwelling people aged >=75 years. Individuals with multiple psychotropic drugs and a regular pattern of use are most susceptible to persistent use. Characteristics associated with incident use include depressive symptoms, cognitive decline and poor general health. PMID- 21298262 TI - Safety and efficacy of tubeless percutaneous nephrolithotomy in patients on anti platelet therapy and cirrhotic patients. AB - Without the temponade effect over nephrostomy tube, postoperative hemorrhage is a major concern to the safety of tubeless percutaneous nephrolithotomy (PCNL) in patients with bleeding tendency. In this study, we would like to report our experience of performing tubeless PCNLs in these patients. At the end of PCNL, we cauterized the bleeding points in access tract for hemostasis to facilitate the achievement of tubeless PCNL. We identified and reviewed 16 patients under antiplatelet agent therapy and 6 patients with liver cirrhosis from 598 tubeless PCNLs performed in a single institute. Among the 16 patients undergoing anti platelet therapy, the average stone size was 2.8 cm. The average operation time was 84.7 min. The stone-free rate was 87.5%. The average postoperative hospital stay was 3.8 days. Two patients (12.5%) experienced urinary tract infections after operation. There was no uncontrolled hemorrhage during and after operation and only one patient needed postoperative blood transfusion. No patient experienced any thromboembolic complication. Of the six patients with liver cirrhosis, the average stone size was 3.3 cm. The average operation time was 77.5 min. The stone-free rate is 83.4%. The average postoperative hospital stay was 4.0 days. No patient received blood transfusion after operation. There was no patient experiencing urinary tract infection after operation. Our results suggest that with careful hemostasis, tubeless PCNL is a safety modality in the treatment of urinary stone disease in patients on chronic anti-platelet therapy and cirrhotic patients. PMID- 21298263 TI - Rice to vegetables: short- versus long-term impact of land-use change on the indigenous soil microbial community. AB - Land-use change is known to have a significant effect on the indigenous soil microbial community, but it is unknown if there are any general trends regarding how this effect varies over time. Here, we describe a comparative analysis of microbial communities from three adjacent agricultural fields: one-century-old paddy field (OP) and two vegetable fields (new vegetable field (NV) and old vegetable field (OV)) that were established on traditional paddy fields 10 and 100 years ago, respectively. Soil chemical and physical analysis showed that both vegetable fields were more nutrient rich than the paddy field in terms of organic C, total N, total P, and available K. The vegetable fields possessed relatively higher abundance of culturable bacteria, fungi, and specific groups of bacteria (Actinomyces, nitrifying bacteria, and cellulose-decomposing bacteria) but lower levels of microbial biomass C and N. Notably, the decrease of biomass was further confirmed by analysis of seven additional soils in chronosequence sampled from the same area. Next we examined the metabolic diversity of the microbial community using the EcoPlate(TM) system from Biolog Inc. (Hayward, CA, USA). The utilization patterns of 31 unique C substrates (i.e., community-level physiological profile) showed that microorganisms in vegetable soil and paddy soil prefer to use different C substrates (polymeric compounds for NV and OV soils, phenolic acids for OP soil). Principal component analysis and the average well color development data showed that the NV is metabolically more distinct from the OV and OP. The effect was likely attributable to the elevated soil pH in NV soil. Furthermore, we assessed the diversity of soil bacterial populations using the cultivation-independent technology of amplified ribosomal DNA restriction analysis (ARDRA). Results showed that levels of bacterial diversity in OP and NV soils were similar (Shannon's diversity index H = 4.83 and 4.79, respectively), whereas bacteria in OV soil have the lowest score of diversity (H = 3.48). The low level of bacterial diversity in OV soil was supported by sequencing of ten randomly selected 16S rDNA clones from each of the three rDNA libraries. Phylogenetic analysis showed that all the ten OV clones belonged to Proteobacteria with eight in the gamma-subdivision and two in the alpha subdivision. In contrast, the ten clones from NV and OP soils were classified into four and eight bacterial classes or unclassified groups, respectively. Taken together, our data suggest that land-use change from rice to vegetables resulted in a decrease of bacterial diversity and soil biomass despite an increase in the abundance of culturable microorganisms and, moreover, the decrease of bacterial diversity occurred during long-term rather than short-term vegetable cultivation. PMID- 21298264 TI - Generation and characterization of the first inhibitory antibody targeting tumour associated carbonic anhydrase XII. AB - The carbonic anhydrases (CAs) constitute a family of almost ubiquitous enzymes of significant importance for many physiological and pathological processes. CAs reversely catalyse the conversion of CO(2) + H(2)O to HCO(3) (-) and H(+), thereby contributing to the regulation of intracellular pH. Above all, CAs are of key importance for cells that perform glycolysis that inevitably leads to the intracellular accumulation of lactate. CA XII is a plasma membrane-associated isoform of the enzyme, which is induced by hypoxia and oestrogen and, consequently, expressed at high levels on various types of cancer and, intriguingly, on cancer stem cells. The enzyme is directly involved in tumour progression, and its inhibition has an anti-tumour effect. Apart from its role in carcinogenesis, the enzyme contributes to various other diseases like glaucoma and arteriosclerotic plaques, among others. CA XII is therefore regarded as promising target for specific therapies. We have now generated the first monoclonal antibody (6A10) that binds to the catalytic domain of CA XII on vital tumour cells and inhibits CA XII enzyme activity at nanomolar concentrations and thus much more effective than acetazolamide. In vitro results demonstrate that inhibition of CA XII by 6A10 inhibits the growth of tumour cells in 3-dimensional structures. In conclusion, we generated the first specific and efficient biological inhibitor of tumour-associated CA XII. This antibody may serve as a valuable tool for in vivo diagnosis and adjuvant treatment of different types of cancer. PMID- 21298265 TI - The facial autologous muscular injection (FAMI) procedure: an anatomically targeted deep multiplane autologous fat-grafting technique using principles of facial fat injection. AB - BACKGROUND: As widely described in the medical literature, facial fat grafting has been limited to the subcutaneous plane, with only vague reference to the muscular plane and deeper tissues. Local infiltration, with or without general anesthesia, is commonly used. The challenges of maintaining volumetric correction, symmetry, and predictability have limited practitioners' confidence in obtaining a desirable result when fat grafting the face. The authors describe a technique for facial fat grafting that targets specific anatomic structures and tissue beds, in effect making the patient's underlying anatomy the template for rejuvenation. Engrafting the muscles of facial expression improves graft retention and therefore predictability and symmetry. The ability to target anatomic structures other than muscle lends itself to the prospect of greater therapeutic advances using adipose-derived stem cells (ADSCs). A set of principles guiding the technique intended to promote successful cellular engraftment is presented. METHODS: Three illustrative cases are presented, each the result of a single session: two from a 10-year experience of 700 patients by the lead author and one by the corresponding author. RESULTS: The majority of cases (80-90%) needed only a single session for creation of permanent improvement in facial volumes and contours. CONCLUSIONS: The facial autologous muscular injection (FAMI) technique offers an anatomically based approach to facial fat grafting with greater predictability and efficiency than current techniques. The principles of the technique put forth apply equally to volumetric enhancements obtained through successful fat grafting and to the promise of ADSCs. PMID- 21298266 TI - Evaluating post-fire forest resilience using GIS and multi-criteria analysis: an example from Cape Sounion National Park, Greece. AB - Forest fires are one of the major causes of ecological disturbance in the mediterranean climate ecosystems of the world. Despite the fact that a lot of resources have been invested in fire prevention and suppression, the number of fires occurring in the Mediterranean Basin in the recent decades has continued to markedly increase. The understanding of the relationship between landscape and fire lies, among others, in the identification of the system's post-fire resilience. In our study, ecological and landscape data are integrated with decision-support techniques in a Geographic Information Systems (GIS) framework to evaluate the risk of losing post-fire resilience in Pinus halepensis forests, using Cape Sounion National Park, Central Greece, as a pilot case. The multi criteria decision support approach has been used to synthesize both bio indicators (woody cover, pine density, legume cover and relative species richness and annual colonizers) and geo-indicators (fire history, parent material, and slope inclination) in order to rank the landscape components. Judgments related to the significance of each factor were incorporated within the weights coefficients and then integrated into the multicriteria rule to map the risk index. Sensitivity analysis was very critical for assessing the contribution of each factor and the sensitivity to subjective weight judgments to the final output. The results of this study include a final ranking map of the risk of losing resilience, which is very useful in identifying the "risk hotspots", where post-fire management measures should be applied in priority. PMID- 21298267 TI - Drug-induced lymphadenopathy with eosinophilia and renal failure mimicking lymphoma disease: dramatic onset of DRESS syndrome associated with antibiotic treatment. PMID- 21298268 TI - A sensitive and reliable RT-nested PCR assay for detection of Citrus tristeza virus from naturally infected citrus plants. AB - A specific and sensitive reverse transcriptase-nested polymerase chain reaction assay (RT-nPCR) was developed for the detection of Citrus tristeza virus (CTV) from naturally infected citrus samples. Two sets of primer pairs were designed by alignment of nucleotide sequences available in GenBank database for different genotypes of CTV. RT-nPCR reaction components and thermal cycling parameters were optimized and reaction conditions were standardized. Sequencing of the PCR products from direct and nested-PCR reactions confirmed the specificity of both primer pairs. Presence of CTV specific amplicons in asymptomatic samples which were collected from diseased orchards indicated the sensitivity of the test. As RT-nPCR technique, developed in the present study, is specific and efficient in detecting CTV, this could be envisioned for diagnostic applications and surveillance. PMID- 21298269 TI - Annexin A5 and anti-annexin antibodies in patients with systemic lupus erythematosus. AB - Plasma levels of annexin A5 (ANX A5) and anti-annexin A5 (aANX A5) antibodies were evaluated in 51 women with systemic lupus erythematosus (SLE). The results were compared between the total SLE group, subgroups on/without immunosuppressive therapy and the control (28 women). The relationships between ANX A5/aANX A5 antibodies levels and laboratory variables (anti-cardiolipin antibodies-aCL, total cholesterol, thrombocyte count, activated partial thromboplastin time-APTT, prothrombin time, international normalized ratio-INR) were performed in the total SLE group and in the patient subgroups identified as the arithmetic mean of ANX A5 concentration in the control plus 1-4 standard deviations (SD). The whole SLE group and the subgroup on immunosuppression showed significantly higher ANX A5 and IgG aANX A5 antibodies concentrations. A weak positive correlation was found between ANX A5 and thrombocyte count, a moderate one between IgG and IgM aANX A5 antibodies, a weak negative correlation between IgG aANX A5 and APTT in the whole SLE group. SLE subgroups with ANX A5 concentrations higher than the control mean plus 3 or 4 SD showed a weak/moderate negative correlation of this parameter with aANX A5 antibodies, moderate one with IgG aCL antibodies levels, a moderate positive correlation with cholesterol concentration, moderate/high positive correlations with thrombocyte count. The association between plasma ANX A5/IgG aANX A5 levels and severity of disease was noticed. The role of aANX A5 and IgG aCL antibodies as causative factors of increased ANX A5 levels was suggested, and the relationship between ANX A5 and thrombocyte count was revealed. PMID- 21298271 TI - The 24th international Mammalian Genome Conference meeting report. PMID- 21298272 TI - Effect of parathyroid hormone on hypogonadism induced bone loss of proximal femur of orchiectomized rat. AB - PURPOSE: Management of hypogonadism-induced osteoporosis in elderly men is still a challenge. We investigated the short-term effects of parathyroid hormone (PTH) treatments on strength, micro-architecture, and mineral density of trochanteric region of orchiectomized rat femur. METHODS: Eight-month-old male Sprague-Dawley rats (n = 44) were divided into two groups: (1) orchiectomized (ORX) and (2) sham group. Twelve weeks after orchiectomy, half of the orchiectomized animals were treated with daily subcutaneously injected PTH (0.040 mg/kg/BW) (ORX-PTH) for 5 weeks. The other half remained untreated (ORX). The sham-operated group was divided and treated in the same way (sham, sham-PTH). After 5 weeks, both femurs were excised for biomechanical and histomorphometric analysis, trabecular measurements, mineral content assessment, and immunofluorescence analysis. RESULTS: The femoral trochanteric strength after PTH treatment was enhanced in the breaking test (ORX-F(max) = 158.7 N vs. ORX + PTH-F(max) = 202 N). Stiffness of treated ORX animals reached nearly the levels observed in untreated sham rats. PTH therapy improved the trabecular connectivity, width, and area (ORX-Tb.Ar = 47.79% vs. ORX + PTH-Tb.Ar = 68.47%, P < 0.05) in the proximal femur. The treated rats showed significantly improved mineral content in ashed femurs (ORX-mineral content = 43.73% vs. ORX + PTH-mineral content = 49.49%) when compared to the untreated animals. A comparison of widths of fluorescence bands in cortical bone of the subtrochanteric cross-sections showed a significant increase in oppositions after the PTH therapy. CONCLUSIONS: Our finding supports the hypothesis that PTH therapy seems to be a rational therapy in patients with hypogonadism induced bone loss and improves the bone strength of trochanteric region of rat femur. PMID- 21298270 TI - Root-targeted biotechnology to mediate hormonal signalling and improve crop stress tolerance. AB - Since plant root systems capture both water and nutrients essential for the formation of crop yield, there has been renewed biotechnological focus on root system improvement. Although water and nutrient uptake can be facilitated by membrane proteins known as aquaporins and nutrient transporters, respectively, there is a little evidence that root-localised overexpression of these proteins improves plant growth or stress tolerance. Recent work suggests that the major classes of phytohormones are involved not only in regulating aquaporin and nutrient transporter expression and activity, but also in sculpting root system architecture. Root-specific expression of plant and bacterial phytohormone related genes, using either root-specific or root-inducible promoters or grafting non-transformed plants onto constitutive hormone producing rootstocks, has examined the role of root hormone production in mediating crop stress tolerance. Root-specific traits such as root system architecture, sensing of edaphic stress and root-to-shoot communication can be exploited to improve resource (water and nutrients) capture and plant development under resource-limited conditions. Thus, root system engineering provides new opportunities to maintain sustainable crop production under changing environmental conditions. PMID- 21298273 TI - Radical cystectomy with orthotopic neobladder for invasive bladder cancer: a critical analysis of long-term oncological, functional, and quality of life results. AB - PURPOSE: The present contribution analyses long-term data regarding oncological, functional, and quality of life aspects of patients subjected to cystectomy due to malignancy with subsequent orthotopic bladder substitution. METHODS: A literature search was conducted to review literature published from 1887 until today. Oncological aspects, special considerations on female patients, quality of life, geriatric patients, and impact of minimally invasive surgery were also addressed and discussed. RESULTS: After more than three decades, orthotopic bladder substitution subsequent to radical cystectomy has stood the test of time by providing adequate long-term survival and low local recurrence rates. Compared to radical cystectomy, neither radiation nor chemotherapy, nor a combination of both, offer similar long-term results. Orthotopic bladder substitution does not compromise oncological outcome and can be performed with excellent results regarding functional and quality of life issues. Chronological age is generally not a contraindication for cystectomy. CONCLUSION: Orthotopic bladder substitution should be the diversion of choice both in men and in women, whenever possible. For orthotopic urinary diversion, a careful patient selection considering tumor extent, patient motivation, preoperative sphincter function, other local and systemic adverse confounding factors, and overall life expectancy must be taken into account. Minimally invasive techniques are promising concepts for the future, awaiting confirmation in larger patient cohorts. PMID- 21298274 TI - Presence of glioma stroma mesenchymal stem cells in a murine orthotopic glioma model. AB - PURPOSE: High-grade gliomas are closely related to the mesenchymal phenotype which might be explained by unorthodox differentiation of glioma cancer stem cells (gCSCs). We reasoned that other non-neural stem cells, especially mesenchymal stem cells (MSCs), might play a role in expressing mesenchymal phenotype of high-grade gliomas. Thus we hypothesized that cells resembling MSCs exist in glioma specimens. METHODS: We created a mouse (m) orthotopic glioma model using human gCSCs. Single-cell suspensions were isolated from glioma specimens and cultured according to the methods for mMSCs or gliomaspheres. These cells were analyzed by fluorescence-activated cell sorting (FACS) for surface markers associated with mMSCs or gCSCs. Glioma stroma (GS)-MSCs were exposed to mesenchymal differentiation conditions. To decide the location of GS-MSCs, sections of orthotopic glioma models were analyzed by immunofluorescent labeling. RESULTS: GS-MSCs were isolated which were morphologically similar to mMSCs. FACS analysis showed that the GS-MSCs had similar surface markers to mMSCs (stem cell antigen-1 [Sca-1](+), CD9(+), CD45(-), CD11b(-), CD31(-), and nerve/glial antigen 2 [NG2](-)). GS-MSCs were capable of mesenchymal differentiation. Immunofluorescent labeling indicated that GS-MSCs are located around blood vessels, are distinct from endothelial cells, and have features that partially overlap with vascular pericytes. CONCLUSIONS: Our results indicate that cells similar to mMSCs exist in glioma specimens. The GS-MSCs might be located around vessels, which suggests that GS-MSCs may provide the mesenchymal elements of the vascular niche. GS-MSCs may represent non-neural stem cells that act as an important source of mesenchymal elements, particularly during the growth of gliomas. PMID- 21298275 TI - The prognostic factors and the outcome of primary isolated fetal ascites. AB - PURPOSE: The purpose of the present study was to evaluate the prognostic factors and review the outcome of primary isolated fetal ascites. METHODS: A retrospective cohort study was conducted for fetuses with primary isolated ascites with a prenatal diagnosis between 1994 and 2009. The patients were divided into the favorable group (Group I) whose ascites were resolved by medical treatment alone and an unfavorable group (Group II) who required surgical intervention after birth due to refractory ascites. RESULTS: There were seven patients in Group I and five patients in Group II. Six of seven patients who developed ascites after 30 weeks' gestation were categorized in Group I, and four of five infants who developed ascites before 30 weeks' gestation were categorized in Group II. There was a negative correlation between the gestational age at diagnosis and the severity of the fetal abdominal distention. In Group II, the ascites resolved in two cases and was reaccommodated in another two cases after surgery. An infant with trisomy 21 received continuous drainage and eventually died of infection. CONCLUSIONS: The prognosis of primary isolated fetal ascites can be predicted based on the gestational age at diagnosis and the severity of the fetal abdominal distention. PMID- 21298276 TI - Minimally invasive combined anterior kyphoplasty for osteolytic C2 and C5 metastases. AB - Kypho- and vertebroplasty are widely accepted for treating patients suffering from pathologic thoracolumbar lesions, in particular diffuse metastatic-induced fractures. They provide rapid pain relief and the restoration of spinal stability. In the cervical spine, attempts have been made to use cement augmentation for these indications. However, the cervical spine's anatomy complicates the transpedicular approach, as well as the pre-formation of a vertebral body cavity and the application of bone cement. We report the case of a 46-year-old woman suffering from symptomatic C2 and C5 osteolysis caused by metastatic breast cancer. Following a surgical staging and classification (Tokuhashi-Score) that indicated palliative procedures, we performed a C2 and C5 kyphoplasty using one minimal-invasive anterior approach through a small incision. We observed an uneventful procedure and postoperative course as well as immediate pain relief and patient mobilization. Last patient follow-up at 3 months showed an excellent outcome. Our observations showed cervical spine kyphoplasty via a minimally invasive anterior approach to be feasible, successful and safe surgical method in the interdisciplinary palliative treatment. PMID- 21298277 TI - Cobalt, chromium and molybdenum ions kinetics in the human body: data gained from a total hip replacement with massive third body wear of the head and neuropathy by cobalt intoxication. AB - INTRODUCTION: A patient with a total hip replacement developed optic, acoustic and peripheral neuropathy from metal ions intoxication, due to the wear products released from the prosthesis. Subsequently the kinetics of the metal ions was studied. MATERIALS AND METHODS: Massive wear and acute intoxication allowed a study of the metal ions kinetics and of EDTA treatment. RESULTS: Plasma and other organic fluids were saturated by each of the metal ions released from the exposed surface according to the solubility of each ion; a larger fraction of Co ions was bound within red cells, while the plasmatic fraction appeared more movable. In a patient with a prosthesis subjected to wear, the ions released are from the prosthetic and from the debris surface (spread in the body). The latter is a function of the number and size of particles. DISCUSSION: Revision of the prosthesis from the point of view of the metal ions kinetics corresponded to a reduction of the releasing surface because of debris washed out by irrigation and tissue excision; however, the metal particles spread by lymphatic circulation continued to release ions even though the source of wear had been removed. Early diagnosis of high metal wear can be ascertained with mass spectrometry and after revision high levels of metal ions can only be reduced with repeated chelating treatment. It is preferable not to revise fractured ceramic components with a polyethylene-metal articulation. PMID- 21298278 TI - Severe frostbite injury in a 19-year-old patient requiring amputation of both distal forearms and lower legs due to delayed rescue: a need for advanced accident collision notification systems? AB - Frostbite injury is a rare but severe injury especially when rescue triage is prolonged. We here report the case of a 19-year-old male patient with severe frostbite injuries requiring amputation of both distal forearms and both lower legs due to delayed admission to medical care. This case demonstrates that even mild ambient temperatures can cause deleterious injuries if the exposure time is long enough paralleling our knowledge of burn trauma. Immediate admission to medical care is, therefore, paramount and GPS-based automated accident collision notification systems would therefore be of great benefit especially in rural areas. PMID- 21298279 TI - Comedolytic effect and reduced skin irritation of a new formulation of all-trans retinoic acid-loaded solid lipid nanoparticles for topical treatment of acne. AB - Novel drug delivery systems, such as solid lipid nanoparticles (SLN), have been proposed to reduce retinoic acid (RA)-induced skin irritation. However, one question still remains: could it be accomplished without reducing efficacy? To evaluate this question the comedolytic effects and epidermal thickening of RA loaded SLN were compared to the conventional RA formulations (gel or cream), as well as the potential of these formulations to induce skin irritation. The comedolytic effects and epidermal thickening of these formulations, both containing RA at 0.01 or 0.05%, were investigated in a rhino mouse model, while the studies of RA-induced skin irritation were evaluated through rabbit skin irritation tests and in the rhino mouse model. RA-loaded SLN, as compared to the placebo, produced a comedolytic effect with a significant reduction of the utricle diameter, which proved to be similar to that observed for marketed gels or creams regardless of the RA concentration. RA formulations (SLN or marketed cream) also induced an epidermal proliferation leading to a thickened epidermis in treated animals. In both animals studied (rhino mice and rabbits), the RA loaded SLN, when compared to conventional formulations, promoted a significant reduction in RA-induced skin irritation (erythema and scaling). Then, RA-loaded SLN represents an interesting alternative to reduce RA-induced skin irritation without reducing efficacy, and constitutes an innovative approach for the topical treatment of acne with RA. PMID- 21298280 TI - Inhibition of basal and ultraviolet B-induced melanogenesis by cannabinoid CB(1) receptors: a keratinocyte-dependent effect. AB - Ultraviolet radiation is the major environmental insult to the skin and stimulates the synthesis of melanin in melanocytes, which then distribute it to the neighboring keratinocytes where it confers photo-protection. Skin color results from the paracrine interaction between these two cell types. Recent studies suggest that endocannabinoids are potential mediators in the skin. Here, we investigated whether cannabinoid drugs play a role in melanogenesis and if ultraviolet radiation modifies the cutaneous endocannabinoid system. We used human melanotic melanoma cell line (SK-mel-1) in monoculture or co-culture with human keratinocytes (HaCat). Endocannabinoid levels, cannabinoid receptors expression, and melanin content were evaluated under basal conditions and after ultraviolet-B irradiation (311 nm). We provide evidence that human melanoma cells (SK-mel-1) express CB(1) receptors, and when in co-culture with keratinocytes (HaCat), the selective CB(1) receptor agonist arachidonyl-2-chloroethylamide (ACEA 1 and 10 MUM) inhibited (by 33.4 and 37.3%, respectively) basal melanogenesis. In addition, ultraviolet-B-induced melanogenesis in co-cultures was abolished by ACEA 10 MUM. Both ACEA inhibitory effects were reversed by AM251 (1 MUM), a selective CB(1) antagonist. Furthermore, ultraviolet-B radiation increased endocannabinoids levels only in keratinocytes, whereas CB(1) cannabinoid receptor expression was up-regulated only in melanoma cells. Our results collectively suggest that ultraviolet radiation activates paracrine CB(1) mediated endocannabinoid signaling to negatively regulate melanin synthesis. The endocannabinoid system in the skin may be a possible target for future therapies in pigmentary disorders. PMID- 21298281 TI - Correlation of myometrial thickness and the latency interval of women with preterm premature rupture of the membranes. AB - OBJECTIVE: To verify the hypothesis that a correlation exists between myometrial thickness (MT) and latency interval (LI) in patients with preterm premature rupture of membrane (PPROM). METHOD: Myometrial thickness was measured ultrasonographically at the mid-anterior (MA), fundal, and posterior parts of the uterus of pregnant women in the following groups: PPROM [n = 45, mean (range), gestational age (GA): 28.6 weeks (w) (24.0-33.0 w)], preterm nonlabor control group (P-CTR) [n = 20, GA: 29.5 w (25.0-32.0 w)] and term nonlabor control (T CTR) [n = 27, GA: 38.4 w (37.0-41.0 w)]. RESULTS: There was a positive correlation between LI and fundal MT (r = 0.34, P = 0.02), mid-MT (r = 0.47, P = 0.001) and LUS (r = 0.74, P = 0.001). The results were similar in the group of <30 w of GA, but in the group of >= 30 w of GA, there was no association. The LUS MT has more area under the ROC curve than MA MT and fundal MT for prediction of LI of <= 8 days. CONCLUSION: Significant positive correlation between LI and MT in patients with PPROM may result in a better decision for taking care of infants of preterm birth. PMID- 21298282 TI - GAD-ab-associated movement disorder in a male patient with breast cancer. PMID- 21298283 TI - Effects of rTMS on Parkinson's disease: a longitudinal fMRI study. AB - Parkinson's disease is a movement disorder whose principal symptoms are tremor, rigidity, bradykinesia and postural instability. Initially, drugs like L: -dopa or dopaminergic agonists are able to control these symptoms, but with the progress of the disease these drugs become less effective. Previous studies have reported that repetitive transcranial magnetic stimulation (rTMS) can improve these motor symptoms. The objective of this study was to investigate the neural mechanisms through which 25 Hz rTMS may improve motor symptoms in Parkinson's disease. In a double-blind placebo-controlled study, we evaluated the effects of 25 Hz. rTMS in 10 Parkinson's disease patients. Fifteen rTMS sessions were performed over the primary cortex on both hemispheres (one after the other) during a 12-week period. The patients were studied using functional magnetic resonance imaging during performance of a simple tapping and a complex tapping task, 1 week before the administration of the first rTMS session and just after the last session. rTMS improved bradykinesia, while functional magnetic resonance imaging showed different cortical patterns in prefrontal cortex when patients performed the complex tapping test. Furthermore, the improvement in bradykinesia is associated with caudate nucleus activity increases in simple tapping. Finally, we observed a relative change in functional connectivity between the prefrontal areas and the supplementary motor area after rTMS. These results show a potential beneficial effect of repetitive transcranial magnetic stimulation on bradykinesia in Parkinson's disease which is substantiated by neural changes observed in functional magnetic resonance imaging. PMID- 21298284 TI - A root proteomics-based insight reveals dynamic regulation of root proteins under progressive drought stress and recovery in Vigna radiata (L.) Wilczek. AB - To understand the complex drought response mechanism in crop plants, a systematic root proteomics approach was adopted to identify and analyze the expression patterns of differentially expressed major root proteins of Vigna radiata during short-term (3 days) and consecutive long-term water-deficit (6 days) as well as during recovery (6 days after re-watering). Photosynthetic gas exchange parameters of the plant were measured simultaneously during the stress treatment and recovery period. A total of 26 major protein spots were successfully identified by mass spectrometry, which were grouped according to their expression pattern during short-term stress as significantly up-regulated (9), down regulated (10), highly down-regulated, beyond detection level of the software (2) and unchanged (5). The subsequent changes in the expression patterns of these proteins during long-term stress treatment and recovery period was analyzed to focus on the dynamic regulation of these functionally important proteins during progressive drought and recovery period. Cytoskeleton-related proteins were down regulated initially (3d) but regained their expression levels during subsequent water-deficit (6d) while glycoprotein like lectins, which were primarily known to be involved in legume-rhizobia symbiosis, maintained their enhanced expression levels during both short and long-term drought treatment indicating their possible role in drought stress response of legumes. Oxidative stress-related proteins including Cu/Zn superoxide dismutase, oxidoreductase and aldehyde reductase were also up-regulated. The analyses of the dynamic regulation of these root proteins during short- and long-term water-deficit as well as recovery period may prove crucial for further understanding of drought response mechanisms in food legumes. PMID- 21298285 TI - Quantification of lignin-carbohydrate linkages with high-resolution NMR spectroscopy. AB - A quantitative approach to characterize lignin-carbohydrate complex (LCC) linkages using a combination of quantitative 13C NMR and HSQC 2D NMR techniques has been developed. Crude milled wood lignin (MWLc), LCC extracted from MWLc with acetic acid (LCC-AcOH) and cellulolytic enzyme lignin (CEL) preparations were isolated from loblolly pine (Pinus taeda) and white birch (Betula pendula) woods and characterized using this methodology on a routine 300 MHz NMR spectrometer and on a 950 MHz spectrometer equipped with a cryogenic probe. Structural variations in the pine and birch LCC preparations of different types (MWL, CEL and LCC-AcOH) were elucidated. The use of the high field NMR spectrometer equipped with the cryogenic probe resulted in a remarkable improvement in the resolution of the LCC signals and, therefore, is of primary importance for an accurate quantification of LCC linkages. The preparations investigated showed the presence of different amounts of benzyl ether, gamma-ester and phenyl glycoside LCC bonds. Benzyl ester moieties were not detected. Pine LCC-AcOH and birch MWLc preparations were preferable for the analysis of phenyl glycoside and ester LCC linkages in pine and birch, correspondingly, whereas CEL preparations were the best to study benzyl ether LCC structures. The data obtained indicate that pinewood contains higher amounts of benzyl ether LCC linkages, but lower amounts of phenyl glycoside and gamma-ester LCC moieties as compared to birch wood. PMID- 21298286 TI - Ductal plates in hepatic ductular reactions. Hypothesis and implications. II. Ontogenic liver growth in childhood. AB - This article discusses the processes of bile duct growth and new lobule formation in the liver during childhood in the light of the ductal plate (DP) hypothesis. Unlike in other organs in which tubular elongation and branching ends with the creation of the organ-specific terminal differentiation products, in the liver a steadily enlarging parenchymal mass needs to establish continuity of its canalicular network with the existing bile duct system. The hypothesis suggests that this occurs by DP formation, like in the embryonic liver, and further assumes that pathological ductular reactions (DRs) induced by cholestasis or hypoxia are amplified equivalents of similar mechanisms operating at low level during liver growth. The concept is confronted with data on porcine liver growth, since swine and non-swine liver growth is thought to be comparable. Relative bile acid load may be the driving force for establishment of new canaliculo-ductular connections, supported in zones of relative hypoxia by hypoxia-inducible factor 1 alpha secreted by hepatocytes. The latter mechanism is at the base for induction of appropriate vascular changes in selected sinusoids, resulting in the development of portal inlet venules and additional draining central veins. The process gives rise to the formation of new single lobules by formation of new portal tracts or to the transformation of single lobules in compound lobules by development of new vascular septa. The concept of postnatal DP formation is important in the elucidation of several unexplained findings in adult liver diseases. PMID- 21298287 TI - Cardiac sarcoidosis and sudden death. The heart may look normal or mimic other cardiomyopathies. AB - Cardiac sarcoidosis has been known to give rise to heart failure, arrhythmias and sudden cardiac death. We have a large database of sudden cardiac death cases at the CRY Centre for Cardiac Pathology at Imperial College, London, UK in which we found 17 of 1,720 cases with a diagnosis of cardiac sarcoid. Macroscopic examination showed a variety of findings including left ventricular hypertrophy, a dilated thin-walled left ventricle, areas of fibrosis, changes resembling arrhythmogenic right ventricular cardiomyopathy and in some cases, no gross abnormalities. Histological examination revealed large areas of fibrosis and focal lymphocytic inflammation mimicking infarction/myocarditis. Careful search had to be made for non-necrotizing granulomata, since the lymphocytic foci, fibrosis and granulation tissue often predominated throughout the heart. The conduction tissue is often not sampled at autopsy despite the history of heart block. The heterogeneous nature of the macroscopic appearance and histological findings means that widespread sampling of the heart and the conduction system is essential in cases of sudden death in order that a diagnosis of myocardial sarcoidosis is not missed. PMID- 21298288 TI - Treatment of advanced non-small-cell lung cancer with Chinese herbal medicine by stages combined with chemotherapy. AB - PURPOSE: To observe the effect of Chinese herbal medicine by stages combined with chemotherapy in treating patients with non-small-cell lung cancer (NSCLC) of stage III or IV. METHODS: Adopting prospective, randomized, controlled, multi centered trial design, 121 patients enrolled were assigned to the treatment group (n = 65) and the control group (n = 56). All the patients were randomized to receive chemotherapy alone or chemotherapy and Chinese herbal medicine combined (Kangliuzengxiao decoction during chemotherapy and Feiyanning decoction after chemotherapy). The main outcome measures were survival time, Karnofsky score, main clinical symptoms, and adverse reactions. RESULTS: Five patients discontinued from the trial due to oral administration of Iressa after disease progression or other reasons, and 116 patients were evaluable for clinical efficacy with 63 in the treatment group and 53 in the control group. The overall response rate were 15.87% vs. 7.55% (P = 0.170), and the disease control rate were 85.71% vs. 71.70% in the treatment and control group (P = 0.063), respectively. The median survival time was 16.17 months vs. 12.00 months in the treatment and control group (P = 0.165), respectively. In addition, adverse reactions such as leucopenia in the treatment group were less than those in the control group (P = 0.039). CONCLUSIONS: Chinese herbal medicine combined with chemotherapy showed favorable effect in improving quality of life and prolonging survival time on patients with advanced NSCLC. PMID- 21298289 TI - Polymorphic variants in tenascin-C (TNC) are associated with atherosclerosis and coronary artery disease. AB - Tenascin-C (TNC) is an extracellular matrix protein implicated in biological processes important for atherosclerotic plaque development and progression, including smooth muscle cell migration and proliferation. Previously, we observed differential expression of TNC in atherosclerotic aortas compared with healthy aortas. The goal of this study was to investigate whether common genetic variation within TNC is associated with risk of atherosclerosis and coronary artery disease (CAD) in three independent datasets. We genotyped 35 single nucleotide polymorphisms (SNPs), including 21 haplotype tagging SNPs, in two of these datasets: human aorta tissue samples (n = 205) and the CATHGEN cardiovascular study (n = 1,325). Eleven of these 35 SNPs were then genotyped in a third dataset, the GENECARD family study of early-onset CAD (n = 879 families). Three SNPs representing a block of linkage disequilibrium, rs3789875, rs12347433, and rs4552883, were significantly associated with atherosclerosis in multiple datasets and demonstrated consistent, but suggestive, genetic effects in all analyses. In combined analysis rs3789875 and rs12347433 were statistically significant after Bonferroni correction for 35 comparisons, p = 2 * 10(-6) and 5 * 10(-6), respectively. The SNP rs12347433 is a synonymous coding SNP and may be biologically relevant to the mechanism by which tenascin-C influences the pathophysiology of CAD and atherosclerosis. This is the first report of genetic association between polymorphisms in TNC and atherosclerosis or CAD. PMID- 21298290 TI - Cross talk between the sporophyte and the megagametophyte during ovule development. AB - In seed plant ovules, the diploid maternal sporophytic generation embeds and sustains the haploid generation (the female gametophyte); thus, two independent generations coexist in a single organ. Many independent studies on Arabidopsis ovule mutants suggest that embryo sac development requires highly synchronized morphogenesis of the maternal sporophyte surrounding the gametophyte, since megagametogenesis is severely perturbed in most of the known sporophytic ovule development mutants. Which are the messenger molecules involved in the haploid diploid dialogue? And furthermore, is this one way communication or is a feedback cross talk? In this review, we discuss genetic and molecular evidences supporting the presence of a cross talk between the two generations, starting from the first studies regarding ovule development and ending to the recently sporophytic identified genes whose expression is strictly controlled by the haploid gametophytic generation. We will mainly focus on Arabidopsis studies since it is the species more widely studied for this aspect. Furthermore, possible candidate molecules involved in the diploid-haploid generations dialogue will be presented and discussed. PMID- 21298291 TI - Psychosocial aspects of caregiving: perceptions of cancer patients and family caregivers. AB - PURPOSE: The care of cancer patients involves collaboration among health care professionals, patients, and family caregivers. As health care has evolved, more complex and challenging care is provided in the home, usually with the support of family members or friends. The aim of the study was to examine perceived needs regarding the psychosocial tasks of caregiving as reported by patients and caregivers. We also evaluated the association of demographic and clinical variables with self-reported caregiving needs. METHODS: Convenience samples of 100 cancer patients and 100 family caregivers were recruited in outpatient medical and radiation oncology waiting areas-the patients and caregivers were not matched dyads. Both groups completed a survey about their perceptions of caregiving tasks, including how difficult the tasks were for them to do. Demographic information was also provided by participants. RESULTS: Caregivers reported providing more help in dealing with feelings than patients endorsed needing. Caregivers were also more likely than patients to report the psychosocial aspects of caregiving were more difficult for them. Lastly, caregivers were more likely to report helping with logistical issues in comparison with patients expressing this need. Race, length of time since diagnosis, and age were associated with patients' expressed needs, while only number of hours spent providing care was associated with the caregivers' reporting of care activities. CONCLUSIONS: Our results suggest that patients may underestimate how difficult caregivers perceive the psychosocial aspects of caregiving to be. Also, it seems that caregivers tend to take on the psychosocial aspects of caregiving, although patients do not tend to report this need. Caregiving needs were only minimally associated with demographic variables, as was participation in caregiving tasks. PMID- 21298292 TI - Diagnosis of ischemic small bowel disease by measurement of serum intestinal fatty acid-binding protein in patients with acute abdomen: a multicenter, observer-blinded validation study. AB - BACKGROUND: Intestinal fatty acid-binding protein (I-FABP) is a low-molecular mass (15 kDa) cytosolic protein found exclusively in the epithelial cells of the small bowel mucosa. We aimed to evaluate the clinical usefulness of serum I-FABP measurement for the diagnosis of ischemic small bowel disease. METHODS: Patients with a clinical diagnosis of acute abdomen were recruited for this multicenter trial at one university hospital and nine city hospitals over a 13-month period. Serum I-FABP levels were measured in 361 eligible patients by an enzyme-linked immunosorbent assay using a specific monoclonal antibody. RESULTS: Of the 361 patients, 242 underwent surgery, and small bowel ischemia was diagnosed in 52 patients. The mean serum I-FABP level in the patients with small bowel ischemia was 40.7 +/- 117.9 ng/ml, which was significantly higher than that in patients with non-ischemic small bowel disease (5.8 +/- 15.6 ng/ml) and those with non small bowel disease (1.8 +/- 1.7 ng/ml). The serum I-FABP cutoff level for the diagnosis of small bowel ischemia was 3.1 ng/ml. Serum I-FABP was more efficient than conventional biochemical markers, in terms of sensitivity and positive and negative predictive values, in the diagnosis of small bowel ischemia. However, its specificity was slightly lower than that of creatinine phosphokinase or lactate dehydrogenase. The positive and negative likelihood ratios of serum I FABP were 3.01 and 0.29, respectively. CONCLUSION: Serum I-FABP measurement is a non-invasive method that is potentially useful for the efficient identification of patients with acute abdomen who are at risk of small bowel ischemia. PMID- 21298293 TI - Identification of a high molecular weight kininogen fragment as a marker for early gastric cancer by serum proteome analysis. AB - BACKGROUND: Serum biomarkers currently available for gastric cancers are not sufficiently sensitive and specific. METHODS: We used matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MS) to generate comparative peptide profiles of serum samples obtained from gastric cancer patients (n = 81) and age- and sex-matched healthy controls (n = 66). RESULTS: Because of initial screening and further validation, we found that the intensities of a 2209 m/z MS peak were increased in the preoperative sera obtained from gastric cancer patients, and we identified this peak, a 2209 Da peptide, as a high molecular weight (HMW) kininogen fragment. Receiver operating characteristic analyses showed that the area under the curve (AUC) for the 2209 Da peptide (AUC = 0.715) was greater than those for conventional tumor markers (carcinoembryonic antigen AUC = 0.593, carbohydrate antigen 19-9 AUC = 0.527) used for the detection of stage I gastric cancers. Inverse correlations were observed between the levels of intact HMW kininogen and the 2209 Da peptide, suggesting that the upregulation of some protease activities is responsible for the overproduction of a kininogen fragment in gastric cancer patients. CONCLUSIONS: Serum levels of the 2209 Da peptide identified in this study have a greater diagnostic ability than those of conventional tumor markers used for the early detection of gastric cancer. PMID- 21298294 TI - A randomized comparison of different doses of intrathecal levobupivacaine combined with fentanyl for elective cesarean section: prospective, double-blinded study. AB - PURPOSE: Levobupivacaine may produce a sensory and motor block different from that produced by bupivacaine, which is the most popular local anesthetic in parturients undergoing cesarean section. The aim of this study was to investigate the block characteristics, the clinical efficacy, surgeon and patient satisfaction, and hemodynamic effects of using different doses of intrathecal plain levobupivacaine combined with fentanyl. METHODS: One hundred twenty women undergoing elective cesarean section with a combined spinal-epidural technique were enrolled. The parturients were randomly assigned to receive one of the following: levobupivacaine 5 mg (group 5), 7.5 mg (group 7.5) or 10 mg (group 10), all combined with fentanyl 25, 15 or 10 MUg, respectively. RESULTS: Anesthesia was effective in 60, 82.5 and 100% of the patients in the levobupivacaine 5, 7.5 and 10 mg groups, respectively. Levobupivacaine 10 mg provided longer durations of analgesia and motor block and greater patient and surgeon satisfaction, although the incidence of hypotension was lower in groups 5 and 7.5 than in group 10 (12.5, 17.5 and 42.5%, respectively). Intraoperative epidural supplementation was higher in group 5 than in group 7.5 (40 and 17.5%, respectively), whereas no patients in group 10 were given an epidural bolus dose. CONCLUSIONS: The incidence of hypotension was higher in the levobupivacaine 10 mg group, even though this group presented more effective anesthesia and greater patient and surgeon satisfaction compared with the levobupivacaine 5 and 7.5 mg groups. As a result, we believe that levobupivacaine 7.5 mg combined with fentanyl 15 MUg is suitable for combined spinal-epidural anesthesia in elective cesarean section. PMID- 21298295 TI - Heart rate variability and diastolic dysfunction in patients with type 2 diabetes mellitus. AB - Cardiovascular autonomic neuropathy is a common form of autonomic dysfunction in diabetes mellitus (DM) and associates abnormalities in heart rate control and in vascular dynamics. This study evaluates the impact of diabetes mellitus on left ventricular diastolic dysfunction (LVDD) and heart rate variability in a group of type 2 diabetes mellitus without signs of cardiovascular disease. The study group consisted of 58 patients, aged 61 +/- 8 years, diagnosed with type 2 DM. The subjects were selected from a series of 104 consecutive diabetic patients. All the subjects were on oral therapy or on diet for DM, and ECG was normal for all the subjects. The control group consisted of 45 healthy subjects, matched for age and sex. Heart rate variability was measured using a 24-h ECG monitoring system, and standard 2D and Doppler echocardiography was performed in all the subjects. There are significant differences between groups regarding disease duration, longer in patients with impaired relaxation (11.22 +/- 9.17 vs. 8.31 +/- 8.95 years), and disease control, worse in impaired relaxation group. Heart rate in impaired relaxation group is significantly higher than in controls, and higher, but not significantly, when compared with normal group (91 +/- 10, vs. 88 +/- 11 and 71 +/- 11, respectively). Cardiac autonomic neuropathy was associated with LVDD in patients with type 2 DM, but without clinically manifest heart disease. Twenty-four-hour ECG monitoring and echocardiography can detect diabetic cardiomyopathy in early stages and should be performed in all subjects. PMID- 21298296 TI - Controversies in neurology: asymptomatic carotid stenosis--intervention or just stick to medical therapy. The argument for carotid endarterectomy. AB - Patients with a significant carotid stenosis are at an increased risk of suffering from a potentially fatal or disabling stroke. The current management strategies available to a patient with an asymptomatic carotid stenosis are either medical therapy alone, or in combination with either carotid endarterectomy, or carotid angioplasty and stenting. Medical therapy alone can reduce the incidence of stroke in general, but whether there is any reduction in stroke attributable to a significant carotid stenosis is less clear. Carotid endarterectomy, on the other hand, has been shown to reduce the incidence of ipsilateral ischaemic stroke in both symptomatic and asymptomatic patients, with the benefits extending into the long-term. Carotid angioplasty and stenting is a newer technique with the benefit of being minimally invasive. The results of trials comparing the technique to endarterectomy have had conflicting results, and the results of large multi-centre trials are awaited. Currently the safest strategy for a patient with a significant asymptomatic carotid stenosis consists of optimal medical therapy with carotid endarterectomy for those less than 75 years of age, who are suitable for surgery. PMID- 21298297 TI - Increased primary amine oxidase expression and activity in white adipose tissue of obese and diabetic db-/- mice. AB - The major form of primary amine oxidase expressed in adipose tissue (AT) is encoded by AOC3 gene and is known as semicarbazide-sensitive amine oxidase, identical to vascular adhesion protein-1 (SSAO/VAP-1). Exogenous substrates of SSAO/VAP-1 (e.g. benzylamine) stimulate glucose transport in adipocytes and improve glucose tolerance when injected in diabetic rodents. Numerous reports on the circulating, soluble SSAO/VAP-1 have univocally evidenced an increase in diabetic conditions. However, only scarce studies have investigated whether obesity and/or diabetes is accompanied with variations of AOC3 expression in AT. Therefore, we compared the SSAO/VAP-1 content in different fat depots of db-/- mice (lacking leptin receptor and being hyperphagic, diabetic and obese) and db+/ littermates (normoglycemic and lean). AOC3 expression was increased in perigonadal and subcutaneous AT of db-/- mice, while the maximal velocity of benzylamine oxidation (V (max), expressed as pmoles of hydrogen peroxide produced/min/mg protein) increased only in the latter. Indeed, the relative abundance of primary amine oxidase was increased in subcutaneous AT of db-/- mice at all the levels: mRNA, protein and activity. While considering the overall capacity to oxidise amines contained in each depot, there was an increase in the hypertrophic fat pads of the obese db-/- mice, irrespective of their anatomical location, as a result of their dramatically larger mass than in lean db+/- control. Such higher amount of AT-bound primary amine oxidase warrants further studies to determine whether SSAO/VAP-1 inhibition or activation may be useful in treating metabolic diseases. PMID- 21298298 TI - Involvement of NMDA receptor complex in the anxiolytic-like effects of chlordiazepoxide in mice. AB - In the present study, we demonstrated that low, ineffective doses of N-methyl-D aspartic acid (NMDA) receptor antagonists [competitive NMDA antagonist, CGP 37849, at 0.312 mg/kg intraperitoneally (i.p.), antagonist of the glycine(B) sites, L-701,324, at 2 mg/kg i.p., partial agonist of glycine(B) sites, D cycloserine, at 2.5 mg/kg i.p.] administered jointly with an ineffective dose of the benzodiazepine, chlordiazepoxide (CDP, 2.5 mg/kg i.p.), significantly increased the percentage of time spent in the open arms of the elevated plus-maze (index of anxiolytic effect). Furthermore, CDP-induced anxiolytic-like activity (5 mg/kg i.p.) was antagonized by NMDA (75 mg/kg i.p.) and by an agonist of glycine(B) sites of the NMDA receptor complex, D-serine [100 nmol/mouse intracerebroventricularly (i.c.v.)]. The present study showed a positive interaction between gamma-aminobutyric acid (GABA) and glutamate neurotransmission in the anxiolytic-like activity in the elevated plus-maze test in mice and this activity seems to particularly involve the NMDA receptors. PMID- 21298299 TI - Extranigral extension of structural midbrain lesions overshadows parkinsonism. AB - We report on a clinicoanatomical analysis of five patients with structural midbrain lesions who shared severe nigrostriatal dopaminergic denervation but presented different involuntary movements. The main clinical phenotype was parkinsonism in only one case; it was choreoballism in three cases and tremor and dystonia in one case. Structural midbrain lesions are likely to involve structures additional to nigral dopaminergic neurons. The extent of extranigral involvement may determine the diverse clinical manifestations associated with the structural midbrain lesions. PMID- 21298300 TI - High prevalence of malignant melanoma in Israeli patients with Parkinson's disease. AB - The risk of melanoma is higher in patients with Parkinson's disease (PD) than in the general population. Whether the association is disease related or treatment related is unclear. The objective of this study was to assess melanoma prevalence in PD patients in Israel using active dermatologic screening. Consecutive patients with idiopathic PD were recruited by 12 Israeli centers. A movement disorder specialist assessed the severity of PD and obtained a medical, neurological, and medication history. Subsequently, a dermatologist assessed melanoma risk factors, recorded a dermatologic history, proactively performed a whole-body skin examination, and biopsied suspicious skin lesions. Of the enrolled patients (n = 1,395, mean age 69.5 +/- 10.6 years, mean PD duration 7.3 +/- 6.0 years), 95.3% were treated with dopaminergic agents. Biopsies revealed 8 patients with melanoma in situ and 1 with invasive malignant melanoma; 14 patients reported a melanoma prior to enrollment. The observed 5-year limited duration prevalence of melanoma in PD patients was 4.4 times greater (95% CI 2.6 7.6) than expected from melanoma prevalence in an age- and sex-matched cohort from the Israel National Cancer Registry. The increase was accounted for by an elevated prevalence of melanoma in situ [relative risk 12.5 (95% CI 6.7-23.2)]. Occurrence of melanoma did not correlate with levodopa therapy or time of onset of PD. Melanoma prevalence in PD patients was higher than expected in the general Israeli population. This was not related to levodopa treatment. PD patients should be actively screened for melanoma on a routine basis. PMID- 21298301 TI - Roles of the actin cytoskeleton and an actin-binding protein in wheat resistance against Puccinia striiformis f. sp. tritici. AB - Elucidating resistance mechanisms of plant cells against pathogens is essential to develop novel strategies of disease control. The actin cytoskeleton was found intimately involved in plant defense. In order to reveal how actin would be involved in the interaction between wheat and the stripe rust Puccinia striiformis f. sp. tritici, prior to fungal inoculation, wheat leaves were treated with cytochalasin A, an inhibitor of actin polymerization. Our results showed reduced incidence of hypersensitive cell death and delayed accumulation of H(2)O(2) in wheat leaves treated with cytochalasin A compared to the control. We also found that the TaPRO profilin gene exhibited significantly different expression levels in host leaves when comparing compatible and incompatible interactions. Real-time PCR analysis revealed that the expression transcript of TaPRO was lower at each time point in incompatible interactions when compared to compatible ones, and the largest difference between the two interactions occurred at 12 h post-inoculation. Both pharmacological and gene expression results collectively support the notion that the compromise of the actin microfilament is linked to the compatible interaction between the stripe rust fungus and the leaves of its wheat host. PMID- 21298302 TI - Degradation of sulfide by dehaloperoxidase-hemoglobin from Amphitrite ornata. AB - Dehaloperoxidase-hemoglobin (DHP) is a unique multifunctional enzyme with a globin fold. The enzyme serves as the respiratory hemoglobin for the marine worm Amphitrite ornata and has been shown to catalyze the conversion of highly toxic trihalophenols to dihaloquinones as a detoxification function for the organism. Given the simplicity of the structure of A. ornata, it is entirely possible that DHP may play an even more general role in detoxification of the organism from sulfide commonly found in the coastal estuaries where A. ornata thrives. Comparison of DHP with other sulfide-binding hemoglobins shows that DHP possesses several distal cavity structural properties, such as an aromatic cage and a hydrogen-bond-donor amino acid (His55), that facilitate sulfide binding. Furthermore, a complete reduction of the ferric heme occurs after sulfide exposure under aerobic or anaerobic conditions to yield either the oxy or the deoxy ferrous states of DHP, respectively. Oxidation of sulfide by the heme leads to sulfur products that are less toxic to A. ornata. This proposed new function for DHP relies on the highly flexible distal His55 for deprotonation of the bound hydrogen sulfide, similar to H(2)O(2) activation of the peroxidase function, and provides further support for the importance of the flexibility of the distal His55 in this novel globin. PMID- 21298303 TI - A hydrogen-bonding network formed by the B10-E7-E11 residues of a truncated hemoglobin from Tetrahymena pyriformis is critical for stability of bound oxygen and nitric oxide detoxification. AB - Truncated hemoglobins (trHbs) are distributed from bacteria to unicellular eukaryotes and have roles in oxygen transport and nitric oxide detoxification. It is known that trHbs exist in ciliates of the Tetrahymena group, but trHb structure and function remain poorly understood. To investigate trHb function with respect to stability of bound oxygen and protein structure, we measured the oxygen binding kinetics of Tetrahymena pyriformis trHb, and determined the crystal structure of the protein. The O(2) association and dissociation rate constants of T. pyriformis trHb were 5.5 MUM(-1 )s(-1) and 0.18 s(-1), respectively. The autooxidation rate constant was 3.8 * 10(-3) h(-1). These values are similar to those of HbN from Mycobacterium tuberculosis. The three dimensional structure of an Fe(II)-O(2) complex of T. pyriformis trHb was determined at 1.73-A resolution. Tyr25 (B10) and Gln46 (E7) were hydrogen-bonded to a heme-bound O(2) molecule. Tyr25 donated a hydrogen bond to the terminal oxygen atom, whereas Gln46 hydrogen-bonded to the proximal oxygen atom. Furthermore, Tyr25 was hydrogen-bonded to the Gln46 and Gln50 (E11) residues. Mutations at Tyr25, Gln46, and Gln50 increased the O(2) dissociation and autooxidation rate constants. An Fe(III)-H(2)O complex of T. pyriformis trHb was formed following reaction of the Fe(II)-O(2) complex of T. pyriformis trHb, in a crystal state, with nitric oxide. This suggests that T. pyriformis trHb functions in nitric oxide detoxification. PMID- 21298304 TI - Management of idiopathic clubfoot by the Ponseti technique: our experience at a tertiary referral centre. AB - BACKGROUND: Clubfoot or congenital talipes equinovarus is a common congenital abnormality of uncertain etiology. The purpose of this study was to assess the results of the Ponseti method in India and to investigate the demography of relapse and resistant cases. METHODS: A total of 86 children (146 feet) below 1 year of age who had presented to the paediatric orthopedic outpatient department of our institution between June 2003 and January 2007 with unilateral or bilateral idiopathic clubfoot deformity were included in our study and treated conservatively by use of the Ponseti technique. RESULTS: 128 feet responded to the Ponseti casting technique initially and 18 feet were resistant to the conservative treatment. Of the responsive feet, for 20 feet there was a relapse of the deformity. Evaluation of the results showed that poor compliance with splintage was the most common cause of relapse; delayed presentation and atypical clubfeet resulted in high resistance to this technique. Correction achieved at our centre was 82.18%. This is less than in many recent studies and could be attributed to increased incidence of delayed presentation, poorer compliance, and atypical feet in our population. CONCLUSION: We conclude that the Ponseti technique is recommended for management of clubfoot and strict compliance with splintage is essential to prevent relapses. People of lower socioeconomic status are at high risk of relapse and must be targeted to create awareness among them about the importance of compliance with splintage. PMID- 21298305 TI - Prevalence and correlates of seclusion and restraint use in children and adolescents: a systematic review. AB - Seclusion and restraint are frequent procedures to intervene in aggressive and potentially dangerous patients in psychiatric settings. However, little is known about their utilization and effectiveness in pediatric populations. We aimed to examine the prevalence and determinants of seclusion and restraint utilization in children and adolescents in psychiatric settings. Using PubMed, PsychInfo and Cinahl, we performed a systematic literature review of studies published in the last 10 years reporting on the prevalence of seclusion and restraint use in psychiatrically ill youth (<21 years old) treated in psychiatric settings. Only seven publications addressed the topic. Primary outcomes were prevalence rates, reported either as the proportion of patients restrained/secluded or as the number of restraints/seclusions per number of patient days. All studies found relatively high baseline rates of seclusion (26% of patients; 67/1,000 patient days), and restraints (29% of patients; 42.7/1,000 patient days). In four studies, an intervention, implemented to reduce seclusion and restraints, resulted in a dramatic weighted mean reduction in the more restrictive use of restraints by 93.2%, with a 54.2% shorter duration. There was a small, weighted mean reduction in the use of less restrictive seclusions (-0.6%), but results were heterogeneous (-97.2 to +71.0%), with the only increase in seclusions being reported in one study in which the intervention-based padded seclusion room was utilized more frequently instead of more restrictive measures. Otherwise, seclusion episodes reduced by 74.7%, including a 32.4% shorter duration. Few studies reported on risk-factors and predictors, consisting of past or current aggression and/or violence, suicidal behavior, more severe psychopathology, non White ethnicity, emergency admissions, out-of-home placement, and poorer family functioning, while findings regarding age were inconsistent Except for duration, data about the effectiveness of seclusion and restraints were missing, although there is some indication that seclusion and restraints can lead to severe psychological and physical consequences. Future research should focus on indications, predictors, preventive and alternative strategies, as well as on clinical outcomes of seclusion and restraints in psychiatrically ill youth. In addition, there is a clear need for transparent policies and guidelines. PMID- 21298306 TI - Irritability in children and adolescents: a challenge for DSM-5. AB - Irritability has recently become a major focus of interest for clinicians and nosologists alike, and its position in the upcoming DSM-5 is currently debated. However, research on irritability has only recently started emerging. Here, I review the recent findings on irritability and its differentially strong relationship to depressive and generalised anxiety disorders compared to disruptive behaviours. Furthermore, I examine the importance of irritability in the recent debate about bipolar disorder in children and adolescents and discuss findings from research into severe mood dysregulation. I next address the relevance of irritability to the two core aims of developmental sensitivity and dimensionality. Finally, I critically discuss the recently proposed putative DSM 5 category of temper dysregulation disorder with dysphoria and make suggestions about future research directions. PMID- 21298307 TI - NICE guidance and current practise of recurrent and bilateral groin hernia repair by Scottish surgeons. AB - BACKGROUND: NICE (National Institute of Health and Clinical Excellence) in England recommended laparoscopic repair for recurrent and bilateral groin hernias in 2004. The aims of this survey were to evaluate the current practise of bilateral and recurrent inguinal hernia surgery in Scotland and surgeons' views on the perceived need for training in laparoscopic inguinal hernia repair (LIHR). METHODS: A postal questionnaire was sent to Scottish consultant surgeons included in the Scottish Audit of Surgical Audit database 2007, asking about their current practice of primary, recurrent and bilateral inguinal hernia surgery. A response was considered valid if the surgeon performed groin hernia surgery; further analysis was based on this group. Those who did not offer LIHR were asked to comment on the possible reasons, and also the perceived need for training in laparoscopic hernia surgery. Only valid responses were stored on Microsoft Excel (Microsoft Corporation, USA) and analysed with SPSS software version 13.0 (SPSS, Chicago, Illinois). RESULTS: Postal questionnaires were sent to 301 surgeons and the overall all response rate was 174/301 (57.8%). A valid response was received from 124 of 174 (71.2%) surgeons and analysed further. Open Lichtenstein's repair seems to be the most common inguinal hernia repair. Laparoscopic surgery was not performed for 26.6 and 31.5% of recurrent and bilateral inguinal hernia, respectively. About 15% of surgeons replied that an LIHR service was not available in their base hospital. Lack of training, financial constraints, and insufficient evidence were thought to be the main reasons for low uptake of LIHR. About 80% of respondents wished to attend hands-on training in hernia surgery. CONCLUSIONS: Current practice by Scottish surgeons showed that one in three surgeons did not offer LIHR for bilateral and recurrent inguinal hernia as recommended by NICE. There is a clear need for training in LIHR. PMID- 21298308 TI - Is surgical repair of an asymptomatic groin hernia appropriate? A review. AB - PURPOSE: Groin herniorrhaphy is the most common operation performed by general surgeons. Annually, more than 20 million groin hernias are repaired worldwide. The general approach towards groin hernias is surgical repair regardless of the presence of symptoms. The rationale to recommend surgery for asymptomatic groin hernias is prevention of visceral strangulation. The goal of this review is to evaluate the appropriateness of surgery in patients with asymptomatic groin hernias. METHODS: The review was based on an extensive literature search of Pubmed, Medline and the Cochrane Library. RESULTS: The risk of incarceration is approximately 4 per 1,000 patients with a groin hernia per year. Risk factors for incarceration are age above 60 years, femoral hernia site and duration of signs less than 3 months. Morbidity and mortality rates of emergency groin hernia repair are higher in patients who are older than 49 years, have a delay between onset of symptoms and surgery of more than 12 h, have a femoral hernia, have nonviable bowel and have an ASA-class of 3 or 4. The recurrence rate after tension-free mesh repair in the management of emergency groin hernias is comparable to that of elective repair. There is no difference in pain and quality of life after elective repair compared to watchful waiting. There is no advantage in cost-effectiveness of elective repair compared to watchful waiting. CONCLUSION: Watchful waiting for asymptomatic groin hernias is a safe and cost effective modality in patients who are under 50 years old, have an ASA class of 1 or 2, an inguinal hernia, and a duration of signs of more than 3 months. PMID- 21298309 TI - Induction of putative stratified epithelial progenitor cells in vitro from mouse induced pluripotent stem cells. AB - Induced pluripotent stem (iPS) cells generally exhibit a normal karyotype, are transcriptionally and epigenetically similar to embryonic stem (ES) cells, and maintain the potential to differentiate into derivatives of all germ layers. Recently, the use of different types of cell or tissue derived from iPS cells for transplantation has become a possibility. However, the differentiation of epithelial lineages from iPS cells has not yet been demonstrated. We attempted to establish a culture technique for the induction of epithelial progenitors from mouse iPS cells. Mouse iPS cells were cultured on dishes coated with type IV collagen in keratinocyte culture medium (KCM) supplemented with or without bone morphogenic protein-4 (BMP-4) or combined with pretreatment of retinoic acid (RA) and BMP-4 in the undifferentiated state. Markers for undifferentiated cells (Oct3/4, Nanog) and for differentiation (p63, cytokeratin14) were analyzed by immunofluorescence staining and real-time RT-PCR. Putative epithelial progenitors were successfully induced in vitro from iPS cells. These progenitors expressed p63, a transcription factor necessary for maintenance of regenerative epithelia and cytokeratin 14 constitutively present in the basal layer of stratified epithelia. Enhancement of putative epithelial progenitor commitment was observed when cultured in KCM with BMP-4 following pretreatment of RA and BMP-4. The differentiation efficiency of putative epithelial progenitors from iPS cell cultures was similar to that of ES cell cultures. This report is the first to demonstrate in vitro differentiation of iPS cells into putative epithelial progenitors. These iPS-derived putative epithelial progenitors provide a powerful tool for understanding the mechanisms of epithelial lineage differentiation. PMID- 21298310 TI - Two cases of dementias with motor neuron disease evaluated by Pittsburgh compound B-positron emission tomography. AB - We described the cases of two patients with dementia associated with motor neuron disease, the former with frontotemporal dementia (FTD) and the latter with Alzheimer's disease (AD), studied by the Pittsburgh compound B-positron emission tomography (PIB-PET). In the FTD patient, the PIB-PET revealed no amyloid accumulation in the cortex, whilst in the AD patient showed amyloid accumulation mainly in the frontal, parietal and lateral temporal lobes, besides the posterior cingulate gyrus and the precuneus. Thus, PIB-PET might facilitate the discrimination of different proteinopathies that cause neurodegenerative diseases, as dementia associated with ALS. PMID- 21298311 TI - Micromorphology and adhesive performance of Er:YAG laser-treated dentin of primary teeth. AB - This study evaluated (1) the micromorphology by scanning electron microscopy (SEM) and (2) the adhesive performance by microtensile bond strength (MUTBS) of diamond bur-treated dentin compared to Er:YAG laser-treated dentin of human primary teeth. (1) For qualitative SEM evaluation, dentin of 18 second primary molars (n = 3/method) was treated with either diamond bur as a control (group 1a: 40 MUm diamond bur only (clinical situation); group 1b: grinding + 40 MUm diamond bur) or with Er:YAG laser (group 2a (clinical situation, manufacturer's settings): 200 mJ/25 Hz (5 W) + 100 mJ/35 Hz (3.5 W) laser only; group 2b (experimental setting "high"): grinding + 400 mJ/20 Hz (8 W); group 2c (manufacturer's setting "finishing"): grinding + 100 mJ/35 Hz (3.5 W); group 2d (experimental setting "low"): grinding + 50 mJ/35 Hz (1.75 W)). (2) For evaluation of adhesive performance, 64 second primary molars were divided into four groups and treated as described for group 1b and groups 2b/c/d (n = 16/method), and MUTBS of Clearfil SE/Clearfil Majesty Esthetic to dentin was measured. The SEM micrographs were qualitatively analyzed. The MUTBS values were compared with a Kruskal-Wallis test. The significance level was set at alpha = 0.05. SEM micrographs showed the typical micromorphologies with a smear layer for the diamond bur groups and open dentin tubules for all laser-treated groups. However, in group 2d, the laser beam had insufficiently irradiated the dentin area, rendering the underlying ground surface partly visible. There were no statistically significant differences between MUTBS values of the four groups (p = 0.394). This suggests that Er:YAG laser treatment of dentin of primary molars provides bond strengths similar to those obtained following diamond bur treatment. PMID- 21298312 TI - Successful treatment of acute promyelocytic leukemia in a patient on hemodialysis. AB - Acute promyelocytic leukemia (APL) has the best prognosis among acute leukemias, but there is little data about APL in patients on hemodialysis. A 64-year-old hemodialysis patient was successfully treated for APL by induction therapy with all-trans retinoic acid (ATRA), three courses of consolidation therapy with Ara C, mitomycin C (MIT), daunorubicin (DNR), and idarubicin (IDR), and maintenance therapy with ATRA. Complete remission has been maintained for 42 months in this patient. With dose modification, ATRA and chemotherapy may be safely given to patients on hemodialysis. PMID- 21298313 TI - Transient stabbing headache from an acute thalamic hemorrhage. AB - Stabbing headache can be encountered in both primary and secondary forms, but has been infrequently reported among patients with stroke, and is not known to be associated with a small well-circumscribed brain lesion. A 95-year-old woman taking warfarin presented with the sudden onset of stabbing headache strictly in the right frontal and supraorbital regions, along with gait imbalance and dysarthria. Neuroimaging revealed a small left thalamic hematoma. This association of an acute thalamic lesion with stabbing headache in the contralateral trigeminal distribution is discussed, along with a brief review of stabbing headache occurring in cerebrovascular disease. PMID- 21298314 TI - Manual therapies for migraine: a systematic review. AB - Migraine occurs in about 15% of the general population. Migraine is usually managed by medication, but some patients do not tolerate migraine medication due to side effects or prefer to avoid medication for other reasons. Non pharmacological management is an alternative treatment option. We systematically reviewed randomized clinical trials (RCTs) on manual therapies for migraine. The RCTs suggest that massage therapy, physiotherapy, relaxation and chiropractic spinal manipulative therapy might be equally effective as propranolol and topiramate in the prophylactic management of migraine. However, the evaluated RCTs had many methodological shortcomings. Therefore, any firm conclusion will require future, well-conducted RCTs on manual therapies for migraine. PMID- 21298315 TI - Experience with onabotulinumtoxinA (BOTOX) in chronic refractory migraine: focus on severe attacks. AB - The objective of this study is to analyse our experience in the treatment of refractory chronic migraine (CM) with onabotulinumtoxinA (BTA) and specifically in its effects over disabling attacks. Patients with CM and inadequate response or intolerance to oral preventatives were treated with pericranial injections of 100 U of TBA every 3 months. The dose was increased up to 200 U in case of no response. The patients kept a headache diary. In addition, we specifically asked on the effect of BTA on the frequency of disabling attacks, consumption of triptans and visits to Emergency for the treatment of severe attacks. This series comprises a total of 35 patients (3 males), aged 24-68 years. All except three met IHS criteria for analgesic overuse. The number of sessions with BTA ranged from 2 to 15 (median 4) and nine (26%) responded (reduction of >50% in headache days). However, the frequency of severe attacks was reduced to an average of 46%. Oral triptan consumption (29 patients) was reduced by 50% (from an average of 22 to 11 tablets/month). Those six patients who used subcutaneous sumatriptan reduced its consumption to a mean of 69% (from 4.5 to 1.5 injections per month). Emergency visits went from an average of 3 to 0.4 per trimester (-83%). Six patients complained of mild adverse events, transient local cervical pain being the most common. Although our data must be taken with caution as this is an open trial, in clinical practice treatment of refractory CM with BTA reduces the frequency of disabling attacks, the consumption of triptans and the need of visits to Emergency, which makes this treatment a profitable option both clinically and pharmacoeconomically. PMID- 21298316 TI - Primary headaches in patients with generalized anxiety disorder. AB - Although anxiety disorders and headaches are comorbid conditions, there have been no studies evaluating the prevalence of primary headaches in patients with generalized anxiety disorder (GAD). The aim of this study was to analyze the lifetime prevalence of primary headaches in individuals with and without GAD. A total of 60 individuals were evaluated: 30 GAD patients and 30 controls without mental disorders. Psychiatric assessments and primary headache diagnoses were made using structured interviews. Among the GAD patients, the most common diagnosis was migraine, which was significantly more prevalent among the GAD patients than among the controls, as were episodic migraine, chronic daily headache and aura. Tension-type headache was equally common in both groups. Primary headaches in general were significantly more common and more severe in GAD patients than in controls. In anxiety disorder patients, particularly those with GAD, accurate diagnosis of primary headache can improve patient management and clinical outcomes. PMID- 21298318 TI - Modeling the inactivation of Bacillus subtilis spores by ethylene oxide processing. AB - Ethylene oxide is currently a dominant agent in medical device sterilization. This work intends to study the main effects and interactions of temperature, ethylene oxide concentration, and relative humidity on commercial spore strips of Bacillus subtilis, var. niger (ATCC 9372) inactivation, the most common microorganism used in controlling the efficacy of the process. Experiments were carried out using a full factorial experimental design at two levels (2(3) factorial design). Limit target exposure conditions for ethylene oxide concentration, temperature, and relative humidity were 250-1,000 mg EO/l, 40-60 degrees C, and 50-90%, respectively. Adopting a different approach from the first order kinetics, a Gompertz model was successfully applied in data fitting of the inactivation curves. Bacillus subtilis kinetic behavior presented a sigmoidal inactivation with an initial shoulder (lambda), followed by a maximum inactivation rate (k(max)), these being model parameters. It was concluded that temperature and ethylene oxide concentration were the most significant factors and consequently, additional experiments were carried out aiming at describing the parameters' dependence on these process factors. Mathematical relations describing such dependences were successfully developed and included in the Gompertz kinetic model. The predictive ability of this integrated model was assessed, and its adequacy in predicting B. subtilis inactivation was proven. PMID- 21298317 TI - Impact of smoking on inflammation: overview of molecular mechanisms. AB - BACKGROUND: Inflammation is a critical component of normal tissue repair, as well as being fundamental to the body's defense against infection. Environmental factors, such as smoking, have been reported to modify the host response and hence modify inflammation progression, severity and outcome. Therefore, a comprehensive understanding of the molecular mechanisms by which smoking affects inflammation is vital for preventive and therapeutic strategies on a clinical level. AIM: The purpose of the present article is to review the potential biological mechanisms by which smoking affects inflammation, emphasizing recent developments. RESULTS: Smoking is reported to effect a number of biological mediators of inflammation through its effect on immune-inflammatory cells, leading to an immunosuppressant state. Recent evidence strongly suggests that the molecular mechanisms behind the modulation of inflammation by smoking mainly involve the nuclear factor-kappa B (NF-kB) family, through the activation of both an inhibitor of IkB kinase (IKK)-dependent and -independent pathway. In addition to NF-kB activation, a number of transcriptional factors including GATA, PAX5 and Smad 3/4, have also been implicated. CONCLUSION: Multiple mechanisms may be responsible for the association of smoking and inflammation, and the identification of potential therapeutic targets should guide future research. PMID- 21298319 TI - Gene expression profiling of a pressure-tolerant Listeria monocytogenes Scott A ctsR deletion mutant. AB - Listeria monocytogenes is a food-borne pathogen of significant threat to public health. High hydrostatic pressure (HHP) treatment can be used to control Listeria monocytogenes in food. The CtsR (class three stress gene repressor) protein negatively regulates the expression of class III heat shock genes. A spontaneous pressure-tolerant ctsR mutant 2-1 that was able to survive under HHP treatment has been identified previously. So far, there is only limited information about the mechanisms of survival and adaptation of this mutant to high pressure. Microarray technology was used to monitor the gene expression profiles of the ctsR mutant 2-1 under HHP treatment. Compared to pressure-treated L. monocytogenes Scott A wild type, 17 genes were up-regulated (>2-fold increase) in the ctsR mutant 2-1, whereas 58 genes were down-regulated (<-2-fold decrease). The entire clpC operon was up-regulated in the ctsR mutant 2-1, indicating that the mutant CtsR protein was not a functional repressor. The increased levels of expression of stress-related genes in ctsR mutant 2-1 may contribute to its survival under high pressure. The reduced expression levels of the genes related to virulence, flagella synthesis, and cell division in the ctsR mutant 2-1 correlate with its characteristics (elongated cells, reduced virulence, and absence of flagella). The gene expression changes determined by microarray assays were confirmed by real-time reverse transcriptase PCR analyses. This study enhances our understanding of how Listeria monocytogenes survives under HHP and may contribute to the design of effective and economically feasible HHP treatment in food processing. PMID- 21298320 TI - Application of an acid proteinase from Monascus purpureus to reduce antigenicity of bovine milk whey protein. AB - An acid proteinase from Monascus purpureus No. 3403, MpuAP, was previously purified and some characterized in our laboratory (Agric Biol Chem 48:1637-1639, 1984). However, further information about this enzyme is lacking. In this study, we investigated MpuAP's comprehensive substrate specificity, storage stability, and prospects for reducing antigenicity of whey proteins for application in the food industry. MpuAP hydrolyzed primarily five peptide bonds, Gln(4)-His(5), His(10)-Leu(11), Ala(14)-Leu(15), Gly(23)-Phe(24) and Phe(24)-Phe(25) in the oxidized insulin B-chain. The lyophilized form of the enzyme was well preserved at 30-40 degrees C for 7 days without stabilizers. To investigate the possibility of reducing the antigenicity of the milk whey protein, enzymatic hydrolysates of the whey protein were evaluated by inhibition ELISA. Out of the three main components of whey protein, casein and alpha-lactalbumin were efficiently degraded by MpuAP. The sequential reaction of MpuAP and trypsin against the whey protein successfully degraded casein, alpha-lactalbumin and beta-lactoglobulin with the highest degree of hydrolysis. As a result, the hydrolysates obtained by using the MpuAP-trypsin combination showed the lowest antigenicity compared with the single application of pepsin, trypsin or pepsin-trypsin combination. Therefore, the overall result suggested that the storage-stable MpuAP and trypsin combination will be a productive approach for making hypoallergic bovine milk whey protein hydrolysates. PMID- 21298321 TI - ISCEV standard for clinical electro-oculography (2010 update). AB - The clinical electro-oculogram (EOG) is an electrophysiological test of function of the outer retina and retinal pigment epithelium (RPE) in which changes in electrical potential across the RPE are recorded during successive periods of dark and light adaptation. This document presents the 2010 EOG Standard from the International Society for Clinical Electrophysiology of Vision (ISCEV: www.iscev.org ). This revision has been reorganized and updated, but without changes to the testing protocol from the previous version published in 2006. It describes methods for recording the EOG in clinical applications and gives detailed guidance on technical requirements, practical issues, and reporting of results. It is intended to promote consistent quality of testing and reporting within and between clinical centers. PMID- 21298322 TI - Health and welfare in animals and humans. AB - This paper contains a brief comparative analysis of some philosophical and scientific discourses on human and animal health and welfare, focusing mainly on the welfare of sentient animals. The paper sets forth two kinds of proposals for the analysis of animal welfare which do not appear in the contemporary philosophical discussion of human welfare, viz. the coping theory of welfare and the theory of welfare in terms of natural behaviour. These proposals are scrutinized in the light of some similar theories dealing with human health and quality of life. My conclusion is that the coping theory and the natural behaviour theory are not in themselves adequate for the characterization of welfare, either for humans or for sentient animals. I contend, finally, that, in the light of the previous discussion, there are good arguments for a particular set of analyses of both animal and human welfare, viz. the ones that are based on the notions of preference satisfaction and positive subjective experiences. PMID- 21298323 TI - How to improve the immunogenicity of chemotherapy and radiotherapy. AB - Chemotherapy or radiotherapy could induce various tumor cell death modalities, releasing tumor-derived antigen as well as danger signals that could either be captured for triggering antitumor immune response or ignored. Exploring the interplay among therapeutic drugs, tumor cell death and the immune cells should improve diagnostic, prognostic, predictive, and therapeutic management of tumor. We summarized some of the cell death-derived danger signals and the mechanism for host to sense and response to cell death in the tumor microenvironment. Based on the recent clinical or experimental findings, several strategies have been suggested to improve the immunogenicity of cell death and augment antitumor immunity. PMID- 21298324 TI - Cellular cytotoxic response induced by highly purified multi-wall carbon nanotube in human lung cells. AB - Carbon nanotubes, a promising nanomaterial with unique characteristics, have applications in a variety of fields. The cytotoxic effects of carbon nanotubes are partially due to the induction of oxidative stress; however, the detailed mechanisms of nanotube cytotoxicity and their interaction with cells remain unclear. In this study, the authors focus on the acute toxicity of vapor-grown carbon fiber, HTT2800, which is one of the most highly purified multi-wall carbon nanotubes (MWCNT) by high-temperature thermal treatment. The authors exposed human bronchial epithelial cells (BEAS-2B) to HTT2800 and measured the cellular uptake, mitochondrial function, cellular LDH release, apoptotic signaling, reactive oxygen species (ROS) generation and pro-inflammatory cytokine release. The HTT2800-exposed cells showed cellular uptake of the carbon nanotube, increased cell death, enhanced DNA damage, and induced cytokine release. However, the exposed cells showed no obvious intracellular ROS generation. These cellular and molecular findings suggest that HTT2800 could cause a potentially adverse inflammatory response in BEAS-2B cells. PMID- 21298325 TI - Anti-inflammatory effect of insulin in the human hepatoma cell line HepG2 involves decreased transcription of IL-6 target genes and nuclear exclusion of FOXO1. AB - The liver is an important target for interleukin-6 (IL-6) action leading to an increased inflammatory response with impaired insulin signaling and action. The aims of this study are to address if insulin is anti-inflammatory and attenuates IL-6-induced inflammation in the human hepatoma cell line HepG2 and if this involves signal transducer and activator of transcription 3 (STAT3) signal transduction. It was found that insulin significantly reduced IL-6-induced gene transcription of serum amyloid 1 (SAA1), serum amyloid 2 (SAA2), haptoglobin, orosomucoid, and plasmin activator inhibitor-1 (PAI-1). However, the authors did not find any evidence that insulin inhibited IL-6 signal transduction, i.e., no effect of insulin was detected on STAT3 phosphorylation or its translocation to cell nucleus. The potential role of PKCdelta was also analyzed but no evidence of its involvement was found. Taken together, these results suggest that the anti inflammatory effect of insulin on IL-6 action is exerted at the level of the transcriptional activation of the genes. Further analysis revealed that insulin regulates nuclear localization of FOXO1, which is an important co-activator for STAT3 mediated transcription. Insulin induced nuclear exit and Thr24 phosphorylation of FOXO1, thus, inhibiting STAT3-mediated transcription. PMID- 21298326 TI - The dietary flavonoid apigenin enhances the activities of the anti-metastatic protein CD26 on human colon carcinoma cells. AB - There is accumulating evidence that secondary plant metabolites such as flavonoids may have anti-cancer properties, and yet the molecular pathways that lead to alterations in cancer cell behaviour remain unclear. We investigated the possible actions of apigenin, a flavone present in leafy vegetables like parsley, on the levels of CD26 in carcinoma cells. CD26 is a multifunctional cell-surface protein that through its associated dipeptidyl peptidase (DPPIV) and ecto adenosine deaminase (eADA) enzyme activities is able to suppress pathways involved in tumour metastasis. CD26 is down-regulated in various cancers including colorectal carcinoma. Apigenin substantially up-regulated cell-surface CD26 on HT-29 and HRT-18 human colorectal cancer cells. Levels of CD26 protein, along with its associated DPPIV enzyme activity, capacity to bind eADA, and ability to link cells to fibronectin, were increased with a maximum after 24-48 h. Elevation of CD26 occurred at concentrations that were at least 10-fold less than those shown to affect cell growth, and 100-fold below those that could affect cell viability. Furthermore, the CD26 effect was enhanced when apigenin was paired with chemotherapeutic agents utilized in the treatment of advanced colorectal cancer including irinotecan, 5-fluorouracil and oxaliplatin. For irinotecan, apigenin caused a 4-fold increase in the potency of the drug. These results demonstrate that apigenin can increase the cellular levels of CD26 and its multiple functions, and may oppose the predicted effect of decreased DPPIV and eADA activities on carcinoma cells, which is to facilitate tumour growth and metastasis. PMID- 21298327 TI - Synthesis of temperature-responsive dextran-MA/PNIPAAm particles for controlled drug delivery using superhydrophobic surfaces. AB - PURPOSE: To implement a bioinspired methodology using superhydrophobic surfaces suitable for producing smart hydrogel beads in which the bioactive substance is introduced in the particles during their formation. METHODS: Several superhydrophobic surfaces, including polystyrene, aluminum and copper, were prepared. Polymeric solutions composed by photo-crosslinked dextran-methacrylated and thermal responsive poly(N-isopropylacrylamide) mixed with a protein (insulin or albumin) were dropped on the superhydrophobic surfaces, and the obtained millimetric spheres were hardened in a dry environment under UV light. RESULTS: Spherical and non-sticky hydrogels particles were formed in few minutes on the superhydrophobic surfaces. The proteins included in the liquid formulation were homogeneously distributed in the particle network. The particles exhibited temperature-sensitive swelling, porosity and protein release rate, with the responsiveness tunable by the dextran-MA/PNIPAAm weight ratio. CONCLUSIONS: The proposed method permitted the preparation of smart hydrogel particles in one step with almost 100% encapsulation yield. The temperature-sensitive release profiles suggest that the obtained spherical-shaped biomaterials are suitable as protein carriers. These stimuli-responsive beads could have potential to be used in pharmaceutical or other biomedical applications, including tissue engineering and regenerative medicine. PMID- 21298328 TI - Fluorescence single particle tracking for the characterization of submicron protein aggregates in biological fluids and complex formulations. AB - PURPOSE: To evaluate the potential of fluorescence single particle tracking (fSPT) for the characterization of submicron protein aggregates in human serum, plasma and formulations containing human serum albumin (HSA). METHODS: A monoclonal IgG was covalently labeled with a fluorescent dye and cross-linked with glutaraldehyde. IgG aggregates and fluorescent beads of 0.1 MUm (control) were diluted in buffer, serum and plasma, and their size distributions were analyzed by fSPT and nanoparticle tracking analysis (NTA). In a separate experiment, IgG and HSA, fluorescently labeled with different dyes, were mixed and subjected to heat stress. The stressed sample was analyzed by fSPT using a dual color mode and by NTA. RESULTS: The accuracy and precision of fSPT proved to be comparable to NTA. fSPT was able to successfully measure all the samples in buffer, serum and plasma. The average size of the cross-linked protein aggregates showed a slight increase in biological fluids. Moreover, fSPT analysis showed that a significant proportion of the aggregates formed by subjecting an IgG/HSA mixture to heat stress were composed of both proteins. CONCLUSION: fSPT is a powerful technique for the characterization of submicron protein aggregates in biological fluids and complex formulations. PMID- 21298329 TI - The effect of skeletal myosin light chain kinase gene ablation on the fatigability of mouse fast muscle. AB - Contraction-induced activation of a skeletal muscle specific Ca(2+) and calmodulin dependent myosin light chain kinase (skMLCK) catalyzes phosphorylation of the myosin regulatory light chain (RLC), a reaction that potentiates twitch force. The purpose of this study was to test the effect of skMLCK gene ablation on the fatigability of mouse extensor digitorum longus (EDL) muscle (in vitro at 25 degrees C). Muscles were isolated from wildtype (WT, n = 10-12) and skeletal MLCK knockout (skMLCK KO, n = 10-12) mice and fatigued using a protocol consisting of 5 min of repeated tetanic stimulation (150 Hz for 1000 ms every 5 s). Both twitch (P(t)) and tetanic (P(o)) force as well as unloaded shortening velocity (V(o)) were assessed before, during and after fatiguing stimulation. Fatiguing stimulation increased RLC phosphorylation in WT but not skMLCK KO muscles (16 +/- 0.01-0.63 +/- 0.02 and 0.07 +/- 0.02-0.08 +/- 0.02 mol phos mol RLC, respectively). Although P(t) was potentiated above baseline in both WT and KO muscles, this increase was greater in WT than in KO muscles (to 1.37 +/- 0.05 vs. 1.14 +/- 0.02 of unpotentiated values, respectively). The difference in P(t) persisted until P(o) had been diminished to ~60% of baseline and thereafter P(t) declined to similar levels in both WT and KO muscles (to ~35% of initial). Overall, the time-course and decline in P(o) for WT and KO was similar (reduced to 0.20 +/- 0.01 and 0.20 +/- 0.01 of baseline, respectively) (P < 0.05). Initial values for V(o) were similar between WT and KO muscles and, moreover, the fatigue related decline in Vo was similar for both muscle genotypes (P < 0.05). Thus, our results demonstrate that skMLCK--catalyzed RLC phosphorylation augments isometric twitch force during moderate, but not severe, levels of fatigue. PMID- 21298330 TI - The family antecedents and the subsequent outcomes of early puberty. AB - The purpose of this study was to examine both the family antecedents and the outcomes of early puberty, with a particular focus on factors related to family socioeconomic status (SES). The study employed a comprehensive measurement of pubertal development and longitudinal data from the Canadian National Longitudinal Survey of Children and Youth. The sample (N = 8,440; 49% girls) included four cohorts of children who were followed biennially for 10 years, starting from age 4-11 to 14-21 years. Data were drawn at different years of age from these cohorts of children. Girls whose fathers were unemployed were more likely to experience early puberty than those whose fathers were employed. For boys, those living with fathers who had not finished secondary school were more likely to experience early puberty. Early maturing girls tended to engage in smoking and drinking at an earlier age compared with their peers. These findings provide support for psychosocial acceleration theory and suggest that different aspects of low family SES may act as a psychosocial stress for early pubertal maturation in boys versus girls, which may lead to engagement in drinking and smoking at a younger age, at least for girls. PMID- 21298331 TI - The role of alexithymia in reduced eye-fixation in Autism Spectrum Conditions. AB - Eye-tracking studies have demonstrated mixed support for reduced eye fixation when looking at social scenes in individuals with Autism Spectrum Conditions (ASC). We present evidence that these mixed findings are due to a separate condition-alexithymia-that is frequently comorbid with ASC. We find that in adults with ASC, autism symptom severity correlated negatively with attention to faces when watching video clips. However, only the degree of alexithymia, and not autism symptom severity, predicted eye fixation. As well as potentially resolving the contradictory evidence in this area, these findings suggest that individuals with ASC and alexithymia may form a sub-group of individuals with ASC, with emotional impairments in addition to the social impairments characteristic of ASC. PMID- 21298332 TI - Hippocampal proton MR spectroscopy in early Alzheimer's disease and mild cognitive impairment. AB - Proton magnetic resonance spectroscopy ((1)H-MRS) studies have previously reported reduced brain N-acetyl aspartate (NAA) and increased myo-inositol (mI) in people with established Alzheimer's disease (AD). The earliest structure affected by AD is the hippocampus but relatively few studies have examined its neuronal integrity by MRS in AD and fewer still in people with amnestic mild cognitive impairment (MCI). We measured the hippocampal concentration of NAA, mI, choline (Cho) and creatine + phosphocreatine (Cr + PCr) in 39 patients with AD, 21 subjects with MCI and 38 age matched healthy elderly controls. Patients with AD had a significantly lower hippocampal [NAA] than controls, with subjects with MCI intermediate between the other two groups. [NAA] was positively correlated with memory in the impaired groups. Using mean hippocampal [NAA] and [Cr + PCr] we correctly classified 72% of people with AD, and 75% of controls. Reductions in [NAA] can be detected in the hippocampi of subjects with MCI and hippocampal [NAA] and [Cr + PCr] can distinguish between mild AD and normal elderly controls. PMID- 21298333 TI - Age-of-onset or behavioral sub-types? A prospective comparison of two approaches to characterizing the heterogeneity within antisocial behavior. AB - There are two common approaches to sub-typing the well-documented heterogeneity within antisocial behavior: age-of-onset (i.e., childhood-onset versus adolescence-onset; see Moffitt 1993) and behavioral (i.e., physical aggression versus non-aggressive rule-breaking). These approaches appear to be associated, such that aggression is more characteristic of childhood-onset antisocial behavior whereas rule-breaking is linked to both child- and adolescence-onset antisocial behavior. However, it remains unclear which approach, if either, better explains the heterogeneity within antisocial behavior. We examined this question in a prospective sample of male twins, assessed at the ages of 11, 14, 17, and 24 years. Although the age-of-onset subtypes predicted adult antisocial behavior in the expected direction when analyzed alone, this association dissipated once we controlled for aggression and rule-breaking. Such findings suggest that the behavioral sub-types of antisocial behavior may be a stronger predictor of later antisocial outcomes than is its age-of-onset. PMID- 21298334 TI - Epithelial-mesenchymal transition and stemness features in circulating tumor cells from breast cancer patients. AB - Currently used methods to detect and enumerate circulating tumor cells (CTCs) rely on the expression of the epithelial cell adhesion molecule (EpCAM) and cytokeratins. This selection may exclude cells that have undergone intrinsic modifications of their phenotype, as epithelial-mesenchymal transition (EMT). Aim of the study was to investigate the expression of EMT and stemness markers in CTCs from breast cancer patients in all stages of disease. 92 female breast cancer patients were enrolled. CTCs were isolated by CELLection Dynabeads coated with the monoclonal antibody toward EpCam. Samples found positive for CTCs presence (CD45-/CK+) were evaluated for the expression of ER alpha, HER2, ALDH1, vimentin, and fibronectin. Samples negative for CTCs presence (CD45-/CK-) were also evaluated for the expression of vimentin and fibronectin, used as markers of EMT. CTCs were found in 66% of patients. The distribution of CTCs presence according to stage and grade of disease was found statistically significant. The expression of ALDH1 on CTCs was found to correlate to stage of disease and to the expression of vimentin and fibronectin. In 34% of patients, we detected cells with negative CK/CD45 expression but positive expression of vimentin and fibronectin. There is an urgent need for optimizing CTCs detection methods through the inclusion of EMT markers. The detection of cells in mesenchymal transition, retaining EMT and stemness features, may contribute to discover additional therapeutic targets useful to eradicate micrometastatic disease in breast cancer. PMID- 21298335 TI - The value of preoperative staging chest computed tomography to detect asymptomatic lung and liver metastasis in patients with primary breast carcinoma. AB - Little is known about the benefits of preoperative staging chest computed tomography (CT) in patients with asymptomatic breast cancer. We therefore investigated the clinical value of preoperative chest CT in detecting lung and liver metastases by retrospectively reviewing the records of 1,703 patients who underwent preoperative chest CT in a single institution between January 2006 and June 2009. Abnormal CT findings, including suspected metastases and indeterminate nodules in the lung or liver, were found in 266 patients (15.6%). Among these, 26 patients (1.5% of all patients and 9.8% of patients with abnormal CT findings) had true metastases, including 17 in the lungs, 3 in the liver, and 6 in both. True metastases were detected in 1 (0.2%), 0 (0%), and 24 (6.0%) patients with stage I, II, and III disease, respectively. The sensitivity, specificity, and positive predictive value of chest CT were 100, 89.1, and 11.3%, respectively, for lung metastasis and 100, 97.6, and 18.4%, respectively, for liver metastasis. All true metastatic lung lesions were all small-sized nodules, ranging from 0.2 to 1.5 cm in largest diameter, and could not be detected on chest X-rays. In conclusion, our results demonstrate the lack of usefulness of routine preoperative chest CT in detecting asymptomatic liver and lung metastasis in patients with early breast cancer. Chest CT, however, upstaged 6.0% of stage III patients to stage IV. PMID- 21298336 TI - Addition of a histone deacetylase inhibitor redirects tamoxifen-treated breast cancer cells into apoptosis, which is opposed by the induction of autophagy. AB - Modulation of estrogen signaling is one of the most successful modalities for the treatment of estrogen receptor (ER)-positive breast cancer, yet de novo and acquired resistance are frequent. Recent data suggests that the induction of autophagy may play a considerable role in promoting tumor cell survival and resistance to anti-estrogen therapy. Hence, bypassing autophagy may offer a novel strategy to enhance the anti-tumor efficacy of anti-estrogens. Histone deacetylases (HDAC) are involved in the regulation of steroid hormone receptor mediated cell signaling and their inhibition potentiates the anti-tumor effects of anti-estrogens. However, the mechanism underlying this anti-tumor activity is poorly understood. In this report, we show that the addition of an HDAC inhibitor redirects the response of ER-positive breast cancer cells when treated with tamoxifen from growth arrest to apoptotic cell death. This redirection requires functional ER signaling and is mediated by a depletion of Bcl-2 and an induction of Bax and Bak, manifesting in cytochrome C release and PARP cleavage. With combined treatment, a subpopulation of cells is refractory to apoptosis and exhibit a strong induction of autophagy. Inhibition of autophagy in these cells, using siRNA directed against Beclin-1 or treatment with chloroquine, further promotes the induction of apoptosis. Thus, supporting prior reports that autophagy acts as a survival mechanism, our findings demonstrate that HDAC and autophagy inhibition directs autophagy-protected cells into apoptotic cell death, which may impair development of tamoxifen resistance. PMID- 21298337 TI - Laboratory parameters of cardiac and kidney dysfunction in cardio-renal syndromes. AB - "Cardio-Renal Syndromes" (CRS) are disorders of the heart and kidneys in which acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. The pathophysiology of CRS is complex, and there is accumulating evidence that various novel biomarkers are useful for diagnosis, prognostication, and risk stratification in patients with heart failure and chronic kidney disease (CRS). When both the heart failure (HF) and CKD occur together, it is important to have biomarkers that are able to risk stratify patients by looking at both their heart and kidney aspects. There are some promising newer renal biomarkers that may contribute to a better evaluation and prediction of prognosis in CRS patients. Most of the renal biomarkers studies in CRS have been performed in the setting of cardiac surgery, acute coronary syndrome (ACS), HF or after exposure to radiocontrast media in diagnostic and/or therapeutic percutaneous coronary procedures. Natriuretic peptides (NPs) have been validated as an important cardiac biomarker for risk stratification and prognostication in HF patients with or without CKD. However, the best cutoff values for each stage of CKD, including those on renal replacement therapy, are yet to be ascertained. In this context, it is likely that panels of multiple biomarkers will be needed for optimal evaluation, risk stratification, timely treatment initiation, and follow-up of patients with CRS. PMID- 21298338 TI - Abnormal development of motor neurons in perfluorooctane sulphonate exposed zebrafish embryos. AB - Perfluorooctane sulfonate (PFOS) is an environmental organic pollutant, the potential neurotoxicity of which is causing great concern in fish. In the present study, we examined the effects of PFOS on motor neurons, and investigated the potential toxicological mechanisms oxidative stress in zebrafish embryos. Six hour post-fertilization (hpf) zebrafish embryos were exposed to 1.0 mg/L PFOS, then we examined the expression of alpha-tubulin, proliferating cell nuclear antigen (PCNA), cyclin-dependent kinase 5 (CDK5), and peroxiredoxin 2 (PRX2) after PFOS exposure until 120 hpf. The results showed that PFOS increased alpha tubulin in the coccygeal spinal cord (CSC) at 96 hpf, whereas decreased alpha tubulin in the brain and spinal cord at 120 hpf. PCNA expression was highly increased in CSC and abdomen compared with control at 96 and 120 hpf after PFOS exposure. In addition, PFOS exposure caused CDK5 expression to be highly increased in brain region following by down-regulation of PRX2 expression at 96 hpf. These results indicated that, at least in part, the effect on motor neurons induced by PFOS was mediated by dynamically interfering with the expression of alpha-tubulin and PCNA. Furthermore, PFOS-induced toxicity was associated with oxidative stress by deregulating CDK5 and PRX2. PMID- 21298339 TI - Superpredation increases mercury levels in a generalist top predator, the eagle owl. AB - Superpredation can increase the length of the food chain and potentially lead to mercury (Hg) bioaccumulation in top predators. We analysed the relationship of Hg concentrations in eagle owls Bubo bubo to diet composition and the percentage of mesopredators in the diet. Hg levels were measured in the adult feathers of eagle owls from 33 owl territories in the south-western Iberian Peninsula, and in three trophic levels of their prey: primary consumers, secondary consumers and mesopredators. In addition, we studied 6,181 prey in the eagle owl diet. Hg concentrations increased along the food chain, but the concentrations in eagle owls showed considerable variation. The Hg concentration in eagle owls increased when the percentage of mesopredators in the diet increased and the percentage of primary consumers decreased. Superpredation is often related to food stress, and the associated increase in accumulation of Hg may cause additional negative effects on vertebrate top predators. Hg levels in these eagle owl populations are relatively low, but future monitoring is recommended. PMID- 21298340 TI - Standardization of bulb and root sample sizes for the Allium cepa test. AB - Although the Allium cepa test has been widely used to identify potentially cytotoxic and genotoxic pollutants in aquatic environments, variable non standardized choices have been made regarding the number of plant bulbs and roots analyzed. We propose numbers for bulbs and roots per bulb when comparing the frequencies of micronuclei, mitotic anomalies and mitotic index with this test. Roots that had been treated with aqueous solutions, such as water samples collected in August 2007 from the Paraiba do Sul River at the Brazilian cities of Tremembe and Aparecida; negative and positive controls were used for bioassays. The presence of pollutants in the river water had been presumed based on our previous cytological data and an official report by the Sao Paulo State Environmental Agency (Brazil) on presence of fecal contaminants (Tremembe and Aparecida) and elevated dissolved aluminium (Aparecida) in the water under study. The sampling of ten bulbs and five roots per bulb was found adequate for comparative studies to evaluate with the A. cepa test the potential damage inflicted by pollutants in aquatic environments. Furthermore, even one bulb and one root per bulb was sufficient in discerning this damage, thereby shortening the time required to attain a statistically confident comparative evaluation. However, to allow for the use of statistical programs based on the evaluation of average values, and to avoid criticism based on genetic variability, we propose that three bulbs and three roots per bulb be considered as standard sample sizes for the A. cepa test. PMID- 21298341 TI - Bioprocess development for the production of mouse-human chimeric anti-epidermal growth factor receptor vIII antibody C12 by suspension culture of recombinant Chinese hamster ovary cells. AB - The mouse-human chimeric anti-epidermal growth factor receptor vIII (EGFRvIII) antibody C12 is a promising candidate for the diagnosis of hepatocellular carcinoma (HCC). In this study, 3 processes were successfully developed to produce C12 by cultivation of recombinant Chinese hamster ovary (CHO-DG44) cells in serum-free medium. The effect of inoculum density was evaluated in batch cultures of shaker flasks to obtain the optimal inoculum density of 5 * 10(5) cells/mL. Then, the basic metabolic characteristics of CHO-C12 cells were studied in stirred bioreactor batch cultures. The results showed that the limiting concentrations of glucose and glutamine were 6 and 1 mM, respectively. The culture process consumed significant amounts of aspartate, glutamate, asparagine, serine, isoleucine, leucine, and lysine. Aspartate, glutamate, asparagine, and serine were particularly exhausted in the early growth stage, thus limiting cell growth and antibody synthesis. Based on these findings, fed-batch and perfusion processes in the bioreactor were successfully developed with a balanced amino acid feed strategy. Fed-batch and especially perfusion culture effectively maintained high cell viability to prolong the culture process. Furthermore, perfusion cultures maximized the efficiency of nutrient utilization; the mean yield coefficient of antibody to consumed glucose was 44.72 mg/g and the mean yield coefficient of glutamine to antibody was 721.40 mg/g. Finally, in small scale bioreactor culture, the highest total amount of C12 antibody (1,854 mg) was realized in perfusion cultures. Therefore, perfusion culture appears to be the optimal process for small-scale production of C12 antibody by rCHO-C12 cells. PMID- 21298342 TI - Identification of thylakoid membrane thermal transitions in Synechocystis sp. PCC6803 photosynthetic mutants. AB - We used differential scanning calorimetry (DSC) as a technique capable of identifying photosynthetic complexes on the basis of their calorimetric transitions. Annotation of thermal transitions was carried out with thylakoid membranes isolated from various photosynthetic mutants of Synechocystis sp. PCC6803. The thylakoid membranes exhibited seven major DSC bands between 40 and 85 degrees C. The heat sorption curves were analyzed both by mathematical deconvolution of the overall endotherms and by a subsequent annealing procedure. The successive annealing procedure proved to be more reliable technique than mathematical deconvolution in assigning thermal transitions. The main DSC band, around 47 degrees C, resulting from the high enthalpy change that corresponds to non-interacting complex of PSII, was assigned using the PSI-less/apcE(-) mutant cells. Another band around 68-70 degrees C relates to the denaturation of PSII surrounded by other proteins of the photosynthetic complexes in wild type and PSI less/apcE(-) cells. A further major transition found at 82-84 degrees C corresponds to the PSI core complex of wild type and PSII-deficient BE cells. Other transition bands between 50-67 and 65-75 degrees C are believed to relate to ATP synthase and cytochrome b(6)f, respectively. These thermal transitions were obtained with thylakoids isolated from PSI(-)/PSII(-) mutant cells. Some minor bands determined at 59 and 83-84 degrees C correspond to an unknown complex and NADH dehydrogenase, respectively. These annotations were done by PSI less/apcE(-) and PSI(-)/PSII(-) mutants. PMID- 21298343 TI - Significance of extensional stresses to red blood cell lysis in a shearing flow. AB - Traditionally, an empirical power-law model relating hemolysis to shear stress and exposure time has been used to estimate hemolysis related to flow--however, this basis alone has been insufficient in attempts to predict hemolysis through computational fluid dynamics. Because of this deficiency, we sought to re-examine flow features related to hemolysis in a shearing flow by computationally modeling a set of classic experiments performed in a capillary tube. Simulating 21 different flows of varying entrance contraction ratio, flowrate and viscosity, we identified hemolysis threshold streamlines and analyzed the stresses present. Constant damage thresholds for radial and axial extensional stresses of approximately 3000 Pa for exposure times on the order of microseconds were observed, while no such threshold was found for the maximum shear stress or gradient of the shear stress. The extensional flow seen at the entrance of the capillary appears to be most consistently related to hemolysis. An account of how extensional stresses can lead to lysis of a red cell undergoing tank-tread motion in a shearing flow is provided. This work shows that extensional components of the stress tensor are integral in causing hemolysis for some flows, and should be considered when attempting to predict hemolysis computationally. PMID- 21298344 TI - Electrically mediated neuronal guidance with applied alternating current electric fields. AB - Applied electric fields (EFs) have previously been presented as a potential method of inducing functional recovery after neural trauma. To date, most of this research has focused on the application of a direct current (DC) stimulus to produce the desired EF and induce neuronal growth. We propose that high duty cycle alternating current (AC) stimulation is capable of inducing similar EFs within the spinal cord and eliciting a neural response with the added benefits of increased field propagation and lower power consumption. Through ex vivo tissue testing of porcine spinal columns and Xenopus laevis cell cultures, 80% duty cycle AC stimulation was compared to DC stimulation for efficacy in field generation and induction of neurite growth. Results from ex vivo measurement show that AC stimulation is capable of producing EFs of greater magnitudes over an increased distance in the spinal cord than DC stimulation at the same current magnitude. Furthermore, stimulation of Xenopus laevis neuronal cultures with 80% duty-cycle rectangular waves indicated a significant increase in neurite length as compared to non-stimulated controls and cathodal preference, growth that was statistically similar to DC-stimulated cells. These results suggest high duty cycle stimulation modalities to be applicable and perhaps preferable to DC stimulation in electrically mediated neuronal therapies. PMID- 21298345 TI - Bioreactor system using noninvasive imaging and mechanical stretch for biomaterial screening. AB - Screening of biomaterial and tissue systems in vitro, for guidance of performance in vivo, remains a major requirement in the field of tissue engineering. It is critical to understand how culture stimulation affects both tissue construct maturation and function, with the goal of eliminating resource-intensive trial and-error screening and better matching specifications for various in vivo needs. In this article a multifunctional and robust bioreactor design that addresses this need is presented. The design enables a range of mechanical inputs, durations, and frequencies to be applied in coordination with noninvasive optical assessments. A variety of biomaterial systems, including micro- and nano-fiber and porous sponge biomaterials, as well as cell-laden tissue engineering constructs were used in validation studies to demonstrate the versatility and utility of this new bioreactor design. The silk-based biomaterials highlighted in these studies offered several unique optical signatures for use in label-free nondestructive imaging that allowed for sequential profiling. Both short- and long-term culture studies were conducted to evaluate several practical scenarios of usage: on a short-term basis, the authors demonstrate that construct cellularity can be monitored by usage of nonpermanent dyes; on a more long-term basis, the authors show that cell ingrowth can be monitored by green-fluorescent protein (GFP)-labeling, and construct integrity probed with concurrent load/displacement data. The ability to nondestructively track cells, biomaterials, and new matrix formation without harvesting designated samples at each time point will lead to less resource-intensive studies and should enhance our understanding and the discovery of biomaterial designs related to functional tissue engineering. PMID- 21298346 TI - Dispelling a few false-positives: a reply to MacGregor and McNamee on doping. AB - McGregor and MacNamee recently, in this journal, offered several criticisms of an earlier article in which I attempted to refute a number of arguments for the claim that doping in sports is morally wrong. Their criticisms are numerous, but focus on four domains. First, they sketch a view on which the risk profiles of different sports may make doping permissible in some and impermissible in others. Second, they suggest that my criticisms of safety-based arguments assume that doping opponents are bent on harm elimination, rather than harm management. Finally, they offer two methodological criticisms, the first pertaining to my use of analogical arguments, and the second pertaining to the general difficulties of making revisionist arguments in ethics. I defend my criticisms of safety-based arguments by showing that these do not rest on the assumptions McGregor and MacNamee attribute to me and by noting that their own view about the variable relevance of safety considerations is underdeveloped. As for their methodological arguments, I endeavor to show that these are misplaced, in that they either rest on misinterpretations of my earlier article or on an excessively high standard for ethical argumentation. PMID- 21298347 TI - Health-related quality of life in adults reporting arthritis: analysis from the National Health Measurement Study. AB - BACKGROUND: Arthritis is the leading cause of disability in the United States. We assess the generic health-related quality-of-life (HRQOL) among a nationally representative sample of U.S. adults with and without self-reported arthritis. METHODS: The NHMS, a cross-sectional survey of 3,844 adults (35-89 years) administered EuroQol-5D (EQ-5D), Health Utilities Index Mark 2 (HUI2) and 3 (HUI3), SF-36v2TM, Quality of Well-being Scale self-administered form (QWB-SA), and the Health and Activities Limitations index (HALex) to each respondent via a telephone interview. Weighted multiple linear regression was used to generate age gender-arthritis-stratified unadjusted HRQOL means and means adjusted for sociodemographic, socioeconomic covariates and comorbidities by arthritis-age category. RESULTS: The estimated population prevalence of self-reported arthritis was 31%. People with arthritis were more likely to be woman, older, of lower socioeconomic status, and had more self-reported comorbidities than were those not reporting arthritis. Adults with arthritis had lower HRQOL on six different indexes compared with adults without arthritis, with overall differences ranging from 0.03 (QWB-SA, age-group 65-74) to 0.17 (HUI3, age-group 35-44; all P-value < .05). CONCLUSION: Arthritis in adults is associated with poorer HRQOL. We provide age-related reference values for six generic HRQOL measures in people with arthritis. PMID- 21298348 TI - Role of MMP14 gene polymorphisms in susceptibility and pathological development to hepatocellular carcinoma. AB - BACKGROUND: Early detection of hepatocellular carcinoma (HCC) is seldom available because of the lack of reliable markers. Matrix metalloproteinase (MMP) 14 is a cell surface proteinase that displays a broad spectrum of activity against extracellular matrix components and promotes the invasion/metastasis of cells. MMP14 is overexpressed in HCC, and the level is correlated with poor overall survival. The purpose of this study was to examine whether the MMP14 gene polymorphisms are associated with the susceptibility and clinicopathological development of HCC. METHODS: A total of 135 patients with HCC and 496 healthy control subjects were recruited. Six single nucleotide polymorphisms (SNPs) of MMP14 genes were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) genotyping and haplotype-base analysis. RESULTS: A significant (p < 0.05) lower risk for HCC was shown in the individuals with MMP14 +6767 G/A and +7096 C/C genotypes compared with those with corresponding wild type homozygotes; high frequency for anti-hepatitis C virus and cirrhosis positive were shown in the HCC patients with MMP14 +7096 TC/CC genotype after adjusting for other confounding factors. The distribution frequency of -165 T: +221 T: +6727 C: +6767 G: +7096 T: +8153 G haplotype and diplotype was significantly higher in the HCC patients than healthy control subjects. CONCLUSIONS: The +6767 and +7096 polymorphic genotypes and haplotype -165 T: +221 T: +6727 C: +6767 G: +7096 T: +8153 G of MMP14 gene might contribute to the prediction of susceptibility and pathological development to HCC. PMID- 21298349 TI - Epigenomic analysis of aberrantly methylated genes in colorectal cancer identifies genes commonly affected by epigenetic alterations. AB - BACKGROUND: Determination of the profile of genes that are commonly methylated aberrantly in colorectal cancer (CRC) will have substantial value for diagnostic and therapeutic applications. However, there is limited knowledge of the DNA methylation pattern in CRC. MATERIALS AND METHODS: We analyzed the methylation profile of 27,578 CpG sites spanning more than 14,000 genes in CRC and in the adjacent normal mucosa with bead-chip array-based technology. RESULTS: We identified 621 CpG sites located in promoter regions and CpG islands that were greatly hypermethylated in CRC compared to normal mucosa. The genes on chromosome 18 showed promoter hypermethylation most frequently. According to gene ontology analysis, the most common biologically relevant class of genes affected by methylation was the class associated with the cadherin signaling pathway. Compared to the genome-wide expression array, mRNA expression was more likely to be downregulated in the genes demonstrating promoter hypermethylation, even though this was not statistically significant. We validated ten CpG sites that were hypermethylated (ADHFE1, BOLL, SLC6A15, ADAMTS5, TFPI2, EYA4, NPY, TWIST1, LAMA1, GAS7) and 2 CpG sites showing hypomethylation (MAEL, SFT2D3) in CRC compared to the normal mucosa in the array studies using pyrosequencing. The methylation status measured by pyrosequencing was consistent with the methylation array data. CONCLUSIONS: Methylation profiling based on bead-chip arrays is an effective method for screening aberrantly methylated genes in CRC. In addition, we identified novel methylated genes that are candidate diagnostic or prognostic markers for CRC. PMID- 21298350 TI - The impact of the introduction of total mesorectal excision on local recurrence rate and survival in rectal cancer: long-term results. AB - PURPOSE: To investigate the influence of the introduction of total mesorectal excision (TME) on local recurrence rate and survival in patients with rectal cancer. METHODS: A total of 171 consecutive patients underwent anterior or abdominoperineal resection for primary rectal cancer. When the TME technique was introduced, the clinical setting, including the surgeons, remained the same. Group 1 (1993-95, n =53) underwent conventional surgery and group 2 (1995-2001, n = 118) underwent TME. All patients were followed for 7 years or until death. RESULTS: Between the two groups, no statistically significant differences were present with regards to patient-, treatment-, or tumor-related characteristics apart from the time point of radiotherapy. The total local recurrence rates were 11 of 53 (20.8%) in group 1 and 7 of 118 (5.9%) in group 2, and the rates of isolated local recurrences were 6 of 53 (11.3%) in group 1 and 2 of 118 (1.7%) in group 2. Both differences were highly statistically significant. The disease-free survival in groups 1 and 2 was 60.4 and 65.3% at 5 years, and 58.5 and 65.3% at 7 years, respectively. Excluding patients with synchronous or metachronous distant metastasis from the analysis, both the disease-free survival and the cancer specific survival were statistically significantly better in group 2 than in group 1. No statistically significant difference between the two groups was detected regarding the overall survival. CONCLUSIONS: The introduction of TME led to an impressive reduction of the local recurrence rate. Survival is mainly determined by the occurrence of distant metastasis, but TME seems to improve survival in patients without systemic disease. PMID- 21298353 TI - Feasibility of ICG fluorescence-guided sentinel node biopsy in animal models using the HyperEye Medical System. AB - BACKGROUND: The sentinel lymph node (SLN) concept is accepted for several types of cancers. Current methods for sentinel node detection involve radioisotopes and blue dye. They have shown good results, but some drawbacks remain. Indocyanine green (ICG) fluorescence using the HyperEye Medical System (HEMS) was evaluated as a new method. METHODS: This was a prospective, nonrandomized, experimental study in four Japanese white rabbits and six Yorkshire pigs. ICG and indigo carmine were injected into the tongue, larynx, or hypopharynx, and ICG fluorescence detection was evaluated using both transcutaneous visualization of lymphatic vessels and intraoperative identification of SLNs. RESULTS: The SLNs appeared as shining fluorescent spots with HEMS transcutaneously in rabbits, but no SLNs were detected transcutaneously in pigs. Eleven procedures identified SLNs, but one did not due to a technical problem. CONCLUSIONS: HEMS could become useful for predicting lymph node metastasis during surgery for head and neck cancer. PMID- 21298352 TI - Two-stage resection for bilobar colorectal liver metastases: R0 resection is the key. AB - BACKGROUND: Two-stage liver resection (2-SLR) is used clinically in conjunction with portal vein embolization for bilobar disease to increase the number of patients suitable for liver resection. The long-term outcomes after 2-SLR for multiple bilobar colorectal liver metastases (CLM) was examined. METHODS: Patients who sought care between November 2003 and April 2006 with multiple CLM considered suitable for 2-SLR were prospectively followed. Clinicopathological data were collected. Surgical outcomes were defined as complete clearance of tumor (R0/R1/R2), postoperative morbidity (within 3 months), 30 day mortality, disease-free survival (DFS), and overall survival (OS). RESULTS: A total of 131 patients with CLM underwent liver resection during the study period, 38 of whom were planned for a 2-SLR for multiple bilobar disease. Only 33 (87%) completed the 2-SLR with a curative intent. Five patients did not undergo stage II resection because of disease progression. The postoperative morbidity was 11 and 33% after stage I and stage II liver resections, respectively. Five patients (13%) encountered postoperative complications specific to liver surgery. The median interval from stage II resection to disease recurrence in the R0 group was 18 months versus 3 months in the R1/R2 group (P < 0.001). R0 resection with curative intent versus R1/R2 noncurative resection has a significantly longer period of DFS (P < 0.001) and OS (P = 0.04). CONCLUSIONS: The 2-SLR combined with portal vein embolization is an effective and safe method for resecting previously unresectable multiple bilobar CLM. However, a positive resection margin leads to poor DFS and OS. PMID- 21298351 TI - Polymorphism in epidermal growth factor receptor intron 1 predicts prognosis of patients with esophageal cancer after chemoradiation and surgery. AB - BACKGROUND: The EGFR gene has been demonstrated to be an important factor influencing treatment response for various cancers, and its expression has been shown to be modified by the polymorphic CA repeat length at the 5'-regulatory sequence in intron 1. We investigated whether this EGFR polymorphism is associated with prognosis in patients with esophageal cancer after concurrent chemoradiotherapy (CCRT) and esophagectomy. METHODS: A cohort of 148 patients with esophageal cancer received cisplatin-based CCRT (concurrently combined with 40 Gy irradiation) and subsequent esophagectomy. Their EGFR genotypes were determined by polymerase chain reaction from leukocyte DNA, which was obtained before treatment and was correlated with patient survival. RESULTS: Patients with the homozygous short allele (<20 CA) of the EGFR gene in intron 1 were more likely to have a shorter duration of survival after CCRT and surgery than those with the homozygous long allele [adjusted hazard ratio (HR) (95% confidence interval [CI]) of death: 1.88 (1.02-3.49); P = 0.045]. This unfavorable prognostic effect of EGFR homozygous short CA repeat was mainly manifested in patients with good response to CCRT [adjusted HR (95% CI) of death 3.40 (1.06 10.89); P = 0.039]; it was less evident in those with poor response to CCRT [adjusted HR (95% CI) 1.40 (0.65-3.02); P = 0.384]. CONCLUSIONS: The EGFR CA repeat genetic polymorphism may act as a valuable molecular predictor of clinical outcome of esophageal cancer after CCRT and esophagectomy, especially in those with good response to CCRT. PMID- 21298355 TI - Review of the methods of determination of directed connectivity from multichannel data. AB - The methods applied for estimation of functional connectivity from multichannel data are described with special emphasis on the estimators of directedness such as directed transfer function (DTF) and partial directed coherence. These estimators based on multivariate autoregressive model are free of pitfalls connected with application of bivariate measures. The examples of applications illustrating the performance of the methods are given. Time-varying estimators of directedness: short-time DTF and adaptive methods are presented. PMID- 21298354 TI - Targeted multifunctional multimodal protein-shell microspheres as cancer imaging contrast agents. AB - PURPOSE: In this study, protein-shell microspheres filled with a suspension of iron oxide nanoparticles in oil are demonstrated as multimodal contrast agents in magnetic resonance imaging (MRI), magnetomotive optical coherence tomography (MM OCT), and ultrasound imaging. The development, characterization, and use of multifunctional multimodal microspheres are described for targeted contrast and therapeutic applications. PROCEDURES: A preclinical rat model was used to demonstrate the feasibility of the multimodal multifunctional microspheres as contrast agents in ultrasound, MM-OCT and MRI. Microspheres were functionalized with the RGD peptide ligand, which is targeted to alpha(v)beta3 integrin receptors that are over-expressed in tumors and atherosclerotic lesions. RESULTS: These microspheres, which contain iron oxide nanoparticles in their cores, can be modulated externally using a magnetic field to create dynamic contrast in MM-OCT. With the presence of iron oxide nanoparticles, these agents also show significant negative T2 contrast in MRI. Using ultrasound B-mode imaging at a frequency of 30 MHz, a marked enhancement of scatter intensity from in vivo rat mammary tumor tissue was observed for these targeted protein microspheres. CONCLUSIONS: Preliminary results demonstrate multimodal contrast-enhanced imaging of these functionalized microsphere agents with MRI, MM-OCT, ultrasound imaging, and fluorescence microscopy, including in vivo tracking of the dynamics of these microspheres in real-time using a high-frequency ultrasound imaging system. These targeted oil-filled protein microspheres with the capacity for high drug-delivery loads offer the potential for local delivery of lipophilic drugs under image guidance. PMID- 21298356 TI - Rectal cancer: 3D dynamic contrast-enhanced MRI; correlation with microvascular density and clinicopathological features. AB - PURPOSE: The primary aim of this prospective study was to evaluate the relationship between three-dimensional dynamic contrast-enhanced magnetic resonance (3D-DCE-MR) imaging parameters and clinicopathological features of rectal cancer and assess their potential as new radiological prognostic predictors. MATERIALS AND METHODS: Three-dimensional DCE-MR was performed on 26 cases of pathologically proved rectal adenocarcinoma 1 week prior to operation. Data were analysed to calculate transfer constant (Ktrans), leakage space (Ve) and rate constant (Kep) of both tumour and normal rectal wall. Microvessel density (MVD) was evaluated by immunohistochemical staining of surgical specimens. All findings were analysed prospectively and correlated with tumour/node/metastasis (TNM) staging, Dukes staging, histological grading, presence of lymph node metastasis, serosal involvement and MVD. RESULTS: Mean Ktrans, Ve and Kep for tumours were as follows: Ktrans 7.123+/-3.850/min, Ve 14.2+/-3.0%, Kep 49.446+/-20.404/min, revealing the significant difference between the tumour and normal rectal wall (p=0.001). There was a significant difference for Ktrans not only between patients with and without lymphatic involvement (p=0.000), but also among Dukes staging (p=0.04) and pTNM staging (p=0.03). Kep showed moderate correlation with TNM stages (r=0.479, p=0.02). Ve and MVD revealed no significant correlation with the clinicopathological findings described above (p>0.05). CONCLUSION: Owing to the moderate and strong relationship between Ktrans and clinicopathological elements, Ktrans might be the prognostic indicator of rectal cancer. Threedimensional DCE high-resolution MR imaging provides a competing opportunity to assess contrast kinetics. PMID- 21298357 TI - Catalytic performance of corn stover hydrolysis by a new isolate Penicillium sp. ECU0913 producing both cellulase and xylanase. AB - A fungal strain, marked as ECU0913, producing high activities of both cellulase and xylanase was newly isolated from soil sample collected near decaying straw and identified as Penicillium sp. based on internal transcribed spacer sequence homology. The cultivation of this fungus produced both cellulase (2.40 FPU/ml) and xylanase (241 IU/ml) on a stepwisely optimized medium at 30 degrees C for 144 h. The cellulase and xylanase from Penicillium sp. ECU0913 was stable at an ambient temperature with half-lives of 28 and 12 days, respectively. Addition of 3 M sorbitol greatly improved the thermostability of the two enzymes, with half lives increased by 2.3 and 188-folds, respectively. Catalytic performance of the Penicillium cellulase and xylanase was evaluated by the hydrolysis of corn stover pretreated by steam explosion. With an enzyme dosage of 50 FPU/g dry substrate, the conversions of cellulose and hemicellulose reached 77.2% and 47.5%, respectively, without adding any accessory enzyme. PMID- 21298358 TI - Randomized controlled trial comparing the effect of 8.4% sodium bicarbonate and 5% sodium chloride on raised intracranial pressure after traumatic brain injury. AB - BACKGROUND: Hypertonic sodium chloride solutions are routinely used to control raised intracranial pressure (ICP) after traumatic brain injury but have the potential to cause a hyperchloremic metabolic acidosis. Sodium bicarbonate 8.4% has previously been shown to reduce ICP and we have therefore conducted a randomized controlled trial to compare these two solutions. METHODS: Patients with severe traumatic brain injury were randomly allocated to receive an equiosmolar dose of either 100 ml of sodium chloride 5% or 85 ml of sodium bicarbonate 8.4% for each episode of intracranial hypertension. ICP and blood pressure were measured continuously. Arterial pCO(2), sodium, chloride, osmolality, and pH were measured at intervals. RESULTS: We studied 20 episodes of intracranial hypertension in 11 patients. Treatments with 8.4% sodium bicarbonate and 5% sodium chloride reduced raised ICP effectively with a significant fall in ICP from baseline at all time points (P < 0.001). There was no significant difference in ICP with time between those episodes treated with 5% sodium chloride or 8.4% sodium bicarbonate, P = 0.504. Arterial pH was raised after treatment with 8.4% sodium bicarbonate. CONCLUSIONS: An equiosmolar infusion of 8.4% sodium bicarbonate is as effective as 5% sodium chloride for reduction of raised ICP after traumatic brain injury when infused over 30 min. PMID- 21298359 TI - Acute kidney injury in patients with severe traumatic brain injury: implementation of the acute kidney injury network stage system. AB - BACKGROUND: There is limited information on the incidence and effect of acute kidney injury (AKI) in patients with severe traumatic brain injury (TBI), although AKI may affect outcome. Recently, acute kidney injury network (AKIN) classification has been widely accepted as a consensus definition for AKI. The aim of this study is to estimate the frequency and level of severity of AKI in patients with severe TBI by using AKIN criteria and to study whether AKI affects outcome. METHODS: The authors retrospectively identified a total of 136 patients with severe TBI admitted to the neurosurgical center during a 3-year period ending May 2010. Demographic data, severity of TBI, serum creatinine, urine output, outcome at 6 month, and death were collected. Renal function was assessed by using AKIN criteria. RESULTS: Thirty-one patients (23%) were classified as having AKI by using AKIN criteria during their hospitalization. Of them, 21 patients (68%) were stratified as stage 1, 7 patients (22%) as stage 2, and 3 patients (10%) as stage 3. Patients who developed AKI were older, had lower Glasgow coma scale at admission, and had higher level of admission serum creatinine and blood urea nitrogen. Patients with AKI had higher mortality and worse outcome when compared with patients with normal renal function. Furthermore, patients with mild renal dysfunction (stage 1 AKI) are also found having increased mortality and worse long-term outcome, compared with patients without renal dysfunction. CONCLUSION: It is demonstrated using the newly defined AKIN criteria for renal dysfunction that AKI is a relatively common feature in patients with severe TBI, and even seemingly insignificant decrease in renal function may be associated with worse outcome. This study highlights the importance of close surveillance of renal function and stresses the value of renal hygiene in the severe TBI population. PMID- 21298360 TI - Thrombin generation in plasma from patients with cirrhosis supplemented with normal plasma: considerations on the efficacy of treatment with fresh-frozen plasma. AB - Cirrhosis is characterized by a complex coagulation defect leading to the prolongation of the prothrombin and activated partial thromboplastin times (PT and APTT). Arbitrary PT cut-off values are still used as a yardstick to guide treatment with fresh-frozen plasma (FFP) or other pro-coagulant agents in patients undergoing invasive procedures. No randomized studies on the FFP efficacy are available, and are unlikely to be carried out because of their complex organization. An interim solution could be to evaluate the in vitro thrombin generation in plasmas from patients with cirrhosis when mixed with appropriate amounts of pooled normal plasma (PNP). The PT, APTT and thrombin generations in the presence of thrombomodulin were examined in 58 patients with cirrhosis and 24 healthy subjects both before and after mixing their plasmas with PNP at a proportion of 4 + 1 (patient + PNP), chosen to mimic in vivo conditions when patients are treated with 10 ml/kg of FFP. The PT and APTT, which were abnormal in the majority of unmixed patient plasmas were shortened considerably, but did not normalize completely when mixed with PNP. Thrombin generation, which was already within normal limits in all unmixed patient plasmas, remained essentially unchanged after mixing with PNP. In conclusion, thrombin generation in patients with cirrhosis does not appreciably change after in vitro addition of PNP despite PT and APTT shortening would suggest otherwise. These results question the validity of the PT as a stand-alone test to guide transfusion of FFP in the setting of chronic liver disease. PMID- 21298361 TI - Screening for asymptomatic coronary artery disease can reduce cardiovascular mortality and morbidity in type 2 diabetic patients. AB - The impact of the screening for asymptomatic coronary artery disease (CAD) on the cardiovascular prognosis in diabetes is controversial. The aim of the study was to investigate whether screening for asymptomatic CAD can have an impact on cardiovascular morbidity and mortality in diabetes. In this nonrandomized longitudinal study, 1,189 consecutive type 2 diabetic patients without a history of CAD were evaluated. They were subdivided into two groups according to whether they were screened (screening group, n = 921) or not (no-screening group, n = 268) for asymptomatic CAD. Among the screened patients, 386 had angiographically proven CAD (CAD group) and 535 did not have silent CAD (no-CAD group). During a mean follow-up period of 4.3 +/- 1.9 years, 130 patients experienced major adverse cardiac events (MACE). The incidence of MACE was significantly greater in the no-screening than in the screening group (22.0 vs. 7.7%; p = 0.001). The Kaplan-Meier method showed that: (1) the screening was associated with a lower rate of MACE (log-rank test, 3-95; p = 0.047); (2) the no-screening group had a risk profile similar to that of CAD group (log-rank test, 2.02; p = 0.154); and (3) cardiovascular prognosis was significantly better in no-CAD than in no screening group (log-rank test, 4.27; p = 0.039). Multivariate Cox regression analysis showed that screening for CAD (HR 0.2; 95% CI 0.2-0.3; p = 0.000) was significantly protective against the occurrence of MACE. Our data suggest that screening for asymptomatic CAD can significantly reduce cardiovascular morbidity and mortality in type 2 diabetic patients. This may be due to specific diagnostic and therapeutic interventions in diabetic patients with proven CAD at screening. PMID- 21298362 TI - Why TNF-alpha inhibition is not sufficient to avoid juxta-articular erosions in chronic arthritis? AB - There is an emerging interest in the role of anti-TNF-alpha therapy in reducing bone damage in chronic arthritis with special regard to rheumatoid arthritis. Accumulation of osteoclasts in rheumatoid synovial tissues, and their activation due to osteoclastogenic cytokines and chemokines at cartilage erosion sites suggest that they may advantageously be considered as therapeutic targets. Given that the primary role of TNF-alpha in osteoclastogenesis, the inhibition of TNF alpha represents an important strategy for reducing bone damage in rheumatoid arthritis. In point of fact, there is evidence that treatment with anti-TNF-alpha agents may avoid or reduce bone damage in rheumatoid arthritis, even if further studies are required to provide a biological explanation and a link for the observation of the advantageous effects of TNF-alpha inhibitors on the progression of bone damage in chronic arthritis. The existence of factors involved in osteoclast activation, including IL-1, IL-6, IL-7, IL-11, IL-17, M CSF, TGF-beta, MIP-1alpha, MIP-1beta, IP-10, MIG, and OSCAR, indicates that TNF alpha is only a single player in the great molecular cauldron of osteoclastogenesis. The presence of mediators behind the TNF-alpha and RANK-RANKL complex that may be independent in inducing osteoclastogenesis, such as NFATc1, suggests that the anti-TNF-alpha therapy will not provide a complete reduction of bone damage in chronic arthritis. PMID- 21298364 TI - Fine mapping QTL for drought resistance traits in rice (Oryza sativa L.) using bulk segregant analysis. AB - Drought stress is a major limitation to rice (Oryza sativa L.) yields and its stability, especially in rainfed conditions. Developing rice cultivars with inherent capacity to withstand drought stress would improve rainfed rice production. Mapping quantitative trait loci (QTLs) linked to drought resistance traits will help to develop rice cultivars suitable for water-limited environments through molecular marker-assisted selection (MAS) strategy. However, QTL mapping is usually carried out by genotyping large number of progenies, which is labour-intensive, time-consuming and cost-ineffective. Bulk segregant analysis (BSA) serves as an affordable strategy for mapping large effect QTLs by genotyping only the extreme phenotypes instead of the entire mapping population. We have previously mapped a QTL linked to leaf rolling and leaf drying in recombinant inbred (RI) lines derived from two locally adapted indica rice ecotypes viz., IR20/Nootripathu using BSA. Fine mapping the QTL will facilitate its application in MAS. BSA was done by bulking DNA of 10 drought-resistant and 12 drought-sensitive RI lines. Out of 343 rice microsatellites markers genotyped, RM8085 co-segregated among the RI lines constituting the respective bulks. RM8085 was mapped in the middle of the QTL region on chromosome 1 previously identified in these RI lines thus reducing the QTL interval from 7.9 to 3.8 cM. Further, the study showed that the region, RM212-RM302-RM8085-RM3825 on chromosome 1, harbours large effect QTLs for drought-resistance traits across several genetic backgrounds in rice. Thus, the QTL may be useful for drought resistance improvement in rice through MAS and map-based cloning. PMID- 21298363 TI - The PANDORA study: peripheral arterial disease in patients with non-high cardiovascular risk. AB - Few studies are available with sufficient sample size to accurately describe the prevalence of low ankle-brachial index (ABI) in patients at 'non-high' cardiovascular (CV) risk. The aim of this study was to evaluate the prevalence of asymptomatic peripheral arterial disease (PAD), as determined by using ABI, in this patient population. A non-interventional, cross-sectional, pan-European study was conducted in patients with >=1 CV risk factor in addition to age, evaluating the prevalence of asymptomatic PAD (ABI <= 0.90). Secondary objectives included assessing the prevalence and treatment of CV risk factors. Patients were consecutively recruited during scheduled visits to the physician's office, or were randomly selected by the physician from a list of eligible patients. Patients with diabetes were excluded as this condition was deemed to be a secondary prevention risk. 10,287 patients were enrolled (9,816 evaluable: mean age 64.3 years; 53.5% male). Prevalence of asymptomatic PAD was 17.8% (99% CI 16.84-18.83). Factors significantly associated with asymptomatic PAD included hypertension, age, alcohol intake, family history of coronary heart disease, low levels of high-density lipoprotein-cholesterol, and smoking (p < 0.0001). Patients treated with statins were significantly less likely to have asymptomatic PAD than those who were not (odds ratio 0.62; 95% CI 0.50-0.76; p < 0.0001). Asymptomatic PAD was highly prevalent in patients with non-high CV risk, the majority of whom would not typically be candidates for ABI assessment. These patients should be carefully screened, and ABI measured, so that therapeutic interventions known to diminish their increased CV risk may be offered. PMID- 21298366 TI - Correlation between T-cadherin gene expression and aberrant methylation of T cadherin promoter in human colon carcinoma cells. AB - Previous researches showed T-cadherin (CDH13) expression was downregulated in colon cancer tissues and was associated with increase of invasive and metastatic potential. This research was to observe the mechanisms responsible for inactivation of T-cadherin gene in colon carcinoma; we investigated the methylation status around the 5' promoter region of T-cadherin gene of Hct116 colon cancer cell line by methylation-specific polymerase chain reaction (MSP), also detected the expression change of T-cadherin mRNA and protein in Hct116 cell line after 5-Aza-CdR treatment by reverse transcriptase polymerase chain reaction and Western blotting, and compared the T-cadherin methylation status with T cadherin mRNA and protein expression. We found that hypermethylation of T cadherin was involved in Hct116 cell line, while T-cadherin mRNA and protein expression was almost lost or downregulated in Hct116 cell line. Therefore, methylation of the T-cadherin promoter region was correlated with the loss or downregulation of T-cadherin mRNA and protein expression in Hct116 colon cancer cell line. Treatment of T-cadherin-negative carcinoma cells with the demethylating agent, 5-aza-2'-deoxycytidine, induced re-expression of this gene. Our findings demonstrate that 5' CpG island methylation is common in colon carcinoma and may play an important role in the inaction of T-cadherin. Our results also suggest that demethylation of the T-cadherin gene may be a potential therapeutic strategy for colon carcinoma. PMID- 21298367 TI - Central nervous system relapse in CD56+, FLT3/ITD+ promyelocytic leukemia. AB - Central nervous system (CNS) involvement in acute promyelocytic leukemia (APL) is rare and tends to be seen mostly following treatment with all-trans retinoic acid (ATRA), due to prolonged patient survival and poor penetration of the drug in the CNS. At least 10% of extramedullary relapses in APL involve the CNS, and associated factors include an increased age, the BCR isoform, the development of differentiation syndrome, a high white cell count at presentation and hemorrhage into the CNS during induction therapy. We present the case of a patient with high risk APL, CD56+, CD2+ in whom a CNS relapse was diagnosed through the presence of a PML/RARalpha rearrangement on PCR of the cerebrospinal fluid (CSF). PMID- 21298365 TI - CXCL12 G801A polymorphism is associated with an increased risk of benign salivary gland tumors in the Chinese population. AB - The chemokine CXCL12 and its receptor CXCR4 have been found to be important in tumor progression. A single-nucleotide polymorphism of CXCL12 G801A has been described and investigated in human immunodeficiency virus-1 (HIV-1) infection and in the susceptibility to several cancers. Here, we investigated the association between the CXCL12 G801A polymorphism and susceptibility to benign and malignant salivary gland tumors (SGTs) by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) in 102 Chinese SGT patients and 101 healthy controls. The frequencies of the AG (P = 0.001; odds ratio (OR), 3.764) and AA (P = 0.004; OR, 6.852) genotypes of CXCL12 were significantly higher in patients with benign SGTs than in the healthy controls. The frequency of the A allele of CXCL12 was also significantly higher in benign SGTs (P = 0.00; OR, 1.395) compared with the healthy controls. However, the AG (P = 0.171; OR, 3.163) and AA (P = 0.854; OR, 0.667) genotypes did not increase the risk of malignant SGTs significantly. The frequency of the CXCL12 A allele was also not found to be higher in malignant SGTs (P = 0.267; OR, 1.917) compared with the controls. Taken together, our results suggested that the CXCL12 G801A polymorphism is associated with an increased risk of benign SGTs, but not malignant SGTs, in the Chinese population. PMID- 21298368 TI - Clinicopathologic features and prognosis analysis of mucinous gastric carcinoma. AB - Mucious gastric carcinoma (MGC) is a subtype of gastric carcinoma and its clinicopathologic features and prognosis still remain unclear. To investigate the clinical significance and surgical outcomes of mucinous gastric carcinoma, 2,769 patients with gastric carcinoma were analyzed in a case control study. We reviewed the records of 196 patients with mucinous gastric carcinoma and 2,573 with nonmucinous gastric carcinoma (NGC). Clinicopathologic features and survival rate of patients were analyzed. In all registered patients, patients with MGC had a larger size, more T3 and T4 invasion to the gastric wall, more positive lymph node metastasis, more III and IV stage and more positive peritoneal dissemination, but less curative gastrectomy. In curative gastrectomy patients, MGC had larger size, deeper invasion to gastric wall, more positive lymph node metastasis and more advanced TNM stage. The overall survival rate in curative gastrectomy patients with MGC was significantly lower than that for patients with NGC (P < 0.021). Age (P = 0.001), location of tumor (P < 0.001), Borrmann type (P = 0.037), depth of invasion (P < 0.001), lymph node metastasis (P < 0.001) and lymphovascular invasion (P = 0.001) were independent prognostic factors of gastric carcinoma, but MGC itself was not. The prognosis of MGC did not have significant difference compared with NGC. Frequently, MGC was of advanced stage at the time of diagnosis. Age, location of tumor, Borrmann type, depth of invasion, lymph node metastasis and lymphovascular invasion are independent prognostic factors of gastric carcinoma, but mucinous histological type itself is not. Further study on the origin and progression of MGC is needed in future. PMID- 21298369 TI - Neural mechanisms of angiotensin II-salt hypertension: implications for therapies targeting neural control of the splanchnic circulation. AB - Chronically elevated plasma angiotensin II (AngII) causes a salt-sensitive form of hypertension that is associated with a differential pattern of peripheral sympathetic outflow. This "AngII-salt sympathetic signature" is characterized by a transient reduction in sympathetic nervous system activity (SNA) to the kidneys, no change in SNA to skeletal muscle, and a delayed activation of SNA to the splanchnic circulation. Studies suggest that the augmented sympathetic influence on the splanchnic vascular bed increases vascular resistance and decreases vascular capacitance, leading to hypertension via translocation of blood volume from the venous to the arterial circulation. This unique sympathetic signature is hypothesized to be generated by a balance of central excitatory inputs and differential baroreceptor inhibitory inputs to sympathetic premotor neurons in the rostral ventrolateral medulla. The relevance of these findings to human hypertension and the future development of targeted sympatholytic therapies are discussed. PMID- 21298370 TI - Nycthemeral relationship between renal function and sodium homeostasis. AB - Nycthemeral changes in renal function have been known for a long time, but our knowledge about the underlying mechanisms is still far from complete. From a theoretical point of view, many physiological systems could be involved in turning the kidney from a sodium-excretory organ during daytime into a sodium conserving organ during nighttime. Although blood pressure itself may regulate sodium output directly through pressure natriuresis, this mechanism can be unmasked only when other influences on the kidney can be eliminated. Hence, there is not enough evidence that pressure natriuresis governs cyclic variations in sodium output in the intact human being. Although the glomerular filtration rate follows a nocturnal variation pattern that is more or less in phase with the pattern of sodium excretion, the amplitudes of both differ so much that it is not likely that filtration alone can account for the changes in electrolyte output. The available data are compatible with tubular mechanisms, notably in the distal parts of the nephron. Recent molecular studies have identified several circadian gene products that may entrain the sodium excretory rhythm. PMID- 21298371 TI - Non-clear cell renal cell carcinoma: how new biological insight may lead to new therapeutic modalities. AB - Treatment for patients with metastatic non-clear cell renal cancer (RCC), who constitute 25% of all RCC patients, is largely undefined and tested algorithms remain unsatisfactory. Response rates to targeted therapy are not as high as in patients with clear cell subtypes, but novel agents provide a clinically meaningful response in some individuals. The research leading to characterization of the pathways involved in clear cell renal cancer has been recognized as a role model for the development of therapies based on genetic and molecular tumor characteristics. Similar research now provides increasing insight into signal transduction in non-clear cell subtypes. This review will present and discuss the current evidence of pathways involved in the most common non-clear cell subtypes. In addition, we will review how this may lead to the development of new treatment modalities. New targets and clinical trials will be highlighted. PMID- 21298373 TI - Backbone and side-chain 1H, 15N and 13C resonance assignments of S18Y mutant of ubiquitin carboxy-terminal hydrolase L1. AB - Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), also known as PGP9.5, is a protein of 223 amino acids. Although it was originally characterized as a deubiquitinating enzyme, recent studies indicate that it also functions as a ubiquitin (Ub) ligase and a mono-Ub stabilizer. It is highly abundant in brain, constituting up to 2% of total brain proteins. Down-regulation and extensive oxidative modification of UCH-L1 have been observed in the brains of Alzheimer's disease (AD) and Parkinson's disease (PD) patients. Mutations in the UCH-L1 gene have been reported to be linked to Parkinson's disease, in particular, the I93 M variant is associated with a higher susceptibility of PD in contrast to a higher protection against PD for the S18Y variant. Hence, the structure of UCH-L1 and the underlying effects of disease associated mutations on the structure and function of UCH-L1 are of considerable interest. Here, we report the NMR spectral assignments of the S18Y human UCH-L1 mutant with the aim to obtain better understanding about the risk of Parkinson's disease against structural and dynamical changes induced by this mutation on UCH-L1. PMID- 21298372 TI - Curable metastatic colorectal cancer. AB - In the United States and Europe, colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer-related death for men and women. In the course of their disease, many patients will present with metastasis, with the liver and lung being the most common locations. Untreated metastatic disease carries a poor prognosis. However, cure is still possible for selected patients with stage IV CRC. Surgical resection provides the best chance for cure, and chemotherapy can be a valuable adjunct when given in a (neo )adjuvant fashion or as conversion therapy to downsize initially unresectable tumors. For unresectable metastases, alternative treatment options include radiofrequency ablation and hepatic artery infusion. Additional local therapies are being explored, including chemoembolization, radioembolization, and stereotactic body radiation therapy. Prospective randomized trials are needed to further clarify the roles of these novel treatment options in the clinician's repertoire for metastatic CRC. PMID- 21298374 TI - Exploring the differential diagnosis of joint complaints in pediatric patients with inflammatory bowel disease. AB - About one quarter of children with inflammatory bowel disease (IBD) experience an extraintestinal manifestation, with the most common being arthritis or arthralgia. Because of the frequency of these joint complaints and their effect on quality of life, it is important to consider all possible etiologies in order to promptly evaluate, diagnose, and possibly refer to other specialists. Pediatric gastroenterologist and IBD specialists are cognizant of the extraintestinal joint manifestations, but may be less familiar with rheumatic disease and the musculoskeletal examination. We explore the differential diagnosis of joint complaints in children, with a focus on IBD-related disease and rheumatic disease. PMID- 21298376 TI - Roles of fine-needle aspiration and core needle biopsy in the diagnosis of breast cancer. AB - BACKGROUND: There is controversy regarding which of the two biopsy methods, fine needle aspiration (FNA) or core needle biopsy (CNB), should be routinely employed for diagnosis of breast cancer. The aim of this study was to evaluate the efficacy of FNA compared to CNB and to explore the value of performing both FNA and CNB. METHODS: Two hundred eighty-one patients with breast cancer received FNA alone (group 1: n = 182), CNB alone (group 2: n = 56), or a combination of FNA and CNB (group 3: n = 43). In group 3, FNA was combined with CNB because of an inadequate smear of FNA on immediate cytological examination. Subsequently, the patients underwent definitive surgery or open surgical biopsy based on the clinical findings, and the tumors were pathologically confirmed to be noninvasive or invasive breast cancer. RESULTS: There was no significant difference in the absolute sensitivity between group 1 (93% for FNA alone) and group 2 (86% for CNB alone). In group 3, on the other hand, the absolute sensitivity was significantly improved to 72% when FNA and CNB were combined (P < 0.05), although it was only 42% for FNA alone and 63% for CNB alone. CONCLUSIONS: The absolute sensitivity of FNA was equivalent to that of CNB when excluding patients who were converted from FNA to CNB based on immediate cytological examination. In the latter patients, however, it was improved by combining FNA and CNB. Therefore, these two techniques should be considered complimentary to one another. PMID- 21298375 TI - Targeted therapies for metastatic esophagogastric cancer. AB - The prognosis and long-term survival for patients with metastatic esophagogastric cancer (EGC) is poor. Historically, the mainstay of treatment has been combination chemotherapy. More recently, a number of targeted therapies have been developed and are being studied with the goal of improving response rate and survival in patients with metastatic EGC. To date, the only targeted therapy which has been clinically approved is trastuzumab which targets the HER2/Neu oncogene. However, only a small group of patients with EGCs are HER2 amplified, and there are other important targets/pathways which play a role in the development of these cancers that are currently being studied. With the identification of these other clinically relevant pathways, it is anticipated that several other therapies will be approved in the future. PMID- 21298378 TI - Esophageal dilator as a substitute for the custom stylet to remove the intubating laryngeal airway after tracheal intubation in children. PMID- 21298379 TI - Effect of extended training on generalization of latent inhibition: an instance of perceptual learning. AB - Four experiments examined generalization of latent inhibition (LI) as a function of the length of preexposure in a conditioned taste aversion procedure with rats. Experiment 1 showed that one or four nonreinforced presentations of a flavor compound (BX) retarded subsequent conditioning to another compound (AX). However, after eight presentations of BX, conditioning to AX occurred at the same rate as with no preexposure. These results indicate that generalization of LI decreased as the length of preexposure to BX increased. Experiment 2 replicated this effect of reducing generalization, as well as demonstrating that LI actually increased as the length of preexposure to AX increased. Experiment 3 extended the generality of the effect to a procedure in which both BX and AX were preexposed. Experiment 4 demonstrated a similar reducing-generalization effect when generalization of LI from BX to X was assessed. All of these data are consistent with the notion that prolonged preexposure to BX enhances its discriminability. Different learning mechanisms that might be responsible for this perceptual learning effect are discussed. PMID- 21298377 TI - Expression of p53, Ki-67 and c-Myc proteins is predictive of the surgical molecular margin in colorectal carcinoma. AB - Surgical resection is the mainstay of treatment for colorectal carcinoma, however, the overall survival is modest due to frequent local recurrence from residual cancer cells after "curative" resection. Therefore, the status of surgical margin (tumor free or positive) has a significant influence on patient's survival. The difference in molecular profile between mucosa neighboring tumor lesions and remote area (surgical margin) may aid in evaluating resection status. 44 colorectal tumor tissues with corresponding adjacent non-neoplastic mucosa (within 3 cm from tumor tissues), and 110 tumor tissues with corresponding surgical margin mucosa (5 cm from tumor tissues) were randomly collected, fixed in 10% formalin and followed by embedding in paraffin. And the expression of p53, Ki-67 and c-Myc were investigated by tissue microarray (TMA) and immunohistochmistry. The expression of p53, Ki-67 and c-Myc were decreased in both adjacent non-neoplastic mucosa and mucosa of surgical margin, comparing to their expression in corresponding cancer cells. Furthermore, the expression of these proteins in mucosa of remote area (surgical margin) was significantly lower than those adjacent to tumor lesions. The expression of p53, Ki-67 and c-Myc in mucosa can be used as molecular marker for assessing surgical margin status in colorectal carcinoma. PMID- 21298380 TI - Molecular genetic models related to schizophrenia and psychotic illness: heuristics and challenges. AB - Schizophrenia is a heritable disorder that may involve several common genes of small effect and/or rare copy number variation, with phenotypic heterogeneity across patients. Furthermore, any boundaries vis-a-vis other psychotic disorders are far from clear. Consequently, identification of informative animal models for this disorder, which typically relate to pharmacological and putative pathophysiological processes of uncertain validity, faces considerable challenges. In juxtaposition, the majority of mutant models for schizophrenia relate to the functional roles of a diverse set of genes associated with risk for the disorder or with such putative pathophysiological processes. This chapter seeks to outline the evidence from phenotypic studies in mutant models related to schizophrenia. These have commonly assessed the degree to which mutation of a schizophrenia-related gene is associated with the expression of several aspects of the schizophrenia phenotype or more circumscribed, schizophrenia-related endophenotypes; typically, they place specific emphasis on positive and negative symptoms and cognitive deficits, and extend to structural and other pathological features. We first consider the primary technological approaches to the generation of such mutants, to include their relative merits and demerits, and then highlight the diverse phenotypic approaches that have been developed for their assessment. The chapter then considers the application of mutant phenotypes to study pathobiological and pharmacological mechanisms thought to be relevant for schizophrenia, particularly in terms of dopaminergic and glutamatergic dysfunction, and to an increasing range of candidate susceptibility genes and copy number variants. Finally, we discuss several pertinent issues and challenges within the field which relate to both phenotypic evaluation and a growing appreciation of the functional genomics of schizophrenia and the involvement of gene * environment interactions. PMID- 21298381 TI - Mouse mutagenesis and disease models for neuropsychiatric disorders. AB - In this chapter, mutant mouse resources which have been developed by classical genetics as well as by modern large-scale mutagenesis projects are summarized. Various spontaneous and induced mouse mutations have been archived since the rediscovery of Mendel's genetics in 1900. Moreover, genome-wide, large-scale mutagenesis efforts have recently been expanding the available mutant mouse resources. Forward genetics projects using ENU mutagenesis in the mouse were started in the mid-1990s. The widespread adoption of reverse genetics, using knockouts and conditional mutagenesis based on gene-targeting technology, followed. ENU mutagenesis has now evolved to provide a further resource for reverse genetics, with multiple point mutations in a single gene and this new approach is described. Researchers now have various options to obtain mutant mice: point mutations, transgenic mouse strains, and constitutional or conditional knockout mice. The established mutant strains have already contributed to modeling human diseases by elucidating the underlying molecular mechanisms as well as by providing preclinical applications. Examples of mutant mice, focusing on neurological and behavioral models for human diseases, are reviewed. Human diseases caused by a single gene or a small number of major genes have been well modeled by corresponding mutant mice. Current evidence suggests that quantitative traits based on polygenes are likely to be associated with a range of psychiatric diseases, and these are now coming within the range of modeling by mouse mutagenesis. PMID- 21298382 TI - Histopathologic evaluation of patent ductus arteriosus stents after hybrid stage I palliation. AB - The aim of this study was to determine the histopathology of patent ductus arteriosus (PDA) in-stent stenosis after hybrid stage I palliation. The hybrid approach to palliation of hypoplastic left heart syndrome can be complicated by the development of in-stent stenosis of the PDA. This may obstruct retrograde aortic arch flow, decrease systemic circulation, and lead to interstage interventional procedures. Stented PDA samples removed from eight patients undergoing comprehensive stage II repair were examined by way of radiography and histochemistry (hematoxylin and eosin, Movat pentachrome, alpha-smooth muscle actin, and proliferating cell nuclear antigen). A retrospective chart review of the patients was also performed. PDA stents were in place in the PDA for a mean period of 169 +/- 28 days in patients who had a mean age of 176 +/- 30 days at the time of stent removal. Stent deployment caused chronic inflammation, caused fibrin deposition, and induced vascular smooth muscle-cell (VSMC) proliferation in the area immediately surrounding the stent struts. The neointimal region was composed largely of smooth muscle cells that appeared to be fully differentiated by the lack of PCNA staining. Neointimal thickening occurs in the PDA after stent placement for hybrid palliation of HLHS and is the result of inflammation, extracellular matrix deposition, and smooth muscle-cell proliferation in the peristrut region. This finding suggests that proliferating VSMCs in the peristrut region may provide the impetus for inward neointimal formation and therefore the manifestation of in-stent stenosis. PMID- 21298383 TI - SCH 1473759, a novel Aurora inhibitor, demonstrates enhanced anti-tumor activity in combination with taxanes and KSP inhibitors. AB - PURPOSE: Aurora kinases are required for orderly progression of cells through mitosis, and inhibition of these kinases by siRNA or small molecule inhibitors results in cell death. We previously reported the synthesis of SCH 1473759, a novel sub-nanomolar Aurora A/B inhibitor. METHODS: We utilized SCH 1473759 and a panel of tumor cell lines and xenograft models to gain knowledge about optimal dosing schedule and chemotherapeutic combinations for Aurora A/B inhibitors. RESULTS: SCH 1473759 was active against a large panel of tumor cell lines from different tissue origin and genetic backgrounds. Asynchronous cells required 24-h exposure to SCH 1473759 for maximal induction of >4 N DNA content and inhibition of cell growth. However, following taxane- or KSP inhibitor-induced mitotic arrest, less than 4-h exposure induced >4 N DNA content. This finding correlated with the ability of SCH 1473759 to accelerate exit from mitosis in response to taxane- and KSP inhibitor-induced arrest. We tested various dosing schedules in vivo and demonstrated SCH 1473759 dose- and schedule-dependent anti-tumor activity in four human tumor xenograft models. Further, the efficacy was enhanced in combination with taxanes and found to be most efficacious when SCH 1473759 was dosed 12-h post-taxane treatment. CONCLUSIONS: SCH 1473759 demonstrated potent mechanism-based activity, and activity was shown to be enhanced in combination with taxanes and KSP inhibitors. This information may be useful for optimizing the clinical efficacy of Aurora inhibitors. PMID- 21298384 TI - Different relation between ERCC1 overexpression and treatment outcomes of two platinum agents in advanced biliary tract adenocarcinoma patients. AB - PURPOSE: The aim of this study is to evaluate the effect of excision repair cross complementation group 1 (ERCC1) expression on treatment outcomes in advanced biliary tract adenocarcinoma (ABTA) patients treated with platinum-based chemotherapy. METHODS: One hundred and six patients with histologically confirmed adenocarcinoma of biliary tract were enrolled at 5 institutions in South Korea between January 2002 and September 2008. Of 106 patients, 93 were assessed by immunohistochemistry from tissue specimens. Sixty-five patients were treated with cisplatin-based regimens and the other 28 treated with oxaliplatin-based ones. RESULTS: For total study population, no significant differences were noted in progression-free survival (PFS) and overall survival (OS) between ERCC1-negative and ERCC1-positive patients, respectively (4.2 vs. 2.9 months, p = 0.116; 7.0 vs. 7.8 months, p = 0.143). In patients treated with cisplatin-based regimens, median PFS and OS were significantly longer in ERCC1-negative group than in ERCC1 positive group, respectively (4.6 vs. 1.9 months, p = 0.014; 9.1 vs. 7.9 months, p = 0.017). Disease control rate (DCR) was better in patients with ERCC1 negative than in patients with ERCC1 positive (p = 0.048). On the other hand, in patients treated with oxaliplatin-containing regimens, median PFS and OS tended to be longer in ERCC1-positive group, but these did not reach statistical significances. Response rate was better in patients with ERCC1 positive (p = 0.005). CONCLUSIONS: ERCC1 shows a significant prognostic value in ABTA patients treated with cisplatin. A survival benefit was observed in ERCC1-negative patients from cisplatin-containing chemotherapy but not from oxaliplatin containing ones. The action mechanism of ERCC1 on cisplatin may be different from that on oxaliplatin. PMID- 21298386 TI - Long-term results of palatal implants for obstructive sleep apnea. AB - Successful results of palatal implants in the treatment of obstructive sleep apnea (OSA) have been reported in the short term; however, there are limited data in the long-term results. The aim of this study was to evaluate the long-term results and to determine factors that predicted the responders in patients undergoing palatal implants in the treatment of OSA. A study was undertaken on 92 OSA patients. Palatal implants were conducted to stiffen the soft palate and data were analyzed. Patients tolerated the procedure well. They were examined between 26 and 32 months after the operation (mean 28.9 +/- 4.8). Age range was 25-65 years (38.4 +/- 10.5) and BMI was 27.3 +/- 2.4 kg/m. The mean preoperative ESS score was 12.3 +/- 2.6 and long-term ESS was 7.9 +/- 1.8 (p < 0.001). The mean VAS for snoring in the baseline was 8.2 +/- 1.2 and long-term VAS was 3.8 +/- 2.3 (p < 0.001). The mean preoperative LSAT and long-term LSAT were 87.4 +/- 6.7 and 89.2 +/- 4.8%, respectively (p < 0.01). The mean AHI decreased from 21.7 +/- 6.8 to 10.8 +/- 4.8 (p < 0.001). Forty-eight (52.2%) patients had long-term surgical response. Responders had significantly lower preoperative BMI, AHI, and MMP level than non-responders. Implant extrusion occurred in seven patients (7.6%) and palatal abscess in one patient (1.1%). Bleeding and airway obstruction were not encountered. Palatal implants in carefully selected patients suffering from mild OSA, give fairly good long-term results and have a low complication rate. PMID- 21298385 TI - Ultrasound-evoked immediate early gene expression in the brainstem of the Chinese torrent frog, Odorrana tormota. AB - The concave-eared torrent frog, Odorrana tormota, has evolved the extraordinary ability to communicate ultrasonically (i.e., using frequencies > 20 kHz), and electrophysiological experiments have demonstrated that neurons in the frog's midbrain (torus semicircularis) respond to frequencies up to 34 kHz. However, at this time, it is unclear which region(s) of the torus and what other brainstem nuclei are involved in the detection of ultrasound. To gain insight into the anatomical substrate of ultrasound detection, we mapped expression of the activity-dependent gene, egr-1, in the brain in response to a full-spectrum mating call, a filtered, ultrasound-only call, and no sound. We found that the ultrasound-only call elicited egr-1 expression in the superior olivary and principal nucleus of the torus semicircularis. In sampled areas of the principal nucleus, the ultrasound-only call tended to evoke higher egr-1 expression than the full-spectrum call and, in the center of the nucleus, induced significantly higher egr-1 levels than the no-sound control. In the superior olivary nucleus, the full-spectrum and ultrasound-only calls evoked similar levels of expression that were significantly greater than the control, and egr-1 induction in the laminar nucleus showed no evidence of acoustic modulation. These data suggest that the sampled areas of the principal nucleus are among the regions sensitive to ultrasound in this species. PMID- 21298387 TI - Transoral removal of hiloparenchymal submandibular calculi: a long-term clinical experience. AB - Traditional management of hiloparenchymal submandibular calculi is based on sialadenectomy. Recently, different minimally invasive and conservative techniques have been developed for the treatment of the submandibular calculi. We aimed to investigate the effectiveness of transoral surgical removal of large hiloparenchymal calculi by monitoring the trend for recurrence with clinical and ultrasonographic follow-up. A consecutive series of 84 patients with large (>7 mm) hilar or hiloparenchymal submandibular calculi underwent the transoral surgical removal under general anaesthesia. A video-assisted endoscopic procedure was performed in eight patients. All the patients underwent diagnostic ultrasonography and colour Doppler ultrasonography and clinical evaluation to define the exact location (hilar vs. parenchymal) and the diameter of the stone. The surgical procedure was successful in all but one of the patients. Stone recurrence was observed in 16 patients but obstructive symptoms were observed in only 12 patients during a median follow-up time of 52 months. The risk for recurrence was higher in patients who previously underwent extracorporeal shockwave lithotripsy. Conservative transoral removal of large hiloparenchymal submandibular calculi is a safe and effective surgical procedure. Future studies with longer follow-up will confirm the risk for recurrence of calculi. PMID- 21298388 TI - Incidental diagnosis of mastoiditis on MRI. AB - The aim of this study was to document patients with clinical mastoiditis who were reported to have mastoiditis by radiologists due to increased fluid signal intensity in the mastoid air cells on magnetic resonance imaging (MRI). Brain and temporal bone MRI reports between January 2004 and November 2009 were obtained from the radiology units of four different hospitals of the same Health Care Group. MRI reports for keyword mastoiditis and 406 patients were reported to have radiological mastoiditis on MRI due to increased fluid signal intensity. Otoscopic examination findings of 275 of these 406 radiological mastoiditis patients were documented and compared with MRI reports for clinical infectious otological disease. Forty-eight (17, 45%) (48/275) patients were found to have clinical otological disease on examination. The remainder of the patients (227/275, 82%) did not show any evidence of clinical otologic infectious disease. Of these 48 patients, 18 patients (37, 5%) had eustachian tube dysfunction, 13 patients (27%) had serous otitis media, nine patients (9%) had chronic otitis media, five patients (10%) had tympanosclerosis, and three patients (6%) had acute otitis media. The results of this study showed that MRI is not an effective diagnostic tool for mastoiditis. 82% of the MRI mastoiditis did not show clinical mastoiditis contradicting MRI reports. Fluid signal in the mastoid on MRI should not always be interpreted as mastoiditis by radiologists. Radiological mastoiditis does not necessarily point out to clinical mastoiditis. PMID- 21298390 TI - Anatomical and surgical aspects of the lobes of the thyroid glands. AB - Variation in the descent of the thyroid gland and during fetal life and regression of the thyroglossal duct is associated with many variations in form of the mature gland. The shape and morphometric details of gland, its extension as the pyramidal lobe (PYR-L) and attachments of the levator glandulae thyroidea were studied in 40 cadavers. We categorized the shape of the thyroid into 12 types. The most frequent type was PYR-L with 22.5% which started from the left lobe and moved across by intercrossing the larynx. Horseshoe-shaped gland and the gland with separate lobes were the most frequently observed glandular shapes, with 17.5 and 20%, respectively. The incidences of the PYR-L and the levator glandulae thyroideae were 60 and 17.5%, respectively. The pyramidal lobe branched off more frequently from the left part of the isthmus (14 specimens) than from the right (5 specimens) or the midline (2 cases). Knowledge about the glandular landmarks and anatomic measurements around the thyroid will be helpful for the surgeon to constitute a simplification of the topographic anatomy, plan and decide on a safe approach to the thyroid gland, and to avoid postoperative complications. PMID- 21298389 TI - Paranasal ossifying fibroma: endoscopic resection or wait and scan? AB - The ossifying fibroma is a fibro-osseous lesion that rarely occurs in the paranasal sinuses. Due to its tendency to behave locally aggressively, complete resection is generally recommended. A subdivision into the aggressive juvenile ossifying fibroma (JOF) and the less aggressive cemento-ossifying fibroma of the adult (COF) is clinically reasonable. The objective of the study was to retrospectively analyze the management and follow-up of the patients diagnosed with ossifying fibroma at our ENT-department from 2006 to 2010. A total of five patients were included, thereby comprising one of the largest case series of paranasal ossifying fibromas. In three patients an exclusively endoscopically controlled resection was performed. Two patients with asymptomatic COF declined surgery. Within the 2-year follow-up, no progression was detected. While the JOF should always be surgically treated, for the asymptomatic paranasal ossifying fibroma of the adult (COF) a wait-and-scan strategy, similar to that recommended for osteomas or fibrous dysplasia, could be an option in selected cases. PMID- 21298393 TI - Pulp-seed attachment is a dominant variable explaining legitimate seed dispersal: a case study on woolly monkeys. AB - Seed dispersal is a mutualistic interaction in which frugivores gain nutrients and plants gain when seeds are transported to adequate places for establishment. However, this relationship is prone to deceit, for example, when frugivores spit out seeds in the proximity of parental trees. Still, few hypotheses have offered explanations on why deceiving strategies are not widespread. In this study, I explore the importance of how difficult it is to mechanically separate the nutritious pulp from the seeds, as a factor that can explain the chance a seed has of being dispersed by woolly monkeys (Lagothrix lagothricha). I completed 1,440 h of focal animal follows during 2 years in order to quantify the chances plant species have of being dispersed. To do so, I evaluated the residuals from the relationship between the number of seeds manipulated and seeds dispersed by a population of woolly monkeys in Tinigua Park (Colombia). For 74 fruit species, I estimated how difficult it is to separate pulp from seeds as the time needed to separate the parts. An exponential model showed that this variable was able to predict 38% of the variation on dispersal probability, demonstrating that, when it is difficult to separate the pulp from the seeds, the probability of legitimate dispersal increases. However, when fruit parts were easy to separate, there was more variation in the outcome. My results suggest that many plants have evolved mechanisms (e.g., small seeds embedded in pulp, strong attachment, irregular seed surface, and thin pulp layer) that preclude deceit by frugivores. PMID- 21298395 TI - Pseudogout of the acromioclavicular joint: report of two cases and review of the literature. AB - Although calcium pyrophosphate dehydrate (CPPD) deposition disease, including pseudogout, is a relatively common disease affecting the major joints, especially the knee, pseudogout in the acromioclavicular (AC) joint is very uncommon. We describe two cases of acute pseudogout attacks of the AC joint in elderly patients. Radiological findings showed chondrocalcinosis in the AC joints. Microscopically, aspirated articular synovial fluid demonstrated CPPD crystals. Conservative therapy with non-steroidal anti-inflammatory drugs completely resolved all symptoms within 1 week. PMID- 21298398 TI - Why not the University of New Orleans? Social disorganization and sexual violence among internally displaced women of Hurricane Katrina. AB - Researchers have reported that natural disasters lead to an increase in sexual violence against women and this is echoed by the current situation in Haiti. This is a social pattern throughout the world during periods of war, as well as natural disasters such as tsunamis, famine, and hurricanes. This article examines the prevalence of sexual violence experienced by women students at the University of New Orleans (UNO) before and after Hurricane Katrina using the CORE Alcohol and Drug Survey. Two hundred and thirty seven women participated in the pre Katrina study and 215 women participated in the post-Katrina study. We hypothesized that, due to the trauma of this disaster, there would be a higher prevalence of sexual aggression against women after Katrina than there was before Katrina. Our analyses yielded no significant differences in any of the measures of sexual violence toward women (nine CORE survey items) pre to post Katrina, so our hypothesis was not supported. We suggest that social organization and cultural attenuation--often indicators of sexual assault in FEMA Greenfield communities--were mitigated by social cohesion found on the UNO campus post Katrina. PMID- 21298392 TI - Evaluation of the early phase of Bell's palsy using 3 T MRI. AB - This prospective study on Bell's palsy investigated the value of 3 T MRI as a diagnostic tool to evaluate pathophysiological changes (i.e. edema) of facial nerve segments and the possibility to differentiate patients with high risk for incomplete recovery from patients who recover completely within 3 days after symptoms onset. For this institutional review board approved investigation, thirty patients (14 male, 16 female, mean age 44 years) with Bell's palsy underwent pre and postcontrast 3 T MRI of the cerebellopontine angle. T1-weighted imaging was performed (TR 20.0 ms, TE 2.46 ms, isotropic voxel size: 0.6 mm). Region-of-interest measurements were performed on the healthy and paralyzed side. To obtain normalized values, signal intensity increase percentage (SIIP) values were divided by contralateral results of the healthy side. Signal intensity measurements of examined nerve segments were compared using Wilcoxon and Mann Whitney U tests and correlated to clinical findings categorized by the House Brackmann score. The lesion side showed significantly higher signal intensities in the premeatal segment before and after contrast agent administration (P < 0.001). SIIP was highest in the premeatal segment compared to the geniculate ganglion (P < 0.001). Correlation analyses revealed no association between signal intensity measurements, clinical findings or early recovery rates after 3 months (P > 0.05). According to our results, early palsy-associated pathophysiological changes in the facial nerve premeatal segment might also be related to accumulation of proteins and not exclusively to edema. However, contrast agent enhancement quantification was not suitable as a diagnostic tool to distinguish different prognostic groups. PMID- 21298391 TI - Clinical characteristics of granular myringitis treated with castellani solution. AB - Aim of the study is to observe clinical manifestations of granular myringitis (GM) treated with castellani solution. Twenty-four patients (18 women and 6 men; mean age, 49.7 years; range, 9-77 years) diagnosed with GM and treated with castellani solution were enrolled retrospectively. Topical treatment using castellani solution with or without curettage of a granular lesion and serial otoendoscopy-aided photographic documentation of the tympanic membrane were performed. Outpatient follow-up period ranged from 3 to 72 months and the mean follow-up period was 14.4 months. GM was classified into marginal/non-marginal type and ulcerative/polypoid subtype using a new scale. According to the scale used in this study, the marginal and ulcerative GM was the predominant type of GM lesion. Bacterial cultures of ear discharges from 19 patients revealed Staphylococcus, Corynebacterium and Providencia stuartii in 12, 5, and 1 patient, respectively and no growth of bacteria in one patient. Of 24 patients, 23 showed complete resolution of GM after treatment with castellani solution. However, one patient had a persistent, small, dry, deepithelialized lesion and eight others required more than 3 months for complete recovery owing to a persistent residual lesion. There was recurrence in two patients but the lesion resolved after additional castellani treatment. Topical application of castellani solution is a simple and effective treatment for GM. This study suggests a potential of castellani solution for treatment of GM with a serial photographic documentation and novel classification scale for description of lesions. A sufficiently long follow-up period is essential to confirm a complete recovery of GM. PMID- 21298399 TI - Sheriffs perceptions of firearm control polices. AB - Public health professionals can maximize their effectiveness in reducing firearm trauma by seeking partners from law enforcement professionals. This study assessed sheriff's support for various types of firearm control measures and their firearm control advocacy activities. A 29 item valid and reliable survey was used for a three- wave mailing to a national random sample of 650 sheriffs. The majority (over 50%) of sheriffs supported 4 of 14 proposed firearm control policies. Almost 55% of responding sheriffs were members of the NRA and being a member of the NRA was significantly associated with less support for 12 of the 14 firearm control policies. The majority (>70%) of sheriffs did not participate in most firearm control advocacy activities. Sheriffs were found to be far less supportive of potentially important firearm control policies than what has been previously found for police chiefs. Thus, sheriffs may be less helpful than police chiefs as colleagues for public health campaigns to reduce firearm trauma. PMID- 21298394 TI - Gene cloning and protein expression of gamma-glutamyltranspeptidases from Thermus thermophilus and Deinococcus radiodurans: comparison of molecular and structural properties with mesophilic counterparts. AB - gamma-Glutamyltranspeptidase (gamma-GT) is an ubiquitous enzyme that catalyzes the hydrolysis of gamma-glutamyl bonds in glutathione and glutamine and the transfer of the released gamma-glutamyl group to amino acids or short peptides. gamma-GTs from extremophiles, bacteria adapted to live in hostile environments, were selected as model systems to study the molecular underpinnings of their adaptation to extreme conditions and to find out special properties of potential biotechnological interest. Here, we report the cloning, expression and purification of two members of gamma-GT family from two different extremophilic species, Thermus thermophilus (TtGT) and Deinococcus radiodurans (DrGT); the first is an aerobic eubacterium, growing at high temperatures (50-82 degrees C), the second is a polyextremophile, as it tolerates radiations, cold, dehydration, vacuum, and acid. TtGT and DrGT were both synthesized as precursor proteins of 59 60 kDa, undergoing an intramolecular auto-cleavage to yield two subunits of 40 and 19-20 kDa, respectively. However, like the gamma-GT from Geobacillus thermodenitrificans, but differently from the other characterized bacterial and eukaryotic gamma-GTs, the two new extremophilic enzymes displayed gamma-glutamyl hydrolase, but not transpeptidase activity in the 37-50 degrees C temperature range, pH 8.0. The comparison of sequences and structural models of these two proteins with experimental-determined structures of other known mesophilic gamma GTs suggests that the extremophilic members of this protein family have found a common strategy to adapt to different hostile environments. Moreover, a phylogenetic analysis suggests that gamma-GTs displaying only gamma-glutamyl hydrolase activity could represent the progenitors of the bacterial and eukaryotic counterparts. PMID- 21298396 TI - Differential gene expression in Arachis diogoi upon interaction with peanut late leaf spot pathogen, Phaeoisariopsis personata and characterization of a pathogen induced cyclophilin. AB - The wild relatives of peanut are resistant to various economically important diseases including late leaf spot (LLS) caused by Phaeoisariopsis personata, compared with the susceptible cultivated peanut (Arachis hypogaea L.). The interaction of the late leaf spot pathogen, Phaeoisariopsis personata and the highly resistant, diploid peanut wild species, Arachis diogoi was analyzed at the molecular level by differential gene expression studies. Genes up-regulated with in 48 h of pathogen challenge were isolated as partial cDNAs. Some of the isolated genes, which are shown to be involved in the first line of defense in plants, were further characterized with respect to their transcriptional regulation in response to pathogen. Among the isolated clones, two were found to encode cyclophilin like proteins. One of the two isolated partial cDNAs encoding cyclophilin like proteins was extended using 5' RACE. The full length cDNA, designated as AdCyp, was 886 bp in length and encodes a polypeptide of 172 amino acids. Southern hybridization suggests that AdCyp is possibly coded by a single gene and at least one more identical gene is present in Arachis diogoi genome. AdCyp exhibits evolutionary conservation across the kingdoms. Phylogenetic analysis showed that AdCyp belongs to the subgroup I of Group I in cyclophilins. A translational fusion of GFP-AdCyp was found to localize to both cytosol and nucleus. AdCyp transcripts were found to accumulate in response to the treatments with pathogen as well as phytohormones. Constitutive heterologous expression of AdCyp resulted in enhanced resistance to Ralstonia solanacearum and reduced susceptibility towards Phytophthora parasitica var. nicotianae in transgenic tobacco and the resistance was associated with higher transcript levels of various defense related genes. PMID- 21298402 TI - Trace metals and radionuclides in macroalgae from Moroccan coastal waters. AB - Macroalgae species Codium sp, Bangia atropurpurea, Membranoptera alata, Plocamium cartilagineum, Dictyota dichotoma, Fucus spiralis and Stypocaulon scoparia were collected from seven stations along the north coast of Morocco. Samples were analysed to determine activities of naturally occurring radionuclides ((210)Pb, U isotopes and (40)K) and concentrations of metals (Zn, Fe, Co, Cu, Ni, Mn, Pb, Cd, As and Cr) using radiometric and ICP-OES techniques, respectively. Metal concentrations were within ranges reported in the scientific literature, and concentrations of bio-essential elements were in the order Mn>Fe> Zn>Cu in all samples. Brown algae had the highest concentrations of almost all metals, and concentrations decreased in the order brown>red>green algae. With respect to radionuclides, the red alga P. cartilagineum had the highest activities of (210)Pb, in most cases an order of magnitude higher than for the green alga Codium sp. (234)U and (238)U activities in all algae samples were in the range 0.96- 7.61 and 1.16-6.14 Bq/kg dry weight, respectively. Our analyses of radionuclide activities and metal concentrations in marine macroalgae showed large differences among taxa. These results provide insights into which algal species should be used for biomonitoring programmes. PMID- 21298400 TI - Mujeres en accion: design and baseline data. AB - The majority of programs designed to promote physical activity in older Hispanic women includes few innovative theory-based interventions that address cultural relevant strategies. The purpose of this report is to describe the design and baseline data for Mujeres en Accion, a physical activity intervention to increase regular physical activity, and cardiovascular health outcomes among older Hispanic women. Mujeres en Accion [Women in Action for Health], a 12 month randomized controlled trial to evaluate the effectiveness of a social support physical activity intervention in midlife and older Hispanic women. This study tests an innovative intervention, Mujeres en Accion, and includes the use of a theory-driven approach to intervention, explores social support as a theoretical mediating variable, use of a Promotora model and a Community Advisory group to incorporate cultural and social approaches and resources, and use of objective measures of physical activity in Hispanic women. PMID- 21298397 TI - Cis-cinnamic acid-enhanced 1 gene plays a role in regulation of Arabidopsis bolting. AB - Cis-cinnamic acid (CA) is one of many cis-phenylpropanoids found in both monocots and dicots. It is produced in planta via sunlight-mediated isomerization of trans cinnamic acid. This pair of isomers plays a differential role in regulation of plant growth. A functional proteomics approach has been adopted to identify genes of cis/trans-CA mixture-enhanced expression. Out of 1,241 proteins identified by mass spectrometry, 32 were CA-enhanced and 13 repressed. Further analysis with the molecular biology approach revealed 2 cis-CA (Z usammen-CA)-E nhanced genes, named ZCE1 and ZCE2, which encode members of the major latex protein-like (MLPL) gene family. The transcript accumulation of both genes is positively correlated with the amount of cis-CA applied externally, ranging from 1 to 100 MUM. ZCE1 transcript accumulation is enhanced largely by cis-CA and slightly by other cis phenylpropanoids. Treatment of several well-characterized plant growth regulator perception-deficient mutants with cis-CA is able to promote ZCE1 transcript accumulation, suggestive of distinct signaling pathways regulating cis-CA response. The zce1 loss-of-function mutant produced via the RNA-interference technique produces an earlier bolting phenotype in Arabidopsis, suggesting that ZCE1 plays a role in promoting vegetative growth and delay flowering. PMID- 21298403 TI - Evidence and the end of medicine. AB - Fifty years ago, in 1961, Feinstein published his first path-breaking articles leading to his seminal work Clinical Judgement and to the establishment of clinical epidemiology. Feinstein had an Aristotelian approach to scientific method: methods must be adapted to the material examined. Feinstein died 10 years ago and few years before his death he concluded that efforts to promote a person oriented medicine had failed. He criticised medicine for not having recognized that only persons can suitably observe, evaluate and rate their own health status. Feinstein's position was-as in Clinical Judgement-methodological. He didn't espouse ethical principles. He pointed to methodological deficiencies in clinical epidemiology and evidence-based medicine. In this article we'll provide a framework for understanding and justifying Feinstein's call for a person oriented medicine which recognizes patients as co-actors in clinical reasoning. It's argued that craftsmanship and practical wisdom are integrated in clinical judgement and reasoning and that clinical reasoning is not only about means to achieve the end, health. We do also reason and deliberate about ends. The 'defining end' of medicine (health) has continuously been negotiated and so been the object of deliberation. For centuries among professionals, in recent years among professionals and patients. These negotiations and deliberations lead to ongoing specifications of health as a 'guiding end', i.e. an end guiding clinical reasoning about what to do in particular situations. Feinstein's self-critical account to clinical epidemiology at the end of his professional career reflects the fact that patients during the last 30-40 years (i.e. in the period after the publication of Clinical Judgement) widely have been recognized as persons with rights to autonomy. Feinstein's lesson is, however, that espousing and recognizing ethical ideals is not enough. A change of clinical practice and its methods is necessary. His critique also implies that clinical epidemiology and evidence-based medicine as practiced haven't provided such a turn. PMID- 21298401 TI - Implementing a Smoke-free Campus: a Medical Center initiative. AB - A large 2-campus Medical Center in Western New York, along with several other large area hospitals, planned for and simultaneously implemented successful "Smoke-Free Campus" initiatives in November of 2006. This coordinated initiative required that each system plan accordingly for the development and implementation of policies, training of employees, clinicians, support staff and provision of tobacco treatment services (directly or via referral). In order to efficiently and competently inform each of these aspects of a system-wide initiative, accurate information was needed on the prevalence of tobacco use among employees, staff, faculty, and clinicians in each system. A multi-system surveillance initiative was implemented, using a brief survey for all employees of several of the partnering institutions. Summary data from the baseline measures are discussed. Also presented are Lessons Learned from the year-long planning and implementation phases, including details on topics categorized by the specific sub-committees that coordinated each area (e.g., Policy and Procedure, Communication, Faculty/Staff/Student Issues, Patient Issues (Inpatient and Outpatient), Tobacco Dependence Treatment and Provider/Staff Training). The effort was effective in instituting system-wide changes in all of the participating hospitals in the greater metropolitan area. A community-wide consortium convened each month for a year, and subcommittees within each hospital allowed planners to break up the initiative into manageable pieces. The extended timeline of 1 year was appropriate for overcoming fears, biases, and barriers which then enabled "buy-in" and support from leadership as well as employees. PMID- 21298404 TI - Super-resolution variable-dose imaging in digital radiography: quality and dose reduction with a fluoroscopic flat-panel detector. AB - PURPOSE: Super-resolution (SR) image processing produces a high-resolution image from a series of low-resolution images. The aim of this study was to evaluate SR images based on fluoroscopic flat-detector (FD) acquisition at different frame rates. METHODS: Fluoroscopic FD-sequences with 20 frames were obtained with varying pulse frequencies of (1) a line pair resolution phantom; (2) a low contrast resolution phantom, and (3) a human knee specimen. Super-resolution digital radiographs (SR-Radiographs) were generated from each sequence. Variable dose images were simulated by constructing SR-Radiographs using 6 and 12 frames from the corresponding fluoroscopic sequence. "Single Shot" and Computed Radiography (CR) images were obtained for comparison based on dynamic range and sharpness of bone detail structures. Patient-derived SR-Radiographic images were constructed to demonstrate clinical examples. RESULTS: The spatial resolution of SR-radiographs obtained at 12.5 frames per second (fps) and 6 fps were comparable with CR and "Single Shot" images, providing ~3.5 line pairs per mm (l p/mm). Similarly, low-contrast resolution of SR-radiographs obtained at 12.5, 6, and 30 fps were equivalent to CR and "Single Shot" images. The human knee specimen SR radiograph obtained using 12 FD images at 12.5 fps was superior to a CR image in overall image quality, with a dose reduction of 75%. Variable-dose SR radiographic simulations suggest a dose saving potential of 90-95% when using 6 FD images at 12.5 fps or 6 fps, respectively. CONCLUSIONS: The phantom testing images and simulation results demonstrate that diagnostic quality SR-radiographic images of skeletal extremities can be synthesized using a flat-panel detector system designed primarily for angiography. SR-images obtained with substantially reduced radiation dose are feasible, and this technology may improve digital radiography for pediatric, neonatal radiography, or mammography applications. Further testing is needed to validate super-resolution techniques in other body regions and for different flat-detector systems. PMID- 21298405 TI - Endothelial cells in co-culture enhance embryonic stem cell differentiation to pancreatic progenitors and insulin-producing cells through BMP signaling. AB - Endothelial cells (ECs) represent the major component of the embryonic pancreatic niche and play a key role in the differentiation of insulin-producing beta cells in vivo. However, it is unknown if ECs promote such differentiation in vitro. We investigated whether interaction of ECs with mouse embryoid bodies (EBs) in culture promotes differentiation of pancreatic progenitors and insulin-producing cells and the mechanisms involved. We developed a co-culture system of mouse EBs and human microvascular ECs (HMECs). An increase in the expression of the pancreatic markers PDX-1, Ngn3, Nkx6.1, proinsulin, GLUT-2, and Ptf1a was observed at the interface between EBs and ECs (EB-EC). No expression of these markers was found at the periphery of EBs cultured without ECs or those co cultured with mouse embryonic fibroblasts (MEFs). At EB-EC interface, proinsulin and Nkx6.1 positive cells co-expressed phospho-Smad1/5/8 (pSmad1/5/8). Therefore, EBs were treated with HMEC conditioned media (HMEC-CM) suspecting soluble factors involved in bone morphogenetic protein (BMP) pathway activation. Upregulation of PDX-1, Ngn3, Nkx6.1, insulin-1, insulin-2, amylin, SUR1, GKS, and amylase as well as down-regulation of SST were detected in treated EBs. In addition, higher expression of BMP-2/-4 and their receptor (BMPR1A) were also found in these EBs. Recombinant human BMP-2 (rhBMP-2) mimicked the effects of the HMEC-CM on EBs. Noggin (NOG), a BMP antagonist, partially inhibited these effects. These results indicate that the differentiation of EBs to pancreatic progenitors and insulin producing cells can be enhanced by ECs in vitro and that BMP pathway activation is central to this process. PMID- 21298406 TI - Anti-NMDA-Receptor Encephalitis and Other Synaptic Autoimmune Disorders. AB - OPINION STATEMENT: Synaptic autoimmunity may result in a wide variety of symptoms, including catatonia, psychosis, movement disorders, short-term memory deficits, and refractory seizures, so these patients are seen by a wide spectrum of practitioners, who need to be aware of these disorders. In some cases, these disorders occur as a paraneoplastic manifestation of an associated cancer. However, in contrast to the well-known paraneoplastic neurologic disorders of the central nervous system that predominate in older individuals, these novel disorders often affect children and young adults. Additionally, for some syndromes, the presence of a tumor does not necessarily indicate a poor prognosis. Successful treatment of the tumor and immunotherapy often result in recovery, supporting the use of surgery for severely ill patients. In all syndromes, deficits may be reversible despite the duration or severity of symptoms. For example, patients with anti-NMDA-receptor encephalitis who had been in a coma or ventilated for 6-10 months have had full recovery after appropriate treatment. PMID- 21298407 TI - Visual memory and visual perception: when memory improves visual search. AB - This study examined the relationship between memory and perception in order to identify the influence of a memory dimension in perceptual processing. Our aim was to determine whether the variation of typical size between items (i.e., the size in real life) affects visual search. In two experiments, the congruency between typical size difference and perceptual size difference was manipulated in a visual search task. We observed that congruency between the typical and perceptual size differences decreased reaction times in the visual search (Exp. 1), and noncongruency between these two differences increased reaction times in the visual search (Exp. 2). We argue that these results highlight that memory and perception share some resources and reveal the intervention of typical size difference on the computation of the perceptual size difference. PMID- 21298408 TI - Heterocyclization of allenes catalyzed by late transition metals: mechanisms and regioselectivity. AB - Regiocontrolled metal-catalyzed preparations of enantiopure tetrahydrofurans, dihydropyrans, and tetrahydrooxepines have been developed starting from gamma allenols derived from 4-oxoazetidine-2-carbaldehydes and D-glyceraldehyde. Regioselectivity control in the O-C functionalization of gamma-allenols can be achieved through the choice of catalyst, protecting group, or tether. Because of the increasing power and availability of computers, and the simultaneous development of well-tested and reliable theoretical methods, the use of computational chemistry as an adjunct to experimental research has increased rapidly. Computational studies can be carried out to assist in understanding experimental data, such as the exploration of reaction mechanisms that are not readily studied by experimental means. As a consequence, density functional calculations were performed to predict the regioselectivity of the gamma-allenol cycloetherification to the five-, six-, and seven-membered oxacycles on the basis of the tether nature, the presence of a protecting group, and characteristics of the metals, and to gain insight into the mechanism of the oxycyclizations. The interactions between computational and experimental chemistry are often brief. However, it should be desirable to keep this close association for long periods. This chapter must be considered as an interesting symbiotic relationship on the field of organic synthesis using metal (Au, Pd, and Pt) catalysis. PMID- 21298409 TI - Cycloisomerization of 1,n-enynes via carbophilic activation. AB - Metal-catalyzed cycloisomerization of 1,n-enynes has appeared as a highly attractive methodology for the synthesis of original carbo- and heterocycles. This chapter intends to propose an overview of the recent and seminal advances in 1,n-enynes cycloisomerization reactions in the presence of carbophilic transition metals. The recent mechanistic insights, the enantioselective versions, and the applications in total synthesis are highlighted. PMID- 21298410 TI - "Active-latent" thioglycosyl donors and acceptors in oligosaccharide syntheses. AB - The fine tuning of thioglycosides used as glycosyl donors occurs through careful manipulations of the aglycon's nucleofugality, for example, by using "active latent" principles. In the first section, the control of the relative leaving group abilities will be discussed in terms of electronic factors, including electron-donating/withdrawing substituents. In the second section, the nucleofugality will be adjusted by steric factors. Quantitative reactivity relationships will then be documented followed by presentation of other controlling elements including locked conformations, solvents, and promoters that will be illustrated throughout. PMID- 21298411 TI - QTL analysis of root-lesion nematode resistance in barley: 1. Pratylenchus neglectus. AB - The root-lesion nematode Pratylenchus neglectus can cause severe losses in barley cultivation. Multiplication rates had been found to vary greatly between different barley accessions. Two winter barley cultivars, Igri and Franka, had been found to differ in their ability to resist this parasite. An existing Igri * Franka doubled haploid population was chosen to genetically map resistance genes after artificial inoculation with P. neglectus in the greenhouse and climate chamber. A continuous phenotypic variation was found indicating a quantitative inheritance of P. neglectus resistance. An existing map was enriched by 527 newly developed Diversity Array Technology markers (DArTs). The new genetic linkage map was comprised of 857 molecular markers that cover 1,157 cM on seven linkage groups. Using phenotypic data collected from four different experiments in 3 years, five quantitative trait loci were mapped by composite interval mapping on four (3H, 5H, 6H and 7H) linkage groups. A quantitative trait locus with a large phenotypic effect of 16% and likelihood of odds (LOD) score of 6.35 was mapped on linkage group 3H. The remaining four QTLs were classified as minor or moderate with LOD scores ranging from 2.71 to 3.55 and R (2) values ranging from 8 to 10%. The DNA markers linked to the resistance QTLs should be quite useful for marker assisted selection in barley breeding because phenotypic selection is limited due to time constraints and labor costs. PMID- 21298412 TI - The effect of antecedent hypoglycaemia on beta2-adrenergic sensitivity in healthy participants with the Arg16Gly polymorphism of the beta2-adrenergic receptor. AB - AIMS/HYPOTHESIS: Homozygosity for glycine at codon 16 (GlyGly) of the beta(2) adrenergic receptor may alter receptor sensitivity upon chronic stimulation and has been implicated in the pathogenesis of hypoglycaemia unawareness. We compared the effect of antecedent hypoglycaemia on beta(2)-adrenergic receptor sensitivity between GlyGly participants and those with arginine 16 homozygosity (ArgArg) for the beta(2)-adrenergic receptor. METHODS: We enrolled 16 healthy participants, who were either GlyGly (n = 8) or ArgArg (n = 8). They participated randomly in two 2 day experiments. Day 1 consisted of two 2-h hyperinsulinaemic hypoglycaemic (2.8 mmol/l) or euglycaemic (4.8 mmol/l) glucose clamps. On day 2, we measured the forearm vasodilator response to the beta(2)-adrenergic receptor agonist salbutamol and the dose of isoprenaline required to increase the heart rate by 25 bpm (IC(25)). RESULTS: The vasodilator response to salbutamol tended to be greater after antecedent hypoglycaemia than after euglycaemia (p = 0.078), consistent with increased beta(2)-adrenergic receptor sensitivity. This effect was driven by a significant increase in beta(2)-adrenergic receptor sensitivity following hypoglycaemia compared with euglycaemia in ArgArg participants (p = 0.019), whereas no such effect was observed in the GlyGly participants. Antecedent hypoglycaemia tended to decrease the IC(25) in ArgArg participants, whereas the reverse occurred in the GlyGly participants (GlyGly vs ArgArg group p = 0.047). CONCLUSION/INTERPRETATION: Antecedent hypoglycaemia did not affect beta(2)-adrenergic receptor sensitivity in healthy GlyGly participants, but increased it in ArgArg participants. If these results also hold for participants with type 1 diabetes, such an increase in beta(2)-adrenergic receptor sensitivity may potentially reduce the risk of repeated hypoglycaemia and the subsequent development of hypoglycaemia unawareness in ArgArg diabetic participants. TRIAL REGISTRATION: ClinicalTrials.gov NCT00160056. PMID- 21298413 TI - Receptor for advanced glycation end-products (RAGE) provides a link between genetic susceptibility and environmental factors in type 1 diabetes. AB - AIMS/HYPOTHESIS: This group of studies examines human genetic susceptibility conferred by the receptor for advanced glycation end-products (RAGE) in type 1 diabetes and investigates how this may interact with a western environment. METHODS: We analysed the AGER gene, using 13 tag SNPs, in 3,624 Finnish individuals from the FinnDiane study, followed by AGER associations with a high risk HLA genotype (DR3)-DQA1*05-DQB1*02/DRB1*0401-DQB1*0302 (n = 546; HLA DR3/DR4), matched in healthy newborn infants from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study (n = 373) using allelic analysis. We also studied islets and circulating RAGE in NODLt mice. RESULTS: The rs2070600 and rs17493811 polymorphisms predicted increased risk of type 1 diabetes, whereas the rs9469089 SNP was related to decreased risk, on a high risk HLA background. Children from the DIPP study also showed a decline in circulating soluble RAGE levels, at seroconversion to positivity for type 1 diabetes-associated autoantibodies. Islet RAGE and circulating soluble RAGE levels in prediabetic NODLt mice decreased over time and were prevented by the AGE lowering therapy alagebrium chloride. Alagebrium chloride also decreased the incidence of autoimmune diabetes and restored islet RAGE levels. CONCLUSIONS/INTERPRETATION: These studies suggest that inherited AGER gene polymorphisms may confer susceptibility to environmental insults. Declining circulating levels of soluble RAGE, before the development of overt diabetes, may also be predictive of clinical disease in children with high to medium risk HLA II backgrounds and this possibility warrants further investigation in a larger cohort. PMID- 21298414 TI - Leucocytes are a major source of circulating nicotinamide phosphoribosyltransferase (NAMPT)/pre-B cell colony (PBEF)/visfatin linking obesity and inflammation in humans. AB - AIMS/HYPOTHESIS: Nicotinamide phosphoribosyltransferase (NAMPT) is a multifunctional protein potentially involved in obesity and glucose metabolism. We systematically studied the association between circulating NAMPT, obesity, interventions and glucose metabolism and investigated potential underlying inflammatory mechanisms. METHODS: Fasting morning NAMPT serum levels were measured in cohorts of lean vs obese children, cohorts of intervention by lifestyle, exercise and bariatric surgery, and during an OGTT. In addition, mRNA expression, protein production and enzymatic activity of NAMPT were assessed from isolated leucocytes and subpopulations. RESULTS: Circulating NAMPT was significantly elevated in obese compared with lean children and declined after obesity interventions concomitantly with the decline in BMI, high-sensitivity C reactive protein (hsCrP) and leucocyte counts. Circulating NAMPT significantly correlated with glucose metabolism and cardiovascular variables in univariate analyses, but only the association with glucose response during an OGTT was independent from BMI. We therefore assessed the NAMPT dynamic following an oral glucose load and found a significant decline of NAMPT levels to 77.0 +/- 0.1% as a function of time, and insulin-to-glucose ratio during an OGTT in obese insulin resistant adolescents. Circulating NAMPT was, however, most strongly associated with leucocyte counts (r = 0.46, p < 0.001). The leucocyte count itself determined significantly and independently from BMI insulin resistance in multiple regression analyses. We systematically evaluated NAMPT expression among several tissues and found that NAMPT was predominantly expressed in leucocytes. In subsequent analyses of leucocyte subpopulations, we identified higher NAMPT protein concentrations in lysates of granulocytes and monocytes compared with lymphocytes, whereas granulocytes secreted highest amounts of NAMPT protein into cell culture supernatant fractions. We confirmed nicotinamide mononucleotide enzymatic activity of NAMPT in all lysates and supernatant fractions. In monocytes, NAMPT release was significantly stimulated by lipopolysaccharide (LPS) exposure. CONCLUSIONS: Leucocytes are a major source of enzymatically active NAMPT, which may serve as a biomarker or even mediator linking obesity, inflammation and insulin resistance. PMID- 21298415 TI - Electrospray ionization-ion mobility spectrometry as a detection system for three phase hollow fiber microextraction technique and simultaneous determination of trimipramine and desipramine in urine and plasma samples. AB - A novel method based on three-phase hollow fiber microextraction technique (HF LPME) coupled with electrospray ionization-ion mobility spectrometry (ESI-IMS) was developed for the simultaneous determination of two antidepressant drugs (trimipramine and desipramine) in urine and plasma samples. The effects of various parameters such as type of organic solvent, composition of donor and acceptor phase, stirring rate, salt addition, extraction time, and temperature were investigated. Under the optimized conditions, the relative standard deviation was in the range of 5-6%, and the method quantitation limit (MQL) of utilizing HF-LPME/ESI-IMS was 5 MUg/L for both drugs. The relative recoveries obtained by the proposed method from urine and plasma samples were in the range 94% to 97% for trimipramine and 92% to 96% for desipramine. Finally, the feasibility of the proposed method was successfully confirmed by extraction and determination of trace amounts of trimipramine and desipramine in biological samples without any significant matrix effect. PMID- 21298416 TI - MALDI-MS and multivariate analysis for the detection and quantification of different milk species. AB - The extensive consumption of milk and dairy products makes these foodstuffs targets for potential adulteration with financial gains for unscrupulous producers. Such practices must be detected as these can impact negatively on product quality, labelling and even health. Matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-ToF-MS) is a potentially useful technique, with proven abilities in protein identification and more recently through the use of internal standards for quantification purposes of specific proteins or peptides. In the current work, we therefore aim to explore the accuracy and attributes of MALDI-ToF-MS with chemometrics for the detection and quantification of milk adulteration. Three binary mixtures containing cows' and goats', cows' and sheep's, and goats' and sheep's milk and a fourth tertiary mixture containing all types of milk were prepared and analysed directly using MALDI-ToF-MS. In these mixtures, the milk concentrations of each milk varied from 0% to 100% in 5% steps. Multivariate statistical methods including partial least squares (PLS) regression and non-linear Kernel PLS regression were employed for multivariate calibration and final interpretation of the results. The results for PLS and KPLS were encouraging with between 2% and 13% root mean squared error of prediction on independent data; KPLS slightly outperformed PLS. We believe that these results show that MALDI-ToF-MS has excellent potential for future use in the dairy industry as a rapid method of detection and enumeration in milk adulteration. PMID- 21298417 TI - Reduction of temazepam to diazepam and lorazepam to delorazepam during enzymatic hydrolysis. AB - It has been previously reported that treatment of urinary oxazepam by commercial beta-glucuronidase enzyme preparations, from Escherichia coli, Helix pomatia and Patella vulgata, results in production of nordiazepam (desmethyldiazepam) artefact. In this study, we report that this unusual reductive transformation also occurs in other benzodiazepines with a hydroxyl group at the C3 position such as temazepam and lorazepam. As determined by liquid chromatography-mass spectrometry analysis, all three enzyme preparations were found capable of converting urinary temazepam into diazepam following enzymatic incubation and subsequent liquid-liquid extraction procedures. For example, when H. pomatia enzymes were used with incubation conditions of 18 h and 50 degrees C, the percentage conversion, although small, was significant--approximately 1% (0.59 1.54%) in both patient and spiked blank urines. Similarly, using H. pomatia enzyme under these incubation conditions, a reductive transformation of urinary lorazepam into delorazepam (chlordesmethyldiazepam) occurred. These findings have both clinical and forensic implications. Detection of diazepam or delorazepam in biological samples following enzyme treatment should be interpreted with care. PMID- 21298418 TI - Fast wheat variety classification by capillary gel electrophoresis-on-a-chip after single-step one-grain high molecular weight glutenin extraction. AB - Wheat variety identification based on one-step single-grain wheat extraction and fast capillary gel electrophoresis-on-a-chip (CGE-on-a-chip) analyses was evaluated for 15 different wheat varieties grown in Austria. The results of the capillary-based separation system were compared to the internationally accepted method from the International Union for the Protection of New Varieties of Plants which is based on time-consuming sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) analysis. Comparable protein patterns were observed making the CGE-on-a-chip system a promising tool for high-throughput analysis in food control. For the development of a robust method protein extraction, shelf life of wheat extracts and the instrument's variability were evaluated. It turned out that a one-step single-grain wheat extraction allowed the sample to be stored at 4 degrees C for up to 4 weeks without losing any valuable protein information. Furthermore, the technical variation of the whole method is very low making the biological variation of the selected wheat grains the only uncertain factor. Additionally, two unsupervised statistical methods (hierarchical cluster analysis and principal component analysis) were used for variety identification. Identification was successful for a reduced data set of 14 samples from five different wheat varieties making the combination of CGE-on-a-chip analysis of one step single-grain extraction in combination with automatic data evaluation a promising tool for fast wheat differentiation (within a day). PMID- 21298419 TI - Optimal experimental designs in RPLC at variable solvent content and pH based on prediction error surfaces. AB - When pH is used as factor in reversed-phase liquid chromatographic (RPLC) separations, the need for providing quality and informative data with the minimal experimental effort becomes imperative. The most rational way to achieve this is by means of experimental designs. The interest in finding optimal designs involving solvent content and pH in RPLC is considerable, since these factors allow large variations in selectivity when ionisable compounds are involved. Unfortunately, the equations that describe the retention of these compounds with pH are nonlinear. As a consequence, factorial and other designs based on geometrical considerations are not well suited, whereas D-optimal and related designs can only be applied in an iterative fashion. In this work, an extension of G-optimal designs, aimed to enhance the quality of the predictions, is examined for problems involving solvent content and pH. The study was carried out with a set of probe ionisable compounds, for which information on retention behaviour was accurately known. A stepwise strategy was used to obtain a rapid estimation of the best design with a given number of experiments. The objective of the study was to investigate the distribution and number of points in the ideal design for compounds of different acid-base behaviour, and the possibility of finding common designs for groups of compounds. A further goal was to derive design construction rules containing the information requirements, without needing any further mathematical treatment. PMID- 21298420 TI - Conjugation reactions in the preparations of quantum dot-based immunoluminescent probes for analysis of proteins by capillary electrophoresis. AB - A number of biologically important molecules, such as DNA, proteins, and antibodies, are routinely conjugated with fluorescent tags for high-sensitivity analyses. Here, the application of quantum dots in the place of bright and size tunable luminophores is studied. Several selected bioconjugation reactions via zero-length cross-linkers, long-chain linkers, and oriented methods for linking of quantum dots with proteins were tested. Anti-ovalbumin, anti-proliferating cell nuclear antigen, anti-hemagglutinin, and anti-CD3 membrane protein as model antibodies and annexin V were used as high-specificity selectors. The reaction yield and efficiency of the prepared immunoluminescent probes were tested by capillary zone electrophoresis with laser-induced fluorescence detection. PMID- 21298421 TI - Urinary 2-hydroxy-5-oxoproline, the lactam form of alpha-ketoglutaramate, is markedly increased in urea cycle disorders. AB - alpha-Ketoglutaramate (KGM) is the alpha-keto acid analogue of glutamine, which exists mostly in equilibrium with a lactam form (2-hydroxy-5-oxoproline) under physiological conditions. KGM was identified in human urine and its concentration quantified by gas chromatography/mass spectrometry (GC/MS). The keto acid was shown to be markedly elevated in urine obtained from patients with primary hyperammonemia due to an inherited metabolic defect in any one of the five enzymes of the urea cycle. Increased urinary KGM was also noted in other patients with primary hyperammonemia, including three patients with a defect resulting in lysinuric protein intolerance and one of two patients with a defect in the ornithine transporter I. These findings indicate disturbances in nitrogen metabolism, most probably at the level of glutamine metabolism in primary hyperammonemia diseases. Urinary KGM levels, however, were not well correlated with secondary hyperammonemia in patients with propionic acidemia or methylmalonic acidemia, possibly as a result, in part, of decreased glutamine levels. In conclusion, the GC/MS procedure has the required lower limit of quantification for analysis of urinary KGM, which is markedly increased in urea cycle disorders and other primary hyperammonemic diseases. PMID- 21298422 TI - The oculogyral illusion: retinal and oculomotor factors. AB - Subjects in a dark chamber exposed to angular acceleration while viewing a head fixed target experience motion and displacement of the target relative to their body. Competing explanations of this phenomenon, known as the oculogyral illusion, have attributed it to the suppression of the vestibulo-ocular reflex (VOR) or to retinal slip. In the dark, the VOR evokes compensatory eye movements in the direction opposite to body acceleration. A head-fixed visual target will tend to suppress these eye movements. The VOR suppression hypothesis attributes the oculogyral illusion to the signals that prevent reflexive deviation of the eyes from the target thus resulting in apparent target displacement in the direction of acceleration. The retinal slip hypothesis attributes the illusion to inadequate fixation of the target with the eyes being involuntarily deviated in the direction opposite acceleration, the retinal slip being interpreted as target displacement in the direction of acceleration. Another possibility is that the illusion could arise from a change in the representation of the perceived head midline. To evaluate these three alternative hypotheses, we tested 8 subjects at 4 acceleration rates (2, 10, 20, 30 degrees /s2) in each of three conditions: (a) fixate and point to a target light; (b) fixate to the target light and point to the head midline; (c) look straight ahead in the dark. The displacement magnitude of the oculogyral illusion was least at 2 degrees /s2 ~ 2 degrees and was ~10 degrees at the other acceleration rates. The presence of the target light significantly attenuated eye movements relative to the dark condition, but eye movements were still present at the 10, 20, and 30 degrees /s2 accelerations. The eye velocity profiles in the dark at different acceleration rates did not show a one-to-one inverse mapping to the magnitude of the oculogyral illusion at those rates. The perceived head midline was not significantly displaced at any of the acceleration rates. The oculogyral illusion thus has at least two contributing factors: the suppression of nystagmus at low acceleration rates and at higher acceleration rates, a partial suppression coupled with an integration of the drift of the eyes with respect to the fixation target. PMID- 21298423 TI - Extraction of visual motion information for the control of eye and head movement during head-free pursuit. AB - We investigated how effectively briefly presented visual motion could be assimilated and used to track future target motion with head and eyes during target disappearance. Without vision, continuation of eye and head movement is controlled by internal (extra-retinal) mechanisms, but head movement stimulates compensatory vestibulo-ocular reflex (VOR) responses that must be countermanded for gaze to remain in the direction of target motion. We used target exposures of 50-200 ms at the start of randomised step-ramp stimuli, followed by > 400 ms of target disappearance, to investigate the ability to sample target velocity and subsequently generate internally controlled responses. Subjects could appropriately grade gaze velocity to different target velocities without visual feedback, but responses were fully developed only when exposure was > 100 ms. Gaze velocities were sustained or even increased during target disappearance, especially when there was expectation of target reappearance, but they were always less than for controls, where the target was continuously visible. Gaze velocity remained in the direction of target motion throughout target extinction, implying that compensatory (VOR) responses were suppressed by internal drive mechanisms. Regression analysis revealed that the underlying compensatory response remained active, but with gain slightly less than unity (0.85), resulting in head-free gaze responses that were very similar to, but slightly greater than, head-fixed. The sampled velocity information was also used to grade head velocity, but in contrast to gaze, head velocity was similar whether the target was briefly or continuously presented, suggesting that head motion was controlled by internal mechanisms alone, without direct influence of visual feedback. PMID- 21298424 TI - Number magnitude to finger mapping is disembodied and topological. AB - It has been shown that humans associate fingers with numbers because finger counting strategies interact with numerical judgements. At the same time, there is evidence that there is a relation between number magnitude and space as small to large numbers seem to be represented from left to right. In the present study, we investigated whether number magnitude to finger mapping is embodied (related to the order of fingers on the hand) or disembodied (spatial). We let healthy human volunteers name random numbers between 1 and 30, while simultaneously tapping a random finger. Either the hands were placed directly next to each other, 30 cm apart, or the hands were crossed such that the left hand was on the right side of the body mid-line. The results show that naming a smaller number than the previous one was associated with tapping a finger to the left of the previously tapped finger. This shows that there is a spatial (disembodied) mapping between number magnitude and fingers. Furthermore, we show that this mapping is topological rather than metrically scaled. PMID- 21298425 TI - Inactivation of the putamen selectively impairs reward history-based action selection. AB - Behavioral decisions and actions are directed to achieve specific goals and to obtain rewards and escape punishments. Previous studies involving the recording of neuronal activity suggest the involvement of the cerebral cortex, basal ganglia, and midbrain dopamine system in these processes. The value signal of the action options is represented in the striatum, updated by reward prediction errors, and used for selecting higher-value actions. However, it remains unclear whether dysfunction of the striatum leads to impairment of value-based action selection. The present study examined the effect of inactivation of the putamen via local injection of the GABA(A) receptor agonist muscimol in monkeys engaged in a manual reward-based multi-step choice task. The monkeys first searched a reward target from three alternatives, based on the previous one or two choices and their outcomes, and obtained a large reward; they then earned an additional reward by choosing the last rewarded target. Inactivation of the putamen impaired the ability of monkeys to make optimal choices during third trial in which they were required to choose a target different from those selected in the two previous trials by updating the values of the three options. The monkeys normally changed options if the last choice resulted in small reward (lose-shift) and stayed with the last choice if it resulted in large reward (win-stay). Task start time and movement time during individual trials became longer after putamen inactivation. But monkeys could control the motivation level depending on the reward value of individual trial types before and after putamen inactivation. These results support a view that the putamen is involved selectively and critically in neuronal circuits for reward history-based action selection. PMID- 21298426 TI - Clinical relevance of different B-type natriuretic peptide decisional cutoff values for the diagnosis of congenital heart disease in the first weeks of life. PMID- 21298427 TI - Cardiomyocyte death: insights from molecular and microstructural magnetic resonance imaging. AB - Cardiomyocytes can die via necrosis, apoptosis, and autophagy. Although the molecular signals and pathways underlying these processes have been well elucidated, the pathophysiology of cardiomyocyte death remains incompletely understood. This review describes the development and application of novel imaging techniques to detect and characterize cardiomyocyte death noninvasively in vivo. It focuses on molecular and microstructural magnetic resonance images (MRIs) and their respective abilities to image cellular events such as apoptosis, inflammation, and myofiber architecture. These in vivo imaging techniques have the potential to provide novel insights into the mechanisms of cardiomyocyte death and to help guide the development of novel cardioprotective therapies. PMID- 21298428 TI - Comparison of MR-arthrography and MDCT-arthrography for detection of labral and articular cartilage hip pathology. AB - OBJECTIVE: To compare the diagnostic ability of MR arthrography (MRa) and MDCT arthrography (CTa) in depicting surgically proven hip labral tears and articular cartilage degradation. MATERIALS AND METHODS: Labral pathology and articular cartilage were prospectively evaluated with MRa and CTa in 14 hips of 10 patients. The findings were evaluated by two independent observers (a musculoskeletal fellow and one senior musculoskeletal radiologist). Sensitivity, specificity, accuracy, and positive predictive value were determined using arthroscopic and open surgery findings as the standard of reference. Interobserver agreement was recorded. All images were assessed for the presence of a labral tear (according to Czerny classification) and for cartilage erosion using a 3 point scale for both methods: 1 = complete visualization-sharp edges, 2 = blurred edges fissuring-partial defects, 3 = exposed bone. The same classification was applied surgically. RESULTS: Disagreement between the senior observer and the fellow observer was recorded in three cases of labral tearing with MRa and six with CTa. Disagreement was also found in four cases of cartilage erosion with both MRa and CTa. The percent sensitivity, specificity, accuracy, and positive predictive value for correctly assessing the labral tear were as follows for MRa/CTa, respectively: 100/15, 50/13, 90/14, and 90/13 (P < 0.05). The same values for cartilage assessment were 63/66, 33/40, 50/57 and 55/66 (P > 0.05). CONCLUSION: Interobserver reproducibility with MRa is very good for labral tearing assessment. MRa is better for assessing labral tears. CTa shows better, but not statistically significant, demonstration of the articular cartilage. PMID- 21298429 TI - Stun gun induced myotendinous injury of the iliopsoas and gluteus minimus. AB - We report a 57-year-old man with a complete tear of his iliopsoas tendon at the distal myotendinous junction, a near complete tear of the iliopsoas tendon at the lesser trochanter of the femur, and a high-grade tear of his gluteus minimus tendon at the greater trochanter of the femur after being struck by a stun gun in the proximal left thigh. The stun gun discharge resulted in a forced contraction of the left hip flexor muscles, which resulted in pain, weakness and difficulty with active hip flexion. Three months after the being struck with the stun gun, the patient underwent magnetic resonance imaging (MRI) of the left hip. MRI of the left hip revealed a complete tear of the left iliopsoas tendon from the lesser trochanter with 4 cm of proximal retraction and a high-grade strain of the gluteus minimus tendon at the greater trochanter. The distal iliopsoas myotendinous junction and lesser trochanter tendon insertion were surgically repaired. This case illustrates that a stun gun can cause acute rupture of the iliopsoas tendon and tear of the gluteus minimus tendon, which is well visualized on MRI. PMID- 21298430 TI - MRI findings of neutrophilic fasciitis in a patient with acute febrile neutrophilic dermatosis (Sweet's syndrome). AB - Acute febrile neutrophilic dermatosis (Sweet's syndrome) is a clinical condition that is histopathologically characterized by infiltration of the dermis with mature neutrophils with or without vessel wall destruction. Frequently, an extracutaneous systemic disease can be seen. We report magnetic resonance imaging (MRI) findings of neutrophilic fasciitis in a 62-year-old man with Sweet's syndrome and musculoskeletal involvement. The musculoskeletal system is rarely involved in Sweet's syndrome and, to our knowledge, no previous report of MRI findings of neutrophilic fasciitis with myofascial involvement exists in the literature. PMID- 21298431 TI - 18F-FDG PET response to neoadjuvant chemotherapy for Ewing sarcoma and osteosarcoma are different. AB - OBJECTIVE: Ewing sarcoma (ES) and osteosarcoma (OS) have different biological characteristics and respond differently to chemotherapy. We reviewed (18)F-FDG PET imaging characteristics of ES and OS patients at baseline and following treatment to determine whether this biological variation is reflected in their imaging phenotype. MATERIALS AND METHODS: A retrospective review of ES and OS patients treated with neoadjuvant chemotherapy and surgery was done, correlating PET results with histologic response to chemotherapy. RESULTS: Change in the maximum standardized uptake value (SUVmax) between baseline and post-treatment scanning was not significantly associated with histologic response for either ES or OS. Metabolic tumor volume (MTV) and the percentage of injected (18)F-FDG dose (%ID) in the primary tumor were found to be different for ES and OS response subgroups. A 50% reduction in MTV (MTV2:1 < 0.5) was found to be significantly associated with favorable histologic response in OS. Using the same criteria for ES incorrectly predicted good responders. Increasing the cut-off values for ES to a 90% reduction in MTV (MTV2:1 < 0.1) resulted in association with favorable histologic response. CONCLUSION: Response to neoadjuvant chemotherapy as reflected by changes in PET characteristics should be interpreted differently for ES and OS. PMID- 21298432 TI - A retroperitoneal mass, systemic lymphadenopathy, and pulmonary nodules in a pregnant woman. Diagnosis: Lymphangioleiomyomatosis (LAM). PMID- 21298433 TI - The influence of cementing technique in hip resurfacing arthroplasty on the initial stability of the femoral component. AB - PURPOSE: In clinical and retrieval analyses, over-penetration of cement, incomplete seating of the prosthesis with a resultant polar cement mass, or both, have been associated with early femoral failures of resurfacing arthroplasties. We used human bone specimens to experimentally compare the initial stability of different cementing techniques. METHODS: Twenty-six pairs of fresh frozen femora were prepared for resurfacing using original instruments (DePuy ASR). ASR femoral resurfacing prostheses were implanted using two different cementing techniques: (1) component filling and (2) cement applicator. Real-time measurements of pressure and temperature during implantation, analyses of cement penetration and micro motions under torque application were performed. RESULTS: Applicator use reduced significantly the cement penetration depth (9.2 mm vs 5.3 mm with the applicator, p = 0.001), polar mantle (8.1 mm vs 2.6 mm, p = 0.008), cement defects (3.7 mm vs 0.1 mm, p = 0.008) and interface temperatures (40.3 degrees C vs 33.1 degrees C, p < 0.001 ). Initial rotational stability showed statistically significant less extreme values with the cement applicator technique (range 3.4 51.7 m degrees /Nm, 11.0-29.7 m degrees /Nm, p = 0.024). CONCLUSIONS: The cement applicator technique significantly reduces cement defects, incomplete seating, over-penetration and interface temperatures with a more consistent initial stability of the ASR femoral resurfacing prostheses. PMID- 21298434 TI - Loss of tolerance to self after transplant. AB - Organ transplantation is the widely accepted treatment for end-stage organ failure. Since the first successful kidney transplant from an identical twin donor in 1954, researchers have been studying the effects of the immune system on transplantation outcomes. Although the surgery is technically successful, the majority of grafts from genetically disparate donors are rejected due to a number of factors that stimulate recipient immune responses, ultimately resulting in graft loss despite the chronic use of immunosuppressive (IS) drugs. Unfortunately, while short-term success has greatly improved with the development of novel IS drugs, the long-term graft survival of solid organs has not improved significantly over the last few decades. The problem of late graft loss is mainly attributed to development of chronic rejection. Therefore, understanding all of the immune mechanisms involved in transplant rejection is important to prevent graft dysfunction, and eventually, graft loss. In this review, we will give an overview of allograft rejection, the progression from acute to chronic rejection, and in addition, the recent discovery of a critical role for loss of self tolerance and development of IL-17-dependent autoimmunity in chronic rejection. PMID- 21298435 TI - Effects of immunoadsorption on endothelial function, circulating endothelial progenitor cells and circulating microparticles in patients with inflammatory dilated cardiomyopathy. AB - BACKGROUND: Immunoadsorption (IA) is used in patients with chronic inflammatory dilative cardiomyopathy (iDCM) to remove cardiotoxic autoantibodies, and to improve myocardial function. We examined the effects of IA on endothelial function, circulating endothelial progenitor cells, and circulating microparticles, including endothelial-derived microparticles, in patients with chronic iDCM. METHODS: Thirteen patients (10 males, 3 females, mean age 52.3 years) with advanced congestive heart failure (NYHA III and IV) secondary due to chronic iDCM (with signs of myocardial inflammation in biopsies, but without persistence of virus genome), and reduced left ventricular ejection fraction (EF < 35%) underwent IA. Blood samples were drawn before an IA course of 5 days, and 6 months after IA. Blood levels of endothelial progenitor cells (EPCs as defined as VEGFR2(+)CD34(+) cells), of microparticles (MPs as defined as Annexin V(+) particles with a diameter between 0.1 and 1 MUm), and of endothelial-derived MPs (eMPs as defined as CD31(+bright) CD42b(-)/Annexin V(+) particles) were analyzed by flow cytometry. Endothelial function (expressed as reactive hyperemia index (RHI)) and arterial stiffness were assessed by PAT-technology (peripheral arterial tone) using fingertips. RESULTS: Left ventricular systolic function (EF%) improved on average at 6 months from 26.3 +/- 4.8 to 37.9 +/- 9.6% (mean +/ SEM; p < 0.05). The LV end-diastolic diameter reduced after 6 months from 68.4 +/- 8.2 to 61.6 +/- 7.9 mm; p < 0.05). Endothelial function improved from 1.53 +/ 0.09 to 1.80 +/- 0.12 (p < 0.05). The arterial stiffness index remained unchanged. Number of total MPs decreased on average by 36.8% (p < 0.05), the number of eMPs by 39.6% (p < 0.05), respectively. The level of circulating EPC remained unchanged (EPC/PMNC 0.26 +/- 0.07 vs. 0.27 +/- 0.05 0/00, p = n.s.). CONCLUSIONS: IA treatment improves endothelial function in patients with chronic iDCM. This effect is associated with a significant drop in circulating microparticles. The causal relationship between circulating microparticles and endothelial function is discussed. PMID- 21298436 TI - Regulation of vascular guanylyl cyclase by endothelial nitric oxide-dependent posttranslational modification. AB - In isolated cells, soluble guanylyl cyclase (sGC) activity is regulated by exogenous nitric oxide (NO) via downregulation of expression and posttranslational S-nitrosylation. The aim of this study was to investigate whether such regulatory mechanism impact on endothelium-dependent vasodilation in a newly developed mouse strain carrying an endothelial-specific overexpression of eNOS (eNOS(++)). When compared with transgene negative controls (eNOS(n)), eNOS(++)-mice showed a 3.3-fold higher endothelial-specific aortic eNOS expression, increased vascular cGMP and VASP phosphorylation, a L-nitroarginine (L-NA)-inhibitable decrease in systolic blood pressure, but normal levels of peroxynitrite and nitrotyrosine formation, endothelium-dependent aortic vasodilation and vasodilation to NO donors. Western blot analysis for sGC showed similar protein levels of sGC-alpha1 and sGC-beta1 subunits in eNOS(n) and eNOS(++). In striking contrast, the activity of isolated sGC was strongly decreased in lungs of eNOS(++). Semiquantitative evaluation of sGC-beta1-S nitrosylation demonstrated that this loss of sGC activity is associated with increased nitrosylation of the enzyme in eNOS(++), a difference that disappeared after L-NA-treatment. Our data suggest the existence of a physiologic NO dependent posttranslational regulation of vascular sGC in mammals involving S nitrosylation as a key mechanism. Because this mechanism can compensate for reduction in vascular NO bioavailability, it may mask the development of endothelial dysfunction. PMID- 21298437 TI - Single-stage treatment of complete dislocation of radial head and forearm deformity using distraction osteogenesis in paediatric patients having multiple cartilaginous exostosis. AB - BACKGROUND: We are reporting the results of single-stage treatment for patients with forearm deformity and radial head luxation due to hereditary multiple exostosis using distraction osteogenesis. METHOD: Six patients with a mean age of 12 years were treated. Morphological evaluation was made according to Masada (3 of the cases were 2a and 3; 2b). Angular deformities of forearm and wrist were evaluated as described by Fogel (distal radial joint angle was 27 degrees , ulnar variance was 12.8 mm and carpal slip was 71.3%). Mean forearm pronation was 48.4 degrees whilst mean supination was 19.2 degrees . Mean elbow range of motion was 26.6 degrees -103.4 degrees and the mean DASH score was 75. Common surgical procedures were deformity correction, ulnar lengthening and gradual radial head reduction using external fixators. RESULTS: Mean follow-up period was 4.2 years and mean external fixation time was 6 months. Mean amount of ulnar lengthening was 2.9 cm and the distraction index was 14.9 cm/day. Mean radial articular angle was 14.3 degrees , ulnar variance 2.3 mm, carpal slip 55%, forearm pronation 65.9 degrees and supination was 55 degrees . Mean elbow range of motion was 15.8 degrees -119.2 degrees . In the last follow-up, the mean value of DASH score was 8.1. Major and minor complications were seen during the follow ups. CONCLUSIONS: Single-stage deformity correction, ulnar lengthening and radial head reduction technique that we have used provide satisfactory functional and cosmetic results. Early surgical correction may lead to even better results. PMID- 21298438 TI - Small cell carcinoma of the ovary of the hypercalcaemic type: an analysis of clinical and prognostic aspects of a rare disease on the basis of cases published in the literature. AB - PURPOSE: Ovarian small cell carcinoma of the hypercalcaemic type is a very rare and highly aggressive malignant disease, mainly affecting young women. Due to the rarity of this tumour entity, prospective randomised trials are unlikely to be conducted, and the only retrospective analysis based on a large case series is from 1994. Since diagnostic and treatment modalities may have changed, we initiated this analysis. METHODS: The aim of our study was to review and analyse cases published since 1975 to validate former findings and to gather more information about therapy options, diagnostic and prognostic factors. A systematic literature search of the PubMed/Medline database was performed assessing all articles until September 2010. All retrieved articles were evaluated and cross-checked for references on the topic. In total, 135 cases were included, selected from 62 case reports and smaller case studies. RESULTS: Small cell carcinoma mostly affects women with a mean age of 23.4 years. They present with unspecific symptoms like abdominal pain or palpable mass, sometimes accompanied by an elevated calcium or CA-125 serum concentration. The tumour appears nearly almost unilaterally, mostly affecting the right ovary. Tumour stage is a clearly prognostic factor. Adjuvant chemotherapy consisting of etoposide, cisplatinum/carboplatinum or vinca alkaloids has shown improved survival, whereas radiotherapy has not. CONCLUSIONS: In spite of limitations this analysis provides new insights especially with respect to therapeutic aspects. This review underlines the importance of case reports in rare tumour entities in order to answer open questions. PMID- 21298439 TI - Malignant mixed Mullerian tumor of the ovary with two cases and review of the literature. AB - INTRODUCTION: Malignant mixed Mullerian tumor (MMMT) of the ovary is a rare and highly aggressive tumor. It accounts <1% of all ovarian carcinomas. It is characterized by the presence of both carcinomatous and sarcomatous components and tends to occur in low parity postmenopausal woman. These are mixed, mostly monoclonal tumors, and the predominance of the stromal component aggravates the prognosis. The staging system for ovarian and primary peritoneal cancer is also used for MMMT. After complete surgical staging, patient with stage II-IV at the time of surgery should have postoperative chemotherapy. Chemotherapy can be considered for stage I MMMT. Its optimal treatment is debatable. Taxane and platinum combination is standard for the epithelial ovarian carcinoma. There is very limited literature reporting this combination therapy in ovarian MMMTs. CASE 1 AND CASE 2: We presented two cases of stage III primary ovarian MMMT. The patients were treated with the taxane/platin combination, without adverse events following surgery, and remained in clinical remission in Case 1 at follow-up. Case 2 has progressed after first line taxane/platin regimen and treated like epithelial ovarian carcinoma. Case 1 was in complete remission in the follow-up visit 2 years later. Case 2 died 14 months later after the tumor was initially diagnosed. CONCLUSION: Predominating carcinomatous or sarcomatous component should be taken into consideration in predicting the response and planning the chemotherapy protocol. PMID- 21298440 TI - The endothelial microenvironment in the venous valvular sinus: thromboresistance trends and inter-individual variation. AB - The valve sinuses of the deep venous system are frequent sites of venous thrombus initiation. We previously reported that, in comparison with the non-valvular lumenal endothelium, the valve sinus endothelium had decreased expression of von Willebrand factor (vWF) and increased expression of endothelial protein C receptor (EPCR) and thrombomodulin (TM), suggesting alteration in the procoagulant/anticoagulant balance. We hypothesized that increased stasis in the deeper recesses of the venous valves would be associated with a gradient of increased thromboresistance. Expression of EPCR, TM, and vWF was analyzed via quantitative confocal immunofluorescence in residual saphenous veins collected following coronary artery bypass procedures. In agreement with our hypothesis, endothelial expression of vWF in the valve sinus decreased from the uppermost to the deepest region of the valve sinus. In contrast to our hypothesis, EPCR expression decreased from the uppermost to the deepest region of the valve sinus (p < 0.001) and TM expression remained unchanged throughout the valve sinus. Comparison of the non-valvular lumenal endothelium with the valve sinus endothelium demonstrated significantly decreased vWF expression (p < 0.001) in the valvular sinus consistent with our previous report; however, we did not observe statistically significant differences in EPCR or TM expression in this comparison. In addition, remarkable inter-individual variation in expression of these three proteins was also observed. These findings suggest that the genesis of these observations is more complex than predicted by our initial hypothesis, likely due, at least in part, to the complex rheology of the valvular sinus microenvironment. PMID- 21298441 TI - Correlations of fish intake and plasma docosahexaenoic acid levels with each congener of PCDDs/PCDFs/dioxin-like PCBs in blood from the Japanese population. AB - PURPOSE: The purpose of the present study was to investigate the factors associated with blood levels of each congener of polychlorinated dibenzo-p dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like polychlorinated biphenyls (DL-PCBs) in the Japanese population. METHODS: A cross sectional study was performed on 1,656 subjects (755 men and 901 women) aged 15 73 years, who were living in 90 different areas of 30 prefectures in Japan. Blood levels of 29 PCDD, PCDF, and DL-PCB congeners were determined by high-resolution gas chromatography/mass spectrometry. In addition, a questionnaire survey on life style, including dietary habit, was carried out. RESULTS: The median total toxicity equivalent (TEQ) was 17 pgTEQ/g lipid. After adjustment for age, sex, body mass index, smoking habit, and consumption of other food groups, six PCDDs/PCDFs with 4-6 substituted chlorine atoms and 10 DL-PCBs, but not HeptaCDD/F or OctaCDD, showed significant positive correlations with the frequency of intake of fish and shellfish. Furthermore, significant positive relationships were also found between plasma levels of docosahexaenoic acid (DHA), a biomarker of fish intake, and 10 PCDDs/PCDFs with 4-6 chlorine atoms and 10 DL-PCBs. The partial correlation coefficients with plasma DHA were significantly higher for DL-PCBs than for PCDDs/PCDFs, and partial correlation coefficients for PCDDs/PCDFs significantly decreased with increasing number of chlorine atoms (Spearman r = -0.80, P = 0.001). CONCLUSIONS: Blood levels of PCDDs/PCDFs with 4-6 chlorine atoms and DL-PCBs were positively associated with fish intake in the Japanese population. These results may be explained by the higher degree of bioaccumulation of these congeners in fish and shellfish in the ecosystem, and the high consumption of fish among the Japanese population. PMID- 21298442 TI - Pulmonary O2 uptake and muscle deoxygenation kinetics are slowed in the upper compared with lower region of the moderate-intensity exercise domain in older men. AB - This study sought to determine the effect of the pre-transition work rate (WR) and WR transition magnitude on the adjustment of pulmonary oxygen uptake (VO(2p) kinetics) in older men. Seven men (69 +/- 5 years; mean +/- SD) each performed 4 6 cycling transitions from 20 W to either a WR corresponding to 90% estimated lactate threshold (full step, FS) or 2 equal-step transitions (lower step, LS; upper step, US) to the same end-exercise WR as in FS. Gas exchange was analysed breath-by-breath and muscle deoxygenation (?[HHb]) was measured with NIRS. The time constant (tau) for VO(2p) was greater in US (53 +/- 17 s) and FS (44 +/- 11 s) compared to LS (37 +/- 9 s); tauVO(2p) for US also trended (p = 0.05) towards being greater than FS. The VO(2p) gain in US (9.97 +/- 0.41 mL/min/W) was greater than LS (9.06 +/- 1.17; p = 0.06) and FS (9.13 +/- 0.54; p < 0.05). The O(2) deficit was greater in US (0.25 +/- 0.08 L) than LS (0.19 +/- 0.06 L); yet the 'accumulated O(2) deficit' (0.44 +/- 0.13 L; O(2) deficit from LS + US) was similar to that of FS (0.42 +/- 0.13 L; p = 0.38). The effective Delta[HHb] response time (tau'?[HHb]) for US (36 +/- 12 s) was greater than LS (27 +/- 6 s; p = 0.07) and FS (26 +/- 4 s; p < 0.05), suggesting that the slowed adjustment of muscle O(2) extraction was associated with the slowed VO(2) kinetics of the US. Despite already slowed VO(2p) kinetics, older men exhibit further slowing when small WR transitions are initiated from an elevated pre-transition WR, yet this results in no cumulative impact on O(2) deficit. This slowing in US compared to LS does not appear to be related to local O(2) availability. PMID- 21298443 TI - Nature of passive musculoarticular stiffness increase of ankle in female subjects with fibromyalgia syndrome. AB - The objective of this study was to assess the passive elastic and viscous stiffness components of ankle in young, middle-aged and old adult female fibromyalgia subjects and compare the results with age-matched healthy control subjects. The passive musculoarticular stiffness of the ankles of 60 fibromyalgia subjects and 52 controls was quantified by measuring the ankle resistance to imposed sinusoidal rotary displacements at nine different oscillation frequencies. For each frequency, the resulting torque response of the ankles was decomposed into elastic and viscous components of the total stiffness. The self perceived stiffness intensity of the ankles was assessed in fibromyalgia subjects by means of a visual analogue scale. Two-way ANOVA test indicated a significant effect of fibromyalgia (P < 0.001) and age (P < 0.001) on elastic stiffness results and a significant effect of age (P < 0.001) on viscous stiffness results. Post hoc Holm-Sidak test indicated that younger and middle-aged fibromyalgia subjects had a significant elastic stiffness increase of more than two times that of controls (P = 0.038 and P < 0.001, respectively). Middle-aged fibromyalgia subjects had a significant viscous stiffness increase of 1.2 times that of controls (P = 0.038). No significant differences in stiffness were observed between older fibromyalgia subjects and controls. In conclusion, the self perceived stiffness increase of ankle reported by younger and middle-aged fibromyalgia subjects is due to changes in elastic and/or viscous musculoarticular structures around the ankle. The absence of changes in older fibromyalgia subjects is probably related to the ageing process of controls. PMID- 21298444 TI - Three-month bilateral hopping intervention is ineffective in initiating bone biomarker response in healthy elderly men. AB - In animal studies, bone adaptation has been initiated successfully without the transient force spike associated with high impact exercises. Consequently, a 12 week bilateral hopping on the balls of the feet intervention was conducted. 25 elderly men (age 72(SD4) years, height 171(6) cm, weight 75(9) kg) were randomly assigned into exercise and control groups. Ten subjects in each group completed the study. Carboxyterminal propeptide of type I collagen (CICP), bone-specific alkaline phosphatase (bALP) and carboxyterminal telopeptide of type I collagen (CTx) were measured from venous blood samples at baseline, at 2 weeks and at the end of the intervention. Maximal ground reaction force (GRF), osteogenic index (OI) and jump height (JH) were determined from bilateral hopping test and balance was assessed with velocity of center of pressure (COP(velocity)) while standing on the preferred leg with eyes open. The intervention consisted of 5-7 sets of 10 s timed bilateral hopping exercise at 75-90% intensity three times/week. There was no significant group * time interaction for GRF, OI and JH (P = 0.065). GRF (11% change from baseline vs. 4%), OI (15 vs. 6%) and COP(velocity) (-10 vs. -1%) were not influenced by the intervention (P > 0.170), while the control group improved JH (P = 0.031) (2 vs. 18%). For the biomarkers, no effect was observed in MANOVA (P = 0.536) or in univariate analyses (P = 0.082 to P = 0.820) (CICP -2 vs. -3%, CTx 8 vs. -12%, bALP 0 vs. -3.7%). Allowing transient impact force spikes may be necessary to initiate a bone response in elderly men as the intervention was ineffective. PMID- 21298445 TI - Gender differences in the passive stiffness of the human gastrocnemius muscle during stretch. AB - The aim of this study was to determine whether muscle stiffness measured in vivo was different between males and females. Distal displacement of the gastrocnemius medialis myotendinous junction was measured directly using ultrasonography during passive dorsiflexion in eight males and eight females (age range 19-28 years). Plantarflexion torque and myotendinous junction displacement were measured at 5 degrees intervals, where 0 degrees was with the foot at right angles to the tibia. Stiffness of the gastrocnemius medialis muscle was calculated between 0 degrees and 25 degrees of dorsiflexion, and defined as passive plantarflexion torque/distal displacement of the myotendinous junction (N m cm(-1)). Relative muscle stiffness was also calculated as distal displacement relative to resting muscle length, and as passive torque relative to plantarflexion maximal voluntary contraction torque. No significant gender difference was observed in passive dorsiflexion torque, or in passive torque/maximal voluntary torque throughout the range of motion. Distal displacement of the gastrocnemius myotendinous junction was 26% more in females than in males (P < 0.05). Myotendinous junction displacement was 5.0 +/- 1.4% of resting gastrocnemius medialis length in females, and 3.9 +/- 0.6% in males. Over 25 degrees of passive dorsiflexion, gastrocnemius medialis muscle stiffness was greater in males than in females by 44% (P < 0.05). In conclusion, based on the in vivo assessment of myotendinous junction displacement, passive gastrocnemius medialis muscle stiffness is greater in males than in females. PMID- 21298446 TI - Genetic variants in TLR2 and TLR4 are associated with markers of monocyte activation: the Atherosclerosis Risk in Communities MRI Study. AB - Markers of monocyte activation play a critical role in atherosclerosis, but little is known about the genetic influences on cellular levels. Therefore, we investigated the influence of genetic variants in monocyte differentiation antigen (CD14), toll-like receptor-4 (TLR4), toll-like receptor-2 (TLR2), and myeloperoxidase (MPO) on monocyte surface receptor levels. The study sample consisted of 1,817 members of a biracial cohort of adults from the Atherosclerosis Risk in Communities Carotid MRI Study. Monocyte receptors were measured using flow cytometry on fasting whole blood samples. TLR2 rs1816702 genotype was significantly associated with CD14+/TLR2+ percent of positive cells (%) and median fluorescence intensity (MFI) in whites but not in blacks (p < 0.001). Specifically, the presence of the minor T-allele was associated with increased receptor levels. In blacks, TLR4 rs5030719 was significantly associated with CD14+/TLR4+ monocytes (MFI) with mean +/- SE intensities of 16.7 +/- 0.05 and 16.0 +/- 0.14 for GG and GT/TT genotypes, respectively (p < 0.001). Variants in TLR2 and TLR4 were associated with monocyte receptor levels of TLR2 and TLR4, respectively, in a biracial cohort of adults. To our knowledge, this is the first study to look at associations between variants in the toll-like receptor family and toll-like receptor levels on monocytes. PMID- 21298447 TI - Predators or prey? Spatio-temporal discrimination of human-derived risk by brown bears. AB - Prey usually adjust anti-predator behavior to subtle variations in perceived risk. However, it is not clear whether adult large carnivores that are virtually free of natural predation adjust their behavior to subtle variations in human derived risk, even when living in human-dominated landscapes. As a model, we studied resting-site selection by a large carnivore, the brown bear (Ursus arctos), under different spatial and temporal levels of human activity. We quantified horizontal and canopy cover at 440 bear beds and 439 random sites at different distances from human settlements, seasons, and times of the day. We hypothesized that beds would be more concealed than random sites and that beds would be more concealed in relation to human-derived risk. Although human densities in Scandinavia are the lowest within bear ranges in Western Europe, we found an effect of human activity; bears chose beds with higher horizontal and canopy cover during the day (0700-1900 hours), especially when resting closer to human settlements, than at night (2200-0600 hours). In summer/fall (the berry season), with more intensive and dispersed human activity, including hunting, bears rested further from human settlements during the day than in spring (pre berry season). Additionally, day beds in the summer/fall were the most concealed. Large carnivores often avoid humans at a landscape scale, but total avoidance in human-dominated areas is not possible. Apparently, bears adjust their behavior to avoid human encounters, which resembles the way prey avoid their predators. Bears responded to fine-scale variations in human-derived risk, both on a seasonal and a daily basis. PMID- 21298448 TI - Bayesian calibration of the Unified budburst model in six temperate tree species. AB - Numerous phenology models developed to predict the budburst date of trees have been merged into one Unified model (Chuine, 2000, J. Theor. Biol. 207, 337-347). In this study, we tested a simplified version of the Unified model (Unichill model) on six woody species. Budburst and temperature data were available for five sites across Belgium from 1957 to 1995. We calibrated the Unichill model using a Bayesian calibration procedure, which reduced the uncertainty of the parameter coefficients and quantified the prediction uncertainty. The model performance differed among species. For two species (chestnut and black locust), the model showed good performance when tested against independent data not used for calibration. For the four other species (beech, oak, birch, ash), the model performed poorly. Model performance improved substantially for most species when using site-specific parameter coefficients instead of across-site parameter coefficients. This suggested that budburst is influenced by local environment and/or genetic differences among populations. Chestnut, black locust and birch were found to be temperature-driven species, and we therefore analyzed the sensitivity of budburst date to forcing temperature in those three species. Model results showed that budburst advanced with increasing temperature for 1-3 days degrees C(-1), which agreed with the observed trends. In synthesis, our results suggest that the Unichill model can be successfully applied to chestnut and black locust (with both across-site and site-specific calibration) and to birch (with site-specific calibration). For other species, temperature is not the only determinant of budburst and additional influencing factors will need to be included in the model. PMID- 21298449 TI - Coping processes relevant to posttraumatic growth: an evidence-based review. AB - OBJECTIVE: This study aims to perform an evidence-based review on the quantitative data regarding coping processes related to posttraumatic growth in the field of oncology to facilitate understanding of posttraumatic growth in oral cavity cancer (OCC) patients. MATERIAL AND METHODS: Pubmed, Medline, and PsycINFO were used for the search and the reference list checked for each selected article. Full articles meeting the inclusion criteria were retrieved. Only English articles were included. RESULTS: The initial search yielded 934 publications; 64 "potentially relevant papers" and 21 "effective" papers formed the basis of this review. Personality traits and social support lead to development of positive coping methods in cancer patients. Overriding influences are benefit finding and meaning making. Specific coping processes were identified to be significantly associated with posttraumatic growth in patients suffering from different cancers and a need for additional prospective research regarding specific processes and outcomes among oral cavity cancer patients. A proposed theoretical model based on the evidence of management of other cancer research fields is suggested for patients with OCC. CONCLUSION: An evidence-based review of coping strategies related to posttraumatic growth was performed which identified key coping strategies and factors that enhance coping processes. A conceptual model of coping strategies to enhance posttraumatic growth in OCC patients based on the scientific evidence attained is suggested to provide a more holistic approach to OCC management. PMID- 21298450 TI - Experiences of patients with laryngectomies as they reintegrate into their community. AB - BACKGROUND: The purpose of this qualitative study is to describe the patient's experiences as they reintegrate into the community following laryngectomy surgery and identify their perceived support and barriers within this transition. METHODS: Using Thorne's interpretive descriptive approach, purposeful sampling was used to recruit participants from two large urban hospitals. In-depth, audio taped interviews were conducted with nine participants 6-12 months following surgery. RESULTS: Enveloped under an overarching theme of a "Constant Accommodation to Life with a Laryngectomy," were three main themes: (1) "Impact of Cancer Diagnosis," (2) "Coping with Illness: Trying to Live Life like Before," and (3) "Transitions in Recovery." Subthemes further illuminated the constant accommodation participants had to make following cancer recurrence, surgery, and returning home. CONCLUSIONS: Patients with laryngectomies face major changes in lifestyle related to altered airway, loss of voice, body image concerns, and challenges with eating. Support of family, friends, and health care professionals is critical for successful transition during this stressful period. Instant messaging, email, Web-based support groups, and video messaging can contribute to a great improvement in communication and engagement for this population. PMID- 21298451 TI - Clinical features and surgical treatment of trigeminal neuralgia caused solely by venous compression. AB - PURPOSE: To summarize our experience and lessons of microvascular decompression surgery for trigeminal neuralgia caused solely by venous compression. METHODS: Fifteen patients with idiopathic trigeminal neuralgia caused by venous compression only underwent microvascular decompression. The entire course of the trigeminal root was explored thoroughly; and coagulating and cutting techniques were preferred in decompressing the culprit veins. Their clinical features, outcomes and operative complications were analyzed. RESULTS: The compressing veins included the transverse pontine vein in five cases (33.3%), the transverse pontine vein and the vein of middle cerebellar peduncle in one (6.7%), the transverse pontine vein and the vein of cerebellopontine fissure in one (6.7%), the superior petrosal vein in three (20%), the pontotrigeminal vein in one (6.7%), the vein of the cerebellopontine fissure in two (13.3%), and the plexus venosus or venule in two (13.3%). After microvascular decompression, 11 cases (73.3%) had "excellent" or "good" pain relief. Four cases (26.7%) failed the first surgery; and two of them underwent re-operation and got "excellent" pain relief. Postoperative facial numbness appeared in four cases, due to injury to trigeminal nerve when coagulation. CONCLUSION: The transverse pontine vein is the most common offending vein. For this type of trigeminal neuralgia, coagulating and cutting techniques are preferred in decompressing the culprit veins. The entire course of the trigeminal root should be explored and decompressed. Following these principles, excellent or good pain relief could be achieved in most cases; and recurrence is rare. However, sometimes injury to the nerve is unavoidable when coagulating the culprit vein. PMID- 21298452 TI - Surgical treatment of pediatric hemifacial spasm patients. AB - PURPOSE: To study the clinical features and outcomes of pediatric primary hemifacial spasm patients who underwent microvascular decompression procedures. METHODS: In this retrospective study, five pediatric (<18 years old) primary hemifacial spasm patients underwent microvascular decompression. After surgery, resolution of spasms and surgical complications were observed. Their social adaptability was evaluated using a social adaptation scale, which was designed specially for Chinese middle-school students. RESULTS: Four typical hemifacial spasm patients had immediate excellent or good relief. However, the microvascular decompression procedure did not help the atypical patient much (50% relief of spasm). The score of social adaptation of the pediatric hemifacial spasm patients was 111.6 +/- 8.2. Compared with the ordinary healthy Chinese middle-school students, whose score is 170.8 +/- 25.4, the patients experienced great difficulty in social adaptation (P < 0.01). After surgery, the scores of two patients increased to a normal level; however, the other three patients remained unchanged. CONCLUSIONS: Microvascular decompression is effective and safe to typical primary hemifacial spasm patients younger than 18 years old. Hemifacial spasm is harmful to the children's social adaptation. However, only some of the patients recovered to the normal social adaptation level even when the spasms were cured. PMID- 21298453 TI - Cognitive outcome after EC-IC bypass surgery in hemodynamic cerebral ischemia. AB - OBJECTIVE: The purpose of this study was to evaluate cognitive functions in patients undergoing extracranial-intracranial (EC-IC) bypass surgery for cerebral ischemia. POPULATION AND METHODS: From August 2003 to January 2009, 276 patients with occluded internal carotid arteries (ICA) were screened. Forty of these met the criteria for a low-flow EC-IC bypass. These patients were identified based on evidence of exhausted vasomotor reactivity (VMR) using the Doppler CO(2) test and CT perfusion. These patients were invited to have a complete battery of neuropsychological tests preoperatively and 12 months after surgery. Complete neurocognitive testing was finished in 20 patients. RESULTS: This group of 20 patients showed preoperative cognitive impairment ranging from mild to medium severe. There were no cases of stroke ipsilateral to the operated side during the follow-up period. VMR improvement was seen in all patients within 6 months of surgery. A comparison using a paired t-test demonstrated significant improvement 12 months after surgery in the following neuropsychological tests: WAIS-R (p = 0.01), Number Collection Test (p = 0.02), Trail Making Test (p = 0.03), and Benton Visual Retention Test (p = 0.05). Repeat analysis of variance (ANOVA) suggested the following predictors associated with cognitive improvement:the presence of ophthalmic collateral flow (p = 0.04), preoperative amaurosis fugax (p = 0.02), and external watershed infarction detected by MRI (p = 0.04). CONCLUSION: Patients with occlusion of the ICA and exhausted VMR have cognitive impairment prior to EC-IC bypass surgery. Twelve months after surgery, there is significant improvement in various areas of cognition. PMID- 21298455 TI - The small nuclear ribonucleoprotein U1A interacts with NS5 from yellow fever virus. AB - The flavivirus NS5 protein is one of the most important proteins of the replication complex, and cellular proteins can interact with it. This study shows for the first time that the yellow fever virus (YFV) NS5 protein is able to interact with U1A, a protein involved in splicing and polyadenylation. We confirmed this interaction by GST-pulldown assay and by co-immunoprecipitation in YFV-infected cells. A region between amino acids 368 and 448 was identified as the site of interaction of the NS5 protein with U1A. This region was conserved among some flaviviruses of medical importance. The implications of this interaction for flavivirus replication are discussed. PMID- 21298454 TI - A possible role for secreted ferritin in tissue iron distribution. AB - Ferritin is known as a well-conserved iron detoxification and storage protein that is found in the cytosol of many prokaryotic and eukaryotic organisms. In insects and worms, ferritin has evolved into a classically secreted protein that transports iron systemically. Mammalian ferritins are found intracellularly in the cytosol, as well as in the nucleus, the endo-lysosomal compartment and the mitochondria. Extracellular ferritin is found in fluids such as serum and synovial and cerebrospinal fluids. We recently characterized the biophysical properties, secretion mechanism and cellular origin of mouse serum ferritin, which is actively secreted by a non-classical pathway involving lysosomal processing. Here, we review the data to support a hypothesis that intracellular and extracellular ferritin may play a role in intra- and intercellular redistribution of iron. PMID- 21298456 TI - Whole-genome analysis of a human rabies virus from Sri Lanka. AB - The complete genome sequence of a human rabies virus, strain H-08-1320, from Sri Lanka was determined and compared with other rabies viruses. The size of the genome was 11,926 nt, and it was composed of a 58-nucleotide 3' leader, five protein genes--N (1353 nt), P (894 nt), M (609 nt), G (1575 nt), and L (6387 nt)- and a 70-nt 5' trailer. The intergenic region G-L contained 515 nt. The sizes of the nucleoprotein, phosphoprotein, matrix-protein, glycoprotein and large-protein was 450, 296, 202, 524 and 2,128 residues, respectively. The phosphoprotein and large protein were one amino acid shorter and longer, respectively, than those of most rabies viruses. The glycoprotein of H-08-1320 had a unique amino acid substitution at antigenic site I. Whole-genome phylogenetic analysis showed that strain H-08-1320 formed an independent lineage and did not cluster with rabies viruses from other countries. PMID- 21298457 TI - Characterization of rabies virus from a human case in Nepal. AB - Rabies is endemic throughout most of Asia, with the majority of human cases transmitted by domestic dogs (Canis familiaris). Here, we report a case of rabies in a 12-year-old girl in the Lalitpur district of Nepal that might have been prevented by better public awareness and timely post-exposure prophylaxis. Molecular characterization of the virus showed 100% identity over a partial nucleoprotein gene sequence to previous isolates from Nepal belonging to the 'arctic-like' lineage of rabies virus. Sequence analysis of both partial nucleoprotein and glycoprotein genes showed differences in consensus sequence after passage in vitro but not after passage in vivo. PMID- 21298458 TI - Human antimicrobial proteins in ear wax. AB - The external auditory canal is vulnerable to bacterial infections, but little is known about thechemical compositions of ear wax regarding antimicrobial peptides. We, therefore, studied the proteinconcentrations of ten well-known human antimicrobial peptides from ear wax.Twenty ear wax samples from healthy individuals were analysed using enzyme-linked immunosorbent assay (ELISA) to determine theprotein concentrations of the antimicrobial peptides hBD1-3, lactoferrin, LL-37, BPI, hSLPI and HNP1-3. All ten antimicrobial peptides are present in ear wax. Some of these proteins seem to be merelycell-bound in ear wax. Antimicrobial peptides in ear wax prevent bacteria and fungi from causing infections inthe external auditory canal. The role and importance of these proteins for the blind-ending ear externalcanal is discussed. If this local defence system fails, infections of the external auditory canal may result.The knowledge about the presence of antimicrobial peptides in cerumen may lead to new concepts ofthe local treatment of external auditory canal diseases in the future. PMID- 21298459 TI - In vitro activity of beta-lactam antibiotics against CTX-M-producing Escherichia coli. AB - Beta-lactam antibiotics have been discussed as options for the treatment of infections caused by multiresistant extended-spectrum beta-lactamase (ESBL) producing bacteria if the minimum inhibitory concentration (MIC) is low. The objective of this study was to investigate the in vitro activity of different beta-lactam antibiotics against CTX-M-producing Escherichia coli. A total of 198 isolates of E. coli with the ESBL phenotype were studied. Polymerase chain reaction (PCR) amplification of CTX-M genes and amplicon sequencing were performed. The MICs for amoxicillin-clavulanic acid, aztreonam, cefepime, cefotaxime, ceftazidime, ceftibuten, ertapenem, imipenem, mecillinam, meropenem, piperacillin-tazobactam, and temocillin were determined with the Etest. Susceptibility was defined according to the breakpoints of the European Committee on Antimicrobial Susceptibility Testing (EUCAST). MIC(50) and MIC(90) values were calculated. Isolates from CTX-M group 9 showed higher susceptibility to the beta lactam antibiotics tested than isolates belonging to CTX-M group 1. More than 90% of the isolates belonging to CTX-M group 9 were susceptible to amoxicillin clavulanic acid, ceftazidime, ceftibuten, piperacillin-tazobactam, and temocillin. The susceptibility was high to mecillinam, being 91%, regardless of the CTX-M group. All isolates were susceptible to imipenem and meropenem, and 99% to ertapenem. This study shows significant differences in susceptibility to different beta-lactam antibiotics among the CTX-M-producing E. coli isolates and a significant difference for many antibiotics tested between the CTX-M-producing groups 1 and 9. The good in vitro activity of other beta-lactam antibiotics compared to carbapenems indicate that clinical studies are warranted in order to examine the potential role of these beta-lactam antibiotics in the treatment of infections caused by multiresistant ESBL-producing E. coli. PMID- 21298460 TI - Clinical evaluation of the Copan ESwab for methicillin-resistant Staphylococcus aureus detection and culture of wounds. AB - The screening for and diagnosis of bacteriological infections often involves the collection and transportation of swab samples. The Copan ESwab was compared with the dry cotton Copan swab for methicillin-resistant Staphylococcus aureus (MRSA) screening (n = 200 paired samples) and with the Amies agar gel swab (Copan) for the sampling of burn and orthopaedic wounds (n = 203 paired samples) in terms of Gram staining and bacterial recovery. Gram stains performed with ESwab liquid showed significantly more Gram-negative rods, streptococci, Gram-positive cocci, Gram-positive rods, polymorphonuclear cells, lymphocytes and red blood cells than Gram stains from dry swabs. Bacterial recovery was significantly higher with ESwab (p < 0.01, for both MRSA screening and wounds, quantitative/semi quantitative method). This lead to a slightly higher detection rate of MRSA (128 vs. 124 MRSA-positive ESwabs and dry swabs, respectively, p = 0.50) and a higher detection rate of coagulase-negative Staphylococcus spp. (44 isolates with ESwab vs. 29 with Amies gel swab, p = 0.001) and Enterococcus spp. (15 isolates with ESwab vs. 7 isolates with Amies gel swab, p = 0.005) with ESwab (quantitative method). We confirmed that ESwab has a high performance for Gram stains and a higher bacterial recovery than dry and Amies gel swabs when using clinical samples for MRSA screening and wound sampling. PMID- 21298461 TI - Successful management of an MRSA outbreak in a neonatal intensive care unit. AB - We report an MRSA outbreak in our 25-bed tertiary neonatal intensive care unit (NICU), which was successfully contained. Methods include a retrospective review of patient files, microbiology records and meeting protocols. During the seven months of outbreak, 27 patients and seven health care workers (HCWs) had positive cultures for MRSA. The outbreak was caused by the epidemic Rhine-Hessen strain; cultured isolates were monoclonal. After a sharp increase of the number of new MRSA-cases the installation of an outbreak management team (OMT) and implementation of comprehensive measures (extensive screening and decolonization strategy including orally applied vancomycin, isolation wards, intensive disinfection regimen) successfully terminated the outbreak within one month. Ten (53%) of 19 patients with completed follow-up and all of the HCWs were decolonized successfully. Gastrointestinal colonization was present in 15 of 27 (56%) neonates, and was associated with poor decolonization success (30% vs. 78% in absence of gastrointestinal colonization). A comprehensive outbreak management can terminate an outbreak in a NICU setting within a short time. Thorough screening of nares, throat and especially stool is necessary for correct cohorting. Gastrointestinal decolonization in neonates seems difficult. PMID- 21298462 TI - Anxiety disorders in headache patients in a specialised clinic: prevalence and symptoms in comparison to patients in a general neurological clinic. AB - Data from several studies indicate an association of headache with anxiety disorders. In this study, we assessed and differentiated anxiety disorders in 100 headache patients by using the PSWQ (Penn State Worry Questionnaire) screening tool for generalised anxiety disorder (GAD) and the ACQ (Agoraphobic Cognitions Questionnaire) and BSQ (Body Sensation Questionnaire) for panic disorder (PD). Control groups were constructed: (1) on the basis of epidemiological studies on PD and GAD in the general population and (2) by including neurological patients. 37.0% of headache patients had a GAD. 27% of headache patients met the score for PD in the BSQ, 4.0% in the ACQ. Significant results were obtained in comparison to the general population (p < 0.001) and with regard to GAD in comparison with a sample of neurological patients (p < 0.005). The BSQ significantly correlated with the number of medication days (p < 0.005). The results confirm the increased prevalence of GAD in headache patients. PD seems to increase the risk of medication overuse. PMID- 21298463 TI - Enhanced secreting expression and improved properties of a recombinant alkaline endoglucanase cloned in Escherichia coli. AB - An alkaline endoglucanase from Bacillus akibai III-3A was successfully expressed in Escherichia coli in active form, and secretion was greatly enhanced by addition of 5 g/l ethylenediamine tetraacetic acid (EDTA) to the culture medium at the induction time of 12 h. Under the optimal culture conditions, extracellular and total endoglucanase activities were 18.5 and 31.2 U/ml, respectively. Both the recombinant and native enzymes exhibited similar properties with respect to broad pH stability, good thermostability, and resistibility to various metal ions and reagents examined. However, unlike the native endoglucanase that was partly inhibited by sodium dodecyl sulfate (SDS), the recombinant enzyme had good resistibility to SDS, being very stable in the commercial detergents, and no decrease in residual activity was observed in 0.2% (w/v) laundry detergent, indicating that it was suitable for application in detergents industry. PMID- 21298464 TI - Why you should read Dr. Cramer's perspective. PMID- 21298465 TI - High-level expression of a suite of thermostable cell wall-degrading enzymes from the chloroplast genome. AB - The biological conversion of plant biomass into fermentable sugars is key to the efficient production of biofuels and other renewable chemicals from plants. As up to more than 90% of the dry weight of higher plants is fixed in the cell wall, this will require the low-cost production of large amounts of cell wall-degrading enzymes. Transgenic plants can potentially provide an unbeatably cheap production platform for industrial enzymes. Transgene expression from the plastid genome is particularly attractive, due to high-level foreign protein accumulation in chloroplasts, absence of epigenetic gene silencing and improved transgene containment. Here, we have explored the potential of transplastomic plants to produce large amounts of thermostable cell wall-degrading enzymes from the bacterium Thermobifida fusca. We show that a set of four enzymes that are required for efficient degradation of cellulose (and the hemicellulose xyloglucan) could be expressed successfully in transplastomic tobacco plants. However, overexpression of the enzymes (to between approximately 5 and 40% of the plant's total soluble protein) resulted in pigment-deficient mutant phenotypes. We demonstrate that the chloroplast-produced cellulolytic enzymes are highly active. Although further optimization is needed, our data indicate that transgenic plastids offer great potential for the production of enzyme cocktails for the bioconversion of cellulosic biomass. PMID- 21298466 TI - Effect of coffee consumption on all-cause and total cancer mortality: findings from the JACC study. AB - Coffee consumption is known to be related to various health conditions. Recently, its antioxidant effects have been suggested to be associated with all-cause or cancer mortality by various cohort studies. However, there has been only one small Asian cohort study that has assessed this association. Thus, we tried to assess the association of coffee with all-cause and total cancer mortality by conducting a large-scale cohort study in Japan. A total of 97,753 Japanese men and women aged 40-79 years were followed for 16 years. Hazard ratios and 95% confidence intervals of all-cause and total cancer mortality in relation to coffee consumption were calculated from proportional-hazards regression models. A total of 19,532 deaths occurred during the follow-up period; 34.8% of these deaths were caused by cancer. The all-cause mortality risk decreased with increasing coffee consumption in both men and women, with a risk elevation at the highest coffee consumption level (>=4 cups/day) compared with the 2nd highest consumption level in women, although the number of subjects evaluated at this level was small. No association was found between coffee consumption and total cancer mortality among men, whereas a weak inverse association was found among women. The present cohort study among the Japanese population suggested that there are beneficial effects of coffee on all-cause mortality among both men and women. Furthermore, the results showed that coffee consumption might not be associated with an increased risk of total cancer mortality. PMID- 21298467 TI - Clinical validity of detecting K-ras mutations for the diagnosis of exocrine pancreatic cancer: a prospective study in a clinically-relevant spectrum of patients. AB - The diagnostic utility of detecting K-ras mutations for the diagnosis of exocrine pancreatic cancer (EPC) has not been properly studied, and few reports have analysed a clinically relevant spectrum of patients. The objective was to evaluate the clinical validity of detecting K-ras mutations in the diagnosis of EPC in a large sample of clinically relevant patients. We prospectively identified 374 patients in whom one of the following diagnoses was suspected at hospital admission: EPC, chronic pancreatitis, pancreatic cysts, and cancer of the extrahepatic biliary system. Mutations in the K-ras oncogene were analysed by PCR and artificial RFLP in 212 patients. The sensitivity and specificity of the K ras mutational status for the diagnosis of EPC were 77.7% (95% CI: 69.2-84.8) and 78.0% (68.1-86.0), respectively. The diagnostic accuracy was hardly modified by sex and age. In patients with either mutated K-ras or CEA > 5 ng/ml, the sensitivity and specificity were 81.0% (72.9-87.6) and 62.6% (72.9-87.6), respectively. In patients with mutated K-ras and CEA > 5 ng/ml the sensitivity was markedly reduced. In comparisons with a variety of non-EPC patient groups sensitivity and specificity were both always greater than 75%. In this clinically relevant sample of patients the sensitivity and specificity of K-ras mutations were not sufficiently high for independent diagnostic use. However, it seems premature to rule out the utility of K-ras analysis in conjunction with other genetic and 'omics' technologies. PMID- 21298468 TI - Age-specific trends in cardiovascular mortality rates in the Netherlands between 1980 and 2009. AB - Recent analyses suggest the decline in coronary heart disease mortality rates is slowing in younger age groups in countries such as the US and the UK. This work aimed to analyse recent trends in cardiovascular mortality rates in the Netherlands. Analysis was of annual all circulatory, ischaemic heart disease (IHD), and cerebrovascular disease mortality rates between 1980 and 2009 for the Netherlands. Data were stratified by sex and 10-year age group (age 35-85+). The annual rate of change and significant changes in the trend were identified using join point Poisson regression. For almost all age and sex groups examined the rate of IHD and cerebrovascular disease mortality in the Netherlands has more than halved between 1980 and 2009. The decline in mortality from both IHD and cerebrovascular disease is continuing for all ages and sex groups, with an acceleration in the decline apparent from the late 1990s/early 2000s. The decline in age-specific all circulatory, coronary heart disease and cerebrovascular disease mortality rates continues for all age and sex groups in the Netherlands. PMID- 21298469 TI - Risk of diabetes after gestational diabetes and preeclampsia. A registry-based study of 230,000 women in Norway. AB - This study aimed to use a population-based Prescription Database to explore later development of diabetes in women registered with gestational diabetes mellitus (GDM) and/or preeclampsia in the Medical Birth Registry of Norway (MBRN) during 2004-8. We used two nationwide Norwegian registries, the Norwegian Prescription Database and the MBRN, to explore the onset of later diabetes after pregnancy complications, indicated by receiving prescriptions of drugs used to treat diabetes, in 230,000 women giving birth in 2004-8. The mean follow-up of the study cohort was 3.7 years. Five years after pregnancy, about 19 and 2% of women with GDM and preeclampsia, respectively, received drugs used to treat diabetes, compared to 0.5% of those without these complications. The risk of being dispensed drugs used to treat diabetes within the first years after pregnancy was estimated to be 41 times (95% CI: 35-47) and 3.0 times (95% CI: 2.4-3.6) higher in women with GDM and preeclampsia, respectively, compared to women without these pregnancy complications. Women with pregnancies complicated with preeclampsia or GDM had an increased risk of later diabetes, especially those having GDM. If the increase in frequency of GDM observed in MBRN in recent years is real, a further increase in diabetic women can be expected. PMID- 21298470 TI - A noteworthy record of Ornithodoros (Alectorobius) coniceps (Ixodida: Argasidae) from Central Italy. AB - The first record of Ornithodoros (Alectorobius) coniceps (Canestrini) was reported for Italy in 1877, inside the interstices of the ancient mosaics at S. Marco Basilica in Venice. Afterwards only few discoveries of the species are reported for Italy; the last record is dated back to 1984, in L'Aquila town (Abruzzo Region). The present study shows the data of a survey carried out as a result of a massive infestation by O. coniceps in an ancient villa in Anzio town (Latium region) recently restored. In the past decades the villa has been fallen into disrepair, becoming an occasional shelter for wild animals mainly pigeons, that colonized the whole building for generations. This case appears worthy of note because it is the first record of this species after more than 25 years in Italy. A total of 136 specimens were collected by three methods: manual, mechanical aspirators and Wilson traps. Wilson trapping indicates positive O. coniceps tropism for CO(2). PMID- 21298471 TI - TGF-beta isoforms inhibit IGF-1-induced migration and regulate terminal differentiation in a cell-specific manner. AB - Following muscle injury, the damaged tissue and influx of inflammatory cells stimulate the secretion of growth factors and cytokines to initiate repair processes. This release of chemotactic signaling factors activates resident precursor cells and stimulates their mobilization and migration to the site of injury where terminal differentiation can occur. The three transforming growth factor-beta (TGF-beta) isoforms, and insulin-like growth factor-1 (IGF-1) are among the known regulatory factors released following muscle damage. We investigated the effect of recombinant active TGF-beta1, -beta2, -beta3 and IGF-1 on C2C12 skeletal muscle satellite cell and P19 embryonal carcinoma cell terminal differentiation and migration. C2C12 myoblast fusion as well as P19 embryoid body formation and myogenic differentiation was assessed following 72 h TGF-beta treatment (5 ng/ml), whereas the effect of the TGF-beta isoforms on migration was determined following 7 h incubation. Our results showed that TGF-beta decreases C2C12 myoblast fusion in an isoform-independent manner, whereas in the P19 cell lineage, results demonstrate that TGF-beta1 specifically and significantly increased P19 embryoid body formation, but not expression of Connexin-43 or Myosin Heavy Chain. IGF-1 significantly increased migration compared to TGF-beta isoforms, which, on their own, had no significant effect on the mobilization of either C2C12 or P19 cells. TGF-beta isoforms decreased IGF-1-induced migration of both cell lineages. By distinguishing the factors involved in, and the molecular signals required for, myoblast recruitment during repair processes, strategies can be developed towards improved cell-mediated therapies for muscle injury. PMID- 21298472 TI - Quality of mental health care at a student-run clinic: care for the uninsured exceeds that of publicly and privately insured populations. AB - Diagnosing and treating depression in a primary care practice is an important, yet difficult task, especially for safety-net practices serving the uninsured. In the United States healthcare system, there is a mismatch between the need for mental health care and access to services. This disparity is most striking among the uninsured. Mental health disorders are more prevalent among the uninsured, and even when diagnosed with mental illness, they are less likely to obtain necessary treatment than insured patients. Given the increasing burden of depression on society, growing numbers of uninsured and negative repercussions of untreated mental illness, improvements in screening and management protocols are becoming more important in primary care practices serving this population. The quality of depression treatment at commercial and public insurance plans in New York City (NYC) and New York State (NYS) were compared to that of the East Harlem Health Outreach Partnership (EHHOP), the student-run clinic of the Mount Sinai School of Medicine. Based on the comparison, the study made recommendations for an integrated, on-site mental health service program at the community health clinic. A cohort of 49 depressed patients were evaluated and treated at the EHHOP clinic. The quality of the mental health care was evaluated according to variables from the Healthcare Effectiveness Data and Information Set (HEDIS). Indicators of quality included demographics, method of diagnosis, type of pharmacological treatment, referral to specialty care, patient adherence to follow-up care and adherence to pharmacologic treatment. When compared to insured patients in NYS, more EHHOP patients had the appropriate number of physician contacts after being diagnosed with depression than patients with commercial health plans (P = 0.008) and Medicaid (P = 0.09). Similarly, a greater number of EHHOP patients had better acute phase (P = 0.001; P = 0.096) and continuous phase (P = 0.049; P = 0.88) pharmacologic treatment than patients with commercial health plans and Medicaid, respectively. EHHOP meets and, in some areas, exceeds the quality of depression treatment when compared to insured populations. Even though EHHOP already surpasses these indicators, the clinic can improve its diagnostic capabilities, prescription medication adherence, and referral care follow-through by creating an on-site mental health clinic. PMID- 21298473 TI - The influence of social networks on patients' attitudes toward type II diabetes. AB - Social networks are increasingly recognized as important determinants of many chronic diseases, yet little data exist regarding the influence of social networks on diabetes. We surveyed diabetic patients to determine how social networks affect their overall level of concern regarding diabetes and its complications. We adapted a previously published instrument and surveyed 240 diabetic patients at two primary care practices. Patients recorded the number of family and friends who had diabetes and rated their level of concern about diabetes on a scale of 0% (no concern) to 100% (extremely concerned). Our primary outcome variable was patients' level of concern (<75% or >=75%). We developed logistic regression models to determine the effect of disease burden in patients' social networks on expressed level of concern about diabetes. We received 154 surveys (64% response rate). We found that for each additional family member with diabetes, patients expressed a greater level of concern about diabetes (AOR 1.5; 95% CI 1.2-2.0) and its potential complications (AOR 1.4; 95% CI 1.1-1.7). Similarly, patients with an increased number of friends with diabetes expressed greater concern about diabetes (AOR 1.5; 95% CI 1.2-1.9) and its complications (AOR 1.3; 95% CI 1.1-1.7). Patients with a higher prevalence of diabetes within their social networks expressed greater concern about diabetes and diabetic complications. Determining disease burden within patients' social networks may allow physicians to better understand patients' perspectives on their disease and ultimately help them achieve meaningful behavioral change. PMID- 21298474 TI - Protective factors at school: reciprocal effects among adolescents' perceptions of the school environment, engagement in learning, and hope. AB - Although some research suggests that schools can be a source of protective factors for students, the processes by which school environments impact students' behavior, performance and adjustment over time are not clear. Guided by both self determination theory and hope theory, this article evaluated reciprocal effects among adolescent perceptions of the school environment, engagement in learning, hope, and academic achievement. Using a sample of 423 students (M age 15.72 years; 46.7% female; 77.6% white; 30.9% eligible for FRPL) from five small secondary schools in the upper Midwest, students' perceptions of the school environment were linked to engagement in learning, which, in turn, was linked to change in academic achievement and hope over the span of 1 year. Evidence was found for reciprocal links between earlier levels of engagement and hope and later perceptions of the environment. These results suggest that the school environment represents a potential leverage point for educational reform, and interventions that target students' perceptions of autonomy, teacher/peer support, and goal orientation may be able to promote engagement, hope, and academic achievement. In addition, such changes may create a positive feedback loop in which change in academic performance and adjustment accelerate over time. PMID- 21298475 TI - Changes in psychotherapy utilization among consumers of services for major depressive disorder in the community mental health system. AB - The goal of this investigation was to explore changes in psychotherapy utilization for patients with major depressive disorder (MDD) treated in community mental health agencies across two cohorts. We used a Medicaid claims database including approximately 300,000 public sector clients. Although the use of psychotherapy alone showed a small decrease, there was a large increase in the use of combined medication and psychotherapy as a treatment for MDD. Race was a significant predictor of both treatment type received and length of treatment. African American consumers were more likely to receive psychotherapy alone than combined treatment and attended significantly fewer psychotherapy sessions. PMID- 21298476 TI - Alpha- and beta-adrenergic receptor (AR) protein expression is associated with poor clinical outcome in breast cancer: an immunohistochemical study. AB - Breast cancer mortality is frequently associated with metastatic disease. Metastasis models have shown adrenoceptor (AR) stimulation induces cell migration which is inhibited by adrenoceptor antagonist drugs. We investigated adrenoceptor protein expression in clinical breast tumours and its association with disease progression and prognosis. Immunohistochemistry on tissue microarrays was used to characterise alpha1b, alpha2c and beta(2)2 adrenoceptor protein expression in operable breast tumours. Associations with tumour-relevant biological markers and clinical outcome were statistically assessed. Strong alpha1b expression occurred in large high grade (P < 0.0001), HER2+ (P < 0.0001) or basal-like (CK5/6, P = 0.0005; CK14, P = 0.0001; EGFR, P = 0.003) cancers, showing increased proliferation (Mib1, P = 0.002), decreased apoptosis (Bcl2, P < 0.0001) and poor NPI membership (P = 0.001). alpha1b expression correlated with poor cancer specific survival (LR = 7.628, P = 0.022) and tumour recurrence (LR = 6.128, P = 0.047). Strong alpha2c was over-expressed in high grade (P = 0.007), HER3+ (P = 0.002) and HER4+ (P < 0.0001) cancers with borderline increase in EGFR, p53 and MIB1 proteins, and inverse association with hormonal (PgR, P = 0.002) phenotype. In contrast, strong beta(2) expression occurred in small-size, luminal-like (ER+, P < 0.001) tumours of low grade (P < 0.001) and lymph node stage (P = 0.027) that showed poor prognosis when hormonal treatment was withheld. Adrenoceptors were not found to be independent predictors of clinical outcome. Alpha1b and alpha2c AR is over-expressed in basal-like breast tumours of poor prognosis. Strong beta(2) adrenoceptor expression is seen in patients with a luminal (ER+) tumour phenotype and good prognosis, due to benefits derived from hormonal therapy. These findings suggest a possible role for targeted therapy using adrenoceptor antagonists. PMID- 21298477 TI - Breast cancer screening and ethnicity in the United States: implications for health disparities research. AB - Ethnic and racial minority women within the U.S. are less likely to use breast cancer screening (BCS) procedures than non-Latina White women, and are more likely to be diagnosed with cancer at later stages of disease. Previous studies examining Latina rates of screening and disease have used aggregated populations for comparison, possibly attenuating important ethnic healthcare disparities and yielding misleading findings. The purpose of this study was to examine if ethnicity matters in understanding current estimates of BCS patterns among U.S. women; to test if healthcare disparities in BCS are present, and if any ethnic/racial groups are primarily affected. The authors used multivariate multinomial regression to examine self-reported mammogram and clinical breast exam in the 2007 full-year U.S. Medical Expenditure Panel Survey. Mexican origin women reported the lowest rates of past-year mammograms and clinical breast examination. Factors enabling healthcare moderated the group's lower likelihood of mammograms and clinical breast examination. Some breast cancer screening parity appears to have been achieved in 2007 for Black and some Latina groups; however, those rates lag behind for the largest Latino ethnic group, Mexican. Factors enabling healthcare access, such as education, income and insurance, attenuated the BCS inequalities found for Mexican origin women. Findings suggest that successful efforts to reduce BCS disparities be strategically redirected to include women of Mexican origin in addition to other underserved populations. PMID- 21298478 TI - Zebrafish HSC70 promoter to express carp muscle-specific creatine kinase for acclimation under cold condition. AB - Zebrafish (Danio rerio) is used as a model system for in vivo studies. To expand the research scope of physical, biochemical and physiological studies, a cold tolerant model of zebrafish was developed. The common carp (Cyprinus carpio) muscle form of creatine kinase (CK, EC 2.7.3.2) can maintain enzymatic activity at a temperature of around 15 degrees C. However, a cold-inducible promoter of zebrafish, hsc 70 (heat shock protein 70 cognate), is able to increase the expression of gene product by 9.8 fold at a temperature of 16 degrees C. Therefore, the carp CK gene was promoted by hsc 70 and transfected into zebrafish embryos. Resulting transgenic zebrafish survived and could maintain its swimming behavior at 13 degrees C, which was not possible with the wild-type zebrafish. The swimming distance of the transgenic fish was 42% greater than that of the wild type at 13 degrees C. This new transgenic fish model is ideal for studies of ectothermal vertebrates in low-temperature environments. PMID- 21298479 TI - Intragastrically administered lysophosphatidic acids protect against gastric ulcer in rats under water-immersion restraint stress. AB - BACKGROUND AND AIM: Lysophosphatidic acid exerts important physiological effects on many types of animal cells through its specific binding to several G protein coupled receptors. In particular, its potent wound-healing effect has attracted much attention. To determine whether lysophosphatidic acids in a foodstuff and Chinese medicine are effective in protecting against gastric ulcer, we subjected rats to water-immersion restraint stress. METHODS AND RESULTS: Three direct administrations of a solution of lysophosphatidic acid with a C18 fatty acyl group to the rat stomach in a concentration range of 0.001-0.1 mM resulted in a significant reduction in the number of gastric ulcers induced during water immersion restraint stress, and the potencies were as follows: linoleoyl species=alpha-linolenoyl species>oleoyl species. Intragastric administrations of a solution of highly purified lysophosphatidic acid from soybean lecithin significantly protected against the stress-induced gastric ulcers at lower concentrations than partially purified lysophosphatidic acid from soybean lecithin did. In addition, administration of a decocted solution of antyu-san, and lysophosphatidic acid-rich Chinese medicine, to the stomach was more effective in protecting against stress-induced ulcer than decoctations of antyu san lacking the corydalis tuber component that is rich in lysophosphatidic acid. CONCLUSIONS: These results clearly show that lysophosphatidic acid is the effective component of soybean lecithin and antyu-san in protection against stress-induced gastric ulcer in the rat model, and suggest that daily intake of lysophosphatidic acid-rich foods or Chinese medicines may be beneficial for prevention of stress-induced gastric ulcer in human subjects. PMID- 21298480 TI - Low grade esophageal eosinophilia in adults: an unrecognized part of the spectrum of eosinophilic esophagitis? AB - BACKGROUND: Eosinophilic esophagitis (EoE) is defined by a minimum of 15 eosinophils (eos) per high-powered field (HPF) on esophageal biopsy, along with esophageal symptoms and the exclusion of gastroesophageal reflux (GERD). The clinical significance of fewer eosinophils is unknown. METHODS: Fifty-nine adult patients without a previous diagnosis of EoE with esophageal biopsies containing 1-14 eos per HPF (low grade eosinophilia) and 418 adult patients with >=15 eos per HPF were identified by retrospective review. Patients were divided into group A (1-9 eos per HPF), group B (10-14 eos per HPF), and group C (>=15 eos per HPF) with a chart review of clinical and demographic data. RESULTS: While dysphagia and atopy (asthma and allergic rhinitis) were more common in patients with >=15 eos per HPF (group C) than those with low grade esophageal eosinophilia (groups A and B) (93 vs. 88%, P = 0.02), food impaction and heartburn occurred at an equal frequency across all patient groups. Endoscopic findings were likewise similar between groups. Of the 14 patients with low grade esophageal eosinophilia who underwent repeat endoscopy a mean interval of 42 weeks (range 8-118 weeks) later, five (36%) met conventional diagnostic criteria for EoE of 15 or greater eos per HPF. Follow-up in ten patients treated with topical corticosteroids noted improvement in nine, with mean follow-up of 8 weeks (range 4-12 weeks). CONCLUSION: Some adult patients with dysphagia and less than 15 eos per HPF have similar endoscopic findings and clinical course to patients meeting the consensus definition of EoE. Further evaluation of patients with low grade esophageal eosinophilia is needed. PMID- 21298481 TI - A multicenter prospective study of the short-term outcome of a newly developed partially covered self-expandable metallic biliary stent (WallFlex((r))). AB - BACKGROUND: Self-expandable metallic stent (SEMS) placement is a widely used, effective therapy for unresectable malignant stricture of the lower bile duct. AIMS: We evaluated the short-term outcome of the newly developed WallFlex((r)) Biliary RX Partially Covered Stent in patients with malignant lower and middle biliary stricture in five tertiary referral centers. METHODS: The subjects of this study were 52 patients in whom WallFlex((r)) Biliary RX Stents were inserted into the bile duct for malignant stenosis of the middle and lower bile duct at five medical facilities between April 2009 and November 2009. RESULTS: The stent placement success rate was 100%. Effective biliary decompression was achieved in all patients. The incidence of early complications was 7.7% (4/52). Stent occlusion occurred in two patients (3.8%) (one dislocation, one migration); cholecystitis occurred in two patients (3.8%). Neither acute pancreatitis nor stent kinking in the bile duct occurred. CONCLUSIONS: The present results revealed that the new WallFlex((r)) Biliary RX Partially Covered SEMSs were useful for the short-term relief of biliary obstruction due to unresectable distal biliary malignancies. PMID- 21298482 TI - An examination of cesarean and vaginal birth histories among Hispanic women entering prenatal care in two California counties with large immigrant populations. AB - Repeat cesarean delivery (CD) rates among US Hispanic women are the highest of all racial/ethnic groups (90%). Vaginal birth after cesarean (VBAC) is an alternative delivery method, but requires medical records documentation of a non vertical incision and favorable conditions in the current pregnancy. VBAC rates for Hispanic women are extremely low. This study explores the birth histories and medical records access among Hispanic women in California, taking into account the potential role of immigration on access to VBAC. Study aims are to describe for a sample of Hispanic women: (1) CD and VBAC histories as well as history of vaginal delivery preceding CD; and (2) medical records access, among women who had previous births in Mexico. Chart review was conducted for prenatal patients from three safety net clinics in two California counties with large Mexican migrant populations between August, 2003 and February 2004--during which VBAC was widely available in these two counties to determine: obstetric histories, CD details, birthplace and whether or not medical records had been requested/obtained for CD. 355 multiparous Hispanic women were included. Thirty three percent had a previous CD, almost two-thirds (64%) had only one CD. Over half of the women (55%) with 2+ births and CD history also reported a vaginal birth history. Medical records for CD were infrequently requested (29%). Of those requested, records were received for 77% of women with a US CD, compared with 13% of women with Mexican CD histories. Policies to address: (1) VBAC opportunities for low risk women, such as those with prior vaginal births and one CD, and (2) overcoming limited medical records access, could mitigate against unnecessary CD and associated medical expenditures and risks for future complications. PMID- 21298483 TI - Prevalence of cardiovascular disease risk factors among older Puerto Rican adults living in Massachusetts. AB - There remains limited research on cardiovascular disease (CVD) risk factors in Puerto Rican adults. We compared lifestyle and CVD risk factors in Puerto Rican men and women with normal fasting glucose (NFG), impaired fasting glucose (IFG), or type 2 diabetes (T2D), and investigated achievement of American Diabetes Association (ADA) treatment goals in those with T2D. Baseline data from the Boston Puerto Rican Health Study were analyzed, which included 1,287 adults aged 45-75 years. Obesity, hyperglycemia, and dyslipidemia were prevalent and increased from NFG to IFG and T2D. In individuals without T2D, fasting insulin correlated significantly with body mass index. Achievement of ADA goals was poor; LDL cholesterol was most achieved (59.4%), followed by blood pressure (27.2%) and glycosylated hemoglobin (27.0%). Poverty, female sex, current alcohol use, and diabetes or anti-hypertensive medication use were associated with not meeting goals. Puerto Rican adults living in the Boston area showed several metabolic abnormalities and high CVD risk, likely due to pervasive obesity and socio economic disparities. PMID- 21298484 TI - Increased urinary 8-hydroxy-2'-deoxyguanosine levels in workers exposed to di-(2 ethylhexyl) phthalate in a waste plastic recycling site in China. AB - BACKGROUND: Di-(2-ethylhexyl) phthalate (DEHP) is a common plasticizer used in industrial and diverse consumer products. Animal studies indicate DEHP caused developmental, reproductive, and hepatic toxicities. However, human studies of the potential effects of DEHP are limited. METHODS: The exposed site with a history of over 20 years of waste plastic recycling was located in Hunan Province, China. The reference site without known DEHP pollution source was about 50 km far away from the exposed site. In this study, 181 workers working in plastic waste recycling and 160 gender-age matched farmers were recruited. DEHP concentrations in water and cultivated soil samples, serum thyroid-stimulating hormone, malondialdehyde (MDA), superoxide dismutase (SOD), urinary 8-hydroxy-2' deoxyguanosine (8-OHdG), and micronuclei frequency in human capillary blood lymphocytes were analyzed. RESULTS: Mean levels of DEHP were greater in environment at the recycling site than at reference site (industry wastewater for the exposed: 42.43 MUg/l; well water: 14.20 vs. 0.79 MUg/l, pond water: 135.68 vs. 0.37 MUg/l, cultivated soil: 13.07 vs. 0.81 mg/kg, p < 0.05 for all). The workers had higher median levels of MDA (3.80 vs. 3.14 nmol/ml) and urinary 8 OHdG (340.37 vs. 268.18 MUmol/mol creatinine) and decreased SOD activities (112.15 vs. 123.82 U/ml) than the reference group (p < 0.01 for all). Multivariate analysis revealed that the history of working in waste plastic recycling was an independent risk factor for the increased urinary 8-OHdG levels in the male workers (p < 0.01). CONCLUSIONS: The occupational DEHP exposure might contribute to oxidative deoxyribonucleic acid damage in the male workers. PMID- 21298485 TI - Racial segregation, income inequality, and mortality in US metropolitan areas. AB - Evidence of the association between income inequality and mortality has been mixed. Studies indicate that growing income inequalities reflect inequalities between, rather than within, racial groups. Racial segregation may play a role. We examine the role of racial segregation on the relationship between income inequality and mortality in a cross-section of US metropolitan areas. Metropolitan areas were included if they had a population of at least 100,000 and were at least 10% black (N = 107). Deaths for the time period 1991-1999 were used to calculate age-adjusted all-cause mortality rates for each metropolitan statistical area (MSA) using direct age-adjustment techniques. Multivariate least squares regression was used to examine associations for the total sample and for blacks and whites separately. Income inequality was associated with lower mortality rates among whites and higher mortality rates among blacks. There was a significant interaction between income inequality and racial segregation. A significant graded inverse income inequality/mortality association was found for MSAs with higher versus lower levels of black-white racial segregation. Effects were stronger among whites than among blacks. A positive income inequality/mortality association was found in MSAs with higher versus lower levels of Hispanic-white segregation. Uncertainty regarding the income inequality/mortality association found in previous studies may be related to the omission of important variables such as racial segregation that modify associations differently between groups. Research is needed to further elucidate the risk and protective effects of racial segregation across groups. PMID- 21298487 TI - Innate immunity signaling pathways: links between immunonutrition and responses to sepsis. AB - Septic infections in patients treated in intensive care units show the highest mortality rates. Despite advances in treatment methods, there is still no therapy available to efficiently reduce the excessive inflammatory response, which can increase the risk of multiple organ failure. One of the ways to discover new, more efficient treatment methods involves regulating the mechanisms of inflammatory response to a massive infection. Toll-like receptors (TLRs) that recognize pathogen-associated molecular patterns play a significant role in innate antibacterial and inflammatory responses. The regulatory impact of immunonutrition on TLR expression in septic patients seems to be a promising research direction. This paper presents the main mechanisms for the innate immune response to lipopolysaccharide, based on the research results for both TLR dependent and independent signaling pathways. Special emphasis was put on the research results for the TLR-dependent immune response and the anti bacterial/anti-inflammatory response after applying immunonutrition with increased concentrations of glutamine and unsaturated fatty acids. PMID- 21298488 TI - Physiological roles of mammalian sulfate transporters NaS1 and Sat1. AB - This review summarizes the physiological roles of the renal sulfate transporters NaS1 (Slc13a1) and Sat1 (Slc26a1). NaS1 and Sat1 encode renal anion transporters that mediate proximal tubular sulfate reabsorption and thereby regulate blood sulfate levels. Targeted disruption of murine NaS1 and Sat1 leads to hyposulfatemia and hypersulfaturia. Sat1 null mice also exhibit hyperoxalemia, hyperoxaluria and calcium oxalate urolithiasis. Dysregulation of NaS1 and Sat1 leads to hypersulfaturia, hyposulfatemia and liver damage. Loss of Sat1 leads additionally to hyperoxaluria with hyperoxalemia, nephrocalcinosis and calcium oxalate urolithiasis. These data indicate that the renal anion transporters NaS1 and Sat1 are essential for sulfate and oxalate homeostasis, respectively. PMID- 21298489 TI - Protein kinase C isoforms in neutrophil adhesion and activation. AB - Neutrophils are the first line of defense against bacterial and mycotic pathogens. In order to reach the pathogens, neutrophils need to transmigrate through the vascular endothelium and migrate to the site of infection. Defense strategies against pathogens include phagocytosis, production and release of oxygen radicals through the oxidative burst, and degranulation of antimicrobial and inflammatory molecules. Protein kinase C (PKC)-delta is required for full assembly of NADPH oxidase and activation of the respiratory burst. Neutrophils also express PKC-alpha and -beta, which may be involved in adhesion, degranulation and phagocytosis, but the evidence is not conclusive yet. This review focuses on the potential impact of protein kinase C isoforms on neutrophil adhesion and activation. PMID- 21298486 TI - gammadelta T cell receptor ligands and modes of antigen recognition. AB - T lymphocytes expressing the gammadelta-type of T cell receptors (TCRs) for antigens contribute to all aspects of immune responses, including defenses against viruses, bacteria, parasites and tumors, allergy and autoimmunity. Multiple subsets have been individualized in humans as well as in mice and they appear to recognize in a TCR-dependent manner antigens as diverse as small non peptidic molecules, soluble or membrane-anchored polypeptides and molecules related to MHC antigens on cell surfaces, implying diverse modes of antigen recognition. We review here the gammadelta TCR ligands which have been identified along the years and their characteristics, with emphasis on a few systems which have been extensively studied such as human gammadelta T cells responding to phosphoantigens or murine gammadelta T cells activated by allogeneic MHC antigens. We discuss a speculative model of antigen recognition involving simultaneous TCR recognition of MHC-like and non-MHC ligands which could fit with most available data and shares many similarities with the classical model of MHC restricted antigen recognition for peptides or lipids by T cells subsets with alphabeta-type TCRs. PMID- 21298490 TI - Assessment of two 3-D fluoroscopic systems for articular fracture reduction: a cadaver study. AB - OBJECTIVE: The most commonly used imaging device for assessment of fracture reduction is the two-dimensional X-ray fluoroscope. Two recently introduced 3D fluoroscopic devices, the Siremobil ISO-C3D (Siemens) and the C-InSight (Mazor Surgical Technologies), enable the surgeon to obtain spatial information for the assessment of articular reduction and hardware placement. The purpose of this study was to assess the reliability and accuracy of these two 3D fluoroscopic systems in measuring articular reduction in a cadaveric tibial plateau fracture. METHODS: Six cadaveric knee specimens were osteotomized at the lateral tibial plateau and fixed with a maximal articular step-off of 0, 1, 2.5, 5 and 7.5 mm. Each specimen was scanned 10 times with two 3D fluoroscopes, the Siremobil ISO C3D and the C-InSight. The resulting images were reformatted and interpreted for articular displacements at four different locations at the plateau level and were compared with high-resolution CT scans by an independent observer. RESULTS: For the non-displaced fracture, no displacement (mean < 0.1 mm) was observed in either modality. The mean scanning time for the ISO-C3D was 2 min, while each C InSight scan took 20 s. The readings at four different points along the malreduced fractures were similar for most measurements with either of the two modalities. The C-InSight readings were less accurate than those of the ISO-C3D, relative to the CT scan, but most errors were within clinically acceptable limits (< 2 mm) and used less radiation. CONCLUSIONS: Intraoperative 3D fluoroscopes can detect clinically significant intra-articular step-off with acceptable measurement errors, using newer devices that enable the use of a conventional C arm and reduced radiation. PMID- 21298491 TI - Predictors of early arrival at the emergency department in acute ischaemic stroke. AB - BACKGROUND: A requirement of an effective acute stroke service is the early arrival of patients to the hospital emergency department (ED). This will allow the possible use of thrombolytic therapy or other acute interventions within a limited time window. AIMS: We investigated the predictors of early arrival in a single hospital serving a mixed urban and rural catchment area. METHODS: A retrospective review of all case notes for 1 year was performed. RESULTS: Of 105 acute strokes, 91 were cerebral infarcts and a total of 71 cases presenting initially to the ED had timing available for analysis. 39.4% presented within 3 h, and 12.7% were potentially suitable for thrombolysis. Those living closer to the hospital were not more likely to arrive within 3 h (Z = -0.411, p = 0.68). Presenting directly to the hospital by emergency services (or private transport) was significantly associated with early arrival in a univariate comparison (p < 0.001), and in a multivariate model. CONCLUSION: The only independent predictor of early arrival to the ED is direct presentation. Improved public education of the importance of recognition of stroke symptoms and rapid contact with the emergency services will improve the early attendance following acute stroke, allowing increased use of acute stroke treatments. PMID- 21298492 TI - Transforming management of patients undergoing splenectomy in an Irish teaching hospital. AB - BACKGROUND: Post-splenectomy infection has a mortality rate of up to 70%. Previously we have published data confirming the poor adherence to best practice guidelines with relation to management of the asplenic patient. A defined protocol of care was established, staff education commenced and a 'patient information leaflet' made available. AIM: To ascertain whether management of the asplenic patient has improved since the implementation of a structured programme of care. METHOD: Retrospective chart review of all splenectomies performed in Beaumont Hospital between 2002 and 2008. RESULTS: Overall, 75.9% of patients were documented as having received the recommended vaccinations. Of these, 48.7% were not timed according to recommended guidelines. Prophylactic antibiotics were documented as prescribed in all but five patients discharged. CONCLUSIONS: These results demonstrate an improvement in post-splenectomy care between 2002 and 2008. However, further improvements are necessary. PMID- 21298494 TI - Health-related quality of life as prognostic factor for response, progression free survival, and survival in women with metastatic breast cancer. AB - The purpose of this study was to, on an exploratory basis, investigate the role of health-related quality of life (HRQoL) at randomization as an independent prognostic factor for response to treatment, progression-free survival (PFS), and survival. In the TEX trial, 287 patients with locally advanced or distant metastatic breast cancer were randomized to either epirubicin and paclitaxel (ET) or epirubicin, paclitaxel, and capecitabine (TEX). Treatment was repeated every 3 weeks. The EORTC QLQ-C30 questionnaire was used to assess HRQoL before randomization. A total of 252 (88%) patients completed EORTC QLQ-C30 before randomization. Clinical conditions included in the multivariate model were age, number of metastases, ECOG performance status, time between diagnosis and randomization, and treatment arm. Univariate analysis revealed an association between prolonged survival and the HRQoL variables global health, physical functioning, role functioning, fatigue, and pain (P < 0.01). After controlling for clinical conditions, only fatigue remained statistically significant. No statistically significant relationships were found between HRQoL and PFS. In the analysis of the association between HRQoL and response to treatment, role functioning, social functioning, fatigue, nausea/vomiting, and appetite loss remained statistically significant. HRQoL variables could act as important predictors of response to treatment, progression-free survival, and overall survival in women with metastatic breast cancer. PMID- 21298493 TI - Transcriptional control mechanisms associated with the nucleotide receptor P2X7, a critical regulator of immunologic, osteogenic, and neurologic functions. AB - The nucleotide receptor P2X(7) is an attractive therapeutic target and potential biomarker for multiple inflammatory and neurologic disorders, and it is expressed in several immune, osteogenic, and neurologic cell types. Aside from its role in the nervous system, it is activated by ATP released at sites of tissue damage, inflammation, and infection. Ligand binding to P2X(7) stimulates many cell responses, including calcium fluxes, MAPK activation, inflammatory mediator release, and apoptosis. Much work has centered on P2X(7) action in cell death and mediator processing (e.g., pro-interleukin-1 cleavage by the inflammasome), but the contribution of P2X(7) to transcriptional regulation is less well defined. This review will focus on the growing evidence for the importance of nucleotide mediated gene expression, highlight several animal models, human genetic, and clinical studies that support P2X(7) as a therapeutic target, and discuss the latest developments in anti-P2X(7) clinical trials. PMID- 21298495 TI - Familial diabetes is associated with reduced risk of cancer in diabetic patients: a possible role for metformin. AB - Type 2 diabetes mellitus (DM2) is a risk factor of a number of malignancies. Therefore, it is important to identify factors linking DM2 and cancer within family units and how current treatment regimens influence the development of cancer in DM2 patients. The present case-controlled study was designed to assess DM2 prevalence among parents or siblings of (a) cancer patients who did not have diabetes (n = 77; age 59.3 +/- 1.3 years) or (b) had overt (n = 197; 63.7 +/- 0.6 years) or latent (n = 25; 61.5 +/- 1.5 years) DM2 and (c) of female DM2 patients without cancer (n = 172; 61.7 +/- 0.6 years). In the families of cancer-free DM2 women, DM2 was found to be significantly more frequent (30.8 +/- 3.5%) than in families of cancer patients without diabetes (in all patients: 6.5 +/- 2.8%; in female patients: 5.0 +/- 3.4%). More importantly, DM2 in families of cancer-free DM2 women was more frequent than in the families of DM2 patients having mammary (9.5 +/- 4.5%), endometrial (6.3 +/- 4.1%) or any other cancer (in all: 15.2 +/- 2.6%; in women: 12.9 +/- 2.8%). Additionally, DM2 patients without cancer, who had parents or siblings with DM2, received biguanide metformin versus sulfonylurea derivatives more often than those with breast or endometrial cancer, either with or without family history of DM2. Our data indicate that familial DM2 may have a protective effect for some cancer types and that the type of anti diabetes therapy may be a factor of influence in the associations observed. PMID- 21298496 TI - Phase II study of oxaliplatin plus leucovorin and 5-fluorouracil in heavily pretreated metastatic breast cancer patients. AB - The aim of this phase II study was to investigate the efficacy and safety of oxaliplatin plus 5-fluorouracil (5-FU) and leucovorin (LV) in metastatic breast cancer (MBC) patients heavily pretreated with anthracyclines, taxanes, vinorelbine, gemcitabine, and capecitabine. Sixty-two women who had received at least 3 above-mentioned drug classes were treated with oxaliplatin 85 mg/m(2) as a 2-h infusion on day 1, LV 200 mg/m(2) as a 2-h infusion followed by bolus 5-FU 400 mg/m(2) on day 1, and a continuous infusion of 5-FU 1,200 mg/m(2) for 44 h. The median patient age was 52 years with a median of two involved organs, and the metastases were mostly in the lung (53.2%), lymph nodes (51.6%), and liver (45.2%). Patients had a median of three prior chemotherapy regimens. Forty-five patients (72.6%) had prior exposure to all 5 classes of drugs. Based on an intention-to-treat analysis, 60 patients were assessable for responses and 11 patients achieved a partial response (PR), giving an overall response rate (ORR) of 18.3%. Twenty-one (35%) patients had stable disease (SD), and of these, 8 achieved long SD (13.3%). The median progression-free survival (PFS) was 3 months, and the median overall survival (OS) was 10 months. Toxicity was mild to moderate with grade 3 or 4 neutropenia, thrombocytopenia, and neuropathy occurring in 14 (22.6%), 9 (14.5%), and 3 (4.8%) patients, respectively. The study demonstrated that the combination of oxaliplatin plus 5-FU/LV was a well tolerated salvage regimen with moderate activity in patients with heavily pretreated MBC. PMID- 21298498 TI - Black esophagus. PMID- 21298497 TI - A phase II trial of doxorubicin and gemcitabine in renal cell carcinoma with sarcomatoid features: ECOG 8802. AB - Sarcomatoid features can arise in renal cell carcinoma of any subtype and are associated with a poor prognosis. Doxorubicin and gemcitabine in a limited series showed activity in aggressive renal tumors and we wished to formally assess the combination in patients with renal cell carcinoma specifically containing sarcomatoid features. The Eastern Cooperative Oncology Group (ECOG) conducted a phase II trial of doxorubicin 50 mg/m(2) IV push and gemcitabine 1,500 mg/m(2) IV over 30 min every 2 weeks in 39 patients with locally advanced or metastatic renal cell carcinoma with sarcomatoid features. Ten patients (26%) had grade 3 toxicity, and four patients (11%) had grade 4 toxicities. Although most toxicity was from myelosuppression, one patient died on study from cardiac dysfunction after a cumulative dose of 450 mg/m(2) doxorubicin. Six (16%) patients experienced responses (5 partial responses and 1 complete response), and ten (26%) patients had stable disease. In addition, another patient had an unconfirmed partial response and an additional patient experienced over 50% decrease in her tumor burden after an initial progression. The median overall survival was 8.8 months, and the median progression-free survival was 3.5 months. We conclude that the combination of doxorubicin and gemcitabine, inactive in patients with mostly clear cell histology, demonstrated responses in patients with RCC with sarcomatoid features. We acknowledge the toxicity of this combination but note that limited treatment options exist for this aggressive histology. Only through prospective multicenter trials with comprehensive central pathology review will better treatment options be identified. PMID- 21298499 TI - Preliminary evidence for the construct and concurrent validity of the DS14 in Hebrew. AB - BACKGROUND: Type D personality is a risk indicator in cardiac patients. While both the validity and reliability of the Type D scale (DS14) have been confirmed in Western Europe, less attention has been paid to the subject in other nations. PURPOSE: The purpose of this study was to examine the validity of the Hebrew version of the DS14 among a sample of cardiac patients in Israel. METHOD: Male patients (N = 94) hospitalized for a first acute coronary syndrome (ACS) completed the DS14 1 month after their ACS. The Brief Symptoms Inventory (BSI) scales for depression and anxiety and the Buss-Durkee Hostility Inventory-Dutch for measuring covert and overt aggressions were administered during the initial hospitalization (baseline). The BSI was administered again at the 6-month follow up. At follow-up, patients were also asked about their participation in a formal cardiac rehabilitation program. RESULTS: The two-factor structure of the DS14 was confirmed and the DS14 subscales were internally consistent (Cronbach's alpha = 0.79/0.80). Type D cardiac patients had a significantly higher mean score on anxiety, depression, and covert aggression at baseline compared to non-Type D patients. At the 6-month follow-up, Type D was associated with more anxiety, more depression, and less attendance at a formal cardiac rehabilitation program. The prevalence of Type D in the current sample (5.3%) was found to be significantly lower than elsewhere in Europe. CONCLUSION: Preliminary evidence suggests that it is possible to use the Hebrew version of the DS14 among Hebrew-speaking cardiac patients in future studies. However, the prevalence of the Type D personality in Israel should be further assessed. PMID- 21298500 TI - Venous drainage from the developing human base of mandible including Meckel's cartilage: the so-called Serres' vein revisited. AB - PURPOSE: The present study describes the venous drainage, especially, that via the so-called Serres' vein, from border areas between two different types of ossifications: the endochondral ossification of Meckel's cartilage in close topographical relation with the membranous ossification of the mandible. METHODS: Frontal and transverse sections of 25 human fetuses between 8 and 16 weeks of post-conception development. All sections were stained with hematoxylin, and eosin and azan. RESULTS: At 9 weeks, a distinct vein (Serres' vein) is seen originating from the endochondral ossification of Meckel's cartilage. At 11 weeks, the vein collects blood sinusoids from both the endochondral and membranous ossification areas. At 12 weeks the vein accompanies a definite bony canal, the Serres' canal. The vein does not extend anteriorly beyond a level of the deciduous canine germ that was located anterior to the mental foramen. Notably, up to 12 weeks, the vein becomes clearly isolated from the inferior alveolar nerve, artery, and vein. CONCLUSION: Serres' vein seems to be a unique drainage route of ossification, not of the tooth germ, and is similar to veins at the usual diaphysis of a long bone. Although the Serres' canal had been termed "canal of the deciduous dentition", there appears to be no topographical relation with deciduous germs. PMID- 21298501 TI - Cerebrospinal fluid diagnostics in first-episode schizophrenia. AB - We evaluated the clinical use and the safety of cerebrospinal fluid diagnostics in 155 patients with the suspected diagnosis of first-episode schizophrenia. Five patients (3.2%) revealed pathological findings that lead to diagnostic re evaluation and changes in clinical management. No serious adverse events occurred, but we documented 16 (10.3%) cases of mild to moderate headache or local pain at the puncture site. Our results underline the value of lumbar puncture in the clinical workup of first-episode patients with suspected schizophrenia. PMID- 21298502 TI - Fetal programming of renal function. AB - Results from large epidemiological studies suggest a clear relation between low birth weight and adverse renal outcome evident as early as during childhood. Such adverse outcomes may include glomerular disease, hypertension, and renal failure and contribute to a phenomenon called fetal programming. Other factors potentially leading to an adverse renal outcome following fetal programming are maternal diabetes mellitus, smoking, salt overload, and use of glucocorticoids during pregnancy. However, clinical data on the latter are scarce. Here, we discuss potential underlying mechanisms of fetal programming, including reduced nephron number via diminished nephrogenesis and other renal (e.g., via the intrarenal renin-angiotensin-aldosterone system) and non-renal (e.g., changes in endothelial function) alterations. It appears likely that the outcomes of fetal programming may be influenced or modified postnatally, for example, by the amount of nutrients given at critical times. PMID- 21298503 TI - Hemodiafiltration: the addition of convective flow to hemodialysis. AB - Hemodiafiltration (HDF) combines both hemofiltration (HF) and hemodialysis in the same procedure. It was initially performed in adults in 1977, and later used in children in the early 1980s. The use of HDF allows a determined convective dialysis dose to be combined with the conventional urea dialysis dose. The dialysis session is better tolerated as a result of the effects of hemofiltration. On-line HDF, i.e., substitution fluid prepared from ultrafiltration of the ultrapure dialysate, can be performed safely due to recent advances in modern technology. However, despite interest and feasibility in children, the majority of pediatric dialysis units across the world still perform hemodialysis using highly permeable membranes, allowing back filtration in the filter and therefore a degree of convective flow, i.e., internal hemodiafiltration. In some countries, government restrictions prohibit the use of on-line hemodiafiltration, (such as the FDA recommendations in North America), and therefore it should not be used in these circumstances. PMID- 21298504 TI - Cachexia and protein-energy wasting in children with chronic kidney disease. AB - Children with chronic kidney disease (CKD) are at risk for "cachexia" or "protein energy wasting" (PEW). These terms describe a pathophysiologic process resulting in the loss of muscle, with or without loss of fat, and involving maladaptive responses, including anorexia and elevated metabolic rate. PEW has been defined specifically in relation to CKD. We review the diagnostic criteria for cachexia and PEW in CKD and consider the limitations and applicability of these criteria to children with CKD. In addition, we present an overview of the manifestations and mechanisms of cachexia and PEW. A host of pathogenetic factors are considered, including systemic inflammation, endocrine perturbations, and abnormal neuropeptide signaling, as well as poor nutritional intake. Mortality risk, which is 100- to 200-fold higher in patients with end-stage renal disease than in the general population, is strongly correlated with the components of cachexia/PEW. Further research into the causes and consequences of wasting and growth retardation is needed in order to improve the survival and quality of life for children with CKD. PMID- 21298505 TI - Postpartum depression according to time frames and sub-groups: a survey in primary health care settings in Rio de Janeiro, Brazil. AB - This study aimed at estimating the prevalence of postpartum depression (PPD) according to postpartum periods and sub-groups in public primary health care settings in Rio de Janeiro, Brazil. A cross-sectional survey was carried out in five primary health care units and included 811 participants randomly selected among mothers of children up to five postpartum months. Women were classified as depressed and given scores on Edinburgh Postnatal Depression Scale (EPDS) above 11. The overall estimate of PPD was 24.3% (95% CI, 21.4-27.4). However, estimates were not homogeneous during the first 5 months postpartum (p value = 0.002). There was a peak of depressive symptoms around 3 months postpartum, when 128 women (37.5%, 95% CI, 29.1-46.5) disclosed scores above 11 on EPDS. Regarding the magnitude of PPD according to some maternal and partners' characteristics, it was consistently higher among women with low schooling, without a steady partner, and whose partners misused alcohol or used illicit drugs. The prevalence of PPD among women attending primary health care units in Rio de Janeiro seems to be higher than general estimates of 10-15%, especially among mothers with low schooling and that receive little (if any) support from partners. Also, the "burden" of PPD may be even higher around 3 months postpartum. These results are particularly relevant for public health policies. Evaluation of maternal mental health should be extended at least until 3 to 4 months postpartum, and mothers presenting a high-risk profile deserve special attention. PMID- 21298506 TI - Prevalence and characteristics of teen motherhood in Canada. AB - The study aims to examine the prevalence and characteristics of adolescent mothers throughout the provinces of Canada. The analysis was based on the Maternity Experience Survey targeting women aged >=15 years who had singleton live births during 2005/2006 in the Canadian provinces and territories. The main dependent variable in this study was the mother's age at the time of delivery divided into teen mothers (<20 years) and average-aged mothers (>=20 and <35 years). Socio-economic factors, demographic factors and pregnancy related factors were considered for a logistic regression analysis comparing teen mothers to average-aged mothers. Bootstrapping was performed to account for the complex sampling design. The sample size was 6,188 weighted to represent 76,110 Canadian women. The proportion of teen mothers in the MES study was 2.9%, and their average age was 18.1 years (SD = 1.1). As compared to average-aged mothers, teen mothers were more likely to have low socio-economic status, be non-immigrants, have no partner, reside in the Western Prairies, have previously experienced physical or sexual abuse and have preferred to have had their pregnancies later into their adulthood. Despite the above, teen mothers were more likely to attend prenatal classes than average-aged mothers (Odds ratio = 2.54, 95% confidence interval: 1.74-3.71). Intervention studies should aim to raise awareness among teens to prevent teen pregnancies. Since teen mothers are very likely to attend prenatal courses, the focus of these classes should be tailored to the needs of teen mothers. More in depth qualitative studies should aim to understand their individual needs. PMID- 21298507 TI - The dynamics of post-operative plasma ACTH values following transsphenoidal surgery for Cushing's disease. AB - Rapid assessment of adrenal function is critical following transsphenoidal surgery (TSS) for Cushing's disease (CD) in order to determine surgical efficacy. We hypothesize that there may be a role for ACTH measurement as a rapid indicator of adrenal function. Following surgery for CD, glucocorticoids were withheld and paired plasma ACTH and serum cortisol levels were measured every 6 h. Post operative hypocortisolemia was defined as serum cortisol <2 mcg/dl or a serum cortisol <5 mcg/dl with the onset of symptoms of adrenal insufficiency within 72 h. We studied 12 subjects, all female, mean age 44.6 years (range 25-55), including 13 surgeries: nine subjects attained hypocortisolemia. Plasma ACTH levels decreased more in subjects with hypocortisolemia (0.9 pg/ml/hr, P = 0.0028) versus those with persistent disease (0 0.2 pg/ml/hr, P = 0.26) within the first 48 h after surgery. In contrast to subjects with persistent disease, all subjects with hypocortisolemia achieved a plasma ACTH <20 pg/ml by 19 h (range 1-19 h). Four of the nine subjects with hypocortisolemia achieved plasma ACTH <20 pg/ml by 13 h and the remaining five subjects by 19 h. Hypocortisolemia occurred between 3-36 h following achievement of a plasma ACTH <20 pg/ml. In CD, a reduction in postoperative plasma ACTH levels differentiates subjects with surgical remission versus subjects with persistent disease. The utility of plasma ACTH measurements in the postoperative management of CD remains to be determined. PMID- 21298508 TI - Improvement in quality of life after laparoscopic sleeve gastrectomy. AB - Few studies have investigated changes in health-related quality of life (HRQOL) in surgical patients who have undergone a laparoscopic sleeve gastrectomy. Prospective data were obtained from 78 consecutive patients undergoing laparoscopic sleeve gastrectomy (LSG; mean age, 42.4 years; mean body weight, 131 kg; mean body mass index (BMI), 47 kg/m(2) (24.4% of superobese patients)). Two HRQOL questionnaires were administered preoperatively and 12 months postsurgery: the generic Medical Outcomes Study Short Form-36 and the weight-specific IWQOL Lite questionnaire. Excess weight loss at 12 months was 57.18%. No mortality was recorded. HRQOL scores revealed a significant improvement in all areas of both questionnaires. However, changes in HRQOL were not associated consistently with amount of weight loss. Laparoscopic sleeve gastrectomy is an effective and safe procedure, with positive changes in health-related quality of life as well as weight reduction. A fruitful area for future research is the investigation of long-term changes in HRQOL after LSG. PMID- 21298509 TI - Nutritional intake and prevalence of nutritional deficiencies prior to surgery in a Spanish morbidly obese population. AB - BACKGROUND: The prevalence of obesity in Spain is on the rise with the consequent increase in bariatric surgery. Studies in non-Mediterranean populations have shown that micronutrient deficits are present before surgery. However, there is no data on this topic in a Spanish population. METHODS: We evaluated food intake and the prevalence of nutritional deficiencies in 231 obese patient (72.3% women, 45.6 +/- 9.9 years, BMI 48.2 +/- 7.8 kg/m(2)) candidates for bariatric surgery. Forty-six normal weight individuals with similar demographic variables except BMI were included for comparison of deficiencies. RESULTS: In obese subjects, the mean estimated energy intake was 2,584 +/- 987 kcal/day in males and 2,094 +/- 669 kcal/day in females (p < 0.05). After adjusting for kilocalorie intake, carbohydrate intake was of 38.7% [CI 36.2 to 41.1] and 39.9% [CI 37.8 to 40.8] (n.s.), lipid intake was 41.9% [CI 39.6 to 44.2] and 43.0% [CI 41.7 to 44.8] (n.s.) and protein intake was 19.1% [CI 17.7 to 20.5] and 17.3% [CI 16.4 to 18.1] (n.s.) for men and women, respectively. The most prevalent deficiency was vitamin D25(OH): obese 94%, control 24%; (p < 0.0001). Above normal PTH levels were observed in 41.0% and 20.0% of obese and normal weight subjects, respectively (p < 0.0497). Increased prevalence of deficiencies in obese patients included magnesium, vitamin B6 and anaemia (p < 0.05). Other vitamin deficiencies were observed although did not reach statistical significance. CONCLUSIONS: Nutritional deficiencies are commonly found in the Spanish obese population undergoing bariatric surgery and are significantly more prevalent than in normal weight individuals. PMID- 21298510 TI - Sleep apnea determines soluble TNF-alpha receptor 2 response to massive weight loss. AB - BACKGROUND: The effects of surgical weight loss (WL) on inflammatory biomarkers associated with sleep apnea remain unknown. We sought to determine if any biomarkers can predict amelioration of sleep apnea achieved by bariatric surgery. We hypothesized that surgical WL would substantially reduce severity of sleep apnea and levels of proinflammatory cytokines. METHODS: Twenty-three morbidly obese adults underwent anthropometric measurements, polysomnography, and serum biomarker profiling prior to and 1 year following bariatric surgery. We examined the effect of WL and amelioration of sleep apnea on metabolic and inflammatory markers. RESULTS: Surgical WL resulted in significant decreases in BMI (16.7 +/- 5.97 kg/m(2)/median 365 days), apnea-hypopnea index (AHI), CRP, IL-6, sTNFalphaR1, sTNFalphaR2, and leptin levels, while ghrelin, adiponectin, and soluble leptin receptor concentrations increased significantly. Utilizing an AHI cutoff of 15 events/h, we found significantly elevated levels of baseline sTNFalphaR2 and greater post-WL sTNFalphaR2 decreases in subjects with baseline AHI >=15 events/h compared to those with AHI <15 events/h despite no significant differences in baseline BMI, age, and DeltaBMI. In a multivariable linear regression model adjusting for sex, age, impaired glucose metabolism, DeltaBMI, and follow-up period, the post-WL decreases in AHI were an independent predictor of the decreases in sTNFalphaR2 and altogether accounted for 46% of the variance of DeltasTNFalphaR2 (P = 0.011) in the entire cohort. CONCLUSIONS: Of all the biomarkers, the decrease in sTNFalphaR2 was independently determined by the amelioration of sleep apnea achieved by bariatric surgery. The results suggest that sTNFalphaR2 may be a specific sleep apnea biomarker across a wide range of body weight. PMID- 21298513 TI - Eliminating frown lines with an endoscopic forehead lift procedure (corrugator muscle disinsertion). AB - BACKGROUND: In certain cases of endoscopic forehead lift without muscle resection, patients were incidentally noted to develop weakness or loss of their ability to frown during the postoperative period despite intact musculature. This finding suggested the possibility of decreasing frown strength using the disinsertion of the relevant muscles. This finding persuaded the authors to try to eliminate or decrease the sensory problems resulting from open or endoscopic frowning muscle resection by disinserting these muscles. We therefore sought to determine the efficacy of a brow/forehead lift that involved disinsertion rather than muscle resection. METHODS: From September 2004 through December 2006, 22 endoscopic forehead lifts (20 females and 2 males) were performed using the conventional corrugator muscle resection technique (group 1). From January 2007 through October 2009, 43 patients (38 females and 5 males) underwent endoscopic forehead lift with a muscle-preserving technique (group 2). In both groups, small scalp incisions were made, and an endoscope was used to elevate the brows and forehead to perform glabellar and forehead muscle resection in group 1 and disinsertion of the frowning muscles in group 2. The skin of the forehead was then reanchored to a more superior location using sutures attached to deep temporal fascia as well as outer table screws and skin staples. RESULTS: Aesthetically pleasing eyebrow and forehead with reduced power in the frowning muscles were achieved in the majority of patients in both groups. A significant decrease in the depth of vertical and horizontal glabellar creases was obtained in these patients. In group 1, 19 of 22 patients completely lost the ability to frown and 3 patients (13.6%) suffered permanent sensory loss. In group 2, 33 of 43 patients lost their ability to frown but only 2 cases (4.5%) developed minimal unilateral forehead partial sensory deficit after a 12-month follow-up period. CONCLUSION: Disinsertion of the corrugator supercilli, procerus, or orbicularis oculi muscles can decrease contractility with less chance of damaging nearby or intermingled sensory nerves than offered by resection. PMID- 21298512 TI - Reward processing in male adults with childhood ADHD--a comparison between drug naive and methylphenidate-treated subjects. AB - RATIONALE: Dysfunctional reward processing has been proposed as a main deficit in attention-deficit/hyperactivity disorder (ADHD), which could be modulated by treatment with methylphenidate (MPH). OBJECTIVES: We examined differences in reward processing in adulthood (independent of actual ADHD) depending on MPH treatment during childhood. METHODS: Eleven males with childhood ADHD treated with MPH, 12 drug-naive males with childhood ADHD, and 12 controls matched by age, handedness, and smoking behavior were studied drug-free using functional magnetic resonance imaging. BOLD-responses were compared during a monetary incentive delay task using an ANOVA design focusing on the ventral striatum during anticipation and the orbitofrontal cortex during outcome. RESULTS: Controls, drug-naive, and treated subjects did not differ significantly in their activations in the ventral striatum and orbitofrontal cortex. Explorative analyses revealed decreased insula activation during outcome of loss avoidance in drug-naive subjects in comparison to both groups, while treated subjects did not differ from controls. Insula activation correlated significantly positive with harm avoidance in the treated group. Furthermore, comparing subjects with actual ADHD symptoms, remitters and controls we observed decreased putamen activition in ADHD persisters. CONCLUSIONS: Basal ganglia reward processing seemed to be unrelated to MPH pretreatment, but was related to remission. On the other hand, the revealed differences between treated and drug-naive subjects with childhood ADHD, i.e., in the insula, give evidence for more pronounced abnormal activation in reward-associated brain regions in untreated subjects with childhood ADHD and underpin the need of prospective studies on long-term effects of psychostimulant treatment. PMID- 21298514 TI - SPA face lift: SMAS plication-anchoring. AB - A variation of the superficial musculoaponeurotic system (SMAS) plication called SPA face lift is here described. An axial line and then two medial and lateral parallel lines are penciled on the skin from the lateral canthus to the earlobe to show the future plication area. The undermining zone is delimited 1 cm beyond the medial line. In face- and neck-lifting, such marks extend vertically to the neck. Once the skin is undermined up to the delimiting marks, the three lines are penciled again on the fat layer, and a running lock suture is used for plication, with big superficial bites between the two distal lines. In fatty faces, a strip of fat is removed along the axial line to avoid bulging that can be seen through the skin. Because the undermining is limited, minor swelling occurs, and the postoperative recovery is shorter and faster. The same three lines can be marked in the contralateral side or can differ in cases of asymmetry. This report describes 244 face-lifts without any facial nerve problems. The author managed five hematoma cases in which surgery to the neck was performed. Three patients had to be touched up for insufficient skin tension. The SPA technique is consistent and easy to learn. PMID- 21298515 TI - The role of upper lateral cartilage in dorsal reconstruction after hump excision: section 1. Spreader flap modification with asymmetric mattress suture and extension of the spreading effect by cartilage graft. AB - A spreader flap, or autospreader flap, is a flap used for dorsal reconstruction in primary rhinoplasty after cartilage dorsum excision. Despite its significant advantages, the spreader flap also has distinct shortcomings. The most common problem encountered in using a spreader flap is the technique's inability to provide adequate dorsal width compared with spreader grafts. Additionally, the use of a spreader flap has not been described for special cases such as crooked noses, cases with minimal dorsal humps, and secondary cases. This report presents the authors' modification of the spreader flap technique to expand its indications and extend the spreader effect down to the entire dorsum. This modification positions and fixes the medial borders of the upper lateral cartilages (ULCs) on both sides of the septum by asymmetric mattress sutures. Using the ULCs without folding affords the opportunity to restore a dorsum with sufficient width. Different entry and exit points of the suture help to maintain the cartilage substance horizontally rather than folded as in the conventional spreader flap technique. Another drawback of the spreader flap technique is its inability to address the lower third of the dorsum when ULCs do not extend down to the anterior septal angle (ASA). In these cases, attempts were made to extend the spreader effect by placing two small cartilage grafts on both sides of the ASA. Over a period of 2 years, the authors operated on 169 patients. For 81 of these patients, the modified spreader flap alone was used, and for the remaining 88 patients, both the modified spreader flap technique and ASA grafting (combined modification) were used. During a mean follow-up period of 17 months, no narrowing in the middle nasal dorsum and no inner valve deficiencies were seen in any of the cases. PMID- 21298516 TI - Lower lateral crural reverse plasty: a technique to correct severe concavities of the lateral crus. AB - BACKGROUND: Excessive concavities of the lower lateral crura can lead to heavy aesthetic disfigurement of the nasal tip and to insufficiencies of the external nasal valve. This study reviewed experience with the lower lateral crural reverse plasty technique that uses the existing cartilage to create the desired lower lateral cartilage contour and provides sufficient alar rim support. METHODS: A retrospective review was conducted with a follow-up period ranging from 9 to 33 months. The technique was applied in primary (n = 13) and secondary (n = 3) open rhinoplasties to correct severe concavities of the lower lateral cartilages. Two case examples and intraoperative photographs are presented to illustrate the technique and its results. RESULTS: The lower lateral crural reverse plasty proved its applicability for the functional and aesthetical correction of severe lower lateral crura concavities. By dissecting the distorted lateral crus, turning it around, and suturing it back in place, surgeons can "reconstruct" a new lateral crus with existing cartilage. No additional cartilage is needed, and no harvesting at a different location needs to be performed. After rhinoplasty, no alar rim instabilities were observed. In three cases, even preexisting instabilities were corrected. Aesthetically enduring results were observed, and no overcorrection or alar retraction was seen. CONCLUSION: With the lower lateral crural reverse plasty, severe concavities of the lower lateral crura can be corrected. This technique is a useful and reproducible procedure, performed without additional tissue to achieve functionally and aesthetically satisfying and enduring results. PMID- 21298517 TI - Therapeutic effect of intermittent hypobaric hypoxia on myocardial infarction in rats. AB - Intermittent hypobaric hypoxia (IHH) preconditioning protects the heart against ischemic injuries. However, little is known about the therapeutic effect of IHH on myocardial infarction (MI). The aim of this study was to test whether IHH treatment influences infarct size and cardiac performance after MI. Seven days after sham operation or left anterior descending coronary artery ligation, male Sprague-Dawley rats were randomly exposed to normoxia or one 6-h period each day of IHH (5,000 m) for 14 and 28 days. Echocardiography analysis showed that IHH significantly reduced left ventricular (LV) dilation and improved cardiac performance after 14- or 28-day treatment compared with MI-normoxic groups. The improvement of LV function was further confirmed in isolated perfused MI-IHH hearts. Such protection was associated with attenuated infarct size, myocardial fibrosis, and apoptotic cardiomyocytes. IHH treatment also enhanced coronary flow and phosphorylation of heat shock protein 27 in both sham and MI groups compared with the control groups. In addition, IHH increased the capillary density and vascular endothelial growth factor expression in peri-infarcted zones compared with sham-IHH and MI-normoxic groups. Our data demonstrated for the first time that IHH treatment exerts a therapeutic effect on MI by attenuating progressive myocardial remodeling and improving myocardial contractility. IHH treatment might provide a unique and promising therapeutic approach for ischemic heart diseases. PMID- 21298518 TI - The podocyte as a target: cyclosporin A in the management of the nephrotic syndrome caused by WT1 mutations. AB - Children with steroid-resistant nephrotic syndrome secondary to WT1-associated glomerulopathies (WT1-GP) were considered unresponsive to cyclosporin A (CsA). This assumption is challenged by the findings of recent studies. The patients of these studies had different types of WT1 mutations and varying clinical presentations. However, all of them were of young age and the favourable response to CsA might be the result of treatment at an early stage of the disease. The additional administration of angiotensin-converting enzyme inhibitors may have contributed to the positive outcome. We review recent data on the role of WT1 in the development of WT1-GP and discuss putative therapeutic targets explaining the therapeutic effect of CsA. PMID- 21298520 TI - Long-term outcome of hybrid surgical approach of video-assisted minithoracotomy sleeve lobectomy for non-small-cell lung cancer. AB - BACKGROUND: The aim of this study was to evaluate the technical feasibility and safety of a hybrid surgical approach of video-assisted minithoracotomy (hybrid VATS) sleeve lobectomy for non-small-cell lung cancer (NSCLC), using success rate as the primary end point. METHODS: Between February 1996 and December 2006, patients with bronchogenic tumors were prospectively registered to undergo hybrid VATS sleeve resection in a single institution. Hybrid VATS involved performing the main procedures via rib spreading and minithoracotomy using a monitor and direct vision. A successful procedure was defined as a patient who had a sleeve lobectomy via hybrid VATS without conversion to thoracotomy and without significant perioperative morbidity or mortality. RESULTS: A total of 148 patients (108 men and 40 women; median age = 58 years) who underwent hybrid VATS sleeve lobectomy for NSCLC were identified in our database. The median duration of the successfully completed procedures was 190 min (range = 145-305 min). The median length of time of chest tube in place was 3 days (range = 1-12 days). Hybrid VATS sleeve lobectomy was performed successfully in 134 of 148 patients for a success rate of 90.5%. The median follow-up period was 65.1 months (range = 34.5-154.8 months). The overall 5-year disease-free survival and overall survival of all patients were 36.7% (95% CI = 27.9-45.5%) and 54.2% (95% CI = 44.8-63.6%), respectively. CONCLUSION: Hybrid VATS sleeve lobectomy is feasible for selected patients with NSCLC in specialized centers. PMID- 21298521 TI - Supplementation of Los Angeles classification with esophageal mucosa index of hemoglobin can predict the treatment response of erosive reflux esophagitis. AB - BACKGROUND: We assessed whether the esophageal mucosa index of hemoglobin (IHb) could assist the Los Angeles (LA) classification in defining the severity of erosive reflux esophagitis (RE) and predicting the treatment response by esomeprazole. METHODS: Five hundred twenty-four subjects (424 RE and 100 controls) with normal body mass index and hemoglobin had undergone endoscopy to confirm the RE grade by LA classification and to check the series of IHb values at every centimeter of the esophageal mucosa while withdrawing the endoscope to above the esophageal-gastric junction (EGJ). The RE cases had received esomeprazole for 8 weeks (40 mg/day) to assess the cumulative proportions of sustained symptomatic response (SSR). RESULTS: The IHb value at the EGJ was higher in RE patients than in controls (P < 0.001). Selecting 70 as the cutoff IHb value at the EGJ, the efficacy to define RE achieved 95.8% (406/424) sensitivity and 94% (94/100) specificity. For the patients with same the LA grade, the length of IHb value >70 above the EGJ (L-IHb70) that is greater than 4 cm correlated with a poor cumulative rate of SSR (P < 0.01). CONCLUSION: The IHb value >70 at the EGJ is a reliable indicator of RE. The L-IHb70 can serve as a supplementary indicator to predict the response to esomeprazole index within the same LA grade. PMID- 21298522 TI - A randomized prospective study of single-port and four-port approaches for hysterectomy in terms of postoperative pain. AB - BACKGROUND: This study aimed to compare single-port transumbilical total laparoscopic hysterectomy (SPLS-TLH) and four-port total laparoscopic hysterectomy (TLH) in terms of postoperative pain. METHODS: The study enrolled 68 patients who underwent TLH from October 2009 to March 2010 and randomly assigned them to one of two groups. Patient demographics, operative outcomes, and postoperative pain were prospectively examined. RESULTS: Four cases in the SPLS TLH group were converted to other laparoscopic approaches. The two study groups did not differ in terms of patient demographics and surgical outcomes. Postoperative pain scores, measured using a visual analog scale, did not differ between the two groups. However, significantly higher total requests for analgesics were observed in the SPLS-TLH group (11.3 +/- 4.1 vs. 7.7 +/- 2.7; p < 0.001). CONCLUSION: Compared with four-port TLH, SPLS-TLH is a feasible approach with comparable operative outcomes. However, reduction of postoperative pain is not evident with SPLS-TLH. PMID- 21298523 TI - A comparison of outcomes between open and laparoscopic surgical repair of recurrent inguinal hernias. AB - BACKGROUND: Inguinal hernia recurrence after surgical repair is a major concern. The authors report their experience with open and laparoscopic repair of recurrent inguinal hernias. METHODS: After institutional review board approval, a retrospective review was performed with the charts of 197 patients who had undergone surgical repair of recurrent inguinal hernias from January 2000 through August 2009, and the data for 172 patients who met the inclusion criteria were analyzed. Surgical variables and clinical outcomes were compared using Student's t test, the Mann-Whitney U test, chi-square, and Fisher's exact test as appropriate. RESULTS: The review showed that 172 patients had undergone either open mesh repair (n=61) or laparoscopic mesh repair (n=111) for recurrent inguinal hernias. Postoperative complications were experienced by 8 patients in the open group and 17 patients in laparoscopic group (p=0.70). Five patients (8.2%) in the open group and four patients (3.6%) in the laparoscopic group had re-recurrent inguinal hernias (p=0.28). Four patients in the open group (9.5%) and no patients in the laparoscopic group had recurrence during long-term follow up evaluation (p=0.046). In the laparoscopic group, 76 patients (68.5%) underwent total extraperitoneal (TEP) repair, and 35 patients (31.5%) had transabdominal preperitoneal (TAPP) repair. Postoperative complications were experienced by 13 patients in the TEP group and 4 patients in the TAPP group (p=0.44). Two patients (2.6%) in the TEP group and two patients (5.7%) in the TAPP group had re recurrent inguinal hernias (p=0.59). CONCLUSIONS: This retrospective review showed no statistical difference in the re-recurrence rate between the two techniques during short-term follow-up evaluation. However, the laparoscopic technique had a significantly lower re-recurrence rate than the open technique during long-term follow-up evaluation. Both procedures were comparable in terms of intra- and postoperative complications. Among laparoscopic techniques, TEP and TAPP repair are acceptable methods for the repair of recurrent inguinal hernia. A multicenter prospective randomized control trial is needed to confirm the findings of this study. PMID- 21298524 TI - Transumbilical single-incision laparoscopic distal gastrectomy for early gastric cancer. AB - BACKGROUND: Laparoscopic gastrectomy is a widely accepted procedure for treating early gastric cancers. This procedure is less invasive than conventional open approaches, and the oncologic outcomes are comparable. Single-incision laparoscopic surgery, developed to reduce the invasiveness of traditional laparoscopy, is applied to various abdominal surgical procedures. However, its application to laparoscopic gastrectomy for the treatment of gastric cancer has not been reported, mainly because of difficulties achieving adequate lymphadenectomy and reconstruction. The authors report their initial clinical experience with single-incision laparoscopic gastrectomy for early gastric cancer. METHODS: A single vertical 2.5-cm intraumbilical incision was made, and three laparoscopic trocars were placed within the umbilicus. A 2-mm mini-loop retractor was inserted in the left upper and middle abdomen, and a roll of gauze was attached to its tip. This instrument is an atraumatic and useful tool for retracting various organs. Gastric mobilization and adequate dissection of lymph nodes were performed. The stomach and duodenum then were transected intracorporeally using linear staplers. Intracorporeal anastomosis was performed for reconstruction. RESULTS: All seven single-incision laparoscopic distal gastrectomies with lymphadenectomy were performed without the use of additional trocars or conversion to laparotomy. The median time for gastric mobilization with lymphadenectomy was 155 min (range, 130-183 min). The median operative time was 344 min (range, 282-385 min), and the median estimated blood loss was 25 ml (range, 0-100 ml). A median total of 67 lymph nodes were retrieved. No serious perioperative complications occurred, and no mortalities were observed in this case series. CONCLUSIONS: The authors' initial experience with single-incision laparoscopic distal gastrectomy showed that it is a feasible and safe procedure for early gastric cancer and gives a favorable cosmetic result. To the authors' knowledge, this is the first report describing successful single-incision laparoscopic gastrectomy for gastric cancer. PMID- 21298527 TI - Three-dimensional stomach analysis with computed tomography after laparoscopic sleeve gastrectomy: sleeve dilation and thoracic migration. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is frequently performed as a definitive bariatric procedure today. Quantitative data on the detailed anatomy of the stomach after LSG are yet sparse. METHODS: Thirty-two multislice computed tomography (MSCT) data sets acquired in 27 LSG patients (22 female, 5 male) with a dedicated examination protocol and post-processing were evaluated for gastric volume, stomach length, sleeve length, antrum length, staple line length, and maximum cross-sectional sleeve area. Obtained parameters were compared to time after surgery, weight loss, and the occurrence of postsurgical regurgitation. RESULTS: Mean gastric volume was 186.5+/-88.4 ml. Gastric volume correlated significantly with the time interval after surgery. Sleeve sizes of 105.3+/-30.2 ml during early follow-up confirmed correct primary sizing of the sleeve, whereas marked dilation to 196.8+/-84.3 ml was found in patients with a follow-up of 6 months and longer (p=0.038). Sleeve area and staple line length were also positively correlated with time after surgery. No correlation was found between gastric volume and excess weight loss. In ten patients an intrathoracic migration of the staple line could be noted, with four of these patients developing persistent regurgitation after LSG. Regurgitation was present in only 2 of 17 patients without sleeve herniation. CONCLUSION: Multislice computed tomography allows for a comprehensive and quantitative evaluation of the anatomy after LSG and thus provides new insights in the process of sleeve dilation. Intrathoracic migration of the staple line could be identified as a possible cause of persistent regurgitation. PMID- 21298528 TI - A novel endoscopic fluorescent clip for the localization of gastrointestinal tumors. AB - BACKGROUND: Accurate tumor localization is essential for gastrointestinal surgery, especially in cases of early cancer. This study was designed to develop a novel fluorescent clip for rapid and exact visualization of tumor sites. METHODS: A transparent polymer matrix containing highly bright fluorochromes was coated on the front end of endoscopic clips. The fluorescent clips were placed on the mucosal surface of a porcine colon and stomach, and the operator then attempted to identify the fluorescent clips from the outer serosal side of the colon and stomach. A 532-nm diode laser and filter glass were used for visualizing the fluorescence signals through the colonic tissue. A 650-nm diode laser and a digital charge-coupled device (CCD) camera equipped with a bandpass emission filter were used for the imaging of the fluorescent clips through the thick stomach tissue. RESULTS: When a green light from a 532-nm diode laser (power density=0.35 mW/cm2) was applied on the serosal surface of the porcine colon, we could identify all clips that had been placed endoscopically on the mucosal surface of the inner colonic wall. By using the light from a 650-nm diode laser (power density=0.7 mW/cm2), we identified all fluorescent clips through the stomach wall in real time. Similar results were also obtained with the filtered xenon lamp. CONCLUSION: An endoscopic fluorescent clip can be useful for the rapid and exact localization of tumors, and this technique can also be useful during laparoscopic surgery. PMID- 21298529 TI - Multimedia article. Laparoscopic modified anterior RAMPS in well-selected left sided pancreatic cancer: technical feasibility and interim results. AB - BACKGROUND: Laparoscopic distal pancreatectomy with splenectomy is regarded as a safe and effective treatment for benign and borderline malignant pancreatic lesions [1, 2]. However, its application for left-sided pancreatic cancer is still debatable [3, 4]. No general consensus, no standardized technique, and no surgical indication exist in applying the laparoscopic approach to left-sided pancreatic cancer. METHODS: According to our institutional experiences of treating left-sided pancreatic cancer, bloodless and margin-negative resection was found to be important. Bloodless and margin-negative laparoscopic distal pancreatosplenectomy would be technically possible in suspicious pancreatic cancers with these tentative conditions: (1) pancreas-confined suspicious pancreatic cancer on preoperative image study (cT2), (2) intact fascia layer between the pancreas and left adrenal gland/left kidney, and (3) tumor more than 1 cm from the celiac axis. A 59-year-old female patient was found to have suspicious left-sided pancreatic cancer. Therefore, we performed laparoscopic anterior radical antegrade modular pancreatosplenectomy (RAMPS) [5, 6] with a curative intent based on selection criteria. RESULTS: The margin-negative (resectional and tangential) curative resection could be obtained by applying laparoscopic anterior RAMPS in well-selected left-sided pancreatic cancer. The operation time was 180 min and estimated blood loss was 100 ml. The diagnosis from pathology was that the tumor was ductal adenocarcinoma of the pancreas (pT3) with lymph node metastasis (pN1, 2 of 23 lymph nodes). The patient went home on the 7th postoperative day. Adjuvant chemotherapy began within 2 weeks after surgery. From June 2007 to August 2010, nine patients underwent minimally invasive (5 laparoscopic and 4 robot-assisted) anterior RAMPS based on the selection criteria. The perioperative outcomes and short-term oncologic results are summarized. CONCLUSION: Laparoscopic modified anterior RAMPS is thought to be technically feasible for curative resection in well-selected pancreatic cancer. The oncologic feasibility of this technique needs to be investigated based on long-term follow-up. More careful study is necessary. PMID- 21298530 TI - Factors affecting insertion time for colonoscopy performed under intramuscular analgesia in patients with history of colorectal resection. AB - BACKGROUND: Colonoscopy can detect both early intraluminal recurrence and metachronous neoplasia after colorectal cancer resection. Because colon length and location change after colorectal resection, factors affecting insertion time during colonoscopy also might be altered. The goal of this study was to examine whether colonoscope insertion time differs between left-sided resection and right sided resection and to identify factors that impact the performance of colonoscopy after colorectal resection. METHODS: We included consecutive patients who underwent colonoscopy between November 2005 and November 2009 after colorectal resection for colorectal cancer. We classified surgical methods into left-sided resection (left hemicolectomy, low anterior resection, anterior resection, Hartman, and Mile's operation) or right-sided resection (right hemicolectomy) and retrospectively evaluated the colonoscope insertion time. Moreover, we analyzed factors that might affect the insertion time. RESULTS: A total of 1,260 patients underwent colonoscopy after colorectal resection during the study period. Of these, 1,248 patients (771 men) who underwent complete colonoscopy were evaluated in this study. The colonoscopy completion rate was 99%, and the mean insertion time was 6.5+/-5.1 min (median, 5 min; range, 0.3-61 min). Right-sided resection, female gender, poor quality of bowel preparation, lower endoscopist case volume, open laparotomy, and colonoscopy performed more than 1 year after colorectal resection were found to be independent factors associated with prolonged insertion time. CONCLUSIONS: This large study identified six factors that affect colonoscope insertion time after colorectal resection. These findings have implications for the practice and teaching of colonoscopy after colorectal resection. PMID- 21298531 TI - Wireless pH-metry at the gastrojejunostomy after Roux-en-Y gastric bypass: a novel use of the BRAVOTM system. AB - BACKGROUND: The number of gastric bypass operations being performed is increasing rapidly due to good weight loss and alleviation of comorbidities in combination with low mortality and morbidity. Stomal ulcers are, however, a clinical problem after gastric bypass, giving patients discomfort, risk of bleeding, or even perforation. To measure the acidity in the proximal jejunum, we adopted the wireless pH-metry (BRAVOTM system) developed for evaluating reflux esophagitis. METHODS: Twenty-five patients (4 men; median age, 44 years; body mass index, 29.3) who had undergone Roux-en-Y gastric bypass (RYGBP) 4 years earlier were recruited. Twenty-one asymptomatic, non-proton pump inhibitor (PPI) users, and in addition, four symptomatic patients (ongoing or stopped PPI treatment) were studied. The wireless BRAVOTM capsule was positioned at the level of the gastrojejunal anastomosis under visual control with the endoscope. pH was registered for up to 48 h. Time with pH<4 was calculated. Two patients were studied with two capsules. RESULTS: Of the 25 recruited patients, capsule placement was successful in all but two patients, and in three patients a constant neutral environment was seen before a premature loss of signal, indicating early loss of position. Thus, 20 successful measurements were made. The mean time of registration was 25.7 (range, 6.1-47.4) h (n=20). In the 16 asymptomatic patients, median percentage of time with pH<4 at the gastrojejunostomy was 10.5% (range, 0.4-37.7%). When dividing the registration time in day (06.00-22.00) and night (22.00-06.00), the median percentage of time with pH<4 was 8.4 and 6.3, respectively (p=0.08). The two double measurements gave similar results indicating consistency. No complications occurred. CONCLUSIONS: Wireless pH measurements in the proximal jejunum after gastric bypass are feasible and safe. The acidity was significant (10.5% of the registration time) even in asymptomatic patients with small gastric pouches. The described method could be useful in evaluation of epigastralgia after gastric bypass and in appraisal of PPI treatment of stomal ulcer. PMID- 21298532 TI - Endoscope system with plasma flushing and coaxial round jet nozzle for off-pump cardiac surgery. AB - BACKGROUND: To develop a new endoscope for performing simple surgical tasks inside the blood-filled cardiac atrium/chamber, that is, "off-pump" cardiac surgeries. METHODS: We developed the endoscope system with plasma flushing and coaxial round jet nozzle. The "plasma flushing" system was invented to observe the interior of the blood-filled heart by displacing blood cells in front of the endoscope tip. However, some areas could not be observed with simple flushing of the liquid because the flushed liquid mixed with blood. Further, a large amount of liquid had to be flushed, which posed a risk of cardiac damage caused by excess volume. Therefore, to safely capture high-resolution images of the interior of the heart, an endoscope with a coaxial round jet nozzle through which plasma is flushed has been developed. And to reduce the volume of flushed liquid, the synchronization system of heartbeat and the endoscope system with plasma flushing has been developed. RESULTS: We conducted an in vivo experiment to determine whether we could observe intracardiac tissues in swine without the use of a heart-lung machine. As a result, we successfully observed intracardiac tissues without using a heart-lung machine. By using a coaxial nozzle, we could even observe the tricuspid valve. Moreover, we were able to save up to 30% of the flushed liquid by replacing the original system with a synchronization system. And we evaluated the performance of the endoscope with the coaxial round jet nozzle by conducting fluid analysis and an in vitro experiment. CONCLUSION: We successfully observed intracardiac tissues without using a heart-lung machine. By using a coaxial nozzle, we could even observe the tricuspid valve. And by replacing an original system to a synchronization system, we were able to save up to 30% of the flushed liquid. As a follow-up study, we plan to create a surgical flexible device for valve disease that can grasp, staple, and repair cardiac valves by endoscopic visualization. PMID- 21298533 TI - Does speed matter? The impact of operative time on outcome in laparoscopic surgery. AB - INTRODUCTION: Controversy exists concerning the importance of operative time on patient outcomes. It is unclear whether faster is better or haste makes waste or similarly whether slower procedures represent a safe, meticulous approach or inexperienced dawdling. The objective of the present study was to determine the effect of operative time on 30-day outcomes in laparoscopic surgery. METHODS: Patients who underwent laparoscopic general surgery procedures (colectomy, cholecystectomy, Nissen fundoplication, inguinal hernia, and gastric bypass) from the ACS-NSQIP 2005-2008 participant use file were identified. Exclusion criteria were defined a priori to identify same-day admission, elective procedures. Operative time was divided into deciles and summary statistics were analyzed. Univariate analyses using a Cochran-Armitage test for trend were completed. The effect of operative time on 30-day morbidity was further analyzed for each procedure type using multivariate regression controlling for case complexity and additional patient factors. Patients within the highest deciles were excluded to reduce outlier effect. RESULTS: A total of 76,748 elective general surgical patients who underwent laparoscopic procedures were analyzed. Univariate analyses of deciles of operative time demonstrated a statistically significant trend (p<0.0001) toward increasing odds of complications with increasing operative time for laparoscopic colectomy (n=10,135), cholecystectomy (n=37,407), Nissen fundoplication (n=4,934), and gastric bypass (n=17,842). The trend was not found to be significant for laparoscopic inguinal hernia repair (n=6,430; p=0.14). Multivariate modeling revealed the effect of operative time to remain significant after controlling for additional patient factors. CONCLUSION: Increasing operative time was associated with increased odds of complications and, therefore, it appears that speed may matter in laparoscopic surgery. These analyses are limited in their inability to adjust for all patient factors, potential confounders, and case complexities. Additional hierarchical multivariate analyses at the surgeon level would be important to examine this relationship further. PMID- 21298534 TI - Laparoscopic and robotic-assisted D2 surgery for gastric cancer: a reality in Europe? PMID- 21298535 TI - Role of the laparoscopic approach to biliary bypass for benign and malignant biliary diseases: a systematic review. AB - BACKGROUND: The laparoscopic approach for biliary bypass surgery is a contemporary management option. This article reviews the evidence available for its role and effectiveness. METHODS: A computerised search was made of the MEDLINE, PubMed, and EMBASE databases for English language publications from the first report of laparoscopic biliary bypass in 1992 to January 2010. RESULTS: Some 89 patients featured in 19 reports underwent 89 laparoscopic biliary bypass procedures for benign (n=17) and malignant (n=72) indications. Of those, 52 patients underwent biliary bypass alone, while 37 patients underwent biliary bypass combined with gastric bypass. The procedures included cholecystojejunostomy (n=64), hepaticojejunostomy (n=14), and choledochoduodenostomy (n=11). The overall success rate in achieving resolution of jaundice was 98.9%, with a morbidity rate of 12.3% and a mortality rate of 5.6%. More than one procedure was required in 1.1% of patients to achieve resolution of obstructive jaundice. During a reported median follow-up period of 13 months, obstructive jaundice recurred in none of the patients. CONCLUSION: The laparoscopic approach to biliary bypass surgery is safe and has a high initial success rate, low reintervention rate, and low morbidity and mortality rates. Longer follow-up data and comparative studies with open surgery and endoscopic stenting are needed. PMID- 21298536 TI - Needle oophoropexy: a new simple technique for ovarian transposition prior to pelvic irradiation. AB - BACKGROUND: Irradiation of the pelvis in the treatment of cancers will result in ovarian failure unless the ovaries are shielded adequately. To protect the ovaries, an oophoropexy may be performed. Our aim was to evaluate the feasibility, morbidity, and efficacy of laparoscopic ovarian transposition using a simple percutaneous needle technique. METHODS: Fifteen patients (ten with rectal cancer and five with Hodgkin's disease) underwent the new laparoscopic oophoropexy technique. Laparoscopic releasing of the ovary was performed by cutting the utero-ovarian ligament followed by placing the ovaries on the anterior abdominal wall. A percutaneous straight needle was introduced through a 2-mm skin incision at the site of fixation. Repositioning of the ovaries was done on an outpatient basis without the need for readmission to the operating theatre. RESULTS: The technique was effective, reliable, and simple with no morbidities. Repositioning was performed simply in the outpatient clinic. At follow-up, 11 patients had evidence of ovarian function. CONCLUSION: Percutaneous needle transposition of the ovaries is a simple, effective, reliable, and easy-to perform technique. It has short learning curve and can be done by less experienced laparoscopic surgeons. PMID- 21298537 TI - A novel ultrasmall composite optical fiberscope. AB - BACKGROUND: Accurately aiming laser energy at a target from a two-dimensional endoscopic view is difficult during endoscopic laser surgery, particularly when the endoscope and the laser fiber are misaligned. We developed a composite optical fiberscope (COF) that can simultaneously visualize a target area and perform laser irradiation. The identical orientation of the endoscope and the laser fiber allows intuitive aiming at a target, even from a two-dimensional endoscopic view. METHODS: We developed an ultrasmall COF (1.1-mm diameter) with a central cauterizing laser fiber surrounded by imaging and illumination fibers as a tool for various surgical applications. Porcine mesenteric blood vessels were laser irradiated in vivo and the procedure was filmed using ultrahigh-speed (max 1,000,000 frames per second) and thermographic cameras. Blood flow and vessel diameters were measured before and after laser irradiation. RESULTS: The target vessels were highly visible and laser energy was delivered to the center of the view. Images from the ultrahigh-speed camera showed the blocking of the target vessel by the laser irradiation. The irradiated point initially became constricted, then discolored, and then decreased in size. Blood flow was decreased by 81.7% after laser irradiation and the diameter of the vessels at the irradiated point was approximately 46-48% smaller than that of the unirradiated vessels. Medical doctors also confirmed that the blood vessel was blocked after the experiments. CONCLUSIONS: Our new laser surgery device may be useful for many surgical applications because it allows simultaneous diagnosis and treatment as well as intuitive aiming at a target despite its ultrasmall 1.1-mm diameter. PMID- 21298538 TI - Is laparoscopic cholecystectomy more challenging in male patients? AB - BACKGROUND: Laparoscopic cholecystectomy (LC) seems to be more challenging in males than in females. The surgery seems to be longer in male patients. There also seems to be an increased rate of conversion to open surgery in male patients. We sought to objectively verify this widespread belief. METHODS: We performed a retrospective analysis of laparoscopic cholecystectomies performed between January 2004 and November 2009 in our hospital. Within this period 1844 cholecystectomies were performed in our community-based hospital. After a strict inclusion procedure, 1571 cases of LC for symptomatic gallbladder disease were analyzed (501 males, 1071 females). The time for surgery, defined as the interval from placement of the Veress needle to wound closure in minutes, and the rate of conversion to open surgery were the main parameters considered. RESULTS: The time for surgery in male patients was significantly longer compared to that for females (p<0.0001). The male cohort was significantly older than the female cohort at the time of surgery (p<0.001). The rate of conversion to open surgery was significantly higher in male patients (5.6%) compared to 2.9% for females (p<0.0001). CONCLUSION: Based on our analysis, LC had a significantly longer duration of surgery in the male cohort. The rate of conversion to open surgery was also significantly higher in male cohort. Thus, LC could be more challenging in male patients. PMID- 21298539 TI - Laparoscopic pancreaticoduodenectomy and distal pancreatectomy: a UK experience and a systematic review of the literature. AB - BACKGROUND: Advances in operative techniques and technology have facilitated laparoscopic distal pancreatectomy (LDP) and laparoscopic pancreaticoduodenectomy (LPD). METHODS: All distal pancreatectomies were attempted laparoscopically, while selected patients underwent LPD. The literature was systematically reviewed. RESULTS: Between 2002 and 2008, 21 patients underwent LDP (n=14) or LPD (n = 7). The mean operating time, blood loss, and hospital stay after LDP were 265 min, 262 ml, and 7.7 days, respectively, and after LPD they were 628 min, 350 ml, and 11.1 days, respectively. The conversion, morbidity, pancreatic fistula, readmission, reoperation, and mortality after LDP were 7.1, 35.7, 28.4, 28.4, 0, and 7.1% respectively, and after LPD they were 0, 28.6, 14.3, 28.6, 0, and 0% respectively. The literature review identified 987 LDP and 126 LPD. Most LDP were for benign disease (83.9%) while most LPD were for malignancy (91.5%). The mean operating time, morbidity, pancreatic fistula, mortality, and hospital stay after LDP were 221.5 min, 24.7%, 16.4%, 0.4%, and 7.7 days, respectively, and after LPD they were 448.3 min, 28.6%, 11.6%, 2.1%, and 16 days, respectively. CONCLUSION: LDP, particularly for benign disease and low-grade malignancy, is increasingly becoming the gold standard approach in experienced hands. In selected patients, LPD is feasible and safe. Long-term follow-up data are needed. PMID- 21298540 TI - A dangerous MIS-correct proposal. PMID- 21298541 TI - The role of laparoendoscopic surgery in acute pancreatitis. PMID- 21298542 TI - Bacterial clearance of biologic grafts used in hernia repair: an experimental study. AB - BACKGROUND: Biologic grafts used in ventral hernia repair are derived from various sources and undergo different post-tissue-harvesting processing, handling, and sterilization techniques. It is unclear how these various characteristics impact graft response in the setting of contamination. We evaluated four materials in an infected hernia repair animal model using fluorescence imaging and quantitative culture studies. METHODS: One hundred seven rats underwent creation of a chronic hernia. They were then repaired with one synthetic polyester control material (n = 12) and four different biologic grafts (n = 24 per material). Biologic grafts evaluated included Surgisis (porcine small intestinal submucosa), Permacol (crosslinked porcine dermis), Xenmatrix (noncrosslinked porcine dermis), and Strattice (noncrosslinked porcine dermis). Half of the repairs in each group were inoculated with Staphylococcus aureus at 10(4) CFU/ml and survived for 30 days without systemic antibiotics. Animals then underwent fluorescence imaging and quantitative bacterial studies. RESULTS: All clean repairs remained sterile. Rates of bacterial clearance were as follows: polyester synthetic 0%, Surgisis 58%, Permacol 67%, Xenmatrix 75%, and Strattice 92% (P=0.003). Quantitative bacterial counts had a similar trend in bacterial clearance: polyester synthetic 1*10(6) CFU/g, Surgisis 4.3*10(5) CFU/g, Permacol 1.7*10(3) CFU/g, Xenmatrix 46 CFU/g, and Strattice 31 CFU/g (P=0.001). Fluorescence imaging was unable to detect low bacterial fluorescence counts observed on bacterial studies. CONCLUSION: Biologic grafts, in comparison to synthetic material, are able to clear a Staphylococcus aureus contamination; however, they are able to do so at different rates. Bacterial clearance correlated to the level of residual bacterial burden observed in our study. Post tissue-harvesting processing, handling, and sterilization techniques may contribute to this observed difference in ability to clear bacteria. PMID- 21298543 TI - Automation of a suturing device for minimally invasive surgery. AB - BACKGROUND: In minimally invasive surgery, hand suturing is categorized as a challenge in technique as well as in its duration. This calls for an easily manageable tool, permitting an all-purpose, cost-efficient, and secure viscerosynthesis. Such a tool for this field already exists: the Autosuture EndoStitch((r)). In a series of studies the potential for the EndoStitch to accelerate suturing has been proven. However, its ergonomics still limits its applicability. The goal of this study was twofold: propose an optimized and partially automated EndoStitch and compare the conventional EndoStitch to the optimized and partially automated EndoStitch with respect to the speed and precision of suturing. METHODS: Based on the EndoStitch, a partially automated suturing tool has been developed. With the aid of a DC motor, triggered by a button, one can suture by one-fingered handling. Using the partially automated suturing manipulator, 20 surgeons with different levels of laparoscopic experience successfully completed a continuous suture with 10 stitches using the conventional and the partially automated suture manipulator. Before that, each participant was given 1 min of instruction and 1 min for training. Absolute suturing time and stitch accuracy were measured. The quality of the automated EndoStitch with respect to manipulation was tested with the aid of a standardized questionnaire. RESULTS: To compare the two instruments, t tests were used for suturing accuracy and time. Of the 20 surgeons with laparoscopic experience (fewer than 5 laparoscopic interventions, n=9; fewer than 20 laparoscopic interventions, n=7; more than 20 laparoscopic interventions, n=4), there was no significant difference between the two tested systems with respect to stitching accuracy. However, the suturing time was significantly shorter with the Autostitch (P=0.01). The difference in accuracy and speed was not statistically significant considering the laparoscopic experience of the surgeons. The weight and size of the Autostitch have been criticized as well as its cable. However, the comfortable handhold, automatic needle change, and ergonomic manipulation have been rated positive. CONCLUSION: Partially automated suturing in minimally invasive surgery offers advantages with respect to the speed of operation and ergonomics. Ongoing work in this field has to concentrate on minimization, implementation in robotic systems, and development of new operation methods (NOTES). PMID- 21298544 TI - Multimedia article. Lateral lymph node dissection with preoperative chemoradiation for locally advanced lower rectal cancer through a laparoscopic approach. AB - BACKGROUND: Lateral lymph node (LLN) dissection contributes to a decrease in local recurrence and prolongs survival in locally advanced lower rectal cancer patients as compared with total mesorectal excision (TME) alone [1, 2]. However, this procedure is also accompanied by increased bleeding and postoperative complications [3, 4]. Recently, laparoscopic TME has become a safe and feasible approach for lower rectal cancer even after preoperative chemoradiation [5-7]. Laparoscopic LLN dissection could be the next promising approach and could not only provide a survival benefit but also minimize bleeding and postoperative complications with enhanced visualization, as reported in gynecological and urological malignancies [8, 9]. METHODS: A total of 14 patients underwent laparoscopic LLN dissection with TME after preoperative chemoradiation. Our standardized procedure for LLN dissection is seen in the video. After completion of TME, as described previously [5, 6], the obturator nerve is identified between the external and internal iliac arteries and the obturator lymph nodes are dissected along this nerve to reach the obturator foramen. The internal iliac lymph nodes are dissected along the surface of the internal iliac vein, carefully preserving the pelvic nerve plexus. RESULTS: The procedure was successfully accomplished in all cases without conversion to laparotomy. The median amount of bleeding and operative time were 25 (range=5-1190) ml and 413 (range=277-596) min, respectively. The median number of retrieved lymph nodes was 23 (range=14 33), and eight cases had metastasis in the retrieved LLNs. Postoperative recovery was excellent, with median time to flatus of 1 (range=1-2) day. Postoperative complications included three wound infections, one anastomotic leakage, and one presacral abscess, and all recovered without surgical intervention. There was no urinary dysfunction. After a mean follow-up of 17 (range=8-43) months, all 14 patients were alive without recurrence. CONCLUSIONS: Laparoscopic LLN dissection can be safely conducted with minimal postoperative complications. PMID- 21298545 TI - Transoral thyroid and parathyroid surgery: still experimental! PMID- 21298546 TI - Transgastric endoscopic peritoneoscopy does not lead to increased risk of infectious complications. AB - BACKGROUND: It remains important to determine the risk of bacterial contamination and infectious complications of the peritoneal cavity as it pertains to transgastric natural orifice translumenal endoscopic surgery (NOTES) procedures. The infectious implications of such procedures have been quantified in animal models. This report discusses the infectious risks of transgastric endoscopic peritoneoscopy (TEP) in a human clinical trial. METHODS: Under institutional review board approval, 40 patients scheduled for laparoscopic Roux-en-Y gastric bypass (LRYGB) participated in this study. The TEP procedure was performed without preoperative gastric decontamination and without laparoscopic guidance. Preoperative intravenous antibiotics were given. Saline aspirates were taken from the gastric lumen before endoscopic gastrotomy creation and from the peritoneal cavity after transgastric access. Samples were sent for culture, identification, and bacterial counts. Subgroup analysis was performed on patients taking proton pump inhibitors (PPIs). These data were compared with data for "sterile" peritoneal aspirates from a historical cohort of 50 patients undergoing LRYGB. RESULTS: The median number of bacteria isolated from the gastric aspirates was 980 colony-forming units (CFU)/ml (n=40). The median number of bacteria isolated from the peritoneal aspirates was 323 CFU/ml. Cross-contamination from the stomach to the peritoneal cavity was documented in eight cases. No abscesses or anastomotic leaks were recorded. One port-site infection occurred. Subgroup analysis of 15 patients receiving PPIs showed elevated bacterial counts in gastric aspirates and the post-TEP peritoneal samples compared with patients not receiving PPIs (n=25). This subgroup on PPI's did not have an increase in infectious complications. CONCLUSIONS: Contamination of the peritoneal cavity does occur with TEP, but this does not lead to an increased risk of infectious complications. Similarly, patients receiving PPIs have an increased gastric bacterial load and increased contamination after TEP but not an increased risk of infectious complications. PMID- 21298547 TI - Problems and pitfalls in modern competency-based laparoscopic training. PMID- 21298548 TI - Minimally invasive oesophagectomy: current status and future direction. AB - BACKGROUND: Oesophagectomy is one of the most challenging surgeries. Potential for morbidity and mortality is high. Minimally invasive techniques have been introduced in an attempt to reduce postoperative complications and recovery times. Debate continues over whether these techniques are beneficial to morbidity and whether oncological resection is compromised. This review article will analyse the different techniques employed in minimally invasive oesophagectomy (MIO) and critically evaluate commonly reported outcome measures from the available literature. METHODS: Medline, Embase, Science Citation Index, Current Contents, and PubMed databases were used to search English language articles published on MIO. Thirty-one articles underwent thorough analysis and the data were tabulated where appropriate. To date, only level III evidence exists. Where appropriate, comparisons are made with a meta-analysis on open oesophagectomy. RESULTS: Positive aspects of MIO include at least comparable postoperative recovery data and oncological resection measures to open surgery. Intensive care unit requirements are lower, as is duration of inpatient stay. Respiratory morbidity varies. Negative aspects include increased technical skill of the surgeon and increased equipment requirements, increased operative time and limitation with respect to local advancement of cancer. With increasing individual experience, improvements in outcome measures and the amenability of this approach to increasing neoplastic advancement has been shown. CONCLUSION: MIO has outcome measures at least as comparable to open oesophagectomy in the setting of benign and nonlocally advanced cancer. Transthoracic oesophagectomy provides superior exposure to the thoracic oesophagus compared to the transhiatal approach and is currently preferred. No multicentre randomised controlled trials exist or are likely to come into fruition. As with all surgery, careful patient selection is required for optimal results from MIO. PMID- 21298549 TI - Laparoscopic appendectomy is safe and efficacious for the elderly: an analysis using the National Surgical Quality Improvement Project database. AB - BACKGROUND: Despite increasing use of laparoscopic appendectomy, data demonstrating outcomes of this technique exclusively among the elderly population are scarce. This study aimed to compare 30-day postoperative morbidity and length of hospital stay among elderly patients after appendectomy. METHODS: Appendicitis patients older than 65 years were extracted from the National Surgical Quality Improvement Project (NSQIP) database. Demographics and rates of complications for patients undergoing open and laparoscopic appendectomies were compared. Uni- and multivariate analyses adjusted for differences between groups compared the end points of major and minor complications as well as the days of hospital stay after initial surgery. RESULTS: A total of 3,335 patients underwent appendectomy, with 2,235 patients (67%) receiving a laparoscopic procedure. The open appendectomy patients were significantly older and more likely to have various preoperative comorbidities (p<0.05). No difference in median operative time between the two techniques was found. Both required 51 min (p=0.11). The open cases had higher rates of both major and minor postoperative complications than the laparoscopic cases (p<0.0001), both overall and before discharge. Multivariate analysis showed no association between operative approach and major complications, and a reduced risk of minor complications with laparoscopy. Length of surgical stay was longer for the open group than for the laparoscopically treated group (median, 4 days vs 2 days; p<0.05). After adjustment, laparoscopy still was significantly associated with a shorter hospital stay than open appendectomy (p<0.0001). CONCLUSIONS: Laparoscopic appendectomy is a safe procedure for elderly patients. During the 30-day postoperative period, no correlation with major complications was found, and the findings showed a beneficial association with regard to minor complications. After adjustment for perioperative factors, laparoscopy is associated with a shorter hospital stay than open appendectomy. PMID- 21298550 TI - Video. Laparoscopic repair of congenital bilateral Morgagni hernia. AB - Morgagni hernia is a rare type of congenital diaphragmatic hernia found in the anterior aspect of the diaphragm. It typically presents in the pediatric population and rarely is diagnosed in adults. Only 3% of diaphragmatic hernias are the Morgagni type, and only 4% of these are found to present bilaterally. Surgical repair of Morgagni hernia has been performed through various approaches including open, laparoscopic, thoracotomy, and video-assisted thoracoscopic surgery (VATS), all with and without mesh. The optimal method of surgical repair is not known due to the rarity of this condition and the limitations of setting up a prospective, randomized trial to evaluate the different methods. Laparoscopic repair with mesh has been described with good short-term results. Few case reports exist in the world literature describing laparoscopic repair of a bilateral Morgagni hernia with mesh. At the University of Washington, the authors present a video showing their technique for laparoscopic repair of a congenital, bilateral Morgagni type hernia with mesh. PMID- 21298551 TI - Personality disorders in women with severe premenstrual syndrome. AB - Premenstrual syndrome (PMS) and its more severe form, premenstrual dysphoric disorder, affect up to 18% of women. Both are commonly associated with other mood related disorders such as major depression, and cause significant life impairment, but their relationship with personality disorders is less clear. After completing the Structured Clinical Interview for DSM-IV-TR disorders, 33 women with severe PMS and 26 asymptomatic women, counterbalanced for menstrual cycle phase, were administered the Structured Interview for DSM-IV Personality Disorders, a diagnostic interview with low transparency, strong inter-rater reliability, and good diagnostic clarity. Women with severe PMS had a higher prevalence of personality disorders (p = 0.003) than asymptomatic women (27% versus 0%), and were more likely to have odd-eccentric, dramatic-erratic, and anxious-fearful personality disorder traits (p < 0.05). Obsessive-compulsive personality disorder (OCPD) was the most common character pathology in the PMS group (n = 6, 18%). OCPD, although not necessarily associated with greater severity of premenstrual symptoms, was related to poorer life functioning in women with PMS. The comorbidity of a personality disorder and severe PMS places an additive burden on general life functioning and may have implications for psychiatric treatment or medication given to those with severe premenstrual symptoms. PMID- 21298552 TI - Expression of VLA-4 molecule in PBMC from patients with hemorrhagic fever with renal syndrome. AB - OBJECTIVE AND DESIGN: The very late antigen-4 (VLA-4) bound to vascular cell adhesion molecule-1 could provide co-stimulatory signals for the activation of T lymphocytes, and these adhesion molecules play key roles in leukocyte adherence and propagation of inflammatory responses. We examined the levels of VLA-4 in the peripheral blood mononuclear cells (PBMC) of patients with hemorrhagic fever with renal syndrome (HFRS). MATERIALS AND METHODS: The levels of VLA-4 in PBMC samples collected from 53 patients by immunohistochemical staining were detected. RESULTS: The expression of VLA-4 in PBMC of HFRS patients at different stages were significantly higher than those in normal controls (P < 0.05), except recovery stage (P > 0.05). The expression of VLA-4 in PBMC of HFRS patients at different types were significantly higher than those in healthy controls (P < 0.05). The levels of VLA-4 in patients with HFRS were positively correlated with serum levels of blood urea nitrogen (BUN) and creatinine (Cr). CONCLUSIONS: VLA-4 might play an important role in the immunopathological lesions of HFRS. We found that VLA-4 levels were closely correlated to the severity of the HFRS and the degree of kidney damage. PMID- 21298553 TI - Conservation genetics of maned wolves in a highly impacted area of the Brazilian Cerrado biome. AB - Maned wolves are large canids currently considered vulnerable to extinction due to habitat loss. They are still commonly found within the urban mesh inside the Brazilian Federal District (Distrito Federal--DF), in nearby Protected Areas (PAs), and in surrounding farms. We evaluated the genetic diversity of maned wolves in three PAs of the DF, using both invasive and noninvasive techniques to obtain DNA that was later amplified for five microsatellite markers. We sampled 23 wolves: 10 with the noninvasive method, three captured in traps, six road killed, and four rescued in urban areas. In Aguas Emendadas Ecological Station (ESECAE) we also used samples from six specimens captured between 1997 and 1998 for a temporal comparison. For maned wolves, non-invasive techniques are affordable and easier to conduct in the field, while laboratory costs are much lower for invasive samples. Hence, a sampling strategy combining both techniques may provide an interesting approach for molecular ecology studies requiring comprehensive coverage of local individuals. On the basis of such integrated sampling scheme, our analyses indicated that none of the investigated populations currently present deviations from Hardy-Weinberg expectations or indication of inbreeding. Furthermore, in ESECAE there was no reduction in genetic diversity during the last 9 years. Overall, maned wolves did not present evidence of genetic structuring among the three sampled PAs. These results thus indicate that individual exchange among PAs is still occurring at sufficient rates to avoid differentiation, and/or that the recent fragmentation in the region has not yet produced measurable effects in the genetic diversity of maned wolves. PMID- 21298554 TI - How Quaternary geologic and climatic events in the southeastern margin of the Tibetan Plateau influence the genetic structure of small mammals: inferences from phylogeography of two rodents, Neodon irene and Apodemus latronum. AB - Phylogeographical studies that focus on the southeastern margin of the Tibetan Plateau are limited. The complex terrain and unique geological history make it a particularly unusual region of the Tibetan Plateau. We carried out a phylogeographical study of two rodent species Neodon irene and Apodemus latronum using the mitochondrial cytochrome b gene sequences. High genetic diversities and deep phylogenetic splits were detected in both rodents. Some haplotypes from one sampling region fell into different evolutionary clades, but most haplotypes from the same sampling regions were clustered together with each other. The results of isolation by distance analysis further substantiated that their genetic diversities were structured along geography. Thus, there were high levels of geographical structure for both rodents. Demographic analyses implied a relatively constant population size for all samples of N. irene and A. latronum in history. However, clade B of N. irene and clade 3 of A. latronum experienced population expansions at 105-32 and 156-47 Kya, respectively. Through comparison with previous studies, we suggest the high mitochondrial DNA diversities in them are probably not a species-specific feature, but a common pattern for small mammals in this unique area. Details of the historical demography of these rodents revealed in this study could provide new insights into how rodents and possibly other small mammals in this region responded to the geological and climatic events. PMID- 21298555 TI - Improved methods for the fatty acid analysis of blood lipid classes. AB - Two improved methods have been developed for preparation of fatty acid methyl esters (FAME) from major O-ester lipid classes in blood, i.e., cholesterol ester, triacylglycerol, and glycerophospholipids. The methods involve simple operations, and use neither harmful solvents such as chloroform or benzene nor highly reactive volatile reagents such as acetyl chloride. The FAME synthesis reaction proceeds under mild temperature conditions. The methods include (1) extraction of lipids from 0.2 ml of blood with 0.2 ml of tert-butyl methyl ether and 0.1 ml of methanol, (2) separation of the total lipids into lipid classes using a solid phase extraction column or thin-layer chromatography, and (3) methanolysis of each lipid class at room temperature or at 45 degrees C. In all the operations, solvent concentration is performed only once prior to gas-liquid chromatography (GC). No noticeable differences in composition determined by GC have been found between FAME prepared by the present methods and those prepared by a conventional method involving lipid extraction with chloroform/methanol. The mild reaction and simplified procedures of the present methods enabled safe and reproducible analysis of the fatty acid compositions of the major ester-lipid classes in blood. PMID- 21298556 TI - Dietary n-3 fatty acid deficiency in mice enhances anxiety induced by chronic mild stress. AB - Docosahexaenoic acid (DHA), is the major polyunsaturated fatty acid in the brain and is important for both the structure and the function of the nervous system. Mice were fed either an n-3 fatty acid deficient (n-3 Def) or adequate (n-3 Adq) diet for two generations. The mice were housed under two conditions, as a group or in isolation and the major point of the study was to determine whether n-3 fatty acid deficiency would enhance isolation-induced anxiety. Isolation stress was assessed using the novelty suppressed feeding paradigm (NSF) after a 3-week period and the test lasted a maximal duration of 10 min. The number of successful mice consuming food pellets within 5 min in the n-3 Def diet group was low in both housing conditions (group housing, 33% and isolated, 30%), but was 92% in the group housed and 50% in the isolated group when fed the n-3 Adq diet. In the subsequent 5 min period, the isolated housing group consuming the n-3 Adq diet increased up to 79% and the group housed animals fed the n-3 Def diet increased to 67%. However, those that consumed the n-3 deficient diet combined with isolation stress exhibited no increase. These results suggested that the n-3 deficient mice had increased anxiety that was enhanced by the chronic mild stress of social isolation. PMID- 21298558 TI - A review of the current profile of gastric cancer presentation in the university college hospital Ibadan, a tertiary health care institution in the tropics. AB - INTRODUCTION: Gastric cancer is the fourth commonest malignancy and the second leading cause of cancer-related death. Although gastric carcinoma is less common throughout Africa than in Europe, there are considerable variations in its incidence and pattern. It accounts for about 5% of cancer-related death. It is characterized with significant morbidity and mortality mainly because of late presentation in developing and poor countries. Previous studies on gastric cancer in Ibadan and other West African centres demonstrated the preponderance of distal (pyloric antrum) gastric lesions when compared to proximal (cardia, fundus) lesions. Nevertheless, recent studies in developed nations show that distal gastric lesions are on the decline while there is an increase in the proportion of proximal gastric lesions. OBJECTIVE: The objective of this study is to review the pattern of presentation of patients with gastric carcinoma managed in our surgical division over a 5-year period and to determine changes in the trend in our environment. METHODOLOGY: A retrospective study of all patients with gastric carcinoma between November 2004 and October 2009 was carried out. Simple descriptive analysis was used to characterize the patients' demographic parameters, symptomatology, clinical and investigative findings along with treatment and outcome modalities. RESULTS: There were 49 cases managed by the division over the period under review. The male to female ratio was 1.45:1 with a mean age of 56 years at presentation. Duration of symptom was less than 5 months (20 weeks) in 47.9% of the patients. Dysphagia was present in 12.2% while 52.6% had a history of suspected peptic ulcer disease. There was electrolyte derangement in 31.7% of the patients while 52.6% had anaemia at presentation. Proximal tumours of the gastro-oesophageal region, cardia and the body constituted 51% of the cases; 51.4% of the patients were blood group O as opposed to 28.6% and 20%, respectively, with blood A and B. Thirty-six patients (73.5%) had a histological diagnosis of adenocarcinoma, five patients (10%) had signet ring variant of adenocarcinoma carcinoma, while three patients (6.1%) were each had gastrointestinal stromal tumours or lymphomas. DISCUSSION: Our review shows a peak age in the sixth and seventh decades at presentation. There is a significant increase in the proportion of proximal gastric lesions and a predominance of blood group O. Gastrointestinal stromal tumour and lymphoma should be considered as differential diagnosis. Patients still present late with advanced diseases, and curative treatment is often impossible. PMID- 21298557 TI - Culture of porcine hepatocytes or bile duct epithelial cells by inductive serum free media. AB - A serum-free, feeder cell-dependent, selective culture system for the long-term culture of porcine hepatocytes or cholangiocytes was developed. Liver cells were isolated from 1-wk-old pigs or young adult pigs (25 and 63 kg live weight) and were placed in primary culture on feeder cell layers of mitotically blocked mouse fibroblasts. In serum-free medium containing 1% DMSO and 1 MUM dexamethasone, confluent monolayers of hepatocytes formed and could be maintained for several wk. Light and electron microscopic analysis showed hepatocytes with in vivo-like morphology, and many hepatocytes were sandwiched between the feeder cells. When isolated liver cells were cultured in medium without dexamethasone but with 0.5% DMSO, monolayers of cholangioctyes formed that subsequently self-organized into networks of multicellular ductal structures, and whose cells had monocilia projecting into the lumen of the duct. Gamma-glutamyl transpeptidase (GGT) was expressed by the cholangiocytes at their apical membranes, i.e., at the inner surface of the ducts. Cellular GGT activity increased concomitantly with the development of ductal structures. Cytochrome P-450 was determined in microsomes following addition of metyrapone to the cultures. In vivo-like levels of P-450s were found in hepatocyte monolayers while levels of P-450 were markedly reduced in cholangiocyte monolayers. Serum protein secretion in conditioned media was analyzed by Western blot and indicated that albumin, transferrin, and haptoglobin levels were maintained in hepatocytes while albumin and haptoglobin declined over time in cholangiocytes. Quantitative RT-PCR analysis showed that serum protein mRNA levels were significantly elevated in the hepatocytes monolayers in comparison to the bile ductule-containing monolayers. Further, mRNAs specific to cholangiocyte differentiation and function were significantly elevated in bile ductule monolayers in comparison to hepatocyte monolayers. The results demonstrate an in vitro model for the study of either porcine hepatocytes or cholangiocytes with in vivo-like morphology and function. PMID- 21298560 TI - Sarcoidosis and small-fiber neuropathy. AB - Chronic pain is one of the most commonly reported symptoms among sarcoidosis patients. Not only does it significantly affect quality of life, but it also is a source of frustration for both the patient and physician because the etiology for pain often is unknown. Although patients typically complain of neuropathic-type pain, nerve conduction studies and other conventional diagnostic procedures frequently fail to reveal objective evidence of neurologic disease. However, in recent years, the growing use of specialized tests such as skin biopsy and sudomotor testing has helped to establish the diagnosis of small-fiber neuropathy as the cause of pain in these patients via objective and quantifiable means. Management of sarcoidosis small-fiber neuropathy should consist of target directed treatment of the underlying disease and appropriate symptomatic therapy. PMID- 21298561 TI - The pathophysiologic basis of secondary narcolepsy and hypersomnia. AB - The symptoms of narcolepsy can occur during the course of other neurologic conditions (ie, symptomatic narcolepsy). Inherited disorders, tumors, and head trauma were the three most frequent causes for symptomatic narcolepsy. Other causes include multiple sclerosis (MS), vascular disorders, and encephalitis. Cerebrospinal fluid hypocretin-1 measures were carried out in some recent cases with symptomatic narcolepsy, and moderate decreases in hypocretin levels were seen in a large majority of these cases. Excessive daytime sleepiness (EDS) in these symptomatic cases was sometimes reversible with an improvement of the causative neurologic disorder and with an improvement of the hypocretin (orexin) status. Recently, we found that several symptomatic narcoleptic cases with MS show unique bilateral symmetric hypothalamic lesions associated with significant hypocretin ligand deficiency. In addition, these patients often share the clinical characteristics of neuromyelitis optica (NMO) and the detection of NMO IgG (or anti-aquaporin-4 [AQP4] antibodies), suggesting a new clinical entity. Further studies of the involvement of the hypocretin system in symptomatic narcolepsy and EDS are helpful to understand the pathophysiologic mechanisms for occurrence of EDS and cataplexy. PMID- 21298562 TI - Nutritional supplements and their effect on glucose control. AB - Type 2 diabetes is a growing health concern. The use of nutritional supplements by patients with type 2 diabetes is estimated at somewhere between 8% to 49%. The objective of this review was to search the scientific literature for advances in the treatment and prevention of type 2 diabetes with nutritional supplements. Twelve databases were searched with a focus on extracting studies published in the past 3 years. The following nutritional supplements were identified as potentially beneficial for type 2 diabetes treatment or prevention: vitamins C and E, alpha-lipoic acid, melatonin, red mold, emodin from Aloe vera and Rheum officinale, astragalus, and cassia cinnamon. Beta-carotene was shown to be ineffective in the prevention of type 2 diabetes. Ranging from preclinical to clinical, there is evidence that nutritional supplements may be beneficial in the treatment or prevention of type 2 diabetes. Health providers should investigate drug-nutritional supplement interactions prior to treatment. PMID- 21298563 TI - The perception of harmonic triads: an fMRI study. AB - We have undertaken an fMRI study of harmony perception in order to determine the relationship between the diatonic triads of Western harmony and brain activation. Subjects were 12 right-handed, male non-musicians. All stimuli consisted of two harmonic triads that did not contain dissonant intervals of 1 or 2 semitones, but differed between them by 0, +/-1, +/-2 or +/-3 semitones and therefore differed in terms of their inherent stability (major and minor chords) or instability (diminished and augmented chords). These musical stimuli were chosen on the basis of a psychoacoustical model of triadic harmony that has previously been shown to explain the fundamental regularities of traditional harmony theory. The brain response to the chords could be distinguished within the right orbitofrontal cortex and cuneus/posterior cingulate gyrus. Moreover, the strongest hemodynamic responses were found for conditions of rising pitch leading from harmonic tension to modal resolution. PMID- 21298564 TI - Secondary structure and 1H, 13C, 15N resonance assignments of the Golgi-specific PH domain of FAPP1. AB - The pleckstrin homology domain of the FAPP1 protein (FAPP1-PH) recognizes phosphatidylinositol 4-phosphate [PtdIns(4)P] and is recruited to the Golgi apparatus in order to mediate trafficking to the cell surface. We report the complete (1)H, (13)C and (15)N resonance assignments of the FAPP1-PH in its free state and those induced by PtdIns(4)P or detergent micelles. PMID- 21298565 TI - 1H, 13C and 15N backbone and side-chain chemical shift assignment of the Fyn SH2 domain and its complex with a phosphotyrosine peptide. AB - SH2 domains are interaction modules uniquely dedicated to recognize phosphotyrosine sites, playing a central role in for instance the activation of tyrosine kinases or phosphatases. Here we report the (1)H, (15)N and (13)C backbone and side-chain chemical shift assignments of the SH2 domain of the human protein tyrosine kinase Fyn, both in its free state and bound to a high-affinity phosphotyrosine peptide corresponding to a specific sequence in the hamster middle-T antigen. The BMRB accession numbers are 17,368 and 17,369, respectively. PMID- 21298566 TI - Signal evaluation environment: a new method for the design of peripheral in vehicle warning signals. AB - An evaluation method called the Signal Evaluation Environment (SEE) was developed for use in the early stages of the design process of peripheral warning signals while driving. Accident analyses have shown that with complex driving situations such as intersections, the visual scan strategies of the driver contribute to overlooking other road users who have the right of way. Salient peripheral warning signals could disrupt these strategies and direct drivers' attention towards these road users. To select effective warning signals, the SEE was developed as a laboratory task requiring visual-cognitive processes similar to those used at intersections. For validation of the SEE, four experiments were conducted using different stimulus characteristics (size, colour contrast, shape, flashing) that influence peripheral vision. The results confirm that the SEE is able to differentiate between the selected stimulus characteristics. The SEE is a useful initial tool for designing peripheral signals, allowing quick and efficient preselection of beneficial signals. PMID- 21298567 TI - Examining workgroup diversity effects: does playing by the (group-retention) rules help or hinder? AB - Group diversity researchers are often faced with the problem of calculating diversity indices for groups that are incomplete due to participant nonresponse. Because participant nonresponse may attenuate the correlations that are observed between group diversity scores and outcome variables, some researchers use group retention rules based on within-group response rates. With this approach, only those groups that have a within-group response rate at, or higher than, the rate prescribed by the group-retention rule are retained for subsequent analyses. We conducted two sets of experiments using computer simulations to determine the usefulness of group-retention rules. We found that group-retention rules are not a substitute for a high response rate and may decrease the accuracy of observed relations, and consequently, we advise against their use in diversity research. PMID- 21298568 TI - Category norm data and relationships with lexical frequency and typicality within verb semantic categories. AB - The aim of the present study was to expand the scope of category norm and typicality data to include verbs for use when investigating semantic memory in fields such as linguistics, psychology, and aphasiology. Two experiments were conducted. In the first, participants were asked to list verbs within 10 semantic categories (e.g. breaking, cleaning, cooking, etc.) and 10 noun categories (e.g. animals, fruit, tools, etc.). In the second experiment, participants were asked to rate the typicality of verbs within 8 of the previously investigated verb categories. Although participants listed fewer verbs in verb categories than nouns in noun categories, the overall patterns with regard to correlation analyses between production frequency, mean rank of responses, lexical frequency, and typicality were consistent with those observed in noun categories. These patterns are also consistent with those observed in previous research. Potential similarities and differences between nouns and verbs, as well as future applications of such data, are discussed. PMID- 21298569 TI - Cross-modal validation of the Leipzig Affective Norms for German (LANG). AB - Affective stimuli are increasingly used in emotion research. Typically, stimuli are selected from databases providing affective norms. The validity of these norms is a critical factor with regard to the applicability of the stimuli for emotion research. We therefore probed the validity of the Leipzig Affective Norms for German (LANG) by correlating valence and arousal ratings across different sensory modalities. A sample of 120 words was selected from the LANG database, and auditory recordings of these words were obtained from two professional actors. The auditory stimuli were then rated again for valence and arousal. This cross-modal validation approach yielded very high correlations between auditory and visual ratings (>.95). These data confirm the strong validity of the Leipzig Affective Norms for German and encourage their use in emotion research. PMID- 21298570 TI - Design, data, and theory regarding a digital hand inclinometer: a portable device for studying slant perception. AB - Palm boards are often used as a nonverbal measure in human slant perception studies. It was recently found that palm boards are biased and relatively insensitive measures, and that an unrestricted hand gesture provides a more sensitive response (Durgin, Hajnal, Li, Tonge, & Stigliani, Acta Psychologica, 134, 182-197, 2010a). In this article, we describe an original design for a portable lightweight digital device for measuring hand orientation. This device is microcontroller-based and uses a micro inclinometer chip as its inclination sensor. The parts are fairly inexpensive. This device, used to measure hand orientation, provides a sensitive nonverbal method for studying slant perception, which can be used in both indoor and outdoor environments. We present data comparing the use of a free hand to palm-board and verbal measures for surfaces within reach and explain how to interpret free-hand measures for outdoor hills. PMID- 21298571 TI - Exploratory regression analysis: a tool for selecting models and determining predictor importance. AB - Linear regression analysis is one of the most important tools in a researcher's toolbox for creating and testing predictive models. Although linear regression analysis indicates how strongly a set of predictor variables, taken together, will predict a relevant criterion (i.e., the multiple R), the analysis cannot indicate which predictors are the most important. Although there is no definitive or unambiguous method for establishing predictor variable importance, there are several accepted methods. This article reviews those methods for establishing predictor importance and provides a program (in Excel) for implementing them (available for direct download at http://dl.dropbox.com/u/2480715/ERA.xlsm?dl=1) . The program investigates all 2(p) - 1 submodels and produces several indices of predictor importance. This exploratory approach to linear regression, similar to other exploratory data analysis techniques, has the potential to yield both theoretical and practical benefits. PMID- 21298572 TI - False recognition production indexes in Spanish for 60 DRM lists with three critical words. AB - A normative study was conducted using the Deese/Roediger-McDermott paradigm (DRM) to obtain false recognition for 60 six-word lists in Spanish, designed with a completely new methodology. For the first time, lists included words (e.g., bridal, newlyweds, bond, commitment, couple, to marry) simultaneously associated with three critical words (e.g., love, wedding, marriage). Backward associative strength between lists and critical words was taken into account when creating the lists. The results showed that all lists produced false recognition. Moreover, some lists had a high false recognition rate (e.g., 65%; jail, inmate, prison: bars, prisoner, cell, offender, penitentiary, imprisonment). This is an aspect of special interest for those DRM experiments that, for example, record brain electrical activity. This type of list will enable researchers to raise the signal-to-noise ratio in false recognition event-related potential studies as they increase the number of critical trials per list, and it will be especially useful for the design of future research. PMID- 21298573 TI - Problematic standard errors and confidence intervals for skewness and kurtosis. AB - Many statistics packages print skewness and kurtosis statistics with estimates of their standard errors. The function most often used for the standard errors (e.g., in SPSS) assumes that the data are drawn from a normal distribution, an unlikely situation. Some textbooks suggest that if the statistic is more than about 2 standard errors from the hypothesized value (i.e., an approximate value for the critical value from the t distribution for moderate or large sample sizes when alpha = 5%), the hypothesized value can be rejected. This is an inappropriate practice unless the standard error estimate is accurate and the sampling distribution is approximately normal. We show distributions where the traditional standard errors provided by the function underestimate the actual values, often being 5 times too small, and distributions where the function overestimates the true values. Bootstrap standard errors and confidence intervals are more accurate than the traditional approach, although still imperfect. The reasons for this are discussed. We recommend that if you are using skewness and kurtosis statistics based on the 3rd and 4th moments, bootstrapping should be used to calculate standard errors and confidence intervals, rather than using the traditional standard. Software in the freeware R for this article provides these estimates. PMID- 21298574 TI - Tumor immune surveillance and ovarian cancer: lessons on immune mediated tumor rejection or tolerance. AB - In the past few years, cancer immunotherapies have produced promising results. Although traditionally considered unresponsive to immune therapy, increasing evidence indicates that ovarian cancers are, in fact, immunogenic tumors. This evidence comes from diverse epidemiologic and clinical data comprising evidence of spontaneous antitumor immune response and its association with longer survival in a proportion of ovarian cancer patients; evidence of tumor immune evasion mechanisms and their association with short survival in some ovarian cancer patients; and finally pilot data supporting the efficacy of immune therapy. Below we will discuss lessons learned on the biology underlying ovarian cancer immune rejection or tolerance and we will discuss its association with clinical outcome. We will discuss the role of angiogenesis and the tumor endothelium on regulation of the antitumor immune response with a special emphasis on the role of vascular endothelial growth factor (VEGF) in the suppression of immunological processes, which control tumor progression and its unique crosstalk with endothelin systems, and how their interactions may shape the antitumor immune response. In addition, we will discuss mechanisms of tumor tolerance through the suppression or exhaustion of effector cells and how these could be countered in the clinic. We believe that understanding these pathways in the tumor microenvironment will lead to novel strategies for enhancing ovarian cancer immunotherapy. PMID- 21298575 TI - The role of nuclear pore complex in tumor microenvironment and metastasis. AB - One of the main reasons for cancer mortality is caused by the highly invasive behavior of cancer cells, which often due to aggressive metastasis. Metastasis is mediated by various growth factors and cytokines, operating through numerous signaling pathways. Remarkably, all these metastatic signaling pathways must enter the nucleus through a single gatekeeper, the nuclear pore complex (NPC). NPCs are the only gateway between the cytoplasm and the nucleus. NPCs are among the largest proteinaceous assemblies in the cell and are composed of multiple copies of around 30 different proteins called nucleoporins. Here, we review what is currently known about the NPC, and its role in the mechanisms of tumor progression. We will also explore potential strategies to target metastatic pathways by manipulating the karyopherins (importins/exportins) of nucleocytoplasmic traffic through NPCs. PMID- 21298576 TI - Mineralocorticoid actions in the brain and hypertension. AB - Mineralocorticoid receptors (MR) and epithelial sodium channels (ENaC) in the brain mediate central aldosterone-induced sympathetic hyperactivity and hypertension. Enzymes for biosynthesis of aldosterone are present in the brain, and aldosterone can be produced locally in the brain. Hypothalamic aldosterone levels increase in Dahl salt-sensitive rats on high-salt diet, and in Wistar rats with chronic central infusion of sodium-rich artificial cerebrospinal fluid (CSF) or with subcutaneous infusion of angiotensin II. Functional studies using antagonists of MR, ENaC, and ouabain-like compounds ("ouabain"), as well as specific aldosterone synthase inhibitors, suggest that an increase in local synthesis of aldosterone via MR and ENaC in the brain increases "ouabain" and thereby causes enhanced AT(1) receptor stimulation, leading to sympathoexcitation and hypertension. An increase in CSF sodium or an increase in angiotensinergic output from circumventricular organs such as the subfornical organ projecting to hypothalamic nuclei may increase local production of aldosterone and "ouabain" in magnocellular neurons in the supraoptic nucleus and paraventricular nucleus. This aldosterone-"ouabain" neuromodulatory mechanism appears to play a major role in salt-induced or angiotensin II-induced hypertension. PMID- 21298577 TI - Vitamin d therapy and cardiovascular health. AB - Vitamin D belongs to the family of nuclear steroid hormones, which has pleiotropic effects on several organ systems. Different vitamin D compounds have been studied as potential cardioprotective agents over the past 20 years. The results of these clinical studies vary based on the form and dosage of vitamin D administered during the trial. In the past 5 years, many have described an association of vitamin D compounds and cardiovascular health through reduction in blood pressure, reduction in inflammatory biomarkers, improved insulin sensitivity, and reduction in cardiovascular disease complications and death. Because there are several vitamin D compounds, it is important to consider the full breadth of the literature when examining vitamin D and cardiovascular health, to assist in hypothesis generation and understanding of the current state of the science. Although a growing body of evidence suggests that nutritional vitamin D supplementation and potentially even treatment with synthetic analogues of vitamin D may be cardioprotective, relatively few studies have examined either of these compounds in a randomized, controlled fashion. Studies examining the benefit of vitamin D supplementation are now beginning, but future studies considering calcitriol and analogue therapy also seem warranted. PMID- 21298579 TI - Metabolic syndrome and heart failure--the risk, paradox, and treatment. AB - The constellation of obesity, hypertension, dyslipidemia, and insulin resistance together referred to as metabolic syndrome (MetS)-is increasing in prevalence in the American population and also worldwide. The individual components of MetS and MetS as a whole increase the risk of heart failure, cardiovascular mortality, and all-cause mortality. Despite this adverse association, numerous studies have documented an obesity paradox, in which overweight and obese people with established cardiovascular disease, including hypertension, coronary heart disease, heart failure, and peripheral arterial disease, have a better prognosis than patients who are not overweight or obese. Current treatment strategies for these patients include weight loss, control of blood pressure and cholesterol levels, and treatment of hyperglycemia. Because of increasing evidence for the obesity paradox, some physicians question whether obesity should be treated when it is associated with heart failure. Several studies have shown improvement in left ventricular function and decreased mortality and morbidity from heart failure with weight loss and treatment of elevated blood pressure, cholesterol, and hyperglycemia. The most reasonable approach at this time appears to be weight loss and exercise, lowering blood pressure to less than 130/80 mm Hg, low-density lipoprotein (LDL) cholesterol to less than 100 mg/dL, and glycosylated hemoglobin levels to less than 7%. PMID- 21298580 TI - Compartmentation of the cerebellar cortex in the naked mole-rat (Heterocephalus glaber). AB - Despite the apparent uniformity in cellular composition of the adult mammalian cerebellar cortex, it is actually highly compartmentalized into transverse zones and within each zone further subdivided into a reproducible array of parasagittal stripes. This basic cerebellar architecture is highly conserved in birds and mammals. However, different species have very different cerebellar morphologies, and it is unclear if cerebellar architecture reflects taxonomic relations or ecological niches. To explore this, we have examined the cerebellum of the naked mole-rat Heterocephalus glaber, a burrowing rodent with adaptations to a subterranean life that include only a rudimentary visual system. The cerebellum of H. glaber resembles that of other rodents with the remarkable exception that cerebellar regions that are prominent in the handling of visual information (the central zone, nodular zone, and dorsal paraflocculus) are greatly reduced or absent. In addition, there is a notable increase in size in the posterior zone, consistent with an expanded role for the trigeminal somatosensory system. These data suggest that cerebellar architecture may be substantially modified to serve a particular ecological niche. PMID- 21298581 TI - Diffusion and extrusion shape standing calcium gradients during ongoing parallel fiber activity in dendrites of Purkinje neurons. AB - Synaptically induced calcium transients in dendrites of Purkinje neurons (PNs) play a key role in the induction of plasticity in the cerebellar cortex (Ito, Physiol Rev 81:1143-1195, 2001). Long-term depression at parallel fiber-PN synapses can be induced by stimulation paradigms that are associated with long lasting (>1 min) calcium signals. These signals remain strictly localized (Eilers et al., Learn Mem 3:159-168, 1997), an observation that was rather unexpected, given the high concentration of the mobile endogenous calcium-binding proteins parvalbumin and calbindin in PNs (Fierro and Llano, J Physiol (Lond) 496:617-625, 1996; Kosaka et al., Exp Brain Res 93:483-491, 1993). By combining two-photon calcium imaging experiments in acute slices with numerical computer simulations, we found that significant calcium diffusion out of active branches indeed takes places. It is outweighed, however, by rapid and powerful calcium extrusion along the dendritic shaft. The close interplay of diffusion and extrusion defines the spread of calcium between active and inactive dendritic branches, forming a steep gradient in calcium with drop ranges of ~13 MUm (interquartile range, 10-18 MUm). PMID- 21298582 TI - A set of high quality colour images with Spanish norms for seven relevant psycholinguistic variables: the Nombela naming test. AB - This paper presents a new corpus of 140 high quality colour images belonging to 14 subcategories and covering a range of naming difficulty. One hundred and six Spanish speakers named the items and provided data for several psycholinguistic variables: age of acquisition, familiarity, manipulability, name agreement, typicality and visual complexity. Furthermore, we also present lexical frequency data derived internet search hits. Apart from the large number of variables evaluated, these stimuli present an important advantage with respect to other comparable image corpora in so far as naming performance in healthy individuals is less prone to ceiling effect problems. Reliability and validity indexes showed that our items display similar psycholinguistic characteristics to those of other corpora. In sum, this set of ecologically valid stimuli provides a useful tool for scientists engaged in cognitive and neuroscience-based research. PMID- 21298583 TI - Cultural resources for health participation: examining biomedicine, acupuncture, and massage therapy for HIV-related peripheral neuropathy. AB - In this article we use a culture-centered approach to understand people's experiences of treatment options for human immunodeficiency virus (HIV)-related peripheral neuropathy. We present from often unheard and marginalized voices the stories of how people live with this chronic illness and negotiate treatment options. Based on individual and group interviews, participants reported that biomedical pills were an important context for understanding decision making regarding neuropathy treatment. While most people spoke of the necessity of these drugs for their survival, they also expressed deep resentment and frustration with biomedically prescribed pills. Complaints about the pills worked to frame the holistic alternatives of acupuncture and massage therapy as better options for neuropathy and to establish a foundation for understanding how participants made particular health treatment decisions. Through strategically refusing certain drugs and choosing holistic treatments instead, participants asserted agency and control over their health decision making. By choosing holistic therapies, these clients were able to make choices about their neuropathy treatment in light of the many issues surrounding drug toxicity and treatment efficacy. PMID- 21298584 TI - Errorless learning and working memory: the impact of errors, distractors, and memory span load on immediate recall in healthy adults. AB - Errorless learning represents an important contribution to current neuropsychological rehabilitation. Previous research has mainly explained the benefits of errorless learning through properties of long-term memory. This study aims to explore how errors affect immediate recall performance. A new, supplementary perspective focusing on the role of working memory in errorless learning is introduced. Sixty university students participated in a within subject design experiment measuring the effect of errors, memory span load, and attentional distractors on a digit recall task. Errors were found to have significant negative impact on immediate recall, while distractors had an effect only in interaction with errors. PMID- 21298585 TI - Avoiding a knowledge gap in a multiethnic statewide social marketing campaign: is cultural tailoring sufficient? AB - In 2007, the State of Hawaii, Healthy Hawaii Initiative conducted a statewide social-marketing campaign promoting increased physical activity and nutrition. The campaign included substantial formative research to develop messages tailored for Hawaii's multiethnic Asian and Pacific Islander populations. The authors conducted a statewide random digital dialing telephone survey to assess the campaign's comparative reach among individuals with different ethnicities and different levels of education and income. This analysis suggests that the intervention was successful in reaching its target ethnic audiences. However, a knowledge gap related to the campaign appeared among individuals with incomes less than 130% of the poverty level and those with less than a high school education. These results varied significantly by message and the communication channel used. Recall of supermarket-based messages was significantly higher among individuals below 130% of the poverty level and those between 18 and 35 years of age, 2 groups that showed consistently lower recall of messages in other channels. Results suggest that cultural tailoring for ethnic audiences, although important, is insufficient for reaching low-income populations, and that broad based social marketing campaigns should consider addressing socioeconomic status related channel preferences in formative research and campaign design. PMID- 21298586 TI - College students' estimation and accuracy of other students' drinking and believability of advertisements featured in a social norms campaign. AB - Social norms campaigns, which are based on correcting misperceptions of alcohol consumption, have frequently been applied to reduce college students' alcohol consumption. This study examined estimation and accuracy of normative perceptions for students during everyday drinking occasions. Students who reported having 4 or fewer drinks underestimated the percentage of other students who had 4 or fewer drinks, while those who drank 5 or more drinks overestimated the percentage of other students who had 5 or more drinks. Believability of advertisements featured in social norms campaigns also played a crucial role in this process. Those who believed the ad more closely estimated alcohol consumption by their peers while ad believability moderated the relation between drinking behaviors and accuracy. PMID- 21298587 TI - Validity of Functional Ambulation Performance Score for the evaluation of spatiotemporal parameters of children's gait. AB - Gait characteristics of a healthy adult population have been used to develop the Functional Ambulation Profile (FAP) score to evaluate gait in patients with neuromuscular or musculoskeletal involvement (A. J. Nelson, 1974). Further technological progress allowed a more precise recording of walk parameters and propitiated the development of the Functional Ambulation Performance Score (FAPS). The authors aimed to explore the evolution of the FAPS in healthy children to determine what the lower limit of age would be to ensure reliability of this score. Participants were 32 children with normal development. A GAITRite(r) walkway was used to log the spatiotemporal parameters. Compared with values obtained in adults, the average FAPS was significantly lower for children under 12 years old. The interparticipant variability was particularly high for the younger children and decreased with age. Similar trends were observed regarding the intraparticipant variability. In conclusion, the authors observed that the FAPS is not suitable to compare the gait of different children younger than 12 years old. At least, the adult standards used to calculate FAPS would need to be modified if the score has to be applied to a pediatric population. PMID- 21298588 TI - Is sexual well-being part of subjective well-being? An empirical analysis of Belgian (Flemish) survey data using an extended well-being scale. AB - Most conventionally used subjective well-being scales do not include any measurement of sexual well-being, despite the fact that most available research and theories indicate that sexuality is to be considered an important and integral part of human well-being. This article proposes a five-item subjective well-being scale that includes sexual well-being. A representative pilot survey in Belgium (n = 2,080) indicated that item non-response on the sexual item was limited. The new scale is strongly one-dimensional and internally coherent. A multivariate analysis demonstrated that including sexual well-being allows for a better understanding of subjective well-being, highlighting the importance of age and having a partner, and the interaction between both variables. This article concludes that the positive impact of having a partner on subjective well-being significantly increases with age. It is argued that sexual well-being should be included in subjective well-being measurements that are routinely being used in population surveys. PMID- 21298589 TI - Task complexity, posture, age, sex: which is the main factor influencing manual laterality in captive Cercocebus torquatus torquatus? AB - Behavioural asymmetries reflect brain asymmetry in nonhuman primates (NHP) as in humans. By investigating manual laterality, researchers can study the evolution of brain hemisphere specialisation. Three dominant theories aim to establish an evolutionary scenario. The most recent theory relates different levels of manual laterality to task complexity. Our investigation aimed to evaluate the importance of two extrinsic factors (posture and the need for manual coordination) and two intrinsic factors (age and sex) on the expression of manual laterality by red capped mangabeys. We observed 19 captive-born mangabeys, in spontaneous situations and under experimental conditions (seven experimental tasks varying in complexity). No directionality was observed in hand preference at the group level whatever the task. But our data revealed an effect of task complexity: more subjects were lateralised than not lateralised for the bipedal task and for the three most complex tasks. Finally, we evidenced an age and a sex effect. We compare our results with data for several other primate species and discuss them in the light of different manual laterality theories. PMID- 21298590 TI - Stimulation of the nicotine antiinflammatory pathway improves food intake and body composition in tumor-bearing rats. AB - Inflammation contributes to the pathogenesis of cancer anorexia-cachexia syndrome. Nicotine administration reduces cytokine levels and mortality during sepsis. Therefore, nicotine administration may result in improved anorexia cachexia. Sixteen male Fischer rats inoculated with MCA sarcoma were assigned to random injections of nicotine (NIC; 200 mg/kg BW/d) or saline (C). Food intake (FI), body weight, body composition, interleukin (IL)-1, IL-6 levels were evaluated. Data were analyzed via Student's t-test for paired and unpaired data and ANOVA. FI started declining 12 days after tumor inoculation both in C and NIC rats, but the decline was significantly attenuated by nicotine administration. At the end of the study, lean body mass wasting was more severe in C rats than in NIC rats (P<0.05), whereas a trend toward attenuation of fat mass depletion was observed. IL-1 circulating levels were significantly lower in NIC rats than in C rats (114+/-21 pg/mL vs. 190+/-35 pg/mL, respectively; P<0.01), whereas the reduction of IL-6 levels in NIC rats was only marginally not significant when compared to C rats (555+/-174 pg/mL vs. 721+/-160 pg/mL, respectively; P=0.06). Our data suggest that the nicotinic antiinflammatory pathway may represent an interesting and possibly effective therapy for anorexia-cachexia syndrome. PMID- 21298591 TI - Effects of nobiletin on PhIP-induced prostate and colon carcinogenesis in F344 rats. AB - The current study was designed to investigate the effects of nobiletin (5,6,7,8,3',4'-hexamethoxy flavone) on 2-amino-1-methyl-6-phenylimidazo[4,5 b]pyridine (PhIP)-induced prostate and colon carcinogenesis. PhIP was administered to 6-wk-old F344 male rats intragastrically (100 mg/kg) twice a wk for 10 wk. The animals were given 0.05% nobiletin or the basal diet for 50 wk. At the end of the experiment, serum testosterone, estrogen, and leptin did not differ between the 2 groups. The body weights of nobiletin-treated rats were significantly higher than controls (P<0.05), and feeding of nobiletin significantly reduced the relative prostate (P<0.05) and testes (P<0.05) weights as well as the Ki67 labeling index in the normal epithelium in the ventral prostate (P<0.01). The incidence and multiplicity of adenocarcinomas in nobiletin treated ventral prostate were 50% and 36%, respectively, of controls, but the differences were not statistically significant. However, nobiletin did significantly reduce the total number of colonic aberrant crypt foci (ACF) compared to the control value (P<0.05). Nobiletin, therefore, may have potential for chemoprevention of early changes associated with carcinogenesis in both the prostate and colon. PMID- 21298592 TI - Exposure to isothiocyanates suppresses urinary mutagenicity in rats treated with heterocyclic amine IQ: lack of association with CYP1 activity. AB - The principal objectives of this study were to evaluate whether exposure of rats to low doses of isothiocyanates modulates the overall metabolism of heterocyclic amine 2-amino-3-methylimidazo-[4,5-f]quinoline (IQ), as exemplified by urinary mutagenicity, a food carcinogen, and to relate any modifications in metabolism to changes in CYP1 and glutathione S-transferase activities. Animals were exposed to isothiocyanates either for 2 wk (long-term) or 1 day (short-term), and all animals were then treated with a single oral dose of IQ, and urine was collected daily for 3 days; animals continued to receive the isothiocyanates during this period. Urinary mutagenic activity was determined using the Ames mutagenicity assay in the presence of an activation system from Aroclor 1254-treated rats. At the end of the study, animals were killed and hepatic methoxy- and ethoxyresorufin dealkylations were determined as well as glutathione S transferase activity. All isothiocyanates studied, namely sulforaphane, erucin, and phenethyl isothiocyanate, decreased urinary mutagenic activity, implying enhanced IQ metabolism, but only after long-term intake. Changes in mutagenic activity were not related to changes of any of the enzyme activities determined. It is concluded that long-term intake of isothiocyanates may stimulate the metabolism of IQ, but this effect is not linked to changes in hepatic CYP1A2 and glutathione S-transferase activities. PMID- 21298593 TI - Losing control in front of a fearful face: the effect of emotional information on cognitive control. AB - How is our cognitive control system modulated by emotional information, especially fearful stimuli? An intuitive hypothesis is that fearful stimuli would enhance cognitive control so that people could switch from the ongoing task to emergent events more quickly to secure themselves. To test this hypothesis, we investigated the influence of emotional information on the shift function of cognitive control by using the task-cueing procedure, in which face images were presented as cues. With the gender of faces indicating which task to do, we manipulated the emotional valence of faces (neutral vs. fearful), finding that the switch costs were larger in the trials containing fearful cues than in the trials containing neutral cues (Experiment 1). This effect was not caused by enlarging task-set interference (Experiment 2), nor by slowing down cue encoding (Experiment 3). Contrary to the intuitive hypothesis, our results suggested that the endogenous task-set reconfiguration process was impaired when fearful faces were presented. We speculated that the benefit of decreasing cognitive flexibility in face of fearful stimuli is to speed up response in a dangerous environment, and this accelerating response is achieved by suppressing the goal directed system to permit the fast, automatic stimulus-driven system to govern behaviours. PMID- 21298594 TI - The role of age and inhibitory efficiency in working memory processing and storage components. AB - In this study, we examined the extent to which inhibitory efficiency accounted for age-related decline in the processing and storage components of working memory. Older and younger adults performed a sequential task, which served as an index of deletion-type inhibition (the ability to suppress no-longer-relevant information). The reading span task was used to measure working memory components by examining processing accuracy, processing time, and end-word recall of sentences presented. Reduced inhibitory efficiency, which was poorer in older adults, predicted age-related decline in recall, over and above the effects of processing speed. Similar results were observed for processing accuracy, although the age effect in this component was marginal. These results highlight the important role of deletion-type inhibition in explaining age-related decline in working memory performance, particularly in the storage component, and extend previous research by examining this relationship at a componential level. PMID- 21298595 TI - [Safety of drug therapy]. PMID- 21298598 TI - [Perceptual and acoustic evaluation of hoarseness]. AB - Voice disturbances require a multidimensional diagnostics. Hoarseness as a common symptom of dysphonia contains the parameters of breathiness and roughness. Perceptual voice assessment is designed to describe voice attributes and serve as a standardised means of communication among clinicians. In Germany a commonly used and researched perceptual scale is the RBH-scale, providing a measure of roughness (R), breathiness (B) and the overall grade (H) of dysphonia as judged by the listener on a scale of 0 to 3 (0: normal, 1: mild, 2: moderate, 3: severe). Acoustic analysis of the voice by means of the Goettingen hoarseness diagram is commonly used as well and enables to quantitatively describe the periodicity (roughness) and the noise content (breathiness) of voices, but not on a scale of 0 to 3. We suggest a possibility to present the result of the Goettingen hoarseness diagram on a scale analogously to the RBH-system to facilitate a better exchange of information about the severity of voice disturbances for colleagues or medical surveyors. PMID- 21298600 TI - [Sensorineural hearing loss after dull head injury or concussion trauma]. AB - A dull head injury can lead to isolated damage of the inner ear (cochlear labyrinthine concussion) or damage of the otolithe organ (vestibular labyrinthine concussion) due to a bone conduction pressure . A typical sign is a high frequency SNHL in form of a c5-dip. The c5-dip can be bilateral or unilateral or different on each side - dependant on the side of injury. In case of a unilateral skull base fracture a contralateral labyrinthine concussion is also possible. Moreover a lot of cases also show an accompanying tinnitus. This knowledge is based on animal and human experiments, as well as data from clinical and medical report examinations over decades. It is important to differentiate between a SNHL caused by accident or uni- or bilateral endogenic degenerative hearing loss. PMID- 21298602 TI - [New Obligations to Inform at not Curative Performances for Doctors and Hospitals]. PMID- 21298603 TI - [Imaging in ENT]. PMID- 21298604 TI - Evidence for mast cell activation in patients with therapy-resistant irritable bowel syndrome. AB - Previous findings suggested an involvement of mast cells in the pathogenesis of irritable bowel syndrome (IBS). The pathophysiological significance of mast cells is defined both by their number in tissue and by their activity. In the present pilot study activity of mast cells in patients with therapy-resistant IBS was investigated for the first time systematically. Twenty patients with therapy resistant IBS were investigated for the presence of a pathologically increased mast cell mediator release by means of a validated structured interview suitable to identify mast cell mediator-related symptoms and by determing selected surrogate parameters for mast cell activity. Nineteen of the 20 patients presented mast cell mediator-related symptoms. Pathologically increased mast cell activity-related coagulation and fibrinolysis parameters were detected in 11 of 12 patients investigated in that regard. One patient had an elevated level of methylhistamine in urine. The present data provide evidence that in patients with therapy-resistant IBS a pathologically increased systemic mast cell activity may occur with high prevalence. This finding fits to the idea of an assumed contribution of activated mast cells in the pathophysiology of IBS. PMID- 21298605 TI - Effectiveness and Safety of PRECISE APC for the treatment of bleeding gastrointestinal angiodysplasia--a retrospective evaluation. AB - BACKGROUND: APC is a thermal coagulation technique that uses ionized argon to transmit high-frequency electrical current, contact-free, to tissue. Precise APC is one of the new modes and is characterized by a small and distinctive energy input, higher reproducibility of tissue effects which is almost independent of the probe distance. The aim of the study was the evaluation of precise APC in patients with bleeding angiodysplasia's in the cecum or the small bowel. AIM/METHODS: Patients (pts.) with bleeding angiodysplasia of the cecum or small bowel were prospectively enrolled. Effectivity and safety of APC was assessed by evaluating the local coagulation effect, number of rebleedings and transfusions and complications (perforation, infection). RESULTS: There were 50 males and 44 females, median age 65.5 +/- 8.5 years. 58 pts. (62 %) had lesions in the small bowel, 28 pts. (30 %) lesions in the cecum and 8 pts. (8 %) lesions in small bowel and cecum. All 234 visible lesions in 94 pts. were coagulated successfully. There was no perforation, active bleeding and tissue carbonization after the procedure. Re-bleeding was recognized in 18 pts. (19 %) after a mean follow-up of 6.1 months and new lesions in the same area were seen in 15 / 18 pts (16 %). CONCLUSION: In a historical comparison to forced or pulsed APC, precise APC may be a more appropriate option for the treatment of bleeding angiodysplasia's in critical locations like the cecum or small bowel. The coagulation effect seems to be comparable and due to its better depth control we assume a better safety, especially in preventing perforations. PMID- 21298606 TI - [Coexistence of multifocal gastric adenocarcinoma with signet-ring cell morphology and a gastrointestinal stromal tumour in a stomach with hp-associated gastritis]. AB - A 79-year-old man was admitted because of anemia during marcumar therapy with suspected bleeding in the gastrointestinal tract. Endoscopy revealed a large mutifocal poorly differentiated gastric signet ring cell adenocarcinoma. After staging by the usual oesophagogastroduodenoscopic method, a total D 2 gastrectomy was performed. In the pathological resection specimen of the stomach, a multifocal poorly differentiated signet ring cell adenocarcinoma, infiltrating the submucosa (so called early cancer of sm-type) and an incidental gastroinstinal stromal tumour, 0.8 cm in diameter, was diagnosed. This is the first case report of the synchronous occurrence of a multifocal poorly differentiated gastric adenocarcinoma with signet-ring cell morphology (diffuse type according to the Lauren classification) and a GIST incidentally within a stomach with Hp-associated gastritis. PMID- 21298607 TI - Pantoprazole induces severe acute hepatitis. AB - A female patient receiving pantoprazole during a corticosteroid therapy for encephalomyelitis disseminata developed severe acute hepatitis one month after initiation of pantoprazole treatment. Other causes of hepatic dysfunction including viral hepatitis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, haemochromatosis or Wilson's disease were excluded. Liver biopsy showed severe hepatic lesions with extensive necroses of the parenchyma. One week after discontinuation of pantoprazole the liver function began to improve and gradually the patient fully recovered. One year earlier the patient had been treated with pantoprazole before and had developed a milder form of hepatitis then. This case argues for an idiosyncratic hepatocellular damage caused by pantoprazole. PMID- 21298608 TI - [Minimal Residual Disease (MRD) in gastric carcinoma--an overview]. AB - Despite recent developments in therapy for gastric cancer, the prognosis of this disease remains poor in advanced stages. In many cases even curatively treated patients without any residual tumour develop metachronous metastases. As in other solid tumours, adjuvant therapies can reduce the metastatic risk, which implies that some of these patients harbour isolated tumour cells or micrometastases (minimal residual disease, MRD) that are undetectable by radiological imaging and conventional histopathology but can still be the cause of tumour recurrence. Therefore, reliable methods for diagnosing MRD would be desirable for individually tailoring therapy for these patients. Unfortunately, testing methods for MRD and interpretation of their results are not standardised and studies published on this topic are difficult to interpret due to methodological differences and small sample sizes. As of now, testing for MRD has not become relevant in clinical routine for any of the anatomic compartments lymph nodes, peritoneal lavage fluid, peripheral blood, and bone marrow in the Western hemisphere. Most reliable data on MRD in gastric cancer patients have been reported for peritoneal lavage fluid. In some centres in Japan, this test is routinely being used for making therapeutic decisions, e. g., on the use of intraperitoneal chemotherapy. MRD in resected lymph nodes will be further evaluated in the context of the sentinel lymph node concept and possibly be employed for designing individualised therapy for patients in early disease stages who are not routinely candidates for multimodal treatment. As for tumour cells in peripheral blood and in bone marrow, studies suggest that these cells are only able to form metastases in the presence of certain molecular factors. Therefore, rather than simply confirming the existence of isolated tumour cells in blood or bone marrow, future studies should concentrate on defining their molecular characteristics and the conditions required for their metastatic potential. This may gain relevance in diagnostics and prognostic evaluation of individual patients as well as in the development of targeted therapies directly interfering with the metastatic process. PMID- 21298609 TI - [Beyond microbiota: genetic factors in post-infectious irritable bowel syndrome]. PMID- 21298610 TI - [Recommendations on therapy for chronic constipation--working group for functional diagnosis and psychosomatics of the austrian society of gastroenterology and hepatology]. AB - Constipation is one of the most frequent gastroenterological problems, especially among elderly people. Chronic constipation is now defined by the new Rome III criteria. Life style counselling is usually only effective in early stages of disease and for mild types. In patients with constipation one should actively screen for possible causative, medically adverse events. Recently new effective opioid antagonists were introduced to act against constipation in patients on long-term opioid therapy. If these actions fail, medical therapy with polyethylene glycol or lactulose should be favoured in the long-term treatment. Psychodiagnostic queries concerning fear should be included in the diagnostic procedures. Biofeedback is an effective therapy in these cases and especially with pelvic floor dyssynergia. Surgical interventions are rarely indicated or successful with the exception of chronic outlet obstruction with severe anatomic changes. PMID- 21298612 TI - Hypogonadism and gynecomastia with duloxetine. PMID- 21298613 TI - Marked reduction of heavy drinking did not reduce nicotine use over 1 year in a clinical sample of alcohol-dependent patients. PMID- 21298614 TI - What causes an improved safety climate among the staff of a dialysis unit? Report of an evaluation in a large network. AB - BACKGROUND: Clinical staff's safety perception is considered an important indicator of the implementation level of safety climate and safety culture. For this purpose, the Safety Climate Survey Questionnaire was submitted to the dialysis clinics staff of the Fresenius Medical Care (FME) network in Italy. Moreover, to explore how standard procedures implementation influences staff opinion of safety levels, the Universal Hygiene Precautions Questionnaire was also submitted. METHODS: Safety Climate Survey and Universal Hygiene Precautions questionnaires were based on 19 and 14 statements, respectively. Staff members (n=346) of 33 dialysis units were involved: 21.4% physicians, 58.1% registered nurses and 20.5% health care assistants (HCAs). RESULTS: Safety Climate mean total score was 81.9%. Medical directors (91.5%) and quality-responsible head nurses (QHRNs) (87.4%) showed higher scores in comparison with staff physicians (82.4%), nurses responsible for hygiene (81.1%) and HCAs (78.8%). Staff nurses (78.9%) showed a significant difference (p<0.05) compared with medical directors. Universal Hygiene Precautions mean total score was 90.8%, not significantly different among medical directors (92%), staff physicians (91.4%), QHRNs (93.2%), nurses responsible for hygiene (91.7%) and staff nurses (91.4%). Only HCAs reported a significantly (p<0.05) lower score (83.6%) compared with medical directors. As the respondents were asked to complete both questionnaires anonymously, a direct correlation between the 2 questionnaires was not possible. CONCLUSION: A relatively high value for Safety Climate was evaluated within the FME network of Italian dialysis clinics. Management showed higher Safety Climate scores than frontline staff. Fostering communication and implementation of training programs are considered valid tools to improve safety. PMID- 21298615 TI - No influence of haemodialysis on interferon production in the QuantiFERON-TB Gold In-Tube test. AB - BACKGROUND: Immunodeficiency in end-stage renal disease (ESRD) can be aggravated by haemodialysis (HD). This results in an increased incidence of reactivation of tuberculosis (TB) in HD patients. The tuberculin skin test to detect a latent TB infection (LTBI) has its limitations in these patients because of a high rate of false negative results due to anergy of T cells. Data on the influence of HD on the performance of interferon-gamma release assays are limited. The aim of this study was to determine the effect of HD on the performance of the QuantiFERON-TB Gold (QFT-G) assay in ESRD patients before, during and after the HD session. METHODS: In HD patients older than 18 years without immunosuppressive medication or other immunocompromising conditions, the QFT-G assay was performed just before starting HD, 30 minutes after start and immediately after the finish of the HD session. RESULTS: Twenty patients were included. No statistically significant differences were found in interferon-gamma production in the nil- and antigen tubes between pre-HD, during and after HD. In 1 patient the predialysis result was indeterminate (one of 60 samples, 1.67%). In all 3 patients with a history of LTBI, the QFT-G test tube results were positive at all time points. In the other 16 patients, all test tubes showed negative results. CONCLUSIONS: The QFT-G assay could be a useful test for the evaluation of the immunological response against Mycobacterium tuberculosis in HD patients. The time point of blood sampling does not seem to affect the interpretation of test results. PMID- 21298616 TI - Fibronectin distribution on demixed nanoscale topographies. AB - PURPOSE: It is known that surface nanotopography influences cell adhesion and differentiation. Our aim is to analyze the effect of nanoscale topography on fibronectin adsorption and, afterwards, on cell adhesion in order to rationalize the cell-material interaction by focusing on the state of the intermediate layer of adsorbed fibronectin at the material interphase. METHODS: Nanotopographic surfaces were produced by demixing of thin film polymer blends - PLLA and PS - during a high speed spin-casting process. Fibronectin (FN) was adsorbed on the different nanotopographies and the protein distribution was directly observed by atomic force microscopy (AFM). The fraction of the surface covered by the protein was quantified by image analysis, as well as the distribution of FN between peaks and valleys. Focal adhesion protein -vinculin- was immunostained and quantified by image analysis on the different nanoscale surfaces. RESULTS: Different nanoscale domains were obtained by changing the composition of the system within a height range of 3 nm to 30 nm. FN tends to adsorb on the peaks of nanoisland topographies, especially in compositions that did not enhance cell adhesion. Moreover, protein distribution between valleys and peaks alters the size of focal adhesion plaques, which grew larger on surfaces with an even distribution of fibronectin. CONCLUSIONS: Our results suggest that the surface nanotopography is a key material property capable of influencing protein adsorption. Additionally, the distribution of the protein on the different samples was correlated to the initial ability of cells to adhere in terms of the size of the focal plaques. PMID- 21298618 TI - First experience with the Prismaflex HF 20 set in four infants. AB - PURPOSE: Renal replacement therapy (RRT) in infants is challenging due to a lack of widely available technology that is specific to this patient population. We present our initial experience with the newly developed Prismaflex HF20 disposable set used on the Prismaflex device in infants with renal failure. PATIENTS: Four infants, age 5 to 24 months, were enrolled. Overall 120 treatment sessions were performed over 300 patient-days. Treatment monitoring included patient weight change and fluid balance, treatment efficacy, number of interventions, and alarms. RESULTS: Desired fluid balance according to the prescribed weight loss was achieved in all patients (R2=0.86, p<0.0001). Treatment efficacy was monitored by blood urea nitrogen (BUN) and serum creatinine values at the start of RRT (59 +/- 17 mg/dL and 5.1 +/- 1.1 mg/dL) and their decrease after 4 hours of RRT (23 +/- 7 mg/dL and 2.2 +/- 0.6 mg/dL). Measured urea and creatinine clearances for the HF20 filter were 23 +/- 7 ml/min and 19 +/- 4 ml/min, respectively. No complications occurred. CONCLUSION: This is the first report on the use of the Prismaflex HF20 set in infants. No adverse events were observed, treatments were well tolerated in all patients, and flow rate adaptability to infants' needs was good. PMID- 21298619 TI - Correlation of mortality and location of arteriovenous fistula in hemodialysis patients. AB - PURPOSE: Since the type of vascular access is very important and a significant risk factor for mortality in patients on hemodialysis, the aim of our study was to determine the impact of AVF positioning on the mortality of our patients. METHODS: The survey was organized as a prospective, clinical and non-randomized study of 538 surgical interventions on 323 patients, which indicates that a large number of patients had more than one fistula. Among these patients, 120 subjects (81 (67.5%) men and 39 (32.5%) women) died during the study period. We analyzed the demographic structure, the site location and type of anastomosis for the arteriovenous fistula, artery and vein lumen and presence of instillation catheters, as well as measuring flow through the fistula and arterial blood pressure. Biochemical parameters thought to have a significant impact on survival were obtained from routine monthly analyses. RESULTS: In patients in whom infection was the cause of death, termino-terminal anastomosis was more frequently present (p=0.035). Variables that were statistically significant predictors of death were elderly individuals (Beta 0.033, p<0.001); patients whose diastolic blood pressure was low (Beta -0.028, p<0.001); and the position of the arteriovenous fistula (distal Beta -0.737, p=0.001; proximal Beta -0.581, p=0.008). Patients with a cubital fistula (p=0.001) had a significantly shorter Kaplan-Meier survival curve. CONCLUSIONS: End-to-end artery and vein connection was a significantly more common form of anastomosis in patients who died as a result of infection. Important parameters of mortality in our study were the position of the arteriovenous fistula, age, and the diastolic component of arterial blood pressure. PMID- 21298620 TI - Relationship between erythropoietin responsiveness, insulin resistance, and malnutrition-inflammation-atherosclerosis (MIA) syndrome in hemodialysis patients with diabetes. AB - BACKGROUND: This study aimed to explore the relationship between recombinant human erythropoietin (EPO) responsiveness, insulin resistance, and malnutrition inflammation-atherosclerosis (MIA) syndrome in hemodialysis patients. METHODS: This was an observational cohort study in hemodialysis patients. Adipokines, inflammatory cytokines, and required EPO dosage were measured in diabetes (DM; n=58) and non-diabetes (non-DM; n=58) groups over 48 weeks. Furthermore, the EPO responsiveness index (required EPO dosage divided by hemoglobin) was evaluated with or without MIA syndrome in both groups. RESULTS: The DM group had significantly higher plasma leptin, interleukin-6 (IL-6), and high sensitivity C reactive protein (hs-CRP) levels but lower plasma high molecular weight (HMW) adiponectin levels compared to the non-DM group. Although hemoglobin levels were not significantly different, required EPO dosage was significantly higher in the DM group than in the non-DM group, particularly in the presence of MIA syndrome. The DM group with MIA syndrome had significantly higher plasma leptin, IL-6, and hs-CRP levels but lower plasma HMW adiponectin levels compared to the non-DM group with MIA syndrome. There was also a significant association between EPO dosage and homeostasis model assessment for insulin resistance (HOMA-IR), hs-CRP, IL-6, tumor necrosis factor a, leptin, and HMW adiponectin levels in DM patients with MIA syndrome. CONCLUSION: Diabetic hemodialysis patients with MIA syndrome have a lower response to EPO and a higher resistance to insulin. This fact may explain the poor outcome of these patients and demonstrate the importance of diagnosis and therapeutic management. PMID- 21298621 TI - Computational finite element model of cardiac torsion. AB - PURPOSE: A novel finite-element model of ventricular torsion for the analysis of the twisting behavior of the left human ventricle was developed, in order to investigate the influence of various biomechanical parameters on cardiac kinematics. METHODS: The ventricle was simulated as a thick-walled ellipsoid composed of nine concentric layers. Arrays of reinforcement bars were embedded in each layer to mimic physiological myocardial anisotropy. The reinforcement bars were activated through an artificial combination of thermal and mechanical effects in order to obtain a contractile behavior which is similar to that of myocardial fibers. The presence of an incompressible fluid inside the ventricular cavity was also simulated and the ventricle was combined with simple lumped parameter hydraulic circuits reproducing preload and afterload. Changes to a number of cardiac parameters, such as preload, afterload and fiber angle orientation were introduced, in order to study the effects of these changes on cardiac torsion. RESULTS: The model is able to reproduce a similar torsional behavior to that of a physiological heart. The results of the simulations showed that there was sound correspondence between the model outcomes and available data from the literature. Results confirmed the importance of symmetric transmural patterns for fiber orientation. CONCLUSIONS: This model represents an important step on the path towards unveiling the complexity of cardiac torsion. It proves to be a practical and versatile tool which could assist clinicians and researchers by providing them with easily-accessible, detailed data on cardiac kinematics for future diagnostic and surgical purposes. PMID- 21298622 TI - Two-incision minimally invasive total hip arthroplasty--results and complications. AB - The purpose of this study was to determine the complication rate and functional result after two-incision minimally invasive total hip arthroplasty in a retrospective consecutive case series of the first 45 patients treated by a single surgeon. The mean follow up period was 2.1 years. There were 4 early major complications (2 peri-operative fractures and 2 re-interventions) and 28 early minor complications (1 superficial infection and 27 patients with a loss of sensation of the lateral aspect of the thigh). One stem loosening required revision within two years. The mean modified Harris Hip Score at final follow-up was 91.5. Our experience shows a relatively high complication risk after two incision minimally invasive total hip arthroplasty, and we have since abandoned this technique. PMID- 21298623 TI - Bone metabolism analyzed by PET and DXA following revision THA using a distally fixed stem. A pilot study. AB - In a pilot study we analyzed bone remodeling using 18F-PET (positron emission tomography) scanning or DXA (dual-energy x-ray absorptiometry) in 3 patient groups, one with a loose femoral stem and 2 after revision using a modular stem (MP). In loose implants (group 1), bone formation activity compared to the contralateral healthy femur was 261 %. In the proximal part of the femur bone formation was increased by 253 % one week after revision (group 2) and did not normalize within 1 year. In the distal region it decreased to normal after one year. In the second revision group DXA showed decreased bone mineral density at 6 and 24 months (group 3). The PET technique provided evidence of bone healing despite osteolysis and prosthetic loosening which continued after revision. Decreasing BMD after revision in the third group is multifactorial, but suggests that despite intensive bone formation resorption was still higher. PMID- 21298624 TI - A review of 202 periprosthetic fractures--stem revision and allograft improves outcome for type B fractures. AB - We report a retrospective review of the outcome of treatment of 202 periprosthetic fractures around total hip arthroplasty (THA) from two specialised arthroplasty centres. Fractures were classified according to the Vancouver classification. The aim was to evaluate treatment methods with respect to stem revision and grafting. Transverse B1 fractures treated with stem revision compared to those treated with open reduction and internal fixation (ORIF) with a plate showed a trend towards improved overall union rate (OR=2, p=0.6, 95% CI:0.14-28.4) and shorter times to union (p=0.038, mean 12 months SD 6.573 for ORIF versus 4.48 months SD 0.757 for stem revision). B2 fractures undergoing stem revision and grafting were significantly more likely to unite compared to ORIF alone (OR=17.3, p=0.018 95%CI:1.63-184.4). B3 fractures presented with significant variation in fracture configuration and bone loss and therefore their treatment was individualised. When treated with stem revision and grafting healing was achieved in a mean time of 7 months (n=81). Periprosthetic fractures of the femur are highly complex and challenging. Stem revision for transverse B1 fractures is now considered as a viable treatment modality as this fracture configuration is difficult to control with single plating, and fixation with a long stem bypassing the distal fracture line is necessary to achieve axial stability and healing. Bone allografting, whether used as a cortical onlay or in morselised impacted form for B2 and B3 fractures enhances fracture healing. PMID- 21298625 TI - The value of routine histopathology during hip arthroplasty in patients with degenerative and inflammatory arthritis. AB - The purpose of this study was to evaluate the effectiveness of routine pathological examination of operative specimens obtained during primary total hip arthroplasty (THA) performed for osteoarthritis (OA) and rheumatoid arthritis (RA). 100 consecutive patients (50 OA, 50 RA) were prospectively evaluated. A radiological score (Kellgren-Lawrence/Larsen) and a clinical score (Harris Hip Score) were calculated in each case. Specimens of bone and cartilage from the femoral head as well as capsule were obtained intraoperatively. A histological grading (Mankin score) was obtained, and additional histological findings were also reported. In patients with RA the clinical and pathological diagnoses were concordant in 37 (74%) and discrepant in 13 patients (26%). In patients with OA there was concordance in 30 (60%) and discrepancy in 20 patients (40%). Discrepancies were additional findings such as focal osteonecrosis amyloidosis or crystal deposits. Discordance (management alteration) did not occur in any case. Histological evaluation of the capsule and the synovium was more informative than evaluation of bone. Calcium pyrophosphate (CPPD) and amyloid was frequently found in OA suggesting that these substances may contribute to joint damage, and control of their production by therapeutic means may prevent degeneration. PMID- 21298626 TI - Femoral head viability following resurfacing arthroplasty. A clinical positron emission tomography study. AB - Hip resurfacing (HR) carries attendant risks of avascular necrosis (AVN) and femoral neck fracture. We used fluoride positron emission tomography (PET) scans to analyze bone metabolism 2-5 years after surgery in 35 cases. Three of the patients had been clinical failures. Using PET scans in the remaining 32 cases, 7 were found to have an area of non-viable bone in the femoral head. This was seen following both posterior and antero lateral approaches. Fluoride PET is a sensitive and useful method for evaluating bone metabolism following HR. PMID- 21298627 TI - Metal-on-metal hip resurfacing in rheumatoid patients. A report on thirteen hips with minimum 3 year follow-up. AB - Rheumatoid disease can be extremely debilitating due to progressive joint destruction and multiple joint involvement. While there are varying results for THR in patients with RA, there is only one report of metal-on-metal resurfacing for rheumatoid patients with hip arthritis. We present preoperative and latest follow-up UCLA scores, SF-12 scores, HHS and range of motion in a series of 13 hips (10 patients). The patients experienced no complications associated with their resurfacing procedure and there have been no failures 3 to 13 years after surgery. Our results show that rheumatoid arthritis patients with hip involvement treated with metal-on-metal resurfacing can have extremely good outcomes. PMID- 21298628 TI - Efficacy of 3 different artificial tears for the treatment of dry eye in frequent computer users and/or contact lens users. AB - PURPOSE: To compare the efficacy of 3 different artificial tears (AT) acting primarily in one of the 3 tear film layers (Tears Again(r), lipidic; Opticol(r), aqueous; Optive(r), mucin) in recovering the tear film changes in patients with dry eye symptoms due to external causes. METHODS: A total of 27 patients, with dry eye symptoms associated with extra hours of computer or contact lenses use, were randomized to 4 treatment groups: A received Tears Again(r); B received Optive(r); C received Opticol(r); D received no treatment (control). Patients were observed in 3 visits: day 0, day 7, and day 30. Tear break-up time (TBUT) and Schirmer tests and the Ocular Surface Disease Index were performed. Data analysis was performed. RESULTS: There were no significant differences between the groups. From day 0 to day 30, there was a decrease in the number of eyes with abnormal TBUT (not significant) and Schirmer (significant in A, B, D; p<0.031). There was an increase in the average TBUT for all groups (significant in A, C; p<0.001) and a decrease in the average Schirmer value in groups B, C, and D (not significant) and an increase in group A (p = 0.002). There was a decrease in the average Ocular Surface Disease Index value in all groups (p<0.045). CONCLUSIONS: All AT were efficient at recovering the tear film, but those acting primarily on the internal and intermediate layer led to a mild decline on lachrymal production. An association of different kinds of AT acting on each layer can be the best treatment for corneal surface diseases affecting eye lubrication. PMID- 21298629 TI - Should unilateral congenital corneal opacities in Peters' anomaly be grafted? AB - PURPOSE: To evaluate the surgical outcomes and visual results after penetrating keratoplasty for congenital unilateral corneal opacities in Peters anomaly. METHODS: This was a retrospective study of 14 children who underwent keratoplasty for a unilateral Peters anomaly between 1999 and 2009. All patients received a topical treatment of cyclosporine and corticosteroids. Suture ablation was performed between the first and second postoperative month and all patients had spectacle correction and amblyopia treatment. Age at time of surgery, posterior segment status evaluated by ultrasonography, axial length, preoperative intraocular pressure, fellow eye status, mean follow-up time, early and late complications, final graft outcome, refraction, and visual acuity upon the last visit were noted. RESULTS: Mean age at the time of surgery was 9 months. Posterior segment was normal in all cases. Mean axial length was 18 mm and mean intraocular pressure was 11 mmHg. Mean follow-up was 30 months. Four children had graft rejection episodes, 2 of which responded to medication. Four underwent cataract surgery, one developed pupil deformation requiring a pupilloplasty, and 2 cases were complicated by surgical glaucoma. A total of 11 eyes (78.6%) had clear grafts at the end of the follow-up. Mean spherical equivalent was -1.5 D. Visual acuity was measurable in 3 cases and was 20/50 in one case, 20/63 in the second, and 20/2000 in the third. Concerning preverbal children, central, steady, and maintained fixation was found in 8 cases. CONCLUSIONS: Operating on a unilateral congenital corneal opacity is a challenging decision and should be taken after explaining the need for long-term follow-up to the parents. Useful vision can be achieved and maintained after strict amblyopia therapy. A multidisciplinary ophthalmologic follow-up is necessary. PMID- 21298630 TI - Diode laser cyclophotocoagulation versus cyclocryotherapy in the treatment of refractory glaucoma. AB - PURPOSE: The aim of the present study was to evaluate the efficacy of diode laser cyclophotocoagulation (DCPC) and cyclocryotherapy (CCT) in the treatment of refractory glaucoma and compare the postoperative complications and discomfort rates. METHODS: In a prospective, randomized, controlled clinical study, 40 eyes of 40 patients with refractory glaucoma were randomly assigned in 2 groups of 20 eyes each to receive either DCPC or CCT. Patients underwent follow-up examinations on the first 3 days and then 1 week and 1, 3, 6, and 12 months after initial treatment. Complications and discomfort after treatment using a visual pain analogue scale were recorded. RESULTS: In the DCPC group, the mean intraocular pressure (IOP) decreased (p<0.05) from 44.3 +/- 16.4 mmHg preoperatively to 24.1 +/- 7.6 mmHg, 22.8 +/- 5.6 mmHg, and 22.5 +/- 5.1 mmHg 3, 6, and 12 months posttreatment, respectively. Regarding the CCT group, the mean IOP was reduced (p<0.05) from 46.5 +/- 10.4 mmHg to 26.6 +/- 12.2 mmHg, 21.2 +/- 7.7 mmHg, and 20.6 +/- 5 mmHg at the same time intervals. In the DCPC group, the mean IOP reduction was strongly correlated with the number of laser effects (r = 0.65; p<0.01), but 35% needed retreatments. The mean postoperative pain was 5.6 +/- 2.9 (DCPC) vs 5.7 +/- 2.3 (CCT) (p = 0.91). No severe complications were observed. CONCLUSIONS: Both DCPC and CCT proved to be safe and effective IOP lowering methods in patients with refractory glaucoma. Diode laser cyclophotocoagulation should be considered as the primary treatment option in refractory glaucoma using an individual treatment dosage. PMID- 21298631 TI - The role of cortisol reactivity in children's and adults' memory of a prior stressful experience. AB - The purpose of this study was to identify whether cortisol reactivity to a stressful laboratory event was related to children's memory of that event and to determine whether this relation was comparable to that observed in adults. Nine- to 12-year-olds and young adults completed an impromptu speech and math task during which repeated cortisol samples and self-reported stress ratings were collected. Two weeks later, participants' memory for the tasks was examined. Greater cortisol reactivity was associated with enhanced memory, most prominently in children. Self-reported stress was unrelated to memory. Findings reveal that an important mechanism underlying the association between emotion and memory in adults, namely activation of the hypothalamic pituitary adrenal axis, appears to operate similarly in late childhood. Findings also demonstrate that positive associations between cortisol reactivity and memory are evident when the event that actually elicited that reactivity serves as the to-be-remembered event. PMID- 21298632 TI - Prenatal treatment with glucocorticoids sensitizes the hpa axis response to stress among full-term infants. AB - The objective of this study was to determine the consequences for HPA axis functioning among healthy full-term newborns of prenatal treatment with the synthetic glucocorticoid (GC), betamethasone, which is the routine treatment for threatened preterm delivery. Ninety full-term infants were recruited into two study groups (30 betamethasone treated; 60 comparison group matched for GA at birth and sex). The cortisol and behavioral response to the painful stress of a heel-stick blood draw was assessed 24 hr after birth. Full-term infants exposed to prenatal betamethasone displayed a larger cortisol response to the heel-stick procedure, despite no differences in baseline levels. Further, within the recommended window of betamethasone administration (24-34 gestational weeks), infants exposed to betamethasone earlier in gestation displayed the largest cortisol response to the heel-stick. These data add to accumulating evidence that prenatal exposure to elevated GCs programs the development of the HPA axis. PMID- 21298633 TI - Cortisol levels in relation to maternal interaction and child internalizing behavior in preterm and full-term children at 18 months corrected age. AB - Cortisol levels were compared in children born preterm at extremely low gestational age (ELGA; 24-28 weeks), very low gestational age (VGLA; 29-32 weeks), and full-term in response to cognitive assessment at 18 months corrected age (CA). Further, we investigated the relationship between maternal interactive behaviors and child internalizing behaviors (rated by the mother) in relation to child cortisol levels. EGLA children had higher "pretest" cortisol levels and a different pattern of cortisol response to cognitive assessment compared to VGLA and full-terms. Higher cortisol levels in ELGA, but not full-term, children were associated with less optimal mother interactive behavior. Moreover, the pattern of cortisol change was related to internalizing behaviors among ELGA, and to a lesser degree VLGA children. In conclusion, our findings suggest altered programming of the hypothalamic-pituitary-adrenal (HPA) axis in preterm children, as well as their greater sensitivity to environmental context such as maternal interactive behavior. PMID- 21298635 TI - Alone in the dark? Modeling the conditions for visual experience in human fetuses. AB - It is commonly assumed that, whereas auditory and olfactory learning take place already during fetal development, visual experience and learning are not possible before birth. This paper explores the conditions for visual experience in the last two months of human gestation, when the fetal visual system is mature enough to permit directed vision if a sufficient amount of light is available. Light transmission from the external environment to the uterine cavity is modeled, based on the measured transmission coefficients of biological tissues. Results indicate that illumination in the uterine cavity is highly variable, depending on factors such as external illumination and the mother's abdominal thickness. At least some fetuses can be predicted to develop in conditions allowing for ample visual experience before birth. This finding could have intriguing implications for the ontogeny of early visuo-motor abilities in newborns and infants. PMID- 21298634 TI - Motor development in 9-month-old infants in relation to cultural differences and iron status. AB - Motor development, which allows infants to explore their environment, promoting cognitive, social, and perceptual development, can be influenced by cultural practices and nutritional factors, such as iron deficiency. This study compared fine and gross motor development in 209 9-month-old infants from urban areas of China, Ghana, and USA (African-Americans) and considered effects of iron status. Iron deficiency anemia was most common in the Ghana sample (55%) followed by USA and China samples. Controlling for iron status, Ghanaian infants displayed precocity in gross motor development and most fine-motor reach-and-grasp tasks. US African-Americans performed the poorest in all tasks except bimanual coordination and the large ball. Controlling for cultural site, iron status showed linear trends for gross motor milestones and fine motor skills with small objects. Our findings add to the sparse literature on infant fine motor development across cultures. The results also indicate the need to consider nutritional factors when examining cultural differences in infant development. PMID- 21298636 TI - Quantification of benign lesion regression as a function of 532-nm pulsed potassium titanyl phosphate laser parameter selection. AB - OBJECTIVES/HYPOTHESIS: Although the potassium titanyl phosphate (KTP) laser is versatile, the variability in laser parameters for laryngeal pathologies and the lack of clinical efficacy data remain problematic. We provide preliminary data regarding these parameters for benign lesion regression. In addition, we describe a novel method for the quantification of the effects of the KTP laser on vocal fold (VF) lesions. STUDY DESIGN: Retrospective chart review. METHODS: Images were captured from examinations before and after in-office KTP treatment in patients with a range of benign lesions. Laser settings were noted for each patient. Imaging software was then used to calculate a ratio of lesion area to VF length. Ten percent of images were requantified to determine inter-rater reliability. RESULTS: Thirty-two patients underwent 47 procedures for lesions including hemorrhagic polyp, nonhemorrhagic polyp, vocal process granuloma, Reinke's edema, cyst/pseudocyst, leukoplakia, and squamous cell carcinoma in situ. No statistically significant differences were observed with regard to the laser parameters used as a function of lesion type. Regardless, by 1 month following treatment, all lesions had significantly decreased in size, except nonhemorrhagic polyps. Similar data were obtained at 2-month follow-up. We then compared the pre KTP lesion size with the smallest lesion size quantified during the 1-year follow up period. All lesions were significantly smaller, with the exception of Reinke's edema. Inter-rater reliability was quite good. CONCLUSIONS: KTP laser effectively reduced VF lesion size, irrespective of the laser parameters used. In addition, our quantification method for lesion size appeared to be both viable and reliable. PMID- 21298637 TI - Sialoendoscopy in the diagnosis and management of obstructive sialadenitis. AB - OBJECTIVE: Sialoendoscopy is a new technology being used at a limited number of institutions for the diagnosis and management of obstructive sialadenitis. This technique is promising for its superior diagnostic potential as well as its decreased morbidity compared to traditional more invasive techniques for managing obstruction. Our objective is to review the sialoendoscopy experience at our institution to identify successes, areas of improvement, and to provide guidance to other programs that may be interested in sialoendoscopy. STUDY DESIGN: We did a retrospective review of all diagnostic and interventional sialoendoscopies performed at this institution from 2007 to 2009. METHODS: Charts were reviewed for epidemiologic and clinical data, as well as procedural techniques, findings, and outcomes. RESULTS: We attempted 37 parotid and submandibular sialoendoscopies, with successful endoscopic canalization of the duct in 36 of these cases. Twenty of 25 stones were removed from 18 patients. Stones that were larger than 5 mm were more difficult to dislodge and remove without fragmentation. Other abnormal findings included strictures, scars, and mucoid debris. There were two failures of technique, and two patients had postoperative purulent sialadenitis that resolved after antibiotics. CONCLUSIONS: As an institution that recently began performing sialoendoscopies, we show similar success rates compared to other programs. Obstacles included the initial cost of acquiring equipment and the associated learning curve of using a new technique. Similar to other programs, successful extraction of sialoliths was limited with larger stones. In the future, we hope to use laser lithotripsy for fragmentation, a technique already being trialed at some institutions. PMID- 21298638 TI - Health-related and specific olfaction-related quality of life in patients with chronic functional anosmia or severe hyposmia. AB - OBJECTIVES/HYPOTHESIS: To measure health-related and olfaction-related quality of life (QoL) in patients with permanent, severe hyposmia or functional anosmia. STUDY DESIGN: A case study in a university ENT department of patients with severe olfactory dysfunction defined by Sniffin' Sticks olfactory test kit with a score for odor threshold, discrimination, and identification (TDI) < 20 and a dysfunction lasting longer than 6 months. METHODS: Assessment of QoL by using the SF-36 Health Survey questionnaire and the Questionnaire for Olfactory Dysfunction (QOD). RESULTS: A total of 958 patients were tested for smell disturbances from 1999 to 2009. Surveys were mailed to 527 patients who fulfilled the inclusion criteria; 280 (53%) returned completed surveys. All SF-36 domains in severely hyposmic and anosmic patients were lower than in the German normal population. Lower SF-36 QoL was found for some domains in female patients, older patients, and hyposmic patients (P < .05 for all groups). Based on the QOD, women showed more parosmia, and anosmic patients had more olfactory-related impairment (P < .05 for both); in general, higher olfactory impairment and higher parosmia score measured by QOD correlated with lower TDI values (all P < .05). Multivariate analysis revealed, for SF-36 domains, the following independent risk factors: female sex was a risk factor for bodily pain; higher age was a risk factor for physical functioning and role, bodily pain, and general health; hyposmia was a risk factor for bodily pain and mental health; QOD QoL was a risk factor for all SF-36 scales; and QOD parosmia was a risk factor for physical role (all P < .05). CONCLUSIONS: QoL is severely impaired in patients with chronic severe hyposmia or anosmia. The QOD allows a more olfaction-specific assessment of QoL than the SF 36 instrument. PMID- 21298640 TI - The comparison of various ventilation modes and the association of risk factors with CO2 retention during suspension laryngoscopy. AB - OBJECTIVES/HYPOTHESIS: To compare the effectiveness of various ventilation modes during suspension laryngoscopy and to investigate risk factors associated with CO(2) retention in high-frequency jet ventilation (HFJV). STUDY DESIGN: Part I: Randomized controlled study; Part II: Outcomes research. METHODS: In Part I, saturation of peripheral oxygen, partial pressure of carbon dioxide (PaCO(2) )(,) and pH were recorded in different ventilation modes in 60 patients. All subjects were randomly divided into four groups. Three groups received different jet ventilations through a catheter inserted transnasally, and one group had tracheal intubation and received intermittent positive pressure ventilation. In Part II, 59 patients received jet ventilation with a fixed rate; CO(2) retention and its potential risk factors were analyzed. Data were collected at the following time points: preinduction (T(0) ), anesthesia induction (T(1) ), laryngoscopic operation (T(2) ), 10 minutes after the initiation of ventilation (T(3) ), extubation (T(4) ), and 10 minutes after extubation (T(5) ). RESULTS: In Part I, mean arterial pressure (MAP) increased and heart rate decreased significantly during T(2) (P < .01), MAP and heart rate increased significantly during T(4) (P < .01), and PaCO(2) increased and pH decreased significantly in T(3) and T(5) (P < .01) in all four groups. Using logistic regression analysis of results from Part II, it was determined that in males, the combination of higher weight, lower height, and body mass index values greater than 25.224 was closely associated with CO(2) retention. CONCLUSIONS: During suspension laryngoscopy surgery, HFJV at 60 beats per minute through a thin transnasal catheter provides adequate ventilation as well as an excellent surgical view. A body mass index of more than 25.224 is the main risk factor for CO(2) retention. PMID- 21298639 TI - The effects of cigarette smoke condensate on vocal fold transepithelial resistance and inflammatory signaling in vocal fold fibroblasts. AB - OBJECTIVES/HYPOTHESIS: In response to chronic cigarette smoke exposure, a subset of patients present with edematous vocal folds, characteristically referred to as Reinke's edema. This phenotype differs from the tissue changes associated with prolonged smoke exposure in the lower airway, and the mechanism underlying Reinke's edema remains poorly described. We hypothesize that the effects of smoke are diffuse and involve both the epithelium and mucosa. STUDY DESIGN: In vitro, ex vivo experiment. METHODS: Transepithelial resistance (R(T) ) was quantified in an ex vivo, viable, porcine vocal fold model. Excised tissue was exposed to cigarette smoke condensate (CSC) and R(T) was computed at baseline and 1 and 4 hours after exposure. In vitro, human vocal fold fibroblasts were exposed to CSC. Cyclooxygenase 2 (COX-2), microsomal prostaglandin E synthase-1, and 15 hydroxyprostaglandin dehydrogenase mRNA expression were assessed at 4 hours. Prostaglandin E2 (PGE2) synthesis was quantified via immunoassay following 24 hours of CSC exposure. RESULTS: CSC had no effect on R(T) . CSC did, however, induce COX-2 mRNA expression as well as its downstream lipid mediator PGE2. PGE2 metabolism appears to be regulated via both synthetic and degradative enzymes in response to cigarette smoke. CONCLUSIONS: In vitro, CSC initiates an inflammatory response in vocal fold fibroblasts. However, in isolation, the epithelial resistance is not altered by CSC, at least acutely. These data may suggest a role for the interaction between the inflammatory response in the mucosa and compromised epithelial barrier function, as has been shown in other tissues. PMID- 21298641 TI - Botulinum toxin treatment of adductor spasmodic dysphonia: longitudinal functional outcomes. AB - OBJECTIVES: Laryngeal botulinum toxin (BoNT) injection is a well-established symptomatic treatment for adductor spasmodic dysphonia (AdSD). Injections may be followed by a period of muscle weakness characterized by breathiness, voice weakness, and dysphagia for liquids. A recent study described some detriment and limited functional improvement with "good voice" for only one-third of the period between successive injections. Our objective was to examine the longitudinal effect of BoNT treatment for AdSD upon functional outcomes and quality of life when using a patient-specific dosing regimen. STUDY DESIGN: Prospective cohort study. METHODS: Patients presenting for BoNT treatment of AdSD were asked to complete evaluation of voice function after each injection using the percentage of normal function (PNF) scale (daily for two weeks, then weekly). Other parameters measured included voice handicap index (VHI), duration of effect, and complications. RESULTS: A total of 133 patients treated continuously between January 2006 and January 2009 with an individuated regime (dose, pattern, and schedule) were included. Of 1,457 treatments, 50.9% experienced some breathiness. Mean VHI improvement was 9.6%. Mean PNF improvement was 30.3%. There was correlation between the two scales. Dysphagia to liquids was reported after 14.2% of treatments. We describe two distinct types of functional outcome curve. A total of 28.5% of treatments were followed by initial functional decline. Mean time below baseline function was 5.7%. Mean proportion of time in plateau phase was 42.5%. CONCLUSIONS: It is important to consider longitudinal functional outcomes in BoNT treatment of AdSD. An individuated dosing regimen helps minimize side effects and maximize functional and quality-of-life outcomes. PMID- 21298642 TI - Perioperative lumbar drain placement: an independent predictor of tension pneumocephalus and intracranial complications following anterior skull base surgery. AB - OBJECTIVE: To measure the effect of routine perioperative lumbar drain placement during anterior skull base surgery on the frequency of: 1) tension pneumocephalus and 2) total intracranial complications. DESIGN: Retrospective review of a series of patients (n = 161) who underwent the transglabellar/subcranial approach to lesions of the anterior skull base between December 1995 and November 2009. A retrospective cohort (n = 45) underwent routine lumbar drain placement at the time of skull base surgery. The remainder of the series did not undergo routine perioperative lumbar drain placement. INTERVENTION: Transglabellar/subcranial surgical approach to the anterior skull base, with or without routine perioperative lumbar drain placement. RESULTS: Routine placement of perioperative lumbar drains was an independent predictor of tension pneumocephalus (P =.022, odds ratio = 11.22 [1.218-103.3]). In addition, this practice was also associated with an increased risk of intracranial complications overall (P =.025, odds ratio = 2.623 [1.104-6.233]). CONCLUSION: Routine placement of perioperative lumbar drain may be associated with an increased risk of tension pneumocephalus and intracranial complications during surgery of the anterior cranial base. PMID- 21298643 TI - Open bedside tracheotomy: impact on patient care and patient safety. AB - OBJECTIVES: Objectives were: 1) to evaluate the impact of open bedside tracheotomy (OBT) on patient care and 2) to determine whether OBT in the intensive care unit (ICU) is a safe, cost-effective procedure. STUDY DESIGN: Retrospective chart-based review. METHODS: A total of 163 consecutive adult patients in the medical or surgical ICU who underwent OBT by the Otorhinolaryngology service from July 2007 to July 2009, in addition to the 163 consecutive adult patients who had undergone open tracheotomy in the operating room immediately prior to July 2007, were included in the study. Data examined included time intervals between initial consultation and performance of tracheotomy, complication rates, ICU length of stay, and cost considerations. RESULTS: In the group of patients examined prior to OBT, time to surgery (TTS) averaged 3.24 days in comparison to an average of 1.48 days for patients who received OBT (P < .05). Review of complications revealed no significant difference in the two study groups (odds ratio [OR], 1.42, 95% confidence interval [CI], 0.44-4.56, P = .56). The length of ICU stay decreased by 0.6 days on average in the OBT group versus the OR group, although not achieving statistical significance (P = .18). Cost analysis suggests a potential savings of $4,575 per case, resulting in approximately $745,700 saved in the OBT group. CONCLUSIONS: Review of our experience demonstrates comparable safety for tracheotomy performed bedside versus in the operating room, while offering shorter time to surgery, decreased costs, and perhaps a reduction in the length of ICU stay. These findings suggest that open bedside tracheotomy is preferable to tracheotomy performed in the operating room for patients in the ICU setting. PMID- 21298644 TI - Temporal bone abnormalities in children with GJB2 mutations. AB - OBJECTIVES: To determine the incidence of temporal bone abnormalities in children with sensorineural hearing loss (SNHL) and pathogenic biallelic GJB2 mutations. STUDY DESIGN: Retrospective analysis of a large cohort of pediatric patients with biallelic GJB2 mutations and SNHL (observational case series). METHODS: Blinded review of all available temporal bone computed tomographic (CT) and magnetic resonance imaging (MRI) studies in this cohort. RESULTS: Out of 158 patients with biallelic GJB2 mutations, 113 had CT and/or MRI studies available for review. Definite, although generally subtle, inner ear abnormalities were present in 12/113. There were malformations of the semicircular canals (SCC) in 4/12, of the internal auditory canal in 2/12, of the cochlear nerve canal (CNC) in 6, and unilateral cochlear malformation in 1/12. MRI in 1/5 showed mildly hypoplastic cochlear nerve. There was no correlation between SNHL severity and presence/absence/type of malformations or genotype. CONCLUSIONS: Our study of 113 biallelic GJB2 patients with SNHL and temporal bone imaging is the largest study to date. We found only 10% had any abnormalities, most subtle, and none had EVA. Additionally, there was no correlation between SNHL severity and presence/absence/type of malformations or genotype. Disparities between our group and previous reports may be due to differences in degree of hearing loss, types of mutations, populations studied, and radiologic factors for both image acquisition and interpretation. PMID- 21298645 TI - Olfactory impairment in older adults: five-year incidence and risk factors. AB - OBJECTIVES/HYPOTHESIS: The objective of this study was to determine the five-year incidence of olfactory impairment and associated risk factors in a general population of older adults. STUDY DESIGN: Longitudinal population-based study. METHODS: Participants (n = 1,556) in the population-based Epidemiology of Hearing Loss Study had olfaction measured at the 5- and 10-year examinations (1998-2000 and 2003-2005, respectively). Olfactory ability was measured by the San Diego Odor Identification Test. RESULTS: The five-year incidence of olfactory impairment was 12.5%. Incidence rates increased with age for men and women. In a multivariate model, age (odds ratio [OR] = 1.79, 95% CI, 1.61-2.00; for every five-year increase), a history of nasal polyps (OR = 2.33, 95% CI, 1.13-4.59), a history of deviated septum (OR = 2.05, 95% CI, 1.14-3.56), and a history of heavy alcohol use (OR = 1.84, 95% CI, 1.13-2.93) were associated with an increased risk of olfactory impairment, whereas use of lipid-lowering agents (OR = 0.68, 95% CI, 0.46-0.99; yes vs. no), exercising at least once a week (OR = 0.69, 95% CI, 0.48 0.98), and oral steroid use (OR = 0.37, 95% CI, 0.11-0.94) were associated with a decreased risk. CONCLUSIONS: The five-year incidence of olfactory impairment is high in this population of older adults. Modifiable risk factors associated with impairment suggest some impairment could be amenable to prevention or treatment. PMID- 21298646 TI - A review of clinical practice guidelines for reflux disease: toward creating a clinical protocol for the otolaryngologist. AB - OBJECTIVES: Reflux disease, including gastroesophageal reflux disease (GERD) and laryngopharyngeal reflux (LPR), is an extremely common condition that is diagnosed and treated routinely in an otolaryngology practice. There is great variability in the methods of both diagnosis and treatment amongst otolaryngologists. Our aim is to review current clinical practice guidelines on reflux disease, to identify areas of agreement and controversy, and to begin to work toward a clinical protocol for reflux disease for the otolaryngologist. STUDY DESIGN: Literature review with discussion. METHODS: A PubMed search was performed looking for clinical practice guidelines on either GERD or LPR. Five hundred seventy articles were identified and the most clinically relevant practice guidelines were selected. RESULTS: Thirteen key articles were identified. Eleven of these come from the gastroenterology literature, and none of them come from the otolaryngology literature. There appears to be a consensus on empiric medication trial as first-line therapy for presumed uncomplicated GERD and on prioritizing early identification of patients with severe disease complications. Areas of controversy include the definition of GERD and LPR, which diagnostic algorithm to use in which patient, and the long-term management of medical therapy. CONCLUSIONS: Although there are many clinical aspects of reflux disease that still remain a mystery, there is enough literature to support a rudimentary clinical protocol at this time. As further data become available from outcomes measurements, such a protocol may result in improved quality and standardization. PMID- 21298647 TI - Diagnosis of the extent of advanced oropharyngeal and hypopharyngeal cancers by narrow band imaging with magnifying endoscopy. AB - OBJECTIVES/HYPOTHESIS: Narrow band imaging combined with magnifying endoscopy (NBI-ME) is useful for the detection of superficial cancer in the oropharynx, hypopharynx, and esophagus. We used NBI-ME to evaluate the frequency of superficial cancer spread (SCS) contiguous with advanced oropharyngeal and hypopharyngeal cancers and esophageal cancers. STUDY DESIGN: Retrospective. METHODS: We retrospectively studied 45 patients with oropharyngeal and hypopharyngeal cancer and 44 with esophageal cancer who underwent NBI-ME from October 2006 through April 2009. The following variables were evaluated: 1) the frequency of SCS contiguous with advanced oropharyngeal and hypopharyngeal cancer and esophageal cancer, and 2) the influence of SCS contiguous with advanced oropharyngeal and hypopharyngeal cancer on clinical T category and clinical stage. RESULTS: SCS contiguous with the primary tumor was found in 49% (22/45) of the patients with advanced oropharyngeal and hypopharyngeal cancer and in 52% (23/44) of those with advanced esophageal cancer. When SCS contiguous with the primary tumor was included in the evaluation of tumor size in advanced oropharyngeal and hypopharyngeal cancer, the clinical T category and clinical stage were revised in 20% (9/45) and 4% (2/45) of patients, respectively; SCS was <= 2 cm in 64% of cases (14/22) and between >2 cm and <= 4 cm in 36% (8/22). CONCLUSIONS: NBI-ME should be included in the pretreatment diagnostic work-up to evaluate lesion extent and decide optimal surgical margins and radiation fields in patients with advanced oropharyngeal and hypopharyngeal cancer. PMID- 21298648 TI - Ion channel therapy of ischemic heart disease: from calcium channel blockers to late sodium current inhibition. AB - What is summarized below relates to the clinical usefulness of various ion channel antagonists reviewed by a clinical cardiologist, not a basic scientist working on ion channel biology. PMID- 21298649 TI - Association of warfarin use with valvular and vascular calcification: a review. AB - Vitamin K is required for the activity of various biologically active proteins in our body. Apart from clotting factors, vitamin K-dependent proteins include regulatory proteins like protein C, protein S, protein Z, osteocalcin, growth arrest-specific gene 6 protein, and matrix Gla protein. Glutamic acid residues in matrix Gla protein are gamma-carboxylated by vitamin K-dependent gamma carboxylase, which enables it to inhibit calcification. Warfarin, being a vitamin K antagonist, inhibits this process, and has been associated with calcification in various animal and human studies. Though no specific guidelines are currently available to prevent or treat this less-recognized side effect, discontinuing warfarin and using an alternative anticoagulant seems to be a reasonable option. Newer anticoagulants such as dabigatran and rivaroxaban offer promise as future therapeutic options in such cases. Drugs including statins, alendronate, osteoprotegerin, and vitamin K are currently under study as therapies to prevent or treat warfarin-associated calcification. Copyright (c) 2011 Wiley Periodicals, Inc. The authors have no funding, financial relationships, or conflicts of interest to disclose. PMID- 21298650 TI - Familial recurrent atrial myxoma: Carney's complex. AB - We report on a family of 4 members, all of whom have had multifocal, recurrent atrial myxomas associated with skin pigmentation, melanotic schwannomas, mucocutaneous myxomas, and tumors of the ovary and pituitary, adrenal, and thyroid glands. Immunochemistry of the myxoma cells is positive for calretinin, confirming their neuroendocrine origin. Genetic studies confirmed mutations in the gene coding protein kinase A, regulatory subunit 1-alpha (PRKAR1alpha). This is Carney's complex, characterized by multiple, mucocutaneous myxomas; pigmented lesions over the lips, conjunctiva, and genitalia; adenomas of the breast and thyroid; schwannomas; and endocrinal abnormalities including Cushing syndrome and acromegaly. Members of the family require vigorous screening, including urinary free cortisol, plasma transforming growth factor-beta(1) and thyrotropin releasing hormone, testicular ultrasound, routine echocardiographic screening, searches for cardiac and mucocutaneous myxomas in multiple locations, and genetic studies for the PRKAR1alpha gene sequence. PMID- 21298651 TI - Myocardial infarction in a patient with down syndrome: a case report and review of the literature. AB - Coronary artery disease and myocardial infarctions are believed to be rare in patients with Down's syndrome. Congenital heart malformations are frequently seen in children born with the syndrome and may represent a substrate for coronary artery embolism in later life. We report a case of myocardial infarction in a patient with Down's syndrome and present a review of the literature. PMID- 21298652 TI - STEMI patients--the more you bleed, the more you die: a comparison between classifications. AB - BACKGROUND: In patients with acute coronary syndromes, an increase in hemorrhagic complications has been observed, and bleeding is now the most frequent noncardiac complication in these patients. Clinical trials and registries have used different scales to classify the severity of bleeding; so far, none of them has been developed for ST-segment elevation myocardial infarction (STEMI) patients in the era of primary percutaneous coronary intervention. METHODS: We analyzed data from our Intensive Cardiac Care Florence STEMI Registry, comprising 991 STEMI patients consecutively admitted to our intensive cardiac care unit after mechanical revascularization, to assess the clinical impact of both Thrombolysis In Myocardial Infarction (TIMI) and Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) classifications in identifying patients with major bleeding at higher risk for in-hospital mortality. RESULTS: Major bleeding events occurred in 8.9% of patients (88/991) in the TIMI classification and in 17.2% of patients (170/991) in the ACUITY classification. Among patients with major bleeding classified according to ACUITY, 82 patients did not meet the TIMI criteria for major bleeding. These patients represent the so-called gray zone, where no transfusion was performed and only 1 patient died. CONCLUSIONS: In STEMI patients who undergo primary percutaneous coronary intervention and receive dual antiplatelet therapy, TIMI is more capable than ACUITY in identifying patients with major bleeding at higher risk for early mortality. The presence of renal failure represents an independent predictor for major bleeding. PMID- 21298653 TI - Impact of preprocedural high-sensitivity C-reactive protein levels on uncovered stent struts: an optical coherence tomography study after drug-eluting stent implantation. AB - BACKGROUND: There are no sufficient data to evaluate the relationship between high-sensitivity C-reactive protein (hs-CRP) and uncovered stent struts on optical coherence tomography (OCT) after drug-eluting stent (DES) implantation. HYPOTHESIS: We evaluated the relationship between the preprocedural level of hs CRP and incomplete neointimal coverage of DES struts on OCT. METHODS: This study was conducted using 124 eligible patients (132 lesions) treated with sirolimus eluting stents (SES) or zotarolimus-eluting stents (ZES). The subjects were divided into 2 groups based on the preprocedural hs-CRP level: high-CRP (>=3 mg/L; 58 lesions) and normal-CRP (<3 mg/L, 74 lesions) groups. The percentage of uncovered struts, calculated as the ratio of uncovered struts to total struts in all OCT cross-sections, was compared between the 2 groups according to initial clinical presentation (stable angina [SA] vs acute coronary syndrome) and the type of implanted DES (SES vs ZES). RESULTS: There was no significant correlation between hs-CRP and the percentage of uncovered struts on OCT in all enrolled lesions. In the SA subgroup, the percentage of uncovered struts was significantly higher in the high-CRP group than in the normal-CRP group (8.1 +/- 11.6% vs 3.8 +/- 7.9%, P = 0.018). There was significant correlation between hs-CRP level and the percentage of uncovered struts in SA patients with SES (r = 0.280, P = 0.039), but not ZES (r = - 0.063, P = 0.729). CONCLUSIONS: Preprocedural hs-CRP level could affect incomplete neointimal coverage of struts after DES implantation depending on the initial clinical presentation and the type of implanted DES. PMID- 21298654 TI - The effects of statin monotherapy and low-dose statin/ezetimibe on lipoprotein associated phospholipase A2. AB - BACKGROUND: Many of the pleiotropic effects of statins remain to be elucidated. HYPOTHESIS: Different statin regimens with similar lipid-lowering efficacy may have different effects on biomarkers of atherothrombosis including lipoprotein associated phospholipase A2 (Lp-PLA2 ). METHODS: After a 4-week dietary lead-in, 82 hypercholesterolemic patients were randomized to 1 of 2 treatment groups: atorvastatin 20 mg or atorvastatin/ezetimibe 5 mg/5 mg. After 8 weeks of drug treatment, the groups were compared for percent change in lipid parameters, Lp PLA2 , interleukin-6 (IL-6), monocyte chemoattractant protein-1, and fibrinogen. RESULTS: Low-density lipoprotein cholesterol (LDL-C) lowering was comparable between the 2 groups (-47% +/- 11% and -49% +/- 7% in the atorvastatin and combination groups, respectively). Although Lp-PLA2 was reduced in both groups, the reduction was greater in the atorvastatin group (-42% and -9% [median], respectively, P = 0.03). Although IL-6 was decreased only in the atorvastatin group, IL-6 changes were not significantly different between the 2 groups. The changes in monocyte chemoattractant protein-1 and fibrinogen were similar in each group. CONCLUSIONS: Atorvastatin monotherapy was stronger at reducing plasma Lp PLA2 than the low-dose atorvastatin/ezetimibe combination after equivalent LDL-C lowering. This result may provide evidence of potential statin effects beyond the lowering of LDL-C. PMID- 21298655 TI - Renal dysfunction in heart failure is due to congestion but not low output. AB - BACKGROUND: Renal dysfunction in heart failure is thought to be due to poor perfusion of the kidney. HYPOTHESIS: We tested the hypothesis that passive congestion is more important than poor perfusion. METHODS: We retrospectively studied the data on 178 patients who underwent right heart catheterization for evaluation of heart failure and had serum creatinine (Cr) measured on the same day. RESULTS: Serum Cr and glomerular filtration rate (GFR) correlated with central venous pressure (r = 0.22, P = 0.001 and r = -0.55, P < 0.0001, respectively) and renal perfusion pressure (r = 0.21, P = 0.001 and r = 0.27, P = 0.015, respectively). Neither correlated with cardiac index or left ventricular ejection fraction. Serum Cr was significantly higher and GFR was significantly lower in the upper tertile of central venous pressure, pulmonary capillary wedge pressure as well as in the lower tertile of renal perfusion pressure. CONCLUSIONS: Renal dysfunction in heart failure is determined more by passive congestion than by low perfusion. PMID- 21298656 TI - Effects of statin treatment on cardiac function in patients with chronic heart failure: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Whether additional benefit can be achieved with the use of statin treatment in patients with chronic heart failure (CHF) remains undetermined. HYPOTHESIS: Statin treatment may be effective in improving cardiac function and ameliorating ventricular remodeling in CHF patients. METHODS: The PubMed, MEDLINE, EMBASE, and EBM Reviews databases were searched for randomized controlled trials comparing statin treatment with nonstatin treatment in patients with CHF. Two reviews independently assessed studies and extracted data. Weighted mean differences (WMD) with 95% confidence intervals (CI) were calculated using random effects models. RESULTS: Eleven trials with 590 patients were included. Pooled analysis showed that statin treatment was associated with a significant increase in left ventricular ejection fraction (WMD: 3.35%, 95% CI: 0.80 to 5.91%, P = 0.01). The beneficial effects of statin treatment were also demonstrated by the reduction of left ventricular end-diastolic diameter (WMD: 3.77 mm, 95% CI: -6.24 to -1.31 mm, P = 0.003), left ventricular end-systolic diameter (WMD: -3.57 mm, 95% CI: -6.37 to -0.76 mm, P = 0.01), B-type natriuretic peptide (WMD: -83.17 pg/mL, 95% CI: -121.29 to -45.05 pg/mL, P < 0.0001), and New York Heart Association functional class (WMD: -0.30, 95% CI: -0.37 to -0.23, P < 0.00001). Meta-regression showed a statistically significant association between left ventricular ejection fraction improvement and follow-up duration (P = 0.03). CONCLUSIONS: The current cumulative evidence suggests that use of statin treatment in CHF patients may result in the improvement of cardiac function and clinical symptoms, as well as the amelioration of left ventricular remodeling. PMID- 21298657 TI - Left atrial volume index over late diastolic mitral annulus velocity (LAVi/A') is a useful echo index to identify advanced diastolic dysfunction and predict clinical outcomes. AB - BACKGROUND: Combined interpretation of late diastolic mitral annulus velocity (A') with left atrial volume index (LAVi) may have additional benefits in the assessment of diastolic dysfunction. HYPOTHESIS: The LAVi/A' ratio may be useful in the identifying advanced diastolic dysfunction (ADD) and predicting clinical outcomes in patients with dyspnea. METHODS: We enrolled 395 consecutive patients hospitalized with dyspnea (New York Heart Association class II-IV) and performed transthoracic Doppler echocardiography and B-type natriuretic peptide (BNP) measurement. LAVi/A' values were evaluated in terms of diagnosing ADD and predicting clinical outcome. RESULTS: On the receiver operation characteristic curve analysis for the determination of ADD, the area under the curves of LAVi/A' in the entire population was comparable to those of BNP (0.94 vs 0.93, P = 0.845) and mitral E/E' (0.94 vs 0.93, P = 0.614) and higher than that of LAVi (0.94 vs 0.87; P = 0.014). A LAVi/A' of 4.0 was the best cut-off value to identify ADD. During a median follow-up of 31.9 months (range, 0.3 to 45.7 months), the group with LAVi/A' >=4.0 had a higher incidence of primary composite outcomes (cardiac death and/or rehospitalization for heart failure) than the group with LAVi/A'<4.0 (25.0% vs 3.3%, P < 0.001). LAVi/A' >=4.0 was an independent predictor of clinical outcomes (odds ratio, 3.245; 95% confidence interval, 1.386-7.598; P = 0.007). CONCLUSIONS: As a new echo index, LAVi/A' is a useful parameter to identify ADD and predict clinical outcomes in patients with dyspnea. PMID- 21298660 TI - Fully integrated PDMS/SU-8/quartz microfluidic chip with a novel macroporous poly dimethylsiloxane (PDMS) membrane for isoelectric focusing of proteins using whole channel imaging detection. AB - A fully integrated polydimethylsiloxane (PDMS)/modified PDMS membrane/SU-8/quartz hybrid chip was developed for protein separation using isoelectric focusing (IEF) mechanism coupled with whole-channel imaging detection (WCID) method. This microfluidic chip integrates three components into one single chip: (i) modified PDMS membranes for separating electrolytes in the reservoirs from the sample in the microchannel and thus reducing pressure disturbance, (ii) SU-8 optical slit to block UV light (below 300 nm) outside the channel aiming to increase detection sensitivity, and (iii) injection and discharge capillaries for continuous operation. Integration of all these components on a single chip is challenging because it requires fabrication techniques for perfect bonding between different materials and is prone to leakage and blockage. This study has addressed all the challenges and presented a fully integrated chip, which is more robust with higher sensitivity than the previously developed IEF chips. This chip was tested by performing protein and pI marker separation. The separation results obtained in this chip were compared with that obtained in commercial cartridges. Side-by side comparison validated the developed chip and fabrication techniques. PMID- 21298661 TI - Metabolomic profiling of human plasma in pancreatic cancer using pressurized capillary electrochromatography. AB - The application of pressurized capillary electrochromatography (pCEC) coupled with ultra violet (UV) detection has been investigated for the production of global metabolite profiles from human plasma, and its capabilities of classifying pancreatic cancer patients. The pCEC separation of plasma samples was performed on a RP column with gradient elution. The applied voltage, detection wavelength and type of acid modifiers on separation of plasma samples were optimized with pooled quality control (QC) sample. The stability and the repeatability of the methodology were also determined by the repeat analysis of QC sample. The effects of different scaling methods on the results of orthogonal partial least-squares discrimination analysis (OPLS-DA) based on pCEC-UV data set were also investigated. The results of the current study clearly showed the different phenotypes of metabolites of pancreatic cancer patients and healthy controls based on pCEC-UV plasma profiles. OPLS-DA data are shown to provide a valuable means of convenient classification. This work indicated that pCEC-UV method can be used as a cost-effective and information-rich, while relatively simple and inexpensive approach for plasma profiling on disease metabolomics studies. PMID- 21298662 TI - Thermal denaturation produced degenerative proteins and interfered with MS for proteins dissolved in lysis buffer in proteomic analysis. AB - In 1-DE, proteins were traditionally mixed with the standard Laemmli buffer and boiled for several minutes. Recently, proteins dissolved in lysis buffer were used to produce better-resolved 2-DE gels, but thermal denaturation procedure still remained in some proteomic analysis. To determine the detailed effects of thermal denaturation on SDS-PAGE and MS, both 1-DE and 2-DE were performed using proteins heated at 100 degrees C for different periods of time, and 17 protein bands/spots were positively identified by MALDI TOF/TOF MS/MS. Protein profiles on both 1-DE and 2-DE gels changed obviously and more polydisperse bands/spots were observed with increased heating time for over-heated samples. Based on these observations, an alternative protein marker-producing method was designed by directly dissolving protein standards without BSA into lysis buffer. This new kind of protein marker could be stored at room temperature for a long time, thus was more convenient for using and shipping. The identification of 17 proteins via MS and comparison of their identities revealed MASCOT-searched scores, number of both matched peptides, total searched peptides and sequence coverage became progressively lower with increasing denaturation intensity, probably due to the interference of thermal denaturation on trypsin cleavage efficiency and produced redundant modified peptides. Therefore, it was concluded that thermal denaturation not only changed the protein profiles and produced more polydisperse protein bands/spots, but also heavily interfered with the subsequent MS analysis, hence not recommended in future proteomic analysis for proteins dissolved in lysis buffer. PMID- 21298663 TI - A SNaPshot assay for genotyping 44 individual identification single nucleotide polymorphisms. AB - Single nucleotide polymorphisms (SNPs), which have relatively low mutation rates and can be genotyped after PCR with shorter amplicons compared with short tandem repeats (STRs), are being considered as potentially useful markers in forensic DNA analysis. Those SNPs with high heterozygosity and low Fst (F-statistics) in human populations are described as individual identification SNPs, which perform the same function as STRs used in forensic routine work. In the present study, we developed a multiplex typing method for analyzing 44 selected individual identification SNPs simultaneously by using multiplex PCR reaction in association with fluorescent labeled single base extension (SBE) technique. PCR primers were designed and the lengths of the amplicons ranged from 69 to 125 bp. The population genetics data of 79 unrelated Chinese individuals for the 44 SNP loci were investigated and a series of experiments were performed to validate the characteristic of the SNP multiplex typing assay, such as sensitivity, species specificity and the performance in paternity testing and analysis of highly degraded samples. The results showed that the 44-SNPs multiplex typing assay could be applied in forensic routine work and provide supplementary data when STRs analysis was partial or failed. PMID- 21298664 TI - Capillary electrophoresis combining three-step multiplex polymerase chain reactions for diagnosing alpha-thalassemia. AB - Capillary electrophoresis (CE) is the most useful tool for DNA separation because of its high resolution. In this study, different kinds of polymers were used to evaluate the separation efficiency by analyzing a 200-bp DNA ladder. Under optimized CE conditions, the CE separation was performed by DB-17 capillary. The running buffer was a 1* TBE buffer containing 0.6% w/v poly(ethylene oxide) (PEO) (Mw: 8,000,000) and 1 MUM YO-PRO-1; applied voltage was -10 kV (detector at anode side) and the separation temperature was 25 degrees C. Under these optimal conditions, 15 DNA fragments with sizes ranging from 0.2 to 3.0 kb were resolved within 11.5 min and the RSD of migration time were less than 0.55% (n=3). This method, combined with three-step multiplex PCR, was applied to detect five alpha thalassemia deletions, including -alpha(3.7) , -alpha(4.2) , - -(SEA) , - -(FIL) and - -(THAI) . A total of 21 patients diagnosed with alpha-thalassemia were analyzed using this developed method and all results agreed with those already obtained by gel electrophoresis. PMID- 21298665 TI - Application of the iPLEXTM Gold SNP genotyping method for the analysis of Amerindian ancient DNA samples: benefits for ancient population studies. AB - Important developments in the matrix-assisted laser desorption/ionization time-of flight mass spectrometry (MALDI-TOF MS) technique have generated new perspectives regarding SNP genotyping, which are particularly promising for ancient population based studies. The main aim of the present study was to investigate the application of a MALDI-TOF MS-based SNP genotyping technique, called iPLEX((r)) Gold, to analyze Amerindian ancient DNA samples. The first objective was to test the sensitivity of the method, which is recommended for DNA quantities between 10 and 5 ng, for ancient biological samples containing DNA molecules that were degraded and present in minute quantities. The second objective was to detail the advantages of this technique for studies on ancient populations. Two multiplexes were designed, allowing the major Amerindian mitochondrial and Y haplogroups to be determined simultaneously. This analysis has never been described before. Results demonstrated the reliability and accuracy of the method; data were obtained for both mitochondrial and nuclear DNA using picogram (pg) quantities of nucleic acid. This technique has the advantages of both MS and minisequencing techniques; thus, it should be included in the protocols for future ancient DNA studies. PMID- 21298666 TI - A PCR amplification method without DNA extraction. AB - To develop a simple and inexpensive method for direct PCR amplification of animal DNA from tissues, we optimized different components and their concentration in lysis buffer systems. Finally, we acquired the optimized buffer system composed of 10 mmol tris(hydroxymethyl)aminomethane (Tris)-Cl (pH 8.0), 2 mmol ethylene diamine tetraacetic (EDTA) (pH 8.0), 0.2 mol NaCl and 200 MUg/mL Proteinase K. Interestingly, the optimized buffer is also very effective when working with common human sample types, including blood, buccal cells and hair. The direct PCR method requires fewer reagents (Tris-Cl, EDTA, Protease K and NaCl) and less incubation time (only 35 min). The cost of treating every sample is less than $0.02, and all steps can be completed on a thermal cycler in a 96-well format. So, the proposed method will significantly improve high-throughput PCR-based molecular assays in animal systems and in common human sample types. PMID- 21298667 TI - Nanochitosan crosslinked with polyacrylamide as the chiral stationary phase for open-tubular capillary electrochromatography. AB - Nanoparticles exhibiting favorable surface-to-volume ratios create efficient stationary phases for electrochromatography. New nanomaterials derived from chitosan (CS) were immobilized onto modified capillaries for use as the chiral stationary phase (CSP) in open-tubular electrochromatography. This immobilization was achieved through the copolymerization of glycidyl methacrylate-modified nano CS with methacrylamide (MAA) and bis-acrylamide crosslinkers (forming the MAA-CS capillary) rather than the attachment of nano-CS to the copolymer of glycidyl methacrylate, MAA, and bis-acrylamide (forming the MAA+CS capillary). The completed MAA-CS capillary and its precursors were examined by SEM and ATR-IR measurements. Before separating chiral samples, the MAA-CS capillary was characterized by electroosmotic flow measurements at varying pH values, concentrations, and volume percentages of organic modifiers in the running buffers. Tryptophan enantiomers were well separated by the MAA-CS capillary, whereas no enantioselectivity was observed in the MAA+CS capillary. With the addition of 80% MeOH into the phosphate buffer, the chiral separation of (+/-) catechin was accomplished in a normal-phase mode. However, the new CSP has its limitations, as only two groups of alpha-tocopherol stereoisomers were separated. PMID- 21298668 TI - A novel DNA selection and direct extraction process and its application in DNA recombination. AB - In the conventional bench-top approach, the DNA recombination process is time- and effort-consuming due to laborious procedures lasting from several hours to a day. A novel DNA selection and direct extraction process has been proposed, integrated and tested on chip. The integrative microfluidic chip can perform the whole procedure of DNA recombination, including DNA digestion, gel electrophoresis, DNA extraction and insert-vector ligation within 1 h. In this high-throughput design, the manual gel cutting was replaced by an automatic processing system that performed high-quality and high-recovery efficiency in DNA extraction process. With no need of gel-dissolving reagents and manipulation, the application of selection and direct extraction process could significantly eliminate the risks from UV and EtBr and also facilitate DNA recombination. Reliable output with high success rate of cloning has been achieved with a significant reduction in operational hazards, required materials, efforts and time. PMID- 21298669 TI - Poly(dimethylsiloxane) photonic microbioreactors based on segmented waveguides for local absorbance measurement. AB - We present the development of microbioreactors (MBRs) based on poly(dimethylsiloxane) (PDMS) segmented waveguides (SWG) for local absorbance measurements. Two different MBRs were studied, either using symmetric or asymmetric SWG (being defined as MBR-S and MBR-A, respectively). Their optical and fluidic performances were numerically analyzed, showing robustness from an optical point of view and distinct fluid flow profile. The optical characterization was done in two steps. Initially, the experimental limit of detection (LOD) and the sensitivity were determined for two different analytes (fluorescein and methylorange). With both systems, a similar limit of detection for both analytes was obtained, being in the micromolar level. Their sensitivities were 20.2+/-0.3 (*10-3) A.U./MUM and 5.5+/-0.2 (*10-3) A.U./MUM for fluorescein and methylorange, respectively. Once validated its applicability for local absorbance measurements, a continuous cultivation of Saccharomyces cerevisiae was done to test the viability of the proposed systems for photonic MBRs. Concretely, the cell growth was locally monitored inside the MBR during 33 h. Spectral analysis showed that the determination of the culture parameters were wavelength dependant, with a growth rate of 0.39+/-0.02 h-1 and a doubling time of 1.65+/-0.09 h at an optimal wavelength of 469.9+/-0.3 nm. Besides the easy and monolithic integration of the SWG into poly(dimethylsiloxane) microfluidic systems, the results presented here are very promising for the application in any disposable photonic lab-on-a-chip systems used for online analysis or photonic MBRs. PMID- 21298670 TI - Cell activity analysis by capillary zone electrophoresis combined with specific cell staining. AB - Capillary zone electrophoresis (CZE) was used to determine Hela cells activity with Hela treated by 0-46 MUM methylmercury (MeHg) as the apoptosis model. The treated and untreated cells were stained by four different dyes (Janus Green B, Rhodamine 123, Neutral Red and Trypan Blue) and analyzed by CZE with UV/Vis detection. The absorbance of cells at 214 nm could indicate the degree of cell shrinkage and component leakage induced by MeHg. The intensity of cell absorbance at maximum visible absorption wavelength of dyes represented mitochondrial activity, lysosome phagocytosis ability and cell membrane integrity. For different concentrations of MeHg treatment, the change of cell activity was in good agreement with Janus Green B uptake colorimetric assay (R2 =0.914) and 3-(4, 5-dimethylthiazol-2-yl)-2, 5-di-phenyltetrazolium bromide (MTT) assay (R2 =0.892). 80% of RSD (n=3) values were in the range of 0.5-15.0%. The established CZE method could be used to analyze intact cells with only UV-Vis detector. The CZE method has some features equivalent to the existing universal method, and it has the potential to be a universal tool for cell activity determination. PMID- 21298671 TI - Analysis of inorganic cations in biological samples by the combination of micro electrodialysis and capillary electrophoresis with capacitively coupled contactless conductivity detection. AB - Micro-electrodialysis (MUED) and CE were combined for rapid pretreatment and subsequent determination of inorganic cations in biological samples. Combination of MUED with CE greatly improved the analytical performance of the latter as the adsorption of high molecular weight compounds present in real samples on the inner capillary wall was eliminated. Fifty microliter of 80-fold diluted human body fluids such as plasma, serum and whole blood was used in the donor compartment of the MUED system requiring less than 1 MUL of the original body fluid per analysis. Inorganic cations that migrated through a cellulose acetate dialysis membrane with molecular weight cut-off value of 500 Da were collected in the acceptor solution and were then analyzed using CE-C4D. Baseline separation of inorganic cations was achieved in a BGE solution consisting of 12.5 mM maleic acid, 15 mM L-arginine and 3 mM 18-crown-6 at pH 5.5. Repeatability of the CE-C4D method was better than 0.5% and 2.5% for migration times and peak areas, respectively; limits of detection of all inorganic cations in the presence of 2 mM excess of Na(+) were around 1 MUM and calibration curves were linear with correlation coefficients better than 0.998. Repeatability of the sample pretreatment procedure was calculated for six independent electrodialysis runs of artificial and real samples and was better than 11.8%. Recovery values between 96.3 and 110% were achieved for optimized electrodialysis conditions of standard solutions and real samples; lifetime of the dialysis membranes for pretreatment of real samples was estimated to 100 runs. PMID- 21298672 TI - High-throughput dielectrophoretic manipulation of bioparticles within fluids through biocompatible three-dimensional microelectrode array. AB - Dielectrophoresis (DEP) has been deemed as a potential and ideal solution for bioparticle manipulation. A 3-D carbon micro-electro-mechanical system (MEMS) fabricated from the latest developed carbon-MEMS approach has advantages of offering low-cost, biocompatible and high-throughput DEP manipulation for bioparticles. In this paper, a typical process for fabrication of various 3-D microelectrode configurations was demonstrated; accurate numerical analysis was presented on electric field gradient distribution and DEP force based on various microelectrode array configurations. The effects of electrode edge angle, electrode edge-to-edge spacing and electrode height on the electric field distributions were investigated, and optimal design considerations and rules were concluded through analysis of results. The outcomes demonstrate that the sharp edge electrode is more effective in DEP manipulation and both electrode edge-to edge spacing and electrode height are critical design parameters for seeking optimal DEP manipulation. The gradient magnitude increases exponentially as the electrode spacing is reduced and the electric field extends significantly as the electrode height increases, both of which contribute to a higher throughput for DEP manipulation. These findings are consistent with experimental observations in the literature and will provide critical guidelines for optimal design of DEP devices with 3-D carbon-MEMS. PMID- 21298673 TI - Continuous-time random walk models of DNA electrophoresis in a post array: part I. Evaluation of existing models. AB - Several continuous-time random walk (CTRW) models exist to predict the dynamics of DNA in micropost arrays, but none of them quantitatively describes the separation seen in experiments or simulations. In Part I of this series, we examine the assumptions underlying these models by observing single molecules of lambda DNA during electrophoresis in a regular, hexagonal array of oxidized silicon posts. Our analysis takes advantage of a combination of single-molecule videomicroscopy and previous Brownian dynamics simulations. Using a custom tracking program, we automatically identify DNA-post collisions and thus study a large ensemble of events. Our results show that the hold-up time and the distance between collisions for consecutive collisions are uncorrelated. The distance between collisions is a random variable, but it can be smaller than the minimum value predicted by existing models of DNA transport in post arrays. The current CTRW models correctly predict the exponential decay in the probability density of the collision hold-up times, but they fail to account for the influence of finite sized posts on short hold-up times. The shortcomings of the existing models identified here motivate the development of a new CTRW approach, which is presented in Part II of this series. PMID- 21298674 TI - Isolation and characterization of Rhodococcus sp. NB5 capable of degrading a high concentration of nitrobenzene. AB - An efficient nitrobenzene degrading bacterium strain NB5, which was able to utilize nitrobenzene as a sole source of carbon, nitrogen and energy under aerobic condition, was isolated from activated sludge in an oil refinery at Hangzhou, China. Based on phenotypic features, 16S rDNA gene sequencing and G + C content analysis, strain NB5 was identified as Rhodococcus sp. NB5. Nitrobenzene degradation experiments using high performance liquid chromatograph (HPLC) showed that strain NB5 could tolerate a high nitrobenzene concentration and completely degrade nitrobenzene with initial concentration ranging from 100 mg . l(-1) to 1000 mg . l(-1) within 144 h. The optimal degradation and cell growth were observed at 30 degrees C, pH 7.0. The addition of second nitrogen source (0.1%) such as urea, peptone, yeast extract and beef extract generally enhanced degradation of nitrobenzene. Rhodococcus sp. strain NB5 could be an excellent candidate for biotreatment of industrial wastewater containing high concentration of nitrobenzene. PMID- 21298675 TI - Characterization of biofilms in different clinical M serotypes of Streptococcus pyogenes. AB - Streptococcus pyogenes is a notorious human pathogen responsible for a wide array of infections. The ability of S. pyogenes to form biofilms is an innate property during the pathogenesis of invasive infections. From the eleven M serotypes tested: M56, M74, M100, M65, M89 and st38 formed dense biofilms in 48 h. The present study is the first of its kind to report about the biofilm formation in the serotypes M56, M65 M74 M100 and st38. XTT reduction assay of the biofilms showed decreased metabolic activity with increase in incubation time. The surface architecture of the biofilms when observed by scanning electron microscopy (SEM) revealed the microcolony formation. Confocal laser scanning microscopy (CLSM) was used to compare the surface topography and thickness of biofilms between the biofilm formers with and without the addition of glucose. Interestingly a non biofilm former (st2147) was induced to form biofilms with the addition of glucose. On correlating the drug (erythromycin) resistance of the various M serotypes with their biofilm forming ability we noticed that erythromycin sensitive strains were found to be good biofilm formers. We also noticed that biofilm formation in S. pyogenes is independent of sil gene. PMID- 21298676 TI - Expression and characterization of a second L-amino acid deaminase isolated from Proteus mirabilis in Escherichia coli. AB - L-amino acid deaminases catalyze the deamination of natural L-amino acids. Two types of L-amino acid deaminase have been identified in Proteus species. One exhibits high levels of activity toward a wide range of aliphatic and aromatic L amino acids, typically L-phenylalanine, whereas the other acts on a relatively narrow range of basic L-amino acids, typically L-histidine. In this study, we cloned, expressed, and characterized a second amino acid deaminase, termed Pm1, from P. mirabilis KCTC 2566. Homology alignment of the deduced amino acid sequence of Pm1 demonstrated that the greatest similarity (96%) was with the L amino acid deaminase (LAD) of P. vulgaris, and that homology with Pma was relatively low (72%). Also, similar to LAD, Pm1 was most active on L-histidine, indicating that Pm1 belongs to the second type of amino acid deaminase. In agreement with this conclusion, the V(max) and K(m) values of Pm1 were 119.7 (MUg phenylpyruvic acid/mg/min) and 31.55 mM phenylalanine, respectively, values lower than those of Pma. The Pml deaminase will be very useful industrially in the preparation of commercially valuable materials including urocanic acid and alpha oxoglutarate. PMID- 21298677 TI - Effect of oral supplementation of Lactobacillus reuteri in reduction of intestinal absorption of aflatoxin B(1) in rats. AB - The goals of this work were to assess the ability of Lactobacillus reuteri to bind aflatoxin B(1) in the intestinal tract and determine its effect on intestinal absorption of the toxin dispensed in either single or multiple doses in a murine model. Male Wistar rats were used, and two experiments were conducted after bacteria were implanted. Experiment one involved a single-oral dose of toxin, and the subsequent flow cytometric analysis of bacteria isolated from the small intestine and treated with specific FITC-labeled AFB(1) antibodies. The second experiment was carried out supplying the toxin in 7 oral sub-doses, and the later quantification of AFB(1)-Lys adducts in blood samples by ELISA assay. The results demonstrated that L. reuteri was able to bind AFB(1) in the intestinal tract, mostly in the duodenum. Furthermore, the AFB(1)-Lys adducts were present at significantly lower levels in those animals receiving AFB(1) plus bacteria than in those receiving only AFB(1). Our findings confirm that probiotic bacteria could act as biological barriers in normal intestinal conditions thereby reducing the bioavailability of AFB(1) ingested orally in a single or multiple doses, thus avoiding its toxic effects. PMID- 21298678 TI - Hexavalent chromium sorption by biomass of chromium tolerant Pythium sp. AB - The removal of Cr(VI) from aqueous solutions by live and pretreated fungal biomass of Pythium sp was investigated in a batch mode. The influence of biomass dose, solution pH, initial metal ion concentration, temperature and pretreatment of biomass on biosorption efficiency was studied. The acid pretreated biomass adsorbed 1.7 times more hexavalent chromium in comparison to untreated biomass. The chromium removal rate increased with decrease in pH and increase in Cr(VI) concentration, biomass dose and temperature. The adsorption data was described well by Freundlich isotherm model. Evaluation of biosorption mechanism using infrared spectroscopy showed the involvement of positively charged amino groups in Cr(VI) biosorption. The biosorption of Cr(VI) by Pythium sp. followed second order kinetics, the biosorption process was found to be spontaneous and endothermic with high affinity of biomass for Cr(VI). PMID- 21298679 TI - The GAL genetic switch: visualisation of the interacting proteins by split-EGFP bimolecular fluorescence complementation. AB - A split-EGFP bimolecular fluorescence complementation assay was used to visualise and locate three interacting pairs of proteins from the GAL genetic switch of the budding yeast, Saccharomyces cerevisiae. Both the Gal4p-Gal80p and Gal80p-Gal3p pairs were found to be located in the nucleus under inducing conditions. However, the Gal80p-Gal1p complex was located throughout the cell. These results support recent work establishing an initial interaction between Gal3p and Gal80p occurring in the nucleus. Labelling of all three protein pairs impaired the growth of the yeast strains and resulted in reduced galactokinase activity in cell extracts. The most likely cause of this impairment is decreased dissociation rates of the complexes, caused by the essentially irreversible reassembly of the EGFP fragments. This suggests that a fully functional GAL genetic switch requires dynamic interactions between the protein components. These results also highlight the need for caution in the interpretation of in vivo split-EGFP experiments. PMID- 21298680 TI - Isolation, characterization and identification of a Paracoccus sp. 2-haloacid degrading bacterium from the marine sponge Hymeniacidon perlevis. AB - A 2-haloacid dehalogenase-producing bacterium, designated DEH99, was isolated from the marine sponge Hymeniacidon perlevis using a modified enrichment medium and a pH indicator method. DEH99 could degrade only half of the racemic mixture 2 chloropropionic acid (2-CPA) in the medium. The dehalogenase of DEH99 was further determined to be a (S)-2-haloacid dehalogenase, which can degrade 2-CPA, 2 bromopropionic acid (2-BPA), and iodoacetic acid. The gene encoding the (S)-2 haloacid dehalogenase was partially sequenced and classified into the Group II family. The 2-haloacid dehalogenase showed the highest sequence similarity (77% with 21% query coverage) to the haloacid dehalogenase (dhlB) gene of Xanthobacter autotrophicus. A phylogenetic analysis of the 16S rDNA sequence demonstrated that the isolate DEH99 is a member of the genus Paracoccus. To our knowledge, this is the first report detailing the isolation of a strain of genus Paracoccus having 2 haloacid dehalogenase activity from marine sponges. PMID- 21298681 TI - The relationship between carotenoids and sunlight response in members of the family Micrococcaceae. AB - The aim of this study was to compare the photoprotective effect of carotenoids in phylogentically related bacteria, which synthesize structurally different pigments. Two organisms were isolated from the same environment. Their 16S rDNA sequences and phenotypic characteristics identified them as members of the family Micrococcaceae. Reverse phase HPLC and absorption spectroscopy revealed that one of them, designated RMB40, synthesized 3 carotenoids with 9 conjugated double bonds, whilst the other, designated RMB42, synthesized a single and more hydrophobic pigment carrying 11 conjugated double bonds. Survival curves were obtained during sunlight exposure for both organisms and for carotenoid deficient mutants derived from them. Increased sunlight sensitivity was found in the carotenoidless mutant derived from RMB42. In contrast, pigment depletion had no appreciable effect on the sunlight response of RMB40. It is concluded that the structure of bacterial carotenoid probably exert an important influence on the effectiveness of these compounds to provide photoprotection in vivo. PMID- 21298682 TI - Mycelium-bound lipase production from Aspergillus niger MYA 135, and its potential applications for the transesterification of ethanol. AB - The potential biotechnological applications of both constitutive and inducible lipase sources from Aspergillus niger MYA 135 were evaluated. To this end, the effect of environmental conditions on mycelium-bound lipase production from this strain was studied, when cultured either in the absence or presence of 2% olive oil. It was previously reported that mycelium-bound lipase from Aspergillus niger MYA 135 possess high stability in reaction mixtures containing ethanol; which could be especially important for their use in biodiesel synthesis. In this connection, the performance of the lipase sources produced in the transesterification of ethanol using p-nitrophenyl palmitate as acyl donor was also explored. Under our assay conditions, hydrolytic and synthetic activity of the mycelia produced in the absence or presence of olive oil were not highly correlated. While the hydrolytic activity was strongly increased by the addition of lipid to the culture medium, the best performance in the transesterification reactions of ethanol were associated with mycelia produced in absence of olive oil. Interestingly, the supplementation of the culture medium with Fe(+3) increased the transesterification activity by 71%, as compared to the activity previously reported for this strain. Therefore, the constitutive lipase sources from Aspergillus niger MYA 135 are considered to be promising for industrial biodiesel-fuel production. PMID- 21298683 TI - Evidence for a chromosomally determined mesenterocin, a bacteriocin produced by Leuconostoc mesenteroides subsp. mesenteroides OZ. AB - Mesenterocin, a small anti-listerial peptide of 3.5 kDa produced by Leuconostoc mesenteroides subsp. mesenteroides OZ at the end of exponential growth was inactivated by proteolytic enymes, stable to cold storage (4 degrees C for 3 d), heat, organic solvents and surfactants, and exhibited maximum bactericidal mode of activity in the pH range 3 to 10. Although Leu. mesenteroides subsp. mesenteroides OZ harboured plasmids ranging in size from 3.6 to 9.7 kbp, no evidence was obtained indicating that mesenterocin was under the control of extrachromosomal plasmids because loss of bacteriocin production following plasmid curing experiments could not be correlated with plasmid loss and the lack of detectable plasmids suggested a chromosomal location for the genetic determinants of mesenterocin. To determine its chromosomal location, genetic determinants of the bacteriocin of Leu. mesenteroides subsp. mesenteroides OZ were tested with previously described bacteriocins of the Leuconostocs through PCR and results of PCR indicated that the gene for mesenterocin activity is located on the chromosome. No papers have been published, to the best of our knowledge, on chromosomal location of bacteriocin of Leuconostoc species. Association of meat spoilage with bacteriocin producing heterofermentative Leu. mesenteroides subsp. mesenteroides OZ is also suggested. PMID- 21298684 TI - Isolation and characterization of a novel thermostable lectin from the wild edible mushroom Agaricus arvensis. AB - A thermostable novel lectin with a molecular weight of 30.4 kDa was isolated from dried fruiting bodies of Agaricus arvensis. It was a dimer made up of two 15.2 kDa subunits. The lectin was unadsorbed on DEAE-cellulose in 10 mM phosphate buffer (pH 7.5), subsequently adsorbed on CM-cellulose in 10 mM NaAc buffer (pH 4.6) and then on SP-Sepharose in 10 mM NaAc buffer (pH 4.6), and finally purified by fast protein liquid chromatography-gel filtration on Superdex 75. The hemagglutinating activity of the lectin was stable at temperatures up to 90 degrees C. The activity was preserved in concentrations of NaOH solution up to 50 mM, but was sensitive to HCl and declined to 12.5% in 12.5 mM HCl. The activity was unaffected by Ca(2+), Mn(2+), Zn(2+) and Mg(2+) ions, but was activated by Al(3+) and Fe(3+) ions. Among the carbohydrates tested, only inulin could inhibit the hemagglutinating activity of the lectin. It did not exhibit anti-HIV reverse transcriptase activity. Proliferation of HepG2 and MCF7 tumor cells was inhibited by the lectin with an IC(50) of 1.64 and 0.82 MUM, respectively. The lectin was devoid of antifungal activity. The lectin has a remarkable thermostablity and a unique N-terminal amino acid sequence, TYAVLNFVYG. The present report is the first report on a lectin from wild mushroom Agaricus arvensis. PMID- 21298685 TI - Chloride-associated adaptive response in aerobic methylotrophic dichloromethane utilising bacteria. AB - Aerobic methylotrophic bacteria able to grow with dichloromethane (DCM) as the sole carbon and energy source possess a specific glutathione S-transferase, DCM dehalogenase, which transforms DCM to formaldehyde, used for biomass and energy production, and hydrochloric acid, which is excreted. Evidence is presented for chloride-specific responses for three DCM-degrading bacteria, Methylobacterium extorquens DM4, Methylopila helvetica DM6 and Albibacter methylovorans DM10. Chloride release into the medium was inhibited by sodium azide and m chlorophenylhydrazone, suggesting an energy-dependent process. In contrast, only nigericin affected chloride excretion in Mb. extorquens DM4 and Mp. helvetica DM6, while valinomycin had the same effect in A. methylovorans DM10 only. Chloride ions stimulated DCM-dependent induction of DCM dehalogenase expression for Mp. helvetica DM6 and A. methylovorans DM10, and shortened the time for onset of chloride release into the medium. Striking chloride-containing structures were observed by electron microscopy and X-ray microanalysis on the cell surface of Mp. helvetica DM6 and A. methylovorans DM10 during growth with DCM, and with methanol in medium supplemented with sodium chloride. Taken together, these data suggest the existence of both general and specific chloride-associated adaptations in aerobic DCM-degrading bacteria. PMID- 21298686 TI - Efflux mediated adaptive and cross resistance to ciprofloxacin and benzalkonium chloride in Pseudomonas aeruginosa of dairy origin. AB - The present study was undertaken to investigate the role of efflux pump activity (EPA) in conferring adaptive and cross resistances against ciprofloxacin (CF) and benzalkonium chloride (BC) in dairy isolates of Pseudomonas aeruginosa. Biofilm formation potential was correlated with development of adaptive resistance in originally resistant strains. Irrespective of parent strains's susceptibility, isolates developed substantial adaptive resistance against CF and BC. Significant difference was observed in ability of non resistant isolates to develop adaptive resistance against CF and BC (P < 0.02) and subsequent cross resistance. EPA was quantified using EtBr (Ethidium Bromide) model and its role was more prominent [confirmed by its inhibition using efflux pump inhibitor (EPI) 2,4-dinitrophenol (DNP)], in conferring adaptive resistance (P = 0.147) than cross resistance (P = 0.343). Reduction in adaptive resistances due to EPI was more evident in originally non resistant strains, which reaffirms EPA as probable mechanism of adaptive resistance. The present study perhaps first of its kind, suggests an active role of EPA in conferring adaptive and cross resistances in food related P. aeruginosa isolates and supports reverse hypothesis that antibiotic-resistant organisms eventually become tolerant to other antibacterial agents as well. PMID- 21298687 TI - Comparative evaluation of prokaryotic 16S rDNA clone libraries and SSCP in groundwater samples. AB - A comparison of ribosomal RNA sequence analysis methods based on clone libraries and single-strand conformational polymorphism technique (SSCP) was performed with groundwater samples obtained between 523-555 meters below surface. The coverage of analyzed clones by phylotype-richness estimates was between 88-100%, confirming that the clone libraries were adequately examined. Analysis of individual bands retrieved from SSCP gels identified 1-6 different taxonomic units per band, suggesting that a single SSCP band does often represent more than one single prokaryotic species. The prokaryotic diversity obtained by both methods showed an overall difference of 42-80%. In comparison to SSCP, clone libraries underestimated the phylogenetic diversity and only 36-66% of the phylotypes observed with SSCP were also detected with the clone libraries. An exception was a sample where the SSCP analysis of Archaea identified only half of the phylotypes retrieved by the clone library. Overall, this study suggests that the clone library and the SSCP approach do not provide an identical picture of the prokaryotic diversity in groundwater samples. The results clearly show that the SSCP method, although this approach is prone to generate methodological artifacts, was able to detect significantly more phylotypes than microbial community analysis based on clone libraries. PMID- 21298688 TI - Establishment of a Caenorhabditis elegans infection model for Vibrio alginolyticus. AB - Vibrio alginolyticus, a common bacterium in the marine environment, is a threat to marine animals and humans by causing serious infections. The present study reveals the establishment of a Caenorhabditis elegans infection model for Vibrio alginolyticus. The infection and colonization was localized in the animal by tagging V. alginolyticus with GFP and using Confocal Laser Scanning Microscopy. Chemotactic response of C. elegans to V. alginolyticus, pharyngeal distention and blockage of vulval region leading to internal hatching were analyzed. The time required for causing infection, and the bacterial loads in the intestine of C. elegans were determined. Regulation of innate immune related genes, lys-7, clec 60 and clec-87, were also analyzed using real time PCR. The pathogen infected animals appeared to ward-off infection by up-regulating the candidate antimicrobial gene(s) for few hours, before succumbing to the pathogen. For the first time, the pathogenicity of V. alginolyticus at both physiological and molecular level has been studied in detail using the model organism C. elegans. PMID- 21298689 TI - Development of a new molecular detection method for Taylorella equigenitalis. AB - On PCR amplification of the intervening sequences (IVSs) in the central (helix 45) region within 23S rRNA gene sequences with T. equigenitalis (n = 34), as well as T. asinigenitalis (n = 35) and Bordetella (n = 11) isolates by using the primer pair of f-/r-23STis2, approximately 0.8 kb of the amplicons were generated, sequenced and analyzed. One IVS of approximately 70 bp in length was identified in all the Taylorella organisms but not Bordetella. PCR amplification was further developed for the convenient and rapid molecular detection of T. equigenitalis organisms with the IVS in the helix 45 region within the 23S rRNA genes as target by using the primer pairs (f-IVSde/r-23de). Thus, these results clearly demonstrated that PCR amplification with the primer pair (f-IVSde/r-23de) can be reliable in order to differentiate the T. equigenitalis isolates from both the T. asinigenitalis and Bordetella organisms. PMID- 21298690 TI - The paf gene product modulates asexual development in Penicillium chrysogenum. AB - Penicillium chrysogenum secretes a low molecular weight, cationic and cysteine rich protein (PAF). It has growth inhibitory activity against the model organism Aspergillus nidulans and numerous zoo- and phytopathogenic fungi but shows only minimal conditional antifungal activity against the producing organism itself. In this study we provide evidence for an additional function of PAF which is distinct from the antifungal activity against putative ecologically concurrent microorganisms. Our data indicate that PAF enhances conidiation in P. chrysogenum by modulating the expression of brlA, the central regulatory gene for mitospore development. A paf deletion strain showed a significant impairment of mitospore formation which sustains our hypothesis that PAF plays an important role in balancing asexual differentiation in P. chrysogenum. PMID- 21298691 TI - A phylogenetic comparison of urease-positive thermophilic Campylobacter (UPTC) and urease-negative (UN) C. lari. AB - In the present study, the reliability of full-length gene sequence information for several genes including 16S rRNA was examined, for the discrimination of the two representative Campylobacter lari taxa, namely urease-negative (UN) C. lari and urease-positive thermophilic Campylobacter (UPTC). As previously described, 16S rRNA gene sequence are not reliable for the molecular discrimination of UN C. lari from UPTC organisms employing both the unweighted pair group method using arithmetic means analysis (UPGMA) and neighbor joining (NJ) methods. In addition, three composite full-length gene sequences (ciaB, flaC and vacJ) out of seven gene loci examined were reliable for discrimination employing dendrograms constructed by the UPGMA method. In addition, all the dendrograms of the NJ phylogenetic trees constructed based on the nine gene information were not reliable for the discrimination. Three composite full-length gene sequences (ciaB, flaC and vacJ) were reliable for the molecular discrimination between UN C. lari and UPTC organisms employing the UPGMA method, as well as among four thermophilic Campylobacter species. PMID- 21298692 TI - Selective removal of human DNA from metagenomic DNA samples extracted from dental plaque. AB - Metagenomic techniques are used to analyse bacterial communities allowing both culturable and unculturable species to be represented. However, the screening of oral metagenomic samples can be hindered by high animal host DNA content. This study evaluated methods for the reduction of human DNA concentrations within oral metagenomic samples. Plaque samples were collected from 27 patients presenting with periodontal disease and treated to remove human DNA using either selective lysis of eukaryotic cells at several buffer concentrations or differential centrifugation after treatment with trypsin and/or detergents. Human and bacterial DNA levels were determined by quantitative polymerase chain reaction (qPCR). The human DNA content of plaque extracts was significantly reduced by all treatments compared with an untreated control (P < 0.05). However, differential centrifugation simultaneously reduced the bacterial DNA content unless samples were pretreated with a detergent. Observations of Gram stained samples that were processed using differential centrifugation without detergent suggest that many bacteria remain adhered to human cells. An approach that uses differential centrifugation in parallel with selective lysis is recommended to fully represent the oral microbiota in metagenomic samples, including those tightly adhered to human cells and more delicate bacteria such as Mycoplasma. PMID- 21298693 TI - "Sarcoid like" granulomatous pulmonary disease in World Trade Center disaster responders. AB - BACKGROUND: More than 20,000 responders have been examined through the World Trade Center (WTC) Medical Monitoring and Treatment Program since September 11, 2001. Studies on WTC firefighters have shown elevated rates of sarcoidosis. The main objective of this study was to report the incidence of "sarcoid like" granulomatous pulmonary disease in other WTC responders. METHODS: Cases of sarcoid like granulomatous pulmonary disease were identified by: patient self report, physician report and ICD-9 codes. Each case was evaluated by three pulmonologists using the ACCESS criteria and only "definite" cases are reported. RESULTS: Thirty-eight patients were classified as "definite" cases. Six-year incidence was 192/100,000. The peak annual incidence of 54 per 100,000 person years occurred between 9/11/2003 and 9/11/2004. Incidence in black responders was nearly double that of white responders. Low FVC was the most common spirometric abnormality. CONCLUSIONS: Sarcoid like granulomatous pulmonary disease is present among the WTC responders. While the incidence is lower than that reported among firefighters, it is higher than expected. PMID- 21298694 TI - Lung diffusing capacity relates better to short-term progression on HRCT abnormalities than spirometry in mild asbestosis. AB - BACKGROUND: Pulmonary function tests (PFT), particularly spirometry and lung diffusing capacity for carbon monoxide (DL(CO) ), have been considered useful methods for the detection of the progression of interstitial asbestos abnormalities as indicated by high-resolution computed tomography (HRCT). However, it is currently unknown which of these two tests correlates best with anatomical changes over time. METHODS: In this study, we contrasted longitudinal changes (3-9 years follow-up) in PFTs at rest and during exercise with interstitial abnormalities evaluated by HRCT in 63 ex-workers with mild-to moderate asbestosis. RESULTS: At baseline, patients presented with low-grade asbestosis (Huuskonen classes I-II), and most PFT results were within the limits of normality. In the follow-up, most subjects had normal spirometry, static lung volumes and arterial blood gases. In contrast, frequency of DL(CO) abnormalities almost doubled (P < 0.05). Twenty-three (36.5%) subjects increased the interstitial marks on HRCT. These had significantly larger declines in DL(CO) compared to patients who remained stable (0.88 vs. 0.31 ml/min/mm Hg/year and 3.5 vs. 1.2%/year, respectively; P < 0.05). In contrast, no between-group differences were found for the other functional tests, including spirometry (P > 0.05). CONCLUSIONS: These data demonstrate that the functional consequences of progression of HRCT abnormalities in mild-to-moderate asbestosis are better reflected by decrements in DL(CO) than by spirometric changes. These results might have important practical implications for medico-legal evaluation of this patient population. PMID- 21298695 TI - Risk of beryllium sensitization in a low-exposed former nuclear weapons cohort from the Cold War era. AB - BACKGROUND: The nuclear weapons industry has long been known as a source of beryllium exposure. METHODS: A total of 1,004 former workers from a nuclear weapons assembly site in the Midwest were screened for sensitization to beryllium (BeS). The screenings were part of the Department of Energy (DOE) Former Worker Program established in 1996. RESULTS: Twenty-three (2.3%) workers were found sensitized to beryllium and this prevalence was comparable to other DOE sites. Occasional, direct exposure to beryllium through machining and grinding of copper beryllium (Cu-Be) 2% alloy tools was found to increase the risk of sensitization compared to background exposure (OR = 3.83; 95% CI: 1.04-14.03) with a statistically significant trend (P = 0.03) revealing that particular jobs are associated with sensitization. Exposure potential in this study was estimated based on job titles and not personal exposure information. CONCLUSIONS: These results confirm the need to screen workers using beryllium alloy tools in other industries and for consideration of altering work practices. PMID- 21298696 TI - Risk factors for lower extremity fatigue among assembly plant workers. AB - BACKGROUND: Work-related fatigue of the lower extremities is a known cause of lost productivity and significant employer costs. Common workplace solutions to reduce fatigue levels include anti-fatigue matting, shoe orthoses, or sit/stand work stations. However, assessment of these anti-fatigue measures within the workplace has been limited. METHODS: This was a cross sectional study in an automotive assembly plant on employees with at least 6 months tenure. Subject data were collected via questionnaires including Likert-scale questions to define fatigue severity. Jobs were evaluated for lower extremity ergonomic exposures via videotaping, pedometers, interviews, and industrial engineering records. RESULTS: Lower extremity fatigue at the end of the work day was associated with a higher prevalence of smoking, rheumatoid arthritis, job dissatisfaction, use of shoes with firmer outsoles, and increased time on the job spent standing or walking. Supervisor support and increased time spent on carpet were protective. Lower extremity fatigue that interfered with activities outside of work had additional risk factors including higher BMI, prior diagnosis of osteoarthritis, and increased hours per week spent working. CONCLUSIONS: While these results identify carpet as being protective against lower extremity fatigue, no similar relationship was identified for anti-fatigue mats. No adverse relationship was found between hard surfaces such as concrete and lower extremity fatigue. Given the high costs associated with work-related fatigue, future areas for potential intervention include smoking cessation, specific shoe recommendations, and enhancing psychosocial aspects of work such as supervisor support. PMID- 21298697 TI - Occupational asthma in the aluminum smelters of Australia and New Zealand: 1991 2006. AB - OBJECTIVE: To examine the incidence of occupational asthma in the seven aluminum smelters of Australia and New Zealand from 1991 to 2006. METHODS: Incidence and exposure data were collected by survey from the smelters prospectively during the study period. RESULTS: The incidence of occupational asthma across all smelters combined was highest in 1992 at 9.46/1,000/year, declining to 0.36/1,000/year in 2006; a 96.2% reduction. The incidence of occupational asthma was correlated with geometric mean total fluoride concentration, measured as personal samples from employees undertaking anode changing (r(s) = 0.497, P < 0.001). CONCLUSIONS: The control of exposures, respiratory protection and pre-placement medical assessments undertaken during the study period seem to have contributed to the substantial decline in occupational asthma incidence. PMID- 21298698 TI - A 4-year intervention to increase adoption of safer dairy farming work practices. AB - BACKGROUND: Traumatic and musculoskeletal injury rates have been high in dairy farming compared to other industries. Previous work has shown that social marketing efforts can persuade farm managers to adopt practices that reduce injury hazards compared to traditional practices if the new practices maintain profits. METHODS: The intervention disseminated information to 4,300 Northeast Wisconsin dairy farm managers about three safer and more profitable production practices (barn lights, silage bags, and calf feed mixing sites) using information channels that these managers were known to rely on. We evaluated rolling, independent, community-based samples, at baseline and then again after each of four intervention years. We also evaluated samples from Maryland's 1,200 dairy farms after the second through the fourth year of the intervention. Maryland dairy managers read many of the same nationally distributed print mass media that we used in the intervention and so were a "partially exposed" comparison group. RESULTS: The intervention to disseminate information about the innovations was successful. In comparisons before and after the intervention, Wisconsin managers reported getting more information about calf sites from public events and equipment dealers, about silage bags from other farmers and equipment dealers, and about barn lights from public events, other farmers, equipment dealers, consultants, and electrical suppliers. Wisconsin managers also reported getting more information than Maryland managers from public events for barn lights and silage bags. During years three and four, the intervention managed to sustain, but not improve, earlier increases in adoption and awareness from the first 2 years. After adjusting for farm manager and operation variables, intervention years was associated with increased Wisconsin manager adoption of two of three practices in comparisons between the baseline and the fourth intervention year: barn lights (odds ratio = 5.58, 95% confidence interval = 3.39 9.17) and silage bags (OR = 2.94, CI = 1.84-4.70). There were similar results for awareness of barn lights and the calf feeding sites. Compared to Maryland managers, Wisconsin managers reported greater awareness of barn lights. CONCLUSIONS: Disseminating information to managers through information channels that they usually consulted was associated with increased reports of getting information and with greater adoption and awareness of safer, profit-enhancing work practices in a high hazard industry. PMID- 21298699 TI - Mercury and methylmercury concentrations in two newly constructed reservoirs in the Wujiang River, Guizhou, China. AB - We studied the distribution of different mercury species in two newly created reservoirs (Hongjiadu [HJD] and Suofengying [SFY] Reservoir) within the Wujiang River, Guizhou Province, China. These reservoirs were sampled four times between January, 2007, and November, 2007. Water, soil, and fish tissue samples were collected and analyzed for organic (methylmercury) and total Hg. Dissolved organic carbon (DOC) content in water was measured as well. In both reservoirs, the DOC concentration was low (range 0.5-4.9 mg/L). Organic matter content in soil collected near the bank of both reservoirs was also low (range 0.4-6.9%). The total MeHg level did not increase significantly with depth in water column, nor did it exhibit a pronounced spatial pattern moving from upstream to the dam. The total MeHg level did not increase significantly with depth in water column, nor did it exhibit a pronounced spatial pattern moving from upstream to the dam. The total Hg content in fish tissue was on average 0.044 mg/kg wet weight, which is a very low content in an international comparison. It is suggested that the studied reservoirs were not active sites of net Hg methylating. Low levels of organic matter (OM) may constrict the evolution of the bulk Hg methylation process occurring in flooded soil. Therefore, we hypothesize that newly constructed reservoirs in the karstic region of Southwest China appear to be much less beset by the problems of MeHg pollution that have been reported for corresponding reservoirs in North America and Europe. However, further research is required to verify this finding. PMID- 21298700 TI - Can sediment total organic carbon and grain size be used to diagnose organic enrichment in estuaries? AB - Eutrophication (i.e., nutrient enrichment, organic enrichment, and oxygen depletion) is one of the most common sources of impairment in Clean Water Act 303(d)-listed waters in the United States. Although eutrophication can eventually cause adverse effects to the benthos, it may be difficult to diagnose. Sediment organic carbon (OC) content has been used as an indicator of enrichment in sediments, but the amount of surface area available for carbon adsorption must be considered. We investigated the utility of the relationship between OC and sediment grain size as an indicator of eutrophication. Data from the U.S. Environmental Protection Agency's Environmental Monitoring and Assessment Program was used to test this relationship. However, anthropogenic contaminants are also capable of causing adverse effects to the benthos and often co-occur with elevated levels of OC. Contaminant analysis and toxicity tests were not consistently related to enrichment status as defined by relationship between total OC and grain size. Although variability in response occurred, reflecting the variance in the water column factors (dissolved oxygen, chlorophyll a, and nutrients) and limited sample sizes, the data supported the hypothesis that sites designated as enriched were eutrophied. Dissolved oxygen levels were reduced at enriched sites, whereas chlorophyll a and nutrients were higher at enriched sites. This suggests that the relationship of OC to grain size can be used as a screening tool to diagnose eutrophication. PMID- 21298701 TI - Acid volatile sulfides oxidation and metals (Mn, Zn) release upon sediment resuspension: laboratory experiment and model development. AB - Sediment from the Anacostia River (Washington, DC, USA) was suspended in aerobic artificial river water for 14 d to investigate the dynamics of dissolved metals release and related parameters including pH, acid volatile sulfides (AVS), and dissolved/solid phase Fe(2+). To better understand and predict the underlying processes, a mathematical model is developed considering oxidation of reduced species, dissolution of minerals, pH changes, and pH-dependent metals' sorption to sediment. Oxidation rate constants of elemental sulfur and zinc sulfide, and a dissolution rate constant of carbonate minerals, were adjusted to fit observations. The proposed model and parameters were then applied, without further calibration, to literature-reported experimental observations of resuspension in an acid sulfate soil collected in a coastal flood plain. The model provided a good description of the dynamics of AVS, Fe(2+), S(0)((s)), pH, dissolved carbonates concentrations, and the release of Ca((aq)), Mg((aq)), and Zn((aq)) in both sediments. Accurate predictions of Mn((aq)) release required adjustment of sorption partitioning coefficient, presumably due to the presence of Mn scavenging by phases not accounted for in the model. The oxidation of AVS (and the resulting release of sulfide-bound metals) was consistent with a two step process, a relatively rapid AVS oxidation to elemental sulfur (S(0)((s))) and a slow oxidation of S(0)((s)) to SO(4)(2-)((aq)), with an associated decrease in pH from neutral to acidic conditions. This acidification was the dominant factor for the release of metals into the aqueous phase. PMID- 21298702 TI - Sorption mechanisms of coexisting PAHs on sediment organic fractions. AB - Sorption of polycyclic aromatic hydrocarbons (PAHs) to natural sediment and isolated organic fractions, including demineralized organic matter (DM), condensed organic matter (COM), and black carbon (BC), was investigated to provide insight into sorption mechanisms. The organic carbon normalized distribution coefficient K(OC) measured for DM was 0.8 to 3.0 times higher than that of bulk sediment, indicating the physical protection of favorable PAH sorption domains by mineral conformation; that is, mineral enwrapping was supposed to prevent physically the accessing process of the sorbate molecules to the sorption domain. Surface area-normalized K(OC) values showed that the differences between COM and BC in the sorption capability were caused largely by their surface areas, additionally indicating the importance of solid physical structure. In considering specific interactions, mature organic fractions with polyaromatic sheets were implied to be affected by pi-pi interaction, whereas the DM sample that contained the electron-repulsive N-H group hardly sorbed PAHs via this interaction. Besides sorbent characteristics, PAH properties were also assumed to influence the sorption process. The hydrophobicity normalized sorption coefficient increased in the order of fluoranthene> phenanthrene> pyrene> fluorine> acenaphthene, with pyrene showing an exceptional order. PMID- 21298703 TI - Fate of the antifungal drug clotrimazole in agricultural soil. AB - Clotrimazole is a broad-spectrum antimycotic drug used for the treatment of dermatological and gynecological infections; it is incompletely broken down during sewage treatment and could potentially reach agricultural land through the application of municipal biosolids or wastewater. In the absence of any environmental fate data, we evaluated the persistence and dissipation pathways of (3)H-clotrimazole during laboratory incubations of agricultural soils. Clotrimazole was removed from a loam (time to dissipate 50% = 68 d), a sandy loam (time to dissipate 50% = 36 d), and a clay loam (time to dissipate 50% = 55 d), with formation of nonextractable residues being the major sink for (3) H. Their parent compound had no significant mineralization, as evidenced by the lack of formation of (3) H(2) O. Up to 15% of the applied radioactivity was recovered in the form of [(3)H]-(2-chlorophenyl)diphenyl methanol. The rate of clotrimazole dissipation in the loam soil did not vary with moisture content, but it was slower at a lower temperature (number of days to dissipate 50% = 275.6 d at 4 degrees C). Addition of municipal biosolids to the loam soil did not vary the clotrimazole dissipation rate. In summary, the present study has established that clotrimazole is dissipated in soil, at rates that varied with soil texture and temperature. Clotrimazole dissipation was accompanied by the formation of nonextractable residues and detectable extractable residues of the transformation product (2-chlorophenyl)diphenyl methanol. PMID- 21298704 TI - Comparison of aerobic and anaerobic [3H]leucine incorporation assays for determining pollution-induced bacterial community tolerance in copper-polluted, irrigated soils. AB - Pollution-induced community tolerance (PICT) constitutes a sensitive and ecologically relevant impact parameter in ecotoxicology. We report the development and application of a novel anaerobic [(3) H]leucine incorporation assay and its comparison with the conventional aerobic [(3) H]leucine incorporation assay for PICT detection in soil bacterial communities. Selection of bacterial communities was performed over 42 d in bulk soil microcosms (no plants) and in rice (Oryza sativa) rhizosphere soil mesocosms. The following experimental treatments were imposed using a full factorial design: two soil types, two soil water regimes, and four Cu application rates (0, 30, 120, or 280 ug g(-1)). Bacterial communities in bulk soil microcosms exhibited similar Cu tolerance patterns when assessed by aerobic and anaerobic PICT assays, whereas aerobic microorganisms tended to be more strongly selected for Cu tolerance than anaerobic microorganisms in rhizosphere soil. Despite similar levels of water extractable Cu, bacterial Cu tolerance was significantly higher in acid sulfate soil than in alluvial soil. Copper amendment selected for significant PICT development in soils subjected to alternate wetting and drying, but not in continuously flooded soils. Our results demonstrate that soil bacterial communities subjected to alternate wetting and drying may be more affected by Cu than bacterial communities subjected to continuous flooding. We conclude that the parallel use of anaerobic and aerobic [(3) H]leucine PICT assays constitutes a valuable improvement over existing procedures for PICT detection in irrigated soils and other redox gradient environments such as sediments and wetlands. PMID- 21298705 TI - Effect of soil metal contamination on glyphosate mineralization: role of zinc in the mineralization rates of two copper-spiked mineral soils. AB - A systematic investigation into lowered degradation rates of glyphosate in metal contaminated soils was performed by measuring mineralization of [(14)C]glyphosate to (14)CO(2) in two mineral soils that had been spiked with Cu and/or Zn at various loadings. Cumulative (14)CO(2) release was estimated to be approximately 6% or less of the amount of [(14)C]glyphosate originally added in both soils over an 80-d incubation. For all but the highest Cu treatments (400 mg kg(-1)) in the coarse-textured Arkport soil, mineralization began without a lag phase and declined over time. No inhibition of mineralization was observed for Zn up to 400 mg kg(-1) in either soil, suggesting differential sensitivity of glyphosate mineralization to the types of metal and soil. Interestingly, Zn appeared to alleviate high-Cu inhibition of mineralization in the Arkport soil. The protective role of Zn against Cu toxicity was also observed in the pure culture study with Pseudomonas aeruginosa, suggesting that increased mineralization rates in high Cu soil with Zn additions might have been due to alleviation of cellular toxicity by Zn rather than a mineralization specific mechanism. Extensive use of glyphosate combined with its reduced degradation in Cu-contaminated, coarse textured soils may increase glyphosate persistence in soil and consequently facilitate Cu and glyphosate mobilization in the soil environment. PMID- 21298706 TI - An enriched stable isotope technique to estimate the availability of soil zinc to Lumbricus terrestris (L.) across a salinization gradient. AB - An enriched stable isotope approach was developed to evaluate Zn bioavailability to Lumbricus terrestris. The decrease in (68)Zn/(66) Zn in organ tissues was used to assess the relative magnitude of the bioavailable soil Zn pool. This tool was then used to specifically evaluate bioavailability as a function of soil cation distribution. Storm-water pond soils were modified using two treatment regimens whereby H(2)O-extractable Zn was varied either by different ZnCl(2) amendments or by constant ZnCl(2) amendment followed by varying the soil cation distribution through salt amendments (NaCl or CaCl(2)). Earthworms previously equilibrated in (68) Zn-spiked soil were introduced to experimental soils, and after 2 d, removed for analysis of isotopic ratios in specific tissues. Despite a wide range of H(2)O-extractable Zn values produced by the salt treatments (0.007-24.3 mg/kg), a significant relationship between Zn turnover rate in earthworm tissues and H(2)O extractable Zn in the salt-treated soils was not observed. Rather, considering both treatment regimens, turnover rate better correlated with Zn present in broader pools, such as that extracted by 6M HNO(3). The bioavailability of trace metals to earthworms may be poorly characterized by loosely bound fractions such as the pore water. Additionally, the turnover rate of (68)Zn in anterior organ tissues may be an effective tool to evaluate the relative magnitude of the bioavailable soil Zn pool. PMID- 21298707 TI - Development of a new enrichment method for simultaneous determination of copper and zinc in water samples. AB - In the present study, an enrichment and separation method for the simultaneous determination of trace amounts of Cu and Zn in water samples was developed. Copper and Zn ions found in water matrix in trace amounts were preconcentrated on Duolite XAD 761 resin without using any chelating agent and determined by flame atomic absorption spectrometer (FAAS). Experimental parameters such as pH, concentration of metal ions, amount of resin, and sample volume for quantitative determination of Cu and Zn ions were optimized. The elution process was performed by using 5 ml of 2 mol/L HCl solution. The preconcentration factors for Cu and Zn were found to be 160 and 200, respectively. Under optimized conditions, limit of detection for Cu and Zn were 2.46 and 3.54 ug/L, respectively. The Langmuir adsorption model was applied to describe the equilibrium isotherm. The Langmuir monolayer adsorption capacity of resin was estimated as 31.2 and 17.7 mg/g for Cu and Zn, respectively. The proposed method was successfully applied to determine the Cu and Zn content of various water samples. PMID- 21298708 TI - Assessing the potential for algae and macrophytes to degrade crop protection products in aquatic ecosystems. AB - Rates of pesticide degradation in aquatic ecosystems often differ between those observed within laboratory studies and field trials. Under field conditions, a number of additional processes may well have a significant role, yet are excluded from standard laboratory studies, for example, metabolism by aquatic plants, phytoplankton, and periphyton. These constituents of natural aquatic ecosystems have been shown to be capable of metabolizing a range of crop protection products. Here we report the rate of degradation of six crop protection products assessed in parallel in three systems, under reproducible, defined laboratory conditions, designed to compare aquatic sediment systems which exclude macrophytes and algae against those in which macrophytes and/or algae are included. All three systems remained as close as possible to the Organisation for Economic Co-operation and Development (OECD) 308 guidelines, assessing degradation of parent compound in the total system in mass balanced studies using ((14) C) labeled compounds. We observed, in all cases where estimated, significant increases in the rate of degradation in both the algae and macrophyte systems when compared to the standard systems. By assessing total system degradation within closed, mass balanced studies, we have shown that rates of degradation are enhanced in water/sediment systems that include macrophytes and algae. The contribution of these communities should therefore be considered if the aquatic fate of pesticides is to be fully understood. PMID- 21298709 TI - Sublethal genotoxicity and cell alterations by organophosphorus pesticides in MCF 7 cells: implications for environmentally relevant concentrations. AB - Organophosphorus pesticide (OPP) toxicity is believed to be mediated through inhibition of acetylcholinesterase (AChE). Given their widespread distribution in aquatic systems and their ability to undergo chemical transformation, their environmental impacts at sublethal concentrations in nontarget organisms have become an important question. We conducted a number of mammalian-cell genotoxic and gene expression assays and examined cellular biochemical changes that followed low-dose exposure of MCF-7 cells to fenitrothion, diazinon, and the aqueous degradate of diazinon, 2-isopropyl-6-methyl-4-pyrimidinol (IMP). After exposure to the OPPs at low concentrations (10(-12) M to 10(-8) M), greater than twofold elevations in micronucleus formation were noted in MCF-7 cell cultures that went on to exhibit greater than 75% clonogenic survival; these levels of chromosomal damage were comparable to those induced by 10(-6) M benzo[a]pyrene, a known genotoxic agent. At this low concentration range, a fenitrothion-induced twofold elevation in B-cell leukemia/lymphoma-2 (BCL-2) and cytochrome P450 isoenzyme (CYP1A1) gene expressions was observed. Principal component analysis linear discriminant analysis (PCA-LDA) of derived infrared (IR) spectra of vehicle control (nonexposed) and OPP-exposed cells highlighted that both fenitrothion and diazinon induced marked biochemical alterations in the lipid, protein, and DNA/RNA absorbance regions. Our findings demonstrate that the two OPP parent chemicals and IMP degradate can mediate a number of toxic effects or cellular alterations at very low concentrations. These are independent of just selective inhibition of AChE, with potential consequences for nontarget organisms exposed at environmentally relevant concentrations. Further assays on relevant aquatic organism cell lines are now recommended to understand the mechanistic low dose toxicity of these chemicals present in aquatic systems. PMID- 21298710 TI - Pesticide has asymmetric effects on two tadpole species across density gradient. AB - Northern leopard frogs (Rana pipiens) have been disappearing throughout their range. The causes for extirpations have been elusive, although habitat alteration appears to be a major factor. Pesticides have been implicated in declines in western amphibians, but no mechanism has been identified. We tested the hypothesis that leopard frog tadpoles would be eliminated from insecticide exposed ponds when they were less abundant than a competitor (American toads, Bufo americanus) by manipulating toad and leopard frog density (16, 50, or 150 of each species) with or without the insecticide carbaryl. Insecticide exposure did not interact with density on either species, indicating that contaminant effects were similar despite drastic differences in competition. The survival of both species decreased with increasing conspecific density, but not heterospecific density. Leopard frogs produced more metamorphs at intermediate densities, whereas toads produced more metamorphs at high density. Leopard frog mass at and time to metamorphosis responded negatively to density. Carbaryl did not affect leopard frog survival but positively affected mass at and time to metamorphosis. In contrast, toad survival was reduced after exposure, but mass at metamorphosis was greater. Pesticide-induced survival reductions may not affect population size if reductions are slight (as in toads, whose fitness may be compensated by increased mass). Management strategies aimed at ameliorating the effects of carbaryl in systems with these two species may not need to consider density. PMID- 21298711 TI - Exposure of sea otters and harlequin ducks in Prince William Sound, Alaska, USA, to shoreline oil residues 20 years after the Exxon Valdez oil spill. AB - We assessed whether sea otters and harlequin ducks in an area of western Prince William Sound, Alaska, USA (PWS), oiled by the 1989 Exxon Valdez oil spill (EVOS), are exposed to polycyclic aromatic hydrocarbons (PAH) from oil residues 20 years after the spill. Spilled oil has persisted in PWS for two decades as surface oil residues (SOR) and subsurface oil residues (SSOR) on the shore. The rare SOR are located primarily on the upper shore as inert, nonhazardous asphaltic deposits, and SSOR are confined to widely scattered locations as small patches under a boulder/cobble veneer, primarily on the middle and upper shore, in forms and locations that preclude physical contact by wildlife and diminish bioavailability. Sea otters and harlequin ducks consume benthic invertebrates that they collect by diving to the bottom in the intertidal and subtidal zones. Sea otters also dig intertidal and subtidal pits in search of clams. The three plausible exposure pathways are through the water, in oil-contaminated prey, or by direct contact with SSOR during foraging. Concentrations of PAH in near-shore water off oiled shores in 2002 to 2005 were at background levels (<0.05 ng/L). Median concentrations of PAH in five intertidal prey species on oiled shores in 2002 to 2008 range from 4.0 to 34 ng/g dry weight, indistinguishable from background concentrations. Subsurface oil residues are restricted to locations on the shore and substrate types, where large clams do not occur and where sea otters do not dig foraging pits. Therefore, that sea otters and harlequin ducks continue to be exposed to environmentally significant amounts of PAH from EVOS 20 years after the spill is not plausible. PMID- 21298712 TI - Pesticide distributions and population declines of California, USA, alpine frogs, Rana muscosa and Rana sierrae. AB - Atmospherically deposited pesticides from the intensively cultivated Central Valley of California, USA, have been implicated as a cause for population declines of several amphibian species, with the strongest evidence for the frogs Rana muscosa and Rana sierrae at high elevation in the Sierra Nevada mountains. Previous studies on these species have relied on correlations between frog population status and either a metric for amount of upwind pesticide use or limited measurements of pesticide concentrations in the field. The present study tested the hypothesis that pesticide concentrations are negatively correlated with frog population status (i.e., fraction of suitable water bodies occupied within 2 km of a site) by measuring pesticide concentrations in multiple media twice at 28 sites at high elevation in the southern Sierra Nevada. Media represented were air, sediment, and Pseudacris sierra tadpoles. Total cholinesterase (ChE), which has been used as an indicator for organophosphorus and carbamate pesticide exposure, was also measured in P. sierra tadpoles. Results do not support the pesticide-site occupancy hypothesis. Among 46 pesticide compounds analyzed, nine were detected with >= 30% frequency, representing both historically and currently used pesticides. In stepwise regressions with a chemical metric and linear distance from the Central Valley as predictor variables, no negative association was found between frog population status and the concentration of any pesticide or tadpole ChE activity level. By contrast, frog population status showed a strong positive relationship with linear distance from the Valley, a pattern that is consistent with a general west to-east spread across central California of the amphibian disease chytridiomycosis observed by other researchers. PMID- 21298713 TI - Biomarker responses and disease susceptibility in juvenile rainbow trout Oncorhynchus mykiss fed a high molecular weight PAH mixture. AB - Juvenile rainbow trout were fed a diet containing an environmentally relevant mixture of 10 high molecular weight polycyclic aromatic hydrocarbons (PAHs) at a dose of 0.66 or 7.82 ug PAH . g fish(-1) . d(-1). At 3, 7, 14, and 28 d, biomarkers of aryl hydrocarbon receptor activation (AHR), hepatic microsomal ethoxyresorufin-O-deethylase (EROD) activity, and cytochrome P4501A (CYP1A) associated staining increased 14- to 26-fold and 6- to 14-fold, respectively, in fish fed 7.82 ug PAH . g fish (-1) . d(-1). Cytochrome P4501A-associated staining increased 2- to 9-fold on days 3, 7, and 28 in fish fed 0.66 ug PAH . g fish(-1) . d(-1). Bile fluorescent aromatic compounds served as a biomarker of exposure and confirmed that PAH exposure was consistent over 50 d. DNA damage in blood cells, protein oxidation, and lipid peroxidation in the kidney were biomarkers of oxidative stress and all increased in fish fed 7.82 ug PAH . g fish(-1) . d(-1). Fish fed 0.66 ug PAH . g fish(-1) . d(-1) had elevated DNA damage in blood cells but increased protein oxidation or lipid peroxidation in the kidney were not observed. Challenge with Aeromonas salmonicida, at lethal concentration (LC) 20, decreased survival in fish previously fed either 0.66 ug PAH . g fish(-1) . d(-1) or 7.82 ug PAH . g fish(-1) . d(-1) relative to fish fed the control diet. In general, biomarkers of both AHR activation and oxidative stress peaked at 3 to 14 d then declined at 28 to 50 d of PAH exposure and an increase in susceptibility to disease was observed at 50 d. These results link PAH exposure to biomarker responses that may be useful as early indicators of population level responses, such as mortality resulting from an increase in disease susceptibility. PMID- 21298714 TI - Production of polycyclic aromatic hydrocarbon metabolites from a peroxynitrite/iron(III) porphyrin biomimetic model and their mutagenicities. AB - Some polycyclic aromatic hydrocarbons (PAHs) are typical promutagens that require metabolic activation to exhibit their mutagenicities and carcinogenicities. The metabolites of three PAHs, pyrene (PY), fluoranthene (FLU), and benzo[a]pyrene (BaP), produced from the peroxynitrite/T(p Cl)PPFeCl(peroxynitrite/(chloride)iron(III)tetrakis(p-chlorophenyl)porphyrin) system, have been identified with high-performance liquid chromatography coupled with electron spray ionization tandem mass spectrometry. The results demonstrated that three major metabolites were the quinone group, OH group, and nitro group. In the Ames test, all three PAH metabolites became mutagenic without using the enzymatic activating system, whereas their parents did not show positive results. Cell transformation assay indicated that 1,3-nitro-BaP and BaP metabolites produced from this biomimetic system have more serious effects in inducing cancer than the BaP parent. PMID- 21298715 TI - A postexposure feeding assay using the marine polychaete Neanthes arenaceodentata suitable for laboratory and in situ exposures. AB - This study examined the suitability for the use of the polychaetous annelid Neanthes arenaceodentata in a short-term sublethal bioassay based on postexposure feeding rate. Quantification of feeding rate was determined by an approximately 1 h feeding period to Artemia franciscana nauplii after a 48-h aqueous exposure. Both lethality and feeding rate were assessed after exposure to Cu and phenanthrene, with the Cu results being compared with those available from similar studies that used the polychaete Hediste diversicolor. Laboratory assessment on the effect of manipulating two common variables in estuarine environments (temperature and salinity) on postexposure feeding to both clean and Cu-spiked seawater samples was also conducted. The 48- and 96-h median lethal concentrations (LC50s) for Cu were 156 and 80 ug/L, respectively, whereas the 48 h median effective concentration (EC50) determined by feeding rate was 57 ug/L. The 48-h LC50 for phenanthrene was 2,224 ug/L, whereas the 48-h feeding rate EC50 was 345 ug/L (more sensitive by a factor of >6). The sensitivity of the postexposure feeding rate endpoint to two representative chemicals that are frequently elevated in contaminated sediments, in addition to rapid exposure time, ecological relevance, and relatively simple approach, suggest that this assay with N. arenaceodentata has potential for use as a tool for sublethal effects assessment, with particular promise for in situ applications. The utility of this assay in actual marine and estuarine sediments is being assessed in situ at several North American sediment sites, and will be reported in future publications. PMID- 21298716 TI - Differential roles of metallothionein-like proteins in cadmium uptake and elimination by the scallop Chlamys nobilis. AB - Metallothionein-like proteins (MTLPs) are important inducible ligands for Cd detoxification, but whether MTLPs are involved in Cd bioaccumulation remains unclear. The present study investigated the potential interrelationships between MTLP turnover and Cd biokinetics in the scallop Chlamys nobilis with or without dissolved Cd pre-exposure. After Cd pre-exposure, increased synthesis rate and standing stock concentration of MTLPs as well as increased dissolved Cd uptake rate, were found in C. nobilis. However, the level of newly sequestrated Cd by MTLPs in the pre-exposed scallops was similar to that of the controls, indicating that MTLPs had no effect on Cd uptake from the dissolved phase. Instead, Cd uptake rate was positively related to the Cd binding rate of cellular debris and organelles. In addition, no significant difference was observed in the Cd dietary assimilation efficiency of the scallops, showing that MTLPs played a minimal role in Cd uptake from the dietary phase. Conversely, the Cd efflux rate constant decreased by 68 to 75% in the pre-exposed scallops in comparison with that in the control. Correspondingly, progressive elevations of MTLP-bound Cd and standing stock MTLP concentration were observed in the pre-exposed individuals during the Cd elimination period. In the pre-exposed scallops, the faster de novo MTLP synthesis could remobilize and recycle more Cd from other intracellular pools, effectively reducing the Cd elimination rate. The present study thus showed the differential roles of MTLPs in Cd uptake and elimination in the bivalves. PMID- 21298717 TI - Accuracy assessment of time-concentration-effect models in predicting chronic lethality from acute toxicity data. AB - Acute-to-chronic (ACE) models (accelerated life testing, ALT; linear regression analysis, LRA) are used to estimate chemical concentrations resulting in low levels of chronic mortality from acute toxicity data, thereby greatly increasing the inferential value of acute data. We applied the ACE models to test data from 72 chemicals and 14 aquatic species (131 acute and 97 chronic tests) and then compared the results with reported chronic no observed effect concentrations (NOEC) and lowest observed effect concentrations (LOEC), as determined by traditional analysis of variance techniques. Acute-to-chronic models produced highly accurate chronic lethality estimates compared with reported chronic NOEC and LOEC values. Lethality estimates fell within two times reported NOEC-LOEC values 71% of the time and within five times 98% of the time. Therefore, ACE models are very appropriate for estimating chronic lethality from acute toxicity data when chronic data are absent and have high applicability in probability based hazard and risk assessments. PMID- 21298718 TI - A mixture toxicity approach for environmental risk assessment of multiple insect resistance genes. AB - Multiple substance considerations applied to chemical mixtures in ecological risk assessments can be logically extended to nontarget organism (NTO) risk assessment for pyramided trait crops expressing multiple insect resistance genes. A case instance is developed that considers a two-protein pyramid of Cry1F and Cry1Ac synthetic proteins expressed in cotton (Gossypium hirsutum L.). A mixture toxicity approach was used to arrive at the aggregated multisubstance potentially affected fraction (msPAF) of NTOs that may be at risk from exposure to Cry1F + Cry1Ac cotton in representative-use environments. Development of the msPAF for putative susceptible NTOs considered laboratory toxicity data for Lepidoptera expressed in terms of additive mixture toxicity as well as data on in planta expression of the Cry1F and Cry1Ac proteins and their translation into environmental loads and exposure concentrations. The msPAF based on tier 1 estimated environmental concentrations (EECs) and toxicity to Lepidoptera species used as surrogate data for adverse effects to a putative susceptible species provided a highly conservative estimate of effects on beneficial species and therefore is a ready means to conduct screening-level NTO risk assessments for pyramided crops. PMID- 21298719 TI - Re: Uroflowmetry in healthy women: development and validation of flow-volume and corrected flow-age nomograms. PMID- 21298720 TI - Surgical anatomy of the dorsal nerve of the clitoris. AB - AIMS: The purpose of this study was to describe the distal pathway of the dorsal nerve of the clitoris (DNC) from gross anatomical and histological studies of cadaver specimens. METHODS: We performed dissections on 14 intact adult cadaver vulva specimens using 2* loupe magnification and microscopy. The DNC was identified by gross dissection and confirmed histologically by staining with hematoxylin and eosin (H&E), Masson's trichrome (MT), and S100 antibody. The DNC pathway and its branches were followed from the pubic rami to the glans clitoris. RESULTS: The DNC travels inferior to the inferior pubic ramus along the superior/posterior edge of the clitoral crus. At the angle of the clitoral body, inferior to the pubic symphysis, the DNC enters the deep component of the suspensory ligament, which attaches to the clitoral body and to the pubic symphysis. The dorsal nerves, at the angle of the clitoral body, travel along the dorsal aspect of the clitoral body at the 11 and 1 o'clock positions. At the base of the clitoral body, the DNC is suspended superiorly away from the tunica. Distally along the clitoral body, the DNC descends and runs along the tunica and enters the glans. Within the glans, the terminal fibers are widely dispersed, and numerous receptors populate the supporting tissue of the glans beneath the epithelium. CONCLUSIONS: The detailed description of the distal course of the nerve presented here has not been previously described in adult humans and is pertinent for surgical procedures involving the clitoris. PMID- 21298721 TI - The correlation between clinical and urodynamic diagnosis in classifying the type of urinary incontinence in women. A systematic review of the literature. AB - AIMS: To determine the reclassification rate of clinically diagnosed stress, mixed, and urge urinary incontinence after urodynamic investigation. METHODS: A systematic review of the published literature in MEDLINE and EMBASE of clinical trials among women with urinary incontinence. Studies were included in case the diagnosis based on symptoms and/or signs was compared with the diagnosis after urodynamic investigation. RESULTS: Twenty-three articles involving 6,282 women with urinary incontinence met the inclusion criteria. A clinical diagnosis of stress urinary incontinence was reclassified into mixed urinary incontinence in 9% of women and into detrusor overactivity (DO) in 7% of cases. The pooled reclassification rate was highest among patients with symptoms of mixed urinary incontinence, where 46% of the patients had stress urinary incontinence and 21% had DO on urodynamic investigation. The available literature does not allow the identification of the additional value of non-invasive test, such as stress test and voiding diary, accessory to symptoms. None of the studies had therapeutic effects as an outcome measure. CONCLUSIONS: This review of clinical studies shows that the level of agreement between classification based on clinical evaluation and based on urodynamic investigation is poor. Urodynamic observations are regarded as gold standard, but based on the poor correlation, this assumption should be questioned. PMID- 21298722 TI - Reconstruction of the second metacarpal bone with a free vascularized scapular bone flap combined with nonvascularized free osteocartilagineous grafts from both second toes: a case report. PMID- 21298723 TI - Covering the below-knee amputation stump with the pedicled dorsalis pedis flap from the ipsilateral foot: a case report. AB - It is important to preserve the length, appropriate durable skin, and sensation of the stump when performing below-knee amputation to achieve functional ambulation with a prosthesis. There are many reports of reconstruction procedures using microvascular surgery to preserve the optimum length of the amputation stump for prosthesis; however, free tissue reconstruction is necessary to accompany with the donor site morbidity. In this report, we describe our experience with a below-knee amputation and stump covering using the pedicled dorsalis pedis flap from the no longer usable foot in the case of a severe osteomyelitis of a lower extremity after highly contaminated Gustilo type IIIB fracture. We achieved a well-healed amputated stump with enough length for a prosthesis and for protective sensation. The pedicled dorsalis pedis flap is easily elevated without microvascular anastomosis and is one useful option for the reconstruction of the below-knee amputated stump in the specific case. PMID- 21298724 TI - Use of 1-desamino-8-D-arginine vasopressin in microsurgical reconstruction in a patient with von Willebrand's disease. PMID- 21298726 TI - Evaluation of the antipeptic ulcer activity of the leaf extract of Plantago lanceolata L. in rodents. AB - The effect of the leaf extract of Plantago lanceolata L. (Plantaginaceae) on gastric secretion and cytoprotection was evaluated using different models of gastroduodenal ulcer, including acetic acid induced chronic gastric ulcer, indomethacin induced gastric ulcer, cysteamine induced duodenal ulcer and pylorus ligation induced gastric ulcer. The aqueous extract was administered at 200 mg/kg and 400 mg/kg and 140 mg/kg and 280 mg/kg for mice and rats, respectively, and compared with vehicle or the standard, ranitidine (50 or 70 mg/kg) or misopristol (280 MUg/kg). In addition, activity of the mucilage (172 mg/kg) was also evaluated in acetic acid induced chronic gastric ulcer. Administration was done orally except in pylorus ligation, where the intraduodenal route was used. In all cases, higher doses of the extract provided better protection than lower doses and the mucilage, hinting at a dose-dependent effect. Whilst higher doses of the extract showed a better healing of the ulcer as well as protection in indomethacin and pylorus ligation models, activities of lesser magnitude than ranitidine were noted in the cysteamine model. Together these findings indicate that higher doses used in the present study provided an overall better protection against gastroduodenal ulcers than the standard drugs employed through antisecretory and cytoprotective mechanisms. PMID- 21298727 TI - Application of the stochastic resonance algorithm to the simultaneous quantitative determination of multiple weak peaks of ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry. AB - The stochastic resonance algorithm (SRA) has been developed as a potential tool for amplifying and determining weak chromatographic peaks in recent years. However, the conventional SRA cannot be applied directly to ultra-performance liquid chromatography/time-of-flight mass spectrometry (UPLC/TOFMS). The obstacle lies in the fact that the narrow peaks generated by UPLC contain high-frequency components which fall beyond the restrictions of the theory of stochastic resonance. Although there already exists an algorithm that allows a high frequency weak signal to be detected, the sampling frequency of TOFMS is not fast enough to meet the requirement of the algorithm. Another problem is the depression of the weak peak of the compound with low concentration or weak detection response, which prevents the simultaneous determination of multi component UPLC/TOFMS peaks. In order to lower the frequencies of the peaks, an interpolation and re-scaling frequency stochastic resonance (IRSR) is proposed, which re-scales the peak frequencies via linear interpolating sample points numerically. The re-scaled UPLC/TOFMS peaks could then be amplified significantly. By introducing an external energy field upon the UPLC/TOFMS signals, the method of energy gain was developed to simultaneously amplify and determine weak peaks from multi-components. Subsequently, a multi-component stochastic resonance algorithm was constructed for the simultaneous quantitative determination of multiple weak UPLC/TOFMS peaks based on the two methods. The optimization of parameters was discussed in detail with simulated data sets, and the applicability of the algorithm was evaluated by quantitative analysis of three alkaloids in human plasma using UPLC/TOFMS. The new algorithm behaved well in the improvement of signal-to-noise (S/N) compared to several normally used peak enhancement methods, including the Savitzky-Golay filter, Whittaker-Eilers smoother and matched filtration. PMID- 21298728 TI - A role for the CAMKK pathway in visual object recognition memory. AB - The role of the CAMKK pathway in object recognition memory was investigated. Rats' performance in a preferential object recognition test was examined after local infusion into the perirhinal cortex of the CAMKK inhibitor STO-609. STO-609 infused either before or immediately after acquisition impaired memory tested after a 24 h but not a 20-min delay. Memory was not impaired when STO-609 was infused 20 min after acquisition. The expression of a downstream reaction product of CAMKK was measured by immunohistochemical staining for phospho-CAMKI(Thr177) at 10, 40, 70, and 100 min following the viewing of novel and familiar images of objects. Processing familiar images resulted in more pCAMKI stained neurons in the perirhinal cortex than processing novel images at the 10- and 40-min delays. Prior infusion of STO-609 caused a reduction in pCAMKI stained neurons in response to viewing either novel or familiar images, consistent with its role as an inhibitor of CAMKK. The results establish that the CAMKK pathway within the perirhinal cortex is important for the consolidation of object recognition memory. The activation of pCAMKI after acquisition is earlier than previously reported for pCAMKII. PMID- 21298725 TI - Considering PTSD from the perspective of brain processes: a psychological construction approach. AB - Posttraumatic stress disorder (PTSD) is a complex psychiatric disorder that involves symptoms from various domains that appear to be produced by the combination of several mechanisms. The authors contend that existing neural accounts fail to provide a viable model that explains the emergence and maintenance of PTSD and the associated heterogeneity in the expression of this disorder (cf. Garfinkel & Liberzon, 2009). They introduce a psychological construction approach as a novel framework to probe the brain basis of PTSD, where distributed networks within the human brain are thought to correspond to the basic psychological ingredients of the mind. The authors posit that it is the combination of these ingredients that produces the heterogeneous symptom clusters in PTSD. Their goal is show that a constructionist approach has significant heuristic value in understanding the emergence and maintenance of PTSD symptoms, and leads to different and perhaps more useful conjectures about the origins and maintenance of the syndrome than the traditional hyperreactive fear account. PMID- 21298729 TI - Calbindin-D28K expression increases in the dorsolateral hippocampus following corticosterone treatment in female zebra finches (Taeniopygia guttata). AB - The hippocampus (HP) in zebra finches (Taeniopygia guttata) is important in the consolidation of spatial memories. Chronic, elevated levels of steroid hormones, like the glucocorticoids, can decrease this type of memory function in birds and mammals; neuronal atrophy, loss, and a decrease in synaptic contacts in the mammalian HP are observed as the underlying cause. Calbindin-D28k is constitutively expressed in cells of the nervous system but increases in concentration following a neurotoxic insult, protecting neurons against apoptotic cell death. We hypothesized that treatment of female zebra finches with a glucocorticoid (corticosterone) would increase calbindin expression in the HP and the caudomedial nidopallium (NCM), a region important for perceptual (song) memories, relative to "blank" controls. Additionally, because the HP in zebra finches appears similar to that in mammals, based on a variety of structural and functional factors, and as particular regions of the HP in mammals are more vulnerable to glucocorticoid-induced damage, we also hypothesized that expression of calbindin would vary among the HP subdivisions. Overall levels of calbindin were higher in the HP of corticosterone-treated birds, due almost entirely to elevated calbindin expression in the dorsolateral subdivision of the HP only. In contrast, the dorsomedial HP, ventral HP, and NCM appear less affected by glucocorticoid exposure. These results suggest a role for glucocorticoids in the modulation of HP- but not NCM-dependent memories as well as a further functional differentiation among the HP subdivisions. PMID- 21298730 TI - Patients' experiences of rheumatoid arthritis education: a short report. PMID- 21298731 TI - Should intravenous iron be upfront therapy for iron deficiency anemia? PMID- 21298732 TI - Ya gotta have heart. PMID- 21298733 TI - A parent's point of view on the American Academy of Pediatrics policy statement: Children as hematopoietic stem cell donors. PMID- 21298734 TI - Protecting the rights and interests of pediatric stem cell donors. PMID- 21298735 TI - In defense of the American Academy of Pediatrics policy statement--children as hematopoietic stem cell donors. PMID- 21298736 TI - Parental adjustment to the completion of their child's cancer treatment. AB - Childhood cancer treatment completion is a significant milestone. However, coming off treatment may be a time of psychological vulnerability for parents. This review assesses published research (1979-2009) on the psychosocial impact of treatment completion on parents. Fifteen articles met all inclusion criteria and demonstrated that while they celebrate treatment completion, parents (particularly mothers) can experience significant distress, including fear of recurrence, fatigue, and loneliness. Distress appears to ease with time, possibly as the perceived risk of relapse declines. Continued psychosocial support specifically targeting parents' risk perceptions, physical and emotional fatigue, social isolation, and parenting concerns post-treatment is warranted. PMID- 21298737 TI - A systematic review of studies on psychosocial late effects of childhood cancer: structures of society and methodological pitfalls may challenge the conclusions. AB - High survival rates after childhood cancer raise attention to possible psychosocial late effects. We focus on predictors of psychosocial outcomes based on diagnosis, treatment, demography, somatic disease, and methodological problems. Overall, survivors evaluate their health-related quality of life to be normal or even better than controls, although virtually all diagnostic subgroups report psychosocial impairment. Central nervous system tumor survivors have significant psychosocial problems. Negative outcomes were associated with cranial radiation therapy, female gender, and young age at diagnosis. Significant methodological problems hamper current knowledge. Systematic registration of psychosocial and somatic problems at diagnosis and prospectively through protocols is needed. PMID- 21298738 TI - Long-term results of AIEOP-8805 protocol for acute B-cell lymphoblastic leukemia of childhood. AB - BACKGROUND: Acute B-cell leukemia (B-ALL) is a rare form of pediatric leukemia characterized by a very high-proliferation index, rapid clinical progression, and a high frequency of central nervous system (CNS) involvement. Commonly, it is treated in the clinical trials for Burkitt lymphoma, of which it represents the leukemic counterpart. PROCEDURE: Children with B-ALL diagnosed between 1988 and 1999 were enrolled in the AIEOP-8805 protocol. Treatment included six high-dose chemotherapy courses. No prophylactic CNS irradiation was administered. RESULTS: Sixty-five consecutive patients were enrolled in the study. L3 morphology was observed in 57 of 65 patients (88%). Twenty-five children (38%) had tumor mass in addition to massive bone marrow infiltration; 11 children (17%) had CNS disease at diagnosis. Sixty-two patients obtained complete morphological remission of which 13 suffered a relapse, including 3 with initial CNS involvement. Ten-year overall survival and event-free survival were 77% and 75%, respectively. Neither relevant long-term toxicity nor second malignancies were observed. CONCLUSIONS: The AIEOP-8805 confirmed that short high-dose chemotherapy is highly effective for the treatment of B-ALL without significant long-term adverse sequelae. Therapy modifications to reduce relapse rate, such as the use of anti-CD20 monoclonal antibody and more effective CNS treatment, are being tested. PMID- 21298739 TI - Risk factors for treatment related mortality in childhood acute lymphoblastic leukaemia. AB - BACKGROUND: In spite of major improvements in the cure rate of childhood acute lymphoblastic leukaemia (ALL), 2-4% of patients still die from treatment related complications. PROCEDURE: We investigated the pattern of treatment related deaths (TRDs) and possible risk factors in the NOPHO ALL-92 and ALL-2000 protocols. Fifty-five TRDs were identified among the 1,645 ALL-92 patients and 33 among the 1,090 ALL-2000 patients. RESULTS: There was no significant difference in the incidence of TRDs between the two protocols (3.4% vs. 3.2%). Five patients died before initiation of therapy (0.2%), and the overall subsequent risk of induction death and death in first complete remission (CR1) was 1.2% and 1.8%, respectively. Infections were the major cause of death comprising 72% of all cases including 9 deaths from Pseudomonas aeruginosa and 11 deaths from fungal infections. Other causes of death included bleeding or thrombosis (eight patients), tumour burden related toxicities (seven patients) and organ toxicity (seven patients). Female gender (hazard ratio (HR): 2.2, 95% confidence interval (95% CI): 1.4-3.4), high white blood cell count (>= 200 * 10(9) /L) at diagnosis (HR: 3.5, 95% CI: 1.7-7.1), T-cell disease (HR: 1.9, 95% CI: 1.01-3.7), Down syndrome (HR: 7.3, 95% CI: 3.6-14.9) and haematopoietic stem cell transplantation in CR1 (HR: 8.0, 95% CI: 3.3-19.5) were identified as independent risk factors for TRD. CONCLUSION: Several TRDs were potentially preventable and future efforts should be directed towards patients at risk. PMID- 21298741 TI - Increased CCL2 and IL-8 in the bone marrow microenvironment in acute lymphoblastic leukemia. AB - BACKGROUND: The interactions of acute lymphoblastic leukemia (ALL) blasts with bone marrow (BM) stromal cells have a positive impact on leukemia cell survival. In the present study, we proposed to identify and investigate the role of molecules critically involved in leukemia--microenvironment crosstalk. PROCEDURE: Gene expression profiling analyses of BM mesenchymal stem cells (BMMSC) were performed following stimulation by ALL cells. CCL2 and IL-8 plasma levels were evaluated from ALL patients and controls. Expression of the CCL2 and IL-8 receptors in ALL was determined by RT-PCR. The biological effects of CCL2, IL-8 or its neutralizing antibodies in primary precursor-B ALL and BMMSC cells were evaluated using in vitro assays. RESULTS: Leukemia stimulation of BMMSC upregulated the expression of several inflammatory chemokines, including CCL2 and IL-8. The BM plasma levels of CCL2 and IL-8 in children at diagnosis were significantly higher than in healthy controls (P < 0.001). Functional studies revealed that CCL2 and IL-8 enhanced the capacity of BMMSC to support adhesion of ALL cells. CCL2 and IL-8 were also found to enhance BMMSC survival and to increase their proliferation. ALL cells were not directly affected by CCL2 or IL 8. CONCLUSIONS: The leukemic BM microenvironment had increased levels of CCL2 and IL-8. These chemokines are known to have suppressive effects in normal hematopoiesis. Our data indicate that CCL2 and IL-8 have a positive impact on BMMSC survival, proliferation, and adhesiveness to ALL cells. Leukemia-associated CCL2 and IL-8 upregulation may represent one possible mechanism of microenvironment perversion in favor of ALL cells. PMID- 21298740 TI - Treatment of children with B-cell non-Hodgkin lymphoma in a low-income country. AB - BACKGROUND: An adapted LMB 96 derived protocol for B-cell non-Hodgkin lymphoma (NHL) was implemented at the pediatric oncology unit of the Children Welfare Teaching Hospital in Baghdad (Iraq) from 2000 to present. The purpose was to evaluate the feasibility and efficacy of this intensive therapeutic regimen in a limited resource country. METHODS: Patients <15 years of age with high grade B cell NHL were included. A modified LMB 96 regimen was employed with a reduction of cyclophosphamide and methotrexate dosages due to inadequate laboratory facilities and supportive care. RESULTS: Between 2000 and 2005, 261 children with non-lymphoblastic NHL were registered; 239 were eligible for the analysis. Two patients had stage I disease, 20 stage II, 179 stage III, and 38 stage IV. Fifty two patients (22%) had bulky disease. Twelve children were assigned to therapeutic group A (low risk), 184 to group B (intermediate risk), and 43 to group C (high risk). One hundred and eighty-four patients (77%) had a complete response after the COP pre-phase. Sixty-nine patients (29%) died during treatment. Twenty-nine patients abandoned treatment. At 24 months, the overall survival rate of the entire patient population was 66% (CI 95%: 62.2-70.6) and the event-free survival rate 53.3% (CI 95%: 50.0-56.8). CONCLUSIONS: The treatment schedule proved effective, but the treatment-related mortality due to infections and metabolic complications was very high owing to the limited supportive care available. The high rate of treatment abandonment was also an important cause of failure, especially for children living far away from the hospital. PMID- 21298742 TI - Treatment and outcomes of patients with relapsed, high-risk neuroblastoma: results of German trials. AB - BACKGROUND: The prognosis of high-risk neuroblastoma patients has improved over the last decades. However, many patients experience relapse after successful initial treatment. We retrospectively analyzed the long-term outcome of relapsed patients of three consecutive national neuroblastoma trials. METHODS: Patients were included when they fulfilled all of the following criteria: Age at diagnosis being 1 year or older, first diagnosis between 1990 and 2007, stage 4 disease or stage 3 neuroblastoma with MYCN amplification, and relapse or progression after successful first-line autologous stem cell transplantation (ASCT). RESULTS: A total of 451 high-risk neuroblastoma patients 1 year or older underwent ASCT during first-line treatment, 253 experienced recurrence of disease, 158 received salvage chemotherapy, and 23 of them finally underwent a second ASCT. These 23 patients had a better median survival (2.08 years) and 3-year survival rate from recurrence (43.5 +/- 10.9%) compared to 74 patients who had no second chemotherapy (median survival 0.24 years, 3-year survival rate 4.0 +/- 2.6%) and 135 patients who underwent second-line chemotherapy but did not undergo second ASCT (median survival of 0.89 years, 3-year survival rate 9.6 +/- 2.8%, P < 0.001). By February 2010, 3/23 patients were in complete remission, 3/23 in very good partial remission, 1/23 in partial remission, 14/23 patients died of disease after successful second ASCT, and 2/23 died of complications due to second ASCT. CONCLUSION: Intensive second-line therapy is feasible. A small subgroup of relapsed high-risk neuroblastoma patients may benefit from intensive relapse chemotherapy and second ASCT. The potential of long-term survival justifies clinical trials on intensive second-line treatment. PMID- 21298743 TI - Differentiated expression of somatostatin receptor subtypes in experimental models and clinical neuroblastoma. AB - BACKGROUND: Neuroblastoma (NB) is a solid tumor of childhood originating from the adrenal medulla or sympathetic nervous system. Somatostatin (SS) is an important regulator of neural and neuroendocrine function, its actions being mediated through five specific membrane receptors. The aim of this study was to investigate the expression of the different somatostatin receptors (SSTRs) in NB tumor cells that may form targets for future therapeutic development. PROCEDURE: Tumor specimens from 11 children with stage II-IV disease were collected before and/or after chemotherapy. Experimental tumors derived from five human NB cell lines were grown subcutaneously in nude mice. Expression of SSRTs, the neuroendocrine marker chromogranin A (CgA) and SS was detected by immunohistochemistry using specific antibodies. RESULTS: SSTR2 was detected in 90%, SSTR5 in 79%, SSTR1 in 74%, SSTR3 in 68% whereas SSTR4 was expressed in 21% of the clinical tumors. The experimental tumors expressed SSTRs in a high but variable frequency. All clinical tumors showed immunoreactivity for CgA but not for SS. CONCLUSION: The frequent expression of SSTRs indicates that treatment with unlabeled or radiolabeled SS analogs should be further explored in NB. PMID- 21298744 TI - Participation in daily activities and quality of life in survivors of retinoblastoma. AB - PURPOSE: To assess the participation and health-related quality of life (HRQOL) of survivors of childhood retinoblastoma (RB). PATIENTS AND METHODS: Parents of 46 survivors of childhood RB between the ages of 2-18 were administered questionnaires relating to their children's participation (CFFS) and HRQOL (CHQ and PedsQL) and children were administered the PedsQL. Results of the HRQOL were compared to population-based norms. RESULTS: The overall QOL of survivors of RB was similar to that of age norms. However, parents' rating of their children's general and emotional health was lower than that of age norms, and survivors reported lower QOL related to school. Survivors of bilateral RB participated less in daily activities and had lower emotional QOL compared to those with unilateral RB, and parents of children who had an eye enucleated reported that their children had lower self-esteem. The level of participation was related to the perceived QOL. CONCLUSION: Our results indicate that children who are survivors of RB have an overall QOL that is similar to their age-peers. However, subgroups of survivors appear to have unique difficulties that require continued follow-up and intervention. Focus should be placed on their participation in daily activities both in the community and at school. PMID- 21298746 TI - Great vessel/cardiac extension and tumor embolism in pleuropulmonary blastoma: a report from the International Pleuropulmonary Blastoma Registry. AB - BACKGROUND: Types II and III pleuropulmonary blastoma (PPB) are aggressive sarcomas of lung and pleura in young children. Similar to cavoatrial extension of Wilms tumor, PPB may extend into thoracic great vessels and the heart and may involve both venous and arterial circulations and right and left cardiac chambers. Serious embolic complications occur. PROCEDURE: Review International PPB Registry databases and literature (1) for PPB cases with vascular/cardiac extension and (2) for neoadjuvant chemotherapy results in vascular extension cases. RESULTS: Among 179 Registry-confirmed and approximately 200 literature Type II and III PPB cases, 11 examples (approximately 3%) of great vessel/cardiac extension were identified; 1 case is presented in detail. Nine cases involved the left circulation, one the right and one both. Various radiographic techniques including echography, computed tomography and gated magnetic resonance imaging identified vascular tumor. Seven children had arterial embolic events: cerebrovascular accidents (six, including one femoral artery occlusion) and acute aortic occlusion (1). Six of these seven died from complications that may be attributed to vascular involvement. In three of four children with vascular involvement, neoadjuvant chemotherapy lessened the involvement; in one the effect could not be assessed. None of these four had embolic events. Effect on survival could not be assessed due to small numbers. CONCLUSIONS: Involvement of thoracic great vessels and the heart is a serious complication of PPB, with fatal embolic complications possible. Radiographic evaluation of the central circulation should be performed in children with suspected or diagnosed PPB to identify this complication. PMID- 21298745 TI - Initial testing (stage 1) of the IGF-1 receptor inhibitor BMS-754807 by the pediatric preclinical testing program. AB - BACKGROUND: BMS-754807 is a small molecule ATP-competitive inhibitor of the type 1 insulin-like growth factor receptor currently in phase 1 clinical trials. PROCEDURES: BMS-754807 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro panel at concentrations ranging from 1.0 nM to 10 uM and was tested against the PPTP in vivo panels at a dose of 25 mg/kg administered orally BID for 6 days, repeated for 6 weeks. RESULTS: In vitro BMS-754807 showed a median EC(50) value of 0.62 uM against the PPTP cell lines. The median EC(50) for the four Ewing sarcoma cell lines was less than that for the remaining PPTP cell lines (0.19 uM vs. 0.78 uM, P = 0.0470). In vivo BMS-754807 induced significant differences in EFS distribution compared to controls in 18 of 32 evaluable solid tumor xenografts (56%) tested, but in none of the ALL xenografts studied. Criteria for intermediate activity for the time to event activity measure (EFS T/C > 2) were met in 7 of 27 solid tumor xenografts evaluable for this measure. The best response was PD2 (progressive disease with growth delay), which was observed in 18 of 32 solid tumor xenografts. PD2 responses were most commonly observed in the rhabdomyosarcoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and Wilms tumor panels. CONCLUSIONS: BMS-754807 activity in vitro is consistent with a specific IGF-1R effect that has half-maximal response in the 0.1 uM range and that is observed in a minority of the PPTP cell lines. In vivo intermediate activity was most commonly observed in the neuroblastoma and rhabdomyosarcoma panels. PMID- 21298747 TI - The use of zoledronic acid in pediatric cancer patients. AB - BACKGROUND: The third generation bisphosphonate zoledronic acid has demonstrated efficacy in reducing skeletal-related events in adult patients with multiple cancer types that have skeletal disease. The use of zoledronic acid in pediatric oncology patients with bone metastases for the purpose of reducing pain, improving bone strength and altering the progression of metastatic disease has not been thoroughly evaluated. PROCEDURE: From October 2005 to December 2008, 19 patients at the Aflac Cancer Center received one or more doses of zoledronic acid as part of their therapy. A retrospective review of these patients was performed and information was collected including indication for treatment, toxicities, and outcomes. RESULTS: Most patients (n = 15) received zoledronic acid following relapse of their malignancy with metastatic disease present in one or more bony sites. Hypocalcemia and hypophosphatemia were frequent, but did not result in clinical symptoms. More significant toxicities associated with zoledronic acid, including clinically apparent renal insufficiency and osteonecrosis of the jaw, were not seen. Overall, zoledronic acid was well tolerated in this population. CONCLUSIONS: The benefits of zoledronic acid seen in randomized trials of adults with bone metastases have sparked interest in its use for children with metastatic cancer. The administration of zoledronic acid in pediatric oncology appears safe, and may result in improved bone strength and pain control. Further evaluation is warranted to prospectively evaluate its efficacy and long-term safety in pediatric patients with cancer and skeletal metastases. PMID- 21298748 TI - Intravenous iron sucrose for children with iron deficiency failing to respond to oral iron therapy. AB - BACKGROUND: For decades, parenteral iron has been used in patients with iron deficiency unresponsive to oral iron therapy and in hemodialysis-dependent patients receiving erythropoietin. Newer intravenous (IV) iron formulations such as iron sucrose have replaced high-molecular weight iron (HMW) dextran in dialysis patients; however, the use of parenteral iron in children without renal disease has not been well defined. PROCEDURE: Pharmacy records were reviewed on children (<= 18 years of age) who received IV iron sucrose at Children's Medical Center Dallas between January 1, 2004 and June 30, 2009. Patients who received iron sucrose for chronic renal disease were excluded from analysis. RESULTS: Thirty-eight children received iron sucrose for non-renal indications, 13 with iron deficiency refractory to oral iron therapy, 13 with iron malabsorption or dependence on parenteral nutrition, 7 for chronic gastrointestinal blood loss, and 5 for miscellaneous indications. Among these 38 children, who received a total of 510 doses of IV iron sucrose, there were only six adverse reactions. Patients in all categories had a good response to the iron sucrose, with a median hemoglobin rise of 1.9-3.1 g/dl depending on the indication. CONCLUSIONS: Parenteral iron is a safe and effective means to treat iron deficiency in children who cannot receive or do not respond to oral iron due to intolerance, poor adherence, or iron malabsorption. PMID- 21298749 TI - Neurocognitive screening with the Brigance preschool screen-II in 3-year-old children with sickle cell disease. AB - BACKGROUND: Neurocognitive deficits have been described in school age children with sickle cell disease (SCD), even in the absence of stroke or silent infarcts. However, the age of onset and factors contributing to this problem have not been well studied. We hypothesized that in children with SCD the failure rate with Brigance screening would be higher than in the normal population. METHODS: We reviewed retrospectively the Brigance Preschool Screen-II test results in 3-year old children with SCD. Findings were correlated with hemoglobinopathy genotype, hemoglobin level, transcranial Doppler ultrasound (TCD) velocities, and treatment with hydroxyurea, as well as with psychosocial factors. RESULTS: Eighty-eight children with SCD followed by the St. Jude Sickle Cell Center (mean age 3.5 years) had neurocognitive screening during their regular clinic visits. Forty four (50%) children had scores below the normal cut-off value for their age (twice the national failure rate of 25%). Failures were associated with less parental education (P = 0.005 for maternal and P = 0.03 for paternal education levels) and with speech deficits (P = 0.01), but were not associated with sickle cell genotype or hemoglobin concentration. CONCLUSION: These preliminary data suggest that psychosocial factors may have more profound effects on early childhood development than disease-related factors in this group of young sickle cell patients. A larger prospective study with appropriate controls is warranted to validate these findings, which have implications for the etiology and prevention of neurocognitive decline in children with SCD. PMID- 21298750 TI - Prevalence and predictors of anthracycline cardiotoxicity in children treated for acute myeloid leukaemia: retrospective cohort study in a single centre in the United Kingdom. AB - BACKGROUND: Anthracycline cardiomyopathy is of concern in children treated for acute myeloid leukaemia (AML), but there are few data on the incidence and natural history of cardiotoxicity after AML treatment in the United Kingdom, where regimens have included high anthracycline exposure. PROCEDURE: Prevalence and predictors of cardiotoxicity were retrospectively reviewed in 124 children treated on the MRC AML 10 and AML 12 trials in a single, large centre from November 1987 to September 2004. Subclinical cardiotoxicity was defined as a shortening fraction of less than 28% and clinical cardiomyopathy as evidence of heart failure, and both were classified as late cardiotoxicity 1 year after completing first line therapy. RESULTS: Cumulative survival was 61% at 10 years. The prevalence of early and late cardiotoxicity was 13.7% (95%-CI: 8.2-22.0%) and 17.4% (95%-CI: 10.9-26.8%), respectively. Early cardiotoxicity was a strong predictor (OR = 9.18; 95%-CI: 2.10-40.11; P < 0.005) and children who received salvage therapy following relapse showed a trend towards increased late cardiotoxicity (OR = 3.53; 95%-CI: 0.86-14.48; P < 0.08). Subclinical cardiotoxicity resolved spontaneously in all but one case, but clinical cardiomyopathy always required continuing therapy. Two children died of cardiomyopathy and six remained on medical therapy. CONCLUSIONS: Anthracycline cardiotoxicity remains a major concern for survivors of childhood AML and correlates with early cardiotoxicity and treatment intensity. Long-term follow-up is required to fully determine the outcome for children with subclinical cardiotoxicity. PMID- 21298751 TI - Hearing impairment after platinum-based chemotherapy in childhood. AB - BACKGROUND: Chemotherapy is used in the treatment of children and adolescents with malignant diseases. Some of the chemotherapeutic agents are highly toxic and may cause a number of side effects. The primary objective of this study was to evaluate the long-term effects on hearing in cancer survivors who had received platinum-based chemotherapy in childhood or adolescence. PROCEDURE: Medical records of 297 patients, who had received treatment for cancer at the Children's Hospital, Landspitali University Hospital in Iceland between 1981 and 2006, were retrospectively reviewed. Fifteen subjects fulfilled the eligibility criteria for the study and underwent an extended audiometric evaluation. RESULTS: The results showed that three of the subjects had a high frequency hearing loss. In one subject, we observed a hearing recovery just after the completion of chemotherapy, but the hearing deteriorated again some years later. Nine of the 15 subjects (60%) had tinnitus after the cancer treatment. An evaluation of subjective hearing disability and handicap (The Hearing Measurements Scale) revealed that some subjects had great difficulties with hearing in certain situations. The Hearing Measurement Scale showed that the pure-tone audiogram findings were only partly associated with the apparent hearing difficulties. CONCLUSION: Regular follow-up hearing examinations, which include both pure-tone audiogram investigations and subjective hearing disability assessments, should be performed during and after chemotherapy to identify subjects who require particular attention. This will ensure that hearing impaired individuals are provided with the most suitable listening devices, to promote good speech and social development. PMID- 21298752 TI - Children receiving treatment for cancer and their caregivers: a mixed methods study of their sleep characteristics. AB - BACKGROUND: Sleep has a significant impact on the daily functioning of children and their parents. The purpose of this study was to describe and gain an understanding of the sleep characteristics of children receiving treatment for cancer and their caregivers using a mixed methods concurrent triangulation design. PROCEDURE: Data were collected from questionnaires completed by 35 caregivers of children receiving treatment for cancer and compared to similar data from 64 caregivers of healthy children. RESULTS: There was considerable variability in the sleep characteristics of the children receiving treatment for cancer as reported by their caregivers. However, as a group, the magnitude of their sleep problems, particularly among the adolescents, was significantly greater than that of the comparison group and had the potential to impact negatively on their participation in everyday life. They had poorer sleep efficiency. Many impairments, particularly pain, nightmares, and symptoms associated with steroid administration, impacted their sleep. Their caregivers also experienced an increased prevalence of sleep issues, which impacted their daytime functioning. Suggestions to prevent and treat the sleep issues of children receiving treatment for cancer focused on practicing good sleep habits, ensuring a safe, secure, and comfortable sleep environment, and using non pharmaceutical and pharmaceutical interventions to address impairments interfering with sleep. Caregivers noted that it was important to take care of themselves by getting sufficient sleep and accepting help from others. CONCLUSIONS: Sleep issues are prevalent in families of children receiving treatment for cancer and should be assessed routinely and addressed. PMID- 21298753 TI - Health-related quality of life after completion of successful treatment for childhood cancer. AB - BACKGROUND: Previous studies have assessed health-related quality of life (HRQOL) during several treatment stages in children with cancer, but there is limited knowledge about HRQOL shortly after completing therapy. This study determined HRQOL of children with cancer shortly after the end of successful treatment compared with normative values. PROCEDURE: Several age-specific HRQOL questionnaires were administered: the ITQOL (generic, proxy-report, 0-4 years), CHQ PF 50 (generic, proxy-report, 5-7 years), Kidscreen (generic, self-report, 8 18 years) and Disabkids (chronic generic, self-report, 8-18 years). RESULTS: Children with cancer (N = 191, mean age 9.25, SD 5.06, 47.1% female) participated. Physical well-being was affected for all ages. Compared to normative values 0- to 7-year-olds were rated significantly lower on the majority of the scales. In addition, 12- to 18-year-olds had significantly better HRQOL than the norm on social scales. Compared to chronically ill norms, 8- to 18-year olds demonstrated no differences, except for 12- to 18-year-olds who experienced significantly more physical limitations. Additionally, we found that HRQOL of parents of 0- to 7-year-olds was poorer than the norm. CONCLUSION: HRQOL in children with cancer and their parents can be impaired compared with the norm. Therefore, HRQOL should be monitored in clinical practice to make paediatric oncologists aware of these problems. For young children, we recommend checking whether certain HRQOL problems can be explained by parental worries. For older children and adolescents, paediatric oncologists need to consider social desirability and the child's adaptive style. PMID- 21298754 TI - Unusual functional manifestations of a novel STX11 frameshift mutation in two infants with familial hemophagocytic lymphohistiocytosis type 4 (FHL4). AB - Familial hemophagocytic lymphohistiocytosis (FHL) is typically an autosomal recessive, early-onset, life-threatening immune disorder. Loss-of-function mutations in STX11 have been found to impair NK cell degranulation and cytotoxicity. Here, we describe two unrelated infants of Punjabi descent presenting with FHL and carrying a novel, homozygous STX11 frameshift mutation [c.867dupG]. Western blot analysis indicated absence of syntaxin-11. Unexpectedly, degranulation by NK cells from one of the patients was not impaired, although patient NK cells showed mildly and significantly decreased cytotoxicity, respectively. Importantly, these observations imply that STX11 should be sequenced in HLH patients even when impaired NK cell degranulation is not found. PMID- 21298755 TI - Hemophagocytic lymphohistiocytosis associated with precursor B acute lymphoblastic leukemia. AB - We report a case of a child with precursor-B acute lymphoblastic leukemia (ALL) who experienced refractory thrombocytopenia and massive splenomegaly during standard induction chemotherapy. He was diagnosed with hemophatocytic lymphohistiocytosis (HLH) during induction. Clinical and laboratory evaluation showed no evidence of infectious cause to HLH. Pancytopenia and HLH persisted after consolidation therapy even with remission from leukemia. After failure to control HLH with ALL-directed therapy and HLH-directed therapy, the patient underwent unrelated donor hematopoietic stem cell transplantation 8 months after diagnosis. He is 34 months post-transplant and in remission from leukemia and HLH. PMID- 21298756 TI - Ehrlichia-induced hemophagocytic lymphohistiocytosis in two children. AB - Two children presented with a history of fever and rash. Lab values revealed pancytopenia, elevated ferritin, coagulopathy, and elevated triglycerides. Both children quickly developed respiratory distress and hypotension requiring admission to the ICU. Bone marrow biopsies revealed hemophagocytosis. Studies for Ehrlichia returned positive. The patients were started on doxycycline and treated for hemophagocytic lymphohistiocytosis (HLH). Each made a full recovery. In both patients, testing for MUNC and perforin genes were found to have no mutation. These two cases demonstrate the importance of considering Ehrlichiosis as a possible trigger of HLH. PMID- 21298757 TI - Immunoglobulin abnormalities and effects of enzyme replacement therapy in children with Gaucher disease. AB - Hyperimmunoglobulinemia is documented in patients with Gaucher disease of all ages. We investigated the frequency of hyperimmunoglobulinemia in 12 pediatric patients with type I and III Gaucher disease and the effects of enzyme replacement therapy on these abnormalities. The incidence of hyperimmunoglobulinemia was 77%, 66%, and 60% at the diagnosis, before and after ERT, respectively. Immunoglobulin G abnormalities were the most commonly seen isotype abnormality. After enzyme replacement therapy normalization of IgA and IgM levels were recorded but decline in IgG levels was less likely to occur. This study indicated the higher frequency of hyperimmunoglobulinemia in pediatric Gaucher patients. PMID- 21298758 TI - Gorham's disease and diffuse lymphangiomatosis in children and adolescents. AB - Gorham's disease is a rare disorder of unknown etiology and variable clinical presentation that is characterized by proliferation of thin-walled vascular channels resulting in destruction and resorption of osseous matrix. The condition is frequently under recognized or misdiagnosed. There is no standard treatment defined for this disease. Here we report on eight children diagnosed with Gorham's disease at our institution over a ten-year period. Soft tissue lymphangioma was present in seven and six children had splenic involvement. Disease stabilization and improvement was observed on treatment with interferon alpha-2b and bisphosphonate therapy. PMID- 21298759 TI - Acquired growth hormone deficiency in a girl with chronic myelogenous leukemia treated with tyrosine kinase inhibitor therapy. AB - Chronic myelogenous leukemia (CML) is caused by the BCR-ABL1 fusion gene that encodes for a constitutively-active tyrosine kinase. Adults and children with CML are typically treated with imatinib mesylate, a BCR-ABL1 tyrosine kinase inhibitor (TKI), or a second-generation TKI. Several case reports have documented growth delay of unknown mechanism in children with CML treated with imatinib. We report a seven-year-old identical twin with CML who developed significant growth delay, as compared to her twin, during five years of TKI therapy. Detailed endocrine evaluation showed acquired growth hormone deficiency, a pathway potentially inhibited by TKIs. PMID- 21298760 TI - Reversible Fanconi syndrome in a pediatric patient on deferasirox. AB - Deferasirox (Exjade(r), Novartis) is a widely used oral iron chelator for the treatment of patients with iron overload due to chronic transfusion therapy for diseases such as beta-thalassemia and sickle cell disease. Renal side effects of deferasirox are common and include non-progressive increases in serum creatinine, however, the effect of deferasirox on proximal tubule function is unclear. We report one pediatric patient with reversible Fanconi syndrome associated with long-term deferasirox therapy and one patient with mild proximal tubular dysfunction. Kidney and proximal tubular function should be periodically monitored in patients receiving deferasirox throughout their course of therapy. PMID- 21298762 TI - The incremental cost of chemotherapy safety. PMID- 21298761 TI - Referral to a specialist paediatric palliative care service in oncology patients. AB - Cancer is the second most common cause of death in children and young people (0 19 years) accounting for 16.2% of deaths in England and Wales in 2005. Only 37.6% children and young people who died from cancer in Yorkshire were referred to Martin House Children's Hospice (MH) during the period 1990-2005. A significantly higher proportion with central nervous system tumours and a significantly lower than expected proportion with leukaemia or lymphoma were referred for palliative care. There is potential to increase the proportion of children and young people with cancer who are referred to specialist palliative care services. PMID- 21298763 TI - Is WTX a suitable target for cancer therapy? PMID- 21298764 TI - MALT lymphoma of the lip. PMID- 21298765 TI - Recurrence of unifocal limbal Langerhans cell histiocytosis with partial response to chemotherapy and prolonged remission. PMID- 21298766 TI - Abstracts of the Histiocyte Society 26th Annual Meeting. Boston, Massachusetts. PMID- 21298767 TI - Male pseudohermaphroditism with mixed germ cell tumor. PMID- 21298768 TI - Local control and outcome in children with localized vaginal rhabdomyosarcoma: a report from the Soft Tissue Sarcoma committee of the Children's Oncology Group. AB - BACKGROUND: The local control approach for girls with non-resected vaginal rhabdomyosarcoma (RMS) enrolled onto Intergroup RMS Study Group (IRSG)/Children's Oncology Group (COG) studies has differed from that used at other primary sites by delaying or eliminating radiotherapy (RT) based on response achieved with chemotherapy and delayed primary resection. PROCEDURES: We reviewed locoregional treatment and outcome for patients with localized RMS of the vagina on the two most recent COG low-risk RMS studies. RESULTS: Forty-one patients with localized vaginal RMS were enrolled: 25 onto D9602 and 16 onto Subset 2 of ARST0331. Only four of the 39 with non-resected tumors received RT. The 5-year cumulative incidence of local recurrence was 26% on D9602, and the 2-year cumulative incidence of local recurrence was 43% on ARST0331. Increased local failure rates appeared to correlate with chemotherapy regimens that incorporated lower cumulative doses of cyclophosphamide. Estimated 5-year and 2-year failure free survival rates were 70% (95% CI: 46%, 84%) on D9602 and 42% (95% CI: 11%, 70%) on ARST0331, respectively. CONCLUSIONS: To prevent local recurrence, we recommend a local control approach for patients with non-resected RMS of the vagina that is similar to that used for other primary sites and includes RT. We recognize that potential long-term effects of RT are sometimes unacceptable, especially for children less than 24 months of age. However, when making the decision to eliminate RT, the risk of local recurrence must be considered especially when using a chemotherapy regimen with a total cumulative cyclophosphamide dose of <= 4.8 g/m2. PMID- 21298769 TI - ANZCCSG BabyBrain99; intensified systemic chemotherapy, second look surgery and involved field radiation in young children with central nervous system malignancy. AB - BACKGROUND: ANZCCSG BabyBrain99 is a trial of intensive systemic chemotherapy with dual stem cell supported treatment, second look surgery and involved field radiation for children less than four years of age with malignant central nervous system tumours. PROCEDURE: Following primary resection, treatment included two courses of cisplatin and oral etoposide, a third course of mobilising chemotherapy (vincristine, etoposide, cyclophosphamide) with stem cell harvest, followed by intensive stem cell supported chemotherapy with high dose cyclophosphamide, etoposide and vincristine. Children were evaluated for second resection before proceeding to a second stem cell supported consolidation therapy consisting of melphalan and carboplatin. Patients then received involved field radiation therapy. RESULTS: Thirty three children with a range of diagnoses were enrolled. Nine percent of children had metastatic disease at diagnosis. Eighteen children completed treatment including irradiation. At the end of induction the event free survival was 70% (54-86). Forty eight percent of children had a complete response, 18% had stable disease and 3% had a partial response. Five year overall survival was 40% (22-56) and event free survival was 33% (17-50). Children in whom a complete resection were achieved had a significantly superior outcome compared to those children without a complete resection, 5 year EFS 60% (45-75), as compared to 22% (13-30), P-value <0.05. CONCLUSIONS: BabyBrain99 confirms that intensive stem cell supported chemotherapy can be safely administered to infants with CNS tumours however overall prognosis remains poor. Importantly, the study reinforces a complete surgical resection as an important favourable prognostic indicator. Pediatr Blood Cancer 2011;56:1055-1061. (c) 2011 Wiley-Liss, Inc. PMID- 21298770 TI - Severe H1N1-associated acute respiratory failure in immunocompromised children. AB - BACKGROUND: Severe pandemic influenza A (H1N1) infection can lead to acute respiratory failure (ARF) with associated high mortality. Children with malignancy may be at higher risk of H1N1-associated ARF because of underlying primary disease or immunosuppression associated with chemotherapy. PROCEDURE: We describe the clinical course and outcome of critically ill pediatric oncology/hematology patients with H1N1-associated ARF. RESULTS: Five patients were admitted to the St. Jude Children's Research Hospital (SJCRH) ICU with H1N1 infection during the 2009-2010 influenza season. Underlying diagnoses included 2 patients with acute lymphoblastic leukemia and one each with neuroblastoma, brainstem glioma, and hemolytic anemia secondary to pyruvate kinase deficiency. All patients were mechanically ventilated secondary to ARF following unsuccessful trials of non-invasive ventilatory support. The majority of patients (4/5) required inotropic support, and none required dialysis. Further measures to support their ARF included high frequency oscillatory ventilation in 2 patients, nitric oxide in 3 patients, and surfactant in 1 patient. Three patients had bronchopleural air leak. All patients received oseltamivir; however, 2 were switched to intravenous zanamivir once resistance to oseltamivir was documented. Mean duration of mechanical ventilation was 24 +/- 6.8 days and mean duration of ICU admission was 37 +/- 12 days. All patients survived to hospital discharge. CONCLUSION: Our series suggests an overall favorable outcome in immunocompromised children with H1N1-related ARF. Our experience underscores the value of aggressive support during H1N1-related ARF, and early detection and management of oseltamivir-resistant H1N1 infection in this high-risk population. PMID- 21298771 TI - Red cell exchange does not appear to increase the rate of allo- and auto immunization in chronically transfused children with sickle cell disease. AB - BACKGROUND: Allo- and auto-antibody development is a well recognized complication of chronic red cell transfusion (RCT) in sickle cell disease (SCD). Limited matching of Rh (C, c, D, E, e) and K red cell antigens reduces the incidence of immunization. PROCEDURE: We reviewed our experience with red cell allo- and auto immunization in pediatric SCD patients receiving chronic and/or exchange transfusions, to evaluate the rate of immunization after limited red cell antigen matching and specifically during red cell exchange (RCE) transfusion. A retrospective chart review of the patients with SCD followed at our center between 2002 and 2006, who were started on chronic RCT before or during that time period, was conducted. RESULTS: Of the 93 patients who met study criteria, 23 (24%) developed antibodies during chronic red cell transfusions. Thirty-four antibodies (15 auto-antibodies, 18 allo-antibodies) developed after the institution of limited red cell antigen matching. The rate of allo- and auto immunization per unit of red cell exposure after limited phenotyping was 1.5%, comparable to other published data. Fifteen patients underwent RCE, utilizing a total of 2,289 packed red cell units. None developed antibodies during RCE. CONCLUSION: We conclude that limited red cell antigen matching is an effective strategy for reducing the incidence of allo- and auto-immunization in chronically transfused children with SCD. RCE does not appear to increase the risk of allo- or auto-immunization, despite exposure to more red cell units. PMID- 21298772 TI - Shared molecular targets in pediatric gliomas and ependymomas. AB - BACKGROUND: Recent advances in multidisciplinary treatment approaches have improved the overall prognosis of pediatric brain tumors, but some patients remain refractory to treatment and do poorly. Several molecularly targeted therapies are under development for the treatment of brain tumors, and high-grade gliomas in adults are a particular area of study. PROCEDURE: To better understand if these new therapies can be used in pediatric populations, we examined the expression of the following seven marker genes involved in signaling pathways targeted by new therapies: beta-catenin, suppressor of fused (SUFU), erythroblastic leukemia viral oncogene homolog (ERBB) 2, platelet-derived growth factor receptoralpha (PDGFRalpha), proliferating cell nuclear antigen (PCNA), secreted protein acid and rich in cysteine (SPARC), and granulocyte colony stimulating factor receptor (G-CSFR). Samples from 27 patients with the primitive neuroectodermal tumor (PNET)/medulloblastomas (MBs) (n = 8), ependymomas (n = 5), or gliomas (n = 14) were assessed by quantitative real-time PCR. [Correction made here after initial online publication]. We assigned an EXP score to compare across samples and determined the levels of gene expression among tumor cell types. RESULTS: Gene expression varied among the different tumors, but, within a tumor type, clear expression patterns were seen. The expression of SUFU, ERBB2, and PCNA in metastatic MBs were greater than that seen in non-metastatic MBs. Most glioma cases highly expressed PDGFRalpha and G-CSFR. Additionally, the expression patterns of gliomas and ependymomas were similar (r = 0.77, P = 0.04), but PNET/MBs substantially differed from gliomas (r = -0.37, P = 0.41) or ependymomas (r = 0.23, P = 0.62). CONCLUSIONS: The development of new drugs targeting up-regulated pathways may be useful for the treatment of pediatric brain tumors. As new drugs are developed, gliomas and ependymomas may be treated with similar compounds. PMID- 21298773 TI - Assessment of late cardiotoxicity of pirarubicin (THP) in children with acute lymphoblastic leukemia. AB - BACKGROUND: Pirarubicin (tetrahydropyranyl-adriamycin: THP) is a derivative of doxorubicin with reportedly less cardiotoxicity in adults. However no studies of cardiotoxicity in children treated with THP have been reported. This study was performed to assess the THP-induced cardiotoxicity for children with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: This study comprised 61 asymptomatic patients aged from 7.6 to 25.7 years old. Median follow-up time after completion of anthracycline treatment was 8.1 years (range: 1.7-12.5). The cumulative dose of THP ranged from 120 to 740 mg/m(2) with a median of 180 mg/m(2) . Patients underwent electrocardiogram (ECG), echocardiography, the 6-min walk test (6MWT), and measurements of serum brain natriuretic peptide (BNP) before and after exercise. RESULTS: All subjects showed normal left ventricular function assessed by echocardiography. Ventricular premature contraction in Holter ECG and reduced exercise tolerance in the 6MWT were detected in 2/46 (3.3%) and 5/41(12.2%), respectively. Abnormal BNP levels were detected in 6/60 (10%) both before and after exercise. The cumulative dose of THP was significantly correlated with BNP levels after exercise (r = 0.27, P = 0.03), but not with any other cardiac measurements. Further analysis revealed that subjects with a high cumulative dose ?300 mg/m(2) had significantly higher BNP levels after exercise compared with subjects with a low cumulative dose <300 mg/m(2) (P = 0.04). CONCLUSIONS: No significant cardiac dysfunction was detected in long term survivors who received THP treatment. The use of post-exercise BNP level to indicate high cardiotoxicity risk should be verified by further study. PMID- 21298774 TI - The antioxidant status and response to therapy in children with soft tissue sarcomas and neuroblastoma. AB - BACKGROUND: Antioxidant systems in cells maintain the proper homeostasis of reactive oxygen species, which at high concentrations can induce carcinogenesis. The aim of this study was to evaluate the serum levels of ischemia-modified albumin (IMA), erythrocyte superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) as markers for prognosis in children with neuroblastoma (NB) and soft tissue sarcomas (STS), two cancer types for which reliable prognostic factors are needed. PROCEDURE: SOD, GSH-Px, and IMA were measured before and during responses to therapy assessment in 99 children with NB and STS and in 30 healthy controls. RESULTS: There were no statistically significant differences in the erythrocyte SOD and GSH-Px activities between the patients with cancer and healthy controls. The levels of IMA in patients with STS and NB were found to be significantly higher than in the controls (P = 0.0013; P = 0.0066, and 0.0164, respectively). Decreased activities of SOD and GSH-Px were found in all patients with poor responding (PRS) cancers and decreased SOD activity was found in patients with PRS NB. An increase in GSH-Px was observed in patients with good-responding (GR) NB. All patients with GR cancers demonstrated higher SOD and GSH-Px activities than patients with PRS cancers. CONCLUSIONS: While determining the levels of specific antioxidants as antioxidant-barrier parameters in children with cancer may be valuable in predicting therapeutic responses as well as outcomes, additional studies are required. PMID- 21298775 TI - Flow cytometric osmotic fragility--an effective screening approach for red cell membranopathies. AB - BACKGROUND: Among the red cell membrane disorders, hereditary spherocytosis (HS) is one of the most common causes of inherited hemolytic anemia. The aim of this study was to compare the flow-cytometric approach for screening of red cell membrane disorders based on osmotic fragility with the eosin-5-maleimide (E5'M) dye test. A group of beta-thalassemia heterozygotes were also studied. METHODS: A red cell suspension was spiked with deionized water during acquisition and the count of residual red cells measured sequentially in real-time using flow cytometry. Fluorescence intensity of red cells stained with eosin-5-maleimide was also measured. RESULTS: The hereditary spherocytosis (HS) group showed significantly decreased percentage residual red cells (9.31% +/- 3.75%) (P = 0.0091) whereas the beta-thalassemia group showed a significant increase (93.56% +/- 12.98%) (P = 0.0008) compared to the normal control group (46.26% +/- 11.33%). The cut off value of the flow cytometric osmotic fragility (FCM OF) test for red cell membrane disorders was 23.59% giving a sensitivity of 100% and specificity of 98%. CONCLUSIONS: The advantages of the FCM OF test are that it is quantitative, time effective and requires only deionized water for the measurement of osmotic fragility. It could be an effective first line screening approach for red cell membrane disorders in hematology laboratories where a flow cytometer is available. PMID- 21298776 TI - Improved compensation of the fluorochrome AmCyan using cellular controls. AB - BACKGROUND: Implementation of polychromatic flow cytometry in the clinical laboratory often requires the use of newer fluorochromes, with which experience may be comparatively limited. In the course of implementing polychromatic flow cytometry in our laboratory, we have observed significant differences in compensation values derived for the violet-excited dye, AmCyan, when cells rather than a commercially available set of polystyrene microparticles (BD CompBeads) are used as compensation controls. METHODS: Compensation values were calculated for AmCyan and several other fluorochromes using the BD CompBeads Set according to the manufacturer's protocol, and using unstained and singly stained lymphocytes as compensation controls. RESULTS: When the BD CompBeads Set was used to determine compensation values, spillover from AmCyan into V450 was overcompensated, while spillover from AmCyan into FITC was undercompensated. In contrast, when compensation values were calculated using unstained and singly stained lymphocytes, spillover into V450 and FITC from cells stained brightly with AmCyan-conjugates was compensated appropriately. Although significant differences were observed in the compensation of spillover from AmCyan into V450 and FITC using cells rather than the BD CompBeads Set as compensation controls (P < 0.0001, two-tailed Wilcoxon signed-rank test), such differences were not observed in control experiments using fluorochromes excited by the blue (FITC and PE) or red (APC) lasers. CONCLUSION: Improved compensation of the violet-excited dye, AmCyan, is obtained when cells rather than the BD CompBeads Set are used as compensation controls. PMID- 21298777 TI - Optimizing antibody panels for efficient and cost-effective flow cytometric diagnosis of acute leukemia. AB - BACKGROUND: Differentiating acute myeloid leukemia (AML) from acute lymphoblastic leukemia (ALL) determines effective patient management and often depends on flow cytometry. Antibodies used in flow cytometry are costly, and the expenses are not always reimbursed. Having observed that AML and ALL have distinct patterns in the CD45/SSC panel, we set to analyze more leukemia cases and establish an algorithm for the efficient diagnosis of acute leukemia. METHODS: We retrospectively analyzed 127 consecutive cases of acute leukemia within the last 2 years and correlated the blast distribution patterns in the CD45/SSC panel, with the morphology and the detailed immunophenotype. RESULTS: Our results show that all the acute leukemias can be initially triaged into AML, ALL, and Indeterminate provisional groups based on the blast distribution patterns in the CD45/SSC panel and morphology. Each group was then further analyzed with tailored AML, ALL, and Indeterminate flow panels. Using this approach, we have efficiently and correctly diagnosed almost all the acute leukemias. Our analysis also determined the minimal numbers of immunological markers needed for the lineage assignment of acute leukemia. CONCLUSION: The algorithmic approach with tailored subsequent antibody selection could maintain diagnostic accuracy while significantly reducing reagent use, labor, and time. With a shrinking reimbursement for flow cytometric studies, an increase in laboratory efficiency without compromising diagnostic accuracy or turnaround time will contribute to preserving revenue and optimizing clinical service. PMID- 21298778 TI - Chiral HPLC separation and absolute configuration assignment of a series of new triazole compounds. AB - A series of novel chiral triazole compounds were synthesized. They were separated into enantiomers by liquid chromatography on an amylose tris(3,5 dimethylphenylcarbamate) (ADMPC) chiral stationary phase (CSP). The absolute configuration of each enantiomer of the investigated compounds was established by combined use of chemical correlation, chiral HPLC and circular dichroism (CD) spectra analysis methods. The influence of the mobile-phase modifiers and the structure of chiral triazole compounds on the chiral separation and retention were investigated. Reversal of the elution order of some enantiomeric pairs upon using different mobile-phase modifier was observed. The temperature effect on the chiral separation and the thermodynamic properties including enthalpy and entropy change of binding to the ADMPC-CSP were also investigated. PMID- 21298779 TI - Microwave-assisted extraction and determination of cyanuric acid residue in pet food samples by liquid chromatography-tandem mass spectrometry. AB - Cyanuric acid (CYA) is attracting more attention due to its potential toxicity. In the present work, microwave-assisted extraction method in combination with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was proposed for the determination of CYA in pet food samples. Among different solvents, diethylamine acetonitrile-water mixture (1:5:4, v/v) was found to be the best one as the extractant due to the strong polarity of CYA in the pet food. An internal standard, (13) C(3) -labeled CYA, was used in the extractions. The separation was performed on a MERCK ZIC HILIC column (150 mm * 2.1 mm id, 5 MUm) with gradient elution of 20 mM ammonium acetate solution-acetonitrile. CYA was well retained (Rt = 5.10 min) and eluted with good peak shape. The method could respond linearly with CYA at concentrations from 1.0 to 50 ng/mL with a quantification limit of 0.25 mg/kg. The intra- and inter-day precision was less than 4.0% and the recovery of the assay was in the range of 90.4-108.1%. In the analysis of practical spiked pet food samples, the new method yielded satisfactory results. Due to its simplicity and accuracy the straightforward method is particularly suitable for routine CYA detection. PMID- 21298780 TI - Analytical and semi-preparative HPLC enantioseparation of novel pyridazin-3(2H) one derivatives with alpha-aminophosphonate moiety using immobilized polysaccharide chiral stationary phases. AB - The direct HPLC enantioseparation of a novel series of chiral pyridazin-3(2H)-one derivatives with alpha-aminophosphonate moiety was performed on two immobilized polysaccharide chiral stationary phases (Chiralpak IA, Chiralpak IC) using n hexane (n-Hex)/dichloromethane (DCM) mobile phase with 5% alcohol additive. Good baseline separation of the enantiomers was achieved using amylose tris-(3,5 dimethylphenylcarbamate) chiral stationary phases (Chiralpak IA) on analytical scale. The analytical method was further scaled up to semi-preparative loading to obtain small amounts of both the enantiomers of pyridazin-3(2H)-one derivative. The semi-preparative resolution of all compounds was successfully achieved with n hexane/dichloromethane/ethanol (EtOH) as mobile phase using a semi-preparative Chiralpak IA column. The first fractions were isolated with purities of >99.9% (enantiomeric excess (e.e.), and the second fractions were obtained with purities of >98.2% (enantiomeric excess). The assignment of the absolute configuration was established for the F1 fraction of compound a-2 by single-crystal X-ray diffraction method. PMID- 21298781 TI - Analysis of low molecular weight acids by monolithic immobilized pH gradient based capillary isoelectric focusing coupled with mass spectrometry. AB - A novel method for the separation and detection of low molecular weight (LMW) acids was developed using monolithic immobilized pH gradient-based capillary isoelectric focusing coupled with mass spectrometry. Two main parameters, focusing conditions and delivery buffer conditions, which might affect separation efficiency, were optimized with the focusing time of 7 min at 350 V/cm and the delivery buffer of 50% (v/v) acetonitrile in 10 mmol/L ammonium formate (pH 3.0). Under these conditions, the linear correlation between the volume of delivery solvent and the pK(a) of the model components was observed. In addition, the separation mechanism of LMW acids was proposed as well. We suppose that this method may provide a useful tool for the characterization of LMW components (e.g. natural organic matter of different origins). PMID- 21298782 TI - Application of liquid-liquid-liquid microextraction and high-performance liquid chromatography for the determination of alkylphenols and bisphenol-A in water. AB - A method termed liquid-liquid-liquid microextraction (LLLME) was utilized to extract 4-t-butylphenol, 4-t-octylphenol, 4-n-nonylphenol, and bisphenol-A from water. The extracted target analytes were separated and quantified by high performance liquid chromatography using a fluorescence detector. In LLLME, the donor phase (i.e. water sample) was made weakly acidic by adding monobasic potassium phosphate (KH(2) PO(4)); the organic phase adopted was 4-chlorotoluene; the acceptor phase (i.e. enriched extract) was 0.2 M tetraethylammonium hydroxide dissolved in ethylene glycol. This study solves a problem associated with the surface activity of long-chain alkylphenolate ions, permitting LLLME to extract long-chain alkylphenols. Experimental conditions such as acceptor phase composition, organic phase identity, acceptor phase volume, sample agitation, extraction time, and salt addition were optimized. The relative standard deviation (RSD, 2.0-5.8%), coefficient of determination (r(2) 0.9977-0.9999), and detection limit (0.017-0.0048 ng/mL) of the proposed method were achieved under the selected optimized conditions. The method was successfully applied to analyses of lake and tap water samples, and the relative recoveries of target analytes from the spiked lake and tap water samples were 92.8-106.3 and 93.6 105.6%, respectively. The results obtained with the proposed method confirm this microextraction technique to be reliable for the monitoring of alkylphenols and bisphenol-A in water samples. PMID- 21298783 TI - Optimization of in situ derivatization SPME by experimental design for GC-MS multi-residue analysis of pharmaceutical drugs in wastewater. AB - This paper presents the development of a procedure, which enables the analysis of nine pharmaceutical drugs in wastewater using gas chromatography-mass spectrometry (GC-MS) associated with solid-phase microextraction (SPME) for the sample preparation. Experimental design was applied to optimize the in situ derivatization and the SPME extraction conditions. Ethyl chloroformate (ECF) was employed as derivatizing agent and polydimethylsiloxane-divinylbenzene (PDMS-DVB) as the SPME fiber coating. A fractional factorial design was used to evaluate the main factors for the in situ derivatization and SPME extraction. Thereafter, a Doehlert matrix design was applied to find out the best experimental conditions. The method presented a linear range from 0.5 to 10 MUg/L, and the intraday and interday precision were lower than 16%. Applicability of the method was verified from real influent and effluent samples of a wastewater treatment plant, as well as from samples of an industry wastewater and a river. PMID- 21298784 TI - Determination of marker residue of Olaquindox in fish tissue by ultra performance liquid chromatography-tandem mass spectrometry. AB - Methyl-3-quinoxaline-2-carboxylic acid (MQCA) is the last major remaining detectable metabolite of Olaquindox in animal tissue. A rapid, sensitive and specific ultra performance liquid chromatography-tandem mass spectrometry (UPLC MS/MS) method was developed for the detection and quantification of MQCA in fish tissue using deuterated quinoxaline-2-carboxylic acid (d(4)-QCA) as internal standard. Various parameters affecting sample preparation, LC separation and MS/MS detection were investigated, and the optimal conditions concerned were determined. Fish tissue samples were subject to hydrochloric acid hydrolysis followed by Oasis MAX solid-phase extraction clean-up; analysis was performed using UPLC coupled to electrospray MS/MS. The chromatographic separation was achieved in less than 5 min. The limit of detection and the limit of quantification were 0.1 and 0.25 ng/g, respectively. The average recoveries of MQCA, spiked at levels of 0.25-50.0 ng/g, were from 92.7 to 104.3%. The relative standard deviation values were <6%. The validated method was successfully applied to analyze 60 batch samples collected from the local market. PMID- 21298785 TI - Determination of doripenem and related substances in medicinal product using capillary electrophoresis. AB - Doripenem, the latest carbapenem antibiotic licensed in the United States (15 October 2007) and the European Union (25 July 2008), has been implemented into therapeutic use along with imipenem, meropenem and ertapenem. The described method of zone electrophoresis in a low pH buffer for the separation of doripenem from its impurities has been successfully performed using field-amplified sample stacking (FASS), followed by UV absorption detection at 214 nm. The best results were obtained with phosphate buffer (100 mM) pH 2.9 containing 10% (v/v) of methanol, as the background electrolyte. Uncoated fused-silica capillary (60/52 cm; 75 MUm id) with normal polarity, and voltage values of 25 kV, was used throughout the investigation. The optimised method of doripenem determination was validated in terms of linearity, accuracy and precision, and provides a detection limit of 3.0 MUg/mL of doripenem. The repeatability, expressed by relative standard deviation (RSD) of the migration time, for doripenem and its degradation products varied from 1.37 to 2.51%, whereas the corrected peak areas were about 0.91-9.87%. Satisfactory separation was achieved within 20 min of electrophoresis; moreover, all carbapenems (imipenem, meropenem, ertapenem and doripenem) were well separated from each other during this time. The evaluated CZE method was applied in the analysis of a medicinal product containing doripenem Doribax((r)) powder for solution for infusion. PMID- 21298786 TI - Understanding the improved sensitivity of spectral library searching over sequence database searching in proteomics data analysis. AB - Spectral library searching has been recently proposed as an alternative to sequence database searching for peptide identification from MS/MS. We performed a systematic comparison between spectral library searching and sequence database searching using a wide variety of data to better demonstrate, and understand, the superior sensitivity of the former observed in preliminary studies. By decoupling the effect of search space, we demonstrated that the success of spectral library searching is primarily attributable to the use of real library spectra for matching, without which the sensitivity advantage largely disappears. We further determined the extent to which the use of real peak intensities and non-canonical fragments, both under-utilized information in sequence database searching, contributes to the sensitivity advantage. Lastly, we showed that spectral library searching is disproportionately more successful in identifying low-quality spectra, and complex spectra of higher- charged precursors, both important frontiers in peptide sequencing. Our results answered important outstanding questions about this promising yet unproven method using well-controlled computational experiments and sound statistical approaches. PMID- 21298787 TI - Generic workflow for quality assessment of quantitative label-free LC-MS analysis. AB - As high-resolution instruments are becoming standard in proteomics laboratories, label-free quantification using precursor measurements is becoming a viable option, and is consequently rapidly gaining popularity. Several software solutions have been presented for label-free analysis, but to our knowledge no conclusive studies regarding the sensitivity and reliability of each step of the analysis procedure has been described. Here, we use real complex samples to assess the reliability of label-free quantification using four different software solutions. A generic approach to quality test quantitative label-free LC-MS is introduced. Measures for evaluation are defined for feature detection, alignment and quantification. All steps of the analysis could be considered adequately performed by the utilized software solutions, although differences and possibilities for improvement could be identified. The described method provides an effective testing procedure, which can help the user to quickly pinpoint where in the workflow changes are needed. PMID- 21298788 TI - A stringent approach to improve the quality of nitrotyrosine peptide identifications. AB - Tyrosine nitration is the consequence of a complex machinery of formation and merging of oxygen and nitrogen radicals, and has been associated with both physiological pathways as well as with several human diseases. The latter turned this posttranslational protein modification into an interesting biomarker, being either a consequence of the disease or a factor contributing to the disease onset. However, the interpretation of MS and MS/MS data of peptides containing nitrotyrosine has proven to be very challenging and consequently, the risk of linking MS/MS spectra to incorrect peptide sequences exists and has been reported. Here, we discuss the causes of data misinterpretation and describe a general method to avoid mistakes of MS/MS spectrum misinterpretation. Central in our approach is the reduction of nitrotyrosine into aminotyrosine and the use of the Peptizer algorithm to inspect MS/MS quality-related assumptions. PMID- 21298789 TI - The good, the bad, the ugly: validating the mass spectrometric analysis of modified peptides. AB - Mass spectrometric characterization of protein modifications is usually based on single peptides. With the advent of large-scale PTM-focussed MS studies, vast amounts of data are generated continuously, providing biologists extremely valuable and virtually never-ending sources for targeted functional research. However, even more than for proteomics in general, appropriate strategies for quality control of the different steps of the analytical strategy are imperative to prevent functional researchers from doing Sisyphos work on false-positive and unconfident PTM assignments. Here, we describe strategies to address the important issue of quality control for PTM analysis on various levels of the analytical pipeline: sample preparation/processing, analysis/identification and finally data interpretation, for qualitative as well as quantitative studies. PMID- 21298790 TI - Simulating and validating proteomics data and search results. AB - The computational simulation of complete proteomic data sets and their utility to validate detection and interpretation algorithms, to aid in the design of experiments and to assess protein and peptide false discovery rates is presented. The simulation software has been developed for emulating data originating from data-dependent and data-independent LC-MS workflows. Data from all types of commonly used hybrid mass spectrometers can be simulated. The algorithms are based on empirically derived physicochemical liquid and gas phase models for proteins and peptides. Sample composition in terms of complexity and dynamic range, as well as chromatographic, experimental and MS conditions, can be controlled and adjusted independently. The effect of on-column amounts, gradient length, mass resolution and ion mobility on search specificity will be demonstrated using tryptic peptides from human and yeast cellular lysates simulated over five orders of magnitude in dynamic range. Initial justification of the simulated data sets is achieved by comparing and contrasting the in silico simulated data to experimentally derived results from a 48 protein mixture, spanning a similar magnitude of five orders of magnitude. Additionally, experimental data from replicate and dilutions series experiments will be utilized to determine error rates at the peptide and protein level with respect to mass, area, retention and drift time. The data presented reveal a high degree of similarity at the ion detection, peptide and protein level when analyzed under similar conditions. PMID- 21298791 TI - A reproducibility-based evaluation procedure for quantifying the differences between MS/MS peak intensity normalization methods. AB - The identification of peptides and proteins from fragmentation mass spectra is a very common approach in the field of proteomics. Contemporary high-throughput peptide identification pipelines can quickly produce large quantities of MS/MS data that contain valuable knowledge about the actual physicochemical processes involved in the peptide fragmentation process, which can be extracted through extensive data mining studies. As these studies attempt to exploit the intensity information contained in the MS/MS spectra, a critical step required for a meaningful comparison of this information between MS/MS spectra is peak intensity normalization. We here describe a procedure for quantifying the efficiency of different published normalization methods in terms of the quartile coefficient of dispersion (qcod) statistic. The quartile coefficient of dispersion is applied to measure the dispersion of the peak intensities between redundant MS/MS spectra, allowing the quantification of the differences in computed peak intensity reproducibility between the different normalization methods. We demonstrate that our results are independent of the data set used in the evaluation procedure, allowing us to provide generic guidance on the choice of normalization method to apply in a certain MS/MS pipeline application. PMID- 21298792 TI - Statistical issues in quality control of proteomic analyses: good experimental design and planning. AB - Quality control is becoming increasingly important in proteomic investigations as experiments become more multivariate and quantitative. Quality control applies to all stages of an investigation and statistics can play a key role. In this review, the role of statistical ideas in the design and planning of an investigation is described. This involves the design of unbiased experiments using key concepts from statistical experimental design, the understanding of the biological and analytical variation in a system using variance components analysis and the determination of a required sample size to perform a statistically powerful investigation. These concepts are described through simple examples and an example data set from a 2-D DIGE pilot experiment. Each of these concepts can prove useful in producing better and more reproducible data. PMID- 21298793 TI - COMPASS: a suite of pre- and post-search proteomics software tools for OMSSA. AB - Here we present the Coon OMSSA Proteomic Analysis Software Suite (COMPASS): a free and open-source software pipeline for high-throughput analysis of proteomics data, designed around the Open Mass Spectrometry Search Algorithm. We detail a synergistic set of tools for protein database generation, spectral reduction, peptide false discovery rate analysis, peptide quantitation via isobaric labeling, protein parsimony and protein false discovery rate analysis, and protein quantitation. We strive for maximum ease of use, utilizing graphical user interfaces and working with data files in the original instrument vendor format. Results are stored in plain text comma-separated value files, which are easy to view and manipulate with a text editor or spreadsheet program. We illustrate the operation and efficacy of COMPASS through the use of two LC-MS/MS data sets. The first is a data set of a highly annotated mixture of standard proteins and manually validated contaminants that exhibits the identification workflow. The second is a data set of yeast peptides, labeled with isobaric stable isotope tags and mixed in known ratios, to demonstrate the quantitative workflow. For these two data sets, COMPASS performs equivalently or better than the current de facto standard, the Trans-Proteomic Pipeline. PMID- 21298797 TI - Editorial: Micro and nanofluidics - applications in biotechnology. PMID- 21298800 TI - Miniaturized lensless imaging systems for cell and microorganism visualization in point-of-care testing. AB - Low-cost, robust, and user-friendly diagnostic capabilities at the point-of-care (POC) are critical for treating infectious diseases and preventing their spread in developing countries. Recent advances in micro- and nanoscale technologies have enabled the merger of optical and fluidic technologies (optofluidics) paving the way for cost-effective lensless imaging and diagnosis for POC testing in resource-limited settings. Applications of the emerging lensless imaging technologies include detecting and counting cells of interest, which allows rapid and affordable diagnostic decisions. This review presents the advances in lensless imaging and diagnostic systems, and their potential clinical applications in developing countries. The emerging technologies are reviewed from a POC perspective considering cost effectiveness, portability, sensitivity, throughput and ease of use for resource-limited settings. PMID- 21298801 TI - Deep wells integrated with microfluidic valves for stable docking and storage of cells. AB - In this paper, we describe a microfluidic mechanism that combines microfluidic valves and deep wells for cell localization and storage. Cells are first introduced into the device via externally controlled flow. Activating on-chip valves was used to interrupt the flow and to sediment the cells floating above the wells. Thus, valves could be used to localize the cells in the desired locations. We quantified the effect of valves in the cell storage process by comparing the total number of cells stored with and without valve activation. We hypothesized that in deep wells external flows generate low shear stress regions that enable stable, long-term docking of cells. To assess this hypothesis we conducted numerical calculations to understand the influence of well depth on the forces acting on cells. We verified those predictions experimentally by comparing the fraction of stored cells as a function of the well depth and input flow rate upon activation of the valves. As expected, upon reintroduction of the flow the cells in the deep wells were not moved whereas those in shallow wells were washed away. Taken together, our paper demonstrates that deep wells and valves can be combined to enable a broad range of cell studies. PMID- 21298802 TI - Picoliter DNA sequencing chemistry on an electrowetting-based digital microfluidic platform. AB - The results of investigations into performing DNA sequencing chemistry on a picoliter-scale electrowetting digital microfluidic platform are reported. Pyrosequencing utilizes pyrophosphate produced during nucleotide base addition to initiate a process ending with detection through a chemiluminescence reaction using firefly luciferase. The intensity of light produced during the reaction can be quantified to determine the number of bases added to the DNA strand. The logic based control and discrete fluid droplets of a digital microfluidic device lend themselves well to the pyrosequencing process. Bead-bound DNA is magnetically held in a single location, and wash or reagent droplets added or split from it to circumvent product dilution. Here we discuss the dispensing, control, and magnetic manipulation of the paramagnetic beads used to hold target DNA. We also demonstrate and characterize the picoliter-scale reaction of luciferase with adenosine triphosphate to represent the detection steps of pyrosequencing and all necessary alterations for working on this scale. PMID- 21298803 TI - Plastic microfluidic chip for continuous-flow polymerase chain reaction: simulations and experiments. AB - A continuous flow polymerase chain reaction (CF-PCR) device comprises a single fluidic channel that is heated differentially to create spatial temperature variations such that a sample flowing through it experiences the thermal cycling required to induce amplification. This type of device can provide an effective means to detect the presence of a small amount of nucleic acid in very small sample volumes. CF-PCR is attractive for global health applications due to its less stringent requirements for temperature control than for other designs. For mass production of inexpensive CF-PCR devices, fabrication via thermoplastic molding will likely be necessary. Here we study the optimization of a PCR assay in a polymeric CF-PCR device. Three channel designs, with varying residence time ratios for the three PCR steps (denaturation, annealing, and extension), were modeled, built, and tested. A standardized assay was run on the three different chips, and the PCR yields were compared. The temperature gradient profiles of the three designs and the residence times of simulated DNA molecules flowing through each temperature zone were predicted using computational methods. PCR performance predicted by simulation corresponded to experimental results. The effects of DNA template size and cycle time on PCR yield were also studied. The experiments and simulations presented here guided the CF-PCR chip design and provide a model for predicting the performance of new CF-PCR designs prior to actual chip manufacture, resulting in faster turn around time for new device and assay design. Taken together, this framework of combined simulation and experimental development has greatly reduced assay development time for CF-PCR in our lab. PMID- 21298804 TI - Elastic phantoms generated by microfluidics technology: validation of an imaged based approach for accurate measurement of the growth rate of lung nodules. AB - This paper focuses on validating our approach for monitoring the development of lung nodules detected in successive chest low-dose computed tomography (LDCT) scans of a patient. Our methodology for monitoring detected lung nodules includes 3D LDCT data registration, which is a non-rigid technique and involves two steps: (i) global target-to-prototype alignment of one scan to another using the experience gained from a prior appearance model, followed by (ii) local alignment to correct for intricate relative deformations. We propose a new approach for validating the accuracy of our algorithm for elastic lung phantoms constructed with state-of-the-art microfluidics technology and in vivo data. Fabricated from a flexible transparent polymer, i.e. polydimethylsiloxane (PDMS), the phantoms mimic the contractions and expansions of the lung and nodules as seen during normal breathing. The in vivo data in our study had been collected from a small control group of four subjects and a larger test group of 27 subjects with known ground truth (biopsy diagnosis. The growth rate and diagnostic results for both phantoms and in vivo data confirm the high accuracy of our algorithm. PMID- 21298805 TI - A three-dimensional in vitro ovarian cancer coculture model using a high throughput cell patterning platform. AB - In vitro 3D cancer models that provide a more accurate representation of disease in vivo are urgently needed to improve our understanding of cancer pathology and to develop better cancer therapies. However, development of 3D models that are based on manual ejection of cells from micropipettes suffer from inherent limitations such as poor control over cell density, limited repeatability, low throughput, and, in the case of coculture models, lack of reproducible control over spatial distance between cell types (e.g., cancer and stromal cells). In this study, we build on a recently introduced 3D model in which human ovarian cancer (OVCAR-5) cells overlaid on MatrigelTM spontaneously form multicellular acini. We introduce a high-throughput automated cell printing system to bioprint a 3D coculture model using cancer cells and normal fi broblasts micropatterned on MatrigelTM . Two cell types were patterned within a spatially controlled microenvironment (e.g., cell density, cell-cell distance) in a high-throughput and reproducible manner; both cell types remained viable during printing and continued to proliferate following patterning. This approach enables the miniaturization of an established macro-scale 3D culture model and would allow systematic investigation into the multiple unknown regulatory feedback mechanisms between tumor and stromal cells and provide a tool for high-throughput drug screening. PMID- 21298806 TI - Atomic layer deposition of titanium dioxide on cellulose acetate for enhanced hemostasis. AB - TiO2 films may be used to alter the wettability and hemocompatibility of cellulose materials. In this study, pure and stoichiometric TiO2 films were grown using atomic layer deposition on both silicon and cellulose substrates. The films were grown with uniform thicknesses and with a growth rate in agreement with literature results. The TiO2 films were shown to profoundly alter the water contact angle values of cellulose in a manner dependent upon processing characteristics. Higher amounts of protein adsorption indicated by blurry areas on images generated by scanning electron microscopy were noted on TiO2 -coated cellulose acetate than on uncoated cellulose acetate. These results suggest that atomic layer deposition is an appropriate method for improving the biological properties of hemostatic agents and other blood-contacting biomaterials. PMID- 21298808 TI - Bovine lactoperoxidase - a versatile one- and two-electron catalyst of high structural and thermal stability. AB - Lactoperoxidase (LPO), a member of the peroxidase-cyclooxygenase superfamily, is found in multiple human exocrine secretions and acts as a first line of defense against invading microorganisms by production of antimicrobial oxidants. Because of its ability to efficiently catalyze one- and two-electron oxidation reactions of inorganic and organic compounds, the heme peroxidase is widely used in food biotechnology, cosmetic industry, and diagnostic kits. In order to probe its structural integrity, conformational, and thermal stability, we have undertaken a comprehensive investigation by using complementary biophysical techniques including UV-Vis, circular dichroism and fluorescence spectroscopy as well as differential scanning calorimetry (DSC). The oxidoreductase exhibits a high chemical and thermal stability under oxidizing conditions but is significantly destabilized by addition of DTT. Due to its unique ester bonds between the prosthetic group and the protein as well as six intra-chain disulfides, unfolding of the central compact (-helical core occurs concomitantly with denaturation of the heme cavity. The corresponding enthalpic and entropic contributions to the free enthalpy of unfolding are presented. Together with spectroscopic data they will be discussed with respect to the known structure of bovine LPO and homologous myeloperoxidase as well as to its practical application. PMID- 21298807 TI - In situ generation of hydrogen peroxide by carbohydrate oxidase and cellobiose dehydrogenase for bleaching purposes. AB - The carbohydrate oxidase from Microdochium nivale (CAOX), heterologously expressed in Aspergillus oryzae, and cellobiose dehydrogenase from Myriococcum thermophilum (MtCDH), were assessed for their ability to generate bleaching species at a pH suitable for liquid detergents. The substrate specificities of CAOX and MtCDH were analyzed on a large variety of soluble and insoluble substrates, using oxygen as an electron receptor. Even insoluble substrates like cellulose were oxidized from both CAOX and MtCDH, but only MtCDH produced H2O2 on cotton as the sole substrate. To enhance the amount of cello-oligosaccharides formed from cotton as substrates for CAOX and MtCDH, various cellulases were used in combination with MtCDH or CAOX, leading to a 10-fold increase in H2O2. As model substrates for colored stains, the degradation of pure anthocyanins and stain removal of blueberry stains by CAOX and MtCDH was examined in the absence and presence of a horseradish peroxidase. Both enzymes were able to produce an amount of H2O2 sufficient to decolorize the pure anthocyanins within 2 h and showed significant cleaning benefits on the stains. PMID- 21298809 TI - Chitin deacetylase product inhibition. AB - Chitin deacetylase is the only known enzyme catalyzing the hydrolysis of the acetamino linkage in the N-acetylglucosamine units of chitin and chitosan. This reaction can play an important role in enzymatic production of chitosan from chitin, or in enzymatic modification of chitosan, which has applications in medicine, pharmacy or plant protection. It was previously shown that acetic acid, a product of the deacetylation process, may act as an inhibitor of chitin deacetylase. Here we show the mechanism of inhibition of chitin deacetylase isolated from Absidia orchidis vel coerulea by acetic acid released during the deacetylation process. The process follows competitive inhibition with respect to acetic acid with an inhibition constant of K(i) = 0.286 mmol/L. These results will help to find the optimal system to carry out the enzymatic deacetylation process for industrial applications. PMID- 21298810 TI - Metabolic engineering of Corynebacterium glutamicum for production of 1,5 diaminopentane from hemicellulose. AB - In the present work, the bio-based production of 1,5-diaminopentane (cadaverine), an important building block for bio-polyamides, was extended to hemicellulose a non-food raw material. For this purpose, the metabolism of 1,5-diaminopentane producing Corynebacterium glutamicum was engineered to the use of the C(5) sugar xylose. This was realized by heterologous expression of the xylA and xylB genes from Escherichia coli, mediating the conversion of xylose into xylulose 5 phosphate (an intermediate of the pentose phosphate pathway), in a defined diaminopentane-producing C. glutamicum strain, recently obtained by systems metabolic engineering. The created mutant, C. glutamicum DAP-Xyl1, exhibited efficient production of the diamine from xylose and from mixtures of xylose and glucose. Subsequently, the novel strain was tested on industrially relevant hemicellulose fractions, mainly containing xylose and glucose as carbon source. A two-step process was developed, comprising (i) enzymatic hydrolysis of hemicellulose from dried oat spelts, and (ii) biotechnological 1,5-diaminopentane production from the obtained hydrolysates with the novel C. glutamicum strain. This now opens a future avenue towards bio-based 1,5-diaminopentane and bio polyamides thereof from non-food raw materials. PMID- 21298811 TI - Design and synthesis of Raman reporter molecules for tissue imaging by immuno SERS microscopy. AB - The design and synthesis of Raman reporter molecules comprising olefin or alkyne moieties with strong and characteristic vibrational Raman bands is presented. Chemisorption onto the surface of colloidal Au/Ag shells yields a self-assembled monolayer. Hydrophilic stabilization of such SERS labels can be achieved by short terminal ethylene glycol units attached to the Raman reporter. Encapsulation by silica with subsequent functionalization of the glass surface allows the conjugation to biomolecules such as antibodies. We demonstrate the use of SERS labeled antibodies for tissue imaging of the tumor suppressor p63 in prostate biopsies. PMID- 21298812 TI - Toward specifying pervasive developmental disorder-not otherwise specified. AB - Pervasive developmental disorder-not otherwise specified (PDD-NOS) is the most common and least satisfactory of the PDD diagnoses. It is not formally operationalized, which limits its reliability and has hampered attempts to assess its validity. We aimed, first, to improve the reliability and replicability of PDD-NOS by operationalizing its DSM-IV-TR description and, second, to test its validity through comparison with autistic disorder (AD) and Asperger's disorder (AsD). In a sample of 256 young people (mean age = 9.1 years) we used Developmental, Diagnostic and Dimensional (3Di) algorithmic analysis to classify DSM-IV-TR AD (n = 97), AsD (n = 93) and PDD-NOS (n = 66). Groups were compared on independent measures of core PDD symptomatology, associated autistic features, and intelligence. Contrary to the assumption that PDD-NOS is heterogeneous, almost all (97%) of those with PDD-NOS had one distinct symptom pattern, namely impairments in social reciprocity and communication, without significant repetitive and stereotyped behaviors (RSB). Compared to AD and AsD, they had comparably severe but more circumscribed social communication difficulties, with fewer non-social features of autism, such as sensory, feeding and visuo-spatial problems. These individuals appear to have a distinct variant of autism that does not merely sit at the less severe end of the same continuum of symptoms. The current draft guidelines for DSM-V, which mandate the presence of RSBs for any PDD diagnosis, would exclude such people from the autistic spectrum. PMID- 21298813 TI - Mass spectral analyses of the two major apolipoproteins of great ape high density lipoproteins. AB - The two major apolipoproteins associated with human and chimpanzee (Pan troglodytes) high density lipoproteins (HDL) are apoA-I and dimeric apoA-II. Although humans are closely related to great apes, apolipoprotein data do not exist for bonobos (Pan paniscus), western lowland gorillas (Gorilla gorilla gorilla) and the Sumatran orangutans (Pongo abelii). In the absence of any data, other great apes simply have been assumed to have dimeric apoA-II while other primates and most other mammals have been shown to have monomeric apoA-II. Using mass spectrometry, we have measured the molecular masses of apoA-I and apoA-II associated with the HDL of these great apes. Each was observed to have dimeric apoA-II. Being phylogenetically related, one would anticipate these apolipoproteins having a high percentage of invariant sequences when compared with human apolipoproteins. However, the orangutan, which diverged from the human lineage between 16 and 21 million years ago, had an apoA-II with the lowest monomeric mass, 8031.3 Da and the highest apoA-I value, 28,311.7 Da, currently reported for various mammals. Interestingly, the gorilla that diverged from the lineage leading to the human-chimpanzee branch after the orangutan had almost identical mass values to those reported for human apoA-I and apoA-II. But chimpanzee and the bonobo that diverged more recently had identical apoA-II mass values that were slightly larger than reported for the human apolipoprotein. The chimpanzee A-I mass values were very close to those of humans; however, the bonobo had values intermediate to the molecular masses of orangutan and the other great apes. With the already existing genomic data for chimpanzee and the recent entries for the orangutan and gorilla, we were able to demonstrate a close agreement between our mass spectral data and the calculated molecular weights determined from the predicted primary sequences of the respective apolipoproteins. Post-translational modification of these apolipoproteins, involving truncation and oxidation of methionine, are also reported. PMID- 21298814 TI - Topical tacrolimus and pimecrolimus: cancer, infections. PMID- 21298815 TI - [All drugs banned soon allowed? (1)]. PMID- 21298816 TI - [Prasugrel--oral (Efient)]. PMID- 21298817 TI - [Laptop on the lap. Testicle heater]. PMID- 21298818 TI - PneumococcaL meningitis in french children before and after the introduction of pneumococcal conjugate vaccine. AB - In France, despite a high rate of pneumococcal conjugate vaccine coverage, the number of cases of pneumococcal meningitis in children did not decline significantly between 2001-2002 (n = 264) and 2007-2008 (n = 244). A decline was observed among children < 2 years old (185 [70.1%] to 134 [54.9%] cases; P = 0.0004), but was counterbalanced by an increase among children >= 2 years old (79 [29.9%] to 110 [45.1%] cases). Mean age increased significantly, from 2.3 (median 0.8) to 3.8 (median 1.5) years. After pneumococcal conjugate vaccine 7 implementation, a wide diversity of serotypes implicated in pneumococcalmeningitis was observed; serotypes 19A and 7F were the most frequent. PMID- 21298819 TI - Microvascular obstruction after infarct reperfusion What does it really mean and what should we do about it? PMID- 21298820 TI - Proceedings of the 14th International Workshop on Quantitative Structure-Activity Relationships in Environmental and Health Sciences (QSAR2010). Montreal, Canada. May 24-28, 2010. PMID- 21298821 TI - Left pulmonary artery agenesis: fortuitous discovery in adulthood. PMID- 21298822 TI - Clinicopathologic features as stronger prognostic factors than histology or grade in risk stratification of primary parotid malignancies. AB - BACKGROUND: The aim of this study, using a retrospective chart review as the primary study design, was to determine the relative contribution of clinicopathologic risk factors versus low- and high-risk grade histologic groups to assist management of primary parotid cancers. METHODS: In all, 168 primary parotid malignancies were treated surgically at a tertiary care center from 1982 to 2005. Of these, 115 patients with complete follow-up information were further analyzed. Pathologic updating and reclassification in 28% of cases enabled comparison of tumor histology or grade with current consensus criteria. Clinical outcomes of high- and low-risk histology and grade were compared with the influence of traditional clinicopathologic risk factors. RESULTS: Of 115 cases, the male:female ratio was equal and the median age was 63 years (range, 15 to 89 years). Mucoepidermoid carcinoma (n = 28) was the most common histology. The median follow-up was 44 months (range, 0-278 months). Of low-risk histology patients who underwent neck dissection 40% had pN+ disease. The median time to recurrence was not reached for low-risk tumors, compared with 29 months for high risk tumors (p = .0001). Interestingly, extracapsular spread (ECS) and margin status were independent prognostic factors and conferred significantly greater prognostic value than histologic grade risk group. Disease-free survival (DFS) and overall survival (OS) at 5 years for the entire cohort were 51% and 57%, respectively. Risk group was a strong independent predictor of OS but not DFS. CONCLUSIONS: Risk group defined by histology and grade was associated with DFS. ECS and margin status were independent predictors of DFS. Inclusion of ECS and margin status substantially improved the prediction of disease recurrence, supporting elective neck dissection and postoperative radiotherapy for high-grade tumors or low-risk histologies with positive margins or ECS. PMID- 21298823 TI - Guest editorial: Special focus on bioinformatics and systems biology. PMID- 21298824 TI - Papers from the 13th International Symposium of the International Society for Neonatal Screening (ISNS )and the 7th International Congress of the Latin- American Society of Inborn Error of Metabolism and Neonatal Screening (SLEIMPN). Cancun, Mexico. December 2009. PMID- 21298825 TI - First food: the essential role of breastfeeding. Proceedings of the Second Annual Summit on Breastfeeding. June 16-17, 2010. Washington, DC, USA. PMID- 21298826 TI - Personalized neonatal medicine. Proceedings of the 6th International Workshop on Neonatology. Cagliari, Italy. October 28-29, 2010. PMID- 21298827 TI - The effects of bacterial resistance on human and animal health. PMID- 21298828 TI - Proceedings of the 2010 Acta Oncologica Symposium. Aarhus, Denmark. May 26-28, 2010. PMID- 21298829 TI - Frequency and clinical course of invasive pneumococcal disease caused by penicillin-resistant and penicillin-sensitive Streptococcus pneumoniae in Thai children. AB - OBJECTIVE: This study assessed clinical differences between invasive pneumococcal disease (IPD) caused by penicillin-resistant and penicillin-sensitive Streptococcus pneumoniae. MATERIAL AND METHOD: Patients with IPD confirmed during January 1996-December 2007 at three hospitals were included. Clinical characteristics and outcomes were compared between patients infected with penicillin-resistant Streptococcus pneumoniae (PRSP) and penicillin-sensitive Streptococcus pneumoniae (PSSP). RESULTS: Sixty-nine patients with IPD were identified during the study period, 20 (29%) of whom were infected with PRSP and 49 (71%) with PSSP. Sex, mean age, underlying diseases and seasonal variation did not differ statistically between the two groups. No significant differences were identified in clinical course as measured by time until defervescence, duration of hospitalization and clinical outcome. Minimum inhibitory concentrations (MIC) for other antibiotics were determined; 20% and 10% of PRSP isolates were nonsusceptible to cephalosporins and meropenem, respectively, but all isolates were sensitive to vancomycin. CONCLUSION: There were no significant differences identified in the clinical epidemiology of lPD cases caused by PRSP and PSSP. PMID- 21298830 TI - Invasive pneumococcal infection in urban Thai children: a 10-year review. AB - OBJECTIVE: To determine the disease frequency, demographic characteristics, clinical manifestations, laboratory findings and drug susceptibility patterns of childhood invasive pneumococcal infections in a hospital setting in Thailand. MATERIAL AND METHOD: A retrospective review was conducted of invasive pneumococcal infections among children aged < 18 years from January 1, 1998 - December 31, 2007 at the Queen Sirikit National Institute of Child Health (QSNICH). Medical records of case-patients were reviewed to collect information on demographics, clinical manifestations, laboratory findings, and drug susceptibility patterns of infecting isolates. RESULTS: Among the 745,983 children receiving care at QSNICH during the study period, culture-proven invasive pneumococcal infections were identified in 126 patients for an estimated incidence of 17 cases per 100,000 patients. Patient diagnoses included bacteremia (59.4%), meningitis (29.3%), and pneumonia (11.3%). Of the 31 pneumococcal meningitis cases, 54.8% were caused by penicillin-nonsusceptible S. pneumoniae (PNSSP), while 25.3% of 75 non-meningitis cases were PNSSP (records not available for the remaining 20 cases). Of 126 PNSSP, 8.2% were resistant to cefotaxime and 12.3% were resistant to ceftriaxone. All of the isolates were susceptible to vancomycin. The case fatality rate was 12.3%; 23.1% offatal cases were associated with HIV infection. Outcomes did not differ significantly between patients infected with penicillin-susceptible and non-susceptible pneumococcal strains. CONCLUSION: The results of this hospital-based study indicate that the incidence of invasive pneumococcal infection in QSNICH remains relatively low, but the case fatality rate is high, especially among those with HIV infection. PMID- 21298831 TI - The heptavalent pneumococcal conjugate vaccine immunization project by Bangkok Metropolitan in Thai infants. AB - BACKGROUND: Streptococcus pneumoniae is the most common cause of bacteremia, sepsis, meningitis, pneumonia, sinusitis and otitis media in children worldwide. Several studies have shown that the heptavalent pneumococcal conjugate vaccine (PCV7) is highly immunogenic, safe and effective against disease caused by serotypes contained in the vaccine. OBJECTIVE: To determine the safety and efficacy of PCV7 administered to Thai infants. MATERIAL AND METHOD: Ninety-seven infants received four doses of PCV7. Three primary doses were given 2 months apart starting at the age of 2-6 months and the booster dose at the age of 12-15 months. Reactogenicity and safety were evaluated from parent reports. The impact of PCV7 on the occurrence of invasive pneumococcal disease (IPD) among vaccinees was examined. RESULTS: PCV7 was well tolerated. Two infants reported low-grade fever. None of the vaccinees developed IPD during the 1-year period following the first PCV7 dose. CONCLUSION: Primary immunization followed by a booster dose of PCV7 appeared safe and efficactive in preventing IPD in Thai children. PMID- 21298832 TI - Fluoroquinolone resistance in Streptococcus pneumoniae from a university hospital, Thailand. AB - The most frequent markers of fluoroquinolone resistance in S. pneumoniae are chromosomal mutations in the quinolone-resistance-determining regions of DNA gyrase and topoisomerase IV encoding for the gyrA, gyrB and parC, parE genes. In 2008, 6.5% of the Streptococcus pneumoniae isolates in a Bangkok university hospital were resistant to ofloxacin. Using PCR and DNA sequencing, we identified mutations in both the gyrA and parC genes of four ofloxacin- and ciprofloxacin resistant S. pneumoniae isolates (minimum inhibitory concentrations > 32 microg/ml). Mutations were found in the gyrA gene at positions Ser81Phe, Glu85Gly, Glu85Lys and in the parC gene at position Ser79Tyr. Three isolates had mutations in both genes. Two of the isolates were serotype 6B and two were serotypes not contained in currently licensed pneumococcal vaccines. This is the first report of the mechanisms of fluoroquinolone resistance in S. pneumoniae in Thailand. PMID- 21298833 TI - Detection of bacterial antigen in cerebrospinal fluid in patients with bacterial meningitis: a literature review. AB - Rapid detection of bacterial pathogen causing meningitis is very important to guide antimicrobial therapy before the standard culture result is available. Other than gram stain, one of the most useful rapid methods is the detection of bacterial antigen in cerebrospinal fluid. This article reviewed the methods of bacterial antigen detection for diagnosis of meningitis as well as a microbiology aspect of this life-threatening disease. PMID- 21298834 TI - Anti-inflammatory, anti-nociceptive and antipyretic effects of the ethanol extract from root of Piper sarmentosum Roxb. AB - BACKGROUND: Piper sarmentosum Roxb. (Cha Phul) is a plant in the Piperaceae family which the whole plant is used as an expectorant and the leaf as a carminative. Many extracts from the plants in this family show anti-nociceptive, anti-inflammatory and antipyretic activities in various animal models. OBJECTIVE: To investigate the anti-inflammatory, anti-nociceptive and antipyretic effects of the ethanol extract from P. sarmentosum root. MATERIAL AND METHOD: In vivo study. RESULTS: P. sarmentosum extract significantly inhibited ethyl phenylpropiolate induced ear edema as well as carrageenan-induced hind paw edema in rats. The extract reduced transudative and granuloma weights of the chronic inflammatory model using the cotton pellet-induced granuloma formation in rats. The extract exerted a pronounced inhibitory activity on the early phase and late phase of the formalin test in mice. In addition, the extract elicited an antipyretic activity on yeast-induced hyperthermia in rats. CONCLUSION: P. sarmentosum extract possessed anti-inflammatory, anti-nociceptive and antipyretic activities. PMID- 21298835 TI - Effectiveness of packed rice-oral rehydration solution among children with acute watery diarrhea. AB - OBJECTIVE: This study aims to compare the effectiveness between the packed rice oral rehydration solution (R-ORS) and the glucose-based oral rehydration solution (G-ORS) in children with acute watery diarrhea. MATERIAL AND METHOD: Randomized control trial was conducted to compare duration of diarrhea, stool frequency, incremental weight gain, intravenous fluid requirement, and duration of admission. Subjects were 70 pediatric patients (9-60 months-old) and were equally divided into two groups (n=35 for each): treatment group (with R-ORS treatment) and control group (with G-ORS treatment). The data were collected during January 1, 2007 to January 2008. All patients were treated with oral rehydration therapy within first 4 hours of admission. Intravenous rehydration was also scheduled. Both groups were fed with rice gruel or lactose-free formula as tolerated. RESULTS: Using survival analysis, both duration of diarrhea and admission was significantly shortened in the treatment group compared to the control group. (27.5 hrs. vs. 40.5 hrs: p = 0.01 and 40.1 hrs. vs. 56.0 hrs: p = 0.02 respectively). However, stool frequency, incremental weight gain and intravenous fluid requirement between the two groups remained insignificantly different. CONCLUSION: R-ORS was more effective in the management of acute watery diarrhea in children. Duration of diarrhea and treatment was shortened when compared to G ORS. PMID- 21298836 TI - Fractional photothermolysis for the treatment of facial wrinkle in Asians. AB - BACKGROUND: Fractional photothermolysis is a novel aesthetic-laser-surgical modality for the treatment of facial wrinkle in Caucasians apart from other conventional treatments. However there are limited reports regarding the effectiveness and side effects of this treatment in Asians' skin. OBJECTIVE: To evaluate the effectiveness and side effects of 1550 nm Erbium fiber Laser as a treatment for facial wrinkle in Asians'skin (Fitzpatrick's skin type III-V). MATERIAL AND METHOD: Twenty patients with mild to moderate facial wrinkle were included in the study. Half of the forehead in each patient was randomized to receive the treatment and the other half served as control. The treatment was done with FINE SCAN 1550 (TNC SPECTRONICS, Bangkok, Thailand), 1550 nm Erbium fiber laser once a week for 8 successive treatments. Photographs had been taken by VISIA at 0, 4 weeks and 12 weeks after the treatment and were evaluated by three experienced dermatologists using a quartile grading scale. Patient satisfaction score and side effects during each treatment were also recorded. RESULTS: At 4 weeks after the treatment, mean wrinkle, dyspigmentation, irregularities and the overall improvement scores were 0.35, 0.10, 0.20 and 0.50 respectively. At 12 weeks post treatment, the score decreased to 0.20, 0.05, 0.10 and 0.20. All of the improvement scores were significantly higher (p < 0.05) in the treatment group than the control group except for the dyspigmentation improvement score. Patients' satisfaction score was graded as 2 (good) in 35% (7/20) of the patients. Side effects included transient erythema and edema which were mild and self-limited. Mean pain score using visual analog scale was 1.32. No serious side effect was observed. CONCLUSION: Fractional photothermolysis with 1550 nm Erbium fiber Laser is one of the effective treatments for facial wrinkle. However; the improvement score decreased with time. Side effects are few and tolerable, even in patients with Fitzpatrick's skin type III-V PMID- 21298837 TI - Biopsychosocial predictors of health-related quality of life in children with thalassemia in Thammasat University Hospital. AB - OBJECTIVES: To determine health-related quality of life (HRQOL) in children with thalassemia in order to explore physical and psychosocial factors affecting on their QOL. MATERIAL AND METHOD: A cross-sectional study was conducted at Thammasat University Hospital, Pathum Thani. Sociodemographic factors and clinical characteristics were obtained from seventy-five of transfusion-dependent and non-transfused thalassemia patients. The PedsQL 4.0 Generic Core Scales (Thai version) were administered to determine the patients and their parents' perspectives. RESULTS: The mean (SD) of total HRQOL score was 78.50 (2.05) for children who were self-reporting and it was 73.41 (2.22) for parent proxy-report, that were comparable with population norms. The stepwise multiple regression analysis indicated that total HRQOL score of child self-report was negatively predicted by lower family income, early age onset of anemia before 2 years and under covered by Universal Health Coverage Scheme. The negative predictors of total HRQOL score of parent proxy-report were regular transfusion every 1-2 months, while self medical payment was positively predictive. CONCLUSION: The HRQOL in children with thalassemia was not only determined by disease severity and treatment but also by family financial impacts for caring of children. Health care interventions should be implemented to support in various domains of life. PMID- 21298838 TI - Antibacterial activity of Thai medicinal plants Pikutbenjakul. AB - BACKGROUND: Bacterial infections caused by resistant strains have been increased dramatically. Pikutbenjakul, a Thai medicinal plant formula containing Piper longum, Piper sarmentosum, Piper interruptum, Plumbago indica and Zingiber officinale have been widely used in Thai traditional medicine. OBJECTIVE: To determine antimicrobial activity of Pikutbenjakul formula and its components in order to develop the medicinal plants for alternative treatment of bacteria causing diarrhea. MATERIAL AND METHOD: Activity of Pikutbenjakul formula and its components was tested using disc diffusion and broth dilution methods against bacteria associated a set of bacteria associated with diarrheal disease including Vibrio cholerae, Vibrio vulnificus, Salmonella, Shigella, Escherichia coli (EIEC, ETEC, EPEC, EAEC and EHEC) and Staphylococcus aureus. The extraction was performed by maceration in 95% ethanol. RESULTS: The results showed all tested strains were susceptible to P. indica while other components were able to inhibit some strains. P. sarmentosum showed antimicrobial activity against Vibrios with the MIC values between 0.625 to > or =5 mg/ml. P. sarmentosum, P. indica and Pikutbenjakul formulas inhibited the growth of all Vibrios. P. interruptum inhibited V. cholerae serogroups O1 and non-O1/non-O139. P. longum was able to inhibit only two isolates of V. cholerae serogroup O139 (MIC = 1.25 mg/ml) and V. vulnificus (MIC > or =5 mg/ml). The activity of Pikutbenjakul containing Zingiber spp. and Pikutbenjakul containing Z. officinal against Vibrios, Shigella spp. and S. aureus was not significantly different. P. indica could inhibit Salmonella (MIC > or =5 mg/ml), E. coli (MIC > or =5 mg/ml) and S. aureus (MIC = 1.25 mg/ml). CONCLUSION: The results support the Thai medicinal plants for treatment of diarrhea caused by these bacteria. This study also provides an insightful knowledge on antimicrobial activity which would lead to further development of an effective formula of Pikutbenjakul for diarrheal disease and other infectious diseases in future. PMID- 21298839 TI - Child abuse and risky behaviors among youths. AB - BACKGROUND: Child abuse is an important health issue but it is little known how abuse experiences in childhood and current health risk behaviors are related. OBJECTIVES: To (a) study the prevalence and characteristics of child abuse experience, (b) test the hypothesis that youths with a history of child abuse would have more health risk behaviors compared to their non-abused counterparts and (c) study the associations between child abuse experience, family and social risk factors, and current health risk behaviors. MATERIAL AND METHOD: A cross sectional population survey was conducted on a sample of 488 young people aged 16 25, living in suburban community of Pathumthani Province. MEASURES: The standard questionnaires used consisted of (1) The Conflict Tactics Scales (CTS) for child abuse experience (2) Health risk behaviors using Diagnostic Interview Schedule (DIS), Alcohol-Use Disorder Identification Test (AUDIT), sexual risk behavior screening test, modified Youth Risk Behavior Survey Questionnaire to measure substance use, alcohol, sexual risk behaviors, other risk behaviors respectively. Linear regression was performed to estimate the independent association of abuse experience with the risky behavioral outcomes. RESULTS: Prevalence of child abuse was approximately 30% of the sampled group. Childhood physical abuse was the most common form of abuse (15%) while sexual abuse was the second most common (12%). There were strong graded relationships between the number of abusive experiences and the health risk behaviors. Factors associated with having health risk behaviors included male gender older age, experiences of abuse, low level of parental education, friends who were involved with potential health risk activities, and no close relatives. CONCLUSION: Child abuse was not uncommon among Thai youths. Abusive experience and some family and social factors increased the risk of risky behaviors among youth. PMID- 21298840 TI - The efficacy and side effects of oral Centella asiatica extract for wound healing promotion in diabetic wound patients. AB - OBJECTIVE: To study clinical efficacy and side effects of the oral Centella asiatica extract capsule in the diabetic wound healing. And to study the side effects of Centella asiatica extract capsule. MATERIAL AND METHOD: This prospective randomized control study enrolled two hundred diabetic patients in the department of Surgery, Thammasat University Hospital. The exclusion criterion were low immune patients, oral steroid intake, age more than 80 year and less than 18 yeas, serum albumin less than 3.0 gm/dl, uncorrected peripheral arterial diseased patients, and uncontrolled infective wound. The termination criterion were patient refusal, wound infection, delayed primary sutured wound secondary healing wound. The patients were divided into two groups randomly, groupA was Centella asiatica extract capsule group and group B was placebo group. Centella asiatica extract capsule and placebo were prescribed in each group under the random sheet. The administration was 2 capsules after meal, three times a day (50 mg of extracted asiaticoside / capsule in group A). The general symptoms, wound characteristics, wound size and depth were examined at day 7, day 14 and day 21 by the same investigator. The demographic data of the sample were analyzed by student t test and comparative wound characteristics were analyzed by Pearson Chi Square test. RESULTS: Wound contraction in the study group is better than placebo group but granulation tissue forming is better in the placebo group. No serious adverse reaction in both groups. CONCLUSION: Centella asiatica extract capsule is the Thai herb preparation capsule that effective in the wound healing promotion and also suppress the scar in diabetic wound patients. There was no demonstrable serious side effect of the Centella asiatica extract capsule group. Centella asiatica extract capsule can shorten the course of diabetic wound and can be prescribed to the diabetic patients safely. PMID- 21298841 TI - Incidence of perioperative myocardial infarction among high risk patients who undergo preoperative evaluation for non-cardiac surgery by cardiologists. AB - BACKGROUND: High risk patients who undergo a non-cardiac surgery often develop a perioperative myocardial infarction (PMI). OBJECTIVE: To study the incidence of PMI among high risk patients who undergo preoperative evaluation for non-cardiac surgery by cardiologists. MATERIAL AND METHOD: This study was a cross-sectional study, performed at Thammasat Hospital for one year Eligible patients were subjects older than 40 years with pre-existing cardiovascular disease or with at least one major cardiovascular risk factor including chronic kidney disease who underwent non-cardiac surgery with preoperative cardiovascular evaluation. The primary outcome is perioperative myocardial infarction. RESULTS: Fifty-three patients (mean age 70.5 years, 54.7% female) were eligible for the study. Most of these patients underwent orthopedic surgery (24 patients, 45.3%) and general surgery (18 patients, 34%). Four female patients developed PMI, representing the incidence of 7.5 percent. Chronic kidney disease and peripheral arterial disease were statistically significant associated with PMI. CONCLUSION: The incidence of PMI in this study was slightly higher than those reported in previous studies. Therefore, physicians should be aware of the diagnosis and proper management of this condition. PMID- 21298842 TI - Antimicrobial susceptibility of enterococci in Thailand from 2000 to 2005. AB - OBJECTIVE: To determine the trends of antimicrobial susceptibility of enterococci in Thailand from 2000 to 2005. MATERIAL AND METHOD: All enterococcal isolates from sterile site obtained from 28 hospitals in Thailand from 2000 to 2005 were tested for their susceptibility to ampicillin, high-level gentamicin, and vancomycin by the disk diffusion (Kirby Bauer) method. The relevant data were collected and analyzed by WHONET software program supported by the World Health Organization. RESULTS: Enterococcus faecalis (47%) and E. faecium (23%) were the two most frequent enterococcal isolates. There was no trend of increasing resistance to ampicillin, high level gentamicin, and vancomycin among E. faecalis isolates during the study period. There was a trend of an increasing resistance to ampicillin and high-level gentamicin among E. faecium isolates. Among E. faecium, the rates of vancomycin resistance were very low, ranging from 0.5% to 1.9%, and there was no trend of increasing rates of resistance. CONCLUSION: In the present study, there is a trend of decreasing susceptibility to ampicillin and high-level gentamicin in E. faecium. In contrast, there is no trend of increasing resistance to vancomycin. This would have effects on selection of empirical antimicrobial treatment on enterococcal infections especially a decision to use ampicillin or gentamicin. PMID- 21298843 TI - Antimicrobial resistance among clinical isolates of Staphylococcus aureus in Thailand from 2000 to 2005. AB - From 2000 to 2005, the data of all clinical isolates of Staphylococcus aureus including methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) from 28 hospitals in the National Antimicrobial Resistance Surveillance, Thailand (NARST) program were reviewed and analyzed for the prevalence and pattern of antimicrobial susceptibility by WHONET software program. Among all isolates, around 26% of MRSA have been noted in each year The rates of erythromycin-resistant MRSA were relatively high, ranging from 94.5% to 96.8%, followed by clindamycin resistant (37.4% to 68.9%), fosfomycin-resistant (7.7% to 17%), vancomycin-resistant (0.1% to 0.8%), and teicoplanin resistant (0.2% to 1.3%). The rates of antimicrobial resistance MSSA were constantly low, with erythromycin resistance ranging from 3.7% to 4.6%, clindamycin resistance ranging from 1.4% to 2.3%, fosfomycin resistance ranging from 0.7% to 1.4%, vancomycin resistance ranging from 0.1% to 1.2%, and teicoplanin resistance ranging from 0.1% to 1.1%. An increasing trend of vancomycin resistance in S. aureus determined by the disk diffusion method should be further confirmed by appropriate susceptibility methods. Molecular typing methods are needed to determine the epidemiological association between these resistant isolates. PMID- 21298844 TI - National antimicrobial resistance surveillance among clinical isolates of Streptococcus pneumoniae in Thailand. AB - As part of the continuing national antimicrobial surveillance, the national antimicrobial resistance surveillance thailand (NARST), data of all clinical isolates of Streptococcus pneumoniae were collected from 28 hospitals in Thailand from 2000 to 2005. Epidemiological and microbiological data were obtained and analyzed using the WHONET software program. Among all isolates tested for antimicrobial susceptibility, the rates of penicillin resistance were constantly high, ranging from 42.4% in 2000 to 47.7% in 2005. The third-generation cephalosporin resistance rate, determined by Epsilon test (E-test) in 10% to 15% of all isolates each year, ranged from 2.1% to 8.4%. The rates of erythromycin resistance ranged from 24.2% to 30.3%. Surprisingly, one isolate in 2005 was resistant to levofloxacin. The rates of multi-drug resistance ranged from 14.8% to 34.3%. In conclusion; the present (NARST) study documents remarkable increase of penicillin, erythromycin, and multi-drug resistance rates in Thailand, especially among isolates from the North, the Center, the East, and Bangkok; from university hospitals; from young children; and from non-sterile specimens. PMID- 21298845 TI - Five-year surveillance for Burkholderia pseudomallei in Thailand from 2000 to 2004: prevalence and antimicrobial susceptibility. AB - OBJECTIVE: To determine the prevalence and antibiotic susceptibility patterns of Burkholderia pseudomallei isolates in Thailand from 2000 to 2004. MATERIAL AND METHOD: the data on WHONET from 28 hospitals participated in the National Antimicrobial Resistance Surveillance Thailand (NARST) surveillance program, was reviewed and analyzed for the prevalence and antimicrobial susceptibility patterns. RESULTS: During the five-year surveillance, the prevalence of B. pseudomallei in clinical isolates was 69% in the Northeast, 14% in the North, 11.8% in the Center, and 5% in the South. Compared to other regions, the prevalence rate in the Northeast had gradually increased from 2000 to 2004. Burirum Hospital had the highest prevalence rate in this area. The majority of isolates were obtained from blood (44.9%), pus (25.6%), respiratory tract (13.3%), and urinary tract (6.3%). The isolates from unusual sites including bone marrow, heart, and placenta were less commonly noted (< 1%). Based on in vitro susceptibility results, all isolates in each region expressed high susceptibility to ceftazidime (> 98.5%), amoxicillin/clavulanic acid (> 95%), cefoperazone/sulbactam (> 98%), imipenem (98.5%), and meropenem (98%), but express less susceptibility to trimethoprim-sulfamethoxazole (< 53%). However, the susceptibility of B. pseudomallei to trimethoprim/ sulfamethoxazole determined by the disk diffusion method is unreliable; it must be performed by the minimal inhibitory concentration method. CONCLUSION: With the exception of the Northeast, the prevalence rate of B. pseudomallei remains stable for all regions in Thailand. The isolates obtained from blood and pus represent more than two-thirds of all clinical isolates. Antimicrobial susceptibility patterns showed no evidence of increased resistance to antimicrobials most commonly prescribed for the treatment of melioidosis. PMID- 21298846 TI - Antimicrobial resistance of Escherichia coli isolated from urine in Thailand from 2000 to 2005. AB - OBJECTIVE: To study the trends of antimicrobial resistance of Escherichia coli in Thailand during 2000 and 2005. MATERIAL AND METHOD: All isolates of E. coli from 28 hospitals across Thailand from 2000 to 2005 were tested for their susceptibility to aminoglycosides, beta-lactams, fluoroquinolones, and trimethoprim-sulfamethoxazole by the disk diffusion method (Kirby Bauer). The relevant data were collected and analyzed by the WHONET software program supported by the World Health Organization. RESULTS: The rate of resistance to ampicillin, ceftriaxone, ceftazidime gentamicin, and ciprofloxacin increased from 79.3% to 85.3%, 12.7% to 28.5%, 10.7% to 15.2%, 25% to 32.9%, and 45.1% to 51% during the 6-year period from 2000 to 2005 among isolates from catheterized urine, respectively. The rate of resistance to gentamicin and ceftriaxone increased from 23.2% to 28.9% and 6.8% to 24.2%, from 2000 to 2005 respectively among isolates in non-intensive care units (non-ICUs). The rate of resistance to gentamicin increased from 18% to 26.1%, and 24.2% to 29.6% among isolates in out patient department (OPD) and non-OPD, respectively. The rate of resistance to ceftriaxone increased from 2.5% to 15.4%, and 7.9% to 25.9% among isolates in OPD and non-OPD, respectively. The rate of resistance to gentamicin and ceftriaxone increased from 23.2% to 28.9%, and 6.8% to 24.2% among isolates in non-ICU, respectively. The rate of resistance to trimethoprim-sulfamethoxazole decreased from 71.2% to 62.6% among isolates in non-ICUs. Isolates from catheterized urine were significantly associated with imipenem resistance (p > 0.05). CONCLUSION: The present study shows a significant correlation between ciprofloxacin resistance and fluoroquinolone use, and indicates that prior fluoroquinolone use seems to be the most important risk factor for ciprofloxacin-resistant E. coli bacteremia. Isolates from catheterized urine were significantly associated with resistance to imipenem, and the ICU hospitalization and OPD attention during the previous year were significantly associated with ofloxacin resistant E. coli. PMID- 21298847 TI - National Antimicrobial Resistance Surveillance, Thailand (NARST) data among clinical isolates of Pseudomonas aeruginosa in Thailand from 2000 to 2005. AB - OBJECTIVE: To determine the prevalence, clinical epidemiology, and antimicrobial susceptibility of Pseudomonas aeruginosa in Thailand from 2000 to 2005. MATERIAL AND METHOD: Using WHONET data from 28 hospitals participating in the National Antimicrobial Resistance Surveillance Thailand (NARST) program, all data were reviewed and analyzed for the prevalence, clinical epidemiology, and antimicrobial susceptibility of clinical isolates of P. aeruginosa from 2000 to 2005. RESULTS: During the six-year surveillance, the prevalence of P. aeruginosa in clinical isolates was constant among 28 hospitals. The most common sites of isolation included sputum, pus, and urine. The most active antimicrobials were netilmicin (88% to 90.8%), cefoperazone/sulbactam (85.1% to 89.5%), imipenem (84.6% to 87.2%), and meropenem (84.5%). The resistance to ceftazidime was very high, ranging from 24.6-27.4%. The prevalence of multidrug-resistant (MDR) P. aeruginosa (resistance to amikacin, ciprofloxacin, and ceftazidime) was constant. Some hospitals in Central and Eastern regions had the prevalence of MDR up to 20% to 30% of the isolates. CONCLUSION: According to NARST data, the antimicrobial resistance rates of P. aeruginosa remains constant with the exception of relatively high rates in ceftazidime. The prevalence of MDR P. aeruginosa is generally low with a moderately high prevalence in some hospitals. PMID- 21298848 TI - Shigella species and serotypes among clinical isolates in Thailand from 2001 to 2005. AB - OBJECTIVE: To study the species and the serotypes of the clinical isolates of Shigella obtained from patients in Thailand. MATERIAL AND METHOD: The World Health Organization National Salmonella and Shigella Center Thailand, had confirmed the species and performed serotype identification of 1,913 clinical isolates of Shigella collected from the laboratory network of Department of Medical Sciences and the collaborated hospitals across Thailand from 2001 to 2005. RESULTS: Between the year 2001 and 2005, 728, 481, 160, 247, 297 clinical isolates were tested, respectively. There were 5 isolates of S. dysenteriae (group A), 416 isolates of S. flexneri (group B), 4 isolates of S. boydii (group C) and 1,488 isolates of S. sonnei (group D). A total of 21 Shigella serotypes were identified and there were 3 serotypes in group A, 11 serotypes in group B, 4 serotypes in group C, and 3 serotypes in group D. Throughout these five years, the five common serotypes were S. sonnei Phases I and II, 28.6% (548 isolates); S. sonnei Phase I, 24.6% (470 isolates); S. sonnei Phase II, 24.6% (470 isolates); S. flexneri Type 2a, 10.9% (208 isolates), and S. flexneri Type 3a, 6.3% (121 isolates), respectively. CONCLUSION: At the national scale in Thailand from 2001 to 2005, S. sonnei was the most frequent Shigella spp. isolated from patients in Thailand. In addition, S. dysenteriae and S. boydii were extremely uncommon. These findings are important in future vaccine development. PMID- 21298849 TI - An overview of antimicrobial susceptibility patterns for gram-negative bacteria from the National Antimicrobial Resistance Surveillance Thailand (NARST) program from 2000 to 2005. AB - The National Antimicrobial Resistance Surveillance Thailand (NARST) has been initiated since 1998 to strengthen the surveillance program for antimicrobial resistant pathogens as well as to standardize the laboratory practices in Thailand. This collaborative network was funded by the World Health Organization, and involved 33 hospitals throughout Thailand at the first phase. Nevertheless, no prior effort has been made to share the antimicrobial resistance data in the national level. In this overview, the authors provide an update on the status of antimicrobial resistance from 2000 to 2005 among important Gram-negative pathogens as well as the implication of these findings. The most striking finding appears to be the emergence of pandrug-resistant (PDR) Acinetobacter baumannii. Carbapenem-resistant A. baumannii has been dramatically increasing from 2.1% in 2000 to 46.7% in 2005. There is a trend towards the increasing incidence rates of ESBL-producing Escherichia coli from 2000 to 2005, but the incidence rates of ESBL-producing Klebseilla pneumoniae remain constant during the same period. The susceptibility of Burkholderia pseudomallei to various antibiotics, particularly ceftazidime and carbapenems, approached 100%. In conclusions, to help strengthen the future surveillance system, NARST needs to develop the data collection tools that include some important patient characteristics and the information that can help distinguish colonizations and infections as well as community-acquired infections and hospital-acquired infections. In addition, an appropriate test for antimicrobial susceptibility including the minimal inhibitory concentration determination should be implemented and carried out for all important pathogens. The NARST data emphasized a need to strengthen the antimicrobial stewardship as well as the infection control measures at the hospital level to help reduce the transmission of antimicrobial-resistant Gram-negative bacteria in Thailand. PMID- 21298850 TI - A cluster of pediatric endemic typhus cases in Orange County, California. AB - Murine typhus is typically a mild febrile illness caused by Rickettsia typhi, generally confined to Texas and Southern California. Clinicians should consider early treatment with doxycycline when presented with a child having protracted fever, rash, and headache.We present 5 pediatric cases and a literature review highlighting the changing epidemiology and diagnostic difficulty of typhus. PMID- 21298851 TI - Incidence of influenza-related hospitalizations in different age groups of children in Finland: a 16-year study. AB - BACKGROUND: children are frequently hospitalized with influenza-associated illnesses. Few virologically confirmed population-based studies of pediatric hospitalizations performed during several consecutive seasons are vailable. METHODS: this 16-year retrospective study consisted of all children <= 16 years of age who were treated for virologically confirmed influenza at the Department of Pediatrics, Turku University Hospital, Finland, between July 1, 1988 and June 30, 2004. Calculation of the population-based rates of hospitalization in different age cohorts was based on children (n = 69,068) who lived within the 38 municipalities whose acute pediatric care was provided solely by Turku University Hospital. RESULTS: during the study period, 401 children were hospitalized with virologically confirmed influenza. The average annual incidences of influenza related hospitalizations were highest among children <6 months (276 [95% confidence interval, 220-336] per 100,000) and 6 to 11 months (173 [95% confidence interval, 129-220] per 100,000) of age. For both influenza A and B, the rates of hospitalization were highest among children younger than 1 year of age. Influenza A accounted for 82% and influenza B for 18% of all hospitalizations. A total of 40 (10.0%) children received treatment at the intensive care unit. Of all 401 children with confirmed influenza infection, only 216 (53.9%) had a discharge International Classification of Diseases code related to influenza. CONCLUSIONS: the high incidence of influenza-associated hospitalization among infants less than 6 months of age underscores the need to find effective ways to prevent influenza in this age group, in which influenza vaccines are not currently licensed for use. PMID- 21298852 TI - Honeybees and bumblebees share similar bacterial symbionts. PMID- 21298853 TI - COMMENTARY. A multidisciplinary approach to the functional and esthetic rehabilitation of amelogenesis imperfecta and open bite deformity: a case report. PMID- 21298854 TI - COMMENTARY. Orthodontic treatment of a congenitally missing maxillary lateral incisor. PMID- 21298855 TI - [Imaging of atherosclerosis]. AB - Atherosclerosis is a chronic disease potentially involving the whole arterial system that causes a spectrum of clinical manifestations ranging from acute myocardial infarction to stable angina or stroke. The continuous accumulation of lipids, fibrous and inflammatory elements in the arterial wall leads to progressive lumen narrowing with subsequent ischemia. Acute coronary syndromes (unstable angina, acute myocardial infarction) have a more complex and dynamic pathogenesis with coronary plaque rupture and thrombosis as the final common pathway. As only some plaques lead to clinical events whereas many others remain asymptomatic life-long, different imaging modalities have been applied to define the atherosclerotic burden and/or the anatomical characteristics of unstable or vulnerable lesions. Carotid ultrasound, multislice computed tomography (MSCT) or nuclear magnetic resonance (NMR) have been applied to assess the atherosclerotic burden in asymptomatic subjects, while coronary angiography has been mainly used to assess unstable plaques at the time of coronary events. Today intravascular ultrasound (IVUS) offers qualitative details on plaque composition, like hard and soft components, that are helpful to assess unstable lesions, but other important details (lipid pool areas or fibrous cap thickness, ulcerations, thrombotic apposition or erosion) are either below the resolution of IVUS or not easily visualized. In the last years novel techniques have been developed to overcome these limitations. Optical coherence tomography and the combination of anatomical and biological imaging using hybrid techniques (like virtual histology or the combination of positron emission tomography and MSCT or NMR) appear to be particularly attractive. These approaches will likely provide new insights into the pathophysiology of acute coronary events and into the effects of aggressive preventive therapies. PMID- 21298856 TI - [Atherosclerosis regression and plaque stabilization: comparison of therapeutic targets]. AB - Atherosclerosis is a systemic disease where atheromatous plaque is the basic lesion. A number of studies have shown that atherosclerotic lesions progress over time, when risk factors such as arterial hypertension and hyperlipidemia are present. Many clinical trials have been conducted in the last decade, both with antihypertensive and lipid-lowering drugs. These trials demonstrated that progression of atherosclerosis can be halted and even regression can be achieved. In studies with lipid-lowering drugs, the best results were achieved with a dramatic decrease in LDL cholesterol levels, obtained with statins, particularly when combined with a concomitant increase in HDL cholesterol. The treatment of hypertension provided better results on the endpoint atheromatous plaque with antihypertensive drugs belonging to the class of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers or calcium antagonists. Some studies were conducted both with antihypertensive and lipid-lowering drugs, and a better control of lesion progression, together with its partial regression, was obtained. The best approach seems to be achieved with the combination of a specific intervention on lipid profile together with a targeted control of blood pressure. PMID- 21298857 TI - [Two decades of statin trials: clinical, intermediate and surrogate endpoints]. AB - In the last 20 years clinical trials evaluating statins showed the importance of LDL-cholesterol lowering in decreasing the risk of cardiovascular disease. The efficacy of statin therapy has been well documented both in primary and secondary prevention, in patients with subclinical atherosclerosis and in those with average cholesterol levels. However, the so-called "residual risk" remains significant and new strategies are needed for reducing it, such as raising HDL cholesterol levels. Recently, the JUPITER study demonstrated the efficacy of statins in reducing the risk in healthy subjects with elevated C-reactive protein levels, highlighting the potential protective mechanisms of these drugs. Different from the setting of primary and secondary prevention, the results of statin trials in patients with heart failure, end-stage renal disease and aortic stenosis have shown no benefit in terms of survival. PMID- 21298858 TI - [The JUPITER study: background and research hypotheses]. AB - Many large-scale studies demonstrated in aggregate that high-sensitivity C reactive protein (hsCRP) levels are a strong, independent predictor of future vascular events and that hsCRP adds prognostic information on risk at all levels of LDL cholesterol, at all levels of the Framingham risk score, and at all levels of the metabolic syndrome. Moreover, hsCRP predicts risk of recurrent coronary events and has important prognostic value in acute coronary ischemia and after coronary interventions. The JUPITER study was aimed to determine whether long term treatment with rosuvastatin (20 mg/die) will reduce the rate of major adverse cardiovascular events, defined as the combined endpoint of cardiovascular death, stroke, myocardial infarction, hospitalization for unstable angina, or arterial revascularization among individuals with LDL cholesterol levels < 130 mg/dl (3.36 mmol/I) who are at high risk because of an enhanced inflammatory response as indicated by hsCRP levels > 2 mg/I. PMID- 21298859 TI - [The JUPITER study: critical review of final results]. AB - Major clinical evidence obtained in the last 15-20 years with statins is reviewed. A tight correlation between LDL cholesterol and occurrence of major cardiovascular events has been observed. Moreover, favorable effects have been shown also in subjects with normal cholesterol blood levels and high levels of high-sensitivity C-reactive protein (hsCRP), a predictive marker of cardiovascular events. In two studies involving patients with acute coronary artery disease the prognosis was better in subjects with cholesterol levels < 70 mg/dl or hsCRP < 2 mg/I. These studies provide the background for the JUPITER trial, a double-blind randomized controlled "globalized" study with rosuvastatin 20 mg in primary prevention, including 17 802 normal cholesterolemic males and females with increased risk for hsCRP > 2 mg/I. The combined primary endpoint included myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes. Rosuvastatin reduced LDL cholesterol levels by 50% and hsCRP levels by 37%. The trial was stopped after a median follow-up period of 1.9 years, due to a significant superiority of rosuvastatin on the incidence of major cardiovascular events. Moreover, long-term adherence to randomized treatment was excellent, and safety was consistent in the two groups. Eligible patients were more than one fourth of the outpatients attending a cardiology clinic; median age of 66 is 5-6 years lower than age of patients admitted to Italian intensive cardiac care units for acute coronary disease, suggesting the usefulness of a primary prevention program with rosuvastatin in this clinical setting. Practical and healthcare planning implications deriving from this study are currently under evaluation by scientific societies and healthcare authorities. PMID- 21298860 TI - [JUPITER, what now?]. AB - The JUPITER study was conducted in apparently healthy, non-dyslipidemic subjects, but with high levels of high-sensitivity C-reactive protein (hsCRP), and showed a decrease in LDL cholesterol and hsCRP of 55% and 36%, respectively, with the administration of rosuvastatin at standard doses (20 mg/die), with a significant reduction in the incidence of major cardiovascular events. The event reduction was maximal in patients whose LDL cholesterol and hsCRP levels were lowered to < 70 mg/dl and <2 mg/I, respectively. The publication of the JUPITER data resulted in a wide debate within the international scientific community, particularly related to clinical implications of major findings. The main implications seem to be the confirmation of "the lower is better" philosophy and of the role of hsCRP as a marker to select, among intermediate risk subjects, patients who are actually at higher risk, who need to be treated with highly effective statins with a low side-effect profile, such as rosuvastatin. Patients with the "JUPITER phenotype" (metabolic syndrome + family history of cardiovascular disease) seem to benefit the most from a treatment that includes measurement of hsCRP and rosuvastatin administration. PMID- 21298861 TI - [New targets for prevention: identification of specific disease mechanisms]. AB - Current therapeutic strategies have proven to be remarkably effective in correcting known cardiovascular risk factors but coronary events still occur in a significant number of patients. New therapeutic targets should be pursued in order to overcome traditional research methodology, which is focused on the reduction of the mean values. Novel clinical approaches should be based on the analysis of the outliers rather than focusing only on the distribution of the mean values. In this subset of patients that deviate most from the average, the identification of peculiar features is easier and may subsequently help to detect the same, but less marked, characteristics in the general patient population. An individually tailored therapy based on the underlying etiologic factors will be more effective than the present optimal treatment. The study of these outliers may lead to identify new cardiovascular risk factors and new therapeutic targets for future pharmacological research. PMID- 21298862 TI - [Questionnaire study to measure patient satisfaction for the treatment with sustained-release formulation of 2 g azithromycin]. PMID- 21298863 TI - [Evaluation of the safety and efficacy of cefditoren pivoxil fine granules for pediatric use in pediatric patients with laryngopharyngitis and tonsillitis caused by Streptococcus pyogenes]. AB - Rheumatic fever and acute glomerulonephritis are known to occur secondary to infection with Streptococcus pyogenes, and early elimination of the Streptococcus pyogenes by treatment with an appropriate antibiotic is required. Treatment with penicillins for 10 days has been recommended for Streptococcus pyogenes infections, but cephems are also now being used, and cefditoren pivoxil (CDTR-PI) is listed as one of the recommended drugs in the Guidelines for the Management of Respiratory Infectious Disease in Children in Japan 2007. We therefore conducted this study in order to collect appropriate use information in the clinical setting of CDTR-PI to treat Streptococcus pyogenes infections. In this study, 790 patients were enrolled in 147 institutions. Of them, 734 and 718 patients were chosen for safety and efficacy analysis, respectively. There were 11 adverse drug reactions in 11 patients, and the incidence of adverse drug reactions was 1.50% (11/734 patients). The most common adverse drug reactions were diarrhea and hematuria, and there were 3 events of each, but a positive urinalysis after administration were only obserbed without the clinical symptoms. With the exception of the 3 patients in which the patient did not return to the hospital and the outcome is unknown, the patients either recovered from all of the adverse drug reactions or they were relieved. No serious adverse drug reactions were reported in this study. The response rate was 98.5% for laryngopharyngitis (457/464 patients) and 98.4% (250/254 patients) for tonsillitis. Examination of the response rates according to patient background showed that they were high, 95% or more, in every group. The Streptococcus pyogenes eradication rate was 94.6% for laryngopharyngitis (194/205 patients) and 92.4% (110/119 patients) for tonsillitis. In summary, CDTR-PI exhibited excellent safety and efficacy in laryngopharyngitis and tonsillitis caused by Streptococcus pyogenes, and CDTR-PI was reconfirmed as a useful drug. PMID- 21298864 TI - [Mutant prevention concentrations of garenoxacin against Streptococcus pneumoniae isolates from otorhinolaryngological infections]. AB - The minimum inhibitory concentrations (MICs) and the mutant prevention concentrations (MPCs) of garenoxacin (GRNX), were compared to those of levofloxacin (LVFX), and moxifloxacin (MFLX) against 78 Streptococcus pneumoniae isolates from otorhinolaryngological infections in Japan during the period January 2007 to June 2007. The MIC and MPC for 90% of the isolates (MIC90 and MPC90) of GRNX were 0.06 and 0.12 microg/mL, respectively, and were the lower values than LVFX and MFLX MIC90s and MPC90s. The ratios of MPC/MIC of GRNX were the lower values than those of LVFX and MFLX. PMID- 21298865 TI - [Evaluation of target attainment rate of pazufloxacin mesilate using Monte Carlo simulation method]. AB - We calculated achievement rates of target attainment of AUC/MIC using Monte Carlo simulation (MCS). Two doses of pazufloxacin mesilate (PZFX) between q.d. and b.i.d. were compared for each species of bacterium. Concentrations for AUC of PZFX of 8 patients were measured at this hospital, and those from a phase I clinical study (phase I, 6 healthy volunteers) were used. MICs of PZFX were determined for each species of bacterium of respiratory organ origin (Pseudomonas aeruginosa, Haemophilus influenzae, Streptococcus pneumoniae, and Klebsiella pneumoniae). AUC per day of 500 mg b.i.d. used twice AUC (PZFX 500 mg x 2/day by patient, PZFX 500 mg x 2/day by phase I). Target attainment of AUC/MIC was AUC/MIC > or = 30 in S. pneumoniae and AUC/MIC > or = 125 in the other species of bacteria (P. aeruginosa, H. influenzae, and K. pneumoniae). As a result, patients showed an about 3 times higher AUC than the phase I subjects (67.9/21.9 microg/mL). In addition, the target attainment of AUC/MIC showed the highest rate in PZFX 500 mg x 2/day in patients with each type of bacteria: H. influenzae (98%), K. pneumoniae (89%), S. pneumoniae (66%), and P aeruginosa (41%). Target attainment of AUC/MIC was H. influenzae (91%), K. pneumoniae (81%), P. aeruginosa (5%), and S. pneumoniae (0%) in phase I. Therefore, the effectiveness of PZFX was estimated to be low using the MCS method with the phase I data. PMID- 21298866 TI - [Guidance of health insurance for diagnosis and treatment of Helicobacter pylori infection]. PMID- 21298867 TI - [When work is health]. PMID- 21298868 TI - [Does work have a meaning? Basis for a positive work culture]. AB - From the anthropological point of view work is the expression and fulfilment of the absolute spirit in the finite sense and is, by its essence, cooperation. This obliges us to reverse the question: "does work have a meaning?", to: "does work have a meaning for workers? Does it allow self-fulfilment?" Work has a meaning if the worker's psychophysical integrity is safeguarded, if by working the individual achieves self-fulfilment as a person, if it has a sense of community. Man as an "actor" achieves self-fulfilment through technical and professional competence, thereby overcoming organizational and social conflicts. Today reducing human and social relations to an economic transaction will lead to the destruction of the meaning of life and work. The study of suicide cases in France Telecom shows that a human being inserted in the working environment wants most of all to obtain recognition. He or she will accept praise or even punishment if this is done with transparency, because the person will acknowledge in such decisions a recognition of his/herself. Many enterprises and consequently many personnel managers do not, in their essence, perceive of any meaning of work, but consider only the instrumental element. The workforce cannot be considered as a commodity, work is embodied in human beings. So either people aim at self fulfilment or fall into anomie and depression, even to the point of the destructive impulse of elimination. The re-humanization of work and the treatment of enterprises (which are "ill" because they no longer possess any meaning of work) is the challenge that awaits us. PMID- 21298869 TI - [Work: disease and health. The role of occupational medicine]. AB - To assess the role of Occupational Medicine in the promotion of workers'health over the last forty years, the author studied the evolution of this discipline from a clinical-diagnostic approach to the current emphasis on prevention. However, it is stressed that in Occupational Medicine even preventive measures are based on clinical methodology, as for example in health surveillance, where the main tasks are the identification of individual hyper-susceptibility and the assessment of early and reversible health effects due to occupational risks. Moreover, the traditional clinical-diagnostic approach is still of utmost importance. In fact, the classical occupational diseases do not present with the specific clinical features of the recent past. Instead, today it is necessary to evaluate whether occupational risk factors play a concomitant role in the origin of diseases that affect the general population. Moreover, new occupational diseases are emerging, due to the continuous changes in manufacturing processes and work organization. To assess the role that Occupational Medicine has played in the binomial expression "disease-health", topics which particularly suit the Author's cultural background are considered and are used as "indicators" of the various scientific, cultural, social, economic, and legislative aspects that contribute to the professional development of Occupational Physicians. Important results have been achieved over the last 40 years, however Occupational Physicians face new problems that impose a continuous updating process, not only on medical topics but also on the development of technological processes. The laws and the recommendations of the most prestigious national and international organizations and the principles of the ICOH Code of Ethics should guide Occupational Physicians in their profession and their actions must imply full professional independence. They must acquire and maintain the necessary competence for their duties and adequate conditions to carry out their tasks according to good practice and professional ethics. PMID- 21298870 TI - [Work as a basic human need and health promoting factor]. AB - The Italian Constitution (1948) defines 'work' as the founding value of the Italian Republic. This choice was not motivated by mere economic reasons, but rather stemmed from the recognition that work is the most appropriate tool for the expression of the human personality in society, that it is an asset and a right that will increase the dignity of every person, and which corresponds to a fundamental human desire to fulfil oneself in relationship with other persons and the entire world This view of work, including its technical and manual aspects, was unknown to the ancient mentality and became familiar to us through the monastic orders of the early middle ages, which began to conceive and practise human work as a means of participating in the work of creation and transmitted this value over the centuries. As we experience today, if occupation is lacking, a basic condition for the development of the person and for his/her contribution to the growth of society is lost. Given the meaning of work in human experience, it is not surprising that unemployment represents not only a worrisome economic indicator, but also the cause of ill health. At the end of 2009 unemployment in the European Union reached 10%, similar to the rate in the US; in Italy it was estimated at 8.5% in December 2009 and is expected to reach 10% in 2010. In Lombardy, although employment had been constantly increasing between 1995 and 2008, and the current unemployment rate is as low as 4.9%, 100,000 jobs were lost in 2009. Several scientific papers have demonstrated the association between lack of occupation and lack of physical and mental health. In the present period of crisis, increases of 30% in cases of anxiety syndrome and of 15% in cases of depression have been reported. An increase in suicides among unemployed persons has been documented in several countries even if there are still problems of interpretation of the causal chain of events. Mortality among the unemployed increased, not only that due to violent causes, but also mortality for all causes, cardiovascular diseases and cancer. A survey in the Turin area, Northern Italy, showed a twofold increase in mortality among unemployed men. Women were affected both by husbands' unemployment and by their own unemployment because of the previous increasing rate of female occupation. The worse the occupational condition (from "seeking work" to "temporary employment" down to "unemployed and no longer seeking work") the higher the mortality: in the latter category, where the most evident problem is marginalization and social exclusion, the increase in mortality was fourfold. The role of occupational health physicians is to recognize the possible negative effects of working conditions and at the same time promote a positive approach to work, even in difficult conditions. This makes prevention more effective and promotes health. To be aware of the meaning of work makes work itself more liveable and more productive. This is how health promotion contributes to the wellbeing of the individual and, at the same time, to the development of the economy and society at large. PMID- 21298871 TI - [Heart disease and work: from rehabilitation to return to work]. AB - Cardiovascular disease is one of the main causes of death and disability in industrialised and post-industrialised countries, including Italy. Improvements in treatment of the acute phase and the efficacy of prevention programmes contribute greatly to extending patient survival, thus increasing the prevalence of the disease even in the population of working age. Thus it is mandatory to provide adequate rehabilitation programmes in order to achieve full social reintegration of such patients, including return to work, which is an important aspect of their quality of life. This report reviews published papers exploring the main factors influencing return to work of patients suffering from a heart complaint. Criteria are also proposed for the assessment of reintegration at work of cardiovascular patients that take account of the residual clinical and functional working capacity of the patient in relation to the specific environmental and organizational work features. With the tools available to monitor the cardiovascular system during work it is possible to pursue to advantage such a comprehensive rehabilitation programme but close cooperation between the occupational physicians and cardiovascular rehabilitation specialists is required In a preliminary phase this can be achieved in hospital outpatient clinics equipped to develop and test specific protocols. PMID- 21298872 TI - [Work and ageing]. AB - The ageing of the general population and thus of working population, too, is one of the crucial aspects of modern society. Consequently, more and more people will be active and able/willing to work after 60 years of age out of personal choice, in relation to prolonged healthy life expectancy, better health conditions and expertise, and also due to economic and political considerations (delayed retirement age). Therefore the main problem is how to maintain the aging population in good health and promote and improve their working life and social integration. It is assumed that maintaining good working capacity depends on both health and occupational status, which are in turn supported by good working conditions (both environmental and relational) and healthy life styles. This leads to better quality of life, higher productivity and, consequently, a more satisfactory retirement period with consequent lower social costs both for the individual and the society. PMID- 21298873 TI - [Ageing and work: technical standards]. AB - Over the last few years, studies on the relationship between ageing and work have attracted growing interest due to the increased probability among workers of developing major health problems as a consequence of ageing of the working population. Negative outcomes for health are possible when an age-related imbalance appears between physical workload and physical work capacity. Interventions based on workload reductions should help to keep workers on the job for as long as allowed by law. Reference masses by age and sex are suggested by the technical standards of the ISO 11228 series, which are also quoted by Italian law D.Lgs. 81/2008, and EN 1005 series, which recommend limits valid also for manual material handling, and pushing and pulling. Decreasing low back pain prevalence or recurrence, in an ageing population with high prevalence of back disorders, could be more effective than many other approaches to enhance workers' quality of life and consequently maintain and improve workers' performance. PMID- 21298874 TI - [Immigration and work. Roles and opportunities for occupational medicine in the health and safety of migrant workers]. AB - BACKGROUND: It is estimated that in Italy there are 4 million migrant workers, accounting for about 10 percent of the total workforce. They contribute to national economic development but they are also heavily involved in the so-called "3D jobs" (dangerous, dirty and demanding/degrading). OBJECTIVES: To draw occupational physicians' (OP) attention to the necessity of dealing with occupational health and safety problems related to migrant workers, highlighting his/her role and opportunities, in order to guarantee access to health services and prevent occupational health inequalities. METHODS: The available data on occupational diseases and accidents among migrant workers are discussed, as well as conditions of individual susceptibility; as an example, data are commented obtained in many years of health surveillance in a foundry. RESULTS: Migrant workers may suffer from occupational health inequalities. The OP, by means of focused risk assessment, health surveillance, fitness for work and health promotion, can substantially improve migrant workers' health. In fact, data from our experience showed how a migrant workforce may be well characterized and also represent an opportunity, instead of being a "risk factor". CONCLUSIONS: Within the framework of needs for further methodological and applied research, the OP can play a proactive role in workplaces, aimed at real integration of migrant workers, with overall benefits for workers, enterprises and society. PMID- 21298875 TI - [Work as a possible means of self-esteem]. AB - Work is recommended as a therapeutic tool in dealing with mental disorders because it makes individuals feel useful since they can use their skills to fulfill what is required. The authors designed customized rehabilitation projects, including work, spread over 25 different manufacturing processes. Every morning, 120 subjects under treatment at the Department of Mental Health were admitted to work, with the chance of being hired by the enterprise that the cooperative society represented. Twenty-one people were hired within the first year of inclusion with more satisfactory results than those reported in the literature. It should be noted that none of the subjects hired ever resorted again to hospitalisation in the psychiatric department. PMID- 21298876 TI - [Work and social rehabilitation]. AB - On the basis of its experience, the Associazione In-Presa accepted the challenge consisting of the alienation of young people by using an educational method which makes it possible to reclaim them for rehabilitation. Children with difficult family situations, negative experience at school, damaged self-esteem, poor ability to connect with reality, are taken on a career course "as a protagonists". A tutor supports them and also closely cooperates with the entrepreneur who offered the youngsters the possibility of learning a trade and at the same time giving them the experience of a job. In 10 years over 120 young people have found steady jobs and regained the faith in themselves and in the world around them. PMID- 21298877 TI - [Does work heal? The role of work in social rehabilitation in prisons]. AB - Less than 18% of current convicts in Italy participate in job rotation (about one month a year) employed by the Prison Administration. Only 1% are employed by cooperative societies or external companies with a regular paid job (with national collective sector contracts). In this 1% relapse into crime is much lower. What features must work possess to reduce recidivism? Work must have a meaning. From the story of several cases key-words emerge that are not referred to strictly occupational categories, but to "affective" categories, such as esteem - good - human context - care of oneself- meaning - value. The expression "high and low" is also used as if the acceptance of a cyclic yield and a never final result could be principles to live with and which work organization must constantly address. Therefore the solution does not consist only in giving work to fragile individuals such as a prison inmates or the disabled, but the real problem is: what kind of work do we want to give them?. Or better, what do we want to give them through work? For the human being, because of human nature itself work has an intrinsic value, via which self-fulfilment and meaning are sought. Self-fulfilment via work, the discovery of one's own capabilities, inclinations and attitudes, allows the human being to know his own possibilities and limits. Work becomes one with the person who, through what he/she person does, can take care of his/herself and of his/her true nature. And it is not the kind of work that makes the difference: in the "noblest" work as in the most humble t is possible to work with diligence, ingenuity and competence. It is possible to achieve a sense of oneself dedicate oneself to the job and discover the positive effects of this attitude to work. PMID- 21298878 TI - [Critical lower limb ischemia]. AB - AIM: To focus the attention on critical limb ischemia, high risk condition not for the limb only, but involving the survey of the patient itself. MATERIAL OF STUDY: Etiology, diagnosis and therapy of arterial occlusive critical pathology (AOCP). Genetics and life style prophylaxis are shortly treated. RESULTS: AOCP is often asymptomatic pathology, underestimated by physicians themselves, though long-term death rate is the same between subjects affected by occlusive arteriopathy and cardiological failure. DISCUSSION: Interventional therapy, ranging from endovascular procedures (PTCA, stenting) to open surgery (by-passes, TEA, prostheses), remains the only effective weapon against critical acute limb ischemia, offering excellent revascularization rates (80-90%). Conservative treatment, comprehending thrombolysis, prostanoids and anticoagulant drugs recruit the role of invasive methods or are limited, alone, to ineligible patients. Genetics is still far from certain and durable results. CONCLUSION: AOCP is a long-term severe condition; multifactoriality and asymptomatology in a great number of patients, often justify misdiagnosed cases. In emergency the acute ischemia involves also demolitive surgery, with short and long-term poor prognosis. PMID- 21298879 TI - [Conservative treatment of chyle fistula of the neck following a reintervention of cervical bilateral lymphectomy for medullary carcinoma of the thyroid. Case report]. AB - Chyle fistula is an uncommon serious complication of neck surgery, occurring in 1 3% of radical neck dissections. An untreated chyle leak is a potentially dangerous condition that may rarely lead to hypovolemia, hyponatremia, hypochloremia, hypoproteinemia and lymphopenia. Anatomic variants of the terminal portion of the thoracic duct and suction drainage in the neck wound play a primary role in causing this kind of lesion. Poor is the literature concerning chyle fistula, due to its rarity, and mostly case reports; still debated- prevalently empiric--is the management of this disease. The Authors report a case of chyle fistula following a reintervention of cervical bilateral lymphectomy for medullary carcinoma of the thyroid in a 75 years old female. In the reported case the chyle fistula was successfully treated conservatively, in early post operative period with a low-fat diet and total parenteral nutrition, definitely followed by sclerosant therapy. The injection of a sclerosant agent (4 g of sterile medical talc diluted in isotonic sodium chloride solution) into the supraclavicular wound bed, through the drainage tube (clamped for 2 hours), determined rapid decline in fistula output, hence obviating surgical intervention. PMID- 21298880 TI - [Volvolus in an adult patient due to intestinal malrotation. Case report and review of literature]. AB - Intestinal malrotation is a rare cause of bowel obstruction in adults and it could create a perplexing situation for surgeons not familiar with this pediatric pathology. Symptomatic patients present either acutely with bowel obstruction and intestinal ischemia with a midgut or cecal volvolus, or chronically with vague abdominal pain. Several modalities can be used to describe the intestinal abnormality such as barium X-ray, computer tomography scans, angiography and sometimes also the explorative laparotomy. The authors report on a case 62 years old women presented to Emergency Center for plurime episodies of biliar emesis and diffuse abdominal pain in the last 5 days and treated for bowel obstruction secondary to a midgut volvolus in anomaly of fetal intestinal rotation. PMID- 21298881 TI - [Intestinal obstruction from undiagnosed rectal and ileal endometriosis. Two clinical cases and review of the most recent literature]. AB - Deep endometriosis is a subserosal growth (for more than 5 mm) of funzional endometrial tissue outside the uterine cavity. Authors report two clinical cases of intestinal endometriosis localized in the anterior wall of the rectum and in the last ileal loop. Both cases were characterized by sub-occlusive symptoms, diagnosis performed by laparoscopy and surgical resection. Authors focus the various pathogenetic theories and dwell itself on the symptomatology often characterized by nonspecific abdominal symptoms such as chronic abdominal pain, sometimes in relation to the menstrual cycle, and intestinal disorders. If rectal bleeding is rare, more frequent are dysmenorrhea, dyspareunia and infertility may occur in up to 50% of patients. The diagnosis of intestinal endometriosis is very difficult and can be made by radiological methods (CT or MRI) or by endoscopic ultrasound only for the rectal localization but nowadays often the diagnosis is due to laparoscopic techniques. In the absence of guidelines the surgical therapy is not well defined. When is not necessary surgical emergency, according to the depth of endometriotic infiltration, elective surgery includes several surgical techniques both conservative and extensive such as segmental intestinal resection with hysterectomy and ovariectomy. In the most recent literature, finally, are reported over 50% of pregnancies after surgery PMID- 21298882 TI - [Experimental model to verify the teaching efficiency of General Surgery II]. AB - The modern university teaching, of the Faculty of Medicine and Surgery typical of the Italian university organization, at least for clinical matters must pursue the aim to develop in the students a clinical and responsible sense of the seriousness of the profession they intend to embrace, both for medical that for surgical pathologies. Therefore it is very important the teaching method, above all in a diagnostic key, hopefully making above all the study of the patient the true "book" to read and meditate. Beyond the necessary attendance of the Students to the wards to learn the diagnostic and therapeutic procedure methods to pursue, it is of the utmost importance to verify on the field the development in them of the clinical sense of the correct professional method. Therefore a method of direct teaching by clinical examples and a model for written verification of the student's preparations has been personally introduced and experimented along more than twelve years of general surgery's teaching by the Author. It consist of a Form, very different from the quiz methods of other cultures, that introduces the student, to the correct way to study of each patient since the phase of learning and then in that of the examination. The typical adopted Form is proposed in advance to the students at the beginning of the course of lessons, so they can conform critically their preparation of the entire subject to study preparing to individuate the correct diagnosis on a proposed card simulating a clinical situation, and then to discuss it with the examinator. This method informs the student to the correct procedure in studying a patient, and give the examiner a way of a possible uniformity in his evaluation of the preparations of the student himself. PMID- 21298883 TI - [Dentist or mouth doctor?]. PMID- 21298884 TI - [Science in general practice]. PMID- 21298885 TI - [Dental education must also be attainable for students with economic and business packets. Yes]. PMID- 21298886 TI - [Dental education must also be attainable for students with economic and business packets. No]. PMID- 21298887 TI - [Actinic Keratosis]. PMID- 21298888 TI - [Living without a spleen]. AB - The spleen plays a significant role in the defence against infections, especially infections caused by encapsulated bacteria, such as Streptococcus pneumoniae. In case of (functional) asplenia, a fulminant sepsis with a high mortality rate may develop in a short time. Preventive measures are therefore recommended for people without a spleen or who have a dysfunctional spleen. A dysfunctional spleen may be present in diseases such as sickle cell anaemia, ulcerative colitis, Crohn's disease and coeliac disease. Preventive measures consist of vaccinations, antibiotics and patient education. Unfortunately, however, it has been shown that these preventive measures are not adequately followed. Currently, a Dutch guideline for healthcare providers is being developed. PMID- 21298889 TI - [Bifid and trifid mandibular canal. A coincidental finding]. AB - A 26-year-old man was suffering from pericoronitis of his mandibular third molars. To determine the position of the mandibular canal in relation to the roots of the third molars, a panoramic radiograph was made. The radiograph revealed at the right side a bifid mandibular canal and the upper part of the canal seemed to be related to the third molar. Additionally, a cone beam CT was made, which revealed a bifid mandibular canal at the left side and a trifid mandibular canal at the right side. Anatomical anomalies of the mandibular canal may have clinical implications, such as an increased risk of injury to the inferior alveolar nerve in case of removing a mandibular third molar and inadequate local anesthetics. PMID- 21298890 TI - [Severe periodontal disease as the cause of a fever of unknown origin]. AB - A 41-year old man was admitted to a university medical centre with a belly ache, bloody diarrhoea and fever with peaks rising up to 39 degrees C. The differential diagnosis included among others infectious bowel disease, tuberculosis and amoeba infection. After the exclusion of other pathologies the diagnosis morbus Crohn was given. A few days later the patient complained about toothache and severe periodontal disease was diagnosed. Instantly after extraction of the entire dentition the fever disappeared. PMID- 21298891 TI - [Patient safety in general dental practice 2009]. AB - In recent years various studies have been published which indicate that adverse events in health care facilities are the result of structural factors. In 2009 a national study was carried out in the Netherlands to gain insight into patient safety in primary care settings, including general dental practices. In 20 randomly selected practices, patient records were investigated and oral care professionals reported, during a period of 2 weeks, adverse events which occurred. For each practice, 2 researchers screened, with the help of a checklist, 50 randomly selected patient records covering a period of 1 year. A total of 8 preventable adverse events were found in the 1000 patient records (0.8%). Anonymous reports made during the 2 weeks of the research period resulted in 7 adverse events. Practically all of the adverse events had to do with diagnostics and treatment and resulted in limited harmful consequences for patients. On the basis of these results, oral care in general dental practice would appear to be safe, but the concept 'patient safety' is not at all or only minimally active among general dental practitioners. Regarding patient safety performance, improvement in the quality of record-keeping would be desirable. PMID- 21298892 TI - [Improving]. PMID- 21298893 TI - [Henk Bleker: a meeting with the state secretary]. PMID- 21298894 TI - [One night alone...]. PMID- 21298895 TI - [Strategic policy plan from 2011 to 2013 sets a new course for KNMVD]. PMID- 21298896 TI - [Surveillance]. PMID- 21298897 TI - [Cachexia in breeding calves; not only from infectious causes]. PMID- 21298898 TI - [Veterinary dental care: effective, efficient, and patient/client focused]. AB - The treatment of dental problems in animals and humans requires a different approach. While a basic knowledge of medicine is sufficient for dentists, a degree in veterinary medicine is a prerequisite for performing dental procedures in animals. Concepts such as oral-health veterinarian and dental care technician will be part of animal dental care in the future. When deciding on the plan of treatment, veterinarians should pay attention to the symptomatology, oral examination, and pain response. A number of treatments that are self-evident in human dentistry are often not recommended in veterinary medicine. Dental treatments for companion animals should be characterized by minimal interventions with maximum results: effective, efficient, and most of all patient/client focused. PMID- 21298899 TI - [New hernia treatment in dogs]. PMID- 21298900 TI - [Pure bred dogs balance on a small genetic base]. PMID- 21298901 TI - [Bart Smit wants to close the gap between desk and members]. PMID- 21298902 TI - [Where is the (traditional) veterinarian?]. PMID- 21298903 TI - [Animal feed hygiene regulation]. PMID- 21298904 TI - [Veterinary medicine]. PMID- 21298905 TI - [Prologue. Recommendations-Clinical practice guideline for subarachnoid hemorrhage caused by ruptured intracranial aneurysm]. AB - To provide evidence-based clinical practice guidelines for managing subarachnoid hemorrhage due to spontaneous rupture of an intracranial aneurysm. The ultimate purpose of the guidelines is to contribute to improving quality of care and reduce unnecessary costs related to the application of futile treatments. Systematic review of the literature indexed in the principal databases. Articles identified were categorized according to levels of evidence (1 to 5) and recommendations that could be derived were classified according to strength (A, B, and C). Some recommendations cannot be based on randomized controlled trials because the utility of certain practices is already clear; no one will investigate them or it would not be ethical to do so. We bore in mind that while many current practices for which no evidence is available may be ineffective, but others may be highly effective even though proof may never be available. Therefore, the guidelines considered that lack of evidence must not be used as the only reason for limiting the use of a diagnostic method or treatment. Nor would lack of evidence be the reason for limiting the use of health care resources. PMID- 21298906 TI - [Subarachnoid hemorrhage: epidemiology, social impact and a multidisciplinary approach]. AB - Cerebrovascular disease, whether ischemic or hemorrhagic, is a worldwide problem, representing personal tragedy, great social and economic consequences, and a heavy burden on the health care system. Estimated to be responsible for up to 10% of mortality in industrialized countries, cerebrovascular disease also affects individuals who are still in the workforce, with consequent loss of productive years. Subarachnoid hemorrhage (SAH) is a type of cerebrovascular accident that leads to around 5% of all strokes. SAH is most often due to trauma but may also be spontaneous, in which case the cause may be a ruptured intracranial aneurysm (80%) or arteriovenous malformation or any other abnormality of the blood or vessels (20%). Although both the diagnosis and treatment of aneurysmal SAH has improved in recent years, related morbidity and mortality remains high: 50% of patients die from the initial hemorrhage or later complications. If patients whose brain function is permanently damaged are added to the count, the percentage of cases leading to severe consequences rises to 70%. The burden of care of patients who are left incapacitated by SAH falls to the family or to private and public institutions. The economic cost is considerable and the loss of quality of life for both the patient and the family is great. Given the magnitude of this problem, the provision of adequate prophylaxis is essential; also needed are organizational models that aim to reduce mortality as well as related complications. Aneurysmal SAH is a condition which must be approached in a coordinated, multidisciplinary way both during the acute phase and throughout rehabilitation in order to lower the risk of unwanted outcomes. PMID- 21298907 TI - [Neuroanesthetic management for surgical clipping of a ruptured cerebral aneurysm: clinical practice guidelines]. AB - Subarachnoid hemorrhage due to spontaneous rupture of a cerebral aneurysm is associated with high rates of morbidity and mortality and requires multidisciplinary treatment. The debate on surgical vs endovascular treatment continues, although short-term clinical outcomes and survival rates are better after endovascular treatment. In Spain, a strong trend toward reduced use of clipping has been noted, and neuroanesthetists are less often called on to provide anesthesia in this setting. Our intervention, however, can be decisive. The neuroscience working group of the Sociedad Espanola de Anestesiologia, Reanimacion y Terapeutica del Dolor has developed guidelines for managing anesthesia in these procedures. Based on a national survey and a systematic review of the literature, the recommendations emphasize the importance of ensuring appropriate intracranial conditions, treating complications, and taking steps to protect against cerebral hemorrhage. PMID- 21298908 TI - [Neuroanesthesia for embolization of a ruptured cerebral aneurysm: clinical practice guidelines]. AB - When the neuroanesthesia working group of the Sociedad Espanola de Anestesiologia, Reanimacion y Terapeutica del Dolor surveyed Spanish anesthesiologists to learn the degree of their involvement in the diagnosis and treatment of spontaneous subarachnoid hemorrhage, a surprising finding was that anesthetists did not participate in endovascular repair of intracranial aneurysms when the procedure was carried out in an interventional radiology department. These interventions, which are considered minimally invasive and are performed outside the operating room, are not risk-free. Based on the survey results and a systematic review of the literature, the working group has provided practice guidelines for the perioperative management of anesthesia for endovascular repair of ruptured cerebral aneurysms. In our opinion, the diversity of practice in the hospitals surveyed calls for the application of practice guidelines based on consensus if we are to reduce variability in clinical and anesthetic approaches as well as lower the rates of morbidity and mortality and shorten the hospital stay of patients undergoing exclusion of an aneurysm. PMID- 21298909 TI - [Neurologic complications of subarachnoid hemorrhage due to intracranial aneurysm rupture]. AB - The high rates of morbidity and mortality after subarachnoid hemorrhage due to spontaneous rupture of an intracranial aneurysm are mainly the result of neurologic complications. Sixty years after cerebral vasospasm was first described, this problem remains unsolved in spite of its highly adverse effect on prognosis after aneurysmatic rupture. Treatment is somewhat empirical, given that uncertainties remain in our understanding of the pathophysiology of this vascular complication, which involves structural and biochemical changes in the endothelium and smooth muscle of vessels. Vasospasm that is refractory to treatment leads to cerebral infarction. Prophylaxis, early diagnosis, and adequate treatment of neurologic complications are key elements in the management of vasospasm if neurologic damage, lengthy hospital stays, and increased use of health care resources are to be avoided. New approaches to early treatment of cerebral lesions and cortical ischemia in cases of subarachnoid hemorrhage due to aneurysm rupture should lead to more effective, specific management. PMID- 21298910 TI - [Systemic complications of subarachnoid hemorrhage from spontaneous rupture of a cerebral aneurysm]. AB - Systemic complications secondary to subarachnoid hemorrhage from an aneurysm are common (40%) and the mortality attributable to them (23%) is comparable to mortality from the primary lesion, rebleeding, or vasospasm. Although nonneurologic medical complications are avoidable, they worsen the prognosis, lengthen the hospital stay, and generate additional costs. The prevention, early detection, and appropriate treatment of systemic complications will be essential for managing the individual patient's case. Treatment should cover major symptoms (headache, nausea, and dizziness) and ambient noise should be reduced, all with the aim of achieving excellence and improving the patient's perception of quality of care. PMID- 21298911 TI - [Statement for an adjustment in the offer of medical resident vacancies in pediatric surgery]. PMID- 21298912 TI - [Nonpalpable testes: short, middle and long-term results with the use of an exclusively laparoscopic technique]. AB - Non palpable testis (NPT) has an incidence of 20% and clinical relevance derived from the possibility of malignant degeneration, fertility disfunction. Recently the development of minimally invasive surgery (MIS) allowed more accurate diagnosis and has become a new therapeutic tool. We carried out a retrospective study that included all the patients who underwent laparoscopic orchidopexy between 1998 and 2008. 156 patients were reviewed, which represent 179 testis units (TU). In 65 occasions the testis was placed in the internal inguinal orifice and in 68 occasions the testis was purely intraabdominal. Testicular atrophy was evidenced in 32 cases (7%). Laparoscopic orchidopexy was carried out in 152 TUs except in those that developed agenesia or atrophy-. A prothesis was placed after removing the remaining testis. 18 cases required a FowlerStephens. Inmediate postoperative complications were oedema (18 cases) and escrotal hematoma (9 cases). Testicular atrophy appeared in 12 cases after descent and in 3 cases after the first stage of the FowlerStephens. In 8 cases it was necessary to proceed to a second descent because of ascent after surgery. Laparoscopic orchidopexy has proved to be an efficient technique for the management of NPT which unifies the advantages of MIS and the outcomes of the conventional opened approach. PMID- 21298913 TI - [Pneumonectomy in children]. AB - BACKGROUND/AIM: Pneumonectomy is seldom indicated in children and its long-term effects are not well known. The aim of the present study was to examine retrospectively the indications and the long-term sequelae in a relatively large cohort of patients treated at our institution. MATERIAL AND METHODS: We reviewed the charts of children undergoing pneumonectomy between 1969 and 2009 with particular attention to indications, techniques, complications, survival, pulmonary function and spine deformities RESULTS: Ten patients (M:F=6/4) aged 102 +/- 66 months underwent pneumonectomy for bronchiectasis (4, one with cystic fibrosis), tumors (4, 1 myofibroblastic inflammatory pseudotumor, 1 bronchial carcinoid, 1 primary pulmonary PNET and 1 massive metastasis of osteosarcoma) and malformations (2, 1 pulmonary sequestration and 1 congenital bilobar emphysema). Overall survival was 90% at 5.6 (0.3-23) years. Patients with bronchiectasis improved markedly except the one with cystic fibrosis who died. All children with tumors cured. Four have some degree of scoliosis which is severe in one with malformative costal fusion. All survivors live unrestristricted normal lives. Postoperative respiratory function is well preserved with FVC of 58% (40-70%), FEV1 of 60% (47-84%) and FEV1/FVC of 92% (87-98%) of the theoretical value for their height and weight. CONCLUSIONS: Pneumonectomy does not affect by itself to the overall survival, and the respiratory function is good and there is no impairment of the quality of life. PMID- 21298914 TI - [Hypertrophic pyloric stenosis: comparison between transversal and supraumbilical incision]. AB - BACKGROUND/PURPOSE: The treatment of hypertrophic pyloric stenosis is the Fredet Ramstedt pyloromyotomy. It is controversial what surgical approach to choose. We evaluate our outcome with the right upper quadrant (RUQ) and the supraumbilical (SU) approach. METHODS: Between 2003 and 2007, we performed 38 pyloromyotomies through a RUQ incision and 18 through a SU approach. We analyze patient demographics and pre and postoperative data. We group the complications in major (duodenal perforation, inadequate pyloromyotomy, and wound dehiscence) and minor (seroma, hematoma, wound infection and incisional hernia). A nonrandomized comparison was performed between the two groups. RESULTS: We find significant differences in morbidity: 22.2% of major complications ocurred in the SU group versus 2.6% in the RUQ group, and 44.4% of minor complications were encountered in the SU group versus 2.6% in the RUQ group (P < 0.005). CONCLUSIONS: In our study we found a significantly higher overall complication rate in the SU group (p < 0.005), possibly because of a more difficult delivery of the pylorus through the SU incision and because of a probably increased rate of wound infection associated with the supraumbilical approach in the pediatric population. PMID- 21298915 TI - [Structural alterations of the smooth muscle and of the EGFR expression and C-kit in congenital pyeloureteral stenosis. Relationship with its pathogenesis]. AB - PURPOSE: To assess the role that the muscular dysplasia, epidermal growth factor (EGFR) and interstitial cells of Cajal (ICC) C-kit +, may have in the pathophysiology of pyeloureteral stenosis (EPU). MATERIALS AND METHODS: 30 samples were studied UPJ (ureteropelvic junction), with 25 UPJ obstruction and 5 controls. Performed with Masson's trichrome staining and immunohistochemical techniques for smooth muscle actin, EGFR (epidermal growth factor) and CD117 (C kit) (Dako). We compared the results statistically. RESULTS: The control group was diffuse positivity of EGFR in the muscle layer in samples of EPU was positive in 4%, weak in 16% and negative in 80%. The controls are C-kit + ICC between the muscle cells showed a decreased density in the samples of obstruction. Masson's trichrome highlighted the increase of inter-and intramuscular collagen and attenuated muscle fibers, thinner and individualized, in the inner muscular layer of the cases of EPU also evident with the actin. Differences between groups were statistically significant (p < 0.001). CONCLUSIONS: Our results suggest that dysplastic changes in the muscle layer, the low expression of EGFR and the decrease or absence of C-kit + ICC, may participate in the pathophysiology of UPJ obstruction. PMID- 21298916 TI - [Treatment of lymphatic malformations with OK-432 sclerosis. Our experience]. AB - INTRODUCTION: The elective treatment of lymphatic malformations has always been surgical resection. However sclerotherapy with a variety of substances is being used as an alternative to surgery specially in the last years. The aim of this essay is to present our results using sclerosis with OK-432. MATERIALS AND METHODS: We have reviewed all patients affected by lymphatic malformation that have been treated by sclerosis with OK-432. Each procedure was performed under general anesthesia by a radiologist and a pediatric surgeon. RESULTS: Fifteen patients have been treated. On the whole, 36 procedures have been performed, with a mean of 2.4 for each patient. The mean amount of OK-432 injected was 1.5 milligrams (mg) in each procedure. 73% of the patients showed nearly complete or complete response. There were two complications; one of them was a limited bleeding and the other one, a case of high fever resolved by antipyretics and antibiotics. Microcystic or mixed malformations required a higher number of procedures and presented poorer response. CONCLUSION: Sclerotherapy with OK-432 is an effective and safe treatment for lymphatic malformation specially the macrocystic ones, therefore it should be considered as first line therapeutic option. PMID- 21298917 TI - [PHACES syndrome]. AB - INTRODUCTION: PHACES syndrome associates a segmental facial hemangioma with cerebral malformations, aortic branches/cranial arteries anomalies, cardiac defects, eye anomalies or ventral wall defects. The aim of this study is to analyze our experience with this syndrome. MATERIAL AND METHODS: Retrospective study of the cases seen at our unit in the last year. RESULTS: We treat 4 cases; 3 girls and 1 child. Besides the segmental hemangioma they presented: 3 vascular cerebral malformations; 2 structural cardiopathies; 2 cerebral malformations, 1 microftalmia. We did not find ventral wall defects. A case received treatment with two cycles of metilprednisolone i.v. and oral prednisone, with favourable course; two cases received initial treatment with oral prednisone continued of oral propanolol in rising pattern up to 2 mg/kg/day, Obtaining both the detention of the tumour growth and regression of the lesion, with very good tolerance. A 7 year-old patient has been treated with colouring pulse laser for her residual lesions. CONCLUSIONS: When we see a segmental facial hemangioma we must perform a wide diagnostic study in order to discard a PHACES syndrome. Multidisciplinar approach to the patient by a wide expert's group gets an earlier diagnose and improves the outcome. Propranolol is a promising therapeutic alternative. PMID- 21298918 TI - [Laparoscopic living donor nephrectomy: functional repercussion in the pediatric recipient]. AB - AIM: The impact of laparoscopic (LDN) vs. open nephrectomy (ODN) on early graft function and survival in pediatric kidney recipient remains unclear. MATERIAL AND METHOD: We retrospectively review the records of 63 pediatric recipient of living donor renal trasplant from 1994 to 2007. We compared those who recieved allograft recovered by LDN (n: 16) with those by ODN (n: 47). The mean recipient age was 9.3 +/- 5 years and the mean donor age was 40.8 +/- 7 years. Outcomes of interest included the incidence of delayer graft function, acute rejection and long-term graft function. RESULTS: Donor, recipient, demographic data and the total time of cold ischemia (1.9 +/- 0.3 hours) were similar in both groups. The mean of kidney warm ischemia was (195 LDN vs. 20 ODN seconds). There were not any significant differences between the two groups, not even in the patient survival after 36 months (100% LDN vs. 98% ODN), neither in the graft survival with proportional hazards Cox analysis. The LDN group needed more days (9.56 +/- 2.3 vs. 4.72 +/- 0.57 ODN) to reach the minimum serum creatinine, but the GF (ml/min/1.73 m2) was similar at 6 months (122 +/- 12 LDN vs. 87 +/- 17 ODN), one year (139 +/- 45 LDN vs. 88 +/- 27 ODN), and two years (110 +/- 64 LDN vs. 82 +/- 30 ODN) after transplant. CONCLUSIONS: LDN delays the recovery of the graft function in pediatric recipient. Pediatric LDN recipient have graft outcomes comparable to those of ODN. PMID- 21298919 TI - [Evaluation of the SNAPPE-II and Metabolic Disorder Index as predictors of mortality in necrotizing enterocolitis]. AB - AIM: Several scores have been proposed to predict the outcome of patients with Necrotizing Enterocolitis (NEC). We compare the SNAPPE-II (Score for Neonatal Acute Physiology-Perinatal Extension-II) and the Metabolic Derangement Index for the outcome of mortality in neonates with NEC. METHODS: 99 patients diagnosed of NEC were reviewed retrospectively. The SNAPPE-II and ITM were applied at three moments: when the first diagnosis was made (T0), first evaluation by a pediatric surgeon (T1), and 24 hours after surgery (T2). ROC curves were obtained for each score. Comparison between curves of the area under the curve (AUC) was done with the method proposed for Hanley and McNeil for related curves. RESULTS: 34 patients underwent surgery. 17 patients died. The AUCs to predict mortality for SNAPPE-II were: 0.68 (CI 95%: 0,55-0,80) at T0; 0,62 (CI 95%: 0,43-0,81) at T1 ; 0.72 (CI 95%: 0,54-0,90) at T2. The AUCs for the metabolic derangement index were 0.67 (CI 95%: 0,54-0,82) at T0; 0,71 (CI 95%: 0,52-0,89) at T1 ; 0.78 (CI 95%: 0,62-0,94) at T2. No differences between AUCs were found using the method proposed by Hanley and McNeil for related curves (p=0,8 at T0; p=0,5 at T1; p=0,6 at T2). CONCLUSIONS: No statistically significant differences were found between the diagnostic performance of the SNAPPE-II and the metabolic derangement index to predict mortality in NEC. The diagnostic performance of both scores is lower than 80%, so its value might be limited. PMID- 21298920 TI - [The risk of necrotizing enterocolitis in newborns with congenital heart disease. a single institution-cohort study]. AB - BACKGROUND/AIM: Necrotizing enterocolitis (NEC) is the most common gastrointestinal surgical disease among neonates. Congenital heart disease (CHD) is also a significant cause of infant morbidity and mortality and it is usually associated with prematurity, low birth weight, pulmonary and gastrointestinal disease, conditions that also account for the development of NEC. Our aim is to analyze the incidence and the risk factors for NEC in neonates with CDH admitted to the Neonatal Intensive Care Unit (NICU) in a 6 years period. METHODS: All patients admitted in the NICU for any type of CDH from January 2003 to December 2008 comprised the cohort of this study. The primary outcome measure was the development of NEC in any stage. Sixteen independent variables were selected to include those factors previously correlated with NEC. Uni and multivariate statistical analysis were performed with SPSS 15.0 for Windows. Relative Risks (RR) are presented with 95% confidence intervals. RESULTS: 935 out of the 7803 neonates admitted during this period, 935 (11.9%) presented a CHD. Among them, 70 also had NEC (RR 8.4-17.8), 31 requiring surgical treatment (Bell stages III and IV). The risk for NEC was specially increased if CHD needed surgical correction (2.1-5.1) and among babies with very low birth weight (VLBW, <1,500 g) (2-4.8). After multivariate analysis the only independent variables associated with an increased risk of NEC were birth weight less than 1,500 g (2.2-7.4), the need of surgical correction of CHD (2.2-7.1) and a clinical picture of septicaemia (1.1 3.9). CONCLUSIONS: The incidence of NEC is greater in neonates with CDH than in the normal newborn population. Early recognition of NEC should be warranted among CHD patients, specially in those with VLBW, surgical treatment of CHD and sepsis. In this sub-cohort of patients an increased risk of NEC should be suspected. PMID- 21298921 TI - [Our experience in the poly-traumatized pediatric patient with criteria for admission to the ICU]. AB - OBJECTIVE: To present our experience with severe pediatric trauma. The pediatric trauma is the leading cause of death in children under 2 years. METHODS: We achieved a retrospective study from 78 pediatric patients admitted to the Intensive Care Unit (UCI) for multiple trauma between 2000 and 2008. Age, sex, season, location, mechanism, Glasgow and ITP, type of injuries, complications, days of hospitalization and deaths were reviewed. It was performed descriptive and analytical study using the SPSS 15.0 and chi square and Pearson correlation were applied. OUTCOMES: The mean age of patients was of 8.5 +/- 4.2 years with 70% boys. Most accidents occurred in summer (37%) and the most common site was the road (47%). There was 15% of mortality, which the 75% occurred in the first 24 hours. There is an association between abdominal trauma and type of mechanism (p < 0.05). The most common mechanism was the traffic accident (45%) followed by a direct hit. Both ITP as Glasgow score were associated significantly with mortality and complications and with the hospital stay in the UCI there was a weak association but significant and negative (p < 0.05). CONCLUSIONS: Mortality is higher than other series but it may be because that these series include minor injuries. The fall down is the most frequent in pediatric emergencies but it was the mechanism that involves less admission to the UCI. Both ITP as Glasgow score are good indicators of severity and if their values decrease, the hospital stay in UCI and the mortality increase. PMID- 21298922 TI - [Thoracoscopic lobectomy: initial experience]. AB - AIM: Analizing our preliminary experience in the treatment of pulmonary malformations with thoracoscopic lobectomy. MATERIAL AND METHODS: We have reviewed our first cases of thoracoscopic lobectomy during last year (2008-09). We have performed 6 thoracoscopic lobectomies in 6 male patients with a mean age of 16 months (6 months-4 years). They were 3 lower lobectomies (2 right and one left), 2 right upper lobectomies and one lingular sparing left upper lobectomy. Lung lesion was a congenital cystic adenomatoid malformation in 5 (2 of them asociated with intralobar sequestration) and one lobar emphysema due to bronquial atresia. RESULTS: Selective bronchial intubation was used in 4 cases and and tracheal intubation with bronchial blocker in 2. There were no conversions to open thoracotomy. Mean operative time was 202' (155-250'). There were no intraoperative nor postoperative complications. None of these patients needed blood transfusion. Mean drainage time was 3.5 days (3-4 d) and mean discharge time was 4.8 days (4-7 d). With a mean follow-up time of 5.3 months (2 m-12 m), all of the patients have no symptoms and X-ray are normal. CONCLUSIONS: Thoracoscopic lobectomy is a safe and efective approach to treat congenital pulmonary pathology. The keys to perform it safely are good anesthetic management, adequate instruments for children size, and careful disection of broncovascular structures. Advantages of the minimal access surgery and implementation and miniaturization of the instruments and sealing devices will favor its progressive use. PMID- 21298923 TI - [Thoracoscopic lobectomy in pediatrics. Our experience and new treatment perspectives]. AB - OBJECTIVES: Pulmonary malformations in the child are a wide clinical and pathologycal spectrum. The congenital cystic adenomatoid malformation and the pulmonary sequestration both produce many symptoms, from the asymptomatic to the most complicated, and its management remains controversial. Moreover, in the last years many new publications show that this surgery can be perfectly accomplished with the thoracoscopic approach as an alternative to the tradicional open surgery. In this paper we analyse our experience in performing lobectomies with thoracoscopy. This technique shows to be safe and has less complications than tradicional thoracotomy. METHODS: During the period 2004-2008 lobectomies were performed in six patiens, with ages between one week and fifteen years. The diagnostics where CAM in four cases, associated to PS in one case; broncogenic cyst in none case, and cavitary pulomonar aspergilloma in one case. RESULTS: Five inferior and one median lobectomies were done. In two cases the patients had no symptoms before intervention, the other four cases were asymptomatic. In all cases the toracoscopy was performed with 3 or 4 ports of 3-5 mm. No mini thoracotomy was done in any case. There were nor intraoperatory neither postoperatory complications. In all patients were placed two thoracic drainages, being retired 3 to 4 days later. All patients, except one, remained five days in hospital. CONCLUSIONS: In this work, thoracoscopic lobectomy is confirmed as safe technique and with less complications and morbidity than the open lobectomy. Therefore, we suggest new posible aplications. PMID- 21298924 TI - [Adaptation in the small intestine: Effect of minimal enteral nutrition and probiotics on proliferation and apoptosis in the intestinal wall]. AB - BACKGROUND: The intestinal wall integrity is central to the barrier function and depends on the balance of proliferation/apoptosis. Short bowel (SB) or Parenteral Nutrition (PN) induce high bacterial translocation (BT) probably by the intestinal barrier bug. Probiotics or minimal enteral nutrition (MEN) have reduced BT in animal models. OBJECTIVE: Determine in two BT animal models (SB or PN) the effect of MEN or probiotics on proliferation and apoptosis rates of the intestinal wall. METHODS: Seventy-one Wistar rats, divided into 4 groups: 1) PN (N = 23): parenteral nutrition; 2) PNMEN (N = 16): PN + MEN (2.9 g/100 g/day standard diet); 3) RES (N = 15): 80% bowel resection and standard oral diet; 4) RESPROB (N = 17): RES + probiotics (7 X 10(9) CFU Bifidobacterium lactis). After 10 days in metabolic cages, mesenteryc lymph nodes, portal blood and peripheral blood were cultured. By immunohistochemistry, proliferation and apoptosis index were calculated as well as the proliferation-apoptosis rate. RESULTS: BT: decreased in PNMEN (45%) and RESPROB groups (35%) versus PN (65%) and RES (67%) groups (p<0.05). Proliferation index: was better in PNMEN (12,07) and RESPROB (13,93) groups than PN (7,45) and RES (5,54) groups. (p0.05). CD34 immunoexpression was higher in the left side tumor location, stage D Dukes'a (p<0.05) and G2 (p<0.05). CONCLUSIONS: These results confirm that sporadic colorectal MMR-defective adenocarcinomas display certain specific morphological characteristics. However, these pathological features are not sufficiently predictive and immunohistochemistry is needed to identify such tumours accurately. The researches on angiogenesis of cancer cells can be used as prognostic factors for the patients with colorectal cancer. PMID- 21298984 TI - [Taxan induction chemotherapy and concomitant chemoradiotherapy with cisplatin in patients with locally advanced head and neck cancer--early results]. AB - The growing number of patients with head and neck cancer is a reason to search for new effective treatment strategies. Results of treatment for locally advanced squamous cell head and neck cancer with surgery and/or radiotherapy are still unsatisfactory. During last decade concomitant chemoradiotherapy became a new standard in this group of patients. The treatment method is charged of high toxicity and real therapeutic advantages are obtained by limited number of patients. Intensive clinical investigations on novel therapeutic strategies are in progress. One of them is the combination of induction chemotherapy with taxan (TPF) and concomitant chemoradiotherapy join with cisplatin. The aim of the study was to estimate the treatment tolerance and early term results with combination of induction chemotherapy with TPF and concomitant chemoradiotherapy join with cisplatin in patients with locally advanced, squamous cell carcinoma of head and neck. MATERIAL AND METHODS: Patients with locally advanced oropharyngeal and larynx cancer treated in the Institute of Oncology in Bialystok at the Department of Radiotherapy II from latter half of 2009 year were included in the study. The treatment protocol consisted of 3 courses of induction chemotherapy TPF (Taxotere 75 mg/m2, DDP 100 mg/m2, 5-Fluorouracyl 1000 mg/m2 every 3 weeks) and conventionally fractionated radiotherapy (Df=2 Gy, 5 x weekly) to total dose of 66-72 Gy and for neck cervical lymph nodes up to 60-66 Gy with concomitant of cisplatin 100 mg/m2 every 3 weeks. Early reactions were estimated according to EORTC/RTOG scales, and chemotherapy tolerance was evaluated according to the CTC scale. Twelve patients with homogenous criteria were included in the study. RESULTS: The treatment tolerance was acceptable. However several adverse reactions were present. The main adverse effect was the extensive mucosal reaction. Neutropenia and anemia were also observed in most of the patients. Some patients complained of diarrhea, vomiting and nausea in mild or moderate intensity which were persisted temporarily. CONCLUSIONS: Induction chemotherapy TPF and concomitant radiochemotherapy with cisplatin in patients with locally advanced head and neck cancer in III-IV clinical stages came out as the treatment of high efficacy. PMID- 21298985 TI - [Influence of low frequency magnetic field on chosen parameters of oxidative stress in rat's muscles]. AB - Free radicals are atoms, molecules or their fragments, which excess leads to the development of the oxidative stress, which is caused of many neoplasmic, neurodegenerative, inflammatory diseases and aging the organism. The main of exogenous sources of free radicals are among others: industrial pollution, tobacco smoke, ionizing radiation, ultrasound and magnetic field. The low magnetic field is applied in the physician therapy. The aim of this study was to evaluate the influence of low magnetic field on the parameters of oxidative stress in rat's muscles. MATERIALS AND METHODS: Thirty male rats, weight of 280 300 g were randomly divided into three experimental groups: control I and treatment II and III (ELFMF-exposed), each containing seven animals. Animals in treat group II were exposed to 40 Hz, 7 mT for 0.5 h/day for 14 days (this kind of the ELFMF is mostly use in magnetotherapy) while, group III was exposed to 40 Hz, 7 mT for 1 h/day for 14 days. Control rats were in separate room without exposing to ELFMF. Immediately after the last exposure, the part of muscles was taken under pentobarbital anaesthesia. The effects of exposure to ELFMF on oxidative states were assessed on the measurements of concentration of -SH group, H2O2, and the concentration of proteins in muscles homogenates. RESULTS: Exposure to ELFMF: 40 Hz, 7 mT, 30 and 60 min/day used for 2 weeks caused significant increase in -SH group concentration and decrease of the protein concentration in the muscles homogenates. CONCLUSION: Low magnetic field used in magnetotherapy causes the significant changes of the generating the reactive forms of oxygen in the muscles which depend on the parameters of low magnetic field. PMID- 21298986 TI - [Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy in Poland]. AB - Results of a multicenter, non-interventional, observational study assessing efficacy and safety of 1st course rituximab treatment with methotrexate in patients with rheumatoid arthritis and a history of inadequate response to anti TNF-therapies, in the routine clinical settings in Poland (MIRACLE-POL 1). The aim of the study was to determine the efficacy and safety of treatment with rituximab and methotrexate in patients with active rheumatoid arthritis (RA) who had inadequate response to anti-TNF-therapies in routine clinical settings in Poland. MATERIAL AND METHODS: We evaluated effectiveness and safety of RTX and MTX therapy in 73 patients enrolled in the multicenter, non-interventional, observational study. Patients with active RA had a history of an inadequate response to 1 or more anti-TNF-alpha agents received 1st course of rituximab consisting of 2 intravenous infusions of 1000 mg each. The end points were: EULAR response criteria at 180 days, changes of Disease Activity Scores in 28 joints (DAS28) from the original baseline at 180 days, rate of remission, rate of low disease activity according to EULAR criteria and rate of adverse events (AEs) during treatment. RESULTS: At 180 days 22% of treated patients demonstrated good to-moderate EULAR response and 12% of patients demonstrated moderate response. In 77% of cases DAS28 decreased > 1.2. 16% of patients achieved remission according to EULAR criteria and 23% of patients achieved low disease activity. After 180 days mean DAS28 score decreased from 6.33 to 4.06. In 16% of patients AEs occurred with the first rituximab infusion, in 12% of patients with the second rituximab one, and in 43% of patients afterwards. All AEs were mild or moderate in severity. There were no serious AEs including serious infections. Infusion associated AEs occurred in a higher proportion during the first infusion. CONCLUSIONS: Results of this multicenter, non-interventional, observational study confirm efficacy and safety of 1st course rituximab treatment with concomitant methotrexate in patients with rheumatoid arthritis who had inadequate response to anti-TNF-therapies in the routine clinical settings in Poland. PMID- 21298987 TI - [Cardiac tumors located of different areas: four cardiac chambers--four cases]. AB - One can seldom meet heart as a place of the cardiac tumors process in reference to both primary and metastatic changes. While taking transthoracic echocardiography one ought to remember of possibility of cardiac tumour in this particular place. In this case report presenting four cases of the cardiac tumors authors underline that this type of tumor can be found in each cardiac chamber. We show varied symptoms of cardiac tubers: beginning from lack of symptoms, through unspecific manifestations (syncopes, embolism) till signs connected with generalization of the proliferative process. PMID- 21298988 TI - [Primary hyperparathyroidism in patient with thyroid papillary cancer--case report]. AB - Patient with primary hyperparathyroidism and papillary thyroid cancer was presented. The female patient, 45 years old, because of papillary thyroid cancer was treated in the typical way by total strumectomy with lymphadenectomy following by 1131 therapy and L-thyroxine suppressive therapy. After 9 years, during one of control routine examinations, the serum levels of calcium and parathormone were increased (Ca2+: 1.449 mmol/l; Ca: 2.91 mmol/l; PTH: 256 pg/ml). Primary hyperparathyroidism was diagnosed and the patient underwent the surgery in the anterior cervical region with removal of parathyroid adenoma, histopathologically confirmed. Serum PTH level together with calcium levels decreased into the normal range. The coexistence of primary hyperparathyroidism and thyroid non-medullary cancer was already reported, but in this case the time of the onset was delayed. Due to the fact that patients after the treatment of thyroid non-medullary cancer, especially after of the neck radiation or radioactive iodine therapy, are more exposed to develop hyperparathyroidism, complete and wide examinations, even many years after treatment of thyroid cancer, are needed. PMID- 21298989 TI - [Vitamins E, A and C as antioxidatives]. AB - It has been found during last years that vitamins A, C, E and carotenoids, besides previously recognized functions of preventing particular lipido- and avitaminosis, significantly participate in the protection of the human body against oxidation stress that is characterized by balance disturbance between speed of free radical creation and reactive oxygen forms with pace of their neutralization by enzymes and antioxidants. The antioxidative system creates special protective barrier which includes numerous chemical form with antiperoxidative proprieties and vitamins are the most important part of it. The aim of this work was the profile of occurrence and antioxidative action of the vitamins A, C and E. PMID- 21298990 TI - [The role of interleukin-6 and C-reactive protein in gastric cancer]. AB - It has been suggested that interleukin-6 (IL-6) and C-reactive protein (CRP) play a potential role in the pathogenesis and growth of malignancies. CRP is produced by hepatocytes in response to inflammatory cytokines, especially IL-6. Production of IL-6 by gastric cancer cell lines has been reported. This cytokine may also act in a paracrine and autocrine fashion in tumor cells. Elevated concentrations of IL-6 and CRP were detected in the blood of patients with colorectal, lung, ovarian and gastric cancer. It has been shown that IL-6 and CRP levels correlated with clinicopathological features of gastric cancer, such as: tumor stage, depth of tumor invasion and the presence of lymph node metastasis. Some clinical investigations have suggested the potential significance of IL-6 as prognostic factor for the survival of gastric cancer patients. PMID- 21298991 TI - [Role of the matrix metalloproteinases activity in inflammatory bowel disease]. AB - Matrix metalloproteinases (MMPs) are a group of proteolytic enzymes participating in the metabolism of connective tissue. Imbalance between synthesis and degradation of MMPs can lead to pathological enhancement of synthetic or destructive processes causing ulceration or tissue fibrosis. The results of recent studies have been suggesting that inflammatory bowel disease may be accompanied by elevated levels of MMPs. PMID- 21298992 TI - [Probiotics in chronic liver diseases]. AB - Recent studies have shown that bacterial intestinal dysbiosis, frequently seen in patients with advanced liver cirrhosis may play an important role in the development of serious complications of this condition. The use of probiotics in this context is an attractive idea because of their ability to modulate intestinal flora, improve gut barrier, and their immunomodulatory and anti inflammatory properties. Both animal and preliminary human studies have demonstrated efficacy of probiotics in reducing infection, hemodynamic disturbance, improving hepatic encephalopathy, parameters of liver function and histology in patients with liver disease. Probiotics are thought to be safe in this group of patients, nonetheless in view of a few studies reporting serious adverse effects in critically ill or immunosupressed patients, caution must be exercised once they are used. PMID- 21298993 TI - [The role of immune system in inflammatory pain pathophysiology]. AB - Despite of many years of research, the data regarding interactions between the peripheral nervous system and the immune system remain incomplete. Most discoveries concern nociceptive signaling pathways. Among pain conditions with the utmost social implications, a large percentage exhibits the inflammatory process as an underlying cause. Here the most prominent are several disorders associated with the trigeminal nerve, including migraine, trigeminal neuralgia, and temporomandibular disorders. The molecular mechanisms of the trigeminal nociceptive transmission in general, and chronic trigeminal pain in particular, are almost completely unknown. Recent studies have shown that cytokines IL-1beta, IL-6 and TNF-alpha play a very important role in the pathogenesis of the immune response within the peripheral endings of trigeminal ganglion neurons. It has also been demonstrated that some proinflammatory cytokines (e.g., IL-1beta, TNF alpha) are capable of sensitizing nociceptive neurons. Modulation of inflammatory response can thus influence pain reaction. PMID- 21298994 TI - [Empathy-building of physicians. Part IV--development of skills enhancing capacity for empathy]. AB - Communication and narrative skills development is considered as an essential prerequisite to acquire and exhibit empathic behavior in clinical context. Students' capacity for empathy can be also enhanced by their ability to control own emotion and stress level. Thus, educators have developed and implemented educational programs to improve students' interpersonal communication and narrative skills as well as stress management skills. The objective of this paper is to describe ways in which communication, narrative, and stress management skills are enhanced and developed in medical students. We also aim at showing the impact of different programs offered to students, on the students' level of empathy. We searched PubMed, ProQuest, ERIC, MedLine, and Polish Medical Bibliography--published from 1990 to the present--for studies that address issues of development of skills positively associated with empathy. Review of relevant papers reveals that students participating in those various forms of training have reported an increased sensitivity to patients' experiences associated with illness. Despite the fact that exposure to role models has been found an important factor for enhancing empathy, the studies show shortage of appropriate role models among medical school faculty. PMID- 21298995 TI - [Frequency and clinical course of biliary lithiasis in patients with severe preeclampsia]. AB - BACKGROUND: Biliary lithiasis in patients with severe preeclampsia has not been well studied. OBJECTIVE: To describe the frequency and clinical course of biliary lithiasis in patients with severe preeclampsia. PATIENTS AND METHOD: Cross sectional study on 141 women with severe preeclampsia who had an abdominal ultrasound performed during the pre-partum period or in the immediate puerperium. Patients were treated in the Intensive Care Unit of the Hospital de Ginecologia y Obstetricia num. 3, Centro Medico Nacional La Raza, IMSS (Mexico), in the period of November 26, 2006 to June 26, 2009. Findings from gallbladder lithiasis (sand, solitary stone, multiple stones or wall calcification) and choledocho conduit were reported. Significant maternal data (clinical and laboratory) and perinatal results of patients without stones (group A) were compared to patients (group B) with stones. Measures of central tendency and dispersion, and T-test were used. RESULTS: Frequency of gallbladder lithiasis was 15% (21 cases). Solitary stone were found in 12 cases, multiple stones in seven cases and gallbladder calcification in two cases. There were no cases of choledocholithiasis. Epigastric pain was present in 13 cases (9.2%: group A, 10 cases [7.1%] vs. group B, 3 cases [2.1%], p = 0.06). There were no complications in patients with lithiasis and none required invasive procedures. Clinical evolution and perinatal results were similar in both groups. Duration of stay in the intensive care unit was similar (group A, 2.2 +/- 0.18 days vs. group B, 2.1 +/- 0.13 days, p = 0.86). CONCLUSION: The frequency of biliary lithiasis in patients with severe preeclampsia was 15%. There were no adverse effects on the maternal clinical course or on the perinatal results. PMID- 21298996 TI - [Pregnancy and labor activity: is there really risk?]. AB - BACKGROUND: In the last decades the participation of women in the family economy has increased causing in theory a higher risk for reproduction. OBJECTIVE: To investigate whether labor negatively influences the course and culmination of pregnancy in women workers. PATIENTS AND METHOD: Descriptive and comparative cross-sectional survey made in the Hospital General de Zona num. 2, of the Instituto Mexicano del Seguro Social, in Aguascalientes city (Mexico), which included 154 working patients and a control group of 154 not working patients selected by pairs. The study period was from 1 February to 31 March 2010. The following variables were analyzed: age, marital status, education degree, occupation, pregnancy number, queries, weight increase, obstetric complications, obstetric event, family planning method after the obstetric event; sex, weight and gestational age of the newborn, years of labor and weekly hours labored. RESULTS: There are significant differences in favor of working women according to the background; while in progress and resolution of pregnancy there is virtually no difference. CONCLUSION: Work does not imply an increased obstetric complication or neonatal morbidity risk. PMID- 21298997 TI - [Pelvic exenterations for cervical cancer (prognosis factors)]. AB - BACKGROUND: Pelvic exenteration offers the last chance of cure for some patients with cervical cancer recurrent after radiation therapy. OBJECTIVE: To analyze factors associated with recurrence and survival after pelvic exenterations, based on a 40 years institutional experience. MATERIAL AND METHOD: Retrospective, longitudinal and closed study from files of patients who survived to exenterative procedures at Oncology Department at the Hospital General de Mexico, from January 1966 to December 2006, were screened in order to know risk factors predicting recurrence and survival in a follow up for at least three years. RESULTS: Prognostic factors in 161 patients eligible for this analysis were: diagnosis of recurrence prior 1 year 44/96 (45.8%) vs. 27/41 (65.8%) diagnosis after this time (p = 0.03), central recurrences 32/38 (84.2%) vs. 14/49 (28.5%) infiltration of lateral wall of the pelvis (0.0001), patients with 35 years old or less had a better prognosis when compared with the others: 23/33 (69%) vs. 60/128 (46%), (0.01); Infiltration of urinary bladder and or rectal wall 30/75 (40%) vs. 53/86 (61%) absence of these (0.006), tumor involving myometrium with or without adnexal metastases 6/25 (24%) vs. 77/136 (56%) absence of these reports (0.002), presence of three or more positive lymph nodes 5/16 (31%) vs. 56/90 (62%) absence of lymph nodes metastasis (0.02) and findings of hydronephrosis 2/15 (13.3%) vs. 13/19 (68.4%) of normal reports (0.01). CONCLUSIONS: Better evolution in this series was for patients who had central recurrences. PMID- 21298998 TI - [Total laparoscopic hysterectomy: descriptive study of institutional experience with 198 cases]. AB - BACKGROUND: Total laparoscopic hysterectomy is a useful surgery in current gynecology, specially, in cases where abdominal access is indicated. Total laparoscopic hysterectomy performance has increased in recent years. OBJECTIVE: To analyze the clinical characteristics and surgical variables of patients undergoing laparoscopic total hysterectomy for benign disease, performed at the Instituto Nacional de Perinatologia Isidro Espinosa de los Reyes, between 2007 and 2009. MATERIAL AND METHOD: Retrospective, longitudinal and descriptive study. Medical records of all patients with a noncancer diagnosis underwent laparoscopic hysterectomy were reviewed, at the Instituto Nacional de Perinatologia, between January 1, 2007 and December 31, 2009. RESULTS: 594 hysterectomies were performed, of which 37.3% were by laparoscopic surgery, within these 89.1% were through the total laparoscopic hysterectomy technique. Surgical indications were 58.6% for fibroids, 23.2% abnormal uterine bleeding and 18.2% for adenomiosis. Studied variables revealed an average surgical time of 139 + 66.9 min (range: 75 225 min), average surgical bleeding of 119.7 +/- 60.5 mL (50-350 mL), average uterine longitude of 12.4 +/- 2 cm (8-16 cm), average uterine weight 222.7 +/- 113.8 g (90-860 g), and average hospital stay of 2.3 +/- 0.5 days (2-4 days), all of these results within the range reported in the literature. CONCLUSIONS: Previous surgical interventions were observed as complications risk factors, 162 (81%) patients had previous surgeries, 29% with 2 c-sections, 20% with 3 or more and 27% had other non-obstetrical interventions. This technique is safe and reliable, it does not replace the vaginal access and with adequate training and equipment it may be performed in an efficient manner with satisfactory results in our population. PMID- 21298999 TI - [Care of insulin resistance in polycystic ovary syndrome]. AB - Polycystic ovary syndrome (PCOS) constitutes the main cause of anovulatory sterility with a near occurrence to 7 %. The PCOS have not a constant hormonal profile, for it has been necessary the employment of approaches like those of Rotterdam to establish the presence of this dysfunction. A surprising discovery was the demonstration of the effect of the insulin on the ovary, that which modified the concept of the specificity in the action of the insulin on certain tissues, therefore a resistance stage to the action of insulin induces a compensatory hyperinsulinism to try to stimulate all the tissues, but in secondary form increases the dysfunction of the ovarian steroidogenesis. There are drugs known as "insulin sensitizers", used in the treatment of certain forms of diabetes mellitus, among those are metformin and tiazolidinediones (roziglitazone and pioglitazone), recently a compound has been used with formulation of amino acids and oligoelements (Diamel) that neutralizes the free radicals reestablishing the intracellular signs of the insulin at cellular level. It is important to guide that long term without correct the PCOS could have back effect since the insulin resistance is associates to a higher risk of increasing impaired glucose, diabetes, dyslipidemia, atherosclerosis and vascular disease. Therefore, preventive measures should be implemented that at present time are to the reach. PMID- 21299000 TI - [First pregnancy achieved by modified natural cycle in a low responder patient's in Centro Medico Nacional 20 de Noviembre, ISSSTE]. AB - There was a patient who went to fertilization in vitro, the control ovarian stimulation was using GnRHa in the luteal phase and FSHr 500 IU, she had poor response so she went into a new stimulation protocol using GnRH antagonist. The follow up was made since the 3rd day of menstruation with ultrasound scans, when the follicle reached 14 mm, the antagonist was started with minimal dosage of FSHr until the administration of hCG 10,000 IU. Oocyte retrieval was performed 36 hours later. The embryo transfer was made after 72 hours, was transferred 1 embryo quality 1+, 2 cells, 10% fragmentation. This protocol is named natural cycle modified and is an option to achieve a pregnancy in patients with poor response with their own cells, when the patient refused oocyte donation or if there isn't that kind of program in the reproductive center like us because is not allowed. PMID- 21299001 TI - [Ballantyne syndrome or mirror syndrome]. AB - Ballantyne syndrome or mirror syndrome is a triad consisting of the presence of fetal hydrops, generalized edema placentomegaly mother. May be related to any cause of fetal hydrops. The fetal prognosis is poor in untreated cases, the mother has reference to be the cause or the termination of pregnancy. Present the case of a 26-year-old who developed mirror syndrome secondary to non-immune fetal hydrops of unknown origin, accompanied by preeclampsia. PMID- 21299002 TI - [Prenatal diagnosis of cleft palate by 3D ultrasound]. AB - A case of a fetus seen at 33.2 weeks of gestation who was diagnosed with cleft lip in the third quarter by routine ultrasound. Describes the sequential steps that led to a multidisciplinary support the diagnosis of cleft palate by three dimensional image reconstruction, which were originally obtained to demonstrate the fetal face surface. Birth confirmed the prenatal findings and established the diagnosis of cleft lip and cleft hard and soft palate. It has been reported that the diagnosis of facial clefts can be done with relative ease prenatally, but the detection rate of facial clefts in routine tests is only 20%. Until recently the diagnosis of cleft palate is not considered possible, however in recent years advances in three-dimensional technology has made possible the development of techniques for the assessment of the palate and various authors have reported promising results of ingenious applications that make think that in the near future will approach the palate a fact. We discuss the advantages and disadvantages of these methods are relatively new and highlights how valuable this information is for parents of the affected creature. PMID- 21299003 TI - [Three auxiliary medications in obstetrics. 1955]. PMID- 21299004 TI - COMMENTARY. In vivo temperature measurement: tooth preparation and restoration with preheated resin composite. PMID- 21299005 TI - COMMENTARY. Effect of artificial aging on the roughness and microhardness of sealed composites. PMID- 21299007 TI - Death in the Hippodrome: sexual politics and legal culture in the reign of Mehmet IV. PMID- 21299006 TI - Radiobiological characterization of post-lumpectomy focal brachytherapy with lipid nanoparticle-carried radionuclides. AB - Post-operative radiotherapy has commonly been used for early stage breast cancer to treat residual disease. The primary objective of this work was to characterize, through dosimetric and radiobiological modeling, a novel focal brachytherapy technique which uses direct intracavitary infusion of beta-emitting radionuclides (186Re/188Re) carried by lipid nanoparticles (liposomes). Absorbed dose calculations were performed for a spherical lumpectomy cavity with a uniformly injected activity distribution using a dose point kernel convolution technique. Radiobiological indices were used to relate predicted therapy outcome and normal tissue complication of this technique with equivalent external beam radiotherapy treatment regimens. Modeled stromal damage was used as a measure of the inhibition of the stimulatory effect on tumor growth driven by the wound healing response. A sample treatment plan delivering 50 Gy at a therapeutic range of 2.0 mm for 186Re-liposomes and 5.0 mm for 188Re-liposomes takes advantage of the dose delivery characteristics of the beta-emissions, providing significant EUD (58.2 Gy and 72.5 Gy for 186Re and 188Re, respectively) with a minimal NTCP (0.046%) of the healthy ipsilateral breast. Modeling of kidney BED and ipsilateral breast NTCP showed that large injected activity concentrations of both radionuclides could be safely administered without significant complications. PMID- 21299008 TI - Unmarried motherhood in twentieth-century England. AB - This article explores the experiences of unmarried mothers who kept and tried to raise their children between World War One and the end of the twentieth century. It argues that there has not been a simple progression from their experiencing social stigma and ostracism to more enlightened attitudes since the 1970s. Rather there is a great deal that has hitherto been unknown about what the evidence suggests were very diverse experiences and attitudes throughout the period. A major change since the 1970s has been from pervasive secrecy about unmarried motherhood, cohabitation, adultery and similar 'irregular' practices, especially among the middle classes, to greater openness. The article uses a variety of sources, including the records of the National Council for the Unmarried Mother and Her Child (founded in 1918, now One Parent Families), oral histories, contemporary interviews and official and unofficial investigations. PMID- 21299009 TI - "Revolting to humanity": oversights, limitations, and complications of the English Legitimacy Act of 1926. AB - This article analyses three areas that limited the effectiveness of the English Legitimacy Act of 1926. First, re-registration was public, expensive, and time consuming. Second, the Treasury Office used the change in the law of intestacy to refuse more distant relatives' claims on estates. Third, the law separated legitimacy from nationality, thus denying citizenship to legitimated children born abroad of British fathers and foreign mothers. In short, both because of parliamentary oversights and civil servants' narrow interpretations of the law, relatively few children took advantage of the Act, and the minority who did, rather than being 'illegitimate' or 'legitimate', were a third category, the 'legitimated'. PMID- 21299010 TI - The other woman and her child: extra-marital affairs and illegitimacy in twentieth-century Britain. AB - This article investigates the numbers of 'other women' and their children up until the 1960s in Britain. It analyses 'irregular and illicit unions' in the records of the National Council for the Unmarried Mother and her Child (now One Parent Families/Gingerbread), and explores evidence on these unions in the debates over the passage of the Divorce Acts of 1923 and 1937 as well as the Legitimacy Acts of 1926 and 1959. It suggests that the prevalence of illicit unions throughout the twentieth century and before allows us to question contemporary concerns about our supposed 'divorcing society' and the decline of family life in modern Britain. PMID- 21299011 TI - The experience of pregnancy and childbirth for unmarried mothers in London, 1760 1866. AB - This article explores the experience of pregnancy and childbirth for unmarried mothers in the metropolis in the eighteenth and nineteenth centuries. It draws upon, in particular, the infanticide cases heard at the Old Bailey between 1760 and 1866. Many of the women in these records found themselves alone and afraid as they coped with the pregnancy and birth of their first child. A great deal is revealed about the birthing body: the ambiguity surrounding the identification of and signs of pregnancy, labour and delivery, the place of birth and the degree of privacy, and the nature of, and dangers associated with, solitary childbirth. PMID- 21299013 TI - "The case for boosting infant male circumcision in the face of rising heterosexual transmission of HIV" ... and now the case against. Comment. PMID- 21299014 TI - Unmarried mothers in Ireland, 1880-1973. AB - This article explores the changing experiences and representation of Ireland's unmarried mothers from 1880 to 1973. It focuses on the stigma of illegitimacy in political and cultural discourse and the representation of unmarried mothers as immoral and their children as a drain on resources. These remained constant themes within the discourse of unmarried motherhood in Ireland throughout the nineteenth and twentieth centuries. The article uses the records of philanthropic, government and religious organisations to chart the rising interest in the moral reformation of unmarried mothers at the end of the nineteenth century and rising tolerance towards them by the end of the twentieth century. PMID- 21299016 TI - "The case for boosting infant male circumcision in the face of rising heterosexual transmission of HIV" ... and now the case against. Comment. PMID- 21299015 TI - Changing notions of lone motherhood in twentieth-century Finland. AB - Through written life stories of lone mothers, this article examines changes in lone motherhood in twentieth-century Finland. While the older life-story writers' narratives are clearly influenced by an 'ethos of survival' and the regulation of female sexuality, the younger writers relate their experiences with the help of scripts on gender equality and the psychological importance of 'good' parenting. These narrative shifts point to important changes in cultural scripts on women's positions in families, on the labour market, and in society. PMID- 21299017 TI - For better or for worse? The dilemmas of unmarried motherhood in mid-twentieth century popular British film and fiction. AB - This article investigates representations of unmarried motherhood in the late 1940s and early 1950s through readings of popular British film and fiction. These sources are used to illustrate contradictions and conflicts in the meanings afforded to unmarried motherhood and, in turn, to highlight how the unmarried mother was used as a motif for exploring post-war normative boundaries around marriage, motherhood, and female sexuality. The article draws upon Raymond Williams's idea of a 'structure of feeling' to make connections between these representations and issues and debates about the role and status of women and mothers more generally in post-war Britain. PMID- 21299018 TI - "The case for boosting infant male circumcision in the face of rising heterosexual transmission of HIV" ... and now the case against. Comment. PMID- 21299019 TI - "The very model of modern urban decay": outsiders' narratives of industry and urban decline in Gary, Indiana. AB - In the eyes of many, the steel city of Gary, Indiana, entered a period of decline in the middle of the twentieth century. The once great city was seemingly racked by job loss, crime, racial division, or moral decay. Which of these caused the decline of the city depended upon the perspective of the story's teller. Each narrative of decline contained a different moment where the city went wrong and it began to decay. For some it was the moral decay of the 1950s, for others it was the rise of black power and politics in the 1960s, for still others it was the white backlash against civil rights in the 1970s. Some saw a microcosm of America, some saw a dangerous cauldron of race and ethnicity. The source of decline and the origins of the urban crisis were largely in the eye of the beholder. The stories people chose to tell about Gary mattered because for much of the twentieth century, Gary was at the center of American narratives about industrialism. These were outsider narratives of decline read onto the Indiana steel city because Gary represented larger debates. People read onto Gary their changing expectations and anxieties about industry and industrial spaces. This article traces the changing attitudes outsiders held toward Gary from the middle of the twentieth century through the period of deindustrialization at the end of the century and examines American narratives about deindustrialization and urban decline. PMID- 21299020 TI - General Neurology. PMID- 21299021 TI - Envisioning disaster in the 1910 Paris flood. AB - This article uncovers the visual narratives embedded within the photography of the 1910 Paris flood. Images offered Parisians multiple ways to understand and construe the significance of the flood and provided interpretive frameworks to decide the meaning of this event. Investigating three interlocking narratives of ruin, beauty, and fraternite, the article shows how photographs of Paris under water allowed residents to make sense of the destruction but also to imagine the city's reconstruction. The article concludes with a discussion of the role of visual culture in recovering from urban disasters. PMID- 21299023 TI - "But burn - no": the rest of the crowd in three civil disorders in 1960s Chicago. AB - Examining the internal dynamics of three civil disturbances on the West Side of Chicago during the late 1960s, this article describes the presence of numerous people who were not participating in the upheaval. It pays particular attention to "counterrioters," civilian residents of the neighborhoods and members of local organizations, who tried to persuade those engaging in violence to stop. Local dissent from the tactic of violence suggests that historians should describe these events using the neutral language of social science rather than the politically loaded labels of "riot" or "rebellion." The article argues that American historians of urban disorders should use the methods of European scholars of the crowd to study the actions of participants in order to ascertain their political content, rather than relying on an examination of their motives. PMID- 21299024 TI - Reconciling beauty and utility in early city planning: the contribution of John Nolen. AB - In the history of city planning, the dichotomy between the aesthetic aspirations of the City Beautiful and City Practical movements is overstated. The aesthetic impulse did not disappear but persisted as an important thread through the development of comprehensive planning approaches into the 1920s. The nexus between beauty and utility was negotiated and expressed across four main discourses: broad social improvement, aesthetic functionality, economic rationality, and holistic design. Ultimately, beauty became wedded to utility within the very nature of the comprehensive city plan itself. The work of the leading city planner John Nolen is central to an understanding of these historic continuities and informed the early evolution of city planning theory and practice. Nolen's challenge to the City Beautiful paradigm, while still retaining an artistic sensibility, reaestheticizes scholars' appreciation of the City Practical. PMID- 21299025 TI - [Public health and agrarian liberal politics in Spain: the Rural Health Bureau (1910-1918).]. AB - This paper reviews the meaning of the Rural Health Bureau (1910-1918) for the history of Spanish public health, thanks to a wealth of previously unknown sources found through a systematic search through medical journals of the time and the Bulletin of the national department of Agriculture. The Bureau was dependent of the Ministry of Development, in the same way as the competences on animal health. It aimed to provide a public health rationale for a plan of agrarian infrastructures, a goal resolved into a huge task of surveillance on hookworm disease, malaria, water supplies, and diet. Thus it becomes a perfect paradigm of the Spanish Liberal tradition of promoting information instead than actual changes into society, as well as a needed complement to the hydraulic policy sponsored by Rafael Gasset. PMID- 21299026 TI - [The professionalization of nursing in Argentina: political and institutional disputes during Peronism.]. AB - This paper discusses the professionalization of nurses in Argentina during Peron's administration (1946-1955). We will focus on two nursing schools during such period: Escuela de Engermas de la Secretaria de Salud Publica (1947) and Escuela de Enfermeras "7 de mayo" member of Fundacion Eva Peron (1950). We will analyze the institutional disputes over budgetary positions in the context of greater government intervention in public health issues. PMID- 21299027 TI - [The government's traffic idiocy]. PMID- 21299028 TI - [Screening, conflict of interest--yellow card]. PMID- 21299029 TI - [Sportsman's hernia]. PMID- 21299030 TI - In the news! An opinion - health for, or health of the people? PMID- 21299032 TI - Outbreak news. Yellow fever, Cote d'Ivoire. PMID- 21299033 TI - Meeting of the Global Advisory Committee on Vaccine Safety, December 2010. PMID- 21299034 TI - Outbreak news. Yellow fever, Cote d'Ivoire -update. PMID- 21299035 TI - Intraoperative imaging. Preface. PMID- 21299036 TI - Microwave effects on biological systems and nanoscience. Foreword. PMID- 21299037 TI - Microwave effects on biological systems and nanoscience. Foreword. PMID- 21299038 TI - Microwave effects on biological systems and nanoscience. Preface. PMID- 21299039 TI - Biological responses of mobile phone frequency exposure. AB - Existence of low level electromagnetic fields in the environment has been known since antiquity and their biological implications are noted for several decades. As such dosimetry of such field parameters and their emissions from various sources of mass utilization has been a subject of constant concern. Recent advancement in mobile communications has also drawn attention to their biological effects. Hand held children and adults alike generally use mobile sources as cordless phones in various positions with respect to the body. Further, an increasing number of mobile communication base stations have led to wide ranging concern about possible health effects of radiofrequency emissions. There are two distinct possibilities by which health could be affected as a result of radio frequency field exposure. These are thermal effects caused by holding mobile phones close to the body and extended conversations over a long period of time. Secondly, there could be possibly non thermal effects from both phones and base stations whereby the affects could also be cumulative. Some people may be adversely affected by the environmental impact of mobile phone base stations situated near their homes, schools or any other place. In addition to mobile phones, appliances like microwave oven etc are also in increasing use. Apart from the controversy over the possible health effects due to the non-thermal effect of electromagnetic fields the electromagnetic interaction of portable radio waves with human head needs to be quantitatively evaluated. Relating to this is the criteria of safe exposure to the population at large. While a lot of efforts have gone into resolving the issue, a clear picture has yet to emerge. Recent advances and the problems relating to the safety criteria are discussed. PMID- 21299040 TI - Effect of magnetic field on food and water intake and body weight of spinal cord injured rats. AB - Chronic (2 h/d x 8 weeks) exposure to magnetic field (MF; 50 Hz, 17.9 microT) in complete spinal cord (T13) transected rats restored food intake (FI), water intake (WI) and body weight (BW) which were decreased in the spinal cord injured rats. The results suggest a significant beneficial effect of chronic exposure to magnetic field of paraplegic rats. PMID- 21299041 TI - Mobile phone usage and male infertility in Wistar rats. AB - A significant decrease in protein kinase C and total sperm count along with increased apoptosis were observed in male Wistar rats exposed to mobile phone frequencies (2 h/day x 35 days at 0.9 W/kg specific absorption rate). The results suggest that a reduction in protein kinase activity may be related to overproduction of reactive oxygen species (ROS) under microwave field exposure. Decrease in sperm count and an increase in apoptosis may be causative factor due to mobile radiation exposure leading to infertility. PMID- 21299042 TI - Localization and characterization of tissue changes by laser backscattering imaging and Monte Carlo simulation. AB - Laser backscattering from biological tissues depends on their composition and blood flow. The onset of the tissue abnormalities is associated with the change in composition at a specific location which may affect laser backscattering. The objective of the present work is to detect the compositional changes in tissue equivalent phantom of fat, prepared by mixing paraffin wax with wax colors, and to characterize these in terms of their optical parameters. For this purpose these phantoms are scanned by a multi-probe non-contact automatic laser scanning system and images of the normalized backscattered intensity (NBI) are constructed. By scanning the background subtracted image of the phantom the location of the abnormality and its size from the full width at half maximum (FWHM) are determined. The data obtained by ultrasonic technique for localization of the abnormalities are in agreement with that as obtained by the present method. The optical parameters of the abnormality are obtained by matching the measured surface profiles of the abnormality with that of the profile obtained by Monte Carlo simulation. This analysis shows the possibility of detection of changes at the onset stage in tissues as required for planning of the photodynamic therapy. PMID- 21299043 TI - Dielectric studies of wheat in powder form at microwave frequencies. AB - Dielectric constant and loss factor of Raj-4120 variety of Indian wheat were determined in powder form (grain size 125 to 150 micron) at room temperature. Microwaves at three different frequencies were employed in C-band, X-band and Ku band respectively for investigating frequency dependence of dielectric parameters of the sample. Bulk dielectric values of the sample were determined by employing the dielectric mixture relations, such as, half power mixture equation, Landau and Lifshitz, Looyenga equation etc. PMID- 21299044 TI - Principles of nanoscience: an overview. AB - The scientific basis of nanotechnology as envisaged from the first principles is compared to bulk behavior. Development of nanoparticles having controllable physical and electronic properties has opened up possibility of designing artificial solids. Top down and bottom up approaches are emphasized. The role of nanoparticle (quantum dots) application in nanophotonics (photovoltaic cell), and drug delivery vehicle is discussed. Fundamentals of DNA structure as the prime site in bionanotechnological manipulations is also discussed. A summary of presently available devices and applications are presented. PMID- 21299045 TI - Scope of atomic force microscopy in the advancement of nanomedicine. AB - One of the most exciting fields of current research is nanomedicine, but its definition and landscape remains elusive due to its continuous expansion in all directions and thus constantly eroding its boundaries and defying definitions. This lack of conceptual framework and confusing definitions was a hurdle for policy makers to enunciate credible goals and allocate resources for the advancement of the field. In this mini review, we have provided a broad framework of nanomedicine which defines its elusive landscape, and we hope this framework will accommodate its explosive growth in the future. Also, we have highlighted the role and scope of atomic force microscopy techniques in the advancement of nanomedicine. For improving health care of all that eventually would require successful intervention at fundamental biological processes, the importance of understanding the structure-function relationship of biomolecules cannot be over emphasized. In this context, AFM and its variants play a pivotal role in contributing towards the nanomedicine knowledge-base that is required for fruitful developments in nano-diagnostics and nano-therapeutics. PMID- 21299046 TI - Interaction of soot derived multi-carbon nanoparticles with lung surfactants and their possible internalization inside alveolar cavity. AB - A systematic investigation of interaction of multi-carbon nanoparticles, obtained from soot, with dipalmitoyl phosphatidylcholine (DPPC), a clinical pulmonary phospholipid surfactant, sold under trade name "Survanta", was undertaken to establish a model for internalization of these nanoparticles inside alveolar cavity. In vitro experiments were carried out to establish the phospholipid assisted dispersion mechanism of carbon nanoclusters (size approximately 150 nm, zeta potential approximately -15 mV) in water. Results obtained from an array of experimental methods, like dynamic laser light scattering, electrophoresis, UV absorption spectroscopy, surface tension studies and transmission electron microscopy, revealed that the carbon nanoparticles interacted with DPPC predominantly via hydrophobic interactions. Selective surface adsorption of DPPC molecules on nanoparticle surface was found to be strongly dependent on the concentration of the phospholipid. DPPC, a gemini surfactant, formed a rigid monolayer around the carbon nanocluster even at nanomolar concentration and provided excellent stability to the dispersion. Based on the experimental data it is proposed that the free-energy gain involved in the hydrophobic interactions will facilitate the internalization of these nanoparticles on the inner wall of the alveolar cavity. PMID- 21299047 TI - Co-polymeric hydrophilic nanospheres for drug delivery: release kinetics, and cellular uptake. AB - Nanobiotechnology focuses on the biological effects and applications of nanoparticles that include nano-safety, drug encapsulation and nanotherapeutics. The present study focuses on hydrophilic nanospheres of copolymers N isopropylacrylamide [NIPAAM] and vinyl pyrrolidone [VP], encapsulating a bioactive derivative of 5-fluorouracil-hexyl-carbamoyl fluorouracil (HCFU). The size of the nanospheres was approximately 58 nm and the surface charge measured was -15.4 mV. Under optimal conditions, the yield was >80%, and the drug loading was 2%. The entrapment efficiency was approximately 75%. Wide-angle X-ray diffraction analysis showed that the entrapped HCFU was present in an amorphous state, which has higher water solubility compared with the crystalline state. Slow drug release from nanospheres was observed in PBS and serum, with approximately 80% released at 37 degrees C after 72 h. The HCFU loaded polymeric nanospheres have been found to be stable in whole blood having negligible RBC toxicity. Cytotoxicity in Mia-Paca 3, pancreatic cancer cell line was done in a 24-72 h assay. Dose dependant cytotoxicity was observed when incubated with various concentrations of HCFU loaded polymeric nanospheres while HCFU per se (<1 mg) showed 90% toxicity within 24 h. PMID- 21299048 TI - Development of transducer matrices based upon nanostructured conducting polymer for application in biosensors. AB - The nanostructured polyaniline (NSPANI) and its gold nano composite (GNP) with controlled size distribution were developed using structure directing agents (SDA). The nano structure of polyaniline were investigated by UV-Visible spectroscopy, transmission electron microscopy (TEM), dynamic light scattering (DLS), fourrier transform spectroscopy (FTIR), X-ray crystallography and scanning electron microscopy(SEM) etc. These characterization techniques reveal the spherical shape of polyaniline nanoparticles and size in the range of 7-50 nm depending on the type of dopant and nature of SDA. In general, these NSCP colloidal solutions are highly stable. UV-Visible spectra show mainly two peaks at 360-430 nm and at 780-870 nm. The bathochromic shift of the UV-Visible bands as compared to bulk polyaniline, reflect high DC conductivity. TEM and DLS results demonstrate the formation of nanostructure with narrow size distribution. Due to remarkable properties of, it is used as an efficient transduction matrice for the development of highly sensitive, reproducible, stable optical cholesterol and H202 biosensors having wide range of linearity and low Km values. PMID- 21299049 TI - Development of improved cleft lip/palate face models for teaching parents of children with cleft lip/palate. AB - OBJECTIVE: The objective of this study was to improve and evaluate cleft lip/palate face models to give support information to the parents whose children have cleft lip/palate. MATERIAL AND METHOD: Cleft lip/palate face models are made from a mold of about the same size as a child'head using rubber, wood and silicone and can be separated into parts to match the severity of the disease. The authors surveyed two representative samples of new candidate parents whose children had cleft lip/palate (10 in a pilot study then 30 in the larger study) and five nurses (who had taken care of the cleft lip/palate patients). The questionnaire was designed by the researchers and it had a Cronbach's reliability of a = 0.72. RESULTS: The result of the pilot evaluation revealed that the overall satisfaction score was high but the color of the models was not realistic so the satisfaction score was medium. After improvements of the colour and the post-surgical scar, the qualification and satisfaction scores were high (average 4.2). CONCLUSION: The authors present an improved cleft lip/palate face models for educational use to parents of children with cleft lip/palate. The models had an overall good level of satisfaction. Using face models to give information helped parents to know and understand about the condition, treatments, caregiving and scheduling age-determined visits for treatments. PMID- 21299050 TI - Craniofacial surgery for craniosynostosis: challenges in diagnosis, management and long-term outcome. AB - BACKGROUND AND OBJECTIVE: Craniofacial surgery for craniosynostosis is one of the most challenging reconstructive procedures. Restoration of particular functional and anatomic requirements is important for development from infancy to adulthood. The purpose of this study is to present the authors' experience of craniofacial surgery for management of patients with craniosynostosis in Srinagarind Hospital, Khon Kaen, Thailand, addressing the challenges of diagnosis, management and outcomes, which may be adapted in other developing countries. MATERIAL AND METHOD: This paper presents the cranial and associated deformities, diagnosis, radiologic findings, preoperative evaluation, craniofacial and maxillary surgeries and outcome(s) of patients with craniosynostosis. The care team, made up of neurosurgeons, plastic surgeons, radiologists, ophthalmologists and pediatricians, established the Tawanchai Center's protocol for craniosynostosis, to manage the timing of craniofacial procedures from infancy to adulthood. RESULTS: The physical examination and radiologic findings of three patients, two with sagittal synostosis and one with plagiocephaly are reported. The clinical, craniofacial and maxillofacial surgeries and long-term outcomes of another three patients were studied one with Apert syndrome and two with Crouzon syndrome. All the latter three patients were lost to follow-up after the initial post-surgical visit. At that time, there were appropriate surgical results vis-a-vis appearance and satisfaction from the perspective of the two patients with Crouzon syndrome and their families. One of the patients with Crouzon syndrome received normal education supported by a successful family, while the other was still continuing her studies at school with good progress. The patient with Apert syndrome continued to live with his parents. Additional reconstructive surgery is recommended for all three patients. Economic problems and lack of adequate information were the main reasons for their discontinuing follow-up appointments. DISCUSSION AND CONCLUSION: Systematic physical examination and radiologic assessments by the craniofacial team are critically important for diagnosis, evaluation, planning of management and outcome assessment of the patients with craniosynostosis. In Thailand and other developing countries, the challenges in management of these patients are the development of standard craniofacial surgery, craniofacial team management and well-coordinated care, planned surgeries and outcome assessments from infancy to adolescence. A supportive government health system and establishment of a craniofacial center and foundation is needed in order to support and provide proper care for these groups of patients. PMID- 21299051 TI - Primary unilateral cleft lip-nose repair: the Tawanchai cleft center's integrated and functional reconstruction. AB - BACKGROUND: The challenges of previously described techniques in unilateral cleft lip repairs inadequately address all deformities of the primary palate, the problems of scar and secondary deformities and achievement of optimum outcome. OBJECTIVE: To propose the integrated and functional reconstruction of primary unilateral cleft lip-nose repair and to present the preliminary outcome and advantages of this technique. MATERIAL AND METHOD: The integrated concepts and functional reconstruction includes analysis of the deformities, interdisciplinary management and The Tawanchai Center's interdisciplinary protocol for cleft lip and palate care, pre-surgical orthopedic treatments, the integrated primary cleft lip-nose repair and post-operative management. This technique of repair includes modified rotation advancement technique for skin surgery, functional muscle reconstruction, the correction of nasal deformities, the reconstruction of vermillion and final skin closure. RESULTS: Between 2002 and 2010, this technique was performed and evaluated on 122 patients who received primary unilateral cleft lip-nose repair, including 72 complete and 50 incomplete, 81 males and 41 females. Six parameters (scar, Cupid's bow symmetry, vermillion border symmetry, philtrum anatomic fidelity, muscle function and nasal symmetry) were used for evaluating the results, based on 4 scales (0-3) by 2 plastic surgeons. Among the mean scores better rating scales were achieved in philtrum anatomic fidelity (0.25) and muscle function (0.36), while the mean of the those with less satisfactory rating scales were achieved found in scar (0.82) and nasal asymmetry (0.72). These preliminary outcomes showed satisfactory results. Secondary reconstruction is less difficult and may be performed at the age of 4-6 years if indicated. DISCUSSION AND CONCLUSION: The authors introduce The Tawanchai Center's integrated concepts and functional reconstruction technique for unilateral cleft lip-nose repair. The technique provides the advantages of integrated assessment of all deformities of the cleft of primary palate, the design of integrated techniques together with the proper perioperative care, presurgical orthodontic treatment and a holistic and well-coordinated interdisciplinary management. The good preliminary outcome has been demonstrated. More improvement in outcome can be achieved by continuing assessment of these groups of patients until they reach maturity, continuing refinement of technique, improvement of interdisciplinary care and benchmarking of the outcome. PMID- 21299052 TI - Community-based network system and interdisciplinary management for children with cleft-lip/palate. AB - OBJECTIVE: To propose a community-based network system and interdisciplinary management for children with cleft lip/ palate, applicable to Thailand and other developing countries. MATERIAL AND METHOD: A network was developed for the care of patients with cleft lip/palate by combining primary health care, community based rehabilitation and institutional expertise (Tawanchai Center), Five workshops were conducted, including: 1) network development for cleft lip-palate care in the new millennium; 2) a multi-center study on the incidence and etiology of oral clefts and associated abnormalities in Northeast Thailand; 3) establishment of a Network for Children with Cleft Lip/Palate care in Northeast Thailand, including: 3.1) Skill development in cleft lip/palate care for parents and family; 3.2) a community-based model for speech disorders for children with cleft lip/palate in developing countries and for holistic nursing care for children with cleft lip/palate in developing countries; and, 4) development of interdisciplinary team system and network for holistic care for community-based quality of life, health promotion, speech and language intervention for Thai cleft lip/palate. RESULTS: A community-based network system model with interdisciplinary care was developed. CONCLUSION: A community-based network system model with interdisciplinary care can be applied for children with cleft lip/ palate in Thailand and developing countries where there exists a lack of coordinated multidisciplinary services. We plan to implement such a system in the near future. PMID- 21299053 TI - Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome in monozygotic twins: two cases report and reviews. AB - Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome (or Hay-Wells syndrome) is a rare congenital malformation. Our first cases were a pair of female monozygotic twins with AEC syndrome at Srinagarind Hospital. In this study, we describe monozygotic female twins concordant for ankyloblephaon, ectodermal dysplasia and helical rim deformities, but discordant for cleft, syndactyly of toes, heart and urinary tract abnormalities. Twin A had syndactyly of the right third and fourth toes with incomplete bilateral cleft lip and complete bilateral cleft palate. Twin B had left ventricular enlargement, caliectasia of both kidneys with complete left unilateral cleft lip and cleft palate. The twins were treated by multidisciplinary teams with satisfactory results. PMID- 21299054 TI - Early maxillary arch changes in complete bilateral cleft lip and palate: a report of four cases. AB - OBJECTIVE: To evaluate early maxillary arch changes in infants with complete bilateral cleft lip and palate (BCLP), using a simple measurement technique. MATERIAL AND METHOD: A measurement model technique simplified from previously reported methods was used to analyze early maxillary changes of four non syndromic complete BCLP. Study models of these cases were evaluated before presurgical orthopedic treatment and lip reconstruction (T1) and prior to palatal closure (T2). Comparisons of maxillary arch changes were performed. RESULTS: At T1, protrusion with or without deviation of the primary palate and different amounts of cleft width were found. Anterior alveolar arch width was larger than the posterior At T2, the primary palate was retracted and initial lateral displacement was corrected. Cleft widths were narrowed at all levels with the narrowest part located anteriorly, corresponding with the increasing of primary palate arch width. Posterior alveolar arch width was wider than the anterior region. Although the posterior alveolar arch was lengthened, total alveolar arch length was decreased which could be attributable to a large retraction of the primary palate. CONCLUSION: Early morphological and positional changes to the three segments of maxillary arch could be visualized and clarified with this technique, using study models and arch form superimposition methods. PMID- 21299055 TI - Falls and dizziness in the elderly. AB - The complaint of dizziness is one of the most common reasons that older adults feel constrained to visit the doctor's office. Because of a growing number of older people in the industrial society the problem grows. Therapeutic process of elderly people with vertigo and dizziness needs more than vestibular diagnostics. In addition to sufficient anamnesis, presence of visual deficits, extrasensory changes and even psychological circumstances are necessary. Frequently the indication and the encouragement of vestibular rehabilitation have significant value. The initiation of fall prevention may also be essential. PMID- 21299056 TI - Immigrant background and orthodontic treatment need. Quantitative and qualitative studies in Swedish adolescents. AB - During the last three decades there has been an increased influx of refugees and immigrants into Scandinavia. The overall aim of this thesis was primarily to improve our knowledge of malocclusion and orthodontic treatment need, both normative and self-perceived, in adolescents of varying geographic origin. A further aim was to determine whether any differences with respect to perception of general appearance and psychosocial well-being were related to geographic origin. Papers I and II concerned self perceived and normative orthodontic treatment need. About 500 12-13 year-old subjects, stratified into different groups: A-Sweden, B-Eastern/Southeastern Europe, C-Asia and D-other countries, answered a questionnaire and underwent clinical examination by the author. In paper III the association between the two variables in papers I and II was investigated. Paper IV was a follow up study, at 18-19 years of age, of the relationship between geographic origin and prevalence of malocclusion, self perceived treatment need, temporomandibular symptoms and psychosocial wellbeing. In Paper V a qualitative study of 19-20-year-old subjects was conducted, to identify the strategies they had adopted to handle the issue of persisting poor dental aesthetics. The main findings were that at 12-13 years of age, immigrant subjects had a lower perceived orthodontic treatment need than subjects of Swedish background. Girls of Swedish background had the highest self-perceived treatment need, whilst girls of non-Swedish background were most concerned that fixed appliance therapy would be painful. In a few of the clinical variables measured at 12-13 years of age, the Swedish group exhibited the greatest space deficiency and irregularity in both the maxillary and mandibular anterior segments and greater overjet, compared to the Eastern/Southeastern European and Asian groups. The clinical implications were negligible. The orthodontic treatment need according to "Index of Orthodontic Treatment Need--Dental Health Component" (IOTN-DHC) grades 4 and 5, ranged from 30 to 40 per cent, without any inter-group differences. There were strong associations between subjects perceiving a need for orthodontic treatment and IOTN-DHC grades 4 and 5, anterior crossbite and avoiding smiling because they were self-conscious about their teeth. At the age of 18-19 years, the frequency of malocclusion was similar in all groups. Subjects of Asian origin had a higher self-perceived orthodontic treatment need than their Swedish counterparts and a higher frequency of headache than those of Eastern/Southeastern European origin. Psychological wellbeing was reduced in nearly one quarter of the sample, more frequently in girls than boys. No association was found between self-perceived orthodontic treatment need and psychological wellbeing. The theory "Being under the pressure of social norms" was generated in Paper V, and it can be applied to improve our understanding of young adults who have adjusted to living with poor dental aesthetics and also aid to identify those who are not as well-adjusted and would probably benefit from treatment. Undisclosed dental fear is an important barrier to acceptance of orthodontic treatment in early adolescence. Despite demographic changes due to immigration, no major change in the prevalence of malocclusion and normative orthodontic treatment need has been disclosed. This does not apply to adolescents and adults who immigrated at an older age. PMID- 21299057 TI - Galanin: a multitalented neuropeptide. AB - Galanin, one of the many (> 100) neuropeptides, was discovered in 1983 based on its C-terminal amidation motif. Over the years, three more members of the galanin family have been identified, and three galanin receptors have been cloned. Work in many laboratories has provided evidence that this peptide can act as a transmitter, modulator, and growth factor and that it is involved in a number of, especially, disease-related processes. In this introduction, we provide some historical aspects on the galanin research and how the field has developed over three decades. PMID- 21299058 TI - Galanin, galanin receptors, and drug targets. AB - Galanin, a neuropeptide widely expressed in the central and peripheral nervous systems and in the endocrine system, has been shown to regulate numerous physiological and pathological processes through interactions with three G protein-coupled receptors, GalR1 through GalR3. Over the past decade, some of the receptor subtype-specific effects have been elucidated through pharmacological studies using subtype selective ligands, as well as through molecular approaches involving knockout animals. In this chapter, we summarize the current data which constitute the basis of targeting GalR1, GalR2, and GalR3 for the treatment of various human diseases and pathological conditions, including seizure, Alzheimer's disease, mood disorders, anxiety, alcohol intake in addiction, metabolic diseases, pain and solid tumors. PMID- 21299059 TI - Galanin acts as a trophic factor to the central and peripheral nervous systems. AB - The neuropeptide galanin is widely, but not ubiquitously, expressed in the adult nervous system. Its expression is markedly up-regulated in many neuronal tissues after nerve injury or disease. Over the last 10 years, we have demonstrated that the peptide plays a developmental survival role to subsets of neurons in the peripheral and central nervous systems with resulting phenotypic changes in neuropathic pain and cognition. Galanin also appears to play a trophic role to adult sensory neurons following injury, via activation of GalR2, by stimulating neurite outgrowth. Furthermore, galanin also plays a neuroprotective role to the hippocampus following excitotoxic injury, again mediated by activation of GalR2. Most recently, we have shown that galanin expression is markedly up-regulated in multiple sclerosis (MS) lesions and in the experimental autoimmune encephalomyelitis (EAE) model of MS. Over-expression of galanin in transgenic mice abolishes disease in the EAE model, whilst loss-of-function mutations in galanin or GalR2 increase disease severity. In summary, these studies demonstrate that a GalR2 agonist might have clinical utility in a variety of human diseases that affect the nervous system. PMID- 21299060 TI - Galanin and spinal pain mechanisms: past, present, and future. AB - Since the discovery of galanin in 1983, one of the most frequently suggested physiological function for this peptide is pain modulation at the level of the spinal cord. This notion, initially based on the preferential distribution of galanin in dorsal spinal cord, has been supported by results from a large number of morphological, molecular, and functional studies. It is generally agreed that spinally applied galanin produces a biphasic, dose-dependent effect on spinal nociception through activation of GalR1 (inhibitory) or GalR2 (excitatory) receptors. Galanin also appears to have an endogenous inhibitory role, particularly after peripheral nerve injury when the synthesis of galanin is increased in sensory neurons. In recent years, small molecule ligands of galanin receptors have been developed, which may lead to the development of analgesic drugs, which affects the galanin system at the spinal cord level. PMID- 21299061 TI - Galanin family of peptides in skin function. AB - The skin, the largest organ of the body, functions as a barrier between the body proper and the external environment, as it is constantly exposed to noxious stressors. During the last few years, the concept of an interactive network involving cutaneous nerves, the neuroendocrine axis, and the immune system has emerged. The neuroendocrine system of the skin is composed of locally produced neuroendocrine mediators that interact with specific receptors. Among these mediators are neuropeptides, including members of the galanin peptide family- galanin, galanin-message associated peptide, galanin-like peptide, and alarin- which are produced in neuronal as well as nonneuronal cells in the skin. Here, we review the expression of the galanin peptides and their receptors in the skin, and the known functions of galanin peptides in different compartments of the skin. We discuss these data in light of the role of the galanin peptide family in inflammation and cell proliferation. PMID- 21299062 TI - Galanin in glia: expression and potential roles in the CNS. AB - The roles of galanin in central nervous system (CNS) development and the normal adult CNS have been extensively reviewed in this volume and elsewhere. There is also ample evidence that galanin expression is induced following neural injury in the CNS, and has neuroprotective properties separate from its role in normal physiology. Although strong injury-mediated up-regulation of galanin occurs in neurons, there is increasing evidence, accumulated over almost two decades, that glial cells can express galanin in the injured brain and during white matter development. In this chapter, we review the available evidence and canvas the potential functional significance of glial galanin expression. PMID- 21299063 TI - Galanin and the neuroendocrine axes. AB - Galanin has diverse physiological functions, including nociception, arousal/sleep regulation, cognition, and many aspects of neuroendocrine activities that are associated with feeding, energy metabolism, thermoregulation, osmotic and water balance, and reproduction. This review will provide a brief overview of galanin action in some major neuroendocrine processes. Most of the recent data are about the role of galanin in the central regulation of food intake and energy metabolism, and to some extent, in the regulation of reproduction. It seems that galanin plays a modulatory role rather than a regulatory one in the central and peripheral branches of the neuroendocrine systems. In the hypothalamus, it functions as a neurotransmitter/ neuromodulator. In the pituitary and the peripheral endocrine glands, it acts via its receptors in a paracrine/autocrine fashion. The development of new, selective, and potent antagonists of GALRs should keep advancing our knowledge not only in the physiology of galanin but also in its pathophysiology. PMID- 21299064 TI - Galanin and consummatory behavior: special relationship with dietary fat, alcohol and circulating lipids. AB - Galanin (GAL) plays an integral role in consummatory behavior. In particular, hypothalamic GAL has a positive, reciprocal relationship with dietary fat and alcohol. In this relationship, GAL increases the consumption of fat or alcohol which, in turn, stimulates the expression of GAL, ultimately leading to overconsumption. Through actions in the amygdala, this relationship may become especially important in stress-induced food or drug intake. These effects of GAL in promoting overconsumption may involve various neurotransmitters, with GAL facilitating intake by stimulating norepinephrine and dopamine and reducing satiety by decreasing serotonin and acetylcholine. In addition, GAL in the hypothalamus stimulates the opioid, enkephalin, throughout the brain, which also promotes overconsumption. The relationship between GAL, fat, and alcohol may involve triglycerides, circulating lipids that are released by fat or alcohol and that correlate positively with hypothalamic GAL expression. In females, levels of endogenous GAL also fluctuate across the reproductive cycle, driven by a rise in the ovarian steroids, estrogen, and progesterone. They peak during the proestrous phase and also at puberty, simultaneous to a sharp increase in preference for fat to meet energy demands. Prenatal exposure to a high-fat diet also enhances hypothalamic expression of GAL into adulthood because of an increase in neurogenesis and proliferation of GAL-expressing neurons in this region. This organizational change may reflect the role of GAL in neuronal development, including neurite growth in adulthood, cell survival in aging, and cell stability in the disease state. By responding positively to fat and alcohol and guiding further neuronal development, GAL potentiates a long-term propensity to overconsume fat and alcohol. PMID- 21299065 TI - Neurochemical modulation of central cardiovascular control: the integrative role of galanin. AB - Galanin (GAL) is a peptide involved in multiple functions, including central cardiovascular control. In this review, the role of GAL and its fragments in the modulation of cardiovascular neuronal networks in the nucleus of the solitary tract is presented, including its interaction with the classical neurotransmitters and other neuropeptides involved in cardiovascular responses in this nucleus. First, we describe the cardiovascular responses of GAL and the pathway involved in these responses. Then we summarize findings obtained in our laboratory on how GAL, through its receptors, interacts with two other neuropeptides--Neuropeptide Y and Angiotensin II and their receptors--as they have particularly conspicuous cardiovascular effects. All these results strengthen the role of GAL in central cardiovascular control and indicate the existence of interactions among GAL receptor subtypes and alpha2-adrenergic receptors, AT1, and Y1 receptor subtypes. These interactions are crucial for understanding the integrative mechanisms responsible for the organization of the cardiovascular responses from the NTS. PMID- 21299066 TI - Galanin impairs cognitive abilities in rodents: relevance to Alzheimer's disease. AB - The neuropeptide galanin and its receptors are localized in brain pathways that mediate learning and memory. Central microinjection of galanin impairs performance of a variety of cognitive tasks in rats. Transgenic mice overexpressing galanin display deficits in some learning and memory tests. The inhibitory role of galanin in cognitive processes, taken together with the fact that overexpression of galanin occurs in Alzheimer's disease, suggests that galanin antagonists may offer a novel therapeutic approach to treat memory loss in patients suffering from Alzheimer's. PMID- 21299068 TI - Galanin, galanin receptor subtypes and depression-like behaviour. AB - The pathophysiology of depression remains unclear, but involves disturbances in brain monoaminergic transmission. Current antidepressant drugs, which act by enhancing this type of neurotransmission, have limited therapeutic efficacy in a number of patients, and also cause serious side-effects, which limits their compliance. Increasing evidence suggests that neuropeptides, including galanin, can be of relevance in mood disorders. Galanin is co-expressed with and modulates noradrenaline and serotonin transmission, both implicated in depression. Pharmacological and genetic studies suggest a role for galanin in depression-like behaviour in rodents, involving specific receptor subtypes. Thus, stimulation of GalR1 and/or GalR3 receptors results in depression-like phenotype, while activation of the GalR2 receptor reduces depression-like behaviour in the rat. These findings suggest that galanin receptor subtypes may represent novel targets for the development of antidepressant drugs. PMID- 21299067 TI - Neuroprotective role for galanin in Alzheimer's disease. AB - Galanin (GAL) and GAL receptors (GALR) are overexpressed in degenerating brain regions associated with cognitive decline in Alzheimer's disease (AD). The functional consequences of GAL plasticity in AD are unclear. GAL inhibits cholinergic transmission in the hippocampus and impairs spatial memory in rodent models, suggesting that GAL overexpression exacerbates cognitive impairment in AD. By contrast, gene expression profiling of individual cholinergic basal forebrain (CBF) neurons aspirated from AD tissue revealed that GAL hyperinnervation positively regulates mRNAs that promote CBF neuronal function and survival. GAL also exerts neuroprotective effects in rodent models of neurotoxicity. These data support the growing concept that GAL overexpression preserves CBF neuron function, which may in turn delay the onset of symptoms of AD. Further elucidation of GAL activity in selectively vulnerable brain regions will help gauge the therapeutic potential of GALR ligands in the treatment of AD. PMID- 21299069 TI - Galanin and epilepsy. AB - Neuroanatomical localization and physiological properties of galanin suggest that the peptide may be involved in the regulation of seizures. Indeed, administration of galanin receptor agonists into brain areas pertinent to the initiation and propagation of epileptic activity attenuated seizure responses under conditions of animal models of epilepsy; pharmacological blocking of galanin receptors exerted proconvulsant effects. Functional deletion of both galanin and galanin type 1 receptor genes produced transgenic mice with either spontaneous seizure phenotype, or with enhanced susceptibility to seizure stimuli. At the same time, overexpression of galanin in seizure pathways, using both transgenic and virus vector transfection techniques, hindered the epileptic process. Galanin exerts anticonvulsant effects through both type 1 and type 2 receptors, with distinct downstream signaling cascades. Several synthetic agonists of galanin receptors with optimized bioavailability have been synthesized and inhibited experimental seizures upon systemic administration, thus opening an opportunity for the development of galanin-based antiepileptic drugs. PMID- 21299070 TI - Galanin and addiction. AB - There has been increasing interest in the ability of neuropeptides involved in feeding to modulate circuits important for responses to drugs of abuse. A number of peptides with effects on hypothalamic function also modulate the mesolimbic dopamine system (ventral tegmental area and nucleus accumbens). Similarly, common stress-related pathways can modulate food intake, drug reward and symptoms of drug withdrawal. Galanin promotes food intake and the analgesic properties of opiates, thus it initially seemed possible that galanin might potentiate opiate reinforcement. Instead, galanin agonists decrease opiate reward, measured by conditioned place preference, and opiate withdrawal signs, whereas opiate reward and withdrawal are increased in knockout mice lacking galanin. This is consistent with studies showing that galanin decreases activity-evoked dopamine release in striatal slices and decreases the firing rate of noradrenergic neurons in locus coeruleus, areas involved in drug reward and withdrawal, respectively. These data suggest that polymorphisms in genes encoding galanin or galanin receptors might be associated with susceptibility to opiate abuse. Further, galanin receptors might be potential targets for development of novel treatments for addiction. PMID- 21299071 TI - Galanin systems and ischemia: peptide and receptor plasticity in neurons and oligodendroglial precursors. AB - Cerebral cortex contains few if any galanin neurons, but receives galanin-ergic inputs from subcortical areas. Apart from our earlier study on the response to cortical spreading depression, little is known about the presence and function of galanin in normal or injured cortex and to gain more insight into its possible roles, we investigated the temporal effects of focal ischemia on the expression of galanin and galanin receptors (GalRs). Focal ischemia induced in the rat by unilateral middle cerebral artery occlusion increased galanin and GalR1 mRNAs in penumbral/undamaged areas on the first and second day post-ischemia, while increased GalR2 mRNA was observed in the same regions only on the second day. Immunohistochemical studies revealed galanin immunoreactive neurons in the frontal/ cingulate cortex and abundant galanin-immunoreactivity in nerve axons/fibres within the penumbral areas, between the third and the seventh day after ischemia. Galanin mRNA and immunoreactivity was also increased in a population of small cells thought to be NG2-positive oligodendrocyte precursors. Up-regulation of galanin and GalRs in various cell populations following severe ischemic injury further demonstrates the marked plasticity of galanin and GalR1/2 expression after brain injury, and together with data reported elsewhere in this volume, suggests a functional role for galanin signalling in such pathophysiological conditions. PMID- 21299072 TI - The galanin system in cancer. AB - Many tumours of neuroendocrine origin, and also an increasing number of non neuroendocrine cancers, have been shown to express neuropeptides and/or their corresponding receptors. These peptides and receptors represent the molecular basis for in vivo diagnostic or therapeutic targeting of cancer with radiolabelled or cytotoxic peptide analogues. Galanin is a classical neuropeptide that functions in diverse physiological processes such as food intake, nociception, and blood pressure regulation, and it can also act as a growth factor for neurons. Expression of galanin peptide has been detected in pheochromocytoma, pituitary adenoma, neuroblastic tumours, gastrointestinal cancer, squamous cell carcinoma, brain tumours, melanoma, breast cancer and embryonal carcinoma. In several cancers and tumour cell lines expression of galanin receptors--three are known (GalR1, 2 and 3)--has been shown as well. Expression of peptide or receptors has been correlated with tumour stage or subtypes of pituitary adenoma, neuroblastic tumours, colon carcinoma and squamous cell carcinoma. Galanin treatment has tumour-reducing effects in murine models of gastrointestinal cancer, whereas in animal experiments on adenoma formation, galanin seems to act as a growth factor, promoting both proliferation and tumour formation. In cell culture experiments on tumour cell lines, galanin has shown growth promoting or inhibiting effects. Activation of GalR1 is generally anti proliferative, whereas activation of GalR2 can have pro- or anti-proliferative effects. Therefore, galanin and its receptors are promising targets for diagnosis and treatment of several types of tumours. PMID- 21299073 TI - Galanin systems in non-mammalian vertebrates with special focus on fishes. AB - Galanin is a well characterized multifunctional neuropeptide in mammals. Galanin has been identified from several fishes, amphibians, reptiles and birds. A large set of data is available on galanin-like protein distribution and peptide and/or mRNA sequences in non-mammalian vertebrates. Galanin receptor sequences from fishes and birds are known, but its distribution and mechanisms of actions are poorly understood. While some biological actions of galanin are known in non mammals, the functional role of galanin in lower vertebrates is limited. For example, galanin has been shown to regulate feeding, pituitary hormone secretion and gut motility in fishes. Several aspects of galanin biology remain unknown, yet, there is enough evidence to implicate galanin as an important physiological modulator in lower vertebrates. Majority of the research articles on galanin in non-mammals arise from studies that used fishes. The objective of this chapter is to provide a summarized discussion of current knowledge on galanin peptide and gene sequences and organization, distribution of galanin gene and protein, and physiological functions of galanin in non-mammalian vertebrates with a special focus on fishes. PMID- 21299074 TI - Galanin-like peptide: neural regulator of energy homeostasis and reproduction. AB - Galanin-like peptide (GALP) was discovered in 1999 in the porcine hypothalamus and was found to be a 60 amino-acid neuropeptide. GALP shares sequence homology to galanin (1-13) in position 9-21 and can bind to and activate the three galanin receptor subtypes (GalR1-3). GALP-expressing cells are limited, and are mainly found in the arcuate nucleus of the hypothalamus (ARC) and the posterior pituitary. GALP-positive neurons in the ARC, project to several brain regions where they appear to make contact with several neuromodulators that are involved in the regulation of energy homeostasis and reproduction, anatomical evidence that suggests a role for GALP in these physiological functions. In support of this idea, GALP gene expression is regulated by several factors that reflect metabolic state including the metabolic hormones leptin and insulin, thyroid hormones, and blood glucose. Considerable evidence now exists to support the hypothesis that GALP has a role in the regulation of energy homeostasis and reproduction; and, that that GALP's role may be independent of the known galanin receptors. In this chapter we (1) provide an overview of the distribution of GALP, and discuss the potential relationship between GALP and other neuromodulators of energy homeostasis and reproduction, (2) discuss the metabolic factors that regulate GALP expression, (3) review the evidence for the role of GALP in energy homeostasis and reproduction, (4) discuss the potential downstream mediators and mechanisms underlying GALP's effects, and (5) discuss the possibility that GALP may mediate it's effects via an as yet unidentified GALP specific receptor. PMID- 21299075 TI - Organizational justice and health; review of evidence. AB - Organizational justice is a construct defining the quality of social interaction at work. Organizational justice can be divided into three categories: procedural justice (fairness of the decision-making procedures), distributive justice (fairness of outcomes) and relational justice (equity and fairness in the interpersonal treatment of employees by their supervisors). Organizational justice is related to employees' health and well-being. Low perceived justice has been shown to be associated with experienced stress reactions and related physiological and behavioral reactions, such as inflammation, sleeping problems, cardiovascular regulation and cognitive impairments, and with a high rate of work absenteeism. This paper is a review of the literature on organizational justice and its impact on workers' health. PMID- 21299076 TI - Impulsiveness and time perception in alcohol dependent patients in alcoholic rehabilitation treatment. AB - INTRODUCTION: To analyze the relationship between alcoholism, impulsiveness, anxiety and depression. Further, we wish to investigate the relationship between these variables and both the period of alcohol abuse and the length of hospitalization. METHODS: The investigation was carried out on a group of alcoholics in residential treatment (N=60) and on a control group (N=60); within the group of alcoholics in treatment, we attempted to investigate possible differences in performance between "pure alcoholics" (N=48) and polyabusers (N=12). A questionnaire assessing anxiety (BAI) and one assessing depression (BDI II) were administered Since many psychological studies agree that impulsiveness is of multidimensional nature, for its assessment a questionnaire (BIS-11) and two computer-based tests (TCIP and Time Paradigm) were used. RESULTS: Alcoholics in treatment seem to be more impulsive than controls in two of the three test used; further, the period of alcohol abuse influences impulsiveness considered as a personality dimension. Significant differences between "pure alcoholics" and polyabusers were obtained only in two of the three tests used. Patients hospitalized for alcohol detoxification do not seem particularly anxious or depressed, and there seems to be no relationship between the duration of alcohol abuse or the length of hospitalization and the psychological distress. CONCLUSIONS: These results clearly show the existence of a relationship between alcoholism and impulsiveness considered as a dimension of personality; however, they do not explain whether it is personality that is a consequence or antecedent of the problematic use of substances. PMID- 21299077 TI - Italian validation of the McGill Quality of Life Questionnaire (MQOL-It). AB - INTRODUCTION: Quality of life is a dynamic concept that can undergo change with time and/or disease progression. The aim of this study was to test the reliability and validity of the Italian version of the McGill Quality of Life Questionnaire (MQOL-It), that we consider useful for assessing quality of life in Palliative Care. METHODS: The MQOL-It was administered by interview to 175 patients (M 108; F 67) admitted to a Unit of Palliative Care. All patients were suffering from advanced disease: cancer, amyotrophic lateral sclerosis, chronic heart failure. Statistical analysis was performed to assess the psychometric properties of the questionnaire. RESULTS: Factor analysis (VARIMAX) revealed four domains of quality of life, though the item composition differed, at composition analysis, from the original MQOL version. "Achieved goals" and "control over life", items classified in the English version as part of the existential domain, in the Italian version fitted the psychological domain; the item "well-being" was grouped into the physical domain and did not load clearly with other factors. Cronbach's alpha for the whole questionnaire was 0.85, with a good internal consistency for the four subscales (Cronbach's alpha > or = 0.65). All MQOL-It subscales were significantly correlated (Spearman correlation) with the Single Item rating Scale (SIS); comparison between the MQOL-It and the Nottingham Health Profile (NHP)-part I showed the instrument's concurrent validity. CONCLUSIONS: MQOL shows robust psychometric properties and appears suitable for evaluating quality of life in palliative care in Italy. PMID- 21299078 TI - The comparative study of depression between gifted children and normal children. AB - BACKGROUND: Gifted children have more depression than normal children because of their expectation to be the first. OBJECTIVE: Compare depression between gifted children and normal children. MATERIAL AND METHOD: The subjects, aged 9-12 years from Patai School, were 40 gifted children and 40 normal children. Their depression conditions were evaluated by using CDI score and taking saliva sample for cortisol measurement. RESULTS: The prevalence of depression by CDI score in 40 gifted children was 37.5% and the prevalence of depression by CDI score in normal children was 27.5%. The data was analysed by Chi-square test and the result was not statistical significant (p > 0.05). The mean salivary cortisol level in 39 gifted children was 4.91 nmol/l (SD = 2.12) and the average salivary cortisol level in 38 normal children was 4.14 nmol/l (SD = 1.92). The data was analysed by unpaired t-test and the result was not statistical significant (p > 0.05). There was no correlation between salivary cortisol and CDI score (r = 0.194). CONCLUSION: Gifted children do not have more depression than normal children. However, a larger sample size should be considered in the future study. PMID- 21299079 TI - Prevalence and risk factors of peripheral arterial disease in type 2 diabetic patients at HRH Princess Maha Chakri Sirindhorn Medical Center. AB - OBJECTIVE: To study the prevalence and risk factors of PAD in type 2 diabetes. MATERIAL AND METHOD: The crossectional study randomly enrolled 219 diabetic patients to study in Year 2006-2007. All subjects were checked up and recorded basic information and affecting factors to risk of PAD. ABI scores were measured by Colin VP-1000 machine. The affecting factors to PAD risk were analyzed to obtain form descriptive (percent and number) and inferential statistics (odds ratio). RESULTS: There were 219 diabetic patients included in this study with 61.2% of females and 38.8% of males. The prevalence of PAD and intermittent claudication symptoms were 60.3% and 60.7%, respectively. The patients who had current smoking, hypertriglyceridemia, low HDL and HbA1c > or = 7.0% have statistically significant increased risk of PAD odds ratio of 31.89 (95% CI = 4.31-236.0), 5.20 (95% CI = 1.67-16.18), 7.05 (95% CI = 2.29-21.72) and 2.74 (95% CI = 1.07-7.06), respectively, while the groups who had older age (> or = 60 years), duration of DM of > or = 10 years and waist circumference of > or = 90 cm. in men or > or = 80 cm. in women have not statistically significant increased risk of odds ratios of 1.84 (95% CI = 0.77-4.43), 1.11 (95% CI = 0.41-3.04) and 1.69 (95% CI = 0.51-5.6). The patients who had combinations of microvascular complication, previous history of CHD and stroke had significantly statistic risk of odds ratio 8.97 (95% CI = 2.82-28.60) and 5.63 (95% CI = 1.91-16.57) although we needed to measure ABI score in all type 2 diabetes with high risks and CVD. CONCLUSION: The diabetic patients with high risk and CVD have high prevalence of PAD. Patients with suspected PAD may needs further examination and patients who have increased risk of PAD may require interventions to prevent vascular complications. PMID- 21299080 TI - Laparoscopic biliary bypass with an autologous tubed gastric flap: a pilot study. AB - Although biliary bypass technique which used jejunum as a conduit is a common procedure in open technique of hepatobiliary tract surgery, its complicated technique made it is not feasible for laparoscopic surgery. Before 1960, stomach was used vastly for biliary drainage but late stricture which resulted from too much tension along suture line made it not much acceptable. The authors report surgical technique of laparoscopic gastric tube flap for biliary bypass in order to made it practicable for laparoscopic surgery. PMID- 21299081 TI - Initial response of endothelial cells to acute stimulation with a lipid component: increase cyclooxygenase activity by induction of COX-2 through activation of tyrosine kinase. AB - OBJECTIVE: To study the initial response of endothelial cells acutely stimulated with a lipid component in the aspect of cyclooxygenase (COX) function which needed for prostacyclin synthesis, an endogenous antiatherogenic agent secreted from endothelial cells. MATERIAL AND METHOD: 25 hydroxycholesterol (25OHC) was used as a representative lipid component for stimulating human umbilical vein endothelial cell (HUVEC) obtained from umbilical cords of healthy newborns with informed consent of their mothers. HUVEC were treated with 25OHC (0.1, 1 or 10 microgram/mL) at times 6, or 24 h. COX activity was measured from amount of 6 keto-PGF(1 alfa) production in the presence of exogenous arachidonic acids (10 micromolar; 10 min) by enzyme immunoassay. The amount of COX-1 and COX-2 protein were detected by Western blot. Cell viability was assessed by using MTT assay. RESULTS: 25OHC induced COX-2 protein production with increasing the activity of COX enzyme in HUVEC without change in amount of COX-1 protein. The induction of COX-2 or increasing in COX activity depended on concentration of 25OHC and time to exposure which seemed to be inhibited by genistein, a specific tyrosine kinase inhibitor. CONCLUSION: Acute stimulation of HUVEC with 25OHC, an atherosclerotic lipid component, increases the activity of COX by inducing COX-2 expression in a manner that depended on concentration and time. The induction of COX-2 expression might possibly mediated through activation protein tyrosine kinase. These responses may be an initial defensive mechanism of endothelial cells from lipid component attack. PMID- 21299082 TI - Clinical features, management and outcomes of high-grade glioma patients in Ramathibodi Hospital. AB - OBJECTIVE: To identify prognostic factors for survival and evaluate the effect of treatment on survival of patients with high-grade glioma treated at Ramathibodi Hospital. MATERIAL AND METHOD: Medical records of patients with diagnosis of high grade glioma registered in Ramathibodi cancer registry were reviewed. A total of 36 patients were reviewed, only 27 patients were included on survival analysis. RESULTS: Of the 36 patients, the male: female ratio was 1:1. Mean age of diagnosis was 41.86 years (range 18-71 years). Histological findings were anaplastic glioma (22.20%), glioblastoma multiforme (63.90%) and mixed glioma (13.90%). Of fifteen patients underwent total tumor removal, 17 patients had partial resection and in 4 cases biopsy alone was done. Two third of the patients had received radiotherapy with mean total dose 5,372 cGy. Nine patients also received chemotherapy (6 temozolomide and 3 BCNU). Median follow-up time was 413.2 days. An overall survival time was 604.04 days and median disease free survival time was 402.45 days. In univariated analysis, the following favorable prognostic factors were identified: histological findings of glioblastoma multiforme (GBM) and mixed glioma, received radiotherapy. In multivariate analysis, radiotherapy improves overall survival significantly. Re-resection at recurrence did not appear to improve overall survival. CONCLUSION: Adult high grade glioma had poor prognosis despite aggressive treatment. Radiotherapy significantly improved survival while surgical tumor removal and chemotherapy did not. However due to the small number of patients the further studies should be performed. PMID- 21299083 TI - Predictive factors for residual disease in the uterine cervix after large loop excision of the transformation zone in patients with cervical intraepithelial neoplasia III. AB - OBJECTIVE: To determine predictive factors for residual disease in uterine cervix after large loop excision of the transformation zone (LLETZ) in patients with cervical intraepithelial neoplasia III (CIN III). MATERIAL AND METHOD: Medical records of patients who underwent LLETZ with CIN III between September 1, 1992 and December 31, 2001 in Ramathibodi Hospital were reviewed. Demographic data, colposcopic findings, and pathologic parameters were analyzed to identify the predictive factors for residual disease in uterine cervix. RESULTS: The total of 541 cases were enrolled in this study. Managements after LLETZ are 1) repeated LLETZ, 2) hysterectomy, and 3) Papanicolaou smear. Residual disease was detected in a total of 156 patients (28.84%), there were 21 cases of CIN I (13.46%), 22 cases of CIN II (14.10%), 107 cases of CIN III (68.59%), and 6 (3.85%) cases of microinvasive squamous cell carcinoma of cervix. 1) Age > or = 50 years old was significant factor associated with residual disease. The incidence of residual disease was 50.00%. 2) Unsatisfactory colposcopy was significant factor associated with residual disease with 38.44% incidence of residual disease. 3) Margins involvement of LLETZ specimen was the only pathological predictive factor identified. The incidence of residual disease with clear margin, endocervical margin, ectocervical margin, and both margins involvement were 14.74, 52.63, 57.14, and 74.19% respectively. Other parameters, including gravidity, parity, menopausal status, cervical gland involvement, and number of quadrants involvement were not predictive of residual disease. CONCLUSION: 1) Age > or = 50 years old, 2) unsatisfactory colposcopy, and 3) margins involvement of LLETZ specimens were the predictive factors for residual disease in uterine cervix. PMID- 21299084 TI - Accuracy of transcutaneous bilirubinometry compare to total serum bilirubin measurement. AB - BACKGROUND: Neonatal hyperbilirubinemia leads to bilirubin neurotoxicity. Noninvasive transcutaneous bilirubin (TcB) levels can be used as a screening tool for total serum bilirubin (TSB) levels. OBJECTIVE: To evaluate the correlation of TcB for TSB levels before, during and after phototherapy and find the most reliable cutoff values of TcB levels with the highest sensitivity and specificity for TSB levels. DESIGN: Diagnostic study. MATERIAL AND METHOD: In this research, forehead TcB measurement was measured by the transcutaneous bilirubinometer (Minolta Airshilds Jaundice Meter, JM 103). The 224 paired TcB-TSB specimens from 74 term and nearterm newborns were study from September 2007 to October 2008. The mean postnatal age at the time of measurement was 57.85 +/- 22.15 hours. The mean gestational age was 38 +/- 1.29 weeks and mean body weight was 2,864.65 +/- 262 g. RESULTS: The TcB and TSB values had linear correlation with significant correlation coefficient (r 0.81, p < 0.001). The correlation equation was TSB = 0.88 + 0.89 x TcB (r2 = 0.65). TcB levels tended be higher than TSB with mean difference of 0.44 mg/dL (95% CI: 0.7433-0.1323 mg/dL) and SD:1.64. TSB confirmation was recommended when TcB cutoff values greater than 9, 12, 13, 15 mg/dL at 24 (TSB:8 mg/dL), 36 (TSB: 10 mg/dL), 48 (TSB: 12 mg/dL) and 72 (TSB: 15 mg/dL) hours' postnatalage, respectively. CONCLUSION: The TcB levels can accurately predict TSB with the different cutoff points at various postnatal ages before phototherapy. PMID- 21299085 TI - Prevalence of cirrhosis registered in Nakhon Nayok, Thailand. AB - OBJECTIVE: To determine population-based prevalence rates of cirrhosis in Nakhon Nayok Province and patterns of the prevalence by sex, age groups and disease type. MATERIAL AND METHOD: A retrospective descriptive study of medical record database was performed in all hospitals in the province of Nakhon Nayok during the year 2007. ICD-10 was used to identify patients with cirrhosis. Patient information was collected, including name, sex, address and age and data of population of Nakhon Nayok Province stratified by 5 year-age groups, sex and district of the province were obtained. Crude and standardised prevalence rates were calculated using WHO (2000) standard population. RESULTS: There were 199 cirrhosis patients comprising 111 males (55.8%) and 88 females (44.2%) with average age of 54.7 years (SD, 13.0). Crude prevalence rate per 100,000 was 86.3 (95% CI: 74.3-98.3) and age standardized prevalence rate was 75.3 (95% CI: 64.8 85.8). Prevalence of alcoholic cirrhosis was 53.6 (95% CI: 44.8-62.5) and 21.7 (95% CI: 16.0-27.4) for non-alcoholic cirrhosis. Alcoholic cirrhosis in male was found in younger age groups than older age. The prevalence rates vary among four districts. DISCUSSION: In this rural area in the central part of Thailand, the standardized prevalence rates is 75.3 per 100,000 and the prevalence is more common in male than female especially for alcoholic cirrhosis. Prevalence of cirrhosis starts to rise from age of 30 to 60 years. Age distributions of non alcoholic cirrhosis in males and females are similar but in alcoholic cirrhosis the magnitude of prevalence in male is higher than female. Alcoholic cirrhosis is 2.6 folds more prevalent than non-alcoholic cirrhosis. PMID- 21299086 TI - Drug-induced secondary glaucoma. AB - Several classes of drugs have potential to cause an elevation of IOP which may occur either by an open-angle mechanism or a close-angle mechanism. Drug-induced elevation of IOP is commonly has an open-angle mechanism. The most commonly recognized medications associated with this mechanism are the corticosteroids. Acute angle closure glaucoma is a potentially blinding side effect of local and systemic drugs, including antipsychotic drugs, antidepressants, monoamine oxidase inhibitors, antihistamines, antiparkinsonian agents, antispasmolytic drugs, mydriatic agents, the sympathetic agents and botulinum toxin, especially in individuals with predisposing narrow angles of the anterior chamber. Sulfamate derivative medications may induce angle closure by a different angle closure mechanism, involving anterior rotation of the ciliary body. Clinicians should be mindful of the possible drug-induced glaucoma, whether or not it is listed as a contraindication and, if in doubt, ophthalmological consultation is recommended. PMID- 21299087 TI - Thailand Diabetic Registry cohort: predicting death in Thai diabetic patients and causes of death. AB - INTRODUCTION: The prevalence of type 2 diabetes in Thailand is 9.8 percent which is double the number forecast by World Health Organization. There is inadequate information to statistically represent all Thai diabetic patients for their causes of death. OBJECTIVE: To determine the clinical characteristics that predicted death and causes of death in Thai diabetic patients. MATERIAL AND METHOD: This prospective cohort was a 3-year follow-up study of the Thai Diabetes Registry project done between April, 2003, and February, 2006, which registered 9,419 diabetic patients attending 11 diabetic clinics in tertiary medical centers in Bangkok and major provinces of Thailand. The dead or alive status (99.5%) was determined. The causes of death were defined by reviewing the medical records. RESULTS: Of the 9,370 diabetic patients registered, 425 patients died, 1.84 percent per year. There was an increased risk of death associated with age, type of healthcare plan, lower education, insulin use, smoking, history of coronary artery disease and cerebrovascular disease, serum creatinine and high HbA1c. Lipid-lowering medication and metformin decreased the risk of death. Cardiovascular disease, infection and cancer were the prevalent causes of death. CONCLUSION: The present study showed risk factors that influenced death and causes of death in Thai diabetics. PMID- 21299088 TI - Breast cancer: five-year survival in Srinagarind Hospital, Thailand. AB - BACKGROUND: Breast cancer is the second most common cancer among Thai women after cancer of the cervix. OBJECTIVE: To investigate the overall five-year survival of breast cancer patients treated at Srinagarind hospital. MATERIAL AND METHOD: Between January 1998 and December 2002, 382 patients with breast cancer who got definite treatment at Srinagarind hospital were included in the present study. Their medical records were reviewed including sex, age, stage at diagnosis, histological types, histological grades, treatment modality and survival. RESULTS: There were 380 female patients (99.5%) and 2 male patients (0.5%). The peak age group was 41-50 years (38.5%), mean age was 48.3 years old. The most common histological type was invasive ductal carcinoma (95.3%). Most patients received surgical treatment (91.9%) and chemotherapy (94.2%). The overall five year survival rate was 63%. The overall five-year survival rate in stage I, II, III and IV were 100%, 85%, 39% and 9% respectively. CONCLUSION: The peak age of breast cancer was 41-50 years old. The overall five-year survival rate was 63%. PMID- 21299089 TI - Risks of repeated visits for uninvestigated dyspepsia in three community hospitals of Khon Kaen, Thailand. AB - BACKGROUND: Uninvestigated dyspepsia (UD) is common and only 26.4% of these are peptic ulcer disease, while 50% are non-ulcer dyspepsia. A recent study found that nephrolithiasis with urinary tract infection may have the dyspeptic symptoms. OBJECTIVE: The authors searched for any associations between repeated UD and pyuria, hematuria and other factors. MATERIAL AND METHOD: A case-control study was performed. It consisted of 489 patients with repeated UD who had visited community hospitals for at least two times per year and 489 controls sampled from the data of the subjects, free of dyspeptic symptoms, from the multi stage random survey for subjective health complaints in the same province. Multivariate logistic regression models were used for case-control comparisons. RESULTS: By logistic regression analysis, UD was significantly associated with problems caused by purine-rich foods (PRFs), chronic fatigue, flank paresthesia, hematuria, myofascial pain, and pyuria. The respective adjusted odds ratios and 95% confidence interval (CI) were: 6.67 (4.58, 9.68), 5.06 (3.46, 7.40), 3.98 (2.41, 6.60), 2.97 (2.01, 4.38), 1.91 (1.32, 2.76) and 1.58 (1.01, 2.45). The variables of age (> 48), sex, dysuria, poly-arthralgia, headache and back pain were not significantly associated with UD. The foods that aggravated UD were bamboo shoots, fermented rice noodles, beef alcohol and insects. The rate of pyuria and hematuria was significantly increased with the number of visits within a year [p-value (Chi-square for trend), 0.015 and 0.032]. CONCLUSION: These findings indicate that pyuria, hematuria, and purine-rich foods were associated with repeated hospital visits for dyspepsia. PMID- 21299090 TI - Alcohol drinking behaviour and economic cost incurred by users in Khon Kaen. AB - BACKGROUND: Alcohol consumption increases health risks and social consequences. It also lowers productivity resulting in economic losses for drinkers and the rest of society. OBJECTIVE: To investigate alcohol drinking behavior and to estimate economic cost incurred by alcohol users in Khon Kaen province in 2007. MATERIAL AND METHOD: A cross-sectional survey targeting the population aged 12-65 years old was conducted in 20 communities. Data were collected using full structured questionnaires through interviews. RESULTS: Among 1,053 respondents, 53.0% drank alcohol sometime in their lives (95% CI: 46.1, 59.9). The percentage of individuals drinking in the past 12 months was 43.3% (95% CI: 37.1, 49.5). The average number of drinking days in past 12 months was 36.8 days. Most respondents drank for social activities, mainly with friends and relatives. Individual costs of alcohol consumption varied greatly. The weighted average cost in 2007 was 975.5 Baht per drinker. The estimated overall cost of alcohol consumption in Khon Kaen, in 2007, was 691.2 million Baht (95% CI: 280.0, 1,102.3 million), or 502.9 Baht per capita. CONCLUSION: More than half of the Khon Kaen population drank alcohol sometime in their lives and 43.3% were current drinkers. The average number of drinking days in past 12 months was 36.8 days. The estimated cost of alcohol consumption in Khon Kaen province was enormous. PMID- 21299091 TI - Comparison of clinical success between CT-guided percutaneous drainage and open surgical drainage of intra-abdominal fluid collection in Srinagarind Hospital. AB - BACKGROUND: Treatment outcome of intra-abdominal fluid collections has improved over the recent decades due to advancement in surgical techniques as well as development of computed tomography (CT) guided percutaneous interventional techniques. OBJECTIVE: To compare clinical success of CT-guided percutaneous drainage with open surgical drainage of intra-abdominal fluid collections in Srinagarind hospital. MATERIAL AND METHOD: The records and images of all patients undergone CT-guided percutaneous drainage (CT-PCD) or open surgical drainage (OSD) from 2004 to 2007 were reviewed. Comparison of clinical success (improvement of lesion, subsidence of clinical sepsis, no complications, and no mortality) between the two groups was determined. RESULTS: There was no statistically significant difference (p-value = 0.520) in the clinical success between CT-PCD group (25/ 29 patients, 86.2%) and OSD group (11/14 patients, 78.5%). Complication in four patients (including one death) was found in the OSD group compared to zero patients in the CT-PCD group. The proportion of lesion subsided after CT-PCD (25/28 patients, 89.3%) was higher than OSD (10/14 patients, 71.4%). The mean times of hospital stay were 20.2 days in PCD and 24.5 days in OSD groups. CONCLUSION: CT-guided percutaneous drainage might be used as a first line treatment of intra-abdominal fluid collections. PMID- 21299093 TI - Diagnostic cytology and morphometry of Penicillium marneffei in the sputum of a hypogammaglobulinemia with hyper-IgM patient. AB - Penicillosis caused by Penicillium marneffei is endemic in Asia and is a highly fatal disease in HIV-AIDS patients. Reports, however; in other immunocompromized diseases are scanty. This report describes the cytological diagnosis of P. marneffei infection from the sputum of a pediatric patient with hypogammaglobulinemia with hyper IgM and severe pneumonia. In this case, rapid, differential identification of the characteristic septated structure of P. marneffei in the macrophages, bronchial epithelium and also extracellularly allowed prompt and proper treatment. In addition, morphometry of P. marneffei obtained from the clinical specimen was reported. This report demonstrated the fungus was not only in the phagocytes, a phenomenon that is well recognized, but also in epithelial cells. Moreover, it also highlights the need for awareness of penicillosis in non-AIDS immunocompromized patients living in, or persons traveling to, P. marneffei-endemic areas. PMID- 21299092 TI - Role of chest radiography in the diagnosis and follow-up of pulmonary metastasis in differentiated thyroid cancer. AB - BACKGROUND: Post-treatment I-131 whole body scan (WBS) is known to be a very sensitive test in detecting metastasis in differentiated thyroid cancer (DTC). Therefore, in the presence of this sensitive method, the role of chest radiography (CXR) in the diagnosis of pulmonary metastasis has been questioned. OBJECTIVE: The present study aimed to find the prevalence of pulmonary metastasis found on CXR in DTC patients who had negative post-treatment WBS. MATERIAL AND METHOD: Retrospective comparison was undertaken of CXR and post-treatment WBS routinely performed in 300 DTC patients during the time of I-131 treatment from January 2003 to December 2006 in the Department of Radiology. Radiographic patterns of pulmonary metastasis classified as single nodule, multiple nodules, lymphangitic metastasis and pleural metastasis were also recorded. RESULTS: Of the 300 DTC patients, 36 pulmonary metastases (12.0%) were diagnosed based on CXR and post-treatment I-131 WBS. Of these 36 cases, 11 (30.6%) were detected by both CXR and WBS, whereas 16 (44.4%) were detected by WBS alone and 9 (25.0%) by CXR alone. Seven of these 9 cases (77.8%) had lymphangitic pattern of pulmonary metastasis. CONCLUSION: Although routine CXR has a limited role in the diagnosis of pulmonary metastasis in DTC patients being treated with I-131, it is helpful in detecting pulmonary metastasis in patients with negative post-treatment WBS. PMID- 21299094 TI - Environmental state and tendencies of the Puerto Morelos CARICOMP site, Mexico. AB - The CARICOMP site at Puerto Morelos, Mexico was monitored from 1993 to 2005. No significant changes in air temperature, wind patterns, periodicity and quantity of rainfall, sea-surface temperature and water transparency were observed between sampling years. During the study four hurricane impacts were registered. At the coral reef site overall mean cover of fleshy algae (47%) and turf algae (36%) were high, whereas cover of corals (2%) and sponges (3%), and abundance of sea urchins (0.04 org m(-2)) were consistently low. Gorgonians were dominant and showed changes in their community structure; the number of species increased from 1993 to 1995, their abundance decreased after Hurricane Roxanne (1995) and recovered by 2001. At four seagrass sites total community biomass remained constant (707.1-929.6 g dry m(-2)) but the above-ground biomass of the seagrass Syringodium filiforme and fleshy algae increased gradually. Total biomass (531 699 g dry m(-2)) and leaf productivity (0.89-1.56 g dry m(-2) d(-1)) of the seagrass Thalassia testudinum remained constant, but the species invested proportionally more biomass in above-ground leaf tissues at the end of the study. The minor hurricanes from 1993 until 2005 had no detectable impacts on the seagrass beds, however, the major Hurricane Wilma (October 2005) changed the community composition at three stations and caused complete burial of the vegetation at a coastal station. The gradual changes in the seagrass and reef communities recorded in the 12 years of continuous monitoring of the CARICOMP site may reflect the increased pollution caused by the rapid augment in urban and tourist developments along the coasts and inland from Puerto Morelos, coupled with poor water management practices. PMID- 21299095 TI - Temporal patterns in coral reef, seagrass and mangrove communities from Chengue bay CARICOMP site (Colombia): 1993-2008. AB - Few monitoring programs have simultaneously assessed the dynamics of linked marine ecosystems (coral reefs, seagrass beds and mangroves) to document their temporal and spatial variability. Based on CARICOMP protocol we evaluated permanent stations in coral reefs, seagrass beds and mangroves from 1993 to 2008 in Chengue Bay at the Tayrona Natural Park, Colombian Caribbean. Overall, the studied ecosystems showed a remarkable stability pattern over the monitoring period. While there were annual variations in coral reefs (coral cover) and mangroves (litterfall) caused by hurricane Lenny in 1999, particular trends in seagrass (leaf area index and leaf productivity) appear to reflect the natural variability in this ecosystem. We suggest that monitoring sites at the three marine ecosystems had in general a healthy development in the last 16 years. Our results are critical to locally improve the management strategies (Tayrona Natural Park) and to understand the long-term dynamics of closely associated marine ecosystems in the Caribbean. PMID- 21299096 TI - The Jamaican CARICOMP site: using a temporal data set to assist in managing coastal resources. AB - Discovery Bay is one of nine sites around Jamaica's coastline, soon to gain the legislative protection of Fish Sanctuary (and Scientific Reserve) status. Cumulative natural and anthropogenic impacts drove the 1980's coral to algae phase shift. Discovery Bay CARICOMP data (1994 to 2007) showed an increase in coral cover from less than 5% reported in the mid 1980's to 11.7 +/- 0.31% (mean +/- SE) despite chronically high a lgal cover (61.4 +/- 2.2%) at 9 m. Coral cover has been sustained despite low urchin densities (0.99 +/- 0.91 urchins m(-2)), low juvenile coral abundance (2.15 +/- 0.19 corals m(-2)) and coral mortality from repeated bleaching events. Community metrics from the CARICOMP site were compared to an adjacent reef habitat which was found to have higher coral cover (16.36 +/- 3.1%), as well as higher urchin (13.7 +/- 0.84 m(-2)) and juvenile coral (9.7 +/- 1.7 m(-2)) densities. Large branching coral species were absent along the CARICOMP transects and sparse at the nearby shallow reef. Both sites continue to be heavily overfished. Local history records the use of spatially and temporally isolated management strategies which have attempt to rehabilitate various aspects of this area. This unique temporal data set (based on the CARICOMP Methods Manual 2000) provides a baseline for evaluating Government (in)action and is used to justify proposals for ecosystem management which could facilitate phase shift reversal in a coral dominated system. An ecosystem approach that implements several concurrent strategies within and adjacent to the Reserve could accelerate the recovery process. The long term viability and benefit of both old and new marine protected or reserve areas could be enhanced through coral gardening on artificial reef structures with a view to restoring the reefs' three-dimensional complexity. Such actions could theoretically accelerate phase reversal to coral dominated reefs common in the area prior to the devastating impacts of the 1980s. PMID- 21299097 TI - Marine spatial planning (MSP): a first step to ecosystem-based management (EBM) in the Wider Caribbean. AB - The rapid decline of coastal ecosystems of the Wider Caribbean is entering its fifth decade. Some of the best science documenting this decline and its causes has been done by the laboratories of the Association of Marine Laboratories of the Caribbean (AMLC). Alarmed at the trends, Caribbean conservation pioneers established marine protected areas (MPAs) which spread throughout the region. Unfortunately, many have little or no protection and are now known to be too small to be effective in sustaining coastal ecosystems. Marine spatial planning (MSP) holds much promise to encompass the large geographic scales of the ecological processes and human impacts that influence coastal ecosystems and adjacent lands. The AMLC, through the scientific expertise and the national political connections of its member institutions, is well-positioned to help implement a pilot project. MSP a first step in ecosystem-based management and has had considerable success elsewhere. It holds our best chance of sustaining human use and conserving the coral reefs and associated ecosystems. PMID- 21299098 TI - The distribution of seagrasses in Dominica, Lesser Antilles. AB - Seagrass beds are the largest organism-built marine habitat in Dominica, yet have only been surveyed since 2007. Standardized examinations along a depth gradient between 0 and 24 m, focusing on magnoliophyte species composition and benthic cover of shoots at 17 seagrass bed sites, were carried out between September 10 and December 7, 2008. The Cymodoceaceae Syringodium filiforme (Kuetzing 1860) and Halodule wrightii (Ascherson 1868), as well as the Hydrocharitaceae Halophila decipiens (Ostenfeld 1902), H. stipulacea (Fosskal & Ascherson 1867) and Thalassia testudinum (Banks ex Konig 1805) displayed distinct regional and horizontal distribution patterns. Syringodium filiforme is the island's dominant seagrass along the western and northern coasts, occurring at depths between 2 and 18 m and with a mean benthic cover ranging from 0.9-10% along the West coast. Along the North coast it grew between 0.2 and 1 m depth with a mean maximum benthic cover of 48.9%. Halodule wrightii grew along the North and West coasts, in depths between 1 and 14m in areas of recent and chronic disturbances. Its delicate morphology and sparse benthic cover (< 0.1%) did not constitute seagrass beds. Halophila decipiens grew along the deep, shallow and lateral margins of west coast S. filiforme beds and monospecifically in depths between 3 and 24m. Halophila stipulacea, an invasive species, was widespread along 45km of the West coast and was found in depths between 5 and 24m. Both Halophila species formed extensive beds at depths beyond the survey limit of 24m thus playing a potentially important role in the resettlement of shallow areas after storms. H. decipiens and H. stipulacea are currently the second and third most common seagrasses on the island respectively, despite their absence along the North coast. T. testudinum was confined to North coast's sheltered reef flats at depths Im or less with mean a benthic cover ranging from 2 to 76%. It grew monospecifically in the most turbulent and in the calmest locations, yet intermixed with S. filiforme in areas of moderate turbulence. Strong surge along the West coast (October 15-16, 2008), associated with Hurricane Omar, caused uprooting and burial of seagrass beds in varying degrees, in particular along the shallow margins between 2 and 10m depth. This event also demonstrated the dynamic nature of Dominica's shallow seagrass bed margins and the resistance level of individual beds to storm disturbances. PMID- 21299099 TI - The effects of a coral disease on the reproductive output of Montastraea faveolata (Scleractinia: Faviidae). AB - The direct impacts of coral diseases on coral populations have been assessed by quantifying coral tissue loss and colony mortality, but the determination of the indirect effects of diseases, such as disruptions in life history functions (e.g. reproduction, growth and maintenance), are more difficult to ascertain and have been scant. This study involved a comparison of various measures of reproductive output from histological slides of healthy tissue samples of Montastraea faveolata and tissue samples from colonies with white plague (WP) infections in Dominica (West Indies). Although the variability in the reproductive data was high, WP had significant negative impacts on the percentage of reproductive polyps per cm2, the percentage of reproductive mesenteries within a polyp, oocyte quantity per polyp, mean oocyte volume (mm3), and fecundity (oocyte volume per cm2 of tissue). However, these effects were only observed in the tissue directly impacted by the WP disease "band" and were not observed in tissue samples taken 20 cm away from the lesion. Therefore, the effects of a coral disease (WP) on reproductive output are localized and not expressed colony-wide. PMID- 21299100 TI - Implications of coral harvest and transplantation on reefs in northwestern Dominica. AB - In June, 2002, the government of Dominica requested assistance in evaluating the coral culture and transplantation activities being undertaken by Oceanographic Institute of Dominica (OID), a coral farm culturing both western Atlantic and Indo-Pacific corals for restoration and commercial sales. We assessed the culture facilities of OID, the condition of reefs, potential impacts of coral collection and benefits of coral transplantation. Coral reefs (9 reefs, 3-20 m depth) were characterized by 35 species of scleractinian corals and a live coral cover of 8 35%. Early colonizing, brooders such as Porites astreoides (14.8% of all corals), P. porites (14.8%), Meandrina meandrites (14.7%) and Agaricia agaricites (9.1%) were the most abundant corals, but colonies were mostly small (mean = 25 cm diameter). Montastraea annularis (complex) was the other dominant taxa (20.8% of all corals) and colonies were larger (mean = 70 cm). Corals (pooled species) were missing an average of 20% of their tissue, with a mean of 1.4% recent mortality. Coral diseases affected 6.4% of all colonies, with the highest prevalence at Cabrits West (11.0%), Douglas Bay (12.2%) and Coconut Outer reef (20.7%). White plague and yellow band disease were causing the greatest loss of tissue, especially among M. annularis (complex), with localized impacts from corallivores, overgrowth by macroalgae, storm damage and sedimentation. While the reefs appeared to be undergoing substantial decline, restoration efforts by OlD were unlikely to promote recovery. No Pacific species were identified at OID restoration sites, yet species chosen for transplantation with highest survival included short-lived brooders (Agaricia and Porites) that were abundant in restoration sites, as well as non-reef builders (Palythoa and Erythropodium) that monopolize substrates and overgrow corals. The species of highest value for restoration (massive broadcast spawners) showed low survivorship and unrestored populations of these species were most affected by biotic stressors and human impacts, all of which need to be addressed to enhance survival of outplants. Problems with culture practices at OID, such as high water temperature, adequate light levels and persistent overgrowth by macroalgae could be addressed through simple modifications. Nevertheless, coral disease and other stressors are of major concern to the most important reef builders, as these species are less amenable to restoration, collection could threaten their survival and losses require decades to centuries to replace. PMID- 21299101 TI - Effect of severe hurricanes on biorock coral reef restoration projects in Grand Turk, Turks and Caicos Islands. AB - Artificial reefs are often discouraged in shallow waters over concerns of storm damage to structures and surrounding habitat. Biorock coral reef restoration projects were initiated in waters around 5 m deep in Grand Turk, at Oasis (October 2006) and at Governor's Beach (November 2007). Hemi-cylindrical steel modules, 6m long were used, four modules at Oasis and six at Governor's Beach. Each project has over 1200 corals transplanted from sites with high sedimentation damage, and are regularly monitored for coral growth, mortality and fish populations. Corals show immediate growth over wires used to attach corals. Growth has been measured from photographs using a software program and is faster at Governor's Beach. After hurricanes Hanna and Ike (September 2008) the Governor's Beach structure was fully standing since the waves passed straight through with little damage, the Oasis structures which were tie-wired rather than welded had one module collapse (since been replaced with a new, welded structure). Hurricane Ike was the strongest hurricane on record to hit Grand Turk. Most cables were replaced following the hurricanes due to damage from debris and high wave action. The projects lost about a third of the corals due to hurricanes. Most of those lost had only been wired a few days before and had not yet attached themselves firmly. These projects have regenerated corals and fish populations in areas of barren sand or bedrock and are now attractive to snorkelers. High coral survival and low structural damage after hurricanes indicate that Biorock reef restoration can be effective in storm-impacted areas. PMID- 21299102 TI - Restoration and monitoring of a vessel grounding on a shallow reef in the Florida Keys. AB - This paper summarizes the results of a monitoring event designed to track the recovery of a repaired coral reef injured by the M/V Alec Owen Maitland vessel grounding incident of October 25, 1989. This grounding occurred within the Florida Keys National Marine Sanctuary. Pursuant to the National Marine Sanctuaries Act, NOAA recovers money for injury to Sanctuary resources, and uses it to restore those resources. A monitoring program tracks patterns of recovery, in order to determine the success of restoration measures. To evaluate success, reference habitats adjacent to the restoration site are concurrently monitored to compare the condition of restored areas with natural areas. Restoration of this site was completed in September 1995 by means of cement and limestone rock, and the monitoring results from summer 2007 are presented. Monitoring consisted of comparison of the biological conditions in the restored area with the reference area. Monitored corals are divided into the Orders: Gorgonians, Milleporans, and Scleractinians. Densities at the restored and reference areas are compared, and are shown to be greater in the restored. Size-class frequency distributions for the most abundant Scleractinians are examined, and reveal that the restoration is converging on the reference area. Also, for the Scleractinians, number and percentage of colonies by species, as well as several common biodiversity indices are provided; measures for the restored area approximate the reference area. A quantitative comparison of colony substrate settlement preference in the restored area is provided for all Orders, and for Scleractinians is further broken down for the two most frequent Genera. PMID- 21299103 TI - Severity of the 1998 and 2005 bleaching events in Venezuela, southern Caribbean. AB - This study describes the severity of the 2005 bleaching event at 15 reef sites across Venezuela and compares the 1998 and 2005 bleaching events at one of them. During August and September 2005, bleached corals were first observed on oceanic reefs rather than coastal reefs, affecting 1 to 4% of coral colonies in the community (3 reef sites, n = 736 colonies). At that time, however, no bleached corals were recorded along the eastern coast of Venezuela, an area of seasonal upwelling (3 reefs, n = 181 colonies). On coastal reefs, bleaching started in October but highest levels were reached in November 2005 and January 2006, when 16% of corals were affected among a wide range of taxa (e.g. scleractinians, octocorals, Millepora and zoanthids). In the Acropora habitats of Los Roques (an oceanic reef),no bleached was recorded in 2005 (four sites,n = 643 colonies). At Cayo Sombrero, a coastal reef site, bleaching was less severe in 1998 than in 2005 (9% of the coral colonies involving 2 species vs. 26% involving 23 species, respectively). Our results indicate that bleaching was more severe in 2005 than in 1998 on Venezuelan reefs; however, no mass mortality was observed in either of these two events. PMID- 21299104 TI - Coral reefs and residents of the U.S. Virgin Islands: a relationship of knowledge, outdoor activities and stewardship. AB - To test the hypotheses that U.S. Virgin Islanders' knowledge about local coral reefs is correlated with behavior, and that different sociological groups of residents have different patterns of knowledge and behavior, a mixed approach to surveying residents was used: (1) personal interviews were held in public locations and (2) an online version of the survey was administered to residents of the U.S. Virgin Islands. From July-October 2008,462 residents over 18 years old were surveyed. Results indicate that people who engaged in outdoor activities knew significantly more about coral reefs (Spearman p < 0.01, r2 = -0.128). Those more knowledgeable about coral reefs engaged in more positive stewardship activities (e.g. beach clean-ups) (Spearman p < 0.01, r2 = 0.127). Negative behaviors (e.g. anchoring on reef) were not significantly correlated with increased knowledge of coral reefs (Spearman p = -0.911, r2 = -0.000025). Fishers did not have greater ability in identifying Acropora palmata coral than non fishers (chi2 = 4.138, p = 0.126); however, swimmers, snorkelers and divers (as a class) were more able to identify A. palmata than non-swimmers (chi2 = 9.764, p = 0.002). Most residents identified sea turtle species as endangered (hawksbill turtle, 78.9%) but only 48.2% of the responses included Acropora spp. as threatened. Resident attitudes towards conservation of local resources were overwhelmingly positive. PMID- 21299105 TI - Anticonvulsant activity of the linalool enantiomers and racemate: investigation of chiral influence. AB - The anticonvulsant activity of the racemate and enantiomers of linalool have been evaluated. Pretreatment of the mice with (S)-(+)-, (R)-(-)- and rac-linalool increased the latency of convulsions significantly in the PTZ model. Only rac linalool had an effect at the dose of 200 mg/kg. The enantiomers and their racemic mixture were effective in inhibiting the convulsant effect of PTZ at the dose of 300 mg/kg. The linalools presented pharmacological activity close to that of diazepam. In the PIC seizure model, (R)-(-)-linalool and rac-linalool presented activity at the dose of 200 mg/kg, but the rac-linalool was more potent than (R)-(-)-linalool; (S)-(+)-linalool had no effect at this dose. On the other hand, at the dose of 300 mg/kg this enantiomer was effective, but less potent than (R)-(-)-linalool and rac-linalool. In the MES model, linalools decreased the convulsion time of the mice in the doses of 200 and 300 mg/kg. rac-Linalool presented maximum effect at 300 mg/kg. Surprisingly, it increased significantly the convulsion time at a dose of 100 mg/kg. Using the parameter of tonic hind convulsions, only (R)-(-)-linalool produced protection from tonic extension at the dose of 200 mg/kg. When the (+)- and (-)-enantiomers, and rac-linalool were administered at the dose of 300 mg/kg they were also effective in preventing tonic convulsions induced by transcorneal electroshock in the animals. The (+)- and (-)-forms were equipotent and the rac-linalool was more effective than phenytoin. We have demonstrated that the two enantiomers have similar qualitative anticonvulsant activity, but show different potencies. PMID- 21299106 TI - Kinetic analysis of genipin degradation in aqueous solution. AB - Degradation of genipin (GP), a low toxicity natural protein crosslinking agent, in aqueous solution was monitored by HPLC at various pH levels. Degradation of GP was consistent with a mechanism consisting of a first order reaction with a reversible first step. Formation of the intermediate was slowest at more neutral pHs while formation of the irreversible product was correlated to increasing alkalinity. Degradation at all pHs was enhanced by the presence of phosphate ions. Degradation of GP most likely proceeds via the reversible opening of the dihydropyran ring by water followed by irreversible polymerization of the intermediate. Degraded solutions containing no detectable GP or intermediate, however, are still capable of crosslinking proteins. PMID- 21299107 TI - Microbial transformation of marine halogenated sesquiterpenes. AB - The sesquiterpene pacifenol is one of the main constituents of the red alga Laurencia claviformis. Earlier work on the semisynthetic derivatives of pacifenol afforded a series of halogenated sesquiterpenes. The aim of the present work was to obtain new hydroxylated derivatives of halogenated sesquiterpenes by means of microbial transformation using Aspergillus niger, Gibberella fujikuroi and Mucor plumbeus. The best results were obtained with M. plumbeus. The microbiological transformation by M. plumbeus of pacifenol, and two semisynthetic derivatives, is described. The structures of the new compounds obtained were determined by spectroscopic means. PMID- 21299108 TI - Two new guaianolides from Amberboa ramosa. AB - Two new sesquiterpene lactones named amberbins A (1) and B (2), have been isolated from the ethyl acetate soluble fraction of Amberboa ramosa, together with jaseocidine (3), crysoeriol (4) and 3beta,8alpha-dihydroxy-11alpha-methyl 1alphaH,5alphaH,6betaH, 7alphaH,11betaH-guai-10(14), 4(15)-dien-6,12-olide (5). The structures of the isolated compounds have been elucidated on the basis of their spectroscopic data. PMID- 21299109 TI - Antiplasmodial and cytotoxic activities of drimane sesquiterpenes from Canella winterana. AB - The hexane extract from the leaves of Canella winterana exhibited strong activity against the chloroquine sensitive (CQS) strain of Plasmodium falciparum (D10) in vitro (IC50 2.53 microg/mL). Bioassay guided fractionation of this extract has led to the isolation of 5 drimane-type sesquiterpenoids: 9-epideoxymuzigadial, 9 deoxymuzigadial, muzigadial, 3-beta-acetoxypolygodial and the newly isolated hemiacetal, named muzigodiol, with IC50-values of 1.01, 2.19, 0.31, 2.77 and 7.43 microg/mL, respectively. The first four compounds were tested for their cytotoxicity using Chinese Hamster Ovarian (CHO) cells, where they showed IC50 values of 1.82, 33.69, 1.18, and 58.31 microg/mL, respectively. A structure activity relationship is discussed. PMID- 21299110 TI - Three new 18-oxygenated ent-kaurane diterpenoids from Isodon leucophyllus. AB - Three new 18-oxygenated ent-kaurane diterpenoids, isoleuconins A-C (1-3) and ten known diterpenoids were isolated from the aerial parts of Isodon leucophyllus. The structures were elucidated by 1D and 2D NMR spectroscopic analysis. All of the compounds were evaluated for their cytotoxicity. Rabdokunmin A (13) showed significant cytotoxicity against HT-29 cells, with an IC50 value of 6.2 microM. PMID- 21299111 TI - Immunomodulatory action of monosulfated triterpene glycosides from the sea cucumber Cucumaria okhotensis: stimulation of activity of mouse peritoneal macrophages. AB - Six monosulfated triterpene glycosides, frondoside A1 (1), okhotoside B1 (2), okhotoside A1-1 (3), frondoside A (4), okhotoside A2-1 (5) and cucumarioside A2-5 (6), isolated from Cucumaria okhotensis Levin et Stepanov, stimulate spreading and lysosomal activity of mouse macrophages and ROS-formation in the macrophages. The highest macrophage spreading and stimulation of their lysosomal activity was induced by glycosides 1, 4 and 6. All glycosides similarly stimulate ROS formation in macrophages, but glycoside 2 caused minimal stimulation. PMID- 21299112 TI - Three new aaptamines from the marine sponge Aaptos sp. and their proapoptotic properties. AB - Three new aaptamine-type alkaloids, 2,3-dihydro-2,3-dioxoaaptamine (1), 6-(N morpholinyl)-4,5-dihydro-5-oxo-demethyl(oxy)aaptamine (2) and 3 (methylamino)demethyl(oxy)aaptamine (3), along with known aaptamines were isolated from the sponge Aaptos sp. Their structures were determined on the basis of detailed analysis of their 1D and 2D NMR spectroscopic and mass spectral data. The isolated compounds induced apoptosis in human leukemia THP-1 cells. PMID- 21299113 TI - Isolation and characterization of crotosparsamide, a new cyclic nonapeptide from Croton sparsiflorus. AB - Crotosparsamide (1), a new cyclic nonapeptide, has been isolated from the n butanol soluble sub-fraction of Croton sparsiflorus along with p-hydroxy methylcinnamate and kaempferol, which are reported for the first time from this species. Their structures were determined by chemical and spectral studies including ESIMS, and 1D and 2D NMR spectroscopic data. PMID- 21299114 TI - Two new lavandulyl flavonoids from Sophora flavescens. AB - Two novel lavandulyl flavonoids, (2S)-7-methoxyl-4",5"-dihydroxynorkurarinone (1) and (2S)-6"-hydroxynorkurarinone-7-O-beta-D-galactoside (2), were isolated from the rhizome of Sophora flavescens. Their structures were elucidated by spectral methods, including 2D NMR spectroscopy. Both compounds showed cytotoxic activity against Hela cells, with 2 being more active than 1. PMID- 21299115 TI - Biotransformation of naringenin to eriodictyol by Saccharomyces cerevisiea functionally expressing flavonoid 3' hydroxylase. AB - To increase the biological activities of flavonoids and to enhance their stability and solubility by functionalization reactions (polymerization, esterification, alkylation, glycosylation and acylation), an increase in the number of hydroxyl groups in these molecules is needed. Hydroxylation reactions may be achieved using either chemical or enzymatic methods, the latter being more highly specific than the former. In our study, the flavonoid 3' hydroxylase (F3'H) from Gerbera hybrid, functionally expressed in Saccharomyces cerevisiae, was used to hydroxylate naringenin (the first flavonoid core synthesized in plants). Furthermore, we studied factors that may affect naringenin hydroxylation by recombinant cell-like yeast growth on selective or rich media and plasmid stability. The whole recombinant cells hydroxylated naringenin at position 3' to give eriodictyol. In a selective media, the yeast failed to grow to high cell densities (maximum 5 g/L), but the plasmid stability was nearly 90%, and naringenin hydroxylation reached 100%. In a rich complex media, the biomass reached 10 g/L, but the yield of naringenin hydroxylation reached only 71%, and the plasmid stability decreased. When yeast functionally expressing F3'H from Gerbera hybrid was used, in a selective media, 200 mg/L of eriodictyol from naringenin was produced. PMID- 21299116 TI - Two new 3-C-carboxylated flavones from the rhizomes of Caragana conferta. AB - Confertins A (1) and B (2), new 3-C-carboxylated flavones, have been isolated from the ethyl acetate soluble fraction of the rhizomes of Caragana conferta. Their structures have been assigned on the basis of spectroscopic studies. PMID- 21299117 TI - Kaempferol glycosides in the flowers of carnation and their contribution to the creamy white flower color. AB - Three flavonol glycosides were isolated from the flowers of carnation cultivars 'White Wink' and 'Honey Moon'. They were identified from their UV, MS, 1H and 13C NMR spectra as kaempferol 3-O-neohesperidoside, kaempferol 3-O-sophoroside and kaempferol 3-O-glucosyl-(1 --> 2)-[rhamnosyl-(1 --> 6)-glucoside]. Referring to previous reports, flavonols occurring in carnation flowers are characterized as kaempferol 3-O-glucosides with additional sugars binding at the 2 and/or 6 positions of the glucose. The kaempferol glycoside contents of a nearly pure white flower and some creamy white flower lines were compared. Although the major glycoside was different in each line, the total kaempferol contents of the creamy white lines were from 5.9 to 20.9 times higher than the pure white line. Thus, in carnations, kaempferol glycosides surely contribute to the creamy tone of white flowers. PMID- 21299118 TI - Factors influencing glabridin stability. AB - Glabridin, a polyphenolic isoflavan of Glycyrrhiza glabra, has shown a variety of pharmaceutical properties. We have previously studied the isolation of glabridin using macroporous resin and found that it is partially degraded, giving a dark color. To illustrate the degradation of glabridin, the present work studied the stability of glabridin under various conditions. Licorice extract containing about 20% glabridin, obtained from G. glabra by silica gel column chromatography, was used in the stability study. Seven different factors (temperature, illumination, humidity, pH, solvent, oxygen, and oxidant) were studied and content changes were determined through HPLC analysis. Except for oxygen, all the above factors had an effect on the stability of glabridin, with illumination being the main one. Moreover, the interactions between temperature and pH, temperature and humidity, and illumination and pH can promote the degradation of glabridin. In conclusion, we suggest that a dark, dry and airtight environment provides the optimized condition for the long-term storage of glabridin. PMID- 21299119 TI - Effect of different strains of Agrobacterium rhizogenes and nature of explants on Plumbago indica hairy root culture with special emphasis on root biomass and plumbagin production. AB - The aim of the present study was to determine the effect of three strains of Agrobacterium rhizogenes (ATCC 15834, A4 and LBA 9402) and the nature of explants (leaf and stem) on hairy root induction, growth and plumbagin production in Plumbago indica. The first appearance of hairy roots, the transformation frequency, dry root biomass and plumbagin accumulation were found to be maximum in hairy roots induced in leaf explants infected with A. rhizogenes ATCC 15834 as compared with the other two bacterial strains. The hairy roots generated from stem explants infected with all three strains were not found to be productive in terms of the selected parameters. Finally, the insertion of the rolB gene of A. rhizogenes ATCC 15834 in hairy roots of P. indica derived from leaf explants was confirmed by PCR analysis. PMID- 21299120 TI - Fujianmycin C, A bioactive angucyclinone from a marine derived Streptomyces sp. B6219. AB - From a marine-derived streptomycete, a new bioactive angucyclinone, fujianmycin C (1), has been isolated along with five known, metabolites fujianmycins A (2) and B (3), ochromycinone (4), ochromycinone methyl ether (5), and tetrangulol methyl ether (6). The structure elucidation of fujianmycin C (1) was performed by detailed analysis of data such as 1H, 13C, 1H, 1H COSY, HSQC, HMBC and NOESY spectra. Fujianmycin C (1) exhibited antibacterial activity against Streptomyces viridochromogenes (Tu57). PMID- 21299121 TI - Dioscorealide B from the traditional Thai medicine Hua-Khao-Yen induces apoptosis in MCF-7 human breast cancer cells via modulation of Bax, Bak and Bcl-2 protein expression. AB - Dioscorealide B is a pharmacologically active compound from the rhizome of the Thai medicinal plant Dioscorea membranacea. Here, we demonstrated that in vitro treatment of dioscorealide B resulted in a cytotoxic effect on MCF-7 human breast cancer cells (IC50 = 2.82 microM). To determine whether this compound induces apoptosis in MCF-7, the Annexin V assay was performed. The data showed that the number of apoptotic cells were increased 7-12 folds over that of the control cells after treatment with various concentrations of dioscorealide B (3, 6 and 12 microM) for 24 hours. Dioscorealide B-induced apoptosis was associated with modulation of the multidomain Bcl-2 family members Bax, Bak and Bcl-2. After treatment with 3 microM dioscorealide B, acceleration of the level of proapoptotic proteins Bax and Bak were observed at 6 hours and 12 hours, respectively, while the decrease in the expression of antiapoptotic protein Bcl-2 was observed 3 hours after the treatment. These effects of dioscorealide B might result in the activation of caspase-8, -9 and -7, which lead to apoptosis in MCF 7 cells. Taken together, the results of this study provide evidence that dioscorealide B possesses an antitumor property against human breast cancer cells and thus provide the molecular basis for the further development of dioscorealide B as a novel chemotherapeutic agent for breast cancer treatment. PMID- 21299122 TI - Inhibition of protein tyrosine phosphatase 1beta by hispidin derivatives isolated from the fruiting body of Phellinus linteus. AB - Protein tyrosine phosphatase 1beta (PTP1beta) acts as a negative regulator of insulin signaling. Selective inhibition of PTP1beta has served as a potential drug target for the treatment of type 2 diabetes mellitus. We evaluated the inhibitory effect of Phellinus linteus against PTP1beta as part of our ongoing search for natural therapeutic and preventive agents for diabetes mellitus. Fractions of the P. linteus extract were found to exhibit significant inhibitory activities against PTP1beta. In an attempt to identify bioactive components, we isolated, from the most active ethyl acetate fraction, five hispidin derivatives (phelligridimer A, davallialactone, hypholomine B, interfungins A, and inoscavin A) and four phenolic compounds (protocatechuic acid, protocatechualdehyde, caffeic acid, and ellagic acid). The chemical structures of these compounds were elucidated from spectroscopic evidence and by comparison with published data. All the compounds strongly inhibited PTP1beta activity in an in vitro assay; their IC50 values ranged from 9.0 +/- 0.01 to 58.2 +/- 0.3 microM. Our results indicated that the hispidin skeleton may be an important moiety for inhibitory activity of the above compounds against PTP1beta. Thus, hispidin derivatives could be a potent new class of natural PTP1beta inhibitors. PMID- 21299123 TI - A new azafluorenone from the roots of Polyalthia cerasoides and its biological activity. AB - Chromatographic separation of the ethyl acetate extract of roots of Polyalthia cerasoides has led to the isolation of the new compound, 6,8-dihydroxy-7-methoxy 1-methyl-azafluorenone. This compound exhibited potent cytotoxic activities with IC50 values in the range of 2.64-3.58 microg x mL(-1) for A549, GLC4 and GLC4/Adr cells, but was not recognized by ABCC1/MRP1 protein. The compound also showed very strong inhibition of M. tuberculosis using a broth microdilution method, with an MIC value of 0.78 microg x mL(-1), which was equal to that of ofloxacin, one of the four antibiotic drugs used as a positive control. PMID- 21299124 TI - Evaluation of antiviral activities of curcumin derivatives against HSV-1 in Vero cell line. AB - Antiviral drug resistance is one of the most common problems in medicine, and, therefore, finding new antiviral agents, especially from natural resources, seems to be necessary. This study was designed to assay the antiviral activity of curcumin and its new derivatives like gallium-curcumin and Cu-curcumin on replication of HSV-1 in cell culture. The research was performed as an in vitro study in which the antiviral activity of different concentrations of three substances including curcumin, Gallium-curcumin and Cu-curcumin were tested on HSV-1. The cytotoxicity of the tested compounds was also evaluated on the Vero cell line. The CC50 values for curcumin, gallium-curcumin and Cu-curcumin were 484.2 microg/mL, 255.8 microg/mL and 326.6 microg/mL, respectively, and the respective IC50 values 33.0 microg/mL, 13.9 microg/mL and 23.1 microg/mL. The calculated SI values were 14.6, 18.4 and 14.1, respectively. The results showed that curcumin and its new derivatives have remarkable antiviral effects on HSV-1 in cell culture. PMID- 21299125 TI - Hyloglyceride and hylodiglyceride: two new glyceride derivatives from Hylodendron gabunensis. AB - Phytochemical investigation of Hylodendron gabunensis resulted in the isolation of two new glyceride derivatives, hyloglyceride (1) and hylodiglyceride (2). The structures of the two new compounds were determined by comprehensive analysis of their 1D and 2D NMR spectroscopic, and HREIMS data. One known compound was also isolated and identified as beta-sitosterol. PMID- 21299126 TI - Chemical composition and bioactivities of the marine alga Isochrysis galbana from Taiwan. AB - The present study investigated the chemical composition of Isochrysis galbana Parke, a marine microalga which is widely used as a feedstock in aquaculture. From gas chromatography/mass spectrometric analysis the mono-sugar compositions of I. galbana were 2.1% fucose, 2.5% rhamnose, 2.7% arabinose, 8.5% xylose, 15.7% mannose, 32.7% galactose and 35.8% glucose. The polysaccharides of I. galbana were able to induce prointerleukin-1beta (pro-IL-1beta) protein expression within murine macrophages. Furthermore, five kinds of chlorophyll and one sterol were separated from the ethanolic extracts, including pheophorbide-a, ethyl pheophorbide-a, 10S-10-hydroxypheophytin-a, 10R-10-hydroxypheophytin-a, (132-R) pheophytin-a, and brassicasterol. In addition, the major soluble components of the ethanol/n-hexane extract were 9-octadecenoic acid (E) (38.4%), hexadecanoic acid (23.3%), tetradecanoic acid (15.7%), and octadecanoic acid (7.2%), but only a few polyunsaturated fatty acids were found, such as 9,12,15-octadecatrienoic acid (1.9%), 9,12-octadecadienoic acid (Z,Z) (3.4%), and docosahexaenoic acid (0.2%). This is the first occasion that polysaccharides from I. galbana have been demonstrated to exert immunomodulatory properties by the induction of IL-1 within macrophages. PMID- 21299127 TI - An efficient protocol for high-frequency direct multiple shoot regeneration from internodes of peppermint (Mentha x piperita). AB - A simple, repeatable and efficient protocol for direct multiple shoot regeneration from internodal explants has been defined in peppermint (Mentha x piperita var. Indus). In vitro regenerated shoots of peppermint were excised into 4 to 8 mm long internodes and cultured on Murashige and Skoog's medium supplemented with different cytokinins. In the hormonal assay, 3.0 mg L(-1) zeatin or 6-isopentenyl adenine independently supplemented to half strength MS medium exhibited multiple shoot regeneration, while thiaduzorn (0.1-3.0 mg L(-1)) showed no morphogenetic effect. A maximum of 85% in vitro cultured explants showed multiple shoot formation with an average of 7 shoots per explant on MS medium supplemented with zeatin. Multiple shoots were initiated within three weeks of cultivation. Internodes with regenerated multiple shoots were transferred to half- strength MS medium without supplementing with any plant growth hormone for shoot elongation and rhizogenesis. Rooted plants acclimatized and grew to maturity under glasshouse conditions. The plantlets developed were phenotypically identical to the parent plant and exhibited 96% survival. PMID- 21299128 TI - Essential oil yield and chemical composition changes during leaf ontogeny of palmarosa (Cymbopogon martinii var. motia). AB - Changes in leaf biomass yield, essential oil yield, and chemical composition were investigated during leaf ontogeny of palmarosa {Cymbopogon martinii (Roxb.) Wats. var. motia Burk., family Poaceae}. Eleven leaves representing different developmental stages, serially numbered from the apex to the base of the plant were utilized for the study. Leaf biomass yield increased up to the eighth leaf. Essential oil recovery increased up to the third leaf; thereafter it decreased. Minimum essential oil recovery was observed in the eleventh leaf. Essential oil yield/leaf increased up to the sixth leaf. Essential oil yield and concentrations of linalool, alpha-terpineol, geranyl isobutyrate and geraniol were relatively higher in the essential oils of mature, older leaves. Essential oil recovery, and percentages of myrcene, beta-caryophyllene, geranyl acetate, (E,Z) farnesol and geranyl hexanoate were higher in the essential oils of young, expanding leaves. PMID- 21299129 TI - Essential oil composition of four endemic Ferulago species growing in Turkey. AB - The essential oils from aerial parts of Ferulago pachyloba (Fenzl) Boiss., F. platycarpa Boiss. & Bal., F. isaurica Penmen, and F. longistylis Boiss. (Apiaceae) were obtained by hydrodistillation and analyzed by GC and GC-MS. The highest oil yield (1.50%) was obtained from F. pachyloba followed by F. longistylis (0.16%), F. isaurica (0.08%) and F. platycarpa (0.07%). Fifty-three compounds were identified in the oil of F. pachyloba with (Z)-beta-ocimene (25.7%) and alpha-pinene (9.8%) as main constituents; sixty-seven in the oil of F. platycarpa with 2,3,6-trimethylbenzaldehyde (29.8%) and cis-chrysanthenyl acetate (24.2%) as main components; seventy-eight in the oil of F. isaurica with nonacosane (25.5%) and hexadecanoic acid (14.8%) as main constituents; and fifty nine in the oil of F. longistylis with 2,3,6-trimethylbenzaldehyde (32.7%) and bornyl acetate (12.6%) as main components. Quantitative and qualitative differences in the oil compositions of these four species were observed. PMID- 21299130 TI - Essential oils of Daucus carota subsp. carota of Tunisia obtained by supercritical carbon dioxide extraction. AB - The essential oils and supercritical CO2 extracts of wild Daucus carota L. subsp. carota from two different sites in Tunisia were investigated. The main components of the essential oil of the flowering and mature umbels with seeds from Sejnane were eudesm-7(11)-en-4-ol (8.2 - 8.5%), carotol (3.5 - 5.2%), sabinene (12.0 14.5%), a-selinene (7.4 - 8.6) and 11-alpha-(H)-himachal-4-en-1-beta-ol (12.7 - 17.4%), whereas the oils from Tunis were predominantly composed of elemicin (31.5 - 35.3%) and carotol (48.0 - 55.7%). The antimicrobial activity of the essential oils were assayed by using the broth dilution method on Escherichia coli ATCC 35218 and Staphylococcus aureus ATCC 43300, and clinical strains of Candida albicans and C. tropicalis 1011 RM. The MIC values obtained were all > 2.5% (v/v). PMID- 21299131 TI - Oil constituents of Artemisia nilagirica var. septentrionalis growing at different altitudes. AB - Oils of Artemisia nilagirica var. septentrionalis plants growing at different altitudes in Himachal Pradesh, India were hydro-distilled and analyzed by GC GC/MS. The major constituents of the oil show variation with changes in altitude. At lower, middle and higher altitudes, the major constituents of the oil were caryophyllene oxide (28.6%), borneol (35.8%) and camphor (46.9%), respectively. The percentages of alpha-humulene and trans-beta-guaiene also increased, but the percentage of sabinene, trans-sabinene hydrate, 4-terpineol, caryophyllene oxide and humulene epoxide-II decreased with an increase in altitude. The characteristic compounds observed in the plants from lower altitudes were 2 hexene-1-ol, beta-thujone, thujanol, myrtenol and linalyl acetate, while the higher altitude plants were characterized by the presence of alpha-pinene, beta pinene, limonene, linalool, gamma-gurijunene, germacrene-D and farnesol. PMID- 21299132 TI - Volatile oil composition of Pogostemon heyneanus and comparison of its composition with patchouli oil. AB - The volatile oil of the leaves of Pogostemon heyneanus Benth. (Lamiaceae) was analyzed by GC and GC-MS. Twenty-six components representing 96.0% of the oil were identified. The major components of the oil were acetophenone (51.0%), beta pinene (5.3%), (E)-nerolidol (5.4%), and patchouli alcohol (14.0%). Comparison of the compositions of the oils of P. heyneanus and P. cablin (Blanco) Benth. (Patchouli oil) showed wide variation between them. Though 13 sesquiterpenes and oxygenated sesquiterpenes were detected in both oils, their concentrations in the oils differed widely. Acetophenone, benzoyl acetone and (E)-nerolidol present in the oil of P. heyneanus were not detected in patchouli oil. PMID- 21299133 TI - Chemical composition of volatile oils of Aquilaria malaccensis (Thymelaeaceae) from Malaysia. AB - Volatile oils of Aquilaria malaccensis Benth. (Thymelaeaceae) from Malaysia were obtained by hydrodistillation and subjected to detailed GC-FID and GC/MS analyses to determine possible similarities and differences in their chemical composition in comparison with the commercial oil. A total of thirty-one compounds were identified compared with twenty-nine identified in the commercial oil. The major compounds identified were 4-phenyl-2-butanone (32.1%), jinkoh-eremol (6.5%) and alpha-guaiene (5.8%), while the major compounds in the commercial oil were alpha guaiene (10.3%), caryophellene oxide (8.6%), and eudesmol (3.2%). The results of the present study showed that more than nine sesquiterpene hydrocarbons were present, which is more than previously reported. Analysis also showed that the number of oxygenated sesquiterpenes in this study were much less than previously reported. Among the compounds detected were alpha-guaiene, beta-agarofuran, alpha bulnesene, jinkoh-eremol, kusunol, selina-3,11-dien-9-one, oxo-agarospirol and guaia-1 (10), 11-dien-15,2-olide. PMID- 21299134 TI - Chemical composition and phytotoxic effects of essential oils from four Teucrium species. AB - The essential oils of four Teucrium species were studied and 131 components, in all, were identified. All oils were rich in sesquiterpenes (50.0-61.9%). Caryophyllene and caryophyllene oxide were the main components of Teucrium arduini; germacrene D, delta-cadinene and gamma-cadinene predominated in Teucrium maghrebinum. Carvacrol and caryophyllene predominated in Teucrium polium ssp. capitatum, while carvacrol, caryophyllene oxide and caryophyllene were the most abundant components in Teucrium montbretii ssp. heliotropiifolium. The germination of radish and garden cress was less sensitive to the four essential oils. The radicle elongation, above all, of radish was significantly inhibited by all oils, in particular by the essential oil of T. arduini, at the highest doses tested. Among the main components of the oils, monoterpenes resulted the more active compounds. PMID- 21299135 TI - Chemical constituents and larvicidal activity of Hymenaea courbaril fruit peel. AB - The chemical compositions of the essential oils from the peel of ripe and unripe fruits of Hymenaea courbaril L., obtained by hydrodistillation, were analyzed by GC and GC-MS. The main constituents of the essential oil from the peel of the ripe fruits were the sesquiterpenes alpha-copaene (11.1%), spathulenol (10.1%) and beta-selinene (8.2%), while germacrene-D (31.9%), beta-caryophyllene (27.1%) and bicyclogermacrene (6.5%) were the major compounds in the oil from unripe fruits. The essential oils were tested against Aedes aegypti larvae and showed LC50 values of 14.8 +/- 0.4 microg/mL and 28.4 +/- 0.3 microg/mL for the ripe and unripe fruit peel oils, respectively. From the peel of the ripe fruits, the diterpenes zanzibaric acid and isoozic acid were isolated, along with the sesquiterpene caryolane-1,9beta-diol. To the best of our knowledge, this is the first report of this sesquiterpene in the genus. The structures of all compounds isolated were identified on the basis of their spectral data (IR, MS, 1D- and 2D NMR) and by comparison with literature spectral data. PMID- 21299136 TI - Caryophyllene oxide-rich essential oils of Lithuanian Artemisia campestris ssp. campestris and their toxicity. AB - The chemical composition of the essential oils of aerial parts of Artemisia campestris ssp. campestris, collected from ten different locations in Lithuania is detailed in this paper. The major component in all the oils was caryophyllene oxide (8.5-38.8%), whereas compounds with the caryophyllane skeleton ranged from 10.2 to 44.5%. Other representative constituents were germacrene D (< or = 15.0%), humulene epoxide II (< or = 8.1%), beta-ylangene (< or = 7.7%), spathulenol (< or = 6.8%), beta-elemene (< or = 6.8%), beta-caryophyllene (< or = 6.2%), junenol (< or = 6.1%) and alpha- or beta-pinene (< or = 5.5%). Eighty seven compounds were identified, comprising 73.6-92.3% of the oils. The chemical composition was highly variable depending on the sample location. Toxicity of A. campestris oils was determined using the brine shrimp (Artemia sp.) assay. LC50 values ranging to 20 microg/mL were obtained for three of the oils after 24 hours of exposure. Data of this test revealed that A. campestris ssp. campestris essential oils with dominant caryophyllene oxide are notably toxic. PMID- 21299137 TI - Comparison of antibacterial activity of natural and hydroformylated essential oil of Thymus capitatus growing wild in north Sardinia with commercial Thymus essential oils. AB - Thymus capitatus growing wild in Sardinia showed different essential oil composition if grown surrounding Cagliari than in north Sardinia. Here we verify the composition and antimicrobial activity of the oil to make it suitable for the cosmetic and confectionery industries. With the aim of improving the scent and the antimicrobical activity of T. capitatus essential oil, a hydroformylation reaction was carried out to transform the unsaturated components of the oil into the corresponding aldehydes. The essential oil of T. capitatus exhibited a significant antibacterial activity (MIC 0.125-0.5 mg/mL), and was also found effective on C. albicans (MIC 0.125 mg/mL). After hydroformylation, several new irregular terpenoid aldehydes were detected. The perfume of the new terpenic-like aldehydes is very agreeable and, therefore, the acceptability of the aroma is remarkably improved, but the antimicrobial activity was not increased. PMID- 21299138 TI - Composition and chemical variability of the leaf oil from Corsican Juniperus thurifera. Integrated analysis by GC(RI), GC-MS and 13C NMR. AB - The composition of 16 samples of leaf oil from Corsican Juniperus thurifera was investigated by integrated techniques, GC, GC-MS and 13C NMR. K-means partitioning and PCA analysis of the data allowed the definition of a main group (14 samples) dominated by limonene (mean = 52.2%, SD = 6.4) and alpha-pinene (mean = 7.2%, SD = 3.8). Limonene and beta-elemol (up to 19.7%) were identified as the major components of two atypic samples. PMID- 21299139 TI - Combined analysis by GC (RI), GC-MS and 13C NMR of the supercritical fluid extract of Abies alba twigs. AB - Two samples (leaves and twigs) of Abies alba Miller from Corsica were extracted using supercritical CO2 and their chemical compositions were compared with those of the essential oils obtained from the same batch of plant material. In total 45 components were identified using combined analysis by GC (RI), GC-MS and 13C NMR. It was observed that the contents of monoterpenes (mainly represented by limonene, alpha-pinene and camphene) were significantly lower in the supercritical fluid extract (SFE) than in the essential oil (EO). Conversely, the proportions of sesquiterpenes were much higher in CO2 extracts than in essential oils (around 30% vs 4%). Cis-abienol, a diterpene alcohol, was identified only in SFE, and the proportions of this constituent (7.5% and 17.3%) were determined using quantitative 13C NMR since it was under estimated using the standard conditions of GC. PMID- 21299140 TI - Eugenol: a natural compound with versatile pharmacological actions. AB - Eugenol, the major constituent of clove oil, has been widely used for its anesthetic and analgesic action in dentistry. Eugenol exhibits pharmacological effects on almost all systems and our aim is to review the research work that has identified these pharmacological actions. Eugenol possesses significant antioxidant, anti-inflammatory and cardiovascular properties, in addition to analgesic and local anesthetic activity. The metabolism and pharmacokinetics of the compound in humans have been studied. Eugenol has also been used as a penetration enhancer. The compound is a very promising candidate for versatile applications, and the design of new drugs based on the pharmacological effects of eugenol could be beneficial. PMID- 21299141 TI - How inside influences are shaping convenient care. PMID- 21299142 TI - Clinical preceptors' tips you didn't learn in school. PMID- 21299143 TI - Negotiating an employment contract. PMID- 21299144 TI - Patient handout. Do you need a multivitamin? Consider several issues. PMID- 21299145 TI - Managing menorrhagia. Evaluating and treating heavy menstrual bleeding. PMID- 21299146 TI - Food allergy Children. An update on diagnosis and treatment. PMID- 21299147 TI - Continence care programs. A new business and treatment model. PMID- 21299148 TI - Pyloric stenosis. Exploring all the options. PMID- 21299149 TI - Comparing incretin-based therapies. Evaluating GLP-1 agonists and DPP-4 inhibitors for type 2 diabetes mellitus. PMID- 21299150 TI - Dietary lipids and NAFLD: suggestions for improved nutrition. AB - Non-alcoholic fatty liver disease (NAFLD) ranges from steatosis and hepatic insulin resistance to non-alcoholic steatohepatitis (NASH), advanced fibrosis and cirrhosis. NAFLD is now considered as the hepatic manifestation of the metabolic syndrome, and both are triggered by mechanisms including inflammation, lipid overload and oxidative stress in adipose tissue and liver. Despite accumulation of numerous data on NAFLD physiopathology, therapeutic modulation of the pathways involved appear insufficiently efficient or associated with serious adverse effects. The increased prevalence of NAFLD and metabolic syndrome during the last decades was associated with deep modifications of dietary habits, especially increased fat intakes. Recent literature provides clues of increased saturated (SFA) and n-6 polyunsaturated fatty acids (PUFA) as well as reduced n-3 PUFA in the diet of NAFLD and NASH patients. Indeed, strong data support the detrimental role of high SFA and n-6/n-3 ratio as well as low monounsaturated fatty acids (MUFA) and n-3 PUFA on metabolic parameters, which are ameliorated by administration of n-3 PUFA and MUFA. Despite governments and health associations having revised their recommendations for n-3 PUFA intakes upward during the last decade, those are still inferior to levels proved of therapeutic efficiency and are still not reached in the general population. This short review discusses these issues and provides consequent pragmatic suggestions for enhanced dietary measures for prevention of NAFLD and metabolic syndrome in the general population. PMID- 21299151 TI - Impact of reimbursement policy in Belgium on the referral pattern and diagnostic yield of capsule endoscopy. A single-centre study. AB - INTRODUCTION: Since the first of July 2008, capsule endoscopy (CE) is partially reimbursed for patients with obscure gastrointestinal bleeding (OGIB). OBJECTIVE: To evaluate the impact of reimbursement of CE on the referral pattern and the diagnostic yield of CE. METHODS: We retrospectively selected data from patients who underwent a CE in the University Hospital of Ghent between July 2002 and June 2009. Following data were analysed: number of CEs, indication, number of transfusion-dependent patients, haemoglobin level and relevance of the CE findings. RESULTS: There was an increase in the number of patients referred for CE after the first of July 2008. Simultaneously, the number of relevant findings was decreasing. Between July 2002 and June 2003, 66.7% of the capsule endoscopies showed relevant bowel lesions. Over the last 2 years, the diagnostic yield has been decreasing to 40.5% in the period July 2007-June 2008 and only 30.2% in the period July 2008-June 2009. Transfusion need and haemoglobin level at the moment of CE had a significant influence on the diagnostic yield (P < 0.001 for both parameters). CONCLUSIONS: The number of patients referred for CE has risen since the reimbursement of CE. However, there is a trend towards referral of less severe bleeders, with less transfusion need and a higher haemoglobin level. This significantly lowers the diagnostic yield of CE. PMID- 21299152 TI - What is the consequence of hyperplastic polyps? Do adenomas and colorectal cancer develop in these patients? A clinical study. AB - AIM: Do patients with hyperplastic polyps (HP) have an increased risk for developing adenomas and colorectal cancer (CRC)? A study was done to detect the number of patients developing adenomas and CRC. MATERIAL AND METHODS: From 1990 1995 all patients with a HP diagnosed via endoscopy and significant follow-up were studied. The patients were separated in three groups; Group 1 HP in patients with previous adenoma and/or CRC. Group 2 HP with a concurrent adenoma and/or CRC. Group 3 patients with only HP. RESULTS: Group 1 consisted of 20 patients, group 2 of 39 patients, and group 3 of 136 patients The follow-up was 12.5, 12.6, and 13.4 years respectively. In group 1 there was one patient with an adenoma in the index investigation.In group 2 adenomas were seen coinciding to hyperplastic polyp(s) in 29 patients, while in 11 cases there was a colorectal cancer. Obviously patients in group 3 only had hyperplastic polyps. In group 1 7 patients previously had an adenoma and 12 previously had colorectal cancer. Four patients in group 3 developed cancer : 13, 14, 15, and 15 years after the detection of a hyperplastic polyp. In group 2 only one patient developed cancer in the cecum 9 years after the index investigation. In the four patients of group 3 who developed cancer no one previously had a serrated adenoma at revision of the original histology. Twelve patients developed an adenoma. CONCLUSION: Only five CRC's developed in patients with HP. Thus, at the best the risk for developing CRC in patients with HP is not very high and equals that of adenomas. PMID- 21299153 TI - Prospective randomized study comparing double layer and Tannenbaum stents in distal malignant biliary stenosis. AB - BACKGROUND AND STUDY AIMS: This prospective randomized study compared the patency and effective drainage rate of two stents with different materials but similar design, in the palliation of inoperable malignant biliary obstruction. PATIENTS AND METHODS: A total of 49 patients (26 women, mean age 72.55 +/- 10.75 years, range: 48-91 years) with obstructive jaundice due to inoperable malignant stricture of the distal common bile duct without previous drainage procedure, were randomly assigned to receive 10F Double Layer (DLS) (n = 24) or 10F Tannenbaum (TAN) (n = 25) biliary plastic stent. The diagnosis included pancreatic cancer (n = 33), cholangiocarcinoma (n = 8), ampullary cancer (n = 7) and metastatic lymphadenopathy (n = 1). The duration of stent patency, the effective drainage, and the adverse events were analyzed. RESULTS: Stent placement was successful in all patients with minor complications. The overall median patency rates between the two groups did not differ (107.5 days for DLS group vs. 101 days for TAN group ; p = 0.066). Effective drainage rate at the end of second week was 95.8% for DLS group and 96% for TAN group, (p = 1.00). Proximal stent migration occurred in one patient with TAN stent. CONCLUSIONS: The present study demonstrated that both DLS and TAN stents are comparable in terms of placement, overall stent patency, and complications. PMID- 21299154 TI - Lessons from a 20 year experience of Home Parenteral Nutrition in adult patients. AB - BACKGROUND: Home Parenteral Nutrition (HPN) is a method commonly used in patients with Chronic Intestinal Failure (CII) related to benign or malignant diseases. We report the experience from a 20 year programme of HPN in a single academic centre. METHODS: In this study, we have reviewed characteristics and outcome of a group of patients enrolled in a HPN program between 1987 and 2007. Focus was given to the prevalence and severity of cholestasis in these patients as well as on their oral food behaviour. RESULTS: In 20 years, 125 patients were included in a HPN programme; 65 patients had benign diseases (BD) and 60 advanced cancer (AC). Short bowel was the most common indications in patients with BD. Almost 40% of patients with BD were weaned off HPN. Median survival was excellent in BD patients and extremely short in AC. Death related to HPN was very rare. Cholestasis has been observed in 84% of patients but it was mild to moderate in the majority of cases. Hyperphagia was observed in 50% of the patients with BD on long-term HPN. CONCLUSIONS: This study confirms that HPN is the first line therapy in CII due to BD. Patients with AC should be carefully selected. Cholestasis is frequent but mostly without clinical impact. Half of the patients with CII due to BD become hyperphagic allowing to reduction of parenteral intake. The role of a multidisciplinary nutrition support team is essential for optimizing HPN. PMID- 21299155 TI - Hepatic encephalopathy. AB - Hepatic encephalopathy (HE) is a neuropsychiatric syndrome which can develop in the course of chronic and acute liver disease. It is characterized by cognitive and motoric deficits of varying severity. HE is functional in nature, potentially reversible and is thought to reflect the clinical manifestation of a low-grade cerebral edema, which exacerbates in response to ammonia and other precipitating factors, such as electrolyte disturbances, bleeding, infections, high protein diet, diuretics and sedatives. The action of these rather heterogeneous factors integrates at the level of oxidative/nitrosative stress and astrocyte swelling, which is associated with an oxidative/nitrosative stress response in the brain with consequences for signal transduction, neurotransmission, synaptic plasticity and oscillatory networks in the brain. Manifest HE is diagnosed on the basis of clinical symptoms according to the West Haven criteria, whereas diagnosis of minimal HE requires psychometric or neurophysiological testings. Here objective and reproducible measures to assess HE severity, such as critical flicker frequency or evoked potentials are superior to paper pencil tests. Identification and treatment of precipitating factors is the mainstay of HE therapy. Also intravenous ornithine aspartate, vegetable protein, oral branched chain amino acids, lactulose enemas and liver transplantation are considered to be effective. Whereas the efficacy of oral lactulose and non-resorbable antibiotics in the treatment of an acute HE attack is under debate, the beneficial effect of lactulose and rifaximin in the secondary HE prophylaxis has recently been established. PMID- 21299156 TI - Hepatitis B and hepatitis C virus and chronic kidney disease. AB - The most common cause of liver disease in patients with chronic kidney disease (CKD) remains infection by hepatitis B virus (HBV) and/or hepatitis C virus (HCV). The adverse effects of HBV and/or HCV infections upon survival in patients with CKD have been repeatedly confirmed. An excess risk of death in HBsAg positive or anti-HCV antibody-positive patients may be at least partially attributed to chronic liver disease with its attendant complications. A negative impact of HCV infection on survival after renal transplantation has been linked to extrahepatic complications, including chronic glomerulonephritis, sepsis, chronic allograft nephropathy, post-transplantation diabetes mellitus, and abnormal metabolism of calcineurin-inhibitors. Transmission of HCV infection by grafts from HCV-infected donors has been unequivocally demonstrated. Registry analyses suggest that recipients of kidneys from anti-HCV antibody positive donors are at increased risk of mortality. Renal grafts from HCV-infected donors should be restricted to viremic anti-HCV positive recipients. Several drugs have been recently licensed for therapy of HBV infection but availabledata in patients with CKD is mostly limited to experience with lamivudine. The standard of care for hepatitis C infection in patients on regular dialysis is monotherapy with conventional interferon, according to recent guidelines. Only dire circumstances justify interferon use after renal transplantation. PMID- 21299157 TI - Sepsis and cirrhosis: many similarities. AB - Sepsis and cirrhosis are both characterised by a hyperdynamic state associated with a low systemic vascular resistance, and the release of many mediators. The haemodynamic characteristics are so similar that sepsis is difficult to recognise in cirrhotic patients. Nevertheless, the occurrence of sepsis in cirrhotic patients is associated with high mortality rates. The resemblance of the two conditions may be in part related to the common translocation of bacterial products in cirrhosis. This article reviews the similarities and differences between sepsis and cirrhosis and defines the basis for the treatment of severe sepsis in cirrhotic patients. PMID- 21299158 TI - Atypical indications for small bowel capsule endoscopy. AB - Obscure bleeding remains the most important indication for small bowel capsule endoscopy, but some other small bowel diseases have also been studied. The aim of this paper is to provide an overview of the recent literature concerning atypical or rare indications for the small bowel capsule endoscopy. PMID- 21299159 TI - Radionuclide therapy for hepatocellular carcinoma. AB - AIM: Several techniques for radionuclide therapy of hepatocellular carcinoma (HCC) have been developed. In this overview the available radionuclide treatment modalities for HCC are presented, with an emphasis on Yttrium-90 (90Y) microspheres. METHODS: We comment on the commercially available products and describe the practical aspects of these treatment modalities. Medical literature was screened for clinical data on these therapies in patients suffering from HCC. The most relevant studies are summarized, focusing on patient selection, safety and outcome. DISCUSSION: Randomized trials are still ongoing or recently initialized. These trials will elucidate the role of 90Y-microspheres in relation to biotherapy and chemoembolization for palliative use in patients not amenable to surgery. CONCLUSION: Large retrospective or cohort studies proof the safety of 90Y-microspheres for palliative use in HCC patients suffering Child-Pugh A or B7 cirrhosis. Future research will yield more information on its efficacy when compared to chemoembolization or sorafenib. Several groups have reported on the use of selective internal radiation therapy (SIRT) for downstaging patients to surgical curative treatment. PMID- 21299160 TI - Angiographic considerations in patients undergoing liver-directed radioembolization with 90Y microspheres. AB - Catheter-directed, transarterial internal brachytherapy, using 90Y radioactive microspheres is gaining acceptance as a valuable treatment option in selected patients with liver malignancies. Knowledge of the radiological anatomy of the visceral arteries, including the variant anatomy of celiac trunk, superior mesenteric artery and end branches as well as technique and catheter skills for careful vessel occlusion prior to 90Y delivery are of major importance to safely and efficiently treat patients with radioembolization. In this review article, normal vascular anatomy, common variants and influence of tumors on the feeding arteries will be discussed. Finally, techniques of pre-treatment vessel occlusion, technique of 90Y-administration and the added value of C-arm computed tomography during work-up and administration of radioactive microspheres will be described. PMID- 21299161 TI - Accurate KRAS mutation testing for EGFR-targeted therapy in colorectal cancer: emphasis on the key role and responsibility of pathologists. AB - Patients with metastatic colorectal cancer and KRAS mutation are unlikely to benefit from treatment with anti-EGFR antibodies, and testing for KRAS mutation in this setting is recommended. Pathologists have a crucial role in accurate testing for KRAS mutations, whether or not testing is performed in their own laboratory, as mutation analysis is performed on paraffin embedded tissue selected by the pathologists. The type of fixative used is a very important issue, as some fixatives do not allow molecular testing. Pathologists must select the most appropriate tumoral tissue block for KRAS mutation analysis and hence, must know the sensitivity of the KRAS mutation detection methodology utilized in their reference laboratory. It is essential that they select a tissue block that contains enough percentage of viable tumour cells, as false negative results will occur when the sample is contaminated with high levels of nontumour elements. Pathologists not only have to recognize the area of invasive carcinoma and distinguish it from non-invasive neoplastic components, but also have to estimate the percentage of necrotic debris and nontumoural elements. For tests that require a high percentage of tumour cells, macrodissection before extraction of nucleic acids is often indicated. The primary pathologists in addition are responsible for preparation of the pathology report for the tissue block on which the KRAS mutation analysis was performed and should transmit the results to the requesting clinician. Pathologists should participate in a multidisciplinary oncologic consult to achieve correct interpretation of the results e.g. in case of potential false negative results. PMID- 21299162 TI - Why should the gastroenterologist bother about obesity? An oncologic point of view. AB - The incidence of obesity worldwide has increased dramatically during recent decades. As a consequence, obesity and associated co-morbidities constitute a serious threat in public health. Substantial epidemiologic evidence indicates that obesity is associated with increased risk of death, and increased incidence and progression of several cancers. Particular attention will be brought here to digestive and liver cancers. Plausible mechanisms by which obesity might participate to increased promotion and progression of cancer will be developed including hyperinsulinemia, insulin resistance and the pro-oxidative pro inflammatory milieu characterizing the metabolic syndrome. We will focus on the specific case of hepatocellular carcinoma since the highest increase in mortality in obese individuals has been observed for this malignancy. Epidemiological evidence will be reviewed. We will next attempt to offer explanation for the higher risk of HCC in obese individuals although, at this point in time, we have insufficient knowledge to point towards the preeminence of factors directly related to obesity or more tightly linked to NASH itself, the underlying liver disease. PMID- 21299163 TI - Cirrhosis and malnutrition: assessment and management. AB - Malnutrition, characterized by protein and energy deficiency, is considered the most prevalent complication of liver disease. The pathofysiology includes reduced food intake, maldigestion and malabsorption but also avoidable iatrogenic factors, such as prescribed fasting, frequent paracenteses and "liver-diets" poor in fat and protein. Liver insufficiency corresponds to a state of accelerated starvation. The diminished glucose tolerance and low glycogen stores in cirrhotic patients result in a reduced availability of glucose as energy source. The prevalence of undernutrition depends upon the severity of the liver insufficiency and the method of nutritional assessment. The aim of the nutritional plan is to realize a sufficient oral diet which includes enough proteins and calories. Several extra calorie supplements are indicated to surmount the lack of available glucose. The evidence in support of branched chain amino acid supplements is limited. Salt intake should be moderately restricted in case of ascites. Nasogastric tube feeding is indicated when patients are unable to maintain an adequate oral intake. In case tube feeding is not possible, total parenteral nutrition may be necessary to maintain an anabolic state. PMID- 21299164 TI - Esophageal fibrovascular polyp removed by cervical esophagotomy. AB - We report a case of esophageal fibrovascular polyp (FVP) removed by cervical esophagotomy. The patient was a 74-year-old man in whom an intraesophageal mass was detected by a chest CT examination during a complete medical check-up. An upper gastrointestinal series showed a large, pedunculated, cervical esophageal mass for which our preoperative diagnosis was a FVP. We studied its features, as well as removal procedures in 45 patients in the literature. Most patients had marked symptoms, but ours had no complaints, and so this case may be a rare one. Various removal procedures were reported, but thoracotomy and esophagectomy are considered to be the inappropriate procedures since FVP is a benign disorder. PMID- 21299165 TI - A two-year old boy with recurrent bouts of acute abdominal pain. AB - In a small number of patients with pancreas divisum (with stenotic minor papilla) a relative obstruction to pancreatic exocrine secretory flow results in pancreatitis. We report a 2-year-old boy presenting with recurrent bouts of abdominal pain. The diagnosis of acute pancreatitis was made based on blood biochemistry results. Ultrasound, computed tomography and magnetic resonance imaging showed several abdominal pseudocysts, peritoneal exsudate and confirmed pancreatitis but initially failed to reveal the aetiology. Ascites and cysts contained pancreatic enzymes. After weeks of combined conservative and surgical treatment, a magnetic resonance cholangiopancreaticography with secretin, showed a pancreas divisum with a cyst between the ducts of Santorini and Wirsung. Based on these findings, two endoscopic papillotomies (minor and major papilla) were performed. Three years follow-up was uneventful. In a child with recurrent pancreatitis or pancreatitis with chronic recurrent abdominal pain it is crucial to search aggressively for congenital abnormalities, including pancreas divisum. Secretin-enhanced magnetic resonance cholangiopancreaticography or diffusion weighted magnetic resonance imaging is a valuable diagnostic tool for visualizing pancreatic duct anatomy. PMID- 21299166 TI - Idiopathic portal hypertension during a catastrophic attack in a patient with primary antiphospholipid syndrome. AB - A 43-year old male patient with hyponatremic hypertensive syndrome was diagnosed as catastrophic primary antiphospholipid syndrome (PAPS). He subsequently developed hepatosplenomegaly. The patient also carried thrombophilia- and haemochromatosis-associated gene mutations. Further investigations upon persistence of splenomegaly indicated development of idiopathic portal hypertension. PMID- 21299167 TI - Ingested toothpick fistula of the ileum mimicking Crohn's disease. AB - Foreign body ingestion is an accidental or an intentional event, with most of the ingested foreign bodies passing spontaneously through the gastrointestinal tract without incidents. About 10-20% of them, especially long and sharp objects like toothpicks, will fail to pass through the entire gastrointestinal tract and may cause symptoms. Toothpick injury of the gastrointestinal tract is often associated with considerable morbidity and mortality. The complications that can be caused by toothpick ingestion are obstruction, perforation, hemorrhage, fistula formation, small bowel inflammation, sepsis and even death. Diagnosis of toothpick injury can be difficult as there are no specific physical findings or laboratory examinations which may aid the diagnosis and even imaging studies are of little help as wooden toothpicks are radiolucent. We report a rare case of incidental toothpick ingestion which caused an ileum fistula and mimicked Crohn's disease. PMID- 21299168 TI - Dilated cardiomyopathy in celiac disease: role of carnitine deficiency. AB - Celiac disease (CD) is an immune-mediated enteropathy in genetically susceptible persons and the disease can present with manifestations in the intestine and in organs outside the gut. An increased prevalence of CD in patients with idiopathic dilated cardiomyopathy or secondary cardiomyopathy and some other cardiac disorders has been reported. Here is described a case of dilated cardiomyopathy in a patient with CD and secondary carnitine deficiency. Dilated cardiomyopathy due to carnitine deficiency may occur in CD patients and carnitine deficiency may present not only at the time of diagnosis of CD but it may also develop during gluten-free diet, particularly in patients with fast weight gain and without carnitine supplementation. PMID- 21299169 TI - Hemosuccus pancreaticus, a diagnostic challenge. PMID- 21299170 TI - Gastric metastasis of breast carcinoma 9 years after mastectomy. PMID- 21299171 TI - A method for conducting intensive psychological studies with early-onset chronically depressed patients. AB - An intensive empirical methodology is introduced to evaluate the efficacy of Cognitive Behavioral Analysis System of Psychotherapy (CBASP) treatment for outpatients with early onset chronic depression. The patient with chronic illness presents a unique measurement challenge to psychotherapists. One of the most prominent reasons is the refractory nature of the disorder. In order to measure the change process, the authors have found it helpful to use an acquisition learning methodology to answer three questions: (1) What are we trying to teach the patient? (2) How much has the patient learned throughout the course of therapy? And, (3) how does the extent of patient learning impact the change indices at the end of treatment and during the follow-up period? Answering questions 2 and 3 allows us to superimpose the change process variables over the performance learning variables on a graph. These combined variables also allow us to test the hypothesis: By learning what psychotherapy teaches, the chronic psychological disorder may be resolved. PMID- 21299172 TI - Paranoia and psychotic process: some clinical applications of projective identification in psychoanalytic psychotherapy. AB - The concept of projective identification has, since its introduction by Melanie Klein over half a century ago, caused much controversy amongst psychoanalysts and psychotherapists. In this paper the author traces some of the key theoretical developments of the concept since its introduction in 1946, including: normal and pathological projective identification, aspects of symbolisation and projective identification as an intrapsychic mechanism. An extended case report of a patient in weekly psychoanalytic psychotherapy is offered in order to expand upon some of the theoretical ideas previously considered. Emphasis is placed on the patient's use of intrapsychic projective mechanisms and the emergence and mutation of such mechanisms in the therapeutic relationship. PMID- 21299173 TI - Relationships between techniques and outcomes for borderline personality disorder. AB - Although a number of psychotherapeutic modalities for borderline personality disorder (BPD) have empirical support, it is unclear what aspects of treatment are responsible for improvement. The present study analyzes the relationships between different techniques and outcomes in a randomized controlled trial of dynamic deconstructive psychotherapy (DDP) for comorbid BPD and alcohol-use disorders. Video recordings of psychotherapy sessions at 3-month intervals were rated to measure therapeutic alliance and the relative frequencies of specific treatment interventions. Outcomes included measures of borderline symptoms, depression, dissociation, social support, alcohol misuse, parasuicide, and institutional care. Discrete sets of techniques were associated with reliable changes in specific outcomes, indicating that treatments for BPD should be tailored to the specific constellation of symptoms presenting in a given individual. The study findings suggest that treatments with a specified set of techniques, such as DDP, dialectical behavior therapy, mentalization-based treatment, schema therapy, supportive therapies, and transference-focused psychotherapy, may be helpful for different individuals, depending on their particular set of symptoms. PMID- 21299174 TI - Conjoint IPT for postpartum depression: literature review and overview of a treatment manual. AB - Distress about the quality of a woman's relationship with her partner has consistently emerged as a risk factor for Postpartum Depression (PPD). In addition to having an increased likelihood of developing PPD, women who are distressed about their relationships, experience more severe depressive symptoms of greater duration, and are more vulnerable to the development of mental health problems. The emotional well-being of partners of depressed mothers is also affected, signalling the need for interventions that incorporate the woman as well as her partner. Few interventions have been designed for women simultaneously experiencing PPD and relationship distress in a conjoint format. This article describes a newly developed Interpersonal Psychotherapy (IPT) conjoint approach to treating PPD in the context of relationship distress. The existing literature on PPD is reviewed, as well as relationship distress and psychotherapy interventions for PPD with couples. This is followed by a description of an IPT conjoint approach to treating PPD with relationship distress. PMID- 21299175 TI - Psychoanalytic constructs in psychotherapy supervision. AB - While the constructs of the working alliance, parallel process, and countertransference have long had transtheoretical appeal for many supervision practitioners, what empirical data--quantitative or qualitative--are there that support their use in psychotherapy supervision? In this paper, I attempt to address that question by: (1) identifying empirical, data-based efforts to research the supervisory working alliance (n = 17), parallel process (n = 7), and countertransference (n = 1); (2) reviewing and determining for each study sample characteristics, measures used, procedure, analyses used, findings, and limitations; (3) identifying the primary conclusions that can be drawn from that review and analysis; and (4) considering the implications and directions for future supervision research and practice. While the data appear strongest for the supervisory working alliance and tentatively support its place in psychotherapy supervision, research on alliance, parallel process, and countertransference is still very much in its infancy and sorely limited empirically. Some avenues for remedying previous study deficiencies are presented, and the hope and caution of future research on these constructs are considered. PMID- 21299176 TI - Physical fitness and anthropometric characteristics of Royal Thai Army personnel. AB - The objective of the present study was to determine the relationship between physical fitness and anthropometric characteristics in Royal Thai Army (RTA) personnel. Body weight, height, waist circumference, hip circumference and blood pressure were measured. Body mass index (BMI) and waist-hip ratio (WHR) were calculated. Subsequently, 4,030 males aged 20 to 60 years were field tested using 2-minute push ups/sit-ups and 2-kilometer run to measure muscular strength/endurance and cardiorespiratory endurance, respectively. Data were analyzed for the relationships between BMI and anthropometric variables and blood pressure and physical fitness results. The average BMI for RTA personnel was 24.0 +/- 3.3 kg/m2. Correlation coefficient between BMI and waist circumference (r = 0.847, p < 0.001) was better than BMI and WHR (r = 0.553, p < 0.001). Both systolic blood pressure (SBP) and diastolic blood pressure (DBP) had a significant positive correlation with BMI. The numbers of push-ups/sit-ups had a negative correlation with BMI (r = -0.121 and -0.109, respectively), whereas 2 kilometer run times had a positive correlation with BMI (r = 0.291, p < 0.001). In conclusion, RTA personnel with increasing BMI tend to have low physical fitness level. PMID- 21299177 TI - Measures for emergency medical technicians in helping victims at scenes guided by the pattern of injuries and bombing attacks in the three most southern provinces of Thailand. AB - Bombing attacks by terrorists in the three most southern provinces of Thailand increased both in frequency and intensity from the year 2004 until now. Patterns of bombing were not only destroying buildings or killing targets victims by dropping bombs under roads and in public places but also harming scene investigators by dropping second bombs nearby. Emergency medical personnel working there also had some risks from these second bombs while helping victims at the scene. The purposes of the present study aimed to describe patterns and risks of bombing attacks, analyze locations of wounds of bombing casualties and propose a standing operation procedure for emergency medical technicians (EMTs) in helping victims at scenes to reduce harm from second bombs. The authors gathered some information about patterns of bombing from the Forward 4th Army Area Explosive Ordnance Disposal (EOD) team and reviewed insurgency related casualty reports from Yala, Pattani and Narathivasrajanakarin Hospital from January 2004 to December 2006. From these reports, data of deep wounds or wounds that caused serious injuries or deaths of 144 improvised explosive devices (IED) victims was collected and separated into fatal (45 casualties) and nonfatal groups (99 casualties). In each group, casualties' demographic data and number of casualties separated by locations of wounds and occupations are shown and compared by percentage of the total number of each group and was found that most of fatal casualties had wounds on head (42.22%), chest (33.33%) and abdomen (33.33%) that should be protected by wearing helmets and body armors. But there was a higher proportion of extremity injuries in non-fatal casualties (63.64%). Thus, the authors proposed measures for EMTs in helping victims at scenes to reduce their risks by wearing helmets and body armors and quickly removal of the injured with minimal medical intervention. PMID- 21299178 TI - Prevalence of prehypertensive state and other cardiovascular risk factors in the First Infantry Regiment, the King's own bodyguard. AB - OBJECTIVE: The objective of the present study was to identify the prevalence of pre-hypertension in the Army officers in a combat unit and to characterize the factors that are associated with increased prevalence of pre-hypertension. MATERIAL AND METHOD: This was a cross sectional study performed in all officers of the 1st Infantry Regiment, the King's own bodyguard, in June 2007. Baseline demographic data were obtained and physical examination was performed in all participants. Apart from serum hemoglobin and urinalysis, which were studied in all participants, other laboratory examination were studied in officers whose age was 35 years old or more. All participants were classified into three groups according to their blood pressure using the Joint National Committee (JNC) 7 criteria; Group 1: Normal (BP < 120/80 mmHg), Group 2: Pre-hypertension (BP 120 139/ 80-89 mmHg), and Group 3: Hypertension (BP > or = 140/90 mmHg). The prevalence of pre-hypertension was calculated and the factors that correlated with increasing prevalence of prehypertension were identified using logistic regression analysis. RESULTS: There were 1,472 officers who participated in the present study, all of them were male. The mean age of the studied population was 36.25 +/- 8.98 years. The mean weight, height, body mass index (BMI) and waist circumference were 68.66 +/- 9.61 kilograms, 169.60 +/- 4.85 centimeters, 23.87 +/- 3.21 and 32.40 +/- 3.39 inches, respectively. The prevalence of normotension, pre-hypertension and hypertension were 40.01%, 41.44% and 18.55% respectively. The factors that were correlated with increasing prevalence of pre-hypertension (p < 0.05) were older age; overweight and obesity (compared with normal BMI); high serum uric acid, hemoglobin, aspatate aminotransferase (AST); and proteinuria and metabolic syndrome. CONCLUSION: The prevalence of pre hypertension in this population was relatively high. Pre-hypertension was found more often in older persons, with the increase in BMI, serum AST, hemoglobin and uric acid, proteinuria and metabolic syndrome. PMID- 21299179 TI - Characteristics and distribution of blast and firearm injuries in Thai military personnel during conflict in southern Thailand. AB - BACKGROUND: The pattern of injury in Thai military personnel had been changed since the conflict in southern Thailand. The increasing number of blast injuries from improvised explosive devices caused more complex injury pattern. The purpose of the present study was to report characteristics of blast and firearm injury and distribution of injuries and body region involvement. MATERIAL AND METHOD: The authors retrospectively reviewed the medical records of Thai military personnel injured from conflict in southern Thailand who required admission and then referred to Phramongkutklao Hospital from January 2007 to December 2007. RESULTS: There were 100 victims with 188 body region injuries. All were male. Most of them (55%) ranged from ages 18 to 30 years. Blast injury was the most common injury and affected 71% of the victims. The most common type of blast injury was type II (bomb fragments), 73.24%. Firearm injury was 29%. All firearm injuries were high-velocity gunshot wounds. The most common region of injuries was extremities 51.6% (blast, 37.8% and firearm, 13.8%). The torso (chest, abdomen, trunk, pelvis) was the second most injured region, 24.5% (blast 18.1% and firearm 6.4%). The third most affected region was other parts of the head 21.8% (blast 19.7% and firearm 2.1%). CONCLUSION: Conflict in southern Thailand has increased the number of blast injuries mostly type II in Thai military personnel and the most common affected region was upper and lower extremities due to no protective suit. The rate of injuries of torso and unprotected part of the head was still in the second and third places that should be of concern. The difference of characteristics and distribution of blast and firearm injuries is very important for effective medical treatment and preparing equipment for prevention of injuries in the future. PMID- 21299180 TI - Economic evaluation of computed radiography comparing to film method in quality control of general X-ray machine at Phramongkutklao Hospital. AB - OBJECTIVE: To evaluate the efficiency of quality control performance for a general x-ray machine between computed radiography (CR) and film method. MATERIAL AND METHOD: CR performance as a quality control method for a general x-ray machine was compared to the film method. Two raters independently analyzed the result of quality control from both methods. Economic evaluation was performed by cost-minimization analysis. All data (result for quality control and cost) were collected from Phramongkutklao Hospital from August 2007 to January 2008. RESULT: Quality control performances of a general x-ray machine by using CR and film method were equivalent. Interobserver agreement for analysis of quality control measurements was almost perfect. Unit cost, test performance time, radiation dose for quality control by CR were less than the film method (p < 0.001). CONCLUSION: The performances of quality control of a general x-ray machine done by the CR method are more efficient than the film method. Using the CR method for quality control performance of the general x-ray machines will save cost enormously. PMID- 21299181 TI - Oral health survey of military personnel in the Phramongkutklao Hospital, Thailand. AB - OBJECTIVE: To evaluate chief complaints, the prevalence of the oral diseases and the treatments needed in military personnel in comparison to the civilians. MATERIAL AND METHOD: The dental records of new patients at Phramongkutklao Hospital from January to December 2003 were reviewed. The retrieved information included demographic status, chief complaint, diagnosis and the treatment needed. Descriptive analysis was used to describe the data. Univariate analysis was used to obtain the odds ratios and 95% CI for the independent association between factors (age, status), chief complaint, diagnosis and treatment needed. RESULTS: A total of 4,662 consecutive dental records were evaluated during the study period, in which, 69.7% persons were civilians, and 30.3% persons were military personnel which included; commissioned officers (COs) 23.6%, non-commissioned officers (NCOs) 15.3%, conscripts 44.8%, and retired officers 16.3%. The military personnel had higher rates of toothache (OR = 1.27, 95% CI = 1.08-1.47), and gum swelling (OR = 1.41, 95% CI = 1.07-1.84) than the civilians. Military personnel showed increased risk of having pulp and periapical diseases (OR = 1.23, 95% CI = 1.05-1.44), and fracture teeth (OR = 1.44, 95% CI = 1.04-1.97) more than those observed in the civilians. Only 1.2% of the active duty military personnel required no dental treatment. It was found that the military personnel had significantly higher treatment needs than the civilians in all categories except for removal of impacted teeth. The conscripts had the highest needs for dental treatments. CONCLUSION: This survey showed that the military personnel, especially the conscripts had a relatively high prevalence for oral diseases. In order to make their oral conditions fit for deployment, the predicted treatment times and resources used were estimated to be convincingly high. PMID- 21299182 TI - Prevalence of disease and non-battle injury, anxiety and depression in the Royal Thai Armed Forces during the operation of the United Nations in Burundi. AB - OBJECTIVE: To determine the prevalence and impact of common disease and non battle injuries (DNBI) among the military personnel deployed to the operations of the United Nations (UN) in Burundi from June to December 2005. MATERIALS AND METHODS: The study population consisted of 175 Thai military personnel. A pre- and post deployment questionnaire assessing demographic data, general health, dental problems, underlying disease and health risk behaviors was performed. The information of DNBI was collected weekly. Data on initial visits for 27 DNBI categories were complied at the unit and event data on morbidity measures for each DNBI category were aggregated for all reporting units on a weekly basis. Anxiety and depression were assessed using the Hospital Anxiety and Depression (HAD) scale. RESULTS: The majority of the troops was in good health at pre- and post deployment. The total weekly initial visit DNBI rate was 337.6 visits per 1,000 persons, which was rather high compared to the Joint Chiefs of Staff (JCS) reference rate. The most common DNBI categories were respiratory illnesses (21.9%), medical/surgical injuries (19.8%) and recreational injuries (15.5%). CONCLUSION: The present data indicated that despite modern preventive medicine measures, illnesses and non-battle injuries were still common, which had a significant impact on military readiness and operational efficiency. PMID- 21299184 TI - Effectiveness comparison between Thai traditional massage and Chinese acupuncture for myofascial back pain in Thai military personnel: a preliminary report. AB - The objective of this randomized comparative study was to provide preliminary data of comparative effectiveness of Thai traditional massage (TTM) and Chinese acupuncture for the treatment of myofascial back pain in young military personnel. Eighteen Thai military personnel, aged ranging from 20-40 years were randomly divided into TTM and acupuncture groups. Each group received 5 sessions of massage or acupuncture during a 10-day period. The Thai version McGill Pain Questionnaire, 100-mm, visual analog scale (VAS) and summation of pain threshold in each trigger point measured by pressure algometer were assessed at day 0, 3, 8 and 10. At the end of treatment protocols, McGill scores decreased significantly in TTM and acupuncture groups (p = 0.024 and 0.002, respectively). VAS also decreased significantly (p = 0.029 and 0.003, respectively). However, the pain pressure threshold increased significantly in the acupuncture group but not in the TTM group (p = 0.006 and 0.08, respectively). When outcomes were compared between the two groups, no significant difference was found in the VAS (p = 0.115) and pain pressure threshold (p = 0.116), whereas the acupuncture group showed significantly lower McGill scores than the TTM group (p = 0.039). In conclusion, five sessions of Thai traditional massage and Chinese acupuncture were effective for the treatment of myofascial back pain in young Thai military personnel. Significant effects in both groups begin after the first session. Acupuncture is more effective than Thai traditional massage when affective aspect is also evaluated. PMID- 21299183 TI - HIV-1 incidence estimates among young Thai men using IgG-capture BED-enzyme immunoassay (BED-CEIA) during 2005-2006. AB - BACKGROUND: Knowledge about the most recent HIV epidemic among young generation in Thailand is crucial for improving the prevention programs. It is important to distinguish between recent and long-term HIV-1 infections among the sero surveillance populations to estimate the HIV-1 incidence. OBJECTIVE: To obtain the HIV-1 incidence estimates in young Thai men from the HIV-1 sero-surveillance among the Royal Thai Army (RTA) conscripts inducted between November 2005 and November 2006. MATERIAL AND METHOD: The confirmed HIV-1 positive serum samples obtained from the November 2005, May 2006, and November 2006 rounds of RTA conscripts induction were selected to be included in the study. The recent HIV-1 infections were detected among the confirmed HIV-1 positive serum samples using an HIV-1 BED incidence EIA Kit (Calypte HIV-1 BED Incidence EIA, Calypte Biomedical Corporation, Maryland, USA. The incidence estimates were obtained in each round of the induction using a consensus formula was agreed upon at the US Centers for Disease Controls and Preventions (CDC). RESULTS: Eighty seven thousand one hundred seventy eight RTA conscripts were tested for HIV-1 infection between November 2005 and November 2006. The prevalence of HIV-1 infection was 0.51%, 0.60%, and 0.50% for the period of November 2005, May 2006, and November 2006, respectively. The HIV-1 incidence estimates were 0.14%/year (95% CI, 0.09 0.20), 0.20% year (95% CI, 0.13-0.28), and 0.17%/year (95% CI, 0.10-0.29) in November 2005, May 2006, and November 2006, respectively. CONCLUSION: We reported the HIV-1 incidence estimates obtained from the IgG-capture BED-enzyme immunoassay (BED-CEIA) method in the RTA conscripts sero-surveillance population. The incidence estimates were ranging from 0.14% - 0.20%/year between November 2005 and November 2006. The estimates could serve as the recent baseline information for future HIV prevention interventions in Thailand. PMID- 21299185 TI - Adverse effect of pioglitazone in military personnel and their families: a preliminary report. AB - BACKGROUND: Thiazolidinediones (rosiglitazone and pioglitazone) whether administered alone or in combination with metformin, sulfonylurea, or insulin, are often accompanied by an increase in weight and/or plasma volume. Several studies have shown the adverse effect of weight gain and edema with rosiglitazone. But there was less data with pioglitazone, especially in military personnel and their families. MATERIAL AND METHOD: The authors prospectively recorded the adverse events in 40 patients with type 2 diabetes mellitus who underwent administration with pioglitazone 15 mg once daily between June 2005 to May 2007. RESULTS: Weight gain was reported in 30/40 of patients (75%). The mean weight gain was 2.25 +/- 2.23 kg and the median was 2 kg. The slightly lower proportion of patients, 21/40 (52.5%) developed edema and some of them were associated with weight gain. CONCLUSION: Pioglitazone was associated with a significant increase in body weight and edema. This finding may lead to increase the risk of myocardial infarction in military personnel and their families, especially those who had underlying disease of congestive heart failure, which was not included in the present study. PMID- 21299186 TI - Injuries of the thoracolumbar spine from tertiary blast injury in Thai military personnel during conflict in southern Thailand. AB - BACKGROUND: There were higher numbers of tertiary blast injuries from terrorist bombing in southern Thailand. There was no previous report about spinal trauma in tertiary blast injury. MATERIAL AND METHOD: Between January 2007 and December 2007, there were 100 Thai military personnel injured in combat and 18 cases were classified to tertiary blast injury (type III). Six patients with spine and back injuries were retrospectively reviewed. RESULTS: Incidence of injury to spine and back region was 6% of total blast injury and 33.3% of total tertiary blast injury. There were 3 fractures of thoracolumbar spine (16.7%) and 3 sprain strains of the thoracolumbar spine (16.7%). One patient with flexion-distraction type of first lumbar spine and one patient with compression fracture of third lumbar spine received conservative treatment. One patient with fracture dislocation of L5/S1 with neurological deficit underwent spinal instrumentation and fusion. The back pain score returned to normal in 9.3 weeks in the fracture group and 6 weeks in the back sprain-strain group. CONCLUSION: The tertiary blast injury affected mostly in the back region. The uncommon flexion-dislocation fracture of thoracolumbar spine with neurological deficit should be treated with spinal instrumentation and fusion with excellent result. Other tertiary blast injury of back region can be treated with conservative treatment. PMID- 21299187 TI - The impact of providing medical assistance to local people of medical unit of the Royal Thai Army task force in East Timor. AB - The Royal Thai Army deployed a large troop overseas to join the United Nation Peace Operation in East Timor in October 1999. The operations included recovering peace, providing security and humanitarian assistance in the area of operations in Baucau and Viqueque. Our level 2 medical unit provided medical assistance to the Timoreses by opening consultation at our medical unit and sending mobile clinics into remote areas. This mission made Thailand uphold its good reputation and good relationship with the Timoreses. To reduce any conflicts and to ensure a high success of UN peacekeeping missions, enhancing a collaborative work and relationship with the NGO who previously pursued health service activities in that area are needed. Additionally, concerning negative impacts to the local people should be considered after implementation of the health service system. They had to adapt themselves to the limitation of their own local health service after the humanitarian assistance was over. There is a need to improve the training of military personnel with internationally accepted guidelines and they understand their potential roles within armed forces and improve the coverage of humanitarian needs for the next mission. PMID- 21299188 TI - How we teach military medicine to medical cadets at Phramongkutklao College of Medicine. AB - Phramongkutklao College of Medicine has a unique curriculum for "Military Medicine." Military Medicine involves prevention, threat assessment, evacuations and clinical management of diseases and injuries resulting from military occupational exposures. The Military Medicine curriculum covers all the entities of knowledge of Military Sciences, Combat Medical Skills, Military Preventive Medicine, Military Applied Physiology and Military Contingency Medicine. The highlight of the curriculum is "Operation Petcharavut" that represents simulated battlefield operations, involving multidisciplinary clinical integration and military regulation. In this course, medical cadets review all the knowledge that they have learnt and in addition, Medical Platoon leader strategies, Advanced Cardiac Life support and Phramongkutklao Traumatic Life support, crucial medical practices. Medical cadets would experience simulated patients with minimal injuries to critical wounds and complications including combat stress syndromes in various situations, from advancing to retreating units and from Battalion Aid Station to Division Medical Operations Center, whether during day or night. Since the medical cadets experience all Military Medicine courses from the second to the sixth year class and pass all medical knowledge-based examinations, Phramongkutklao College of Medicine expects all graduates to be excellent in not only all standard requirements of the medical professional set forth by the Medical Council of Thailand but also ready to serve the nation effectively in the Royal Thai Armed Forces. PMID- 21299189 TI - Efficient phosphorescent polymer yellow-light-emitting diodes based on solution processed small molecular electron transporting layer. AB - Based on a solution-processed small molecular electron transporting layer, efficient multilayer solution-processed polymer yellow-light-emitting diodes were successfully fabricated. The maximum luminance efficiency and power efficiency reached 41.7 cd/A and 12.5 lm/W, respectively, which are comparable to and even over those from the PLEDs based on the vacuum-deposited electron-transporting layer. The solution-processed small molecular electron transporting layer is based on a mixture of three electron-transporting materials TmPyPB, TAZ, and TPBI. By utilization of this mixed system, not only the thickness of the electron transporting layer can be easily adjusted, but also device efficiency can be improved because of their excellent synthetic properties. PMID- 21299190 TI - Seeing big with scanning electrochemical microscopy. PMID- 21299191 TI - Mechanism of recombination losses in bulk heterojunction P3HT:PCBM solar cells studied using intensity modulated photocurrent spectroscopy. AB - Intensity modulated photocurrent (IMPS) and photovoltage (IMVS) spectroscopies were used to study the mechanism of photoprocesses in P3HT:PCBM bulk heterojunction organic solar cells at various light intensities. The use of the frequency domain techniques allowed us to separate the bulk and interfacial processes and gain a valuable insight into the mechanism of losses in these devices. The results provide direct evidence that interfacial nongeminate recombination is one of the dominant loss and aging mechanisms in bulk heterojunction organic solar cells. The trapping of photoexcited holes in the P3HT phase was found to contribute to the increased recombination rate. The results suggest that promising ways of improving the efficiency of bulk heterojunction solar cells may be reducing the charge trapping both at and near the P3HT:PCBM interface, as well as improving the efficiency of charge extraction at contacts. PMID- 21299193 TI - Novel characterization of microdrops and microbubbles in emulsions and foams using atomic force microscopy. AB - The nature of the interface of drops or bubbles and the dynamic interactions between them often mediate or control macroscopic behavior in the formulation and processing of emulsions and foams in solvent extraction, froth flotation, food, personal care products, and microfluidics as well as in many biological processes. Characterization of these interfaces is often complicated due to the small size of the drops and bubbles that may range from the micrometer scale to hundreds of micrometers. We report the direct measurement of the surface or interfacial tension of drops or bubbles in aqueous solutions as a function of the concentration and type of surfactant, using atomic force microscopy (AFM) and a recently developed nanoneedle AFM cantilever. We also demonstrate the viability of imaging drops or bubbles of this size in both tapping and contact imaging modes through a systematic study of parameters, including cantilever spring constant, tip geometry, imaging force, and feedback settings as well as the AFM manufacturer. The imaging study demonstrates the viability of using AFM to visualize complex structures at the oil-water or air-water interface as well as how concentric ring artifacts observed in the literature are the result of earlier AFM instrument limitations. PMID- 21299192 TI - In vivo formation of a glutathione conjugate derived from thalidomide in humanized uPA-NOG mice. AB - Metabolism of the teratogen thalidomide is proposed to be relevant to its toxicological action. We demonstrated the formation of the glutathione (GSH) conjugate of (R)-5-hydroxythalidomide in vivo in chimeric NOD-scid IL2Rg(null) mice with humanized livers (uPA-NOG mice). After an oral administration of racemic thalidomide (270 mg/kg), plasma concentrations of 5-hydroxythalidomide were significantly higher in humanized mice than in control mice. The GSH conjugate of 5-hydroxythalidomide was detected in the plasma. These results indicate that livers of humanized mice mediate thalidomide 5-hydroxylation and further oxidation leading to the GSH conjugate in vivo as well as in vitro and suggest that thalidomide activation occurs. PMID- 21299194 TI - Isoreticular metal-organic frameworks and their membranes with enhanced crack resistance and moisture stability by surfactant-assisted drying. AB - Here we report a new strategy that can not only prevent the formation of cracks and fractures in the crystals and films of metal-organic frameworks (MOFs) but also substantially enhance their stability with respect to moisture. It involves the addition of surfactants during a drying process. Surfactants reduce interfacial tension, thereby repressing the formation of fractures and cracks during the final drying process. It was found that, once dried, surfactants adsorbed on the crystal surface render the surface hydrophobic, leading to the enhancement in the stability toward moisture. Using this new strategy, the first crack-free IRMOF-3 membrane was successfully prepared, and its gas permeation performance was tested. IRMOF-3 membranes are found to favor CO2 over C3H8 mainly due to the affinity of CO2 to the amine groups in the structure. In addition, crack-free IRMOF-3 membranes were postsynthetically modified with heptanoic anhydride, thereby changing the effective pore size and surface property of the MOF. Once modified with the anhydride, the membranes favor C3H8 over CO2 due to the increased solubility of C3H8 in the presence of the hydrocarbon moiety. PMID- 21299195 TI - Magnetically switchable bioelectrocatalytic system based on ferrocene grafted iron oxide nanoparticles. AB - A simple and versatile method for the introduction of redox unites onto the surface of magnetic nanoparticles has been developed based on "click" chemistry. Azide-functionalized Fe2O3 magnetic nanoparticles were synthesized and further reacted with ethynylferrocene via Cu(I)-catalyzed azide alkyne 1,3-dipolar cycloaddition (CuAAC) reaction. The functionalized magnetic nanoparticles were characterized using a powder X-ray diffractometer (XRD), transmission electron microscope (TEM), Fourier transform infrared spectroscope (FTIR), and vibrating sample magnetometer (VSM). The resulting materials have properties of both magnetism and electrochemistry, and the electrochemical properties of the nanoparticles are dependent on the features of ethynylferrocene, while the magnetic properties remain independent of ethynylferrocene. Because of the magnetism of Fe2O3 nanoparticles and the electrocatalytic activity of ferrocene unites, a recyclable, magneto-switchable bioelectrocatalytic system for glucose oxidation in the presence of glucose oxidase is developed by alternate positioning of an external magnet, and the system has a linear response for glucose biosensing over the range of 1.0-10.0 mM. PMID- 21299196 TI - Multidimensional analysis of single algal cells by integrating microspectroscopy with mass spectrometry. AB - We demonstrate a facile label-free approach for performing multidimensional chemical analysis on individual single-cell organisms by combining optical, fluorescence, and Raman microspectroscopy with matrix-free laser desorption/ionization mass spectrometry (MS). Single unicellular algae are seeded on a bare stainless steel plate and analyzed microspectroscopically. This provides information on the content and distribution of photoactive species, such as beta-carotene, as well as chlorophyll and other components of the photosynthetic apparatus. Exactly the same cells are then analyzed by mass spectrometry in the negative ion mode. Phospholipid species are readily ionized by laser desorption/ionization of intact cells, without the need for an auxiliary matrix. This not only facilitates sample preparation but also preserves high spatial resolution and high sensitivity. Using this method, we were able to study the content and arrangement of proplastids and photosystem components, as well as the amounts of various phospholipid species in individual algal cells. The methodology can be used in the fundamental biological studies on these unicellular organisms, which require information on the internal structure as well as the chemical composition of individual cells. PMID- 21299197 TI - Tetradentate N2S2 vanadyl(IV) coordination complexes: synthesis, characterization, and reactivity studies. AB - The versatile N(2)S(2) tetradentate ligands (bme-daco)(2-), (bme-dach)(2-), and (ema)(4-) are known to accommodate many divalent transition-metal ions (M = Ni(II), Pd(II), Pt(II), Pb(II), Zn(II), Cd(II), Cu(II), and Fe(II)) while maintaining reactivity at the S-thiolate sites of the respective N(2)S(2)M complexes. The vanadyl ion, of interest for its pharmacological possibilities and its spin-label reporter properties for bioinorganic studies, also shows an affinity for such mixed nitrogen/sulfur-donor environments. Thus, (V=O)(2+) analogues of a well-characterized series of N(2)S(2)Ni complexes have been prepared as mimics of possible N(2)S(2)(V=O) formed from in vivo binding sites of the tripeptide motif, Cys-X-Cys. The nucleophilicity of the S-thiolate in these systems is explored with alkylating agents. IR [nu(VO)], electronic spectral, and electron paramagnetic resonance measurements are presented. X-ray diffraction studies of (bme-daco)(V=O), (bme-dach)(V=O), and [Et(4)N](2)[(ema)(V=O)] further characterize the vanadyl complexes. A comparison of the spectral properties with the product of vanadyl interaction with the CGC tripeptide, the biological analogue of the tetraanionic N(2)S(2) ligand, is given. PMID- 21299198 TI - Large-scale phosphoproteomics analysis of whole saliva reveals a distinct phosphorylation pattern. AB - In-depth knowledge of bodily fluid phosphoproteomes, such as whole saliva, is limited. To better understand the whole saliva phosphoproteome, we generated a large-scale catalog of phosphorylated proteins. To circumvent the wide dynamic range of phosphoprotein abundance in whole saliva, we combined dynamic range compression using hexapeptide beads, strong cation exchange HPLC peptide fractionation, and immobilized metal affinity chromatography prior to mass spectrometry. In total, 217 unique phosphopeptides sites were identified representing 85 distinct phosphoproteins at 2.3% global FDR. From these peptides, 129 distinct phosphorylation sites were identified of which 57 were previously known, but only 11 of which had been previously identified in whole saliva. Cellular localization analysis revealed salivary phosphoproteins had a distribution similar to all known salivary proteins, but with less relative representation in "extracellular" and "plasma membrane" categories compared to salivary glycoproteins. Sequence alignment showed that phosphorylation occurred at acidic-directed kinase, proline-directed, and basophilic motifs. This differs from plasma phosphoproteins, which predominantly occur at Golgi casein kinase recognized sequences. Collectively, these results suggest diverse functions for salivary phosphoproteins and multiple kinases involved in their processing and secretion. In all, this study should lay groundwork for future elucidation of the functions of salivary protein phosphorylation. PMID- 21299199 TI - A highly selective colorimetric and ratiometric two-photon fluorescent probe for fluoride ion detection. AB - A naphthalimide-based highly selective colorimetric and ratiometric fluorescent probe for the fluoride ion displayed both one- and two-photon ratiometric changes. Upon reaction with the F(-) (TBA(+) and Na(+) salts) anion in CH(3)CN as well as in aqueous buffer solution, probe 1 shows dramatic color changes from colorless to jade-green and remarkable ratiometric fluorescence enhancements signals. These properties are mechanistically ascribed to a fluoride-triggered Si O bond cleavage that resulted in a green fluorescent 4-amino-1,8-naphthalimide. PMID- 21299200 TI - Chemical functionalization of oligodeoxynucleotides with multiple boronic acids for the polyvalent binding of saccharides. AB - A novel saccharide host containing four boronic acid recognition units on a single DNA duplex terminus was constructed. This construct allowed boronic acid sugar recognition in the context of double-stranded DNA to be established while highlighting the benefits of multivalency. Following the solid-phase synthesis of a bis-boronic acid tag, two end-functionalized oligonucleotides with complementary sequences were functionalized through amide ligation. By annealing the boronic acid-DNA conjugates, a tetra-boronic acid DNA duplex was assembled. The saccharide binding ability of this tetra-boronic acid host was revealed through cellulose paper chromatography in the absence and presence of various saccharides. While no appreciable saccharide binding was seen in the case of a bis-boronic DNA conjugate, the increased migration of the tetra-boronic acid host relative to the control sequences in the presence of selected monosaccharides underscored the importance of multivalent effects. We thus identified a requirement for multiple recognition sites in these conjugate systems and expect the results to facilitate future efforts toward applying synthetic recognition systems to the realm of macromolecules. PMID- 21299202 TI - Dioxygenases, key enzymes to determine the aglycon structures of fusicoccin and brassicicene, diterpene compounds produced by fungi. AB - Fusicoccin A and cotylenin A are structurally related diterpene glucosides and show a phytohormone-like activity. However, only cotylenin A induces the differentiation of human myeloid leukemia cells. Since the cotylenin A producer lost its ability to proliferate during preservation, a study on the relationship between structure and activity was carried out and a modified fusicoccin A with hydroxyl group at the 3-position showed a similar biological activity with that of cotylenin A. We then searched for an enzyme source that catalyzes the introduction of a hydroxyl group into the 3-position and found that brassicicene C, which is structurally related to fusicoccin A with hydroxyl group at the 3 position, was produced by Alternaria brassicicola ATCC96836. We recently cloned a brassicicene C biosynthetic gene cluster including the genes encoding fusicocca 2,10(14)-diene synthase and two cytochrome P450s, which were responsible for the formation of fusicocca-2,10(14)-diene-8beta,16-diol. In this study, we report that a alpha-ketoglutarate dependent dioxygenase, the gene coding for which was located in the cluster, catalyzed a hydroxylation at the 3-position of fusicocca 2,10(14)-diene-8beta,16-diol. On the other hand, a alpha-ketoglutarate-dependent dioxygenase, which had been identified in a fusicoccin A biosynthetic gene cluster, catalyzed the 16-oxidation of fusicocca-2,10(14)-diene-8beta,16-diol to yield an aldehyde (8beta-hydroxyfusicocca-1,10(14)-dien-16-al), although both dioxygenases had 51% amino acid sequence identity. These findings suggested that the dioxygenases played critical roles for the formation of the fusicoccin A-type and cotylenin A-/brassicicene C-type aglycons. Moreover, we showed that short chain dehydrogenase/reductase located in the fusicoccin A biosynthetic gene cluster catalyzed the reduction of the aldehyde to yield fusicocca-1,10(14)-diene 8beta,16-diol. PMID- 21299201 TI - Radiolabeled affibody-albumin bioconjugates for HER2-positive cancer targeting. AB - Affibody molecules have received significant attention in the fields of molecular imaging and drug development. However, Affibody scaffolds display an extremely high renal uptake, especially when modified with chelators and then labeled with radiometals. This unfavorable property may impact their use as radiotherapeutic agents in general and as imaging probes for the detection of tumors adjacent to kidneys in particular. Herein, we present a simple and generalizable strategy for reducing the renal uptake of Affibody molecules while maintaining their tumor uptake. Human serum albumin (HSA) was consecutively modified by 1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic acid mono-N-hydroxysuccinimide ester (DOTA-NHS ester) and the bifunctional cross-linker sulfosuccinimidyl 4-[N maleimidomethyl]cyclohexane-1-carboxylate (Sulfo-SMCC). The HER2 Affibody analogue, Ac-Cys-Z(HER2:342), was covalently conjugated with HSA, and the resulting bioconjugate DOTA-HSA-Z(HER2:342) was further radiolabeled with 64Cu and 111In and evaluated in vitro and in vivo. Radiolabeled DOTA-HSA-Z(HER2:342) conjugates displayed a significant and specific cell uptake into SKOV3 cell cultures. Positron emission tomography (PET) investigations using 64Cu-DOTA-HSA Z(HER2:342) were performed in SKOV3 tumor-bearing nude mice. High tumor uptake values (>14% ID/g at 24 and 48 h) and high liver accumulations but low kidney accumulations were observed. Biodistribution studies and single-photon emission computed tomography (SPECT) investigations using 111In-DOTA-HSA-Z(HER2:342) validated these results. At 24 h post injection, the biodistribution data revealed high tumor (16.26% ID/g) and liver (14.11% ID/g) uptake but relatively low kidney uptake (6.06% ID/g). Blocking studies with coinjected, nonlabeled Ac Cys-Z(HER2:342) confirmed the in vivo specificity of HER2. Radiolabeled DOTA-HSA Z(HER2:342) Affibody conjugates are promising SPECT and PET-type probes for the imaging of HER2 positive cancer. More importantly, DOTA-HSA-Z(HER2:342) is suitable for labeling with therapeutic radionuclides (e.g., 90Y or 177Lu) for treatment studies. The approach of using HSA to optimize the pharmacokinetics and biodistribution profile of Affibodies may be extended to the design of many other targeting molecules. PMID- 21299203 TI - Indium tin oxide nanorod electrodes for polymer photovoltaics. AB - We have deposited indium tin oxide (ITO) nanorods on glass and glass/ITO substrates by DC sputtering and by e-beam deposition. The properties of the nanorods deposited by different methods and on different substrates have been investigated. The ITO nanorods were also used as an electrode in bulk heterojunction polymer solar cells. We found that the nanorod morphology and sheet resistance had a significant effect on the solar cell performance, with significant improvements in the efficiency compared to commercial ITO film substrates in all cases except for e-beam deposited nanorods on glass that had high sheet resistance. The best power conversion efficiency achieved was 3.2 % (for sputtered ITO nanorods on ITO), compared to 2.1 % for commercial ITO substrates. PMID- 21299204 TI - Guest diffusion in interpenetrating networks of micro- and mesopores. AB - Pulsed field gradient NMR is applied for monitoring the diffusion properties of guest molecules in hierarchical pore systems after pressure variation in the external atmosphere. Following previous studies with purely mesoporous solids, also in the material containing both micro- and mesopores (activated carbon MA2), the diffusivity of the guest molecules (cyclohexane) is found to be most decisively determined by the sample "history": at a given external pressure, diffusivities are always found to be larger if they are measured after pressure decrease (i.e., on the "desorption" branch) rather than after pressure increase (adsorption branch). Simple model consideration reproduces the order of magnitude of the measured diffusivities as well as the tendencies in their relation to each other and their concentration dependence. PMID- 21299205 TI - Controlling ion motion in polymer light-emitting diodes containing conjugated polyelectrolyte electron injection layers. AB - The properties and function of an anionic conjugated polyelectrolyte (CPE) containing ion-conducting polyethylene oxide pendant (PF(PEO)CO(2)Na) as electron injection layers (EILs) in polymer light-emitting diodes (PLEDs) are investigated. A primary goal was to design a CPE structure that would enable acceleration of the device temporal response through facilitation of ion motion. Pristine PLEDs containing PF(PEO)CO(2)Na exhibit luminance response times on the order of tenths of seconds. This delay is attributed to the formation of ordered structures within the CPE film, as observed by atomic force microscopy. Complementary evidence is provided by electron transport measurements. The ordered structures are believed to slow ion migration within the CPE EIL and hence result in a longer temporal response time. It is possible to accelerate the response by a combination of thermal and voltage treatments that "lock" ions within the interfaces adjacent to PF(PEO)CO(2)Na. PLED devices with luminance response times of microseconds, a 10(5) fold enhancement, can therefore be achieved. Faster luminance response time opens up the application of PLEDs with CPE layers in display technologies. PMID- 21299206 TI - Syntheses and structures of isomeric diaminotriazinyl-substituted 2,2' bipyridines and 1,10-phenanthrolines. AB - Isomeric 2,2'-bipyridines 4a-6a and 1,10-phenanthrolines 7a-9a with two diaminotriazinyl (DAT) substituents were synthesized to explore their dual ability to direct association by the chelation of metals and the characteristic hydrogen bonding of DAT groups. Crystals of compounds 4a-6a and 7a-9a were grown under diverse conditions, and their structures were solved by X-ray crystallography. Analysis revealed multiple shared features analogous to those observed in the structures of simpler DAT-substituted pyridines 1-3. For example, the bipyridines and phenanthrolines favor flattened conformations except in the cases of compounds 8a and 9a, where the patterns of substitution prevent the DAT groups from lying in the plane of the phenanthroline core. As expected, the DAT groups form approximately coplanar hydrogen bonds according to standard motifs I III, which play a key role in directing molecular organization. However, the structures of simple pyridines 1-3, which favor efficiently packed chains and sheets, differ predictably from those of bipyridines 4a-6a and phenanthrolines 7a 9a in two ways: (1) The larger number of DAT groups in compounds 4a-9a typically leads to complex three-dimensional networks held together by a larger number of hydrogen bonds per molecule, and (2) the need to respect multiple directional interactions prevents compounds 4a-9a from forming closely packed structures, and significant quantities of guests are included. Together, these observations confirm the effectiveness of incorporating special groups such as DAT within more complex molecular structures to control association according to reliable patterns. Bipyridines 4a-6a and phenanthrolines 7a-9a promise to be particularly rich sources of new supramolecular chemistry because they have well-defined molecular topologies and a dual ability to direct association by chelating metals and by engaging in multiple hydrogen bonds according to reliable patterns. PMID- 21299207 TI - Practical syntheses of a CXCR3 antagonist. AB - Two new, reliable syntheses of a pyrido[2,3-d]-pyrimidine inhibitor of the CXCR3 receptor are described. A nine-step synthesis of the CXCR3 inhibitor (1) from 2 aminonicotinic acid was demonstrated on a multikilogram scale and incorporates a classic resolution to deliver the enantioenriched active pharmaceutical ingredient (API). A second synthesis of the CXCR3 inhibitor starts from (+)-(D) Boc alanine and 2-chloronicotinic acid and utilizes a Goldberg coupling. This second synthesis, performed on a gram scale, intersects the former route at a common intermediate thereby completing a formal synthesis of the enantioenriched API in higher overall yield without the need for a resolution. PMID- 21299208 TI - Alteration of the H-bond to the A(1A) phylloquinone in Photosystem I: influence on the kinetics and energetics of electron transfer. AB - In Photosystem I, the backbone nitrogen of Leu722(PsaA) forms a hydro-gen bond with the C(4) carbonyl oxygen of phylloquinone in the A(1A) site. A previous low temperature EPR study indicated that substitution of Leu722(PsaA) with a bulky Trp residue results in a weakened H-bond. Here, we employ room temperature, time resolved optical spectroscopy and variable temperature, transient EPR spectroscopy to probe the effect of the altered H-bond on the energetics and kinetics of electron transfer. Relative to the wild type, we find that the rate of electron transfer from A(1A)(-) to F(X) in the L722W(PsaA) variant is faster by a factor of 3. This change is attributed to a lowered midpoint potential of A(1A)/A(1A)(-), resulting in a larger Gibbs free energy change between A(1A)/A(1A)(-) and F(X)/F(X)(-). An activation energy of 180+/-10 meV is determined for the A(1A)(-)-to-F(X) forward electron transfer step in the L722W(PsaA) variant compared with 220+/-10 meV in the wild type. The Arrhenius plot shows a break at ~200 K, below which the rate becomes nearly independent of temperature. This behavior is described using a quantum mechanical treatment that takes the zero-point energy into account as well as an alternative model that invokes a dynamical transition in the protein at ~200 K. PMID- 21299209 TI - 1-arsa-3-germaallene Tip(t-Bu)Ge?C?AsMes*: the heaviest mixed group 14 and 15 heteroallenic compound. AB - The 1-arsa-3-germaallene Tip(t-Bu)Ge?C?AsMes* (1, Tip = 2,4,6-triisopropylphenyl, Mes* = 2,4,6-tri-tert-butylphenyl), a stable heavier group 14 and 15 congener of allenes, has been synthesized by debromofluorination of Tip(t-Bu)Ge(F) C(Br)?AsMes*. It reacts with methanol and 2,3-dimethyl-1,3-butadiene by the Ge?C double bond. The allenic-type structure of 1, featuring cumulated Ge?C and C?As double bonds, has been evidenced by means of spectroscopic and single-crystal X ray determination. The electronic properties involved in this new system were obtained from DFT calculations. The mechanism of the reaction between 1 and the dimethylbutadiene is also described to understand the observed regio- and chemoselectivity. PMID- 21299210 TI - A miniature, nongassing electroosmotic pump operating at 0.5 V. AB - Electroosmotic pumps are arguably the simplest of all pumps, consisting merely of two flow-through electrodes separated by a porous membrane. Most use platinum electrodes and operate at high voltages, electrolyzing water. Because evolved gas bubbles adhere and block parts of the electrodes and the membrane, steady pumping rates are difficult to sustain. Here we show that when the platinum electrodes are replaced by consumed Ag/Ag(2)O electrodes, the pumps operate well below 1.23 V, the thermodynamic threshold for electrolysis of water at 25 degrees C, where neither H(2) nor O(2) is produced. The pumping of water is efficient: 13 000 water molecules are pumped per reacted electron and 4.8 mL of water are pumped per joule at a flow rate of 0.13 mL min(-1) V(-1) cm(-2), and a flow rate per unit of power is 290 mL min(-1) W(-1). The water is driven by protons produced in the anode reaction 2Ag(s) + H(2)O -> Ag(2)O(s) + 2H(+) + 2e(-), traveling through the porous membrane, consumed by hydroxide ions generated in the cathode reaction Ag(2)O(s) + 2 H(2)O + 2e(-) -> 2Ag(s) + 2 OH(-). A pump of 2 mm thickness and 0.3 cm(2) cross-sectional area produces flow of 5-30 MUL min(-1) when operating at 0.2-0.8 V and 0.04-0.2 mA. Its flow rate can be either voltage or current controlled. The flow rate suffices for the delivery of drugs, such as a meal associated boli of insulin. PMID- 21299211 TI - Oxyallyl exposed: an open-shell singlet with picosecond lifetimes in solution but persistent in crystals of a cyclobutanedione precursor. AB - Photoinduced decarbonylation of 2,4-bis(spirocyclohexyl)-1,3-cyclobutanedione 1 in the crystalline solid state resulted in formation of a deep blue transient with lambda(max) = 550 nm and a half-life of 42 min at 298 K, identified as kinetically stabilized oxyallyl. Support for an open-shell singlet species was obtained by spectroscopic analysis and (4/4) CASSCF calculations with the 6 31+G(d) basis set and multireference MP2 corrections. The electronic spectrum of the singlet biradical, confirmed by femtosecond pump-probe studies in solution, was matched by coupled cluster calculations with single and double corrections. PMID- 21299213 TI - Preparation of strained axially chiral (1,5)naphthalenophanes by photo-dehydro Diels-Alder reaction. AB - The preparation of 10 (1,5)naphthalenophanes (10a-j) by photo-dehydro-Diels-Alder (PDDA) reaction is described. Owing to hindered rotation around the biaryl axis, compounds 10 are axially chiral and the separation of enantiomers by chiral HPLC was demonstrated in three cases (10a,b,e). The absolute configuration of the isolated enantiomers could be unambiguously determined by comparison of calculated and measured circular dichroism (CD) spectra. Furthermore, we analyzed ring strain phenomena of (1,5)naphthalenophanes 10. Depending on the length of the linker units, one can distinguish three classes of naphthalenophanes. Compounds 10a-c are highly strained (E(STR) = 7-31 kcal/mol), and the strain is caused by small bond angles in the linker unit and deformation of the naphthalene moiety. Another type of strain is observed if the linker unit becomes relatively long (10g,h) originating from transannular interactions and is comparable with the well-known strain of medium sized rings. The naphthalenophanes 10d-f with a linker length of 10-14 atoms are only marginally strained. To clearly discriminate the different sources of strain, we defined two geometrical parameters (average central dihedral angle delta(C) and naphthalene thickness D(N)) and demonstrated that they are well-suited to indicate naphthalene deformation of our naphthalenophanes 10 as well as of ten model naphthalenophanes (I-X) with different linker lengths and linking positions. PMID- 21299212 TI - Fungal indole alkaloid biosynthesis: genetic and biochemical investigation of the tryptoquialanine pathway in Penicillium aethiopicum. AB - Tremorgenic mycotoxins are a group of indole alkaloids which include the quinazoline-containing tryptoquivaline (2) that are capable of eliciting intermittent or sustained tremors in vertebrate animals. The biosynthesis of this group of bioactive compounds, which are characterized by an acetylated quinazoline ring connected to a 6-5-5 imidazoindolone ring system via a 5 membered spirolactone, has remained uncharacterized. Here, we report the identification of a gene cluster (tqa) from P. aethiopicum that is involved in the biosynthesis of tryptoquialanine (1), which is structurally similar to 2. The pathway has been confirmed to go through an intermediate common to the fumiquinazoline pathway, fumiquinazoline F, which originates from a fungal trimodular nonribosomal peptide synthetase (NRPS). By systematically inactivating every biosynthetic gene in the cluster, followed by isolation and characterization of the intermediates, we were able to establish the biosynthetic sequence of the pathway. An unusual oxidative opening of the pyrazinone ring by an FAD-dependent berberine bridge enzyme-like oxidoreductase has been proposed based on genetic knockout studies. Notably, a 2-aminoisobutyric acid (AIB) utilizing NRPS module has been identified and reconstituted in vitro, along with two putative enzymes of unknown functions that are involved in the synthesis of the unnatural amino acid by genetic analysis. This work provides new genetic and biochemical insights into the biosynthesis of this group of fungal alkaloids, including the tremorgens related to 2. PMID- 21299214 TI - [2,2']paracyclophane-based pi-conjugated molecular wires reveal molecular junction behavior. AB - The electronic coupling as well as the attenuation factor (beta), which depends primarily on the nature of the molecular bridge and is used as a benchmark to test the molecular wire behavior, have been determined in a systematic study carried out on a series of ZnP/C(60) conjugates connected through a [2,2']paracyclophane-oligophenylenevinylene (pCp-oPPV). The convergent synthesis involves a series of Horner-Emmons olefination reactions or double palladium catalized Heck-type reactions. ZnP-pCp-C(60) conjugates were finally obtained by the 1,3-dipolar cycloaddition reaction of the in situ-generated azomethyne ylide containing the ZnP-pCp moiety to the [60]fullerene using Prato conditions. Experimental (UV-vis, fluorescence, transient absorption spectroscopy, and solution electrochemistry) and theoretical studies revealed that the pCps act as molecular junctions. If hole transfer is assumed to be the dominant charge transfer (CT) mechanism, CT is facilitated in one direction (from C(60) to ZnP via pCp) but disfavored in the other direction (from ZnP to C(60) via pCp). PMID- 21299215 TI - Chemical composition of distillers grains, a review. AB - In recent years, increasing demand for ethanol as a fuel additive and decreasing dependency on fossil fuels have resulted in a dramatic increase in the amount of grains used for ethanol production. Dry-grind is the major process, resulting in distillers dried grains with solubles (DDGS) as a major coproduct. Like fuel ethanol, DDGS has quickly become a global commodity. However, high compositional variation has been the main problem hindering its use as a feed ingredient. This review provides updated information on the chemical composition of distillers grains in terms of nutrient levels, changes during dry-grind processing, and causes for large variation. The occurrence in grain feedstock and the fate of mycotoxins during processing are also covered. During processing, starch is converted to glucose and then to ethanol and carbon dioxide. Most other components are relatively unchanged but concentrated in DDGS about 3-fold over the original feedstock. Mycotoxins, if present in the original feedstock, are also concentrated. Higher fold of increases in S, Na, and Ca are mostly due to exogenous addition during processing, whereas unusual changes in inorganic phosphorus (P) and phytate P indicate phytate hydrolysis by yeast phytase. Fermentation causes major changes, but other processing steps are also responsible. The causes for varying DDGS composition are multiple, including differences in feedstock species and composition, process methods and parameters, the amount of condensed solubles added to distiller wet grains, the effect of fermentation yeast, and analytical methodology. Most of them can be attributed to the complexity of the dry-grind process itself. It is hoped that information provided in this review will improve the understanding of the dry-grind process and aid in the development of strategies to control the compositional variation in DDGS. PMID- 21299216 TI - Enhancement of trichothecene production in Fusarium graminearum by cobalt chloride. AB - The effects of cobalt chloride on the production of trichothecene and ergosterol in Fusarium graminearum were examined. Incorporation experiments with (13)C labeled acetate and leucine confirmed that both 3-acetyldeoxynivalenol and ergosterol were biosynthesized via a mevalonate pathway by the fungus, although hydroxymethyl-glutaryl CoA (HMG-CoA) from intact leucine was able to be partially used for ergosterol production. Addition of cobalt chloride at concentrations of 3-30 MUM into liquid culture strongly enhanced 3-acetyldeoxynivalenol production by the fungus, whereas the amount of ergosterol and the mycelial weight of the fungus did not change. The mRNA levels of genes encoding trichothecene biosynthetic proteins (TRI4 and TRI6), ergosterol biosynthetic enzymes (ERG3 and ERG25), and enzymes involved in the mevalonate pathway (HMG-CoA synthase (HMGS) and HMG-CoA reductase (HMGR)) were all strongly up-regulated in the presence of cobalt chloride. Precocene II, a specific trichothecene production inhibitor, suppressed the effects of cobalt chloride on Tri4, Tri6, HMGS, and HMGR, but did not affect erg3 and erg25. These results indicate that cobalt chloride is useful for investigating regulatory mechanisms of trichothecene and ergosterol production in F. graminearum. PMID- 21299217 TI - RapA, Escherichia coli RNA polymerase SWI/SNF subunit-dependent polyadenylation of RNA. AB - In this work, we describe RapA-dependent polyadenylation of model RNA substrates and endogenous, RNA polymerase-associated nucleic acid fragments. We demonstrate that the Escherichia coli RNA polymerase obtained through the classic purification procedure carries endogenous RNA oligonucleotides, which, in the presence of ATP, are polyriboadenylated in a RapA-dependent manner by an accessory poly(rA) polymerase. RNA polymerase isolated from poly(A) polymerase- (PAP-) and polynucleotide phosphorylase- (PNP-) deficient E. coli strain lacks accessory (rA)(n)-synthetic activity. Experiments with reconstituted RNA polymerase-PAP and RNA polymerase-PNP mixtures suggest that RapA enables the polyadenylation by PAP of RNA polymerase-associated RNA. Mutations disrupting RapA's ATP-hydrolytic function disrupt RapA-dependent polyadenylation, and the rapA(-)E. coli strain displays a measurable reduction in RNA polyadenylation. RapA-dependent polyadenylation can also be modulated by mutations in the section of RapA's SWI/SNF domain linked to interaction with single-stranded nucleic acid. We have developed enzymatic assays in which model, synthetic RNAs are polyriboadenylated in a RapA-dependent manner. Taken together, our results are consistent with RapA acting as an RNA polymerase-associated, ATP-dependent RNA translocase. Our work further links RapA to RNA remodeling and provides new mechanistic insights into the functional interaction between RNA polymerase and RapA. PMID- 21299218 TI - Chlorate analyses in matrices of animal origin. AB - Sodium chlorate is being developed as a potential food-safety tool for use in the livestock industry because of its effectiveness in decreasing concentrations of certain Gram-negative pathogens in the gastrointestinal tracts of food animals. A number of studies with sodium chlorate in animals have demonstrated that concentrations of chlorate in meat, milk, wastes, and gastrointestinal contents range from parts per billion to parts per thousand, depending upon chlorate dose, matrix, and time lapse after dosing. Although a number of analytical methods exist for chlorate salts, very few were developed for use in animal-derived matrices, and none have anticipated the range of chlorate concentrations that have been observed in animal wastes and products. To meet the analytical needs of this development work, LC-MS, ion chromatographic, and colorimetric methods were developed to measure chlorate residues in a variety of matrices. The LC-MS method utilizes a Cl(18)O(3)(-) internal standard, is applicable to a variety of matrices, and provides quantitative assessment of samples from 0.050 to 2.5 ppm. Due to ion suppression, matrix-matched standard curves are appropriate when using LC-MS to measure chlorate in animal-derived matrices. A colorimetric assay based on the acid-catalyzed oxidation of o-tolidine proved valuable for measuring >=20 ppm quantities of chlorate in blood serum and milk, but not urine, samples. Ion chromatography was useful for measuring chlorate residues in urine and in feces when chlorate concentrations exceeded 100 ppm, but no effort was made to maximize ion chromatographic sensitivity. Collectively, these methods offer the utility of measuring chlorate in a variety of animal-derived matrices over a wide range of chlorate concentrations. PMID- 21299219 TI - Allium discoloration: the precursor and formation of the red pigment in giant onion (Allium giganteum Regel) and some other subgenus Melanocrommyum species. AB - The precursor of the orange-red pigment formed upon wounding the bulbs of Allium giganteum (Allium subg. Melanocrommyum) was isolated and shown to be S-(2 pyrrolyl)cysteine S-oxide. In addition, two other pyrrolylsulfinyl derivatives were found in an extract from the bulbs, namely, 3-(2-pyrrolylsulfinyl)lactic acid and S-(3-pyrrolyl)cysteine S-oxide. Contrary to a previous report, the latter compound was shown not to serve as the precursor of the pigment, being in fact only an artifact formed during isolation. The formation of pyrrolyl containing compounds following disruption of A. giganteum bulbs was studied by a combination of LC-MS, LC-NMR and DART-MS. It was found that S-(2 pyrrolyl)cysteine S-oxide is cleaved by a C-S lyase (alliinase) to yield 2 pyrrolesulfenic acid. Two molecules of the latter compound give rise to highly reactive S-(2-pyrrolyl) 2-pyrrolethiosulfinate which in turn converts into red 2,2'-epidithio-3,3'-dipyrrole (dipyrrolo[2,3-d:2',3'-e]-1,2-dithiin). Several other pyrrolyl-containing compounds were detected in A. giganteum for the first time, including S-methyl 2-pyrrolethiosulfinate, S-(2-pyrrolyl) methanethiosulfinate, di(2-pyrrolyl) disulfide, and S-(2-pyrrolyl) 2 pyrrolethiosulfonate. It can be concluded that the formation of the orange-red pigment in Allium subg. Melanocrommyum species, despite sharing several analogous features, is of a different nature than the pink discoloration of onion (A. cepa). PMID- 21299220 TI - The unique Alzheimer's beta-amyloid triangular fibril has a cavity along the fibril axis under physiological conditions. AB - Elucidating the structure of Abeta(1-40) fibrils is of interest in Alzheimer's disease research because it is required for designing therapeutics that target Abeta(1-40) fibril formation at an early stage of the disease. M35 is a crucial residue because of its potential oxidation and its strong interactions across beta-strands and across beta-sheets in Abeta fibrils. Experimentally, data for the three-fold symmetry structure of the Abeta(9-40) fibril suggest formation of tight hydrophobic core through M35 interactions across the fibril axis and strong I31-V39 interactions between different cross-beta units. Herein, on the basis of experimental data, we probe conformers with three-fold symmetry of the full length Abeta(1-40). Our all-atom molecular dynamics simulations in explicit solvent of conformers based on the ssNMR data reproduced experimental observations of M35-M35 and I31-V39 distances. Our interpretation of the experimental data suggests that the observed ~5-7 A M35-M35 distance in the fibril three-fold symmetry structure is likely to relate to M35 interactions along the fibril axis, rather than across the fibril axis, since our measured M35 M35 distances across the fibril axis are consistently above 15 A. Consequently, we revealed that the unique Abeta(1-40) triangular structure has a large cavity along the fibril axis and that the N-termini can assist in the stabilization of the fibril by interacting with the U-turn domains or with the C-termini domains. Our findings, together with the recent cyroEM characterization of the hollow core in Abeta(1-42) fibrils, point to the relevance of a cavity in Abeta(1-40/1-42) oligomers which should be considered when targeting oligomer toxicity. PMID- 21299221 TI - Profiles of carotenoids, anthocyanins, phenolics, and antioxidant activity of selected color waxy corn grains during maturation. AB - Waxy corns are becoming increasingly consumed as fresh foods or as raw materials for whole grain foods facilitating human consumption in China, so they are usually harvested before complete maturity. Unfortunately, information on functional properties of immature waxy corns is very limited. Therefore, we investigated the profiles of carotenoids, anthocyanins, phenolics, and the antioxidant activity in three types of waxy corn with different colors (white, yellow, and black) during maturation, as well as a normal corn (yellow) used as control. The results showed that black waxy corn had the highest quantity of anthocyanins, phenolics and the best antioxidant activity, yellow corn contained a relatively large amount of carotenoids, while white corn had the lowest amounts of carotenoids, anthocyanins, phenolics, and antioxidant capacity. For each type of waxy corn, the higher carotenoids were found at the M2 stage (no major difference between the M1 and M2 stages for yellow corn). The levels of anthocyanin and phenolics decreased for white and yellow corns, contrary to those for black corn during maturation. The antioxidant activity determined by scavenging 2,2-diphenyl-1-picrylhydrazyl (DPPH), the ferric reducing antioxidant power (FRAP), and the Trolox equivalent antioxidant capacity (TEAC) assays increased with ripening, but no difference was found between the M2 and maturity stages for yellow and black corns. For white corn, the DPPH radical scavenging activity first increased and then decreased, while the antioxidant activity determined by TEAC and FRAP assay decreased during maturation. Differences in these parameters indicate that types and harvesting time have significant influences on functional properties of waxy corns. PMID- 21299222 TI - PMMA highlights the layering transition of PDMS in Langmuir films. AB - We report a system consisting of a mixed Langmuir monolayer, made of water insoluble, spreadable, fluid-like polymers polydimethylsiloxane (PDMS) and polymethylmethacrylate (PMMA) with a minority P(DMS-b-MMA) copolymer. We have performed both Langmuir trough pressure/area isotherm measurements and Brewster angle microscopy (BAM) observations and complement the experiments with molecularly detailed self-consistent field (SCF) calculations. PDMS undergoes a layering transition that is difficult to detect by BAM. Addition of PMMA gives contrast in BAM, now showing a two-phase system: if this would consist of separate two-dimensional (2D) PMMA and PDMS phases, a PDMS-PMMA diblock should accumulate at the phase boundary. However, the diblock copolymer of PDMS-PMMA failed to show the expected "lineactant" behavior, i.e., failed to accumulate at the phase boundary. The calculations point to a nontrivial arrangement of the polymer chains at the interface: in mixtures of the two homopolymers, in a rather wide composition ratio, we find a vertical (with respect to the air/water interfacial plane) configuration, with PMMA sitting preferably at the PDMS/water interface of the thicker PDMS film, during the PDMS layering phase transition. This also explains why the diblock copolymer is not a lineactant. Both PMMA and P(DMS-b-MMA) are depleted from the thin-thick PDMS film interface, and the line tension between the phases is, consequently, increased, in the binary mixtures as well as in the ternary ones. PMID- 21299223 TI - Effects of self-assembled monolayers on solid-state CdS quantum dot sensitized solar cells. AB - Quantum dot sensitized solar cells (QDSSCs) are of interest for solar energy conversion because of their tunable band gap and promise of stable, low-cost performance. We have investigated the effects of self-assembled monolayers (SAMs) with phosphonic acid headgroups on the bonding and performance of cadmium sulfide (CdS) solid-state QDSSCs. CdS quantum dots ~2 to ~6 nm in diameter were grown on SAM-passivated planar or nanostructured TiO(2) surfaces by successive ionic layer adsorption and reaction (SILAR), and photovoltaic devices were fabricated with spiro-OMeTAD as the solid-state hole conductor. X-ray photoelectron spectroscopy, Auger electron spectroscopy, ultraviolet-visible spectroscopy, scanning electron microscopy, transmission electron microscopy, water contact angle measurements, ellipsometry, and electrical measurements were employed to characterize the materials and the resulting device performance. The data indicate that the nature of the SAM tailgroup does not significantly affect the uptake of CdS quantum dots on TiO(2) nor their optical properties, but the presence of the SAM does have a significant effect on the photovoltaic device performance. Interestingly, we observe up to ~3 times higher power conversion efficiencies in devices with a SAM compared to those without the SAM. PMID- 21299224 TI - Spectroscopic evidence for the formation of an N intermediate during the photocycle of sensory rhodopsin II (phoborhodopsin) from Natronobacterium pharaonis. AB - Sensory rhodopsin II is a seven transmembrane helical retinal protein and functions as a photoreceptor protein in negative phototaxis of halophilic archaea. Sensory rhodopsin II from Natronomonas pharaonis (NpSRII) is stable under various conditions and can be expressed functionally in Escherichia coli cell membranes. Rhodopsins from microorganisms, known as microbial rhodopsins, exhibit a photocycle, and light irradiation of these molecules leads to a high energy intermediate, which relaxes thermally to the original pigment after passing through several intermediates. For bacteriorhodopsin (BR), a light-driven proton pump, the photocycle is established as BR -> K -> L -> M -> N -> O -> BR. The photocycle of NpSRII is similar to that of BR except for N, i.e., M thermally decays into the O, and N has not been well characterized in the photocycle. Thus we here examined the second half of the photocycle in NpSRII, and in the present transient absorption study we found the formation of a new photointermediate whose absorption maximum is ~500 nm. This intermediate becomes pronounced in the presence of azide, which accelerates the decay of M. Transient resonance Raman spectroscopy was further applied to demonstrate that this intermediate contains a 13-cis retinal protonated Schiff base. However, detailed analysis of the transient absorption data indicated that M-decay does not directly produce N but rather produces O that is in equilibrium with N. These observations allowed us to propose a structural model for a photocycle that involves N. PMID- 21299225 TI - Dictyostatin flexibility bridges conformations in solution and in the beta tubulin taxane binding site. AB - Dictyostatin (DCT, 1) is a complex, flexible polyketide macrolide that demonstrates potent microtubule-polymerization activity. Both a solution structure (2a) and a possible binding mode for DCT (Conf-1) have been proposed by earlier NMR experiments. In the present study, the conformational landscape of DCT in DMSO-d(6) and methanol-d(4) was explored using extensive force-field-based conformational searches combined with geometric parameters derived from solution NMR data. The results portray a diversity of conformations for dictyostatin that illustrates the molecule's flexibility and excludes the previously suggested dominant solution conformation 2a. One conformation present in DMSO-d(6) with a 7% population (Conf-2, 0.6 kcal/mol above the global minimum at 298 degrees ) also satisfies the TR-NOESY NMR parameters of Canales et al. that characterize the taxane binding-site interaction between DCT and assembled microtubules in water. Application of several docking methods (Glide, Autodock, and RosettaLigand) has identified a low-energy binding model of the DCT/beta-tubulin complex (Pose-2/Conf-2) that is gratifyingly compatible with the emerging DCT structure-activity data. PMID- 21299226 TI - Molecular dynamics simulations of CXCL-8 and its interactions with a receptor peptide, heparin fragments, and sulfated linked cyclitols. AB - CXCL-8 (Interleukin 8) is a CXC chemokine with a central role in the human immune response. We have undertaken extensive in silico analyses to elucidate the interactions of CXCL-8 with its various binding partners, which are crucial for its biological function. Sequence and structure analyses showed that residues in the thirdq beta-sheet and basic residues in the heparin binding site are highly variable, while residues in the second beta-sheet are highly conserved. Molecular dynamics simulations in aqueous solution of dimeric CXCL-8 have been performed with starting geometries from both X-ray and NMR structures showed shearing movements between the two antiparallel C-terminal helices. Dynamic conservation analyses of these simulations agreed with experimental data indicating that structural differences between the two structures at quaternary level arise from changes in the secondary structure of the N-terminal loop, the 3(10)-helix, the 30s, 40s, and 50s loops and the third beta-sheet, resulting in a different interhelical separation. Nevertheless, the observation of these different states indicates that CXCL-8 has the potential to undergo conformational changes, and it seems likely that this feature is relevant to the mode of binding of glycosaminoglycan (GAG) mimetics such as cyclitols. Simulations of the receptor peptide fragment-CXCL-8 complex identified several specific interactions of the receptor peptide with CXCL-8 that could be exploited in the structure-based design of competitive peptides and nonpeptidic molecules targeting CXCL-8 for combating inflammatory diseases. Simulations of the CXCL-8 dimer complexed with a 24-mer heparin fragment and of the CXCL-8-receptor peptide complex revealed that Arg60, Lys64, and Arg68 in the dimer bind to cyclitols in a horseshoe pattern, defining a region which is spatially distinct from the receptor binding site. There appears to be an optimum number of sulfates and an optimum length of alkyl spacers required for the interaction of cyclitol inhibitors with the dimeric form of CXCL-8. Calculation of the binding affinities of cyclitol inhibitors reflected satisfactorily the ranking of experimentally determined inhibitory potencies. The findings of these molecular modeling studies will help in the search for inhibitors which can modulate various CXCL-8 biological activities and serve as an excellent model system to study CXC-inhibitor interactions. PMID- 21299228 TI - Mechanism of carbon-halogen bond reductive cleavage in activated alkyl halide initiators relevant to living radical polymerization: theoretical and experimental study. AB - The mechanism of reductive cleavage of model alkyl halides (methyl 2 bromoisobutyrate, methyl 2-bromopropionate, and 1-bromo-1-chloroethane), used as initiators in living radical polymerization (LRP), has been investigated in acetonitrile using both experimental and computational methods. Both theoretical and experimental investigations have revealed that dissociative electron transfer to these alkyl halides proceeds exclusively via a concerted rather than stepwise manner. The reductive cleavage of all three alkyl halides requires a substantial activation barrier stemming mainly from the breaking C-X bond. The activation step during single electron transfer LRP (SET-LRP) was originally proposed to proceed via formation and decomposition of RX(*-) through an outer sphere electron transfer (OSET) process (Guliashvili, T.; Percec, V. J. Polym. Sci., Part A: Polym. Chem. 2007, 45, 1607). These radical anion intermediates were proposed to decompose via heterolytic rather than homolytic C-X bond dissociation. Here it is presented that injection of one electron into RX produces only a weakly associated charge-induced donor-acceptor type radical anion complex without any significant covalent sigma type bond character between carbon-centered radical and associated anion leaving group. Therefore, neither homolytic nor heterolytic bond dissociation applies to the reductive cleavage of C-X in these alkyl halides inasmuch as a true radical anion does not form in the process. In addition, the whole mechanism of SET-LRP has to be revisited since it is based on presumed OSET involving intermediate RX(*-), which is shown here to be nonexistent. PMID- 21299227 TI - Structure-activity relationships in nucleotide oligomerization domain 1 (Nod1) agonistic gamma-glutamyldiaminopimelic acid derivatives. AB - N-acyl-gamma-glutamyldiaminopimelic acid is a prototype ligand for Nod1. We report a detailed SAR of C(12)-gamma-D-Glu-DAP. Analogues with glutaric or gamma aminobutyric acid replacing the glutamic acid show greatly attenuated Nod1 agonistic activity. Substitution of the meso-diaminopimelic (DAP) acid component with monoaminopimelic acid, L- or D-lysine, or cadaverine also results in reduced activity. The free amine on DAP is crucial. However, the N-acyl group on the D glutamyl residue can be substituted with N-alkyl groups with full preservation of activity. The free carboxylates on the DAP and Glu components can also be esterified, resulting in more lipophilic but active analogues. Transcriptomal profiling showed a dominant up-regulation of IL-19, IL-20, IL-22, and IL-24, which may explain the pronounced Th2-polarizing activity of these compounds and also implicate cell signaling mediated by TREM-1. These results may explain the hitherto unknown mechanism of synergy between Nod1 and TLR agonists and are likely to be useful in designing vaccine adjuvants. PMID- 21299229 TI - DNA melting in slit pores: a reaction density functional theory. AB - A reaction density functional theory (R-DFT) is developed for chemical reactions in confined space by integrating reaction thermodynamics and DFT for chain fluids. The theory is applied to investigate DNA melting in slit pores, with nucleotides represented by coarse-grained charged Lennard-Jones particles. Three types of slit pores are considered for DNA melting: repulsive pore, attractive pore, and under electric field. In repulsive pores, the melting temperature increases slightly with reducing pore width, and the increase magnitude is nearly the same for DNA of different chain lengths. The double-strand DNA (dsDNA) and single-strand DNA (ssDNA) are located in the slit center, particularly for long DNA due to the effect of configuration entropy. In attractive pores, the melting temperature increases with increasing wall-fluid interaction. The DNA chains are preferentially adsorbed near the slit walls with a strong wall-fluid interaction. Under electric field, the melting temperature increases slightly and is more distinct for shorter DNA. PMID- 21299230 TI - Effects of water contamination on the supercooled dynamics of a hydrogen-bonded model glass former. AB - Broad-band dielectric spectroscopy is a commonly used tool in the study of glass forming liquids. The high sensitivity of the technique together with the wide range of probed time scales makes it a powerful method for investigating the relaxation spectra of liquids. One particularly important class of glass-forming liquids that is often studied using this technique consists of liquids dominated by hydrogen (H) bond interactions. When investigating such liquids, particular caution has to be taken during sample preparation due to their often highly hygroscopic nature. Water can easily be absorbed from the atmosphere, and dielectric spectroscopy is a very sensitive probe of such contamination due to the large dipole moment of water. Our knowledge concerning the effects of small quantities of water on the dielectric properties of these commonly investigated liquids is limited. We here demonstrate the effects due to the presence of small amounts of water on the dielectric response of a typical H-bonded model glass former, tripropylene glycol. We show how the relaxation processes present in the pure liquid are affected by addition of water, and we find that a characteristic water induced relaxation response is observed for water contents as low as 0.15 wt%. We stress the importance of careful purification of hygroscopic liquids before experiments and quantify what the effects are if such procedures are not undertaken. PMID- 21299231 TI - Comparative studies on the reactions of acetyl and thioacetyl halides with NH3 in the gas phase and in aqueous solution: a theoretical study. AB - The reactions of acetyl halides, CH3C(? O)X and corresponding sulfur analogues, thioacetyl halides, CH3C(=S)X, where X = F and Cl, with NH3 nucleophile were studied theoretically, at the QCISD level of theory, in the gas phase and in aqueous solution. All reactions occurred via the tetrahedral species, and reactions through neutral intermediates both in the gas phase and in aqueous solution could be ruled out, except for the case of the gas-phase reaction of acetyl fluoride. The tetrahedral structure was a transition state (TS) in the reactions of acetyl chloride, while it was a stable intermediate in reactions of thioacetyl halides. These differences could be caused by the pi-bond strength of C ? O and C ? S. In the case of acetyl fluoride, the T(+/-)-type species was neither a saddle point nor an energy minimum in the gas phase, but existed as a stable intermediate in aqueous solution due to solvation. Moreover, in reactions of thioacetyl chloride, the rate-limiting step changed from the first step in the gas phase to the second step in aqueous solution, since the zwitterionic intermediates become more stabilized in aqueous solution. However, lower activation energies (DeltaG(?)) in aqueous solution were not caused by the solvent effects, but smaller deformation effects, in going from reactants through the TS. PMID- 21299232 TI - Predicted structures and dynamics for agonists and antagonists bound to serotonin 5-HT2B and 5-HT2C receptors. AB - Subtype 2 serotonin (5-hydroxytryptamine, 5-HT) receptors are major drug targets for schizophrenia, feeding disorders, perception, depression, migraines, hypertension, anxiety, hallucinogens, and gastrointestinal dysfunctions. (1) We report here the predicted structure of 5-HT2B and 5-HT2C receptors bound to highly potent and selective 5-HT2B antagonist PRX-08066 3, (pKi: 30 nM), including the key binding residues [V103 (2.53), L132 (3.29), V190 (4.60), and L347 (6.58)] determining the selectivity of binding to 5-HT2B over 5-HT2A. We also report structures of the endogenous agonist (5-HT) and a HT2B selective antagonist 2 (1-methyl-1-1,6,7,8-tetrahydro-pyrrolo[2,3-g]quinoline-5-carboxylic acid pyridine-3-ylamide). We examine the dynamics for the agonist- and antagonist bound HT2B receptors in explicit membrane and water finding dramatically different patterns of water migration into the NPxxY motif and the binding site that correlates with the stability of ionic locks in the D(E)RY region. PMID- 21299233 TI - A peptidomics strategy to elucidate the proteolytic pathways that inactivate peptide hormones. AB - Proteolysis plays a key role in regulating the levels and activity of peptide hormones. Characterization of the proteolytic pathways that cleave peptide hormones is of basic interest and can, in some cases, spur the development of novel therapeutics. The lack, however, of an efficient approach to identify endogenous fragments of peptide hormones has hindered the elucidation of these proteolytic pathways. Here, we apply a mass spectrometry (MS) based peptidomics approach to characterize the intestinal fragments of peptide histidine isoleucine (PHI), a hormone that promotes glucose-stimulated insulin secretion (GSIS). Our approach reveals a proteolytic pathway in the intestine that truncates PHI at its C-terminus to produce a PHI fragment that is inactive in a GSIS assay, a result that provides a potential mechanism of PHI regulation in vivo. Differences between these in vivo peptidomics studies and in vitro lysate experiments, which showed N- and C-terminal processing of PHI, underscore the effectiveness of this approach to discover physiologically relevant proteolytic pathways. Moreover, integrating this peptidomics approach with bioassays (i.e., GSIS) provides a general strategy to reveal proteolytic pathways that may regulate the activity of peptide hormones. PMID- 21299234 TI - Sampling wand for an ion trap mass spectrometer. AB - A new sampling wand concept for ion trap mass spectrometers equipped with discontinuous atmospheric pressure interfaces (DAPI) has been implemented. The ion trap/DAPI combination facilitates the operation of miniature mass spectrometers equipped with ambient ionization sources. However, in the new implementation, instead of transferring ions pneumatically from a distant source, the mass analyzer and DAPI are separated from the main body of the mass spectrometer and installed at the end of a 1.2 m long wand. During ion introduction, ions are captured in the ion trap while the gas in which they are contained passes through the probe and is pumped away. The larger vacuum volume due to the extended wand improves the mass analysis sensitivity. The wand was tested using a modified hand-held ion trap mass spectrometer without additional power or pumping being required. Improved sensitivity was obtained as demonstrated with nano-electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), and low temperature plasma (LTP) probe analysis of liquid, gaseous, and solid samples, respectively. PMID- 21299235 TI - Steric and electronic effects in the host-guest hydrogen bonding in clathrate hydrates. AB - Clathrate hydrates with polar guest molecules (dimethyl ether, ethylene oxide, trimethylene oxide, tetrahydrofuran, and tetrahydropyran) were studied by means of the density functional theory. A model of a large cage of structure-I clathrate was employed. Optimal configurations of encaged guests were investigated with a focus on the host-guest hydrogen bond formation. Weak hydrogen bonds were found to be formed by each guest, while for THP a strong hydrogen bond and formation of L-defect was also observed. This is in accord with previous computational and experimental studies. Steric factors were shown to play a key role for the strength of the hydrogen bond formed. Interestingly, the host-guest binding is influenced not only by the size of a guest molecule but also by its shape. This work demonstrates that both electronic and steric properties of a polar guest should be considered for a full description of clathrate systems. PMID- 21299236 TI - Assessment of periodic and cluster-in-vacuo models for first principles calculation of EPR parameters of paramagnetic defects in crystals: Rh2+ defects in NaCl as case study. AB - In order to find a reliable and efficient calculation scheme for electron paramagnetic resonance (EPR) spectroscopic parameters for transition metal complexes in ionic solids from first principles, periodic and finite cluster-in vacuo density functional theory (DFT) simulations are performed for g tensors, ligand hyperfine tensors (A), and quadrupole tensors (Q) for Rh(2+)-related centers in NaCl. EPR experiments on NaCl:Rh single crystals identified three Rh(2+) monomer centers, only differing in the number of charge compensating vacancies in their local environment, and one dimer center. Periodic and cluster calculations, both based on periodically optimized structures, are able to reproduce experimentally observed trends in the ligand A and Q tensors and render very satisfactory numerical agreement with experiment. Taking also computation time into account as a criterion, a full periodic approach emerges as most appropriate for these parameters.The g tensor calculations, on the other hand, prove to be insufficiently accurate for model assessment. The calculations also reveal parameters of the complexes which are not directly accessible through experiments, in particular related to their geometry. PMID- 21299237 TI - Anion-induced structures and luminescent properties of chiral lanthanide-organic frameworks assembled by an achiral tripodal ligand. AB - To confirm how different anions influence sup-ramolecular self-assembly of lanthanide-organic frameworks (LnOFs) as well as their luminescent properties, a new flexible achiral tripodal ligand, 1,1,1-tris-{[(2' benzylaminoformyl)phenoxyl]methyl}ethane (L) and the LnOFs {[EuL(NO(3))(3)].1.5CHCl(3)}(n) and [EuL(pic)(3)](n) have been designed and assembled. In the two LnOFs, {[EuL(NO(3))(3)].1.5CHCl(3)}(n) demonstrates an unprecedented chiral noninterpenetrated two-dimensional (2D) honeycomblike (6,3) (hcb, Schlafli symbol 6(3), vertex symbol 6.6.6) topological network, and [EuL(pic)(3)](n) confirms an unusual chiral LnOF with three-dimensional (3D) (10,3)-a (srs, SrSi(2), Schlafli symbol 10(3), vertex symbol 10(2).10(4).10(4)) topological framework. Also the anion-induced structures and energy transfer processes in the luminescence behavior of the two LnOFs were discussed in detail. PMID- 21299238 TI - Investigation into the possible natural occurence of semicarbazide in Macrobrachium rosenbergii prawns. AB - In the past year there has been an increased incidence in Belgium of cases of positive semicarbazide (SEM) tests in imported freshwater Macrobrachium rosenbergii prawns, seemingly indicating the possible abuse of nitrofurazone, a banned antimicrobial agent. This was in contrast to all other European countries where no significant increase in SEM-positive samples was detected. A possible explanation for this discrepancy between Belgium and the other European Union member states could be the fact that only in Belgium were whole prawns (meat + shell) analyzed for the presence of tissue-bound metabolites of nitrofurans, whereas in the other countries only the edible part (meat) of these prawns was analyzed. To investigate the possible natural occurrence of SEM in freshwater prawns, an animal trial was set up. In this experiment two groups of 10 juvenile M. rosenbergii, previously raised under standardized laboratory conditions, were stocked into two separate aquaria, a control group under reference conditions (no addition of nitrofurazone) and a group exposed to a daily dose of 50 mg of nitrofurazone L(-1) of culture water. Results of this animal trial proved that SEM naturally occurs in M. rosenbergii prawns but that at the current minimum required performance limit (MRPL) no tissue-bound SEM can be found in the meat of nontreated animals. In addition to this animal trial, commercial samples of other crustacean species, the shell and meat of which were analyzed separately, were also analyzed for the presence of SEM. PMID- 21299239 TI - Versatile site-specific conjugation of small molecules to siRNA using click chemistry. AB - We have previously demonstrated that conjugation of small molecule ligands to small interfering RNAs (siRNAs) and anti-microRNAs results in functional siRNAs and antagomirs in vivo. Here we report on the development of an efficient chemical strategy to make oligoribonucleotide-ligand conjugates using the copper catalyzed azide-alkyne cycloaddition (CuAAC) or click reaction. Three click reaction approaches were evaluated for their feasibility and suitability for high throughput synthesis: the CuAAC reaction at the monomer level prior to oligonucleotide synthesis, the solution-phase postsynthetic "click conjugation", and the "click conjugation" on an immobilized and completely protected alkyne oligonucleotide scaffold. Nucleosides bearing 5'-alkyne moieties were used for conjugation to the 5'-end of the oligonucleotide. Previously described 2'- and 3' O-propargylated nucleosides were prepared to introduce the alkyne moiety to the 3' and 5' termini and to the internal positions of the scaffold. Azido functionalized ligands bearing lipophilic long chain alkyls, cholesterol, oligoamine, and carbohydrate were utilized to study the effect of physicochemical characteristics of the incoming azide on click conjugation to the alkyne oligonucleotide scaffold in solution and on immobilized solid support. We found that microwave-assisted click conjugation of azido-functionalized ligands to a fully protected solid-support bound alkyne-oligonucleotide prior to deprotection was the most efficient "click conjugation" strategy for site-specific, high throughput oligonucleotide conjugate synthesis tested. The siRNA conjugates synthesized using this approach effectively silenced expression of a luciferase gene in a stably transformed HeLa cell line. PMID- 21299240 TI - Effect of aqueous and lipophilic mullet (Mugil cephalus) Bottarga extracts on the growth and lipid profile of intestinal Caco-2 cells. AB - The importance of n-3 polyunsaturated fatty acid (n-3 PUFA) intake has long been recognized in human nutrition. Although health benefits, n-3 PUFA are subject to rapid and/or extensive oxidation during processing and storage, resulting in potential alteration in nutritional composition and quality of food. Bottarga, a salted and semi-dried mullet ( Mugil cephalus ) ovary product, is proposed as an important source of n-3 PUFA, having high levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). In this work, we investigated the extent of lipid oxidation of grated bottarga samples during 7 months of storage at -20 degrees C and room temperature under light exposure. Cell viability, lipid composition, and lipid peroxidation were measured in intestinal differentiated Caco-2 cell monolayers after 6-48 h of incubation with lipid and hydrophilic extracts obtained from bottarga samples at different storage conditions. The storage of bottarga did not affect the n-3 PUFA level, but differences were observed in hydroperoxide levels in samples from different storage conditions. All tested bottarga extracts did not show a toxic effect on cell viability of differentiated Caco-2 cells. Epithelial cells incubated with bottarga oil had significant changes in fatty acid composition but not in cholesterol levels with an accumulation of EPA, DHA, and 22:5. Cell hydroperoxides were higher in treated cells, in relation to the oxidative status of bottarga oil. Moreover, the bottarga lipid extract showed an in vitro inhibitory effect on the growth of a colon cancer cell line (undifferentiated Caco-2 cells). PMID- 21299241 TI - Multifunctional iron-carbon nanocomposites through an aerosol-based process for the in situ remediation of chlorinated hydrocarbons. AB - Spherical iron-carbon nanocomposites were developed through a facile aerosol based process with sucrose and iron chloride as starting materials. These composites exhibit multiple functionalities relevant to the in situ remediation of chlorinated hydrocarbons such as trichloroethylene (TCE). The distribution and immobilization of iron nanoparticles on the surface of carbon spheres prevents zerovalent nanoiron aggregation with maintenance of reactivity. The aerosol-based carbon microspheres allow adsorption of TCE, thus removing dissolved TCE rapidly and facilitating reaction by increasing the local concentration of TCE in the vicinity of iron nanoparticles. The strongly adsorptive property of the composites may also prevent release of any toxic chlorinated intermediate products. The composite particles are in the optimal range for transport through groundwater saturated sediments. Furthermore, those iron-carbon composites can be designed at low cost, the process is amenable to scale-up for in situ application, and the materials are intrinsically benign to the environment. PMID- 21299242 TI - Electronic structure of trioxide, oxoperoxide, oxosuperoxide, and ozonide clusters of the 3d elements: density functional theory study. AB - The trioxide clusters with stoichiometry MO3, and the structural isomers with side-on and end-on bonded oxygen atoms, are studied by DFT with the B1LYP functional. For the first half of the 3d elements row (Sc to Cr), pyramidal or distorted pyramidal structures dominate among the trioxide and oxoperoxide ground states, while the remaining elements form planar trioxides, oxoperoxides, oxosuperoxides, and ozonides. Low-lying trioxide clusters are formed by Ti, V, Cr, and Mn, among which the distorted pyramidal VO3 in the (2)A'' state, the pyramidal CrO3 in the (1)A1 state, and the planar MnO3 in the (2)A1' state are global minima. With the exception of the middle-row elements Mn, Fe, and Co, the magnetic moment of the ground-state clusters is formed with a major contribution from unpaired electrons located at the oxygen atoms. The stability of trioxides and oxoperoxides toward release of molecular oxygen is significantly higher for Sc, Ti, and V than for the remaining elements of the row. A trend of increasing the capability to dissociate one oxygen molecule is observed from Cr to Cu, with the exception of OFe(O2) being more reactive than OCo(O2). A gradual increase of reactivity from Ti to Cu is observed for the complete fragmentation reaction M + O + O2. PMID- 21299243 TI - A facile route to polysubstituted indoles via three-component reaction of 2 ethynylaniline, sulfonyl azide, and nitroolefin. AB - A copper-catalyzed three-component reaction of 2-ethynylaniline, sulfonyl azide, and nitroolefin is reported. This reaction generates functionalized indoles in good yields and proceeds smoothly under mild conditions. Some hits as an HCT-116 inhibitor are found from the preliminary biological screening. PMID- 21299244 TI - Potent farnesyltransferase inhibitors with 1,4-diazepane scaffolds as novel destabilizing microtubule agents in hormone-resistant prostate cancer. AB - A new class of potent farnesyltransferase inhibitors based on a 1,4-diazepane scaffold was synthesized with protein farnesyltransferase inhibition potencies in the low nanomolar range. The compounds block the growth on two hormone-resistant tumor prostatic cell lines (DU145 and PC3). The advanced cellular evaluation of the more potent farnesyltransferase inhibitors was explored and revealed a disorganization of tubulin in PC3 cells. PMID- 21299245 TI - Rapid and reliable measurement for evaluating directly the reactivity of N acetylcysteine with glucose degradation products in peritoneal dialysis fluids. AB - In this report, we analyzed the reactivity of N-acetyl-L-cysteine (NAC) with glucose degradation products (GDPs) and the stability of NAC in peritoneal dialysis fluids (PDFs) using RP-HPLC and LC-ESI-TOF-MS. NAC reduced the amount of 3,4-dideoxyglucosone-3-ene (3,4-DGE), most toxic among GDPs in PDFs by forming NAC-DGE conjugate under nonenzymatic conditions. NAC was retained as a reduced monomer form in the high-glucose compartment of dual-chambered neutral-pH type PDF, whereas it easily formed a homodimer in an incubation-time-dependent manner in other solutions. The present investigation suggests that NAC can be employed as an adjuvant added into the high-glucose compartment of neutral-pH type PDFs (N PDF) to reduce GDP-mediated peritoneal membrane failure in patients on long-term peritoneal dialysis (PD) treatment. PMID- 21299246 TI - Gallic acid induces G2/M phase arrest of breast cancer cell MCF-7 through stabilization of p27(Kip1) attributed to disruption of p27(Kip1)/Skp2 complex. AB - Gallic acid (GA), 3,4,5-trihydroxybenzoic acid, is a natural polyphenolic acid and widely found in gallnuts, tea leaves and various fruits. Previous studies have shown that GA possesses anti-inflammatory, antiallergic and anticarcinogenic activity. In the present study, we aim to investigate the antitumor effects of GA on breast cancer cell. Our results revealed that GA treatment significantly reduced the cell growth of human breast cancer cell MCF-7 in a dose-dependent manner. Further flow cytometric analysis showed that GA induced significant G2/M phase arrest but slightly affected the population of sub-G1MCF-7 cells. Therefore, levels of cyclins, cyclin-dependent kinases (CDKs), and their regulatory proteins involved in S-G2/M transition were investigated. Our findings revealed that levels of cyclin A, CDK2, cyclin B1 and cdc2/CDK1 were diminished; in contrast, levels of the negative regulators p27(Kip1) and p21(Cip1) were increased by GA treatment. Additionally, Skp2, a specific ubiquitin E3 ligase for polyubiquitination of p27(Kip1) was reduced by GA treatment. Further investigation showed that GA attenuated Skp2-p27(Kip1) association and diminished polyubiquitination of p27(Kip1) in MCF-7 cells. Moreover, knockdown of p27(Kip1) but not p21(Cip1) significantly alleviated GA-induced accumulation of G2/M phase. These findings indicate that GA may upregulate p27(Kip1) level via disruption of p27(Kip1)/Skp2 association and the consequent degradation of p27(Kip1) by proteosome, leading to G2/M phase arrest of MCF-7 cell. It is suggested that GA should be beneficial to treatment of breast cancer and p27(Kip1)-deficient carcinomas. PMID- 21299247 TI - Self-directed reconstitution of proteorhodopsin with amphiphilic block copolymers induces the formation of hierarchically ordered proteopolymer membrane arrays. AB - Manipulating recognition and transport at the nanoscale holds great promise for technological breakthroughs in energy conversion, catalysis, and information processing. Living systems evolve specialized membrane proteins (MPs) embedded in lipid bilayers to exquisitely control communications across the insulating membrane boundaries. Harnessing MP functions directly in synthetic systems opens up enormous opportunities for nanotechnology, but there exist fundamental challenges of how to address the labile nature of lipid bilayers that renders them of inadequate value under a broad range of harsh non-biological conditions, and how to reconstitute MPs coherently in two or three dimensions into non-lipid based artificial membranes. Here we show that amphiphilic block copolymers can be designed to direct proteorhodopsin reconstitution and formation of hierarchically ordered proteopolymer membrane arrays spontaneously, even when the membrane forming polymer blocks are in entangled states. These findings unfold a viable approach for the development of robust and chemically versatile nanomembranes with MP-regulated recognition and transport performance. PMID- 21299249 TI - Nanoscale mapping and affinity constant measurement of signal-transducing proteins by atomic force microscopy. AB - Atomic force microscope (AFM) was used to measure the interaction force between two signal-transducing proteins, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Ras homologue enriched in brain (Rheb), and to analyze the binding of glyceraldehyde-3-phosphate (Gly-3-P) to GAPDH. To enhance the recognition efficiency and avoid undesirable multiple interactions, the AFM probe and the substrate were each modified with a dendron, glutathione S-transferase (GST) fused proteins were employed, and reduced glutathione (GSH) was conjugated at the apex of each immobilized dendron. The resulting median specific force between GAPDH and Rheb was 38 +/- 1 pN at a loading rate of 3.7 * 10(3) pN/s. The measurements showed that the GAPDH-Rheb interaction was inhibited by binding of Gly-3-P. An adhesion force map showed individual GADPHs on the surface and that the number density of GAPDH decreased with the concentration of Gly-3-P. Maps obtained in the presence of various Gly-3-P concentrations provided information on the binding behavior, yielding a thermodynamic association constant of 2.7 * 10(5) M(-1). PMID- 21299248 TI - Structural and metal binding characterization of the C-terminal metallochaperone domain of membrane fusion protein SilB from Cupriavidus metallidurans CH34. AB - Detoxification of heavy metal ions in Proteobacteria is tightly controlled by various systems regulating their sequestration and transport. In Cupriavidus metallidurans CH34, a model organism for heavy metal resistance studies, the sil determinant is potentially involved in the efflux of silver and copper ions. Proteins SilA, SilB, and SilC form a resistance nodulation cell division (RND) based transport system in which SilB is the periplasmic adaptor protein belonging to the membrane fusion protein (MFP) family. In addition to the four domains typical of known MFPs, SilB has a fifth additional C-terminal domain, called SilB(440-521), which is characterized here. Structure and backbone dynamics of SilB(440-521) have been investigated using nuclear magnetic resonance, and the residues of the metal site were identified from (15)N- and (13)C-edited HSQC spectra. The solution structure and additional metal binding experiments demonstrated that this C-terminal domain folds independently of the rest of the protein and has a conformation and a Ag(+) and Cu(+) binding specificity similar to those determined for CusF from Escherichia coli. The small protein CusF plays a role in metal trafficking in the periplasm. The similarity with CusF suggests a potential metallochaperone role for SilB(440-521) that is discussed in the context of simultaneous expression of different determinants involved in copper resistance in C. metallidurans CH34. PMID- 21299250 TI - Mannosylated dextran derivatives labeled with fac-[M(CO)3]+ (M = (99m)Tc, Re) for specific targeting of sentinel lymph node. AB - Despite being widely used in the clinical setting for sentinel lymph node detection (SLND), (99m)Tc-based colloids (e.g., (99m)Tc-human serum albumin colloids) present a set of properties that are far from ideal. Aiming to design novel compounds with improved biological properties, we describe herein the first class of fully characterized (99m)Tc(CO)3-mannosylated dextran derivatives with adequate features for SLND. Dextran derivatives, containing the same number of pendant mannose units (13) and a variable number (n) of tridentate chelators (9, n = 1; 10, n = 4, 11, n= 12), have been synthesized and fully characterized. Radiolabeled polymers of the type fac-[(99m)Tc(CO)3(k3-L)] (12, L = 9, 13, L = 10, 14, L = 11) have been obtained quantitatively in high radiochemical purity (>= 98%) upon reaction of the dextran derivatives with fac-[(99m)Tc(CO)3(H2O)3]+. The highly stable compounds 13 and 14 were identified by comparing their HPLC chromatograms with the ones obtained for the corresponding rhenium surrogates fac [Re(CO)3(k3-10)] (13a) and fac-[Re(CO)3(k3-11)] (14a), which have been characterized both at the chemical (NMR and IR spectroscopy, and HPLC) and physical level (DLS, AFM and LDV). Compounds 13a and 14a present a positive zeta potential (+ 7.1 mV, pH 7.4) and a hydrodynamic diameter in the range 8.4-8.7 nm. Scintigraphic imaging and biodistribution studies in Wistar rats have shown good accumulation in the sentinel node at 60 min postinjection (6.71 +/- 2.35%, 13; and 7.53 +/- 0.69%, 14), with significant retention up to 180 min. A clear delineation of the sentinel lymph node without significant washout to other regions was observed in the scintigraphic images. The popliteal extraction of 94.47 +/- 2.45% for 14 at 1 h postinjection, as compared to 61.81 +/- 2.4% for 13, indicated that 14 is a very promising compound to be further explored as SLN imaging agent. PMID- 21299251 TI - Nuclear shieldings with the SSB-D functional. AB - The recently reported SSB-D functional [J. Chem. Phys. 2009, 131, 094103] is used to check the performance for obtaining nuclear magnetic resonance (NMR) shielding constants. Four different databases were studied, which contain a diversity of molecules and nuclear shielding constants. The SSB-D functional is compared with its "parent" functionals (PBE, OPBE), the KT2 functional that was designed specially for NMR applications and the coupled cluster CCSD(T) method. The best performance for the experimentally most-used elements ((1)H, (13)C) is obtained for the SSB-D and KT2 functionals. PMID- 21299252 TI - Solvent dependence of absorption intensities and wavenumbers of the fundamental and first overtone of NH stretching vibration of pyrrole studied by near infrared/infrared spectroscopy and DFT calculations. AB - Near-infrared (NIR) and IR spectra were measured for pyrrole in CCl(4), CHCl(3), and CH(2)Cl(2) to study solvent dependence of absorption intensities and wavenumbers of the fundamental and first overtone of NH stretching vibration. It was found that the wavenumbers of the NH fundamental and its first overtone decrease in the order of CCl(4), CHCl(3), and CH(2)Cl(2), which is the increasing order for of the dielectric constant of the solvents. Their absorption intensities increase in the same order, and the intensity increase is more significant for the fundamental than the overtone. These results for the solvent dependence of the wavenumbers and absorption intensities of NH stretching bands of pyrrole are quite different from those due to the formation of hydrogen bonds. Quantum chemical calculations of the wavenumbers and absorption intensities of NH stretching bands by using the 1D Schrodinger equation based on the self consistent reaction field (SCRF)/isodensity surface polarized continuum model (IPCM) suggest that the decreases in the wavenumbers of both the fundamental and the overtone of the NH stretching mode with the increase in the dielectric constant of the solvents arise from the anharmonicity of vibrational potential and their intensity increases come from the gradual increase in the slope of the dipole moment function. PMID- 21299253 TI - Development of a sensitive Indirect Competitive Enzyme-Linked Immunosorbent Assay (ic-ELISA) based on the monoclonal antibody for the detection of the imidaclothiz residue. AB - An indirect competitive enzyme-linked immunosorbent assay (ic-ELISA) based on monoclonal antibodies (MoAbs) for imidaclothiz was developed. The hapten of imidaclothiz was synthesized and conjugated to bovine serum albumin (BSA) and ovalbumin (OVA) to form the artificial antigens. MoAbs were obtained by immunizing BALB/c mice. Under the optimized conditions (10% methanol, 0.14 M Na(+), and pH 7.4), the half-maximal inhibition concentration (IC(50)) was 0.0875 +/- 0.0034 mg/L and the limit of detection (IC(20)) was 0.0178 +/- 0.0018 mg/L for imidaclothiz. There were no obvious cross-reactivities with most of the structural analogues of neonicotinoid insecticides, except imidacloprid. The recoveries of imidaclothiz in environmental and agricultural samples, including tap water, paddy water, soil, and cabbage, ranged from 80.43 to 113.83%, well within the requirements of residue detection. These results showed that this immunoassay could be used for the determination of imidaclothiz in environmental and agricultural samples. PMID- 21299255 TI - Norman Garmezy (1918-2009). AB - Norman Garmezy, a pioneer in research on risk and resilience, died in Nashville, Tennessee, on November 21, 2009, at the age of 91. He was a legendary mentor as well as an eminent scientist in clinical psychology. Norm was born on June 18, 1918, in New York City and grew up in the Bronx in a Jewish neighborhood where educational attainment was highly valued. The scientific study of resilience as conceived by Norman Garmezy, his peers, and students has transformed the science and practice of multiple disciplines, from the molecular level to the global ecosystem, infusing a strength-based and recovery-oriented approach into psychology, education, social work, and psychiatry. Current research on resilience ranges from studies of plasticity in brain development to effective planning for resilience in the context of disaster. Norm's influential ideas and research earned him international acclaim and many honors for lifetime achievements in science. Throughout his career, Norm held many leadership roles. Throughout his life, Norm spoke with great love about his wife of 63 years, Edie Garmezy (who died just months before him in 2009), and their children. In addition to his work and his family, Norm had three abiding passions-theater, movies, and politics. During the last two decades of his life, Norm and those who loved him endured his long decline from Alzheimer's, which slowly stole his brilliant mind and hilarious sense of humor. Nonetheless, the incredible spirit and humanity of this giant scholar continued to shine through this terrible disease. To the end of his life, Norm's face would light up with a smile as he greeted the people he loved, and he would often exclaim, "Wonderful!" Norman Garmezy was a remarkable person and scholar who left an extraordinary legacy of love and work to inspire future generations in their efforts to understand and promote the human capacity for competence and resilience. PMID- 21299254 TI - Pleiotropic effects of sevelamer beyond phosphate binding in end-stage renal disease patients: a randomized, open-label, parallel-group study. AB - BACKGROUND AND OBJECTIVE: Hyperphosphataemia in end-stage renal disease (ESRD) is a major contributor to the development of cardiovascular disease. It has been proposed that the phosphate binder sevelamer has pleiotropic properties. The aim of this study was to evaluate the effects of sevelamer compared with calcium acetate on serum lipid profiles, uric acid and reactive oxygen species in haemodialysis patients with hyperphosphataemia. METHODS: An 8-week, randomized, open-label, parallel-group study was conducted after a 2-week washout period. A total of 52 patients with ESRD on maintenance haemodialysis were screened for enrolment; 26 patients were randomized to each of the sevelamer and calcium acetate groups. Reactive oxygen species (ROS) production, i.e. superoxide and hydrogen peroxide (H2O2)-related radicals, were detected by chemiluminescence measurement with lucigenin and luminol, respectively. RESULTS: There were no significant differences between treatment groups in changes in serum phosphorus (p=0.378) and adjusted serum calcium levels (p=0.980), but there were more hypercalcaemic events in the calcium acetate group (12.0% vs 3.7%) during treatment. Total serum cholesterol (p<0.001) and low-density lipoprotein (LDL) cholesterol (p<0.001) levels decreased significantly compared with baseline in the sevelamer group. The decreases in total serum cholesterol and LDL cholesterol were correlated with the reductions in serum phosphorus levels during sevelamer treatment (correlation coefficient [r]=0.266 and 0.386, respectively). Serum uric acid decreased significantly in the sevelamer group (p=0.020), and this change was correlated with serum phosphorus changes (r=0.458). Decreases in plasma H2O2 related radicals, the major oxidative stressor in ROS (p<0.001), but not superoxide (p=0.593), were observed after sevelamer treatment. CONCLUSION: The improvements in multiple lipid surrogates, uric acid and ROS seen in this study show that sevelamer is a promising therapy for treatment of hyperphosphataemia in maintenance haemodialysis patients with a high risk of cardiovascular disease. PMID- 21299262 TI - Methods and mechanisms in the efficacy of psychodynamic psychotherapy. AB - Comments on the original article, "The efficacy of psychodynamic psychotherapy," by J. Shedler (see record 2010-02208-012). Shedler summarized a large body of research that shows psychodynamic therapy to have a substantial effect size, comparable to that for many empirically supported treatments. This is an important finding, in part refuting the concerns raised by Bornstein (2001, 2002) regarding the future of psychodynamic approaches had there been no substantial changes in how practitioners and researchers approached the science to demonstrate efficacy. Further, Shedler showed that the efficacy of psychoanalytic psychotherapy is due to therapeutic methods commonly employed in cognitive behavior therapy (CBT), one of the most frequently cited empirically supported approaches for a wide range of psychological conditions. From a methodological perspective, there are some important limitations to the claim of psychodynamic psychotherapy's comparable efficacy to other empirically supported approaches. PMID- 21299263 TI - Is there room for criticism of studies of psychodynamic psychotherapy? AB - Comments on the original article, "The efficacy of psychodynamic psychotherapy," by J. Shedler (see record 2010-02208-012). Shedler declared unequivocally that "empirical evidence supports the efficacy of psychodynamic therapy" (p. 98). He did not mention any specific criticisms that have been made of evidence on psychodynamic psychotherapies or address possible distinctions between evidence for short-term versus long-term psychodynamic psychotherapies. Instead, he attributed dissenting views to biases in evidence dissemination and review, which he suggested are rooted in a "lingering distaste in the mental health professions professions for past psychoanalytic arrogance and authority" related to a "hierarchical medical establishment that denied training to non-MDs and adopted a dismissive stance toward research" (Shedler, 2010, p. 98). Shedler (2010) justified his blanket dismissal of criticisms of evidence supporting psychodynamic psychotherapy on the basis of several published meta-analyses. The validity of conclusions from metaanalyses depends on the quality of the evidence synthesized, the nature of the studies included, and the rigor of the statistical analyses employed. Many meta-analyses, however, are not performed rigorously, which can result in treatment efficacy estimates that obscure important intertrial differences and that are unlikely to be replicated in clinical practice. PMID- 21299264 TI - When it comes to evaluating psychodynamic therapy, the devil is in the details. AB - Comments on the original article, "The efficacy of psychodynamic psychotherapy," by J. Shedler (see record 2010-02208-012). As Shedler noted, some researchers have reflexively and stridently dismissed psychodynamic therapy (PT) as ineffective without granting outcome studies on this modality a fair hearing. We applaud Shedler's efforts to bring PT into the scientific mainstream and hope that his article encourages investigators to evaluate claims regarding PT's efficacy with a more objective eye. Nevertheless, as Shedler also observed, one reason for the scientific community's premature dismissal of PT is traceable to some psychodynamic practitioners' historical antipathy toward controlled research and propensity to overstate PT's efficacy. Regrettably, Shedler falls prey to the latter error by glossing over key methodological details, ignoring crucial findings that run counter to his position, and overstating the quality and quantity of the evidence base for PT. Because of space constraints, we focus only on a handful of the more serious shortcomings of Shedler's analysis (a more complete review of these issues is available from the first author on request). PMID- 21299265 TI - No ownership of common factors. AB - Comments on the original article, "The efficacy of psychodynamic psychotherapy," by J. Shedler (see record 2010-02208-012). Shedler's informative article raised several issues worthy of comment. His choice of the word distinctive (p. 98) in describing aspects of psychodynamic technique is open to at least two interpretations. On the one hand, distinctive can have a qualitative meaning and indicate the presence of a characteristic that is not shared. For example, a sign in the Bronx Zoo distinguishes birds from all other creatures as follows: "If it has feathers it's a bird, if it doesn't, it isn't." On the other hand, distinctive can have a quantitative meaning and indicate that one practice has more of a common element than another practice. Careful reading of Shedler's article and the article by Blagys and Hilsenroth (2000) that forms the basis of the "seven features [that] reliably distinguished psychodynamic therapies from other therapies" (Shedler, 2010, p. 98) shows that Shedler subscribes to the latter, quantitative, definition of distinctive. In other words, the seven features he presented are present in both psychodynamic therapies and the cognitive-behavioral therapies to which he compares them. For example, although Shedler did not mention it, dialectical behavior therapy explicitly focuses on six of the seven features, namely, "focus on affect and expression of emotion," "exploration of attempts to avoid distressing thoughts and feelings," "identification of recurring themes and patterns," "discussion of past experience," "focus on interpersonal relations," and "focus on the therapy relationship" (Shedler, 2010, p. 99). However, in the articles that Blagys and Hilsenroth reviewed, psychodyamic therapists engaged in more of these behaviors than did cognitive-behavioral therapists. PMID- 21299267 TI - Integrative perspectives on acculturation. AB - Comments on the original article, "Rethinking the concept of acculturation: Implications for theory and research," by S. J. Schwartz, J. B. Unger, B. L. Zamboanga, and J. Szapocznik (see record 2010-08987-001). Schwartz et al are to be commended for their attempts "to propose an expanded, multidimensional model of acculturation and of the demographic and contextual forces that can influence the acculturation process" (p. 238). In their article, they called attention to key factors such as the generational status of immigrants and their children; the role of location, particularly in ethnic enclaves; and the context of reception that immigrants enter, including the potential discrimination they may face. These variables are the crucial backdrop for the authors' call to "focus on the higher order construct of receiving-culture acquisition as well as on the individual dimensions of this higher order construct-practices, values, and identifications" (p. 246). As a sociologist trained in social psychology, I am pleased by their incorporation of some of the sociological literature on these processes. However, I was surprised by important gaps in their discussion of Portes and Rumbaut's (1996, 2006) work and by their neglect of one of the most widely used terms employed by sociologists to hypothesize outcomes for the very questions Schwartz et al were posing. PMID- 21299269 TI - Dynamical systems and Jung, with a note on language. AB - Comments on the original article "Rethinking intractable conflict: The perspective of dynamical systems," by R. R. Vallacher, P. T. Coleman, A. Nowak, and L. Bui-Wrzosinska (see record 2010-08987-003). Vallacher et al presented an intriguing description of dynamical systems theory as applied to the understanding of intractable conflicts ranging from the intrapsychic to the international. It seems clear from the authors' text that the term hysteresis (p. 267) was not their coinage but came from the mathematical history of dynamical systems theory. The concept is fascinating: A single-time measure of an event in a dynamical system is meaningless without knowledge of the whole status of the system, its history, and the current direction of periodic cycles maintained by the system's attractors. Unfortunately, the sound of the term is reminiscent of "hysteria," as if it included notions of feminine unpredictability, periodicity, and emotional catastrophe. Scholars of ancient Greek may find etymological counterweights to this concern, but the use of the word in today's literature runs the risk of intractable conflict with feminist theorists, whose justifiable objection should be intense. I propose the terms bivalence for hysteresis, trivalence when there are three attractors, and so on, up to multivalence for complex systems. PMID- 21299270 TI - Work gets unfair for the depressed: cross-lagged relations between organizational justice perceptions and depressive symptoms. AB - The organizational justice literature has consistently documented substantial correlations between organizational justice and employee depression. Existing theoretical literature suggests this relationship occurs because perceptions of organizational (in)justice lead to subsequent psychological health problems. Building on recent research on the affective nature of justice perceptions, in the present research we broaden this perspective by arguing there are also theoretical arguments for a reverse effect whereby psychological health problems influence perceptions of organizational justice. To contrast both theoretical perspectives, we test longitudinal lagged effects between organizational justice perceptions (i.e., distributive justice, interactional justice, interpersonal justice, informational justice, and procedural justice) and employee depressive symptoms using structural equation modeling. Analyses of 3 samples from different military contexts (N1 = 625, N2 = 134, N3 = 550) revealed evidence of depressive symptoms leading to subsequent organizational justice perceptions. In contrast, the opposite effects of organizational justice perceptions on depressive symptoms were not significant for any of the justice dimensions. The findings have broad implications for theoretical perspectives on psychological health and organizational justice perceptions. PMID- 21299271 TI - Cognition-based and affect-based trust as mediators of leader behavior influences on team performance. AB - We develop a model in which cognitive and affective trust in the leader mediate the relationship between leader behavior and team psychological states that, in turn, drive team performance. The model is tested on a sample of 191 financial services teams in Hong Kong and the U.S. Servant leadership influenced team performance through affect-based trust and team psychological safety. Transformational leadership influenced team performance indirectly through cognition-based trust. Cognition-based trust directly influenced team potency and indirectly (through affect-based trust) influenced team psychological safety. The effects of leader behavior on team performance were fully mediated through the trust in leader variables and the team psychological states. Servant leadership explained an additional 10% of the variance in team performance beyond the effect of transformational leadership. We discuss implications of these results for research on the relationship between leader behavior and team performance, and for efforts to enhance leader development by combining knowledge from different leadership theories. PMID- 21299272 TI - Gestalt principles in the control of motor action. AB - We argue that 4 fundamental gestalt phenomena in perception apply to the control of motor action. First, a motor gestalt, like a perceptual gestalt, is holistic in the sense that it is processed as a single unit. This notion is consistent with reaction time results indicating that all gestures for a brief unit of action must be programmed prior to initiation of any part of the movement. Additional reaction time results related to initiation of longer responses are consistent with processing in terms of a sequence of indivisible motor gestalts. Some actions (e.g., many involving coordination of the hands) can be carried out effectively only if represented as a unitary gestalt. Second, a perceptual gestalt is independent of specific sensory receptors, as evidenced by perceptual constancy. In a similar manner a motor gestalt can be represented independently of specific muscular effectors, thereby allowing motor constancy. Third, just as a perceptual pattern (e.g., a Necker cube) is exclusively structured into only 1 of its possible configurations at any moment in time, processing prior to action is limited to 1 motor gestalt. Fourth, grouping in apparent motion leads to stream segregation in visual and auditory perception; this segregation is present in motor action and is dependent on the temporal rate. We discuss congruence of gestalt phenomena across perception and motor action (a) in relation to a unitary perceptual-motor code, (b) with respect to differences in the role of awareness, and (c) in conjunction with separate neural pathways for conscious perception and motor control. PMID- 21299273 TI - Looking beyond the boundaries: time to put landmarks back on the cognitive map? AB - Since the proposal of Tolman (1948) that mammals form maplike representations of familiar environments, cognitive map theory has been at the core of debates on the fundamental mechanisms of animal learning and memory. Traditional formulations of cognitive map theory emphasize relations between landmarks and between landmarks and goal locations as the basis of the map. More recently, several models of spatial coding have taken the boundaries of an environment as the basis of the cognitive map, with landmark relations being processed through alternative, operant learning mechanisms. In this review, the evidence for this proposed dichotomy is analyzed. It is suggested that 2 factors repeatedly confound efforts to compare spatial coding based on landmark arrays, formed by 2 or more landmarks, and that based on the boundaries of an environment. The factors are the perceived stability of the landmark arrays and their placement relative to the larger environment. Although the effects of landmark stability and of placement on spatial navigation have been studied extensively, the implications of this work for debates concerning the role of boundaries in cognitive map formation have not been fully realized. It is argued that when these 2 factors are equated between landmark arrays and bounded environments, current evidence supports a commonality of spatial coding mechanism rather than a dichotomy. The analysis places further doubt on the existence of a dedicated geometric module for reorientation and is consistent with models of navigation containing mapping and operant learning components, both taking as input local views (Sheynikhovich et al., 2009). PMID- 21299274 TI - Telephone-administered cognitive behavioral therapy for veterans served by community-based outpatient clinics. AB - OBJECTIVE: Multiple trials have found telephone-administered cognitive behavioral therapy (T-CBT) to be effective for the treatment of depression. The aim of this study was to evaluate T-CBT for the treatment of depression among veterans served by community-based outpatient clinics (CBOCs) outside of major urban areas. METHOD: Eighty-five veterans meeting Diagnostic and Statistical Manual of Mental Disorders (4th ed.; American Psychiatric Association, 1994) criteria for major depressive disorder were randomized to receive 16 sessions of T-CBT over 20 weeks or treatment as usual through the CBOC. Veterans were assessed at baseline, 12 weeks, 20 weeks (posttreatment), and 6-month follow-up using the Hamilton Depression Rating Scale (Hamilton, 1960), the Patient Health Questionnaire-9 (Kroenke, Spitzer, & Williams, 2001), and a standardized psychiatric interview. RESULTS: There were no significant Time * Treatment effects (ps > .20). Patients were compliant, with 38 (92.7%) completing at least 12 sessions, and 32 (78.0%) having no missed sessions whatsoever. Ratings of audiotaped sessions showed the therapists to be highly competent. CONCLUSIONS: This trial yielded negative results for an intervention that has been shown to be effective under other circumstances. We speculate that veterans served within the Veterans Affairs system are more refractory to treatment than other populations, and they may require a more rigorous intervention. TRIAL REGISTRATION: clinicaltrials.gov NCT00223652. PMID- 21299275 TI - Relational benefits of relational aggression: adaptive and maladaptive associations with adolescent friendship quality. AB - Two longitudinal studies examined associations between relational aggression and friendship quality during adolescence. In Study 1, 62 adolescents in Grades 6 (25.8%), 7 (32.3%), and 8 (41.9%) completed assessments of friendship affiliations, relational and overt aggression, and friendship quality at 2 time points, 1 year apart. Results using actor partner interdependence modeling indicated that high levels of relational aggression predicted increases in self reported positive friendship quality 1 year later. In Study 2, 56 adolescents in Grades 9 (66.7%) and 10 (33.3%) attended a laboratory session with a friend in which their conversations were videotaped and coded for relationally aggressive talk. Target adolescents completed measures of positive and negative friendship quality during the laboratory session and during a follow-up phone call 6 months later. Analyses revealed that high levels of relationally aggressive talk at Time 1 predicted increases in negative friendship quality 6 months later. In addition, among adolescents involved in a reciprocal best friendship, high levels of observed relationally aggressive talk predicted increases in positive friendship quality over time. Taken together, these studies provide support for the idea that relational aggression may be associated with adaptive as well as maladaptive outcomes within the dyadic context of adolescent friendship. PMID- 21299276 TI - A special issue on the patient-centered medical home. AB - This special issue on the Patient-Centered Medical Home (PCMH) reflects its times. At the present time, the PCMH is an aspirational model with a few pilots functioning well around the country. How long the current period of idealism, fueled by the energy of early adopters, the consensus of diverse stakeholders, and the dollars of the Affordable Care Act will continue is anybody's guess. Representing the thinking of some of the best minds in the field, the articles in this issue have an aspirational and idealistic tone as much as a descriptive and analytic one. A year ago the balance would have been tipped more toward idealism and model building and a year from now it would, in all likelihood, tip more toward model description and analysis. The authors in this volume have been personally responsible for helping to move behavioral health to a more central position in the PCMH model. PMID- 21299277 TI - Attending to the whole person in the patient-centered medical home: the case for incorporating mental healthcare, substance abuse care, and health behavior change. AB - The foundation of the U.S. healthcare system is faulty, and the consequences have become inescapable (Committee of Quality of Health Care in America, 2001). We are first among nations in spending on healthcare, whether measured in absolute dollars, per capita expenditures, or proportion of our national budget. Yet our citizens are the least healthy in the developed world. (Anderson & Hussey, 2001) Our nation's healthcare system is simply not a high-quality system. This shortfall is serious enough to cause tens of thousands of unnecessary deaths each year and to compromise our capacity for further economic growth (Anderson & Hussey, 2001; Anderson, Frogner, Johns, & Reinhardt, 2006; Macinko, Starfield, & Shi, 2003), yet it ramifies into so many of our political, financial, and social institutions that change is difficult and fraught with serious unintended consequences. PMID- 21299278 TI - Operational and clinical components for integrated-collaborative behavioral healthcare in the patient-centered medical home. AB - Behavioral healthcare will be an essential piece of meeting the patient-centered medical home (PCMH) principles of easy access and whole person, coordinated, and integrated care as primary care clinics transform themselves into PCMHs. As this transformation occurs, PCMH clinic staff and behavioral health providers must carefully consider how to adapt their operations to include the provision of integrated-collaborative behavioral health services within the PCMH. Without this careful consideration, integrated-collaborative behavioral healthcare will likely fail to reach its full potential. We discuss the operational and clinical components that appear to be important for success when integrating behavioral healthcare into the PCMH. PMID- 21299279 TI - Building a medical home around the patient: what it means for behavior. AB - A great deal has already been written on "patient-centered health care." This article aims to organize and make readily visible some of that work in context of the "patient-centered medical home" (PCMH). Patient-centered provider and patient behaviors are both required if PCMH is to become a successful innovation in practice. These behaviors are shown together on one page as dimensions of patient centeredness. A medical home that achieves patient-centered results will require different behaviors and attitudes from both patients and providers. PMID- 21299280 TI - Creating collaborative learning environments for transforming primary care practices now. AB - The renewal of primary care waits just ahead. The patient-centered medical home (PCMH) movement and a refreshing breeze of collaboration signal its arrival with demonstration projects and pilots appearing across the country. An early message from this work suggests that the development of collaborative, cross-disciplinary teams may be essential for the success of the PCMH. Our focus in this article is on training existing health care professionals toward being thriving members of this transformed clinical care team in a relationship-centered PCMH. Our description of the optimal conditions for collaborative training begins with delineating three types of teams and how they relate to levels of collaboration. We then describe how to create a supportive, safe learning environment for this type of training, using a different model of professional socialization, and tools for building culture. Critical skills related to practice development and the cross-disciplinary collaborative processes are also included. Despite significant obstacles in readying current clinicians to be members of thriving collaborative teams, a few next steps toward implementing collaborative training programs for existing professionals are possible using competency-based and adult learning approaches. Grasping the long awaited arrival of collaborative primary health care will also require delivery system and payment reform. Until that happens, there is an abundance of work to be done envisioning new collaborative training programs and initiating a nation-wide effort to motivate and reeducate our colleagues. PMID- 21299281 TI - Comprehensiveness and continuity of care and the inseparability of mental and behavioral health from the patient-centered medical home. AB - Comprehensiveness and continuity of care are key elements of primary care system redesign. Comprehensiveness encompasses evaluating the whole person and dealing with the full range of physical, mental, and behavioral healthcare issues; and continuity is based on building healing relationships over time. This article suggests that a focus on comprehensiveness and continuity implies that responding to mental health, behavioral health, and substance use must be core elements of the patient-centered medical home. A list of necessary next steps toward achieving comprehensive and integrated care is recommended. PMID- 21299282 TI - A purveyor team's experience: lessons learned from implementing a behavioral health care program in primary care settings. AB - A growing body of literature indicates that evidence-based behavioral health practices and programs are not being implemented into clinical settings effectively. As a result, many adolescents living with a behavioral health problem are not receiving the quality of services they need. This feasibility study addressed this science-to-service gap through the implementation of an evidence-based adolescent behavioral health screening, assessment, and brief intervention protocol in five distinct primary care settings. This case study documents the authors' experiences in utilizing Fixsen, Naoom, Blase, Friedman, and Wallace's (2005) implementation framework to guide their purveyor efforts, and outlines solutions to overcoming the challenges purveyors may face when implementing evidence-based programs into primary care. PMID- 21299283 TI - Therapeutic assessment of families in healthcare settings: a case presentation of the model's application. AB - In this article, we present a case study of a Therapeutic Assessment (TA) with an 11-year-old boy who had two unexplained behavioral episodes suggesting neurological impairment, which led to two emergency department visits at a children's hospital. TA is a semistructured approach that blends the extensive conceptualizing benefits of psychological assessment with the principles and techniques of evidence-based child and family interventions. We use this case to illustrate how TA is an adaptive and flexible approach to child-centered family assessment that can meet the goals of psychologists working in pediatric and general medical hospitals, primary care clinics, family medicine practices, and other health care settings. With the current case, the clinician was able to use the procedures of TA to clarify for the family their son's unexplained behaviors, while also providing them with a therapeutic experience. In addition to addressing the family's concerns, the clinician also addressed a number of specific questions provided by the referring neurologist that informed ongoing care of the child. This case illustrates the potential utility and effectiveness of the TA model with children and families referred to a typical psychology service in a health care setting. This case is one of the first applications of the TA model with this population and its success suggests further research in this area is warranted. PMID- 21299284 TI - Collaborative care needs a more active policy voice. AB - If you are reading this, there is a high likelihood you think collaborative care, or, the integration of mental health and physical health systems, is important to healthcare delivery and healthcare policy. Despite over 30 years of work, broad federal and state policy has been slow to adopt specific integration strategies that allow for more tightly coordinated, comprehensive whole-person care (Butler et al., 2008; Collins, Hewson, Munger, & Wade, 2010; Institute of Medicine, 2001; Institute of Medicine 2006). In the last year, policy shifts have brought integrated or collaborative care into the spotlight, but there is very little history of formal policy discussion in this area to guide progress. If FSH is to impact healthcare policy, enhance the quality of care, and move the healthcare system toward team-based collaborative care, we need more policy statements and discussions grounded in the research. By publishing these types of articles, FSH can help the collaborative care community be more influential in healthcare policy. PMID- 21299289 TI - Psychological and physical health at age 70 in the Lothian Birth Cohort 1936: links with early life IQ, SES, and current cognitive function and neighborhood environment. AB - OBJECTIVE: Researchers in many fields are interested in the robust observation that higher socioeconomic status (SES) is associated with better mental and physical health. Prominent explanations for the association involve effects of stress due to relative material and social adversity in lower socioeconomic environments, but early-life intelligence may also contribute directly to both later-life socioeconomic status and health. Here, we evaluated the effects of early-life IQ on mental and physical health outcomes at age 70, in the context of effects of SES. DESIGN: The Lothian Birth Cohort of 1936 took part in the Scottish Mental Survey of 1947, providing a measure of IQ at age 11. They have been extensively surveyed at age 70. MAIN OUTCOME MEASURES: Body mass index, constraints on daily life activities, hospital anxiety and depression, number of diseases, level of physical activity, weekly units of alcohol consumption, and pack-years of smoking. RESULTS AND CONCLUSION: SES had apparently direct effects on most outcomes, but age 11 IQ was also involved in several, either directly or because it contributed to SES. Several interactions helped to integrate these associations. High age-11 IQ tended to buffer effects of adverse environments on physical and mental problems in old age. PMID- 21299290 TI - How and for whom are decision aids effective? Long-term psychological outcome of a randomized controlled trial in women with newly diagnosed breast cancer. AB - OBJECTIVE: The current study evaluates the long-term psychological impact of a decision aid intervention for surgical and systemic treatment in women with newly diagnosed breast cancer from a previous reported randomized, controlled trial (Vodermaier et al., 2009). METHODS: Patients (n = 111) were randomized into usual care, or a 20-min decision aid intervention plus an information brochure prior to consultation planning with the senior physician. The retention rate at 1 year was 88%. RESULTS: Linear mixed model analyses demonstrated that the intervention group experienced less decisional conflict (p = .047; d = .19), which was driven by perceptions of a more effective choice (p = .029; d = .20) over time. Subgroup analyses revealed that patients in the intervention group who participated in chemotherapy decision making showed better long-term body image outcomes (p = .009; d = .44), which were mediated by reduced depressive coping (p = .049). No effects emerged for anxiety and depressive symptoms, or for quality of life. Internal health locus of control moderated group effects on 'uncertainty with the decision' (p = .003). CONCLUSIONS: The study results provide novel evidence on the role of individual differences and the mechanisms behind decision aid effectiveness, and demonstrate the long-term impact of decision aid interventions on some indices of well-being. PMID- 21299291 TI - Stress buffering effects of daily spousal support on women's daily emotional and physical experiences in the context of breast cancer concerns. AB - OBJECTIVE: This study examined whether the relationship between daily spousal support and daily psychological and physical outcomes varied as a function of level of breast cancer related concern (stress buffering model). DESIGN: Ninety five women with early stage breast cancer completed daily reports of emotional and physical experiences and satisfaction with spousal support for 30 days. Women also rated problems dealing with three types of cancer specific concerns: emotional, physical, and social. MAIN OUTCOME MEASURES: Women's positive and negative affect and cancer related pain and fatigue. RESULTS: Multilevel analyses supported a stress buffering effect for social concerns and a reverse stress buffering effect for emotional and physical concerns. CONCLUSION: Daily spousal support appears to be an important contributor to the daily emotional and physical wellbeing of women with breast cancer. Contrary to the tenets of the stress buffering model, these data suggest that the buffering effect of spousal support is attenuated when breast cancer related emotional and physical concerns reach high levels. PMID- 21299292 TI - Changes in functional health, changes in medication beliefs, and medication adherence. AB - OBJECTIVE: Medication adherence often lies below recommendations although it is crucial for effective therapies, particularly in older adults with multiple illnesses. Medication beliefs are important factors for individual adherence, but little is known about their origin. We examine whether changes in functional health predict changes in medication beliefs, and whether such changes in beliefs predict subsequent medication adherence. DESIGN: At three points in time over a 6 month period, 309 older adults (65-85 years) with multiple illnesses were assessed. Latent true change modeling was used to explore changes in functional health and medication beliefs. Adherence was regressed on changes in beliefs. MAIN OUTCOME MEASURES: Medication beliefs were measured by the Beliefs About Medicines Questionnaire; medication adherence by the Reported Adherence to Medication Scale. RESULTS: Functional health and medication beliefs changed over time. Increasing physical limitations predicted increases in specific necessity and specific concern beliefs, but not in general beliefs. Changes in specific necessity beliefs predicted intentional adherence lapses, changes in general overuse beliefs predicted unintentional adherence lapses. CONCLUSIONS: Medication beliefs partly depend on health-related changes, and changes in beliefs affect individual adherence, suggesting to target such beliefs in interventions and to support older adults in interpreting health changes. PMID- 21299293 TI - Racial differences in eligibility and enrollment in a smoking cessation clinical trial. AB - OBJECTIVE: The purpose of this study was to compare the recruitment, eligibility screening, and enrollment of African American and White smokers into an intensive smoking cessation intervention trial [The Chicago STOP Smoking Trial (C-STOP)]. METHODS: We compared demographic, smoking, substance use, and medical/psychiatric screening data from the recruitment records of 1,189 non-Hispanic, African American and White smokers screened for eligibility in the last year of a randomized pharmacological and behavioral smoking cessation trial. The study took place at a large urban medical center and two satellite locations within the Chicago metropolitan area. RESULTS: Interest levels in the study were high among African American smokers, with twice as many African Americans as Whites contacting study staff for information and an initial screening. However, African Americans were nearly three times as likely not to be enrolled in the trial as Whites, because of higher ineligibility rates, failure to attend a screening session, and lower participation rates even among those meeting eligibility requirements. CONCLUSIONS: Racial differences were observed nearly at all levels of enrollment determination. These critical barriers to inclusion of African Americans in smoking cessation research limit our understanding of treatment efficacy and ultimately the ability to reduce the health disparities in tobacco related disease experienced by African Americans. PMID- 21299294 TI - A randomized, controlled trial of adding expired carbon monoxide feedback to brief stop smoking advice: evaluation of cognitive and behavioral effects. AB - OBJECTIVE: To determine the effect of adding biomarker feedback (expired air carbon monoxide) to standard quit advice on cognitive antecedents of behavior change and smoking cessation and to identify potential effect moderators and mediators. DESIGN: Smokers (N = 160) were randomized to a control (quit advice plus leaflet) or an intervention condition (as control group plus carbon-monoxide level feedback). Cognitive measures were assessed immediately after the intervention and behavioral measures at 6 months' follow-up. MAIN OUTCOME MEASURES: Primary outcome measures were threat and efficacy appraisal, fear arousal, and intention to stop smoking. Secondary outcome measures were quit attempts within the last 6 months and 7-day point prevalence abstinence. RESULTS: Threat appraisal was significantly enhanced in the intervention compared with the control group, t(158) = 2.29, p = .023, as was intention to stop smoking in the next month, t(151) = 2.9, p = .004. However, this effect on intention to stop smoking was short-lived. Groups did not differ in terms of quit attempts or abstinence at follow-up, but the intervention increased the likelihood of cessation in smokers with higher self-efficacy, chi2(1) = 5.82, p = .016. CONCLUSIONS: Carbon-monoxide level feedback enhances the effect of brief quit advice on cognitive antecedents of behavior change and smoking cessation rates but further research is required to confirm the longevity of this effect and its applicability to smokers with low self-efficacy. PMID- 21299295 TI - Socioeconomic disparities in pain: the role of economic hardship and daily financial worry. AB - OBJECTIVE: Socioeconomic disparities in pain may be attributable to both greater frequency in stressful financial events as well as greater vulnerability to economic hardship for those at the lower end of the socioeconomic spectrum. This study investigated the effects of economic hardship and daily financial worry on daily pain among women with a chronic musculoskeletal condition. DESIGN: The sample consisted of 250 women with osteoarthritis (N = 105), fibromyalgia (N = 46), or both (N = 99). During an initial assessment, participants' chronic pain diagnosis, level of economic hardship, and demographic information were ascertained. For a period of 30 days, daily diary assessments recorded daily financial worries and daily pain severity. Hypotheses were tested using multilevel modeling for repeated measures in SAS PROC MIXED. MAIN OUTCOME MEASURE: Daily pain severity. RESULTS: Conditions of economic hardship and daily ratings of financial worry both had significant detrimental effects on daily pain. Participants with greater levels of economic hardship reported greater pain severity in response to daily financial worries than their counterparts with little or no economic hardship. Further, participants in the sample who were not employed and who reported higher levels of economic hardship exhibited the most pain reactivity in response to daily financial worries. CONCLUSION: Economic hardship was associated not only with greater exposure to daily financial worries but also with greater vulnerability to pain on days when daily financial worries were experienced. PMID- 21299296 TI - The invisible benefits of exercise. AB - OBJECTIVE: To examine whether--and why--people underestimate how much they enjoy exercise. DESIGN: Across four studies, 279 adults predicted how much they would enjoy exercising, or reported their actual feelings after exercising. MAIN OUTCOME MEASURES: Main outcome measures were predicted and actual enjoyment ratings of exercise routines, as well as intention to exercise. RESULTS: Participants significantly underestimated how much they would enjoy exercising; this affective forecasting bias emerged consistently for group and individual exercise, and moderate and challenging workouts spanning a wide range of forms, from yoga and Pilates to aerobic exercise and weight training (Studies 1 and 2). We argue that this bias stems largely from forecasting myopia, whereby people place disproportionate weight on the beginning of a workout, which is typically unpleasant. We demonstrate that forecasting myopia can be harnessed (Study 3) or overcome (Study 4), thereby increasing expected enjoyment of exercise. Finally, Study 4 provides evidence for a mediational model, in which improving people's expected enjoyment of exercise leads to increased intention to exercise. CONCLUSION: People underestimate how much they enjoy exercise because of a myopic focus on the unpleasant beginning of exercise, but this tendency can be harnessed or overcome, potentially increasing intention to exercise. PMID- 21299298 TI - Systematic review of maintenance of behavior change following physical activity and dietary interventions. AB - OBJECTIVE: In the past decade, there has been no systematic review of the evidence for maintenance of physical activity and/or dietary behavior change following intervention (follow-up). This systematic review addressed three questions: 1) How frequently do trials report on maintenance of behavior change? 2) How frequently do interventions achieve maintenance of behavior change? 3) What sample, methodologic, or intervention characteristics are common to trials achieving maintenance? DESIGN: Systematic review of trials that evaluated a physical activity and/or dietary behavior change intervention among adults, with measurement at preintervention, postintervention, and at least 3 months following intervention completion (follow-up). MAIN OUTCOME MEASURES: Maintenance of behavior change was defined as a significant between-groups difference at postintervention and at follow-up, for one or more physical activity and/or dietary outcome. RESULTS: Maintenance outcomes were reported in 35% of the 157 intervention trials initially considered for review. Of the 29 trials that met all inclusion criteria, 21 (72%) achieved maintenance. Characteristics common to trials achieving maintenance included those related to sample characteristics (targeting women), study methods (higher attrition and pretrial behavioral screening), and intervention characteristics (longer duration [>24 weeks], face to-face contact, use of more intervention strategies [>6], and use of follow-up prompts). CONCLUSIONS: Maintenance of physical activity and dietary behavior change is not often reported; when it is, it is often achieved. To advance the evidence, the field needs consensus on reporting of maintenance outcomes, controlled evaluations of intervention strategies to promote maintenance, and more detailed reporting of interventions. PMID- 21299297 TI - Exercise improves executive function and achievement and alters brain activation in overweight children: a randomized, controlled trial. AB - OBJECTIVE: This experiment tested the hypothesis that exercise would improve executive function. DESIGN: Sedentary, overweight 7- to 11-year-old children (N = 171, 56% girls, 61% Black, M +/- SD age = 9.3 +/- 1.0 years, body mass index [BMI] = 26 +/- 4.6 kg/m2, BMI z-score = 2.1 +/- 0.4) were randomized to 13 +/- 1.6 weeks of an exercise program (20 or 40 min/day), or a control condition. MAIN OUTCOME MEASURES: Blinded, standardized psychological evaluations (Cognitive Assessment System and Woodcock-Johnson Tests of Achievement III) assessed cognition and academic achievement. Functional MRI measured brain activity during executive function tasks. RESULTS: Intent to treat analysis revealed dose response benefits of exercise on executive function and mathematics achievement. Preliminary evidence of increased bilateral prefrontal cortex activity and reduced bilateral posterior parietal cortex activity attributable to exercise was also observed. CONCLUSION: Consistent with results obtained in older adults, a specific improvement on executive function and brain activation changes attributable to exercise were observed. The cognitive and achievement results add evidence of dose-response and extend experimental evidence into childhood. This study provides information on an educational outcome. Besides its importance for maintaining weight and reducing health risks during a childhood obesity epidemic, physical activity may prove to be a simple, important method of enhancing aspects of children's mental functioning that are central to cognitive development. This information may persuade educators to implement vigorous physical activity. PMID- 21299300 TI - The role of planning and self-efficacy in condom use among men who have sex with men: an application of the Health Action Process Approach model. AB - OBJECTIVE: In Hong Kong, men who have sex with men (MSM) remain a high risk group for HIV infection. This study applied the Health Action Process Approach (HAPA) to study the motivational and behavioral patterns of local MSM in condom use. DESIGN: Four hundred ten sexually active MSM completed the questionnaire on site at Time 1; 217 who remained sexually active were interviewed during a 1-month follow-up. MAIN OUTCOME MEASURES: Risk perception, outcome expectancy, action self-efficacy, intention, planning, maintenance self-efficacy, and recovery self efficacy were measured at Time 1. Actual condom use was measured at both time points. RESULTS: The HAPA model had a good fit to the data (chi2 = 300.71, df = 111, p < .001, CFI = .95, NNFI = .93, RMSEA = .065). Time 2 condom use was predicted by Time 1 planning, maintenance self-efficacy, and intention, which, in turn, was predicted by action self-efficacy, outcome expectancy, and risk perception. Planning mediated the association between intention and actual condom use. No group difference between MSM partners of different sex roles was found. CONCLUSION: It is demonstrated that the HAPA model could be applied to understand safer sex behavior among Chinese MSM. Its principles can help develop HIV prevention programs targeting safer sex practices by MSM. PMID- 21299299 TI - Sorting through chickens and eggs: a longitudinal examination of the associations between attitudes, norms, and sexual risk behavior. AB - OBJECTIVE: Health behavior theories posit that health-relevant attitudes, beliefs, and behavioral skills drive subsequent actions people take to protect themselves from health threats. Within the realm of HIV-related sexual risk behavior, much of the research in support of this notion is cross-sectional, rather than longitudinal, particularly in studies of gay and bisexual men. Other psychological theories (e.g., self-perception or cognitive dissonance theories) suggest that the opposite could be true--that health-relevant attitudes and beliefs might change as a function of previous risk or precautionary behavior. Appreciating the complex nature of these associations is essential for modifying theory and developing appropriate interventions. DESIGN: Using longitudinal data from gay and bisexual men (n = 1465), we used structural equation modeling to examine three possibilities--that perceived norms and attitudes about sexual risk would be (a) related to unprotected anal intercourse cross-sectionally, (b) related to unprotected anal intercourse at a subsequent time point, and/or (c) predicted from previous instances of unprotected anal intercourse. RESULTS: Safe sex norms and attitudes were related to unprotected anal intercourse cross sectionally, but did not predict unprotected sex longitudinally. Rather, perceived norms and attitudes changed as a function of previous risk behavior. CONCLUSIONS: These results raise the possibility that modified theoretical models might be necessary to adequately describe sexual risk behavior among gay and bisexual men. PMID- 21299301 TI - Naturalistically observed sighing and depression in rheumatoid arthritis patients: a preliminary study. AB - OBJECTIVE: This study tested the degree to which naturalistically observed sighing in daily life is a behavioral indicator of depression and reported physical symptoms (i.e., experienced pain and flare days) in rheumatoid arthritis (RA) patients. DESIGN: Thirteen RA patients wore the Electronically Activated Recorder (EAR), an observational ambulatory assessment tool, for two weekends (Friday through Sunday) approximately one month apart. The EAR periodically recorded snippets of ambient sounds from participants' momentary environments (50 s every 18 min). Sighs were coded from the sampled ambient sounds. MAIN OUTCOME MEASURES: Depression was assessed with the Center for Epidemiological Studies Depression Scale and the Beck Depression Inventory. Pain during the past month was assessed with a 10-cm visual-analog scale, and number of flare days during the prior 6 months was reported. RESULTS: Sighing was significantly and strongly related to patients' levels of depression and nonsignificantly and less strongly related to their reported pain and number of flare days. CONCLUSION: The findings suggest that sighing can serve as an observable marker of depression in RA patients. Because the sample size was small, the findings should be considered preliminary. PMID- 21299302 TI - Hierarchical diffusion models for two-choice response times. AB - Two-choice response times are a common type of data, and much research has been devoted to the development of process models for such data. However, the practical application of these models is notoriously complicated, and flexible methods are largely nonexistent. We combine a popular model for choice response times-the Wiener diffusion process-with techniques from psychometrics in order to construct a hierarchical diffusion model. Chief among these techniques is the application of random effects, with which we allow for unexplained variability among participants, items, or other experimental units. These techniques lead to a modeling framework that is highly flexible and easy to work with. Among the many novel models this statistical framework provides are a multilevel diffusion model, regression diffusion models, and a large family of explanatory diffusion models. We provide examples and the necessary computer code. PMID- 21299303 TI - Estimating, testing, and comparing specific effects in structural equation models: the phantom model approach. AB - The phantom model approach for estimating, testing, and comparing specific effects within structural equation models (SEMs) is presented. The rationale underlying this novel method consists in representing the specific effect to be assessed as a total effect within a separate latent variable model, the phantom model that is added to the main model. The following favorable features characterize the method: (a) It enables the estimation, testing, and comparison of arbitrary specific effects for recursive and nonrecursive models with latent and manifest variables; (b) it enables the bootstrapping of confidence intervals; and (c) it can be applied with all standard SEM programs permitting latent variables, the specification of equality constraints, and the bootstrapping of total effects. These features along with the fact that no manipulation of matrices and formulas is required make the approach particularly suitable for applied researchers. The method is illustrated by means of 3 examples with real data sets. PMID- 21299304 TI - A demonstration of dual-task performance without interference in some older adults. AB - Highly efficient dual-task processing is demonstrated when reaction time to each of two tasks does not differ between the dual-task situation and the single-task situation. This has been demonstrated reliably in younger adults; nevertheless, the two extant studies of extensive dual-task training did not find evidence for it in any elderly adult. The origins of age-related differences after training were explored in a study in which the stimuli for the two tasks were perfectly redundant although two distinct responses were required. The dual-task situation thus greatly reduced the demands of stimulus categorization while still requiring two response selections and two response executions. After only limited training 8 of 8 younger adults and 5 of 8 older adults showed performance consistent with highly efficient processing. Three older adults failed to show this even after 12 training sessions. The results implicate stimulus categorization more than response selection as an important locus of inefficient dual-task processing, particularly for older adults. PMID- 21299305 TI - The tenacious goal pursuit and flexible goal adjustment scales: a validation study. AB - The flexible goal adjustment (FLEX) and tenacious goal pursuit (TEN) scales are used regularly in aging research. The current study examined their validity in a sample of 517 women (30-75 years) in multiple ways. Overall, the findings show that the scales do not clearly distinguish between FLEX and TEN. The direction in which the items were formulated was just as important as what was being measured. Moreover, face validity of the inversely phrased items in particular appeared to be weak. On the basis of these findings, the authors recommend a revision of the concept definitions as well as of the items. PMID- 21299306 TI - The structure of working memory abilities across the adult life span. AB - The present study addresses three questions regarding age differences in working memory: (1) whether performance on complex span tasks decreases as a function of age at a faster rate than performance on simple span tasks; (2) whether spatial working memory decreases at a faster rate than verbal working memory; and (3) whether the structure of working memory abilities is different for different age groups. Adults, ages 20-89 (n = 388), performed three simple and three complex verbal span tasks and three simple and three complex spatial memory tasks. Performance on the spatial tasks decreased at faster rates as a function of age than performance on the verbal tasks, but within each domain, performance on complex and simple span tasks decreased at the same rates. Confirmatory factor analyses revealed that domain-differentiated models yielded better fits than models involving domain-general constructs, providing further evidence of the need to distinguish verbal and spatial working memory abilities. Regardless of which domain-differentiated model was examined, and despite the faster rates of decrease in the spatial domain, age group comparisons revealed that the factor structure of working memory abilities was highly similar in younger and older adults and showed no evidence of age-related dedifferentiation. PMID- 21299307 TI - Predicting recidivism with the Psychopathy Checklist: are factor score composites really necessary? AB - In two previous studies on general and violent recidivism (Walters & Heilbrun, 2010; Walters, Knight, Grann, & Dahle, 2008), the summed composite antisocial facet of the Psychopathy Checklist displayed incremental validity relative to the other 3 facets (interpersonal, affective, lifestyle), whereas the other 3 facets generally failed to demonstrate incremental validity relative to the antisocial facet. Because summed composite scores do not account for ordinal item distributions, the 6 Walters et al. (2008) samples were reanalyzed with factor score composites derived from a 4-factor confirmatory factor analysis. The results, however, showed little change from what had been obtained earlier with summed composite scores. Two additional samples not previously included in any incremental validity analyses of the Psychopathy Checklist evidenced a 3-factor structure, with the lifestyle and antisocial facets merged into a single factor. This single factor displayed incremental validity relative to the interpersonal and affective facets, but the reverse was not true regardless of whether summed composite scores or factor score composites were used. A comparison of zero-order correlations from all 8 samples revealed that the antisocial summed composite score predicted significantly better than the summed composite scores for the other 3 facets and that a superordinate factor failed to improve on the performance of either the antisocial summed composite score or the antisocial factor score composite. PMID- 21299308 TI - Perceived past, present, and future control and adjustment to stressful life events. AB - Perceived control is a central construct in psychology and is key to understanding individual differences in poststress outcomes (Frazier, Berman, & Steward, 2001). The goals of the current studies (using 4 samples of undergraduate students, total N = 1,421) were to examine the relations between different aspects of perceived control and poststress outcomes and to differentiate perceived control over specific events from related constructs (i.e., general control beliefs, coping strategies). To accomplish these goals, we first developed a new measure of perceived past, present, and future control over stressful life events. The data supported the content validity, factor structure, internal consistency and test-retest reliability, and convergent and discriminant validity of the new measure. Consistent with the temporal model of control (Frazier et al., 2001), these 3 forms of control had very different relations with adjustment. Present control was consistently related to lower distress levels in cross-sectional, longitudinal, and prospective analyses. Present control also predicted outcomes beyond the effects of general control beliefs and coping strategies. Past and future control had nonsignificant or positive relations with distress, although future control was associated with better outcomes (i.e., course grades) when the stressor was controllable. Thus, our measure can be used to assess the relations between perceived past, present, and future control and outcomes across a range of stressors. Because the relations between these 3 forms of control and outcomes differ markedly, measures that combine these aspects of control hinder the understanding of the important role of perceived control in adjustment to stress. PMID- 21299309 TI - The structure of musical preferences: a five-factor model. AB - Music is a cross-cultural universal, a ubiquitous activity found in every known human culture. Individuals demonstrate manifestly different preferences in music, and yet relatively little is known about the underlying structure of those preferences. Here, we introduce a model of musical preferences based on listeners' affective reactions to excerpts of music from a wide variety of musical genres. The findings from 3 independent studies converged to suggest that there exists a latent 5-factor structure underlying music preferences that is genre free and reflects primarily emotional/affective responses to music. We have interpreted and labeled these factors as (a) a Mellow factor comprising smooth and relaxing styles; (b) an Unpretentious factor comprising a variety of different styles of sincere and rootsy music such as is often found in country and singer-songwriter genres; (c) a Sophisticated factor that includes classical, operatic, world, and jazz; (d) an Intense factor defined by loud, forceful, and energetic music; and (e) a Contemporary factor defined largely by rhythmic and percussive music, such as is found in rap, funk, and acid jazz. The findings from a fourth study suggest that preferences for the MUSIC factors are affected by both the social and the auditory characteristics of the music. PMID- 21299310 TI - When self-destructive thoughts flash through the mind: Failure to meet standards affects the accessibility of suicide-related thoughts. AB - When individuals realize that they fail to attain important standards or expectations, they may be motivated to escape the self, which could lead thoughts of suicide to become more accessible. Six studies examined this hypothesis, mainly derived from escape theory (Baumeister, 1990). The results indicated that whenever individuals realize that they fail to attain an important standard, they experience increased accessibility of suicide-related thoughts (Studies 1-6). In line with the idea that such effects reflect motivations to escape from negative self-awareness, they were especially pronounced when associated with high levels of self-consciousness and escapist motivations (Study 1) and with a large discrepancy between self and standards (Studies 2-4). Moreover, failure to attain standards increased suicide-thought accessibility along with the desire for an altered state of consciousness (Study 5). Finally, increases in suicide-thought accessibility after failure were associated with simultaneous increases in accessibility of general concepts related to escape (Study 6). Implications of these findings for escape and terror management theories are discussed. PMID- 21299311 TI - Spurious? Name similarity effects (implicit egotism) in marriage, job, and moving decisions. AB - Three articles published in the Journal of Personality and Social Psychology have shown that a disproportionate share of people choose spouses, places to live, and occupations with names similar to their own. These findings, interpreted as evidence of implicit egotism, are included in most modern social psychology textbooks and many university courses. The current article successfully replicates the original findings but shows that they are most likely caused by a combination of cohort, geographic, and ethnic confounds as well as reverse causality. PMID- 21299312 TI - The influence of mortality and socioeconomic status on risk and delayed rewards: a life history theory approach. AB - Why do some people take risks and live for the present, whereas others avoid risks and save for the future? The evolutionary framework of life history theory predicts that preferences for risk and delay in gratification should be influenced by mortality and resource scarcity. A series of experiments examined how mortality cues influenced decisions involving risk preference (e.g., $10 for sure vs. 50% chance of $20) and temporal discounting (e.g., $5 now vs. $10 later). The effect of mortality depended critically on whether people grew up in a relatively resource-scarce or resource-plentiful environment. For individuals who grew up relatively poor, mortality cues led them to value the present and gamble for big immediate rewards. Conversely, for individuals who grew up relatively wealthy, mortality cues led them to value the future and avoid risky gambles. Overall, mortality cues appear to propel individuals toward diverging life history strategies as a function of childhood socioeconomic status, suggesting important implications for how environmental factors influence economic decisions and risky behaviors. PMID- 21299313 TI - Mind the gap: Increasing associations between the self and Blacks with approach behaviors. AB - Although perceived differences between outgroup social categories and the self are often cited as a major contributor to prejudice and intergroup tension, surprisingly few studies have examined ways to improve associations between the self and racial outgroups. The present research investigated one strategy to increase these associations-approach training. Specifically, 3 studies investigated the impact of training participants to conceptually approach Blacks on 3 separate measures: 2 response latency measures indexing the strength of association between the self and Blacks and a psychophysiological measure indexing brain activity in response to Blacks in the context of the self. A fourth study examined the link between earlier research on the impact of approach training on implicit prejudice against Blacks and the current results related to self-Black associations. Together, these findings provided consistent evidence that training in approaching Blacks increases associations between the self and Blacks that in turn reduce implicit prejudice against Blacks. PMID- 21299314 TI - The interplay of controlled and automatic processing in the expression of spontaneously inferred traits: A PDP analysis. AB - Inferences made about actors influence subsequent processing about those actors. Three experiments conducted in the context of spontaneous trait inference (STI) making demonstrate that such influences occur can either occur via automatic processes or via controlled processes. Results from Experiment 1 demonstrated that processing goals manipulated prior to encoding actor behavior affected the extent to which STIs automatically influenced subsequent responses but did not alter the extent to which STIs influenced those responses via controlled processes. Results from Experiment 2 showed that the extent to which STIs affected subsequent responding via the action of controlled processes were more affected by a delay between exposure to an actor behavior and the response task than the extent to which STIs affected task performance via the action of automatic processes. Finally, results from Experiment 3 showed that participants' subjective experience of awareness of their trait inferences is related to estimates of the extent to which controlled processing is involved in the production of their future responses but not to estimates of the extent to which those responses are affected by automatic processing. PMID- 21299315 TI - Through the looking glass clearly: accuracy and assumed similarity in well adjusted individuals' first impressions. AB - Do well-adjusted individuals have particularly accurate insight into what others are like or are they biased, primarily seeing their own characteristics in others? In the current studies, the authors examined how psychologically adjusted individuals tend to see new acquaintances, directly comparing their levels of distinctive accuracy (accurately perceiving others' unique characteristics), normative accuracy (perceiving others as similar to the average person), and assumed similarity (perceiving others as similar to the self). Across two interactive, round-robin studies, well-adjusted individuals, compared with less adjusted individuals, did not perceive new acquaintances' unique characteristics more accurately but did perceive new acquaintances, on average, as similar to the average person, reflecting an accurate understanding of what people generally tend to be like. Furthermore, well-adjusted individuals had a biased tendency to perceive their own unique characteristics in others. Of note, both pre-existing perceiver adjustment and target-specific liking independently predicted greater accuracy and assumed similarity in first impressions. In sum, well-adjusted individuals see through the looking glass clearly: although they erroneously see others as possessing their own unique characteristics, they accurately understand what others generally tend to be like. PMID- 21299316 TI - Grouping information for judgments. AB - Models of cue weighting in judgment have typically focused on how decision-makers weight cues individually. Here, the authors propose that people might recognize and weight groups of cues. They examine how judgments change when decision-makers focus on cues individually or as parts of groups. Several experiments demonstrate that people can spontaneously pack information into cue groups. Moreover, group level weighting depends on how people assess similarity or how they think of categorical hierarchies. PMID- 21299317 TI - The pain was greater if it will happen again: the effect of anticipated continuation on retrospective discomfort. AB - Across 7 laboratory studies and 1 field study, we demonstrated that people remembered an unpleasant experience as more aversive when they expected this experience to return than when they had no such expectation. Our results indicate that this effect results from people's tendency to brace for unpleasant experiences. Specifically, when faced with the anticipated return of the experience, people prepare for the worst, leading them to remember the initial experience as more aversive. This bracing can be reduced either by limiting people's self-regulatory resources or by denying them the time to brace. These results indicate that people's tendency to remember aversive experiences as less unpleasant than they actually were (as demonstrated in prior research) does not necessarily imply that people are willing to re-engage in these experiences because the anticipation of repeating the experience may counteract the initial memory bias. PMID- 21299318 TI - Predicting reasoning from memory. AB - In an effort to assess the relations between reasoning and memory, in 8 experiments, the authors examined how well responses on an inductive reasoning task are predicted from responses on a recognition memory task for the same picture stimuli. Across several experimental manipulations, such as varying study time, presentation frequency, and the presence of stimuli from other categories, there was a high correlation between reasoning and memory responses (average r = .87), and these manipulations showed similar effects on the 2 tasks. The results point to common mechanisms underlying inductive reasoning and recognition memory abilities. A mathematical model, GEN-EX (generalization from examples), derived from exemplar models of categorization, is presented, which predicts both reasoning and memory responses from pairwise similarities among the stimuli, allowing for additional influences of subtyping and deterministic responding. PMID- 21299319 TI - The nature of gestures' beneficial role in spatial problem solving. AB - Co-thought gestures are hand movements produced in silent, noncommunicative, problem-solving situations. In the study, we investigated whether and how such gestures enhance performance in spatial visualization tasks such as a mental rotation task and a paper folding task. We found that participants gestured more often when they had difficulties solving mental rotation problems (Experiment 1). The gesture-encouraged group solved more mental rotation problems correctly than did the gesture-allowed and gesture-prohibited groups (Experiment 2). Gestures produced by the gesture-encouraged group enhanced performance in the very trials in which they were produced (Experiments 2 & 3). Furthermore, gesture frequency decreased as the participants in the gesture-encouraged group solved more problems (Experiments 2 & 3). In addition, the advantage of the gesture encouraged group persisted into subsequent spatial visualization problems in which gesturing was prohibited: another mental rotation block (Experiment 2) and a newly introduced paper folding task (Experiment 3). The results indicate that when people have difficulty in solving spatial visualization problems, they spontaneously produce gestures to help them, and gestures can indeed improve performance. As they solve more problems, the spatial computation supported by gestures becomes internalized, and the gesture frequency decreases. The benefit of gestures persists even in subsequent spatial visualization problems in which gesture is prohibited. Moreover, the beneficial effect of gesturing can be generalized to a different spatial visualization task when two tasks require similar spatial transformation processes. We concluded that gestures enhance performance on spatial visualization tasks by improving the internal computation of spatial transformations. (PsycINFO Database Record (c) 2010 APA, all rights reserved). PMID- 21299320 TI - Subjective confidence in perceptual judgments: a test of the self-consistency model. AB - Two questions about subjective confidence in perceptual judgments are examined: the bases for these judgments and the reasons for their accuracy. Confidence in perceptual judgments has been claimed to rest on qualitatively different processes than confidence in memory tasks. However, predictions from a self consistency model (SCM), which had been confirmed for general-information questions (Koriat, 2010) and social attitudes (Koriat & Adiv, 2010), are shown to hold true also for perceptual judgments. In SCM, confidence is modeled by the procedure for assessment of statistical level of confidence: For a 2-alternative, forced-choice item, confidence is based on the consistency with which the choice is favored across a sample of representations of the item, and acts as a monitor of the likelihood that a new sample will yield the same choice. Assuming that these representations are drawn from commonly shared populations of representations associated with each item, predictions regarding the basis of confidence were confirmed by results concerning the functions relating confidence and choice latency to interparticipant consensus and to intraparticipant consistency for majority and minority choices. With regard to the confidence accuracy (C/A) relationship, the consensuality principle, documented for general knowledge tasks (Koriat, 2008a), was replicated for perceptual judgments: Confidence correlated with the consensuality of the choice rather than with its correctness, suggesting that the C/A correlation is due to the relationship between confidence and self-consistency and is positive only as long as the correct choices are the consistently made choices. SCM provides a general model for the basis and accuracy of confidence judgments across different domains. PMID- 21299322 TI - Dilution, not load, affects distractor processing. AB - Lavie and Tsal (1994) proposed that spare attentional capacity is allocated involuntarily to the processing of irrelevant stimuli, thereby enabling interference. Under this view, when task demands increase, spare capacity should decrease and distractor interference should decrease. In support, Lavie and Cox (1997) found that increasing perceptual load by increasing search set size decreased interference from an irrelevant distractor. In three experiments, we manipulated the cue set size (number of cued locations) independently of the display set size (number of letters presented). Increasing the display set size reduced distractor interference regardless of whether the additional letters were relevant to the task. In contrast, increasing the cue set size increased distractor interference. Both findings are inconsistent with the load explanation, but are consistent with a proposed two-stage dilution account. PMID- 21299323 TI - Is there semantic interference in delayed naming? AB - The semantic interference effect in the picture-word interference task is interpreted as an index of lexical competition in prominent speech production models. Janssen, Schirm, Mahon, and Caramazza (2008) challenged this interpretation on the basis of experiments with a novel version of this task, which introduced a task-switching component. Participants either named the picture or read the word, depending on the word's color. Janssen et al. reported semantic interference in picture naming, regardless of whether the word appeared simultaneously with the picture (immediate naming) or 1,000 ms after the picture (delayed naming). Because picture name retrieval is completed in less than 1,000 ms, the finding in delayed naming was taken as evidence against the lexical competition account. In 3 sets of experiments conducted in German and English, we tested for semantic effects in Janssen et al.'s task-switching version and in the standard picture-word interference task. Using identical materials, we obtained sizeable interference effects in the standard task (Experiments 2, 4, and 6) but no effects in the task-switching version (Experiments 1, 3, and 5). When the word reading trials of the task-switching version were replaced with no-go trials (Experiment 7), semantic interference reemerged in immediate naming but was still absent in delayed naming. The experiments question the reliability of Janssen et al.'s critical finding and suggest that theoretical inferences about the origin of semantic effects in the standard picture-word interference task based on results from the task-switching version used by Janssen et al. are difficult to draw. PMID- 21299324 TI - Analogical transfer from a simulated physical system. AB - Previous research has consistently found that spontaneous analogical transfer is strongly tied to concrete and contextual similarities between the cases. However, that work has largely failed to acknowledge that the relevant factor in transfer is the similarity between individuals' mental representations of the situations rather than the overt similarities between the cases themselves. Across several studies, we found that participants were able to transfer strategies learned from a perceptually concrete simulation of a physical system to a task with very dissimilar content and appearance. This transfer was reflected in better performance on the transfer task when its underlying dynamics were consistent rather than inconsistent with the preceding training task. Our data indicate that transfer in these tasks relies on the perceptual and spatial nature of the training task but does not depend on direct interaction with the system, with participants performing equally well after simply observing the concrete simulation. We argue that participants generated a spatial, dynamic, and force based mental model while interacting with the training simulation and tended to spontaneously interpret the transfer task according to this primed model. Unexpectedly, our data consistently show that transfer was independent of reported recognition of the analogy between tasks: Although such recognition was associated with better overall performance, it was not associated with better transfer (in terms of applying an appropriate strategy). Together, these findings suggest that analogical transfer between overtly dissimilar cases may be much more common--and much more relevant to our cognitive processing--than is generally assumed. PMID- 21299325 TI - Individual differences in susceptibility to inattentional blindness. AB - Inattentional blindness refers to the finding that people do not always see what appears in their gaze. Though inattentional blindness affects large percentages of people, it is unclear if there are individual differences in susceptibility. The present study addressed whether individual differences in attentional control, as reflected by variability in working memory capacity, modulate susceptibility to inattentional blindness. Participants watched a classic inattentional blindness video (Simons & Chabris, 1999) and were instructed to count passes among basketball players, wherein 58% noticed the unexpected: a person wearing a gorilla suit. When participants were accurate with their pass counts, individuals with higher working memory capacity were more likely to report seeing the gorilla (67%) than those with lesser working memory capacity (36%). These results suggest that variability in attentional control is a potential mechanism underlying the apparent modulation of inattentional blindness across individuals. PMID- 21299326 TI - Working memory capacity and go/no-go task performance: selective effects of updating, maintenance, and inhibition. AB - The ability to temporarily maintain information in order to successfully perform a task is important in many daily activities. However, the ability to quickly and accurately update existing mental representations in distracting situations is also imperative in many of these same circumstances. In the current studies, individuals varying in working memory capacity (WMC) performed different varieties of go/no-go tasks that have been hypothesized to measure inhibitory ability. The results indicated that low-WMC individuals relative to high-WMC individuals showed worse performance specifically in certain conditions of the conditional go/no-go task. Further analyses showed that increasing the temporal lag/number of intervening items between the previous target and the current lure had a deleterious effect on the performance of the low-WMC group only. The results indicate a relationship between WMC and the ability to selectively update, maintain, and retrieve information, especially in interference-rich conditions. PMID- 21299328 TI - An observation on the spontaneous noticing of prospective memory event-based cues. AB - In event-based prospective memory, current theories make differing predictions as to whether intention-related material can be spontaneously noticed (i.e., noticed without relying on preparatory attentional processes). In 2 experiments, participants formed an intention that was contextually associated to the final phase of the experiment, and lures that overlapped to differing degrees with the features of the intention-related cues were embedded in the initial phase. When participants were outside of the appropriate responding context (i.e., the initial phase), they exhibited slower latencies to lures that exactly matched the features of their intention compared with other types of lures and control words. In addition, on a final remember/know recognition test, participants reported having greater subjective recollection for the occurrence of the exact-match lures. These results suggest that exact-match lures were spontaneously noticed and differentially processed in the absence of any observable preparatory attentional processes. The findings have implications for the theoretical debate over whether preparatory attention must always be relied upon to notice intention related material. PMID- 21299327 TI - Hindsight bias from 3 to 95 years of age. AB - Upon learning the outcome to a problem, people tend to believe that they knew it all along (hindsight bias). Here, we report the first study to trace the development of hindsight bias across the life span. One hundred ninety-four participants aged 3 to 95 years completed 3 tasks designed to measure visual and verbal hindsight bias. All age groups demonstrated hindsight bias on all 3 tasks; however, preschoolers and older adults exhibited more bias than older children and younger adults. Multinomial processing tree analyses of these data revealed that preschoolers' enhanced hindsight bias resulted from them substituting the correct answer for their original answer in their recall (a qualitative error). Conversely, older adults' enhanced hindsight bias resulted from them forgetting their original answer and recalling an answer closer to, but not equal to, the correct answer (a quantitative error). We discuss these findings in relation to mechanisms of memory, perspective taking, theory of mind, and executive function. PMID- 21299329 TI - Small samples do not cause greater accuracy--but clear data may cause small samples: comment on Fiedler and Kareev (2006). AB - Fiedler and Kareev (2006) have claimed that taking a small sample of information (as opposed to a large one) can, in certain specific situations, lead to greater accuracy--beyond that gained by avoiding fatigue or overload. Specifically, they have argued that the propensity of small samples to provide more extreme evidence is sufficient to create an accuracy advantage in situations of high caution and uncertainty. However, a close examination of Fiedler and Kareev's experimental results does not reveal any strong reason to conclude that small samples can cause greater accuracy. We argue that the negative correlation between sample size and accuracy that they reported (found only for the second half of Experiment 1) is also consistent with mental fatigue and that their data in general are consistent with the causal structure opposite to the one they suggest: Rather than small samples causing clear data, early clear data may cause participants to stop sampling. More importantly, Experiment 2 provides unequivocal evidence that large samples result in greater accuracy; Fiedler and Kareev only found a small sample advantage here when they artificially reduced the data set. Finally, we examine the model that Fiedler and Kareev used; they surmised that decision makers operate with a fixed threshold independent of sample size. We discuss evidence for an alternative (better performing) model that incorporates a dynamic threshold that lowers with sample size. We conclude that there is no evidence currently to suggest that humans benefit from taking a small sample, other than as a tactic for avoiding fatigue, overload, and/or opportunity cost-that is, there is no accuracy advantage inherent to small samples. PMID- 21299330 TI - Semantic cuing and the scale insensitivity of recency and contiguity. AB - In recalling a set of previously experienced events, people exhibit striking effects of recency, contiguity, and similarity: Recent items tend to be recalled best and first, and items that were studied in neighboring positions or that are similar to one another in some other way tend to evoke one another during recall. Effects of recency and contiguity have most often been investigated in tasks that require people to recall random word lists. Similarity effects have most often been studied in tasks that require people to recall categorized word lists. Here we examine recency and contiguity effects in lists composed of items drawn from 3 distinct taxonomic categories and in which items from a given category are temporally separated from one another by items from other categories, all of which are tested for recall. We find evidence for long-term recency and for long range contiguity, bolstering support for temporally sensitive models of memory and highlighting the importance of understanding the interaction between temporal and semantic information during memory search. PMID- 21299331 TI - Functional equivalence of spatial images from touch and vision: evidence from spatial updating in blind and sighted individuals. AB - This research examined whether visual and haptic map learning yield functionally equivalent spatial images in working memory, as evidenced by similar encoding bias and updating performance. In 3 experiments, participants learned 4-point routes either by seeing or feeling the maps. At test, blindfolded participants made spatial judgments about the maps from imagined perspectives that were either aligned or misaligned with the maps as represented in working memory. Results from Experiments 1 and 2 revealed a highly similar pattern of latencies and errors between visual and haptic conditions. These findings extend the well-known alignment biases for visual map learning to haptic map learning, provide further evidence of haptic updating, and most important, show that learning from the 2 modalities yields very similar performance across all conditions. Experiment 3 found the same encoding biases and updating performance with blind individuals, demonstrating that functional equivalence cannot be due to visual recoding and is consistent with an amodal hypothesis of spatial images. PMID- 21299332 TI - Different confidence-accuracy relationships for feature-based and familiarity based memories. AB - Participants studied naturalistic pictures presented for varying brief durations and then received a recognition test on which they indicated whether each picture was old or new and rated their confidence. In 1 experiment they indicated whether each "old"/"new" response was based on memory for a specific feature in the picture or instead on the picture's general familiarity; in another experiment, we defined pictures that tended to elicit feature versus familiarity responses. Thus, feature/familiarity was a dependent variable in 1 experiment and an independent variable in the other. In both experiments feature-based responses were more accurate than those that were familiarity based, and confidence and accuracy increased with duration for both response types. However, when confidence was controlled for, mean accuracy was higher for familiarity-based than for feature-based responses. The theoretical implication is that confidence and accuracy arise from different underlying information. The applied implication is that confidence differences should not be taken as implying accuracy differences when the phenomenal basis of the memory reports differ. PMID- 21299333 TI - Increasing capacity: practice effects in absolute identification. AB - In most of the long history of the study of absolute identification--since Miller's (1956) seminal article--a severe limit on performance has been observed, and this limit has resisted improvement even by extensive practice. In a startling result, Rouder, Morey, Cowan, and Pfaltz (2004) found substantially improved performance with practice in the absolute identification of line lengths, albeit for only 3 participants and in a somewhat atypical paradigm. We investigated the limits of this effect and found that it also occurs in more typical paradigms, is not limited to a few virtuoso participants or due to relative judgment strategies, and generalizes to some (e.g., line inclination and tone frequency) but not other (e.g., tone loudness) dimensions. We also observed, apart from differences between dimensions, 2 unusual aspects of improvement with practice: (a) a positive correlation between initial performance and the effect of practice and (b) a large reduction in a characteristic trial-to-trial decision bias with practice. PMID- 21299334 TI - Task-switching performance with 1:1 and 2:1 cue-task mappings: not so different after all. AB - When task-switching studies use the task-cuing procedure with a 1:1 cue-task mapping, task switching and cue switching are confounded, which is problematic for interpreting switch costs. The use of a 2:1 cue-task mapping is a potential solution to this problem, but it is possible that introducing more cues may also introduce marked changes in task-switching performance. In 5 experiments involving 160 subjects, the authors compared performance with 1:1 and 2:1 mappings across several methodological changes. Differences in switch costs between mappings were small and, in most analyses, nonsignificant. In all experiments, both mappings yielded significant reductions in switch cost across cue-target interval, and there were significant cue-switching effects with the 2:1 mapping. A model of cue encoding fit the data from both mappings about equally well. Overall, task-switching performance was more similar than it was different between mappings, leading the authors to suggest that the use of a 2:1 mapping is a viable solution to the problem associated with a 1:1 mapping. PMID- 21299335 TI - Social determinants of health among African Americans in a rural community in the Deep South: an ecological exploration. AB - INTRODUCTION: African Americans living in rural USA experience multiple health disparities as a result of both race and rural geography. An increasing literature suggests that social determinants of health, the social contexts in which people live their lives, are key contributors to these health disparities. Ecological theory provides a valuable conceptual framework for exploring social determinants of health in communities, but few US rural health community-based studies have utilized this approach, or engaged ecological theory to explore rural contexts. This exploratory study blended a community-based, qualitative approach with ecological theory with the objective of identifying potential social determinants of health among African Americans in a rural community in the Deep South, from the perspectives of participants. METHODS: In-depth interviews were conducted with rural, Deep South African Americans participants who were purposefully sampled to incorporate a range of perspectives. Interview guides structured around five ecological levels (individual, relational, environmental, structural, and superstructural) were used to frame interviews. Iterative content analysis of interview transcripts and field notes identified potential social determinants of health. An 'editing' approach to content analysis was used. Data and analysis quality was tested by triangulation at the level of the researcher, and by member checking with community members. RESULTS: Potential determinants of health were identified at all five levels of the ecological framework. At the individual level, lack of engagement with personal health and health promotion was a recurring theme. Participation in preventive health activities and education was minimal, even when offered in community settings. At the relational level, lack of social capital emerged as another potential social determinant of health, with estrangement between the younger and elder generations as one source, and fractiousness among churches (key institutions in the community) representing another. At the environmental level, the community built environment was an area of concern as it lacked opportunities for physical activity and access to healthy foods. The local job environment was identified as a potential social determinant of health, given the strong ties between income and health. At the structural level, participants complained of cronyism and nepotism favoring Whites in access to jobs, including those where local policies and funding allocations were made (eg funding for the local health department). In education, school system tracking policies were perceived to discourage African Americans from university education. At the superstructural level, high rates of poverty and racism emerged as potential social determinants. Poverty directly limited many African Americans' access to quality health care, and subtle racism was perceived in some delivery of care. Persistent stress from poverty and racism was reported, which creates health risks through physiologic pathways. CONCLUSION: This study identified potential social determinants of health, at multiple ecological levels, among African Americans in a rural community in the Deep South. The social determinants identified had the ability to impact a variety of health behaviors and health outcomes. The results demonstrate the value of this approach to conducting rural, community-based research. This descriptive and exploratory study highlights the need for quantitative exploration of these issues, as well as the development of context-appropriate, community-based health interventions that address multiple ecological levels. PMID- 21299336 TI - Effect of vascular endothelial growth factor treatment in experimental traumatic spinal cord injury: in vivo longitudinal assessment. AB - Vascular endothelial growth factor (VEGF) is thought to provide neuroprotection to the traumatically injured spinal cord. We examined whether supplementing the injured environment with VEGF(165) via direct intraspinal injection into the lesion epicenter during the acute phase of spinal cord injury (SCI) results in improved outcome. The effect of treatment was investigated using longitudinal multi-modal magnetic resonance imaging (MRI), neurobehavioral assays, and end point immunohistochemistry. We observed on MRI that rats treated with VEGF(165) after SCI had increased tissue sparing compared to vehicle-treated animals at the earlier time points. However, these favorable effects were not maintained into the chronic phase. Histology revealed that VEGF(165) treatment resulted in increased oligodendrogenesis and/or white matter sparing, and therefore may eventually lead to improved functional outcome. The increase in spared tissue as demonstrated by MRI, coupled with the possible remyelination and increased neurosensory sensitivity, suggests that VEGF(165) treatment may play a role in promoting plasticity in the sensory pathways following SCI. However, VEGF-treated animals also demonstrated an increased incidence of persistent allodynia, as indicated on the von Frey filament test. PMID- 21299337 TI - Preferential and bidirectional labeling of the rubrospinal tract with adenovirus GFP for monitoring normal and injured axons. AB - The rodent rubrospinal tract (RST) has been studied extensively to investigate regeneration and remodeling of central nervous system (CNS) axons. Currently no retrograde tracers can specifically label rubrospinal axons and neurons (RSNs). The RST can be anterogradely labeled by injecting tracers into the red nucleus (RN), but accurately locating the RN is a technical challenge. Here we developed a recombinant adenovirus carrying a green fluorescent protein reporter gene (Adv GFP) which can preferentially, intensely, and bi-directionally label the RST. When Adv-GFP was injected into the second lumbar spinal cord, the GFP was specifically transported throughout the entire RST, with peak labeling seen at 2 weeks post-injection. When Adv-GFP was injected directly into the RN, GFP was anterogradely transported throughout the RST. Following spinal cord injury (SCI), injection of Adv-GFP resulted in visualization of GFP in transected, spared, or sprouted RST axons bi-directionally. Thus Adv-GFP could be used as a novel tool for monitoring and evaluating strategies designed to maximize RST axonal regeneration and remodeling following SCI. PMID- 21299339 TI - Malignant transformation of perianal and enterocutaneous fistulas is rare: results of 17 years of follow-up from The Netherlands. AB - OBJECTIVE: Malignant transformation of fistulas has been observed, particularly in perianal fistulas in Crohn's disease (CD) patients. The prevalence of adenocarcinoma in enterocutaneous fistulas and non-CD-related fistulas, however, is unknown. We investigated adenocarcinoma originating from perianal and enterocutaneous fistulas in both CD patients and non-CD patients from nine large, mostly tertiary referral, hospitals in The Netherlands. METHODS: Patients suffering from fistulizing disease and either dysplasia or adenocarcinoma between January 1990 and January 2007 were identified using the nationwide automated pathology database (PALGA). Clinical and histopathological data were collected and verified using hospital patient-charts and reported by descriptive statistics. The total CD-population comprised 6058 patients. RESULTS: In a study period of 17 years, 2324 patients with any fistula were reported in PALGA. In 542 patients, dysplasia or adenocarcinoma was also mentioned. After initial review and additional detailed chart review, 538 patients were excluded, mainly because the adenocarcinoma was not related to the fistula. In the remaining four patients, all suffering from CD, adenocarcinoma originating from the fistula tract was confirmed. The malignancies developed 25 years (IQR 10-38) after CD diagnosis, and 10 years (IQR 6-22) after fistula diagnosis. Median age at time of adenocarcinoma diagnosis was 48.3 years (IQR 43-58). Only one patient had clinical symptoms indicative for adenocarcinoma. In three other patients, the adenocarcinoma was found coincidently. CONCLUSIONS: Adenocarcinoma complicating perianal or enterocutaneous fistula-tracts is a rare finding. Only 4 out of 6058 CD patients developed a fistula-associated adenocarcinoma. We could not identify any malignant transformations in non-CD-related fistulas in our 17 years study period. PMID- 21299340 TI - High-dose busulfan and melphalan as conditioning regimen for autologous peripheral blood progenitor cell transplantation in high-risk neuroblastoma patients. AB - The aim of this retrospective study was to analyze the outcome and identify risk factors associated with progression-free survival (PFS) in 36 children with high risk neuroblastoma who underwent autologous peripheral blood progenitor cell (PBPC) transplantation between 1994 and 2010. The conditioning regimen used in all cases consisted of high-dose of busulfan and melphalan. Median age at transplantation was 3 years (range: 0.7-14 years). The median times to neutrophil and platelet engraftment were 11 days (range: 9.16 days) and 13 days (range: 9.33), respectively. Twenty-one patients developed nonhematologic toxicity: 15 patients had mucositis, 4 patients developed an engraftment syndrome, and there were 2 cases of liver toxicity. No toxic deaths were observed. There were 15 patients who relapsed. The median time to relapse was 6 months after the transplant (range: 3-13 months). With a median follow-up of 55 months (range: 4 180 months), the PFS was 57% +/- 8.5% for the whole group. In multivariate analysis, age below 3 years (P < .005), complete remission (CR) pretransplantation (P < .07) and 1p germline status (P < .01) were variables associated with better outcomes. Patients who were or achieved early CR following transplantation (3 months posttransplantation) had a probability of PFS of 91% +/ 6% as compared to patients who did not (PFS 9% +/- 8%) (P < .0001). This retrospective study shows that high dose of busulfan and melphalan as conditioning regimen in children with high-risk neuroblastoma is associated with very low morbidity and no mortality in the authors' hands. Younger patients with no 1p deletions and in first CR at transplantation had the better outcome. PMID- 21299341 TI - Acute monocytic leukemia blasts with cuplike nuclear morphology: a case report. PMID- 21299342 TI - Prenatal diagnosis of fetal hepatoblastoma with a good neonatal outcome: case report and narrative literature review. AB - The authors report a case of congenital hepatoblastoma that was diagnosed in the antenatal period at 39 weeks' gestation. The infant was delivered vaginally without rupture of the tumor. The neonate then received chemotherapy and underwent surgical excision of the tumor. After 1 year, no tumor recurrence has been noted. PMID- 21299343 TI - A rare cause of intestinal obstruction: neonatal gastrointestinal stromal tumor. AB - Gastrointestinal stromal tumors (GISTs) are rare in the childhood period. The authors reported a case who was admitted to the neonatal intensive care unit (NICU) on a suspicion of intestinal obstruction. She was operated and a mass in a size of 6 x 4.5 x 4 cm was resected from the ileum. Histologic and immunohistochemical studies showed a GIST. CD34, small muscle actin (SMA), and desmin were positive. The baby was discharged on the 13th day after operation. PMID- 21299344 TI - Ultrastructural variations in platelets and platelet mitochondria: a novel feature in amyotrophic lateral sclerosis. AB - Platelets are characterized as a systemic tool to elucidate mitochondria-allied perturbance in neurological diseases. The authors studied ultrastructural changes in platelets and platelet mitochondria using a case-control approach in amyotrophic lateral sclerosis (ALS). Subjects were sporadic ALS cases (n = 22) and age- and sex-matched controls (n = 16). Phlebotomy was performed, platelet concentrates (PCs) were prepared, and mitochondria were extracted. PCs and mitochondria were processed for ultrastructure study using transmission electron microscopy. Image analysis was done using Image-J. Transmission electron microscopy demonstrated both qualitative and quantitative variations in ALS platelets and platelet mitochondria. Heterogeneous distribution of granules, formation of vacuoles, blebs, pseudopodia, loose demarcation of cell membrane with a significant increase in area (20.3%), perimeter (17.82%), integrated density (21.44%), electron-lucent granules (41.79%), and vacuoles (36.58%) were observed in ALS platelets. Conversely, control platelets exhibited an increase of circularity (11.7%) and electron-dense granules (36.89%). In parallel, nonuniformity of matrix, faint cristae, greater lysosomal bodies, and lesser intramitochondrial granules were seen in ALS platelet mitochondria. Significantly greater area (26.88%), perimeter (15%), circularity (3.76%), and integrated density (25.18%) were observed in control platelet mitochondria. Ultastructural divergence in platelets of ALS patients underlines a potential dependence of platelets on modest mitochondrial functioning. These observations also support the view that systemic involvement might be a novel feature in ALS pathophysiology. PMID- 21299345 TI - Effects of prolonged warm and cold ischemia in a solitary kidney animal model after partial nephrectomy: an ultrastructural investigation. AB - Ischemia-reperfusion injury can be detrimental to the solitary kidney, especially when it is accompanied by ablation. To the authors' knowledge, the effects of partial nephrectomy with prolonged application of ischemia have never been described at the ultrastructural level. Therefore, the authors used an animal model and focused on putative structural effects in the glomerular basement membrane and the podocytes. They demonstrate the advantageous role of cold ischemia, even in up to 120 min. In contrast, more than 60 min of warm ischemia leads to catastrophic lesions in all the cellular structures, as is reflected by mortality due to acute renal failure. PMID- 21299346 TI - Mitotic catastrophe in malignant epithelial tumors: the pathologist's viewpoint. AB - Mitotic catastrophe is a common phenomenon occurring in tumor cells with impaired p53 function exposed to various cytotoxic and genotoxic agents. The defective p53 checkpoint causes improper segregation of chromosomes, resulting in aberrant mitosis, multiple micronuclei, multinucleate giant cells, and eventual necrosis like death and centrosome aberration. Although various descriptions explaining mitotic catastrophe exist, there is still no generally accepted definition of this phenomenon. However, the syndrome of mitotic catastrophe may be a unifying morphological concept of particular interest to cancer research, as it integrally links cell death to checkpoints of the cell cycle. Morphological findings compatible with mitotic catastrophe may be found in pleomorphic, giant cell carcinomas--neoplasms characterized by a poor prognosis. The inclusion of mitotic catastrophe as part of the microscopic evaluation of tumors will add further insight to the pathobiology of tumor progression and in novel therapeutic designs. Finally, the possibility of assimilating mitotic catastrophe into a prognostic score is discussed. PMID- 21299347 TI - CD44(+)/CD24(-) cells are transit progenitors and do not determine the molecular subtypes and clinical parameters in breast carcinomas. AB - CD44(+)/CD24(-) cells have been associated with breast cancer stem/progenitor cell features. However, the status of this phenotype cells in normal, benign and malignant breast tissues has not been studied, and the clinical correlation of this subpopulation in breast cancer is not fully understood. The present study sought to identify these cells in a series of normal, benign, and malignant breast tissues and explore their correlation to the molecular subtypes of breast carcinoma and conventional pathological features. Double-staining immunohistochemistry (DIHC) of CD44 and CD24 was performed on 30 normal breast tissues, 30 breast fibroadenomas (FA), 60 breast invasive ductal carcinomas (IDC), and 3 breast cancer cell lines (MCF-7, MDA-MB-468, and MDA-MB-231). In the normal breast tissues and FAs, three phenotypes were observed including CD44(+)/CD24(+), CD44(+)/CD24(-), and CD44(-)/CD24(-) cells. In the IDCs, CD44( )/CD24(+) cells were detected, in addition to the three aforementioned phenotypes. The strong positive rate (+++, incidence >60%) of CD44(+)/CD24(-) was significantly increased from normal breast tissue, FAs to IDCs (0.0%-->6.7%- >21.7%). However, the CD44(+)/CD24(-) cells didn't correlate with ages of patients, lymph node metastasis, tumor size, molecular subtypes, and the expression of ER, PR, HER-2, PS2, Bcl-2, nm23. The proportion of CD44(+)/CD24(-) cells in MCF-7, MDA-MB-468, and MDA-MB-231 was about 1, 5, and 80%, respectively. The results indicate that the CD44(+)/CD24(-) cells are transit progenitors and have no association with the molecular subtypes and clinicopathological parameters in the IDCs. PMID- 21299348 TI - The expression pattern of Von Hippel-Lindau tumor suppressor protein, MET proto oncogene, and TFE3 transcription factor oncoprotein in renal cell carcinoma in Upper Egypt. AB - BACKGROUND: Genetic alterations in renal cell carcinoma (RCC) involve tumor suppressor genes such as Von Hippel-Lindau (VHL); proto-oncogenes such as MET and transcription factors such as TFE3 oncoprotein. AIM: To examine the clinicopathologic features and the expression of some oncogenic molecules in various RCCs in patients from Upper Egypt. MATERIALS AND METHODS: The authors examined the expression pattern of pVHL; MET; and TFE3 proteins in 59 RCC using immunoperoxidase staining methods. The study group consisted of clear cell RCCs (CRCC); papillary RCCs type 1 (PRCC1); papillary RCCs type 2 (PRCC2); Xp11-2 translocation RCCs (XP11.2RCC); chromophobe RCCs (ChRCC); and sarcomatoid RCCs (SRCC). RESULTS: Variations were found in the expression of these molecules in the different types of RCCs. The mean age of RCCs among Egyptians was 52.70 +/- 1.73 years; with male sex predominance. Mass lesion; pain; and hematuria were the main presenting features. Metastatic disease was more frequent with CRCC variant. pVHL expression was strong in PCRCC2; Xp11.2RCC; and ChRCC; moderate in CRCC; and weak in both PRCC1 and sarcomatoid RCC. MET protein expression was moderate in Xp11.2RCC; PRCC1; PRCC2; and sarcomatoid RCC. TFE3 protein expression was strong in Xp11.2RCC and PRCC2 variants. The expression was moderate in PRCC1; CRCC; ChRCC; and sarcomatoid RCC. Positive correlation was found in the expression of the different proteins (pVHL; MET; and TFE3) and some histological features (tumor grade; inflammation; necrosis and metastasis) and the presence of metastasis and some histological features (inflammation and/or necrosis). CONCLUSIONS: This study provides the first indication about the clinicopathologic features of RCCs in Upper Egypt. The variable expression of these molecules in the different variants of RCC suggests that several oncogenic pathways are operational in their development. PMID- 21299349 TI - Microvillous inclusion disease--an ultrastructural diagnosis: with a review of the literature. AB - Microvillous inclusion disease is a rare disorder of infancy associated with protracted diarrhea. This malady reveals distinct ultrastructural changes. The surface enterocytes of the duodenum show vesicles lined with microvilli and the surface microvilli are poorly formed. The authors present one case of microvillous inclusion disease with a review of the literature. PMID- 21299350 TI - Unexpected Fabry disease in a renal allograft kidney: an underrecognized cause of poor allograft function. AB - Fabry disease is an X-linked recessive lysosomal storage disease caused by a deficiency of alpha-galactosidase A, with characteristic ultrastructural cytoplasmic myelin-like inclusions. Renal lesions are seen in male and variably in heterozygous female patients. One previous report has described Fabry disease involving a renal allograft from a deceased female donor with no history of Fabry disease. The authors describe another case, in which suspicion for Fabry disease was raised ultrastructurally. This serves as a reminder that proteinuria after renal transplantation may be due to donor-derived disease. Fabry disease is probably an underrecognized cause of graft dysfunction. This case provides further justification for ultrastructural examination of renal allograft biopsies. PMID- 21299351 TI - Significant retinal capillary basement membrane thickening in hyperglycemic and normoglycemic diabetic-prone (DP) BB Wistar rats. AB - The diabetic-prone BioBreeding Wistar (BB/DP) rat is an autoimmune model of insulin-dependent diabetes mellitus. Approximately 90% of the animals (BB/DPh) are hyperglycemic by 90-120 days of age, while the remaining ~10% (BB/DPn) and diabetes-resistant rats (BB/DR) are normoglycemic for life. The transmission electron microscope data from this study demonstrate expected significant age- and diabetes-related increases in retinal capillary basement membrane (RCBM) widths in (BB/DPh) rats relative to BB/DR animals. However, the data show, for the first time, an unexpected significant RCBM thickening in (BB/DPn) rats compared to BB/DR animals at 6 months and 1 year post-onset of hyperglycemia. PMID- 21299352 TI - Type 1 and Type 2 cytokines imbalance in adult male C57BL/6 mice following a 7 day oral exposure to perfluorooctanesulfonate (PFOS). AB - Previous studies indicate that exposure to perfluorooctanesulfonate (PFOS), a ubiquitous and highly persistent environmental contaminant induces immunotoxicity in mice. However, clear mechanisms to explain any PFOS-induced immunotoxicity are still unknown. The study here sought to examine the ability of PFOS to potentially perturb T-helper (T(H))-1 and -2 cell cytokine secreting activities, as well as to cause shifts in antibody isotype levels, as possible mechanisms involved in PFOS-induced immunotoxicity. Adult male C57BL/6 mice were given by gavage 0, 5, or 20 mg PFOS/kg/d for 7 days. One day after the final exposure, spleens from these hosts were isolated and used for analyses of the ex vivo production of T(H)1-type (interleukin-2 (IL-2), interferon-gamma (IFNgamma), T(H)2-type (IL-4), and IL-10 cytokines by isolated splenocytes. In addition, serum was isolated from these mice in order to assess their levels of immunoglobulin M (IgM) and IgG antibodies. In all studies, levels of the cytokines of the antibodies were quantified via enzyme-linked immunosorbent assay or enzyme-linked immunosorbent spot. The results here showed that IL-2 and IFNgamma formation was reduced, but that IL-4 production increased by the 5 and 20 mg PFOS/kg/d treatments. Serum IgM levels decreased significantly (in dose related manner) as a result of the PFOS exposures; serum IgG levels increased markedly with 5 mg PFOS/kg/d, but decreased slightly with the 20 mg PFOS/kg/d regimens PFOS exposure increased serum corticosterone levels in a dose-dependent manner. These results indicated that, after a high-dose short-term exposure to PFOS, a host's immune state is likely to be characterized by a shift toward a more T(H)2-like state that, in turn, may lead to suppression of their cellular response and enhancement of their humoral response. PMID- 21299353 TI - Evaluation of suppressive effects of paraquat on innate immunity in Balb/c mice. AB - The toxic effect of paraquat (PQ), an herbicide that has been used widely in agriculture, on some parameters of the immune system was investigated. PQ was administered to Balb/c mice as intraperitoneal doses of 0.01, 0.1, or 1.0 mg PQ/kg body weight (BW) for a total of 28 days. Besides the histopathological examination of each host?s vital organs, measures of their splenic and bone marrow cellularity, blood macrophage/granulocyte phagocytic activity, total serum immunoglobulin M (IgM) and IgG, complement C3, and splenic CD49b (natural killer) cell levels, as well as of serum aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase and complement-mediated lytic activity (CH50), activities, were then performed following the respective final treatments. The results indicate that high and medium doses of PQ (i.e., 1 and 0.1 mg/kg) could lead to suppressed phagocytic activity by circulating macrophages/granulocytes. The data also revealed that the high PQ dose induced a significant decrease (p<0.05) in spleen cellularity and splenic CD49b cell levels, along with numerous histopathological changes in the spleen. However, at none of the doses tested did PQ produce changes in serum levels of C3, total IgG or IgM, or in the CH50. At 0.01 mg PQ/kg/day, no histopathological or functional disturbances were detected. These results indicate that PQ at doses more than 0.1?mg/kg has toxic effects on the cellular components of the innate immune system of Balb/c mice. The present results, however, indicate that at an exposure level below the recommended acceptable daily intake limit of 0.005 mg/kg, no observable immunotoxicity effect might be expected. PMID- 21299354 TI - The hair dyes PPD and PTD fail to induce a T(H)2 immune response following repeated topical application in BALB/c mice. AB - 1,4-Phenylenediamine (PPD) and the structurally-related 1,4-toluenediamine (PTD) are frequently used oxidative hair dye precursors that can induce a delayed-type hypersensitivity reaction known as contact allergy. Very rare cases of Type 1 (IgE-mediated) allergic responses associated with PPD or PTD have been reported among hair dye users. As part of an effort to determine if repeated dermal exposure to the dyes could induce a T-helper-2 (T(H)2) response, we used a dermal exposure regimen in mice reported to identify a T(H)2 response. Ear swelling was evident at post-final exposure to PPD and PTD, indicating that an immune response was observed. However, cytokine mRNA after repeated topical exposure to these two chemicals showed no shift in the expression toward the typical T(H)2 cytokines interleukin (IL)-4 and IL-10 compared to the T(H)1 cytokine interferon (IFN) gamma. Consistent with these cytokine profiles, no concomitant increase in total serum IgE antibody titer or in B220+IgE+ lymphocytes in lymph nodes and skin application site skin was detected. In contrast, using an identical exposure regimen, animals topically exposed to the known respiratory (Type 1) allergen toluene 2,4-diisocyanate (TDI) showed significant expression of IL-4 and IL-10 mRNA compared to IFN? as well as an increase in total serum IgE and in B220+IgE+ cells in lymph nodes and skin application site. The data generated are consistent with the pattern of adverse reactions to hair dyes seen clinically, which overwhelmingly is of delayed rather than immediate-type hypersensitivity. Although current animal models have a limited ability to detect rare T(H)2 responses to contact allergens, the present study results support the view that exposure to hair dyes is not associated with relevant T(H)2 induction. PMID- 21299355 TI - Theoretical aspects of autism: causes--a review. AB - Autism, a member of the pervasive developmental disorders (PDDs), has been increasing dramatically since its description by Leo Kanner in 1943. First estimated to occur in 4 to 5 per 10,000 children, the incidence of autism is now 1 per 110 in the United States, and 1 per 64 in the United Kingdom, with similar incidences throughout the world. Searching information from 1943 to the present in PubMed and Ovid Medline databases, this review summarizes results that correlate the timing of changes in incidence with environmental changes. Autism could result from more than one cause, with different manifestations in different individuals that share common symptoms. Documented causes of autism include genetic mutations and/or deletions, viral infections, and encephalitis following vaccination. Therefore, autism is the result of genetic defects and/or inflammation of the brain. The inflammation could be caused by a defective placenta, immature blood-brain barrier, the immune response of the mother to infection while pregnant, a premature birth, encephalitis in the child after birth, or a toxic environment. PMID- 21299356 TI - Theoretical aspects of autism: biomarkers--a review. AB - Autism is dramatically increasing in incidence and is now considered an epidemic. There are no objective means to diagnose the disorder. Diagnosis is made subjectively, based on the perceived behavior of the subject. This review presents an approach toward development of an objective measure of autism. Covering the literature from 1943 to the present in the PubMed and Ovid Medline databases, this review summarizes evidence of hormones, metabolites, amino acids, and other biomarkers present in significantly different quantities in autistic subjects compared to age- and sex-matched controls. These differences can be measured in the gastrointestinal, immunologic, neurologic, and toxicologic systems of the body, with some biomarkers showing ubiquitous application. In addition, there are unifying concepts, i.e., increased vulnerability to oxidative stress, immune glutamatergic dysfunction, and pineal gland malfunction. The variances of the biomarkers from the norm present the opportunity to create biomarker arrays that when properly developed and analyzed could result in an objective diagnosis with a ranking of the severity of autism for each subject. The contribution of each biomarker to the overall diagnosis could be calculated, thus providing a profile pattern unique to the individual. This profile could consequently provide information for therapeutic interventions on an individual basis. PMID- 21299358 TI - The impact of clinical maternal chorioamnionitis on neurological and psychological sequelae in very-low-birth weight infants: a case-control study. AB - AIMS: To assess the relationship between clinically maternal chorioamnionitis and outcome in preterm very-low-birth weight (VLBW) infants. METHODS: An observational case-control study was conducted in the neonatology departments of 12 acute care teaching hospitals in Spain. Between January 2004 and December 2006, all consecutive VLBW (<=1500 g) infants who were born to a mother with clinical chorioamnionitis were enrolled. The controls included infants who were born to mothers without chorioamnionitis, matched by gestational age, and immediately born after each index case. At a corrected age of 24 months, a neurological examination and a psychological assessment of the surviving children were performed. RESULTS: Sixty-six of the newborn infants died; therefore, 262 infants from the original sample were available for the study. Follow-up data were obtained at a corrected age of 24 months from a total of 209 children (106 cases and 103 controls, 80% of the original sample size). Seventy children (33.5%) were diagnosed with some type of sequelae. The following conditions were all more prevalent in infants born to mothers with chorioamnionitis in comparison to controls: low development quotient (98.3+/-12.15 vs. 95.9+/-15.64; P=0.497), cerebral palsy (4.9% vs. 10.4%; P=0.138), seizures (1.0% vs. 3.8%; P=0.369), and other neurological or sensorial sequelae (32.0% vs. 34.9%; P=0.611). CONCLUSIONS: After controlling for gestational age, the study population demonstrated that the neurological outcomes in infants at a corrected age of 24 months was not worsened by chorioamnionitis. PMID- 21299357 TI - Maternal and early postnatal polychlorinated biphenyl exposure in relation to total serum immunoglobulin concentrations in 6-month-old infants. AB - Animal data indicate that developmental tetrachlorodibenzo-p-dioxin exposure alters immune function; however, the potential immunotoxicity of dioxin-like and non-dioxin-like polychlorinated biphenyls (PCBs) in the developing infant is an understudied area. The aim of the current study is to examine the association between maternal and early postnatal PCB concentrations in relation to total infant serum immunoglobulin concentrations determined at 6-months-of-age. We selected 384 mother-infant pairs participating in a birth cohort study in Eastern Slovakia. PCB concentrations of several congeners were determined in maternal and cord serum samples and in infant serum samples collected at 6-months-of-age using gas chromatography with electron capture detection. Total immunoglobulin (Ig) G, A, and M concentrations were determined by nephelometry, and IgE concentrations were determined by enzyme-linked immunoassay. Linear regression models with adjustment for potential confounding factors were used to estimate the associations between maternal, cord, and 6-month infant PCB concentrations and total serum immunoglobulins. The median maternal serum concentration of PCB-153 was 140?ng/g lipid, ?10-fold higher than concentrations in childbearing-age women in the United States during the same period. Maternal, cord, or 6-month infant PCB concentrations were not associated with total serum immunoglobulin levels at 6 months, regardless of the timing of PCB exposure, PCB congener, or specific immunoglobulin. In this population, which has high PCB concentrations relative to most populations in the world today, we did not observe any association between maternal and early postnatal PCB concentrations and total immunoglobulin measures of IgG, IgA, IgM, or IgE. PMID- 21299359 TI - Retinol-binding protein-4 is decreased in patients with preeclampsia in comparison with normal pregnant women. AB - AIMS: The aim of this study was to investigate retinol-binding protein-4 (RBP4) levels in maternal and umbilical cord serum in patients in the third trimester of pregnancy with preeclampsia in comparison to levels in normal pregnant women. METHODS: The RBP4 levels in maternal and umbilical cord serum were measured and compared by enzyme-linked immunosorbent assay in 16 normal pregnant and 16 patients with preeclampsia. RESULTS: Both maternal and umbilical cord serum RBP4 levels were significantly decreased in patients with preeclampsia, as compared to normal pregnant women (maternal serum, median 168.0 MUg/mL vs. 202.0 MUg/mL, P<0.001; umbilical cord serum, median 147.9 MUg/mL vs. 193.0 MUg/mL, P<0.001). Preeclampsia was independently related to RBP4 levels of maternal and umbilical cord serum. CONCLUSION: Both maternal and umbilical cord serum RBP4 levels were lower in patients with preeclampsia than in normal pregnant women in the third trimester of pregnancy. PMID- 21299361 TI - Competitive solid-phase immunoassay of gastrin in serum using time-resolved fluorometry. AB - BACKGROUND: A competitive solid-phase assay for the measurement of gastrin in serum using time-resolved fluorescence was developed as an alternative to conventional radioimmunoassay (RIA) technology. METHODS: The assay depends on the competitive binding of unlabelled versus Eu-labelled gastrin to specific gastrin antibodies--bound to anti-rabbit IgG immobilized on polystyrene microtitration strips. The bound Eu(3+)-label was dissociated from the bound gastrin and converted to a fluorescent beta-diketone chelate which was measured by fluorometry with time-resolution. RESULTS: Using a sample volume of 50 MUl the lower limit of detection was below 10 pmol/L. Dilution of samples showed an excellent linearity. Spiking with gastrin-17 in known concentrations showed a recovery of 103% indicating that there is no bias inherent in the assay. The method correlated fully with the routine in-house radioimmunoassay in the concentration range 10-400 pmol/L (slope = 0.98 with r(2) = 0.98). Thus the reference interval for clinical samples does not require modification when changing from one method to the other. CONCLUSION: We have described a convenient and accurate competitive assay for measurement of gastrin in serum based on solid phase technology using time-resolved fluorometric detection as a realistic alternative to the established state-of-the-art RIA-technology. PMID- 21299360 TI - Concussive brain trauma in the mouse results in acute cognitive deficits and sustained impairment of axonal function. AB - Concussive brain injury (CBI) accounts for approximately 75% of all brain-injured people in the United States each year and is particularly prevalent in contact sports. Concussion is the mildest form of diffuse traumatic brain injury (TBI) and results in transient cognitive dysfunction, the neuropathologic basis for which is traumatic axonal injury (TAI). To evaluate the structural and functional changes associated with concussion-induced cognitive deficits, adult mice were subjected to an impact on the intact skull over the midline suture that resulted in a brief apneic period and loss of the righting reflex. Closed head injury also resulted in an increase in the wet weight:dry weight ratio in the cortex suggestive of edema in the first 24 h, and the appearance of Fluoro-Jade-B labeled degenerating neurons in the cortex and dentate gyrus of the hippocampus within the first 3 days post-injury. Compared to sham-injured mice, brain-injured mice exhibited significant deficits in spatial acquisition and working memory as measured using the Morris water maze over the first 3 days (p<0.001), but not after the fourth day post-injury. At 1 and 3 days post-injury, intra-axonal accumulation of amyloid precursor protein in the corpus callosum and cingulum was accompanied by neurofilament dephosphorylation, impaired transport of Fluoro-Gold and synaptophysin, and deficits in axonal conductance. Importantly, deficits in retrograde transport and in action potential of myelinated axons continued to be observed until 14 days post-injury, at which time axonal degeneration was apparent. These data suggest that despite recovery from acute cognitive deficits, concussive brain trauma leads to axonal degeneration and a sustained perturbation of axonal function. PMID- 21299362 TI - Dendritic cell-tumor cell hybrids and immunotherapy: what's next? AB - Dendritic cells (DC) are professional antigen-presenting cells currently being used as a cellular adjuvant in cancer immunotherapy strategies. Unfortunately, DC based vaccines have not demonstrated spectacular clinical results. DC loading with tumor antigens and DC differentiation and activation still require optimization. An alternative technique for providing antigens to DC consists of the direct fusion of dendritic cells with tumor cells. These resulting hybrid cells may express both major histocompatibility complex (MHC) class I and II molecules associated with tumor antigens and the appropriate co-stimulatory molecules required for T-cell activation. Initially tested in animal models, this approach has now been evaluated in clinical trials, although with limited success. We summarize and discuss the results from the animal studies and first clinical trials. We also present a new approach to inducing hybrid formation by expression of viral fusogenic membrane glycoproteins. PMID- 21299363 TI - JACIE celebrates its 10-year anniversary with the demonstration of improved clinical outcome. PMID- 21299364 TI - Elevated procalcitonin predicts Gram-negative sepsis in haematological patients with febrile neutropenia. AB - OBJECTIVE: To compare semi-quantitative procalcitonin with C-reactive protein in predicting bacteraemia in haematological patients with neutropenic fever. METHODS: A total of 77 patients treated with intensive chemotherapy for haematological malignancy at Kuopio University Hospital were candidates for study entry. Eleven of these patients did not fulfil the criteria for neutropenic fever, and 66 patients were finally included. Nineteen patients had acute myeloid leukaemia and 47 had received high-dose chemotherapy supported by autologous stem cell transplant. Ninety neutropenic fever episodes in these 66 patients fulfilled the study entry criteria, with microbiological cultures, procalcitonin and C reactive protein measurements available. Serum procalcitonin and C-reactive protein were analyzed at the onset of each neutropenic fever episode on day 0, and then daily from days 1 to 4. RESULTS: Bacteraemia was observed in 21 episodes (23%) and the criteria for severe sepsis were fulfilled in 13 episodes (14%). Half of the bacteraemic episodes were caused by Gram-negative bacteria. The kinetics of procalcitonin and C-reactive protein were similar, with increasing levels for 2 to 4 days after the onset of fever. The procalcitonin level on days 1, 2, 3 and 4 was associated with bacteraemia and Gram-negative bacteraemia, but not with the development of severe sepsis. On day 1, a procalcitonin level above 0.5 ng/ml had a sensitivity of 57% and 70% and specificity of 81% and 77% to predict bacteraemia and Gram-negative bacteraemia, respectively. CONCLUSIONS: An elevated level of procalcitonin within 24 h after the onset of neutropenic fever predicts bacteraemia and Gram-negative bacteraemia in haematological patients. PMID- 21299365 TI - Antibiotic prescribing in outpatients: Hospital and seasonal variations in Ujjain, India. AB - BACKGROUND: We prospectively explored prescribing patterns, with an emphasis on seasonal and hospital differences, for adults and children under 5 y of age reporting to the outpatient clinics of 2 hospitals (1 teaching hospital and 1 non teaching hospital) in Ujjain, India. METHODS: The study was done over 15 months from November 2007 to February 2009, covering 4 seasons (2 winters, 1 summer and 1 rainy season). The treating consultant completed diagnosis prescribing forms for first consultations with outpatients for selected infectious disease complaints (n = 5623). Antibiotics were coded according to the World Health Organization, Anatomic Therapeutic Chemical classification with defined daily dose (ATC/ DDD). All DDD were calculated per 1000 patients per diagnosis (DDD/TPD). RESULTS: The study covered 80% of all first consultations. Antibiotics were prescribed to 66.3% (3732/5623) of patients. Indications of antibiotic prescribing were respiratory tract infections (42.9%), vaginal discharge (24.2%), urinary tract infections (11.5%), skin and soft tissue infections (10.5%), diarrhoea (9.4%), dysentery (1.2%) and prophylaxis (0.6%). The most commonly prescribed antibiotic group was the quinolones. The antibiotic prescribing rate differed by diagnosis, age group, education, hospital and season, and was 11.3 percentage units less in the teaching hospital compared to the non-teaching hospital (p < 0.001). The study showed higher prescribing of broad-spectrum antibiotics in the non-teaching hospital, with a peak-prescribing rate (75%) during the summer, while the teaching hospital had a peak prescribing rate (70%) during the rainy season. CONCLUSIONS: The peak prescribing rates during the summer and rainy season probably reflect the higher diagnostic and follow-up uncertainties faced by the treating physicians. The method used in this study could be used in busy outpatient settings. PMID- 21299366 TI - Pharyngeal Chlamydia trachomatis is not uncommon any more. AB - BACKGROUND: The significance of Chlamydia trachomatis (Ct) infection in the pharynx, and possible symptoms, are under discussion. Most studies have involved only homo/bisexual men. We report findings of pharyngeal Ct (PhCt) infections in patients with long-lasting throat discomfort and the prevalence of PhCt in genitally Ct-infected young people in a Swedish primary care setting. METHOD: Sub study 1 (SS1) included 48 persons aged 15-35 y, with pharyngeal discomfort for more than 14 days. Sub-study 2 (SS2) included 150 persons, aged 15-35 y, with genital Ct. Questionnaires concerning symptoms, sexual behaviour and sexual identity were completed for both groups. Samples for Ct testing were taken from the pharynx, and in SS1, samples were also collected to ascertain genital Ct. RESULTS: In SS1, 2 of 48 persons (4%) with pharyngeal discomfort had PhCt. In all, 35 of the 48 persons (73%) included in SS1 reported unprotected oral sex during the previous year. In SS2, 11 of 92 women (12%) and 4 of 58 men (7%) tested positive for PhCt. More women (94%) than men (83%) had given unprotected oral sex. Persons with PhCt had more symptoms from the upper respiratory tract (p = 0.04). CONCLUSIONS: Some primary care patients with long-lasting throat discomfort have a PhCt infection. PhCt infection is not uncommon in genitally infected sexually active people. More heterosexual women than heterosexual men had given unprotected oral sex and were infected by Ct in the pharynx. Thus, research on PhCt should not focus on homo/bisexual men only. Information about Ct should include the risk of contracting a PhCt infection as well as a gender perspective. PMID- 21299367 TI - Loss of activities and its effect on the well-being of substance abusers. AB - AIMS: Participation in everyday activities positively influences well-being, but few have studied how participation in activities influences well-being among patients with substance use disorders. The authors examined the number of past, recent, and desired future activities of patients being admitted to five units for inpatient substance abuse treatment at a Norwegian university hospital. MAJOR FINDINGS: The total number of activities had dropped significantly compared with before the respondents started abusing substances, and the respondents desired an increase in activities in the future. A lower level of well-being as measured by the WHO-5 was predicted by a more pronounced drop in number of activities from past to recent and by more severe use of alcohol and other substances. Principal conclusion. Substance abuse is associated with a change in number of activities. Losing activities may contribute to a decrease in well-being. Helping substance abuse patients regain positive activities could improve well-being. PMID- 21299368 TI - Assessing change in the family impact of caries in young children after treatment under general anaesthesia. AB - OBJECTIVE: To examine the properties, validity and responsiveness of the Family Impact Scale in a consecutive clinical sample of patients undergoing dental treatment under general anaesthesia. MATERIALS AND METHODS: A consecutive clinical sample of parents/caregivers of children receiving dental treatment under general anaesthesia provided data using the Family Impact Scale (FIS) component of the COHQOL((c)) Questionnaire. The first questionnaire was completed before treatment, the follow-up questionnaire 1-4 weeks afterward. Treatment associated changes in the FIS and its components were determined by comparing baseline and follow-up data. RESULTS: Baseline and follow-up data were obtained for 202 and 130 participants, respectively (64.4% follow-up). All FIS items showed large relative decreases in prevalence, the greatest seen in those relating to having sleep disrupted, blaming others, being upset, the child requiring more attention, financial difficulties and having to take time off work. Factor analysis largely confirmed the underlying factor structure, with three sub-scales (parental/family, parental emotions and family conflict) identified. The parental/family and parental emotions sub-scales showed the greatest treatment-associated improvement, with large effect sizes. There was a moderate improvement in scores on the family conflict sub-scale. The overall FIS showed a large improvement. CONCLUSION: Treating children with severe caries under general anaesthesia results in OHRQoL improvements for the family. Severe dental caries is not merely a restorative and preventive challenge for those who treat children; it has far-reaching effects on those who share the household and care for the affected child. PMID- 21299369 TI - Expression of the erbB/HER receptor family in the bovine uterus during the sexual cycle and the relation of this family to serum sex steroids. AB - Our study was designed to investigate immunohistochemically the expression of the receptors of the erbB/HER family (erbB1/HER1, erbB2/HER2, erbB3/HER3, erbB4/HER4) in the bovine uterus during the follicular and luteal phases of the sexual cycle, and the relation to ovarian sex steroids. The stage of the estrous cycle in 30 Holstein bovine was assessed based on the gross and histological appearance of the ovaries and uterus, and on blood steroid hormone levels. Tissue samples taken from the uterus were fixed in 10% formaldehyde for routine histological processing. Positive membrane and cytoplasmic staining of varying intensity were determined in the uterus during the follicular and luteal phases of the sexual cycle for erbB/HER receptors in luminal and glandular epithelial cells, connective tissue, smooth muscle and vascular endothelial and smooth muscle cells. We demonstrated that the apical and basal membranes of luminal epithelial cells and the apical membrane of glandular epithelial cells reacted with erbB1/HER1 and erbB2/HER2 during both the follicular and luteal phases. The reaction for erbB3/HER3 and erbB4/HER4 was stronger in the cytoplasm of luminal and glandular epithelial cells, but was heterogeneous. During both the follicular and luteal phases, the percentage and staining intensity of luminal and superficial glandular epithelial cells reacting positively with the receptors erbB1/HER1, erbB2/HER2, erbB3/HER3 and erbB4/HER4 were greater than those of deep glandular epithelial and connective tissue cells (p < 0.05). We demonstrated that the expression of the erbB/HER receptor family varied with different cell types in the bovine uterus during the follicular and luteal phases. PMID- 21299370 TI - Tolerance of a virtual reality intervention for attention remediation in persons with severe TBI. AB - OBJECTIVE: To evaluate the feasibility of applying virtual reality and robotics technology to improve attention in patients with severe traumatic brain injury (TBI) in the early stages of recovery. METHODS: A sample of TBI patients (n=18, aged 19-73) who were receiving acute inpatient rehabilitation completed three dimensional cancellation exercises over two consecutive days in an interactive virtual environment that minimized distractions and that integrated both visual and haptic (tactile) stimuli. Observations of behaviour during the intervention and of the instructions needed to encourage compliance were recorded. Performance data were compiled to assess improvement across three different treatment conditions. OUTCOMES: Fifteen of the 18 patients demonstrated tolerance of the virtual environment by completing the entire treatment protocol. Within-subjects comparisons of target acquisition time during treatment showed that a treatment condition that included haptic cues produced improved performance compared to a condition in which such cues were not provided. Separating out participants who were in post-traumatic amnesia showed that this group also demonstrated improvement in performance across trials despite their memory impairment. CONCLUSIONS: It is proposed that attention exercises using virtual environments are well-tolerated and engaging and that they could be beneficial for inpatients with severe TBI. PMID- 21299371 TI - Causes of traumatic brain injury in patients admitted to Rafidia, Al-Ittihad and the specialized Arab hospitals, Palestine, 2006?2007. AB - PRIMARY OBJECTIVE: The eruption of Al-Aqsa Intifada created a war situation in Palestine, increasing the number of firearms injuries caused by occupying Israeli forces as well as disabling head injuries. No data were available to the Palestinian Ministry of Health and other health organizations on traumatic brain injury (TBI) in Palestine. This study, therefore, sought to determine the causes and outcomes of TBI in patients who were admitted to three hospitals in Nablus, Palestine. RESEARCH DESIGN: Retrospective review of medical records and contacts with patients and/or caregivers. METHODS AND PROCEDURES: The medical records of patients who were diagnosed with TBI (n=312) and admitted to any one of the three hospitals in 2006 and 2007 were reviewed. Data were also obtained from follow-up home visits and telephone calls with consenting patients and/or caregivers. MAIN OUTCOMES AND RESULTS: The major causes of TBI were assault (33%), falls (32.1%), road traffic crashes (29.8%) and impacts from heavy objects (3.2%). Gunshot wounds are a major cause of head injury in Palestine. CONCLUSIONS: The study shows that assault with firearms is the most frequent cause of TBI in this population and that patients with head injuries due to assault have poorer outcomes at discharge than those injured in other ways. PMID- 21299372 TI - Aspergillus viridinutans: an agent of adult chronic invasive aspergillosis. AB - In contrast with the common hematogenous dissemination of invasive aspergillosis (IA), we present case with a protracted course through anatomical planes in an immunocompromised adult male. The unusual clinical features and laboratory findings led to fungal genotyping and identification of the mold as Aspergillus viridinutans. It appears to be the first described case of IA caused by this agent in an adult patient. PMID- 21299373 TI - Primary subcutaneous Alternaria alternata infection of the hand in an immunocompromised host. AB - We describe a case of a progressive subcutaneous Alternaria alternata infection in the hand of a patient with chronic lymphocytic leukemia (CLL). The diagnosis was based upon the examination of tissue biopsy and isolation of the etiologic agent in culture. The identity of the isolate was determined by phenotypic characteristics and by sequencing the ITS and D1/D2 regions of the rDNA. Despite combination therapy with voriconazole and micafungin, the lesion continued to progress. Posaconazole therapy, along with surgical excision of the infected tissue, resulted in the eradication of infection. The limitations of the clinical management of invasive Alternaria infections are discussed. PMID- 21299374 TI - The evaluation of in vitro pharmacodynamic properties of amphotericin B, voriconazole and caspofungin against A. fumigatus isolates by the conventional and colorimetric time-kill assays. AB - Aspergillus fumigatus is an opportunistic pathogen responsible for life threatening infections in immuncompromised patients. Data about the in vitro pharmacodynamics of antifungals against A. fumigatus are limited. In the present study, we investigated the fungicidal activities, at concentrations of 1, 4 and 16 times the minimum inhibitory concentration (MIC), of caspofungin (CAS), amphotericin B (AMB) and voriconazole (VORI) against eight A. fumigatus isolates through the use of time kill and 2,3-Bis [2-methoxy-4-nitro-5-(sulfenylamino) carbonyl-2H-tetrazolium-hydroxide] (XTT) reduction tests. By the conventional time kill test, AMB was fungicidal (>=99.9% reduction in colony forming units; CFU) for all isolates at 4-16 MICs after 48 h incubation. The fungicidal effect for VORI was determined at 4 * MIC for one isolate and at 16 * MIC for four isolates at 48 h of exposure. CAS was also fungicidal at 1 * MIC for one isolate and at 4-16 MICs for two isolates at 48 h. While the percentage of median killing of AMB was found by the time-kill method with XTT as 99% at 4 * MIC and 99.28% at 16 * MIC, that of VORI was 94.5% at 4 * MIC and 92.88% at 16 * MIC after 48 h of incubation. However, a significant increase was observed compared to initial inoculum size with CAS after 48 h. Since the XTT method measures all cellular viability in media, it may give more reliable results about pharmacodynamics of antifungal agents against Aspergillus spp. than the time kill test. PMID- 21299375 TI - Free-field correction values for Interacoustics DD 45 supra-aural audiometric earphones. AB - OBJECTIVE: This paper reports free-field correction values for the Interacoustics DD 45 audiometric earphone. The free-field correction values for earphones provide the loudness based equivalence to loudspeaker presentation. Correction values are especially used for the calibration of audiometric equipment for speech audiometry performed with headphones. Calibration values may be found in, e.g. the ISO 389 series of standards. DESIGN: The free-field correction values were determined by means of loudness balance measurements of one-third octave noises (centre frequencies 125 Hz to 8000 Hz) presented alternately from a loudspeaker in a free field and from the earphones. The procedure was essentially in accordance with the free-field frequency response procedure described in IEC 60268-7: Headphones and earphones. STUDY SAMPLE: Four earphones and 14 test subjects. RESULTS: Free field correction values are reported for the acoustic coupler IEC 60318-3 (NBS 9-A) and for the ear simulator IEC 60318-1. The results are in good agreement with the results of another independent investigation. CONCLUSIONS: The reported free-field correction values may be used as part of the basis for future standardization of the DD 45 earphone. PMID- 21299376 TI - Implementation of a fast method for measuring psychophysical tuning curves. AB - OBJECTIVE: To implement a fast method for measuring psychophysical tuning curves (PTCs) for use in clinical applications, such as assessment of frequency selectivity and detection of dead regions in the cochlea. DESIGN: The method is based on that described by Sek et al (2005) and has been implemented in software that can be run on a PC with a good-quality sound card. In addition to the main narrowband noise masker, a lowpass noise masker can be generated to prevent detection of a distortion band corresponding to the simple difference tone. RESULTS: The software includes a routine for measuring the absolute threshold at the signal frequency and includes methods for estimating the frequency at the tip of the PTC. A PTC can typically be determined in about three minutes. A small amount of practice (two to three runs) may be required to achieve stable results. CONCLUSIONS: The software implementation allows PTCs to be measured quickly without a requirement for specialised equipment. PMID- 21299377 TI - An adaptive clinical test of temporal resolution: age effects. AB - OBJECTIVE: Children with auditory processing disorder, as well as older adults with and without hearing loss, often report difficulty understanding speech in the presence of noise. There is evidence that deficient temporal resolution contributes to this difficulty. The purpose of this study was to establish within channel (WC) and across-channel (AC) gap detection thresholds (GDTs) for participants ages 7 to 84 years. DESIGN: GDTs were measured using narrow-band noise markers for two conditions of the Adaptive Tests of Temporal Resolution (ATTR): WC and AC. STUDY SAMPLE: Participants were 29 children (ages 7-12 years) with normal hearing, 30 younger adults (ages 22-41 years) with normal hearing, and 60 older adults (ages 50 to 84 years) with varying hearing sensitivity. RESULTS: GDTs are smallest and least variable for younger adults with normal hearing and are largest and most variable for the youngest children (ages 7-8 years). The GDTs of the other groups fell between those of the younger adults and youngest children. Group differences were more apparent for AC than WC conditions. CONCLUSIONS: WC and AC gap detection ability changes across the lifespan. The ATTR is an efficient tool for the assessment of temporal resolution at both ends of the lifespan. PMID- 21299378 TI - Non-invasive simultaneous recording of neuronal and vascular signals in subacute ischemic stroke. AB - In acute focal cerebral ischemia blood flow and neuronal activity change dramatically. A better understanding of the pathophysiological interactions of these two important parameters is limited owing to the lack of noninvasive techniques to simultaneously measure these parameters in humans. In this feasibility study, we used DC-magnetoencephalography and near-infrared spectroscopy to find out whether blood flow and neuronal activity as well as neurovascular coupling can be analyzed in patients suffering from subacute ischemic stroke. In a simple motor test condition, six patients with subacute ischemic stroke performed self-paced finger movements (30-s periods of movement, separated by 30-s periods of rest; for a total of 15 min). Combined DC magnetoencephalography and near-infrared spectroscopy were recorded over the affected and unaffected hemispheres. As a control group, four healthy subjects were investigated. In four out of six patients, the time courses of both signals closely followed the motor task cycles revealing significant differences between movement and rest periods. The vascular signal reached a maximum 1-5 s later than the neuronal signals. This proof-of-principle study demonstrates that it has become feasible to simultaneously and noninvasively monitor neuronal and vascular signal changes in patients in the subacute state of ischemic stroke. PMID- 21299379 TI - Mesenchymal stem cells enhance the engraftment and myelinating ability of allogeneic oligodendrocyte progenitors in dysmyelinated mice. AB - Multiple sclerosis is an autoimmune disease characterized by demyelination and axonal loss throughout the central nervous system. No regenerative treatment exists for patients who fail to respond to conventional immunosuppressive and immunomodulating drugs. In this scenario, stem cell therapy poses as a rational approach for neurological regeneration. Transplantation of embryonic-derived oligodendrocyte progenitor cells (OPCs) has been shown to promote remyelination and ameliorate animal models of neurodegenerative diseases. However, its therapeutic application is limited due to potential transplant rejection. In multiple sclerosis, an added concern is that transplant rejection would be most pronounced at sites of previous lesions, exacerbating a hyperactive immune response which could prevent remyelination and precipitate additional demyelination. Routine systemic immunosuppression may not be sufficient to prevent transplant rejection-associated immune reactions in the cerebral microenvironment. Mesenchymal stem cells (MSCs), due to their homing properties and inherent immunosuppressive nature, are a promising tool for clinical application targeted toward immunosuppression at sites of injury. In this study, we used a co-transplantation strategy to investigate the effect of syngeneic MSCs on the survival and remyelination abilities of allogeneic OPCs in adult nonimmunosuppressed shiverer mice. At all time points examined, cotransplantation with MSCs increased OPC engraftment, migration, and maturation in myelinating oligodendrocytes, which produced widespread myelination in the host corpus callosum. In addition, MSCs reduced microglia activation and astrocytosis in the brain of transplanted animals as well as T-cell proliferation in vitro. These data suggest that combining the immunomodulatory and trophic properties of MSCs with the myelinating ability of OPCs might be a suitable strategy for promoting neurological regeneration in demyelinating diseases. PMID- 21299380 TI - Can we add chlorhexidine into glass ionomer cements for band cementation? AB - OBJECTIVE: To test if the addition of chlorhexidine digluconate (CHD) might influence the mechanical properties and antibacterial properties of two different conventional glass ionomer cements (GICs) used for band cementation. MATERIALS AND METHODS: Two commercial brands of conventional GICs were used: Ketac Cem Easymix (3M/ESPE, St Paul, Minn) and Meron (Voco, Cuxhaven, Germany). The cements were manipulated in their original composition and also with 10% and 18% CHD in the liquid to create a total of six groups. Diametral tensile strength, compressive strength, microhardness, shear bond strength, and antibacterial effects in 5, 45, and 65 days against Streptococcus mutans were tested in all groups, and the data were submitted to statistical analyses. RESULTS: There were no significant differences between the groups of the same material in diametral tensile, compressive strength, and shear bond strength (P > .05). There was significant improvement in the microhardness to the Ketac Cem Easymix (P < .001). GICs with the addition of CHD showed significant inhibition of S. mutans growth in comparison with the control groups at the three time points evaluated (P < .001). The addition of 18% CHD resulted in higher bacterial inhibition (P < .001). CONCLUSIONS: The addition of chlorhexidine digluconate to conventional GICs does not negatively modify the mechanical properties and may increase the antibacterial effects around the GICs even for relatively long periods of time. PMID- 21299381 TI - Orofacial airway dimensions in subjects with Class I malocclusion and different growth patterns. AB - OBJECTIVE: To test the null hypotheses that there are no significant differences in craniofacial structures and orofacial airway dimensions in subjects with Class I malocclusion and different growth patterns. MATERIALS AND METHODS: Lateral cephalometric radiographs of 31 low angle (mean age, 14.0 +/- 2.0 years; range, 10.3-16.5 years), 40 high angle (mean age, 12.7 +/- 1.6 years; range, 10.1-16.2 years), and 33 normal growth (mean age, 13.9 +/- 1.3 years; range, 11.2-16.8 years) subjects with Class I malocclusion were examined. In total, 34 measurements (27 craniofacial and 7 orofacial airways) were evaluated. Groups were constituted according to the SN-MP angle. Group differences were analyzed with analysis of variance (ANOVA) and the Tukey test, at the P < .05 level. RESULTS: According to ANOVA, only 5 of the 27 craniofacial measurements showed no statistically significant differences among different growth patterns. For orofacial airway measurements, statistically significant differences were found in nasopharyngeal airway space (P < .01), palatal tongue space (P < .05), upper posterior airway space (PAS) (P < .05), and tongue gap (P < .001). No statistically significant orofacial airway differences were determined between low angle and normal growth subjects. High angle subjects had a larger tongue gap than those with normal and low angles (P < .01). Additionally, nasopharyngeal airway space (P < .01) and upper PAS (P < .05) measurements were larger and palatal tongue space (P < .05) was narrower in low angle than in high angle subjects. CONCLUSIONS: The null hypotheses were rejected. Significant differences in craniofacial morphology and orofacial airway dimensions of Class I subjects with different growth patterns were identified. PMID- 21299382 TI - Influence of thermal or chemical degradation on the frictional force of an experimental coated NiTi wire. AB - OBJECTIVE: To evaluate the friction force in sliding systems composed of coated NiTi archwires, coated NiTi subjected to thermal cycling, and coated NiTi subjected to acid solution immersion, and compare them to NiTi and polymeric wires. The null hypothesis is that there will be no difference among the wires as to friction force. MATERIALS AND METHODS: Samples of NiTi (n = 05), coated NiTi (n = 15), and OPTIS (n = 05) 0.016 inches in diameter and 50 mm long, in conjunction with Metafasix ligatures and saliva in InVu brackets, were submitted to friction testing. Among the 15 coated NiTi samples, 5 were submitted to thermal cycling for 3000 cycles; the other 5 samples were immersed in acid solution for 30 days. The results were statistically analyzed at P > .05 or P > .01. Microscopic analysis was performed in the coated NiTi wires before and after thermal cycling and acid solution immersion. RESULTS: The mean (+/- standard deviation) maximum friction force for NiTi, coated NiTi, and OPTIS was 105.20 +/- (2.63); 99.65 +/- (0.64); 59.76 +/- (4.93) (P = .000), respectively. There was no significant difference in NiTi, coated NiTi, and acid-immersed coated NiTi (P > .05). Among the thermal-cycled or acid-immersed coated NiTi wires there was lower friction force in those undergoing thermal cycling (P = .001). The coated NiTi and the OPTIS presented homogeneous surfaces, whereas NiTi wires presented a heterogeneous surface. Fractures were observed in the coated NiTi wires that underwent thermal cycling. CONCLUSION: OPTIS, thermal-cycled coated NiTi, coated NiTi, NiTi, and acid-immersed coated NiTi presented, respectively, increasing values of maximum friction force. PMID- 21299383 TI - Can commonly used profile planes be used to evaluate changes in lower lip position? AB - OBJECTIVES: To determine the validity of five profile planes commonly used to describe the horizontal changes of the lower lip during orthodontic treatment. MATERIALS AND METHODS: Pretreatment and posttreatment cephalograms of 79 patients (12.4 +/- 2.8 years of age) were evaluated. Lower lip (labrale inferiorus) changes over time were measured relative to the Rickett's E-line, Steiner's S1 line, Burstone's B-line, Sushner's S2-line, and Holdaway's H-line. As an independent measure of actual horizontal lip changes, the labrale inferiorus was measured relative to a stable reference plane registered on the sella and oriented on the SN-7 degrees . RESULTS: The lower lip actually moved anteriorly 2.35 +/- 3.35 mm during orthodontic treatment; the five profile planes indicated that the lower lip moved to a more retrusive, posterior position. The five profile planes also showed no statistically significant sex differences in terms of the treatment changes that occurred, while the actual lip changes showed that males exhibited significantly greater changes than females. Actual treatment changes showed that the lower lip moved to a more protrusive position with nonextraction than with extraction treatments, changes that were not evident based on the five profile lines. While lip changes based on the five profile planes demonstrated moderately high to high intercorrelations ranging from 0.81 to 0.97, they showed only weak correlations (r < .35) with the actual horizontal changes of the labrale inferiorus. CONCLUSIONS: While all five planes measured similar aspects of positional change, none of them closely reflected the actual lower lip changes that occurred. These planes should not be used to measure changes in lip position that occur during treatment. PMID- 21299384 TI - Biomechanical response of the maxillofacial skeleton to transpalatal orthopedic force in a unilateral palatal cleft. AB - OBJECTIVES: To assess the skeletal and dental effects of rapid maxillary expansion in a patient with unilateral cleft deformity of secondary palate and alveolus using the finite element method. MATERIALS AND METHODS: A patient specific composite skull model was developed from a patient computed tomographic scan and a surface scan of the patient's maxillary cast using MIMICS imaging analysis software. For volumetric meshing and the finite element analysis, Abaqus (6.7) was used. RESULTS: The typical wedge-shaped opening that occurs after RME, seen in non-cleft patients, is not seen in cleft patients. A clockwise rotation of the maxilla as a result of maxillary expansion was evident. The areas of maximum stress were the intact primary palate region, inferior orbital foramen of the non-cleft and the cleft sides, and the zygomatic buttress of the cleft side. During expansion, the intact primary palate showed high stress and acted as a region of major resistance, followed by the zygomatic buttress on the cleft side. CONCLUSIONS: Clinicians should consider a need for customization of expansion therapy for cleft patients depending on the patient's age, the type of cleft present (primary or secondary palate), and the desired area of expansion (anterior or posterior). PMID- 21299385 TI - Dentofacial characteristics of women with oversized mandible and temporomandibular joint internal derangement. AB - INTRODUCTION: To analyze dentofacial characteristics of temporomandibular joint internal derangement (TMJ ID) in orthodontic patients with oversized mandible (skeletal Class III pattern). MATERIALS AND METHODS: The sample consisted of 66 women whose mandibular body length to anterior cranial base ratio is greater than 1.12. They were divided into three groups based on magnetic resonance images of bilateral TMJs: bilateral normal disk position (BN), bilateral disk displacement with reduction (DDR), and bilateral disk displacement without reduction (DDNR). Thirty-five cephalometric variables regarding their lateral cephalograms were analyzed by Kruskal-Wallis test to evaluate differences in dentofacial morphology among the three groups. RESULTS: Subjects with TMJ ID had a clockwise rotation of the ramus, with backward position of mandible, labial tipping of mandibular incisors, and protrusion of upper and lower lips. However, TMJ ID did not significantly influence vertical skeletal relationships. Most of the significant dentofacial changes were found between BN and DDR, and dentofacial changes between DDR and DDNR were minimal. CONCLUSIONS: This study suggests that dentofacial changes associated with TMJ ID begin to appear when TMJ ID develops to DDR from BN in patients with oversized mandible. PMID- 21299386 TI - Patients' self-perception of dentofacial attractiveness before and after exposure to facial photographs. AB - OBJECTIVE: To determine whether exposure to pretreatment photographs of themselves influenced patients' self-perception of dentofacial attractiveness and willingness to undergo treatment. MATERIALS AND METHODS: A total of 100 subjects of white ancestry aged 18 years or older (Study Group) and 100 sex- and age matched controls (Control Group) were selected. Photographs of the frontal view of the face and the profile view of the face, both at rest and while smiling, were taken of each participant. Only Study Group subjects were given a printed copy of their own images to be examined at home between the initial observation (T0) and a set date an average of 30 days later (T1). Each of the 200 subjects in the study completed a questionnaire at T0 and T1 exploring happiness regarding their smiles and their facial profiles, as well as willingness to undergo treatment. RESULTS: At T1 in the Study Group, 50% of subjects responded with a lower opinion of their facial profiles than at T0; 11% and 45% were willing to undergo more comprehensive procedures to change the appearance of their smiles and profiles, respectively. No statistically significant change was seen in questionnaire answers between T0 and T1 for the Control Group. CONCLUSION: Laypeople generally are not aware of their facial profiles. Pretreatment photograph exposure can increase profile self-awareness, an important factor in reducing the discrepancy between orthodontists' and patients' visual emphasis on dentofacial esthetics. PMID- 21299387 TI - Effect of RME and headgear treatment on the eruption of palatally displaced canines: a randomized clinical study. AB - OBJECTIVE: To determine the effectiveness of orthodontic treatment finalized on the maintenance/improvement the upper arch perimeter to assist in the successful eruption of palatally displaced maxillary canines (PDCs). MATERIALS AND METHODS: The randomized prospective design comprised 64 subjects with PDCs who were randomly assigned to one of three groups: cervical pull headgear (HG); rapid maxillary expansion and cervical pull headgear (RME/HG); or untreated control group (CG). Panoramic radiographs and lateral cephalograms were evaluated at the time of initial observation (T1) and after an average period of 18 months (T2). At T2 the success of canine eruption was evaluated. A superimposition study on lateral cephalograms was undertaken to evaluate the T1-T2 changes in the sagittal position of the upper molars in the three groups. RESULTS: The prevalence of successful eruption was 85.7% in the RME/HG group and 82.3% in the HG group. Both these prevalence rates were significantly greater than the success rate in untreated control subjects (36%). The cephalometric superimposition study showed a significant mesial movement of the upper first molars in the CG compared with the HG and RME/HG groups. CONCLUSIONS: The use of rapid maxillary expansion and headgear (or headgear alone) in PDC cases increases the success rate of eruption of the canine significantly (almost three times more than in untreated controls). PMID- 21299388 TI - Correlation between skeletal changes by maxillary protraction and upper airway dimensions. AB - OBJECTIVE: To describe the correlation between the skeletal changes induced by maxillary protraction treatment and the sagittal airway dimension associated with tongue, soft palate, and hyoid bone position in skeletal Class III children. MATERIALS AND METHODS: Twenty Class III patients (5 boys, 15 girls; mean age, 9.4 +/- 1.8 years) treated with a maxillary protraction appliance were included in this study. Pretreatment and posttreatment cephalometric radiographs were analyzed; linear and angular measurements were performed by an expert orthodontist. The correlation between treatment changes in craniofacial morphology and those in upper airway, tongue, soft palate, and hyoid position was evaluated by Pearson's correlation analysis. RESULTS: A significant increase in maxillary forward displacement, inhibition of mandibular forward growth, and clockwise rotation of the mandible were observed. Simultaneously, nasopharyngeal airway measurements PNS-ad1 and PNS-ad2 significantly increased by 1.4 mm and 1.9 mm, respectively. A correlation analysis revealed that maxillary protraction had a positive relationship with PNS-ad1 and PNS-ad2. CONCLUSIONS: The nasopharyngeal airway dimensions can be improved in the short term with maxillary protraction in skeletal Class III children. PMID- 21299389 TI - Mechanical properties of beta-titanium wires. AB - OBJECTIVE: To evaluate the force-deflection behavior of six beta-titanium wires using a three-point bending test. MATERIALS AND METHODS: The wires timolium (TIM), titanium molybdenum (ORG), beta titanium (BETA), resolve (RES), titanium molybdenum alloy (TMA), and TMA low friction (TMAL) were adapted into two stainless steel brackets, with no angulation or torque. Both brackets were bonded to an acrylic jig with a 10-mm interbracket distance. A testing machine (Instron) applied deflections of 0.2 to 2.0 mm. Force-deflection diagrams were determined from a passive position to an activation of 2 mm and then during deactivation. Forces of activation and deactivation at a deflection of 1 mm were compared by analysis of variance. RESULTS: Results demonstrated that significant differences (P < .05) in force were observed among wires. During activation, forces for the wires were ranked from lowest to highest as TMAL = TMA = RES= 0.30, P < 0.001) and format of delivery (after school, pull out from physical education, or health education curriculum) (t[3.41], beta >= 0.24, P < 0.001) influenced knowledge. CONCLUSIONS: Thus, distributed interactive learning was more effective than its passive counterpart, and a more structured delivery enhanced knowledge, as did opportunities to self-regulate learning. Attention to these process components will facilitate effective interventions by educators in schools. PMID- 21299393 TI - Continuous glucose monitoring using a novel glucose/galactose binding protein: results of a 12-hour feasibility study with the becton dickinson glucose/galactose binding protein sensor. AB - AIM: This study evaluated the performance characteristics of a prototype Becton Dickinson (BD) (Franklin Lakes, NJ) glucose/galactose binding protein (GGBP) sensor placed intradermally (BD-ID) or subcutaneously (BD-SC) for continuous glucose monitoring. MATERIALS AND METHODS: The performance characteristics of the prototype BD GGBP sensor after intradermal or subcutaneous placement were assessed, and its accuracy was compared with that of a glucose oxidase (GOx) based sensor and a standard laboratory method (YSI STAT2300 analyzer, Yellow Springs Instrument, Yellow Springs, OH) under glucose clamp conditions and during an off-clamp meal challenge in 40 patients with type 1 or 2 diabetes in a 12-h feasibility study. RESULTS: BD-ID and BD-SC sensors performed as well as or better than the GOx-based sensor (differences in median absolute percentage error 2-4 points in hyperglycemic and euglycemic regions, >= 10 points in the hypoglycemic region). For glucose values <= 100 mg/dL, the percentage of measurement values in consensus error plot Zone A was substantially higher with the GGBP sensors than the GOx-based sensor. CONCLUSIONS: The BD prototype sensor demonstrated competitive accuracy relative to a GOx-based sensor and a YSI blood standard with a single calibration and minimal warm-up. Current development work is focused on the design and manufacture of a commercially feasible device that will include marked enhancements to device robustness and longevity. PMID- 21299394 TI - Changes of platelet antioxidative enzymes during oxidative stress: the protective effect of polyphenol-rich extract from berries of Aronia melanocarpa and grape seeds. AB - Aronia melanocarpa fruits (Rosaceae) and grape seeds (seeds of Vitis vinifera, Vitaceae) are two of the richest plant sources of phenolic substances, and they have been shown to have various biological activities. The aim of the present study was to investigate and compare the action of phenolic extracts (at concentrations 5-100 ug/mL) of two different plants, berries of A. melanocarpa (chokebbery) and grape seeds, on the activities of various antioxidative enzymes, the amount of glutathione (as an important component of redox status) in control the platelets and platelets treated with H(2)O(2) (the strong physiological oxidant) in vitro. The properties of these two tested extracts were also compared with the action of a well characterized antioxidative and antiplatelet commercial monomeric polyphenol - resveratrol. The extract from berries of A. melanocarpa, like the extract from grape seeds, reduced the changes in activities of different antioxidative enzymes (glutathione peroxidase, superoxide dismutase, and catalase) in platelets treated with H(2)O(2). The action of the two tested plant extracts and H(2)O(2) evoked a significant increase of reduced glutathione in platelets compared with platelets treated with H(2)O(2) only. Comparative studies indicate that the two tested plant extracts had similar antioxidative properties, and were found to be more reactive in blood platelets than the solution of resveratrol. PMID- 21299395 TI - Interprofessional simulated learning: the need for 'sociological fidelity'. PMID- 21299396 TI - Suggested algorithm for cytomegalovirus surveillance in low-risk pregnancies. AB - Cytomegalovirus (CMV) is the most common cause of intrauterine infection, occurring in 0.2-2.2% of all neonates. The rare but serious neonatal manifestations have prompted widespread discussions of the use of CMV surveillance during pregnancy. This study describes a decision-analysis algorithm for a surveillance protocol to detect the maximal number of primary CMV infections in low-risk pregnancies. The steps of the protocol adhere to the routine antenatal follow-up schedule. All calculations were based on the most stringent data in the literature as applied to a theoretical cohort of 100,000 pregnant women in the general population. By the time of delivery, the protocol failed to detect only four potentially ill neonates in the study group. These cases may be diagnosed and treated postnatally. Incorporation of the protocol in antenatal follow-up can reduce diagnostic confusion, assist clinicians in timing invasive procedures, and potentially spare patients unnecessary terminations of pregnancy. PMID- 21299397 TI - Full-term neonatal intenstive care unit admission in an urban community hospital: the role of respiratory morbidity. AB - OBJECTIVE: To investigate the incidence of respiratory morbidity among full-term neonatal intenstive care unit (NICU) admissions and identify risk factors for such admissions. METHODS: We performed a retrospective cohort study of NICU admissions between 1/06 and 12/08. We included neonates between 37 and 40 weeks with a diagnosis of transient tachypnea of the newborn (TTN), respiratory distress syndrome (RDS), pneumonia, pneumothorax, and meconium aspiration syndrome. Obstetrical outcomes were compared with a control group of women during the same period whose neonates were not admitted to the NICU. RESULTS: Two hundred two infants admitted to the NICU with respiratory morbidity were compared with 9580 controls. TTN comprised the majority of the respiratory morbidity. Only RDS was associated with cesarean delivery. CONCLUSION: RDS remains a significant morbidity in full-term NICU admission. When compared with controls, admissions to our NICU with any respiratory morbidity were more likely to be delivered by cesarean to a mother with hypertension or diabetes during pregnancy. PMID- 21299398 TI - Evolution of beta-Cell Replacement Therapy in Diabetes Mellitus: Pancreas Transplantation. AB - Diabetes mellitus remains one of the leading causes of morbidity and mortality worldwide. According to the Centers for Disease Control and Prevention, approximately 23.6 million people in the United States are affected. Of these individuals, 5-10% have been diagnosed with type 1 diabetes mellitus (TIDM), an autoimmune disease. Although it often appears in childhood, T1DM may manifest at any age. The effects of T1DM can be devastating, as the disease often leads to significant secondary complications, morbidity, and decreased quality of life. Since the late 1960s, surgical treatment for diabetes mellitus has continued to evolve and has become a viable alternative to chronic insulin administration. In this review, the historical evolution, current status, graft efficacy, benefits, and complications of pancreas transplantation are explored. PMID- 21299399 TI - The role of early voice therapy in the incidence of motility recovery in unilateral vocal fold paralysis. AB - OBJECTIVES. Vocal fold paralysis can have a significant impact on a patient's quality of life. The aim of this study was to analyze, in terms of vocal improvement and motility recovery, the post-vocal treatment results of patients with unilateral vocal fold paralysis (UVFP) who underwent early voice therapy. Study design. A 7 years prospective study of patients with an UVFP who underwent our multidimensional diagnostic-therapeutic assessment. MATERIAL AND METHODS. Seventy-four patients with UVFP were included in the study. All patients underwent a voice therapy based on forcible exercises supplemented by manipulations and maneuvers. A pre and post-treatment objective voice evaluation and self-assessment was made. RESULTS: Out of 74 patients with UVFP, 51 (68.9%) recovered vocal fold motility. In 23 (31.1%), UVFP persisted after voice therapy. In this group of patients, a complete glottal closure was seen in 5 before voice therapy and in 13 after; An important and significant (p <0.0001) reduction in fundamental frequency (F(o)) was found; a manifest improvement was seen for the mean values of Jitter (Jitt%; p = 0.001), Shimmer (Shim%; p <0.0001) and noise-to harmonic ratio (NHR) (p <0.0001). The same statistical comparisons calculated for male patients alone was not significant for Jitt% (0.102), Shim% (0.112) and NHR (0.155), as a result of the reduced number of patients in this group. Voice Handicap Index (VHI) values showed a clear and significant improvement and mean maximum phonation time (MPT) increased significantly. CONCLUSION. Early voice therapy based on an energetic approach, combined with patient co-operation, motivation and understanding through educated participation in the voice restoration process, strengthen the idea that patients with UVFP have a good chance of recovering vocal fold motility or improving their voice quality. PMID- 21299400 TI - Role of chronic and acute hyperglycemia in the development of diabetes complications. AB - Chronic hyperglycemia, as assessed by hemoglobin A1c (HbA1c) levels, has been associated with the development of microvascular and macrovascular complications of diabetes. Several studies have shown that acute hyperglycemia can add to the effect of chronic hyperglycemia in inducing tissue damage. Acute hyperglycemia can activate the same metabolic and hemodynamic pathways as chronic hyperglycemia. In particular, it is associated with increased mitochondrial production of reactive oxidant species, which have been suggested as the link between hyperglycemia and the activation of downstream pathways, mediating tissue damage. Studies performed in subjects with diabetes have shown that there is a positive association between HbA1c and both fasting and postprandial glucose levels. However, it appears that the contribution of these two parameters to the total HbA1c concentrations varies according to the degree of metabolic control. Postprandial glucose excursions are predominant in patients with a good or mild glycemic control, whereas the contribution of fasting hyperglycemia is stronger as glycemic control worsens. Glucose variability, like the intra-day glucose fluctuations from peaks to nadirs, is another important parameter, which, mainly in subjects with type 2 diabetes, has emerged as an HbA1c-independent risk factor for the development of vascular complications. Based on the current knowledge on the association not only of HbA1c, but also of fasting and postprandial glucose, with diabetes complications, it is paramount that antidiabetes strategies are directed at improving all these components in order to reduce the burden associated with diabetes. PMID- 21299401 TI - Optimal sampling intervals to assess long-term glycemic control using continuous glucose monitoring. AB - AIMS AND HYPOTHESIS: The optimal duration and frequency of short-term continuous glucose monitoring (CGM) to reflect long-term glycemia have not been determined. The Juvenile Diabetes Research Foundation CGM randomized trials provided a large dataset of longitudinal CGM data for this type of analysis. METHODS: The analysis included 185 subjects who had 334 3-month intervals of CGM data meeting specific criteria. For various glucose indices, correlations (r2) were computed for the entire 3-month interval versus selected sampling periods ranging from 3 to 15 days. Other computed agreement measures included median relative absolute difference, values within +/- 10% and +/- 20% of full value, and median absolute difference. RESULTS: As would be expected, the more days of glucose data that were sampled, the higher the correlation with the full 3 months of data. For 3 days of sampling, the r2 value ranged from 0.32 to 0.47, evaluating mean glucose, percentage of values 71-180 mg/dL, percentage of values > 180 mg/dL, percentage of values <= 70 mg/dL, and coefficient of variation; in contrast, for 15 days of sampling, the r2 values ranged from 0.66 to 0.75. The results were similar when the analysis intervals were stratified by age group (8-14, 15-24, and >= 25 years), by baseline hemoglobin A1c level (< 7.0% and >= 7.0%), and by CGM device type. CONCLUSIONS AND INTERPRETATION: Our data suggest that a 12-15-day period of monitoring every 3 months may be needed to optimally assess overall glucose control. Shorter periods of sampling can be useful, but the correlation with 3 month measures of glycemic control is lower. PMID- 21299402 TI - Associations between health literacy, diabetes knowledge, self-care behaviors, and glycemic control in a low income population with type 2 diabetes. AB - OBJECTIVE: This study assessed associations among health literacy, diabetes knowledge, self-care, and glycemic control in a low income, predominately minority population with type 2 diabetes. METHODS: One hundred twenty-five adults with diabetes were recruited from a primary care clinic. Subjects completed validated surveys to measure health literacy, diabetes knowledge, and self-care (medication adherence, diet, exercise, blood sugar testing, and foot care). Hemoglobin A1c values were extracted from the medical record. Spearman's correlation and multiple linear regression were used to assess the relationship among health literacy, diabetes knowledge, self-care, and glycemic control controlling for covariates. RESULTS: Cronbach's alpha was 0.95 for the Revised Rapid Estimate of Adult Literacy in Medicine. The majority of the sample was <65 years old (50.7%), female (72.5%), and African American (71.4%), had less than a high school education (68.2%) and a household income < $15,000 (64.2%), and reported their health status as worse than last year (73.9%). In adjusted models that examined the associations among health literacy, diabetes knowledge, medication adherence, and self-care, health literacy was only significantly associated with diabetes knowledge (beta = 0.55; 95% confidence interval [CI] 0.29, 0.82). In the final adjusted model for independent factors associated with glycemic control, both diabetes knowledge (beta = 0.12; 95% CI 0.01, 0.23) and perceived health status (beta = 1.14; 95% CI 0.13, 2.16) were significantly associated with glycemic control, whereas health literacy was not associated with glycemic control (beta = -0.03; 95% CI -0.19, 0.13). CONCLUSIONS: Diabetes knowledge and perceived health status are the most important factors associated with glycemic control in this population. Health literacy appears to exert its influence through diabetes knowledge and is not directly related to self-care or medication adherence. PMID- 21299403 TI - Effects of isoflurane anesthesia and pilocarpine on rat parotid saliva flow. AB - The purpose of this study was to investigate the effects of isoflurane on unstimulated and pilocarpine-stimulated parotid saliva secretion. Ten male Sprague-Dawley rats weighing 350-400 g were randomized into two groups, and the saliva flow rate and lag phase were measured at two doses of isoflurane in a crossover study design. Increasing the isoflurane concentration from 1% to 2% was associated with a 19% decrease in saliva secretion rate, and the lag to saliva secretion was increased by 155%. To clarify whether the effect of isoflurane (1.5%) on the parotid flow varied with stimulus intensity, we measured the parotid flow induced by seven different doses of pilocarpine on sham-irradiated rats and rats irradiated with single doses of 15 Gy. A maximal pilocarpine response was obtained with 1.5 mg/kg in both irradiated and sham-irradiated rats; however, the parotid flow of the irradiated rats was 50% slower than that of the sham-irradiated rats. In conclusion, 1.5% isoflurane was found to be a good compromise between proper anesthesia and isoflurane-induced inhibition of saliva secretion. Pilocarpine induces saliva secretion in a dose-dependent matter, with supra-maximal stimulation achieved using 1.5 mg/kg. PMID- 21299404 TI - Impaired repair of ionizing radiation-induced DNA damage in Cockayne syndrome cells. AB - Cockayne syndrome (CS) cells are defective in transcription-coupled repair (TCR) and sensitive to oxidizing agents, including ionizing radiation. We examined the hypothesis that TCR plays a role in ionizing radiation-induced oxidative DNA damage repair or alternatively that CS plays a role in transcription elongation after irradiation. Irradiation with doses up to 100 Gy did not inhibit RNA polymerase II-dependent transcription in normal and CS-B fibroblasts. In contrast, RNA polymerase I-dependent transcription was severely inhibited at 5 Gy in normal cells, indicating different mechanisms of transcription response to X rays. The frequency of radiation-induced base damage was 2 * 10(-7) lesions/base/Gy, implying that 150 Gy is required to induce one lesion/30-kb transcription unit; no TCR of X-ray-induced base damage in the p53 gene was observed. Therefore, it is highly unlikely that defective TCR underlies the sensitivity of CS to ionizing radiation. Overall genome repair levels of radiation-induced DNA damage measured by repair replication were significantly reduced in CS-A and CS-B cells. Taken together, the results do not provide evidence for a key role of TCR in repair of radiation-induced oxidative damages in human cells; rather, impaired repair of oxidative lesions throughout the genome may contribute to the CS phenotype. PMID- 21299406 TI - Fracture of anterior iliac crest following bone graft harvest in an anorexic patient: case report and review of the literature. AB - In the treatment of jaw bone atrophies, autologus bone is still considered the gold standard because of its excellent osteoconductive, osteoinductive, and osteogenetic proprieties and lack of immunogenicity, which allow better graft integration and stability. Although various donor sites are available, the iliac crest represents the best source of corticocancellous bone, and literature suggests that it has low morbidity. However, this case report emphasizes that patients with systemic diseases such as anorexia should be carefully evaluated before such an operation, because unfavorable bone conditions may jeopardize the outcome. A 47-year-old woman needing rehabilitation of the upper arch was considered for iliac crest harvesting. She stated that she had suffered from anorexia for 30 years. A corticocancellous block was harvested by a bone saw using an anterolateral approach to the outer table of the right anterior iliac crest. The postoperative course was uneventful, but 13 days later, she complained of a sudden pain in the operated area, and X rays revealed a fracture of the anterior iliac crest. So far, the literature has mentioned 50 cases of iliac crest fractures after bone harvesting, and 28 cases among these are due to harvesting in the anterior part of the iliac crest. Several factors seem to be responsible for this complication, including the area of harvesting, residual bone thickness, technique used, and age and gender of the patient. To our knowledge, our case is the first of hip fracture after bone harvesting in a patient suffering from anorexia. Both low weight and osteoporosis are probably responsible for this complication. In our opinion, patients suffering from anorexia should be considered at risk for bone harvesting, and an appropriate mini-invasive surgical technique should be carried out instead. PMID- 21299407 TI - Effects of facemask treatment anchored with miniplates after alternate rapid maxillary expansions and constrictions; a pilot study. AB - OBJECTIVE: To describe the dentoskeletal and soft tissue effects of facemask treatment anchored with miniplates after alternate rapid maxillary expansions and constrictions (Alt-RAMEC) in maxillary retrusion patients. MATERIALS AND METHODS: The sample consisted of 15 patients with a mean skeletal age of 11.6 +/- 1.59 years undergoing 8 weeks of Alt-RAMEC followed by maxillary protraction. Three hundred fifty to 400 g of force per side was applied to the facemask from the titanium miniplates inserted on the lateral nasal wall of the maxilla. Total treatment time was 9.9 +/- 2.63 months. Treatment changes were evaluated cephalometrically and analyzed by means of the dependent t-test and the Wilcoxon signed rank test. RESULTS: The miniplates withstood the orthopedic forces exerted during the treatment. Cephalometric findings showed that the maxilla moved forward by 2 mm, with an 0.8 degrees counterclockwise rotation and without maxillary incisor movement. The mandible moved slightly in a downward and backward direction (1.2 degrees ). The inclinations of the mandibular incisors decreased significantly (2 degrees ). Statistically significant increases were observed in the vertical dimension (1 degrees -1.3 degrees ). Soft tissue changes were more marked in the upper lip and soft tissue pogonion than in the lower lip. CONCLUSIONS: This treatment approach can offer an advantage for correcting mild/moderate maxillary retrusion in Class III patients. PMID- 21299408 TI - Treatment and posttreatment outcomes induced by the Mandibular Advancement Repositioning Appliance; a controlled clinical study. AB - OBJECTIVE: To evaluate the treatment and posttreatment dentoskeletal effects induced by the Mandibular Advancement Repositioning Appliance (MARA) in the treatment of Class II malocclusion. MATERIALS AND METHODS: The treated sample consisted of 23 consecutively treated patients at prepubertal or pubertal stages, as assessed by the cervical vertebral maturation method. A control group of untreated Class II subjects was generated from published normative growth data. Lateral cephalograms were digitized and superimposed via cephalometric software at three different times: T1, pretreatment; T2, post-MARA treatment; and T3, at least 1 year after T2. The T1-T2, T2-T3, and T1-T3 changes in the treated group were compared to those in the control group with independent-sample Student's t tests. RESULTS: Skeletal and dentoalveolar effects of MARA were assessed after the active phase of the treatment (T1-T2). Mandibular elongation in length (Co Gn, +2.2 mm) was evident together with lower incisor proclination (IMPA, +5.8 mm). A relapse tendency for IMPA was noticed after removing the appliance (IMPA, 2.1 degrees during T2-T3). Significant skeletal effects (Co-Gn, +2.0 mm) and headgear effects on the maxilla (SNA, -1.2 degrees ) were significant in the long term (T1-T3). CONCLUSIONS: The MARA appliance provides an effective correction of Class II malocclusion, which is maintained at a posttreatment observation with a moderate skeletal effect. PMID- 21299409 TI - The relationship between temporomandibular joint disk displacement and mandibular asymmetry in skeletal Class III patients. AB - OBJECTIVE: To investigate the relationship between temporomandibular joint disk displacement (TMJ DD) and facial asymmetry in skeletal Class III patients. MATERIALS AND METHODS: The subjects comprised 97 skeletal Class III adult patients seeking orthodontic treatment. In addition to the routine lateral and posteroanterior (PA) cephalograms, and regardless of the TMJ status, each subject consented to magnetic resonance imaging (MRI) to evaluate their TMJs. According to MRI readings, subjects were classified into four groups: group 1, bilateral normal disk position; group 2, bilateral DD with or without reduction; group 3, DD more advanced on the right side; and group 4, DD more advanced on the left side. PA and lateral cephalometric variables were analyzed to compare the four groups. RESULTS: When the TMJ DD was more advanced on one side than on the other, the chin point usually deviated to the advanced side. When the TMJ DD status was equal or bilaterally normal, the amount of mandibular deviation was not significant. CONCLUSIONS: If a skeletal Class III patient has an asymmetric face, especially in the mandibular region, careful examination is necessary with regard to the status of the TMJ during orthodontic diagnosis and treatment planning. PMID- 21299410 TI - Effectiveness of comprehensive fixed appliance treatment used with the Forsus Fatigue Resistant Device in Class II patients. AB - OBJECTIVE: To assess the dental, skeletal, and soft tissue effects of comprehensive fixed appliance treatment combined with the Forsus Fatigue Resistant Device (FRD) in Class II patients. MATERIALS AND METHODS: Thirty-two Class II patients (mean age 12.7 +/- 1.2 years) were treated consecutively with the FRD protocol and compared with a matched sample of 27 untreated Class II subjects (mean age 12.8 +/- 1.3 years). Lateral cephalograms were taken before therapy and at the completion of comprehensive therapy. The mean duration of comprehensive treatment was 2.4 +/- 0.4 years. Statistical comparisons were carried out with the Student's t-test (P < .05). RESULTS: The success rate was 87.5%. The FRD group showed a significant restraint in the sagittal skeletal position of the maxilla (also at the soft tissue level), a significant increase in mandibular length, and a significant improvement in maxillo-mandibular sagittal skeletal relationships. The treated group exhibited a significant reduction in overjet and a significant increase in molar relationship. The lower incisors were significantly proclined and intruded, while the lower first molars moved significantly in a mesial and vertical direction. CONCLUSIONS: The FRD protocol is effective in correcting Class II malocclusion with a combination of skeletal (mainly maxillary) and dentoalveolar (mainly mandibular) modifications. PMID- 21299411 TI - Influence of four systems for dental bleaching on the bond strength of orthodontic brackets. AB - OBJECTIVE: To compare the influence of four systems for dental bleaching on the shear bond strength (SBS) of orthodontic brackets. MATERIALS AND METHODS: One hundred and fifty freshly extracted bovine teeth were randomly divided into five groups. In group I the teeth were untreated (control). In the remaining groups the teeth were bleached, as follows: group II: 38% hydrogen peroxide; group III: 10% carbamide peroxide; group IV: resin-based coating material (RBCM), Beauty Coat; and group V: RBCM, White Coat. In all groups the enamel was conditioned with a self-etching primer and brackets were bonded with composite resin. Samples were stored (37 degrees C, 24 hours), tested, and statistically analyzed, with significance predetermined at P <= .05. The adhesive remnant index (ARI) was also evaluated and analyzed. RESULTS: The SBS of group V (22.49 +/- 5.34 MPa) was significantly higher than that of all other groups (I: 17.1 +/- 5.11 MPa; II: 14.72 +/- 5.42 MPa; III: 12.04 +/- 5.29 MPa; and IV: 18.23 +/- 5.58 MPa). In contrast, the SBS of group III was significantly lower than that of all groups (except group II). Significant differences in the ARI scores were present between groups. CONCLUSIONS: The use of RBCM for dental bleaching before bonding orthodontic brackets did not reduce the SBS. In contrast, hydrogen and carbamide peroxides negatively affected the SBS. The SBS yielded after bleaching with carbamide peroxide was significantly lower. PMID- 21299412 TI - Comparison of anchorage capacity between implant and headgear during anterior segment retraction. AB - OBJECTIVE: To compare the anchorage effects of the implants and the headgear for patients with anterior teeth retraction in terms of incisor retraction, anchorage loss, inclination of maxillary incisors, positional change of maxillary basal bone, and treatment duration. MATERIALS AND METHODS: An electronic search for relative randomized controlled trials (RCTs) prospective and retrospective controlled trials was done through the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, Medline, and CNKI, regardless of language of study. Study selection, methodological quality assessment, and data extraction were performed by two reviewers independently. Meta-analysis was performed when possible; otherwise descriptive assessment was done. RESULTS: The search yielded 35 articles, of which eight met the inclusion criteria and were categorized into five groups according to types of intervention. For the midpalatal implant, the anchorage loss was much less than for the headgear group, with insignificant differences in terms of anterior teeth retraction, maxillary incisor inclination, positional change of basal bone, and treatment duration. For the mini-implant, greater anterior teeth retraction and less anchorage loss were demonstrated, with inconsistent results for the other measures. For the onplant, less anchorage loss was noted, with insignificant differences for the other measures. CONCLUSIONS: The skeletal anchorage of the midpalatal implant, mini-implant, and onplant offer better alternatives to headgear, with less anchorage loss and more anterior teeth retraction. There were inconsistent results from the included studies in terms of maxillary incisor inclination, positional change of maxillary basal bone, and treatment duration. More qualified RCTs are required to provide clear recommendations. PMID- 21299413 TI - PEST motif sequence regulating human NANOG for proteasomal degradation. AB - A number of transcriptional factors are required for pluripotency of stem cells. NANOG, a homeobox transcription factor, plays a critical role in regulating embryonic stem cell (ESC) pluripotency. The expression level of NANOG is tightly regulated, and perturbation in its expression level can lead to significant difference in the morphology, expression of cell surface markers, and growth factor dependence of human and mouse ESCs. Here, we demonstrate that the proteolysis of human NANOG is regulated by the ubiquitin-proteasomal pathway. The inhibition of proteasome activity by proteasome inhibitor MG132 showed increase in protein levels of endogenous NANOG in a dose-dependent manner in human ESCs (hESCS). We demonstrated that the inhibition of the proteasome activity and cotransfection with exogenous ubiquitin promotes endogenous ubiquitination of NANOG by coimmunoprecipitation assay. In addition, we showed that both K48- and K63-branched polyubiquitin chains can conjugate with NANOG in vivo. Moreover, NANOG was an unstable protein and exhibited relatively short half-life of about 120 min in hESCs. Pretreatment of hESCs with proteasome inhibitor MG132 inhibits NANOG protein degradation and extends its half-life. Finally, we found that a PEST motif sequence (rich in proline, glutamine, serine, and threonine) from amino acid 47 to 72 located toward the N-terminus of NANOG was shown to target the protein for degradation. Deletion of the PEST motif reduced ubiquitination of NANOG, leading to NANOG stabilization. Collectively, these results indicate that the expression level, stability, and activity of NANOG are modulated by post translational mechanisms. PMID- 21299414 TI - Characterization of porcine multipotent stem/stromal cells derived from skin, adipose, and ovarian tissues and their differentiation in vitro into putative oocyte-like cells. AB - The present study evaluated the alkaline phosphatase activity, cell cycle stage, expression of markers and early transcriptional factors, and in vitro differentiation into selected cell lineages of porcine stem/stromal cells (SCs) isolated from skin (SSCs), adipose, and ovarian (OSCs) tissues. Skin and adipose SCs were isolated from a 6-month-old miniature pig, whereas OSCs were isolated from a newly born piglet. Isolated cells exhibited fibroblast-like cell population with significant renewal capacity and formed colonies by cells out growth. All cells were positive for alkaline phosphatase activity and showed a relatively lower population at G0/G1 phase of the cell cycle. SCs derived from all tissues were strongly positive for cell surface markers, such as CD29, CD44, CD90, and vimentin. Further, relatively lower expression of cytokeratin and immunophenotype markers, such as major histocompatibility complex II (MHCII) and swine leukocyte antigen (SLA), was also observed. SCs derived from all tissues positively expressed the transcription factors, such as Oct-3/4, Nanog, and Sox 2. After induction, all SCs successfully differentiated into osteocytes and adipocytes and expressed the lineage specific marker genes. Further, cells from all tissues exhibited their potential for in vitro oogenesis with morphological changes and expression of markers during the germ-cell formation, namely Oct-4, growth differentiation factor 9b, c-Mos, Vasa, deleted in azoospermia-like gene, zona pellucida C, and follicle stimulating hormone receptor. Apart from basic features and selected lineage potential among all types of cells, OSCs possessed a greater ability to differentiate into the germ cell lineage in vitro. PMID- 21299415 TI - Importance and genetic diversity of vegetable-infecting tospoviruses in India. AB - A survey for Peanut bud necrosis virus (PBNV), Watermelon bud necrosis virus (WBNV), Capsicum chlorosis virus (CaCV), and Iris yellow spot virus (IYSV) was conducted between 2002 and 2009 in the major vegetable-growing areas in India. PBNV was documented widely in tomato and chili peppers in 14 states representing southern, north-western, north-eastern, and central regions and WBNV was predominantly detected in watermelons and cucurbits in all except north-eastern regions. In addition, the expanded host range of PBNV to watermelons and other cucurbits and WBNV to tomato and chili peppers was observed leading to natural mixed infection of the two viruses. IYSV was found in onion in southern, central, and north-eastern regions and CaCV in tomato and chili peppers in northern and southern regions, respectively. Phylogenetic analysis of the nucleocapsid gene revealed segregation of field isolates of PBNV and WBNV into two distinct subclades, whereas isolates of CaCV and IYSV each clustered into a single clade. A proposal for establishing WBNV as a distinct tospovirus species is made based on the molecular characterization of small- (S) and medium- (M) RNA segments. PMID- 21299416 TI - Feline responses to hypoglycemia in people with type 1 diabetes. PMID- 21299417 TI - Biorhythm theory does not predict admission for acute myocardial infarction. AB - OBJECTIVES: Temporal variations in the incidence of acute myocardial infarction (AMI) have been described. However, AMI occurrence and biorhythm theory, which proposes the existence of three endogenous independent infradian cycles and AMI occurrence, has not been well studied. The purpose of this study is to determine whether specific days in the biorhythm cycles are related to AMI incidence. MEASURES: Patients (40-85 years old) admitted for AMI at the Sherbrooke University Hospital Center, 1993-2008 were subjects of this study. Potential vulnerable days and performance days of the biorhythm cycles were calculated using birth and admission dates from the warehouse database. Observed AMI frequencies were compared to those expected using chi2 tests. RESULTS: There were 11,395 admissions for AMI. No relation was noted between single, double, or triple critical or noncritical days and AMI (chi2 = 3.78; p > 0.05). Observed and expected AMI frequencies for maximal and minimal performance days were similar (chi2 = 15.06; p > 0.05). CONCLUSIONS: We found no evidence for a possible relationship between the date of AMI and critical maximum and minimum performance days of an individual's physical, emotional, or intellectual biorhythm cycles. We conclude that biorhythm theory does not predict admission for AMI. PMID- 21299418 TI - Divergence-based vector quantization. AB - Supervised and unsupervised vector quantization methods for classification and clustering traditionally use dissimilarities, frequently taken as Euclidean distances. In this article, we investigate the applicability of divergences instead, focusing on online learning. We deduce the mathematical fundamentals for its utilization in gradient-based online vector quantization algorithms. It bears on the generalized derivatives of the divergences known as Frechet derivatives in functional analysis, which reduces in finite-dimensional problems to partial derivatives in a natural way. We demonstrate the application of this methodology for widely applied supervised and unsupervised online vector quantization schemes, including self-organizing maps, neural gas, and learning vector quantization. Additionally, principles for hyperparameter optimization and relevance learning for parameterized divergences in the case of supervised vector quantization are given to achieve improved classification accuracy. PMID- 21299419 TI - Traveling bumps and their collisions in a two-dimensional neural field. AB - A neural field is a continuous version of a neural network model accounting for dynamical pattern forming from populational firing activities in neural tissues. These patterns include standing bumps, moving bumps, traveling waves, target waves, breathers, and spiral waves, many of them observed in various brain areas. They can be categorized into two types: a wave-like activity spreading over the field and a particle-like localized activity. We show through numerical experiments that localized traveling excitation patterns (traveling bumps), which behave like particles, exist in a two-dimensional neural field with excitation and inhibition mechanisms. The traveling bumps do not require any geometric restriction (boundary) to prevent them from propagating away, a fact that might shed light on how neurons in the brain are functionally organized. Collisions of traveling bumps exhibit rich phenomena; they might reveal the manner of information processing in the cortex and be useful in various applications. The trajectories of traveling bumps can be controlled by external inputs. PMID- 21299420 TI - On the performance of voltage stepping for the simulation of adaptive, nonlinear integrate-and-fire neuronal networks. AB - In traditional event-driven strategies, spike timings are analytically given or calculated with arbitrary precision (up to machine precision). Exact computation is possible only for simplified neuron models, mainly the leaky integrate-and fire model. In a recent paper, Zheng, Tonnelier, and Martinez (2009) introduced an approximate event-driven strategy, named voltage stepping, that allows the generic simulation of nonlinear spiking neurons. Promising results were achieved in the simulation of single quadratic integrate-and-fire neurons. Here, we assess the performance of voltage stepping in network simulations by considering more complex neurons (quadratic integrate-and-fire neurons with adaptation) coupled with multiple synapses. To handle the discrete nature of synaptic interactions, we recast voltage stepping in a general framework, the discrete event system specification. The efficiency of the method is assessed through simulations and comparisons with a modified time-stepping scheme of the Runge-Kutta type. We demonstrated numerically that the original order of voltage stepping is preserved when simulating connected spiking neurons, independent of the network activity and connectivity. PMID- 21299421 TI - Refinements of universal approximation results for deep belief networks and restricted Boltzmann machines. AB - We improve recently published results about resources of restricted Boltzmann machines (RBM) and deep belief networks (DBN)required to make them universal approximators. We show that any distribution pon the set {0,1}(n) of binary vectors of length n can be arbitrarily well approximated by an RBM with k-1 hidden units, where k is the minimal number of pairs of binary vectors differing in only one entry such that their union contains the support set of p. In important cases this number is half the cardinality of the support set of p (given in Le Roux & Bengio, 2008). We construct a DBN with 2n/ 2(n-b) , b ~ log n, hidden layers of width n that is capable of approximating any distribution on {0,1}(n) arbitrarily well. This confirms a conjecture presented in Le Roux and Bengio (2010). PMID- 21299422 TI - The dynamics of integrate-and-fire: mean versus variance modulations and dependence on baseline parameters. AB - The leaky integrate-and-fire (LIF) is the simplest neuron model that captures the essential properties of neuronal signaling. Yet common intuitions are inadequate to explain basic properties of LIF responses to sinusoidal modulations of the input. Here we examine responses to low and moderate frequency modulations of both the mean and variance of the input current and quantify how these responses depend on baseline parameters. Across parameters, responses to modulations in the mean current are low pass, approaching zero in the limit of high frequencies. For very low baseline firing rates, the response cutoff frequency matches that expected from membrane integration. However, the cutoff shows a rapid, supralinear increase with firing rate, with a steeper increase in the case of lower noise. For modulations of the input variance, the gain at high frequency remains finite. Here, we show that the low-frequency responses depend strongly on baseline parameters and derive an analytic condition specifying the parameters at which responses switch from being dominated by low versus high frequencies. Additionally, we show that the resonant responses for variance modulations have properties not expected for common oscillatory resonances: they peak at frequencies higher than the baseline firing rate and persist when oscillatory spiking is disrupted by high noise. Finally, the responses to mean and variance modulations are shown to have a complementary dependence on baseline parameters at higher frequencies, resulting in responses to modulations of Poisson input rates that are independent of baseline input statistics. PMID- 21299423 TI - Time-free spiking neural P systems. AB - Different biological processes take different times to be completed, which can also be influenced by many environmental factors. In this work, a realistic definition of nonsynchronized spiking neural P systems (SN P systems, for short) is considered: during the work of an SN P system, the execution times of spiking rules cannot be known exactly (i.e., they are arbitrary). In order to establish robust systems against the environmental factors, a special class of SN P systems, called time-free SN P systems, is introduced, which always produce the same computation result independent of the execution times of the rules. The universality of time-free SN P systems is investigated. It is proved that these P systems with extended rules (several spikes can be produced by a rule) are equivalent to register machines. However, if the number of spikes present in the system is bounded, then the power of time-free SN P systems falls, and in this case, a characterization of semilinear sets of natural numbers is obtained. PMID- 21299424 TI - Hidden Markov models for the stimulus-response relationships of multistate neural systems. AB - Given recent experimental results suggesting that neural circuits may evolve through multiple firing states, we develop a framework for estimating state dependent neural response properties from spike train data. We modify the traditional hidden Markov model (HMM) framework to incorporate stimulus-driven, non-Poisson point-process observations. For maximal flexibility, we allow external, time-varying stimuli and the neurons' own spike histories to drive both the spiking behavior in each state and the transitioning behavior between states. We employ an appropriately modified expectation-maximization algorithm to estimate the model parameters. The expectation step is solved by the standard forward-backward algorithm for HMMs. The maximization step reduces to a set of separable concave optimization problems if the model is restricted slightly. We first test our algorithm on simulated data and are able to fully recover the parameters used to generate the data and accurately recapitulate the sequence of hidden states. We then apply our algorithm to a recently published data set in which the observed neuronal ensembles displayed multistate behavior and show that inclusion of spike history information significantly improves the fit of the model. Additionally, we show that a simple reformulation of the state space of the underlying Markov chain allows us to implement a hybrid half-multistate, half histogram model that may be more appropriate for capturing the complexity of certain data sets than either a simple HMM or a simple peristimulus time histogram model alone. PMID- 21299425 TI - Revisiting tests for neglected nonlinearity using artificial neural networks. AB - Tests for regression neglected nonlinearity based on artificial neural networks (ANNs) have so far been studied by separately analyzing the two ways in which the null of regression linearity can hold. This implies that the asymptotic behavior of general ANN-based tests for neglected nonlinearity is still an open question. Here we analyze a convenient ANN-based quasi-likelihood ratio statistic for testing neglected nonlinearity, paying careful attention to both components of the null. We derive the asymptotic null distribution under each component separately and analyze their interaction. Somewhat remarkably, it turns out that the previously known asymptotic null distribution for the type 1 case still applies, but under somewhat stronger conditions than previously recognized. We present Monte Carlo experiments corroborating our theoretical results and showing that standard methods can yield misleading inference when our new, stronger regularity conditions are violated. PMID- 21299426 TI - Mechanisms that modulate the transfer of spiking correlations. AB - Correlations between neuronal spike trains affect network dynamics and population coding. Overlapping afferent populations and correlations between presynaptic spike trains introduce correlations between the inputs to downstream cells. To understand network activity and population coding, it is therefore important to understand how these input correlations are transferred to output correlations.Recent studies have addressed this question in the limit of many inputs with infinitesimal postsynaptic response amplitudes, where the total input can be approximated by gaussian noise. In contrast, we address the problem of correlation transfer by representing input spike trains as point processes, with each input spike eliciting a finite postsynaptic response. This approach allows us to naturally model synaptic noise and recurrent coupling and to treat excitatory and inhibitory inputs separately.We derive several new results that provide intuitive insights into the fundamental mechanisms that modulate the transfer of spiking correlations. PMID- 21299427 TI - Detection of hidden structures in nonstationary spike trains. AB - We propose an algorithm for simultaneously estimating state transitions among neural states and nonstationary firing rates using a switching state-space model (SSSM). This algorithm enables us to detect state transitions on the basis of not only discontinuous changes in mean firing rates but also discontinuous changes in the temporal profiles of firing rates (e.g., temporal correlation). We construct estimation and learning algorithms for a nongaussian SSSM, whose nongaussian property is caused by binary spike events. Local variational methods can transform the binary observation process into a quadratic form. The transformed observation process enables us to construct a variational Bayes algorithm that can determine the number of neural states based on automatic relevance determination. Additionally, our algorithm can estimate model parameters from single-trial data using a priori knowledge about state transitions and firing rates. Synthetic data analysis reveals that our algorithm has higher performance for estimating nonstationary firing rates than previous methods. The analysis also confirms that our algorithm can detect state transitions on the basis of discontinuous changes in temporal correlation, which are transitions that previous hidden Markov models could not detect. We also analyze neural data recorded from the medial temporal area. The statistically detected neural states probably coincide with transient and sustained states that have been detected heuristically. Estimated parameters suggest that our algorithm detects the state transitions on the basis of discontinuous changes in the temporal correlation of firing rates. These results suggest that our algorithm is advantageous in real data analysis. PMID- 21299428 TI - Beliefs, decision-making, and dialogue about complementary and alternative medicine (CAM) within families using CAM: a qualitative study. AB - BACKGROUND: The rise in complementary and alternative medicine (CAM) use is well documented. Surveys provide varying estimates of the prevalence of CAM use. Qualitative research has explored individuals' decision-making regarding CAM. This study aimed to examine the family as a context for beliefs, decision-making, and dialogue about CAM. METHODS: Families were recruited via the Avon Longitudinal Study of Parents and Children. A subsample of CAM users was targeted using purposeful sampling. Focus groups and interviews were conducted with 15 families and the data were analyzed thematically. RESULTS: Family understandings and beliefs about CAM: CAM was understood as treatments provided outside mainstream care, offering a more "natural" and "holistic" approach, tailored to individual needs and overlapping with wider healthy lifestyle practices. Hierarchies of acceptability of CAM: Physical and "mainstream" therapies were widely supported, with "fringe" therapies producing the most polarized views. There was a belief particularly among fathers and young people that certain therapies rely on "placebo" effects and their value was contested. Types of CAM users within families: Family members were predominantly "pragmatic" CAM users, with "committed" users (all mothers) characterized by deeper philosophical commitment to CAM and skepticism toward conventional medicine. Family dynamics of CAM decision-making: Mothers tended to "champion" CAM within families, while not determining family CAM use. Fathers largely positioned themselves as lacking expertise or skeptical of CAM. Young people were beginning to articulate independent and more critical views of CAM, some directly challenging their mother's perspective. However, all families shared openness to CAM as part of broader beliefs in proactive healthy lifestyles. CONCLUSIONS: Family focus groups and interviews allow a window on beliefs, decision-making, and dialogue about CAM within families, illuminating the CAM "champion" role held by mothers, and young people's developing autonomy regarding health beliefs and decision-making. PMID- 21299430 TI - A suspected case of somatoform disorder successfully treated with an herbal medicine. AB - OBJECTIVE: Subjective physical symptoms, irrespective of whether they are psychosomatic or not, do not always show obvious or reasonable signs in examinations, which often makes the differential diagnosis between somatoform disorders and actual physical disease difficult for psychiatrists. In addition, psychiatrists have few clues as to how to treat diverse "medically unexplained" symptoms. This difficulty has highlighted the need for alternative treatments for somatoform disorders. SUBJECT: A 16-year-old high school baseball player was suffering from coxalgia and was unable to walk without crutches over 6 months. No painkiller was effective, the orthopedist found no remarkable signs in any examinations, and the patient was psychiatrically diagnosed with undifferentiated somatoform disorder. However, conventional therapies such as psychotherapy and selective serotonin reuptake inhibitors were ineffective. INTERVENTIONS AND OUTCOME: The therapeutic strategy was reevaluated from the perspective of Kampo diagnostics and keishikajutsubuto, a traditional Japanese herbal (Kampo) medicine, was chosen to be prescribed, which had a remarkable effect. His leg function improved within 2 weeks, and his pain and need for crutches disappeared in 6 weeks. CONCLUSIONS: Keishikajutsubuto has a different pain-relieving effect from conventional therapies. Kampo medicine thus provides an alternative approach for treating medically unexplained symptoms without strictly distinguishing between physically existing illness and psychologically caused somatoform disorders. Although details regarding the therapeutic mechanisms of Kampo medicine remain unclear and further studies are needed to increase its usefulness in clinical practice, Kampo medicine should be considered as an alternative treatment, especially for somatoform disorders. PMID- 21299429 TI - Mechanical loading activates beta-catenin signaling in periodontal ligament cells. AB - OBJECTIVE: To determine whether beta-catenin signaling is responsive to mechanical loading in periodontal ligament (PDL) cells. MATERIALS AND METHODS: To determine whether Wnt/beta-catenin signaling pathway components are present and functional, PDL cells were treated with lithium chloride or Wnt3a-conditioned media. To determine whether mechanical strain activates beta-catenin signaling, PDL cells were subjected to compressive loading. Activation of the beta-catenin signaling pathway was determined by immunofluorescence, Western immunoblotting, and TOPflash assay. RESULTS: Mimicking Wnt signaling stimulates beta-catenin nuclear translocation and T-cell factor/lymphoid enhancer binding factor dependent transcriptional activation in PDL cells. Mechanical loading stimulates a transient accumulation of dephosphorylated beta-catenin in the cytoplasm and its translocation to the nucleus. This effect of strain acts through activation of protein kinase B and phosphorylation of glycogen synthase kinase-3 beta. These strain-related changes do not involve the low-density lipoprotein receptor related protein 5/Wnt receptor. CONCLUSIONS: The Wnt/beta-catenin signaling pathway components are functional and activated by mechanical loading in PDL cells. beta-catenin serves as an effector of mechanical signals in PDL cells. PMID- 21299431 TI - Antibacterial activity of the indigenous earthworms Lampito mauritii (Kinberg) and Perionyx excavatus (Perrier). AB - INTRODUCTION: Earthworms respond to microbial infection through cellular and humoral defense mechanisms such as antimicrobial protein secretions. Most of the humoral defense proteins are synthesized in the skin itself. MATERIALS AND METHODS: In the present study, a dried powder was prepared from two indigenous earthworms (Lampito mauritii and Perionyx excavatus) and tested against two gram positive bacteria (Staphylococcus aureus and Staphylococcus epidermidis) and five gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, and Pseudomonas aeruginosa). RESULTS: The dried earthworm powder of two species shows a strong antibacterial activity against the S. aureus, P. mirabilis, and P. aeruginosa bacterial strains. Of these, the 60 MUg/mL/disc of P. excavatus earthworm powder shows more activity than the L. mauritii. PMID- 21299432 TI - Synthesis, spectral analysis and in vitro microbiological evaluation of novel ethyl 4-(naphthalen-2-yl)-2-oxo-6-arylcyclohex-3-enecarboxylates and 4,5-dihydro 6-(napthalen-2-yl)-4-aryl-2H-indazol-3-ols. AB - A series of ethyl 4-(naphthalen-2-yl)-2-oxo-6-arylcyclohex-3-enecarboxylates 8-14 and 4,5-dihydro-6-(naphthalen-2-yl)-4-aryl-2H-indazol-3-ols 15-21 were synthesised and characterised by their spectroscopic data. In vitro microbiological evaluations were carried out for all the newly synthesised compounds 8-21 against clinically isolated bacterial and fungal strains. Compounds 9, 12 and 20 against Staphylococcus aureus, 10, 12, 20 against beta haemolytic streptococcus, 11, 17 against Bacillus subtilis, 12, 16 and 20 against Vibreo cholerae, 13, 16 against Escherichia coli, 13, 16, 18, 19 against Salmonella typhii, 12, 18 against Shigella flexneri, 10 against Salmonella typhii, 10, 13, 17, 18 against Aspergillus flavus, 12, 17, 21 against Aspergillus niger, 12, 15, 17, 18, 20 against Mucor, Rhizopus and Microsporeum gypsuem exhibit potent antimicrobial activity. PMID- 21299434 TI - Development of a robust QSAR model to predict the affinity of pyrrolidine analogs for dipeptidyl peptidase IV (DPP- IV). AB - QSAR analysis using multiple linear regression and partial least squares methods were conducted on a data set of 47 pyrrolidine analogs acting as DPP IV inhibitors. The QSAR models generated (both MLR and PLS) were robust with statistically significant s, F, r, r(2) and r(2) (CV) values. The analysis helped to ascertain the role of shape flexibility index, Ipso atom E-state index and electrostatic parameters like dipole moment, in determining the activity of DPP IV inhibitors. In addition to QSAR modeling, Lipinski's rule of five was also employed to check the pharmacokinetic profile of DPP IV inhibitors. Since none of the compounds violated the Lipinski's rule of five indicating that the DPP IV inhibitors reported herein have sound pharmacokinetic profile and can be considered as potential drug candidates for diabetes mellitus Type II. PMID- 21299433 TI - Antioxidative iridoid glycosides from the sky flower (Duranta repens Linn). AB - Phytochemical investigations were performed on the EtOAc-soluble fraction of the whole plant of the sky flower (Duranta repens) which led to the isolation of the iridoid glycosides 1-6. Their structures were elucidated by both 1D and 2D NMR spectroscopic analysis. All the compounds showed potent antioxidative scavenging activity in four different tests, with half maximal inhibitory concentration (IC(50)) values in the range 0.481-0.719 mM against DPPH radicals, 4.07-17.21 MUM for the hydroxyl radical (.OH) inhibitory activity test, 43.3-97.37 MUM in the total reactive oxygen species (ROS) inhibitory activity test, and 3.39-18.94 MUM in the peroxynitrite (ONOO(-)) scavenging activity test. Duranterectoside A (1) displayed the strongest scavenging potential with IC(50) values of (0.481 +/- 0.06 mM, 4.07 +/- 0.03, 43.30 +/- 0.05, 3.39 +/- 0.02 MUM) for the DPPH radicals, .OH inhibitory activity test, total ROS inhibitory activity test and the ONOO(-) scavenging activity test, respectively. PMID- 21299435 TI - Derivation of physiological inhalation rates in children, adults, and elderly based on nighttime and daytime respiratory parameters. AB - The methodology developed in our previous studies ( Brochu et al. 2006a-c ) for the determination of physiological daily inhalation rates was improved by integrating into the calculation process, both nighttime and daytime respiratory parameters, namely oxygen uptake factors (H) and ventilatory equivalents (VQ). H values during fasting (0.2057+/-0.0018 L of O2/kcal; mean+/-SD) and postprandial phases (0.2059+/-0.0019 L of O2/kcal) as well as VQ values for subjects at rest (27.4+/-4.8 to 32.2+/-3.1, unitless) and during the aggregate daytime activities (29.9+/-4.2 to 33.7+/-7.2) were determined and combined with published doubly labeled water measurements for the calculation of daily inhalation rates in normal-weight males and females aged 0.22-96 years (n=1235). Depending upon the unit value chosen, the highest 99th percentiles for inhalation data were found in males aged 35 to <45 years (35.40 m3/day), 2.6 to <6 months (1.138 m3/kg-day), and 10 to <16.5 years (22.29 m3/m2-day). Means and percentiles expressed in m3/kg day as well as in m3/m2-day suggest generally higher intakes of air pollutants in children than in adults and in males than in females (in g/kg-day or g/m2-day) for identical exposure concentrations and conditions. For instance, means in boys aged 2.6 to <6 months of 10.99+/-3.50 m3/m2-day and 0.572+/-0.191 m3/kg-day are 1.3- and 2.5-folds higher, respectively, than those in adult males 65?96 years old (8.42+/-2.13 m3/m2-day, 0.225+/-0.059 m3/kg-day). PMID- 21299436 TI - Cardiovascular consequences of poor compliance to antihypertensive therapy. AB - Despite the proven efficacy of current strategies for cardiovascular (CV) risk reduction, a considerable gap remains between the risk reductions achieved in clinical trials and those seen in clinical practice. A major reason for this is poor compliance to medication, which has been extensively documented for antihypertensive therapy. Low adherence results in suboptimal blood pressure control, which is associated with adverse CV outcomes and increased treatment costs. Adverse effects of medication are an important cause of diminished adherence. Angiotensin II receptor blockers (ARBs) may offer better long-term tolerability than other classes of antihypertensive agent, and this is likely to be a major factor in the high levels of adherence and persistence seen with these agents. This could have implications for CV protection, as confirmed by the results of recent clinical trials. Thus, ARBs should be considered as an alternative to angiotensin-converting enzyme inhibitors in patients at risk of low adherence. PMID- 21299437 TI - Immunotherapy of multifocal motor neuropathy. AB - INTRODUCTION: Multifocal motor neuropathy (MMN) is an immune-mediated disease, which usually runs a chronic course. Current treatments are aiming at modulation of the immune response to maintain functional status. Although patients can remain stable with prolonged maintenance intravenous immunoglobuin (IVIg) treatment, most patients slowly deteriorate over many years despite increasing IVIg doses. AREAS COVERED: The paper identifies studies since 1985 for patients with MMN. Randomised and non-randomized studies examining the effects of any therapeutic agent were selected, to give a full overview of the different treatments for MMN. The review provides a treatment algorithm together with our views on current treatments, ongoing trials and possible directions for further research. EXPERT OPINION: IVIg remains the only proven treatment for MMN, although questions around dosages and duration of treatment remain. The presence of an effective therapy for MMN should not discourage but stimulate further research into alternative treatments as ongoing axonal damage results in increasing impairment in patients with MMN. PMID- 21299438 TI - Intradermal influenza vaccine and new devices: a promising chance for vaccine improvement. AB - INTRODUCTION: The main public health strategy for reducing the influenza burden is annual vaccination. However, because the immune response in the elderly and frail subjects is known to be less vigorous than in younger adults, novel strategies have been explored in the last decade to augment immune response after immunization. These have included an increased dosage, multiple dose vaccinations, use of vaccine adjuvants and more efficient routes of vaccine delivery. AREAS COVERED: This review discusses recent advances in intradermally administered influenza vaccines with particular attention to immunogenicity and safety data from clinical trials performed using appropriate injection systems which, combining consistent injection depth and volume, safety, simplicity and ease-of-use, allowed large scale evaluation. EXPERT OPINION: Substantial experience has been accumulated with Intanza(r) 9 and Intanza 15 MUg/IDflu(r) 15 MUg, administered using BD's SoluviaTM device, and are the first intradermal trivalent inactivated split-virion influenza vaccines to be licensed for use in 18 - 59 year adults and in elderly people, respectively. Clinical data showed that they are safe and immunogenic and can offer significant advantages in terms of higher acceptability, higher immunogenicity in the elderly and dose-sparing in adults younger than 60 years when compared with intramuscularly administered vaccine. PMID- 21299439 TI - Clinical gene therapy for the treatment of RPE65-associated Leber congenital amaurosis. AB - INTRODUCTION: The positive results of pioneering clinical trials using gene therapy as treatment for patients with Leber congenital amaurosis (LCA) have ushered in a new era of molecular retinal therapeutics for LCA, other blinding retinal disorders and gene therapy applications. AREAS COVERED: This review describes the role of retinal pigment epithelium-specific 65 kDa protein (RPE65) in the visual cycle and how RPE65 deficiency results in LCA; the extensive preclinical studies with recombinant adeno-associated virus (rAAV)-RPE65 gene vectors; and the human rAAV-RPE65 and related gene therapy clinical trials and studies. The literature search included a review of primary sources (e.g., journal articles) that reported study data results and key secondary sources such as meta-reviews available through PubMed, as well as reviews of clinical trial descriptions and results as reported in clinicaltrials.gov, conference publications and news releases. EXPERT OPINION: LCA-RPE65 gene therapy is an example of successful, innovative, translational research. Further research is needed regarding how retinal gene therapy can be improved. PMID- 21299440 TI - Mitral deceleration index is associated with aortic root dilatation and not to biventricular structural changes in essential hypertension. AB - BACKGROUND AND AIM. The ratio of deceleration time to early mitral wave velocity (mitral deceleration index, MDI) has been recently shown to predict cardiovascular events more precisely than deceleration time alone in human hypertension. Data, however, about the relationship of this parameter with cardiac structure are scant. In the present study, we investigated such an association in uncomplicated essential hypertensives. METHODS. A total of 329 hypertensive subjects categorized in tertiles of MDI were considered for the analysis. All patients underwent the following procedures: (i) physical examination and clinic blood pressure measurement; (ii) routine laboratory investigations; (iii) M-mode, two-dimensional and Doppler echocardiography aimed at a comprehensive assessment of left- and right-sided chambers. RESULTS. Unadjusted left ventricular (LV) mass, right ventricular (RV) and aortic root diameter were significantly higher in the upper MDI tertile, but only aortic root diameter remained significant after adjustment for covariates. A progressive, non significant increase in biventricular hypertrophy occurred across the MDI tertiles. In a multivariate analysis, MDI was significantly associated with age (beta = 0.229, p = 0.001) and aortic root diameter (beta = 0.226, p = 0.001); this was not the case for deceleration time alone. No association between MDI and LV as well as RV structural parameters was found. CONCLUSION. Our findings indicate that MDI is unrelated to LV and RV structural changes. Altered LV diastolic function, as assessed by MDI but not by deceleration time alone, is independently associated with aortic root dilatation, a phenotype predictive of incident cardiovascular morbidity and mortality. PMID- 21299441 TI - Current and future directions in mammalian target of rapamycin inhibitors development. AB - INTRODUCTION: The mammalian target of the rapamycin (mTOR) signalling pathway has a central role in the regulation of cell growth, survival and angiogenesis and the frequent dysregulation of this pathway in tumor cells makes it a crucial target in the treatment of cancer. Temsirolimus and everolimus are approved for use in metastatic renal cell carcinoma and temsirolimus is also approved for mantle cell lymphoma. All three rapalogs, temsirolimus, everolimus and deforolimus, are currently being evaluated in Phase III studies in several tumors. AREAS COVERED: This paper provides a review of the published literature on the mTOR pathway and related pathway signaling, analogs and novel mTOR inhibitors. The most recent and important data on the mTOR pathway, the role of mTOR inhibitors in cancer treatment and the current status of development of second-generation highly potent and selective mTOR inhibitors are overviewed. EXPERT OPINION: The published data on new mTOR inhibitors are still limited, but the available preclinical results indicate that they have a potent antiproliferative activity against a broad panel of tumor cell lines, have a favorable safety profile, can obtain disease stabilization or even tumor regression and, in some cases, enhance the efficacy of other targeted or standard of-care anticancer drugs when used in vivo in preclinical studies. PMID- 21299442 TI - The role of cytokines in the regulation of drug disposition: extended functional pleiotropism? AB - INTRODUCTION: Drug disposition, metabolism and drug-drug interactions are important considerations for most drugs. Cytokines are integral to the successful resolution of many diseases. Data are emerging on a role for cytokines in regulation of the expression and activity of drug transporters and drug metabolising enzymes. Investigation of the interaction between pharmacological and immunological responses is key to understanding the complex relationships involved in patient response to therapy. AREAS COVERED: Evidence detailing the ability of cytokines to regulate drug disposition and metabolism is reviewed in the context of different cell and tissue types. The literature search undertaken provides an overview of the current understanding of the interrelationship between pharmacological and immunological factors which may influence successful drug therapy. EXPERT OPINION: Dysregulation of cytokines and cytokine networks is a hallmark of a number of diseases such as HIV and cancer. The mechanisms by which the immune system can influence drug disposition are relatively understudied but recent work has highlighted the necessity for examining its impact on pharmacokinetics and pharmacodynamics. A more comprehensive approach in clinical studies will allow better determination of the impact of cytokines on drug disposition. In addition, determining the mechanisms that underpin the differential effects of cytokines across different cell types will clarify the responses reported in these studies. PMID- 21299443 TI - Herp zoster at the site of infliximab infusion: case report. AB - Worldwide, many patients have been treated with tumor necrosis factor-alpha (TNF alpha) antagonists for indications that include chronic inflammatory diseases such as rheumatoid and psoriatic arthritis, inflammatory bowel disease and others. Since their approval, concerns regarding safety have been raised. Increased susceptibility to bacterial infections, especially due to intracellular bacteria like Mycobacterium tuberculosis that is responsible for the most serious complications associated with this treatment. Viral infections are less frequently reported but probably relatively common, representing an important cause of morbidity to remember. Varicella zoster virus is one of the most frequently implicated viruses. We present the case of a 20-year-old man with Crohn's disease under infliximab treatment who developed herpes zoster at the site of infliximab's 7th and 9th infusion. PMID- 21299444 TI - Pharmacokinetic evaluation of ambrisentan. AB - INTRODUCTION: Pulmonary arterial hypertension (PAH) is a life-threatening and progressive disease characterized by increasing pulmonary vascular resistance leading to right ventricular failure and premature death. Current therapies target three major pathways involving endothelin, prostacyclin and NO. Ambrisentan is an oral, once daily, selective endothelin receptor antagonist. AREAS COVERED: This review focuses on, and critically appraises, the clinical efficacy and safety of ambrisentan as well as its pharmacokinetic and pharmacodynamic properties. The article also gives an expert perspective on the role of ambrisentan in the management of PAH. EXPERT OPINION: Ambrisentan is an effective and safe treatment which is, in the authors' opinion, a valuable addition to the armamentarium against PAH. Ambrisentan offers a relative lack of drug interactions, once daily dosing and reassuring liver safety, offering safety and convenience advantages over bosentan. Presently, there is a lack of comparative studies between PDE5 inhibitors and endothelin receptor antagonists and a lack of data comparing bosentan with ambrisentan. This is hindering data based conclusions regarding relative efficacy and further studies are needed to define the role of ambrisentan in the management of PAH. PMID- 21299445 TI - Update on stem cell therapy for cerebral palsy. AB - INTRODUCTION: Due to the publicity about stem cell transplantation for the treatment of cerebral palsy, many families seek information on treatment, and many travel overseas for cell transplantation. Even so, there is little scientific confirmation of benefit, and therefore existing knowledge in the field must be summarized. AREAS COVERED: This paper addresses the clinical protocols examining the problem, types of stem cells available for transplant, experimental models used to test the benefit of the cells, possible mechanisms of action, potential complications of cell treatment and what is needed in the field to help accelerate cell-based therapies. EXPERT OPINION: While stem cells may be beneficial in acute injuries of the CNS the biology of stem cells is not well enough understood in chronic injuries or disorders such as cerebral palsy. More work is required at the basic level of stem cell biology, in the development of animal models, and finally in well-conceived clinical trials. PMID- 21299446 TI - Incorporating DNA barcodes into a multi-year inventory of the fishes of the hyperdiverse Lower Congo River, with a multi-gene performance assessment of the genus Labeo as a case study. AB - BACKGROUND AND AIMS: Here we describe preliminary efforts to integrate DNA barcoding into an ongoing inventory of the Lower Congo River (LCR) ichthyofauna. The 350 km stretch of the LCR from Pool Malebo to Boma includes the world's largest river rapids. The LCR ichthyofauna is hyperdiverse and rich in endemism due to high habitat heterogeneity, numerous dispersal barriers, and its downstream location in the basin. MATERIALS AND METHODS: We have documented 328 species from the LCR, 25% of which are thought to be endemic. In addition to detailing progress made to generate a reference sequence library of DNA barcodes for these fishes, we ask how DNA can be used at the current stage of the Fish Barcode of Life initiative, as a work in progress currently of limited utility to a wide audience. Two possibilities that we explore are the potential for DNA barcodes to generate discrete diagnostic characters for species, and to help resolve problematic taxa lacking clear morphologically diagnostic characters such as many species of the cyprinid genus Labeo, which we use as a case study. RESULTS: Our molecular analysis helped to clarify the validity of some species that were the subject of historical debate, and we were able to construct a molecular key for all monophyletic and morphologically recognizable species. Several species sampled from across the Congo Basin and widely distributed throughout Central and West Africa were recovered as paraphyletic based on our molecular data. CONCLUSION: Our study underscores the importance of generating reference barcodes for specimens collected from, or in close proximity to, type localities, particularly where species are poorly understood taxonomically and the extent of their geographical distributions have yet to be established. PMID- 21299447 TI - Short-course adjuvant trastuzumab therapy in early stage breast cancer in Finland: cost-effectiveness and value of information analysis based on the 5-year follow-up results of the FinHer Trial. AB - BACKGROUND: Trastuzumab is a standard treatment of HER2-positive early breast cancer in many countries, and it is usually given as a one year adjuvant treatment. However, its cost-effectiveness has not been assessed in Finland. The Finland Herceptin (FinHer) trial has compared a shorter 9-week treatment protocol against no trastuzumab with promising results. The aim of this study was to assess the potential cost-effectiveness of the 9-week treatment based on the recently published five-year follow-up results of the FinHer trial. METHODS: An evaluation model of breast cancer treatment was constructed using fitted survival estimates and a long-term Markov model. The cost-effectiveness of 9-week adjuvant treatment was assessed in a Finnish setting, compared to treatment without trastuzumab. The analysis was performed from a societal perspective, and a 3% discount rate was applied for future costs and outcomes. Value of information analysis was performed to estimate the potential value of further research. RESULTS: According to the probabilistic analysis, the incremental cost effectiveness ratio was ?12 000 per quality adjusted life year (QALY), and ?9300 per life year gained (LYG), when comparing adjuvant trastuzumab therapy to standard treatment without trastuzumab. The modelled incremental outcomes for trastuzumab treatment were 0.66 QALY and 0.85 LYG for a lifetime perspective. Value of information analysis showed that additional research on treatment effects would be most valuable for reducing uncertainty in the adoption decision. CONCLUSIONS: Adjuvant 9-week trastuzumab is likely to be a cost-effective treatment in the Finnish setting. Results from an ongoing trial comparing adjuvant 9-week treatment with the 12-month treatment will play a key role in addressing the uncertainty related to the treatment effect and potential cost effectiveness of these two treatment protocols. PMID- 21299448 TI - Dose-tailoring of FEC adjuvant chemotherapy based on leukopenia is feasible and well tolerated. Toxicity and dose intensity in the Scandinavian Breast Group phase 3 adjuvant Trial SBG 2000-1. AB - The SBG 2000-1 trial is a randomised study that investigates if dose-tailored adjuvant FEC therapy based on the individual's leukocyte nadir value can improve outcome. The study has included 1535 women with medium and high-risk breast cancer. PATIENTS AND METHODS: After a first standard dosed FEC course (5 fluorouracil 600 mg/m(2), epirubicin 60 mg/mg(2) and cyclophosphamide 600 mg/m(2)), patients who did not reach leukopenia grade III or IV were randomised to standard doses (group standard) or doses tailored to achieve grade III leukopenia (group tailored) at courses 2-7. Patients who achieved leukopenia grade III or more after the first course were not randomised but continued on standard doses (group registered). RESULTS: Both planned and actually delivered number of courses (seven) were the same in all three arms. The relative dose intensity was increased by a factor of 1.31 (E 1.22, C 1.43) for patients in the tailored arm compared to the expected on standard dose. Ninety percent of the patients in the tailored arm achieved leukopenia grade III-IV compared with 29% among patients randomised to standard dosed therapy. Dose tailoring was associated with acceptable acute non-haematological toxicity with more total alopecia, nausea, vomiting and fatigue. CONCLUSION: Dose tailoring according to leukopenia was feasible. It led to an increased dose intensity and was associated with acceptable excess of acute non-haematological toxicity. PMID- 21299449 TI - Spatial density of primary malignant melanoma in sun-shielded body sites: A potential guide to melanoma genesis. AB - UV radiation is a major factor in melanoma genesis, but non-UV linked factors are also operational, since primary malignant melanomas can emerge in body sites that never see the sun. The scarcity of melanomas in sun-shielded body sites reflects only the absolute number of melanomas, not the number of tumours per square unit of the surface in which they emerge. Studies on melanoma density conducted by us and others are here briefly reviewed. The access to reliable numbers along with measurable anatomical areas directed our choice of melanomas at the sun-shielded locations described here. Melanomas at the body surface. Calculations of surface areas bearing melanomas relative to the total body surface included sites on the vulva, subungual tissues, volar and palmar skin, and, for comparison melanomas of the face during the same period of time. The density of vulvar melanomas was identical to that in chronically sun-exposed facial skin. Subungual melanomas were almost nine times denser than expected whereas melanomas of palms and soles showed a lower density than expected. Melanomas beneath the body surface. The densities of melanomas in the vagina, anal canal and uvea, were calculated separately and compared to the average density of cutaneous melanomas (CMMs) during the same period of time. Melanomas of the anal canal displayed a density almost twice the average for CMMs, whereas the vaginal melanomas were similar in density to CMMs. In contrast, the density of the uveal melanomas was calculated as 50 and 41 times (men and women, respectively) the average density of CMMs. CONCLUSION: The high density of some melanomas in sun-shielded body areas indicates the presence of factors underlying the origins of these tumours that seem to be equivalent in strength to UV radiation and also implies that specific anatomical sites favour the emergence and proliferation of melanomas, independent of UV radiation. PMID- 21299451 TI - Suicide inactivation of tyrosinase in its action on tetrahydropterines. AB - Tetrahydrobiopterin (BH(4)), methyl-tetrahydropterin (MBH(4)) and dimethyl tetrahydropterin (DMBH(4)) are oxidized by tyrosinase in a process during which the suicide inactivation of tyrosinase may occur. From the kinetic study of this process, [Formula: see text] (apparent maximum constant for the suicide inactivation), [Formula: see text] (Michaelis constant for the substrate) and r (number of turnovers that the enzyme makes before the inactivation) can be obtained. From the results obtained, it can be deduced that the velocity of the inactivation governed by ([Formula: see text]) and the potency of the same ([Formula: see text]) follow the order: BH(4) > MBH(4) > DMBH(4). PMID- 21299450 TI - A latent class analysis of psychiatric symptoms among 125 adolescents in a bariatric surgery program. AB - OBJECTIVE: The purpose of this study was to examine whether subgroups could be identified among a sample of adolescents presenting for bariatric surgery. METHODS: Participants were 125 severely obese adolescents enrolled in a bariatric surgery program referred for a psychiatric evaluation. A latent class analysis was conducted with self-report and clinician-rated measures of depressive symptoms, total problems by the Youth Self-Report Scale, anxiety severity, eating pathology, psychiatric diagnoses, quality of life, and family functioning. RESULTS: A 3-class model yielded the best overall fit to the data. Adolescents in the ?eating pathology? class demonstrated high levels of both eating disordered and other psychopathology. The second class, or ?low psychopathology? class exhibited the fewest psychosocial problems, whereas adolescents in the third class were intermediate on measures of psychopathology, which is consistent with ?non-specific psychopathology.? CONCLUSIONS: The latent class analysis identified homogeneous subgroups with different levels of psychopathology among a heterogeneous sample of severely obese adolescents. The identification of clinically relevant subgroups in this study offers an important initial means for examining psychopathology among adolescent bariatric surgery candidates and suggests a number of avenues for future research. CLINICAL TRIALS REGISTRY: Laparoscopic Adjustable Gastric Banding (LAGB) as a Treatment for Morbid Obesity in Adolescents, NCT01045499. PMID- 21299452 TI - Steroidal 5alpha-reductase inhibitors using 4-androstenedione as substrate. AB - The aim of this study was to determine the capacity of some progesterone derivatives, to inhibit the conversion of labeled androstenedione ([(3)H] 4 dione) to [(3)H]dihydrotestosterone ([(3)H]DHT) in prostate nuclear membrane fractions, where the 5alpha-reductase activity is present. The enzyme 5alpha reductase catalyzes the 5alpha-reduction of 4-dione whereas the 17beta hydroxysteroid dehydrogenase catalyzes the transformation of 4-dione to testosterone or 5alpha-dione to dihydrotestosterone (DHT). Moreover, we also investigated the role of unlabeled 5alpha-dione in these pathways. In order to determine the inhibitory effect of different concentrations of the progesterone derivatives in the conversion of [(3)H] 4-dione to [(3)H]DHT, homogenates of human prostate were incubated with [(3)H] 4-dione, NADPH and increasing concentrations of non-labeled 5alpha-dione. The incubating mixture was extracted and purified using thin layer chromatography. The fraction of the chromatogram corresponding to the standard of DHT was separated and the radioactivity determined. The results showed that the presence of [(3)H] 4-dione plus unlabelled 5alpha-dione produced similar levels of DHT as compared to [(3)H] 4 dione. On the other hand, the results indicated that 17alpha-hydroxypregn-4-ene 3,20-dione 5 and 4-bromo-17alpha-hydroxypregn-4-ene-3,20-dione 7b, were the most potent steroids to inhibit the conversion of [(3)H] 4-dione to [(3)H]DHT, showing IC(50) values of 2 and 1.6 nM, respectively. PMID- 21299453 TI - Nerve-sparing procedure in radical prostatectomy: a risk factor for hernia repair following open retropubic, pure laparoscopic and robot-assisted laparoscopic procedures. AB - OBJECTIVE: To identify risk factors for hernia repair following open retropubic, pure laparoscopic and robot-assisted laparoscopic radical prostatectomy. MATERIAL AND METHODS: The medical records of 632 patients who had undergone radical prostatectomy (open retropubic n = 430, pure laparoscopic n = 49, and robot assisted laparoscopic n = 202) were reviewed retrospectively. Patients with postprostatectomy inguinal hernia were defined as those who had undergone subsequent hernia repair. The mean period of follow-up was 19.5 months (median 19, range 1 to 42). RESULTS: Hernia repairs were performed in 27 of the 632 patients (4.3%). The site of the repair was right in 15 patients (55.6%), left in 9 patients (33.3%), and bilateral in 3 patients (11.1%). The timing of the hernia repair ranged from 4 to 35 months (mean 13.1) following radical prostatectomy. No difference in hernia-repair-free rates was observed between the extraperitoneal open and transperitoneal pure or robot-assisted laparoscopic radical prostatectomy procedures (p = 0.225, log-rank test). The log-rank test revealed that the nerve sparing procedure (p = 0.019) and the absence of diabetes (p = 0.017) were significant risk factors for postprostatectomy hernia repair. In the multivariate Cox proportional hazards model, neurovascular bundle saving was the only significant risk factor for postprostatectomy inguinal hernia repair (Hazard ratio, 2.64, 95% confidence interval 1.09 to 6.41, p = 0.032). CONCLUSIONS: These findings suggest that the nerve sparing procedure may increase the risk of hernia repair. Prospective studies are warranted to investigate the possible adverse effects of the nerve sparing technique. PMID- 21299455 TI - Techniques for risk stratification of newly diagnosed patients with chronic myeloid leukemia. AB - Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by BCR ABL, a constitutively active tyrosine kinase generated as a result of the t(9;22)(q34;q11). The natural history of CML is progression from a relatively benign chronic phase to an acute leukemia termed blast crisis. Imatinib, an inhibitor of BCR-ABL tyrosine kinase activity, has a dramatic effect on the natural history of the disease. Despite the favorable outcomes with imatinib, a subset of patients have primary refractory disease, or experience relapse after an initial response. Recently identified molecular predictors of drug response might help predict outcome with tyrosine kinase inhibitor therapy more accurately than clinical prognostication scores, but have not yet been introduced into clinical routine. These techniques include analysis of drug transport proteins, in vitro drug assays, measurement of imatinib plasma levels, BCR-ABL activity monitoring, and gene expression profiling. In this article we review the current status of these technologies, which may ultimately allow us to tailor therapy to a specific patient. PMID- 21299456 TI - Mechanisms of resistance to BCR-ABL kinase inhibitors. AB - Since the introduction of imatinib mesylate (IM) for the treatment of chronic myeloid leukemia (CML), impressive clinical responses have been observed in the majority of patients in chronic phase. However, not all patients experience an optimal response to IM or even to the more potent, second-generation tyrosine kinase inhibitors (TKIs). Furthermore, responses are not sustained in a number of patients, and it is yet unclear whether the inhibitors can be safely discontinued in patients who achieve long-term remission. The emergence of resistance to TKIs has become a significant problem that has led to extensive studies on the causal mechanisms. This review describes our current state of knowledge on why and how CML cells can develop resistance to TKIs. PMID- 21299457 TI - Chronic myeloid leukemia cells refractory/resistant to tyrosine kinase inhibitors are genetically unstable and may cause relapse and malignant progression to the terminal disease state. AB - BCR-ABL1 kinase-induced chronic myeloid leukemia in chronic phase (CML-CP) usually responds to treatment with ABL tyrosine kinase inhibitors (TKIs) such as imatinib, dasatinib, and nilotinib. In most patients TKIs reduce the leukemia cell load substantially, but some leukemia cells, for example leukemia stem cells (LSCs), are intrinsically refractory to TKIs. In addition, some patients who respond initially may later become resistant to TKIs due to accumulation of point mutations in BCR-ABL1 kinase. LSCs or their progeny, leukemia progenitor cells (LPCs), at some stage may acquire additional genetic changes that cause the leukemia to transform further to a more advanced blast phase (CML-BP), which responds poorly to treatment and is usually fatal. We postulate that LSCs and/or LPCs refractory or resistant to TKIs may be 'ticking time-bombs' accumulating additional genetic aberrations and eventually 'exploding' to generate additional TKI-resistant clones and CML-BP clones with complex karyotypes. PMID- 21299459 TI - Regulation of mammalian target of rapamycin and mitogen activated protein kinase pathways by BCR-ABL. AB - A large body of evidence has established that BCR-ABL regulates engagement and activation of mammalian target of rapamycin (mTOR) and mitogen activated protein kinase (MAPK) signaling cascades. mTOR-mediated signals, as well as signals transduced by ERK, JNK, and p38 MAPK, are important components of the aberrant signaling induced by BCR-ABL. Such deregulation of mTOR or MAPK pathways contributes to BCR-ABL leukemogenesis, and their targeting with selective inhibitors provides an approach to enhance antileukemic responses and/or overcome leukemic cell resistance in chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). This review explores recent advances in our understanding of mTOR and MAPK signaling in BCR ABL-expressing leukemias and discusses the potential therapeutic targeting of these pathways in CML and Ph+ ALL. PMID- 21299460 TI - Chronic myeloid leukemia stem cells and developing therapies. AB - Chronic myeloid leukemia therapy has remarkably improved with the use of frontline BCR-ABL kinase inhibitors such that newly diagnosed patients have minimal disease manifestations or progression. Effective control of disease may also set the stage for eventual 'cure' of this leukemia. However, the existence of Philadelphia chromosome-positive leukemic cells that are unaffected by BCR-ABL inhibition represents a major barrier that may delay or prevent curative therapy with the current approaches. The most commonly reported mechanism of resistance to tyrosine kinase inhibitor-based therapies involves BCR-ABL gene mutations and amplification, but these changes may not be solely responsible for disease relapse when inhibitor-based therapies are curtailed. Therefore new targets may need to be defined before significant advancement in curative therapies is possible. Emerging evidence suggests that persistence of chronic myeloid leukemia stem cells or acquisition of stem cell-like characteristics prevents complete elimination of chronic myeloid leukemia by tyrosine kinase inhibition alone. This review focuses on several recently emerging concepts regarding the existence and characteristics of chronic myeloid leukemia stem cells. Definitions based on human primary cells and animal model studies are highlighted as are the potential signaling pathways associated with disease repopulating cells. Finally, several recently defined therapeutic targets and active compounds that have emerged from stem cell studies are described. Our goal is to provide an unbiased report on the current state of discovery within the chronic myeloid leukemia stem cell field and to orient the reader to emerging therapeutic targets and strategies that may lead to elimination of this leukemia. PMID- 21299458 TI - BCR-ABL1 kinase-dependent alteration of mRNA metabolism: potential alternatives for therapeutic intervention. AB - The use of first- and second-generation tyrosine kinase inhibitors (TKIs) significantly improves prognosis for patients with early chronic phase chronic myeloid leukemia (CML) and efficiently counteracts leukemia in most patients with CML bearing a disease characterized by the expression of BCR-ABL1 mutants. However, the so-called 'tinib' TKIs (e.g. imatinib, nilotinib, dasatinib, and bosutinib) are both ineffective in patients who undergo blastic transformation and unable to eradicate CML at the stem cell level. This raises a few important questions. Is BCR-ABL1 expression and/or activity essential for blastic transformation? Is blastic transformation the result of genetic or epigenetic events that occur at the stem cell level which only become apparent in the granulocyte-macrophage progenitor (GMP) cell pool, or does it arise directly at the GMP level? As altered mRNA metabolism contributes to the phenotype of blast crisis CML progenitors (decreased translation of tumor suppressor genes and transcription factors essential for terminal differentiation and increased translation of anti-apoptotic genes), one attractive concept is to restore levels of these essential molecules to their normal levels. In this review, we discuss the mechanisms by which mRNA processing, translation, and degradation are deregulated in BCR-ABL1 myeloid blast crisis CML progenitors, and present encouraging results from studies with pharmacologic inhibitors which support their inclusion in the clinic. PMID- 21299461 TI - New developments in the treatment of chronic myeloid leukemia and Philadelphia positive acute lymphoblastic leukemia. AB - Although imatinib revolutionized the management of chronic myeloid leukemia (CML), recent data indicate a transformation in the treatment approach likely in the near future. The superiority of second-generation tyrosine kinase inhibitors (TKIs) over imatinib in newly diagnosed disease has been recognized. Several investigational agents specific for those patients with the T315I mutation remain under evaluation. In Philadelphia-positive (Ph-positive) acute lymphoblastic leukemia (ALL), the addition of imatinib improved response rates. However, short remission durations with single agent therapy limit the benefit on survival. Early molecular remissions achieved with dasatinib will enable more patients to proceed to stem cell transplant (SCT), with increased likelihood of positive outcomes post-SCT. PMID- 21299462 TI - Malignancy-associated hemophagocytic lymphohistiocytosis in adults: a retrospective population-based analysis from a single center. AB - A retrospective, population-based study was conducted to evaluate the incidence, clinical features, and outcome of malignancy-associated hemophagocytic lymphohistiocytosis (M-HLH) in adults. Between January 1996 and December 2009, eight out of 887 (0.9%) patients diagnosed with hematological malignancies developed aggressive M-HLH in an area inhabited by approximately 160,000 people. Thus the estimated annual incidence of M-HLH in adulthood was 0.36/100,000 individuals/year. The clinical course of M-HLH was aggressive in all patients. Six patients were treated with a modified HLH-94 protocol; three achieved remission (durable in one case) while the others did not respond and died within an average of 2.4 months (range 1.5-3.5) after M-HLH diagnosis. Infection complicating the course of M-HLH occurred in four (50%) patients, all of whom developed fulminant M-HLH and died. Although the small study population limits the results, the long observation period strengthens its value. PMID- 21299463 TI - Molecular evidence of a genotypically novel large T-cell lymphoma after anti-CD4 therapy for refractory mycosis fungoides. PMID- 21299464 TI - Paired box gene 5 may modulate Proviral Integration of Moloney virus 2 gene and protein expression in mature B-cells. AB - Deregulated transcription factor Paired box gene 5 (Pax-5) expression has been implicated in B-cell lymphoma in human disease. Proviral Integration of Moloney virus 2 (Pim-2) kinase may play a role in apoptosis and chemotherapy resistance. We characterized the expression of Pax-5 and Pim-2 in mature B-cell lines and 293T cells transfected with human isoforms of Pax-5. By quantitative real-time polymerase chain reaction (qRT-PCR), we showed that Pax-5 isoforms significantly increased Pim-2 mRNA expression in 293T cells and that mRNAs for both Pax-5 and Pim-2 were two-fold significantly expressed in mature malignant B-cells. Western blot analysis showed that Pim-2 protein expression was increased in 293T cells transiently transfected with human isoforms of Pax-5 and that Pax-5 isoforms and Pim-2 proteins were expressed in mature B-cell lines. By electrophoretic mobility shift analysis, we showed that Pax-5 isoforms were able to bind to the Pim-2 promoter region. Taken together, these results suggest that Pax-5 may act as a transcription factor to modulate the expression of Pim-2 and that both proteins may play a role in the oncogenesis of mature B-cell lymphoma. PMID- 21299466 TI - Successful treatment of cyclophosphamide-induced haemorrhagic cystitis with intravesical prostaglandin E1 in a child with non-Hodgkin's lymphoma. AB - Abstract A 5-year-old male patient with non-Hodgkin's lymphoma developed haemorrhagic cystitisgrade IV due to cyclophosphamide. Intravesical prostaglandin E(1)was administered safely and successfully. This case demonstrates that intravesical prostaglandin E(1) is a safe, easyand effective treatment method in resistant grade IV haemorrhagic cystitis. PMID- 21299465 TI - Pamidronate versus observation in asymptomatic myeloma: final results with long term follow-up of a randomized study. AB - A prospective, multicenter, randomized trial comparing pamidronate administration (60-90 mg once a month for 1 year) versus simple observation in 177 patients with asymptomatic myeloma was performed to explore whether the administration of this drug reduces the rate of and/or the time to progression to overt, symptomatic disease. No relevant side effects were recorded in pamidronate-treated patients. With a minimum follow-up of 5 years for live patients, there were 56/89 (62.9%) progressions in the pamidronate-treated group and 55/88 (62.5%) within the controls (p = NS). Median time to progression was 46 and 48 months, respectively (p = NS). Overall survival was also similar between the two groups. Skeletal related events at the time of progression were observed in 40/55 (72.7%) controls, but only in 22/56 (39.2%) pamidronate-treated patients (p = 0.009). In conclusion, the administration of pamidronate in asymptomatic myeloma, while reducing bone involvement at progression, did not decrease the risk of transformation and the time to progression into overt myeloma. PMID- 21299467 TI - Redox-regulated peptide transfer from the transporter associated with antigen processing to major histocompatibility complex class I molecules by protein disulfide isomerase. AB - Most antigenic peptides are generated by proteasomes in the cytosol and are transported by the transporter associated with antigen processing (TAP) into the endoplasmic reticulum, where they bind with nascent major histocompatibilitiy complex class I molecule (MHC-I). Although the overall process of peptide-MHC-I complex assembly is well studied, the mechanism by which free peptides are delivered from TAP to MHC-I is unknown. In this study, we investigated the possible role of protein disulfide isomerase (PDI) as a peptide carrier between TAP and MHC-I. Analysis of PDI-peptide complexes reconstituted in vitro showed that PDI exhibits some degree of specificity for peptides corresponding to antigenic ligands of various human leukocyte antigen (HLA) alleles. Mutations of either anchor residues of the peptide ligand or the peptide-binding site of PDI inhibited the PDI-peptide interaction. The PDI-peptide interaction increased under reducing conditions, whereas binding of the peptide to PDI decreased under oxidizing conditions. TAP-associated PDI was predominantly present in the reduced form, whereas the MHC-I-associated PDI was present in the oxidized form. Further, upon binding of optimal peptides, PDI was released from TAP and sequentially associated with HLA-A2.1. Our data revealed a redox-regulated chaperone function of PDI in delivering antigenic peptides from TAP to MHC-I. PMID- 21299468 TI - Nitroxyl (HNO): a novel redox signaling molecule. AB - Nitroxyl (HNO), the one electron reduced and protonated congener of nitric oxide, is emerging as a novel nitrogen oxide with distinct chemistry and biological actions as compared with its redox sibling. The "thiophilic" nature of HNO underlies many of its unique properties, and attention has been focused on its regulation of cellular function and therapeutic potential, particularly in the treatment of cardiovascular disease. The present Forum issue summarizes the intriguing chemistry and biology of HNO and highlights its impact in the cardiovascular and central nervous systems. Recent advances in the development of new HNO donors and their potential use as tools to study HNO signaling and therapeutic agents are discussed. Evidence is also provided for a role of HNO as a putative, endogenous regulator of vascular function. However, as highlighted in this Forum issue, the development of sensitive methods for HNO detection in a biological system is needed to conclusively prove its in vivo generation. As research expands in this area, it is likely that new targets and pharmacological applications of HNO will be discovered. PMID- 21299469 TI - The medical treatment of overactive bladder, including current and future treatments. AB - INTRODUCTION: Oveactive bladder (OAB) is a common condition that affects patients' quality of life. The role of antimuscarinics and future treatments in the management of this bothersome condition is reviewed. AREAS COVERED: The current literature on the efficacy, suitability and safety of current and future treatments is reviewed based on a search of Medline/Pubmed for relevant articles published in English between 1980 and 2010. EXPERT OPINION: Currently, antimuscarinic drugs are the cornerstone of OAB treatment; clinically recommended doses of these agents decrease the ability of the bladder to contract during the storage phase and so increase cystometric bladder capacity. In general, these agents are safe and have mild adverse effects. There is also evidence that, despite having different tolerability profiles, available drugs are well tolerated compared with placebo. Antimuscarinic agents, as a class, have similar efficacy. They offer substantial help in the alleviation of OAB symptoms, providing significant improvement to quality of life. Investigation to provide pharmacological alternatives whenever antimuscarinic drugs do not provide symptomatic relief or cause intolerable side effects is intense. Beta-adrenergic agents may be the next pharmacologic agents for OAB. However, many other areas of research may soon provide new pharmacological agents for OAB treatment. PMID- 21299470 TI - The multidomain thioredoxin-monothiol glutaredoxins represent a distinct functional group. AB - Monothiol glutaredoxins (Grxs) with a noncanonical CGFS active site are found in all kingdoms of life. They include members with a single domain and thioredoxin Grx fusion proteins. In Saccharomyces cerevisiae, the multidomain Grx3 and Grx4 play an essential role in intracellular iron trafficking. This crucial task is mediated by an essential Fe/S cofactor. This study shows that this unique physiological role cannot be executed by single domain Grxs, because the thioredoxin domain is indispensable for function in vivo. Mutational analysis revealed that a CPxS active site motif is fully compatible with Fe/S cluster binding on Grx4, while a dithiol active site results in cofactor destabilization and a moderate impairment of in vivo function. These requirements for Fe/S cofactor stabilization on Grx4 are virtually the opposite of those previously reported for single domain Grxs. Grx4 functions as iron sensor for the iron sensing transcription factor Aft1 in S. cerevisiae. We found that Aft1 binds to a conserved binding site at the C-terminus of Grx4. This interaction is essential for the regulation of Aft1. Collectively, our analysis demonstrates that the multidomain monothiol Grxs form a unique protein family distinct from that of the single domain Grxs. PMID- 21299471 TI - Understanding tobacco related changes in lung parenchyma is key to effective disease prevention. PMID- 21299472 TI - Rapid fall in lung density following smoking cessation in COPD. AB - INTRODUCTION: Whether smoking-induced lung inflammation subsides after smoking cessation is currently a matter of debate. We used computed tomography (CT) to evaluate the effect of smoking cessation on lung density in patients with COPD. MATERIAL AND METHODS: Thirty-six patients quit smoking out of 254 current smokers with COPD who were followed with annual CT and lung function tests (LFT) for 2?4 years as part of a randomised placebo-controlled trial of the effect of inhaled budesonide on CT-lung density. Lung density was expressed as the 15th percentile density (PD15) and relative area of emphysema below -910 HU (RA-910). From the time-trends in the budesonide and placebo groups the expected CT-lung densities at the first visit after smoking cessation were calculated by linear regression and compared to the observed densities. RESULTS: Following smoking cessation RA 910 increased by 2.6% (p = 0.003) and PD15 decreased by -4.9 HU (p = 0.0002). Furthermore, changes were larger in the budesonide group than the placebo group (PD15: -7.1 vs -2.8 HU. RA-910 3.7% vs 1.7%). These differences were, however, not statistically significant. The LFT parameters (FEV(1) and diffusion capacity) were not significantly influenced by smoking cessation. CONCLUSION: Inflammation partly masks the presence of emphysema on CT and smoking cessation results in a paradoxical fall in lung density, which resembles rapid progression of emphysema. This fall in density is probably due to an anti-inflammatory effect of smoking cessation. PMID- 21299473 TI - The frequency of chronic rhinosinusitis/nasal polyp in COPD and its effect on the severity of COPD. AB - This study aimed to investigate the effect of chronic rhinosinusitis/nasal polyposis on the severity of COPD and to find out whether the 'united airway disease' hypothesis is valid for COPD. The study enrolled 90 patients diagnosed and staged according to criteria of an international guideline for diagnosis and management of COPD. The patients in stages I and II were classified as Group 1 and the patients in stages III and IV as Group 2. All the patients were questioned about the presence of major and minor criteria of sinusitis, underwent paranasal sinus computed tomography (PNS-CT) scans, and answered a questionnaire based on a quality of life test for sinusitis (SNOT-20). Sinusitis was present in 48 (53%) patients according to criteria of major and minor symptoms, and in 58 (64%) patients according to Lund-Mackay scoring system of PNS-CT. There was no significant difference in CT score between Group 1 and Group 2 (2.3 +/- 0.5 vs. 2.1 +/- 0.4, p > 0.05). However, the frequency of minor symptoms was greater in Group 2. SNOT-20 score was significantly higher in Group 2 than in Group 1 (28.7 +/- 1.7 and 22.2 +/- 1.9, respectively, p = 0.014). A significant correlation was determined between Lund-Mackay and SNOT-20 scores. The presence of CRS should be assessed in COPD patients, especially in those with severe disease. Further research is needed to disclose possible common immunopathological mechanisms in the pathogeneses of COPD and CRS. PMID- 21299474 TI - Kurtosis and skewness of density histograms on inspiratory and expiratory CT scans in smokers. AB - The aim of this study is to evaluate the relationship between lung function and kurtosis or skewness of lung density histograms on computed tomography (CT) in smokers. Forty-six smokers (age range 46?81 years), enrolled in the Lung Tissue Research Consortium, underwent pulmonary function tests (PFT) and chest CT at full inspiration and full expiration. On both inspiratory and expiratory scans, kurtosis and skewness of the density histograms were automatically measured by open-source software. Correlations between CT measurements and lung function were evaluated by the linear regression analysis. Although no significant correlations were found between inspiratory kurtosis or skewness and PFT results, expiratory kurtosis significantly correlated with the following: the percentage of predicted value of forced expiratory volume in the first second (FEV(1)), the ratio of FEV(1) to forced vital capacity (FVC), and the ratio of residual volume (RV) to total lung capacity (TLC) (FEV(1)%predicted, R = -0.581, p < 0.001; FEV(1)/FVC, R = -0.612, p < 0.001; RV/TLC, R = 0.613, p < 0.001, respectively). Similarly, expiratory skewness showed significant correlations with PFT results (FEV(1)%predicted, R = -0.584, p < 0.001; FEV(1)/FVC, R = -0.619, p < 0.001; RV/TLC, R = 0.585, p < 0.001, respectively). Also, the expiratory/inspiratory (E/I) ratios of kurtosis and skewness significantly correlated with FEV(1)%predicted (p < 0.001), FEV(1)/FVC (p < 0.001), RV/TLC (p < 0.001), and the percentage of predicted value of diffusing capacity for carbon monoxide (kurtosis E/I ratio, p = 0.001; skewness E/I ratio, p = 0.03, respectively). We conclude therefore that expiratory values and the E/I ratios of kurtosis and skewness of CT densitometry reflect airflow limitation and air-trapping. Higher kurtosis or skewness on expiratory CT scan indicates more severe conditions in smokers. PMID- 21299476 TI - Informed consent process in Alpha-1 testing of at-risk children: views of parents and adults tested as children. AB - Targeted testing programs are identifying increasing numbers of adults affected by Alpha-1 Antitrypsin Deficiency (Alpha-1) who are making decisions about genetic testing for their at-risk children. Although there are possible benefits, there are also potential risks. The purpose of this pilot study was to explore attitudes toward testing at-risk children from the first hand perspective of those involved, identify the benefits and risks experienced therein, and compare the views of parents and adults tested as children (ATC). The results of this pilot study suggest that ATC were significantly more favorable to including children in testing decisions than parents. ATC strongly indicated that they want to be involved in the testing decision and give permission prior to testing (p = 0.007). While the majority of ATC and parents were in favor of newborn screening for Alpha-1, parents had more extreme views, both positive and negative (p = 0.04). Both ATC and parents expressed significantly higher likelihoods of possible risks and benefits following Alpha-1 testing than they actually experienced. Results do not reveal serious harms from testing at-risk children. The two groups indicated that they want information regarding access to insurance, inheritance and expression, impact on anxiety, association with smoking, and usefulness in future planning prior to a decision to test or not to test at risk children. From the resulting data and ethical analysis we recommend that parents and children have relevant information prior to testing for Alpha-1 and that at risk children are directly involved in the decision-making process prior to testing. PMID- 21299475 TI - Randomized trial of zileuton for treatment of COPD exacerbations requiring hospitalization. AB - RATIONALE: Leukotrienes have been implicated in the pathogenesis of acute exacerbations of COPD, but leukotriene modifiers have not been studied as a possible therapy for exacerbations. OBJECTIVE: We sought to test the safety and efficacy of adding oral zileuton (a 5-lipoxygenase inhibitor) to usual treatment for acute exacerbations of COPD requiring hospitalization. METHODS: Randomized double-blind, placebo-controlled, parallel group study of zileuton 600 mg orally, 4 times daily versus placebo for 14 days starting within 12 hours of hospital admission for COPD exacerbation. Primary outcome measure was hospital length of stay; secondary outcomes included treatment failure and biomarkers of leukotriene production. MAIN FINDINGS: Sixty subjects were randomized to zileuton and 59 to placebo (the study was stopped short of enrollment goals because of slow recruitment). There was no difference in hospital length of stay (3.75 +/- 2.19 vs. 3.86 +/- 3.06 days for zileuton vs. placebo, p = 0.39) or treatment failure (23% vs. 27% for zileuton vs. placebo, p = 0.63) despite a decline in urinary LTE(4) levels in the zileuton-treated group as compared to placebo at 24 hours (change in natural log-transformed ng/mg creatinine -1.38 +/- 1.19 vs. 0.14 +/- 1.51, p < 0.0001) and 72 hours (-1.32 +/- 2.08 vs. 0.26 +/- 1.93, p<0.006). Adverse events were similar in both groups. PRINCIPAL CONCLUSIONS: While oral zileuton during COPD exacerbations that require hospital admission is safe and reduces urinary LTE(4) levels, we found no evidence suggesting that this intervention shortened hospital stay, with the limitation that our sample size may have been insufficient to detect a modest but potentially meaningful clinical improvement. PMID- 21299478 TI - The COPD pipeline VIII. PMID- 21299480 TI - Sperm DNA damage or progressive motility: which one is the better predictor of fertilization in vitro? AB - Sperm progressive motility has been reported to be one of the key factors influencing in vitro fertilization rates. However, recent studies have shown that sperm DNA fragmentation is a more robust predictor of assisted reproductive outcomes including reduced fertilization rates, embryo quality, and pregnancy rates. This study aimed to compare the usefulness of sperm progressive motility and DNA damage as predictive tools of in vitro fertilization rates. Here, 136 couples provided 1,767 eggs with an overall fertilization rate of 64.2%. The fertilization rate in vitro correlated with both sperm progressive motility (r2 = 0.236; P = 0.002) and DNA fragmentation (r2 = -0.318; P < 0.001). The relative risk of a poor fertilization rate was 9.5 times higher in sperm of men with high DNA fragmentation (>40%) compared with 2.6 times in sperm with poor motility (<40%). Further, sperm DNA fragmentation gave a higher specificity (93.3%) in predicting the fertilization rate than progressive motility (77.8%). Finally, the odds ratio to determine fertilization rate (>70%) was 4.81 (1.89-12.65) using progressive motility compared with 24.18 (5.21-154.51) using DNA fragmentation. This study shows that fertilization rates are directly dependent upon both sperm progressive motility and DNA fragmentation, but sperm DNA fragmentation is a much stronger test. PMID- 21299481 TI - Managing patients with advanced cancer: the benefits of early referral for palliative care. AB - Palliative care is becoming fundamental in the starting line-up of care choices. PMID- 21299482 TI - Evidence-based primary health care workforce reforms: priority areas for research. AB - To respond to changing population and workforce needs and expectations, evidence must inform policy investment, implementation and evaluation. PMID- 21299483 TI - A population-based study of thrombolysis for acute stroke in South Australia. AB - OBJECTIVE: To report the rate of thrombolysis for treating acute stroke in South Australia from October 2007 to September 2009. We hypothesised that the rate of thrombolytic therapy would be related to distance from an acute stroke unit. DESIGN, SETTING AND PATIENTS: An observational, population-based, retrospective review of case notes and imaging, using multiple case-ascertainment methods. Patients administered a thrombolytic agent by any method for suspected ischaemic stroke in urban, rural, public and private hospitals in SA (covering a population of 1.5 million people) were included. MAIN OUTCOME MEASURES: Absolute and relative contraindications for thrombolysis administration in each case, according to the 2007 National Stroke Foundation guidelines; incidence of haemorrhage; and population thrombolysis rates according to distance from an acute stroke unit. RESULTS: A total of 158 cases of thrombolytic therapy for suspected acute ischaemic stroke were identified in 157 patients. Fifteen patients (10%) had symptomatic intracranial haemorrhage, of whom eight (5%) died within 3 months. Seven patients had symptomatic extracranial haemorrhage. Five patients (3%) received thrombolysis despite absolute contraindications. Patients living closer to stroke units were more likely to receive thrombolysis. CONCLUSIONS: Rates of symptomatic haemorrhage after thrombolysis were similar to those in voluntary registries. A large proportion of South Australians are currently missing out on acute stroke therapy as a result of poor access to acute stroke units in both urban and rural settings. It is estimated that fewer than 2% of ischaemic stroke patients are administered thrombolysis in SA. PMID- 21299484 TI - Changing epidemiology of invasive pneumococcal disease in Australian children after introduction of a 7-valent pneumococcal conjugate vaccine. AB - OBJECTIVE: To evaluate trends in the incidence and serotype profile of invasive pneumococcal disease (IPD) in Australian children under 2 years of age after the introduction of the 7-valent pneumococcal conjugate vaccine (7vPCV). DESIGN AND SETTING: Analysis of incidence rates calculated using IPD surveillance data (including age, Indigenous status and serotype of the pneumococcal isolate) from 2002 to 2007 obtained from the National Notifiable Diseases Surveillance System and population estimates obtained from the Australian Bureau of Statistics. MAIN OUTCOME MEASURES: Trends in IPD incidence among Indigenous and non-Indigenous children between 2002 and 2007; change in the serotype profile of IPD in non Indigenous children after the introduction of universal 7vPCV vaccination in 2005. RESULTS: Overall incidence of IPD decreased by 74% in all children < 2 years of age between 2002 and 2007 (P < 0.001). While the incidence of IPD caused by 7vPCV serotypes decreased significantly among both Indigenous and non Indigenous children, the incidence of non-7vPCV serotype IPD increased significantly in non-Indigenous children (from 9.7 to 15.7 per 100 000, P < 0.001). Compared with a pre-vaccination period (2002-2004), the 2007 incidence of serotype 19A IPD in non-Indigenous children increased significantly (from 2.7 to 8.6 per 100 000, P < 0.001). In 2007, 19A was the predominant serotype causing IPD (37.7%) in all children aged < 2 years. CONCLUSIONS: The overall incidence of IPD decreased from 2002 to 2007, primarily driven by a reduction in IPD caused by 7vPCV serotypes. However, this was partially offset by a significant increase in the incidence of IPD caused by non-7vPCV serotypes, particularly 19A, in non Indigenous children. PMID- 21299485 TI - Conflicts of interest: a review of institutional policy in Australian medical schools. AB - OBJECTIVE: To examine the adequacy of policies at Australian medical schools for managing potential conflicts of interest with the pharmaceutical industry. DESIGN, SETTING AND PARTICIPANTS: National survey of 20 Australian medical schools to assess their policies regarding disclosure and management of conflict of interest, undertaken in October 2009, using the American Medical Student Association's PharmFree Scorecard. MAIN OUTCOME MEASURES: Policy scores and grades for Australian medical schools. RESULTS: Compared with United States medical schools, Australian medical schools performed better in only the curriculum domain and had a lower mean score overall (44% v 58%; P < 0.001). CONCLUSION: Our results indicate a need for improved self-regulation of conflicts of interest in Australian medical schools. PMID- 21299486 TI - Iodine status of Aboriginal teenagers in the Darwin region before mandatory iodine fortification of bread. AB - OBJECTIVE: To determine the iodine status of participants in the Aboriginal Birth Cohort Study who resided in the Darwin Health Region (DHR) in the "Top End" of the Northern Territory prior to the introduction of mandatory iodine fortification of bread. DESIGN, SETTING AND PARTICIPANTS: Participants in our study had been recruited at birth and were followed up at a mean age of 17.8 years. Spot urine samples were collected and assessed for iodine concentration at a reference laboratory. The median urinary iodine concentration (MUIC) of residents of the DHR was calculated and compared with international criteria for iodine status. Analyses were conducted for subgroups living in urban areas (Darwin-Palmerston) and remote communities (rural with an Aboriginal council). We collected a repeat sample in a subset of participants to explore the impact of within-person variation on the results. MAIN OUTCOME MEASURE: MUIC for residents of the DHR. RESULTS: Urine specimens were provided by 376 participants in the DHR. Overall MUIC was 58 MUg/L when weighted to the 2006 Census population. Urban boys had higher values (MUIC = 77 MUg/L) than urban and remote-dwelling non pregnant girls (MUIC = 55 MUg/L), but all these groups were classified as mildly iodine deficient. Remote-dwelling boys had the lowest MUIC (47 MUg/L, moderate deficiency). Pregnant girls and those with infants aged less than 6 months also had insufficient iodine status. Correction for within-person variation reduced the spread of the population distribution. CONCLUSIONS: Previously, iodine deficiency was thought to occur only in the south-eastern states of Australia. This is the first report of iodine deficiency occurring in residents of the NT. It is also the first study of iodine status in a defined Indigenous population. Future follow-up will reassess iodine status in this group after the introduction of iodine fortification of bread. PMID- 21299487 TI - Vitamin D insufficiency in Aboriginal Australians. AB - OBJECTIVE: To investigate the adequacy of vitamin D status in a South Australian Aboriginal population, and to examine the relationship between serum 25 hydroxyvitamin D (25-OHD) levels and biochemical variables of calcium and bone mineral homeostasis, as well as other factors which may influence vitamin D synthesis, storage and metabolism. DESIGN, SETTING AND PARTICIPANTS: A single visit, observational study of 58 adults from two Aboriginal community-controlled health services in Adelaide and Yalata, South Australia. Participants were recruited between May 2008 and December 2009. MAIN OUTCOME MEASURES: Serum levels of 25-OHD, parathyroid hormone (PTH), fasting glucose and fasting C-terminal telopeptides of type I collagen (beta-CTx). RESULTS: Serum 25-OHD levels showed clear seasonal variation, being higher in summer (P < 0.001). The overall mean level was 56.8 nmol/L (SD, 22.1), which is below the recommended target level of 60 nmol/L. Serum 25-OHD levels correlated significantly with beta-CTx (P = 0.03), but not with age, body mass index (BMI), PTH levels or levels of fasting glucose. A significant association was found between BMI and PTH levels (P = 0.001). A significant inverse association between serum 25-OHD levels and BMI, observed in other studies, was not found in our study. CONCLUSIONS: Vitamin D insufficiency is highly prevalent in this population of adult Aboriginal Australians, with low mean values found in all seasons other than summer. PMID- 21299488 TI - Clinical predictive value of the ABCD2 score for early risk of stroke in patients who have had transient ischaemic attack and who present to an Australian tertiary hospital. AB - OBJECTIVE: To determine the predictive value of the ABCD(2) score for early risk of stroke in Australian patients who have had transient ischaemic attack (TIA). DESIGN, PARTICIPANTS AND SETTING: Cohort study of 512 consecutive patients with suspected TIA referred by the emergency department to the acute stroke unit (in accordance with the TIA pathway) of an urban tertiary hospital in Melbourne, Victoria, between 1 June 2004 and 30 November 2007. MAIN OUTCOME MEASURES: Overall accuracy, estimated by the area under the curve (AUC) of receiver operating characteristic plots (of true positive rate v false positive rate), and sensitivity, specificity, predictive values and likelihood ratios at prespecified cut-off ABCD(2) scores for stroke within 2, 7 and 90 days. RESULTS: 24 patients were excluded because their symptoms lasted more than 24 hours. All included patients were reviewed by a stroke physician; TIA was confirmed in 301/488 (61.7%). Most (289/301; 96.0%) had complete follow-up. Stroke occurred in 4/292 patients (1.37%; 95% CI, 0.37%-3.47%) within 2 days and 7/289 (2.42%; 95% CI, 0.98%-4.93%) within 90 days; no patient had a stroke between 2 and 7 days. The AUCs for stroke in patients with confirmed TIA were 0.80 (95% CI, 0.68-0.91) and 0.62 (95% CI, 0.40-0.83) for stroke within 2 days and 90 days, respectively. At a cut-off of >= 5, the ABCD(2) score had modest specificity for stroke within 2 days (0.58) and 90 days (0.58), but positive predictive values (2 days, 0.03; 90 days, 0.04) and positive likelihood ratios (2 days, 2.40; 90 days, 1.71) were both poor. The score performed similarly poorly at other prespecified cut-off scores. CONCLUSIONS: Given its poor predictive value, the use of the ABCD(2) score alone may not be dependable for guiding clinical treatment decisions or service organisation in an Australian tertiary setting. Validation in other Australian settings is recommended before it can be applied with confidence. PMID- 21299489 TI - Female genital mutilation: Australian law, policy and practical challenges for doctors. AB - The issue of whether medical practitioners should perform "ritual nicks" as a method of meeting demand for female genital mutilation (FGM) has recently been debated in the United States and Australia. Due to increasing numbers of people arriving and settling in Australia from African nations in which FGM is customary, demand for FGM in Australia is present and may be increasing. Australian law clearly prohibits performance of any type of FGM. FGM is also prohibited by the most recent policy of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG). For legal, medical and social reasons, the RANZCOG policy is sound, and medical practitioners should not administer FGM in any form. Development of an evidence base regarding incidence of and attitudes towards FGM, and the need for post-FGM treatment, would help inform sound policy and practical responses. Strategies adopted in African nations to abolish FGM may assist in refining educational and supportive efforts. PMID- 21299490 TI - Migratory lung lesions in an elderly man. AB - In the absence of evidence of infection with the hepatitis C virus (HCV), detecting the immunological disorder of mixed cryoglobulinaemia is a challenge. Only after extensive investigation did we suspect that our patient's recurrent acute dyspnoea, lower limb paraesthesia and renal impairment with active urinary sediment were attributable to the rare phenomenon of non-HCV-related mixed essential cryoglobulinaemia - our suspicion was confirmed by significant serum levels of cryoglobulins. PMID- 21299491 TI - Salicylate intoxication from teething gel in infancy. PMID- 21299492 TI - Alarm about computed tomography scans is unjustified. PMID- 21299493 TI - Risk of brain damage in babies from naphthalene in mothballs: call to consider a national ban. PMID- 21299494 TI - Doctors' knowledge of patient radiation exposure from diagnostic imaging requested in the emergency department. PMID- 21299495 TI - Lowering Australia's defence against infectious diseases. PMID- 21299496 TI - Endopolyploid and proliferating trophoblast cells express different patterns of intracellular cytokeratin and glycogen localization in the rat placenta. AB - The presence of keratin intermediate filaments is a characteristic of trophoblast differentiation. Meantime, their intracellular localization in the functionally different subtypes of placental trophoblast is poorly investigated in rodent, whereas their placentae are being broadly investigated in recent years as a model of the feto-maternal interaction. The purpose was to study the intracellular distribution of cytokeratin filaments in correlation with glycogen deposits, both being important constituents of the trophoblast cells in rat placenta. Different rat trophoblast cell populations exhibited different patterns of cytokeratin immunolocalization. The most intensive immunostaining was observed in the highly endopolyploid SGTCs (secondary giant trophoblast cells) at the border with decidua basalis. The most prominent cytokeratin-positive threads were found at the periphery of cytoplasm and in the extensive system of cytoplasmic sprouts by which the SGTC connect each other. Similar cytokeratin intensity and distribution was detected in the TSC (trabecular spongiotrophoblast cells) of the junctional zone of placenta that line the lacunae with the maternal blood. Clusters of highly proliferative pre-glycogen as well as glycogen cells showed some weaker cytokeratin signals mostly in the perinuclear and peripheral zones of cytoplasm. At the 11.5th to the 13.5th day of gestation, the interstitial and endovascular invasive endopolyploid TGTCs (tertiary giant trophoblast cells) prove the intensive cytokeratin staining throughout the cytoplasm and its sprouts. Meantime, the TGTCs were glycogen negative. By contrast, glycogen was heavily accumulated in the glycogen cells that belong both to the junctional zone of placenta and the cuff of the central arterial channel underlying the monolayer of endovascularly invading TGTCs. Thus, the TGTCs that are first to penetrate into the depth of the uterine wall do not contain glycogen but are accompanied by the glycogen-rich cells. The SGTC also contained the prominent deposits of glycogen at the periphery of cytoplasm and in the cytoplasmic sprouts. At the 16th day of gestation, an extensive interstitial invasion of the cytokeratin-positive glycogen trophoblast cells from the junctional zone was observed. The patterns of cytokeratin and glycogen intracellular localization are specific for each subtype of the rat trophoblast; that is, most probably, accounted for by the functional diversity of different trophoblast populations, i.e. patterns of invasion/phagocytosis and their involvement in a barrier at the feto-maternal interface. PMID- 21299497 TI - Functional regulation of cystic fibrosis transmembrane conductance regulator containing macromolecular complexes: a small-molecule inhibitor approach. AB - CFTR (cystic fibrosis transmembrane conductance regulator) has been shown to form multiple protein macromolecular complexes with its interacting partners at discrete subcellular microdomains to modulate trafficking, transport and signalling in cells. Targeting protein-protein interactions within these macromolecular complexes would affect the expression or function of the CFTR channel. We specifically targeted the PDZ domain-based LPA2 (type 2 lysophosphatidic acid receptor)-NHERF2 (Na+/H+ exchanger regulatory factor-2) interaction within the CFTR-NHERF2-LPA2-containing macromolecular complexes in airway epithelia and tested its regulatory role on CFTR channel function. We identified a cell-permeable small-molecule compound that preferentially inhibits the LPA2-NHERF2 interaction. We show that this compound can disrupt the LPA2 NHERF2 interaction in cells and thus compromises the integrity of macromolecular complexes. Functionally, it elevates cAMP levels in proximity to CFTR and upregulates its channel activity. The results of the present study demonstrate that CFTR Cl- channel function can be finely tuned by modulating PDZ domain-based protein-protein interactions within the CFTR-containing macromolecular complexes. The present study might help to identify novel therapeutic targets to treat diseases associated with dysfunctional CFTR Cl- channels. PMID- 21299498 TI - Involvement of the recoverin C-terminal segment in recognition of the target enzyme rhodopsin kinase. AB - NCS (neuronal Ca2+ sensor) proteins belong to a family of calmodulin-related EF hand Ca2+-binding proteins which, in spite of a high degree of structural similarity, are able to selectively recognize and regulate individual effector enzymes in a Ca2+-dependent manner. NCS proteins vary at their C-termini, which could therefore serve as structural control elements providing specific functions such as target recognition or Ca2+ sensitivity. Recoverin, an NCS protein operating in vision, regulates the activity of rhodopsin kinase, GRK1, in a Ca2+ dependent manner. In the present study, we investigated a series of recoverin forms that were mutated at the C-terminus. Using pull-down assays, surface plasmon resonance spectroscopy and rhodopsin phosphorylation assays, we demonstrated that truncation of recoverin at the C-terminus significantly reduced the affinity of recoverin for rhodopsin kinase. Site-directed mutagenesis of single amino acids in combination with structural analysis and computational modelling of the recoverin-kinase complex provided insight into the protein protein interface between the kinase and the C-terminus of recoverin. Based on these results we suggest that Phe3 from the N-terminal helix of rhodopsin kinase and Lys192 from the C-terminal segment of recoverin form a cation-pi interaction pair which is essential for target recognition by recoverin. Taken together, the results of the present study reveal a novel rhodopsin-kinase-binding site within the C-terminal region of recoverin, and highlights its significance for target recognition and regulation. PMID- 21299499 TI - IQ-motif selectivity in human IQGAP2 and IQGAP3: binding of calmodulin and myosin essential light chain. AB - The IQGAP [IQ-motif-containing GAP (GTPase-activating protein)] family members are eukaryotic proteins that act at the interface between cellular signalling and the cytoskeleton. As such they collect numerous inputs from a variety of signalling pathways. A key binding partner is the calcium-sensing protein CaM (calmodulin). This protein binds mainly through a series of IQ-motifs which are located towards the middle of the primary sequence of the IQGAPs. In some IQGAPs, these motifs also provide binding sites for CaM-like proteins such as myosin essential light chain and S100B. Using synthetic peptides and native gel electrophoresis, the binding properties of the IQ-motifs from human IQGAP2 and IQGAP3 have been mapped. The second and third IQ-motifs in IQGAP2 and all four of the IQ-motifs of IQGAP3 interacted with CaM in the presence of calcium ions. However, there were differences in the type of interaction: while some IQ-motifs were able to form complexes with CaM which were stable under the conditions of the experiment, others formed more transient interactions. The first IQ-motifs from IQGAP2 and IQGAP3 formed transient interactions with CaM in the absence of calcium and the first motif from IQGAP3 formed a transient interaction with the myosin essential light chain Mlc1sa. None of these IQ-motifs interacted with S100B. Molecular modelling suggested that all of the IQ-motifs, except the first one from IQGAP2 formed alpha-helices in solution. These results extend our knowledge of the selectivity of IQ-motifs for CaM and related proteins. PMID- 21299500 TI - The continuing dilemma of stillbirth. PMID- 21299501 TI - The Auckland Stillbirth study, a case-control study exploring modifiable risk factors for third trimester stillbirth: methods and rationale. AB - BACKGROUND: In high-income countries, stillbirth rates have been static in recent decades. Unexplained stillbirths account for up to 50% of these deaths. METHODS: A case-control study was conducted in Auckland, New Zealand, from July 2006 to June 2009 to explore modifiable risk factors for late stillbirth (>=28 weeks of gestation). Eligible participants were women who had a singleton late stillbirth without a congenital abnormality. Two controls with ongoing pregnancies were randomly selected at the same gestation as each case. Data were collected through face-to-face interviews and from clinical records. RESULTS: A total of 155/215 (72%) cases and 310/429 (72%) controls consented to take part in the study. Women who had a late stillbirth were more likely to be of Pacific ethnicity and of parity >=4 (OR = 1.7, 95% CI: 1.1-2.6 and 2.7, 95% CI: 1.4-5.3, respectively). The median gestational age at diagnosis of fetal death was 261 days (IQR 239 279), and the median gestation at which the controls were interviewed was 264.5 days (IQR 240-274) P = 0.48. 'Unexplained antepartum death' (n = 61, 39.4%) and 'fetal growth restriction' (n = 29, 18.7%) accounted for almost 60% of stillbirths. The post-mortem rate for all cases was 47% (73/155) and 43% (26/61) for those classified as 'unexplained antepartum death'. CONCLUSION: This study of risk factors for stillbirth is novel in that it used gestation-matched controls with ongoing pregnancies. Its detailed investigation into maternal health and behaviour during pregnancy has the potential to lead to a better understanding of modifiable risk factors for late stillbirth. PMID- 21299503 TI - Gathering the evidence: cord gases and placental histology for births with low Apgar scores. AB - BACKGROUND: Acute intrapartum hypoxia is an uncommon cause of cerebral palsy. The exclusion of acute intrapartum hypoxia utilizes two vital pieces of information that can be obtained at the time of birth: (i) cord blood gas to exclude a severe metabolic acidosis, and (ii) placental histology to suggest an alternative aetiology other than acute intrapartum hypoxia. Although recommendations exist to encourage this practice in high-risk deliveries, their compliance in an Australian setting is not known. AIMS: To evaluate the frequency and utility of cord blood gases and placental histology following delivery with an Apgar score <=6 at five minutes. METHODS: A retrospective study of 12,887 consecutive deliveries at a tertiary obstetric centre, of which 100 live births had Apgar scores <=6 at five minutes. Cord blood gases and placental histology were examined. There were also 132 stillbirths where placental histology was sought. RESULTS: Cord gases were measured in 52 of 100 live births with a low Apgar score. Seven of these had severe metabolic acidaemia and 26 had normal cord gases. Placental histology was requested in 40 of these births and 30 showed abnormal histology, suggesting alternative aetiologies. Of the 132 stillbirths, placental histology was available in 50. Abnormal histology was present in 39 of these stillbirths. CONCLUSIONS: Cord gases and placental histology should be sought in all babies with low Apgar scores for the benefit of understanding causation, counselling of the parents, research and professional liability assessment. Heightened awareness for adverse perinatal outcomes is required by health care professionals when a neonate requires resuscitation. PMID- 21299502 TI - Socio-demographic disparities in the uptake of prenatal screening and diagnosis in Western Australia. AB - INTRODUCTION: Since the early 1980s, prenatal screening using ultrasound and biochemical markers has been used to refine the risk of Down syndrome and other fetal anomalies prior to considering fetal karyotyping. The performance of prenatal screening is subject to ongoing monitoring in Western Australia. The collection of these data can also assist in the identification of any potential inequities of access to prenatal screening within the state-wide programme. METHODS: Prenatal screening data (2005-2006) were collected from accredited ultrasound and pathology laboratories in Western Australia. Screening data were linked to diagnostic and pregnancy outcome data. Performance characteristics of screening and uptake by socio-demographic characteristics were analysed. RESULTS: Complete screening data were collected for 35,142 of the estimated 38,081 women screened during 2005 and 2006. There were 59,999 births related to this screening period. The lowest uptake of screening was among women who were Aboriginal (14.9%), living in remote areas (38.0%), under the age of 25 (40.2%), in the lowest quintile of the SEIFA index (41.6%) and with three or more children (48.4%). Logistic regression analysis showed all socio-demographic factors to be strongly associated with screening behaviour, with adjustment for ethnicity, socio-economic status, age, parity and area of residence. DISCUSSION: Our results have important implications for the delivery of prenatal screening services in Western Australia. While the screening programme meets international and national performance standards, the disparities in screening uptake suggest inequity in access to services, particularly for Aboriginal, remote and socio-economically disadvantaged women. PMID- 21299504 TI - Challenging the glucose challenge test. AB - BACKGROUND: To reduce the number of patients needing oral glucose tolerance test (OGTT), screening options have been considered, balancing patient comfort, cost and risk of missed diagnosis. Australian Diabetes in Pregnancy Society (ADIPS) recommends glucose challenge test (GCT) as screening for gestational diabetes mellitus (GDM), while others suggest fasting plasma glucose (FPG). International Association of Diabetes and Pregnancy Study Group (IADPSG) recently recommended new diagnostic criteria for GDM using one-step OGTT. AIM: (i) To determine how many GDM patients would be missed with GCT/OGTT or FPG/OGTT compared to OGTT alone. (ii) To assess GCT in screening for GDM using new IADPSG criteria. METHODS: Austin Pathology database was searched from 2005 to 2007; 8486 episodes of GCT and OGTT were found. Test characteristics were determined for: (i) Simulated GCT/OGTT, where the 60-min OGTT value was regarded as equivalent to 60 min GCT value; (ii) Simulated FPG/OGTT, investigating the utility of different FPG values to indicate need for OGTT. RESULTS: Oral glucose tolerance test (one step procedure): Of 5473 patients who had OGTT alone, 14% had GDM (ADIPS criteria). Actual GCT/OGTT: Of 2407 GCT, 17.3% were abnormal, with 75% having normal follow-up OGTT. Simulated studies: In the simulated GCT/OGTT, using ADIPS criteria, GCT had a sensitivity of 87%, specificity of 74% and would miss 13% of cases. Although simulated FG/OGTT had similar sensitivity of 82% for FPG >=4.4 mmol/L, specificity was 42%. Using IADPSG criteria, 19% were diagnosed with GDM, screening GCT had a sensitivity of 83%, specificity of 75% and would miss 17% of cases. CONCLUSION: Oral glucose tolerance test alone is the best procedure without prior preliminary testing. PMID- 21299505 TI - Risk factors for gestational diabetes mellitus: implications for the application of screening guidelines. AB - BACKGROUND: Recent evidence has shown the importance of ensuring that all pregnancies with gestational diabetes mellitus (GDM) are identified and managed appropriately. However, there remains a lack of consensus as to how to best identify these women. AIM: To review risk profiles of women with GDM and to evaluate international GDM screening recommendations. METHODS: A retrospective observational study was carried out at a tertiary referral hospital (Monash Medical Centre, Victoria). Data of singleton pregnancies in women (without pre existing diabetes mellitus) giving birth in 2007 from the Birthing Outcomes System were analysed and the performance of the British National Institute for Health and Clinical Excellence (NICE), the American Diabetes Association (ADA) and the Australasian Diabetes in Pregnancy Society (ADIPS) GDM selective screening guidelines were evaluated. Predictors of GDM were identified with logistic regression, and sensitivity and specificity of international screening guidelines were calculated. RESULTS: The strongest independent risk factors for GDM were a past history of GDM (OR = 10.7; 95% CI: 5.4-21.1), maternal age >=40 years (OR 7.0; 95% CI 2.9-17.2) and BMI >=35 kg/m(2) (OR 6.1; 95% CI 3.0-12.1). The sensitivity and specificity of the NICE, ADA and ADIPS guidelines were 92.7% and 32.4%, 100% and 3.9% and 98.6% and 13.7%, respectively. CONCLUSIONS: Increasing age and BMI and previous GDM were the most significant risk factors for GDM. Current selective screening guidelines have high sensitivity but low specificity and offer little over universal screening. PMID- 21299506 TI - Maternal smoking, weight status and dietary behaviours during pregnancy: findings from first-time mothers in south-west Sydney, Australia. AB - BACKGROUND: Few studies have been conducted examining the relationship between maternal smoking, weight status and dietary behaviours during pregnancy. AIM: The objective of the study was to examine the relationship between maternal smoking, weight status and dietary behaviours during pregnancy. METHODS: An analysis of cross-sectional baseline survey data was conducted with 406 first-time mothers participating in the Healthy Beginnings Trial (HBT) conducted in south-west Sydney, Australia. Mothers' reports of their smoking status, dietary behaviours and pre-pregnancy weight and height were collected through face-to-face interviews. The relationships were examined using log-binomial regression modelling. RESULTS: Maternal smoking status was not associated with weight status. However, smoking was positively associated with soft drink consumption and negatively associated with daily fruit intake. After adjusting for age, marital status and education level, mothers who reported consuming >1 cup of soft drink per day were more likely to smoke than those consuming less soft drink (adjusted risk ratio, ARR 1.48, 95% CI 1.02-2.22, P = 0.05). Mothers who reported having >=2 serves of fruit daily were significantly less likely to smoke than those having less fruit (ARR 0.54, 95% CI 0.29-0.95, P = 0.04). CONCLUSIONS: The study found no evidence linking maternal smoking and weight status and did not support the notion that smoking could lead to a lower weight status. However, maternal smoking was associated with fruit and soft drink consumption and needs to be considered while examining dietary behaviours and weight status. PMID- 21299507 TI - Decreased sleep efficiency, increased wake after sleep onset and increased cortical arousals in late pregnancy. AB - BACKGROUND: Anecdotal reports of sleep disturbance during pregnancy are abundant; however, objective measurement of sleep changes has so far produced conflicting results. AIMS: To objectively measure sleep architecture and investigate subjective sleep quality in the first and third trimester of pregnancy, when compared to the nonpregnant state. METHODS: Twenty-seven women in the third trimester of pregnancy, 21 women in the first trimester of pregnancy and 24 nonpregnant control women underwent overnight polysomnography and completed questionnaires regarding sleep quality and mood. RESULTS: Women in the third trimester of pregnancy had poorer sleep efficiency, more awakenings, less stage 4 sleep, more stage 1 sleep and fewer minutes in rapid eye movement sleep when compared to the control group. Cortical arousals were seen more often during pregnancy, particularly in response to respiratory events and limb movements. Sleep during the first trimester was affected to a lesser extent, with more wake time after sleep onset and less stage 4 sleep when compared to the controls. CONCLUSIONS: Sleep during pregnancy is compromised by higher amounts of wake and cortical arousals leading to sleep fragmentation, with greater amounts of light sleep and less deep sleep. Mood state did not have an effect on sleep. Given the impact of sleep on well-being, this study increases our understanding of the characteristics of sleep during pregnancy, to help recognise when severe sleep disruption may warrant referral to a specialist for appropriate diagnosis and treatment. PMID- 21299508 TI - Over expression of HSP70 and HSF1 in endothelial cells during pre-eclamptic placental stress. AB - BACKGROUND AIM: Pre-eclampsia is a hypertensive disorder characterised by endothelial dysfunction and is one of the leading cause of preterm birth. Increasing oxidative stress and antioxidant disequilibria promote apoptosis and may play a defining role in the development of pre-eclampsia. Heat shock protein 70 (HSP70) is an effective molecular chaperone, playing a role in cell protection from damage in response to stress stimuli. This study focus on the expression of HSP70 in endothelial cells during pre-eclampsia compared with normotensive pregnant women. METHOD: The conjugated diene (CD), lipid hydro peroxide (LHP), total antioxidant capacity (TAC) analysis and glutathione redox ratio (GRR) are the stress specific parameters assessed in the placental endothelial cells of normotensive and pre-eclamptic subjects to evaluate the oxidative stress status. As the synthesis of HSP70 is regulated by a transcription factor, heat shock factor 1 (HSF1), its expression was also analysed. RESULTS: There was a significant decrease in the viability (P < 0.05) of the endothelial cells isolated from pre-eclamptic subjects compared to normotensive subjects. The level of CD (P < 0.01) and LHP (P < 0.01) was increased with a simultaneous decrease in GRR (P < 0.05) and TAC (P < 0.05) levels in the endothelial cells of pre eclamptic subjects compared to normotensive subjects. The expression of HSP70 (P < 0.05) and HSF1 (P < 0.05) was increased in pre-eclamptic subjects compared to normotensive subjects. CONCLUSION: The over expression of HSP70 and HSF1 seen in the pre-eclamptic endothelial cells suggests its possible protective role as stress specific natural adaptive response against the generated stress. PMID- 21299509 TI - Men's emotional responses to their partner's pregnancy and their views on support and information received. AB - The main aim of this study was to extend previous research of men's experiences of pregnancy; 48 Australian men and their pregnant partners took part. Most men reported feeling positive about the pregnancy, emotionally well supported and well informed. Men reported receiving more valuable information from their partner than from doctors/obstetricians, family or the internet and were accurate observers of women's depression levels. PMID- 21299510 TI - Basic surgical skills training: does it work? AB - BACKGROUND AND AIM: We assessed the RANZCOG Basic Surgical Skills Workshop (BSSW) with regards to trainees' basic knowledge and skill using a laparoscopic pelvi trainer. METHODS: First-year trainees answered a multiple choice questionnaire (MCQ) and performed timed simulated laparoscopic exercises with a pelvi-trainer before completing a 2-day workshop. Assessment was repeated following the workshop, at 6 months and 5 years. RESULTS: MCQ results improved immediately after the workshop (baseline 16/34 vs post-course 23/34; P = 0.0001) declined at 6 months (post-course 24/34 vs 6 months 20/34; P = 0.009) with no change at 5 years (20/34 at 5 years). The time to complete both the simple and the complex laparoscopic exercises improved significantly following the workshop (simple: baseline 30 s, post-course 23 s; P = 0.008, complex: baseline 219 s, post-course 145 s; P = 0.0001) and was maintained at 6 months (simple: post-course 22 s, 6 months 23 s; P = 0.644, complex: post-course 124 s, 6 months 125 s; P = 0.958), but the time to complete the simple exercise was no better at 5 years and the time to complete the complex exercise was increased at 5 years (6 months 115 s, 5 years 172 s, P = 0.023). CONCLUSIONS: First-year trainees' basic knowledge of electrosurgery, hysteroscopy and laparoscopy and the time to perform skills on a laparoscopic pelvi-trainer improved after a BSSW but there was no further improvement at 5 years. PMID- 21299511 TI - Surgical outcomes following total Prolift: colpopexy versus hysteropexy. AB - BACKGROUND: Total Prolift((r)) is a pelvic floor repair system that is performed transvaginally and can be carried out with or without the uterus in situ. AIM: To compare surgical outcomes following total Prolift colpopexy (TPC) and total Prolift hysteropexy (TPH). METHODS: This was a retrospective cohort study of women that underwent TPC (n = 65) or TPH (n = 24). Outcomes were compared between groups using Student's t-test, ANCOVA and Fisher's exact tests (P <= 0.05). RESULTS: There were no significant differences between TPC and TPH for all peri operative variables. Patients were followed 6-12 months after surgery. Post operatively, TPC patients had significantly higher pelvic organ prolapse quantification (POP-Q) point C measurements (P = 0.05); however, all other POP-Q measurements were similar, including POP-Q apical stage of prolapse, with 99% in the TPC group and 92% in the TPH group at stage I or less. Post-operative mesh erosion, prolapse symptoms, surgical satisfaction, sexual activity and dyspareunia rates did not significantly differ between groups. CONCLUSIONS: This study showed that TPC and TPH have similar surgical outcomes, except for vaginal vault measurements reflected by POP-Q point C. PMID- 21299512 TI - Distribution of HPV genotypes in women with cervical cancer in Auckland, New Zealand; a review of 50 specimens between 2000-2006. AB - BACKGROUND: In New Zealand, around two hundred women are diagnosed with cervical cancer annually, with approximately seventy deaths from cervical cancer per year. AIM: Our aim was to determine the distribution of oncogenic HPV genotypes in biopsy specimens from women with diagnosed cervical cancers in the Auckland region of New Zealand between 2000-2006. MATERIALS AND METHODS: Confirmed cases of cervical carcinoma were identified from the local pathology register, and representative tissue samples were taken from these blocks. Sections were deparaffinised, and DNA was extracted according to standard protocols. Samples were subject to PCR amplification using L1 consensus primer sets MY09/11 and GP5/6. Further type-specific amplification was performed on positive samples, using an in-house primer sequence based on target sequences within the E6 gene. Remaining samples were typed by a Linear Array Assay, or by DNA sequencing. RESULTS: HPV DNA was detected in 100% of cases. In 49/50 samples, the HPV genotype was identified, with a total of 14 different HPV genotypes detectable. Together HPV-16 and 18 were found in 41/49 cases (83.6%) either singly or in combination. DISCUSSION: Our findings suggest that the distribution of HPV genotypes in New Zealand is similar to that of other geographic areas. CONCLUSION: Ongoing surveillance is warranted to ensure appropriate genotype selection for prophylactic HPV vaccinations. PMID- 21299513 TI - High prevalence of symptoms associated with ovarian cancer among Australian women. AB - BACKGROUND: Symptoms associated with ovarian cancer are often vague and non specific, such as abdominal bloating and pain. Presently, nothing is known about the prevalence of these symptoms among women in the community. AIMS: To identify the prevalence and correlates of symptoms associated with ovarian cancer in a nationally representative sample of Australian women. METHODS: Women answered questions about symptoms associated with ovarian cancer via computer-assisted telephone interviews. Binomial regression was used to assess the association between reporting symptoms, demographic characteristics and sexual problems. RESULTS: Data on 2235 women aged 18-70 who had not had an oophorectomy or hysterectomy were analysed. Prevalences of symptoms were abdominal bloating 52%, abdominal pain 37%, increased abdominal size 30%, pelvic pain 29%, feeling full quickly 18% and unable to eat normally 15%. One-third of women (32%) reported three or more symptoms, 2% reported all six and 32% of women reported none. Severe symptoms were generally reported by <10% of women reporting symptoms, and symptoms usually persisted for 5 days or less a month. Older women were less likely to report symptoms, as were women who had been pregnant. There was an association between symptoms and sexual difficulties whereby women who reported multiple ovarian cancer symptoms were more likely to report sexual problems. CONCLUSIONS: There is a high prevalence of ovarian cancer symptoms in the Australian community. Because of this, awareness campaigns will likely impact a large number of women who do not have ovarian cancer. PMID- 21299514 TI - Vasopressin versus a combination of vasopressin and tourniquets: a comparison of blood loss in patients undergoing abdominal myomectomies. AB - OBJECTIVE: To compare blood loss and need for blood transfusions in women who underwent abdominal myomectomies after receiving vasopressin or combined vasopressin and tourniquet. METHODS: A retrospective chart review was performed reviewing abdominal myomectomies that took place at our institution. Subjects were divided into three groups: no intervention, vasopressin, or combined vasopressin and tourniquet. Blood loss, need for blood transfusion, and drop in hemoglobin and hematocrit were compared across all groups. RESULTS: One-hundred and thirty-two subjects were included in the study. No statistically significant difference was found between groups in blood loss, drop in hemoglobin or hematocrit, or blood transfusions. CONCLUSION: Combined vasopressin and tourniquets was not associated with a statistically significant decrease in blood loss or need for blood transfusion. PMID- 21299515 TI - Barriers to continuing in vitro fertilisation--why do patients exit fertility treatment? AB - BACKGROUND: Many couples do not complete IVF treatment. There is little published data regarding this issue and also what changes might lead to better compliance rates. AIMS: To investigate what proportion of patients discontinue IVF prematurely, why they stop treatment, and what factors are important for them to restart. MATERIALS & METHODS: Survey of 1310 patients undergoing IVF treatment over a 3-year period at a single IVF provider. Information was collection on demographics and the outcomes of treatment. For those who discontinued treatment two further questions were completed: reasons why treatment was discontinued (primary outcome measure) and factors required to reactivate fertility treatment (secondary outcome measure). RESULTS: 40.2% response rate. 15.0% of patients discontinued IVF prematurely; 77.0% had a live birth or were currently pregnant. Those who discontinued treatment were more likely to be older and have a trade qualification. Of those who discontinued treatment; failing to become pregnant, cost, and stress were identified as factors. Less expensive treatment and a guaranteed baby were important factors for patients to restart treatment. Numerous comments were made regarding having readily available counselling services and continuity of care. DISCUSSION: Reasons for stopping treatment are multifactorial. Our data set is limited by a low response rate. Further research is needed to into this issue, including differences between private and public cessation rates are barriers to completion of treatment. CONCLUSIONS: The majority of patients having IVF achieve either a live birth or fall pregnant through IVF. Service may be improved by decreasing cost, optimising outcomes and increasing availability of counselling services. PMID- 21299516 TI - Peritoneal fibrosis leading to small bowel obstruction two years after first-line intraperitoneal chemotherapy for optimally debulked ovarian cancer. PMID- 21299517 TI - Intravenous uterine leiomyomatosis extending into the right heart. PMID- 21299518 TI - Second pregnancy outcome in a patient with Gitelman syndrome without the use of parenteral electrolyte supplementation. PMID- 21299519 TI - Response to Dennerstein letter: Bowel resection for severe endometriosis: an Australian series of 177 cases. PMID- 21299520 TI - Letter in response to Levonorgestrel-releasing intrauterine system (Mirena(r)) and Depot medroxyprogesterone acetate (Depo-Provera) as long-term maintenance therapy for patients with moderate and severe endometriosis: a randomised trial by Wong AYK, Tang LCH, Chin RKH Aust N Z J Obstet Gynaecol 2010; 50 (3): 273-279. PMID- 21299521 TI - Current approaches to the management of highly sensitized kidney transplant patients. AB - With the introduction of sensitive antibody detection techniques, effective antibody elimination devices, therapeutic agents, such as bortezomib and eculizumab, and new concepts, such as Heidelberg algorithm, kidney paired exchange, and acceptable mismatch programs, several effective options are now available for the management of highly sensitized kidney transplant patients. However, as the number of human leukocyte antigen-mismatched transplantations is increasing with each year and as long as the elimination or long-term control of donor-specific antibody-producing clones remains an unresolved issue, sensitization will continue to represent a major problem in kidney transplantation. PMID- 21299522 TI - 'Immunogenetics of Aging': report on the activities of the 15th International HLA and Immunogenetics Working Group and 15th International HLA and Immunogenetics Workshop. AB - 'Immunogenetics of Aging' is a component that was first included in the 14th International HLA and Immunogenetics Workshop (IHIWS) and developed further within the 15th Workshop. The aim of this component was to assess the impact of human leukocyte antigen (HLA) genes, cytokine genes, and some innate immunity genes such as killer-cell immunoglobulin-like receptors (KIRs) and mannose binding lectin 2 (MBL2) in successful aging and their contribution to the better understanding of immune dysfunction in old age. Within the 15th IHIWS new populations were included in the analysis. Additional cytokine gene polymorphisms were assessed and innate immunity genes were analyzed for possible relevance in longevity. The results showed that longevity might be associated with anti inflammatory cytokine gene profiles, decreased frequency of interleukin-10 (IL 10) and transforming growth factor-B1 haplotypes associated with a low level of gene expression, and increased frequency of haplotypes determining a high level of expression. Extended tumor necrosis factor-A and IL-12B genotypes were also likely relevant to longevity. Data also showed that innate immunity genes are associated with susceptibility to infections in the elderly and showed that these genes might be an important genetic marker in aging. Decreased frequencies of KIR2DS5 and A1B10 haplotypes, and an increased proportion of MBL2-deficient haplotypes were found in the group with higher cytomegalovirus-specific IgG antibody levels. Together, these studies emphasize the relevance of genes regulating immune functions in maintaining human longevity and stress the importance of further clarifying their impact on successful aging. PMID- 21299523 TI - Linkage disequilibrium between HLA-G*0104 and HLA-E*0103 alleles in Tswa Pygmies. AB - Nonclassical human leukocyte antigen (HLA)-G and -E loci are separated by approximately 660 kb on the short arm of chromosome 6. Interestingly, some functional and expression characteristics are relatively identical or associated for both molecules. For example, expression of HLA-E on the cell surface has been linked to preferential binding of nonameric leader peptides derived from the signal sequence of HLA-G. It has been suggested that these two molecules act synergistically in modulating susceptibility to infectious or chronic inflammatory diseases. A possible explanation for these observations is that HLA E and HLA-G are evolving under analogous selective pressures and have functions that place them under selective regimes differing from classical HLA genes. The purpose of this study was to investigate the consistency of this hypothesis based on the characterization of the molecular polymorphism of these two genes and their linkage disequilibrium (LD) in three populations, i.e. Southeastern French (n = 57), Teke Congolese (n = 84) and Tswa Pygmies (n = 74). Allelic frequencies observed for HLA-G and HLA-E and for 14-bp ins/del polymorphism in the three populations were similar to those observed in the literature for populations from corresponding geographic areas. Only one of the recently described HLA-G polymorphisms (HLA-G*01:07-01:16) was found, i.e. HLA-G*01:15 in one individual from Congo. We showed that two haplotypes in Tswa Pygmies, i.e. HLA-G*01:04 E*01:03:01 and G*01:04-E*01:01, exhibited highly significant positive and negative D' values respectively. Although these LD could have functional implications, it is more likely because of the genetic drift as the two other populations did not display any significant LD. PMID- 21299524 TI - Sequence-based typing of major histocompatibility complex class I chain-related gene A alleles by use of exons 2-5 information. AB - The polymorphic MICA (major histocompatibility complex class I chain-related gene A) (Gene ID: 100507436) gene products are a ligand of the activating natural killer cell receptor, NKG2D. Their clinical importance spans from solid organ transplantation to bone marrow transplantation and disease susceptibility. Typing of MICA genes by sequencing is hampered by an exon 5 short tandem repeat, the definition of which is critical for the final allelic and functional assignment. We present a novel sequencing approach, which uses group-specific (7T/8T) exon 5 polymerase chain reactions (PCRs) and facilitates hemizygous exon 5 MICA-PCR in approximately 70% of the tested individuals. With this method we typed the International Histocompatibility Workshop Group MICA reference panel (40 cell lines) as well as 110 healthy South German blood donors. All ambiguities, with the exception of MICA*008:01/008:04 (synonymous substitution in exon 1) and MICA*009:01/049 (nonsynonymous substitution in exon 6), could be resolved with our method. Analysis of Hardy-Weinberg equilibrium for our cohort showed no significant difference between expected and observed frequencies of MICA alleles (P = 0.6142). The three most frequent alleles in our blood donor cohort were MICA*008:01/008:04 (40.5%), MICA*002:01 (13.2%), and MICA*009:01/049 (8.6%). The 7T polymorphism was observed in 67.7% and the 8T polymorphism in 32.3% of our blood donor cohort. Individuals (24.5%) tested were homozygous. The approach described in this paper is suitable for accurate sequencing of large sample numbers, including direct readout of exon 5 sequences. It is compatible with laboratory automation and commercial human leukocyte antigen analysis software tools. It may therefore be applied in large clinical trials. PMID- 21299525 TI - A multi-site study using high-resolution HLA genotyping by next generation sequencing. AB - The high degree of polymorphism at human leukocyte antigen (HLA) class I and class II loci makes high-resolution HLA typing challenging. Current typing methods, including Sanger sequencing, yield ambiguous typing results because of incomplete genomic coverage and inability to set phase for HLA allele determination. The 454 Life Sciences Genome Sequencer (GS FLX) next generation sequencing system coupled with conexio atf software can provide very high resolution HLA genotyping. High-throughput genotyping can be achieved by use of primers with multiplex identifier (MID) tags to allow pooling of the amplicons generated from different individuals prior to sequencing. We have conducted a double-blind study in which eight laboratory sites performed amplicon sequencing using GS FLX standard chemistry and genotyped the same 20 samples for HLA-A, -B, C, DPB1, DQA1, DQB1, DRB1, DRB3, DRB4, and DRB5 (DRB3/4/5) in a single sequencing run. The average sequence read length was 250 base pairs and the average number of sequence reads per amplicon was 672, providing confidence in the allele assignments. Of the 1280 genotypes considered, assignment was possible in 95% of the cases. Failure to assign genotypes was the result of researcher procedural error or the presence of a novel allele rather than a failure of sequencing technology. Concordance with known genotypes, in cases where assignment was possible, ranged from 95.3% to 99.4% for the eight sites, with overall concordance of 97.2%. We conclude that clonal pyrosequencing using the GS FLX platform and CONEXIO ATF software allows reliable identification of HLA genotypes at high resolution. PMID- 21299526 TI - Up-regulation of HLA-G expression in cervical premalignant and malignant lesions. AB - The human leukocyte antigen G (HLA-G) molecule, a non-classical major histocompatibility complex class I antigen, exhibits highly limited tissue distribution and gene variation. Recent studies indicate strong immunoinhibitory properties in tumor cells that may favor their escape from anti-tumor immune responses. However, the role of HLA-G in cervical premalignant and malignant lesions has not been defined clearly. In our study, HLA-G expression was studied in cervical tissue from 119 patients with lesions and 22 normal cervical tissue specimens by immunohistochemistry. HLA-G was expressed in 45% (54/119) of cervical lesion-containing tissues while it was rarely detectable (0/22) in the control specimens (P = 0.000). ROC curve analysis showed that HLA-G has an area under the curve (AUC) of 0.694. Furthermore, we investigated soluble HLA-G expression in the plasma of 172 patients with cervical lesions and 20 healthy controls. Significant increases were also observed in soluble HLA-G levels (median, 191.4 vs 45.18 U/ml, P < 0.001). The relative operating characteristic (ROC) curves for soluble HLA-G (sHLA-G), squamous cell carcinoma (SCC), and carbohydrate antigen 125 (CA125) show an AUC of 0.710, 0.634, and 0.588, respectively. At the cut-off values of 108.20 U/ml for sHLA-G, 1.5 ng/ml for SCC, and 35 U/ml for CA125, the sensitivity was 73.30%, 47.83%, and 44.83%, respectively. The detection of soluble HLA-G in plasma may have significance in the early detection of cervical malignant lesions. PMID- 21299527 TI - Challenging the golden standard in defining donor-specific antibodies: does the solid phase assay meet the expectations? AB - The purpose of the study was to compare three different methods defining donor specific antibodies (DSA): complement-dependent cytotoxicity (CDC), the flow cytometry method (FCM), and a special for that purpose commercially available Luminex-based solid phase assay (SPA). A panel of human monoclonal antibodies (HuMabs) with well-defined human leukocyte antigen (HLA) specificities was used as antibody source and single HLA antigen expressing cell lines (SAL) were used as targets. Two methods yielded identical results (CDC and FCM). However, the SPA, the method by which solubilized HLA molecules from the SAL are captured by microspheres, showed two additional reactions which could not be explained, neither by the epitope recognized by the HuMab nor by the widely accepted sensitivity of the SPA methodology. These unexplained results suggest that by capturing solubilized HLA molecules on microspheres, conformational changes might occur. Positive results obtained by similar Luminex-based microsphere methods should be therefore taken with caution and the 'recognized' HLA antigens should not automatically be considered as unacceptable for transplantation. PMID- 21299528 TI - The HLA-DP2 protein binds the immunodominant epitope from myelin basic protein, MBP85-99, with high affinity. AB - Myelin basic protein (MBP) is a candidate autoantigen in multiple sclerosis (MS). The immunodominant epitope for T-cell responses is assigned to the amino acid sequence MBP84-102, which binds to human leukocyte antigen (HLA)-DR2a (DRB5*0101) and HLA-DR2b (DRB1*1501) of the HLA-DR2 haplotype carrying the strongest genetic association with MS. In contrast with HLA-DR and -DQ molecules, HLA-DP molecules are poorly characterized with respect to the binding of self-peptides. We show here that HLA-DP2 binds MBP85-99 with high affinity, and that the amino acid residues in position MBP91, MBP92 and MBP93 are influencing the binding, as shown by alanine scans. We further used a series of truncated peptides to identify the core of the binding. Moving the frame along the peptide from residues 87-97 to 89 99 progressively decreased the binding affinity for HLA-DP2, while moving further towards the C-terminal completely abrogated the binding of peptides to HLA-DP2. The data suggest that the docking of the MBP85-99 peptide into the HLA-DP2 groove is dependent on MBP88V and MBP89V and may use either of them as primary anchor for the p1 position. HLA-DP2 might thus present the MBP85-99 peptide in the same register as the HLA-DRB1*1501, where the MBP89V is preferred as the p1 anchor. Notably, full-length MBP was able to compete for peptide binding with an affinity similar to that seen for the high-affinity binding peptides, DRalpha170-83 and IIP53-65. In summary, the HLA-DP2 molecule binds the immunodominant epitope in MS, MBP85-99, possibly in more than one register. PMID- 21299529 TI - Distribution of HLA alleles and haplotypes in the Maldivian population. AB - The study of human leukocyte antigen (HLA), allele and haplotype frequencies within populations provides an important source of information for anthropological investigation, organ and hematopoietic stem-cell transplantation purposes as well as disease association studies. As of today, there are no data available in the literature on the HLA structure of the Maldivian population. Altogether 106 families were studied. We used the parents of each family (212 unrelated individuals) to analyze the frequencies of HLA class I and class II allele groups and haplotypes. PMID- 21299530 TI - Genetic association of Fc receptor-like 3 polymorphisms with susceptibility to primary biliary cirrhosis: ethnic comparative study in Japanese and Italian patients. AB - A functional variant in the Fc receptor-like 3 (FCRL3) gene is associated with the susceptibility to several autoimmune diseases. In this study, we examined whether the FCRL3 is associated with susceptibility to primary biliary cirrhosis (PBC) by comparing the two different ethnic groups, Japanese and Italians. We enrolled 232 patients with PBC and 230 controls in Japanese, and 216 PBC and 180 controls in Italians. Minor allele frequency of fcrl3_3 (-169 T>C) in the patients with PBC and controls was 0.20 and 0.09 in Japanese and 0.24 and 0.21 in Italians, respectively. We found a significant association of fcrl3_3 with PBC only in Japanese (P = 9.64 * 10(-7) ). These findings support the presence of common FCRL3-related pathological pathways in several autoimmune diseases, especially in Asians. PMID- 21299531 TI - A processed HLA-A*24:02 pseudogene found in the peripheral blood of a father and his son. AB - We encountered a case that exhibited a discrepancy in human leukocyte antigen-A (HLA-A) type determined by sequence-based typing (SBT) and sequence-specific primer (SSP) molecular typing. The child of this case was identified as A* 02:01 homozygote and A* 02, A* 24, respectively. The HLA-A type of his father was A* 02:01, 26:01, but low-resolution SSP also showed unexpected amplification with A* 24 primers as with the child. Serologic typing of the child and the father was A2/blank and A2/A26, respectively. Sequencing analysis of the A* 24 variant in the child and the father showed a complete deletion of all introns of the A* 24:02 allele. Though rare, this type of processed pseudogene variant can be one of the causes of discrepancies between high- and low-resolution HLA typing. PMID- 21299532 TI - Resolution of HLA class I sequence-based typing ambiguities by group-specific sequencing primers. AB - The increasing demand for allele-level human leukocyte antigen (HLA) typing has led the sequence-based typing (SBT) to become the preferred method. In turn, the steady increase in the number of HLA alleles driven by the adoption of SBT as the ultimate typing method leads to the ever increasing number of cis/trans ambiguities. Over the last few years, additional sequencing with the commercially available group-specific sequencing primers (GSSPs) has replaced sequence specific primer-polymerase chain reaction and group-specific amplification as the means of resolving cis/trans ambiguities in many laboratories. Here we summarize our 3-year experience in designing and utilizing GSSPs for resolution of HLA class I ambiguities. The panel of GSSPs used in our laboratory includes 14 primers for HLA-A, 18 for HLA-B, and 13 primers for HLA-C. The panel resolves 99.9% of all ambiguities. PMID- 21299533 TI - A gene-specific primer extension and liquid bead array system for killer-cell immunoglobulin-like receptor genotyping. AB - A simple and accurate method for killer-cell immunoglobulin-like receptor (KIR) genotyping is developed using KIR gene-specific primer extension (GSPE) followed by bead array hybridization (GSPE method). After amplification of exons 4, 5, and 9, KIR GSPE and bead array hybridization were performed to verify the presence or absence of 16 KIR subfamilies. GSPE method was validated with natural killer/KIR reference panel I consisting of 48 cell types provided by 13th International Histocompatibility Working Group (IHWG) and genomic DNA from 17 peripheral blood cells, 8 cell lines, and 8 buccal cells. The results of reference panel from GSPE method were 100% concordant with the IHWG reference typing information. All genomic DNAs except reference panel were typed for KIR genes with sequence specific primer methods and showed 100% identical typing results using this novel system. In addition, GSPE method can obtain results in 8 h from DNA with 10 ng genomic DNA in a 96-well-based assay format. PMID- 21299534 TI - Identification of a new HLA-A*11:78N allele by polymerase chain reaction sequence based typing. AB - Nucleotide sequence of HLA-A*11:78N allele was different from that of HLA A*11:01:01 by two nucleotides deletion at positions 286 and 287, resulting in reading frameshift and has premature stop codon at position 73 in exon 2. PMID- 21299535 TI - Identification of a novel HLA-B*35 variant allele, B*35:151. AB - HLA-B*35:151 differs from HLA-B*35:68:02 by one nucleotide at codon 116 (TCC>TTC) resulting in an amino acid substitution, serine to phenylalanine. PMID- 21299536 TI - Characterization of a novel HLA allele, HLA-B*40:128, in a Chinese individual. AB - Nucleotide sequence of HLA-B*40:128 has a single nucleotide difference at position 539 T>G compared with that of HLA-B*40:01:01, with an amino acid change from Leu to Arg at codon 156. PMID- 21299537 TI - A new human leukocyte antigen-B allele, HLA-B*52:11. AB - A new HLA-B*52 allele differs from B*52:01:01 by a single nucleotide exchange at position 583 where a 'C' to 'T'. PMID- 21299538 TI - Identification of a novel HLA-B allele, B*56:31, by sequence-based typing in a Lithuanian individual. AB - A novel allele HLA-B*56:31 differs from HLA-B*56:18 by three nucleotide substitutions resulting in a missense mutation Tyr171His (TAC to CAC) encoded in exon 3 and two silent substitutions at codon 188His (CAC to CAT) and codon 228Thr (ACT to ACC) encoded in exon 4. PMID- 21299539 TI - Identification of new HLA-DRB1 alleles in Kazakh individuals. AB - Seven novel human leukocyte antigen (HLA)-DRB1 alleles were identified during routine sequence-based typing (SBT) of healthy Kazakh individuals. PMID- 21299540 TI - Identification of nine novel HLA-DRB1 alleles, HLA-DRB1*04:91, DRB1*07:18, DRB1*11:01:12, DRB1*12:02:05, DRB1*12:22, DRB1*12:23, DRB1*13:100, DRB1*15:45, and DRB1*15:46 by polymerase chain reaction--sequence-based typing. AB - Nine novel human leukocyte antigen-DRB1 (HLA-DRB1) alleles were identified in Chinese individuals. PMID- 21299541 TI - HLA-C*03:93, a novel HLA-C*03 allele identified by sequence-based typing. AB - The new allele C*03:93 showed one nucleotide difference with C*03:04:01 at codon 140 (GCT/ACT). PMID- 21299542 TI - Nomenclature for factors of the HLA system, update September 2010. PMID- 21299543 TI - Influence of the Notch system in the therapeutic response of American tegumentary leishmaniasis. AB - BACKGROUND: The evolution and therapeutic outcome of American tegumentary leishmaniasis (ATL) depend upon many factors, including the balance between Th1 and Th2 cytokines to control parasite multiplication and lesion extension. Other cytokines known for their role in inflammatory processes such as interleukin IL 17 or IL-18 as well as factors controlling keratinocyte differentiation and the inflammatory process in the skin, like the Notch system, could also be involved in the disease outcome. Notch receptors are a group of transmembrane proteins that regulate cell fate decisions during development and adulthood in many tissues, including keratinocyte differentiation and T-cell lineage commitment, depending on their activation by specific groups of ligands (Delta-like or Jagged). OBJECTIVES: To compare the in situ expression of Notch system proteins (receptors, ligands and transcriptional factors) and cytokines possibly involved in the disease outcome (IL-17, IL-18, IL-23 and transforming growth factor-beta) in ATL cutaneous and mucosal lesions, according to the response to therapy with N methyl glucamine. METHODS: Cutaneous and mucosal biopsies obtained from patients prior to therapy with N-methyl glucamine were analysed by immunohistochemistry and real-time polymerase chain reaction. RESULTS: Notch receptors and Delta-like ligands were found increased in patients with ATL, particularly those with poor response to therapy or with mucosal lesions. CONCLUSIONS: The increase of Notch receptors and Delta-like ligands in patients with a poor response to treatment suggests that these patients would require a more aggressive therapeutic approach or at least a more thorough and rigorous follow-up. PMID- 21299544 TI - Expression of tachykinins and their receptors in plaque psoriasis with pruritus. AB - BACKGROUND Various mediators of pruritus have been suggested that might be responsible for the mechanism of pruritus in psoriasis. OBJECTIVES: To study the expression levels of members of the tachykinin family, substance P and neurokinin (NK) A and their receptors, NK-1 and NK-2, in psoriasis and to correlate their expression with the intensity of pruritus. A possible correlation with chronic stress and depression was also evaluated. METHODS: Biopsies were obtained from 28 patients with chronic plaque psoriasis; the majority had pruritus. The samples were taken from lesional and nonlesional areas on the back and also from 10 healthy controls, for immunohistochemistry staining, and from lesional skin for radioimmunoassay. Prior to biopsy, the clinical severity of the psoriasis of each patient was assessed by the Psoriasis Area and Severity Index (PASI) and the intensity of pruritus was measured by using a visual analogue scale (VAS). Levels of depression and stress were measured using Beck's Depression Inventory (BDI) and the salivary cortisol test, respectively. RESULTS: Substance P-, NKA- and NK 2 receptor-immunoreactive nerves, and non-neuronal inflammatory cells positive for substance P and NKA and their respective receptors, NK-1 and NK-2, were numerous in psoriasis compared with healthy controls. The numbers of substance P positive nerves and NK-2 receptor-positive cells in lesional skin were significantly correlated to pruritus intensity. The cortisol ratio was inversely correlated with the number of NK-1 receptor-immunoreactive inflammatory cells in lesional and nonlesional psoriasis skin. There was also a positive correlation between the BDI score and the number of substance P-positive cells in nonlesional skin and with NK-1 receptor-positive cells in lesional and nonlesional skin. CONCLUSIONS: Tachykinins may play a role in psoriasis per se, in addition to pruritus in this disease. Targeting the combined NK-1 and NK-2 receptors might be a possible treatment. PMID- 21299545 TI - Reflectance confocal microscopy can differentiate dermoscopic white dots of the scalp between sweat gland ducts or follicular infundibulum. PMID- 21299546 TI - A case of taxane-induced scleroderma: a different expression profile of Fli1 proteins in dermal fibroblasts and microvascular endothelial cells compared with systemic sclerosis. PMID- 21299547 TI - Impact of family functioning on quality of life in patients with psychogenic nonepileptic seizures versus epilepsy. AB - PURPOSE: To evaluate different contributions of aspects of family functioning (FF) on health-related quality of life (HRQOL) in patients with psychogenic nonepileptic seizures (PNES) versus epileptic seizures (ES). METHODS: Forty-five participants with PNES and 32 with ES completed self-report measures of FF (Family Assessment Device; FAD), HRQOL (Quality of Life in Epilepsy-31), and depression (Beck Depression Inventory-II; BDI-II). The FAD is a self-report questionnaire that assesses FF along six dimensions and general functioning. Regression analyses were used to evaluate the contribution of FF to HRQOL above and beyond the effects of disease severity and depression. KEY FINDINGS: Mean Family General Functioning fell in the unhealthy range in participants with ES or PNES. On further analysis, male participants in each group endorsed unhealthy levels of FF compared to female participants. Patients with PNES reported poorer HRQOL and greater depressive symptoms compared to ES participants; there were no gender differences in HRQOL. Regression analyses indicated that the FAD Roles subscale predicted reduced HRQOL in patients with PNES after controlling for illness duration, seizure frequency, and depression. After controlling for the same factors, Communication and Affective Involvement subscales scores predicted HRQOL in ES participants. SIGNIFICANCE: Family dysfunction was reported in both ES and PNES participants, but greater family dysfunction was experienced by male participants in both groups. Aspects of FF predicted HRQOL in patients with PNES and ES differentially. FF may be an important treatment target to enhance coping in these groups, although the treatments may need to target different aspects of FF in PNES versus ES. PMID- 21299548 TI - Pneumocystis jirovecii colonization in patients treated with infliximab. AB - BACKGROUND: Infliximab, a chimeric antitumour necrosis factor (TNF) monoclonal antibody, has become an established effective therapy for inflammatory rheumatic disease. However, TNF is a critical factor in host defence, and the suppression of its biological activity may be associated with the increased risk of opportunistic infections. The frequent use of infliximab in clinical practice has identified Pneumocystis jirovecii pneumonia (PcP) as a serious complication. Individuals colonized with Pneumocystis may be at high risk of development of PcP when they have undergone immunosuppression. Hence, we addressed the question of the frequency of Pneumocystis colonization among patients treated with infliximab. DESIGN: We examined 125 oropharyngeal washes collected from 78 individuals with rheumatoid arthritis, 30 with ankylosing spondylitis and 17 with psoriatic arthritis, half of them underwent infliximab therapy, using a real-time polymerase chain reaction assay that employs specific primers from a portion of the mitochondrial large-subunit rRNA gene of P. jirovecii. RESULTS: Pneumocystis jirovecii colonization was detected in 32 (25.6%) patients. In a multivariate regression model, only duration of infliximab treatment for more than 3 years and use of corticosteroid were significantly and independently associated with risk of Pneumocystis colonization. However, the effect of corticosteroid on P. jirovecii colonization rate was not linearly dose dependent as showed other logistic regression analysis. CONCLUSIONS: There is a high rate of P. jirovecii colonization among patients with rheumatologic diseases treated with infliximab. The identification of patients colonized by P. jirovecii before starting the treatment with infliximab could be a strategy for PcP prevention. PMID- 21299549 TI - Serum MMP 2 and TIMP 2 in patients with inguinal hernias. AB - BACKGROUND: More than sixty thousand inguinal hernia operations are performed every year in Poland. Despite many years of related research, the exact pathologic mechanism of this condition is still not fully understood. Recent studies suggested a pronounced relationship between the molecular structure of collagen fibers and the activity of metalloproteinases, the enzymes taking part in the degradation of collagen, as well as their tissue inhibitors. MATERIALS AND METHODS: A prospective study has been established to measure serum levels of the matrix metalloproteinase 2 (MMP-2) and Matrix metalloproteinase tissue inhibitor 2 (TIMP-2) in 150 males between the ages of 26 and 70. The control group (CG) consisted of thirty healthy male volunteers of a similar age distribution. RESULTS: Our results indicate that MMP-2 was highest in the direct hernia group, a statistically very significant elevation (P<0(.) 05) of 1562ng mL(-1) against the CG 684ng mL(-1) . The highest level of TIMP, 78ng mL(-1) , was found in the group with recurrent hernia, against 49(.) 5ng mL(-1) of the CG (statistical significance of P<0(.) 05). DISCUSSION: The MMP-2 and TIMP-2 levels were concurrently elevated only in the recurrent hernia group. CONCLUSIONS: The patients with inguinal hernia have a statistically significant increase in serum levels of MMP-2. Our finding of the MMP-2 and TIMP-2 distinctly higher in the patients suffering from recurrence of direct inguinal hernia (reflecting a previous surgical failure) may suggest the theory that the extracellular matrix defect lies at the basis of this disorder. PMID- 21299550 TI - Modelling the resource implications of managing adults with Fabry disease in Italy. AB - AIMS: This study estimated the resource implications and budget impact of managing adults with Fabry disease in Italy, from the perspective of the Servizio Sanitario Nazionale (SSN). METHODS: A decision model was constructed using published clinical outcomes and clinician-derived resource utilisation estimates depicting the management of adults with Fabry disease in Italy. RESULTS: The expected annual cost of managing 220 existing and 20 new Fabry patients in Italy was estimated to be ?28.3 million. In an average year, patients receiving enzyme replacement therapy (ERT) with 0.2 mg kg(-1) agalsidase alfa (Replagal; Shire Human Genetic Therapies, Basingstoke, Hampshire, UK) or 1.0 mg kg(-1) agalsidase beta (Fabrazyme; Genzyme Europe BV, Naarden, The Netherlands) are collectively expected to make 4500 hospital attendances to a day ward for infusions, which equates to 2000 eight-h days on the day ward associated with ERT. If all ERT treated patients received their infusions at home, there would be a marginal reduction in the annual health care cost to manage these patients, and the total annual number of days on the day ward associated with ERT in the second year could potentially be reduced from a mean 2000 to zero, thereby releasing substantial hospital resources for use by non-Fabry patients. Currently, only agalsidase alfa is licensed for home treatment in Italy; hence, only patients receiving this enzyme could be offered home treatment. CONCLUSION: Use of agalsidase alfa (0.2 mg kg(-1) ) instead of agalsidase beta (1.0 mg kg(-1)) has the potential to reduce health care costs and release hospital resources in different specialities for alternative use by non-Fabry patients, thereby improving the efficiency of the public health care system in Italy. PMID- 21299551 TI - Serum markers for prediction of spontaneous preterm delivery in preterm labour. AB - BACKGROUND: Simple, more sensitive markers to predict spontaneous preterm delivery in preterm labour are needed. The aim of this study is to compare the clinical effectiveness of various serum inflammatory markers and cervix length for prediction of spontaneous preterm delivery. MATERIALS AND METHODS: We retrospectively reviewed medical records of 175 patients hospitalized for preterm labour (102 with preterm delivery and 73 with term delivery). For all study subjects, haematological markers and cervix length were recorded on admission. Because neutrophil to lymphocyte ratio (NLR) showed the potential as a diagnostic marker, we designed a combined marker by dividing cervix length by NLR. The diagnostic and prognostic accuracy of the combined marker was analysed using multivariate analyses. RESULTS: The levels of combined marker (P < 0.001), neutrophil (P < 0.001), lymphocyte (P = 0.02), NLR (P < 0.001), C-reactive protein (P = 0.016) and the cervix length (P < 0.001) in preterm delivery group were significantly different from those of term delivery group. Compared to cervix length or systemic inflammatory markers alone, combined marker showed higher sensitivity (64.2%) and specificity (88.3%) for prediction of preterm delivery. On Cox multivariate analysis, combined marker positive (< 0.29) and short cervix length (< 1.7 cm) were independent poor prognostic factors and combined marker positive was the most powerful prognostic marker for spontaneous preterm delivery (hazard ratio = 5.60, P < 0.001). CONCLUSIONS: Combined marker could be used as a simple and sensitive parameter for identifying women at risk of spontaneous preterm delivery. PMID- 21299552 TI - Increased plasma CXCL16 levels in patients with chronic kidney diseases. AB - BACKGROUND: C-X-C chemokine ligand 16 (CXCL16) is a scavenger receptor for oxidized low-density lipoprotein that has been shown to promote atherogenic effects in vivo and to predict the long-term mortality in acute coronary syndrome. We conducted a cross-sectional study to test the hypothesis that elevated CXCL16 concentrations are associated with the change in renal function in patients with chronic kidney disease (CKD) at different stages of disease. MATERIALS AND METHODS: Two hundred and forty subjects including 200 patients with CKD (146 CKD from outpatients and 54 CKD with long-term haemodialysis) and 40 normal control subjects were recruited into this study. All CKD subjects underwent echocardiograms to assess left ventricular mass index. Plasma levels of CXCL16 and other relevant clinical and biochemical parameters in all subjects were obtained upon standard clinical examinations. RESULTS: Plasma CXCL16 levels were significantly increased with the development of CKD from early- and end stage (P < 0.001 for trend) and significantly higher in CKD subjects than those of normal subjects (P<0.001). Furthermore, plasma CXCL16 levels in CKD patients with type 2 diabetes mellitus (DM) were higher than those of CKD patients without DM. Multiple stepwise regression analyses indicated that plasma CXCL16 levels were independently associated with estimated glomerular filtration rate, C reactive protein and adiponectin (all P<0.05). CONCLUSIONS: Plasma CXCL16 levels are significantly increased with the development of early- to end-stage CKD and are independently associated with the change in renal function. Elucidating the role of CXCL16 as a biomarker or disease modifier in CKD progression requires further study. PMID- 21299553 TI - Diet-induced dyslipidemia impairs reverse cholesterol transport in hamsters. AB - BACKGROUND: Reverse cholesterol transport (RCT) is an anti-atherogenic process by which cholesterol is effluxed from peripheral tissues by high-density lipoprotein (HDL) and returned to the liver for excretion into the bile and faeces. Dyslipidemia is thought to impair RCT through higher triglyceride-rich lipoprotein (TRL), low HDL-cholesterol and higher activity of cholesteryl ester transfer protein (CETP), which transfers cholesteryl esters from HDL to TRL for further hepatic uptake. As CETP pathway would represent a major route in human RCT, we therefore investigated whether diet-induced dyslipidemia impairs RCT in hamster, a CETP-expressing species. MATERIALS AND METHODS: Golden Syrian hamsters were fed a chow or chow+0.3% cholesterol diet over 4 weeks. Biochemical parameters and in vivo VLDL-triglycerides secretion (Triton WR-1339 injection) were then measured. In vitro macrophage cholesterol efflux was measured, and in vivo macrophage-to-faeces RCT was also assessed after an intraperitoneal injection of (3) H-cholesterol-labelled hamster primary macrophages. RESULTS: Cholesterol-enriched diet increased plasma total cholesterol (144%), triglycerides (101%), VLDL-triglycerides secretion (175%), CETP activity (44%) and reduced HDL-cholesterol/total cholesterol ratio by 20% (P < 0.01 vs. chow). Cholesterol-enriched diet significantly increased hepatic total cholesterol and triglycerides by 459 and 118% and increased aortic total cholesterol content by 304%. In vitro cholesterol efflux from macrophages to plasma was significantly reduced by 25% with plasma from cholesterol-fed hamsters. In vivo RCT experiments showed a significant 75% reduction of macrophage-derived cholesterol faecal excretion in cholesterol-fed hamsters. CONCLUSIONS: Overall, these data demonstrate that diet-induced dyslipidemia severely impairs in vivo RCT in hamsters. PMID- 21299554 TI - Remission of diabetic nephropathy in type 2 diabetic Asian population: role of tight glucose and blood pressure control. AB - BACKGROUND: Asian has higher prevalence of diabetic nephropathy (DN) and end stage renal disease when compared to Caucasian. No study to date has evaluated whether multifactorial intervention was associated with remission of microalbuminuria in type 2 diabetic Asian population. We evaluated the effect of tightly controlling multiple factors on the remission of DN in type 2 diabetic Chinese with microalbuminuria. MATERIALS AND METHODS: A longitudinal cohort study was collected 587 type 2 diabetic patients with microalbuminuria. Cohort members received intensified treatment to meet the following ADA recommended goals: HbA1c <7%, systolic blood pressure (SBP) <130mmHg, diastolic blood pressure <80 mmHg, low-density lipoprotein cholesterol <100mgdL(-1) , triglyceride < 150mgdL(-1) , high-density lipoprotein cholesterol >40mgdL(-1) for men and >50mgdL(-1) for women. Remission of microalbuminuria was defined as shift of albumin-creatinine ratio from mircoalbuminuria to normoalbuminuria. RESULTS: During the 4.5-year period, 210 (35.8%) patients achieved remission to normoalbuminuria. A significant association was found between the achievement of ADA goals, including HbA1c < 7% [hazard ratio (HR)=1.345; 95% confidence interval (CI), 1.010-1.792; P=0.04] and SBP <130mmHg (HR, 1.516; 95% CI, 1.100-2.089; P=0.01) and remission of microalbuminuria. The intensive SBP control (<120mmHg) was significantly associated with remission of microalbuminuria (HR, 2.076; 95% CI, 1.347-3.198; P<0.001). CONCLUSIONS: The remission of DN could be achieved under multifactorial intervention. Therapeutic focus on remission by tight glycemic and blood pressure control should be considered in Asian population with diabetes and microalbuminuria. PMID- 21299555 TI - Remediation of NAPL source zones: lessons learned from field studies at Hill and Dover AFB. AB - Innovative remediation studies were conducted between 1994 and 2004 at sites contaminated by nonaqueous phase liquids (NAPLs) at Hill and Dover AFB, and included technologies that mobilize, solubilize, and volatilize NAPL: air sparging (AS), surfactant flushing, cosolvent flooding, and flushing with a complexing-sugar solution. The experiments proved that aggressive remedial efforts tailored to the contaminant can remove more than 90% of the NAPL-phase contaminant mass. Site-characterization methods were tested as part of these field efforts, including partitioning tracer tests, biotracer tests, and mass flux measurements. A significant reduction in the groundwater contaminant mass flux was achieved despite incomplete removal of the source. The effectiveness of soil, groundwater, and tracer based characterization methods may be site and technology specific. Employing multiple methods can improve characterization. The studies elucidated the importance of small-scale heterogeneities on remediation effectiveness, and fomented research on enhanced-delivery methods. Most contaminant removal occurs in hydraulically accessible zones, and complete removal is limited by contaminant mass stored in inaccessible zones. These studies illustrated the importance of understanding the fluid dynamics and interfacial behavior of injected fluids on remediation design and implementation. The importance of understanding the dynamics of NAPL-mixture dissolution and removal was highlighted. The results from these studies helped researchers better understand what processes and scales are most important to include in mathematical models used for design and data analysis. Finally, the work at these sites emphasized the importance and feasibility of recycling and reusing chemical agents, and enabled the implementation and success of follow-on full-scale efforts. PMID- 21299556 TI - Toward a cognitive view of trait mindfulness: distinct cognitive skills predict its observing and nonreactivity facets. AB - Dispositional variations in mindfulness and its facets have garnered considerable recent interest in the clinical and personality literatures. Theoretically, high mindful individuals have been characterized as more attuned to momentary sensations and perceptions and/or better able to execute behavior in a controlled manner, yet data of this relatively cognitive type have not been reported. In addition, perceptual attunement and executive control are distinct skills that may underlie, or at least correlate with, distinct facets of mindfulness. In 3 studies involving college students (N = 297), support for the latter idea was found. Individuals high in the observing (but not nonreactivity) facet of mindfulness demonstrated superior perceptual abilities in visual working memory (Study 1) and temporal order (Study 2) tasks. On the other hand, individuals high in the nonreactivity (but not observing) facet of mindfulness exhibited greater cognitive control flexibility (Study 3). Implications for understanding the cognitive basis of mindfulness facets are discussed. PMID- 21299557 TI - Anxious attachment and relationship processes: an interactionist perspective. AB - Relationship processes in adult romantic relationships have been vastly studied under the aegis of attachment theory. Attachment theory is interactionist in nature, proposing that individual differences in levels of both attachment avoidance and anxiety predict an individual's thoughts, feelings, and behaviors in contexts that activate attachment concerns. A growing body of research is beginning to systematically test the conditions in which individual differences in attachment orientations both predict and fail to predict relationship processes. In this article, we focus on anxious attachment and review a program of research showing that the potentially destructive relationship processes typically observed in highly anxious individuals do not always appear in neutral or benign contexts, or when security needs are met. We argue that research needs to more thoroughly investigate the conditions that should, or should not, activate attachment concerns and thus result in links between individual differences in attachment orientations and relationship processes. PMID- 21299559 TI - Integrating the dynamics of personality and close relationship processes: methodological and data analytic implications. AB - A common theme that has emerged from classic and contemporary theoretical work in both the fields of personality and relationship science is a focus on process. Current process-focused theories bearing on personality invoke a view of the individual in ongoing action and interaction with the environment, reflecting a flow of experience rather than a static depiction. To understand the processes by which personality interacts with the social environment (particularly dyads), investigations must capture individuals interacting in multiple interpersonal situations, which likely necessitates complex study designs and corresponding data analytic strategies. Using an illustrative simulated data set, we focus on diary methods and corresponding individual and dyadic multilevel models to capture person-situation interaction within the context of processes in daily close relationship life. Finally, we consider future directions that conceptualize personality and close relationship processes from a dynamical systems theoretical and methodological perspective. PMID- 21299558 TI - Five-factor personality traits and age trajectories of self-rated health: the role of question framing. AB - We examined the influence of personality traits on mean levels and age trends in 4 single-item measures of self-rated health: general rating, comparison to age peers, comparison to past health, and expectations for future health. Community dwelling participants (N = 1,683) completed 7,474 self-rated health assessments over a period of up to 19 years. In hierarchical linear modeling analyses, age associated declines differed across the 4 health items. Across age groups, high Neuroticism and low Conscientiousness, low Extraversion, and low Openness were associated with worse health ratings, with notable differences across the 4 health items. Furthermore, high Neuroticism predicted steeper declines in health ratings involving temporal comparisons. We consider theoretical implications regarding the mechanisms behind associations among personality traits and self rated health. PMID- 21299560 TI - The disguise of sobriety: unveiled by alcohol in persons with an aggressive personality. AB - This investigation examined the factor structure of 8 well-validated self-report measures that assess traits that fall under the rubric of an "aggressive personality" and then determined how those factor(s) moderated the association between alcohol intoxication and aggression. Participants were 518 (252 men and 266 women) healthy social drinkers between 21 and 35 years of age. Following the consumption of an alcoholic or a placebo beverage, participants were tested on a laboratory aggression paradigm in which electric shocks were received from, and administered to, a fictitious opponent. Aggression was operationalized as the shock intensities and durations administered to the opponent. Results demonstrated a unidimensional factor structure for the aggressive personality traits, which were then combined into a latent variable. The aggressive personality variable moderated the alcohol-aggression relation. Specifically, alcohol was significantly more likely to increase aggression in persons with higher, compared with lower, aggressive personality scores. PMID- 21299561 TI - The role of scripts in personal consistency and individual differences. AB - This article examines the role of scripts in personal consistency and individual differences. Scripts are personally distinctive rules for understanding emotionally significant experiences. In 2 studies, scripts were identified from autobiographical memories of college students (Ns = 47 and 50) using standard categories of events and emotions to derive event-emotion compounds (e.g., Affiliation-Joy). In Study 1, scripts predicted responses to a reaction-time task 1 month later, such that participants responded more quickly to the event from their script when asked to indicate what emotion would be evoked by a series of events. In Study 2, individual differences in 5 common scripts were found to be systematically related to individual differences in traits of the Five-Factor Model. Distinct patterns of correlation revealed the importance of studying events and emotions in compound units, that is, in script form (e.g., Agreeableness was correlated with the script Affiliation-Joy but not with the scripts Fun-Joy or Affiliation-Love). PMID- 21299562 TI - Conciliatory gestures facilitate forgiveness and feelings of friendship by making transgressors appear more agreeable. AB - The authors examined how conciliatory gestures exhibited in response to interpersonal transgressions influence forgiveness and feelings of friendship with the transgressor. In Study 1, 163 undergraduates who had recently been harmed were examined longitudinally. Conciliatory gestures exhibited by transgressors predicted higher rates of forgiveness over 21 days, and this relationship was mediated by victims' perceptions of their transgressors' Agreeableness. Study 2 was an experiment including 145 undergraduates who experienced a breach in trust from an anonymous partner during an iterated prisoner's dilemma. When transgressors apologized and offered financial compensation, participants reported higher levels of forgiveness and feelings of friendship when compared to a control condition and an aggravating condition. The effects of apology/compensation on forgiveness and perceived friendship were mediated by victims' perceptions of their transgressors' Agreeableness. Results suggest that conciliatory gestures promote forgiveness in part by depicting transgressors as more sympathetic, considerate, fair, and just (i.e., agreeable). PMID- 21299563 TI - A process-content approach to adolescent identity formation: examining longitudinal associations between identity styles and goal pursuits. AB - Research on identity focuses on the processes involved (e.g., identity style) or its content (e.g., goals and values), but limited research has addressed both issues simultaneously. The present study investigates cross-lagged relations between identity styles (i.e., informational, normative, and diffuse-avoidant) and goals (i.e., intrinsic vs. extrinsic and openness to change vs. conservation) in a 3-wave adolescent sample (N = 806). Results support a reciprocal model, with process and content influencing each other. As for process effects, the informational and diffuse-avoidant style predicted decreases in conservation goals, and the normative style predicted increases in conservation and extrinsic goals. As for content effects, conservation goals increased the normative style, and extrinsic goals decreased the informational and increased the diffuse avoidant style. PMID- 21299564 TI - Inactivation of the ELIP1 and ELIP2 genes affects Arabidopsis seed germination. AB - Light regulates Arabidopsis seed germination through the phyB/PIL5 (PHYTOCHROME INTERACTING FACTOR 3-LIKE 5) transduction pathway, and we have previously shown that the Dof transcription factor DOF AFFECTING GERMINATION1 (DAG1) is a component of this pathway. By means of microarray analysis of dag1 and wild type developing siliques, we identified the EARLY LIGHT-INDUCED PROTEIN1 and 2 (ELIP1 and ELIP2) genes among those deregulated in the loss-of-function dag1 mutant. We analysed seed germination of elip single and double mutants, of elip dag1 double mutants as well as of elip1 elip2 dag1 triple mutant under different environmental conditions. We show that ELIP1 and ELIP2 are involved in opposite ways in the control of this developmental process, in particular under abiotic (light, temperature, salt) stress conditions. PMID- 21299565 TI - Regulatory mechanisms underlying C4 photosynthesis. AB - C4 photosynthesis is an adaptation that evolved to alleviate the detrimental effects of photorespiration as a result of the gradual decline in atmospheric carbon dioxide levels. In most C4 plants, two cell types, bundle sheath and mesophyll, cooperate in carbon fixation, and, in so doing, are able to alleviate photorespiratory losses. Although much of the biochemistry is well characterized, little is known about the genetic mechanisms underlying the cell-type specificity driving C4 . However, several studies have shown that regulation acts at multiple levels, including transcriptional, post-transcriptional, post-translational and epigenetic. One example of such a regulatory mechanism is the cell-specific accumulation of major photorespiratory transcripts/proteins in bundle sheath cells, where ribulose-1,5-bisphosphate carboxylase/oxygenase is localized. Although many of the genes are expressed in the bundle sheath, some are expressed in both cell types, implicating post-transcriptional control mechanisms. Recently, ultra-high-throughput sequencing techniques and sophisticated mass spectrometry instrumentation have provided new opportunities to further our understanding of C4 regulation. Computational pipelines are being developed to accommodate the mass of data associated with these techniques. Finally, we discuss a readily transformable C4 grass--Setaria viridis--that has great potential to serve as a model for the genetic dissection of C4 photosynthesis in the grasses. PMID- 21299566 TI - Aerenchymatous phellem in hypocotyl and roots enables O2 transport in Melilotus siculus. AB - * Aerenchymatous phellem (secondary aerenchyma) has rarely been studied in roots. Its formation and role in internal aeration were evaluated for Melilotus siculus, an annual legume of wet saline land. * Plants were grown for 21 d in aerated or stagnant (deoxygenated) agar solutions. Root porosity and maximum diameters were measured after 0, 7, 14 and 21 d of treatment. Phellem anatomy was studied and oxygen (O(2)) transport properties examined using methylene blue dye and root sleeving O(2) electrodes. * Interconnecting aerenchymatous phellem developed in hypocotyl, tap root and older laterals (but not in aerial shoots), with radial intercellular connections to steles. Porosity of main roots containing phellem was c. 25%; cross-sectional areas of this phellem were threefold greater for stagnant than for aerated treatments. Root radial O(2) loss was significantly reduced by complete hypocotyl submergence; values approached zero after disruption of hypocotyl phellem below the waterline or, after shoot excision, by covering hypocotyl phellem in nontoxic cream. * Aerenchymatous phellem enables hypocotyl-to-root O(2) transport in M. siculus. Phellem increases radially under stagnant conditions, and will contribute to waterlogging tolerance by enhancing root aeration. It seems likely that with hypocotyl submerged, O(2) will diffuse via surface gas-films and internally from the shoot system. PMID- 21299567 TI - Seasonal variability of optical properties in a highly turbid lake (Laguna Chascomus, Argentina). AB - We study the underwater light field seasonality in a turbid lake, Laguna Chascomus (Buenos Aires, Argentina). We report (1) relationships between optical properties (OPs) and optically active substances (OASs); (2) relationships between inherent (IOPs) and apparent (AOPs) optical properties; and (3) the seasonal variability in OASs and OPs. Light absorption was dominated by the particulate fraction. The contributions of phytoplankton pigments and unpigmented components were similar. The best predictors of total particulate absorption, unpigmented particulate absorption, turbidity and vertical attenuation coefficient were total suspended solids or their ash content. Many OASs and OPs varied seasonally. The concentrations of OASs were higher during spring and summer, resulting in lower transparency and higher turbidity. However, mass specific absorption coefficients displayed lower values during spring and summer. Thus, the higher light attenuation observed during spring and summer resulted from higher concentrations of relatively less absorptive OASs. Collectively, these results suggest that: (1) light extinction is enhanced during spring and summer; (2) the enhanced light extinction is due to changes in the particulate fraction; (3) the enhanced light extinction is mostly due to an increase in the amount of particulate material; and (4) the increase of particulate matter also enhanced light extinction through increased scattering. PMID- 21299568 TI - Time, space and touch at work: body work and labour process (re)organisation. AB - With 'efficiency savings' the watchword for health and social care services, reorganisation and labour rationalisation are the order of the day. This article examines the difficulties involved in (re)organising work which takes bodies as its object, or material of production. It shows that working on bodies ('body work') systematically delimits possibilities for labour process rationalisation which, in turn, constrains reorganisation of the health and social care sector. It does this in three main ways. First: rigidity in the ratio of workers to bodies-worked-upon limits the potential to increase capital-labour ratios or cut labour. Secondly: the requirement for co-presence and temporal unpredictability in demand for body work diminish the spatial and temporal malleability of the labour process. Thirdly: the nature of bodies as a material of production- complex, unitary and responsive--makes it difficult to standardise, reorganise or rationalise work. A wide-ranging analysis of body work in health and social care, as well as other sectors, fleshes out these three constraints and shows that attempts to overcome them and reorganise the sector in pursuit of cost savings or 'efficiency', generate problems for workers and the patients, whose bodies they work upon. PMID- 21299569 TI - Managing the body work of home care. AB - Body work is a key element of home healthcare. Recent restructuring of health and social care services means the home is increasingly a key site of long-term care. While there is a growing literature on the social dynamics between care recipients and their family caregivers, less is known about the formal work dynamic between paid care workers and care recipients and family caregivers. Drawing on interview data from an Ontario-based study of long-term home care, we explore how body work is negotiated through the embodied practices of care in the home and through care relationships associated with home care. In particular we focus on how the practices of intimate body care (such as bathing, toileting, and catheter management) show the diverse dynamics of care work through which caregivers, care recipients and homespace are constituted. We argue that the practices of care are shaped by a complex interweaving of regulatory mechanisms associated with home care along with the physical and affective dimensions of intimate body work. In turn this suggests the need for new ways of understanding body work in contemporary landscapes of care. PMID- 21299570 TI - Actions speak louder than words: the embodiment of trust by healthcare professionals in gynae-oncology. AB - Trust is vital for quality healthcare outcomes, yet existing research neglects the 'embodiedness' of the interactions on which trust is based. This article draws on qualitative data from semi-structured interviews with cervical cancer patients. The significance of body work in winning or, on occasions, undermining trust emerged as a key theme within the responses. Interpretations of professionals' verbal and non-verbal presentations-of-self were often mutually reinforcing and intrinsically linked--forming a more general locus of meaning from which assumptions of competence and care were drawn. Yet it also became apparent that, whilst verbal communication was useful in establishing the agenda of the professional in relation to that of the patient, it was body work which was crucial in corroborating and validating beliefs pertaining to the ability and willingness of the professional to deliver this agenda in the future. The multi temporal nature of trust makes apparent how certain seemingly distinct forms of body work--as presentation-of-self versus more hands-on modes--are inherently intertwined. Trust, and the affective relationship in which it is rooted, bridges the present with the future and thus makes apparent how seemingly 'detached' forms of body work are connected to the emotion-work of the caring role and the craftwork of body work as touch. PMID- 21299571 TI - Body work in respiratory physiological examinations. AB - This article focuses on respiratory physiological examinations conducted in the respiratory physiological lab of a Norwegian hospital ward. The examinations were aimed at producing exact and objective measures of patients' respiratory functions or capacities. The quality of the examinations depended on correct use of technology and adequate body work by professionals and patients. The concept of 'body work' has several meanings. The professionals' body work was not direct hands-on work. Their contact with the patient was communicative and informed or guided by technical devices. Although the patient's objective body constituted the focus of examination, it necessitated an active and compliant patient. The concrete outcome of the examination was a textual artefact that in the examination situation counted as the accurate and objective representation of the patient's respiratory physiological status. These examinations represented a mutually constitutive process between various agents, bodies and bodily modes required for and aimed at by the examination; different articulations of body work were essential for these processes. The objective of the article is to examine the kinds of body work that are conducted, paying particular attention to the conceptions of bodies that are practically generated during these examinations. PMID- 21299572 TI - Afterword: Body work and the sociological tradition. PMID- 21299573 TI - Eikelboom's morphotype 0803 in activated sludge belongs to the genus Caldilinea in the phylum Chloroflexi. AB - Micromanipulated filamentous bacteria from bulking and foaming activated sludge morphologically identified as Eikelboom type 0803 were shown to be affiliated to the genus Caldilinea within the phylum Chloroflexi. Specific FISH probes were designed for their in situ detection and quantification in seven Danish wastewater treatment plants with biological nutrient removal. The survey applied all species-specific probes for Chloroflexi of relevance in activated sludge treatment plants as well as the phylum-specific probes. Type 0803 filaments constituted around 20% of the total Chloroflexi population. In four of the treatment plants, type 0803 and type 0092 co-occurred and were the dominating fraction of the Chloroflexi population. In the other plants, most Chloroflexi could not be identified beyond the phylum level, suggesting a yet far larger diversity. On average, for all plants, the total Chloroflexi population constituted 12% of the entire microbial population and seems to play an important structural role in the sludge floc formation. Ecophysiological characterization of type 0803 showed their potential role in macromolecule conversion as evident by high levels of exoenzyme expression. Acetate was not consumed. Glucose was consumed with oxygen, nitrite and nitrite as electron acceptors, suggesting that type 0803 may be a denitrifier. Their surfaces were hydrophobic, explaining their occasional occurrence in foaming incidents. PMID- 21299574 TI - Isolation and characterization of new facultative alkaliphilic Bacillus flexus strains from maize processing waste water (nejayote). AB - AIMS: This work describes the isolation and characterization of two new alkaliphilic micro-organisms present in nejayote. METHODS AND RESULTS: Samples of fresh industrial nejayote were plated on nejayote medium and incubated for 4 days at 37 degrees C. Isolates were identified based on morphological and physiological characteristics, as well as 16S rDNA sequence analysis. Two gram positive strains, NJY2 and NJY4, able to hydrolyse starch, xylan, and gelatin were isolated from nejayote. Comparative sequence analysis of 16S rDNA and phylogenetic studies indicate that the micro-organisms studied were closely related to members of the Bacillus flexus species. The strains were identified as facultative alkaliphilic salt tolerant bacteria. Isolate NJY2 produced cell associated phenolic acid esterases, able to release ferulic acid from nixtamalised corn bran and ethyl and methyl esters. CONCLUSIONS: The isolated strains of B. flexus NJY2 and NJY4 showed important physiological properties to produce high-value molecules from agroindustrial by-products. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report about the isolation of alkaliphilic micro-organisms from nejayote and the first report of phenolic acid esterases synthesised by alkaliphiles. The new alkaliphilic micro-organisms have potential application in the treatment and transformation of tortilla industry residues. PMID- 21299575 TI - Effects of cyclic AMP on development and secondary metabolites of Monascus ruber M-7. AB - AIM: To study effects of cyclic adenosine monophosphate (cAMP) on development and secondary metabolites of Monascus ruber M-7. METHODS AND RESULTS: Plate culture, liquid-state fermentation (LSF) and solid-state fermentation (SSF) were used to evaluate effects of cAMP on colonial growth, spore formation and polyketide production of Strain M-7. The results revealed that the variation trends of colonial sizes, numbers of sexual spores and red pigment contents of M-7 were in a dose-dependent manner. And generally they increased and decreased with cAMP concentrations in the ranges of low cAMP concentrations and high cAMP concentrations, respectively. But the variation trends of numbers of asexual spores and citrinin production in both LSF and SSF were opposite to those of colonial sizes, sexual sporulation and red pigment. CONCLUSIONS: The regulation of cAMP on development and secondary metabolites in Strain M-7 was in a dose dependent pattern. And red pigment might convert to citrinin under changing cAMP concentrations. SIGNIFICANCE AND IMPACT OF THE STUDY: The effects of cAMP on Strain M-7 in SSF give a new clue to enhance beneficial polyketides and reduce citrinin produced by M. ruber. PMID- 21299576 TI - Isolation and characterization of phages infecting Bacillus cereus. AB - AIM: To isolate and characterize bacteriophages (phages) that infect the foodborne pathogen Bacillus cereus. METHODS AND RESULTS: Two phages were isolated from soil based on their ability to form plaques on four indicator hosts including Bacillus thuringiensis subsp. israelensis, and three isolates of B. cereus. The purified phages were characterized by morphology, host range, single step growth curves and restriction enzyme digestion profiles. The phages appeared to be of the Myoviridae family based on their structure in electron micrographs. The phages lysed bacteria of several species, produced average burst sizes of 322 and 300 phages per infected cell, and both had genomes over 90 kb. The phages were chloroform-resistant and stable at 4 degrees C. They reduced the concentration of B. cereus in mashed potatoes by >6 log(10) CFU ml(-1) within 24 h at room temperature, when applied at a high concentration. CONCLUSIONS: The relatively narrow host range within B. cereus might mean that these phages need to be used as part of a 'cocktail' of phages for biocontrol, but their efficacy for the control of their host in food was demonstrated. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report of biocontrol by phages of B. cereus in food. PMID- 21299577 TI - Isolation of Laribacter hongkongensis from Little Egrets (Egretta garzetta) in Hangzhou, China. AB - AIMS: Laribacter hongkongensis is well adapted to diverse freshwater environments and is associated with human community-acquired gastroenteritis and traveller's diarrhoea. The study intended to investigate whether L. hongkongensis could be detected in Little Egrets (Egretta garzetta, a widespread aquatic bird) in Hangzhou, China. METHODS AND RESULTS: A total of 176 faecal specimens from three habitats in Hangzhou were obtained for this study. L. hongkongensis was isolated from 12 (6.8%) specimens. Identification of the 12 L. hongkongensis isolates was achieved through a combination of phenotypic characterization and 16S rRNA gene sequence analysis. CONCLUSIONS: The results illustrate that L. hongkongensis is present in the faeces of Little Egrets from three different habitats in Hangzhou, China. SIGNIFICANCE AND IMPACT OF THE STUDY: This study suggests the possibility that Little Egrets serve as mechanical carriers of L. hongkongensis, thus potentially transmitting the organism between bodies of water. PMID- 21299578 TI - Intra-laboratory validation of the Ridascreen(r) SET Total kit for detecting staphylococcal enterotoxins SEA to SEE in cheese. AB - AIM: To determine the performance of the Ridascreen(r) SET Total kit, after sample extraction and concentration by dialysis, with regard to its use in official controls for staphylococcal enterotoxins under European Regulation (EC) No. 2073/2005 modified. This study was conducted on naturally contaminated cheese samples and compared with the results of the previously validated Vidas(r) SET2 kit. METHODS AND RESULTS: The effectiveness of the Ridascreen(r) SET Total kit on naturally contaminated cheeses was compared to that of the Vidas(r) SET2 kit by applying the EN ISO 16140 standard. Sensitivity and specificity were also compared using spiked buffer solutions and cheese samples with SEA to SEE toxins. CONCLUSIONS: This study showed that the Ridascreen(r) SET Total kit is as effective as the Vidas(r) SET2 kit. SIGNIFICANCE AND IMPACT OF THE STUDY: The Ridascreen(r) SET Total kit was found to specifically detect SEA to SEE in cheeses. The Ridascreen(r) SET Total can therefore be used to check the staphylococcal enterotoxin content and ensure consumer protection. PMID- 21299579 TI - Expression of acrB and ramA in fluoroquinolone resistant mutants from multi-drug resistant Salmonella enterica serovar Haardt. AB - AIMS: To identify the effect of elevation of resistance in multi-drug resistant Salmonella enterica serovar Haardt with reduced susceptibility to ciprofloxacin, a parental strain SAL59-FC-KF04 was exposed to fluoroquinolone. Sequence of quinolone resistance determining region (QRDR) was analysed and expression level of efflux pump related genes was compared between the parental strain and the derived mutants. METHODS AND RESULTS: The molecular expression levels of efflux pump genes (acrB, acrF) and transcriptional regulatory genes (marA, ramA, robA and soxS) were quantified using qRT-PCR. For the confirmation of the impact of efflux pump on drug-resistance, efflux inhibition test and sequence analysis of QRDR were performed. Two mutants were obtained by point mutation on QRDR and the increased level of expression of acrB and ramA. CONCLUSIONS: As a result of in vitro exposure to fluoroquinolones for parental strain, elevated fluoroquinolone resistance and overexpression of acrB and ramA have been observed. One of the mutants combined with additional QRDR point mutation showed increase of resistance to fluoroquinolone and several antimicrobials in other classes. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrates how continuous usage of antimicrobials affects the increase of drug-resistance in Salmonella enterica induced by QRDR mutation and efflux pump related genes. PMID- 21299580 TI - Novel multiplex polymerase chain reaction primer set for identification of Lactococcus species. AB - AIMS: The gram-positive bacterial genus Lactococcus has been taxonomically classified into seven species (Lactococcus lactis, Lactococcus garvieae, Lactococcus piscium, Lactococcus plantarum, Lactococcus raffinolactis, Lactococcus chungangensis and Lactococcus fujiensis). This study aimed to develop a novel multiplex polymerase chain reaction (PCR) primer set for the identification of the seven lactococcal species, as well as to differentiate the two industrially important dairy subspecies, L. lactis subsp. lactis and L. lactis subsp. cremoris. METHODS AND RESULTS: A multiplex PCR primer set was designed based on the nucleotide sequences of the 16S rRNA gene of the seven lactococcal species. The specificity of the established one-step multiplex PCR scheme was verified using more than 200 bacterial strains, in which a complete sequence match was confirmed by partial sequencing of their 16S rRNA gene. CONCLUSIONS: The one-step multiplex PCR enables the identification and speciation of bacterial strains belonging to the genus Lactococcus and the differentiation of strains of L. lactis subsp. lactis and L. lactis subsp. cremoris. SIGNIFICANCE AND IMPACT OF THE STUDY: This work provides an efficient method for identification of lactococcal strains of industrial importance. PMID- 21299581 TI - Analysis of antibiotic utilization and bacterial resistance changes in a surgical clinic of Clinical Centre, Nis. AB - WHAT IS KNOWN AND OBJECTIVE: There is little published information about antibiotic utilization and resistance amongst hospital inpatients in Serbia. The purpose of this study was to analyse the variation of antibiotic utilization and the relation between antibiotic utilization and bacterial resistance. METHODS: This analysis was performed in the surgical clinic of one of the biggest Serbian tertiary hospitals, during 2005-2008. Data on the use of antibiotics in surgical inpatients were obtained and expressed as defined daily doses per 100 bed-days. Bacterial resistances were given as percentages of resistant isolates. Following the implementation of a restriction policy in 2005, the prescription of reserve antibiotics was placed under control. RESULTS AND DISCUSSION: During the investigation period the total consumption of antibiotics decreased significantly by 37.8%. Hospital aminoglycoside consumption continued to decrease from 25.1% of the total consumption in 2005 to 5.1% in 2008. During the same period there was a substantial decrease in the use of ceftriaxone (47.8%), ciprofloxacin and metronidazole. Reduction in Escherichia coli resistance to gentamicin correlated significantly with its utilization, while the resistance for all isolates decreased from 58.5% to 44.8%. WHAT IS NEW AND CONCLUSION: This analysis confirms the association between the use of antibiotics and the prevalence of resistance in a surgical clinic. Surveillance of bacterial resistance should be done periodically according to local guidelines for antibiotic therapy of surgical infections, as well as for external comparison. PMID- 21299582 TI - Monitoring unfractionated heparin therapy in dogs by measuring thrombin generation. AB - BACKGROUND: The calibrated automated thrombogram (CAT), an assay that permits measurement of thrombin generation in plasma, may be useful in studying hemostatic disorders and anticoagulant therapy in animals. OBJECTIVES: The aims of the study were to measure thrombin generation in healthy Beagle dogs and to evaluate the potential use of the CAT assay for monitoring therapy with unfractionated heparin (UFH). METHODS: Individual platelet-poor plasma samples and a plasma pool from 20 healthy adult Beagles were prepared. Serial UFH plasma dilutions were used to establish an in vitro heparin-sensitivity curve. The pharmacodynamic effects of heparin in vivo were evaluated in Beagles using the CAT assay to measure thrombin generation with tissue factor at a concentration of 5 pM for initiation. RESULTS: In healthy Beagles, the range of endogenous thrombin potential (ETP) was 238.7-414.0 nM/min (mean +/- SD, 340.4 +/- 63.1 nM/min). ETP intra-assay and interassay variations were 7.1% and 12.9%, respectively. In vitro, a UFH concentration >=0.4 U/mL resulted in total inhibition of thrombin generation. In vivo, the maximal effect of UFH on ETP was observed at 170 +/- 36 minutes (range, 120-210 minutes) and resulted in a decrease in ETP of 38.5 +/- 7.8% (range, 26.5-50.3%). In 210-420 minutes, ETP returned to baseline in 5 dogs. CONCLUSION: Our study demonstrates that thrombin generation can be measured in canine plasma and may be useful in assessing the degree of anticoagulation provided by UFH. PMID- 21299583 TI - Validation of a species-optimized enzyme-linked immunosorbent assay for determination of serum concentrations of insulin in dogs. AB - BACKGROUND: Measurement of canine serum insulin has relied on methods developed to measure human insulin. A species-optimized test for measurement of serum insulin in dogs is now commercially available. OBJECTIVE: The purpose of this study was to validate the canine ELISA for determination of serum insulin concentration in dogs. METHODS: Precision was determined by evaluating intra- and interassay coefficient of variation (CV), and accuracy was determined by dilution and spike recovery studies. A method comparison study with samples from 34 clinically healthy dogs and 73 dogs examined for various illnesses and disorders ("patients") was performed using the canine ELISA and an ELISA for human insulin. Biologic relevance of the canine assay was evaluated by measuring insulin in samples collected from 8 healthy dogs after administration of glucagon. A stability study was preformed with 6 samples stored at 20 degrees C, 4-8 degrees C, and -20 degrees C. RESULTS: For the canine ELISA, intra- and interassay CVs were 4.3-7.8% and 4.4-7.7%, respectively. Mean recovery after dilution was 99% and recovery after spiking with porcine insulin was 116%. The canine and human ELISAs correlated well (r(2) =.94 for healthy dogs, r(2) =.88 for patient samples). After glucagon injection serum insulin concentrations increased significantly in 8 dogs. Insulin was stable for 30 days in 6 serum samples stored at -20 degrees C and in most samples for 8 days at 4-8 degrees C. Insulin was stable for <3 days at room temperature (20 degrees C). CONCLUSIONS: The new canine serum insulin ELISA had good precision and accuracy and correlated well with the previously used assay. PMID- 21299584 TI - Oxidant and antioxidant profile of hyperketonemic ewes affected by pregnancy toxemia. AB - BACKGROUND: Negative energy balance during late pregnancy in ewes is an important cause of hyperketonemia. Ketone bodies can generate superoxide radicals and cause oxidative stress and cellular dysfunction, as noted in cows with subclinical ketosis or in diabetic people. OBJECTIVE: The aim of this study was to evaluate the role of hyperketonemia in initiating the process of lipid peroxidation. METHODS: The study included 10 pregnant ewes (aged 3.5-6 years) with pregnancy toxemia, 10 clinically healthy pregnant ewes, and 10 clinically healthy nonpregnant ewes. Serum concentrations of beta-hydroxybutyrate (BHB), cortisol, and glucose, plasma activities of glutathione peroxidase, superoxide dismutase, and catalase, and plasma concentrations of thiobarbituric acid reactive substances (TBARS), markers of lipid peroxidation, and reduced glutathione were measured. Data from the 3 groups were statistically analyzed and compared. RESULTS: Serum concentrations of BHB, cortisol, and TBARS were significantly higher in ewes with pregnancy toxemia when compared with concentrations in healthy pregnant and nonpregnant groups (P<=.05). In ewes with pregnancy toxemia, a strong positive correlation was found between concentrations of TBARS and BHB (r=.80; P=.002) and between concentrations of BHB and cortisol (r=.76; P=.005). CONCLUSIONS: Oxidative stress and lipid peroxidation are involved in the development and complications of pregnancy toxemia. An association between hyperketonemia and the products of lipid peroxidation has also been demonstrated, suggesting that ketosis is a risk factor in the development of lipid peroxidation and oxidative stress in ewes affected by pregnancy toxemia. PMID- 21299585 TI - Comparison of gel column agglutination with monoclonal antibodies and card agglutination methods for assessing the feline AB group system and a frequency study of feline blood types in northern Italy. AB - BACKGROUND: A new commercial gel column agglutination system is reported to have high sensitivity in detecting cats with blood type AB. OBJECTIVES: The aims of this study were to compare gel column agglutination and card agglutination methods for feline blood-typing and to determine the frequency distribution of feline blood types in northern Italy. METHODS: Blood-typing was performed on 120 cats using both a commercial gel column containing monoclonal antibodies (ID Gel Test Micro Typing System) and a card agglutination method (RapidVet-H Feline). Results were confirmed with back-typing. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for the 2 methods. A second group of 140 Domestic Shorthair (DSH) cats was blood-typed using the gel column technique to determine the frequency distribution of feline blood types in northern Italy. RESULTS: The card agglutination method demonstrated poor sensitivity in identification of type-AB cats (61%) and was only 95% specific when identifying type-B cats. The gel column agglutination technique demonstrated 100% sensitivity and specificity for typing all 3 blood types (A, B, and AB). The frequency distribution study of 140 cats demonstrated that 127 (90.7%) cats were type A, 10 (7.1%) were type B, and 3 (2.1%) were type AB. CONCLUSION: When blood-typing cats of breeds with a relatively high frequency of blood types B and AB, methods that use monoclonal antibodies for detection of blood types B and AB are recommended. Alternatively, blood type can be confirmed by more sensitive supplemental testing, such as back-typing. The high frequency of blood type A in DSH cats in northern Italy was comparable to previously reported frequencies in Italy and world-wide. PMID- 21299586 TI - What is your diagnosis? Aspirate of a lung nodule in a dog. Paragonimiasis. PMID- 21299587 TI - Temporomandibular disorder patients' journey through care. AB - Temporomandibular disorders (TMDs) are a common group of chronic disorders (illnesses) that health care providers can find difficult to diagnose and explain. Similar difficulties in the diagnosis of other chronic conditions have been shown to have a negative impact on health. An understanding of TMD patients' experiences and journey through care could indicate time points and strategies to help patients. OBJECTIVE: To develop a robust empirically derived map of TMD sufferers' journey through care. METHODS: A qualitative study using semi structured interviews was undertaken using a purposive sample of patients with TMDs. Analysis followed the principles of the constant comparative method where data collection and thematic analysis occurred concurrently and continued until data saturation (n = 29). RESULTS: The experiences of patients could be grouped into three key stages: genesis of problem, seeking help in primary care and secondary care intervention. A wide variety of negative effects were described throughout these stages. An empirically derived map of the patients' reported journey through care emerged. CONCLUSIONS: The experiences of patients with TMDs mirror experiences of other types of chronic illness. Mapping the journey through care for TMDs highlights the potential for interaction between the stages of the journey and the individual's illness. It may be possible to target interventions at specific stages on the map to help minimize the psychosocial effects of TMDs. PMID- 21299588 TI - Prevalence and risk indicators for chronic periodontitis in adolescents and young adults in south Brazil. AB - AIM: To describe the distribution of clinical attachment loss (CAL) and to study risk indicators for chronic periodontitis in a large population-based sample of adolescents and young adults from south Brazil. MATERIAL AND METHODS: This cross sectional study used a subset of data from a larger survey representative of Porto Alegre, Brazil. The sample consisted of 612 individuals (291 males/321 females) aged 14-29 years. Full-mouth, six sites per tooth clinical examinations were performed by calibrated periodontists. Chronic periodontitis was defined as CAL 3mm affecting two or more teeth. Aggressive periodontitis cases were excluded from the analysis. RESULTS: CAL 3 and 5mm affected 50.4% and 17.4% of subjects and 9.7% and 1.1% of teeth, respectively. Prevalence of chronic periodontitis ranged between 18.2% and 72.0% among subjects 14-19 and 24-29 years old, respectively. In the multivariable logistic regression analysis, older age [odds ratio (OR)=2.6, 95% confidence interval (CI)=1.7-3.9 and OR=7.2, 95% CI=3.7-14.0 for 20-24 and 25-29 years old, respectively], low socioeconomic status (OR=1.9, 95% CI=1.4-2.7), heavy smoking (OR=1.7, 95% CI=1.1-2.7) and larger amounts of calculus (OR=2.0, 95% CI=1.2-3.2) were significantly associated with chronic periodontitis. CONCLUSION: This population of adolescents and young adults had a high prevalence of chronic periodontitis, and its presence was associated with age, socioeconomic status, smoking and calculus. PMID- 21299589 TI - Sleep bruxism and sleep arousal: an experimental challenge to assess the role of cyclic alternating pattern. AB - Rhythmic masticatory muscle activity (RMMA) is the characteristic electromyographic pattern of sleep bruxism (SB), a sleep-related motor disorder associated with sleep arousal. Sleep arousals are generally organised in a clustered mode known as the cyclic alternating pattern (CAP). CAP is the expression of sleep instability between sleep maintaining processes (phase A1) and stronger arousal processes (phases A2 and A3). This study aimed to investigate the role of sleep instability on RMMA/SB occurrence by analysing CAP and electroencephalographic (EEG) activities. The analysis was performed on the sleep recordings of 8 SB subjects and 8 controls who received sensory stimulations during sleep. Baseline and experimental nights were compared for sleep variables, CAP, and EEG spectral analyses using repeated measure ANOVAs. Overall, no differences in sleep variables and EEG spectra were found between SB subjects and controls. However, SB subjects had higher sleep instability (more phase A3) than controls (P= 0.05). The frequency of phase A3 was higher in the pre-REM sleep periods (P < 0.001), where peaks in RMMA/SB activity were also observed (P = 0.05). When sleep instability was experimentally increased by sensory stimuli, both groups showed an enhancement in EEG theta and alpha power (P = 0.04 and 0.02, respectively) and significant increases in sleep arousal and all CAP variables. No change in RMMA/SB index was found within either groups (RMMA/SB occurred in all SB subjects and only one control during the experimental night). These findings suggest that CAP phase A3 may act as a permissive window rather than a generator of RMMA/SB activity in predisposed individuals. PMID- 21299590 TI - Review: The role of mitochondria in the pathogenesis of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of upper and lower motor neurones leading to muscle weakness and paralysis. Despite recent advances in the genetics of ALS, the mechanisms underlying motor neurone degeneration are not fully understood. Mitochondria are known to be involved in the pathogenesis of ALS, principally through mitochondrial dysfunction, the generation of free radicals, and impaired calcium handling in ALS patients and models of disease. However, recent studies have highlighted the potential importance of altered mitochondrial morphology and defective axonal transport of mitochondria in ALS. Here, we review the evidence for mitochondrial involvement in ALS and discuss potential therapeutic strategies targeting mitochondria. PMID- 21299591 TI - Paediatric parenting stress in inflammatory bowel disease: application of the Pediatric Inventory for Parents. AB - BACKGROUND: The psychosocial functioning of caregivers of adolescents managing inflammatory bowel disease (IBD) has been understudied; yet, poor caregiver functioning can place youth at risk for compromised disease management. The current study addressed this limitation by examining a sample of caregivers of adolescents with IBD. Study aims included (1) documenting rates of paediatric parenting stress; (2) identifying associated sociodemographic predictors of parenting stress; and (3) comparing previously published rates of parenting stress to those within other paediatric chronic conditions, including cancer, type 1 diabetes, obesity, sickle cell disease, bladder exstrophy. METHODS: Caregivers of adolescents with an IBD diagnosis (M(age) = 15.4 +/- 1.4, 44.4% female, 88.7% Caucasian) and receiving tertiary care within a gastroenterology clinic (n = 62) completed the Pediatric Inventory for Parents (PIP) as a measure of paediatric parenting stress with frequency and difficulty as PIP subscales. Paediatric gastroenterologists provided disease severity assessments. RESULTS: Adolescents with IBD were experiencing relatively mild disease activity. Bivariate correlations revealed that PIP-difficulty was positively associated with Crohn's disease severity (r = 0.38, P < 0.01). Caregiver age was negatively associated with the frequency of parenting stress total (r = -0.25, P = 0.05) and communication scores (r = -0.25, P < 0.05). The frequency and difficulty of parenting stressors within the IBD sample were similar to rates within type 1 diabetes, but were significantly lower than rates identified in other paediatric chronic conditions. CONCLUSIONS: Caregivers of adolescents with IBD seem to experience low rates of parenting stress when their adolescents are receiving outpatient care and during phases of IBD relative inactivity. The sociodemographic characteristics of IBD families (i.e. primarily Caucasian, well educated and higher socio-economic status) likely encourage greater access to financial and psychosocial resources, which may aid in promoting more optimal stress management. PMID- 21299592 TI - Predictors of crying, feeding and sleeping problems: a prospective study. AB - BACKGROUND: Infant regulatory problems, that is, excessive crying, feeding and/or sleeping difficulties, are precursors of adverse development. However, the aetiology of regulatory problems is still unclear. The aim of this study was to investigate pre-, peri- and post-natal neurophysiological and psychosocial predictors of single and multiple regulatory problems at 5 months of age. METHODS: This prospective longitudinal study included all children born at neonatal risk in a geographically defined area in southern Germany. The data of n = 5093 singleton infants (83.6%) were analysed using crude and multivariate logistic regression analyses. As outcome measures we used single and multiple regulatory problems, that is, crying, feeding and/or sleeping difficulties at 5 months of age, which were assessed via a standardized interview with the parents by study paediatricians as part of a neurodevelopmental examination. RESULTS: In total, 30.7% of the sample suffered from single or multiple regulatory problems at 5 months. Breastfeeding increased the odds of single sleeping problems 5.12 fold, but decreased the odds of single feeding problems [odds ratio (OR) 0.51; 95% confidence interval (CI) 0.35-0.74]. Very preterm birth was predictive of single feeding (OR 1.79; 95% CI 1.25-2.55) and multiple regulatory problems (OR 2.03; 95% CI 1.19-3.46), and foetal abnormalities increased the odds of single feeding and multiple regulatory problems from 1.53- to 1.64-fold. Family adversity and psychosocial stress factors were associated with single crying and multiple regulatory problems. CONCLUSIONS: Pre-, peri- and post-natal neurophysiological and psychosocial factors are predictive of single and multiple regulatory problems. The results may be useful in terms of early recognition of at risk groups for regulatory problems. PMID- 21299593 TI - The roles of gender, age and cognitive development in children's pedestrian route selection. AB - OBJECTIVE: Thousands of American children under the age of 10 years are injured annually as pedestrians. Despite the scope of this public health problem, knowledge about behavioural control and developmental factors involved in the aetiology of child pedestrian safety is limited. The present study examined the roles of gender, age and two aspects of cognitive development (visual search and efficiency of processing) in children's safe pedestrian route selection. METHODS: Measures of cognitive functioning (visual search and efficiency) and selections of risky pedestrian routes were collected from 65 children aged 5-9 years. RESULTS: Boys, younger children and those with less developed cognitive functioning selected riskier pedestrian routes. Cognitive functioning also subsumed age as a predictor of risky route selections. CONCLUSIONS: Our findings suggest developmental differences, specifically less developed cognitive functioning, play important roles in children's pedestrian decision making. Directions for future examination are discussed. PMID- 21299595 TI - Clinical communication as a creative art: an alternative way forward. PMID- 21299596 TI - Gender, identities and intersectionality in medical education research. PMID- 21299597 TI - Creativity in clinical communication: from communication skills to skilled communication. AB - Medical Education 2011: 45: 217-226 Objectives The view that training in communication skills produces skilled communication is sometimes criticised by those who argue that communication is individual and intuitive. We therefore examine the validity of the concept of communication as a skill and identify alternative principles to underpin future development of this field. Methods We critically examine research evidence about the nature of clinical communication, and draw from theory and evidence concerning education and evaluation, particularly in creative disciplines. Results Skilled communication cannot be fully described using the concept of communication skills. Attempts to do so risk constraining and distorting pedagogical development in communication. Current education practice often masks the difficulties with the concept by introducing subjectivity into the definition and assessment of skills. As all clinical situations differ to some extent, clinical communication is inherently creative. Because it is rarely possible to attribute specific effects to specific elements of communication, communication needs to be taught and evaluated holistically. Conclusions For communication teaching to be pedagogically and clinically valid in supporting the inherent creativity of clinical communication, it will need to draw from education theory and practice that have been developed in explicitly creative disciplines. PMID- 21299598 TI - Method and reporting quality in health professions education research: a systematic review. AB - CONTEXT: Studies evaluating reporting quality in health professions education (HPE) research have demonstrated deficiencies, but none have used comprehensive reporting standards. Additionally, the relationship between study methods and effect size (ES) in HPE research is unknown. OBJECTIVES: This review aimed to evaluate, in a sample of experimental studies of Internet-based instruction, the quality of reporting, the relationship between reporting and methodological quality, and associations between ES and study methods. METHODS: We conducted a systematic search of databases including MEDLINE, Scopus, CINAHL, EMBASE and ERIC, for articles published during 1990-2008. Studies (in any language) quantifying the effect of Internet-based instruction in HPE compared with no intervention or other instruction were included. Working independently and in duplicate, we coded reporting quality using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement, and coded study methods using a modified Newcastle-Ottawa Scale (m-NOS), the Medical Education Research Study Quality Instrument (MERSQI), and the Best Evidence in Medical Education (BEME) global scale. RESULTS: For reporting quality, articles scored a mean+/ standard deviation (SD) of 51+/-25% of STROBE elements for the Introduction, 58+/ 20% for the Methods, 50+/-18% for the Results and 41+/-26% for the Discussion sections. We found positive associations (all p<0.0001) between reporting quality and MERSQI (rho=0.64), m-NOS (rho=0.57) and BEME (rho=0.58) scores. We explored associations between study methods and knowledge ES by subtracting each study's ES from the pooled ES for studies using that method and comparing these differences between subgroups. Effect sizes in single-group pretest/post-test studies differed from the pooled estimate more than ESs in two-group studies (p=0.013). No difference was found between other study methods (yes/no: representative sample, comparison group from same community, randomised, allocation concealed, participants blinded, assessor blinded, objective assessment, high follow-up). CONCLUSIONS: Information is missing from all sections of reports of HPE experiments. Single-group pre-/post-test studies may overestimate ES compared with two-group designs. Other methodological variations did not bias study results in this sample. PMID- 21299599 TI - Attention to gender in communication skills assessment instruments in medical education: a review. AB - CONTEXT: Gender is increasingly regarded as an important factor in doctor-patient communication education. This review aims to assess if and how gender is addressed by current assessment instruments for communication skills in medical education. METHODS: In 2009 at Radboud University Nijmegen Medical Centre, an online search was conducted in the bibliographic databases PubMed, PsycINFO and ERIC for references about communication skills assessment instruments designed to be completed by trained faculty staff and used in medical education. The search strategy used the following search terms: 'consultation skills'; 'doctor-patient communication'; 'physician-patient relations'; 'medical education'; 'instruments'; 'measurement', and 'assessment'. Papers published between January 1999 and June 2009 were included. The assessment instruments identified were analysed for gender-specific content. RESULTS: The search yielded 21 communication skills assessment instruments. Only two of the 17 checklists obtained explicitly considered gender as a communication-related issue. Only six of 21 manuals considered gender in any way and none gave specific details to explain which aspects of communication behaviour should be assessed with regard to gender. CONCLUSIONS: Very few communication assessment instruments in medical education focus on gender. Nevertheless, interest exists in using gender in communication skills assessment. The criteria for and purpose of assessing gender in communication skills in medical education are yet to be clarified. PMID- 21299600 TI - Gender and the pre-clinical experiences of female medical students: a taxonomy. AB - CONTEXT: The number of women entering medical school has increased substantially in recent years. However, practising female doctors still report gender associated professional challenges. We focused on female medical students to characterise how gender shapes the range of their professional experiences during the pre-clinical years of medical school. METHODS: We conducted a qualitative study from 2006 to 2007 using in-depth interviews with 12 Year 3 female medical students at a private New England medical school who had completed their pre clinical years of training. All transcripts were analysed using a grounded theory approach; the code structure was developed through a process of inductive reasoning. Coding team members coded all transcripts line by line, using a constant comparative method of analysis. RESULTS: The resulting taxonomy identifies three domains that capture the recurrent gender-associated experiences of our participants: (i) observations of the effect of gender on pre-clinical educational experiences through instructor, student and institutional behaviour; (ii) responses to observations of gender-based occurrences in terms of emotional reactions and strategic responses, and (iii) gender-associated expectations for the clinical years and beyond brought about by a heightened awareness of gender. Participants reported subtle as well as overt gender-based experiences and emotional consequences of both. CONCLUSIONS: Female medical students continue to report numerous gender-based experiences during their pre-clinical training. Such experiences have both emotional and educational consequences and institutions should develop multifaceted approaches to address the full spectrum of gender based experiences that affect medical students. PMID- 21299601 TI - Active learning on the ward: outcomes from a comparative trial with traditional methods. AB - CONTEXT: Academic activity during internship is essentially practical and ward rounds are traditionally considered the cornerstone of clinical education. However, the efficacy and effectiveness of ward rounds for learning purposes have been under-investigated and it is necessary to assess alternative educational paradigms for this activity. OBJECTIVES: This study aimed to compare the educational effectiveness of ward rounds conducted with two different learning methodologies. METHODS: Student subjects were first tested on 30 true/false questions to assess their initial degree of knowledge on pneumonia and diarrhoea. Afterwards, they attended ward rounds conducted using an active and a traditional learning methodology. The participants were submitted to a second test 48hours later in order to assess knowledge acquisition and were asked to answer two questions about self-directed learning and their opinions on the two learning methodologies used. RESULTS: Seventy-two medical students taking part in a paediatric clinic rotation were enrolled. The active methodology proved to be more effective than the traditional methodology for the three outcomes considered: knowledge acquisition (33 students [45.8%] versus 21 students [29.2%]; p=0.03); self-directed learning (38 students [52.8%] versus 11 students [15.3%]; p<0.001), and student opinion on the methods (61 students [84.7%] versus 38 students [52.8%]; p<0.001). CONCLUSIONS: The active methodology produced better results than the traditional methodology in a ward-based context. This study seems to be valuable in terms of the new evidence it demonstrates on learning methodologies in the context of the ward round. PMID- 21299602 TI - Pre-clinical patient contacts and the application of biomedical and clinical knowledge. AB - CONTEXT: Real-patient contacts in problem-based undergraduate medical education are promoted as a good way to introduce biomedical and (in)formal clinical knowledge early in the curriculum and thereby to foster the development of coherent and integrated knowledge networks. There are concerns, however, that such contacts may cause students to focus on clinical knowledge to the neglect of biomedical knowledge, and that group discussions may be dominated by teachers. We examined these concerns by addressing the following questions in the context of group sessions in which students prepare for and report on real-patient contacts. To what extent are biomedical and (in)formal clinical knowledge addressed? To what extent are these knowledge types addressed by students or tutors? Are connections made between biomedical and clinical knowledge? METHODS: We videotaped and transcribed six preparation and six reporting group sessions (two preparation and two reporting phases for each of three groups) held with students in Year 3 of the problem-based curriculum at Maastricht University. During this year, real patients rather than paper patients are used. Qualitative analysis software was used to code propositions in the transcriptions in order to identify different kinds of knowledge and different functions of biomedical knowledge. RESULTS: Formal clinical knowledge was the subject of 40.7% and 34.8% of propositions during the preparation and reporting phases, respectively. The corresponding percentages for biomedical knowledge were 15.0% and 28.0%. Tutors accounted for 63.4% of propositions during the preparation phase, and students for 80.1% during the reporting phase. Nearly all biomedical knowledge was related to clinical knowledge. CONCLUSIONS: It appears that pre-clinical patient encounters can stimulate students to pay attention to both clinical and biomedical knowledge and to how they are connected. Tutor dominance was evident only during the preparation phase. Further research is needed to investigate whether pre-clinical patient contacts promote the development of coherent and integrated knowledge networks. PMID- 21299603 TI - Evaluating candidate reactions to selection practices using organisational justice theory. AB - OBJECTIVES: This study aimed to examine candidate reactions to selection practices in postgraduate medical training using organisational justice theory. METHODS: We carried out three independent cross-sectional studies using samples from three consecutive annual recruitment rounds. Data were gathered from candidates applying for entry into UK general practice (GP) training during 2007, 2008 and 2009. Participants completed an evaluation questionnaire immediately after the short-listing stage and after the selection centre (interview) stage. Participants were doctors applying for GP training in the UK. Main outcome measures were participants' evaluations of the selection methods and perceptions of the overall fairness of each selection stage (short-listing and selection centre). RESULTS: A total of 23,855 evaluation questionnaires were completed (6893 in 2007, 10,497 in 2008 and 6465 in 2009). Absolute levels of perceptions of fairness of all the selection methods at both the short-listing and selection centre stages were consistently high over the 3years. Similarly, all selection methods were considered to be job-related by candidates. However, in general, candidates considered the selection centre stage to be significantly fairer than the short-listing stage. Of all the selection methods, the simulated patient consultation completed at the selection centre stage was rated as the most job relevant. CONCLUSIONS: This is the first study to use a model of organisational justice theory to evaluate candidate reactions during selection into postgraduate specialty training. The high-fidelity selection methods are consistently viewed as more job-relevant and fairer by candidates. This has important implications for the design of recruitment systems for all specialties and, potentially, for medical school admissions. Using this approach, recruiters can systematically compare perceptions of the fairness and job relevance of various selection methods. PMID- 21299604 TI - Reasons selectors give for accepting and rejecting medical applicants before interview. AB - CONTEXT: The introduction of aptitude testing in the selection of applicants for medical and dental school, in the UK, has led to growing scrutiny of current selection practices. There is increasing difficulty in discriminating between the high numbers of very able candidates who apply to study medicine based on traditional academic criteria. Concerns have been raised that the current selection methods of screening Universities and Colleges Admission Service (UCAS) forms in the UK and holding interviews are essentially subjective and their abilities to predict success at medical school are largely unknown. In particular, questions on the validity and reliability of screening students' personal statements are highlighted. OBJECTIVES: This study aims to further examine this subjectivity and elucidate the reasons given by selectors in one medical school for accepting or rejecting candidates, prior to interview, based on the screening of UCAS forms. METHODS: Three focus groups, totalling 17 participant selectors, explored current selector practices at one London-based medical school. Additionally, reasons given on selector marking forms for rejecting candidates prior to interview were analysed by content analysis. Data were then triangulated with themes derived from the focus groups exploring why selectors accepted or rejected candidates for interview. RESULTS: Selectors identified clear criteria for selecting or rejecting candidates for interview. They described the 'ideal' candidate as one who possessed positive attributes, including academic ability, enthusiasm and motivation. These views correlated with the reasons for rejecting candidates given by selectors on selector marking forms. CONCLUSIONS: This study describes selector practice in one medical school and clarifies selector reasons for accepting or rejecting candidates for interview. Although it provides criteria for the 'ideal' candidate, this study highlights the subjective nature of the selection process and the difficulties in quantifying applicant aptitude, and raises the need for a more open, transparent and reliable way of selecting future medical students. PMID- 21299605 TI - Predicting medical student performance from attributes at entry: a latent class analysis. AB - OBJECTIVES: The objectives of this study were two-fold. Firstly, we aimed to model 'typologies' of student examination performance by grouping students into like categories based on measures of prior academic achievement (particularly in the science subjects) and interview rating at time of entry to a medical degree course, and outcome measures of subsequent performance across the course. Secondly, we aimed to illustrate and evidence the utility of the latent class analysis (LCA) clustering technique to provide meaningful information on the effectiveness of a student selection process with respect to the likelihood of poor examination performance. METHODS: For this retrospective study, anonymised data on two sequential cohorts of students who graduated from a 5-year Bachelor of Medicine, Bachelor of Surgery degree course were analysed using LCA. In order to triangulate the findings, the same data were analysed using the more conventional approach of logistic regression. RESULTS: The LCA identified three distinct classes or typologies of student examination performance using measures of prior academic achievement and interview rating at time of course entry. Measures of prior academic achievement and score on a structured admissions interview made significant contributions to the model's ability to discriminate between typologies. Strong prior academic achievement, especially in chemistry, and high interview score were positively related to the likelihood of successful test performance. These findings were supported by the logistic regression analysis. CONCLUSIONS: The LCA clustering technique provided meaningful information on the performance of a selection process. As a complementary tool to existing methods used in this area of research, LCA has the potential to empirically inform the selection process. PMID- 21299606 TI - First, do no harm: using simulated patient death to enhance learning? PMID- 21299607 TI - What's the problem with the mini-CEX? PMID- 21299608 TI - Aurora B kinase expression in laryngeal squamous cell carcinoma and its prognostic implications. AB - AIMS: To investigate the clinical and prognostic significance of Aurora B in laryngeal squamous cell carcinomas (LSCC). METHODS AND RESULTS: Aurora B protein expression was analysed in 259 LSCC. The proliferation index (Ki67) and the expression of other cell cycle control proteins, such as Aurora A, survivin and p53 was also determined. Aurora B was highly expressed in 55.4% of LSCC. High Aurora B expression levels were correlated with tumour recurrence (P=0.01), death from disease (P=0.05) and decreased disease-free survival (P=0.013) and overall survival (P=0.04). Survivin expression was neither associated with clinicopathological characteristics nor with survival. However, survivin expression in the nucleus paralleled Aurora B expression (P=0.014). Aurora A expression was associated significantly with increased tumour grade (P=0.008). Multivariate analysis indicated that Aurora B was an independent predictor for LSCC-specific disease-free survival [hazard ratio (HR), 2.10; 95% confidence interval (95% CI), 1.25-3.52 (P=0.005)] and overall survival [HR, 1.91; 95% CI 1.01-3.34 (P=0.023)]. CONCLUSIONS: Aurora B may be a novel prognostic biomarker for LSCC and a potential therapeutic target in this type of tumour. PMID- 21299609 TI - Nuclear localization of E-cadherin but not beta-catenin in human ovarian granulosa cell tumours and normal ovarian follicles and ovarian stroma. AB - AIMS: The role of misregulated Wnt/beta-catenin signalling in human ovarian granulosa cell tumour (GCT) has not been well characterized. The aim of this study was to confirm subcellular localization of key molecules of Wnt signalling (beta-catenin and E-cadherin) in human ovarian GCTs. METHODS AND RESULTS: Tissue samples taken from 32 human ovarian GCTs and 19 human normal ovaries containing 68 follicles were stained immunohistochemically using monoclonal anti-beta catenin and anti-E-cadherin antibodies. None of the 32 GCTs and none of the 68 ovarian follicles showed beta-catenin nuclear expression (0%). On the other hand, 28 of 32 GCTs (88%) and 53 of 68 normal ovarian follicles (78%) showed nuclear expression of E-cadherin in granulosa cells. The ovarian stroma in all 19 normal ovaries showed nuclear expression of E-cadherin but not beta-catenin. Membranous and cytoplasmic expression was observed variously in ovarian GCT, follicles and stroma. CONCLUSIONS: We have confirmed frequent nuclear localization of E cadherin but not beta-catenin in human ovarian GCT, ovarian follicles and stroma. There is no evidence of misregulated Wnt/beta-catenin signalling (represented by nuclear expression of beta-catenin) in human ovarian GCT. Nuclear translocation of E-cadherin might contribute to ovarian folliculogenesis or granulosa/stromal cell differentiation. PMID- 21299610 TI - Breastfeeding and early child development: a prospective cohort study. AB - AIM: Breastfeeding has been associated with multiple developmental advantages for the infant; however, there have also been a number of studies that find no significant benefits to child development. We examined the relationship between breastfeeding for 4 months or longer and child development at age 1, 2 and 3 years. METHODS: Women were enrolled in the Western Australian Pregnancy Cohort (Raine) Study (N = 2900) and their live born children (N = 2868) were followed to the age of 3 years (N = 2280). Infant feeding data were collected at each age, and the mothers completed the Infant/Child Monitoring Questionnaire (IMQ), which measures progress towards developmental milestones in the domains of gross and fine motor skills, adaptability, sociability and communication. Factors adjusted for in multivariable analyses included maternal sociodemographic characteristics and stressful life events. RESULTS: Infants breastfed for 4 months or longer had significantly higher mean scores (representing better functioning) for fine motor skills at age 1 and 3, significantly higher adaptability scores up to age two, and higher communication scores at age 1 and 3 years. Infants who were breastfed for <4 months were more likely to have at least one atypical score across the five developmental domains than those who were breastfed for 4 months or longer. CONCLUSION: Although our effect sizes were small, breastfeeding for 4 months or longer was associated with improved developmental outcomes for children aged one to 3 years after adjustment for multiple confounding factors. PMID- 21299611 TI - Motor performance and haptic perception in preschool boys with specific impairment of expressive language. AB - AIM: The aim of this study was to investigate motor performance and haptic object recognition (HOR) in 5-year-old boys with minor to moderate specific impairment of expressive language (expressive-SLI). METHODS: Twenty-eight boys with expressive-SLI and 26 boys with typical language development as controls were recruited from ordinary kindergartens. An assessment of the voluntary isometric force production and relaxation capacity of the leg extensor muscles, manual dexterity, ball skills, balance and HOR was performed and the results were compared with those for age-matched control group. RESULTS: Reaction times to voluntary contraction and relaxation of the leg extensor muscles as well as manual dexterity did not differ significantly in the measured groups. Boys with expressive-SLI demonstrated poorer results in ball skills (p < 0.01), balance (p < 0.01), less leg extensors strength (p < 0.05) and made considerably more (p < 0.001) errors in haptic perception test when compared to controls. CONCLUSIONS: Deviations in gross-motor performance and haptic perception are very common in children with minor to moderate expressive-SLI, being embodied especially in less muscle strength of lower extremities, poorer ball skills, balance and HOR. PMID- 21299612 TI - Immunodeficiency in a child with partial trisomy 6p. AB - AIM: We present a mentally retarded boy with partial trisomy of the short arm of chromosome 6 as a result of an interstitial tandem duplication of 6p12.2-p21.31 and immunodeficiency. Patients with mental retardation because of a chromosomal disorder or eponymous syndrome often experience recurrent respiratory tract infections as a result of their associated anatomical or neurological abnormalities. However, associated immune defects may also significantly contribute to their susceptibility to infections. Timely recognition and appropriate treatment of their immunodeficiency will greatly improve quality of life in these patients. CONCLUSION: Immunodeficiency may be the direct cause of recurrent respiratory tract infections in patients with mental retardation because of a chromosomal disorder or eponymous syndrome, even in the face of feeding difficulties and multiple episodes of aspiration, as is illustrated in this boy with partial trisomy 6p. PMID- 21299613 TI - Intestinal polypoid arteriovenous malformation: unusual presentation in a child and review of the literature. AB - AIM: We report a jejuno-jejunal intussusception with a polypoid arteriovenous malformation as a lead point in a 12-year-old boy, presenting with lower abdominal pain and non-bloody non-projectile vomiting. METHODS: A computed tomography scan of the abdomen and pelvis showed proximal jejuno-jejunal intussusception in the right upper quadrant. Exploratory laparotomy revealed a 5.5 * 2.5 * 2 cm polypoid mass within the wall of the jejunum. Consequently, jejunal segment resection was performed with end to end jejunostomy. Our case is distinctive because it involves a rare vascular lesion at an atypical site, the jejunum, in a child with an unusual presentation of intussusception treated surgically. CONCLUSION: Many paediatric benign and surgical conditions present with similar clinical symptoms; the physician in the emergency department should try to narrow the differential diagnosis and recognize surgical emergencies to avoid any delay in intervention that could be life-threatening. PMID- 21299614 TI - Fully-covered, self-expandable metal stents (CSEMS) in malignant distal biliary strictures: mid-term evaluation. AB - BACKGROUND AND AIMS: Limited data exist regarding fully-covered, self-expandable metal stents (CSEMS) with anchoring fins for the management of malignant distal biliary strictures. The aim of this study is to evaluate their safety and patency. METHODS: Over a period of 2 years, 70 patients (45 males, 66 +/- 13 years) underwent endoscopic retrograde cholangiopancreatography (ERCP) with placement of a 10-mm (67 patients) or 8-mm diameter (3 patients) CSEMS for the palliation of distal malignant biliary obstruction (pancreatic [53] or other [17]). Data were collected prospectively for survival and stent patency; complications were evaluated retrospectively. RESULTS: After CSEMS placement, 17 patients proceeded to surgery, and 53 patients were deemed unresectable. Mean survival for non-surgical candidates was 180 days (range: 15-1091), and 170 days (range: 9-589) for patients who underwent surgical management. CSEMS were left in place and remained patent for a mean of 163 days (range: 15-1091) in non-surgical candidates, and a mean of 55 days (range: 5-126) in surgical candidates. Complications during placement included wire perforations (4) and proximal deployment requiring repositioning (4), one of which was complicated by a bile leak. Post-procedure complications were observed in 24 cases (34%) and included post-ERCP pancreatitis (8, with 2 of them severe), post-procedure pain (5, with 3 requiring admission), cholecystitis (3), stent occlusion (3), cholangitis (2), proximal migration (1), post-sphincterotomy bleeding (1), and sepsis leading to death (1). CONCLUSION: CSEMS appear to provide acceptable short-term patency rates; however, their limited long-term patency and high complication rate might limit their widespread use. Further long-term prospective data are required to confirm this observation. PMID- 21299615 TI - Autoimmune pancreatitis: current diagnostic criteria are suboptimal. AB - BACKGROUND AND AIMS: The preoperative diagnosis of autoimmune pancreatitis (AIP) is difficult, given its similar clinical presentation to pancreatic cancer. The aims of the study are to describe our center's experience with AIP and apply the Japanese AIP diagnostic criteria to a cohort of patients with histologically proven AIP in order to assess their performance characteristics. METHODS: A prospective pathology database was queried for AIP patients who were evaluated and/or treated at Johns Hopkins Hospital from 2002 to 2009. AIP histology was defined by the presence of lymphoplasmacytic infiltration, periductal inflammation, fibrosis, and periphlebitis. Imaging, clinical, and biochemical data were analyzed. RESULTS: Thirty patients had pancreatic resection with pathological confirmation of AIP. Imaging revealed pancreatic mass (45%), focal prominence without mass lesion (24%), diffuse enlargement (17%), and normal pancreas (14%). Twenty-four patients underwent an endoscopic retrograde cholangiopancreatography and/or magnetic resonance cholangiopancreatography, and 4/24 (17%) had pancreatic ductal narrowing or irregularity. Extrapancreaticobiliary organ involvement was found in 6% (n = 2) of patients. Biliary strictures were present in 87% of patients. Of 16 patients who underwent preoperative tissue biopsy, 10 had non-diagnostic pathology, five had cellular atypia, and one had AIP. Serum immunoglobulin G4 (IgG4) levels were elevated in 12 of 29 (41%) patients. Three (10%) patients had evidence of extrapancreatic manifestations of AIP. When applying the Japanese criteria to the 27 patients who had serum IgG4 measurement, preoperative biopsy, and cross-sectional abdominal imaging, only 44% of the patients would have been diagnosed accurately. CONCLUSIONS: When applied to a highly-selected single-center referral population in the USA, current Japanese guidelines for the diagnosis of AIP are found to have suboptimal sensitivity. PMID- 21299616 TI - Comparing endoscopic submucosal dissection with transanal resection for non invasive rectal tumor: a retrospective study. AB - BACKGROUND AND AIM: Endoscopic submucosal dissection (ESD) is an alternative to transanal resection (TAR) in treating rectal adenomas, intramucosal cancers, and superficial submucosal cancers. The purpose of this study is to compare the clinical efficacy between ESD and TAR for non-invasive rectal tumors. METHODS: Between January 1998 and December 2006, 85 patients with preoperative diagnosis of non-invasive rectal tumors were treated by ESD or TAR. En-bloc resection, local recurrence, complication, procedure time, and hospital stay were evaluated retrospectively using a prospectively-completed database. RESULTS: Mean resection sizes were 40 mm and 39 mm in diameter for the ESD and TAR groups, respectively. En-bloc resections with a negative resection margin were achieved in 67% (35/52) of the ESD group, which was significantly higher than the 42% (14/33) in the TAR group. Sixty-three lesions were diagnosed as curative resection, histopathologically. There was no local recurrence in the ESD group, but five local recurrences developed in the TAR group. Two rectal perforations, one minor delayed bleeding, and one subcutaneous emphysema in the ESD group were successfully managed conservatively. There were one minor delayed bleeding and two anesthesia-related complications in the TAR group. The ESD group had a shorter hospital stay than the TAR group (4.9 days vs 7 days), but a longer procedure time (131 min vs 63 min). CONCLUSION: ESD was more effective than TAR in treating non-invasive rectal tumors, with a lower recurrence rate and shorter hospital stay. PMID- 21299617 TI - Fungal infections in severe acute pancreatitis. AB - Severe acute pancreatitis (SAP) is associated with significant morbidity and mortality. The majority of deaths related to SAP are the result of infectious complications. Although bacterial infections are most commonly encountered, fungal infections are increasingly being recognized. Candida is the most common fungal infection. The occurrence of fungal infection in patients with acute pancreatitis adversely affects the clinical course, leading to a higher incidence of systemic complications, and possibly mortality as well. Important risk factors for fungal infection in patients with acute pancreatitis include broad-spectrum antibiotics, prolonged hospitalization and surgical/endoscopic interventions, use of total parenteral nutrition, and mechanical ventilation. Patients with higher severity of pancreatitis are at a greater risk. The pathogenesis of fungal infection in patients with acute pancreatitis is multifactorial. Translocation of microorganisms across the gut epithelium, lymphocyte dysfunction, and the virulence of the invading microorganisms play important roles. Histological demonstration of fungi remains the gold standard of diagnosis, but a positive biopsy is rarely obtained. The role of biomarkers in the diagnosis is being investigated. As early diagnosis and treatment can lead to improved outcome, a high index of suspicion is required for prompt diagnosis. Limiting the use of broad-spectrum antibiotics, early introduction of enteral nutrition, and timely change of vascular catheters are important preventive strategies. The role of antifungal prophylaxis remains controversial. Surgical necrosectomy with antifungal therapy is the most widely used treatment approach. Clinical trials on antifungal prophylaxis are needed, and indications for surgical intervention need to be clearly defined. PMID- 21299618 TI - Old age and male sex are associated with increased risk of asymptomatic erosive esophagitis: analysis of data from local health examinations by the Korean National Health Insurance Corporation. AB - BACKGROUND AND AIMS: Silent gastroesophageal reflux disease (GERD) is often detected during routine screening esophagogastroduodenoscopy (EGD). However, the risk factors and clinical implications of silent GERD remain unclear. In the present study, we investigated the risk factors for asymptomatic erosive esophagitis by analyzing the local area health examination data. METHODS: The Korean National Health Insurance Corporation provides a bi-annual health examination performed by qualified local hospitals for the early detection of cancer in medical insurance holders over 40 years of age. Participants who completed self-reported questionnaires on health, followed by EGD at the Myongji Hospital (Goyang, Korea), were enrolled in this study. RESULTS: The data of a total of 5301 participants who underwent EGD between January 2005 and December 2008 were analyzed. The prevalence of erosive esophagitis was 6%. In the multivariate analysis, erosive esophagitis was strongly associated with an age greater than 60 years (odds ratio [OR]: 0.7, 95% confidence interval [CI]: 0.6 1.0), male sex (OR: 2.3, 95% CI: 1.7-3.0), hiatus hernia (OR: 2.9, 95% CI: 2.1 4.0), duodenal ulcer (OR: 1.6, 95% CI: 1.1-2.5), hypertension (OR: 1.5, 95% CI: 1.2-2.0), and smoking (OR: 1.4, 95% CI: 1.0-1.8). Of the 320 participants with erosive esophagitis, 145 (45.3%) were asymptomatic participants, and those who were more frequently greater than 60 years (OR: 1.8, 95% CI: 1.1-3.1) and male (OR: 1.8, 95% CI: 1.1-3.2). CONCLUSIONS: Asymptomatic erosive esophagitis in adults older than 40 years is strongly associated with old age (>= 60 years) and male sex compared with symptomatic erosive esophagitis. PMID- 21299619 TI - Feeding the child with liver disease: a review and practical clinical guide. AB - Nourishing children with liver disease is a challenging task; however, appropriate assessment and well-timed nutritional interventions are paramount for a good long-term outcome in these patients. An appropriate balance of macronutrients, micronutrients, and vitamins is important, as is the route of administration. This review aims to highlight the practical points in nutrition assessment and also provides a guide to the various nutritional interventions available for children with chronic liver disease. PMID- 21299620 TI - Clinical outcomes and factors for response prediction after the first course of corticosteroid therapy in patients with active ulcerative colitis. AB - BACKGROUND AND AIMS: Both clinical outcomes and factors predictive for poor response after an initial course of corticosteroids have not yet been well established in the treatment of moderate to severe ulcerative colitis (UC). We therefore evaluated the short- and long-term effects of corticosteroids and prognostic factors in UC patients after such therapy. METHODS: We recruited consecutive patients who had moderate to severe UC and were treated with the first course of systemic corticosteroids between November 1996 and December 2007 using the database of Severance Hospital in Seoul, Korea. We then evaluated clinical outcomes at 1 month, 3 months, and 1 year after the initiation of corticosteroid treatment. RESULTS: Our study included a total of 177 patients. At 1 month, complete remission was achieved in 70 patients (39.5%) and partial remission in 88 (49.7%). Fifteen patients (8.5%) were refractory to the treatment, and four (2.3%) underwent proctocolectomy. We observed prolonged response in 111 (64.9%) at 3 months and 95 (59.4%) patients at 1 year, corticosteroid dependency in 49 (28.7%) and 51 (31.9%) patients, and no response in 11 (6.4%) and 14 (8.7%) patients. A higher initial Mayo score was found to be the only poor prognostic factor at 1 month (P = 0.032) and 1 year (P < 0.001). CONCLUSIONS: Our data showed that most Korean patients with active UC responded well to the first course of corticosteroid treatment. However, a considerable number of patients eventually turned out to be refractory to or dependent on this therapy. The initial higher Mayo score was strongly associated with poor outcomes. PMID- 21299621 TI - Cardiac varix presenting as a right atrial mass. AB - A cardiac varix is an unusual tumor of vascular origin that is rarely discovered antemortem. Here, we report the incidental finding of this lesion in the right atrium of a patient with concomitant prostate cancer. PMID- 21299622 TI - Spontaneous rupture of the right sinus of valsalva mimicking an ascending aortic intramural hematoma. AB - Spontaneous ruptures of the ascending aorta are extremely rare and require emergent surgical intervention. We report a case of a delayed diagnosis of a spontaneous, localized periostial rupture of a nondilated right sinus of Valsalva, which mimicked an intramural hematoma of the ascending aorta. The diagnosis and surgical management of this unusual pathology is the subject of this case report. PMID- 21299623 TI - Hemolytic anemia secondary to mitral leaflet prolapse. PMID- 21299624 TI - Congenital intrathoracic kidney in a patient undergoing coronary artery bypass surgery. AB - Intrathoracic kidney is a rare congenital anomaly. It appears as a posterior mediastinal mass on chest X-ray. Most cases are asymptomatic and are discovered accidentally. We present a 48-year-old male patient with intrathoracic kidney discovered during routine investigation for coronary artery bypass surgery. PMID- 21299625 TI - Ascending aortopulmonary fistula 40 years after previous cardiac surgery. AB - We present a case of a 64-year-old female presenting with hemoptysis and an ultimate diagnosis of ascending aortopulmonary fistula 40 years after an atrial septal defect repair. A literature review of this rare complication of ascending aortic cannulation includes the pathogenesis and etiology of this rare diagnosis. Aortobronchopulmonary fistula is a rare diagnosis with grave consequences if not treated urgently. We present a case of such diagnosis that was treated with a good outcome. PMID- 21299626 TI - Motion artifact resulting in a false positive CT angiogram for a presumed aortic dissection. PMID- 21299627 TI - Aneurysm of a patent ductus arteriosus. PMID- 21299628 TI - High-flux dialyzers, backfiltration, and dialysis fluid quality. AB - Currently, high-flux hemodialysis is the most common mode of dialysis therapy worldwide. Its steadily increasing use is largely based on the desire to reduce the excessively high morbidity and mortality of end-stage renal disease patients maintained on conventional dialysis (low-flux, mostly cellulosic membranes) by offering better biocompatibility and enhanced removal of uremic toxins. Two large randomized trials suggest a survival benefit for selected subgroups of high-flux dialysis patients such as diabetics, patients with hypoalbuminemia, or patients who have been on dialysis for a long period (>3.7 years). The major disadvantage of high-flux hemodialysis relates to the use of dialysis fluid, which is commonly not pure and may endanger patients treated with high-flux hemodialysis. Endotoxin fragments and other bacterial substances derived from bacteriologically contaminated dialysis fluid may, even at bacterial counts or endotoxin concentrations within the limits of accepted standards of dialysis fluid purity, enter from the dialysate into the patient's blood either by convective transfer (backfiltration) or by movement down the concentration gradient (backdiffusion). Repeated exposure of high-flux hemodialysis patients to backtransport of dialysate contaminants aggravates the uremia-associated inflammatory response syndrome and contributes to long-term morbidity. At present, the only solution to circumvent the risks of backtransport is the use of dry powder cartridges for bicarbonate concentrate and the use of bacteria- and endotoxin-retentive filters for the online production of ultrapure dialysis fluid. Use of ultrapure dialysis fluid (bacteria <0.1 CFU/ml and endotoxin <0.03 IU/ml) has been found to reduce inflammation and comorbidities in clinical investigations compared to commercial dialysis fluid. The European Renal Association and a number of national societies in Europe or in Japan strongly recommend the use of ultrapure dialysis for high flux hemodialysis. PMID- 21299629 TI - Suggested guidelines for performing procedures in patients with chronic kidney disease in outpatient centers. AB - Maintenance of hemodialysis vascular access is increasingly performed on an outpatient basis by physicians trained in interventional techniques. The adoption of guidelines by national reputable organizations will help identify patients eligible for such outpatient treatments and help optimize the safety and efficacy of their procedures in the outpatient setting. PMID- 21299630 TI - Reducing the risk of re-fracture in the dialysis population: is it time to consider therapy with PTH analogues? AB - Dialysis patients are at high risk for fracture, with published rates in excess of a 20% probability of fracture over the next 10 years of dialysis. Unfortunately, there is no accepted methodology for quantifying this risk in advance of the first fracture; conventional bone densitometry performs unreliably in this role, in contrast to its utility in elderly patients with osteoporosis. The KDIGO clinical guidelines emphasize the importance of bone turnover in the development of renal osteodystrophy with high bone turnover strongly associated with uncontrolled secondary hyperparathyroidism, and adynamic bone disease (ABD) defined as a very low bone turnover state associated with functional hypoparathyroidism. It is likely that fractures occur in association with both extremes of uremic bone turnover, in addition to the known risk factors for developing osteoporosis prior to an individual developing end-stage renal failure. No systematic evidence has been forthcoming on therapy to reduce the risk of re-fracture after a dialysis patient presents with a first fracture. Anti resorptive therapy might be effective in high turnover uremic bone disease and has been demonstrably effective in reducing fracture risk in osteoporotic patients, but there is only post hoc evidence that cinacalcet might reduce the incidence of fractures, and almost no evidence on outcomes from the use of bisphosphonates in dialysis patients. Fractures associated with ABD present a particular challenge. Although aluminum intoxication has been an important cause of skeletal fracturing in the past, this is a rare event today, when nonaluminum containing dietary phosphate binders are routinely prescribed. We suggest that the use of an anabolic agent would be a more plausible approach to the management of ABD (rather than anti-resorptive agents) and propose that a "proof-of-concept" trial with a PTH analogue such as teriparatide should be considered for these patients. PMID- 21299631 TI - A mysterious leak in a peritoneal dialysis patient's catheter. PMID- 21299632 TI - What we know about oxidative stress in patients with chronic kidney disease on dialysis--clinical effects, potential treatment, and prevention. AB - Patients with chronic kidney disease (CKD) experience accelerated atherosclerosis leading to excessive cardiovascular death. This cannot be fully explained by traditional cardiovascular risk factors. Oxidative stress is currently receiving attention as an important pathogenetic mediator of tissue damage. Oxidative stress is highly prevalent in patients with CKD. Increased prooxidant activity (age, diabetes, hypertension, inflammation, incompatibility of dialysis membranes, and solutions) goes together with reduced antioxidant defense (reduced activity of the glutathione system, low levels of vitamin E, C). Oxidative stress has been linked to several surrogate markers of atherosclerosis in patients with CKD, such as endothelial dysfunction and intima-media thickness. However, large epidemiological studies testing hard endpoints are lacking. Oxidative stress may also influence response to erythropoiesis-stimulating agents. Among possible therapeutic approaches, the use of vitamin E seems to be the most promising. Given orally, it has been shown to significantly improve cardiovascular outcomes in a relatively small clinical trial. When bonded to biocompatible dialysis membranes, it may be effective in improving erythropoiesis-stimulating agents' responsiveness. Similarly, vitamin C may be effective in reducing cardiovascular events in haemodialysis patients. Further well-designed, randomized controlled clinical trials with antioxidants are required to establish their potential to make a substantive difference in clinical practice. PMID- 21299633 TI - Two-year clinical outcomes with paclitaxel-eluting coronary stents in patients with chronic total occlusions: analysis from the TAXUS ARRIVE program. AB - AIMS: To examine the incidence of clinical events after implantation of the TAXUS Express paclitaxel-eluting stent (PES) in chronic total occlusions (CTO) in an unselected patient population. METHODS AND RESULTS: The TAXUS ARRIVE registries compiled data on 7,492 patients, including 113 patients with CTO (TIMI flow 0). Patients enrolled at procedure start with no mandated inclusion/exclusion criteria; all cardiac events were monitored with independent end-point adjudication. Two-year follow-up was 89% (101/113) for CTO patients who had significantly more baseline comorbidities/complex disease than simple-use patients undergoing native coronary intervention (N = 2,698) and significantly longer lesions/smaller vessels than other expanded-use patients (N = 4,681 without CTO). Among CTO patients the rate of 2-year major cardiac events (MCE, including cardiac death, myocardial infarction, and target vessel revascularization) was 22.3%, significantly higher than in simple-use patients (10.3%, P < 0.001). CTO MCE was similar to that for other expanded-use patients (16.5%, P = 0.14) but target lesion revascularization was significantly higher in year 2 (6.9% vs. 2.7%, P = 0.02). Academic Research Consortium definite/probable stent thrombosis through 2 years was 5.7%, significantly higher than simple-use patients but similar to other expanded-use cases. CONCLUSION: In a "real-world" setting, PES use in CTO was associated with increased MCE compared to simple- use patients, but achieved long-term outcomes similar to that observed in other complex patient/lesion cases. PMID- 21299634 TI - Extra-renal living donor transplants with special reference to segmental pancreas transplantation. PMID- 21299635 TI - Value of preemptive CYP2C19 genotyping in allogeneic stem cell transplant patients considered for pentamidine administration. AB - Pneumocystis jirovecii prophylaxis is standard in allogeneic stem cell transplantation (alloSCT), sometimes with pentamidine at a low dose inhaled monthly. Human metabolism of pentamidine depends on cytochrome P450 2C19 (CYP2C19). The frequency of mutant CYP2C19 forms with decreased function (from 2% of Caucasians to 30% of Asians and 79% of certain Polynesians), together with common use of CYP2C19 inhibitors in the alloSCT process, creates risk for impaired pentamidine clearance resulting in toxicity ordinarily expected only with high doses given for active infection. We examined the charts of 32 consecutive pentamidine-prophylaxed alloSCT patients at our center. We assessed hospital charges for the management of toxicities unexplained at the time but likely attributable, in retrospect, to pentamidine. Twenty-eight percent experienced significant toxicities (incurring added charges of at least US$5000). Thirteen percent suffered major toxicity (incurring added charges of at least US$25, 000; median added charge $351, 701) and shorter survival (326 vs. 622 d for all pentamidine recipients), including 6% who died of pentamidine toxicities [one proven postmortem to have a (non-functional) homozygous CYP2C19*2 mutation]. Charges for care attributable to pentamidine toxicity exceeded what preemptive genotyping would have cost by 73-fold. These findings encourage routine use of preemptive CYP2C19 genotyping in alloSCT patients considered for pentamidine. PMID- 21299636 TI - Pharmacokinetics and pharmacodynamics of mycophenolate sodium (EC-MPS) co administered with cyclosporine in the early-phase post-kidney transplantation. AB - Mycophenolate drug levels are decreased by co-administration of cyclosporine. However, mycophenolate levels may be associated with insufficient immunosuppression. We investigated the pharmacokinetics of 720 mg mycophenolate sodium (EC-MPS) and inosine monophosphate dehydrogenase (IMPDH) activity under co medication with cyclosporine and steroids within the first 30 d after kidney transplantation (n = 24). Blood samples were drawn at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 h after the morning dose. Plasma concentrations of mycophenolic acid, its glucuronide metabolites (MPAG; AcMPAG), and free MPA were determined using validated HPLC-DAD. IMPDH activity in leukocytes was analyzed chromatographically. Only six of 24 patients had an MPA-AUC(12h) within the putative therapeutic range of 40-60 mg/L.h. MPA clearance was high with 29 L/h. fMPA-AUC(12h) (r = -0.429, p = 0.04) and MPAG-AUC(12h) correlated significantly with the glomerular filtration rate, while total MPA did not. The MPAG-AUC(12h) was about 52-fold higher than the corresponding values for MPA, whereas the AcMPAG-AUC(12h) reached about 20.4% of the respective MPA-AUC(12h.) We found significant correlations between IMPDH inhibition and MPA concentration (r = 0.665; p < 0.0001), fMPA (r = -0.446; p = 0.003), and AcMPAG (r = -0.459; p = 0.002) but not with MPAG. Only 25% of the patients attained the therapeutic range for MPA-AUC under standard EC-MPS dose during the early-phase post transplantation. We recommend that EC-MPS should be given in higher doses (3 * 720 mg) in the early post-transplant period when co-administered with cyclosporine. PMID- 21299638 TI - Attitudes toward organ donation, moral pluralism, and acculturation in society. PMID- 21299637 TI - Poor compliance with antifungal drug use guidelines by transplant physicians: a framework for educational guidelines and an international consensus on patient safety. AB - The rate of compliance with antifungal drug use guidelines by transplant physicians is mostly unknown. We performed a nationwide electronic survey to assess antifungal use by different types of transplant physicians. Sixty-one percent (53/87) of the transplant programs responded (accounting for 85% of heart transplant procedures, 65% of kidney transplantations, and 71.5% of liver transplantations). Antifungal prophylaxis was used in 41.5% programs (liver 93.3%, heart 30.8%, and kidney 16%). Prophylaxis was universal in 32% of the programs and targeted only to selected patients in 68%, mainly indicated after re transplantation (73.3%), re-intervention (66.7%) and hemodialysis (60%). Main drugs for universal prophylaxis were fluconazole and itraconazole (42.9% each), while fluconazole (60%), L-amphotericin B (AMB), and caspofungin (13.4% each) were preferred for targeted prophylaxis. Overall, 84.9% of the programs used galactomannan for the diagnosis of invasive aspergillosis (only 34% in BAL) and 66.6% used voriconazole as first-line monotherapy. Combination first-line therapy for invasive aspergillosis was used by 31.3%, mainly with voriconazole with caspofungin (40%) or anidulafungin (26.7%) or L-AMB-caspofungin (26.7%). Adherence of transplant physicians to current recommendations on antifungal treatment and prophylaxis is poor. An international consensus that responds to differences in patients and centers and emphasizes patient safety is clearly needed. PMID- 21299639 TI - Urological involvement in renal transplantation. AB - Historically, urologists were the primary surgeons in renal transplantation. Specialization and increased complexity of the field of transplantation, coupled with a de-emphasis of vascular surgical training in urology, has created a situation where many renal transplants are carried out by surgeons with a general surgery background. Because of its genitourinary nature, however, urological input in renal transplantation is still vital. For living donors, a urologist should be involved to help evaluate and prepare certain patients for eventual donation. This could involve both medical and surgical intervention. Additionally, urologists who carry out living donor nephrectomy maintain a sense of ownership in the renal transplant process and provide a unique opportunity to the trainees of that particular program. For renal transplant recipients, preoperative evaluation of voiding dysfunction and other genitourinary anomalies might be necessary before the transplant. Also, occasional surgical intervention to prepare a patient for renal transplant might be necessary, such as in a patient with a small renal mass that is detected by a screening pretransplant ultrasound. Intraoperatively, for patients with complex urological reconstructions that might be related to the etiology of the renal failure (urinary diversion, bladder augmentation), a urologist who is familiar with the anatomy should be available. Postoperatively, urological evaluation and intervention might be necessary for patients who had a pre-existing urological condition or who might have developed something de novo after the transplant. Although renal transplant programs could consult an on-call urologist for particular issues on an as-needed basis, having a urologist, who has repeated exposure to the particular issues and procedures that are involved with renal transplantation, and who is part of a dedicated multidisciplinary renal transplant team, provides optimal quality of care to these complex patients. PMID- 21299640 TI - Robotic bladder diverticulectomy: technique and surgical outcomes. AB - OBJECTIVES: Indications for surgical treatment of bladder diverticula include tumor, lower urinary tract symptoms refractory to medical treatment, renal dysfunction or recurrent urinary tract infections. We describe the technique and report the outcomes of robotic bladder diverticulectomy at our institution. METHODS: A chart review of patients who underwent robotic bladder diverticulectomy at our institution from 2007 to 2010 was carried out. Indications for the procedure were: lower urinary tract symptoms (LUTS) not responding to medical treatment (2 patients), ureteral obstruction (1 patient), tumor arising in a diverticulum (2 patients) and diverticulum secondary to neurogenic bladder (1 patient). One patient also had renal dysfunction associated with ureteral insertion into the diverticulum and therefore underwent ipsilateral ureteroneocystostomy. Other additional procedures included transurethral resection of the prostate (1 patient) and bilateral pelvic lymph node dissection (1 patient). Perioperative and postoperative outcomes were analyzed. RESULTS: Six patients (median age 61.5 years, range 19-75) underwent da Vinci diverticulectomy using a transperitoneal approach without the need for open conversion. Median operative time was 232 min (135-360 min.). Median estimated blood loss was 100 mL (50-150 mL). The Foley catheter was removed after a negative cystogram and median time to catheter removal was 7 days (7-12 days). Median hospital stay was 3 days (2-5 days). The only complication was a urinary tract infection managed with antibiotics. CONCLUSIONS: Robotic surgery represents a reasonable minimally invasive treatment option for resection of bladder diverticula when indicated. PMID- 21299641 TI - Concentration matters!! ppGpp, from a whispering to a strident alarmone. AB - Bacteria have developed sophisticated signal transduction pathways to sense and respond to environmental stresses. These pathways include intracellular regulators that elicit adaptive changes in the physiology of the cell. Extensive work, mostly performed in Escherichia coli, showed that the modified nucleotide ppGpp plays a key regulatory role by co-ordinating the cellular responses to adverse environmental conditions. In this issue of Molecular Microbiology, Traxler et al. define two sets of ppGpp-dependent genes that are expressed at different times after induction of ppGpp synthesis. Their results suggest that quantitative differences in the ppGpp intracellular concentration determine the precise pattern of gene expression during adaptation process: low levels of ppGpp suffice to activate the Lrp regulon, which, by activating the synthesis of some amino acid pathways, can generate a negative feedback loop while high levels activate RpoS and a feed-forward amplification of the general stress response. These dose-dependent effects on gene expression open new perspectives on the complex regulatory pathways mediated by ppGpp during environmental adaptation. PMID- 21299642 TI - Discretely calibrated regulatory loops controlled by ppGpp partition gene induction across the 'feast to famine' gradient in Escherichia coli. AB - Bacteria comprehensively reorganize their global gene expression when faced with starvation. The alarmone ppGpp facilitates this massive response by co-ordinating the downregulation of genes of the translation apparatus, and the induction of biosynthetic genes and the general stress response. Such a large reorientation requires the activities of multiple regulators, yet the regulatory network downstream of ppGpp remains poorly defined. Transcription profiling during isoleucine depletion, which leads to gradual starvation (over > 100 min), allowed us to identify genes that required ppGpp, Lrp and RpoS for their induction and to deduce the regulon response times. Although the Lrp and RpoS regulons required ppGpp for their activation, they were not induced simultaneously. The data suggest that metabolic genes, i.e. those of the Lrp regulon, require only a low level of ppGpp for their induction. In contrast, the RpoS regulon was induced only when high levels of ppGpp accumulated. We tested several predictions of a model that explains how bacteria allocate transcriptional resources between metabolism and stress response by discretely tuning two regulatory circuits to different levels of ppGpp. The emergent regulatory structure insures that stress survival circuits are only triggered if homeostatic metabolic networks fail to compensate for environmental deficiencies. PMID- 21299643 TI - The DNA-binding activity of the Neisseria gonorrhoeae LexA orthologue NG1427 is modulated by oxidation. AB - Neisseria gonorrhoeae is a human-specific organism that is not usually exposed to UV light or chemicals but is likely to encounter reactive oxygen species during infection. Exposure of N. gonorrhoeae to sublethal hydrogen peroxide revealed that the ng1427 gene was upregulated sixfold. N. gonorrhoeae was thought to lack an SOS system, although NG1427 shows amino acid sequence similarity to the SOS response regulator LexA from Escherichia coli. Similar to LexA and other S24 peptidases, NG1427 undergoes autoproteolysis in vitro, which is facilitated by either the gonococcal or E. coli RecA proteins or high pH, and autoproteolysis requires the active and cleavage site residues conserved between LexA and NG1427. NG1427 controls a three gene regulon: itself; ng1428, a Neisseria-specific, putative integral membrane protein; and recN, a DNA repair gene known to be required for oxidative damage survival. Full NG1427 regulon de-repression requires RecA following methyl methanesulphonate or mitomycin C treatment, but is largely RecA-independent following hydrogen peroxide treatment. NG1427 binds specifically to the operator regions of the genes it controls, and DNA binding is abolished by oxidation of the single cysteine residue encoded in NG1427. We propose that NG1427 is inactivated independently of RecA by oxidation. PMID- 21299644 TI - Genetic mapping of the interface between the ArsD metallochaperone and the ArsA ATPase. AB - The ArsD metallochaperone delivers trivalent metalloids, As(III) or Sb(III), to the ArsA ATPase, the catalytic subunit of the ArsAB As(III) efflux pump. Transfer of As(III) increases the affinity of ArsA for As(III), allowing resistance to environmental arsenic concentrations. As(III) transfer is channelled from chaperone to ATPase, implying that ArsD and ArsA form an interface at their metal binding sites. A genetic approach was used to test this hypothesis. Thirteen ArsD mutants exhibiting either weaker or stronger interaction with ArsA were selected by either repressed transactivator yeast two-hybrid or reverse yeast two-hybrid assays. Additionally, Lys-37 and Lys-62 were identified as being involved in ArsD function by site-directed mutagenesis and chemical modification. Substitution at either position with arginine was tolerated, suggesting participation of a positive charge. By yeast two-hybrid analysis K37A and K62A mutants lost interaction with ArsA. All 15 mutations were mapped on the surface of the ArsD structure, and their locations are consistent with a structural model generated by in silico docking. Four are close to metalloid binding site residues Cys-12, Cys-13 and Cys-18, and seven are on the surface of helix 1. These results suggest that the interface involves one surface of helix 1 and the metalloid binding site. PMID- 21299645 TI - CcpA-mediated repression of Clostridium difficile toxin gene expression. AB - The presence of glucose or other rapidly metabolizable carbon sources in the bacterial growth medium strongly represses Clostridium difficile toxin synthesis independently of strain origin. In Gram-positive bacteria, carbon catabolite repression (CCR) is generally regarded as a regulatory mechanism that responds to carbohydrate availability. In the C. difficile genome all elements involved in CCR are present. To elucidate in vivo the role of CCR in C. difficile toxin synthesis, we used the ClosTron gene knockout system to construct mutants of strain JIR8094 that were unable to produce the major components of the CCR signal transduction pathway: the phosphotransferase system (PTS) proteins (Enzyme I and HPr), the HPr kinase/phosphorylase (HprK/P) and the catabolite control protein A, CcpA. Inactivation of the ptsI, ptsH and ccpA genes resulted in derepression of toxin gene expression in the presence of glucose, whereas repression of toxin production was still observed in the hprK mutant, indicating that uptake of glucose is required for repression but that phosphorylation of HPr by HprK is not. C. difficile CcpA was found to bind to the regulatory regions of the tcdA and tcdB genes but not through a consensus cre site motif. Moreover in vivo and in vitro results confirmed that HPr-Ser45-P does not stimulate CcpA-dependent binding to DNA targets. However, fructose-1,6-biphosphate (FBP) alone did increase CcpA binding affinity in the absence of HPr-Ser45-P. These results showed that CcpA represses toxin expression in response to PTS sugar availability, thus linking carbon source utilization to virulence gene expression in C. difficile. PMID- 21299646 TI - A novel role for a glycosylphosphatidylinositol-anchored aspartyl protease, CgYps1, in the regulation of pH homeostasis in Candida glabrata. AB - Proteases, key virulence factors of many bacterial and fungal pathogens, are pivotally important for nutrient acquisition, invasion and adherence to host cells and evasion/escape from host immune cells. In this study, we report a novel role for CgYps1, member of a family of 11 GPI-linked aspartyl proteases, in a human opportunistic fungal pathogen, Candida glabrata, in the regulation of pH homeostasis under acidic environmental conditions. We show that CgYps1 is required to survive low-external-pH environment and the inability of Cgyps1Delta mutant to maintain pH homeostasis results in intracellular acidification and increased reactive oxygen species (ROS) production. We also provide evidence that the reduced intracellular pH in Cgyps1Delta mutant under acidic conditions is, partly, owing to the diminished activity of a plasma membrane proton pump, CgPma1, an orthologue of a key component of pH homeostasis machinery in Saccharomyces cerevisiae, Pma1. In addition, we have examined C. glabrata's response to low environmental pH via genome-wide expression analysis and several genes required for protein folding/modification and stress response pathways including seven of the CgYPS genes were found to be upregulated. Lastly, we show that C. glabrata responds to acidic environment by reducing total beta-glucan levels in the cell wall in a CgYps1-dependent manner. PMID- 21299647 TI - Suppressors of DnaA(ATP) imposed overinitiation in Escherichia coli. AB - Chromosome replication in Escherichia coli is limited by the supply of DnaA associated with ATP. Cells deficient in RIDA (Regulatory Inactivation of DnaA) due to a deletion of the hda gene accumulate suppressor mutations (hsm) to counteract the overinitiation caused by an elevated DnaA(ATP) level. Eight spontaneous hda suppressor mutations were identified by whole-genome sequencing, and three of these were analysed further. Two mutations (hsm-2 and hsm-4) mapped in the dnaA gene and led to a reduced ability to initiate replication from oriC. One mutation (hsm-1) mapped to the seqA promoter and increased the SeqA protein level in the cell. hsm-1 cells had prolonged origin sequestration, reduced DnaA protein level and reduced DnaA-Reactivating Sequence (DARS)-mediated rejuvenation of DnaA(ADP) to DnaA(ATP) , all of which could contribute to the suppression of RIDA deficiency. Despite of these defects hsm-1 cells were quite similar to wild type with respect to cell cycle parameters. We speculate that since SeqA binding sites might overlap with DnaA binding sites spread throughout the chromosome, excess SeqA could interfere with DnaA titration and thereby increase free DnaA level. Thus, in spite of reduction in total DnaA, the amount of DnaA molecules available for initiation may not be reduced. PMID- 21299648 TI - SAP1 is a critical post-transcriptional regulator of infectivity in malaria parasite sporozoite stages. AB - Plasmodium salivary gland sporozoites upregulate expression of a unique subset of genes, collectively called the UIS (upregulated in infectious sporozoites). Many UIS were shown to be essential for early liver stage development, although little is known about their regulation. We previously identified a conserved sporozoite specific protein, SAP1, which has an essential role in Plasmodium liver infection. Targeted deletion of SAP1 in Plasmodium yoelii caused the depletion of a number of selectively tested UIS transcripts in sporozoites, resulting in a complete early liver stage arrest. Here, we use a global gene expression survey to more comprehensively identify transcripts that are affected by SAP1 deletion. We find an effect upon both the transcript abundance of UIS genes, as well as of select genes previously not grouped as UIS. Importantly, we show that the lack of SAP1 causes the specific degradation of these transcripts. Collectively, our data suggest that SAP1 is involved in a selective post-transcriptional mechanism to regulate the abundance of transcripts critical to the infectivity of sporozoites. Although Pysap1(-) sporozoites are depleted of many of these important transcripts, they confer long-lasting sterile protection against wild-type sporozoite challenge in mice. SAP1 is therefore an appealing candidate locus for attenuation of Plasmodium falciparum. PMID- 21299649 TI - The zinc cluster transcription factor Ahr1p directs Mcm1p regulation of Candida albicans adhesion. AB - Biofilm development by Candida albicans requires cell adhesion for the initial establishment of the biofilm and the continued stability after hyphal development occurs; however, the regulation of the process has not been fully established. Using chromatin immunoprecipitation coupled to microarray analysis (ChIP-chip) we have characterized a regulon containing the Mcm1p factor that is required for the initial surface adhesion during biofilm formation. In the yeast Saccharomyces cerevisiae several Mcm1p regulons have been characterized in which regulatory specificity is achieved through cofactors binding a sequence adjacent to the Mcm1p binding site. This new Mcm1p regulon in C. albicans also requires a cofactor, which we identify as the transcription factor Ahr1p. However, in contrast to the other yeast regulons, Ahr1p alone binds the target promoters, which include several key adhesion genes, and recruits Mcm1p to these sites. Through transcription profiling and qPCR analysis, we demonstrate that this Ahr1p Mcm1p complex directly activates these adhesion genes. When the regulatory circuit was disrupted by deleting AHR1, the strain displayed reduced adherence to a polystyrene surface. We also demonstrate a role for the regulon in hyphal growth and in virulence. Our work thus establishes a new mechanism of Mcm1p directed regulation distinct from those observed for other Mcm1p co-regulators. PMID- 21299650 TI - Function of the usher N-terminus in catalysing pilus assembly. AB - The chaperone/usher (CU) pathway is a conserved bacterial secretion system that assembles adhesive fibres termed pili or fimbriae. Pilus biogenesis by the CU pathway requires a periplasmic chaperone and an outer membrane (OM) assembly platform termed the usher. The usher catalyses formation of subunit-subunit interactions to promote polymerization of the pilus fibre and provides the channel for fibre secretion. The mechanism by which the usher catalyses pilus assembly is not known. Using the P and type 1 pilus systems of uropathogenic Escherichia coli, we show that a conserved N-terminal disulphide region of the PapC and FimD ushers, as well as residue F4 of FimD, are required for the catalytic activity of the ushers. PapC disulphide loop mutants were able to bind PapDG chaperone-subunit complexes, but did not assemble PapG into pilus fibres. FimD disulphide loop and F4 mutants were able to bind chaperone-subunit complexes and initiate assembly of pilus fibres, but were defective for extending the pilus fibres, as measured using in vivo co-purification and in vitro pilus polymerization assays. These results suggest that the catalytic activity of PapC is required to initiate pilus biogenesis, whereas the catalytic activity of FimD is required for extension of the pilus fibre. PMID- 21299652 TI - Insertional mutagenesis combined with an inducible filamentation phenotype reveals a conserved STE50 homologue in Cryptococcus neoformans that is required for monokaryotic fruiting and sexual reproduction. AB - Cryptococcus neoformans typically grows in a yeast-like morphology; however, under specific conditions the fungus can produce hyphae that are either dikaryotic or monokaryotic. In this study, we developed a simple method for inducing robust monokaryotic fruiting and combined the assay with Agrobacterium tumefaciens insertional mutagenesis to screen for hyphal mutants. A C. neoformans homologue of the Saccharomyces cerevisiae STE50 gene was identified and characterized. STE50 was found to be required for sexual reproduction and monokaryotic fruiting. Ste50p has conserved SAM and RA domains, as well as two SH3 domains specific to basidiomycetous Ste50 proteins. Analysis of protein protein interaction showed that Ste50p can interact with Ste11p and Ste20p, and epistasis experiments placed STE50 between STE20 and STE11. Genetic analysis of the role of STE50 in sexual reproduction showed that it was required for all steps, from response to pheromone to production of hyphae. Analysis of the effect of individual Ste50p domains on sexual reproduction and monokaryotic fruiting revealed domain-specific effects for both processes. This study revealed that the C. neoformans STE50 gene has both conserved and novel functions during sexual reproduction and monokaryotic fruiting, and these functions are domain-dependent. PMID- 21299651 TI - Cell wall integrity is linked to mitochondria and phospholipid homeostasis in Candida albicans through the activity of the post-transcriptional regulator Ccr4 Pop2. AB - The cell wall is essential for viability of fungi and is an effective drug target in pathogens such as Candida albicans. The contribution of post-transcriptional gene regulators to cell wall integrity in C. albicans is unknown. We show that the C. albicans Ccr4-Pop2 mRNA deadenylase, a regulator of mRNA stability and translation, is required for cell wall integrity. The ccr4/pop2 mutants display reduced wall beta-glucans and sensitivity to the echinocandin caspofungin. Moreover, the deadenylase mutants are compromised for filamentation and virulence. We demonstrate that defective cell walls in the ccr4/pop2 mutants are linked to dysfunctional mitochondria and phospholipid imbalance. To further understand mitochondrial function in cell wall integrity, we screened a Saccharomyces cerevisiae collection of mitochondrial mutants. We identify several mitochondrial proteins required for caspofungin tolerance and find a connection between mitochondrial phospholipid homeostasis and caspofungin sensitivity. We focus on the mitochondrial outer membrane SAM complex subunit Sam37, demonstrating that it is required for both trafficking of phospholipids between the ER and mitochondria and cell wall integrity. Moreover, in C. albicans also Sam37 is essential for caspofungin tolerance. Our study provides the basis for an integrative view of mitochondrial function in fungal cell wall biogenesis and resistance to echinocandin antifungal drugs. PMID- 21299653 TI - Repression of ergosterol biosynthesis is essential for stress resistance and is mediated by the Hog1 MAP kinase and the Mot3 and Rox1 transcription factors. AB - Hyperosmotic stress triggers a complex adaptive response that is dominantly regulated by the Hog1 MAP kinase in yeast. Here we characterize a novel physiological determinant of osmostress tolerance, which involves the Hog1 dependent transcriptional downregulation of ergosterol biosynthesis genes (ERG). Yeast cells considerably lower their sterol content in response to high osmolarity. The transcriptional repressors Mot3 and Rox1 are essential for this response. Both factors together with Hog1 are required to rapidly and transiently shut down transcription of ERG2 and ERG11 upon osmoshock. Mot3 abundance and its binding to the ERG2 promoter is stimulated by osmostress in a Hog1-dependent manner. As an additional layer of control, the expression of the main transcriptional activator of ERG gene expression, Ecm22, is negatively regulated by Hog1 and Mot3/Rox1 upon salt shock. Oxidative stress also triggers repression of ERG2, 11 transcription and a profound decrease in total sterol levels. However, this response was only partially dependent on Mot3/Rox1 and Hog1. Finally, we show that the upc2-1 mutation confers stress insensitive hyperaccumulation of ergosterol, overexpression of ERG2, 11 and severe sensitivity to salt and oxidative stress. Our results indicate that transcriptional control of ergosterol biosynthesis is an important physiological target of stress signalling. PMID- 21299655 TI - Functional dissection of the three-domain SepJ protein joining the cells in cyanobacterial trichomes. AB - Heterocyst-forming cyanobacteria grow as filaments of cells (trichomes) in which, under nitrogen limitation, two interdependent cell types, the vegetative cells performing oxygenic photosynthesis and the nitrogen-fixing heterocysts, exchange metabolites and regulatory compounds. SepJ is a protein conspicuously located at the cell poles in the intercellular septa of the filaments that has three well defined domains: an N-terminal coiled-coil domain, a central linker and a C terminal permease domain. Mutants of Anabaena sp. strain PCC 7120 carrying SepJ proteins with specific deletions showed that, whereas the linker domain is dispensable, the coiled-coil domain is required for polar localization of SepJ, filament integrity, normal intercellular transfer of small fluorescent tracers and diazotrophy. An Anabaena strain carrying the SepJ protein from the filamentous, non-heterocyst-forming cyanobacterium Trichodesmium erythraeum, which lacks the linker domain, made long filaments in the presence of combined nitrogen but fragmented extensively under nitrogen deprivation and did not grow diazotrophically. In contrast, a chimera made of the Trichodesmium coiled-coil domain and the Anabaena permease allowed heterocyst differentiation and diazotrophic growth. Thus, SepJ provides filamentous cyanobacteria with a cell cell anchoring function, but the permease domain has evolved in heterocyst formers to provide intercellular molecular exchange functions required for diazotrophy. PMID- 21299656 TI - Cone arrestin confers cone vision of high temporal resolution in zebrafish larvae. AB - Vision of high temporal resolution depends on careful regulation of photoresponse kinetics, beginning with the lifetime of activated photopigment. The activity of rhodopsin is quenched by high-affinity binding of arrestin to photoexcited phosphorylated photopigment, which effectively terminates the visual transduction cascade. This regulation mechanism is well established for rod photoreceptors, yet its role for cone vision is still controversial. In this study we therefore analyzed arrestin function in the cone-dominated vision of larval zebrafish. For both rod (arrS ) and cone (arr3 ) arrestin we isolated two paralogs, each expressed in the respective subset of photoreceptors. Labeling with paralog specific antibodies revealed subfunctionalized expression of Arr3a in M- and L cones, and Arr3b in S- and UV-cones. The inactivation of arr3a by morpholino knockdown technology resulted in a severe delay in photoresponse recovery which, under bright light conditions, was rate-limiting. Comparison to opsin phosphorylation-deficient animals confirmed the role of cone arrestin in late cone response recovery. Arr3a activity partially overlapped with the function of the cone-specific kinase Grk7a involved in initial response recovery. Behavioral measurements further revealed Arr3a deficiency to be sufficient to reduce temporal contrast sensitivity, providing evidence for the importance of arrestin in cone vision of high temporal resolution. PMID- 21299654 TI - Chromosomal instability in enterohaemorrhagic Escherichia coli O157:H7: impact on adherence, tellurite resistance and colony phenotype. AB - Tellurite (Tel) resistant enterohaemorrhagic Escherichia coli (EHEC) O157:H7 is a global pathogen. In strain EDL933 Tel resistance (Tel(R) ) is encoded by duplicate ter cluster in O islands (OI) 43 and 48, which also harbour iha, encoding the adhesin and siderophore receptor Iha. We identified five EHEC O157:H7 strains that differentiate into large (L) colonies and small (S) colonies with high and low Tel minimal inhibitory concentrations (MICs) respectively. S colonies (Tel-MICs <= 4 ug ml-1) sustained large internal deletions within the Tel(R) OIs via homologous recombination between IS elements and lost ter and iha. Moreover, complete excision of the islands occurred by site-specific recombination between flanking direct repeats. Complete excision of OI 43 and OI 48 occurred in 1.81 * 10-3 and 1.97 * 10-4 cells in culture, respectively; internal deletion of OI 48 was more frequent (9.7 * 10-1 cells). Under iron limitation that promotes iha transcription, iha-negative derivatives adhered less well to human intestinal epithelial cells and grew slower than did their iha positive counterparts. Experiments utilizing iha deletion and complementation mutants identified Iha as the major factor responsible for these phenotypic differences. Spontaneous deletions affecting Tel(R) OIs contribute to EHEC O157 genome plasticity and might impair virulence and/or fitness. PMID- 21299657 TI - Glucocorticoid-mediated nycthemeral and photoperiodic regulation of tph2 expression. AB - In the Syrian hamster dorsal and median raphe nuclei, the tryptophan hydroxylase 2 gene (tph2), which codes the rate-limiting enzyme of serotonin synthesis, displays daily variations in its expression in animals entrained to a long but not to a short photoperiod. The present study aimed to assess the role of glucocorticoids in the nycthemeral and photoperiodic regulation of daily tph2 expression. In hamsters held in long photoperiod from birth, after adrenalectomy and glucocorticoid implants the suppression of glucocorticoid rhythms induced an abolition of the daily variations in tph2-mRNA concentrations, a decrease in the amplitude of body temperature rhythms and an increase in testosterone levels. All these effects were reversed after experimental restoration of a clear daily rhythm in the plasma glucocorticoid concentrations. We conclude that the photoperiod-dependent rhythm of glucocorticoids is the main regulator of tph2 daily expression. PMID- 21299658 TI - The pepper receptor-like cytoplasmic protein kinase CaPIK1 is involved in plant signaling of defense and cell-death responses. AB - Certain protein kinases have been shown to be crucial for plant cell signaling pathways associated with plant immune responses. Here we identified a pepper (Capsicum annuum) receptor-like cytoplasmic protein kinase (RLCK) gene (CaPIK1) that is transcriptionally activated by infection with Xanthomonas campestris pv. vesicatoria (Xcv). Silencing of CaPIK1 in pepper plants confers enhanced susceptibility to Xcv infection. Salicylic acid-dependent defense responses are attenuated in the CaPIK1-silenced plants, including expression of salicylic acid dependent genes, but not of a jasmonic acid-regulated gene. Induction of salicylic acid accumulation by Xcv infection is compromised in CaPIK1-silenced plants. The functional CaPIK1 protein not only autophosphorylates, but also phosphorylates myelin basic protein. CaPIK1 exists in the cytoplasm and also localizes to the plasma membrane of plant cells via its N-terminus. Transient expression of CaPIK1 in pepper leaves leads to generation of reactive oxygen species (ROS), ultimately leading to hypersensitive cell death. Over-expression (OX) of CaPIK1 in Arabidopsis enhances the basal resistance to infection with Pseudomonas syringae pv. tomato and Hyaloperonospora arabidopsidis, associated with elevated ROS bursts. Salicylic acid levels in CaPIK1-OX plants are higher than those in wild-type plants. Together, these results suggest that CaPIK1 modulates the signaling required for the salicylic acid-dependent defense response to pathogen infection. PMID- 21299659 TI - Genome-wide atlas of transcription during maize development. AB - Maize is an important model species and a major constituent of human and animal diets. It has also emerged as a potential feedstock and model system for bioenergy research due to recent worldwide interest in developing plant biomass based, carbon-neutral liquid fuels. To understand how the underlying genome sequence results in specific plant phenotypes, information on the temporal and spatial transcription patterns of genes is crucial. Here we present a comprehensive atlas of global transcription profiles across developmental stages and plant organs. We used a NimbleGen microarray containing 80,301 probe sets to profile transcription patterns in 60 distinct tissues representing 11 major organ systems of inbred line B73. Of the 30,892 probe sets representing the filtered B73 gene models, 91.4% were expressed in at least one tissue. Interestingly, 44.5% of the probe sets were expressed in all tissues, indicating a substantial overlap of gene expression among plant organs. Clustering of maize tissues based on global gene expression profiles resulted in formation of groups of biologically related tissues. We utilized this dataset to examine the expression of genes that encode enzymes in the lignin biosynthetic pathway, and found that expansion of distinct gene families was accompanied by divergent, tissue-specific transcription patterns of the paralogs. This comprehensive expression atlas represents a valuable resource for gene discovery and functional characterization in maize. PMID- 21299660 TI - Chinese primiparous women's experiences of early motherhood: factors affecting maternal role competence. AB - AIM: The aim of this study was to explore Chinese women's perceptions of maternal role competence and factors contributing to maternal role competence during early motherhood. BACKGROUND: Developing a sense of competence and satisfaction in the maternal role are considered critical components in maternal adaptation, which have a significant impact on parenting behaviours and the psychosocial development of the child. However, qualitative studies that address maternal role competence are limited in the Chinese population. DESIGN: This was an exploratory descriptive study. METHOD: A purposive sample of 26 Chinese primiparous mothers participated in a childbirth psychoeducation programme and was interviewed at six weeks postpartum. Data were analysed using content analysis. RESULTS: Women perceived a competent mother as being able to make a commitment to caring for the physical and emotional well-being of child, while cultivating appropriate values for childhood. Personal knowledge and experience of infant care, success in breastfeeding, infant's well-being, availability of social support and contradictory information from various sources were major factors affecting maternal role competency. CONCLUSION: The findings highlight the importance of understanding Chinese cultural attitudes to childrearing and maternal role competence. New Chinese mothers need information on child care, positive experiences of infant care, social support and consistent information to enhance their maternal role competency. Recommendations are made for Chinese culturally specific guidelines and healthcare delivery interventions to enhance maternal role competence in early motherhood. RELEVANCE TO CLINICAL PRACTICE: Nursing and midwifery care should always take into account the cultural beliefs and enable adaptation of traditional postpartum practices. Providing consistent information and positive experience on parenting skills and infant behaviour as well as enhancing effective coping strategies could strengthen Chinese women's maternal role competency. PMID- 21299661 TI - Potential for evolutionary coupling and decoupling of larval and adult immune gene expression. AB - Almost all studies of the immune system of animals with metamorphosis have focused on either larval or on adult immunity, implicitly assuming that these traits are either perfectly correlated or evolutionarily independent. In this study, we use 80 crosses among 21 Drosophila melanogaster lines to investigate the degree and constancy of genetic correlation in immune system activity between larvae and adults. The constitutive transcription of Diptericin, a gene encoding a defensive antimicrobial peptide, was controlled by the same genetic factors in larvae and adults, with variation in expression determined exclusively by nonadditive genetic effects. This contrasted with another peptide-encoding gene, Drosomycin, in which larval transcription was highly variable and determined by additive effects but adult transcription genetically invariant. We found no evidence for a fitness cost to the transcription of these genes in our study. The shared genetic control of larval and adult Diptericin transcription stands in contrast to predictions of the adaptive decoupling hypothesis, which states that distinct life-stages should permit the independent evolution of larval and adult phenotypes. Importantly, genetic correlations between larval and adult immunities imply that parasite pressure on one life-stage can drive the evolution of immunity (and resistance) in the other life-stage. PMID- 21299662 TI - All roads lead to home: panmixia of European eel in the Sargasso Sea. AB - European eels (Anguilla anguilla) spawn in the remote Sargasso Sea in partial sympatry with American eels (Anguilla rostrata), and juveniles are transported more than 5000 km back to the European and North African coasts. The two species have been regarded as classic textbook examples of panmixia, each comprising a single, randomly mating population. However, several recent studies based on continental samples have found subtle, but significant, genetic differentiation, interpreted as geographical or temporal heterogeneity between samples. Moreover, European and American eels can hybridize, but hybrids have been observed almost exclusively in Iceland, suggesting hybridization in a specific region of the Sargasso Sea and subsequent nonrandom dispersal of larvae. Here, we report the first molecular population genetics study based on analysis of 21 microsatellite loci in larvae of both Atlantic eel species sampled directly in the spawning area, supplemented by analysis of European glass eel samples. Despite a clear East-West gradient in the overlapping distribution of the two species in the Sargasso Sea, we only observed a single putative hybrid, providing evidence against the hypothesis of a wide marine hybrid zone. Analyses of genetic differentiation, isolation by distance, isolation by time and assignment tests provided strong evidence for panmixia in both the Sargasso Sea and across all continental samples of European eel after accounting for the presence of sibs among newly hatched larvae. European eel has declined catastrophically, and our findings call for management of the species as a single unit, necessitating coordinated international conservation efforts. PMID- 21299664 TI - Alcohol marketing research: the need for a new agenda. AB - AIMS: This paper aims to contribute to a rethink of marketing research priorities to address policy makers' evidence needs in relation to alcohol marketing. METHOD: Discussion paper reviewing evidence gaps identified during an appraisal of policy options to restrict alcohol marketing. FINDINGS: Evidence requirements can be categorized as follows: (i) the size of marketing effects for the whole population and for policy-relevant population subgroups, (ii) the balance between immediate and long-term effects and the time lag, duration and cumulative build up of effects and (iii) comparative effects of partial versus comprehensive marketing restrictions on consumption and harm. These knowledge gaps impede the appraisal and evaluation of existing and new interventions, because without understanding the size and timing of expected effects, researchers may choose inadequate time-frames, samples or sample sizes. To date, research has tended to rely on simplified models of marketing and has focused disproportionately on youth populations. The effects of cumulative exposure across multiple marketing channels, targeting of messages at certain population groups and indirect effects of advertising on consumption remain unclear. CONCLUSION: It is essential that studies into marketing effect sizes are geared towards informing policy decision makers, anchored strongly in theory, use measures of effect that are well justified and recognize fully the complexities of alcohol marketing efforts. PMID- 21299665 TI - Do alcohol portrayals in movies and commercials directly affect consumption? PMID- 21299666 TI - New approaches to alcohol marketing research. PMID- 21299667 TI - It's not just researchers who need a new agenda. PMID- 21299668 TI - Alcohol marketing research agenda-let us look at how the industry maintains its hegemony. PMID- 21299669 TI - Advertising research-calls for an even more ambitious agenda? PMID- 21299670 TI - Commentary on Phillips et al. (2011): Alcohol and SIDS - a cause-effect association? PMID- 21299671 TI - Commentary on Kraft et al. (2011): Treatment of neonatal abstinence syndrome - morphine, buprenorphine and beyond. PMID- 21299672 TI - Commentary on Shand et al. (2011): Opioid use disorder as a condition of graded severity, similar to other substance use disorders. PMID- 21299673 TI - Commentary on Ross et al. (2011): Beyond cigarette taxes - the need for research on other cigarette pricing policies. PMID- 21299674 TI - Commentary on Fidler et al. (2011): Identifying quitters who are at increased risk of relapse - where to from here? PMID- 21299675 TI - Commentary on Lopez-Quintero et al. (2011): Remission and relapse - the Yin-Yang of addictive disorders. PMID- 21299676 TI - Leonard Goldberg (1911-2010) - occupant of the first university chair in alcohol research. PMID- 21299679 TI - Believing in nicotine addiction: does it really make quitting more likely? PMID- 21299680 TI - Does belief that one is addicted promote or deter attempts at abstinence? PMID- 21299681 TI - Preventing venous thrombosis in critically ill children: what is the right approach? AB - BACKGROUND: The incidence of venous thromboembolic (VTE) events in children has increased in recent years (J Neurosurg, 101, 2004, 32; J Thromb Haemost, 1, 2003, 1443) yet there is currently no consensus as to what VTE prophylaxis, if any, should be applied to the pediatric population. OBJECTIVES/AIMS: Our aim was to audit current practice in pediatric VTE prophylaxis across England and Wales and to advocate simple measures for prevention. We illustrate the importance of the condition with a series of cases from the South West Paediatric Burns and Neurosurgical Services based in Bristol. METHODS: Every pediatric intensive care unit (PICU) and burns center admitting children in England and Wales was invited to participate in a structured telephone questionnaire designed to find out how VTE in children were being prevented. We performed a literature review of specific risk factors and management of these factors. RESULTS: Only one of the 24 units surveyed had written guidelines specific for children. Four other units used modified adult guidelines in older children. In the remaining 19 units that had no written guidelines, decisions regarding prophylaxis were based on individual cases and consultant-led. CONCLUSION: There is no consensus in England and Wales as to which VTE prophylactic measures should be applied in patients <18 years of age. The National Institute for Health and Clinical Excellence (NICE) guidelines apply to adults only. Given the rarity of VTE events in children, it is unlikely that randomized controlled trials will provide the answer. We therefore propose that simple empirical measures be formally implemented in critically ill children to reduce the risk of developing this important but under recognized condition. PMID- 21299682 TI - An audit of laryngoscopes and application of a new ISO standard. AB - OBJECTIVE: The International Organization for Standardization (ISO) recently published an International Standard (ISO 7376:2009) which specifies illuminance levels and tests for illumination from hook-on type laryngoscopes used for intubation. A clinical study examining luminance for laryngoscopy found that 100 cd.m(-2) was the minimum level acceptable for laryngoscopy. The purpose of this study was to measure the quality of light from laryngoscopes available for use by anesthetists in an anesthetic department and compare them to the ISO illuminance standard and published minimum acceptable luminance limits. METHODS: A measuring device was constructed to support each laryngoscope in a standardized manner. For 190 reusable laryngoscopes, illuminance was measured with a lux meter at the base of this device. Eighteen clinically available laryngoscopes were then examined in detail, as a snapshot study, with multiple light recordings according to the ISO Standard. We also measured the luminance provided by each laryngoscope. RESULTS: Only two of the 18 laryngoscopes met the minimum illuminance level of 500 lux after 10 min. Nine laryngoscopes provided a luminance <100 cd.m(-2), which is the reported minimum required luminance for laryngoscopy. None of the 18 laryngoscopes tested complied with the ISO standard for laryngoscope light distribution. CONCLUSIONS: Laryngoscope light should be regularly audited. Results from these audits can be used to retire or repair substandard laryngoscopes to maintain acceptable standards of laryngoscope light. Audit results produce tangible evidence that is useful when applying for capital expenditure. Light measurements are not easy to make. There needs to be a convenient device to reliably measure laryngoscope illumination. PMID- 21299683 TI - Anesthesia can be safely provided for children in a high-field intraoperative magnetic resonance imaging environment. AB - OBJECTIVES: To describe the challenges associated with providing safe anesthesia and perioperative care for children in a remote intraoperative magnetic resonance (iMR) operating room (OR) and to identify perioperative anesthesia outcomes, including adverse events related to the iMR environment. BACKGROUND: Increasingly, children undergo neurosurgical procedures in a high-field iMR OR. We describe a 10-year experience of providing anesthesia for children in this environment with a mobile 1.5-Tesla magnet. METHODS: A 10-year retrospective analysis was conducted of children who underwent neurosurgical procedures in a high-field mobile iMR OR. Primary outcomes related to perioperative adverse events and recovery profiles. Results were expressed as mean +/- sd or median (range), as appropriate. RESULTS: One hundred and five procedures were performed on 98 children, aged 4 months-18 years, weighing 6-112 kg. The commonest two diagnostic categories were tumor (n = 52) and seizures (n = 27). Median anesthetic time was 439 (185-710) mins. There were no significant adverse events related to the iMR environment. The mean postanesthetic care unit admission temperature was 37 +/- 0.9 degrees C and the mean modified Aldrete Score at 30 mins was 7.2 +/- 0.9. Two patients experienced seizures in the immediate postoperative period, readily controlled with propofol. There was one breach of MR safety protocol, and no adverse events related to patient transport. CONCLUSIONS: Anesthesia and perioperative care of children in an iMR setting were associated with a very low incidence of complications, despite the duration of the procedures involved. Such success depends upon a cohesive team-based approach. PMID- 21299684 TI - Effect of caudal block on sevoflurane requirement for lower limb surgery in children with cerebral palsy. AB - BACKGROUND: Caudal block is a widely used technique for providing perioperative pain management in children. In this randomized double-blinded study, we evaluated the effects of preoperative caudal block on sevoflurane requirements in children with cerebral palsy (CP) undergoing lower limb surgery while bispectral index (BIS) values were maintained between 45 and 55. METHODS: 52 children undergoing Achilles-tendon lengthening were randomized to receive combined general-caudal anesthesia (caudal group, n = 27) or general anesthesia alone (control group, n = 25). Caudal block was performed with a single dose of 0.7 ml.kg(-1) of 1.0% lidocaine containing epinephrine at 5 MUg.ml(-1). The control group received no preoperative caudal block. The endtidal sevoflurane concentrations (ET(sev)) were adjusted every minute to maintain the BIS values between 45 and 55. RESULTS: The ET(sev) required to maintain the BIS values were not significantly different between the control and caudal groups after induction of anesthesia [2.1 (0.2) vs 2.2 (0.4); P = 0.773]. However, significantly higher ET(sev) was observed in the control group before surgical incision [2.0 (0.2) vs 1.8 (0.3); P = 0.013] and during the first 20 min after surgical incision [2.2 (0.3) vs 1.4 (0.3); P < 0.001]. There was no significant difference in BIS values between the control and caudal groups throughout the study period (P > 0.05). In the caudal group, the caudal block was successful in 25 of 27 (92.6%) patients. CONCLUSIONS: Caudal block effectively reduced sevoflurane requirements by 36% compared to general anesthesia alone in children with CP undergoing lower limb surgery while BIS values were maintained between 45 and 55. PMID- 21299685 TI - A survey of blood transfusion practice in French-speaking pediatric anesthesiologists. AB - BACKGROUND: There are so far no existing consensus guidelines regarding red blood cell transfusion during pediatric surgery, and there is a little information regarding red blood cell transfusion policy among pediatric anesthesiologists. OBJECTIVES: To determine the transfusion threshold and the volumes of packed red blood cell (PRBC) transfusion among French-speaking pediatric anesthesiologists. MATERIALS AND METHODS: A questionnaire of case scenarios was sent to active members of the French Language Society of Pediatrics Anesthesiologists (ADARPEF). RESULTS: Of the 324 active members of the ADARPEF, 175 (54%) completed the questionnaire. The threshold for blood transfusion varied from 6 to 12 g.dl(-1) depending on the scenario. The hemoglobin threshold for blood transfusion and the volume of blood transfused vary among ADARPEF physicians, for the same class of patients. The median [95% CI] hemoglobin threshold for starting blood transfusion was 7.9 [6.9-8.9], 7.3 [6.4-8.2], and 8.1 [7.0-9.2] g.dl(-1) in the pre-, intra-, and postoperative phase, respectively. The median [95% CI] PRBC volume transfused was 11.7 [6.6-16.8] ml.kg(-1), and the median hemoglobin target was 11.3 [9.8 12.8] g.dl(-1). Physicians ranked age (79%), clinical tolerance of anemia (99%), underlying medical conditions (95%), hemodynamic instability (89%), hemostasis disorder (86%), and sepsis (79%) as the most significant factors affecting their transfusion decisions. Most pediatric anesthesiologists (89%) measure the hemoglobin level before PRBC transfusion. CONCLUSIONS: This survey identifies significant differences in transfusion practice patterns among pediatric anesthesiologists with a median transfusion threshold of 7.6 [6.6-8.6] g.dl(-1) and a median PRBC volume transfusion of 11.7 [16.8-6.6] ml.kg(-1). PMID- 21299686 TI - Diagnostic accuracy of T-cell interferon-gamma release assays in tuberculous pleurisy: a meta-analysis. AB - BACKGROUND AND OBJECTIVE: The diagnosis of tuberculous pleurisy by analysis of pleural fluid using standard diagnostic tools is difficult. Recently, T-cell interferon-gamma release assays (IGRA) have been introduced for the diagnosis of tuberculous pleurisy. The aim of the present meta-analysis was to establish the overall diagnostic accuracy of IGRA on both pleural fluid and peripheral blood, for diagnosing tuberculous pleurisy. METHODS: A systematic review was performed of English language publications. Sensitivity, specificity and other measures of the accuracy of IGRA for the diagnosis tuberculous pleurisy using both pleural fluid and blood were pooled using a random-effects model or a fixed-effects model. Receiver operating characteristic curves were used to summarize overall test performance. RESULTS: Seven out of eight studies met the inclusion criteria. The summary estimates of sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, positive predictive value, negative predictive value and diagnostic odds ratio were, for pleural fluid: 0.75, 0.82, 3.49, 0.24, 0.85, 0.70 and 19.04, respectively; and for blood: 0.80, 0.72, 2.86, 0.28, 0.78, 0.74 and 11.06, respectively. CONCLUSIONS: As almost 20% of non-tuberculosis patients would be erroneously treated for tuberculosis and 25% of patients with tuberculous pleurisy would be missed, pleural fluid IGRA are not useful for the clinical diagnosis of tuberculous pleurisy. PMID- 21299687 TI - Applying gene expression microarrays to pulmonary disease. AB - Gene expression microarrays are high throughput technologies that can simultaneously measure the expression levels of most known genes in the human genome within a biological sample. The study of gene expression has revealed new understanding into the biological complexities of the cell and can impact the field of medicine by providing new insights into disease. Examining gene expression in samples from patients with pulmonary disease can elucidate molecular mechanisms responsible for disease pathogenesis or uncover novel molecular subtypes within a disease. Gene expression signatures of disease pathogenesis can further be used to suggest novel therapeutic compounds. Biomarkers can be developed from gene expression data that can aid clinicians in diagnosing disease or can guide clinicians in tailoring therapeutic strategies to individual patients. To demonstrate the applications of gene expression microarray technology, we will review several studies in pulmonary disease that utilize gene expression profiling techniques to gain biological insights into disease or to develop clinically relevant biomarkers for disease management. PMID- 21299688 TI - A multicentre surveillance study on the characteristics, bacterial aetiologies and in vitro antibiotic susceptibilities in patients with acute exacerbations of chronic bronchitis. AB - BACKGROUND AND OBJECTIVE: Antimicrobial resistance is a global problem and the prevalence is high in many Asian countries. METHODS: A prospective observational study of the prevalence of bacterial pathogens and their antimicrobial susceptibilities in patients with acute exacerbations of chronic bronchitis (AECB) was conducted in Indonesia, Philippines, Korea, Thailand, Malaysia, Taiwan and Hong Kong from August 2006 to April 2008. The diagnosis of AECB was based on increased cough and worsening of two of following: dyspnoea, increased sputum volume or purulence. Patients who had taken antibiotics within 72 h of presentation were excluded. All bacterial strains were submitted to a central laboratory for re-identification and antimicrobial susceptibility testing to 16 antimicrobial agents according to Clinical and Laboratory Standards Institute. RESULTS: Four hundred and seven isolates were identified among 447 patients of AECB. The most frequent organisms isolated were Klebsiella pneumoniae and associated species (n = 91 + 17), Haemophilus influenzae (n = 71), Pseudomonas aeruginosa (n = 63), Streptococcus pneumoniae (n = 32), Acinetobacter baumannii (n = 22) and Moraxella catarrhalis (n = 21). According to Clinical and Laboratory Standards Institute susceptibility breakpoints, 85.7% and >90% of these pathogens were susceptible to levofloxacin and cefepime respectively. Other options with overall lower susceptibilities include imipenem, ceftazidime, ceftriaxone and amoxicillin/clavulanate. CONCLUSIONS: Gram-negative bacteria including Klebsiella spp., P. aeruginosa and Acinetobacter spp. constitute a large proportion of pathogens identified in patients with AECB in some Asian countries. Surveillance on the local prevalence and antibiotic resistance of these organisms is important in guiding appropriate choice of antimicrobials in the management of AECB. PMID- 21299689 TI - Idiopathic pulmonary fibrosis-related pulmonary hypertension; an exercising diagnosis? PMID- 21299691 TI - 'Blue sky' epidemiology: definition, examples and a plea for understanding. PMID- 21299692 TI - Tuberculosis in the Australian Indigenous population: history, current situation and future challenges. PMID- 21299693 TI - Leprosy control, public health paradigms and stigma. PMID- 21299694 TI - The linguistic demography of Australians living with chronic hepatitis B. AB - OBJECTIVE: The prevalence of chronic hepatitis B virus (HBV) infection is increasing in Australia, and most affected individuals were born overseas. Estimating the English literacy of predominantly affected populations and determining the languages other than English (LOTE) spoken is essential for the development of appropriate resources. METHOD: Data from the Australian Bureau of Statistics and Department of Immigration and Citizenship were used to estimate the number of Australian residents by birth country, English literacy and LOTE spoken, with a focus on those arriving in the past two decades. Prevalence of chronic HBV infection was estimated using source country seroprevalence. The results were compared to Victorian surveillance notification data and published Australian epidemiological and clinical studies. RESULTS: Chinese languages and Vietnamese are the dominant languages spoken by Australians living with chronic HBV infection who speak limited or no English. Estimates of predominant source countries for people living with chronic HBV infection derived from Census data were generally coherent with existing epidemiological and clinical studies but differences exist, particularly for groups targeted for screening such as humanitarian entrants. CONCLUSIONS: This study emphasises the need for LOTE resources for Australians living with chronic HBV infection and suggests priority languages. The notable differences observed between Census-derived estimates and surveillance data suggest there are particularly under-diagnosed groups within the community. IMPLICATIONS: This study has clear implications for prioritising the translation of resources targeting Australians living with chronic HBV infection. PMID- 21299695 TI - Chronic hepatitis B surveillance in Victoria, 1998-2008: instituting a 21st century approach to an old disease. AB - OBJECTIVE: To describe the epidemiology and assess the quality of the Victorian chronic hepatitis B (CHB) surveillance data in light of revised recommendations for the management of people with CHB infection published by the Centers for Disease Control (CDC). METHODS: Records of confirmed non-acute hepatitis B cases notified from 1998-2008 were extracted from the Victorian Notifiable Infectious Diseases Surveillance database. Age-standardised notification rates were calculated using population data from the Australian Bureau of Statistics. Descriptive epidemiological analyses were conducted on demographic fields and notifications were assessed for identity of notifier and completeness, especially for country of birth data as prioritised by the CDC. RESULTS: There were 19,024 notifications of CHB from 1998-2008. The annual age-standardised notification rates ranged from 28-38 per 100,000 population, with an upward trend from 2006. Country of birth information reflected the heterogeneity of HBV prevalence worldwide. A decreasing trend of doctor notifications resulted in poor completeness of risk factor fields such as Indigenous status (37%) and country of birth (27%). CONCLUSION: This analysis highlighted the burden of CHB in Victorians born in high prevalence countries; however a true estimate of this burden was limited by the high proportion of incomplete notifications. IMPLICATIONS: Improving the information collected from notifications will improve surveillance for CHB and ability to target appropriate responses. We suggest a pilot of enhanced surveillance to meet revised standards from CDC. PMID- 21299696 TI - Prevalence of chronic hepatitis B in South Western Sydney: evaluation of the country of birth method using maternal seroprevalence data. AB - OBJECTIVE: To estimate the prevalence of hepatitis B infection and evaluate the country of birth (Census) method of describing hepatitis B distribution in an Australian health service with a large migrant population. METHODS: The prevalence of chronic hepatitis B in Sydney South West Area Health Service (SSWAHS, population 1.3 million) was estimated by applying the prevalence of hepatitis B surface antigen (HBsAg) in high or intermediate hepatitis B prevalence countries to SSWAHS residents from those countries, using 2006 Census data. The Australian hepatitis B prevalence (0.7%) was applied to the remainder. This method was validated using HBsAg seroprevalence in 42,274 women aged 15-44 years who delivered at SSWAHS public maternity hospitals during 2007 to 2009. RESULTS: The SSWAHS prevalence of HBsAg using the Census method was 2.0% for all ages and 2.3% for 15-44 year old women. The seroprevalence in 15-44 year old mothers was 1.8%. The adjusted population prevalence was 1.6%. The two methods produced broadly similar descriptions of relative hepatitis B burden by local government area and country of birth. CONCLUSION: The Census method overestimates the prevalence of hepatitis B infection by 30%, but produces similar patterns of hepatitis B burden across the area. Health services can estimate the prevalence and distribution of chronic hepatitis B using readily available data to focus delivery of prevention and treatment services. PMID- 21299697 TI - Life-threatening cellulitis after traditional Samoan tattooing. AB - OBJECTIVE: Traditional Samoan tattooing is a significant and valued cultural practice. Any tattooing carries a risk of complications, including the potential for serious bacterial infection. We discuss the complex nature of the public health investigation into two cases of serious bacterial infection following traditional tattooing occurring in the same region in New Zealand within a six week period. APPROACH: Description of two cases of life-threatening cellulitis (one with necrotising fasciitis) related to traditional Samoan tattooing and presentation of findings from the public health investigation. Discussion of the complex legal and cultural issues that arose. CONCLUSION: Our paper illustrates the potential for serious bacterial infection by tattooing when performed in a non-sterile manner. There are gaps in the regulatory framework available in New Zealand to address the public health risks of unsafe tattooing practices. IMPLICATIONS: It is important to balance the fundamental right to perform the traditional cultural practice of tattooing with the need for meticulous infection control. Reducing the risk of infection will require working in partnership with the community to develop acceptable standards and guidelines and to improve the regulatory framework. PMID- 21299698 TI - Ethnic and Indigenous access to early childhood healthcare services in Australia: parents' perceived unmet needs and related barriers. AB - OBJECTIVE: To evaluate the parents' perceived unmet needs in early childhood healthcare services among Indigenous, non-English-speaking background (NESB) and English-speaking background (ESB) children and the related barriers. METHOD: Data was from the Longitudinal Study of Australian Children (LSAC). Rao-Scott chi square was used to examine the level of parents' perceived unmet needs in three ethnic groups in early childhood healthcare services over a 12 month period. Survey logistic regression was used to assess the association between the groups of infants and the barriers to utilisation. RESULTS: Ten per cent of Australian infants have at least one parents' perceived unmet need in early childhood healthcare services. NESB (15.3%) and Indigenous (15.1%) infants were more likely than ESB infants (9.9%, p<0.001) to have parents' perceived unmet needs in health care services. The barriers to service access include cost, transport problems, child care difficulties, service availability and family reasons. Parents of ESB infants were more likely to cite operating hours as the major barrier to accessing services. CONCLUSION: There were parents' perceived unmet needs in a number of health services for all Australian infants, but at different levels by Indigenous, NESB and ESB groups. The most common barrier to services utilisation related to cost or private health insurance, availability and accessibility of service provision and other socioeconomic issues. IMPLICATIONS: Policy attention and operational changes are required to improve equity in accessing early childhood services, as well as to improve the overall access to healthcare services for all Australian infants. PMID- 21299699 TI - Smoking, nutrition, alcohol and physical activity interventions targeting Indigenous Australians: rigorous evaluations and new directions needed. AB - OBJECTIVE: To describe and critique methodological aspects of interventions targeting reductions in smoking, poor nutrition, alcohol misuse and physical inactivity (SNAP risk factors) among Indigenous Australians. METHODS: An electronic search of eight databases and a manual search of reference lists of literature reviews and reference libraries for Indigenous-specific intervention studies published in peer-reviewed journals (January 1990 to August 2007) were undertaken. Alcohol, smoking, nutrition or physical activity needed to be the primary focus of the study and the intervention needed to specifically target Indigenous Australians. RESULTS: Twenty studies were selected for inclusion in the review. Methodologically, few studies employed randomisation or a control group, most omitted important details (e.g. costs), some did not report process measures (e.g. attrition rates), and some did not use validated measures. Two thirds of interventions were implemented at the community level and employed multiple strategies. CONCLUSION: There is a need for more rigorous evaluations of interventions targeting reductions in SNAP risk factors among Indigenous Australians, and to establish the reliability and validity of measures to quantify their effect. IMPLICATIONS: It may be beneficial for future Indigenous specific intervention research to focus on the evaluation of secondary prevention to complement the current concentration of effort targeting primary prevention. Community-wide interventions, combining strategies of greater intensity for high risk individuals with those of less intensity targeting lower risk individuals, might also offer considerable promise. PMID- 21299700 TI - A review of the barriers preventing Indigenous Health Workers delivering tobacco interventions to their communities. AB - OBJECTIVE: To review available literature addressing the issue of whether smoking status of Indigenous Health Workers (IHWs) impedes provision of health information about smoking tobacco to their communities. METHOD: Databases were searched for publications that examined IHWs' smoking status or quit support programs for IHWs. Studies were categorised as reviews and commentaries, intervention studies or descriptive research. RESULTS: Fourteen studies met inclusion criteria. Overall, the literature suggests that IHWs' smoking status is a barrier. However, the poor quality of most studies weakens the evidence for this conclusion. The issue of IHWs smoking status as a barrier is peripheral to all but two of the studies. Literature cited and reviewed was often not exhaustive and relied on only a few preceding empirical studies. Most studies were unclear about whether IHWs' views were reported as distinct from views of health staff in general. CONCLUSIONS AND IMPLICATIONS: The recent COAG investment to Tackling Smoking is an important contribution to Closing the Gap in the health of Indigenous Australians. However, there remain potential barriers faced by IHWs that may undermine efforts to reduce Indigenous smoking. Overcoming these barriers and assisting IHWs to quit smoking may provide an opportunity to address high rates of smoking in Indigenous communities. Further research is required with a balance between descriptive research to assess the issue and intervention research to address it. PMID- 21299701 TI - Moving urban trips from cars to bicycles: impact on health and emissions. AB - OBJECTIVE: To estimate the effects on health, air pollution and greenhouse gas emissions if short trips (<=7 km) were undertaken by bicycle rather than motor car. METHOD: Existing data sources were used to model effects, in the urban setting in New Zealand, of varying the proportion of vehicle kilometres travelled by bicycle instead of light motor vehicle. RESULTS: Shifting 5% of vehicle kilometres to cycling would reduce vehicle travel by approximately 223 million kilometres each year, save about 22 million litres of fuel and reduce transport related greenhouse emissions by 0.4%. The health effects would include about 116 deaths avoided annually as a result of increased physical activity, six fewer deaths due to local air pollution from vehicle emissions, and an additional five cyclist fatalities from road crashes. In economic terms, including only fatalities and using the NZ Ministry of Transport Value of a Statistical Life, the health effects of a 5% shift represent net savings of about $200 million per year. CONCLUSION: The health benefits of moving from cars to bikes heavily outweigh the costs of injury from road crashes. IMPLICATIONS: Transport policies that encourage bicycle use will help to reduce air pollution and greenhouse emissions and improve public health. PMID- 21299702 TI - Equity of colorectal cancer screening: cross-sectional analysis of National Bowel Cancer Screening Program data for South Australia. AB - OBJECTIVE: The National Bowel Cancer Screening Program (NBCSP) is a population based screening program based on a mailed screening invitation and immunochemical faecal occult blood test. Initial published evidence from the NBCSP concurs with international evidence on similar colorectal cancer screening programs about the unequal participation by different population sub-groups. The aim of the paper is to present an analysis of the equity of the NBCSP for South Australia, using the concept of horizontal equity, in order to identify geographical areas and population groups which may benefit from targeted approaches to increase participation rates in colorectal cancer screening. METHOD: De-identified data from the NBCSP (February 2007 to July 2008) were provided by Medicare Australia. Univariate and multivariate statistical analyses were undertaken in order to identify the predictors of participation rates in the NBCSP. RESULTS: The overall participation rate was 46.1%, although this was statistically significantly different (p<0.001) by gender (42.6% for males and 49.5% for females), socioeconomic status (40% in most deprived quintile through to 48.1% in most affluent quintile) and remoteness (45.6% for metropolitan, 46% for remote and 48.6% for rural areas). These findings were confirmed in multivariate analyses. Of the NBCSP participants, 0.24% (CI 95% 0.20-0.30) identified themselves as Indigenous and 8% (CI 95% 7.7-8.3) reported speaking a language other than English at home. CONCLUSION: Findings from this study suggest inequities in participation in the NBCSP on the basis of gender, geographical location, Indigenous status and language spoken at home. PMID- 21299703 TI - Framing responsibility: coverage of lung cancer among smokers and non-smokers in Australian television news. AB - OBJECTIVE: To analyse news portrayals of lung cancer and associated inferences about responsibility in Australian television news. METHODS: Analysis of television news reports, broadcast on Sydney's five free-to-air television channels between 2 May 2005 and 31 August 2009, for all statements pertaining to lung cancer. RESULTS: Of 2,042 reports mentioning any cancer, 45 made reference to lung cancer, and 28 (62%) referred to diagnoses of lung cancer in non-smokers. Of 157 statements in these reports, 107 (68%) noted that the person featured was a non-smoker. Non-smokers were portrayed sympathetically and as tragic victims, implying they were not responsible for their condition, the sub-text being that smokers are responsible for theirs. CONCLUSIONS: Television news portrays non smokers with lung cancer with considerable sympathy. Conversely, smokers are implicitly and occasionally explicitly depicted as responsible for their disease. IMPLICATIONS: The marginalisation of tobacco caused lung cancer in news, together with sympathetic reporting of lung cancer in non-smokers may contribute to stigma surrounding smoking caused disease that may promote delay in seeking treatment, and de-emphasise the role of the tobacco industry's decades-long smoker reassurance program in promoting smoking. PMID- 21299704 TI - Price discounting of cigarettes in milk bars near secondary schools occurs more frequently in areas with greater socioeconomic disadvantage. AB - OBJECTIVE: To examine differences in price discounting of cigarettes in milk bars located near secondary schools in metropolitan areas of Victoria, according to neighbourhood socioeconomic status (SES). METHOD: Milk bars within one km of randomly selected secondary schools in Victorian metropolitan areas were audited to assess the advertised price of the most popular cigarette brands. RESULTS: Cigarette brands were available below the recommended retail price (RRP) at between 10% to 14% of the 62 milk bars visited. Price discounting was occurring significantly more frequently in areas of lower SES, with between 23% and 33% of milk bars in these neighbourhoods selling the leading cigarette brands at below RRP. CONCLUSIONS: Price discounting was found to be occurring to a greater extent in milk bars near secondary schools in low SES areas compared to mid to high SES areas. IMPLICATIONS: Promotional tools that make cigarettes more affordable risk undermining efforts to reduce smoking prevalence, especially in price sensitive populations of lower SES. PMID- 21299705 TI - Squeezing new life out of an old Sponge: how to modernise an anti-smoking media campaign to capture a new market. AB - OBJECTIVES: The iconic Sponge anti-smoking television advertisement was first made in Sydney, Australia, in 1979. In 2007, it was re-made for a new generation of smokers. This paper examines the impact of the re-made Sponge advertisement. METHODS: Qualitative evaluation of the original Sponge ad by younger and older smokers (n=51) was followed by an online pre-test survey of the modernised version (n=301). A continuous tracking telephone survey of smokers and recent quitters (quit in past 12 months) over 18 years monitored performance of the modernised version while on air in late 2007 (total n=453; seen ad n=380). RESULTS: Qualitative research found that the concept of the original Sponge ad may motivate younger smokers--who had not previously seen the ad--to quit. Online pre-testing demonstrated that the modernised version provided new information to 54% of 18-24 year olds (compared to 31% of older smokers). Tracking survey results indicated that believability of the modernised version was highest among 18-24 year olds (92%), that the ad was 'attention-grabbing' (86%), and that it was effective at influencing quitting intentions. Effects were amplified by the generation of pressure from family and friends. IMPLICATIONS: The re-made Sponge advertisement had a positive impact on smokers, and was particularly effective among the new market of smokers aged less than 40 years. Adapting successful mass media campaign material can be an effective and economical strategy to influence smokers. PMID- 21299706 TI - Strong smoker interest in 'setting an example to children' by quitting: national survey data. AB - OBJECTIVE: To further explore smoker views on reasons to quit. METHODS: As part of the multi-country ITC Project, a national sample of 1,376 New Zealand adult (18+ years) smokers was surveyed in 2007/08. This sample included boosted sampling of Maori, Pacific and Asian New Zealanders. RESULTS: 'Setting an example to children' was given as 'very much' a reason to quit by 51%, compared to 45% giving personal health concerns. However, the 'very much' and 'somewhat' responses (combined) were greater for personal health (81%) than 'setting an example to children' (74%). Price was the third ranked reason (67%). In a multivariate analysis, women were significantly more likely to state that 'setting an example to children' was 'very much' or 'somewhat' a reason to quit; as were Maori, or Pacific compared to European; and those suffering financial stress. CONCLUSION: The relatively high importance of 'example to children' as a reason to quit is an unusual finding, and may have arisen as a result of social marketing campaigns encouraging cessation to protect families in New Zealand. IMPLICATIONS: The policy implications could include a need for a greater emphasis on social reasons (e.g. 'example to children'), in pack warnings, and in social marketing for smoking cessation. PMID- 21299707 TI - Funding for child obesity prevention in Australia. PMID- 21299708 TI - Engaging adolescents and young adults in a longitudinal health study: experience from the Top End cohort. PMID- 21299709 TI - Validity of dental screening questions in an Indigenous young adult population. PMID- 21299710 TI - Sugar consumption from beverages and the potential effects of a text-based information label. PMID- 21299711 TI - Resending a consent form and information package to non-responders increases school-based consent return rate. PMID- 21299712 TI - Hepatitis B immunisation leads to the decline of hepatitis B virus prevalence in Gansu province, China. PMID- 21299713 TI - Impact of swine flu education on coughing in the doctor's face during examination. PMID- 21299714 TI - Road safety attitudes and opinions of newly licensed Maori car drivers: New Zealand Drivers Study. PMID- 21299715 TI - Alcohol restrictions and STIs: is there a link? PMID- 21299716 TI - Adiponectin supports cell survival in glucose deprivation through enhancement of autophagic response in colorectal cancer cells. AB - Adiponectin is known to have suppressive effects on tumor growth and is thought to be a key molecule in the positive correlation between obesity and cancer. However, the detailed mechanisms regulating tumor cell activity have not been elucidated. In this study, we found that both full-length (f-Ad) and globular adiponectin (g-Ad) inhibited cell growth in colon cancer cell lines in glucose containing medium, whereas it supported cell survival in glucose-deprived medium, with an increase in AdipoR1 and AdipoR2 expression. The latter effect of adiponectin in glucose deprivation was significantly inhibited by adding autophagy inhibitors, chloroquine, 3-methyl adenine or a combination of pepstatin A and E-64d, suggesting that the effect of supporting cell growth was dependent, at least in part, on the induction of autophagy. The enhancement of autophagy was confirmed morphologically using green fluorescent protein (GFP)-microtubule associated protein 1 light chain 3 (LC3) fusion proteins under a fluorescence microscope using stably transfected DLD-1 cells expressing GFP-LC3. Western blot analysis revealed that adiponectin increased the expression of LC3-1, LC3-2, phosphorylated AMPKalpha and PPARalpha but decreased that of phosphorylated mTOR, insulin like growth factor (IGF)-1, phosphorylated serine/threonine kinase (Akt) and phosphorylated phosphatidylinositol 3-kinase (PI3K) in glucose-deprived medium. We conclude that adiponectin supports cell survival in glucose deprivation through enhancement of the autophagic machinery by AMPKalpha and PPARalpha activation and IGF-1/PI3k/Akt/mTOR pathway inhibition. The bimodal effects of adiponectin are thought to be clinically important in the pathophysiology of tumor development and progression. PMID- 21299717 TI - Histone deacetylase inhibitors block nuclear factor-kappaB-dependent transcription by interfering with RNA polymerase II recruitment. AB - Histone deacetylase inhibitors (HDACi) have been shown to exhibit anti inflammatory activity, but their mechanism of action is poorly understood. Trichostatin A (TSA) and the cyclic tetrapeptide class inhibitor Ky-2 inhibit both lipopolysaccharide-induced tumor necrosis factor-alpha (TNF-alpha) production in rats and TNF-alpha-induced expression of inflammatory genes in HeLa cells. We assessed the molecular mechanism underlying TSA-induced anti inflammatory activity by genetically dissecting activation of the nuclear factor kappaB (NF-kappaB) pathway following stimulation with TNF-alpha. Trichostatin A did not inhibit degradation of IkappaBalpha, nuclear translocation and DNA binding of NF-kappaB; also, the drug did not affect transient expression from exogenous kappaB-reporter plasmids. However, endogenous expression of inflammatory cytokines such as interleukin-8 (IL-8) was greatly reduced, even in the absence of de novo protein synthesis, suggesting that HDACi directly inhibits NF-kappaB-induced transcription. Indeed, chromatin immunoprecipitation (ChIP) analysis showed that events related to transcriptional activation of the IL-8 gene region in response to TNF-alpha, including recruitment of RNA polymerase II (Pol II), were compromised in the presence of TSA. These data indicate that HDAC activity is required for the efficient initiation and/or elongation of inflammatory gene transcription mediated by NF-kappaB. PMID- 21299718 TI - Novel virtual cytological analysis for the detection of endometrial cancer cells using autoscan fluoromicroscopy. AB - The current medical examinations for detecting endometrial cancer can sometimes be stressful and inconvenient for examinees and examiners. Therefore, we attempted to develop an autoscan-virtual cytology system for detecting endometrial cancer without relying on judgment by the human eye. Exfoliated cells from the uterus were retrieved using a tampon inserted for 3 h. More than 100 monoclonal antibodies (mAb) developed by us were screened in three steps of immunohistochemistry to find mAb sets that would enable the cancer and normal endometrium to be perfectly distinguished. The exfoliated cells provided by 30 endometrial cancer patients and a total of 37 samples of 14 non-malignant volunteers including the menstrual cycle were analyzed using imaging cytometry. All samples contained epithelial cells and dysplasia cells, but the pathologist could not definitively diagnose all of them as endometrial cancer cells because most cells had degenerated. Twenty-two of 28 endometrial cancer tissues (79%) were positive with four mAb sets, CRELD1, GRK5, SLC25A27 and STC2, and 22 of 22 normal endometriums (100%) were negative. Our newly developed autoscan-virtual cytology for exfoliated endometrial cells showed overall sensitivity for endometrial cancer patients and overall specificity for volunteers of 50% (15/30) and 95% (35/37), respectively. Our autoscan-virtual cytology combined with cancer specific mAb and imaging cytometry could be useful for endometrial cancer detection. Autoscan-virtual cytology for endometrial cancer deserves further evaluation for future endometrial cancer screening. PMID- 21299719 TI - Enteric neuropathy evoked by repeated cisplatin in the rat. AB - BACKGROUND: Acute administration of the antitumoral drug cisplatin can induce nausea/emesis and diarrhea. The long-term effects of cisplatin on gastrointestinal motility, particularly after repeated administration, are not well known. Because cisplatin is highly neurotoxic, myenteric neurons can be affected. Our aim was to study the prolonged effects of repeated cisplatin administration in a rat model, focusing on gastrointestinal motor function and myenteric neurons. METHODS: Rats received saline or cisplatin (1 or 3 mg kg(-1), i.p.) once weekly for 5 weeks. One week after treatment, both upper gastrointestinal transit and colonic activity were evaluated, and tissue samples from ileum, colon and rectum were processed for histological analysis. Intestinal transit was measured invasively (charcoal method). Colonic activity was determined electromyographically. The gut wall structure was evaluated in sections using conventional histology and immunohistochemistry. Whole-mount preparations from the distal colon were labeled for different markers, including nitric oxide synthase (NOS) and calcitonin-gene related peptide (CGRP) to determine relative proportions of myenteric neurons vs the total neuronal population labeled with HuC/D. KEY RESULTS: One week after repeated cisplatin exposure, the upper gastrointestinal transit rate and colonic activity were dose dependently reduced. The number of NSE- or HuC/D-immunoreactive myenteric neurons per ganglion was decreased; the proportion of CGRP-immunoreactive neurons was decreased, whereas that of NOS-immunoreactive cells was increased. CONCLUSIONS & INFERENCES: Chronic cisplatin may induce an enteric neuropathy characterized by changes in myenteric neurons associated with marked gastrointestinal motor dysfunction. PMID- 21299720 TI - Intragastric pressure during food intake: a physiological and minimally invasive method to assess gastric accommodation. AB - BACKGROUND: The stomach relaxes upon food intake and thereby provides a reservoir while keeping the intragastric pressure (IGP) low. We set out to determine whether we could use IGP as a measurement for stomach accommodation during food intake. METHODS: In fasted healthy volunteers (n = 7-17) a manometer and an infusion catheter were positioned in the proximal stomach. After a stabilization period a nutrient drink was intragastrically infused at 15, 30 and 60 mL min(-1). To investigate the effect of impaired accommodation the effect of N(G)-monomethyl L-arginine (L-NMMA) was examined. The volunteers scored satiation until maximum, when the experiment ended. The IGP was presented as a change from baseline (mean +/- SEM) and compared with repeated measures anova. KEY RESULTS: Independent on the ingestion speed, the IGP decreased initially and gradually increased thereafter. Volunteers scored maximal satiation after 699 +/- 62, 809 +/- 90 and 997 +/- 120 mL nutrient drink infused (15, 30 and 60 mL min(-1) respectively; P < 0.01). Maximum IGP decrease was 3.4 +/- 0.5 mmHg after 205 +/- 28 mL, 5.1 +/- 0.7 mmHg after 212 +/- 46 mL, and 5.2 +/- 0.7 mmHg after 296 +/- 28 mL infused volume [15, 30 and 60 mL min(-1) respectively; not significant (ns)]. Post hoc analysis showed significant correlations between IGP and satiation score increase. During L-NMMA infusion IGP was significantly increased while subjects drank significantly less (816 +/- 91 vs 1032 +/- 71 mL; P < 0.005). Interestingly, the correlation between IGP increase and satiation score increase did not differ after L-NMMA treatment. CONCLUSIONS & INFERENCES: The IGP during nutrient drink ingestion provides a minimally invasive alternative to the barostat for the assessment of gastric accommodation. These findings furthermore indicate that IGP is a major determinant of satiation. PMID- 21299721 TI - A survey of staff attitudes and responses to people with dementia who are aggressive in residential care settings. AB - Aggression is reportedly common among older people with dementia in residential care. The attitudes of staff in care homes and strategies they use are under researched. Theoretical models that may be used to both understand and respond to such behaviour exist. They are the standard and person-centred paradigms. The aim of this study was to explore the views of nursing staff about aggressive behaviour in people with dementia and strategies used in practice. A survey of the attitudes of staff in six dementia care units using the Management of Aggression in People with Dementia Attitude Questionnaire was conducted including an audit of aggressive incidents using the Staff Observation Aggression Scale Revised over a 3-month period. Staff expressed views reflective of a person centred as opposed to standard paradigm. They viewed aggressive behaviour by people with dementia as deriving from the environment, situation or interactions with others. Participants strongly supported interpersonal means of responding to aggression, the moderate use of medication, and were largely opposed to physical restraint. Aggressive incidents were managed using less intrusive strategies such as distraction and de-escalation. Responses to aggressive behaviour, while pragmatic, were largely underpinned by a person-centred ethic as reflected in the attitudes expressed by staff. PMID- 21299722 TI - Supporting mental health nurses to address the physical health needs of people with serious mental illness in acute inpatient care settings. AB - There is overwhelming evidence that the physical health needs of those with serious mental illness have been neglected by health service professionals. Mental health nurses (MHNs) could play a key role in meeting these needs particularly during hospital admissions, yet they are uncertain about their role, have variable levels of confidence and lack appropriate skills and training. This study investigated MHNs' views and practices of physical health management for adults receiving acute inpatient treatment and found a difference between MHNs' perceived responsibility and their practice, which highlighted a need for role clarification and further skills training. PMID- 21299723 TI - The implementation of a self-administration of medication programmes within Older Persons Mental Health. AB - This paper aims to report on the literature related to self-medication programmes that contributed to the development of an Older Persons Mental Health (OPMH) specific pathway for a self-administration of medication (SAM) programme. The traditional methods used within mental health inpatient environments to administer medication are paternalistic and resonant of the medical approach to care. There is a need to investigate innovative methods in the management of depression in older adults that reflect an individualized, innovative approach to redress the power imbalance for patients. Electronic databases were searched using the search strategy of Hek et al. to identify key themes in the implementation of self-administration programmes. Seven themes emerged from the literature review: the structure of SAM, assessments and risks associated with SAM, patient education, SAM and medication adherence, the patients' perspective, advantages and barriers to SAM, and professional issues. These findings were then used as the foundation for a project to develop an OPMH specific pathway for the implementation of SAM. There is a distinct lack of implementation of SAM programmes across the UK, especially within mental health services. Older Persons Mental Health is ready for the implementation of change in medicines management for older adults. Self-administration of medication can ensure all the principles of NHS plan relating to individualized person-centred care are achieved. Nurses have the opportunity to actively contribute to this process, facilitating and empowering those in their care to be experts within their journey and take control of their illness. PMID- 21299724 TI - Educational and support intervention to help families assist in the recovery of relatives with eating disorders. AB - The aim of this study was to develop and test an educational and support nursing intervention in Iceland to help families assist with the recovery of relatives with eating disorders. Studies indicate that if families receive adequate help in the recovery process of a relative with an eating disorder, the prognosis is better. The study is a pre-post design. The intervention was based on the Calgary Family Intervention Model. An educational and support intervention, which lasted for 3 weeks, was provided for 21 family members of individuals with eating disorders. The patients had been diagnosed with anorexia nervosa, bulimia nervosa or an eating disorder not otherwise specified. Participants were divided into three groups. The main findings revealed a significant improvement according to the scales used for measuring understanding in the level of expressed emotion questionnaire and for measuring eating behaviour, concern with weight and food, and denial of the problem in the anorectic behaviour observation scale. The participants' responses to the research questions about their satisfaction with the educational and support intervention were positive. The study indicates that an educational and support intervention can prove beneficial for families and patients with eating disorders. PMID- 21299725 TI - Real mental health promotion requires a reorientation of nursing education, practice and research. AB - The evidence for the individual, social and economic benefits of mental health promotion is now well established. The indication is that a broader public health approach that addresses social and environmental factors related to mental health and well-being is required. Mainstream mental health services, however, continue to operate in relative isolation, allocating the greatest proportion of funding and resources to the treatment of mental illness and disorder. Relevant to health promotion, this paper explores the bidirectional link between physical and mental health and the social determinants of mental health. The growing interest in the positive aspects of health and well-being which focuses on wellness rather than illness is also discussed. One example of how mental health nurses can adopt principles of positive mental health to education, practice and research is presented. The author proposes that as the largest professional group in health care, nurses must become more actively involved in initiatives that reorientate practices and services away from an illness culture towards the adoption of wider mental health promotion principles. PMID- 21299726 TI - Employed women with depression in Korea. AB - Korean women have been reported to be more susceptible to depressive symptoms than men. In this study we explored the important predictors of depression among employed Korean women using modified Hauenstein's Nursing Practice Paradigm for Depressed Rural Women, focusing on the relationship of stressful life events and three resources (physiological, social, and psychological). In particular, we examined the moderating effects of resources on the stress-depression relationship among a community-based sample of employed Korean women. In this cross-sectional study, survey data were collected with 767 employed women in Korea over a 2-month period in 2006. Of these respondents, 286 depressed participants' data were analysed to test moderating effects of the three resources on depression. Our hierarchical multiple regression results revealed that stressful life events directly affected depression. However, after including the product terms of the three resources (i.e. regular exercise, self-efficacy, and closeness) and stressful life events, the main effect of stressful life events disappeared, confirming significant moderating effects of the resources. The findings would contribute to development of a body of culturally sensitive knowledge for clinical practice with depressed employed Korean women. PMID- 21299727 TI - Family members' expectation of the psychiatric healthcare professionals' approach towards them. AB - The importance of involving family members in the care of individuals with schizophrenia or other psychotic illnesses has received increasing attention within psychiatric healthcare services. However, several studies suggest that family members often experience a lack of involvement. Furthermore, research indicates that family members' experience of the professional's approach has bearing on whether they feel involved or not. Thus, the aims of this study were to investigate the level of importance that the family members of individuals with schizophrenia or other psychotic illnesses ascribe to the professionals' approach, the level of agreement between their experiences and what they consider as important, and aspects they consider to be important with regards to contact with professionals. Seventy family members from various parts of Sweden participated. Data were collected by the Family Involvement and Alienation Questionnaire and open-ended questions. The median level and quartiles were used to describe the distribution, and percentage agreement was analysed. Open-ended questions were analysed by qualitative content analysis. The results reveal that the majority of the participants consider Openness, Confirmation, and Cooperation as important aspects of a professional's approach. Continuity emerged as an additional aspect. The results show a low level of agreement between the participants' experience and what they consider as important. PMID- 21299728 TI - Ways of coping in adolescents with schizophrenia. AB - The purpose of this study was to explore ways of coping and its association with specific stress responses in adolescents with schizophrenia. Additionally, subjects and healthy controls were compared to identify stress responses. Forty subjects were drawn from a self-management therapy study for youth with schizophrenia. Thirty community-dwelling controls were selected. A revised Ways of Coping scale and the Symptom of Stress at baseline, 6, 30 and 54 weeks measured coping and stress response. Descriptive statistics, cluster analysis and Pearson correlation provided data analysis. Thirty-two subjects were male, and eight were female. Average age was 17.25 (SD=1.37) years. Twenty-two (55%) were Caucasian; 18 (45%) were non-Caucasian. Seventeen (57%) of the 30 controls were female. The mean age was 17.10 years old (SD=1.16). Adolescents with schizophrenia used emotion-focused coping more than problem-focused coping at baseline and 6 weeks (P<0.01). Subjects reported higher stress than controls (t=4.73, P<0.01) and used emotion-focused coping with emotional stress responses (r=0.34, P=0.05). Adolescent coping strategies may persist into adulthood unless new skills are introduced. Developing effective coping skills for adolescents with schizophrenia is important for practice and future studies. PMID- 21299729 TI - Educational interventions in secondary education aiming to affect pupils' attitudes towards mental illness: a review of the literature. AB - Dealing with persons who have mental health problems is an issue that many people are likely to face with, whether they are health professionals or not. Positive attitudes towards people with mental illness play a major factor in their quality of life and social inclusion. Since adolescents will become active adult members of their communities in the near future, this paper reviews educational interventions in secondary education and how they aim to affect adolescent attitudes towards mental illness. Twelve studies conducted on the relevant issue have been identified. The results indicate a positive impact on attitudes towards mental illness and improvements in the knowledge of mental health and illness among secondary school pupils. However, the limited number of studies highlights the need for further research. PMID- 21299730 TI - The shoulder: taking the strain during restraint. AB - The decision to use or utilize physical intervention techniques is a contentious one. There has been much discussion on the complex legal and ethical dimensions framing the use of force. The risk of injury has also been considered in detail, but almost all of the published work has focused on restraint asphyxia, the prone restraint hold and the use of particular pain compliance techniques such as the wrist flexion hold. This paper focuses on the structure and function of the shoulder and examines how physical interventions and a variety of risk factors can threaten its physical integrity. This paper is for practitioners such as training commissioners, trainers, frontline staff and investigators or regulators who have to make considered determinations on the potential immediate physical impact of a variety of holds and escape manoeuvres. Sound risk assessment must be premised on a sound understanding of anatomy and physiology. PMID- 21299731 TI - A phenomenological study of child and adolescent mental health consultation in primary care. PMID- 21299732 TI - Correlation between the flow pattern of the circle of Willis and segmental perfusion asymmetry after carotid artery revascularization. AB - BACKGROUND: To correlate cerebral perfusion and flow patterns after carotid artery revascularization within the circle of Willis (CoW). METHODS: Sixty-five patients (male/female ratio: 38/27; mean age: 63.2+/-8.4years; range: 44-82years) with symptomatic carotid artery stenosis underwent magnetic resonance (MR) angiography and perfusion imaging prior to and after carotid artery stenting (CAS). Regions of interest (ROIs) on the MR perfusion maps included the corona radiata (CR), centrum semiovale (CSO), occipital region (O), and basal ganglia region (BA) in both stented and non-stented hemispheres. The non-stented hemisphere was used as internal control. RESULTS: Subjects were assigned to the altered CoW group (N=31) vs. the static CoW group (N=34). Thirty-one subjects (47.6%) had an altered flow pattern in the CoW after CAS, and thirty-four (52.4%) retained a static CoW configuration. Relative cerebral blood volume (rCBV) interhemispheric index correlated with CoW morphologic alterations after carotid stenting. Altered CoW group had a higher regional interhemispheric index of rCBV in the CR (1.23+/-0.15 vs. 0.87+/-0.13; P=0.03) and basal ganglia (1.25+/-0.12 vs. 0.91+/-0.11; P=0.03) compared to the static group. CONCLUSIONS: An association between the regional cerebral blood volume (rCBV) interhemispheric asymmetry and CoW collateralization was observed. In addition, the CR, rather than CSO, was found to have topographic significance. PMID- 21299733 TI - Thrombolysis as a factor associated with favorable outcomes in patients with unclear-onset stroke. AB - BACKGROUND AND PURPOSE: Clinical and radiological features of patients with unclear-onset stroke do not differ significantly from those with known-onset stroke. There is a lack of evidence for the safety and efficacy of thrombolysis in patients with unclear-onset stroke. We sought to provide supportive data on the safety and efficiency of thrombolysis in patients with unclear-onset stroke. METHODS: We retrospectively identified patients with unclear-onset stroke (<3 h of first found abnormal time) from our stroke registry. We performed following protocols for thrombolysis in patients with unclear-onset stroke; initial conventional CT-based intravenous thrombolysis (IVT), repeat MRI during IVT, and then decision to maintain IVT or to perform combined intra-arterial thrombolysis. In addition, we compared clinical outcomes and safety between thrombolyzed and non-thrombolyzed patients. RESULTS: A total of 78 patients with unclear-onset stroke were included. Twenty-nine patients underwent thrombolysis. Thrombolysis (OR, 6.842; 95% CI, 1.950-24.004; P = 0.003) and baseline NIHSS (OR, 0.769; 95% CI, 0.645-0.917; P = 0.003) were associated with favorable outcomes at 3 months in multivariate logistic regression analysis. The frequency of hemorrhagic transformation and symptomatic ICH was not significantly different between the thrombolyzed and non-thrombolyzed patients (34.4% vs. 40.7% and 10.3% vs. 8.2%, respectively). CONCLUSION: The results of this study suggest that thrombolysis in unclear-onset stroke could be independently associated with favorable outcomes at 3 months and that thrombolysis based on repeat imaging appears to be safely applied to patients with unclear-onset stroke. PMID- 21299734 TI - Cytokine gene polymorphisms in multiple sclerosis: a meta-analysis of 45 studies including 7379 cases and 8131 controls. AB - Many environmental and genetic factors have been implicated in the development of multiple sclerosis. However, the aetiology has not been clarified yet. Therefore, using a meta-analytic approach, we tried to probe the potential association between various cytokine gene polymorphisms and the occurrence of multiple sclerosis. A comprehensive literature search yielded 45 eligible studies, which involved 7379 cases and 8131 controls. Totally, the effect of eight polymorphisms, i.e. IL-1A C[-889]T, IL-1B C[-511]T, IL-1B C[3953]T, IL-4 C[33]T, IL-10 C[-819]T, IL-10 G[-1082]A, tumour necrosis factor-a (TNFA) G[-308]A and TNFA G[-238]A, was evaluated in a random-effects meta-analysis. There was no evidence of statistically significant association between the aforementioned polymorphisms and multiple sclerosis. Publication bias and heterogeneity were absent in most analyses. Within its limitations, the current literature-based meta-analysis does not indicate that specific polymorphic variations of genes encoding pro-inflammatory and anti-inflammatory cytokines affect susceptibility to multiple sclerosis. PMID- 21299735 TI - Familial Mediterranean fever (FMF) and multiple sclerosis: an association study in one of the world's largest FMF cohorts. AB - BACKGROUND AND PURPOSE: To describe and characterize the association between familial Mediterranean fever (FMF) and multiple sclerosis (MS). METHODS: The patient registry of The National Center for FMF was screened for the coexistence of FMF and MS. Tel-Hashomer criteria were used for the diagnosis of FMF, and FMF severity was evaluated, using the simplified FMF severity scale. McDonald criteria were used for the diagnosis of MS, and neurologic disability was measured using the expanded disability status scale (EDSS). RESULTS: We identified nine patients, affected with both FMF and MS. The onset of the FMF averaged 15.6 (3-37) years. Most patients suffered from abdominal and joint attacks, and 50% of the patients sustained a moderate to severe FMF. The onset of the MS was at an average age of 31.6 (17-50) years. Neurologic manifestations varied individually, without a dominant deficit, and the course was in a relapsing-remitting pattern in most. The median EDSS was in general of low score (3.0), apart from the patients who were homozygous for the M694V mutation, in whom the MS was more severe. Based on our case series, the frequency of MS in our FMF population is 0.075%, twice higher the expected rate in the general population (P=0.0057). CONCLUSIONS: Multiple sclerosis is more common in FMF than in the general Israeli population. Homozygosity for the M694V MEFV mutation may aggravate the phenotype of MS and predispose FMF patients to develop MS. PMID- 21299736 TI - Identification of oxidized serum albumin in the cerebrospinal fluid of ischaemic stroke patients. AB - BACKGROUND AND PURPOSE: Extensive evidence has shown that oxidative stress mediates neuronal death in animal models of hypoxic-ischaemia. Brain biomarkers of oxidative stress need to be identified in order to better understand and treat brain damage in human stroke patients. The present study was conducted to identify potential target proteins of oxidative stress in the cerebrospinal fluid (CSF) of stroke patients with acute ischaemic brain injury. METHODS: We performed two-dimensional polyacrylamide gel electrophoresis to separate protein samples obtained from the CSF of control and stroke patients. To determine protein oxidation levels, oxyblot was then used to detect protein carbonyls that were determined by formation of a stable 2,4-dinitrophenylhydrazine (DNP) product using an anti-DNP antibody. RESULTS: We found that oxidation of serum albumin was increased in the CSF from stroke patients as well as rats who underwent permanent middle cerebral artery occlusion (6.5%, 23%, respectively). In stroke patients, oxidized albumin levels correlated to neurologic indications. CONCLUSIONS: The present study suggests that oxidized albumin in CSF can be utilized as an oxidative stress marker in human stroke patients. PMID- 21299737 TI - Use of emergency medical identification in the paediatric haemophilia population: a national study. AB - The use of emergency medical identification (EMI) such as MedicAlert((r)) has been recommended for use in a variety of medical conditions; however, there is no consensus as to what form should be used and where they should be placed. There are also no uniform guidelines to direct first responders to where they should look for EMI in an emergency. The aim of this study was to identify current paediatric haemophilia nursing practice in educating families about EMI and their perceptions of patient/family adherence to using EMI. US haemophilia nurses listed on the Center for Disease Control's website received an email invitation to participate in a 30-item questionnaire posted on Survey-Monkey. Survey responses showed a wide variety of responses concerning recommendations about the form and location of EMI, particularly in the infant population. Nurses also reported that EMI was often not worn on the body and had low overall adherence. In the infant and preschool population, this was due to safety concerns, sizing, cost and parents not seeing the need for EMI. In school age and adolescents, the barrier to wearing EMI included stigma, cost and sizing. Collaboration is needed among nursing and medical staff, first responders, emergency room staff and manufacturers of EMI to develop standardized EMI which address these issues. Standard educational guidelines are needed to teach nurses and patient/families about the forms and location of EMI. Additionally, national guidelines are needed for the identification of paediatric EMI by first responders and emergency room staff. PMID- 21299738 TI - Surgical treatment of arteriovenous fistula and brachial artery aneurysm in a patient with mild haemophilia A. PMID- 21299739 TI - A commentary on the differences in pharmacokinetics between recombinant and plasma-derived factor IX and their implications for dosing. AB - This commentary aims to summarize all aspects of the difference in pharmacokinetics (PK) between recombinant factor IX (rFIX) and plasma-derived factor IX (pdFIX) and their implications for dosing. PK data were compiled from 17 published studies. The average clearance (CL) of rFIX normally ranged between 7.5 and 9.1 mL h(-1) kg(-1), whereas that of pdFIX was 3.8-5.4 mL h(-1) kg(-1). The average terminal half-life was 18-24 h among all 72-h studies on rFIX, in contrast to (normally) 29-43 h for pdFIX. In vivo recovery was more variable. Judging from the pooled data, the typical recovery of rFIX is around two-third that of pdFIX. The difference in PK between rFIX and pdFIX is thus clear-cut and has implications for dosing. As estimated from the compiled data, the dose required to reach any peak level of FIX immediately after administration would be 1.5 times higher for rFIX than for pdFIX, most probably with considerable individual variation. Calculated doses for a patient on a twice weekly prophylactic treatment to achieve a predetermined trough FIX level depended markedly on CL and were about twice as high with rFIX as with pdFIX. In summary, conversion factors between rFIX and pdFIX of 1.5 for single doses and 2 for prophylactic dosing can tentatively be applied; however, the interindividual variance both in recovery and CL of rFIX and pdFIX and the unknown variance in ratios between these PK parameters call for careful monitoring if a switch of treatment is made. PMID- 21299740 TI - Trends in bleeding patterns during prophylaxis for severe haemophilia: observations from a series of prospective clinical trials. AB - Replacement therapy or prophylaxis, has become the standard of care for the treatment of severe haemophilia A. To describe bleeding patterns in children, adolescents and adults on prophylaxis and their observed relationships to times of infusion (during the week and during the day) as well as season of the year. Data from Advate pre-licensure prospective clinical trials from 145 patients with factor VIII (FVIII) <1%, were used. All patients underwent a 48-h pharmacokinetic study. The 10-65 year group had >= 75 exposure days on fixed prophylaxis (25-40 IU kg(-1) 3-4x per week). Prophylaxis was not fixed but similar for 1-6 year olds. Bleeding patterns were analysed. Overall, 700 bleeds were observed in 110/145 patients. All were treated with prophylaxis, mean dose 108 IU kg(-1) week(-1) in on average 2.9 infusions (1-6 years), 86 IU kg (-1) week(-1) in 2.7 infusions (10-17 years), and 75 IU kg (-1) week(-1) in 2.6 infusions (18-65 years), respectively. On prophylaxis, median total bleeds per year were low at 3.1 for patients aged 1-6 years, 3.3 for those aged 10-17 years and 2.1 for patients aged 18-65 years. Patients aged 1-6 years had predominantly soft tissue bleeds (79%). Incidence of joint bleeding was not associated with season, but was significantly lower in patients who infused FVIII in the mornings: median 0 per year (IQR 0.0-0.4) compared to those who infused later [median 1.8 per year (IQR 0.0-5.2)]. Older patients predominantly experienced joint bleeds (50% and 62%, respectively). More joint bleeds occurred during the summer [43 and 46% respectively, (P < 0.01)]. Bleeding patterns in patients on prophylaxis varied according to age. In addition, the 10-65 year olds showed increased bleeding during the summer. After confirmation in prospective studies, this information may be used to improve tailoring of prophylactic treatment. PMID- 21299741 TI - Incomplete tyrosine 1680 sulphation in recombinant FVIII concentrates. PMID- 21299742 TI - A study of reported factor IX use around the world. AB - Replacement therapy has significantly improved the life expectancy and lifestyle of people with haemophilia. The objectives of this article were to study the reported factor IX (FIX) use on a country-by-country basis and address the following question: Does the reported FIX use vary by national economies? We obtained data on the reported number of international units (IUs) of FIX used for 90 countries from the Marketing Research Bureau and the World Federation of Hemophilia. Results show that the reported FIX use varies considerably across national economies, even among the wealthiest of countries.Trends suggest that the reported FIX usage increases with increasing economic capacity and has been increasing over time. Trends also suggest that consumption of FIX has been increasing at a greater rate in high income countries. Given these trends, there will likely be an overall increase in the amount of FIX concentrates used in the treatment of haemophilia B. We also found that FIX use both in terms of IUs per capita and IUs per person provide a complete picture of the level of haemophilia care within a country. Such information is critical for planning efforts of national healthcare agencies to determine realistic budget priorities and pharmaceutical manufacturers to determine adequate production levels of FIX concentrates. By improving the data collection and surveillance of FIX use for the treatment of people with haemophilia B, we can identify trends and needs of patients and highlight best treatment practices among countries. PMID- 21299743 TI - Recombinant factor concentrates may increase inhibitor development: a single centre cohort study. AB - Recent reports have raised concerns regarding potential risk factors for inhibitor development. In Israel, all haemophilia patients (n = 479) are followed by the National Hemophilia Center. Most children are neonatally exposed to factor concentrate (due to circumcision performed at the age of 8 days). The impact of early exposure and recombinant FVIII products (rFVIII) administration (approved in Israel since 1996) upon inhibitor occurrence in our cohort of haemophilia A (HA) patients was analysed. Two hundred ninety-two consecutive paediatric cases with a first symptomatic onset of HA were enrolled and followed over a median time of 7 years [min-max: 9 months to 17 years]. Study endpoint was inhibitor development against factor VIII. In addition, the treatment regimens applied, i.e. bolus administration or 'continuous infusion' and the family history of inhibitor development were investigated. During the follow-up period 31/292 children (10.6%) developed high titre inhibitors. Inhibitors occurred in 14/43 (32.5%) HA patients neonatally exposed to rFVIII, as compared to 22/249 previously treated with Plasma Derived (PD) products (8.8%). The odds ratio for inhibitor formation in rFVIII treated HA patients was 3.43 (95% CI: 1.36-8.65). Transient inhibitor evolved among 2/43 paediatric HA patients, only among those treated with rFVIII. The risk of inhibitor detection significantly increased among HA children treated by continuous infusion (P = 0.025). Our experience shows that the risk of inhibitor formation may be increased by early exposure to recombinant concentrates. The multiple variables affecting inhibitor incidence deserve further attention by larger prospective studies. PMID- 21299744 TI - A patient-prioritized ability assessment in haemophilia: the Canadian Occupational Performance Measure. AB - Assessment of musculoskeletal function in individuals with haemophilia has been attempted with clinimetric instruments, which use predetermined domains for assessing the same. This study introduces the application of an instrument, the Canadian Occupational Performance Measure (COPM), which is an open-ended questionnaire that allows patients to prioritize their needs and rate their performance in different tasks of daily living as well as their satisfaction in performing them. To study the utility of COPM in evaluating the musculoskeletal functional status of patients with haemophilia and to assess its effectiveness in planning individualized management plans for them. COPM was administered to 67 individuals with haemophilia aged 10-55 years and the data were compared with functional deficits identified through FISH (Functional Independence Score for Haemophilia). A total of 31 performance difficulties in the areas of self-care (62%), productivity (21%) and leisure (17%) were identified by COPM. All eight domains of FISH were identified in COPM as problems in self-care. In addition to these, COPM identified problems in the areas of productivity and leisure. In 78% of the responses on COPM, there was concordance between the performance and satisfaction scores. However, there was discordance between the two in the remaining 22% of responses. COPM is a useful tool for assessment of musculoskeletal dysfunction in haemophilia. It provides a greater insight into the needs of each patient and helps in planning individualized intervention strategies. PMID- 21299746 TI - Comparison of physical activity and sedentary behaviours between young haemophilia A patients and healthy adolescents. AB - In recent studies, adolescent haemophilia A patients and healthy adolescents have been encouraged to participate in physical activity (PA) based on its many established health benefits. However, none of the studies to date has used objective measures of PA and sedentary behaviour. The aims of the current study included: (i) to determine the amount and intensity of habitual PA among haemophilia A and healthy adolescents, and in haemophilia A patients with and without bleeding episodes in the previous year, and (ii) to identify the type and determine the time spent in sedentary activities in which both groups participate to obtain a broadened view of their daily activities. A total of 41 adolescent haemophiliacs and 25 healthy adolescents, between the ages of 8 and 18 years, participated in this cross-sectional study. A triaxial accelerometer was used to measure PA and the Adolescent Sedentary Activity Questionnaire to assess sedentary behaviours among members of both groups. Adolescent haemophilia A patients showed a higher daily mean time engaged in light, moderate and moderate to-vigorous PAs relative to their healthy counterparts (P < 0.001). Patients who had experienced bleeding episodes during the previous year also spent more time participating in vigorous PAs than healthy adolescents (P = 0.002). With regard to sedentary behaviours, healthy adolescents spent more time listening to music than haemophilia A adolescents (P = 0.003), whereas haemophilia A adolescents spent more time watching TV (P < 0.001) and playing videogames (P = 0.003) than healthy counterparts. Findings suggest that increased participation in moderate intensity PAs and reduced sedentary behaviours should be recommended among adolescents with haemophilia A. PMID- 21299745 TI - Alloantibodies to factor VIII in haemophilia. AB - Up to one-third of haemophilia A patients develop factor VIII (FVIII) alloantibodies (inhibitors). The Bethesda assay detects inhibitors but is relatively insensitive. Recently, a new fluorescence-based immunoassay (FLI) was developed for antibody detection. The aim of this study was to assess the prevalence of inhibitors as measured by FLI. Assays of FVIII, FVIII inhibitor by Bethesda assay with Nijmegen modification, and FVIII inhibitor by FLI were performed on adult patients with haemophilia A. Data were complete for 46 patients (median age 39), of whom 72% were severe, 7% moderate and 22% mild. The Bethesda assay was positive in only two patients (4%), while FLI was positive in 23 of 46 patients (50%), with values ranging from 0.4 to 33.7 nm (median 3.5 nm). FLI titres exceeded 7.0 nm in 19.5% of patients, all but one of whom had severe haemophilia. FLI antibody-positive patients were less likely to be HIV positive (30% vs. 70%, P = 0.02). The use of a prophylaxis regimen was associated with a lower incidence of antibody; only two of 23 patients with detectable antibody and none of those with antibody >7 nm were on a prophylaxis regimen, while nine of 23 patients without antibody were on prophylaxis, (P = 0.03). There was no difference in inhibitor presence in patients using recombinant versus plasma derived factor. Antibodies detected by FLI are frequent in patients with haemophilia A, but are less common in those who are HIV positive or are receiving regular FVIII prophylaxis. PMID- 21299747 TI - A clinical study assessing the pharmacokinetics, efficacy and safety of AlphaNine((r)) , a high-purity factor IX concentrate, in patients with severe haemophilia B. AB - Effective treatment with factor IX (FIX) requires a thorough consideration of the properties of the concentrate to be used as replacement therapy, to date, the only available treatment for haemophilia B. The aim of the study was to determine the pharmacokinetics, clinical efficacy and safety in routine clinical use of AlphaNine((r)) , a high-purity human FIX concentrate. This open, single-arm, multicentre, non-randomized trial included 25 subjects (age >= 12) with moderate/severe haemophilia B. Pharmacokinetics was assessed at baseline and after a 6-month follow-up. The degree of haemostasis control achieved was evaluated during a 12-month follow-up. Safety was evaluated in terms of tolerance, thrombogenicity, immunogenicity and viral safety. Mean recovery was 1.01 +/- 0.19 IU dL(-1) per IU kg(-1) at baseline and 1.23 +/- 0.34 IU dL(-1) per IU kg(-1) 6 months later. Terminal half-life was 34.5 +/- 6.2 h and 33.7 +/- 5.4 h, respectively. Ratios of each parameter between the two pharmacokinetic studies were all close to 1. A total of 1,576,890 IU AlphaNine((r)) were administered in 889 infusions (mean dose per infusion: 1774 IU; 3.2 infusions per month per patient). The main reasons for infusion were mild/moderate bleeding (62.3%) and prophylaxis (20.5% continuous, 15.6% intermittent). Overall, 93.0% of the efficacy assessments were rated as excellent/good and 88.8% of bleedings resolved after the first infusion. Twenty-one adverse events were reported in eight patients, none of which was considered related to the study medication. AlphaNine((r)) showed a pharmacokinetic profile in agreement with that of other plasma-derived FIX concentrates and provides safe and clinically effective substitution therapy for patients with haemophilia B. PMID- 21299748 TI - Long-term follow-up of prophylaxis with recombinant activated factor VII in patients with congenital factor VII deficiency. PMID- 21299749 TI - The Swedish version of the Haemophilia Activity List. AB - There has been increasing interest in the patient's perspective on outcome of treatment. The Haemophilia Activity List (HAL) has been developed as a disease specific questionnaire for haemophilia patients and is a validated self-report measure of function developed according to WHO's International Classification of Functioning, Disability and Health. To validate HAL in Sweden. The Dutch and English versions of HAL were translated into Swedish using 'the forward-backward translation' method and merged into a final Swedish version. Validation was performed against the Swedish version of the questionnaires Arthritis Impact Measurement 2 (AIMS 2) and Impact on Participation and Autonomy (IPA). Two hundred and twenty-five patients with severe and moderate forms of haemophilia A and B from three centres were invited to participate in the study. Spearman's rank correlation test was used for validation, and internal consistency of the HAL was calculated with Cronbach's alpha. Eighty-four patients (39%) (18-80 years old) filled out the questionnaires. The internal consistency of the Swedish version of HAL was high, with Cronbach's alpha being 0.98-0.71. Function of the legs had the highest consistency and transportation had the lowest. The correlation was excellent between the HAL sum score and AIMS 2 physical (r = 0.84, P < 0.01), IPA autonomy indoors (r = 0.83, P < 0.01) and autonomy outdoors (r = 0.89, P < 0.01). The Swedish version of HAL has both internal consistency and convergent validity and may complement other functional tests to gather information on the patient's self-perceived ability. PMID- 21299750 TI - Exposure and safety of higher doses of recombinant factor VIIa >=250 MUg kg(-1) in individuals with congenital haemophilia complicated by alloantibody inhibitors: the Haemophilia and Thrombosis Research Society Registry experience (2004-2008). AB - Recombinant factor VIIa (rFVIIa) is a well-established treatment for managing bleeding episodes in individuals with congenital haemophilia complicated by alloantibody inhibitors (CHwI). The safety and efficacy of standard dosing (90 120 MUg kg(-1) every 2-3 h) are well-established; however, the desire to optimize therapy with one or more higher doses instead of multiple lower doses has created a need for evidence of the safety and efficacy of such regimens. Analysis of data from the Haemophilia and Thrombosis Research Society (HTRS) Registry was performed on episodes where doses of >=250 MUg kg(-1) were reported. From 2041 rFVIIa-treated bleeds, 172 bleeding episodes were identified in 25 individuals with CHwI who were treated with >=1 higher doses (>=250 MUg kg(-1) , >=270 MUg kg(-1) or >=300 MUg kg(-1) ) of rFVIIa between January 2004 and November 2008. Bleeds occurred in individuals ranging in age from 0.4 to 41.7 years who were predominantly non-Hispanic and white (40%) with haemophilia A (88%). Bleed types most frequently treated with higher doses of rFVIIa were spontaneous (62-65%) or traumatic (27-32%). Bleed locations most frequently treated with higher doses of rFVIIa were joint (60-68%) or muscle (20-25%). A total of 1521 rFVIIa doses were administered (median, three doses per bleed); 26% were 250 MUg kg(-1) or higher (initial dose, 82%). Bleeding stopped in 93% (160/172) of bleeds treated with rFVIIa 250 MUg kg(-1) or higher. No serious adverse drug-related events or thrombotic complications were reported. This data analysis from the HTRS Registry provides evidence of the safe and effective use of higher doses of rFVIIa (>=250 MUg kg(-1) ) in US practice. PMID- 21299751 TI - I need to pay more attention to mild haemophilia patients. PMID- 21299753 TI - Roles of Drosophila deltex in Notch receptor endocytic trafficking and activation. AB - Cell signaling mediated by the Notch receptor (N) regulates many cell-fate decisions and is partly controlled by the endocytic trafficking of N. Drosophila deltex (dx) encodes an evolutionarily conserved regulator of N signaling, an E3 ubiquitin ligase, which ubiquitinates N's intracellular domain. Although Dx was shown to function in N endocytosis in studies of dx over-expression, the roles of endogenous Dx have remained hidden. Here, we investigated N endocytosis in a dx null Drosophila mutant and found that endogenous Dx is required for at least two steps of N trafficking: the incorporation of N into endocytic vesicles from the plasma membrane and the transport of N from early endosomes to lysosomes. In the absence of Dx functions, N was stabilized in unknown endocytic compartments, where it was probably insulated from transport to lysosomes. We also found that canonical N signaling and Dx-mediated N signaling are activated in two different endocytic compartments, before N is incorporated into multivesicular body (MVB) interluminal vesicles and after N is transported from MVBs, respectively. The endocytic compartment in which Dx-mediated N signaling is activated appears to coincide with the activity of endogenous Dx in N trafficking. These findings extend our understanding of how N's trafficking and activation are correlated. PMID- 21299754 TI - CNOT2 depletion disrupts and inhibits the CCR4-NOT deadenylase complex and induces apoptotic cell death. AB - Eukaryotic mRNA decay is initiated by shortening of the poly (A) tail; however, neither the molecular mechanisms underlying deadenylation nor its regulation is well understood. The human CCR4-NOT complex is a major cytoplasmic deadenylase consisting of a combination of at least nine subunits, four of which have deadenylase activity. The roles of the other subunits remain obscure. Here, we show that CNOT2 depletion by siRNA induces apoptosis. We also show that CNOT2 depletion destabilizes the complex, resulting in the formation of a complex smaller than that formed in control siRNA-treated cells. The deadenylase activity of the CNOT6L subunit-containing complex prepared from CNOT2-depleted cells was less than that from control cells. Intriguingly, the formation of P-bodies, where mRNA degradation supposedly takes place, was largely suppressed in CNOT2-depleted cells. Furthermore, CNOT2 depletion enhanced CHOP mRNA levels, suggesting that endoplasmic reticulum (ER) stress was occurring, which causes apoptosis in a caspase-dependent manner. These results suggest that CNOT2 is important for controlling cell viability through the maintenance of the structural integrity and enzymatic activity of the CCR4-NOT complex. PMID- 21299752 TI - Dopamine transporter genotype modulation of neural responses to smoking cues: confirmation in a new cohort. AB - Previously we demonstrated profound effects of dopamine transporter (DAT) SLC6A3 genotype on limbic responses to smoking cues (SCs). Probands carrying at least one copy of the 9-repeat allele (9-repeat carriers) had greater neural responses to SCs in the anatomically interconnected rostral ventral striatum/medial orbitofrontal cortex (VS/mOFC), compared with homozygotes for the 10-repeat allele (10/10-repeats). To test the reliability of the initial findings, we examined perfusion functional magnetic resonance images acquired during SC exposure in a new cohort of smokers (N=26) who were genotyped for the SLC6A3 polymorphism. In smokers overall, activity was enhanced in the VS/mOFC (t=3.77). Contrasts between allelic groups revealed that 9-repeat carriers had a greater response to SCs in the VS (t=3.12) and mOFC (t=3.19). In separate groups, 9 repeat carriers showed increased activity in the VS (t=5.47) and mOFC (T=4.96), while no increases were observed in 10-repeats. Subjective reports of craving correlated with increased activity in reward-related structures including the extended amygdala, insula and post-central gyrus, and decreased activity in the dorsolateral prefrontal cortex, and were DAT-genotype dependent (r=0.63-0.96). In secondary analyses, we found that The Fagerstrom Test for Nicotine Dependence scores correlated with enhanced SC-induced perfusion in 10/10-repeats in the insula, mOFC, medial temporal and superior frontal gyri (r=0.50-0.82), while correlations were absent in 9-repeat carriers. Despite heterogeneity introduced by a host of factors, including variance in other genes involved in smoking behavior, we confirm that DAT genotype predicts the direction and location of neural responses to SCs. PMID- 21299755 TI - What's in this issue? PMID- 21299756 TI - A model to support the ethical elements of decisions made by advanced level practitioners. PMID- 21299757 TI - Advanced critical care nursing: a novel role with ancient history and unprecedented challenges worldwide. PMID- 21299758 TI - Literature review of the impact of nurse practitioners in critical care services. AB - AIMS: The comprehensive review sought to examine the impact of Critical Care Nurse Practitioner models, roles, activities and outcomes. METHOD: The Medical Literature Analyses and Retrieval (MEDLINE), The Cumulative Index of Nursing and Allied Health Literature (CINAHL); PubMED; PROQUEST; ScienceDirect; and the Cochrane database were accessed for the review. Alternative search engines were also included. The search was conducted with the key words: critical care, intensive care, acute, adult, paediatric, trauma, disease management programs, disease management, case management, neonatal, cardiology, neurological, retrieval, transfer and combined with Nurse Practitioner. From the identified 1048 articles 47 studies were considered relevant. RESULTS: Internationally, Critical Care Nurse Practitioners were located in all intensive care areas and services including post intensive care discharge follow-up, intensive care patient retrieval and transfers and follow-up outpatient services. The role focussed on direct patient management, assessment, diagnosis, monitoring and procedural activities. Critical Care Nurse Practitioners improved patient flow and clinical outcomes by reducing patient complication, morbidity and mortality rates. Studies also demonstrated positive financial outcomes with reduced intensive care unit length of stay, hospital length of stay and (re)admission rates. CONCLUSIONS: Internationally, Critical Care Nurse Practitioners are demonstrating substantial positive patient, service and nursing outcomes. Critical Care Nurse Practitioner models were cost effective, appropriate and efficient in the delivery of critical care services. RELEVANCE TO CLINICAL PRACTISE: In Australia, there was minimal evidence of Critical Care Nurse Practitioner impact on adult, paediatric or neonatal intensive care units. The international evidence suggests that the contribution of the role needs to be strongly considered in light of future Australian service demands and workforce supply needs. In Australia, the Critical Care Nurse Practitioner role and range of activities falls well short of international evidence. Hence, it was necessary to scope the international literature to explore the potential for and impact of the Critical Care Nurse Practitioner role. The review leaves little doubt that the role offers significant potential for enhancing and contributing towards more equitable health services. PMID- 21299759 TI - Steering a course towards advanced nurse practitioner: a critical care perspective. AB - AIM: This article is a report of a study of the experiences of expert critical care nurses in their transition to the role of advanced nurse practitioner within an intensive care unit (ICU) setting. BACKGROUND: The advanced nurse practitioner role was developed to support the ICU team and to undertake many of the roles traditionally associated with junior medical staff in this specialized area. The impetus for this study therefore was generated from the need to explore the role development experiences of trainee advanced nurse practitioners to inform future developments and practice. METHODS: This study used grounded theory methodology to conduct and analyse data from 25 participants. The data were collected between March 2010 and August 2010, using interview format. Data collection and analysis was conducted simultaneously using methods associated with grounded theory, theoretical sampling and the constant comparative method. RESULTS: 'Staying the course to advanced nursing practice' emerged as the core category, with four related major categories and substantive codes. In conjunction, the substantive theory explaining the essential processes involved comprised of three inextricably linked processes: situational, development and conceptual meaning. The developed conceptual model captures the unique experiences of expert critical care nurses during their transition to confident and competent advanced nurse practitioners. CONCLUSION: This study provides an account of the role transition from expert critical care nurse to advanced nurse practitioner, specifically the synthesis of expert nursing practice with traditional medical values. The conceptual model has the potential to be utilized as a framework for others embarking upon similar projects, informing advanced nurse practitioner roles within and out with critical care settings. PMID- 21299760 TI - The effect of nursing interventions on the intracranial pressure in paediatric traumatic brain injury. AB - AIMS AND OBJECTIVES: The aim of this research was to investigate the effect of five selected intensive care nursing interventions on the intracranial pressure (ICP) of moderate to severe traumatic brain-injured children in intensive care. BACKGROUND: The physiological effects of many nursing interventions in paediatric intensive care (PIC) are not known. This results in the lack of an evidence base for many PIC nursing practices. DESIGN: Prospective observational cohort study conducted over 3 years in a single tertiary referral paediatric intensive care unit (PICU) in the North West of England. METHODS: Five selected commonly performed nursing interventions were studied: endotracheal suctioning and manual ventilation (ETSMV), turning via a log-rolling (LR) approach, eye care, oral care and washing. These were studied in the first 72 h after injury. RESULTS: A total of 25 children with moderate to severe traumatic brain injury and intraparenchymal ICP monitoring in intensive care (aged 2-17 years) were enrolled. Both ETSMV and LR were associated with clinically and statistically significant changes in ICP from baseline to maximal ICP (p = 0.001 ETSMV; p = < 0.001 LR) and from maximal post-ICP (p = < 0.001 ETSMV; p = < 0.001 LR). Eye care, oral care or washing did not cause any clinically significant change in ICP from baseline. After decompressive craniectomy, none of the interventions caused significant changes in ICP. CONCLUSIONS: Only two of the five nursing interventions, endotracheal suctioning and LR, caused intracranial hypertension in moderate to severe traumatic brain-injured children, and after craniectomy, no care interventions caused any significant change in ICP. RELEVANCE TO CLINICAL PRACTICE: Knowledge about the physiological effects of many intensive care nursing interventions is lacking and this is magnified in paediatrics. This study provides a significant addition to the evidence base in this area and allows intensive care nurses to plan, implement and evaluate more effectively their nursing care for brain-injured children. PMID- 21299761 TI - Trust between nursing management and staff in critical care: a literature review. AB - AIM: This paper aims to provide a comprehensive review of the topic of trust between nurses and nurse managers in the context of critical care units. METHOD: A comprehensive literature review exploring the concept of trust between nurse and nurse managers was undertaken. Search terms were used both singularly and in combination and 71 relevant citations were found. Abstracts were read and in total 20 peer reviewed articles were retained as a result of consistency with project aims. RESULTS: Trust emerged as an essential component in the nurse patient relationship. However, trust among staff and management received little attention. CONCLUSIONS: Trust emerges as an important attribute of effective nurse managers. Nurse managers need to appreciate the importance of fostering a trustworthy relationship with subordinates. Engendering trust between management and staff empowers staff and has positive organizational outcomes. PMID- 21299762 TI - Inappropriate trust in technology: implications for critical care nurses. AB - AIMS AND OBJECTIVES: To explore evidence from the literature that critical care nurses may have inappropriate levels of trust in the technological equipment they use and the implications of this for patient safety. BACKGROUND: Nurses in intensive care units are required to observe the operation of an array of complex equipment. Failure of this equipment can have potentially fatal consequences for the patient. Research from other settings, such as the work of airline pilots, suggests that experienced operators of highly reliable automation may display inappropriately high levels of trust in the automation and this can lead to inadequate monitoring of the equipment by the operator. Inadequate monitoring means that the operator may fail to notice that the equipment is not functioning correctly which may have serious consequences. SEARCH METHODS: An initial search was made of a number of databases including Academic Search Premier, CINAHL, Pubmed and ScienceDirect. Extensive use was also made of citations found in articles uncovered by this initial search. CONCLUSIONS: Evidence suggests that there is potential for critical care nurses to display complacent attitudes. In addition, there are a number of reasons why the consequences of this complacency are not as visible as in other settings. IMPLICATIONS FOR PRACTICE: If nurses are not aware of the potential and consequences of inappropriate trust, there is a real possibility that patients may suffer harm because of it. There is an urgent need for more research to identify direct evidence of complacency and its consequences. There is also a need for these issues to be highlighted in the training of intensive care nurses and there are implications for intensive care unit practice protocols and equipment manufacturers. PMID- 21299763 TI - The objective structured clinical examination within intensive care nursing education. AB - BACKGROUND: The objective structured clinical examination is commonly referred to as an 'OSCE' and is a way of assessing a student's competency with clinical skills. The OSCE involves the student demonstrating a skill during a simulated clinical situation in a controlled environment instead of using real patients in the practice setting. Post-registered nursing courses are now beginning to use the OSCE as a form of summative assessment either as replacement for or in addition to skills assessed by a mentor in practice. AIM: This paper aims to reflect back on a recent experience of introducing an OSCE into a post registered, degree level intensive care nursing programme. METHODS: The process of reflection will be used throughout the analysis following the Six Thinking Hats tool. CONCLUSIONS: Organizing and implementing an OSCE for an intensive care nursing programme required a great deal of preparation and time of the teacher but also offered various benefits and advantages compared with other forms of assessment. Disadvantages and limitations of the OSCE are also identified in this article along with recommendations and practical advice for other teachers, examiners and students participating in OSCEs. PMID- 21299770 TI - Kinetics of carbon sharing in a bacterial consortium revealed by combining stable isotope probing with fluorescence-activated cell sorting. AB - AIMS: To determine the kinetics of substrate fluxes in a microbial community in order to elucidate the roles of the community members. METHODS AND RESULTS: The kinetics of substrate sharing in a bacterial consortium were measured by a new analytical approach combining immunostaining, stable isotope probing and fluorescence-activated cell sorting (FACS). The bacterial consortium, consisting of four strains and growing on 4-chlorosalicylate (4-CS), was pulse-dosed with the degradation intermediate [U-(13) C]-4-chlorocatechol (4-CC). Cells were stained with strain-specific antibodies sorted by FACS and the (13) C incorporation into fatty acids of the two most abundant members of the community was determined by isotope ratio mass spectrometry. From the two most abundant strains, the primary degrader Pseudomonas reinekei MT1 incorporated the labelled substrate faster than strain Achromobacter spanius MT3 but the maximal incorporation in strain MT3 was almost three times higher than in MT1. CONCLUSIONS: It has been reported that strain MT1 produces 4-CC as an intermediate but has a lower LD50 for it than strain MT3; therefore, MT3 still degrades 4-CC when the concentrations of 4-CC are already too toxic, even lethal, for MT1. By degrading 4-CC, produced by MT1, MT3 protects the entire community against this toxin. The higher affinity but lower tolerance of strain MT1 for 4 chlorocatechol compared to strain MT3 explains the complementary function these two strains have in the consortium adding exceptional stability to the entire community. SIGNIFICANCE AND IMPACT OF THE STUDY: The novel approach can reveal carbon fluxes in microbial communities generating quantitative data for systems biology of the microbial community. PMID- 21299771 TI - Phosphate-solubilization mechanism and in vitro plant growth promotion activity mediated by Pantoea eucalypti isolated from Lotus tenuis rhizosphere in the Salado River Basin (Argentina). AB - AIMS: To isolate and characterize phosphate-solubilizing strains from a constrained environment such as the Salado River Basin and to assess their phosphate-solubilizing mechanisms, to further selection of the most promising strains to inoculate and improve the implantation and persistence of Lotus tenuis in the most important area devoted to meat-cow production in Argentina. METHODS AND RESULTS: Fifty isolates were obtained and through BOX-PCR analysis, 17 non redundant strains were identified. Subsequently, they were found to be related to Pantoea, Erwinia, Pseudomonas, Rhizobium and Enterobacter genera, via 16S rRNA gene sequence analysis. This was in agreement with the clusters obtained by antibiotic resistance analysis. All isolates were tested for their phosphate solubilizing activity and selected strains were inoculated onto L. tenuis plants. The most efficient isolate, was identified as Pantoea eucalypti, a novel species in terms of plant growth-promoting rhizobacteria. CONCLUSIONS: The isolates obtained in this study showed a significant in vitro plant-growth promoting activity onto Lotus tenuis and the best of them solubilizes phosphate mainly via induction of the metabolism through secretion and oxidation of gluconic acid. SIGNIFICANCE AND IMPACT OF THE STUDY: The use of these bacteria as bioinoculants, alone or in combination with nitrogen-fixing micro-organisms, could be a sustainable practice to facilitate the nutrient supply to Lotus tenuis plants and preventing negative side-effects such as eutrophication. PMID- 21299772 TI - JC virus-associated nephropathy in a renal transplant recipient and comparative analysis of previous cases. AB - We report JC virus (JCV)-associated nephropathy in a renal allograft recipient and summarize the clinical and laboratory data of the 8 previous cases. A 28-year old male renal allograft recipient received a preemptive transplant from his father. Six months later, a kidney biopsy was performed because of deterioration of allograft function. Biopsy revealed tubulointerstitial mononuclear infiltrates with normal glomeruli; on hematoxylin and eosin staining, basophilic nuclear inclusions were seen in the nucleus of tubular cells. Urinary cytology failed to demonstrate decoy cells, but polymerase chain reaction of a urinary sample was positive for JCV 3.15 * 10(10) copies/mL. Additionally, polyomavirus (SV40) immunohistochemical staining was performed and was positive in the enlarged nuclei of tubular epithelial cells in the kidney biopsy sample. After the diagnosis of polyomavirus-associated nephropathy (PVAN) was confirmed by kidney biopsy, immunosuppressive agents were reduced. Intravenous immunoglobulin was administered 5 times at a dose of 500 mg/kg every other 3 weeks. Two months after diagnosis, the serum creatinine became stable and urinary viral load of JCV was decreased. Because viruria was still present, tacrolimus was converted to sirolimus. Four months after immunosuppressive agent conversion from tacrolimus to sirolimus, the viruria had disappeared. Review of the literature and our case demonstrates that male gender, previous acute rejection episode, low incidence of JCV viremia, PVAN pattern B histology, and reducing immunosuppression are the diagnostic touchstones for PVAN due to JCV. PMID- 21299773 TI - JC virus-associated nephropathy: lack of convincing documentation of the diagnosis. PMID- 21299774 TI - Renal allograft recipient with melioidosis of the urinary tract. PMID- 21299775 TI - Hafnia alvei pyelonephritis in a renal transplant recipient: case report and review of an under-recognized nosocomial pathogen. AB - We describe the first case to our knowledge of Hafnia alvei pyelonephritis in a renal transplant recipient. Clinicians should consider this under-recognized pathogen when clinically evaluating immunosuppressed patients with a history of invasive procedures. PMID- 21299776 TI - Ofloxacin: new applications for the prevention of urinary tract infections in renal graft recipients. AB - BACKGROUND: Urinary tract infections (UTIs), the most common form of bacterial infection in kidney transplant recipients, recently have been demonstrated to be detrimental for long-term graft outcome. Therefore, reinforcing antibiotic prophylaxis might be vital, in addition to basic hygiene recommendations, surgical care, and prophylaxis by trimethoprim-sulfamethoxazole. METHODS: In 2006, a Legionella pneumophila contamination of our department's water pipes meant that all the patients undergoing renal transplantation underwent a 1-month regimen of ofloxacin (OFLO) (200 mg every other day). We took this opportunity to measure the incidence of UTI, including acute pyelonephritis (APN), in 100 consecutive patients transplanted before (n = 50) and after (n = 50) this treatment decision was reached. We also studied the antimicrobial resistance profiles in our department and in the rest of the hospital. RESULTS: No patient developed Legionnaire's disease. A dramatic decrease in the incidence of UTI ( 63%) was also seen in patients undergoing OFLO treatment. Logistic regression analysis demonstrated that the use of OFLO was independently associated with a reduction in UTI (odd ratio [OR] = 0.31%, 95% confidence interval [CI] 0.11-0.84, P = 0.02) and APN (OR = 0.21%, 95% CI 0.07-0.98, P = 0.045). This protection was sustained during the whole first year post transplantation. As for resistance rates, we observed a decrease in the susceptibility of Pseudomonas aeruginosa to ciprofloxacin in our nephrology department, compared with that observed in the rest of the hospital. The incidence of multi-resistant bacteria was stable. DISCUSSION: Our unintentional extension of prophylactic antibiotherapy with OFLO gave rise to a dramatic decrease in the 1-year incidence of UTI and APN in kidney recipients. Emergence of resistant strains is, however, a major concern. PMID- 21299777 TI - Clostridium difficile and cytomegalovirus colitis co-infection: search for the hidden 'bug'. AB - Few cases of co-infection with cytomegalovirus (CMV) and Clostridium difficile colitis have been reported previously. We describe 2 cases of CMV and C. difficile colitis, and review 7 previously published reports. We aim to raise awareness of possible CMV-C. difficile co-infection, especially in refractory cases of C. difficile colitis. PMID- 21299778 TI - Incretin-based therapies--review of the physiology, pharmacology and emerging clinical experience. AB - Diabetes therapies based on manipulation of the incretin system are now widely available, with millions of people receiving treatment. The incretin hormones, glucose-dependent insulinotropic peptide and glucagon-like peptide-1 are released from endocrine cells in the small intestinal mucosa primarily in response to oral nutrient ingestion. They have various effects, but those most relevant to metabolic dysfunction include stimulation of insulin and suppression of glucagon secretion, with resultant reduction in fasting and postprandial glucose. Incretin secretion and/or action is impaired in type 2 diabetes, leading to development of strategies aimed at redressing this abnormality. These strategies include pharmacological inhibition of dipeptidyl peptidase-4, the enzyme responsible for the short half-life of endogenous incretins, and administration of long-acting dipeptidyl peptidase-4-resistant peptides that bind to and activate the glucagon like peptide-1 receptor. In this review, we address aspects of incretin biology and pharmacotherapy with a view to highlighting potentially clinically relevant issues and areas of basic research that may impinge on these. PMID- 21299779 TI - Radiographic osteoarthritis and pain are independent predictors of knee cartilage loss: a prospective study. AB - BACKGROUND: There is controversy about whether pain and radiographic osteoarthritis (ROA) predict subsequent cartilage loss. The aim of this study was to describe the relationship between ROA, pain and cartilage loss in the knee. METHODS: We studied randomly selected subjects at baseline and approximately 2.9 years later (n= 399). The presence of ROA was assessed at baseline with a standing anteroposterior semiflexed radiograph scored using the Osteoarthritis Research Society International atlas for osteophytes (OP) and joint space narrowing (JSN). Pain was assessed by the Western Ontario McMaster Osteoarthritis Index. Subjects' medial and lateral tibial cartilage volumes were determined by magnetic resonance imaging at both time points. RESULTS: In cross-sectional analysis, both medial and lateral tibial cartilage volumes were lower in those with ROA. Any medial ROA predicted medial tibial cartilage loss (3.2% (standard deviation (SD) 5.6) vs 1.9% (SD 5.3) per annum) while any lateral ROA predicted both medial (4.0% (SD 6.0) vs 2.2% (SD 5.3) per annum) and lateral (3.5% (SD 5.8) vs 1.6% (SD 4.2) per annum) tibial cartilage loss (all P < 0.05). In multivariate analysis, JSN and OP at both medial and lateral sites had independent dose response associations with tibial cartilage loss at both sites. Pain was an independent predictor of lateral, but not medial, tibial cartilage loss after taking ROA into account. CONCLUSIONS: Subjects with ROA (either JSN or OP) and, to a lesser extent, pain lose cartilage faster than subjects without ROA and the more severe the ROA the greater the rate of loss. These findings have implications for the design of clinical trials. PMID- 21299780 TI - General practitioners' knowledge and management of viral hepatitis in the migrant population. AB - BACKGROUND: Escalating morbidity and mortality associated with hepatitis B virus (HBV) and hepatitis C virus (HCV) infections represent a major health burden in Australia, particularly among migrants from endemic areas who may present late. METHODS AND AIMS: We evaluated the knowledge and educational needs of general practitioners (GPs) in the St George Division, Sydney which serves a large migrant population. The aims of the study were to identify gaps in knowledge about viral hepatitis that may affect management and referral patterns. GPs completed a survey comprised of 15 questions. They were also invited to comment on barriers to managing viral hepatitis in migrant patients. RESULTS: A 44% response rate was achieved from 280 eligible GPs. Forty-two per cent of GPs lacked confidence in interpreting HCV serology and 20% for HBV serology. Twenty two per cent of GPs did not recognise HCC as a complication of HBV and 18% for HCV. Twenty per cent of GPs were unaware of treatment for HBV. Forty-seven per cent of GPs were uncertain whether pregnant women could receive HCV treatment. Twenty-three per cent and 21% of respondents believed that all HCV- or HBV infected mothers, respectively, should not breast-feed. Eighty-nine per cent of GPs identified language difficulties as the main barrier to treatment among the migrant population. CONCLUSIONS: There were gaps in the knowledge of GPs particularly concerning natural history, diagnosis, treatment availability and management of pregnant or lactating women with viral hepatitis. Specific educational initiatives targeting these deficits are required as well as increased availability of language resources for managing patients from a non English-speaking background. PMID- 21299781 TI - Reporting clinical trial information: colorectal cancer trials at Sydney Cancer Centre. AB - BACKGROUND: Clinical trial units are integral to the functioning of a medical oncology department with patient access to clinical trials an important component in patient care. There has been a paucity of potential key performance indicators in medical oncology and clinical trial information may be utilised for this purpose. The aim of this study was to record retrospectively and collate prospectively collected information regarding basic demographics, response rate, progression and survival plus grade 3 or 4 toxicity in patients enrolled in clinical trials for metastatic colorectal cancer at the Sydney Cancer Centre between 1999 and 2007. METHODS: Baseline patient demographics, clinical response, progression dates, grade 3 or 4 toxicities plus treatment-related fatalities were collected from individual clinical trials. Outcome measures were clinical response, progression-free survival and overall survival. RESULTS: There was a total of 14 trials undertaken during the defined period for patients with metastatic colorectal cancer. There was available information for 243 patient trials with sufficient information regarding response rates, toxicity, progression and survival. Tumour response rates ranged from 27% to 66% for first line chemotherapy trials and 0% to 20% for non-first line chemotherapy trials. The overall progression-free survival was 6.4 months and overall survival 14.0 months for all trials. There was one treatment-related fatality on clinical trial during this period. CONCLUSIONS: Results of our clinical database have been used here to illustrate the concept and value of reporting clinical trial information in medical oncology. Public reporting of such information may allow for comparisons between units and for quality improvement. PMID- 21299782 TI - Smoking cessation post-discharge following nicotine replacement therapy use during an inpatient admission. AB - BACKGROUND: Cigarette smoking remains a health issue despite declining prevalence in Australia. The burden of tobacco-related morbidity affects hospitals, particularly those in lower socioeconomic areas where prevalence is highest. AIM: We have shown that nicotine replacement therapy (NRT) use during hospitalization increases motivation to quit post-discharge. We postulated that subjects using the nicotine patch post-discharge, in comparison to the inhaler, would have higher rates of abstinence at 12 months after discharge. The aim was to compare the efficacy of the nicotine patch or inhaler formulation for cessation post discharge, following use during admission. METHODS: Post-discharge, subjects chose their preferred formulation (patch or inhaler) based on their experience with NRT during admission. Tailored, medium-intensity support was provided with subsidized NRT during outpatient visits. Subjects were followed for 12 months. Exhaled breath CO confirmed non-smoking. RESULTS: Of 123 subjects enrolled, 37 elected to use the inhaler, 50 the patch and 36 no NRT. At 12 months continuous abstinence rates were 38%, 38% and 25% respectively. DISCUSSION: This study built upon the 'teachable moment' provided by hospitalization and the inpatient use of NRT, encouraging cessation post-discharge. Both NRT formulations provided similar 12 month cessation rates, and were superior to those achieved by subjects electing not to use NRT. Although the patch was the most popular formulation, the inhaler provided an equally efficacious alternative which addressed other facets of cigarette addiction. Subjects electing not to use NRT were less successful. Continuous abstinence rates were equivalent to community-based studies using NRT. We recommend a similar programme to other hospitals. PMID- 21299783 TI - Myelodysplasia in the Wellington region 2002-2007: disease incidence and treatment patterns. AB - AIMS: To obtain accurate incidence data for myelodysplasia in the Wellington Region of New Zealand (NZ), to analyse the treatment these patients received and to review their outcome. METHODS: Patients diagnosed with myelodysplasia between 1 January 2002 and 1 September 2007 were identified. Their bone marrow biopsy, clinical record, cytogenetic analysis and transfusion record were analyzed. RESULTS: Seventy myelodysplastic patients were identified yielding an incidence of 2.75 per 100,000 per year. Median survival was 23 months, and transformation to acute leukaemia occurred in five patients (7.1%). Three patients (4.3%) received an allogeneic bone marrow transplant, and five patients (7.1%) received disease modifying treatment. Fifty-six of 70 patients (80%) received a blood transfusion, a mean of 32.9 red blood cell (RBC) units were transfused to each transfusion recipient during the study period of 68 months. One of 70 patients developed a clinical syndrome of iron overload. CONCLUSION: The incidence of myelodysplasia in Wellington, NZ is similar to incidence figures from previously published studies. The treatment these patients received was predominantly supportive through RBC transfusion. Effective iron chelation therapy measures were not used although there appeared to be a low incidence of clinical iron overload in the study population. The data in this study will be available for comparison with future studies to assess trends in incidence, treatment and outcome in myelodysplastic patients in NZ. PMID- 21299784 TI - Socioeconomic deprivation, readmissions, mortality and acute exacerbations of bronchiectasis. AB - BACKGROUND: Bronchiectasis is known to cause significant morbidity in children in New Zealand. Little is known of the disease in adults. AIM: Our objective was to characterise a cohort of adults who presented to hospital with acute exacerbations of the disease. METHODS: We retrospectively collected information on all exacerbations treated as inpatients from a single hospital in South Auckland, New Zealand during 2002. RESULTS: We collected information on 307 exacerbations in 152 patients. Twenty-seven per cent were of Maaori ethnic origin, and 44% Pacific. Seventy per cent lived in areas categorised as the 20% most deprived in New Zealand. Comorbid conditions were present in 80% of patients - most commonly chronic obstructive pulmonary disease, asthma, diabetes and cardiac disease. Seventy (46%) patients had at least one readmission and 32 patients (21%) died within 12 months of admission to hospital. Greater deprivation was associated with increased mortality at 12 months after admission after adjusting for other factors (OR 11, 95% CI 2.0-61, P= 0.006). In the subgroup who underwent high-resolution computed tomographic scanning (93), increasing severity of bronchiectasis (modified Bhalla score) was associated with readmission within 12 months (P= 0.004), but not mortality (P= 0.419). CONCLUSIONS: We have shown that exacerbations of bronchiectasis in South Auckland are more common in patients who are predominantly of Maaori or Pacific descent and are socioeconomically deprived. Admission to hospital for an exacerbation is associated with high readmission and mortality rates. PMID- 21299785 TI - Guidelines for patient selection and performance of carotid artery stenting. AB - The endovascular treatment of carotid atherosclerosis with carotid artery stenting (CAS) is controversial. The inter-collegiate Carotid Stenting Guidelines Committee (CSGC) recommends that CAS should not be performed in the majority of patients requiring carotid revascularization. CAS may be considered for specific high risk patients with symptomatic severe carotid stenosis who have contraindications for carotid endarterectomy, or in those under 70years of age where carotid re-vascularization is considered appropriate. Advances in endovascular technologies and the long-term results of randomized controlled trials will guide future revisions of these guidelines. PMID- 21299786 TI - Diagnostic utility of endobronchial ultrasound-guided transbronchial needle aspiration compared with transbronchial and endobronchial biopsy for suspected sarcoidosis. AB - BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is an accurate and minimally invasive technique that has been shown to have excellent diagnostic yield in the investigation of mediastinal and hilar lymphadenopathy. There is, however, little evidence comparing this procedure to the traditional diagnostic approach of transbronchial lung (TBLB) and endobronchial (EB) biopsies combined with characteristic clinical and radiological features in sarcoidosis. AIM: To compare the diagnostic yield of EBUS-TBNA, TBLB and EB in patients with suspected sarcoidosis. METHODS: Data from 40 consecutive patients with suspected sarcoidosis who underwent combined EBUS TBNA with TBLB and EB biopsies were recorded. RESULTS: A total of 37 patients was confirmed as sarcoidosis, and three had other diagnoses. There was no difference in diagnostic accuracy rates between EBUS-TBNA and TBLB for all stages of sarcoidosis (84% vs 78%, P= 0.77). Combined EBUS-TBNA and TBLB procedures yielded a diagnostic accuracy of 100%. There was a highly significant difference in diagnostic accuracy between EBUS-TBNA and EB in stage I (80% vs 27%) (P < 0.01) and stage II disease (86% vs 27%) (P < 0.01). Similarly, a highly significant difference in diagnostic accuracy was seen between TBLB and EB (P < 0.01). No adverse events occurred. CONCLUSION: Endobronchial ultrasound-guided transbronchial needle aspiration alone has a high diagnostic yield with a very low complication rate for patients with suspected sarcoidosis. PMID- 21299787 TI - Prevalence and determinants of QT interval prolongation in medical inpatients. AB - BACKGROUND: QT interval prolongation carries an increased risk of torsade de pointes and death. AIM: We sought to determine the prevalence of QT prolongation in medical inpatients and to identify determinants of this condition. METHODS: We enrolled consecutive patients who were admitted to the internal medicine ward and who had an electrocardiogram performed within 24 h of admission. We collected information on baseline patient characteristics and the use of QT-prolonging drugs. Two blinded readers manually measured the QT intervals. QT intervals were corrected for heart rate using the traditional Bazett formula and the linear regression-based Framingham formula. We used logistic regression to identify patient characteristics and drugs that were independently associated with QTc prolongation. RESULTS: Of 537 inpatients, 22.3% had a prolonged QTc based on the Bazett formula. The adjusted odds for QTc prolongation based on the Bazett correction were significantly higher in patients who had liver disease (OR 2.9, 95% CI: 1.5-5.6), hypokalaemia (OR 3.3, 95% CI: 1.9-5.6) and who were taking >=1 QT-prolonging drug at admission (OR 1.7, 95% CI: 1.1-2.6). Overall, 50.8% of patients with QTc prolongation received additional QT-prolonging drugs during hospitalisation. CONCLUSIONS: The prevalence of QTc prolongation was high among medical inpatients but depended on the method used to correct for heart rate. The use of QT-prolonging drugs, hypokalaemia and liver disease increased the risk of QTc prolongation. Many patients with QTc prolongation received additional QT prolonging drugs during hospitalisation, further increasing the risk of torsade de pointes and death. PMID- 21299788 TI - Orthopaedic joint infections - a challenge today as it was in the past. PMID- 21299789 TI - Living donor transplantation: is there inequality of access? PMID- 21299790 TI - Annual Scientific Congress, May 2010 - through the eyes of a pre-SET trainee. PMID- 21299791 TI - Early post-operative fever. PMID- 21299793 TI - A systematic review of dermal fillers for age-related lines and wrinkles. AB - BACKGROUND: Dermal fillers are gaining popularity for rapid aesthetic improvement. Long-term efficacy and safety have not been well documented. The aim of this systematic review was to assess the safety and efficacy of injectable dermal fillers compared with other facial augmentation techniques for the management of age-related lines and wrinkles. METHODS: Studies including patients receiving injectable semi-permanent or permanent dermal fillers for age-related lines and wrinkles were included in this review. Efficacy outcomes (including changes in skin thickness and patient satisfaction) and safety outcomes (including mortality, lumps and infections) were examined. RESULTS: Three randomized control trials and six case series were included. Permanent and semi permanent dermal fillers improved subjective ratings of appearance and resulted in higher patient satisfaction than temporary fillers. Long-term efficacy appeared good in the few studies that reported it. Short-term safety appeared favourable. Lumps were reported in all but one study but received little follow up. Long-term safety data were limited. CONCLUSIONS: The treatment of age-related lines and wrinkles with permanent and semi-permanent dermal fillers is more efficacious compared with temporary fillers in those studies that compared them. Case series evidence suggests that these fillers achieve their objective, which is to decrease the visible effects of age-related changes. These fillers appear at least as safe as temporary fillers in the short term in those studies that compared them. Long-term safety could not be determined. PMID- 21299794 TI - Autologous chondrocyte implantation: an overview of technique and outcomes. AB - Articular cartilage is susceptible to damage; however, it has limited capacity for repair. Damage can lead to persistent symptoms including pain, swelling, and loss of function and may ultimately progress to symptomatic degeneration of the joint. To restore function and minimize symptoms, many advocate surgical intervention in selected candidates, which can range from arthroscopic debridement to restorative procedures depending on patient and lesion characteristics. Autologous Chondrocyte Implantation (ACI) is a two-stage, typically second-line intervention where cultured autologous chondrocytes are used with the aim of resurfacing symptomatic chondral defects with hyaline or hyaline-like cartilage. Careful patient selection is important. We present an overview of this procedure including indications and contraindications, surgical technique, and post-operative management. A review of published ACI outcomes is then presented. PMID- 21299795 TI - Variation in rates of hip and knee joint replacement in Australia based on socio economic status, geographical locality, birthplace and indigenous status. AB - BACKGROUND: Our understanding of the incidence of joint replacement across different subgroups of the Australian population is limited. This study investigated whether rates of hip and knee joint replacement vary according to socio-economic status, geographical locality, birthplace and indigenous status. METHODS: Data from the National Hospital Morbidity Database were obtained. All separations for primary hip or knee joint replacement with the principal diagnosis of arthritis were identified. Age-standardized procedure rates were compared based on socio-economic status, geographical locality, birthplace and indigenous status. RESULTS: Compared with age- and gender-matched individuals, rates of joint replacement overall were significantly lower in people living in the most disadvantaged (P < 0.05) and remote areas (P < 0.001), people born outside Australia (P < 0.05) and indigenous people (P < 0.001). However, there were some exceptions. Knee replacement rates were higher in the most disadvantaged areas than in the least disadvantaged areas (P < 0.01), and both hip and knee replacement rates were higher in regional areas than in major cities (P < 0.05). Males and females born in New Zealand and females born in the United Kingdom, Ireland and parts of Europe had a greater rate of hip replacement, and females from North Africa and the Middle East had a greater rate of knee replacement, than Australia-born people (P < 0.001). CONCLUSIONS: There is significant variation in the rates of primary total hip and knee replacement in Australia. Further investigation is needed to determine whether this simply reflects patterns of disease and disease risk factors, or is because of inequalities in health care, unmet need, and/or surgical or patient-related factors. PMID- 21299796 TI - Prosthetic joint infection: challenges of diagnosis and treatment. AB - Arthroplasty for arthritis has led to remarkable improvement in patient quality of life and alleviation of symptoms. A major complication of this surgery is infection. This review examines current understanding of epidemiology, diagnosis, treatment and prevention of prosthetic joint infections. In particular, this article focuses on the role of biofilm formation in the pathogenesis of device infections and the diagnostic and treatment challenges associated with this process. PMID- 21299797 TI - Significance of sentinel infective events in haematogenous prosthetic knee infections. AB - BACKGROUND: Infection after primary knee arthroplasty is devastating. The aim of this study was to determine the significance of sentinel infective events prior to the development of haematogenous prosthetic knee infection. METHODS: A retrospective single-centre case control study of 1641 primary knee arthroplasties was conducted between 1998 and 2006. Seventeen haematogenous prosthesis infections were identified and were matched with 51 controls. Perioperative data were collected prospectively, and co-morbidities, infection parameters and sentinel events were collected from patient files and questionnaires. Analysis was performed between controls and the 17 haematogenous infections. RESULTS: The overall prosthetic infection rate was 2.2%. Acute infections accounted for 1.2% with late haematogenous accounting for 1%. The mean time to infection in the haematogenous infection group was 2.3 years (range 3 months to 11 years), and the mean follow-up was 3.8 years (range 7 months to 11 years). Significant risk factors included the number of co-morbidities (relative risk 3.4) and a sentinel event of cellulitis (relative risk 2.7). Fifteen of 17 cases described a sentinel event prior to infection compared with 31 of 51 controls (P= 0.041). The commonest preceding event was skin or soft tissue infection in nine (53%) cases. The most common infecting organism was Staphylococcus aureus in 12 patients (four methicillin-resistant Staphylococcus aureus, eight methicillin-sensitive Staphylococcus aureus). CONCLUSIONS: Fifteen of 17 (88%) patients who developed late haematogenous infection had a preceding sentinel event with the commonest source being skin and soft tissue infection. Haematogenous infections are more likely to occur in patients with multiple co morbidities. PMID- 21299799 TI - Quality of life after penile reconstruction using the radial forearm flap in adult bladder exstrophy patients - technique and outcomes. AB - BACKGROUND: Patients who have undergone reconstruction of bladder extrophy can have an extremely short penis, which can be functionally and psychologically debilitating. Penile reconstruction with the radial forearm free flap has the potential to provide these patients with improved genital appearance and sexual function. Quality of life after penile reconstruction is an important outcome measure in evaluation of the procedure. METHODS: We describe five patients who underwent total penile reconstruction with radial forearm free flaps and interview them with a quality of life questionnaire. RESULTS: Responses were overwhelmingly positive with regard to improved self-image as well as sexual function. CONCLUSIONS: This series supports the overwhelmingly positive change in quality of life to be gained with radial forearm free flap penile reconstruction for patients with an extremely short native penis in the adult exstrophy patient. PMID- 21299798 TI - Influence of screw diameter and number on reduction loss after plating of distal radius fractures. AB - BACKGROUND: The current options for plate-screw combinations in volar locking distal radius plates used for the treatment of distal radius fractures are either plates with a single distal screw row or plates with multiple distal screw rows. Additionally, the screws themselves may have either fixed angle locking or polyaxial locking mechanisms. To date, there is no evidence or consensus regarding the optimal plate-screw combination. The aim of this study was to assess the biomechanical behaviour of different plate-screw combinations with respect to total distal screw number, number of distal screw rows and screw projection surface area of the most distal row. METHODS: Biomechanical study to assess six different plating configurations in five different volar locking plate models in a Sawbone distal radius fracture model. The specimens were loaded with 800 Newton loads for 2.000 cycles at 1 Hz. After cyclic loading, load-to-failure testing was performed. RESULTS: With cyclical testing, there was a significant and positive correlation between rigidity and a greater projection area of the most distal screws. Dorsal tilting was significantly more pronounced in plate models with a lesser projection area of the most distal screws and a smaller number of distal screws. With load-to-failure testing, there was a significant increase in rigidity with increasing screw projection area of the most distal row and total number of distal screws. CONCLUSIONS: Additional distal screw rows in volar locking distal radius plates might not add substantially to resistance against loss of reduction in the post-operative period. PMID- 21299800 TI - Survey of trends in minimally invasive intervention for necrotizing pancreatitis. AB - BACKGROUND: Minimally invasive techniques to manage infected pancreatic necrosis have been recently developed and changes in their pattern of use are unknown. The aims of this survey were to determine the trends in the role of minimally invasive techniques to manage infected complications of necrotizing pancreatitis and the barriers to performing minimally invasive necrosectomy in Australia and New Zealand. METHODS: Members of the Australian and New Zealand Hepatic Pancreatic and Biliary Association were surveyed. Participant demographics and necrotizing pancreatitis caseload were determined. The perceived role of percutaneous catheter drainage and minimally invasive necrosectomy for pancreatic abscess, infected pseudocyst and infected pancreatic necrosis were scored on Likert scales, comparing 2002 with 2007. Barriers to performing minimally invasive necrosectomy were scored. RESULTS: The response rate was 49% (44/90). Between 2002 and 2007, the role of percutaneous catheter drainage became more important as primary (P= 0.05) and secondary (P= 0.01) treatment for pancreatic abscess, and prior to minimally invasive necrosectomy for abscess, pseudocyst and necrosis (P < 0.01). Minimally invasive necrosectomy became increasingly important as primary treatment for infected necrosis (P < 0.01) and had been used by 47% of respondents. The greatest barriers to performing minimally invasive necrosectomy were lack of training and experience in the techniques, and the anatomical position and complexity of the target lesion. CONCLUSION: Minimally invasive techniques have an increasingly important perceived role in the management of pancreatic abscess, infected pseudocyst and infected pancreatic necrosis. Further evidence is required to determine the best techniques for treating each form of infection associated with necrotizing pancreatitis. PMID- 21299801 TI - Intraoperative radiotherapy in women with early breast cancer treated by breast conserving therapy. AB - BACKGROUND: Previous studies demonstrated the feasibility of intraoperative radiotherapy (IORT) to the primary tumour bed using a miniature electron beam driven X-ray source for early breast cancer. This study aimed to evaluate the feasibility of IORT as a tumour bed boost after whole breast irradiation (WBI) in breast conserving therapy. METHODS: This was a single-arm prospective trial for women with breast cancer measuring <3 cm. After breast-conserving surgery, a single IORT dose of 5 Gray (Gy) prescribed to 10 mm from the applicator surface was delivered to the breast tissues using 50 kV X-ray followed by standard WBI. The feasibility rate of protocol therapy was defined as the percentage of all women who completed both IORT and WBI. A desirable completion rate was >90%. The protocol therapy would be considered unsuitable for further development if the completion rate was <75% or severe acute toxicity occurred in >15% of women who received IORT. RESULTS: Sixty patients were recruited for the study. IORT and WBI were delivered in 58 and 55 patients, respectively. Thus, the feasibility rates of IORT alone and both IORT and WBI were 97% (95% confidence interval (CI), 89 99%) and 92% (95% CI, 83-97%), respectively. A severe surgical complication or grade 3 or 4 acute radiation toxicity were identified in 10% (6/58) of women who had IORT. CONCLUSION: Tumour bed boost using IORT in women with early breast cancer treated with conservative surgery and WBI was shown to be feasibly consistent with previous studies. PMID- 21299802 TI - Preoperative fine needle cytology and imaging facilitates the management of submandibular salivary gland lesions. AB - BACKGROUND: Lesions of the submandibular gland represent a pleomorphically diverse group in which benign and malignant pathologies are difficult to differentiate from each other. Accurate diagnosis and surgical intervention relies upon clinical presentation, examination and investigations to guide appropriate management. The current series aimed to identify the roles of preoperative cytology and imaging with subsequent histopathology in the management of these lesions. METHODS: Between 1998 and 2008, 54 patients of median age 54 years (range 25-94), with a male : female ratio of 1:3.5 were identified, of which, 50 patients underwent 52 excisions of the submandibular gland. Demographic data were recorded. The utility of imaging and cytology were analysed, and the accuracy of cytology correlated with histology. RESULTS: Pathologies of resected specimens were sialadenitis 17 (32%), pleomorphic adenomas nine (17%), calculi eight (15%), lymphoma five (10%), squamous cell carcinoma two (4%), adenoid cystic carcinoma one (2%) and other 10 (20%). Twenty eight patients (52%) underwent fine-needle aspiration cytology/core biopsies, of which 25 (89%) were correlated with histology. The accuracy, sensitivity and specificity of the fine-needle aspiration cytology correlation with histology were 88.0%, 71.4% and 94.4%, respectively. Overall, the complication rate was 9.6%; involving five temporary nerve palsies of the marginal mandibular branch of the facial nerve, including one temporary lingual nerve palsy. CONCLUSION: This series demonstrates histological outcomes in patients specific to the submandibular salivary gland. The malignancy rate was low compared to current published literature. The transcervical surgical approach to submandibular gland pathology is a safe and effective method with minimal morbidity when performed by experienced surgeons. No single investigative modality can be solely aligned with diagnosing a specific lesion of the submandibular gland. PMID- 21299803 TI - Endoscopic ultrasound guided fine needle aspiration (EUS-FNA) of mediastinal lesions. AB - BACKGROUND: Mediastinal endoscopic ultrasound guided fine needle aspiration (EUS FNA) is a recognized diagnostic and staging procedure for non-small cell lung carcinoma (NSCLC). The aim of this study was to report the experience of mediastinal EUS in an Australian tertiary hospital. METHODS: A retrospective review was conducted on all patients undergoing mediastinal EUS from February 2002 until August 2007 at St Vincent's Hospital, Melbourne. Data were obtained from the EUS databases at St Vincent's Hospital and patient endoscopy reports. The results of EUS-FNA were compared with final diagnosis to calculate sensitivity and specificity. Surgical pathology or long-term follow-up was used to identify false positive or negative results. RESULTS: One hundred forty-eight mediastinal EUS procedure were performed. Males comprised 63.5% and the mean age was 64.3 (range 27-85). Referrals (47%) were from respiratory physicians and 27% were from cardiothoracic surgeons. Indications for EUS-FNA included unexplained mediastinal lymphadenopathy and/or lung lesion for investigation and staging of known NSCLC. Full data were available on 124 (83.8%) cases. Data were analysed from a subset of 112 where FNA was performed. For each indication, EUS-FNA had a high sensitivity and specificity: staging of known NSCLC (sensitivity 92.9%, specificity 88.9%), mediastinal lymphadenopathy (sensitivity 100%, specificity 100%) and lung lesion (sensitivity 94.4%, specificity 85.7%). There were no major complications. CONCLUSION: This large series of mediastinal EUS shows that it is an important and useful tool for the assessment of mediastinal pathology. It is safe and highly accurate, and should be incorporated into the staging algorithm for NSCLC. PMID- 21299804 TI - Validation of five contemporary prognostication systems for primary pancreatic endocrine neoplasms: results from a single institution experience with 61 surgically treated cases. AB - BACKGROUND: Presently, several systems for the prognostication of pancreatic endocrine neoplasms (PENs) exist and the most appropriate classification system has not been clearly defined. This study aims to validate the performance of the 2004 World Health Organization (WHO), European Neuroendocrine Tumor Society (ENETS), Memorial Sloan-Kettering Cancer Center (MSKCC), American Joint Committee for Cancer (AJCC) TNM staging and Bilimoria criteria in a cohort of patients with PENs who underwent surgery at a single institution. METHODS: This study is a retrospective review of 61 consecutive patients who underwent surgical treatment for PEN. Actuarial disease-specific survival (DSS) of all 61 patients and recurrence-free survival (RFS) of 53 patients who had curative resection were analysed. RESULTS: On univariate analyses, tumour size >=50 mm, non-curative resection, lymph node involvement, presence of distant metastases, presence of necrosis, mitotic count >=2/10 hpf and poor differentiation were associated with decreased DSS. Tumour size >=50 mm, lymph node involvement, lymphovascular invasion, presence of necrosis and mitotic count >=2/10 hpf were associated with decreased actuarial RFS. All five staging systems were useful in stratifying the 61 patients according to actuarial DSS. However, the MSKCC grading and ENETS grading systems were not statistically significant in stratifying DSS in the 61 patients. In the 53 patients who underwent curative resection, the WHO, ENETS, MSKCC, AJCC staging and the MSKCC grading systems were successful in stratifying the patients according to actuarial RFS. However, the Bilimoria scoring and ENETS grading systems were not useful in prognosticating these 53 patients. CONCLUSION: All five classification systems were useful for the prognostication of surgically treated PENs in our patient cohort. PMID- 21299805 TI - A large inguinoscrotal hernia with stomach content. PMID- 21299806 TI - Traumatic pseudoaneurysm of the superficial temporal artery. PMID- 21299813 TI - Criticism of ASOHNS guidelines incorrect (Re: ANZ J. Surg. 80: 480-2). PMID- 21299815 TI - An overview of the Annual Scientific Congress. PMID- 21299816 TI - Unusual metastasis from a rectal adenocarcinoma: penile metastasis. PMID- 21299817 TI - Temporal artery biopsies (Re: ANZ J. Surg. 2010; 80: 479-80). PMID- 21299818 TI - Blunt trauma to horseshoe kidney. PMID- 21299819 TI - Massive localized lymphoedema. PMID- 21299820 TI - A pulsatile and painful buttock. PMID- 21299821 TI - A simple device to reduce noise generated by Simpulse(r). PMID- 21299822 TI - Emphysematous cholecystitis: a rare presentation of a life-threatening disease. PMID- 21299824 TI - A global experiment suggests climate warming will not accelerate litter decomposition in streams but might reduce carbon sequestration. AB - The decomposition of plant litter is one of the most important ecosystem processes in the biosphere and is particularly sensitive to climate warming. Aquatic ecosystems are well suited to studying warming effects on decomposition because the otherwise confounding influence of moisture is constant. By using a latitudinal temperature gradient in an unprecedented global experiment in streams, we found that climate warming will likely hasten microbial litter decomposition and produce an equivalent decline in detritivore-mediated decomposition rates. As a result, overall decomposition rates should remain unchanged. Nevertheless, the process would be profoundly altered, because the shift in importance from detritivores to microbes in warm climates would likely increase CO(2) production and decrease the generation and sequestration of recalcitrant organic particles. In view of recent estimates showing that inland waters are a significant component of the global carbon cycle, this implies consequences for global biogeochemistry and a possible positive climate feedback. PMID- 21299823 TI - A herbivore that manipulates plant defence. AB - Phytopathogens and herbivores induce plant defences. Whereas there is evidence that some pathogens suppress these defences by interfering with signalling pathways involved in the defence, such evidence is scarce for herbivores. We found that the invasive spider mite Tetranychus evansi suppresses the induction of the salicylic acid and jasmonic acid signalling routes involved in induced plant defences in tomato. This was reflected in the levels of inducible defence compounds, such as proteinase inhibitors, which in mite-infested plants were reduced to even lower levels than the constitutive levels in herbivore-free plants. Additionally, the spider mite suppressed the release of inducible volatiles, which are implicated in plant defence. Consequently, the mites performed much better on previously attacked plants than on non-attacked plants. These findings provide a new perspective on plant-herbivore interactions, plant protection and plant resistance to invasive species. PMID- 21299825 TI - The interrelationship between crypsis and colour polymorphism. AB - The mechanisms behind the evolution and maintenance of conspicuous visible polymorphisms comprising tens of morphs present a challenge to evolutionary theory. However, for cryptic forms Endler (Evol. Biol., 11, 1978, 319) conjectured that complex backgrounds facilitate polymorphism because in such habitats there are several ways to resemble the resting surface. We use computer simulation to explore the evolution of cryptic morphs on increasingly complex backgrounds under regimes that include selection for crypsis, apostatic predation and dietary wariness. We show that there is a monotonic increase in the number of morphs evolving in a population as the potential number of cryptic morphs increases. The relationship is very weak with selection for crypsis alone, but much stronger with the addition of apostatic selection. In contrast, when dietary wariness is added to the model the plot of number of morphs maintained, as a function of the potential number of cryptic forms available, is minimized at an intermediate number of cryptic forms, i.e. is V-shaped. These counter-intuitive patterns are robust to varying strengths of apostatic selection and different implementations of dietary wariness, and are more pronounced when predator and prey generation lengths are similar. PMID- 21299826 TI - Posttransplantation hepatitis B prophylaxis with combination oral nucleoside and nucleotide analog therapy. AB - Liver transplant recipients are at risk of developing recurrent hepatitis B after liver transplantation for hepatitis B virus (HBV)-related liver disease. We evaluated the efficacy of a new hepatitis B prophylaxis regimen involving conversion from at least 12 months of HBIg with lamivudine to combination therapy with an oral nucleoside and nucleotide analog. Between June 2008 and May 2010, a total of 61 liver transplant recipients were converted to a combination of a nucleoside and nucleotide analog. The mean (+/-standard deviation) follow-up time after conversion was 15.0 (+/-6.1) months. Recurrent HBV occurred in two (3.3%) patients at 3.1 and 16.6 months after HBIg cessation. The overall person time incidence rate for HBV recurrence after HBIg cessation was 2.7 cases per 100 person-years. The estimate of HBV recurrence was 1.7% at 1 year after HBIg cessation. HBIg cessation a minimum of 12 months after liver transplantation with subsequent combination therapy with a nucleoside and nucleotide analog provides effective prophylaxis against recurrent HBV infection. The clinical implications of HBsAg detection without clinical, biochemical or molecular manifestations of recurrent hepatitis B require further study. PMID- 21299827 TI - Kidney transplantation outcomes in HIV infection: the European experience. PMID- 21299828 TI - Outcome of patients with preformed donor-specific antibodies following alemtuzumab induction and tacrolimus monotherapy. AB - It has been shown that low-level preformed donor-specific antibodies (DSAbs) detected by luminex beads in the setting of a negative CDC and flow cytometry crossmatch (CDC/FCXM) are associated with inferior allograft outcomes. The relevance of preformed DSAbs in patients receiving alemtuzumab induction and tacrolimus monotherapy has not been studied. Four hundred and eighty renal transplant recipients with a negative CDC/FCXM had their pretransplant sera retrospectively screened for DSAbs. 45/480 (9.4%) of patients were found to have preformed DSAbs. Females and patients receiving regrafts were more likely to have a DSAb (p = 0.008 and p < 0.0001, respectively). Patients with DSAbs had inferior allograft survival (p = 0.047), increased incidence of antibody-mediated rejection (p < 0.0001) and inferior allograft function at 6 months posttransplant (p = 0.017). Patients with HLA class I DSAb (alone or in combination with a Class II DSAb) with high mean fluorescence intensities (MFIs) were at highest risk. We conclude that patients with preformed DSAb are at high risk of adverse outcomes when receiving a minimal immunosuppressive regime incorporating alemtuzumab induction. Patients found to have a preformed DSAb despite a negative crossmatch might benefit from augmented immunosuppression. PMID- 21299829 TI - The impact of pandemic influenza A H1N1 2009 on Australian lung transplant recipients. AB - Influenza A H1N1 2009 led to 189 deaths during the Australian pandemic. Community acquired respiratory viruses not only can cause prolonged allograft dysfunction in lung transplant recipients but have also been linked to bronchiolitis obliterans syndrome (BOS). We report the impact of the 2009 H1N1 pandemic on Australian lung transplant recipients. An observational study of confirmed H1N1 cases was conducted across five Australian lung transplant programs during the pandemic. An electronic database collected patient demographics, clinical presentation, management and outcomes up to a year follow-up. Twenty-four H1N1 cases (mean age 43 +/- 14 years, eight females) were identified, incidence of 3%. Illness severity varied from upper respiratory tract symptoms only in 29% to lung allograft dysfunction (>=10% decline FEV1) in 75% to death in 5 (21%) cases (pre existing BOS grade 3, n = 4). Treatment with oseltamivir occurred in all but one case confirmed after death, reduced immunosuppression, n = 1, augmented corticosteroid therapy, n = 16, and mechanical/noninvasive ventilation, n = 4. There was BOS grade decline within a year in six cases (32%). In conclusion, Australian lung transplant recipients were variably affected by the H1N1 pandemic mirroring the broader community with significant morbidity and mortality. After initial recovery, a considerable proportion of survivors have demonstrated BOS progression. PMID- 21299830 TI - Duodenal villous atrophy: a cause of chronic diarrhea after solid-organ transplantation. AB - Persistent diarrhea is commonly observed after solid organ transplantation (SOT). A few cases of mycophenolate mofetil (MMF)-induced duodenal villous atrophy (DVA) have been previously reported in kidney-transplant patients with chronic diarrhea. Herein, we report on the incidence and characteristics of DVA in SOT patients with chronic diarrhea. One hundred thirty-two SOT patients with chronic diarrhea underwent an oesophago-gastroduodenoscopy (OGD) and a duodenal biopsy after classical causes of diarrhea have been ruled out. DVA was diagnosed in 21 patients (15.9%). It was attributed to mycophenolic acid (MPA) therapy in 18 patients (85.7%) (MMF [n = 14] and enteric-coated mycophenolate sodium [n = 4]). MPA withdrawal or dose reduction resulted in diarrhea cessation. The incidence of DVA was significantly higher in patients with chronic diarrhea receiving MPA compared to those who did not (24.6% vs. 5.1%, p = 0.003). DVA was attributed to a Giardia lamblia parasitic infection in two patients (9.5%) and the remaining case was attributed to azathioprine. In these three patients, diarrhea ceased after metronidazole therapy or azathioprine dose reduction. In conclusion, DVA is a frequent cause of chronic diarrhea in SOT recipients. MPA therapy is the most frequent cause of DVA. An OGD should be proposed to all transplant recipients who present with persistent diarrhea. PMID- 21299831 TI - A description of the costs of living and standard criteria deceased donor kidney transplantation. AB - Kidney transplantation improves quality of life and survival and is associated with lower health care costs compared with dialysis. We described and compared the costs of living and standard criteria for deceased donor kidney transplantation. Patients included adult recipients of a first kidney-only transplant between April 1, 1998, and March 31, 2006, as well as their donor information. All costs (outpatient care, diagnostic imaging, inpatient care, physician claims, laboratory tests and transplant medications) for 2 years after transplant for recipients and transplant-related costs prior to transplant (donor workup and management) were included. Complete cost information was available for 357 recipients. The mean total 2-year cost of transplantation, including donor costs, for recipients of living and deceased donors was $118 347 (95% confidence interval [CI], 110 395-126 299) and $121 121 (95% CI 114 287-127 956), respectively (p = 0.7). The mean cost for a living donor was $18 129 (95% CI 16 845-19 414) and for a deceased donor was $36 989 (95% CI 34 421-39 558). Living donor kidney transplantation has similar costs at 2 years compared with deceased donor transplantation. These results can be used by health care decision makers to inform strategies to increase donation. PMID- 21299832 TI - Making a B-line for transplantation tolerance. PMID- 21299833 TI - Response to 'When disaster strikes: death of a living organ donor'. PMID- 21299835 TI - Donation after cardiac death: community views about 'decent' intervals. AB - Donation after cardiac death (DCD) offers an alternative pathway to donation for some donors. Successful recovery of organs for transplantation following DCD requires that organ recovery surgery commence as soon as possible after death has occurred. This limits the amount of time that family and friends can spend with the donor prior to surgery. The aim of this study was to identify community views about the timing of organ recovery in DCD. Data were collected from two sources in South Australia: 32 members of the public participated in four focus groups, and 2693 adults participated in a representative population survey. Respondents were asked their views about a decent interval to wait after death prior to organ recovery surgery. Focus group participants identified a tension between preserving organ viability and allowing families time with the deceased. Of the survey respondents, 45.2% selected a timeframe compatible with potentially viable donations; 34.1% selected a timeframe incompatible with viable donations; and 20.8% gave an indeterminate answer. These findings provide information about public perceptions of DCD, can be used to inform educational campaigns about DCD and serve as a baseline for evaluating such campaigns, and identify a number of areas for further investigation. PMID- 21299834 TI - Elevated plasma clara cell secretory protein concentration is associated with high-grade primary graft dysfunction. AB - Primary graft dysfunction (PGD) is the leading cause of early posttransplant morbidity and mortality after lung transplantation. Clara cell secretory protein (CC16) is produced by the nonciliated lung epithelium and may serve as a plasma marker of epithelial cell injury. We hypothesized that elevated levels of CC16 would be associated with increased odds of PGD. We performed a prospective cohort study of 104 lung transplant recipients. Median plasma CC16 levels were determined at three time points: pretransplant and 6 and 24 h posttransplant. The primary outcome was the development of grade 3 PGD within the first 72 h after transplantation. Multivariable logistic regression was performed to evaluate for confounding by donor and recipient demographics and surgical characteristics. Twenty-nine patients (28%) developed grade 3 PGD within the first 72 h. The median CC16 level 6 h after transplant was significantly higher in patients with PGD [13.8 ng/mL (IQR 7.9, 30.4 ng/mL)] than in patients without PGD [8.2 ng/mL (IQR 4.5, 19.1 ng/mL)], p = 0.02. Elevated CC16 levels were associated with increased odds of PGD after lung transplantation. Damage to airway epithelium or altered alveolar permeability as a result of lung ischemia and reperfusion may explain this association. PMID- 21299836 TI - A hierarchical communication model of the antecedents of health care professionals' support for donations after cardiac death. AB - Using structural equation modeling, the direct and indirect impact of five variables on the support of donation after cardiac death from the perspective of health care professionals were investigated: knowledge, trust in the transplant team, whether patients are in a state of irreversibility, whether health care professionals participate in a patient's death, and perceptions about the brain death versus cardiac death donation process. In total, 10/15 relationships posited in the model had significant pathways. The results provide insight into sequential communication strategies for generating support for donations after cardiac death. PMID- 21299837 TI - Posttransplantation encapsulating peritoneal sclerosis contributes significantly to mortality after kidney transplantation. AB - Encapsulating peritoneal sclerosis (EPS) is a severe complication of peritoneal dialysis (PD) and may present after kidney transplantation, a condition known as posttransplantation EPS. The prevalence and impact of posttransplantation EPS on survival after kidney transplantation is unknown. From January 1, 1996 until July 1, 2007, 1241 PD patients were transplanted. Thirty-eight cases of posttransplantation EPS (3%) were identified from the Dutch multicenter EPS study. In EPS patients the mean pretransplant dialysis duration was longer than in the controls (71.4 +/- 37.5 months vs. 34.7 +/- 25.5, p < 0.0001). The majority of EPS cases were observed within the first 2 years after transplantation, but some cases appeared many years after transplantation. Two hundred and one (16.2%) patients died after transplantation, of which 17 were EPS patients. After infection (23.9%), cardiovascular disease (21.9%) and malignancy (10.9%), EPS (8.5%) was the fourth known cause of death after transplantation. Kaplan-Meier analysis showed a significant decreased survival for transplanted patients with posttransplantation EPS compared to transplanted patients without EPS. In conclusion, posttransplantation EPS is rare but carries a high mortality. A prolonged clinical vigilance and a high index of suspicion for the diagnosis are warranted, specifically in PD patients with a relatively long cumulative pretransplant duration of PD. PMID- 21299838 TI - Broad antibiotic resistance profile of the subclass B3 metallo-beta-lactamase GOB 1, a di-zinc enzyme. AB - The metallo-beta-lactamase (MBL) GOB-1 was expressed via a T7 expression system in Escherichia coli BL21(DE3). The MBL was purified to homogeneity and shown to exhibit a broad substrate profile, hydrolyzing all the tested beta-lactam compounds efficiently. The GOB enzymes are unique among MBLs due to the presence of a glutamine residue at position 116, a zinc-binding residue in all known class B1 and B3 MBL structures. Here we produced and studied the Q116A, Q116N and Q116H mutants. The substrate profiles were similar for each mutant, but with significantly reduced activity compared with that of the wild-type. In contrast to the Q116H enzyme, which bound two zinc ions just like the wild-type, only one zinc ion is present in Q116A and Q116N. These results suggest that the Q116 residue plays a role in the binding of the zinc ion in the QHH site. PMID- 21299839 TI - Enzymes of mannitol metabolism in the human pathogenic fungus Aspergillus fumigatus--kinetic properties of mannitol-1-phosphate 5-dehydrogenase and mannitol 2-dehydrogenase, and their physiological implications. AB - The human pathogenic fungus Aspergillus fumigatus accumulates large amounts of intracellular mannitol to enhance its resistance against defense strategies of the infected host. To explore their currently unknown roles in mannitol metabolism, we studied A. fumigatus mannitol-1-phosphate 5-dehydrogenase (AfM1PDH) and mannitol 2-dehydrogenase (AfM2DH), each recombinantly produced in Escherichia coli, and performed a detailed steady-state kinetic characterization of the two enzymes at 25 degrees C and pH 7.1. Primary kinetic isotope effects resulting from deuteration of alcohol substrate or NADH showed that, for AfM1PDH, binding of D-mannitol 1-phosphate and NAD(+) is random, whereas D-fructose 6 phosphate binds only after NADH has bound to the enzyme. Binding of substrate and NAD(H) by AfM2DH is random for both D-mannitol oxidation and D-fructose reduction. Hydride transfer is rate-determining for D-mannitol 1-phosphate oxidation by AfM1PDH (k(cat) = 10.6 s(-1)) as well as D-fructose reduction by AfM2DH (k(cat) = 94 s(-1)). Product release steps control the maximum rates in the other direction of the two enzymatic reactions. Free energy profiles for the enzymatic reaction under physiological boundary conditions suggest that AfM1PDH primarily functions as a D-fructose-6-phosphate reductase, whereas AfM2DH acts in D-mannitol oxidation, thus establishing distinct routes for production and mobilization of mannitol in A. fumigatus. ATP, ADP and AMP do not affect the activity of AfM1PDH, suggesting the absence of flux control by cellular energy charge at the level of D-fructose 6-phosphate reduction. AfM1PDH is remarkably resistant to inactivation by heat (half-life at 40 degrees C of 20 h), consistent with the idea that formation of mannitol is an essential component of the temperature stress response of A. fumigatus. Inhibition of AfM1PDH might be a useful target for therapy of A. fumigatus infections. PMID- 21299840 TI - Twelve years' detection of respiratory viruses by immunofluorescence in hospitalised children: impact of the introduction of a new respiratory picornavirus assay. AB - BACKGROUND: Direct immunofluorescence assays (DFA) are a rapid and inexpensive method for the detection of respiratory viruses and may therefore be used for surveillance. Few epidemiological studies have been published based solely on DFA and none included respiratory picornaviruses and human metapneumovirus (hMPV). We wished to evaluate the use of DFA for epidemiological studies with a long-term observation of respiratory viruses that includes both respiratory picornaviruses and hMPV. METHODS: Since 1998 all children hospitalized with respiratory illness at the University Hospital Bern have been screened with DFA for common respiratory viruses including adenovirus, respiratory syncytial virus (RSV), influenza A and B, and parainfluenza virus 1-3. In 2006 assays for respiratory picornaviruses and hMPV were added. Here we describe the epidemiological pattern for these respiratory viruses detected by DFA in 10'629 nasopharyngeal aspirates collected from 8'285 patients during a 12-year period (1998-2010). RESULTS: Addition of assays for respiratory picornaviruses and hMPV raised the proportion of positive DFA results from 35% to 58% (p < 0.0001). Respiratory picornaviruses were the most common viruses detected among patients >= 1 year old. The seasonal patterns and age distribution for the studied viruses agreed well with those reported in the literature. In 2010, an hMPV epidemic of unexpected size was observed. CONCLUSIONS: DFA is a valid, rapid, flexible and inexpensive method. The addition of assays for respiratory picornaviruses and hMPV broadens its range of viral detection. DFA is, even in the "PCR era", a particularly adapted method for the long term surveillance of respiratory viruses in a pediatric population. PMID- 21299842 TI - Cacao seeds are a "Super Fruit": A comparative analysis of various fruit powders and products. AB - BACKGROUND: Numerous popular media sources have developed lists of "Super Foods" and, more recently, "Super Fruits". Such distinctions often are based on the antioxidant capacity and content of naturally occurring compounds such as polyphenols within those whole fruits or juices of the fruit which may be linked to potential health benefits. Cocoa powder and chocolate are made from an extract of the seeds of the fruit of the Theobroma cacao tree. In this study, we compared cocoa powder and cocoa products to powders and juices derived from fruits commonly considered "Super Fruits". RESULTS: Various fruit powders and retail fruit products were obtained and analyzed for antioxidant capacity (ORAC (MUM TE/g)), total polyphenol content (TP (mg/g)), and total flavanol content (TF (mg/g)). Among the various powders that were tested, cocoa powder was the most concentrated source of ORAC and TF. Similarly, dark chocolate was a significantly more concentrated source of ORAC and TF than the fruit juices. CONCLUSIONS: Cocoa powder and dark chocolate had equivalent or significantly greater ORAC, TP, and TF values compared to the other fruit powders and juices tested, respectively. Cacao seeds thus provide nutritive value beyond that derived from their macronutrient composition and appear to meet the popular media's definition of a "Super Fruit". PMID- 21299841 TI - Alcohol consumption and binge drinking in adolescents: comparison of different migration backgrounds and rural vs. urban residence--a representative study. AB - BACKGROUND: Binge drinking is a constant problem behavior in adolescents across Europe. Epidemiological investigations have been reported. However, epidemiological data on alcohol consumption of adolescents with different migration backgrounds are rare. Furthermore representative data on rural-urban comparison concerning alcohol consumption and binge drinking are lacking. The aims of the study are the investigation of alcohol consumption patterns with respect to a) urban-rural differences and b) differences according to migration background. METHODS: In the years 2007/2008, a representative written survey of N = 44,610 students in the 9th. grade of different school types in Germany was carried out (net sample). The return rate of questionnaires was 88% regarding all students whose teachers respectively school directors had agreed to participate in the study. Weighting factors were specified and used to make up for regional and school-type specific differences in return rates. 27.4% of the adolescents surveyed have a migration background, whereby the Turkish culture is the largest group followed by adolescents who emigrated from former Soviet Union states. The sample includes seven large cities (over 500,000 inhabitants) (12.2%), independent smaller cities ("urban districts") (19.0%) and rural areas ("rural districts") (68.8%). RESULTS: Life-time prevalence for alcohol consumption differs significantly between rural (93.7%) and urban areas (86.6% large cities; 89.1% smaller cities) with a higher prevalence in rural areas. The same accounts for 12-month prevalence for alcohol consumption. 57.3% of the rural, respectively 45.9% of the urban adolescents engaged in binge drinking in the 4 weeks prior to the survey. Students with migration background of the former Soviet Union showed mainly drinking behavior similar to that of German adolescents. Adolescents with Turkish roots had engaged in binge drinking in the last four weeks less frequently than adolescents of German descent (23.6% vs. 57.4%). However, in those adolescents who consumed alcohol in the last 4 weeks, binge drinking is very prominent across the cultural backgrounds. CONCLUSIONS: Binge drinking is a common problem behavior in German adolescents. Obviously adolescents with rural residence have fewer alternatives for engaging in interesting leisure activities than adolescents living in cities. This might be one reason for the more problematic consumption patterns there. Common expectations concerning drinking behavior of adolescents of certain cultural backgrounds ('migrants with Russian background drink more'/'migrants from Arabic respectively Oriental-Islamic countries drink less') are only partly affirmed. Possibly, the degree of acculturation to the permissive German alcohol culture plays a role here. PMID- 21299843 TI - Concordance between vocal and genetic diversity in crested gibbons. AB - BACKGROUND: Gibbons or small apes are, next to great apes, our closest living relatives, and form the most diverse group of contemporary hominoids. A characteristic trait of gibbons is their species-specific song structure, which, however, exhibits a certain amount of inter- and intra-individual variation. Although differences in gibbon song structure are routinely applied as taxonomic tool to identify subspecies and species, it remains unclear to which degree acoustic and phylogenetic differences are correlated. To trace this issue, we comparatively analyse song recordings and mitochondrial cytochrome b gene sequence data from 22 gibbon populations representing six of the seven crested gibbon species (genus Nomascus). In addition, we address whether song similarity and geographic distribution can support a recent hypothesis about the biogeographic history of crested gibbons. RESULTS: The acoustic analysis of 92 gibbon duets confirms the hypothesised concordance between song structure and phylogeny. Based on features of male and female songs, we can not only distinguish between N. nasutus, N. concolor and the four southern species (N. leucogenys, N. siki, N. annamensis, N. gabriellae), but also between the latter by applying more detailed analysis. In addition to the significant correlation between song structure and genetic similarity, we find a similar high correlation between song similarity and geographic distance. CONCLUSIONS: The results show that the structure of crested gibbon songs is not only a reliable tool to verify phylogenetic relatedness, but also to unravel geographic origins. As vocal production in other nonhuman primate species appears to be evolutionarily based, it is likely that loud calls produced by other species can serve as characters to elucidate phylogenetic relationships. PMID- 21299844 TI - Paliperidone ER and oral risperidone in patients with schizophrenia: a comparative database analysis. AB - BACKGROUND: To compare the efficacy and tolerability of paliperidone extended release (ER) with risperidone immediate-release using propensity score methodology. METHODS: Six double-blind, randomized, placebo-controlled, short term clinical trials for acute schizophrenia with availability of individual patient-level data were identified (3 per compound). Propensity score pairwise matching was used to balance observed covariates between the paliperidone ER and risperidone patient populations. Scores were generated using logistic regression models, with age, body mass index, race, sex, baseline Positive and Negative Syndrome Scale (PANSS) total score and baseline Clinical Global Impressions Severity (CGI-S) score as factors. The dosage range of paliperidone ER (6-12 mg/day) was compared with 2 risperidone dosage ranges: 2-4 and 4-6 mg/day. The primary efficacy measure was change in PANSS total score at week 6 end point. Tolerability end points included adverse event (AE) reports and weight. AEs with rates >= 5% and with a >= 2% difference between paliperidone ER and risperidone were identified. RESULTS: Completion rates for placebo-treated subjects in paliperidone ER trials (n = 95) and risperidone trials (n = 122) groups were 36.8% and 51.6%, respectively; end point changes on PANSS total scores were similar (p = 0.768). Completion rates for subjects receiving paliperidone ER 6-12 mg/day (n = 179), risperidone 2-4 mg/day (n = 113) or risperidone 4-6 mg/day (n = 129) were 64.8%, 54.0% and 66.7%, respectively (placebo-adjusted rates: paliperidone ER vs risperidone 2-4 mg/day, p = 0.005; paliperidone ER vs risperidone 4-6 mg/day, p = 0.159). PANSS total score improvement with paliperidone ER was greater than with risperidone 2-4 mg/day (difference in mean change score, -6.7; p < 0.05) and similar to risperidone 4-6 mg/day (0.2; p = 0.927). Placebo-adjusted AEs more common with paliperidone ER were insomnia, sinus tachycardia and tachycardia; more common with risperidone were somnolence, restlessness, nausea, anxiety, salivary hypersecretion, akathisia, dizziness and nasal congestion. Weight changes with paliperidone ER and risperidone were similar (paliperidone ER vs risperidone 2-4 mg/day, p = 0.489; paliperidone ER vs risperidone 4-6 mg/day, p = 0.236). CONCLUSIONS: This indirect database analysis suggested that paliperidone ER 6-12 mg/day may be more efficacious than risperidone 2-4 mg/day and as efficacious as risperidone 4-6 mg/day. The AE adjusted incidence rates suggest differences between treatments that may be relevant for individual patients. Additional randomized, direct, head-to-head clinical trials are needed to confirm these findings. PMID- 21299845 TI - A multicenter, prospective, randomized, controlled trial evaluating the safety and efficacy of intracoronary cell infusion mobilized with granulocyte colony stimulating factor and darbepoetin after acute myocardial infarction: study design and rationale of the 'MAGIC cell-5-combination cytokine trial'. AB - BACKGROUND: Bone marrow derived stem/progenitor cell transplantation after acute myocardial infarction is safe and effective for improving left ventricular systolic function. However, the improvement of left ventricular systolic function is limited. This study will evaluate novel stem/progenitor cell therapy with combination cytokine treatment of the long-acting erythropoietin analogue, darbepoetin, and granulocyte colony-stimulating factor (G-CSF) in patients with acute myocardial infarction. METHODS: The 'MAGIC Cell-5-Combination Cytokine Trial' is a multicenter, prospective, randomized, 3-arm, controlled trial with blind evaluation of the endpoints. A total of 116 patients will randomly receive one of the following three treatments: an intravenous darbepoetin infusion and intracoronary infusion of peripheral blood stem cells mobilized with G-CSF (n = 58), an intracoronary infusion of peripheral blood stem cells mobilized with G CSF alone (n = 29), or conventional therapy (n = 29) at phase I. Patients with left ventricular ejection fraction < 45% at 6 months, in the patients who received stem cell therapy at phase I, will receive repeated cell therapy at phase II. The objectives of this study are to evaluate the safety and efficacy of combination cytokine therapy with erythropoietin and G-CSF (phase I) and repeated progenitor/stem cell treatment (phase II). DISCUSSION: This is the first study to evaluate the safety and efficacy of combination cytokine based progenitor/stem cell treatment. TRIAL REGISTRATION: http://www.ClinicalTrials.gov identifier: NCT00501917. PMID- 21299846 TI - The formyl peptide receptor like-1 and scavenger receptor MARCO are involved in glial cell activation in bacterial meningitis. AB - BACKGROUND: Recent studies have suggested that the scavenger receptor MARCO (macrophage receptor with collagenous structure) mediates activation of the immune response in bacterial infection of the central nervous system (CNS). The chemotactic G-protein-coupled receptor (GPCR) formyl-peptide-receptor like-1 (FPRL1) plays an essential role in the inflammatory responses of host defence mechanisms and neurodegenerative disorders such as Alzheimer's disease (AD). Expression of the antimicrobial peptide cathelicidin CRAMP/LL-37 is up-regulated in bacterial meningitis, but the mechanisms underlying CRAMP expression are far from clear. METHODS: Using a rat meningitis model, we investigated the influence of MARCO and FPRL1 on rCRAMP (rat cathelin-related antimicrobial peptide) expression after infection with bacterial supernatants of Streptococcus pneumoniae (SP) and Neisseria meningitides (NM). Expression of FPRL1 and MARCO was analyzed by immunofluorescence and real-time RT-PCR in a rat meningitis model. Furthermore, we examined the receptor involvement by real-time RT-PCR, extracellular-signal regulated kinases 1/2 (ERK1/2) phosphorylation and cAMP level measurement in glial cells (astrocytes and microglia) and transfected HEK293 cells using receptor deactivation by antagonists. Receptors were inhibited by small interference RNA and the consequences in NM- and SP-induced Camp (rCRAMP gene) expression and signal transduction were determined. RESULTS: We show an NM induced increase of MARCO expression by immunofluorescence and real-time RT-PCR in glial and meningeal cells. Receptor deactivation by antagonists and small interfering RNA (siRNA) verified the importance of FPRL1 and MARCO for NM- and SP induced Camp and interleukin-1beta expression in glial cells. Furthermore, we demonstrated a functional interaction between FPRL1 and MARCO in NM-induced signalling by real-time RT-PCR, ERK1/2 phosphorylation and cAMP level measurement and show differences between NM- or SP-induced signal transduction. CONCLUSIONS: We propose that NM and SP induce glial cell activation and rCRAMP expression also via FPRL1 and MARCO. Thus the receptors contribute an important part to the host defence against infection. PMID- 21299847 TI - Early uptake of HIV counseling and testing among pregnant women at different levels of health facilities--experiences from a community-based study in Northern Vietnam. AB - BACKGROUND: HIV counselling and testing for pregnant women is a key factor for successful prevention of mother to child transmission of HIV. Women's access to testing can be improved by scaling up the distribution of this service at all levels of health facilities. However, this strategy will only be effective if pregnant women are tested early and provided enough counselling. OBJECTIVE: To assess early uptake of HIV testing and the provision of HIV counselling among pregnant women who attend antenatal care at primary and higher level health facilities. METHODS: A community based study was conducted among 1108 nursing mothers. Data was collected during interviews using a structured questionnaire focused on socio-economic background, reproductive history, experience with antenatal HIV counselling and testing as well as types of health facility providing the services. RESULTS: In all 91.0% of the women interviewed had attended antenatal care and 90.3% had been tested for HIV during their most recent pregnancy. Women who had their first antenatal checkup at primary health facilities were significantly more likely to be tested before 34 weeks of gestation (OR = 43.2, CI: 18.9-98.1). The reported HIV counselling provision was also higher at primary health facilities, where women in comparison with women attending higher level health facilities were nearly three or and four times more likely to receive pre-test (OR = 2.7; CI:2.1-3.5) and post-test counseling (OR = 4.0; CI: 2.3-6.8). CONCLUSIONS: The results suggest that antenatal HIV counseling and testing can be scaled up to primary heath facilities and that such scaling up may enhance early uptake of testing and provision of counseling. PMID- 21299848 TI - Progressive cholinergic decline in Alzheimer's Disease: consideration for treatment with donepezil 23 mg in patients with moderate to severe symptomatology. AB - Of the estimated 5.3 million people with Alzheimer's disease in the United States, more than half would be classified as having moderate or severe disease. Alzheimer's disease is a progressive disorder with the moderate to severe stages generally characterized by significant cognitive, functional, and behavioral dysfunction. Unsurprisingly, these advanced stages are often the most challenging for both patients and their caregivers/families. Symptomatic treatments for moderate to severe Alzheimer's disease are approved in the United States and include the acetylcholinesterase inhibitor donepezil and the glutamate receptor antagonist memantine. Progressive symptomatic decline is nevertheless inevitable even with the available therapies, and therefore additional treatment options are urgently needed for this segment of the Alzheimer's disease population. An immediate-release formulation of donepezil has been available at an approved dose of 5-10 mg/d for the past decade. Recently, the United States Food and Drug Administration approved a higher-dose (23 mg/d) donepezil formulation, which provides more gradual systemic absorption, a longer time to maximum concentration (8 hours) versus the immediate-release formulation (3 hours), and higher daily concentrations. Herein, we review (1) the scientific data on the importance of cholinergic deficits in Alzheimer's disease treatment strategies, (2) the rationale for the use of higher-dose acetylcholinesterase inhibitors in patients with advanced disease, and (3) recent clinical evidence supporting the use of higher-dose donepezil in patients with moderate to severe Alzheimer's disease. PMID- 21299849 TI - BCR-ABL1-independent PI3Kinase activation causing imatinib-resistance. AB - BACKGROUND: The BCR-ABL1 translocation occurs in chronic myeloid leukemia (CML) and in 25% of cases with acute lymphoblastic leukemia (ALL). The advent of tyrosine kinase inhibitors (TKI) has fundamentally changed the treatment of CML. However, TKI are not equally effective for treating ALL. Furthermore, de novo or secondary TKI-resistance is a significant problem in CML. We screened a panel of BCR-ABL1 positive ALL and CML cell lines to find models for imatinib-resistance. RESULTS: Five of 19 BCR-ABL1 positive cell lines were resistant to imatinib induced apoptosis (KCL-22, MHH-TALL1, NALM-1, SD-1, SUP-B15). None of the resistant cell lines carried mutations in the kinase domain of BCR-ABL1 and all showed resistance to second generation TKI, nilotinib or dasatinib. STAT5, ERK1/2 and the ribosomal S6 protein (RPS6) are BCR-ABL1 downstream effectors, and all three proteins are dephosphorylated by imatinib in sensitive cell lines. TKI resistant phosphorylation of RPS6, but responsiveness as regards JAK/STAT5 and ERK1/2 signalling were characteristic for resistant cell lines. PI3K pathway inhibitors effected dephosphorylation of RPS6 in imatinib-resistant cell lines suggesting that an oncogene other than BCR-ABL1 might be responsible for activation of the PI3K/AKT1/mTOR pathway, which would explain the TKI resistance of these cells. We show that the TKI-resistant cell line KCL-22 carries a PI3Kalpha E545G mutation, a site critical for the constitutive activation of the PI3K/AKT1 pathway. Apoptosis in TKI-resistant cells could be induced by inhibition of AKT1, but not of mTOR. CONCLUSION: We introduce five Philadelphia chromosome positive cell lines as TKI-resistance models. None of these cell lines carries mutations in the kinase domain of BCR-ABL1 or other molecular aberrations previously indicted in the context of imatinib-resistance. These cell lines are unique as they dephosphorylate ERK1/2 and STAT5 after treatment with imatinib, while PI3K/AKT1/mTOR activity remains unaffected. Inhibition of AKT1 leads to apoptosis in the imatinib-resistant cell lines. In conclusion, Ph+ cell lines show a form of imatinib-resistance attributable to constitutive activation of the PI3K/AKT1 pathway. Mutations in PIK3CA, as observed in cell line KCL-22, or PI3K activating oncogenes may undelie TKI-resistance in these cell lines. PMID- 21299850 TI - Serotonin transporter (SERT) and translocator protein (TSPO) expression in the obese ob/ob mouse. AB - BACKGROUND: An ever growing body of evidences is emerging concerning metabolism hormones, neurotransmitters or stress-related biomarkers as effective modulators of eating behavior and body weight in mammals. The present study sought at examining the density and affinity of two proteins related to neurotransmission and cell metabolism, the serotonin transporter SERT and the cholesterol import benzodiazepine site TSPO (translocator protein), in a rodent leptin-lacking mutant, the obese ob/ob mouse. Binding studies were thus carried out in brain or peripheral tissues, blood platelets (SERT) and kidneys (TSPO), of ob/ob and WT mice supplied with a standard diet, using the selective radiochemical ligands [3H]-paroxetine and [3H]-PK11195. RESULTS: We observed comparable SERT number or affinity in brain and platelets of ob/ob and WT mice, whilst a significantly higher [3H]-PK11195 density was reported in the brain of ob/ob animals. TSPO binding parameters were similar in the kidneys of all tested mice. By [3H] PK11195 autoradiography of coronal hypothalamic-hippocampal sections, an increased TSPO signal was detected in the dentate gyrus (hippocampus) and choroids plexus of ob/ob mice, without appreciable changes in the cortex or hypothalamic-thalamic regions. CONCLUSIONS: These findings show that TSPO expression is up-regulated in cerebral regions of ob/ob leptin-deficient mice, suggesting a role of the translocator protein in leptin-dependent CNS trophism and metabolism. Unchanged SERT in mutant mice is discussed herein in the context of previous literature as the forerunner to a deeper biochemical investigation. PMID- 21299851 TI - A first assessment of the genetic diversity of Mycobacterium tuberculosis complex in Cambodia. AB - BACKGROUND: Cambodia is among the 22 high-burden TB countries, and has one of the highest rates of TB in South-East Asia. This study aimed to describe the genetic diversity among clinical Mycobacterium tuberculosis complex (MTC) isolates collected in Cambodia and to relate these findings to genetic diversity data from neighboring countries. METHODS: We characterized by 24 VNTR loci genotyping and spoligotyping 105 Mycobacterium tuberculosis clinical isolates collected between 2007 and 2008 in the region of Phnom-Penh, Cambodia, enriched in multidrug resistant (MDR) isolates (n = 33). RESULTS: Classical spoligotyping confirmed that the East-African Indian (EAI) lineage is highly prevalent in this area (60% 68% respectively in whole sample and among non-MDR isolates). Beijing lineage is also largely represented (30% in whole sample, 21% among non-MDR isolates, OR = 4.51, CI 95% [1.77, 11.51]) whereas CAS lineage was absent. The 24 loci MIRU-VNTR typing scheme distinguished 90 patterns with only 13 multi-isolates clusters covering 28 isolates. The clustering of EAI strains could be achieved with only 8 VNTR combined with spoligotyping, which could serve as a performing, easy and cheap genotyping standard for this family. Extended spoligotyping suggested relatedness of some unclassified "T1 ancestors" or "Manu" isolates with modern strains and provided finer resolution. CONCLUSIONS: The genetic diversity of MTC in Cambodia is driven by the EAI and the Beijing families. We validate the usefulness of the extended spoligotyping format in combination with 8 VNTR for EAI isolates in this region. PMID- 21299852 TI - The "Clubs against Drugs" program in Stockholm, Sweden: two cross-sectional surveys examining drug use among staff at licensed premises. AB - BACKGROUND: The objective of this study is to examine self-reported drug use among staff at licensed premises, types of drugs used, attitudes towards drugs, and observed drug use among guests. Results are presented from two measurement points (in 2001 and 2007/08). This study was carried out within the framework of the "Clubs against Drugs" program, which is a community-based multi-component intervention targeting licensed premises in Stockholm, Sweden. METHODS: Two cross sectional surveys were conducted, the first in 2001 and the second in 2007/08. Staff at licensed premises attending server training were asked to participate in the anonymous survey. A survey was administered in a classroom setting and consisted of four sections: 1) demographics, 2) respondents' own drug use experience, 3) respondents' attitudes towards drug use, and 4) observed drug use among guests at licensed premises. RESULTS: Data were collected from 446 staff in 2001 and 677 staff in 2007/08. The four most commonly used drugs among staff were cannabis, cocaine, amphetamine, and ecstasy. The highest rates of drug use were reported by staff in the two youngest age groups, i.e., those younger than 25 and those between the ages of 25 and 29. In 2007/08 staff reported significantly lower rates of drug use than staff in 2001. Last year drug use for the sample in 2007/08 was 19% compared to 27% for the 2001 sample. While drug-using staff compared to non drug-using staff reported more observations of drug use among guests, they were less inclined to intervene. Overall, staff reported restrictive attitudes towards drugs. CONCLUSIONS: The prevalence of life-time and last year drug use among staff at licensed premises is high compared to the general population in Sweden. Lower rates of self-reported drug use among staff were reported in 2007/08. The results of this study highlight that staff at licensed premises represent an important target population in club drug prevention programs. PMID- 21299854 TI - Impaired glucose tolerance in healthy men with low body weight. AB - BACKGROUND: Impaired glucose tolerance (IGT) and high body mass index (BMI) are recognized risk factors for type 2 diabetes mellitus (T2DM). However, data suggest that also underweight predisposes people to develop T2DM. Here, we experimentally tested if already moderate underweight is associated with impaired glucose tolerance as compared to normal weight controls. Obese subjects were included as additional reference group. METHOD: We included three groups of low weight, normal weight, and obese subjects comprising 15 healthy male participants each. All participants underwent a standardized hyperinsulinemic-euglycemic glucose clamp intervention to determine glucose tolerance. In addition, insulin sensitivity index (ISI) was calculated by established equation. RESULTS: ISI values were higher in low and normal weight than in obese subjects (P < 0.010) without any difference between low and normal weight groups (P = 0.303). Comparable to obese participants (P = 0.178), glucose tolerance was found decreased in low weight as compared with normal weight subjects (P = 0.007). Pearson's correlation analysis revealed a positive relationship between glucose tolerance and BMI in low (P = 0.043) and normal weight subjects (P = 0.021), an effect that was found inverse in obese participants (P = 0.028). CONCLUSION: Our study demonstrates that not only obese but also healthy people with moderate underweight display glucose intolerance. It is therefore suggested that all deviations from normal BMI may be accompanied by an increased risk of developing T2DM in later life indicating that the maintenance of body weight within the normal range has first priority in the prevention of this disease. PMID- 21299853 TI - Synchrotron soft X-ray imaging and fluorescence microscopy reveal novel features of asbestos body morphology and composition in human lung tissues. AB - BACKGROUND: Occupational or environmental exposure to asbestos fibres is associated with pleural and parenchymal lung diseases. A histopathologic hallmark of exposure to asbestos is the presence in lung parenchyma of the so-called asbestos bodies. They are the final product of biomineralization processes resulting in deposition of endogenous iron and organic matter (mainly proteins) around the inhaled asbestos fibres. For shedding light on the formation mechanisms of asbestos bodies it is of fundamental importance to characterize at the same length scales not only their structural morphology and chemical composition but also to correlate them to the possible alterations in the local composition of the surrounding tissues. Here we report the first correlative morphological and chemical characterization of untreated paraffinated histological lung tissue samples with asbestos bodies by means of soft X-ray imaging and X-Ray Fluorescence (XRF) microscopy, which reveals new features in the elemental lateral distribution. RESULTS: The X-ray absorption and phase contrast images and the simultaneously monitored XRF maps of tissue samples have revealed the location, distribution and elemental composition of asbestos bodies and associated nanometric structures. The observed specific morphology and differences in the local Si, Fe, O and Mg content provide distinct fingerprints characteristic for the core asbestos fibre and the ferruginous body. The highest Si content is found in the asbestos fibre, while the shell and ferruginous bodies are characterized by strongly increased content of Mg, Fe and O compared to the adjacent tissue. The XRF and SEM-EDX analyses of the extracted asbestos bodies confirmed an enhanced Mg deposition in the organic asbestos coating. CONCLUSIONS: The present report demonstrates the potential of the advanced synchrotron-based X ray imaging and microspectroscopy techniques for studying the response of the lung tissue to the presence of asbestos fibres. The new results obtained by simultaneous structural and chemical analysis of tissue specimen have provided clear evidence that Mg, in addition to Fe, is also involved in the formation mechanisms of asbestos bodies. This is the first important step to further thorough investigations that will shed light on the physiopathological role of Mg in tissue response to the asbestos toxicity. PMID- 21299855 TI - Acute effects of decaffeinated coffee and the major coffee components chlorogenic acid and trigonelline on incretin hormones. AB - Coffee consumption is associated with a lower risk of type 2 diabetes. We tested the hypothesis that this is mediated by incretin hormones by measuring the acute effects of decaffeinated coffee and coffee components on GLP-1 and GIP concentrations. A randomized cross-over trial of the effects of 12 g decaffeinated coffee, 1 g chlorogenic acid, 500 mg trigonelline, and placebo on total and intact GLP-1 and GIP concentrations during an oral glucose tolerance test took place in fifteen overweight men. No treatment significantly affected the overall GLP-1 or GIP secretion pattern following an OGTT relative to placebo. Decaffeinated coffee slightly increased total GLP-1 concentration 30 minutes after ingestion (before the OGTT) relative to placebo (2.7 pmol/L, p = 0.03), but this change did not correspond with changes in glucose or insulin secretion. These findings do not support the hypothesis that coffee acutely improves glucose tolerance through effects on the secretion of incretin hormones. Chronic effects of coffee and its major components still need to be investigated. PMID- 21299856 TI - Gender differences in disability after sickness absence with musculoskeletal disorders: five-year prospective study of 37,942 women and 26,307 men. AB - BACKGROUND: Gender differences in the prevalence and occupational consequences of musculoskeletal disorders (MSDs) are consistently found in epidemiological studies. The study investigated whether gender differences also exist with respect to chronicity, measured as the rate of transition from sickness absence into permanent disability pension (DP). METHODS: Prospective national cohort study in Norway including all cases with a spell of sickness absence > eight weeks during 1997 certified with a MSD, 37,942 women and 26,307 men. The cohort was followed-up for five years with chronicity measured as granting of DP as the endpoint. The effect of gender was estimated in the full sample adjusting for sociodemographic factors and diagnostic distribution. Gender specific analyses were performed with the same explanatory variables. Finally, the gender difference was estimated for nine diagnostic subgroups. RESULTS: The crude rate of DP was 22% for women and 18% for men. After adjusting for all sociodemographic variables, a slightly higher female risk of DP remained. However, additional adjustment for diagnostic distribution removed the gender difference completely. Having children and working full time decreased the DP risk for both genders, whereas low socioeconomic status increased the risk similarly. There was a different age effect as more women obtained a DP below the age of 50. Increased female risk of chronicity remained for myalgia/fibromyalgia, back disorders and "other/unspecified" after relevant adjustments, whereas men with neck disorders were at higher risk of chronicity. CONCLUSIONS: Women with MSDs had a moderately increased risk of chronicity compared to men, when including MSDs with a traumatic background. Possible explanations are lower income, a higher proportion belonging to diagnostic subgroups with poor prognosis, and a younger age of chronicity among women. When all sociodemographic and diagnostic variables were adjusted for, no gender difference remained, except for some diagnostic subgroups. PMID- 21299857 TI - Administration of hydrogen sulfide via extracorporeal membrane lung ventilation in sheep with partial cardiopulmonary bypass perfusion: a proof of concept study on metabolic and vasomotor effects. AB - INTRODUCTION: Although inhalation of 80 parts per million (ppm) of hydrogen sulfide (H2S) reduces metabolism in mice, doses higher than 200 ppm of H2S were required to depress metabolism in rats. We therefore hypothesized that higher concentrations of H2S are required to reduce metabolism in larger mammals and humans. To avoid the potential pulmonary toxicity of H2S inhalation at high concentrations, we investigated whether administering H2S via ventilation of an extracorporeal membrane lung (ECML) would provide means to manipulate the metabolic rate in sheep. METHODS: A partial venoarterial cardiopulmonary bypass was established in anesthetized, ventilated (fraction of inspired oxygen = 0.5) sheep. The ECML was alternately ventilated with air or air containing 100, 200, or 300 ppm H2S for intervals of 1 hour. Metabolic rate was estimated on the basis of total CO2 production (VCO2) and O2 consumption (VO2). Continuous hemodynamic monitoring was performed via indwelling femoral and pulmonary artery catheters. RESULTS: VCO2, VO2, and cardiac output ranged within normal physiological limits when the ECML was ventilated with air and did not change after administration of up to 300 ppm H2S. Administration of 100, 200 and 300 ppm H2S increased pulmonary vascular resistance by 46, 52 and 141 dyn.s/cm5, respectively (all P <= 0.05 for air vs. 100, 200 and 300 ppm H2S, respectively), and mean pulmonary artery pressure by 4 mmHg (P <= 0.05), 3 mmHg (n.s.) and 11 mmHg (P <= 0.05), respectively, without changing pulmonary capillary wedge pressure or cardiac output. Exposure to 300 ppm H2S decreased systemic vascular resistance from 1,561 +/- 553 to 870 +/- 138 dyn.s/cm(5) (P <= 0.05) and mean arterial pressure from 121 +/- 15 mmHg to 66 +/- 11 mmHg (P <= 0.05). In addition, exposure to 300 ppm H2S impaired arterial oxygenation (PaO2 114 +/- 36 mmHg with air vs. 83 +/- 23 mmHg with H2S; P <= 0.05). CONCLUSIONS: Administration of up to 300 ppm H2S via ventilation of an extracorporeal membrane lung does not reduce VCO2 and VO2, but causes dose-dependent pulmonary vasoconstriction and systemic vasodilation. These results suggest that administration of high concentrations of H2S in venoarterial cardiopulmonary bypass circulation does not reduce metabolism in anesthetized sheep but confers systemic and pulmonary vasomotor effects. PMID- 21299858 TI - Maggot metabolites and their combinatory effects with antibiotic on Staphylococcus aureus. AB - BACKGROUND: Maggot therapy has been in practice for effective debridement, disinfection and healing of chronic wounds. Due to their antiseptic action during wound healing, their metabolites have been investigated in the past for antibacterial activity. They have been particularly useful for treatment of wounds infected with multi-drug resistant Staphylococcus aureus. Antibiotics, on the other hand, can predispose bacteria to develop resistance. Substances that are able to modulate or delay the occurrence of resistance in bacteria are under investigation by many researchers around the world. In the present study, antibacterial activity in excretions/secretions (ES) from maggots of Lucilia cuprina blowfly was demonstrated. The extracts were also screened in combination with antibiotic, ciprofloxacin. METHODS: L. cuprina blowfly maggots were reared for extraction of its metabolites. The ES extracted was screened against S. aureus, alone and in combination with ciprofloxacin, both for short term and long term exposure analysis. A microchannel-based device and system was used for experiments instead of conventional techniques. RESULTS: The original ES had shown partial bacterial growth inhibition. However, in combination with ciprofloxacin, at sub-inhibitory concentrations, certain combinations revealed anti-staphylococcal activity, with bacterial reduction of up to 50%, after 24 hours. The six day study on S. aureus exposed to ES-ciprofloxacin combination suggested a potential delay in development of adaptive resistance as opposed to when ciprofloxacin was used as single agent. CONCLUSIONS: The combination effect of ES and ciprofloxacin at sub-MIC levels showed enhanced antibacterial activity compared to the effect of ES and ciprofloxacin as single agents. Based on the results of ES-ciprofloxacin combinations, a more effective means of treatment for S. aureus can be proposed. PMID- 21299859 TI - Betel quid chewing as a source of manganese exposure: total daily intake of manganese in a Bangladeshi population. AB - BACKGROUND: A relationship between betel quid chewing in Bangladeshi populations and the development of skin lesions and tremor has been previously reported, for people exposed to high levels of arsenic (As) through drinking contaminated groundwater. Exposure to manganese (Mn) is also known to induce neurotoxicity and levels of Mn in Bangladeshi groundwater are also high. The present study evaluates betel quid chewing as an overlooked source of Mn exposure in a Bangladeshi population. METHODS: Inductively coupled plasma mass spectrometry (ICP-MS) was used to determine (1) urinary Mn levels for 15 chewers and 22 non chewers from the ethnic Bangladeshi community in the United Kingdom, and (2) Mn levels in betel quids, its individual components and other Bangladeshi foods. RESULTS: Betel quid chewers displayed a significantly higher (P = 0.009) mean Mn concentration in urine (1.93 MUg L(-1)) compared to non-chewers (0.62 MUg L(-1)). High levels of Mn were detected in Piper betel leaves with an overall average of 135 mg kg(-1) (range 26 -518 mg kg(-1)). The mean concentration of Mn in betel quid was 41 mg kg(-1) (SD 27) and the daily intake of Mn in the Bangladeshi population was estimated to be 20.3 mg/day. Chewing six betel quids could contribute up to 18% of the maximum recommended daily intake of Mn. CONCLUSION: We have demonstrated that Mn in betel quids is an overlooked source of exposure to Mn in humans. Chewers display a 3.1 fold increased urinary Mn concentration compared to non-chewers. The practice of betel quid chewing contributes a high proportion of the maximum recommended daily intake of Mn, which could make chewers in Bangladesh more vulnerable to Mn neurotoxicity. PMID- 21299860 TI - Strengthening evaluation and implementation by specifying components of behaviour change interventions: a study protocol. AB - BACKGROUND: The importance of behaviour change in improving health is illustrated by the increasing investment by funding bodies in the development and evaluation of complex interventions to change population, patient, and practitioner behaviours. The development of effective interventions is hampered by the absence of a nomenclature to specify and report their content. This limits the possibility of replicating effective interventions, synthesising evidence, and understanding the causal mechanisms underlying behaviour change. In contrast, biomedical interventions are precisely specified (e.g., the pharmacological 'ingredients' of prescribed drugs, their dose and frequency of administration). For most complex interventions, the precise 'ingredients' are unknown; descriptions (e.g., 'behavioural counseling') can mean different things to different researchers or implementers. The lack of a method for specifying complex interventions undermines the precision of evidence syntheses of effectiveness, posing a problem for secondary, as well as primary, research.We aim to develop a reliable method of specifying intervention components ('techniques') aimed at changing behaviour. METHODS/DESIGN: The research will be conducted in three phases. The first phase will develop the nomenclature. We will refine a preliminary list of techniques and definitions. Using a formal consensus method, experts will then define the key attributes of each technique and how it relates to, and differs from, others. They will evaluate the techniques and their definitions until they achieve an agreed-upon list of clearly defined, nonredundant techniques. The second phase will test the nomenclature. Trained experts (primary researchers and systematic reviewers), equipped with a coding manual and guidance, will use the nomenclature to code published descriptions of complex interventions. Reliability between experts, over time, and across types of users will be assessed. We will assess whether using the nomenclature to write intervention descriptions enhances the clarity and replicability of interventions. The third phase will develop a web-based users' resource of clearly specified and nonredundant techniques, which will aid the scientific understanding of, and development of, effective complex interventions. Dissemination throughout the project will be through stakeholder meetings, targeted multidisciplinary workshops, conference presentation, journal publication, and publication in an interactive web-based platform (a Wiki). DISCUSSION: The development of a reliable method of specifying intervention components aimed at changing behaviour will strengthen the scientific basis for developing, evaluating, and reporting complex interventions. It will improve the precision of evidence syntheses of effectiveness, thus enhancing secondary, as well as primary, research. PMID- 21299861 TI - Lidocaine for systemic sclerosis: a double-blind randomized clinical trial. AB - BACKGROUND: Systemic sclerosis (scleroderma; SSc) is an orphan disease with the highest case-specific mortality of any connective-tissue disease. Excessive collagen deposit in affected tissues is a key for the disease's pathogenesis and comprises most of the clinical manifestations. Lidocaine seems to be an alternative treatment for scleroderma considering that: a) the patient's having excessive collagen deposits in tissues affected by scleroderma; b) the patient's demonstrating increased activity of the enzyme prolyl hydroxylase, an essential enzyme for the biosynthesis of collagen; and c) lidocaine's reducing the activity of prolyl hydroxylase. The aim of this study was to evaluate the efficacy and safety of lidocaine in treating scleroderma. METHODS: A randomized double-blind clinical trial included 24 patients with scleroderma randomized to receive lidocaine or placebo intravenously in three cycles of ten days each, with a one month interval between them. OUTCOMES: cutaneous (modified Rodnan skin score), oesophageal (manometry) and microvascular improvement (nailfold capillaroscopy); improvement in subjective self-assessment and in quality of life (HAQ). RESULTS: There was no statistically significant difference between the groups for any outcome after the treatment and after 6-months follow-up. Improvement in modified Rodnan skin score occurred in 66.7% and 50% of placebo and lidocaine group, respectively (p = 0.408). Both groups showed an improvement in subjective self assessment, with no difference between them. CONCLUSIONS: Despite the findings of a previous cohort study favouring the use of lidocaine, this study demonstrated that lidocaine at this dosage and means of administration showed a lack of efficacy for treating scleroderma despite the absence of significant adverse effects. However, further similar clinical trials are needed to evaluate the efficacy of lidocaine when administered in different dosages and by other means. PMID- 21299863 TI - Polymorphic microsatellites in the human bloodfluke, Schistosoma japonicum, identified using a genomic resource. AB - Re-emergence of schistosomiasis in regions of China where control programs have ceased requires development of molecular-genetic tools to track gene flow and assess genetic diversity of Schistosoma populations. We identified many microsatellite loci in the draft genome of Schistosoma japonicum using defined search criteria and selected a subset for further analysis. From an initial panel of 50 loci, 20 new microsatellites were selected for eventual optimization and application to a panel of worms from endemic areas. All but one of the selected microsatellites contain simple tri-nucleotide repeats. Moderate to high levels of polymorphism were detected. Numbers of alleles ranged from 6 to 14 and observed heterozygosity was always >0.6. The loci reported here will facilitate high resolution population-genetic studies on schistosomes in re-emergent foci. PMID- 21299862 TI - During hormone depletion or tamoxifen treatment of breast cancer cells the estrogen receptor apoprotein supports cell cycling through the retinoic acid receptor alpha1 apoprotein. AB - INTRODUCTION: Current hormonal adjuvant therapies for breast cancer including tamoxifen treatment and estrogen depletion are overall tumoristatic and are severely limited by the frequent recurrence of the tumors. Regardless of the resistance mechanism, development and progression of the resistant tumors requires the persistence of a basal level of cycling cells during the treatment for which the underlying causes are unclear. METHODS: In estrogen-sensitive breast cancer cells the effects of hormone depletion and treatment with estrogen, tamoxifen, all-trans retinoic acid (ATRA), fulvestrant, estrogen receptor alpha (ER) siRNA or retinoic acid receptor alpha (RARalpha) siRNA were studied by examining cell growth and cycling, apoptosis, various mRNA and protein expression levels, mRNA profiles and known chromatin associations of RAR. RARalpha subtype expression was also examined in breast cancer cell lines and tumors by competitive PCR. RESULTS: Basal proliferation persisted in estrogen-sensitive breast cancer cells grown in hormone depleted conditioned media without or with 4 hydroxytamoxifen (OH-Tam). Downregulating ER using either siRNA or fulvestrant inhibited basal proliferation by promoting cell cycle arrest, without enrichment for ErbB2/3+ overexpressing cells. The basal expression of RARalpha1, the only RARalpha isoform that was expressed in breast cancer cell lines and in most breast tumors, was supported by apo-ER but was unaffected by OH-Tam; RAR-beta and -gamma were not regulated by apo-ER. Depleting basal RARalpha1 reproduced the antiproliferative effect of depleting ER whereas its restoration in the ER depleted cells partially rescued the basal cycling. The overlapping tamoxifen insensitive gene regulation by apo-ER and apo-RARalpha1 comprised activation of mainly genes promoting cell cycle and mitosis and suppression of genes involved in growth inhibition; these target genes were generally insensitive to ATRA but were enriched in RAR binding sites in associated chromatin regions. CONCLUSIONS: In hormone-sensitive breast cancer, ER can support a basal fraction of S-phase cells (i) without obvious association with ErbB2/3 expression, (ii) by mechanisms unaffected by hormone depletion or OH-Tam and (iii) through maintenance of the basal expression of apo-RARalpha1 to regulate a set of ATRA-insensitive genes. Since isoform 1 of RARalpha is genetically redundant, its targeted inactivation or downregulation should be further investigated as a potential means of enhancing hormonal adjuvant therapy. PMID- 21299864 TI - The motor development of orphaned children with and without HIV: Pilot exploration of foster care and residential placement. AB - BACKGROUND: The AIDS epidemic has lead to an increase in orphaned children who need residential care. It is known that HIV leads to delayed motor development. However, the impact of place of residence on motor function has not been investigated in the South African context. The aim of the study was therefore to establish if children in institutionalised settings performed better or worse in terms of gross motor function than their counterparts in foster care. A secondary objective was to compare the performance of children with HIV in these two settings with those of children who were HIV negative. METHODS: Forty-four children both with and without HIV, were recruited from institutions and foster care families in Cape Town. The Peabody Development Motor Scale (PDMS II) was used to calculate the total motor quotient (TMQ) at baseline and six months later. Comparisons of TMQ were made between residential settings and between children with and without HIV. RESULTS: Twenty-one children were infected with HIV and were significantly delayed compared to their healthy counterparts. Antiretroviral therapy was well managed among the group but did not appear to result in restoration of TMQ to normal over the study period. HIV status and place of residence emerged as a predictor of TMQ with children in residential care performing better than their counterparts in foster care. All children showed improvement over the six months of study. CONCLUSIONS: Foster parents were well supported administratively in the community by social welfare services but their children might have lacked stimulation in comparison to those in institutional settings. This could have been due to a lack of resources and knowledge regarding child development. The assumption that foster homes provide a better alternative to institutions may not be correct in a resource poor community and needs to be examined further. PMID- 21299865 TI - Bone mineral density and body composition in postmenopausal women with psoriasis and psoriatic arthritis. AB - INTRODUCTION: The aim of the present study was to compare bone mineral density (BMD) and body composition (BC) measurements as well as identify risk factors for low BMD and osteoporotic fractures in postmenopausal women with psoriasis (Ps) and psoriatic arthritis (PsA). METHODS: A cross-sectional study was carried out in 45 PsA women, 52 Ps women and 98 healthy female controls (HC). Clinical risk factors for low bone density and osteoporotic fracture were evaluated by a specific questionnaire. An X-ray absorptiometry (DXA) at the lumbar spine, total femur and total body was performed on all patients. Skin and joint outcomes were measured by specific tools (PASI, HAQ and DAS28). Morphometric vertebral fractures were evaluated by lumbar and thoracic spine X-ray, according to Genant's method. RESULTS: There were no significant differences in age, body mass index (BMI), total lean mass and bone mineral density among the groups. However, the PsA group had a significantly higher body fat percentage (BF%) than the Ps and HC groups. Osteoporotic fractures were more frequently observed in PsA and Ps groups than in the HC group (P = 0.01). Recurrent falls and a longer duration of disease increased the risk of fracture (odds ratio (OR) = 18.3 and 1.08, respectively) in the PsA group (P = 0.02). Disability was the main factor related to osteoporotic fracture in the Ps group (odds ratio (OR) = 11.1) (P = 0.02). CONCLUSIONS: Ps and PsA patients did not present lower BMD. However, they had a higher prevalence of osteoporotic fractures and higher risk of metabolic syndrome. Patients with a longer duration of disease, disability and recurrent falls need preventive measures. PMID- 21299867 TI - Delineating inflammatory and mechanical sub-types of low back pain: a pilot survey of fifty low back pain patients in a chiropractic setting. AB - BACKGROUND: An instrument known as the Mechanical and Inflammatory Low Back Pain (MAIL) Scale was drafted using the results of a previous expert opinion study. A pilot survey was conducted to test the feasibility of a larger study designed to determine the MAIL Scale's ability to distinguish two potential subgroups of low back pain: inflammatory and mechanical. METHODS: Patients with a primary complaint of low back pain (LBP) presenting to chiropractic clinics in Perth, Western Australia were asked to fill out the MAIL Scale questionnaire. The instrument's ability to separate patients into inflammatory and mechanical subgroups of LBP was examined using the mean score of each notional subgroup as an arbitrary cut-off point. RESULTS: Data were collected from 50 patients. The MAIL Scale did not appear to separate cases of LBP into the two notionally distinct groups of inflammatory (n = 6) or mechanical (n = 5). A larger "mixed symptom" group (n = 39) was revealed. CONCLUSIONS: In this pilot study the MAIL Scale was unable to clearly discriminate between what is thought to be mechanical and inflammatory LBP in 50 cases seen in a chiropractic setting. However, the small sample size means any conclusions must be viewed with caution. Further research within a larger study population may be warranted and feasible. PMID- 21299866 TI - Characterization of BoHV-5 field strains circulation and report of transient specific subtype of bovine herpesvirus 5 in Argentina. AB - BACKGROUND: Bovine herpesvirus 5 (BoHV-5) is a member of the subfamily Alphaherpesvirinae responsible for meningo-encephalitis in young cattle. The first case of bovine meningo-encephalitis associated with a herpesvirus infection was reported in Australia. The current geographical distribution of BoHV-5 infection is mainly restricted to South America, especially Brazil and Argentina. Outbreaks of BoHV-5 are regularly observed in Argentina suggesting the circulation of the virus in the bovine population. RESULTS: Seventeen field strains of BoHV-5 isolated from 1984 to now were confirmed by differential PCR and subjected to restriction endonuclease analysis (REA). Viral DNA was cleaved with BstEII which allows the differentiation among subtypes a, b and non a, non b. According to the REA with BstEII, only one field strain showed a pattern similar to the Argentinean A663 strain (prototype of BoHV-5b). All other isolates showed a clear pattern similar to the Australian N569 strain (prototype of BoHV 5a) consistent with the subtypes observed in Brazil, the other South-American country where BoHV-5 is known to be prevalent. The genomic region of subtype b responsible for the distinct pattern was determined and amplified by PCR; specifically a point mutation was identified in glycoprotein B gene, on the BstEII restriction site, which generates the profile specific of BoHV-5b. CONCLUSIONS: This is the first report of circulation of BoHV-5a in Argentina as the prevailing subtype. Therefore the circulation of BoHV-5b was restricted to a few years in Argentina, speculating that this subtype was not able to be maintained in the bovine population. The mutation in the gB gene is associated with the difference in the restriction patterns between subtypes "a" and "b". PMID- 21299868 TI - Use of structure-activity landscape index curves and curve integrals to evaluate the performance of multiple machine learning prediction models. AB - BACKGROUND: Standard approaches to address the performance of predictive models that used common statistical measurements for the entire data set provide an overview of the average performance of the models across the entire predictive space, but give little insight into applicability of the model across the prediction space. Guha and Van Drie recently proposed the use of structure activity landscape index (SALI) curves via the SALI curve integral (SCI) as a means to map the predictive power of computational models within the predictive space. This approach evaluates model performance by assessing the accuracy of pairwise predictions, comparing compound pairs in a manner similar to that done by medicinal chemists. RESULTS: The SALI approach was used to evaluate the performance of continuous prediction models for MDR1-MDCK in vitro efflux potential. Efflux models were built with ADMET Predictor neural net, support vector machine, kernel partial least squares, and multiple linear regression engines, as well as SIMCA-P+ partial least squares, and random forest from Pipeline Pilot as implemented by AstraZeneca, using molecular descriptors from SimulationsPlus and AstraZeneca. CONCLUSION: The results indicate that the choice of training sets used to build the prediction models is of great importance in the resulting model quality and that the SCI values calculated for these models were very similar to their Kendall tau values, leading to our suggestion of an approach to use this SALI/SCI paradigm to evaluate predictive model performance that will allow more informed decisions regarding model utility. The use of SALI graphs and curves provides an additional level of quality assessment for predictive models. PMID- 21299869 TI - Functional characterization of Trip10 in cancer cell growth and survival. AB - BACKGROUND: The Cdc42-interacting protein-4, Trip10 (also known as CIP4), is a multi-domain adaptor protein involved in diverse cellular processes, which functions in a tissue-specific and cell lineage-specific manner. We previously found that Trip10 is highly expressed in estrogen receptor-expressing (ER+) breast cancer cells. Estrogen receptor depletion reduced Trip10 expression by progressively increasing DNA methylation. We hypothesized that Trip10 functions as a tumor suppressor and may be involved in the malignancy of ER-negative (ER-) breast cancer. To test this hypothesis and evaluate whether Trip10 is epigenetically regulated by DNA methylation in other cancers, we evaluated DNA methylation of Trip10 in liver cancer, brain tumor, ovarian cancer, and breast cancer. METHODS: We applied methylation-specific polymerase chain reaction and bisulfite sequencing to determine the DNA methylation of Trip10 in various cancer cell lines and tumor specimens. We also overexpressed Trip10 to observe its effect on colony formation and in vivo tumorigenesis. RESULTS: We found that Trip10 is hypermethylated in brain tumor and breast cancer, but hypomethylated in liver cancer. Overexpressed Trip10 was associated with endogenous Cdc42 and huntingtin in IMR-32 brain tumor cells and CP70 ovarian cancer cells. However, overexpression of Trip10 promoted colony formation in IMR-32 cells and tumorigenesis in mice inoculated with IMR-32 cells, whereas overexpressed Trip10 substantially suppressed colony formation in CP70 cells and tumorigenesis in mice inoculated with CP70 cells. CONCLUSIONS: Trip10 regulates cancer cell growth and death in a cancer type-specific manner. Differential DNA methylation of Trip10 can either promote cell survival or cell death in a cell type-dependent manner. PMID- 21299870 TI - MicroRNA-203 inhibits cell proliferation by repressing DeltaNp63 expression in human esophageal squamous cell carcinoma. AB - BACKGROUND: This study was performed to investigate the effect of microRNA-203 (miR-203) and DeltaNp63 on cell proliferation and the functional connection between miR-203 and DeltaNp63 in ESCC. METHODS: We employed 2 human ESCC cell lines, Eca109 and TE-1, as the model system. The effect of miR-203 and DeltaNp63 on cell proliferation was determined in cells transfected with miR-203 mimic and DeltaNp63 small interfering RNA (siRNA), respectively. The regulation of DeltaNp63 expression in ESCC cells by miR-203 was studied by luciferase reporter assay, RT-PCR and western blot analysis in cells transfected with miR-203. The effect of DeltaNp63 re-expression on miR-203 induced inhibition of cell proliferation was studied by cell proliferation assay in cells cotransfected with miR-203 and pcDNA-DeltaNp63 plasmid (without the 3'-UTR of DeltaNp63). RESULTS: We found that both miR-203 and DeltaNp63 siRNA signicantly inhibited cell proliferation in ESCC. MiR-203 could down-regulate endogenous DeltaNp63 expression at the posttranscriptional level. Moreover, re-expression of DeltaNp63 in cells transfected with miR-203 significantly attenuated the miR-203 induced inhibition of cell proliferation. CONCLUSIONS: Our data implied that miR-203 could inhibit cell proliferation in human ESCC through DeltaNp63-mediated signal pathway. Therefore, we propose that miR-203 might be used as a therapeutic agent for human ESCC. PMID- 21299871 TI - Xylitol production from xylose mother liquor: a novel strategy that combines the use of recombinant Bacillus subtilis and Candida maltosa. AB - BACKGROUND: Xylose mother liquor has high concentrations of xylose (35%-40%) as well as other sugars such as L-arabinose (10%-15%), galactose (8%-10%), glucose (8%-10%), and other minor sugars. Due to the complexity of this mother liquor, further isolation of xylose by simple method is not possible. In China, more than 50,000 metric tons of xylose mother liquor was produced in 2009, and the management of sugars like xylose that present in the low-cost liquor is a problem. RESULTS: We designed a novel strategy in which Bacillus subtilis and Candida maltosa were combined and used to convert xylose in this mother liquor to xylitol, a product of higher value. First, the xylose mother liquor was detoxified with the yeast C. maltosa to remove furfural and 5-hydromethylfurfural (HMF), which are inhibitors of B. subtilis growth. The glucose present in the mother liquor was also depleted by this yeast, which was an added advantage because glucose causes carbon catabolite repression in B. subtilis. This detoxification treatment resulted in an inhibitor-free mother liquor, and the C. maltosa cells could be reused as biocatalysts at a later stage to reduce xylose to xylitol. In the second step, a recombinant B. subtilis strain with a disrupted xylose isomerase gene was constructed. The detoxified xylose mother liquor was used as the medium for recombinant B. subtilis cultivation, and this led to L arabinose depletion and xylose enrichment of the medium. In the third step, the xylose was further reduced to xylitol by C. maltosa cells, and crystallized xylitol was obtained from this yeast transformation medium. C. maltosa transformation of the xylose-enriched medium resulted in xylitol with 4.25 g L 1.h-1 volumetric productivity and 0.85 g xylitol/g xylose specific productivity. CONCLUSION: In this study, we developed a biological method for the purification of xylose from xylose mother liquor and subsequent preparation of xylitol by C. maltosa-mediated biohydrogenation of xylose. PMID- 21299872 TI - Utility of electronic patient records in primary care for stroke secondary prevention trials. AB - BACKGROUND: This study aimed to inform the design of a pragmatic trial of stroke prevention in primary care by evaluating data recorded in electronic patient records (EPRs) as potential outcome measures. The study also evaluated achievement of recommended standards of care; variation between family practices; and changes in risk factor values from before to after stroke. METHODS: Data from the UK General Practice Research Database (GPRD) were analysed for 22,730 participants with an index first stroke between 2003 and 2006 from 414 family practices. For each subject, the EPR was evaluated for the 12 months before and after stroke. Measures relevant to stroke secondary prevention were analysed including blood pressure (BP), cholesterol, smoking, alcohol use, body mass index (BMI), atrial fibrillation, utilisation of antihypertensive, antiplatelet and cholesterol lowering drugs. Intraclass correlation coefficients (ICC) were estimated by family practice. Random effects models were fitted to evaluate changes in risk factor values over time. RESULTS: In the 12 months following stroke, BP was recorded for 90%, cholesterol for 70% and body mass index (BMI) for 47%. ICCs by family practice ranged from 0.02 for BP and BMI to 0.05 for LDL and HDL cholesterol. For subjects with records available both before and after stroke, the mean reductions from before to after stroke were: mean systolic BP, 6.02 mm Hg; diastolic BP, 2.78 mm Hg; total cholesterol, 0.60 mmol/l; BMI, 0.34 Kg/m2. There was an absolute reduction in smokers of 5% and heavy drinkers of 4%. The proportion of stroke patients within the recommended guidelines varied from less than a third (29%) for systolic BP, just over half for BMI (54%), and over 90% (92%) on alcohol consumption. CONCLUSIONS: Electronic patient records have potential for evaluation of outcomes in pragmatic trials of stroke secondary prevention. Stroke prevention interventions in primary care remain suboptimal but important reductions in vascular risk factor values were observed following stroke. Better recording of lifestyle factors in the GPRD has the potential to expand the scope of the GPRD for health care research and practice. PMID- 21299873 TI - Accumulation of lysosulfatide in the brain of arylsulfatase A-deficient mice. AB - Lysosomal storage diseases are a group of disorders where accumulation of catabolites is manifested in the lysosomes of different cell types. In metachromatic leukodystrophy (Arylsulfatase A [EC.3.1.6.8] deficiency) storage of the glycosphingolipid sulfatide in the brain leads to demyelination, resulting in neuromotor co-ordination deficits and regression. In a mouse model for metachromatic leukodystrophy, the ASA null mutant mouse, the accumulation of sulfatide in correlation to phenotype has been thoroughly investigated. Another lipid species reported to accumulate in patients with metachromatic leukodystrophy is the sulfatide related lipid lysosulfatide. Lysosulfatide was shown to be a cytotoxic compound in cell culture experiments and thus suggested to be involved in the pathology of metachromatic leukodystrophy. In this study, we further investigated the developmental profile of lysosulfatide in the brain of ASA null mutant mice by using high performance liquid chromatography. Lysosulfatide could be detected in the brain of normal mice (ASA +/+) from 1.8 months up to 23.1 months of age. From the age of 8.8 months the lysosulfatide levels remained constant at 1 pmol/mg wet tissue. The developmental change (< 20 months) of brain lysosulfatide showed an accumulation in ASA null mutant mice at ages above one month compared to its normal counterpart (ASA +/+). Thus, the ASA null mutant mouse might be a suitable model to further investigate the role of lysosulfatide in the pathogenesis of metachromatic leukodystrophy. PMID- 21299874 TI - Intravenous magnesium sulphate for aneurysmal subarachnoid hemorrhage: an updated systemic review and meta-analysis. AB - INTRODUCTION: Previous meta-analyses of magnesium sulphate infusion in the treatment of aneurysmal subarachnoid hemorrhage (SAH) have become outdated due to recently published clinical trials. Our aim was thus to perform an up-to-date systemic review and meta-analysis of published data on the use of magnesium sulphate infusion in aneurysmal SAH patients. METHODS: A systemic review and meta analysis of the literature was carried out on published randomized controlled clinical trials that investigated the efficacy of magnesium sulphate infusion in aneurysmal SAH patients. The results were analyzed with regard to delayed cerebral ischemia (DCI), delayed cerebral infarction, and favorable neurological outcomes at three and six months. The risks of bias were assessed using the Jadad criteria, with a Jadad score >3 indicating a lower such risk. Meta-analyses are presented in terms of relative risk (RR) with 95% confidence intervals (CIs). RESULTS: Six eligible studies with 875 patients were reviewed. The pooled RR for DCI was 0.87 (95% CI, 0.36 to 2.09; P = 0.75). That for delayed cerebral infarction was 0.58 (95% CI, 0.35 to 0.97; P = 0.04), although this result did not persist if only randomized clinical trials with a lower risk of bias were included (RR 0.61, 95% CI, 0.31 to 1.22; P = 0.17). The pooled RR for a favorable outcome at three months was 1.14 (95% CI, 0.99 to 1.31; P = 0.07), and that for a favorable outcome at six months was 1.08 (95% CI, 0.94 to 1.24; P = 0.29). CONCLUSIONS: The present findings do not lend support to a beneficial effect of magnesium sulphate infusion on delayed cerebral infarction. The reduction in DCI and improvement in the clinical outcomes of aneurysmal SAH patients following magnesium sulphate infusion observed in previous pilot studies are not confirmed, although a beneficial effect cannot be ruled out because of sample size limitation. PMID- 21299875 TI - Health state preferences associated with weight status in children and adolescents. AB - BACKGROUND: Childhood obesity is a substantial public health problem. The extent to which health state preferences (utilities) are related to a child's weight status has not been reported. The aims of this study were (1) to use a generic health state classification system to measure health related quality of life and calculate health utilities in a convenience sample of children and adolescents and (2) to determine the extent to which these measures are associated with weight status and body mass index (BMI). METHODS: We enrolled 76 children 5-18 years of age from a primary care clinic and an obesity clinic in Boston MA. We administered the Health Utilities Index (HUI) and used the HUI Mark 3 single- and multi-attribute utility functions to calculate health utilities. We determined BMI percentile and weight status based on CDC references. We examined single attribute and overall utilities in relation to weight status and BMI. RESULTS: Mean (range) age was 10.8 (5-18) years. Mean (SD) BMI percentile was 76 (26); 55% of children were overweight or obese. The mean (SD) overall utility was 0.79 (0.17) in the entire sample. For healthy-weight children, the mean overall utility was higher than for overweight or obese children (0.81 vs. 0.78), but the difference was not statistically significant (difference 0.04, 95% CI -0.04, 0.11). CONCLUSIONS: Our results provide a quantitative estimate of the health utility associated with overweight and obesity in children, and will be helpful to researchers performing cost effectiveness analyses of interventions to prevent and/or treat childhood obesity. PMID- 21299876 TI - Isolation and purification of Cu-free methanobactin from Methylosinus trichosporium OB3b. AB - BACKGROUND: The isolation of highly pure copper-free methanobactin is a prerequisite for the investigation of the biogeochemical functions of this chalkophore molecule produced by methane oxidizing bacteria. Here, we report a purification method for methanobactin from Methylosinus trichosporium OB3b cultures based on reversed-phase HPLC fractionation used in combination with a previously reported resin extraction. HPLC eluent fractions of the resin extracted product were collected and characterized with UV-vis, FT-IR, and C-1s NEXAFS spectroscopy, as well as with elemental analysis and ESI-MS. RESULTS: The results showed that numerous compounds other than methanobactin were present in the isolate obtained with resin extraction. Molar C/N ratios, mass spectrometry measurements, and UV-vis spectra indicated that methanobactin was only present in one of the HPLC fractions. On a mass basis, methanobactin carbon contributed only 32% to the total organic carbon isolated with resin extraction. Our spectroscopic results implied that besides methanobactin, the organic compounds in the resin extract comprised breakdown products of methanobactin as well as polysaccharide like substances. CONCLUSION: Our results demonstrate that a purification step is indispensable in addition to resin extraction in order to obtain pure methanobactin. The proposed HPLC purification procedure is suitable for semi preparative work and provides copper-free methanobactin. PMID- 21299877 TI - A demonstration of an affinity between pyrite and organic matter in a hydrothermal setting. AB - One of the key-principles of the iron-sulphur world theory is to bring organic molecules close enough to interact with each other, using the surface of pyrite as a substrate in a hydrothermal setting. The present paper explores the relationship of pyrite and organic matter in a hydrothermal setting from the geological record; in hydrothermal calcite veins from Carboniferous limestones in central Ireland. Here, the organic matter is accumulated as coatings around, and through, pyrite grains. Most of the pyrite grains are euhedral-subhedral crystals, ranging in size from ca 0.1-0.5 mm in diameter, and they are scattered throughout the matrix of the vein calcite. The organic matter was deposited from a hydrothermal fluid at a temperature of at least 200 degrees C, and gives a Raman signature of disordered carbon. This study points to an example from a hydrothermal setting in the geological record, demonstrating that pyrite can have a high potential for the concentration and accumulation of organic materials. PMID- 21299878 TI - Factors affecting the accuracy of urine-based biomarkers of BSE. AB - BACKGROUND: Transmissible spongiform encephalopathy diseases are untreatable, uniformly fatal degenerative syndromes of the central nervous system that can be transmitted both within as well as between species. The bovine spongiform encephalopathy (BSE) epidemic and the emergence of a new human variant of Creutzfeldt-Jakob disease (vCJD), have profoundly influenced beef production processes as well as blood donation and surgical procedures. Simple, robust and cost effective diagnostic screening and surveillance tools are needed for both the preclinical and clinical stages of TSE disease in order to minimize both the economic costs and zoonotic risk of BSE and to further reduce the risk of secondary vCJD. OBJECTIVE: Urine is well suited as the matrix for an ante-mortem test for TSE diseases because it would permit non-invasive and repeated sampling. In this study urine samples collected from BSE infected and age matched control cattle were screened for the presence of individual proteins that exhibited disease specific changes in abundance in response to BSE infection that might form the basis of such an ante-mortem test. RESULTS: Two-dimensional differential gel electrophoresis (2D-DIGE) was used to identify proteins exhibiting differential abundance in two sets of cattle. The known set consisted of BSE infected steers and age matched controls throughout the course of the disease. The blinded unknown set was composed of BSE infected and control samples of both genders, a wide range of ages and two different breeds. Multivariate analyses of individual protein abundance data generated classifiers comprised of the proteins best able to discriminate between the samples based on disease state, breed, age and gender. CONCLUSION: Despite the presence of confounding factors, the disease specific changes in abundance exhibited by a panel of urine proteins permitted the creation of classifiers able to discriminate between control and infected cattle with a high degree of accuracy. PMID- 21299879 TI - Weight-related concerns and weight-control behaviors among overweight adolescents in Delhi, India: a cross-sectional study. AB - BACKGROUND: Obesity is emerging as a public health problem among adolescents in India. The aim of this study was to describe specific weight-related concerns among school-going youth in Delhi, India and to assess the prevalence of weight control behaviors, including healthy and unhealthy ones. Differences by weight status, gender, grade level, and school-type (a proxy for SES in this setting) are considered. METHODS: This study is cross-sectional by design. A sample of eighth and tenth graders (n=1818) enrolled in Private (middle-high SES) and Government (low SES) schools (n=8) in Delhi, India participated. All students' height and weight were measured. Students participated in a survey of weight related concerns and weight-control behaviors, as well. Mixed-effects regression models were used to test for differences in weight-related concerns and weight control behaviors across key factors of interest (i.e., weight status, gender, grade level, and SES). RESULTS: The combined prevalence of obesity and overweight was 16.6%, overall. Controlling one's weight was important to overweight and non overweight youth, alike (94.2% v. 84.8%, p<0.001). Significantly more overweight or obese youth reported trying to control their weight last year, compared to those who were not overweight (68.1% v. 18.0%, p<0.001). Healthy weight control behaviors were more common than unhealthy or extreme practices, although the latter were still prevalent. Half of the overweight or obese students misclassified their weight status, while about 1 in 10 non-overweight youth did the same. Body dissatisfaction was highest among overweight youth and girls. CONCLUSIONS: Interventions to promote healthy weight control should be pertinent to and well-received by school-going youth in India. Healthy weight control practices need to be explicitly encouraged and unhealthy practices reduced. Future interventions should address issues specific to body image, too, as body dissatisfaction was not uncommon among youth. PMID- 21299880 TI - A new chitinase-like xylanase inhibitor protein (XIP) from coffee (Coffea arabica) affects Soybean Asian rust (Phakopsora pachyrhizi) spore germination. AB - BACKGROUND: Asian rust (Phakopsora pachyrhizi) is a common disease in Brazilian soybean fields and it is difficult to control. To identify a biochemical candidate with potential to combat this disease, a new chitinase-like xylanase inhibitor protein (XIP) from coffee (Coffea arabica) (CaclXIP) leaves was cloned into the pGAPZalpha-B vector for expression in Pichia pastoris. RESULTS: A cDNA encoding a chitinase-like xylanase inhibitor protein (XIP) from coffee (Coffea arabica) (CaclXIP), was isolated from leaves. The amino acid sequence predicts a (beta/alpha)8 topology common to Class III Chitinases (glycoside hydrolase family 18 proteins; GH18), and shares similarity with other GH18 members, although it lacks the glutamic acid residue essential for catalysis, which is replaced by glutamine. CaclXIP was expressed as a recombinant protein in Pichia pastoris. Enzymatic assay showed that purified recombinant CaclXIP had only residual chitinolytic activity. However, it inhibited xylanases from Acrophialophora nainiana by approx. 60% when present at 12:1 (w/w) enzyme:inhibitor ratio. Additionally, CaclXIP at 1.5 MUg/MUL inhibited the germination of spores of Phakopsora pachyrhizi by 45%. CONCLUSIONS: Our data suggests that CaclXIP belongs to a class of naturally inactive chitinases that have evolved to act in plant cell defence as xylanase inhibitors. Its role on inhibiting germination of fungal spores makes it an eligible candidate gene for the control of Asian rust. PMID- 21299881 TI - High prevalence of urinary schistosomiasis in two communities in South Darfur: implication for interventions. AB - BACKGROUND: There are few data on the prevalence of schistosomiasis in Darfur. We conducted this study in response to reports of 15 laboratory confirmed cases of schistosomiasis and visible haematuria among children from two communities in South Darfur. The aim of the study was to estimate the prevalence of schistosomiasis in the area and to decide on modalities of intervention. METHODS: A cross-sectional survey involving 811 children and adults from schools and health facilities was conducted in two communities of South Darfur in March 2010. Urine samples were collected and examined for ova of Schistosoma haematobium using a sedimentation technique. A semi-structured format was used to collect socio-demographic characteristics of the participants. RESULTS: Eight hundred eleven (811) urine samples were collected, 415 from Alsafia and 396 from Abuselala. Of the collected samples in 56.0% (95% Confidence Interval (CI); 52.6 59.4) Schistosoma eggs were found. The prevalence was high in both Abuselala 73.3% (95% CI; 68.9-77.6) and Alsafia 39.5% (95% CI; 34.8-44.2). More males (61.7%, 95%CI; 56.5-64.9) were infected than females (52.1%, 95%CI; 48.2-56.0). Children in the age group 10-14 has the highest (73.0%, 95%CI; 68.7-77.2) infection rate. School age children (6-15 years) are more likely to be infected than those >15 years (Adjusted Odds Ratio (AOR) = 2.70, 95% CI; 1.80-4.06). Individuals in Abuselala are more likely to be infected than those who live in Alsafia (AOR = 4.3, 95% CI; 3.2-5.9). CONCLUSION: The findings of this study indicate that S. hematobium is endemic in Alsafia and Abuselala South Darfur in Sudan with a high prevalence of infection among older children. This signifies the importance of urgent intervention through Mass Drug Administration (MDA) to halt the infection cycle and tailored health messages to targeted groups. Based on the findings MDA was conducted in the villages. PMID- 21299882 TI - Human papillomavirus genotype distribution in tonsil cancers. AB - BACKGROUND: The incidence of tonsil cancers has increased in several countries. French data on HPV prevalence in tonsil cancers are scarce. The objective of this study was thus to assess the overall and type specific HPV prevalence in tonsil histological samples. METHODS: This French retrospective multicenter study involved 12 centres located throughout the country. Were included 185 histological samples collected from year 2000 to 2009 with a validated diagnosis of tonsil invasive carcinomas. HPV prevalence was studied according to gender, age and histological type of cancer. RESULTS: Overall HPV prevalence was 57% in tonsil cancers. Mean age of diagnosis was comparable in HPV positive tonsils cases (60 +/- 11.2) and HPV negative tonsil cases (59 +/- 9.6). HPV prevalence was significantly higher in female than in male cases (28/35 versus 78/150 in tonsil cases, respectively, P = 0.003). About 53% of tonsil cases were infected by a single HPV type. Only eight (4%) samples were infected by more than one HPV type. Among HPV positive samples, HPV 16 was found in 89% of tonsil cases. All other HPV types had prevalence below 5%. CONCLUSIONS: Our results indicate that HPV is common in tonsil carcinomas and emphasize the predominant role of HPV 16. PMID- 21299883 TI - An agonist sensitive, quick and simple cell-based signaling assay for determination of ligands mimicking prostaglandin E2 or E1 activity through subtype EP1 receptor: Suitable for high throughput screening. AB - BACKGROUND: Conventionally the active ingredients in herbal extracts are separated into individual components, by fractionation, desalting, and followed by high-performance liquid chromatography (HPLC). In this study we have tried to directly screen water-soluble fractions of herbs with potential active ingredients before purification or extraction. We propose that the herbal extracts mimicking prostaglandin E(1) (PGE(1)) and E(2) (PGE(2)) can be identified in the water-soluble non-purified fraction. PGE(1) is a potent anti inflammatory molecule used for treating peripheral vascular diseases while PGE(2) is an inflammatory molecule. METHODS: We used cell-based assays (CytoFluor multi well plate reader and fluorescence microscopy) in which a calcium signal was generated by the recombinant EP(1) receptor stably expressed in HEK293 cells (human embryonic kidney). PGE(1) and PGE(2) were tested for their ability to generate a calcium signal. Ninety-six water soluble fractions of Treasures of the east (single Chinese herb dietary supplements) were screened. RESULTS: After screening, the top ten stimulators were identified. The identified herbs were then desalted and the calcium fluorescent signal reconfirmed using fluorescence microscopy. Among these top ten agonists identified, seven stimulated the calcium signaling (1-40 MUM concentration) using fluorescence microscopy. CONCLUSIONS: Fluorescence microscopy and multi-well plate readers can be used as a target specific method for screening water soluble fractions with active ingredients at a very early stage, before purification. Our future work consists of purifying and separating the active ingredients and repeating fluorescence microscopy. Under ordinary circumstances we would have to purify the compounds first and then test all the extracts from 96 herbs. Conventionally, for screening natural product libraries, the procedure followed is the automated separation of all constituents into individual components using fractionation and high performance liquid chromatography. We, however, demonstrated that the active ingredients of the herbal extracts can be tested before purification using an agonist sensitive, quick and simple cell-based signaling assay for ligands mimicking the agonists, PGE(1) and PGE(2). PMID- 21299884 TI - Reduction in antioxidant enzyme expression and sustained inflammation enhance tissue damage in the subacute phase of spinal cord contusive injury. AB - BACKGROUND: Traumatic spinal cord injury (SCI) forms a disadvantageous microenvironment for tissue repair at the lesion site. To consider an appropriate time window for giving a promising therapeutic treatment for subacute and chronic SCI, global changes of proteins in the injured center at the longer survival time points after SCI remains to be elucidated. METHODS: Through two-dimensional electrophoresis (2DE)-based proteome analysis and western blotting, we examined the differential expression of the soluble proteins isolated from the lesion center (LC) at day 1 (acute) and day 14 (subacute) after a severe contusive injury to the thoracic spinal cord at segment 10. In situ apoptotic analysis was used to examine cell apoptosis in injured spinal cord after adenoviral gene transfer of antioxidant enzymes. In addition, administration of chondroitinase ABC (chABC) was performed to analyze hindlimb locomotor recovery in rats with SCI using Basso, Beattie and Bresnahan (BBB) locomotor rating scale. RESULTS: Our results showed a decline in catalase (CAT) and Mn-superoxide dismutase (MnSOD) found at day 14 after SCI. Accordingly, gene transfer of SOD was introduced in the injured spinal cord and found to attenuate cell apoptosis. Galectin-3, beta actin, actin regulatory protein (CAPG), and F-actin-capping protein subunit beta (CAPZB) at day 14 were increased when compared to that detected at day 1 after SCI or in sham-operated control. Indeed, the accumulation of beta-actin+ immune cells was observed in the LC at day 14 post SCI, while most of reactive astrocytes were surrounding the lesion center. In addition, chondroitin sulfate proteoglycans (CSPG)-related proteins with 40-kDa was detected in the LC at day 3 14 post SCI. Delayed treatment with chondroitinase ABC (chABC) at day 3 post SCI improved the hindlimb locomotion in SCI rats. CONCLUSIONS: Our findings demonstrate that the differential expression in proteins related to signal transduction, oxidoreduction and stress contribute to extensive inflammation, causing time-dependent spread of tissue damage after severe SCI. The interventions by supplement of anti-oxidant enzymes right after SCI or delayed administration with chABC can facilitate spinal neural cell survival and tissue repair. PMID- 21299885 TI - The effects of spatial population dataset choice on estimates of population at risk of disease. AB - BACKGROUND: The spatial modeling of infectious disease distributions and dynamics is increasingly being undertaken for health services planning and disease control monitoring, implementation, and evaluation. Where risks are heterogeneous in space or dependent on person-to-person transmission, spatial data on human population distributions are required to estimate infectious disease risks, burdens, and dynamics. Several different modeled human population distribution datasets are available and widely used, but the disparities among them and the implications for enumerating disease burdens and populations at risk have not been considered systematically. Here, we quantify some of these effects using global estimates of populations at risk (PAR) of P. falciparum malaria as an example. METHODS: The recent construction of a global map of P. falciparum malaria endemicity enabled the testing of different gridded population datasets for providing estimates of PAR by endemicity class. The estimated population numbers within each class were calculated for each country using four different global gridded human population datasets: GRUMP (~1 km spatial resolution), LandScan (~1 km), UNEP Global Population Databases (~5 km), and GPW3 (~5 km). More detailed assessments of PAR variation and accuracy were conducted for three African countries where census data were available at a higher administrative unit level than used by any of the four gridded population datasets. RESULTS: The estimates of PAR based on the datasets varied by more than 10 million people for some countries, even accounting for the fact that estimates of population totals made by different agencies are used to correct national totals in these datasets and can vary by more than 5% for many low-income countries. In many cases, these variations in PAR estimates comprised more than 10% of the total national population. The detailed country-level assessments suggested that none of the datasets was consistently more accurate than the others in estimating PAR. The sizes of such differences among modeled human populations were related to variations in the methods, input resolution, and date of the census data underlying each dataset. Data quality varied from country to country within the spatial population datasets. CONCLUSIONS: Detailed, highly spatially resolved human population data are an essential resource for planning health service delivery for disease control, for the spatial modeling of epidemics, and for decision-making processes related to public health. However, our results highlight that for the low-income regions of the world where disease burden is greatest, existing datasets display substantial variations in estimated population distributions, resulting in uncertainty in disease assessments that utilize them. Increased efforts are required to gather contemporary and spatially detailed demographic data to reduce this uncertainty, particularly in Africa, and to develop population distribution modeling methods that match the rigor, sophistication, and ability to handle uncertainty of contemporary disease mapping and spread modeling. In the meantime, studies that utilize a particular spatial population dataset need to acknowledge the uncertainties inherent within them and consider how the methods and data that comprise each will affect conclusions. PMID- 21299887 TI - Skin and soft-tissue infections in suburban primary care: epidemiology of methicillin-resistant Staphylococcus aureus and observations on abscess management. AB - BACKGROUND: Reports from urban medical centers suggest that methicillin-resistant Staphylococcus aureus (MRSA) has become the most common cause of skin and soft tissue infections (SSTIs). Risk factors for MRSA have been identified but have not been clinically useful. FINDINGS: From May 2006-April 2007, we performed an observational study of 529 SSTIs among ambulatory patients in the urgent care departments of a large suburban primary-care practice. SSTIs were included if they produced pus or fluid. The proportion of MRSA was determined overall (defined as prevalence) and by SSTI diagnosis. Potential risk factors for MRSA were examined with multivariate analysis, and descriptive statistics were generated for follow-up and abscess management. The prevalence of MRSA was 22% and did not rise during the study. MRSA was isolated from 36% of abscesses, 15% of cellulitis, and 14% of other SSTIs. Independent risk factors for MRSA included a prior history of MRSA (adjusted odds ratio [aOR], 41.05; 95% confidence interval [CI], 11.4-147.3), a close contact with prior MRSA (aOR, 12.83; 95% CI, 4.2-39.2), erythema >=10 cm (aOR, 2.59; 95% CI, 1.5-4.4), and abscess diagnosis (aOR, 3.19; 95% CI, 2.1-5.0). Prior MRSA had a positive predictive value of 88% for current MRSA. When both abscess diagnosis and erythema >=10 cm were present, the proportion of MRSA was 59%. The vast majority of SSTIs (96 percent) resolved or improved within one week. Most abscesses, even small ones, were treated with antibiotics. Resource utilization was highest in those abscesses with erythema >=10 cm. CONCLUSIONS: The prevalence of MRSA is relatively low among SSTIs in suburban primary care. However, MRSA is common in the subgroup of abscesses with large erythema. While the effectiveness of adjunctive antibiotic therapy for large abscesses is unknown, drugs chosen for these infections should be active against MRSA. Most non-abscess SSTIs do not require treatment with a MRSA-active drug, and antibiotics are probably overused for small abscesses. A history of prior MRSA should be recorded in a patient's health record. PMID- 21299886 TI - Defining ovarian reserve to better understand ovarian aging. AB - Though a widely utilized term and clinical concept, ovarian reserve (OR) has been only inadequately defined. Based on Medline and PubMed searches we here define OR in its various components, review genetic control of OR, with special emphasis on the FMR1 gene, and discuss whether diminished OR (DOR) is treatable. What is generally referred to as OR reflects only a small portion of total OR (TOR), a pool of growing (recruited) follicles (GFs) at different stages of maturation. Functional OR (FOR) depends on size of the follicle pool at menarche and the follicle recruitment rate. Both vary between individuals and, at least partially, are under genetic control. The FMR1 gene plays a role in defining FOR at all ages. Infertility treatments have in the past almost exclusively only centered on the last two weeks of folliculogenesis, the gonadotropin-sensitive phase. Expansions of treatments into earlier stages of maturation will offer opportunity to significantly improve ovarian stimulation protocols, especially in women with DOR. Dehydroepiandrosterone (DHEA) may represent a first such intervention. Data generated in DHEA-supplemented women, indeed, suggest a new ovarian aging concept, based on aging of ovarian environments and not, as currently is believed, aging oocytes. PMID- 21299888 TI - Socioeconomic status and mortality after acute myocardial infarction: a study from Iran. AB - BACKGROUND: Studies have shown an inverse relationship between socioeconomic status (SES) and mortality due to coronary heart disease (CHD). Little is known about this association in Iran. This study aimed to investigate whether mortality after myocardial infarction (MI) varies by SES. METHODS: In a retrospective study, 1283 MI patients who hospitalized in Tehran Heart Center from March 2005 to March 2006 were followed up in March 2008. Demographic, clinical and SES data were collected from case records and by telephone interviews. Multiple logistic regression analysis was performed to estimate the predictive effect of socioeconomic factors on outcome. RESULTS: In all 664 patients were studied. Of these, 500 patients were alive and 164 were dead due to MI (64 died at hospital and 100 died at home). The results of regression analysis showed that in addition to treatment (OR = 9.52, 95%CI 4.84-18.7), having diabetes (OR = 1.78, 95% CI 1.12-2.81) or hyperlipidemia (OR = 1.82, 95% CI 1.14-2.90), socioeconomic variables including living area in square per person (lowest level vs. upper level OR = 4.92, 95% CI 2.11-11.4), unemployment (OR = 3.50, 95% CI 1.50-8.13) and education (OR for illiterate patients = 2.51, 95% CI 1.00-6.31) were the most significant contributing factors to increased mortality after MI. CONCLUSION: Although the findings should be interpreted with caution, the study results indicated that socioeconomic variables were significant contributing factors to increased mortality after myocardial infarction. The underlying role of socioeconomic status on increased mortality after MI deserves further investigation. PMID- 21299889 TI - Citrobacter freundii infection after acute necrotizing pancreatitis in a patient with a pancreatic pseudocyst: a case report. AB - INTRODUCTION: Infections are the most frequent and severe complications of acute necrotizing pancreatitis with a mortality rate of up to 80 percent. Although experimental and clinical studies suggest that the microbiologic source of pancreatic infection could be enteric, information in this regard is controversial. CASE PRESENTATION: We describe a Citrobacter freundii isolation by endoscopy ultrasound fine needle aspiration in a 80-year-old Caucasian man with pancreatic pseudocyst after acute necrotizing pancreatitis. CONCLUSION: Our case report confirms that this organism can be recovered in patients with a pancreatic pseudocyst. On-site cytology feedback was crucial to the successful outcome of this case as immediate interpretation of the fine needle aspiration sample directed the appropriate cultures and, ultimately, the curative therapy. To the best of our knowledge, this is the first reported case of isolated pancreatic C. freundii diagnosed by endoscopy ultrasound fine needle aspiration. PMID- 21299890 TI - Budd-Chiari syndrome in a 25-year-old woman with Behcet's disease: a case report and review of the literature. AB - INTRODUCTION: The risk that patients with Behcet's disease will develop thrombotic complications has been previously described. Although it is distributed worldwide, Behcet's disease is rare in the Americas and Europe. Even though the pathogenic mechanisms of vascular complications of Budd-Chiari syndrome in patients with Behcet's disease are unknown, severe vascular complications of Budd-Chiari syndrome associated with Behcet's disease seem to affect mainly young men. CASE PRESENTATION: We report a case of Budd-Chiari syndrome, a severe vascular complication that developed in a 25-year-old Afro Brazilian woman with Behcet's disease. CONCLUSION: Severe vascular complications of Budd-Chiari syndrome in patients with Behcet's disease are much more common in young adult male patients; we present a rare case of Budd-Chiari syndrome in a young Afro-Brazilian woman with Behcet's disease. PMID- 21299891 TI - In-depth analysis of the chicken egg white proteome using an LTQ Orbitrap Velos. AB - BACKGROUND: Hen's egg white has been the subject of intensive chemical, biochemical and food technological research for many decades, because of its importance in human nutrition, its importance as a source of easily accessible model proteins, and its potential use in biotechnological processes. Recently the arsenal of tools used to study the protein components of egg white has been complemented by mass spectrometry-based proteomic technologies. Application of these fast and sensitive methods has already enabled the identification of a large number of new egg white proteins. Recent technological advances may be expected to further expand the egg white protein inventory. RESULTS: Using a dual pressure linear ion trap Orbitrap instrument, the LTQ Orbitrap Velos, in conjunction with data analysis in the MaxQuant software package, we identified 158 proteins in chicken egg white with two or more sequence unique peptides. This group of proteins identified with very high confidence included 79 proteins identified in egg white for the first time. In addition, 44 proteins were identified tentatively. CONCLUSIONS: Our results, apart from identifying many new egg white components, indicate that current mass spectrometry technology is sufficiently advanced to permit direct identification of minor components of proteomes dominated by a few major proteins without resorting to indirect techniques, such as chromatographic depletion or peptide library binding, which change the composition of the proteome. PMID- 21299893 TI - Primary extranodal soft-tissue B-cell lymphoma with abundant immunoglobulin inclusions mimicking adult rhabdomyoma: a case report. AB - INTRODUCTION: Immunoglobulin inclusions are found in B-cell neoplasms as well as in crystal-storing histiocytosis associated with B-cell lymphoproliferative disorders. At times, the deposits may be so profound as to obscure the diagnosis and may even lead to misdiagnosis. We report one case of low-grade extranodal lymphoplasmacytic lymphoma with abundant immunoglobulin inclusions and emphasize the need for immunophenotyping and molecular assay to make the right decision in diagnosis. To the best of our knowledge, this is the first report of extranodal B cell lymphoma with abundant intracellular immunoglobulin accumulation. CASE PRESENTATION: A 62-year-old Asian man from China presented with a 13-year history of a right shoulder mass with recent ongoing pain. A desmoplastic fibroma located in the posterior muscles of the neck was suggested by magnetic resonance imaging, and extended local excision was performed. A biopsy, however, revealed large, isolated rhabdoid cells in a diffuse pattern with mild atypia and eosinophilic cytoplasm. Clustered lymphoid cells were interspersed among these cells. The diagnosis was initially suggested to be adult rhabdomyoma. The final diagnosis of lymphoma was made after immunohistochemical, ultrastructural and molecular studies. CONCLUSION: We emphasize this histopathologic and immunohistochemical finding because of the potential for confusion with other tumors or disorders, such as adult rhabdomyoma or crystal-storing histiocytosis. PMID- 21299892 TI - Bimodal distribution of RNA expression levels in human skeletal muscle tissue. AB - BACKGROUND: Many human diseases and phenotypes are related to RNA expression, levels of which are influenced by a wide spectrum of genetic and exposure-related factors. In a large genome-wide study of muscle tissue expression, we found that some genes exhibited a bimodal distribution of RNA expression, in contrast to what is usually assumed in studies of a single healthy tissue. As bimodality has classically been considered a hallmark of genetic control, we assessed the genome wide prevalence, cause, and association of this phenomenon with diabetes-related phenotypes in skeletal muscle tissue from 225 healthy Pima Indians using exon array expression chips. RESULTS: Two independent batches of microarrays were used for bimodal assessment and comparison. Of the 17,881 genes analyzed, eight (GSTM1, HLA-DRB1, ERAP2, HLA-DRB5, MAOA, ACTN3, NR4A2, and THNSL2) were found to have bimodal expression replicated in the separate batch groups, while 24 other genes had evidence of bimodality in only one group. Some bimodally expressed genes had modest associations with pre-diabetic phenotypes, of note ACTN3 with insulin resistance. Most of the other bimodal genes have been reported to be involved with various other diseases and characteristics. Association of expression with cis genetic variation in a subset of 149 individuals found all but one of the confirmed bimodal genes and nearly half of all potential ones to be highly significant expression quantitative trait loci (eQTL). The rare prevalence of these bimodally expressed genes found after controlling for batch effects was much lower than the prevalence reported in other studies. Additional validation in data from separate muscle expression studies confirmed the low prevalence of bimodality we observed. CONCLUSIONS: We conclude that the prevalence of bimodal gene expression is quite rare in healthy muscle tissue (<0.2%), and is much lower than limited reports from other studies. The major cause of these clearly bimodal expression patterns in homogeneous tissue appears to be cis-polymorphisms, indicating that such bimodal genes are, for the most part, eQTL. The high frequency of disease associations reported with these genes gives hope that this unique feature may identify or actually be an underlying factor responsible for disease development. PMID- 21299894 TI - The influence of bisphosphonates on human osteoblast migration and integrin aVb3/tenascin C gene expression in vitro. AB - BACKGROUND: Bisphosphonates are therapeutics of bone diseases, such as Paget's disease, multiple myeloma or osteoclastic metastases. As a severe side effect the bisphosphonate induced osteonecrosis of the jaw (BONJ) often requires surgical treatment and is accompanied with a disturbed wound healing.Therefore, the influence on adhesion and migration of human osteoblasts (hOB) after bisphosphonate therapy has been investigated by morphologic as well as gene expression methods. METHODS: By a scratch wound experiment, which measures the reduction of defined cell layer gap, the morphology and migration ability of hOB was evaluated. A test group of hOB, which was stimulated by zoledronate 5 * 10( 5)M, and a control group of unstimulated hOB were applied. Furthermore the gene expression of integrin aVb3 and tenascin C was quantified by Real-Time rtPCR at 5 data points over an experimental period of 14 days. The bisphosphonates zoledronate, ibandronate and clodronate have been compared with an unstimulated hOB control. RESULTS: After initially identical migration and adhesion characteristics, zoledronate inhibited hOB migration after 50 h of stimulation. The integrinavb3 and tenascin C gene expression was effected by bisphosphonates in a cell line dependent manner with decreased, respectively inconsistent gene expression levels over time. The non-nitrogen containing bisphosphonates clodronate led to decreased gene expression levels. CONCLUSION: Bisphosphonates seem to inhibit hOB adhesion and migration. The integrin aVb3 and tenascin C gene expression seem to be dependent on the cell line. BONJ could be enhanced by an inhibition of osteoblast adhesion and migration. The gene expression results, however, suggest a cell line dependent effect of bisphosphonates, which could explain the interindividual differences of BONJ incidences. PMID- 21299895 TI - Impaired desensitization of a human polymorphic alpha2B-adrenergic receptor variant enhances its sympatho-inhibitory activity in chromaffin cells. AB - BACKGROUND: alpha2-adrenergic receptors (ARs) mediate many cellular actions of epinephrine and norepinephrine and inhibit their secretion from adrenal chromaffin cells. Like many other G-protein coupled receptors (GPCRs), they undergo agonist-dependent phopshorylation and desensitization by GPCR Kinases (GRKs), a phenomenon recently shown to play a major role in the sympathetic overdrive that accompanies and aggravates chronic heart failure. A deletion polymorphism in the human alpha2B-AR gene (Glu301-303) causes impaired agonist promoted receptor phosphorylation and desensitization in heterologous cell lines. Given the importance of alpha2-ARs in regulation of catecholamine secretion from chromaffin cells, we sought to investigate, in the present study, the desensitization properties and the sympatho-inhibitory activity of this variant in a chromaffin cell line. For this purpose, we expressed this variant and its wild type counterpart in the well-established chromaffin cell line PC12, and performed receptor phosphorylation and desensitization studies, as well as in vitro catecholamine secretion assays. RESULTS: Both the agonist-induced phosphorylation and agonist-dependent desensitization of the human Glu301-303 deletion polymorphic alpha2B-AR are significantly impaired in PC12 cells, resulting in enhanced signaling to inhibition of cholinergic-induced catecholamine secretion in vitro. CONCLUSION: This alpha2B-AR gene polymorphism (Glu301-303 deletion) might confer better protection against conditions characterized and aggravated by sympathetic/catecholaminergic overstimulation in vivo. PMID- 21299896 TI - The porcine circovirus type 1 capsid gene promoter improves antigen expression and immunogenicity in a HIV-1 plasmid vaccine. AB - BACKGROUND: One of the promising avenues for development of vaccines against Human immunodeficiency virus type 1 (HIV-1) and other human pathogens is the use of plasmid-based DNA vaccines. However, relatively large doses of plasmid must be injected for a relatively weak response. We investigated whether genome elements from Porcine circovirus type 1 (PCV-1), an apathogenic small ssDNA-containing virus, had useful expression-enhancing properties that could allow dose-sparing in a plasmid vaccine. RESULTS: The linearised PCV-1 genome inserted 5' of the CMV promoter in the well-characterised HIV-1 plasmid vaccine pTHgrttnC increased expression of the polyantigen up to 2-fold, and elicited 3-fold higher CTL responses in mice at 10-fold lower doses than unmodified pTHgrttnC. The PCV-1 capsid gene promoter (Pcap) alone was equally effective. Enhancing activity was traced to a putative composite host transcription factor binding site and a "Conserved Late Element" transcription-enhancing sequence previously unidentified in circoviruses. CONCLUSIONS: We identified a novel PCV-1 genome-derived enhancer sequence that significantly increased antigen expression from plasmids in in vitro assays, and improved immunogenicity in mice of the HIV-1 subtype C vaccine plasmid, pTHgrttnC. This should allow significant dose sparing of, or increased responses to, this and other plasmid-based vaccines. We also report investigations of the potential of other circovirus-derived sequences to be similarly used. PMID- 21299899 TI - Uncovering high rates of unsafe injection equipment reuse in rural Cameroon: validation of a survey instrument that probes for specific misconceptions. AB - BACKGROUND: Unsafe reuse of injection equipment in hospitals is an on-going threat to patient safety in many parts of Africa. The extent of this problem is difficult to measure. Standard WHO injection safety assessment protocols used in the 2003 national injection safety assessment in Cameroon are problematic because health workers often behave differently under the observation of visitors. The main objective of this study is to assess the extent of unsafe injection equipment reuse and potential for blood-borne virus transmission in Cameroon. This can be done by probing for misconceptions about injection safety that explain reuse without sterilization. These misconceptions concern useless precautions against cross-contamination, i.e. "indirect reuse" of injection equipment. To investigate whether a shortage of supply explains unsafe reuse, we compared our survey data against records of purchases. METHODS: All health workers at public hospitals in two health districts in the Northwest Province of Cameroon were interviewed about their own injection practices. Injection equipment supply purchase records documented for January to December 2009 were compared with self-reported rates of syringe reuse. The number of HIV, HBV and HCV infections that result from unsafe medical injections in these health districts is estimated from the frequency of unsafe reuse, the number of injections performed, the probability that reused injection equipment had just been used on an infected patient, the size of the susceptible population, and the transmission efficiency of each virus in an injection. RESULTS: Injection equipment reuse occurs commonly in the Northwest Province of Cameroon, practiced by 44% of health workers at public hospitals. Self-reported rates of syringe reuse only partly explained by records on injection equipment supplied to these hospitals, showing a shortage of syringes where syringes are reused. Injection safety interventions could prevent an estimated 14-336 HIV infections, 248-661 HBV infections and 7-114 HCV infections each year in these health districts. CONCLUSIONS: Injection safety assessments that probe for indirect reuse may be more effective than observational assessments. The autodisable syringe may be an appropriate solution to injection safety problems in some hospitals in Cameroon. Advocacy for injection safety interventions should be a public health priority. PMID- 21299900 TI - Quantifying intervertebral disc mechanics: a new definition of the neutral zone. AB - BACKGROUND: The neutral zone (NZ) is the range over which a spinal motion segment (SMS) moves with minimal resistance. Clear as this may seem, the various methods to quantify NZ described in the literature depend on rather arbitrary criteria. Here we present a stricter, more objective definition. METHODS: To mathematically represent load-deflection of a SMS, the asymmetric curve was fitted by a summed sigmoid function. The first derivative of this curve represents the SMS compliance and the region with the highest compliance (minimal stiffness) is the NZ. To determine the boundaries of this region, the inflection points of compliance can be used as unique points. These are defined by the maximum and the minimum in the second derivative of the fitted curve, respectively. The merits of the model were investigated experimentally: eight porcine lumbar SMS's were bent in flexion-extension, before and after seven hours of axial compression. RESULTS: The summed sigmoid function provided an excellent fit to the measured data (r2 > 0.976). The NZ by the new definition was on average 2.4 (range 0.82-7.4) times the NZ as determined by the more commonly used angulation difference at zero loading. Interestingly, NZ consistently and significantly decreased after seven hours of axial compression when determined by the new definition. On the other hand, NZ increased when defined as angulation difference, probably reflecting the increase of hysteresis. The methods thus address different aspects of the load deflection curve. CONCLUSIONS: A strict mathematical definition of the NZ is proposed, based on the compliance of the SMS. This operational definition is objective, conceptually correct, and does not depend on arbitrarily chosen criteria. PMID- 21299898 TI - Cleaning up the 'Bigmessidae': molecular phylogeny of scleractinian corals from Faviidae, Merulinidae, Pectiniidae and Trachyphylliidae. AB - BACKGROUND: Molecular phylogenetic studies on scleractinian corals have shown that most taxa are not reflective of their evolutionary histories. Based principally on gross morphology, traditional taxonomy suffers from the lack of well-defined and homologous characters that can sufficiently describe scleractinian diversity. One of the most challenging clades recovered by recent analyses is 'Bigmessidae', an informal grouping that comprises four conventional coral families, Faviidae, Merulinidae, Pectiniidae and Trachyphylliidae, interspersed among one another with no apparent systematic pattern. There is an urgent need for taxonomic revisions in this clade, but it is vital to first establish phylogenetic relationships within the group. In this study, we reconstruct the evolutionary history of 'Bigmessidae' based on five DNA sequence markers gathered from 76 of the 132 currently recognized species collected from five reef regions in the central Indo-Pacific and the Atlantic. RESULTS: We present a robust molecular phylogeny of 'Bigmessidae' based on the combined five gene data, achieving a higher degree of resolution compared to previous analyses. Two Pacific species presumed to be in 'Bigmessidae' are more closely related to outgroup clades, suggesting that other unsampled taxa have unforeseen affinities. As expected, nested within 'Bigmessidae' are four conventional families as listed above, and relationships among them generally corroborate previous molecular analyses. Our more resolved phylogeny supports a close association of Hydnophora (Merulinidae) with Favites + Montastraea (Faviidae), rather than with the rest of Merulinidae, i.e., Merulina and Scapophyllia. Montastraea annularis, the only Atlantic 'Bigmessidae' is sister to Cyphastrea, a grouping that can be reconciled by their septothecal walls, a microstructural feature of the skeleton determined by recent morphological work. Characters at the subcorallite scale appear to be appropriate synapomorphies for other subclades, which cannot be explained using macromorphology. Indeed, wide geographic sampling here has revealed more instances of possible cryptic taxa confused by evolutionary convergence of gross coral morphology. CONCLUSIONS: Numerous examples of cryptic taxa determined in this study support the assertion that diversity estimates of scleractinian corals are erroneous. Fortunately, the recovery of most 'Bigmessidae' genera with only minor degrees of paraphyly offers some hope for impending taxonomic amendments. Subclades are well defined and supported by subcorallite morphological features, providing a robust framework for further systematic work. PMID- 21299897 TI - Curcumin: A review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma. AB - Curcumin (diferuloylmethane) is a polyphenol derived from the Curcuma longa plant, commonly known as turmeric. Curcumin has been used extensively in Ayurvedic medicine for centuries, as it is nontoxic and has a variety of therapeutic properties including anti-oxidant, analgesic, anti-inflammatory and antiseptic activity. More recently curcumin has been found to possess anti-cancer activities via its effect on a variety of biological pathways involved in mutagenesis, oncogene expression, cell cycle regulation, apoptosis, tumorigenesis and metastasis. Curcumin has shown anti-proliferative effect in multiple cancers, and is an inhibitor of the transcription factor NF-kappaB and downstream gene products (including c-myc, Bcl-2, COX-2, NOS, Cyclin D1, TNF-alpha, interleukins and MMP-9). In addition, curcumin affects a variety of growth factor receptors and cell adhesion molecules involved in tumor growth, angiogenesis and metastasis. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and treatment protocols include disfiguring surgery, platinum-based chemotherapy and radiation, all of which may result in tremendous patient morbidity. As a result, there is significant interest in developing adjuvant chemotherapies to augment currently available treatment protocols, which may allow decreased side effects and toxicity without compromising therapeutic efficacy. Curcumin is one such potential candidate, and this review presents an overview of the current in vitro and in vivo data supporting its therapeutic activity in head and neck cancer as well as some of the challenges concerning its development as an adjuvant chemotherapeutic agent. PMID- 21299901 TI - Hormonal responses upon return of spontaneous circulation after cardiac arrest: a retrospective cohort study. AB - INTRODUCTION: Cardiac arrest is often fatal and can be extremely stressful to patients, even if spontaneous rhythm is returned. The purpose of this study was to analyze the hormonal response after return of spontaneous circulation (ROSC). METHODS: This is a retrospective review of the chart and laboratory findings in a single medical facility. The patients admitted to the intensive care unit after successful resuscitation after out-of-hospital cardiac arrest were retrospectively identified and evaluated. Patients with hormonal diseases, patients who received cortisol treatment, those experiencing trauma, and pregnant women were excluded. Serum cortisol, adrenocorticotropic hormone (ACTH), and anti diuretic hormone (ADH (vasopressin)) were analyzed and a corticotropin stimulation test was performed. Mortality at one week and one month after admission, and neurologic outcome (cerebral performance category (CPC)) one month after admission were evaluated. RESULTS: A total of 117 patients, including 84 males (71.8%), were evaluated in this study. One week and one month after admission, 87 (74.4%) and 65 patients (55.6%) survived, respectively. Relative adrenal insufficiency, and higher plasma ACTH and ADH levels were associated with shock-related mortality (P = 0.046, 0.005, and 0.037, respectively), and ACTH and ADH levels were also associated with late mortality (P = 0.002 and 0.004, respectively). Patients with relative adrenal insufficiency, ACTH ?5 pg/mL, and ADH ?30 pg/mL, had a two-fold increased risk of a poor outcome (shock-related mortality): (odds ratio (OR), 2.601 and 95% confidence interval (CI), 1.015 to 6.664; OR, 2.759 and 95% CI, 1.060 to 7.185; OR, 2.576 and 95% CI, 1.051 to 6.313, respectively). Thirty-five patients (29.9%) had a good CPC (1 to 2), and 82 patients (70.1%) had a bad CPC (3 to 5). Age ?50 years and an ADH ?30 pg/mL were associated with a bad CPC (OR, 4.564 and 95% CI, 1.794 to 11.612; OR, 6.568 and 95% CI, 1.918 to 22.483, respectively). CONCLUSIONS: The patients with relative adrenal insufficiency and higher blood levels of ACTH and ADH upon ROSC after cardiac arrest had a poor outcome. The effectiveness of administration of cortisol and ADH to patients upon ROSC after cardiac arrest is uncertain and additional studies are needed. PMID- 21299902 TI - Evaluating the effectiveness of rosuvastatin in preventing the progression of diastolic dysfunction in aortic stenosis: A substudy of the aortic stenosis progression observation measuring effects of rosuvastatin (ASTRONOMER) study. AB - BACKGROUND: Tissue Doppler imaging (TDI) is a noninvasive echocardiographic method for the diagnosis of diastolic dysfunction in patients with varying degrees of aortic stenosis (AS). Little is known however, on the utility of TDI in the serial assessment of diastolic abnormalities in AS. OBJECTIVE: The aim of the current proposal was to examine whether treatment with rosuvastatin was successful in improving diastolic abnormalities in patients enrolled in the Aortic Stenosis Progression Observation Measuring Effects of Rosuvastatin (ASTRONOMER) study. METHODS: Conventional Doppler indices including peak early (E) and late (A) transmitral velocities, and E/A ratio were measured from spectral Doppler. Tissue Doppler measurements including early (E') and late (A') velocities of the lateral annulus were determined, and E/E' was calculated. RESULTS: The study population included 168 patients (56 +/- 13 years), whose AS severity was categorized based on peak velocity at baseline (Group I: 2.5-3.0 m/s; Group II: 3.1-3.5 m/s; Group III: 3.6-4.0 m/s). Baseline and follow-up hemodynamics, LV dimensions and diastolic functional parameters were evaluated in all three groups. There was increased diastolic dysfunction from baseline to follow-up in each of the placebo and rosuvastatin groups. In patients with increasing severity of AS in Groups I and II, the lateral E' was lower and the E/E' (as an estimate of increased left ventricular end-diastolic pressure) was higher at baseline (p < 0.05). However, treatment with rosuvastatin did not affect the progression of diastolic dysfunction from baseline to 3.5 year follow up between patients in any of the three predefined groups. CONCLUSION: In patients with mild to moderate asymptomatic AS, rosuvastatin did not attenuate the progression of diastolic dysfunction. PMID- 21299903 TI - Molecular identification and transmission studies of X-cell parasites from Atlantic cod Gadus morhua (Gadiformes: Gadidae) and the northern black flounder Pseudopleuronectes obscurus (Pleuronectiformes: Pleuronectidae). AB - BACKGROUND: Epidermal pseudotumours from Hippoglossoides dubius and Acanthogobius flavimanus in Japan and gill lesions in Limanda limanda from the UK have been shown to be caused by phylogenetically related protozoan parasites, known collectively as X-cells. However, the phylogenetic position of the X-cell group is not well supported within any of the existing protozoan phyla and they are currently thought to be members of the Alveolata.Ultrastructural features of X cells in fish pseudotumours are somewhat limited and no typical environmental stages, such as spores or flagellated cells, have been observed. The life cycles for these parasites have not been demonstrated and it remains unknown how transmission to a new host occurs. In the present study, pseudobranchial pseudotumours from Atlantic cod, Gadus morhua, in Iceland and epidermal pseudotumours from the northern black flounder, Pseudopleuronectes obscurus, in Japan were used in experimental transmission studies to establish whether direct transmission of the parasite is achievable. In addition, X-cells from Atlantic cod were sequenced to confirm whether they are phylogenetically related to other X-cells and epidermal pseudotumours from the northern black flounder were analysed to establish whether the same parasite is responsible for infecting different flatfish species in Japan. RESULTS: Phylogenetic analyses of small subunit ribosomal DNA (SSU rDNA) sequence data from Atlantic cod X-cells show that they are a related parasite that occupies a basal position to the clade containing other X-cell parasites. The X-cell parasite causing epidermal pseudotumours in P. obscurus is the same parasite that causes pseudotumours in H. dubius. Direct, fish to fish, transmission of the X-cell parasites used in this study, via oral feeding or injection, was not achieved. Non-amoeboid X-cells are contained within discrete sac-like structures that are loosely attached to epidermal pseudotumours in flatfish; these X-cells are able to tolerate exposure to seawater. A sensitive nested PCR assay was developed for the sub clinical detection of both parasites and to assist in future life cycle studies. PCR revealed that the parasite in P. obscurus was detectable in non-pseudotumourous areas of fish that had pseudotumours present in other areas of the body. CONCLUSIONS: The inability to successfully transmit both parasites in this study suggests that either host detachment combined with a period of independent development or an alternate host is required to complete the life cycle for X cell parasites. Phylogenetic analyses of SSU rDNA confirm a monophyletic grouping for all sequenced X-cell parasites, but do not robustly support their placement within any established protist phylum. Analysis of SSU rDNA from X-cells in Japanese flatfish reveals that the same parasite can infect more than one species of fish. PMID- 21299904 TI - Age-related sensitivity and pathological differences in infections by 2009 pandemic influenza A (H1N1) virus. AB - BACKGROUND: The highly pandemic 2009 influenza A H1N1 virus infection showed distinguished skewed age distribution with majority of infection and death in children and young adults. Although previous exposure to related antigen has been proposed as an explanation, the mechanism of age protection is still unknown. METHODS: In this study, murine model of different ages were inoculated intranasally with H1N1 (A/Beijing/501/09) virus and the susceptibility and pathological response to 2009 H1N1 infection were investigated. RESULTS: Our results showed that the younger mice had higher mortality rate when infected with the same dose of virus and the lethal dose increased with age. Immunohistochemical staining of H1N1 antigens in mice lung indicated infection was in the lower respiratory tract. Most bronchial and bronchiolar epithelial cells in 4-week mice were infected while only a minor percentage of those cells in 6-month and 1-year old mice did. The young mice developed much more severe lung lesions and had higher virus load in lung than the two older groups of mice while older mice formed more inducible bronchus-associated lymphoid tissue in their lungs and more severe damage in spleen. CONCLUSIONS: These results suggest that young individuals are more sensitive to H1N1 infection and have less protective immune responses than older adults. The age factor should be considered when studying the pathogenesis and transmission of influenza virus and formulating strategies on vaccination and treatment. PMID- 21299905 TI - Selection and geographic isolation influence hummingbird speciation: genetic, acoustic and morphological divergence in the wedge-tailed sabrewing (Campylopterus curvipennis). AB - BACKGROUND: Mesoamerica is one of the most threatened biodiversity hotspots in the world, yet we are far from understanding the geologic history and the processes driving population divergence and speciation for most endemic taxa. In species with highly differentiated populations selective and/or neutral factors can induce rapid changes to traits involved in mate choice, promoting reproductive isolation between allopatric populations that can eventually lead to speciation. We present the results of genetic differentiation, and explore drift and selection effects in promoting acoustic and morphological divergence among populations of Campylopterus curvipennis, a lekking hummingbird with an extraordinary vocal variability across Mesoamerica. RESULTS: Analyses of two mitochondrial genes and ten microsatellite loci genotyped for 160 individuals revealed the presence of three lineages with no contemporary gene flow: C. c. curvipennis, C. c. excellens, and C. c. pampa disjunctly distributed in the Sierra Madre Oriental, the Tuxtlas region and the Yucatan Peninsula, respectively. Sequence mtDNA and microsatellite data were congruent with two diversification events: an old vicariance event at the Isthmus of Tehuantepec (c. 1.4 Ma), and a more recent Pleistocene split, isolating populations in the Tuxtlas region. Hummingbirds of the excellens group were larger, and those of the pampa group had shorter bills, and lineages that have been isolated the longest shared fewer syllables and differed in spectral and temporal traits of a shared syllable. Coalescent simulations showed that fixation of song types has occurred faster than expected under neutrality but the null hypothesis that morphological divergence resulted from drift was not rejected. CONCLUSIONS: Our phylogeographic analyses uncovered the presence of three Mesoamerican wedge-tailed sabrewing lineages, which diverged at different time scales. These results highlight the importance of the Isthmus of Tehuantepec and more recent Pleistocene climatic events in driving isolation and population divergence. Coalescent analyses of the evolution of phenotypic traits suggest that selection is driving song evolution in wedge-tailed sabrewings but drift could not be rejected as a possibility for morphological divergence. PMID- 21299906 TI - Ethanol extract of Scutellaria baicalensis Georgi prevents oxidative damage and neuroinflammation and memorial impairments in artificial senescense mice. AB - Aging is a progressive process related to the accumulation of oxidative damage and neuroinflammation. We tried to find the anti-amnesic effect of the Scutellaria baicalens Georgia (SBG) ethanol extract and its major ingredients. The antioxidative effect of SBG on the mice model with memory impairment induced by chronic injection of D-galactose and sodium nitrate was studied. The Y-maze test was used to evaluate the learning and memory function of mice. The activities of superoxide dismutase, catalase and the content of malondialdehyde in brain tissue were used for the antioxidation activities. Neuropathological alteration and expression of bcl-2 protein were investigated in the hippocampus by immunohistochemical staining. ROS, neuroinflammation and apoptosis related molecules expression such as Cox-2, iNOS, procaspase-3, cleaved caspase-3, 8 and 9, bcl-2 and bax protein and the products of iNOS and Cox-2, NO, PGE2, were studied using LPS-activated Raw 264.7 cells and microglia BV2 cells. The cognition of mice was significantly improved by the treatment of baicalein and 50 and 100 mg/kg of SBG in Y-maze test. Both SBG groups showed strong antioxidation, antiinflammation effects with significantly decreased iNOS and Cox-2 expression, NO and PGE2 production, increased bcl-2 and decreased bax and cleaved caspase-3 protein expression in LPS induced Raw 264.7 and BV2 cells. We also found that apoptotic pathway was caused by the intrinsic mitochondrial pathway with the decreased cleaved caspase-9 and unchanged cleaved caspase-8 expression. These findings suggest that SBG, especially high dose, 100 mg/kg, improved the memory impairments significantly and showed antioxidation, antiinflammation and intrinsic caspase-mediated apoptosis effects. PMID- 21299907 TI - Squamocin modulates histone H3 phosphorylation levels and induces G1 phase arrest and apoptosis in cancer cells. AB - BACKGROUND: Histone modifications in tumorigenesis are increasingly recognized as important epigenetic factors leading to cancer. Increased phosphorylation levels of histone H3 as a result of aurora B and pMSK1 overexpression were observed in various tumors. We selected aurora B and MSK1 as representatives for testing various compounds and drugs, and found that squamocin, a bis-tetrahydrofuran annonaceous acetogenin, exerted a potent effect on histone H3 phosphorylation. METHODS: GBM8401, Huh-7, and SW620 cells were incubated with 15, 30, and 60 MUM squamocin for 24 h. The expressions of mRNA and proteins were analyzed by qRT-PCR and Western blotting, respectively. The cell viability was determined by an MTT assay. Cell cycle distribution and apoptotic cells were analyzed by flow cytometry. RESULTS: Our results showed that squamocin inhibited the proliferation of GBM8401, Huh-7, and SW620 cells, arrested the cell cycle at the G1 phase, and activated both intrinsic and extrinsic pathways to apoptosis. In addition, we demonstrated that squamocin had the ability to modulate the phosphorylation levels of H3S10 (H3S10p) and H3S28 (H3S28p) in association with the downregulation of aurora B and pMSK1 expressions. CONCLUSIONS: This study is the first to show that squamocin affects epigenetic alterations by modulating histone H3 phosphorylation at S10 and S28, providing a novel view of the antitumor mechanism of squamocin. PMID- 21299908 TI - Consequences of spinal pain: do age and gender matter? A Danish cross-sectional population-based study of 34,902 individuals 20-71 years of age. AB - BACKGROUND: While low back pain (LBP) and neck pain (NP) have been extensively studied, knowledge on mid back pain (MBP) is still lacking. Furthermore, pain from these three spinal areas is typically studied or reported separately and in depth understanding of pain from the entire spine and its consequences is still needed. OBJECTIVES: To describe self-reported consequences of pain in the three spinal regions in relation to age and gender. METHODS: This was a cross-sectional postal survey, comprising 34,902 twin individuals, representative of the general Danish adult population. The variables of interest in relation to consequences of spinal pain were: Care-seeking, reduced physical activity, sick-leave, change in work situation, and disability pension. RESULTS: Almost two-thirds of individuals with spinal pain did not report any consequence. Generally, consequences due to LBP were more frequently reported than those due to NP or MBP. Regardless of area of complaint, care seeking and reduced physical activities were the most commonly reported consequences, followed by sick-leave, change of work, and disability pension. There was a small mid-life peak for care-seeking and a slow general increase in reduced activities with increasing age. Increasing age was not associated with a higher reporting of sick-leave but the duration of the sick leave increased somewhat with age. Disability pension due to spinal pain was reported exceedingly rare before the age of 50. Typically, women slightly more often than men reported some kind of consequences due to spinal pain. CONCLUSIONS: Most people reporting spinal pain manage without any serious consequences. Low back pain more commonly results in some kind of consequence when compared to NP and MBP. Few age-related trends in consequences were seen with a slight predominance of women reporting consequences. PMID- 21299909 TI - High T-cell immune activation and immune exhaustion among individuals with suboptimal CD4 recovery after 4 years of antiretroviral therapy in an African cohort. AB - BACKGROUND: Antiretroviral therapy (ART) partially corrects immune dysfunction associated with HIV infection. The levels of T-cell immune activation and exhaustion after long-term, suppressive ART and their correlation with CD4 T-cell count reconstitution among ART-treated patients in African cohorts have not been extensively evaluated. METHODS: T-cell activation (CD38+HLA-DR+) and immune exhaustion (PD-1+) were measured in a prospective cohort of patients initiated on ART; 128 patient samples were evaluated and subcategorized by CD4 reconstitution after long-term suppressive treatment: Suboptimal [median CD4 count increase 129 (-43-199) cells/MUl], N = 34 ], optimal [282 (200-415) cells/MUl, N = 64] and super-optimal [528 (416-878) cells/MUl, N = 30]. RESULTS: Both CD4+ and CD8 T cell activation was significantly higher among suboptimal CD4 T-cell responders compared to super-optimal responders. In a multivariate model, CD4+CD38+HLADR+ T cells were associated with suboptimal CD4 reconstitution [AOR, 5.7 (95% CI, 1.4 23, P = 0.014)]. T-cell exhaustion (CD4+PD1+ and CD8+PD1+) was higher among suboptimal relative to optimal (P < 0.001) and super-optimal responders (P < 0.001). T-cell exhaustion was significantly associated with suboptimal responders [AOR, 1.5 (95%CI, 1.1-2.1), P = 0.022]. CONCLUSION: T-cell activation and exhaustion persist among HIV-infected patients despite long-term, sustained HIV RNA viral suppression. These immune abnormalities were associated with suboptimal CD4 reconstitution and their regulation may modify immune recovery among suboptimal responders to ART. PMID- 21299911 TI - Udder pathogens and their resistance to antimicrobial agents in dairy cows in Estonia. AB - BACKGROUND: The goal of this study was to estimate the distribution of udder pathogens and their antibiotic resistance in Estonia during the years 2007-2009. METHODS: The bacteriological findings reported in this study originate from quarter milk samples collected from cows on Estonian dairy farms that had clinical or subclinical mastitis. The samples were submitted by local veterinarians to the Estonian Veterinary and Food Laboratory during 2007-2009. Milk samples were examined by conventional bacteriology. In vitro antimicrobial susceptibility testing was performed with the disc diffusion test. Logistic regression with a random herd effect to control for clustering was used for statistical analysis. RESULTS: During the study period, 3058 clinical mastitis samples from 190 farms and 5146 subclinical mastitis samples from 274 farms were investigated. Positive results were found in 57% of the samples (4680 out of 8204), and the proportion did not differ according to year (p > 0.05). The proportion of bacteriologically negative samples was 22.3% and that of mixed growth was 20.6%. Streptococcus uberis (Str. uberis) was the bacterium isolated most frequently (18.4%) from cases of clinical mastitis, followed by Escherichia coli (E. coli) (15.9%) and Streptococcus agalactiae (Str. agalactiae) (11.9%). The bacteria that caused subclinical mastitis were mainly Staphylococcus aureus (S. aureus) (20%) and coagulase-negative staphylococci (CNS) (15.4%). The probability of isolating S. aureus from milk samples was significantly higher on farms that had fewer than 30 cows, when compared with farms that had more than 100 cows (p < 0.005). A significantly higher risk of Str. agalactiae infection was found on farms with more than 600 cows (p = 0.034) compared with smaller farms. The proportion of S. aureus and CNS isolates that were resistant to penicillin was 61.4% and 38.5%, respectively. Among the E. coli isolates, ampicillin, streptomycin and tetracycline resistance were observed in 24.3%, 15.6% and 13.5%, respectively. CONCLUSIONS: This study showed that the main pathogens associated with clinical mastitis were Str. uberis and E. coli. Subclinical mastitis was caused mainly by S. aureus and CNS. The number of S. aureus and Str. agalactiae isolates depended on herd size. Antimicrobial resistance was highly prevalent, especially penicillin resistance in S. aureus and CNS. PMID- 21299913 TI - The role of immunity in the epidemiology of gonorrhoea, chlamydial infection and trichomoniasis: insights from a mathematical model. AB - Most mathematical models of sexually transmitted infections (STIs) assume that infected individuals become susceptible to re-infection immediately after recovery. This paper assesses whether extending the standard model to allow for temporary immunity after recovery improves the correspondence between observed and modelled levels of STI prevalence in South Africa, for gonorrhoea, chlamydial infection and trichomoniasis. Five different models of immunity and symptom resolution were defined, and each model fitted to South African STI prevalence data. The models were compared in terms of Bayes factors, which show that in the case of gonorrhoea and chlamydial infection, models that allow for immunity provide a significantly better fit to STI prevalence data than models that do not allow for immunity. For all three STIs, estimates of the impact of changes in STI treatment and sexual behaviour are significantly lower in models that allow for immunity. Mathematical models that do not allow for immunity could therefore overestimate the effectiveness of STI interventions. PMID- 21299912 TI - Associations between the time of conception and the shape of the lactation curve in early lactation in Norwegian dairy cattle. AB - BACKGROUND: This study was carried out to determine if an association exists between the shape of the lactation curve before it is influenced by the event of conception and the time from calving to conception in Norwegian dairy cattle. Lactation curves of Norwegian Red cows during 5 to 42 days in milk (DIM) were compared between cows conceiving between 43 and 93 DIM and cows conceiving after 93 DIM. METHODS: Data from 23,049 cows, represented by one lactation each, with 219,538 monthly test days were extracted from the Norwegian Dairy Herd Recording System, which represents 97% of all Norwegian dairy cows. Besides veterinary treatments, these records also included information on daily milk yield at monthly test days. The data were stratified by parity groups (1, 2, and 3 and higher) and time to conception periods (43-93 DIM and >93 DIM). The sample was selected using the following selection criteria: conception later than 42 DIM, calving season July to September, no records of veterinary treatment and the level of energy fed as concentrates between 8.69 and 12.83 MJ. The shape of the lactation curves were parameterized using a modified Wilmink-model in a mixed model analysis. Differences in the parameters of the lactation curves with different conception times were evaluated using confidence intervals. RESULTS: Lactation curves characterized by a low intercept and a steep ascending slope and a steep descending slope were associated with early conception across all parities. The peak milk yield was not associated with time of conception. CONCLUSIONS: A practical application of the study results is the use of the shape of the lactation curve in future herd management. Groups of cows with impaired reproductive performance may be identified due to an unfavorable shape of the lactation curve. Monitoring lactation curves and adjusting the feeding strategy to adjust yield therefore may be useful for the improvement of reproductive performance at herd level. PMID- 21299914 TI - The impact of mobility on HIV control: a modelling study. AB - Mobility is associated with HIV due to more risky sexual behaviour of mobile groups such as travellers and migrants. Limited participation of such groups may reduce the effectiveness of HIV interventions disproportionally. The established STDSIM model, which simulates transmission and control of HIV and STD, was extended to simulate mobility patterns based on data from Tanzania. We explored the impact of non-participation of mobile groups (travellers and recent migrants) on the effectiveness of two interventions: condom promotion and health education aiming at partner reduction. If mobile groups do not participate, the effectiveness of both interventions could be reduced by 40%. The impact of targeting travellers with a combined HIV campaign is close to that of a general population intervention. In conclusion, it is important to account for possible non-participation of migrants and travellers. If non-participation is substantial, impact of interventions can be greatly improved by actively approaching these people. PMID- 21299910 TI - A brief review on molecular, genetic and imaging techniques for HCV fibrosis evaluation. AB - BACKGROUND: Chronic HCV is one of the major causes of morbidity and mortality in the present day world. The assessment of disease progression not only provides useful information for diagnosis and therapeutic supervision judgment but also for monitoring disease. Different invasive and non invasive methods are applied to diagnose the disease from initial to end stage (mild fibrosis to cirrhosis). Although, liver biopsy is still considered as gold standard to identify liver histological stages, an assessment of the disease development based on non invasive clinical findings is also emerging and this may replace the need of biopsy in near future. This review gives brief insight on non-invasive methods currently available for predicting liver fibrosis in HCV with their current pros and cons to make easier for a clinician to choose better marker to assess liver fibrosis in HCV infected patients. METHODS: More than 200 studies regarding invasive and noninvasive markers available for HCV liver disease diagnosis were thoroughly reviewed. We examined year wise results of these markers based on their sensitivity, specificity, PPV, NPV and AUROCs. RESULTS: We found that in all non-invasive serum markers for HCV, FibroTest, Forn's Index, Fibrometer and HepaScore have high five-year predictive value but with low AUROCs (0.60~0.85) and are not comparable to liver biopsy (AUROC = 0.97). Even though from its beginning, Fibroscan is proved to be best with high AUROCs (> 0.90) in all studies, no single noninvasive marker is able to differentiate all fibrosis stages from end stage cirrhosis. Meanwhile, specific genetic markers may not only discriminate fibrotic and cirrhotic liver but also differentiate individual fibrosis stages. CONCLUSIONS: There is a need of marker which accurately determines the stage based on simplest routine laboratory test. Genetic marker in combination of imaging technique may be the better non invasive diagnostic method in future. PMID- 21299915 TI - Factors related to household food insecurity in the Republic of Korea. AB - OBJECTIVE: To examine the prevalence of food insecurity and to identify factors that contribute to it in the Republic of Korea. DESIGN: A cross-sectional study. SETTING: Data were selected from a secondary data set, the third Korean Welfare Panel Study. Household food insecurity was measured with a six-item Korean version of the US Household Food Security Survey Module. The differences in proportions or means of household characteristics, householder's characteristics, economic status and social benefits by food insecurity status were tested with the chi2 or t test. The independent associations of food insecurity with each characteristic were assessed with multivariate logistic regression analysis. SUBJECTS: The sample size consisted of 6238 households. RESULTS: The prevalence of food insecurity was 5.3 % among all households and 25.7 % among low-income households. Risk factors that were associated with a higher risk of food insecurity included living alone, unemployment, no job, low household income and living in a leased or rented home. For low-income households, living in a leased or rented home increased the risk of food insecurity. Among food-insecure households, 26.1 % of the full sample of households and 34.3 % of low-income households were participating in food assistance programmes. CONCLUSIONS: Food insecurity among the Korean population was related to household type, income, job status and housing. Food assistance programmes were not enough to completely alleviate food insecurity. PMID- 21299916 TI - Factors associated with childhood obesity in Spain. The OBICE study: a case control study based on sentinel networks. AB - OBJECTIVE: To estimate the association strength of dietary behaviour and sedentary habits in relation to childhood obesity in Spain. DESIGN: A matched case-control study was carried out using data collected by sentinel network paediatricians in general practices. SETTING: Five Spanish autonomous communities. SUBJECTS: Cases were 437 children (2-14 years old) with BMI >95th percentile according to Spanish reference tables. Controls were 751 children (2 14 years old; two paired per case) with BMI <84th percentile. Data were collected in two phases: individual (questionnaires filled in by sentinel paediatricians) and family (self-administered questionnaires filled in a family environment). Crude OR and adjusted OR (ORc and adj OR) for the given variables were calculated using a simple and multiple conditional logistic regression analysis. RESULTS: The factors with the greatest effect on obesity were family history of obesity: both parents (adj OR = 11.2), mother but not father (adj OR = 9.1), father but not mother (adj OR = 6.1), siblings (adj OR = 2.7); and eating between meals (adj OR = 2.5) and consumption of sweets and soft drinks >2 times/week (adj OR = 2.0). The highest protection effect was found for five meals per day (adj OR = 0.5), the regular consumption of breakfast (adj OR = 0.5) and for eating fruit for dessert (adj OR = 0.6). Factors related to sedentary habits did not appear as noteworthy. CONCLUSIONS: We have determined the association between certain dietary behaviour and family history with childhood obesity in several Spanish regions. PMID- 21299917 TI - Development of a diet quality index assessing adherence to the Swedish nutrition recommendations and dietary guidelines in the Malmo Diet and Cancer cohort. AB - OBJECTIVE: To develop a diet quality index (DQI) that assesses adherence to the Swedish nutrition recommendations (SNR) and the Swedish dietary guidelines (SDG). DESIGN: A cross-sectional study within the Malmo Diet and Cancer (MDC) cohort. A diet history method collected dietary data, a structured questionnaire lifestyle and socio-economic information, and anthropometric data were collected by direct measurements. The index (DQI-SNR) included six components: SFA, PUFA, fish and shellfish, dietary fibre, fruit and vegetables, and sucrose. SETTING: Malmo, Sweden. SUBJECTS: Men (n 4525) and women (n 8491) of the MDC cohort enrolled from September 1994 to October 1996. RESULTS: For participants with high DQI-SNR scores, nutrient and food intakes were close to recommendations. However, most of the study population exceeded the recommended intake for SFA (98%) and few reached recommended intakes for dietary fibre (24%), fruit and vegetables (32%), vitamin D (18%) and folate (2%). A high DQI-SNR score was positively associated with age, physical activity, not smoking, past food habit change, education and socio-economic status. Individuals with high scores were more likely to have a diabetes diagnosis or experienced a cardiovascular event. CONCLUSIONS: Results suggest that the DQI-SNR is a useful tool for assessing adherence to the SNR 2005 and the SDG in the MDC cohort. No index has previously been developed with the aim of evaluating adherence to the current dietary recommendations in Sweden. Further validation of the DQI-SNR, and evaluation of its utility, is needed. PMID- 21299918 TI - Dietary patterns, food and macronutrient intakes among adults in three ethnic groups in rural Kenya. AB - OBJECTIVE: To compare dietary patterns and food and macronutrient intakes among adults in three ethnic groups in rural Kenya. DESIGN: In the present cross sectional study, dietary intake was estimated in adult volunteers using two non consecutive interactive 24 h recalls. Dietary patterns were assessed from the number of meals and snacks per day and from the food items and major food groups registered, and their contribution to energy intake (EI) was calculated. Anthropometric values were measured and sociodemographic data obtained using a questionnaire. SETTING: A cross-sectional study was conducted in the Bondo, Kitui and Transmara districts of rural Kenya. A high prevalence of food insecurity in Kenya underlines the importance of describing the dietary patterns and intakes in different Kenyan ethnic groups. SUBJECTS: A total of 1163 (61 % women) adult Luo, Kamba and Maasai, with a mean age of 38.6 (range: 18-68) years, volunteered to participate. RESULTS: Dietary patterns and food groups contributing to EI differed significantly among the ethnic groups. Mean EI ranged from 5.8 to 8.6 MJ/d among women and from 7.2 to 10.5 MJ/d among men, with carbohydrates contributing between 55.7 % and 74.2 % and fat contributing between 14.5 % and 30.2 % of total EI. Mean protein intake ranged from 0.72 to 1.3 g/kg per d, and EI:BMR ratio ranged between 1.1 and 1.6 in both sexes, and was highest among the Luo. Prevalence of underweight (BMI < 18.5 kg/m2) was 13.7 %, 20.5 % and 24.2 % in the Luo, Kamba and Maasai, respectively. CONCLUSIONS: The degree of food insecurity measured as a degree of undernutrition and as dietary patterns differed considerably among the ethnic groups. The Maasai and Kamba in particular were exposed to food insecurity. PMID- 21299919 TI - Factors modifying drug and placebo responses in randomized trials for bipolar mania. AB - Randomized placebo-controlled trials (RCTs) are standard for assessing efficacy and safety of treatments. We pursued preliminary indications that some factors are associated differentially with responses to placebo or drugs in RCTs for bipolar mania. We meta-analysed data from RCTs to assess influences of study-site count, subjects' age, sex distribution, diagnostic subgroups, clinical features, trial-completion rates, and publication year on mean difference (MD) in mania ratings between intake and final assessments. In 38 RCTs involving 3812 placebo treated and 6988 drug-treated patients, symptomatic improvement was similar in placebo arms of trials of effective (6.77, 95% CI 5.77-7.76) and ineffective (7.61, 95% CI 5.47-8.75) drugs. Lesser placebo responses (MD) and greater drug placebo differences (Hedges' g) were associated with fewer study sites, younger patients' age, and male sex. More patients with initial psychotic features and more trial completion in drug arms were associated with greater drug-associated improvement (MD) and drug-placebo contrast (Hedges' g), whereas more mixed-state diagnoses decreased both measures. Identifying modifying factors can support more efficient and cost-effective designs of therapeutic trials. In trials for mania, fewer sites may limit placebo response and enhance drug-placebo contrasts. PMID- 21299921 TI - Sialoendoscopy for diagnosis and treatment of non-neoplastic obstruction in the salivary glands. AB - INTRODUCTION: The objective of this study was to evaluate our experience with sialoendoscopies for diagnosis and treatment of obstructive disease in the large salivary glands in Eastern Denmark and to broaden awareness of the procedure. MATERIAL AND METHODS: A retrospective study was designed including the first 100 consecutive sialoendoscopies in 91 patients performed at Hillerod Hospital and Rigshospitalet, in the 2004-2009 period. RESULTS: The median age of the 91 patients was 45 years (range 9-74 years) with a female-to-male ratio of 1.68. A total of 53 parotid and 47 submandibular endoscopies were performed. The indications for sialoendoscopy were sialolithiasis, stenosis, recurrent swelling and recurrent infections. We found an overall success rate of 91% in 100 diagnostic endoscopies and 62% in 65 interventional endoscopies. We observed an improvement in success rates over the course of the study period. Symptom relief was obtained in 69% of the patients with pathology following intervention. No serious complications occurred. CONCLUSION: Sialoendoscopy is a safe, effective and minimally invasive method for diagnosis and treatment of obstructive salivary gland disease. PMID- 21299920 TI - White matter alterations related to P300 abnormalities in individuals at high risk for psychosis: an MRI-EEG study. AB - BACKGROUND: Psychosis onset is characterized by white matter and electrophysiologic abnormalities. The relation between these factors in the development of illness is almost unknown. We studied the relation between white matter volumes and P300 in prodromal psychosis. METHODS: We assessed white matter volume (detected using magnetic resonance imaging) and electrophysiologic response during an oddball task (P300) in healthy controls and individuals at high clinical risk for psychosis (with an "at-risk mental state" [ARMS]). RESULTS: We included 41 controls and 39 patients with an ARMS in our study. A psychotic disorder developed in 26% of the ARMS group within the follow-up period of 2 years. The P300 amplitude was significantly lower in the ARMS group than in the control group. The ARMS group showed reduced volume of white matter underlying the left superior temporal gyrus and the left superior frontal gyrus and increased volume of white matter underlying the right insula and the right angular gyrus compared with controls. Relative to individuals who did not later become psychotic, the subgroup in whom psychosis subsequently developed had a smaller volume of white matter underlying the left precuneus and the right middle temporal gyrus and increased volume in the white matter underlying the right middle frontal gyrus. We observed a significant interaction in the right middle frontal gyrus: white matter volume was negatively associated with P300 amplitude in the ARMS group and positively associated with P300 amplitude in the control group. LIMITATIONS: The voxel-based morphometry method alone cannot determine whether abnormal white matter volumes are due to an altered number of axonal connections or decreased myelination. CONCLUSION: P300 abnormalities precede the onset of psychosis and are directly related to white matter alterations, representing a correlate of an increased vulnerability to disease. PMID- 21299922 TI - The Sino-Nasal Outcome Test 22 validated for Danish patients. AB - INTRODUCTION: Chronic rhinosinusitis (CRS) is a significant health problem whose incidence and prevalence is rising. It calls into attention consensus about diagnosing, assessing symptoms and treatment of patients with CRS. Therefore, a validated Danish measure of health-related quality of life in sinonasal disease is needed. MATERIAL AND METHODS: The Sino-Nasal Outcome Test 22 (SNOT-22) was translated into Danish and its reproducibility was evaluated by test-retesting 40 patients with CRS. The statistical analyses used were Pearson's correlation coefficient, Cronbach's alpha, kappa and Bland-Altman's plot. Reproducibility was also tested for SNOT-22 subscales. RESULTS: The results show good internal correlation with a Cronbach's alpha of 0.83 in the initial test and one of 0.92 in the retest. Pearson's correlation coefficient was 0.70 (p < 0.001), revealing good correlation between the initial scores and the retests scores. Kappa was calculated for each item with a mean value of 0.61 showing substantial agreement. The paired t-test revealed no significant difference between the subscales. CONCLUSION: The Danish version of SNOT-22 is recommended for Danish clinicians and researchers as a patient-reported measure of outcome in sinonasal disorders such as rhinosinusitis and nasal polyposis. PMID- 21299923 TI - Estimation of kidney function in cancer patients. AB - INTRODUCTION: The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula has not been validated in patients with cancer. The present investigation was undertaken in order to study how well estimated glomerular filtration rate (eGFR) using the new CKD-EPI equation correlates with measured GFR (mGFR) by (51)chrome ethylene diamine tetraacetic acid ((51)Cr-EDTA) clearance in a group of patients with cancer not known as having cancer. MATERIAL AND METHODS: We investigated 185 patients with cancer who were referred for isotope measurement of GFR with (51)Cr-EDTA before initiating chemotherapy treatment. The agreement between CKD-EPI and (51)Cr-EDTA was assessed using a Bland-Altman plot. Test performance was analysed in a contingency table and bias, precision and the percentage of estimates within 30% of the mGFR (P30) were assessed. RESULTS: Bland-Altman plot analysis showed a limit of agreement in the range from -25.59 to 27.92 ml/min./1.73 m(2). This formula was therefore not interchangeable with (51)Cr-EDTA, as the above differences are of clinical importance. Bias was low: 1.16 ml/min./1.73 m(2); P30 was high: 89.73%; and precision was 13.37 ml/min./1.73 m(2). As a screening test, the CKD-EPI had a high specificity of 98% (95% confidence interval (CI): 96 to 100%) and a high negative predictive value 97% (95% CI: 95 to 100%). The accuracy of the validation test was 96% (95% CI: 93 to 99%). CONCLUSION: The CKD-EPI may be used as a screening tool for CKD in the general population, but cannot replace isotope tests when a high GFR measurement accuracy is needed. PMID- 21299924 TI - Data completeness can be optimized in clinical databases. AB - INTRODUCTION: The aim of the present paper was to analyse the incidence of and reasons for data incompleteness in reporting of colorectal cancer from a single department to a national database. MATERIAL AND METHODS: A list of errors comparing the database with the National Patient Registry is drawn up monthly and has been used for data completeness analysis for several years as part of the department's daily routine. In May 2009, this system was revised and we identified a number of new errors which we previously thought had been corrected. The nature of these errors has been analysed in detail. RESULTS: According to the National Patients Registry, a total of 1,530 patients were treated for a first time colorectal cancer. In 60 cases (3.9%) patients were missing in the database. Erroneous registration of the diagnosis in the National Patient Registry on the part of the department was the primary reason why data were missing. This was followed by clerical errors at the department. All mistakes were explainable, but changes in the registry structure prevented some of the mistakes discovered from being corrected retrospectively. CONCLUSION: The number of missing patients in the database could be minimized by a meticulous effort at controlling data and comparing them with data in national registries. PMID- 21299926 TI - International or national publication of case reports. AB - INTRODUCTION: Case reports are often regarded as second-class research, but are an important part of medical science as they often present first evidence of new discoveries. We here describe the type of case reports published in a Danish general medical journal. MATERIAL AND METHODS: We included all case reports published in Ugeskrift for Laeger in 2009. For each report, two authors extracted information on study characteristics and classified the relevance and the role of the report. RESULTS: We included 139 case reports written in Danish. Thirty-nine (28%) were of general relevance and 100 (72%) of speciality relevance. The median number of authors was three (range: 1-7). The first author was a non-specialist physician in 119 (86%) of the reports and the last author a specialist in 103 (78%). A total of 124 (89%) reports had an educational role, six (4%) dealt with new diseases, two (1%) with new side effects, three (2%) with new mechanisms and four (3%) were curiosities. A total of 59 (42%) reports were surgical, 64 (46%) non-surgical and 16 (12%) paraclinical. CONCLUSION: We found that most case reports published in Ugeskrift for Laeger were of speciality relevance and had an educational perspective. The journal may consider focusing on cases of more general educational relevance and should also consider whether the current form and language suit the aim and role of the various types of case reports. PMID- 21299925 TI - No effect of steroids on seroma formation after mastectomy. AB - INTRODUCTION: Seroma formation is a common problem after breast surgery. Studies indicate that seroma formation is a result of the postoperative inflammatory process. Glucocorticoid inhibits the inflammatory response. MATERIAL AND METHODS: In a randomized pilot study, we measured the effect of glucocorticoid on drainage volume and seroma formation after breast surgery. A total of 42 patients with operable primary breast cancer scheduled for total mastectomy were randomized to either 125 mg methylprednisolone sodium succinate intravenously as a single bolus before the start of surgery or to a control group. RESULTS: There was no difference between the groups as to the number of patients having drains from day to day. The drainage volume was lower in the methylprednisolone sodium succinate group than in the control group; however, the difference was not significant (7,979 ml versus 9,267 ml). There was a tendency towards a higher seroma formation in the methylprednisolone sodium succinate group, but the tendency was not significant (15,803 versus 13,987 ml), and there was no significant difference in the number of seroma aspirations after surgery (92 versus 99). CONCLUSION: Injection of a bolus of 125 mg of methylprednisolone sodium succinate before mastectomy did not reduce drainage volume or seroma formation. If intravenous glucocorticoid did have an effect, the case material was too small to prove it. PMID- 21299927 TI - Measuring integrated care. AB - The positive outcomes of coordination of healthcare services are to an increasing extent becoming clear. However the complexity of the field is an inhibiting factor for vigorously designed trial studies. Conceptual clarity and a consistent theoretical frame-work are thus needed. While researchers respond to these needs, patients and providers face the multiple challenges of today's healthcare environment. Decision makers, planners and managers need evidence based policy options and information on the scope of the integrated care challenges they are facing. The US managed care organization Kaiser Permanente has been put forward as an example for European healthcare systems to follow, although the evidence base is far from conclusive. The thesis has five objectives: 1) To contribute to the understanding of the concept of integration in healthcare systems and to identify measurement methods to capture the multi-dimensional aspects of integrated healthcare delivery. 2) To assess the level of integration of the Danish healthcare system. 3) To assess the use of joint health plans as a tool for coordination between the regional and local level in the Danish healthcare system. 4) To compare the inputs and performance of the Danish healthcare system and the managed care organization Kaiser Permanente, California, US. 5) To compare primary care clinicians' perception of clinical integration in two healthcare systems: Kaiser Permanente, Northern California and the Danish healthcare system. Further to examine the associations between specific organizational factors and clinical integration within each system. The literature was systematically searched to identify methods for measurement of integrated healthcare delivery. A national cross-sectional survey was conducted among major professional stake-holders at five different levels of the Danish healthcare system. The survey data were used to allow for analysis of the level of integration achieved. Data from the survey were additionally used to investigate the use of joint health planning as a tool for coordination of regional-local healthcare delivery. Analysis of secondary data from the Danish healthcare system and Kaiser Permanente, California were used to compare population characteristics, professional staff, delivery structure, utilisation, quality measures and direct costs. A cross-sectional survey among primary care clinicians in Denmark and in Kaiser Permanente, Northern California was completed to allow for comparison of clinical integration in the two systems and system specific associated factors. In this thesis a conceptual framework and a model for assessment of the conditions for integrations as an intermediate healthcare system outcome are presented. Furthermore, the results show that integrated healthcare delivery can be measured: 24 methods are available and some are highly developed. However, the field is still in its early phase and guidelines for how to proceed are devised. It was confirmed on a national level that integration of care is a widespread challenge, and that only half or less than half of patients in need of integrated services receive such care. Options for decision makers and managers are discussed. From a theoretical perspective joint health plans as applied in Denmark do not match the degree of complexity in the healthcare system. It was therefore in agreement with the theoretical findings when major stakeholders agreed that the joint health plans had not been effective as a tool for coordination. Joint health planning processes should actively engage all stakeholders and a high degree of recurrent feedback are warranted. When comparing Kaiser Permanente, California with the Danish healthcare system, our study suggest that Kaiser Permanente has a population with more documented disease and higher operating costs, and performs better than the Danish healthcare system on the observed quality measures. Substantial differences were found in the perception of clinical integration in the two settings. More primary care clinicians in the Northern California region of Kaiser Permanente reported being part of a clinical integrated environment than did Danish general practitioners. By measuring the level of clinical integration in Kaiser Permanente using the Danish healthcare system as a point of reference our findings support the literature that points to the importance of integrated healthcare delivery as a driver for the performance results of Kaiser Permanente. However caution must be advised before making concrete conclusions due to the complexity of the matter and until more studies have been conducted. With this thesis an initial step has been taken into a new research field. Ongoing research will make it possible to deliver the evidence needed by decision makers, planners and managers - ultimately to benefit the patients. PMID- 21299928 TI - New physiological effects of the incretin hormones GLP-1 and GIP. AB - With approximately 400 million people worldwide today being obese, we are facing a major public health problem due to the increasing prevalence of the related comorbidities such as type 2 diabetes, hypertension and coronary heart disease. To date, pharmacological treatment of obesity has been largely unsuccessful, only achieving modest and short-lasting reductions in body weight and with adverse effects. Scientific interest in recent years has concentrated on both the secretion and function of the incretin hormones, GLP-1 and GIP, and their suitability as new target drugs. The potential of GLP-1 to reduce gastric emptying, appetite and food intake makes it an attractive tool in the fight against obesity and several companies are developing weight lowering drugs based on GLP-1. Currently, it is not known whether the inhibiting effects of GLP-1 on gastric emptying, appetite and food intake are directly mediated by GLP-1, or if the effects are secondary to the robust insulin responses, and thereby amylin responses, elicited by GLP-1. The first study aimed to further elucidate the mechanisms of these effects in order to strengthen the development of anti diabetic drugs with potential weight lowering capabilities. We found that GLP-1 mediates its effect on gastrointestinal motility, appetite, food intake and glucagon secretion directly and thereby in an amylin-independent fashion. In vitro and animal studies indicate that GIP exerts direct effects on adipose tissue and lipid metabolism, promoting fat deposition. Due to its therapeutic potential in obesity treatment, a rapidly increasing number of functional studies are investigating effects of acute and chronic loss of GIP signaling in glucose and lipid homeostasis. However, the physiological significance of GIP as a regulator of lipid metabolism in humans remains unclear. In the second study, we investigated the effects of GIP on the removal rate of plasma TAG and FFA concentrations, which were increased after either a mixed meal or infusion of Intralipid and insulin. Under these experimental conditions, we were not able to demonstrate any effects of GIP on the removal rate of either chylomicron-TAG or Intralipid-derived TAG concentrations. However, we found evidence for enhanced FFA re-esterification under conditions with combined high GIP and insulin concentrations. Based on findings from this study, the third study was designed to evaluate the direct effects of GIP on regional adipose tissue and splanchnic metabolism. Regional net substrate fluxes across the subcutaneous, abdominal adipose tissue and the splanchnic tissues were examined by direct measurements of arterio-venous concentration differences of various metabolites in combination with regional blood flow measurements (Fick's principle). GIP in combination with hyperinsulinemia and hyperglycemia increased blood flow, glucose uptake, and FFA re-esterification, resulting in increased TAG deposition in abdominal, subcutaneous adipose tissue. Finally, it was not possible to demonstrate any effect of GIP per se on net lipid metabolism in the splanchnic area either during fasting conditions or in combination with hyperinsulinemia and hyperglycemia. PMID- 21299929 TI - Is sarcoidosis a rickettsiosis? AB - The pathogenesis of sarcoidosis is still largely unknown. The generally accepted theory is that genetically predisposed individuals develop the sarcoid disease reaction as a response to one or more unknown antigen(s). A single study by Nilsson et al has related the development of sarcoidosis to an infection with Rickettsia helvetica. The aim of this thesis was to investigate whether a rickettsial infection is involved in the pathogenesis of sarcoidosis. We used different microbiological methods as serology, polymerase chain reaction, and fluorescent in situ hybridization (FISH) on samples from patients with sarcoidosis and control patients. The thesis compiles the results from four separate studies: The second paper describes a serological survey in historical patient sera. None of the results from the studies supported the hypothesis of Rickettsia being involved in the pathogenesis of sarcoidosis. In conclusion, we could not find evidence to support the primary hypothesis of the study, that a rickettsial infection should be involved in the pathogenesis of sarcoidosis. PMID- 21299930 TI - Danish Hernia Database recommendations for the management of inguinal and femoral hernia in adults. AB - The nationwide Danish Hernia Database, recording more than 10,000 inguinal and 400 femoral hernia repairs annually, provides a unique opportunity to present valid recommendations in the management of Danish patients with groin hernia. The cumulated data have been discussed at biannual meetings and guidelines have been approved by the Danish Surgical Society. Diagnosis of groin hernia is based on clinical examination. Ultrasonography, CT or MRI are rarely needed, while herniography is not recommended. In patients with indicative symptoms of hernia, but no detectable hernia, diagnostic laparoscopy may be an option. Once diagnosed, hernia repair is recommended in the presence of symptoms affecting daily life. In male patients with minimal or absent symptoms watchful waiting is recommended. In females, however, repair is recommended also in asymptomatic patients. In male patients with primary unilateral or bilateral groin hernia the preferred method is mesh repair, either at open surgery (Lichtenstein) or laparoscopically, irrespective of age. Conventional tension-producing methods like Bassini, McVay or Shouldice are no longer recommended in a routine elective setting. Whether repair should be done by open or laparoscopic technique, depends on local expertise, economical considerations and patient preference. Compared to the Lichtenstein operation laparoscopic repair is associated with less acute pain and faster recovery. Furthermore, available data suggest less chronic long-term pain after laparoscopic repair. In female patients laparoscopic repair is the recommended method. In patients with recurrent hernia laparoscopic repair is preferred in patients with a previous open repair, while patients with recurrence after laparoscopic repair should undergo open mesh repair. In open repair it is recommended to use a mesh secured with a nonabsorbable monofilament suture. In laparoscopic repair a mesh without a slit and with a minimum size of 15 by 10 cm is used. For mesh fixation absorbable or nonabsorbable tacks or glue can be used. Elective surgery for groin hernia should be performed in an outpatient setting, using cost-effective local anaesthesia in open mesh repair and general anaesthesia for laparoscopic repair. Spinal anaesthesia is not recommended. Routine prophylactic antibiotics are not indicated. In the early convalescence period there are no physical restrictions. These guidelines will also be available at the website for the Danish Hernia Database (www.herniedatabasen.dk). The guidelines will be updated when new substantial evidence becomes available. PMID- 21299931 TI - [Professionalization of surgeons' handling of operations]. PMID- 21299932 TI - [Surgeons also need non-technical skills]. AB - Good clinical skills and dexterity alone do not make a good surgeon. Skills in leadership, decision-making, communication and teamwork, so-called non-technical skills, are also needed. Research on the effect of training non-technical skills is sparse but improvement in communication and teamwork has been achieved due to team training. Implementation of a preoperative briefing also improves communication and reduces the number of postoperative complications. Focus should be directed towards the training of surgeons in non-technical skills in order to improve outcome after surgery. PMID- 21299933 TI - [The past decade's infectious diseases]. AB - The past decade saw emerging infections such as SARS, avian and pandemic influenza, food-borne infections and the bioterror threat. New vaccines became available and novel technologies for detection and typing of microorganisms were applied. In the years to come, control of antimicrobial drug resistance and nosocomial infections will continue to pose challenges in the light of an increasing number of senior citizens and individuals with chronic diseases. There will also be unknown challenges: We have not faced the last HIV, ebola, SARS or avian or swine flu epidemic. PMID- 21299934 TI - [Microbial biofilm in rhinosinusitis and cystic fibrosis]. AB - Microbial biofilms are known to cause persistent foreign-body infections and have recently been acknowledged as involved in more than 65% of all human infections. Microbial biofilms have been detected in chronic rhinosinusitis, and chronic rhinosinusitis is mandatory in patients with cystic fibrosis. We believe that a reservoir for a sustained lung infection in these patients might be found in the nasal sinuses, and that the sinuses may act as a reservoir for reinfection after CF-patient lung transplants. Further studies are necessary. PMID- 21299935 TI - [Short QT syndrome as an inherited condition]. AB - Inherited ion-channel disorders can lead to life-threatening cardiac arrhythmias. A recent, rare entity has been discovered and termed short QT syndrome due to its electrocardiac features in conjunction with atrial and ventricular tachyarrhythmias as well as syncope and sudden cardiac death. The basis of the new syndrome is genetic and this review covers the genes responsible for the condition as well as the pathophysiology and diagnostic challenges involved in the syndrome. Furthermore, treatment for this new arrhythmic syndrome is reviewed. PMID- 21299936 TI - [Polycystic ovary syndrome and miscarriage]. AB - Polycystic ovary syndrome (PCOS) causes impaired fertility and is assumed to be associated with increased risk of miscarriage. This paper reviews the literature according to the principles of evidence-based medicine to establish whether PCOS and the clinical findings lead to an increased miscarriage rate. It is not possible to confirm any association between PCOS and miscarriage. Increased luteinizing hormone, androgens and plasminogen activator inhibitor-1 activity as well as obesity and impaired endometrial blood flow are to some degree associated with miscarriage. PMID- 21299937 TI - [Haemangiopericytoma in the hypopharynx]. AB - This article describes an unusual case of acute upper airway obstruction. A 69 year-old man was brought to the emergency room with what was initially thought to be angioedema of the throat. However, later examination revealed a haemangiopericytoma in the hypopharynx. The tumour was removed surgically, and the patient discharged for follow-up. Haemangiopericytomas rarely occur in the ear-nose-throat region. They are usually not malignant, and their symptoms are generally a consequence of cavity filling. Haemangiocytomas of the hypopharynx are extremely rare. PMID- 21299938 TI - [Picture of the month: cold panniculitis]. PMID- 21299939 TI - Caries-preventive effect of resin-modified glass-ionomer cement (RM-GIC) versus composite resin: a quantitative systematic review. AB - AIM: To determine whether resin-modified glass-ionomer cement (RM-GIC), when compared with composite resins (CR), offers a significant caries-preventive effect. STUDY DESIGN: Quantitative systematic review. METHODS: Five databases were searched until 29 July 2010. Inclusion criteria were: relevant to review question related to orthodontic or restorative treatment; published in English; prospective clinical 2-arm study. Exclusion criteria were: no computable data reported; study groups not followed up in the same way. References of included articles were checked. The outcome measure was absence of carious lesions. Dichotomous datasets for both groups were extracted from accepted trials. Trials were assessed for selection-, detection/performance, attrition and publication bias. RESULTS: Of the 11 trials included, 6 were accepted and 24 datasets extracted; 17 datasets showed no difference after 4 weeks to >25 months. There were 7 datasets that favoured (p < 0.05) RM-GIC after 12 - 24 months. The results are limited by risk of selection-, detection-/performance bias and attrition bias. Risk of publication bias was identified. CONCLUSIONS: The overall results showed either no difference between the materials, or indicated that RM-GIC has a superior caries-preventive effect. The clinical meaning of this result remains uncertain due to risk of bias. High-quality randomised control trials are needed in order to answer the review question conclusively. PMID- 21299940 TI - Nanoleakage related to bond strength in RM-GIC and adhesive restorations. AB - AIM: This was to investigate the nanoleakage of Resin Modified Glass Ionomer Cement (RMGIC) and composite resin (CR) restorations in sound and caries-affected primary dentine, submitted to load cycling and cariogenic challenge in vitro. METHOD: Occlusal cavities were prepared in 60 sound exfoliated primary second molars and 30 specimens were subjected to chemical induction of artificial caries lesions and the others were restored without caries induction. All prepared teeth were divided into 2 groups according to restorative materials. From each dentine condition 5 restored teeth and restorative material were subjected to microtensile bond strength and nanoleakage tests immediately or after load cycling or submitted to the pH-cycling procedure before testing. RESULTS: The adhesive presented bigger areas of silver leakage at the interfaces on caries affected dentine (2.46+/-0.47)mm2 than sound dentine (0.90+/-0.19)mm2. RMGIC nanoleakage was not influenced by the sound (1.75+/-0.11)mm2 or caries-affected (2.08+/-0.39) condition of the substrate. A significant moderate inverse correlation was revealed between the bond strength and silver leakage area at the interface, (r= -0.55, p<0.001). CONCLUSIONS: Nanoleakage is greater in caries affected primary teeth dentine than sound dentine in adhesive restorations although at the interfaces of RMGIC does not differ. As nanoleakage increases, bond strength decreases significantly. PMID- 21299941 TI - Influence of Salvadora persica (miswak) extract on physical and antimicrobial properties of glass ionomer cement. AB - AIM: To investigate physical and antimicrobial properties of Glass Ionomer Cement (GIC) combined with Salvadora Persica Extract (SPE). METHODS: SPE was added to GIC (Fuji IX) in concentrations of 1%, 2% and 4% w/w. The compressive strength and diametral tensile strength were measured at 1 h, 24 h and 7 days. The antimicrobial effect was tested in agar dilution assay in blood agar plates with Candida albicans, Streptococcus mutans, Streptococcus sanguis, Streptococcus mitis, Streptococcus salivarius and Actinomyces naeslundii as test organisms. GIC containing 5% chlorhexidine served as positive control. RESULTS: Significant differences were found for the compressive strength and diametral tensile strength as a result of adding SPE to GIC (p<0.05). GIC with 2 or 4 % SPE was significantly weaker than the GIC control, while GIC with 1% SPE was not different from the control. The mean values for the 4% SPE-containing specimens and the GIC control group ranged from 108.7MPa to 141.1MPa for CS and from 8.2MPa to 12.5MPa for DTS. The 1% SPE-containing specimens were not different in physical properties compared to the control GIC specimens; the 2% SPE-containing specimens were statistically slightly less strong (p<0.05), but within an acceptable range. As compared with pure GIC the antimicrobial properties of the SPE-containing specimens were increased significantly (p<0.01). It has been found up to a 2-fold increased inhibition compared to the GIC with increasing concentrations of SPE. For most microorganisms tested the SPE group inhibited less than Chlorhexidine, but significantly better than pure GIC (p<0.01). CONCLUSION: SPE could be a promising natural material as an additive to GICs. Further studies should include in vivo tests and other antimicrobial and physical properties of this combination. PMID- 21299942 TI - A study of dental development in a Caucasian population compared with a non Caucasian population. AB - AIM: The aim of the present investigation was to compare dental development in children from a non-Caucasian population (Saudi Arabia) with age- and gender- matched children from a Caucasian population (Australia). STUDY DESIGN: Randomised study comparing two population groups using a common set of standards. METHODS: Dental ages of 842 Australian and 456 Saudi Arabian children were assessed from orthopantomograms (OPGs) using the method of Demirjian and co workers. The children were divided into male and female groups of 5-6, 7-8, 9-10, 11-12, and 13-14 year-olds, and the dental age of each child compared to that the corresponding calendar age group. RESULTS: In both Australian and Saudi Arabian children, the dental ages were higher than the corresponding calendar ages. The largest difference between calendar and dental ages (1.10+/-0.80 years, p<0.001) was noted in 11-12 year-old Saudi Arabian girls, and the smallest difference (0.33+/-1.19 years, p<0.01) in 11-12 year-old Australian boys. These discrepancies between calendar and dental ages were significantly different between Australian and Saudi Arabian children (p<0.01). CONCLUSIONS: Although the results suggest that dental development of both Caucasian and non-Caucasian children are generally underestimated by current standards, a few age-specific differences between the two types of population can be discerned. PMID- 21299943 TI - Molar incisor hypomineralisation: prevalence in Jordanian children and clinical characteristics. AB - AIM: To investigate Molar Incisor Hypomineralisation (MIH) in Jordanian children in terms of prevalence, distribution and severity of defects. METHODS: A crosssectional national study with a representative sample was used. A multistage random sampling system yielded 3,666, 7-9 year-old schoolchildren, from 97 public, private and UNRWA schools from Amman, Irbid and Al-Karak. A questionnaire of six sections was sent to the parents with a consent form to participate in the study. A total of 3,241 children participated resulting in a response rate of 88.4%. A single calibrated investigator examined all children using established criteria for MIH and molar hypomineralisation (MH). Analysis of data was performed with a p value set at 0.05. RESULTS: Of the children examined, 570 (17.6%) were diagnosed with MIH with more females affected than males (53% vs. 47%). The 570 subjects were distributed as MIH cases in 196 children (34.4%) and MH cases in 374 children (65.6%) given that at least one incisor was erupted. Mandibular molars and maxillary central incisors were more frequently affected (p<0.05). No significant difference was found between right and left sides of the mouth. Most defects were mild in severity (44%) and severity increased with age and was related to the number of teeth affected (p<0.05). MIH teeth were more severely affected than MH teeth. CONCLUSIONS: MIH was common among 7-9 year-old Jordanian children with a prevalence of 17.6% and was gender related. MH was more common than MIH and can be considered a mild form of an MIH spectrum. Majority of MIH and MH cases were mild in nature but demonstrated an agerelated severity. PMID- 21299944 TI - Assessment of time taken to treat dental trauma in Nigerian children. AB - AIM: To assess the clinical time (diagnosis and treatment times) to manage traumatic dental injuries (TDIs) in children attending paediatric dental clinics in Nigeria. STUDY DESIGN: Cross sectional observational pilot study on children presenting at four government hospitals in South West Nigeria over a 3-month period. METHODS: Dental injury was classified using the method recommended by Andreasen et al. [2003]. A standardized protocol was followed and the details of the diagnosis time, treatment time and total clinical time for management of different traumatic injuries to the primary and permanent dentition were recorded and calculated on a data collection form. RESULTS: There were 73 dental injuries in 39 children. For the primary dentition, complicated crown fracture had the highest average total treatment time namely 76.0+/-48.1 minutes as well as the highest average number of visits (2.6 visits). More time was spent manageing the same level of injury in the permanent dentition than in the primary dentition. For the permanent dentition, extrusive luxation injury had the highest average total treatment time (103.3+/-11.5 minutes). CONCLUSION: The clinical time for management of dental injuries in children was relatively high and varied by type of injury. PMID- 21299945 TI - Clinical audit of children with permanent tooth injuries treated at a dental hospital in Ireland. AB - AIM: To audit key demographic and clinical factors relating to treatment of trauma to the permanent dentition at the Paediatric Dental Department, Cork University Dental School and Hospital, Ireland and to compare clinical management with guideline recommendations. STUDY DESIGN: Clinical audit. METHODS: Consecutive clinical records for children attending for treatment of dental trauma were audited with regard to age, gender and distance travelled. The number of teeth per patient, the cause, type and prevalence of injury were examined. Splinting of mobilisation injuries and the prevalence of pulp extirpation were compared with published guidelines. RESULTS: Records were available for 94 children (65 male, 29 female) with a mean age at time of injury of 10.1 (SD+/ 2.64) years. There were 82% of children living within 50 km of the Hospital. A total of 168 teeth were involved. Dental injuries comprised 39 uncomplicated crown fractures, 18 complicated crown fractures, 37 subluxations, 9 root fractures, 10 extrusions, 14 lateral luxations, 7 intrusions, 30 avulsions and 4 were unclassified. Sport injuries accounted for 23.2% of injuries to teeth, falls for 22.6%, bicycles were involved in 15.5%, other domestic accidents 6.5%, assault 4.2%, vehicles 3.0%, swimming 0.6%. and the remaining 24.4% were unclassified. In some instances of avulsion, lateral luxation, subluxation and extrusion injuries, a tendency to splint for durations longer than that recommended in guidelines was observed. Prevalence of pulpal extirpation for replanted teeth was in keeping with recommendations. CONCLUSION: General adherence to guidelines in respect of splinting and prevalence of pulp extirpation was demonstrated. Utilising a standardised recording system would facilitate the clinical audit process. PMID- 21299946 TI - Case report: hypophosphatemic rickets and aggressive periodontitis: a review of the role of dentine matrix protein 1 in the pathogenesis. AB - BACKGROUND: The association between hypophosphatemic rickets (HR) and excessive periodontal breakdown was reported in mice models of HR. In humans, this is the first report of a possible association between HR and periodontal breakdown. CASE REPORT: The following presents a report of a case of a 15 yearold child diagnosed with HR at age 9 years, with atypical premature spontaneous loss of teeth due to periodontal defects in the absence of dental abscesses, dental caries, or trauma. The case is discussed in the context of relevant literature; the possible role of dentine matrix protein 1 in the aetiology of such periodontal defects in patients with HR is also discussed. CONCLUSION: Spontaneous loss of teeth in the absence of abscess formation is not one of the reported features of HR, however, this report may alert clinicians of the possibility of such association especially in the autosomal recessive type. Further case reports and more elaborate genetic and molecular testing is needed to verify this especially in late diagnosis cases. PMID- 21299948 TI - [Beyond brain imaging, modeling brain function]. PMID- 21299949 TI - [Reduced neuronal inhibition and spasticity following spinal cord injury]. PMID- 21299951 TI - [Elongation of the embryo results from random cell motion]. PMID- 21299950 TI - [HDL and its transporters ABCA1 and ABCG1 regulate innate immunity and hematopoietic stem cell proliferation]. PMID- 21299952 TI - [Towards mapping mechanical tensions inside cells?]. PMID- 21299953 TI - [Feeling the pressure? Identification of two proteins activated by mechanical forces]. PMID- 21299954 TI - [Cell-traction mediated configuration of the cell/extracellular-matrix interface plays a key role in stem cell fate]. PMID- 21299955 TI - [Prediction of the metastatic potential of sarcomas on the basis of a gene expression signature related to genome complexity]. PMID- 21299956 TI - [Human BDCA3 dendritic cells: a promising target for the design of innovative vaccines]. PMID- 21299957 TI - [SNARE, V-ATPase and neurotransmission]. PMID- 21299958 TI - [Resveratrol acts by modulating miRNAs]. PMID- 21299959 TI - [CD81 has a key role in B lymphocyte function]. PMID- 21299961 TI - [Autophagy and pathogens: "Bon appetit Messieurs!"]. AB - Autophagy is a highly conserved, self-degradative pathway for clearance and recycling of cytoplasmic contents. This ubiquitous cell intrinsic process can be used as a defence mechanism against intracellular pathogens. Indeed autophagy is increased upon pathogen detection, and experimental extinction in vitro and in vivo of this cellular process has been demonstrated as a crucial role to control intracellular pathogens. Co-evolution between host-cells and pathogens has selected numerous micoorganisms able to avoid or usurp autophagy to their own benefit. Understanding mechanisms underlying the anti-microbial properties of autophagy as well as those used by certain pathogens to escape this cellular process might be crucial to manipulate this cellular function in order to prevent or treat infectious diseases. PMID- 21299962 TI - [Deimination or citrullination, a post-translational modification with many physiological and pathophysiological facets]. AB - Deimination or citrullination, is a post-translational modification with many facets. It is involved in several basic cellular processes, including gene regulation, embryonic development and terminal differentiation, and also in various pathophysiological mechanisms linked to severe human diseases such as multiple sclerosis and rheumatoid arthritis. Deimination, the calcium-dependent enzymatic conversion of peptidyl-arginine to peptidyl-citrulline, induces a decrease in the charge of the modified proteins with major consequences on their conformation, stability and/or interactions, and therefore on their functions. Five isotypes of peptidylarginine deiminases (1-4 and 6), exist in humans with a variable tissue expression. These highly conserved enzymes are closely regulated at transcriptional and post-transcriptional levels, probably including auto deimination. PMID- 21299963 TI - [Tubulo-interstitial fibrosis: an emerging major health problem]. AB - The incidence of chronic kidney disease leading to end-stage renal disease has significantly increased and may reach epidemic proportions over the next decade. Regardless of the initial insult, the progression of most forms of renal disease results in tubulo-interstitial fibrosis. This has been closely correlated to the future appearance of renal failure and has therefore been associated with poor long-term prognosis. New molecules and agents to limit the development of tubulo interstitial fibrosis and slow down the progression towards end-stage renal disease are needed. In the past twenty years, many efforts have been made to understand the mechanisms of tubulo-intersititial fibrosis with the final goal to develop new therapeutic strategies. In this context, this review will focus on the mechanisms and factors involved in the development and the progression of renal fibrosis and will discuss the new promising therapeutic strategies in animal and humans. PMID- 21299964 TI - [What defines the genetic map? The specification of meiotic recombination sites]. AB - During meiosis, homologous reciprocal recombination events or crossing-over determine the genetic map and are known not to be randomly distributed in the genome. Recent studies in yeasts and mammals reveal some key features of the molecular mechanism involved in this distribution. Through different molecular processes, specific histone post-translational modifications are induced at specific genomic sites, called hotspots, where initiation of meiotic recombination takes place. These sites are some transcription promoters in S. cerevisiae or binding sites for transcription factors in S. pombe, where chromatin modifiers are recruited. In mammals, the sites are DNA sequences recognized by the PRDM9 protein which has the ability both to bind DNA and to induce the trimethylation of the lysine 4 of histone H3. The properties of the chromatin at these sites, and potentially the binding of additional factors, allow the recruitment of proteins involved in the formation of DNA double strand breaks that initiate meiotic recombination. PMID- 21299965 TI - [Curing mental retardation: searching for balance]. AB - Mental retardation (MR) occurs in 2 to 3 % of the general population and is still not therapeutically addressed. Milder forms of MR result from deficient synaptogenesis and/or impaired synaptic plasticity during childhood. These alterations would result from disequilibrium in signalling pathways regulating the balance between long term potentiation (LTP) and long term depression (LTD) in certain neurons such as hippocampus neurons. To provide mentally retarded children with increased cognitive abilities, novel experimental approaches are currently being developed to characterize signalling status associated with MR and to identify therapeutic targets that would restore lost equilibrium. Several studies also highlighted the major role played by molecular switches like kinases, phosphatases, small G proteins and their regulators in the coordination and integration of signalling pathways associated with synaptic plasticity. These proteins may therefore constitute promising therapeutic targets for a number of cognitive deficiencies. PMID- 21299966 TI - [Neuroimaging technique: a diagnostic tool to detect altered states of consciousness]. AB - Vegetative and minimally conscious states diagnosis remained a major clinical challenge. New paradigms such as measurement of the global cerebral metabolism, the structural and functional integrity of fronto-parietal network, or the spontaneous activity in resting state have been shown to be helpful to disentangle vegetative from minimally conscious patients. Active neuroimagery paradigms also allow detecting voluntary and conscious activity in non communicative patients. The implementation of these methods in clinical routine could permit to reduce the current high rate of misdiagnosis (40%). PMID- 21299967 TI - [Functional brain mapping of pain perception]. AB - In this review, we summarize the contribution of functional imaging to the question of nociception in humans. In the beginning of the 90's, brain areas supposed to be involved in physiological pain processes were almost exclusively the primary somatosensory area (SI), thalamus, and anterior cingulate cortex. In spite of these a priori hypotheses, the first imaging studies revealed that the main brain areas and those providing the most consistent activations in pain conditions were the insular and the SII cortices, bilaterally. This has been confirmed with other techniques such as intracerebral recordings of evoked potentials after nociceptive stimulations with laser showing a consistent response in the operculo-insular area which amplitude correlates with pain intensity. In spite of electrode implantations in other areas of the brain, only rare and inconsistent responses have been found outside the operculo-insular cortices. With electrical stimulation delivered directly in the brain, it has also been shown that stimulation in this area only--and not in other brain areas- was able to elicit a painful sensation. Thus, over the last 15 years, the operculo-insular cortex has been re-discovered as a main area of pain integration, mainly in its sensory and intensity aspects. In neuropathic pain also, these areas have been demonstrated as being abnormally recruited, bilaterally, in response to innocuous stimuli. These results suggest that plastic changes may occur in brain areas that were pre-defined for generating pain sensations. Conversely, when the brain activations concomitant to pain relief is taken into account, a large number of studies pointed out medial prefrontal and rostral cingulate areas as being associated with pain controls. Interestingly, these activations may correlate with the magnitude of pain relief, with the activation of the PAG, and, at least in some instances, with the involvement of endogenous opioids. PMID- 21299968 TI - [The brain and its representations in early modern Europe]. AB - The history of the representations of the brain is broadly the history of the brain itself, since observations and ideas which concern it are closely linked, and are even depending on each other. These representations are images, but are also materials produced by manipulating, cutting, fixing the brain; they are also the descriptions of these objects. The interpretations, structured by the representations, ultimately organize the knowledge. PMID- 21299969 TI - [Direct-to-consumer genetic testing through Internet: marketing, ethical and social issues]. AB - We probably did not anticipate all the consequences of the direct to consumer genetic tests on Internet, resulting from the combined skills of communication and genomic advances. What are the commercial strategies used by the companies offering direct-to-consumer genetic tests on Internet and what are the different social expectations on which they focus? Through a quantitative and qualitative analysis of the web sites offering such tests, it seems that these companies target a triple market based on: the "healthism" which raises health and hygiene to the top of the social values; the contemporary demands of the users to become actual actors of health decisions; and finally on the need for bio-social relationships. These three commercial strategies underlie various ethical and societal issues justifying a general analysis. PMID- 21299970 TI - [An undercover investigation of DTC testing]. PMID- 21299971 TI - [The model of the two-hit of Knudson applies to the auto-immune diseases: the example of the lymphoproliferative syndrome with auto-immunity]. PMID- 21299972 TI - Healthcare reform in the United States 2010: an academic neurosurgeon's perspective. PMID- 21299973 TI - Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma. PMID- 21299974 TI - Better definition for brainstem tumors: advances in diffusion tensor imaging. PMID- 21299975 TI - The origin of cranial surgery. PMID- 21299976 TI - Believe it or not. PMID- 21299977 TI - Mitochondrial dysfunction and neurodegenerative diseases. PMID- 21299978 TI - Effect of high-intensity focused ultrasound on daily practice in neurosurgery. PMID- 21299979 TI - Neurosurgery certification in member societies of the World Federation of Neurosurgical Societies (WFNS). The Americas. AB - INTRODUCTION: This article aims to objectively compare the complexity and diversity of the certification process in neurologic surgery in member societies of the World Federation of Neurosurgical Societies. METHODS: This study centers on the certification processes in the geographic regions of North, South, and Central America. It presents a subgroup analysis based on the responses provided to a 13-item survey. The data received were analyzed and three Regional Complexity Scores (RCSs) were designed. To compare national board experience, eligibility requirements to access the certification process, and the degree to which exams were obligatory, an RCS-Organizational score was created (RCS-O, 20 points maximum). To analyze the complexity of the examination, an RCS-Components score was designed (RCS-C, 20 points maximum). The sum of both is presented as the Global RCS (RCS-G) score. In addition, a descriptive summary of the certification process for each responding society is also provided. RESULTS: On the basis of the data provided by the RCS system, the United States and Brazil seem to have the most developed certification processes in the American continent (20 points each), followed by Canada (18 points) and Mexico (17 points). CONCLUSION: The experience from these leading countries should be of value and reference to other countries, allowing future improvement within the region. Peer Review Article. PMID- 21299980 TI - Training in endovascular surgical neuroradiology. AB - BACKGROUND: During the past few years, the field of endovascular surgical neuroradiology has been expanding. Neurosurgeons, radiologists, and neurologists are currently being trained. We analyzed data from a national survey of endovascular training programs to assess the current training status and future projections. METHODS: Survey participation requests were sent out to program directors and members of the Society of Endovascular Neurosurgery, the Society of Neurointerventional Surgery, and the Society of Vascular and Interventional Neurology. The format was an on-line survey designed by the authors, and completed through the SurveyMonkey.com website. Forty-three programs were identified and invited to participate. RESULTS: We achieved a response rate of 81% (n = 35). Twenty-seven (79%) of the 35 respondents listed their training program as academic, and 7 (20%) listed it as a mixture of academic with private practice. The training program faculty consisted of 57 radiologists, 39 neurosurgeons, and 10 neurologists. Length of fellowship offered was the same for all specialties in 43%, and differed based on clinical experience/background in 51%. Of the programs, 86% offered a 2-year fellowship, 49% had a mandatory resident rotation, 17% offered an infolded complete fellowship for residents, and 34% offered an infolded partial fellowship. Only 9% reported no resident exposure at all. There were 12% of respondents who reported to have knowledge of vascular surgeons or cardiologists performing intracranial procedures. At the time of the survey, there were 68 fellows in training, and most entered training immediately after residency (38%), whereas 26% entered after a fellowship and another 26% trained while in residency. There will be a 14% increase of graduates within the next 5 years. Comparing the past 5 years (2003-2007) with future 5-year projections (2008-2012), the number of radiologists is declining by 37% (73 vs. 46), whereas the number of neurosurgeons (74 vs. 106) and neurologists (20 vs. 37) is increasing by 42.5% and 112%, respectively. CONCLUSIONS: This survey suggests that there is a strong interest in endovascular surgical neuroradiology. The overall number of graduates is increasing, particularly in neurosurgery and neurology. Although the majority of current faculty is still comprised of neuroradiologists, the number of graduates in radiology will be decreasing during the next 5 years, reflecting a trend toward greater subspecialization within the fields of neurosurgery and neurology. Peer-Review Article. PMID- 21299981 TI - The status of neurosurgery in the United States: 2010 and beyond. PMID- 21299982 TI - Neurosurgery in Latin America. PMID- 21299983 TI - Neurosurgery in Mexico. PMID- 21299984 TI - Canadian health care and neurosurgery: the good, the bad and the ugly. PMID- 21299985 TI - The National Library of Medicine. PMID- 21299986 TI - Great hospitals of North America: Cleveland Clinic Neurological Surgery. AB - The Cleveland Clinic Department of Neurological Surgery is highly specialized and integrated with other disciplines in a patient- and disease-centric manner. In order to understand the current state of the Department within the context of the Cleveland Clinic and its international reach, an appreciation of the foundation upon which it stands is critical. We review its history from inception to current state and highlight the notable figures that have influenced the department and residency training program over the years. We conclude with a look at the future and the contributions of Cleveland Clinic neurosurgery that may shape the way Neurosurgery and medicine is practiced. PMID- 21299987 TI - A history of the Barrow Neurological Institute. AB - The Barrow Neurological Institute (BNI), founded in 1961, is in partnership with St. Joseph's Hospital and Medical Center and part of the Catholic Healthcare West system. The BNI is a relative newcomer to academic neuroscience. However, since its inception it has grown to become an international destination for neurologic disease. This article describes the history of the institute as it has grown over the years in its commitment to excellence in patient care, education, and research. PMID- 21299988 TI - Medical and surgical practice as represented in cultural figures from the pre conquest Mesoamerican territories. AB - OBJECTIVE: To review medical and surgical practices in pre-Conquest Mexico in the Olmec and Mayan regions and areas of West Mexico as depicted on terra-cotta, stone, and stelae figures. METHODS: A search was undertaken to locate and describe interesting and unusual medical and surgical figures from the pre Conquest period of Mesoamerica. Using the details of these figures, descriptions of medical and surgical practices are outlined. RESULTS: Neurosurgery was not a defined or developed surgical technique in the Mesoamerican territories; nevertheless, elements of medical and surgical practice were clearly widespread. Two important cultures that developed in the pre-Conquest period were the Olmec and the Mayan civilizations. Both cultures had a written language; however, most of their manuscripts were destroyed by the Spanish during the Conquest in the 16th and 17th centuries. These early cultures were rich in sculpted artifacts: stone and terra-cotta figures depict scenes that reveal much about this period and, in particular, early medical and neurosurgical practice. A similar but not quite so advanced civilization was also developing in West Mexico in what are now the States of Colima, Nayarit, and Jalisco. Sculptures and figures from these periods illustrate some of the early medical and surgical practices and provide interesting insights into the rich and varied cultures of these Mesoamerican territories. The focus of this article is on two important cultures and periods: the Olmec (1200 bc-200 ad) and the classical Mayan (200 ad-900 ad) societies, as well as the West Mexico cultures (100 bc-500 ad). CONCLUSION: Review of the data and images reveals a sophisticated society clearly interested in detailing various medical and surgical practices in Mesoamerica and hints at some early neurosurgical practices in this era. PMID- 21299989 TI - Preconquest mesoamerican medicine: historical perspective. PMID- 21299990 TI - Informatic surgery: the union of surgeon and machine. PMID- 21299991 TI - Therapeutic hypothermia for out-of-hospital cardiac arrest: an update for neurosurgeons. PMID- 21299992 TI - Radiosurgery: a useful first-line treatment of prolactinomas? PMID- 21299993 TI - Fiber tracking--a reliable tool for neurosurgery? PMID- 21299994 TI - Technological convergence in the neurosurgical operating room. PMID- 21299995 TI - Simultaneous transsphenoidal and intraventricular endoscopic approaches for macroadenomas with extensive suprasellar extension: surgery from below, above, or both? PMID- 21299996 TI - Operative strategies for minimizing hearing loss associated with microvascular decompression for trigeminal neuralgia. PMID- 21299997 TI - Access to craniocervical junction: comparison between transoral and extraoral transcervical approach. PMID- 21299998 TI - Minimal invasion--is it the future? PMID- 21299999 TI - Advances in spinal hemangioblastoma surgery. PMID- 21300000 TI - Informatic surgery: the union of surgeon and machine. AB - OBJECTIVE: Surgical robotics present new and unique opportunities for the training and practice of neurosurgery, beyond the promise of the minimally invasive paradigm. METHODS: Robotic systems have been developed that simulate the sight, sound, and touch of surgery allowing surgical training to evolve past an apprenticeship and patient-based model towards standardization and virtual training. RESULTS: The development of data-driven surgery, incorporating all information available to the human senses and advanced imaging modalities, give the modern surgeon an abundance of knowledge of the operative objectives and surgical site. Notwithstanding the automation of computers, the surgeon must not be excluded from this feedback loop as computer hardware and software is as-yet unable to compare to human data synthesis and decision making. CONCLUSIONS: It is this union of surgeon and machine and the continued evolution of surgery toward a data-driven science rather than an experiential art that are required for the definitive advancement of patient outcomes. PMID- 21300001 TI - Therapeutic hypothermia for out-of-hospital cardiac arrest: an update for neurosurgeons. AB - BACKGROUND: Neurosurgeons have been familiar with the idea that hypothermia is protective against various types of brain injuries, including traumatic brain injury (TBI). Recent randomized controlled trials, however, have failed to demonstrate the efficacy of therapeutic hypothermia (TH) in patients with TBI. On the other hand, TH becomes popular in the treatment of out-of-hospital cardiac arrest (OHCA) survivors, after randomized controlled trials have shown that survival rate and functional outcome is improved with the use of TH in selected patients. We believe that knowledge on the recent progress in TH for OHCA is useful for neurosurgeons, because feedback of information obtained in the treatment of OHCA may revitalize the interest in TH for neurosurgical disorders, particularly TBI. METHODS: A review of the literature was conducted with the use of PubMed. RESULTS: Various cooling techniques and devices have been developed and trialed in the treatment of OHCA survivors, including prehospital cooling with bolus ice-cold saline, endovascular cooling catheters, and new generation surface cooling devices, some of which have already been known to neurosurgeons. The efficacy of these new methods and devices has been demonstrated in many preliminary studies, and phase III trials are also expected. CONCLUSIONS: Neurosurgeons and critical care medicine physicians pursue the same goal of rescuing the brain from the secondary injury despite the difference in etiology (focal trauma vs. global ischemia), with the presumption that earlier and faster implementation of TH will result in better outcome. Thoughtful application of knowledge and techniques obtained in OHCA to TBI under a rigorously controlled situation will make a small, but significant difference in the outcome of TBI victims. PMID- 21300002 TI - Neuropsychologic impact of treatment modalities in subarachnoid hemorrhage: clipping is no different from coiling. AB - OBJECTIVE: This study assesses the impairment in activities of everyday life using a novel test battery following subarachnoid hemorrhage (SAH) and its treatment. METHODS: A one-off neuropsychologic assessment was conducted for all patients who agreed to participate in the study. The date of the interview was at least 12 months after the ictus. The aspects tested included attention, memory, mood, and executive functions. Thirty normal subjects were also assessed using the same battery of tests to act as controls. The data was analyzed using JMP, version 8.0.2. The project was approved by the local research ethics committee and was performed under the tenets of the Helsinki declaration. RESULTS: Analysis from 77 patients and 30 controls is presented. Patients in the SAH group had significant deficits of sustained attention and attentional switching and executive functions when compared to normal controls (P < 0.05, chi(2)). Within the SAH patient group, the deficits were independent of the subgroup to which the patients belonged (coiled, clipped, and perimesencephalic hemorrhage, P > 0.05, chi(2)). The perimesencephalic hemorrhage group had fewer deficits as compared to the coiled and clipped groups, but because there were very few patients in this group, statistical significance was not achieved for these results. CONCLUSION: Our results reflect a change in UK practice in treating aneurysms, the majority being treated with endovascular coiling. After more than 12 months postictus, attention and executive functions were found to be significantly impaired. Significant deficits remain in various cognitive domains following an SAH, but these appear to be independent of the treatment modality according to our data. PMID- 21300003 TI - Outcome following symptomatic cerebral vasospasm on presentation in aneurysmal subarachnoid hemorrhage: coiling vs. clipping. AB - BACKGROUND: Cerebral vasospasm complicates both surgical and endovascular treatment of ruptured aneurysms. The present study analyzes patients with presentation vasospasm (PVSP) treated in the acute setting and compares outcomes in those treated with surgical clipping versus endovascular coiling. METHODS: Data from 600 aneurysmal subarachnoid hemorrhage (aSAH) patients who were admitted to the University of Illinois Medical Center in Chicago between June 2002 and July 2007 were retrospectively reviewed. Patients with clinical vasospasm on presentation were compared with patients who developed delayed vasospasm during hospitalization. Subgroup analysis compared outcomes in patients with vasospasm on presentation treated with surgical clipping versus endovascular coiling. RESULTS: Of the 600 aSAH patients, 30 (5%) patients presented with symptomatic vasospasm (PVSP) confirmed by cerebral angiography and 179 (30%) patients were diagnosed with symptomatic vasospasm following admission (delayed vasospasm after admission [DVSP]). Patients admitted with vasospasm showed longer latency to admission after the rupture (5.5 vs. 1.5 day, P <= 0.001) but comparable latency to onset of symptomatic vasospasm after rupture. There was no significant difference between the two groups with respect to unfavorable outcome (modified Rankin Scale score > 3), death, or stroke. Therefore, aneurysm treatment during the vasospasm period did not result in increased morbidity in those patients. Within the subgroup of patients presenting with vasospasm on admission, there was no significant difference in outcome between patients who were treated with clipping versus coiling. CONCLUSIONS: Outcome did not differ between aSAH patients treated in the presence of symptomatic vasospasm compared to those with subsequent vasospasm. The outcome of patients presenting with vasospasm was not influenced by the modality of aneurysm treatment. This suggests that both surgical and endovascular intervention for the treatment of ruptured aneurysms are equally valid options in the setting of existing symptomatic vasospasm. PMID- 21300004 TI - X-configuration stent-assisted coiling. AB - BACKGROUND: Proximal basilar artery aneurysms are rare and when they occur they are often found in association with a fenestrated basilar artery. These lesions are often amenable to treatment by endovascular techniques CASE DESCRIPTION: A 48 year-old woman with a proximal basilar artery aneurysm was treated by reconstructing the fenestrated basilar artery, placing two stents in an X configuration, and subsequent coiling of the wide-necked aneurysm. The lesion was successfully coiled without new neurological deficit and there was no recanalization at 15 month follow-up. CONCLUSIONS: Reconstructing the fenestrated basilar artery with two stents in an X-configuration allows coiling of wide necked aneurysms and is preferable to sacrificing a limb of the fenestrated basilar artery due to possibility of a physiologic significant branch off of the sacrificed limb. PMID- 21300005 TI - The Aurora A F31I polymorphism is not a risk factor for glioblastoma. AB - BACKGROUND: The Aurora A F31I polymorphism has been linked to increased risk of several human cancers. Glioblastoma (GBM) is the most malignant glioma as well as the most frequent adult primary brain tumor. METHODS: In this case-control study we investigated the association of Aurora A F31I polymorphism with GBM risk. RESULTS: A total of 96 histologically confirmed patients with GBM and 93 health individuals were analyzed for the Aurora A F31I single nucleotide polymorphism. The single nucleotide polymorphism data were compared and risks associated with individual genotypes and allelotypes were evaluated in terms of odd ratios. CONCLUSIONS: The data obtained from this case-control study demonstrates that the Aurora A F31I polymorphism is not a significant risk for GBMs. PMID- 21300006 TI - Gamma knife radiosurgery for patients with prolactin-secreting pituitary adenomas. AB - OBJECTIVE: To evaluate the efficacy of stereotactic radiosurgery (SRS) for patients with prolactin (PRL)-secreting pituitary adenomas that were refractory to medical management. METHODS: Retrospective review of 22 patients treated with SRS from 1994 until 2006. All patients were either intolerant or their tumors were unresponsive to dopamine agonist therapy. Nine patients (41%) had undergone prior transsphenoidal surgery. The median serum PRL concentration before SRS was 88.4 ng/mL (range, 25-943). The median treatment volume was 2.2 cm(3) (range, 0.4 29.0); the median margin radiation dose was 25 Gy (range, 16-30). The median endocrinologic follow-up was 60 months (range, 16-129). RESULTS: Tumor control after SRS was 100%. Serum PRL concentration was significantly lower (median, 28.4 ng/mL) (P = 0.006) at last follow-up, but the 4-year actuarial rate of biochemical remission off medications was only 17%. No tested variable was associated with biochemical remission off medications. Overall, four patients (18%) had biochemical remission off medications and clinical improvement, three patients (14%) had normal serum PRL concentrations and clinical improvement on dopamine agonist therapy, seven patients (32%) had improved symptoms off medications but continued to have elevated serum PRL levels, and eight patients (36%) continued to be symptomatic with elevated PRL levels either on (n = 3) or off (n = 5) dopamine agonist therapy. The incidence of new anterior pituitary deficits was 42% at 4 years. CONCLUSIONS: SRS was effective in controlling tumor growth for patients with PRL-secreting pituitary adenomas, and the majority of patients were clinically improved. PMID- 21300007 TI - Intraoperative tractography and motor evoked potential (MEP) monitoring in surgery for gliomas around the corticospinal tract. AB - BACKGROUND: Our goal is to indicate the importance of combining intraoperative tractography with motor-evoked potential (MEP) monitoring for glioma surgery in motor eloquent areas. METHODS: Tumor removal was performed in 28 patients with gliomas in and around the corticospinal tract (CST), in an operation theater equipped with an integrated high-field intraoperative magnetic resonance imaging and a neuronavigation system. Diffusion-tensor imaging-based tractography of the CST was implemented preoperatively and intraoperatively. When the surgically manipulated area came close to the corticospinal pathway, MEP responses were elicited by subcortical stimulation. Responsive areas were compared with the locations of fibers traced by preoperative and intraoperative tractography. Imaging and functional outcomes were reviewed. RESULTS: Intraoperative tractography demonstrated significant inward or outward shift during surgery. MEP responses were observed around the tract at various intensities, and the distance between MEP responsive sites and intraoperative tractography was significantly correlated with the stimulation intensity (P < 0.01). The distance from preoperative tractography was not correlated. A more than subtotal resection was achieved in 24 patients (85.7%). Transient motor deterioration was seen in 12 patients (42.8%), and a permanent deficit was seen in 1 patient (3.5%). CONCLUSIONS: We found that intraoperative tractography demonstrated the location of the CST more accurately than preoperative tractography. The results of the linear regression between distance and stimulation intensity were informative for guiding approaches to tumor remnants without impinging on the CST. The combination of intraoperative tractography and MEP monitoring can enhance the quality of surgery for gliomas in motor eloquent areas. PMID- 21300008 TI - Combined endoscopic transsphenoidal-transventricular approach for resection of a giant pituitary macroadenoma. AB - OBJECTIVES: Sellar lesions, such as pituitary adenomas, even when extended to the suprasellar space may be usually removed through a trans-sphenoidal approach. Larger lesions extending well beyond the edges of the sellar diaphragm such as giant adenomas are best controlled with craniotomy and/or a combined approach that implies both, transphenoidal and transcranial route. Currently, the availability of more sophisticated endoscopes in this type of surgery has provided optimal angles of view and rendered the trans-sphenoidal route less invasive yet, more effective. CASE DESCRIPTION: The authors report a case of a giant pituitary adenoma successfully managed by a simultaneous, combined endoscopic trans-sphenoidal-transventricular approach. CONCLUSION: In selected case of giant pituitary adenoma with ventricular extension, this technique may help to achieve a gross total removal avoiding the need of staged procedures allowing also a direct visualization of the extent of removal. Finally this approach can potentially improve gross total resection rate of different types of tumor involving this region such as cranipharyngiomas while reducing morbidity and mortality. PMID- 21300009 TI - Tumor-to-tumor metastasis from hematopoietic neoplasms to meningiomas: report of two patients with significant cerebral edema. AB - BACKGROUND: Tumor-to-tumor metastasis is a rare, but well-reported, curiosity in which one type of primary neoplasm metastasizes to another primary tumor type within the same person. Often there are limited clinical consequences and the condition is an incidental finding identified only on microscopic examination of a resected specimen. OBJECTIVE: To report two examples of benign meningiomas in which metastatic tumor deposits from the patient's hematopoietic neoplasm to the meningioma caused significant peritumoral edema, necessitating semiemergent surgical resection. Clinical suspicion in both patients was an atypical or anaplastic meningioma due to the edema. RESULTS: One patient had multiple myeloma associated with extensive necrosis within his otherwise benign convexity meningioma; first diagnosis of his IgG, kappa-restricted plasma cell dyscrasia was made from this tumor-to-tumor meningioma specimen. Subsequent workup revealed systemic disease. The second patient carried a diagnosis of marginal zone lymphoma but then presented 5 years later with symptoms referable to a large dural-based mass with significant surrounding edema, prompting surgical removal. Dural marginal zone lymphoma was identified within epidural, intradural, and subdural spaces, in the same location as an underlying benign meningioma. CONCLUSIONS: Although rare, neurosurgeons should be aware of the entity of tumor to-tumor metastasis as, in large series, meningiomas are the third most frequent recipient tumor type and pituitary adenomas, the fifth most frequent, probably reflecting their rich vascularity. In examples where the donor tumor type is a hematopoietic neoplasm, significant edema can be produced by the tumor-to-tumor metastasis. PMID- 21300010 TI - Operative strategies for minimizing hearing loss and other major complications associated with microvascular decompression for trigeminal neuralgia. AB - OBJECTIVE: To retrospectively assess the surgical outcomes and complication rates following microvascular decompression (MVD) for trigeminal neuralgia, using a targeted, restricted retrosigmoid approach. METHODS: During the period 1994-2009, a total of 119 patients underwent MVD for trigeminal neuralgia. A retrospective review was conducted in order to assess pain outcomes following surgery and at most recent follow-up. The intraoperative findings, Barrow Neurologic Institute (BNI) pain scores, medication usage, brainstem auditory evoked potential records, and complication rates (including postoperative hearing status) were reviewed and subsequently analyzed. RESULTS: Of the 119 patients who underwent MVD, 61 (51%) were male and 58 (49%) were female. The mean age was 60 years (range 22-86 years). Operative findings included 94 patients (79%) with arterial compression, 16 patients (13%) with isolated venous compression, 1 patient (1%) with a small arteriovenous malformation, and 8 patients (7%) with no obvious source of compression. No perioperative deaths or major complications, including hearing loss, occurred in any patients. Minor complications occurred in 9 patients (8%), including a transient trochlear nerve palsy in 1 patient, transient nystagmus in 1 patient, cerebrospinal fluid leak requiring revision in 1 patient, wound infections requiring revision in 3 patients, and wound infections requiring antibiotics alone in 3 patients. Follow-up data were available for 109 patients, of whom 88 (81%) had excellent outcomes (BNI Score I-II). Ninety-eight patients (90%) had good outcomes (BNI scores I-IIIb), 7 patients (6%) had persistent pain that was not controlled with medications (BNI Score IV), and 4 patients (4%) experienced no relief following surgery (BNI Score V). CONCLUSION: The use of a small craniectomy (<20 mm) in conjunction with a restricted retrosigmoid approach, inferolateral cerebellar retraction, and maintenance of the vestibular nerve arachnoid may minimize complications and optimize surgical outcomes associated with microvascular decompression for trigeminal neuralgia. PMID- 21300011 TI - Comparison of extraoral and transoral approaches to the craniocervical junction: morphometric and quantitative analysis. AB - BACKGROUND: The transoral (TO) approach to the craniocervical junction provides similar access to the periclival and subaxial spine compared with the extraoral anterolateral prevascular (EAP) approach, but the additional exposure gained by the EAP approach has not been quantified. This study quantitatively compared the two surgical exposures. METHODS: Ten silicon-injected fixed cadaver heads were used for the TO approach and another 5 heads (10 sides) were dissected for the EAP approach. For the TO approach, mouth opening was standardized to 5.5 cm using a Spetzler-Sonntag retractor, and the soft palate was split 1.5 cm to access the periclival area. A frameless stereotactic device was used to calculate the lengths, angles, and areas of surgical exposure for different anatomic targets. RESULTS: The vertical working length on the dura progressively increased 61% (336 +/- 26 mm to 539 +/- 16 mm [mean +/- standard deviation]; P < 0.001), and the vertical working angle increased 23% (98 +/- 3 degrees to 121 +/- 5 degrees; P < 0.0) using the TO versus the EAP approach. In the TO approach, the bilateral average horizontal working length on the C1 arch was less on the ipsilateral side than for the EAP approach (11 +/- 1 mm vs. 17 +/- 1 mm, 61%; P < 0.01). The mean periclival and subaxial exposures were 546 +/- 72 mm(2) and 932 +/- 70 mm(2) with the TO approach and 874 +/- 75 mm(2) and 1644 +/- 107 mm(2) with the EAP approach (mean increases 62% and 77%, respectively; both P < 0.001). CONCLUSIONS: Both the TO and EAP approaches improved surgical exposure, but the EAP approach provides more significant and consistent gains to the anterolateral periclival and subaxial areas. PMID- 21300012 TI - A clear map of the lower cranial nerves at the superior carotid triangle. AB - BACKGROUND: The lower cranial nerves must be identified to avoid iatrogenic injury during skull base and high cervical approaches. Prompt recognition of these structures using basic landmarks could reduce surgical time and morbidity. METHODS: The anterior triangle of the neck was dissected in 30 cadaveric head sides. The most superficial segments of the glossopharyngeal, vagus and its superior laryngeal nerves, accessory, and hypoglossal nerves were exposed and designated into smaller anatomic triangles. The midpoint of each nerve segment inside the triangles was correlated to the angle of the mandible (AM), mastoid tip (MT), and bifurcation of the common carotid artery. RESULTS: A triangle bounded by the styloglossus muscle, external carotid artery, and facial artery housed the glossopharyngeal nerve. This nerve segment was 0.06 +/- 0.71 cm posterior to the AM and 2.50 +/- 0.59 cm inferior to the MT. The vagus nerve ran inside the carotid sheath posterior to internal carotid artery and common carotid artery bifurcation in 48.3% of specimens. A triangle formed by the posterior belly of digastric muscle, sternocleidomastoid muscle, and internal jugular vein housed the accessory nerve, 1.90 +/- 0.60 cm posterior to the AM and 2.30 +/- 0.57 cm inferior to the MT. A triangle outlined by the posterior belly of digastric muscle, internal jugular vein, and common facial vein housed the hypoglossal nerve, which was 0.82 +/- 0.84 cm posterior to the AM and 3.64 +/- 0.70 cm inferior to the MT. CONCLUSIONS: Comprehensible landmarks can be defined to help expose the lower cranial nerves to avoid injury to this complex region. PMID- 21300013 TI - The transspinous mini-open approach for resection of intradural spinal neoplasms: cadaveric feasibility study and report of 3 clinical cases. AB - OBJECTIVE: Standard approaches to thoracic intradural tumors often involve a large incision and significant tissue destruction. Minimally invasive techniques have been applied successfully for a variety of surgical decompression procedures but have rarely been used for the removal of intradural thoracic tumors. Here, we demonstrate the feasibility and initial clinical experience with a new minimally invasive approach for resection of intradural tumors. METHODS: Initially, 12 procedures were performed on six cadavers to determine the feasibility of the transspinous mini-open approach (using an expandable tubular retractor) and to compare this approach to a standard open approach. The body mass index (BMI) of all specimens was noted. Measurements were taken to compare the mini-open approach with the open approach in terms of the number of lamina accessed and the length of the incision. Subsequently, the transspinous mini-open approach was used to biopsy one clinical case of intradural, intramedullary tumor (glioblastoma multiforme) and to remove two intradural, extramedullary tumors (meningiomas) in two other patients. RESULTS: The BMI of the cadavers ranged from 18 to 43. Regardless the BMI, up to three-level laminectomies could be performed in all the cadavers via a mini-open approach. In specimens with a BMI of <22, an additional half-level could be accessed. The incision length did not exceed 4.5 cm in all cadavers undergoing the mini-open approach. In the same cadavers, with the standard open approach, the incision length increased with increasing BMI from 8.0 to 15 cm. The three clinical cases were successfully performed through a mini-open transspinous approach without any complications. The mean operative time was 31/2 hours (range = 3-4 hours), mean blood loss was 133 mL (range 100 150 mL), and the mean hospital stay was 51/2 days (range = 4-7 days). CONCLUSIONS: The mini-open approach allows complete dorsal access to the spinal canal, with less tissue disruption than with a standard open procedure. This is especially true in obese patients where the incision length may be 3 times smaller compared to a standard open approach. The mini-open transspinous resection of thoracic intradural tumors can be performed safely. PMID- 21300014 TI - Surgical technique of temporary arterial occlusion in the operative management of spinal hemangioblastomas. AB - BACKGROUND: Spinal hemangioblastomas (SH) are definitively treated by en bloc microsurgical resection. Although benign, their highly vascular nature makes resection challenging. A major difficulty involves intraoperative differentiation of vessels supplying the tumor from those supplying the spinal cord. METHODS: Twenty patients with SH treated surgically at a single institution were reviewed. Median age was 49 years (range 24 to 70 years). Eleven patients had von Hippel Lindau syndrome. Six underwent preoperative angiography, of which five underwent embolization. All tumors were posterior and resected through a laminectomy approach. Temporary arterial occlusion (TAO) by aneurysm clip placement with concurrent neuromonitoring was used at the tumor edge to differentiate arteries supplying the tumor from those supplying the healthy spinal cord. Arteries were assumed to not supply important regions of the cord and divided at the tumor surface if there was no change in evoked potentials after 4 minutes of occlusion. RESULTS: Of the 20 patients, 5 improved, 13 remained stable, and 2 worsened. Of the five treated with TAO, two improved, three remained stable, and none worsened. Median McCormick's functional grade of patients treated with TAO was II and improved to I after the operation, whereas that of those not treated with TAO remained unchanged at II (Wilcoxon rank-sum, P = .35). CONCLUSIONS: Temporary arterial occlusion with neuromonitoring is a safe, effective, and simple method of differentiating arteries supplying the tumor only from those that supply the functionally normal spinal cord in the operative management of difficult SH. PMID- 21300015 TI - UVB light regulates expression of antioxidants and inflammatory mediators in human corneal epithelial cells. AB - The cornea is highly sensitive to ultraviolet B (UVB) light-induced oxidative stress, a process that results in the production of inflammatory mediators which have been implicated in tissue injury. In the present studies, we characterized the inflammatory response of human corneal epithelial cells to UVB (2.5 25mJ/cm(2)). UVB caused a dose-dependent increase in the generation of reactive oxygen species in the cells. This was associated with increases in mRNA expression of the antioxidants Cu,Zn superoxide dismutase (SOD), Mn-SOD, catalase and heme oxygenase-1 (HO-1), as well as the glutathione S-transferases (GST), GSTA1-2, GSTA3, GSTA4, GSTM1, and mGST2. UVB also upregulated expression of the proinflammatory cytokines, IFNgamma, IL-1beta, TGFbeta and TNFalpha, and enzymes important in prostaglandin (PG) biosynthesis including cyclooxygenase-2 (COX-2) and the PG synthases mPGES-2, PGDS, PGFS and thromboxane synthase, and in leukotriene biosynthesis including 5-lipoxygenase (5-LOX), 15-LOX-2, and the epidermal and platelet forms of 12-LOX. UVB was found to activate JNK and p38 MAP kinases in corneal epithelial cells; ERK1/2 MAP kinase was found to be constitutively active, and its activity increased following UVB treatment. Inhibition of p38 blocked UVB-induced expression of TNFalpha, COX-2, PGDS and 15 LOX-2, while JNK inhibition suppressed TNFalpha and HO-1. These data indicate that UVB modulates corneal epithelial cell expression of antioxidants and proinflammatory mediators by distinct mechanisms. Alterations in expression of these mediators are likely to be important in regulating inflammation and protecting the cornea from UVB-induced oxidative stress. PMID- 21300016 TI - High frequency of PfCRT 76T in two Malian villages and its prevalence in severe relative to non-severe malaria. AB - We investigated PfCRT 76T mutation in severe and non-severe malaria in Southern Mali. One hundred and ninety three severe malaria cases were each matched against two non-severe malaria cases. Patients with G6PD deficiency and any known hemoglobin abnormality were excluded. PfCRT 76T was present in 60.8% (n=386) non severe malaria cases and in 77.2% (n=193) severe malaria cases (p<0.0001). In children 5 years or younger, these proportions were 62.9% (n=294) vs. 73.5% (n=147), respectively (p<0.01). PfCRT 76T was therefore associated with malaria severity in this setting of Mali. PMID- 21300017 TI - Insecticide resistance status of Aedes aegypti in 10 localities in Colombia. AB - Insecticide resistance is one of the major threats to the effectiveness of vector control programs. In order to establish a baseline susceptibility profile of Aedes aegypti in the southwest of Colombia, 10 localities in four Departments (States) were evaluated. Standardized WHO bioassay, CDC bottle bioassay and microplate biochemical assays of non-specific beta-esterase (NSE), mixed function oxidases (MFO) and acetylcholinesterase were used. Cross resistance was evaluated with field collected mosquitoes that underwent selection pressure in the laboratory from DDT, propoxur and lambdacyhalothrin during three alternate generations. Mosquitoes with mortality rates below 80% in bioassays were considered resistant. Insecticide resistance varied geographically. Insecticide resistance was observed in 100% of localities in which mosquitoes were exposed to DDT, bendiocarb and temephos using both assays. WHO bioassays showed susceptibility to pyrethroids in all the localities evaluated, however CDC bottle bioassays showed decreases in susceptibility especially with lambdacyhalothrin. All localities showed susceptibility to the organophosphate malathion. Mosquitoes from eight regions with evidence of resistance to any of the insecticide evaluated were also evaluated biochemically. Mosquitoes from five of these regions had increased levels of NSE and two regions had increased levels of MFO. Increase levels of NSE explain partially the low susceptibility to temephos found in all the localities. However, the biochemical mechanisms evaluated do not explain all the resistance observed. Cross resistance was observed between the DDT-selected strain and lambdacyhalothrin, and between the lambdacyhalothrin selected strain and propoxur and vice versa. The selected strains do not show changes in the biochemical assays evaluated, therefore the observed cross resistance suggests different biochemical mechanisms. This study shows that Ae. aegypti from Colombia can develop resistance to most of the insecticide classes in the market. Periodic surveillance of insecticide resistance is necessary in order to maintain effective interventions. This study helped to establish the National Network for the surveillance of the insecticide resistance in Colombia. PMID- 21300018 TI - Analysis of glycated hemoglobin A1c by capillary electrophoresis and capillary isoelectric focusing. AB - Two capillary electrophoretic methods were developed and evaluated for measurement of glycated hemoglobin A1c (HbA1c). First, a capillary electrophoresis analysis is performed with a sodium tetraborate buffer (pH 9.3) as background electrolyte in a neutrally coated capillary. HbA1c is separated from HbA0 due to specific interactions of borate anions with the cis-diol pattern in the saccharide moiety of glycohemoglobin. Second, a capillary isoelectric focusing method, which exploits a difference in pI values of HbA0 and HbA1c, is performed with Servalyt pH 6-8 or alternatively with Biolyte pH 6-8 carrier ampholytes spiked with a narrow pH cut of pH 7.2 prepared by preparative fractionation of Servalyt pH 4-9 carrier ampholytes. Both methods reflect recent developments in the methodology of capillary electrophoresis. They allow quantifying HbA1c in generic capillary electrophoresis analyzer with specificity that is consistent with previously reported electrophoretic assays in slab gels and capillaries. PMID- 21300019 TI - Chemiluminescence detection of telomere DNA in human cells on a membrane by using fluorescein-5-isothiocyanate-labeled primers. AB - Telomere DNA is related to cell aging and cancer genesis because the telomeric region of DNA sequences at chromosome ends are shortened with cell divisions. Therefore, a sensitive and specific detection method is required for the telomere DNA. Here we propose a chemiluminescence (CL)-based method for the sensitive detection of telomere DNA in human cells. In this study, the telomere DNA was amplified by polymerase chain reaction (PCR) using special forward and reverse primers labeled with fluorescein-5-isothiocyanate (FITC) at the 5' end, and then the FITC-containing PCR products were detected by CL reaction with 3,4,5 trimethoxyphenylglyoxal (TMPG) after electrophoresis followed by Southern blot onto a nylon membrane. The TMPG reagent specifically reacted with guanine moiety in DNA at room temperature and provided CL intensities. The CL intensities from the PCR products could be enhanced approximately 10-fold using FITC-labeled primers as compared with those using nonlabeled primers. The detection limit of the PCR products with the proposed method was 0.3 ng on the membrane. The developed CL method could quantitatively determine the telomere DNA in a small number of human cells (~350) and gave approximately 10 times higher sensitivity than a conventional fluorescence-based method. PMID- 21300020 TI - Isolation of high-quality RNA from various tissues of Jatropha curcas for downstream applications. AB - A method for isolating transcriptionally active RNA for downstream applications from diverse tissues of Jatropha curcas, a plant rich in latex, lipids, waxes, polysaccharide, polyphenols, and secondary metabolites, is described. The described method uses alkaline borate buffer during tissue homogenization to negate the formation of viscous gel observed in guanidium-salt-containing methods. By this method, quality RNA was extracted from leaf, immature inflorescence, endosperm, and root tissues with yields ranging from 1.80 to 7.80mg/100mg fresh weight (FW). The total RNA obtained was found to be suitable for poly(A)(+)RNA purification, complementary DNA (cDNA) synthesis, cloning of full-length cDNA, and cDNA library construction. PMID- 21300021 TI - Characterization of Forster resonance energy transfer in a botulinum neurotoxin protease assay. AB - Our previous article described a fluorescence-based assay for monitoring the proteolytic activity of botulinum neurotoxin types A and E (BoNT/A and BoNT/E). As detailed in that article, the assay is based on depolarization due to Forster resonance energy transfer between blue fluorescent protein (BFP) and green fluorescent protein (GFP) moieties linked via residues 134-206 of SNAP-25 (synaptosome-associated protein of 25kDa), the protein substrate for BoNT/A and BoNT/E. Before cleavage of this recombinant substrate, the polarization observed for the GFP emission, excited near the absorption maximum of the BFP, is very low due to depolarization following energy transfer from BFP to GFP. After substrate cleavage and diffusion of the fluorescent proteins beyond the energy transfer distance, the polarization is high due to observation of the emission only from directly excited GFP. This change in fluorescence polarization allows an assay, termed DARET (depolarization after resonance energy transfer), that is robust and sensitive. In this article, we characterize the spectroscopic parameters of the system before and after substrate cleavage, including excitation and emission spectra, polarizations, and lifetimes. PMID- 21300022 TI - Depolarization after resonance energy transfer (DARET): a sensitive fluorescence based assay for botulinum neurotoxin protease activity. AB - The DARET (depolarization after resonance energy transfer) assay is a coupled Forster resonance energy transfer (FRET)-fluorescence polarization assay for botulinum neurotoxin type A or E (BoNT/A or BoNT/E) proteolytic activity that relies on a fully recombinant substrate. The substrate consists of blue fluorescent protein (BFP) and green fluorescent protein (GFP) flanking SNAP-25 (synaptosome-associated protein of 25 kDa) residues 134-206. In this assay, the substrate is excited with polarized light at 387 nm, which primarily excites the BFP, whereas emission from the GFP is monitored at 509 nm. Energy transfer from the BFP to the GFP in the intact substrate results in a substantial depolarization of the GFP emission. The energy transfer is eliminated when the fluorescent domains separate on cleavage by the endopeptidase, and emission from the directly excited GFP product fragment is then highly polarized, resulting in an overall increase in polarization. This increase in polarization can be monitored to assay the proteolytic activity of BoNT/A and BoNT/E in real time. It allows determination of the turnover rate of the substrate and the kinetic constants (V(max) and k(cat)) based on the concentration of cleaved substrate determined directly from the measurements using the additivity properties of polarization. The assay is amenable to high-throughput applications. PMID- 21300023 TI - Cholestatic liver fibrosis and toxin-induced fibrosis are exacerbated in matrix metalloproteinase-2 deficient mice. AB - Matrix metalloproteinase (MMP) plays an important role in homeostatic regulation of the extracellular environment and degradation of matrix. During liver fibrosis, several MMPs, including MMP-2, are up-regulated in activated hepatic stellate cells, which are responsible for exacerbation of liver cirrhosis. However, it remains unclear how loss of MMP-2 influences molecular dynamics associated with fibrogenesis in the liver. To explore the role of MMP-2 in hepatic fibrogenesis, we employed two fibrosis models in mice; toxin (carbon tetrachloride, CCl4)-induced and cholestasis-induced fibrosis. In the chronic CCl4 administration model, MMP-2 deficient mice exhibited extensive liver fibrosis as compared with wild-type mice. Several molecules related to activation of hepatic stellate cells were up-regulated in MMP-2 deficient liver, suggesting that myofibroblastic change of hepatic stellate cells was promoted in MMP-2 deficient liver. In the cholestasis model, fibrosis in MMP-2 deficient liver was also accelerated as compared with wild type liver. Production of tissue inhibitor of metalloproteinase 1 increased in MMP-2 deficient liver in both models, while transforming growth factor beta, platelet-derived growth factor receptor and MMP 14 were up-regulated only in the CCl4 model. Our study demonstrated, using 2 experimental murine models, that loss of MMP-2 exacerbates liver fibrosis, and suggested that MMP-2 suppresses tissue inhibitor of metalloproteinase 1 up regulation during liver fibrosis. PMID- 21300024 TI - Deletion of vitamin D receptor leads to premature emphysema/COPD by increased matrix metalloproteinases and lymphoid aggregates formation. AB - Deficiency of vitamin D is associated with accelerated decline in lung function. Vitamin D is a ligand for nuclear hormone vitamin D receptor (VDR), and upon binding it modulates various cellular functions. The level of VDR is reduced in lungs of patients with chronic obstructive pulmonary disease (COPD) which led us to hypothesize that deficiency of VDR leads to significant alterations in lung phenotype that are characteristics of COPD/emphysema associated with increased inflammatory response. We found that VDR knock-out (VDR(-/-)) mice had increased influx of inflammatory cells, phospho-acetylation of nuclear factor-kappaB (NF kappaB) associated with increased proinflammatory mediators, and up-regulation of matrix metalloproteinases (MMPs) MMP-2, MMP-9, and MMP-12 in the lung. This was associated with emphysema and decline in lung function associated with lymphoid aggregates formation compared to WT mice. These findings suggest that deficiency of VDR in mouse lung can lead to an early onset of emphysema/COPD because of chronic inflammation, immune dysregulation, and lung destruction. PMID- 21300025 TI - Epigallocatechin gallate (EGCG), a major component of green tea, is a dual phosphoinositide-3-kinase/mTOR inhibitor. AB - The PI3K signaling pathway is activated in a broad spectrum of human cancers, either directly by genetic mutation or indirectly via activation of receptor tyrosine kinases or inactivation of the PTEN tumor suppressor. The key nodes of this pathway have emerged as important therapeutic targets for the treatment of cancer. In this study, we show that (-)-epigallocatechin-3-gallate (EGCG), a major component of green tea, is an ATP-competitive inhibitor of both phosphoinositide-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) with K(i) values of 380 and 320nM respectively. The potency of EGCG against PI3K and mTOR is within physiologically relevant concentrations. In addition, EGCG inhibits cell proliferation and AKT phosphorylation at Ser473 in MDA-MB-231 and A549 cells. Molecular docking studies show that EGCG binds well to the PI3K kinase domain active site, agreeing with the finding that EGCG competes for ATP binding. Our results suggest another important molecular mechanism for the anticancer activities of EGCG. PMID- 21300026 TI - Silencing tissue inhibitors of metalloproteinases (TIMPs) with short interfering RNA reveals a role for TIMP-1 in hepatic stellate cell proliferation. AB - Myofibroblastic, activated hepatic stellate cells (HSC) play a pivotal role in the development of liver fibrosis through the secretion of fibrillar collagens and the tissue inhibitors of metalloproteinase (TIMP)-1 and -2. TIMPs are believed to promote hepatic fibrosis by inhibiting both matrix degradation and apoptosis of HSC. In other cell types, there is evidence that TIMP-1 has effects on proliferation, however the role of TIMPs in the regulation of HSC proliferation remains unexplored. Therefore, we have used short interfering RNA (siRNA) to investigate the effects of autocrine TIMP-1 and -2 on HSC proliferation. TIMP-1 and -2 siRNA were highly effective, producing peak target protein knockdown compared to negative control siRNA of 92% and 63%, respectively. Specific silencing of TIMP-1, using siRNA, significantly reduced HSC proliferation. TIMP-1 was localised in part to the HSC nucleus and TIMP-1 siRNA resulted in loss of both cytoplasmic and nuclear TIMP-1. Attenuated proliferation was associated with reduced Akt phosphorylation and was partially rescued by addition of recombinant TIMP-1. We have revealed a novel autocrine mitogenic effect of TIMP-1 on HSC, which may involve Akt-dependent and specific nuclear mechanisms of action. We suggest that TIMP-1 might promote liver fibrosis by means other than its previously described anti-apoptotic effect on HSC. Moreover, these findings, together with our previous reports and the emerging data from in vivo studies of TIMP inhibition, provide strong evidence that TIMP-1 is mechanistically central to liver fibrosis and an important potential therapeutic target. PMID- 21300028 TI - Statin or fibrate chronic treatment modifies the proteomic profile of rat skeletal muscle. AB - Statins and fibrates can cause myopathy. To further understand the causes of the damage we performed a proteome analysis in fast-twitch skeletal muscle of rats chronically treated with different hypolipidemic drugs. The proteomic maps were obtained from extensor digitorum longus (EDL) muscles of rats treated for 2 months with 10mg/kg atorvastatin, 20 mg/kg fluvastatin, 60 mg/kg fenofibrate and control rats. The proteins differentially expressed were identified by mass spectrometry and further analyzed by immunoblot analysis. We found a significant modification in 40 out of 417 total spots analyzed in atorvastatin treated rats, 15 out of 436 total spots in fluvastatin treated rats and 21 out of 439 total spots in fenofibrate treated rats in comparison to controls. All treatments induced a general tendency to a down-regulation of protein expression; in particular, atorvastatin affected the protein pattern more extensively with respect to the other treatments. Energy production systems, both oxidative and glycolytic enzymes and creatine kinase, were down-regulated following atorvastatin administration, whereas fenofibrate determined mostly alterations in glycolytic enzymes and creatine kinase, oxidative enzymes being relatively spared. Additionally, all treatments resulted in some modifications of proteins involved in cellular defenses against oxidative stress, such as heat shock proteins, and of myofibrillar proteins. These results were confirmed by immunoblot analysis. In conclusions, the proteomic analysis showed that either statin or fibrate administration can modify the expression of proteins essential for skeletal muscle function suggesting potential mechanisms for statin myopathy. PMID- 21300029 TI - A comprehensive understanding of thioTEPA metabolism in the mouse using UPLC-ESI QTOFMS-based metabolomics. AB - ThioTEPA, an alkylating agent with anti-tumor activity, has been used as an effective anticancer drug since the 1950s. However, a complete understanding of how its alkylating activity relates to clinical efficacy has not been achieved, the total urinary excretion of thioTEPA and its metabolites is not resolved, and the mechanism of formation of the potentially toxic metabolites S carboxymethylcysteine (SCMC) and thiodiglycolic acid (TDGA) remains unclear. In this study, the metabolism of thioTEPA in a mouse model was comprehensively investigated using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI QTOFMS) based-metabolomics. The nine metabolites identified in mouse urine suggest that thioTEPA underwent ring-opening, N-dechloroethylation, and conjugation reactions in vivo. SCMC and TDGA, two downstream thioTEPA metabolites, were produced from thioTEPA from two novel metabolites 1,2,3 trichloroTEPA (VII) and dechloroethyltrichloroTEPA (VIII). SCMC and TDGA excretion were increased about 4-fold and 2-fold, respectively, in urine following the thioTEPA treatment. The main mouse metabolites of thioTEPA in vivo were TEPA (II), monochloroTEPA (III) and thioTEPA-mercapturate (IV). In addition, five thioTEPA metabolites were detected in serum and all shared similar disposition. Although thioTEPA has a unique chemical structure which is not maintained in the majority of its metabolites, metabolomic analysis of its biotransformation greatly contributed to the investigation of thioTEPA metabolism in vivo, and provides useful information to understand comprehensively the pharmacological activity and potential toxicity of thioTEPA in the clinic. PMID- 21300027 TI - Friendly, and not so friendly, roles of Rac1 in islet beta-cell function: lessons learnt from pharmacological and molecular biological approaches. AB - Glucose-stimulated insulin secretion [GSIS] involves a sequence of metabolic events leading to small G-protein [e.g., Rac1]-mediated cytoskeletal remodeling to promote granule mobilization toward the plasma membrane for fusion and release of insulin. Existing evidence supports a positive modulatory role for Rac1 in GSIS. Specific regulatory factors of Rac1 function, including the guanine nucleotide exchange factors [e.g., Tiam1] have also been identified and studied in the islet. Inhibition of Tiam1/Rac1 signaling axis attenuates GSIS suggesting its pivotal role in insulin secretion. In addition to its positive [i.e., friendly] roles in GSIS, Rac1 also plays "non-friendly" role[s] in the islet function. For example, it up-regulates the intracellular reactive oxygen species [ROS] levels via activation of phagocyte-like NADPH oxidase [Nox]. Despite the emerging evidence that a tonic increase in intracellular ROS is necessary for GSIS, experimental evidence also suggests that chronic exposure of beta-cells to high glucose, palmitate or cytokines results in the onset of oxidative stress leading to reduction in mitochondrial membrane potential, cytosolic accumulation of cytochrome C and activation of caspase-3 leading to beta-cell apoptosis. Pharmacological and molecular biological inhibition of Rac1 activation affords partial protection against Nox-induced oxidative stress and mitochondrial dysfunction induced by elevated glucose, lipids or cytokines. Herein, we overview the existing evidence to suggest positive as well as negative modulatory roles of Rac1 in islet function. Potential avenues for future research including development of inhibitors to halt the Rac1-Nox activation and generation of oxidative stress leading to the metabolic dysfunction of the beta-cell are discussed. PMID- 21300030 TI - In search of the Holy Grail: Folate-targeted nanoparticles for cancer therapy. AB - Targeted drug therapy or "smart" drug delivery, potentially combined with simultaneous imaging modalities to monitor the delivery of drugs to specific tissues, is arguably the "holy grail" of pharmacology. Therapeutic approaches that exploit nanoparticles to deliver drugs selectively to cancer cells are currently considered one of the most promising avenues in the area of cancer therapeutics and imaging. The potential to deliver active chemotherapeutic drugs in the vicinity or directly within specific tumors via receptor mediated pathways, and to image tumors through the use of nanoparticles has been conceptually and experimentally shown for several classes of nanoparticles. Nanoparticles functionalized with the vitamin folic acid are of particular interest as a variety of malignant tumors are known to overexpress the folate receptor(s). Indeed, several nanoparticle architectures with improved retention time, administration route, biocompatibility, absorption, and clearance are being proposed and are in late stage clinical development. This commentary highlights some of the most important concepts related to nanoparticles and folate-mediated drug delivery and imaging in cancer research. PMID- 21300031 TI - Dose-dependent differential effects of risedronate on gene expression in osteoblasts. AB - Bisphosphonates have multiple effects on bone. Their actions on osteoclasts lead to inhibition of bone resorption, at least partially through apoptosis. Effects on osteoblasts vary, with modifications in the molecule and concentration both resulting in qualitatively different responses. To understand the mechanism of the differential effects of high and low bisphosphonate concentrations on osteoblast activity, we compared the effects of 10-8 M and 10-4 M risedronate on gene expression in UMR-106 rat osteoblastic cells. Two targeted arrays, an 84 gene signaling array and an 84-gene osteogeneic array were used. Gene expression was measured at 1 and 24 h. Although some genes were regulated similarly by low and high concentrations of the drug, there was also differential regulation. At 1 h, 11 genes (1 signaling and 10 osteogenesis) were solely regulated by the low concentration, and 7 genes (3 signaling, 4 osteogenesis) were solely regulated by the high concentration. At 24 h, 8 genes (3 signaling, 5 osteogenesis) were solely regulated by the low concentration and 30 genes (16 signaling and 14 osteogenesis) were solely regulated by the high concentration. Interestingly, the low, but not the high concentration of risedronate transiently and selectively upregulated several genes associated with cell differentiation. A number of genes related to apoptosis were regulated, and could be involved in effects of bisphosphonates to promote osteoblast apoptosis. Also, observed gene changes associated with decreased angiogenesis and decreased metastasis could, if they occur in other cell types, provide a basis for the effectiveness of bisphosphonates in the prevention of cancer metastases. PMID- 21300032 TI - IL-1beta potently stabilizes IL-6 mRNA in human astrocytes. AB - Uncontrolled expression of IL-6 in the central nervous system is associated with neurodegenerative pathology and glioma development. Astrocytes are the predominant source of IL-6 in the central nervous system, and they are characteristically susceptible to synergistic IL-6 expression. Combined beta adrenergic and TNF-receptor triggering induces synergistic IL-6 expression in 1321N1 cells via a transcriptional enhancer mechanism. Here, we have investigated the molecular basis of the very potent "super"-synergistic IL-6 expression that is apparent after combined treatment of astrocytes with a beta-adrenergic agonist, isoproterenol, and the inflammatory cytokines TNF-alpha and IL-1beta. We found that IL-1beta treatment strengthens the IL-6 synergy by inducing a distinct stabilization of IL-6 mRNA. Surprisingly, the mRNA-stabilizing effect seems to be dependent on protein kinase C (PKC), but not on the prototypical mRNA-stabilizing kinase p38. Moreover, although the mRNA-binding protein HuR basally stabilizes IL 6 mRNA, the mRNA-stabilizing effect of IL-1beta is independent of HuR. Our data using pharmacological inhibitors suggest PKC is an important modulator of IL-6 expression in the central nervous system and this might have therapeutic implications. PMID- 21300033 TI - The different HMGA1 expression of total population of glioblastoma cell line U251 and glioma stem cells isolated from U251. AB - The high-mobility group A1 (HMGA1) protein is a non-histone architectural nuclear factor and participates in diverse biological processes, including gene transcription, embryogenesis, cell cycle regulation, apoptosis, and even neoplastic transformation. In our study, glioma stem cells (GSCs) expressing the surface marker CD133 from human glioblastoma cell line U251 were isolated using MACS column and were analyzed using immunofluorescence and flow cytometry (FCM). The different expression of HMGA1 was detected using real-time RT-PCR and Western blot at transcriptional and translational levels between U251 and isolated GSCs. The results show that GSCs were successfully isolated from U251 and cultured in serum-free medium (SMF). The percentage of GSCs in U251 was 0.32%+/-0.07%. HMGA1 expression was significantly higher in GSCs than in glioblastoma cells (P<0.05), up to 6.13+/-0.25-fold and 2.75+/-0.99-fold at transcriptional and translational levels, respectively. These results indicated HMGA1 is overexpressed in GSCs as compared to glioblastoma cell line U251, which points to the expression of HMGA1 being closely related to malignant proliferation, invasion, and differentiation of tumors from the prospective of tumor stem cells (TSCs). We conclude that HMGA1 may be a potential biomarker and rational therapeutic target for glioblastoma and GSC. PMID- 21300034 TI - Antenatal maternal stress alters functional brain responses in adult offspring during conditioned fear. AB - Antenatal maternal stress has been shown in rodent models and in humans to result in altered behavioral and neuroendocrine responses, yet little is known about its effects on functional brain activation. Pregnant female rats received a daily foot-shock stress or sham-stress two days after testing plug-positive and continuing for the duration of their pregnancy. Adult male offspring (age 14 weeks) with and without prior maternal stress (MS) were exposed to an auditory fear conditioning (CF) paradigm. Cerebral blood flow (CBF) was assessed during recall of the tone cue in the nonsedated, nontethered animal using the ((14))C iodoantipyrine method, in which the tracer was administered intravenously by remote activation of an implantable minipump. Regional CBF distribution was examined by autoradiography and analyzed by statistical parametric mapping in the three-dimensionally reconstructed brains. Presence of fear memory was confirmed by behavioral immobility ("freezing"). Corticosterone plasma levels during the CF paradigm were measured by ELISA in a separate group of rats. Antenatal MS exposure altered functional brain responses to the fear conditioned cue in adult offspring. Rats with prior MS exposure compared to those without demonstrated heightened fear responsivity, exaggerated and prolonged corticosterone release, increased functional cerebral activation of limbic/paralimbic regions (amygdala, ventral hippocampus, insula, ventral striatum, and nucleus accumbens), the locus coeruleus, and white matter, and deactivation of medial prefrontal cortical regions. Dysregulation of corticolimbic circuits may represent risk factors in the future development of anxiety disorders and associated alterations in emotional regulation. PMID- 21300035 TI - Tetrandrine attenuates spatial memory impairment and hippocampal neuroinflammation via inhibiting NF-kappaB activation in a rat model of Alzheimer's disease induced by amyloid-beta(1-42). AB - BACKGROUND: The neuroinflammation characterized by glial activation and release of proinflammatory mediators is considered to play a critical role in the pathogenesis of Alzheimer's disease (AD). Tetrandrine, a bisbenzylisoquinoline alkaloid isolated from the Chinese herb radix Stephania tetrandra, has been demonstrated to decrease the expression of proinflammatory mediators by inhibition of nuclear factor-kappaB (NF-kappaB) activation. The purpose of the study was to investigate effects of tetrandrine on experimental model of AD. MATERIALS AND METHODS: Tetrandrine was administered in a rat model of AD induced by amyloid-beta (Abeta)(1-42). The learning and memory impairment was examined using Morris water maze; the extent of histological injury in hippocampus was determined by Nissl staining; NF-kappaB DNA binding activity was assessed by electrophoretic mobility shift assay; the expression of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta was measured by enzyme-linked immunosorbent assay. RESULTS: A significant improvement was observed in learning and memory impairment in rats with tetrandrine, and the increase in NF-kappaB DNA binding activity, the over-expression in IL-1beta and TNF-alpha as well as the increased histological injury in hippocampus in rats induced by Abeta(1-42) were significantly reduced following administration of tetrandrine. CONCLUSION: Tetrandrine could significantly ameliorate Abeta(1-42)-induced spatial learning and memory impairment, and the beneficial effect of tetrandrine treatment could be linked, at least in part, to the inhibition of NF-kappaB activity and the downregulation of expression of IL-1beta and TNF-alpha, suggesting that administration of tetrandrine may provide a therapeutic approach for AD. PMID- 21300036 TI - Focal cerebral ischemia and mitochondrial dysfunction in the TNFalpha-transgenic rat. AB - Post-ischemic neurodegeneration may be accelerated by a cytokine-receptor mediated apoptotic pathway, as shown in a transgenic rat overexpressing tumor necrosis factor-alpha (TNFalpha) in brain. To further investigate the mechanism of ischemic cellular injury in this animal, we tested the hypothesis that increased synthesis of TNFalpha augments neuronal death by promoting mitochondrial dysfunction, calcium dysregulation, and oxidative stress. Adult male TNFalpha-transgenic (TNFalpha-Tg) and non-transgenic (non-Tg) littermates underwent reversible middle cerebral artery occlusion (MCAO) for 1 hour followed by 1 hour of reperfusion. Cortical mitochondria were isolated from injured (ipsilateral) and uninjured (contralateral) hemispheres of ischemic rats or from pooled hemispheres of control animals. ATP synthesis was attenuated in non ischemic TNFalpha-Tg rats, demonstrated by reduction of state III and respiratory control ratio, increased production of reactive oxygen species, and earlier formation of the calcium-induced membrane permeability transition pore. After MCAO, mitochondrial dysfunction was augmented more significantly in ischemic TNFalpha-Tg brain mitochondria than in non-Tg rats. These results show that mitochondrial dysfunction may be caused by increased brain levels of TNFalpha without physiological stress but will be exacerbated after MCAO. We conclude that ischemic stress and synthesis of inflammatory cytokines synergistically augment mitochondrial dysfunction to promote neuronal death. PMID- 21300037 TI - Hypoxic-ischemic brain injury stimulates inflammatory response and enzymatic activities in the hippocampus of neonatal rats. AB - Brain damage from neonatal hypoxia-ischemia (HI) plays a major role in neonatal mortality and morbidity. Using the Rice-Vannucci model of HI in rats, we verified that 8 days after HI injury, adenosine deaminase (ADA), N-acetyl-glucosaminidase (NAG) and myeloperoxidase (MPO) activities increased in the left hemisphere hippocampus (HI group); however, the activity of 5'-nucleotidase (5'NT) remained unchanged. In the hematoxylin-eosin analysis (HE), we detected selective and delayed degeneration of hippocampal pyramidal neurons and astroglial reaction accompanied by glial fibrillary acidic protein (GFAP)-positive and vimentin positive in the immunohistochemistry analysis in the HI group compared with the control group. We observed the selective necrosis of neurons, vascular endothelial proliferation and inflammatory response accompanied by the increase of the key enzyme of adenosine metabolism in the HI group. The increase of ADA activity, despite the 5'NT activity was not altered, indicates the predominance of ADA activity in the postischemic homeostasis of extra cellular adenosine. The presence of leukocytes into the ischemic areas displays the possible importance of the neutrophil-macrophages associated with the increase of MPO and NAG activities 8 days after HI. These findings may contribute to the evaluation of some consequences of the damage caused by neonatal HI. PMID- 21300038 TI - Central CRH administration changes formalin pain responses in male and female rats. AB - Corticotropin-releasing hormone (CRH) is suggested to be involved in the regulation of pain. To better evaluate the CRH-mediated behavioral alterations in the formalin inflammatory pain test, we administered CRH or the CRH receptor antagonist alpha-helical CRH(9-41) (ahCRH) intracerebroventricularly to male and female rats and compared the effects with those of saline control. Nociceptive stimulation was carried out through a subcutaneous injection of dilute formalin (50MUL, 10%) in the plantar surface of the hind paw. In both sexes, formalin induced responses, recorded for 60min, were affected by CRH but not by ahCRH treatment. Paw flexing duration was decreased in both sexes during the formalin interphase period in the CRH-treated group compared to saline control groups; however, licking of the injected paw was markedly increased by the same treatment at other time periods. Treatments induced only a few changes in spontaneous non pain behaviors, which do not account for the effects on pain response. In conclusion, these data demonstrate the ability of CRH to affect the behavioral responses to an inflammatory nociceptive stimulus, and that the effects can be in opposite directions depending on the behavioral response considered. PMID- 21300039 TI - Role of the insular cortex in morphine-induced conditioned taste avoidance. AB - The present study investigated the role of the insular cortex (IC) in morphine induced conditioned taste avoidance. The results of Experiment 1 revealed that IC lesions impaired taste neophobia, retarded acquisition of conditioned saccharin avoidance and apparently attenuated the magnitude of that response at asymptote. Using neurologically intact subjects, Experiment 2 established that a safe and familiar saccharin stimulus supports substantially weaker conditioned avoidance at asymptote than does a potentially dangerous and novel saccharin stimulus. This pattern of results does not support the hypothesis that IC lesions disrupt the learning mechanism responsible for morphine-induced conditioned taste avoidance. The data are, however, consistent with the hypothesis that IC lesions impair the perception of the danger and/or novelty of the taste stimulus. PMID- 21300040 TI - Cortical and hippocampal EEG effects of neurotransmitter agonists in spontaneously hypertensive vs. kainate-treated rats. AB - To analyze mediatory mechanisms underlying attention-deficit hyperactivity disorder (ADHD) and their association with epilepsy, the electroencephalogram (EEG) responses to various centrally applied neurotransmitter agonists were studied in spontaneously hypertensive (SH), kainate-treated (KA), and normotensive (control) rats, with chronically implanted electrodes into the frontal cortex and hippocampus and a cannula into the lateral cerebral ventricle. In SH rats, the baseline EEG showed increased delta and beta2 activity in the hippocampus and decreased alpha/beta1 activity in both brain areas. In KA rats, these delta and alpha/beta1 effects were observed 2 weeks post-kainate, while the beta2 activity increase occurred after 5 weeks in the hippocampus and, to a greater extent, 9 weeks post-injection in both brain areas. In SH rats, NMDA increased delta and decreased alpha/beta1 activity, similar to KA rats 5 weeks post-injection. In SH rats, clonidine augmented theta/beta2 increase in the cortex and alpha suppression in both brain areas, in parallel with induction of beta2 activity in the hippocampus. These beta2 effects were observed 5 and 9 weeks post-kainate. In SH rats, baclofen produced robust delta/theta enhancement and alpha/beta1 suppression in both brain areas, with additional beta2 activity increase in the hippocampus, while muscimol was ineffective in both groups of rats. In KA rats, EEG responses to GABA agonists were similar to those in control. Our results demonstrate sensitization of NMDA receptors and alpha2 adrenoceptors both in SH and KA rats and that of GABAb receptors specifically in SH rats. PMID- 21300041 TI - Resveratrol ameliorates early diabetic nephropathy associated with suppression of augmented TGF-beta/smad and ERK1/2 signaling in streptozotocin-induced diabetic rats. AB - Diabetic nephropathy (DN) is the major cause of end-stage renal disease. The early changes in DN are characterized by an increased in kidney size, glomerular volume, and kidney function, followed by the accumulation of glomerular extracellular matrix, increased urinary albumin excretion (UAE), glomerular sclerosis, and tubular fibrosis. Resveratrol (RSV) has been shown to ameliorate hyperglycemia and hyperlipidemia in streptozotocin-induced diabetic rats. In the present study, we examined the beneficial effects of RSV on DN and explored the possible mechanism of RSV action. Male Sprague-Dawley rats were injected with streptozotocin at 65mg/kg body weight. The induction of diabetes mellitus (DM) was confirmed by a fasting plasma glucose level >=300mg/dL and symptoms of polyphagia and polydipsia. The DM rats were treated with or without RSV at 0.75mg/kg body weight 3 times a day for 8 weeks. Animals were sacrificed and kidney histology was examined by microscopy. Urinary albumin excretion, glomerular hypertrophy and expressions of fibronectin, collagen IV, and TGF-beta in the glomeruli were alleviated in RSV-treated DM rats, but not in untreated DM rats. In addition, RSV treatment reduced the thickness of the glomerular basement membrane (GBM) to the original thickness and increased nephrin expressions to normal levels in DM rats. Moreover, RSV inhibited phosphorylation of smad2, smad3 and ERK1/2 in diabetic rat kidneys. This is the first report showing that RSV alleviates early glomerulosclerosis in DN through TGF-beta/smad and ERK1/2 inhibition. In addition, podocyte injuries of diabetic kidneys are lessened by RSV. PMID- 21300042 TI - Bioinformatic and biochemical characterization of DCXR and DHRS2/4 from Caenorhabditis elegans. AB - Several reductases belonging to the large enzyme superfamily of the short-chain dehydrogenases/reductases (SDR) are involved in the reductive metabolism of carbonyl containing xenobiotics. In order to characterize the human enzymes dicarbonyl/l-xylulose reductase (DCXR), and dehydrogenase/reductase members 2 and 4 (DHRS2, DHRS4) in terms of metabolism of xenobiotics, orthologues from the model organism Caenorhabditis elegans (C. elegans) were identified by using hidden Markov models that were developed in the present study. Accordingly, we describe the characterization of proteins from C. elegans as orthologous to the human enzymes DCXR and DHRS2/4 using a combined approach of bioinformatic and biochemical methods. With the hidden Markov model based system we identified the C. elegans proteins SDR20C18, SDR25C21 and SDR25C22 as being homologous to the human enzymes DCXR, and DHRS2 or DHRS4, respectively. After cloning and overexpression of these three C. elegans genes in Escherichia coli we could purify SDR20C18 and SDR25C22 as soluble proteins by Ni-affinity chromatography, whereas recombinant SDR25C21 was only found in inclusion bodies. Both SDR20C18 (UniProtAcc: Q21929) and SDR25C22 (UniProtAcc: Q93790) were tested with a variety of xenobotic carbonyl compounds as substrates. A comparison of the catalytic activities of SDR20C18 and SDR25C22 with well-known substrates of the human forms revealed that SDR20C18 is the DCXR-orthologue enzyme to the human enzyme and that SDR25C22 might be a DHRS2/4 homologue. Due to their high sequence identity, it was so far not possible to distinguish between SDR25C22 and the human DHRS2/4 proteins by means of sequence analysis alone. However, the study of homologue genes in the model organism C. elegans can provide valuable information on the putative physiological role of the corresponding human form. PMID- 21300043 TI - Serum tartrate-resistant acid phosphatase isoform 5a (TRACP5a) as a potential risk marker in cardiovascular disease. AB - OBJECTIVE: This study was undertaken to determine the association between serum tartrate-resistant acid phosphatase 5a (TRACP5a) and cardiovascular disease (CVD) risk. METHODS: Four hundred patients were enrolled including, 291 asymptomatic subjects grouped by the number of traditional risk factors, 36 patients undergoing cardiac arteriography, 34 undergoing percutaneous cardiac intervention, and 39 with acute myocardial infarction. Serum was collected at baseline and, in arteriograpy and intervention groups, periodically for 1 week afterward. In addition to laboratory and clinical evaluation for risk assessment, serum TRACP5a, C-reactive protein (CRP) and interleukin-6 (IL-6) were determined. RESULTS: All biomarkers rose with increasing CVD risk. Only serum TRACP5a, logCRP and cholesterol were elevated in symptomatic patients. Serum TRACP5a was higher in men and correlated with age, logCRP, logIL-6 and log-triglycerides, and in symptomatic patients, with the number of diseased coronary arteries. IL-6 and CRP showed acute phase responses, whereas TRACP5a did not change over 1 week after arteriography or intervention. After adjustment for all other variables and risk factors, TRACP5a and logCRP were the only biomarkers to associate with symptomatic disease. TRACP5a was more specific than CRP to predict myocardial infarction among all subjects. CONCLUSIONS: Serum TRACP5a is a macrophage-derived inflammation marker associated with CVD risk, and with coronary vessel disease and its severity and may be a useful marker for screening and assessment of CVD risk. PMID- 21300044 TI - Molecular diagnosis of X-linked adrenoleukodystrophy: experience from a clinical genetic laboratory in mainland China with report of 13 novel mutations. AB - BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder characterized by progressive demyelination of the nervous system, adrenocortical insufficiency and increase of very long chain fatty acids (VLCFAs) in the plasma and tissues. METHODS: A total of 131 individuals from 30 Chinese pedigrees were involved in this study, including 42 symptomatic patients, 44 female carriers, and 15 high-risk fetuses from 13 families. The mutation was first pinpointed through long distance RT-PCR-based RNA approach and confirmed through peripheral blood DNA approach. RESULTS: A total of 28 mutations were identified, of which 19 were missense, 3 nonsense and 6 frame-shift mutations. Thirteen mutations were novel, i.e. p.R280L, p.P580L, p.G343V, p.S108X, p.R259W, p.P534R, p.fs A246, p.L576P, p.K602X, p.A314P, p.N148D, p.H283R, and p.fs R89. Two mutations occurred de novo, for they were not found in somatic cells of their parents. Three females from the same family developed AMN-like symptoms and they were heterozygous for the p.H283R mutation. Four asymptomatic boys were diagnosed as X-ALD patients and prenatal molecular diagnosis were provided for 13 X-ALD-stricken families. CONCLUSIONS: Our work extended the spectrum of mutations in X-ALD and benefited genetic counseling through reliable identification of heterozygous females and asymptomatic males. PMID- 21300045 TI - Beta-2 microglobulin as an immunological marker to assess the progression of human immunodeficiency virus infected patients on highly active antiretroviral therapy. AB - BACKGROUND: Acquired immune deficiency syndrome (AIDS) defines the end stage of Human immunodeficiency viral (HIV) infection before the introduction of highly active antiretroviral therapy (HAART). This study was carried out to assess the serum beta-2 microglobulin (B2M) as a marker for progression of HIV infected patients undergoing HAART. METHODS: Blood samples were collected from 50 subjects of HIV infected patients residing at semi urban area undergoing treatment at Chellam Hospital, Salem, India. Twenty five age-matched healthy subjects were taken as control group. Serum B2M level was measured by using enzyme immunoassay, absolute CD4 and CD8 counts were carried out by single platform (SP) technology using a flow cytometer. Viral RNA was measured by real time PCR. The serum LDH level and total WBC count were also measured. RESULTS: Our result showed a statistically high significant increase in B2M in HIV patients on HAART non complaint group whereas absolute CD4, CD8 count, CD4/CD8 ratio and WBC count were decreased significantly when compared to control and HAART complaint group. Statistically a significant negative correlation was observed between B2M and absolute CD4, CD8 count, CD4/CD8 ratio and WBC count. B2M showed a significantly positive correlation with viral RNA and LDH values. CONCLUSIONS: The increase of B2M and reduced absolute CD4, CD8 count, CD4/CD8 ratio and WBC count in HIV patients on HAART non complaint group may have a contributory role in the immune progression of HIV with interruption of HAART. B2M plays an important role in the diagnosis of HIV and might indicate HIV progression. PMID- 21300046 TI - Cervicovaginal interleukin-6 as a predictor of preterm birth in African American women. AB - BACKGROUND: Identification of women who will deliver preterm may reduce infant morbidity and mortality. In heterogeneous populations, fetal fibronectin (fFN) and interleukin-6 are excellent predictors of women who will not deliver within two weeks. African-Americans are at higher risk for preterm birth than Caucasians. This study compares the diagnostic utility of fFN and interleukin-6 in cervicovaginal fluid (CVF) to predict preterm birth within 14 days of sampling in African-American and Caucasian women. METHODS: Interleukin-6 was measured in 667 CVF samples from 580 women with and without symptoms of labor. The utility of CVF interleukin-6 and fFN to predict delivery was determined in the total population and in African-Americans and Caucasians separately. RESULTS: fFN positive (>=50 MUg/l) results were associated with delivery in <=14 days in African-Americans (Odds Ratios (OR) 8.7; Likelihood Ratio (LR) 3.7) (p<0.0001) and Caucasians (OR 11.9; LR 5.7) (p<0.01). A positive interleukin-6 (>=250 ng/l) was associated with delivery in <=14 days in African-Americans (OR 12.7; LR 5.25) (p<0.0001), but not in Caucasians (OR 4.1; LR 3.2) (p=0.13). CONCLUSIONS: CVF interleukin-6 and fFN have similar diagnostic utilities in a diverse population. Interleukin-6 more accurately predicts delivery within 14 days in African Americans, while fFN is more accurate in Caucasians. PMID- 21300047 TI - Angiopoietin-2: a potential novel diagnostic marker in multiple myeloma. AB - BACKGROUND: Multiple myeloma (MM) was the first hematological malignancy in which a prognostic relevance of bone marrow (BM) angiogenesis was reported. Microenvironment formed by reactive oxygen species, growth factors and chemokines initiates the process of BM angiogenesis. Among the angiopoietins, angiopoietin-1 is involved in vessel stability, whereas angiopoietin-2 is involved in vessel sprouting. DESIGN AND METHODS: Circulatory levels of angiopoietin-1, angiopoietin 2 and VEGF in 62 MM patients and 50 healthy controls were determined using ELISA. RESULTS: Significant increase in VEGF and angiopoietin-2 level was observed in patients which correlated positively with the severity of the disease, whereas no alteration was observed in angiopoietin-1 levels. CONCLUSION: Significant elevation in angiopoietin-2 and VEGF levels and their correlation with severity of the disease indicate their utility as potential tumor markers along with beta(2)- microglobulin and might also suggest new therapeutic target for anticancer treatment. PMID- 21300048 TI - Noninvasive urinary organic acids test to assess biochemical and nutritional individuality in autistic children. AB - OBJECTIVES: Quantitative organic acid testing can give information about potential problems, especially with energy production, neurotransmitter metabolism, intestinal dysbiosis and nutritional individuality which is very important in autistic children. The aim of this study was to find out potential differences between the levels of organic acids in the urine of autistic and non autistic children. DESIGN AND METHODS: The organic acids in the urine were determined by capillary gas chromatography/mass spectrometry (GC/MS). All overnight urine samples were collected from 35 autistic children and 36 neurologically normal children as healthy controls (4-10 years). RESULTS: Significant differences were found between the autistic children and the control group in organic acids: 2-oxoglutaric, isocitric, citric, 4-hydroxybenzoic, 4 hydroxyphenylacetic, hippuric, adipic, suberic (all with p<0.05). CONCLUSION: Organic acids test can be used to assess an individual need for nutrient and biochemical abnormalities, especially important for autistic children. PMID- 21300049 TI - Cooperative functions of Hes/Hey genes in auditory hair cell and supporting cell development. AB - Notch-mediated lateral inhibition has been reported to regulate auditory hair cell and supporting cell development from common precursors. While the Notch effector genes Hes1, Hes5 and Hey1 are expressed in the developing cochlea, inactivation of either of them causes only mild abnormality, suggesting their functional redundancy. To explore the roles of Hes/Hey genes in cochlear development, we examined compound heterozygous or homozygous mutant mice that lacked Hes1, Hes5 and Hey1 alleles. We found that a reduction in Hes/Hey gene dosage led to graded increase of hair cell formation. However, if at least one allele of Hes1, Hes5 or Hey1 was intact, excessive hair cells were accompanied by overproduction of supporting cells, suggesting that the hair cell increase does not occur at the expense of supporting cells, and that each Hes/Hey gene functions to induce supporting cells. By contrast, when all alleles of Hes1, Hes5 and Hey1 were inactivated, the number of hair cells increased more drastically, whereas that of supporting cells was unchanged compared with control, suggesting that supporting cell formation was balanced by their overproduction and fate conversion into hair cells. The increase of the cell numbers seemed to occur after the prosensory domain formation in the mutants because the proliferation state and the size of the prosensory domain were not affected. Thus, Hes1, Hes5 and Hey1 cooperatively inhibit hair cell formation, and one allele of Hes1, Hes5 or Hey1 is sufficient for supporting cell production probably by lateral inhibition in the sensory epithelium. Strikingly, Hes/Hey mutations lead to disorganized cell alignment and polarity and to hearing loss despite hair cell overproduction. These results suggest that Hes/Hey gene dosage is essential not only for generation of appropriate numbers of hair cells and supporting cells by controlling cell proliferation and lateral inhibition but also for the hearing ability by regulating the cell alignment and polarity. PMID- 21300051 TI - Hydrogen sulfide gas has cell growth regulatory role. AB - Hydrogen sulfide (H(2)S) has been classified as a third novel gasotransmitter signaling molecule alongside nitric oxide and carbon monoxide. H(2)S rapidly travels through the cell membranes without using any specific receptors/transporters and signaling intracellular proteins. Recently, it has been shown that H(2)S induces DNA damage and alter cell cycle in various mammalian cells. Endogenously produced or exogenously treated H(2)S has a role in the accumulation or proliferation of cells and further may provide for development of a novel therapeutic approach in conditions associated with uncontrolled cell growth. However, the potential biological and clinical significance of H(2)S are subject of intense debate in recent years and despite considerable progress in our understanding about H(2)S, much still needs to be learned about their production at the site of tissue injury and its downstream signaling pathways on cell growth. Here, we provide an overview of the recent findings on its role in DNA damage/repair and cell growth followed by its potential translational implications. PMID- 21300050 TI - The endogenous cannabinoid anandamide shares discriminative stimulus effects with ?(9)-tetrahydrocannabinol in fatty acid amide hydrolase knockout mice. AB - The endogenous cannabinoid system has been noted for its therapeutic potential, as well as the psychoactivity of cannabinoids such as Delta9-tetrahydrocannabinol (THC). However, less is known about the psychoactivity of anandamide (AEA), an endocannabinoid ligand. Thus, the goals of this study were to establish AEA as a discriminative stimulus in transgenic mice lacking fatty acid amide hydrolase (i.e., FAAH -/- mice unable to rapidly metabolize AEA), evaluate whether THC or oleamide, a fatty acid amide, produced AEA-like responding, and assess for CB(1) mediation of AEA's discriminative stimulus. Mice readily discriminated between 6mg/kg AEA and vehicle in a two-lever drug discrimination task. AEA dose dependently generalized to itself. THC elicited full AEA-like responding, whereas oleamide failed to substitute. The CB(1) antagonist rimonabant attenuated AEA- and THC-induced AEA-appropriate responding, demonstrating CB(1) mediation of AEA's discriminative stimulus. These findings suggest that, in the absence of FAAH, AEA produces intoxication comparable to THC, and consequently to marijuana. PMID- 21300052 TI - Association between melanism, physiology and behaviour: a role for the melanocortin system. AB - The melanocortin system is implicated in the expression of many phenotypic traits. Activation of the melanocortin MC(1) receptor by melanocortin hormones induces the production of brown/black eumelanic pigments, while activation of the four other melanocortin receptors affects other physiological and behavioural functions including stress response, energy homeostasis, anti-inflammatory and sexual activity, aggressiveness and resistance to oxidative stress. We recently proposed the hypothesis that some melanocortin-physiological and -behavioural traits are correlated within individuals. This hypothesis predicts that the degree of eumelanin production may, in some cases, be associated with the regulation of glucocorticoids, immunity, resistance to oxidative stress, energy homeostasis, sexual activity, and aggressiveness. A review of the zoological literature and detailed experimental studies in a free-living population of barn owls (Tyto alba) showed that indeed melanic coloration is often correlated with the predicted physiological and behavioural traits. Support for predictions of the hypothesis that covariations between coloration and other phenotypic traits stem from pleiotropic effects of the melanocortin system raises a number of theoretical and empirical issues from evolutionary and pharmacological point of views. PMID- 21300053 TI - Delayed postoperative latent pain sensitization revealed by the systemic administration of opioid antagonists in mice. AB - The long-lasting post-surgical changes in nociceptive thresholds in mice, indicative of latent pain sensitization, were studied. The contribution of kappa opioid and N-methyl-d-aspartate (NMDA) receptors was assessed by the administration of nor-binaltorphimine or MK-801; dynorphin levels in the spinal cord were also determined. Animals underwent a plantar incision and/or a subcutaneous infusion of remifentanil (80MUg/kg), and mechanical thresholds (von Frey) were evaluated at different times. On day 21, after complete recovery of mechanical thresholds and healing of the wound, one of the following drugs was administered subcutaneously: (-)-naloxone (1mg/kg), (+)-naloxone (1mg/kg), naloxone-methiodide (3mg/kg), or nor-binaltorphimine (5mg/kg). Another group received subcutaneous MK-801 (0.15mg/kg) before nor-binaltorphimine administration. Dynorphin on day 21 was determined in the spinal cord by immunoassay. In mice receiving remifentanil during surgery, the administration of (-)-naloxone or nor-binaltorphimine induced significant hyperalgesia even 5months after manipulation. Nociceptive thresholds remained unaltered after (+)-naloxone or naloxone-methiodide. On day 21 after manipulation, the administration of MK 801 prevented nor-binaltorphimine-induced hyperalgesia. No changes in dynorphin levels were observed before or after opioid antagonist administration. In conclusion, surgery produced latent pain sensitization evidenced by opioid antagonist-precipitated hyperalgesia. The effect was stereospecific, centrally originated, and mediated by kappa opioid receptors. The blockade of nor binaltorphimine-induced hyperalgesia by MK-801, suggests that NMDA receptors are also involved. Our results show for the first time that surgery induces latent, long-lasting changes in the processing of nociceptive information that can be induced by non-nociceptive stimuli such as the administration of opioid antagonists. PMID- 21300054 TI - Donepezil attenuated oxygen-glucose deprivation insult by blocking Kv2.1 potassium channels. AB - Excessive K(+) efflux via activated voltage-gated K(+) channels (Kv channels) and the consequent intracellular K(+) depletion during and after ischemia/hypoxia induced long-lasting membrane depolarization promotes neuronal apoptosis. Although it has been suggested as an important potassium channel subtype in oxidative stress induced neuron apoptosis, whether Kv2.1 mediates ischemic apoptosis remains undefined. In the present study, the role of Kv2.1 played in hypoxia/anoxia induced cell apoptosis and correlated protective effect of donepezil were evaluated. Kv2.1 transfected HEK293 cell line (Kv2.1/HEK293) was used to study oxygen-glucose deprivation (OGD) induced cell apoptosis. We found Kv2.1 transfection increased the vulnerability of HEK293 cells to OGD insult, blocking Kv2.1 potassium channel by tetraethylammonium (TEA, 10mM) could attenuated OGD induced Kv2.1/HEK293 cell apoptosis significantly. OGD slightly reduced Kv2.1 currents without affecting channel kinetic activity. However, the membrane potential of Kv2.1/HEK293 cells depolarized to around 0mV after OGD treatment, a potential which could activated Kv2.1 persistently. Donepezil blocked Kv2.1 currents in a dose-dependent manner (IC(50)=7.59MUM). Under OGD condition, donepezil (30MUM) effectively inhibited Kv2.1 currents by accelerating channel inactivation and decreased Kv2.1/HEK293 cell apoptosis rate. In conclusion, our study revealed both the conducting role of Kv2.1 in OGD induced cell apoptosis and the importance of Kv2.1 as a target for neuronal protection. In addition, besides anti-acetylcholinesterase activity, Kv2.1 blockade capability of donepezil may attribute to its neuroprotective effects against ischemic apoptosis. PMID- 21300055 TI - Quantitative study of the antagonistic effect of (-)-cis-1-Methyl-7-[[4-(2,6 dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111) on nociceptin/orphanin FQ-mediated potassium channel activation in rat periaqueductal gray slices. AB - Nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor, a non-opioid branch of the opioid receptor family, shows structural similarities to traditional opioid receptors but binds opioid with very poor affinity. This receptor has been implicated in many physiological functions including pain regulation. This study quantitatively investigated the effect of (-)-cis-1-Methyl-7-[[4-(2,6 dichlorophenyl)piperidin-1 -yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5 ol (SB-612111), a novel non-peptide ligand of NOP receptor, on the native NOP receptors in the midbrain ventrolateral periaqueductal gray (vlPAG), a crucial region for pain regulation. SB-612111 concentration-dependently antagonized N/OFQ induced G-protein coupled inwardly rectifying K(+) (GIRK) current in vlPAG neurons. The IC(50) value of SB-612111 estimated from dose-response curves is 87.7+/-1.2nM. SB-612111 had no intrinsic agonistic activity and did not affect the GIRK current induced by [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin, a mu opioid receptor agonist, when tested at concentrations of up to 1MUM. It is concluded that SB-612111 is a pure, potent and selective antagonist of NOP receptors that mediate GIRK channel activation in the vlPAG neurons. PMID- 21300056 TI - Investigating the function of an aldosterone response pathway in primary human adrenocortical cells obtained from Conn's and phaeochromocytoma patients. AB - The components of the classical renal aldosterone response pathway are expressed in human adrenocortical cells; however, studies in H295R cells have shown that pharmacological manipulation of this pathway has no effect on aldosterone production. We have characterised aldosterone and cortisol production by primary human adrenocortical cells and tested the hypothesis that a mineralocorticoid response pathway modulates aldosterone secretion. Aldosterone production by cells obtained from normal adrenal cortex was stimulated by angiotensin II, extracellular K(+) and a reduction in extracellular Na(+). Conn's adenoma cells, in comparison, produced higher aldosterone/cortisol ratios and were less responsive to angiotensin II and extracellular Na(+). Close coupling of aldosterone and cortisol secretion was observed in all adrenocortical cells. The mineralocorticoid receptor antagonists, eplerenone and potassium canrenoate, had no significant effect on aldosterone or cortisol production. In contrast, the glucocorticoid receptor antagonist, mifepristone, and the Na(+) uptake inhibitor, amiloride, had significant inhibitory effects on steroid production. Our current experiments do not support the hypothesis that an adrenal aldosterone-response pathway mediates the negative feedback of aldosterone on its own release, but do raise interest in the glucocorticoid receptor and downstream targets of the mineralocorticoid receptor as mediators of corticosteroid production. PMID- 21300057 TI - A humanized anti-osteopontin antibody protects from Concanavalin A induced-liver injury in mice. AB - Osteopontin has been implicated in various inflammatory diseases including rheumatoid arthritis, multiple sclerosis, Crohn's disease, and fulminant hepatitis. Increased expression of osteopontin has been detected in pathological foci of these diseases. RA and fulminant hepatitis have been successfully treated by administration of neutralizing anti-osteopontin antibody in mice. However, rodent antibodies are highly immunogenic in humans and therefore limited in their clinical application. Here, a murine monoclonal antibody 23C3 against human osteopontin, was humanized by complementarity-determining region grafting method based on computer-assisted molecular modeling. The humanized version of 23C3, denoted as Hu23C3, was shown to possess affinity comparable to that of its parental antibody. Hu23C3 could also inhibit monocyte migration in response to osteopontin in vitro. Furthermore, in vivo data showed that Hu23C3 significantly protects mice from Concanavalin A (Con A) induced-liver injury in association with the reduction of transaminase activities and improvement of liver injury. Mechanistic studies demonstrated that Hu23C3 inhibited T and NKT cell infiltration, and activation of nuclear factor kappaB (NF-kappaB) in the liver, resulting in reduction of TNF-alpha and IFN-gamma production. Thus, our data strongly support that the humanized anti-osteopontin antibody, Hu23C3, may have a potential for the treatment of T cell mediated-hepatitis in human. PMID- 21300058 TI - Acidosis induces relaxation mediated by nitric oxide and potassium channels in rat thoracic aorta. AB - We investigated the mechanism by which extracellular acidification promotes relaxation in rat thoracic aorta. The relaxation response to HCl-induced extracellular acidification (7.4 to 6.5) was measured in aortic rings pre contracted with phenylephrine (Phe, 10(-6) M) or KCl (45mM). The vascular reactivity experiments were performed in endothelium-intact and denuded rings, in the presence or absence of indomethacin (10(-5) M), L-NAME (10(-4) M), apamin (10(-6) M), and glibenclamide (10(-5) M). The effect of extracellular acidosis (pH 7.0 and 6.5) on nitric oxide (NO) production was evaluated in isolated endothelial cells loaded with diaminofluorescein-FM diacetate (DAF-FM DA, 5MUM). The extracellular acidosis failed to induce any changes in the vascular tone of aortic rings pre-contracted with KCl, however, it caused endothelium-dependent and independent relaxation in rings pre-contracted with Phe. This acidosis induced-relaxation was inhibited by L-NAME, apamin, and glibenclamide, but not by indomethacin. The acidosis (pH 7.0 and 6.5) also promoted a time-dependent increase in the NO production by the isolated endothelial cells. These results suggest that extracellular acidosis promotes vasodilation mediated by NO, K(ATP) and SK(Ca), and maybe other K(+) channels in isolated rat thoracic aorta. PMID- 21300059 TI - The novel and orally active thrombin receptor antagonist E5555 (Atopaxar) inhibits arterial thrombosis without affecting bleeding time in guinea pigs. AB - Thrombin is a powerful agonist for platelets, the action of which is mediated by the thrombin receptor protease-activated receptor-1 (PAR-1). Recently, we discovered that E5555 (1-(3-tert-butyl-4-methoxy-5-morpholinophenyl)-2-(5,6 diethoxy-7-fluoro-1-imino-1,3-dihydro-2H-isoindol-2-yl) ethanone hydrobromide) is a potent thrombin receptor antagonist. We evaluated the anti-platelet and anti thrombotic effects of E5555. E5555 inhibited the binding of a high-affinity thrombin receptor-activating peptide ([(3)H]haTRAP) to PAR-1 with a half maximal inhibitory concentration (IC(50)) value of 0.019MUM. E5555 showed potent inhibitory effects on human platelet aggregation induced by thrombin and TRAP with IC(50) values of 0.064 and 0.031MUM, respectively, but had no effect on platelet aggregation induced by either ADP or collagen. Similarly, E5555 showed potent and selective inhibitory effects on guinea pig platelet aggregation induced by thrombin and TRAP with IC(50) values of 0.13 and 0.097MUM, respectively. The antithrombotic activity of E5555 in vivo was evaluated in a photochemically-induced thrombosis (PIT) model using guinea pigs. Oral administration of E5555 at 30 and 100mg/kg prolonged the time to occlusion by 1.8 fold and 2.4-fold, respectively, compared with controls. Furthermore, E5555 did not prolong bleeding time in guinea pigs at the highest tested dosage of 1000mg/kg. The drug interactions between E5555 and tissue plasminogen activator (tPA) were evaluated. Intravenous administration of 1mg/kg tPA significantly prolonged bleeding time, and its effects were not altered by the oral co administration of 300mg/kg E5555. These results suggest that E5555 could be a therapeutic option for atherothrombotic disease. PMID- 21300061 TI - Anti-cytokine therapies for psoriasis. AB - Current approaches for the treatment of psoriasis with anti-cytokine therapies involve the blockade of TNF-alpha, or the p40 sub-unit of IL-12 and IL-23. However, the field is currently evolving to test more selective antagonists, such as anti-IL-23p19, IL-17 and other inflammatory cytokines. Here we discuss our current understanding of dendritic cell and T cell subsets that are relevant in psoriasis, and the pharmacologic strategies that temper their activity in this disease. PMID- 21300060 TI - Down-regulation of PKHD1 induces cell apoptosis through PI3K and NF-kappaB pathways. AB - Mutations in PKHD1 (polycystic kidney and hepatic disease gene 1) gene cause the autosomal recessive polycystic kidney disease (ARPKD). Fibrocystin/polyductin (FPC), encoded by PKHD1, is a membrane-associated receptor-like protein. Although it is widely accepted that cystogenesis is mostly due to aberrant cell proliferation and apoptosis, it is still unclear how apoptosis is regulated. The aim of this study is to analyze the relationship among apoptosis, phosphatidylinositol 3-kinase (PI3K)/Akt and nuclear factor kappaB (NF-kappaB) in FPC knockdown kidney cells. We show that PKHD1-silenced HEK293 cells demonstrate a higher PI3K/Akt activity. Selective inhibition of PI3K/Akt using LY294002 or wortmannin in these cells increases serum starvation-induced HEK293 cell apoptosis with a concomitant decrease in cell proliferation and higher caspase-3 activity. PI3K/Akt inhibition also leads to increased NF-kappaB activity in these cells. We conclude that the PI3K/Akt pathway is involved in apoptotic function in PKHD1-silenced cells, and PI3K/Akt inhibition correlates with upregulation of NF kappaB activity. These observations provide a potential platform for determining FPC function and therapeutic investigation of ARPKD. PMID- 21300062 TI - Echinococcus multilocularis: purification and characterization of glycoprotein antigens with serodiagnostic potential for canine infection. AB - We show that a conventionally purified glycoprotein component of Echinococcus multilocularis protoscolex, designated as Emgp-89, may be useful as a serodiagnostic antigen for detecting E. multilocularis infection in dogs domesticated in endemic areas. Emgp-89 was obtained from the parasite material by a simple procedure using Con A-agarose and subsequent gel filtration chromatography. The purified fraction showed a molecular weight of >4000kDa upon gel filtration and reacted with a series of lectins that specifically bind to mannose, galactose, N-acetylglucosamine, and N-acetylgalactosamine. Subsequently, serodiagnostic performance of Emgp-89 was evaluated through enzyme-linked immunosorbent assays (ELISAs) by using sera from normal, domestic dogs and dogs infected with other helminths. Emgp-89 positively reacted with all 16 serum samples from E. multilocularis-infected dogs, thus showing that this antigen is highly sensitive. On the other hand, the specificity of Emgp-89-based ELISA, determined using 41 serum samples from dogs infected with other helminths, was relatively low (83%). As an attempt to improve the specificity of Emgp-89-based ELISA, we pretreated Emgp-89 with proteinase K or sodium periodate, expecting that these treatments would enable discrimination of true positives from false positives. The ELISA value increased after treatment with sodium periodate in most false-positive samples, whereas significant decreases were observed in sera from all dogs infected with E. multilocularis. Further evaluation of this antigen should be performed using sera from dogs infected with closely-related parasites, including taeniid cestodes, which are expected to prove that this serodiagnostic system is sufficiently specific for clinical and field applications. PMID- 21300063 TI - Defective relocalization of ALS2/alsin missense mutants to Rac1-induced macropinosomes accounts for loss of their cellular function and leads to disturbed amphisome formation. AB - Loss of ALS2/alsin function accounts for several recessive motor neuron diseases. ALS2 is a Rab5 activator and its endosomal localization is regulated by Rac1 via macropinocytosis. Here, we show that the pathogenic missense ALS2 mutants fail to be localized to Rac1-induced macropinosomes as well as endosomes, which leads to loss of the ALS2 function as a Rab5 activator on endosomes. Further, these mutants lose the competence to enhance the formation of amphisomes, the hybrid organelle formed upon fusion between autophagosomes and endosomes. Thus, Rac1 induced relocalization of ALS2 might be crucial to exert the ALS2 function associated with the autophagy-endolysosomal degradative pathway. PMID- 21300064 TI - PPARbeta/delta activation induces enteroendocrine L cell GLP-1 production. AB - BACKGROUND & AIMS: Glucagon-like peptide (GLP)-1, an intestinal incretin produced by L cells through proglucagon processing, is secreted after nutrient ingestion and acts on endocrine pancreas beta cells to enhance insulin secretion. Peroxisome proliferator-activated receptor (PPAR) beta/delta is a nuclear receptor that improves glucose homeostasis and pancreas islet function in diabetic animal models. Here, we investigated whether PPARbeta/delta activation regulates L cell GLP-1 production. METHODS: Proglucagon regulation and GLP-1 release were evaluated in murine GLUTag and human NCI-H716 L cells and in vivo using wild-type, PPARbeta/delta-null, and ob/ob C57Bl/6 mice treated with the PPARbeta/delta synthetic agonists GW501516 or GW0742. RESULTS: PPARbeta/delta activation increased proglucagon expression and enhanced glucose- and bile acid induced GLP-1 release by intestinal L cells in vitro and ex vivo in human jejunum. In vivo treatment with GW0742 increased proglucagon messenger RNA levels in the small intestine in wild-type but not in PPARbeta/delta-deficient mice. Treatment of wild-type and ob/ob mice with GW501516 enhanced the increase in plasma GLP-1 level after an oral glucose load and improved glucose tolerance. Concomitantly, proglucagon and GLP-1 receptor messenger RNA levels increased in the small intestine and pancreas, respectively. Finally, PPARbeta/delta agonists activate the proglucagon gene transcription by interfering with the beta catenin/TCF-4 pathway. CONCLUSIONS: Our data show that PPARbeta/delta activation potentiates GLP-1 production by the small intestine. Pharmacologic targeting of PPARbeta/delta is a promising approach in the treatment of patients with type 2 diabetes mellitus, especially in combination with dipeptidyl peptidase IV inhibitors. PMID- 21300065 TI - The chemokine receptor CCR9 is required for the T-cell-mediated regulation of chronic ileitis in mice. AB - BACKGROUND & AIMS: A balance between effector and regulatory T-cell (Treg) responses is required to maintain intestinal homeostasis. To regulate immunity, T cells migrate to the intestine using a combination of adhesion molecules and chemokine receptors. However, it is not known whether the migration pathways of effector cells and Tregs are distinct or shared. We sought to determine whether interaction between the chemokine receptor 9 (CCR9) and its ligand, chemokine ligand 25 (CCL25), allows effectors or Tregs to localize to chronically inflamed small intestine. METHODS: By using a mouse model that develops Crohn's-like ileitis (tumor necrosis factor Deltaadenosine uracyl-rich element [TNFDeltaARE] mice) we examined the role of CCL25-CCR9 interactions for effector and Treg traffic using flow cytometry, quantitative reverse-transcription polymerase chain reaction, immunohistochemistry, immunoneutralization, and proliferation analyses. RESULTS: In TNFDeltaARE mice, expression of CCL25 and the frequency of CCR9 expressing lymphocytes increased during late-stage disease. In the absence of CCR9, TNFDeltaARE mice developed exacerbated disease, compared with their CCR9 sufficient counterparts, which coincided with a deficiency of CD4(+)/CD25(+)/forkhead box P3(+) and CD8(+)/CD103(+) Tregs within the intestinal lamina propria and mesenteric lymph nodes. Furthermore, the CD8(+)/CCR9(+) subset decreased the proliferation of CD4(+) T cells in vitro. Administration of a monoclonal antibody against CCR9 to TNFDeltaARE mice exacerbated ileitis in vivo, confirming the regulatory role of CD8(+)/CCR9(+) cells. CONCLUSIONS: Signaling of the chemokine CCL25 through its receptor CCR9 induces Tregs to migrate to the intestine. These findings raise concerns about the development of reagents to disrupt this pathway for the treatment of patients with Crohn's disease. PMID- 21300067 TI - Spectral sensitivity of a colour changing spider. AB - Vision plays a paramount role in some spider families such as the Salticidae, Lycosidae and Thomisidae, as it is involved in prey hunting, orientation or choice of substrate. In the thomisid Misumena vatia, for which the substrate colour affects the body colour, vision seems to mediate morphological colour changes. However, nothing is known about which component of visual signals from the substrate might be perceived, nor whether M. vatia possesses the physiological basis for colour vision. The aim of this study is thus to investigate the vision of this spider species by measuring the spectral sensitivities of the different pairs of eyes using electrophysiological methods. Extra- and intracellular electrophysiological recordings combined with selective adaptation revealed the presence of two classes of photoreceptor cells, one sensitive in the UV region of the spectrum (around 340 nm) and one sensitive in the green (around 520 nm) regions in the four pairs of eyes. We conclude that M. vatia possesses the physiological potential to perceive both chromatic and achromatic components of the environment. PMID- 21300068 TI - Interaction of the Bacillus thuringiensis delta endotoxins Cry1Ac and Cry3Aa with the gut of the pea aphid, Acyrthosiphon pisum (Harris). AB - Hemipteran pests including aphids are not particularly susceptible to the effects of insecticidal Cry toxins derived from the bacterium Bacillus thuringiensis. We examined the physiological basis for the relatively low toxicity of Cry1Ac and Cry3Aa against the pea aphid, Acyrthosiphon pisum (Harris). Cry1Ac was efficiently hydrolyzed by aphid stomach membrane associated cysteine proteases (CP) producing a 60kDa mature toxin, whereas Cry3Aa was incompletely processed and partially degraded. Cry1Ac bound to the aphid gut epithelium but showed low aphid toxicity in bioassays. Feeding of aphids on Cry1Ac in the presence or absence of GalNAc, suggested that Cry1Ac gut binding was glycan mediated. In vitro binding of biotinylated-Cry1Ac to gut BBMVs and competition assays using unlabeled Cry1Ac and GalNAc confirmed binding specificity as well as glycan mediation of Cry1Ac binding. Although Cry3Aa binding to the aphid gut membrane was not detected, Cry3Aa bound 25 and 37kDa proteins in aphid gut BBMV in ligand blot analysis and competition assays confirmed the binding specificity of Cry3Aa. This, combined with low toxicity in feeding assays, suggests that Cry3Aa does bind the gut epithelium to some extent. This is the first systematic examination of the physiological basis for the low efficacy of Cry toxins against aphids, and analysis of Cry toxin-aphid gut interaction. PMID- 21300066 TI - Cellular changes in diabetic and idiopathic gastroparesis. AB - BACKGROUND & AIMS: Cellular changes associated with diabetic and idiopathic gastroparesis are not well described. The aim of this study was to describe histologic abnormalities in gastroparesis and compare findings in idiopathic versus diabetic gastroparesis. METHODS: Full-thickness gastric body biopsy specimens were obtained from 40 patients with gastroparesis (20 diabetic) and matched controls. Sections were stained for H&E and trichrome and immunolabeled with antibodies against protein gene product (PGP) 9.5, neuronal nitric oxide synthase (nNOS), vasoactive intestinal peptide, substance P, and tyrosine hydroxylase to quantify nerves, S100beta for glia, Kit for interstitial cells of Cajal (ICC), CD45 and CD68 for immune cells, and smoothelin for smooth muscle cells. Tissue was also examined by transmission electron microscopy. RESULTS: Histologic abnormalities were found in 83% of patients. The most common defects were loss of ICC with remaining ICC showing injury, an abnormal immune infiltrate containing macrophages, and decreased nerve fibers. On light microscopy, no significant differences were found between diabetic and idiopathic gastroparesis with the exception of nNOS expression, which was decreased in more patients with idiopathic gastroparesis (40%) compared with diabetic patients (20%) by visual grading. On electron microscopy, a markedly increased connective tissue stroma was present in both disorders. CONCLUSIONS: This study suggests that on full thickness biopsy specimens, cellular abnormalities are found in the majority of patients with gastroparesis. The most common findings were loss of Kit expression, suggesting loss of ICC, and an increase in CD45 and CD68 immunoreactivity. These findings suggest that examination of tissue can lead to valuable insights into the pathophysiology of these disorders and offer hope that new therapeutic targets can be found. PMID- 21300069 TI - JKTBP1 is involved in stabilization and IRES-dependent translation of NRF mRNAs by binding to 5' and 3' untranslated regions. AB - Heterogeneous nuclear ribonucleoprotein D-like protein (JKTBP) 1 was implicated in cap-independent translation by binding to the internal ribosome entry site in the 5' untranslated region (UTR) of NF-kappaB-repressing factor (NRF). Two different NRF mRNAs have been identified so far, both sharing the common 5' internal ribosome entry site but having different length of 3' UTRs. Here, we used a series of DNA and RNA luciferase reporter constructs comprising 5', 3' or both NRF UTRs to study the effect of JKTBP1 on translation of NRF mRNA variants. The results indicate that JKTBP1 regulates the level of NRF protein expression by binding to both NRF 5' and 3' UTRs. Using successive deletion and point mutations as well as RNA binding studies, we define two distinct JKTBP1 binding elements in NRF 5' and 3' UTRs. Furthermore, JKTBP1 requires two distinct RNA binding domains to interact with NRF UTRs and a short C-terminal region for its effect on NRF expression. Together, our study shows that JKTBP1 contributes to NRF protein expression via two disparate mechanisms: mRNA stabilization and cap-independent translation. By binding to 5' UTR, JKTBP1 increases the internal translation initiation in both NRF mRNA variants, whereas its binding to 3' UTR elevated primarily the stability of the major NRF mRNA. Thus, JKTBP1 is a key regulatory factor linking two pivotal control mechanisms of NRF gene expression: the cap independent translation initiation and mRNA stabilization. PMID- 21300070 TI - A mathematical model of adult GnRH neurons in mouse brain and its bifurcation analysis. AB - GnRH neurons are hypothalamic neurons that secrete gonadotropin-releasing hormone (GnRH) which stimulates the release of gonadotropins, one of the crucial hormones for sexual development, fertility and maturation. A mathematical model was built to help elucidate the mechanisms underlying electrical bursting and synchronous [Ca2(+)] transients in GnRH neurons (Lee et al., 2010). The model predicted that bursting in GnRH neurons (at least of the short-bursting type) requires the existence of a [Ca2(+)]-dependent slow after-hyperpolarisation current (sI(AHP UCL)), and this predicted current was found experimentally. GnRH behaviour under a wide range of conditions (inhibition of Na(+) channels, IP3 receptors, [Ca2(+)] dependent K(+) channels, or Ca2(+) pumps, or in the presence of zero extracellular [Ca2(+)]) is successfully reproduced by the model. In this paper, a simplified version of the previous model, with the same qualitative behaviour, is constructed and studied using timescale separation techniques and bifurcation analysis. PMID- 21300071 TI - How does the resistance threshold in spatially explicit epidemic dynamics depend on the basic reproductive ratio and spatial correlation of crop genotypes? AB - We examined the fraction of resistant cultivars necessary to prevent a global pathogen outbreak (the resistance threshold) using a spatially explicit epidemiological model (SIR model) in a finite, two-dimensional, lattice structured host population. Infectious diseases in our model could be transmitted to susceptible nearest-neighbour sites, and the infected site either recovered or died after an exponentially distributed infectious period. Threshold behaviour of this spatially explicit SIR model cannot be reduced to that of bond percolation, as was previously noted in the literature, unless extreme assumptions (synchronized infection events with a fixed lag) are imposed on infection process. The resistance threshold is significantly lower than that of conventional mean-field epidemic models, and is even lower if the spatial configuration of resistant and susceptible crops are negatively correlated. Finite size scaling applied to the resistance threshold for a finite basic reproductive ratio rho of pathogen reveals that its difference from static percolation threshold (0.41) is inversely proportional to rho. Our formula for the basic reproductive ratio dependency of the resistance threshold produced an estimate for the critical basic reproductive ratio (4.7) in a universally susceptible population, which is much larger than the corresponding critical value (1) in the mean-field model and nearly three times larger than the critical growth rate of a basic contact process (SIS model). Pair approximation reveals that the resistance threshold for preventing a global epidemic is factor 1/(1 eta) greater with spatially correlated planting than with random planting, where eta is initial correlation in host genotypes between nearest-neighbour sites. Thus the eradication is harder with a positive spatial correlation (eta>0) in mixed susceptible/resistant plantings, and is easier with a negative correlation (eta<0). The effect of finite field size (L), which corresponded to the mean distance between sources of infections, is given by the increased resistance threshold (by the amount L-0.75) from its infinite size limit. Implications of these results on effective planting strategies in multi-line control plans are discussed. PMID- 21300072 TI - Nonlinear analysis of lipid tubules by nonlocal beam model. AB - Postbuckling, nonlinear bending and nonlinear vibration analyses are presented for lipid tubules. The lipid tubule is modeled as a nonlocal micro/nano-beam which contains small scale effect. The material properties are assumed to be size dependent. The governing equation is solved by a two-step perturbation technique. The numerical results reveal that the small scale parameter e0a reduces the postbuckling equilibrium paths, the static large deflections and natural frequencies of lipid tubules. In contrast, it increases the nonlinear to linear frequency ratios slightly for the lipid tubule with immovable end conditions. PMID- 21300074 TI - A model for the control of malaria using genetically modified vectors. AB - Recent works have considered the problem of using transgenic mosquitoes to control a malaria epidemic. These insects have been genetically engineered to reduce their capacity to infect humans with malaria parasites. We analyze a model of the mosquito population dynamics when genetically modified individuals are introduced into a wild type population so that the effect of their introduction can be assessed. The model describes the dynamics of gene selection under sexual reproduction in a closed vector population. Our results show that the fitness of the resulting heterozygous population is the key parameter for the success of the invasion, independently of the fitness of homozygous vectors. The vector population dynamics model is then combined with an epidemiological model to study the feasibility of controlling a malaria epidemic. Basic reproductive numbers are calculated for both models, and conditions are obtained for preventing reappearance of the epidemic. Simulations on this model show that it may be possible to reduce or even eradicate the epidemic only if the heterozygous population is better adapted than the wild type. They also show that this can be achieved without completely eliminating the wild type mosquitoes. PMID- 21300073 TI - Mathematical model of a three-stage innate immune response to a pneumococcal lung infection. AB - Pneumococcal pneumonia is a leading cause of death and a major source of human morbidity. The initial immune response plays a central role in determining the course and outcome of pneumococcal disease. We combine bacterial titer measurements from mice infected with Streptococcus pneumoniae with mathematical modeling to investigate the coordination of immune responses and the effects of initial inoculum on outcome. To evaluate the contributions of individual components, we systematically build a mathematical model from three subsystems that describe the succession of defensive cells in the lung: resident alveolar macrophages, neutrophils and monocyte-derived macrophages. The alveolar macrophage response, which can be modeled by a single differential equation, can by itself rapidly clear small initial numbers of pneumococci. Extending the model to include the neutrophil response required additional equations for recruitment cytokines and host cell status and damage. With these dynamics, two outcomes can be predicted: bacterial clearance or sustained bacterial growth. Finally, a model including monocyte-derived macrophage recruitment by neutrophils suggests that sustained bacterial growth is possible even in their presence. Our model quantifies the contributions of cytotoxicity and immune-mediated damage in pneumococcal pathogenesis. PMID- 21300075 TI - Rb1 postconditioning attenuates liver warm ischemia-reperfusion injury through ROS-NO-HIF pathway. AB - AIMS: Ginsenoside Rb1 could prevent ischemic neuronal death and focal cerebral ischemia, but its roles to liver warm I/R injury remain to be defined. We determined if Rb1 would attenuate warm I/R injury in mice. MAIN METHODS: Mice were divided into sham, I/R, Rb1+I/R (Rb1 postconditioning, 20mg/kg, i.p. after ischemia), sham+L-NAME, I/R+L-NAME, and Rb1+I/R+L-NAME groups using 60min of the liver median and left lateral lobes ischemia. Serum levels of alanine aminotransferase (ALT) were measured and morphology changes of livers were evaluated. Contents of nitric oxide (NO) and nitric oxide synthase (NOS), malondialdehye (MDA) and activity of superoxide dismutase (SOD) were measured. Expressions of Akt, p-Akt, iNOS, HIF-1alpha, tumor necrosis factor-a (TNF-alpha) and intercellular adhesion molecule-1 (ICAM-1) were also determined by western blot or immunohistochemistry. KEY FINDINGS: Rb1 postconditioning attenuated the dramatically functional and morphological injuries. The levels of ALT were significantly reduced in Rb1 group (p<0.05). Rb1 upregulated the concentrations of NO, iNOS in serum, iNOS, and activity of SOD in hepatic tissues (p<0.05), while it dramatically reduced the concentration of MDA (p<0.05). Protein expressions of p-Akt, iNOS and HIF-1alpha were markedly enhanced in Rb1 group. Protein and mRNA expressions of TNF-alpha and ICAM-1 were markedly suppressed by Rb1 (p<0.05). SIGNIFICANCE: We found that Rb1 postconditioning could protect liver from I/R injury by upregulating the content of NO and NOS, and also HIF 1alpha protein expression. These protective effects could be abolished by L-NAME. These findings suggested Rb1 may have the therapeutic potential through ROS-NO HIF pathway for management of liver warm I/R injury. PMID- 21300076 TI - Co-expression of serotonin 5-HT(1B) and 5-HT(4) receptors in p11 containing cells in cerebral cortex, hippocampus, caudate-putamen and cerebellum. AB - p11 is an adaptor protein which binds to serotonin 5-HT(1B) receptors and 5-HT(4) receptors and regulates their localization at the cell surface. In the present study, we examined to what extent p11 containing neurons co-expressed 5-HT(1B)R and/or 5-HT(4)R in cerebral cortex, hippocampus, cerebellum and caudate-putamen. A triple-labeling immunohistochemical approach was taken using antibodies to detect native p11 and 5-HT(1B)R combined with visualization of EGFP driven under the 5-HT(4)R promoter in BAC-transgenic mice. In the caudate-putamen, the hippocampal pyramidal cell layer of CA1 and the hippocampal granule cell layer of dentate gyrus, most p11 containing cells co-expressed both 5-HT(1B)R and 5 HT(4)R. In the cingulate cortex, stratum radiatum/oriens of CA1, hilus of the dentate gyrus and cerebellar cortex, many cells co-expressed p11 and 5-HT(1B)R, but not 5-HT(4)R. In the studied brain regions, few cells solely expressed p11 without any significant expression of 5-HT(1B)R or 5-HT(4)R. It can be concluded that p11 is anatomically positioned to modulate serotonin neurotransmission, via 5-HT(1B)R and 5-HT(4)R, in brain regions important for emotionality, cognition and locomotion. PMID- 21300077 TI - Mechanism of action of lolitrem B, a fungal endophyte derived toxin that inhibits BK large conductance Ca2+-activated K+ channels. AB - The aim of this study was to compare the mode of action of the commonly used BK inhibitor paxilline with that of the more recently discovered lolitrem B. Similarities and differences in characteristics of inhibition between the two compounds were investigated. We have previously shown that lolitrem B does not affect the BK channel G-V, in contrast to the rightward shift produced by paxilline. These different effects on the voltage-dependence of activation suggest different modes of action for these two compounds. In this study we show that inhibition by both paxilline and lolitrem B is characterized by an open state preference for BK (hSlo) channels. Both compounds had a 3-fold higher apparent affinity under conditions likely to favour the open state, suggesting they have a similar BK conformational preference for binding. Furthermore, both compounds had a calcium concentration-dependence to their inhibitory effects. The G-V shift induced by paxilline was calcium concentration-dependent. PMID- 21300078 TI - Toxicity of Bothrops neuwiedi complex ("yarara chica") venom from different regions of Argentina (Serpentes, Viperidae). AB - We report a study of toxic and enzymatic activities of Bothrops neuwiedi complex venoms collected from specimens of different regions of Argentina and a pool of these same venoms. Were determined lethal, hemorrhagic and pro-coagulant (plasma and fibrinogen) doses and the neutralization of these activities by a bivalent antivenom. The electrophoretic pattern of different regions venom was studied by SDS-PAGE. All samples exhibited lethal potencies, hemorrhagic and coagulant (plasma and fibrinogen) activities with potencies concordant with previous studies. The only conspicuous difference in the toxicological pattern of Bothrops diporus venoms was the low-thrombin-like activity found in one sample. The antivenom used in this study could neutralize all the toxic activities tested and the neutralizing potency of the antivenom was comparable for all samples. Despite the wide distribution of B. neuwiedi complex throughout Argentina and the evident morphological variation between B. diporus (B. neuwiedi complex), this study establishes a remarkably similar toxicity profile throughout its range. This is the first systematic study on the regional variation of enzymatic and toxic activities of venom from species belonging to the B. neuwiedi complex, one of the snakes of highest sanitary importance in South America and their neutralization by the type of antivenom most commonly used in the South of South America. PMID- 21300079 TI - Impaired spatial and binocular summation for motion direction discrimination in strabismic amblyopia. AB - Amblyopia is characterised by visual deficits in both spatial vision and motion perception. While the spatial deficits are thought to result from deficient processing at both low and higher level stages of visual processing, the deficits in motion perception appear to result primarily from deficits involving higher level processing. Specifically, it has been argued that the motion deficit in amblyopia occurs when local motion information is pooled spatially and that this process is abnormally susceptible to the presence of noise elements in the stimulus. Here we investigated motion direction discrimination for abruptly presented two-frame Gabor stimuli in a group of five strabismic amblyopes and five control observers. Motion direction discrimination for this stimulus is inherently noisy and relies on the signal/noise processing of motion detectors. We varied viewing condition (monocular vs. binocular), stimulus size (5.3-18.5 degrees ) and stimulus contrast (high vs. low) in order to assess the effects of binocular summation, spatial summation and contrast on task performance. No differences were found for the high contrast stimuli; however the low contrast stimuli revealed differences between the control and amblyopic groups and between fellow fixing and amblyopic eyes. Control participants exhibited pronounced binocular summation for this task (on average a factor of 3.7), whereas amblyopes showed no such effect. In addition, the spatial summation that occurred for control eyes and the fellow eye of amblyopes was significantly attenuated for the amblyopic eyes relative to fellow eyes. Our results support the hypothesis that pooling of local motion information from amblyopic eyes is abnormal and highly sensitive to noise. PMID- 21300080 TI - Effects of calorie restriction on the age-dependent accumulation of mutations in the small intestine of lacZ-transgenic mice. AB - To understand the effect of calorie restriction on genome maintenance systems, the age-dependent accumulation of mutations in animals maintained on high and low calorie diets was examined using lacZ-transgenic mice. Mice were fed a diet of 95 kcal/w or 65 kcal/w from 2 to 17 months of age. The mutation frequencies in the lacZ gene in epithelial tissues from the small intestine were examined at 12 and 17 months. Mutation frequencies were found to be lower in mice fed with a low calorie diet than in mice fed with a high calorie diet at the two age points. The molecular nature of the mutations was examined with DNA sequencing. It showed a predominance of transversions from G:C to T:A, and this is a typical type of mutation induced by reactive oxygen species. The fraction of this type of mutation among the different types of mutations detected was not affected by calorie restriction. The percentage of the other types of mutation was not influenced either. These results suggest that calorie restriction reduces the age dependent accumulation of mutations by stimulating or inducing various types of DNA protection and repair systems rather than protecting cells against any specific type of DNA alteration. PMID- 21300081 TI - A multiscale hybrid approach for vasculogenesis and related potential blocking therapies. AB - Solid tumors must recruit and form new blood vessels for maintenance, growth and detachments of metastases. Discovering drugs that block malignant angiogenesis is thus an important approach in cancer treatment and has given rise to multiple in vitro and in silico models. The present hybrid individual cell-based model incorporates some underlying biochemical events relating more closely the classical Cellular Potts Model (CPM) parameters to subcellular mechanisms and to the activation of specific signaling pathways. The model spans the three fundamental biological levels: at the extracellular level a continuous model describes secretion, diffusion, uptake and decay of the autocrine VEGF; at the cellular level, an extended lattice CPM, based on a system energy reduction, reproduces cell dynamics such as migration, adhesion and chemotaxis; at the subcellular level, a set of reaction-diffusion equations describes a simplified VEGF-induced calcium-dependent intracellular pathway. The results agree with the known interplay between calcium signals and VEGF dynamics and with their role in malignant vasculogenesis. Moreover, the analysis of the link between the microscopic subcellular dynamics and the macroscopic cell behaviors confirms the efficiency of some pharmacological interventions that are currently in use and, more interestingly, proposes some new therapeutic approaches, that are counter intuitive but potentially effective. PMID- 21300082 TI - Accelerometer-determined moderate intensity lifestyle activity and cardiometabolic health. AB - OBJECTIVE: Objective To assess the relationship between moderate intensity lifestyle activity (LA) and cardiometabolic health using accelerometer data from the National Health and Nutrition Examination Survey (NHANES) 2005-2006. METHODS: One thousand three hundred and seventy-one adults (50% men; 71% non-Hispanic white) provided valid data to quantify time in LA [760-2019 counts per minute (CPM)] and moderate-to-vigorous physical activity (MVPA; >= 2020 CPM). Associations between LA [minutes per day (min/day); steps per day (steps/day)], and cardiometabolic risk factors [triglycerides, HDL-cholesterol (HDL-C), blood pressure, glucose, waist circumference], metabolic syndrome, self-reported hypertension and diabetes were investigated using logistic regression. Analyses were adjusted for age, gender, race/ethnicity, and MVPA categories. RESULTS: Greater time in LA (min/day), independent from MVPA, was associated with lower odds of elevated triglycerides (OR, 95% CI per 30 LA minutes: (0.88, 0.80-0.98), low HDL-C (0.88, 0.83-0.94), elevated waist circumference (0.89, 0.84-0.95), metabolic syndrome (0.88, 0.80-0.97), and diabetes (0.65, 0.51-0.83) [corrected]. The same cardiometabolic risk factors were also significantly associated with LA steps/day. No significant association was found between LA (min/day or steps/day) and glucose or blood pressure. CONCLUSION: Accumulation of time or steps in LA is independently related to lower odds for certain cardiometabolic risk factors. Research should consider the effects of increasing LA, which could influence future physical activity recommendations. PMID- 21300083 TI - Efficacy of a workplace-based weight loss program for overweight male shift workers: the Workplace POWER (Preventing Obesity Without Eating like a Rabbit) randomized controlled trial. AB - OBJECTIVE: To evaluate the feasibility and efficacy of a workplace-based weight loss program (Workplace POWER-WP) for male shift workers. METHOD: A prospective, two-armed randomized controlled trial of 110 overweight/obese (BMI 25-40) (mean [SD] age = 44.4 [8.6] years; BMI = 30.5 [3.6]) male employees at Tomago Aluminium aged 18-65. In October (2009) men were randomized to either (i) WP program (n=65) or (ii) a 14-week wait-list control group (n=45). The 3-month program involved one information session, program booklets, group-based financial incentives and an online component. Men were assessed at baseline and at 14-week follow-up for weight (primary outcome), waist circumference, BMI, blood pressure, resting heart rate, self-reported physical activity and dietary variables, and physical activity and dietary cognitions. RESULTS: Intention-to-treat analysis using linear mixed models revealed significant between group differences for weight loss after 14 weeks (P < .001, Cohen's d = 0.34). Significant intervention effects were also found for waist circumference (P < .001, d = 0.63), BMI (P < .001, d = 0.41), systolic blood pressure (P = .02, d = 0.48), resting heart rate (P < .001, d = 0.81), physical activity (P = .03, d = 0.77), sweetened beverages (P < .02, d = 0.5-0.6) and physical activity-related cognitions (P < .02, d=0.6). CONCLUSION: The WP program was feasible and efficacious and resulted in significant weight loss and improved health-related outcomes and behaviours in overweight male shift workers. PMID- 21300084 TI - Sulfated modification and antioxidant activity of exopolysaccahrides produced by Enterobacter cloacae Z0206. AB - Nine modification conditions were designed to sulfate exopolysaccharides (EPS) produced by Enterobacter cloacae Z0206 by chlorosulfonic acid-pyridine (CSA-Pyr) method according to the orthogonal test and focusing on three affecting factors such as the ratio of CSA to Pyr, reaction temperature and reaction time. And nine sulfated derivatives with various degrees of substitution (DS) were obtained. Their antioxidant activities were evaluated in vitro, by scavenging abilities on superoxide radical and hydroxyl radical. The results indicated that sulfated derivatives of EPS showed noticeable effects on scavenging superoxide radical and hydroxyl radical compared with native one, and sulfated derivative with moderate DS of 0.60 showed highest antioxidant activities. The optimum sulfated conditions of EPS were the ratio of CSA to Pyr of 1:2, the reaction time of 2h and reaction temperature of 70 degrees C. PMID- 21300085 TI - Preparation of rich handles soft cellulosic fabric using amino silicone based softener, part II: colorfastness properties. AB - The preparation of amino silicone based softeners with different emulsifiers was carried out and adsorbed onto the surfaces of cotton and blends of cotton/polyester fabrics. The softened fabrics have high surface area, so poorly performance in washing and rubbing fastness. It is obvious from the results of colorfastness to rubbing and washing that some of the samples of the dyed fabric treated with prepared softeners have shown some poor rating as compared to the untreated fabrics. However the other two samples have shown acceptable rubbing fastness results without losing softness and permanent handle. It can be observed that washing of the printed treated fabric remains unaffected almost in all the studied samples. Moreover, the application of the prepared softeners has imparted anti pilling property to the fabric. It can be seen that there is a remarkable increase in weights of treated fabrics as compared to the untreated fabrics. PMID- 21300086 TI - Shrimp waste fermentation with Pseudomonas aeruginosa A2: optimization of chitin extraction conditions through Plackett-Burman and response surface methodology approaches. AB - A Box-Bhenken design with four variables (shrimp shell concentration (SSC), glucose concentration, incubation time and inoculum size) and three levels was used for the determination of the deproteinization and demineralization efficiencies in fermented shrimp shells by Pseudomonas aeruginosa A2. The fermentation variables were selected in accordance with Plackett-Burman design. Maximum demineralization of 96%, with about 89% of protein removal occurs under the following conditions: SSC 50 g/l, glucose 50 g/l, 5 days and inoculum of 0.05 OD. This environment friendly method (biological treatment) can be considered as an effective pretreatment to produce a high-quality chitin. PMID- 21300087 TI - Biodegradability and mechanical properties of starch films from Andean crops. AB - Different Andean crops were used to obtain starches not previously reported in literature as raw material for the production of biodegradable polymers. The twelve starches obtained were used to prepare biodegradable films by casting. Water and glycerol were used as plasticizers. The mechanical properties of the starch based films were assessed by means of tensile tests. Compost tests and FTIR tests were carried out to assess biodegradability of films. The results show that the mechanical properties (UTS, Young's modulus and elongation at break) of starch based films strongly depend on the starch source used for their production. We found that all the starch films prepared biodegrade following a three stage process and that the weight loss rate of all the starch based films tested was higher than the weight loss rate of the cellulose film used as control. PMID- 21300088 TI - Self-aggregates formation and mucoadhesive property of water-soluble beta cyclodextrin grafted with chitosan. AB - Water-soluble beta-cyclodextrin grafted with chitosan (CD-g-CS) was carried out by quaternizing the CD-g-CS with glycidyltrimethyl ammonium chloride (GTMAC) under mild acidic condition, corresponding to the quaternized CD-g-CS (QCD-g-CS). The degrees of substitution (DS) and quaternization (DQ), ranging from 5% to 23% and 66% to 80%, respectively, were determined by (1)H NMR spectroscopy. Self aggregates formation of all QCD-g-CSs were investigated in water using dynamic light scattering (DLS), atomic force microscopy (AFM), and transmission electron microscopy (TEM) techniques. The result revealed that all QCD-g-CSs are able to form self-aggregates in water. Large particle sizes ranged from 800 to 3000nm were obtained by DLS while zeta-potentials were ranging from 25 to 40mV. AFM and TEM depicted a spherical shape with particle sizes ranging from 100 to 900nm. Mucoadhesive and cytotoxic properties of all QCD-g-CSs were evaluated using a mucin particle method and MTT assay compared to quaternized chitosan (QCS). It was found that the mucoadhesive property increased with decreasing DS due to less quaternary ammonium moiety into the chitosan backbone. On the other hand, the cytotoxicity increased with increasing DS even though the DQ is decreased. PMID- 21300089 TI - Amyloid fibril formation by circularly permuted and C-terminally deleted mutants. AB - The natural N- and C-termini, i.e., the given order of secondary structure segments, are critical for protein folding and stability, as shown by several studies using circularly permuted proteins, mutants that have their N- and C termini linked and are then digested at another site to create new termini. A previous work showed that circularly permuted mutants of sperm whale myoglobin (Mb) are functional, have native-like folding and bind heme, but are less stable than the wild-type protein and aggregate. The ability of wild-type myoglobin to form amyloid fibrils has been established recently, and because circularly permuted mutations are destabilizing, we asked whether these permutations would also affect the rate of amyloid fibril formation. Our investigations revealed that, indeed, the circularly permuted mutants formed cytotoxic fibrils at a rate higher than that of the wild-type. To further investigate the role of the C terminus in the overall stability of the protein, we investigated two C terminally deleted mutant, Mb(1-123) and Mb(1-99), and found that Mb(1-123) formed cytotoxic fibrils at a higher rate than that of the wild-type while Mb(1 99) formed cytotoxic fibrils at a similar rate than that of the wild-type. Collectively, our findings show that the native position of both the N-and C termini is important for the precise structural architecture of myoglobin. PMID- 21300090 TI - Transduction of binding affinity by B lymphocytes: a new dimension in immunological regulation. AB - To date, immunologists have operated with two primary paradigms governing the antibody response: (1) that affinity maturation is primarily dependent upon antigen-driven selection of both the germline and somatically amended repertoires, and (2) that antibody effector function is isotypically determined. The teleost model now suggests that these classical paradigms should be broadened to incorporate the ability of the B cell to transduce the strength of antigen recognition (affinity) into structural modifications of its antibody product, which, in turn, modulates the antibody's effector function. Although this relationship, thus far, has only been examined and demonstrated in the teleost, we find a number of the individual elements of this structural/functional relationship have been reported for mammalian IgM, which prompts future investigations into its universality. In sum, these findings suggest a heretofore unrecognized feature of B lymphocyte affinity discrimination, which transduces the affinity of antigen recognition into functionally modified antibodies. PMID- 21300092 TI - Amplified antigen-specific immune responses in HIV-1 infected individuals in a double blind DNA immunization and therapy interruption trial. AB - Immunotherapy in patients with HIV-1 infection aims to restore and broaden immunological competence, reduce viral load and thereby permit longer periods without combined antiretroviral treatment (cART). Twelve HIV-1-infected patients on cART were immunized on the skin with DNA plasmids containing genes of several HIV-1 subtypes with or without the addition of hydroxyurea (HU), or with placebo. The mean net gain of HIV-specific CD8+ T cell responses were higher and broader in the HIV DNA vaccine groups compared to non-vaccinated individuals (p<0.05). The vaccine-induced immune responses per se had no direct effect on viral replication. In all patients combined, including placebo, the viral set point after a final structured therapy interruption (STI) was lower than prior to initiation of cART (p=0.003). Nadir CD4 levels appeared to strongly influence the post-STI viral titers. After the sixth immunization or placebo, patients could stay off cART for a median time of 15 months. The study shows that HIV DNA immunization induces broader and higher magnitudes of HIV-specific immune responses compared to structured therapy interruptions alone. Although compromised by small numbers of patients, the study also demonstrates that well monitored STI may safely function as an immunological read out of HIV vaccine efficacy. PMID- 21300091 TI - Methylmercury-induced alterations in astrocyte functions are attenuated by ebselen. AB - Methylmercury (MeHg) preferentially accumulates in glia of the central nervous system (CNS), but its toxic mechanisms have yet to be fully recognized. In the present study, we tested the hypothesis that MeHg induces neurotoxicity via oxidative stress mechanisms, and that these effects are attenuated by the antioxidant, ebselen. Rat neonatal primary cortical astrocytes were pretreated with or without 10 MUM ebselen for 2h followed by MeHg (0, 1, 5, and 10 MUM) treatments. MeHg-induced changes in astrocytic [(3)H]-glutamine uptake were assessed along with changes in mitochondrial membrane potential (DeltaPsi(m)), using the potentiometric dye tetramethylrhodamine ethyl ester (TMRE). Western blot analysis was used to detect MeHg-induced ERK (extracellular-signal related kinase) phosphorylation and caspase-3 activation. MeHg treatment significantly decreased (p<0.05) astrocytic [(3)H]-glutamine uptake at all time points and concentrations. Ebselen fully reversed MeHg's (1 MUM) effect on [(3)H]-glutamine uptake at 1 min. At higher MeHg concentrations, ebselen partially reversed the MeHg-induced astrocytic inhibition of [(3)H]-glutamine uptake [at 1 min (5 and 10 MUM) (p<0.05); 5 min (1, 5 and 10 MUM) (p<0.05)]. MeHg treatment (1h) significantly (p<0.05) dissipated the DeltaPsi(m) in astrocytes as evidenced by a decrease in mitochondrial TMRE fluorescence. Ebselen fully reversed the effect of 1 MUM MeHg treatment for 1h on astrocytic DeltaPsi(m) and partially reversed the effect of 5 and 10 MUM MeHg treatments for 1h on DeltaPsi(m). In addition, ebselen inhibited MeHg-induced phosphorylation of ERK (p<0.05) and blocked MeHg induced activation of caspase-3 (p<0.05-0.01). These results are consistent with the hypothesis that MeHg exerts its toxic effects via oxidative stress and that the phosphorylation of ERK and the dissipation of the astrocytic mitochondrial membrane potential are involved in MeHg toxicity. In addition, the protective effects elicited by ebselen reinforce the idea that organic selenocompounds represent promising strategies to counteract MeHg-induced neurotoxicity. PMID- 21300093 TI - Vaccination with the defined chlamydial secreted protein CPAF induces robust protection against female infertility following repeated genital chlamydial challenge. AB - We previously have shown the efficacy of recombinant (r) chlamydial protease-like activity factor (CPAF) vaccination against hydrosalpinx development following primary genital chlamydial challenge. In this study, we evaluated further the protection induced by rCPAF vaccination against infertility. Following primary challenge, fertility levels were not significantly different between the mock- and CPAF-vaccinated and Chlamydia alone challenged mice. However, following secondary genital chlamydial challenge, mock (PBS) immunized mice displayed a significant reduction of fertility compared to age-matched naive mice, while mice vaccinated intranasally with rCPAF+CpG displayed significant prevention of infertility. These results suggest that hydrosalpinx may be a reliable indicator of impending infertility, and that rCPAF is a promising candidate to prevent infertility resulting from repeated genital chlamydial infections. PMID- 21300094 TI - Text message reminders to promote human papillomavirus vaccination. AB - OBJECTIVE: To implement and evaluate text message reminders for the second (HPV2) and third (HPV3) vaccine doses. DESIGN: Site-based intervention. SETTING: Nine pediatric sites (5 academic and 4 private) located in New York City. PARTICIPANTS: Parents of adolescents 9-20 years who received HPV1 or HPV2 during the intervention period, January-June 2009. INTERVENTION: Parents who enrolled received up to three weekly text message reminders that their daughter was due for her next vaccine dose. OUTCOME MEASURE: On-time receipt of the next vaccine dose, within one month of its due date. RESULTS: During the intervention period, of 765 eligible HPV vaccine events, 434 enrollment instructions were distributed to parents (56.7% of doses). Parents of 124 adolescent girls (28.6% of those handed instructions) activated text message reminders. Comparing children of parents who enrolled versus those who did not, on-time receipt of next HPV vaccine dose occurred among 51.6% (95% CI 42.8-60.4%) versus 35.0% (95% CI 29.6 40.2%) of adolescents (p=.001). Similarly, among a historical cohort of adolescents, receiving HPV1 or HPV2 in the six months prior to the intervention period, on-time receipt of next vaccine dose was noted for 38.1% (95% CI 35.2 41.0%) (p=.003). Increases in receipt of next vaccine dose among intervention subjects were sustained at 4 months following the vaccine due date. Using a logistic regression model, after controlling for insurance and site of care, intervention subjects were significantly more likely than either control population to receive their next HPV vaccine dose on-time. CONCLUSION: Among those choosing to enroll, text message reminders were an effective intervention to increase on-time receipt of HPV2 or HPV3. PMID- 21300095 TI - Sex differences in the vaccine-specific and non-targeted effects of vaccines. AB - Vaccines have non-specific effects (NSE) on subsequent morbidity and mortality from non-vaccine related infectious diseases. Thus NSE refers to any effect that cannot be accounted for by the induction of immunity against the vaccine-targeted disease. These effects are sex-differential, generally being more pronounced in females than males. Furthermore, the NSE are substantial causing greater than fifty percent changes in all cause mortality in certain settings, yet have never been systematically tested despite the fact that millions of children receive vaccines each year. As we strive to eliminate infectious diseases through vaccination programmes, the relative impact of NSE of vaccines on mortality is likely to increase, raising important questions regarding the future of certain vaccine schedules. A diverse group of scientists met in Copenhagen to discuss non specific and sex-differential effects of vaccination, and explore plausible biological explanations. Herein we describe the contents of the meeting and the establishment of the 'Optimmunize' network aimed at raising awareness of this important issue among the wider scientific community. PMID- 21300096 TI - Room temperature stabilization of oral, live attenuated Salmonella enterica serovar Typhi-vectored vaccines. AB - Foam drying, a modified freeze drying process, was utilized to produce a heat stable, live attenuated Salmonella Typhi 'Ty21a' bacterial vaccine. Ty21a vaccine was formulated with pharmaceutically approved stabilizers, including sugars, plasticizers, amino acids, and proteins. Growth media and harvesting conditions of the bacteria were also studied to enhance resistance to desiccation stress encountered during processing as well as subsequent storage at elevated temperatures. The optimized Ty21a vaccine, formulated with trehalose, methionine, and gelatin, demonstrated stability for approximately 12 weeks at 37 degrees C (i.e., time required for the vaccine to decrease in potency by 1log(10)CFU) and no loss in titer at 4 and 25 degrees C following storage for the same duration. Furthermore, the foam dried Ty21a elicited a similar immunogenic response in mice as well as protection in challenge studies compared to VivotifTM, the commercial Ty21a vaccine. The enhanced heat stability of the Ty21a oral vaccine, or Ty21a derivatives expressing foreign antigens (e.g. anthrax), could mitigate risks of vaccine potency loss during long-term storage, shipping, delivery to geographical areas with warmer climates or during emergency distribution following a bioterrorist attack. Because the foam drying process is conducted using conventional freeze dryers and can be readily implemented at any freeze drying manufacturing facility, this technology appears ready and appropriate for large scale processing of foam dried vaccines. PMID- 21300097 TI - Mothers' support for voluntary provision of HPV vaccine in schools. AB - HPV vaccination rates among adolescents in the United States lag behind some other developed countries, many of which routinely offer the vaccine in schools. We sought to assess mothers' willingness to have their adolescent daughters receive HPV vaccine at school. A national sample of mothers of adolescent females ages 11-14 completed our internet survey (response rate=66%). The final sample (n=496) excluded mothers who did not intend to have their daughters receive HPV vaccine in the next year. Overall, 67% of mothers who intended to vaccinate their daughters or had vaccinated their daughters reported being willing to have their daughters receive HPV vaccine at school. Mothers were more willing to allow their daughters to receive HPV vaccine in schools if they had not yet initiated the vaccine series for their daughters or resided in the Midwest or West (all p<.05). The two concerns about voluntary school-based provision of HPV vaccine that mothers most frequently cited were that their daughters' doctors should keep track of her shots (64%) and that they wished to be present when their daughters were vaccinated (40%). Our study suggests that most mothers who support adolescent vaccination for HPV find school-based HPV vaccination an acceptable option. Ensuring communication of immunization records with doctors and allowing parents to be present during immunization may increase parental support. PMID- 21300098 TI - The HPV vaccine: are dosing recommendations being followed? AB - The aims of this study were to determine the percentage of females who after initiating the human papillomavirus (HPV) vaccine series, both completed it and completed it on-time, as well as to examine factors associated with series completion and on-time completion. Using data from the North Carolina Immunization Registry, of 138,823 females analyzed, 55% completed the series, and 28% completed it on-time. Over 83% of those who initiated the vaccine series in 2006 completed it by the final study date, as compared to 32% of those who initiated the vaccine in 2009. On-time dosing rates, however, are declining, and have been hovering at 25% for the last two years of the study. Factors such as African-American race and public funding were significantly associated with lower rates of on-time dosing as well as series completion when compared to White race and private funding, respectively. Among girls and young women who initiate the HPV vaccination series, overall completion rates are low, but if given enough time most of those who begin the series will complete it. Our results suggest that strategies to improve the timely completion of the HPV vaccination series may be needed. PMID- 21300099 TI - Probing the attenuation and protective efficacy of a candidate chikungunya virus vaccine in mice with compromised interferon (IFN) signaling. AB - Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes explosive outbreaks of febrile illness associated with rash, and painful arthralgia. The CHIK vaccine strain 181/clone25 (181/25) developed by the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) was shown to be well tolerated and highly immunogenic in phase I and II clinical trials although it induced transient arthralgia in some healthy adult volunteers. In an attempt to better understand the host factors that are involved in the attenuating phenotype of CHIK 181/25 vaccine virus we conducted studies in interferon (IFN)-compromised mice and also evaluated its immunogenic potential and protective capacity. Infection of AG129 mice (defective in IFN-alpha/beta and IFN-gamma receptor signaling) with CHIK 181/25 resulted in rapid mortality within 3-4 days. In contrast, all infected A129 mice (defective in IFN-alpha/beta receptor signaling) survived with temporary morbidity characterized by ruffled appearance and body weight loss. A129 heterozygote mice that retain partial IFN-alpha/beta receptor signaling activity remained healthy. Infection of A129 mice with CHIK 181/25 induced significant levels of IFN-gamma and IL-12 while the inflammatory cytokines, TNFalpha and IL-6 remained low. A single administration of the CHIK 181/25 vaccine provided both short-term and long-term protection (38 days and 247 days post-prime, respectively) against challenge with wt CHIKV-La Reunion (CHIKV LR). This protection was at least partially mediated by antibodies since passively transferred immune serum protected both A129 and AG129 mice from wt CHIKV-LR and 181/25 virus challenge. Overall, these data highlight the importance of IFNs in controlling CHIK 181/25 vaccine and demonstrate the ability of this vaccine to elicit neutralizing antibody responses that confer short-and long-term protection against wt CHIKV-LR challenge. PMID- 21300101 TI - Implementation and evaluation of the Reaching Every District (RED) strategy in Assam, India, 2005-2008. AB - In 2005, UNICEF and the Centers for Disease Control and Prevention implemented and evaluated the Reaching Every District (RED) approach, an intervention designed to improve key components of immunization services including planning, outreach, community mobilization, supervision, and monitoring, in select districts of Assam, India. Two intervention and 3 comparison districts were selected for a 2-year evaluation trial. In intervention districts, immunization staff received comprehensive training and ongoing supervision by a fulltime consultant, and regular monitoring of progress was conducted. Population-based vaccination coverage surveys were conducted at baseline and 2 years after the start of implementation in the 5 districts. Post-intervention process indicators were systematically collected and focus group discussions were held. At follow up, children in both the intervention and comparison districts were twice as likely to be fully vaccinated as they were at baseline. However, sites that received intervention training were better performing than those that did not, as measured by process indicators, including a higher number of outreach visits planned and held (p=0.02), having a monitoring chart (p<0.01), and correctly calculating dropout (p<0.01). The number of supervisory visits was significantly and positively associated with other key process indicators. Although coverage did not differ significantly between intervention and comparison districts, among individual districts, process data indicate significant improvements in program quality in the intervention districts. Further studies are needed to determine if the improved process indicators have sustainable impact on maintaining improvements in coverage. PMID- 21300100 TI - Aerosol vaccination induces robust protective immunity to homologous and heterologous influenza infection in mice. AB - Live-attenuated influenza vaccine (LAIV) delivered by large droplet intranasal spray is efficacious against infection. However, many of the large droplets are trapped in the external nares and do not reach the target nasal airway tissues. Smaller droplets might provide better distribution yielding similar protection with lower doses. We evaluated 20 and 30 MUm aerosol delivery of influenza virus in mice. A 15s aerosol exposure optimally protected against homologous and heterologous influenza infection and induced a robust immune response. These results demonstrate the feasibility of nasal vaccination using aerosolized particles, providing a strategy to improve vaccine efficacy and delivery. PMID- 21300102 TI - B. melitensis rough strain B115 is protective against heterologous Brucella spp. infections. AB - Brucellosis is one of the most serious zoonoses all over the world, with B. melitensis, B. abortus and B. suis being the most pathogenic species for humans. Vaccination of domesticated livestock still represents the most efficient way to prevent human infection. However, the available Brucella vaccines retain an important residual virulence and induce antibodies interfering with surveillance programs. Moreover, each vaccine shows different protective effects versus different Brucella species and different animal hosts. Nowadays, while B. melitensis and B. suis infections in cattle are emerging as a significant problem, there are no available vaccines to overcome such issue. B. melitensis strain B115, a natural, attenuated rough strain in our previous studies proved to be highly protective against B. melitensis and B. ovis infections in mice, without inducing interfering antibodies. In this study, we tested the efficiency of B115 as vaccine against B. abortus and B. suis. Vaccination of mice with 10(8) CFU/mouse of B. melitensis B115 conferred a satisfactory protection against B. abortus 2308. On the contrary, mice vaccinated once with 10(8) or 10(9) CFU/mouse of B115 were weakly protected against B. suis infection. Conversely, when mice were vaccinated twice with 10(9) CFU B115/mouse, the protective activity significantly increased. Unlike its rough phenotype, B115 showed an adequate persistence in mice accompanied to a solid humoral and cell-mediated immunity. All together, these findings suggest the potential usefulness of B115 to control brucellosis in animal hosts due to heterologous challenges. PMID- 21300103 TI - Immunostimulatory and antigen delivery properties of liposomes made up of total polar lipids from non-pathogenic bacteria leads to efficient induction of both innate and adaptive immune responses. AB - Novel liposomes prepared from total polar lipids of non-pathogenic bacteria, viz. Leptospira biflexa serovar Potac (designated leptosomes) and Mycobacterium smegmatis (designated smegmosomes) were evaluated for their adjuvant effects with various antigen presenting cells (APCs), viz. murine macrophage cell line, J774A.1 and bone marrow derived dendritic cells (BMDCs). These liposomes induced strong membrane fusion as evident from resonance energy transfer (RET) assays and effectively transferred the fluorescent probe to the membrane of these APCs. Moreover, both vesicles caused significant activation of APCs as revealed by release of proinflammatory cytokines (IL-6, IL-12, TNF-alpha) and enhanced expression of co-stimulatory signals and maturation markers (CD80, CD86, MHCII), which was significantly higher for smegmosomes as compared to leptosomes. Additionally, activation of APCs by liposomes correlated with their ability to stimulate allospecific T cell proliferation and IFN-gamma release. In contrast, conventional PC/chol liposomes failed to fuse and induced only a very low level of APC activation. Interestingly, the stimulatory activity of these lipid vesicles was restricted to APCs as they did not cause any significant activation or mitogenic effect on lymphocytes (B and T cells) in vitro. Overall, the activation of APCs by both leptosomes and smegmosomes correlated with activation of strong humoral and cell mediated immune responses in C57/BL6 mice to entrapped ovalbumin (OVA) and was significantly higher than those induced by conventional liposomes and alum, which failed to activate cytotoxic T lymphocytes (CTLs). Taken together these results demonstrate the adjuvant potential of these novel lipid vesicles that may simultaneously induce both innate and adaptive immune responses due to their immune stimulatory and antigen delivery properties. PMID- 21300104 TI - The epidemiology of Clostridium difficile in Scotland. AB - The objective of this study was to characterise the epidemiology of Clostridium difficile in Scotland by determining the distribution of PCR ribotypes and antimicrobial susceptibility in 1613 isolates collected from all healthboard areas of Scotland in the period November 2007-December 2009. Three PCR ribotypes predominated amongst the Scottish isolates of C. difficile; ribotype 106 (29.4%), ribotype 001 (22%) and ribotype 027 (12.6%) followed by the less prevalent ribotypes including 002, 015, 014, 078, 005, 023 and 020. The distribution of ribotypes varied between healthboard areas. Ribotype 106 or 001 was the predominant ribotype in 10 healthboard areas, while ribotype 027 was the predominant type in two neighbouring areas. Antimicrobial susceptibility testing of C. difficile isolates showed high frequencies of resistance to moxifloxacin, levofloxacin, erythromycin and cefotaxime in the epidemic C. difficile ribotypes 001, 027 and 106 compared to other less common ribotypes. Furthermore, reduced susceptibility to metronidazole was found only in the epidemic strains. These findings are compatible with the hypothesis that fluoroquinolones, macrolides and cephalosporins may play a role in the spread of C. difficile in Scotland (while the role of metronidazole needs further investigations), and highlights the role of antimicrobial stewardship in preventing and controlling C. difficile infection (CDI). PMID- 21300105 TI - Infective endocarditis mislabelled as "swine influenza". PMID- 21300106 TI - Progesterone induces a switch in oligosaccharyltransferase isoform expression: consequences on IgG N-glycosylation. AB - The presence of additional N-glycans in the Fab region of IgG has shown to dramatically modify the properties and functionality of these molecules including changes in antibody affinity and stability. However, the underlying molecular mechanism responsible for the presence or absence of these glycans remains unknown. Polypeptide N-linked glycosylation is catalyzed in the lumen of the endoplasmic reticulum by the oligosaccharyltransferase complex. Mammalian cells can express two isoforms of the oligosaccharyltransferase catalytic subunit (STT3 A and STT3-B), which are endowed with distinct enzymatic properties. In this work we employed a murine hybridoma cell culture to study whether the expression of STT3 isoforms could be modulated by progesterone, thus altering the pattern of IgG N-glycosylation. We found that progesterone induces a switch of STT3 isoform expression, increasing IgG N-glycosylation. These effects were dependent on the progesterone-induced blocking factor (PIBF), whose concentration was modulated by progesterone. PIBF was previously found to be an immunomodulatory molecule relevant for the maintenance of pregnancy. We concluded that the STT3-B/STT3-A ratio modulates the N-glycosylation level of IgG, in agreement with previous data showing that full N-glycosylation of polypeptides requires cooperation between both catalytic isoforms. This work provides the first evidence that STT3 isoforms can be hormonally modulated, with marked consequences on IgG N-glycosylation. PMID- 21300107 TI - Proteomic analysis of known and candidate rice allergens between non-transgenic and transgenic plants. AB - Salt-soluble proteins extracted from non-transgenic and transgenic rice were evaluated for the presence of known and potential allergens by proteomic techniques. The salt-soluble proteins were extracted, separated by 1D and 2D electrophoresis, and analyzed by Western blotting. 1D immunoblot analysis with patients' sera revealed few qualitative differences between the IgE-binding proteins of the non-transgenic and transgenic rice. 1D immunoblot with antigen specific-animal sera revealed no qualitative or quantitative differences in two known allergens, RAG2 and glyoxalase I, between non-transgenic and transgenic rice. Multiple spots containing known and novel IgE-binding proteins were detected among the salt-soluble proteins of non-transgenic rice by 2D immunoblotting. Two globulin-like proteins, a 52 kDa protein and a 63 kDa protein, were identified as novel IgE-binding proteins that are candidates for rice allergens. These globulin-like proteins were homologous to Cupin superfamily allergens. Quantitative analysis of 19, 52, and 63 kDa globulins with protein specific-animal sera showed no significant differences in the expression of these proteins between the transgenic rice and non-transgenic rice. These results indicate that none of the known or novel endogenous IgE-binding proteins detected in this study appear to be altered by genetic modification. PMID- 21300108 TI - Unsuitability of exhaled breath condensate for the detection of herpesviruses DNA in the respiratory tract. AB - Exhaled breath condensate is a non-invasive method for detecting a wide number of molecules as well as genomic DNA in the airways. No study investigated the detection of viral DNA in exhaled breath condensate, while only one study excluded its usefulness for detection of influenza virus RNA. In this study, the suitability of exhaled breath condensate for detecting herpesviruses infection or reactivation in the respiratory tract of lung transplant recipients was evaluated. Twenty-four matched samples (exhaled breath condensate, bronchoalveolar lavage, whole blood, transbronchial biopsy) were evaluated for the detection of human cytomegalovirus (HCMV), human herpesvirus (HHV-6 and -7), Epstein-Barr virus (EBV) DNA by real-time PCR. Eighteen bronchoalveolar lavages (75%), six whole blood samples (25%), and two transbronchial biopsies (8.3%) were positive for at least one herpesvirus. Only one exhaled breath condensate specimen was positive for HCMV DNA (and positive also in the bronchoalveolar lavage, with low viral load in both specimens); while no other patient, irrespective of the viral load in any specimen or the presence of clinical symptoms and signs, had a positive exhaled breath condensate. These findings seem to exclude the suitability of exhaled breath condensate for non-invasive detection of viral DNA in the respiratory tract of lung transplant recipients. PMID- 21300109 TI - Generation and immunogenicity of transgenic potato expressing the GP5 protein of porcine reproductive and respiratory syndrome virus. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is an important pathogen that has caused huge economic losses in the global swine industry. The advent of molecular farming has provided a cost-effective strategy for the development of transgenic plants as bioreactors to produce recombinant proteins. In this study, transgenic potato expressing GP5 protein of PRRSV was produced by Agrobacterium-mediated transformation, and confirmed using Southern blot and RT PCR analyses. Recombinant GP5 protein was detected by ELISA and Western blot analyses. Mice immunized with transgenic potato extracts generated both serum and gut mucosal-specific antibodies, although low levels of neutralizing antibodies were elicited. This study provides a new approach for the production of vaccines against PRRSV. PMID- 21300110 TI - Development of a high-throughput human rhinovirus infectivity cell-based assay for identifying antiviral compounds. AB - Asthma and chronic obstructive pulmonary disease exacerbations are associated with human rhinovirus (HRV) lung infections for which there are no current effective antiviral therapies. To date, HRV infectivity of cells in vitro has been measured by a variety of biochemical and immunological methods. This paper describes the development of a high-throughput HRV infectivity assay using HeLa OHIO cells and a chemiluminescent-based ATP cell viability system, CellTiter-Glo from Promega, to measure HRV-induced cytopathic effect (CPE). This CellTiter-Glo assay was validated with standard antiviral agents and employed to screen AstraZeneca compounds for potential antiviral activity. Compound potency values in this assay correlated well with the quantitative RT-PCR assay measuring HRV infectivity and replication in human primary airway epithelial cells. In order to improve pan-HRV screening capability, compound potency was also measured in the CellTiter-Glo assay with a combination of 3 different HRV serotypes. This HRV serotype combination assay could be used to identify quickly compounds with desirable broad spectrum antiviral activity. PMID- 21300111 TI - The lateral hypothalamus: a site for integration of nutrient and fluid balance. AB - This paper reviews seemingly obligatory relations between nutrient and fluid balance. A relatively novel neuronal pathway involving interplay between acetylcholine and the melanocortins, alphaMSH and AGRP in the arcuate nucleus (Arc) of the hypothalamus projecting to the lateral hypothalamus (LH) may bridge this gap. In the fasted condition, increased expression of MCH (due to muscarinic 3 receptor stimulation and low melanocortin tone) and neuronal release of MCH (via Orexin signaling) underlies a drive towards positive energy balance, increased B cell capacity to secrete insulin, and this is associated with optimal fluid homeostasis. A hypohydrated state is hypothesized to yield downregulation of leptin signaling (potentially via inhibitory effects of osmotic stress on mTOR), but osmotic stress may prevent MCH expression via the OVLT-SFO complex. If this occurs in an obese state, impaired pancreatic B cell capacity and peripheral insulin insensitivity as a result of hypohydration may underlie cardio-metabolic diseases. PMID- 21300112 TI - Age and amount of exposure to a foreign language during childhood: behavioral and ERP data on the semantic comprehension of spoken English by Japanese children. AB - Children's foreign-language (FL) learning is a matter of much social as well as scientific debate. Previous behavioral research indicates that starting language learning late in life can lead to problems in phonological processing. Inadequate phonological capacity may impede lexical learning and semantic processing (phonological bottleneck hypothesis). Using both behavioral and neuroimaging data, here we examine the effects of age of first exposure (AOFE) and total hours of exposure (HOE) to English, on 350 Japanese primary-school children's semantic processing of spoken English. Children's English proficiency scores and N400 event-related brain potentials (ERPs) were analyzed in multiple regression analyses. The results showed (1) that later, rather than earlier, AOFE led to higher English proficiency and larger N400 amplitudes, when HOE was controlled for; and (2) that longer HOE led to higher English proficiency and larger N400 amplitudes, whether AOFE was controlled for or not. These data highlight the important role of amount of exposure in FL learning, and cast doubt on the view that starting FL learning earlier always produces better results. PMID- 21300113 TI - Alexithymia and regional gray matter alterations in schizophrenia. AB - Alexithymia is characterized by deficits in emotional self-awareness. Although alexithymia refers to a deficit in recognizing one's own emotions, some studies have focused on the relation between alexithymia and impaired social cognition. An association between alexithymia and schizophrenia has been previously reported, but the brain structures involved remain unclear. The present study investigated associations between alexithymia and specific brain structures to determine whether these regions overlapped with key structures underlying social cognition. Twenty-one patients with schizophrenia and 24 age-, gender- and education level-matched healthy controls underwent structural magnetic resonance imaging. Alexithymia was assessed using the 20-item Toronto Alexithymia Scale (TAS-20). We applied voxel-based morphometry to investigate the correlation between TAS-20 scores and regional brain alterations. TAS-20 scores were significantly higher in patients than controls. Bilateral ventral striatum and left ventral premotor cortex volumes were negatively correlated with TAS-20 total scores in controls, while left supramarginal gyrus (SMG) volume was negatively correlated with TAS-20 total scores in patients. These results suggest that schizophrenia is associated with alexithymia, and that gray matter alterations of the left SMG constitute a key pathology underlying alexithymia in schizophrenia. This association may be related to deficits in self-other distinction, self disturbance, and language processing in schizophrenia. PMID- 21300114 TI - Effects of chronic systemic treatment with peroxisome proliferator-activated receptor alpha activators on neuroinflammation induced by intracerebral injection of lipopolysaccharide in adult mice. AB - We examined whether chronic systemic treatment with agonists for peroxisome proliferator-activated receptor alpha (PPARalpha) influences neuroinflammation induced by lipopolysaccharide (LPS) injection into the somatosensory cortex in adult mice. Mice were pretreated with Wy-14643 or fenofibrate, both at 30 mg/kg, for 7 days. These treatment protocols increased the amount of PPARalpha mRNA and active form of PPARalpha protein in the brain. LPS injection reduced the PPARalpha mRNA level in the brain. On the contrary, TNFalpha, IL-1beta, IL-6, iNOS, COX-2, ICAM-1, VCAM-1, and PECAM-1 were elevated at 6h after LPS. Wy-14643 and fenofibrate inhibited the elevations of TNFalpha, IL-1beta, IL-6, COX-2, ICAM 1, and VCAM-1. Wy-14643, but not fenofibrate, also attenuated the iNOS elevation. At 3 days after LPS, Wy-14643 and fenofibrate showed similar inhibitions in these molecules. LPS injection also elevated IL-6 protein levels in the brain and serum at 6h, which was inhibited by fenofibrate. Histological analyses showed that Wy 14643 and fenofibrate profoundly attenuated microglia/macrophage activation, neutrophil recruitment, and neuronal injury at 3 days after LPS. These findings suggest that activation of PPARalpha attenuates neuroinflammation in the adult mouse brain, implicating that PPARalpha may be a potential therapeutic target for CNS diseases in which neuroinflammation plays a substantial role. PMID- 21300115 TI - Advances in oral transmucosal drug delivery. AB - The successful delivery of drugs across the oral mucosa represents a continuing challenge, as well as a great opportunity. Oral transmucosal delivery, especially buccal and sublingual delivery, has progressed far beyond the use of traditional dosage forms with novel approaches emerging continuously. This review highlights the physiological challenges as well as the advances and opportunities for buccal/sublingual drug delivery. Particular attention is given to new approaches which can extend dosage form retention time or can be engineered to deliver complex molecules such as proteins and peptides. The review will also discuss the physiology and local environment of the oral cavity in vivo and how this relates to the performance of transmucosal delivery systems. PMID- 21300116 TI - Novel insights in the interplay between inflammation and metabolic diseases: a role for the pathogen sensing kinase PKR. PMID- 21300117 TI - Effect of treatment with polyunsaturated fatty acids on HCV- or diet-induced fatty liver. PMID- 21300118 TI - Will the pathomolecular classification of hepatocellular adenomas improve their clinical management? PMID- 21300119 TI - Effects on DHEA levels by estrogen in rat astrocytes and CNS co-cultures via the regulation of CYP7B1-mediated metabolism. AB - The neurosteroid dehydroepiandrosterone (DHEA) is formed locally in the CNS and has been implicated in several processes essential for CNS function, including control of neuronal survival. An important metabolic pathway for DHEA in the CNS involves the steroid hydroxylase CYP7B1. In previous studies, CYP7B1 was identified as a target for estrogen regulation in cells of kidney and liver. In the current study, we examined effects of estrogens on CYP7B1-mediated metabolism of DHEA in primary cultures of rat astrocytes and co-cultures of rat CNS cells. Astrocytes, which interact with neurons in several ways, are important for brain neurosteroidogenesis. We found that estradiol significantly suppressed CYP7B1 mediated DHEA hydroxylation in primary mixed CNS cultures from fetal and newborn rats. Also, CYP7B1-mediated DHEA hydroxylation and CYP7B1 mRNA were markedly suppressed by estrogen in primary cultures of rat astrocytes. Interestingly, diarylpropionitrile, a well-known agonist of estrogen receptor beta, also suppressed CYP7B1-mediated hydroxylation of DHEA. Several previous studies have reported neuroprotective effects of estrogens. The current data indicate that one of the mechanisms whereby estrogen can exert protective effects in the CNS may involve increase of the levels of DHEA by suppression of its metabolism. PMID- 21300120 TI - ACS84, a novel hydrogen sulfide-releasing compound, protects against amyloid beta induced cell cytotoxicity. AB - Hydrogen sulfide (H(2)S) is a novel neurotransmitter. We studied here the effect of ACS 84, a new H(2)S releasing compound, on the cytotoxicity induced by amyloid beta (Abeta) in microglia. Treatment with Abeta(1-40) (25MUmol/L) for 24h significantly inhibited MTT reduction and increased lactate dehydrogenase release in BV-2 microglia cells. Pretreatment with ACS 84 (10MUM) for 30min attenuated the above cytotoxicity caused by Abeta(1-40), suggesting that ACS 84 may protect microglia against Abeta(1-40)-induced cell injury. ACS 84 also significantly attenuated nitric oxide release and TNF-alpha production in BV-2 cells treated with Abeta peptides (Abeta(1-40) or Abeta(1-42)), but had no significant effect on the up-regulated protein expression of cyclooxygenase 2. These data suggest that ACS 84 may produce anti-inflammatory effect via inhibition of the release of inflammatory cytokines but not via suppression of the prostanoids production. Furthermore, pretreatment with ACS 84 also attenuated mitochondrial membrane potential loss (Deltapsi(m)) caused by Abeta(1-40) in both microglia and neurons. To examine the underlying signaling mechanism, we detected the phosphorylation of p38-, JNK- and ERK-MAPKs. It was found that Abeta(1-40) stimulated phosphorylation of all above three types of MAKPs. However, ACS 84 only attenuated the activation of p38 and JNK, but had no significant effect on that of ERK. Taken together, our data suggest that ACS 84 may protect Abeta-induced cell injury via anti-inflammation and preservation of mitochondrial function in a p38 and JNK dependent mechanism. Our work suggests that ACS 84 may have potential for the treatment of neurodegenerative diseases. PMID- 21300121 TI - Glutamate antagonism fails to reverse mitochondrial dysfunction in late phase of experimental neonatal asphyxia in rats. AB - Neonatal asphyxia is a primary contributor to neonatal mortality and neuro developmental disorders. It progresses in two distinct phases, as initial primary process and latter as the secondary process. A dynamic relationship exists between excitotoxicity and mitochondrial dysfunction during the progression of asphyxic injury. Study of status of glutamate and mitochondrial function in tandem during primary and secondary processes may give new leads to the treatment of asphyxia. Neonatal asphyxia was induced in rat pups on the day of birth by subjecting them to two episodes (10min each) of anoxia, 24h apart by passing 100% N(2) into an enclosed chamber. The NMDA antagonist ketamine (20mg/kg/day) was administered either for 1 day or 7 days after anoxic exposure. Tissue glutamate and nitric oxide were estimated in the cerebral cortex, extra-cortex and cerebellum. The mitochondria from the above brain regions were used for the estimation of malondialdehyde, and activities of superoxide dismutase and succinate dehydrogenase. Mitochondrial membrane potential was evaluated by using Rhodamine dye. Anoxia during the primary process increased glutamate and nitric oxide levels; however the mitochondrial function was unaltered in terms of succinate dehydrogenase and membrane potential. Acute ketamine treatment reversed the increase in both glutamate and nitric oxide levels and partially attenuated mitochondrial function in terms of succinate dehydrogenase activity. The elevated glutamate and nitric oxide levels were maintained during the secondary process but however with concomitant loss of mitochondrial function. Repeated ketamine administration reversed glutamate levels only in the cerebral cortex, where as nitric oxide was decreased in all the brain regions. However, repeated ketamine administration was unable to reverse anoxia-induced mitochondrial dysfunction. The failure of glutamate antagonism in the treatment of asphyxia may be due to persistence of mitochondrial dysfunction. Therefore, additionally targeting mitochondrial function may prove to be therapeutically beneficial in the treatment of asphyxia. PMID- 21300122 TI - Regenerative medicine in multiple sclerosis: identifying pharmacological targets of adult neural stem cell differentiation. AB - Progressive axonal loss from chronic demyelination in multiple sclerosis (MS) is the key contributor to clinical decline. Failure to regenerate myelin by adult oligodendrocyte precursor cells (OPCs), a widely distributed neural stem cell population in the adult brain, is one of the major causes of axonal degeneration. In order to develop successful therapies to protect the integrity of axons in MS, it is important to identify and understand the key molecular pathways involved in myelin regeneration (remyelination) by adult OPCs. This review highlights recent findings on the critical signaling pathways associated with OPC differentiation following CNS demyelination. We discuss the role of LINGO-1, Notch, Wnt, and retinoid X receptor (RXR) signaling, and how they might be useful pharmacological targets to overcoming remyelination failure in MS. PMID- 21300123 TI - Metabotropic glutamate receptor 5 modulates the nitric oxide-cGMP pathway in cerebellum in vivo through activation of AMPA receptors. AB - Metabotropic glutamate receptors (mGluRs) modulate important processes in cerebellum including long-term depression, which also requires formation of nitric oxide (NO) and cGMP. Some reports suggest that mGluRs could modulate the NO-cGMP pathway in cerebellum. However this modulation has not been studied in detail. The aim of this work was to assess by microdialysis in freely moving rats whether activation of mGluR5 modulates the NO-cGMP pathway in cerebellum in vivo and to analyze the underlying mechanisms. We show that mGluR5 activation increases extracellular glutamate, citrulline and cGMP in cerebellum. Blocking NMDA receptors with MK-801 does not prevent any of these effects, indicating that NMDA receptors activation is not required. However in the presence of MK-801 the effects are more transient, returning faster to basal levels. Blocking AMPA receptors prevents the increase in citrulline and cGMP induced by mGluR5 activation, but not the increase in glutamate. The release of glutamate is prevented by tetrodotoxin but not by fluoroacetate, indicating that glutamate is released from neurons and not from astrocytes. Activation of AMPA receptors increases citrulline and cGMP. These data indicate that activation of mGluR5 induces an increase of extracellular glutamate which activates AMPA receptors, leading to activation of nitric oxide synthase and increased NO, which activates guanylate cyclase, increasing cGMP. The response mediated by AMPA receptors desensitize rapidly. Activation of AMPA receptors also induces a mild depolarization, allowing activation of NMDA receptors which prolongs the duration of the effect initiated by activation of AMPA receptors. These data support that the three types of glutamate receptors: mGluR5, AMPA and NMDA cooperate in the modulation of the grade and duration of activation of the NO-cGMP pathway in cerebellum in vivo. This pathway would modulate cerebellar processes such as long term depression. PMID- 21300124 TI - Post-ischemic hypothermia promotes generation of neural cells and reduces apoptosis by Bcl-2 in the striatum of neonatal rat brain. AB - Hypothermia is a potential therapy for cerebral hypoxic ischemic injury in adults and neonates. However, the mechanism of hypothermia neuroprotection after hypoxic ischemia (HI) on the developing rat brain remains unclear. In this research, 7 day-old rats were subjected to left carotid artery ligation followed by 8% oxygen for 2h. They were divided into hypothermia (rectal temperature, 32-33 degrees C for 24h) and normothermia (36-37 degrees C for 24h) groups immediately after hypoxia-ischemia. All rats were given 50mg/kg/day 5-bromodeoxyuridine (BrdU) intraperitoneally at 4-6 days and sacrificed at 1 or 2 weeks after HI. There was a significant decrease in infarct volume in the hypothermia group at 7 days after HI compared with that in the normothermia group. The numbers of nestin-labeled cells did not change greatly, but beta-tubulin III (Tuj-1) immuno-positive cells increased significantly in the striatum at 1 and 2 weeks after HI in the hypothermia compared to normothermia group. Neurogenesis was assessed by double immunohistochemical/immunofluorescent labeling of BrdU with nestin, Tuj-1 or microtubule-associated protein 2 (Map-2). Newborn neural progenitors (BrdU(+) nestin(+)) did not change dramatically, but newborn immature (BrdU(+)-Tuj-1(+)) and mature (BrdU(+)-Map-2(+)) neurons increased significantly in the hypothermia compared with normothermia group. Meanwhile, the apoptosis rate of neural precursors, immature and mature neurons, assessed by double labeling of active Casp-3 with nestin/Tuj-1/Map-2, decreased noticeably in the hypothermia compared with normothermia group. We also found that hypothermia significantly increased expression of Bcl-2, which coexisted with nestin/Tuj-1/Map-2. Inhibition of Bcl-2 expression reversed the decreased apoptosis rate of neural precursors and neurons in hypothermia animal striatum of neonatal rat brain. These results suggest that neuroprotection effects of hypothermia on injured developing rat brain may associate with enhanced generation of neuronal cells and Bcl-2-mediated reduction of apoptosis of these cells. These observations are noteworthy regarding clinical hypothermia therapy following cerebral HI injury during the perinatal period. PMID- 21300125 TI - Impact of early developmental arsenic exposure on promotor CpG-island methylation of genes involved in neuronal plasticity. AB - Epigenetic mechanisms are crucial to regulate the expression of different genes required for neuronal plasticity. Neurotoxic substances such as arsenic, which induces cognitive deficits in exposed children before any other manifestation of toxicity, could interfere with the epigenetic modulation of neuronal gene expression required for learning and memory. This study assessed in Wistar rats the effects that developmental arsenic exposure had on DNA methylation patterns in hippocampus and frontal cortex. Animals were exposed to arsenic in drinking water (3 and 36ppm) from gestation until 4 months of age, and DNA methylation in brain cells was determined by flow cytometry, immunohistochemistry and methylation-specific polymerase chain reaction (PCR) of the promoter regions of reelin (RELN) and protein phosphatase 1 (PP1) at 1, 2, 3 and 4 months of age. Immunoreactivity to 5 methyl-cytosine was significantly higher in the cortex and hippocampus of exposed animals compared to controls at 1 month, and DNA hypomethylation was observed the following months in the cortex at high arsenic exposure. Furthermore, we observed a significant increase in the non-methylated form of PP1 gene promoter at 2 and 3 months of age, either in cortex or hippocampus. In order to determine whether this exposure level is associated with memory deficits, a behavioral test was performed at the same age points, revealing progressive and dose-dependent deficits of fear memory. Our results demonstrate alterations of the methylation pattern of genes involved in neuronal plasticity in an animal model of memory deficit associated with arsenic exposure. PMID- 21300126 TI - Integration of efficacy, pharmacokinetic and safety assessment of interleukin-1 receptor antagonist in a preclinical model of arthritis. AB - Pharmacokinetic properties and safety profile of a drug are likely influenced by the disease state of a patient. In this study, we investigated the influence of arthritic processes on pharmacokinetics and immunotoxicity of interleukin-1 receptor antagonist (Anakinra) in the rat adjuvant arthritis model. Anakinra dose dependently suppressed joint inflammation and degradation as demonstrated by reduced clinical arthritis score, paw thickness, synovial infiltration and bone degradation. In addition, plasma levels of chemokines MCP-1 and GRO/KC were reduced. Pharmacokinetic behaviour of Anakinra was influenced by disease state of the rats as judged from a decrease in C(max) and an increase of the MRT as the disease progressed at a dose of 24 and 72 mg Anakinra/kg body weight. The pharmacokinetic parameters increased dose-dependently, but non-proportionally with increasing dose. Low level anti-Anakinra antibody formation was observed at prolonged exposure to the biologic. Safety parameters, including haematology, splenic lymphocyte subset analysis, ex vivo stimulation of spleen cells and histopathology of immune system organs were affected by the disease itself to such extent that no additional effects of Anakinra could be observed. In conclusion, we demonstrated that pharmacokinetic behaviour of Anakinra was influenced by the arthritis background of the rats resulting in decreased internal exposure. PMID- 21300127 TI - Reading marmoset behavior 'semantics' under particular social context by multi parameters correlation analysis. AB - Social interactions are a fundamental aspect of human and animal behavior. Although neuroimaging and other non-invasive methods have progressed recently, the neurobiology of social behavior requires the use of animal models. Here, we introduced a multi-behavior parameter integration method and applied it to female male interaction of adult common marmosets (Callithrix jacchus). Based on the correlated parameters and meeting context, we found that the behavioral endpoints clustered in four distinct categories, which could be interpreted as active, freeze, alert, and affinity emotional states. The relevance of this interpretation was supported as the female behavior category change positively correlated with serum cortisol and progesterone levels after social interaction. Thus, our multi-behavior parameter integration method may be useful to evaluate social emotionality in animal models, as well as to quantify social behavior in human psychiatric disorders. PMID- 21300128 TI - COMT Val158Met variant and functional haplotypes associated with childhood ADHD history in women with bulimia nervosa. AB - Up to one third of patients with bulimia nervosa (BN) report a history of ADHD symptoms, and both disorders may also be associated with dopaminergic abnormalities. COMT gene, coding for an enzyme responsible for the degradation of dopamine, may play a part in the etiology of ADHD and BN. This study aimed to (1) examine if certain variants of the COMT genetic markers (rs6269, rs4633, rs4818 and rs4680) are more common in BN versus controls; (2) assess transmission of COMT alleles in BN families; and (3) explore the role of COMT genotypes and haplotypes in bulimic women with childhood ADHD history. 72 BN probands and unaffected relatives were genotyped for COMT rs4680 (Val158Met) and three adjacent markers. The remaining 165 probands were matched with nonpsychiatric controls. We also investigated if COMT variants and haplotypes were associated with childhood ADHD history in a subgroup of 86 BN probands who completed the Wender Utah Rating Scale (WURS). Our results showed that cases and controls did not differ in COMT allele and haplotype frequencies. In contrast, specific alleles of all four COMT markers and the medium-activity haplotype were preferentially transmitted to the offspring with BN. COMT Val158 allele was overrepresented and the medium-activity haplotype was underrepresented in BN with childhood ADHD history (p=0.010). These findings suggest a possible role for COMT variants and related haplotypes in BN and its subphenotypes. If replicated, these preliminary findings may have implications for the prevention and treatment of BN that emerges in the context of childhood ADHD. PMID- 21300129 TI - Adhesio interthalamica alterations in schizophrenia spectrum disorders: A systematic review and meta-analysis. AB - Magnetic resonance imaging (MRI) studies have reported a variety of brain abnormalities in association with schizophrenia. These include a higher prevalence of an absent adhesio interthalamica (AI; also known massa intermedia), a gray matter junction that is present between the two thalami in approximately 80% of healthy subjects. In this meta-analytic review, we describe and discuss the main AI MRI findings in schizophrenia spectrum disorders (SSDs) to date. The MEDLINE and ISI Web of Knowledge databases were searched up to December 2010, for studies that used MRI to assess AI in patients with SSD and controls. From fourteen potential reports, eleven were eligible to be part of the current review. These studies included 822 patients with SSD and 718 healthy volunteers. There was a large degree of variability in the MRI methods they employed. Patients with SSD had a higher prevalence of absent AI than healthy volunteers (odds ratio = 1.98; 95% confidence interval 1.33-2.94; p = 0.0008). This association was evident in both male and female SSD subjects, and there was no evidence that the prevalence was related to age or duration of illness. The significance of the absence of an AI for SSD may be clarified by studies in large, longitudinal community-based samples using standardized methods. PMID- 21300130 TI - Non-destructive 3D imaging of composite restorations using optical coherence tomography: marginal adaptation of self-etch adhesives. AB - OBJECTIVES: To investigate the potential use of swept-source optical coherence tomography (SS-OCT) as a new tool to evaluate marginal adaptation of composite restorations in class I cavities. METHODS: Round-shaped class I cavities (3mm diameter * 1.5mm depth) were prepared on buccal enamel of bovine teeth with cavity floor located in dentine. The cavities were restored with a flowable resin composite (Clearfil Majesty LV) using two-step self-etch adhesive (SE Bond), all in-one self-etch adhesive (G-Bond) or no adhesive (Control). The specimens were subjected to water storage (37 degrees C, 24 h) or thermal stress challenge (5000 cycles, 5 degrees C and 55 degrees C). 3D scans (4 mm*4 mm*2.6 mm obtained in 4 s) of the restoration were obtained using SS-OCT before and after immersion into a contrast agent. 2D images obtained from the 3D scans (n=30/group) were analysed to evaluate marginal adaptation. Area fraction of pixels with high brightness values at the interfacial zone was calculated using a digital image analysis software. The results were statistically compared with statistical significance defined as p<=0.05. RESULTS: Wilcoxon signed ranks test showed that there was no statistically significant difference in the results of SS-OCT before and after infiltration of the contrast agent when a ranking transformation was applied on to the data (p>0.05). A significant positive linear correlation was found between the two SS-OCT images. Confocal laser scanning photomicrographs of samples cut after silver infiltration confirmed the presence of gap. CONCLUSIONS: 3D imaging by SS-OCT can be considered as a non-invasive technique for fast detection of gaps at the restoration interface. PMID- 21300131 TI - Fractals in dentistry. AB - OBJECTIVES: To systematically review applications of fractal geometry in different aspects of dental practice. In this review, we present a short introduction to fractals and specifically address the following topics: treatment and healing monitoring, dental materials, dental tissue, caries, osteoporosis, periodontitis, cancer, Sjogren's syndrome, diagnosis of several other conditions and a discussion on the reliability of FD determinations from dental radiographs. SOURCES: Google Scholar, Ovid MEDLINE, ScienceDirect, etc. (up to August 2010). STUDY SELECTION: The review considered original studies, reviews and conference proceedings, published in English or Spanish. Abstracts and posters were not taken into account. CONCLUSIONS: Fractal geometry has found plenty of applications in several branches of dental practice. It provides a way to quantify the complexity of structures. Whereas one desires to study a radiograph, an histological section or the signal from a transducer, there are several methods available to determine the degree of complexity using fractal analysis. Several pathological conditions can alter the complexity of anatomical structures, and this change can be detectable with the help of fractal parameters. Although during the last two decades there have been plenty of works on the field, reported cases having enough reproducibility, with different groups showing similar results are not very common. Further replications are needed before we can establish statistically significant correlations amongst fractal parameters and pathological conditions. PMID- 21300132 TI - Proteomic characterization of Jurkat T leukemic cells after dopamine stimulation: A model of circulating dopamine-sensitive cells. AB - T-cells are circulating dopamine-sensitive cells and may mirror, at the peripheral level, biochemical modifications occurring in dopaminergic neurons. The human CD4+ T leukemic Jurkat cell line has been thoroughly used and characterized as a suitable cell model to investigate T-cell signaling and apoptosis. Here, we describe their characterization as a model of circulating dopamine-sensitive cells and their response to a dopamine challenge by analyzing changes in the cell proteome. Jurkat cells express both D1- and D2-like dopamine receptors and both membrane and vesicular transporters, while they lack D4 receptor and tyrosine hydroxylase expression. A saturating, non-toxic, non oxidant 50 MUM dopamine challenge induces the upregulation of an interacting chaperone network known to protect specifically dopaminergic neurons, thus validating T-cells as a biomarker discovery source in Parkinson's disease. Remodeling of the distribution pattern of beta-actin and 14-3-3 isoforms is consistently observed upon dopamine treatment. As a whole, dopamine-specific alterations here observed might represent a biosensor for dopamine response at the peripheral level. PMID- 21300133 TI - Cell cycle arrest evidence, parasiticidal and bactericidal properties induced by L-amino acid oxidase from Bothrops atrox snake venom. AB - The present article describes an l-amino acid oxidase from Bothrops atrox snake venom as with antiprotozoal activities in Trypanosoma cruzi and in different species of Leishmania (Leishmania braziliensis, Leishmania donovani and Leishmania major). Leishmanicidal effects were inhibited by catalase, suggesting that they are mediated by H(2)O(2) production. Leishmania spp. cause a spectrum of diseases, ranging from self-healing ulcers to disseminated and often fatal infections, depending on the species involved and the host's immune response. BatroxLAAO also displays bactericidal activity against both Gram-positive and Gram-negative bacteria. The apoptosis induced by BatroxLAAO on HL-60 cell lines and PBMC cells was determined by morphological cell evaluation using a mix of fluorescent dyes. As revealed by flow cytometry analysis, suppression of cell proliferation with BatroxLAAO was accompanied by the significant accumulation of cells in the G0/G1 phase boundary in HL-60 cells. BatroxLAAO at 25 MUg/mL and 50 MUg/mL blocked G0-G1 transition, resulting in G0/G1 phase cell cycle arrest, thereby delaying the progression of cells through S and G2/M phase in HL-60 cells. This was shown by an accentuated decrease in the proportion of cells in S phase, and the almost absence of G2/M phase cell population. BatroxLAAO is an interesting enzyme that provides a better understanding of the ophidian envenomation mechanism, and has biotechnological potential as a model for therapeutic agents. PMID- 21300134 TI - Upregulation of mdr1 gene is related to activation of the MAPK/ERK signal transduction pathway and YB-1 nuclear translocation in B-cell lymphoma. AB - OBJECTIVE: Multidrug resistance (MDR) in human B-cell lymphoma constitutes a major obstacle to the effectiveness of chemotherapy. The aim of this study was to investigate the molecular mechanism of MDR in B-cell lymphoma. MATERIALS AND METHODS: The B-cell lymphoma MDR sublines were developed by exposing the parental Daudi cells to stepwise increasing concentrations of doxorubicin. Interaction of Y-box binding protein-1 (YB-1) with the Y-box motif of the mdr1 gene promoters was studied by electrophoretic mobility shift assay. The effects of YB-1 on mdr1 promoter activity were examined by luciferase assay. After silencing of YB-1 gene by shRNA, the role of YB-1 nuclear translocation in the formation of induced MDR was examined. Expression of mdr1 and YB-1 was examined further after Daudi cells were pretreated with mitogen-activated protein kinase (MAPK) inhibitor PD98059 for 1 hour. RESULTS: Doxorubicin-resistant sublines was generated from the Daudi cell line by stepwise selection in doxorubicin. We found that acquisition of MDR is associated with enhanced YB-1 nuclear translocation and MAPK/extracellular signal-regulated kinase (ERK) activity. Electrophoretic mobility shift assay revealed that doxorubicin increased binding of YB-1 to the Y-box of mdr1 promoter. Luciferase reporter assays demonstrated that the Y-box region is essential for YB-1 regulation of mdr1 expression. The introduction of exogenous YB-1 shRNA into Daudi cells resulted in decreased levels of the expression of mdr1 gene and P-glycoprotein induced by doxorubicin. When Daudi cells were pretreated with MAPK inhibitor PD98059, the phosphorylation of ERK was effectively inhibited as well as the nuclear translocation of YB-1 and the expression of mdr1 gene. CONCLUSION: Doxorubicin can increase expression of mdr1/P-glycoprotein through activating MAPK/ERK transduction pathway, then increasing expression of YB-1, inducing YB-1 nuclear translocation, and enhancing DNA-binding activity of YB-1. PMID- 21300135 TI - Lipopolysaccharide stimulates adrenal steroidogenesis in rodent cells by a NFkappaB-dependent mechanism involving COX-2 activation. AB - Stimulation of adrenal steroidogenesis is involved in the HPA response to exogenous noxa. Although inflammatory cytokines can mediate the LPS-triggered activation of the HPA, direct effects of LPS on glucocorticoid release have been described. Present studies were undertaken to characterize the molecular mechanisms underlying the effect of LPS on steroid secretion in isolated rodent adrenal cells, assessing the participation of NFkappaB and COX-2 activities in this response. Our results show that LPS treatment stimulates steroidogenesis in murine and rat adrenocortical cells, and that Y1 cells express the binding transducing complex TLR-4/CD14/MD-2, as demonstrated by RT-PCR. NFkappaB activity and COX-2 protein levels are increased in this cell line by LPS treatment, and pharmacologic and molecular manipulation of the NFkappaB pathway significantly affected both COX-2 protein levels and steroid production. Finally, pharmacological inhibition of COX-2 activity significantly impairs steroid production. Thus, our results strongly suggest that the mechanism involved in the stimulation of steroidogenesis by LPS in rodent adrenal cells involves the activation of the NFkappaB signaling pathway and the induction of COX-2. PMID- 21300137 TI - P2 receptor stimulation induces amyloid precursor protein production and secretion in rat cortical astrocytes. AB - Amyloid precursor protein (APP) is ubiquitously expressed in a variety of tissues but is predominantly expressed in the brain. The expression of APP has been well studied in neurons but little is known about its presence in astrocytes. The study presented here shows that purinergic signaling is involved in the production and secretion of APP in primary cultures of rat cortical astrocytes. Extracellular ATP caused an increase in APP production and release in a time- and concentration-dependent manner and was inhibited by antagonists of P2 receptors. Further agonist and antagonist studies revealed involvement of P2Y2 and P2Y4 receptors in nucleotide-stimulated production and release of APP. In addition, signaling studies with various protein kinase inhibitors demonstrated that blockade of mitogen-activated protein kinases, but not Akt, inhibited nucleotide stimulated APP expression and release. These results indicate that APP production and secretion can be regulated by activation of P2Y2/4 receptors coupled to protein kinase signaling pathways and suggest that astrocytes can be a potential source of APP. PMID- 21300136 TI - Apocynin administration does not improve behavioral and neuropathological deficits in a transgenic mouse model of Alzheimer's disease. AB - In addition to mitochondria, NADPH oxidase (NOX) is a source of oxidative stress, which can induce oxidative damage in Alzheimer's disease (AD). For this reason, several groups have investigated the effect of its inhibition. In AD mice, NADPH oxidase 2 (NOX2) deficiency improved behavior and cerebrovascular function, and reduced oxidative stress. In our study, we administered the NOX inhibitor apocynin to Tg19959 mice, and found that it did not improve cognitive and synaptic deficits, and did not decrease amyloid deposition, microgliosis and hyperphosphorylated tau. However, apocynin reduced carbonyl levels in the cerebral cortex but not the hippocampus, which may have not been sufficient to ameliorate symptoms. Also, the reduction of NOX-mediated oxidative stress may not be sufficient to prevent AD, since other sources of reactive oxygen species such as mitochondria may be more important. PMID- 21300138 TI - Event-related potential effects of superior action anticipation in professional badminton players. AB - The ability to predict the trajectory of a ball based on the opponent's body kinematics has been shown to be critical to high-performing athletes in many sports. However, little is known about the neural correlates underlying such superior ability in action anticipation. The present event-related potential study compared brain responses from professional badminton players and non-player controls when they watched video clips of badminton games and predicted a ball's landing position. Replicating literature findings, the players made significantly more accurate judgments than the controls and showed better action anticipation. Correspondingly, they showed enlarged amplitudes of two ERP components, a P300 peaking around 350ms post-stimulus with a parietal scalp distribution and a P2 peaking around 250ms with a posterior-occipital distribution. The P300 effect was interpreted to reflect primed access and/or directing of attention to game related memory representations in the players facilitating their online judgment of related actions. The P2 effect was suggested to reflect some generic learning effects. The results identify clear neural responses that differentiate between different levels of action anticipation associated with sports expertise. PMID- 21300139 TI - mGluRs modulate neuronal firing in the auditory midbrain. AB - The mechanisms underlying sound-evoked suppression of neuronal firing in the auditory system are poorly understood. To explore these mechanisms in the inferior colliculus (IC), agonists and antagonists targeting different groups of metabotropic glutamate receptors (mGluRs) were applied iontophoretically to IC neurons in awake mice. We found that a group I-specific mGluR agonist predominantly increased neuronal firing in 52% of neurons, whereas group I antagonist had the opposite effect in 51% of neurons. A group II specific agonist showed no effect on neuronal firing but an antagonist increased firing rate in 48% of neurons. Neither a group III-specific mGluR agonist nor an antagonist had an effect on neuronal firing in the IC. We also found that sound stimuli triggered suppression of spontaneous firing in 70% of IC neurons. This suppression was reversibly blocked by group I mGluR antagonists. There is a possible link between this suppression and two perceptual phenomena: forward masking and "residual inhibition," the brief reduction/elimination of tinnitus following an appropriate masking sound. PMID- 21300140 TI - Early c-Jun N-terminal kinase-dependent phosphorylation of activating transcription factor-2 is associated with degeneration of retinal ganglion cells. AB - Neuron death due to deprivation of target-derived neurotrophic factors depends on protein synthesis regulated by transcription factor activity. We investigated the content and phosphorylation of activating transcription factor 2 (ATF-2) in axon damaged retinal ganglion cells of neonatal rats. In the retina of neonatal rats, the ATF-2 protein is predominantly located in the nucleus of the ganglion cells. A gradual loss of the immunoreactivity for ATF-2 occurred after explantation. ATF 2 is phosphorylated early after explantation, with a peak within 3 hours, preceding the peak of cell death that occurs at 18 hours. Both the phosphorylation of ATF-2 and ganglion cell death were blocked by treatment with an inhibitor of c-Jun N-terminal kinase (JNK), whereas an inhibitor of p38 reduced only slightly the rate of ganglion cell death with no effect upon phosphorylation of ATF-2. Inhibitors of phosphatidyl inositol 3 kinase (PI-3K), protein kinase C (PKC) or extracellular regulated kinase (ERK) had no effect. Finally, the inhibitor of JNK blocked the upregulation of both c-Jun and Hrk in the GCL after retinal explantation. The data show that phosphorylation of ATF-2 by JNK is associated with retinal ganglion cell death after axon damage. PMID- 21300141 TI - Cellular mechanisms underlying Hyperin-induced relaxation of rat basilar artery. AB - BACKGROUND AND AIM: Hyperin, a flavonol compound extracted from the Chinese herb Abelmoschus manihot L. Medic, is reported to exert protective actions in cerebral ischemic injury. The specific aim of the present study was to study the relaxation of Hyperin in rat isolated basilar artery and identify the underlying cellular mechanisms. METHODS: Rat isolated basilar artery segments were cannulated and perfused while being superfused with PSS solution. Vessel images were recorded by video microscopy and diameters measured. Membrane potential was recorded using glass microelectrodes to evaluate the basilar artery smooth muscle cell hyperpolarization. RESULTS: Perfusion of Hyperin (1~100 MUM) elicited a concentration-dependent relaxation of basilar artery segments preconstricted with 0.1 MUM U46619. The response was significantly inhibited by the removal of the endothelium. Hyperin also elicited marked and concentration-dependent hyperpolarization of smooth muscle cells. 30 MUM nitro-L-arginine (an inhibitor of nitric oxide synthase) and indomethacin (an inhibitor of cyclooxygenase), partially inhibited Hyperin-induced relaxation and hyperpolarization leaving an attenuated, but significant, endothelium-dependent relaxation and hyperpolarization. This remaining effect was almost completely blocked by 1mM tetraethylammonium (an inhibitor of Ca(2+)-activated K(+) channels), or by 100 MUM DL-propargylglycine, an inhibitor of cystathionine-gamma-lyase (a synthase of the endogenous H(2)S). CONCLUSION: These findings show that Hyperin produces significant hyperpolarization in rat basilar artery smooth muscle cells and relaxation through both endothelium-dependent and endothelium-independent mechanisms. The underlying mechanisms appeared to be multi-factorial involving nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF). Our data further suggest that endogenous H(2)S is a component of the EDHF mediated hyperpolarization and relaxation to Hyperin. PMID- 21300142 TI - Low occupational exposure to benzene in a petrochemical plant: modulating effect of genetic polymorphisms and smoking habit on the urinary t,t-MA/SPMA ratio. AB - The identification of reliable biomarkers is critical for the assessment of occupational exposure of benzene: S-phenylmercapturic acid (SPMA) and trans,trans muconic acid (t,t-MA) are the most currently used. t,t-MA is an open-ring metabolite, but it is also a metabolite of the food preservative sorbic acid, while SPMA is formed by conjugation with glutathione, and several studies suggested that the genetic polymorphism of glutathione S-transferases modulates its production. This study compared the ability of these metabolites to assess the benzene exposure in a big group of petrochemical workers. Furthermore, investigated how genetic polymorphism of glutathione S-transferase theta 1 (GSTT1), glutathione S-transferase mu 1 (GSTM1), glutathione S-transferase pi 1 (GSTP1) and smoking habits, may influence their excretion. Results showed that occupational exposure to benzene was negligible compared to that from smoking and confirmed the modulating effect of the genetic polymorphism of GSTT1 on the urinary excretion of SPMA, but not of t, t-MA, even at very low levels of benzene exposure. The same effect was found for GSTM1, but only for smokers. The t,t MA/SPMA ratio was not a constant value and resulted to be higher than the corresponding Biological Exposure Index (BEI) ratio, which is currently equal to 20. Higher values of metabolite have been associated with the GSTT1 or GSTM1 null genotype and these are responsible for increase health risk. We suggest that this ratio could be used as a marker of individual susceptibility for subjects with benzene exposure. PMID- 21300143 TI - DJ-1 mediates paraquat-induced dopaminergic neuronal cell death. AB - There are two causes of Parkinson's disease (PD): environmental insults and genetic mutations of PD-associated genes. Environmental insults and genetic mutations lead to mitochondrial dysfunction, and a combination of mitochondrial dysfunction and increased oxidative stress in dopaminergic neurons is thought to contribute to the pathogenesis of PD. Among the PD-associated genes, DJ-1 acts as a redox sensor for oxidative stress and has been also proposed to maintain mitochondrial complex I activity. To understand molecular functions of DJ-1 in the cell, we have generated DJ-1 null cells from the DJ-1(-/-) mouse embryos. Using these null cells, we investigated the susceptibility to an environmental toxin, paraquat, which is known to inhibit mitochondrial complex I. Interestingly, we found that DJ-1 null cells showed a resistance to paraquat induced apoptosis, including reduced poly (ADP-ribose) polymerase and procaspase 3. Also DJ-1 null cells generated less superoxide than SN4741 cells by paraquat treatment. Consistent with the reduced paraquat sensitivity, DJ-1 null cells showed reduced complex I activity, which was partially rescued by ectopic DJ-I expression. In summary, our results suggest that DJ-1 is critical to maintain mitochondrial complex I and complex I could be a key target in interaction of paraquat toxicity and DJ-1 for giving rise to PD. PMID- 21300144 TI - Induction of the bystander effect in Chinese hamster V79 cells by actinomycin D. AB - Bystander effect (BE) can be induced by ionizing radiation and chemicals, including alkylating agents. Ionizing radiation mostly induces the bystander effect by causing double-strand DNA breakage in the exposed cells. However, the chemical-induced bystander effect is poorly studied. Here we chose actinomycin D (ACTD), a genotoxic chemotherapeutic drug, to investigate whether it could cause bystander effect in Chinese hamster V79 cells. Results are that (1) ACTD induced apoptosis in V79 cells and an optimal apoptosis model in V79 cells was established with ACTD (4 mg/L, 1h); (2) using apoptosis rate, chromosome aberration, and ultrastructure changes as endpoints of bystander effect, ACTD could induce bystander effect in V79 cells; (3) as in the exposed cells, ACTD mainly induced apoptosis in bystander V79 cells cultured in different period conditioned medium; (4) the strongest bystander effect was induced by 4 h conditioned medium collected from cells treated with ACTD. It suggests that ACTD could cause BE through the medium soluble factors excreted from exposed cells during apoptosis and ACTD-induced BE was a novel quantitative and kinetic response. PMID- 21300145 TI - Aristolochic acid I induced oxidative DNA damage associated with glutathione depletion and ERK1/2 activation in human cells. AB - Aristolochic acid I (AAI) has been widely found in herbal remedies and linked to the development of nephropathy and urothelial carcinoma in humans. This study elucidated the mechanism of oxidative stress and DNA damage mediated by AAI in human cells. Treatment of human promyelocytic leukemia cells (HL-60) and human renal proximal tubular cells (HK-2) with AAI led to a dose-dependent increase of reactive oxygen species (ROS). AAI also elevated the levels of DNA strand breaks and 8-hydroxy guanosine in HL-60 and HK-2 cells. Antioxidants, including Tiron, N acetyl-l-cysteine (NAC) and glutathione (GSH), effectively suppressed the AAI induced ROS and AAI-elicited genotoxicity, indicating that AAI induced the DNA damage through oxidative stress. GSH depletion was also found in AAI-treated cultures and proceeded prior to ROS formation. Exposure of HL-60 cells with AAI activated both ERK1/2 and p38 kinase phosphorylation, while only MEK1/2 inhibitor, U0126, significantly decreased AAI-mediated ROS. Preincubation of cells with thiol-containing compounds (NAC and GSH) inhibited the caspase 3 activity triggered by AAI, but non-thiol Tiron did not show a similar effect. This study demonstrated that AAI treatment results in oxidative stress-related DNA damage through GSH depletion and ERK1/2 activation; AAI-induced apoptosis is associated with GSH loss, but is independent of ROS generation. PMID- 21300146 TI - Immediate and prolonged effects of alcohol exposure on the activity of the hypothalamic-pituitary-adrenal axis in adult and adolescent rats. AB - Alcohol stimulates the hypothalamic-pituitary-adrenal (HPA) axis. Part of this influence is likely exerted directly at the level of the corticotropin-releasing factor (CRF) gene, but intermediates may also play a role. Here we review the effect of alcohol on this axis, provide new data on the effects of binge drinking during adolescence, and argue for a role of catecholaminergic circuits. Indeed, acute injection of this drug activates brain stem adrenergic and noradrenergic circuits, and their lesion, or blockade of alpha1 adrenergic receptors significantly blunts alcohol-induced ACTH release. As alcohol can influence the HPA axis even once discontinued, and alcohol consumption in young people is associated with increased adult drug abuse (a phenomenon possibly mediated by the HPA axis), we determined whether alcohol consumption during adolescence modified this axis. The number of CRF-immunoreactive (ir) cells/section was significantly decreased in the central nucleus of the amygdala of adolescent self-administering binge-drinking animals, compared to controls. When another group of adolescent binge-drinking rats was administered alcohol in adulthood, the number of colocalized c-fos-ir and PNMT-ir cells/brain stem section in the C3 area was significantly decreased, compared to controls. As the HPA axis response to alcohol is blunted in adult rats exposed to alcohol vapors during adolescence, a phenomenon which was not observed in our model of self-administration, it is possible that the blood alcohol levels achieved in various models play a role in the long-term consequences of exposure to alcohol early in life. Collectively, these results suggest an important role of brain catecholamines in modulating the short- and long-term consequences of alcohol administration. PMID- 21300147 TI - Identification and characterization of a copper-binding site in alphaA crystallin. AB - Previous studies have shown that both alphaA- and alphaB-crystallins bind Cu2+, suppress the formation of Cu2+-mediated active oxygen species, and protect ascorbic acid from oxidation by Cu2+. alphaA- and alphaB-crystallins are small heat shock proteins with molecular chaperone activity. In this study we show that the mini-alphaA-crystallin, a peptide consisting of residues 71-88 of alphaA crystallin, prevents copper-induced oxidation of ascorbic acid. Evaluation of binding of copper to mini-alphaA-crystallin showed that each molecule of mini alphaA-crystallin binds one copper molecule. Isothermal titration calorimetry and nanospray mass spectrometry revealed dissociation constants of 10.72 and 9.9 MUM, respectively. 1,1'-Bis(4-anilino)naphthalene-5,5'-disulfonic acid interaction with mini-alphaA-crystallin was reduced after binding of Cu2+, suggesting that the same amino acids interact with these two ligands. Circular dichroism spectrometry showed that copper binding to mini-alphaA-crystallin peptide affects its secondary structure. Substitution of the His residue in mini-alphaA crystallin with Ala abolished the redox-suppression activity of the peptide. During the Cu2+-induced ascorbic acid oxidation assay, a deletion mutant, alphaADelta70-77, showed about 75% loss of ascorbic acid protection compared to the wild-type alphaA-crystallin. This difference indicates that the 70-77 region is the primary Cu2+-binding site(s) in human native full-size alphaA-crystallin. The role of the chaperone site in Cu2+ binding in native alphaA-crystallin was confirmed by the significant loss of chaperone activity by the peptide after Cu2+ binding. PMID- 21300149 TI - The LAR protein tyrosine phosphatase enables PDGF beta-receptor activation through attenuation of the c-Abl kinase activity. AB - The receptor tyrosine phosphatase (RPTP) LAR negatively regulates the activity of several receptor tyrosine kinases. To investigate if LAR affects the platelet derived growth factor (PDGF) receptor signaling, mouse embryonic fibroblasts (MEFs) from mice where the LAR phosphatase domains were deleted (LARDeltaP), and wt littermates, were stimulated with 20ng/ml PDGF-BB. In LAR phosphatase deficient MEFs, the phosphorylation of the PDGF beta-receptor was surprisingly reduced, an event that was rescued by re-expression of wt LAR. The decreased phosphorylation of the PDGF beta-receptor was observed independent of ligand concentration and occurred on all tyrosine residues, as determined by immunoblotting analysis using site-selective phosphotyrosine antibodies. This suggests that LAR is required for full PDGF beta-receptor kinase activation. Downstream of receptor activation, phosphorylation of Akt and PLCgamma were decreased in LARDeltaP MEFs, whereas Src and Erk MAP kinase pathways were less affected. The proliferation of LARDeltaP MEFs in response to PDGF-BB was also reduced. The inhibitory effect on the PDGF beta-receptor in LARDeltaP cells was exerted via increased basal activity of c-Abl, since inhibition of c-Abl, by AG957 or siRNA, restored PDGF beta-receptor phosphorylation. These observations suggest that LAR reduces the basal c-Abl activity thereby allowing for PDGF beta receptor kinase activation. PMID- 21300148 TI - PARP inhibition alleviates diabetes-induced systemic oxidative stress and neural tissue 4-hydroxynonenal adduct accumulation: correlation with peripheral nerve function. AB - This study evaluated the role of poly(ADP-ribose) polymerase (PARP) in systemic oxidative stress and 4-hydoxynonenal adduct accumulation in diabetic peripheral neuropathy. Control and streptozotocin-diabetic rats were maintained with or without treatment with the PARP inhibitor, 1,5-isoquinolinediol, 3 mg kg(-1) day( 1), for 10 weeks after an initial 2 weeks. Treatment efficacy was evaluated by poly(ADP-ribosyl)ated protein content in peripheral nerve and spinal cord (Western blot analysis) and dorsal root ganglion neurons and nonneuronal cells (fluorescence immunohistochemistry), as well as by indices of peripheral nerve function. Diabetic rats displayed increased urinary isoprostane and 8-hydroxy-2' deoxyguanosine excretion (ELISA) and 4-hydroxynonenal adduct accumulation in endothelial and Schwann cells of the peripheral nerve, neurons, astrocytes, and oligodendrocytes of the spinal cord and neurons and glial cells of the dorsal root ganglia (double-label fluorescence immunohistochemistry), as well as motor and sensory nerve conduction velocity deficits, thermal hypoalgesia, and tactile allodynia. PARP inhibition counteracted diabetes-induced systemic oxidative stress and 4-hydroxynonenal adduct accumulation in peripheral nerve and spinal cord (Western blot analysis) and dorsal root ganglion neurons (perikarya, fluorescence immunohistochemistry), which correlated with improvement of large and small nerve fiber function. The findings reveal the important role of PARP activation in systemic oxidative stress and 4-hydroxynonenal adduct accumulation in diabetic peripheral neuropathy. PMID- 21300150 TI - Identification of chemically diverse, novel inhibitors of 17beta-hydroxysteroid dehydrogenase type 3 and 5 by pharmacophore-based virtual screening. AB - 17beta-Hydroxysteroid dehydrogenase type 3 and 5 (17beta-HSD3 and 17beta-HSD5) catalyze testosterone biosynthesis and thereby constitute therapeutic targets for androgen-related diseases or endocrine-disrupting chemicals. As a fast and efficient tool to identify potential ligands for 17betaHSD3/5, ligand- and structure-based pharmacophore models for both enzymes were developed. The models were evaluated first by in silico screening of commercial compound databases and further experimentally validated by enzymatic efficacy tests of selected virtual hits. Among the 35 tested compounds, 11 novel inhibitors with distinct chemical scaffolds, e.g. sulfonamides and triazoles, and with different selectivity properties were discovered. Thereby, we provide several potential starting points for further 17beta-HSD3 and 17beta-HSD5 inhibitor development. Article from the Special issue on Targeted Inhibitors. PMID- 21300152 TI - Towards a new era for dystonia, a high priority for biomedical research. PMID- 21300151 TI - Endocrine disruption via estrogen receptors that participate in nongenomic signaling pathways. AB - When inappropriate (non-physiologic) estrogens affect organisms at critical times of estrogen sensitivity, disruption of normal endocrine functions can result. Non physiologic estrogen mimetics (environmental, dietary, and pharmaceutical) can signal rapidly and potently via the membrane versions of estrogen receptors, as can physiologic estrogens. Both physiologic and non-physiologic estrogens activate multiple signaling pathways, leading to altered cellular functions (e.g. peptide release, cell proliferation or death, transport). Xenoestrogens' mimicry of physiologic estrogens is imperfect. When superimposed, xenoestrogens can alter endogenous estrogens' signaling and thereby disrupt normal signaling pathways, leading to malfunctions in many tissue types. Though these xenoestrogen actions occur rapidly via nongenomic signaling pathways, they can be sustained with continuing ligand stimulation, combinations of ligands, and signaling that perpetuates downstream, eventually also impinging on genomic regulation by controlling the activation state of transcription factors. Because via these pathways estrogens and xenoestrogens cause nonmonotonic stimulation patterns, they must be carefully tested for activity and toxicity over wide dose ranges. Nongenomic actions of xenoestrogens in combination with each other, and with physiologic estrogens, are still largely unexplored from these mechanistic perspectives. PMID- 21300153 TI - Long-term intake of a milk casein hydrolysate attenuates the development of hypertension and involves cardiovascular benefits. AB - Essential hypertension is considered a serious health problem and diet can play an important role in its prevention and treatment. The aim of this study was to evaluate the effect of the long-term intake of a product based on milk casein hydrolysate on the development of hypertension in spontaneously hypertensive rats (SHR). A daily dose of 800 mg/kg body weight of the casein hydrolysate product was administered dissolved in drinking water during 6 weeks. Systolic and diastolic blood pressures were measured weekly by the tail-cuff method. Endothelial function in aorta and mesenteric segments, left ventricular hypertrophy, endothelial nitric oxide synthase (eNOS) expression in aorta and plasmatic angiotensin conversion enzyme (ACE) activity were also evaluated at the end of treatment. The development of hypertension was attenuated in the group treated with the casein hydrolysate product; in this sense the systolic blood pressure increased 33+/-3 mmHg in control group and only 18+/-5 mmHg in the treated group during the experimental period. In addition, the treatment improved aorta and mesenteric acetylcholine relaxations and increased the eNOS expression in aorta. Left ventricular hypertrophy decreased in treated SHR accompanied by a significant decrease in interstitial fibrosis. These results warrant evaluation in humans to determine if the product based on a casein hydrolysate could be used as a functional food ingredient to prevent blood pressure increased with additional cardiovascular benefits. PMID- 21300154 TI - Nucleic acid aptamers targeting cell-surface proteins. AB - Aptamers are chemical antibodies that bind to their targets with high affinity and specificity. These short stretches of nucleic acids are identified using a repetitive in vitro selection and partitioning technology called SELEX (Systematic Evolution of Ligands by EXponential enrichment). Since the emergence of this technology, many modifications and variations have been introduced to enable the selection of specific ligands, even for implausible targets. For membrane protein, the selection scheme can be chosen depending upon the availability of the system, the protein characteristics and the application required. Aptamers have been generated for a significant number of disease associated membrane proteins and have been shown to have considerable diagnostic and therapeutic importance. In this article, we review the SELEX process used for identification of aptamers that target cell-surface proteins and recapitulate their use as therapeutic and diagnostic reagents. PMID- 21300155 TI - Expression and purification of functional Clostridium perfringens alpha and epsilon toxins in Escherichia coli. AB - The alpha and epsilon toxins are 2 of the 4 major lethal toxins of the pathogen Clostridium perfringens. In this study, the expression of the epsilon toxin (etx) gene of C. perfringens was optimized by replacing rare codons with high-frequency codons, and the optimized gene was synthesized using overlapping PCR. Then, the etx gene or the alpha-toxin gene (cpa) was individually inserted into the pTIG Trx expression vector with a hexahistidine tag and a thioredoxin (Trx) to facilitate their purification and induce the expression of soluble proteins. The recombinant alpha toxin (rCPA) and epsilon toxin (rETX) were highly expressed as soluble forms in the recipient Escherichia coli BL21 strain, respectively. The rCPA and rETX were purified using Ni(2+)-chelating chromatography and size exclusion chromatography. And the entire purification process recovered about 40% of each target protein from the starting materials. The purified target toxins formed single band at about 42kDa (rCPA) or 31kDa (rETX) in sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and their functional activity was confirmed by bioactivity assays. We have shown that the production of large amounts of soluble and functional proteins by using the pTIG-Trx vector in E. coli is a good alternative for the production of native alpha and epsilon toxins and could also be useful for the production of other toxic proteins with soluble forms. PMID- 21300156 TI - The second bactericidal permeability increasing protein (BPI) and its revelation of the gene duplication in the Pacific oyster, Crassostrea gigas. AB - A novel homolog of BPI was cloned from the hemocyte cDNA of Crassostrea gigas and designed as Cg-BPI2, which share the highest sequence identity with the well known Cg-BPI (designed as Cg-BPI1). The complete cDNA of Cg-BPI2 included an open reading frame (ORF) of 1440 bp, and 3' and 5' untranslated regions (UTR's) of 49 bp and 166 bp, respectively. The ORF encoded a putative protein of 479 amino acids with predicted 22-aa hydrophobic signal peptide. The phylogenetic analysis showed that one of the gene duplications could have resulted in the emergence of two homologs of BPI in oysters, which probably might have occurred after the gastropod-bivalve divergence. Furthermore, molecular modeling analysis showed that both Cg-BPIs are similar to a highly extended boomerang like shape of human BPI, consisting of an N- and C-terminal barrel and a central beta-sheet. Comparison of the electrostatic surface potentials revealed that surfaces of Cg BPI2 have more intense positive charge than that of human BPI and the Cg-BPI1. The recombinant N-terminal barrel domain showed a high affinity to LPS and can effectively kill Gram-negative bacteria. The mRNAs of two Cg-BPIs were observed in all tissues examined with the highest expression in gills. The mRNAs expression profiles in response to bacterial challenge revealed that they were inducible under infection, but with a distinct and complementary expression patterns between Cg-BPI1 and Cg-BPI2. Our findings of this second BPI gene demonstrated presence of its gene duplication for the first time in invertebrate and it appears to be one of effective LPS-binding AMPs in elimination of Gram negative pathogens C. gigas. PMID- 21300157 TI - A novel clip domain serine proteinase (SPs) gene from the haemocytes of Indian white shrimp Fenneropenaeus indicus: molecular cloning, characterization and expression analysis. PMID- 21300158 TI - Passive immune-protection of small abalone against Vibrio alginolyticus infection by anti-Vibrio IgY-encapsulated feed. AB - Small abalone (Haliotis diversicolor supertexta) is a high value-added shellfish. It however has been suffering Vibrio alginolyticus infections, which cause mass death of small abalone and thus great economic losses, particularly in artificial aquaculture. In this study, we attempted to treat small abalone with anti-Vibrio IgY to elicit a passive immunity directly against V. alginolyticus infections. Anti-Vibrio IgY was alginate encapsulated in egg powders as feed, which may avoid antibody inactivation in the gastrointestinal tract of small abalone. The feed was tested for the stability of anti-Vibrio IgY in a gastrointestinal mimic environment. The result showed anti-Vibrio IgY retained activity as high as 90% after 4 h exposure to pancreatic enzymes. Addition of 0, 5 or 10% anti-Vibrio IgY encapsulated egg powders into a basal diet to form abalone diet formulae. Small abalones fed with the anti-Vibrio IgY formulae showed a relatively high respiratory burst activity than those without anti-Vibrio IgY treatments. The survival rates of small abalones fed with 5 or 10% anti-Vibrio IgY egg powders were in the range of 65-70% 14 days post-V. alginolyticus challenge (1 x 106 c.f.u.), which was significantly higher than 0% of those fed without anti-Vibrio IgY. The anti-Vibrio IgY-encapsulated formulae were thus concluded to be an effective means to prevent small abalone from V. alginolyticus infection, and may be practical in use in abalone aquaculture. PMID- 21300159 TI - Influence of diet enriched with green tea on innate humoral and cellular immune response of kelp grouper (Epinephelus bruneus) to Vibrio carchariae infection. AB - Effect of diet enriched with green tea at 0, 0.01, 0.1 or 1.0% levels on immune responses such as non-specific humoral (lysozyme, antiprotease and complement) and cellular (myeloperoxidase content, production of reactive oxygen, and nitrogen species) and disease resistance on week 1, 2 or 4 in kelp grouper Epinephelus bruneus challenged with Vibrio carchariae (2.47 * 10(8) CFU ml(-1)) was quantified. At all doses green tea supplementation significantly enhanced the serum lysozyme activity from weeks 1 to 4. On the other hand, after week 2 the serum hemolytic complement activity, leucocyte myeloperoxidase content and reactive nitrogen species protection significantly increased in groups fed with 0.01 and 0.1% green tea supplementation diets. The serum antiprotease activity significantly increased in group fed with at 1.0% green tea from week 1 to 4. However, all diets except at 0.01% level resulted in a significant decrease in reactive oxygen species protection during the experimental period. Challenged groups fed with green tea enriched diet at 0.01 and 0.1% level had a higher relative percent survival than with 1.0% diet on week 1, 2 or 4. The results suggest that dietary administration of green tea supplementation at a concentration of 0.01 and 0.1% level positively enhances the non-specific humoral and cellular immune responses and disease resistance of kelp grouper E. bruneus to V. carchariae. PMID- 21300160 TI - Immunomodulatory effect of probiotics enriched diets on Uronema marinum infected olive flounder. AB - The effect of five probiotics, Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus sakei, Bacillus subtilis, and Saccharomyces cerevisiae as individual and mixed enriched diet on the seasonal prevalence, activity and intensity of Uronema marinum infection in olive flounder Paralichthys olivaceus is reported. The growth performance, feed efficiency, blood biochemistry, survival rate, and non-specific immune response of U. marinum infected olive flounder on week 0, 1, 2, 4, 6, and 8 were quantified. The prevalence and infection intensity reached a peak from June to December and then it declined from December to March. The scuticocidal activity in the serum was significantly higher when fed with L. plantarum, L. acidophilus, and S. cerevisiae diets on weeks 2-8. All enriched diets significantly enhanced the weight gain significantly between week 6 and 8; the feed efficiency registered a significantly increase from week 4 to 8 when compared to infected fish fed with control diet. Infected fish fed with L. plantarum-supplemented diet had higher survival rate than with other enriched diets. The serum aspartate aminotransferase (GOT) and alanine aminotransferase (GPT) levels significantly increased when fed with L. plantarum, L. acidophilus or S. cerevisiae supplemented diet. Total protein (TP) and glucose (GLU) level significantly increased with any enriched diet from week 4 to 8. The superoxide anion production and serum lysozyme activity registered a significant increase when fed with L. plantarum, L. acidophilus, and S. cerevisiae-supplemented diet from week 4-8. The present study concludes that L. plantarum, L. acidophilus, and S. cerevisiae-supplemented diets act as immunostimulants enhancing the growth, feed efficiency, blood biochemistry, survival rate, and non-specific immune response in U. marinum infected olive flounder. PMID- 21300161 TI - A new Akirin1 gene in turbot (Scophthalmus maximus): molecular cloning, characterization and expression analysis in response to bacterial and viral immunological challenge. AB - SmAkirin1, a member of the NF-kappaB signaling pathway, was isolated from turbot by RACE. Its cDNA was 564 bp and encoded a putative protein of 187 amino acids with a predicted molecular mass of 21 kDa and an isoelectric point (pI) of 9.05. Amino acid sequence alignments showed that SmAkirin1 was 91% identical to the Salvelinus alpinus Akirin1 protein ACV49694. Transient expression of SmAkirin1 GFP in the turbot kidney cell line SMKC revealed a nuclear localization of the protein, and a typical NLS signal was found at the N-terminal region of the SmAkirin1 protein. Trans-activation assay in yeast demonstrated that SmAkirin1 has no transcriptional activation. Transcriptional analysis showed that SmAkirin1 was expressed in all of the tissues examined, with the highest expression in the spleen and brain. Real-time quantitative reverse-transcriptase polymerase chain reaction analysis showed that the SmAkirin1 transcript was induced by bacterial and viral infection. PMID- 21300162 TI - Developmental effects of reward on sustained attention networks. AB - Adolescence is typified by significant maturation in higher-level attention functions coupled with less developed control over motivation, and enhanced sensitivity to novelty and reward. This study used event-related functional magnetic resonance imaging (fMRI) in seventy male and female participants aged between 10 and 43 years to identify age-related linear changes in cognitive sustained attention systems and the impact of reward on these systems, using a sustained attention task with and without a rewarded condition. For the non rewarded sustained attention contrast, increasing age was associated with activation increases in typical regions of sustained attention including right inferior frontal, superior temporo-parietal and cerebellar cortices. Age-related activation decreases were observed within more posterior regions including posterior cingulate, insula and posterior cerebellar cortices, presumably mediating visual-spatial saliency detection. The effect of reward on sustained attention networks was associated with increased activation with age in regions associated with both executive attention control and reward processing, including dorsolateral, inferior and ventromedial prefrontal cortices (PFC), striatum, and temporo-parietal regions, suggestive of greater integration and executive control of motivation and cognition with maturity. Activation in paralimbic posterior cingulate and inferior temporal brain regions of visual-spatial saliency processing was progressively reduced in activation with increasing development. Thus, with increasing development between adolescence and adulthood, reward appears to enhance maturing cognitive sustained attention and executive reward processing networks, whilst reducing paralimbic regions of saliency detection. These findings may be the neural underpinnings for the progressive maturation of motivational control over risk taking behaviours between adolescence and adulthood. PMID- 21300163 TI - Evolution of the 5.8S nrDNA gene and internal transcribed spacers in Carapichea ipecacuanha (Rubiaceae) within a phylogeographic context. AB - Nuclear ribosomal DNA (nrDNA) constitutes a multicopy gene family that is used widely to test evolutionary hypotheses across a broad range of organisms. It is presumed that, as a result of concerted evolution, tandem nrDNA repeats are homogeneous within species and different between species. We sampled 77 specimens of a disjunct species (Carapichea ipecacuanha) from throughout its three geographic ranges and obtained 266 nrDNA sequences, of which 26 were obtained by direct sequencing and 240 by cloning of PCR products. Complementary sequence analyses, which included analyses of secondary structure stability, the pattern of base substitutions, GC content, and the presence of conserved motifs, were used to characterize the internal transcribed spacer (ITS) region (ITS1-5.8S nrDNA-ITS2). Our results showed that concerted evolution of the ITS region was incomplete in C. ipecacuanha, particularly in the Atlantic range. In the highly polymorphic populations of the Atlantic range, intraindividual variation was observed and involved 56 functional paralogs and 15 pseudogenes from two highly divergent ribogroups. The Amazonian range (with 12 functional paralogs) and the Central-American range (with five functional paralogs) were genetically depauperate and exhibited no pseudogenes. In the two latter ranges, almost complete homogenization of the ITS sequences had occurred. We argue that it is important to consider past evolutionary history when making inferences about the efficiency with which concerted evolution homogenizes tandem nrDNA repeats a single sequence. PMID- 21300164 TI - Resolving and dating the phylogeny of Cornales--Effects of taxon sampling, data partitions, and fossil calibrations. AB - The order Cornales descends from the earliest split in the Asterid clade of flowering plants. Despite a few phylogenetic studies, relationships among families within Cornales remain unclear. In the present study, we increased taxon and character sampling to further resolve the relationships and to date the early diversification events of the order. We conducted phylogenetic analyses of sequence data from 26S rDNA and six chloroplast DNA (cpDNA) regions using parsimony (MP), maximum likelihood (ML), and Bayesian inference (BI) methods with different partition models and different data sets. We employed relaxed, uncorrelated molecular clocks on BEAST to date the phylogeny and examined the effects of different taxon sampling, fossil calibration, and data partitions. Our results from ML and BI analyses of the combined cpDNA sequences and combined cpDNA and 26S rDNA data suggested the monophyly of each family and the following familial relationships ((Cornaceae-Alangiaceae)-(Curtisiaceae-Grubbiaceae)) (((Nyssaceae-Davidiaceae)-Mastixiaceae)-((Hydrostachyaceae-(Hydrangeaceae Loasaceae))). These relationships were strongly supported by posterior probability and bootstrap values, except for the sister relationship between the N-D-M and H-H-L clades. The 26S rDNA data and some MP trees from cpDNA and total evidence suggested some alternative alignments for Hydrostachyaceae within Cornales, but results of SH tests indicated that these trees were significantly worse explanations of the total data. Phylogenetic dating with simultaneous calibration of multiple nodes suggested that the crown group of Cornales originated around the middle Cretaceous and rapidly radiated into several major clades. The origins of most families dated back to the late Cretaceous except for Curtisiaceae and Grubbiaceae which may have diverged in the very early Tertiary. We found that reducing sampling density within families and analyzing partitioned data sets from coding and noncoding cpDNA, 26S rDNA, and combined data sets produced congruent estimation of divergence times, but reducing the number and changing positions of calibration points resulted in very different estimations. PMID- 21300165 TI - Basic poster discussion: summary. AB - Twelve posters were presented in the section on Basic Research. They were discussed in a session chaired by Paul Davenport (Gainesville, US) and Marian Kollarik (Boston, US), with each poster presenter first briefly describing his/her poster. PMID- 21300166 TI - Tacrolimus-induced pulmonary injury in rheumatoid arthritis patients. AB - BACKGROUND: Tacrolimus (TAC) was approved in Japan in 2005 for rheumatoid arthritis (RA) patients having inadequate response to other disease-modifying anti-rheumatic drugs. As of May 2007, spontaneous reports identified twenty-seven cases of exacerbation or new development of interstitial pneumonia among RA patients given TAC in Japan. OBJECTIVE: To describe the clinical and radiological characteristics of TAC-induced pulmonary injury (TIPI). PATIENTS AND METHODS: Eleven RA patients diagnosed with de novo pulmonary injury or exacerbation of IP during treatment with TAC were identified. Clinical, radiological, and laboratory data of ten of these cases were retrospectively analyzed. RESULTS: Baseline data for the ten patients were a mean age of 69.7 years; gender, 70% female; mean RA disease duration, 9.1 years; and pulmonary comorbidities, 90%. Six cases were classified as presumptive TAC-induced pulmonary injury (TIPI) and four as probable TIPI. Among the six presumptive cases, TIPI developed at an average of 84 days after initiation of treatment (n = 5) or four days after reinstitution of TAC (n = 1). Five cases were an exacerbation of pre-existing interstitial pneumonia and one was a de novo pulmonary injury. Radiological patterns of thoracic computed tomography (CT) scans of patients in the presumptive TIPI cases were hypersensitivity pneumonia like-pattern (n = 3), ground-glass opacity (n = 2), and organizing pneumonia-pattern (n = 1). All patients with presumptive TIPI were treated with high dosage glucocorticosteroids and one received concomitant immunosuppressants. Two of the six presumptive TIPI patients died. CONCLUSION: Rheumatologists should be aware of this rare but potentially life-threatening adverse event in RA patients receiving TAC. PMID- 21300167 TI - Does domestication process affect stress response in juvenile Eurasian perch Perca fluviatilis? AB - The objective was to evaluate the impact of domestication process on the physiological stress response of cultured Eurasian perch confronted to a chronic stress situation. Briefly, F1 and F4 juveniles were submitted to chronic confinement and investigated on days 5, 15 and 30. Capture and 15min-anesthesia were imposed on fish to assess the effect of preceding confinement on acute stress response. On day 30, the fish were finally challenged with Aeromonas hydrophila and sampled after 5 and 10 days for immune parameter measurements. Cortisol and glucose levels were not affected by confinement but increased significantly after acute stressor exposure. Moreover, cortisol rise following capture and anesthesia was higher in F1 confined-fish, suggesting that they have previously been affected by chronic confinement. A higher HSP70 level was also observed on day 30 in F1 confined-juveniles. During bacterial challenge, regardless of confinement level, F4 juveniles displayed higher lysozyme activity and agglutination response than F1 which may indicate a higher immune capacity in domesticated fish. In conclusion, chronic confinement stressor induced few physiological responses but may increase the responsiveness to other aquacultural stressors. Domestication process also seems to improve chronic stress resistance, growth as well as the immune status of the fish. PMID- 21300168 TI - Meat-type chickens have a higher efficiency of mitochondrial oxidative phosphorylation than laying-type chickens. AB - Meat-type chickens show high feed efficiency and have a very rapid growth rate compared with laying-type chickens. To clarify whether the type-specific difference in feed conversion efficiency is involved in mitochondrial bioenergetics, modular kinetic analysis was applied to oxidative phosphorylation in skeletal muscle mitochondria of both type chickens. Mitochondria from skeletal muscle of meat-type chickens showed greater substrate oxidation and phosphorylating activities, and less proton leak than those of the laying-type, resulting in a higher efficiency of oxidative phosphorylation. Gene expression and protein content of uncoupling protein (avUCP) but not adenine nucleotide translocase (avANT) gene expression were lower in skeletal muscle mitochondria of meat-type chickens than the laying-type. The current results regarding a higher efficiency of oxidative phosphorylation and UCP content may partially support the high feed efficiency of meat-type chickens. PMID- 21300169 TI - Relationship between metabolism, sex and reproductive tactics in young Atlantic salmon (Salmo salar L.). AB - Atlantic salmon can differ markedly in their growth and in the timing of reproductive maturation, leading to the dramatic contrast between the large anadromous adults and the diminutive mature male parr. This study examined the growth rates, anatomical and physiological characteristics of parr during the adoption of their discrete life histories to ascertain whether these properties can explain tactic choice. To minimise the impact of habitat differences upon these attributes, salmon were reared in the laboratory until 1.5years of age, when the "decisions" to undergo smoltification or to mature as parr had been taken. At 1.5years, both males and females showed bimodal size-frequency distributions. Neither the population of origin nor the paternal reproductive tactic influenced the "decision" to mature or the growth trajectories. Growth rate (% massday(-1) during their final 10months) and the % male and female offspring in the upper modal group were strongly correlated and varied markedly among families. Mean growth rate per family was negatively correlated with mean metabolic rate per family at emergence. Growth rate decreased as a function of parr size in January and the growth rates of upper modal fish were displaced upwards relative to those of lower modal fish. Most males in the smaller size mode matured, whereas all other fish began smoltification. Mature male parr did not differ from similarly sized female pre-smolt in routine metabolic rate, but these smaller fish had higher metabolic rates than larger male and female pre smolts. However, mature parr differed markedly from similarly sized females and from larger male and female pre-smolts in possessing higher oxidative and lower glycolytic capacities in muscle. Overall, these data are consistent with the interpretation that growth rates dictate the distribution of parr between upper and lower modal groups. Individuals from faster growing families would be more likely to pass the threshold for smoltification and to accelerate growth, whereas those from slower growing families would remain in the lower mode. The use of metabolic capacities, e.g. metabolic rate, was linked with modal group, whereas muscle oxidative capacity was linked with male maturity. Mean family metabolic rate at emergence was negatively linked with mean growth during the subsequent year, suggesting that metabolic efficiency facilitates growth and eventually smoltification. PMID- 21300170 TI - Neural pathways to cardioaccelerator neurons in the isopod crustacean Bathynomus doederleini: Cholinergic activation by somatic movements. AB - We investigated the excitatory and inhibitory input to cardioaccelerator (CA) and cardioinhibitor (CI) neurons located in the thoracic ganglia of the isopod crustacean Bathynomus doederleini by extracellular and intracellular recording. Electrical stimuli applied to the anterior and posterior connectives of single ganglion preparations, containing either the 2nd or 3rd thoracic ganglion alone, and each of three paired ganglionic nerve roots produced excitatory postsynaptic potentials (EPSPs) in the cell body of a CA neuron. Artificial movements of appendages, such as the thoracic limbs and the swimmerets, also evoked EPSPs in the CA neuron. Electrical stimuli applied to the peripheral nerves running to appendages induced inhibitory postsynaptic potentials (IPSPs) in a CI neuron. Since artificial movements of the appendages caused decrease of CI impulse rate, these IPSPs in the CI neuron may be caused by mechanoproprioceptors in the appendages. Since tachycardia was accompanied by excitation of CA neurons and inhibition of CI neurons, activation of the mechanoproprioceptors may be responsible for tachycardia. EPSPs in CA neurons produced by stimulation of peripheral nerves were augumented by eserinization and blocked by curarization. The activation of CA neurons by ganglionic roots may be mediated by cholinergic processes ascending from mechanoproprioceptors. PMID- 21300171 TI - Evolutionary engineered Saccharomyces cerevisiae wine yeast strains with increased in vivo flux through the pentose phosphate pathway. AB - Amplification of the flux toward the pentose phosphate (PP) pathway might be of interest for various S. cerevisiae based industrial applications. We report an evolutionary engineering strategy based on a long-term batch culture on gluconate, a substrate that is poorly assimilated by S. cerevisiae cells and is metabolized by the PP pathway. After adaptation for various periods of time, we selected strains that had evolved a greater consumption capacity for gluconate. (13)C metabolic flux analysis on glucose revealed a redirection of carbon flux from glycolysis towards the PP pathway and a greater synthesis of lipids. The relative flux into the PP pathway was 17% for the evolved strain (ECA5) versus 11% for the parental strain (EC1118). During wine fermentation, the evolved strains displayed major metabolic changes, such as lower levels of acetate production, higher fermentation rates and enhanced production of aroma compounds. These represent a combination of novel traits, which are of great interest in the context of modern winemaking. PMID- 21300173 TI - Buccal iontophoresis: an opportunity for drug delivery and metabolite monitoring. PMID- 21300172 TI - Stromal-epithelial metabolic coupling in cancer: integrating autophagy and metabolism in the tumor microenvironment. AB - Cancer cells do not exist as pure homogeneous populations in vivo. Instead they are embedded in "cancer cell nests" that are surrounded by stromal cells, especially cancer associated fibroblasts. Thus, it is not unreasonable to suspect that stromal fibroblasts could influence the metabolism of adjacent cancer cells, and visa versa. In accordance with this idea, we have recently proposed that the Warburg effect in cancer cells may be due to culturing cancer cells by themselves, out of their normal stromal context or tumor microenvironment. In fact, when cancer cells are co-cultured with fibroblasts, then cancer cells increase their mitochondrial mass, while fibroblasts lose their mitochondria. An in depth analysis of this phenomenon reveals that aggressive cancer cells are "parasites" that use oxidative stress as a "weapon" to extract nutrients from surrounding stromal cells. Oxidative stress in fibroblasts induces the autophagic destruction of mitochondria, by mitophagy. Then, stromal cells are forced to undergo aerobic glycolysis, and produce energy-rich nutrients (such as lactate and ketones) to "feed" cancer cells. This mechanism would allow cancer cells to seed anywhere, without blood vessels as a food source, as they could simply induce oxidative stress wherever they go, explaining how cancer cells survive during metastasis. We suggest that stromal catabolism, via autophagy and mitophagy, fuels the anabolic growth of tumor cells, promoting tumor progression and metastasis. We have previously termed this new paradigm "The Autophagic Tumor Stroma Model of Cancer Metabolism", or the "Reverse Warburg Effect". We also discuss how glutamine addiction (glutaminolysis) in cancer cells fits well with this new model, by promoting oxidative mitochondrial metabolism in aggressive cancer cells. PMID- 21300174 TI - Immunogenicity of biotherapeutics in the context of developing biosimilars and biobetters. AB - Issues concerning the approval of biosimilars are currently being addressed by the US Food and Drug Administration and the European Medicines Agency. There appears to be a consensus that immunogenicity impacts comparability studies and the interchangeability of biosimilars. In addition, preclinical immunogenicity assessment and mitigation, if validated in clinical studies, might impact patient safety and development costs, and also facilitate the development of 'biobetters' and other protein therapeutics. This review addresses recent advances in the field of biosimilars and focuses on predictive immunology, with an emphasis on preclinical immunogenicity assessments of protein therapeutics other than vaccines and their corresponding clinical outcomes. PMID- 21300175 TI - Effects of UV radiation on marine ectotherms in polar regions. AB - Ozone-related increase in solar ultraviolet radiation (UVR) during the last decades provided an important ecological stressor, particularly for polar ecosystems since these are less adapted to such changes. All life forms appear to be susceptible to UVR to a highly variable extent that depends on individual species and their environment. Differences in sensitivity between organisms may relate to efficiency differences of their protection mechanisms and repair systems. UVR impacts are masked by large seasonal and geographic differences even in confined areas like the polar regions. UVR has effects and responses on various integration levels: from genetics, physiology, biology, populations, communities, to functional changes as in food webs with consequences on material and energy circulations through ecosystems. Even at current levels, solar UV-B affects consumer organisms, such as ectotherms (invertebrates and fish), particularly through impediments on critical phases of their development (early life history stages such as gametes, zygotes and larvae). Despite the overall negative implications of UVR, effect sizes vary widely in, e.g., molecular damage, cell and tissue damage, survival, growth, behavior, histology, and at the level of populations, communities and ecosystems. PMID- 21300176 TI - Cardiac resynchronization therapy in patients with left ventricular systolic dysfunction and right bundle branch block: a systematic review. AB - BACKGROUND: Whether patients with right bundle branch block (RBBB) benefit from cardiac resynchronization therapy (CRT) is unclear. OBJECTIVE: The purpose of this study was to systematically review the published data from randomized clinical trials of CRT on the outcomes in patients with baseline RBBB. METHODS: Randomized controlled trials of CRT in heart failure and left ventricular systolic dysfunction were identified from MEDLINE (1950-2010), EMBASE (1980-2010, week 45), Cochrane Controlled Trials Register (2009), Cochrane Database of Systematic Reviews, National Institutes of Health Clinical Trials.gov database. RESULTS: A total of 112 references were retrieved. Four publications from five studies reported data on patients with RBBB and were included in this investigation, with 259 patients randomized to CRT and 226 randomized to non-CRT. None of the available data showed more favorable outcomes (soft or hard) in patients with CRT. CONCLUSION: None of the available data showed more favorable outcomes with CRT in patients with RBBB. A meta-analysis of RBBB patients from the major CRT trials is urgently needed. Results of the meta-analysis can direct further research, perhaps indicating a need for randomized trials in RBBB. Physicians and patients should be aware of the likely reduced benefit form CRT in patients with RBBB, and this should be factored into decision making. However, until more data are available it is too early to change guidelines. PMID- 21300178 TI - A questionnaire-based survey of participants' decisions regarding recruitment and retention in a randomised controlled trial - lessons learnt from the SCoRD trial. AB - Successful recruitment and retention on trials is critical to ensuring that adequate power is conferred, results are generalisable and trials are completed within the allocated time and resources. Nested within an existing pragmatic randomised controlled trial a process evaluation was conducted to explore the reasons for a much higher than anticipated recruitment (120% of required sample size) and retention rate (96% completed follow-up). A questionnaire was designed to ascertain patient's views on reasons affecting consent and retention. 148 patients still enrolled in the trial at their final follow-up were either given or mailed a questionnaire of which 102 were returned (69%). 96% rated the written information as very or somewhat important in their decision to consent. Verbal information given to them by the operating surgeon was considered very or somewhat important by 86% and the relative inconvenience was rated as important by 79% of patients. Reasons for consenting for a large proportion of patents were the wish to help in research which may benefit others in the future and the perception that this was an important and relevant study. There was also some evidence that patients weighed up the demands with the potential benefits to them. High levels of satisfaction were expressed with trial personnel and trial procedures. The inclusion of a trial process evaluation such as the one presented here is an efficient method for gathering information of participants' decisions regarding recruitment and retention in a trial and can help to inform the successful planning of future trials. PMID- 21300177 TI - Kids and adults now! Defeat Obesity (KAN-DO): rationale, design and baseline characteristics. AB - BACKGROUND: Prevention of childhood obesity is a public health priority. Parents influence a child's weight by modeling healthy behaviors, controlling food availability and activity opportunities, and appropriate feeding practices. Thus interventions should target education and behavioral change in the parent, and positive, mutually reinforcing behaviors within the family. METHODS: This paper presents the design, rationale and baseline characteristics of Kids and Adults Now! - Defeat Obesity (KAN-DO), a randomized controlled behavioral intervention trial targeting weight maintenance in children of healthy weight, and weight reduction in overweight children. 400 children aged 2-5 and their overweight or obese mothers in the Triangle and Triad regions of North Carolina are randomized equally to control or the KAN-DO intervention, consisting of mailed family kits encouraging healthy lifestyle change. Eight (monthly) kits are supported by motivational counseling calls and a single group session. Mothers are targeted during a hypothesized "teachable moment" for health behavior change (the birth of a new baby), and intervention content addresses: parenting skills ((e.g., emotional regulation, authoritative parenting), healthy eating, and physical activity. RESULTS: The 400 mother-child dyads randomized to trial are 75% white and 22% black; 19% have a household income of $30,000 or below. At baseline, 15% of children are overweight (85th-95th percentile for body mass index) and 9% are obese (>= 95th percentile). CONCLUSION: This intervention addresses childhood obesity prevention by using a family-based, synergistic approach, targeting at risk children and their mothers during key transitional periods, and enhancing maternal self-regulation and responsive parenting as a foundation for health behavior change. PMID- 21300179 TI - Data withdrawal in randomized controlled trials: Defining the problem and proposing solutions: a commentary. AB - It is not uncommon for a participant to withdraw from a randomized controlled trial (RCT). The withdrawal of a participant results in missing data and the potential for withdrawal bias. Data withdrawal, or a request from a participant to withdraw all of their previously collected data from a study, is particularly problematic because it leaves little opportunity to characterize or statistically address those that have withdrawn to minimize withdrawal bias. The aim of this commentary is to (1) provide a synthesis of available information on the ethical and methodological issues related to data withdrawal in RCTs and (2) provide some suggestions on how to minimize the impact of data withdrawal during the execution or analysis phases of an RCT. We searched PubMed, EMBASE and JSTOR for published articles on data withdrawal. In addition, we used internet sources as an additional tool to identify content on data withdrawal from research ethics guidelines, legislation, research ethics boards, funding agencies, professional organizations and researchers. We did not find any definitive guidelines for dealing with data withdrawal. We propose recommendations for minimizing the occurrence of data withdrawal, including explicit and clear descriptions in consent forms of how data will be handled after participant withdrawal. We also suggest using imputation techniques to deal with the missing data during analysis. The current commentary can be used to minimize the impact of data withdrawal in RCTs. PMID- 21300180 TI - Clinical validation study to measure the performance of the Nerve Root Sedimentation Sign for the diagnosis of lumbar spinal stenosis. AB - Lumbar spinal stenosis is a common degenerative disorder of the spine in elderly patients that can be effectively treated with decompression surgery in some patients. Radiological findings in the diagnostic work-up of the patients do not always correlate well with clinical symptoms, and guidance about when to proceed to surgery is inconsistent. The recently described Nerve Root Sedimentation Sign in magnetic resonance scans has been shown to discriminate well between selected patients with and without lumbar spinal stenosis, but the performance of this new test, when used in a broad patient population, is not yet known. We describe the design of a single-centre retrospective chart review to assess the clinical validity of the Sedimentation Sign by evaluating its association with health outcomes in patients with suspected lumbar spinal stenosis. The Sedimentation Sign will be cross-classified with decisions for surgery based on existing tests and patient outcomes in follow-up examinations at 24months. The results will be used to estimate: i) how well the Sedimentation Sign can distinguish between patients that do or do not benefit from surgery, and ii) the concordance between the Sedimentation Sign and existing tests to explore its possible value as a triage test. This study design will provide data to estimate the potential benefits and harms of using the Sedimentation Sign to guide surgical decisions. The observed proportion of discordant test results will help inform the design of future randomised controlled trials of the Sedimentation Sign. PMID- 21300182 TI - All four zebrafish Wnt7 genes are expressed during early brain development. AB - Wnt-signalling is involved in a number of biological processes in the course of embryonic development, cell fate determination, proliferation, stem cell maintenance and oncogenesis. Wnt ligands are secreted glycoproteins and the number of Wnt isoforms varies between five in nematodes and 27 in fish. The highly conserved group of Wnt7 genes has been found to signal via at least three Wnt-signalling pathways dependent on the developmental context. These ligands have been identified as important regulators in a number of processes ranging from formation of bones, lungs, kidneys, reproductive organs and placenta to vasculogenesis and synaptogenesis in the brain. The importance of Wnt7 function is underscored by their implication in disease syndromes in man. Unlike the single Wnt7a and Wnt7b mammalian genes we find that the zebrafish genome contains two paralogues genes for each Wnt7 ligand. Here, we compare these four Wnt7 genes evolutionarily and analyse their expression during the first two days of embryonic development. We find Wnt7 genes mainly expressed in a number of CNS structures at developmental stages at which patterning and neural specification takes place. The timely and spatially overlapping as well as complementary gene expression suggests diverse as well as redundant involvements during brain development. PMID- 21300181 TI - Adaptive seamless design for an efficacy trial of replication-competent adenovirus-mediated suicide gene therapy and radiation in newly-diagnosed prostate cancer (ReCAP Trial). AB - PURPOSE: Cumulative evidence has suggested investigation of the efficacy of Replication-Competent Adenovirus-mediated Suicide Gene Therapy in newly-diagnosed Prostate Cancer (ReCAP). There is a challenge in designing an efficacy trial for newly-diagnosed prostate cancer given its long natural history. The regulatory agency recommended a Phase II trial for safety before conducting the efficacy trial. EXPERIMENTAL DESIGN: The ReCAP trial is an adaptive seamless, multi-site open-label, randomized Phase II/III trial. Two hundred eighty men will be randomized to receive either replication-competent adenovirus-mediated suicide gene therapy followed by radiation (Arm 1) or radiation alone (Arm 2). Phase II trial component will include the first 21 patients in Arm 1 with complete toxicity through day 90 for safety evaluation. The primary efficacy endpoint is the time free from biochemical and/or clinical failure (FFF). The secondary efficacy endpoints are 2-year prostate biopsies and overall survival. Unequal spaced interim looks are proposed with the adaptive sample-size re-estimation. RESULTS: This trial has been approved by the FDA for the study therapy investigation and is currently recruiting patients. CONCLUSIONS: Challenges remain in designing newly-diagnosed prostate cancer trials. Adaptive seamless design is time-saving and a cost-effective design in the development of novel medical therapies, but requires a specified statistical plan in the decision process involved. PMID- 21300183 TI - Proteomic identification of rhythmic proteins in rice seedlings. AB - Many aspects of plant metabolism that are involved in plant growth and development are influenced by light-regulated diurnal rhythms as well as endogenous clock-regulated circadian rhythms. To identify the rhythmic proteins in rice, periodically grown (12h light/12h dark cycle) seedlings were harvested for three days at six-hour intervals. Continuous dark-adapted plants were also harvested for two days. Among approximately 3000 reproducible protein spots on each gel, proteomic analysis ascertained 354 spots (~12%) as light-regulated rhythmic proteins, in which 53 spots showed prolonged rhythm under continuous dark conditions. Of these 354 ascertained rhythmic protein spots, 74 diurnal spots and 10 prolonged rhythmic spots under continuous dark were identified by MALDI-TOF MS analysis. The rhythmic proteins were functionally classified into photosynthesis, central metabolism, protein synthesis, nitrogen metabolism, stress resistance, signal transduction and unknown. Comparative analysis of our proteomic data with the public microarray database (the Plant DIURNAL Project) and RT-PCR analysis of rhythmic proteins showed differences in rhythmic expression phases between mRNA and protein, suggesting that the clock-regulated proteins in rice are modulated by not only transcriptional but also post transcriptional, translational, and/or post-translational processes. PMID- 21300184 TI - Matrix metalloproteinase-sensitive thermogelling polymer for bioresponsive local drug delivery. AB - Development of a successful bioresponsive drug delivery system requires exquisite engineering of the materials so that they are able to respond to signals stemming from the physiological environment. In this study we propose a new Pluronic((r)) based thermogelling system containing matrix metalloproteinase-2 (MMP2) responsive peptide sequences. A novel thermosensitive multiblock co-polymer comprising an MMP2-labile octapeptide (Gly-Pro-Val-Gly-Leu-Ile-Gly-Lys) was synthesized from a Pluronic((r)) triblock co-polymer. The polymer was designed to form a thermogel at body temperature and degrade in the presence of MMP overexpressed in a tumor. The synthesized polymer was a multiblock co-polymer with ~2.5 U of Pluronic((r)). The multiblock co-polymer solutions exhibited reverse thermal gelation around body temperature. The gelation temperatures of the multiblock co-polymer solutions were lower than those of the corresponding Pluronic((r)) monomer at a particular concentration. The cytotoxicity of the synthesized polymer was lower compared with the monomer. The solubility of the hydrophobic anticancer drug paclitaxel was enhanced in the polymer solutions by micelle formation. The synthesized polymer was preferentially degraded in the presence of MMP. Paclitaxel release was dependent on the enzyme concentration. These findings suggest that the synthesized polymer has potential as a controlled drug delivery system due to its unique phase transition and bioresponsive behavior. PMID- 21300186 TI - Initial cell pre-cultivation can maximize ECM mineralization by human mesenchymal stem cells on silk fibroin scaffolds. AB - Fast remineralization of bone defects by means of tissue engineering is one of many targets in orthopedic regeneration. This study investigated the influence of a range of pre-culture durations for human bone marrow derived mesenchymal stem cells (hMSC) before inducing differentiation into osteoblast-like cells. The aim was to find the conditions that lead to maximal extracellular matrix (ECM) mineralization, in terms of both amount and best distribution. Additionally, the influence of silk fibroin scaffold pore size on mineralization was assessed. The formation of mineralized ECM by hMSCs cultured in osteogenic medium on silk fibroin scaffolds was monitored and quantified for up to 72 days in culture using non-invasive time-lapse micro-computed tomography (micro-CT). ECM mineralization increased linearly 3 weeks after the beginning of the experiment with addition of differentiation medium. Biochemical end-point assays measured the amount of DNA, calcium deposits, alkaline phosphatase activity and cell metabolic activity to corroborate the hypothesis that an initial pre-culture period of hMSCs on silk fibroin scaffolds can accelerate mineralized ECM formation. According to the micro-CT analysis mineralization on silk fibroin scaffolds with pores of 112-224 MUm diameter was most efficient with an initial cell pre-culture period of 9 days, showing 6.87+/-0.81* higher mineralization values during the whole cultivation period than without an initial cell pre-culture period. PMID- 21300185 TI - Poly(beta-amino amine) cross-linked PEIs as highly efficient gene vectors. AB - To increase the release of DNA into the cytoplasm and further improve transgene expression of nucleic acid novel polymeric gene carriers were prepared which would be biodegradable under the reducing conditions in the cytoplasm. Disulfide containing poly(beta-amino amine)s were first synthesized and then used to cross link low molecular weight polyethyleneimine (1800 Da) through Michael addition to obtain SS-PBAA-PEIs as the final gene carriers. The physicochemical characteristics of SS-PBAA-PEI/DNA complexes were characterized. In vitro transfection mediated by the SS-PBAA-PEIs under serum conditions was carried out. Cell uptake of the gene delivery systems was observed by confocal laser scanning microscopy. The results of the physicochemical characterisation demonstrated that the SS-PBAA-PEIs could efficiently condense DNA. In vitro transfection under serum conditions showed that SS-PBAA-PEIs had comparable or even higher transfection efficiencies than 25 kDa PEI. And SS-PBAA-PEIs showed much lower cytotoxicity compared with 25 kDa PEI. In summary, the SS-PBAA-PEIs possess great potential as non-viral gene vectors and exhibit high transfection efficiency under serum conditions. PMID- 21300187 TI - Development of robust biocompatible silicone with high resistance to protein adsorption and bacterial adhesion. AB - A new biocompatible silicone comprising a carboxybetaine (CB) ester analogue, 3 methacryloxypropyltris(trimethylsiloxy)silane (TRIS) and an organic silicone macromer (bis-alpha,omega-(methacryloxypropyl) polydimethylsiloxane) has been developed using photo-polymerisation. Following interfacial hydrolysis of the CB ester, the resulting zwitterionic material became significantly more hydrophilic and exhibited high resistance to both non-specific protein adsorption and bacterial adhesion. Moreover, the stability of these non-fouling properties was dramatically improved by using a slow and controlled rate of ester hydrolysis of the original protective hydrophobic matrix. The subsequent ability to maintain the original optical and mechanical properties of the bare silicone following surface activation makes this material an ideal candidate for preparing contact lenses and other medical devices. PMID- 21300188 TI - The effect of polyethylene glycol structure on paclitaxel drug release and mechanical properties of PLGA thin films. AB - Thin films of poly(lactic acid-co-glycolic acid) (PLGA) incorporating paclitaxel typically have slow release rates of paclitaxel of the order of 1 MUg day(-1) cm( 2). For implementation as medical devices a range of zero order release rates (i.e. 1-15 MUg day(-1) cm(-2)) is desirable for different tissues and pathologies. Eight and 35 kDa molecular weight polyethylene glycol (PEG) was incorporated at 15%, 25% and 50% weight ratios into PLGA containing 10 wt.% paclitaxel. The mechanical properties were assessed for potential use as medical implants and the rates of release of paclitaxel were quantified as per cent release and the more clinically useful rate of release in MUg day(-1) cm(-2). Paclitaxel quantitation was correlated with the release of PEG from PLGA, to further understand its role in paclitaxel/PLGA release modulation. PEG release was found to correlate with paclitaxel release and the level of crystallinity of the PEG in the PLGA film, as measured by Raman spectrometry. This supports the concept of using a phase separating, partitioning compound to increase the release rates of hydrophobic drugs such as paclitaxel from PLGA films, where paclitaxel is normally homogeneously distributed/dissolved. Two formulations are promising for medical device thin films, when optimized for tensile strength, elongation, and drug release. For slow rates of paclitaxel release an average of 3.8 MUg day(-1) cm(-2) using 15% 35k PEG for >30 days was achieved, while a high rate of drug release of 12 MUg day(-1) cm(-2) was maintained using 25% 8 kDa PEG for up to 12 days. PMID- 21300189 TI - Quantitative shot-gun proteomics and MS-based activity assay for revealing gender differences in enzyme contents for rat liver microsome. AB - Liver microsomes are subcellular fractions that contain many metabolizing enzymes for drugs and endogeneous compounds. Some of these enzymes are regulated by sex hormonal control and exhibit sex-dependent expression pattern and metabolizing speed. Studying these enzymes, however, are complicated by the presence of isoforms such as cytochrome P450 (CYP450), which families share more than 50% amino acid identities. In this study, we applied quantitative shot-gun proteomics approach coupled with stable-isotope dimethyl labeling, two-dimensional reversed phase peptide separation and tandem mass spectrometry (MS) to explore the gender dependent expression of rat liver microsomal proteins. A total of 391 proteins were identified and quantified by this approach, and 56% of quantified proteins were enzymes. Although shot-gun approach is rarely used for identifying protein isoforms, we identified 53 isoforms by at least one unique peptide including 21 isoforms of CYP450s. Moreover, by quantitative and statistics assessment, we were able to classify them into 28 male dominant enzymes including CYP2C12 CYP2C11, CYP2C13, CYP2B3, CYP2C11, CYP2C70 and CYP3A2 which are known to be male specific, 21 female dominant enzymes including CYP2A1, CYP2C7, CYP2C12, CYP2D26, alcohol dehydrogenase 1, carboxylesterase 3, glutathione S-transferase, liver carboxylesterase 4, UDP-glucuronosyltransferase 2B1, and glyceraldehyde-3 phosphate dehydrogenase which are known to be female specific; and 125 sex independent enzymes. However, most of the sex specificities revealed from this study, such as the male specificity of CYP2D1, were novel and not yet reported. We then conducted a mass spectrometry-multiple reaction mode (MS-MRM) based enzyme activity method to determine the catalyzing rate of CYP2D1 in male and female liver microsomes using carteolol as its specific substrate. The reaction rate catalyzed by CYP2D1 in female rats was determined to differ significantly with the rate in male rats. Moreover, the ratio (female/male) of reaction rate (0.68) was found to correlate with their relative protein abundance (0.72). This study revealed novel sex dependences of many rat liver enzymes and also demonstrated a unique MS-based analytical platform that could identify novel iso enzymes and further quantify their abundance and enzyme activity. PMID- 21300191 TI - Psychosomatic medicine and consultation-liaison psychiatry: scope of practice, processes, and competencies for psychiatrists working in the field of CL psychiatry or psychosomatics. [corrected] A consensus statement of the European Association of Consultation-Liaison Psychiatry and Psychosomatics (EACLPP) and [corrected] the Academy of Psychosomatic Medicine (APM). [corrected] AB - OBJECTIVE: In 2008, the Board of the European Association of Consultation-Liaison Psychiatry and Psychosomatics (EACLPP) [corrected] and the Academy of Psychosomatic Medicine (APM) Council commissioned the creation of a task force to study consensus-based summaries of core roles, scope of clinical practice, and basic competencies for psychiatrists working in the field of Psychosomatic Medicine (PM) and/or Consultation-Liaison Psychiatry (CLP). METHOD: The task force used existing statements of competencies and feedback from EACLPP and APM symposia and workshops to develop a draft document. After review by the EACLPP and APM committees, and the EACLPP Board and APM Council, a period of comment from the field preceded a final draft resubmitted for consideration of the EACLPP Board and APM Council in February 2010. RESULTS: The two organizations completed approval of final publication of the consensus statement on June 11, 2010. This consensus statement is a summary of clinical competencies, scope of clinical effort, and roles considered by the sponsoring organizations to be fundamental to the practice of this subspecialty or special area of expertise, anywhere, of PM or CLP. CONCLUSION: This consensus statement delineates a set of basic competencies and roles of a PM/CLP psychiatrist to serve as an internationally recognized base that may be used by national societies and institutions to formulate their own competencies, scope of practice, and roles or help with guideline formulation. PMID- 21300190 TI - A review of treating depression in diabetes: emerging findings. AB - BACKGROUND: Depression in patients with diabetes is associated with poorer adherence and worse health outcomes, however treating depression may help improve these outcomes. OBJECTIVE: The present systematic review identified published papers to evaluate treatments for depression in patients with diabetes. RESULTS: Seventeen studies that met criteria were identified, indicating that psychosocial interventions, particularly cognitive-behavior therapy, anti-depressant medications, and collaborative care are effective in the treatment of depression in patients with diabetes. CONCLUSION: Evidence for the efficacy of these interventions in improving glycemic control was mixed. No study targeted adherence to treatment or health behaviors in addition to depression, which may be necessary to maximize improvement in diabetes outcomes such as glycemic control. PMID- 21300192 TI - A collaborative care depression management program for cardiac inpatients: depression characteristics and in-hospital outcomes. AB - BACKGROUND: Depression in cardiac patients is common, under-recognized, and independently associated with mortality. OBJECTIVES: Our objectives in this initial report from a 6-month longitudinal trial were to determine whether a collaborative care program improves rates of depression treatment by discharge among patients hospitalized with acute cardiovascular disease, and to assess key clinical characteristics of depression in this cohort. METHOD: This was a prospective, randomized trial comparing collaborative care and usual care interventions for depressed cardiac patients who were admitted to cardiac units in an urban academic medical center. For collaborative care subjects, the care manager performed a multi-component depression intervention in the hospital that included patient education and treatment coordination; usual care subjects' inpatient providers were informed of the depression diagnosis. RESULTS: The mean Patient Health Questionnaire-9 for subjects (N = 175) was 17.6 (SD 3.5; range 11 26), consistent with moderate-severe depression. The majority of subjects had depression for over one month (n = 134; 76.6%) and a prior depressive episode (n = 124; 70.8%); nearly one-half (n = 75; 42.9%) had thoughts that life was not worth living in the preceding 2 weeks. Collaborative care subjects were far more likely to receive adequate depression treatment by discharge (71.9% collaborative care vs. 9.5% usual care; p < 0.001). CONCLUSION: Depression identified by systematic screening in hospitalized cardiac patients appears was prolonged, and of substantial severity. A collaborative care depression management model appears to vastly increase rates of appropriate treatment by discharge. PMID- 21300193 TI - Survivors of self-inflicted gunshot wounds: a 20-year chart review. AB - OBJECTIVE: Due to the small number of individuals who survive self-inflicted gunshot wounds (SIGSWs), little is known about this population. This study describes a sample of 497 survivors of SIGSWs, and examines patterns of demographics (gender, ethnicity, and age) and circumstances surrounding the incident (location of wound, intoxication, intentionality, and psychiatric diagnosis), which may bear on clinical work with this at-risk population. METHOD: We conducted a retrospective chart review of psychiatry consult records over a 20 year period from a community-based medical hospital with a trauma center. Of the 9,226 patients who had psychiatry consults from 1987 to 2007, 5% involved a SIGSW. A number of factors ascertained via clinical interview regarding demographics and circumstances were examined. RESULTS: Several significant patterns emerged from the sample: (1) there was an overrepresentation of men compared with women; (2) African American survivors were younger and had a greater likelihood of being female compared with Caucasians; (3) male survivors shot themselves in the face/head/neck whereas the women shot themselves in the abdomen with more frequency; and (4) younger persons had a greater likelihood of being intoxicated at the time of the incident, initially claim the SIGSW was an accident, and receive a diagnosis of an adjustment disorder rather than a more serious depressive condition. CONCLUSIONS: This is the most comprehensive examination of SIGSW survivors conducted to date (to our knowledge). Given the usual lethality of SIGSWs, utilizing survivor data can provide critical insights, which may have implications for future research and clinical work with this vulnerable population. PMID- 21300194 TI - Impulsive behavior and associated clinical variables in Parkinson's disease. AB - BACKGROUND: Parkinson's disease (PD) is a degenerative brain disorder accompanied by the loss of dopaminergic neurons and the presence of motor and non-motor symptoms. OBJECTIVE: We performed a cross-sectional, questionnaire-based analysis of impulsive behavior in our PD clinic population to assess prevalence and associated characteristics. RESULTS: We found a higher prevalence of impulsive behavior (29.7%) than previously reported, and found multiple, concurrent impulsive behaviors in 26% of subjects reporting impulsive behavior. CONCLUSIONS: Our findings contribute to the growing awareness of impulsive behavior in PD, and support the need for longitudinal studies to assess changes in impulsive behaviors in Parkinson's patients. PMID- 21300195 TI - A provisional screening instrument for four common mental disorders in adult primary care patients. AB - OBJECTIVE: To develop an adult self-report instrument for provisional diagnosis of four common mental disorders in primary care patients. METHODS: Primary care patients were evaluated during routine clinic visits with a self-report screening tool comprised of 85 DSM-IV symptom-based candidate questions. Patients with a physician-assessed provisional diagnosis for generalized anxiety disorder (GAD), major depressive episode (MDE), past/present mania, and adult attention deficit/hyperactivity disorder (ADHD), or none of these, completed additional self-report clinical questionnaires, and then were interviewed on the telephone by a trained rater for a SCID/ACDS diagnosis. Responses to the symptom-based candidate questions were used to calculate sensitivity and specificity for a SCID/ACDS diagnosis (GAD, N = 24; MDE, N = 89; Mania, N = 24; ADHD, N = 65) and to select the optimal four questions for each diagnosis to be included in the instrument. RESULTS: Analyses resulted in a 17-item instrument for provisional differential diagnosis of GAD, MDE, past/present mania, and ADHD. Comparison of limited symptom-based versus full DSM-IV criteria-based diagnosis showed minimal differences for relative diagnostic accuracy. Sensitivities and specificities, respectively, were 83% and 75% for GAD, 80% and 80% for MDE, 83% and 82% for mania, and 82%and 73% for ADHD. CONCLUSIONS: Based on this preliminary work, the Provisional Diagnostic Instrument-4 is a brief, easily scored, self-report instrument that may assist primary care physicians to identify potential cases of GAD, MDE, past/present mania, and ADHD. PMID- 21300196 TI - Predictors of psychological distress after diagnosis in breast cancer patients and patients with benign breast problems. AB - OBJECTIVE: The objective of this study was to determine how age and psychological characteristics assessed prior to diagnosis could predict psychological distress in outpatients immediately after disclosure of their diagnosis. METHODS: This is a longitudinal and prospective study, and participants were breast cancer patients and patients with benign breast problems (BBP). Patients were asked to complete questionnaires to determine levels of the following: trait anxiety (State-Trait Anxiety Inventory), negative emotional suppression (Courtauld Emotional Control Scale), life stress events (Life Experiences Survey), and psychological distress (Profile of Mood Status) prior to diagnosis. They were asked to complete a questionnaire measuring psychological distress after being told their diagnosis. We analyzed a total of 38 women diagnosed with breast cancer and 95 women diagnosed with a BBP. RESULTS: A two-way analysis of variance (prior to, after diagnosis * cancer, benign) showed that psychological distress after diagnosis among breast cancer patients was significantly higher than in patients with a BBP. The multiple regression model accounted for a significant amount of variance in the breast cancer group (model adjusted R(2) = 0.545, p < 0.001), and only trait anxiety was statistically significant (beta = 0.778, p < 0.001). In the BBP group, the multiple regression analysis yielded a significant result (model adjusted R(2) = 0.462, p < 0.001), with trait anxiety and negative life changes as statistically significant factors (beta = 0.449 and 0.324 respectively; p < 0.01). CONCLUSIONS: In both groups, trait anxiety assessed prior to diagnosis was the significant predictor of psychological distress after diagnosis, and might have prospects as a screening method for psychologically vulnerable women. PMID- 21300197 TI - Relationship between physical activity and mental health in a nationwide sample of Korean adults. AB - OBJECTIVE: There is widespread recognition of the effect of physical activity on mental health. The authors examined the relationships between physical activity and mental health in a nationwide sample of Korean adults. METHODS: A total of 6,510 subjects aged 18 to 64 years participated in the study. The short form of the International Physical Activity Questionnaire was used to estimate the level of physical activity. Mental health was assessed using the Composite International Diagnostic Interview, the Epidemiological Studies Depression Scale (CES-D), and the General Health Questionnaire (GHQ). Logistic regression analysis was used to compare the prevalence of CES-D and GHQ cases and psychiatric disorders among the following physical activity categories: inactive, minimally active, and health-enhancing physical activity (HEPA) active. RESULTS: HEPA active or minimally active subjects were less likely to be classified as "depressed" on the CES-D (>=21) and "psychologically distressed" on the GHQ (>=3) than were physically inactive subjects. HEPA was associated with a significantly decreased 1-year prevalence of major depressive disorder and obsessive-compulsive disorder, and with a significantly increased 1-year prevalence of alcohol abuse, relative to physical inactivity. In addition, HEPA was associated with a significantly increased 1 year prevalence of alcohol abuse, relative to minimal physical activity. Physical inactivity was associated with a significantly increased 1-year prevalence of alcohol dependence, relative to physical inactivity. CONCLUSIONS: The results indicate a negative association between physical activity and depressive and anxiety disorders. A high level of physical activity seems to be associated with alcohol abuse, but a moderate level of physical activity may play a role in preventing alcohol dependence. PMID- 21300198 TI - Manganese neurotoxicity presenting with depression, psychosis and catatonia. PMID- 21300199 TI - Voltage-gated potassium channel-complex antibody-associated limbic encephalitis. PMID- 21300200 TI - Psychiatric manifestations of anti-NMDA receptor encephalitis in a man without tumor. PMID- 21300201 TI - A case report of closed-eye visual hallucinations. PMID- 21300202 TI - Zolpidem-associated parasomnia with serious self-injury: a shot in the dark. PMID- 21300203 TI - Mirtazapine-induced worsening of restless legs syndrome (RLS) and ropinirole induced psychosis: challenges in management of depression in RLS. PMID- 21300204 TI - Re: Psychiatric evaluation of mental capacity in the general hospital: a significant teaching opportunity. PMID- 21300205 TI - Interferon-alpha as an appropriate model of substance-induced depression. PMID- 21300206 TI - Foreword. Poly(ADP-ribose) polymerase inhibitors in clinical development. PMID- 21300208 TI - [2010 hot topics in respiratory diseases. Introduction]. PMID- 21300209 TI - [Advances in asthma: review of publications in Archivos de Bronconeumologia in the last year]. AB - Interest in asthma research among Spanish pneumologists is increasing. In the last year, 22 articles on asthma have been published in Archivos de Bronconeumologia, six more than in the previous year. Furthermore, 56 communications were presented at the National Congress of the Spanish Society of Pneumology and Thoracic Surgery and were published in a supplement of the journal, representing 60% more than in the previous year's congress. A critical review of all these articles is provided. The original articles contribute further knowledge on epidemiological and clinical aspects of the disease and basic research. A notable contribution is the publication of two clinical practice guidelines, the Spanish Guideline for the Management of Asthma 2009 and the ALERTA-2 Guideline for the Management of Asthma Exacerbations. These two guidelines represent not only an update but also a change in the methodology used in their drafting, thus improving their scientific quality. PMID- 21300207 TI - PARP inhibitor treatment in ovarian and breast cancer. PMID- 21300210 TI - [Pulmonary circulation: what has 2010 brought?]. AB - In both thromboembolic disease and pulmonary hypertension, 2010 has been a prodigious year for interesting publications. Some data have helped to elucidate the factors associated with a greater risk of thromboembolic disease, such as long journeys and certain polymorphisms. New recommendations on diagnosis have been made, giving a greater role to computed tomography angiography. Magnetic resonance imaging is also gaining ground. More accurate risk evaluation is one of the objectives of the new guidelines of the European Society of Cardiology, which substitute some terms such as massive or submassive for high- and low-risk. Maintaining anticoagulation indefinitely in idiopathic pulmonary thromboembolism is recommended. Evidence on the efficacy of new drugs such as rivaroxaban, dabigatran and indraparinux is beginning to appear. In pulmonary hypertension, smoking seems to play a role as a risk factor. Some registries indicate that new treatments have not improved survival. Greater knowledge has been gained of the role of inflammation in the pathogenesis of the disease and a Spanish study supports the role of the 6-minute walk test in patient evaluation. Some drugs are highlighted in the literature. Imatinib is promising but probably only in some patients. Riociguat provides good results and inhaled treprostinil has emerged as a new option. PMID- 21300211 TI - [Video-assisted thoracic surgery, lung transplantation and mediastinitis: major issues in thoracic surgery in 2010]. AB - We reviewed the major issues in thoracic surgery relating to the advances made in our specialty in 2010. To do this, the 43(rd) Congress of the Spanish Society of Pneumology and Thoracic Surgery held in La Coruna and the articles published in the Society's journal, Archivos de Bronconeumologia, were reviewed. The main areas of interest were related to the development of video-assisted thoracic surgery, lung transplantation and descending mediastinitis. The new tumor-node metastasis (TNM) classification (7(th) edition), presented last year, was still a topical issue this year. The First Forum of Thoracic Surgeons and the Update in Thoracic Surgery together with the Nurses' Area have constituted an excellent teaching program. PMID- 21300212 TI - [Publications in respiratory nursing and physiotherapy]. AB - The Respiratory Nursing and Physiotherapy Section of the Spanish Society of Pneumology and Thoracic Surgery, established as a working group more than 19 years ago, has been characterized by a high degree of involvement and collaboration with all the research studies requiring nursing and physiotherapy techniques. However, publication of articles by this collective is scarce compared with that of the rest of the Society and the characteristics, attitudes and limitations of this section pose an obstacle to increasing the number of its publications. This article aims to explain some of the possible reasons that could have given rise to this situation. The new tendencies and the attitude of this collective and the rest of the Society are encouraging and suggest that the work of the Respiratory Nursing and Physiotherapy Section will be better reflected in the future. PMID- 21300213 TI - [Chronic obstructive pulmonary disease in Archivos de Bronconeumologia in 2010]. AB - Chronic obstructive pulmonary disease (COPD) continues to cause concern among health professionals treating respiratory diseases worldwide. The reasons for the increasing tendency in prevalence, morbidity and mortality rates are under constant investigation. Areas of research include identification of new phenotypes, predisposing factors, and physiopathological and epidemiological features that are still not completely known, as well as the systemic behavior of this disease and its relationship with other, associated pathological states. New and encouraging alternative treatments are also being investigated. This unceasing search for scientific knowledge is reflected in the number of studies published in each of the sections of Archivos de Bronconeumologia throughout 2010, which deal with most of the pressing issues concerning this disease and which will be summarized in the present article. More than 60% of the contents of the journal's supplements were related to COPD. A monographic issue, produced for training purposes, was published and consisted of three units: the first was entitled "The thousand and one faces of COPD", the second "COPD: from etiopathogenesis to treatment" and the third "COPD: how can patient care be improved?". The authors of these units provide an in-depth and up-to-date analysis of topics relating COPD to various pathological states and include an analysis of the disease in two population groups that have aroused recent interest, namely, women and non-smokers. The third unit of the monograph deals exclusively with the patient. PMID- 21300214 TI - [The air belongs to us: the importance of maintaining air quality]. AB - Interest in identifying the long-term harmful effects of atmospheric pollution on respiratory health, and concern about this issue, has prompted several studies, whose results have been published throughout this year. On the occasion of the Spanish Society of Pneumology and Thoracic Surgery's Year of the Environment, from the Section of Occupational and Environmental Respiratory Diseases, we review the advances made in the effects of atmospheric pollution on respiratory health and the actions undertaken by the Society. The main objective of the Society's Year of the Environment is to inform citizens in general and respiratory patients in particular of the benefits of breathing clean air. The first step in achieving this aim is education. The goal is to educate young people in lasting habits that promote a respectful attitude to the environment, inculcating them with the need for sustainable development through responsible energy consumption and reduction of the emission of pollutants. Informed citizens will demand public health policies aimed at maintaining the quality of the air we breathe from politicians. The website www.elaireesnuestro.com provides information and educational material on the subject. PMID- 21300215 TI - [Treatment of lung cancer with chest wall invasion]. AB - The aim of this study was to analyze chest wall invasion, the indication and multidisciplinary nature of treatment, the methods used for parietal reconstruction and the technical problems posed by this procedure in patients with lung cancer and chest wall invasion. Chest wall invasion from adjacent malignancies affects 5% of patients with a bronchogenic carcinoma. Preoperative determination of parietal invasion aids the planning of an appropriate therapeutic approach. Positron emission tomography combined with computed tomography (PET/CT) improves the study of T-factor and metastatic nodal involvement and distant metastases. As a rule, surgical treatment should attempt complete tumoral resection: lobectomy, resection of the parietal pleura and/or of the chest wall--ensuring tumor-free margins--and hilar and mediastinal lymphadenectomy. We also analyzed the distinct prognostic factors for survival, as well as the indication for induction or adjuvant therapy. Chest wall reconstruction involves recreating the most anatomical and physiological conditions possible in the chest cavity and surrounding muscles. The ideal reconstruction would achieve adequate parietal stability and coverage to preserve functionality, with the cosmetic result being an important, but secondary, consideration. Many materials are available for reconstruction and the choice of material should be individualized in each patient. A multidisciplinary team able to plan and perform the resection and subsequent reconstruction, oversee postoperative management and treat complications early is essential. PMID- 21300216 TI - [Advances in respiratory health 2010: the perspective from the Smoking and Health Section]. AB - The Smoking and Health Section of the Spanish Society of Pneumology and Thoracic Surgery has been highly active in research throughout 2010. Many of the research studies performed have led to interesting publications. The present article analyzes the main clinical and basic research articles published by the distinct members of the Society's Smoking and Health Section. The various disciplines included under the heading of smoking are reviewed: diagnosis and treatment, epidemiology, genetics, bibliometry and tobacco-related diseases. PMID- 21300217 TI - [Advances in respiratory health 2010: Techniques and Transplantation Section]. AB - Five articles and an editorial on interventional pneumology were published in Archivos de Bronconeumologia. Two of these articles deal with bronchoscopy, one with lung biopsy with cryoprobes, one with thermoplasty in asthma and the last with tracheobronchomalacia. We also review several publications in international journals, with special emphasis on endobronchial ultrasound. Four original articles on idiopathic pulmonary fibrosis were published in Archivos de Bronconeumologia: one special article comparing two treatments and a Cochrane systematic review on the efficacy of non-steroidal drugs in this disease. Finally, we highlight studies in lung transplantation, consisting of 14 publications from different continents and with highly diverse contents: one editorial, one letter to the editor, one procedures manual and nine international publications on donor characteristics, various types of complications, experimental results in the field of preservation, and the casuistics obtained in distinct diseases in which transplantation is an option. PMID- 21300218 TI - [Hot topics in respiratory infections]. AB - We review the most interesting articles on respiratory infections published in the last trimester of 2009 and in 2010. Notable publications in bronchiectasis were the Guidelines of the British Thoracic Society, as well as several articles on the natural course of the process, the impact of exacerbations on the course of the disease, and treatment with inhaled antibiotics. Other notable publications were the SEPAR-SEIMC consensus document for the management of tuberculosis and articles on the use of interferon-gamma in the diagnosis of tuberculosis infection. The new recommendations of the Spanish Society of Pneumology and Thoracic Surgery on community-acquired pneumonia have recently been published. Equally important are studies on the viral etiology of community acquired pneumonia, the impact of corticosteroid treatment in pneumonia, the duration of antibiotic therapy and preventive measures in both community-acquired and nosocomial pneumonia. PMID- 21300219 TI - [Sleep-apnea syndrome, mechanical ventilation and critical care in Archivos de Bronconeumologia (December 2009-December 2010)]. AB - The present study aims to review all the major articles on respiratory sleep disorders, mechanical ventilation, and respiratory critical care published in the last year in Archivos de bronconeumologia. Between December 2009 and November 2010, 15 studies on these topics were published in Archivos de bronconeumologia. Ten of these studies dealt with respiratory sleep disorders, consisting of six original articles, one special article, one review article, one letter to the editor and one supplement on chronic obstructive pulmonary disease and its association with sleep apneas. Five articles were published on non-invasive mechanical ventilation: one editorial, one special article, one article in a supplement and two original articles. As in previous years, there was a marked difference in the number of articles published on non-invasive mechanical ventilation and sleep-apnea syndrome, with a greater number of articles being published on the latter. Although some articles highlight the importance of the place where ventilation is commenced, no study specifically dealing with intermediate care units was published in Archivos de bronconeumologia in 2010. This absence could be interpreted as a result of the low implantation of this type of unit in Spain, contrasting with the high activity undertaken in this field by pneumology services. PMID- 21300220 TI - Orthodontic extractions and the Internet: quality of online information available to the public. AB - INTRODUCTION: The aim of this study was to evaluate the quality of information available on the Internet for a person interested in orthodontic extractions. METHODS: The term "orthodontic extractions" was entered into the search engines of both Google and Yahoo, and the first 50 Web links for each were pooled and examined. Exclusion criteria consisted of repetitions, sites requiring registration or login, and those accessing scientific articles. Sites fulfilling the criteria for inclusion were examined by using the LIDA instrument, a validated method of evaluating health care Web sites, based on accessibility, usability, and reliability. The readability of each site was further assessed by using the Flesch reading ease score. RESULTS: Of the 100 Web sites identified, 21 were suitable for inclusion and scoring. Overall, the mean total LIDA score was 93 of a possible 144 (65%) (range, 71-116 or 49%-81%). No Web site scored above an arbitrary gold standard of 90%; however, most (20 of 21) scored above 50%. With the LIDA instrument, average accessibility was 70%, average usability was 72%, and average reliability was 41%. The average Flesch reading ease score was 58.3. CONCLUSIONS: Overall, the quality of information available on the Internet with regard to orthodontic extractions is variable. Although readability is generally good, reliability is a cause for concern, and patients should interpret many of these sites with caution. The top-rated Web sites in a search engine are not necessarily those of the highest quality. PMID- 21300221 TI - Duration of treatment and occlusal outcome using Damon3 self-ligated and conventional orthodontic bracket systems in extraction patients: a prospective randomized clinical trial. AB - INTRODUCTION: This was a prospective randomized clinical trial comparing the effect of bracket type on the duration of orthodontic treatment and the occlusal outcome as measured by the peer assessment rating (PAR). METHODS: A multi-center randomized clinical trial was carried out in 2 orthodontic clinics. Sixty-two subjects (32 male, 30 female; mean age, 16.27 years) with a mean pretreatment PAR score of 39.40, mandibular irregularity from 5 to 12 mm, and prescribed extractions including mandibular first premolars were randomly allocated to treatment with either the Damon3 self-ligated or the Synthesis conventional ligated preadjusted bracket systems (both, Ormco, Glendora, Calif). An identical archwire sequence was used in both groups excluding the finishing archwires: 0.014-in, 0.014 * 0.025-in, and 0.018 * 0.025-in copper-nickel-titanium aligning archwires, followed by 0.019 * 0.025-in stainless steel working archwires. Data collected at the start of treatment and after appliance removal included dental study casts, total duration of treatment, number of visits, number of emergency visits and breakages during treatment, and number of failed appointments. RESULTS: Sixty-two patients were recruited at the start of treatment, and the records of 48 patients were analyzed after appliance removal. Accounting for pretreatment and in-treatment covariates, bracket type had no effect on overall treatment duration, number of visits, or overall percentage of reduction in PAR scores. Time spent in space closure had an effect on treatment duration, and the pretreatment PAR score influenced only the reduction in PAR as a result of treatment. CONCLUSIONS: Use of the Damon3 bracket does not reduce overall treatment time or total number of visits, or result in a better occlusal outcome when compared with conventional ligated brackets in the treatment of extraction patients with crowding. PMID- 21300222 TI - Effect of bone thickness on alveolar bone-height measurements from cone-beam computed tomography images. AB - INTRODUCTION: Cone-beam computed tomography (CBCT) has been used to assess alveolar bone changes after rapid palatal expansion. The purpose of this study was to investigate the accuracy of alveolar bone-height measurements from CBCT images with varied bone thicknesses and imaging resolutions. METHODS: Eleven maxillary specimens from 6-month-old pigs were measured for alveolar bone height (distance between drilled reference holes and alveolar crests) at 6 locations with a digital caliper, followed by CBCT scanning at 0.4-mm and 0.25-mm voxel sizes. Buccal alveolar bone of these locations was then reduced approximately by 0.5 to 1.5 mm, followed by CBCT rescanning with the same voxel sizes. The CBCT images were measured by using 3-dimensional software to determine alveolar bone height and thickness in buccolingual slices by independent, blinded raters. The specimens were subsequently cut into buccolingual sections at reference-hole levels, and direct bone height and thickness were measured from these sections. Intrarater and interrater repeatability and the differences between CBCT and direct measurements were assessed. RESULTS: Excellent intrarater (intraclass correlations, r = 0.89-0.98) and good interrater (r = 0.64-0.90) repeatability values were found for alveolar bone-height measurements from the CBCT images. Before alveolar bone reduction, the thickness was much greater than the CBCT voxel size (0.4 mm), and bone-height measurements from the CBCT images were 0.5 to 1 mm more than the direct measurements (paired t tests, P <0.017 at most locations). After bone reduction, the thickness at the subcrest 1-mm level was near or below the CBCT voxel size (0.4 mm), and bone-height measurements from the CBCT images were 0.9 to 1.2 mm less than the direct measurements (paired t tests, P <0.017 at most locations). These measurement inaccuracies were substantially improved by decreasing the CBCT voxel size to 0.25 mm. CONCLUSIONS: Alveolar bone height measurements from conventional clinical 0.4-mm voxel size CBCT images might overestimate alveolar bone-height loss associated with rapid palatal expansion. PMID- 21300223 TI - External apical root resorption in patients treated by serial extractions followed by mechanotherapy. AB - INTRODUCTION: In the course of orthodontic treatment with serial extractions (SE), spontaneous unraveling of crowded incisors occurs. It was hypothesized that SE followed by mechanotherapy will cause less external apical root resorption (EARR) than orthodontic treatment with late extractions (LE). METHODS: The records of 24 patients who underwent SE and mechanotherapy and 24 control patients who underwent LE and mechanotherapy were examined. The groups were matched for sex, central incisor root development and morphology, malocclusion class, ANB angle, and overjet. Lateral cephalograms taken before mechanotherapy (T1) and after mechanotherapy (T2) were traced and superimposed on the palatal plane with registration on the osseous details superior to the maxillary incisors and on the palatal curve. The T1 and T2 central incisor lengths, changes in the axial inclination, and horizontal and vertical apical movements were measured. RESULTS: The tooth lengths in both groups were reduced: the EARR values were 1.8 mm (+/- 1.1) in the SE group and 2.1 mm (+/- 1.4) in the LE group, and the difference between the groups was not significant. The movements of the teeth in both groups were similar in absolute values. CONCLUSIONS: The spontaneous unraveling of incisor crowding with SE treatment does not prevent the common EARR seen in patients treated with LE, when the patients are treated by mechanotherapy after the SE. PMID- 21300224 TI - Evaluation of upper airway obstruction in Class II children with fluid-mechanical simulation. AB - INTRODUCTION: The purpose of this study was to test the null hypothesis that dolichofacial and brachyfacial children with Class II malocclusion do not differ in upper airway obstruction. Furthermore, the ability of fluid-mechanical simulation to detect airway obstruction within the limitations of simulation was examined. METHODS: Forty subjects from 7 to 11 years of age with Class II malocclusion participated and were divided into 2 groups, dolichofacial and brachyfacial, based on their Frankfort mandibular plane angles. Cone-beam computed tomography images supplied the shape of the entire airway. Two measures of respiratory function, air velocity and pressure, were simulated by using 3 dimensional images of the airway. The images and simulations were compared between the 2 facial types. RESULTS: The size of the upper airway did not differ statistically between facial types; however, the simulated maximal pressure and velocity of the dolichofacial type were significantly higher than those of the brachyfacial type. CONCLUSIONS: Airway obstruction differs with the Frankfort mandibular plane angle, even though the depth and cross-sectional area of the airway do not. The fluid-mechanical simulation system developed in this study detected differences in airway obstruction that were not apparent from morphologic studies. PMID- 21300225 TI - Effect of miniscrew angulation on anchorage resistance. AB - INTRODUCTION: Even though the use of titanium miniscrews to provide orthodontic anchorage has become increasingly popular, there is no universally accepted screw placement protocol. Variables include the presence or absence of a pilot hole, placement through attached or unattached soft tissue, and angle of placement. The purpose of this in-vitro study was to test the hypothesis that screw angulation affects screw-anchorage resistance. METHODS: Three-dimensional finite element models were created to represent screw-placement orientations of 30 degrees , 60 degrees , and 90 degrees , while the screw was displaced to 0.6 mm at a distance of 2.0 mm from the bone surface. In a parallel cadaver study, 96 titanium alloy screws were placed into 24 hemi-sected maxillary and 24 hemi-sected mandibular specimens between the first and second premolars. The specimens were randomly and evenly divided into 3 groups according to screw angulation (relative to the bone surface): 90 degrees vs 30 degrees screw pairs, 90 degrees vs 60 degrees screw pairs, and 30 degrees vs 60 degrees screw pairs. All screws were subjected to increasing forces parallel to the occlusal plane, pulling mesially until the miniscrews were displaced by 0.6 mm. A paired-samples t test was used to assess the significance of differences between 2 samples consisting of matched pairs of subjects, with matched pairs of subjects including 2 measurements taken on the same subject. One-way analysis of variance (ANOVA) with the post-hoc Tukey studentized range test was conducted to determine whether there were significant differences, and the order of those differences, in anchorage resistance values among the 3 screw angulations at maxillary and mandibular sites. RESULTS: The finite element analysis showed that 90 degrees screw placement provided greater anchorage resistance than 60 degrees and 30 degrees placements. In the cadaver study, although the maximum anchorage resistance provided by screws placed at 90 degrees to the cadaver bone surface exceeded, on average, the anchorage resistance of the screws placed at 60 degrees , which likewise exceeded the anchorage resistance of screws placed at 30 degrees , these differences were not statistically significant. CONCLUSIONS: Placing orthodontic miniscrews at angles less than 90 degrees to the alveolar process bone surface does not offer force anchorage resistance advantages. PMID- 21300226 TI - Three-dimensional analysis of peri-bone-implant contact of rough-surface miniscrew implants. AB - INTRODUCTION: In this study, we evaluated the effects of surface modifications of miniscrew implants (MSIs) and force application on bone surrounding MSIs. METHODS: Seven skeletally mature male foxhound dogs were followed for 9 weeks; a randomized split-mouth design was used to compare 21 MSIs with sandblasted, large grit, and acid-etched (SLA) surfaces and 21 identical machine-surfaced MSIs. MSIs immediately loaded with 200-g nickel-titanium coil springs were compared with unloaded MSIs. Bone volume to total volume ratios of cortical and noncortical bone regions were measured at 6 to 24 MUm and 24 to 42 MUm from the entire MSI surface using microcomputed tomography with an isotropic resolution of 6 MUm. RESULTS: Clinical success of SLA-surfaced MSIs was 100%, compared with 85.7% for machine-surfaced MSIs. There was significantly (P <0.05) more bone at the coronal aspects of the SLA-surfaced than the machine-surfaced MSIs; the SLA-surfaced MSIs also showed significantly greater decreases in bone between their most coronal and apical aspects. MSIs that were loaded demonstrated significantly (P <0.05) greater decreases in surrounding bone than unloaded MSIs. The amount of bone within 6 to 24 MUm of the MSIs was significantly less than that within 24 to 42 MUm. Mean placement torque was higher for the SLA-surfaced (42 Ncm) than the machine-surfaced (39 Ncm) MSIs, but the difference was not statistically significant. CONCLUSIONS: SLA surface treatment and loadings have significant effects on bone surrounding the MSIs; this might be related to higher success rates and greater secondary stability. PMID- 21300227 TI - New model for surgical and nonsurgical therapy in adults with Class III malocclusion. AB - INTRODUCTION: Not all adult Class III malocclusion patients are candidates for surgical correction. In patient assessment and selection, major issues remain regarding diagnosis and treatment planning. The purpose of this investigation was to ascertain whether adding a transverse parameter to a discriminant analysis could improve the classification of adults with Class III malocclusion into 2 groups of patients: those who can effectively be treated by orthodontic therapy and those who require orthognathic surgery. METHODS: Cephalograms, plaster casts, and extraoral photos of 69 adults with Class III malocclusion were analyzed. A discriminant analysis was performed to identify the variables that best separate the 2 groups. RESULTS: Stepwise variable selection resulted in a new, highly significant (P <0.0001) model of 4 variables that provided the best discriminant function to distinguish between patients with and without indications for surgical correction. The resulting equation was the following: score = -10.988 + 0.243 * Wits + 0.055 * M/M ratio + 0.068 * NSAr - 0.589 * mand MLD. The percentage of patients correctly classified by this equation was 91.3%. The sensitivity was 0.92, and the specificity was 0.89. CONCLUSIONS: In the discriminant analysis, the mandibular midline deviation as a transverse component was included. The addition of the transverse variable led to an improved model concerning the predictive value in Class III malocclusion patients with surgical requirements. PMID- 21300228 TI - How important are lateral cephalometric radiographs in orthodontic treatment planning? AB - INTRODUCTION: The purpose of this study was to investigate whether lateral cephalometric radiographs influence orthodontic treatment planning. It aimed to compare the odds of a change in treatment plan in three groups of orthodontists who treatment planned six cases on two occasions, T1 and T2, with the provision of a lateral cephalometric radiograph being varied. METHODS: The records of 6 orthodontic patients were copied onto compact discs and sent to the 199 participating orthodontists. The orthodontists were allocated to 3 groups, A, B, and C. Clinicians in group A were given all records except the lateral cephalometric radiographs at the T1 and T2 planning sessions. Clinicians in group B were given all records except the lateral cephalometric radiograph at T1 and all records including the lateral cephalometric radiograph and tracing at T2. Clinicians in group C were given all records including the lateral cephalometric radiographs and tracings at T1 and T2. All participants were sent records at T1; those who returned the treatment-planning questionnaire were sent the second set of records and questionnaire at T2, 8 weeks later. Invitations to participate were distributed to all specialist orthodontists who were members of the British Orthodontic Society (n = 950). Of these, 199 orthodontists agreed to take part, a response rate of 21%. Of the 199 who agreed to participate, 149 completed the first treatment-planning questionnaire (T1), for a response rate of 75%. Of the 149 who completed that questionaire, 114 completed the second treatment-planning questionnaire (T2), for a 77% response rate. RESULTS: The availability of a lateral cephalometric radiograph and its tracing did not make a significant difference to any treatment-planning decisions, with the exception of the decision to extract or not between groups B and C for all 6 patients combined, and between groups B and C and groups B and A for patient 4 (Class I incisor relationship on a Class II skeletal base). CONCLUSIONS: For most treatment planning decisions in these 6 patients, the availability of a lateral cephalometric radiograph and its tracing did not make a significant difference to the treatment decisions. For 1 patient, there was a significant change in the extraction decision when a lateral cephalometric radiograph was provided. This highlights the uncertainty surrounding the necessity for lateral cephalometric radiographs in treatment planning. Further research in this area is encouraged to resolve this dichotomy. PMID- 21300229 TI - Factors controlling anterior torque with C-implants depend on en-masse retraction without posterior appliances: biocreative therapy type II technique. AB - INTRODUCTION: Our objective was to evaluate the factors that affect effective torque control during en-masse anterior retraction by using intrusion overlay archwire and partially osseointegrated C-implants as the exclusive sources of anchorage without posterior bonded or banded attachments. METHODS: Base models were constructed from a dental study model. No brackets or bands were placed on the posterior maxillary dentition during retraction. Different heights of the anterior retraction hooks to the working segment archwire and different intrusion forces with an overlay archwire placed in the 0.8-mm diameter hole of the C implant were applied to generate torque on the anterior segment of the teeth. The amount of tooth displacement after finite element analysis was exaggerated 70 times and compared with tooth axis graphs of the central and lateral incisors and the canine. RESULTS: The height of the anterior retraction hook and the amount of intrusion force had a combined effect on the labial crown torque applied to the incisors during en-masse retraction. The difference of anterior retraction hook length highly affected the torque control and also induced a tendency for canine extrusion. CONCLUSIONS: Three-dimensional en-masse retraction of the anterior teeth as an independent segment can be accomplished by using partially osseointegrated C-implants as the only source of anchorage, an intrusion overlay archwire, and a retraction hook (biocreative therapy type II technique). PMID- 21300233 TI - Treatment effects of the light-force chincup. PMID- 21300230 TI - Physical properties of root cementum: part 15. Analysis of elemental composition by using proton-induced x-ray and gamma-ray emissions in orthodontically induced root resorption craters of rat molar cementum after exposure to systemic fluoride. AB - INTRODUCTION: Root resorption resulting from orthodontic treatment is an unpredictable adverse effect. Literature examining the potential protective influence of tooth cementum minerals against orthodontically induced inflammatory root resorption has been sparse. Fluorine could have a role in minimizing the extent and severity of resorptive lesions. The purpose of this study was to examine the elemental content of tooth cementum in orthodontically induced inflammatory root resorption lesions and the effect of systemic fluoride. METHODS: Twenty 7-week-old Wistar rats were divided into 2 groups of 10 and exposed to systemic fluoride (100 ppm) or nonfluoridated drinking water for 2 weeks. Orthodontic tooth movement was implemented with a nickel-titanitum closing coil with a force of 100 g. The molars were then extracted, dissected, and prepared for cross-sectioning through the largest mesial midroot crater. The samples were mounted and scanned by using the Commonwealth Scientific and Industrial Research Organisation and the Australian Research Council's National Key for Geochemical Evolution and Metallogeny of Continents Nuclear Microprobe (Melbourne, Victoria, Australia). Analysis of variance (ANOVA) was used for statistical comparison of the elements and to determine the effect of fluoride, and unaffected tooth structure compared with root resorption craters. The Student t test was used to compare root crater lengths and depths of the fluoride vs no fluoride groups. RESULTS: Root resorption lesions of the group exposed to fluoride were significantly reduced in length and depth (P <0.01). The mineral content of the root resorption craters of the fluoride group had higher concentrations of fluorine and zinc (P <0.01). There was less calcium in the craters of the no-fluoride group compared with the fluoride group (P <0.05). CONCLUSIONS: Cementum quality (influenced by systemic fluoride exposure) might impact the extent of orthodontically induced resorptive defects. PMID- 21300234 TI - Systematic review of self-ligating brackets. PMID- 21300236 TI - Systematic review of glass-ionomer adhesives. PMID- 21300238 TI - Three-dimensional evaluation of soft-tissue changes. PMID- 21300239 TI - Clinical research for the good of the specialty: bravo! PMID- 21300241 TI - Avoiding collaborative failure. PMID- 21300243 TI - Stability of treatment for anterior open-bite malocclusion: a meta-analysis. AB - INTRODUCTION: Anterior open-bite (AOB) treatment is considered challenging because of difficulties in determining and addressing etiologic factors and the potential for relapse in the vertical dimension after treatment. In this review, we compiled evidence on the long-term stability of the major therapeutic interventions for correcting AOB. Our objective was to review and compile evidence for the stability of surgical and nonsurgical therapies for AOB malocclusion. Our data sources were PubMed, EMBASE, Cochrane Library, limited gray literature search, and hand searching. METHODS: A search was performed of the electronic health literature on the stability of AOB after treatment. Hand searching of major orthodontic journals and limited gray literature searching was also performed, and all pertinent abstracts were reviewed for inclusion. Full articles were retrieved for abstracts or titles that met the initial inclusion criteria or lacked sufficient detail for immediate exclusion. Studies accepted for analysis were reviewed and their relevant data retrieved for pooling. The long-term stability estimates were pooled into nonsurgical and surgical groups, and summary statistics were generated. RESULTS: One hundred five abstracts met the initial search criteria, and 21 articles were included in final analyses. Rejected articles failed to exhibit follow-up times of 12 months or more, did not include measurements of overbite (OB), or did not meet inclusion criteria. All included articles were divided into a surgical group (SX) with a mean age of 23.3 years and a nonsurgical group (NSX) with a mean age of 16.4 years. All studies were case series. Random-effects statistical models were used to pool the mean OB measures before and after treatment and also at the long-term follow-up. The pretreatment adjusted means of OB were -2.8 mm for the SX and -2.5 mm for the NSX. AOB closures up to +1.6 mm (SX) and +1.4 mm (NSX) were achieved. Relapse in the SX group during the mean 3.5 years of follow-up reduced the OB to +1.3 mm; the NSX group relapsed to +0.8 mm in the mean 3.2 years of follow-up. Pooled results indicated reasonable stability of both the SX (82%) and NSX (75%) treatments of AOB measured by positive OB at 12 or more months after the treatment interventions. CONCLUSIONS: In the included case series publications, success of both the SX and NSX treatments of AOB appeared to be greater than 75%. Because the SX and the NSX were examined in different studies and applied to different clinical populations, no direct assessment of comparative effectiveness was possible. The pooled results should be viewed with caution because of the lack of within-study control groups and the variability among studies. PMID- 21300244 TI - Body dysmorphic disorder: a screening guide for orthodontists. AB - Body dysmorphic disorder is a psychiatric condition that affects about 2% of the population. The objective of this article was to create awareness among orthodontists of this disorder and offer guidelines for its detection. As clinicians providing cosmetic services, orthodontists are likely to have patients with body dysmorphic disorder requesting treatment. PMID- 21300245 TI - Smile line assessment comparing quantitative measurement and visual estimation. AB - INTRODUCTION: Esthetic analysis of dynamic functions such as spontaneous smiling is feasible by using digital videography and computer measurement for lip line height and tooth display. Because quantitative measurements are time-consuming, digital videography and semiquantitative (visual) estimation according to a standard categorization are more practical for regular diagnostics. Our objective in this study was to compare 2 semiquantitative methods with quantitative measurements for reliability and agreement. METHODS: The faces of 122 male participants were individually registered by using digital videography. Spontaneous and posed smiles were captured. On the records, maxillary lip line heights and tooth display were digitally measured on each tooth and also visually estimated according to 3-grade and 4-grade scales. Two raters were involved. An error analysis was performed. Reliability was established with kappa statistics. RESULTS: Interexaminer and intraexaminer reliability values were high, with median kappa values from 0.79 to 0.88. Agreement of the 3-grade scale estimation with quantitative measurement showed higher median kappa values (0.76) than the 4 grade scale estimation (0.66). Differentiating high and gummy smile lines (4 grade scale) resulted in greater inaccuracies. The estimation of a high, average, or low smile line for each tooth showed high reliability close to quantitative measurements. CONCLUSIONS: Smile line analysis can be performed reliably with a 3 grade scale (visual) semiquantitative estimation. For a more comprehensive diagnosis, additional measuring is proposed, especially in patients with disproportional gingival display. PMID- 21300246 TI - Factors affecting demineralization during orthodontic treatment: a post-hoc analysis of RCT recruits. AB - INTRODUCTION: Our aim was to determine predictors for the presence and degree of demineralization during orthodontic treatment. This study was a post-hoc analysis of recruits for a randomized controlled trial. Two hundred thirty patients were included in this study and assessed for demineralization at debond by using quantitative light-induced fluorescence to determine their eligibility for a randomized controlled trial assessing the effectiveness of various toothpastes at reducing demineralization during retention. METHODS: Data about patients' demographics, treatments, oral hygiene, and pretreatment status of the first permanent molars were extracted from case notes. Data on the presence and severity of white spot lesions (WSLs) were obtained from the trial's data base. Univariate analyses and multiple regression were undertaken to assess for associations between the factors and the presence and severity of WSLs. RESULTS: Sixty-five patients (28.3%) had no WSLs, and 165 (71.7%) had 1 to 12. The mean number of WSLs per patient with demineralization was 2.9 (95% CI, 2.5 and 3.3). Patients with WSLs were significantly (P = 0.002) younger and more likely to have diseased first molars (P = 0.04). Participants with inadequate pretreatment oral hygiene developed more WSLs (P = 0.03). Boys (P = 0.001) and participants with diseased first molars (P = 0.06) had significantly greater demineralization. CONCLUSIONS: Sex, pretreatment age, oral hygiene, and clinical status of the first molars can be used as predictors for the development and severity of WSLs during orthodontic treatment. PMID- 21300247 TI - Release of bisphenol-A from a light-cured adhesive bonded to lingual fixed retainers. AB - INTRODUCTION: Our aim was to quantitatively determine the bisphenol-A (BPA) released from a light-cured orthodontic adhesive used to bond lingual fixed retainers. METHODS: Eighteen recently extracted premolars, divided into 3 groups of 6 teeth each, were embedded in plaster in an arch shape. A light-cured adhesive (Transbond XT, 3M Unitek, Monrovia, Calif) was bonded to a .0195-in, 3 strand heat-treated twist flex wire (Wildcat, GAC International, Bohemia, NY) adjusted to the lingual surface of the teeth, and the arches were immersed in doubled-distilled water for 10, 20, and 30 days. The concentration of BPA in the 3 eluents was investigated with gas chromatography-mass spectroscopy; all assays were performed in triplicate, and the results were averaged. RESULTS: Measurable amounts of BPA were identified for all groups, with the highest found in the immersion media of the 1-month groups (2.9 MUg/L), whereas the control (tooth storage solution) had 0.16 MUg/L. CONCLUSIONS: The BPA released from a light cured adhesive used to bond lingual fixed retainers might be assigned to the application mode of the material that differs from conventional use. Further testing including estrogenicity assays will assess the potential estrogenic action of this application. Composite restorative resins should replace orthodontic adhesives that were not intended to function with their surfaces in the oral cavity; alternatively, canine-bonded fixed retainers might reduce the amount of adhesive used. PMID- 21300248 TI - Effects of fluoride intake on orthodontic tooth movement and orthodontically induced root resorption. AB - INTRODUCTION: Even though the beneficial effects of fluoride on enamel and root caries have been well documented, limited data are available concerning the effect of fluoride on orthodontically induced root resorption and tooth movement. Our objective was to investigate the effect of systemic fluoride administered from birth to 12 weeks on orthodontically induced root resorption and tooth movement in rat molars. METHODS: Fifty male Wistar rats were randomly divided into 5 groups. The negative control group received no sodium fluoride and had no tooth movement. The positive control group received no sodium fluoride but had tooth movement. Three experimental groups received sodium fluoride at 45 ppm from birth to 2, 4, and 12 weeks, respectively. At week 10, a 50-g nickel-titanium coil spring was applied to the maxillary left first molar for 2 weeks. The rats were killed at 12 weeks of age. Movement of the maxillary first molars was measured in relation to the maxillary second molar on digitized cephalometric radiographs. Mesial and distal roots were examined by using scanning electron and 3-dimensional laser microscopes. RESULTS: Fluoride reduced the depth, volume, and roughness of the resorption craters in the experimental groups. However, the area was similar to that in the positive control group. Regarding the duration of fluoride intake, the longer fluoride was administered via drinking water, the smaller the amount of tooth movement observed. CONCLUSIONS: Fluoride in drinking water from birth reduced the severity of orthodontically induced root resorption, but the amount of tooth movement was also decreased. PMID- 21300249 TI - Comparison of the force systems of 3 appliances on palatally impacted canines. AB - INTRODUCTION: Although much imaging research has focused on the localization and the management of impacted canines, optimal biomechanics for successful recovery are not clear. The purpose of this research was to compare the 3 mechanics- Kilroy spring, elastic chain, and steel ligature wire--used for the management of impacted canines by quantifying the 6 components of force systems involved with each system. METHODS: A dentoform model was modified to simulate a palatally impacted canine. Load cells installed in the dentoform simultaneously measured the 3 forces (Fx, Fy, Fz) and the 3 moments (Tx, Ty, Tz) on the canine. The activation range and force system attenuation as the canine moved were also measured. The results were analyzed statistically. RESULTS: The Kilroy spring has an activation range of 13 mm (Fz), the elastic chain has an activation range of 12 mm (Fz), and the ligature wire has an activation range of 1 mm (Fz). The full range of the elastic chain cannot be used because of its limited elastic behavior. CONCLUSIONS: The 3-dimensional force system for canine recovery mechanics can be quantified by using these devices. Quantification of the force system provides critical information for appropriate selection of an optimal appliance. PMID- 21300250 TI - Changes in oral health-related quality of life during fixed orthodontic appliance therapy: an 18-month prospective longitudinal study. AB - INTRODUCTION: There is an increasing research interest in quality of life issues in orthodontics. In this study, we aimed to investigate changes in oral health related quality of life (OHRQoL) among adults during fixed orthodontic appliance therapy (FOAT). METHODS: Two hundred thirty-two adult patients were enrolled from a consecutive sample at a university dental hospital. OHRQoL was assessed by 2 standardized instruments (OHIP-14 and OHQoL-UK) at 4 times: before treatment (T0), 6 months after bonding and banding (T1), 12 months after bonding and banding (T2), and 18 months after bonding and banding (T3). Friedman 2-way analysis of variance (ANOVA) and Wilcoxon signed rank tests were used to compare the relative changes of OHRQoL among the different time points. RESULTS: Significant changes in the summary scores of both the OHIP-14 and OHQoL-UK were observed during fixed orthodontic treatment (P <0.001). There were significant OHRQoL deteriorations at T1 and T2 compared with T0; these were reflected by summary scores of both the OHIP-14 and OHQoL-UK as well as some of their domain scores (P <0.05). However, at T3, the OHIP-14 suggested deterioration in OHRQoL, but the OHQoL-UK suggested improvement in OHRQoL. CONCLUSIONS: Changes in OHRQoL occur during fixed orthodontic appliance therapy. In the early phase of treatment, the greatest deterioration in OHRQoL occurs. With ongoing treatment, the detrimental effects to OHRQoL are reduced. PMID- 21300251 TI - Orthodontic education programs: an international comparison of students' views and experiences. AB - INTRODUCTION: The purpose of this study was to identify the demographic characteristics of students completing certificate programs in orthodontics, and the curriculum and financial characteristics of orthodontic programs in the English-speaking world. METHODS: An online survey was used to question orthodontic students studying in the 93 programs worldwide in countries where the first language is English. The questionnaire was built by using the online survey tool www.surveymonkey.com, and the students were predominantly contacted directly via e-mail. RESULTS: Of the 301 respondents (an estimated response rate of 33%), the majority were men, had an average age of 29.8 years, and were mostly from programs in the United States. The mean program durations were 31.0 months in the United States and 37.1 months in the Commonwealth, with mean total patient loads of 84 and 106, respectively. Various treatment modalities were used in both groups. The mean annual tuition fee was considerably higher in the United States. The overall mean debt at graduation was $118,200, and the mean expected income 5 years after graduation was $283,200. Private practice was the most popular career path (90.3%), with fewer than a third of the respondents stating that they would consider an academic career. CONCLUSIONS: This study indicates that the demographic characteristics of orthodontic students are similar to those most recently reported, with the proportion of female students continuing to increase. The numbers of transitional dentition patients and total patient case loads are increasing, and students are being exposed to an increasingly wide range of treatment techniques. A continuing increase in tuition fees was reported, along with increased levels of debt at graduation, and fewer students intend to have an academic career. PMID- 21300252 TI - Effect of maxillary anteroposterior position on profile esthetics in headgear treated patients. AB - INTRODUCTION: Headgears have been used to treat Class II malocclusions for over a century. The purpose of this retrospective study was to investigate the profile esthetic changes resulting from headgear use in growing Class II patients with protrusive, normal, and retrusive maxillae. METHODS: Profile silhouettes were created from pretreatment and posttreatment lateral cephalometric tracings of growing Class II patients treated with headgear followed by conventional fixed appliances. Ten patients had an initially protrusive maxilla (FH:NA, >92 degrees ), 10 had an initially normally positioned maxilla (FH:NA, 88 degrees -92 degrees ), and 10 had an initially retrusive maxilla (FH:NA, <88 degrees ). A panel of 20 laypersons judged the profile esthetics of the randomly sorted silhouettes. Descriptive statistics, correlation analysis, and anlaysis of variance (ANOVA) with post-hoc Tukey-Kramer tests were used to ascertain differences between groups and the effects of treatment. RESULTS: A significant moderate correlation was found between initial ANB magnitude and the improvement in profile esthetic score with treatment (r = 0.49, P <0.01). No significant correlations were found between the initial anteroposterior position of the maxilla (FH:NA) and the initial, final, or change in profile esthetic scores. There were average improvements with headgear treatment in profile esthetics for all groups. CONCLUSIONS: In Class II growing patients with protrusive, normally positioned, or retrusive maxillae, headgear treatment used with fixed orthodontic appliances is effective in improving facial profile esthetics: the greater the initial ANB angle, the greater the profile esthetic improvement with treatment. PMID- 21300253 TI - Prospective patients rate practice factors: development of a questionnaire. AB - INTRODUCTION: The importance that prospective patients place on practice characteristics when choosing an orthodontic practice has not been extensively reported. The objective of this research was to develop a valid and reliable questionnaire to address the relative importance of orthodontic office and doctor characteristics for prospective patients or parents of child patients during the initial orthodontic office consultation. METHODS: An initial questionnaire, based on published literature, was field-tested on 16 subjects to assess its validity. Based on the field test, the questionnaire was modified and tested for reliability by using a test-retest method. The questionnaire covered the following areas: doctor, office, staff, and finances. The reliability study included 2 groups of subjects: 12 consecutive prospective adult patients and 41 consecutive parents of prospective child patients. The questionnaires consisted of 43 and 50 questions for the adult patients and the parents of patients, respectively. The subjects rated the importance of practice characteristics in their selection of an orthodontic practice using a 100-mm visual analog scale anchored at "not important at all" and "most important." RESULTS: Reliability was analyzed by using the intraclass correlation coefficient (ICC). Summary scores of all 53 subjects showed excellent reliability (ICC, 0.88; range, 0.61-1.0). Summary scores of all 50 questions showed acceptable reliability (ICC, 0.70; range, 0.45-0.88). Twenty-one questions had excellent reliability (ICC, >.75), and 29 questions had fair-to-good reliability (ICC, 0.41-0.75). No questions showed poor reliability (ICC, <0.4). CONCLUSIONS: The pilot study data indicated that the overall reliability of the questionnaire is acceptable. PMID- 21300254 TI - Comparative study of nasopharyngeal soft-tissue characteristics in patients with Class III malocclusion. AB - INTRODUCTION: The aims of our study were to assess nasopharyngeal soft-tissue characteristics in white patients with Class III malocclusion and to compare the results with patients with ideal occlusion. METHODS: A sample of 71 patients with Class III malocclusion was selected from the Dental School at the Complutense University of Madrid. None of the subjects had a history of upper airway disease, adenoidectomy, or pathology in the pharynx. Lateral cephalograms were digitized, and linear and area measures were made to define the airway characteristics. Error analysis was performed to prevent systematic or random errors. Independent means t tests and Pearson correlation analysis were used to evaluate sex differences and the correlations among the variables. A discriminant analysis was also used to identify different groups with excellent occlusion and Class III malocclusion. RESULTS: Nasopharyngeal soft-tissue characteristics in Class III subjects were different in male and female subjects. Adenoidal tissue and upper airway length were greater in the men. Three groups of variables tended to be related among themselves but not with others. A discriminant analysis showed that changes in cranial base length are directly related to nasopharyngeal morphology in Class III malocclusion. A discriminant equation was also obtained. CONCLUSIONS: This study suggests new lines of investigation about the relationship between skeletal and dental anomalies and airway obstruction, and possible specific respiratory characteristics for each type of malocclusion. PMID- 21300255 TI - Miniscrew implant-supported maxillary canine retraction with and without corticotomy-facilitated orthodontics. AB - INTRODUCTION: The purpose of this study was to clinically evaluate miniscrew implant-supported maxillary canine retraction with corticotomy-facilitated orthodontics. METHODS: The sample consisted of 13 adult patients (5 men, 8 women; mean age, 19 years) exhibiting Class II Division 1 malocclusion with increased overjet requiring the therapeutic extraction of the maxillary first premolars, with subsequent retraction of the maxillary canines. Corticotomy-facilitated orthodontics was randomly assigned to 1 side of the maxillary arch at the canine premolar region, and the other side served as the control. By using miniscrews as anchorage, canine retraction was initiated via closed nickel-titanium coil springs applying 150 g of force per side. The following variables were examined over a 4-month follow-up period: rate of tooth movement, molar anchorage loss, plaque index, gingival index, probing depth, attachment loss, and gingival recession. RESULTS: The average daily rate of canine retraction was significantly higher on the corticotomy than the control side by 2 times during the first 2 months after the corticotomy surgery. This rate of tooth movement declined to only 1.6 times higher in the third month and 1.06 times higher by the end of the fourth month. No molar anchorage loss occurred during canine retraction on either the operated or the nonoperated side. There was no statistically significant difference between preoperative and postoperative measurements of plaque index, probing depth, attachment loss, and gingival recession. CONCLUSIONS: Corticotomy facilitated orthodontics can be a feasible treatment modality for adults seeking orthodontic treatment with reduced treatment times. PMID- 21300256 TI - Patient with Pfeiffer's syndrome treated by midfacial distraction and comprehensive orthodontics. AB - Treatment for patients with craniofacial anomalies always presents a great challenge to orthodontists. Treatment usually requires both comprehensive orthodontic treatment and orthognathic surgery. In this article, we report on a patient with Pfeiffer's syndrome treated by midfacial distraction and comprehensive orthodontics. PMID- 21300257 TI - Controlled tooth movement to correct an iatrogenic problem. AB - This case report describes the treatment of a 9-year old boy, who had his maxillary central incisors extruded by noncontrolled elastic mechanics to close a diastema. The article describes the consequences of this movement and how the problem was solved with controlled intrusion. PMID- 21300258 TI - Foreign body ingestion of orthodontic origin. AB - Foreign bodies in the ear, nose, and throat are commonly seen in family medicine, usually in children. Occasionally, orthodontic appliances or parts of orthodontic appliances are accidentally swallowed and have caused problems with either the airway or the gastrointestinal tract. The purposes of this article were to describe the type of appliances most likely to cause problems and to discuss their clinical management. The case of a patient who swallowed a key for turning fixed expansion appliances is presented. The key became lodged in the patient's pharynx but subsequently passed through the gastrointestinal tract. Suggestions are made to prevent the problems that were encountered in this case and others reported in the literature in orthodontic patients. PMID- 21300259 TI - Litigation and legislation. When horses refuse to drink. PMID- 21300260 TI - [Food diversification]. PMID- 21300261 TI - [History of complementary feeding]. AB - Complementary feeding, which embraces all solid and liquid foods other than breast milk or infant formula, is strongly influenced by cultural, familial and economic factors. For many times, there was a strong taboo on the use of colostrum ("the white blood") during the first week after delivery, sometimes even the first month. Therefore, the newborn baby received complementary foods as gruel, or panada. However, in the Greek civilization, wet nurses were asked by contract to breastfeed exclusively for the first 6 months and to start complementary feeding thereafter. From the sixteenth century onwards, many writers deplored the practice of giving gruel and panada during the first six months before the teeth erupted. In 1921, a Swedish pediatrician, Jundell, reported for the first time that starting complementary feeding at 6 months of age was associated with a better growth and resistance to infections. The recommendation of the World Health Organization to start complementary feeding after a 6-month period of exclusive breastfeeding is often in contradiction with the habits of the populations to propose very early other food sources than breast milk. PMID- 21300262 TI - [Place of milks in the course of food diversification in infants and juvenile children in France]. AB - Food diversification in infants and children is associated with major changes in both macronutrient and micronutrient intake. During this nutritional transition period, it is essential to continue to meet their nutritional needs for maintaining health and reducing morbidity. It has long been known that breast milk, when associated with an adequate intake of non-dairy food, is the ideal milk for meeting this objective. Clearly, all mothers do not want or cannot carry on breastfeeding throughout this period of diversification, and bottle-feeding has to be used. There is very little information on how a nutritionally adequate diet should be formulated in this situation. A recent French study provides new data however. It shows that a diet based on cow's milk is likely, in a high percentage of infants and young children, to give rise to an insufficient intake of essential fatty acids, iron, vitamin C and vitamin D. The use of supplemented formulas as a substitute for cow's milk avoids these nutritional risks, with the exception of vitamin D. It appears therefore appropriate during the period of food diversification to recommend the use of infant formula for infants less than 6-months-old, follow-on formula from 6 to 12 months, and fortified toddler milk from 12 to 36 months. PMID- 21300263 TI - [When should we introduce gluten into the feeding of the new-born babies?]. AB - Celiac disease (CD) is an auto-immune enteropathy, triggered in genetically predisposed individuals by the ingestion of dietary gluten. Gluten is the alcohol soluble protein component of the cereals wheat, rye and barley. CD is a multifactorial condition, originating from the interplay of genetic and environmental factors. The necessary environmental trigger is gluten, while the genetic predisposition has been identified in the major histocompatibility complex region on chromosome 6, with over 90% of CD patients expressing HLA DQ2 and the remaining celiac patients express DQ8. The fact that only about 4 % of DQ2/8-positive individuals exposed to gluten develop CD, has led to the recognition that other genetic and environmental factors are also necessary. In the last few years, several epidemiological studies have suggested that the timing of the introduction of gluten, as well as the pattern of breastfeeding, may play an important role in the subsequent development of CD. Here, we present and review the most recent evidences regarding the effect of timing of gluten introduction during weaning, the amount of gluten introduced and simultaneous breastfeeding, on the development of CD. PMID- 21300264 TI - [Obesity and complementary feeding time: a period at risk]. AB - Relation between rapid growth during the first months of life and secondary risk of excessive adiposity is well demonstrated. Many works have indicated a birth feeding effect on weight gain during the first year of life and a protective effect towards later childhood and adult obesity. However all these studies are observational and several works denied this protective effect. Concerning complementary feeding, 3 interventional, randomized, studies achieved between 4 and 6 months of age, showed a good regulation of caloric intake and no weight gain modification due to complementary foods. Most of others studies are observational and don't show any relation between time of introduction of complementary foods and later fat mass. However 3 recent studies indicate, respectively at 7, 10 and 42 years of age, an increased adiposity, suggesting the possibility of a programmed excessive fat gain induced by an early complementary foods introduction. Very few studies have evaluated, besides the time of weaning, the kind, quantity and caloric density of foods used as complements, whereas other recent studies show the importance of appetite differences since the first months of life and the importance of genetic influence on these variations. Others works have emphasized the possible role of an excessive protein intake during the first 2 years of life. So, it appears that it may be necessary to pay attention not only on the date, but also on the kind and quantity of complementary foods, particularly in infants at risk for obesity, because of parental obesity, rapid weight growth or an excessive appetite. PMID- 21300265 TI - [Food diversification and taste building]. AB - Before the age of two years, children have very adaptive behaviors in the food domain: they feel pleasure to consume what is nourishing, are attracted by the smells with which they were familiarized in utero or during breastfeeding and are not picky. This period of openness is thus ideal to teach to the child to appreciate a wide variety of foods. Beyond two years of age, most of the children cross a normal phase of neophobia during which they are reluctant to appreciate unknown foods and vegetables. The most effective method to help them to exceed this phase of closure is to propose these rejected foods in a repeated manner. It seems moreover that the more the children would have consumed a wide variety of food during the phase of openness, the less they would elicit neophobia during the phase of closure. PMID- 21300266 TI - [The need of efficient chewing function in young children as prevention of dental malposition and malocclusion]. AB - The eating behaviors (including breast-feeding, early edge to edge incisor bite and the chewing cycle) progressively induce, among children, continuous stimulations of the growth of the maxillaries and of the dento-alveolar structures. Unfortunately, with our usual modern soft, tenderized or semi-fluid diet, there is now a failing chewing function and the stress on the growth process are often insufficient. Many dental malpositions and malocclusions result from such "functional atrophies" of the maxillaries due to an underdevelopment of the dental arches involving incisal crowdings and lateral cross-bites. The lack of progressive natural grindings of the primary teeth and the consequent lack of development of an attritional occlusion in the deciduous dentition are signs of a poorly trained mastication and a bad prognosis for the alignment of the permanent incisors. PMID- 21300267 TI - [Manufactured baby food: safety expectations]. AB - Food safety is a concern for parents of infants, and healthcare professionals are often questioned by them about this topic. Baby food European regulation ensures high levels of safety and is more rigorous than common food regulation. Maximal limit for pesticides in baby food demonstrates the high level of requirements. This limit must be below the 10 ppb detection threshold, whatever the chemical used. Other contaminants such as nitrates are also the subject of greater expectations in baby food. Food safety risks control needs a specific know-how that baby food manufacturers have acquired and experienced, more particularly by working with producers of high quality raw material. PMID- 21300268 TI - [Food diversification: accepted ideas and scientific proofs]. AB - Guidelines about complementary feeding should be evidence based. It is now clearly established that timing of the first introduction of solid food should not be delayed in allergy at-risk infants. All complementary food can be introduced between 4 and 6 months of age. After introduction of complementary foods, protein intakes are almost always higher than the recommended needs, but no deleterious effects have been demonstrated. The frequent restriction of lipid intakes after weaning is not justified, especially since recommended needs have been increased. Excess of sweetened foods should be avoided to prevent deficiencies, but it does not increase the risk of further obesity. No dietary intervention during weaning has ever demonstrated any efficacy in obesity prevention. Reduction of infants formulas consumption increases the risk of iron deficiency, which could only be avoided by growing-up milk and meat consumption. A better information of health care practitioners may contribute to reducing the diffusion of erroneous opinions about complementary feeding in infants. PMID- 21300269 TI - Polarisation vision. PMID- 21300270 TI - Structural and functional fractionation of right superior parietal cortex in bistable perception. PMID- 21300271 TI - Repeated colonization and hybridization in Lake Malawi cichlids. PMID- 21300272 TI - Chromosome segregation: keeping kinetochores in the loop. AB - The Ndc80 complex is a key component of the kinetochore-microtubule interface. Two studies now demonstrate that a conserved loop region within the extended coiled-coil of Ndc80 plays an unexpected role in recruiting proteins to the kinetochore. PMID- 21300273 TI - Cell evolution: gene transfer agents and the origin of mitochondria. AB - Recently, alpha-proteobacteria have been shown to possess virus-like gene transfer agents that facilitate high frequency gene transfer in natural environments between distantly related lineages. This system could have driven the genomic integration of the mitochondrial progenitor and its proto-eukaryote host and contributed to the evolutionary mosaic of genes seen in modern-day prokaryotic and eukaryotic genomes. PMID- 21300274 TI - Super-resolution microscopy: a new dimension in focal adhesions. AB - Super-resolution light microscopy images of integrin-mediated adhesions have revealed that signaling and cytoskeletal proteins reside at characteristic vertical distances between the plasma membrane and F-actin. PMID- 21300275 TI - Animal cognition: concepts from apes to bees. AB - New research shows that honeybees can classify arrangements of two visual patterns according to their spatial configuration. Can bees learn relational concepts of 'above' and 'below'? And are the underlying psychological processes comparable in humans and other primates facing similar tasks? PMID- 21300276 TI - Cytokinesis: thinking outside the cell. AB - How might the extracellular matrix contribute to cytokinesis? In a recent report, evidence is presented that the conserved extracellular matrix protein hemicentin(HIM-4) is required for cytokinesis in worms and mice. PMID- 21300277 TI - Cell-cell fusion: a new function for invadosomes. AB - Podosomes are cytoskeletal-based structures involved in extracellular matrix remodeling and cellular motility. A new study now implicates podosomes in pore formation during myoblast fusion. PMID- 21300278 TI - Neuroscience: what we cannot model, we do not understand. AB - To understand computations in neuronal circuits, a model of a small patch of cortex has been developed that can describe the firing regime in the visual system remarkably well. PMID- 21300280 TI - Kindlins. PMID- 21300279 TI - Molecular regulation of lumen morphogenesis. AB - The asymmetric polarization of cells allows specialized functions to be performed at discrete subcellular locales. Spatiotemporal coordination of polarization between groups of cells allowed the evolution of metazoa. For instance, coordinated apical-basal polarization of epithelial and endothelial cells allows transport of nutrients and metabolites across cell barriers and tissue microenvironments. The defining feature of such tissues is the presence of a central, interconnected luminal network. Although tubular networks are present in seemingly different organ systems, such as the kidney, lung, and blood vessels, common underlying principles govern their formation. Recent studies using in vivo and in vitro models of lumen formation have shed new light on the molecular networks regulating this fundamental process. We here discuss progress in understanding common design principles underpinning de novo lumen formation and expansion. PMID- 21300281 TI - Double take on Piwi protein/piRNA complex structure. AB - Two recent studies by the Carlomagno/Pillai labs (Simon et al., 2011) and the Patel group (Tian et al., 2011) report the structures of complexes of Piwi PAZ domains with piRNA, utilizing two major methods in structural biology, NMR spectroscopy, and X-ray crystallography, and derive very similar structures with similar resolution. PMID- 21300282 TI - Recognition of archaeal CRISPR RNA: No P in the alindromic repeat? AB - In this issue, Wang et al. (2011) show that the CRISPR endonuclease Cas6 wraps an unstructured CRISPR RNA repeat around its surface to achieve recognition and cleavage, suggesting that palindromic RNA is not a feature of many CRISPR subtypes. PMID- 21300283 TI - Protein kinase C regulation: C1 meets C-tail. AB - In a recent issue of Cell, Leonard et al. (2011) describe the structure of PKCbetaII, an AGC kinase, revealing an unanticipated intramolecular autoinhibitory interaction between its C-terminal tail and the diacylglycerol and phorbol ester binding site of its C1b domain. PMID- 21300284 TI - A ferritin-based label for cellular electron cryotomography. AB - Electron cryotomography provides nanometer resolution structural detail of thin biological specimens in a near-native state. Currently, its application is limited by the lack of a specific label for the identification of molecules. Our aim was to develop such a label, analogous to GFP used in fluorescence microscopy. Here, we demonstrate the use of Escherichia coli ferritin FtnA protein as a clonable label for electron cryotomography. Overproduced ferritin is visible in E. coli cells using cryotomography and fusing this label to a short membrane targeting sequence correctly directs the ferritin fusion to the membrane. Using two proteins with known subcellular localization patterns with this ferritin tag, also including GFP, we obtained essentially the same labeling patterns using electron cryotomography as compared with fluorescence light microscopy. Hence, the ferritin label localizes efficiently and faithfully and it will be a valuable tool for the unambiguous identification of molecules in cellular electron cryotomograms. PMID- 21300285 TI - Cross-crystal averaging with search models to improve molecular replacement phases. AB - The application of molecular replacement (MR) in macromolecular crystallography can be limited by the "model bias" problem. Here we propose a strategy to reduce model bias when only part of a new structure is known: after the MR search, structure determination of the unknown part of the new structure can be facilitated by cross-crystal averaging of the known part of the new structure with the search model. This strategy dramatically improves electron density in the unknown part of the new structure. It has enabled us to determine the structures of two coronavirus receptor-binding domains each complexed with their receptor at moderate resolutions. In a test case, it also enabled automated model building when >50% of an antigen-antibody complex was absent. These results suggest that this averaging strategy can be routinely used after MR to enhance the interpretability of electron density associated with missing model. PMID- 21300287 TI - Structural insights into the oligomerization and architecture of eukaryotic membrane pore-forming toxins. AB - Pore-forming toxins (PFTs) are proteins that are secreted as soluble molecules and are inserted into membranes to form oligomeric transmembrane pores. In this paper, we report the crystal structure of Fragaceatoxin C (FraC), a PFT isolated from the sea anemone Actinia fragacea, at 1.8 A resolution. It consists of a crown-shaped nonamer with an external diameter of about 11.0 nm and an internal diameter of approximately 5.0 nm. Cryoelectron microscopy studies of FraC in lipid bilayers reveal the pore structure that traverses the membrane. The shape and dimensions of the crystallographic oligomer are fully consistent with the membrane pore. The FraC structure provides insight into the interactions governing the assembly process and suggests the structural changes that allow for membrane insertion. We propose a nonameric pore model that spans the membrane by forming a lipid-free alpha-helical bundle pore. PMID- 21300286 TI - Decoy strategies: the structure of TL1A:DcR3 complex. AB - Decoy Receptor 3 (DcR3), a secreted member of the Tumor Necrosis Factor (TNF) receptor superfamily, neutralizes three different TNF ligands: FasL, LIGHT, and TL1A. Each of these ligands engages unique signaling receptors which direct distinct and critical immune responses. We report the crystal structures of the unliganded DcR3 ectodomain and its complex with TL1A, as well as complementary mutagenesis and biochemical studies. These analyses demonstrate that DcR3 interacts with invariant backbone and side-chain atoms in the membrane-proximal half of TL1A which supports recognition of its three distinct TNF ligands. Additional features serve as antideterminants that preclude interaction with other members of the TNF superfamily. This mode of interaction is unique among characterized TNF:TNFR family members and provides a mechanistic basis for the broadened specificity required to support the decoy function of DcR3, as well as for the rational manipulation of specificity and affinity of DcR3 and its ligands. PMID- 21300288 TI - Structural basis of Streptococcus pyogenes immunity to its NAD+ glycohydrolase toxin. AB - The virulence of Gram-positive bacteria is enhanced by toxins like the Streptococcus pyogenes beta-NAD(+) glycohydrolase known as SPN. SPN-producing strains of S. pyogenes additionally express the protein immunity factor for SPN (IFS), which forms an inhibitory complex with SPN. We have determined crystal structures of the SPN-IFS complex and IFS alone, revealing that SPN is structurally related to ADP-ribosyl transferases but lacks the canonical binding site for protein substrates. SPN is instead a highly efficient glycohydrolase with the potential to deplete cellular levels of beta-NAD(+). The protective effect of IFS involves an extensive interaction with the SPN active site that blocks access to beta-NAD(+). The conformation of IFS changes upon binding to SPN, with repacking of an extended C-terminal alpha helix into a compact shape. IFS is an attractive target for the development of novel bacteriocidal compounds functioning by blocking the bacterium's self-immunity to the SPN toxin. PMID- 21300289 TI - Structural model and trans-interaction of the entire ectodomain of the olfactory cell adhesion molecule. AB - The ectodomain of olfactory cell adhesion molecule (OCAM/NCAM2/RNCAM) consists of five immunoglobulin (Ig) domains (IgI-V), followed by two fibronectin-type 3 (Fn3) domains (Fn3I-II). A complete structural model of the entire ectodomain of human OCAM has been assembled from crystal structures of six recombinant proteins corresponding to different regions of the ectodomain. The model is the longest experimentally based composite structural model of an entire IgCAM ectodomain. It displays an essentially linear arrangement of IgI-V, followed by bends between IgV and Fn3I and between Fn3I and Fn3II. Proteins containing IgI-IgII domains formed stable homodimers in solution and in crystals. Dimerization could be disrupted in vitro by mutations in the dimer interface region. In conjunction with the bent ectodomain conformation, which can position IgI-V parallel with the cell surface, the IgI-IgII dimerization enables OCAM-mediated trans-interactions with an intercellular distance of about 20 nm, which is consistent with that observed in synapses. PMID- 21300290 TI - Molecular mimicry and ligand recognition in binding and catalysis by the histone demethylase LSD1-CoREST complex. AB - Histone demethylases LSD1 and LSD2 (KDM1A/B) catalyze the oxidative demethylation of Lys4 of histone H3. We used molecular dynamics simulations to probe the diffusion of the oxygen substrate. Oxygen can reach the catalytic center independently from the presence of a bound histone peptide, implying that LSD1 can complete subsequent demethylation cycles without detaching from the nucleosomal particle. The simulations highlight the role of a strictly conserved active-site Lys residue providing general insight into the enzymatic mechanism of oxygen-reacting flavoenzymes. The crystal structure of LSD1-CoREST bound to a peptide of the transcription factor SNAIL1 unravels a fascinating example of molecular mimicry. The SNAIL1 N-terminal residues bind to the enzyme active-site cleft, effectively mimicking the H3 tail. This finding predicts that other members of the SNAIL/Scratch transcription factor family might associate to LSD1/2. The combination of selective histone-modifying activity with the distinct recognition mechanisms underlies the biological complexity of LSD1/2. PMID- 21300291 TI - Mechanism for the alteration of the substrate specificities of template independent RNA polymerases. AB - PolyA polymerase (PAP) adds a polyA tail onto the 3'-end of RNAs without a nucleic acid template, using adenosine-5'-triphosphate (ATP) as a substrate. The mechanism for the substrate selection by eubacterial PAP remains obscure. Structural and biochemical studies of Escherichia coli PAP (EcPAP) revealed that the shape and size of the nucleobase-interacting pocket of EcPAP are maintained by an intra-molecular hydrogen-network, making it suitable for the accommodation of only ATP, using a single amino acid, Arg(197). The pocket structure is sustained by interactions between the catalytic domain and the RNA-binding domain. EcPAP has a flexible basic C-terminal region that contributes to optimal RNA translocation for processive adenosine 5'-monophosphate (AMP) incorporations onto the 3'-end of RNAs. A comparison of the EcPAP structure with those of other template-independent RNA polymerases suggests that structural changes of domain(s) outside the conserved catalytic core domain altered the substrate specificities of the template-independent RNA polymerases. PMID- 21300292 TI - The extracellular architecture of adherens junctions revealed by crystal structures of type I cadherins. AB - Adherens junctions, which play a central role in intercellular adhesion, comprise clusters of type I classical cadherins that bind via extracellular domains extended from opposing cell surfaces. We show that a molecular layer seen in crystal structures of E- and N-cadherin ectodomains reported here and in a previous C-cadherin structure corresponds to the extracellular architecture of adherens junctions. In all three ectodomain crystals, cadherins dimerize through a trans adhesive interface and are connected by a second, cis, interface. Assemblies formed by E-cadherin ectodomains coated on liposomes also appear to adopt this structure. Fluorescent imaging of junctions formed from wild-type and mutant E-cadherins in cultured cells confirm conclusions derived from structural evidence. Mutations that interfere with the trans interface ablate adhesion, whereas cis interface mutations disrupt stable junction formation. Our observations are consistent with a model for junction assembly involving strong trans and weak cis interactions localized in the ectodomain. PMID- 21300293 TI - Interaction of the Cas6 riboendonuclease with CRISPR RNAs: recognition and cleavage. AB - The CRISPRs (Clustered Regularly Interspaced Short Palindromic Repeats) found in prokaryotic genomes confer small RNA-mediated protection against viruses and other invaders. CRISPR loci contain iterations of a short repeat sequence alternating with small segments of varying invader-derived sequences. Distinct families of CRISPR-associated Cas proteins function to cleave within the repeat sequence of CRISPR transcripts and produce the individual invader-targeting crRNAs. Here, we report the crystal structure of Pyrococcus furiosus Cas6 bound with a repeat RNA at 3.2 A resolution. In contrast to other Cas families of endonucleases, Cas6 clasps nucleotides 2-9 of the repeat RNA using its two ferredoxin-like domains, and the enzyme-anchored 5' end tethers the distal cleavage site of the RNA between nucleotides 22 and 23 to the predicted enzyme active site on the opposite side of the ferrodoxin-like domains. Our findings suggest a wrap-around mechanism for CRISPR RNA recognition and cleavage by Cas6 and related processing endonucleases. PMID- 21300294 TI - Realizing the allosteric potential of the tetrameric protein kinase A RIalpha holoenzyme. AB - PKA holoenzymes containing two catalytic (C) subunits and a regulatory (R) subunit dimer are activated cooperatively by cAMP. While cooperativity involves the two tandem cAMP binding domains in each R-subunit, additional cooperativity is associated with the tetramer. Of critical importance is the flexible linker in R that contains an inhibitor site (IS). While the IS becomes ordered in the R:C heterodimer, the overall conformation of the tetramer is mediated largely by the N-Linker that connects the D/D domain to the IS. To understand how the N-Linker contributes to assembly of tetrameric holoenzymes, we engineered a monomeric RIalpha that contains most of the N-Linker, RIalpha(73-244), and crystallized a holoenzyme complex. Part of the N-linker is now ordered by interactions with a symmetry-related dimer. This complex of two symmetry-related dimers forms a tetramer that reveals novel mechanisms for allosteric regulation and has many features associated with full-length holoenzyme. A model of the tetrameric holoenzyme, based on this structure, is consistent with previous small angle X ray and neutron scattering data, and is validated with new SAXS data and with an RIalpha mutation localized to a novel interface unique to the tetramer. PMID- 21300296 TI - In praise of idleness. PMID- 21300297 TI - Highlights of the 2010 scientific sessions of the Heart Failure Society of America, San Diego, California, September 12-15, 2010. PMID- 21300298 TI - Tricuspid annular plane systolic excursion and response to cardiac resynchronization therapy: results from the REVERSE trial. AB - BACKGROUND: The aims of this study were to evaluate tricuspid annular plane systolic excursion (TAPSE) as a predictor of left ventricular (LV) reverse remodeling and clinical benefit of cardiac synchronization therapy (CRT) and to evaluate the effect of CRT on TAPSE in patients with mildly symptomatic systolic heart failure as a substudy of the REsyncronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) trial. METHODS AND RESULTS: Patients (n = 450) were randomized in a 2:1 fashion to CRT ON or CRT OFF and followed for 12 months. End points were reverse LV remodeling defined as a reduction in LV end-systolic volume of >=20 mL/m(2) by echocardiography and a clinical composite score, defined as freedom from clinical deterioration. TAPSE was an independent predictor of reverse remodeling, OR = 1.08 (95% CI 1.03-1.14) per mm increase and a favorable clinical composite score, OR = 1.08 (95% CI 1.02 1.14). No significant interactions were observed between TAPSE and CRT ON. CRT ON was not associated with a significant effect on TAPSE compared to CRT OFF, -0.8 +/- 4.7 vs. 0.3 +/- 5 mm, P = .06. CONCLUSION: TAPSE is an independent predictor of clinical response and improved reverse remodeling in patients with mildly symptomatic heart failure. The effect of CRT is not modified by TAPSE in the present population. CRT is not associated with a clinically significant effect on TAPSE. PMID- 21300295 TI - Report from a consensus conference on antibody-mediated rejection in heart transplantation. AB - BACKGROUND: The problem of AMR remains unsolved because standardized schemes for diagnosis and treatment remains contentious. Therefore, a consensus conference was organized to discuss the current status of antibody-mediated rejection (AMR) in heart transplantation. METHODS: The conference included 83 participants (transplant cardiologists, surgeons, immunologists and pathologists) representing 67 heart transplant centers from North America, Europe, and Asia who all participated in smaller break-out sessions to discuss the various topics of AMR and attempt to achieve consensus. RESULTS: A tentative pathology diagnosis of AMR was established, however, the pathologist felt that further discussion was needed prior to a formal recommendation for AMR diagnosis. One of the most important outcomes of this conference was that a clinical definition for AMR (cardiac dysfunction and/or circulating donor-specific antibody) was no longer believed to be required due to recent publications demonstrating that asymptomatic (no cardiac dysfunction) biopsy-proven AMR is associated with subsequent greater mortality and greater development of cardiac allograft vasculopathy. It was also noted that donor-specific antibody is not always detected during AMR episodes as the antibody may be adhered to the donor heart. Finally, recommendations were made for the timing for specific staining of endomyocardial biopsy specimens and the frequency by which circulating antibodies should be assessed. Recommendations for management and future clinical trials were also provided. CONCLUSIONS: The AMR Consensus Conference brought together clinicians, pathologists and immunologists to further the understanding of AMR. Progress was made toward a pathology AMR grading scale and consensus was accomplished regarding several clinical issues. PMID- 21300299 TI - Effects of exercise training on high-mobility group box-1 levels after acute myocardial infarction. AB - BACKGROUND: High-mobility group box-1 (HMGB1) is a novel predictor of adverse postinfarction clinical outcomes, playing a crucial role in the appropriate postinfarction healing process. METHODS AND RESULTS: Seventy-five postinfarction patients were enrolled in a single-center randomized study (clinicaltrial.gov identifier: NCT00755131). Group T patients (training, n = 37) underwent 6-month exercise-based cardiac rehabilitation (CR) program, whereas group C patients (controls, n = 38) were discharged with generic instructions for maintaining physical activity and a correct lifestyle. After 6 months, HMGB1 levels were significantly reduced in the total population (26.1 +/- 23.5 vs. 16.2 +/- 12.9 ng/mL; P = .0006). After adjusting for several confounders, linear regression analysis showed that the inclusion in the training group (beta = -10.54, P = .043) was associated with marked reduction of HMGB1 levels. After 6 months, HMGB1 levels were significantly lower in trained patients compared to controls (11.7 +/ 7.0 vs. 20.5 +/- 15.6 ng/mL, P = .0027, respectively). In trained patients, decreased HMGB1 levels were significantly associated with the improvement in peak oxygen consumption (beta = -3.879, P = .003) and heart rate recovery (beta = 2.492, P = .002), and with reduced left ventricular end-diastolic volume (beta = 1.412, P = .001) and wall motion score index (beta = 1.138, P = .002). CONCLUSIONS: The decrease in HMGB1 levels after anterior myocardial infarction was associated with exercise training and with the improvement of cardiopulmonary and autonomic function, and with favorable cardiac remodeling. PMID- 21300300 TI - Polymorphisms of matrix metalloproteinases in systolic heart failure: role on disease susceptibility, phenotypic characteristics, and prognosis. AB - BACKGROUND: The role of matrix metalloproteinases (MMPs) polymorphisms on heart failure (HF) susceptibility, phenotypic characteristics, and prognosis has been poorly explored. METHODS AND RESULTS: We studied 313 HF patients with left ventricular systolic dysfunction and 367 healthy control subjects. Genotyping of MMP-1 (-1607 1G/2G), MMP-3 (-1171 5A/6A), and MMP-9 (-1562 C/T) polymorphisms was performed by polymerase chain reaction. Allelic and genotypic frequencies of MMP 1, -3, and -9 were similar in HF patients and controls. MMP1 2G allele carriers were positively associated to ischemic etiology and history of myocardial infarction (all P values <.05). Patients were followed-up for a median of 40 months and 58 HF-related deaths occurred during this period. HF-related survival was significantly better in MMP1 2G allele carriers (71% versus 42% for 1G/1G patients, P = .002) and in MMP-3 6A allele carriers (70% versus 61% for 5A/5A patients, P = .064), particularly in non-ischemic patients (P = .039). MMP1 2G allele was independently associated to HF survival after adjustment for several other predictors of risk (hazard ratio 0.47, 95% confidence interval 0.27 to 0.82; P = .008). CONCLUSIONS: MMP-1, -3, and -9 polymorphisms were not associated to HF susceptibility. However, MMP1 2G allele carriers were related to a higher prevalence of ischemic etiology among patients with systolic HF and better HF related prognosis. PMID- 21300301 TI - Racial disparities in health literacy and access to care among patients with heart failure. AB - BACKGROUND: Previous work has shown that there is a higher frequency of hospitalizations among black heart failure patients relative to white heart failure patients. We sought to determine whether racial differences exist in health literacy and access to outpatient medical care, and to identify factors associated with these differences. METHODS: We evaluated data from 1464 heart failure patients (644 black and 820 white). Health literacy was assessed using the Rapid Estimate of Adult Literacy in Medicine-Revised (ie, REALM-R), and access to care was assessed through participants' self-report. RESULTS: Black race was strongly associated with worse health literacy and all measures of poor access to care in unadjusted analyses. After adjusting for demographics, noncardiac comorbidity, social support, insurance status, and socioeconomic status (income and education), the strongest associations were seen between race and: health literacy (OR 2.13, 95% CI 1.46 to 3.10), absence of a medical home (OR 1.76, 1.19-2.61), and cost as a deterrent to seeking health care (OR 1.55, 1.07 to 2.23). CONCLUSIONS: Our findings highlight that important racial differences in health literacy and access to care exist among patients with heart failure. These differences persist even after adjustment for a broad range of potential mediators, including educational attainment, income, and insurance status. PMID- 21300302 TI - Impact of left ventricular remodeling on diagnostic and prognostic value of tissue Doppler indices in chronic systolic heart failure. AB - BACKGROUND: The ratio of peak transmitral pulsed Doppler early velocity to early diastolic tissue Doppler velocity (TDI) of the lateral or septal mitral annulus (E/Ea) is considered a reliable estimation of LV filling pressure. We aim to examine the impact of left ventricular (LV) dimensions on the relationship between lateral and septal E/Ea in the determination of diastolic dysfunction patterns in the setting of chronic systolic heart failure (HF). METHODS AND RESULTS: In 207 patients with chronic systolic HF (LV ejection fraction <=40%, New York Heart Association Classes I-IV), comprehensive transthoracic echocardiography was performed and long-term outcomes followed up to a median of 40 months. The median lateral and septal Ea (interquartile range) were 7.0 (4.7 to 9.5) cm/s and 4.5 (3.5 to 5.6) cm/s, respectively. The median E/lateral Ea, E/septal Ea, and E/average Ea (interquartile range) were 10.8 (7.1 to 15.1), 16.1 (11.1 to 23.0), and 12.7 (8.8 to 17.7), respectively. In the first 2 tertiles of indexed left ventricular end-diastolic volume (LVEDVi) (<92 mL/m(2) and 92 to 130 mL/m(2)), all 3 E/Ea indices rise with increasing diastolic stage (all P < .001). However, in the highest tertile of indexed LVEDVi (>=130 mL/m(2)), E/average Ea and E/septal Ea (but not E/lateral Ea) increased with increasing diastolic stage, and only E/septal Ea correlated with natriuretic peptide levels (r = 0.38, P = .018) and adverse cardiac events (Hazard ratio 1.91, 95% confidence interval 1.25 to 2.96, P = .003). CONCLUSIONS: In the setting of chronic systolic heart failure with extensive cardiac remodeling, septal TDI measurements may be more reliable and clinically relevant than lateral TDI measurements in the assessment of diastolic dysfunction. PMID- 21300303 TI - The L-arginine-asymmetric dimethylarginine ratio is strongly related to the severity of chronic heart failure. No effects of exercise training. AB - BACKGROUND: The aim of this study was to relate levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase, L arginine, the substrate for NO generation, and radical oxygen species (ROS) formation to severity of chronic heart failure. The effect of 4 months' group based exercise training was further investigated. METHOD AND RESULTS: Eighty patients, aged 45-85 years with New York Heart Association (NYHA) functional class II-IIIb, all on optimal medical treatment, were included. A 6-minute walking test and a bicycle exercise test were performed, and fasting blood samples were collected for determination of N-terminal pro-brain natriuretic peptide (NT-proBNP), L-arginine, ADMA, and ROS generation in circulating leukocytes. ADMA levels were significantly higher in patients in NYHA functional class III versus II (P = .024), and the L-arginine-ADMA ratio was significantly lower (P = .005). After adjustment for covariates, L-arginine-ADMA ratio was associated with 6-minute walking distance (P = .004), exercise capacity (P = .026), and inversely with NT-proBNP (P = .015). Stimulated levels of peroxynitrite on monocytes were inversely related to left ventricular ejection fraction (P = .005). No effect of 4 weeks' exercise training on the measured variables was obtained. CONCLUSIONS: The strong relationship seen between L arginine-ADMA ratio, ROS formation in leukocytes, and severity of chronic heart failure contributes to increased knowledge of endothelial dysfunction related to the NO pathway in such patients. PMID- 21300304 TI - Evaluation of the Health Utilities Index Mark-3 in heart failure. AB - BACKGROUND: The purpose of this study was to evaluate the reliability, validity, and responsiveness to change of the Health Utilities Index Mark-3 (HUI-3) in heart failure (HF) for use in cost-effectiveness studies. METHODS AND RESULTS: Two hundred eleven patients with HF recruited from outpatient clinics were enrolled; 165 completed the 26-week study. Patients completed 4 health-related quality of life questionnaires (baseline and 4, 8, and 26 weeks), including the HUI-3, the Medical Outcomes Study Short-form 12 (SF-12), the Minnesota Living with Heart Failure Questionnaire (LHFQ), and the Chronic Heart Failure Questionnaire (CHQ). The HUI-3 indicated moderate or fair health-related quality of life overall; the attributes most impaired were pain, ambulation, cognition, and emotion. Internal consistency reliability (Cronbach's alpha = 0.51) was low and test-retest reliability (intraclass correlation coefficient = 0.68) was adequate. The HUI-3 total score was significantly associated with the SF-12, LHFQ, and CHQ total scores. It discriminated among patients with varying New York Heart Association class (P < .001) and varying perceived health (P < .001). The HUI-3 was less responsive to perceived change in health condition than the LHFQ or the CHQ. CONCLUSIONS: The HUI-3 demonstrated satisfactory reliability and validity in this sample supporting its use in cost-effectiveness studies. PMID- 21300305 TI - Health-related quality of life in a multicenter randomized controlled comparison of telephonic disease management and automated home monitoring in patients recently hospitalized with heart failure: SPAN-CHF II trial. AB - BACKGROUND: Although disease management programs have been shown to provide a number of clinical benefits to patients with heart failure (HF), the incremental impact of an automated home monitoring (AHM) system on health-related quality of life (HRQL) is unknown. METHODS AND RESULTS: We performed a prospective randomized investigation, examining the additive value of AHM to a previously described nurse-directed HF disease management program (SPAN-CHF), with attention to HRQL, in patients with a recent history of decompensated HF. A total of 188 patients were randomized to receive the SPAN-CHF intervention for 90 days, either with (AHM group) or without (NAHM, standard-care group) AHM, with a 1:1 randomization ratio after HF-related hospitalization. HRQL, measured by the Minnesota Living With Heart Failure Questionnaire (MLHFQ) (Physical, Emotional, and Total scores on MLHFQ) was assessed at 3 time points: baseline, 45 days, and 90 days. Although both treatments (AHM and NAHM) improved HRQL at 45 and 90 days compared with baseline with respect to Physical, Emotional, and Total domain scales, no significant difference emerged between AHM and NAHM groups. CONCLUSIONS: AHM and NAHM treatments demonstrated improved HRQL scores at 45 and 90 days after baseline assessment. When comparing 2 state-of the-art disease management programs regarding HRQL outcomes, our results did not support the added value of AHM. PMID- 21300306 TI - The positive inotropic effect of relaxin-2 in human atrial myocardium is preserved in end-stage heart failure: role of G(i)-phosphoinositide-3 kinase signaling. AB - BACKGROUND: Relaxin-2, a candidate drug for acute heart failure, has been tested successfully in the first human trials. We investigated relaxin's inotropic effects in human myocardium. METHODS AND RESULTS: In atrial samples from donor (n = 7) and failing (n = 7) hearts, relaxin-2 evoked remarkable positive inotropic effects: showing a half maximum effective concentration of < 1 nmol/L, the maximum peak developed tension (PDT) rose to approximately 270% of baseline, without differences between failing and nonfailing myocardium. The effects critically depended on protein kinase A activation and inhibition of the transient potassium outward current; phosphoinositide-3 kinase inhibition and pertussis toxin pretreatment moderately blunted the effects in nonfailing but markedly suppressed them in failing myocardium. Action potential recordings revealed identical effects of inhibition of the transient potassium outward current and relaxin. In ventricular myocardium, however, relaxin did not show any inotropic effects. The expression of the RXFP1 receptor was moderately decreased in failing compared with nonfailing atrial myocardium but not detectable in any ventricular samples. CONCLUSIONS: Relaxin is a positive inotrope in nonfailing and failing human atria, with critical involvement of protein kinase A and inhibition of the transient potassium outward current and an increasing role for G(i) protein-phosphoinositide-3 kinase signaling in failing myocardium. PMID- 21300307 TI - Chronic baroreflex activation: a potential therapeutic approach to heart failure with preserved ejection fraction. AB - Heart failure with preserved ejection fraction (HFpEF) is a substantial public health issue, equal in magnitude to heart failure with reduced ejection fraction. Clinical outcomes of HFpEF patients are generally poor, related annual accrual of health care expenses amount to billions of dollars, and no therapy has been shown to be effective in randomized clinical trials. Baroreflex activation therapy (BAT) produced by stimulating the carotid sinuses using an implanted device (Rheos) is being studied for the treatment of hypertension, the primary comorbidity of HFpEF. Other potential benefits include regression of left ventricular hypertrophy, normalization of the sympathovagal balance, inhibition of the renin-angiotensin-aldosterone system, arterio- and venodilation, and preservation of renal function. This paper reviews the evidence suggesting that BAT may be a promising therapy for HFpEF and introduces the HOPE4HF trial (ClinicalTrials.gov Identifier: NCT00957073), a randomized outcomes trial designed to evaluate the clinical safety and efficacy of BAT in the HFpEF population. PMID- 21300308 TI - Foreword: Celebrating Charles Darwin in disagreement. PMID- 21300309 TI - Defining Darwinism. AB - Evolutionary theory seems to lend itself to all sorts of misunderstanding. In this paper I strive to decrease such confusions, for example, between Darwinism and Darwinians, propositions and people, organisms and individuals, species as individuals versus species as classes, homologies and homoplasies, and finally essences versus histories. PMID- 21300310 TI - Is Darwinism past its "sell-by" date? The Origin of Species at 150. AB - Many people worry that the theory of evolution that Charles Darwin gave in his Origin of Species is now dated and no longer part of modern science. This essay challenges this claim, arguing that the central core of the Origin is as vital today as it ever was, although naturally the science keeps moving on. Darwin provided the foundation not the finished product. PMID- 21300311 TI - Social Darwinism: from reality to myth and from myth to reality. AB - Considering the variety of contradictory definitions which have been attributed to the term in the course of more than a century, one may be tempted to admit that 'Social Darwinism' can be reduced to a social myth. But it seems nevertheless necessary to answer the question: what has been called 'Social Darwinism' for more than one century and why was the expression used in a negative way to express contradictory opinions which sometimes have nothing to do with Darwin's theory. What we still call 'Social Darwinism' is the result of a misunderstanding: the theories expressed under that phrase have little to do with the Darwinian concepts of natural selection or descent with modification. They have their origin in a pre-darwinian conception of the struggle for existence, which Darwin used in a metaphorical sense. This confusion will then appear to refer clearly to the relationship we establish between biology and society, whether biological laws are directly prolonged in society, or more or less intermingle in a close network. The issue of the definition of Social Darwinism depends obviously on the possible answers to this question, and so does the issue of redefining Darwinism at large. PMID- 21300312 TI - Ethics in Darwin's melancholy vision. AB - Darwinian natural selection draws on Malthus' harsh vision of human society to explain how organisms come to be adapted to their environments. Natural selection produces the appearance of teleology, but requires only efficient causal processes: undirected, heritable variation combined with effects of the variations on survival and reproduction. This paper draws a sharp distinction between the resulting form of backwards-directed teleology and the future directed teleology we ascribe to intentional human activity. Rather than dismiss teleology as mere illusion, the paper concludes with an account of how future directed teleology came to be a justifiable part of how we understand ourselves. PMID- 21300313 TI - Darwinism after Mendelism: the case of Sewall Wright's intellectual synthesis in his shifting balance theory of evolution (1931). AB - Historians of science have long been agreeing: what many textbooks of evolutionary biology say, about the histories of Darwinism and the New Synthesis, is just too simple to do justice to the complexities revealed to critical scholarship and historiography. There is no current consensus, however, on what grand narratives should replace those textbook histories. The present paper does not offer to contribute directly to any grand, consensual, narrational goals; but it does seek to do so indirectly by showing how, in just one individual case, details of intellectual biography connect with big picture issues. To this end, I examine here how very diverse scientific and metaphysical commitments were integrated in Sewall Wright's own personal synthesis of biology and philosophy. Taking as the decisive text the short final section of Wright's long 1931 paper on 'Evolution in Mendelian populations,' I examine how his shifting balance theory (SBT) related to his optimum breeding strategy research, his physiological genetics, his general theory of homogenising and heterogenesing causation and his panpsychist view of mind and matter; and I discuss how understanding these relations can clarify Wright's place in the longue duree of evolutionary thought. PMID- 21300314 TI - Utopianism in the British evolutionary synthesis. AB - In this paper I propose a new interpretation of the British evolutionary synthesis. The synthetic work of J. B. S. Haldane, R. A. Fisher and J. S. Huxley was characterized by both an integration of Mendelism and Darwinism and the unification of different biological subdisciplines within a coherent framework. But it must also be seen as a bold and synthetic Darwinian program in which the biosciences served as a utopian blueprint for the progress of civilization. Describing the futuristic visions of these three scientists in their synthetic heydays, I show that, despite a number of important divergences, their biopolitical ideals could be biased toward a controlled and regimented utopian society. Their common ideals entailed a social order where liberal and democratic principles were partially or totally suspended in favor of bioscientific control and planning for the future. Finally, I will argue that the original redefinition of Darwinism that modern synthesizers proposed is a significant historical example of how Darwinism has been used and adapted in different contexts. The lesson I draw from this account is a venerable one: that, whenever we wish to define Darwinism, we need to recognize not only its scientific content and achievements but expose the other traditions and ideologies it may have supported. PMID- 21300315 TI - What was really synthesized during the evolutionary synthesis? A historiographic proposal. AB - The 1920-1960 period saw the creation of the conditions for a unification of disciplines in the area of evolutionary biology under a limited number of theoretical prescriptions: the evolutionary synthesis. Whereas the sociological dimension of this synthesis was fairly successful, it was surprisingly loose when it came to the interpretation of the evolutionary mechanisms per se, and completely lacking at the level of the foundational epistemological and metaphysical commitments. Key figures such as Huxley, Simpson, Dobzhansky, and Rensch only paid lip service to the conceptual dimension of the evolutionary synthesis, as they eventually realized that a number of evolutionary phenomena could not be explained by its narrow theoretical corpus. Apparently, the evolutionary synthesis constituted a premature event in the development of evolutionary biology. Not only are the real achievements of the evolutionary synthesis in need of reevaluation, but this reassessment also has important implications for the historiography of Darwinism and the current debates about the darwinian movement. PMID- 21300316 TI - Phylogenetic inertia and Darwin's higher law. AB - The concept of 'phylogenetic inertia' is routinely deployed in evolutionary biology as an alternative to natural selection for explaining the persistence of characteristics that appear sub-optimal from an adaptationist perspective. However, in many of these contexts the precise meaning of 'phylogenetic inertia' and its relationship to selection are far from clear. After tracing the history of the concept of 'inertia' in evolutionary biology, I argue that treating phylogenetic inertia and natural selection as alternative explanations is mistaken because phylogenetic inertia is, from a Darwinian point of view, simply an expected effect of selection. Although Darwin did not discuss 'phylogenetic inertia,' he did assert the explanatory priority of selection over descent. An analysis of 'phylogenetic inertia' provides a perspective from which to assess Darwin's view. PMID- 21300317 TI - What will result from the interaction between functional and evolutionary biology? AB - The modern synthesis has been considered to be wrongly called a "synthesis", since it had completely excluded embryology, and many other disciplines. The recent developments of Evo-Devo have been seen as a step in the right direction, as complementing the modern synthesis, and probably leading to a "new synthesis". My argument is that the absence of embryology from the modern synthesis was the visible sign of a more profound lack: the absence of functional biology in the evolutionary synthesis. I will consider the reasons for this absence, as well as the recent transformations which favoured a closer interaction between these two branches of biology. Then I will describe two examples of recent work in which functional and evolutionary questioning were tightly linked. The most significant part of the paper will be devoted to the transformation of evolutionary theory that can be expected from this encounter: a deep transformation, or simply an experimental confirmation of this theory? I will not choose between these two different possibilities, but will discuss some of the difficulties which make the choice problematic. PMID- 21300318 TI - Extending and expanding the Darwinian synthesis: the role of complex systems dynamics. AB - Darwinism is defined here as an evolving research tradition based upon the concepts of natural selection acting upon heritable variation articulated via background assumptions about systems dynamics. Darwin's theory of evolution was developed within a context of the background assumptions of Newtonian systems dynamics. The Modern Evolutionary Synthesis, or neo-Darwinism, successfully joined Darwinian selection and Mendelian genetics by developing population genetics informed by background assumptions of Boltzmannian systems dynamics. Currently the Darwinian Research Tradition is changing as it incorporates new information and ideas from molecular biology, paleontology, developmental biology, and systems ecology. This putative expanded and extended synthesis is most perspicuously deployed using background assumptions from complex systems dynamics. Such attempts seek to not only broaden the range of phenomena encompassed by the Darwinian Research Tradition, such as neutral molecular evolution, punctuated equilibrium, as well as developmental biology, and systems ecology more generally, but to also address issues of the emergence of evolutionary novelties as well as of life itself. PMID- 21300319 TI - The Mastodon in the room: how Darwinian is neo-Darwinism? AB - Failing to acknowledge substantial differences between Darwinism and neo Darwinism impedes evolutionary biology. Darwin described evolution as the outcome of interactions between the nature of the organism and the nature of the conditions, each relatively autonomous but both historically and spatially intertwined. Furthermore, he postulated that the nature of the organism was more important than the nature of the conditions, leading to natural selection as an inevitable emergent product of biological systems. The neo-Darwinian tradition assumed a creative rather than selective view of natural selection, with the nature of the organism determined by the nature of the conditions, rendering the nature of the organism and temporal contingency unnecessary. Contemporary advances in biology, specifically the phylogenetics revolution and evo-devo, underscore the significance of history and the nature of the organism in biology. Darwinism explains more biology better, and better resolves apparent anomalies between living systems and more general natural laws, than does neo-Darwinism. The "extended" or "expanded" synthesis currently called for by neo-Darwinians is Darwinism. PMID- 21300320 TI - Adaptation as process: the future of Darwinism and the legacy of Theodosius Dobzhansky. AB - Conceptions of adaptation have varied in the history of genetic Darwinism depending on whether what is taken to be focal is the process of adaptation, adapted states of populations, or discrete adaptations in individual organisms. I argue that Theodosius Dobzhansky's view of adaptation as a dynamical process contrasts with so-called "adaptationist" views of natural selection figured as "design-without-a-designer" of relatively discrete, enumerable adaptations. Correlated with these respectively process and product oriented approaches to adaptive natural selection are divergent pictures of organisms themselves as developmental wholes or as "bundles" of adaptations. While even process versions of genetical Darwinism are insufficiently sensitive to the fact much of the variation on which adaptive selection works consists of changes in the timing, rate, or location of ontogenetic events, I argue that articulations of the Modern Synthesis influenced by Dobzhansky are more easily reconciled with the recent shift to evolutionary developmentalism than are versions that make discrete adaptations central. PMID- 21300321 TI - The three faces of ecological fitness. AB - This paper argues that fitness is most usefully understood as those properties of organisms that are explanatory of survival in the broadest sense, not merely descriptive of reproductive success. Borrowing from Rosenberg and Bouchard (2009), fitness in this sense is ecological in that it is defined by the interactions between organisms and environments. There are three sorts of ecological fitness: the well-documented ability to compete, the ability to cooperate (as in mutualistic symbiosis), and a third sense of fitness that has received insufficient attention in evolutionary theory, the ability to construct. Following Lotka, it can be understood thermodynamically as the ability to maintain or enlarge the energy-circulating capacity of an ecosystem. An organism that does this could end with its gene frequency unchanged but its probability of survival enhanced since it would sustain or increase the total carrying capacity of its ecosystem. Photosynthesizers and other autotrophs are obvious candidates for organisms that are fit in the constructive sense, but any organisms, including heterotrophs, can exhibit constructive fitness if they have some mechanism for channeling external flows of free energy into their ecosystems. I will briefly examine the prospects for the human species in the light of these considerations. PMID- 21300322 TI - Darwinism without populations: a more inclusive understanding of the "Survival of the Fittest". AB - Following Wallace's suggestion, Darwin framed his theory using Spencer's expression "survival of the fittest". Since then, fitness occupies a significant place in the conventional understanding of Darwinism, even though the explicit meaning of the term 'fitness' is rarely stated. In this paper I examine some of the different roles that fitness has played in the development of the theory. Whereas the meaning of fitness was originally understood in ecological terms, it took a statistical turn in terms of reproductive success throughout the 20th Century. This has lead to the ever-increasing importance of sexually reproducing organisms and the populations they compose in evolutionary explanations. I will argue that, moving forward, evolutionary theory should look back at its ecological roots in order to be more inclusive in the type of systems it examines. Many biological systems (e.g. clonal species, colonial species, multi species communities) can only be satisfactorily accounted for by offering a non reproductive account of fitness. This argument will be made by examining biological systems with very small or transient population structures. I argue this has significant consequences for how we define Darwinism, increasing the significance of survival (or persistence) over that of reproduction. PMID- 21300323 TI - [Treatment of severe to profound mixed hearing loss with the BAHA Cordelle II]. AB - GOALS: Evaluation of the audiological outcome and subjective satisfaction of BAHA Cordelle II in the treatment of patients with severe to profound bilateral mixed hearing loss. MATERIAL AND METHOD: Retrospective study of 12 patients suffering a severe to profound bilateral sensorineural hearing loss, using pure tone audiometry (PTA), speech audiometry and subjective evaluation before and after the implantation of a BAHA Cordelle II (Cochlear((r))). RESULTS: The average gain in conversational frequencies (0.5 to 4kHz) with BAHA in free field was 43, 51, 47 and 44dB, respectively. We observed a GAP over closure in 10 of the 12 patients. Speech audiometry improved from 85% at 83dB of maximum discrimination to 96% at 62dB. The subjective evaluation questionnaires showed great satisfaction with a slight decrease in noisy or windy environments. The great majority of our patients used the BAHA device throughout the entire day. CONCLUSIONS: The BAHA Cordelle II (Cochlear((r))) is a good option in the treatment of severe to profound bilateral mixed hearing loss. Its best advantages are a low risk of labyrinthization, high result predictability, easy and step-by step surgery, no need for general anaesthesia, and the GAP over closure in all frequencies. Active middle ear devices represent another alternative, but specific indications have not been defined yet because of low universal experience. When the intelligibility of the patient is poor, cochlear implantation should be considered. PMID- 21300324 TI - Synchronization in repetitive smooth movement requires perceptible events. AB - Accurate timing performance during auditory-motor synchronization has been well documented for finger tapping tasks. It is believed that information pertaining to an event in movement production aids in detecting and correcting for errors between movement cycle completion and the metronome tone. Tasks with minimal event-related information exhibit more variable synchronization and less rapid error correction. Recent work from our laboratory has indicated that a task purportedly lacking an event structure (circle drawing) did not exhibit accurate synchronization or error correction (Studenka & Zelaznik, in press). In the present paper we report on two experiments examining synchronization in tapping and circle drawing tasks. In Experiment 1, error correction processes of an event timed tapping timing task and an emergently timed circle drawing timing task were examined. Rapid and complete error correction was seen for the tapping, but not for the circle drawing task. In Experiment 2, a perceptual event was added to delineate a cycle in circle drawing, and the perceptual event of table contact was removed from the tapping task. The inclusion of an event produced a marked improvement in synchronization error correction for circle drawing, and the removal of tactile feedback (taking away an event) slightly reduced the error correction response of tapping. Furthermore, the task kinematics of circle drawing remained smooth providing evidence that event structure can be kinematic or perceptual in nature. Thus, synchronization and error correction, characteristic of event timing (Ivry, Spencer, Zelaznik, & Diedrichsen, 2002; Repp, 2005), depends upon the presence of a distinguishable source of sensory information at the timing goal. PMID- 21300325 TI - [Referrals to dermatology: proportion of banal disorders]. AB - BACKGROUND AND OBJECTIVE: Skin diseases account for a large number of consultations in primary care. The objective of this study was to determine the characteristics and cost of referrals from primary care to a dermatology clinic. MATERIAL AND METHODS: Descriptive cross-sectional study of referrals from a primary care health center to a dermatology clinic. The dermatology clinic was situated in the same health center and was attended by a dermatologist from Complejo Hospitalario Universitario in Albacete, Spain. The study was performed on 10 days selected at random between April 21, 2009, and June 26, 2009. The data gathered included age, sex, use of cryotherapy, and diagnostic group. Patients were divided into 4 diagnostic groups: A) benign degenerative disease or trivial disorders whose treatment may not merit involvement of the national health service, B) diseases resolved with a single dermatology consultation at the health center, C) diseases requiring evaluation in hospital-based dermatology outpatients, and D) diseases referred for surgical treatment. RESULTS: Data were gathered on 257 patients with a mean age was 41.18 years and there was a slight female predominance. The majority of patients were in diagnostic group B (53.7%), followed by groups A (19.1%), C (19.1%), and D (8.2%). The total estimated cost of these 257 visits was ?29 750.32, of which ?5672.24 was for trivial disorders. CONCLUSIONS: The current high prevalence of trivial disorders in the caseload of dermatology clinics by trivial disorders makes it necessary to control referrals from primary care more strictly. PMID- 21300326 TI - Breath-hold T2-weighted MRI of the liver at 3T using the BLADE technique: impact upon image quality and lesion detection. AB - AIM: To compare image quality and lesion detection in the liver using magnetic resonance imaging (MRI) at 3T between T2-weighted imaging using a standard rectilinear k-space trajectory (standard T2WI) and using the BLADE technique (BLADE-T2WI), a technique that employs periodically rotated overlapping parallel lines with enhanced reconstruction for motion correction. MATERIALS AND METHODS: Twenty-eight consecutive patients who underwent MRI examination of the liver at 3T including standard T2WI and BLADE-T2WI, both performed using multiple breath holds, comprised the study cohort. Images were reviewed in consensus by two radiologists during separate sessions for a number of measures regarding artefacts and image quality. These two readers also assessed the two image sets for the presence of liver lesions and measured liver-to-lesion contrast. Binary logistic regression for correlated data was used to compare the sequences in terms of sensitivity and positive predictive value (PPV) for lesion detection. RESULTS: BLADE-T2WI received significantly higher scores than did standard T2WI for in-plane respiratory motion (p=0.0195), other ghosting artefacts (p<0.0001), sharpness of the liver edge (p=0.0004), sharpness of intra-hepatic vessels (p<0.0001), flow signal suppression (p<0.0001), and overall image quality (p<0.0001). There was a non-significant trend toward improved B(1)-inhomogeneity artefact with BLADE-T2WI (p=0.0571). There was no difference in through-plane respiratory motion (p=0.6836). BLADE-T2WI demonstrated a significant improvement in PPV for lesion detection (p=0.0129) as well as in liver-to-lesion contrast (p=0.0054). There was no difference regarding lesion sensitivity (p=1.0). CONCLUSIONS: Use of the BLADE technique for T2-weighted MRI of the liver at 3T may lead to a significant improvement in image artefacts and improved PPV for lesion detection. PMID- 21300327 TI - Imaging findings prevent unnecessary surgery in vasitis: an under-reported condition mimicking inguinal hernia. PMID- 21300328 TI - Pulmonary artery embolization for recurrent haemoptysis in cavitatory sarcoidosis. PMID- 21300329 TI - Scan length optimization for pulmonary embolism at CT angiography: analysis based on the three-dimensional spatial distribution of 370 emboli in 100 patients. AB - AIM: To determine the size and three-dimensional spatial distribution of pulmonary emboli (PE) at computed tomography angiography (CTA) to optimize the scan length. MATERIALS AND METHODS: Two experienced radiologists jointly reviewed 100 consecutive, positive PE CTA studies performed in the Emergency Department (53 women; age 61+/-17 years). All studies were conducted on a 16-detector row CT machine. In each case, the number of emboli was counted and the proximal and distal spatial coordinates of each embolus documented. Coordinates of the main pulmonary artery bifurcation (MPAb) and carina were recorded. For normalization, the thoracic cavity height (H)-from inlet to lowest hemidiaphragm-was measured. The minimal scan lengths for (a) capturing all emboli and (b) rendering a positive diagnosis were determined. RESULTS: Three hundred and seventy (370) emboli were detected. The average number of PE per patient was 3.7 (maximum 12, minimum 1). Their average length was 2.7 cm. Nine patients had saddle emboli (9%), and 71% of emboli were at or below the MPAb. An 18 cm (0.90*H) scan length, centred 4 cm (0.18*H) below the carina, captures all PE in this dataset while reducing z-axis coverage by 29% (34% for normalized data). Moreover, a 14.2 cm (0.78*H) scan length appropriately centred captures at least one embolus in all patients while reducing coverage by 44% (43%). Decreasing scan length to the lesser of 14.2 cm and 0.78*H per patient reduces coverage by 47%. CONCLUSION: Scan length at CTA for PE can be reduced by up to 47% while preserving diagnostic accuracy for PE detection. PMID- 21300330 TI - MRI findings in X-linked Charcot-Marie-Tooth disease associated with a novel connexin 32 mutation. PMID- 21300331 TI - Can prepubertal human testicular tissue be cryopreserved by vitrification? AB - OBJECTIVE: To assess vitrification of prepubertal human testicular tissue in vitro. DESIGN: Case report. SETTING: Academic research unit. PATIENT(S): Two patients (6 and 12 years of age) who were to start gonadotoxic treatment for chronic granulomatous disease and acute lymphoblastic leukemia. INTERVENTION(S): Long-term (10-day) organotypic culture performed immediately after vitrification and warming. Fresh tissue and tissue cryopreserved by slow-freezing were used as control samples. MAIN OUTCOMES MEASURE(S): Spermatogonial cell survival (MAGE-A4) and proliferation (Ki67) were evaluated by immunohistochemistry (IHC) and tubular integrity by light microscopy. RESULT(S): Qualitative analysis revealed that histologic characteristics of spermatogonia and Sertoli cells were preserved, as were cell-cell cohesion and cell adhesion to the basement membrane, in vitrified tissue as well as in frozen and fresh control samples. Survival of spermatogonia and their ability to proliferate as evidenced by IHC was also confirmed in cultured fresh, slow-frozen, and vitrified tissue. CONCLUSION(S): Vitrification, having the advantage of being a faster and more convenient method, shows promise as an alternative strategy to slow-freezing in the emerging field of immature testicular tissue cryopreservation. PMID- 21300332 TI - Transabdominal follicular aspiration for oocyte retrieval in patients with ovaries inaccessible by transvaginal ultrasound. AB - OBJECTIVE: To investigate the efficacy of ultrasound-guided transabdominal follicular aspiration when the ovaries are not accessible transvaginally. DESIGN: Retrospective case-control study. SETTING: University-hospital based in vitro fertilization (IVF) clinic. PATIENT(S): 69 women undergoing transabdominal follicular aspiration for oocyte retrieval, including 12 cases of mixed abdominal/vaginal aspiration, compared with controls matched by age, follicle number, and year of procedure undergoing standard transvaginal aspiration. INTERVENTION(S): Transabdominal follicular aspiration when one or more ovaries could not be retrieved via standard transvaginal aspiration. MAIN OUTCOME MEASURE(S): Total and mature oocytes retrieved, damaged oocytes, fertilization rate, embryo number and quality, and clinical and ongoing pregnancy rates. RESULT(S): Cases of transabdominal aspiration had slightly fewer oocytes retrieved, but no statistically significant differences were found for damaged oocytes, fertilization rates, embryo number and quality, or pregnancy rates. In 12 years, one complication requiring hospitalization was noted. CONCLUSION(S): This study demonstrates that transabdominal ultrasound-guided follicular aspiration is safe and efficacious, yielding clinical results in women with significant ovarian displacement, comparable with results achieved by transvaginal aspiration in women with normally positioned ovaries. Transabdominal ultrasound-guided aspiration should be the modality of choice when the ovaries are not accessible transvaginally. PMID- 21300333 TI - Effects of I-131 therapy on gonads and pregnancy outcome in patients with thyroid cancer. AB - We examined the effects of I-131 therapy for thyroid cancer on female and male gonads and pregnancy outcome. After an extensive review of the published literature we concluded that ablative administration of I-131 therapy may result in transient abnormalities of ovarian and testicular function, but subsequent pregnancies are safe without any significant consequences to offspring outcome. PMID- 21300334 TI - Administration of a gonadotropin-releasing hormone antagonist during the 3 days before the initiation of the in vitro fertilization/intracytoplasmic sperm injection treatment cycle: impact on ovarian stimulation. A pilot study. AB - OBJECTIVE: To investigate the impact on the number of cumulus-oocyte complexes (COC) when a 3-day course of GnRH antagonist treatment precedes the initiation of controlled ovarian stimulation with gonadotropins in a GnRH antagonist protocol for IVF/intracytoplasmic sperm injection (ICSI). DESIGN: Randomized controlled trial. SETTING: Tertiary referral center. PATIENT(S): Sixty-nine women undergoing controlled ovarian hyperstimulation for IVF/ICSI. INTERVENTION(S): The control group (n = 36) received a standard treatment with daily injections of recombinant FSH (rFSH), starting on day 2 of the cycle at a dose of 150-225 IU/day, and GnRH antagonists from cycle day 7 onward. In the pretreatment group (n = 33), a GnRH antagonist was administered from day 2 of the menstrual cycle onward during 3 consecutive days; thereafter controlled ovarian stimulation was initiated with the same protocol as used in the control group. MAIN OUTCOME MEASURE(S): The primary endpoint was the number of COCs at egg retrieval. RESULT(S): Both groups had comparable baseline characteristics. The duration of rFSH stimulation and consumption of gonadotropins were similar in both groups. The number of COCs was higher in the pretreatment group (12.8; SD, 7.8) compared with in the control group (9.9; SD, 4.9), although this increment was not significant (between-group difference of 2.9 [95% confidence interval {CI} -0.2 to 6.0]). The ongoing pregnancy rates per started cycle of 14/33 (42%) versus 12/36 (33%) for pretreatment versus control did not differ significantly (between-group difference, 9.1%; 95% CI, -13% to 30%). CONCLUSION(S): Among women under 36 years old, early follicular phase GnRH antagonist pretreatment in a fixed GnRH antagonist protocol results in a trend toward a higher number of retrieved oocytes but does not yield significantly higher pregnancy rates. PMID- 21300335 TI - Role of androgen-mediated enhancement of erythropoiesis in the increased body iron stores of patients with polycystic ovary syndrome. AB - OBJECTIVE: To determine whether androgen excess contributes to the increased body iron stores of polycystic ovary syndrome (PCOS) by stimulating erythropoietic activity, by measuring serum soluble transferrin receptor (sTfR) concentrations and its ratio to ferritin levels in patients with PCOS, as surrogate markers of erythropoietic activity and of the appropriateness of cellular iron demands for the total body iron contents, respectively. DESIGN: Case-control study. SETTING: Academic hospital. PATIENT(S): One hundred-four patients with PCOS and 100 controls without androgen excess. INTERVENTION(S): Blood sampling and oral glucose tolerance test. MAIN OUTCOME MEASURE(S): Serum sTfR and ferritin concentrations, as well as indexes of androgen excess, inflammation, obesity, and insulin and glucose metabolism. RESULT(S): Serum ferritin levels increased in women presenting with PCOS, obesity, and/or abnormal glucose tolerance, but these disorders did not influence sTfR concentrations. The sTfR/ferritin ratio decreased with obesity and abnormal glucose tolerance, and its logarithm correlated inversely with body mass index, free T, and C-reactive protein levels and directly with the insulin sensitivity and disposition indexes. A stepwise multiple regression analysis indicated that the changes in the insulin sensitivity index explained 7% of the variability of the logarithm of sTfR/ferritin ratio. CONCLUSION(S): Increased serum ferritin levels in patients with PCOS are associated with a reduction in insulin sensitivity but do not result from a putative enhancement of erythropoiesis by androgen excess. PMID- 21300337 TI - Pregnancy in women with PCOS. PMID- 21300338 TI - The role of inositol supplementation in patients with polycystic ovary syndrome, with insulin resistance, undergoing the low-dose gonadotropin ovulation induction regimen. AB - In an attempt to evaluate the role of inositol supplementation in insulin resistant patients with polycystic ovary syndrome (PCOS), undergoing gonadotropin ovulation induction using the low-dose step-down regimen, we conducted a prospective longitudinal study comparing the stimulation characteristics of 15 patients treated with inositol, to a cohort, matched by age and body mass index (BMI), without inositol. Inositol nutritional supplementation produced very good clinical results with a significant reduction in cancellation rate (0 vs. 40%) and the consequent improvement in clinical pregnancy rate (PR) (33.3% vs. 13.3%). PMID- 21300339 TI - Randomized trial of leuprolide versus continuous oral contraceptives in the treatment of endometriosis-associated pelvic pain. AB - OBJECTIVE: To compare the efficacy of leuprolide and continuous oral contraceptives in the treatment of endometriosis-associated pain. DESIGN: Prospective, randomized, double-blind controlled trial. SETTING: Academic medical centers in Rochester, New York, and Boston, Massachusetts. PATIENT(S): Forty seven women with endometriosis-associated pelvic pain. INTERVENTION(S): Forty eight weeks of either depot leuprolide, 11.25 mg IM every 12 weeks with hormonal add-back using norethindrone acetate 5 mg orally, daily; or a generic monophasic oral contraceptive (1 mg norethindrone + 35 mg ethinyl estradiol) given daily. MAIN OUTCOME MEASURE(S): Biberoglu and Behrman (B&B) pain scores, numerical rating scores (NRS), Beck Depression Inventory (BDI), and Index of Sexual Satisfaction (ISS). RESULT(S): Based on enrollment of 47 women randomized to continuous oral contraceptives and to leuprolide, there were statistically significant declines in B&B, NRS, and BDI scores from baseline in both groups. There were no significant differences, however, in the extent of reduction in these measures between the groups. CONCLUSION(S): Leuprolide and continuous oral contraceptives appear to be equally effective in the treatment of endometriosis associated pelvic pain. PMID- 21300341 TI - Derivation of developmentally competent oocytes by in vitro culture of preantral follicles retrieved from aged mice. AB - Mature oocytes were derived from cultured preantral follicles retrieved from aged (63-67 weeks old) mice with decreased fecundity; IVF of the oocytes resulted in cleaving embryos. There was no difference in developmental competence of 4-cell embryos to the blastocyst stage between the adult and the aged groups, although general retardation of follicle development and oocyte maturation and development after IVF was detected. PMID- 21300340 TI - Nasal embryonic LHRH factor (NELF) mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome. AB - OBJECTIVE: To determine if mutations in NELF, a gene isolated from migratory GnRH neurons, cause normosmic idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS). DESIGN: Molecular analysis correlated with phenotype. SETTING: Academic medical center. PATIENT(S): A total of 168 IHH/KS patients as well as unrelated control subjects were studied for NELF mutations. INTERVENTION(S): NELF coding regions/splice junctions were subjected to polymerase chain reaction (PCR)-based DNA sequencing. Eleven additional IHH/KS genes were sequenced in three patients with NELF mutations. MAIN OUTCOME MEASURE(S): Mutations were confirmed by sorting intolerant from tolerant, reverse transcription (RT)-PCR, and Western blot analysis. RESULT(S): Three novel NELF mutations absent in 372 ethnically matched control subjects were identified in 3/168 (1.8%) IHH/KS patients. One IHH patient had compound heterozygous NELF mutations (c.629-21G>C and c.629-23C>G), and he did not have mutations in 11 other known IHH/KS genes. Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c.1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3). In vitro evidence of these NELF mutations included reduced protein expression and splicing defects. CONCLUSION(S): Our findings suggest that NELF is associated with normosmic IHH and KS, either singly or in combination with a mutation in another gene. PMID- 21300342 TI - Multiplying recipients paired with oocyte donors optimizes the use of donated oocytes. AB - OBJECTIVE: To review donor-egg assisted reproductive technology (ART) activity using young fertile donors (<37 years of age) paired with multiple recipients. DESIGN: Age-matched cohort study. SETTING: Tertiary ART center at Cochin Hospital, Paris. PATIENT(S): A total of 125 oocyte donors and 361 age-matched control subjects. Donated oocytes were attributed to 163 different recipients undertaking 258 transfer cycles. INTERVENTION(S): Donor-egg and regular ART. MAIN OUTCOME MEASURE(S): Controlled ovarian hyperstimulation (COH) outcome-oocytes provided-was compared in donors and control subjects. Clinical pregnancy (cPR), ongoing pregnancy (oPR), and implantation (IR) rates per transfer in recipients were compared with age-matched controls. IRs were analyzed in the various recipients as a function of the number of oocytes harvested. RESULT(S): COH outcome was similar in donors and control subjects. cPR (37.5%), oPR (28.4%), and IR (24.4%) were slightly but significantly lower in donor-egg recipients compared with control subjects (44.9%, 37.4%, and 31.8%, respectively). More embryos (average +2.06) were transferred fresh and fewer frozen. In recipients, IRs were independent from the number of oocytes received in the donor. CONCLUSION(S): Multiplying recipients paired with oocyte donors slightly lowered per-transfer outcome, but enabled more (average +2.06) embryos to be transferred fresh. PMID- 21300343 TI - Prospective evaluation of basal stromal Doppler studies in women with good ovarian reserve and infertility undergoing in vitro fertilization-embryo transfer treatment: patients with polycystic ovary syndrome versus ovulatory patients. AB - OBJECTIVE: To gain insight into the ovarian stromal blood flow in women with polycystic ovary syndrome (PCOS) as compared with women with normal ovulation, good ovarian reserve, and infertility and to evaluate the role of stromal flow in these patients to predict clinical pregnancy in an assisted reproductive technologies setting. DESIGN: A prospective observational cohort study. SETTING: A university-affiliated reproductive medicine unit. PATIENT(S): Eighteen consecutive patients with PCOS (study) compared with 101 patients with normal ovulation and infertility (control), undergoing their first IVF-ET treatment at our unit. Women with low ovarian reserve were excluded a priori from evaluation. Basal ovarian reserve parameters and stromal flow studies were conducted as routinely performed in our unit, in a natural cycle before starting treatment. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Basal ovarian endocrine, sonographic, and stromal flow studies were compared between the groups. After completion of treatment, the stromal flow studies were compared between conception and nonconception cycles. RESULT(S): Patients' characteristics and basal ovarian reserve, including endocrine and sonographic parameters, were similar between the PCOS and control groups. Only antral follicle count and LH/FSH ratio were higher in the PCOS as compared with the control group, corresponding to 15.11 +/- 6.05 versus 9.05 +/- 4.77 and 1.14 +/- 0.64 versus 0.79 +/- 0.37, respectively. Basal stromal flow indices were similar between the PCOS group and the group with normal ovulation and good ovarian reserve. Clinical pregnancy rate per initiated cycle was 50.0% and 39.6% in the PCOS and control groups, respectively, with no significant difference. Flow indices were similar between conception cycles in the PCOS and control groups. As well, the indices did not differ significantly between conception and nonconception cycles within the PCOS and control groups. CONCLUSION(S): Basal ovarian stromal blood flow does not differ between women with PCOS and women with normal ovulation, good ovarian reserve, and infertility. Moreover, stromal flow has no predictive value, in these patients, for clinical pregnancy achievement in an IVF-ET setting. PMID- 21300344 TI - Anastrozole vs. clomiphene citrate in infertile women with ovulatory dysfunction: a phase II, randomized, dose-finding study. AB - OBJECTIVE: To determine an effective multiple-dose regimen of anastrozole compared with clomiphene citrate (CC) to induce follicular growth and ovulation in infertile women with ovulatory dysfunction. DESIGN: Phase II, prospective, randomized, double-blind, multicenter, dose-finding, noninferiority study. SETTING: Outpatient. PATIENT(S): Infertile women (n = 271) with ovulatory dysfunction, aged 18-40 years, with body mass index <37 kg/m(2). INTERVENTION(S): Five days of anastrozole at 1, 5, or 10 mg/d or CC at 50 mg/d. MAIN OUTCOME MEASURE(S): The primary endpoint was the ovulation rate (mid-luteal phase serum P level >= 10 ng/mL or clinical pregnancy) in the first treatment cycle (cycle 1). RESULT(S): In cycle 1 the ovulation rates for anastrozole at 1, 5, and 10 mg/d were 30.4% (n = 24), 36.8% (n = 28), and 35.9% (n = 14), respectively, compared with 64.9% (n = 50) for CC at 50 mg/d. In up to three cycles of treatment, cumulative ovulation rates did not differ between groups. No cases of ovarian hyperstimulation syndrome were reported, and both anastrozole and CC were well tolerated. CONCLUSION(S): In terms of ovulation rates, 5-day anastrozole at 1, 5, and 10 mg/d was less effective than CC at 50 mg/d for cycle 1 (noninferiority was not shown). PMID- 21300345 TI - The first case described: monozygotic twin sisters with the fragile X premutation but with a different phenotype for premature ovarian failure. AB - OBJECTIVE: To describe the first case of monozygotic twin sisters with fragile X premutation and discordance for premature ovarian failure (POF). DESIGN: A descriptive case study. SETTING: Academic center. PATIENT(S): Monozygotic twin sisters with fragile X premutation and discordance for POF. INTERVENTION(S): Serum laboratory testing, fragile X premutation screening, zygosity testing, X inactivation ratio and Southern blot studies. MAIN OUTCOME MEASURE(S): Incidence of POF in this twin cohort. RESULT(S): Zygosity analysis using polymerase chain reaction of 15 polymorphic markers via capillary gel electrophoresis in these patients confirmed their monozygosity. X-inactivation studies were performed using the human androgen receptor (HUMARA) gene and revealed similar X inactivation ratios for both the patient and her sister (11:89 and 12:88, respectively) from peripheral serum samples. Southern blot evaluation of the proband and her sister revealed a similar methylation pattern in which the premutation allele was unmethylated much more than the normal allele. The contribution of the premutation on the active allele as determined by Southern blot analysis was consistent between sisters. CONCLUSION(S): The inactivation ratio studies and subsequent Southern blot analysis do not show differences between the patients; therefore, we are unable to identify a causative mechanism for the identical sisters' discordant phenotypes. It is possible that the inactivation ratios observed from the peripheral blood specimens obtained from the sisters do not represent the allele expression and skewing present at the level of the ovary. PMID- 21300346 TI - One patient, two uteri, two endometrial ablations: case report of thermal balloon ablation in uterine didelphys. AB - OBJECTIVE: To describe the clinical application and outcomes after endometrial ablation with ThermachoiceIII (Ethicon, Somerville, NJ) in a patient with uterine didelphys with heavy menstrual bleeding. DESIGN: Case report. SETTING: Inner-city community obstetrics and gynecology clinic. PATIENT(S): A 44-year-old Hispanic woman, gravida 3, para 0, with three spontaneous abortions. INTERVENTION(S): The patient underwent diagnostic hysteroscopy, gynecologic dilation and curettage, and endometrial ablation with ThermachoiceIII. MAIN OUTCOME MEASURE(S): Menstrual pattern at 3 months postoperatively, as either amenorrhea (complete lack of menstrual flow), hypomenorrhea (scant or minimal flow lasting <5 days, requiring only light pads), or failure (flow similar to pretreatment state or requiring any other therapy), as well as dysmenorrhea reduction from baseline. Hemoglobin value at 3 months was compared with baseline. RESULT(S): At 3 months, hypomenorrhea was maintained. Bleeding days were 10 per month at baseline and 2 per month after therapy. Visual analogue scale score for dysmenorrhea was 8 at baseline and 2 (mean) at study end. Hemoglobin was 8.9 g/dL at baseline (preoperatively) and 11.1 g/dL at 3 months postoperatively. CONCLUSION(S): Successful conservative therapy of menorrhagia seems possible with thermal balloon ablation in a uterine didelphic patient. PMID- 21300348 TI - Vitrified human ovaries have fewer primordial follicles and produce less antimullerian hormone than slow-frozen ovaries. AB - Slow-freezing and vitrification methods of human ovarian tissue cryopreservation were compared in terms of primordial follicle count and in vitro antimullerian hormone (AMH) and estradiol production. Compared with fresh and slow-frozen ovaries, vitrified ovaries contained statistically significantly fewer primordial follicles and produced statistically significantly less AMH in vitro. Estradiol production from slow-frozen and vitrified ovaries was similar but statistically significantly lower than from fresh cultured strips. PMID- 21300347 TI - Replication of association of a novel insulin receptor gene polymorphism with polycystic ovary syndrome. AB - OBJECTIVE: To evaluate association with polycystic ovary syndrome (PCOS) of 295 variants in 39 genes central to metabolic insulin signaling and glycogen synthase kinase 3beta (GSK-3beta) regulation, followed by replication efforts. DESIGN: Case-control association study, with discovery and replication cohorts. SETTING: Subjects were recruited from reproductive endocrinology clinics, and controls were recruited from communities surrounding the University of Alabama at Birmingham and Erasmus Medical Center, Rotterdam. PATIENT(S): A total of 273 cases with PCOS and 173 control subjects in the discovery cohort; and 526 cases and 3,585 control subjects in the replication cohort. All subjects were caucasian. INTERVENTION(S): Phenotypic and genotypic assessment. MAIN OUTCOME MEASURE(S): Detection of 295 single-nucleotide polymorphisms (SNPs), PCOS status. RESULT(S): Several SNPs were associated with PCOS in the discovery cohort. Four insulin receptor (INSR) SNPs and three insulin receptor substrate 2 (IRS2) SNPs associated with PCOS were genotyped in the replication cohort. One INSR SNP (rs2252673) replicated association with PCOS. The minor allele conferred increased odds of PCOS in both cohorts, independent of body mass index. CONCLUSION(S): A pathway-based tagging SNP approach allowed us to identify novel INSR SNPs associated with PCOS, one of which confirmed association in a large replication cohort. PMID- 21300349 TI - A power law approach to orifice flow rate calibration. AB - Although standards for orifice flow meter design, installation, and calibration are supported herein, noncompliant devices exist in many pilot-, lab-scale, and on-board applications. For these, a common calibration practice is to preserve the ideal square root relation and determine a device specific discharge coefficient value. This work provides theoretical and empirical analyses to support relaxing the square root relation between orifice pressure drop and flow rate for noncompliant devices. The resulting power law relation is shown to improve accuracy, precision, and rangeability. Whether a device specific square root or power law model is used, it requires off-line or in-line calibration data. As such, a power law calibration model may only be useful for on-board and small-scale applications. PMID- 21300350 TI - Subtherapeutic, low-dose fluvastatin improves functional and morphological arterial wall properties in apparently healthy, middle-aged males--a pilot study. AB - OBJECTIVE: Early arterial wall changes are already present in the apparently healthy, middle-aged population and continuously progress with age. The aim of our study was to investigate whether 30 days low-dose fluvastatin treatment could improve and reverse these arterial changes that are primarily associated with ageing, in otherwise healthy middle-aged males. METHODS: In a double blind, randomized study, 50 middle-aged males received either placebo or fluvastatin (10mg) for 30 days. Brachial artery flow-mediated dilation (FMD), pulse wave velocity (PWV) and beta-stiffness of the common carotid artery were measured on the 1st, 14th and 30th day of the study using an Aloka instrument by integrated eTracking. RESULTS: In 77% of subjects, impaired endothelial function was revealed at inclusion in the study. All the parameters were improved already after 14 days, and after 30 days of treatment FMD improved by 91.5 +/- 15.6%, while PWV and beta-stiffness improved by 6.2 +/- 1.1% and 10.7 +/- 1.5%, respectively (all P<0.001). After therapy discontinuation, the beneficial effects progressively decreased, but were still detectable after 5 months. During the study the lipid profile remained unchanged, thus the beneficial effects obtained were attributed to the pleiotropic effects of fluvastatin. CONCLUSIONS: We found that subtherapeutic low-dose fluvastatin (10mg daily; 30 days) considerably improves and reverses early functional and morphological arterial wall impairments that are present in apparently healthy, middle-aged males. It might be supposed that such a new and original approach could be valuable in cardiovascular prevention. PMID- 21300351 TI - Inhibition of IL-17A in atherosclerosis. AB - OBJECTIVE: To determine the effects of interleukin (IL)-17A inhibition on experimental atherosclerosis. METHODS AND RESULTS: ApoE(-/-) mice were treated with either rat anti-mouse IL-17A, mouse anti-mouse IL-17A or isotype-matched control antibodies for 12 weeks (n=8-10 per group). Ldlr(-/-) mice were transplanted with IL-17A-deficient or wild type bone marrow (n=8 per group). Rat anti-mouse IL-17A treatment obviously reduced plaque size by 43% (p<0.01) without evidence of reduced IL-17A signaling. In contrast, mouse anti-mouse IL-17A treatment and IL-17A deficiency in bone marrow cells did not alter lesion size despite significant reduction of IL-17A production. CONCLUSIONS: Inhibition of IL 17A signaling does not alter lesion development in Th1-biased C57BL/6 ApoE(-/-) and Ldlr(-/-) mice with already low levels of IL-17A production. Alteration of lesion development after repeated injections of rat anti-mouse IL-17A antibody in ApoE(-/-) mice could not be attributed to blockade of IL-17A signaling. PMID- 21300352 TI - Regulatory effects of sulfur dioxide on the development of atherosclerotic lesions and vascular hydrogen sulfide in atherosclerotic rats. AB - OBJECTIVE: This study was designed to examine the effect of sulfur dioxide (SO(2)) on atherosclerotic progression and endogenous vascular hydrogen sulfide (H(2)S) in rats with atherosclerosis (AS). METHODS: Twenty-eight male rats were randomly divided into control, AS and AS+SO(2) groups. Rats were given a single dose of vitamin D(3) and fed a high-cholesterol diet for 8 weeks to induce AS. Plasma lipids, aortic ultrastructure, and atherosclerotic lesions were detected at the termination of experiment. Plasma and aortic SO(2) were measured using high-performance liquid chromatography, and aspartate aminotransferase (AAT) 1 and AAT2 mRNAs were detected by real-time PCR. Plasma and aortic H(2)S levels were determined with a sulfide-sensitive electrode. Cystathionine-gamma-lyase (CSE) mRNA and protein expression was detected. Plasma glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities, malondialdehyde (MDA) and nitric oxide (NO) contents, inducible NO synthase (iNOS) and eNOS activities, and aortic SOD1 and SOD2 expressions were detected. RESULTS: Marked atherosclerotic lesions with elevated levels of TC and LDL-C were observed in AS rats. While, there were decreased plasma SO(2) levels and aortic SO(2) production, with a reduced aortic AAT activity in atherosclerotic rats. Plasma GSH-Px and SOD activities were decreased but MDA level increased. Plasma NO content and iNOS activity were also increased. SO(2) donor, however, significantly decreased the atherosclerotic lesions with an increased aortic H(2)S/CSE pathway. It elevated plasma GSH-Px and SOD activities, reduced plasma MDA level, and increased NO/NOS pathway. CONCLUSIONS: SO(2) has a marked anti-atherogenic effect with an increase in endogenous H(2)S production in rats with AS. PMID- 21300353 TI - Differential expression of oxidized/native lipoprotein(a) and plasminogen in human carotid and cerebral artery plaques. AB - OBJECTIVE: Lipoprotein(a) [Lp(a)] is a risk factor for stroke, as has recently been further confirmed by meta analysis, and consists of low-density lipoprotein and apolipoprotein(a), which shares a significant amino acid homology with plasminogen. Oxidized Lp(a) [Ox-Lp(a)] is a more pathogenic species of Lp(a). A monoclonal antibody, specific to Ox-Lp(a), distinguishes immunolocalization of Ox Lp(a) from that of Lp(a) and that of plasminogen which carries highly homologous domains. It is worth examining their possibly differential immunolocalizations around atherosclerotic lesions in human carotid and cerebral arteries. METHODS AND RESULTS: Stage-related differences in immunolocalization of Ox-Lp(a), native Lp(a), and plasminogen were investigated in various atherosclerotic lesions of the human carotid (obtained from 13 patients undergoing carotid endarterectomy) and cerebral arteries (from 11 cadavers). Native Lp(a) was seen in the fibrous cap, extracellular matrix, endothelial cells, and subendothelial layer. Unorganized mural thrombi were positive for plasminogen, but not Lp(a). In contrast, fibrin deposits in thickened intima were positive for Lp(a), but not plasminogen. Ox-Lp(a)-like immunoreactivity was seen in endothelial cells in the early stage of atherosclerosis. Ox-Lp(a) deposition was more abundant in synthetic phase vascular smooth muscle cells (VSMC) than in contractile phase VSMC. CONCLUSION: We demonstrated differential immunoexpression patterns between native Lp(a) and plasminogen, and suggested that Lp(a)-plasminogen interaction may play a part in differential mechanisms in all atherosclerotic lesions of human carotid and cerebral arteries. The preferential presence of Ox-Lp(a) seen in endothelial cells suggests initial dysfunction of endothelial cells in atherosclerosis. The relative abundance of Ox-Lp(a) in synthetic phase VSMC is associated with their phenotypic changes during the progression of atherosclerosis. PMID- 21300354 TI - Nitric oxide production is increased in severely obese children and related to markers of oxidative stress and inflammation. AB - OBJECTIVE: Nitric oxide (NO) is the major endothelium-derived relaxing factor. The aim of the present study was to evaluate NO synthesis and metabolism in severely obese children with different degrees of metabolic risk and to ascertain their relation with the parameters of oxidative stress and inflammation. METHODS: The study involved 60 obese children evaluated with respect to metabolic risk factors (MRFs) (32<4 MRFs and 28 >= 4 MRFs) and 50 normal weight children between 7 and 14 years of age. Nutritional status was assessed by clinical and anthropometric examination. MRFs (serum lipid profile, insulin resistance indexes, blood pressure) in addition to uric acid, homocysteine, leptin, and inflammatory markers were measured. Plasma nitrite, nitrate and nitrotyrosine concentrations, and urinary nitrate were determined as markers of NO production and nitrosative stress. Malondialdehyde, 8-isoprostane F(2alpha), and advanced oxidation protein products were analyzed in plasma to assess oxidative stress. RESULTS: Compared with healthy controls, the obese children had significantly increased concentrations of markers of NO synthesis and nitrosative and oxidative stress that were correlated with each another. Increased NO production in obese children was associated with MRFs; plasma nitrate to waist circumference (r=0.388, p=0.003), uric acid (r=0.404, p<0.001), and tumor necrosis factor alpha (r=0.302, p=0.021), and plasma nitrite to triglycerides (r=0.432, p<0.001). CONCLUSION: NO synthesis and nitrosative stress are increased in severely obese children and correlated with anthropometric parameters indicative of abdominal obesity, oxidative stress and inflammatory markers. PMID- 21300355 TI - Carotid intima-media and adventitial thickening: comparison of new and established ultrasound and magnetic resonance imaging techniques. AB - OBJECTIVE: Carotid intima-media thickness is a well established non-invasive surrogate marker of cardiovascular disease, however there is evidence that structural modification of the arterial adventitia also accompanies cardiovascular risk factors and might be involved causally in atherosclerosis. We sought to determine the relative contributions of the intima-media and adventitia to variation in ultrasound and magnetic resonance derived measures of carotid wall thickness. METHODS: Carotid ultrasound and magnetic resonance imaging were undertaken in 20 participants. Carotid intima-media thickness, carotid extra media thickness (which incorporates the arterial adventitia) and total wall thickness (a combined near-wall intima-media thickness and carotid extra-media thickness) using high-resolution ultrasound, and wall thickness using magnetic resonance imaging, were obtained. RESULTS: All ultrasound-derived measures of the arterial wall thickness were highly correlated with wall thickness by magnetic resonance imaging (all P<0.001); as expected the total wall thickness by ultrasound measure was most tightly correlated (correlation coefficient=0.814, P<0.0001). In multivariable models, there was evidence that both carotid intima media thickness and carotid extra-media thickness contributed independently to the variance in wall thickness by magnetic resonance imaging, especially for the most severe focal thickening. Measures of carotid wall thickness that incorporated all three layers of the arterial wall were more closely correlated with the number of cardiovascular risk factors than carotid intima-media thickness alone. CONCLUSIONS: These results indicate that the arterial adventitia is an important contributor to the wall thickness measure derived by magnetic resonance imaging, and that carotid extra-media thickness likely provides additional information concerning arterial structure than that obtained from carotid intima-media thickness alone. PMID- 21300356 TI - Diabetes and the risk of coronary heart disease in the general Japanese population: the Japan Public Health Center-based prospective (JPHC) study. AB - OBJECTIVE: Although diabetes has a great impact on coronary heart disease (CHD) in Western populations, there is limited evidence that diabetes influences CHD in the Japanese population. METHODS: The Japan Public Health Center-based prospective (JPHC) study conducted a follow-up of 31,192 individuals aged 40-69 years with no history of cardiovascular disease or cancer. Subjects were classified at baseline as normal, borderline diabetic or diabetic based on fasting and non-fasting blood glucose levels and the use of medication to treat diabetes. A Cox proportional hazards model was used to determine the association between diabetes and the risk of fatal and non-fatal CHD events after adjustment for potential confounders. RESULTS: During 12.9 years of follow-up (1990-2006), we identified 266 fatal and non-fatal coronary events using validated criteria. With normal individuals serving as a control, the hazard ratios for total incident CHD events after adjusting for sex, age, study community and fasting were 1.65 (95% CI, 1.19-2.29) and 3.05 (2.03-4.59) in the borderline and diabetic groups, respectively. These associations remained significant after adjustment for conventional risk factors. The population attributable fractions (PAF) of borderline diabetes and diabetes for CHD events were 6.9% and 6.3%, respectively. Furthermore, there was a trend for an association between an impaired fasting glucose (5.6-6.9 mmol/l) and an increased risk of CHD events. CONCLUSIONS: This prospective study suggests that diabetes and elevated glucose levels are associated with incident CHD in the general Japanese population. The PAF of diabetes for fatal and non-fatal coronary events was estimated to be moderate. PMID- 21300357 TI - Effects of estrogen on stress-induced premature senescence of vascular smooth muscle cells: a novel mechanism for the "time window theory" of menopausal hormone therapy. AB - OBJECTIVES: To investigate the effects of estrogen on stress-induced premature senescence of vascular smooth muscle cells (VSMCs) and the underlying mechanisms. METHODS: VSMCs of passage 2-3 cultured from young (2 months) and old (18 months) female SD rats were induced into premature senescence by exposure to 150 MUmol/L H(2)O(2) in the presence or absence of different concentrations of 17beta estradiol (E(2)). The expression or activation of senescence-associated beta galactosidase (SA-beta-Gal), DcR2, oncogene Ras, p38, PRAK, p53, p21, p16 and Rb was detected by flow cytometry, pull-down assay or Western blot. RESULTS: Flow cytometry analysis showed that in the VSMCs from young rats pre-administration of E(2) significantly suppressed the H(2)O(2)-induced premature senescence (reducing both percentage of SA-beta-Gal positive cells and cellular expression of DcR2) in a dose-dependent manner; these senescent-inhibiting effects of E(2) could be blocked by an estrogen receptor antagonist ICI 182,780 (10(-5)mol/L). Pull-down assay or Western blot analysis revealed that pre-administration of 10(-8)mol/L E(2) significantly reduced the H(2)O(2)-induced activation of oncogene Ras, as well as activity of p16 and p38 MAPK, and expression of PRAK, p53, p21 and p-Rb. Unexpectedly, in the VSMCs from old rats the senescent-inhibiting effect of E(2) disappeared and switched to a senescent-promoting action at 10(-8)mol/L. This senescent-promoting effect could be enhanced by ICI 182,780 and eliminated by a cytochrome P450s inhibitor ABT. CONCLUSION: Estrogen inhibits stress-induced premature senescence of VSMCs from young female through its receptor-mediated suppression of both Ras-p38-PRAK-p53-p21-Rb and Ras-p16-Rb pathways, but this effect disappeared and even more switched to a senescent-promoting action in the cells from old body probably due to a side effect of estrogen metabolites. PMID- 21300358 TI - Finite element simulations of a focal knee resurfacing implant applied to localized cartilage defects in a sheep model. AB - Articular resurfacing metal implants have recently been tested in animal models to treat full thickness localized articular cartilage defects, showing promising results. However, the mechanical behavior of cartilage surrounding the metal implant has not been studied yet as it is technically challenging to measure in vivo contact areas, pressures, stresses and deformations from the metal implant. Therefore, we implemented a detailed numerical finite element model by approximating one of the condyles of the sheep tibiofemoral joint and created a defect of specific size to accommodate the implant. Using this model, the mechanical behavior of the surrounding of metal implant was studied. The model showed that the metal implant plays a significant role in the force transmission. Two types of profiles were investigated for metal implant. An implant with a double-curved profile, i.e., a profile fully congruent with the articular surfaces in the knee, gives lower contact pressures and stresses at the rim of the defect than the implant with unicurved spherical profile. The implant should be placed at a certain distance into the cartilage to avoid damage to opposing biological surface. Too deep positions, however, lead to high shear stresses in the cartilage edges around the implant. Mechanical sealing was achieved with a wedge shape of the implant, also useful for biochemical sealing of cartilage edges at the defect. PMID- 21300359 TI - Asymmetrical flow field-flow fractionation with multi-angle light scattering and quasi elastic light scattering for characterization of poly(ethyleneglycol-b-E caprolactone) block copolymer self-assemblies used as drug carriers for photodynamic therapy. AB - Poly(ethyleneoxide-b-E-caprolactone) (PEO-b-PCL) self-assemblies in water were characterized by asymmetrical flow field-flow fractionation (AsFlFFF), with on line coupling with quasi-elastic light scattering (QELS), multi-angle light scattering (MALS), refractive index and UV/Vis detection. We report here the AsFlFFF analysis of three different nanoparticular self-assembled systems of PEO PCL polymers in aqueous media, each polymer differing by the mass of the PEO and PCL fragments. Thus, self-assembled water samples of {PEO(2000)-b-PCL(2600)}, {PEO(5000)-b-PCL(1400)} and {PEO(5000)-b-PCL(4000)} were analyzed by AsFlFFF. In most cases, the size obtained by AsFlFFF was similar to the one characterized by DLS. However, in some instances, only AsFlFFF revealed the presence of several self-assemblies with very different sizes. These nanoparticles being used for the targeted delivery of photosensitizers in photodynamic therapy, it was important to fully characterize the samples in terms of size and size distribution, molecular weight, Ip, aggregation number and also to assess whether the photosensitizer was inside the nanoparticles. AsFlFFF proved to be a very efficient technique which enabled this study without any destruction of the nanoparticles. PMID- 21300360 TI - Dynamic adsorption of diarrhetic shellfish poisoning (DSP) toxins in passive sampling relates to pore size distribution of aromatic adsorbent. AB - Solid-phase adsorption toxin tracking (SPATT) technology was developed as an effective passive sampling method for dissolved diarrhetic shellfish poisoning (DSP) toxins in seawater. HP20 and SP700 resins have been reported as preferred adsorption substrates for lipophilic algal toxins and are recommended for use in SPATT testing. However, information on the mechanism of passive adsorption by these polymeric resins is still limited. Described herein is a study on the adsorption of OA and DTX1 toxins extracted from Prorocentrum lima algae by HP20 and SP700 resins. The pore size distribution of the adsorbents was characterized by a nitrogen adsorption method to determine the relationship between adsorption and resin porosity. The Freundlich equation constant showed that the difference in adsorption capacity for OA and DTX1 toxins was not determined by specific surface area, but by the pore size distribution in particular, with micropores playing an especially important role. Additionally, it was found that differences in affinity between OA and DTX1 for aromatic resins were as a result of polarity discrepancies due to DTX1 having an additional methyl moiety. PMID- 21300361 TI - Adsorption of deamidated antibody variants on macroporous and dextran-grafted cation exchangers: II. Adsorption kinetics. AB - Single and multicomponent batch adsorption kinetics were obtained for deamidated mAb variants on two commercial cation exchangers, one with an open macroporous structure--UNOsphere S--and the other with charged dextran grafts--Capto S. The adsorption kinetics for the macroporous matrix was found to be controlled largely by pore diffusion. The effective diffusivity estimated from single component data was a fraction of the mAb free solution diffusivity, and its value could be used to accurately predict the adsorption kinetics for two- and three-component systems. In this case, when two or more variants were adsorbed simultaneously, both experimental and predicted results showed a temporary overshoot of the amount adsorbed above the equilibrium value for the more deamidated variant followed by a gradual approach to equilibrium. Adsorption rates on the dextran grafted material were much faster than those observed for the macroporous matrix for both single component and simultaneous adsorption cases. In this case, no significant overshoot was observed for the more deamidated forms. The Capto S adsorption kinetics could be described well by a diffusion model with an adsorbed phase driving force for single component adsorption and for the simultaneous adsorption of multiple variants. However, this model failed to predict the adsorption kinetics when more deamidated forms pre-adsorbed on the resin were displaced by less deamidated ones. In this case, the kinetics of the displacement process was much slower indicating that the pre-adsorbed components severely hindered transport of the more strongly bound variants. Overall, the results indicate that despite the lower capacity, the macroporous resin may be more efficient in process applications where displacement of one variant by another takes place as a result of the faster and more predictable kinetics. PMID- 21300362 TI - Fast and efficient size-based separations of polymers using ultra-high-pressure liquid chromatography. AB - Ultra-high-pressure liquid chromatography (UHPLC) has great potential for the separations of both small molecules and polymers. However, the implementation of UHPLC for the analysis of macromolecules invokes several problems. First, to provide information on the molecular-weight distribution of a polymer, size exclusion (SEC) columns with specific pore sizes are needed. Development of packing materials with large pore diameters and pore volumes which are mechanically stable at ultra-high-pressures is a technological challenge. Additionally, narrow-bore columns are typically used in UHPLC to minimize the problem of heat dissipation. Such columns pose stringent requirements on the extra-column dispersion, especially for large (slowly diffusing) molecules. Finally, UHPLC conditions generate high shear rates, which may affect polymer chains. The possibilities and limitations of UHPLC for size-based separations of polymers are addressed in the present study. We demonstrate the feasibility of conducting efficient and very fast size-based separations of polymers using conventional and wide-bore (4.6 mm I.D.) UHPLC columns. The wider columns allow minimization of the extra-column contribution to the observed peak widths down to an insignificant level. Reliable SEC separations of polymers with molecular weights up to ca. 50 kDa are achieved within less than 1 min at pressures of about 66 MPa. Due to the small particles used in UHPLC it is possible to separate high-molecular-weight polymers (50 kDa <= M(r) <= 1-3 MDa, upper limit depends on the flow rate) in the hydrodynamic-chromatography (HDC) mode. Very fast and efficient HDC separations are presented. For very large polymer molecules (typically larger than several MDa, depending on the flow rate) two chromatographic peaks are observed. This is attributed to the onset of molecular deformation at high shear rates and the simultaneous actions of hydrodynamic and slalom chromatography. PMID- 21300363 TI - Liquid chromatography coupled with tandem mass spectrometry method for thirty three pesticides in natural water and comparison of performance between classical solid phase extraction and passive sampling approaches. AB - The aim of this study is to propose an analytical method for determining different classes of pesticides in water using LC-ESI-MS/MS. Two techniques of field-sampling and analyte extraction were used: solid phase extraction (SPE) of water samples from active sampling and field exposure of Polar Organic Chemical Integrative Samplers (POCIS). We have worked with thirty-three molecules representing eight pesticide classes: carbamates, chloroacetanilides, dicarboximides, morpholines, organophosphorous, phenylureas, strobilurines and triazines. First, liquid chromatography separation protocols and the optimization of the ESI-MS/MS parameters were developed. Then, the SPE step was optimized to obtain acceptable levels of recovery for the various classes of molecules. The matrix effect that may significantly lower the ionization efficiency with ESI interfaces was evaluated and minimized. The performances (limits of quantification, accuracy and precision) of the SPE and POCIS techniques were evaluated, and a comparison between the active and passive sampling techniques was carried out with a field application. PMID- 21300364 TI - Calibration of mass selective detector in non-target analysis of volatile organic compounds in the air. AB - Volatile organic compounds (VOCs) play an important role in the chemistry of the atmosphere and in biogeochemistry. They contribute to the oxidative capacity of the atmosphere, particle and air pollutants, as well as to the production of greenhouse gases (for instance ozone). Among analytical techniques for their determination in the atmosphere gas chromatography coupled with mass spectrometry (GC-MS) offers several advantages. However, for an accurate quantification calibration with standard substances is necessary. A quantitative structure property relationship (QSPR) model for the prediction of MS response factors was developed on basis of our experimental measurements for the quantification of ozone precursors present in the atmosphere. A linear correlation between chemical structures and response factors was established by using a 7-parameter MLR model. The average error in the prediction of response factors was calculated by cross validation procedure and was below 20%, which is sufficient for the determination of VOCs in the air. The proposed procedure is time consuming so it is more suited for the quantification of tentatively identified organic compounds during the reprocessing of MS chromatograms in cases when the original sample is no longer available. PMID- 21300365 TI - Tin oxide (SnO2) nanoparticles/electrospun carbon nanofibers (CNFs) heterostructures: controlled fabrication and high capacitive behavior. AB - Tin oxide (SnO(2))/carbon nanofibers (CNFs) heterostructures were fabricated by combining the versatility of the electrospinning technique and template-free solvent-thermal process. The results revealed that the SnO(2) nanostructures were successfully grown on the primary electrospun carbon nanofibers substrates. And, the coverage density of SnO(2) nanoparticles coating on the surface of the CNFs could be controlled by simply adjusting the mass ratio of CNFs to SnCl(4).5H(2)O in the precursor during the solvent-thermal process for the fabrication of SnO(2)/CNFs heterostructures. The electrochemical performances of the SnO(2)/CNFs heterostructures as the electrode materials for supercapacitors were evaluated by cyclic voltammetry (CV) and galvanostatic charge-discharge measurement in 1 M H(2)SO(4) solution. At different scan rates, all the samples with different coverage densities of SnO(2) showed excellent capacitance behavior. And, the sample CS2 (the mass ratio of CNFs to SnCl(4).5H(2)O reached 1:7) exhibited a maximum specific capacitance of 187 F/g at a scan rate of 20 mV/s. Moreover, after 1000 cycles, the specific capacitance retention of this sample was over 95%. The high capacitive behavior could be ascribed to the low resistance of SnO(2)/CNFs heterostructures and rapid transport of the electrolyte ions from bulk solution to the surface of SnO(2). PMID- 21300366 TI - Effect of double quaternary ammonium groups on micelle formation of partially fluorinated surfactant. AB - To investigate the effect of divalency on the micelle properties, we synthesized divalent cationic surfactants composed of fluorocarbons and double quaternary ammonium groups N,N-dimethyl-N-[2-(N'-trimethylammonium)ethyl]-1-(3 perfluoroalkyl-2-hydroxypropyl) ammonium bromide [C(n)(F)C(3)-2Am; where n (=8 or 10) represents the number of carbon atoms in the fluorocarbon chain]. The double quaternary ammonium groups are continuously combined by the ethylene spacer in the surfactant head group, which clearly distinguishes the molecular design of the surfactant from those of the other typical divalent surfactants, bolaform and gemini types. The presence of the divalent head group results in an advantageous increase in their solubility [i.e., rise in the critical micelle concentration (cmc)]; however, the extra electrostatic repulsion between divalent cations decreases the surface activity in comparison with monovalent homologous fluorinated surfactants. The cmc, surface tension at cmc, and area occupied by a surfactant molecule in aqueous solution at 298.2K are 4.32 mM, 30.6 mN m(-1), and 0.648 nm(2 )molecule(-1), respectively, for C(8)(F)C(3)-2Am, and 1.51 mM, 30.4 mN m(-1), and 0.817 nm(2) molecule(-1), respectively, for C(10)(F)C(3)-2Am. The micellar size and shape were investigated by dynamic light scattering and freeze fracture transmission electron microscopy (TEM). The TEM micrographs show that C(n)(F)C(3)-2Am (n=8 and 10) mainly forms ellipsoidal micelles approximately 10 100 nm in size for n=8 and approximately 10-20 nm in size for n=10. The degree of counterion binding to micelle was determined by selective electrode potential measurements, and the results of 0.7-0.8 agree with the average values for conventional monovalent ionic surfactants. PMID- 21300367 TI - Hierarchical positioning of gold nanoparticles into periodic arrays using block copolymer nanoring templates. AB - We report a simple and versatile self-assembly method for controlling the placement of functional gold nanoparticles on silicon substrates using micellar templates. The hierarchical positioning of gold nanoparticles is achieved in one step during the spontaneous phase inversion of spherical poly(styrene)-block poly(2-vinylpyridine) copolymer micelles into nanoring structures. The placement is mainly driven by the establishment of electrostatic interactions between the nanoparticle ligands and the pyridine groups exposed at the interface. In particular, we show the formation of ordered arrangements of single gold nanoparticles or nanoparticle clusters and demonstrate that their morphologies, densities and periodicities can be tuned by simply varying the initial block copolymer molecular weight or the deposition conditions. Besides gold nanoparticles, the method can be used for controlling the assembly of a large variety of nanoscale building blocks, thus opening an attractive pathway for generating functional hybrid surfaces with periodic nanopatterns. PMID- 21300368 TI - Imidazolium camphorsulfonamides: chiral catanionic liquid crystals with tunable thermal properties. AB - We report the synthesis of novel chiral catanionic liquid crystals bearing camphorsulfonamide substructures. The phase behaviour of these long-chain substituted imidazolium sulphates and sulfonates was investigated using X-ray diffraction (XRD), polarizing optical microscopy (POM) and differential scanning calorimetry (DSC). We observed that the phase behaviour clearly depends on the substitution of both cation and anion. The chiral camphorsulfonamide substructures have an unfavourable influence on the formation of liquid crystalline (LC-) phases. Contrary to N,N'-di-alkyl-imidazolium salts, the formation of LC phases was only observed when both cation and anion are substituted with long alkyl chains (C(12) or C(16)). Furthermore, the phase transition temperatures depend on the chain length of the alkyl groups, as higher phase transition temperatures were observed for compounds bearing longer alkyl chains. However, no macroscopic evidence for the formation of chiral mesophases was obtained. PMID- 21300370 TI - Are we adequately protecting vulnerable patients in longitudinal observational studies? PMID- 21300369 TI - Relationship between elevated arterial stiffness and increased left ventricular mass in adolescents and young adults. AB - OBJECTIVE: To determine whether arterial stiffness relates to left ventricular mass (LVM) in adolescents and young adults. STUDY DESIGN: Demographic, anthropometric, laboratory, echo, carotid ultrasound and arterial stiffness data were obtained in 670 subjects 10 to 24 years of age (35% male, 62% non Caucasian). Global stiffness index (GSI) was calculated from five measures of carotid artery stiffness, augmentation index, brachial distensibility, and pulse wave velocity (1 point if >=95th% for subjects with body mass index <85th%). Stiff arteries (S = 73) were defined as GSI >=95th%. Differences between flexible (F = 597) and S groups were evaluated by t tests. Models were constructed to determine whether GSI was an independent determinant of LVM index or relative wall thickness (RWT). RESULTS: The S group had more adverse cardiovascular risk factors, higher LVM index and RWT (P <= .05) with a trend for abnormal cardiac geometry. Independent determinants of LVM index were higher GSI, age, body mass index, systolic blood pressure, heart rate, glycated hemoglobin A1c, male sex, and sex-by-heart rate interaction (r(2) = 0.52; P <= .05). GSI was also an independent determinant of RWT. CONCLUSIONS: Increased arterial stiffness in adolescents and young adults is associated with LVM index independently of traditional cardiovascular risk factors. Screening for arterial stiffness may be useful to identify high risk adolescents and young adults. PMID- 21300372 TI - Identification of pneumothorax in very preterm infants. AB - OBJECTIVE: To compare respiratory and other morbidities between very preterm infants with and without a pneumothorax and to determine whether infants at higher risk of pneumothorax can be identified early in their course. STUDY DESIGN: Preterm infants at 23 to 28 weeks' gestation with pneumothorax were compared with matched control subjects. Demographic and clinical data from birth through the first 72 hours were compared. RESULTS: Sixty-two (9.2%) of 675 infants had pneumothorax. There were no significant differences in the baseline maternal and infant characteristics. Mortality was significantly higher in the pneumothorax group (43%) versus control subjects (13%). There was no significant difference in continuous positive airway pressure or surfactant treatment or rates of intraventricular hemorrhage or bronchopulmonary dysplasia. Infants treated with early continuous positive airway pressure in the delivery room typically had pneumothorax on day 2 of life. Those who had pneumothorax had higher inspired fraction of oxygen before its diagnosis and over the first 12 hours of life than did control subjects. CONCLUSIONS: Pneumothorax is associated with increased mortality and with severity of lung disease in the first day of life. It may be possible to identify babies at highest risk of pneumothorax on the basis of inspired fraction of oxygen in the first 12 hours of life. PMID- 21300373 TI - Calcium absorption in very low birth weight infants with and without bronchopulmonary dysplasia. AB - OBJECTIVE: To evaluate the effects of early bronchopulmonary dysplasia (BPD) on calcium (Ca) metabolism and growth in very low birth weight (VLBW) infants. STUDY DESIGN: A dual-tracer, stable isotope method was used to assess Ca absorption in VLBW infants. Infants with early BPD received energy-dense feedings and mild fluid restriction. RESULTS: Sixteen of 41 preterm infants were classified as having early BPD. Fractional Ca absorption (early BPD, 58.4 +/- 4.6% versus no early BPD, 50.3 +/- 4.0%, P = .2), total Ca absorption (early BPD, 127 +/- 14 mg/kg/d versus no early BPD, 104 +/- 9 mg/kg/d, P = .9), and Ca retention (early BPD, 99.6 +/- 10.0 mg/kg/d versus no early BPD, 91.0 +/- 9.8 mg/kg/d, P = .2) were similar among groups. There was no significant difference in weight gain, linear growth, or head circumference growth between groups. CONCLUSIONS: The ability of VLBW infants with early BPD and fluid restriction to grow and accrete calcium is similar to those without early BPD. The use of high caloric density feedings in VLBW infants with early BPD can help achieve bone and overall growth outcomes close to those achievable in utero. PMID- 21300374 TI - Tonsillectomy in children with periodic fever with aphthous stomatitis, pharyngitis, and adenitis syndrome. AB - OBJECTIVE: To seek evidence supporting a role for tonsillectomy or adenotonsillectomy in the management of affected children with periodic fever with aphthous stomatitis, pharnygitis, and adenitis (PFAPA) syndrome. STUDY DESIGN: A comprehensive literature search was conducted to identify all published English-language observational and randomized studies evaluating the efficacy of tonsillectomy or adenotonsillectomy on PFAPA syndrome. A combination of keywords was used to identify relevant articles. RESULTS: A total of 15 studies including 149 treated children were found, including 13 observational noncomparative studies and 2 randomized controlled trials. The pooled rate of complete resolution emerging from the combined analysis of all treated children was 83% (95% CI, 77%-89%). A meta-analysis of the two randomized controlled trials showed homogeneity of the results (P=.37, Breslow-Day test) and a common odds ratio for complete resolution of 13 (95% CI, 4-43; P<.001). CONCLUSIONS: Surgery appears to be a possible option for management of PFAPA syndrome. Available evidence is limited, however, and the precise role of surgery remains to be clarified. We suggest considering this option when symptoms markedly interfere with the child's quality of life and medical treatment has failed. PMID- 21300375 TI - Neutrophil gelatinase-associated lipocalin concentrations predict development of acute kidney injury in neonates and children after cardiopulmonary bypass. AB - OBJECTIVES: To investigate neutrophil gelatinase-associated lipocalin (NGAL) as an early acute kidney injury (AKI) biomarker after neonatal and pediatric cardiopulmonary bypass (CPB). STUDY DESIGN: Serum and urine samples were obtained before and at intervals after CPB from 374 patients. AKI was defined as a serum creatinine (S(Cr)) concentration increase from baseline >=0.3 mg/dL in neonates and >=50% in children within 48 hours of CPB. Logistic regression was used to assess predictors and clinical outcomes associated with AKI. RESULTS: AKI developed in 30% of patients. Plasma and urine NGAL thresholds significantly increased in patients with AKI at 2 hours after CPB and remained elevated at all points, with 2-hour NGAL the earliest, strongest predictor of AKI. In non neonates, 2-hour plasma and urine NGAL thresholds strongly correlated with length of hospital stay and severity and duration of AKI. CONCLUSION: Plasma and urine NGAL thresholds are early predictive biomarkers for AKI and its clinical outcomes after CPB. In neonates, we recommend a 2-hour plasma NGAL threshold of 100 ng/mL and 2-hour urine NGAL threshold of 185 ng/mL for diagnosis of AKI. In non neonates, recommended AKI thresholds are 50 ng/mL for both 2-hour plasma and urine NGAL. PMID- 21300376 TI - The cortisol awakening response predicts subclinical depressive symptomatology in Mexican American adults. AB - While childhood trauma appears to be a risk factor for the onset of depression and subclinical depressive symptomatology in Mexican Americans, the specific physiological mechanisms contributing to this relationship remain to be clarified. Stress-induced dysregulation of the Hypothalamic-Pituitary-Adrenal (HPA) axis is associated with depressive symptomatology in non-Hispanics. The current study assessed the extent to which the cortisol awakening response (CAR) predicts subclinical depressive symptomatology beyond the influence of childhood trauma in a sample of 55 Mexican American males and females ages 18-38 years, without a diagnosis of clinical depression. Participants were assessed for exposure to early trauma and current depressive symptomatology. Salivary cortisol samples were collected on two consecutive days at awakening, 30, 45, and 60 min thereafter, and again at 3 p.m., 6 p.m. and 9 p.m. Data were analyzed using general linear models with repeated measures at four morning time points, and again, at three afternoon and evening time points. Results indicated a significant Symptoms*Time interaction for the CAR(p<0.05). The Symptom*Time interaction was not significant for afternoon and evening cortisol concentrations. Moreover, subclinical symptomatology was associated with attenuation of the initial rise in CAR, after controlling for the total frequency of exposure to childhood traumas. Hierarchical analyses show attenuation of the initial rise in the CAR was the best predictor of greater subclinical depressive symptomatology beyond the influence of trauma, and independent of a current diagnosis of major depression in a sample of adult Mexican Americans. PMID- 21300378 TI - Performance-based assessment of functional skills in severe mental illness: results of a large-scale study in China. AB - Performance-based assessments of everyday living skills have been shown to be highly correlated with cognitive functioning in schizophrenia and bipolar disorder, as well as being predictive of deficits in real-world outcomes such as independent living and employment. In this study, we expand our assessments of impairments in everyday living skills to China, evaluating people with schizophrenia, bipolar disorder, and major depression, and comparing their performance to that of healthy controls. Samples of people with schizophrenia (n = 272), bipolar disorder (n = 61), major depression (n = 50), and healthy controls (n = 284) were examined with the Chinese version of the UCSD performance based assessment, brief version (UPSA-B). Performance was compared across the groups and the association between age, gender, educational attainment, marital status, and UPSA-B scores was evaluated. When the performance on the UPSA was compared across the groups, with education as a covariate, significant effects of both diagnosis (F = 86.3, p < .001) and education were found (F = 228.3, p < .001). Sex and age did not contribute significantly when age and education were considered. Post-hoc comparisons revealed that total UPSA-B scores were lowest in the schizophrenia patients, followed by the patients with major depression. Patients with bipolar disorder did not differ from the healthy comparison subjects on overall performance. Scores for all groups were lower than previously reported in western samples (e.g., HC mean = 64). While diagnostic differences in UPSA-B scores are similar to those previously seen in western samples, the education effect is considerably more substantial. These data suggest that in developing countries educational attainment may be strongly associated with levels of adaptive outcomes and the utilization and interpretation of functional capacity measures be adjusted accordingly. PMID- 21300377 TI - Impact of prior pharmacotherapy on remission of psychotic depression in a randomized controlled trial. AB - Having failed to respond to an adequate antidepressant treatment course predicts poorer treatment outcomes in patients with major depression. However, little is known about the impact of prior treatment on the outcome of major depression with psychotic features (MDpsy). We examined the effect of prior treatment history on the outcome of pharmacotherapy of MDpsy in patients who participated in the STOPD PD study, a randomized, double-blind, clinical trial comparing a combination of olanzapine plus sertraline vs. olanzapine plus placebo. The strength of treatment courses received prior to randomization was classified using a validated method. A hierarchy of outcomes was hypothesized based on treatments received prior to randomization and randomized treatment. A high remission rate was observed in subjects with a history of no prior treatment or inadequate treatment who were treated with a combination of olanzapine and sertraline. A low remission rate was observed in subjects who had previously failed to respond to an antidepressant alone and who were treated with olanzapine monotherapy. A low remission rate was also observed in subjects who had previously failed to respond to a combination of an antipsychotic and an antidepressant. Similar to patients with major depression, these results emphasize the impact of prior pharmacotherapy on treatment outcomes in patients with MDpsy. PMID- 21300379 TI - Neuromyelitis optica: an update. AB - Neuromyelitis optica (NMO) is an inflammatory condition characterized by the selective involvement of the optic nerves and spinal cord, and by a frequent relapsing course. Many clinical, laboratory and neuroimaging studies have provided useful means to distinguish NMO from multiple sclerosis (MS). The detection of aquaporin-4 (AQP4) antibodies has broadened the spectrum of the disorder, which now includes limited variants (either recurrent myelitis or optic neuritis), Asian opticospinal MS, and "atypical" forms with brain involvement. Many in vitro and in vivo evidence have recently demonstrated that AQP4 antibody plays a relevant pathogenetic role in NMO by inducing an increase of BBB permeability, complement cascade activation and astrocytic cytotoxicity. While corticosteroids and plasma exchange are better therapeutic options during NMO attacks, other treatments should be aimed at the prevention of recurrence, possibly by targeting autoantibody production and/or effector mechanisms. Rituximab and Mofetil Mycophenolate appear at the moment the most promising drugs. Since even the most sensitive AQP4 antibody tests fail to mark about 20 30% of the NMO cases, while 20-30% of positive patients have "atypical" or MS like variants, it remains to be clarified if NMO, as a clinical entity, can still be considered a disease rather than a syndrome, with more possible pathogenetic mechanisms. PMID- 21300380 TI - Airborne sensors for detecting large marine debris at sea. AB - The human eye is an excellent, general-purpose airborne sensor for detecting marine debris larger than 10 cm on or near the surface of the water. Coupled with the human brain, it can adjust for light conditions and sea-surface roughness, track persistence, differentiate color and texture, detect change in movement, and combine all of the available information to detect and identify marine debris. Matching this performance with computers and sensors is difficult at best. However, there are distinct advantages over the human eye and brain that sensors and computers can offer such as the ability to use finer spectral resolution, to work outside the spectral range of human vision, to control the illumination, to process the information in ways unavailable to the human vision system, to provide a more objective and reproducible result, to operate from unmanned aircraft, and to provide a permanent record that can be used for later analysis. PMID- 21300381 TI - Effects of polychlorinated biphenyls on liver function and sexual characteristics in Japanese medaka (Oryzias latipes). AB - The effects of polychlorinated biphenyls (PCBs) on liver function and their differences between sexes were analyzed in Japanese medaka (Oryzias latipes) exposed to PCB126 or Kanechlor-400 (KC-400) using microarray. PCB exposure induced vitellogenin 1 expression in female medaka while suppressing choriogenin genes, which suggests that the effects of PCBs on estrogen-responsive genes do not occur directly through an estrogen receptor-mediated pathway. Reduction of androgen receptor alpha expression was also observed, and the gene expression pattern in PCB-exposed males changed to become more similar to that of females. Furthermore, changes in glycolysis-related genes indicate that PCB exposure might enhance glucose production via gluconeogenesis in the liver of medaka. Taken together, our results suggest that PCBs disrupt the endocrine system, especially androgen function, and may have the potential to cause demasculinizing effects. Additionally, induction of gluconeogenesis might be a response to maintain glucose levels consumed as a result of PCB exposures. PMID- 21300382 TI - [Impaired fasting glucose and risk of diabetes mellitus at 10 years. Cohort study]. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to define the incidence of type 2 diabetes mellitus in patients with impaired fasting glucose and its association with risk factors. PATIENTS AND METHOD: 115 patients aged > 18 years old, randomly selected in a Healthcare Center, diagnosed of impaired fasting glucose with 1997 American Diabetes Association criteria, followed 10 years. Predictive factors for developing diabetes mellitus were: age, sex, smoking, hypertension, hypercholesterolemia, family history of type 2 diabetes mellitus, antecedent of diabetes in pregnancy, and obesity. RESULTS: During the 10 years of follow-up, 33 patients developed type 2 diabetes mellitus (28.7%; 95% CI 20.4 37.0%), 57 patients progressed to normoglycaemia (49.6%; 95% CI 40.4-58.7%), and 25 patients remained with an impaired fasting glucose (21.7%; 95% CI 14.2-29.3%). Only obesity was associated with progression to type 2 diabetes mellitus (adjusted hazard ratio 2.01; 95% CI 1.00-4.03, p=0.050). CONCLUSIONS: Half of the patients with impaired fasting glucose normalized their glycaemia, and 28.7% developed diabetes mellitus, especially patients with obesity. These results suggest a different natural history to respect glucose intolerance. PMID- 21300383 TI - [The role of tutors in training residents: future outlook]. AB - Introduced late in the Spanish system of training residents, the figure of the tutor has been detailed in the new legislation governing the training of medical specialists. The law also details the functions of tutors, some of which have been relegated to the regional governments. The functions of tutors are outlined in six sections: planning training activity, receiving new residents, proposing individual training plans, acting as a reference for residents, promoting residents' participation in educational activities and research, and participating in the evaluation of residents. The recognition of tutors' work has hardly gone beyond the recognition of their managerial functions and of their need for special training. The future publication of new regulations by the regional governments might increase this recognition. On the other hand, the development of the new core curriculum with different training trunks will probably pose new challenges and increase tutors' workload. PMID- 21300384 TI - [Comparison of the scientific quality of spanish radiologists that publish in international radiology journals and in spanish radiology journals]. AB - OBJECTIVE: To determine that the quality, measured by the Hirsch index, of Spanish authors who publish in international radiology journals with an impact factor (AJR, European Radiology, Investigative Radiology, Radiographics, and Radiology) is higher of those who publish only in Spanish journals or in both types of journals. MATERIAL AND METHODS: We analyzed a total of 6 radiology journals, including 5 international journals and one national (Radiologia). We selected Spanish authors of original articles published in 2008 and 2009 who were working at Spanish centers when their articles were written. We classified the authors into three categories: a) those who published only in international journals; b) those who published only in Radiologia, and c) those who published in Radiologia and in an international journal. We calculated the Hirsch index score for each author and analyzed the groups using the Kolmogorov-Smirnov goodness-of-fit test, the Kruskal-Wallis nonparametric test, and the median test to evaluate the differences. RESULTS: Of the 440 identified Spanish authors as having published in the two-year period, 248 (56%) published only in Radiologia, 172 (39%) only in international journals, and 20 (5%) in both. The mean Hirsch index score for the group of authors who published only in Radiologia (1.15+/ 2.35) was lower than for those who published only in international journals (2.59+/-3.39). Authors who published in both international journals and Radiologia had the highest score on the Hirsch index (4.1+/-3.89) (P<.001). CONCLUSIONS: The Spanish authors with the highest prestige and quality publish both in international journals and in Radiologia. PMID- 21300385 TI - Cytokine-enhanced vaccine and interferon-beta plus suicide gene as combined therapy for spontaneous canine sarcomas. AB - Eleven soft tissue- and five osteosarcoma canine patients were subjected to: (i) periodic subcutaneous injection of irradiated xenogeneic cells secreting hGM-CSF and hIL-2 mixed with allogeneic or autologous tumor homogenates; and (ii) injections of cIFN-beta and HSVtk-carrying lipoplexes and ganciclovir, marginal (after surgery) and/or intratumoral (in the case of partial tumor resection, local relapse or small surface tumors). This treatment alone (4 patients) or as surgery adjuvant (12 patients), was safe and well tolerated. In those patients presenting local disease (6/11), the suicide gene plus cIFN-beta treatment induced local antitumor activity evidenced by the objective responses (3 complete, 2 partial) and stable diseases (2). In addition, the treatment prevented or delayed local relapse, regional metastases (lymph nodes developed only in 3/16) and distant metastases (0/16), suggesting a strong systemic antitumor immunity. The most encouraging result was the long survival times of 10 patients (>1 year, with good quality of life). PMID- 21300386 TI - Outbreak of bovine clinical mastitis caused by Mycoplasma bovis in a North Italian herd. AB - This report describes an outbreak of Mycoplasma bovis mastitis affecting 45 cows in a herd of 122 dairy cattle in Northern Italy. Clinically, the outbreak was characterized by agalactia, multiple swollen and painless quarters, high milk somatic cell count and unresponsiveness to conventional antibiotic therapy. M. bovis was isolated from the milk samples of all the 32 affected cows tested and from the mammary tissue of three affected cows that underwent necropsy. No other pathogens were isolated from these samples. Lesions in two of the necropsied cows were characterized by mild chronic suppurative mastitis and galactophoritis. The other necropsied cow showed a chronic necrosuppurative and pyogranulamaous galactophoritis, a condition not previously associated with M. bovis. M. bovis was detected immunohistochemically in the lumen of the affected mammary ducts suggesting that ascending infection via the teat canal was the likely route of transmission. No other intralesional pathogens were demonstrated microscopically. PMID- 21300387 TI - Consideration of different outbreak conditions in the evaluation of preventive culling and emergency vaccination to control foot and mouth disease epidemics. AB - In recent foot and mouth disease outbreaks, many healthy animals have been culled to prevent disease transmission. Emergency vaccination is discussed as an alternative to culling of unaffected animals. A spatial and temporal Monte-Carlo simulation model was used to compare preventive culling and emergency vaccination. Different outbreaks are described using additional influence factors such as airborne spread, farm density, type of index-case farm and delay until establishment of the control strategies. The fewest farms were infected establishing a combined strategy including a 1 km preventive culling and 1-10 km emergency vaccination zone around each outbreak farm. Taking the number of culled and vaccinated farms into account, vaccination around the first diagnosed farm combined with the baseline strategy (culling of outbreak farms, protection and surveillance zone, contact tracing) is to be preferred. In the present study, emergency vaccination was an effective control strategy especially in densely populated regions. PMID- 21300388 TI - Effect of information provisioning on attitude toward surgical castration of male piglets and alternative strategies for avoiding boar taint. AB - Pork consumers know little about boar taint and the methods used to avoid it. As such, relevant information is necessary to assist consumers to judge the acceptability of different strategies to avoid boar taint. The effect of basic (T1) or extensive (T2) written information or T2 with supplementary audio-visual information (AV) on the opinion concerning immunocastration (IC), raising entire male pigs (EM) and surgical castration with anaesthesia (SA) as compared to castration without anaesthesia (SC) was investigated in a student population. Overall, IC was significantly preferred over SC. The information condition influenced the preference for IC and EM as compared to SC. Participants exposed to AV were more positive to IC than participants exposed to T1 and T2, and more positive to EM than participants exposed to T2. The impact of information condition was not affected by gender, farming experience, knowledge about the boar taint issue or personal relevance of pig welfare. Potential effects of providing background information and media campaigns on public surveys ought to be considered. Supplementary audio-visual information increased the impact of information provisioning. PMID- 21300389 TI - Serum osteocalcin in dairy cows: age-related changes and periparturient variation. AB - We evaluated age-related changes in serum osteocalcin concentrations in non periparturient cows and variations in serum osteocalcin concentration in periparturient primiparous and multiparous cows. The serum osteocalcin levels were evaluated in 144 non-periparturient Holstein dairy cows aged 11 days to 10 years; these levels were the highest in the youngest cows, appeared to steadily decrease with age until the time of the first calving, and were subsequently maintained at low levels. Between 14 days before calving and 21 days after calving, the serum osteocalcin levels were significantly higher in the primiparous cows than in the multiparous cows. A comparison between age-matched non-periparturient and periparturient cows showed that serum osteocalcin levels were significantly lowered during late gestation in both primiparous and multiparous cows. These results suggest that serum osteocalcin measurement might be useful for the detection of mineral imbalances at the time of parturition in cows. PMID- 21300390 TI - Solid pseudopapillary tumor of the pancreas: can malignancy be predicted? AB - BACKGROUND: The objective of this study was to examine the clinicopathologic characteristics of solid pseudopapillary tumors (SPTs) of the pancreas, including the risk factors for disease recurrence and their effects on survival. METHODS: The medical records of 114 patients who underwent surgery for a pathologically confirmed SPT between January 1995 and December 2007 were reviewed retrospectively. RESULTS: Of the 114 patients, 98 (86.9%) were female, and the median age was 36 years (range, 11-75). All 114 patients underwent curative intent surgery and 13 (11.4%) underwent laparoscopic surgery. Of the 114 patients, 26 (22.8%) had solid pseudopapillary carcinoma (SPC). There were no differences in any clinical factors between the benign SPT and SPC groups; however, the only 4 recurrences identified were in the SPC group. After follow-up ranging from 11 to 177 months, all 114 patients were alive, with only 4 showing evidence of recurrence. Recurrence was observed in young patients with metastasis at first operation, invasion of an adjacent organ, and a large mass (>=13 cm). CONCLUSION: Adequate operative resection including laparoscopic surgery is the mainstay of treatment for SPT. Although statistically significant risk factors for recurrence cannot be determined, tumor metastasis at the first operation, invasion of adjacent organ, large tumor size, young patient age, tumor rupture, and inadequate resection may increase the risk of recurrence. Our results demonstrate that long-term survival could be achieved by aggressive operative resection and interventional treatment of recurrent disease. PMID- 21300391 TI - Gaussian-DPSM (G-DPSM) and Element Source Method (ESM) modifications to DPSM for ultrasonic field modeling. AB - In the last few years, Distributed Point Source Method (DPSM) a mesh-free semi analytical technique has been developed. In spite of its many advantages, one shortcoming of the conventional DPSM method is that the field obtained by conventional DPSM method needs to be scaled to match the theoretical solutions. Two modification techniques called Gaussian-DPSM (G-DPSM) and Element Source Method (ESM) are developed here to avoid the scaling need. G-DPSM technique introduces additional fictitious point sources around every parent point source. Gaussian weight functions determine the strength of these additional fictitious point sources that are denoted as child point sources. ESM replaces discrete point sources used in the conventional DPSM by continuous sources. In the ESM formulation individual point sources are denoted as nodes. Special elements are formed on the boundary by connecting these nodes. The source strength inside the element can vary linearly or non-linearly depending on the order of the interpolation function used inside the element. Results generated by both these methods are compared with the conventional DPSM solution and analytical solution. It is shown that the ultrasonic field in front of the transducer computed by G DPSM and ESM matches very well with the theory without using any scaling factor. PMID- 21300392 TI - Barriers to success: how baculoviruses establish efficient systemic infections. AB - The mechanisms used by baculoviruses to exit the midgut and cause systemic infection of their insect hosts have been debated for decades. After being ingested, baculoviruses reach the midgut, where several host barriers need to be overcome in order to establish successful infection. One of these barriers is the basal lamina, a presumably virus-impermeable extracellular layer secreted by the epithelial cells lining the midgut and trachea. This review discusses new evidence that demonstrates how these viruses breach the basal lamina and establish efficient systemic infections. The biochemical mechanisms involved in dismantling basal lamina during baculovirus infection may also provide new insights into the process of basal lamina remodeling in invertebrate and vertebrate animals. PMID- 21300393 TI - Electrochemical sulfide removal from synthetic and real domestic wastewater at high current densities. AB - Hydrogen sulfide generation is the key cause of sewer pipe corrosion, one of the major issues in water infrastructure. Current abatement strategies typically involve addition of various types of chemicals to the wastewater, which incurs large operational costs. The transport, storage and application of these chemicals also constitute occupational and safety hazards. In this study, we investigated high rate electrochemical oxidation of sulfide at Ir/Ta mixed metal oxide (MMO) coated titanium electrodes as a means to remove sulfide from wastewater. Both synthetic and real wastewaters were used in the experiments. Electrochemical sulfide oxidation by means of indirect oxidation with in-situ produced oxygen appeared to be the main reaction mechanism at Ir/Ta MMO coated titanium electrodes. The maximum obtained sulfide removal rate was 11.8 +/- 1.7 g S m(-2) projected anode surface h(-1) using domestic wastewater at sulfide concentrations of >= 30 mg L(-1) or higher. The final products of the oxidation were sulfate, thiosulfate and elemental sulfur. Chloride and acetate concentrations did not entail differences in sulfide removal, nor were the latter two components affected by the electrochemical oxidation. Hence, the use of electrodes to generate oxygen in sewer systems may constitute a promising method for reagent-free removal of sulfide from wastewater. PMID- 21300394 TI - Crystal structure of delta-isobutoxypentabromo-cyclododecanes, kinetics and selectivity of their isomerization during thermal treatment of flame-proofed polystyrenes. AB - Hexabromocyclododecanes (HBCDs) are persistent organic pollutants now ubiquitous in the environment. Technical HBCD mixtures and with it flame-proofed polystyrenes (FP-PS) also contain isobutoxypentabromocyclododecanes (iBPBCDs) as minor constituents, which are possibly released together with HBCDs. So far, eight diastereomeric pairs of enantiomers named as alpha-, beta-, gamma-, delta-, epsilon-, xi-, eta-, and theta-iBPBCDs with proportions of 10%, 5%, 2%, 21%, 11%, 11%, 12% and 28% were found in technical HBCD. Herein the crystal structure of racemic delta-iBPBCD, the second most prominent diastereomer, is presented and assigned to (1S)-1-isobutoxy-(2R,5R,6S,9S,10S)-2,5,6,9,10-pentabromocyclododecane and its enantiomer. During thermal treatment of FP-PS, e.g. the production of extruded polystyrenes (XPS), proportions of delta-iBPBCDs decrease and those of other stereoisomers increase. Evidence was found that delta-iBPBCDs isomerize stereo- and regioselectively to beta-iBPBCDs. Based on structural and kinetic data, a transformation mechanism was proposed. Apparent first-order rate constants (k(iso)) of 0.0019, 0.0050, and 0.012min(-1) are found for the delta- to beta-iBPBCD isomerization at 120, 130, and 140 degrees C, respectively, corresponding to half-lives of 360, 140, and 56min. These transformations also occur during the production of XPS, which predominantly contain beta-iBPBCDs, whereas delta-iBPBCDs dominate in materials experiencing lower thermal stress, e.g. expanded polystyrenes (EPS). The relative configurations of delta- and theta iBPBCDs are TtCtCt, like the one of gamma-HBCDs. gamma-HBCDs are the kinetically and alpha-HBCDs with a TcCtCc configuration the thermodynamically favored products. In analogy, beta-iBPBCDs are assumed to have a TcCtCc configuration like alpha-HBCDs because they are formed from delta-iBPBCDs under thermodynamic control. In conclusion, HBCD- and iBPBCD-patterns in flame-proofed polystyrenes vary substantially, reflecting the thermal stress these materials have experienced. When released to the environment, these patterns might further change, as observed for HBCDs. PMID- 21300395 TI - Determination of n-octanol/water partition coefficient for DDT-related compounds by RP-HPLC with a novel dual-point retention time correction. AB - n-Octanol/water partition coefficients (P) for DDTs and dicofol were determined by reversed-phase high performance liquid chromatography (RP-HPLC) on a C(18) column using methanol-water mixture as mobile phase. A dual-point retention time correction (DP-RTC) was proposed to rectify chromatographic retention time (t(R)) shift resulted from stationary phase aging. Based on this correction, the relationship between logP and logk(w), the logarithm of the retention factor extrapolated to pure water, was investigated for a set of 12 benzene homologues and DDT-related compounds with reliable experimental P as model compounds. A linear regression logP=(1.10+/-0.04) logk(w) - (0.60+/-0.17) was established with correlation coefficient R(2) of 0.988, cross-validated correlation coefficient R(cv)(2) of 0.983 and standard deviation (SD) of 0.156. This model was further validated using four verification compounds, naphthalene, biphenyl, 2,2-bis(4 chlorophenyl)-1,1-dichloroethane (p,p'-DDD) and 2,2-bis(4-chlorophenyl)-1,1 dichloroethene (p,p'-DDE) with similar structure to DDT. The RP-HPLC-determined P values showed good consistency with shake-flask (SFM) or slow-stirring (SSM) results, especially for highly hydrophobic compounds with logP in the range of 4 7. Then, the P values for five DDT-related compounds, 2-(2-chlorophenyl)-2-(4 chlorophenyl)-1,1,1-trichloroethane (o,p'-DDT), 2-(2-chlorophenyl)-2-(4 chlorophenyl)-1,1-dichloroethane (o,p'-DDD), 2-(2-chlorophenyl)-2-(4 chlorophenyl)-1,1-dichloroethene (o,p'-DDE), and 2,2,2-trichloro-1,1-bis(4 chlorophenyl)ethanol (dicofol) and its main degradation product 4,4' dichlorobenzophenone (p,p'-DBP) were evaluated by the improved RP-HPLC method for the first time. The excellent precision with SD less than 0.03 proved that the novel DP-RTC protocol can significantly increases the determination accuracy and reliability of P by RP-HPLC. PMID- 21300396 TI - Leaching of Cu and Zn from discarded boat paint particles into tap water and rain water. AB - We studied the leaching of copper and zinc from particles of discarded boat paint added to tap water (pH 7.3) and rain water (pH=4.7), simulating conditions encountered during the hosing or runoff of antifouling waste. Leaching rates appeared to be diffusion-controlled and were greater in rain water than in tap water and were greater for Zn than for Cu. After a period of 120h, between about 0.5% and 3% of total Cu and 5-30% of total Zn had been released to the aqueous phase. These observations suggest that Cu and Zn mobilised from fine antifouling particulates during washdown or rainfall events may be important contaminants of runoff and soils in the vicinity of boat repair facilities. PMID- 21300397 TI - The effect of housing characteristics and occupant activities on the respiratory health of women and children in Lao PDR. AB - The paper presents the results of a study conducted into the relationship between dwelling characteristics and occupant activities with the respiratory health of resident women and children in Lao People's Democratic Republic (PDR). Lao is one of the least developed countries in south-east Asia with poor life expectancies and mortality rates. The study, commissioned by the World Health Organisation, included questionnaires delivered to residents of 356 dwellings in nine Districts in Lao PDR over a five month period (December 2005-April 2006), with the aim of identifying the association between respiratory health and indoor air pollution, in particular exposures related to indoor biomass burning. Adjusted odds ratios were calculated for each health outcome separately using binary logistic regression. After adjusting for age, a wide range of symptoms of respiratory illness in women and children aged 1-4 years were positively associated with a range of indoor exposures related to indoor cooking, including exposure to a fire and location of the cooking place. Among women, "dust always inside the house" and smoking were also identified as strong risk factors for respiratory illness. Other strong risk factors for children, after adjusting for age and gender, included dust and drying clothes inside. This analysis confirms the role of indoor air pollution in the burden of disease among women and children in Lao PDR. PMID- 21300398 TI - CA125 surveillance increases optimal resectability at secondary cytoreductive surgery for recurrent epithelial ovarian cancer. AB - OBJECTIVE: Recent data suggest that serial CA125 surveillance following remission in asymptomatic patients with epithelial ovarian cancer (EOC) does not impact overall survival. However, earlier detection of recurrence may influence resectability at secondary cytoreductive surgery (SCS). We hypothesized that a shorter time interval between CA125 elevation and SCS correlates with a higher likelihood of optimal resection among eligible patients. METHODS: We identified patients with recurrent epithelial ovarian cancer who underwent SCS from 1995 to 2009 at our institution. All patients initially underwent primary cytoreductive surgery followed by platinum-based chemotherapy. CA125 elevation was considered the first value two-times the patient's nadir level. Our "study interval" was the time between CA125 elevation and SCS. Optimal SCS was defined as microscopic residual disease (<=0.5cm). Our analysis compared patients who underwent optimal vs. suboptimal SCS. RESULTS: Seventy-four patients who underwent SCS for recurrent EOC met inclusion criteria. Median disease-free interval prior to SCS was 19 vs. 12months for the optimal and suboptimal SCS groups. More patients undergoing suboptimal SCS had ascites (21% vs. 2%, p=0.01) and carcinomatosis (42% vs. 5%, p<0.0001). Patients who underwent optimal SCS went to the operating room 5.3 vs. 16.4weeks (HR 1.03, 95% CI 1.01-1.06, p=0.04) from the time of their CA125 elevation. Optimal SCS was associated with a longer overall survival (47 vs. 23months, p<0.0001). CONCLUSIONS: Each week delay after first CA125 elevation correlated with a 3% increased chance of suboptimal resection at SCS. Serial CA125 surveillance for early detection of recurrence may increase rates of optimal SCS and potentially influence overall survival. PMID- 21300399 TI - EEG decoding of semantic category reveals distributed representations for single concepts. AB - Achieving a clearer picture of categorial distinctions in the brain is essential for our understanding of the conceptual lexicon, but much more fine-grained investigations are required in order for this evidence to contribute to lexical research. Here we present a collection of advanced data-mining techniques that allows the category of individual concepts to be decoded from single trials of EEG data. Neural activity was recorded while participants silently named images of mammals and tools, and category could be detected in single trials with an accuracy well above chance, both when considering data from single participants, and when group-training across participants. By aggregating across all trials, single concepts could be correctly assigned to their category with an accuracy of 98%. The pattern of classifications made by the algorithm confirmed that the neural patterns identified are due to conceptual category, and not any of a series of processing-related confounds. The time intervals, frequency bands and scalp locations that proved most informative for prediction permit physiological interpretation: the widespread activation shortly after appearance of the stimulus (from 100 ms) is consistent both with accounts of multi-pass processing, and distributed representations of categories. These methods provide an alternative to fMRI for fine-grained, large-scale investigations of the conceptual lexicon. PMID- 21300400 TI - Objects, events and "to be" verbs in Spanish--an ERP study of the syntax semantics interface. AB - In Spanish, objects and events at subject position constrain the selection of different forms of the auxiliary verb "to be": locative predicates about objects require "estar en", while those relating to events require "ser en", both translatable as "to be in". Subjective ratings showed that while the "object+ser+en" is considered as incorrect, the "event+estar+en" combination is also perceived as unacceptable but to a lesser degree. In an ERP study, we evaluated the impact of a purely semantic distinction (object versus events) on the subsequent processing of these auxiliary verbs followed by locatives in Spanish. For the "ser en" predicate, the P600 component was larger when the subject was an object than when it was an event. This P600 effect is consistent with an online repair of the defining predicate when it does not fit with the adequate semantic properties of the subject. On the other hand, for the "estar en" predicate, event subjects when compared to object subjects showed more positive ongoing amplitudes between 280 and 380 ms after the presentation of the "en" preposition, followed by a longer positive wave starting around 400 ms and lasting until 700 ms after the presentation of the following determiner, with central and frontal scalp distributions respectively. Thus, the different subject predicate combinations, depending on the semantic features of the subjects, triggered syntactic reparatory processes at a structural level. These findings are consistent with an incremental interpretation of sentence meaning based on the interaction between syntactic and semantic information. PMID- 21300401 TI - Homing of endogenous stem/progenitor cells for in situ tissue regeneration: Promises, strategies, and translational perspectives. AB - Stem cell-based therapy has been one of the best documented approaches in regenerative medicine, promising cures for a multitude of diseases and disorders. However, the ex vivo expansion of stem cells and their in vivo delivery are restricted by the limited availability of stem cell sources, the excessive cost of commercialization, and the anticipated difficulties of clinical translation and regulatory approval. An alternative to adoptively transferred stem cells are cell populations already present in a patient's body, including stem/progenitor cells, which can be actively attracted to sites of injury. This technique, known as endogenous cell homing, has the potential to provide new therapeutic options for in situ tissue regeneration. Such options would be less costly and complex than approaches that require substantial ex vivo cell manipulation and that use artificial vehicles for cell delivery. Tissue regeneration methods that rely on endogenous stem/progenitor cell homing, local tissue responses, and functional stimulation thus offer new insights into in vivo tissue engineering and hold great promise for the future of translational medicine. Although such methods that take advantage of the latent endogenous regenerative potential of the patient are promising for the repair of damaged tissue, they are in need of further experimental support before application in late-stage diseases or severe tissue injury. This review is not meant to be exhaustive but gives a brief outlook on the promises, strategies, and current applications of endogenous stem cell homing for in situ tissue regeneration, with particular emphasis placed upon pharmacological means based on cell-instructive scaffolds and release technology to direct cell mobilization and recruitment. In the future these exciting paradigms are likely to help reconcile the clinical and commercial pressures in regenerative medicine. PMID- 21300403 TI - Review: Transport of maternal cholesterol to the fetal circulation. AB - Data obtained from recent studies in humans, rodents, and cell culture demonstrate that circulating maternal cholesterol can be transported to the fetus. The two major cell types responsible for the transport are trophoblasts and endothelial cells of the fetoplacental vasculature. Maternal lipoprotein cholesterol is initially taken up by trophoblasts via receptor-mediated and receptor-independent processes, is transported by any number of the sterol transport proteins expressed by cells, and is effluxed or secreted out of the basal side via protein-mediated processes or by aqueous diffusion. This cholesterol is then taken up by the endothelium and effluxed to acceptors within the fetal circulation. The ability to manipulate the mass of maternal cholesterol that is taken up by the placenta and crosses to the fetus could positively impact development of fetuses affected with the Smith-Lemli-Opitz Syndrome (SLOS) that have reduced ability to synthesize cholesterol and possibly impact growth of fetuses unaffected by SLOS but with low birthweights. PMID- 21300402 TI - The effects of thrombin and cytokines upon the biomechanics and remodeling of isolated amnion membrane, in vitro. AB - Abruption-induced thrombin generation and inflammation/infection induced cytokine production have both been associated with fetal membrane (FM) weakening and preterm premature rupture of the fetal membranes (PPROM). Using our in vitro model system we have demonstrated that thrombin, and separately the cytokines, tumor necrosis factor-alpha (TNFalpha) and interleukin-1-beta (IL-1beta), remodel and weaken full thickness FM. Additionally, we have reported that the anti oxidant and NFkappaB inhibitor, alpha-lipoic acid (LA), blocks these thrombin and cytokine induced effects. The purpose of these studies was to determine whether thrombin and cytokines directly weaken the amnion membrane (AM), the major load bearing component of FM. Isolated AM or full thickness FM fragments from unlabored Cesarean deliveries were incubated with thrombin, TNFalpha, or IL 1beta, for 48 h. Rupture strength (breaking force) of each fragment was thereafter determined using our published methodology. Biochemical evidence of remodeling and apoptosis; immunoreactive Matrix Metalloproteinase 9 (MMP9), Tissue Inhibitor of Matrix Metalloproteinase 3 (TIMP3) and cleaved poly (ADP ribose) polymerase (C-PARP) levels in tissue extracts, were determined by western blot and densitometry. Thrombin induced a dose-dependent weakening of isolated AM (P < 0.001) coupled with dose dependent increases in PARP cleavage, and reciprocal increases and decreases, respectively, in MMP9 and TIMP3 protein (all P < 0.01). Thrombin receptor activating peptide-6 (TRAP) also weakened isolated AM. Neither TNFalpha nor IL-1beta weakened isolated AM. However, both cytokines weakened AM when it was incubated together with the choriodecidua as part of full thickness FM (P < 0.001). Cytokine-conditioned choriodecidua medium also weakened isolated AM (P < 0.001). Under conditions in which cytokines weakened the AM, the changes in MMP9, TIMP3 and PARP cleavage were consistent with those seen after thrombin incubation. LA blocked the FM weakening and remodeling effects. In summary, thrombin weakens AM directly whereas cytokines weaken AM indirectly by causing the release of soluble intermediates from the choriodecidua. PMID- 21300404 TI - Neural progenitors generated from the mesenchymal stem cells of first-trimester human placenta matured in the hypoxic-ischemic rat brain and mediated restoration of locomotor activity. AB - Term placenta is a great reservoir of mesenchymal stem cells (MSCs), however, the potential of the earlier placenta is largely unknown. In this report, we established 17 MSC lines from 19 first-trimester human placenta (fPMSC). fPMSC proliferated for 90-150 days in vitro and by enhanced cellular interaction, fPMSC differentiated into nestin-expressing neural progenitor cells (fPMSC-NP), accompanied by inductions of immature neuron-specific genes. Therapeutic effect of the fPMSC-NP was tested in the animal model of hypoxia-ischemia (HI) which was devastating to dopaminergic neurons and to locomotor activity. Improvement of motor activity was evident as early as 2 weeks after transplantation of the fPMSC NP into bilateral striatum and became indistinguishable from that of the age matched normal animals by 8 weeks but no spontaneous recovery was observed in the control-grafted animals. Immunohistochemical analyses revealed that the implanted fPMSC-NP matured into ectodermal cells including the tyrosine hydroxylase (TH) expressing neurons in the recipient striatum. So, the improved motor behavior was likely due to the dopaminergic differentiation of the implanted fPMSC-NP in the dopaminergic-denervated host brain. Based on this result, we propose that progenitors may be more advantageous than the terminally differentiated cells for the purpose of cell replacement therapies since the progenitors are easily obtainable and are expected to be more pliable to the new environment. PMID- 21300405 TI - Ileal ulceration during all-trans-retinoic acid therapy for acute promyelocytic leukemia. PMID- 21300406 TI - Chemical and bioanalytical characterization of dioxins in indoor dust in Hong Kong. AB - In the present work, air-conditioner filter dust samples collected from commercial office, secondary school, shopping mall, electronic factory and manufacturing plant in Hong Kong were collected for 7-ethoxyresorufin O deethylase (EROD) assay using a hepatoma cell line (H4IIE) and chemical analysis of dioxins including polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and PCBs with dioxin-like structure. The result of EROD assay showed that bioassay derived TEQ of 2,3,7,8-TCDD (TEQ(bio)) of dust samples varied from 320 to 730 pg/g. Chemical analyses revealed that chemical derived TEQ of 2,3,7,8 TCDD (TEQ(cal)) of dust samples ranged from 134 to 531 pg/g. In addition, the TEQ(cal) of samples were significantly correlated with TEQ(bio) of samples (R=0.83, P<0.01). The average daily doses (ADDs) of dioxins via indoor dust with the estimated ADDs of dioxins via air and food were compared. The results showed that indoor dust is an important medium of exposure to dioxins. PMID- 21300407 TI - Susceptibility genes, social environmental risk factors and their interactions in internalizing disorders among mainland Chinese undergraduates. AB - BACKGROUND: Analyses of large scale psychiatric epidemiology surveys suggest that common mental disorders can be generalized into two underlying dimensions, internalizing disorders (e.g. depression, and anxiety) and externalizing disorders (e.g. addictions). The present study explores the interactions among the genes (SLC6A4, BDNF, and MAOA) and selected environment factors (G*E), and gene*gene (G*G) interactions for internalizing disorders in the sample of Chinese university students. METHODS: This is a genetic case control study. 259 undergraduates affected with internalizing disorders and 269 healthy controls were included. Multiple logistic regression was used to explore the potential environmental risk factors. G*E interactions were analyzed using the method developed by Mukherjee et al. (2008). Analyses of G*G interactions were conducted by generalized multifactor dimensionality reduction (GMDR) (Lou et al., 2007). We have previously reported on the polymorphism information for ten single nucleotide polymorphisms (SNPs) on SLC6A4, BDNF, and MAOA genes (Meng et al., 2009; Meng, 2010). RESULTS: We found that an offspring's reported parents' negative mood, subject's unwillingness to express emotion, being an only child, having an unfulfilling relationship with his/her mother, and increased activity and behavior restrictions by his/her father were social environment risk factors for internalizing disorders. No statistically significant interactions were found in the G*E analyses. G*G analyses found that subjects with mutational alleles concurrently on rs10835210 and rs2030324 (BDNF gene) were significantly likely to develop internalizing disorders. Those with one mutated allele on either SNPs were 1.761 times, and those with both mutated alleles were 3.353 times, more likely to develop internalizing disorders. CONCLUSION: A negative family emotional environment was found to be associated with internalizing disorders. BDNF gene variants were also found to be similarly associated. Using conservative statistical analyses we did not find any G*E interactions. PMID- 21300408 TI - Insomnia as a predictor of depression: a meta-analytic evaluation of longitudinal epidemiological studies. AB - BACKGROUND: In many patients with depression, symptoms of insomnia herald the onset of the disorder and may persist into remission or recovery, even after adequate treatment. Several studies have raised the question whether insomniac symptoms may constitute an independent clinical predictor of depression. This meta-analysis is aimed at evaluating quantitatively if insomnia constitutes a predictor of depression. METHODS: PubMed, Medline, PsycInfo, and PsycArticles databases were searched from 1980 until 2010 to identify longitudinal epidemiological studies simultaneously investigating insomniac complaints and depressed psychopathology. Effects were summarized using the logarithms of the odds ratios for insomnia at baseline to predict depression at follow-up. Studies were pooled with both fixed- and random-effects meta-analytic models in order to evaluate the concordance. Heterogeneity test and sensitivity analysis were computed. RESULTS: Twenty-one studies met inclusion criteria. Considering all studies together, heterogeneity was found. The random-effects model showed an overall odds ratio for insomnia to predict depression of 2.60 (confidence interval [CI]: 1.98-3.42). When the analysis was adjusted for outliers, the studies were not longer heterogeneous. The fixed-effects model showed an overall odds ratio of 2.10 (CI: 1.86-2.38). LIMITATIONS: The main limit is that included studies did not always consider the role of other intervening variables. CONCLUSIONS: Non-depressed people with insomnia have a twofold risk to develop depression, compared to people with no sleep difficulties. Thus, early treatment programs for insomnia might reduce the risk for developing depression in the general population and be considered a helpful general preventive strategy in the area of mental health care. PMID- 21300410 TI - The importance of clinical trials in unraveling the mysteries of multiple sclerosis. AB - Despite a number of new therapies that are effective in reducing the inflammatory component of multiple sclerosis, the underlying cause of the disease remains uncertain. One of the most powerful tools available to an investigator to help in unraveling the underlying disease mechanisms in MS is the incorporation of careful imaging and laboratory studies into clinical trials. Regardless of the outcome of the trial with respect to modification of clinical disease, probing the biological effects of the treatment in relationship to the clinical outcome can provide important insights into the disease. Unfortunately, careful proof-of principle laboratory studies are often not supported by the sponsors of clinical trials and mechanisms for rapid funding of supporting laboratory studies is difficult. Consequently important opportunities to better understand the disease are missed. PMID- 21300409 TI - Does telomere length mediate associations between inbreeding and increased risk for bipolar I disorder and schizophrenia? AB - We have recently found that consanguinity is a risk factor for bipolar I disorder (BP1) and schizophrenia (SZ) in Egypt. Inbreeding has been associated with increased cellular stress and impaired physiological function in plants and animals. Previous studies have reported that telomere length (TL), an index of oxidative stress and cellular senescence is significantly reduced among patients with SZ or mood disorders compared with control individuals. Hence we evaluated TL as a possible mediator of the observed association between consanguinity and BP1/SZ risk. Patients with BP1 (n=108), or SZ (n=60) were compared with screened adult controls in separate experiments. TL was estimated using a quantitative PCR (qPCR) based assay. The inbreeding coefficient/consanguinity rate was estimated in two ways: using 64 DNA polymorphisms ('DNA-based' rate); and from family history data ('self report'). Significant correlation between TL and DNA based inbreeding was not observed overall, though suggestive trends were present among the SZ cases. No significant case-control differences in TL were found after controlling for demographic variables. In conclusion, reduced TL may not explain a significant proportion of observed associations between consanguinity and risk for BP1/SZ. PMID- 21300411 TI - A comparison of the speech recognition and pitch ranking abilities of children using a unilateral cochlear implant, bimodal stimulation or bilateral hearing aids. AB - OBJECTIVE: The present study compared the speech recognition and pitch ranking abilities of normally hearing children (n=15) to children using a cochlear implant (CI) alone (n=8), bilateral hearing aids (HAs) (n=6), or bimodal stimulation (BMS) (n=9). It was hypothesised that users of BMS would score higher on tasks of speech and pitch perception than children using a CI alone, but not children using HAs. METHODS: Participants were assessed on tasks of monosyllabic word recognition in quiet, sentence recognition in quiet and noise (10 dB signal to-noise ratio), and a pitch ranking task using pairs of sung vowels one, half, and a quarter of an octave apart. RESULTS: There were no significant differences between the mean percentage-correct scores of the four participant groups for either words in quiet or sentences in quiet and noise. However, the proportion of bimodal users who scored >80% correct (80%) was significantly greater than the proportion of high-scoring unilateral CI (25%) or bilateral HA users (17%). Contrary to expectations, there was also no significant difference between the pitch ranking scores of users of BMS and users of a CI alone for all three interval sizes (p<0.05, RM-ANOVA). However participants using only acoustic hearing (i.e. the NH and HA groups) scored significantly higher than participants using electrical stimulation (i.e. the CI and BMS groups) on the pitch ranking task (p<0.05; RM-ANOVA). CONCLUSIONS: Contrary to findings in postlingually deafened adults, we found no significant bimodal advantage for pitch perception in prelingually deafened children. However, the performance of children using electrical stimulation was significantly poorer than children using only acoustic stimulation. Further research is required to investigate the contribution of the non-implanted ears of users of BMS to pitch perception, and the effect of hearing loss on the development of pitch perception in children. PMID- 21300412 TI - The role of movement restrictions and pre-emptive destruction in the emergency control strategy against CSF outbreaks in domestic pigs. AB - Classical swine fever (CSF) outbreaks in domestic pig herds lead to the implementation of standard control measures according to legislative regulations. Ideal outbreak control entails the swift and efficient culling of all pigs on premises detected positive for CSF virus. Often all pig holdings around the detected cases are pre-emptively destroyed to exclude transmission into the neighbourhood. In addition to these measures, zones are defined in which surveillance and protection measures are intensified to prevent further distant disease spread. In particular, all movements are prohibited within standstill areas. Standstill also excludes the transport of fattened pigs to slaughter. Historical outbreaks provide evidence of the success of this control strategy. However, the extent to which the individual strategy elements contribute to this success is unknown. Therefore, we applied a spatially and temporally explicit epidemic model to the problem. Its rule-based formulation is tailored to a one-by one model implementation of existing control concepts. Using a comparative model analysis the individual contributions of single measures to overall control success were revealed. From the results of the model we concluded that movement restrictions had the dominant impact on strategy performance suggesting a reversal of the current conceptual thinking. Additional measures such as pre emptive culling only became relevant under imperfect compliance with movement restrictions. The importance of movement restrictions for the overall control success illustrates the need for explicit consideration of this measure when contingency strategies are being amended (e.g. emergency vaccination) and associated risks assessed. PMID- 21300413 TI - A stochastic predictive model for the natural spread of bluetongue. AB - In recent years the vector-borne diseases (VBD) are (re)-emerging and spreading across the world having a profound impact on human and veterinary health, ecology, socio-economics and disease management. Arguably the best-documented example of veterinary importance is the recent twofold invasion of bluetongue (BT) in Europe. Much attention has been devoted to derive presence-absence habitat distribution models and to model transmission through direct contact. Limited research has focused on the dynamic modelling of wind mediated BT spread. This paper shows the results of a stochastic predictive model used to assess the spread of bluetongue by vectors considering both wind-independent and wind mediated movement of the vectors. The model was parameterised using epidemiological knowledge from the BTV8 epidemic in 2006/2007 and the BTV1 epidemic in 2008 in South-France. The model correctly reflects the total surface of the infected zone (overall accuracy=0.77; sensitivity=0.94; specificity=0.65) whilst slightly overestimating spatial case density. The model was used operationally in spring 2009 to predict further spread of BTV1. This allowed veterinary officers in Belgium to decide whether there was a risk of introduction of BTV1 from France into Belgium and thus, whether there was a need for vaccination. Given the far distance from the predicted infected zone to the Belgian border, it was decided not to vaccinate against BTV1 in 2009 in Belgium. PMID- 21300414 TI - Consumers, health insurance and dominated choices. AB - We analyze employee health plan choices when the choice set offered by their employer includes a dominated plan. During our study period, one-third of workers were enrolled in the dominated plan. Some may have selected the plan before it was dominated and then failed to switch out of it. However, a substantial number actively chose the dominated plan when they had an unambiguously better choice. These results suggest limitations in the ability of health reform based solely on consumer choice to achieve efficient outcomes and that implementation of health reform should anticipate, monitor and account for this consumer behavior. PMID- 21300415 TI - The effects of maternity leave on children's birth and infant health outcomes in the United States. AB - This paper evaluates the impacts of unpaid maternity leave provisions of the 1993 Family and Medical Leave Act (FMLA) on children's birth and infant health outcomes in the United States. My identification strategy uses variation in pre FMLA maternity leave policies across states and variation in which firms are covered by FMLA provisions. Using Vital Statistics data and difference-in difference-in-difference methodology, I find that maternity leave led to small increases in birth weight, decreases in the likelihood of a premature birth, and substantial decreases in infant mortality for children of college-educated and married mothers, who were most able to take advantage of unpaid leave. My results are robust to the inclusion of numerous controls for maternal, child, and county characteristics, state, year, and month fixed effects, and state-year interactions, as well as across several different specifications. PMID- 21300416 TI - Parotid gland as a risk organ in whole brain radiotherapy. AB - BACKGROUND AND PURPOSE: Since the introduction of CT-based simulation for use in whole brain radiotherapy (WBRT), we have observed that a large volume of the parotid glands is included in the radiation fields. The purpose of this study is to analyze the dose-volume statistics of the parotid glands in patients undergoing WBRT. MATERIALS AND METHODS: Thirty-two patients received WBRT using CT-based simulation with bilateral two-field arrangement. Daily fraction was 3 Gy with total dose of 30 Gy in 2 weeks. We analyzed the radiation dose from WBRT to the parotid glands. RESULTS: Average of the mean parotid dose was 17.5 Gy (range, 10.5-26.2) for both glands. Mean parotid doses >=20 and >=25 Gy were observed in 22 (34.4%) and 4 (6.3%) of 64 individual glands. The numbers of patients with a mean parotid dose of both glands >=20Gy and >=25 Gy were 12 (37.5%) and 1 (3.1%), respectively. CONCLUSIONS: Mean parotid dose was variable in patients with WBRT. According to the parotid dose and combined potential risk factors, parotid glands can be regarded as a risk organ in WBRT for improvement of patient quality of life. PMID- 21300417 TI - Diabetes mellitus and oral mucosa alterations: prevalence and risk factors. AB - AIMS: To investigate the prevalence of oral mucosa alterations in patients with type 2 diabetes and to identify possible risk factors related to oral mucosa alterations. METHODS: 146 patients with type 2 diabetes and 111 age- and gender matched healthy controls subjects were consecutively recruited from Araraquara School of Dentistry to answer a structured questionnaire designed to collect demographic data as well as current and former history of diabetes. Clinical examination of the oral mucosa was carried out by a stomatologist. RESULTS: A higher prevalence of oral mucosa alterations was found in patients with diabetes than in patients without diabetes (p<0.001), with significant difference to development conditions (p<0.0001), potentially malignant disorders (p<0.0001) and fungal infections (p<0.05). In the multiple logistic regression, diabetes (odds ratio 9.9 IC 5.11-19.16) and smoking habit (odds ratio 3.17 IC 1.42-7.12) increased the odds of oral mucosa alterations significantly. CONCLUSIONS: Patients with diabetes mellitus not only showed an increased prevalence of oral mucosa alterations but also a significant percentage of potentially malignant disorders. These findings elucidate the necessity of regular clinical examination to ensure early diagnosis and prompt management of oral mucosa lesions in patients with diabetes. PMID- 21300418 TI - [Relationship between sensory hearing loss and depression in elderly people: a literature review]. AB - Advances in health, social and economic conditions in the developed countries have increased life expectancy and the number of elderly people. However, although health conditions have improved, age-related diseases are still increasing. One of the most common ailments is the age-related hearing loss, which has several pathophysiological causes and may be influenced by age-related morpho-functional changes. Hearing loss may also have underlying conditions in each individual. Sensory hearing loss tends to negatively affect the quality of life of the elderly, interfering with their capacity to communicate and affecting mood and the level of participation in social life. This may be independent of the cognitive and physical state of individuals, which in the long term and in many cases may end in depression. Detection and early treatment of hearing loss is an important bio-psycho-social benefit to the elderly. PMID- 21300419 TI - Exploring student's perceptions and experience of personal tutors. AB - There are a variety of arrangements to support pre-registration nursing students whilst they engage with the theoretical and practical elements of their course; these includes academic supervisor and a personal tutor. The personal tutor system is recognized as an effective method of ensuring that each student has access to a wide range of support services and that the individual's academic progress and personal development are monitored by a skilled member of academic staff (Harrison, 1990). However, there is a dearth of studies relating to the role of the personal tutor in nurse education from the students' perspective. This study set out to explore the pre-registration students nurse's experience of personal tutoring at one School of Nursing and Midwifery in a Higher Education Institution (HEI) in the UK. Focus groups and a semi-structured questionnaire were used to collect data from pre-registration nursing participants. Data analysed revealed both positive and negative experiences; most rated their advice and support good with many positive aspects to their personal tutoring expressed however many felt the need for more contact time, more support academically and whilst on clinical placements, and more structured support with their personal development planning. This paper also describes how the study was conducted, the importance that students place on the role, and the need for further research and areas for improvement. PMID- 21300420 TI - Prevalence of the notification of malnutrition in the departments of internal medicine and its prognostic implications. AB - BACKGROUND & AIMS: Detection and notification of malnutrition are essential to adopt a support plan and take costs into account. The aim of this study was to describe how often discharge sheets from Internal Medicine (IM) units include malnutrition among diagnoses (notification frequency) using the International Classification of Diseases, 9th Revision Clinical Modification -ICD-9. Factors associated with this diagnosis and its prognostic implications are also assessed. MATERIAL AND METHODS: The Minimum Basic Data Set from the Spanish hospitals (Ministry of Health and Consumer Affairs) was revised, and patients with diagnosis of malnutrition (ICD-9: 260-263.9) were identified. RESULTS: 1,567,659 patients were analysed (21,804-1.4%- with malnutrition). These patients were older (72.4 vs 70.8 years of age), had a greater degree of comorbidity (Charlson >2: 28% vs 23.5%), and resided in nursing homes more often (3.9% vs 1.9%) than the non-undernourished. The malnutrition associated diagnoses were: dementia, cancer, HIV infection and chronic renal failure. Mortality (19.5% vs 9.8%), hospital stay (18.1 vs 9.8 days), costs (5228.46 vs 3537.8 ?) and relative weights applied to each Diagnosis Related Group (2.6 vs 1.1) were higher (p < 0.001 for all comparisons). CONCLUSIONS: Notification of malnutrition in IM departments is low, below the prevalence described in inpatients. This diagnosis is associated with an increase in morbidity, mortality and costs. PMID- 21300421 TI - Detection of fullerenes (C60 and C70) in commercial cosmetics. AB - Detection methods are necessary to quantify fullerenes in commercial applications to provide potential exposure levels for future risk assessments of fullerene technologies. The fullerene concentrations of five cosmetic products were evaluated using liquid chromatography with mass spectrometry to separate and specifically detect C60 and C70 from interfering cosmetic substances (e.g., castor oil). A cosmetic formulation was characterized with transmission electron microscopy, which confirmed that polyvinylpyrrolidone encapsulated C60. Liquid liquid extraction of fullerenes from control samples approached 100% while solid phase and sonication in toluene extractions yielded recoveries of 27-42%. C60 was detected in four commercial cosmetics ranging from 0.04 to 1.1 MUg/g, and C70 was qualitatively detected in two samples. A single-use quantity of cosmetic (0.5 g) may contain up to 0.6 MUg of C60, demonstrating a pathway for human exposure. Steady-state modeling of fullerene adsorption to biosolids is used to discuss potential environmental releases from wastewater treatment systems. PMID- 21300422 TI - Influence of extracellular polymeric substances (EPS) on Cd adsorption by bacteria. AB - The role of extracellular polymeric substances (EPS) in Cd adsorption by Bacillus subtilis and Pseudomonas putida was investigated using a combination of batch adsorption experiments, potentiometric titrations, Fourier transform infrared spectroscopy (FTIR). An increased adsorption capacity of Cd was observed for untreated bacteria relative to that for EPS-free bacteria. Surface complexation modeling of titration data showed the similar pKa values of functional groups (carboxyl, phosphate and hydroxyl) between untreated and EPS-free bacteria. However, site concentrations on the untreated bacteria were found to be higher than those on the EPS-free bacteria. FTIR spectra also showed that no significant difference in peak positions was observed between untreated and EPS-free bacteria and carboxyl and phosphate groups were responsible for Cd adsorption on bacterial cells. The information obtained in this study is of fundamental significance for understanding the interaction mechanisms between heavy metals and biofilms in natural environments. PMID- 21300423 TI - PBDD/F impurities in some commercial deca-BDE. AB - The study presented the concentrations and distributions of polybrominated dibenzo-p-dioxins and polybrominated dibenzofurans (PBDD/Fs) as impurities in some commercial decabromodiphenyl ether (DBDE) mixtures that were produced by several manufacturers. The total concentrations of 12 2,3,7,8-substituted tetra- to octa-BDD/F congeners were found to be in the range of 3.4-13.6 (mean 7.8) MUg/g, averagely accounting for 99% of total PBDD/Fs. OBDF was the prevailing congener, followed by 1,2,3,4,6,7,8-HpBDF. In addition, OBDD and 1,2,3,4,7,8 HxBDF were also obviously detectable. The total concentrations of PBDD/Fs varied both between the manufacturers and between the lots. On the basis of the global demand for the commercial DBDE in 2001, the annual potential emissions of PBDD/Fs were calculated coarsely to be 0.43 (range: 0.21-0.78) tons. The major dioxin congeners, OBDF and 1,2,3,4,6,7,8-HpBDF, presenting in DBDE, were estimated to be formed from BDE-209, BDE-206, and/or BDE-207 via an intra-molecular elimination of Br2/HBr. PMID- 21300424 TI - Aquatic subsidies transport anthropogenic nitrogen to riparian spiders. AB - Stable nitrogen isotopic composition (delta15N) of aquatic biota increases with anthropogenic N inputs such as sewage and livestock waste downstream. Increase in delta15N of riparian spiders downstream may reflect the anthropogenic pollution exposure through predation on aquatic insects. A two-source mixing model based on stable carbon isotopic composition showed the greatest dependence on aquatic insects (84%) by horizontal web-building spiders, followed by intermediate (48%) and low (31%) dependence by cursorial and vertical web-building spiders, respectively. The spider body size was negatively correlated with the dietary proportion of aquatic insects and spider delta15N. The aquatic subsidies transported anthropogenic N to smaller riparian spiders downstream. This transport of anthropogenic N was regulated by spider's guild designation and body size. PMID- 21300425 TI - Patchwork diagnoses: the production of coherence, uncertainty, and manageable bodies. AB - Using a material semiotics methodology, this paper explores the link between diagnostic practices, patient awareness of the body, and biopolitical governance. We collected video and audio recordings of a patient with chest pain involved in three medical interactions (a general practitioner [GP] consultation, an electrocardiogram stress test and a consultation with a cardiologist) in Wellington, New Zealand. Following the work of Annemarie Mol, we argue that each of these diagnostics interactions bring together a range of material and non material entities that enact the body and disease. Consequently, we note how the diagnostic practices associated with cardiovascular medicine enable and prompt an awareness of the body based on uncertainty, and thus promotes the self-management of cardiac health and risk. This paper illustrates that a material semiotics methodology makes important contributions to the sociology of diagnosis. Firstly, it draws attention to the relationship between humans and material entities in rendering the body intelligible. Secondly, it illustrates that different diagnostic procedures can produce multiple, potentially conflicting, forms of self-awareness. Alongside these practices generating multiplicity, however, are those that presuppose and produce singularity and coherence. We illustrate how the cardiologist "patches" two potentially conflicting diagnoses together in order to provide a sense of coherence to the interactions. Thirdly, material semiotics illustrates how various diagnostic practices can reify risk, and produce bodies that lend themselves to particular forms of governance. PMID- 21300426 TI - Bed rest after embryo transfer. AB - In in vitro fertilization (IVF), embryo implantation is a very complex event influenced by embryo quality and endometrial receptivity. Many interventions have been used to increase the implantation rate, but bed rest is probably the most commonly prescribed. Since the etiology of implantation failure in most cases is not related to an excess of activity, however, it is unlikely that bed rest could be an effective strategy to improve pregnancy outcome. We performed a systematic review to evaluate the effect of prescription of bed rest to increase pregnancy rate. A systematic literature search in MEDLINE, EMBASE, and the Chinese Biomedical Database (CBM) was performed to identify articles reporting randomized controlled trials (RCTs) which compared different time length of bed rest in infertile women undergoing embryo transfer (ET). Two authors independently searched the abstracts, identified relevant papers, assessed inclusion and trial quality, and extracted the relevant data. Three trials involving three different comparison groups were included in the review and enrolled a total of 724 randomized subjects. The quality of the included studies was high. The conclusion was that there was insufficient evidence to support the routine use of bed rest to improve pregnancy outcome in women undergoing ET in IVF cycles. PMID- 21300427 TI - Is intrapartum fetal blood sampling a gold standard diagnostic tool for fetal distress? AB - Developed in 1960s, cardiotocography is a screening test and fetal blood sampling (FBS) is an adjunctive, diagnostic technique to detect fetal hypoxia. A fetal blood sample pH value of less than 7.20 has a higher specificity than a pathological CTG to predict low Apgar score at 1 min. Though with a pathological CTG and despite a normal FBS pH value the risk of delivering a hypoxic infant is 30-50%, FBS has assumed considerable importance in purportedly reducing unnecessary obstetric intervention. The evidence for this is weak: the use of FBS with CTG has been shown to reduce operative vaginal deliveries though not Caesarean sections due to fetal distress. There is no difference in the umbilical artery pH at delivery with the use of intermittent FBS with CTG compared to CTG alone. FBS is an invasive procedure: obtaining an adequate blood sample is often difficult and the pH results are affected by handling of the sample, aerobic contamination and processing. Validation of intrapartum FBS requires that the pH and other values obtained are compared to a 'gold standard' technique. Although FBS has been compared to other tests such as scalp lactate, pulse oximetry, fetal ECG waveform analysis, and central haemodynamics in labouring rhesus monkeys, none of these can be considered as 'gold standard'. In the light of the existing evidence, the role of intrapartum FBS as a gold standard diagnostic technique is unproven. PMID- 21300428 TI - Incidence and prevention of neural tube defects in Slovenia. PMID- 21300429 TI - The dual-specificity protein phosphatase MkpB, homologous to mammalian MKP phosphatases, is required for D. discoideum post-aggregative development and cisplatin response. AB - Dual-specificity protein phosphatases participate in signal transduction pathways inactivating mitogen-activated protein kinases (MAP kinases). These signaling pathways are of critical importance in the regulation of numerous biological processes, including cell proliferation, differentiation and development. The social ameba Dictyostelium discoideum harbors 14 genes coding for proteins containing regions very similar to the dual-specificity protein phosphatase domain. One of these genes, mkpB, additionally codes for a region similar to the Rhodanase domain, characteristic of animal MAP kinase-phosphatases, in its N terminal region. Cells that over-express this gene show increased protein phosphatase activity. mkpB is expressed in D. discoideum ameba at growth but it is greatly induced at 12h of multicellular development. Although it is expressed in all the cells of developmental structures, mkpB mRNA is enriched in cells with a distribution typical of anterior-like cells. Cells that express a catalytically inactive mutant of MkpB grow and aggregate like wild-type cells but show a greatly impaired post-aggregative development. In addition, the expression of cell-type specific genes is very delayed, indicating that this protein plays an important role in cell differentiation and development. Cells expressing the MkpB catalytically inactive mutant show increased sensitivity to cisplatin, while cells over-expressing wild type MkpB, or MkpA, proteins or mutated in the MAP kinase erkB gene are more resistant to this chemotherapeutic drug, as also shown in human tumor cells. PMID- 21300430 TI - Epithelial-to-mesenchymal transition, cell polarity and stemness-associated features in malignant pleural mesothelioma. AB - Epithelial-to-mesenchymal transition (EMT) is the fundamental process by which an epithelial cell loses its epithelial characteristics including cell polarity and acquires mesenchymal and stemness-related features. Therefore, we investigated whether malignant pleural mesothelioma (MPMs) histologies were associated with specific patterns of expression of a selected set of genes related to EMT, cell polarity and stemness features. The association between MPM histologies and genes expression were explored using active and passive Principal Components Analysis based biplots and PAM analysis that provided evidence that with respect to normal tissues, MPMs histologies were better characterized by specific patterns of expression of genes involved in EMT activation, cell polarity and stemness. PMID- 21300431 TI - Does waterborne citalopram affect the aggressive and sexual behaviour of rainbow trout and guppy? AB - Citalopram is one of several selective serotonin reuptake inhibitors (SSRIs) commonly found in treated sewage effluents. Accordingly, there are concerns about possible adverse effects of SSRIs on aquatic organisms, particularly behavioural effects similar to those associated with SSRI use in humans. Rainbow trout fry and adult male guppies were therefore exposed to waterborne citalopram, ranging from environmentally relevant to high concentrations (1, 10, 100 MUg/L) for 3-7 days. Under these experimental conditions citalopram does not appear to cause significant effects on aggression in rainbow trout fry or on sexual behaviour in male guppies. This may be explained by a relatively low uptake of citalopram from water to fish. PMID- 21300432 TI - Characterization of metal removal of immobilized Bacillus strain CR-7 biomass from aqueous solutions. AB - Bacillus strain CR-7 of multiple metal and antibiotic resistances was isolated. Its metal adsorption under different pretreatments and immobilizations from aqueous solution was characterized. Pretreatment with NaOH (0.1 mol L(-1)) significantly improved Cu(2+) adsorption capacity of the bacterial biomass. Sodium alginate (2%) was the ideal immobilization matrix. The immobilized and pretreated biomass had an obvious "orderliness", following the order of Cu(2+)>Zn(2+) in the solution containing these two metals, and following the order of Pb(2+)>Al(3+)>Cr(6+)>Cu(2+)>Fe(3+)>Zn(2+) = Ni(2+)>Cd(2+) = Co(2+)>Mn(2+) in the solution containing these 10 metals. DeltaH degrees and DeltaS degrees of Cu(2+) adsorption were +7.68 J/mol and +16.628 J/mol K, respectively. The infrared peak of -N-H shifted greatly after Cu(2+) adsorption. After adsorption treatment, some molecular groups disappeared in un-immobilized biomass but were still present in the immobilized biomass. Cu(2+) adsorption fit both Langmuir and Freundlich isotherm models. It was concluded (1) that the Cu(2+) adsorption process was endothermic, (2) that -N-H is a most important Cu(2+)-binding group, (3) that immobilization prevents loss or damage of the Cu(2+)-binding molecular groups, and (4) that Cu(2+) adsorption of pretreated and immobilized biomass is homogeneous. PMID- 21300433 TI - Use of biogenic and abiotic elemental selenium nanospheres to sequester elemental mercury released from mercury contaminated museum specimens. AB - Mercuric chloride solutions have historically been used as pesticides to prevent bacterial, fungal and insect degradation of herbarium specimens. The University of Manchester museum herbarium contains over a million specimens from numerous collections, many preserved using HgCl(2) and its transformation to Hg(v)(0) represents a health risk to herbarium staff. Elevated mercury concentrations in work areas (~ 1.7 MUg m(-3)) are below advised safe levels (<25 MUg m(-3)) but up to 90 MUg m(-3) mercury vapour was measured in specimen boxes, representing a risk when accessing the samples. Mercury vapour release correlated strongly with temperature. Mercury salts were observed on botanical specimens at concentrations up to 2.85 wt% (bulk); XPS, SEM-EDS and XANES suggest the presence of residual HgCl(2) as well as cubic HgS and HgO. Bacterially derived, amorphous nanospheres of elemental selenium effectively sequestered the mercury vapour in the specimen boxes (up to 19 wt%), and analysis demonstrated that the Hg(v)(0) was oxidised by the selenium to form stable HgSe on the surface of the nanospheres. Biogenic Se(0) can be used to reduce Hg(v)(0) in long term, slow release environments. PMID- 21300434 TI - A comparison of basic dye adsorption onto zeolitic materials synthesized from fly ash. AB - This investigation reveals the adsorption characteristics of two basic dyes, thionine (TH) and safranine T (ST), onto fly ash (FA) and its three zeolitized products prepared at different hydrothermal conditions. Typical two-step isotherms were observed for TH adsorption onto four adsorbents, whereas the isotherms of the larger ST molecules were S-shaped. The adsorption capacities of the zeolitized fly ash (ZFA) estimated from the first plateau region of the TH isotherms was nearly twice the FA capacity. The capacities increased by up to five times in the second plateau region. The adsorption capacity of FA for ST is equivalent that of TH, whereas the capacities of ZFA are lower than those found for TH. The equilibrium results were well-described by the Freundlich isotherm model. The kinetic data obtained in the temperature range of 298-318 K was analyzed using Paterson's and Nernst Plank's approximations based on the homogeneous surface diffusion model (HSDM). The thermodynamic functions for the transition state were evaluated from the temperature-dependence of the surface diffusion coefficients by applying the Eyring model. PMID- 21300435 TI - Recycling of aluminum and caustic soda solution from waste effluents generated during the cleaning of the extruder matrixes of the aluminum industry. AB - Anodising industries use a concentrated caustic soda solution to remove aluminum from extruder matrixes. This procedure produces very alkaline effluents containing high amounts of aluminum. The work reported here was focussed on recycling aluminum, as aluminum hydroxide, from these effluents and regenerating an alkaline sodium hydroxide solution. Briefly, the method comprises a dilution step (necessary for reducing the viscosity of the effluent and allowing the subsequent filtration) followed by a filtration to eliminate a substantial amount of the insoluble iron. Then, sulphuric acid was added to neutralize the waste solution down to pH 12 and induce aluminum precipitation. The purity of the aluminum salt was improved after washing the precipitate with deionised water. The characterization of the solid recovered, performed by thermogravimetric analysis, Fourier transform infrared spectroscopy and X-ray diffraction, indicated characteristics typical of bayerite. The proposal method allowed recovering 82% of the aluminum present in the wastewater with high purity (99.5%). Additionally, a sufficiently concentrated caustic soda solution was also recovered, which can be reused in the anodising industries. This procedure can be easily implemented and ensures economy by recycling reagents (concentrated caustic soda solution) and by recovering commercial by-products (aluminum hydroxide), while avoiding environmental pollution. PMID- 21300436 TI - Leaching copper from shredded particles of waste printed circuit boards. AB - Leaching copper from shredded particles of waste printed circuit boards (PCBs) was carried out in sulfuric acid solution using hydrogen peroxide as an oxidant at room temperature. The influence of system variables on copper recovery by leaching was investigated, such as sulfuric concentration, amount of hydrogen peroxide addition, waste PBCs particle size, presence of cupric ion, temperature and time. The results shown that the optimum addition amount was 100mL 15 (wt%) sulfuric acid solution and 10 mL of 30% hydrogen peroxide for leaching 10 g waste PCBs powder with a solid/liquid ratio of 1/10 for 3h at room temperature (~23 degrees C). Moreover leaching temperature and initial copper ion concentration had insignificant effect on the leaching recovery of copper. The effect of different particle size of shredded waste PCBs on leaching of copper was investigated under the optimum leaching condition. The results revealed that shredding pieces of waste PCBs smaller than 1mm was efficient and suitable for copper leaching. Then the leaching solution was concentrated to crystallize CuSO(4).5H(2)O, and crystal liquor was reused for the next cycles. PMID- 21300437 TI - Nickel removal from nickel-5,10,15,20-tetraphenylporphine using supercritical water in absence of catalyst: a basic study. AB - Reactions of nickel-5,10,15,20-tetraphenylporphine (Ni-TPP) were studied in supercritical water in the presence of toluene without the addition of any catalyst, H(2) or H(2)S that is called a green process. The objective of this study was to remove nickel from Ni-TPP, the most common metal compound present in heavy crude, in high extent at low reaction time. All experiments were carried out in an 8.8 mL batch reactor fabricated from hastelloy C-276. The ability of supercritical water (SCW) to remove nickel from Ni-TPP was studied at temperatures of 450-490 degrees C and water partial pressures of 25-35 MPa. Water partial pressure had no effect on overall conversion at temperatures of 450 degrees C and a reaction time of 60 min. The overall Ni-TPP conversion was 89.80%, a figure above that of previous catalytic studies. The percentage of nickel removal was estimated as a function of reaction time and temperature. It were temperature 490 degrees C and pressure 25 MPa at reaction time 90 min where 65.68% nickel were removed by the action of SCW and toluene, as a co-solvent. It was determined that Ni-TPP undergoes a series of reactions, ending in demetallation and ring fragmentation. The obtained results suggest that supercritical water has a capability to remove nickel from Ni-TPP. PMID- 21300438 TI - Correlation between loss of efficacy of macrocyclic lactone heartworm anthelmintics and P-glycoprotein genotype. AB - Macrocyclic lactone (ML) molecules have been used for heartworm control for more than 25 years. However, in recent years, there have been reports of loss of efficacy of ML heartworm preventatives against Dirofilaria immitis in some locations in the United States. Macrocyclic lactone resistance is a common problem in nematode parasites of livestock, and more recently, evidence of ivermectin resistance has been reported in the human filarial nematode Onchocerca volvulus. In this study, four D. immitis sample groups from the United States with different treatment histories were investigated for evidence of ML-driven genetic selection. DNA from individual adult worms and microfilariae was amplified by polymerase chain reaction to investigate a gene encoding a P glycoprotein, a protein class known to be involved in ML pharmacology. A significant correlation of a GG-GG genotype with ivermectin response phenotype was found. Moreover, a significant loss of heterozygosity was found in a low responder group; loss of heterozygosity is commonly seen in loci when a population has been under selection. Further studies are required to confirm ML resistance in heartworm populations. However, the genetic changes observed in this study may be useful as a marker to monitor for ML resistance in D. immitis. PMID- 21300439 TI - Changing climate and changing vector-borne disease distribution: the example of Dirofilaria in Europe. AB - Climatic changes, together with an increase in the movement of dogs across Europe, have caused an increase in the geographical range of Dirofilaria infections. The present paper is focuses on northeastern European countries, where survey data have shown an increase of Dirofilaria repens infections both in animals and humans. A growing degree day-based forecast model has been developed to predict the occurrence. The model is based on evidence that there is a threshold of 14 degrees C below which Dirofilaria development will not proceed in mosquitoes, there is a requirement of 130 growing degree-days (GDDs) for larvae to reach infectivity, and there is a maximum life expectancy of 30 days for a mosquito vector. The output of this model predicted that the summer temperatures (with peaks in August) are sufficient to facilitate extrinsic incubation of Dirofilaria even at latitudes of 56 degrees N and longitudes of 39 degrees E. Despite the fact that both Dirofilaria immitis and D. repens have the same temperature requirement for extrinsic incubation in mosquitoes, empirical data has shown that D. repens is the main cause of dirofilarial infections in both humans and animals. Clinical signs are absent in most canine infections with D. repens. Furthermore, diagnosis is problematic and in-clinic serological tests, such as those for D. immitis, do not exist. Therefore, most infections go undiagnosed, allowing the infection to spread undetected. PMID- 21300440 TI - Supplemental diagnosis of a myxozoan parasite from common carp Cyprinus carpio: synonymy of Thelohanellus xinyangensis with Thelohanellus kitauei. AB - Thelohanellus kitauei Egusa et Nakajima, 1981, was described from common carp Cyprinus carpio L. in Japan. In China, a myxosporean infecting the intestinal tissue of the same host species was described as Thelohanellus xinyangensis Xie, Gong, Xiao, Guo, Li et Guo, 2000, despite many similarities to T. kitauei. To examine the potential conspecificity of these species, a morphological and molecular investigation of T. xinyangensis was conducted. Comparing myxospore morphology, the mean spore length and width of each species is not identical between species, but ranges of dimensions overlap. These data are more suggestive of intraspecific variation than distinct species. Comparison of relative ratios of spore length to polar capsule length and spore width to polar capsule width of T. xinyangensis and T. kitauei reveal no differences and scanning electron microscopy reveals a smooth spore surface of T. xinyangensis, which is consistent with that of T. kitauei. Most convincingly, DNA sequences of the small subunit ribosomal RNA (ssrRNA) gene of the two species were identical. From the morphological and molecular biological data, we propose T. xinyangensis from the intestine of common carp is not a distinct species and is synonymous with T. kitauei. PMID- 21300441 TI - The relationship between coping strategies, alcohol expectancies, drinking motives and drinking behaviour. AB - Numerous models have been proposed in an attempt to explain both alcohol use and alcohol abuse. Many of these models propose that drinking behaviour is the result of a complex interplay of cognitive and behavioural variables including coping strategies, alcohol expectancies and motives for drinking. However few studies have explored how these elements may work together to predict drinking. The current study proposed a mediational model of alcohol use in which coping strategies are related to alcohol expectancies, which in turn are related to drinking motives. Drinking motives were then viewed as proximal predictors of drinking behaviour. There were 454 participants (55.78% female) who completed self-report questionnaires assessing the above constructs. Approximately half the participants completed the questionnaires online, while the others completed the paper and pencil versions of the same measures. Findings generally supported the hypothesised model. The relationship between avoidant coping and drinking behaviour was mediated by alcohol expectancies of increased confidence and tension reduction, which in turn were related to drinking motives. As expected, drinking motives were positively related to drinking behaviour. Negative expectancies were also directly related to drinking behaviour. The results are discussed in light of cognitive models of drinking, and implications for prevention and early intervention of alcohol-use problems. PMID- 21300442 TI - Mirror neural training induced by virtual reality in brain-computer interfaces may provide a promising approach for the autism therapy. AB - Previous studies have suggested that the dysfunction of the human mirror neuron system (hMNS) plays an important role in the autism spectrum disorder (ASD). In this work, we propose a novel training program from our interdisciplinary research to improve mirror neuron functions of autistic individuals by using a BCI system with virtual reality technology. It is a promising approach for the autism to learn and develop social communications in a VR environment. A test method for this hypothesis is also provided. PMID- 21300443 TI - Synthetic surfactant food additives can cause intestinal barrier dysfunction. AB - In addition to genetic factors and antigen exposure, intestinal barrier dysfunction plays a key role in the pathogenesis of numerous allergic and autoimmune diseases. The hypothesis of this article is that synthetic surfactant food additives (also called emulsifiers) - which are applied in relatively high concentrations in even the most frequently consumed foods -cause increased intestinal permeability, hence they can play a significant role in the increasing incidence of numerous allergic and autoimmune diseases. In many cases the surfactants added to foods are exactly the same as the ones used in pharmaceutics as absorption enhancers. Numerous synthetic surfactant food additives have been shown to increase the intestinal permeability through paracellular and/or transcellular mechanisms and some of them were also shown to inhibit P glycoprotein. Additionally, based on the general characteristics of surfactants it can be predicted that they decrease the hydrophobicity of the mucus layer, which has also been shown to associate with increased intestinal permeability. PMID- 21300444 TI - Accuracy of near infrared spectroscopy for prediction of chemical composition, salt content and free amino acids in dry-cured ham. AB - The capability of near infrared (NIR) spectroscopy was examined for the purposes of quality control of the traditional Slovenian dry-cured ham "Kraski prsut." Predictive models were developed for moisture, salt, protein, non-protein nitrogen, intramuscular fat and free amino acids in biceps femoris muscle (n = 135). The models' quality was assessed using statistical parameters: coefficient of determination (R(2)) and standard error (se) of cross-validation (CV) and external validation (EV). Residual predictive deviation (RPD) was also assessed. Best results were obtained for salt content and salt percentage in moisture/dry matter (R(CV)(2)>0.90, RPD>3.0), it was satisfactory for moisture, non-protein nitrogen, intramuscular fat and total free amino acids (R(CV)(2) = 0.75-0.90, RPD = 2.0-3.0), while not so for protein content and proteolysis index (R(CV)(2) = 0.65-0.75, RPD<2.0). Calibrations for individual free amino acids yielded R(CV)(2) from 0.40 to 0.90 and RPD from 1.3 to 2.9. Additional external validation of models on independent samples yielded comparable results. Based on the results, NIR spectroscopy can replace chemical methods in quality control of dry-cured ham. PMID- 21300445 TI - Role of ROC1 protein in the control of cyclin D1 protein expression in skin melanomas. AB - A decrease in the level of the ROC1 protein, which is involved in cyclin D1 degradation, might explain an increase in cyclin D1 protein in the absence of gene overexpression. This study aimed to investigate the relationship between ROC1 and cyclin D1 expression in skin melanomas. A total of 62 cases of primary skin melanomas and 58 cases of compound melanocytic nevi were assessed. Immunohistochemistry was performed using cyclin D1 and ROC1 antibodies, and fluorescent in situ hybridization was used to assess the amplification of the CCND1 gene. ROC1 was expressed in >50% of cells in 87.9% of the melanocytic nevus cases and in 45.2% of the melanoma cases (p=0.0014). There was a significant negative correlation between ROC1 and cyclin D1 expression in all cases (p=0.0008985). In comparison with cyclin D1, ROC1 expression was increased in 86.2% of the melanocytic nevi and in 45.2% of the melanomas (p<0.001). Among the non-amplified melanomas, 50% expressed cyclin D1 in >50% of the cells and expressed ROC1 in <25%. ROC1 expression is negatively correlated with cyclin D1 expression, demonstrating its importance in the degradation of cyclin D1 in melanomas. PMID- 21300446 TI - Constitutive STAT5 activation correlates with better survival in cervical cancer patients treated with radiation therapy. AB - PURPOSE: Constitutively activated signal transducers and activators of transcription (STAT) factors, in particular STAT1, STAT3, and STAT5, have been detected in a wide variety of human primary tumors and have been demonstrated to directly contribute to oncogenesis. However, the expression pattern of these STATs in cervical carcinoma is still unknown, as is whether or not they have prognostic significance. This study investigated the expression patterns of STAT1, STAT3, and STAT5 in cervical cancer and their associations with clinical outcomes in patients treated with radical radiation therapy. METHODS AND MATERIALS: A total of 165 consecutive patients with International Federation of Gynecology and Obstetrics (FIGO) Stages IB to IVA cervical cancer underwent radical radiation therapy, including external beam and/or high-dose-rate brachytherapy between 1989 and 2002. Immunohistochemical studies of their formalin-fixed, paraffin-embedded tissues were performed. Univariate and multivariate analyses were performed to identify and to evaluate the effects of these factors affecting patient survival. RESULTS: Constitutive activations of STAT1, STAT3, and STAT5 were observed in 11%, 22%, and 61% of the participants, respectively. While STAT5 activation was associated with significantly better metastasis-free survival (p < 0.01) and overall survival (p = 0.04), STAT1 and STAT3 activation were not. Multivariate analyses showed that STAT5 activation, bulky tumor (>= 4 cm), advanced stage (FIGO Stages III and IV), and brachytherapy (yes vs. no) were independent prognostic factors for cause-specific overall survival. None of the STATs was associated with local relapse. STAT5 activation (odds ratio = 0.29, 95% confidence interval = 0.13-0.63) and advanced stage (odds ratio = 2.54; 95% confidence interval = 1.03-6.26) were independent predictors of distant metastasis. CONCLUSIONS: This is the first report to provide the overall expression patterns and prognostic significance of specific STATs in cervical carcinoma. Our results indicate that constitutive STAT5 activation correlates with better metastasis-free survival and overall survival in cervical cancer patients who have received radiation therapy. PMID- 21300447 TI - Acute toxicity profile and compliance to accelerated radiotherapy plus carbogen and nicotinamide for clinical stage T2-4 laryngeal cancer: results of a phase III randomized trial. AB - PURPOSE: To report the acute toxicity profile and compliance from a randomized Phase III trial comparing accelerated radiotherapy (AR) with accelerated radiotherapy plus carbogen and nicotinamide (ARCON) in laryngeal cancer. METHODS AND MATERIALS: From April 2001 to February 2008, 345 patients with cT2-4 squamous cell laryngeal cancer were randomized to AR (n = 174) and ARCON (n = 171). Acute toxicity was scored weekly until Week 8 and every 2-4 weeks thereafter. Compliance to carbogen and nicotinamide was reported. RESULTS: Between both treatment arms (AR vs. ARCON) no statistically significant difference was observed for incidence of acute skin reactions (moist desquamation: 56% vs. 58%, p = 0.80), acute mucosal reactions (confluent mucositis: 79% vs. 85%, p = 0.14), and symptoms related to acute mucositis (severe pain on swallowing: 53% vs. 58%, p = 0.37; nasogastric tube feeding: 28% vs. 28%, p = 0.98; narcotic medicines required: 58% vs. 58%, p = 0.97). There was a statistically significant difference in median duration of confluent mucositis in favor of AR (2.0 vs 3.0 weeks, p = 0.01). There was full compliance with carbogen breathing and nicotinamide in 86% and 80% of the patients, with discontinuation in 6% and 12%, respectively. Adjustment of antiemesis prophylaxis was needed in 42% of patients. CONCLUSION: With the exception of a slight increase in median duration of acute confluent mucositis, the present data reveal a similar acute toxicity profile between both regimens and a good compliance with ARCON for clinical stage T2-4 laryngeal cancers. Treatment outcome and late morbidity will determine the real therapeutic benefit. PMID- 21300448 TI - Improved planning time and plan quality through multicriteria optimization for intensity-modulated radiotherapy. AB - PURPOSE: To test whether multicriteria optimization (MCO) can reduce treatment planning time and improve plan quality in intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: Ten IMRT patients (5 with glioblastoma and 5 with locally advanced pancreatic cancers) were logged during the standard treatment planning procedure currently in use at Massachusetts General Hospital (MGH). Planning durations and other relevant planning information were recorded. In parallel, the patients were planned using an MCO planning system, and similar planning time data were collected. The patients were treated with the standard plan, but each MCO plan was also approved by the physicians. Plans were then blindly reviewed 3 weeks after planning by the treating physician. RESULTS: In all cases, the treatment planning time was vastly shorter for the MCO planning (average MCO treatment planning time was 12 min; average standard planning time was 135 min). The physician involvement time in the planning process increased from an average of 4.8 min for the standard process to 8.6 min for the MCO process. In all cases, the MCO plan was blindly identified as the superior plan. CONCLUSIONS: This provides the first concrete evidence that MCO-based planning is superior in terms of both planning efficiency and dose distribution quality compared with the current trial and error-based IMRT planning approach. PMID- 21300449 TI - IMRT for image-guided single vocal cord irradiation. AB - PURPOSE: We have been developing an image-guided single vocal cord irradiation technique to treat patients with stage T1a glottic carcinoma. In the present study, we compared the dose coverage to the affected vocal cord and the dose delivered to the organs at risk using conventional, intensity-modulated radiotherapy (IMRT) coplanar, and IMRT non-coplanar techniques. METHODS AND MATERIALS: For 10 patients, conventional treatment plans using two laterally opposed wedged 6-MV photon beams were calculated in XiO (Elekta-CMS treatment planning system). An in-house IMRT/beam angle optimization algorithm was used to obtain the coplanar and non-coplanar optimized beam angles. Using these angles, the IMRT plans were generated in Monaco (IMRT treatment planning system, Elekta CMS) with the implemented Monte Carlo dose calculation algorithm. The organs at risk included the contralateral vocal cord, arytenoids, swallowing muscles, carotid arteries, and spinal cord. The prescription dose was 66 Gy in 33 fractions. RESULTS: For the conventional plans and coplanar and non-coplanar IMRT plans, the population-averaged mean dose +/- standard deviation to the planning target volume was 67 +/- 1 Gy. The contralateral vocal cord dose was reduced from 66 +/- 1 Gy in the conventional plans to 39 +/- 8 Gy and 36 +/- 6 Gy in the coplanar and non-coplanar IMRT plans, respectively. IMRT consistently reduced the doses to the other organs at risk. CONCLUSIONS: Single vocal cord irradiation with IMRT resulted in good target coverage and provided significant sparing of the critical structures. This has the potential to improve the quality-of-life outcomes after RT and maintain the same local control rates. PMID- 21300450 TI - Comparison of physical examination and fluorodeoxyglucose positron emission tomography/computed tomography 4-6 months after radiotherapy to assess residual head-and-neck cancer. AB - PURPOSE: To retrospectively compare fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) and physical examination 4-6 months after radiotherapy for assessing residual head-and-neck cancer (HNC). METHODS AND MATERIALS: From July 2002 through March 2006, 52 HNC patients underwent definitive radiotherapy or chemoradiotherapy. Categoric assessments of residual tumor by PET/CT and physical examination 4-6 months after therapy were correlated and compared with clinical outcomes. Pretreatment data, including tumor stage and primary site standardized uptake value, were also gathered retrospectively and correlated with clinical outcomes. Median follow-up time was 58 months. RESULTS: Twenty-one patients had either locoregionally "positive" (17 of 21) or "equivocal" (4 of 21) PET/CT scans, whereas 31 patients had locoregionally negative scans. Four patients failed treatment and had biopsy-confirmed residual or recurrent local disease. All patients, including patients with locally suspicious scans or examinations who refused biopsies, were followed clinically for a minimum of 29 months after therapy, with no other cases of treatment failure detected during this time. No patient had residual nodal disease after therapy. Sensitivities of PET/CT vs. physical examination for early detection of treatment failure were 100% vs. 50%, whereas the specificities of the two modalities were 64.6% vs. 89.6%, respectively. Higher initial T stage and American Joint Commission on Cancer stage correlated with increased incidence of positive/equivocal PET/CT results and treatment failure. Maximal standardized uptake value was not predictive of any clinical outcome. CONCLUSIONS: A negative result on PET/CT obtained 4-6 months after radiotherapy is highly sensitive and correlates with successful locoregional control. Patients with negative scans may reasonably be spared invasive diagnostic procedures, such as biopsy and neck dissection, unless recurrent disease is suspected on clinical grounds. Close follow-up is prudent for HNC patients with abnormal findings on posttherapy PET/CT scan. PMID- 21300451 TI - Determination of prognostic factors for vaginal mucosal toxicity associated with intravaginal high-dose rate brachytherapy in patients with endometrial cancer. AB - PURPOSE: The objective of this study was to determine the patient- and treatment related prognostic factors associated with vaginal toxicity in patients who received intravaginal high dose rate (HDR) brachytherapy alone as adjuvant treatment for endometrial cancer. Secondary goals of this study included a quantitative assessment of optimal dilator use frequency and a crude assessment of clinical predictors for compliant dilator use. METHODS AND MATERIALS: We retrospectively reviewed the charts of 100 patients with histologically confirmed endometrial cancer who underwent total hysterectomy and bilateral salpingo oophorectomy with or without lymph node dissection and adjuvant intravaginal brachytherapy between 1995 and 2009 at the Hospital of the University of Pennsylvania. The most common treatment regimen used was 21 Gy in three fractions (71 patients). Symptoms of vaginal mucosal toxicity were taken from the history and physical exams noted in the patients' charts and were graded according to the Common Toxicity Criteria for Adverse Events v. 4.02. RESULTS: The incidence of Grade 1 or asymptomatic vaginal toxicity was 33% and Grade 2-3 or symptomatic vaginal toxicity was 14%. Multivariate analysis of age, active length, and dilator use two to three times a week revealed odds ratios of 0.93 (p = 0.013), 3.96 (p = 0.008), and 0.17 (p = 0.032) respectively. CONCLUSION: Increasing age, vaginal dilator use of at least two to three times a week, and shorter active length were found to be significantly associated with a decreased risk of vaginal stenosis. Future prospective studies are necessary to validate our findings. PMID- 21300452 TI - The effect of pro-qura case volume on post-implant prostate dosimetry. AB - PURPOSE: To evaluate the effect of prostate brachytherapy case volume on postimplant dosimetric quality in Pro-Qura proctored programs. METHODS AND MATERIALS: From August 1999 to December 2008, the computed tomography datasets for 6,600 prostate implants performed by 129 brachytherapists were submitted to Pro-Qura for dosimetric analysis. Brachytherapists were divided into three roughly equal-sized terciles based on total case volume. Postimplant computed tomography scans were obtained at a median of 30 days. Excellent target coverage was defined by a V100>=90% and D90>=100% minimum prescribed peripheral dose. To determine if the number of excellent implants improved with increasing case numbers, each brachytherapist's series of implants was bisected into early and late experience by a moveable critical point. RESULTS: For the entire cohort, the mean V100 and D90 were 89.2% and 102.8%, respectively, with 47.7% of the implants scored as excellent. Brachytherapists in the highest-case tercile had a significantly greater fraction of excellent target coverage (57.9%) than did those in the two lower terciles (39.5% and 45.7%, p=0.015). Twenty-one (25.6%) of the 82 brachytherapists with sufficient case volume for dosimetric improvement analyses demonstrated quality improvement over time. Although there was no significant difference between prostate volume and seed strength, the number of seeds used was significantly greater in adequate implants. CONCLUSIONS: The highest-volume brachytherapists were most likely to obtain excellent target coverage. We are encouraged that in general practice, nearly 48% of all implants were scored excellent. It is conceivable that with greater expert third-party involvement, an even greater percentage of cases with excellent target coverage will become reality. PMID- 21300453 TI - Prediction of chest wall toxicity from lung stereotactic body radiotherapy (SBRT). AB - PURPOSE: To determine patient, tumor, and treatment factors related to the development of late chest wall toxicity after lung stereotactic body radiotherapy (SBRT). METHODS AND MATERIALS: We reviewed a registry of 134 patients treated with lung SBRT to 60 Gy in 3 fractions who had greater than 1 year of clinical follow-up and no history of multiple treatments to the same lobe (n = 48). Patients were treated as per Radiation Therapy Oncology Group Protocol 0236 without specific chest wall avoidance criteria. The chest wall was retrospectively contoured. Thirty-two lesions measured less than 3 cm, and sixteen measured 3 to 5 cm. The median planning target volume was 29 cm(3). RESULTS: With a median follow-up of 18.8 months, 10 patients had late symptomatic chest wall toxicity (4 Grade 1 and 6 Grade 2) at a median of 8.8 months after SBRT. No patient characteristics (age, diabetes, hypertension, peripheral vascular disease, or body mass index) were predictive for toxicity, whereas there was a trend for continued smoking (p = 0.066; odds ratio [OR], 4.4). Greatest single tumor dimension (p = 0.047; OR, 2.63) and planning target volume (p = 0.040; OR, 1.04) were correlated with toxicity, whereas distance from tumor edge to chest wall and gross tumor volume did not reach statistical significance. Volumes of chest wall receiving 30 Gy (V30) through 70 Gy (V70) were all highly significant, although this correlation weakened for V65 and V70 and maximum chest wall point dose only trended to significance (p = 0.06). On multivariate analysis, tumor volume was no longer correlated with toxicity and only V30 through V60 remained statistically significant. CONCLUSIONS: Tumor size and chest wall dosimetry are correlated to late chest wall toxicity. Only chest wall V30 through V60 remained significant on multivariate analysis. Restricting V30 to 30 cm(3) or less and V60 to 3 cm(3) or less should result in a 10% to 15% risk of late chest wall toxicity or lower. PMID- 21300454 TI - Anatomic tumor location influences the success of contemporary limb-sparing surgery and radiation among adults with soft tissue sarcomas of the extremities. AB - PURPOSE: To examine the influence of anatomic location in the upper extremity (UE) vs. lower extremity (LE) on the presentation and outcomes of adult soft tissue sarcomas (STS). METHODS AND MATERIALS: From 2001 to 2008, 118 patients underwent limb-sparing surgery (LSS) and external beam radiotherapy (RT) with curative intent for nonrecurrent extremity STS. RT was delivered preoperatively in 96 and postoperatively in 22 patients. Lesions arose in the UE in 28 and in the LE in 90 patients. Patients with UE lesions had smaller tumors (4.5 vs. 9.0 cm, p < 0.01), were more likely to undergo a prior excision (43 vs. 22%, p = 0.03), to have close or positive margins after resection (71 vs. 49%, p = 0.04), and to undergo postoperative RT (32 vs. 14%, p = 0.04). RESULTS: Five-year actuarial local recurrence-free and distant metastasis-free survival rates for the entire group were 85 and 74%, with no difference observed between the UE and LE cohorts. Five-year actuarial probability of wound reoperation rates were 4 vs. 29% (p < 0.01) in the UE and LE respectively. Thigh lesions accounted for 84% of the required wound reoperations. The distribution of tumors within the anterior, medial, and posterior thigh compartments was 51%, 26%, and 23%. Subset analysis by compartment showed no difference in the probability of wound reoperation between the anterior and medial/posterior compartments (29 vs. 30%, p = 0.68). Neurolysis was performed during resection in (15%, 5%, and 67%, p < 0.01) of tumors in the anterior, medial, and posterior compartments. CONCLUSIONS: Tumors in the UE and LE differ significantly with respect to size and management details. The anatomy of the UE poses technical impediments to an R0 resection. Thigh tumors are associated with higher wound reoperation rates. Tumor resection in the posterior thigh compartment is more likely to result in nerve injury. A better understanding of the inherent differences between tumors in various extremity sites will assist in individualizing treatment. PMID- 21300455 TI - Relationship between radiation treatment time and overall survival after induction chemotherapy for locally advanced head-and-neck carcinoma: a subset analysis of TAX 324. AB - PURPOSE: To analyze the relationship between overall survival (OS) and radiation treatment time (RTT) and overall treatment time (OTT) in a well-described sequential therapy paradigm for locally advanced head-and-neck carcinoma (LAHNC). METHODS AND MATERIALS: TAX 324 is a Phase III study comparing TPF (docetaxel, cisplatin, and fluorouracil) with PF (cisplatin and fluorouracil) induction chemotherapy (IC) in LAHNC patients; both arms were followed by carboplatin-based chemoradiotherapy (CRT). Prospective radiotherapy quality assurance was performed. This analysis includes all patients who received three cycles of IC and a radiation dose of >=70 Gy. Radiotherapy treatment time was analyzed as binary (<=8 weeks vs. longer) and continuous (number of days beyond 8 weeks) functions. The primary analysis assessed the relationship between RTT, OTT, and OS, and the secondary analysis explored the association between treatment times and locoregional recurrence (LRR). RESULTS: A total of 333 (of 501) TAX 324 patients met the criteria for inclusion in this analysis. There were no significant differences between the treatment arms in baseline or treatment characteristics. On multivariable analysis, PF IC, World Health Organization performance status of 1, non-oropharynx site, T3/4 stage, N3 status, and prolonged RTT (hazard ratio 1.63, p=0.006) were associated with significantly inferior survival. Performance status, T3/4 disease, and prolonged RTT (odds ratio 1.68, p=0.047) were independently and negatively related to LRR on multivariable analysis, whereas PF was not. Overall treatment time was not independently associated with either OS or LRR. CONCLUSIONS: In this secondary analysis of the TAX 324 trial, TPF IC remains superior to PF IC after controlling for radiotherapy delivery time. Even with optimal IC and concurrent chemotherapy, a non-prolonged RTT is a crucial determinant of treatment success. Appropriate delivery of radiotherapy after IC remains essential for optimizing OS in LAHNC. PMID- 21300456 TI - Ten-year locoregional recurrence risks in women with nodal micrometastatic breast cancer staged with axillary dissection. AB - PURPOSE: To compare the locoregional recurrence (LRR) rates in patients with nodal mirometastases (pNmic) with those in patients with node-negative (pN0) and macroscopic node-positive (pNmac) breast cancer; and to evaluate the LRR rates according to locoregional treatment of pNmic disease. METHODS AND MATERIALS: The subjects were 9,616 women diagnosed between 1989 and 1999 with Stage pT1-T2, pN0, pNmic, or pNmac, M0 breast cancer. All women had undergone axillary dissection. The Kaplan-Meier local recurrence, regional recurrence, and LRR rates were compared among those with pN0 (n=7,977), pNmic (n=490) and pNmac (n=1,149) and according to locoregional treatment. Multivariate analysis was performed to identify the significant factors associated with LRR. RESULTS: The median follow up was 11 years. The 10-year Kaplan-Meier recurrence rate in the pN0, pNmic, and pNmac cohorts was 6.1%, 6.8%, and 8.7% for local recurrence; 3.1%, 6.2%, and 10.3% for regional recurrence; and 8.0%, 11.6%, and 15.2% for LRR, respectively (all p<.001). In the pNmic patients, the 10-year regional recurrence rate was 6.4% with breast-conserving surgery plus breast radiotherapy (RT), 5.4% with breast-conserving surgery plus locoregional RT, 4.6% with mastectomy alone, 11.1% with mastectomy plus chest wall RT, and 10.7% with mastectomy plus locoregional RT. In patients with pNmic disease and age<45 years, Grade 3 histologic features, lymphovascular invasion, nodal ratio>0.25, and estrogen receptor-negative disease, the 10-year LRR rates were 15-20%. On multivariate analysis of the entire cohort, pNmic was associated with greater LRR than Stage pN0 (hazard ratio [HR], 1.6; p=.002). On multivariate analysis of pNmic patients only, age<45 years was associated with significantly greater LRR (HR, 1.9; p=.03), and trends for greater LRR were observed with a nodal ratio>0.25 (HR, 2.0; p=.07) and lymphovascular invasion (HR, 1.7; p=.07). CONCLUSION: Women with pNmic had a greater risk of LRR than those with pN0 disease. Patients with pNmic in association with young age, Grade 3 histologic features, lymphovascular invasion, nodal ratio>0.25, and estrogen receptor-negative disease experienced 10-year LRR rates of ~15-20%, warranting consideration of locoregional RT. PMID- 21300457 TI - Patient-specific quality assurance for prostate cancer patients receiving spot scanning proton therapy using single-field uniform dose. AB - PURPOSE: To describe our experiences with patient-specific quality assurance (QA) for patients with prostate cancer receiving spot scanning proton therapy (SSPT) using single-field uniform dose (SFUD). METHODS AND MATERIALS: The first group of 249 patients with prostate cancer treated with SSPT using SFUD was included in this work. The scanning-beam planning target volume and number of monitor units were recorded and checked for consistency. Patient-specific dosimetric measurements were performed, including the point dose for each plan, depth doses, and two-dimensional (2D) dose distribution in the planes perpendicular to the incident beam direction for each field at multiple depths. The gamma-index with 3% dose or 3-mm distance agreement criteria was used to evaluate the 2D dose distributions. RESULTS: We observed a linear relationship between the number of monitor units and scanning-beam planning target volume. The difference between the measured and calculated point doses (mean +/- SD) was 0.0% +/- 0.7% (range, 2.9% to 1.8%). In general, the depth doses exhibited good agreement except at the distal end of the spread-out Bragg peak. The pass rate of gamma-index (mean +/- SD) for 2D dose comparison was 96.2% +/- 2.6% (range, 90-100%). Discrepancies between the measured and calculated dose distributions primarily resulted from the limitation of the model used by the treatment planning system. CONCLUSIONS: We have established a patient-specific QA program for prostate cancer patients receiving SSPT using SFUD. PMID- 21300458 TI - Fractionated stereotactic radiotherapy in patients with optic nerve sheath meningioma. AB - PURPOSE: To evaluate the effectiveness of fractionated stereotactic radiotherapy (SFRT) in the treatment of optic nerve sheath meningioma (ONSM). METHODS AND MATERIALS: Between 1993 and 2005, 109 patients (113 eyes) with primary (n = 37) or secondary (n = 76) ONSM were treated according to a prospective protocol with SFRT to a median dose of 54 Gy. All patients underwent radiographic, ophthalmologic, and endocrine analysis before and after SFRT. Radiographic response, visual control, and late side effects were endpoints of the analysis. RESULTS: Median time to last clinical, radiographic, and ophthalmologic follow up was 30.2 months (n = 113), 42.7 months (n = 108), and 53.7 months (n = 91), respectively. Regression of the tumor was observed in 5 eyes and progression in 4 eyes, whereas 104 remained stable. Visual acuity improved in 12, deteriorated in 11, and remained stable in 68 eyes. Mean visual field defects reduced from 33.6% (n = 90) to 17.8% (n = 56) in ipsilateral and from 10% (n = 94) to 6.7% (n = 62) in contralateral eyes. Ocular motility improved in 23, remained stable in 65, and deteriorated in 3 eyes. Radiographic tumor control was 100% at 3 years and 98% at 5 years. Visual acuity was preserved in 94.8% after 3 years and in 90.9% after 5 years. Endocrine function was normal in 90.8% after 3 years and in 81.3% after 5 years. CONCLUSIONS: SFRT represents a highly effective treatment for ONSM. Interdisciplinary counseling of the patients is recommended. Because of the high rate of preservation of visual acuity we consider SFRT the standard approach for the treatment of ONSM. Prolonged observation is warranted to more accurately assess late visual impairment. Moderate de-escalation of the radiation dose might improve the preservation of visual acuity and pituitary gland function. PMID- 21300459 TI - Visual outcome in meningiomas around anterior visual pathways treated with linear accelerator fractionated stereotactic radiotherapy. AB - PURPOSE: Meningiomas threatening the anterior visual pathways (AVPs) and not amenable for surgery are currently treated with multisession stereotactic radiotherapy. Stereotactic radiotherapy is available with a number of devices. The most ubiquitous include the gamma knife, CyberKnife, tomotherapy, and isocentric linear accelerator systems. The purpose of our study was to describe a case series of AVP meningiomas treated with linear accelerator fractionated stereotactic radiotherapy (FSRT) using the multiple, noncoplanar, dynamic conformal rotation paradigm and to compare the success and complication rates with those reported for other techniques. PATIENTS AND METHODS: We included all patients with AVP meningiomas followed up at our neuro-ophthalmology unit for a minimum of 12 months after FSRT. We compared the details of the neuro ophthalmologic examinations and tumor size before and after FSRT and at the end of follow-up. RESULTS: Of 87 patients with AVP meningiomas, 17 had been referred for FSRT. Of the 17 patients, 16 completed >12 months of follow-up (mean 39). Of the 16 patients, 11 had undergone surgery before FSRT and 5 had undergone FSRT as first-line management. Tumor control was achieved in 14 of the 16 patients, with three meningiomas shrinking in size after RT. Two meningiomas progressed, one in an area that was outside the radiation field. The visual function had improved in 6 or stabilized in 8 of the 16 patients (88%) and worsened in 2 (12%). CONCLUSIONS: Linear accelerator fractionated RT using the multiple noncoplanar dynamic rotation conformal paradigm can be offered to patients with meningiomas that threaten the anterior visual pathways as an adjunct to surgery or as first line treatment, with results comparable to those reported for other stereotactic RT techniques. PMID- 21300460 TI - Clinical outcomes of 174 nasopharyngeal carcinoma patients with radiation-induced temporal lobe necrosis. AB - PURPOSE: To retrospectively study the clinical outcomes of nasopharyngeal carcinoma patients with radiation-induced temporal lobe necrosis (TLN) treated with steroids, surgery, or observation only. METHODS AND PATIENTS: We performed a retrospective analysis of 174 consecutive patients diagnosed with TLN between 1990 and 2008. Before 1998, symptomatic patients were treated with oral steroids, while asymptomatic patients were treated conservatively. After 1998, most symptomatic and asymptomatic patients with a large volume of necrosis were treated by intravenously pulsed-steroid therapy with a standardized protocol. We examined factors affecting grade 4 complication-free survival and overall survival. Outcomes of the three treatment groups, those receiving conservative treatment, those receiving oral steroid, and those receiving intravenous pulse steroid, were compared. RESULTS: The mean follow-up time was 115 months. Rates of grade 4 complication-free survival at 2 years and at 5 years after diagnosis of TLN were 72.2% and 54.1%, respectively. The 2-year and 5-year overall survival rates were 57.5% and 35.4%, respectively. Multivariate analysis revealed that being symptomatic at diagnosis (relative risk [RR], 4.5; p = 0.0001), re irradiation of the nasopharynx (NP) (RR, 1.56; p = 0.008), salvage brachytherapy to the NP (RR, 1.75; p = 0.012), and a short latency period before the diagnosis of TLN (RR, 0.96, p < 0.0001) were independent prognosticators of poor grade 4 complication-free survival. Patients with all four factors had a 100% risk of developing grade 4 complications within 5 years; whereas if no factor was present, the risk was 12.5%. Intravenous pulse steroid therapy was associated with a higher clinical response rate compared with conventional steroid therapy (p < 0.0001); however, it did not affect complication-free survival in multivariate analysis. CONCLUSIONS: TLN patients with good prognosticators could be observed without active treatment. Although treatment with intravenously pulsed steroid was associated with better clinical response than conventional steroid delivery, it did not affect the complication-free survival rate of TLN patients. PMID- 21300461 TI - Volumetric-modulated arc therapy for stereotactic body radiotherapy of lung tumors: a comparison with intensity-modulated radiotherapy techniques. AB - PURPOSE: To demonstrate the potential of volumetric-modulated arc therapy (VMAT) compared with intensity-modulated radiotherapy (IMRT) techniques with a limited number of segments for stereotactic body radiotherapy (SBRT) for early-stage lung cancer. METHODS AND MATERIALS: For a random selection of 27 patients eligible for SBRT, coplanar and noncoplanar IMRT and coplanar VMAT (using SmartArc) treatment plans were generated in Pinnacle(3) and compared. In addition, film measurements were performed using an anthropomorphic phantom to evaluate the skin dose for the different treatment techniques. RESULTS: Using VMAT, the delivery times could be reduced to an average of 6.6 min compared with 23.7 min with noncoplanar IMRT. The mean dose to the healthy lung was 4.1 Gy for VMAT and noncoplanar IMRT and 4.2 Gy for coplanar IMRT. The volume of healthy lung receiving>5 Gy and >20 Gy was 18.0% and 5.4% for VMAT, 18.5% and 5.0% for noncoplanar IMRT, and 19.4% and 5.7% for coplanar IMRT, respectively. The dose conformity at 100% and 50% of the prescribed dose of 54 Gy was 1.13 and 5.17 for VMAT, 1.11 and 4.80 for noncoplanar IMRT and 1.12 and 5.31 for coplanar IMRT, respectively. The measured skin doses were comparable for VMAT and noncoplanar IMRT and slightly greater for coplanar IMRT. CONCLUSIONS: Coplanar VMAT for SBRT for early-stage lung cancer achieved plan quality and skin dose levels comparable to those using noncoplanar IMRT and slightly better than those with coplanar IMRT. In addition, the delivery time could be reduced by <=70% with VMAT. PMID- 21300462 TI - Boron neutron capture therapy in the treatment of locally recurred head-and-neck cancer: final analysis of a phase I/II trial. AB - PURPOSE: To investigate the efficacy and safety of boron neutron capture therapy (BNCT) in the treatment of inoperable head-and-neck cancers that recur locally after conventional photon radiation therapy. METHODS AND MATERIALS: In this prospective, single-center Phase I/II study, 30 patients with inoperable, locally recurred head-and-neck cancer (29 carcinomas and 1 sarcoma) were treated with BNCT. Prior treatments consisted of surgery and conventionally fractionated photon irradiation to a cumulative dose of 50 to 98 Gy administered with or without concomitant chemotherapy. Tumor responses were assessed by use of the RECIST (Response Evaluation Criteria in Solid Tumors) and adverse effects by use of the National Cancer Institute common terminology criteria version 3.0. Intravenously administered L-boronophenylalanine-fructose (400 mg/kg) was administered as the boron carrier. Each patient was scheduled to be treated twice with BNCT. RESULTS: Twenty-six patients received BNCT twice; four were treated once. Of the 29 evaluable patients, 22 (76%) responded to BNCT, 6 (21%) had tumor growth stabilization for 5.1 and 20.3 months, and 1 (3%) progressed. The median progression-free survival time was 7.5 months (95% confidence interval, 5.4-9.6 months). Two-year progression-free survival and overall survival were 20% and 30%, respectively, and 27% of the patients survived for 2 years without locoregional recurrence. The most common acute Grade 3 adverse effects were mucositis (54% of patients), oral pain (54%), and fatigue (32%). Three patients were diagnosed with osteoradionecrosis (each Grade 3) and one patient with soft tissue necrosis (Grade 4). Late Grade 3 xerostomia was present in 3 of the 15 evaluable patients (20%). CONCLUSIONS: Most patients who have inoperable, locally advanced head-and-neck carcinoma that has recurred at a previously irradiated site respond to boronophenylalanine-mediated BNCT, but cancer recurrence after BNCT remains frequent. Toxicity was acceptable. Further research on novel modifications of the method is warranted. PMID- 21300463 TI - Evaluation of microscopic disease in oral tongue cancer using whole-mount histopathologic techniques: implications for the management of head-and-neck cancers. AB - PURPOSE: To map the distribution of microscopic disease (MD) in head-and-neck cancer by analyzing digital images of whole-mounted serial sections of tongue cancer specimens. METHODS AND MATERIALS: Ten T1-3 oral tongue cancer specimens were evaluated. The specimens were sliced into 3-mm blocks from which one or more 4-MUm slides were taken and digitized to create whole-mounted serial sections. Gross tumor and microscopic disease were digitally contoured on each slide. Lines perpendicular to the gross tumor volume (GTV) edge were created at 0.05-mm intervals and the distance between GTV and MD measured. RESULTS: Of 88 slides assessed, 44 (50%) had evidence of MD. Of the 63,809 perpendicular lines drawn along the GTV edges, 2320 (3.6%) encountered microscopic disease along their path. The majority of MD abutted the GTV, and only 26.7% was noncontiguous with the GTV edge. The maximum distance from the border was 7.8 mm. Ninety-nine percent of all MD was within 4.75 mm and 95% was within 3.95 mm of the GTV. CONCLUSION: In this study we were able to assess the distribution of MD more accurately than has been possible with routine pathologic techniques. The results indicate that when the GTV is correctly identified, there is very little MD to be found outside this volume. This has implications for the volume of tissue resected at surgery and the volume included in the clinical target volume in conformal radiotherapy planning. PMID- 21300464 TI - Assessment of early toxicity and response in patients treated with proton and carbon ion therapy at the Heidelberg ion therapy center using the raster scanning technique. AB - PUROPOSE: To asses early toxicity and response in 118 patients treated with scanned ion beams to validate the safety of intensity-controlled raster scanning at the Heidelberg Ion Therapy Center. PATIENTS AND METHODS: Between November 2009 and June 2010, we treated 118 patients with proton and carbon ion radiotherapy (RT) using active beam delivery. The main indications included skull base chordomas and chondrosarcomas, salivary gland tumors, and gliomas. We evaluated early toxicity within 6 weeks after RT and the initial clinical and radiologic response for quality assurance in our new facility. RESULTS: In all 118 patients, few side effects were observed, in particular, no high numbers of severe acute toxicity were found. In general, the patients treated with particle therapy alone showed only a few single side effects, mainly Radiation Therapy Oncology Group/Common Terminology Criteria grade 1. The most frequent side effects and cumulative incidence of single side effects were observed in the head-and-neck patients treated with particle therapy as a boost and photon intensity-modulated RT. The toxicities included common radiation-attributed reactions known from photon RT, including mucositis, dysphagia, and skin erythema. The most predominant imaging responses were observed in patients with high-grade gliomas and those with salivary gland tumors. For skull base tumors, imaging showed a stable tumor outline in most patients. Thirteen patients showed improvement of pre-existing clinical symptoms. CONCLUSIONS: Side effects related to particle treatment were rare, and the overall tolerability of the treatment was shown. The initial response was promising. The data have confirmed the safe delivery of carbon ions and protons at the newly opened Heidelberg facility. PMID- 21300466 TI - Concomitant cisplatin and hyperfractionated radiotherapy in locally advanced head and neck cancer: 10-year follow-up of a randomized phase III trial (SAKK 10/94). AB - PURPOSE: To compare the long-term outcome of treatment with concomitant cisplatin and hyperfractionated radiotherapy versus treatment with hyperfractionated radiotherapy alone in patients with locally advanced head and neck cancer. METHODS AND MATERIALS: From July 1994 to July 2000, a total of 224 patients with squamous cell carcinoma of the head and neck were randomized to receive either hyperfractionated radiotherapy alone (median total dose, 74.4 Gy; 1.2 Gy twice daily; 5 days per week) or the same radiotherapy combined with two cycles of cisplatin (20 mg/m(2) for 5 consecutive days during weeks 1 and 5). The primary endpoint was the time to any treatment failure; secondary endpoints were locoregional failure, metastatic failure, overall survival, and late toxicity assessed according to Radiation Therapy Oncology Group criteria. RESULTS: Median follow-up was 9.5 years (range, 0.1-15.4 years). Median time to any treatment failure was not significantly different between treatment arms (hazard ratio [HR], 1.2 [95% confidence interval {CI}, 0.9-1.7; p = 0.17]). Rates of locoregional failure-free survival (HR, 1.5 [95% CI, 1.1-2.1; p = 0.02]), distant metastasis-free survival (HR, 1.6 [95% CI, 1.1-2.5; p = 0.02]), and cancer specific survival (HR, 1.6 [95% CI, 1.0-2.5; p = 0.03]) were significantly improved in the combined-treatment arm, with no difference in major late toxicity between treatment arms. However, overall survival was not significantly different (HR, 1.3 [95% CI, 0.9-1.8; p = 0.11]). CONCLUSIONS: After long-term follow-up, combined-treatment with cisplatin and hyperfractionated radiotherapy maintained improved rates of locoregional control, distant metastasis-free survival, and cancer-specific survival compared to that of hyperfractionated radiotherapy alone, with no difference in major late toxicity. PMID- 21300465 TI - Simultaneous 68Ga-DOTATOC-PET/MRI for IMRT treatment planning for meningioma: first experience. AB - PURPOSE: To evaluate intensity-modulated radiotherapy (IMRT) treatment planning based on simultaneous positron-emission tomography and magnetic resonance imaging (PET/MRI) of meningioma. METHODS AND MATERIALS: A meningioma patient was examined prior to radiotherapy with dedicated planning computed tomography (CT), MRI, PET/CT with gallium-68-labeled DOTATOC (68Ga-DOTATOC), and simultaneous 68Ga DOTATOC-PET/MRI. The first gross target volume (GTV) was defined based on a combination of separate MR and 68Ga-DOTATOC-PET/CT imaging (GTVPET/CT+MR). Then, the simultaneous PET/MR images were used to delineate a second GTV (GTVPET/MR) by following exactly the same delineation strategy. After an isotropic expansion of those volumes by a 4-mm safety margin, the resulting planning target volumes (PTVs) were compared by calculating the intersection volume and the relative complements. A cross-evaluation of IMRT plans was performed, where the treatment plan created for the PTVPET/CT+MR was applied to the PET/MR-based PTVPET/MR. RESULTS: Generally, target volumes for IMRT treatment planning did not differ between MRI plus 68Ga-DOTATOC-PET/CT and simultaneous PET/MR imaging. Only in certain regions of the GTV were differences observed. The overall volume of the PET/MR-based PTV was approximately the same as that obtained from PET/CT data. A small region of infiltrative tumor growth next to the main tumor mass was better visualized with combined PET/MR due to smaller PET voxel sizes and improved recovery. An IMRT treatment plan was optimized for the PTVPET/CT+MR. The evaluation of this plan with respect to the PTVPET/MR showed parts of the target volume that would not have received the full radiation dose after delineation of the tumor, based on simultaneous PET/MR. CONCLUSION: This case showed that differences in target volumes delineated on the basis of separate MR and PET/CT and simultaneous PET/MR may be observed that can have significant consequences for an effectively applied radiotherapy treatment plan. PMID- 21300467 TI - Outcomes of positron emission tomography-staged clinical N3 breast cancer treated with neoadjuvant chemotherapy, surgery, and radiotherapy. AB - PURPOSE: To evaluate the treatment outcome and efficacy of regional lymph node irradiation after neoadjuvant chemotherapy (NCT) and surgery in positron emission tomography (PET)-positive clinical N3 (cN3) breast cancer patients. METHODS AND MATERIALS: A total of 55 patients with ipsilateral infraclavicular (ICL), internal mammary (IMN), or supraclavicular (SCL) lymph node involvement in the absence of distant metastases, as revealed by an initial PET scan, were retrospectively analyzed. The clinical nodal stage at diagnosis (2002 AJCC) was cN3a in 14 patients (26%), cN3b in 12 patients (22%), and cN3c in 29 patients (53%). All patients were treated with NCT, followed by mastectomy or breast conserving surgery and subsequent radiotherapy (RT) with curative intent. RESULTS: At the median follow-up of 38 months (range, 9-80 months), 20 patients (36%) had developed treatment failures, including distant metastases either alone or combined with locoregional recurrences that included one ipsilateral breast recurrence (IBR), six regional failures (RF), and one case of combined IBR and RF. Only 3 patients (5.5%) exhibited treatment failure at the initial PET positive clinical N3 lymph node. The 5-year locoregional relapse-free survival, disease-free survival (DFS), and overall survival rates were 80%, 60%, and 79%, respectively. RT delivered to PET-positive IMN regions in cN3b patients and at higher doses (>=55 Gy) to SCL regions in cN3c patients was not associated with improved 5-year IMN/SCL relapse-free survival or DFS. CONCLUSION: NCT followed by surgery and RT, including the regional lymph nodes, resulted in excellent locoregional control for patients with PET-positive cN3 breast cancer. The primary treatment failure in this group was due to distant metastasis rather than RF. Neither higher-dose RT directed at PET-positive SCL nodes nor coverage of PET positive IMN nodes was associated with additional gains in locoregional control or DFS. PMID- 21300468 TI - Noninvasive and curative radiation therapy for sebaceous carcinoma of the eyelid. AB - PURPOSE: Sebaceous carcinoma of the eyelid is a rare malignancy. Surgical excision remains the standard and most reliable curative treatment. However, surgery is sometimes not possible because many patients are elderly, and it frequently causes functional and cosmetic impairment of the eyelid. We therefore carried out a study to determine the role of radiation therapy in relation to sebaceous carcinoma of the eyelid. METHODS AND MATERIALS: Thirteen patients with sebaceous carcinoma of the eyelid underwent radiation therapy with curative intent. There were 6 men and 7 women, and their ages at irradiation ranged from 60 to 85 years (median, 78 years). Only 1 patient had cervical lymph node metastasis, and none of the patients had distant metastasis. A total dose of 50 to 66.6 Gy (median, 60 Gy) was delivered to tumor sites in 22 to 37 fractions. RESULTS: All irradiated tumors were controlled at a median follow-up period of 55 months. Only 1 patient had recurrence of cervical lymph node metastasis outside the radiation field, at 22 months after irradiation. The 5-year local progression free and disease-free rates were 100% and 89%, respectively. The overall and disease-free survival rates at 5 years were 100% and 89%, respectively. Although acute and transient therapy-related reactions of Grade 2 or less were observed, there were no severe toxicities of Grade 3 or greater. CONCLUSIONS: Radiation therapy is a safe and effective treatment for patients with sebaceous carcinoma of the eyelid. It appears to contribute to prolonged survival as a result of good tumor control, and it also facilitates functional and cosmetic preservation of the eyelid. PMID- 21300469 TI - Verification of calculated skin doses in postmastectomy helical tomotherapy. AB - PURPOSE: To verify the accuracy of calculated skin doses in helical tomotherapy for postmastectomy radiation therapy (PMRT). METHODS AND MATERIALS: In vivo thermoluminescent dosimeters (TLDs) were used to measure the skin dose at multiple points in each of 14 patients throughout the course of treatment on a TomoTherapy Hi.Art II system, for a total of 420 TLD measurements. Five patients were evaluated near the location of the mastectomy scar, whereas 9 patients were evaluated throughout the treatment volume. The measured dose at each location was compared with calculations from the treatment planning system. RESULTS: The mean difference and standard error of the mean difference between measurement and calculation for the scar measurements was -1.8% +/- 0.2% (standard deviation [SD], 4.3%; range, -11.1% to 10.6%). The mean difference and standard error of the mean difference between measurement and calculation for measurements throughout the treatment volume was -3.0% +/- 0.4% (SD, 4.7%; range, -18.4% to 12.6%). The mean difference and standard error of the mean difference between measurement and calculation for all measurements was -2.1% +/- 0.2% (standard deviation, 4.5%: range, -18.4% to 12.6%). The mean difference between measured and calculated TLD doses was statistically significant at two standard deviations of the mean, but was not clinically significant (i.e., was <5%). However, 23% of the measured TLD doses differed from the calculated TLD doses by more than 5%. CONCLUSIONS: The mean of the measured TLD doses agreed with TomoTherapy calculated TLD doses within our clinical criterion of 5%. PMID- 21300470 TI - High stromal carbonic anhydrase IX expression is associated with decreased survival in P16-negative head-and-neck tumors. AB - PURPOSE: Head-and-neck squamous cell carcinoma (HNSCC) is the fifth most common malignancy worldwide. Alcohol use and tobacco use are the most established risk factors; however, human papilloma virus (HPV) infection is a major risk factor for a subset of HNSCCs. Although HPV-positive tumors typically present at a more advanced stage at diagnosis, they are associated with a better prognosis. Tumor hypoxia confers poor prognosis and treatment failure, but direct tumor oxygen measurement is challenging. Endogenous markers of hypoxia (EMHs) have been proposed but have not replicated the prognostic utility of direct oxygen measurement. The expression of endogenous markers of hypoxia may be influenced by oxygen-independent factors, such as the HPV status of the tumor. METHODS AND MATERIALS: Consecutive cases of locally advanced HNSCC, treated with a uniform regimen of combined radiotherapy and chemotherapy, were identified. Tissue microarrays were assembled from triplicate 0.6-mm cores of archived tumor tissue. HPV status was inferred from semiquantitative p16 immunostaining and directly measured by use of HPV-specific chromogenic in situ hybridization and polymerase chain reaction. Automated quantitative fluorescent immunohistochemistry was conducted to measure epithelial and stromal expression of carbonic anhydrase IX (CAIX) and glucose transporter 1 (GLUT1). RESULTS: High stromal CAIX expression was associated with significantly reduced overall survival (p = 0.03) in patients with p16-negative tumors. CONCLUSIONS: This is the first study to use quantitative immunohistochemistry to examine endogenous markers of hypoxia stratified by tumor p16/HPV status. Assessment of CAIX expression in p16-negative HNSCC could identify patients with the least favorable prognosis and inform therapeutic strategies. PMID- 21300471 TI - Retrospective comparison of chemoradiotherapy followed by adjuvant chemotherapy, with or without prior gliadel implantation (carmustine) after initial surgery in patients with newly diagnosed high-grade gliomas. AB - PURPOSE: Retrospective study of patients treated for high-grade glioma, with or without biodegradable carmustine wafers and according to the Stupp protocol. METHODS AND MATERIALS: Between May 2007 and June 2008, 65 patients underwent surgery for high-grade glioma, 28 had implantation of Gliadel and 37 patients did not. Patients received radiotherapy with concomitant temozolomide followed by 5 consecutive days of temozolomide every month for 6 months. RESULTS: Overall median follow-up was 17.1 months; the median relapse-free survival (RFS) was 14 months with a RFS of 54% at 12 months, and 38% at 24 months. For patient with and without Gliadel, median and 1-year RFS were 12.9 months and 52% vs. 14 months and 42%, respectively (p = 0.89). According to pathology, Gliadel did not influence RFS of patients with Grade III or glioblastoma. However, for all patients, in multivariate analysis, non-methylated methylguanine methyltransferase (MGMT) was the only unfavorable prognostic factor of RFS (p = 0.017; HR 2.8; CI [1.2-7]). Median overall survival (OS) was 20.8 months; the OS rate at 12 months was 78.5%, and at 24 months 35.4%. For patients treated with and without Gliadel, median and 1-year OS were 20.6 months and 78.6% vs. 20.8 months and 78.4%, respectively. According to pathology, Gliadel did not influence OS of patients with Grade III or glioblastoma. For all patients, in multivariate analysis, unfavorable prognosticators for OS were non-methylated MGMT (p = 0.001; HR: 6.5; CI [2-20]) and irradiation dose <60 Gy (p = 0.02; HR: 6.3; CI [2-20]). With carmustine wafers, before irradiation, median gross tumor volume plus edema was 84 mL (27 229), whereas it was 68 mL (10-362) without carmustine (p = nonsignificant). Four cases of Grade 3 thrombopenia occurred, all in the carmustine wafer group. CONCLUSION: In patients with high-grade gliomas, adding Gliadel before performing a Stupp protocol did not improve survival. PMID- 21300472 TI - Optimal normal tissue sparing in craniospinal axis irradiation using IMRT with daily intrafractionally modulated junction(s). AB - PURPOSE: To develop a treatment technique for craniospinal irradiation using intensity-modulated radiotherapy (IMRT) with improved dose homogeneity at the field junction(s), increased target volume conformity, and minimized dose to the organs at risk (OARs). METHODS AND MATERIALS: Five patients with high-risk medulloblastoma underwent CT simulation in supine position. For each patient, an IMRT plan with daily intrafractionally modulated junction(s) was generated, as well as a treatment plan based on conventional three-dimensional planning (3DCRT). A dose of 39.6 Gy in 22 daily fractions of 1.8 Gy was prescribed. Dose volume parameters for target volumes and OARs were compared for the two techniques. RESULTS: The maximum dose with IMRT was <107% in all patients. V<95 and V>107 were <1 cm3 for IMRT compared with 3-9 cm3 for the craniospinal and 26 43 cm3 for the spinal-spinal junction with 3DCRT. These observations corresponded with a lower homogeneity index and a higher conformity index for the spinal planning target volume with IMRT. IMRT provided considerable sparing of acute and late reacting tissues. V75 for the esophagus, gastroesophageal junction, and intestine was 81%, 81%, and 22% with 3DCRT versus 5%, 0%, and 1% with IMRT, respectively. V75 for the heart and thyroid was 42% and 32% vs. 0% with IMRT. CONCLUSION: IMRT with daily intrafractionally modulated junction results in a superior target coverage and junction homogeneity compared with 3DCRT. A significant dose reduction can be obtained for acute as well as late-reacting tissues. PMID- 21300473 TI - Stereotactic radiotherapy for adrenal gland metastases: university of Florence experience. AB - PURPOSE: To evaluate a retrospective single-institution outcome after hypofractionated stereotactic body radiotherapy (SBRT) for adrenal metastases. METHODS AND MATERIALS: Between February 2002 and December 2009, we treated 48 patients with SBRT for adrenal metastases. The median age of the patient population was 62.7 years (range, 43-77 years). In the majority of patients, the prescription dose was 36 Gy in 3 fractions (70% isodose, 17.14 Gy per fraction at the isocenter). Eight patients were treated with single-fraction stereotactic radiosurgery and forty patients with multi-fraction stereotactic radiotherapy. RESULTS: Overall, the series of patients was followed up for a median of 16.2 months (range, 3-63 months). At the time of analysis, 20 patients were alive and 28 patients were dead. The 1- and 2-year actuarial overall survival rates were 39.7% and 14.5%, respectively. We recorded 48 distant failures and 2 local failures, with a median interval to local failure of 4.9 months. The actuarial 1 year disease control rate was 9%; the actuarial 1- and 2-year local control rate was 90%. CONCLUSION: Our retrospective study indicated that SBRT for the treatment of adrenal metastases represents a safe and effective option with a control rate of 90% at 2 years. PMID- 21300474 TI - Long-term outcomes from a prospective trial of stereotactic body radiotherapy for low-risk prostate cancer. AB - PURPOSE: Hypofractionated radiotherapy has an intrinsically different normal tissue and tumor radiobiology. The results of a prospective trial of stereotactic body radiotherapy (SBRT) for prostate cancer with long-term patient-reported toxicity and tumor control rates are presented. METHODS AND MATERIALS: From 2003 through 2009, 67 patients with clinically localized low-risk prostate cancer were enrolled. Treatment consisted of 36.25 Gy in 5 fractions using SBRT with the CyberKnife as the delivery technology. No patient received hormone therapy. Patient self-reported bladder and rectal toxicities were graded on the Radiation Therapy Oncology Group scale (RTOG). RESULTS: Median follow-up was 2.7 years. There were no grade 4 toxicities. Radiation Therapy Oncology Group Grade 3, 2, and 1 bladder toxicities were seen in 3% (2 patients), 5% (3 patients), and 23% (13 patients) respectively. Dysuria exacerbated by urologic instrumentation accounted for both patients with Grade 3 toxicity. Urinary incontinence, complete obstruction, or persistent hematuria was not observed. Rectal Grade 3, 2, and 1 toxicities were seen in 0, 2% (1 patient), and 12.5% (7 patients), respectively. Persistent rectal bleeding was not observed. Low-grade toxicities were substantially less frequent with QOD vs. QD dose regimen (p = 0.001 for gastrointestinal and p = 0.007 for genitourinary). There were two prostate specific antigen (PSA), biopsy-proven failures with negative metastatic workup. Median PSA at follow-up was 0.5 +/- 0.72 ng/mL. The 4-year Kaplan-Meier PSA relapse-free survival was 94% (95% confidence interval, 85%-102%). CONCLUSION: Significant late bladder and rectal toxicities from SBRT for prostate cancer are infrequent. PSA relapse-free survival compares favorably with other definitive treatments. The current evidence supports consideration of stereotactic body radiotherapy among the therapeutic options for localized prostate cancer. PMID- 21300475 TI - Enhancer of zeste homolog 2 overexpression in nasopharyngeal carcinoma: an independent poor prognosticator that enhances cell growth. AB - PURPOSE: As a key component of polycomb-repressive complex 2, enhancer of zeste homolog 2 (EZH2) represses target genes through histone methylation and is frequently overexpressed and associated with poor prognosis in common carcinomas. For the first time, we reported EZH2 expression and its biological and clinical significance in nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: In NPC cell lines and specimens, endogenous expression of EZH2 mRNA and protein was determined by semiquantitative reverse transcription-polymerase chain reaction and immunoblotting, respectively. To analyze the effect on cell growth, stable silencing of EZH2 was established in EZH2-expressing TW02 NPC cells with RNA interference. EZH2 immunolabeling was assessable for 89 primary NPC biopsy samples and correlated with clinicopathological variables, disease-specific survival (DSS), and overall survival (OS). RESULTS: Growth activity of TW02 cells was significantly suppressed (p < 0.001) with stable EZH2 silencing. Compared with normal nasopharyngeal tissue, expression levels of EZH2 transcript and protein were apparently upregulated in NPC specimens. As a continuous variable, higher EZH2 expression preferentially occurred in NPCs of T3 to T4 stages (p = 0.03) and significantly predicted inferior DSS (p = 0.0010) and OS (p = 0.004). The prognostic implications for DSS (p = 0.010) and OS (p = 0.006) still remained valid when using the median (>= 60%) of EZH2 immunolabeling index to dichotomize the cohort. In the multivariate model, higher EZH2 expression was an independent adverse factor of both DSS (p = 0.012) and OS (p = 0.011), along with American Joint Committee on Cancer Stages III to IV (p = 0.024 for DSS, p = 0.017 for OS). CONCLUSION: At least partly through promoting cell growth, EZH2 implicates disease progression, confers tumor aggressiveness, and represents an independent adverse prognosticator in patients with NPC. PMID- 21300476 TI - Cost-effectiveness analysis of stereotactic body radiotherapy and radiofrequency ablation for medically inoperable, early-stage non-small cell lung cancer. AB - PURPOSE: The standard management of medically inoperable Stage I non-small-cell lung cancer (NSCLC) conventionally has been fractionated three-dimensional conformal radiation therapy (3D-CRT). The relatively poor local control rate and inconvenience associated with this therapy have prompted the development of stereotactic body radiotherapy (SBRT), a technique that delivers very high doses of irradiation typically over 3 to 5 sessions. Radiofrequency ablation (RFA) has also been investigated as a less costly, single-day therapy that thermally ablates small, peripheral tumors. The cost-effectiveness of these three techniques has never been compared. METHODS AND MATERIALS: We developed a Markov model to describe health states of 65-year-old men with medically inoperable NSCLC after treatment with 3D-CRT, SBRT, and RFA. Given their frail state, patients were assumed to receive supportive care after recurrence. Utility values, recurrence risks, and costs were adapted from the literature. Sensitivity analyses were performed to model uncertainty in these parameters. RESULTS: The incremental cost-effectiveness ratio for SBRT over 3D-CRT was $6,000/quality adjusted life-year, and the incremental cost-effectiveness ratio for SBRT over RFA was $14,100/quality-adjusted life-year. One-way sensitivity analysis showed that the results were robust across a range of tumor sizes, patient utility values, and costs. This result was confirmed with probabilistic sensitivity analyses that varied local control rates and utilities. CONCLUSION: In comparison to 3D-CRT and RFA, SBRT was the most cost-effective treatment for medically inoperable NSCLC over a wide range of treatment and disease assumptions. On the basis of efficacy and cost, SBRT should be the primary treatment approach for this disease. PMID- 21300477 TI - Prostate specific antigen bounce is related to overall survival in prostate brachytherapy. AB - PURPOSE: To investigate the association between prostate specific antigen (PSA) bounce and disease outcome after prostate brachytherapy. METHODS AND MATERIALS: We analyzed 975 patients treated with (125)I implantation monotherapy between 1992 and 2006. All patients had tumor Stage <= 2c, Gleason score <= 7 prostate cancer, a minimum follow-up of 2 years with at least four PSA measurements, and no biochemical failure in the first 2 years. Median follow-up was 6 years. Bounce was defined as a PSA elevation of +0.2 ng/mL with subsequent decrease to previous nadir. We used the Phoenix +2 ng/mL definition for biochemical failure. Additional endpoints were disease-specific and overall survival. Multivariate Cox regression analysis was performed to adjust for potential confounding factors. RESULTS: Bounce occurred in 32% of patients, with a median time to bounce of 1.6 years. More than 90% of bounces took place in the first 3 years after treatment and had disappeared within 2 years of onset. Ten-year freedom from biochemical failure, disease-specific survival, and overall survival rates were, respectively, 90%, 99%, and 88% for the bounce group and 70%, 93%, and 82% for the no-bounce group. Only 1 patient (0.3%) died of prostate cancer in the bounce group, compared with 40 patients (6.1%) in the no-bounce group. Adjusted for confounding, a 70% biochemical failure risk reduction was observed for patients experiencing a bounce (hazard ratio 0.31; 95% confidence interval 0.20-0.48). CONCLUSIONS: A PSA bounce after prostate brachytherapy is strongly related to better outcome in terms of biochemical failure, disease-specific survival, and overall survival. PMID- 21300478 TI - Predicting pelvic lymph node involvement in current-era prostate cancer. AB - PURPOSE: The Roach formula [2/3 * prostate-specific antigen + (Gleason score--6) * 10], derived in 1993 during the early prostate specific antigen (PSA) screening era, has been used to predict the risk of pelvic lymph node involvement in patients with prostate cancer. In the current era of widespread PSA screening with a shift to earlier disease stages, there is evidence to suggest that the Roach score overestimates risk of nodal metastasis. This study retrospectively reviews the validity of this formula as a prediction tool. METHODS AND MATERIALS: We conducted a retrospective institutional review including men with clinical T1c T3 prostate cancer, with baseline PSA levels and biopsy-obtained Gleason scores who underwent radical prostatectomy with pelvic node dissection from 2001 through 2009 (N = 1,022). The predicted risk of nodal involvement was calculated for each patient using the Roach formula and then compared with actual rates following surgery. RESULTS: The study included 1,022 patients; 99.6% had clinical T1c/T2 disease, with a mean of 10.3 lymph nodes surgically evaluated. Overall, 42 patients (4.1%) had nodal metastasis. For every range of scores, the Roach formula overestimates the risk of nodal involvement. Observed nodal positivity was 1%, 6.3%, 10%, 15.2%, and 16.7% for Roach scores <= 10%, >10%-20%, >20%-30%, >30%-40%, and >40%, respectively. The Roach score overestimates the risk by approximately 4.5-fold in patients with scores <= 10%, by 2.5-fold for all scores between 10% and 40%, and by 4-fold for scores >40%. CONCLUSION: The Roach formula overpredicts the risk of pelvic nodal involvement in current-era prostate cancer patients undergoing regular PSA screening and with mainly T1c/T2 disease. Contemporary patients are much less likely to have nodal involvement for a given PSA and Gleason score. PMID- 21300479 TI - Redox protein expression predicts radiotherapeutic response in early-stage invasive breast cancer patients. AB - PURPOSE: Early-stage invasive breast cancer patients have commonly undergone breast-conserving surgery and radiotherapy. In a large majority of these patients, the treatment is effective; however, a proportion will develop local recurrence. Deregulated redox systems provide cancer cells protection from increased oxidative stress, such as that induced by ionizing radiation. Therefore, the expression of redox proteins was examined in tumor specimens from this defined cohort to determine whether such expression could predict response. METHODS AND MATERIALS: The nuclear and cytoplasmic expression of nine redox proteins (glutathione, glutathione reductase, glutaredoxin, glutathione peroxidase 1, 3, and 4, and glutathione S-transferase-theta, -pi, and -alpha) was assessed using conventional immunohistochemistry on a tissue microarray of 224 tumors. RESULTS: A high cytoplasmic expression of glutathione S-transferase-theta significantly correlated with a greater risk of local recurrence (p = .008) and, when combined with a low nuclear expression (p = .009), became an independent predictive factor (p = .002) for local recurrence. High cytoplasmic expression of glutathione S-transferase-theta also correlated with a worse overall survival (p = .009). Low nuclear and cytoplasmic expression of glutathione peroxidase 3 (p = .002) correlated with a greater risk of local recurrence and was an independent predictive factor (p = .005). These proteins did not correlate with tumor grade, suggesting their function might be specific to the regulation of oxidative stress rather than alterations of tumor phenotype. Only nuclear (p = .005) and cytoplasmic (p = .001) expression of glutathione peroxidase 4 correlated with the tumor grade. CONCLUSIONS: Our results support the use of redox protein expression, namely glutathione S-transferase-theta and glutathione peroxidase 3, to predict the response to radiotherapy in early-stage breast cancer patients. If incorporated into routine diagnostic tests, they have the potential to aid clinicians in their stratification of patients into more tailored treatment regimens. Future targeted therapies to these systems might improve the efficacy of reactive oxygen species-inducing therapies, such as radiotherapy. PMID- 21300480 TI - Dynamic MRI analysis of tumor and organ motion during rest and deglutition and margin assessment for radiotherapy of head-and-neck cancer. AB - PURPOSE: To quantify swallowing frequency and tumor and normal structure displacements during deglutition using dynamic magnetic resonance imaging (MRI) and to determine planning target volume (PTV) margins to account for resting and deglutition-induced displacements in patients with head-and-neck cancer (HNC). METHODS AND MATERIALS: Twenty-two patients with HNC were imaged in the treatment position using dynamic MRI. Sagittal images were acquired. Two-dimensional displacement was analyzed using contours of normal structures and GTV drawn for one swallowing event. Deglutition-induced displacements were quantified based on position change during deglutition relative to preswallow structure location for anterior (A), posterior (P), superior (S), and inferior (I) directions. Additional long-time MRI series were obtained from a subset of 11 patients while they were resting in order to determine swallowing frequency and duration. PTV margins to account for setup error, frequency and duration of deglutition, and resting and deglutition-induced GTV motion were calculated. RESULTS: Mean maximum resting displacements ranged from 1.5 to 3.1 mm for combined GTV subsites. Mean maximum swallowing GTV displacement for combined subsites ranged from 4.0 to 11.6 mm. Swallowing was nonperiodic, with a frequency ranging from 0 to 19 swallows over 12.8 min and mean swallow duration of 3.5 s. Based on the average swallowing characteristics in this cohort, the average PTV margins to account for setup error and tumor motion are estimated to be 4.7 mm anteriorly, 4.2 mm posteriorly, 4.7 mm inferiorly, and 6.0 mm superiorly. CONCLUSIONS: The measurable mean maximum resting displacement for the GTV indicates that tumor motion occurs even when the patient is not swallowing. Nonuniform margins should be used as a standard PTV margin that accounts for setup error and tumor motion in radiotherapy of HNC unless adaptive radiotherapy with respect to intrafraction tumor motion is performed. The PTV margin can be individualized to a single patient's swallowing characteristics or calculated as an average based on the swallowing data from the cohort. PMID- 21300481 TI - Heat shock protein 27-targeted heptapeptide of the PKCDelta catalytic V5 region sensitizes tumors with radio- and chemoresistance. AB - PURPOSE: Previous data suggest that the PKCdelta catalytic V5 (PKCdelta-V5) heptapeptide (HEPT) (FEQFLDI) binds HSP27 and blocks HSP27-mediated radio- or chemoresistance. Here we investigated further the in vivo function of the PKCdelta-V5 HEPT. METHODS AND MATERIALS: Labeling of HEPT with Cy5.5 or fluorescein isothiocyanate was performed to evaluate in vitro or in vivo distribution of HEPT. A clonogenic survival assay, flow cytometry, and Western blotting of cleaved caspase-3 were performed to determine in vitro sensitization effects of HEPT plus ionizing radiation (IR) versus IR alone or those of HEPT plus cisplatin(Cis) versus Cis alone. A nude mouse xenografting system was also applied to detect in vivo sensitizing effects of HEPT. RESULTS: HEPT efficiently bound to HSP27 and showed sensitization after combined treatment with IR versus treatment with Cis alone in NCI-H1299 lung carcinoma cells, with higher HSP27 expression, which was similar to that of combined treatment with IR or with Cis alone in NCI-H460 lung carcinoma cells with lower HSP27 expression. In vivo image analysis using Cy5.5-labeled HEPT showed that HEPT was retained in HSP27 overexpressing cancer cells after xenografting to nude mice. Combined treatment of HEPT with IR versus that with Cis alone in xenografted mice showed that HEPT increased radio- or chemosensitization in NCI-H1299 cells compared to that in mice xenografted with NCI-H460 cells. CONCLUSIONS: The novel PKCdelta-V5 HEPT may help overcome HSP27-mediated radio- or chemoresistance. PMID- 21300482 TI - Stage-to-stage comparison of preoperative and postoperative chemoradiotherapy for T3 mid or distal rectal cancer. AB - PURPOSE: To investigate, in a comparative analysis, the prognostic implications of postchemoradiotherapy (post-CRT) pathologic stage (ypStage) vs. postoperative pathologic stage (pStage) in rectal cancer. METHODS AND MATERIALS: Between May 2001 and December 2006, 487 patients with T3 mid or distal rectal cancer were analyzed retrospectively. Concurrent CRT was administered preoperatively (n = 364, 74.7%) or postoperatively (n = 123, 25.3%). The radiation dose was 50.4 Gy in 28 fractions. All patients underwent a total mesorectal excision and received adjuvant chemotherapy. Disease-free survival (DFS) was estimated using the Kaplan Meier method. Differences in DFS, stratified by ypStage and pStage, were compared using the log-rank test. RESULTS: For surviving patients, the median follow-up period was 68 months (range, 12-105 months). The 5-year local recurrence-free survival rate was not different, at 95.3% and 92.1% in preoperative and postoperative CRT groups, respectively (p = 0.402), but the 5-year distant metastasis-free survival rate was significantly different, at 81.6% (preoperative CRT) vs. 65.4% (postoperative CRT; p = 0.001). The 5-year DFS rate of 78.8% in the preoperative CRT group was significantly better than the 63.0% rate in the postoperative CRT group (p = 0.002). Post-CRT pathologic Stage 0-I occurred in 42.6% (155 of 364) of the patients with preoperative CRT. The 5-year DFS rates were 90.2% (ypStage 0-I), 83.5% (ypStage II), 77.3% (pStage II), 58.6% (ypStage III), and 54.7% (pStage III). The DFS rate of ypStage 0-I was significantly better than that of ypStage II or pStage II. Post-CRT pathologic Stage II and III had similar DFS, compared with pStage II and III, respectively. CONCLUSIONS: Disease-free survival predicted by each ypStage was similar to that predicted by the respective pStage. Improved DFS with preoperative vs. postoperative CRT was associated with the ypStage 0-I group that showed a similarly favorable outcome to pStage I rectal cancer. PMID- 21300483 TI - The role of pretreatment FDG-PET in nasopharyngeal carcinoma treated with intensity-modulated radiotherapy. AB - PURPOSE: Pretreatment with 2- [(18)F] fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET) was evaluated as a predictor of local failure-free survival (LFFS), disease-free survival (DFS), and overall survival (OS) in patients with nonkeratinizing nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT) alone or concurrently with chemotherapy (CCRT). PATIENTS AND METHODS: Seventy-five M0 NPC patients who received FDG-PET before treatment were analyzed. The primary tumor FDG uptake was measured as the maximum standardized uptake value (SUVmax). The LFFS, DFS, and OS were calculated by the Kaplan-Meier method, and the differences were evaluated on log-rank test. The prognostic significance was assessed by univariate and multivariate analyses. RESULTS: Eighteen patients received IMRT alone and 57 received CCRT. The mean SUVmax was significantly higher in 12 patients with locoregional or distant failure than in those without failure (p <0.001). On multivariate analysis, the SUVmax was the only significant variable for 5-year LFFS (p = 0.017) and DFS (p = 0.000) but not for OS (p = 0.065). CONCLUSION: SUVmax is a potential independent prognostic predictor of clinical outcomes in patients with nasopharyngeal carcinoma treated with IMRT alone or with CCRT. A high (18)F-FDG uptake (SUVmax >5) indicates poor outcome in patients with NPC. PMID- 21300484 TI - 3'-deoxy-3'-[18F]fluorothymidine PET quantification of bone marrow response to radiation dose. AB - PURPOSE: The purpose of this study was to quantify the relationship of bone marrow response to radiation dose, using 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT)-labeled uptake quantified in positron-emission tomography (PET) scans. METHODS AND MATERIALS: Pre- and post-Week 1 treatment [(18)F]FLT PET images were registered to the CT images used to create the radiation treatment plan. Changes in [(18)F]FLT uptake values were measured using profile data of standardized uptake values (SUVs) and doses along the vertebral bodies located at a field border where a range of radiation doses were present for 10 patients. Data from the profile measurements were grouped into 1 Gy dose bins from 1 to 9 Gy to compare SUV changes for all patients. Additionally, the maximum pretreatment, the post-Week 1 treatment, and the dose values located within the C6-T7 vertebrae that straddled the field edge were measured for all patients. RESULTS: Both the profile and the individual vertebral data showed a strong correlation between SUV change and radiation dose. Relative differences in SUVs between bins >1 Gy and <7 Gy were statistically significant (p < 0.01, two-sample t test). The reduction in SUV was approximately linear until it reached a reduction threshold of 75%-80% in SUV for doses greater than 6 Gy/week for both the dose-binned data and the vertebral maximum SUVs. CONCLUSIONS: The change in SUV observed in head and neck cancer patients treated with chemoradiation shows the potential for using [(18)F]FLT PET images for identifying active bone marrow and monitoring changes due to radiation dose. Additionally, the change in [(18)F]FLT uptake observed in bone marrow for different weekly doses suggests potential dose thresholds for reducing bone marrow toxicity. PMID- 21300485 TI - Comparison of 45 variable number tandem repeat (VNTR) and two direct repeat (DR) assays to restriction endonuclease analysis for typing isolates of Mycobacterium bovis. AB - Restriction endonuclease analysis (REA), developed 25 years ago for genotyping Mycobacterium bovis strains, is an important tool for bovine tuberculosis control in New Zealand. While REA gives excellent discrimination, it is technically difficult to perform compared to PCR-based typing systems which are faster and simpler to operate. Genotyping of M. bovis by the use of variable number tandem repeat loci (VNTR) and spoligotyping, either alone or together, has now become the preferred approach for typing M. bovis. Here, we evaluated the widest range of VNTR loci yet investigated for M. bovis, including two VNTR loci not previously studied, one of which (4155) had particular utility for characterizing New Zealand isolates. VNTR typing provided substantial geographical resolution of 26 of the most commonly found REA types and this was improved by the addition of two PCR assays based on parts of the direct repeat (DR) locus. Overall, 68 REA types of M. bovis common in New Zealand were discriminated into 33 VNTR/DR groups by using a minimum of nine VNTR and two DR assays. These 11 VNTR/DR assays concorded for three isolates each of 45 of the REA types but showed some variation with at least one of the VNTR/DR assays for the remaining 23 REA types. Major differences were found in allelic variation of some VNTRs between isolates from New Zealand and other countries, emphasizing the importance of adapting M. bovis typing systems to suit individual countries. PMID- 21300486 TI - Influence of the lipopolysaccharide structure of Salmonella enterica serovar Enteritidis on interactions with pig neutrophils. AB - The key process for immune response development is the recognition of bacteria by the immune system of the host based on the sensing of pathogen-associated molecular patterns (PAMP). One of the most important PAMP is the lipopolysaccharide (LPS) molecule, a complex molecule present in the outer membrane of Gram negative bacteria. In this study we were interested in how different parts of the LPS of Salmonella enterica serovar Enteritidis are recognized by porcine neutrophils. To this aim, we constructed S. Enteritidis mutants with rfaL and rfaC genes disabled in the attachment of the O-antigen and in the synthesis of the inner oligosaccharide core of LPS, respectively. We found that in the absence of serum, both the rfa mutants associated with neutrophils and stimulated them for reactive oxygen species (ROS) production significantly more than the wild-type strain. Addition of polymyxin B, which neutralized lipid A, the endotoxic moiety of LPS, effectively decreased the association of the wild type strain and the rfaC mutant with neutrophils, but not the rfaL mutant. This indicates that the oligosaccharide core newly exposed on the surface in the rfaL mutant, protected from interaction in the wild-type strain by the O-antigen but completely absent in the rfaC mutant, may represent a new ligand for porcine neutrophils that cannot be neutralized by polymyxin B. PMID- 21300487 TI - Modeling of the human fetal skull base growth: interest in new volumetrics morphometric tools. AB - BACKGROUND: Research on the skull base is important to improve our understanding of the growth and development of the modern human skull. To study the growth of the human fetal skull base, we assessed a new geometric morphometric tool, which does not require the use of bone landmarks. MATERIAL AND METHODS: Seven dry fetal skulls of an estimated gestational age ranging from 15 to 27 weeks were studied. Each skull was scanned using a standard CT scan and the image sets were post processed to extract volumetric data by segmenting the skull base into predefined regions of interest. Our method of analysis was based on the inertial properties of reconstructed volumes. RESULTS: The volumetric study of the skulls highlighted an asynchronous speed of growth between the pre and post-chordal parts of the skull base whose preferential growth are in the vertical and horizontal planes. We also found different speeds of growth in the pre-chordal part depending on the type of ossification (endochondral or membranous). The overall shape of the skull base bones were preserved during the period studied except for the petrous pyramids. The expansion of bone parts was isometric with reference to a central point that was located at the intrasphenoidal synchondrosis. Finally, the analysis of the basicranial angles corroborated data from the literature in the sagittal plane and allowed their study also in the frontal and horizontal planes. CONCLUSIONS: This three-dimensional volumetric approach is a necessary complement to studies that are performed in the sagittal plane and are based on the identification of landmarks. The geometric morphometric method used by authors permitted to obtain original informations on the growth kinetics and bone tridimensional movements of the human fetal skull base. PMID- 21300488 TI - Novel non-identical MECP2 mutations in Rett syndrome family: a rare presentation. AB - INTRODUCTION: Rett syndrome (RS), an X-linked neurodevelopmental disorder and the common cause of mental retardation in females, is caused by methyl CpG binding protein 2 (MECP2) gene mutations with a frequency of more than 95% in classical Rett patients. Majority of RS cases are sporadic but few familial cases caused by either skewed X-chromosome inactivation in healthy female carriers or mosaicism in male carriers are also reported. Most of the times, the mutation carried in a family is the same as found in affected child. METHODS AND RESULTS: Here we report a unique family carrying non-identical MECP2 mutations in exon 2 wherein the proband with classical RS was carrying a de-novo early truncating frameshift mutation while her asymptomatic mother was carrying a missense mutation, both predicted as pathogenic mutations. CONCLUSIONS: These findings further validate the importance of MECP2 mutation screening in parents of all mutation positive patients and careful evaluation of the pathogenicity of the mutation found in asymptomatic carriers before providing genetic counseling to the family. The results also propose the role of other factors including other gene mutations, environmental and epigenetics factors in modifying the expression of MECP2 mutations. PMID- 21300489 TI - Research progress on resting state fMRI of epilepsy. AB - As a study method of resting state network (RSN), resting state functional MRI (rfMRI) can be applied to detect low frequency fluctuate (LFF) in various cerebral areas based on resting state blood oxygen level dependence (BOLD) signals; and it is easier and more consistent than task-related fMRI. The development, features and methods of rfMRI as well as the application in epilepsy were reviewed in this article. PMID- 21300490 TI - Maternal micronutrients (folic acid and vitamin B(12)) and omega 3 fatty acids: implications for neurodevelopmental risk in the rat offspring. AB - Altered maternal micronutrients (folic acid, vitamin B(12)) are suggested to be at the heart of intra-uterine programming of adult diseases. We have recently described interactions of folic acid, vitamin B(12) and docosahexaenoic acid in one carbon metabolism that is considered to play a key role in regulation oxidative stress and chromatin methylation. However its impact on fetal oxidative stress and brain fatty acid levels has been relatively unexplored. The present study examined the effect of imbalance in maternal micronutrients (folic acid and vitamin B(12)) and maternal omega 3 fatty acid supplementation on oxidative stress parameters and brain fatty acids and in the offspring at birth. Pregnant female rats were divided into six groups at two levels of folic acid both in the presence and absence of vitamin B(12). Both the vitamin B(12) deficient groups were supplemented with omega 3 fatty acid. Oxidative stress marker (malondialdehyde) and polyunsaturated fatty acid profiles in plasma and brain were analyzed in dam and offspring at d20. Our results for the first time indicate that imbalance in maternal micronutrients (excess maternal folic acid supplementation on a B(12) deficient diet) increases (p<0.01) oxidative stress in both mother and pups. This increased maternal oxidative stress resulted in lower (p<0.01) fetal brain DHA levels. Omega 3 fatty acid supplementation was able to restore (p<0.05) the levels of brain DHA in both the vitamin B(12) deficient groups. Our data has implications for implications for neurodevelopmental disorders since micronutrients and DHA are important modulators for neural functioning. PMID- 21300491 TI - Evaluation of a new computerized analysis system developed for the processing of CT follow-up scans after EVR of infrarenal aneurysm. AB - PURPOSE: The aim of this retrospective study was to present a new computerized analysis system developed for the evaluation of follow-up CT scans after endovascular repair (EVR) of infrarenal aneurysm and to compare it to the conventional evaluation method as regards preciseness and ease of application. The system is based on the extraction of the surface of the stent-graft (SG) and that of the spinal canal and the overlay of surfaces obtained at different points in time. MATERIALS AND METHODS: A total of 116 CT follow-up data sets obtained from 49 patients after EVR of infrarenal aneurysm were evaluated using both, the conventional method and the new computerized system. Two parameters were analyzed: SG length and the distance between the most ventral point of the SG and the vertebral column. The correlation between the results of the two methods and the correlation between the results obtained by two independent observers (radiologist and lay person) using the new system were assessed by statistical analysis. RESULTS: Comparison of the two methods yielded a very high correlation for both parameters, (correlation coefficients of around 0.9 and p<0.001). Comparison of the results obtained by the two observers yielded an equally high correlation (correlation coefficients of around 0.9 and p<0.001). CONCLUSION: Our results show that the new computerized system is as precise and reliable as the conventional method, but allows better visualization and quantification of SG changes by surface overlay. Moreover, it is easier to apply and less time consuming and can be easily integrated into existing systems. PMID- 21300492 TI - HRCT findings in idiopathic pneumonia syndrome with documentation of the disease course. AB - OBJECTIVE: To analyze extent and patterns of lung involvement in patients with idiopathic pneumonia syndrome (IPS) following allogeneic stem cell transplantation (SCT), and demonstrate their course during therapy. METHODS: 14 consecutive patients (age 29-64 years, mean 46.2 years) who experienced IPS after allogeneic SCT (as defined by current guidelines of NIH) were treated with either steroids (n = 5), or steroids and the TNF-alpha blocker etanercept in more severe cases (n = 9). CT-scans obtained before, during and after IPS were evaluated retrospectively. Quantification of pulmonary involvement was performed by visual estimation. Surveillance time ranged from 21 to 914 days with a total of 99 CT scans (2-12 CT-scans per patient) obtained. RESULTS: IPS was mainly confined to the central lung regions (71%) with a bilateral and symmetric distribution (71%). Ground-glass opacity (93%) was the prominent CT-morphologic correlate, whereas concomitant consolidation of lung areas (noted in 43% of patients at the time of maximum infiltrates) only occurred in severe courses of IPS (p<0.01). Favourable courses (50%) showed an earlier peak with respect to extent and CT-attenuation of IPS infiltrates (p<0.01) followed by a rapid decline (median IPS duration 8 days) whereas a significantly more protracted course was observed in severe (unfavorable) cases (median IPS duration 52 days, p = 0.01). The death rate in the first and the latter groups (all of the severe cases receiving TNF blockage) was 0% and 43%, respectively. Pulmonary sequelae were recorded in almost all patients during follow-up with fibrotic residues. CONCLUSION: HRCT-features of IPS are non-specific, but predictable. Response monitoring in IPS can be well accomplished via HRCT and the course of pulmonary infiltrates heralds patient's outcome. PMID- 21300493 TI - Temporomandibular joint (TMJ) pain revisited with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). AB - PURPOSE: We aimed to assess the contrast enhancement patterns of the retrodiscal tissue with dynamic contrast-enhanced MR imaging (DCE-MRI) with respect to different temporomandibular joint disc pathologies. Additionally, we questioned the relationship between the temporomandibular joint (TMJ) pain and the contrast enhancement pattern of the retrodiscal tissue regardless of the TMJ disc position. MATERIALS AND METHODS: 52 joints of 26 patients (4 males and 22 females) who have pain in at least at one of their TMJ were included in this study. For the qualitative analysis, the joints were divided into four groups in terms of their disc positions: normal (1), partially displaced with or without reduction (2), totally dislocated with reduction (3) and totally dislocated without reduction (4). Besides, two different joint groups were constituted, namely the painful group and painless group according to the clinical findings without taking the TMJ disc positions into account. Quantitative analyses were made by means of measuring signal intensity ratios (SI) ratio at the retrodiscal tissue (from internal side and external side of the each joint) using DCE-MRI and these measurements were analyzed with paired samples t test to define the difference between the measurements. At the second stage, the time-dependent arithmetical mean values of the SI ratios were calculated for each joint group and significant differences between the groups were questioned using analysis of variance (ANOVA) test. Besides, painful and painless groups which were classified on the basis of the clinical data were compared according to the mean SI ratios found for each joint and the significant differences between these two groups were assessed by means of Student's T test. The results were assessed in 95% confidence interval where the significance level was p<0.05. RESULTS: A significant difference was observed between the internal and external contrast enhancement of the joints with partial displacement. Another significant difference was found between the average time versus SI ratio curves of the four groups. In consequence of the comparison made between the joints classified as painful and painless on the basis of the clinical data, one more significant difference was observed according to the mean SI ratios of the groups without taking the TMJ disc position into account. CONCLUSION: The contrast enhancement patterns in the retrodiscal tissues of the painful joints showed significant differences in comparison with the painless joints. This result supports the hypothesis defending that inflammation and increased vascularity are responsible from the TMJ pain. Besides, the measurements from the retrodiscal tissues of the joints with partial displacement show significant difference between the signals of the displaced and non-displaced parts of the joints. Dynamic contrast-enhanced imaging revealed that different disc malpositions create different contrast enhancement patterns. On this basis, it is assessed that the types of the disc malpositions, which are believed to be acquired pathologies, are correlated with the retrodiscal inflammation degrees. PMID- 21300494 TI - Clinic application of Epub of medical imaging film in CT workflow. AB - OBJECTIVE: To investigate the clinical effects of the Epub of medical imaging film (EMIF) in CT workflow. METHODS: All experiments were approved by the ethics committee of the local district. An EMIF application is fully implemented in PACS according to the DICOM 3.0 standard. For a statistical comparison in the effects of the EMIF in CT workflow, consecutive 50,000 CT hardcopy film prints have been randomly selected before and after the EMIF application in PACS, respectively. The role of the EMIF in the application of hardcopy films, the clinic practice, the integrality of the quality control data archived in PACS/RIS and so on is investigated. RESULTS: For consecutive 50,000 CT hardcopy films before vs. after the EMIF application respectively, the counts of wasted films are 21 vs. 14 sheets due to the hardware problem, 28 vs. 0 sheets owing to operation errors, and 24 vs. 0 sheets caused by serious defects in image layout. Reissuing films for lost films and other special needs is 60 vs. 55 sheets. The average reissuing film time for each case is 16.97+/-6.14 vs. 4.36+/-1.26 min (t=5.94, p<0.01). The EMIF application has offered more convenience for medical viewing and reviewing, and has enhanced the integrality of the quality control data archived in PACS/RIS (chi2=320.835, P<0.01). CONCLUSION: EMIF application in clinical healthcare can help enhance the function of PACS/RIS, and improve the quality and efficiency in CT routine work. PMID- 21300495 TI - Changes in cerebral hemodynamics after carotid stenting of symptomatic carotid artery. AB - PURPOSE: To evaluate changes in cerebral hemodynamics after carotid stenting of symptomatic carotid artery in the patients who underwent ischemic stroke caused by carotid artery stenosis. METHODS: Twenty patients with unilateral symptomatic carotid artery stenosis received brain computer tomography perfusion (CTP) scan a week before and a week after carotid artery stenting. Three absolute values including mean transit time (MTT), cerebral blood volume (CBV), and cerebral blood flow (CBF) were acquired and analyzed by use of the post-processing software. Six vascular territories such as ACA territory, MCA territory, PCA territory, basal ganglia, watershed between ACA and MCA territory (frontal watershed), watershed between MCA and PCA territory (posterior watershed) were chosen for comparison. Relative parameter values were defined as rCBF (relative CBF), rCBV (relative CBV), rMTT (relative MTT) through comparing absolute values in symptomatic hemispheres to absolute values in asymptomatic hemispheres. The relative perfusion parameter values before treatment were compared with post treatment values. These analyses were performed by using the paired t test. RESULTS: The mean rMTT decreased significantly in ACA territory, MCA territory and two watershed after treatment, while the mean rCBF increased significantly in those areas after treatment. But the mean rCBV had no significant changes in all six vascular territories. In PCA territory, all the parameters had no significant changes. CONCLUSION: Carotid artery stenting yields satisfactory cerebral perfusion in ACA territory, MCA territory, basal ganglia and two watersheds. PMID- 21300496 TI - Assessment of cerebral circulation in normal fetuses by three-dimensional power Doppler ultrasonography. AB - OBJECTIVE: To assess the three-dimensional power Doppler ultrasonography (3D power Doppler) vascular indices in the middle cerebral artery (MCA), anterior cerebral artery (ACA) and posterior cerebral artery (PCA) territories. METHODS: A cross-sectional study was carried out on 111 normal pregnancies between 26 and 34 weeks. The MCA, ACA and PCA territories closest to the transducer were scanned and volumes were calculated by using the VOCAL (Virtual Organ Computer-aided Analysis) program. The 3D power Doppler indices--vascularization index (VI), flow index (FI) and vascularization-flow index (VFI) were calculated. Scatter graphs, Pearson correlation coefficients (r) and linear regression models were used. RESULTS: Only the FI-MCA (r=0.38 and p<0.001), VFI-MCA (r=0.23 and p=0.016) and FI-PCA (r=0.191 and p=0.040) had a low correlation with gestational age. The other 3D power Doppler indices VI-MCA (r=0.153 and p=0.150), VI-ACA (r=0.105 and p=0.271), FI-ACA (r=0.154 and p=0.106), VFI-ACA (r=0.134 and p=0.161), VI-PCA (r=0.105 and p=0.270) and VFI-PCA (r=0.126 and p=0.180) showed no statistically significant correlation with gestational. CONCLUSION: It was observed a low correlation between gestational age and the FI-MCA, VFI-MCA and FI-PCA. PMID- 21300497 TI - Branching patterns of the main portal vein: effect on estimated remnant liver volume in preoperative evaluation of donors for liver transplantation. AB - OBJECTIVES: To compare estimated remnant liver volume (ERLV) ratios among the major main portal vein (MPV) variants. METHODS: Eighty-five potential donors underwent multidetector CT examination. Arterial, portal and hepatic venous phase images were obtained. CT volumetric measurements were performed by using summation-of-area method. MPV variants were classified into three groups. In type 1 (group 1), the MPV branches into the right portal vein (RPV) and the left portal vein (LPV). In type 2 (group 2), the MPV trifurcates into the right anterior portal vein (RAPV), right posterior portal vein (RPPV) and LPV. In type 3 (group 3), the RPPV arises from the MPV as a first branch, and the RAPV emerges directly from the LPV. RESULTS: No differences were observed between groups 1 and 2 with respect to ERLV ratios. However, significant differences were discovered between groups 1 and 3 and between groups 2 and 3 (p<0.001 and p<0.05, respectively). CONCLUSIONS: The ERLV proportions in the donors with a type 3 MPV variation were significantly lower than those in the donors with type 1 and type 2 MPV variations and six (31.6%) donors in group 3 presented an ERLV percentage below 30% of the total liver volume. PMID- 21300498 TI - Magnetic resonance imaging evaluation of residual ductal carcinoma in situ following preoperative chemotherapy in breast cancer patients. AB - OBJECTIVES: To retrospectively evaluate the ability of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) in helping to distinguish between lesions with and without residual ductal carcinoma in situ (DCIS) in patients showing no residual invasive cancer after preoperative chemotherapy. METHODS: DCE-MR images of 46 consecutive breast cancer patients (mean age, 47 years; range, 30-69 years) with no residual invasive cancer (15 had residual DCIS and 31 had no residual DCIS) following preoperative chemotherapy and surgery were blindly reviewed and categorized by two radiologists in consensus. Thereafter, DCE-MRI findings that could be helpful in distinguishing lesions with and without residual DCIS were analyzed. RESULTS: When any enhancement was present, 93% (14 of 15) sensitivity and 35% (11 of 31) specificity for the detection of residual DCIS on post chemotherapy MRI were achieved. Although 65% (20 of 31) of lesions without residual cancer had some enhancing findings, the lesion to fibroglandular signal intensity ratio showed 86.7% (13 of 15) sensitivity and 83.9% (26 of 31) specificity with an Az value of 0.854 (95% confidence interval: 0.718, 0.940) when a cut-off point of a ratio of 1.34 was used. CONCLUSION: DCE-MRI has the potential in distinguishing between lesions with and without residual DCIS in patients showing no invasive cancer after preoperative chemotherapy. PMID- 21300499 TI - Low field MR imaging of sellar and parasellar lesions: experience in a developing country hospital. AB - BACKGROUND: Magnetic resonance imaging (MRI), an advancement which followed computed tomography (CT) is expensive and inaccessible in most developing countries. However it is the procedure of choice in evaluating sellar and parasellar lesions. Its major advantages are its superior soft tissue contrast differentiation, its capacity for multiplanar imaging and nonexistence of ionising radiation. Its use is relatively new in Nigeria, a developing economy in Africa. Since its introduction in 2005, it has been utilised extensively for neuroimaging at the University College Hospital (UCH), Ibadan; a large hospital in south-western Nigeria. OBJECTIVE: To review the role and pattern of low field MR Imaging in sellar and parasellar lesions presenting to a tertiary care centre in Nigeria. METHODS: All 62 patients with clinically suspected sellar and parasellar masses, referred to the Department of Radiology, UCH Ibadan for MRI between December 2006 and January 2010 were retrospectively analysed. The examinations were performed using an open 0.2T permanent magnet MR unit. T1W, T2W, T2/FLAIR, TOF and T1W post gadolinium DTPA sequences of the sellar region were obtained. RESULTS: Of the 62 patients, there were 27 males and 35 females. The modal age group was 40-49 years with a mean age of 39.94 years (+/-16.65 years). Twenty-four cases (38.7%) had histological diagnosis, of which 20 (83.3%) were consistent with initial MRI diagnosis. Pituitary adenomas were the commonest (58.06%) lesions of the sellar and parasellar regions. Others include parasellar meningiomas, cranipharyngiomas, and giant aneurysms. Headache and visual impairment were the major presenting features and showed no significant correlation with tumour size. CONCLUSION: The use of low field MRI in the diagnostic evaluation of patients with suspected sellar or parasellar lesions in developing countries of low economic resource is commendable as it provides beneficial outcomes in management. PMID- 21300500 TI - Sonography-guided percutaneous microwave ablation of intrahepatic primary cholangiocarcinoma. AB - OBJECTIVE: To evaluate the efficacy and safety of sonography-guided percutaneous microwave ablation of intrahepatic primary cholangiocarcinoma. MATERIALS AND METHODS: From May 2006 to March 2010, 15 patients (11 men, 4 women; mean age, 57.4 years) with 24 histologically proven intrahepatic primary cholangiocarcinoma lesions (mean tumor size, 3.2+/-1.9 cm; range, 1.3-9.9 cm) were treated with microwave ablation. RESULTS: Thirty-eight sessions were performed for 24 nodules in 15 patients. The follow-up period was 4-31 months (mean, 12.8+/-8.0 months). The ablation success rate, the technique effectiveness rate, and the local tumor progression rate were 91.7% (22/24), 87.5% (21/24), and 25% (6/24) respectively according to the results of follow-up. The cumulative overall 6, 12, 24 month survival rates were 78.8%, 60.0%, and 60.0%, respectively. Major complication occurred including liver abscess in two patients (13.3%) and needle seeding in one patient (6.7%). Both complications were cured satisfied with antibiotic treatment combined to catheter drainage for abscess and resection for needle seeding. The minor complications and side effects were experienced by most patients which subsided with supportive treatment. CONCLUSION: Microwave ablation can be used as a safe and effective technique to treat intrahepatic primary cholangiocarcinoma. PMID- 21300501 TI - Neurochemical-structural changes evaluation of brain in patients with obstructive sleep apnea syndrome. AB - PURPOSE: To evaluate neurochemical and structural changes in the patients with newly diagnosed obstructive sleep apnea syndrome (OSAS) by MR spectroscopy (MRS), T2 relaxometry, and diffusion weighted imaging (DWI). MATERIAL AND METHODS: Following the acquisition of routine cranial MR, MRS, T2 relaxometry, and DWI images; spectroscopic metabolite ratios and DWI-T2 relaxometry findings of the thalami, hippocampi, frontal white matter (FWM) and frontal cortex of 24 OSAS patients and 9 controls were statistically compared. The relationship between two groups was evaluated with Mann-Whitney test. RESULTS: Spectroscopic measurements in the frontal cortex and frontal white matter of the OSAS patients revealed significantly lower NAA/Cr ratios than those of the control group (P=0.004 and P=0.006, respectively). The measurements in the frontal white matter of the OSAS patients exhibited significantly lower NAA/Cho ratios compared with those of the control group (P=0.005). Thalamic Cho/Cr ratios of the patient group were significantly higher than those of the control group (P=0.002). In terms of the ADC-T2 relaxometry values, there was no significant relationship between the patient and the control groups (P>0.05). CONCLUSION: MRS is a useful and non invasive modality in showing neurochemical changes in various regions of the brain but our data does not show any change on diffusion weighting or T2 quantification in the OSAS group. DWI and T2 relaxometry appear to be not effective techniques to evaluate the brain structural changes of the patients with newly diagnosed OSAS. PMID- 21300502 TI - Utility of screening computed tomography of chest, abdomen and pelvis in patients after heart transplantation. AB - INTRODUCTION: Malignancy is a late cause of mortality in heart transplant recipients. It is unknown if screening computed tomography scan would lead to early detection of such malignancies or serious vascular anomalies post heart transplantation. METHODS: This is a single center observational study of patients undergoing surveillance computed tomography of chest, abdomen and pelvis at least 5 years after transplantation. Abnormal findings, included pulmonary nodules, lymphadenopathy and intra-thoracic and intra-abdominal masses and vascular anomalies such as abdominal aortic aneurysm. The clinical follow up of each of these major abnormal findings is summarized. RESULTS: A total of 63 patients underwent computed tomography scan of chest, abdomen and pelvis at least 5 years after transplantation. Of these, 54 (86%) were male and 9 (14%) were female. Mean age was 52+/-9.2 years. Computed tomography revealed 1 lung cancer (squamous cell) only. Non specific pulmonary nodules were seen in 6 patients (9.5%). The most common incidental finding was abdominal aortic aneurysms (N=6 (9.5%)), which necessitated follow up computed tomography (N=5) or surgery (N=1). Mean time to detection of abdominal aortic aneurysms from transplantation was 14.6+/-4.2 years. Mean age at the time of detection of abdominal aortic aneurysms was 74.5+/ 3.2 years. CONCLUSION: Screening computed tomography scan in patients 5 years from transplantation revealed only one malignancy but lead to increased detection of abdominal aortic aneurysms. Thus the utility is low in terms of detection of malignancy. Based on this study we do not recommend routine computed tomography post heart transplantation. PMID- 21300503 TI - Percutaneous excisional biopsy of clinically benign breast lesions with vacuum assisted system: comparison of three devices. AB - PURPOSE: The aim of this study was to compare three devices in percutaneous excisional biopsy of clinically benign breast lesions in terms of complete excision rate, duration of procedure and complications. MATERIALS AND METHODS: In a retrospective study from March 2005 to May 2009, 983 lesions underwent ultrasound-guided excisional biopsy with three vacuum-assisted systems, respectively. The lesions were category 3 lesions as determined by ultrasound imaging according to Breast Imaging Reporting and Data System (BI-RADS) (n=951) or had been confirmed as benign by a previous core needle biopsy (n=32). The completely excision rate, duration of procedure and complications (hematoma, pain and ecchymosis) were recorded. RESULTS: 99.7% (980/983) lesions were demonstrated to be benign by pathology after percutaneous excisional biopsy. The overall complete excision rate was 94.8% (932/983). In lesions whose largest diameter equal to or larger than 1.5cm, the complete excision rates of EnCor((r)) group (97.8%, 348/356) and Mammotome((r)) group (97.2%, 139/143) were significantly higher than that of Vacora((r)) group (91.9%, 445/484) (P<0.05). The EnCor((r)) group (6.6+/-6.5min) had a significant less duration than Mammotome((r)) (10.6+/ 9.3min) and Vacora((r)) group (25.6+/-23.3min) (P<0.05). Hematoma occurred more in EnCor((r)) group and Mammotome((r)) group than in Vacora((r)) group (P<0.05). CONCLUSIONS: All these three vacuum-assisted systems are highly successful for excisional biopsy of benign breast lesions. PMID- 21300504 TI - Evaluation of contrast medium enhancement and [(18)F]-FDG uptake of liver metastasis in PET/CT prior to therapy. AB - OBJECTIVE: To evaluate the contrast medium enhancement and [(18)F]-FDG uptake of liver metastases in patients suffering from colon or breast carcinoma prior to therapy. MATERIAL AND METHODS: PET/CT (Philips Gemini) with 200MBq [(18)F]-FDG and contrast medium was performed in 50 patients with colon and 39 patients with breast carcinoma. Lesions were characterized with the presence or the absence of a rim enhancement. The area size, the HU(mean), HU(max), SUV(mean), SUV(max) of the lesion and of the liver were determined. The standard uptake values (SUVs) were correlated with the tumor markers CEA and CA 15-3. RESULTS: The lesions of colon carcinoma had HU(mean)-values of 70.7+/-19.2 and of breast carcinoma 88.1+/ 21.7 (p<0.0001). In breast cancer the SUV(mean) was 3.9+/-1.3 versus 4.4+/-1.9 in colon carcinoma (p=0.0182). Lesion of colon carcinoma with rim enhancement had a significantly higher SUV(mean) (4.4+/-1.5 versus 3.6+/-1.2; p=0.001) and SUV(max) (6.7+/-2.6 versus 5.1+/-2.1; p=0.000) than lesions without a rim enhancement. A good correlation between tumor markers and SUVs(max) could be found in both tumor groups; r=0.83 (p<0.01) for colon carcinoma and r=0.82 (p<0.01) for breast carcinoma. CONCLUSIONS: The rim enhancement of the lesions in colon carcinoma indicate a significantly higher SUV. PMID- 21300505 TI - Potential role of combined FDG PET/CT & contrast enhancement MRI in a rectal carcinoma model with nodal metastases characterized by a poor FDG-avidity. AB - PURPOSE: To investigate the additional role of MRI contrast enhancement (CE) in the primary tumor and the FDG uptake at PET in the lymph-node metastases. MATERIALS AND METHODS: A model of colorectal cancer induced by orthotopic HT-29 cells microinjection, producing pelvic lymph node metastases, was assessed using CE-MRI and FDG-PET. Histology and GLUT-1 immunohistochemistry were performed on primary tumors and iliac lymph nodes. RESULTS: Primary tumors were characterized by low FDG-uptake but high CE-MRI, particularly at tumor periphery. Undetectable FDG-uptake characterized the metastatic lymph-nodes. Histology revealed large stromal bundles at tumor periphery and a dense network of stromal fibers and neoplastic cells in the inner portion of the tumors. Both primary tumors and positive lymph nodes showed poor GLUT-1 staining. CONCLUSION: Our data support the complementary role of MRI-CE and FDG PET in some types of carcinomas characterized by abundant cancer-associated stroma and poor FDG avidity consequent to poor GLUT-1 transported. In these tumors FDG-PET alone may be not completely adequate to obtain an adequate tumor radiotherapy planning, and a combination with dual CE-MRI is strongly recommended. PMID- 21300506 TI - Precision and accuracy in CT attenuation measurement of vascular wall using region-of-interest supported by differentiation curve. AB - OBJECTIVES: To evaluate the precision and accuracy in CT attenuation measurement of vascular wall using region-of-interest (ROI) supported by differentiation curves. STUDY DESIGN: We used vascular models (actual attenuation value of the wall: 87HU) with wall thicknesses of 1.5, 1.0, or 0.5mm, filled with contrast material of 250, 348, or 436HU. The nine vascular models were scanned with a 64 detector CT. The wall attenuation values were measured using three sizes (diameter: 0.5, 1.0, and 1.5mm) of ROIs without differentiation curves. Sixteen measurements were repeated for each vascular model by each of two operators. Measurements supported by differentiation curves were also performed. We used analyses of variance with repeated measures for the measured attenuations for each size of the ROI. RESULTS: Without differentiation curves, there were significant differences in the attenuation values of the wall among the three densities of contrast material, and the attenuation values tended to be overestimated more as the contrast material density increased. Operator dependencies were also found in measurements for 0.5- and 1.5-mm thickness models. With differentiation curves, measurements were not possible for 0.5- and 1.0-mm thickness models. Using differentiation curves for 1.5-mm thickness models with a ROI of 1.0- or 1.5-mm diameter, the wall attenuations were not affected by the contrast material densities and were operator independent, measuring between 75 and 103HU. CONCLUSIONS: The use of differentiation curves can improve the precision and accuracy in wall attenuation measurement using a ROI technique, while measurements for walls of <=1.0mm thickness are difficult. PMID- 21300507 TI - Diversity and dynamics of bacterial populations during spontaneous sorghum fermentations used to produce ting, a South African food. AB - Ting is a spontaneously fermented sorghum food that is popular for its sour taste and unique flavour. Insight of the microbial diversity and population dynamics during sorghum fermentations is an essential component of the development of starter cultures for commercial production of ting. In this study, bacterial populations associated with spontaneous sorghum fermentations were examined using a culture-independent strategy based on denaturing gradient gel electrophoresis and sequence analysis of V3-16S rRNA gene amplicons, and a culture-dependent strategy using conventional isolation based on culturing followed by 16S rRNA and/or pheS gene sequence analysis. The entire fermentation process was monitored over a 54 h period and two phases were observed with respect to pH evolution and microbial succession. The first phase of the process (0-6h) was characterized by relatively high pH conditions and the presence of Enterococcus mundtii, albeit that this species was only detected with the culture-dependent approach. The second phase of the fermentation process (12-54 h) was characterized by increased acidity and the predominance of a broader range of lactic acid bacteria, including Lactococcus lactis, Lactobacillus fermentum, Lactobacillus plantarum, Lactobacillus rhamnosus, Weissella cibaria, Enterococcus faecalis, and a close relative of Lactobacillus curvatus, as well as some members of the Enterobacteriaceae family. The Lb. curvatus-like species was only detected with PCR-DGGE, while the majority of the other species was only detected using the culture-dependent approach. These findings highlighted the fact that a combination of both approaches was essential in revealing the microbial diversity and dynamics during spontaneous sorghum fermentations. PMID- 21300508 TI - Phenotypic and genotypic analyses of lactic acid bacteria in local fermented food, breast milk and faeces of mothers and their babies. AB - Lactic acid bacteria (LAB) are generally accepted as beneficial to the host and their presence is directly influenced by ingestion of fermented food or probiotics. While the intestinal lactic microbiota is well-described knowledge on its routes of inoculation and competitiveness towards selective pressure shaping the intestinal microbiota is limited. In this study, LAB were isolated from faecal samples of breast feeding mothers living in Syria, from faeces of their infants, from breast milk as well as from fermented food, typically consumed in Syria. A total of 700 isolates were characterized by genetic fingerprinting with random amplified polymorphic DNA (RAPD) and identified by comparative 16S rDNA sequencing and Matrix Assisted Laser Desorption Ionization-Time-Of-Flight Mass Spectrometry (MALDI-TOF-MS) analyses. Thirty six different species of Lactobacillus, Enterococcus, Streptococcus, Weissella and Pediococcus were identified. RAPD and MALDI-TOF-MS patterns allowed comparison of the lactic microbiota on species and strain level. Whereas some species were unique for one source, Lactobacillus plantarum, Lactobacillus fermentum, Pediococcus pentosaceus and Lactobacillus brevis were found in all sources. Interestingly, identical RAPD genotypes of L. plantarum, L. fermentum, L. brevis, Enterococcus faecium, Enterococcus faecalis and P. pentosaceus were found in the faeces of mothers, her milk and in faeces of her babies. Diversity of RAPD types found in food versus human samples suggests the importance of host factors in colonization and individual host specificity, and support the hypothesis that there is a vertical transfer of intestinal LAB from the mother's gut to her milk and through the milk to the infant's gut. PMID- 21300510 TI - MALDI-TOF MS: a return to phenotyping in microbial identification? PMID- 21300509 TI - Identification of Staphylococcus intermedius Group by MALDI-TOF MS. AB - The Staphylococcus intermedius Group includes S. intermedius, S. pseudintermedius and S. delphini, coagulase-positive bacteria commonly isolated from animals. The identification of organisms belonging to this group is presently carried out using molecular methods. This study assessed the suitability of MALDI-TOF MS for their identification. 69 strains of different biological and geographic origins, identified by partial hsp60 gene sequencing as S. intermedius (n=15), S. pseudintermedius (n=32) and S. delphini (n=22), were analyzed by MALDI-TOF MS. The estimated sensitivity, specificity and efficiency were calculated. In addition we computed the agreement between the outcome of MALDI-TOF MS identification and partial hsp60 gene sequencing. The sensitivity of MALDI-TOF MS was higher for S. intermedius [0.95 (95% CI: 0.68-0.99)], than for S. pseudintermedius [0.78 (95% CI: 0.60-0.90)] and S. delphini [0.64 (95% CI: 0.41 0.83)], whereas the specificity was 1 for S. intermedius and S. delphini and 0.97 (95% CI: 0.86-0.99) for S. pseudintermedius. The Cohen's kappa coefficient indicated almost perfect agreement between MALDI-TOF MS and hsp60 gene sequencing for the identification of S. intermedius [0.96 (95% CI: 0.87-1.04)], and substantial agreement for S. delphini and S. pseudintermedius [0.70 (95% CI: 0.52 0.89) and 0.76 (95% CI: 0.616-0.92), respectively]. The overall efficiency of the proteomic identification ranged between 0.88 (95% CI: 0.78-0.95) for S. pseudintermedius and S. delphini and 0.99 (95% CI: 0.92-0.99) for S. intermedius. MALDI-TOF MS is thus a valuable and reliable tool for the rapid and accurate identification of bacteria belonging to the S. intermedius Group. PMID- 21300511 TI - Stability-indicating study of the anti-Alzheimer's drug galantamine hydrobromide. AB - Galantamine hydrobromide was subjected to different stress conditions (acidic, alkaline, thermal, photolytic and oxidative). Degradation was found to occur under acidic, photolytic and oxidative conditions, while the drug was stable under alkaline and elevated temperature conditions. A stability-indicating reversed-phase liquid chromatographic method was developed for the determination of the drug in the presence of its degradation products. The method was validated for linearity, precision, accuracy, specificity, selectivity and intermediate precision. Additionally, the degradation kinetics of the drug was assessed in relevant cases. The kinetics followed a first order behavior in the case of acidic and photolytic degradation, while a two-phase kinetics behavior was found for the oxidative degradation. The degradation products were characterized by mass spectrometry and nuclear magnetic resonance spectroscopy. Dehydration, epimerization and N-oxidation were the main processes observed during the degradation of galantamine. Moreover, if sufficient material could be isolated the inhibitory activity against the target enzyme acetylcholinesterase was also assessed. PMID- 21300512 TI - Development and validation of immunoassays to quantify the half-antibody exchange of an IgG4 antibody, natalizumab (Tysabri(r)) with endogenous IgG4. AB - Natalizumab is a humanized IgG4 monoclonal antibody which binds human alpha4 integrin and is approved for treatment of multiple sclerosis and Crohn's disease. Assessment of the in vivo disposition of natalizumab presents a unique assay development challenge due to the ability of human IgG4 antibodies to undergo half antibody exchange in vivo. Such exchange generates IgG4 molecules of mixed specificity comprising a natalizumab heavy-light chain pair coupled to an IgG4 heavy-light chain pair of unknown specificity. Since exchanged and non-exchanged species cannot be quantified independently using a single enzyme linked immunosorbent assay (ELISA), a novel quantitation strategy was developed employing two ELISAs: one measuring total natalizumab including both intact and exchanged molecules, and the second measuring only intact natalizumab. The presence and amount of exchanged natalizumab in serum is calculated by the difference in values obtained in the two assays. To evaluate assay performance, a control reagent was created from natalizumab and an irrelevant humanized monoclonal IgG4 antibody. Subsequent validation demonstrated that both assays are specific, accurate, and precise within the working ranges of the assays (1.5 10MUg/mL for total and 0.5-12MUg/mL for intact natalizumab assays). The mean accuracy, intra- and inter-assay precision for both assays were 82-113%, <=9% and <=20%, respectively. Additionally, the limits of detection of intact and exchanged natalizumab were established using statistical methods. The utility of the two-assay strategy was confirmed by analyzing samples from a pharmacokinetic study in rats using different variants of natalizumab administered along with another human IgG4 antibody as an exchange partner. PMID- 21300513 TI - Vitamin D3 quantification in a cod liver oil-based supplement. AB - A reliable, accurate and reproducible method to quantify vitamin D3 (Vit. D3) in oily dietary supplements was developed after three Vit. D3 intoxications were diagnosed as reasonably resulting from a dietary administration of a cod liver oil based supplement. Liquid chromatography coupled to mass spectrometry operating in atmospheric pressure chemical ionization conditions (LC-APCI) and by using a deuterium labelled internal standard resulted to be an effective technique to reach the analytical aim. Due to the complexity of the oily matrix, the new analytical approach required a solid phase extraction step prior to analysis. The amount of Vit. D3 declared on the label of the cod liver oil based supplement for each soft capsule is 1.5MUg. Consequently, the method was developed to quantify Vit. D3 amounts in the range 1-5MUg/mL. To improve reliability of obtained data, both MS and MS/MS acquisition methods were employed. The method was evaluated by measuring the characteristic parameters such as linearity, precision, accuracy and robustness and cross checked against a certified pharmaceutical preparation. The LC-APCI-MS and MS/MS methods were applied in order to assess the Vit. D3 content in the dietary supplements taken by the intoxicated patients, found about three order of magnitude higher than that declared. The Vit. D3 content of other batches of the same commercial product was found as declared. PMID- 21300514 TI - Perception of empathy in the therapeutic encounter: effects on the common cold. AB - OBJECTIVE: To evaluate the effects of patient-practitioner interaction on the severity and duration of the common cold. METHODS: We conducted a randomized controlled trial of 719 patients with new cold onset. Participants were randomized to three groups: no patient-practitioner interaction, "standard" interaction or an "enhanced" interaction. Cold severity was assessed twice daily. Patients randomized to practitioner visits used the Consultation and Relational Empathy (CARE) measure to rate clinician empathy. Interleukin-8 (IL-8) and neutrophil counts were obtained from nasal wash at baseline and 48 h later. RESULTS: Patients' perceptions of the clinical encounter were associated with reduced cold severity and duration. Encounters rated perfect on the CARE score had reduced severity (perfect: 223, sub-perfect: 271, p=0.04) and duration (perfect: 5.89 days, sub-perfect: 7.00 days, p=0.003). CARE scores were also associated with a more significant change in IL-8 (perfect: mean IL-8 change 1586, sub-perfect: 72, p=0.02) and neutrophil count (perfect: 49, sub-perfect: 12, p=0.09). CONCLUSIONS: When patients perceive clinicians as empathetic, rating them perfect on the CARE tool, the severity, duration and objective measures (IL 8 and neutrophils) of the common cold significantly change. PRACTICE IMPLICATIONS: This study helps us to understand the importance of the perception of empathy in a therapeutic encounter. PMID- 21300515 TI - Who listens to our advice? A secondary analysis of data from a clinical trial testing an intervention designed to decrease delay in seeking treatment for acute coronary syndrome. AB - OBJECTIVE: Prolonged prehospital delay in persons experiencing acute coronary syndrome (ACS) remains a problem. Understanding which patients respond best to particular interventions designed to decrease delay time would provide mechanistic insights into the process by which interventions work. METHODS: In the PROMOTION trial, 3522 at-risk patients were enrolled from 5 sites in the United States (56.4%), Australia and New Zealand; 490 (N=272 intervention, N=218 control) had an acute event within 2 years. Focusing on these 490, we (1) identified predictors of a rapid response to symptoms, (2) identified intervention group subjects with a change in these predictors over 3 months of follow-up, and (3) compared intervention group participants with and without the favorable response pattern. Hypothesized predictors of rapid response were increased perceived control and decreased anxiety. Knowledge, attitudes, and beliefs were hypothesized to differ between responders and non-responders. RESULTS: Contrary to hypothesis, responders had low anxiety and low perceived control. Only 73 (26.8%) subjects showed this pattern 3 months following the intervention. No differences in ACS knowledge, attitudes, or beliefs were found. CONCLUSION: The results of this study challenge existing beliefs. PRACTICE IMPLICATIONS: New intervention approaches that focus on a realistic decrease in anxiety and perceived control are needed. PMID- 21300517 TI - "I am not only a disease, I am so much more". Patients with rheumatic diseases' experiences of an emotion-focused group intervention. AB - OBJECTIVE: To obtain understanding of how patients with rheumatic diseases experienced participation in an emotion-focused group intervention in terms of influences on their emotional well-being and coping behavior and the processes whereby these influences arose. METHODS: The intervention, Vitality Training (VTP), was conducted in 10 group sessions over 4 months. Qualitative data were collected from 10 focus group interviews (n=69) two weeks after the intervention. Data were analyzed with a qualitative content analysis approach. RESULTS: Five categories were identified from the analyses: (1) recognizing oneself as both ill and healthy, (2) recognizing own emotions, (3) awareness of own needs, (4) being part of a community and (5) being recognized as a credible patient. CONCLUSION: The VTP addressed participants' awareness of emotional and bodily reactions in a process-oriented and supportive group. The program had enhanced participants' recognition of their disease-related emotions and helped them to more actively relate to their own needs. PRACTICAL IMPLICATIONS: This study has highlighted how a process-oriented group intervention that combines topics related to life, rather than disease, and learning methods that enhance emotional awareness and adaptive emotional expression can enhance emotional well-being and coping behavior in patients with rheumatic diseases. PMID- 21300516 TI - Knowing the ABCs: a comparative effectiveness study of two methods of diabetes education. AB - OBJECTIVE: To test an active-learning, empowerment approach to teaching patients about the "diabetes ABCs" (hemoglobin A(1)C, systolic blood pressure, and low density lipoprotein cholesterol). METHODS: 84 (97%) diabetic patients who participated in a randomized effectiveness trial of two clinic-based group educational methods and completed a post-intervention assessment. The empowerment arm participated in a group session that incorporated two educational innovations (a conceptual metaphor to foster understanding, and team-based learning methods to foster active learning). The traditional diabetes education arm received a didactic group session focused on self-management and educational materials about the diabetes ABCs. Participants in both arms received individual review of their current ABC values. RESULTS: A questionnaire evaluated knowledge, understanding, and recall of the diabetes ABCs was administered three months after enrollment in the study. At three months, participants in the empowerment group demonstrated greater understanding of the diabetes ABCs (P<0.0001), greater knowledge of their own values (P<0.0001), and greater knowledge of guideline-derived target goals for the ABCs compared with participants in the traditional arm (P<0.0001). CONCLUSION: An active-learning, empowerment-based approach applied to diabetes education can lead to greater understanding and knowledge retention. PRACTICE IMPLICATIONS: An empowerment approach to education can facilitate informed, activated patients and increase performance of self-management behaviors. PMID- 21300519 TI - Palliative gastrectomy and other factors affecting overall survival in stage IV gastric adenocarcinoma patients receiving chemotherapy: a retrospective analysis. AB - OBJECTIVE: Most patients with gastric cancer present with locally advanced or metastatic disease and usually receive palliative therapy. We sought to identify factors influencing overall survival in patients with stage IV gastric cancer receiving palliative chemotherapy. PATIENTS AND METHODS: The records of 311 patients with histological diagnosis of gastric adenocarcinoma were retrospectively reviewed and 17 clinicopathological and therapeutic parameters were evaluated for their influence on overall survival. RESULTS: In multivariate analysis nine factors were found to independently influence survival: no previous palliative gastrectomy [Hazard ratio (HR, 12; CI 7.969-18.099)], single agent chemotherapy instead of combination chemotherapy (HR, 1.35; CI 1.068-1.721), histological grade III (HR, 1.39; 95% CI 1.098-1.782), the presence of hepatic (HR, 1.6; 95% CI 1.246-2.073) and abdominal metastasis (HR, 1.33; 95% CI 1.039 1.715), CA 72-4 > 7 U/L (HR, 1.39; 95% CI 1.026-1.887), LDH > 225 U/L (HR, 1.72; 95% CI 1.336-2.236], need for blood transfusions (HR, 1.58; 95% CI 1.213-2.082), and weight loss > 5% (HR, 1.96; 95% CI 1.352-2.853) at the time of initial diagnosis. Patients were stratified as low (0-2 factors), intermediate (3-6 factors) and high (7-9 factors) risk and the median survival was 76, 40 and 11 weeks, respectively. CONCLUSION: Nine clinical and laboratory factors that adversely affect survival in patients with stage IV gastric cancer who receive chemotherapy were identified. Their concurrent presence seems to have an additive effect as patients with seven to nine factors have the worse prognosis. Palliative gastrectomy and combination chemotherapy appear to be associated with improved survival. PMID- 21300520 TI - Selective information enhancement learning for creating interpretable representations in competitive learning. AB - In this paper, we propose a new information-theoretic method, called "selective information enhancement learning," to explicitly interpret final representations created by learning. More specifically, we aim to make class boundaries obtained by learning as overt as possible by picking up the small number of important variables. The variable selection is performed by information enhancement in which mutual information between input patterns and competitive units is measured, while focusing upon a specific input variable. When this information is larger, the importance of the variable is higher. With selected and important variables, a network is retrained by free energy minimization. With this free energy minimization, we can obtain connection weights by considering the importance of specific variables. We applied the method to an artificial data problem, the Senate problem and the voting attitude problem, all of which are easily obtained for purposes of reproduction. Experimental results for all three problems showed that clear class boundaries could be obtained with a smaller number of variables. In addition, we could observe that a smaller number of input variables tended to have the majority of information on input patterns. This tendency became more explicit when the network size was large. PMID- 21300518 TI - Validity of a low literacy version of the Decisional Conflict Scale. AB - OBJECTIVE: To evaluate the psychometric properties of the 4-factor low literacy Decisional Conflict Scale (DCS-LL) with men eligible for prostate cancer screening (PCS). METHODS: We used baseline (T0; n=149) and post-intervention (T2; n=89) data from a randomized, controlled trial of a PCS decision aid to assess internal consistency reliability and construct, discriminant, and factor validity. RESULTS: There was evidence of excellent internal consistency reliability (alpha's>=.80) and fair construct validity (most r's>=.40) for the DCS-LL except for the Supported subscale. The DCS-LL was able to discriminate between men who had decided and those who had not. There was evidence for the original 4-factor model at T0 but exploratory analysis suggested a 3-factor solution at T0 and T2 with Informed and Value Clarity as one factor. CONCLUSION: For men eligible for PCS, feeling informed and feeling clear about values may not reflect distinct cognitive processes. Feeling supported may not be a factor contributing to uncertainty. PRACTICE IMPLICATIONS: Research should address whether current DCS subscales best represent the factors that contribute to uncertainty for PCS and for other screening decisions. Research should also explore the influence of health literacy on the factor structure of the DCS-LL. PMID- 21300521 TI - Automatic recognition of five types of white blood cells in peripheral blood. AB - This paper proposes image processing algorithms to recognize five types of white blood cells in peripheral blood automatically. First, a method based on Gram Schmidt orthogonalization is proposed along with a snake algorithm to segment nucleus and cytoplasm of the cells. Then, a variety of features are extracted from the segmented regions. Next, most discriminative features are selected using a Sequential Forward Selection (SFS) algorithm and performances of two classifiers, Artificial Neural Network (ANN) and Support Vector Machine (SVM), are compared. The results demonstrate that the proposed methods are accurate and sufficiently fast to be used in hematological laboratories. PMID- 21300522 TI - Propofol treatment in adult refractory status epilepticus. Mortality risk and outcome. AB - OBJECTIVES: To retrospectively study effect and safety of propofol treatment in adult refractory generalised tonic clonic status epilepticus. BACKGROUND: Therapy refractory status epilepticus (RSE) is defined as a status that does not respond to 1st or 2nd line of treatment. Different anaesthetics are used to treat RSE, but no definite recommendations or priority has been scientifically established. METHODS: Propofol has been the preferred agent for treating RSE at our intensive care unit since 2001. We present treatment mode, effect and outcome in 18 patients with 27 consecutive cases of RSE treated 2001-2010. Fifteen patients had 1 episode, and 3 patients had 2, 3 and 7 episodes, respectively. Mortality risk for each case of RSE was estimated using the Simplified Acute Physiology (SAPS) II score. RESULTS: Probable trigger factors were identified for 22 of the 27 RSE episodes. In 16/27 episodes seizures lasted more than 2h before anaesthesia was induced. A mean total dose of 7885.1mg was given for a mean duration of 34.4h. Break through seizures occurred in 8 of the patients and in 2 episodes of RSE in one patient, i.e. 9/27 episodes of RSE. Propofol was changed to another anaesthetic agent in 2 episodes. Complications occurred in 17 of the RSE episodes, the most frequent was pneumonia (9/27). One patient had complications that could be related to a propofol infusion syndrome (PRIS). In 8 of 18 patients and 14/27 RSE episodes no sequelae occurred. Seven episodes were associated with mild and 4 with severe sequelae and 2 of the patients died. We found a trend only for SAPS II score being higher in patients with more severe sequelae. CONCLUSIONS: Our data support propofol as an effective anaesthetic for treating RSE. Close clinical observation for possible PRIS is warranted if propofol is given for more than 48h. PMID- 21300523 TI - Spontaneous epileptiform discharges in a mouse model of Alzheimer's disease are suppressed by antiepileptic drugs that block sodium channels. AB - Previous studies have demonstrated an increased risk of epilepsy in patients with Alzheimer's disease (AD). Also, in many mouse models of AD, animals have spontaneous seizures and frequent epileptiform discharges (EDs). Abnormal function of sodium channels has been proposed to contribute to hyperexcitability in a manner suggesting that drugs that block sodium channels might exacerbate the condition. Here we addressed this question by investigating whether common antiepileptic drugs (AEDs) that block sodium channels, including carbamazepine (CBZ), phenytoin (DPH), or valproic acid (VPA) have any effect on spontaneous seizures or EDs in APdE9 mice. Mice were successively treated with vehicle, followed by CBZ (10mg/kg, t.i.d.), DPH (10mg/kg, t.i.d.), or VPA (260 mg/kg, b.i.d.) for 3d. After wash-out and new vehicle treatment, higher doses of CBZ (40 mg/kg, t.i.d.), DPH (40 mg/kg, t.i.d.), or VPA (400mg/kg, b.i.d.) were administered for 3d (DPH) or 5d (CBZ, VPA). During the entire experiment, mice were under continuous (24/7) video-EEG monitoring. Our data show that each treatment reduced the number of spontaneous electrographic EDs. VPA was the most effective by reducing the ED frequency below 50% of that at baseline in 75% of mice. Western blot analysis of the Na(v)1.1 protein levels in the ventral temporal cortex and the hippocampus did not reveal any differences between the genotypes. Under the conditions tested, sodium channel blocking AEDs suppressed epileptiform activity in APdE9 mice with increased amyloid pathology. Whether this applies to other mouse models of AD with different APP mutations and/or genetic background remains to be explored. PMID- 21300524 TI - Neuroanatomical abnormalities in schizophrenia: a multimodal voxelwise meta analysis and meta-regression analysis. AB - Despite an increasing number of published voxel based morphometry studies of schizophrenia, there has been no adequate attempt to examine gray (GM) and white matter (WM) abnormalities and the heterogeneity of published findings. In the current article, we used a coordinate based meta-analysis technique to simultaneously examine GM and WM abnormalities in schizophrenia and to assess the effects of gender, chronicity, negative symptoms and other clinical variables. 79 studies meeting our inclusion criteria were included in the meta-analysis. Schizophrenia was associated with GM reductions in the bilateral insula/inferior frontal cortex, superior temporal gyrus, anterior cingulate gyrus/medial frontal cortex, thalamus and left amygdala. In WM analyses of volumetric and diffusion weighted images, schizophrenia was associated with decreased FA and/or WM in interhemispheric fibers, anterior thalamic radiation, inferior longitudinal fasciculi, inferior frontal occipital fasciculi, cingulum and fornix. Male gender, chronic illness and negative symptoms were associated with more severe GM abnormalities and illness chronicity was associated with more severe WM deficits. The meta-analyses revealed overlapping GM and WM structural findings in schizophrenia, characterized by bilateral anterior cortical, limbic and subcortical GM abnormalities, and WM changes in regions including tracts that connect these structures within and between hemispheres. However, the available findings are biased towards characteristics of schizophrenia samples with poor prognosis. PMID- 21300525 TI - Exploring logical reasoning abilities in schizophrenia patients. AB - OBJECTIVE: To assess deductive reasoning in schizophrenia patients with special reference to whether accuracy varies across type of stimulus problem. Previous research suggests that patients, unlike healthy controls, are insensitive to emotionally provocative (salient) problem content. METHOD: A syllogistic reasoning task consisting of five argument types varying in salience, congruence with commonly held beliefs and meaningfulness was administered along with standard intellectual and symptom measures to 25 schizophrenia patients and 26 healthy control participants. RESULTS: Patients performed below control participants in all reasoning task conditions, but group differences were non significant after controlling for IQ. There were no significant interactions between group and argument type in terms of reasoning accuracy and both patients and controls performed better when reasoning with belief congruent material. In addition, no relation between deduction and paranoid symptoms was found. CONCLUSION: Formal deductive reasoning abnormalities in schizophrenia are a reflection of the broadly based cognitive impairment documented in the illness. PMID- 21300526 TI - Ganciclovir treatment in children: evidence of subtherapeutic levels. AB - Ganciclovir (GCV) is used to treat babies and older children with cytomegalovirus related disease. Treatment courses are generally derived from adult studies and there are few data relating to the pharmacokinetics of GCV in children. In adults, low trough GCV levels have been associated with treatment failure and virological resistance. Data regarding suitable drug levels for use in therapeutic drug monitoring (TDM) in the paediatric age group do not currently exist. In this study, anonymised data for all GCV levels sent to the UK Antibiotic Reference Laboratory from 1 November 1999 to 31 March 2007 were reviewed and analysed by age group. In total, 339 specimens were received from 129 patients; 192 specimens were from patients aged <18 years. There were significantly more trough GCV levels <0.5 mg/L in those aged <6 months and 6-12 months compared with adults (64.8% and 53.9%, respectively, vs. 15.9%; P<0.001). Those aged 5-18 years also had significantly more trough samples with levels <0.5 mg/L (80.0% vs. 15.9%; P<0.001). There was a significant difference between median peak GCV levels in those aged <6 months and adults (4.8 mg/L vs. 5.7 mg/L, respectively; P=0.047). In conclusion, GCV levels associated with treatment failure and considered subtherapeutic in adult patients were observed more often in specimens from paediatric patients. These lower levels may have implications for dosing in the paediatric age group, particularly during periods of rapid change in renal function such as the neonatal period. Clinicians should be aware of the relatively low drug exposure noted in this study and consider TDM and increasing drug dose where virological response is poor. PMID- 21300527 TI - Prulifloxacin: a review focusing on its use beyond respiratory and urinary tract infections. AB - Prulifloxacin is a fluoroquinolone antibiotic that has been approved in several European countries for the treatment of lower urinary tract infections and exacerbations of chronic bronchitis. In this review, PubMed and Scopus databases were searched for potential uses of prulifloxacin beyond respiratory and urinary tract infections. Nine individual articles (eight randomised controlled trials and one cohort study) were regarded as eligible for inclusion in the review. Three of the studies were double-blinded, whilst six were open-label trials. Three studies referred to the treatment of patients with chronic bacterial prostatitis (CBP), one to prophylaxis of patients undergoing transrectal prostate biopsy, one to prophylaxis of women undergoing surgical abortion, two to patients with traveller's diarrhoea, one to diabetic patients with soft tissue infections or osteomyelitis, and one to improving tolerance of Bacillus Calmette-Guerin (BCG) instillations in patients with bladder cancer. Regarding CBP, prulifloxacin was non-inferior to its comparators, with a trend towards better microbiological outcomes at follow-up. Regarding traveller's diarrhoea, prulifloxacin resulted in better clinical and microbiological outcomes compared with placebo. Finally, prulifloxacin decreased the adverse events associated with BCG instillations in patients with bladder cancer, without affecting cancer recurrence rates. In summary, prulifloxacin appears to be a promising agent for the treatment of bacterial prostatitis and traveller's diarrhoea. PMID- 21300528 TI - Management of serious meticillin-resistant Staphylococcus aureus infections: what are the limits? AB - Severe (life-threatening) meticillin-resistant Staphylococcus aureus (MRSA) infection continues to be treated with vancomycin despite accumulating evidence of poor outcome, increasing resistance and unachievable pharmacokinetic/pharmacodynamic (PK/PD) targets. The minimum inhibitory concentration (MIC) susceptibility breakpoint for vancomycin was recently reduced to 2 mg/L. Whilst the great majority of clinical isolates are thus still classified as susceptible, the available clinical evidence argues for a method dependent breakpoint of 0.5 mg/L (broth dilution) or 1.0 mg/L (Etest), which would classify many strains as resistant, or at best intermediate. However, automated susceptibility testing systems are not currently capable of performing accurately at this low level, and such low breakpoints are unsatisfactory because the poor reproducibility of tests (plus or minus one doubling dilution) results in a critical non-reproducibility around the modal MIC of 1 mg/L described in most published data. Therefore, vancomycin should be used with caution in severe (life-threatening) staphylococcal disease and the MIC should always be reported by method. Daptomycin is generally preferred for bacteraemia/endocarditis and linezolid for pneumonia. Better outcome data for vancomycin, based on achievable PK/PD targets and using robust MIC tests, are urgently required. PMID- 21300529 TI - A facile approach to construct hyaluronic acid shielding polyplexes with improved stability and reduced cytotoxicity. AB - A facile approach for polymer gene carriers was used to construct hyaluronic acid (HA) shielding polyplexes due to the electrostatic interaction. By adding HA to PEI/DNA complexes, the xi-potential of ternary polyplexes was changed from positive to negative. Spherical particles with diameter about 250nm were observed. Ethidium bromide exclusion assay indicated that the electrostatic complexation was loosened after addition of HA. However, DNA disassembly did not occur. The proper reason was that the intensity of negative charges was not strong enough to release DNA from the complexes in our experiment. The stability of PEI/DNA/HA polyplexes in physiological condition was improved and the cytotoxicity was reduced. Comparing with PEI/DNA polyplexes, the uptake and transfection efficiency of HA shielding polyplexes was lower for HEK293T cells probably due to the reduced adsorptive endocytosis, whereas it was higher for HepG2 cells due to HA receptor mediated endocytosis. This facile approach to constructing HA shielding polyplexes might have great potential application in non-viral gene delivery research and tumor therapy. PMID- 21300530 TI - Dielectric studies of the paracetamol-lenticular tissue interactions. AB - This paper reports on the effect of paracetamol on the dielectric behavior of the rabbit lens. Measurements were performed over the frequency range of 100 Hz-100 kHz in air and at the temperature of 35 degrees C. The frequency dependencies of the relative permittivity and dielectric loss for the control and paracetamol control lenses are described in terms of a power-low, Debye and Cole-Cole relations. The effect of paracetamol on the dielectric properties of the lens is visible in the lower values of the relative permittivity than those for the control sample at the same frequency. In addition, the relaxations around 18 and 46 kHz for the paracetamol-control lens are shifted to lower frequencies compared with the control lens. The results of this work indicate that the present method is useful in detection of the lens toxicity elicited by overdoses of paracetamol in animal. PMID- 21300531 TI - Antidiabetic effect of a newly identified component of Opuntia dillenii polysaccharides. AB - The aim of this study was to determine the most effective hypoglycemic component of polysaccharides from Opuntia dillenii Haw. by preliminary screening and to specifically study the antidiabetic effects of O. dillenii polysaccharide (ODP) Ia in mice with streptozotocin (STZ)-induced diabetes. Three kinds of ODPs - ODP Ia, ODP-Ib, and ODP-II' - were isolated by using an ultrasonic extraction method and diethylaminoethyl (DEAE)-Sepharose fast-flow column chromatography. The mice were administered ODPs for 3 weeks. Gavage administration of ODP-Ia significantly decreased (P<0.05) their intake of food and water; the fasting levels of blood glucose (BG), total cholesterol (TC), triglycerides (TGs), plasma urea nitrogen (PUN), and malondialdehyde (MDA); and the activity of glucose-6-phosphatase (G-6 Pase). In contrast, it significantly increased (P<0.05) the body weights, hepatic glycogen (HG) levels, high-density lipoprotein cholesterol (HDL-C) levels, and the hepatic superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity in diabetic mice. However, ODP-Ia did not significantly increase insulin levels in the mice with STZ-induced diabetes. We propose that ODP-Ia exerts its antihyperglycemic effect by protecting the liver from peroxidation damage and by maintaining tissue function, thereby improving the sensitivity and response of target cells in diabetic mice to insulin. PMID- 21300532 TI - Editorial overview. PMID- 21300533 TI - The transition to harm reduction: understanding the role of non-governmental organisations in Malaysia. AB - BACKGROUND: The transition of drug policy from prohibition to harm reduction has never been easy. The deeply entrenched belief in prohibition shared by policy makers and religious leaders provided little room for alternatives, and change came only slowly. The non-governmental organisations (NGOs) in Malaysia played a pivotal role in effecting such a change. Understanding how they did so may be instructive for other similarly placed countries. METHODS: Data collected via reviews of published secondary sources, media reports and in-depth interviews with pioneers of harm reduction drawn from NGOs, medical practitioners and the police were analysed to construct the paper. RESULTS: The policy change was the outcome of competition between three groups in the drug policy subsystem--the state, the Muslim religious lobby and the NGOs. Developments such as the poor outcomes from the prohibition programmes and the outbreak of HIV/AIDS did not change policy but did lead to a rethink of core beliefs in the state alliance and spawned a state-NGO partnership. The subsequent failure to meet the Millennium Development Goal with respect to HIV/AIDS in 2005 was seen as a failure of the Health Ministry which then led the final charge for a policy change arguing that a health crisis was imminent. The NGOs played a pivotal role in this process by educating their partners in the state coalition, by drawing academics and medical practitioners into advocacy and by engaging the religious lobby (albeit with varying success). They were also frontline players in implementing harm reduction programmes and successfully deflected criticisms from unconvinced Islamic groups away from the state. CONCLUSION: Given their central role in the needle-syringe exchange programme, the NGOs are well positioned to convince injecting drug users to opt for voluntary medical treatment. This can potentially reduce both the harm from drug use and the prevalence of it. PMID- 21300534 TI - Magnetic protein microbead-aided indirect fluoroimmunoassay for the determination of canine virus specific antibodies. AB - Rabies, canine distemper, and canine parvovirus are common contagious viral diseases of dogs and many other carnivores, and pose a severe threat to the population dynamics of wild carnivores, as well as endangering carnivore conservation. However, clinical diagnosis of these diseases, especially canine distemper and canine parvovirus, is difficult because of the broad spectrum of symptoms that may be confused with other respiratory and enteric diseases of dogs. The most frequently used and proven techniques for diagnosing viral diseases include the conventional enzyme-linked immunosorbent assay (ELISA), rapid fluorescent focus inhibition test (RFFIT), mouse neutralisation test (MNT), and fluorescent antibody virus neutralization (FAVN) test. However, these methods still have some inherent limitations. In this study, a magnetic protein microbead aided indirect fluoroimmunoassay was developed to detect canine virus specific antibodies, human rabies immunoglobulin, CDV McAbs, and CPV McAbs. In this assay, an avidin-biotin system was employed to combine magnetic microbeads and virus antigens (rabies virus, canine distemper virus, and canine parvovirus). Quantification of the targeted virus antibodies was analyzed through indirect fluoroimmunoassay using the specific antigen-antibody reaction, as well as their corresponding FITC-labeled detection antibodies (mouse anti-human IgG/FITC conjugate or rabbit anti-dog IgG/FITC conjugate). The results indicated that the fluorescence intensity increased when a higher concentration of the targeted analyte was used, but the control had almost no fluorescence, much like the conventional ELISA. For human rabies immunoglobulin, CDV McAbs, and CPV McAbs, the minimum detectable concentrations were 0.2 IU/mL, 0.3 ng/mL, and 0.5 ng/mL, respectively. All of these results indicate that this assay can be employed to determine the presence of canine virus specific antibodies. In addition, the method devised here can be utilized as a general protocol in other bacterial and viral marker analysis. PMID- 21300535 TI - Synthesis and characterization of a molecularly imprinted polymer optosensor for TEXs-screening in drinking water. AB - A molecularly imprinted polymer (MIP) was synthesized using toluene as template, and was implemented in a fluorescence optosensor (lambda(exc)=260 nm, lambda(em)=284 nm) for the screening of TEXs (toluene, ethylbenzene and xylenes) in drinking water. All the parameters which can affect the sensitivity and selectivity of the optical sensing phase, were carefully optimized. The screening test runs without the need for any pre-concentration step, thus rendering it suitable for routine use in water-quality-control laboratories. The test recognizes contaminated samples rapidly (81 s) and inexpensively with a cut-off level of 700 MUg L(-1) ethylbenzene which corresponds with the maximum contaminant level (MCL) established by US Environmental Protection Agency (EPA) in drinking water. The threshold value of the screening test for the cut-off level was 8.27+/-0.57 a.u. (95% confidence level, n=10). The reliability of the screening test was 32% false positives and 0% false negatives for 50 samples, and its applicability has been demonstrated by analyzing 15 samples of mineral, tap and river waters obtaining 0% false negatives. PMID- 21300536 TI - Rapid diagnosis of multidrug resistance in cancer by electrochemical sensor based on carbon nanotubes-drug supramolecular nanocomposites. AB - The multidrug resistance (MDR) in cancer is a major chemotherapy obstacle, rendering many currently available chemotherapeutic drugs ineffective. The aim of this study was to explore the new strategy to early diagnose the MDR by electrochemical sensor based on carbon nanotubes-drug supramolecular interaction. The carbon nanotubes modified glassy carbon electrodes (CNTs/GCE) were directly immersed into the cells suspension of the sensitive leukemia cells K562 and/or its MDR cells K562/A02 to detect the response of the electrochemical probe of daunorubicin (DNR) residues after incubated with cells for 1h. The fresh evidence from the electrochemical studies based on CNTs/GCE demonstrated that the homogeneous, label-free strategy could directly measure the function of cell membrane transporters in MDR cancer cells, identify the cell phenotype (sensitive or MDR). When the different ratios of the sensitive leukemia cells K562 and its MDR ones K562/A02 were applied as a model of MDR levels to simulate the MDR occurrence in cancer, the cathodic peak current showed good linear response to the fraction of MDR with a correlation coefficient of 0.995. Therefore, the MDR fraction can be easily predicted based on the calibration curve of the cathodic peak current versus the fraction of MDR. These results indicated that the sensing strategy could provide a powerful tool for assessment of MDR in cancer. The new electrochemical sensor based on carbon nanotubes-drug supramolecular nanocomposites could represent promising approach in the rapid diagnosis of MDR in cancer. PMID- 21300537 TI - Recommendations for capture, validation and summarisation of data from studies using RECIST. AB - Response Evaluation Criteria in Solid Tumors (RECIST) is commonly used in oncology clinical trials and provides a standard approach for the assessment of treatment. However, data capture, validation and summarisation are complex. This article focuses on managing solid tumour lesion and response assessment data from capture through summarisation. Conventions for capturing lesion data, as well as considerations for data validation and summarisation, are provided. Recommendations are based on a review of data capture forms (including data items and instructions), data validation practices and algorithms for data summarisation across solid tumour studies at a single company. The intent of the authors is to share our experiences at GSK in the spirit of harmonisation by transparently describing our decisions and methods. PMID- 21300538 TI - Three-stage enzymatic hydrolysis of steam-exploded corn stover at high substrate concentration. AB - The feasibility of three-stage hydrolysis of steam-exploded corn stover at high substrate concentration was investigated. When substrate concentration was 30% and enzyme loading was 15-30 FPU/g cellulose, three-stage (9+9+12 h) hydrolysis could reach a hydrolysis yield of 59.9-81.4% in 30 h. Compared with one-stage hydrolysis for 72 h, an increase of 34-37% in hydrolysis yield could be achieved. When steam-exploded corn stover was used as the substrate for enzyme synthesis and hydrolysis was conducted at a substrate concentration of 25% with an enzyme loading of 20 FPU/g cellulose, a hydrolysis yield of 85.1% was obtained, 19% higher than that the commercial cellulase could reach under the same conditions. The removal of end products was suggested to improve the adsorption of cellulase on the substrate and enhance the productivity of enzymatic hydrolysis. PMID- 21300539 TI - Reduction of ammonia and volatile organic compounds from food waste-composting facilities using a novel anti-clogging biofilter system. AB - The performance of a pilot-scale anti-clogging biofilter system (ABS) was evaluated over a period of 125days for treating ammonia and volatile organic compounds emitted from a full-scale food waste-composting facility. The pilot scale ABS was designed to intermittently and automatically remove excess biomass using an agitator. When the pressure drop in the polyurethane filter bed was increased to a set point (50 mm H(2)O m(-1)), due to excess biomass acclimation, the agitator automatically worked by the differential pressure switch, without biofilter shutdown. A high removal efficiency (97-99%) was stably maintained for the 125 days after an acclimation period of 1 week, even thought the inlet gas concentrations fluctuated from 0.16 to 0.55 g m(-3). Due the intermittent automatic agitation of the filter bed, the biomass concentration and pressure drop in the biofilter were maintained within the ranges of 1.1-2.0 g-DCW g PU(-1) and below 50 mm H(2)O m(-1), respectively. PMID- 21300540 TI - Production and purification of a novel exopolysaccharide from lactic acid bacterium Streptococcus phocae PI80 and its functional characteristics activity in vitro. AB - Optimum culture conditions which ease the synthesis of a novel exopolysaccharide (EPS) from a potent marine strain Streptococcus phocae was proposed in this study. The strain grows well at 35 degrees C, pH 7.0 and NaCl (2%) with lactose and yeast extract as best carbon and nitrogen sources. The maximum yield of EPS (11.75 and 12.14 g/L) was obtained in the presence of lactose and yeast extract at a concentration of 20 g/L respectively. EPS was refined by gel filtration chromatography using phenyl Sepharose column which revealed the presence of arabinose, fructose and galactose sugar units with molecular mass about 2.8 * 10(5) Da. Emulsifying and flocculating stability of EPS compared with three commercial hydrocolloids. EPS exhibited better activities which are similar to that of commercial hydrocolloids. Both crude and purified EPS exhibited strong antioxidant potential by quenching hydroxyl and superoxide anion radicals. Antibiofilm activity by inhibition of Gram positive and Gram negative biofilm forming bacteria was evident in our studies. Potential antioxidant activity and biofilm inhibiting property of EPS may lead to the development of novel food grade adjuncts. PMID- 21300541 TI - Comparative production of cellulases by mutants of Penicillium janthinellum NCIM 1171 and its application in hydrolysis of Avicel and cellulose. AB - Mutants of Penicillium janthinellum NCIM 1171 were evaluated for cellulase production using both submerged fermentation (SmF) and solid state fermentation (SSF). Mutant EU2D-21 gave highest yields of cellulases in both SmF and SSF. Hydrolysis of Avicel and cellulose were compared using SmF and SSF derived enzyme preparations obtained from EU2D-21. Surprisingly, the use of SSF derived preparation gave less hydrolysis compared to SmF derived enzymes. This may be due to inactivation of beta-glucosidase at 50 degrees C in SSF derived enzyme preparations. SmF derived enzyme preparations contained both thermostable and thermosensitive beta-glucosidases where as SSF derived enzyme preparations contained predominantly thermosensitive beta-glucosidase. This is the first report on less thermostability of SSF derived beta-glucosidase which is the main reason for getting less hydrolysis. PMID- 21300542 TI - Improvement of corn stover bioconversion efficiency by using plant glycoside hydrolase. AB - Plant cell wall is the most abundant substrate for bioethanol production, and plants also represent a key resource for glycoside hydrolase (GH). To exploit efficient way for bioethanol production with lower cellulase loading, the potential of plant GH for lignocellulose bioconversion was evaluated. The GH activity for cell wall proteins (CWPs) was detected from fresh corn stover (FCS), and the synergism of which with Trichoderma reesei cellulase was also observed. The properties for the GH of FCS make it a promising enzyme additive for lignocellulose biodegradation. To make use of the plant GH, novel technology for hydrolysis and ethanol fermentation was developed with corn stover as substrate. Taking steam-exploded corn stover as substrate for hydrolysis and ethanol fermentation, compared with T. reesei cellulase loaded alone, the final glucose and ethanol accumulation increased by 60% and 63% respectively with GH of FCS as an addition. PMID- 21300543 TI - Anti-tumor pyrimidinylpiperazines bind to the prosurvival Bcl-2 protein family member Bcl-XL. AB - Overexpression of prosurvival or underexpression of pro-death Bcl-2 family proteins can lead to cancer cell resistance to chemotherapy and radiation treatment. Inhibition of the prosurvival Bcl-2 family proteins has become a strategy for cancer therapy and inhibitors are currently being evaluated in the clinic both as single agents and in combination with established drugs. Here we describe the design, synthesis, and evaluation of pyrimidylpiperazines that were discovered to be inhibitors of the prosurvival Bcl-2 protein family member Bcl XL. This study identified compound 21 which demonstrated a GI(50) value of 8.4 MUM against A549 lung adenocarcinoma cells and a binding affinity K(i) value for Bcl-XL of 127 nM. PMID- 21300544 TI - Synthesis of 3-phenylpyrazolopyrimidine-1,2,3-triazole conjugates and evaluation of their Src kinase inhibitory and anticancer activities. AB - A series of two classes of 3-phenylpyrazolopyrimidine-1,2,3-triazole conjugates were synthesized using click chemistry approach. All compounds were evaluated for inhibition of Src kinase and human ovarian adenocarcinoma (SK-Ov-3), breast carcinoma (MDA-MB-361), and colon adenocarcinoma (HT-29). Hexyl triazolyl substituted 3-phenylpyrazolopyrimidine exhibited inhibition of Src kinase with an IC(50) value of 5.6 MUM. 4-Methoxyphenyl triazolyl-substituted 3 phenylpyrazolopyrimidine inhibited the cell proliferation of HT-29 and SK-Ov-3 by 73% and 58%, respectively, at a concentration of 50 MUM. PMID- 21300545 TI - 3,5-diarylazoles as novel and selective inhibitors of protein kinase D. AB - The synthesis and preliminary studies of the SAR of novel 3,5-diarylazole inhibitors of Protein Kinase D (PKD) are reported. Notably, optimized compounds in this class have been found to be active in cellular assays of phosphorylation dependant HDAC5 nuclear export, orally bioavailable, and highly selective versus a panel of additional putative histone deacetylase (HDAC) kinases. Therefore these compounds could provide attractive tools for the further study of PKD/HDAC5 signaling. PMID- 21300546 TI - The design and synthesis of novel N-hydroxyformamide inhibitors of ADAM-TS4 for the treatment of osteoarthritis. AB - Two series of N-hydroxyformamide inhibitors of ADAM-TS4 were identified from screening compounds previously synthesised as inhibitors of matrix metalloproteinase-13 (collagenase-3). Understanding of the binding mode of this class of compound using ADAM-TS1 as a structural surrogate has led to the discovery of potent and very selective inhibitors with favourable DMPK properties. Synthesis, structure-activity relationships, and strategies to improve selectivity and lower in vivo metabolic clearance are described. PMID- 21300547 TI - (R)-/(S)-10-camphorsulfonyl-substituted aromatic/heterocyclic sulfonamides selectively inhibit mitochondrial over cytosolic carbonic anhydrases. AB - A series of aromatic and heterocyclic sulfonamides incorporating R- and S camphorsulfonyl moieties were synthesized and investigated for the inhibition of several mammalian isoforms of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). The new sulfonamides selectively inhibited the mitochondrial isozymes hCA VA and VB (h=human isoform) over the cytosolic, off-target ones hCA I and II, with inhibition constants in the low nanomolar range. The chirality and position of the groups substituting the sulfonamide scaffold greatly influenced CA inhibitory properties. These compounds are excellent leads for designing isoform selective enzyme inhibitors targeting mitochondrial CAs involved in lipogenesis and obesity. PMID- 21300548 TI - Gait kinematics and passive knee joint range of motion in children with hypermobility syndrome. AB - Hypermobility syndrome (HMS) is characterised by generalised joint laxity and musculoskeletal complaints. Gait abnormalities have been reported in children with HMS but have not been empirically investigated. The extent of passive knee joint range of motion (ROM) has also not been well reported in children with HMS. This study evaluated gait kinematics and passive knee joint ROM in children diagnosed with HMS and healthy controls. Thirty-seven healthy children (mean age+/-SD=11.5+/-2.6 years) and 29 children with HMS (mean age+/-SD=11.9+/-1.8 years) participated. Sagittal knee motion and gait speed were evaluated using a VICON 3D motion analysis system. Passive knee ROM was measured with a manual goniometer. Independent t-tests compared the values of sagittal knee motion and gait speed between the two groups. Mann-Whitney U tests compared passive knee ROM between groups. Passive ROM (extension and flexion) was significantly higher (both p<0.001) in children with HMS than the healthy controls. Peak knee flexion (during loading response and swing phase) during walking was significantly lower (both p<0.001) in children with HMS. Knee extension in mid stance during walking was significantly increased (p<0.001) in children with HMS. However, gait speed was not statistically (p=0.496) different between the two groups. Children with HMS had higher passive knee ROM than healthy children and also demonstrated abnormal knee motion during gait. Gait re-education and joint stability exercise programmes may be of value to children with HMS. PMID- 21300549 TI - A quantitative assessment of varus thrust in patients with medial knee osteoarthritis. AB - Varus thrust is an abnormal lateral knee motion frequently seen in patients with medial knee osteoarthritis (OA) during gait. It is a worsening of the alignment in the stance phase of the gait cycle and closely relates to disease progression. In this study, we measured the thrust quantitatively using skin markers and examined the relationship to other static and dynamic parameters. Forty-four knees in 32 patients (mean age, 72years; range, 64-81years) who exhibited the radiographic OA at least grade 2 according to the Kellgren-Lawrence (K-L) scale were enrolled. Gait analysis was performed for each patient to measure the amount of thrust and knee adduction moment. The amounts of thrust in subjects with K-L grades 2 (25 knees), 3 (13 knees), and 4 (6 knees) were 2.4 degrees (+/-1.3 degrees ), 2.8 degrees (+/-1.4 degrees ), and 7.2 degrees (+/-5.3 degrees ), respectively and the knee adduction moments were 3.6(+/-1.5) %BW*Ht, 3.9(+/-1.2) %BW*Ht and 6.9(+/-2.2%) BW*Ht, respectively. The amount of thrust also exhibited significant correlation to static radiographic alignment (R=0.47: 95% confidence interval 0.67-0.21, p=0.0038) and showed greater correlation to the knee adduction moment (R=0.73: 95% confidence interval 0.84-0.55, p<0.001), which has been identified as an important dynamic index of the disease. The amount of thrust, which is able to be measured by simple inexpensive equipment, correlated to static and dynamic parameters and may offer an important clinical index for knee OA. PMID- 21300550 TI - Enhancement of growth and salt tolerance of red pepper seedlings (Capsicum annuum L.) by regulating stress ethylene synthesis with halotolerant bacteria containing 1-aminocyclopropane-1-carboxylic acid deaminase activity. AB - Three 1-aminocyclopropane-1-carboxylic acid (ACC) deaminase-producing halotolerant bacteria were isolated from West Coast soil of Yellow Sea, Incheon, South Korea and evaluated for their efficiency in improving red pepper plant growth under salt stress. The strains RS16, RS656 and RS111 were identified by 16S rRNA gene sequencing as Brevibacterium iodinum, Bacillus licheniformis and Zhihengliuela alba, respectively. Two hour exposure of 100, 150 and 200 mM NaCl stress on 8 day old red pepper seedlings caused 44, 64 and 74% increase ethylene production, while at 150 mM NaCl stress, inoculation of B. licheniformis RS656, Z. alba RS111, and Br. iodinum RS16 reduces ethylene production by 44, 53 and 57%, respectively. Similarly, 3 week old red pepper plants were subjected to salt stress for two weeks and approximately ~50% reduction in growth recorded at 150 mM NaCl stress compared to negative control whereas bacteria inoculation significantly increase the growth compared to positive control. Salt stress also caused 1.3-fold reduction in the root/shoot dry weight ratio compared to the absence of salt while bacteria inoculation retained the biomass allocation similar to control plants. The salt tolerance index (ratio of biomass of salt stressed to non-stressed plant) was also significantly increased in inoculated plants compared to non-inoculated. Increase nutrient uptakes under salt stress by red pepper further evident that bacteria inoculation ameliorates salt stress effect. In summary, this study indicates that the use of ACC deaminase-producing halotolerant bacteria mitigates the salt stress by reducing salt stress-induced ethylene production on growth of red pepper plants. PMID- 21300551 TI - Expression of defense genes and activities of antioxidant enzymes in rice resistance to rice stripe virus and small brown planthopper. AB - The rice variety Tai06-1 is resistant to rice stripe disease and Xiushui63 is a highly susceptible rice variety to this disease. These two varieties were used to analyze the expression patterns of defense genes and antioxidant defense responses at the seedling stage, upon feeding with viruliferous small brown planthopper (SBPH) and nonviruliferous SBPH, respectively. The expression levels of CP (coat protein) gene of rice stripe virus (RSV) were higher upon feeding with viruliferous SBPH in Xiushui63 than in Tai06-1 throughout most of the experimental period, suggesting that RSV replicaiton is disturbed in Tai06-1 but not in Xiushui63, therefore, the resistance to RSV is higher in Tai06-1 than in Xiuhsui63. We found that defense genes PR1a (pathogenesis-related class 1a), PAL (phenylalanine ammonia-lyase), and CHS (chalcone synthase) may play roles in the defense responses to both RSV and SBPH in Tai06-1, and PR4 and PR10a may only participate in defending against SBPH attack but not against RSV infection in Tai06-1. Our data reveal that Gns1 (1,3; 1,4-beta-glucanase) may participate in the defense responses to both RSV and SBPH in Xiushui63 but not in Tai06-1, and LOX (lipoxygenase) may only participate in defending against to SBPH in both Tai06-1 and Xiushui63. The antioxidant enzymes superoxide dismutase, peroxidase, catalase, hydrogen peroxide, and malondialdehyde coordinately participate in the resistance to RSV in Tai06-1, and that oxidative damage is less in Tai06-1 than in Xiushui63. PMID- 21300552 TI - Evaluation of post-surgical relapse in maxillary surgery using resorbable plate. AB - BACKGROUND: This study was carried out to evaluate the vertical and horizontal changes after maxillary surgery using resorbable plates made of an l-lactic acid and d-lactic acid copolymer of PLA (P(L/DL)LA), and to analyze factors of skeletal pattern and surgical movement affecting the post-surgical change. MATERIALS AND METHODS: The subjects consisted of 20 patients who underwent bimaxillary surgery using P(L/DL)LA resorbable plate (Inion CPS, Inion Ltd., Tampere, Finland). Lateral cephalograms were taken at 1 month before (T0), 1 month after (T1) and 6 months after surgery (T2). They were divided into two groups, one showing less relapse (LR) and one more relapse (MR) using K-means clustering analysis of post-surgical relapse (T2-T1). In terms of linear and angular variables of maxillary relapse, the two groups were compared with measurements at the pre-surgical stage (T0), the surgical change obtained (T1-T0) and post-surgical relapse (T2-T1) using Mann-Whitney test. RESULTS: Because Frankfort horizontal (FH) to anterior nasal spine (ANS) showed the largest variance in post-surgical relapse of the maxilla, it was used for clustering analysis to define the MR and LR groups. Comparison between the MR and LR groups showed that a short preoperative anterior facial height (AFH) was a significant factor in maxillary relapse. The AFH of the MR group was significantly shorter pre-surgically (p<0.01) and was significantly increased postoperatively (p<0.05) when compared to the LR group. In post-surgical relapse, AFH, FH to A, FH to ANS and the palatal plane angle of the MR group were significantly decreased. CONCLUSIONS: In the case of a short AFH, P(L/DL)LA resorbable plates may not provide enough vertical stability in the maxillary position due to the muscle force. Facial height might be an important factor when deciding to use P(L/DL)LA resorbable plates for maxillary surgery. PMID- 21300553 TI - UV-ABC screens of luteolin derivatives compared to edelweiss extract. AB - Pure luteolin is a remarkably heat (200 degrees C/6 days) and UV stable UV-A screen, however, native luteolin enriched to 37% in an edelweiss extract lost its UV-A screen properties upon UV irradiation (~4MJm(-2)). This contrasting behavior led to the examination of a series of purified luteolin derivatives as UV screen candidates. 3',4',5,7-Tetralipoyloxyflavones were synthesized from luteolin (3',4',5,7-tetrahydroxyflavone) and fatty acid chlorides. These acylated semi biomolecules show a hypsochromic shift in UV-Vis spectra of about Deltalambda(A >B)=58nm and absorbed in the centre of the harmful UV-B band (lambda(max)=295nm). Luteolin was also hydroxyethylated with Br(CH(2))(2)OH. This substitution has no effect on the lambda(max)=330nm absorption of luteolin (UV-A band). Finally the natural 4'-O-beta-glucosyl-3',5,7-trihydroxyflavone was extracted from edelweiss and used as a purified natural benchmark. Glycosylated and hydroxyethylated luteolin are both UV stable. Fully acylated luteolin derivatives degrade upon UV exposure to a stable UV-C screen with a hypsochroic shift Deltalambda(B->C)=35nm. All in all, three molecular structures based on luteolin with sunscreen properties were found, distinguishable in: UV-A, UV-B, and UV-C filters. The natural product based UV-absorbers show promise as alternatives to synthetic molecules and nanoparticles in sunscreen products. PMID- 21300554 TI - Photodynamic antimicrobial activity of hypocrellin A. AB - Antimicrobial photodynamic therapy is a recently developed therapeutic option that combines a non-toxic photosensitizer with harmless visible light to damage the microbial cell. Hypocrellin A (HA), a natural occurring lipid-soluble perylenequinone pigment, has gained considerable interest since its anticancer and antiviral activities have been reported. Here, we examined the antimicrobial activity of HA against Gram-positive (Staphylococcus aureus, Bacillus subtilis) and Gram-negative bacteria (Escherichia coli, Salmonella typhimurium). The results indicate that HA has a photodynamic antimicrobial activity against both Gram-positive and Gram-negative bacteria when CaCl(2) or MgCl(2) was employed. A loose binding has been established between HA and the organisms. Molecular oxygen is significantly involved in the photodynamic action of HA. Furthermore, HA maintains a photodynamic activity in terms of both types I and II reactions. Our results confirm the potential of HA to be used as a photosensitizer in antimicrobial photodynamic therapy. PMID- 21300555 TI - D1 protein turnover is involved in protection of Photosystem II against UV-B induced damage in the cyanobacterium Arthrospira (Spirulina) platensis. AB - By using two strains of Arthrospira (Spirulina)platensis, an economically important filamentous cyanobacterium, we compared the impairment of PSII activity and loss of D1 protein content under UV-B radiation. Our study showed that UV-B radiation induced a gradual loss of the oxygen-evolving activity to about 56% after 180 min UV-B irradiation both in strains 439 and D-0083, which have been kept under indoor and an outdoor culturing conditions, respectively for a prolonged period of time. The loss of oxygen evolution was accelerated in both strains in the presence of lincomycin, an inhibitor of protein synthesis, and the amount of D1 protein showed a decrease comparable to that of oxygen evolution during the UV-B exposure. However, the UV-B induced loss of oxygen-evolving activity and D1 protein amount was largely prevented when A. platensis cells were exposed to UV-B irradiance supplemented with visible light. Comparison of the two strains also showed a smaller extent of D1 protein synthesis dependent PSII repair in the indoor strain. Our results show that turnover of the D1 protein is an important defense mechanism to counteract the UV-B induced damage of PSII in A. platensis, and also that visible light plays an important role in maintaining the function of PSII under simultaneous exposure to UV-B and visible light. PMID- 21300556 TI - Thermostability of glucose oxidase in silica gel obtained by sol-gel method and in solution studied by fluorimetric method. AB - The thermostability of glucose oxidase entrapped in silica gel obtained by sol gel method was studied by thermostimulated fluorescence of FAD at pH 5 and 7 and compared with that of the native enzyme in the solution and at the presence of ethanol. The unfolding temperatures were found to be lower for the enzyme immobilised in gel as compared with the native enzyme but higher as for the enzyme at the presence of ethanol. In gel, the thermal denaturation of glucose oxidase is independent on pH while in solution the enzyme is more stable at pH 5. The investigation the enzyme in different environment by steady-state fluorescence of FAD and tryptophan, synchronous fluorescence and time-resolved fluorescence of tryptophan indicates that the state of the molecule (tertiary structure and molecular dynamics) is different in gel and in solution. The ethanol produced during gel precursor hydrolysis is not the main factor influencing the thermostability of the enzyme but more important are interactions of the protein with the gel lattice. PMID- 21300557 TI - Tumor necrosis factor alpha (TNF-alpha) inactivates the PI3-kinase/PKB pathway and induces atrophy and apoptosis in L6 myotubes. AB - Muscle atrophy poses a serious concern to patients inflicted with inflammatory diseases. An increasing body of evidence implies that TNF-alpha plays a critical role in muscle atrophy in a number of these clinical settings. The mechanisms mediating its effects are not completely understood and conflicting data regarding its anabolic and catabolic actions exists. To examine the functional significance and detailed morphological characteristics of TNF-alpha-induced muscle proteolysis, differentiated L6 myotubes were subjected to increasing concentrations of recombinant TNF-alpha for 24 and 48 h. Data analysis of cell death showed that TNF-alpha induced a combination of apoptosis and necrosis in high concentrations. TNF-R1, rather than TNF-R2, was significantly upregulated. In addition, the transcription factors, NF-kappaB and FKHR were rapidly activated thus leading to increased expression of ubiquitin ligases, MuRF-1 and MAFbx. Muscle fiber diameter decreased with increasing TNF-alpha concentrations and was associated with attenuation of the PI3-K/Akt pathway as well as significant reductions in differentiation markers. Furthermore, treatment of L6 myotubes with exogenous TNF-alpha strongly potentiates its proteolytic effects through certain MAPKs that are activated. These observations suggest that TNF-alpha induces muscle proteolysis in a dose-dependent manner via various signal transduction pathways. PMID- 21300558 TI - What you cannot see can help you: the effect of exposure to unreportable stimuli on approach behavior. AB - We examined effects of exposure to unreportable images of spiders on approach towards a tarantula. Pretests revealed awareness of the stimuli was at chance. Participants high or low (top and bottom 15%) on fear of spiders were randomly assigned to receive computer-generated exposure to unreportable pictures of spiders or outdoor scenes. They then engaged in a Behavioral Approach Task (BAT) with a live tarantula. Non-fearful participants completed more BAT items than spider-fearful individuals. Additionally, as predicted, a significant interaction (F(1,48)=5.12, p<.03) between fear of spiders and stimulus demonstrated that spider-fearful participants exposed to spiders completed more BAT items than spider-fearful participants exposed to control stimuli (but not as many as non fearful participants). The findings support the hypothesis that exposure to unreportable feared stimuli promotes approach towards the feared object. Future research and clinical implications were discussed. PMID- 21300559 TI - Analysis of two stacked cylindrical dielectric resonators in a TE102 microwave cavity for magnetic resonance spectroscopy. AB - The frequency, field distributions and filling factors of a DR/TE102 probe, consisting of two cylindrical dielectric resonators (DR1 and DR2) in a rectangular TE102 cavity, are simulated and analyzed by finite element methods. The TE(+++) mode formed by the in-phase coupling of the TE01(delta)(DR1), TE01(delta)(DR2) and TE102 basic modes, is the most appropriate mode for X-band EPR experiments. The corresponding simulated B(+++) fields of the TE(+++) mode have significant amplitudes at DR1, DR2 and the cavity's iris resulting in efficient coupling between the DR/TE102 probe and the microwave bridge. At the experimental configuration, B(+++) in the vicinity of DR2 is much larger than that around DR1 indicating that DR1 mainly acts as a frequency tuner. In contrast to a simple microwave shield, the resonant cavity is an essential component of the probe that affects its frequency. The two dielectric resonators are always coupled and this is enhanced by the cavity. When DR1 and DR2 are close to the cavity walls, the TE(+++) frequency and B(+++) distribution are very similar to that of the empty TE102 cavity. When all the experimental details are taken into account, the agreement between the experimental and simulated TE(+++) frequencies is excellent. This confirms that the resonating mode of the spectrometer's DR/TE102 probe is the TE(+++) mode. Additional proof is obtained from B1(x), which is the calculated maximum x component of B(+++). It is predominantly due to DR2 and is approximately 4.4 G. The B1(x) maximum value of the DR/TE102 probe is found to be slightly larger than that for a single resonator in a cavity because DR1 further concentrates the cavity's magnetic field along its x axis. Even though DR1 slightly enhances the performance of the DR/TE102 probe its main benefit is to act as a frequency tuner. A waveguide iris can be used to over couple the DR/TE102 probe and lower its Q to ~150. Under these conditions, the probe has a short dead time and a large bandwidth. The DR/TE102 probe's calculated conversion factor is approximately three times that of a regular cavity making it a good candidate for pulsed EPR experiments. PMID- 21300560 TI - Genetic variation of the ATP-binding cassette transporter A1 and susceptibility to coronary heart disease. AB - ATP-binding cassette transporter A1 (ABCA1) is a member of a superfamily of membrane proteins that has attracted considerable attention as a candidate gene for coronary heart disease (CHD) based on its enzyme function as a key factor in regulating plasma HDL-C and apo A-I metabolism. It has been suggested that polymorphisms in the ABCA1 gene are risk factors for CHD, but a large number of studies have reported apparently conflicting results. To investigate this inconsistency and derive a more precise estimation of the relationship, a meta analysis of 14,040 cases and 28,607 controls from 31 published case-control studies was performed. Five potential sources of heterogeneity including ethnicity, source of control, sample size, HWE status and genotyping method of study were also assessed. Overall, significantly decreased CHD risk was associated with 219K allele of R219K polymorphism when all studies were pooled into the meta-analysis. In the subgroup analysis by ethnicity, significantly decreased risks were found in Asians and other ethnic population for the polymorphism in all genetic models; while no significant associations were found among Caucasians. When stratified by source of controls, both population and hospital based studies get consistent positive results. However, no significant results were observed for I883M polymorphism of ABCA1 in all genetic models. In conclusion, this meta-analysis suggests that K allele of ABCA1 R219K polymorphism is a protective factor associated with decreased CHD susceptibility, but these associations vary in different ethnic populations. PMID- 21300561 TI - Ethanol enrichment from ethanol-water mixtures using high frequency ultrasonic atomization. AB - The influence of high frequency ultrasound on the enrichment of ethanol from ethanol-water mixtures was investigated. Experiments performed in a continuous enrichment system showed that the generated atomized mist was at a higher ethanol concentration than the feed and the enrichment ratio was higher than the vapor liquid equilibrium curve for ethanol-water above 40 mol%. Well-controlled experiments were performed to analyze the effect of physical parameters; temperature, carrier gas flow and collection height on the enrichment. Droplet size measurements of the atomized mist and visualization of the oscillating fountain jet formed during sonication were made to understand the separation mechanism. PMID- 21300562 TI - Hypersexuality and compulsive over-eating associated with transdermal dopamine agonist therapy. PMID- 21300563 TI - Rapid tremor frequency assessment with the iPhone accelerometer. AB - The physician is often seeking more efficient ways of performing patient assessments. Currently, measuring tremor frequency requires expensive and bulky equipment. We propose the use of the in-built accelerometer of the iPhone via the iSeismo application for rapid measurement of tremor frequency. We use this device in a series of 7 different tremor cases, and show that the frequency measurements on the iSeismo graph closely match the more sophisticated EMG analysis during tremor. This is a preliminary confirmation of the usefulness of this device in the clinical setting for quick assessment of the dominant frequency component in a variety of tremors. PMID- 21300564 TI - Spectrophotometric and fluorescence quenching studies of the charge transfer complexation of (4-dimethylamino-benzylidene)-(4,6-dimethyl-pyrimidin-2-yl)-amine with some organic acceptors. AB - The interaction of organic acceptors such as tetrafluoro-1,4-benzoquinone (p TFQ), tetrachloro-1,4-benzoquinone (p-TCQ), tetrachloro-1,2-benzoquinone (o-TCQ), tetrabromo-1,4-benzoquinone (p-TBQ), tetrabromo-1,2-benzoquinone (o-TBQ) and 2,3 dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) with (4-dimethylamino-benzylidene) (4,6-dimethyl-pyrimidin-2-yl)-amine (SB) as donor is studied spectrophotometrically and fluoremetrically in dichloromethane and trichloromethane. The association constant (K), thermodynamic parameters (DeltaG degrees , DeltaH degrees and DeltaS degrees ), oscillator strength (f), transition dipole moment (MU) and stoichiometric ratio are calculated using Benezi-Hildbrand's, Job and straight-line methods, respectively. The results reveal that the interaction between the donor and acceptors is due to pi-pi* transitions by the formation of radical ion pairs. The fluorescence quenching of SB with different organic acceptors is investigated. The results reveal that the fluorescence quenching obeys the static type mechanism via charge transfer complex formation in the ground state. The effect of temperature on the equilibrium constants of the CT complexes is also studied. PMID- 21300565 TI - An exploration of the impact of computerized patient documentation on clinical collaboration. AB - PURPOSE: The purpose of this study was to explore the experience of experienced users of computerized patient documentation for the purpose of collaboration and coordination. A secondary analysis of qualitative data using Clark's theoretical framework of communication was conducted with the goal of bringing research findings into design. METHODS: Physicians, nurses and administrative staff volunteered to participate in focus groups at 4 VA sites. Each focus group lasted 1.5h and targeted experience and issues with using computerized documentation. All focus groups were audio-taped and transcribed and submitted to extensive qualitative analysis using ATLAS, iterative identification of concepts and categories. The communication category was targeted for secondary theoretical analysis in order to deepen understanding of the findings. Clark's theory of communication, joint action and common ground heuristics was used to analyze concepts. RESULTS: Key concepts included: (1) CPD has changed the way that narrative documentation is used in clinical settings to include more communication functions, strategies to establish joint action in both negative and positive ways; (2) functionality added to CPD to increase the efficiency of input may have increased the efficiency of CPD to support shared situation models, joint and action and the establishment of common ground; (3) new usage of CPD may increase tensions between clinical and administrative roles as the role of narrative is re-defined. CONCLUSIONS: This study demonstrates how socio technical systems co-evolve to support essential human function of coordination and collaboration. Users adapted the system in unique and useful ways that provide insight to future development. PMID- 21300566 TI - Vaccine-induced HIV seropositivity: a problem on the rise. AB - BACKGROUND: Vaccine-induced antibodies to envelope proteins frequently cause HIV seroconversion in uninfected recipients of HIV vaccine candidates and may thus have an impact on the vaccinee's ability to donate blood or acquire a life insurance policy. OBJECTIVE: To determine the occurrence of positive test results when commonly used HIV immunoassays are used to screen sera of HIV-uninfected volunteers who received an adjuvanted HIV-1 vaccine candidate containing HIV-1 antigens p24, reverse transcriptase, Nef and p17. STUDY DESIGN: Sera of 50 subjects who received this polyprotein vaccine in a single center in Belgium were tested with 6 HIV screening assays and 1 confirmation test. All samples were drawn one year after the administration of the first of two vaccine doses given with one month interval. RESULTS: Forty-five (90%) sera showed a positive test result in at least one of the 7 HIV tests used. The positivity rates were 88% in the Elecsys HIV Combi assay, 74% in the ADVIA Centaur EHIV and 48% in the PRISM HIV O Plus assay. CONCLUSIONS: Interpretation of HIV test results is becoming increasingly complex with the growing number of volunteers participating in prophylactic HIV vaccine trials worldwide and the rising number of viral antigens included in these vaccine candidates. The results of this study in recipients of a highly immunogenic adjuvanted polyprotein HIV vaccine candidate devoid of envelope proteins, illustrate the increasing need for approaches that can discriminate HIV infection-induced antibodies from those elicited by a vaccine. PMID- 21300567 TI - Distinguishing in a puddle the water from two rains: a crucial methodological issue. PMID- 21300568 TI - Neurophysiological mapping of muscle endplate location: precise targeting improves the efficacy of Botulinum neurotoxin injections. PMID- 21300569 TI - Megacystis secondary to congenital urethral stricture. AB - Functional bladder capacity at a certain age can be accurately estimated and expressed as a function of age. We present a 13-year-old boy with abdominal distention who was presumed to have ascites. Abdominal ultrasound revealed that the bladder was severely distended, and cystoscopy showed a short stricture in the bulbar urethra followed by a large bladder without obvious borders. Under general anesthesia, bladder capacity was 9250 cc. Reduction cystoplasty was performed. At the 2-year follow-up, he voided spontaneously with 20 cc post-void residual urine. PMID- 21300570 TI - Parameters of the classical complement pathway predict disease severity in hereditary angioedema. AB - Functional C1-inhibitor (C1-inh) and C4 are potential severity markers of hereditary angioedema due to deficiency of C1-inh (HAE-C1-inh), and the complexes generated through complement activation may be relevant. We studied the association between disease severity and complement parameters in 105 HAE-C1-inh patients. Disease severity was characterized by the number of angioedema attacks or alternatively, by the number of C1-inh concentrate ampoules (C1-inh-amp) used for the treatment of attacks. Median C1rC1sC1-inh level was higher (32.8 U/ml vs. 3.4 U/ml; p<0.0001) in patients, compared to controls. C1rC1sC1-inh and C1-inh strongly correlated with attack number and C1-inh-amp, both in the whole patient population and in the subgroup on danazol prophylaxis. Both C1rC1sC1-inh and C1 inh are suitable for predicting disease severity based on attack frequency and C1 inh-amp (OR=4.38[1.43-13.43], p=0.010 and 11.78[2.54-54.67], p=0.002, respectively). We presume that both C1rC1sC1-inh and C1-inh might prove sensitive predictors of the severity of HAE-C1-inh. PMID- 21300571 TI - Increase of regulatory T cells and the ratio of specific IgE to total IgE are candidates for response monitoring or prognostic biomarkers in 2-year sublingual immunotherapy (SLIT) for Japanese cedar pollinosis. AB - The aims of this study were to examine the therapeutic effects of sublingual immunotherapy (SLIT) and to identify potential biomarkers that would predict the therapeutic response in a randomized, double-blind, placebo-controlled clinical trial. The trial was carried out over two pollinosis seasons in 2007 and 2008. Carry-over therapeutic effects were analyzed in 2009. SLIT significantly ameliorated the symptoms of pollinosis during the 2008 and 2009 pollen seasons. Cry j 1-specific cytokine production in a subgroup of patients with mild disease in the SLIT group was significantly attenuated. The ratio of specific IgE to total IgE before treatment correlated with the symptom-medication score in the SLIT group in 2008. Patients with increased Cry j 1-iTreg in the SLIT group had significantly improved QOL and QOL-symptom scores. In summary, the specific IgE to total IgE ratio and upregulation of Cry j 1-iTreg are candidates for biomarker of the clinical response to SLIT. PMID- 21300572 TI - Preparations of intravenous immunoglobulins diminish the number and proinflammatory response of CD14+CD16++ monocytes in common variable immunodeficiency (CVID) patients. AB - We have studied the effect of intravenous immunoglobulins (IVIG) on monocyte subpopulations and cytokine production in patients with CVID. The absolute number of CD14(+)CD16(++) monocytes decreased on average 2.5-fold 4h after IVIG and after 20h returned to the baseline. The cytokine level in the supernatants of peripheral blood mononuclear cells (PBMC) after ex vivo LPS stimulation demonstrated the >2-fold decrease in TNF production 4h after IVIG. The TNF expression, which is higher in the CD14(+)CD16(++) monocytes, was decreased in these cells by IVIG in 4/7 CVID cases. In vitro exposure of the healthy individuals' monocytes to the IVIG preparation resulted in reduced TNF production, which was overcome by blockade of the FcgammaRIIB in the CD14(+)CD16(++) CD32B(high) monocytes. Our data suggest that reduction in the number of CD14(+)CD16(++) monocytes and the blockade of their cytokine production via triggering CD32B can contribute to the anti-inflammatory action of IVIG. PMID- 21300573 TI - ADHD and epilepsy: contributions from the use of behavioral rating scales to investigate psychiatric comorbidities. AB - Children with epilepsy have a high incidence of psychiatric comorbidities, especially attention-deficit/hyperactivity disorder (ADHD). This observational cross-sectional study investigated the presence of ADHD in 30 children with idiopathic epilepsy. The Brazilian versions of the Child Behavior Checklist (CBCL), the Teacher Report Form (TRF), and the MTA-SNAP-IV questionnaire were used to assess comorbid psychiatric conditions. ADHD diagnosis was confirmed in 53.3% of children. The combined type was the most prevalent (43.7%), followed by the hyperactive-impulsive (37.5%) and inattentive (18.7%) types. Scores above the cutoff point on these scales were strongly correlated with the presence of ADHD. The high prevalence of ADHD in association with other psychiatric comorbidities in children with epilepsy justifies the use of behavioral rating scales as screening tests. PMID- 21300574 TI - Effects of altitude in high-rise building on the autonomic nervous modulation in healthy subjects. AB - This study intended to study the effects of altitude in the high-rise building on the automatic nervous modulation in healthy subjects. Heart rate variability (HRV) analysis was performed to assess the automatic nervous modulation of the subjects at three different altitudes in the air-conditioned high-rise building, i.e., the first basement (4 m beneath sea level), the 31st floor (133 m above sea level), and the 46 th floor (200 m above sea level). We found that the heart rate was significantly decreased, whereas the standard deviation of RR intervals (SD(RR)), total power and high frequency power were significantly increased when the subject was elevated to a higher altitude. The normalized low frequency power and low-/high-frequency power ratio on the 31st and 46 th floors were significantly different between genders; however, no such difference was found on the first basement. The age correlated significantly and positively with the percentage change in the SD(RR) and coefficient of variation of RR intervals when the subjects were elevated from the first basement to the 46 th floor. In conclusion, higher altitude in an air-conditioned high-rise building can lead to an increase in HRV/vagal modulation. The stay at a higher altitude in a high-rise building may lead to increased overall HRV and vagal modulation of a subject, especially for the elder people and the people who had a small HRV at ground level. PMID- 21300575 TI - Nicotinic receptor agonist-induced salivation and its cellular mechanism in parotid acini of rats. AB - Cigarette smoking and nicotine enhance parotid saliva secretion, however, the underlying mechanism is unclear. To address the mechanism of nicotine-induced salivation and to explore the possibility that nicotinic receptor agonists act as sialogogues, we investigated the effects of nicotinic receptor agonists on salivary secretion in vivo and on intracellular Ca2+ concentration in digested parotid acini in vitro in rats. In urethane-anesthetized rats, intravenous administration of nicotinic receptor agonists, nicotine and cytisine, at 3 MUmol/kg increased whole saliva output accompanied by a pressor response with nicotine, but not with cytisine. Using Ca2+-imaging system on digested parotid acini in which autonomic nerve terminals were kept intact, nicotine and cytisine dose-dependently increased intracellular Ca2+ concentration at MUM level. This was not observed in single acinar cells containing no nerve terminal. The nicotine-induced Ca2+ response was largely blocked by a muscarinic receptor antagonist and partly blocked by an adrenergic receptor antagonist. Furthermore, the same nicotine-induced Ca2+ response was blocked by mecamylamine, a relatively selective nicotinic antagonist for alpha3beta4 subtype receptor, but not by other selective antagonists, dihydro-beta-erythroidine for alpha4-containing receptor and methyllycaconitine for alpha7 nicotinic receptors. These results suggest that nicotinic agonists-induced salivation is due to a release of acetylcholine and noradrenaline from autonomic nerve terminals through activation of alpha3beta4 nicotinic receptor subtype. In addition, considering the blood pressure response and development of addiction with nicotine, cytisine may be a better therapeutic candidate to serve as a sialogogue for xerostomia patients. PMID- 21300576 TI - Depletion of the bloom syndrome helicase stimulates homology-dependent repair at double-strand breaks in human chromosomes. AB - Mutation of BLM helicase causes Blooms syndrome, a disorder associated with genome instability, high levels of sister chromatid exchanges, and cancer predisposition. To study the influence of BLM on double-strand break (DSB) repair in human chromosomes, we stably transfected a normal human cell line with a DNA substrate that contained a thymidine kinase (tk)-neo fusion gene disrupted by the recognition site for endonuclease I-SceI. The substrate also contained a closely linked functional tk gene to serve as a recombination partner for the tk-neo fusion gene. We derived two cell lines each containing a single integrated copy of the DNA substrate. In these cell lines, a DSB was introduced within the tk-neo fusion gene by expression of I-SceI. DSB repair events that occurred via homologous recombination (HR) or nonhomologous end-joining (NHEJ) were recovered by selection for G418-resistant clones. DSB repair was examined under conditions of either normal BLM expression or reduced BLM expression brought about by RNA interference. We report that BLM knockdown in both cell lines specifically increased the frequency of HR events that produced deletions by crossovers or single-strand annealing while leaving the frequency of gene conversions unchanged or reduced. We observed no change in the accuracy of individual HR events and no substantial alteration of the nature of individual NHEJ events when BLM expression was reduced. Our work provides the first direct evidence that BLM influences DSB repair pathway choice in human chromosomes and suggests that BLM deficiency can engender genomic instability by provoking an increased frequency of HR events of a potentially deleterious nature. PMID- 21300577 TI - Plasma and cerebral spinal fluid tranexamic acid quantitation in cardiopulmonary bypass patients. AB - A method for the determination of tranexamic acid (TXA) in human plasma and cerebral spinal fluid (CSF) was developed. Analyses were performed by ultra performance liquid chromatography with tandem mass spectrometry detection (UPLC MS/MS) using E-aminocaproic acid (ACA) as an internal standard. TXA and ACA were extracted from a 50 MUL sample of plasma or CSF using a methanol protein crash protocol, and chromatographic separation was performed on an ACQUITYTM TQD mass spectrometer using a UPLC C18 BEH 1.7 MUm column with a water and methanol gradient containing 0.1% formic acid. The detection and quantitation was performed by positive ion electrospray ionization using the multiple reaction monitoring (MRM) mode. The method was linear over the concentration range of 0.1 10.0 MUg/mL, with lower limit of quantitation of 0.1 MUg/mL for TXA. The intra- and inter-assay precision was less than 12% and 13% respectively at the plasma and CSF TXA concentrations tested. The present method provides a relatively simple and sensitive assay with short turn-around-time. The method has been successfully applied to assess the plasma and CSF concentrations of tranexamic acid achieved with only one dosing regimen of tranexamic acid in patients undergoing cardiopulmonary bypass surgery (CPB). PMID- 21300578 TI - Rapid and simultaneous determination of amoxicillin, penicillin G, and their major metabolites in bovine milk by ultra-high-performance liquid chromatography tandem mass spectrometry. AB - A rapid, sensitive, and specific method for the determination of amoxicillin (AMO), amoxicilloic acid (AMA), amoxicillin diketopiperazine-2',5'-dione (DIKETO), penicillin G (PEN G), benzylpenicilloic acid (BPA-1), benzylpenilloic acid (BPA-2), and benzylpenillic acid (BPA-3) in bovine milk using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was developed and validated. The method used penicillin V (PEN V) as the internal standard and ethanol for the deproteinisation of bovine milk. Chromatographic separation of the components was performed on a Waters Acquity UPLC(r) HSS T3 column (100 mm x 2.1 mm, 1.8 MUm) using a mixture of 0.15% formic acid in water with 5mM ammonium acetate and acetonitrile as the mobile phase. Gradient elution was performed at a flow rate of 0.25 mL min-1. The mass spectrometer was operated in the positive electrospray ionisation MS/MS mode. The method was fully validated according to EU requirements, including linearity, precision, trueness, limit of quantification, limit of detection, and specificity. The results were within the ranges specified. The established method was successfully applied in the determination of AMO, PEN G, and their major metabolites in 40 commercial bovine milk samples. The results showed that 8 samples were contaminated with BPA 1 or BPA-2. The mean levels (occurrence) of BPA-1 and BPA-2 in positive samples were 287 (50%) and 320 (100%) ng mL-1, respectively. No sample was found to be contaminated with AMO, AMA, DIKETO, PEN G, and BPA-3. These findings could play an important role in food safety, because BPA-1 and BPA-2 metabolites pose possible health risks, although they are not included in the maximum residue limit legislation. PMID- 21300579 TI - [Methylene blue: usefulness in the treatment of refractory hypotension in premature infants]. PMID- 21300580 TI - Usefulness of surveys of consultant clinical practice. PMID- 21300581 TI - The scalp as a donor site for split-thickness skin graft: a rare complication case report. AB - The scalp is a useful and reliable donor site for the paediatric burn population that can be harvested several times with minimal morbidity. However, the scalp cannot be used as skin graft donor site with impunity. Scalp alopecia and chronic folliculitis can be observed among the complications. In these cases, the reconstruction phase offers different surgical procedures such as primary closure, staged excision or tissue expansion. We report the case of a patient (29 years-old), treated 20 years ago for second-degree burns covering up to 20% total body surface area (TBSA) by using thin split-thickness skin grafts of his scalp. As a teenager, he developed multiple episodes of folliculitis at the donor site of the scalp and then of recurrent abscesses, resistant to all existing medical treatments. Surgical treatment consisted in the skin excision of his scalp donor site which was immediately covered by a thin split-thickness skin graft. Four months after surgery, the patient was satisfied with the functional and aesthetic result. PMID- 21300583 TI - Evolution of reports of randomised clinical trials in plastic surgery. AB - Well-designed, well-conducted and well-reported randomised clinical trials (RCTs) can significantly impact medical care, by contributing to a strong evidence base from which clinical guidelines can be derived. In a previous study, we assessed the quality of reports of RCTs in plastic surgery published from 1966 to 2003. The aim of the present study was to verify what have changed over the last years. RCTs in plastic surgery published from 2004 to 2008 were identified through electronic searches, and classified according to their allocation concealment. Trials with allocation concealment appropriately described were evaluated as to their quality. Two independent reviewers performed the evaluations, using two tools: the Delphi List and the Jadad's quality scale. From 3840 identified studies, 96 were selected for classification according to allocation concealment; 28 (29%) of them appropriately described allocation concealment. From 1966 to 2003, 34 (17%) RCTs appropriately described allocation concealment (chi2=22.98, p<0.000). In the evaluation of the 28 RCTs by the Delphi List, the agreement coefficient between raters (kw) was 0.46 (z=7.24, p<0.000). Groups were similar at baseline in 96.4% of these trials, and this was the only item of the Delphi List, which significantly improved when compared with the period from 1966 to 2003 (chi2=18.53, p<0.000). When evaluated by Jadad's criteria, 14% of the RCTs were scored two points or less and thus considered of low quality (kw=0.72, z=8.57, p<0.001). From 1966 to 2003, 59% of RCTs were scored two points or less (chi2=17.07, p<0.004). We concluded that the quality of reports of RCTs in plastic surgery (as measured by the Jadad's criteria and only one component of the nine components of the Delphi List) significantly increased over the last years. PMID- 21300582 TI - Anatomic basis of interfascicular nerve splitting of innervated partial latissimus dorsi muscle flap. AB - PURPOSE: To study the anatomic basis for the interfascicular nerve-splitting technique applied to the innervated latissimus dorsi muscle flap to preserve the remnant muscle function. Cadaveric dissection was performed to study the distribution of the thoracodorsal nerve and artery, and simulation of the surgical technique was also executed. METHODS: A total of 42 latissimus dorsi muscles from 21 preserved cadavers were dissected, and the distribution of the nerves and arteries were studied. The thoracodorsal neurovascular bundles were identified entering the muscle, and the distance from the upper margin and lateral margin of the muscle, and the distance from the angle of scapula were measured. The distance from the brachial plexus to the branching of the thoracodorsal nerve were measured and the distance between the branching of the nerve and artery were also measured. Interfascicular splitting of the thoracodorsal nerve was performed under operating microscope and the validity of the technique was confirmed by histology. RESULTS: The thoracodorsal neurovascular bundle entered the muscle at a distance of 39.1 +/- 8.8 mm from the upper margin, and 23.8 +/- 10.3 mm from the lateral margin. In addition, from the angle of scapula, the distance was 47.8 +/- 17.8 mm in the transverse axis, and 48.9 +/- 13.5 mm in the sagittal axis. The distance from the brachial plexus to the first branching of the thoracodorsal nerve was 78.5 +/- 11.0 mm, and distance to the second branching was 96.3 +/- 12.9 mm. The thoracodorsal nerve always branched before the artery, and the distance from the first branching of the nerve to the first branching of the artery was 20.4 +/- 8.9 mm. Interfascicular dissection of the nerve was performed under operating microscope, by opening the epineurium and splitting the fascicles with utter care not to injure the perineurium. This procedure was very similar to splitting a wire cable. Histological analysis of the dissected nerve confirmed that the interfascicular dissection was performed without injuring the fascicules and the perineurium was intact. CONCLUSION: We simulated and confirmed that the preservation of the remnant muscle function was possible by using the nerve-splitting technique in the innervated latissimus dorsi muscle flap. It is easy and simple to separate the nerve branch entering the muscle flap from the nerve branch entering the remnant muscle without injury, which results in increasing the nerve length while preserving the muscle function of the donor site. Further, the distribution of the thoracodorsal neurovascular bundle was studied in 42 muscles, which can be used as a reference point during surgery. With this novel technique, preservation of the remnant muscle function is possible when using innervated muscle flaps, which can be applied in areas such as reconstruction of facial paralysis and reconstruction of the chest wall in Poland syndrome. PMID- 21300584 TI - Comparative evaluation of bone regeneration using spherical and irregularly shaped granules of interconnected porous hydroxylapatite. A beagle dog study. AB - PURPOSE: Bone regeneration stimulated by two different shapes of interconnected porous calcium hydroxyapatite (IP-CHA) granules was evaluated in the mandibles of 3 beagle dogs. METHODS: Deferent shapes of IP-CHA were used, spherical (spherical shaped IP-CHA granules) and irregular shapes (irregularly shaped IP-CHA granules). Two bone sockets (3mm in diameter and 5mm in depth) were prepared in the right edentulous mandible of each animal where right premolars had been extracted and sites healed for 3 months. The two types of IP-CHA were filled into the sockets to stimulate bone regeneration. New bone formation was evaluated histologically at 4, 8 and 12 weeks after filling. RESULTS: At 4 weeks, little bone formation was apparent in any of the bony sockets. At 8 weeks, newly formed bone was detected between the granules but not in the pores. In contrast, at 12 weeks, bone formation was clearly observed not only between the granules but also inside the granule pores. Comparing the two sites at 8 and 12 weeks, more bone formation was detected in sites receiving irregularly shaped IP-CHA than in sites receiving spherical IP-CHA. CONCLUSION: These results indicate that use of irregularly shaped IP-CHA may enhance bone regeneration. The results of this preliminary study suggest that irregularly shaped IP-CHA granules may have more possible usefulness than spherically shaped granules as a scaffold for bone regeneration. PMID- 21300585 TI - Comparison of the microshear bond strength of feldspathic porcelain to enamel with three luting resins. AB - PURPOSE: The purpose of this study was to compare microshear bond strength of three different luting resins using a new microshear method closely simulating clinical condition. METHODS: Thirty 1-mm-thick slices of intact human first molars and thirty 0.8-mm-diameter feldspathic porcelain rods were etched by 37% phosphoric acid for enamels and 9.5% hydrofluoric acid for porcelains. Adhesive (Margin bond) was applied on both silaned porcelain and enamel surfaces. Three luting agents were used as follows: (1) dual polymerized cement (DP) (Variolink II refill), (2) light polymerized cement (LP) (Variolink II base), and (3) flow composite (FC) (Tetrick flow). Porcelain rods were attached to flat enamel surfaces followed by cementation. The specimens were thermal cycled for 500 cycles between 5 and 55 degrees C, and microshear test was then performed with wire and loop method using Dillon Quantrol. Modes of failure were identified by stereomicroscope, and one sample of each group was observed with SEM. finally collected data were statistically analyzed using one-way ANOVA (P<.05). RESULTS: The mean microshear bond strengths were 21.48 (DP), 23.92 (LP) and 24.57 (FC) in MPa units. Most cohesive failures occurred in groups LP and FC, whereas most adhesive failures were observed in group DP. CONCLUSION: Bond strength of feldspathic porcelain to enamel with studied luting resins were not significantly different among the groups based on current method (P<.05). PMID- 21300586 TI - Evaluation of a newly developed polymethyl methacrylate powder for brush-dip technique. AB - PURPOSE: The aim of this study is to evaluate a newly developed polymethyl methacrylate (PMMA) powder. METHODS: The particle size distribution, surface area, and particle shape of both new and traditional powders were compared. The shear bond strength of the resin cement with the new powder to a silver-palladium copper-gold alloy was determined and compared to that for a cement with the traditional powder. Also, the weight of mixture held by the brush at one time of both powders was also calculated and compared as an index of mixability. RESULTS: The surface area of the new powder was smaller than that of the traditional powder, while the particles size distributions were similar. The new powder included various-sized spherical particles as well as irregular particles, while the traditional powder consisted of only irregular particles. The new powder showed significantly higher mixability, although its bond strength was not significantly different from that of traditional powder. CONCLUSION: The results of this study show that the interminglement of spherical and irregular particles cannot influence the bond strength to the alloy but is helpful to improve the working properties. PMID- 21300587 TI - Survival of immediate implant restoration: a retrospective study through 9-year observation. AB - PURPOSE: The purpose of this retrospective study was to assess the implant survival rate and the risk factors associated with implant failure in patients who had undergone immediate implant restoration. MATERIALS AND METHODS: We performed a retrospective review and an outcome assessment of all patients who received immediate implant restoration between 2000 and 2010 in our department at Tokushima University Hospital. The patients were divided into groups on the basis of the predictor variables: age, gender, implant location, and number of implants per jaw. The cumulative implant survival rate in the paired groups was determined by using Kaplan-Meier analysis and the log-rank test. Cox proportional hazards model was subsequently used to identify exposures associated with implant failure. RESULTS: Using the Kaplan-Meier method, the survival rates at 1, 3, and 9 years were calculated to be 98.8%, 98.0%, and 94.7%, respectively. No statistically significant association was observed between the implant survival rates and the predictor variables: gender, age, location, and number of implants. CONCLUSIONS: Immediate implant restoration is a reliable prosthetic procedure with an acceptable survival rate compared to the conventional implant procedure. PMID- 21300589 TI - [Validation and application of a risk scale: more data, better]. PMID- 21300591 TI - GAVI takes steps to address funding woes. PMID- 21300592 TI - Doctors in distress. PMID- 21300593 TI - Progress patchy on health-worker crisis. PMID- 21300595 TI - Narrative epileptology. PMID- 21300596 TI - Richard Bing. PMID- 21300598 TI - Multiple inflammatory nodules: a differential diagnosis of new pulmonary nodules in oncology patients. AB - New pulmonary nodules in an oncology patient are often considered metastatic unless proven otherwise. However, the possibility of an inflammatory cause needs to be considered in this setting. Clinicopathologic correlation is always needed in such cases to establish a diagnosis, especially before initiating a new treatment. The multiplicity of inflammatory nodules in this case, in the form of multiple pulmonary nodules and a spinal soft tissue mass, can be a considerable diagnostic challenge. The potential ramifications of not being familiar with inflammatory pseudotumors and not knowing when to suggest it involve unnecessary and incorrect patient treatment including chemotherapy, and may have medicolegal implications for the radiologist. Therefore all radiologists, especially those involved in oncologic imaging, need to be aware of this entity. PMID- 21300599 TI - [The surgery after. . . retroperitoneal lymph node dissection and surgery of the residual masses after chemotherapy for advanced testicular cancer]. AB - Thirty-six cases of retroperitoneal lymph node dissections for residual mass after chemotherapy for testicular cancer are reported. In a reference center, the recruitment is modified by the severity of the situations related to very big masses, tumors of poor prognosis and resistant tumors. Lymph node dissection is often atypical and surgery of metastatic residual masses is frequent (13 operations). The 8-year global survival remains stable, over 90%. The 5-year cumulated risk of recurrence is 20%, but these situations can be overtaken. PMID- 21300600 TI - [Surgery after chemotherapy: gastric cancer]. AB - Perioperative chemotherapy for gastric cancer is validated by two phase III studies. The impact of the preoperative neoadjuvant sequence is probably major in the benefit of this treatment. This chemotherapy increases the R0 resection without increasing either morbidity or mortality. Furthermore, it reduces local and systemic recurrence improving disease-free survival and overall survival. The drugs used are 5-FU or its oral prodrugs, platinum salts (cisplatin or oxaliplatin) and anthracyclines. The perioperative chemotherapy must be proposed to all patients with a T3 or N+ gastric adenocarcinoma. This requirement imposes a rigorous preoperative evaluation including thoraco-abdominal computed tomography and for all non-metastatic patients an echo-endoscopy with biopsies. For patients not receiving preoperative chemotherapy, multidisciplinary consultations have the choice between an adjuvant chemotherapy based on 5-FU validated by a meta-analysis or a postoperative radio-chemotherapy whose application is validated by this phase III study. PMID- 21300601 TI - [Breast surgery after neoadjuvant chemotherapy]. AB - The aim of this work is to specify surgical procedures for the breast and the axillary lymph node area after neoadjuvant chemotherapy. The extent of glandular resection was chosen using a rational based on the goals of neoadjuvant chemotherapy, the prognostical impact of response level and the evaluation of this response. The results of sentinel lymph node procedure before or after neoadjuvant chemotherapy are presented. PMID- 21300602 TI - [Hepatectomy for colorectal liver metastases after neoadjuvant chemotherapy]. AB - The majority of patients with colorectal liver metastases receive systemic chemotherapy. In the context of unresectable liver metastases, the objective of chemotherapy based on new and more effective regimens is not only to prolong survival, but also to induce enough response and shrinkage of the tumor to render resectable patients initially not deemed to be surgical candidates. In patients with resectable liver metastases, the goal of chemotherapy is to improve the outcome after surgery and especially to decrease the risk of recurrence. Although the principles of combined modality treatment become widely accepted, this therapeutic strategy is also associated with potential risks related to the preoperative use of chemotherapy. PMID- 21300603 TI - Sarcoidosis coexisting with eruptive xanthoma. PMID- 21300606 TI - Tight junctions in epidermis: from barrier to keratinization. AB - Tight junctions (TJs) are one type of intercellular junction. TJs prevent diffusion of solutes through the intercellular spaces in simple and stratified epithelia. Mice lacking claudin-1 (an adhesion molecule at TJs) show dehydration from the skin by impaired barrier function of epidermal TJs. Meanwhile, a human hereditary disease with ichthyosis (NISCH syndrome) has been found to be a claudin-1-deficient disease. The two models of lacking-claudin-1 indicate that TJs are related not only to the epidermal barrier but also to keratinization. Research of TJs in epidermis is reviewed in view of the barrier to keratinization. PMID- 21300607 TI - Rapid and complete resolution of lichen planopilaris in juvenile chronic arthritis treated with rituximab. PMID- 21300608 TI - Dermoscopy pattern of cutaneous angiosarcoma. PMID- 21300609 TI - Cutaneous plasmacytoma and leukemia cutis on the penis. PMID- 21300610 TI - [Gastrointestinal stromal tumours in pediatrics: a summary of the literature on this orphan disease]. AB - Recommendations for the management of gastrointestinal stromal tumours (GIST) in children and adolescents do presently not exist. Thus, a summary of the current literature was conducted serving as a basis for the development of optimal management strategies for childhood GIST. Pediatric cases of GIST may occur sporadically, or within a predisposition syndrome such as Carney triad or Carney Stratakis syndrome. Moreover, cases with familial GIST have been reported. The frequency of mutations of the oncogenes KIT and PDGFRalpha in sporadic GIST is substantially lower as compared with adults with GIST. An international prospective registration based on national registries has recently been started in order to acquire more clinical and molecular data and to develop appropriate management strategies for children and adolescents with GIST. PMID- 21300611 TI - [Salvage surgery: cancer of the esophagus]. AB - Neoadjuvant chemoradiotherapy is the gold standard of the treatment of advanced oesophageal cancer. The role of surgery after chemoradiotherapy is still debated. Feasibility of curative resection depends on dose of radiotherapy, morbimortality rates, and nutrition status at the end of the protocol especially for non responders patients. Adding surgery to radiochemotherapy improves local tumour control but does not increase overall survival of patients with advanced oesophageal cancer. According to the two randomised trials published on the subject, surgery is not recommended after chemoradiotherapy for responders. Recommendations of French National Thesaurus are: exclusive chemoradiotherapy as reference, esophagectomy for residual tumour as alternative for operable patients. Surgery may be proposed for selected non-responders patients and some complete pathological response in expert center. PMID- 21300612 TI - [Complete response for rectal carcinoma after neoadjuvant therapy: to operate or not to operate? Surgeon's view]. AB - A complete response to neoadjuvant therapy occurs in a significant group of patients with rectal cancer. Management of these patients is controversial. This review evaluates the tumoral response, the surgical management and the potential results. PMID- 21300613 TI - [Plea for radical salvage surgery for recurrent cancer of the anal canal]. AB - Salvage abdomino-perineal resection is justified in case of failure of the conservative treatment of a cancer of the anal canal. This surgery must be offered if surgery could be complete. In case of R0 resection, more than a patient on two will be alive after 5 years. The rate of perineal complication is important and gives proof to accomplish associated procedure to fill up the perineal cavity as muscular flap taken from the abdominal wall, the perineal colostomy that avoids the iliac colostomy or the simple flap of gracilis. This linked procedure allows to diminish the length of healing and improves postoperative time. PMID- 21300615 TI - The need for forward-looking decision analyses to guide cervical cancer prevention. PMID- 21300616 TI - Challenges with demographic disparities in gastric cancer care and survival: spectral rather than black and white. PMID- 21300617 TI - Demographic disparities in patterns of care and survival outcomes for patients with resected gastric adenocarcinoma. AB - BACKGROUND: Several reports showed incomplete adoption of adjuvant radiotherapy (RT) for resectable gastric cancer since the publication of Intergroup 0116 trial results. The aims of this study were to identify demographic factors associated with omission of adjuvant RT and assess the impact of this omission on survival. METHODS: SEER database was queried for cases of resected gastric cancer. Multivariate analyses with logistic and Cox regressions were used to examine (a) likelihood of receiving adjuvant RT for different patient and county demographics and (b) effect of demographics on survival outcomes. RESULTS: A total of 7,348 patients met the study criteria. Adjuvant RT was used in 33.1% of cases diagnosed in 1998-2001 and in 45.3% of cases in 2002-2007 (P < 0.001). Controlling for independent covariates, African Americans were 8.9% less likely to receive adjuvant RT than Caucasians or Asians (P < 0.001). Correspondingly, overall survival rates were significantly lower for African Americans than other races (HR = 1.38, P < 0.001). Furthermore, both the likelihood of receiving RT and the survival rates were significantly affected by county demographics: percent of population without high school education, percent of households below the poverty line, and median household income. Survival rates were highest among Asians, but this finding did not reflect more frequent use of RT. CONCLUSIONS: Race and socioeconomic factors are significant predictors of treatment and survival outcomes for patients with resectable gastric cancer. IMPACT: The findings of this and similar studies may aide the medical community in designing more effective strategies to ameliorate the standards of care nationwide. PMID- 21300618 TI - Incident cervical HPV infections in young women: transition probabilities for CIN and infection clearance. AB - BACKGROUND: We describe transition probabilities for incident human papillomavirus (HPV) 16/18/31/33/35/45/52/58/59 infections and cervical intraepithelial neoplasia (CIN) 1 lesions. METHODS: Women ages 16 to 23 years underwent cytology and cervical swab PCR testing for HPV at approximately 6-month intervals for up to 4 years in the placebo arm of an HPV vaccine trial. The cumulative proportion of incident HPV infections with diagnosed CIN, clearing (infection undetectable), or persisting without CIN, were estimated. RESULTS: Most incident infections cleared, without detection of CIN, ranging at 36 months from 66.9% for HPV31 to 91.1% for HPV59. There was little variation in the 36 month proportion of incident HPV16, 18, and 31 infections followed by a CIN1 lesion positive for the relevant HPV type (range 16.7%-18.6%), with lower risks for HPV59 (6.4%) and HPV33 (2.9%). Thirty-six-month transition probabilities for CIN2 ranged across types from 2.2% to 9.1%; however, the number of events was generally too small for statistically significant differences to be seen across types for this endpoint, or CIN3. CONCLUSIONS: Some incident HPV types appear more likely to result in diagnosed CIN1 than others. The relative predominance of HPV16, vis-a-vis some other high-risk HPV types (e.g., HPV33) in prevalent CIN2/3, appears more directly associated with relatively greater frequency of incident HPV16 infections within the population, than a higher risk of infection progression to CIN2/3. IMPACT: Nearly all incident HPV infections either manifest as detectable CIN or become undetectable within 36 months. Some HPV types (e.g., 16 and 33) appear to have similar risk of CIN2/3 despite widely varied incidence. PMID- 21300619 TI - Assessment of type of allergy and antihistamine use in the development of glioma. AB - BACKGROUND: Allergies have been associated with decreased risk of glioma; but, associations between duration and timing of allergies, and antihistamine use and glioma risk have been less consistent. The objective was to investigate this association by analyzing types, number, years since diagnosis, and age at diagnosis of allergies, and information on antihistamine usage, including type, duration, and frequency of exposure. METHODS: Self-report data on medically diagnosed allergies and antihistamine use were obtained for 419 glioma cases and 612 hospital-based controls from Duke University and NorthShore University HealthSystem. RESULTS: High- and low-grade glioma cases were statistically significantly less likely to report any allergy than controls (OR = 0.66, 95% CI: 0.49-0.87 and OR = 0.44, 95% CI: 0.25-0.76, respectively). The number of types of allergies (seasonal, medication, pet, food, and other) was inversely associated with glioma risk in a dose-response manner (P value for trend < 0.05). Age at diagnosis and years since diagnosis of allergies were not associated with glioma risk. Oral antihistamine use was statistically significantly inversely associated with glioma risk, but when stratified by allergy status, remained significant only for those with high-grade glioma and no medically diagnosed allergy. CONCLUSIONS: All types of allergies appear to be protective with reduced risk for those with more types of allergies. Antihistamine use, other than in relationship with allergy status, may not influence glioma risk. IMPACT: A comprehensive study of allergies and antihistamine use using standardized questions and biological markers will be essential to further delineate the biological mechanism that may be involved in brain tumor development. PMID- 21300620 TI - High-risk human papillomavirus in esophageal squamous cell carcinoma--letter. PMID- 21300622 TI - FunSecKB: the Fungal Secretome KnowledgeBase. AB - The Fungal Secretome KnowledgeBase (FunSecKB) provides a resource of secreted fungal proteins, i.e. secretomes, identified from all available fungal protein data in the NCBI RefSeq database. The secreted proteins were identified using a well evaluated computational protocol which includes SignalP, WolfPsort and Phobius for signal peptide or subcellular location prediction, TMHMM for identifying membrane proteins, and PS-Scan for identifying endoplasmic reticulum (ER) target proteins. The entries were mapped to the UniProt database and any annotations of subcellular locations that were either manually curated or computationally predicted were included in FunSecKB. Using a web-based user interface, the database is searchable, browsable and downloadable by using NCBI's RefSeq accession or gi number, UniProt accession number, keyword or by species. A BLAST utility was integrated to allow users to query the database by sequence similarity. A user submission tool was implemented to support community annotation of subcellular locations of fungal proteins. With the complete fungal data from RefSeq and associated web-based tools, FunSecKB will be a valuable resource for exploring the potential applications of fungal secreted proteins. Database URL: http://proteomics.ysu.edu/secretomes/fungi.php. PMID- 21300623 TI - Attention deficit hyperactivity disorder and environmental toxic metal exposure in the United Arab Emirates. AB - No systematic studies have been carried out on the effects of toxic metals on childhood behavior in the Gulf Region including the UAE. The relationship between blood levels of heavy metals and Attention Deficit Hyperactivity disorder (ADHD) were explored in school-aged children of UAE and it was found that increased blood concentrations of lead (Pb), manganese (Mn) and zinc (Zn) were significantly associated with ADHD. The findings suggest that monitoring for exposure to heavy metal levels and education on potential child health hazards related to them are indicated. PMID- 21300624 TI - New IBD genetics: common pathways with other diseases. AB - Complex disease genetics has been revolutionised in recent years by the advent of genome-wide association (GWA) studies. The chronic inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis have seen notable successes culminating in the discovery of 99 published susceptibility loci/genes (71 Crohn's disease; 47 ulcerative colitis) to date. Approximately one-third of loci described confer susceptibility to both Crohn's disease and ulcerative colitis. Amongst these are multiple genes involved in IL23/Th17 signalling (IL23R, IL12B, JAK2, TYK2 and STAT3), IL10, IL1R2, REL, CARD9, NKX2.3, ICOSLG, PRDM1, SMAD3 and ORMDL3. The evolving genetic architecture of IBD has furthered our understanding of disease pathogenesis. For Crohn's disease, defective processing of intracellular bacteria has become a central theme, following gene discoveries in autophagy and innate immunity (associations with NOD2, IRGM, ATG16L1 are specific to Crohn's disease). Genetic evidence has also demonstrated the importance of barrier function to the development of ulcerative colitis (HNF4A, LAMB1, CDH1 and GNA12). However, when the data are analysed in more detail, deeper themes emerge including the shared susceptibility seen with other diseases. Many immune mediated diseases overlap in this respect, paralleling the reported epidemiological evidence. However, in several cases the reported shared susceptibility appears at odds with the clinical picture. Examples include both type 1 and type 2 diabetes mellitus. In this review we will detail the presently available data on the genetic overlap between IBD and other diseases. The discussion will be informed by the epidemiological data in the published literature and the implications for pathogenesis and therapy will be outlined. This arena will move forwards very quickly in the next few years. Ultimately, we anticipate that these genetic insights will transform the landscape of common complex diseases such as IBD. PMID- 21300625 TI - Modelling batched Gaussian longitudinal weight data in mice subject to informative dropout. AB - Modelling longitudinal data subject to informative dropout is an active area in statistical research. This article focuses on modelling such longitudinal data when the outcome at each follow-up time is collected in batches rather than individually collected. The problem occurred in a study that compared the weight of mice over time between a control and a treatment group, where animal weight was measured in batches of five animals per cage. We develop both a shared parameter and a pattern mixture modelling approach for accounting for potentially informative dropout due to an animal's death. Our methodology suggests that animals receiving the treatment have a lower weight in mid-life, and have a slower decline in weight in the later period of life. Our simulations suggest that both the shared random parameter and pattern mixture modelling approaches work well under a correctly specified model. However, the pattern mixture model is more robust against model misspecification than the shared random parameter model, but the shared random parameter model parameters have a more direct interpretation than those of the pattern mixture modelling approach. PMID- 21300626 TI - A generalized p-value approach for assessing noninferiority in a three-arm trial. AB - The existing generalized p-value approach, from statistical literature, is applied to assess noninferiority of an experimental treatment in a three-arm clinical trial including a placebo. Two generalized test functions (GTFs) are constructed and Monte Carlo simulations are used to compute the p-value. The GTFs perform well in terms of maintaining the Type-I error probabilities, and the power of the tests are shown to increase to 1 as both the sample size and the parameter denoting the fraction of the effect of the reference drug with respect to placebo increase. The generalized confidence intervals are shown to retain the coverage probabilities. A published dataset is re-analysed using the proposed test and the results are in agreement with earlier findings. PMID- 21300627 TI - Comparing measurement error correction methods for rate-of-change exposure variables in survival analysis. AB - In this article we focus on comparing measurement error correction methods for rate-of-change exposure variables in survival analysis, when longitudinal data are observed prior to the follow-up time. Motivational examples include the analysis of the association between changes in cardiovascular risk factors and subsequent onset of coronary events. We derive a measurement error model for the rate of change, estimated through subject-specific linear regression, assuming an additive measurement error model for the time-specific measurements. The rate of change is then included as a time-invariant variable in a Cox proportional hazards model, adjusting for the first time-specific measurement (baseline) and an error-free covariate. In a simulation study, we compared bias, standard deviation and mean squared error (MSE) for the regression calibration (RC) and the simulation-extrapolation (SIMEX) estimators. Our findings indicate that when the amount of measurement error is substantial, RC should be the preferred method, since it has smaller MSE for estimating the coefficients of the rate of change and of the variable measured without error. However, when the amount of measurement error is small, the choice of the method should take into account the event rate in the population and the effect size to be estimated. An application to an observational study, as well as examples of published studies where our model could have been applied, are also provided. PMID- 21300628 TI - Concentrations and size distributions of airborne influenza A viruses measured indoors at a health centre, a day-care centre and on aeroplanes. AB - The relative importance of the aerosol transmission route for influenza remains contentious. To determine the potential for influenza to spread via the aerosol route, we measured the size distribution of airborne influenza A viruses. We collected size-segregated aerosol samples during the 2009-2010 flu season in a health centre, a day-care facility and onboard aeroplanes. Filter extracts were analysed using quantitative reverse transcriptase polymerase chain reaction. Half of the 16 samples were positive, and their total virus concentrations ranged from 5800 to 37,000 genome copies m(-3). On average, 64 per cent of the viral genome copies were associated with fine particles smaller than 2.5 um, which can remain suspended for hours. Modelling of virus concentrations indoors suggested a source strength of 1.6+/-1.2*10(5) genome copies m(-3) air h(-1) and a deposition flux onto surfaces of 13+/-7 genome copies m(-2) h(-1) by Brownian motion. Over 1 hour, the inhalation dose was estimated to be 30+/-18 median tissue culture infectious dose (TCID50), adequate to induce infection. These results provide quantitative support for the idea that the aerosol route could be an important mode of influenza transmission. PMID- 21300629 TI - The role of the couch in psychoanalysis: proposed research designs and some preliminary data. AB - Ever since Freud, the couch has been viewed as an important--some would argue essential--component of psychoanalysis. Although many theoretical papers and case reports have addressed the use of the couch in psychoanalysis, no empirical study has investigated its effect on psychoanalytic process or outcome. After a review of the literature, a number of research designs are proposed that might be used in such an investigation. Finally, preliminary empirical data are presented from archived audiotapes of two psychoanalyses: one in which the patient switched from lying down to sitting up, and one in which the opposite occurred. The aim is to stimulate research-oriented psychoanalysts to undertake empirical investigations of the theoretical concepts underlying use of the couch and, more generally, to present a specific example of research as a paradigm for a broader research agenda for empirical investigation of the key theoretical ideas underlying psychoanalysis. PMID- 21300630 TI - Two surveys: an introduction. PMID- 21300632 TI - Percutaneous coronary intervention for acute coronary syndromes: no difference in 30-day efficacy or safety of high- and low-dose aspirin; double-dose clopidogrel reduces 30-day risk of cardiovascular death, myocardial infarction or stroke compared with standard dose but increases risk of major bleeding. PMID- 21300633 TI - Spatial and sustained attention in relation to smoking status: behavioural performance and brain activation patterns. AB - Nicotine enhances attentional functions. Since chronic nicotine exposure through smoking induces neuroadaptive changes in the brain at a structural and molecular level, the present functional MRI (fMRI) study aimed at investigating the neural mechanisms underlying visuospatial and sustained attention in smokers and non smokers. Visuospatial attention was assessed with a location-cueing paradigm, while sustained attention was measured by changes in response speed over time. During invalid trials, neural activity within the basal forebrain was selectively enhanced in smokers and higher basal forebrain activity was associated with increased parietal cortex activation. Moreover, higher levels of expired carbon monoxide in smokers before scanning were associated with higher parietal cortex activation and faster responses to invalidly cued targets. Smokers showed a slowing of responses and additionally recruited an area within the right supramarginal gyrus with increasing time on task. Activity decreases over time were observed in visual areas in smokers. The data provide evidence for altered attentional functions in smokers as compared with non-smokers, which were partly modulated by residual nicotine levels and were observed at a behavioural level for sustained and at a neural level for spatial and sustained attention. PMID- 21300634 TI - Impact of pharmacological treatments on outcome in adult rodents after traumatic brain injury: a meta-analysis. AB - Pharmacological treatments have been widely investigated in pre-clinical animal trials to evaluate their usefulness in reducing cognitive, behavioural and motor problems after traumatic brain injury (TBI). However, the relative efficacy of these agents has yet to be evaluated, making it difficult to assess the strength of evidence for their use in a clinical population. A meta-analytic review of research (1980-2009) was therefore conducted to examine the impact of pharmacological treatments administered to adult male rodents after experimental TBI on cognitive, behavioural, and motor outcome. The PubMed and PsycInfo databases were searched using 35 terms. Weighted Cohen's d effect sizes, percent overlap, Fail-Safe N statistics and confidence intervals were calculated for each treatment. In total, 91 treatments were evaluated in 223 pre-clinical trials, comprising 5988 rodents. Treatments that were investigated by multiple studies and showed large and significant treatment effects were of greatest interest. Of the 16 treatments that were efficacious, six improved cognition, 10 improved motor function and no treatment improved behaviour (depression/anxiety, aggression, zoosocial behaviour). Treatment benefits were found across a range of TBI models. Drug dosage and treatment interval impacted on treatment effects. PMID- 21300635 TI - Onabotulinum toxin A treatment of cervicogenic headache: a randomised, double blind, placebo-controlled crossover study. AB - AIMS: Preliminary reports regarding injections in the neck of onabotulinum toxin A have been positive in cervicogenic headache (CeH). The aim was to perform the first methodologically rigorous trial. METHODS: A randomised, placebo-controlled, patient-, injector- and evaluator-blinded crossover study included 28 adult patients with a long-standing and treatment-resistant CeH. After a baseline period, injections of either onabotulinum toxin A or placebo were given in fixed sites in the neck muscles on the pain side. Second injections were given after >=8 weeks. Patients were thereafter followed for another 8 weeks. A detailed headache calendar was filled in, and patients were followed with quality-of-life (QoL) questionnaires, algometry and neck mobility measurements. RESULTS: There was no significant difference between verum and placebo in a mixed linear model analysis (p = 0.084) with regard to the primary end-point, reduction of days with moderate to severe headache. Six patients withdrew from the study before the second injections, but an intention-to-treat (ITT) analysis gave a similar result (p = 0.27). There were no significant differences favouring verum in any of the secondary efficacy measures. Side-effects of onabotulinum toxin A were minor and short-lasting. CONCLUSION: Onabotulinum toxin A in neck muscles does not seem to be beneficial in CeH. PMID- 21300636 TI - CGRP in migraine. PMID- 21300637 TI - Migraine attributed to genetic disorder: proposal of a new category. PMID- 21300638 TI - Escherichia coli YafP protein modulates DNA damaging property of the nitroaromatic compounds. AB - Escherichia coli SOS functions constitute a multifaceted response to DNA damage. We undertook to study the role of yafP, a SOS gene with unknown function. yafP is part of an operon also containing the dinB gene coding for DNA Polymerase IV (PolIV). Our phylogenetic analysis showed that the gene content of this operon is variable but that the dinB and the yafP genes are conserved in the majority of E. coli natural isolates. Therefore, we studied if these proteins are functionally linked. Using a murine septicaemia model, we showed that YafP activity reduced the bacterial fitness in the absence of PolIV. Similarly, YafP increased cytotoxicity of two DNA damaging nitroaromatic compounds, 4-nitroquinoline-1 oxide (NQO) and nitrofurazone, in the absence of PolIV. The fact that PolIV counterbalances YafP-induced cytotoxicity could explain why these two genes are transcriptionally linked. We also studied the involvement of YafP in genotoxic stress induced mutagenesis and found that PolIV and YafP reduced NQO-induced mutagenicity. The YafP antimutator activity was independent of the PolIV activity. Given that YafP was annotated as a putative acetyltransferase, it could be that YafP participates in the metabolic transformation of genotoxic compounds, hence modulating the balance between their mutagenicity and cytotoxicity. PMID- 21300639 TI - ModeRNA: a tool for comparative modeling of RNA 3D structure. AB - RNA is a large group of functionally important biomacromolecules. In striking analogy to proteins, the function of RNA depends on its structure and dynamics, which in turn is encoded in the linear sequence. However, while there are numerous methods for computational prediction of protein three-dimensional (3D) structure from sequence, with comparative modeling being the most reliable approach, there are very few such methods for RNA. Here, we present ModeRNA, a software tool for comparative modeling of RNA 3D structures. As an input, ModeRNA requires a 3D structure of a template RNA molecule, and a sequence alignment between the target to be modeled and the template. It must be emphasized that a good alignment is required for successful modeling, and for large and complex RNA molecules the development of a good alignment usually requires manual adjustments of the input data based on previous expertise of the respective RNA family. ModeRNA can model post-transcriptional modifications, a functionally important feature analogous to post-translational modifications in proteins. ModeRNA can also model DNA structures or use them as templates. It is equipped with many functions for merging fragments of different nucleic acid structures into a single model and analyzing their geometry. Windows and UNIX implementations of ModeRNA with comprehensive documentation and a tutorial are freely available. PMID- 21300640 TI - Efficient detection of RNA-protein interactions using tethered RNAs. AB - The diverse localization of transcripts in cells suggests that there are many specific RNA-protein interactions that have yet to be identified. Progress has been limited, however, by the lack of a robust method to detect and isolate the RNA-binding proteins. Here we describe the use of an RNA aptamer, scaffolded to a tRNA, to create an affinity matrix that efficiently pulls down transcript specific RNA-binding proteins from cell lysates. The addition of the tRNA scaffold to a Streptavidin aptamer (tRSA) increased binding efficiency by ~ 10 fold. The tRSA system with an attached G-quartet sequence also could efficiently and specifically capture endogenous Fragile X Mental Retardation Protein (FMRP), which recognizes this RNA sequence. An alternative method, using biotinylated RNA, captured FMRP less efficiently than did our tRSA method. Finally we demonstrate the identification of novel RNA-binding proteins that interact with intron2 or 3'-UTR of the polarity protein Crumbs3 transcript. Proteins captured by these RNA sequences attached to the tRNA scaffold were identified by mass spectrometry. GFP-tagged versions of these proteins also showed specific interaction with either the Crb3 intron2 or 3'-UTR. Our tRSA technique should find wide application in mapping the RNA-protein interactome. PMID- 21300641 TI - Amplification ratio control system for copy number variation genotyping. AB - We describe a generic design for ratiometric analysis suitable for determination of copy number variation (CNV) class of a gene. Following two initial sequence specific PCR priming cycles, both ends of both amplicons (one test and one reference) in a duplex reaction, are all primed by the same universal primer (UP). Following each amplification denaturation step, the UP target and its reverse complement (UP') in each strand form a hairpin. The bases immediately beyond the 3'-end of the UP and 5' of UP' are chosen such as not to base pair in the hairpin (otherwise priming is ablated). This hairpin creates a single constant environment for priming events and chaperones free 3'-ends of amplicon strands. The resultant 'amplification ratio control system' (ARCS) permits ratiometric representation of amplicons relative to the original template into PCR plateau phase. These advantages circumvent the need for real-time PCR for quantitation. Choice of different %(G+C) content for the target and reference amplicons allows liquid phase thermal melt discrimination and quantitation of amplicons. The design is generic, simple to set up and economical. Comparisons with real-time PCR and other techniques are made and CNV assays demonstrated for haptoglobin duplicon and 'chemokine (C-C motif) ligand 3-like 1' gene. PMID- 21300642 TI - Biochemical behavior of N-oxidized cytosine and adenine bases in DNA polymerase mediated primer extension reactions. AB - To clarify the biochemical behavior of 2'-deoxyribonucleoside 5'-triphosphates and oligodeoxyribonucleotides (ODNs) containing cytosine N-oxide (C(o)) and adenine N-oxide (A(o)), we examined their base recognition ability in DNA duplex formation using melting temperature (T(m)) experiments and their substrate specificity in DNA polymerase-mediated replication. As the result, it was found that the T(m) values of modified DNA-DNA duplexes incorporating 2' deoxyribonucleoside N-oxide derivatives significantly decreased compared with those of the unmodified duplexes. However, single insertion reactions by DNA polymerases of Klenow fragment (KF) (exo(-)) and Vent (exo(-)) suggested that C(o) and A(o) selectively recognized G and T, respectively. Meanwhile, the kinetic study showed that the incorporation efficiencies of the modified bases were lower than those of natural bases. Ab initio calculations suggest that these modified bases can form the stable base pairs with the original complementary bases. These results indicate that the modified bases usually recognize the original bases as partners for base pairing, except for misrecognition of dATP by the action of KF (exo(-)) toward A(o) on the template, and the primers could be extended on the template DNA. When they misrecognized wrong bases, the chain could not be elongated so that the modified base served as the chain terminator. PMID- 21300643 TI - A novel method for the efficient and selective identification of 5 hydroxymethylcytosine in genomic DNA. AB - Recently, 5-hydroxymethylcytosine (5hmC) was identified in mammalian genomic DNA. The biological role of this modification remains unclear; however, identifying the genomic location of this modified base will assist in elucidating its function. We describe a method for the rapid and inexpensive identification of genomic regions containing 5hmC. This method involves the selective glucosylation of 5hmC residues by the beta-glucosyltransferase from T4 bacteriophage creating beta-glucosyl-5-hydroxymethylcytosine (beta-glu-5hmC). The beta-glu-5hmC modification provides a target that can be efficiently and selectively pulled down by J-binding protein 1 coupled to magnetic beads. DNA that is precipitated is suitable for analysis by quantitative PCR, microarray or sequencing. Furthermore, we demonstrate that the J-binding protein 1 pull down assay identifies 5hmC at the promoters of developmentally regulated genes in human embryonic stem cells. The method described here will allow for a greater understanding of the temporal and spatial effects that 5hmC may have on epigenetic regulation at the single gene level. PMID- 21300645 TI - Human imprinted retrogenes exhibit non-canonical imprint chromatin signatures and reside in non-imprinted host genes. AB - Imprinted retrotransposed genes share a common genomic organization including a promoter-associated differentially methylated region (DMR) and a position within the intron of a multi-exonic 'host' gene. In the mouse, at least one transcript of the host gene is also subject to genomic imprinting. Human retrogene orthologues are imprinted and we reveal that human host genes are not imprinted. This coincides with genomic rearrangements that occurred during primate evolution, which increase the separation between the retrogene DMRs and the host genes. To address the mechanisms governing imprinted retrogene expression, histone modifications were assayed at the DMRs. For the mouse retrogenes, the active mark H3K4me2 was associated with the unmethylated paternal allele, while the methylated maternal allele was enriched in repressive marks including H3K9me3 and H4K20me3. Two human retrogenes showed monoallelic enrichment of active, but not of repressive marks suggesting a partial uncoupling of the relationship between DNA methylation and repressive histone methylation, possibly due to the smaller size and lower CpG density of these DMRs. Finally, we show that the genes immediately flanking the host genes in mouse and human are biallelically expressed in a range of tissues, suggesting that these loci are distinct from large imprinted clusters. PMID- 21300644 TI - Use of divalent metal ions in the DNA cleavage reaction of topoisomerase IV. AB - It has long been known that type II topoisomerases require divalent metal ions in order to cleave DNA. Kinetic, mutagenesis and structural studies indicate that the eukaryotic enzymes utilize a novel variant of the canonical two-metal-ion mechanism to promote DNA scission. However, the role of metal ions in the cleavage reaction mediated by bacterial type II enzymes has been controversial. Therefore, to resolve this critical issue, this study characterized the DNA cleavage reaction of Escherichia coli topoisomerase IV. We utilized a series of divalent metal ions with varying thiophilicities in conjunction with oligonucleotides that replaced bridging and non-bridging oxygen atoms at (and near) the scissile bond with sulfur atoms. DNA scission was enhanced when thiophilic metal ions were used with substrates that contained bridging sulfur atoms. In addition, the metal-ion dependence of DNA cleavage was sigmoidal in nature, and rates and levels of DNA cleavage increased when metal ion mixtures were used in reactions. Based on these findings, we propose that topoisomerase IV cleaves DNA using a two-metal-ion mechanism in which one of the metal ions makes a critical interaction with the 3'-bridging atom of the scissile phosphate and facilitates DNA scission by the bacterial type II enzyme. PMID- 21300646 TI - Indoor coal use and early childhood growth. AB - OBJECTIVE: To examine whether indoor coal combustion for heating, which releases pollutants into the air, affects early childhood growth. DESIGN: A prospective longitudinal study, with growth measurements extracted from medical records of the children's well-child care visits at age 36 months. Data were compiled from self-administered questionnaires and medical records, both completed at 2 time points: delivery and follow-up. SETTING: Teplice and Prachatice districts in the Czech Republic. PARTICIPANTS: A total of 1133 children followed from birth to age 36 months. MAIN EXPOSURE: Maternally reported use of coal for heating. MAIN OUTCOME MEASURE: The z score for height for age and sex at age 36 months. RESULTS: Adjusted for covariates, indoor coal use was significantly associated with a lower z score for height for age and sex at age 36 months (z score = 0.37; 95% confidence interval, -0.60 to -0.14). This finding translates into a reduction in height of about 1.34 cm (95% confidence interval, 0.51 to 2.16) for boys and 1.30 cm (95% confidence interval, 0.50 to 2.10) for girls raised in homes that used coal. The association between coal use and height was modified by postnatal cigarette smoke exposure. CONCLUSIONS: Pollution from indoor coal use may impair early childhood skeletal growth to age 36 months. Because a significant proportion of the world population still uses coal indoors, the finding has public health consequences. PMID- 21300647 TI - Cost-effectiveness of respiratory syncytial virus prophylaxis in various indications. AB - OBJECTIVES: To evaluate the cost-effectiveness of immunoprophylaxis against respiratory syncytial virus (RSV) infections with palivizumab based on actual cost and observed incidence rates in various pediatric risk groups. DESIGN: Decision tree analysis comparing children with various combinations of the following indications: chronic lung disease, congenital heart disease, or prematurity (<=32 weeks gestation), and children with none of these indications. One-way sensitivity analyses and Monte Carlo simulations were used to quantify parameter uncertainty. SETTING: Florida during the 2004-2005 RSV season. PARTICIPANTS: A total of 159,790 Medicaid-eligible children aged 0 to 2 years. INTERVENTION: Palivizumab prophylaxis compared with no prophylaxis. OUTCOMES MEASURE: Incremental cost (2010 US dollars) per hospitalization for RSV infection avoided. RESULTS: The mean cost of palivizumab per dose ranged from $1661 for infants younger than 6 months of age to $2584 for children in their second year of life. Among preterm infants younger than 6 months of age without other indications, immunoprophylaxis with palivizumab cost $302,103 (95% confidence interval, $141,850-$914,798) to prevent 1 RSV-related hospitalization. Given a mean cost of $8910 for 1 RSV-related hospitalization in this subgroup, palivizumab would be cost-neutral at a per-dose cost of $47. Incremental cost effectiveness ratios for the other subgroups ranged from $361,727 to more than $1.3 million per RSV-related hospitalization avoided in children up to 2 years of age with chronic lung disease and no additional risk factors. Younger age and multiple indications were associated with improvements in the incremental cost effectiveness ratio. CONCLUSIONS: The cost of immunoprophylaxis with palivizumab far exceeded the economic benefit of preventing hospitalizations, even in infants at highest risk for RSV infection. PMID- 21300648 TI - Adding fuel to the fire: increasing evidence for developmental toxicity of indoor solid fuel combustion. PMID- 21300649 TI - Influenza coinfection and outcomes in children with complicated pneumonia. AB - OBJECTIVE: To determine the impact of influenza coinfection on outcomes for children with complicated pneumonia. DESIGN: Retrospective cohort study. SETTING: Forty children's hospitals that contribute data to the Pediatric Health Information System. PARTICIPANTS: Children discharged from participating hospitals between January 1, 2004, and June 30, 2009, with complicated pneumonia requiring a pleural drainage procedure. MAIN EXPOSURE: Influenza coinfection. MAIN OUTCOME MEASURES: Intensive care unit admission, receipt of mechanical ventilation, receipt of vasoactive infusions, receipt of blood product transfusions, in-hospital death, readmission within 14 days of hospital discharge, hospital length of stay, and cost of hospitalization. RESULTS: Overall, 3382 of 9680 children with complicated pneumonia underwent pleural fluid drainage; 105 patients (3.1%) undergoing pleural drainage had influenza coinfection. A bacterial pathogen was identified in 1201 cases (35.5%); the most commonly identified bacteria were Staphylococcus aureus in children with influenza coinfection (22.9% of cases) and Streptococcus pneumoniae in children without coinfection (20.0% of cases). In multivariable analysis, influenza coinfection was associated with higher odds of intensive care unit admission and receipt of mechanical ventilation, vasoactive infusions, and blood product transfusions as well as higher costs and a longer hospital stay. Children with influenza coinfection were less likely to require readmission, although there was a trend toward higher odds of mortality for patients with coinfection. In a subanalysis stratified by bacteria, outcomes remained worse for coinfected children in the subgroups of children with S aureus and with no specified bacteria. CONCLUSIONS: Influenza coinfection occurred in 3.1% of children with complicated pneumonia. Clinical outcomes for children with complicated pneumonia and influenza coinfection were more severe than for children without documented influenza coinfection. PMID- 21300650 TI - Effect of hospital-based comprehensive care clinic on health costs for Medicaid insured medically complex children. AB - OBJECTIVE: To evaluate the effect on all state Medicaid costs of a children's hospital-based multidisciplinary clinic that provides comprehensive and coordinated care for medically complex children. DESIGN: Before-after intervention study. Patients' health care costs for up to 1 year before enrollment in the clinic were compared with patients' health care costs for up to 1 year after enrollment in the clinic. Patients were enrolled in our study from August 2006 to May 2008. SETTING: Tertiary care children's hospital in a rural state. PARTICIPANTS: A total of 225 medically complex children who had at least 2 chronic medical conditions and who were followed up by at least 2 pediatric subspecialists. INTERVENTION: Multidisciplinary teams ensure that each patient receives all the necessary medical, nutritional, and developmental care and that there is improved coordination of care with primary care providers, subspecialists, hospitalists, and community-based services. MAIN OUTCOME MEASURES: Using Arkansas Medicaid claims data, we examined the medical costs for all outpatient, inpatient, emergency department, and prescription drug claims. Costs were calculated on a per month per patient basis and summarized for annual costs. RESULTS: The mean annual cost per patient per month decreased by $1766 for inpatient care (P < .001) and by $6.00 for emergency department care (P < .001). Although the cost per patient per month for outpatient claims (P < .05) and prescriptions (P < .001) increased, the overall cost to Medicaid per patient per month decreased by $1179 (P < .001). CONCLUSIONS: This hospital-based multidisciplinary clinic resulted in a significant decrease in total Medicaid costs for medically complex children. PMID- 21300651 TI - Pediatrics, public health, and infant mortality in the early 20th century. PMID- 21300652 TI - The limit of viability: a single regional unit's experience. AB - OBJECTIVE: To establish the limit between beneficial and futile management in the extremely preterm infant, born at the limit of viability, at 22 to 26 weeks of gestational age (GA). DESIGN: Retrospective study (11-year study period). SETTING: A tertiary regional neonatal unit. PARTICIPANTS: Inborn infants (n = 841) with a birth weight of 1000 g or less and GA 2207 through 2667 weeks. INTERVENTION: We compared mortality and neurodevelopmental outcome between 2 periods, epoch 1 (January 1998 to June 2003) and epoch 2 (July 2003 to December 2008). For neurodevelopmental data, epoch 2 extended only to December 2006. MAIN OUTCOME MEASURES: We reviewed survival rates and adverse neurodevelopmental outcome rates at 18 to 24 months' corrected age. RESULTS: In the past decade, survival rates continued to increase while neurodevelopmental impairment rates in the extremely preterm infant decreased. From epoch 1 to epoch 2, the increase in survival rate occurred in infants born at 22 weeks' estimated GA, from 20% to 40%, while the decrease in neurodevelopmental impairment (54% to 28%) and severe neurodevelopmental impairment (35% to 8%) occurred in infants born at 23 to 24 weeks' estimated GA. CONCLUSIONS: Novel and aggressive neonatal therapies continue to affect neonatal outcome, mainly in infants born at the limit of viability. Our data suggest that each center offer prospective parents an assessment of the limits of viability based on their updated outcome results. PMID- 21300653 TI - Neurodevelopmental outcomes in children with hemifacial microsomia. AB - OBJECTIVE: To determine whether preadolescent children with hemifacial microsomia (HFM) have higher risk of neurodevelopmental delays than unaffected control individuals. DESIGN: Case-control follow-up study of neurodevelopment in children with and without HFM. SETTING: Case individuals were originally recruited from 26 craniofacial centers across the United States and Canada, and controls were recruited through community pediatricians. PARTICIPANTS: One hundred thirty-six children with HFM (cases) and 568 unaffected children (controls). Main Exposure History of HFM. MAIN OUTCOME MEASURES: The Peabody Picture Vocabulary Test-Third Edition, the Beery-Buktenica Developmental Test of Visual Motor Integration-Fifth Edition, and the Academic Competence scales from the Child Behavior Checklist and the Teacher Report Form. RESULTS: Children with HFM scored lower than controls on all measures (effect size = -0.27 to -0.45; P < .001 to P = .008). Compared with controls, cases were 2 to 3 times as likely to score in the at-risk range. Relative to controls, outcomes were worse for male cases and those whose mothers were 25 years or younger at the time of their birth. Cases with HFM plus other malformations had poorer outcomes, as did cases with hearing, vision, or speech impairments. CONCLUSIONS: This is the first study, to our knowledge, to show that children with HFM have poorer neurodevelopmental outcomes than unaffected children, but further study using more detailed assessments is indicated. Clinically, the findings suggest that early neurodevelopmental screening is warranted for all children with HFM. PMID- 21300654 TI - Post-high school service use among young adults with an autism spectrum disorder. AB - OBJECTIVES: To produce nationally representative population estimates of rates of service use among young adults with an autism spectrum disorder during their first few years after leaving high school and to examine correlates of use. DESIGN: Nationally representative telephone survey from April 2007 to February 2008. SETTING: United States. PARTICIPANTS: Parents and guardians of young adults with autism spectrum disorders aged 19 to 23 years. Main Exposure Autism spectrum disorder. MAIN OUTCOME MEASURES: Use of the following services in the prior 2 years or since leaving high school: mental health services, medical evaluation and assessment, speech therapy, and case management. RESULTS: Rates of service use ranged from 9.1% for speech therapy to 41.9% for case management; 39.1% of youths with an autism spectrum disorder represented by the survey received no services. The adjusted odds of no services were higher among African American participants and those with low incomes. The adjusted odds of case management were lower among youths with high functional skills and those with low incomes. CONCLUSIONS: Rates of service disengagement are high after exiting high school. Disparities by race and socioeconomic status indicate a need for targeted outreach and services. PMID- 21300655 TI - Depictions of tobacco use in 2007 broadcast television programming popular among US youth. AB - OBJECTIVES: To determine the quantity of tobacco use in network television programming popular among US youth and to examine variation in tobacco depictions by TV Parental Guidelines system rating and television network. DESIGN: A content analysis was conducted of broadcast network television programming popular among youth. Nielsen viewership rating data were used to identify a sample of top-rated television series for youth aged 12 to 17 years during the fall 2007 television season. Depictions of tobacco use per television episode were examined by TV Parental Guidelines rating and television network. chi(2) testing was used to examine differences in proportions of tobacco depictions across television episode ratings and networks. SETTING: Data collection and analysis were conducted at the American Legacy Foundation (now known as Legacy). SUBJECTS: Broadcast television viewers in 2007. MAIN OUTCOME MEASURE: Tobacco use depictions on broadcast television were examined. RESULTS: Forty percent of television episodes examined had at least 1 depiction of tobacco use. Of these depictions, 89% were of cigarettes. Among episodes rated TV-PG (ie, parental guidance suggested) (N = 73), 50% showed 1 or more incidents of cigarette use, in contrast to 26% of TV-14 (ie, parents strongly cautioned) episodes. The percentage of episodes with any tobacco use depictions was highest on the FOX network (44%; n = 32), followed closely by The CW (CBS-Warner Brothers) (41%; n = 30). CONCLUSIONS: Substantial tobacco use was observed in television shows popular among youth. It is projected that almost 1 million youth were exposed to tobacco depictions through the programming examined. Tobacco use on television should be a cause for concern, particularly because of the high volume of television viewing among younger audiences. PMID- 21300656 TI - Health outcomes and family services in kinship care: analysis of a national sample of children in the child welfare system. AB - OBJECTIVES: To comprehensively assess family services, health, and health care outcomes for US children in kinship care vs foster care. DESIGN: A 3-year prospective cohort study. SETTING: National Survey of Child and Adolescent Well Being. PARTICIPANTS: The sample consisted of 1308 US children entering out-of home care following reported maltreatment. MAIN EXPOSURE: Kinship care vs foster care. MAIN OUTCOME MEASURES: Baseline caregivers' support services and the children's behavioral, mental health, and health service use outcomes 3 years after placement. RESULTS: Kinship caregivers were more likely than foster caregivers to have a low socioeconomic status but reported significantly fewer support services (caregiver subsidies, parent training, peer support, and respite care). Kinship care was associated with a lower risk ratio (RR) of continuing behavioral problems (RR = 0.59; 95% confidence interval [CI], 0.41-0.80), low social skills (RR = 0.61; 95% CI, 0.40-0.87), mental health therapy use (RR = 0.45; 95% CI, 0.27-0.73), and psychotropic medication use (RR = 0.46; 95% CI, 0.24-0.82) but higher risk of substance use (RR = 1.88; 95% CI, 0.92-3.20) and pregnancy (RR = 4.78; 95% CI, 1.07-17.11). CONCLUSIONS: Kinship caregivers received fewer support services than foster caregivers. Children in kinship care fared better with behavioral and social skills problems, mental health therapy use, and psychotropic medication use. Adolescents in kinship care may be at higher risk for substance use and pregnancy. PMID- 21300657 TI - Impact of the American Heart Association scientific statement on screening electrocardiograms and stimulant medications. AB - OBJECTIVE: To evaluate the impact of the American Heart Association (AHA) scientific statement regarding electrocardiograms (ECGs) and stimulant medications on the practice of community pediatricians. DESIGN: Retrospective evaluation and survey analysis. SETTING: Academic tertiary care center. PARTICIPANTS: Patients with ECGs referred to our institution by pediatricians with an indication of stimulant medication screening in the year after the AHA statement. INTERVENTION: We compared the ECG ordering practices of community pediatricians and the outcomes of further evaluation and estimated the associated cost before and after the AHA scientific statement. MAIN OUTCOME MEASURES: Abnormal ECG findings, further workup, and change in clinical practice. RESULTS: In the year after publication of the 2008 AHA scientific statement, 372 ECGs were ordered with an indication of stimulant medication screening. Before publication of this statement, a mean (SD) of 6.9 (3.2) ECGs per month were referred for this indication. Despite continuing controversy, this number increased 4-fold to 31.2 (9.5) ECGs per month in the subsequent year. Twenty-four ECGs (6.4%) had abnormal findings. Eighteen patients were referred for further evaluation, and, at last follow-up, none had been found to have definitive disease. Six of 24 patients with abnormal ECG findings (25.0%) had a perceived significant delay in therapy because of the process. In responding pediatricians, 34.6% reported that the scientific statement had clearly affected their practice. CONCLUSIONS: The clinical practice of community pediatricians in regard to screening ECGs and stimulant medications has been affected by the recent AHA scientific statement. The yield of performing ECGs with an indication of stimulant medication screening is very low. PMID- 21300658 TI - Management of the transgender adolescent. AB - Transgender individuals are people whose self-identification as male, female, both, or neither (gender identity) does not match their assigned gender (identification by others as male or female based on natal sex). The phenomenon of transgender is uncommon, but as more media attention is directed toward the subject, more adolescents and young adults are "coming out" at an earlier age. Transgender adolescents are an underserved and poorly researched population that has very specific medical and mental health needs. Primary care physicians are in a unique and powerful position to promote health and positive outcomes for transgender youth. While not all transgender adolescents desire phenotypic transition to match their gender and physical body, most do. The process of transitioning is complex and requires the involvement of both a mental health therapist specializing in gender and a physician. Finding comprehensive medical and mental health services is extremely difficult for these youth, who are at risk for multiple psychosocial problems including family and peer rejection, harassment, trauma, abuse, inadequate housing, legal problems, lack of financial support, and educational problems. This review supports and describes timely medical intervention to achieve gender/body congruence paired with affirmative mental health therapy as an appropriate approach to minimize negative health outcomes and maximize positive futures for transgender adolescents. PMID- 21300659 TI - Picture of the month. Contact vaccinia. PMID- 21300660 TI - Conflict of interest: when media conglomerates rate their productions. PMID- 21300661 TI - Advice for patients. Gay, lesbian, bisexual, transgender, and questioning youth. PMID- 21300662 TI - Estrogen receptor-beta signals left ventricular hypertrophy sex differences in normotensive deoxycorticosterone acetate-salt mice. AB - We found earlier that deoxycorticosterone acetate-salt treatment causes blood pressure-independent left ventricular hypertrophy, but only in male mice. To test the hypothesis that the estrogen receptor-beta (ERbeta) protects the females from left ventricular hypertrophy, we treated male and female ERbeta-deficient (ERbeta(-/-)) mice and their male and female littermates (wild-type [WT]) with deoxycorticosterone acetate-salt and made them telemetrically normotensive with hydralazine. WT males had increased (+16%) heart weight/tibia length ratios compared with WT females (+7%) at 6 weeks. In ERbeta(-/-) mice, this situation was reversed. Female WT mice had the greatest heart weight/tibia length ratio increases of all of the groups (+23%), even greater than ERbeta(-/-) males (+10%). Echocardiography revealed concentric left ventricular hypertrophy in male WT mice, whereas ERbeta(-/-) females developed dilative left ventricular hypertrophy. The hypertrophic response in female ERbeta(-/-) mice was accompanied by the highest degree of collagen deposition, indicating maladaptive remodeling. ERbeta(+/+) females showed robust protective p38 and extracellular signal regulated kinase 1/2 signaling relationships compared with other groups. Calcineurin Abeta expression and its positive regulator myocyte-enriched calcineurin-interacting protein 1 were increased in deoxycorticosterone acetate salt female ERbeta(-/-) mice, yet lower than in WT males. Endothelin increased murine cardiomyocyte hypertrophy in vitro, which could be blocked by estradiol and an ERbeta agonist. We conclude that a functional ERbeta is essential for inducing adaptive p38 and extracellular signal-regulated kinase signaling, while reducing maladaptive calcineurin signaling in normotensive deoxycorticosterone acetate female mice. Our findings address the possibility of sex-specific cardiovascular therapies. PMID- 21300663 TI - Early sympathetic activation in the initial clinical stages of chronic renal failure. AB - Direct and indirect indices of neuroadrenergic function have shown that end-stage renal disease is characterized by a marked sympathetic overdrive. It is unknown, however, whether this phenomenon represents a peculiar feature of end-stage renal disease or whether it is also detectable in the early clinical phases of the disease. The study has been performed in 73 hypertensive patients, of which there were 42 (age: 60.7+/-1.8 years, mean+/-SEM) with a stable moderate chronic renal failure (mean estimated glomerular filtration rate: 40.7 mL/min per 1.73 m2, MDRD formula) and 31 age-matched controls with a preserved renal function. Measurements included anthropometric variables, sphygmomanometric and beat-to beat blood pressure, heart rate (ECG), venous plasma norepinephrine (high performance liquid chromatography), and efferent postganglionic muscle sympathetic nerve activity (microneurography, peroneal nerve). For similar anthropometric and hemodynamic values, renal failure patients displayed muscle sympathetic nerve activity values significantly and markedly greater than controls (60.0+/-2.1 versus 45.7+/-2.0 bursts per 100 heartbeats; P<0.001). Muscle sympathetic nerve activity showed a progressive and significant increase from the first to the fourth quartile of the estimated glomerular filtration rate values (first: 41.0+/-2.7; second: 51.9+/-1.7; third: 59.8+/-3.0; fourth: 61.9+/ 3.3 bursts per 100 heartbeats), the statistical significance (P<0.05) between groups being maintained after adjustment for confounders. In the population as a whole, muscle sympathetic nerve activity was significantly and inversely correlated with the estimated glomerular filtration rate (r=-0.59; P<0.0001). Thus, adrenergic activation is a phenomenon not confined to advanced renal failure but already detectable in the initial phases of the disease. The sympathetic overdrive parallels the severity of the renal failure, state and, thus, it might participate, in conjunction with other factors, at the disease progression. PMID- 21300664 TI - Sympathetic activation in chronic kidney disease: out of the shadow. PMID- 21300665 TI - A single beta-amino acid substitution to angiotensin II confers AT2 receptor selectivity and vascular function. AB - Novel AT(2)R ligands were designed by substituting individual beta-amino acid in the sequence of the native ligand angiotensin II (Ang II). Relative ATR selectivity and functional vascular assays (in vitro AT(2)R-mediated vasorelaxation and in vivo vasodepressor action) were determined. In competition binding experiments using either AT(1)R- or AT(2)R- transfected HEK-293 cells, only beta-Asp(1)-Ang II and Ang II fully displaced [(125)I]-Ang II from AT(1)R. In contrast, beta-substitutions at each position of Ang II exhibited AT(2)R affinity, with beta-Tyr(4)-Ang II and beta-Ile(5)-Ang II exhibiting ~ 1000-fold AT(2)R selectivity. In mouse aortic rings, beta-Tyr(4)-Ang II and beta-Ile(5)-Ang II evoked vasorelaxation that was sensitive to blockade by the AT(2)R antagonist PD123319 and the nitric oxide synthase inhibitor L-NAME. When tested with a low level of AT(1)R blockade, beta-Ile(5)-Ang II (15 pmol/kg per minute IV for 4 hours) reduced blood pressure (BP) in conscious spontaneously hypertensive rats (beta-Ile(5)-Ang II plus candesartan, -24 +/- 4 mm Hg) to a greater extent than candesartan alone (-11 +/- 3 mm Hg, n=7, P<0.05), an effect that was abolished by concomitant PD123319 infusion. However, in an identical experimental protocol, beta-Tyr(4)-Ang II had no influence on BP (n=10), and it was less stable than beta-Ile(5)-Ang II in plasma stability assays. Thus, this study demonstrated that a single beta-amino acid substitution resulted in a compound that demonstrated both in vitro vasorelaxation and in vivo depressor activity via AT(2)R. This approach to the design and synthesis of novel AT(2)R-selective peptidomimetics shows great potential to provide insight into AT(2)R function. PMID- 21300666 TI - Why do black Americans have higher prevalence of hypertension?: an enigma still unsolved. PMID- 21300667 TI - Health behaviors and racial disparity in blood pressure control in the national health and nutrition examination survey. AB - Minorities have a higher prevalence of hypertension, a major risk factor for cardiovascular disease, which contributes to racial/ethnic disparities in morbidity and mortality in the United States. Many modifiable health behaviors have been associated with improved blood pressure control, but it is unclear how racial/ethnic differences in these behaviors are related to the observed disparities in blood pressure control. Cross-sectional analyses were conducted among 21 489 US adults aged >20 years participating in the National Health and Nutrition Examination Survey from 2001 to 2006. Secondary analyses were conducted among those with a self-reported diagnosis of hypertension. Blood pressure control was defined as systolic values <140 mm Hg and diastolic values <90 mm Hg (or <130 mm Hg and <80 mm Hg among diabetics, respectively). In primary analyses, non-Hispanic blacks had 90% higher odds of poorly controlled blood pressure compared with non-Hispanic whites after adjustment for sociodemographic and clinical characteristics (P<0.001). In secondary analyses among hypertensive subjects, non-Hispanic blacks and Mexican Americans had 40% higher odds of uncontrolled blood pressure compared with non-Hispanic whites after adjustment for sociodemographic and clinical characteristics (P<0.001). For both analyses, the racial/ethnic differences in blood pressure control persisted even after further adjustment for modifiable health behaviors, which included medication adherence in secondary analyses (P<0.001 for both analyses). Although population level adoption of healthy behaviors may contribute to reduction of the societal burden of cardiovascular disease in general, these findings suggest that racial/ethnic differences in some health behaviors do not explain the disparities in hypertension prevalence and control. PMID- 21300668 TI - Equol-stimulated mitochondrial reactive oxygen species activate endothelial nitric oxide synthase and redox signaling in endothelial cells: roles for F-actin and GPR30. AB - We reported previously that dietary isoflavones modulate arterial blood pressure in vivo and that the daidzein metabolite equol rapidly activates endothelial NO synthase (eNOS) via Akt and extracellular signal-regulated kinase 1/2-dependent signaling. In this study, we report the first evidence in human endothelial cells that acute stimulation of mitochondrial superoxide generation by equol (100 nmol/L) is required for eNOS activation. Scavengers of superoxide (superoxide dismutase and manganese [III] tetrakis[1-methyl-4-pyridyl]porphyrin) abrogated equol stimulated Akt and eNOS phosphorylation, and the mitochondrial complex I inhibitor rotenone inhibited Akt, extracellular signal-regulated kinase 1/2, and eNOS phosphorylation, as well as NO-mediated increases in intracellular cGMP. Equol also induced rapid alterations in F-actin fiber distribution, with depolymerization of F-actin with cytochalasin D abrogating equol-stimulated mitochondrial superoxide generation. Treatment of cells with pertussis toxin or inhibition of GPR30/epidermal growth factor receptor kinase transactivation prevented equol-induced activation of extracellular signal-regulated kinase 1/2 via c-Src, Akt, and eNOS. Moreover, inhibition of epidermal growth factor receptor kinase activation with AG-1478 abrogated equol-stimulated mitochondrial reactive oxygen species generation and subsequent kinase and eNOS activation. Our findings suggest that equol-stimulated mitochondrial reactive oxygen species modulate endothelial redox signaling and NO release involving transactivation of epidermal growth factor receptor kinase and reorganization of the F-actin cytoskeleton. Identification of these novel actions of equol may provide valuable insights for therapeutic strategies to restore endothelial function in cardiovascular disease. PMID- 21300669 TI - Role of lipoxygenase metabolites of arachidonic acid in enhanced pulmonary artery contractions of female rabbits. AB - Pulmonary arterial hypertension is characterized by elevated pulmonary artery pressure and vascular resistance. In women the incidence is 4-fold greater than that in men. Studies suggest that sustained vasoconstriction is a factor in increased vascular resistance. Possible vasoconstrictor mediators include arachidonic acid-derived lipoxygenase (LO) metabolites. Our studies in rabbits showed enhanced endothelium-dependent contractions to arachidonic acid in pulmonary arteries from females compared with males. Because treatment with a nonspecific LO inhibitor reduced contractions in females but not males, the present study identified which LO isoform contributes to sex-specific pulmonary artery vasoconstriction. The 15- and 5- but not 12-LO protein expressions were greater in females. Basal and A23187-stimulated release of 15-, 5-, and 12 hydroxyeicosatetraenoic acids (HETEs) from females and males were measured by liquid chromatography/mass spectrometry. Only 15-HETE synthesis was greater in females compared with males under both basal and stimulated conditions. Vascular contractions to 15-HETE were enhanced in females compared with males (maximal contraction: 44+/-6%versus 25+/-3%). The specific 15-LO inhibitor PD146176 (12 MUmol/L) decreased arachidonic acid-induced contractions in females (maximal contraction: 93+/-4% versus 57+/-10%). If male pulmonary arteries were incubated with estrogen (1 MUmol/L, 18 hours), protein expression of 15-LO and 15-HETE production increased. Mechanisms to explain the increased incidence of pulmonary hypertension in women are not known. Results suggest that the 15-LO pathway is different between females and males and is regulated by estrogen. Understanding this novel sex-specific mechanism may provide insight into the increased incidence of pulmonary hypertension in females. PMID- 21300670 TI - Massive aspiration past the tracheal tube cuff caused by closed tracheal suction system. AB - BACKGROUND: Aspiration past the tracheal tube cuff has been recognized to be a risk factor for the development of ventilator-associated pneumonia (VAP). This study investigated the effect of closed tracheal suctioning on aspiration of fluid past the tracheal tube cuff in an in vitro benchtop model. METHODS: High volume low pressure tube cuffs of 7.5 mm internal diameter (ID) were placed in a 22 mm ID artificial trachea connected to a test lung. Positive pressure ventilation (PPV) with 15 cm H2O peak inspiratory pressure and 5 cm H2O positive end-expiratory pressure (PEEP) was used. A closed tracheal suction system (CTSS) catheter (size 14Fr) was attached to the tracheal tube and suction was performed for 5, 10, 15, or 20 seconds under 200 or 300 cm H2O suction pressures. Amount of fluid (mL) aspirated along the tube cuff and the airway pressure changes were recorded for each suction procedure. Fluid aspiration during different suction conditions was compared using Kruskal-Wallis and Mann-Whitney test (Bonferroni correction [alpha = .01]). RESULTS: During 10, 15, and 20 seconds suction, airway pressure consistently dropped down to -8 to -13 cm H2O (P < .001) from the preset level. Fluid aspiration was never observed under PPV + PEEP but occurred always during suctioning. Aspiration along the tube cuff was higher with -300 cm H2O than with -200 cm H2O suction pressure (P < .001) and was much more during 15 and 20 seconds suction time as compared to 5 seconds (P < .001). CONCLUSION: Massive aspiration of fluid occurs along the tracheal tube cuff during suction with the closed tracheal suction system. PMID- 21300671 TI - Influenza A 2009 (H1N1) virus in admitted and critically ill patients. AB - INTRODUCTION: The influenza A 2009 (H1N1) virus is a pandemic respiratory infection commanding international attention. More information is needed on patient demographics, illness severity, and risk indicators. METHODS: A total of 43 patients with H1N1 influenza A 2009 presenting to 2 urban academic medical centers during the first wave were assessed for demographics, triage vital signs, hemograms, and serum chemistries including lactate. Chest X-rays were assessed for infiltrate or effusion. Illness severity markers were recorded including anion gap (AG), strong ion gap (SIG), systemic inflammatory response syndrome score, shock index, confusion, uremia, respiratory rate, blood pressure, and age >= 65 years (CURB-65) score, and pneumonia severity index. Subgroup analysis was performed on asthmatic, pregnant, and intensive care unit (ICU) versus non-ICU patients. RESULTS: Eighty-one percent of patients were women. Pregnancy (34.8%), asthma (39.5%), diabetes mellitus (18.6%), and sickle cell (6.98%) were the most frequent comorbidities. In all, 91% had positive influenza nasopharyngeal direct antigen test, while 9% tested positive only by viral culture or real-time reverse transcriptase polymerase chain reaction (rRT-PCR); 14% required ICU admission; and 20.8% had infiltrate on chest X-ray. A trend toward greater incidence of ICU admission existed among patients with elevated SIG (P = .08), however contrary to our prior studies in noninfluenza patients, an elevated SIG in the presence of normal AG and lactate measurements did not correlate with ICU admission. CONCLUSION: A high percentage of patients with H1N1 presented with underlying comorbid conditions including asthma and pregnancy. Traditional markers of pneumonia severity including CURB-65 score, Pneumonia Severity Index (PSI), serum lactate, and AG did not correlate with ICU admission in patients with H1N1. Strong ion gap effectively identified significant acid-base disturbances not identified by lactate or AG, however the trend of greater ICU admission rates among patients with elevated SIG did not reach statistical significance. Further study is needed to identify clinical tools to aid in risk-stratifying H1N1 patients. PMID- 21300672 TI - Current concepts in resuscitation. AB - Early recognition and differentiation of shock, as well as goal-directed resuscitation, are fundamental principles in the care of the critically ill or injured patient. Substantial progress has been made over the last decade in the understanding of both shock and resuscitation. Specific areas of advancement, particularly pertaining to hemorrhagic shock, include a heightened appreciation of dynamic measurements of preload responsiveness (e.g., respiratory-induced pulse pressure and venous diameter variability), an improved awareness of the detrimental effects of blood product transfusion, and better recognition of the complications of overzealous volume expansion. However, several areas of controversy remain regarding the optimal resuscitation strategy. These include the optimal targets for perfusion pressure and oxygen delivery, endpoints of resuscitation, resuscitative fluid, and transfusion strategies for packed red blood cells and blood products. This article reviews the diagnosis and differentiation of shock, measurements of tissue perfusion, current evidence regarding various resuscitative techniques, and complications of resuscitation. PMID- 21300673 TI - Human immune responses to Burkholderia pseudomallei characterized by protein microarray analysis. AB - BACKGROUND: We aimed to determine the antibody and T cell responses to Burkholderia pseudomallei of humans to select candidate vaccine antigens. METHODS: For antibody profiling, a protein microarray of 154 B. pseudomallei proteins was probed with plasma from 108 healthy individuals and 72 recovered patients. Blood from 20 of the healthy and 30 of the recovered individuals was also obtained for T cell assays. RESULTS: Twenty-seven proteins distinctively reacted with human plasma following environmental exposure or clinical melioidosis. We compared the responses according to the patient's history of subsequent relapse, and antibody response to BPSL2765 was higher in plasma from individuals who had only 1 episode of disease than in those with recurrent melioidosis. A comparison of antibody and T cell responses to 5 B. pseudomallei proteins revealed that BimA and flagellin-induced responses were similar but that BPSS0530 could induce T cell responses in healthy controls more than in recovered patients. CONCLUSIONS: By combining large-scale antibody microarrays and assays of T cell-mediated immunity, we identified a panel of novel B. pseudomallei proteins that show distinct patterns of reactivity in different stages of human melioidosis. These proteins may be useful candidates for development of subunit based vaccines and in monitoring the risks of treatment failure and relapse. PMID- 21300674 TI - Long-term results of an obesity program in an ethnically diverse pediatric population. AB - OBJECTIVE: To determine if beneficial effects of a weight-management program could be sustained for up to 24 months in a randomized trial in an ethnically diverse obese population. PATIENTS AND METHODS: There were 209 obese children (BMI > 95th percentile), ages 8 to 16 of mixed ethnic backgrounds randomly assigned to the intensive lifestyle intervention or clinic control group. The control group received counseling every 6 months, and the intervention group received a family-based program, which included exercise, nutrition, and behavior modification. Lifestyle intervention sessions occurred twice weekly for the first 6 months, then twice monthly for the second 6 months; for the last 12 months there was no active intervention. There were 174 children who completed the 12 months of the randomized trial. Follow-up data were available for 76 of these children at 24 months. There were no statistical differences in dropout rates among ethnic groups or in any other aspects. RESULTS: Treatment effect was sustained at 24 months in the intervention versus control group for BMI z score ( 0.16 [95% confidence interval: -0.23 to -0.09]), BMI (-2.8 kg/m(2) [95% confidence interval: -4.0-1.6 kg/m(2)]), percent body fat (-4.2% [95% confidence interval: -6.4% to -2.0%]), total body fat mass (-5.8 kg [95% confidence interval: -9.1 kg to -2.6 kg]), total cholesterol (-13.0 mg/dL [95% confidence interval: -21.7 mg/dL to -4.2 mg/dL]), low-density lipoprotein cholesterol (-10.4 mg/dL [95% confidence interval: -18.3 mg/dL to -2.4 mg/dL]), and homeostasis model assessment of insulin resistance (-2.05 [95% confidence interval: -2.48 to 1.75]). CONCLUSIONS: This study, unprecedented because of the high degree of obesity and ethnically diverse backgrounds of children, reveals that benefits of an intensive lifestyle program can be sustained 12 months after completing the active intervention phase. PMID- 21300675 TI - Patterns of comorbidity, functioning, and service use for US children with ADHD, 2007. AB - OBJECTIVE: To determine patterns of comorbidity, functioning, and service use for US children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Bivariate and multivariable cross-sectional analyses were conducted on data from the 2007 National Survey of Children's Health on 61 779 children ages 6 to 17 years, including 5028 with ADHD. RESULTS: Parent-reported diagnosed prevalence of ADHD was 8.2%. Children with ADHD were more likely to have other mental health and neurodevelopmental conditions. Parents reported that 46% of children with ADHD had a learning disability versus 5% without ADHD, 27% vs 2% had a conduct disorder, 18% vs 2% anxiety, 14% vs 1% depression, and 12% vs 3% speech problems (all P < .05). Most children with ADHD had at least 1 comorbid disorder: 33% had 1, 16% had 2, and 18% had 3 or more. The risk for having 3 or more comorbidities was 3.8 times higher for poor versus affluent children (30% vs 8%). Children with ADHD had higher odds of activity restriction (odds ratio: 4.14 [95% confidence interval: 3.34-5.15]), school problems (odds ratio: 5.18 [95% confidence interval: 4.47-6.01]), grade repetition, and poor parent-child communication, whereas social competence scores were lower and parent aggravation higher. Functioning declined in a stepwise fashion with increasing numbers of comorbidities, and use of health and educational services and need for care coordination increased. CONCLUSIONS: Clinical management of ADHD must address multiple comorbid conditions and manage a range of adverse functional outcomes. Therapeutic approaches should be responsive to each child's neurodevelopmental profile, tailored to their unique social and family circumstances, and integrated with educational, mental health and social support services. PMID- 21300676 TI - Prenatal factors for childhood blood pressure mediated by intrauterine and/or childhood growth? AB - OBJECTIVE: Some prenatal factors may program an offspring's blood pressure, but existing evidence is inconclusive and mechanisms remain unclear. We examined the mediating roles of intrauterine and childhood growth in the associations between childhood systolic blood pressure (SBP) and 5 potentially modifiable prenatal factors: maternal smoking during pregnancy; prepregnancy BMI; pregnancy weight gain; chronic hypertension; and preeclampsia-eclampsia. METHODS: The sample contained 30 461 mother-child pairs in the Collaborative Perinatal Project. Prenatal data were extracted from obstetric forms, and children's SBP was measured at 7 years of age. Potential mediation by intrauterine growth restriction (IUGR) and childhood growth was examined by the causal step method. RESULTS: Heavy maternal smoking during pregnancy was significantly associated with higher offspring SBP (adjusted mean difference versus nonsmoking: 0.73 mm Hg [95% confidence interval (CI): 0.32-1.14]), which attenuated to null (0.13 [95% CI: -0.27-0.54]) after adjustment for changes in BMI from birth to 7 years of age. Prepregnancy overweight-obesity was significantly associated with higher offspring SBP (versus normal weight: 0.89 mm Hg [95% CI: 0.52-1.26]), which also attenuated to null (-0.04 mm Hg [95% CI: -0.40-0.31]) after adjustment for childhood BMI trajectory. Adjustment for BMI trajectory augmented the association between maternal pregnancy weight gain and offspring SBP. Adjustment for childhood weight trajectory similarly changed these associations. However, all these associations were independent of IUGR. CONCLUSIONS: Childhood BMI and weight trajectory, but not IUGR, may largely mediate the associations of maternal smoking during pregnancy and prepregnancy BMI with an offspring's SBP. PMID- 21300678 TI - Racial bias in child protection? A comparison of competing explanations using national data. AB - OBJECTIVE: Cases of child abuse and neglect that involve black children are reported to and substantiated by public child welfare agencies at a rate approximately twice that of cases that involve white children. A range of studies have been performed to assess the degree to which this racial disproportionality is attributable to racial bias in physicians, nurses, and other professionals mandated to report suspected child victimization. The prevailing current explanation posits that the presence of bias among reporters and within the child welfare system has led to the current large overrepresentation of black children. A competing explanation is that overrepresentation of black children is mainly the consequence of increased exposure to risk factors such as poverty. METHODS: We tested the competing models by using data drawn from national child welfare and public health sources. We compared racial disproportionality ratios on rates of victimization from official child welfare organizations to rates of key public health outcomes not subject to the same potential biases (eg, general infant mortality). RESULTS: We found that racial differences in victimization rate data from the official child welfare system are consistent with known differences for other child outcomes. We also found evidence supporting the presence of cultural protective factors for Hispanic children, termed the "Hispanic paradox." CONCLUSIONS: Although our findings do not preclude the possibility of racial bias, these findings suggest that racial bias in reporting and in the child welfare system are not large-scale drivers of racial disproportionality. Our data suggest that reduction of black/white racial disproportionality in the child welfare system can best be achieved by a public health approach to reducing underlying risk factors that affect black families. PMID- 21300677 TI - Impact of prenatal exposure to piperonyl butoxide and permethrin on 36-month neurodevelopment. AB - OBJECTIVE: Recent pesticide-monitoring results suggest that a shift in residential pesticide exposure from organophosphorus insecticides to pyrethroid insecticides has occurred. Pyrethroid insecticides are potential neurodevelopmental toxicants and have not been evaluated for developmental toxicity. Our objective was to explore the association between prenatal exposure to permethrin (a common pyrethroid) and piperonyl butoxide (a pyrethroid synergist) and 36-month neurodevelopment. METHODS: Participants is this study were part of a prospective cohort of black and Dominican mothers and newborns living in low-income neighborhoods in New York City. We examined 36-month cognitive and motor development (using the Bayley Scales of Infant Development, second edition) as a function of permethrin levels measured in maternal and umbilical cord plasma collected on delivery and permethrin and piperonyl butoxide levels measured in personal air collected during pregnancy. All models were controlled for gender, gestational age, ethnicity, maternal education, maternal intelligence, quality of the home environment, and prenatal exposure to environmental tobacco smoke and chlorpyrifos. RESULTS: Prenatal exposure to permethrin in personal air and/or plasma was not associated with performance scores for the Bayley Mental Developmental Index or the Psychomotor Developmental Index. After data adjustment, children more highly exposed to piperonyl butoxide in personal air samples (>4.34 ng/m(3)) scored 3.9 points lower on the Mental Developmental Index than those with lower exposures (95% confidence interval: 0.25 to -7.49). CONCLUSIONS: Prenatal exposure to piperonyl butoxide was negatively associated with 36-month neurodevelopment. PMID- 21300679 TI - Injection site and risk of medically attended local reactions to acellular pertussis vaccine. AB - OBJECTIVE: To assess whether the risk of medically attended local reactions to the fifth dose of the diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine varies according to injection site (arm versus thigh). METHODS: We conducted a retrospective cohort study of children aged 4 through 6 years in the Vaccine Safety Datalink population who received a DTaP vaccination during the period from 2002 through 2006. Medically attended local reactions to the DTaP vaccine were presumptively identified from administrative data and were confirmed by medical record review. RESULTS: Among the 233,616 children in the study population, 1017 (0.4%) had a confirmed medically attended local reaction to the fifth dose of the DTaP vaccine. The rate of those reactions was significantly higher with vaccinations given in the arm (47.4 per 10,000 vaccinations) compared with vaccinations given in the thigh (32.1 per 10,000 vaccinations) (P < .001). In a multivariable analysis adjusted for age, gender, and study site, children vaccinated in the arm had a 78% higher risk of a local reaction (relative risk: 1.78 [95% confidence interval: 1.43-2.21]). CONCLUSIONS: Local reactions to the fifth dose of the DTaP vaccine that require medical evaluation are uncommon, but the risk of those reactions is significantly higher when the vaccine is injected in the arm. These findings suggest that the thigh should be considered as an acceptable site of injection for this vaccination. PMID- 21300680 TI - Executive and memory function in adolescents born very preterm. AB - BACKGROUND: Many preterm children display school difficulties, which may be mediated by impairment in executive function and memory. OBJECTIVE: To evaluate executive and memory function among adolescents born preterm compared with term controls at 16 years. METHODS: A total of 337 of 437 (77%) adolescents born in 1989 to 1992 with a birth weight < 1250 g and 102 term controls were assessed with a battery of executive function and memory tasks. Multiple regression analyses were used to compare groups and to identify associations between selected factors and outcomes among preterm subjects. RESULTS: Adolescents born preterm, compared with term controls, showed deficits in executive function in the order of 0.4 to 0.6 SD on tasks of verbal fluency, inhibition, cognitive flexibility, planning/organization, and working memory as well as verbal and visuospatial memory. After exclusion of adolescents with neurosensory disabilities and full-scale IQ < 70, significant group differences persisted on most tests. Preterm subjects, compared with term controls, were at increased risk of exhibiting problems related to executive dysfunction, as measured with the Behavior Rating Inventory of Executive Function, on the Metacognition Index (odds ratio [OR]: 2.5 [95% confidence interval (CI): 1.2-5.1]) and the Global Executive Composite (OR: 4.2 [95% CI: 1.6-10.9]), but not on the Behavioral Regulation index (OR: 1.5 [95% CI: 0.7-3.5]). Among adolescents born preterm, severe brain injury on neonatal ultrasound and lower maternal education were the most consistent factors associated with poor outcomes. CONCLUSIONS: Even after exclusion of preterm subjects with significant disabilities, adolescents born preterm in the early 1990s were at increased risk of deficits in executive function and memory. PMID- 21300681 TI - Timing of solid food introduction and risk of obesity in preschool-aged children. AB - OBJECTIVE: To examine the association between timing of introduction of solid foods during infancy and obesity at 3 years of age. METHODS: We studied 847 children in Project Viva, a prospective pre-birth cohort study. The primary outcome was obesity at 3 years of age (BMI for age and gender >= 95th percentile). The primary exposure was the timing of introduction of solid foods, categorized as <4, 4 to 5, and >= 6 months. We ran separate logistic regression models for infants who were breastfed for at least 4 months ("breastfed") and infants who were never breastfed or stopped breastfeeding before the age of four months ("formula-fed"), adjusting for child and maternal characteristics, which included change in weight-for-age z score from 0 to 4 months-a marker of early infant growth. RESULTS: In the first 4 months of life, 568 infants (67%) were breastfed and 279 (32%) were formula-fed. At age 3 years, 75 children (9%) were obese. Among breastfed infants, the timing of solid food introduction was not associated with odds of obesity (odds ratio: 1.1 [95% confidence interval: 0.3 4.4]). Among formula-fed infants, introduction of solid foods before 4 months was associated with a sixfold increase in odds of obesity at age 3 years; the association was not explained by rapid early growth (odds ratio after adjustment: 6.3 [95% confidence interval: 2.3-6.9]). CONCLUSIONS: Among formula-fed infants or infants weaned before the age of 4 months, introduction of solid foods before the age of 4 months was associated with increased odds of obesity at age 3 years. PMID- 21300682 TI - Hypertrophic lupus erythematosus complicating long-standing systemic lupus erythematosus. PMID- 21300683 TI - Chloroquine-induced myopathy. PMID- 21300684 TI - Systemic lupus erythematosus presenting as ischaemic proctitis. AB - Ischaemic colitis is relatively uncommon in systemic lupus erythematosus (SLE), with only very few case reports or case series in world literature. Ischaemic colitis occurs when SLE activity is high and is inarguably due to small vessel vasculitis affecting the large or small intestine. Ischaemic proctitis with rectal ulceration, as a presenting feature in SLE, is even rarer with only two case reports in the world to date. We present the case of a 38-year-old woman, who presented with haematochezia which subsequently proved to be due to ischaemic proctitis with a large rectal ulcer in a case that was subsequently diagnosed as SLE. The clinical course in this patient greatly improved with aggressive management with systemic steroids. PMID- 21300685 TI - Sick Building Syndrome and autoimmunity. PMID- 21300686 TI - Acute hemolysis following iodine tincture ingestion. AB - Iodine tincture poisoning is uncommon regardless of its widespread use as an antiseptic in daily practice. Previously reported effects of iodine-containing antiseptic poisoning included topical irritation, corrosive effects, allergic response, and hepatic or renal injury, which mainly resulted from complications of topical use during surgical procedures. We herein reported an unusual case of severe hemolysis and acute renal failure following intentional ingestion of iodine tincture containing 60 mg/ml iodine and 40 mg/ml potassium iodide in 70% v/v ethanol. The patient completely recovered 8 weeks later after receiving supportive treatment, plasma exchange, and temporary hemodialysis. PMID- 21300687 TI - Depilatory Agents intoxication and factors contributing to its mortality: a 9 year review. AB - Poisoning with depilatory agents is a rather uncommon entity in western countries. In this study, we describe poisoning with a corrosive arsenic-based depilatory agent (CABD) and factors related to its mortality in a poisoning center in Tehran. In a retrospective study, the medical records of all patients with CABD intoxication who attended the emergency ward of Loghman-Hakim hospital, the only poisoning center in Tehran, over a 9-year period between 2000 and 2009 were reviewed. The majority of patients were men (78.7%, n = 122 vs. women: 21.3%, n = 33). The mean age was 35.55 +/- 16.68 years. Mean time of arrival to hospital was 3.63 hours (SD = 4.07). The mortality rate was 5.8% and increased significantly with higher amounts of ingestion and delay in arrival to hospital. CABD poisoning may be lethal if not treated promptly and correctly. Restriction or, if not practical, reduction of harmful components of this substance should be considered. PMID- 21300688 TI - Lipid patterns in the saliva of smoking young adults. AB - Salivary lipids are important for the maintenance of oral cavity health. Elevated salivary lipid levels are associated with an increase of caries incidence, plaque development, calculus formation and periodontal disease. However, the regulation of lipid salivary levels is scarcely known. Cigarette smoke is considered a risk factor for oral cavity diseases. We study how cigarette smoke may affect the secretion of salivary lipids. To this purpose, we determine the salivary levels of cholesterol and of glycerolipids in saliva sampled from smokers and non smokers at various times of day. We observe an increase of glycerophospholipid and a decrease of cholesterol levels in the smokers' saliva collected at 10 p.m. On the other hand, unsaturated fatty acids in chief phospholipids of saliva are lower in smokers at 7 a.m. Therefore, for the first time, we demonstrate that cigarette smoke induces variations of saliva lipid pattern in young people even moderately smoking. PMID- 21300689 TI - Polymorphism in CYP1A1, GSTMI, GSTT1 genes and organochlorine pesticides in the etiology of hypospadias. AB - Exposure to endocrine-disrupting chemicals (EDCs) and maternal endogenous estrogen may cause hypospadias, common congenital anomaly. Several organochlorine pesticides (OCPs) have been reported to possess an endocrine-disrupting potential. Cytochrome P4501A1 (CYP1A1) and glutathione S-transferases (GSTM1 and GSTT1) of xenobiotic metabolizing enzyme family are involved in the metabolism of various environmental toxicants and steroidal hormones. Hence, the present study was designed to evaluate the role of CYP1A1, GSTM1, GSTT1 genes polymorphism, OCPs levels and risk of hypospadias. A total of 80 hypospadiac and 120 age matched control boys were included. OCP levels in blood were determined using Gas Chromatograph equipped with electron capture detector (GC-ECD) and polymorphism in CYP1A1, GSTM1 and GSTT1 genes was evaluated by RFLP and multiplex PCR method. We observed significant high levels of beta-hexachlorohexane (HCH), gamma-HCH, and p,p'-dichlorodiphenyl-dichloroethylene (p,p'-DDE) in the cases. CYP1A1 polymorphisms were not significantly different among cases and controls, whereas concomitant deletion of GSTM1 and GSTT1 genotypes was significantly higher in cases as compared to controls. However, after adjusting for low birth weight and maternal occupational exposure, the results did not remain significant but odds of risk was higher (OR = 1.72, p = 0.14) among cases. In conclusion, our study suggests irrespective of genetic predisposition, higher level of some OCPs may be associated with increased risk of hypospadias. PMID- 21300690 TI - Capsaicin may induce breast cancer cell death through apoptosis-inducing factor involving mitochondrial dysfunction. AB - The majority of breast cancer patients are resistant to chemotherapy or radiotherapy due to the down-regulation or lack of caspase-3 expression. Capsaicin was found to inhibit cancer cell growth in caspase-3-deficient human breast cancer cells. This study aimed to investigate the growth-inhibitive effect of capsaicin and its mechanisms in human breast cancer cell lines, MCF-7 and BT 20. The results showed that cell viability decreased in a dose-dependent manner in both the caspase-3-deficient and non-deficient cells through inducing cell apoptosis and arresting the cell cycle in the S phase. Capsaicin significantly decreased mitochondria membrane potential, induced the cleavage of PARP-1, and decreased procaspase-7 expression in both cells. Apoptosis-inducing factor (AIF) was distinctly released from mitochondria and translocated into the cytoplasm and nucleus in MCF-7 cells (52.9%), but not in BT-20 cells (2%) after treatment with 200 MUM of capsaicin for 24 hours. Capsaicin inhibited breast cancer cell growth through inducing cell apoptosis and cell cycle arrest in the S phase. This apoptotic effect could be induced through the mitochondrial pathway, and PARP-1 subsequently cleaved by activation of caspase-7. The application of capsaicin in clinical therapy could be useful for breast cancer patients. PMID- 21300691 TI - Sodium sulfite aggravated allergic sensitization and airway inflammation in mite allergen sensitized BALB/c mice. AB - Sulfur dioxide is a typical air pollutant. Sulfite, which is formed at the bronchial mucosa from inhaled sulfur dioxide, might play a role in the exacerbation of asthma. In this study, we investigated the effects of sodium sulfite and its interaction with a house dust mite (Dermatophagoides pteronyssinus, Der p) on allergic sensitization and airway inflammation. BALB/c mice were divided into four groups: control (n = 10), mite intranasal (mIN, n = 12), sodium sulfite intranasal (sIN, n = 12) and mIN + sIN (n = 12). In non control groups, the mice were sensitized on day 8 and day 15 with mite allergen subcutaneously. Mite allergen was then administrated intranasally from day 15 to day 22 in mIN and mIN+sIN groups. Sodium sulfite was administrated in sIN and mIN + sIN groups intranasally from day 1 to day 22. Plasma Der p-specific IgE, IgG2a, lung histopathology and cytokine levels (IL-5 and IFN-gamma) were analyzed. In comparison between mIN (or sIN) and mIN + sIN group, Der p-specific IgE levels were significantly higher in mIN + sIN group (p < 0.01). Besides, Der p-specific IgG2a level was significantly lower in mIN + sIN group than mIN (or sIN) group (p < 0.01). The peribronchiolar, alveolar and total inflammatory scores were increased in the mIN + sIN group comparing with the control group (p < 0.05, p < 0.01, p < 0.01, respectively). Lung supernatant in mIN + sIN group has higher IL 5/IFN-gamma ratio than control, mIN or sIN group (all p < 0.05). Our study concluded sodium sulfite may enhance allergic sensitization as well as airway inflammation in mite allergen sensitized BALB/c mice. PMID- 21300692 TI - Microarray assessment of the influence of the conceptus on gene expression in the mouse uterus during decidualization. AB - During pregnancy in several species including humans and rodents, the endometrium undergoes decidualization. This process of differentiation from endometrial to decidual tissue occurs only after the onset of implantation in mice. It can also be artificially induced causing the formation of deciduomal tissue. The purpose of this study was to compare the gene expression profile of the developing decidua in pregnant mice with the deciduoma formed after artificial induction in an effort to identify conceptus-influenced changes in uterine gene expression during decidualization. We induced decidualization artificially by transferring blastocyst-sized ConA-coated agarose beads into the uterus on day 2.5 of pseudopregnancy. Recently published work has found this model to be more 'physiological' than other methods. Total RNA was isolated from blastocyst and bead-induced 'implantation' sites of the uteri of day 7.5 pregnant (decidua) and pseudopregnant (deciduoma) mice respectively. This RNA was then used for microarray analysis using Mouse Illumina BeadArray chips. This analysis revealed potential differential mRNA levels of only 45 genes between the decidua and bead induced deciduoma tissues. We confirmed the differential mRNA levels of 31 of these genes using quantitative RT-PCR. Finally, the level and localization of some of the mRNAs for select genes (Aldh3a1, Bcmo1, Guca2b, and Inhbb) identified by our microarray analysis were examined in more detail. This study provides the identity of a small set of genes whose expression in the uterus during decidualization may be influenced by molecular signals from the conceptus. PMID- 21300693 TI - Expression of steroidogenic enzymes during equine testicular development. AB - In the mammalian testis, Leydig cells are primarily responsible for steroidogenesis. In adult stallions, the major endocrine products of Leydig cells include testosterone and estrogens. 3beta-hydroxysteroid dehydrogenase/Delta(5) Delta(4)-isomerase (3betaHSD) and 17alpha-hydroxylase/17,20-lyase (P450c17) are two key steroidogenic enzymes that regulate testosterone synthesis. Androgens produced by P450c17 serve as substrate for estrogen synthesis. The aim of this study was to investigate localization of the steroidogenic enzymes P450c17, 3betaHSD, and P450arom and to determine changes in expression during development in the prepubertal, postpubertal, and adult equine testis based upon immunohistochemistry (IHC) and real-time quantitative PCR. Based on IHC, 3betaHSD immunolabeling was observed within seminiferous tubules of prepubertal testes and decreased after puberty. On the other hand, immunolabeling of 3betaHSD was very weak or absent in immature Leydig cells of prepubertal testes and increased after puberty. HSD3B1 (3betaHSD gene) mRNA expression was higher in adult testes compared with prepubertal (P=0.0001) and postpubertal testes (P=0.0041). P450c17 immunolabeling was observed in small clusters of immature Leydig cells in prepubertal testes and increased after puberty. CYP17 (P450c17 gene) mRNA expression was higher in adult testes compared with prepubertal (P=0.030) and postpubertal testes (P=0.0318). A weak P450arom immunolabel was observed in immature Leydig cells of prepubertal testes and increased after puberty. Similarly, CYP19 (P450arom gene) mRNA expression was higher in adult testes compared with prepubertal (P=0.0001) and postpubertal (P=0.0001) testes. In conclusion, Leydig cells are the primary cell type responsible for androgen and estrogen production in the equine testis. PMID- 21300695 TI - Expanded polyglutamine domain possesses nuclear export activity which modulates subcellular localization and toxicity of polyQ disease protein via exportin-1. AB - Polyglutamine (polyQ) diseases are a group of late-onset, progressive neurodegenerative disorders caused by CAG trinucleotide repeat expansion in the coding region of disease genes. The cell nucleus is an important site of pathology in polyQ diseases, and transcriptional dysregulation is one of the pathologic hallmarks observed. In this study, we showed that exportin-1 (Xpo1) regulates the nucleocytoplasmic distribution of expanded polyQ protein. We found that expanded polyQ protein, but not its unexpanded form, possesses nuclear export activity and interacts with Xpo1. Genetic manipulation of Xpo1 expression levels in transgenic Drosophila models of polyQ disease confirmed the specific nuclear export role of Xpo1 on expanded polyQ protein. Upon Xpo1 knockdown, the expanded polyQ protein was retained in the nucleus. The nuclear disease protein enhanced polyQ toxicity by binding to heat shock protein (hsp) gene promoter and abolished hsp gene induction. Further, we uncovered a developmental decline of Xpo1 protein levels in vivo that contributes to the accumulation of expanded polyQ protein in the nucleus of symptomatic polyQ transgenic mice. Taken together, we first showed that Xpo1 is a nuclear export receptor for expanded polyQ domain, and our findings establish a direct link between protein nuclear export and the progressive nature of polyQ neurodegeneration. PMID- 21300694 TI - The COPI vesicle complex binds and moves with survival motor neuron within axons. AB - Spinal muscular atrophy (SMA), an inherited disease of motor neuron dysfunction, results from insufficient levels of the survival motor neuron (SMN) protein. Movement of the SMN protein as granules within cultured axons suggests that the pathogenesis of SMA may involve defects in neuronal transport, yet the nature of axon transport vesicles remains enigmatic. Here we show that SMN directly binds to the alpha-subunit of the coat protein I (COPI) vesicle coat protein. The alpha COP protein co-immunoprecipitates with SMN, small nuclear ribonucleoprotein associated assembly factors and beta-actin mRNA. Although typically Golgi associated, in neuronal cells alpha-COP localizes to lamellipodia and growth cones and moves within the axon, with a subset of these granules traveling together with SMN. Depletion of alpha-COP resulted in mislocalization of SMN and actin at the leading edge at the lamellipodia. We propose that neurons utilize the Golgi-associated COPI vesicle to deliver cargoes necessary for motor neuron integrity and function. PMID- 21300696 TI - Added value of molecular targeted agents in oncology. AB - The treatment of certain cancers has been revolutionised in recent years by the introduction of novel drugs designed to target specific molecular factors implicated in tumour growth. Notable examples include trastuzumab, a humanized monoclonal antibody (mAb) against human epidermal growth factor receptor (HER)-2 in women with HER2-positive breast cancer; rituximab, an anti-CD20 mAb in patients with non-Hodgkin's lymphoma; imatinib, a tyrosine kinase inhibitor in KIT-positive gastrointestinal stromal tumours and sunitinib, another tyrosine kinase inhibitor, in metastatic renal cell carcinoma. For regulatory reasons, new molecular targeted agents are first evaluated in advanced and metastatic disease, wherein they prolong survival. However, their most profound impact has been observed in the adjuvant setting, where they may contribute to curative therapy rather than mere palliation. Expansion in the use of molecular targeted therapies will have important cost implications for health care systems. Although expensive, on a monthly basis, molecular targeted therapies may not be more costly than treatments for other major chronic diseases, especially considering the contribution of cancer to the global disease burden, the associated socioeconomic costs and the long-term benefits of therapy. Nevertheless, the use of these agents must be optimised, in part using molecular biomarkers associated with drug response. PMID- 21300698 TI - Phage display can select over-hydrophobic sequences that may impair prediction of natural domain-peptide interactions. AB - MOTIVATION: The phage display peptide selection approach is widely used for defining binding specificities of globular domains. PDZ domains recognize partner proteins via C-terminal motifs and are often used as a model for interaction predictions. Here, we investigated to which extent phage display data that were recently published for 54 human PDZ domains can be applied to the prediction of human PDZ-peptide interactions. RESULTS: Promising predictions were obtained for one-third of the 54 PDZ domains. For the other two-thirds, we detected in the phage display peptides an important bias for hydrophobic amino acids that seemed to impair correct predictions. Therefore, phage display-selected peptides may be over-hydrophobic and of high affinity, while natural interaction motifs are rather hydrophilic and mostly combine low affinity with high specificity. We suggest that potential amino acid composition bias should systematically be investigated when applying phage display data to the prediction of specific natural domain-linear motif interactions. PMID- 21300697 TI - An empirical assessment of validation practices for molecular classifiers. AB - Proposed molecular classifiers may be overfit to idiosyncrasies of noisy genomic and proteomic data. Cross-validation methods are often used to obtain estimates of classification accuracy, but both simulations and case studies suggest that, when inappropriate methods are used, bias may ensue. Bias can be bypassed and generalizability can be tested by external (independent) validation. We evaluated 35 studies that have reported on external validation of a molecular classifier. We extracted information on study design and methodological features, and compared the performance of molecular classifiers in internal cross-validation versus external validation for 28 studies where both had been performed. We demonstrate that the majority of studies pursued cross-validation practices that are likely to overestimate classifier performance. Most studies were markedly underpowered to detect a 20% decrease in sensitivity or specificity between internal cross-validation and external validation [median power was 36% (IQR, 21 61%) and 29% (IQR, 15-65%), respectively]. The median reported classification performance for sensitivity and specificity was 94% and 98%, respectively, in cross-validation and 88% and 81% for independent validation. The relative diagnostic odds ratio was 3.26 (95% CI 2.04-5.21) for cross-validation versus independent validation. Finally, we reviewed all studies (n = 758) which cited those in our study sample, and identified only one instance of additional subsequent independent validation of these classifiers. In conclusion, these results document that many cross-validation practices employed in the literature are potentially biased and genuine progress in this field will require adoption of routine external validation of molecular classifiers, preferably in much larger studies than in current practice. PMID- 21300699 TI - uMELT: prediction of high-resolution melting curves and dynamic melting profiles of PCR products in a rich web application. AB - uMelt(SM) is a flexible web-based tool for predicting DNA melting curves and denaturation profiles of PCR products. The user defines an amplicon sequence and chooses a set of thermodynamic and experimental parameters that include nearest neighbor stacking energies, loop entropy effects, cation (monovalent and Mg(++)) concentrations and a temperature range. Using an accelerated partition function algorithm along with chosen parameter values, uMelt interactively calculates and visualizes the mean helicity and the dissociation probability at each sequence position at temperatures within the temperature range. Predicted curves display the mean helicity as a function of temperature or as derivative plots. Predicted profiles display stability as a function of sequence position either as 50% helicity temperatures or as the helicity probability at specific temperatures. The loss of helicity associated with increasing temperature may be viewed dynamically to visualize domain formation within the molecule. Results from fluorescent high-resolution melting experiments match the number of predicted melting domains and their relative temperatures. However, the absolute melting temperatures vary with the selected thermodynamic parameters and current libraries do not account for the rapid melting rates and helix stabilizing dyes used in fluorescent melting experiments. uMelt provides a convenient platform for simulation and design of high-resolution melting assays. AVAILABILITY AND IMPLEMENTATION: The application was developed in Actionscript and can be found online at http://www.dna.utah.edu/umelt/umelt.html. Adobe Flash is required to run in all browsers. PMID- 21300700 TI - BioGRID REST Service, BiogridPlugin2 and BioGRID WebGraph: new tools for access to interaction data at BioGRID. AB - The Biological General Repository for Interaction Datasets (BioGRID) representational state transfer (REST) service allows full URL-based access to curated protein and genetic interaction data at the BioGRID database. Appending URL parameters allows filtering of data by various attributes including gene names and identifiers, PubMed ID and evidence type. We also describe two visualization tools that interface with the REST service, the BiogridPlugin2 for Cytoscape and the BioGRID WebGraph. AVAILABILITY AND IMPLEMENTATION: BioGRID data and applications are completely free for commercial and non-commercial use. http://webservice.thebiogrid.org/resources/interactions (REST Service), http://wiki.thebiogrid.org/doku.php/biogridrest(REST Service parameter list and help), http://webservice.thebiogrid.org/resources/application.wadl(REST Service WADL), http://thebiogrid.org/download.php (BiogridPlugin2, v2.1 download), http://wiki.thebiogrid.org/doku.php/biogridplugin2 (BiogridPlugin2 help) and http://tyerslab.bio.ed.ac.uk/tools/BioGRID_webgraph.php(BioGRID WebGraph). PMID- 21300701 TI - HLA*IMP--an integrated framework for imputing classical HLA alleles from SNP genotypes. AB - MOTIVATION: Genetic variation at classical HLA alleles influences many phenotypes, including susceptibility to autoimmune disease, resistance to pathogens and the risk of adverse drug reactions. However, classical HLA typing methods are often prohibitively expensive for large-scale studies. We previously described a method for imputing classical alleles from linked SNP genotype data. Here, we present a modification of the original algorithm implemented in a freely available software suite that combines local data preparation and QC with probabilistic imputation through a remote server. RESULTS: We introduce two modifications to the original algorithm. First, we present a novel SNP selection function that leads to pronounced increases (up by 40% in some scenarios) in call rate. Second, we develop a parallelized model building algorithm that allows us to process a reference set of over 2500 individuals. In a validation experiment, we show that our framework produces highly accurate HLA type imputations at class I and class II loci for independent datasets: at call rates of 95-99%, imputation accuracy is between 92% and 98% at the four-digit level and over 97% at the two digit level. We demonstrate utility of the method through analysis of a genome wide association study for psoriasis where there is a known classical HLA risk allele (HLA-C*06:02). We show that the imputed allele shows stronger association with disease than any single SNP within the region. The imputation framework, HLA*IMP, provides a powerful tool for dissecting the architecture of genetic risk within the HLA. AVAILABILITY: HLA*IMP, implemented in C++ and Perl, is available from http://oxfordhla.well.ox.ac.uk and is free for academic use. PMID- 21300702 TI - tigre: Transcription factor inference through gaussian process reconstruction of expression for bioconductor. AB - tigre is an R/Bioconductor package for inference of transcription factor activity and ranking candidate target genes from gene expression time series. The underlying methodology is based on Gaussian process inference on a differential equation model that allows the use of short, unevenly sampled, time series. The method has been designed with efficient parallel implementation in mind, and the package supports parallel operation even without additional software. AVAILABILITY: The tigre package is included in Bioconductor since release 2.6 for R 2.11. The package and a user's guide are available at http://www.bioconductor.org. PMID- 21300703 TI - Aging and the shape of cognitive change before death: terminal decline or terminal drop? AB - OBJECTIVES: Relative to typical age-related cognitive decrements, the terms "terminal decline" and "terminal drop" refer to the phenomenon of increased cognitive decline in proximity to death. Given that these terms are not necessarily synonymous, we examined the important theoretical distinction between the two alternative trajectories or shapes of changes they imply. METHODS: We used 12-year (5-wave) data from the Victoria Longitudinal Study to directly test whether pre-death cognitive decrements follow a terminal decline (generally gradual) or a terminal drop (more abrupt) shape. Pre-death trajectories of cognitive decline for n=265 decedents (Mage = 72.67 years, SD = 6.44) were examined separately for 5 key cognitive constructs (verbal speed, working memory, episodic memory, semantic memory, and crystallized ability). RESULTS: Several classes of linear mixed models evaluated whether cognitive decline increased per additional year closer to death. Findings indicated that the shape of pre-death cognitive change was predominantly characterized by decline that is steeper as compared with typical aging-related change, but still best described as slow and steady decline, especially as compared with precipitous drop. DISCUSSION: The present findings suggest that terminal decline and terminal drop trajectories may not be mutually exclusive but could rather reflect distinct developmental trajectories within the same individual. PMID- 21300704 TI - Long-term impact of mild chronic kidney disease in patients with acute coronary syndrome undergoing percutaneous coronary interventions. AB - BACKGROUND: Accumulating evidence shows that chronic kidney disease (CKD) is an independent risk factor for major adverse cardiac and cerebrovascular events (MACCE) after acute coronary syndrome (ACS). However, it is not known whether mild renal insufficiency affects long-term clinical outcomes. METHODS: This is a post-hoc analysis from the Extended-ESTABLISH trial, which was designed to estimate the impact of renal insufficiency on patients with ACS after percutaneous coronary intervention over the long term. One hundred and eighty patients were divided into three groups based on the estimated glomerular filtration rate (eGFR) at time of ACS: moderate-to-severe CKD, <60 mL/min/1.73 m(2) (n = 31, 17.2%); mild CKD, 60-90 mL/min/1.73 m(2) (n = 100, 55.6%) and non CKD, >=90 mL/min/1.73 m(2) (n = 47, 26.1%). The eGFR was calculated using the new Japanese equation. Long-term outcomes were compared over a follow-up period of 1538 +/- 707 days. RESULTS: Cumulative incidence rates of MACCE did not significantly differ between groups 1 year after ACS onset (P = 0.384), whereas significant differences appeared during the long-term follow-up (10.6 versus 27.0% versus 35.4% in the non-CKD, mild CKD and moderate-to-severe CKD groups, respectively; log-rank test, P = 0.022). In a multivariate Cox hazard regression model, moderate-to-severe CKD and mild CKD were associated with a higher rate of MACCE after adjusting for confounding variables (hazard ratios = 3.46 and 2.67, respectively; P = 0.043). CONCLUSIONS: The presence of mild CKD at ACS occurrence is associated with a worse outcome in the long term, but not the short term. PMID- 21300707 TI - Switzerland is to fund complementary therapies for six years while effectiveness is evaluated. PMID- 21300705 TI - Nortriptyline reverses corticosteroid insensitivity by inhibition of phosphoinositide-3-kinase-delta. AB - Corticosteroid insensitivity represents a major barrier to the treatment of chronic obstructive pulmonary disease (COPD) and severe asthma. It is caused by oxidative stress, leading to reduced histone deacetylase-2 (HDAC2) function through activation of phosphoinositide-3-kinase-delta (PI3Kdelta). The tricyclic antidepressant nortriptyline has been identified in high-throughput screens as an agent that increases corticosteroid responsiveness. The aim of this study was to identify the molecular mechanism whereby nortriptyline increases corticosteroid sensitivity. Phosphorylation of Akt, a footprint of PI3K activation, and HDAC activity were evaluated by Western blotting and fluorescent activity assay in U937 monocytic cells. Corticosteroid sensitivity was evaluated by the inhibition of tumor necrosis factor alpha (TNFalpha)-induced interleukin 8 (IL-8) production by budesonide. Hydrogen peroxide (H(2)O(2)) or cigarette smoke extract (CSE) increased the level of phosphorylated Akt (pAkt) and reduced HDAC activity. Pretreatment with nortriptyline inhibited pAkt induced by CSE and H(2)O(2) as well as restored HDAC activity that had been decreased by H(2)O(2) and CSE. In addition, nortriptyline inhibited PI3Kdelta activity, but had no effect on the PI3Kalpha and PI3Kgamma isoforms. Although CSE reduced the effects of budesonide on TNFalpha-induced IL-8 production in U937 cells, nortriptyline reversed CSE induced corticosteroid insensitivity. Nortriptyline restores corticosteroid sensitivity induced by oxidative stress via direct inhibition of PI3Kdelta and is a potential treatment for corticosteroid-insensitive diseases such as COPD and severe asthma. PMID- 21300706 TI - Characterization of pharmacological and wake-promoting properties of the dopaminergic stimulant sydnocarb in rats. AB - Sydnocarb is a psychomotor stimulant structurally similar to d-amphetamine (D AMPH) and is used in Russia for the treatment of a variety of neuropsychiatric comorbidities. The nature of sydnocarb-induced facilitation of dopamine (DA) neurotransmission [DA release versus DA transporter (DAT) inhibition] is not clear. The present study characterized the pharmacological actions and behavioral effects of intraperitoneal sydnocarb in male Sprague-Dawley rats. Where relevant, comparisons were made with intraperitoneal D-AMPH. Unlike D-AMPH, which causes release of DA from rat synaptosomes (EC(50) = 0.10 MUM; 95% confidence limits, 0.06-0.18), sydnocarb (up to 100 MUM) did not. Sydnocarb potently (K(i) = 8.3 +/- 0.7 nM) blocked recombinant human DAT expressed in Chinese hamster ovary-K1 cells and less potently blocked the norepinephrine transporter (K(i) = 10.1 +/- 1.5 MUM). Sydnocarb at 10 MUM did not bind to 64 other targets. In rats, 10 and 30 mg/kg sydnocarb showed a 2-fold longer half-life in plasma and brain and a 5-fold lower brain-to-plasma ratio compared with 0.3 and 1 mg/kg D-AMPH. In the Irwin assay, sydnocarb was well tolerated up to 30 mg/kg; D-AMPH-like stereotypic behaviors were evident at 100 mg/kg. Behavioral effects of 30 mg/kg sydnocarb and 0.3 mg/kg D-AMPH were comparable. In a sleep/wake assay, 10 mg/kg sydnocarb and 1 mg/kg D-AMPH increased wakefulness comparably; however, sydnocarb (up to 30 mg/kg) did not induce D-AMPH-like rebound hypersomnolence (RHS). Like D-AMPH, sydnocarb enhanced theta power, an electrophysiological measure of cognitive function. In conclusion, sydnocarb is a selective and potent DAT inhibitor that produces robust increases in the wake state without RHS, and with potential cognitive-enhancing properties. PMID- 21300708 TI - US Republicans try to restrict health insurance cover for abortion. PMID- 21300709 TI - Conventional versus automated measurement of blood pressure in primary care patients with systolic hypertension: randomised parallel design controlled trial. AB - OBJECTIVE: To compare the quality and accuracy of manual office blood pressure and automated office blood pressure using the awake ambulatory blood pressure as a gold standard. DESIGN: Multi-site cluster randomised controlled trial. SETTING: Primary care practices in five cities in eastern Canada. PARTICIPANTS: 555 patients with systolic hypertension and no serious comorbidities under the care of 88 primary care physicians in 67 practices in the community. INTERVENTIONS: Practices were randomly allocated to either ongoing use of manual office blood pressure (control group) or automated office blood pressure (intervention group) using the BpTRU device. The last routine manual office blood pressure (mm Hg) was obtained from each patient's medical record before enrollment. Office blood pressure readings were compared before and after enrollment in the intervention and control groups; all readings were also compared with the awake ambulatory blood pressure. MAIN OUTCOME MEASURE: Difference in systolic blood pressure between awake ambulatory blood pressure minus automated office blood pressure and awake ambulatory blood pressure minus manual office blood pressure. RESULTS: Cluster randomisation allocated 31 practices (252 patients) to manual office blood pressure and 36 practices (303 patients) to automated office blood pressure measurement. The most recent routine manual office blood pressure (149.5 (SD 10.8)/81.4 (8.3)) was higher than automated office blood pressure (135.6 (17.3)/77.7 (10.9)) (P < 0.001). In the control group, routine manual office blood pressure before enrollment (149.9 (10.7)/81.8 (8.5)) was reduced to 141.4 (14.6)/80.2 (9.5) after enrollment (P < 0.001/P = 0.01), but the reduction in the intervention group from manual office to automated office blood pressure was significantly greater (P < 0.001/P = 0.02). On the first study visit after enrollment, the estimated mean difference for the intervention group between the awake ambulatory systolic/diastolic blood pressure and automated office blood pressure (-2.3 (95% confidence interval -0.31 to -4.3)/-3.3 (-2.7 to -4.4)) was less (P = 0.006/P = 0.26) than the difference in the control group between the awake ambulatory blood pressure and the manual office blood pressure (-6.5 (-4.3 to -8.6)/-4.3 (-2.9 to -5.8)). Systolic/diastolic automated office blood pressure showed a stronger (P < 0.001) within group correlation (r = 0.34/r = 0.56) with awake ambulatory blood pressure after enrollment compared with manual office blood pressure versus awake ambulatory blood pressure before enrollment (r = 0.10/r = 0.40); the mean difference in r was 0.24 (0.12 to 0.36)/0.16 (0.07 to 0.25)). The between group correlation comparing diastolic automated office blood pressure and awake ambulatory blood pressure (r = 0.56) was stronger (P < 0.001) than that for manual office blood pressure versus awake ambulatory blood pressure (r = 0.30); the mean difference in r was 0.26 (0.09 to 0.41). Digit preference with readings ending in zero was substantially reduced by use of automated office blood pressure. CONCLUSION: In compliant, otherwise healthy, primary care patients with systolic hypertension, introduction of automated office blood pressure into routine primary care significantly reduced the white coat response compared with the ongoing use of manual office blood pressure measurement. The quality and accuracy of automated office blood pressure in relation to the awake ambulatory blood pressure was also significantly better when compared with manual office blood pressure. Trial registration Clinical trials NCT 00214053. PMID- 21300710 TI - Measurement of blood pressure in primary care. PMID- 21300711 TI - Strategy for intention to treat analysis in randomised trials with missing outcome data. PMID- 21300713 TI - US Senate doesn't repeal health reform, but states defy the act. PMID- 21300712 TI - Improving cardiovascular health at population level: 39 community cluster randomised trial of Cardiovascular Health Awareness Program (CHAP). AB - OBJECTIVE: To evaluate the effectiveness of the community based Cardiovascular Health Awareness Program (CHAP) on morbidity from cardiovascular disease. DESIGN: Community cluster randomised trial. SETTING: 39 mid-sized communities in Ontario, Canada, stratified by location and population size. PARTICIPANTS: Community dwelling residents aged 65 years or over, family physicians, pharmacists, volunteers, community nurses, and local lead organisations. INTERVENTION: Communities were randomised to receive CHAP (n = 20) or no intervention (n = 19). In CHAP communities, residents aged 65 or over were invited to attend volunteer run cardiovascular risk assessment and education sessions held in community based pharmacies over a 10 week period; automated blood pressure readings and self reported risk factor data were collected and shared with participants and their family physicians and pharmacists. MAIN OUTCOME MEASURE: Composite of hospital admissions for acute myocardial infarction, stroke, and congestive heart failure among all community residents aged 65 and over in the year before compared with the year after implementation of CHAP. RESULTS: All 20 intervention communities successfully implemented CHAP. A total of 1265 three hour long sessions were held in 129/145 (89%) pharmacies during the 10 week programme. 15,889 unique participants had a total of 27,358 cardiovascular assessments with the assistance of 577 peer volunteers. After adjustment for hospital admission rates in the year before the intervention, CHAP was associated with a 9% relative reduction in the composite end point (rate ratio 0.91, 95% confidence interval 0.86 to 0.97; P = 0.002) or 3.02 fewer annual hospital admissions for cardiovascular disease per 1000 people aged 65 and over. Statistically significant reductions favouring the intervention communities were seen in hospital admissions for acute myocardial infarction (rate ratio 0.87, 0.79 to 0.97; P = 0.008) and congestive heart failure (0.90, 0.81 to 0.99; P = 0.029) but not for stroke (0.99, 0.88 to 1.12; P = 0.89). CONCLUSIONS: A collaborative, multi-pronged, community based health promotion and prevention programme targeted at older adults can reduce cardiovascular morbidity at the population level. Trial registration Current controlled trials ISRCTN50550004. PMID- 21300714 TI - Safety agency calls for old syringe drivers to be phased out, after deaths. PMID- 21300715 TI - New male doctors earned 17% more than female doctors in US in 2008. PMID- 21300716 TI - New patent rules boost profits while safe drugs elude the world's poor, says Oxfam. PMID- 21300717 TI - Death row prisoners sue FDA for allowing unapproved execution drug to be imported. PMID- 21300718 TI - List of "wanted" US healthcare thieves is posted on the web. PMID- 21300719 TI - International agencies call for end to female genital mutilation. PMID- 21300720 TI - Researcher didn't get ethical approval for 68 studies, investigators say. PMID- 21300722 TI - The role of transmembrane domain 3 in the actions of orthosteric, allosteric, and atypical agonists of the M4 muscarinic acetylcholine receptor. AB - Despite the discovery of a diverse range of novel agonists and allosteric modulators of the M(4) muscarinic acetylcholine (ACh) receptor (mAChR), little is known about how such ligands activate the receptor. We used site-directed mutagenesis of conserved residues in transmembrane 3 (TMIII), a key region involved in G protein-coupled receptor activation, to probe the binding and function of prototypical orthosteric mAChR agonists, allosteric modulators, and "atypical" agonists. We found that most mutations did not affect the binding of the allosteric modulators, with the exception of W108(3.28)A and L109(3.29)A (which may contribute directly to the interface between allosteric and orthosteric sites) and mutation D112(3.32)N (which may cause a global disruption of a hydrogen bond network). Although numerous mutations affected signaling, we did not identify amino acids that were important for the functional activity of any one class of agonist (orthosteric, allosteric, or atypical) to the exclusion of any others, suggesting that TMIII is key for the transmission of stimulus irrespective of the agonist. We also identified two key residues, Trp108(3.28) and Asp112(3.32), that are essential for the transmission of binding cooperativity between 3-amino-5-chloro-6-methoxy-4-methyl-thieno[2,3-b]pyridine- 2-carboxylic acid cyclopropylamide (LY2033298) and ACh. Finally, we found that LY2033298 was able to rescue functionally impaired signaling of ACh at the majority of mutants tested in a manner that was inversely correlated with the ACh signaling efficacy, indicating that a key part of the mechanism of the positive cooperativity mediated by LY2033298 on the endogenous agonist involves a global drive of the receptor toward an active conformation. PMID- 21300721 TI - Simulation of multiple ion channel block provides improved early prediction of compounds' clinical torsadogenic risk. AB - AIMS: The level of inhibition of the human Ether-a-go-go-related gene (hERG) channel is one of the earliest preclinical markers used to predict the risk of a compound causing Torsade-de-Pointes (TdP) arrhythmias. While avoiding the use of drugs with maximum therapeutic concentrations within 30-fold of their hERG inhibitory concentration 50% (IC(50)) values has been suggested, there are drugs that are exceptions to this rule: hERG inhibitors that do not cause TdP, and drugs that can cause TdP but are not strong hERG inhibitors. In this study, we investigate whether a simulated evaluation of multi-channel effects could be used to improve this early prediction of TdP risk. METHODS AND RESULTS: We collected multiple ion channel data (hERG, Na, L-type Ca) on 31 drugs associated with varied risks of TdP. To integrate the information on multi-channel block, we have performed simulations with a variety of mathematical models of cardiac cells (for rabbit, dog, and human ventricular myocyte models). Drug action is modelled using IC(50) values, and therapeutic drug concentrations to calculate the proportion of blocked channels and the channel conductances are modified accordingly. Various pacing protocols are simulated, and classification analysis is performed to evaluate the predictive power of the models for TdP risk. We find that simulation of action potential duration prolongation, at therapeutic concentrations, provides improved prediction of the TdP risk associated with a compound, above that provided by existing markers. CONCLUSION: The suggested calculations improve the reliability of early cardiac safety assessments, beyond those based solely on a hERG block effect. PMID- 21300723 TI - Orthodontic anchoring techniques and its influence on pain, discomfort, and jaw function--a randomized controlled trial. AB - The aim of this trial was to evaluate and compare perceived pain, discomfort, and jaw function impairment between orthodontic treatments combined with skeletal anchorage and treatment using conventional anchorage with headgear or transpalatal bar. A total of 120 adolescent patients in order to start orthodontic treatment were consecutively recruited and randomized into three groups with different anchorage. Group A underwent installation of a skeletal anchorage (Onplant or Orthosystem implant), group B received headgear, and group C a transpalatal bar. Questionnaires were used to assess pain intensity, discomfort, analgesic consumption, and jaw function impairment from baseline to the end of treatment. Pain scores overall peaked on day 2 and were almost back to baseline on day 7. The site with the highest pain scores during treatment was incisors in contact but with no differences between groups. Pain intensity from molars was significantly less in the skeletal anchorage group A compared to the transpalatal bar group C the first 4 days in treatment and with no sign differences compared to headgear. The results confirm that there were very few significant differences between patients' perceptions of skeletal and conventional anchorage systems during orthodontic treatment. Consequently, these new appliances were well accepted by the patients in a long time perspective and can thus be recommended. PMID- 21300724 TI - Sex hormones receptors play a crucial role in the control of femoral and mandibular growth in newborn mice. AB - Sex hormones are important for bone growth. However, the mechanism by which sex hormone receptors influence bone growth remains unclear. In orthodontic treatment, there is a need to develop an indicator of bone maturity to accurately predict the beginning and end of growth. This indicator might be developed from the screening of sex hormones. The purpose of this study was to investigate the role of each sex hormone receptor on bone growth in newborn mice. Five-day-old C57BL/6J mice were used in this experiment. Forty mice underwent an orchiectomy (ORX), ovariectomy (OVX), or sham surgery. One week after surgery, the femur and the mandible were resected for immunohistochemical staining. Alternatively, 80 mice were daily injected with antagonist against receptors oestrogen alpha (ERalpha), beta (ERbeta), or androgen receptor (AR). One week after the first injection, radiographs of the femur and mandible were taken and then measured. Analysis of variance and pairwise comparisons (Fisher) were performed to examine the differences in values measured among the groups In the sham-operated male and female mice, ERbeta was found to be more prominent than ERalpha and AR during all experimental periods. In the ORX and OVX groups, the expressions of all receptors were significantly reduced in comparison with the sham-operated control group throughout the experiment. Moreover, femur and mandibular growth were significantly affected in the group injected with ERbeta antagonist. The deficiency of any sex hormone leads to reduced bone growth. In particular, a disturbance in ERbeta produces a greater aberrance in both male and female mice immediately after birth. PMID- 21300725 TI - Three-dimensional longitudinal assessment of facial symmetry in adolescents. AB - Recent advances in laser scanning technology provide the opportunity to examine faces in three dimensions. The aim of this prospective clinical study was to explore facial symmetry in healthy growing individuals and determine whether asymmetric changes occur during adolescent growth. Non-invasive laser surface scanning was performed to capture facial images of 60 Caucasian Finnish adolescents (30 males and 30 females, mean 11.5 years). Facial symmetry was analysed on images obtained at the initial scanning (T1), 2.5 (T2), and 4.5 (T3) years thereafter. The final sample consisted of 39 adolescents (19 males and 20 females, mean 16 years). Three-dimensional images were processed and analysed using an in-house developed subroutine for commercial software. A mirror image was generated and superimposed on the original image to create a symmetric face and establish the midsagittal plane. The surface matching of the original face and the mirror face (amount of symmetry) was measured for the whole face, upper, middle, and lower thirds at tolerance level 0.5 mm and presented with colour maps. Three angular and 14 linear measurements were made based on 21 soft tissue landmarks, which have proven to be reliable. The results of the Friedman test showed that facial symmetry parameters did not significantly differ over time (P > 0.05). Mann-Whitney U-test did not reveal statistically significant differences between genders at any time point (P > 0.05). Facial growth of healthy individuals during adolescence is symmetric, although further investigation on larger randomized sample is suggested. PMID- 21300726 TI - Ossification of the midpalatal suture after surgically assisted rapid maxillary expansion. AB - The purpose of this study was to evaluate ossification of the midpalatal suture in adult patients immediately after surgically assisted rapid maxillary expansion (SARME) until 120 days post-surgery. The sample comprised 126 standardized occlusal radiographs of 21 adults (14 females and 7 males; mean age: 25.33 years) taken pre-expansion (T1), immediately after expansion (T2), and post-expansion (30, 60, 90, and 120 days of retention, respectively: T3, T4, T5, and T6) who had undergone SARME. The radiographs were digitized and the images were analysed and compared in relation to the morphology and radiopacity at the different treatment stages, especially concerning the characteristics of the midpalatal suture. Data were statistically analysed using analysis of variance and Tukey's test. The results demonstrated that from T2 to T6, the mean optical density (OD) increased. However, these values were not similar to those observed at T1. A retention period of 120 days was not sufficient for the re-establishment of OD and complete ossification within the suture in the evaluated patients. PMID- 21300727 TI - Anti-dentine antibodies with root resorption during orthodontic treatment. AB - The aim of this study was to analyse serum IgG levels and salivary secretory IgA (sIgA) levels in human dentine extract (HDE) before (T0) and 6 months after (T6) orthodontic treatment and to correlate anti-HDE autoantibodies to root resorption. Fifty orthodontic patients were selected, 19 males (15.6 +/- 8.5 years) and 31 females (21.4 +/- 11.2 years), 19 in the mixed dentition (10.3 +/- 1.9 years) and 31 in the permanent dentition (24.6 +/- 9.9 years). Fifty individuals not undergoing orthodontic treatment matched by gender and age were selected as the controls. Periapical radiographs of the upper central incisors and saliva sampling were obtained of all patients at T0 and T6. Serum samples were collected from the permanent dentition patients (n = 31). Antibody levels were determined by means of immunoenzyme assay. At T6, root resorption was classified as grade 0 (no resorption), grade 1 (slight resorption), and grade 2 (moderate to severe resorption). Differences between antibody levels at T0 and T6 and among different grades of resorption were determined by paired t- and Kruskal Wallis tests, respectively. Spearman's rank correlation coefficient was applied to detect correlation between sIgA and IgG levels, and logistic regression to determine the association of root resorption grade and the studied variables. Differences were considered significant at P < 0.05. Serum anti-HDE IgG levels decreased (P < 0.01) in grade 2 root resorption patients during treatment and was not correlated to salivary sIgA levels or other variables. Patients who had grade 2 root resorption at T6 showed higher levels of anti-HDE sIgA (P < 0.001). Anti HDE sIgA levels at T0 and root shape were the main factors associated with the degree of root resorption. The results suggest that variations to systemic and local humoural immune response to dentine antigens may occur during orthodontic treatment. High levels of salivary sIgA before treatment were associated with more advanced lesions after 6 months of treatment. PMID- 21300728 TI - Precision of measurements on conventional negative 'bones white' and inverted greyscale 'bones black' digital lateral cephalograms. AB - The objective of this study was to determine whether the accuracy of measurement data from inverted greyscale digital cephalometric radiographs equals that obtained from conventional negative digital cephalometric radiographs. Fifty-five consecutively lateral cephalometric radiographs from a university orthodontic clinic obtained for treatment planning were used for this study. A 5 MB conventional negative 'bones white' and inverted greyscale 'bones black' TIFF digital image of each radiograph was produced. These were allocated a unique identifier and were analysed in random order by one clinician. Eighteen cephalometric landmarks were digitized using the Opal 2.1 package and the angles were calculated. The angular measurements were compared using two-sample t-tests (P < 0.05). The angular measurements from the conventional negative bones white and inverted greyscale bones black lateral cephalometric radiographs were neither statistically significantly different nor clinically different from each other. Therefore, measurements derived from conventional negative bones white and inverted greyscale bones black lateral cephalometric radiographs have a similar level of precision. PMID- 21300729 TI - Bonding with self-etching primers--pumice or pre-etch? An in vitro study. AB - The purpose of this study was to compare the shear bond strengths (SBSs) of orthodontic brackets bonded with self-etching primer (SEP) using different enamel surface preparations. A two-by-two factorial study design was used. Sixty human premolars were harvested, cleaned, and randomly assigned to four groups (n = 15 per group). Teeth were bathed in saliva for 48 hours to form a pellicle. Treatments were assigned as follows: group 1 was pumiced for 10 seconds and pre etched for 5 seconds with 37 per cent phosphoric acid before bonding with SEP (Transbond Plus). Group 2 was pumiced for 10 seconds before bonding. Group 3 was pre-etched for 5 seconds before bonding. Group 4 had no mechanical or chemical preparation before bonding. All teeth were stored in distilled water for 24 hours at 37 degrees C before debonding. The SBS values and adhesive remnant index (ARI) score were recorded. The SBS values (+/- 1 SD) for groups 1-4 were 22.9 +/- 6.6, 16.1 +/- 7.3, 36.2 +/- 8.2, and 13.1 +/- 10.1 MPa, respectively. Two-way analysis of variance and subsequent contrasts showed statistically significant differences among treatment groups. ARI scores indicated the majority of adhesive remained on the bracket for all four groups. Pre-etching the bonding surface for 5 seconds with 37 per cent phosphoric acid, instead of pumicing, when using SEPs to bond orthodontic brackets, resulted in greater SBSs. PMID- 21300730 TI - A comparison of single-lead atrial pacing with dual-chamber pacing in sick sinus syndrome. AB - AIMS: In patients with sick sinus syndrome, bradycardia can be treated with a single-lead pacemaker or a dual-chamber pacemaker. Previous trials have revealed that pacing modes preserving atrio-ventricular synchrony are superior to single lead ventricular pacing, but it remains unclear if there is any difference between single-lead atrial pacing (AAIR) and dual-chamber pacing (DDDR). METHODS AND RESULTS: We randomly assigned 1415 patients referred for first pacemaker implantation to AAIR (n = 707) or DDDR (n = 708) pacing and followed them for a mean of 5.4 +/- 2.6 years. The primary outcome was death from any cause. Secondary outcomes included paroxysmal and chronic atrial fibrillation, stroke, heart failure, and need for pacemaker reoperation. In the AAIR group, 209 patients (29.6%) died during follow-up vs. 193 patients (27.3%) in the DDDR group, hazard ratio (HR) 1.06, 95% confidence interval (CI) 0.88-1.29, P = 0.53. Paroxysmal atrial fibrillation was observed in 201 patients (28.4%) in the AAIR group vs. 163 patients (23.0%) in the DDDR group, HR 1.27, 95% CI 1.03-1.56, P = 0.024. A total of 240 patients underwent one or more pacemaker reoperations during follow-up, 156 (22.1%) in the AAIR group vs. 84 (11.9%) in the DDDR group (HR 1.99, 95% CI 1.53-2.59, P < 0.001). The incidence of chronic atrial fibrillation, stroke, and heart failure did not differ between treatment groups. CONCLUSION: In patients with sick sinus syndrome, there is no statistically significant difference in death from any cause between AAIR pacing and DDDR pacing. AAIR pacing is associated with a higher incidence of paroxysmal atrial fibrillation and a two-fold increased risk of pacemaker reoperation. These findings support the routine use of DDDR pacing in these patients. CLINICAL TRIAL REGISTRATION: URL http://www.clinicaltrials.gov. Unique identifier: NCT00236158. PMID- 21300731 TI - Heterotopic transcatheter tricuspid valve implantation: first-in-man application of a novel approach to tricuspid regurgitation. AB - AIMS: Transcatheter treatment of heart valve disease is well established today. However, for the treatment of tricuspid regurgitation (TR), no effective catheter based approach is available. Herein, we report the first human case description of transcatheter treatment of severe TR in a 79-year-old patient with venous congestion and associated non-cardiac diseases. In this patient, surgical treatment had been declined and pharmacological therapy had been ineffective. After ex vivo and animal studies, the treatment of TR was performed by percutaneous caval valve implantation. METHODS AND RESULTS: In a transcatheter approach through the right femoral vein, a custom-made self-expanding heart valve was implanted into the inferior vena cava (IVC). The device was anchored in the IVC at the cavoatrial junction with the level of the valve aligned immediately above the hepatic inflow and protruding into the right atrium. After deployment, excellent valve function was observed resulting in a marked reduction in caval pressure and an abolition of the ventricular wave in the IVC. Sequential echocardiographic exams over a follow-up period of 8 weeks confirmed continuous device function without paravalvular leakage or remaining venous regurgitation. The patient experienced improved physical capacity and was able to resume off-bed activities. There was no recurrence of right heart failure during follow-up and a partial reduction of ascites. The patient was discharged from hospital into a rehabilitation programme. CONCLUSION: Transcatheter treatment of severe TR by caval valve implantation is feasible resulting in an immediate abolition of IVC regurgitation and mid-term clinical improvement. Thus, in selected non-surgical patients, caval valve implantation may become a therapeutic option to treat venous regurgitation and improve associated non-cardiac diseases. Further confirmatory experience with longer follow-up is required to evaluate the long term clinical benefit of the procedure as well as potential deleterious effects. PMID- 21300732 TI - Sleep duration predicts cardiovascular outcomes: a systematic review and meta analysis of prospective studies. AB - Aims To assess the relationship between duration of sleep and morbidity and mortality from coronary heart disease (CHD), stroke, and total cardiovascular disease (CVD). Methods and results We performed a systematic search of publications using MEDLINE (1966-2009), EMBASE (from 1980), the Cochrane Library, and manual searches without language restrictions. Studies were included if they were prospective, follow-up >3 years, had duration of sleep at baseline, and incident cases of CHD, stroke, or CVD. Relative risks (RR) and 95% confidence interval (CI) were pooled using a random-effect model. Overall, 15 studies (24 cohort samples) included 474 684 male and female participants (follow-up 6.9-25 years), and 16 067 events (4169 for CHD, 3478 for stroke, and 8420 for total CVD). Sleep duration was assessed by questionnaire and incident cases through certification and event registers. Short duration of sleep was associated with a greater risk of developing or dying of CHD (RR 1.48, 95% CI 1.22-1.80, P < 0.0001), stroke (1.15, 1.00-1.31, P = 0.047), but not total CVD (1.03, 0.93-1.15, P = 0.52) with no evidence of publication bias (P = 0.95, P = 0.30, and P = 0.46, respectively). Long duration of sleep was also associated with a greater risk of CHD (1.38, 1.15-1.66, P = 0.0005), stroke (1.65, 1.45-1.87, P < 0.0001), and total CVD (1.41, 1.19-1.68, P < 0.0001) with no evidence of publication bias (P = 0.92, P = 0.96, and P = 0.79, respectively). Conclusion Both short and long duration of sleep are predictors, or markers, of cardiovascular outcomes. PMID- 21300733 TI - Long-term effects of radiotherapy on cardiovascular risk factors in acromegaly. AB - OBJECTIVE: Radiation therapy (RT) is a useful adjuvant tool for acromegalic patients not cured by surgery and/or not responding to pharmacotherapy. However, its specific effects on cardio- and cerebrovascular morbidity are still on debate. DESIGN: Retrospective analysis of 42 acromegalic patients cured after conventional radiotherapy (CRT, n=31) or radiosurgery by gamma-knife (GKRS, n=11) followed for a median period of 16.5 years (range: 2-40). Totally, 56 patients cured by surgery alone, with similar GH/IGF1 levels and duration of disease remission, served as control group. METHODS: Changes in cardiovascular risk factors, such as body mass index, glucose metabolism, insulin resistance, blood pressure, and lipid profile (pre-defined primary end point) and occurrence of new major cardio- and cerebrovascular events (secondary end point) during follow-up. RESULTS: The number of obese, hypertensive, and dyslipidemic subjects increased over time only in patients cured with RT. In contrast, the glucose response to the oral glucose tolerance test and the percentage of subjects with glucose alterations improved only in controls. As expected, the percentage of patients with pituitary failure was deeply higher among RT patients than among controls (86 vs 30%, P<0.0005). Despite these findings, a similar number of RT patients and controls developed major cardio- or cerebrovascular events (4/42 vs 3/56, P: NS). No differences were found between CRT and GKRS subgroups. CONCLUSIONS: Previous RT seems to be associated with a worse metabolic profile in acromegalic patients studied after a long-term follow-up. Nevertheless, a direct link between RT and cardiovascular events remains to be proven. PMID- 21300734 TI - Effect of optic neuritis on progressive axonal damage in multiple sclerosis patients. AB - OBJECTIVE: The objective of this research was to study the effect of optic neuritis (ON) on axonal damage in multiple sclerosis (MS) patients. Specifically, we compared changes over 2 years in the retinal nerve fibre layer (RNFL) between affected and contralateral eyes in MS patients with a prior history of ON. METHODS: Thirty-four patients with one unilateral definitive episode of ON were included and underwent a complete ophthalmic examination, optical coherence tomography (OCT), scanning laser polarimetry, visual evoked potentials (VEP) and pattern electroretinogram (pERG). All patients were re-evaluated at 12 and 24 months. Parameters were compared between ON-affected and contralateral eyes in an initial exploration and over the course of the follow-up. Correlations between parameter changes were analysed. RESULTS: RNFL thickness and functional parameters showed more affection in ON eyes (p <= 0.05), but changes in measurements during the study were similar between both groups of eyes. CONCLUSIONS: Progressive axonal loss can be detected in the optic nerve, but ON is not a risk factor for increased chronic damage in MS patients without ophthalmic relapses. Loss of the RNFL is caused by progressive degeneration associated with the disease. PMID- 21300735 TI - Wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) syndrome in a patient with neuromyelitis optica spectrum disorder and anti-aquaporin-4 antibody. AB - This report describes, for the first time, an occurrence of wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) in a 19-year-old female with neuromyelitis optica (NMO) spectrum disorder, who had anti-aquaporin-4 (AQP4) antibody. A high signal intensity lesion on T2-weighted MRI was detected in the midbrain tegmentum adjacent to the aqueduct, and presumably involved the medial longitudinal fasciculus bilaterally at the caudal levels. Plasma exchange resolved both WEBINO syndrome and the midbrain lesion. Although WEBINO syndrome is occasionally reported in multiple sclerosis patients, diagnosis of NMO should not be excluded in patients with WEBINO syndrome, because AQP4 is expressed abundantly around the periaqueductal region. PMID- 21300736 TI - Change in quality of life in patients with relapsing-remitting multiple sclerosis over 2 years in relation to other clinical parameters: results from a trial of intramuscular interferon {beta}-1a. AB - BACKGROUND: A randomized, placebo-controlled, multicenter study of weekly intramuscular injections of interferon beta-1a (IFNbeta-1a) in relapsing remitting multiple sclerosis included the Sickness Impact Profile (SIP), a validated measure of patient-reported quality of life (QoL). OBJECTIVE: To demonstrate the impact of moderate to severe SIP disability at baseline and change in QoL as measured by SIP over 2 years in relation to other study parameters. METHODS: In 158 patients, SIP scores were determined at baseline and 2 years. Scores were correlated with disease progression and treatment. RESULTS: Patients who experienced disability progression, as defined by Expanded Disability Status Scale (EDSS) and annualized relapse rate, during the study demonstrated significant worsening in Physical SIP scores compared with patients who did not progress (p=0.031). In patients with low SIP scores, indicating moderate or severe disability at baseline, treatment with IFNbeta-1a significantly improved Physical SIP subscores. CONCLUSIONS: Patients with disability progression defined using EDSS, the physician-derived primary outcome measure, had Physical SIP scores indicating worsening disability, validating the physician-derived primary outcome measure using patient self-report. Treatment with IFNbeta-1a had beneficial effects on QoL in patients with worse SIP scores at baseline. PMID- 21300737 TI - Strategies in the prevention of ventilator-associated pneumonia. AB - Ventilator-associated pneumonia (VAP) remains a significant problem in the hospital setting, with very high morbidity, mortality, and cost. We performed an evidence-based review of the literature focusing on clinically relevant pharmacological and nonpharmacological interventions to prevent VAP. Owing to the importance of this condition the implementation of preventive measures is paramount in the care of mechanically ventilated patients. There is evidence that these measures decrease the incidence of VAP and improve outcomes in the intensive care unit. A multidisciplinary approach, continued education, and ventilator protocols ensure the implementation of these measures. Future research will continue to investigate cost/benefit relationships, antibiotic resistance, as well as newer technologies to prevent contamination and aspiration in mechanically ventilated patients. PMID- 21300738 TI - The potential for inhaled treprostinil in the treatment of pulmonary arterial hypertension. AB - Inhaled treprostinil is a safe and well-tolerated approved pharmaceutical for the treatment of pulmonary arterial hypertension. In a series of open-label studies and in the pivotal trial with 253 patients, this long-acting prostacyclin analogue demonstrated pronounced pulmonary selectivity of vasodilatory effects, improved physical capacity and excellent tolerability and safety following aerosol administration. For efficient treatment, only four daily inhalations of treprostinil are necessary compared with six to nine in iloprost aerosol therapy. This review describes in detail the development of inhaled treprostinil, starting with intravenous epoprostenol followed by inhaled iloprost and subcutaneous treprostinil, all three representing well-established and widely approved prostanoid therapies for pulmonary hypertension. In order to circumvent the drawbacks of intravenous epoprostenol, stable prostacyclin analogues with similar pharmacological properties have been investigated. In addition, alternative routes of administration have been proposed and evaluated, mainly inhaled and subcutaneous delivery. The concept of inhaled treprostinil was to combine the pulmonary selectivity of an aerosolized vasodilator with the long-acting effects of a stable prostacyclin analogue. Pulmonary arterial hypertension remains, however, a severe, life-threatening disease, in spite of the enormous progress in specific drug therapy over the last decade. Therefore, further improvement of drug therapy will be essential, with clear potential for inhaled treprostinil: a reduction of inhalation frequency and duration would markedly improve quality of life and compliance, and a longer-lasting local prostanoid effect might further enhance the efficacy of inhaled treprostinil. The advantageous pharmacological properties of treprostinil offer the opportunity to establish a convenient metered dose inhaler as a delivery system, to combine inhaled treprostinil with available or future drugs for pulmonary arterial hypertension, or to develop sustained release formulations of treprostinil suitable for inhalation based on liposomes or biodegradable nanoparticles. PMID- 21300739 TI - A liquid chromatography-tandem mass spectrometry method for salivary testosterone with adult male reference interval determination. PMID- 21300740 TI - The journey to regulation of protein-based multiplex quantitative assays. AB - BACKGROUND: Clinical proteomics presents great promise in biology and medicine because of its potential for improving our understanding of diseases at the molecular level and for detecting disease-related biomarkers for diagnosis, prognosis, and prediction of therapeutic responses. To realize its full potential to improve clinical outcome for patients, proteomic studies have to be well designed, from biosample cohorts to data and statistical analyses. One key component in the biomarker development pipeline is the understanding of the regulatory science that evaluates diagnostic assay performance through rigorous analytical and clinical review criteria. CONTENT: The National Cancer Institute's Clinical Proteomic Technologies for Cancer (CPTC) initiative has proposed an intermediate preclinical "verification" step to close the gap between protein based biomarker discovery and clinical qualification. In collaboration with the US Food and Drug Administration (FDA), the CPTC network investigators recently published 2 mock submission review documents, first-of-their-kind educational materials that may help the scientific community interested in developing products for the clinic in understanding the likely analytical evaluation requirements for multiplex protein technology-based diagnostic tests. CONCLUSIONS: Building on this momentum, the CPTC continues with this report its collaboration with the FDA, as well as its interactions with the AACC and the Centers for Medicare and Medicaid Services, to further the understanding of regulatory requirements for approving multiplex proteomic platform-based tests and analytically validating multiple analytes. PMID- 21300742 TI - Reemphasizing the role of fructose intake as a risk factor for dementia. PMID- 21300741 TI - Age-related pseudocapillarization of the liver sinusoidal endothelium impairs the hepatic clearance of acetaminophen in rats. AB - We investigated the effect of age-related pseudocapillarization of the liver sinusoidal endothelium on the hepatic disposition of acetaminophen. The multiple indicator dilution technique assessed the hepatic disposition of tracer (14)C acetaminophen and reference markers in isolated perfused livers of young (n = 11) and old (n = 12) rats. Electron microscopy confirmed defenestration of the sinusoidal endothelium in old rats compared with young rats. Acetaminophen recovery following a single pass through the liver was significantly increased in old rats (0.64 +/- 0.04, old; 0.59 +/- 0.05, young; p < .05). In old age, there was significant reduction of the intercompartmental rate constant k(1) (0.34 +/- 0.10 s(-1), old; 0.61 +/- 0.38 s(-1), young; p < .05) and the permeability surface area product for the transfer of acetaminophen across the sinusoidal endothelium (0.034 +/- 0.006 mL/s/g, old; 0.048 +/- 0.014 mL/s/g, young; p < .005). There was no difference in k(3), the measure of sequestration of acetaminophen that reflects enzyme activity. Age-related pseudocapillarization of the liver sinusoid resulted in increased acetaminophen recovery and decreased transfer of acetaminophen into the liver. PMID- 21300743 TI - Body mass index misclassification due to kyphotic posture in Japanese community dwelling adults aged 65 years and older. AB - BACKGROUND: In older adults, kyphosis (slouching posture) can lead to underestimation of height, which may in turn lead to overestimation of body mass index (BMI). We investigated the extent to which inaccurate BMI assessments led to misclassification of elderly people as normal weight (when they were actually underweight) or overweight (actually normal weight). METHODS: Anthropometric measurements were taken in 2005 and 2006 for 842 residents aged 65 years or older (women: 491; men: 351). We calculated BMI from measured height and weight (observed BMI) and then predicted BMI from height as determined by demi-span, which is unaffected by kyphosis (predicted BMI). Kyphosis was assessed by the number of blocks placed under the occiput required for the supine participant to achieve a neutral head position. Participants were classified as underweight (BMI < 18.5), normal weight, or overweight (BMI >= 25.0) according to both observed and predicted BMI; classification accordance was investigated by cross tabulation. RESULTS: Kyphosis was present in 17.2% of the participants overall and in 23.6% of those aged 75 years or older. Predicted BMI measurements showed that 11% of participants with kyphosis requiring >= 3 blocks were misclassified as normal weight and that 10% were erroneously classified as overweight. In those aged 75 years or older, the corresponding figures were 15% and 12%. CONCLUSIONS: Our results suggest that inaccurate BMIs due to kyphosis lead to substantial numbers of older adults being misclassified as normal weight or overweight, which can cause significant distortions in data on the impact of underweight and overweight on health outcomes. PMID- 21300744 TI - The relationship of aspiration status with tongue and handgrip strength in healthy older adults. AB - BACKGROUND: Recently, subclinical aspiration has been identified in approximately 30% of community-dwelling older adults. Given that the tongue is a key component of the safe swallow, we hypothesized healthy older adults who aspirate will generate less tongue strength than adults who do not aspirate. Furthermore, as muscle weakness may reflect a global effect of aging, we further investigated whether tongue strength is correlated with handgrip strength. METHODS: We assessed 78 healthy community-dwelling older adults (M = 77.3 years, SD = 7.26) for aspiration status (37% aspirators) via flexible endoscopic evaluation of swallowing. Maximal isometric anterior and posterior tongue strength, anterior and posterior swallowing tongue strength, and maximum handgrip strength were measured. RESULTS: Isometric tongue strength was significantly lower in aspirators versus nonaspirators (p = .03) at both the anterior (463 vs 548 mmHg, respectively) and posterior lingual locations (285 vs 370 mmHg, respectively). Likewise, swallowing tongue strength was significantly lower in aspirators versus nonaspirators at both the anterior (270 vs 317 mmHg, respectively) and posterior lingual locations (220 vs 267 mmHg, respectively). There was no difference between aspirators and nonaspirators' handgrip strength (p > .05), although handgrip strength was correlated with posterior tongue strength (r = .34, p = .005). CONCLUSIONS: Lower anterior and posterior isometric and swallowing tongue strength were dependent on aspiration status. Lower lingual strength in healthy adults may predispose them to aspiration. The correlation between tongue and handgrip strength is consistent with the hypothesis that impaired oropharyngeal strength reflects global age-related declines in muscle strength. PMID- 21300745 TI - Relation of late-life social activity with incident disability among community dwelling older adults. AB - BACKGROUND: We tested the hypothesis that a higher level of social activity was associated with decreased risk of incident disability in older adults. METHODS: Data came from older adults in the Rush Memory and Aging Project, an ongoing longitudinal cohort study of aging. Analyses were restricted to persons without clinical dementia and reporting no need for help performing any task in the particular functional domain assessed. Participants were followed for an average of 5.1 years (SD = 2.5). Social activity, based on 6 items (visiting friends or relatives; going to restaurants, sporting events, or playing games; group meetings; church/religious services; day or overnight trips; unpaid community/volunteer work), was assessed at baseline. Disability in basic activities of daily living, mobility disability, and instrumental activities of daily living was assessed annually. Proportional hazard models adjusted for age, sex, and education were used to examine the association between social activity and incident disability. Fully adjusted models included terms for depression, vascular diseases and risk factors, body mass index, social networks, and self reported physical activity. RESULTS: In fully adjusted models, among 954 persons without baseline disability, the risk of developing disability in activities of daily living decreased by 43% (hazard ratio = 0.57, 95% confidence interval = 0.46, 0.71) for each additional unit of social activity. Social activity was also associated with decreased risk of developing mobility disability (hazard ratio = 0.69, 95% confidence interval = 0.54, 0.88) and disability in instrumental activities of daily living (hazard ratio = 0.71, 95% confidence interval = 0.55, 0.93). CONCLUSIONS: Social activity is associated with a decreased risk of incident disability in activities of daily living, mobility, and instrumental activities of daily living, among community-dwelling older adults. PMID- 21300746 TI - BK channel beta1 subunits regulate airway contraction secondary to M2 muscarinic acetylcholine receptor mediated depolarization. AB - The large conductance calcium- and voltage-activated potassium channel (BK channel) and its smooth muscle-specific beta1 subunit regulate excitation contraction coupling in many types of smooth muscle cells. However, the relative contribution of BK channels to control of M2- or M3-muscarinic acetylcholine receptor mediated airway smooth muscle contraction is poorly understood. Previously, we showed that knockout of the BK channel beta1 subunit enhances cholinergic-evoked trachea contractions. Here, we demonstrate that the enhanced contraction of the BK beta1 knockout can be ascribed to a defect in BK channel opposition of M2 receptor-mediated contractions. Indeed, the enhanced contraction of beta1 knockout is eliminated by specific M2 receptor antagonism. The role of BK beta1 to oppose M2 signalling is evidenced by a greater than fourfold increase in the contribution of L-type voltage-dependent calcium channels to contraction that otherwise does not occur with M2 antagonist or with beta1 containing BK channels. The mechanism through which BK channels oppose M2-mediated recruitment of calcium channels is through a negative shift in resting voltage that offsets, rather than directly opposes, M2-mediated depolarization. The negative shift in resting voltage is reduced to similar extents by BK beta1 knockout or by paxilline block of BK channels. Normalization of beta1 knockout baseline voltage with low external potassium eliminated the enhanced M2-receptor mediated contraction. In summary, these findings indicate that an important function of BK/beta1 channels is to oppose cholinergic M2 receptor-mediated depolarization and activation of calcium channels by restricting excitation-contraction coupling to more negative voltage ranges. PMID- 21300747 TI - Altered electroretinograms in patients with KCNJ10 mutations and EAST syndrome. AB - The K+ channel expressed by the KCNJ10 gene (Kir4.1) has previously demonstrated importance in retinal function in animal experiments. Recently, mutations in KCNJ10 were recognised as pathogenic in man, causing a constellation of symptoms, including epilepsy, ataxia, sensorineural deafness and a renal tubulopathy designated as EAST syndrome. We have studied the impact of KCNJ10 mutations on the human electroretinogram (ERG) in four unrelated patients with EAST syndrome. Corneal ganzfeld ERGs were elicited in response to flash stimuli of strengths of 0.001-10 phot cd s/m2 presented scotopically, and 0.3-10 phot cd s/m2 presented photopically. ERG waveforms from light-adapted retinae of all patients showed reduced amplitudes of the photopic negative response (PhNR) (P < 0.001). The photopic ERGs showed a delay in b-wave time to peak, but the photopic hill, i.e. the relative variation of time to peak and amplitude with luminance flash strength, was preserved. Scotopic ERGs to flash strengths 0.01 to 0.1 phot cd s/m2 showed a delay of up to 20 ms before the onset of the b-wave in two patients compared to controls. Stimulus-response functions were fitted by Michaelis-Menten equations and showed significantly lower retinal sensitivity in two patients than in controls (P < 0.001). Our study for the first time in the human ERG shows changes in association with KCNJ10 mutations affecting a Muller cell K+ channel. These data illustrate the role of KCNJ10 function in the physiology of proximal and possibly also the distal human retina. PMID- 21300748 TI - Is connexin36 critical for GABAergic hypersynchronization in the hippocampus? AB - Synchronous bursting of cortical GABAergic interneurons is important in epilepsies associated with excitatory GABAergic signalling. If electrical coupling was critical for the generation of this pathological activity, then the development of selective blockers of connexin36-based interneuronal gap junctions could be of therapeutic value. We have addressed this issue in the 4 aminopyridine model of epilepsy in vitro by comparing GABAergic epileptiform currents and their sensitivity to gap junction blockers in wild-type vs. connexin36 knockout mice. Although electrical coupling was abolished in stratum lacunosum-moleculare interneurons from knockout animals, epileptiform currents were not eliminated. Furthermore, epileptiform currents propagated similarly across hippocampal layers in the two genotypic groups. Blockade of electrical coupling with carbenoxolone suppressed amplitude, frequency and half-width of the epileptiform currents both in wild-type and in knockout animals, whereas mefloquine had no effects. Carbenoxolone also depressed responses to exogenous and synaptic GABA application onto interneurons. We conclude that, in the 4 aminopyridine model of epilepsy in vitro, connexin36 is not critical for the generation of epileptiform discharges in GABAergic networks and that the observed antiepileptic effects of carbenoxolone are likely to be due to blockade of GABAA receptors and not of connexin36-based gap junctions. Lastly, because of its chemical structure and its effects on amplitude and kinetics of GABAergic currents, we tested the hypothesis that carbenoxolone acted via specific sites on GABAA receptors, such as the one mediating the effects of the neurosteroid pregnenolone sulfate, or the allosteric regulatory site of benzodiazepines/beta carbolines. Our results suggest that neither of these is involved. PMID- 21300749 TI - Desensitization of neurotransmitter-gated ion channels during high-frequency stimulation: a comparative study of Cys-loop, AMPA and purinergic receptors. AB - Changes in synaptic strength allow synapses to regulate the flow of information in the neural circuits in which they operate. In particular, changes lasting from milliseconds to minutes ('short-term changes') underlie a variety of computational operations and, ultimately, behaviours. Most studies thus far have attributed the short-term type of plasticity to activity-dependent changes in the dynamics of neurotransmitter release (a presynaptic mechanism) while largely dismissing the role of the loss of responsiveness of postsynaptic receptor channels to neurotransmitter owing to entry into desensitization. To better define the response of the different neurotransmitter-gated ion channels (NGICs) to repetitive stimulation without interference from presynaptic variables, we studied eight representative members of all three known superfamilies of NGICs in fast-perfused outside-out patches of membrane. We found that the responsiveness of all tested channels (two nicotinic acetylcholine receptors, two glycine receptors, one GABA receptor, two AMPA-type glutamate receptors and one purinergic receptor) declines along trains of brief neurotransmitter pulses delivered at physiologically relevant frequencies to an extent that suggests that the role of desensitization in the synaptic control of action-potential transmission may be more general than previously thought. Furthermore, our results indicate that a sizable fraction (and, for some NGICs, most) of this desensitization occurs during the neurotransmitter-free interpulse intervals. Clearly, an incomplete clearance of neurotransmitter from the synaptic cleft between vesicle-fusion events need not be invoked to account for NGIC desensitization upon repetitive stimulation. PMID- 21300750 TI - Insulin acts in the arcuate nucleus to increase lumbar sympathetic nerve activity and baroreflex function in rats. AB - Although the central effects of insulin to activate the sympathetic nervous system and enhance baroreflex gain are well known, the specific brain site(s) at which insulin acts has not been identified. We tested the hypotheses that (1) the paraventricular nucleus of the hypothalamus (PVN) and the arcuate nucleus (ArcN) are necessary brain sites and (2) insulin initiates its effects directly in the PVN and/or the ArcN. In alpha-chloralose anaesthetised female Sprague-Dawley rats, mean arterial pressure (MAP), heart rate (HR) and lumbar sympathetic nerve activity (LSNA) were recorded continuously, and baroreflex gain of HR and LSNA were measured before and during a hyperinsulinaemic-euglycaemic clamp. After 60 min, intravenous infusion of insulin (15 mU kg-1 min-1), but not saline, significantly increased (P < 0.05) basal LSNA (to 228 +/- 28% control) and gain of baroreflex control of LSNA (from 3.8 +/- 1.1 to 7.4 +/- 2.4% control mmHg-1). These effects were reversed (P < 0.05) by local inhibition (bilateral microinjection of musimol) of the PVN (LSNA to 124 +/- 8.8% control; LSNA gain to 3.9 +/- 1.7% control mmHg-1) or of the ArcN (LSNA in % control: from 100 +/- 0 to 198 +/- 24 (insulin), then 133 +/- 23 (muscimol) LSNA gain in % control mmHg-1: from 3.9 +/- 0.3 to 8.9 +/- 0.9 (insulin), then 5.1 +/- 0.5 (muscimol)). While insulin receptor immunoreactivity was identified in neurons in pre-autonomic PVN subnuclei, microinjection of insulin (0.6, 6 and 60 nU) into the PVN failed to alter LSNA or LSNA gain. However, ArcN insulin increased (P < 0.05) basal LSNA (in % control to 162 +/- 19, 0.6 nU; 193 +/- 19, 6 nU; and 205 +/- 28, 60 nU) and LSNA baroreflex gain (in % control mmHg-1 from 4.3 +/- 1.2 to 6.9 +/- 1.0, 0.6 nU; 7.7 +/- 1.2, 6 nU; and 7.8 +/- 1.3, 60 nU). None of the treatments altered MAP, HR, or baroreflex control of HR. Our findings identify the ArcN as the site at which insulin acts to activate the sympathetic nervous system and increase baroreflex gain, via a neural pathway that includes the PVN. PMID- 21300751 TI - Early activation of mTORC1 signalling in response to mechanical overload is independent of phosphoinositide 3-kinase/Akt signalling. AB - The mammalian target of rapamycin complex 1 (mTORC1) functions as a central integrator of a wide range of signals that modulate protein metabolism and cell growth. However, the contributions of individual pathways regulating mTORC1 activity in skeletal muscle are poorly defined. The purpose of this study was to determine the regulatory mechanisms that contribute to mTORC1 activation during mechanical overload-induced skeletal muscle hypertrophy. Consistent with previous studies, mechanical overload induced progressive hypertrophy of the plantaris muscle which was associated with significant increases in total RNA content and protein metabolism. mTORC1 was activated after a single day of overload as indicated by a significant increase in S6K1 phosphorylation at T389 and T421/S424. In contrast, Akt activity, as assessed by Akt phosphorylation status (T308 and S473), phosphorylation of direct downstream targets (glycogen synthase kinase 3 beta, proline-rich Akt substrate 40 kDa and tuberous sclerosis 2 (TSC2)) and a kinase assay, was not significantly increased until 2-3 days of overload. Inhibition of phosphoinositide 3-kinase (PI3K) activity by wortmannin was sufficient to block insulin-dependent signalling but did not prevent the early activation of mTORC1 in response to overload. We identified that the mitogen activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) dependent pathway was activated at day 1 after overload. In addition, a target of MEK/ERK signalling, phosphorylation of TSC2 at S664, was also increased at this early time point. These observations demonstrate that in vivo, mTORC1 activation at the early phase of mechanical overload in skeletal muscle occurs independently of PI3K/Akt signalling and provide evidence that the MEK/ERK pathway may contribute to mTORC1 activation through phosphorylation of TSC2. PMID- 21300752 TI - Cytosolic H+ microdomain developed around AE1 during AE1-mediated Cl-/HCO3- exchange. AB - Microdomains, regions of discontinuous cytosolic solute concentration enhanced by rapid solute transport and slow diffusion rates, have many cellular roles. pH regulatory membrane transporters, like the Cl-/HCO3- exchanger AE1, could develop H+ microdomains since AE1 has a rapid transport rate and cytosolic H+ diffusion is slow. We examined whether the pH environment surrounding AE1 differs from other cellular locations. As AE1 drives Cl-/HCO3- exchange, differences in pH, near and remote from AE1, were monitored by confocal microscopy using two pH sensitive fluorescent proteins: deGFP4 (GFP) and mNectarine (mNect). Plasma membrane (PM) pH (defined as ~1 MUm region around the cell periphery) was monitored by GFP fused to AE1 (GFP.AE1), and mNect fused to an inactive mutant of the Na+-coupled nucleoside co-transporter, hCNT3 (mNect.hCNT3). GFP.AE1 to mNect.hCNT3 distance was varied by co-expression of different amounts of the two proteins in HEK293 cells. As the GFP.AE1-mNect.hCNT3 distance increased, mNect.hCNT3 detected the Cl-/HCO3- exchange-associated cytosolic pH change with a time delay and reduced rate of pH change compared to GFP.AE1. We found that a H+ microdomain 0.3 MUm in diameter forms around GFP.AE1 during physiological HCO3- transport. Carbonic anhydrase isoform II inhibition prevented H+ microdomain formation. We also measured the rate of H+ movement from PM GFP.AE1 to endoplasmic reticulum (ER), using mNect fused to the cytosolic face of ER resident calnexin (CNX.mNect). The rate of H+ diffusion through cytosol was 60 fold faster than along the cytosolic surface of the plasma membrane. The pH environment surrounding pH regulatory transport proteins may differ as a result of H+ microdomain formation, which will affect nearby pH-sensitive processes. PMID- 21300753 TI - Local release of ATP into the arterial inflow and venous drainage of human skeletal muscle: insight from ATP determination with the intravascular microdialysis technique. AB - Intraluminal ATP could play an important role in the local regulation of skeletal muscle blood flow, but the stimuli that cause ATP release and the levels of plasma ATP in vessels supplying and draining human skeletal muscle remain unclear. To gain insight into the mechanisms by which ATP is released into plasma, we measured plasma [ATP] with the intravascular microdialysis technique at rest and during dynamic exercise (normoxia and hypoxia), passive exercise, thigh compressions and arterial ATP, tyramine and ACh infusion in a total of 16 healthy young men. Femoral arterial and venous [ATP] values were 109 +/- 34 and 147 +/- 45 nmol l(-1) at rest and increased to 363 +/- 83 and 560 +/- 111 nmol l( 1), respectively, during exercise (P < 0.05), whereas these values did not increase when exercise was performed with the other leg. Hypoxia increased venous plasma [ATP] at rest compared to normoxia (P < 0.05), but not during exercise. Arterial ATP infusion (<=1.8 MUmol min(-1) increased arterial plasma [ATP] from 74 +/- 17 to 486 +/- 82 nmol l(-1) (P < 0.05), whereas it remained unchanged in the femoral vein at ~150 nmol l(-1). Both arterial and venous plasma [ATP] decreased during acetylcholine infusion (P < 0.05). Rhythmic thigh compressions increased arterial and venous plasma [ATP] compared to baseline conditions, whereas these values did not change during passive exercise or tyramine infusion. These results demonstrate that ATP is released locally into arterial and venous plasma during exercise and during hypoxia at rest. Compression of the vascular system could contribute to the increase during exercise whereas there appears to be little ATP release in response to increased blood flow, vascular stretch or sympathetic ATP release. Furthermore, the half-life of arterially infused ATP is <1 s. PMID- 21300754 TI - Acute and chronic effects of hypercalcaemia on cortical excitability as studied by 5 Hz repetitive transcranial magnetic stimulation. AB - We designed the present study to disclose changes in cortical excitability in humans with hypercalcaemia, by delivering repetitive transcranial magnetic stimulation (rTMS) over the primary motor area (M1). In 22 patients with chronic hypercalcaemia related to primary hyperparathyroidism and 22 age-matched healthy subjects 5 Hz-rTMS was delivered at rest and during a sustained voluntary contraction of the target muscle. Changes in the resting motor threshold (RMT), motor evoked potential (MEP) amplitudes and cortical silent period (CSP) duration were measured and compared in patients and healthy controls. Two of the 22 patients were re-tested after parathyroidectomy when serum calcium had normalized. In a subgroup of healthy subjects, changes in the rTMS parameters were tested before and after acute hypercalcaemia. No significant difference between healthy normocalcaemic subjects and chronic hypercalcaemic patients was found in the RMT values and MEP amplitude and CSP duration evoked by the first stimulus of the trains. During the course of 5 Hz-rTMS trains, MEP size increased significantly less in patients with chronic hypercalcaemia than in healthy subjects, whereas the CSP duration lengthened to a similar extent in both groups. In the two patients studied after parathyroidectomy, rTMS elicited a normal MEP amplitude facilitation. Our findings indicate that acute hypercalcaemia significantly decreased the MEP amplitude facilitation. Given that 5 Hz-rTMS modulates cortical excitability through mechanisms resembling short-term synaptic enhancement, the reduction of MEP amplitude facilitation by hypercalcaemia may be related to Ca2+-dependent changes in synaptic plasticity. PMID- 21300755 TI - The interaction of visual, vestibular and extra-retinal mechanisms in the control of head and gaze during head-free pursuit. AB - The ability to co-ordinate the eyes and head when tracking moving objects is important for survival. Tracking with eyes alone is controlled by both visually dependent and extra-retinal mechanisms, the latter sustaining eye movement during target extinction. We investigated how the extra-retinal component develops at the beginning of randomised responses during head-free pursuit and how it interacts with the vestibulo-ocular reflex (VOR). Subjects viewed horizontal step ramp stimuli which occurred in pairs of identical velocity; velocity was randomised between pairs, ranging from +/-5 to 40 deg s-1. In the first of each pair (short-ramp extinction) the target was visible for only 150 ms. In the second (initial extinction), after a randomised fixation period, the target was extinguished at motion onset, remaining invisible for 750 ms before reappearing for the last 200 ms of motion. Subjects used motion information acquired in the short-ramp extinction presentation to track the target from the start of unseen motion in the initial extinction presentation, using extra-retinal drive to generate smooth gaze and head movements scaled to target velocity. Gaze velocity rose more slowly than when visually driven, but had similar temporal development in head-free and head-fixed conditions. The difference in eye-in-head velocity between head-fixed and head-free conditions was closely related to head velocity throughout its trajectory, implying that extra-retinal drive was responsible for countermanding the VOR in the absence of vision. Thus, the VOR apparently remained active during head-free pursuit with near-unity gain. Evidence also emerged that head movements are not directly controlled by visual input, but by internal estimation mechanisms similar to those controlling gaze. PMID- 21300756 TI - Perturbation of wood cellulose synthesis causes pleiotropic effects in transgenic aspen. AB - Genetic manipulation of cellulose biosynthesis in trees may provide novel insights into the growth and development of trees. To explore this possibility, the overexpression of an aspen secondary wall-associated cellulose synthase (PtdCesA8) gene was attempted in transgenic aspen (Populus tremuloides L.) and unexpectedly resulted in silencing of the transgene as well as its endogenous counterparts. The main axis of the transgenic aspen plants quickly stopped growing, and weak branches adopted a weeping growth habit. Furthermore, transgenic plants initially developed smaller leaves and a less extensive root system. Secondary xylem (wood) of transgenic aspen plants contained as little as 10% cellulose normalized to dry weight compared to 41% cellulose typically found in normal aspen wood. This massive reduction in cellulose was accompanied by proportional increases in lignin (35%) and non-cellulosic polysaccharides (55%) compared to the 22% lignin and 36% non-cellulosic polysaccharides in control plants. The transgenic stems produced typical collapsed or 'irregular' xylem vessels that had altered secondary wall morphology and contained greatly reduced amounts of crystalline cellulose. These results demonstrate the fundamental role of secondary wall cellulose within the secondary xylem in maintaining the strength and structural integrity required to establish the vertical growth habit in trees. PMID- 21300757 TI - The role of the plasma membrane H+-ATPase in plant-microbe interactions. AB - Plasma membrane (PM) H+-ATPases are the primary pumps responsible for the establishment of cellular membrane potential in plants. In addition to regulating basic aspects of plant cell function, these enzymes contribute to signaling events in response to diverse environmental stimuli. Here, we focus on the roles of the PM H+-ATPase during plant-pathogen interactions. PM H+-ATPases are dynamically regulated during plant immune responses and recent quantitative proteomics studies suggest complex spatial and temporal modulation of PM H+ ATPase activity during early pathogen recognition events. Additional data indicate that PM H+-ATPases cooperate with the plant immune signaling protein RIN4 to regulate stomatal apertures during bacterial invasion of leaf tissue. Furthermore, pathogens have evolved mechanisms to manipulate PM H+-ATPase activity during infection. Thus, these ubiquitous plant enzymes contribute to plant immune responses and are targeted by pathogens to increase plant susceptibility. PMID- 21300758 TI - Functional roles of Src and Fgr in ovarian carcinoma. AB - PURPOSE: Src is an attractive target because it is overexpressed in a number of malignancies, including ovarian cancer. However, the effect of Src silencing on other Src family kinases (SFKs) is not known. We hypothesized that other SFK members could compensate for the lack of Src activity. EXPERIMENTAL DESIGN: Cell viability after either Src or Fgr silencing was examined in ovarian cancer cell lines by MTT assay. Expression of SFKs after Src silencing in ovarian cancer cells was examined by real-time reverse transcriptase (RT)-PCR. Therapeutic effect of in vivo Src and/or Fgr silencing was examined using siRNA incorporated into chitosan nanoparticles (siRNA/CH-NP). Microvessel density, cell proliferation, and apoptosis markers were determined by immunohistochemical staining in ovarian tumor tissues. RESULTS: Src silencing enhanced cytotoxicity of docetaxel in both SKOV3ip1 and HeyA8 cells. In addition, Src silencing using siRNA/CH-NP in combination with docetaxel resulted in significant inhibition of tumor growth compared with control siRNA/CH-NP (81.8% reduction in SKOV3ip1, P = 0.017; 84.3% reduction in HeyA8, P < 0.005). These effects were mediated by decreased tumor cell proliferation and angiogenesis, and increased tumor cell apoptosis. Next, we assessed the effects of Src silencing on other SFK members in ovarian cancer cell lines. Src silencing resulted in significantly increased Fgr levels. Dual Src and Fgr silencing in vitro resulted in increased apoptosis that was mediated by increased caspase and AKT activity. In addition, dual silencing of Src and Fgr in vivo using siRNA/CH-NP resulted in the greatest reduction in tumor growth compared with silencing of either Src or Fgr alone in the HeyA8 model (68.8%, P < 0.05). CONCLUSIONS: This study demonstrates that, in addition to Src, Fgr plays a biologically significant role in ovarian cancer growth and might represent an important target. PMID- 21300759 TI - EGFR L858R mutation and polymorphisms of genes related to estrogen biosynthesis and metabolism in never-smoking female lung adenocarcinoma patients. AB - PURPOSE: To assess whether polymorphisms of genes related to estrogen biosynthesis and metabolism are associated with EGFR mutations. EXPERIMENTAL DESIGN: We studied 617 patients with lung adenocarcinoma, including 302 never smoking women. On the basis of multiple candidate genes approach, the effects of polymorphisms of CYP17, CYP19A1, ERalpha, and COMT in association with the occurrence of EGFR mutations were evaluated using logistic regression analysis. RESULTS: In female never-smokers, significant associations with EGFR L858R mutation were found for the tetranucleotide (TTTA)(n) repeats in CYP19A1 (odds ratio, 2.6; 95%CI, 1.2-5.7 for 1 or 2 alleles with (TTTA)(n) repeats >7 compared with both alleles with (TTTA)(n) repeats <= 7), and the rs2234693 in ERalpha (OR, 2.1; 95% CI, 1.1-4.0 for C/T and C/C genotypes compared with T/T genotype). The C/C genotype (vs. T/T genotype) of ERalpha was significantly associated with EGFR L858R mutation (OR, 3.0; 95% CI, 1.1-8.1), in-frame deletion (OR, 2.9; 95% CI, 1.1-7.6) and other mutations (OR, 4.3; 95% CI, 1.3-14.0). The genotype of COMT rs4680 was significantly associated with EGFR L858R mutation in female and male never-smokers showing OR's (95% CI) of 1.8 (1.0-3.2) and 3.6 (1.1-11.3), respectively, for genotypes G/A and G/G compared with genotype A/A. The number of risk alleles of CYP17, CYP19A1, ERalpha, and COMT was associated with an increasing OR of EGFR L858R mutation in female never-smokers (P = 0.0002 for trend). CONCLUSIONS: The L858R mutation of EGFR is associated with polymorphisms of genes related to estrogen biosynthesis and metabolism in never-smoking female lung adenocarcinoma patients. PMID- 21300760 TI - Pharmacokinetics of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors: the role of alpha-1-acid glycoprotein binding. AB - PURPOSE: In a phase I trial for patients with refractory solid tumors, hedgehog pathway inhibitor vismodegib (GDC-0449) showed little decline in plasma concentrations over 7 days after a single oral dose and nonlinearity with respect to dose and time after single and multiple dosing. We studied the role of GDC 0449 binding to plasma protein alpha-1-acid glycoprotein (AAG) to better understand these unusual pharmacokinetics. EXPERIMENTAL DESIGN: Sixty-eight patients received GDC-0449 at 150 (n = 41), 270 (n = 23), or 540 (n = 4) mg/d, with pharmacokinetic (PK) sampling at multiple time points. Total and unbound (dialyzed) GDC-0449 plasma concentrations were assessed by liquid chromatography/tandem mass spectrometry, binding kinetics by surface plasmon resonance-based microsensor, and AAG levels by ELISA. RESULTS: A linear relationship between total GDC-0449 and AAG plasma concentrations was observed across dose groups (R(2) = 0.73). In several patients, GDC-0449 levels varied with fluctuations in AAG levels over time. Steady-state, unbound GDC-0449 levels were less than 1% of total, independent of dose or total plasma concentration. In vitro, GDC-0449 binds AAG strongly and reversibly (K(D) = 13 MUmol/L) and human serum albumin less strongly (K(D) = 120 MUmol/L). Simulations from a derived mechanistic PK model suggest that GDC-0449 pharmacokinetics are mediated by AAG binding, solubility-limited absorption, and slow metabolic elimination. CONCLUSIONS: GDC-0449 levels strongly correlated with AAG levels, showing parallel fluctuations of AAG and total drug over time and consistently low, unbound drug levels, different from previously reported AAG-binding drugs. This PK profile is due to high-affinity, reversible binding to AAG and binding to albumin, in addition to solubility-limited absorption and slow metabolic elimination properties. PMID- 21300761 TI - MHC class I-presented tumor antigens identified in ovarian cancer by immunoproteomic analysis are targets for T-cell responses against breast and ovarian cancer. AB - PURPOSE: The purpose of this study is to test whether peptide epitopes chosen from among those naturally processed and overpresented within MHC molecules by malignant, but not normal cells, when formulated into cancer vaccines, could activate antitumor T-cell responses in humans. EXPERIMENTAL DESIGN: Mixtures of human leukocyte antigen A2 (HLA-A2)-binding ovarian cancer-associated peptides were used to activate naive T cells to generate antigen-specific T cells that could recognize ovarian and breast cancers in vitro. Combinations of these peptides (0.3 mg of each peptide or 1 mg of each peptide) were formulated into vaccines in conjunction with Montanide ISA-51 and granulocyte monocyte colony stimulating factor which were used to vaccinate patients with ovarian and breast cancer without evidence of clinical disease in parallel pilot clinical trials. RESULTS: T cells specific for individual peptides could be generated in vitro by using mixtures of peptides, and these T cells recognized ovarian and breast cancers but not nonmalignant cells. Patient vaccinations were well tolerated with the exception of local erythema and induration at the injection site. Nine of the 14 vaccinated patients responded immunologically to their vaccine by inducing peptide-specific T-cell responses that were capable of recognizing HLA-matched breast and ovarian cancer cells. CONCLUSION: Mixtures of specific peptides identified as naturally presented on cancer cells and capable of activating tumor specific T cells in vitro also initiate or augment immune responses toward solid tumors in cancer patients. PMID- 21300762 TI - Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors. AB - PURPOSE: The hedgehog (Hh) signaling pathway, a key regulator of cell growth and differentiation during development is implicated in pathogenesis of certain cancers. Vismodegib (GDC-0449) is a small-molecule inhibitor of smoothened, a key component of Hh signaling. This phase I trial assessed GDC-0449 treatment in patients with solid tumors refractory to current therapies or for which no standard therapy existed. EXPERIMENTAL DESIGN: Sixty-eight patients received GDC 0449 at 150 mg/d (n = 41), 270 mg/d (n = 23), or 540 mg/d (n = 4). Adverse events, tumor responses, pharmacokinetics, and pharmacodynamic down-modulation of GLI1 expression in noninvolved skin were assessed. RESULTS: Thirty-three of 68 patients had advanced basal cell carcinoma (BCC), 8 had pancreatic cancer, 1 had medulloblastoma; 17 other types of cancer were also represented. GDC-0449 was generally well-tolerated. Six patients (8.8%) experienced 7 grade 4 events (hyponatremia, fatigue, pyelonephritis, presyncope, resectable pancreatic adenocarcinoma, and paranoia with hyperglycemia), and 27.9% of patients experienced a grade 3 event [most commonly hyponatremia (10.3%), abdominal pain (7.4%), and fatigue (5.9%)]. No maximum tolerated dose was reached. The recommended phase II dose was 150 mg/d, based on achievement of maximal plasma concentration and pharmacodynamic response at this dose. Tumor responses were observed in 20 patients (19 with BCC and 1 unconfirmed response in medulloblastoma), 14 patients had stable disease as best response, and 28 had progressive disease. Evidence of GLI1 down-modulation was observed in noninvolved skin. CONCLUSIONS: GDC-0449 has an acceptable safety profile and encouraging anti tumor activity in advanced BCC and medulloblastoma. Further study in these and other cancer types is warranted. PMID- 21300763 TI - Can a metastatic gene expression profile outperform tumor size as a predictor of occult lymph node metastasis in oral cancer patients? AB - PURPOSE: To determine the differential gene expression between oral squamous cell carcinoma (OSCC) with and without metastasis to cervical lymph nodes and to assess prediction of nodal metastasis by using molecular features. EXPERIMENTAL DESIGN: We used Affymetrix U133 2.0 plus arrays to compare the tumor genome-wide gene expression of 73 node-positive OSCCs with 40 node-negative OSCCs (>= 18 months). Multivariate linear regression was used to estimate the association between gene expression and nodal metastasis. Stepwise logistic regression and receiver operating characteristics (ROC) analysis were used to generate predictive models and to compare these with models by using tumor size alone. RESULTS: We identified five genes differentially expressed between node-positive and node-negative OSCCs after adjusting for tumor size and human papillomavirus status: REEP1, RNF145, CTONG2002744, MYO5A, and FBXO32. Stepwise regression identified a four-gene model (MYO5A, RFN145, FBXO32, and CTONG2002744) as the most predictive of nodal metastasis. A leave-one-out ROC analysis revealed that our model had a higher area under the curve (AUC) for identifying occult nodal metastasis compared with that of a model by tumor size alone (respective AUC: 0.85 and 0.61; P = 0.011). A model combining tumor size and gene expression did not further improve the prediction of occult metastasis. Independent validation using 31 metastatic and 13 nonmetastatic cases revealed a significant underexpression of CTONG2002744 (P = 0.0004). CONCLUSIONS: These results suggest that our gene expression markers of OSCC metastasis hold promise for improving current clinical practice. Confirmation by others and functional studies of CTONG2002744 is warranted. PMID- 21300764 TI - The efficacy of radiotherapy relies upon induction of type i interferon-dependent innate and adaptive immunity. AB - The most widely held explanation for the efficacy of local radiotherapy (RT) is based on direct cytotoxicity to cancer cells through the induction of lethal DNA damage. Recent studies have shown that local ablative radiation of established tumors can lead to increased T-cell priming and T-cell-dependent tumor regression, but the underlying mechanism remains unclear. Here, we describe an essential role for type I IFN in local RT-mediated tumor control. We show that ablative RT increases intratumoral production of IFN-beta and, more surprisingly, the antitumor effect of RT is abolished in type I IFN nonresponsive hosts. Furthermore, the major target of RT-induced type I IFN is the hematopoietic compartment. RT drastically enhances the cross-priming capacity of tumor infiltrating dendritic cells (TIDC) from wild-type mice but not type I IFN receptor-deficient mice. The enhanced cross-priming ability of TIDCs after RT was dependent on autocrine production of type I IFNs. By using adenoviral-mediated expression of IFN-beta, we show that delivery of exogenous IFN-beta into the tumor tissue in the absence of RT is also sufficient to selectively expand antigen-specific T cells leading to complete tumor regression. Our study reveals that local high-dose RT can trigger production of type I IFN that initiates a cascading innate and adaptive immune attack on the tumor. PMID- 21300765 TI - Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-kappaB/IL-8 pathway that drives tumor angiogenesis. AB - Lactate generated from pyruvate fuels production of intracellular NAD(+) as an end result of the glycolytic process in tumors. Elevated lactate concentration represents a good indicator of the metabolic adaptation of tumors and is actually correlated to clinical outcome in a variety of human cancers. In this study, we investigated whether lactate could directly modulate the endothelial phenotype and thereby tumor vascular morphogenesis and perfusion. We found that lactate could enter endothelial cells through the monocarboxylate transporter MCT-1, trigger the phosphorylation/degradation of IkappaBalpha, and then stimulate an autocrine NF-kappaB/IL-8 (CXCL8) pathway driving cell migration and tube formation. These effects were prevented by 2-oxoglutarate and reactive oxygen species (ROS) inhibitors, pointing to a role for prolyl-hydroxylase and ROS in the integration of lactate signaling in endothelial cells. PHD2 silencing in endothelial cells recapitulated the proangiogenic effects of lactate, whereas a blocking IL-8 antibody or IL-8-targeting siRNA prevented them. Finally, we documented in mouse xenograft models of human colorectal and breast cancer that lactate release from tumor cells through the MCT4 (and not MCT1) transporter is sufficient to stimulate IL-8-dependent angiogenesis and tumor growth. In conclusion, our findings establish a signaling role for lactate in endothelial cells and they identify the lactate/NF-kappaB/IL-8 pathway as an important link between tumor metabolism and angiogenesis. PMID- 21300766 TI - MRE11 deficiency increases sensitivity to poly(ADP-ribose) polymerase inhibition in microsatellite unstable colorectal cancers. AB - Microsatellite instability (MSI) is displayed by approximately 15% of colorectal cancers (CRC). Defective DNA mismatch repair generates mutations at repetitive DNA sequences such as those located in the double strand break (DSB) repair gene MRE11. We assessed the mutational status of MRE11 in a panel of 17 CRC cell lines and 46 primary tumors and found a strong correlation with MSI status in both cell lines and tumors. Therefore, we hypothesized that deficiency in MRE11 may sensitize CRC cells to poly(ADP-ribose) polymerase (PARP-1) inhibition based on the concept of synthetic lethality. We further assessed the activity of the PARP 1 inhibitor, ABT-888, in CRC cell lines and observed preferential cytotoxicity in those MSI cell lines harboring mutations in MRE11 compared with both wild-type cell lines and microsatellite stable (MSS) cell lines. A significant correlation between MRE11 expression levels and cytotoxicity to ABT-888 at 10 MUM was observed (R2 = 0.915, P < 0.001). Using two experimental approaches, including short hairpin RNA knocking down MRE11 in the wild-type and MSS cell line SW-480 and a second cell line model transfected with mutant MRE11, we experimentally tried to confirm the role of MRE11 in conferring sensitivity to PARP-1 inhibition. Both models led to changes in proliferation in response to ABT-888 at different concentrations, and a drug-response effect was not observed, suggesting a possible contribution of additional genes. We conclude that MSI colorectal tumors deficient in DSB repair secondary to mutation in MRE11 show a higher sensitivity to PARP-1 inhibition. Further clinical investigation of PARP-1 inhibitors is warranted in MSI CRCs. PMID- 21300767 TI - Evaluation of cytotoxicity and anticarcinogenic potential of Mentha leaf extracts. AB - We examined the possible molecular mechanisms underlying the cytotoxicity and anticarcinogenic potential of Mentha leaf extracts (petroleum ether, benzene, chloroform, ethyl acetate, methanol, and water extracts) on 6 human cancer (HeLa, MCF-7, Jurkat, T24, HT-29, MIAPaCa-2) and normal (IMR-90, HEK-293) cell lines. Of all the extracts tested, chloroform and ethyl acetate extracts of M piperita showed significant dose- and time-dependent anticarcinogenic activity leading to G1 cell cycle arrest and mitochondrial-mediated apoptosis, perturbation of oxidative balance, upregulation of Bax gene, elevated expression of p53 and p21 in the treated cells, acquisition of senescence phenotype, while inducing pro inflammatory cytokines response. Our results provide the first evidence of direct anticarcinogenic activity of Mentha leaf extracts. Further, bioassay-directed isolation of the active constituents might provide basis for mechanistic and translational studies for designing novel anticancer drugs to be used alone or as adjuvant for prevention of tumor progression and/or treatment of human malignancies. PMID- 21300768 TI - Differences in rat models used in routine toxicity studies. AB - The discussion on whether the Sprague Dawley (SD), the Fischer F344, or the Hannover Wistar rat is the most appropriate model for toxicity studies in rodents is ongoing. A substantial quantity of data on these strains concerning their source, diet, and housing conditions have been published. Generally, before starting a toxicology program in rodents, it should be taken into account that oncogenicity studies will be required for the majority of compounds successfully completing development. Survival, body weight development, incidence, type, time of onset of age-dependent lesions and neoplasms, as well as some special considerations of the rat model selected may be decisive. Therefore, an understanding of the historical background data is essential. These aspects demonstrate why the use of a specific rat model should be carefully considered at the beginning of the toxicology program. PMID- 21300769 TI - Sodium pyruvate modulates cell death pathways in HaCaT keratinocytes exposed to half-mustard gas. AB - 2-Chloroethyl ethyl sulfide (CEES) or half-mustard gas, a sulfur mustard (HD) analog, is a genotoxic agent that causes oxidative stress and induces both apoptotic and necrotic cell death. Sodium pyruvate induced a necrosis-to apoptosis shift in HaCaT cells exposed to CEES levels <= 1.5 mmol/L and lowered markers of DNA damage, oxidative stress, and inflammation. This study provides a rationale for the future development of multicomponent therapies for HD toxicity in the skin. We hypothesize that a combination of pyruvates with scavengers/antioxidants encapsulated in liposomes for optimal local delivery should be therapeutically beneficial against HD-induced skin injury. However, the latter suggestion should be verified in animal models exposed to HD. PMID- 21300770 TI - Complementation of Rickettsia rickettsii RelA/SpoT restores a nonlytic plaque phenotype. AB - Spotted fever group rickettsiae are known to produce distinct plaque phenotypes. Strains that cause lytic infections in cell culture form clear plaques, while nonlytic strains form opaque plaques in which the cells remain intact. Clear plaques have historically been associated with more-virulent species or strains of spotted fever group rickettsiae. We have selected spontaneous mutant pairs from two independent strains of Rickettsia rickettsii, the virulent R strain and the avirulent Iowa strain. A nonlytic variant of R. rickettsii R, which typically produces clear plaques, was isolated and stably maintained. A lytic variant of the Iowa strain, which characteristically produces opaque plaques, was also selected and maintained. Genomic resequencing of the variants identified only a single gene disrupted in each strain. In both cases, the mutation was in a gene annotated as relA/spoT-like. In the Iowa strain, a single mutation introduced a premature stop codon upstream from region encoding the predicted active site of RelA/SpoT and caused the transition to a lytic plaque phenotype. In R. rickettsii R, the nonlytic plaque phenotype resulted from a single-nucleotide substitution that shifted a tyrosine residue to histidine near the active site of the enzyme. The intact relA/spoT gene thus occurred in variants with the nonlytic plaque phenotype. Complementation of the truncated relA/spoT gene in the Iowa lytic plaque variant restored the nonlytic phenotype. The relA/spoT mutations did not affect the virulence of either strain in a Guinea pig model of infection; R strain lytic and nonlytic variants both induced fever equally, and the mutation in Iowa to a lytic phenotype did not cause them to become virulent. PMID- 21300771 TI - Involvement of quorum sensing and heat-stable enterotoxin a in cell damage caused by a porcine enterotoxigenic Escherichia coli strain. AB - Enterotoxigenic Escherichia coli (ETEC) strains with K88 fimbriae are often associated with the outbreaks of diarrhea in newborn and weaned piglets worldwide. In the present study, we observed that 108 CFU/ml of K88(+) ETEC strain JG280 caused more death of pig intestinal IPEC-J2 cells than did 109 CFU/ml, suggesting that ETEC-induced cell death was cell density dependent and that quorum sensing (QS) may play a role in pathogenesis. Subsequent investigations demonstrated a positive correlation between autoinducer 2 (AI-2) activity of JG280 and death of IPEC-J2 cells during the infection for up to 3 h. However, there was a negative correlation between AI-2 activity and expression of the JG280 enterotoxin genes estA and estB when IPEC-J2 cells were exposed to the pathogen at 108 CFU/ml. We therefore cloned the luxS gene (responsible for AI-2 production) from JG280 and overexpressed it in E. coli DH5alpha, because deletion of the luxS gene was retarded by the lack of suitable antibiotic selection markers and the resistance of this pathogen to a wide range of antibiotics. The addition of culture fluid from E. coli DH5alpha with the overexpressed luxS reduced cell death of IPEC-J2 cells by 108 CFU/ml JG280. The addition also reduced the estA expression by JG280. Nonpathogenic K88(+) strain JFF4, which lacks the enterotoxin genes, caused no death of IPEC-J2 cells, although it produced AI-2 activity comparable to that produced by JG280. These results suggest the involvement of AI-2-mediated quorum sensing in K88(+) ETEC pathogenesis, possibly through a negative regulation of STa production. PMID- 21300772 TI - Putative ATP-binding cassette transporter is essential for Brucella ovis pathogenesis in mice. AB - Brucella ovis is a major cause of reproductive failure in sheep, which is associated with epididymitis and infertility in rams. Importantly, B. ovis is one of the few Brucella species that is not zoonotic. Due to the scarcity of studies on B. ovis infection, a murine model of infection was developed. The roles of B. ovis genes encoding a putative hemagglutinin and an ABC transporter were investigated in the mouse model. The kinetics of B. ovis infection were similar in BALB/c and C57BL/6 mice, and both strains of mice developed multifocal microgranulomas in the liver and spleen, but only minimal colonization and histopathological changes were observed in the genital tract. Therefore, the mouse was considered a suitable infection model for B. ovis but not for B. ovis induced genital disease. Two mutant strains were generated in this study (the DeltaabcAB and Deltahmg strains). The B. ovis DeltaabcAB strain was attenuated in the spleens and livers of BALB/c mice compared to the wild-type (WT) strain (P < 0.001). Conversely, the Deltahmg strain infected mice at the same level as WT B. ovis, suggesting that a putative hemagglutinin is not required for B. ovis pathogenesis. Additionally, the DeltaabcAB strain did not survive in peritoneal macrophages, extracellularly in the peritoneal cavity, or in RAW 264.7 macrophages. Moreover, infection with the DeltaabcAB strain was not lethal for male regulatory factor 1-knockout mice, whereas infection with the B. ovis WT strain was 100% lethal within 14 days postinfection. These results confirm that the predicted ABC transporter is required for the full virulence and survival of B. ovis in vivo. PMID- 21300773 TI - Extensive polymorphism and evidence of immune selection in a highly dominant antigen recognized by bovine CD8 T cells specific for Theileria annulata. AB - Although parasite strain-restricted CD8 T cell responses have been described for several protozoa, the precise role of antigenic variability in immunity is poorly understood. The tick-borne protozoan parasite Theileria annulata infects leukocytes and causes an acute, often fatal lymphoproliferative disease in cattle. Building on previous evidence of strain-restricted CD8 T cell responses to T. annulata, this study set out to identify and characterize the variability of the target antigens. Three antigens were identified by screening expressed parasite cDNAs with specific CD8 T cell lines. In cattle expressing the A10 class I major histocompatibility complex haplotype, A10-restricted CD8 T cell responses were shown to be focused entirely on a single dominant epitope in one of these antigens (Ta9). Sequencing of the Ta9 gene from field isolates of T. annulata demonstrated extensive sequence divergence, resulting in amino acid polymorphism within the A10-restricted epitope and a second A14-restricted epitope. Statistical analysis of the allelic sequences revealed evidence of positive selection for amino acid substitutions within the region encoding the CD8 T cell epitopes. Sequence differences in the A10-restricted epitope were shown to result in differential recognition by individual CD8 T cell clones, while clones also differed in their ability to recognize different alleles. Moreover, the representation of these clonal specificities within the responding CD8 T cell populations differed between animals. As well as providing an explanation for incomplete protection observed after heterologous parasite challenge of vaccinated cattle, these results have important implications for the choice of antigens for the development of novel subunit vaccines. PMID- 21300774 TI - The Neisseria gonorrhoeae biofilm matrix contains DNA, and an endogenous nuclease controls its incorporation. AB - Neisseria gonorrhoeae has been shown to produce biofilms both in experimental flow chambers and in the human host. Our laboratory has shown that extracellular DNA is an essential component of the gonococcal matrix. We have also identified a gene in N. gonorrhoeae, which we designated nuc. This gene has homology with the staphylococcus-secreted thermonuclease. Our laboratory has characterized nuc through phenotypic analysis of a nuc deletion mutant. Biofilms grown with this strain are significantly thicker and of greater biomass than the N. gonorrhoeae 1291 parent strain. Confocal microscopy indicates that the increased size of the mutant biofilms appears to be due to elevated amounts of extracellular DNA in the biofilm matrix. Chromosomal complementation of the nuc mutation restored the wild type biofilm phenotype. In addition, we have cloned and expressed the Nuc protein in Escherichia coli, and our data indicate that it has the ability to digest multiple forms of DNA and is a thermonuclease. The ability of Nuc to digest DNA also extends to its ability to disrupt established gonococcal biofilms through degradation of the DNA in the biofilm matrix. Our studies indicate that the N. gonorrhoeae biofilm contains DNA and that the Nuc protein appears to play a role in biofilm formation and remodeling. PMID- 21300775 TI - The cluster 1 type VI secretion system is a major virulence determinant in Burkholderia pseudomallei. AB - The Burkholderia pseudomallei K96243 genome encodes six type VI secretion systems (T6SSs), but little is known about the role of these systems in the biology of B. pseudomallei. In this study, we purified recombinant Hcp proteins from each T6SS and tested them as vaccine candidates in the BALB/c mouse model of melioidosis. Recombinant Hcp2 protected 80% of mice against a lethal challenge with K96243, while recombinant Hcp1, Hcp3, and Hcp6 protected 50% of mice against challenge. Hcp6 was the only Hcp constitutively produced by B. pseudomallei in vitro; however, it was not exported to the extracellular milieu. Hcp1, on the other hand, was produced and exported in vitro when the VirAG two-component regulatory system was overexpressed in trans. We also constructed six hcp deletion mutants (Deltahcp1 through Deltahcp6) and tested them for virulence in the Syrian hamster model of infection. The 50% lethal doses (LD(50)s) for the Deltahcp2 through Deltahcp6 mutants were indistinguishable from K96243 (<10 bacteria), but the LD(50) for the Deltahcp1 mutant was >10(3) bacteria. The hcp1 deletion mutant also exhibited a growth defect in RAW 264.7 macrophages and was unable to form multinucleated giant cells in this cell line. Unlike K96243, the Deltahcp1 mutant was only weakly cytotoxic to RAW 264.7 macrophages 18 h after infection. The results suggest that the cluster 1 T6SS is essential for virulence and plays an important role in the intracellular lifestyle of B. pseudomallei. PMID- 21300776 TI - Toll-like receptor 9 is required for full host resistance to Mycobacterium avium infection but plays no role in induction of Th1 responses. AB - To investigate the role of Toll-like receptor 9 (TLR9) in innate immunity to Mycobacterium avium, TLR9, TLR2, and MyD88 knockout (KO) mice were infected with this bacterium. Bacterial burdens were higher in the spleens, livers, and lungs of infected TLR9 KO mice than in those of C57BL/6 mice, indicating that TLR9 is required for efficient control of M. avium infection. However, TLR9 KO or TLR2 KO spleen cells displayed normal M. avium-induced tumor necrosis factor alpha (TNF alpha) and gamma interferon (IFN-gamma) responses. This finding was confirmed by determining the number of splenic CD4(+) T cells producing IFN-gamma by flow cytometry. Furthermore, TLR2 and MyD88, but not TLR9, played a major role in interleukin-12 and TNF-alpha production by M. avium-infected macrophages and dendritic cells (DCs). We also found that major histocompatibility complex class II molecule expression on DCs is regulated by TLR2 and MyD88 signaling but not by TLR9. Finally, lack of TLR9, TLR2, or MyD88 reduced the numbers of macrophages, epithelioid cells, and lymphocytes in M. avium-induced granulomas but only MyD88 deficiency affected the number of liver granulomas. In summary, our data demonstrated that the involvement of TLR9 in the control of M. avium infection is not related to the induction of Th1 responses. PMID- 21300777 TI - Preterm infants have deficient monocyte and lymphocyte cytokine responses to group B streptococcus. AB - Group B streptococcus (GBS) is an important cause of early- and late-onset sepsis in the newborn. Preterm infants have markedly increased susceptibility and worse outcomes, but their immunological responses to GBS are poorly defined. We compared mononuclear cell and whole-blood cytokine responses to heat-killed GBS (HKGBS) of preterm infants (gestational age [GA], 26 to 33 weeks), term infants, and healthy adults. We investigated the kinetics and cell source of induced cytokines and quantified HKGBS phagocytosis. HKGBS-induced tumor necrosis factor (TNF) and interleukin 6 (IL-6) secretion was significantly impaired in preterm infants compared to that in term infants and adults. These cytokines were predominantly monocytic in origin, and production was intrinsically linked to HKGBS phagocytosis. Very preterm infants (GA, <30 weeks) had fewer cytokine producing monocytes, but nonopsonic phagocytosis ability was comparable to that for term infants and adults. Exogenous complement supplementation increased phagocytosis in all groups, as well as the proportion of preterm monocytes producing IL-6, but for very preterm infants, responses were still deficient. Similar defective preterm monocyte responses were observed in fresh whole cord blood stimulated with live GBS. Lymphocyte-associated cytokines were significantly deficient for both preterm and term infants compared to levels for adults. These findings indicate that a subset of preterm monocytes do not respond to GBS, a defect compounded by generalized weaker lymphocyte responses in newborns. Together these deficient responses may increase the susceptibility of preterm infants to GBS infection. PMID- 21300778 TI - Parity and placental infection affect antibody responses against Plasmodium falciparum during pregnancy. AB - Women are at higher risk of Plasmodium falciparum infection when pregnant. The decreasing risk of malaria with subsequent pregnancies is attributed to parity dependent acquisition of antibodies against placental parasites expressing variant surface antigens, VAR2CSA, that mediate placental sequestration through adhesion to chondroitin sulfate A (CSA). However, modulation of immunity during pregnancy may also contribute to increase the risk of malaria. We compared antibody responses among 30 Mozambican primigravidae and 60 multigravidae at delivery, 40 men, and 40 children. IgG levels were measured against the surface antigens of erythrocytes infected with P. falciparum isolated from 12 pregnant women (4 placental and 8 peripheral blood isolates) and 26 nonpregnant hosts. We also measured IgG levels against merozoite recombinant antigens and total IgG. Placental P. falciparum infection was associated with increased levels of total IgG as well as IgG levels against merozoite antigens and parasite isolates from pregnant and nonpregnant hosts. We therefore stratified comparisons of antibody levels by placental infection. Compared to multigravidae, uninfected primigravidae had lower total IgG as well as lower levels of IgGs against peripheral blood isolates from both pregnant and nonpregnant hosts. These differences were not explained by use of bed nets, season at delivery, neighborhood of residence, or age. Compared to men, infected primigravidae had higher levels of IgGs against isolates from pregnant women and CSA-binding lines but not against other isolates, supporting the concept of a pregnancy-specific development of immunity to these parasite variants. Results of this study show that parity and placental infection can modulate immune responses during pregnancy against malaria parasites. PMID- 21300779 TI - SPATA18, a spermatogenesis-associated gene, is a novel transcriptional target of p53 and p63. AB - The transcription factor p53 functions not only to suppress tumorigenesis but also to maintain normal development and homeostasis. Although p53 was implicated in different aspects of fertility, including spermatogenesis and implantation, the mechanism underlying p53 involvement in spermatogenesis is poorly resolved. In this study we describe the identification of a spermatogenesis-associated gene, SPATA18, as a novel p53 transcriptional target and show that SPATA18 transcription is induced by p53 in a variety of cell types of both human and mouse origin. p53 binds a consensus DNA motif that resides within the first intron of SPATA18. We describe the spatiotemporal expression patterns of SPATA18 in mouse seminiferous tubules and suggest that SPATA18 transcription is regulated in vivo by p53. We also demonstrate the induction of SPATA18 by p63 and suggest that p63 can compensate for the loss of p53 activity in vivo. Our data not only enrich the known collection of p53 targets but may also provide insights on spermatogenesis defects that are associated with p53 deficiency. PMID- 21300780 TI - Regulated antisense transcription controls expression of cell-type-specific genes in yeast. AB - Transcriptome profiling studies have recently uncovered a large number of noncoding RNA transcripts (ncRNAs) in eukaryotic organisms, and there is growing interest in their role in the cell. For example, in haploid Saccharomyces cerevisiae cells, the expression of an overlapping antisense ncRNA, referred to here as RME2 (Regulator of Meiosis 2), prevents IME4 expression. In diploid cells, the a1-alpha2 complex represses the transcription of RME2, allowing IME4 to be induced during meiosis. In this study we show that antisense transcription across the IME4 promoter region does not block transcription factors from binding and is not required for repression. Mutational analyses found that sequences within the IME4 open reading frame (ORF) are required for the repression mediated by RME2 transcription. These results support a model where transcription of RME2 blocks the elongation of the full-length IME4 transcript but not its initiation. We have found that another antisense transcript, called RME3, represses ZIP2 in a cell-type-specific manner. These results suggest that regulated antisense transcription may be a widespread mechanism for the control of gene expression and may account for the roles of some of the previously uncharacterized ncRNAs in yeast. PMID- 21300781 TI - Psm3 acetylation on conserved lysine residues is dispensable for viability in fission yeast but contributes to Eso1-mediated sister chromatid cohesion by antagonizing Wpl1. AB - In budding yeast and humans, cohesion establishment during S phase requires the acetyltransferase Eco1/Esco1-2, which acetylates the cohesin subunit Smc3 on two conserved lysine residues. Whether Smc3 is the sole Eco1/Esco1-2 effector and how Smc3 acetylation promotes cohesion are unknown. In fission yeast (Schizosaccharomyces pombe), as in humans, cohesin binding to G(1) chromosomes is dynamic and the unloading reaction is stimulated by Wpl1 (human ortholog, Wapl). During S phase, a subpopulation of cohesin becomes stably bound to chromatin in an Eso1 (fission yeast Eco1/Esco1-2)-dependent manner. Cohesin stabilization occurs unevenly along chromosomes. Cohesin remains largely labile at the rDNA repeats but binds mostly in the stable mode to pericentromere regions. This pattern is largely unchanged in eso1Delta wpl1Delta cells, and cohesion is unaffected, indicating that the main Eso1 role is counteracting Wpl1. A mutant of Psm3 (fission yeast Smc3) that mimics its acetylated state renders cohesin less sensitive to Wpl1-dependent unloading and partially bypasses the Eso1 requirement but cannot generate the stable mode of cohesin binding in the absence of Eso1. Conversely, nonacetylatable Psm3 reduces the stable cohesin fraction and affects cohesion in a Wpl1-dependent manner, but cells are viable. We propose that Psm3 acetylation contributes to Eso1 counteracting of Wpl1 to secure stable cohesin interaction with postreplicative chromosomes but that it is not the sole molecular event by which this occurs. PMID- 21300782 TI - Identification of PITX1 as a TERT suppressor gene located on human chromosome 5. AB - Telomerase, a ribonucleoprotein enzyme that maintains telomere length, is crucial for cellular immortalization and cancer progression. Telomerase activity is attributed primarily to the expression of telomerase reverse transcriptase (TERT). Using microcell-mediated chromosome transfer (MMCT) into the mouse melanoma cell line B16F10, we previously found that human chromosome 5 carries a gene, or genes, that can negatively regulate TERT expression (H. Kugoh, K. Shigenami, K. Funaki, J. Barrett, and M. Oshimura, Genes Chromosome Cancer 36:37 47, 2003). To identify the gene responsible for the regulation of TERT transcription, we performed cDNA microarray analysis using parental B16F10 cells, telomerase-negative B16F10 microcell hybrids with a human chromosome 5 (B16F10MH5), and its revertant clones (MH5R) with reactivated telomerase. Here, we report the identification of PITX1, whose expression leads to the downregulation of mouse tert (mtert) transcription, as a TERT suppressor gene. Additionally, both human TERT (hTERT) and mouse TERT (mtert) promoter activity can be suppressed by PITX1. We show that three and one binding site within the hTERT and mtert promoters, respectively, that express a unique conserved region are responsible for the transcriptional activation of TERT. Furthermore, we showed that PITX1 binds to the TERT promoter both in vitro and in vivo. Thus, PITX1 suppresses TERT transcription through direct binding to the TERT promoter, which ultimately regulates telomerase activity. PMID- 21300783 TI - Lipin is a central regulator of adipose tissue development and function in Drosophila melanogaster. AB - Lipins are evolutionarily conserved proteins found from yeasts to humans. Mammalian and yeast lipin proteins have been shown to control gene expression and to enzymatically convert phosphatidate to diacylglycerol, an essential precursor in triacylglcerol (TAG) and phospholipid synthesis. Loss of lipin 1 in the mouse, but not in humans, leads to lipodystrophy and fatty liver disease. Here we show that the single lipin orthologue of Drosophila melanogaster (dLipin) is essential for normal adipose tissue (fat body) development and TAG storage. dLipin mutants are characterized by reductions in larval fat body mass, whole-animal TAG content, and lipid droplet size. Individual cells of the underdeveloped fat body are characterized by increased size and ultrastructural defects affecting cell nuclei, mitochondria, and autophagosomes. Under starvation conditions, dLipin is transcriptionally upregulated and functions to promote survival. Together, these data show that dLipin is a central player in lipid and energy metabolism, and they establish Drosophila as a genetic model for further studies of conserved functions of the lipin family of metabolic regulators. PMID- 21300784 TI - Lineage conversion of murine extraembryonic trophoblast stem cells to pluripotent stem cells. AB - In mammals, the first cell fate decision is initialized by cell polarization at the 8- to 16-cell stage of the preimplantation embryo. At this stage, outside cells adopt a trophectoderm (TE) fate, whereas the inside cell population gives rise to the inner cell mass (ICM). Prior to implantation, transcriptional interaction networks and epigenetic modifications divide the extraembryonic and embryonic fate irrevocably. Here, we report that extraembryonic trophoblast stem cell (TSC) lines are converted to induced pluripotent stem cells (TSC-iPSCs) by overexpressing Oct4, Sox2, Klf4, and cMyc. Methylation studies and gene array analyses indicated that TSC-iPSCs had adopted a pluripotent potential. The rate of conversion was lower than those of somatic reprogramming experiments, probably due to the unique genetic network controlling extraembryonic lineage fixation. Both in vitro and in vivo, TSC-iPSCs differentiated into tissues representing all three embryonic germ layers, indicating that somatic cell fate could be induced. Finally, TSC-iPSCs chimerized the embryo proper and contributed to the germ line of mice, indicating that these cells had acquired full somatic differentiation potential. These results lead to a better understanding of the molecular processes that govern the first lineage decision in mammals. PMID- 21300785 TI - Inhibition of homologous recombination by DNA-dependent protein kinase requires kinase activity, is titratable, and is modulated by autophosphorylation. AB - How a cell chooses between nonhomologous end joining (NHEJ) and homologous recombination (HR) to repair a double-strand break (DSB) is a central and largely unanswered question. Although there is evidence of competition between HR and NHEJ, because of the DNA-dependent protein kinase (DNA-PK)'s cellular abundance, it seems that there must be more to the repair pathway choice than direct competition. Both a mutational approach and chemical inhibition were utilized to address how DNA-PK affects HR. We find that DNA-PK's ability to repress HR is both titratable and entirely dependent on its enzymatic activity. Still, although requisite, robust enzymatic activity is not sufficient to inhibit HR. Emerging data (including the data presented here) document the functional complexities of DNA-PK's extensive phosphorylations that likely occur on more than 40 sites. Even more, we show here that certain phosphorylations of the DNA-PK large catalytic subunit (DNA-PKcs) clearly promote HR while inhibiting NHEJ, and we conclude that the phosphorylation status of DNA-PK impacts how a cell chooses to repair a DSB. PMID- 21300786 TI - Selective abrogation of BiP/GRP78 blunts activation of NF-kappaB through the ATF6 branch of the UPR: involvement of C/EBPbeta and mTOR-dependent dephosphorylation of Akt. AB - Subtilase cytotoxin (SubAB) that selectively cleaves BiP/GRP78 triggers the unfolded protein response (UPR) and protects mice from endotoxic lethality and collagen arthritis. We found that pretreatment of cells with SubAB suppressed tumor necrosis alpha (TNF-alpha)-induced activation of NF-kappaB and NF-kappaB dependent chemokine expression. To elucidate underlying mechanisms, the involvement of C/EBP and Akt, putative regulators of NF-kappaB, was investigated. Among members of the C/EBP family, SubAB preferentially induced C/EBPbeta. Overexpression of C/EBPbeta suppressed TNF-alpha-induced NF-kappaB activation, and knockdown of C/EBPbeta attenuated the suppressive effect of SubAB on NF kappaB. We identified that the ATF6 branch of the UPR plays a crucial role in the induction of C/EBPbeta. In addition to this effect, SubAB depressed basal and TNF alpha-induced phosphorylation of Akt via the UPR. It was mediated by the induction of ATF6 and consequent activation of mTOR that dephosphorylated Akt. Inhibition of Akt attenuated activation of NF-kappaB by TNF-alpha, suggesting that the mTOR-Akt pathway is another target for SubAB-initiated, UPR-mediated NF kappaB suppression. These results elucidated that SubAB blunts activation of NF kappaB through ATF6-dependent mechanisms, i.e., preferential induction of C/EBPbeta and mTOR-dependent dephosphorylation of Akt. PMID- 21300787 TI - Deficiency of sorting nexin 27 (SNX27) leads to growth retardation and elevated levels of N-methyl-D-aspartate receptor 2C (NR2C). AB - Phox (PX) domain-containing sorting nexins (SNXs) are emerging as important regulators of endocytic trafficking. Sorting nexin 27 (SNX27) is unique, as it contains a PDZ (Psd-95/Dlg/ZO1) domain. We show here that SNX27 is primarily targeted to the early endosome by interaction of its PX domain with PtdIns(3)P. Although targeted ablation of the SNX27 gene in mice did not significantly affect growth and survival during embryonic development, SNX27 plays an essential role in postnatal growth and survival. N-Methyl-d-aspartate (NMDA) receptor 2C (NR2C) was identified as a novel SNX27-interacting protein, and this interaction is mediated by the PDZ domain of SNX27 and the C-terminal PDZ-binding motif of NR2C. Increased NR2C expression levels, together with impaired NR2C endocytosis in SNX27(-/-) neurons, indicate that SNX27 may function to regulate endocytosis and/or endosomal sorting of NR2C. This is consistent with a role of SNX27 as a general regulator for sorting of membrane proteins containing a PDZ-binding motif, and its absence may alter the trafficking of these proteins, leading to growth and survival defects. PMID- 21300788 TI - Cross-sectional associations of albuminuria and C-reactive protein with functional disability in older adults with diabetes. AB - OBJECTIVE: To examine the relationship between albuminuria, inflammation, and disability in older adults with diabetes. RESEARCH DESIGN AND METHODS: Data were from 1,729 adults (>= 60 years) with diabetes in the National Health and Nutrition Examination Survey, 1999-2008. Disability in activities of daily living (ADL), instrumental activities of daily living (IADL), leisure and social activities (LSA), general physical activities (GPA), and lower-extremity mobility (LEM) was obtained from self-reports. Urinary albumin-to-creatinine ratio (UACR) (mg/g) was categorized into normal (UACR <30 mg/g), microalbuminuria (UACR 30-300 mg/g), and macroalbuminuria (UACR >300 mg/g). C-reactive protein (CRP) levels were quantified by latex-enhanced nephelometry. RESULTS: In the full-adjusted model, microalbuminuria was associated with disability in ADL, LSA, and LEM with corresponding odds ratios (ORs) (95% CIs) of 1.51 (1.16-1.98), 1.62 (1.23-2.14), and 1.34 (1.03-1.74), respectively, compared with participants without albuminuria. Macroalbuminuria was associated with disability in ADL, IADL, and LEM with corresponding ORs (95% CIs) of 1.94 (1.24-3.03), 1.93 (1.23-3.02), and 2.20 (1.38-3.49), respectively, compared with participants without albuminuria. Elevated CRP (>0.3 mg/dL) was associated with increased odds of disability in ADL and LEM, with corresponding ORs (95% CIs) of 1.28 (1.00-1.62) and 1.68 (1.34 2.11), respectively. Subjects with both albuminuria and elevated CRP had higher odds of disability than individuals with no albuminuria and normal CRP. CONCLUSIONS: Albuminuria and inflammation were independent correlates for disability among older adults with diabetes. There was an interaction of albuminuria and elevated CRP on disability, suggesting that the presence of subclinical inflammation may amplify the effect of albuminuria on disability in older adults living with diabetes. PMID- 21300789 TI - Impaired glucose tolerance, but not impaired fasting glucose, underlies left ventricular diastolic dysfunction. AB - OBJECTIVE: Glucose intolerance is recognized as a predictor of congestive heart failure (CHF). However, the association of postprandial hyperglycemia or fasting hyperglycemia with CHF has not been clarified. We determined the impact of the total spectrum of glucose abnormalities on left ventricular (LV) geometry and diastolic function. RESEARCH DESIGN AND METHODS: Two hundred and eighty-seven Japanese subjects who visited the university hospital to be checked for glucose intolerance or known type 2 diabetes were consecutively recruited. Participants underwent an oral glucose tolerance test if they had no history of diabetes, and LV geometry and LV systolic and diastolic function were analyzed by Doppler echocardiography. RESULTS: The frequency of LV diastolic dysfunction in subjects with normal glucose tolerance, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), newly detected diabetes, and known diabetes were 13, 22, 50, 51, and 61%, respectively (chi(2) = 54.2, P < 0.0001). IGT was a predictor for LV diastolic dysfunction after adjusting for age, sex, systolic blood pressure, and heart rate (odds ratio 3.43 [95% CI 1.09-11.2]), but IFG was not (0.49 [0.06 3.08]). IGT was a predictor after adjusting for established CHF risk factors but was no longer significant after adjusting for BMI and homeostasis model assessment of insulin resistance. CONCLUSIONS: In this hospital-based registry of subjects without CHF, the prevalence of LV diastolic dysfunction was higher in subjects with IGT but not in those with IFG. Results suggest that IGT, as well as newly detected and known diabetes, could be linked to an increased risk of cardiovascular events, partly through LV diastolic dysfunction. PMID- 21300790 TI - Investigating the potential for toxicity from long-term use of the herbal products, goldenseal and milk thistle. AB - Two-year toxicity studies were conducted on the widely used herbal products, goldenseal and milk thistle, in male and female F344/N rats and B6C3F1 mice. With goldenseal root powder, the primary finding was an increase in liver tumors in rats and mice, and with milk thistle extract, a decrease in spontaneous background tumors including mammary gland tumors in female rats and liver tumors in male mice. Increased tumorigenicity in rodents exposed to goldenseal root powder may be due in part to the topoisomerase inhibition properties of berberine, a major alkaloid constituent in goldenseal, or its metabolite, berberrubine. In the clinic, use of topoisomerase-inhibiting agents has been associated with secondary tumor formation and inhibition in DNA repair processes. In contrast, the radical-scavenging and antioxidant properties of silibinin and other flavonolignans in milk thistle extract may have contributed to the decrease in background tumors in rodents in the present studies. The fate of the active constituents of goldenseal and milk thistle is similar in humans and rodents; therefore, the modes of action may translate across species. Further studies are needed to extrapolate the findings to humans. PMID- 21300791 TI - Spontaneous complex polysaccharide inclusions in the skeletal muscle of purpose bred beagle dogs. AB - Amylase-resistant, periodic acid-Schiff (PAS)-positive inclusions were identified in the skeletal muscle of four of twenty-four purpose-bred beagle dogs from a routine toxicology study. Affected myofibers contained amorphous material filling up to 20% of the sarcoplasm that stained lightly basophilic with hematoxylin and eosin and was strongly PAS-positive with amylase resistance. Transmission electron micrographic examination of the inclusions revealed granular, non membrane-bound, electron-dense material, consistent with polysaccharide. Although skeletal muscle inclusions with similar features have been reported in dogs in conjunction with systemic metabolic disorders and less often in muscle adjacent to nonmyogenic sarcomas, all four of these dogs lacked clinical or pathological findings diagnostic of a concurrent systemic metabolic or localized skeletal muscle disorder. Furthermore, these skeletal muscle inclusions were present in both vehicle- and test article-treated dogs and were considered an incidental finding that may occur spontaneously in clinically normal beagle dogs; as such, their presence in drug-treated animals should be interpreted with caution. PMID- 21300792 TI - Best practices for evaluation of bone marrow in nonclinical toxicity studies. AB - This manuscript is intended to provide a best practice approach to accurately and consistently assess toxicant-induced bone marrow effects of test articles. In nonclinical toxicity studies, complete blood count data in conjunction with the histological examination of the bone marrow are recommended as the foundation for assessing the effect of test articles on the hematopoietic system. This approach alone can be used successfully in many studies. However, in some situations it may be necessary to further characterize effects on the different hematopoietic lineages, either by cytological or flow cytometric evaluation of the bone marrow. Both modalities can be used successfully, and which one is selected will depend on the expertise, preference of the facility, and the nature of the change in the bone marrow. Other specialized techniques such as clonogenic assays or electron microscopy are used rarely to further characterize hematotoxicity. The indications and techniques to successfully employ histological, cytological, or flow cytometric evaluation as well as clonogenic assays and electron microscopy are reviewed. PMID- 21300793 TI - Par6B and atypical PKC regulate mitotic spindle orientation during epithelial morphogenesis. AB - Cdc42 plays an evolutionarily conserved role in promoting cell polarity and is indispensable during epithelial morphogenesis. To further investigate the role of Cdc42, we have used a three-dimensional matrigel model, in which single Caco-2 cells develop to form polarized cysts. Using this system, we previously reported that Cdc42 controls mitotic spindle orientation during cell division to correctly position the apical surface in a growing epithelial structure. In the present study, we have investigated the specific downstream effectors through which Cdc42 controls this process. Here, we report that Par6B and its binding partner, atypical protein kinase C (aPKC), are required to regulate Caco-2 morphogenesis. Depletion or inhibition of Par6B or aPKC phenocopies the loss of Cdc42, inducing misorientation of the mitotic spindle, mispositioning of the nascent apical surface, and ultimately, the formation of aberrant cysts with multiple lumens. Mechanistically, Par6B and aPKC function interdependently in this context. Par6B localizes to the apical surface of Caco-2 cysts and is required to recruit aPKC to this compartment. Conversely, aPKC protects Par6B from proteasomal degradation, in a kinase-independent manner. In addition, we report that depletion or inhibition of aPKC induces robust apoptotic cell death in Caco-2 cells, significantly reducing both cyst size and number. Cell survival and apical positioning depend upon different thresholds of aPKC expression, suggesting that they are controlled by distinct downstream pathways. We conclude that Par6B and aPKC control mitotic spindle orientation in polarized epithelia and, furthermore, that aPKC coordinately regulates multiple processes to promote morphogenesis. PMID- 21300794 TI - Tissue transglutaminase-mediated glutamine deamidation of beta-amyloid peptide increases peptide solubility, whereas enzymatic cross-linking and peptide fragmentation may serve as molecular triggers for rapid peptide aggregation. AB - Tissue transglutaminase (TGase) has been implicated in a number of cellular processes and disease states, where the enzymatic actions of TGase may serve in both, cell survival and apoptosis. To date, the precise functional properties of TGase in cell survival or cell death mechanisms still remain elusive. TGase mediated cross-linking has been reported to account for the formation of insoluble lesions in conformational diseases. We report here that TGase induces intramolecular cross-linking of beta-amyloid peptide (Abeta), resulting in structural changes of monomeric Abeta. Using high resolution mass spectrometry (MS) of cross-linked Abeta peptides, we observed a shift in mass, which is, presumably associated with the loss of NH3 due to enzymatic transamidation activity and hence intramolecular peptide cross-linking. We have observed that a large population of Abeta monomers contained an 0.984 Da increase in mass at a glutamine residue, indicating that glutamine 15 serves as an indispensable substrate in TGase-mediated deamidation to glutamate 15. We provide strong analytical evidence on TGase-mediated Abeta peptide dimerization, through covalent intermolecular cross-linking and hence the formation of Abeta1-40 dimers. Our in depth analyses indicate that TGase-induced post-translational modifications of Abeta peptide may serve as an important seed for aggregation. PMID- 21300795 TI - Involvement of autophagy in oncogenic K-Ras-induced malignant cell transformation. AB - Autophagy has recently been implicated in both the prevention and progression of cancer. However, the molecular basis for the relationship between autophagy induction and the initial acquisition of malignancy is currently unknown. Here, we provide the first evidence that autophagy is essential for oncogenic K-Ras (K Ras(V12))-induced malignant cell transformation. Retroviral expression of K Ras(V12) induced autophagic vacuole formation and malignant transformation in human breast epithelial cells. Interestingly, pharmacological inhibition of autophagy completely blocked K-Ras(V12)-induced, anchorage-independent cell growth on soft agar. Both mRNA and protein levels of ATG5 and ATG7 (autophagy specific genes 5 and 7, respectively) were increased in cells overexpressing K Ras(V12). Targeted suppression of ATG5 or ATG7 expression by short hairpin (sh) RNA inhibited cell growth on soft agar and tumor formation in nude mice. Moreover, inhibition of reactive oxygen species (ROS) with antioxidants clearly attenuated K-Ras(V12)-induced ATG5 and ATG7 induction, autophagy, and malignant cell transformation. MAPK pathway components were activated in cells overexpressing K-Ras(V12), and inhibition of JNK blunted induction of ATG5 and ATG7 and subsequent autophagy. In addition, pretreatment with antioxidants completely inhibited K-Ras(V12)-induced JNK activation. Our results provide novel evidence that autophagy is critically involved in malignant transformation by oncogenic K-Ras and show that reactive oxygen species-mediated JNK activation plays a causal role in autophagy induction through up-regulation of ATG5 and ATG7. PMID- 21300796 TI - Protein targeting to exosomes/microvesicles by plasma membrane anchors. AB - Animal cells secrete small vesicles, otherwise known as exosomes and microvesicles (EMVs). A short, N-terminal acylation tag can target a highly oligomeric cytoplasmic protein, TyA, into secreted vesicles (Fang, Y., Wu, N., Gan, X., Yan, W., Morell, J. C., and Gould, S. J. (2007) PLoS Biol. 5, 1267 1283). However, it is not clear whether this is true for other membrane anchors or other highly oligomeric, cytoplasmic proteins. We show here that a variety of plasma membrane anchors can target TyA-GFP to sites of vesicle budding and into EMVs, including: (i) a myristoylation tag; (ii) a phosphatidylinositol-(4,5) bisphosphate (PIP(2))-binding domain; (iii), a phosphatidylinositol-(3,4,5) trisphosphate-binding domain; (iv) a prenylation/palmitoylation tag, and (v) a type-1 plasma membrane protein, CD43. However, the relative budding efficiency induced by these plasma membrane anchors varied over a 10-fold range, from 100% of control (AcylTyA-GFP) for the myristoylation tag and PIP(2)-binding domain, to one-third or less for the others, respectively. Targeting TyA-GFP to endosome membranes by fusion to a phosphatidylinositol 3-phosphate-binding domain induced only a slight budding of TyA-GFP, ~2% of control, and no budding was observed when TyA-GFP was targeted to Golgi membranes via a phosphatidylinositol 4 phosphate-binding domain. We also found that a plasma membrane anchor can target two other highly oligomeric, cytoplasmic proteins to EMVs. These observations support the hypothesis that plasma membrane anchors can target highly oligomeric, cytoplasmic proteins to EMVs. Our data also provide additional parallels between EMV biogenesis and retrovirus budding, as the anchors that induced the greatest budding of TyA-GFP are the same as those that mediate retrovirus budding. PMID- 21300797 TI - Investigation of the functional link between ATM and NBS1 in the DNA damage response in the mouse cerebellum. AB - Ataxia-telangiectasia (A-T) and Nijmegen breakage syndrome (NBS) are related genomic instability syndromes characterized by neurological deficits. The NBS1 protein that is defective in NBS is a component of the Mre11/RAD50/NBS1 (MRN) complex, which plays a major role in the early phase of the complex cellular response to double strand breaks (DSBs) in the DNA. Among others, Mre11/RAD50/NBS1 is required for timely activation of the protein kinase ATM (A T, mutated), which is missing or inactivated in patients with A-T. Understanding the molecular pathology of A-T, primarily its cardinal symptom, cerebellar degeneration, requires investigation of the DSB response in cerebellar neurons, particularly Purkinje cells, which are the first to be lost in A-T patients. Cerebellar cultures derived from mice with different mutations in DNA damage response genes is a useful experimental system to study malfunctioning of the damage response in the nervous system. To clarify the interrelations between murine Nbs1 and Atm, we generated a mouse strain with specific disruption of the Nbs1 gene in the central nervous system on the background of general Atm deficiency (Nbs1-CNS-Delta//Atm(-/-)). This genotype exacerbated several features of both conditions and led to a markedly reduced life span, dramatic decline in the number of cerebellar granule neurons with considerable cerebellar disorganization, abolishment of the white matter, severe reduction in glial cell proliferation, and delayed DSB repair in cerebellar tissue. Combined loss of Nbs1 and Atm in the CNS significantly abrogated the DSB response compared with the single mutation genotypes. Importantly, the data indicate that Atm has cellular roles not regulated by Nbs1 in the murine cerebellum. PMID- 21300799 TI - Dual-specific phosphatase-6 (Dusp6) and ERK mediate AMPA receptor-induced oligodendrocyte death. AB - Oligodendrocytes, the myelinating cells of the CNS, are highly vulnerable to glutamate excitotoxicity, a mechanism involved in tissue damage in multiple sclerosis. Thus, understanding oligodendrocyte death at the molecular level is important to develop new therapeutic approaches to treat the disease. Here, using microarray analysis and quantitative PCR, we observed that dual-specific phosphatase-6 (Dusp6), an extracellular regulated kinase-specific phosphatase, is up-regulated in oligodendrocyte cultures as well as in optic nerves after AMPA receptor activation. In turn, Dusp6 is overexpressed in optic nerves from multiple sclerosis patients before the appearance of evident damage in this structure. We further analyzed the role of Dusp6 and ERK signaling in excitotoxic oligodendrocyte death and observed that AMPA receptor activation induces a rapid increase in ERK1/2 phosphorylation. Blocking Dusp6 expression, which enhances ERK1/2 phosphorylation, significantly diminished AMPA receptor-induced oligodendrocyte death. In contrast, MAPK/ERK pathway inhibition with UO126 significantly potentiates excitotoxic oligodendrocyte death and increases cytochrome c release, mitochondrial depolarization, and mitochondrial calcium overload produced by AMPA receptor stimulation. Upstream analysis demonstrated that MAPK/ERK signaling alters AMPA receptor properties. Indeed, Dusp6 overexpression as well as incubation with UO126 produced an increase in AMPA receptor-induced inward currents and cytosolic calcium overload. Together, these data suggest that levels of phosphorylated ERK, controlled by Dusp6 phosphatase, regulate glutamate receptor permeability and oligodendroglial excitotoxicity. Therefore, targeting Dusp6 may be a useful strategy to prevent oligodendrocyte death in multiple sclerosis and other diseases involving CNS white matter. PMID- 21300798 TI - Regulation of the activity and cellular localization of the circadian clock protein FRQ. AB - Eukaryotic circadian clocks employ autoregulatory negative feedback loops to control daily rhythms. In the filamentous fungus Neurospora, FRQ, FRH, WC-1, and WC-2 are the core components of the circadian negative feedback loop. To close the transcription-based negative feedback loop, the FRQ-FRH complex inhibits the activity of the WC complex in the nucleus by promoting the casein kinases mediated WC phosphorylation. Despite its essential role in the nucleus, most FRQ is found in the cytoplasm. In this study, we mapped the FRQ regions that are important for its cellular localization. We show that the C-terminal part of FRQ, particularly the FRQ-FRH interaction domain, plays a major role in controlling FRQ localization. Both the mutation of the FRQ-FRH interaction domain and the down-regulation of FRH result in the nuclear enrichment of FRQ, suggesting that FRH regulates FRQ localization via a physical interaction. To study the role of FRQ phosphorylation, we examined the FRQ localization in wild-type as well as an array of FRQ kinase, FRQ phosphatase, and FRQ phosphorylation site mutants. Collectively, our results suggest that FRQ phosphorylation does not play a significant role in regulating its cellular localization. Instead, we find that phosphorylation of FRQ inhibits its transcriptional repressor activity in the circadian negative feedback loop. Such an effect is achieved by inhibiting the ability of FRQ to interact with WCC and casein kinase 1a. Our results indicate that the rhythmic FRQ phosphorylation profile observed is an important part of the negative feedback mechanism that drives robust circadian gene expression. PMID- 21300800 TI - Destruction of amyloid fibrils of keratoepithelin peptides by laser irradiation coupled with amyloid-specific thioflavin T. AB - Mutations in keratoepithelin are associated with blinding ocular diseases, including lattice corneal dystrophy type 1 and granular corneal dystrophy type 2. These diseases are characterized by deposits of amyloid fibrils and/or granular non-amyloid aggregates in the cornea. Removing the deposits in the cornea is important for treatment. Previously, we reported the destruction of amyloid fibrils of beta(2)-microglobulin K3 fragments and amyloid beta by laser irradiation coupled with the binding of an amyloid-specific thioflavin T. Here, we studied the effects of this combination on the amyloid fibrils of two 22 residue fragments of keratoepithelin. The direct observation of individual amyloid fibrils was performed in real time using total internal reflection fluorescence microscopy. Both types of amyloid fibrils were broken up by the laser irradiation, dependent on the laser power. The results suggest the laser induced destruction of amyloid fibrils to be a useful strategy for the treatment of these corneal dystrophies. PMID- 21300802 TI - Mechanistic and structural insights into the regioselectivity of an acyl-CoA fatty acid desaturase via directed molecular evolution. AB - Membrane-bound fatty acid desaturases and related enzymes play a pivotal role in the biosynthesis of unsaturated and various unusual fatty acids. Structural insights into the remarkable catalytic diversity and wide range of substrate specificities of this class of enzymes remain limited due to the lack of a crystal structure. To investigate the structural basis of the double bond positioning (regioselectivity) of the desaturation reaction in more detail, we relied on a combination of directed evolution in vitro and a powerful yeast complementation assay to screen for Deltax regioselectivity. After two selection rounds, variants of the bifunctional Delta12/Delta9-desaturase from the house cricket (Acheta domesticus) exhibited increased Delta9-desaturation activity on shorter chain fatty acids. This change in specificity was the result of as few as three mutations, some of them near the putative active site. Subsequent analysis of individual substitutions revealed an important role of residue Phe-52 in facilitating Delta9-desaturation of shorter chain acyl substrates and allowed for the redesign of the cricket Delta12/Delta9-desaturase into a 16:0-specific Delta9 desaturase. Our results demonstrate that a minimal number of mutations can have a profound impact on the regioselectivity of acyl-CoA fatty acid desaturases and include the first biochemical data supporting the acyl-CoA acyl carrier specificity of a desaturase able to carry out Delta12-desaturation. PMID- 21300801 TI - Ncb5or deficiency increases fatty acid catabolism and oxidative stress. AB - The endoplasmic reticulum-associated NADH cytochrome b(5) oxidoreductase (Ncb5or) is widely distributed in animal tissues. Ncb5or(-/-) mice develop diabetes at age 7 weeks and have increased susceptibility to the diabetogenic oxidant streptozotocin. Ncb5or deficiency also results in lipoatrophy and increased hepatocyte sensitivity to cytotoxic effects of saturated fatty acids. Here we investigate the mechanisms of these phenomena in prediabetic Ncb5or(-/-) mice and find that, despite increased rates of fatty acid uptake and synthesis and higher stearoyl-CoA desaturase (SCD) expression, Ncb5or(-/-) liver accumulates less triacylglycerol (TAG) than wild type (WT). Increased fatty acid catabolism and oxidative stress are evident in Ncb5or(-/-) hepatocytes and reflect increased mitochondrial content, peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) expression, fatty acid oxidation rates, oxidative stress response gene expression, and oxidized glutathione content. Ncb5or(-/-) hepatocytes readily incorporate exogenous fatty acids into TAG but accumulate more free fatty acids (FFA) and have greater palmitate-induced oxidative stress responses and cell death than WT, all of which are alleviated by co-incubation with oleate via TAG channeling. A high fat diet rich in palmitate and oleate stimulates both lipogenesis and fatty acid catabolism in Ncb5or(-/-) liver, resulting in TAG levels similar to WT but increased intracellular FFA accumulation. Hepatic SCD-specific activity is lower in Ncb5or(-/-) than in WT mice, although Ncb5or(-/-) liver has a greater increase in Scd1 mRNA and protein levels. Together, these findings suggest that increased FFA accumulation and catabolism and oxidative stress are major consequences of Ncb5or deficiency in liver. PMID- 21300803 TI - Recruitment of SWI/SNF complex is required for transcriptional activation of the SLC11A1 gene during macrophage differentiation of HL-60 cells. AB - The solute carrier family 11 member 1 (SLC11A1) gene is strictly regulated and exclusively expressed in myeloid lineage cells. However, little is known about the transcriptional regulation of the SLC11A1 gene during myeloid development. In this study, we used HL-60 cells as a model to investigate the regulatory elements/factors involved in the transactivation of the SLC11A1 gene during phorbol 12-myristate 13-acetate (PMA)-induced macrophage differentiation of HL-60 cells. Promoter deletion analysis showed that a 7-base AP-1-like element (TGACTCT) was critical for the responsiveness of the SLC11A1 promoter to PMA. Stimulation by PMA induced the binding of ATF-3 and the recruitment of two components of the SWI/SNF complex, BRG1 and beta-actin, to this element in an ATF 3-dependent manner. RNAi-mediated depletion of ATF-3 or BRG1 markedly decreased SLC11A1 gene expression and its promoter activity induced by PMA. Luciferase reporter experiments demonstrated that ATF-3 cooperated with BRG1 and beta-actin to activate the SLC11A1 promoter. Furthermore, we showed that PMA can induce the proximal (GT/AC)(n) repeat sequence to convert to the Z-DNA structure in the SLC11A1 gene promoter, and depletion of BRG1 resulted in a significant decrease of Z-DNA formation. Our results demonstrated that recruitment of the SWI/SNF complex initiated Z-DNA formation and subsequently helped to transactivate the SLC11A1 gene. PMID- 21300804 TI - Lobe-specific functions of Ca2+.calmodulin in alphaCa2+.calmodulin-dependent protein kinase II activation. AB - N-methyl-D-aspartic acid receptor-dependent long term potentiation (LTP), a model of memory formation, requires Ca2+.calmodulin-dependent protein kinase II (alphaCaMKII) activity and Thr286 autophosphorylation via both global and local Ca2+ signaling, but the mechanisms of signal transduction are not understood. We tested the hypothesis that the Ca2+-binding activator protein calmodulin (CaM) is the primary decoder of Ca2+ signals, thereby determining the output, e.g. LTP. Thus, we investigated the function of CaM mutants, deficient in Ca2+ binding at sites 1 and 2 of the N-terminal lobe or sites 3 and 4 of the C-terminal CaM lobe, in the activation of alphaCaMKII. Occupancy of CaM Ca2+ binding sites 1, 3, and 4 is necessary and sufficient for full activation. Moreover, the N- and C-terminal CaM lobes have distinct functions. Ca2+ binding to N lobe Ca2+ binding site 1 increases the turnover rate of the enzyme 5-fold, whereas the C lobe plays a dual role; it is required for full activity, but in addition, via Ca2+ binding site 3, it stabilizes ATP binding to alphaCaMKII 4-fold. Thr286 autophosphorylation is also dependent on Ca2+ binding sites on both the N and the C lobes of CaM. As the CaM C lobe sites are populated by low amplitude/low frequency (global) Ca2+ signals, but occupancy of N lobe site 1 and thus activation of alphaCaMKII requires high amplitude/high frequency (local) Ca2+ signals, lobe-specific sensing of Ca2+-signaling patterns by CaM is proposed to explain the requirement for both global and local Ca2+ signaling in the induction of LTP via alphaCaMKII. PMID- 21300805 TI - Adiponectin inhibits osteoclastogenesis and bone resorption via APPL1-mediated suppression of Akt1. AB - Adiponectin is an adipokine playing an important role in regulating energy homeostasis and insulin sensitivity. However, the effect of adiponectin on bone metabolism shows contradictory results according to different research studies. In this study femurs were isolated from genetically double-labeled mBSP9.0Luc/beta-ACT-EGFP transgenic mice and were transplanted into adiponectin knock-out mice or wild type mice to investigate the effect of temporary exposure to adiponectin deficiency on bone growth and metabolism. We found that the growth of bone explants in adiponectin knock-out mice was significantly retarded. Histological analysis, microcomputed tomography analysis, and tartrate-resistant acid phosphatase staining revealed reduced trabecular bone volume, decreased cortical bone, and increased osteoclast number in bone explants in adiponectin knock-out mice. We then found that adiponectin inhibits RANKL-induced osteoclastogenesis from RAW264.7 cells and down-regulates RANKL-enhanced expressions of osteoclastogenic regulators including NFAT2, TRAF6, cathepsin K, and tartrate-resistant acid phosphatase. Adiponectin also increases osteoclast apoptosis and decreases survival/proliferation of osteoclast precursor cells. Using siRNA specifically targeting APPL1, the first identified adaptor protein of adiponectin signaling, we found that the inhibitory effect of adiponectin on osteoclasts was induced by APPL1-mediated down-regulation of Akt1 activity. In addition, overexpression of Akt1 successfully reversed adiponectin-induced inhibition in RANKL-stimulated osteoclast differentiation. In conclusion, adiponectin is important in maintaining the balance of energy metabolism, inflammatory responses, and bone formation. PMID- 21300806 TI - Intensity of deoxycytidine deamination of HIV-1 proviral DNA by the retroviral restriction factor APOBEC3G is mediated by the noncatalytic domain. AB - APOBEC3G is a single-stranded (ss) DNA deaminase that restricts replication of HIV-1 by inducing viral genome mutagenesis through deamination of cytosine to uracil on HIV-1 cDNA. APOBEC3G has polydisperse oligomeric states and deaminates ssDNA processively through jumping and sliding. APOBEC3G has a catalytically inactive N-terminal CD1 domain that mediates processivity and an active C terminal CD2 domain that catalyzes deaminations. Here, we assess the determinants of APOBEC3G deamination efficiency mediated by the CD1 domain by comparing native APOBEC3G and two CD1 mutants, a monomeric mutant (F126A/W127A) and a clinical mutant associated with high viral loads (H186R). Biochemical assays on ssDNA or partially dsDNA and with a reconstituted HIV replication system demonstrate that both mutants of Apo3G have altered DNA scanning properties in either jumping (F126A/W127A) or sliding (H186R), which results in decreased abilities to induce mutagenesis during reverse transcription. The data reveal a functionality for Apo3G oligomers in deamination and provide the first biochemical characterization of the clinical mutant H186R. The data demonstrate that the balance between the jumping and sliding of Apo3G is needed for efficient mutational inactivation of HIV-1. PMID- 21300807 TI - Single chain forms of the enhancer binding protein PspF provide insights into geometric requirements for gene activation. AB - Genetic information in the DNA is accessed by the molecular machine RNA polymerase following a highly conserved process, invariably involving the transition between double-stranded and single-stranded DNA states. In the case of the bacterial enhancer-dependent RNA polymerase (which is essential for adaptive responses and bacterial pathogenesis), the DNA melting event depends on specialized hexameric AAA+ ATPase activators. Involvement of such factors in transcription was demonstrated 25 years ago, but why these activators need to be hexameric, whether all the subunits operate identically, what is the contribution of each of the six subunits within the hexamer (structural, functional, or both), and how many active subunits are required for transcription activation remain open questions. Using engineered single-chain polypeptides covalently linking two or three subunits of the activator (allowing the subunit distribution within a hexamer to be fixed), we now show that (i) individual subunits have differential contributions to the activities of the oligomer and (ii) only a fraction of the subunits within the hexameric ATPase is directly required for gene activation. We establish that nucleotide-dependent coordination across three subunits of the hexameric bacterial enhancer binding proteins (bEBPs) is necessary for engagement and remodeling of the closed complex (RPc). Outcomes revealed features of bEBP, distinguishing their mode of action from fully processive AAA+ proteins or from simple bimodal switches. We now propose that the hexamer functions with asymmetric organization, potentially involving a split planar (open ring) or spiral character. PMID- 21300808 TI - The influence of arm and shoulder position on the bear-hug, belly-press, and lift off tests: an electromyographic study. AB - BACKGROUND: Clinical testing for the integrity of the subscapularis muscle includes the belly-press, lift-off, and bear-hug examinations. While these tests have been widely applied in clinical practice, there is considerable variation in arm positioning within each clinical examination. HYPOTHESIS: To determine the ideal arm and shoulder positions for isolating the subscapularis muscle while performing the bear-hug, belly-press, and lift-off tests. STUDY DESIGN: Controlled laboratory study. METHODS: The activity of 7 muscles was monitored in 20 healthy participants: upper and lower divisions of the subscapularis, supraspinatus, infraspinatus, latissimus dorsi, teres major, triceps, pectoralis major. Electromyogram data were collected and compared across each clinical test at varying arm positions: bear-hug (ideal position, 10 degrees superior, 10 degrees inferior to the shoulder line), belly-press (ideal position, maximum shoulder external rotation, and maximal shoulder internal rotation), and lift-off (ideal position, hand position 5 in. [12.7 cm] superior and 5 in. [12.7 cm] inferior to the midlumbar spine). RESULTS: Regardless of arm and shoulder position, the upper and lower subscapularis muscle activities were significantly greater than all other muscles while performing each test. No significant differences were observed between the upper and lower subscapularis divisions at any position within and across the 3 tests. There were no significant differences in subscapularis electromyogram activities across the 3 tests. CONCLUSION: The level of subscapularis muscle activation was similar among the bear-hug, belly press, and lift-off tests. The 3 tests activated the subscapularis significantly more than all other muscles tested but were not different from one another when compared across tests and positions. Although the bear-hug and lift-off tests have been described to activate differential portions of the subscapularis, the findings of this study do not support the preferential testing of a specific subscapular division across the 3 tests. As such, all 3 tests are effective in testing the integrity of the entire subscapularis muscle, although there does not appear to be an ideal position for selectively testing its divisions. CLINICAL RELEVANCE: Clinicians may feel comfortable in using any of the 3 tests, depending on the patient, to isolate the function of the subscapularis as a single muscle. Furthermore, clinicians should not solely focus on a patient's arm position when administering an examination but also compare the affected arm to the contralateral shoulder when appropriate. PMID- 21300809 TI - A novel imaging method for osteochondral lesions of the talus--comparison of SPECT-CT with MRI. AB - BACKGROUND: Magnetic resonance imaging (MRI) is the current standard in noninvasive diagnostics of osteochondral lesions (OCLs) of the talus. Single photon emission computed tomography-computed tomography (SPECT-CT) is a new technique that displays different imaging qualities. The influence of the aforementioned diagnostic information on treatment decision making in talar OCLs is not known. PURPOSE: The aim of the study was to evaluate SPECT-CT in comparison with MRI for image interpretation and decision making in OCLs of the talus. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Magnetic resonance imaging and SPECT-CT of 25 patients (average age, 32 years; range, 18 69 years) were analyzed by 3 independent orthopaedic surgeons blinded to the study. Raters had to analyze images for predefined criteria of cartilage, subchondral bone plate, and subchondral bone, including bone marrow edema on MRI and scintigraphic activity on SPECT-CT. For MRI alone, SPECT-CT alone, and their combination, the treatment decision had to be defined. RESULTS: In comparison with MRI alone, treatment decision making changed in 48% of the cases with SPECT CT alone and 52% with SPECT-CT and MRI combined. While cartilage showed good correlation for interpretation between MRI and SPECT-CT, the subchondral bone plate and subchondral bone showed substantial differences. Poor intrarater correlation highlighted the different information provided by the 2 imaging techniques. Poor interrater correlation showed a high heterogeneity in the treatment decision making of OCLs. CONCLUSION: Compared with MRI, SPECT-CT provides additional information and influences the decision making of OCL treatment. For thorough diagnostic evaluation in OCLs, performing both MRI and SPECT-CT is recommended. Further clinical investigation is needed to see if SPECT CT in addition to MRI results in improved treatment outcomes. PMID- 21300810 TI - Disposal ponds and tailing dams. PMID- 21300811 TI - Recent randomized controlled trial (RCT) by Dr Pagonis and coworkers. PMID- 21300812 TI - "Return to play after anterior cruciate ligament reconstruction in National Football League athletes" by Shah et al. PMID- 21300813 TI - National pastime. PMID- 21300816 TI - In memoriam. Anthony Moran 1960-2010. PMID- 21300819 TI - Apolipoprotein A-II suppressed concanavalin A-induced hepatitis via the inhibition of CD4 T cell function. AB - Con A-induced hepatitis has been used as a model of human autoimmune or viral hepatitis. During the process of identifying immunologically bioactive proteins in human plasma, we found that apolipoprotein A-II (ApoA-II), the second major apolipoprotein of high-density lipoprotein, inhibited the production of IFN-gamma by Con A-stimulated mouse and human CD4 T cells. Con A-induced hepatitis was attenuated by the administration of ApoA-II. The beneficial effect of ApoA-II was associated with reduced leukocyte infiltration and decreased production of T cell related cytokines and chemokines in the liver. ApoA-II inhibited the Con A induced activation of ERK-MAPK and nuclear translocation of NFAT in CD4 T cells. Interestingly, exacerbated hepatitis was observed in ApoA-II-deficient mice, indicating that ApoA-II plays a suppressive role in Con A-induced hepatitis under physiological conditions. Moreover, the administration of ApoA-II after the onset of Con A-induced hepatitis was sufficient to suppress disease. Thus, the therapeutic effect of ApoA-II could be useful for patients with CD4 T cell related autoimmune and viral hepatitis. PMID- 21300820 TI - IL-10 controls cystatin C synthesis and blood concentration in response to inflammation through regulation of IFN regulatory factor 8 expression. AB - Cystatin C (CstC) is a cysteine protease inhibitor of major clinical importance. Low concentration of serum CstC is linked to atherosclerosis. CstC can prevent formation of amyloid beta associated with Alzheimer's disease and can itself form toxic aggregates. CstC regulates NO secretion by macrophages and is a TGF-beta antagonist. Finally, the serum concentration of CstC is an indicator of kidney function. Yet, little is known about the regulation of CstC expression in vivo. In this study, we demonstrate that the transcription factor IFN regulatory factor 8 (IRF-8) is critical for CstC expression in primary dendritic cells. Only those cells with IRF-8 bound to the CstC gene promoter expressed high levels of the inhibitor. Secretion of IL-10 in response to inflammatory stimuli downregulated IRF-8 expression and consequently CstC synthesis in vivo. Furthermore, the serum concentration of CstC decreased in an IL-10-dependent manner in mice treated with the TLR9 agonist CpG. CstC synthesis is therefore more tightly regulated than hitherto recognized. The mechanisms involved in this regulation might be targeted to alter CstC production, with potential therapeutic value. Our results also indicate that caution should be exerted when using the concentration of serum CstC as an indicator of kidney function in conditions in which inflammation may alter CstC production. PMID- 21300821 TI - Anti-NeuGcGM3 antibodies, actively elicited by idiotypic vaccination in nonsmall cell lung cancer patients, induce tumor cell death by an oncosis-like mechanism. AB - 1E10 is a murine anti-idiotypic mAb specific for an idiotypic mAb that reacts with NeuGc-containing gangliosides, sulfatides, and Ags expressed in some human tumors. In melanoma, breast, and lung cancer patients, this anti-idiotypic Ab was able to induce a specific Ab response against N-glycosylated gangliosides, attractive targets for cancer immunotherapy as these glycolipids are not naturally expressed in humans. A clinical study with nonsmall cell lung cancer patients showed encouraging clinical benefits. Immunological studies performed in 20 of these patients suggested a correlation between the induction of Abs against NeuGcGM3 and longer survival times. The induced anti-NeuGcGM3 Abs recognized and directly killed tumor cells expressing the Ag, by a mechanism independent of complement activation. In the present work, we show that this cytotoxicity differs from apoptosis because it is temperature independent, no chromatin condensation or caspase 3 induction are detected, and the DNA fragmentation induced has a different pattern than the one characteristic for apoptosis. It is a very quick process and involves cytosqeleton reorganization. The Abs induce cellular swelling and the formation of big membrane lesions that allow the leakage of cytoplasm and the loss of the cell membrane integrity. All of these characteristics resemble a process of oncotic necrosis. To our knowledge, this is the first report of the active induction in cancer patients of NeuGcGM3-specific Abs able to induce complement independent oncotic necrosis to tumor cells. These results contribute to reinforcing the therapeutic potential of anti-idiotypic vaccines and the importance of NeuGcGM3 ganglioside as antitumor target. PMID- 21300822 TI - DNA alkylating therapy induces tumor regression through an HMGB1-mediated activation of innate immunity. AB - Dysregulation of apoptosis is associated with the development of human cancer and resistance to anticancer therapy. We have previously shown in tumor xenografts that DNA alkylating agents induce sporadic cell necrosis and regression of apoptosis-deficient tumors. Sporadic tumor cell necrosis is associated with extracellular release of cellular content such as the high mobility group box 1 (HMGB1) protein and subsequent recruitment of innate immune cells into the tumor tissue. It remained unclear whether HMGB1 and the activation of innate immunity played a role in tumor response to chemotherapy. In this study, we show that whereas DNA alkylating therapy leads to a complete tumor regression in an athymic mouse tumor xenograft model, it fails to do so in tumors deficient in HMGB1. The HMGB1-deficient tumors have an impaired ability to recruit innate immune cells including macrophages, neutrophils, and NK cells into the treated tumor tissue. Cytokine array analysis reveals that whereas DNA alkylating treatment leads to suppression of protumor cytokines such as IL-4, IL-10, and IL-13, loss of HMGB1 leads to elevated levels of these cytokines upon treatment. Suppression of innate immunity and HMGB1 using depleting Abs leads to a failure in tumor regression. Taken together, these results indicate that HMGB1 plays an essential role in activation of innate immunity and tumor clearance in response to DNA alkylating agents. PMID- 21300824 TI - CCL20/CCR6 feedback exaggerates epidermal growth factor receptor-dependent MUC5AC mucin production in human airway epithelial (NCI-H292) cells. AB - Mucous hypersecretion is an important feature of obstructive airway diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Multiple stimuli induce mucin production via activation of an epidermal growth factor receptor (EGFR) cascade, but the mechanisms that exaggerate mucin production in obstructive airway diseases remain unknown. In this study, we show that binding of CCL20, a G protein-coupled receptor (GPCR) ligand that is upregulated in the airways of subjects with obstructive airway diseases, to its unique GPCR CCR6 induces MUC5AC mucin production in human airway epithelial (NCI-H292) cells via metalloprotease TNF-alpha-converting enzyme (TACE)-dependent EGFR activation. We also show that EGFR activation by its potent ligand TGF-alpha induces reactivation of EGFR via binding of endogenously produced CCL20 to its receptor CCR6 in NCI-H292 cells but not in normal human bronchial epithelial (NHBE) cells, exaggerating mucin production in the NCI-H292 cells. In NCI-H292 cells, TGF-alpha stimulation induced two phases of EGFR phosphorylation (EGFR-P). The second EGFR P was TACE-dependent and was responsible for most of the total mucin induced by TGF-alpha. Binding of endogenously produced CCL20 to CCR6 increased the second EGFR-P and subsequent mucin production induced by TGF-alpha. In NHBE cells, TGF alpha-induced EGFR activation did not lead to significant CCL20 production or to EGFR rephosphorylation, and less mucin was produced. We conclude that NCI-H292 cells but not NHBE cells produce CCL20 in response to EGFR activation, which leads to a second phase of EGFR-P and subsequent exaggerated mucin production. These findings have potentially important therapeutic implications in obstructive airway diseases. PMID- 21300823 TI - CD2 costimulation reveals defective activity by human CD4+CD25(hi) regulatory cells in patients with multiple sclerosis. AB - Studying the activity of homogeneous regulatory T cell (Treg) populations will advance our understanding of their mechanisms of action and their role in human disease. Although isolating human Tregs exhibiting low expression of CD127 markedly increases purity, the resulting Treg populations are still heterogeneous. To examine the complexity of the Tregs defined by the CD127 phenotype in comparison with the previously described CD4(+)CD25(hi) subpopulations, we subdivided the CD25(hi) population of memory Tregs into subsets based on expression of CD127 and HLA-DR. These subsets exhibited differences in suppressive capacity, ability to secrete IL-10 and IL-17, Foxp3 gene methylation, cellular senescence, and frequency in neonatal and adult blood. The mature, short telomere, effector CD127(lo)HLA-DR(+) cells most strongly suppressed effector T cells within 48 h, whereas the less mature CD127(lo)HLA-DR( ) cells required 96 h to reach full suppressive capacity. In contrast, whereas the CD127(+)HLA-DR(-) cells also suppressed proliferation of effector cells, they could alternate between suppression or secretion of IL-17 depending upon the stimulation signals. When isolated from patients with multiple sclerosis, both the nonmature and the effector subsets of memory CD127(lo) Tregs exhibited kinetically distinct defects in suppression that were evident with CD2 costimulation. These data demonstrate that natural and not induced Tregs are less suppressive in patients with multiple sclerosis. PMID- 21300825 TI - Microenvironment-derived IL-1 and IL-17 interact in the control of lung metastasis. AB - Inflammatory cytokines modulate immune responses in the tumor microenvironment during progression/metastasis. In this study, we have assessed the role of IL-1 and IL-17 in the control of antitumor immunity versus progression in a model of experimental lung metastasis, using 3LL and B16 epithelial tumor cells. The absence of IL-1 signaling or its excess in the lung microenvironment (in IL-1beta and IL-1R antagonist knockout [KO] mice, respectively) resulted in a poor prognosis and reduced T cell activity, compared with WT mice. In IL-1beta KO mice, enhanced T regulatory cell development/function, due to a favorable in situ cytokine network and impairment in APC maturation, resulted in suppressed antitumor immunity, whereas in IL-1R antagonist KO mice, enhanced accumulation and activity of myeloid-derived suppressor cells were found. Reduced tumor progression along with improved T cell function was found in IL-17 KO mice, compared with WT mice. In the microenvironment of lung tumors, IL-1 induces IL-17 through recruitment of gamma/delta T cells and their activation for IL-17 production, with no involvement of Th17 cells. These interactions were specific to the microenvironment of lung tumors, as in intrafootpad tumors in IL-1/IL-17 KO mice, different patterns of invasiveness were observed and no IL-17 could be locally detected. The results highlight the critical and unique role of IL-1, and cytokines induced by it such as IL-17, in determining the balance between inflammation and antitumor immunity in specific tumor microenvironments. Also, we suggest that intervention in IL-1/IL-17 production could be therapeutically used to tilt this balance toward enhanced antitumor immunity. PMID- 21300826 TI - Evaluations of shorter exposures of contact lens cleaning solutions against Fusarium oxysporum species complex and Fusarium solani species complex to simulate inappropriate usage. AB - An outbreak of Fusarium keratitis in contact lens users resulted in withdrawal of ReNu with MoistureLoc solution, although the exact cause of the outbreak remains enigmatic. We evaluated current and discontinued multipurpose cleaning solutions (MPSs; MoistureLoc, Equate, MultiPlus, and OptiFree Express) against plankton- and biofilm-derived cells of Fusarium oxysporum species complex (FOSC) and F. solani species complex (FSSC). The methods included a traditional assay based on CFU counts and a novel flow cytometry (FC) assay based on percent cell subpopulation (PCS) stained with two fluorochromes (Sytox Red and 5 chloromethylfluorescein diacetate). The tests were done with the respective manufacturers' recommended cleaning regimens (240 to 360 min) and under shorter exposures (15 to 60 min) to simulate inappropriate usage by the customers. FC assay measured PCS, which was available rapidly, in 5 to 7 h, whereas 24 to 48 h was needed for CFU counts, and there was good correlation between the two methods (r2=0.97). FC assays allowed identification of injured fungal cells, which are likely to be missed with growth assays. In general, a time- and inoculum dependent survival pattern was seen for both FOSC and FSSC cells, and biofilm derived cells were more resistant than plankton-derived cells. MultiPlus and Equate produced 100% sterilization of fungi even under shorter exposures. However, biofilm FOSC and FSSC cells survived for up to 4 h in MoistureLoc solution and up to 6 h in OptiFree Express solution under shorter exposure times. This finding was enigmatic, as OptiFree Express is not associated with any outbreak of Fusarium keratitis. This study provides additional support for possible roles that improper lens cleaning regimens and fungal biofilms could play as predisposing factors for Fusarium keratitis. PMID- 21300827 TI - Development of tetravalent, bispecific CCR5 antibodies with antiviral activity against CCR5 monoclonal antibody-resistant HIV-1 strains. AB - In this study, we describe novel tetravalent, bispecific antibody derivatives that bind two different epitopes on the HIV coreceptor CCR5. The basic protein formats that we applied were derived from Morrison-type bispecific antibodies: whole IgGs to which we connected single-chain antibodies (scFvs) via (Gly4Ser)n sequences at either the C or N terminus of the light chain or heavy chain. By design optimization, including disulfide stabilization of scFvs or introduction of 30-amino-acid linkers, stable molecules could be obtained in amounts that were within the same range as or no less than 4-fold lower than those observed with monoclonal antibodies in transient expression assays. In contrast to monospecific CCR5 antibodies, bispecific antibody derivatives block two alternative docking sites of CCR5-tropic HIV strains on the CCR5 coreceptor. Consequently, these molecules showed 18- to 57-fold increased antiviral activities compared to the parent antibodies. Most importantly, one prototypic tetravalent CCR5 antibody had antiviral activity against virus strains resistant to the single parental antibodies. In summary, physical linkage of two CCR5 antibodies targeting different epitopes on the HIV coreceptor CCR5 resulted in tetravalent, bispecific antibodies with enhanced antiviral potency against wild-type and CCR5 antibody resistant HIV-1 strains. PMID- 21300828 TI - Anthelmintics are substrates and activators of nematode P glycoprotein. AB - P glycoproteins (Pgp), members of the ABC transporter superfamily, play a major role in chemoresistance. In nematodes, Pgp are responsible for resistance to anthelmintics, suggesting that they are Pgp substrates, as they are in mammalian cells. However, their binding to nematode Pgp and the functional consequences of this interaction have not been investigated. Our study showed that levamisole and most of the macrocyclic lactones (MLs) are Pgp substrates in nematodes. Ivermectin, although a very good substrate in mammalian cells, is poorly transported. In contrast to their inhibitory effect on mammalian Pgp, these drugs had a stimulatory effect on the transport activity of the reference Pgp substrate rhodamine 123 (R123) in the nematode. This may be due to a specific sequence of nematode Pgp, which shares only 44% identity with mammalian Pgp. Other factors, such as the affinity of anthelmintics for Pgp and their concentration in the Pgp microenvironment, could also differ in nematodes, as suggested by the specific relationship observed between the octanol-water partition coefficient (log P) of MLs and R123 efflux. Nevertheless, some similarities were also observed in the functional activities of the mammalian and nematode Pgp. As in mammalian cells, substrates known to bind the H site (Hoechst 33342 and colchicine) activated the R site, resulting in an increased R123 efflux. Our findings thus show that ML anthelmintics, which inhibit Pgp-mediated efflux in mammals, activate transport activity in nematodes and suggest that several substituents in the ML structure are involved in modulating the stimulatory effect. PMID- 21300829 TI - Benzimidazole analogs inhibit human herpesvirus 6. AB - Several benzimidazole nucleoside analogs, including 1H-beta-D-ribofuranosyl-2 bromo-5,6-dichlorobenzimidazole (BDCRB) and 1H-beta-L-ribofuranosyl-2 isopropylamino-5,6-dichlorobenzimidazole (maribavir [MBV]), inhibit the replication of human cytomegalovirus. Neither analog inhibited the related betaherpesvirus human herpesvirus 6 (HHV-6). Additional analogs of these compounds were evaluated against both variants of HHV-6, and two L-analogs of BDCRB had good antiviral activity against HHV-6A, as well as more modest inhibition of HHV-6B replication. PMID- 21300830 TI - Penetration of meropenem into epithelial lining fluid of patients with ventilator associated pneumonia. AB - Antibiotic penetration to the infection site is critical for obtaining a good clinical outcome in patients with ventilator-associated pneumonia (VAP). Surprisingly few studies have quantified the penetration of beta-lactam agents into the lung, as measured by the ratio of area under the concentration-time curve (AUC) in epithelial lining fluid (ELF) to AUC in plasma (AUC(ELF)/AUC(plasma) ratio). These have typically involved noninfected patients. This study examines the penetration and pharmacodynamics of meropenem in the ELF among patients with VAP. Meropenem plasma and ELF concentration-time data were obtained from patients in a multicenter clinical trial. Concentration-time profiles in plasma and ELF were simultaneously modeled using a three-compartment model with zero-order infusion and first-order elimination and transfer (big nonparametric adaptive grid [BigNPAG]). A Monte Carlo simulation was performed to estimate the range of ELF/plasma penetration ratios one would expect to observe in patients with VAP, as measured by the AUC(ELF)/AUC(plasma) ratio. The range of AUC(ELF)/AUC(plasma) penetration ratios predicted by the Monte Carlo simulation was large. The 10th percentile of lung penetration was 3.7%, while the 90th percentile of penetration was 178%. The variability of ELF penetration is such that if relatively high ELF exposure targets are required to attain multilog kill or resistance suppression for bacteria like Pseudomonas aeruginosa, then even receiving the largest licensed dose of meropenem with an optimal prolonged infusion may not result in target attainment for a substantial fraction of the population. PMID- 21300831 TI - Bioactivity and the first transmission electron microscopy immunogold studies of short de novo-designed antimicrobial peptides. AB - In light of the era of microbial drug resistance, the current study aimed to better understand the relationships between sequence, higher-order structure, and mechanism of action for five designed peptides against multidrug-resistant (MDR) pathogens. All peptides studied were 15 residues long, were polycationic, adopted alpha-helical structures within hydrophobic environments (excluding the d-amino acid-substituted peptide MA-d), and contained N-terminal glycine residues, a novel antimicrobial peptide (AMP) design principle. Increasing hydrophobicity enhanced MICs (<=500 MUg/ml to <=7.4 MUg/ml) without significantly increasing hemolytic activity (18% maximum hemolysis at 3,400 MUg/ml). To the best of our knowledge, this is the first study to have successfully adapted and used a transmission electron microscopy (TEM) immunogold method to investigate the mechanism of action of short (~15 residues long) AMPs within bacteria. We propose a "floodgate" mechanism to possibly explain membrane deformation and the relative absence of membrane-associated peptides 10 h into incubation. PMID- 21300832 TI - Distribution of intrinsic plasmid replicase genes and their association with carbapenem-hydrolyzing class D beta-lactamase genes in European clinical isolates of Acinetobacter baumannii. AB - Ninety-six genetically diverse multidrug-resistant clinical isolates of Acinetobacter baumannii from 25 hospitals in 17 European countries were screened by PCR for specific carbapenemase-hydrolyzing class D beta-lactamase (CHDL) genes and by PCR-based replicon typing for the presence of 19 different plasmid replicase (rep) gene homology groups (GRs). Results were confirmed by DNA sequencing where necessary. All 96 isolates contained at least 1 (with a maximum of 4) of the 19 groups of rep genes. Groups detected were GR6 (repAci6; 93 isolates), GR2 (including repAci1 [67 isolates] and repAci2 [3 isolates]), GR16 (repApAB49; 12 isolates), GR12 (p2ABSDF0001; 10 isolates), GR3 (repAci3; 4 isolates), GR4 (repAci4; 3 isolates), GR10 (repAciX; 1 isolate), and GR14 (repp4AYE; 1 isolate). Variations in rep gene content were observed even among epidemiologically related isolates. Genes encoding OXA-58-like CHDLs (22 isolates) were associated with carriage of the repAci1, repAci3, repAci4, and repAciX genes, genes encoding OXA-40-like CHDLs (6 isolates) were associated with repAci2 and p2ABSDF0001, and genes encoding OXA-23-like CHDLs (8 isolates) were associated with repAci1. Most intrinsic Acinetobacter plasmids are non-self transferable, but the almost ubiquitous repAci6 gene was strongly associated with a potential tra locus that could serve as a general system for plasmid mobilization and consequent horizontal transmission of plasmids and their associated antibiotic resistance genes among strains of A. baumannii. PMID- 21300833 TI - The marine sponge-derived polyketide endoperoxide plakortide F acid mediates its antifungal activity by interfering with calcium homeostasis. AB - Plakortide F acid (PFA), a marine-derived polyketide endoperoxide, exhibits strong inhibitory activity against the opportunistic fungal pathogens Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus. In the present study, transcriptional profiling coupled with mutant and biochemical analyses were conducted using the model organism Saccharomyces cerevisiae to investigate the mechanism of action of this compound. PFA elicited a transcriptome response indicative of a Ca(2+) imbalance, affecting the expression of genes known to be responsive to altered cellular calcium levels. Several additional lines of evidence obtained supported a role for Ca(2+) in PFA's activity. First, mutants lacking calcineurin and various Ca(2+) transporters, including pumps (Pmr1 and Pmc1) and channels (Cch1 and Mid1), showed increased sensitivity to PFA. In addition, the calcineurin inhibitors FK506 and cyclosporine strongly enhanced PFA activity in wild-type cells. Furthermore, PFA activated the transcription of a lacZ reporter gene driven by the calcineurin-dependent response element. Finally, elemental analysis indicated a significant increase in intracellular calcium levels in PFA-treated cells. Collectively, our results demonstrate that PFA mediates its antifungal activity by perturbing Ca(2+) homeostasis, thus representing a potentially novel mechanism distinct from that of currently used antifungal agents. PMID- 21300834 TI - Population pharmacokinetics and pharmacodynamics of caspofungin in pediatric patients. AB - We describe the pharmacokinetics (PKs) of caspofungin, an echinocandin antifungal, administered once daily as a 1-hour intravenous infusion in children and adolescents (ages, 3 months to 17 years), based on pooled data from four prospective pediatric studies. Caspofungin dosing was body-surface-area (BSA) based (50 mg/m2 daily after 70 mg/m2 on day 1). The area under the concentration time curve from time zero to 24 h (AUC0-24), the concentration at the end of infusion (1 h after the start of infusion; C1), and the trough concentration (24 h after the start of infusion; C24) were obtained for 32 pediatric patients with invasive candidiasis, 10 with invasive aspergillosis, and 82 in the setting of empirical therapy with fever and neutropenia. Exposures were modestly higher (93 to 134% for C1, 45 to 78% for C24, ~40% for AUC0-24) in pediatric patients than in adults receiving the standard 50-mg daily dose. The potential for covariates (age, gender, weight, race, renal status, serum albumin level, and disease state) to alter PKs was evaluated with a multiple-linear-regression model. Weight and disease state had statistically significant (P<0.05) yet small effects on caspofungin PKs in pediatric patients. Concomitant use of dexamethasone (a cytochrome p450 inducer) was associated with a statistically significant reduction (44%) in C24 in a limited number of patients (n=4). Odds ratios were estimated for the association between log-transformed PKs and treatment outcome or adverse events. No PK parameter or hybrid parameter (AUC/MIC, C1/MIC, and C24/MIC) was significantly correlated with treatment outcome or adverse events in the setting of similar response levels as adults, which suggests that the concentrations examined fall within the therapeutic window for caspofungin in pediatric patients. These results support a 50-mg/m2 daily dosing regimen (after a 70-mg/m2 loading dose) in children ages 3 months to 17 years. PMID- 21300835 TI - Use of pharmacokinetic-pharmacodynamic analyses to optimize therapy with the systemic antifungal micafungin for invasive candidiasis or candidemia. AB - Echinocandins have become a first-line therapy for invasive candidiasis (IC). Using phase 3 trial data for patients with IC, pharmacokinetic-pharmacodynamic (PK-PD) relationships for efficacy for micafungin were examined. Micafungin exposures were estimated using a population pharmacokinetic model, and univariable and multivariable logistic regressions were used to identify factors associated with outcome, including the micafungin area under the concentration time curve (AUC)/MIC ratio. Monte Carlo simulation was used to evaluate the probability of achieving AUC/MIC ratios associated with efficacy. Mycological and clinical success rates for evaluable cases were 89.4 and 90.9, respectively. MIC50s and MIC90s for Candida species inhibition were 0.008 and 0.5 mg/liter, respectively. The median AUC/MIC ratio was 15,511 (range, 41.28 to 98,716). Univariable analyses revealed a significant relationship between the AUC/MIC ratio and mycological response, with the worst response being among patients with lower (<=3,000) AUC/MIC ratios (P=0.005). For patients with Candida parapsilosis, AUC/MIC ratios of >=285 were predictive of a higher mycological response (P=0.11). Multivariable logistic regression demonstrated the AUC/MIC ratio, APACHE II score, and history of corticosteroid use to be significant independent predictors of a favorable response. PK-PD target attainment analyses suggested that 76.7% and 100% of patients would achieve an AUC/MIC ratio of >=3,000 for an MIC of 0.03 mg/liter and an AUC/MIC ratio of >=285 for an MIC of <0.5 mg/liter, respectively. The identification of a lower AUC/MIC ratio target for C. parapsilosis than other Candida species suggests consideration of species specific echinocandin susceptibility breakpoints and values that are lower than those currently approved by regulatory agencies. PMID- 21300836 TI - Vibrio cholerae triggers SOS and mutagenesis in response to a wide range of antibiotics: a route towards multiresistance. AB - Antibiotic resistance development has been linked to the bacterial SOS stress response. In Escherichia coli, fluoroquinolones are known to induce SOS, whereas other antibiotics, such as aminoglycosides, tetracycline, and chloramphenicol, do not. Here we address whether various antibiotics induce SOS in Vibrio cholerae. Reporter green fluorescent protein (GFP) fusions were used to measure the response of SOS-regulated promoters to subinhibitory concentrations of antibiotics. We show that unlike the situation with E. coli, all these antibiotics induce SOS in V. cholerae. PMID- 21300837 TI - Treatment of yellow fever virus with an adenovirus-vectored interferon, DEF201, in a hamster model. AB - Interferon (IFN) is an innate immune response protein that is involved in the antiviral response during viral infection. Treatment of acute viral infections with exogenous interferon may be effective but is generally not feasible for clinical use due to many factors, including cost, stability, and availability. To overcome these limitations, an adenovirus type 5-vectored consensus alpha IFN, termed DEF201, was constructed as a potential way to deliver sustained therapeutic levels of systemic IFN. To demonstrate the efficacy of DEF201 against acute flaviviral disease, various concentrations of the construct were administered as a single intranasal dose prior to virus infection, which resulted in a dose-responsive, protective effect in a hamster model of yellow fever virus (YFV) disease. A DEF201 dose of 5*10(7) PFU/animal administered intranasally just prior to YFV challenge protected 100% of the animals, while a 10-fold lower DEF201 dose exhibited lower, although significant, levels of protection. Virus titers in the liver and serum and levels of serum alanine aminotransferase were all significantly reduced as a result of DEF201 administration at all doses tested. No toxicity, as indicated by weight loss or gross morbidity, was observed in non-YFV-infected animals treated with DEF201. Protection of YFV-infected animals was observed when DEF201 was delivered as early as 7 days prior to virus challenge and as late as 2 days after virus challenge, demonstrating effective prophylaxis and therapy in a hamster model of disease. Overall, it appears that DEF201 is effective in the treatment of YFV in a hamster model. PMID- 21300838 TI - An improved model of the Aspergillus fumigatus CYP51A protein. AB - Azole resistance is an increasing clinical problem for Aspergillus fumigatus, with the majority of published resistance arising from mutations in the azole target gene CYP51A. Previous structural studies of this protein have suffered from a nonorthologous, low-homology template for homology modeling. Here we present a new model based on the human CYP51A orthologue that provides a higher quality model for A. fumigatus CYP51A. PMID- 21300839 TI - Molecular detection of mutations associated with first- and second-line drug resistance compared with conventional drug susceptibility testing of Mycobacterium tuberculosis. AB - The emergence of multi- and extensively drug-resistant tuberculosis is a significant impediment to the control of this disease because treatment becomes more complex and costly. Reliable and timely drug susceptibility testing is critical to ensure that patients receive effective treatment and become noninfectious. Molecular methods can provide accurate and rapid drug susceptibility results. We used DNA sequencing to detect resistance to the first line antituberculosis drugs isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) and the second-line drugs amikacin (AMK), capreomycin (CAP), kanamycin (KAN), ciprofloxacin (CIP), and ofloxacin (OFX). Nine loci were sequenced: rpoB (for resistance to RIF), katG and inhA (INH), pncA (PZA), embB (EMB), gyrA (CIP and OFX), and rrs, eis, and tlyA (KAN, AMK, and CAP). A total of 314 clinical Mycobacterium tuberculosis complex isolates representing a variety of antibiotic resistance patterns, genotypes, and geographical origins were analyzed. The molecular data were compared to the phenotypic data and the accuracy values were calculated. Sensitivity and specificity values for the first line drug loci were 97.1% and 93.6% for rpoB, 85.4% and 100% for katG, 16.5% and 100% for inhA, 90.6% and 100% for katG and inhA together, 84.6% and 85.8% for pncA, and 78.6% and 93.1% for embB. The values for the second-line drugs were also calculated. The size and scope of this study, in numbers of loci and isolates examined, and the phenotypic diversity of those isolates support the use of DNA sequencing to detect drug resistance in the M. tuberculosis complex. Further, the results can be used to design diagnostic tests utilizing other mutation detection technologies. PMID- 21300840 TI - In vitro studies indicate a high resistance potential for the lantibiotic nisin in Staphylococcus aureus and define a genetic basis for nisin resistance. AB - Lantibiotics such as nisin (NIS) are peptide antibiotics that may have a role in the chemotherapy of bacterial infections. A perceived benefit of lantibiotics for clinical use is their low propensity to select resistance, although detailed resistance studies with relevant bacterial pathogens are lacking. Here we examined the development of resistance to NIS in Staphylococcus aureus, establishing that mutants, including small-colony variants, exhibiting substantial (4- to 32-fold) reductions in NIS susceptibility could be selected readily. Comparative genome sequencing of a single NISr mutant exhibiting a 32 fold increase in NIS MIC revealed the presence of only two mutations, leading to the substitutions V229G in the purine operon repressor, PurR, and A208E in an uncharacterized protein encoded by SAOUHSC_02955. Independently selected NISr mutants also harbored mutations in the genes encoding these products. Reintroduction of these mutations into the S. aureus chromosome alone and in combination revealed that SAOUHSC_02955(A208E) made the primary contribution to the resistance phenotype, conferring up to a 16-fold decrease in NIS susceptibility. Bioinformatic analyses suggested that this gene encodes a sensor histidine kinase, leading us to designate it "nisin susceptibility-associated sensor (nsaS)." Doubling-time determinations and mixed-culture competition assays between NISr and NISs strains indicated that NIS resistance had little impact on bacterial fitness, and resistance was stable in the absence of selection. The apparent ease with which S. aureus can develop and maintain NIS resistance in vitro suggests that resistance to NIS and other lantibiotics with similar modes of action would arise in the clinic if these agents are employed as chemotherapeutic drugs. PMID- 21300841 TI - Trioxaquine PA1259 alkylates heme in the blood-feeding parasite Schistosoma mansoni. AB - Trioxaquine PA1259 is an efficient drug on larval- and adult-stage schistosomes, able to alkylate heme inside worms treated with it, leading to the formation of covalent heme-drug adducts. Such a mechanism, similar to one reported for other trioxaquines in Plasmodium, indicates that heme may be a common target of these trioxane-based drugs in different blood-feeding parasites. PMID- 21300842 TI - Carbonylation contributes to SERCA2a activity loss and diastolic dysfunction in a rat model of type 1 diabetes. AB - OBJECTIVE: Approximately 25% of children and adolescents with type 1 diabetes will develop diastolic dysfunction. This defect, which is characterized by an increase in time to cardiac relaxation, results in part from a reduction in the activity of the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a), the ATP driven pump that translocates Ca(2+) from the cytoplasm to the lumen of the sarcoplasmic reticulum. To date, mechanisms responsible for SERCA2a activity loss remain incompletely characterized. RESEARCH DESIGN AND METHODS: The streptozotocin (STZ)-induced murine model of type 1 diabetes, in combination with echocardiography, high-speed video detection, confocal microscopy, ATPase and Ca(2+) uptake assays, Western blots, mass spectrometry, and site-directed mutagenesis, were used to assess whether modification by reactive carbonyl species (RCS) contributes to SERCA2a activity loss. RESULTS: After 6-7 weeks of diabetes, cardiac and myocyte relaxation times were prolonged. Total ventricular SERCA2a protein remained unchanged, but its ability to hydrolyze ATP and transport Ca(2+) was significantly reduced. Western blots and mass spectroscopic analyses revealed carbonyl adducts on select basic residues of SERCA2a. Mutating affected residues to mimic physio-chemical changes induced on them by RCS reduced SERCA2a activity. Preincubating with the RCS, methylglyoxal (MGO) likewise reduced SERCA2a activity. Mutating an impacted residue to chemically inert glutamine did not alter SERCA2a activity, but it blunted MGO's effect. Treating STZ-induced diabetic animals with the RCS scavenger, pyridoxamine, blunted SERCA2a activity loss and minimized diastolic dysfunction. CONCLUSIONS: These data identify carbonylation as a novel mechanism that contributes to SERCA2a activity loss and diastolic dysfunction during type 1 diabetes. PMID- 21300843 TI - Glycosylation failure extends to glycoproteins in gestational diabetes mellitus: evidence from reduced alpha2-6 sialylation and impaired immunomodulatory activities of pregnancy-related glycodelin-A. AB - OBJECTIVE: Gestational diabetes mellitus (GDM) is a common metabolic disorder of pregnancy. Patients with GDM are at risk for high fetal mortality and gestational complications associated with reduced immune tolerance and abnormal carbohydrate metabolism. Glycodelin-A (GdA) is an abundant decidual glycoprotein with glycosylation-dependent immunomodulatory activities. We hypothesized that aberrant carbohydrate metabolism in GDM was associated with changes in glycosylation of GdA, leading to defective immunomodulatory activities. RESEARCH DESIGN AND METHODS: GdA in the amniotic fluid from women with normal (NGdA) and GDM (DGdA) pregnancies was purified by affinity chromatography. Structural analysis of protein glycosylation was preformed by lectin-binding assay and mass spectrometry. Cytotoxicity, cell death, cytokine secretion, and GdA binding of the GdA-treated lymphocytes and natural killer (NK) cells were determined. The sialidase activity in the placental tissue from normal and GDM patients was measured. RESULTS: GDM affected the glycosylation but not the protein core of GdA. Specifically, DGdA had a lower abundance of alpha2-6-sialylated and high mannose glycans and a higher abundance of glycans with Sda (NeuAcalpha2 3[GalNAcbeta1-4]Gal) epitopes compared with NGdA. DGdA had reduced immuosuppressive activities in terms of cytotoxicity on lymphocytes, inhibitory activities on interleukin (IL)-2 secretion by lymphocytes, stimulatory activities on IL-6 secretion by NK cells, and binding to these cells. Desialylation abolished the immunomodulation and binding of NGdA. Placental sialidase activity was increased in GDM patients, which may account for the reduced sialic acid content of DGdA. CONCLUSIONS: Taken together, this study provides the first direct evidence for altered enzymatic glycosylation and impaired bioactivity of GdA in GDM patients. PMID- 21300844 TI - Chronic methylglyoxal infusion by minipump causes pancreatic beta-cell dysfunction and induces type 2 diabetes in Sprague-Dawley rats. AB - OBJECTIVE: The incidence of high dietary carbohydrate-induced type 2 diabetes is increasing worldwide. Methylglyoxal (MG) is a reactive glucose metabolite and a major precursor of advanced glycation end products (AGEs). MG levels are elevated in diabetic patients. We investigated the effects of chronic administration of MG on glucose tolerance and beta-cell insulin secreting mechanism in 12-week-old male Sprague-Dawley rats. RESEARCH DESIGN AND METHODS: MG (60 mg/kg/day) or 0.9% saline was administered by continuous infusion with a minipump for 28 days. We performed glucose and insulin tolerance tests and measured adipose tissue glucose uptake and insulin secretion from isolated pancreatic islets. We also used cultured INS-1E cells, a pancreatic beta-cell line, for molecular studies. Western blotting, quantitative PCR, immunohistochemistry, and transferase mediated dUTP nick-end labeling (TUNEL) assay were performed. RESULTS: In rats treated with MG and MG + l-buthionine sulfoximine (BSO), MG levels were significantly elevated in plasma, pancreas, adipose tissue, and skeletal muscle; fasting plasma glucose was elevated, whereas insulin and glutathione were reduced. These two groups also had impaired glucose tolerance, reduced GLUT-4, phosphoinositide-3-kinase activity, and insulin-stimulated glucose uptake in adipose tissue. In the pancreatic beta-cells, MG and MG + BSO reduced insulin secretion, pancreatic duodenal homeobox-1, MafA, GLUT-2, and glucokinase expression; increased C/EBPbeta, nuclear factor-kappaB, MG-induced AGE, N(epsilon)-carboxymeythyllysine, and receptor for AGEs expression; and caused apoptosis. Alagebrium, an MG scavenger and an AGE-breaking compound, attenuated the effects of MG. CONCLUSIONS: Chronic MG induces biochemical and molecular abnormalities characteristic of type 2 diabetes and is a possible mediator of high carbohydrate-induced type 2 diabetes. PMID- 21300845 TI - Identification of metabolic modifiers that underlie phenotypic variations in energy-balance regulation. AB - OBJECTIVE: Although recent studies have shown that human genomes contain hundreds of loci that exhibit signatures of positive selection, variants that are associated with adaptation in energy-balance regulation remain elusive. We reasoned that the difficulty in identifying such variants could be due to heterogeneity in selection pressure and that an integrative approach that incorporated experiment-based evidence and population genetics-based statistical judgments would be needed to reveal important metabolic modifiers in humans. RESEARCH DESIGN AND METHODS: To identify common metabolic modifiers that underlie phenotypic variation in diabetes-associated or obesity-associated traits in humans, or both, we screened 207 candidate loci for regulatory single nucleotide polymorphisms (SNPs) that exhibited evidence of gene-environmental interactions. RESULTS: Three SNPs (rs3895874, rs3848460, and rs937301) at the 5' gene region of human GIP were identified as prime metabolic-modifier candidates at the enteroinsular axis. Functional studies have shown that GIP promoter reporters carrying derived alleles of these three SNPs (haplotype GIP(-1920A)) have significantly lower transcriptional activities than those with ancestral alleles at corresponding positions (haplotype GIP(-1920G)). Consistently, studies of pregnant women who have undergone a screening test for gestational diabetes have shown that patients with a homozygous GIP(-1920A/A) genotype have significantly lower serum concentrations of glucose-dependent insulinotropic polypeptide (GIP) than those carrying an ancestral GIP(-1920G) haplotype. After controlling for a GIPR variation, we showed that serum glucose concentrations of patients carrying GIP(-1920A/A) homozygotes are significantly higher than that of those carrying an ancestral GIP(-1920G) haplotype (odds ratio 3.53). CONCLUSIONS: Our proof-of concept study indicates that common regulatory GIP variants impart a difference in GIP and glucose metabolism. The study also provides a rare example that identified the common variant-common phenotypic variation pattern based on evidence of moderate gene-environmental interactions. PMID- 21300846 TI - Maximally efficient modeling of DNA sequence motifs at all levels of complexity. AB - Identification of transcription factor binding sites is necessary for deciphering gene regulatory networks. Several new methods provide extensive data about the specificity of transcription factors but most methods for analyzing these data to obtain specificity models are limited in scope by, for example, assuming additive interactions or are inefficient in their exploration of more complex models. This article describes an approach--encoding of DNA sequences as the vertices of a regular simplex--that allows simultaneous direct comparison of simple and complex models, with higher-order parameters fit to the residuals of lower-order models. In addition to providing an efficient assessment of all model parameters, this approach can yield valuable insight into the mechanism of binding by highlighting features that are critical to accurate models. PMID- 21300847 TI - Maria Blasco: Keeping a cap on cancer and aging. Interview by Caitlin Sedwick. PMID- 21300848 TI - Circulating tumor cells: approaches to isolation and characterization. AB - Circulating tumor cells (CTCs) shed from primary and metastatic cancers are admixed with blood components and are thus rare, making their isolation and characterization a major technological challenge. CTCs hold the key to understanding the biology of metastasis and provide a biomarker to noninvasively measure the evolution of tumor genotypes during treatment and disease progression. Improvements in technologies to yield purer CTC populations amenable to better cellular and molecular characterization will enable a broad range of clinical applications, including early detection of disease and the discovery of biomarkers to predict treatment responses and disease progression. PMID- 21300849 TI - Clustering heterochromatin: Sir3 promotes telomere clustering independently of silencing in yeast. AB - A general feature of the nucleus is the organization of repetitive deoxyribonucleic acid sequences in clusters concentrating silencing factors. In budding yeast, we investigated how telomeres cluster in perinuclear foci associated with the silencing complex Sir2-Sir3-Sir4 and found that Sir3 is limiting for telomere clustering. Sir3 overexpression triggers the grouping of telomeric foci into larger foci that relocalize to the nuclear interior and correlate with more stable silencing in subtelomeric regions. Furthermore, we show that Sir3's ability to mediate telomere clustering can be separated from its role in silencing. Indeed, nonacetylable Sir3, which is unable to spread into subtelomeric regions, can mediate telomere clustering independently of Sir2-Sir4 as long as it is targeted to telomeres by the Rap1 protein. Thus, arrays of Sir3 binding sites at telomeres appeared as the sole requirement to promote trans interactions between telomeres. We propose that similar mechanisms involving proteins able to oligomerize account for long-range interactions that impact genomic functions in many organisms. PMID- 21300850 TI - Barth syndrome mutations that cause tafazzin complex lability. AB - Deficits in mitochondrial function result in many human diseases. The X-linked disease Barth syndrome (BTHS) is caused by mutations in the tafazzin gene TAZ1. Its product, Taz1p, participates in the metabolism of cardiolipin, the signature phospholipid of mitochondria. In this paper, a yeast BTHS mutant tafazzin panel is established, and 18 of the 21 tested BTHS missense mutations cannot functionally replace endogenous tafazzin. Four BTHS mutant tafazzins expressed at low levels are degraded by the intermembrane space AAA (i-AAA) protease, suggesting misfolding of the mutant polypeptides. Paradoxically, each of these mutant tafazzins assembles in normal protein complexes. Furthermore, in the absence of the i-AAA protease, increased expression and assembly of two of the BTHS mutants improve their function. However, the BTHS mutant complexes are extremely unstable and accumulate as insoluble aggregates when disassembled in the absence of the i-AAA protease. Thus, the loss of function for these BTHS mutants results from the inherent instability of the mutant tafazzin complexes. PMID- 21300851 TI - Full characterization of GPCR monomer-dimer dynamic equilibrium by single molecule imaging. AB - Receptor dimerization is important for many signaling pathways. However, the monomer-dimer equilibrium has never been fully characterized for any receptor with a 2D equilibrium constant as well as association/dissociation rate constants (termed super-quantification). Here, we determined the dynamic equilibrium for the N-formyl peptide receptor (FPR), a chemoattractant G protein-coupled receptor (GPCR), in live cells at 37 degrees C by developing a single fluorescent-molecule imaging method. Both before and after liganding, the dimer-monomer 2D equilibrium is unchanged, giving an equilibrium constant of 3.6 copies/um(2), with a dissociation and 2D association rate constant of 11.0 s(-1) and 3.1 copies/um(2)s(-1), respectively. At physiological expression levels of ~2.1 receptor copies/um(2) (~6,000 copies/cell), monomers continually convert into dimers every 150 ms, dimers dissociate into monomers in 91 ms, and at any moment, 2,500 and 3,500 receptor molecules participate in transient dimers and monomers, respectively. Not only do FPR dimers fall apart rapidly, but FPR monomers also convert into dimers very quickly. PMID- 21300852 TI - Modeling spinal muscular atrophy in Drosophila links Smn to FGF signaling. AB - Spinal muscular atrophy (SMA), a devastating neurodegenerative disorder characterized by motor neuron loss and muscle atrophy, has been linked to mutations in the Survival Motor Neuron (SMN) gene. Based on an SMA model we developed in Drosophila, which displays features that are analogous to the human pathology and vertebrate SMA models, we functionally linked the fibroblast growth factor (FGF) signaling pathway to the Drosophila homologue of SMN, Smn. Here, we characterize this relationship and demonstrate that Smn activity regulates the expression of FGF signaling components and thus FGF signaling. Furthermore, we show that alterations in FGF signaling activity are able to modify the neuromuscular junction defects caused by loss of Smn function and that muscle specific activation of FGF is sufficient to rescue Smn-associated abnormalities. PMID- 21300853 TI - Cell behaviors regulated by guidance cues in collective migration of border cells. AB - Border cells perform a collective, invasive, and directed migration during Drosophila melanogaster oogenesis. Two receptor tyrosine kinases (RTKs), the platelet-derived growth factor/vascular endothelial growth factor-related receptor (PVR) and the epidermal growth factor receptor (EGFR), are important for reading guidance cues, but how these cues steer migration is not well understood. During collective migration, front, back, and side extensions dynamically project from individual cells within the group. We find that guidance input from both RTKs affects the presence and size of these extensions, primarily by favoring the persistence of front extensions. Guidance cues also control the productivity of extensions, specifically rendering back extensions nonproductive. Early and late phases of border cell migration differ in efficiency of forward cluster movement, although motility of individual cells appears constant. This is caused by differences in behavioral effects of the RTKs: PVR dominantly induces large persistent front extensions and efficient streamlined group movement, whereas EGFR does not. Thus, guidance receptors steer movement of this cell group by differentially affecting multiple migration-related features. PMID- 21300854 TI - Physical activity, television viewing time, and retinal microvascular caliber: the multi-ethnic study of atherosclerosis. AB - Physical activities and sedentary behaviors are 2 broad classes of behavior that may be clearly distinguished from each other and have different patterns of determinants. The authors examined the associations of physical activity and television viewing time with retinal vascular caliber among US adults (n = 5,893) from 4 racial/ethnic groups in the Multi-Ethnic Study of Atherosclerosis (2002 2004) that included non-Hispanic whites, blacks, Hispanics, and Chinese. Physical activity and television viewing time were assessed by using a questionnaire, and vascular calibers (arteriolar and venular) were measured from digital retinal photographs. Those in the lowest quartile of physical activity had wider retinal venular caliber compared with those in the highest quartile in multivariate models adjusted for demographic, cardiovascular, behavioral, and inflammatory risk factors. This was noted in non-Hispanic whites and Hispanics but not in blacks or Chinese. For television viewing time, non-Hispanic whites (but not the other racial/ethnic groups) who were in the highest quartile of television viewing time had wider retinal venular caliber compared with those in the lowest quartile. No associations were noted with arteriolar caliber. Lower levels of physical activity (among non-Hispanic whites and Hispanics) and higher levels of television viewing time (among whites) are associated with wider retinal venules. PMID- 21300855 TI - Cross-national comparisons of time trends in overweight inequality by socioeconomic status among women using repeated cross-sectional surveys from 37 developing countries, 1989-2007. AB - Chronic diseases are now among the leading causes of morbidity and mortality in lower income countries. Although traditionally related to higher individual socioeconomic status (SES) in these contexts, the associations between SES and chronic disease may be actively changing. Furthermore, country-level contextual factors, such as economic development and income inequality, may influence the distribution of chronic disease by SES as well as how this distribution has changed over time. Using overweight status as a health indicator, the authors studied repeated cross-sectional data from women aged 18-49 years in 37 developing countries to assess within-country trends in overweight inequalities by SES between 1989 and 2007 (n=405,550). Meta-regression was used to examine the associations between gross domestic product and disproportionate increases in overweight prevalence by SES, with additional testing for modification by country level income inequality. In 27 of 37 countries, higher SES (vs. lower) was associated with higher gains in overweight prevalence; in the remaining 10 countries, lower SES (vs. higher) was associated with higher gains in overweight prevalence. Gross domestic product was positively related to faster increase in overweight prevalence among the lower wealth groups. Among countries with a higher gross domestic product, lower income inequality was associated with faster overweight growth among the poor. PMID- 21300856 TI - Re: "Improvement of risk prediction by genomic profiling: reclassification measures versus the area under the receiver operating characteristic curve". PMID- 21300857 TI - Re: "Risk of incident cardiovascular disease among users of smokeless tobacco in the Atherosclerosis Risk in Communities (ARIC) Study". PMID- 21300858 TI - Findings and recommendations from the interim evaluation of the Bright Futures for Women's Health and Wellness Physical Activity and Healthy Eating tools. AB - The Bright Futures for Women's Health and Wellness Initiative (BFWHW) Physical Activity and Healthy Eating tools encourage patient-provider discussion in the primary care setting, and promote patient self-management, goal setting, and behavior change. An interim evaluation of the BFWHW tools with 274 female adult patients, 18 providers, and 4 site administrators was conducted at 4 health care sites in the United States. Results suggest that patients, particularly overweight women, were interested in discussing healthy eating and physical activity with their provider during the health care visit and that the tools were helpful for goal setting. Nearly three quarters of providers reported that the materials strengthened their discussion of healthy eating with patients; 67% reported an enhanced conversation about physical activity. Site administrators reported several common themes, including the need for flexibility to adopt new routines and using a patient self-management approach. Barriers to implementation included lack of time in the clinical visit and lack of reimbursement. Recommendations for new approaches to address multiple structural, financial, and literacy barriers in order to facilitate the integration of gender-specific health promotion materials into primary care settings are discussed. PMID- 21300859 TI - RETRACTED: Ascending aortic diameter and curvature are prognostic for aortic complications after complete supra-aortic vessel transposition and arch endografting: [Interact CardioVasc Thorac Surg 2011 Published on February 7, 2011]. PMID- 21300860 TI - Skint-1 is a highly specific, unique selecting component for epidermal T cells. AB - alphabeta T-cell repertoire selection is mediated by peptide-MHC complexes presented by thymic epithelial or myeloid cells, and by lipid-CD1 complexes expressed by thymocytes. gammadelta T-cell repertoire selection, by contrast, is largely unresolved. Mice mutant for Skint-1, a unique Ig superfamily gene, do not develop canonical Vgamma5Vdelta1(+) dendritic epidermal T cells. This study shows that transgenic Skint-1, across a broad range of expression levels, precisely and selectively determines the Vgamma5Vdelta1(+) dendritic epidermal T-cell compartment. Skint-1 is expressed by medullary thymic epithelial cells, and unlike lipid-CD1 complexes, must be expressed by stromal cells to function efficiently. Its unusual transmembrane-cytoplasmic regions severely limit cell surface expression, yet increasing this or, conversely, retaining Skint1 intracellularly markedly compromises function. Each Skint1 domain appears nonredundant, including a unique decamer specifying IgV-domain processing. This investigation of Skint-1 biology points to complex events underpinning the positive selection of an intraepithelial gammadelta repertoire. PMID- 21300861 TI - Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria. AB - Ozonide OZ439 is a synthetic peroxide antimalarial drug candidate designed to provide a single-dose oral cure in humans. OZ439 has successfully completed Phase I clinical trials, where it was shown to be safe at doses up to 1,600 mg and is currently undergoing Phase IIa trials in malaria patients. Herein, we describe the discovery of OZ439 and the exceptional antimalarial and pharmacokinetic properties that led to its selection as a clinical drug development candidate. In vitro, OZ439 is fast-acting against all asexual erythrocytic Plasmodium falciparum stages with IC(50) values comparable to those for the clinically used artemisinin derivatives. Unlike all other synthetic peroxides and semisynthetic artemisinin derivatives, OZ439 completely cures Plasmodium berghei-infected mice with a single oral dose of 20 mg/kg and exhibits prophylactic activity superior to that of the benchmark chemoprophylactic agent, mefloquine. Compared with other peroxide-containing antimalarial agents, such as the artemisinin derivatives and the first-generation ozonide OZ277, OZ439 exhibits a substantial increase in the pharmacokinetic half-life and blood concentration versus time profile in three preclinical species. The outstanding efficacy and prolonged blood concentrations of OZ439 are the result of a design strategy that stabilizes the intrinsically unstable pharmacophoric peroxide bond, thereby reducing clearance yet maintaining the necessary Fe(II)-reactivity to elicit parasite death. PMID- 21300862 TI - Cocaine dynamically regulates heterochromatin and repetitive element unsilencing in nucleus accumbens. AB - Repeated cocaine exposure induces persistent alterations in genome-wide transcriptional regulatory networks, chromatin remodeling activity and, ultimately, gene expression profiles in the brain's reward circuitry. Virtually all previous investigations have centered on drug-mediated effects occurring throughout active euchromatic regions of the genome, with very little known concerning the impact of cocaine exposure on the regulation and maintenance of heterochromatin in adult brain. Here, we report that cocaine dramatically and dynamically alters heterochromatic histone H3 lysine 9 trimethylation (H3K9me3) in the nucleus accumbens (NAc), a key brain reward region. Furthermore, we demonstrate that repeated cocaine exposure causes persistent decreases in heterochromatization in this brain region, suggesting a potential role for heterochromatic regulation in the long-term actions of cocaine. To identify precise genomic loci affected by these alterations, chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-Seq) was performed on NAc. ChIP-Seq analyses confirmed the existence of the H3K9me3 mark mainly within intergenic regions of the genome and identified specific patterns of cocaine induced H3K9me3 regulation at repetitive genomic sequences. Cocaine-mediated decreases in H3K9me3 enrichment at specific genomic repeats [e.g., long interspersed nuclear element (LINE)-1 repeats] were further confirmed by the increased expression of LINE-1 retrotransposon-associated repetitive elements in NAc. Such increases likely reflect global patterns of genomic destabilization in this brain region after repeated cocaine administration and open the door for future investigations into the epigenetic and genetic basis of drug addiction. PMID- 21300863 TI - Testosterone administration impairs cognitive empathy in women depending on second-to-fourth digit ratio. AB - During social interactions we automatically infer motives, intentions, and feelings from bodily cues of others, especially from the eye region of their faces. This cognitive empathic ability is one of the most important components of social intelligence, and is essential for effective social interaction. Females on average outperform males in this cognitive empathy, and the male sex hormone testosterone is thought to be involved. Testosterone may not only down-regulate social intelligence organizationally, by affecting fetal brain development, but also activationally, by its current effects on the brain. Here, we show that administration of testosterone in 16 young women led to a significant impairment in their cognitive empathy, and that this effect is powerfully predicted by a proxy of fetal testosterone: the right-hand second digit-to-fourth digit ratio. Our data thus not only demonstrate down-regulatory effects of current testosterone on cognitive empathy, but also suggest these are preprogrammed by the very same hormone prenatally. These findings have importance for our understanding of the psychobiology of human social intelligence. PMID- 21300864 TI - The significance of self-control. PMID- 21300865 TI - Brief predator sound exposure elicits behavioral and neuronal long-term sensitization in the olfactory system of an insect. AB - Modulation of sensitivity to sensory cues by experience is essential for animals to adapt to a changing environment. Sensitization and adaptation to signals of the same modality as a function of experience have been shown in many cases, and some of the neurobiological mechanisms underlying these processes have been described. However, the influence of sensory signals on the sensitivity of a different modality is largely unknown. In males of the noctuid moth, Spodoptera littoralis, the sensitivity to the female-produced sex pheromone increases 24 h after a brief preexposure with pheromone at the behavioral and central nervous level. Here we show that this effect is not confined to the same sensory modality: the sensitivity of olfactory neurons can also be modulated by exposure to a different sensory stimulus, i.e., a pulsed stimulus mimicking echolocating sounds from attacking insectivorous bats. We tested responses of preexposed male moths in a walking bioassay and recorded from neurons in the primary olfactory center, the antennal lobe. We show that brief exposure to a bat call, but not to a behaviorally irrelevant tone, increases the behavioral sensitivity of male moths to sex pheromone 24 h later in the same way as exposure to the sex pheromone itself. The observed behavioral modification is accompanied by an increase in the sensitivity of olfactory neurons in the antennal lobe. Our data provide thus evidence for cross-modal experience-dependent plasticity not only on the behavioral level, but also on the central nervous level, in an insect. PMID- 21300866 TI - Model for the regulation of Arabidopsis thaliana leaf margin development. AB - Biological shapes are often produced by the iterative generation of repeated units. The mechanistic basis of such iteration is an area of intense investigation. Leaf development in the model plant Arabidopsis is one such example where the repeated generation of leaf margin protrusions, termed serrations, is a key feature of final shape. However, the regulatory logic underlying this process is unclear. Here, we use a combination of developmental genetics and computational modeling to show that serration development is the morphological read-out of a spatially distributed regulatory mechanism, which creates interspersed activity peaks of the growth-promoting hormone auxin and the cup-shaped cotyledon2 (CUC2) transcription factor. This mechanism operates at the growing leaf margin via a regulatory module consisting of two feedback loops working in concert. The first loop relates the transport of auxin to its own distribution, via polar membrane localization of the pinformed1 (PIN1) efflux transporter. This loop captures the potential of auxin to generate self organizing patterns in diverse developmental contexts. In the second loop, CUC2 promotes the generation of PIN1-dependent auxin activity maxima while auxin represses CUC2 expression. This CUC2-dependent loop regulates activity of the conserved auxin efflux module in leaf margins to generate stable serration patterns. Conceptualizing leaf margin development via this mechanism also helps to explain how other developmental regulators influence leaf shape. PMID- 21300867 TI - Proper formation of whisker barrelettes requires periphery-derived Smad4 dependent TGF-beta signaling. AB - Mammalian somatosensory topographic maps contain specialized neuronal structures that precisely recapitulate the spatial pattern of peripheral sensory organs. In the mouse, whiskers are orderly mapped onto several brainstem nuclei as a set of modular structures termed barrelettes. Using a dual-color iontophoretic labeling strategy, we found that the precise topography of barrelettes is not a result of ordered positions of sensory neurons within the ganglion. We next explored another possibility that formation of the whisker map is influenced by periphery derived mechanisms. During the period of peripheral sensory innervation, several TGF-beta ligands are exclusively expressed in whisker follicles in a dynamic spatiotemporal pattern. Disrupting TGF-beta signaling, specifically in sensory neurons by conditional deletion of Smad4 at the late embryonic stage, results in the formation of abnormal barrelettes in the principalis and interpolaris brainstem nuclei and a complete absence of barrelettes in the caudalis nucleus. We further show that this phenotype is not derived from defective peripheral innervation or central axon outgrowth but is attributable to the misprojection and deficient segregation of trigeminal axonal collaterals into proper barrelettes. Furthermore, Smad4-deficient neurons develop simpler terminal arbors and form fewer synapses. Together, our findings substantiate the involvement of whisker-derived TGF-beta/Smad4 signaling in the formation of the whisker somatotopic maps. PMID- 21300868 TI - QnAs with Vern L. Schramm. Interview by Prashant Nair. PMID- 21300869 TI - Early onset of neural synchronization in the contextual associations network. AB - Objects are more easily recognized in their typical context. However, is contextual information activated early enough to facilitate the perception of individual objects, or is contextual facilitation caused by postperceptual mechanisms? To elucidate this issue, we first need to study the temporal dynamics and neural interactions associated with contextual processing. Studies have shown that the contextual network consists of the parahippocampal, retrosplenial, and medial prefrontal cortices. We used functional MRI, magnetoencephalography, and phase synchrony analyses to compare the neural response to stimuli with strong or weak contextual associations. The context network was activated in functional MRI and preferentially synchronized in magnetoencephalography (MEG) for stimuli with strong contextual associations. Phase synchrony increased early (150-250 ms) only when it involved the parahippocampal cortex, whereas retrosplenial-medial prefrontal cortices synchrony was enhanced later (300-400 ms). These results describe the neural dynamics of context processing and suggest that context is activated early during object perception. PMID- 21300870 TI - An adhesion protein of Salmonella enterica serovar Typhi is required for pathogenesis and potential target for vaccine development. AB - More than half of all Salmonella enterica serovar Typhi genes still remain unannotated. Although pathogenesis of S. Typhi is incompletely understood, treatment of typhoid fever is complicated by the emergence of drug resistance. Effectiveness of the currently available vaccines is also limited. In search of novel virulence proteins, we have identified several putative adhesins of S. Typhi through computational approaches. Our experiment shows that a 27-kDa outer membrane protein (T2544) plays a major role in bacterial adhesion to the host through high-affinity binding to laminin. Its role in bacterial pathogenesis is underscored by reduced systemic invasion and a 10-fold higher LD(50) of the mutant bacteria in mice. T2544 is strongly immunogenic as revealed by the detection of sustained high titers of serum IgG and intestinal secretory IgA in the immunized mice. In vitro, T2544 antiserum enhanced uptake and clearance of Salmonella by macrophages and augmented complement-mediated lysis, indicating a contribution of T2544-specific antibodies to the killing process. This correlates well with the observed protection of mice immunized with recombinant T2544 or passively immunized with T2544 antiserum against subsequent bacterial challenge, suggesting that T2544-specific antibodies are involved in protection. The present study describes an adhesion protein of S. Typhi that contributes to bacterial pathogenesis. Protective antibodies in mice, rapid seroconversion of naturally infected individuals with increasing titers of anti-T2544 IgG from acute to convalescent sera suggesting antibody response in humans, and wide distribution and conservation of the cell-surface adhesin in the clinical isolates of different Salmonella serovars make T2544 a potential vaccine candidate. PMID- 21300871 TI - Corepressor SMRT promotes oxidative phosphorylation in adipose tissue and protects against diet-induced obesity and insulin resistance. AB - The ligand-dependent competing actions of nuclear receptor (NR)-associated transcriptional corepressor and coactivator complexes allow for the precise regulation of NR-dependent gene expression in response to both temporal and environmental cues. Here we report the mouse model termed silencing mediator of retinoid and thyroid hormone receptors (SMRT)(mRID1) in which targeted disruption of the first receptor interaction domain (RID) of the nuclear corepressor SMRT disrupts interactions with a subset of NRs and leads to diet-induced superobesity associated with a depressed respiratory exchange ratio, decreased ambulatory activity, and insulin resistance. Although apparently normal when chow fed, SMRT(mRID1) mice develop multiple metabolic dysfunctions when challenged by a high-fat diet, manifested by marked lipid accumulation in white and brown adipose tissue and the liver. The increased weight gain of SMRT(mRID1) mice on a high-fat diet occurs predominantly in fat with adipocyte hypertrophy evident in both visceral and s.c. depots. Importantly, increased inflammatory gene expression was detected only in the visceral depots. SMRT(mRID1) mice are both insulin insensitive and refractory to the glucose-lowering effects of TZD and AICAR. Increased serum cholesterol and triglyceride levels were observed, accompanied by increased leptin and decreased adiponectin levels. Aberrant storage of lipids in the liver occurred as triglycerides and cholesterol significantly compromised hepatic function. Lipid accumulation in brown adipose tissue was associated with reduced thermogenic capacity and mitochondrial biogenesis. Collectively, these studies highlight the essential role of NR corepressors in maintaining metabolic homeostasis and describe an essential role for SMRT in regulating the progression, severity, and therapeutic outcome of metabolic diseases. PMID- 21300872 TI - Transcript origin analysis identifies antigen-presenting cells as primary targets of socially regulated gene expression in leukocytes. AB - To clarify the biological rationale for social regulation of gene expression, this study sought to identify the specific immune cell types that are transcriptionally sensitive to subjective social isolation (loneliness). Using reference distributions for the expression of each human gene in each major leukocyte subtype, we mapped the cellular origin of transcripts found to be differentially expressed in the circulating immune cells from chronically lonely individuals. Loneliness-associated genes derived primarily from plasmacytoid dendritic cells, monocytes, and, to a lesser extent, B lymphocytes. Those dynamics reflected per-cell changes in the expression of inducible genes and related more strongly to the subjective experience of loneliness than to objective social network size. Evolutionarily ancient myeloid antigen-presenting cells appear to have evolved a transcriptional sensitivity to socioenvironmental conditions that may allow them to shift basal gene expression profiles to counter the changing microbial threats associated with hostile vs. affine social conditions. PMID- 21300873 TI - MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer. AB - The efficacy of computed tomography (CT) screening for early lung cancer detection in heavy smokers is currently being tested by a number of randomized trials. Critical issues remain the frequency of unnecessary treatments and impact on mortality, indicating the need for biomarkers of aggressive disease. We explored microRNA (miRNA) expression profiles of lung tumors, normal lung tissues and plasma samples from cases with variable prognosis identified in a completed spiral-CT screening trial with extensive follow-up. miRNA expression patterns significantly distinguished: (i) tumors from normal lung tissues, (ii) tumor histology and growth rate, (iii) clinical outcome, and (iv) year of lung cancer CT detection. Interestingly, miRNA profiles in normal lung tissues also displayed remarkable associations with clinical features, suggesting the influence of a permissive microenvironment for tumor development. miRNA expression analyses in plasma samples collected 1-2 y before the onset of disease, at the time of CT detection and in disease-free smokers enrolled in the screening trial, resulted in the generation of miRNA signatures with strong predictive, diagnostic, and prognostic potential (area under the ROC curve >= 0.85). These signatures were validated in an independent cohort from a second randomized spiral-CT trial. These results indicate a role for miRNAs in lung tissues and plasma as molecular predictors of lung cancer development and aggressiveness and have theoretical and clinical implication for lung cancer management. PMID- 21300874 TI - Responses to the Assurance game in monkeys, apes, and humans using equivalent procedures. AB - There is great interest in the evolution of economic behavior. In typical studies, species are asked to play one of a series of economic games, derived from game theory, and their responses are compared. The advantage of this approach is the relative level of consistency and control that emerges from the games themselves; however, in the typical experiment, procedures and conditions differ widely, particularly between humans and other species. Thus, in the current study, we investigated how three primate species, capuchin monkeys, chimpanzees, and humans, played the Assurance (or Stag Hunt) game using procedures that were, to the best of our ability, the same across species, particularly with respect to training and pretesting. Our goal was to determine what, if any, differences existed in the ways in which these species made decisions in this game. We hypothesized differences along phylogenetic lines, which we found. However, the species were more similar than might be expected. In particular, humans who played using "nonhuman primate-friendly" rules did not behave as is typical. Thus, we find evidence for similarity in decision-making processes across the order Primates. These results indicate that such comparative studies are possible and, moreover, that in any comparison rating species' relative abilities, extreme care must be taken in ensuring that one species does not have an advantage over the others due to methodological procedures. PMID- 21300875 TI - Paternal MHC expression on mouse trophoblast affects uterine vascularization and fetal growth. AB - The mammalian fetus represents a semiallograft within the maternal uterus yet is not rejected. This situation is particularly pronounced in species with a hemochorial type of placentation, such as humans and rodents, where maternal tissues and blood are in direct contact with fetal trophoblast and thus potentially with paternal antigens. The main polymorphic antigens responsible for graft rejection are MHC antigens. In humans the trophoblast cells invading into the decidua have a unique pattern of MHC class I expression characterized by both classical (HLA-C) and nonclassical (HLA-G and HLA-E) molecules. Whether such an unusual MHC repertoire on the surface of trophoblast is a conserved feature between species with hemochorial placentation has not been resolved. Here we demonstrate, using a range of methods, that C57BL/6 mouse trophoblast predominantly expresses only one MHC class I antigen, H2-K, at the cell surface of giant cells but lacks expression of nonclassical MHC molecules. Antigenic disparity between parental MHCs affects trophoblast-induced transformation of the uterine vasculature and, consequently, placental and fetal gowth. Maternal uterine blood vessels were more dilated, allowing for increased blood supply, in certain combinations of maternal and paternal MHC haplotypes, and these allogeneic fetuses and placentas were heavier at term compared with syngeneic controls. Thus, maternal-fetal immune interactions are instrumental to optimize reproductive success. This cross-talk has important implications for human disorders of pregnancy, such as preeclampsia and fetal growth restriction. PMID- 21300876 TI - ORAI1-mediated calcium influx is required for human cytotoxic lymphocyte degranulation and target cell lysis. AB - Lymphocytes mediate cytotoxicity by polarized release of the contents of cytotoxic granules toward their target cells. Here, we have studied the role of the calcium release-activated calcium channel ORAI1 in human lymphocyte cytotoxicity. Natural killer (NK) cells obtained from an ORAI1-deficient patient displayed defective store-operated Ca(2+) entry (SOCE) and severely defective cytotoxic granule exocytosis leading to impaired target cell lysis. Similar findings were obtained using NK cells from a stromal interaction molecule 1 deficient patient. The defect occurred at a late stage of the signaling process, because activation of leukocyte functional antigen (LFA)-1 and cytotoxic granule polarization were not impaired. Moreover, pharmacological inhibition of SOCE interfered with degranulation and target cell lysis by freshly isolated NK cells and CD8(+) effector T cells from healthy donors. In addition to effects on lymphocyte cytotoxicity, synthesis of the chemokine macrophage inflammatory protein-1beta and the cytokines TNF-alpha and IFN-gamma on target cell recognition was impaired in ORAI1-deficient NK cells, as previously described for T cells. By contrast, NK cell cytokine production induced by combinations of IL 12, IL-15, and IL-18 was not impaired by ORAI1 deficiency. Taken together, these results identify a critical role for ORAI1-mediated Ca(2+) influx in granule exocytosis for lymphocyte cytotoxicity as well as for cytokine production induced by target cell recognition. PMID- 21300877 TI - Self-organization is a dynamic and lineage-intrinsic property of mammary epithelial cells. AB - Loss of organization is a principle feature of cancers; therefore it is important to understand how normal adult multilineage tissues, such as bilayered secretory epithelia, establish and maintain their architectures. The self-organization process that drives heterogeneous mixtures of cells to form organized tissues is well studied in embryology and with mammalian cell lines that were abnormal or engineered. Here we used a micropatterning approach that confined cells to a cylindrical geometry combined with an algorithm to quantify changes of cellular distribution over time to measure the ability of different cell types to self organize relative to each other. Using normal human mammary epithelial cells enriched into pools of the two principal lineages, luminal and myoepithelial cells, we demonstrated that bilayered organization in mammary epithelium was driven mainly by lineage-specific differential E-cadherin expression, but that P cadherin contributed specifically to organization of the myoepithelial layer. Disruption of the actomyosin network or of adherens junction proteins resulted in either prevention of bilayer formation or loss of preformed bilayers, consistent with continual sampling of the local microenvironment by cadherins. Together these data show that self-organization is an innate and reversible property of communities of normal adult human mammary epithelial cells. PMID- 21300879 TI - Fructose sensitivity is suppressed in Arabidopsis by the transcription factor ANAC089 lacking the membrane-bound domain. AB - In living organisms sugars not only provide energy and carbon skeletons but also act as evolutionarily conserved signaling molecules. The three major soluble sugars in plants are sucrose, glucose, and fructose. Information on plant glucose and sucrose signaling is available, but to date no fructose-specific signaling pathway has been reported. In this study, sugar repression of seedling development was used to study fructose sensitivity in the Landsberg erecta (Ler)/Cape Verde Islands (Cvi) recombinant inbred line population, and eight fructose-sensing quantitative trait loci (QTLs) (FSQ1-8) were mapped. Among them, FSQ6 was confirmed to be a fructose-specific QTL by analyzing near-isogenic lines in which Cvi genomic fragments were introgressed in the Ler background. These results indicate the existence of a fructose-specific signaling pathway in Arabidopsis. Further analysis demonstrated that the FSQ6-associated fructose signaling pathway functions independently of the hexokinase1 (HXK1) glucose sensor. Remarkably, fructose-specific FSQ6 downstream signaling interacts with abscisic acid (ABA)- and ethylene-signaling pathways, similar to HXK1-dependent glucose signaling. The Cvi allele of FSQ6 acts as a suppressor of fructose signaling. The FSQ6 gene was identified using map-based cloning approach, and FSQ6 was shown to encode the transcription factor gene Arabidopsis NAC (petunia No apical meristem and Arabidopsis transcription activation factor 1, 2 and Cup shaped cotyledon 2) domain containing protein 89 (ANAC089). The Cvi allele of FSQ6/ANAC089 is a gain-of-function allele caused by a premature stop in the third exon of the gene. The truncated Cvi FSQ6/ANAC089 protein lacks a membrane association domain that is present in ANAC089 proteins from other Arabidopsis accessions. As a result, Cvi FSQ6/ANAC089 is constitutively active as a transcription factor in the nucleus. PMID- 21300878 TI - Analysis of cellular and behavioral responses to imiquimod reveals a unique itch pathway in transient receptor potential vanilloid 1 (TRPV1)-expressing neurons. AB - Despite its clinical importance, the mechanisms that mediate or generate itch are poorly defined. The identification of pruritic compounds offers insight into understanding the molecular and cellular basis of itch. Imiquimod (IQ) is an agonist of Toll-like receptor 7 (TLR7) used to treat various infectious skin diseases such as genital warts, keratosis, and basal cell carcinoma. Itch is reportedly one of the major side effects developed during IQ treatments. We found that IQ acts as a potent itch-evoking compound (pruritogen) in mice via direct excitation of sensory neurons. Combined studies of scratching behavior, patch clamp recording, and Ca(2+) response revealed the existence of a unique intracellular mechanism, which is independent of TLR7 as well as different from the mechanisms exploited by other well-characterized pruritogens. Nevertheless, as for other pruritogens, IQ requires the presence of transient receptor potential vanilloid 1 (TRPV1)-expressing neurons for itch-associated responses. Our data provide evidence supporting the hypothesis that there is a specific subset of TRPV1-expressing neurons that is equipped with diverse intracellular mechanisms that respond to histamine, chloroquine, and IQ. PMID- 21300881 TI - Geminin promotes neural fate acquisition of embryonic stem cells by maintaining chromatin in an accessible and hyperacetylated state. AB - Formation of the complex vertebrate nervous system begins when pluripotent cells of the early embryo are directed to acquire a neural fate. Although cell intrinsic controls play an important role in this process, the molecular nature of this regulation is not well defined. Here we assessed the role for Geminin, a nuclear protein expressed in embryonic cells, during neural fate acquisition from mouse embryonic stem (ES) cells. Whereas Geminin knockdown does not affect the ability of ES cells to maintain or exit pluripotency, we found that it significantly impairs their ability to acquire a neural fate. Conversely, Geminin overexpression promotes neural gene expression, even in the presence of growth factor signaling that antagonizes neural transcriptional responses. These data demonstrate that Geminin's activity contributes to mammalian neural cell fate acquisition. We investigated the mechanistic basis of this phenomenon and found that Geminin maintains a hyperacetylated and open chromatin conformation at neural genes. Interestingly, recombinant Geminin protein also rapidly alters chromatin acetylation and accessibility even when Geminin is combined with nuclear extract and chromatin in vitro. Together, these data support a role for Geminin as a cell intrinsic regulator of neural fate acquisition that promotes expression of neural genes by regulating chromatin accessibility and histone acetylation. PMID- 21300882 TI - Gene clustering pattern, promoter architecture, and gene expression stability in eukaryotic genomes. AB - A balance between gene expression stability and evolvability is essential for the long-term maintenance of a living system. In this paper, we studied whether the genetic and epigenetic properties of the promoter affect gene expression variability. We hypothesized that upstream distance and orientation (head-to-head or head-to-tail) are important for the promoter architecture and gene expression variability. We found that in budding yeast genes with a short upstream distance tend to have low gene expression variability, and their promoter is flanked by strongly positioned nucleosomes and tends to have low nucleosome occupancy. These observations suggest that in vivo positioning of the flanking nucleosomes facilitates stable nucleosome depletion at the core promoter region and enhances gene expression stability. Head-to-head genes have, on average, lower gene expression variability, greater nucleosome depletion at the core promoter region, and more strongly positioned nucleosomes that flank the core promoter than do head-to-tail genes. These observations hold for diverse eukaryotes. In complex organisms such as mammals, only a small fraction of head-to-tail genes have retained a short upstream distance, probably because the promoter may not be flanked by a strongly positioned nucleosome on the upstream side. PMID- 21300883 TI - Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells. AB - Poly(ADP-ribose) polymerase (PARP) inhibitors are strikingly toxic to cells with defects in homologous recombination (HR). The mechanistic basis for these findings is incompletely understood. Here, we show that PARP inhibitor treatment induces phosphorylation of DNA-dependent protein kinase substrates and stimulates error-prone nonhomologous end joining (NHEJ) selectively in HR-deficient cells. Notably, inhibiting DNA-dependent protein kinase activity reverses the genomic instability previously reported in these cells after PARP inhibition. Moreover, disabling NHEJ by using genetic or pharmacologic approaches rescues the lethality of PARP inhibition or down-regulation in cell lines lacking BRCA2, BRCA1, or ATM. Collectively, our results not only implicate PARP1 catalytic activity in the regulation of NHEJ in HR-deficient cells, but also indicate that deregulated NHEJ plays a major role in generating the genomic instability and cytotoxicity in HR deficient cells treated with PARP inhibitors. PMID- 21300884 TI - Endogenous retrovirus drives hitherto unknown proapoptotic p63 isoforms in the male germ line of humans and great apes. AB - TAp63, but not its homolog p53, eliminates oocytes that suffered DNA damage. An equivalent gene for guarding the male germ line is currently not known. Here we identify hitherto unknown human p63 transcripts with unique 5'-ends derived from incorporated exons upstream of the currently mapped TP63 gene. These unique p63 transcripts are highly and specifically expressed in testis. Their most upstream region corresponds to a LTR of the human endogenous retrovirus 9 (ERV9). The insertion of this LTR upstream of the TP63 locus occurred only recently in evolution and is unique to humans and great apes (Hominidae). A corresponding p63 protein is the sole p63 species in healthy human testis, and is strongly expressed in spermatogenic precursors but not in mature spermatozoa. In response to DNA damage, this human male germ-cell-encoded TAp63 protein (designated GTAp63) is activated by caspase cleavage near its carboxyterminal domain and induces apoptosis. Human testicular cancer tissues and cell lines largely lost p63 expression. However, pharmacological inhibition of histone deacetylases completely restores p63 expression in testicular cancer cells (>3,000-fold increase). Our data support a model whereby testis-specific GTAp63 protects the genomic integrity of the male germ line and acts as a tumor suppressor. In Hominidae, this guardian function was greatly enhanced by integration of an endogenous retrovirus upstream of the TP63 locus that occurred 15 million years ago. By providing increased germ-line stability, this event may have contributed to the evolution of hominids and enabled their long reproductive periods. PMID- 21300885 TI - Overexpression of BCL2 enhances survival of human embryonic stem cells during stress and obviates the requirement for serum factors. AB - The promise of pluripotent stem cells as a research and therapeutic tool is partly undermined by the technical challenges of generating and maintaining these cells in culture. Human embryonic stem cells (hESCs) are exquisitely sensitive to culture conditions, and require constant signaling by growth factors and cell cell and cell-matrix interactions to prevent apoptosis, senescence, and differentiation. Previous work from our laboratory demonstrated that overexpression of the prosurvival gene BCL2 in mouse embryonic stem cells overrode the requirement of serum factors and feeder cells to maintain mESCs in culture. To determine whether this prosurvival gene could similarly protect hESCs, we generated hESC lines that constitutively or inducibly express BCL2. We find that BCL2 overexpression significantly decreases dissociation-induced apoptosis, resulting in enhanced colony formation from sorted single cells, and enhanced embryoid body formation. In addition, BCL2-hESCs exhibit normal growth in the absence of serum, but require basic fibroblast growth factor to remain undifferentiated. Furthermore, they maintain their pluripotency markers, form teratomas in vivo, and differentiate into all three germ layers. Our data suggest that the BCL2 signaling pathway plays an important role in inhibiting hESC apoptosis, such that its overexpression in hESCs offers both a survival benefit in conditions of stress by resisting apoptosis and obviates the requirement for serum or a feeder layer for maintenance. PMID- 21300886 TI - Intronic delay is essential for oscillatory expression in the segmentation clock. AB - Proper timing of gene expression is essential for many biological events, but the molecular mechanisms that control timing remain largely unclear. It has been suggested that introns contribute to the timing mechanisms of gene expression, but this hypothesis has not been tested with natural genes. One of the best systems for examining the significance of introns is the oscillator network in the somite segmentation clock, because mathematical modeling predicted that oscillating expression depends on negative feedback with a delayed timing. The basic helix-loop-helix repressor gene Hes7 is cyclically expressed in the presomitic mesoderm (PSM) and regulates the somite segmentation. Here, we found that introns lead to an ~19-min delay in the Hes7 gene expression, and mathematical modeling suggested that without such a delay, Hes7 oscillations would be abolished. To test this prediction, we generated mice carrying the Hes7 locus whose introns were removed. In these mice, Hes7 expression did not oscillate but occurred steadily, leading to severe segmentation defects. These results indicate that introns are indeed required for Hes7 oscillations and point to the significance of intronic delays in dynamic gene expression. PMID- 21300887 TI - Microbubbles reveal chiral fluid flows in bacterial swarms. AB - Flagellated bacteria can swim within a thin film of fluid that coats a solid surface, such as agar; this is a means for colony expansion known as swarming. We found that micrometer-sized bubbles make excellent tracers for the motion of this fluid. The microbubbles form explosively when small aliquots of an aqueous suspension of droplets of a water-insoluble surfactant (Span 83) are placed on the agar ahead of a swarm, as the water is absorbed by the agar and the droplets are exposed to air. Using these bubbles, we discovered an extensive stream (or river) of swarm fluid flowing clockwise along the leading edge of an Escherichia coli swarm, at speeds of order 10 MUm/s, about three times faster than the swarm expansion. The flow is generated by the action of counterclockwise rotating flagella of cells stuck to the substratum, which drives fluid clockwise around isolated cells (when viewed from above), counterclockwise between cells in dilute arrays, and clockwise in front of cells at the swarm edge. The river provides an avenue for long-range communication in the swarming colony, ideally suited for secretory vesicles that diffuse poorly. These findings broaden our understanding of swarming dynamics and have implications for the engineering of bacterial driven microfluidic devices. PMID- 21300888 TI - In vivo Atoh1 targetome reveals how a proneural transcription factor regulates cerebellar development. AB - The proneural, basic helix-loop-helix transcription factor Atoh1 governs the development of numerous key neuronal subtypes, such as cerebellar granule and brainstem neurons, inner ear hair cells, and several neurons of the proprioceptive system, as well as diverse nonneuronal cell types, such as Merkel cells and intestinal secretory lineages. However, the mere handful of targets that have been identified barely begin to account for Atoh1's astonishing range of functions, which also encompasses seemingly paradoxical activities, such as promoting cell proliferation and medulloblastoma formation in the cerebellum and inducing cell cycle exit and suppressing tumorigenesis in the intestine. We used a multipronged approach to create a comprehensive, unbiased list of over 600 direct Atoh1 target genes in the postnatal cerebellum. We found that Atoh1 binds to a 10 nucleotide motif (AtEAM) to directly regulate genes involved in migration, cell adhesion, metabolism, and other previously unsuspected functions. This study expands current thinking about the transcriptional activities driving neuronal differentiation and provides a framework for further neurodevelopmental studies. PMID- 21300889 TI - Jumonji domain-containing protein 6 (Jmjd6) is required for angiogenic sprouting and regulates splicing of VEGF-receptor 1. AB - JmjC domain-containing proteins play a crucial role in the control of gene expression by acting as protein hydroxylases or demethylases, thereby controlling histone methylation or splicing. Here, we demonstrate that silencing of Jumonji domain-containing protein 6 (Jmjd6) impairs angiogenic functions of endothelial cells by changing the gene expression and modulating the splicing of the VEGF receptor 1 (Flt1). Reduction of Jmjd6 expression altered splicing of Flt1 and increased the levels of the soluble form of Flt1, which binds to VEGF and placental growth factor (PlGF) and thereby inhibits angiogenesis. Saturating VEGF or PlGF or neutralizing antibodies directed against soluble Flt1 rescued the angiogenic defects induced by Jmjd6 silencing. Jmjd6 interacts with the splicing factors U2AF65 that binds to Flt1 mRNA. In conclusion, Jmjd6 regulates the splicing of Flt1, thereby controlling angiogenic sprouting. PMID- 21300890 TI - Cancer genetics-guided discovery of serum biomarker signatures for diagnosis and prognosis of prostate cancer. AB - A key barrier to the realization of personalized medicine for cancer is the identification of biomarkers. Here we describe a two-stage strategy for the discovery of serum biomarker signatures corresponding to specific cancer-causing mutations and its application to prostate cancer (PCa) in the context of the commonly occurring phosphatase and tensin homolog (PTEN) tumor-suppressor gene inactivation. In the first stage of our approach, we identified 775 N-linked glycoproteins from sera and prostate tissue of wild-type and Pten-null mice. Using label-free quantitative proteomics, we showed that Pten inactivation leads to measurable perturbations in the murine prostate and serum glycoproteome. Following bioinformatic prioritization, in a second stage we applied targeted proteomics to detect and quantify 39 human ortholog candidate biomarkers in the sera of PCa patients and control individuals. The resulting proteomic profiles were analyzed by machine learning to build predictive regression models for tissue PTEN status and diagnosis and grading of PCa. Our approach suggests a general path to rational cancer biomarker discovery and initial validation guided by cancer genetics and based on the integration of experimental mouse models, proteomics-based technologies, and computational modeling. PMID- 21300891 TI - Intramembrane cavitation as a unifying mechanism for ultrasound-induced bioeffects. AB - The purpose of this study was to develop a unified model capable of explaining the mechanisms of interaction of ultrasound and biological tissue at both the diagnostic nonthermal, noncavitational (<100 mW . cm(-2)) and therapeutic, potentially cavitational (>100 mW . cm(-2)) spatial peak temporal average intensity levels. The cellular-level model (termed "bilayer sonophore") combines the physics of bubble dynamics with cell biomechanics to determine the dynamic behavior of the two lipid bilayer membrane leaflets. The existence of such a unified model could potentially pave the way to a number of controlled ultrasound assisted applications, including CNS modulation and blood-brain barrier permeabilization. The model predicts that the cellular membrane is intrinsically capable of absorbing mechanical energy from the ultrasound field and transforming it into expansions and contractions of the intramembrane space. It further predicts that the maximum area strain is proportional to the acoustic pressure amplitude and inversely proportional to the square root of the frequency (epsilon A,max ? P(A)(0.8f - 0.5) and is intensified by proximity to free surfaces, the presence of nearby microbubbles in free medium, and the flexibility of the surrounding tissue. Model predictions were experimentally supported using transmission electron microscopy (TEM) of multilayered live-cell goldfish epidermis exposed in vivo to continuous wave (CW) ultrasound at cavitational (1 MHz) and noncavitational (3 MHz) conditions. Our results support the hypothesis that ultrasonically induced bilayer membrane motion, which does not require preexistence of air voids in the tissue, may account for a variety of bioeffects and could elucidate mechanisms of ultrasound interaction with biological tissue that are currently not fully understood. PMID- 21300892 TI - Understanding current causes of women's underrepresentation in science. AB - Explanations for women's underrepresentation in math-intensive fields of science often focus on sex discrimination in grant and manuscript reviewing, interviewing, and hiring. Claims that women scientists suffer discrimination in these arenas rest on a set of studies undergirding policies and programs aimed at remediation. More recent and robust empiricism, however, fails to support assertions of discrimination in these domains. To better understand women's underrepresentation in math-intensive fields and its causes, we reprise claims of discrimination and their evidentiary bases. Based on a review of the past 20 y of data, we suggest that some of these claims are no longer valid and, if uncritically accepted as current causes of women's lack of progress, can delay or prevent understanding of contemporary determinants of women's underrepresentation. We conclude that differential gendered outcomes in the real world result from differences in resources attributable to choices, whether free or constrained, and that such choices could be influenced and better informed through education if resources were so directed. Thus, the ongoing focus on sex discrimination in reviewing, interviewing, and hiring represents costly, misplaced effort: Society is engaged in the present in solving problems of the past, rather than in addressing meaningful limitations deterring women's participation in science, technology, engineering, and mathematics careers today. Addressing today's causes of underrepresentation requires focusing on education and policy changes that will make institutions responsive to differing biological realities of the sexes. Finally, we suggest potential avenues of intervention to increase gender fairness that accord with current, as opposed to historical, findings. PMID- 21300893 TI - Number without a language model. AB - Cross-cultural studies suggest that access to a conventional language containing words that can be used for counting is essential to develop representations of large exact numbers. However, cultures that lack a conventional counting system typically differ from cultures that have such systems, not only in language but also in many other ways. As a result, it is difficult to isolate the effects of language on the development of number representations. Here we examine the numerical abilities of individuals who lack conventional language for number (deaf individuals who do not have access to a usable model for language, spoken or signed) but who live in a numerate culture (Nicaragua) and thus have access to other aspects of culture that might foster the development of number. These deaf individuals develop their own gestures, called homesigns, to communicate. We show that homesigners use gestures to communicate about number. However, they do not consistently extend the correct number of fingers when communicating about sets greater than three, nor do they always correctly match the number of items in one set to a target set when that target set is greater than three. Thus, even when integrated into a numerate society, individuals who lack input from a conventional language do not spontaneously develop representations of large exact numerosities. PMID- 21300894 TI - The influence of volume exclusion by chromatin on the time required to find specific DNA binding sites by diffusion. AB - Within the nuclei of eukaryotic cells, the density of chromatin is nonuniform. We study the influence of this nonuniform density, which we derive from microscopic images [Schermelleh L, et al. (2008) Science 320:1332-1336], on the diffusion of proteins within the nucleus, under the hypothesis that chromatin density is proportional to an effective potential that tends to exclude the diffusing protein from regions of high chromatin density. The constant of proportionality, which we call the volume exclusivity of chromatin, is a model parameter that we can tune to study the influence of such volume exclusivity on the random time required for a diffusing particle to find its target. We consider randomly chosen binding sites located in regions of low (20th-30th percentile) chromatin density, and we compute the median time to find such a binding site by a protein that enters the nucleus at a randomly chosen nuclear pore. As the volume exclusivity of chromatin increases from zero, we find that the median time needed to reach the target binding site at first decreases to a minimum, and then increases again as the volume exclusivity of chromatin increases further. Random permutation of the voxel values of chromatin density abolishes the minimum, thus demonstrating that the speedup seen with increasing volume exclusivity at low to moderate volume exclusivity is dependent upon the spatial structure of chromatin within the nucleus. PMID- 21300895 TI - Dispensability of Escherichia coli's latent pathways. AB - Gene-knockout experiments on single-cell organisms have established that expression of a substantial fraction of genes is not needed for optimal growth. This problem acquired a new dimension with the recent discovery that environmental and genetic perturbations of the bacterium Escherichia coli are followed by the temporary activation of a large number of latent metabolic pathways, which suggests the hypothesis that temporarily activated reactions impact growth and hence facilitate adaptation in the presence of perturbations. Here, we test this hypothesis computationally and find, surprisingly, that the availability of latent pathways consistently offers no growth advantage and tends, in fact, to inhibit growth after genetic perturbations. This is shown to be true even for latent pathways with a known function in alternate conditions, thus extending the significance of this adverse effect beyond apparently nonessential genes. These findings raise the possibility that latent pathway activation is in fact derivative of another, potentially suboptimal, adaptive response. PMID- 21300896 TI - Blanks, a nuclear siRNA/dsRNA-binding complex component, is required for Drosophila spermiogenesis. AB - Small RNAs and a diverse array of protein partners control gene expression in eukaryotes through a variety of mechanisms. By combining siRNA affinity chromatography and mass spectrometry, we have identified the double-stranded RNA binding domain protein Blanks to be an siRNA- and dsRNA-binding protein from Drosophila S2 cells. We find that Blanks is a nuclear factor that contributes to the efficiency of RNAi. Biochemical fractionation of a Blanks-containing complex shows that the Blanks complex is unlike previously described RNA-induced silencing complexes and associates with the DEAD-box helicase RM62, a protein previously implicated in RNA silencing. In flies, Blanks is highly expressed in testes tissues and is necessary for postmeiotic spermiogenesis, but loss of Blanks is not accompanied by detectable transposon derepression. Instead, genes related to innate immunity pathways are up-regulated in blanks mutant testes. These results reveal Blanks to be a unique component of a nuclear siRNA/dsRNA binding complex that contributes to essential RNA silencing-related pathways in the male germ line. PMID- 21300897 TI - Metabolic cross-talk allows labeling of O-linked beta-N-acetylglucosamine modified proteins via the N-acetylgalactosamine salvage pathway. AB - Hundreds of mammalian nuclear and cytoplasmic proteins are reversibly glycosylated by O-linked beta-N-acetylglucosamine (O-GlcNAc) to regulate their function, localization, and stability. Despite its broad functional significance, the dynamic and posttranslational nature of O-GlcNAc signaling makes it challenging to study using traditional molecular and cell biological techniques alone. Here, we report that metabolic cross-talk between the N acetylgalactosamine salvage and O-GlcNAcylation pathways can be exploited for the tagging and identification of O-GlcNAcylated proteins. We found that N azidoacetylgalactosamine (GalNAz) is converted by endogenous mammalian biosynthetic enzymes to UDP-GalNAz and then epimerized to UDP-N azidoacetylglucosamine (GlcNAz). O-GlcNAc transferase accepts UDP-GlcNAz as a nucleotide-sugar donor, appending an azidosugar onto its native substrates, which can then be detected by covalent labeling using azide-reactive chemical probes. In a proof-of-principle proteomics experiment, we used metabolic GalNAz labeling of human cells and a bioorthogonal chemical probe to affinity-purify and identify numerous O-GlcNAcylated proteins. Our work provides a blueprint for a wide variety of future chemical approaches to identify, visualize, and characterize dynamic O-GlcNAc signaling. PMID- 21300898 TI - Spectrally and spatially configurable superlenses for optoplasmonic nanocircuits. AB - Energy transfer between photons and molecules and between neighboring molecules is ubiquitous in living nature, most prominently in photosynthesis. While energy transfer is efficiently utilized by living systems, its adoption to connect individual components in man-made plasmonic nanocircuits has been challenged by low transfer efficiencies that motivate the development of entirely new concepts for energy transfer. We introduce herein optoplasmonic superlenses that combine the capability of optical microcavities to insulate molecule-photon systems from decohering environmental effects with the superior light nanoconcentration properties of nanoantennas. The proposed structures provide significant enhancement of the emitter radiative rate and efficient long-range transfer of emitted photons followed by subsequent refocusing into nanoscale volumes accessible to near- and far-field detection. Optoplasmonic superlenses are versatile building blocks for optoplasmonic nanocircuits and can be used to construct "dark" single-molecule sensors, resonant amplifiers, nanoconcentrators, frequency multiplexers, demultiplexers, energy converters, and dynamical switches. PMID- 21300899 TI - Nanopatterned protein microrings from a diatom that direct silica morphogenesis. AB - Diatoms are eukaryotic microalgae that produce species-specifically structured cell walls made of SiO(2) (silica). Formation of the intricate silica structures of diatoms is regarded as a paradigm for biomolecule-controlled self-assembly of three-dimensional, nano- to microscale-patterned inorganic materials. Silica formation involves long-chain polyamines and phosphoproteins (silaffins and silacidins), which are readily soluble in water, and spontaneously form dynamic supramolecular assemblies that accelerate silica deposition and influence silica morphogenesis in vitro. However, synthesis of diatom-like silica structure in vitro has not yet been accomplished, indicating that additional components are required. Here we describe the discovery and intracellular location of six novel proteins (cingulins) that are integral components of a silica-forming organic matrix (microrings) in the diatom Thalassiosira pseudonana. The cingulin containing microrings are specifically associated with girdle bands, which constitute a substantial part of diatom biosilica. Remarkably, the microrings exhibit protein-based nanopatterns that closely resemble characteristic features of the girdle band silica nanopatterns. Upon the addition of silicic acid the microrings become rapidly mineralized in vitro generating nanopatterned silica replicas of the microring structures. A silica-forming organic matrix with characteristic nanopatterns was also discovered in the diatom Coscinodiscus wailesii, which suggests that preassembled protein-based templates might be general components of the cellular machinery for silica morphogenesis in diatoms. These data provide fundamentally new insight into the molecular mechanisms of biological silica morphogenesis, and may lead to the development of self assembled 3D mineral forming protein scaffolds with designed nanopatterns for a host of applications in nanotechnology. PMID- 21300900 TI - Biogenesis of the pore architecture of a voltage-gated potassium channel. AB - The pore domain of voltage-gated potassium (Kv) channels consists of transmembrane helices S5 and S6, the turret, the pore helix, the selectivity filter, and the loop preceding S6, with a tertiary reentrant structure between S5 and S6. Using biogenic intermediates, mass tagging (pegylation), and a molecular tape measure, we explored the possibility that the first stages of pore formation occur prior to oligomerization of the transmembrane core. Pegylation of introduced cysteines shows that the pore helix, but not the turret, forms a compact secondary structure in the terminal 20 A of the ribosomal tunnel. We assessed the tertiary fold of the pore loop in monomeric constructs by determining the relative accessibilities of select cysteines using the kinetics of pegylation. Turret residues are accessible at the extracellular surface. In contrast, pore helix residues are less accessible. All-atom molecular dynamics simulations of a single Kv monomer in a solvated lipid membrane indicate that secondary and tertiary folds are stable over 650 ns. These results are consistent with acquisition of a tertiary reentrant pore architecture at the monomer stage of Kv biogenesis and begin to define a plausible sequence of folding events in the formation of Kv channels. PMID- 21300901 TI - Unique active site promotes error-free replication opposite an 8-oxo-guanine lesion by human DNA polymerase iota. AB - The 8-oxo-guanine (8-oxo-G) lesion is the most abundant and mutagenic oxidative DNA damage existing in the genome. Due to its dual coding nature, 8-oxo-G causes most DNA polymerases to misincorporate adenine. Human Y-family DNA polymerase iota (poliota) preferentially incorporates the correct cytosine nucleotide opposite 8-oxo-G. This unique specificity may contribute to poliota's biological role in cellular protection against oxidative stress. However, the structural basis of this preferential cytosine incorporation is currently unknown. Here we present four crystal structures of poliota in complex with DNA containing an 8 oxo-G lesion, paired with correct dCTP or incorrect dATP, dGTP, and dTTP nucleotides. An exceptionally narrow poliota active site restricts the purine bases in a syn conformation, which prevents the dual coding properties of 8-oxo-G by inhibiting syn/anti conformational equilibrium. More importantly, the 8-oxo-G base in a syn conformation is not mutagenic in poliota because its Hoogsteen edge does not form a stable base pair with dATP in the narrow active site. Instead, the syn 8-oxo-G template base forms the most stable replicating base pair with correct dCTP due to its small pyrimidine base size and enhanced hydrogen bonding with the Hoogsteen edge of 8-oxo-G. In combination with site directed mutagenesis, we show that Gln59 in the finger domain specifically interacts with the additional O(8) atom of the lesion base, which influences nucleotide selection, enzymatic efficiency, and replication stalling at the lesion site. Our work provides the structural mechanism of high-fidelity 8-oxo-G replication by a human DNA polymerase. PMID- 21300902 TI - Deletion of the ubiquitin ligase Nedd4L in lung epithelia causes cystic fibrosis like disease. AB - Cystic fibrosis is caused by impaired ion transport due to mutated cystic fibrosis transmembrane conductance regulator, accompanied by elevated activity of the amiloride-sensitive epithelial Na(+) channel (ENaC). Here we show that knockout of the ubiquitin ligase Nedd4L (Nedd4-2) specifically in lung epithelia (surfactant protein C-expressing type II and Clara cells) causes cystic fibrosis like lung disease, with airway mucus obstruction, goblet cell hyperplasia, massive inflammation, fibrosis, and death by three weeks of age. These effects of Nedd4L loss are likely caused by enhanced ENaC function, as reflected by increased ENaC protein levels, increased lung dryness at birth, amiloride sensitive dehydration of lung explants, and elevated ENaC currents in primary alveolar type II cells analyzed by patch clamp recordings. Moreover, the lung defects were rescued with administration of amiloride into the lungs of young knockout pups via nasal instillation. Our results therefore suggest that the ubiquitin ligase Nedd4L can suppress the onset of cystic fibrosis symptoms by inhibiting ENaC in lung epithelia. PMID- 21300903 TI - Antarctic and Arctic populations of the ciliate Euplotes nobilii show common pheromone-mediated cell-cell signaling and cross-mating. AB - Wild-type strains of the protozoan ciliate Euplotes collected from different locations on the coasts of Antarctica, Tierra del Fuego and the Arctic were taxonomically identified as the morpho-species Euplotes nobilii, based on morphometric and phylogenetic analyses. Subsequent studies of their sexual interactions revealed that mating combinations of Antarctic and Arctic strains form stable pairs of conjugant cells. These conjugant pairs were isolated and shown to complete mutual gene exchange and cross-fertilization. The biological significance of this finding was further substantiated by demonstrating that close homology exists among the three-dimensional structures determined by NMR of the water-borne signaling pheromones that are constitutively secreted into the extracellular space by these interbreeding strains, in which these molecules trigger the switch between the growth stage and the sexual stage of the life cycle. The fact that Antarctic and Arctic E. nobilii populations share the same gene pool and belong to the same biological species provides new support to the biogeographic model of global distribution of eukaryotic microorganisms, which had so far been based exclusively on studies of morphological and phylogenetic taxonomy. PMID- 21300904 TI - Low-resolution structure of a vesicle disrupting α-synuclein oligomer that accumulates during fibrillation. AB - One of the major hallmarks of Parkinson disease is aggregation of the protein alpha-synuclein (alphaSN). Aggregate cytotoxicity has been linked to an oligomeric species formed at early stages in the aggregation process. Here we follow the fibrillation process of alphaSN in solution over time using small angle X-ray scattering and resolve four major coexisting species in the fibrillation process, namely monomer, dimer, fibril and an oligomer. By ab initio modeling to fit the data, we obtain a low-resolution structure of a symmetrical and slender alphaSN fibril in solution, consisting of a repeating unit with a maximal distance of 900 A and a diameter of ~180 A. The same approach shows the oligomer to be shaped like a wreath, with a central channel and with dimensions corresponding to the width of the fibril. The structure, accumulation and decay of this oligomer is consistent with an on-pathway role for the oligomer in the fibrillation process. We propose an oligomer-driven alphaSN fibril formation mechanism, where the fibril is built from the oligomers. The wreath-shaped structure of the oligomer highlights its potential cytotoxicity by simple membrane permeabilization. This is confirmed by the ability of the purified oligomer to disrupt liposomes. Our results provide the first structural description in solution of a potentially cytotoxic oligomer, which accumulates during the fibrillation of alphaSN. PMID- 21300905 TI - Modeling aqueous solvation with semi-explicit assembly. AB - We describe a computational solvation model called semi-explicit assembly (SEA). SEA water captures much of the physics of explicit-solvent models but with computational speeds approaching those of implicit-solvent models. We use an explicit-water model to precompute properties of water solvation shells around simple spheres, then assemble a solute's solvation shell by combining the shells of these spheres. SEA improves upon implicit-solvent models of solvation free energies by accounting for local solute curvature, accounting for near-neighbor nonadditivities, and treating water's dipole as being asymmetrical with respect to positive or negative solute charges. SEA does not involve parameter fitting, because parameters come from the given underlying explicit-solvation model. SEA is about as accurate as explicit simulations as shown by comparisons against four different homologous alkyl series, a set of 504 varied solutes, solutes taken retrospectively from two solvation-prediction events, and a hypothetical polar solute series, and SEA is about 100-fold faster than Poisson-Boltzmann calculations. PMID- 21300906 TI - Structural dependence of HET-s amyloid fibril infectivity assessed by cryoelectron microscopy. AB - HET-s is a prion protein of the fungus Podospora anserina which, in the prion state, is active in a self/nonself recognition process called heterokaryon incompatibility. Its prionogenic properties reside in the C-terminal "prion domain." The HET-s prion domain polymerizes in vitro into amyloid fibrils whose properties depend on the pH of assembly; above pH 3, infectious singlet fibrils are produced, and below pH 3, noninfectious triplet fibrils. To investigate the correlation between structure and infectivity, we performed cryo-EM analyses. Singlet fibrils have a helical pitch of approximately 410 A and a left-handed twist. Triplet fibrils have three protofibrils whose lateral dimensions (36 * 25 A) and axial packing (one subunit per 9.4 A) match those of singlets but differ in their supercoiling. At 8.5-A resolution, the cross-section of the singlet fibril reconstruction is largely consistent with that of a beta-solenoid model previously determined by solid-state NMR. Reconstructions of the triplet fibrils show three protofibrils coiling around a common axis and packed less tightly at pH 3 than at pH 2, eventually peeling off. Taken together with the earlier observation that fragmentation of triplet fibrils by sonication does not increase infectivity, these observations suggest a novel mechanism for self-propagation, whereby daughter fibrils nucleate on the lateral surface of singlet fibrils. In triplets, this surface is occluded, blocking nucleation and thereby explaining their lack of infectivity. PMID- 21300907 TI - Elongation factor 4 (EF4/LepA) accelerates protein synthesis at increased Mg2+ concentrations. AB - Elongation factor 4 (EF4) is one of the most conserved proteins present in bacteria as well as in mitochondria and chloroplasts of eukaryotes. Although EF4 has the unique ability to catalyze the back-translocation reaction on posttranslocation state ribosomes, the physiological role of EF4 remains unclear. Here we demonstrate that EF4 is stored at the membrane of Escherichia coli cells and released into the cytoplasm upon conditions of high ionic strength or low temperature. Under such conditions, wild-type E. coli cells overgrow mutant cells lacking the EF4 gene within 5-10 generations. Elevated intracellular Mg(2+) concentrations or low temperature retard bacterial growth and inhibit protein synthesis, probably because of formation of aberrant elongating ribosomal states. We suggest that EF4 binds to these stuck ribosomes and remobilizes them, consistent with the EF4-dependent enhancement (fivefold) in protein synthesis observed under these unfavorable conditions. The strong selective advantage conferred by the presence of EF4 at high intracellular ionic strength or low temperatures explains the ubiquitous distribution and high conservation of EF4. PMID- 21300908 TI - Oral delivery of RNase P ribozymes by Salmonella inhibits viral infection in mice. AB - Safe, effective, and tissue-specific delivery is a central issue for the therapeutic application of nucleic-acid-based gene interfering agents, such as ribozymes and siRNAs. In this study, we constructed a functional RNase P-based ribozyme (M1GS RNA) that targets the overlapping mRNA region of M80.5 and protease, two murine cytomegalovirus (MCMV) proteins essential for viral replication. In addition, a novel attenuated strain of Salmonella, which exhibited efficient gene transfer activity and little cytotoxicity and pathogenicity in mice, was constructed and used for delivery of anti-MCMV ribozyme. In MCMV-infected macrophages treated with the constructed attenuated Salmonella strain carrying the functional M1GS RNA construct, we observed an 80 85% reduction in the expression of M80.5/protease and a 2,500-fold reduction in viral growth. Oral inoculation of the attenuated Salmonella strain in mice efficiently delivered antiviral M1GS RNA into spleens and livers, leading to substantial expression of the ribozyme without causing significant adverse effects in the animals. Furthermore, the MCMV-infected mice that were treated orally with Salmonella carrying the functional M1GS sequence displayed reduced viral gene expression, decreased viral titers, and improved survival compared to the untreated mice or mice treated with Salmonella containing control ribozyme sequences. Our results provide direct evidence that oral delivery of M1GS RNA by Salmonella-based vectors effectively inhibits viral gene expression and replication in mice. Moreover, this study demonstrates the utility of Salmonella mediated oral delivery of RNase P ribozyme for gene-targeting applications in vivo. PMID- 21300910 TI - Formation of high-field magnetic white dwarfs from common envelopes. AB - The origin of highly magnetized white dwarfs has remained a mystery since their initial discovery. Recent observations indicate that the formation of high-field magnetic white dwarfs is intimately related to strong binary interactions during post-main-sequence phases of stellar evolution. If a low-mass companion, such as a planet, brown dwarf, or low-mass star, is engulfed by a post-main-sequence giant, gravitational torques in the envelope of the giant lead to a reduction of the companion's orbit. Sufficiently low-mass companions in-spiral until they are shredded by the strong gravitational tides near the white dwarf core. Subsequent formation of a super-Eddington accretion disk from the disrupted companion inside a common envelope can dramatically amplify magnetic fields via a dynamo. Here, we show that these disk-generated fields are sufficiently strong to explain the observed range of magnetic field strengths for isolated, high-field magnetic white dwarfs. A higher-mass binary analogue may also contribute to the origin of magnetar fields. PMID- 21300909 TI - p31comet Promotes disassembly of the mitotic checkpoint complex in an ATP dependent process. AB - Accurate segregation of chromosomes in mitosis is ensured by a surveillance mechanism called the mitotic (or spindle assembly) checkpoint. It prevents sister chromatid separation until all chromosomes are correctly attached to the mitotic spindle through their kinetochores. The checkpoint acts by inhibiting the anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase that targets for degradation securin, an inhibitor of anaphase initiation. The activity of APC/C is inhibited by a mitotic checkpoint complex (MCC), composed of the APC/C activator Cdc20 bound to the checkpoint proteins MAD2, BubR1, and Bub3. When all kinetochores acquire bipolar attachment the checkpoint is inactivated, but the mechanisms of checkpoint inactivation are not understood. We have previously observed that hydrolyzable ATP is required for exit from checkpoint-arrested state. In this investigation we examined the possibility that ATP hydrolysis in exit from checkpoint is linked to the action of the Mad2-binding protein p31(comet) in this process. It is known that p31(comet) prevents the formation of a Mad2 dimer that it thought to be important for turning on the mitotic checkpoint. This explains how p31(comet) blocks the activation of the checkpoint but not how it promotes its inactivation. Using extracts from checkpoint-arrested cells and MCC isolated from such extracts, we now show that p31(comet) causes the disassembly of MCC and that this process requires beta,gamma-hydrolyzable ATP. Although p31(comet) binds to Mad2, it promotes the dissociation of Cdc20 from BubR1 in MCC. PMID- 21300911 TI - Defective IL-10 signaling in hyper-IgE syndrome results in impaired generation of tolerogenic dendritic cells and induced regulatory T cells. AB - Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by recurrent staphylococcal infections and atopic dermatitis associated with elevated serum IgE levels. Although defective differentiation of IL-17-producing CD4(+) T cells (Th17) partly accounts for the susceptibility to staphylococcal skin abscesses and pneumonia, the pathogenesis of atopic manifestations in HIES still remains an enigma. In this study, we examined the differentiation and function of Th1, Th2, regulatory T cells (T(reg) cells), and dendritic cells (DCs) in HIES patients carrying either STAT3 or TYK2 mutations. Although the in vitro differentiation of Th1 and Th2 cells and the number and function of T(reg) cells in the peripheral blood were normal in HIES patients with STAT3 mutations, primary and monocyte-derived DCs showed defective responses to IL-10 and thus failed to become tolerogenic. When treated with IL-10, patient DCs showed impaired up-regulation of inhibitory molecules on their surface, including PD-L1 and ILT-4, compared with control DCs. Moreover, IL-10-treated DCs from patients displayed impaired ability to induce the differentiation of naive CD4(+) T cells to FOXP3(+) induced T(reg) cells (iT(reg) cells). These results suggest that the defective generation of IL-10-induced tolerogenic DCs and iT(reg) cells may contribute to inflammatory changes in HIES. PMID- 21300912 TI - PD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice. AB - Stimulatory and inhibitory co-receptors play fundamental roles in the regulation of the immune system. We describe a new mouse model of spontaneous autoimmune disease. Activation-induced cytidine deaminase-linked autoimmunity (aida) mice harbor a loss-of-function mutation in the gene encoding lymphocyte activation gene 3 (LAG-3), an inhibitory co-receptor. Although LAG-3 deficiency alone did not induce autoimmunity in nonautoimmune-prone mouse strains, it induced lethal myocarditis in BALB/c mice deficient for the gene encoding the inhibitory co receptor programmed cell death 1 (PD-1). In addition, LAG-3 deficiency alone accelerated type 1 diabetes mellitus in nonobese diabetic mice. These results demonstrate that LAG-3 acts synergistically with PD-1 and/or other immunoregulatory genes to prevent autoimmunity in mice. PMID- 21300913 TI - Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development. AB - Dendritic cells (DCs) in the thymus (tDCs) are predominantly accumulated in the medulla and contribute to the establishment of self-tolerance. However, how the medullary accumulation of tDCs is regulated and involved in self-tolerance is unclear. We show that the chemokine receptor XCR1 is expressed by tDCs, whereas medullary thymic epithelial cells (mTECs) express the ligand XCL1. XCL1-deficient mice are defective in the medullary accumulation of tDCs and the thymic generation of naturally occurring regulatory T cells (nT reg cells). Thymocytes from XCL1-deficient mice elicit dacryoadenitis in nude mice. mTEC expression of XCL1, tDC medullary accumulation, and nT reg cell generation are diminished in Aire-deficient mice. These results indicate that the XCL1-mediated medullary accumulation of tDCs contributes to nT reg cell development and is regulated by Aire. PMID- 21300914 TI - Dynamic variation in cycling of hematopoietic stem cells in steady state and inflammation. AB - Hematopoietic stem cells (HSCs) maintain blood production. How often mouse HSCs divide and whether each HSC contributes simultaneously, sequentially, or repetitively to hematopoiesis remains to be determined. We track division of 5 (and-6)-carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled HSC in vivo. We found that, in steady-state mice, bone marrow cells capable of reconstituting lifelong hematopoiesis are found within both fast-cycling (undergoing five or more divisions in 7 wk) and quiescent (undergoing zero divisions in 12-14 wk) lineage marker-negative c-Kit(+) Sca-1(+) populations. The contribution of each population to hematopoiesis can fluctuate with time, and cells with extensive proliferative history are prone to return to quiescence. Furthermore, injection of the bacterial component lipopolysaccharide increased the proliferation and self-renewal capacity of HSCs. These findings suggest a model in which all HSCs undergo dynamic and demand-adapted entry into and exit out of the cell cycle over time. This may facilitate a similar degree of turnover of the entire HSC pool at the end of life. PMID- 21300915 TI - CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity. AB - Loss of CXCL12, a leukocyte localizing cue, from abluminal surfaces of the blood brain barrier occurs in multiple sclerosis (MS) lesions. However, the mechanisms and consequences of reduced abluminal CXCL12 abundance remain unclear. Here, we show that activation of CXCR7, which scavenges CXCL12, is essential for leukocyte entry via endothelial barriers into the central nervous system (CNS) parenchyma during experimental autoimmune encephalomyelitis (EAE), a model for MS. CXCR7 expression on endothelial barriers increased during EAE at sites of inflammatory infiltration. Treatment with a CXCR7 antagonist ameliorated EAE, reduced leukocyte infiltration into the CNS parenchyma and parenchymal VCAM-1 expression, and increased abluminal levels of CXCL12. Interleukin 17 and interleukin 1beta increased, whereas interferon-gamma decreased, CXCR7 expression on and CXCL12 internalization in primary brain endothelial cells in vitro. These findings identify molecular requirements for the transvascular entry of leukocytes into the CNS and suggest that CXCR7 blockade may have therapeutic utility for the treatment of MS. PMID- 21300916 TI - Pithy protection: Nicotiana attenuata's jasmonic acid-mediated defenses are required to resist stem-boring weevil larvae. AB - Folivory is the best studied plant-herbivore interaction, but it is unclear whether the signaling and resistance traits important for the defense of leaves are also important for other plant parts. Larvae of the tobacco stem weevil, Trichobaris mucorea, burrow into stems of Nicotiana attenuata and feed on the pith. Transgenic N. attenuata lines silenced in signaling and foliar defense traits were evaluated in a 2-year field study for resistance against attack by naturally occurring T. mucorea larva. Plants silenced in early jasmonic acid (JA) biosynthesis (antisense [as]-lipoxygenase3 [lox3]; inverted repeat [ir]-allene oxide cyclase), JA perception (as-coronatine insensitive1), proteinase inhibitors (ir-pi), and nicotine (ir-putrescine methyl-transferase) direct defenses and lignin (ir-cad) biosynthesis were infested more frequently than wild-type plants. Plants unable to emit C(6) aldehydes (as-hpl) had lower infestation rates, while plants silenced in late steps in JA biosynthesis (ir-acyl-coenzyme A oxidase, ir opr) and silenced in diterpene glycoside production (ir-geranylgeranyl pyrophosphate synthase) did not differ from wild type. Pith choice assays revealed that ir-putrescine methyl-transferase, ir-coronatine insensitive1, and ir-lox3 pith, which all had diminished nicotine levels, were preferred by larvae compared to wild-type pith. The lack of preference for ir-lox2 and ir-cad piths, suggest that oviposition attraction and vascular defense, rather than pith palatability accounts for the higher attack rates observed for these plants. We conclude that traits that influence a plant's apparency, stem hardness, and pith direct defenses all contribute to resistance against this herbivore whose attack can be devastating to N. attenuata's fitness. PMID- 21300917 TI - On the controls of leaf-water oxygen isotope ratios in the atmospheric Crassulacean acid metabolism epiphyte Tillandsia usneoides. AB - Previous theoretical work showed that leaf-water isotope ratio (delta(18)O(L)) of Crassulacean acid metabolism epiphytes was controlled by the delta(18)O of atmospheric water vapor (delta(18)O(a)), and observed delta(18)O(L) could be explained by both a non-steady-state model and a "maximum enrichment" steady state model (delta(18)O(L-M)), the latter requiring only delta(18)O(a) and relative humidity (h) as inputs. delta(18)O(L), therefore, should contain an extractable record of delta(18)O(a). Previous empirical work supported this hypothesis but raised many questions. How does changing delta(18)O(a) and h affect delta(18)O(L)? Do hygroscopic trichomes affect observed delta(18)O(L)? Are observations of changes in water content required for the prediction of delta(18)O(L)? Does the leaf need to be at full isotopic steady state for observed delta(18)O(L) to equal delta(18)O(L-M)? These questions were examined with a climate-controlled experimental system capable of holding delta(18)O(a) constant for several weeks. Water adsorbed to trichomes required a correction ranging from 0.50/00 to 10/00. delta(18)O(L) could be predicted using constant values of water content and even total conductance. Tissue rehydration caused a transitory change in delta(18)O(L), but the consequent increase in total conductance led to a tighter coupling with delta(18)O(a). The non-steady-state leaf water models explained observed delta(18)O(L) (y = 0.93*x - 0.07; r(2) = 0.98) over a wide range of delta(18)O(a) and h. Predictions of delta(18)O(L-M) agreed with observations of delta(18)O(L) (y = 0.87*x - 0.99; r(2) = 0.92), and when h > 0.9, the leaf did not need to be at isotopic steady state for the delta(18)O(L-M) model to predict delta(18)O(L) in the Crassulacean acid metabolism epiphyte Tillandsia usneoides. PMID- 21300918 TI - Partners in time: EARLY BIRD associates with ZEITLUPE and regulates the speed of the Arabidopsis clock. AB - The circadian clock of the model plant Arabidopsis (Arabidopsis thaliana) is made up of a complex series of interacting feedback loops whereby proteins regulate their own expression across day and night. early bird (ebi) is a circadian mutation that causes the clock to speed up: ebi plants have short circadian periods, early phase of clock gene expression, and are early flowering. We show that EBI associates with ZEITLUPE (ZTL), known to act in the plant clock as a posttranslational mediator of protein degradation. However, EBI is not degraded by its interaction with ZTL. Instead, ZTL counteracts the effect of EBI during the day and increases it at night, modulating the expression of key circadian components. The partnership of EBI with ZTL reveals a novel mechanism involved in controlling the complex transcription-translation feedback loops of the clock. This work highlights the importance of cross talk between the ubiquitination pathway and transcriptional control for regulation of the plant clock. PMID- 21300919 TI - Molecular analysis of a family of Arabidopsis genes related to galacturonosyltransferases. AB - We are studying a Galacturonosyltransferase-Like (GATL) gene family in Arabidopsis (Arabidopsis thaliana) that was identified bioinformatically as being closely related to a group of 15 genes (Galacturonosyltransferase1 [GAUT1] to 15), one of which (GAUT1) has been shown to encode a functional galacturonosyltransferase. Here, we describe the phylogeny, gene structure, evolutionary history, genomic organization, protein topology, and expression pattern of this gene family in Arabidopsis. Expression studies (reverse transcription-polymerase chain reaction) demonstrate that all 10 AtGATL genes are transcribed, albeit to varying degrees, in Arabidopsis tissues. Promoter::beta glucuronidase expression studies show that individual AtGATL gene family members have both overlapping and unique expression patterns. Nine of the 10 AtGATL genes are expressed in all major plant organs, although not always in all cell types of those organs. AtGATL4 expression appears to be confined to pollen grains. Most of the AtGATL genes are expressed strongly in vascular tissue in both the stem and hypocotyl. Subcellular localization studies of several GATL proteins using yellow fluorescent protein tagging provide evidence supporting the Golgi localization of these proteins. Plants carrying T-DNA insertions in three AtGATL genes (atgatl3, atgatl6, and atgatl9) have reduced amounts of GalA in their stem cell walls. The xylose content increased in atgatl3 and atgatl6 stem walls. Glycome profiling of cell wall fractions from these mutants using a toolkit of diverse plant glycan directed monoclonal antibodies showed that the mutations affect both pectins and hemicelluloses and alter overall wall structure, as indicated by altered epitope extractability patterns. The data presented suggest that the AtGATL genes encode proteins involved in cell wall biosynthesis, but their precise roles in wall biosynthesis remain to be substantiated. PMID- 21300920 TI - Trajectory of performance status and symptom scores for patients with cancer during the last six months of life. AB - PURPOSE: Ontario's cancer system is unique because it has implemented two standardized assessment tools population-wide to improve care: the Edmonton Symptom Assessment System (ESAS) measures severity of nine symptoms (scale 0 to 10; 10 indicates the worst) and the Palliative Performance Scale (PPS) measures performance status (scale 0 to 100; 0 indicates death). This article describes the trajectory of ESAS and PPS scores 6 months before death. PATIENTS AND METHODS: Observational cohort study of cancer decedents between 2007 and 2009. Decedents required >=1 ESAS or PPS assessment in the 6 months before death for inclusion. Outcomes were the decedents' average ESAS and PPS scores per week before death. RESULTS: Ten thousand seven hundred fifty-two (ESAS) and 7,882 (PPS) decedents were included. The mean age was 65 years, half were female, and approximately 75% of assessments occurred in cancer clinics. Average PPS score declined slowly over the 6 months before death, starting at approximately 70 and ending at 40, declining more rapidly in the last month. For ESAS symptoms, average pain, nausea, anxiety, and depression scores remained relatively stable over the 6 months. Conversely, shortness of breath, drowsiness, well-being, lack of appetite, and tiredness increased in severity over time, particularly in the month before death. More than one third of the cohort reported moderate to severe scores (ie, 4 to 10) for most symptoms in the last month of life. CONCLUSION: In this large outpatient cancer population, trajectories of mean ESAS scores followed two patterns: increasing versus generally flat. The latter was perhaps due to available treatment (eg, prescriptions) for those symptoms. Future research should prioritize addressing symptoms that worsen over time. PMID- 21300921 TI - Targeting epidermal growth factor receptor to optimize chemoradiotherapy in locally advanced head and neck cancer: has biology been taken into account? PMID- 21300922 TI - Cerebrospinal fluid cytology diagnosis of HER2-positive leptomeningeal carcinomatosis from HER2-positive metastatic gastric cancer: case report. PMID- 21300923 TI - Quality of life of older patients with early-stage breast cancer receiving adjuvant chemotherapy: a companion study to cancer and leukemia group B 49907. AB - PURPOSE: A phase III trial (Cancer and Leukemia Group B CALGB-49907) was conducted to test whether older patients with early-stage breast cancer would have equivalent relapse-free and overall survival with capecitabine compared with standard chemotherapy. The quality of life (QoL) substudy tested whether capecitabine treatment would be associated with a better QoL than standard chemotherapy. PATIENTS AND METHODS: QoL was assessed in 350 patients randomly assigned to either standard chemotherapy (cyclophosphamide, methotrexate, and fluorouracil [CMF] or doxorubicin and cyclophosphamide [AC]; n = 182) or capecitabine (n = 168). Patients were interviewed by telephone before treatment (baseline), midtreatment, within 1 month post-treatment, and at 12, 18, and 24 months postbaseline by using questionnaires from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ C30), a breast systemic adverse effects scale (EORTC BR23), and the Hospital Anxiety and Depression Scale (HADS). RESULTS: Compared with patients who were treated with standard chemotherapy, patients who were treated with capecitabine had significantly better QoL, role function, and social function, fewer systemic adverse effects, less psychological distress, and less fatigue during and at the completion of treatment (P <= .005). Capecitabine treatment was associated with less nausea, vomiting, and constipation and with better appetite than standard treatment (P <= .004), but worse hand-foot syndrome and diarrhea (P < .005). These differences all resolved by 12 months. CONCLUSION: Standard chemotherapy was superior to capecitabine in improving relapse-free and overall survival for older women with early-stage breast cancer. Although capecitabine was associated with better QoL during treatment, QoL was similar for both groups at 1 year. The brief period of poorer QoL with standard treatment is a modest price to pay for a chance at improved survival. PMID- 21300925 TI - Life after adjuvant chemotherapy for breast cancer: the news is mostly good. PMID- 21300924 TI - Phase II study of vorinostat for treatment of relapsed or refractory indolent non Hodgkin's lymphoma and mantle cell lymphoma. AB - PURPOSE: We performed a phase II study of oral vorinostat, a histone and protein deacetylase inhibitor, to examine its efficacy and tolerability in patients with relapsed/refractory indolent lymphoma. PATIENTS AND METHODS: In this open label phase II study (NCT00253630), patients with relapsed/refractory follicular lymphoma (FL), marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL), with <= 4 prior therapies were eligible. Oral vorinostat was administered at a dose of 200 mg twice daily on days 1 through 14 of a 21-day cycle until progression or unacceptable toxicity. The primary end point was objective response rate (ORR), with secondary end points of progression-free survival (PFS), time to progression, duration of response, safety, and tolerability. RESULTS: All 35 eligible patients were evaluable for response. The median number of vorinostat cycles received was nine. ORR was 29% (five complete responses [CR] and five partial responses [PR]). For 17 patients with FL, ORR was 47% (four CR, four PR). There were two of nine responders with MZL (one CR, one PR), and no formal responders among the nine patients with MCL, although one patient maintained stable disease for 26 months. Median PFS was 15.6 months for patients with FL, 5.9 months for MCL, and 18.8 months for MZL. The drug was well-tolerated over long periods of treatment, with the most common grade 3 adverse events being thrombocytopenia, anemia, leucopenia, and fatigue. CONCLUSION: Oral vorinostat is a promising agent in FL and MZL, with an acceptable safety profile. Further studies in combination with other active agents in this setting are warranted. PMID- 21300926 TI - Adverse prognostic factors for testicular cancer-specific survival: a population based study of 27,948 patients. AB - PURPOSE: The prognostic significance of age at testicular cancer (TC) diagnosis, socioeconomic status (SES), race, and marital status on TC-specific mortality is not well-characterized. In a cancer that is so curable, it is important to identify any influence that confers an increased risk of TC-specific mortality. PATIENTS AND METHODS: Using multivariate cause-specific Cox regression models that accounted for competing risks, hazard ratios (HRs) were calculated for 10 year TC-specific mortality among 27,948 patients with TC reported to the Surveillance, Epidemiology and End Results program (1978 to 2006). Independent predictors were age at diagnosis, SES, race, marital status, extent of disease (EOD), calendar year of diagnosis, radiotherapy, and retroperitoneal lymph node dissection (RPLND). RESULTS: Compared with younger patients, diagnostic age 40+ was associated with increased mortality (seminoma, HR, 2.00, P < .001; nonseminoma, HR, 2.09; P < .001; most evident in metastatic disease, HR, 8.62; P < .001; HR, 6.35; P < .001, respectively). Unmarried men had two-to three-fold excess mortality compared to married men (HR, 2.97; P < .001; HR, 1.54; P < .001, respectively). Among nonseminoma patients, decreasing SES (P trend < .001) and nonwhite race (HR, 2.11; P < .001) increased mortality. Diagnosis after 1987 resulted in reduced mortality compared to earlier calendar years (HR, 0.58; P = .001; HR, 0.74; P = .001, respectively). Lack of RPLND was associated with seven fold increase in death (P < .001). CONCLUSION: TC-specific mortality is doubled among US patients diagnosed with seminoma or nonseminoma after age 40, even when initial treatment and EOD are taken into account. Among men with nonseminoma, nonwhite race and lower SES also significantly increase TC-specific mortality. Additional research is needed, enabling the development of interventional strategies and preventive approaches, as applicable. PMID- 21300927 TI - Amoebic abscess diagnosed on fluorodeoxyglucose positron emission tomography scan in patient with recurrent oropharyngeal squamous cell carcinoma. PMID- 21300928 TI - Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study. AB - PURPOSE: Abnormal cytokine expression accompanies myelofibrosis and might be a therapeutic target for Janus-associated kinase (JAK) inhibitor drugs. This study describes the spectrum of plasma cytokine abnormalities in primary myelofibrosis (PMF) and examines their phenotypic correlates and prognostic significance. PATIENTS AND METHODS: Patients included in this study were required to have archived plasma, bone marrow biopsy, and cytogenetic information available at the time of first referral to the Mayo Clinic. Multiplex biometric sandwich immunoassay was used to measure plasma levels of 30 cytokines. RESULTS: In total, 127 PMF patients were studied; comparison with normal controls (n = 35) revealed significantly increased interleukin-1beta (IL-1beta), IL-1RA, IL-2R, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15, tumor necrosis factor alpha (TNF-alpha), granulocyte colony-stimulating factor (G-CSF), interferon alfa (IFN-alpha), macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, hepatocyte growth factor (HGF), IFN-gamma-inducible protein 10 (IP-10), monokine induced by IFN-gamma (MIG), monocyte chemotactic protein 1 (MCP-1), and vascular endothelial growth factor (VEGF) levels and decreased IFN-gamma levels. In treatment-naive patients (n = 90), increased levels of IL-8 (P < .001), IL-2R (P < .001), IL-12 (P < .001), IL-15 (P = .001), and IP-10 (P = .003) were independently predictive of inferior survival. A similar multivariable analysis that included all 127 study patients confirmed the prognostic value of these five cytokines, and IL-8, IL-2R, IL-12, and IL-15 remained significant when risk stratification, according to the recently revised Dynamic International Prognostic Scoring System (DIPSS plus), was added to the multivariable model. Leukemia-free survival was predicted by IL 8, which was also the only cytokine associated with >= 1% circulating blasts. Other cytokine-phenotype associations included increased IL-8 and constitutional symptoms; IL-2R, IL-12, and transfusion need; IL-2R, IL-8, and leukocytosis; IP 10 and thrombocytopenia; HGF, MIG, IL-1RA, and marked splenomegaly; and IL-1RA, IL-2R, IP-10, MIP-1beta, and JAK2V617F. A two-cytokine (IL-8/IL-2R) -based risk categorization delineated prognostically different groups within specific DIPSS plus risk categories. CONCLUSION: This study signifies the presence of specific cytokine-phenotype associations in PMF and a prognostically relevant plasma cytokine signature that might prove useful as a laboratory tool for predicting and monitoring treatment response. PMID- 21300929 TI - Phase I/II study of pemetrexed with or without ABT-751 in advanced or metastatic non-small-cell lung cancer. AB - PURPOSE: ABT-751 is an antimitotic and vascular disrupting agent with potent preclinical anticancer activity. We conducted a phase I and randomized double blind phase II study of pemetrexed with ABT-751 or placebo in patients with recurrent advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS: One hundred seventy-one patients received intravenous pemetrexed 500 mg/m(2) day 1 and oral ABT-751 or placebo days 1 to 14 of 21-day cycles. The primary end point was progression-free survival (PFS). Secondary end point included overall survival (OS); pharmacokinetic and pharmacodynamic parameters were also analyzed. RESULTS: The recommended phase II dose of ABT-751 with pemetrexed is 200 mg. Fatigue, constipation, anemia, nausea, and diarrhea were the most common toxicities in both study arms. No pharmacokinetic interactions were observed. Median PFS in the ABT-751 arm was 2.3 months versus 1.9 for placebo (P = .819, log-rank) for the intention-to-treat population. However, differences in PFS (P = .112, log-rank) and OS (P = .034, log-rank; median 3.3 v 8.1 months) favoring ABT 751 were seen in the squamous NSCLC subgroup. Baseline circulating tumor cell concentrations were predictive of improved OS (P = .013). Changes from baseline of greater than 20% in plasma levels of placenta growth factor (P = .056), squamous cell carcinoma antigen (P = .03), and cytokeratin 19 fragment antigen 21 1 (P = .01) were markers best associated with improved OS. CONCLUSION: Addition of ABT-751 to pemetrexed is well-tolerated, but does not improve outcome in unselected patients with recurrent NSCLC. ABT-751 may have therapeutic potential in squamous NSCLC. Exploratory cellular and molecular analyses in this study identified biomarkers that may correlate with survival. PMID- 21300931 TI - Physical and psychosocial recovery in the year after primary treatment of breast cancer. AB - PURPOSE: The 2000 National Institutes of Health Consensus Conference on Adjuvant Therapy of Breast Cancer recommended chemotherapy for all women with invasive cancer greater than 1 centimeter. Studies of long-term breast cancer survivors have found poorer quality of life (QOL) in women who received adjuvant chemotherapy. The aim of this article is to characterize physical and psychosocial recovery as a function of chemotherapy receipt in the year after medical treatment completion. PATIENTS AND METHODS: Prospective longitudinal survey data (RAND SF-36 and Breast Cancer Prevention Trial [BCPT] Symptom Scales) collected from 558 women with breast cancer enrolled on the Moving Beyond Cancer (MBC) psychoeducational intervention trial were compared according to receipt of chemotherapy. MBC study enrollment occurred within 4 weeks after the end of primary treatment (eg, surgery, chemotherapy, radiation). Self-report questionnaire data collected at enrollment and at 2, 6, and 12 months thereafter were examined, controlling for intervention and with propensity score adjustment for imbalance of covariates. Outcome analyses were carried out by fitting linear mixed models by using SAS PROC MIXED. RESULTS: Longitudinal SF-36 scale scores did not differ by chemotherapy treatment exposure, and both groups improved significantly (P < .01) in the year after primary treatment ended. However, adjuvant chemotherapy treatment was associated with significantly more severe physical symptoms, including musculoskeletal pain (P = .01), vaginal problems (P < .01), weight problems (P = .01), and nausea (P = .03). CONCLUSION: Physical and psychosocial functioning improved significantly after breast cancer treatment, independent of receipt of adjuvant chemotherapy. Women who received chemotherapy experienced more severe and persistent physical symptoms that should be more effectively managed as part of survivorship care. PMID- 21300932 TI - Clinical trial did not demonstrate benefits of screening patients with cancer for distress. PMID- 21300930 TI - Menstrual history and quality-of-life outcomes in women with node-positive breast cancer treated with adjuvant therapy on the NSABP B-30 trial. AB - PURPOSE: Premenopausal women with breast cancer receiving adjuvant chemotherapy are at risk for amenorrhea. The National Surgical Adjuvant Breast and Bowel Project B-30 trial included menstrual history (MH) and quality-of-life (QOL) studies to compare treatments on these outcomes. PATIENTS AND METHODS: Patients were randomly assigned to sequential doxorubicin (A) and cyclophosphamide (C) followed by docetaxel (T; AC->T), concurrent TAC, or AT, which varied in duration (24, 12, 12 weeks, respectively), and use of C. Endocrine therapy was prescribed for women with hormone receptor-positive tumors. MH and QOL were assessed with standardized questionnaires at baseline; cycle 4, day 1; and every 6 months through 24 months. Prespecified analyses examined rates of amenorrhea by treatment arm, the relationship between amenorrhea and QOL, and QOL by treatment arm. RESULTS: Amenorrhea 12 months after random assignment was significantly different between treatment groups: 69.8% for AC->T, 57.7% for TAC, and 37.9% for AT (P < .001). The AT group without tamoxifen had the lowest rate of amenorrhea. QOL was poorer for patients receiving AC->T at 6 months but similar to others by 12 months. Post-treatment symptoms were increased above baseline for all treatments. Multivariable repeated measures modeling demonstrated that treatment arm, time point, age, and tamoxifen use were significantly associated with symptom severity (all P values < .002). CONCLUSION: Amenorrhea rates differed significantly by treatment arm, with the AT arm having the lowest rate. Patients treated with longer duration therapy (AC->T) had greater symptom severity and poorer QOL at 6 months, but did not differ from shorter duration treatments at 12 months. PMID- 21300934 TI - A rare case of CD30(+), radiation-induced cutaneous angiosarcoma misdiagnosed as T-cell lymphoma. PMID- 21300933 TI - Cetuximab plus capecitabine and irinotecan compared with cetuximab plus capecitabine and oxaliplatin as first-line treatment for patients with metastatic colorectal cancer: AIO KRK-0104--a randomized trial of the German AIO CRC study group. AB - PURPOSE: The AIO KRK-0104 randomized phase II trial investigated the efficacy and safety of cetuximab combined with capecitabine and irinotecan (CAPIRI) or capecitabine and oxaliplatin (CAPOX) in the first-line treatment of metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: A total of 185 patients with mCRC were randomly assigned to cetuximab (400 mg/m(2) day 1, followed by 250 mg/m(2) weekly) plus CAPIRI (irinotecan 200 mg/m(2), day 1; capecitabine 800 mg/m(2) twice daily days 1 through 14, every 3 weeks; or cetuximab plus CAPOX (oxaliplatin 130 mg/m(2) day 1; capecitabine 1,000 mg/m(2) twice daily day 1 through 14, every 3 weeks). The primary study end point was objective response rate (ORR). RESULTS: In the intention-to-treat patient population (n = 177), ORR was 46% (95% CI, 35 to 57) for CAPIRI plus cetuximab versus 48% (95% CI, 37 to 59) for CAPOX plus cetuximab. Analysis of the KRAS gene mutation status was performed in 81.4% of the intention to treat population. Patients with KRAS wild type in the CAPIRI plus cetuximab arm showed an ORR of 50.0%, a PFS of 6.2 months and an OS of 21.1 months. In the CAPOX plus cetuximab arm, an ORR of 44.9%, a PFS of 7.1 months and an OS of 23.5 months were observed. While ORR and PFS were comparable in KRAS wild-type and mutant subgroups, a trend toward longer survival was associated with KRAS wild-type. Both regimens had manageable toxicity profiles and were safe. CONCLUSION: This randomized trial demonstrates that the addition of cetuximab to CAPIRI or CAPOX is effective and safe in first-line treatment of mCRC. In the analyzed regimens, ORR and PFS did not differ according to KRAS gene mutation status. PMID- 21300935 TI - Art in oncology: how patients add life to their days. PMID- 21300936 TI - Features predicting sentinel lymph node positivity in Merkel cell carcinoma. AB - PURPOSE: Merkel cell carcinoma (MCC) is a relatively rare, potentially aggressive cutaneous malignancy. We examined the clinical and histologic features of primary MCC that may correlate with the probability of a positive sentinel lymph node (SLN). METHODS: Ninety-five patients with MCC who underwent SLN biopsy at the University of Michigan were identified. SLN biopsy was performed on 97 primary tumors, and an SLN was identified in 93 instances. These were reviewed for clinical and histologic features and associated SLN positivity. Univariate associations between these characteristics and a positive SLN were tested for by using either the chi(2) or the Fisher's exact test. A backward elimination algorithm was used to help create a best multiple variable model to explain a positive SLN. RESULTS: SLN positivity was significantly associated with the clinical size of the lesion, greatest horizontal histologic dimension, tumor thickness, mitotic rate, and histologic growth pattern. Two competing multivariate models were generated to predict a positive SLN. The histologic growth pattern was present in both models and combined with either tumor thickness or mitotic rate. CONCLUSION: Increasing clinical size, increasing tumor thickness, increasing mitotic rate, and infiltrative tumor growth pattern were significantly associated with a greater likelihood of a positive SLN. By using the growth pattern and tumor thickness model, no subgroup of patients was predicted to have a lower than 15% to 20% likelihood of a positive SLN. This suggests that all patients presenting with MCC without clinical evidence of regional lymph node disease should be considered for SLN biopsy. PMID- 21300937 TI - Systematic review of early cardiometabolic outcomes of the first treated episode of psychosis. AB - CONTEXT: The increased mortality associated with schizophrenia is largely due to cardiovascular disease. Treatment with antipsychotics is associated with weight gain and changes in other cardiovascular risk factors. Early identification of modifiable cardiovascular risk factors is a clinical imperative but prospective longitudinal studies of the early cardiometabolic adverse effects of antipsychotic drug treatment other than weight gain have not been previously reviewed. OBJECTIVES: To assess the methods and reporting of cardiometabolic outcome studies of the first treated episode of psychosis, review key findings, and suggest directions for future research. DATA SOURCES: PsycINFO, MEDLINE, and Scopus from January 1990 to June 2010. STUDY SELECTION: Subjects were experiencing their first treated episode of psychosis. Subjects were antipsychotic naive or had been exposed to antipsychotics for a short known period at the beginning of the study. Cardiometabolic indices were assessed. Studies used a longitudinal design. DATA EXTRACTION: Sixty-four articles were identified describing 53 independent studies; 25 studies met inclusion criteria and were retained for detailed review. DATA SYNTHESIS: Consolidated Standards of Reporting Trials and Strengthening the Reporting of Observational Studies in Epidemiology checklists were used to assess the methods and reporting of studies. A qualitative review of findings was conducted. CONCLUSIONS: Two key hypotheses were identified based on this review: (1) in general, there is no difference in cardiovascular risk assessed by weight or metabolic indices between individuals with an untreated first episode of psychosis and healthy controls and (2) cardiovascular risk increases after first exposure to any antipsychotic drug. A rank order of drugs can be derived but there is no evidence of significant class differences. Recommended directions for future research include assessing the effect on cardiometabolic outcomes of medication adherence and dosage effects, determining the therapeutic window for antipsychotic use in adults and youth, and testing for moderation of outcomes by demographic factors, including sex and age, and clinical and genetic factors. PMID- 21300938 TI - National study of suicide in all people with a criminal justice history. AB - CONTEXT: Previous research has focused on suicide among male prisoners and ex prisoners, but little is known about risk in the wider offender population. OBJECTIVE: To examine suicide risk over 3 decades among all people processed by a national criminal justice system. DESIGN: Nested case-control study. SETTING: The whole Danish population. PARTICIPANTS: Interlinked national registers identified all adult suicides during 1981 to 2006 according to any criminal justice system contact since 1980. Exposure was defined according to history of criminal justice adjudication, up to and including each subject's last judicial verdict before suicide (or date of matching for controls). There were 27 219 suicides and 524 899 controls matched on age, sex, and time, ie, controls were alive when their matched case died. MAIN OUTCOME MEASURE: Suicide. RESULTS: More than a third of all male cases had a criminal justice history, but relative risk against the general population was higher for women than men. Independent effects linked with criminal justice exposure persisted with confounder adjustment. Suicide risk was markedly elevated with custodial sentencing, but the strongest effects were with sentencing to psychiatric treatment and with charges conditionally withdrawn. Risk was raised even in people with a criminal justice history but without custodial sentences or guilty verdicts. It was especially high with recent or frequent contact and in people charged with violent offenses. CONCLUSIONS: We examined a section of society in which major health and social problems frequently coexist including offending, psychopathology, and suicidal behavior. The need for developing more far-reaching national suicide prevention strategies is indicated. In particular, improved mental health service provision is needed for all people in contact with the criminal justice system, including those not found guilty and those not given custodial sentences. Our findings also suggest that public services should be better coordinated to tackle co-occurring health and social problems more effectively. PMID- 21300939 TI - Cannabis use and earlier onset of psychosis: a systematic meta-analysis. AB - CONTEXT: A number of studies have found that the use of cannabis and other psychoactive substances is associated with an earlier onset of psychotic illness. OBJECTIVE: To establish the extent to which use of cannabis, alcohol, and other psychoactive substances affects the age at onset of psychosis by meta-analysis. DATA SOURCES: Peer-reviewed publications in English reporting age at onset of psychotic illness in substance-using and non-substance-using groups were located using searches of CINAHL, EMBASE, MEDLINE, PsycINFO, and ISI Web of Science. STUDY SELECTION: Studies in English comparing the age at onset of psychosis in cohorts of patients who use substances with age at onset of psychosis in non substance-using patients. The searches yielded 443 articles, from which 83 studies met the inclusion criteria. DATA EXTRACTION: Information on study design, study population, and effect size were extracted independently by 2 of us. DATA SYNTHESIS: Meta-analysis found that the age at onset of psychosis for cannabis users was 2.70 years younger (standardized mean difference = -0.414) than for nonusers; for those with broadly defined substance use, the age at onset of psychosis was 2.00 years younger (standardized mean difference = -0.315) than for nonusers. Alcohol use was not associated with a significantly earlier age at onset of psychosis. Differences in the proportion of cannabis users in the substance-using group made a significant contribution to the heterogeneity in the effect sizes between studies, confirming an association between cannabis use and earlier mean age at onset of psychotic illness. CONCLUSIONS: The results of meta analysis provide evidence for a relationship between cannabis use and earlier onset of psychotic illness, and they support the hypothesis that cannabis use plays a causal role in the development of psychosis in some patients. The results suggest the need for renewed warnings about the potentially harmful effects of cannabis. PMID- 21300940 TI - Functional magnetic resonance imaging investigation of the amphetamine sensitization model of schizophrenia in healthy male volunteers. AB - CONTEXT: Recent work suggests that the amphetamine sensitization model of schizophrenia can safely be induced in healthy volunteers and is associated both with behavioral and dopaminergic hypersensitivity to amphetamine. However, the effects of a sensitization on brain function remain unclear. OBJECTIVE: To assess the impact of a sensitizing dosage regimen of dextroamphetamine on human cortical functioning and cognition. DESIGN: Randomized, double-blind, parallel-groups design using pharmacological functional magnetic resonance imaging. SETTING: The neuroimaging research unit at the Institute of Psychiatry, King's College London, London, England. PARTICIPANTS: Healthy male volunteers (n = 22). INTERVENTIONS: Dextroamphetamine (20 mg) or placebo administration at 4 testing sessions, using a dosage regimen shown to induce sensitization (ie, 3 doses administered with a 48-hour interdose interval and a final dose after a 2-week washout period). MAIN OUTCOME MEASURES: Sensitization was characterized by enhanced subjective response to the drug, changes in behavioral performance (reaction time and accuracy), and functional magnetic resonance imaging measurements of brain activity during an N back working memory task. RESULTS: Sensitization was associated with more rapid responding during the performance of an intermediate-load working memory challenge. During a high-load cognitive challenge, sensitization did not produce performance deficits, but functional magnetic resonance imaging showed hyperactivity of the dorsolateral prefrontal cortex and aberrant recruitment of the superior temporal gyrus, caudate nucleus, and thalamus. Furthermore, the change in striatal activity was negatively correlated with the enhanced subjective effects of the drug, whereas prefrontal hyperactivity was positively correlated with sensitized measures of alertness. CONCLUSIONS: These transient load-dependent abnormalities of frontal and temporal activity induced by amphetamine sensitization support neuroimaging findings in schizophrenic patients, implying that amphetamine sensitization may help to bridge pathophysiological theories of schizophrenia that focus on pharmacological (dopaminergic) and cognitive mechanisms, respectively. PMID- 21300941 TI - Las Meninas (The Maids of Honor). PMID- 21300942 TI - Antipsychotic medications and brain volume: do we have cause for concern? PMID- 21300943 TI - Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia. AB - CONTEXT: Progressive brain volume changes in schizophrenia are thought to be due principally to the disease. However, recent animal studies indicate that antipsychotics, the mainstay of treatment for schizophrenia patients, may also contribute to brain tissue volume decrement. Because antipsychotics are prescribed for long periods for schizophrenia patients and have increasingly widespread use in other psychiatric disorders, it is imperative to determine their long-term effects on the human brain. OBJECTIVE: To evaluate relative contributions of 4 potential predictors (illness duration, antipsychotic treatment, illness severity, and substance abuse) of brain volume change. DESIGN: Predictors of brain volume changes were assessed prospectively based on multiple informants. SETTING: Data from the Iowa Longitudinal Study. PATIENTS: Two hundred eleven patients with schizophrenia who underwent repeated neuroimaging beginning soon after illness onset, yielding a total of 674 high-resolution magnetic resonance scans. On average, each patient had 3 scans (>=2 and as many as 5) over 7.2 years (up to 14 years). MAIN OUTCOME MEASURE: Brain volumes. RESULTS: During longitudinal follow-up, antipsychotic treatment reflected national prescribing practices in 1991 through 2009. Longer follow-up correlated with smaller brain tissue volumes and larger cerebrospinal fluid volumes. Greater intensity of antipsychotic treatment was associated with indicators of generalized and specific brain tissue reduction after controlling for effects of the other 3 predictors. More antipsychotic treatment was associated with smaller gray matter volumes. Progressive decrement in white matter volume was most evident among patients who received more antipsychotic treatment. Illness severity had relatively modest correlations with tissue volume reduction, and alcohol/illicit drug misuse had no significant associations when effects of the other variables were adjusted. CONCLUSIONS: Viewed together with data from animal studies, our study suggests that antipsychotics have a subtle but measurable influence on brain tissue loss over time, suggesting the importance of careful risk-benefit review of dosage and duration of treatment as well as their off-label use. PMID- 21300944 TI - Emotion processing, major depression, and functional genetic variation of neuropeptide Y. AB - CONTEXT: Despite recent progress in describing the common neural circuitry of emotion and stress processing, the bases of individual variation are less well understood. Genetic variants that underlie psychiatric disease have proven particularly difficult to elucidate. Functional genetic variation of neuropeptide Y (NPY) was recently identified as a source of individual differences in emotion. Low NPY levels have been reported in major depressive disorder (MDD). OBJECTIVE: To determine whether low-expression NPY genotypes are associated with negative emotional processing at 3 levels of analysis. DESIGN: Cross-sectional, case control study. SETTING: Academic medical center. PARTICIPANTS: Among 44 individuals with MDD and 137 healthy controls, 152 (84%) had an NPY genotype classified as low, intermediate, or high expression according to previously established haplotype-based expression data. MAIN OUTCOME MEASURES: Healthy subjects participated in functional magnetic resonance imaging while viewing negative (vs neutral) words (n = 58) and rated positive and negative affect during a pain-stress challenge (n = 78). Genotype distribution was compared between 113 control subjects and 39 subjects with MDD. RESULTS: Among healthy individuals, negatively valenced words activated the medial prefrontal cortex. Activation within this region was inversely related to genotype-predicted NPY expression (P = .03). Whole-brain regression of responses to negative words showed that the rostral anterior cingulate cortex activated in the low-expression group and deactivated in the high-expression group (P < .05). During the stress challenge, individuals with low-expression NPY genotypes reported more negative affective experience before and after pain (P = .002). Low-expression NPY genotypes were overrepresented in subjects with MDD after controlling for age and sex (P = .004). Population stratification did not account for the results. CONCLUSIONS: These findings support a model in which NPY genetic variation predisposes certain individuals to low NPY expression, thereby increasing neural responsivity to negative stimuli within key affective circuit elements, including the medial prefrontal and anterior cingulate cortices. These genetically influenced neural response patterns appear to mediate risk for some forms of MDD. PMID- 21300945 TI - Higher-order genetic and environmental structure of prevalent forms of child and adolescent psychopathology. AB - CONTEXT: It is necessary to understand the etiologic structure of child and adolescent psychopathology to advance theory and guide future research. OBJECTIVE: To test alternative models of the higher-order structure of etiologic effects on 11 dimensions of child and adolescent psychopathology using confirmatory factor analyses of genetic and environmental covariances. DESIGN: Representative sample of twins. SETTING: Home interviews. PARTICIPANTS: A total of 1571 pairs of 9- to 17-year-old twins. MAIN OUTCOME MEASURES: Structured assessments of psychopathology using adult caregivers and youth as informants. RESULTS: The best-fitting genetic model revealed that most genetic factors nonspecifically influence risk for either all 11 symptom dimensions or for dimensions of psychopathology within 1 of 2 broad domains. With some notable exceptions, dimension-specific genetic influences accounted for modest amounts of variance. CONCLUSIONS: To inform theory and guide molecular genetic studies, an etiologic model is offered in which 3 patterns of pleiotropy are hypothesized to be the principal modes of genetic risk transmission for common forms of child and adolescent psychopathology. Some common environmental influences were found, but consistent with a "generalist genes, specialist environments" model, there was little sharing of environmental influences. This implies that prevalent dimensions of child and adolescent psychopathology mostly share their genetic liabilities but are differentiated by nonshared experiences. PMID- 21300946 TI - Trends in antipsychotic use in dementia 1999-2007. AB - CONTEXT: Use of atypical antipsychotics for neuropsychiatric symptoms of dementia increased markedly in the 1990s. Concerns about their use began to emerge in 2002, and in 2005, the US Food and Drug Administration warned that use of atypical antipsychotics in dementia was associated with increased mortality. OBJECTIVE: To examine changes in atypical and conventional antipsychotic use in outpatients with dementia from 1999 through 2007. DESIGN: Time-series analyses estimated the effect of the various warnings on atypical and conventional antipsychotic usage using national Veterans Affairs data across 3 periods: no warning (1999-2003), early warning (2003-2005), and black box warning (2005 2007). SUBJECTS: Patients aged 65 years or older with dementia (n = 254 564). MAIN OUTCOME MEASURES: Outpatient antipsychotic use (percentage of patients, percentage of quarterly change, and difference between consecutive study periods). RESULTS: In 1999, 17.7% (95% confidence interval [CI], 17.2-18.1) of patients with dementia were using atypical or conventional antipsychotics. Overall use began to decline during the no-warning period (rate per quarter, 0.12%; 95% CI, -0.16 to -0.07; P < .001). Following the black box warning, the decline continued (rate, -0.26%; 95% CI, -0.34 to -0.18; P < .001), with a significant difference between the early and black box warning periods (P = .006). Use of atypical antipsychotics as a group increased during the no-warning period (rate, 0.23; 95% CI, 0.17-0.30; P < .001), started to decline during the early-warning period (rate, -0.012; 95% CI, -0.14 to 0.11; P = .85), and more sharply declined during the black box warning period (rate, -0.27; 95% CI, -0.36 to -0.18; P < .001). Olanzapine and risperidone showed declining rates and quetiapine showed an increase during the early-warning period, but rates of use for all 3 antipsychotics declined during the black box warning period. In the black box warning period, there was a small but significant increase in anticonvulsant prescriptions (rate, 0.117; 95% CI, 0.08-0.16; P < .001). CONCLUSIONS: Use of atypical antipsychotics began to decline significantly in 2003, and the Food and Drug Administration advisory was temporally associated with a significant acceleration in the decline. PMID- 21300947 TI - The brain-derived neurotrophic factor Val66Met polymorphism and prediction of neural risk for Alzheimer disease. AB - CONTEXT: The brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism may predict the risk of Alzheimer disease (AD). However, genetic association studies of the BDNF gene with AD have produced equivocal results. Imaging-genetics strategies may clarify the manner in which BDNF gene variation predicts the risk of AD via characterization of its effects on at-risk structures or neural networks susceptible in this disorder. OBJECTIVE: To determine whether the BDNF Val66Met gene variant interacts with age to predict brain and cognitive measures in healthy volunteers across the adult lifespan in an intermediate phenotype pattern related to AD by examining (1) cortical thickness, (2) fractional anisotropy of white matter tracts (ie, white matter integrity), and (3) episodic memory performance. DESIGN: A cross-sectional study using genetics, high-resolution magnetic resonance imaging, diffusion tensor imaging, and cognitive testing in healthy individuals spanning the adult lifespan. SETTING: University hospital. PARTICIPANTS: A total of 69 healthy volunteers ranging from 19 to 82 years of age. MAIN OUTCOME MEASURES: The BDNF Val66Met genotype, apolipoprotein E genotype, cortical thickness, microstructural integrity of white matter tracts, and episodic memory performance were evaluated. RESULTS: The BDNF Val66Met polymorphism interacted with age to predict (1) cortical thickness (prominently at the entorhinal cortex and temporal gyri), (2) fractional anisotropy of white matter tracts (prominently at white matter tracts connecting to the medial temporal lobe), and (3) episodic memory performance. For each of these findings, the pattern was similar: valine/valine individuals in late life were susceptible, and in early adult life, methionine allele carriers demonstrated susceptibility. CONCLUSIONS: The BDNF gene confers risk in an age dependent manner on the brain structures and cognitive functions that are consistent with the neural circuitry vulnerable in the earliest stages of AD. Our novel findings provide convergent evidence in vivo for a BDNF genetic mechanism of susceptibility in an intermediate phenotype related to AD. PMID- 21300948 TI - The role of clusterin, complement receptor 1, and phosphatidylinositol binding clathrin assembly protein in Alzheimer disease risk and cerebrospinal fluid biomarker levels. AB - CONTEXT: Two recent and simultaneously published genome-wide association studies independently implicated clusterin (CLU), complement receptor 1 (CR1), and phosphatidylinositol binding clathrin assembly protein (PICALM) as putative novel Alzheimer disease (AD) risk loci. Despite their strong statistical support, all 3 signals emerged from heterogeneous case-control populations and lack replication in different settings. OBJECTIVE: To determine whether genetic variants in CLU, CR1, and PICALM confer risk for AD in independent data sets (n = 4254) and to test the impact of these markers on cerebrospinal fluid (CSF)-Abeta42 and total tau protein levels (n = 425). DESIGN: Genetic association study using family based and case-control designs. SETTING: Ambulatory or hospitalized care. PARTICIPANTS: Family samples originate from mostly multiplex pedigrees recruited at different centers in the United States (1245 families, 2654 individuals with AD, and 1175 unaffected relatives). Unrelated case-control subjects originate from 1 clinical center in Germany (214 individuals with AD and 211 controls). All subjects were of European descent. MAIN OUTCOME MEASURES: The association between 5 genetic variants in CLU, CR1, and PICALM and risk for AD, and the correlation between these 5 genetic variants and CSF-Abeta42 and tau levels. RESULTS: All 3 investigated loci showed significant associations between risk for AD (1-tailed P values ranging from <.001 to .02) and consistent effect sizes and direction. For each locus, the overall evidence of association was substantially strengthened on meta-analysis of all available data (2-tailed P values ranging from 1.1 * 10(-16) to 4.1 * 10-7). Of all markers tested, only rs541458 in PICALM was shown to have an effect on CSF protein levels, suggesting that the AD risk allele is associated with decreased CSF Abeta42 levels (2-tailed P = .002). CONCLUSIONS: This study provides compelling independent evidence that genetic variants in CLU, CR1, and PICALM are genetically associated with risk for AD. Furthermore, the CSF biomarker analyses provide a first insight into the potentially predominant pathogenetic mechanism(s) underlying the association between AD risk and PICALM. PMID- 21300949 TI - Preservation of the capacity to appoint a proxy decision maker: implications for dementia research. AB - CONTEXT: Research involving persons with impaired decision-making capacity (such as persons with Alzheimer disease [AD]) remains ethically challenging, especially when the research involves significant risk. If individuals incapable of consenting to research studies were able to appoint a research proxy, it would allow for an appointed surrogate (rather than a de facto surrogate) to represent the subject. OBJECTIVE: To assess the extent to which persons with AD retain their capacity to appoint a research proxy. DESIGN: Interview study. SETTING: Academic research. PARTICIPANTS: One hundred eighty-eight persons with AD were interviewed for their capacity to appoint a proxy for research and to provide consent to 2 hypothetical research scenarios, a lower-risk randomized clinical trial testing a new drug (drug RCT) and a higher-risk randomized clinical trial testing neurosurgical cell implants using a sham control condition (neurosurgical RCT). Categorical capacity status for each subject was determined by independent videotaped reviews of capacity interviews by 5 experienced psychiatrists. MAIN OUTCOME MEASURES: Categorical capacity determinations for the capacity to appoint a research proxy, capacity to consent to a drug RCT, and capacity to consent to a neurosurgical RCT. RESULTS: Data showed that 37.7% (40 of 106) of those deemed incapable of consenting to the drug RCT and 54.8% (86 of 157) of those deemed incapable of consenting to the neurosurgical RCT were found capable of appointing a research proxy. Only 7 of 186 (3.8%) were deemed capable of consenting to the neurosurgical RCT by all 5 psychiatrists. CONCLUSIONS: A substantial proportion of persons with AD who were thought incapable of consenting to lower-risk or higher-risk studies have preserved capacity for appointing a research proxy. Because few persons are found to be unequivocally capable of providing independent consent to higher-risk AD research, providing for an appointed surrogate even after the onset of AD, which might best be done in the early stages of the illness, may help address key ethical challenges to AD research. PMID- 21300950 TI - Another score to predict ischemic stroke mortality? PMID- 21300951 TI - IScore: a risk score to predict death early after hospitalization for an acute ischemic stroke. AB - BACKGROUND: A predictive model of stroke mortality may be useful for clinicians to improve communication with and care of hospitalized patients. Our aim was to identify predictors of mortality and to develop and validate a risk score model using information available at hospital presentation. METHODS AND RESULTS: This retrospective study included 12 262 community-based patients presenting with an acute ischemic stroke at multiple hospitals in Ontario, Canada, between 2003 and 2008 who had been identified from the Registry of the Canadian Stroke Network (8223 patients in the derivation cohort, 4039 in the internal validation cohort) and the Ontario Stroke Audit (3720 for the external validation cohort). The mortality rates for the derivation and internal validation cohorts were 12.2% and 12.6%, respectively, at 30 days and 22.5% and 22.9% at 1 year. Multivariable predictors of 30-day and 1-year mortality included older age, male sex, severe stroke, nonlacunar stroke subtype, glucose >=7.5 mmol/L (135 mg/dL), history of atrial fibrillation, coronary artery disease, congestive heart failure, cancer, dementia, kidney disease on dialysis, and dependency before the stroke. A risk score index stratified the risk of death and identified low- and high- risk individuals. The c statistic was 0.850 for 30-day mortality and 0.823 for 1-year mortality for the derivation cohort, 0.851 for the 30-day model and 0.840 for the 1-year mortality model in the internal validation set, and 0.790 for the 30-day model and 0.782 for the 1-year model in the external validation set. CONCLUSION: Among patients with ischemic stroke, factors identifiable within hours of hospital presentation predicted mortality risk at 30 days and 1 year. The predictive score may assist clinicians in estimating stroke mortality risk and policymakers in providing a quantitative tool to compare facilities. PMID- 21300952 TI - Upstream clopidogrel use and the efficacy and safety of early eptifibatide treatment in patients with acute coronary syndrome: an analysis from the Early Glycoprotein IIb/IIIa Inhibition in Patients with Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) trial. AB - BACKGROUND: In the Early Glycoprotein IIb/IIIa Inhibition in Patients with Non-ST Segment Elevation Acute Coronary Syndrome (EARLY ACS) trial, routine preangiography eptifibatide use was not superior to delayed provisional use but led to more bleeding. This analysis examines efficacy and safety of early eptifibatide in the setting of concurrent upstream clopidogrel use. METHODS AND RESULTS: In EARLY-ACS, clopidogrel use and timing were determined by treating physicians, but randomization to early eptifibatide versus placebo was stratified by the intent to use upstream clopidogrel. Among 9166 non-ST-elevation acute coronary syndrome patients who underwent coronary angiography, intent to use upstream clopidogrel was declared in 6895 (75%), and 7068 (77%) received upstream clopidogrel. After multivariable adjustment, intended upstream clopidogrel use did not differentially influence the effect of early eptifibatide on the primary end point of 96-hour death/myocardial infarction/recurrent ischemia requiring urgent revascularization/thrombotic bailout (interaction P=0.988). Early eptifibatide use reduced 30-day death/myocardial infarction among patients with intended upstream clopidogrel (adjusted odds ratio 0.85; 95% confidence interval 0.73 to 0.99) but not among those without intended upstream clopidogrel use (adjusted odds ratio 1.02; 95% confidence interval 0.80 to 1.30). However, the clopidogrel by randomized treatment interaction term was not significant (P=0.23). Thrombolysis in Myocardial Infarction major bleeding risk was increased with early eptifibatide in the setting of upstream clopidogrel use. Results were similar using actual clopidogrel treatment strata. CONCLUSIONS: Routine early eptifibatide use, compared with delayed provisional use, may be associated with lower 30-day ischemic risk in non-ST-elevation acute coronary syndrome patients also treated with clopidogrel before angiography. The benefit-risk ratio of intensive platelet inhibition with combined early use of antiplatelet agents needs further evaluation in prospective randomized trials. PMID- 21300953 TI - Remote ischemic preconditioning protects the brain against injury after hypothermic circulatory arrest. AB - BACKGROUND: Ischemic preconditioning (IPC) is a mechanism protecting tissues from injury during ischemia and reperfusion. Remote IPC (RIPC) can be elicited by applying brief periods of ischemia to tissues with ischemic tolerance, thus protecting vital organs more susceptible to ischemic damage. Using a porcine model, we determined whether RIPC of the limb is protective against brain injury caused by hypothermic circulatory arrest (HCA). METHODS AND RESULTS: Twelve piglets were randomized to control and RIPC groups. RIPC was induced in advance of cardiopulmonary bypass by 4 cycles of 5 minutes of ischemia of the hind limb. All animals underwent cardiopulmonary bypass followed by 60 minutes of HCA at 18 degrees C. Brain metabolism and electroencephalographic activity were monitored for 8 hours after HCA. Assessment of neurological status was performed for a week postoperatively. Finally, brain tissue was harvested for histopathological analysis. Study groups were balanced for baseline and intraoperative parameters. Brain lactate concentration was significantly lower (P<0.0001, ANOVA) and recovery of electroencephalographic activity faster (P<0.05, ANOVA) in the RIPC group. RIPC had a beneficial effect on neurological function during the 7-day follow-up (behavioral score; P<0.0001 versus control, ANOVA). Histopathological analysis demonstrated a significant reduction in cerebral injury in RIPC animals (injury score; mean [interquartile range]: control 5.8 [3.8 to 7.5] versus RIPC 1.5 [0.5 to 2.5], P<0.001, t test). CONCLUSIONS: These data demonstrate that RIPC protects the brain against HCA-induced injury, resulting in accelerated recovery of neurological function. RIPC might be neuroprotective in patients undergoing surgery with HCA and improve long-term outcomes. Clinical trials to test this hypothesis are warranted. PMID- 21300954 TI - Listing and transplanting adults with congenital heart disease. AB - BACKGROUND: An increasing number of patients with congenital heart disease (CHD) are reaching adulthood and may require heart transplantation. The survival of these patients after listing and transplantation has not been evaluated. METHODS AND RESULTS: A total of 41 849 patients (aged >18 years) were listed for primary transplantation during 1995-2009. Patients with a history of CHD (n=1035; 2.5%) were compared with those with other causes (non-CHD group) (n=40 814; 97.5%); 26 055 (62.3%) reached transplantation and were subdivided into those with (reoperation group; n=10 484; 40.2%) and without (nonreoperation group; n=15 571; 59.8%) a previous sternotomy. Survival on the waiting list was similar between groups, but mechanical ventricular assistance was not associated with superior survival to transplantation among CHD patients. CHD patients were more likely to have body mass index <18.5 at transplantation (P<0.0001), were younger, and had fewer comorbidities. Early mortality among patients with CHD was high (reoperation, 18.9% versus 9.6%; P<0.0001; nonreoperation, 16.6% versus 6.3%; P<0.0001), but by 10 years, overall survival was equivalent (53.8% versus 53.6%). Analysis was limited by the lack of specific information regarding the CHD diagnosis in most patients. CONCLUSIONS: Adults with CHD have high 30-day mortality but better late survival after heart transplantation. Mechanical circulatory assistance does not improve waiting list survival in these patients. This may be due to a combination of highly complex reoperative surgery and often poor preoperative systemic health. PMID- 21300956 TI - Remote ischemic preconditioning: making the brain more tolerant, safely and inexpensively. PMID- 21300957 TI - Percutaneous transcatheter valve-in-valve implantation in stenosed tricuspid valve bioprosthesis. PMID- 21300955 TI - Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels. AB - BACKGROUND: C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels. METHODS AND RESULTS: We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body mass index with LEPR (P<2.9*10(-6)). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained ~5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease. CONCLUSIONS: We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation. PMID- 21300958 TI - Platypnea-orthodeoxia syndrome associated with bioprosthetic tricuspid valve stenosis and reverse Lutembacher syndrome. PMID- 21300959 TI - Letter by Ribichini et al regarding article, "Cystatin C and contrast-induced acute kidney injury". PMID- 21300961 TI - Novel percutaneous cardiac assist devices: the science of and indications for hemodynamic support. PMID- 21300962 TI - Impact of genetic insights into mendelian disease on cardiovascular clinical practice. PMID- 21300964 TI - Resistant pericardial tamponade. PMID- 21300965 TI - Teaching video neuroimages: hypothalamic hamartoma: an overlooked entity. PMID- 21300966 TI - Teaching neuroimages: reversal sign on CT in a child with hypoxic-ischemic brain injury. PMID- 21300963 TI - Assessing the role of circulating, genetic, and imaging biomarkers in cardiovascular risk prediction. PMID- 21300967 TI - Reorganization in cognitive networks with progression of multiple sclerosis: insights from fMRI. AB - OBJECTIVES: Cognitive dysfunction (CD) is frequent in multiple sclerosis (MS) and can occur at early stages. Whereas functional reorganization with disease progression has been described for the motor system in MS using fMRI, no such studies exist for cognition. We attempted to assess the concept of functional reorganization concerning cognition using a simple "Go/No-go" fMRI paradigm. METHODS: Patients with a clinically isolated syndrome (CIS, n = 10), relapsing remitting MS (RRMS) (n = 10), or secondary progressive MS (SPMS) (n = 10), and 28 healthy controls (HC), underwent a comprehensive neuropsychological test battery, clinical examination, structural imaging, and an fMRI Go/No-go discrimination task at 3 T. RESULTS: Patients performed worse than HC regarding memory, sustained attention and concentration, and information processing. These differences were driven by patients with SPMS. The fMRI task elicited activation in a widespread network including bilateral mesial and dorsolateral frontal, parietal, insular, basal ganglia, and cerebellar regions. Task performance was similar between phenotypes, but deviation from the activation pattern observed in HC and patients with CIS increased with disease progression. Patients with RRMS showed increased brain activation in the precuneus, both superior parietal lobes, and the right fusiform gyrus, and recruited the hippocampus with increasing demands. Patients with SPMS demonstrated the most abnormal network function, including recruitment of pre-SMA, bilateral superior and inferior parietal, dorsolateral prefrontal, right precentral, bilateral postcentral, and right temporal brain areas. CONCLUSION: Using a cognitive fMRI paradigm, we were able to confirm adaptive changes of neuronal activation with progressing MS and to provide strong evidence for their compensatory nature, at least partially. PMID- 21300968 TI - Ultra-high-field imaging distinguishes MS lesions from asymptomatic white matter lesions. AB - OBJECTIVES: To investigate whether multiple sclerosis (MS) and non-MS white matter brain lesions can be distinguished by their appearance on 7 T T2*-weighted MRI. METHODS: This was an observational study of 28 patients with MS and 17 patients with cerebral white matter lesions who did not have MS. Subjects were imaged using 7 T T2*-weighted imaging. White matter lesions were identified and analyzed for volume, location, and perivenous appearance. RESULTS: Out of 901 lesions identified in patients with MS, 80% were perivenous. In comparison, 19% of 428 lesions identified in patients without MS had a perivenous appearance. Seven-Tesla T2*-weighted MRI reliably distinguished all patients with clinically definite MS (>40% lesions appeared perivenous) from those without clinical MS (<40% lesions appeared perivenous). Perivenous lesion appearance was more predictive of MS (odds ratio [OR] 14, p < 0.001) than subcortical or periventricular lesion location (OR 4.5, p < 0.001, and OR 2.4, p = 0.009). Perivenous lesion appearance was observed with a similar frequency in patients with clinically isolated syndrome of demyelination and in early (gadolinium enhancing) MS lesions. CONCLUSION: Perivenous lesion location on 7 T T2*-weighted imaging is predictive of the presence of demyelination. Optimization of this imaging technique at lower magnetic resonance field strengths would offer benefit for the diagnosis of MS. PMID- 21300969 TI - Sun exposure and vitamin D are independent risk factors for CNS demyelination. AB - OBJECTIVES: To examine whether past and recent sun exposure and vitamin D status (serum 25-hydroxyvitamin D [25(OH)D] levels) are associated with risk of first demyelinating events (FDEs) and to evaluate the contribution of these factors to the latitudinal gradient in FDE incidence in Australia. METHODS: This was a multicenter incident case-control study. Cases (n = 216) were aged 18-59 years with a FDE and resident within one of 4 Australian centers (from latitudes 27 degrees S to 43 degrees S), from November 1, 2003, to December 31, 2006. Controls (n = 395) were matched to cases on age, sex, and study region, without CNS demyelination. Exposures measured included self-reported sun exposure by life stage, objective measures of skin phenotype and actinic damage, and vitamin D status. RESULTS: Higher levels of past, recent, and accumulated leisure-time sun exposure were each associated with reduced risk of FDE, e.g., accumulated leisure time sun exposure (age 6 years to current), adjusted odds ratio (AOR) = 0.70 (95% confidence interval [CI] 0.53-0.94) for each ultraviolet (UV) dose increment of 1,000 kJ/m(2) (range 508-6,397 kJ/m(2)). Higher actinic skin damage (AOR = 0.39 [95% CI 0.17-0.92], highest grade vs the lowest) and higher serum vitamin D status (AOR = 0.93 [95% CI 0.86-1.00] per 10 nmol/L increase in 25(OH)D) were independently associated with decreased FDE risk. Differences in leisure-time sun exposure, serum 25(OH)D level, and skin type additively accounted for a 32.4% increase in FDE incidence from the low to high latitude regions. CONCLUSIONS: Sun exposure and vitamin D status may have independent roles in the risk of CNS demyelination. Both will need to be evaluated in clinical trials for multiple sclerosis prevention. PMID- 21300970 TI - Serum elements and oxidative status in clinically isolated syndromes: imbalance and predictivity. AB - BACKGROUND: Metals are suspected of being involved in the pathogenesis of various neurologic diseases. We previously found a complex imbalance in serum chemical elements and oxidative status in patients with clinically definite multiple sclerosis (CDMS). OBJECTIVE: To understand whether this imbalance affects people with clinically isolated syndrome (CIS) and, if so, whether it predicts conversion to CDMS. METHODS: We studied 22 chemical elements and the oxidative status in 49 patients with CIS, 49 patients with CDMS, and 49 healthy donors (HD). Univariate and multivariate approaches were used to identify profiles for each group. A logistic regression analysis was used to identify the predictive potential of baseline data (elements, oxidative status, and MRI findings) for conversion to CDMS over 36 months. RESULTS: Several elements and oxidative status values differed significantly among the 3 groups. Discriminant analysis revealed a major contribution of Ca, Fe, Sn, Zn, serum antioxidant capacity, and serum oxidative status, which resulted in distinct profiles (the prediction of group membership was 96% [cross-validated 92%] for HD, 92% [cross-validated 92%] for CDMS, and 90% [cross-validated 86%] for CIS). A weighted combination of element concentrations and oxidative status values, adjusting for all other predictors, would predict a reduction in the risk of conversion to CDMS within 3 years (odds ratio 0.37; 95% confidence interval 0.18-0.76; p = 0.007), thereby proving more effective than MRI at baseline. CONCLUSIONS: The peculiar imbalance in serum elements and oxidative status that characterizes patients with CIS and may predict conversion to CDMS warrants studies on larger sample sizes. PMID- 21300971 TI - Video-EEG monitoring in newborns with hypoxic-ischemic encephalopathy treated with hypothermia. AB - BACKGROUND: Therapeutic hypothermia (TH) is becoming standard of care in newborns with hypoxic-ischemic encephalopathy (HIE). The prognostic value of the EEG and the incidence of seizures during TH are uncertain. OBJECTIVE: To describe evolution of EEG background and incidence of seizures during TH, and to identify EEG patterns predictive for MRI brain injury. METHODS: A total of 41 newborns with HIE underwent TH. Continuous video-EEG was performed during hypothermia and rewarming. EEG background and seizures were reported in a standardized manner. Newborns underwent MRI after rewarming. Sensitivity and specificity of EEG background for moderate to severe MRI brain injury was assessed at 6-hour intervals during TH and rewarming. RESULTS: EEG background improved in 49%, remained the same in 38%, and worsened in 13%. A normal EEG had a specificity of 100% upon initiation of monitoring and 93% at later time points. Burst suppression and extremely low voltage patterns held the greatest prognostic value only after 24 hours of monitoring, with a specificity of 81% at the beginning of cooling and 100% at later time points. A discontinuous pattern was not associated with adverse outcome in most patients (73%). Electrographic seizures occurred in 34% (14/41), and 10% (4/41) developed status epilepticus. Seizures had a clinical correlate in 57% (8/14) and were subclinical in 43% (6/14). CONCLUSIONS: Continuous video-EEG monitoring in newborns with HIE undergoing TH provides prognostic information about early MRI outcome and accurately identifies electrographic seizures, nearly half of which are subclinical. PMID- 21300972 TI - Lessons from the clinic: a case of natalizumab-associated PML. PMID- 21300973 TI - Indolent course of progressive multifocal leukoencephalopathy during natalizumab treatment in MS. PMID- 21300974 TI - CNS infection, CSF matrix metalloproteinase concentrations, and clinical/laboratory features. PMID- 21300975 TI - Generic antiepileptic drugs and associated medical resource utilization in the United States. PMID- 21300976 TI - Pure sensory infarct in the territories of anterior cerebral artery. PMID- 21300977 TI - Viral induction and targeted inhibition of galectin-1 in EBV+ posttransplant lymphoproliferative disorders. AB - Posttransplant lymphoproliferative disorders (PTLDs) are potentially fatal, EBV driven B-cell malignancies that develop in immunocompromised solid organ or hematopoietic stem cell recipients. In PTLD, the expression of EBV proteins, including latent membrane protein 1 (LMP1) and LMP2A, viral immune evasion strategies, and impaired host immune surveillance foster the proliferation of EBV transformed B cells. Current PTLD treatment strategies include reduction of immunosuppression, which increases the risk of graft rejection, anti-CD20 treatment, combination chemotherapy, and administration of EBV-specific cytotoxic T cells. In the present study, we report that EBV-transformed lymphoblastoid B cell lines (LCLs) and primary PTLDs overexpress galectin-1 (Gal1), a carbohydrate binding lectin that induces tolerogenic dendritic cells and triggers the selective apoptosis of CD4(+) Th1 and Th17 cells and cytotoxic T cells. In transcriptional reporter assays, LMP2A and LMP1 each increased Gal1-driven luciferase expression, and the combination of LMP2A and LMP1 was additive. In addition, small interfering RNA (siRNA)-mediated depletion of LMP2A decreased Gal1 protein abundance in EBV-transformed LCLs. Gal1 expression in LCLs was dependent on both activating protein 1 (AP-1) and PI3K. A newly developed neutralizing Gal1 mAb selectively inhibited Gal1-mediated apoptosis of EBV specific CD8(+) T cells. Given the tolerogenic and immunosuppressive function of Gal1, antibody-mediated Gal1 neutralization may represent a novel immunotherapeutic strategy for PTLD and other Gal1-expressing tumors. PMID- 21300978 TI - The rate of hemolysis in sickle cell disease correlates with the quantity of active von Willebrand factor in the plasma. AB - Vaso-occlusion, hemolysis, and oxidative stress are hallmarks of sickle cell disease (SCD). This pathology is accompanied by systemic endothelial activation, rendering the endothelium more adhesive for blood cells, including sickle erythrocytes. Activated endothelial cells display or secrete several adhesive molecules, including von Willebrand factor (VWF). We assessed several VWF parameters in SCD patients at baseline: multimer pattern, antigen concentration (VWF:Ag), activation factor (VWF:AF), and total active VWF (VWF:TA). VWF:AF was determined using a llama nanobody (AU/VWFa-11) that detects a platelet-binding conformation of the A1 domain; VWF:TA was calculated by multiplying VWF:Ag by VWF:AF. SCD plasma contained elevated VWF:Ag and ultralarge VWF multimers. VWF:TA, a measure of total VWF reactivity, correlated closely with hemolysis, as determined by serum lactate dehydrogenase. ADAMTS13 activity and antigen were normal in all patients. These findings suggest an important role for hyperreactive VWF in SCD pathology and connect SCD to other microangiopathies, particularly thrombotic thrombocytopenic purpura. PMID- 21300979 TI - Molecular identification of an MHC-independent ligand recognized by a human {alpha}/{beta} T-cell receptor. AB - During an analysis of T-cell responses against human renal cell carcinoma (RCC), we identified a CD4(+) T-cell line that showed TCR-mediated recognition and lysis of nearly all RCC lines regardless of MHC type. We have now elucidated the nature of the ligand for this alpha/beta TCR, and it contains no MHC-related moiety and does not involve classic peptide processing. First, matrix metalloproteinase 14 (MMP14) expressed on RCC cells releases membrane-bound TRAIL expressed by the T cell; then, soluble TRAIL binds to its receptor DR4 (TRAIL-R1), which is expressed on tumor cells, and this TRAIL-DR4 complex is recognized by the TCR through a complementarity-determining region 3alpha (CDR3alpha)-mediated interaction. Direct and specific antigen-TCR interaction was demonstrated when the immobilized recombinant TRAIL/DR4 complex stimulated the TCR. In addition, amino acid substitutions in the CDR3alpha of the TCR either obliterated or enhanced target-specific recognition. This description of the molecular nature of a non-MHC target structure recognized by a naturally occurring alpha/beta TCR not only broadens our concept of what the TCR can recognize, but also raises the question of whether such a T cell could be of clinical utility against RCC. PMID- 21300980 TI - The tumor marker Fascin is strongly induced by the Tax oncoprotein of HTLV-1 through NF-kappaB signals. AB - Oncogenic transformation of CD4(+) T cells by human T-cell lymphotropic virus type 1 (HTLV-1) is understood as the initial step to adult T-cell leukemia/lymphoma, a process that is mainly initiated by perturbation of cellular signaling by the viral Tax oncoprotein, a potent transcriptional regulator. In search of novel biomarkers with relevance to oncogenesis, we identified the tumor marker and actin-bundling protein Fascin (FSCN1) to be specifically and strongly up-regulated in both HTLV-1-transformed and adult T-cell leukemia/lymphoma patient-derived CD4(+) T cells. Fascin is important for migration and metastasis in various types of cancer. Here we report that a direct link can exist between a single viral oncoprotein and Fascin expression, as the viral oncoprotein Tax was sufficient to induce high levels of Fascin. Nuclear factor-kappaB signals were important for Tax-mediated transcriptional regulation of Fascin in T cells. This suggests that Fascin up-regulation by Tax contributes to the development of HTLV 1-associated pathogenesis. PMID- 21300981 TI - Application of dual affinity retargeting molecules to achieve optimal redirected T-cell killing of B-cell lymphoma. AB - We describe the application of a novel, bispecific antibody platform termed dual affinity retargeting (DART) to eradicate B-cell lymphoma through coengagement of the B cell-specific antigen CD19 and the TCR/CD3 complex on effector T cells. Comparison with a single-chain, bispecific antibody bearing identical CD19 and CD3 antibody Fv sequences revealed DART molecules to be more potent in directing B-cell lysis. The enhanced activity with the CD19xCD3 DART molecules was observed on all CD19-expressing target B cells evaluated using resting and prestimulated human PBMCs or purified effector T-cell populations. Characterization of a CD19xTCR bispecific DART molecule revealed equivalent potency with the CD19xCD3 DART molecule, demonstrating flexibility of the DART structure to support T cell/B-cell associations for redirected T cell-killing applications. The enhanced level of killing mediated by DART molecules was not accompanied by any increase in nonspecific T-cell activation or lysis of CD19(-) cells. Cell-association studies indicated that the DART architecture is well suited for maintaining cell to-cell contact, apparently contributing to the high level of target cell killing. Finally, the ability of the CD19xTCR DART to inhibit B-cell lymphoma in NOD/SCID mice when coadministered with human PBMCs supports further evaluation of DART molecules for the treatment of B-cell malignancies. PMID- 21300982 TI - c-JUN promotes BCR-ABL-induced lymphoid leukemia by inhibiting methylation of the 5' region of Cdk6. AB - The transcription factor c-JUN and its upstream kinase JNK1 have been implicated in BCR-ABL-induced leukemogenesis. JNK1 has been shown to regulate BCL2 expression, thereby altering leukemogenesis, but the impact of c-JUN remained unclear. In this study, we show that JNK1 and c-JUN promote leukemogenesis via separate pathways, because lack of c-JUN impairs proliferation of p185(BCR-ABL) transformed cells without affecting their viability. The decreased proliferation of c-Jun(Delta/Delta) cells is associated with the loss of cyclin-dependent kinase 6 (CDK6) expression. In c-Jun(Delta/Delta) cells, CDK6 expression becomes down-regulated upon BCR-ABL-induced transformation, which correlates with CpG island methylation within the 5' region of Cdk6. We verified the impact of Cdk6 deficiency using Cdk6(-/-) mice that developed BCR-ABL-induced B-lymphoid leukemia with significantly increased latency and an attenuated disease phenotype. In addition, we show that reexpression of CDK6 in BCR-ABL-transformed c-Jun(Delta/Delta) cells reconstitutes proliferation and tumor formation in Nu/Nu mice. In summary, our study reveals a novel function for the activating protein 1 (AP-1) transcription factor c-JUN in leukemogenesis by antagonizing promoter methylation. Moreover, we identify CDK6 as relevant and critical target of AP-1 regulated DNA methylation on BCR-ABL-induced transformation, thereby accelerating leukemogenesis. PMID- 21300983 TI - Deletion of cIAP1 and cIAP2 in murine B lymphocytes constitutively activates cell survival pathways and inactivates the germinal center response. AB - B cells require signals delivered through B-cell activating factor of the TNF family receptor (BAFF-R) and CD40 to survive and produce antibody responses in vivo. In vitro data indicate that these signals are controlled by the homologous RING finger proteins cIAP1 and cIAP2, in collaboration with TRAF2 and TRAF3. There is also mounting evidence that all 4 of these signaling molecules can act as tumor suppressors in human B-lineage malignancies. However, it has not been possible to identify the roles of cIAP1 and cIAP2 in controlling B-cell physiology because of the absence of an appropriate in vivo model. Here we describe a unique genetically modified mouse in which the linked cIap1 and cIap2 genes can be independently inactivated. Deletion of cIAP1 plus cIAP2 (but not either protein alone) rendered primary B cells independent of BAFF-R for their survival and led to their uncontrolled accumulation in vivo. B cells deficient in cIAP1 and cIAP2 were also incapable of forming germinal centers, a key step in antibody-mediated immunity. These data define a fundamental role for cIAP1/cIAP2 in regulating B-cell survival and responsiveness, show this requires direct binding to TRAF2, and suggest how mutations of TRAF2, TRAF3, and cIAP1/cIAP2 contribute to B-lineage malignancies, such as multiple myeloma. PMID- 21300985 TI - Manipulations of AMP metabolic genes increase growth rate and cold tolerance in Escherichia coli: implications for psychrophilic evolution. AB - Diverse organisms have adapted to thrive at low temperatures (i.e., <20 degrees C, termed psychrophiles), colonizing the majority of earth's biosphere. In contrast with mesophiles (20-40 degrees C thermal range), all observed psychrophiles increase intracellular adenosine 5'-triphosphate concentrations as temperatures decline; this phenomenon has been described as an important compensatory mechanism to deal with decreases in thermal energy and molecular motion. We considered purine metabolic pathways in class gammaproteobacteria (n = 115) to investigate metabolic and evolutionary bases of this process. A survey of the KEGG database indicated that psychrophilic purine metabolic pathways tend to be enriched with de novo adenosine 5'-monophosphate (AMP) synthetic enzymes, whereas mesophiles tend to be enriched with AMP degradative enzymes. Function of the observed psychrophilic pathway structure was tested by engineering the mesophilic gammaproteobacterium Escherichia coli to reflect psychrophilic purine metabolism, specifically by expressing adenylosuccinate synthetase (purA) from the psychrophilic gammaproteobacterium, Psychrobacter cryohalolentis, in an AMP nucleosidase (amn)-deficient background. Modified E. coli was capable of growing up to ~70% faster at low temperatures and became up to ~10-fold more cold tolerant relative to wild type. These findings highlight potentially important transitional steps in psychrophilic evolution. PMID- 21300986 TI - Approximate Bayesian analysis of Drosophila melanogaster polymorphism data reveals a recent colonization of Southeast Asia. AB - Southeast Asian populations of the fruit fly Drosophila melanogaster differ from ancestral African and derived European populations by several morphological characteristics. It has been argued that this morphological differentiation could be the result of an early colonization of Southeast Asia that predated the migration of D. melanogaster to Europe after the last glacial period (around 10,000 years ago). To investigate the colonization process of Southeast Asia, we collected nucleotide polymorphism data for more than 200 X-linked fragments and 50 autosomal loci from a population of Malaysia. We analyzed this new single nucleotide polymorphism data set jointly with already existing data from an African and a European population by employing an Approximate Bayesian Computation approach. By contrasting different demographic models of these three populations, we do not find any evidence for an early divergence between the African and the Asian populations. Rather, we show that Asian and European populations of D. melanogaster share a non-African most recent common ancestor that existed about 2,500 years ago. PMID- 21300984 TI - The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. AB - The World Health Organization classification of lymphoid neoplasms updated in 2008 represents a worldwide consensus on the diagnosis of these tumors and is based on the recognition of distinct diseases, using a multidisciplinary approach. The updated classification refined the definitions of well-recognized diseases, identified new entities and variants, and incorporated emerging concepts in the understanding of lymphoid neoplasms. However, some questions were unresolved, such as the extent to which specific genetic or molecular alterations define certain tumors, and the status of provisional entities, categories for which the World Health Organization working groups felt there was insufficient evidence to recognize as distinct diseases at this time. In addition, since its publication, new findings and ideas have been generated. This review summarizes the scientific rationale for the classification, emphasizing changes that have had an effect on practice guidelines. The authors address the criteria and significance of early or precursor lesions and the identification of certain lymphoid neoplasms largely associated with particular age groups, such as children and the elderly. The issue of borderline categories having overlapping features with large B-cell lymphomas, as well as several provisional entities, is reviewed. These new observations chart a course for future research in the field. PMID- 21300991 TI - The influence of formulation and medicine delivery system on medication administration errors in care homes for older people. AB - INTRODUCTION: Older people in care homes are at increased risk of medication errors and adverse drug events. The effect of formulation on administration errors is not known, that is whether the medicine is a tablet or capsule, liquid or device such as an inhaler. Also, the impact on administration errors of monitored dosage systems (MDS), commonly used in UK care homes to dispense tablets and capsules, is not known. This study investigated the influence of formulation and MDS on administration errors. METHODS: Administration errors were identified by pharmacists (using validated definitions) observing two drug rounds of residents randomly selected from a purposive sample of UK nursing and residential homes. Errors were classified and analysed by formulation and medicine delivery system. RESULTS: The odds of administration errors by formulation, when compared with tablets and capsules in MDS, were: liquids 4.31 (95% CI 2.02 to 9.21; p = 0.0002); topicals/transdermals/injections 19.61 (95% CI 6.90 to 55.73; p < 0.0001); inhalers 33.58 (95% CI 12.51 to 90.19; p < 0.0001). The odds of administration errors for tablets and capsules not in MDS were double those that were dispensed in MDS (adjusted OR 2.14, 95% CI 1.02 to 4.51; p = 0.04). CONCLUSIONS: Inhalers and liquid medicines were associated with significantly increased odds of administration errors. Training of staff in safe administration of these formulations needs implementing. Although there was some evidence that MDS reduced the odds of an administration error, the use of MDS impacts on other aspects of medicines management. Because of this, and as the primary topic of our study was not MDS, a prospective trial specifically designed to evaluate the overall impact of MDS on medicine management in care homes is needed. PMID- 21300993 TI - Are dietary patterns in childhood associated with IQ at 8 years of age? A population-based cohort study. AB - BACKGROUND: Little is known about the effects of overall diet in childhood and intelligence later in life. METHODS: The current study, based on the Avon Longitudinal Study of Parents and Children, uses data on children's diet reported by parents in food-frequency questionnaires at 3, 4, 7 and 8.5 years of age. Dietary patterns were identified using principal-components analysis and scores computed at each age. IQ was assessed using the Wechsler Intelligence Scale for Children at 8.5 years. Data on a number of confounders were collected, and complete data were available for 3966 children. RESULTS: After adjustment, the 'processed' (high fat and sugar content) pattern of diet at 3 years of age was negatively associated with IQ assessed at 8.5 years of age-a 1 SD increase in dietary pattern score was associated with a 1.67 point decrease in IQ (95% CI 2.34 to -1.00; p<0.0001). The 'health-conscious' (salad, rice, pasta, fish, fruit) pattern at 8.5 years was positively associated with IQ: a 1 SD increase in pattern score led to a 1.20 point increase in IQ (95% CI 0.52 to 1.88; p=0.001). CONCLUSION: There is evidence that a poor diet associated with high fat, sugar and processed food content in early childhood may be associated with small reductions in IQ in later childhood, while a healthy diet, associated with high intakes of nutrient rich foods described at about the time of IQ assessment may be associated with small increases in IQ. PMID- 21300992 TI - The safety implications of missed test results for hospitalised patients: a systematic review. AB - BACKGROUND: Failure to follow-up test results is a critical safety issue. The objective was to systematically review evidence quantifying the extent of failure to follow-up test results and the impact on patient outcomes. METHODS: The authors searched Medline, CINAHL, Embase, Inspec and the Cochrane Database from 1990 to March 2010 for English-language articles which quantified the proportion of diagnostic tests not followed up for hospital patients. Four reviewers independently reviewed titles, abstracts and articles for inclusion. RESULTS: Twelve studies met the inclusion criteria and demonstrated a wide variation in the extent of the problem and the impact on patient outcomes. A lack of follow-up of test results for inpatients ranged from 20.04% to 61.6% and for patients treated in the emergency department ranged from 1.0% to 75% when calculated as a proportion of tests. Two areas where problems were particularly evident were: critical test results and results for patients moving across healthcare settings. Systems used to manage follow-up of test results were varied and included paper based, electronic and hybrid paper-and-electronic systems. Evidence of the effectiveness of electronic test management systems was limited. CONCLUSIONS: Failure to follow up test results for hospital patients is a substantial problem. Evidence of the negative impacts for patients when important results are not actioned, matched with advances in the functionality of clinical information systems, presents a convincing case for the need to explore solutions. These should include interventions such as on-line endorsement of results. PMID- 21300994 TI - The process and benefits of a university and state health agency collaboration for alcohol-free pregnancies in Oregon. AB - BACKGROUND: A significant number of college women are at risk for alcohol-exposed pregnancies because the ages of the heaviest alcohol consumption is typically 18 through 21 years, and contraception may be used ineffectively or not at all. These risks call for greater prevention efforts. OBJECTIVE: Collaboration between a higher education institution and a government health agency to reduce alcohol exposed pregnancies in Oregon. METHODS: Health professionals from the Fetal Alcohol Syndrome (FAS) Prevention Program of the Oregon Public Health Division presented current research and explained the mission of a Center for Disease Control (CDC) cooperative agreement to university students in a Health Communication course. The students then developed social marketing messages that targeted alcohol use and/or contraception behavior. RESULTS: At the end of the course, the students presented their campaigns campus-wide, and to the state agency. Four of the theory-based messages are illustrated in this article. CONCLUSION: The students brought to the state FAS Program a specific range of knowledge, vocabulary and creative skills to create messages for young adults. University students reported benefits of becoming familiar with government agencies and working on "real-life" projects that had the potential to be used in community settings. PMID- 21300995 TI - [The treatment of depression during pregnancy]. AB - The treatment of depression during pregnancy--the medical treatment or it's interruption should be considered based both on its inherent dangers and on its potential benefits--requires complex thinking of the psychiatrist, because the mother's and the fetus' health should be also considered. The area of reproductive psychiatry is evolving rapidly, which is highly necessary, in order to enhance the competence of psychiatrists. It is estimated that 20-25% of women in the stage of reproductive age require psychiatric care, so this type of maternal disease needs specific care for family planning. The methodology of the treatment depression during pregnancy is highly important, because present studies suggest that this is one of the most serious teratogenic risk to the fetus and to the new-born's development. PMID- 21300996 TI - [Hungarian psychiatry in the light of the Hungarian Presidency of the Council of the European Union]. AB - In order to get an accurate picture of mental health and psychiatric care, the article reviews the relevant structures and functioning of the European Union. It examines a few, important professional events that reflect the gaining significance of the issue of mental health within the EU; the 2005 World Health Organization's European Ministerial Conference, the 2008 European Pact for Mental Health and Well-being, and the results of the so-called Thematic Conferences. For the future of the European Union, the articles stresses the crucial need for the continuing research and development, and highlights the benefits of the European Research Region an its framework programmes especially in the fields of brain research and mental health research. The issue of mental health, its care providing system, and the atmosphere of the work place, as the surveying of the Eurobarometer underscored, should be treated as priorities for the EU and during the Hungarian presidency. The programme of the Hungarian Presidency of the Council of the European Union provides priority to the presentation of the European Pact for Mental Health and Well-being to the Council Conclusion, as well as to the organization of a priority research presidential conference on the regions R and D, entitled "Discovery research in neuropsychiatry: depression, anxiety and schizophrenia in focus." The articles emphasizes the challenges of Hungarian psychiatry, first and foremost the difficulties of human resources, the theoretical context and determined perspectives for the establishment of the new National Psychiatry and Addictology Institute, the need of the move towards GP's and community care, and the importance of the cooperation with civil organizations, and scientific information gathering. The given tasks can only be achieved along with the professional development of psychiatry, with a change of perspectives towards EU since a concentrated multi level allocation of resources is only possible in the forms of collaboration between different national and international bodies. Taking advantage of the Hungarian Presidency in order to achieve these goals will influence the future of both the European and Hungarian psychiatry. PMID- 21300997 TI - [Screening childhood behavior problems using short questionnaires II.: The Hungarian version of the SWAN-scale (Strength and Weakness of ADHD-symptoms and Normal-behavior) for screening attention deficit/hyperactivity disorder]. AB - INTRODUCTION: The SWAN (Strength and Weakness of ADHD-symptoms and Normal behavior) Questionnaire is a short instrument suitable for screening attention deficit/hyperactivity disorder. Its completion by parents or teachers requires a few minutes. Positive re-wording of attention- and activity-related behaviors and the extended 7- point rating scale anchored to average behavior make the instrument especially suitable for normal populations. Here, we report the Hungarian version of SWAN and compare its scales with relevant scales of the Child Behavior Checklist (CBCL) and the Strengths and Difficulties Questionnaire (SDQ). METHOD: Questionnaire data were collected from parents of 156 six-year-old children in a community sample. Of the 156 children 89 were participants of the longitudinal Budapest Infant-Parent Study (BIPS). RESULTS: Internal consistency of the Hungarian SWAN scales was excellent (Cronbach alfa: 0.87-0.93), correlations with relevant CBCL and SDQ scales were as expected (0.40-0.49 and 0.67-0.74) showing that the short questionnaire was suitable for detection of attention and hyperactivity problems. SWAN scores in our sample were normally distributed and scale means were also similar to foreign studies. CONCLUSIONS: These initial Hungarian data confirm international experience with the SWAN. Psychometric indices, distribution of scale scores in the sample and across the sexes were consistent with foreign studies. Following collection of normative data, the Hungarian version of SWAN might be suitable for assessing mental health of children and adolescents, and for screening problem cases. Due to the wider range and the normal distribution of scores, SWAN provides a more suitable phenotype for genetic studies, than symptom scales. PMID- 21300998 TI - [The role of emotional intelligence in addiction disorders]. AB - Role of emotions in the background of addictions is a long-studied question. Clinical observations and comorbidity studies unambiguously indicate that psychoactive substance use and dependence are related to emotional problems as well. Emotional intelligence is a relatively new concept of the study of managing emotions. On the revelation of this construct's relationship with psychoactive substance use and dependence only a few studies have been carried out so far. Present study systematically reviews articles born between 1990 and October 1, 2010 dealing with the relationship of these two factors. Out of the identified altogether 54 studies, 37 fitted the criteria of analysis. Studies overall indicate that lower levels of emotional intelligence are associated with more intensive drinking, smoking and illicit substance use and also more likely correlate with internet addiction, bulimia, gambling and impulsive buying. According to their results, especially the components called "recognizing emotions" and "regulation of emotions" of emotional intelligence play important roles regarding substance use. PMID- 21300999 TI - [The effect of taboo word on language processing]. AB - Knowledge about how we process taboo words brings us closer to the and emotional processes, and broadens the interpretative framework in psychiatry and psychotherapy. In this study the lexical decision paradigm was used. Subjects were presented neutral words, taboo words and pseudowords in a random order, and they had to indicate whether the presented word was meaningful (neutral and taboo words) or meaningless (pseudowords). Each target word was preceded by a prime word (either taboo or neutral). SOA differed in the two experimental conditions (it was 250 msec in the experimental group, and 500 msec in the control group). In the experimental group, response latencies increased for target words that were preceded by taboo prime words, as compared to those that were preceded by neutral prime words. In the control group prime had no such differential effects on response latencies. Results indicate that emotional processing of taboo words occur very early and the negative effect of taboo words on the following lexical decision fades away in 500 msec. Our experiment and other empirical data are presented in this paper. PMID- 21301000 TI - [Control or involvement? Relationship between parenting style and adolescent depression]. AB - BACKGROUND AND AIMS OF THE STUDY: A number of studies have pointed out that parenting style has a longstanding impact on psychological health. Besides parental/familial risk factors certain aspects of the parent-adolescent relationship may serve as a protective factor and help prevent adolescent depression such as the authoritative parenting style. The aim of the present study has been to analyze interrelationships between adolescent depressive symptomatology, authoritative parenting style, negative and positive parental links. METHOD: The study was carried out on in all primary and secondary schools in Mako and the surrounding region in the spring of 2010, students of grades 7-12 (N = 2072), 49.2% of the sample were males and 50.8% females; 38.1% primary school pupils and 61.9% high school students. Self-administered questionnaires contained items of measuring depressive symptoms (CDI) and parental variables beyond sociodemographics. After descripive statistics, correlation and multiple linear regression analyses have been used to detect interrelationships. RESULTS: Data support the protective effect of authoritative parenting style in relation to adolescent depression, particularly among girls. Among boys, only mother's responsive behavior proved to be a protective factor. Among girls, however, both elements of the father's authoritative parenting style were decisive; not only responsiveness but also demandingness. The parenting style of the opposite-sex parent was prevailing in both sexes. Negative family interactions served as a risk factor, whereas positive parental identification was a protective factor during adolescence as well. CONCLUSION: There is a need to strengthen the role of the authoritative parenting style and to guarantee the presence of the opposite sex parents in the adolescents' lives. Nowadays there are family-oriented interventions which put forward the effectiveness of parenting and problem solving and aiming at harmonizing the parent-adolescent relationship. PMID- 21301001 TI - [Analysis of psychic problems of university students continuing their studies for a significantly longer time than the average]. AB - BACKGROUND: Keniston introduced the term 'postadolescence' to describe the spreading phenomenon of young people not seceding from their parents and remaining in a functional child role longer. One aspect of this phenomenon is the increased time of studies. Research about postadolescent students struggling with their studies is scarce. METHODS: I analysed the psychopathological features, family dynamic specialties, cognitive style of 12 university students characterised by significant delay in the duration of their studies as a major problem, or associated with other symptoms, whom I examined and/or treated between 01/01/2004 and 12/31/2009. I analysed the data of students who could not finish the first 2 study years in 4 years, or could not complete their studies during the recommended duration within 2 extra years. RESULTS: 9 of the 12 (7 male, 5 female) examined students had an Axis I. diagnosis according to DSM-IV TR., with high comorbidity. 8 patients suffered from personality disorder. The family environment as well as parents' and partners' attitudes were often pathological: they either had irrealistic expectations about the students' performance, or played an important role in maintaining the pathological balance by not setting any requirements, hereby maintaining the pathological state. The students, partners and parents were often characterised by dysfunctional attitudes, maladaptive cognitive schemas. CONCLUSIONS: Behind delayed studies there is often severe mental disorder with marked dysfunctional cognitive functioning which needs to be treated. The treatment options of the students' mental problems include pharmacotherapy and/or individual psychotherapy, often accompanied by systemic interventions. PMID- 21301003 TI - Treatment issues surrounding hepatitis C in renal transplantation: a review. AB - Hepatitis C infection is prevalent in candidates for and recipients of solid organ transplants. In the renal transplant population, HCV infection has been shown to decrease long-term patient and graft survival. The outcomes of HCV in recipients of other solid organ transplants are yet to be established and prospective studies will be needed in the future. In the absence of effective and safe antiviral treatment for HCV infection in renal, heart, and lung transplant recipients, the management of these patients remains a challenge and has led to an increased focus on identifying and treating hepatitis C in patients prior to transplantation. Interferon-based therapy for HCV prior transplantation appears to improve outcomes after transplantation. On the other hand, post-transplant interferon therapy is associated with an increased risk of graft rejection. Given the paucity of information on HCV treatment in solid organ transplant recipients, there is a great need for large-scale, multi-centre randomized controlled trials to determine the optimal approach to HCV infection in this population. This article will summarize the current peer-reviewed literature focusing on the efficacy of amantadine, ribavirin and both standard and pegylated interferon in the treatment of chronic hepatitis C in renal, transplant recipients. PMID- 21301004 TI - Prevalence and risk factors for bacterial skin infection and mortality in cirrhosis. AB - BACKGROUND: Bacterial infections are often associated with significant morbidity and mortality in cirrhosis. The common practice of outdoor barefoot walking in the developing world may predispose cirrhotic individuals to skin infection. Aims. To determine the prevalence, risk factors, spectrum of infective organism and outcome of bacterial skin infection in cirrhosis. METHODS: Consecutive newly diagnosed patients with cirrhosis (n = 200) between September 2007 and September 2008 were studied. Patients with congestive heart failure (n = 50) and chronic kidney disease (n = 50) on follow up at the same institution served as controls. Baseline demographic details, history of outdoor barefoot walking, details of skin infection along with cultures from skin and blood were obtained. The association between patient factors and risk of skin infection was evaluated using logistic regression. RESULTS: Alcoholism was the predominant etiology for cirrhosis. (50%) Most of them were of Child B cirrhosis. Walking on barefoot was found to be similar in cases and controls. 21(10.5%) patients with cirrhosis had skin infection, three fourth of them had a history of barefoot walking. None of the controls had skin infection. Cellulitis with hemorrhagic bullae, leg ulcers, infected callosity and abscess were observed. The infective organism could be isolated in 17 patients. Escherichia coli was the most frequent organism identified. Logistic regression showed outdoor barefoot walking and serum albumin < 2.5 gm/dL as risk factors for skin infection. Four patients died. CONCLUSION: The prevalence of skin infection in cirrhosis was 10.5% with a mortality of 19%. Escherichia coli was the commonly implicated organism. Outdoor barefoot walking was a strong risk factor for skin infection in cirrhosis. PMID- 21301005 TI - Advanced hepatocellular carcinoma. Review of targeted molecular drugs. AB - Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world in terms of incidence, accounting for approximately 630 thousand new cases per year; in addition, HCC is the third most common cause of cancer death. Worldwide, the greatest risk factors for HCC are the infections caused by hepatitis B and C viruses, which increase the risk of developing the disease by about 20 times. The standard treatment in the early stages of the disease, such as surgical resection, local ablation and liver transplantation, are able to cure a proportion of patients, but most cases of HCC present in advanced stages, precluding the use of such treatments with curative intent. In these advanced stages, systemic treatments are commonly used. Unfortunately, chemotherapy with conventional cytotoxic agents is ineffective and does not seem to modify the natural history of disease. Treatment options for patients with advanced HCC are extremely limited, but the identification of signaling pathways, and the recognition of the role of these pathways in the pathogenesis of the disease resulted in the development of drugs directed at specific therapeutic targets. One such drug is Sorafenib, a kinase inhibitor with antiangiogenic and antiproliferative properties. In conclusion, Sorafenib has demonstrated survival benefits in patients with advanced HCC, thus representing a new standard reference for systemic treatment in these cases. PMID- 21301006 TI - Does HLA-DR7 differentiate the overlap syndrome of auto-immune hepatitis-primary biliary cirrhosis (AIH-PBC) from those with auto-immune hepatitis type 1? AB - INTRODUCTION: Autoimmune hepatitis (AIH) and overlap-syndrome (OS) are autoimmune liver diseases of unknown etiology. Although HLA-DR3/DR4 plays a susceptibility role in AIH but there is limited information in regard to OS. OBJECTIVE: Determine the genetic expression of HLA-DR among patients with AIH versus OS in order to establish susceptibility alleles in comparison to healthy controls (HC). METHODS: 26 patients with AIH and 15 patients with OS were studied. Ninety-nine healthy historical controls without autoimmunity were evaluated. Patients with AIH and OS were selected based on the international group for the study of AIH criteria and the Chazouilleres criteria for OS. Patients had at least one liver biopsy. Characterization of HLA-DR was extracted from peripheral blood leukocytes. Alleles were obtained for AIH, OS and HC and comparisons were made between groups. RESULTS: There was a significant increase in HLADR3 and DR1 in AIH compared with the HC group (p = 0.04, OR 2.6, 0.87-7.9, 95% CI). In the AIH group there was a decreased frequency in allele HLA-DR8 when compared with HC (p = 0.04, OR 3.2). There were no statistical differences between the genetic frequencies in the OS group compared with HC. However, HLA-DR7 was able to distinguish between OS patients from those with AIH (p = 0.02, OR 9.8, 1.02 233.6, 95% CI). CONCLUSIONS: HLA-DR1/DR3 is increased in AIH, but contrary to data reported in AIH, HLA-DR7 frequency is increased in OS, suggesting increased susceptibility which distinguishes patients with AIH from those with OS. PMID- 21301007 TI - Nonalcoholic fatty liver disease in Brazil. Clinical and histological profile. AB - BACKGROUND: The epidemiology and clinical characteristics of nonalcoholic fatty liver disease (NAFLD) in South America are not well known. Brazil is a largest country in this part of the world and the present study aimed to contribute with this information. METHODS: This descriptive study included patients from medical centers around Brazil, who had diagnosis of NAFLD. They were selected from chart review and also prospectively in Hepatology out-clinics. Patients with history of alcohol intake and others liver diseases were excluded. Histological diagnosis included: steatosis or steatohepatitis (steatosis, ballooning of hepatocytes or fibrosis). The criteria to perform a liver biopsy was ALT or AST > 1.5 x normal levels. RESULTS: A total of 1280 patients from 16 Brazilian centers and all five regions were included. The mean age was 49.68 +/- 13.59 years; 53.3% were males and 85% were asymptomatic. Hyperlipidemia was observed in 66.8% cases, obesity in 44.7%, overweight in 44.4%, diabetes in 22.7%, and toxins exposure in 10%. Metabolic syndrome was observed in 41.3% cases. Elevated levels of ALT, AST and GGT were observed in 55.8%, 42.2% and 63.1% cases, respectively. Liver biopsy performed in 437 cases showed: isolate steatosis in 42% cases, steatohepatitis in 58% and 27% of them also presented fibrosis. Cirrhosis was observed in 15.4% and hepatocellular carcinoma in 0.7%. CONCLUSIONS: NAFLD in Brazil is more frequent in asymptomatic males; steatohepatitis with fibrosis and cirrhosis were a significant diagnosis. The genetic predisposition and lifestyle should be influenced in the spectrum; however these findings deserve a future investigation. PMID- 21301008 TI - Liver transplantation: A new risk factor for intestinal intussusceptions. AB - BACKGROUND: Intestinal intussusception in adults is associated with chronic inflammatory bowel disease, celiac disease, abdominal tumors or previous abdominal surgery but most often of unknown origin. AIM: The aim of our study was to evaluate circumstances and identify risk factors for intussusceptions. METHODS: All 65,928 abdominal ultrasound examinations performed at our tertiary medical center between January 2001 and June 2008 were analyzed retrospectively for the diagnosis "intussusception". After identifying individuals with sonographically proven intussusception we analyzed various patients' characteristics including age, gender and underlying disease as well as sonographic findings such as localization of the intussusception, absence or presence of ascites and lymph nodes. RESULTS: We identified 32 cases of intussusceptions [mean age 45 years (range 18 to 88); 18 patients were male]. Twelve patients (38%) had a history of abdominal surgery including 8 patients who had undergone liver transplantation (2 patients with primary sclerosing cholangitis, 1 patient with cystic fibrosis, 1 patient with sarcoidosis, 1 patient with hepatocellular carcinoma and HCV infection, 1 patient with autoimmune hepatitis, 1 patient with Crigler-Najar-syndrome and one patient with echinococcus). A hepaticojejunostomy had been performed in 4 of the patients after liver transplantation. Liver transplanted patients were significantly overrepresented in the intussusceptions group compared with the overall cohort of patients undergoing abdominal ultrasound examination (25% vs. 8%, Chi-Square test, p = 0.0023). CONCLUSION: In our retrospective study liver transplantation, in particular with hepaticojejunostomy, was identified as a new major risk factor for intestinal intussusceptions PMID- 21301009 TI - Epidemiological assessment of liver disease in northeastern Brazil by means of a standardized liver biopsy protocol. AB - BACKGROUND/AIM: The main objective of this study was to describe the profile of patients who were benefitted in a collective effort to perform liver biopsies in Bahia, Brazil. METHOD: A cross-sectional study was conducted with a sample composed of all the patients who were submitted to liver biopsy during a collective effort carried out in Bahia between July 2007 and November 2009. At the time of the procedure, date on the age and gender of patients and the reason for performing the biopsy were recorded. Data on the degree of fibrosis and the presence of co-morbidities. Following statistical analysis, the frequency of the liver diseases that led to the biopsy procedure was described, and the profile of the patients was stratified into groups according to the most prevalent etiologies. RESULTS: Of the 550 patients evaluated, 55.3% were men and 44.7% women. Mean age was 46.63 +/- 11.59 years and there was no statistically significant difference in age between males and females. Of the 550 patients, 72% had hepatitis C and the mean age of these patients was 48.49 +/- 10.1 years, significantly higher than the mean age of the patients with hepatitis B (40.41 +/ 12.43 years). Furthermore, 70.7% of the patients with hepatitis C were between 41 and 60 years of age. The most frequent fibrosis grade was F2 (44%) and the prevalence of advanced fibrosis was 27.7%. Overall, 85 patients, most of them men, had some degree of iron overload. With respect to the safety of the biopsy procedure, severe complications occurred in only two patients. CONCLUSION: Hepatitis C is the predominant liver disease that demanded liver biopsy. The profile of the patients who benefitted from this collective effort is similar to that of patients in the rest of the country. Moreover, non-Ultrasonography guided liver biopsy is safe and the collective effort to carry out liver biopsies in Bahia was found to be a viable venture. PMID- 21301010 TI - Relation of osteocalcin with insulin resistance and histopathological changes of non alcoholic fatty liver disease. AB - BACKGROUND: Osteocalcin is a hormone with a complex cross-talk between adipose tissue and the skeleton. The aim of the present study was to explore the relation of osteocalcin with histopathological changes of NALFD patients. SUBJECTS: A population of 69 NAFLD patients was analyzed. A liver biopsy was realized. Weight, fat mass, body mass index, basal glucose, insulin, insulin resistance (HOMA), total cholesterol, LDLcholesterol, HDL-cholesterol, triglycerides and osteocalcin levels were measured. RESULTS: Patients were divided in two groups by median osteocalcin value (11.34 ng/mL), group I (patients with the low values) and group II (patients with the high values). Only liver fibrosis frequencies were different between groups (group I: 22.9% vs group II: 9.4%; p < 0.05). Patients in group I had higher levels of glucose (115.6 +/- 28.1 mg/dL vs. 103.7 +/- 24.3 mg/dL; p < 0.04), HOMA (4.6 +/- 3.1 units vs. 3.6 +/- 1.8 units; p < 0.04), weight (102.9 +/- 32.4 kg vs. 85.9 +/- 16.8 kg; p = 0.002) and body mass index (38.3 +/- 11.4 kg/m(2) vs. 30.1 +/- 5.7 kg/m(2); p = 0.001)) than patients in group II. Osteocalcin was inverse correlated with glucose (r =-0.4; p = 0.002) and HOMA (r = -0.3:p = 0.01). CONCLUSION: Osteocalcin is associated with liver fibrosis. However, this association disappeared in a multivariate analysis, and HOMA remained as an independent factor. PMID- 21301011 TI - The impact of diabetes mellitus in mortality of patients with compensated liver cirrhosis-a prospective study. AB - BACKGROUND: It has been suggested that DM may reduce survival of patients with liver cirrhosis (LC). Nevertheless only few prospective studies assessing the impact of DM on mortality of cirrhotic patients have been published, none in compensated LC. AIMS: (i) to study the impact of DM on mortality and (ii) to identify predictors of death. METHODS: Patients with compensated LC with and without DM were studied. Survival was analyzed by the Kaplan-Meier Method. Univariate and multivariate analysis was performed to determine independent predictors of mortality. RESULTS: 110 patients were included: 60 without DM and 50 with DM. Diabetic patients had significantly higher frequency of cryptogenic cirrhosis, anemia, hypoalbuminemia, and hypercreatininemia. They also had significantly higher BMI and Child-Pugh score. The 2.5-years cumulative survival was significantly lower in patients with DM (48 vs. 69%, p < 0.05). By univariate analysis: DM, female gender, serum creatinine > 1.5 mg/dL, Child-Pugh score class C and cryptogenic cirrhosis were significant. However, only serum creatinine > 1.5 mg/dL and Child-Pugh score class C were independent predictors of death. CONCLUSION: DM was associated with a significant increase in mortality in patients with compensated liver cirrhosis. Serum creatinine > 1.5 mg/dL and Child Pugh score class C were independent predictors of death. PMID- 21301013 TI - Protective effect of four Mexican plants against CCl4-induced damage on the Huh7 human hepatoma cell line. AB - BACKGROUND: Centaurea americana, Krameria ramosissima, Juglans mollis and Turnera diffusa are used by traditional healers in the northeastern region of Mexico to protect against liver damage. However, the hepatoprotective properties of these plants have not been investigated scientifically. This study reports on the protective effects of these plants using an in vitro assay. MATERIAL AND METHODS: Extracts of plants were tested for antioxidant activity using the 2,2-diphenyl-1 picrylhydrazyl (DPPH) radical scavenging method. The effects of extracts from these plants on a human hepatoma cell line (Huh7) were evaluated according to cell viability and aspartate aminotransferase and malondialdehyde levels before and after exposure of the cells to carbon tetrachloride (CCl(4)). RESULTS: All extracts reduced DPPH levels by more than 50%. C. americana flower and stem/leaf extracts, the aerial part of T. diffusa, and the nut, leaf and bark of J. mollis extracts were used to assess hepatoprotective activity. The extract of the aerial part of K. ramosissima was toxic. Pretreatment of Huh7 cells with extracts from the flower of C. americana (FCA), the stem/leaf fraction of C. americana (S/LCA), the leaf of J. mollis (LJM) and the bark of J. mollis (BJM) prior to the CCl(4) challenge, protected against CCl(4)-induced liver damage, as evidenced by a significant decrease in the activity of the medium enzyme. The FCA, S/LCA, LJM and BJM extracts showed significant antilipid peroxidant effects in vitro. In conclusion, the hepatoprotective effects of the FCA, S/LCA, LJM and BJM extracts observed in this study may result from their antioxidative properties. PMID- 21301012 TI - Protective and curative effects of polyphenolic extracts from Ichnocarpus frutescense leaves on experimental hepatotoxicity by carbon tretrachloride and tamoxifen. AB - The aim of this study was to investigate prophylactic and curative effect of polyphenolic extract of Ichnocarpus frutescense against carbon tetrachloride and tamoxifen induced hepatotoxicity in rats. Carbon tetrachloride and tamoxifen caused liver damage in rats manifested by significant rise in serum enzymes levels. Models of carbon tetrachloride and tamoxifen intoxication elicited significant declines in the reduced glutathione concomitant with significant elevations in malondialdehyde levels. The oral administration of polyphenolic extract to carbon tetrachloride and tamoxifen intoxicated ats, produced significant increments in the reduced glutathione concomitant with significant decrements in malondialdehyde and liver transaminases levels. Prophylactic and curative treatments with the polyphenolic extract generally resulted in a relatively good protection against both carbon tetrachloride and tamoxifen intoxicated rats. The histopathological changes of liver sections showed an improved histological appearance. The extract inhibits CYP monoxygenases aminopyrine-N-demethylase and aniline hydroxylase, suggesting a plausible hepatoprotective mechanism. However prophylactic treatment with the polyphenolic extract exhibited a higher activity compared to curative treatment. The normalization of phenobarbitone induced sleeping time suggests the restoration of liver CYP enzymes. The study shows that hepatoprotective activity of polyphenol extract is by regulating the levels of hepatic microsomal drug metabolising enzymes. These results supported the use of this plant for the treatment of hepatitis in oriental traditional medicine. PMID- 21301014 TI - Incisional intercostal hernia with prolapse of the liver. PMID- 21301015 TI - Undifferentiated embryonal sarcoma of liver in an adult masquerading as complicated hydatid cyst. AB - Benign or malignant hepatic lesions may rarely mimic inflammatory lesions on imaging. We describe a case of young adult male presenting with pain abdomen and fever of short duration. Imaging revealed large complex multiseptated lesion in the right lobe of liver. Complicated hydatid cyst was kept as first differential diagnosis depending on clinic-radiologic findings. However, due to few atypical imaging features, FNAC of the lesion was performed which confirmed the lesion as UESL. PMID- 21301016 TI - Effectiveness of add-on pegylated interferon alfa-2a therapy in a lamivudine treated patient with chronic hepatitis B. AB - Hepatitis B virus (HBV) surface antigen (HBsAg) to anti-HBsAg (anti-HBs) antibody seroconversion is the best, final objective for all available chronic hepatitis B (CHB) treatments. Unfortunately, this goal is rarely obtained with the currently utilized therapeutic approaches. Here we describe the case of a CHB patient who was very successfully treated with a particular therapeutic schedule. The patient was initially treated with lamivudine for four years. Subsequently, pegylated interferon alpha-2a was introduced for a period of one year. During this period of combined therapies, the patient showed a flare of aminotransferase values followed by complete normalization of liver biochemistry parameters and HBsAg/anti-HBs seroconversion that persisted up to 24 months after all therapies had been stopped. PMID- 21301017 TI - Arcuate ligament compression as a cause of early-onset thrombosis of the hepatic artery after liver transplantation. AB - BACKGROUND: Early hepatic artery thrombosis (HAT) is a potentially lethal complication after orthotopic liver transplantation (OLT) requiring immediate intervention. AIM: To report an infrequent cause of HAT after OLT and by itself a controversial clinical entity, the median arcuate ligament celiac artery compression. CASE REPORT: A 59-year-old female with hepatitis C virus-induced cirrhosis, Child B, MELD 15, underwent cadaveric-donor OLT with complete vena cava exclusion. Type 1 hepatic artery anatomy was found both in the donor and the recipient, the gastroduodenal artery was ligated. During the first eight postoperative days, clinical and analytical evolution was satisfactory and Doppler ultrasound showed no abnormalities. On the ninth postoperative day, the patient developed hypovolemic shock due to bleeding at the hepatic artery anastomosis, surgical reconstruction was performed. Postoperative color Doppler showed absent hepatic artery flow and an angiography suggested celiac artery compression. The patient was explored again the same day, liberating the celiac artery from the median arcuate ligament and performing thrombectomy and reconstruction of the hepatic artery anastomosis. The patient made a satisfactory recovery and color Doppler showed adequate flow in the hepatic artery. She is alive, free of biliary complications and enjoying a good quality of life 12 months after transplantation. CONCLUSION: Median arcuate ligament celiac artery compression is an infrequent anatomical variant that should be intentionally evaluated in the recipient at the time of arterial reconstruction in OLT and specifically be considered in early HAT to allow recognition and effective correction. PMID- 21301018 TI - Acute and fulminant hepatitis induced by flutamide: case series report and review of the literature. AB - Flutamide is a non-steroidal anti-androgenic drug, commonly used in the treatment of advanced prostate cancer, acne and hirsutism. This drug may induce various degrees of liver injury, including acute liver failure (ALF), with further need for liver transplantation. Here, we present a report of 10 consecutive patients seen in a period of 14 years, with acute liver toxicity induced by flutamide (in most cases severe hepatotoxicity): 3 men and 7 women, with a mean age of 75 and 29 years old, respectively. All men received flutamide as treatment of advanced prostate carcinoma and they developed hepatotoxicity without ALF, and three months after withdrawal of the drug, they recovered completely. In contrast, in 7 young female with liver toxicity caused by flutamide as treatment of various hyperandrogenic conditions (acne and hirsutism), ALF was observed in 5 patients, all of them requiring urgent liver transplantation, with excellent outcome and survival in 4 of them. Based on the above, we believe that flutamide treatment should be preferentially avoided in young female patients with benign pathologies, or if it is used, patients should be warned of its potential severe complications. Also, serial liver tests should be closely monitored and, in case of elevations, the drug should be immediately withdrawn. PMID- 21301019 TI - Thalidomide for the treatment of metastatic hepatic epithelioid hemangioendothelioma: a case report with a long term follow-up. AB - Hepatic epithelioid hemangioendothelioma (HEH) is an unusual, low-grade malignant vascular tumor of the liver. Here we describe a case of a 40-year-old woman who presented with abdominal pain in the upper right quadrant and giant hepatomegaly, in which imaging studies and a fine-needle liver biopsy confirmed the presence of a large EHE with an isolated lung metastasis. After balancing all possible therapeutic modalities the patient was treated conservatively with thalidomide (300 mg/day). The drug was well tolerated with minimal toxicity and the patient continues on therapy 109 months after treatment was started with no disease progression. Current therapeutic options for HEH are discussed in light of the clinical case with particular emphasis on anti-angiogenic therapies. PMID- 21301020 TI - The unfulfilled promise of efficacy trials in HIV/hepatitis C co-infected patients. PMID- 21301021 TI - Biliverdin and heme oxygenase antiviral activity against hepatitis C virus. PMID- 21301022 TI - Efficient visibility encoding for dynamic illumination in direct volume rendering. AB - We present an algorithm that enables real-time dynamic shading in direct volume rendering using general lighting, including directional lights, point lights, and environment maps. Real-time performance is achieved by encoding local and global volumetric visibility using spherical harmonic (SH) basis functions stored in an efficient multiresolution grid over the extent of the volume. Our method enables high-frequency shadows in the spatial domain, but is limited to a low-frequency approximation of visibility and illumination in the angular domain. In a first pass, level of detail (LOD) selection in the grid is based on the current transfer function setting. This enables rapid online computation and SH projection of the local spherical distribution of visibility information. Using a piecewise integration of the SH coefficients over the local regions, the global visibility within the volume is then computed. By representing the light sources using their SH projections, the integral over lighting, visibility, and isotropic phase functions can be efficiently computed during rendering. The utility of our method is demonstrated in several examples showing the generality and interactive performance of the approach. PMID- 21301023 TI - Output-Sensitive Construction of Reeb Graphs. AB - The Reeb graph of a scalar function represents the evolution of the topology of its level sets. This paper describes a near-optimal output-sensitive algorithm for computing the Reeb graph of scalar functions defined over manifolds or non manifolds in any dimension. Key to the simplicity and efficiency of the algorithm is an alternate definition of the Reeb graph that considers equivalence classes of level sets instead of individual level sets. The algorithm works in two steps. The first step locates all critical points of the function in the domain. Critical points correspond to nodes in the Reeb graph. Arcs connecting the nodes are computed in the second step by a simple search procedure that works on a small subset of the domain that corresponds to a pair of critical points. The paper also describes a scheme for controlled simplification of the Reeb graph and two different graph layout schemes that help in the effective presentation of Reeb graphs for visual analysis of scalar fields. Finally, the Reeb graph is employed in four different applications-surface segmentation, spatially-aware transfer function design, visualization of interval volumes, and interactive exploration of time-varying data. PMID- 21301024 TI - Natural Interaction Metaphors for Functional Validations of Virtual Car Models. AB - Natural Interaction in virtual environments is a key requirement for the virtual validation of functional aspects in automotive product development processes. Natural Interaction is the metaphor people encounter in reality: the direct manipulation of objects by their hands. To enable this kind of Natural Interaction, we propose a pseudophysical metaphor that is both plausible enough to provide realistic interaction and robust enough to meet the needs of industrial applications. Our analysis of the most common types of objects in typical automotive scenarios guided the development of a set of refined grasping heuristics to support robust finger-based interaction of multiple hands and users. The objects' behavior in reaction to the users' finger motions is based on pseudophysical simulations, which also take various types of constrained objects into account. In dealing with real-world scenarios, we had to introduce the concept of Normal Proxies, which extend objects with appropriate normals for improved grasp detection and grasp stability. An expert review revealed that our interaction metaphors allow for an intuitive and reliable assessment of several functionalities of objects found in a car interior. Follow-up user studies showed that overall task performance and usability are similar for CAVE and HMD environments. For larger objects and more gross manipulation, using the CAVE without employing a virtual hand representation is preferred, but for more fine grained manipulation and smaller objects, the HMD turns out to be beneficial. PMID- 21301025 TI - Frankenrigs: building character rigs from multiple sources. AB - We present a new rigging and skinning method which uses a database of partial rigs extracted from a set of source characters. Given a target mesh and a set of joint locations, our system can automatically scan through the database to find the best-fitting body parts, tailor them to match the target mesh, and transfer their skinning information onto the new character. For the cases where our automatic procedure fails, we provide an intuitive set of tools to fix the problems. When used fully automatically, the system can generate results of much higher quality than a standard smooth bind, and with some user interaction, it can create rigs approaching the quality of artist-created manual rigs in a small fraction of the time. PMID- 21301026 TI - Autocalibrating Tiled Projectors on Piecewise Smooth Vertically Extruded Surfaces. AB - In this paper, we present a novel technique to calibrate multiple casually aligned projectors on fiducial-free piecewise smooth vertically extruded surfaces using a single camera. Such surfaces include cylindrical displays and CAVEs, common in immersive virtual reality systems. We impose two priors to the display surface. We assume the surface is a piecewise smooth vertically extruded surface for which the aspect ratio of the rectangle formed by the four corners of the surface is known and the boundary is visible and segmentable. Using these priors, we can estimate the display's 3D geometry and camera extrinsic parameters using a nonlinear optimization technique from a single image without any explicit display to camera correspondences. Using the estimated camera and display properties, the intrinsic and extrinsic parameters of each projector are recovered using a single projected pattern seen by the camera. This in turn is used to register the images on the display from any arbitrary viewpoint making it appropriate for virtual reality systems. The fast convergence and robustness of this method is achieved via a novel dimension reduction technique for camera parameter estimation and a novel deterministic technique for projector property estimation. This simplicity, efficiency, and robustness of our method enable several coveted features for nonplanar projection-based displays. First, it allows fast recalibration in the face of projector, display or camera movements and even change in display shape. Second, this opens up, for the first time, the possibility of allowing multiple projectors to overlap on the corners of the CAVE-a popular immersive VR display system. Finally, this opens up the possibility of easily deploying multiprojector displays on aesthetic novel shapes for edutainment and digital signage applications. PMID- 21301027 TI - A Framework for 3D Model-Based Visual Tracking Using a GPU-Accelerated Particle Filter. AB - A novel framework for acceleration of particle filtering approaches to 3D model based, markerless visual tracking in monocular video is described. Specifically, we present a methodology for partitioning and mapping the computationally expensive weight-update stage of a particle filter to a graphics processing unit (GPU) to achieve particle- and pixel-level parallelism. Nvidia CUDA and Direct3D are employed to harness the massively parallel computational power of modern GPUs for simulation (3D model rendering) and evaluation (segmentation, feature extraction, and weight calculation) of hundreds of particles at high speeds. The proposed framework addresses the computational intensity that is intrinsic to all particle filter approaches, including those that have been modified to minimize the number of particles required for a particular task. Performance and tracking quality results for rigid object and articulated hand tracking experiments demonstrate markerless, model-based visual tracking on consumer-grade graphics hardware with pixel-level accuracy up to 95 percent at 60+ frames per second. The framework accelerates particle evaluation up to 49 times over a comparable CPU only implementation, providing an increased particle count while maintaining real time frame rates. PMID- 21301028 TI - Change Blindness Phenomena for Virtual Reality Display Systems. AB - In visual perception, change blindness describes the phenomenon that persons viewing a visual scene may apparently fail to detect significant changes in that scene. These phenomena have been observed in both computer-generated imagery and real-world scenes. Several studies have demonstrated that change blindness effects occur primarily during visual disruptions such as blinks or saccadic eye movements. However, until now the influence of stereoscopic vision on change blindness has not been studied thoroughly in the context of visual perception research. In this paper, we introduce change blindness techniques for stereoscopic virtual reality (VR) systems, providing the ability to substantially modify a virtual scene in a manner that is difficult for observers to perceive. We evaluate techniques for semiimmersive VR systems, i.e., a passive and active stereoscopic projection system as well as an immersive VR system, i.e., a head mounted display, and compare the results to those of monoscopic viewing conditions. For stereoscopic viewing conditions, we found that change blindness phenomena occur with the same magnitude as in monoscopic viewing conditions. Furthermore, we have evaluated the potential of the presented techniques for allowing abrupt, and yet significant, changes of a stereoscopically displayed virtual reality environment. PMID- 21301029 TI - Single-Pass Composable 3D Lens Rendering and Spatiotemporal 3D Lenses. AB - We present a new 3D lens rendering technique and a new spatiotemporal lens. Interactive 3D lenses, often called volumetric lenses, provide users with alternative views of data sets within 3D lens boundaries while maintaining the surrounding overview (context). In contrast to previous multipass rendering work, we discuss the strengths, limitations, and performance costs of a single-pass technique especially suited to fragment-level lens effects, such as color mapping, lighting, and clipping. Some object-level effects, such as a data set selection lens, are also incorporated, with each object's geometry being processed once by the graphics pipeline. For a substantial range of effects, our approach supports several composable lenses at interactive frame rates without performance loss during increasing lens intersections or manipulation by a user. Other cases, for which this performance cannot be achieved, are also discussed. We illustrate possible applications of our lens system, including Time Warp lenses for exploring time-varying data sets. PMID- 21301030 TI - Interactive curvilinear reformatting in native space. AB - Curvilinear reformatting of 3D magnetic resonance imaging data has been recognized by the medical community as a helpful noninvasive tool for displaying the cerebral anatomy. It consists of automatically creating, with respect to a reference surface, a series of equidistant curvilinear slices at progressively deeper cuts. In comparison with planar slices, it allows more precise localization of lesions and identification of subtle structural abnormalities. However, current curvilinear reformatting tools either rely on the time-consuming manual delineation of guiding curves on 2D slices, or require costly automatic brain segmentation procedures. In addition, they extract the skin and skull, impeding a precise topographic correlation between the location of the brain lesion and skin surface. This impairs planning of craniotomy for neurosurgery, and of the appropriate implantation of electrodes for intracranial electroencephalography in presurgical evaluation. In this work, we present a novel approach based on direct manipulation of the visualized volume data. By using a 3D painting metaphor, the reference surface can be defined incrementally, according to the principle that the user interacts with what she/he sees. As a response, an animation of the reformatting process is displayed. The focus of this paper is a new volume tagging algorithm behind user interactions. It works at an interactive frame rate on current graphics hardware. PMID- 21301031 TI - A spectral approach to protein structure alignment. AB - A new intrinsic geometry based on a spectral analysis is used to motivate methods for aligning protein folds. The geometry is induced by the fact that a distance matrix can be scaled so that its eigenvalues are positive. We provide a mathematically rigorous development of the intrinsic geometry underlying our spectral approach and use it to motivate two alignment algorithms. The first uses eigenvalues alone and dynamic programming to quickly compute a fold alignment. Family identification results are reported for the Skolnick40 and Proteus300 data sets. The second algorithm extends our spectral method by iterating between our intrinsic geometry and the 3D geometry of a fold to make high-quality alignments. Results and comparisons are reported for several difficult fold alignments. The second algorithm's ability to correctly identify fold families in the Skolnick40 and Proteus300 data sets is also established. PMID- 21301032 TI - Uncovering hidden phylogenetic consensus in large data sets. AB - Many of the steps in phylogenetic reconstruction can be confounded by "rogue" taxa-taxa that cannot be placed with assurance anywhere within the tree, indeed, whose location within the tree varies with almost any choice of algorithm or parameters. Phylogenetic consensus methods, in particular, are known to suffer from this problem. In this paper, we provide a novel framework to define and identify rogue taxa. In this framework, we formulate a bicriterion optimization problem, the relative information criterion, that models the net increase in useful information present in the consensus tree when certain taxa are removed from the input data. We also provide an effective greedy heuristic to identify a subset of rogue taxa and use this heuristic in a series of experiments, with both pathological examples from the literature and a collection of large biological data sets. As the presence of rogue taxa in a set of bootstrap replicates can lead to deceivingly poor support values, we propose a procedure to recompute support values in light of the rogue taxa identified by our algorithm; applying this procedure to our biological data sets caused a large number of edges to move from "unsupported" to "supported" status, indicating that many existing phylogenies should be recomputed and reevaluated to reduce any inaccuracies introduced by rogue taxa. We also discuss the implementation issues encountered while integrating our algorithm into RAxML v7.2.7, particularly those dealing with scaling up the analyses. This integration enables practitioners to benefit from our algorithm in the analysis of very large data sets (up to 2,500 taxa and 10,000 trees, although we present the results of even larger analyses). PMID- 21301033 TI - Extensions and improvements to the chordal graph approach to the multistate perfect phylogeny problem. AB - The multistate perfect phylogeny problem is a classic problem in computational biology. When no perfect phylogeny exists, it is of interest to find a set of characters to remove in order to obtain a perfect phylogeny in the remaining data. This is known as the character removal problem. We show how to use chordal graphs and triangulations to solve the character removal problem for an arbitrary number of states, which was previously unsolved. We outline a preprocessing technique that speeds up the computation of the minimal separators of a graph. Minimal separators are used in our solution to the missing data character removal problem and to Gusfield's solution of the perfect phylogeny problem with missing data. PMID- 21301035 TI - [Yuasa-Mitsuyama disease]. AB - Frontotemporal dementia (FTD) is a clinical entity that comprises at least two distinct diseases: Pick's disease with Pick bodies and frontotemporal lobar degeneration with tau-negative and ubiquitin-positive inclusions (FTLD-U). FTLD-U is now usually referred to as FTLD-TAR DNA binding protein 43 (TDP-43). FTLD-TDP 43, but not Pick's disease with tau-positive Pick bodies, is often associated with motor neuron disease (MND). More than 200 cases of this combined form, i.e., FTD-MND, have been reported in Japan. The neuropathological characteristics of MND in patients with FTD are essentially similar to the MND in patients without dementia. However the other characteristics of the combination of FTD and MND are such that the author has considered this disease a unique clinicopathological entity. These characteristics are as follows: (1) frontotemporal lobe-type dementia with insidious onset, usually in the presenile period; (2) neurogenic muscular wasting during the course of the illness [amyotrophic lateral sclerosis (ALS)]-- or [spinal progressive muscular atrophy (SPMA)]-like symptoms); (3) duration from the onset of illness to death is 2-5 years (average duration, 30.6 months); (4) both extrapyramidal symptoms and definite sensory deficiency are less commonly observed; (5) no characteristic abnormalities in the cerebrospinal fluid (CSF) or on the electroencephalogram (EEG) in screening tests; (6) no known parental consanguinity or familial occurrence; and (7) nonspecific mild-to-slight degenerative changes in the frontotemporal cortex, hypoglossal nuclei, spinal cord, and frequently in the substantia nigra. FTD-MND is characterized by ubiquitin-immunoreactive intraneuronal inclusions in cortical layers II and III and the hippocampal dentate granule cells. The occurrence of ubiquitin-positive, tau-negative and ubiquitinated TDP-43 positive inclusions could be the key to determining the pathological background of this disease. Further studies are required clinicopathological differentiation between FTD-MND and ALS-dementia (ALS-D). PMID- 21301034 TI - [Carasil]. AB - Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a single-gene disorder directly affecting the cerebral small blood vessels, that is caused by mutations in the HTRA1 gene encoding HtrA serine peptidase/protease 1 (HTRA1). CARASIL is the second known genetic form of ischemic, nonhypertensive, cerebral small-vessel diseases with an identified gene, following CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). The exact prevalence of CARASIL is currently unknown, and so far about 50 patients have been reported, most of them from Japan and two from China. Genetically no founder haplotype has been identified, and so the disease is expected to be found more widely. The main clinical manifestations are ischemic stroke or stepwise deterioration in brain functions, progressive dementia, premature baldness, and attacks of severe low back pain or spondylosis deformans/disk herniation. The most characteristic brain MRI findings are homogeneously confluent white-matter changes and multiple lacunar infarctions in the basal ganglia and thalamus. Histopathologically, CARASIL is characterized by intense arteriosclerosis, mainly in the small penetrating arteries, without granular osmiophilic materials (GOM) or amyloid deposition. CARASIL is a prototype single-gene disorder of cerebral small vessels, secondary to and distinct from CADASIL. CARASIL-associated mutant HTRA1s exhibited decreased protease activity and failed to repress transforming growth factor-beta (TGF-beta) family signaling, indicating that the increased TGF-beta signaling causes arteriopathy in CARASIL. Therefore, HTRA1 represents another new gene to be considered in future studies of the mechanisms and therapeutic strategies of cerebral small-vessel diseases, as well as alopecia and degenerative vertebral/disk diseases. PMID- 21301036 TI - [Muro disease: amyotrophic lateral sclerosis/parkinsonism-dementia complex in Kii peninsula of Japan]. AB - Muro disease refers to the endemic amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) in the high incidence ALS focus in the Muro district of the Kii peninsula. Kii paralysis was first described in the 1680s in a folk literature, and as ALS in the medical literature by Kin-no-suke Miura in 1911. Two high-incidence ALS foci were discovered in 1960s by Kimura and Yase, and retro- and anterospective epidemiological surveys were started. Kii ALS was neuropathologically characterized by classical ALS pathology together with many neurofibrillary tangles (NFTs) in the brain, similar to Guamanian ALS. The incidence rates of ALS dramatically declined during the 1950s and 1980s, resulting in the disappearance of the high-incidence foci. In the early 1990s, however, Kuzuhara found existence of high-incidence of ALS in the region, and, in addition, of a high-incidence of PDC with abundant NFTs, similar to Guamanian PDC. The incidence rates of PDC dramatically rose during the 1980s and 1990s, and PDC replaced ALS. Unsuccessful attempts were made to identify cause and pathogenesis of the disease in minerals and environmental factors. More than 70% of patients in the endemic region had a family history of ALS or PDC; therefore, genetic factors were suspected as the cause. The authors analyzed the causative and risk candidate genes in the affected and unaffected family members, but failed to find genes related to ALS/PDC. The changing pattern of Muro disease from ALS with a younger onset and rapid progression to PDC with a later onset and longer survival suggests that some unknown environmental factor(s) might modulate the disease process, which basically might be programmed in the gene(s). PMID- 21301037 TI - [Crow-Fukase syndrome (POEMS syndrome)]. AB - In 1971, the author reported an autopsy case of a 48-year-old Japanese man with polyneuropathy, skin hyperpigmentation, diabetes mellitus, and monoclonal gammopathy. Previously, a total of 2 cases of solitary myeloma accompanied by polyneuropathy and endocrinological disorders have been reported by Fukase et al in 1968 and by Shimomori and Kusumoto in 1970 in Japan. The author's case is the first reported non-myeloma case where polyneuropathy associated with dermatoendocrionological changes and dysglobulinemia was observed. In 1956, Crow reported the British case of a 54-year-old man with osteosclerotic myeloma, polyneuropathy, edema, skin hyperpigmentation, clubbed fingers, white nails, and lymphadenopathy. The term Crow-Fukase syndrome was first used in 1984 in a study performed by Nakanishi et al that involved 102 Japanese patients. In 1986, Bardwick et al suggested the acronym POEMS-i.e., polyneuropathy (P), organomegaly (O), endocrinopathy (E), M-protein (M), and skin changes (S)-that represents the most constant and important features of this syndrome. In this paper, the author has described 3 cases that have been reported earlier by the author and has reviewed important Japanese and international literature related to this syndrome. Recent studies have revealed that the signs and symptoms of patients with this syndrome dramatically recover on using recently developed therapies for myeloma, such as autologous peripheral blood stem cell transplantation and thalidomide therapy. PMID- 21301038 TI - [Satoyoshi syndrome]. AB - Satoyoshi syndrome is a rare disorder of unknown case characterized by progressive painful intermittent muscle spasms, alopecia, malabsorption amenorrhea and skeletal abnormalities mimicking a skeletal dysplasia. PMID- 21301039 TI - [Miyoshi distal muscular dystrophy (Miyoshi myopathy)]. AB - We present an overview of autosomal recessive distal muscular dystrophy (ARDMD), including recent molecular genetic findings. ARDMD is often referred to as Miyoshi-type distal muscular dystrophy (MDMD) or Miyoshi myopathy (MM). The onset of MDMD occurs in early adulthood. Muscle atrophy is most dominant in distal leg muscles, especially the flexor muscles, i.e., gastrocnemius and soleus. As MDMD advances, muscle atrophy progresses to the thigh and hip muscles. Toe standing is impaired but heel standing can still be accomplished early in the disease course. This is followed by difficulty in standing and walking. The patients rarely become confined to bed. Serum creatine kinase level is markedly elevated, e.g., 100 times the upper limit of the normal range early in the disease course. Pre symptomatic patients may also have high creatine kinase levels. Heterozygous individuals may have only slightly elevated creatine kinase levels. Recent development revealed that MDMD and LGMD2B are both caused by mutations in the dysferlin gene (DYSF). C1939G, G3370T, 3746delG, and 4870delT are reported to be common mutations among patients with MDMD. The dysferlin protein is presumably involved in the repair of muscle cell membranes. Among the patients reported originally by Miyoshi et al., 3 affected individuals from 3 different families were confirmed carriers of dysferlin mutations. Additionally, 1 heterozygous individual was identified. Although MDMD and LGMD2B are caused by the mutation of the same gene, ARDMD is characterized by initial involvement of leg flexors while LGMD2B is characterized by involvement of the proximal leg muscles. The difference in the distribution becomes obscure as the 2 diseases progress. The temporal profiles of functional impairment in the 2 diseases are reportedly very similar. When MDMD is suspected, it is important to carefully observe the relevant leg, more specially the flexor muscle group. PMID- 21301040 TI - [Clinical aspects of leprous neuropathy]. AB - For the last 5 years, not a single new case of leprosy has been reported among native Japanese people, but several new cases of leprosy have been reported every year among foreigners in Japan. Because most leprosy patients consult doctors not for skin rashes but for the neurological symptoms of leprous neuropathy, every neurologist should be well aware of the clinical features of leprous neuropathy. The finding that the clinical pictures of leprous neuropathy differ greatly between patients from the main Japanese islands and those from Okinawa is of clinical importance the former comprise the lepromatous type while the latter are of the borderline group. The clinical features of leprous neuropathy among people from leprosy-prone areas in the world wide are usually of the tuberculoid type or of the borderline group. Further, the clinical pictures of each type of leprous neuropathy are so distinct that these conditions can be diagnosed with the simple classical neurological examination. One of the most important issues in managing leprosy patients with neurological deficits is protection of the areas of analgesia caused by leprous neuropathy from injuries or burns. Protection against entrapment neuropathies of thickened peripheral nerve trunks, which are quite likely to be compressed during various activities of daily living, is also important. PMID- 21301041 TI - [Gene mutations in familial amyotrophic lateral sclerosis]. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle weakness that reflects degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem, and spinal cord. Most ALS cases are sporadic, but about 5%-10% are familial. The majority of familial ALS (FALS) cases follow an autosomal dominant inheritance pattern, and include the following mutations: ALS1, Cu/Zn superoxide dismutase (SOD1); ALS3; ALS4, senataxin; ALS6, fused in sarcoma (FUS); ALS7; ALS8, vesicle-associated membrane protein; ALS9, angiogenin; ALS10, TAR DNA-binding protein (TARDBP); and ALS11/FIG4. Some of these gene mutations are rarely seen in sporadic ALS cases. ALS2/alsin and ALS5 show an autosomal recessive inheritance pattern. Recently, mutations in the gene encoding optineurin, earlier reported to be a causative gene for primary open-angle glaucoma, have also been found in patients with ALS. It has also been demonstrated that a mutation in the D-amino acid oxidase gene is associated with classic adult-onset FALS. However, these genetic defects occur in only about 20%-30% FLAS cases, while most genes causing FALS remain unknown. PMID- 21301042 TI - [Two cases of spontaneous intracranial hypotension with bilateral chronic subdural hematomas]. AB - Spontaneous intracranial hypotension (SIH) is characterized by postural headaches without obvious cause and is occasionally related to chronic subdural hematomas (CSHs). Brain sag due to decrease in cerebrospinal fluid, and growing CSHs may occur secondary to a decrease in intracranial pressure. Therapy for this condition differs from that for mere traumatic CSHs and is controversial. We report 2 cases of CSH related to SIH. One patient required drainage of the CSHs and an epidural self-blood patch. Furthermore, this patient had to undergo reoperation for drainage of the CSHs. The other patient was cured after the first time the CSHs were drained. PMID- 21301043 TI - [Case of ipsilateral monoparesis by lacunar infarction: a consideration on the pathological mechanism]. AB - An 81-year-old man had sudden-onset dysarthria and weakness in the right leg, and was admitted to our hospital in July 2009. Neurological examination showed right leg monoparesis, sensory disturbance on the right limbs, dysarthria, and decreased deep tendon reflexes. Brain MRI revealed an acute lacunar infarction in the right corona radiata and an old lacunar infarction in the left centrum semiovale, which occurred 4 years before. MR tractography disclosed impaired motor fibers in the right corona radiata, and transcranial magnetic stimulation (TMS) suggested diminished innervation from the bilateral cerebral cortices to the right leg. These results collectively indicated that reorganization of the pyramidal fibers were responsible for the monoparesis ipsilateral to the lacunar infarction, although anomalous pyramidal fibers with ipsilateral innervation were responsible for ipsilateral hemiplegia a previous study. PMID- 21301044 TI - [Vasospasm of Adamkiewicz artery after subarachnoid hemorrhage]. PMID- 21301045 TI - POLQ in breast cancer. PMID- 21301046 TI - Phosphatidylcholine metabolic transformation and progression signature as a pharmacodynamic biomarker. PMID- 21301047 TI - Src and Abl hijack the Robo1 pathway. PMID- 21301048 TI - Prognostic impact of the MDM2SNP309 allele in leukemia and lymphoma. AB - A T-to-G germline single nucleotide polymorphism in the promoter region of MDM2 (SNP309) has been reported to markedly accelerate tumor formation in humans suggesting that it may represent a powerful cancer predisposing allele. Since its first description in 2004, a large number of retrospective analyses involving a wide variety of human malignancies have been reported, showing conflicting results regarding the impact of Mdm2SNP309 status on cancer risk and response to cancer therapy. Here, we appraise the available information on the effect of Mdm2SNP309 in lymphoma and leukemia and discuss the factors that likely account for the conflicting results observed in the studies reported to date. PMID- 21301049 TI - Src activates Abl to augment Robo1 expression in order to promote tumor cell migration. AB - Cell migration is an essential step in cancer invasion and metastasis. A number of orchestrated cellular events involving tyrosine kinases and signaling receptors enable cancer cells to dislodge from primary tumors and colonize elsewhere in the body. For example, activation of the Src and Abl kinases can mediate events that promote tumor cell migration. Also, activation of the Robo1 receptor can induce tumor cell migration. However, while the importance of Src, Abl, and Robo1 in cell migration have been demonstrated, molecular mechanisms by which they collectively influence cell migration have not been clearly elucidated. In addition, little is known about mechanisms that control Robo1 expression. We report here that Src activates Abl to stabilize Robo1 in order to promote cell migration. Inhibition of Abl kinase activity by siRNA or kinase blockers decreased Robo1 protein levels and suppressed the migration of transformed cells. We also provide evidence that Robo1 utilizes Cdc42 and Rac1 GTPases to induce cell migration. In addition, inhibition of Robo1 signaling can suppress transformed cell migration in the face of robust Src and Abl kinase activity. Therefore, inhibitors of Src, Abl, Robo1 and small GTPases may target a coordinated pathway required for tumor cell migration. PMID- 21301051 TI - Synchronous bilateral seminoma. AB - OBJECTIVE: To present a case of synchronous bilateral seminoma and perform a bibliographic review about this rare presentation of testicular neoplasia, with important physical and psychological consequences. METHODS: 25-year old man with bilateral multifocal testicular neoplasias and azoospermia. We performed a bilateral inguinal radical orchiectomy, with the pathologic exam diagnosing bilateral seminoma. Adjuvant lumbar-aortic radiotherapy was initiated. More than a year after the surgery the patient is asymptomatic and without evidence of disease, although dependent of testosterone supplement. RESULTS: Germ cell testicular neoplasias are more frequent in young men between 15 and 35 years old. There is a 2-3% incidence of bilateral neoplasm, either synchronous or metachronous. Bilateral radical orchiectomy remains as standard of treatment, rendering the patient infertile and depending on exogenous androgens, which causes several psychological problems. However, a testis-sparing surgery could be performed in selected cases; our patient, having multiple bilateral neoplasias, was not eligible for this procedure. With a great incidence of carcinoma in situ on spared testicular parenchyma, scrotal radiotherapy is indicated. In spite of infertility, this treatment presents very good oncological results with androgen independence and consequent physical and psychological advantages. CONCLUSION: Bilateral orchiectomy still remains as "gold-standard" treatment for bilateral seminoma. However, there are other possibilities of treatment, such as partial orchiectomy, feasible in selected cases of small volume testicular tumours in solitary testis / bilateral tumour in men without preoperative androgen deficiency and who could be object of close clinical and imaging follow-up. This way you could avoid additional loss of quality of life, without any prejudice on oncological results. PMID- 21301052 TI - Massive left renal infarction. PMID- 21301050 TI - PEAK1, a novel kinase target in the fight against cancer. PMID- 21301053 TI - Extraperitoneal bladder perforation by bull horn. PMID- 21301054 TI - What did happen in the operative room? PMID- 21301055 TI - Fabrication of uniaxially aligned 3D electrospun scaffolds for neural regeneration. AB - Nanofibrous scaffolds are very promising physical guidance substrates for regenerating nerves to traverse larger nerve gaps. In this study, we have attempted to develop 2D random and 3D longitudinally oriented nanofibers of poly(lactide-co-glycolide) (PLGA) by the modified electrospinning process and characterized the surface morphology, mechanical properties, porosity, degradation and wettability. The orientation of aligned fibers was optimized by varying the speed of the rotating mandrel in the electrospinning process. The mean diameter of random PLGA nanofibers was 197 +/- 72 nm, whereas that of the aligned PLGA fiber was 187 +/- 121 nm. The pore size of aligned PLGA nanofibers (3.5 +/- 1.1 um) was significantly lower than their respective random nanofibers (8.0 +/- 2.0 um) (p < 0.05). However, the percentage porosity of both scaffolds was comparable (p > 0.05). The mass loss percentage and molecular weight loss percentage due to degradation was higher in random PLGA fibers when compared to aligned PLGA after 5 weeks (p < 0.05). The tensile strength and Young's modulus of random PLGA fibers were significantly higher than those of the aligned PLGA nanofibers (p < 0.05). Both random and longitudinally aligned scaffolds were used for the in vitro culture of Schwann cells. Morphology and cell proliferation results demonstrated that the aligned fibers assist the direction of Schwann cells and a better proliferation rate than their random fibers. The results confirmed that aligned nanofibers have better deformability, slow degradation, comparable porosity and orientation cues than random nanofibers. Hence the longitudinally aligned nanofibers may be ideal scaffolds for nerve regeneration. PMID- 21301056 TI - Two-photon laser-generated microtracks in 3D collagen lattices: principles of MMP dependent and -independent collective cancer cell invasion. AB - Cancer invasion into an extracellular matrix (ECM) results from a biophysical reciprocal interplay between the expanding cancer lesion and tissue barriers imposed by the adjacent microenvironment. In vivo, connective tissue provides both densely packed ECM barriers adjacent to channel/track-like spaces and loosely organized zones, both of which may impact cancer invasion mode and efficiency; however little is known about how three-dimensional (3D) spaces and aligned tracks present in interstitial tissue guide cell invasion. We here describe a two-photon laser ablation procedure to generate 3D microtracks in dense 3D collagen matrices that support and guide collective cancer cell invasion. Whereas collective invasion of mammary tumor (MMT) breast cancer cells into randomly organized collagen networks required matrix metalloproteinase (MMP) activity for cell-derived collagen breakdown, re-alignment and track generation, preformed tracks supported MMP-independent collective invasion down to a track caliber of 3 um. Besides contact guidance along the track of least resistance and initial cell deformation (squeezing), MMP-independent collective cell strands led to secondary track expansion by a pushing mechanism. Thus, two-photon laser ablation is useful to generate barrier-free microtracks in a 3D ECM which guide collective invasion independently of pericellular proteolysis. PMID- 21301058 TI - The influence of chromosome density variations on the increase in nuclear disorder strength in carcinogenesis. AB - Microscopic structural changes have long been observed in cancer cells and used as a marker in cancer diagnosis. Recent development of an optical technique, partial-wave spectroscopy (PWS), enabled more sensitive detection of nanoscale structural changes in early carcinogenesis in terms of the disorder strength related to density variations. These nanoscale alterations precede the well-known microscopic morphological changes. We investigate the influence of nuclear density variations due to chromosome condensation on changes of disorder strength by computer simulations of model chromosomes. Nuclear configurations with different degrees of chromosome condensation are realized from simulations of decondensing chromosomes and the disorder strength is calculated for these nuclear configurations. We found that the disorder strength increases significantly for configurations with slightly more condensed chromosomes. Coupled with PWS measurements, the simulation results suggest that the chromosome condensation and the resulting spatial density inhomogeneity may represent one of the earliest events in carcinogenesis. PMID- 21301059 TI - Biophysics of selectin-ligand interactions in inflammation and cancer. AB - Selectins (L-, E- and P-selectin) are calcium-dependent transmembrane glycoproteins that are expressed on the surface of circulating leukocytes, activated platelets, and inflamed endothelial cells. Selectins bind predominantly to sialofucosylated glycoproteins and glycolipids (E-selectin only) present on the surface of apposing cells, and mediate transient adhesive interactions pertinent to inflammation and cancer metastasis. The rapid turnover of selectin ligand bonds, due to their fast on- and off-rates along with their remarkably high tensile strengths, enables them to mediate cell tethering and rolling in shear flow. This paper presents the current body of knowledge regarding the role of selectins in inflammation and cancer metastasis, and discusses experimental methodologies and mathematical models used to resolve the biophysics of selectin mediated cell adhesion. Understanding the biochemistry and biomechanics of selectin-ligand interactions pertinent to inflammatory disorders and cancer metastasis may provide insights for developing promising therapies and/or diagnostic tools to combat these disorders. PMID- 21301057 TI - Cell cycle-dependent alteration in NAC1 nuclear body dynamics and morphology. AB - NAC1, a BTB/POZ family member, has been suggested to participate in maintaining the stemness of embryonic stem cells and has been implicated in the pathogenesis of human cancer. In ovarian cancer, NAC1 upregulation is associated with disease aggressiveness and with the development of chemoresistance. Like other BTB/POZ proteins, NAC1 forms discrete nuclear bodies in non-dividing cells. To investigate the biological role of NAC1 nuclear bodies, we characterized the expression dynamics of NAC1 nuclear bodies during different phases of the cell cycle. Fluorescence recovery after photobleaching assays revealed that NAC1 was rapidly exchanged between the nucleoplasm and NAC1 nuclear bodies in interphase cells. The number of NAC1 bodies significantly increased and their size decreased in the S phase as compared to the G0/G1 and G2 phases. NAC1 nuclear bodies disappeared and NAC1 became diffuse during mitosis. NAC1 nuclear bodies reappeared immediately after completion of mitosis. These results indicate that a cell cycle-dependent regulatory mechanism controls NAC1 body formation in the nucleus and suggest that NAC1 body dynamics are associated with mitosis or cytokinesis. PMID- 21301060 TI - Regulation of tumor invasion by interstitial fluid flow. AB - The importance of the tumor microenvironment in cancer progression is undisputed, yet the significance of biophysical forces in the microenvironment remains poorly understood. Interstitial fluid flow is a nearly ubiquitous and physiologically relevant biophysical force that is elevated in tumors because of tumor-associated angiogenesis and lymphangiogenesis, as well as changes in the tumor stroma. Not only does it apply physical forces to cells directly, but interstitial flow also creates gradients of soluble signals in the tumor microenvironment, thus influencing cell behavior and modulating cell-cell interactions. In this paper, we highlight our current understanding of interstitial fluid flow in the context of the tumor, focusing on the physical changes that lead to elevated interstitial flow, how cells sense flow and how they respond to changes in interstitial flow. In particular, we emphasize that interstitial flow can directly promote tumor cell invasion through a mechanism known as autologous chemotaxis, and indirectly support tumor invasion via both biophysical and biochemical cues generated by stromal cells. Thus, interstitial fluid flow demonstrates how important biophysical factors are in cancer, both by modulating cell behavior and coupling biophysical and biochemical signals. PMID- 21301061 TI - Adhesion dynamics and durotaxis in migrating cells. AB - When tissue cells are plated on a flexible substrate, durotaxis, the directed migration of cells toward mechanically stiff regions, has been observed. Environmental mechanical signals are not only important in cell migration but also seem to influence all aspects of cell differentiation and development, including the metastatic process in cancer cells. Based on a theoretical model suggesting that this mechanosensation has a mechanical basis, we introduce a simple model of a cell by considering the contraction of F-actin bundles containing myosin motors (stress fibers) mediated by the movement of adhesions. We show that, when presented with a linear stiffness gradient, this simple model exhibits durotaxis. Interestingly, since stress fibers do not form on soft surfaces and since adhesion sliding occurs very slowly on hard surfaces, the model predicts that the expected cell velocity reaches a maximum at an intermediate stiffness. This prediction can be experimentally tested. We therefore argue that stiffness-dependent cellular adaptations (mechanosensation) and durotaxis are intimately related and may share a mechanical basis. We therefore identify the essential physical ingredients, which combined with additional biochemical mechanisms can explain durotaxis and mechanosensation in cells. PMID- 21301062 TI - Adipose progenitor cells increase fibronectin matrix strain and unfolding in breast tumors. AB - Increased stiffness represents a hallmark of breast cancer that has been attributed to the altered physicochemical properties of the extracellular matrix (ECM). However, the role of fibronectin (Fn) in modulating the composition and mechanical properties of the tumor-associated ECM remains unclear. We have utilized a combination of biochemical and physical science tools to evaluate whether paracrine signaling between breast cancer cells and adipose progenitor cells regulates Fn matrix assembly and stiffness enhancement in the tumor stroma. In particular, we utilized fluorescence resonance energy transfer imaging to map the molecular conformation and stiffness of Fn that has been assembled by 3T3-L1 preadipocytes in response to conditioned media from MDA-MB231 breast cancer cells. Our results reveal that soluble factors secreted by tumor cells promote Fn expression, unfolding, and stiffening by adipose progenitor cells and that transforming growth factor-beta serves as a soluble cue underlying these changes. In vivo experiments using orthotopic co-transplantation of primary human adipose derived stem cells and MDA-MB231 into SCID mice support the pathological relevance of our results. Insights gained by these studies advance our understanding of the role of Fn in mammary tumorigenesis and may ultimately lead to improved anti-cancer therapies. PMID- 21301063 TI - Toward an Ising model of cancer and beyond. AB - The holy grail of tumor modeling is to formulate theoretical and computational tools that can be utilized in the clinic to predict neoplastic progression and propose individualized optimal treatment strategies to control cancer growth. In order to develop such a predictive model, one must account for the numerous complex mechanisms involved in tumor growth. Here we review the research work that we have done toward the development of an 'Ising model' of cancer. The Ising model is an idealized statistical-mechanical model of ferromagnetism that is based on simple local-interaction rules, but nonetheless leads to basic insights and features of real magnets, such as phase transitions with a critical point. The review begins with a description of a minimalist four-dimensional (three dimensions in space and one in time) cellular automaton (CA) model of cancer in which cells transition between states (proliferative, hypoxic and necrotic) according to simple local rules and their present states, which can viewed as a stripped-down Ising model of cancer. This model is applied to study the growth of glioblastoma multiforme, the most malignant of brain cancers. This is followed by a discussion of the extension of the model to study the effect on the tumor dynamics and geometry of a mutated subpopulation. A discussion of how tumor growth is affected by chemotherapeutic treatment, including induced resistance, is then described. We then describe how to incorporate angiogenesis as well as the heterogeneous and confined environment in which a tumor grows in the CA model. The characterization of the level of organization of the invasive network around a solid tumor using spanning trees is subsequently discussed. Then, we describe open problems and future promising avenues for future research, including the need to develop better molecular-based models that incorporate the true heterogeneous environment over wide range of length and time scales (via imaging data), cell motility, oncogenes, tumor suppressor genes and cell-cell communication. A discussion about the need to bring to bear the powerful machinery of the theory of heterogeneous media to better understand the behavior of cancer in its microenvironment is presented. Finally, we propose the possibility of using optimization techniques, which have been used profitably to understand physical phenomena, in order to devise therapeutic (chemotherapy/radiation) strategies and to understand tumorigenesis itself. PMID- 21301064 TI - Stochastic dynamics of cancer initiation. AB - Most human cancer types result from the accumulation of multiple genetic and epigenetic alterations in a single cell. Once the first change (or changes) have arisen, tumorigenesis is initiated and the subsequent emergence of additional alterations drives progression to more aggressive and ultimately invasive phenotypes. Elucidation of the dynamics of cancer initiation is of importance for an understanding of tumor evolution and cancer incidence data. In this paper, we develop a novel mathematical framework to study the processes of cancer initiation. Cells at risk of accumulating oncogenic mutations are organized into small compartments of cells and proliferate according to a stochastic process. During each cell division, an (epi)genetic alteration may arise which leads to a random fitness change, drawn from a probability distribution. Cancer is initiated when a cell gains a fitness sufficiently high to escape from the homeostatic mechanisms of the cell compartment. To investigate cancer initiation during a human lifetime, a 'race' between this fitness process and the aging process of the patient is considered; the latter is modeled as a second stochastic Markov process in an aging dimension. This model allows us to investigate the dynamics of cancer initiation and its dependence on the mutational fitness distribution. Our framework also provides a methodology to assess the effects of different life expectancy distributions on lifetime cancer incidence. We apply this methodology to colorectal tumorigenesis while considering life expectancy data of the US population to inform the dynamics of the aging process. We study how the probability of cancer initiation prior to death, the time until cancer initiation, and the mutational profile of the cancer-initiating cell depends on the shape of the mutational fitness distribution and life expectancy of the population. PMID- 21301065 TI - Cancer tumors as Metazoa 1.0: tapping genes of ancient ancestors. AB - The genes of cellular cooperation that evolved with multicellularity about a billion years ago are the same genes that malfunction to cause cancer. We hypothesize that cancer is an atavistic condition that occurs when genetic or epigenetic malfunction unlocks an ancient 'toolkit' of pre-existing adaptations, re-establishing the dominance of an earlier layer of genes that controlled loose knit colonies of only partially differentiated cells, similar to tumors. The existence of such a toolkit implies that the progress of the neoplasm in the host organism differs distinctively from normal Darwinian evolution. Comparative genomics and the phylogeny of basal metazoans, opisthokonta and basal multicellular eukaryotes should help identify the relevant genes and yield the order in which they evolved. This order will be a rough guide to the reverse order in which cancer develops, as mutations disrupt the genes of cellular cooperation. Our proposal is consistent with current understanding of cancer and explains the paradoxical rapidity with which cancer acquires a suite of mutually supportive complex abilities. Finally we make several predictions and suggest ways to test this model. PMID- 21301066 TI - Promotion of experimental thrombus formation by the procoagulant activity of breast cancer cells. AB - The routine observation of tumor emboli in the peripheral blood of patients with carcinomas raises questions about the clinical relevance of these circulating tumor cells. Thrombosis is a common clinical manifestation of cancer, and circulating tumor cells may play a pathogenetic role in this process. The presence of coagulation-associated molecules on cancer cells has been described, but the mechanisms by which circulating tumor cells augment or alter coagulation remains unclear. In this study we utilized suspensions of a metastatic adenocarcinoma cell line, MDA-MB-231, and a non-metastatic breast epithelial cell line, MCF-10A, as models of circulating tumor cells to determine the thrombogenic activity of these blood-foreign cells. In human plasma, both metastatic MDA-MB 231 cells and non-metastatic MCF-10A cells significantly enhanced clotting kinetics. The effect of MDA-MB-231 and MCF-10A cells on clotting times was cell number-dependent and inhibited by a neutralizing antibody to tissue factor (TF) as well as inhibitors of activated factor X and thrombin. Using fluorescence microscopy, we found that both MDA-MB-231 and MCF-10A cells supported the binding of fluorescently labeled thrombin. Furthermore, in a model of thrombus formation under pressure-driven flow, MDA-MB-231 and MCF-10A cells significantly decreased the time to occlusion. Our findings indicate that the presence of breast epithelial cells in blood can stimulate coagulation in a TF-dependent manner, suggesting that tumor cells that enter the circulation may promote the formation of occlusive thrombi under shear flow conditions. PMID- 21301067 TI - AFM stiffness nanotomography of normal, metaplastic and dysplastic human esophageal cells. AB - The mechanical stiffness of individual cells is important in tissue homeostasis, cell growth, division and motility, and the epithelial-mesenchymal transition in the initiation of cancer. In this work, a normal squamous cell line (EPC2) and metaplastic (CP-A) as well as dysplastic (CP-D) Barrett's Esophagus columnar cell lines are studied as a model of pre-neoplastic progression in the human esophagus. We used the combination of an atomic force microscope (AFM) with a scanning confocal fluorescence lifetime imaging microscope to study the mechanical properties of single adherent cells. Sixty four force indentation curves were taken over the nucleus of each cell in an 8 x 8 grid pattern. Analyzing the force indentation curves, indentation depth-dependent Young's moduli were found for all cell lines. Stiffness tomograms demonstrate distinct differences between the mechanical properties of the studied cell lines. Comparing the stiffness for indentation forces of 1 nN, most probable Young's moduli were calculated to 4.7 kPa for EPC2 (n = 18 cells), 3.1 kPa for CP-A (n = 10) and 2.6 kPa for CP-D (n = 19). We also tested the influence of nuclei and nucleoli staining organic dyes on the mechanical properties of the cells. For stained EPC2 cells (n = 5), significant stiffening was found (9.9 kPa), while CP A cells (n = 5) showed no clear trend (2.9 kPa) and a slight softening was observed (2.1 kPa) in the case of CP-D cells (n = 16). Some force-indentation curves show non-monotonic discontinuities with segments of negative slope, resembling a sawtooth pattern. We found the incidence of these 'breakthrough events' to be highest in the dysplastic CP-D cells, intermediate in the metaplastic CP-A cells and lowest in the normal EPC2 cells. This observation suggests that the microscopic explanation for the increased compliance of cancerous and pre-cancerous cells may lie in their susceptibility to 'crumble and yield' rather than their ability to 'bend and flex'. PMID- 21301068 TI - An in vitro correlation of mechanical forces and metastatic capacity. AB - Mechanical forces have a major influence on cell migration and are predicted to significantly impact cancer metastasis, yet this idea is currently poorly defined. In this study we have asked if changes in traction stress and migratory properties correlate with the metastatic progression of tumor cells. For this purpose, four murine breast cancer cell lines derived from the same primary tumor, but possessing increasing metastatic capacity, were tested for adhesion strength, traction stress, focal adhesion organization and for differential migration rates in two-dimensional and three-dimensional environments. Using traction force microscopy (TFM), we were surprised to find an inverse relationship between traction stress and metastatic capacity, such that force production decreased as the metastatic capacity increased. Consistent with this observation, adhesion strength exhibited an identical profile to the traction data. A count of adhesions indicated a general reduction in the number as metastatic capacity increased but no difference in the maturation as determined by the ratio of nascent to mature adhesions. These changes correlated well with a reduction in active beta-1 integrin with increasing metastatic ability. Finally, in two dimensions, wound healing, migration and persistence were relatively low in the entire panel, maintaining a downward trend with increasing metastatic capacity. Why metastatic cells would migrate so poorly prompted us to ask if the loss of adhesive parameters in the most metastatic cells indicated a switch to a less adhesive mode of migration that would only be detected in a three dimensional environment. Indeed, in three-dimensional migration assays, the most metastatic cells now showed the greatest linear speed. We conclude that traction stress, adhesion strength and rate of migration do indeed change as tumor cells progress in metastatic capacity and do so in a dimension-sensitive manner. PMID- 21301069 TI - Single-cell bioelectrical impedance platform for monitoring cellular response to drug treatment. AB - The response of cells to a chemical or biological agent in terms of their impedance changes in real-time is a useful mechanism that can be utilized for a wide variety of biomedical and environmental applications. The use of a single cell-based analytical platform could be an effective approach to acquiring more sensitive cell impedance measurements, particularly in applications where only diminutive changes in impedance are expected. Here, we report the development of an on-chip cell impedance biosensor with two types of electrodes that host individual cells and cell populations, respectively, to study its efficacy in detecting cellular response. Human glioblastoma (U87MG) cells were patterned on single- and multi-cell electrodes through ligand-mediated natural cell adhesion. We comparatively investigated how these cancer cells on both types of electrodes respond to an ion channel inhibitor, chlorotoxin (CTX), in terms of their shape alternations and impedance changes to exploit the fine detectability of the single-cell-based system. The detecting electrodes hosting single cells exhibited a significant reduction in the real impedance signal, while electrodes hosting confluent monolayer of cells showed little to no impedance change. When single cell electrodes were treated with CTX of different doses, a dose-dependent impedance change was observed. This enables us to identify the effective dose needed for this particular treatment. Our study demonstrated that this single cell impedance system may potentially serve as a useful analytical tool for biomedical applications such as environmental toxin detection and drug evaluation. PMID- 21301070 TI - The role of IDH1 mutated tumour cells in secondary glioblastomas: an evolutionary game theoretical view. AB - Recent advances in clinical medicine have elucidated two significantly different subtypes of glioblastoma which carry very different prognoses, both defined by mutations in isocitrate dehydrogenase-1 (IDH-1). The mechanistic consequences of this mutation have not yet been fully clarified, with conflicting opinions existing in the literature; however, IDH-1 mutation may be used as a surrogate marker to distinguish between primary and secondary glioblastoma multiforme (sGBM) from malignant progression of a lower grade glioma. We develop a mathematical model of IDH-1 mutated secondary glioblastoma using evolutionary game theory to investigate the interactions between four different phenotypic populations within the tumor: autonomous growth, invasive, glycolytic, and the hybrid invasive/glycolytic cells. Our model recapitulates glioblastoma behavior well and is able to reproduce two recent experimental findings, as well as make novel predictions concerning the rate of invasive growth as a function of vascularity, and fluctuations in the proportions of phenotypic populations that a glioblastoma will experience under different microenvironmental constraints. PMID- 21301071 TI - The role of the cytoskeleton in cellular force generation in 2D and 3D environments. AB - To adhere and migrate, cells generate forces through the cytoskeleton that are transmitted to the surrounding matrix. While cellular force generation has been studied on 2D substrates, less is known about cytoskeletal-mediated traction forces of cells embedded in more in vivo-like 3D matrices. Recent studies have revealed important differences between the cytoskeletal structure, adhesion, and migration of cells in 2D and 3D. Because the cytoskeleton mediates force, we sought to directly compare the role of the cytoskeleton in modulating cell force in 2D and 3D. MDA-MB-231 cells were treated with agents that perturbed actin, microtubules, or myosin, and analyzed for changes in cytoskeletal organization and force generation in both 2D and 3D. To quantify traction stresses in 2D, traction force microscopy was used; in 3D, force was assessed based on single cell-mediated collagen fibril reorganization imaged using confocal reflectance microscopy. Interestingly, even though previous studies have observed differences in cell behaviors like migration in 2D and 3D, our data indicate that forces generated on 2D substrates correlate with forces within 3D matrices. Disruption of actin, myosin or microtubules in either 2D or 3D microenvironments disrupts cell-generated force. These data suggest that despite differences in cytoskeletal organization in 2D and 3D, actin, microtubules and myosin contribute to contractility and matrix reorganization similarly in both microenvironments. PMID- 21301072 TI - Micromechanics of human mitotic chromosomes. AB - Eukaryote cells dramatically reorganize their long chromosomal DNAs to facilitate their physical segregation during mitosis. The internal organization of folded mitotic chromosomes remains a basic mystery of cell biology; its understanding would likely shed light on how chromosomes are separated from one another as well as into chromosome structure between cell divisions. We report biophysical experiments on single mitotic chromosomes from human cells, where we combine micromanipulation, nano-Newton-scale force measurement and biochemical treatments to study chromosome connectivity and topology. Results are in accord with previous experiments on amphibian chromosomes and support the 'chromatin network' model of mitotic chromosome structure. Prospects for studies of chromosome organizing proteins using siRNA expression knockdowns, as well as for differential studies of chromosomes with and without mutations associated with genetic diseases, are also discussed. PMID- 21301073 TI - Development of a pattern to measure multiscale deformation and strain distribution via in situ FE-SEM observations. AB - We investigated a method for measuring deformation and strain distribution in a multiscale range from nanometers to millimeters via in situ FE-SEM observations. A multiscale pattern composed of a grid as well as random and nanocluster patterns was developed to measure the localized deformation at the specimen surface. Our in situ observations of a carbon fiber-reinforced polymer matrix composite with a hierarchical microstructure subjected to loading were conducted to identify local deformation behaviors at various boundaries. We measured and analyzed the multiscale deformation and strain localizations during various stages of loading. PMID- 21301074 TI - Preparation of LaFeO3 nanofibers by electrospinning for gas sensors with fast response and recovery. AB - LaFeO(3) nanofibers are successfully prepared by the electrospinning method. XRD patterns show that the materials belong to a cubic system. After calcination at 600 degrees C for 3 h, SEM photographs show that the diameters of the nanofibers are about 80-90 nm and their surfaces are smooth. The response-recovery properties of an LaFeO(3) nanofiber sensor to ethanol are better than those of an LaFeO(3) nanobelt and nanoparticle sensor. LaFeO(3) nanofibers have relatively low resistance, and they improve the weakness of LaFeO(3) nanoparticles upon application. An LaFeO(3) nanofiber sensor also has good reversibility and selectivity to ethanol and is a very good p-type semiconductor material. PMID- 21301075 TI - Multifunctional transparent ZnO nanorod films. AB - Transparent ZnO nanorod (NR) films that exhibit extreme wetting states (either superhydrophilicity or superhydrophobicity through surface chemical modification), high transmittance, UV protection and antireflection have been prepared via the facile ammonia hydrothermal method. The periodic 1D ZnO NR arrays showed extreme wetting states as well as antireflection properties due to their unique surface structure and prevented the UVA region from penetrating the substrate due to the unique material property of ZnO. Because of the simple, time efficient and low temperature preparation process, ZnO NR films with useful functionalities are promising for fabrication of highly light transmissive, antireflective, UV protective, antifogging and self-cleaning optical materials to be used for optical devices and photovoltaic energy devices. PMID- 21301076 TI - Controlled deformation of Si3N4 nanopores using focused electron beam in a transmission electron microscope. AB - The controllable deformation of nanopores was realized by moving a convergent electron beam in a high-resolution transmission electron microscope. Nanostructures with the desired geometries were successfully fabricated from the original nanopores in 100 nm-thick and 260 nm-thick Si(3)N(4) membranes. The formation dynamics is a competition process between the knock-on effect of the high-energy electron beam and surface tension driven shrinkage. This approach can be used to finely tune critical dimensions and deform nanopores to particular desired geometries with single-nanometer precision, which offers substantial opportunities in flexibly fabricating nanostructures for various applications such as nanoelectronics and nanofluidics. PMID- 21301077 TI - Controlled AFM manipulation of small nanoparticles and assembly of hybrid nanostructures. AB - We demonstrate controlled manipulation of semiconductor and metallic nanoparticles (NPs) with 5-15 nm diameters and assemble these NPs into hybrid structures. The manipulation is accomplished under ambient environment using a commercial atomic force microscope (AFM). There are particular difficulties associated with manipulating NPs this small. In addition to spatial drift, the shape of an asymmetric AFM tip has to be taken into account in order to understand the intended and actual manipulation results. Furthermore, small NPs often attach to the tip via electrostatic interaction and modify the effective tip shape. We suggest a method for detaching the NPs by performing a pseudo manipulation step. Finally, we show by example the ability to assemble these small NPs into prototypical hybrid nanostructures with well-defined composition and geometry. PMID- 21301078 TI - Preparation and characterization of iridium dioxide-carbon nanotube nanocomposites for supercapacitors. AB - A thin film of novel hierarchical structure, suitable for supercapacitor applications, has been developed through combining conductive multi-wall carbon nanotubes (MWCNTs) and square IrO(2) nanotubes (IrO(2)NT) of nanometer size. Synthesis of this hierarchical structure with open porosity is performed by depositing IrO(2) short tubes densely along the long wires of carbon nanotube on a substrate of stainless steel. A IrO(2) tube of rutile structure grows in the [001] direction, with an opening at its top, surrounded by very thin walls. The IrO(2) addition on the MWCNT template increases the capacitance of the CNT thin film effectively, because of pseudocapacitance of the IrO(2) surface. For this particular composite, featured with two tubular nanostructures, the specific capacitance increases from 15 F g(-1) (MWCNT) to 69 F g(-1) (IrO(2)NT/MWCNT), measured using the galvanostatic discharge experiment. Its property of fast retrieval of the stored charge is assured in the impedance measurement, showing that the internal resistance of the IrO(2)NT/MWCNT nanocomposite electrode is lower than that of the bare MWCNTs. PMID- 21301079 TI - Synthesis of BiFeO3/ZnO core-shell hetero-structures using ZnO nanorod positive templates. AB - We report the synthesis, morphology, and magnetization characteristics of BiFeO(3) (BFO)-covered ZnO nanorod arrays (ZNAs). High quality and well-aligned ZNAs were grown by a hydrothermal method. BFO shells were deposited by sputtering at ambient temperature and then annealing in an oxygen atmosphere. The BFO shells crystallized to form a perovskite structure at 450 degrees C. Scanning electron microscopy and high resolution transmission electron microscopy demonstrated that the BFO shell was polycrystalline and randomly oriented, covering the ZnO nanorods well. The magnetization-magnetic field loops measured at 5 and 300 K indicate that the BFO/ZNA hetero-structure exhibits ferromagnetic order. The BFO/ZNA displays enhanced coercivity and saturated magnetization as compared with BFO thin films. PMID- 21301080 TI - Nonvolatile gating effects on radicals-containing vanadium oxide nanowires by gas molecule absorption and diffusion. AB - The charge conduction of a single nanowire of radicals-containing vanadium oxides was experimentally studied and found to be modulated by different gas exposures, showing a gating effect by the adsorption and absorption of different gas molecules. After N(2) and O(2) gas are introduced, the nanowires show an abrupt increase of the resistance but show the opposite trend within a longer timescale of several ks. The introduction of N(2) and O(2) can respectively 'write' the nanowire into high and low resistance states, which are metastable in a high vacuum. The long-term gating effect which was attributed to the interlayer diffusion of the gas molecules can be registered on the nanowire in the high vacuum environment. PMID- 21301081 TI - Ultrahigh resolution focused electron beam induced processing: the effect of substrate thickness. AB - It is often suggested that the growth in focused electron beam induced processing (FEBIP) is caused not only by primary electrons, but also (and even predominantly) by secondary electrons (SEs). If that is true, the growth rate for FEBIP can be changed by modifying the SE yield. Results from our Monte Carlo simulations show that the SE yield changes strongly with substrate thickness for thicknesses below the SE escape depth. However, our experimental results show that the growth rate is independent of the substrate thickness. Deposits with an average size of about 3 nm were written on 1 and 9 nm thick carbon substrates. The apparent contradiction between simulation and experiment is explained by simulating the SE emission from a carbon substrate with platinum deposits on the surface. It appears that the SE emission is dominated by the deposits rather than the carbon substrate, even for deposits as small as 0.32 nm(3). PMID- 21301082 TI - Structure of GlnK1, a signalling protein from Archaeoglobus fulgidus. AB - GlnB and GlnK are ancient signalling proteins that play a crucial role in the regulation of nitrogen assimilation. Both protein types can be present in the same genome as either single or multiple copies. However, the gene product of glnK is always found in an operon together with an amt gene encoding an ammonium transport (Amt) protein. Complex formation between GlnK and Amt blocks ammonium uptake and depends on the nitrogen level in the cell, which is regulated through the binding of specific effector molecules to GlnK. In particular, an ammonium shock to a cell culture previously starved in this nitrogen source or the binding of ATP to purified GlnK can stimulate effective complex formation. While the binding of ATP/ADP and 2-oxoglutarate (as a signal for low intracellular nitrogen) to GlnK have been reported and several GlnB/K protein structures are available, essential functional questions remain unanswered. Here, the crystal structure of A. fulgidus GlnK1 at 2.28 A resolution and a comparison with the crystal structures of other GlnK proteins, in particular with that of its paralogue GlnK2 from the same organism, is reported. PMID- 21301083 TI - Structure of the putative dihydroorotate dehydrogenase from Streptococcus mutans. AB - Streptococcus mutans is one of the pathogenic species involved in dental caries, especially in the initiation and development stages. Here, the crystal structure of SMU.595, a putative dihydroorotate dehydrogenase (DHOD) from S. mutans, is reported at 2.4 A resolution. DHOD is a flavin mononucleotide-containing enzyme which catalyzes the oxidation of L-dihydroorotate to orotate, which is the fourth step and the only redox reaction in the de novo biosynthesis of pyrimidine nucleotides. The reductive lysine-methylation procedure was applied in order to improve the diffraction qualities of the crystals. Analysis of the S. mutans DHOD crystal structure shows that this enzyme is a class 1A DHOD and also suggests potential sites that could be exploited for the design of highly specific inhibitors using the structure-based chemotherapeutic design technique. PMID- 21301084 TI - Structure of the catalytic domain of glucoamylase from Aspergillus niger. AB - Glucoamylase from Aspergillus niger is an industrially important biocatalyst that is utilized in the mass production of glucose from raw starch or soluble oligosaccharides. The G1 isoform consists of a catalytic domain and a starch binding domain connected by a heavily glycosylated linker region. The amino terminal catalytic domain of the G1 isoform generated by subtilisin cleavage has been crystallized at pH 8.5, which is a significantly higher pH condition than used for previously characterized glucoamylase crystals. The refined structure at 1.9 A resolution reveals the active site of the enzyme in complex with both Tris and glycerol molecules. The ligands display both unique and analogous interactions with the substrate-binding site when compared with previous structures of homologous enzymes bound to inhibitors. PMID- 21301085 TI - The structure of a haemopexin-fold protein from cow pea (Vigna unguiculata) suggests functional diversity of haemopexins in plants. AB - The haemopexin fold is present in almost all life forms and is utilized for carrying out diverse physiological functions. The structure of CP4, a haemopexin fold protein from cow pea (Vigna unguiculata), was determined at 2.1 A resolution. The protein exists as a monomer both in solution and in the crystal. The structure revealed a typical four-bladed beta-propeller topology. The protein exhibits 42% sequence similarity to LS-24 from Lathyrus sativus, with substantial differences in the surface-charge distribution and in the oligomeric state. A structure-based sequence analysis of haemopexin-fold proteins of plant and mammalian origin established a sequence signature associated with the haemopexin motif. This signature sequence enabled the identification of other proteins with possible haemopexin-like topology of both plant and animal origin. Although CP4 shares a structural fold with LS-24 and other haemopexins, biochemical studies indicated possible functional differences between CP4 and LS-24. While both of these proteins exhibit spermine-binding potential, CP4 does not bind to haem, unlike LS-24. PMID- 21301086 TI - Structure of the dimeric form of CTP synthase from Sulfolobus solfataricus. AB - CTP synthase catalyzes the last committed step in de novo pyrimidine-nucleotide biosynthesis. Active CTP synthase is a tetrameric enzyme composed of a dimer of dimers. The tetramer is favoured in the presence of the substrate nucleotides ATP and UTP; when saturated with nucleotide, the tetramer completely dominates the oligomeric state of the enzyme. Furthermore, phosphorylation has been shown to regulate the oligomeric states of the enzymes from yeast and human. The crystal structure of a dimeric form of CTP synthase from Sulfolobus solfataricus has been determined at 2.5 A resolution. A comparison of the dimeric interface with the intermolecular interfaces in the tetrameric structures of Thermus thermophilus CTP synthase and Escherichia coli CTP synthase shows that the dimeric interfaces are almost identical in the three systems. Residues that are involved in the tetramerization of S. solfataricus CTP synthase according to a structural alignment with the E. coli enzyme all have large thermal parameters in the dimeric form. Furthermore, they are seen to undergo substantial movement upon tetramerization. PMID- 21301087 TI - Structure of flap endonuclease 1 from the hyperthermophilic archaeon Desulfurococcus amylolyticus. AB - Flap endonuclease 1 (FEN1) is a key enzyme in DNA repair and DNA replication. It is a structure-specific nuclease that removes 5'-overhanging flaps and the RNA/DNA primer during maturation of the Okazaki fragment. Homologues of FEN1 exist in a wide range of bacteria, archaea and eukaryotes. In order to further understand the structural basis of the DNA recognition, binding and cleavage mechanism of FEN1, the structure of FEN1 from the hyperthermophilic archaeon Desulfurococcus amylolyticus (DaFEN1) was determined at 2.00 A resolution. The overall fold of DaFEN1 was similar to those of other archaeal FEN1 proteins; however, the helical clamp and the flexible loop exhibited a putative substrate binding pocket with a unique conformation. PMID- 21301088 TI - Crystallization and preliminary X-ray crystallographic studies of enoyl-acyl carrier protein reductase (FabI) from Psuedomonas aeruginosa. AB - During fatty-acid biosynthesis, enoyl-acyl carrier protein (enoyl-ACP) reductase catalyzes the reduction of trans-2-enoyl-ACP to fully saturated acyl-ACP via the ubiquitous fatty-acid synthase system. NADH-dependent enoyl-ACP reductase (FabI) from Pseudomonas aeruginosa has been purified and crystallized as an apoenzyme and in a complex form with NADH and triclosan. Triclosan is an inhibitor of FabI and forms a stable ternary complex in the presence of NADH. The crystals of native and complexed FabI diffracted to resolutions of 2.6 and 1.8 A, respectively. The crystals both belonged to space group P2(1), with unit-cell parameters a = 117.32, b = 155.844, c = 129.448 A, beta = 111.061 degrees for the native enzyme and a = 64.784, b = 107.573, c = 73.517 A, beta = 116.162 degrees for the complex. Preliminary molecular replacement further confirmed the presence of four tetramers of native FabI and one tetramer of the complex in the asymmetric unit, corresponding to Matthews coefficients (V(M)) of 2.46 and 2.05 A(3) Da(-1) and solvent contents of 50.1 and 40.1%, respectively. PMID- 21301089 TI - Crystallization and preliminary crystallographic analysis of beta-mannanase from Bacillus licheniformis. AB - The mannan endo-1,4-beta-mannosidase (ManB) from Bacillus licheniformis strain DSM13 was overexpressed in Escherichia coli. Purification of the thermostable and alkali-stable recombinant mannanase yielded approximately 50 mg enzyme per litre of culture. Crystals were grown by hanging-drop vapour diffusion using a precipitant solution consisting of 12%(w/v) PEG 8000, 0.2 M magnesium acetate tetrahydrate and 0.1 M MES pH 6.5. The protein crystallized in the monoclinic space group P2(1), with two molecules per asymmetric unit and unit-cell parameters a = 48.58, b = 91.75, c = 89.55 A, beta = 98.29 degrees , and showed diffraction to 2.3 A resolution. PMID- 21301090 TI - Crystallization and preliminary X-ray analysis of the human long myosin light chain kinase 1-specific domain IgCAM3. AB - Myosin light-chain kinase-dependent tight junction regulation is a critical event in inflammatory cytokine-induced increases in epithelial paracellular permeability. MLCK is expressed in human intestinal epithelium as two isoforms, long MLCK1 and long MLCK2, and MLCK1 is specifically localized to the tight junction, where it regulates paracellular permeability. The sole difference between these long MLCK splice variants is the presence of an immunoglobulin-like cell-adhesion molecule domain, IgCAM3, in MLCK1. To gain insight into the structure of the IgCAM3 domain, the IgCAM3 domain of MLCK1 has been expressed, purified and crystallized. Preliminary X-ray diffraction data were collected to 2.0 A resolution and were consistent with the primitive trigonal space group P2(1)2(1)2(1). PMID- 21301091 TI - Purification, crystallization and preliminary X-ray analysis of a thermostable direct haemolysin from Grimontia hollisae. AB - Vibrio hollisae, a halophilic species recently reclassified as Grimontia hollisae, is a causative agent of gastroenteritis and septicaemia. One important pathogenic Vibrio factor, thermostable direct haemolysin (TDH), has been purified and crystallized in two crystal forms using the vapour-diffusion method. The crystals belonged to an orthorhombic space group, with unit-cell parameters a = 104.8, b = 112.4, c = 61.3 A and a = 122.9, b = 123.3, c = 89.8 A. The crystals contained either four or eight molecules per asymmetric unit, with predicted solvent contents of 49.4 and 46.3% and Matthews coefficients (V(M)) of 2.4 and 2.3 A(3) Da(-1), respectively. These crystals were suitable for structure determination, which would yield structural details related to the cytotoxicity and oligomeric structure of this pore-forming toxin. PMID- 21301092 TI - Crystallization and preliminary crystallographic studies of a cysteine protease inhibitor from the human nematode parasite Ascaris lumbricoides. AB - The cysteine protease inhibitor from Ascaris lumbricoides, a roundworm that lives in the human intestine, may be involved in the suppression of human immune responses. Here, the molecular cloning, protein expression and purification, preliminary crystallization and crystallographic characterization of the cysteine protease inhibitor from A. lumbricoides are reported. The rod-shaped crystal belonged to space group C2, with unit-cell parameters a = 99.40, b = 37.52, c = 62.92 A, beta = 118.26 degrees . The crystal diffracted to 2.1 A resolution and contained two molecules in the asymmetric unit. PMID- 21301093 TI - Crystallization and preliminary X-ray crystallographic studies of beta transaminase from Mesorhizobium sp. strain LUK. AB - beta-Transaminase (beta-TA) catalyzes the transamination reaction between beta aminocarboxylic acids and keto acids. This enzyme is a particularly suitable candidate for use as a biocatalyst for the asymmetric synthesis of enantiochemically pure beta-amino acids for pharmaceutical purposes. The beta-TA from Mesorhizobium sp. strain LUK (beta-TAMs) belongs to a novel class in that it shows beta-transaminase activity with a broad and unique substrate specificity. In this study, beta-TAMs was overexpressed in Escherichia coli with an engineered C-terminal His tag. beta-TAMs was then purified to homogeneity and crystallized at 293 K. X-ray diffraction data were collected to a resolution of 2.5 A from a crystal that belonged to the orthorhombic space group C222(1), with unit-cell parameters a = 90.91, b = 192.17, c = 52.75 A. PMID- 21301094 TI - Crystallization and preliminary X-ray diffraction analysis of a class II phospholipase D from Loxosceles intermedia venom. AB - Phospholipases D are the major dermonecrotic component of Loxosceles venom and catalyze the hydrolysis of phospholipids, resulting in the formation of lipid mediators such as ceramide-1-phosphate and lysophosphatidic acid which can induce pathological and biological responses. Phospholipases D can be classified into two classes depending on their catalytic efficiency and the presence of an additional disulfide bridge. In this work, both wild-type and H12A-mutant forms of the class II phospholipase D from L. intermedia venom were crystallized. Wild type and H12A-mutant crystals were grown under very similar conditions using PEG 200 as a precipitant and belonged to space group P12(1)1, with unit-cell parameters a = 50.1, b = 49.5, c = 56.5 A, beta = 105.9 degrees . Wild-type and H12A-mutant crystals diffracted to maximum resolutions of 1.95 and 1.60 A, respectively. PMID- 21301095 TI - Crystallization, X-ray diffraction analysis and preliminary structure determination of the TIR domain from the flax resistance protein L6. AB - The Toll/interleukin-1 receptor (TIR) domain is a protein-protein interaction domain that is found in both animal and plant immune receptors. In animal Toll like receptor signalling, both homotypic TIR-domain interactions between two receptor molecules and heterotypic interactions between receptors and TIR-domain containing adaptors are required for initiation of an innate immune response. The TIR domains in cytoplasmic nucleotide-binding/leucine-rich repeat (NB-LRR) plant disease-resistance proteins are not as well characterized, but recent studies have suggested a role in defence signalling. In this study, the crystallization, X-ray diffraction analysis and preliminary structure determination of the TIR domain from the flax resistance protein L6 (L6TIR) are reported. Plate-like crystals of L6TIR were obtained using PEG 200 as a precipitant and diffracted X rays to 2.3 A resolution. Pseudo-translation complicated the initial assignment of the crystal symmetry, which was ultimately found to correspond to space group P2(1)2(1)2 with two molecules per asymmetric unit. The structure of L6TIR was solved by molecular replacement using the structure of the TIR-domain-containing protein AT1G72930 from Arabidopsis as a template. PMID- 21301097 TI - Crystallization and preliminary crystallographic analysis of Arabidopsis thaliana EDS1, a key component of plant immunity, in complex with its signalling partner SAG101. AB - In plants, the nucleocytoplasmic protein EDS1 (Enhanced disease susceptibility1) is an important regulator of innate immunity, coordinating host-cell defence and cell-death programs in response to pathogen attack. Arabidopsis thaliana EDS1 stabilizes and signals together with its partners PAD4 (Phytoalexin deficient4) and SAG101 (Senescence-associated gene101). Characterization of EDS1 molecular configurations in vitro and in vivo points to the formation of structurally and spatially distinct EDS1 homomeric dimers and EDS1 heteromeric complexes with either PAD4 or SAG101 as necessary components of the immune response. EDS1, PAD4 and SAG101 constitute a plant-specific protein family with a unique 'EP' (EDS1 PAD4-specific) domain at their C-termini and an N-terminal domain resembling enzymes with an alpha/beta-hydrolase fold. Here, the expression, purification and crystallization of a functional EDS1 complex formed by EDS1 and SAG101 from Arabidopsis thaliana are reported. The crystals belonged to the orthorhombic space group P2(1)2(1)2(1), with unit-cell parameters a = 101.8, b = 115.9, c = 122.8 A, and diffracted to 3.5 A resolution. PMID- 21301096 TI - Purification, crystallization and preliminary X-ray diffraction of a disulfide cross-linked complex between bovine poly(A) polymerase and a chemically modified 15-mer oligo(A) RNA. AB - Poly(A) polymerase (PAP) synthesizes the polyadenine tail at the 3'-end of messenger RNA. A disulfide cross-linking strategy was implemented to obtain a complex between bovine PAP (bPAP) and a 15-mer oligo(A). All seven endogenous cysteines were mutated to eliminate nonspecific cross-linked complexes. A cysteine residue was introduced at several different positions and A152C was found to achieve maximum specific cross-linking efficiency. The resulting bPAP construct was active and, when mixed with a chemically modified RNA, yielded crystals of a bPAP-RNA complex. The crystals, which belonged to space group P2 and harbored two protein-RNA complexes per asymmetric unit, diffracted X-rays to 2.25 A resolution. PMID- 21301098 TI - Crystallization and preliminary X-ray diffraction analysis of a Lys49 phospholipase A2 complexed with caffeic acid, a molecule with inhibitory properties against snake venoms. AB - Phospholipases A(2) (PLA(2)s) are one of the main components of bothropic venoms; in addition to their phospholipid hydrolysis action, they are involved in a wide spectrum of pharmacological activities, including neurotoxicity, myotoxicity and cardiotoxicity. Caffeic acid is an inhibitor that is present in several plants and is employed for the treatment of ophidian envenomations in the folk medicine of many developing countries; as bothropic snake bites are not efficiently neutralized by conventional serum therapy, it may be useful as an antivenom. In this work, the cocrystallization and preliminary X-ray diffraction analysis of the Lys49-PLA(2) piratoxin I from Bothrops pirajai venom in the presence of the inhibitor caffeic acid (CA) are reported. The crystals diffracted X-rays to 1.65 A resolution and the structure was solved by molecular-replacement techniques. The electron-density map unambiguously indicated the presence of three CA molecules that interact with the C-terminus of the protein. This is the first time a ligand has been observed bound to this region and is in agreement with various experiments previously reported in the literature. PMID- 21301099 TI - Crystallization and preliminary X-ray diffraction analysis of the wild-type haloalkane dehalogenase DhaA and its variant DhaA13 complexed with different ligands. AB - Haloalkane dehalogenases make up an important class of hydrolytic enzymes which catalyse the cleavage of carbon-halogen bonds in halogenated aliphatic compounds. There is growing interest in these enzymes owing to their potential use in environmental and industrial applications. The haloalkane dehalogenase DhaA from Rhodococcus rhodochrous NCIMB 13064 can slowly detoxify the industrial pollutant 1,2,3-trichloropropane (TCP). Structural analysis of this enzyme complexed with target ligands was conducted in order to obtain detailed information about the structural limitations of its catalytic properties. In this study, the crystallization and preliminary X-ray analysis of complexes of wild-type DhaA with 2-propanol and with TCP and of complexes of the catalytically inactive variant DhaA13 with the dye coumarin and with TCP are described. The crystals of wild-type DhaA were plate-shaped and belonged to the triclinic space group P1, while the variant DhaA13 can form prism-shaped crystals belonging to the orthorhombic space group P2(1)2(1)2(1) as well as plate-shaped crystals belonging to the triclinic space group P1. Diffraction data for crystals of wild-type DhaA grown from crystallization solutions with different concentrations of 2-propanol were collected to 1.70 and 1.26 A resolution, respectively. A prism-shaped crystal of DhaA13 complexed with TCP and a plate-shaped crystal of the same variant complexed with the dye coumarin diffracted X-rays to 1.60 and 1.33 A resolution, respectively. A crystal of wild-type DhaA and a plate-shaped crystal of DhaA13, both complexed with TCP, diffracted to atomic resolutions of 1.04 and 0.97 A, respectively. PMID- 21301101 TI - Expression, crystallization and preliminary crystallographic study of octaprenyl pyrophosphate synthase from Helicobacter pylori. AB - Octaprenyl pyrophosphate synthase (OPPs) is involved in the synthesis of the side chains of ubiquinone and menaquinone and catalyzes consecutive condensation reactions of farnesyl pyrophosphate with isopentenyl pyrophosphate to generate polyprenyl pyrophosphate and pyrophosphate. In order to investigate the roles played by OPPs in the metabolism of ubiquinone and menaquinone and the enzymatic mechanisms of these enzymes, analysis of the structure-function relationship of OPPs from Helicobacter pylori was initiated. The gene for OPPs was cloned, the protein was expressed, purified and crystallized and a diffraction data set was collected to 2.00 A resolution. The crystals belonged to space group P4(1)2(1)2 or P4(3)2(1)2, with unit-cell parameters a = b = 109.33, c = 103.41 A. PMID- 21301100 TI - Preliminary joint neutron time-of-flight and X-ray crystallographic study of human ABO(H) blood group A glycosyltransferase. AB - The biosyntheses of oligosaccharides and glycoconjugates are conducted by glycosyltransferases. These extraordinarily diverse and widespread enzymes catalyze the formation of glycosidic bonds through the transfer of a monosaccharide from a donor molecule to an acceptor molecule, with the stereochemistry about the anomeric carbon being either inverted or retained. Human ABO(H) blood group A alpha-1,3-N-acetylgalactosaminyltransferase (GTA) generates the corresponding antigen by the transfer of N-acetylgalactosamine from UDP-GalNAc to the blood group H antigen. To understand better how specific active site-residue protons and hydrogen-bonding patterns affect substrate recognition and catalysis, neutron diffraction studies were initiated at the Protein Crystallography Station (PCS) at Los Alamos Neutron Science Center (LANSCE). A large single crystal was subjected to H/D exchange prior to data collection and time-of-flight neutron diffraction data were collected to 2.5 A resolution at the PCS to ~85% overall completeness, with complementary X-ray diffraction data collected from a crystal from the same drop and extending to 1.85 A resolution. Here, the first successful neutron data collection from a glycosyltransferase is reported. PMID- 21301102 TI - Purification, crystallization and preliminary X-ray crystallographic analysis of Lmo0540 from Listeria monocytogenes. AB - Penicillin-binding proteins catalyze the biosynthesis of the peptidoglycan chains of the bacterial cell wall, which protects cells from osmotic pressure. Although Lmo0540 has been identified as a putative penicillin-binding protein that contributes to the virulence of Listeria monocytogenes, the biochemical role of Lmo0540 remains unclear. To provide insights into its biochemical function, Lmo0540 was overexpressed, purified and crystallized by the sitting-drop vapour diffusion method. Diffraction data were collected to 1.5 A resolution using synchrotron radiation. The crystal belonged to the C-centred monoclinic space group C2, with unit-cell parameters a = 82.5, b = 75.7, c = 75.9 A, alpha = gamma = 90, beta = 121.8 degrees . A full structural determination is under way in order to elucidate the structure-function relationship of this protein. PMID- 21301103 TI - Purification, crystallization and preliminary crystallographic analysis of the SH2 domain of IL-2-inducible T-cell kinase. AB - Proline is a unique amino acid owing to the relatively small energy difference between the cis and trans conformations of its peptide bond. The X-Pro imide bond readily undergoes cis-trans isomerization in the context of short peptides as well as some proteins. However, the direct detection of cis-trans proline isomerization in folded proteins is technically challenging. NMR spectroscopy is well suited to the direct detection of proline isomerization in folded proteins. It is less clear how well X-ray crystallography can reveal this conformational exchange event in folded proteins. Conformational heterogeneity owing to cis trans proline isomerization in the Src homology 2 (SH2) domain of the IL-2 inducible T-cell kinase (ITK) has been extensively characterized by NMR. Using the ITK SH2 domain as a test system, an attempt was made to determine whether proline isomerization could be detected in a crystal structure of the ITK SH2 domain. As a first step towards this goal, the purification, crystallization and preliminary characterization of the ITK SH2 domain are described. PMID- 21301104 TI - Crystallization and initial crystallographic analysis of the Streptococcus parasanguinis FW213 Fap1-NRalpha adhesive domain at pH 5.0. AB - The adhesin fimbriae-associated protein 1 (Fap1) is a surface protein of Streptococcus parasanguinis FW213 and plays a major role in the formation of dental plaque in humans. Increased adherence is highly correlated to a reduction in pH and acid activation has been mapped to a subdomain: Fap1-NR(alpha). Here, Fap1-NR(alpha) has been crystallized at pH 5.0 and diffraction data have been collected to 3.0 A resolution. The crystals belonged to space group P4(1)2(1)2 or P4(3)2(1)2, with unit-cell parameters a = b = 122.0, c = 117.8 A. It was not possible to conclusively determine the number of molecules in the asymmetric unit and heavy-atom derivatives are now being prepared. PMID- 21301105 TI - Overexpression, purification, crystallization and preliminary X-ray crystallographic analysis of the C-terminal domain of the GyrA subunit of DNA gyrase from Staphylococcus aureus strain Mu50. AB - DNA gyrase is a type II topoisomerase that is essential for chromosome segregation and cell division owing to its ability to modify the topological form of bacterial DNA. In this study, the C-terminal domain of the GyrA subunit of DNA gyrase from Staphylococcus aureus Mu50 strain was overexpressed in Escherichia coli, purified and crystallized. Diffraction data were collected to 2.80 A resolution using a synchrotron-radiation source. The crystal belonged to space group P2(1), with unit-cell parameters a = 37.28, b = 80.19, c = 50.22 A, beta = 110.64 degrees . The asymmetric unit contained one molecule, with a corresponding V(M) of 2.02 A(3) Da(-1) and a solvent content of 39.2%. PMID- 21301106 TI - Purification, crystallization and preliminary X-ray crystallographic analysis of the C-terminal cytoplasmic domain of FlhB from Aquifex aeolicus. AB - FlhB is a key protein in the regulation of protein export by the bacterial flagellar secretion system. It is composed of two domains: an N-terminal transmembrane domain and a C-terminal cytoplasmic domain (FlhBc). Here, the crystallization and preliminary crystallographic analysis of FlhBc from Aquifex aeolicus are reported. Purified protein was crystallized using the vapour diffusion technique. The crystals diffracted to 2.3 A resolution and belonged to space group C2, with unit-cell parameters a = 114.49, b = 33.89, c = 122.13 A, beta = 107.53 degrees . PMID- 21301108 TI - Expression, crystallization and preliminary X-ray analysis of the phosphoribosylglycinamide formyltransferase from Streptococcus mutans. AB - Phosphoribosylglycinamide formyltransferase (PurN) from Streptococcus mutans was recombinantly expressed in Escherichia coli. An effective purification protocol was established. The purified protein, which had a purity of >95%, was identified by SDS-PAGE and MALDI-TOF MS. The protein was crystallized using the vapour diffusion method in hanging-drop mode with PEG 3350 as the primary precipitant. X ray diffraction data were collected to 2.1 A resolution. Preliminary X-ray analysis indicated that the crystal belonged to space group P2(1)2(1)2(1), with unit-cell parameters a = 52.25, b = 63.29, c = 131.81 A. PMID- 21301107 TI - Preliminary joint X-ray and neutron protein crystallographic studies of endoxylanase II from the fungus Trichoderma longibrachiatum. AB - Room-temperature X-ray and neutron diffraction data were measured from a family 11 endoxylanase holoenzyme (XynII) originating from the filamentous fungus Trichoderma longibrachiatum to 1.55 A resolution using a home source and to 1.80 A resolution using the Protein Crystallography Station at LANSCE. Crystals of XynII, which is an important enzyme for biofuel production, were grown at pH 8.5 in order to examine the effect of basic conditions on the protonation-state distribution in the active site and throughout the protein molecule and to provide insights for rational engineering of catalytically improved XynII for industrial applications. PMID- 21301109 TI - Preparation, crystallization and preliminary X-ray diffraction analysis of two intestinal fatty-acid binding proteins in the presence of 11 (dansylamino)undecanoic acid. AB - Fatty-acid binding proteins (FABPs) are abundantly expressed proteins that bind a range of lipophilic molecules. They have been implicated in the import and intracellular distribution of their ligands and have been linked with metabolic and inflammatory responses in the cells in which they are expressed. Despite their high sequence identity, human intestinal FABP (hIFABP) and rat intestinal FABP (rIFABP) bind some ligands with different affinities. In order to address the structural basis of this differential binding, diffraction-quality crystals have been obtained of hIFABP and rIFABP in complex with the fluorescent fatty acid analogue 11-(dansylamino)undecanoic acid. PMID- 21301110 TI - Retronasal perception and flavour thresholds of iron and copper in drinking water. AB - Drinking water flavour has a strong role in water quality perception, service satisfaction, willingness to pay and selection of water sources. Metallic flavours are often caused by the dissolved iron and copper, commonly found in groundwater or introduced to tap water by corroding infrastructure. Taste thresholds of iron and copper have been investigated by several studies; however, reported results and test methods vary considerably. This study determined the taste thresholds of ferrous and cuprous ions in room temperature reagent water by using the one-of-five test with multi-nation panellists in the United States. For ferrous and cuprous ions, individual thresholds ranged from 0.003 to >5 mg l(-1) and 0.035 to >5 mg l(-1), respectively. Population thresholds were determined by logistic regression and geometric mean methods as 0.031 and 0.05 mg l(-1) for ferrous ion, and 0.61 mg l(-1) for cuprous ion by both methods. The components of metallic sensation were investigated by use of nose-clips while panellists ingested iron and copper solutions. Results showed that metallic sensation has a significant odour component and should be treated as a flavour instead of a taste. Ferrous, cuprous and cupric ions also produced weak bitter and salty tastes as well as astringent mouthfeel. In comparison, ferric ion produced no sensation. PMID- 21301111 TI - Incorporating parameter uncertainty into Quantitative Microbial Risk Assessment (QMRA). AB - Modern statistical models and computational methods can now incorporate uncertainty of the parameters used in Quantitative Microbial Risk Assessments (QMRA). Many QMRAs use Monte Carlo methods, but work from fixed estimates for means, variances and other parameters. We illustrate the ease of estimating all parameters contemporaneously with the risk assessment, incorporating all the parameter uncertainty arising from the experiments from which these parameters are estimated. A Bayesian approach is adopted, using Markov Chain Monte Carlo Gibbs sampling (MCMC) via the freely available software, WinBUGS. The method and its ease of implementation are illustrated by a case study that involves incorporating three disparate datasets into an MCMC framework. The probabilities of infection when the uncertainty associated with parameter estimation is incorporated into a QMRA are shown to be considerably more variable over various dose ranges than the analogous probabilities obtained when constants from the literature are simply 'plugged' in as is done in most QMRAs. Neglecting these sources of uncertainty may lead to erroneous decisions for public health and risk management. PMID- 21301112 TI - Evaluation of electropositive filtration for recovering norovirus in water. AB - The virus adsorption-elution (VIRADEL) technique has been widely used in the recovery of various enteric viruses in water, and an electropositive filter such as 1 MDS has been commonly applied. However, effective methods of monitoring waterborne norovirus (NoV) have not yet been well characterized and optimized. Hence, in this study, the VIRADEL technique was evaluated and optimized for effectively detecting NoV in water by two commonly used electropositive filters (1MDS and NanoCeram filter). Various elution and concentration methods were evaluated by using both murine norovirus (MNV) and human NoV. Among the tested elution buffers, the most effective was 1.5% beef extract plus 0.01% Tween 80 for both 1MDS (67.5%) and NanoCeram (85.7%) microfilters. The recovery rate of GII-4 human NoV was higher by organic flocculation (86.6%) than by polyethylene glycol (PEG) precipitations (11.6~73.6%). When both 1MDS and NanoCeram filters were tested to detect NoV in surface and groundwater, the sensitivity of NoV recovered by these filters appeared to depend on the types and conditions of environmental water. The results of this study will help to set a standard of detection method for NoV in water. PMID- 21301113 TI - Amoebae and Legionella pneumophila in saline environments. AB - Amoeboid protists that harbor bacterial pathogens are of significant interest as potential reservoirs of disease-causing organisms in the environment, but little is known about them in marine and other saline environments. We enriched amoeba cultures from sediments from four sites in the New England estuarine system of Mt. Hope Bay, Massachusetts and from sediments from six sites in the Great Salt Lake, Utah. Cultures of amoebae were enriched using both minimal- and non nutrient agar plates, made with fresh water, brackish water or saltwater. Recovered amoeba cultures were assayed for the presence of Legionella species using nested polymerase chain reactions (PCR) and primers specific for the genus. Positive samples were then screened with nested amplification using primers specific for the macrophage infectivity potentiator surface protein (mip) gene from L. pneumophila. Forty-eight percent (185 out of 388) of isolated amoeba cultures were positive for the presence of Legionella species. Legionella pneumophila was detected by PCR in 4% of the amoeba cultures (17 out of 388), and most of these amoebae were growing on marine media. Our results show that amoebae capable of growing in saline environments may harbor not only a diverse collection of Legionella species, but also species potentially pathogenic to humans. PMID- 21301114 TI - Inactivation of human adenovirus by sequential disinfection with an alternative UV technology and free chlorine. AB - There has been growing concern over human exposure to adenoviruses through drinking water due to the extreme resistance of human adenoviruses to the traditional UV technology (low-pressure (LP) UV). As an effort to develop an effective treatment strategy against human adenoviruses in drinking water, we determined the effectiveness of sequential disinfection with an alternative UV technology (medium-pressure (MP) UV) and free chlorine. Human adenovirus 2 (Ad2) was irradiated with a low dose of MP UV irradiation (10 mJ/cm(2)) through UV collimated apparatus and then exposed to a low dose of free chlorine (0.17 mg/L) at pH 8 and 5 degrees C using a bench-scale chemical disinfection system. A significant inactivation (e.g. 4 log(10)) of Ad2 was achieved with the low doses of MP UV and free chlorine within a very short contact time (~1.5 min) although there was no apparent synergistic effect on Ad2 between MP UV and free chlorine. Overall, it is likely that the sequential disinfection with UV irradiation and free chlorine should control the contamination of drinking water by human adenoviruses within practical doses of UV and free chlorine typically used in drinking water treatment processes. PMID- 21301115 TI - Differential behaviour of Escherichia coli and Campylobacter spp. in a stream draining dairy pasture. AB - The faecal indicator bacterium Escherichia coli and thermotolerant Campylobacter spp., which are potentially pathogenic, were investigated in the Toenepi Stream draining a pastoral catchment dominated by dairying. Bacteria concentrations were monitored routinely at fortnightly intervals over 12 months and intensively during storm events to compare the transport dynamics of bacterial indicator and pathogen under varying hydro-meteorological conditions. Routine monitoring indicated median concentrations of 345 E. coli MPN 100 ml(-1) and relatively low concentrations of 2.3 Campylobacter MPN 100 ml(-1). The bacterial flux was three orders of magnitude greater under elevated stream flow compared with base-flow. E. coli peak concentrations occurred very close to the turbidity peak and consistently ahead of the Campylobacter spp. peak (which was close to the hydrograph peak). We postulate that, under flood conditions, the E. coli peak reflects the entrainment and mobilisation of in-stream stores on the flood wave front. In contrast, Campylobacter spp. are derived from wash-in from land stores upstream and have travelled at the mean water velocity which is slower than the speed of the flood wave. Our findings of different dynamics for E. coli and Campylobacter spp. suggest that mitigation to reduce faecal microbial impacts from farms will need to take account of these differences. PMID- 21301116 TI - Microbial risk classifications for recreational waters and applications to the Swan and Canning Rivers in Western Australia. AB - Protecting recreational water quality where 'whole-of-body contact' activities occur is important from a public health and economic perspective. Numerous studies have demonstrated that infectious illnesses occur when swimming in faecally polluted waters. With the release of the 2008 Australian recreational water guidelines, the Western Australian (WA) Department of Health conducted a formal evaluation to highlight the advantages of applying the microbial risk management framework to 27 swimming beaches in the Swan and Canning Rivers in Perth, WA. This involved a two-phase approach: (i) calculation of 95th percentiles using historical enterococci data; and (ii) undertaking sanitary inspections. The outcomes were combined to assign provisional risk classifications for each site. The classifications are used to promote informed choices as a risk management strategy. The study indicates that the majority of swimming beaches in the Swan-Canning Rivers are classified as 'very good' to 'good' and are considered safe for swimming. The remaining sites were classified as 'poor', which is likely to be attributed to environmental influences. Information from the study was communicated to the public via a series of press releases and the Healthy Swimming website. The guidelines provide a sound approach to managing recreational water quality issues, but some limitations were identified. PMID- 21301117 TI - Knowledge, attitudes, practices and implications of safe water management and good hygiene in rural Bangladesh: assessing the impact and scope of the BRAC WASH programme. AB - A substantial component of BRAC's WASH programme involves educating rural Bangladeshis about safe water management, good hygiene and the causes of diarrhoea. By conducting questionnaires and focus group discussions in two BRAC WASH villages and one control village, this investigation sought to assess the impact of BRAC's programme on knowledge, practices and diarrhoeal burden, to explore the extent to which knowledge determines practices, and to evaluate which factors were most predictive of diarrhoeal incidence. It was found that the programme had a beneficial effect on the subjects' knowledge and practices, and on the diarrhoeal incidence among their children. Furthermore, except for where personal financial expenditure was required, practices tended to follow on from knowledge. However, BRAC's intervention affected neither the frequency of soap use in handwashing by the mother, nor the child's consumption of unclean water outside of the home. These factors, along with the child's consumption of unclean water inside the home, were shown to be those most predictive of diarrhoeal incidence among the under-fives. It is recommended that BRAC continues to emphasize the importance of these points, while also potentially promoting the use of less costly alternatives to soap and cheaper point-of-use treatment materials, to induce positive behaviour change. PMID- 21301119 TI - A strategic approach for Water Safety Plans implementation in Portugal. AB - Effective risk assessment and risk management approaches in public drinking water systems can benefit from a systematic process for hazards identification and effective management control based on the Water Safety Plan (WSP) concept. Good results from WSP development and implementation in a small number of Portuguese water utilities have shown that a more ambitious nationwide strategic approach to disseminate this methodology is needed. However, the establishment of strategic frameworks for systematic and organic scaling-up of WSP implementation at a national level requires major constraints to be overcome: lack of legislation and policies and the need for appropriate monitoring tools. This study presents a framework to inform future policy making by understanding the key constraints and needs related to institutional, organizational and research issues for WSP development and implementation in Portugal. This methodological contribution for WSP implementation can be replicated at a global scale. National health authorities and the Regulator may promote changes in legislation and policies. Independent global monitoring and benchmarking are adequate tools for measuring the progress over time and for comparing the performance of water utilities. Water utilities self-assessment must include performance improvement, operational monitoring and verification. Research and education and resources dissemination ensure knowledge acquisition and transfer. PMID- 21301118 TI - Variability of E. coli density and sources in an urban watershed. AB - The objective of this study was to characterize the variability of Escherichia coli density and sources in an urban watershed, particularly to focus on the influences of weather and land use. E. coli as a microbial indicator was measured at fourteen sites in four wet weather events and four dry weather conditions in the upper Blackstone River watershed. The sources of E. coli were identified by ribotyping. The results showed that wet weather led to sharp increases of E. coli densities. Interestingly, an intense storm of short duration led to a higher E. coli density than a moderate storm of long duration (p<0.01). The ribotyping patterns revealed microbial sources were mainly attributed to humans and wildlife, but varied in different weather conditions and were associated with the patterns of land use. Human sources accounted for 24.43% in wet weather but only 9.09% in dry weather. In addition, human sources were more frequently observed in residential zones (>30% of the total sources), while wildlife sources were dominant in open land and forest zones (54%). The findings provide useful information for developing optimal management strategies aimed at reducing the level of pathogens in urban watersheds. PMID- 21301120 TI - Estimating changes in river faecal coliform loading using nonparametric multiplicative regression. AB - Faecal coliform (FC) concentration was monitored weekly in the Tangipahoa River over an eight year period. Available USGS discharge and precipitation data were used to construct a nonparametric multiplicative regression (NPMR) model for both forecasting and backcasting of FC density. NPMR backcasting and forecasting of FC allowed for estimation of concentration for any flow regime. During this study a remediation effort was undertaken to improve disinfection systems of contributing municipal waste water treatment plants in the watershed. Time-series analysis of FC concentrations demonstrated a drop in FC levels coinciding with remediation efforts. The NPMR model suggested the reduction in FC levels was not due to climate variance (i.e. discharge and precipitation changes) alone. Use of the NPMR method circumvented the need for construction of a more complex physical watershed model to estimate FC loading in the river. This method can be used to detect and estimate new discharge impacts, or forecast daily FC estimates. PMID- 21301121 TI - Detection and subtype identification of Blastocystis isolates from wastewater samples in the Philippines. AB - To provide further evidence of waterborne transmission of Blastocystis, a total of 31 wastewater treatment plants from geographically distinct locations across the Philippines were sampled for influent and effluent sewage samples. In vitro cultivation was the method of choice to increase sensitivity of detection. Blastocystis cysts were detected in 15% (9/62) of the samples using in vitro culture. Moreover, influent and effluent samples were 23% (7/31) and 7% (2/31) positive for the parasite, respectively. The presence of viable cysts in treated samples may be an indication of the inefficiency of the treatment process in preventing Blastocystis from entering the environment. Polymerase chain reaction and sequencing of the full-length small subunit ribosomal RNA (SSU rRNA) genes of the nine wastewater isolates were performed. The SSU rRNA gene sequences of the isolates showed very high similarity (98 to 99%) to homologous sequences of Blastocystis described previously. The phylogenetic tree constructed showed that the wastewater isolates clustered with each other with good bootstrap support and belonged to two subtypes (ST) - ST1 and ST2. This is the first report of subtyping Blastocystis isolates from wastewater samples and gives further emphasis to the remarkable genetic diversity of the parasite. PMID- 21301122 TI - Prevalence of virulence factors in Escherichia coli isolated from healthy animals and water sources in Brazil. AB - The aim of this work was to verify the presence of seven virulence factors (ST, LT, eae, stx(1), stx(2), INV and EAEC) among Escherichia coli strains isolated from healthy humans, bovines, chickens, sheep, pigs and goats, from two sewage treatment plants and from the Tiete River. We have found a high prevalence of eae, stx(1) and stx(2) in ruminants. The EAEC gene was only found in humans and sewage. No strains presented ST, LT or INV. BOX-PCR fingerprints revealed a high diversity among the strains analysed and a non-clonal origin of strains that presented the same virulence factors. Therefore, we concluded that ruminants may constitute an important reservoir of most diarrheagenic E. coli in Brazil, except for EAEC strains. These results emphasize the importance of the identification of the animal source of fecal contamination for the correct water risk assessment. PMID- 21301123 TI - Coping with poor water supplies: empirical evidence from Kathmandu, Nepal. AB - The authors examined the demand for clean drinking water using treatment behaviors in Kathmandu, Nepal. Water supply is inadequate, unreliable and low quality. Households engage in several strategies to cope with the unreliable and poor quality of water supplies. Some of the major coping strategies are hauling, storing, and point-of-use treatment. Boiling, filtering, and use of Uro-guard are some of the major treatment methods. Using Water Survey of Kathmandu, the authors estimated the effect of wealth, education, information, gender, caste/ethnicity and opinion about water quality on drinking water treatment behaviors. The results show that people tend to increase boiling and then filtering instead of only one method if they are wealthier. In addition, people boil and then filter instead of boiling only and filtering only if they think that water delivered to the tap is dirty. Exposure to information has the strongest effect in general for the selection of all available treatment modes. PMID- 21301124 TI - Novel Bacteroides host strains for detection of human- and animal-specific bacteriophages in water. AB - Bacteriophages active against specific Bacteroides host strains were shown to be suitable for detection of human faecal pollution. However, the practical application of this finding is limited because some specific host strains were restricted to certain geographic regions. In this study, novel Bacteroides host strains were isolated that discriminate human and animal faecal pollution in Switzerland. Two strains specific for bacteriophages present in human faecal contamination and three strains specific for bacteriophages indicating animal faecal contamination were evaluated. Bacteriophages infecting human strains were exclusively found in human wastewater, whereas animal strains detected bacteriophages only in animal waste. The newly isolated host strains could be used to determine the source of surface and spring water faecal contamination in field situations. Applying the newly isolated host Bacteroides thetaiotaomicron ARABA 84 for detection of bacteriophages allowed the detection of human faecal contamination in spring water. PMID- 21301125 TI - Microbial risk assessment for recreational use of the Chicago area waterway system. AB - A microbial risk assessment was conducted to estimate the human health risks from incidental contact recreational activities such as canoeing, boating and fishing in the Chicago Area Waterway System (CAWS) receiving secondary treated, but non disinfected, effluent from three municipal water reclamation plants. Actual concentrations of the pathogens (pathogenic E. coli [estimated], Giardia, Cryptosporidium, adenovirus, norovirus, enteric virus) detected from the waterway field data collection at locations upstream and downstream of the effluent outfall during dry and wet weather conditions within the recreation season were included in the risk assessment. The results under the current treatment scheme with no disinfection indicated that the total expected gastrointestinal illness (GI) rate per 1000 incidental contact recreational exposure events during combined weather (dry and wet) conditions ranged from 0.10 to 2.78 in the CAWS, which is below the eight illnesses per 1000 swimmers considered tolerable by the United States Environmental Protection Agency. Wet weather conditions contribute to elevated pathogen load to the CAWS; therefore this study determined that disinfecting the effluents of three major WRPs that discharge to the CAWS would result in an extremely small reduction in the aggregate recreation season risk to incidental contact recreators. PMID- 21301126 TI - Pathogen destruction and solids decomposition in composting latrines: study of fundamental mechanisms and user operation in rural Panama. AB - The relationship between temperature, high pH, desiccation, decomposition, pathogen destruction, and user operation in active double vault urine diverting (DVUD) composting latrines located in the Bocas del Toro region of Panama was assessed. Latrine samples were analyzed for temperature, pH, % moisture, carbon to-nitrogen (C/N) ratio, and presence of specific pathogens. Surveys and visual inspections were used to verify use and type of dry material desiccant added. Measurements supported findings that compost latrines do not reach temperatures sufficient to destroy all pathogens. pH measurements showed that many latrines were operating within the range for ideal aerobic decomposition, a pH of 7.5-8.5, but only 17% of latrines measured pH 9 or above. Almost 100% of composting latrine users added sawdust and wood ash, to lower moisture level and provide carbon for decomposition. However, the recommended amount of desiccant added was insufficient to reduce moisture to the suggested 25% for pathogen destruction and C/N ratios remained in the range of raw human faeces. Importantly, pathogens, mainly helminths, were still present in compost stored for the 6-month contact time. The latrines have conflicting goals of pathogen destruction and aerobic decomposition. Recommendations are made regarding operation of composting latrines and disposal of composted material. PMID- 21301127 TI - Waterborne diseases in the state of Mexico, Mexico (2000-2005). AB - This paper reports a spatial-temporal examination of waterborne disease data from the State of Mexico, 2000 to 2005, by county as the spatial unit. It was found that the incidence of waterborne disease did not decrease during the period under study. Inequality between metropolitan areas and rural zones was observed. People living in population centres had lower incidence of water-related diseases, possibly due to better access to services. In all cases, children under five years old suffered a much higher relative morbidity than the population in general. Improvement of the water distribution network between 2000 and 2005 could explain the decrease in morbidity from 30% to 15%, for the total population, and from 34% to 18.5%, for children under five years old. Coverage of sewer services over the period was not substantially improved; as a result the coefficient of determination remained nearly constant: 16.5% for the total population and 25% for children under five. Maintenance and operation deficiencies in the water distribution and wastewater sanitation systems play an important role in the incidence of this type of disease. It was found that the institutional division of the territory does not correspond to the actual distribution of the risk areas. PMID- 21301129 TI - Idiopathic ventricular tachycardia in children. PMID- 21301128 TI - PCR assay targeting virulence genes of Helicobacter pylori isolated from drinking water and clinical samples in Lahore metropolitan, Pakistan. AB - Helicobacter pylorus is considered for chronic gastritis, gastric ulcers and adenocarcinoma and its high infection rate is observed in overcrowded and lower socioeconomic groups in developing countries. This study was designed to identify the role of drinking water in the transmission and prevalence of H. pylori (HP). Selective HP medium was developed for enrichment and presumptive identification of H. pylori by urease, catalase and species specific 16S rRNA tests. The virulence genes (vacA 's' and 'm' regions and cagA) of H. pylori in 90 out of 225 H. pylori positive drinking water samples were present (40%). Ten out of 18 biopsies (55.55%) and 15 out of 50 vomiting fluids of gastric disease patients (30%) were also positive for virulence genes. Anti-H. pylori antibodies were also detected in 31 out of 50 patients' sera. The presence of virulence genes was also directly confirmed by hybridization studies using non-radioactive DNA probes of 16S rRNA, vacA and cagA genes. The presence of H. pylori in water is due to poor sanitary conditions, improper waste disposal and lack of public health education. PCR-based analysis and colony hybridization can be used for detection of H. pylori in clinical and environmental samples. PMID- 21301130 TI - Can we predict electroanatomical remodeling of left atrium in patients with non valvular atrial fibrillation by transforming growth factor-beta and tissue inhibitor of metalloproteinase-1? PMID- 21301131 TI - Intracellular calcium and the mechanism of anodal supernormal excitability in langendorff perfused rabbit ventricles. AB - BACKGROUND: Anodal stimulation hyperpolarizes the cell membrane and increases the intracellular Ca(2+) (Ca(i)) transient. This study tested the hypothesis that the maximum slope of the Ca(i) decline (-(dCa(i)/dt)(max)) corresponds to the timing of anodal dip on the strength-interval curve and the initiation of repetitive responses and ventricular fibrillation (VF) after a premature stimulus (S(2)). METHODS AND RESULTS: We simultaneously mapped the membrane potential (V(m)) and Ca(i) in 23 rabbit ventricles. A dip in the anodal strength-interval curve was observed. During the anodal dip, ventricles were captured by anodal break excitation directly under the S(2) electrode. The Ca(i) following anodal stimuli is larger than that following cathodal stimuli. The S(1)-S(2) intervals of the anodal dip (203+/-10 ms) coincided with the -(dCa(i)/dt)(max) (199+/-10 ms, P=NS). BAPTA-AM (n=3), inhibition of the electrogenic Na(+)-Ca(2+) exchanger current (I(NCX)) by low extracellular Na(+) (n=3), and combined ryanodine and thapsigargin infusion (n=2) eliminated the anodal supernormality. Strong S(2) during the relative refractory period (n=5) induced 29 repetitive responses and 10 VF episodes. The interval between S(2) and the first non-driven beat was coincidental with the time of -(dCa(i)/dt)(max). CONCLUSIONS: Larger Ca(i) transient and I(NCX) activation induced by anodal stimulation produces anodal supernormality. The time of maximum I(NCX) activation is coincidental to the induction of non-driven beats from the Ca(i) sinkhole after a strong premature stimulation. PMID- 21301132 TI - Impact of obstructive sleep apnea on myocardial tissue perfusion in patients with ST-segment elevation myocardial infarction. AB - BACKGROUND: Vascular endothelial dysfunction has been recognized as an essential feature of obstructive sleep apnea (OSA). This study was designed to examine the hypothesis that OSA may impair the coronary microcirculation in patients with ST segment elevation myocardial infarction (STEMI). METHODS AND RESULTS: The present study included 100 patients with a first STEMI who underwent primary percutaneous coronary intervention (PCI) within 12h from onset. Coronary flow velocity at baseline and at maximum hyperemia was measured using a Doppler guidewire following PCI. Total ST-segment elevation was calculated at baseline and 30 min after PCI. All patients underwent polysomnography at 14 days to diagnose OSA. Coronary flow velocity reserve (CFVR) was used for quantitative analysis of myocardial tissue perfusion. Systolic retrograde flow (SRF) and ST-segment resolution (STR) <50% were used as an index of microvascular injury. Forty-eight patients presented with OSA. CFVR was comparable between the 2 groups. The incidence of SRF was higher in OSA patients than in the control patients (6% vs. 31%, P=0.005). Patients with OSA had a higher incidence of STR <50% (31% vs. 60%, P=0.003). Multiple logistic regression showed that OSA was an independent positive predictor of SRF and STR <50% (odds ratio=4.46, P=0.044; odds ratio=3.79, P=0.010). CONCLUSIONS: OSA may impair myocardial tissue perfusion following primary PCI. PMID- 21301134 TI - Development and evaluation of a perfusion decellularization porcine heart model- generation of 3-dimensional myocardial neoscaffolds. AB - BACKGROUND: Reports about the generation of 3-dimensional neoscaffolds for myocardial tissue engineering are limited. The architecture provided by perfusion decellularization of whole hearts would support the production of human-sized 3 dimensional living tissues from an acellular matrix. The aim of this study was to evaluate the potential of a perfusion decellularization model for whole heart tissue engineering. METHODS AND RESULTS: Hearts were obtained from 12 German Landrace pigs from a selected abattoir. After preparation, the hearts were mounted and perfused on a modified Langendorff decellularization model specifically constructed for this reason. Decellularization was achieved by an ionic detergent-based perfusion protocol. The quality of the decellularization process was quantified by histology and fluorescence microscopy. Data regarding the presence of residual DNA within the decellularized hearts was measured with spectrophotometric quantification and compared to controls. After histological examination, all hearts lacked intracellular components but retained various types of collagen, proteoglycan and elastin. Quantitative DNA analysis demonstrated a significant reduction of DNA in decellularized hearts compared to controls (84.32+/-3.99 ng DNA/mg tissue vs. 470.13+/-18.77 ng DNA/mg tissue (P<0.05)). CONCLUSIONS: The modified Langendorff perfusion decellularization model described here is applicable for whole porcine hearts by removing cellular content and DNA. The resulting 3-dimensional matrix provides an interesting tool for further studies in the field of whole heart tissue engineering. PMID- 21301133 TI - Utility of magnetic resonance imaging-based finite element analysis for the biomechanical stress analysis of hemorrhagic and non-hemorrhagic carotid plaques. AB - BACKGROUND: Biomechanical stress analysis has been used for plaque vulnerability assessment. The presence of plaque hemorrhage (PH) is a feature of plaque vulnerability and is associated with thromboembolic ischemic events. The purpose of the present study was to use finite element analysis (FEA) to compare the stress profiles of hemorrhagic and non-hemorrhagic profiles. METHODS AND RESULTS: Forty-five consecutive patients who had suffered a cerebrovascular ischemic event with an underlying carotid artery disease underwent high-resolution magnetic resonance imaging (MRI) of their symptomatic carotid artery in a 1.5-T MRI system. Axial images were manually segmented for various plaque components and used for FEA. Maximum critical stress (M-Cstress(SL)) for each slice was determined. Within a plaque, the maximum M-Cstress(SL) for each slice of a plaque was selected to represent the maximum critical stress of that plaque (M Cstress(PL)) and used to compare hemorrhagic and non-hemorrhagic plaques. A total of 62% of plaques had hemorrhage. It was observed that plaques with hemorrhage had significantly higher stress (M-Cstress(PL)) than plaques without PH (median [interquartile range]: 315 kPa [247-434] vs. 200 kPa [171-282], P=0.003). CONCLUSIONS: Hemorrhagic plaques have higher biomechanical stresses than non hemorrhagic plaques. MRI-based FEA seems to have the potential to assess plaque vulnerability. PMID- 21301135 TI - Midodrine hydrochloride is effective in the treatment of children with postural orthostatic tachycardia syndrome. AB - BACKGROUND: The study was carried out to examine the effect of selective alpha1 adrenoceptor agonist midodrine hydrochloride vs. beta-adrenergic blockade metoprolol in the treatment of children with postural orthostatic tachycardia syndrome (POTS). METHODS AND RESULTS: Fifty-three children with POTS were divided into group I (midodrine hydrochloride plus conventional therapy), group II (metoprolol plus conventional therapy) and group III (conventional therapy). Standing test was conducted for all participants. The cure rate, improvement rate, effective rate and score of symptoms were compared among the 3 groups. A Kaplan-Meier survivorship curve was used to describe the proportion of symptom free cases during a long term follow-up. The cure rate and effective rate at the end of short term follow-up in group I were significantly higher than those of group II and group III (68.42% vs. 42.11% vs. 20.00%, P<0.05; 89.47% vs. 57.89% vs. 53.33%, P<0.05). After treatment, the symptom score in group I was significantly lower than group II and group III, respectively (1.1+/-2.2 vs. 2.8+/-2.4 vs. 3.7+/-2.0, P<0.05), and it also had significant difference between group II and group III (P<0.05). The symptom recurrent rate in group I was significantly lower than that of group II and group III, respectively (P<0.05), but it did not differ between group II and group III (P>0.05). CONCLUSIONS: Midodrine hydrochloride is effective in the treatment of children with POTS. PMID- 21301136 TI - Physiological assessment of myocardial perfusion using nuclear cardiology would enhance coronary artery disease patient care: which imaging modality is best for evaluation of myocardial ischemia? (SPECT-side). AB - Nuclear cardiology has played an important role in both diagnosis and risk assessments of coronary artery disease since early 1970. Among the non-invasive diagnostic tests, the great advantage of nuclear imaging is that this technique can obtain physiological information, such as myocardial perfusion, which is difficult to obtain by other techniques. When patients have inducible myocardial ischemia and sufficient viable myocardium, coronary revascularization treatment should be performed. Both stress myocardial perfusion imaging (MPI) and viability imaging provide important information. Another important aspect of stress perfusion imaging is that normal stress perfusion is associated with low risk for future cardiac events. Therefore, stress MPI plays an important role in the selection of an invasive therapeutic regime and also in avoiding unnecessary invasive procedures. As is the case for other imaging techniques, there have been many technical and instrumental developments in recent years in nuclear cardiology imaging, including new single-photon-emission computed tomography tracers, new pharmacological stress agents, a new generation of gamma camera, and positron emission tomography. This review will address the advantages of nuclear cardiology in the clinical setting and recent developments in nuclear cardiology. PMID- 21301137 TI - Cardiac magnetic resonance imaging: choice of the year: which imaging modality is best for evaluation of myocardial ischemia? (MRI-side). AB - The increasing variety of available cardiac imaging techniques have made the investigation of coronary artery disease more complex. On the one hand, nuclear cardiology or myocardial perfusion imaging (MPI) allows accurate and reliable quantitative measurement of myocardial blood flow. On the other hand, a newer technique, cardiac magnetic resonance imaging (CMR) is an attractive alternative for achieving similar purposes without exposing patients to radiation hazards. With a higher spatial resolution, CMR is more sensitive for detecting subendocardial ischemia; small myocardial infarction and/or fibrosis, which cannot be achieved in a nuclear study. Nuclear MPI has dominated clinical practice over the past 3 decades on the basis of an extensive amount of research. More upcoming research on CMR would warrant more evidence-based data of its value for disease diagnosis, prognosis and risk stratification and incorporating it into the clinical diagnostic and management algorithm. PMID- 21301138 TI - Bioresorbable scaffold technologies. AB - Fully bioabsorbable scaffolds (BRS) are a novel approach that provides transient vessel support with drug delivery capability without the long-term limitations of the metallic drug-eluting stents (DES), such as permanent caging with or without malapposition. The technology has the potential to overcome many of the safety concerns associated with metallic DES, and possibly even convey further clinical benefit. Although the technology is still in its infancy, several devices have been tested in clinical trials and the initial results have been very promising. This review will discuss the emerging need for BRS, the theoretical advantages of this new technology over current generation metallic DES and review the status of the currently available BRS. In addition, we will discuss the ideal duration of bioresorption, the proven and potential clinical benefits and future perspectives of this rapidly progressing technology. PMID- 21301139 TI - [Preservation of health]. PMID- 21301141 TI - [Management of elderly hypertension]. PMID- 21301140 TI - [Clinical guidelines for elderly patients with diabetes mellitus]. PMID- 21301142 TI - [Ageing and endocrinological function: endocrinological aspects of disease in elderly]. PMID- 21301143 TI - [Malnutrition and cachexia in the elderly]. PMID- 21301144 TI - [Clinical approach for dementia]. PMID- 21301145 TI - [Perspective of longevity genes]. PMID- 21301146 TI - [CKD]. PMID- 21301147 TI - [The secrets how to examine elderly stroke patients]. PMID- 21301148 TI - [Impact of influenza to the elderly]. PMID- 21301149 TI - [Clinical characteristics of patients with lung cancer associated with pneumonia]. PMID- 21301151 TI - [Novel strategies for preventing aspiration pneumonia in the elderly]. PMID- 21301150 TI - [Tuberculosis in the elderly]. PMID- 21301152 TI - [Sepsis in the elderly]. PMID- 21301153 TI - [Urinary tract infection in elderly patients]. AB - Urinary tract infections (UTIs) in the elderly are common. The pathophysiology of increased susceptibility is multifactorial. Age-related changes include a decline in cell-mediated immunity, neurogenic bladder dysfunction, structural urinary tract abnormalities (e.g., benign prostatic hyperplasia), systemic diseases (e.g., diabetes mellitus) and increased incidence of urethral catheter placement. Catheter-associated bacteriuria is the most common hospital-acquired infection. Many elderly patients, including those with catheter-associated bacteriuria, are asymptomatic. Escherichia coli remains the most common uropathogen. However, polymicrobial infection is more common among the elderly. The use of antimicrobial agents needs to be guided by current surveillance studies of targeted uropathogenic bacteria before being implemented. However, UTIs in the elderly may lead to severe renal infections. Therefore surgical intervention may be needed in these infections. PMID- 21301154 TI - [Antibiotic-associated colitis in the elderly]. PMID- 21301155 TI - [Past, present and future of geriatric education in Japan]. PMID- 21301156 TI - [Correlations between clinical laboratory data and telomere length in the leukocytes of patients with hypertension]. AB - AIM: We investigated the correlation between age, telomere length of peripheral blood leukocytes and blood laboratory data of women with mild hypertension, to identify laboratory data that may reflect the biological aging process of individuals. METHODS: The subjects were women with mild hypertension who were being treated with a low dose of amlodipine and who regularly visited the outpatient clinic of the Department of Cardiovascular, Respiratory, and Geriatric Medicine at Kyushu University Hospital. The laboratory data of patients were collected and the telomere length parameters in their peripheral blood leukocytes were determined by Southern blotting. We assessed the laboratory data and the telomere length parameters to determine any correlations. RESULTS: The telomere length of the patients correlated positively with high-density lipoprotein cholesterol, albumin, hemoglobin levels and red blood cell counts, but negatively with globulin levels. CONCLUSION: Among the analyzed laboratory data, the albumin/globulin rates were the best candidate indicators for individual somatic genomic aging. PMID- 21301157 TI - [Analysis of medical accident cases and current status of medical care for the elderly at a mixed-care hospital]. AB - AIM: To conduct a survey on medical accident cases (MACs) in a mixed-care geriatric hospital. METHODS: We extracted the data on 339 MACs of 1,374 incident/ accident reports in a 1-year study period between January 2009 and December 2009. The incidences of MACs and accident-related factors were investigated and compared among medical care areas in our hospital (acute care unit: AU, long-term care unit: LU, convalescent rehabilitation unit: CU, palliative care unit: PU, and other medical care areas). RESULTS: In 339 MACs, epidermal exfoliation (E), bruises (B), cuts or lacerations (CL), and fractures (F) were the most common episodes, and E was most frequent (183 cases: 54.0%). However, in 33.9% of E cases the cause could not be clarified. A comparative study demonstrated that the incidence of E was higher in the LU than in the other medical care unit, or B or F in the CU, or CL in the AU. E was caused mainly by nursing care, especially during transfers. The mean total functional independence measure (FIM) score in the LU (38.8 +/- 21.3), where E occurred most frequently, was significantly lower than that in the AU (61.4 +/- 34.4, p<0.01), CU (58.9 +/- 25.2, p<0.05), and PU (72.8 +/- 22.9, p<0.05) CONCLUSIONS: E, B, CL, and F were frequently found in a mixed-care geriatric hospital. E had the highest frequency among all of the accident episodes, and appeared related to nursing care, such as transfer, and reduced ADL level. PMID- 21301158 TI - [The relationships between the basic checklist score, physical function, and improvement in physical function]. AB - AIM: The objectives of this study were to examine the relationship between a screening score for frailty in the elderly, the Basic checklist, and physical function, and to investigate the factors associated with the effects of exercise intervention in community-dwelling frail elderly in Japan. METHODS: We enrolled 44 subjects aged 65 years and older (average age 73.9 +/- 5.1) in this study. The subjects participated in exercise intervention, including high-intensity muscle strength training, twice a week for three months. The Basic checklist and functional performance measures (walking ability, balance functions, flexibility, leg strength), psychological tests (Geriatric Depression Scale (GDS), Modified Fall Efficacy Scale (MFES), and health-related quality of life test (SF-8)) were administered at the start and end of the intervention. We evaluated the correlation between the Basic checklist and other measurements at baseline. In addition, we evaluated any relationships between the Basic checklist and improvements in physical function. We used partial correlation analysis and multiple linear regression analysis to evaluate those relationships. RESULTS: The Basic checklist was significantly correlated with GDS, functional reach and one leg standing measurements at baseline. Functional performance measures were significantly improved after exercise intervention. Although there were weak negative relationships between the basic checklist and the amount of change in functional reach tests, we could not find a relationship between the Basic checklist and the improvement of physical function. CONCLUSION: These results suggest that there was little relation between the Basic checklist and physical functions, in particular the improvement of physical functions. Therefore, we should consider how we can assess the improvement of physical function. These results strongly support the need to assess physical function before exercise intervention. PMID- 21301159 TI - [Association of physical functions with leisure-time, household, and occupational physical activity in community-dwelling older adults]. AB - AIM: The study objective was to cross-sectionally examine the relationships among leisure-time, household, and occupational physical activity with physical functions in Japanese older adults. METHODS: We randomly enrolled 189 community dwelling older adults, aged 65 to 85 years, as subjects from the Basic Resident Register of Kasama City, Ibaraki prefecture. Physical activity was assessed by the Physical Activity Scale for the Elderly. Analysis of covariance was performed to determine the relationships between physical activity and physical functions, after adjustment for age and sex. RESULTS: Leisure-time physical activity significantly correlated with one-leg balance with eyes open, sit and reach, timed standing test from along sitting position on the floor, functional reach, 5 repetition sit-to-stand, timed up and go, 5-m habitual walk, choice stepping reaction time, and power in sit-to-stand tests. Household physical activity was significantly related to 5-repetition sit-to-stand and ability in sit-to-stand. Total (leisure-time plus household plus occupational) activity was significantly correlated with one-leg balance with eyes open, functional reach, and power in sit-to-stand tests. Post-hoc testing indicated that the levels of physical functions were higher in the subjects of the third tertile than in those of the first or second tertile. No difference was found in physical functions between the first and second tertile. CONCLUSION: Leisure-time physical activity was related to many physical functions. Household physical activity was also related to lower-extremity functions. Our data suggest that medium- or high-level physical activity may be necessary for older adults to maintain their physical functions. PMID- 21301160 TI - [Prevention of decline in subjectively perceived physical function of the elderly by regular participation in a community-based exercise group]. AB - AIM: The objective of this study was to evaluate the effect of a community-based group exercise program on physical functioning among elderly people. METHODS: This prospective observational study enrolled 494 persons aged 70-84 years who volunteered for the study and completed a baseline measurement in 2006 and were re-evaluated 1 year later in 2007. The exercise regimen consisted of resistance training and recreational exercise for 1.5 hours conducted twice a month. Physical functioning was evaluated by a self-administered questionnaire consisting of the Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-IC) and Motor Fitness Scale (MFS). Decline in physical functioning was defined as a reduction in either TMIG-IC or MFS scores of more than 2 points deviation from the median change of each score. RESULTS: TMIG-IC and MFS results were obtained from 494 and 392 eligible subjects, respectively. After 1 year, 68 subjects (TMIG-IC) and 88 subjects (MFS) reported a decline in physical functioning. After adjustment for confounding factors, the odds ratio of reduced physical functioning, as assessed by the TMIG-IC among the subjects who did not participate in the exercise group and those who did, were 1.00 (control) and 0.15 (95% confidence interval, 0.01-0.75). Similar results were obtained when assessed on the MFS. CONCLUSION: These results suggest that participation in a community based exercise group of elderly people was effective in maintaining self-reported physical function. PMID- 21301161 TI - [Effects of a motor function improvement program on alleviation of knee osteoarthritis]. AB - AIM: The purposes of this study were to develop a new exercise program for the elderly with knee pain, and to evaluate the effects of the program. METHODS: The participants in the present study were 37 community-dwelling elderly people (75 +/- 7 years) with knee pain who were living in Tokyo. The participants were instructed to do a walking exercise with weights attached to each ankle together with an exercise to develop their ability to recognize pain objectively, at a weekly meeting, with training on alternate days at home. The measurements of this study were: one-leg standing time, functional reach (FR), timed up and go, 5 m walking time, knee extension strength, health-related quality of life (QOL) questionnaire (SF-36) and the Japanese Knee Osteoarthritis Measure (JKOM). RESULTS: The total JKOM scores decreased significantly (p<0.01). Each subscale of the JKOM decreased significantly (p<0.05). Furthermore, knee extension strength and FR increased significantly (p<0.01). Among the SF-36 subscale scores, physical functioning, role physical, role emotional and mental health improved significantly (p<0.05). CONCLUSION: The current results suggest that the new program introduced in the present study reduces knee pain and improves the activity of participants. PMID- 21301162 TI - [Study of medical decisions in adult guardianship]. AB - AIMS: The present study investigated the current situation of medical decision making for patients who cannot express their intentions, especially elderly patients. METHODS: We sent a questionnaire to 63 medical institutions and 11 individual caseworkers in Miyagi prefecture. The questionnaire was designed to investigate: 1) the use of adult guardianship; 2) the process of obtaining medical consent; and 3) possible systems which would benefit patients. RESULTS: Forty-four institutions (69.8%) and 11 (100%) caseworkers answered our questionnaires. Five institutions and 8 caseworkers had been required to make medical consent for their patients by clinicians. Four patients could not receive medical treatment because clinicians could not identify responsible persons for medical consent. Eighteen institutions and 8 caseworkers suggested an adult guardian would be a possible person to give medical consent if satisfying legal conditions. CONCLUSIONS: The present study indicated the urgency of an appropriate system to obtain medical consent when patients cannot express their intentions. PMID- 21301163 TI - [A very elderly case of acute-onset autoimmune type 1 diabetes mellitus]. AB - An 80-year-old man had systemic malaise and pollakiuria, which developed about 40 days before admission. He underwent treatment at a urology department, but his symptoms did not improve. Since dry mouth additionally developed, he visited his family doctor. As his casual blood glucose level was 629 mg/dl and HbA1c was 12.4%, the patient was referred to our department and admitted on the same day. Continuous intravenous infusion of fast-acting insulin and saline were initiated after admission, and dietary therapy at 1,520 kcal/day was initiated on the following day. Anti-GAD antibody and anti-IA-2 antibody were positive, confirming that the disease was acute-onset autoimmune type 1 diabetes mellitus. A sliding scale of fast-acting insulin followed by intensified therapy using insulin glargine and insulin aspart was performed in the early phase, but the treatment was switched to twice-daily biphasic insulin aspart 30 injection because no diabetic complication was present, although the patient was already totally blind and required assistance from his family for self-injection and to improve his quality of life (QOL). Blood glucose control was favorable, and the patient was discharged on April 2. PMID- 21301164 TI - [Successful treatment of thoracic drainage using urokinase for empyema in an elderly man]. AB - A 76-year-old man was admitted to our hospital because of progressive dyspnea, fever, and consciousness disturbance. Empyema was diagnosed by chest image findings and laboratory findings of pleural effusion and serum. The patient was first given an antimicrobial agent, and chest drainage was performed. Although his general condition improved, his systemic inflammation and chest radiograph findings did not. Then, thoracoscopy under local anesthesia was considered. However, surgery was almost impossible, because he was hemiparetic, with mild conscious disturbance following cerebral hemorrhage. We decided to insert another drain into the thoracic cavity and continued to perform irrigation with saline in addition to the systemic administration of antibiotics for 3 weeks. His general condition gradually improved. Although the volume of drained fluid from the thoracic cavity decreased, the empyema lesions did not completely disappear. We then performed irrigation with saline and urokinase for 3 days, from the 40th hospital day. Irrigation drainage using saline was more effective than previously, before urokinase administration; his symptoms and empyema lesions markedly improved without antibiotics treatment. He was discharged on the 95th hospital day. For the treatment of chronic emypema, surgery using recently developed thoracoscopic techniques should be considered first, but may not be appropriate for frail elderly with severe systemic complications. Conventional intrathoracic irrigation using saline containing urokinase may be a treatment of choice for intractable empyema in frail older patients with hemiplegia caused by cerebral infarction. PMID- 21301165 TI - Polymorphism of 270 A > G in BRAP is Associated with Lower Ankle-Brachial Index in a Taiwanese Population. AB - AIMS: The single nucleotide polymorphism (SNP) rs11066001 of BRAP has been shown to be associated with myocardial infarction (MI), coronary atherosclerosis and carotid atherosclerosis, but it is not clear whether it also plays a role in peripheral artery disease (PAD). The ankle-brachial index (ABI) is often used as a non-invasive measure of PAD; therefore, the aim of this study was to test for a relationship between the SNP rs11066001 and ABI. METHODS: A total of 537 high risk subjects with a family history of MI or stroke completed a health survey, including a physical examination, blood test and measurement of ABI. Among them, 523 subjects had the genotypes. Association analyses between the genotype of BRAP and ABI were performed by multiple linear and logistic regressions with adjustment for covariates. RESULTS: We found that the GG genotype is significantly associated with a lower ABI value. For the lowest ABI tertile, the GG genotype had an OR of 2.87 (p =0.018) when compared with the middle ABI tertile, and OR of 2.92 (p =0.015) when compared to the highest ABI tertile. Women with the GG genotype had a lower ABI value than men with the same genotype (p =0.012). Accordingly, women carrying this GG risk genotype may have a higher risk for PAD. CONCLUSION: Our findings provide additional evidence that support the genetic effect of BRAP on diverse cardiovascular phenotypes. PMID- 21301166 TI - [Reformation of the IT revolution on the medical scene (discussion)]. PMID- 21301167 TI - [Upper gastrointestinal study using onomatopoeic sounds and signs]. AB - We have made new instructions with onomatopoeic sounds and their own signs in order to improve the accuracy of the upper gastrointestinal study, and compared these new instructions with the conventional ones. After the examinations, we asked the patients to fill out a questionnaire regarding how they felt about the new instructions. In the esophagus X-ray fluoroscopy, the number of patients who took the proper amount of Barium meal showed a rate of increase of 31.6 percent compared to the conventional method. For the patients' movements in the right rotation direction, the number of the patients showed a rate of increase of 18.2 percent using the oral instructions with onomatopoeic sounds, and 25.0 percent using the oral instruction with onomatopoeic sounds and signs. From the results of the questionnaire, 87.6 percent of the patients answered that the signs were "Effective" or "Very Effective." Including the answer "Doesn't Matter," the sign instructions being useful increased to 94.8 percent of the patients. Ninety-four point eight percent of the patients answered that the oral instructions during this X-ray examination were "Easy To Understand" or "Very Easy To Understand." With these results, I believe we should give the oral instructions using onomatopoeic sounds and signs. PMID- 21301168 TI - [Comparison of a dental cone beam CT with a multi-detector row CT on effective doses and physical image quality]. AB - The purpose of this study was to compare a dental cone beam computed tomography (dental CBCT) and a multi-detector row CT (MDCT) using effective doses and physical image quality. A dental mode (D-mode) and an implant mode (I-mode) were employed for calculating effective doses. Field of view (FOV) size of the MDCT was 150 mm. Three types of images were obtained using 3 different reconstruction functions: FC1 (for abdomen images), FC30 (for internal ear and bone images) and FC81 (for high resolution images). Effective doses obtained with the D-mode and with the I-mode were about 20% and 50% of those obtained with the MDCT, respectively. Resolution properties obtained with the D-mode and I-mode were superior to that of the MDCT in a high frequency range. Noise properties of the D mode and the I-mode were better than those with FC81. It was found that the dental CBCT has better potential as compared with MDCT in both dental and implant modes. PMID- 21301169 TI - [A study of the transport of three dimensional medical images to remote institutions for telediagnosis]. AB - Using a 3D-imaging-create-function server and network services by IP-VPN, we began to deliver 3D images to the remote institution. An indication trial of the primary image, a rotary trial of a 3D image, and a reproducibility trial were studied in order to examine the practicality of using the system in a real network between Hakodate and Sapporo (communication distance of about 150 km). In these trials, basic data (time and receiving data volume) were measured for every variation of QF (quality factor) or monitor resolution. Analyzing the results of the system using a 3D image delivery server of our hospital with variations in the setting of QF and monitor resolutions, we concluded that this system has practicality in the remote interpretation-of-radiogram work, even if the access point of the region has a line speed of 6 Mbps. PMID- 21301170 TI - [Basic examination for three-dimensional phase-sensitive inversion recovery (3D PSIR) method by late gadolinium enhancement of non-breath-hold cardiac magnetic resonance image]. AB - PURPOSE: We studied imaging parameters for the three-dimensional phase-sensitive inversion recovery by a late gadolinium enhancement (3D PSIR) method. METHOD: In the 3D PSIR method using a 1.5 Tesla MRI system and a polyvinyl alcohol (PVA) gel phantom, we evaluated the relation of the signal intensity at multiple inversion times (TI), 100-500 ms; flip angles (FA), 15-35 degrees ; and segments, 20-45. In 30 patients with chronic myocardial infarction, we measured and compared the late gadolinium enhancement (LGE) image area of ratio for each of 3 sections on both 3D LGE images by a non-breath hold and two-dimensional inversion recovery (2D IR) method non-breath hold. RESULT: In the 3D PSIR method, we recognized the signal intensity to make the width of step, maximum, and we recognized that the TI range, to keep the effective signal intensity difference constant, was limited on each phantom. The more this TI range decreased the bigger the difference in the FA and signal intensity. The set-up range of TI for the segment number remained the same. In the clinical setting, we recognized a good correlation between the 3D PSIR method (TI 300 ms, FA 20 degrees ) and the IR method (r=0.905, p<0.001). The imaging parameter that can be used in the clinical setting with the 3D PSIR method is FA 20 degrees TI 200-300 ms, with the segment number adjusted by the cardiac cycle. PMID- 21301171 TI - [Optimal scan timing in 64-row MDCT angiography of the lower extremities: 2-point ROI detection bolus-tracking method]. AB - In CT angiography of the lower extremities, we have developed a 2-point ROI detection bolus-tracking method (2ROI-BTM) to provide the optimal contrast medium concentration and reduce contrast medium. The time to reach the ankle from the abdominal aorta was 22.5 s (95% central range, 14.6-40.1 s). The mean scan time was 13.6 s (range, 11.5-15.0 s). In the 2ROI-BTM (n=78), the mean CT number was 516 HU in the aorta, 427 HU in the popliteal artery, and 323 HU in the tibial artery. Compared with the TIM (n=66), the CT number was low in only 3% or less of cases, and the usual contrast medium dose of 20 ml for test injection could be reduced. With the 2ROI-BTM, the optimal scan timing can be determined more easily than with the TIM, allowing the contrast medium dose to be reduced by 26% and providing contrast enhancement with superior reproducibility of morphological characteristics for the generation of 3D images. PMID- 21301172 TI - [Usefulness of the adaptive dose shield for the infant CT]. AB - The spiral scan with a wide detector row such as the 64-detector row computed tomography (CT) system may increase radiation exposure for infants because the irradiation range is wider than the planned range. The adaptive dose shield (ADS) prevents radiation exposure greater than the planned range. We examined the usefulness of the protection effect of the ADS for the infant inner ear CT. To confirm the protection effect of the ADS, we scanned X-ray films by using the 64 detector row CT system and measured the difference of the planned range and the irradiation range. The result of that is that when the planned range was small, the protection effect for the scan ending side was inferior to the scan starting side. And also, when the gantry rotation speed and pitch factor (PF) were high values, the protection effect was inferior to a low gantry rotation speed and low PF. There was a combination of gantry rotation speed and PF at which the protection effect decreases. Due to changes of the scanning direction and PF for the infant inner ear, the crystalline lens radiation exposure dose decreased from 11.89 mGy to 4.37 mGy. In conclusion, the ADS can reduce the radiation exposure dose of an adjacent organ. Therefore, it was thought that the ADS was a useful radiation exposure reduction function for infants in the 64-detector row CT system. PMID- 21301173 TI - [ABC of radiation protection: introductory guidance to potential radiation workers in medical fields]. PMID- 21301174 TI - [Role of CT images for preoperative planning of spine surgery]. PMID- 21301175 TI - [Medical imaging processing and evaluation in radiation therapy]. PMID- 21301176 TI - [Basic theory and practice of NEQ and DQE]. PMID- 21301178 TI - [7. Let's write a research paper soon after returning; introduction of the international journals related to radiological technology and members' real experiences]. PMID- 21301177 TI - [10. Summary for basic thinking of image analysis]. PMID- 21301179 TI - [Report on the short-time overseas study in 2010]. PMID- 21301180 TI - [Outline of "Guideline for remote maintenance service about diagnostic imaging equipment etc"]. PMID- 21301181 TI - Determination and molecular analysis of the complete genome sequence of two wild type rabies viruses isolated from a haematophagous bat and a frugivorous bat in Brazil. AB - The complete genome sequences of two Brazilian wild-type rabies viruses (RABV), a BR-DR1 isolate from a haematophagous bat (Desmodus rotundus) and a BR-AL1 isolate from a frugivorous bat (Artibeus lituratus), were determined. The genomes of the BR-DR1 and BR-AL1 had 11,923 and 11,922 nt, respectively, and both encoded the five standard genes of rhabdoviruses. The complete nucleotide sequence identity between the BR-DR1 and BR-AL1 isolates was 97%. The BR-DR1 and BR-AL1 isolates had some conserved functional sites revealed by the fixed isolates, whereas both isolates had unique amino acid substitutions in the antigenic region IV of the nucleocapsid gene. Therefore, it is speculated that both isolates were nearly identical in virologic character. According to our phylogenetic analysis based on the complete genomes, both isolates belonged to genotype 1, and to the previously defined "vampire bat-related RABV lineage" which consisted of mainly D. rotundus- and A. lituratus-isolates; however, a branch pattern with high bootstrap values suggested that BR-DR1 was more closely related to the 9001FRA isolate, which was collected from a dog bitten by a bat in French Guiana, than to BR-AL1. This result suggests that the vampire bat-related RABV lineage includes Brazilian vampire bat and Brazilian frugivorous bat RABV and is further divided into Brazilian vampire bat and Brazilian frugivorous bat RABV sub-lineages. The phylogenetic analysis based on the complete genomes was valuable in discriminating among very closely related isolates. PMID- 21301182 TI - Enhanced protection against Heligmosomoides polygyrus in IL-2 receptor beta-chain overexpressed transgenic mice with intestinal mastocytosis. AB - IL-2 receptor beta-chain overexpressed transgenic (Tg2Rbeta) mice lack NK cells, but the development of other lymphocyte subsets and macrophages remained apparently intact. These mice also exhibit intestinal mastocytosis. Helminth infection induces various immune responses, such as mast cells, goblet cells, eosinophils and IgE, mediated by Th2 cytokines. IL-4 is also important in the regulation of resistance and susceptibility to Heligmosomoides polygyrus infection. However, there are contradictory results about the relation between resistance to H. polygyrus and intestinal mastocytosis. The present study showed that Tg2Rbeta mice suppressed worm fecundity with mastocytosis without an increase of the levels of goblet cells, eosinophils and IgE compared with control mice. These results clearly indicated that mast cells have the ability for to protect against H. polygyrus infection. However, additional studies are required to evaluate protective effector mechanisms against H. polygyrus. PMID- 21301183 TI - A low pathogenic H5N2 influenza virus isolated in Taiwan acquired high pathogenicity by consecutive passages in chickens. AB - H5N2 viruses were isolated from cloacal swab samples of apparently healthy chickens in Taiwan in 2003 and 2008 during surveillance of avian influenza. Each of the viruses was eradicated by stamping out. The official diagnosis report indicated that the Intravenous Pathogenicity Indexes (IVPIs) of the isolates were 0.00 and 0.89, respectively, indicating that these were low pathogenic strains, although the hemagglutinin of the strain isolated in 2008 (Taiwan08) had multibasic amino acid residues at the cleavage site (PQRKKR/G). In the present study, these H5N2 viruses were assessed for their intravenous and intranasal pathogenicity for chickens. It was examined whether Taiwan08 acquires pathogenicity through consecutive passages in chickens. Intravenous pathogenicity of Taiwan08 depended upon the age of the chickens used for the IVPI test; all of the eight-week-old chickens intravenously inoculated with Taiwan08 showed clinical signs but survived for ten days post inoculation (IVPI=0.68), whereas all the six-week-old chickens died (IVPI=1.86). Taiwan08-P8, which were passaged in chickens for eight times, killed all the eight-week-old chickens (IVPI=2.36). The four-week-old chickens died after intranasal inoculation of Taiwan08-P8, indicating that Taiwan08 must have become highly pathogenic during circulation in chicken flocks. These results emphasize the importance of a stamping out policy for avian influenza even if the IVPI of the causal virus is low. PMID- 21301184 TI - Repeat stereotactic radiosurgery in the management of brain metastases from non small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) is characterized by brain metastases that occur in about 30 to 50% of patients. To control tumor growth potential with maintaining neurocognitive function is important in the recent radiotherapy against brain metastases. From this viewpoint, we investigated the utility of repeat stereotactic radiosurgery (SRS) with a linear accelerator in the management of brain metastases from NSCLC. Between October 1998 and May 2010, 28 patients harboring brain metastases received repeat SRS (20 men and 8 women, with the age ranged from 51 to 79). The total number of SRS sessions ranged from 2 to 5, and the total number of lesions in one patient ranged from 1 to 8. Neurological decline due to uncontrolled brain lesions was identified in 9 of 28 patients after the repeat SRS, while the remaining 19 patients showed no neurological decline. Out of the 28 patients, 18 patients died by July 1, 2010; 12 patients died of active extracranial disease and 6 patients died from progressive brain lesions, considered neurological death. The 2-year and 4-year overall survival rates were 51% and 23%, respectively, and the median survival time was 26 months. In conclusion, repeat SRS is a preferred option to manage brain metastases from NSCLC, leading to a long survival with a decreased neurological decline. Repeat SRS is promising to preserve neurocognition, because the convergent dose distribution decreases the unfavorable influences from radiation on germinal niches, thereby preserving neural stem cells that are responsible for the nervous system repair. PMID- 21301185 TI - Limited role of auxiliary endobronchial biopsy in the diagnosis of Japanese patients with sarcoidosis. AB - The diagnosis of sarcoidosis, a multisystem granulomatous disease of unknown etiology, is established when clinicoradiological findings are supported by histological evidence of non-caseating epithelioid cell granulomas. For pathological diagnosis, an endobronchial biopsy of normal-appearing bronchial mucosa in combination with transbronchial lung biopsy (TBLB) has been reported to be useful for sarcoidosis patients in Europe or the U.S. This is the first report assessing the utility of endobronchial biopsy for diagnosis of Japanese patients with sarcoidosis. Eighteen consecutive patients with strongly suspected sarcoidosis were evaluated by endobronchial biopsy of normal-appearing bronchial mucosa, together with TBLB and bronchoalveolar lavage. The TBLB specimens demonstrated non-caseating epithelioid cell granulomas in the lungs of 11 patients (61.1%), but not any specific findings in those of other 7 patients. In contrast, endobronchial biopsy specimens confirmed a diagnosis of sarcoidosis in only one patient that required steroid therapy for deterioration of pulmonary sarcoidosis. All 18 patients of this study, including 5 patients with pathological findings obtained from extrapulmonary sites, met the pathological or clinical diagnostic criteria. In conclusion, endobronchial biopsy of normal appearing bronchial mucosa in combination with TBLB does not improve the diagnostic capacity for detecting sarcoidosis in Japanese patients, despite earlier reports. Thus, this method is of limited usefulness as a conventional diagnostic modality for Japanese patients with suspicious sarcoidosis. The present study also suggests the racial difference in the endobronchial involvement in pulmonary sarcoidosis. PMID- 21301186 TI - Chemotaxonomy of Trichoderma spp. Using mass spectrometry-based metabolite profiling. AB - In this study, seven Trichoderma species (33 strains) were classified using secondary metabolite profile-based chemotaxonomy. Secondary metabolites were analyzed by liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS-MS) and multivariate statistical methods. T. longibrachiatum and T. virens were independently clustered based on both internal transcribed spacer (ITS) sequence and secondary metabolite analyses. T. harzianum formed three subclusters in the ITS-based phylogenetic tree and two subclusters in the metabolitebased dendrogram. In contrast, T. koningii and T. atroviride strains were mixed in one cluster in the phylogenetic tree, whereas T. koningii was grouped in a different subcluster from T. atroviride and T. hamatum in the chemotaxonomic tree. Partial least-squares discriminant analysis (PLS-DA) was applied to determine which metabolites were responsible for the clustering patterns observed for the different Trichoderma strains. The metabolites were hetelidic acid, sorbicillinol, trichodermanone C, giocladic acid, bisorbicillinol, and three unidentified compounds in the comparison of T. virens and T. longibrachiatum; harzianic acid, demethylharzianic acid, homoharzianic acid, and three unidentified compounds in T. harzianum I and II; and koninginin B, E, and D, and six unidentified compounds in T. koningii and T. atroviride. The results of this study demonstrate that secondary metabolite profiling-based chemotaxonomy has distinct advantages relative to ITSbased classification, since it identified new Trichoderma clusters that were not found using the latter approach. PMID- 21301187 TI - Targeted gene disruption and functional complementation of cytochrome P450 Hydroyxlase involved in cyclosporin A hydroxylation in Sebekia benihana. AB - A cyclic undecapeptide-family natural product, cyclosporin A (CyA), which is one of the most valuable immunosuppressive drugs, is produced nonribosomally by a multifunctional cyclosporin synthetase enzyme complex in a filamentous fungal strain named Tolypocladium niveum. Previously, structural modifications of cyclosporins such as a regionspecific hydroxylation at the 4th N-methyl leucine in a rare actinomycetes called Sebekia benihana were reported to lead to dramatic changes in their bioactive spectra. However, the reason behind this change could not be determined since a system to genetically manipulate S. benihana has not yet been developed. To address this limitation, in this study, we utilized the most commonly practiced gene manipulation techniques including conjugation-based foreign gene transfer-and-expression as well as targeted gene disruption to genetically manipulate S. benihana. Using these optimized genetic manipulation systems, a putative cytochrome P450 hydroxylase (CYP) gene named CYP506, which is involved in CyA hydroxylation in S. benihana, was specifically disrupted and genetically complemented. The S. benihana deltaCYP506 exhibited a significantly reduced CyA hydroxylation yield as well as considerable yield restoration by functional complementation of the S. benihana CYP506 gene, suggesting that the genetically manipulated S. benihana CYP mutant strains may serve as a more efficient bioconversion host for various valuable metabolites including CyA. PMID- 21301188 TI - Purification and characterization of manganese-dependent alkaline serine protease from Bacillus pumilus TMS55. AB - The purification and characterization of a Mn2+-dependent alkaline serine protease produced by Bacillus pumilus TMS55 were investigated. The enzyme was purified in three steps: concentrating the crude enzyme using ammonium sulfate precipitation, followed by gel filtration and cation-exchange chromatography. The purified protease had a molecular mass of approximately 35 kDa, was highly active over a broad pH range of 7.0 to 12.0, and remained stable over a pH range of 7.5 to 11.5. The optimum temperature for the enzyme activity was found to be 60 degreesC. PMSF and AEBSF (1 mM) significantly inhibited the protease activity, indicating that the protease is a serine protease. Mn2+ ions enhanced the activity and stability of the enzyme. In addition, the purified protease remained stable with oxidants (H2O2, 2%) and organic solvents (25%), such as benzene, hexane, and toluene. Therefore, these characteristics of the protease and its dehairing ability indicate its potential for a wide range of commercial applications. PMID- 21301189 TI - Amphotericin B aggregation inhibition with novel nanoparticles prepared with poly(epsilon-caprolactone)/poly(n,n-dimethylamino-2-ethyl methacrylate) diblock copolymer. AB - Diblock copolymers composed of poly(epsilon-caprolactone) (PCL) and poly(N,N dimethylamino-2-ethyl methacrylate) (PDMAEMA), or methoxy polyethylene glycol(PEG), were synthesized via a combination of ring-opening polymerization and atom-transfer radical polymerization in order to prepare polymeric nanoparticles as an antifungal drug carrier. Amphotericin B (AmB), a natural antibiotic, was incorporated into the polymeric nanoparticles. The physical properties of AmB-incorporated polymeric nanoparticles with PCL-b-PDMAEMA and PCL b-PEG were studied in relation to morphology and particle size. In the aggregation state study, AmB-incorporated PCL-b- PDMAEMA nanoparticles exhibited a monomeric state pattern of free AmB, whereas AmB-incorporated PCL-b- PEG nanoparticles displayed an aggregated pattern. In in vitro hemolysis tests with human red blood cells, AmBincorporated PCL-b-PDMAEMA nanoparticles were seen to be 10 times less cytotoxic than free AmB (5 microgram/ml). In addition, an improved antifungal activity of AmBincorporated polymeric nanoparticles was observed through antifungal activity tests using Candida albicans, whereas polymeric nanoparticles themselves were seen not to affect activity. Finally, in vitro AmB release studies were conducted, proving the potential of AmB incorporated PCL-b-PDMAEMA nanoparticles as a new formulation candidate for AmB. PMID- 21301190 TI - Bioconversion of acrylonitrile to acrylic acid by rhodococcus ruber strain AKSH 84. AB - A new versatile acrylonitrile-bioconverting strain isolated from a petroleum contaminated sludge sample and identified as Rhodococcus ruber AKSH-84 was used for optimization of medium and biotransformation conditions for nitrilase activity to produce acrylic acid. A simple and rapid HPLC protocol was optimized for quantification of acrylic acid, acrylamide, and acrylonitrile. The optimal medium conditions for nitrilase activity were pH of 7.0, temperature of 30degreesC, agitation of 150 rpm, and inoculum level of 2%. Glycerol as a carbon source and sodium nitrate as the nitrogen source provided good nutritional sources for achieving good biotransformation. Nitrilase activity was constitutive in nature and was in the exponential growth phase after 24 h of incubation under optimal conditions without addition of any inducer. The substrate preference was acrylonitrile and acetonitrile. The present work demonstrates the biotransformation of acrylonitrile to acrylic acid with the new strain, R. ruber AKSH-84, which can be used in green biosynthesis of acrylic acid for biotechnological processes. The nitrilase produced by the isolate was purified and characterized. PMID- 21301191 TI - Microbiological purification of L-arabitol from xylitol mother liquor. AB - As a rare sugar alcohol, L-arabitol can be used in food and can prevent extra fat deposits in the intestinal tract. Commercially, L-arabitol is prepared from pure L-arabinose by hydrogenation, which needs a high temperature and high pressure, leading to a high production cost for Larabitol. Therefore, this study describes a novel L-arabitol production method based on biological purification from the xylitol mother liquor, a cheap and readily available raw material that contains a high concentration of Larabitol. First, a novel Bacillus megaterium strain was screened that can utilize xylitol, sorbitol, and mannitol, yet not L-arabitol. The isolated strain was inoculated into a medium containing the xylitol mother liquor under formulated culture conditions, where a high L-arabitol yield (95%) and high purity (80%) were obtained when the medium was supplemented with 50 g/l of xylitol mother liquor. Upon further purification of the fermentation broth by ion exchange and decolorization, L-arabitol was crystallized with a purity of 98.5%. PMID- 21301192 TI - Phenotypic and genotypic characterization of Salmonella spp. Isolated from pigs and their farm environment in Korea. AB - This study's objective was to determine the prevalence of Salmonella spp. in pigs and their farm environments in Korea, and to investigate the relationship between the strains based on their phenotypic and genotypic characteristics. A total of 36 Salmonella spp. were isolated in this study: 18 isolates from 492 pigs (3.7%) and 18 isolates from 418 (4.3%) farmhouse environmental samples from 16 different pig farms. Of the Salmonella strains isolated from the numerous environmental samples, the highest prevalence was observed in slurry or manure, followed by partitions, farmer's hands, floors, water/ nipples, ventilation sources, and feed, respectively. All the Salmonella isolates originating from different farms were genetically distinct. In three farms, however, identical phage types and pulse-field gel electrophoresis patterns were observed among Salmonella isolates from pig feces and environmental samples. This study suggests that environments contaminated with Salmonella could pose an infection risk to pigs on pig farms. PMID- 21301193 TI - Molecular genetic identification of yeast strains isolated from egyptian soils for solubilization of inorganic phosphates and growth promotion of corn plants. AB - Forty yeast strains isolated from soils taken from different locations in Egypt were tested for their P-solubilizing activities on the basis of analyzing the clear zone around colonies growing on a tricalcium phosphate medium after incubation for 5 days at 25degreesC, denoted as the solubilization index (SI). Nine isolates that exhibited P-solubilization potential with an SI ranging from 1.19 to 2.76 were genetically characterized as five yeasts belonging to the genus Saccharomyces cerevisiae and four non-Saccharomyces, based on a PCR analysis of the ITS1-26S region amplied by SC1/SC2 species-specific primers. The highest Psolubilization efficiency was demonstrated by isolate PSY- 4, which was identified as Saccharomyces cerevisiae by a sequence analysis of the variable D1/D2 domain of the 26S rDNA. The effects of single and mixed inoculations with yeast PSY-4 and Bacillus polymyxa on the P-uptake and growth of corn were tested in a greenhouse experiment using different levels of a phosphorus chemical fertilizer (50, 100, and 200 kg/ha super phosphate 15.5% P2O5). The results showed that inoculating the corn with yeast PSY-4 or B. polymyxa caused significant increases in the shoot and root dry weights and P-uptake in the shoots and roots. The P-fertilization level also had a significant influence on the shoot and root dry weights and P-uptake in the shoots and roots when increasing the P-level from 50 up to 200 kg/ha. Dual inoculation with yeast strain PSY-4 and B. polymyxa at a P-fertilization level of 200 kg/ha gave higher values for the shoot and root dry weights and P-uptake in the shoots and roots, yet these increases were nonsignificant when compared with dual inoculation with yeast strain PSY-4 and B. polymyxa at a P-fertilization level of 100 kg/ha. The best increases were obtained from dual inoculation with yeast strain PSY-4 and B. polymyxa at a P-fertilization level of 100 kg/ha, which induced the following percentage increases in the shoot and root dry weights, and P-uptake in the shoots and roots; 16.22%, 46.92%, 10.09%, and 31.07%, respectively, when compared with the uninoculated control (fertilized with 100 kg/ha). PMID- 21301194 TI - In vitro antagonistic activity evaluation of Lactic Acid Bacteria (LAB) combined with cellulase enzyme against campylobacter jejuni growth in co-culture. AB - The antibacterial effects of nine lactic acid bacteria (LAB) against Campylobacter jejuni were investigated by using agar gel diffusion and co-culture assays. Some differences were recorded between the inhibition effects measured with these two methods. Only two LAB, Lb. pentosus CWBI B78 and E. faecium THT, exhibited a clear anti- Campylobacter activity in co-culture assay with dehydrated poultry excreta mixed with ground straw (DPE/GS) as the only growth substrate source. It was observed that the supplementation of such medium with a cellulase A complex (Beldem S.A.) enhanced the antimicrobial effect of both LAB strains. The co-culture medium acidification and the C. jejuni were positively correlated with the cellulase A concentration. The antibacterial effect was characterized by the lactic acid production from the homofermentative E. faecium THT and the lactic and acetic acids production from the heterofermentative Lb. pentosus CWBI B78. The antagonistic properties of LAB strains and enzyme combination could be used in strategies aiming at the reduction of Campylobacter prevalence in the poultry production chain and consequently the risk of human infection. PMID- 21301195 TI - Biodegradation of diazinon by Serratia marcescens DI101 and its use in bioremediation of contaminated environment. AB - Four diazinon-degrading bacteria were isolated from agricultural soil by using an enrichment technique. The biochemical analysis and molecular method including RFLP indicated that these isolates were identical, and one strain designated DI101 was selected for further study. Phylogenetic analysis based on 16S rDNA sequencing indicated that the strain DI101 clearly belongs to the Serratia marcescens group. The ability of the strain to utilize diazinon as a source of carbon and phosphorus was investigated under different culture conditions. The DI101 strain was able to completely degrade 50 mg/l diazinon in MSM within 11 days with a degradation rate of 0.226 day-1. The inoculation of sterilized soil treated with 100 mg/kg of diazinon with 10(6) CFU/g DI101 resulted in a faster degradation rate than was recorded in non-sterilized soil. The diazinon degradation rate by DI101 was efficient at temperatures from 25 to 30degrees C and at pHs from 7.0 to 8.0. The degradation rate of diazinon was not affected by the absence of a phosphorus supplement, and addition of other carbon sources (glucose or succinate) resulted in the slowing down of the degradation rate. The maximum degradation rate (Vmax) of diazinon was 0.292 day-1 and its saturation constant (Ks) was 11 mg/l, as determined by a Michaelis-Menten curve. The strain was able to degrade diethylthiophosphate-containing organophosphates such as chlorpyrifos, coumaphos, parathion, and isazofos when provided as a source of carbon and phosphorus, but not ethoprophos, cadusafos, and fenamiphos. These results propose useful information for the potential application of the DI101 strain in bioremediation of pesticide-contaminated environments. PMID- 21301196 TI - Evaluation of anti-phytoplasma properties of surfactin and tetracycline towards lime witches' broom disease using real-time PCR. AB - The anti-phytoplasma activities of surfactin (derived from Iranian native Bacillus subtilis isolates) and tetracycline towards Candidatus "Phytoplasma aurantifolia", the agent of lime Witches' broom disease, were investigated. HPLC was used to quantify the surfactin production in four previously characterized native surfactin-producing strains, and the one producing the highest amount of surfactin (about 1,500 mg/l) was selected and cultivated following optimized production and extraction protocols. Different combinations of purified surfactin and commercial tetracycline were injected into artificially phytoplasmainfected Mexican lime seedlings using a syringe injection system. An absolute quantitative real-time PCR system was developed to monitor the phytoplasma population shifts in the lime phloem during 3 months following the injections. The results revealed that the injections of surfactin or tetracycline had a significant inhibitory effect on Candidatus "P. aurantifolia". However, the combined treatment with both surfactin and tetracycline (1:1) resulted in the highest inhibition due to a synergic effect, which suppressed the phytoplasma population from about 2*10(5) to less than 10 phytoplasma units/g plant tissue. PMID- 21301197 TI - Rapid multiplex PCR assay for the simultaneous detection of the Brucella Genus, B. abortus, B. melitensis, and B. suis. AB - The routine identification and differentiation of Brucella species is a time consuming and labor-intensive process, which frequently places personnel at risk of laboratoryacquired infection. Here, we describe the development of a rapid multiplex PCR assay for the confirmation of presumptive Brucella isolates. The assay was able to identify and differentiate major human pathogens, namely B. abortus, B. melitensis, and B. suis, in a single test of less than an hour and a half. PMID- 21301198 TI - Synthesis and optimization of cholesterol-based diquaternary ammonium Gemini Surfactant (Chol-GS) as a new gene delivery vector. AB - Amongst a number of potential nonviral vectors, cationic liposomes have been actively researched, with both gemini surfactants and bola amphiphiles reported as being in possession of good structures in terms of cell viability and in vitro transfection. In this study, a cholesterol-based diquaternary ammonium gemini surfactant (Chol-GS) was synthesized and assessed as a novel nonviral gene vector. Chol-GS was synthesized from cholesterol by way of four reaction steps. The optimal efficiency was found to be at a weight ratio of 1:4 of lipid:DOPE (1,2-dioleoyl-L-alpha- glycero-3-phosphatidylethanolamine), and at a ratio of between 10:1~15:1 of liposome:DNA. The transfection efficiency was compared with commercial liposomes and with Lipofectamine, 1,2-dimyristyloxypropyl-3 dimethylhydroxyethylammonium bromide (DMRIE-C), and N-[1-(2,3-dioleoyloxy)propyl] N,N,N-trimethylammonium chloride (DOTAP). The results indicate that the efficiency of Chol-GS is greater than that of all the tested commercial liposomes in COS7 and Huh7 cells, and higher than DOTAP and Lipofectamine in A549 cells. Confirmation of these findings was observed through the use of green fluorescent protein expression. Chol-GS exhibited a moderate level of cytotoxicity, at optimum concentrations for efficient transfection, indicating cell viability. Hence, the newly synthesized Chol-GS liposome has the potential of being an excellent nonviral vector for gene delivery. PMID- 21301199 TI - Validation of a real-time RT-PCR method to quantify Newcastle Disease Virus (NDV) titer and comparison with other quantifiable methods. AB - A method for the rapid detection and quantification of Newcastle disease virus (NDV) produced in an animal cell culture-based production system was developed to enhance the speed of the NDV vaccine manufacturing process. A SYBR Green I-based real-time RT-PCR was designed with a conventional, inexpensive RT-PCR kit targeting the F gene of the NDV LaSota strain. The method developed in this study was validated for specificity, accuracy, precision, linearity, limit of detection (LOD), limit of quantification (LOQ), and robustness. The validation results satisfied the predetermined acceptance criteria. The validated method was used to quantify virus samples produced in an animal cell culture-based production system. The method was able to quantify the NDV samples from mid- or late production phases, but not effective on samples from the early-production phase. For comparison with other quantifiable methods, immunoblotting, plaque assay, and tissue culture infectious dose 50 (TCID50) assay were also performed with the NDV samples. The results demonstrated that the real-time RT-PCR method is suitable for the rapid quantification of virus particles produced in an animal cell culture-based production system irrespective of viral infectivity. PMID- 21301200 TI - Bioethanol production from the hydrolysate of rape stem in a surface-aerated fermentor. AB - In this study, we investigated the feasibility of producing bioethanol from the hydrolysate of rape stem. Specifically, the most ideal yeast strain was screened, and the microaeration was performed by surface aeration on a liquid medium surface. Among the yeast strains examined, Pichia stipitis CBS 7126 displayed the best performance in bioethanol production during the surface-aerated fermentor culture. Pichia stipitis CBS 7126 produced maximally 9.56 g/l of bioethanol from the initial total reducing sugars (about 28 g/l). The bioethanol yield was 0.397 (by the DNS method). Furthermore, this controlled surface aeration method holds promise for use in the bioethanol production from the xylose-containing lignocellulosic hydrolysate of biomass. PMID- 21301201 TI - Prematurity and insulin sensitivity. AB - Nowadays, an increased number of premature infants survive. The medical challenge is to reduce their postnatal morbidities with a special focus towards a decrease in metabolic risks. In this manuscript, we will examine available evidence of perinatal, infancy, and childhood consequences of prematurity on insulin sensitivity and glucose homeostasis. Moreover, we add some recent data on how nutritional intervention could modify these risks. PMID- 21301202 TI - Re-thinking the definitions of subclinical thyroid disease in pregnancy. PMID- 21301203 TI - Bone metabolism in adolescents with anorexia nervosa. AB - Adolescents with anorexia nervosa (AN) are at risk for low bone mass at multiple sites, associated with decreased bone turnover. Bone microarchitecture is also affected, with a decrease in bone trabecular volume and trabecular thickness, and an increase in trabecular separation. The adolescent years are typically the time when marked increases occur in bone mass accrual towards the attainment of peak bone mass, an important determinant of bone health and fracture risk in later life. AN often begins in the adolescent years, and decreased rates of bone mass accrual at this critical time are therefore also concerning for deficits in peak bone mass. Factors contributing to low bone density and decreased rates of bone accrual include alterations in body composition such as low body mass index and lean body mass, and hormonal alterations such as hypogonadism, a nutritionally acquired resistance to GH and low levels of IGF-I, relative hypercortisolemia, low levels of leptin, and increased adiponectin (for fat mass) and peptide YY. Therapeutic strategies include optimizing weight and menstrual recovery, and adequate calcium and vitamin D replacement. Oral estrogen-progesterone combination pills are not effective in increasing bone density in adolescents with AN. Recombinant human IGF-I increases levels of bone formation markers in the short term, while long-term effects remain to be determined. Bisphosphonates act by decreasing bone resorption, and are not optimal for use in adolescents with AN, in whom the primary defect is low bone formation. PMID- 21301205 TI - Atg1 allows second-signaled autophagic cell death in Dictyostelium. AB - We investigated the role of Atg1 in autophagic cell death (ACD) in a Dictyostelium monolayer model. The model is especially propitious, not only because of genetic tractability and absence of apoptosis machinery, but also because induction of ACD requires two successive exogenous signals, first the combination of starvation and cAMP, second the differentiation factor DIF-1. This enables one to analyze separately first-signal-induced autophagy and subsequent second-signal-induced ACD. We used mutants of atg1, a gene that plays an essential role in the initiation of autophagy. Upon starvation/cAMP, in contrast to parental cells, atg1 mutant cells showed irreversible lesions, clearly establishing a protective role for Atg1. Upon subsequent exposure to DIF-1 or to more ACD-specific second signals, starved parental cells progressed to ACD, but starved atg1 mutant cells did not, showing that Atg1 was required for ACD. Thus, in the same cells Atg1 was required in two apparently opposite ways, upon first signaling for cell survival and upon second-signaling for ACD. Our findings strongly suggest that Atg1, thus presumably autophagy, protects the cells from starvation-induced cell death, allowing subsequent induction of ACD by the second signal. ACD is therefore not only "with" autophagy (since it showed signs of autophagy throughout), but is also "allowed by" autophagy. This does not exclude a role for autophagy also after second signaling. These results may account for discrepancies reported in the literature, encourage searches for second signals in different developmental models of ACD, and incite caution in autophagy-related therapeutic attempts. PMID- 21301206 TI - Histone deacetylase 1 is required for exocrine pancreatic epithelial proliferation in development and cancer. AB - Histone deacetylases (HDACs) play important roles in the epigenetic control of development, and aberrant expression of HDACs has been implicated in human diseases including cancer. Among the mammalian HDACs, HDAC1 has been extensively studied, but its role in exocrine pancreatic morphogenesis and cancer is still poorly understood. The goal of this study is to determine the functional role of HDAC1 in normal development of exocrine pancreas using zebrafish as the model organism as well as in human pancreatic adenocarcinoma. The zebrafish germline loss-of-function mutation hdac1(hi1618) caused impaired cell cycle progression in pancreatic epithelia, resulting in growth arrest and dysmorphogenesis of exocrine pancreas. In human pancreatic adenocarcinoma tissues and cell lines, HDAC1 was expressed at variably elevated levels. RNA interference-induced silencing of HDAC1 diminished proliferation of the cancer cells and cell cycle progression. The proliferative arrest in the developing exocrine pancreas and pancreatic cancer cells was associated with up-regulated expression of the cyclin-dependent kinase inhibitors and the sonic hedgehog signaling components. This study indicates that HDAC1 is required for pancreatic epithelial proliferation in development and cancer. We hypothesize that aberrant expression of HDAC1 modulates the developmental and signaling pathways in exocrine pancreatic epithelia and consequently the genes required for cellular proliferation during development and progression of pancreatic neoplasia. PMID- 21301207 TI - Targeting tumors that lack methylthioadenosine phosphorylase (MTAP) activity: current strategies. AB - Many solid tumors and hematologic malignancies lack expression of the enzyme methylthioadenosine phosphorylase (MTAP), due either to deletion of the MTAP gene or to methylation of the MTAP promoter. In cells that have MTAP, its natural substrate, methylthioadenosine (MTA), generated during polyamine biosynthesis, is cleaved to adenine and 5-methylthioribose-1-phosphate. The latter compound is further metabolized to methionine. Adenine and methionine are further metabolized and hence salvaged. In MTAP-deficient cells, however, MTA is not cleaved and the salvage pathway for adenine and methionine is absent. As a result, MTAP-deficient cells are more sensitive than MTAP-positive cells to inhibitors of de novo purine synthesis and to methionine deprivation. The challenge has been to take advantage of MTAP deficiency, and the changes in metabolism that follow, to design a strategy for targeted treatment. In this review, the frequency of MTAP-deficiency is presented and past and recent strategies to target such deficient cells are discussed, including one in which MTA is administered, followed by very high doses of a toxic purine or pyrimidine analog. In normal host cells, adenine, generated from MTA, blocks conversion of the analog to its toxic nucleotide. In MTAP-deficient tumor cells, conversion proceeds and the tumor cells are selectively killed. Successful mouse studies using this novel strategy were recently reported. PMID- 21301208 TI - Beclin 1 or not Beclin 1... PMID- 21301204 TI - Oncocytic mania: a review of oncocytic lesions throughout the body. AB - Oncocytic lesions are characterized pathologically by an abundance of oncocytes, that is by enlarged, eosinophilic, and finely granular cells enriched in mitochondria. They can arise in numerous organs and tissues, often in endocrine glands, and have been associated with hyperplasia, autoimmunity, and neoplasia. The causes and mechanisms that transform a normal cell into an oncocyte remain to be elucidated. Aim of this article is to review the most common oncocytic lesions, highlighting their key pathological features and clinical significance. PMID- 21301209 TI - The miRNA-targetome of KSHV and EBV in human B-cells. AB - Micro-RNAs (miRNAs) are small non-coding RNA molecules which provide a subtle layer of regulation to thousands of cellular genes. The identification of virally encoded miRNAs added another layer of complexity to the dense interaction between viruses and their natural hosts. While it has been shown that viral miRNAs can regulate both cellular and viral gene expression, target identification has been a difficult and cumbersome task. The immunoprecipitation of Argonaute (Ago) protein containing RNA-induced silencing complexes (RISC) followed by microarray analysis (RIP-Chip) allows the identification of miRNA-targetomes at whole transcriptome level. We applied Ago2-based RIP-Chip to identify cellular transcripts targeted by Kaposi's sarcoma-associated herpesvirus (KSHV, n=114), Epstein-Barr virus (EBV, n=44) and cellular miRNAs (n=2,337) in six latently infected or stably transduced human B-cell lines. While RIP-Chip yields a plethora of high-confidence miRNA targets and provides a quantitative estimate of miRNA function, additional biochemical methods like HITS-CLIP or PAR-CLIP and bioinformatic analysis are required to identify individual miRNA binding sites. Together, these methods will be useful to unravel the network of regulation exerted by both viral and cellular miRNAs, thereby providing the basis for functional studies on miRNA-mediated regulation of gene expression in herpesvirus infections. PMID- 21301210 TI - Aging and impaired immunity to influenza viruses: implications for vaccine development. AB - Influenza infections are responsible for significant morbidity and mortality each year, with the highest infection rates found in the elderly population. The main strategy to reduce the impact of influenza infections in the elderly population is vaccination. However, the efficacy of influenza vaccines that are licensed for use in the elderly is relatively low (17-53%). The complex age-related changes that occur in both innate and adaptive immunity are thought to hamper the immune response to influenza immunization and to reduce protection against infection in the elderly. For the development of improved vaccines that overcome the limitations of an aged immune system, it is crucial to understand the mechanisms that lead to immune dysfunction. Here, we review the recent progress in unravelling the mechanisms behind the age-related immune dysfunction in elderly, as well as the recent developments in improving influenza vaccines and identification of new correlates of protection. PMID- 21301211 TI - Epidemiological analysis of severe hospitalized 2009 pandemic influenza A (H1N1) cases in Catalonia, Spain. AB - From 25th April 2009 to 20th January 2010, 771 laboratory confirmed cases of 2009 pandemic influenza A (H1N1) were admitted to intensive care units (ICU) or hospitalized in medical wards with clinical criteria of severe disease (hospitalized pneumonias, multiorganic failure, septic shock or admitted to ICU or death while hospitalized). 82% of cases were hospitalized between epidemiological week 43 and 48 (25th October - 5th December 2009). Median age of patients was 40 years (range 0-89 years) and 56% were males. 38.7% cases were in the 15-44 year age-group, 29.4% in the 45-64 and 21.8% were children under 15 years of age. 36.8% were admitted to an ICU and 48 died. Underlying conditions were absent in 29% of patients (up to 38% among those under 15 years old). Differences in the prevalence of underlying conditions were found between children and adults. In children less than 15 years old, asthma (16.2%), other respiratory diseases (12.7%), cognitive disorders (10.2%), epilepsy (8.7%) and neuromuscular disorders (7.1%) were the most frequent. In adults, chronic obstructive pulmonary disease (14.8%), cardiovascular diseases (12.6%), asthma (11.5%), diabetes (11.2%) and morbid obesity (10.6%) were the most frequent. Further surveillance is needed to better characterize the epidemiology of this pandemic. PMID- 21301212 TI - Cytokinin receptors in sporophytes are essential for male and female functions in Arabidopsis thaliana. AB - Arabidopsis has three cytokinin receptors genes: CRE1, AHK2, and AHK3. Availability of plants that are homozygous mutant for these three genes indicates that cytokinin receptors in the haploid cells are dispensable for the development of male and female gametophytes. The triple mutants form a few flowers but never set seed, indicating that reproductive growth is impaired. We investigated which reproductive processes are affected in the triple mutants. Anthers of mutant plants contained fewer pollen grains and did not dehisce. Pollen in the anthers completed the formation of the one vegetative nucleus and the two sperm nuclei, as seen in wild type. The majority of the ovules were abnormal: 78% lacked the embryo sac, 10% carried a female gametophyte that terminated its development before completing three rounds of nuclear division, and about 12% completed three rounds of nuclear division but the gametophytes were smaller than those of the wild type. Reciprocal crosses between the wild type and the triple mutants indicated that pollen from mutant plants did not germinate on wild-type stigmas, and wild-type pollen did not germinate on mutant stigmas. These results suggest that cytokinin receptors in the sporophyte are indispensable for anther dehiscence, pollen maturation, induction of pollen germination by the stigma, and female gametophyte formation and maturation. PMID- 21301213 TI - Ontogenetic changes in the scaling of cellular respiration with respect to size among sunflower seedlings. AB - The respiration rates R (oxygen uptake per min) and body mass M (mg per individual) of sunflower (Helianthus annuus L.) seedlings were measured for populations raised in the dark (scotomorphogenesis) and for plants subsequently grown in white light (photomorphogenesis) to determine the allometric (scaling) relationship for R vs. M. Based on ordinary least squares and reduced major axis regression protocols, cellular respiration rates were found to increase non linearly as a 'broken-stick' curve of increasing M. During germination, the scaling was ca. 7.5-fold higher than after the emergence of the cotyledons from the seed coat, which can be attributed to the hypoxic conditions of the enclosed embryo. During seedling development, R was found to scale roughly as the 3/7 power of body mass (i.e., R ~ M(-3/7)), regardless of whether plants were grown in the dark or subsequently in white light. The numerical value of 3/7 statistically significantly differs from that reported across field- or laboratory-grown plants (i.e., R ~ M(-1.0)). It also differs from the expectations of recent allometric theory (i.e., R ~ M(-0.75) to M(-1.0)). This difference is interpreted to be the result of species-specific tissue compositions that affect the volume fractions of metabolically active and less active cells. These findings, which are supported by cytological and ultrastructural observations (i.e., scanning- and transmission electron micrographs), draw attention to the need to measure R of developing plants in a tissue- or organ-specific context. PMID- 21301214 TI - Diversity in spindle morphology in Arabidopsis root tip. AB - A primary function of the spindle apparatus is to segregate chromosomes into two equal sets in a dividing cell. It is unclear whether spindles in different cell types play additional roles in cellular regulation. As a first step in revealing new functions of spindles, we investigated spindle morphology in different cell types in Arabidopsis roots in the wild-type and the cytokinesis defective1 (cyd1) mutant backgrounds. cyd1 provides cells larger than those of the wild type for testing the cell size effect on spindle morphology. Our observations indicate that cell type (shape), not cell size, is likely a factor affecting spindle morphology. At least three spindle types were observed, including small spindles with pointed poles in narrow cells, large barrel-shaped spindles (without pointed poles) in wide cells, and spindles intermediate in pole focus and size in other cells. We hypothesize that the cell-type-associated spindle diversity may be an integral part of the cell differentiation processes. PMID- 21301215 TI - Molecular analysis of endo-beta-mannanase genes upon seed imbibition suggest a cross-talk between radicle and micropylar endosperm during germination of Arabidopsis thaliana. AB - The endo-beta-mannanase (MAN) family is represented in the Arabidopsis genome by eight members, all with canonical signal peptides and only half of them being expressed in germinating seeds. The transcripts of these genes were localized in the radicle and micropylar endosperm (ME) before radicle protrusion and this expression disappears as soon as the endosperm is broken by the emerging radicle tip. However, only three of these MAN genes, AtMAN5, AtMAN7 and especially AtMAN6 influence the germination time (t50) as assessed by the analysis of the corresponding knock-out lines. The data suggest a possible interaction between embryo and ME regarding the role of MAN during the Arabidopsis germination process. PMID- 21301216 TI - UV radiation reduces epidermal cell expansion in Arabidopsis thaliana leaves without altering cellular microtubule organization. AB - Upon chronic UV treatment pavement cell expansion in Arabidopsis leaves is reduced, implying alterations in symplastic and apoplastic properties of the epidermal cells. In this study, the effect of UV radiation on microtubule patterning is analysed, as microtubules are thought to serve as guiding rails for the cellulose synthase complexes depositing cellulose microfibrils. Together with hemicelluloses, these microfibrils are regarded as the load-bearing components of the cell wall. Leaves of transgenic plants with fluorescently tagged microtubules (GFP-TUA6) were as responsive to UV as wild type plants. Despite the UV-induced reduction in cell elongation, confocal microscopy revealed that cellular microtubule arrangements were seemingly not affected by the UV treatments. This indicates an unaltered deposition of cellulose microfibrils in the presence of UV radiation. Therefore, we surmise that the reduction in cell expansion in UV treated leaves is most probably due to changes in cell wall loosening and/or turgor pressure. PMID- 21301217 TI - RPK2 functions in diverged CLE signaling. AB - Shoot apical meristem is a well organized undifferentiated tissue which produces plant body. CLV3 peptide hormone regulates SAM homeostasis, and is perceived by several receptor complexes, CLV1, CLV2-SOL2/CRN, and RPK2. CLV1 homologues are encoded in various plants genome. However CLV2 and SOL2/CRN homologues are found only in higher plants. Here we show that the RPK2 homologues were found not only in moss, Physcomitrella patens, but also in liverwort, Marchantia polymorpha. Although CLV2-SOL2/CRN might have specific function in SAM homeostasis, CLV1 and RPK2 may regulate various plant physiological events during plant evolution. PMID- 21301218 TI - Glutathione in Synechocystis 6803: a closer look into the physiology of a ?gshB mutant. AB - Glutathione (GSH) is a low molecular weight thiol compound that plays many roles in photosynthetic organisms. We utilized a ?gshB (glutathione synthetase) mutant strain as a tool to evaluate the role of GSH in the cyanobacterium Synechocystis sp. PCC 6803 (hereafter Synechocystis 6803), a model photosynthetic organism. The ?gshB mutant does not synthesize glutathione, but instead accumulates the GSH precursor, gamma-glutamylcysteine (gamma-EC), to millimolar levels. We found that gamma-EC was sufficient to permit cellular proliferation during optimal conditions, but not when cells were exposed to conditions promoting oxidative stress. Furthermore, we found that many factors affecting growth rate and photosynthetic activities strongly influenced cellular thiol content. Here, we are providing some additional insights into the role of GSH and gamma-EC in Synechocystis 6803 during conditions promoting oxidative stress. PMID- 21301219 TI - Function of B-BOX under shade. AB - Plants are capable of perceiving changes in the light environment and finely adjust their growth and development. Reductions of red to far-red ratio (R:FR) generated by an increase of the plant canopy above the plant are sensed by the phytochrome system triggering the shade-avoidance syndrome (SAS) that includes elongation of vegetative structures, reduction of branching and acceleration of flowering. Albeit the SAS is a strategy of major adaptative significance in plant communities, involving massive changes in gene expression, our knowledge of the SAS signaling network is still fragmented. By a selection and characterization of a T-DNA mutant with a long hypocotyl under shade, we identified BBX21, a protein with two B-box domains involved in the SAS. BBX21 belongs to a small eight member family of B-box containing proteins with both opposite and additive functions in the SAS signaling. BBX21 down-regulates the gene expression of auxin, brassinosteroid and ethylene signaling pathway components under shade. Furthermore BBX21 is a transcription factor that interacts genetically with COP1. We propose a model in which a dynamic balance of positive and negative B-box transcriptional regulators acts as a gas-and-brake mechanism into the COP1 signaling to regulate the expression of SAS. PMID- 21301220 TI - A model of the C14-EPIC complex indicates hotspots for a protease-inhibitor arms race in the oomycete-potato interaction. AB - The oomycete pathogen Phytophthora infestans secretes cystatin-like effector proteins (EPICs) that inhibit secreted host proteases during infection. We recently found that the C14 protease is a relevant target of EPICs and that this protease is under diversifying selection in wild potato species with which P. infestans has coevolved. Here we generated a model of the EPIC-C14 complex based on cystatin-papain crystal structures and discovered three regions where variant residues in C14 might be the result of an arms race between enzyme and inhibitor at the plant-pathogen interface. PMID- 21301221 TI - Cytoskeleton and plant salt stress tolerance. AB - The plant cytoskeleton is a highly dynamic component of plant cells and mainly based on microtubules (MTs), and actin filaments (AFs). The important functions of dynamic cytoskeletal networks have been indicated for almost every intracellular activity, from cell division to cell movement, cell morphogenesis and cell signal transduction. Recent studies have also indicated a close relationship between the plant cytoskeleton and plant salt stress tolerance. Salt stress is a significant factor that adversely affects crop productivity and quality of agricultural fields worldwide. The complicated regulatory mechanisms of plant salt tolerance have been the subject of intense research for decades. It is well accepted that cellular changes are very important in plant responses to salt stress. Because the organization and dynamics of cytoskeleton may play an important role in enhancing plant tolerance through various cell activities, study on salt stress-induced cytoskeletal network has been a vital topic in the subject of plant salt stress tolerance mechanisms. In this article, we introduce our recent work and review some current information on the dynamic changes and functions of cytoskeletal organization in response to salt stress. The accumulated data point to the existence of highly dynamic cytoskeletal arrays and the activation of complex cytoskeletal regulatory networks in response to salt stresses. The important role played by cytoskeleton in mediating the plant cell's response to salt stresses is particularly emphasized. PMID- 21301223 TI - Consultancy and surveillance of post-immunisation adverse events in the Veneto region of Italy for 1992-2008. AB - Prevention and control of adverse events following immunization (AEFI) are fundamental activities of successful immunisation programs. AEFI reporting, investigation and analysis, integrated by consultancy for subjects needing a specialized evaluation, represent an ideal model for vaccine safety surveillance. In the Veneto Region of Italy the Green Channel Centre has been created by the local Public Health authority, to offer a consultancy activity for vaccinations at risk of adverse events and to ensure an efficient AEFI surveillance system with regular feedback data for vaccine personnel. This report updates the overall activity provided by the Green Channel between 1992 and 2008, concerning consultations for previous AEFI and contraindications to vaccinations and analysis of AEFI reports. After 1280 consultancy cases, 998 (78%) subjects were found eligible for vaccination, with personalized precautions suggested in 42% of cases. Of a total of 724 patients actually vaccinated as per the Green Channel instructions, only 55 subjects (7.6%) reported mild symptoms and one (0.3%) a moderate allergic reaction. Since 1993, a total of 5,006 AEFI reports have been collected and evaluated by the Green Channel against more than 20 millions of vaccine doses administered with an estimate mean AEFI rate of 2.3 x 10.000 doses per year. The majority of them (94%) were found in causal relationship with vaccines; of these, 267 reports (5,6% - 0.1/10,000 doses) were serious and 9 of these subjects, affected by a neurological event, were not recovered or were still on therapy at follow up. This regional activity has proven efficacious in evaluating and managing individual cases at potential risk of AEFI and integrating the national passive surveillance system. PMID- 21301222 TI - Genetic interaction of two abscisic acid signaling regulators, HY5 and FIERY1, in mediating lateral root formation. AB - Root architecture is continuously shaped in a manner that helps plants to better adapt to the environment. Gene regulation at the transcriptional or posttranscriptional levels largely controls this environmental response. Recently, RNA silencing has emerged as an important player in gene regulation and is involved in many aspects of plant development, including lateral root formation. In a recent study, we found that FIERY1, a bifunctional abiotic stress and abscisic acid (ABA) signaling regulator and an endogenous RNA silencing suppressor, mediates auxin response during lateral root formation in Arabidopsis. We proposed that FRY1 regulates lateral root development through its activity on adenosine 3', 5'-bisphosphate (PAP), a strong inhibitor of exoribonucleases (XRNs). Interestingly, some of the phenotypes of fry1, such as enhanced response to light in repressing hypocotyl elongation and hypersensitivity to ABA in lateral root growth, are opposite to those of another light- and ABA-signaling mutant, hy5. Here we analyzed the hy5 fry1 double mutant for root and hypocotyl growth. We found that the hy5 mutation can suppress the enhanced light sensitivity in fry1 hypocotyl elongation and restore the lateral root formation. The genetic interaction between HY5 and FRY1 indicates that HY5 and FRY1 may act in overlapping pathways that mediate light signaling and lateral root development. PMID- 21301224 TI - HP1c casts light on dark matter. AB - Heterochromatin protein 1a (HP1a) is well known as a silencing protein and regulates gene expression through its binding to methylated histone H3K9. Despite sharing a nearly identical domain architecture, most eukaryotes have at least three HP1 homologs that have differential localization patterns and functions in heterochromatin and euchromatin. Among the three main HP1 paralogs in Drosophila, HP1c functions the least like the canonical heterochromatic HP1, HP1a. HP1c exclusively localizes to euchromatin. In contrast to a key role of HP1a in heterochromatin formation and gene silencing, recent studies link transcriptional elongation by RNA polymerase II to euchromatic HP1c or HP1gamma. These findings expand the role for HP1c in targeting euchromatin, suggesting that HP1c acts as a positive regulator in active transcription in euchromatin. Here, we highlight recent data on the specificity and function of HP1c. PMID- 21301225 TI - Controlling the cell cycle: the role of calcium/calmodulin-stimulated protein kinases I and II. AB - Many studies have implicated Ca2+ and calmodulin (CaM) as regulators of the cell cycle. Ca2+/CaM-stimulated proteins, including the family of multifunctional Ca2+/CaM-stimulated protein kinases (CaMK), have also been identified as mediators of cell cycle progression. CaMKII is the best-characterized member of this family, and is regulated by multi-site phosphorylation and targeting. Using pharmacological inhibitors that were believed to be specific for CaMKII, CaMKII has been implicated in every phase of the cell cycle. However, these 'specific' inhibitors also produce effects on other CaMKs. These additional effects are usually ignored, and the effects of the inhibitors are normally attributed to CaMKII without further investigation. Using new specific molecular techniques, it has become clear that CaMKI is an important regulator of G1, whereas CaMKII is essential for regulating G2/M and the metaphase-anaphase transition. If the mechanisms controlling these events can be fully elucidated, new targets for controlling proliferative diseases may be identified. PMID- 21301227 TI - Fate of primary cells at the G1/S boundary after polo-like kinase 1 inhibition by SBE13. AB - Human polo-like kinase 1 (Plk1), a key regulator of mitosis, is over-expressed in various human tumors. It is a negative prognostic factor for cancer patients and a measure for the aggressiveness of a tumor. Thus, targeting Plk1 might be a promising approach for cancer therapy. Plk1 inhibitors represent attractive tools for cancer research and for the mechanistic investigation of checkpoint control. Here, we show the impact of Plk1 inhibition on cell cycle regulation in primary cells. After treatment with SBE13 the G1//S checkpoint was intact, indicated by reduced pRb, resulting in slower cell cycle progression but overall cell proliferation was not significantly impaired. Thus, we provide strong evidence that SBE13 leaves checkpoint control in primary cells unaffected making it a remarkable future anti-cancer therapeutic. PMID- 21301226 TI - Nek1 kinase functions in DNA damage response and checkpoint control through a pathway independent of ATM and ATR. AB - Never-in-mitosis A related protein kinase 1 (Nek1) is involved early in a DNA damage sensing/repair pathway. We have previously shown that cells without functional Nek1 fail to activate the more distal kinases Chk1 and Chk2 and fail to arrest properly at G1/S or M-phase checkpoints in response to DNA damage. As a consequence, foci of damaged DNA in Nek1 null cells persist long after the instigating insult, and Nek1 null cells develop unstable chromosomes at a rate much higher than identically cultured wild type cells. Here we show that Nek1 functions independently of canonical DNA damage responses requiring the PI3 kinase-like proteins ATM and ATR. Chemical inhibitors of ATM/ATR or mutation of the genes that encode them fail to alter the kinase activity of Nek1 or its localization to nuclear foci of DNA damage. Moreover ATM and ATR activities, including the localization of the proteins to DNA damage sites and phosphorylation of early DNA damage response substrates, are intact in Nek1 -/- murine cells and in human cells with Nek1 expression silenced by siRNA. Our results demonstrate that Nek1 is important for proper checkpoint control and characterize for the first time a DNA damage response that does not directly involve one of the known upstream mediator kinases, ATM or ATR. PMID- 21301229 TI - Dynamic innovation. Editorial. PMID- 21301230 TI - Healthcare and physician leadership. AB - At a recent social policy conference - Recovering Together? Fiscal Pressures, Federalism and Social Policy, hosted by Queen's International Institute on Social Policy - there was much discussion of "healthcare's crowding out" of others of the determinants of health, education and income security being the predominant examples. I was struck by the loose language, four words/phrases in particular, used to describe reality - healthcare, system, single-payer and publicly funded. Physicians are increasingly moving beyond their already-demanding clinical roles to become chief executive officers (CEOs), chiefs of staff, clinical leaders, board members, deans and directors. Is this a good thing, and should physician leadership be encouraged? Or as Ron Liepert (2009, August), minister of Alberta Health and Wellness, asserts, are physicians better at diagnosing and treating people than running $8 billion organizations? PMID- 21301231 TI - Don't tinker, transform: launching a primary healthcare revolution. PMID- 21301228 TI - The DNA damage effector Chk1 kinase regulates Cdc14B nucleolar shuttling during cell cycle progression. AB - Chk1 is a critical effector of DNA damage checkpoints necessary for the maintenance of chromosome integrity during cell cycle progression. Here we report, that Chk1 co-localized with the nucleolar marker, fibrillarin in response to radiation-induced DNA damage in human cells. Interestingly, in vitro studies using GST pull down assays identified the dual-specificity serine/threonine nucleolar phosphatase Cdc14B as a Chk1 substrate. Furthermore, Chk1, but not a kinase-dead Chk1 control, was shown to phosphorylate Cdc14B using an in vitro kinase assay. Co-immunoprecipitation experiments using exogenous Cdc14B transfected into human cells confirmed the interaction of Cdc14B and Chk1 during cell cycle. In addition, reduction of Chk1 levels via siRNA or UCN-01 treatment demonstrated that Chk1 activation following DNA damage was required for Cdc14B export from the nucleolus. These studies have revealed a novel interplay between Chk1 kinase and Cdc14B phosphatase involving radiation-induced nucleolar shuttling to facilitate error-free cell cycle progression and prevent genomic instability. PMID- 21301232 TI - Opportunities to improve diabetes prevention and care in Canada. AB - The prevalence of diabetes in Canada is expected to more than double by 2030. Additionally, the costs associated with diabetes have nearly doubled between 2000 and 2010 and will continue to rise unless improvements are made. Fortunately, more effective policies and programs can reduce both the prevalence of diabetes and the complications associated with the disease. We used responses from the Canadian Community Health Survey to assess whether Canadians with diabetes report (1) receiving from healthcare professionals the recommended tests to screen for complications, (2) performing sufficient self-care for their diabetes and, (3) for those in lower-income households, receiving less recommended care. The results show that only one in three (32%) Canadian adults with diabetes reported having received all four recommended tests during the previous year. Lower-income Canadians were more likely to report having diabetes and less likely to report receiving the four diabetes care tests. Only half of adults with diabetes reported checking their blood sugar levels daily, and only two in five reported checking their feet for injuries and ulcers. Improvements to adherence to diabetes care guidelines are needed to reduce the likelihood that Canadians, especially lower-income Canadians, will develop complications from diabetes. Bending the cost curve downward is possible through more effective policies and programs that prevent diabetes in the first place and that ensure Canadians with diabetes get both recommended care from their healthcare providers and enough support for effective self-care. PMID- 21301233 TI - Geographical variation in opioid prescribing and opioid-related mortality in Ontario. PMID- 21301234 TI - Small steps ... improving quality one team at a time in Saskatchewan. AB - Saskatchewan's Health Quality Council (HQC) was launched in 2003 with a mandate to not only measure and report on healthcare but also work with a range of partners to improve the province's health system. In late 2007, HQC's board decided it was time for Saskatchewan to reinvent its healthcare system, using the highest-performing systems in the world as its model. And in 2008, HQC launched Accelerating Excellence, a multi-level program to rethink, redesign and renew healthcare. To help maintain momentum and show other provinces whether high performing healthcare can be achieved in Canada, HQC is documenting its journey. This fifth article in this series discusses the incremental steps needed to effect and sustain change. PMID- 21301235 TI - In conversation with Bill Barrable. Interview by Ken Tremblay. PMID- 21301236 TI - Front-line services development: The key element for the success of Quebec's Healthcare Reform. PMID- 21301237 TI - Improving mental healthcare by primary care physicians in British Columbia. AB - This article describes a new and innovative training program to assist family physicians to better care for their patients with mental health conditions. Trained family physician leaders train other family physicians. The training package includes a wide range of tools that can be used by physicians in their own offices. Preliminary results indicate that physicians want to be trained, and data indicate a high degree of success for the training module. Some 91% of physicians who attended the training indicated that it had improved their practice, and 94% indicated that it had improved patient care. The training materials are online for those who wish to learn more. PMID- 21301238 TI - From benefits evaluation to clinical adoption: making sense of health information system success in Canada. AB - This article proposes a Clinical Adoption Framework for making sense of health information system (HIS) success in Canada. It extends Canada Health Infoway's Benefits Evaluation Framework with contextual factors that influence HIS adoption by clinicians, which include people, organization, implementation, and the macro environment. Our hypothesis is that successful clinical adoption of an HIS requires explicit recognition, strategies and actions that address the factors described in the framework. Validation of this framework by stakeholders and literature has thus far been favourable. Its potential application with selected evaluation approaches in specific settings, the implications and work ahead are discussed. PMID- 21301239 TI - Assessing information technology investments: 10 questions healthcare executives should ask. PMID- 21301240 TI - Feasibility of physician peer assessment in an academic health sciences centre. AB - Peer assessment has become an important component of physician evaluation. In an academic health sciences centre, in addition to clinical care there is a significant focus on education, training and research. The literature suggests that the use of a 360-degree evaluation can provide physicians with valuable information on many aspects of their practice and can inform both professional and personal development. We conducted a pilot study to determine the feasibility of using peer assessment as part of the evaluation of our academic physicians. To maintain anonymity, an outside company was engaged to conduct the study. Participants completed a self-assessment and provided the names of eight physician peers and eight non-physician peers who were then requested to complete an evaluation. In addition, 25 patients were asked to provide their feedback. All questionnaires were forwarded directly to the outside company, which then compiled the data and provided each participant with a final report. Results indicate that it is feasible to carry out peer assessment within an academic health sciences centre. Participants noted the value of the process for career development and quality improvement. PMID- 21301241 TI - Enabling transformational change: the Ontario shores experience. AB - This case study outlines key considerations for healthcare organizations experiencing significant transformational change, based on the experience of Ontario Shores Centre for Mental Health Sciences (Ontario Shores), formerly Whitby Mental Health Centre. Significant systemic change requires specific and intentional efforts from the leaders tasked with carrying out transformational activities. This article presents the perspectives of leaders involved in the transformation of Ontario Shores as it moved from a government-based agency to a stand-alone specialty psychiatric hospital in 2006. During this time, several conventional strategies were employed to manage the transition, but various critical approaches also emerged that assisted the organization to effect significant change and achieve marked improvements over key evaluation metrics. These critical strategies included maximizing the distinct and collective roles of governance and leadership; balancing strategy and action through a culture of accountability; leveraging strategic communication opportunities; and shifting the organizational mindset. PMID- 21301242 TI - Organizational model and process for clinical best practice in rehabilitation and complex continuing care. AB - Toronto Rehabilitation Institute developed its Clinical Best Practice Model and Process (TR-CBPMP) to facilitate a systematic and consistent approach to best practice with the goal of shortening the path between best knowledge and clinical care and linking this process to patient needs and outcomes. The TR-CBPMP guides clinicians, inter-professional teams, administrators and leaders in identifying patient needs, reviewing present practice, determining best practice priorities, analyzing gaps, preparing for and implementing best practice, evaluating patient based outcomes and sustaining the best practice. The TR-CBPMP has been used successfully to develop program-specific, profession-specific and organization wide best practices. PMID- 21301243 TI - Home First: reducing ALC and achieving better outcomes for seniors through inter organizational collaboration. AB - Like many hospitals, those in the Mississauga Halton Local Health Integration Network (MH LHIN) have used inter-professional collaboration to maximize system processes. Process improvements previously occurring in silos have started crossing hospital programs and systems within and beyond the hospital. The challenge is that few healthcare organizations consider, never mind implement, process improvements that traverse the LHIN. This article discusses an innovation with a unique feature: concentration not only on inter-professional collaboration but on inter-organizational collaboration by professionals and providers throughout the LHIN. The Home First approach exemplifies what is possible when culture is adapted to necessitate and enable intra- and inter-organizational collaboration and partnerships based on trust and respect. This approach has been spread and sustained successfully across the LHIN, with alternative level of care patients being reduced by 50% or greater. PMID- 21301244 TI - Red light-green light: from kids' game to discharge tool. AB - Lean manufacturing methods are being evaluated in the healthcare sector. Improving the flow of patients in acute care should the eliminate delays that contribute to the cost of healthcare. Our patient care unit uses the colours of a traffic light to visually identify the expected date of discharge. This facilitates the distribution of the work relating to discharge over a couple of days, rather than the usual concentration within the last couple of hours of a patient's stay. The Red Light-Green Light system contributes to reduced backlogs in the emergency department and fewer cancellations of elective surgeries due to a lack of in-patient beds. PMID- 21301245 TI - Hospital resource use by patients with schizophrenia: reduction after conversion from oral treatment to risperidone long-acting injection. AB - The chronic relapsing nature of schizophrenia is associated with significant resource use. The William Osler Health System, Brampton Civic Hospital site, in Brampton, Ontario, provides comprehensive in-patient and outpatient mental health services to the community it serves, including patients with schizophrenia. The clinical benefits observed in patients with schizophrenia treated through the injection clinic led the hospital to evaluate the costs, resource use and potential savings associated with injectable compared with oral therapy. The substantial savings accruing to the hospital and the healthcare system provide a strong economic rationale for injectable therapy as an alternative level of care for patients with schizophrenia. PMID- 21301246 TI - Successful implementation of a professional development program for: wound care in the community care setting. PMID- 21301247 TI - An integrated outsourcing solution at York Central Hospital. AB - Canadian hospitals struggle to balance the need to increase and improve operational services and quality with diminishing resources. Many realize that sustaining their organization depends on how well they focus their resources and talents on their core business, clinical care delivery. Outsourcing of non-core, non-clinical support services is a solution for many organizations. Most often, this is put into action one service provider at a time. In 2007, however, York Central Hospital (YCH) implemented Sodexo's integrated Comprehensive Service Solutions (CSS) for all its support service functions. In doing so, YCH achieved significant improvements in patient and staff satisfaction rates, substantial cost savings through improved operational efficiency from process improvements and leveraging technology investments, and increased retail food revenue. PMID- 21301248 TI - Our healthcare "system" - what system? PMID- 21301249 TI - Engaging the forces of change. PMID- 21301250 TI - Dr. Joy Richards, 2010 recipient, Margret Comack Award in nursing leadership. PMID- 21301251 TI - Leadership: Catalyst for quality and performance. PMID- 21301252 TI - Clinician executives: a new breed of leader. PMID- 21301253 TI - The growing health leadership gap: a response from a non-clinician recovering CEO. PMID- 21301254 TI - "Just because a nurse is a really good nurse doesn't mean she will be a good manager!". PMID- 21301255 TI - The "old internationals": Canadian nurses in an international nursing community. AB - The vast devastation caused by both the First World War and the influenza pandemic of 1918 led to an increased worldwide demand for public health nurses. In response to this demand, a number of new public health training programs for nurses were started at both national and international levels. At the international level, one of two influential programs in this area included a year long public health nursing course offered by the League of Red Cross Societies, in conjunction with Bedford College in London, England. In total, 341 nurses from 49 different countries have been documented as participants in this initiative throughout the interwar period, including 20 Canadians. Using archival material from the Canadian Nurses Association and the Royal College of Nursing, as well as articles from the journals Canadian Nurse, American Journal of Nursing and British Journal of Nursing, this paper examines these nurses' commitment to internationalism throughout their careers and explores the effect of this commitment on the development of nursing education and professionalization at the national level. PMID- 21301256 TI - A Delphi approach to developing a core competency framework for family practice registered nurses in Ontario. AB - This paper describes the results of a Delphi panel process to gain consensus on a role description and competency framework for family practice registered nurses (FP-RNs) in Ontario. Based on the findings from interviews and focus groups with family practice registered nurses and their inter-professional colleagues throughout Ontario, a core competency framework for FP-RNs emerged consisting of six distinct roles - Professional, Expert, Communicator, Synergist, Health Educator and Lifelong Learner - with accompanying enabling competency statements. This framework was refined and validated by a panel of experts from various nursing and family medicine associations and organizations through a Delphi consensus process. This core competency framework for FP-RNs was developed as a stepping stone for clarifying this very important and poorly understood role in family practice. As a result of this research, we expect a greater acknowledgement of the contributions and expertise of the FP-RN as well as the need to celebrate and profile this role. This work has already led to the establishment of a network of stakeholders from nursing organizations in Ontario who are considering opportunities to move the development and use of the competency framework forward. PMID- 21301257 TI - A partnership model evolves from a living inventory of engagement. AB - This university-community partnership developed when practitioners at a community health centre within a regional health authority collaborated with nursing faculty at the University of New Brunswick in Saint John, New Brunswick, Canada. A philosophical match and work context facilitated this collaboration. Partners acknowledged that continued maintenance of the partnership, or its termination, was dependent on the acceptance of principles of partnership engagement. Even though the common philosophy of primary healthcare brought these partners together and reciprocal capacity building was the glue that nurtured their partnership, the tensions that arose fuelled its continued growth and development. Roles and responsibilities of members were discerned and space was created to acknowledge and integrate the lessons learned when tensions were examined. Within this environmental context, a model of partnership emerged. Tensions within this model were accepted as opportunities that resulted in beliefs being challenged, relevant questions generated and partnership alliances strengthened. In this spiral process, new relevant knowledge was constructed and new norms for best practice and policy were developed. The utility of this inter professional Partnership Model: Living Inventory of Engagement is demonstrated through case examples. PMID- 21301259 TI - This is the decade for nursing. PMID- 21301260 TI - Nausea and vomiting in HIV/AIDS. AB - HIV infection has become a chronic illness with the availability of potent antiretroviral agents. Many of the agents used to manage HIV, however, have been associated with distressing symptoms such as nausea and vomiting posing challenges to maintain adherence to therapy and quality of life. This article highlights the mechanism, evaluation, and management of HIV-associated nausea and vomiting. Supportive symptom management information is also presented. PMID- 21301261 TI - The incidence of upper extremity injuries in Canadian endoscopy nurses. AB - Work-related musculoskeletal injuries occur at an epidemic rate in Canada. Many thousands of workers are temporarily or permanently removed from the workforce annually because of this type of injury. Workers who are most susceptible to this type of injury are those who perform physical, repetitive work involving sustained activity in awkward positions and cramped environments. Workers in the healthcare sector experience one of the highest rates of this type of injury annually. Injury prevention programs are being developed and instituted by government agencies and employers in an attempt to reduce the frequency of occurrence of this type of injury. In spite of attempts to prevent these injuries, musculoskeletal injuries of the upper extremity, neck, and back continue to occur in healthcare workers including nurses. Endoscopy nurses experience upper extremity injuries at work. The purpose of this study was to explore whether the occurrence of upper extremity injuries is common in this population of nurses and to identify factors that may be associated with these injuries. Results reveal that for this sample of Canadian nurses, older endoscopy nurses are at greater risk of injury. Nurses with injuries tended to self prescribe treatment of their injuries. They also took anti-inflammatory medications and painkillers for their symptoms and saw their doctors for their conditions. Physiotherapist involvement was not common. Thirty-two percent of the endoscopy nurses in this study missed work because of upper extremity pain. Considering the number of nurses working in Canada, this percentage suggests a significant number of sick days, indicating a cause for concern, exploration, and further prevention measures. PMID- 21301262 TI - Promoting community awareness of the need for colorectal cancer prevention and screening: a replication study. AB - The American Cancer Society estimated that 152,260 people would be diagnosed with, and 50,630 people would die of, colorectal cancer in 2009. It recommends that screening for average-risk adults should start at the age of 50 years; however, less than half have been screened according to the guidelines. Colorectal cancer can be prevented by diet and lifestyle, in addition to polypectomy, and the morbidity and mortality can be reduced by early intervention. The purpose of this replication study was to evaluate the effectiveness of a health belief model-based colorectal cancer education session to increase awareness of the need for prevention and screening and to promote such discussions between the participants and their doctors. Participants attended education sessions at three agencies in the Midwest. Participants' beliefs, before and after the sessions, were evaluated by survey. The results support that the education sessions were successful in increasing awareness of the need for a healthy lifestyle and adhering to the screening guidelines. A longitudinal study would help to track awareness over time and evaluate the efficacy toward long-term healthy lifestyles. PMID- 21301263 TI - Perceptions of simulation-based training in crisis resource management in the endoscopy unit. AB - Simulation-based training (SBT) teaches healthcare teams to manage critical events, using crisis resource management skills. The purpose of this study was to assess staff perceptions of using SBT in the endoscopy suite. Nurses and technicians were invited to participate in a training program that used simulation of endoscopy-based scenarios to teach crisis resource management skills. Participants completed surveys prior to, immediately following, and 1 month following SBT. Surveys assessed the usefulness, enjoyment, applicability, and realism of SBT using 5-point Likert scales. Eleven (92%) of the 12 nurses (10 = female, median age = 45 years) and four (80%) of five technicians (3 = female, 37 years of age) participated. Prior to participation, nurses with more than 5 years' experience rated their expected enjoyment of SBT to be lower than less experienced peers (mean = 2.6 vs. 4.5, p =.005). When surveyed immediately after participation, both groups reported SBT to be highly useful (mean +/- SD, 4.6 +/- 0.9 vs. 5.0 +/- 0), enjoyable (3.8 +/- 0.8 vs. 4.6 +/- 0.5), applicable (4.0 +/- 0.8 vs. 4.7 +/- 0.8), and realistic (4.0 +/- 0.7 vs. 4.7 +/- 0.8). One month after training, 14 of the 15 participants expressed interest in future programs, using simulation to practice crisis resource management skills. Findings suggest that SBT may serve as an enjoyable, applicable, and realistic tool to enhance a team's performance in the endoscopy suite across all caregivers and different levels of experience. PMID- 21301264 TI - The isolating and insulating effects of hepatitis C: a substantive grounded theory. AB - Hepatitis C has a global prevalence of 3%, causing chronic infection in 75% of cases, and is currently the main cause of liver transplant in the United Kingdom. This study reviewed patients' and service providers' perspectives on hepatitis C as an enduring condition, using a constructivist grounded theory approach. A constant comparative approach to data collection and analyses incorporating a coding paradigm was applied to semistructured interviews, focus groups, and memos. Sixteen patients and three focus groups of staff (n = 17) were recruited via purposive theoretical sampling (February through August 2008). A negative synergistic relationship between the condition hepatitis C, patients, and service providers that creates isolating and insulating effects for the relevant parties emerged from the data as a middle-range theory. Stigma and contagion create a "real" or perceived sense of isolation for hepatitis C comorbid and itinerant patients, who require the right support at the right time. Healthcare staff adhere to professional demarcation lines to manage potentially untenable patient caseloads. In turn, patients and professionals perceive that a crisis may be required to bring about successful therapeutic intervention. A service that incorporates seamless outreach services and facilitates interdisciplinary working is needed to manage complex patients with this enduring condition. PMID- 21301265 TI - Successful outcome using C1-inhibitor concentrate in acute pancreatitis caused by hereditary angioedema. PMID- 21301266 TI - Shared governance: a pathway to leadership. PMID- 21301267 TI - Unique propofol considerations. PMID- 21301268 TI - Reviewing for the journal: my personal prescription. PMID- 21301269 TI - Pediatric home care: the best-kept secret... PMID- 21301271 TI - Children and grief: but what about the children? A guide for home care and hospice clinicians. PMID- 21301273 TI - From hospital to home healthcare: the need for medication reconciliation. AB - Medication reconciliation is a process of comparing medications being used by a client to a current list of prescribed medications to verify its accuracy, and is a best-practice strategy to reduce medication errors. In home healthcare, medication reconciliation includes comparing medications specified in hospital discharge instructions, those taken before the hospitalization, and those now taken by the client, and documenting action taken to resolve discrepancies noted. This exploratory study was designed to describe the adequacy of medication reconciliation in a Midwestern home healthcare agency. PMID- 21301274 TI - Case report: Cranberry juice and warfarin. PMID- 21301275 TI - An evidence-based pediatric fall risk assessment tool for home health practice. PMID- 21301277 TI - Bringing children home: bridging the gap between inpatient pediatric care and home healthcare. AB - Pediatric home care is an emerging need. Eleven years ago, six community-based, not-for-profit home care agencies in New Hampshire and Vermont took action by progressively forming the Visiting Nurse Association Health System of Northern New England, Inc. (VNAHSNNE) workgroup to improve pediatric home care. The focus of a pediatric home care initiative called Bringing Children Home was created to provide enhanced training for pediatric nurses and bridge the gap between inpatient pediatric care and home care, thus improving home care for children with complex medical needs. The goal of the workgroup is to enhance the transition from hospital to home, ultimately providing improved quality care to the patient and the family. PMID- 21301279 TI - Children's health insurance programs: do they provide the coverage that is needed? PMID- 21301282 TI - Nontechnical skills. Introduction. PMID- 21301280 TI - Unique bonds that form when visiting patients in their homes: one nurse's perspective. PMID- 21301283 TI - Training and nontechnical skills: the politics of terminology. PMID- 21301284 TI - Commentary: preparing for health care reform: ten recommendations for academic health centers. AB - Health care reform, the subject of intense national debate and discussion during the presidential campaign and the first year of the Obama presidency, is now reality. The Patient Protection and Affordable Care Act of 2010 (PPACA) became law in March 2010. Despite efforts by the new Republican majority in the House of Representatives of the 112th Congress to repeal the bill, some aspects of PPACA have already taken effect, and the majority of the remainder are scheduled to be implemented by 2014. PPACA will change the U.S. health care system in fundamental ways. Perhaps more than other entities in the U.S. health care system, academic health centers (AHCs) will bear the impact of the struggle to care for 32 million new, primarily low-income insurance beneficiaries. A large influx of new patients trying to access the health care system through AHCs will coincide with major changes in the financing of health care, the training of health professions students, and the conduct of biomedical research. Although many of the sweeping changes coming through PPACA will not happen until later in this decade, AHCs must begin planning for the future now if they are to prosper, or even survive, in the brave new world of health care reform. The author of this commentary first briefly analyzes some of the most important effects PPACA will have on AHCs and then makes recommendations for how AHCs can prepare to take advantage of the opportunities and mitigate the challenges inherent in implementing PPACA. PMID- 21301286 TI - A new simple technique to correct nipple inversion using 2 V-Y advancement flaps. AB - Nipple inversion is a particular condition characterized by shorter galactophorous ducts, periductal fibrosis, and lack of soft tissue under the nipple base. It can be congenital or acquired, and it affects about 10% of the female population. Many operative techniques have been described seeking to correct this deformity, but a unique landmark strategy does not exist yet. Although acceptable results have been reported, every surgical technique has its drawbacks. We describe our 5 years' experience in correcting inverted nipples by using a simple personal approach. Between January 2004 and January 2009, we treated 52 patients presenting with nipple inversion using 2 V-Y dermoglandular flaps performed in the dermoglandular portion of the nipple. This method is effective in the correction of moderate and severe inverted nipple deformities. Follow-up period ranged from 1 to 6 years. Results showed recurrence in 1 case and postoperative complications in 3 patients. The authors have found this to be an ideal procedure for correcting inverted nipple; the use of an easy to perform V-Y flap ensures nipple protrusion and support, lactation, and minimal scars. PMID- 21301287 TI - American plastic surgery and global health: a brief history. AB - Access to essential surgical care in resource-poor settings is gaining recognition as a major component of international public health efforts. As evidence is mounting about the burden of surgically treatable disease in low- and middle-income countries, so too is the evidence for the significant need for plastic surgery treatment of disease rising in these areas. American plastic surgery has a long history with international surgical efforts in resource-poor regions around the world. Early experiences were not formalized until after World War II, when a foundation partnership provided a venue for interested plastic surgeons to volunteer. These efforts progressed and advanced throughout the 1960s 1970s, but were ultimately devastated by the Vietnam War. Subsequent international plastic surgical experiences by American surgeons over the last 40 years have been largely through several nongovernmental organizations. American plastic surgical involvement in global surgery has changed significantly over the last 70 years. Although quality care is being delivered to resource-poor regions around the world, many of the challenges of regionally appropriate, sustainable care persist today. PMID- 21301288 TI - Three-year experience using near infrared spectroscopy tissue oximetry monitoring of free tissue transfers. AB - Early recognition of threatened free-flap failure is paramount to flap salvage. A noninvasive, reproducible, sensitive monitoring tool would be a useful adjunct to clinical examination. The purpose of this study was to examine outcomes using a near-infrared spectroscopy (NIRS) tissue oximeter for postoperative flap monitoring. A total of 128 free flaps were performed in 113 patients over a 3 year period. The patients were divided into 2 cohorts: conventional monitoring (group 1) and conventional monitoring plus NIRS oximetry (group 2). Overall flap survival was 90.6% in group 1 and 98.7% in group 2 (P = 0.05). Overall survival of threatened flaps was 0% (0/5) in the conventional group and 87.5% (6/7) in the oximeter group, P = 0.005. Salvage of operated flaps was significantly improved in group 2: 0% (0/4) in group 1 versus 100% (3/3) in group 2, P = 0.03. The sensitivity, specificity, and predictive values for detecting threatened flap loss were 100%. The NIRS tissue oximeter is a highly reliable, sensitive, and specific, noninvasive method for postoperative free tissue transfer monitoring. PMID- 21301289 TI - Pediatric compartment syndrome caused by intravenous infiltration. AB - BACKGROUND: The small diameter and fragility of infant veins increases the risk of intravenous (IV) fluid extravasation. Modern pump delivery systems, designed with pressure sensors to detect and respond to flow obstructions in the IV line, are in wide use to limit the amount of fluid that reaches the extravascular space. In some instances, the pump safety systems can fail to detect rising pressure and may lead to compartment syndrome. METHODS: Retrospective chart review of patients treated for extremity compartment syndrome as a result of an IV infiltration. RESULTS: Three infants (mean age, 9 months) were identified. Each patient had a large volume of IV fluid delivered into the subcutaneous tissue through a pump infusion system. In all cases, the sensor failed to alarm and to disable the system, and the problem was identified only after routine nursing evaluation of the IV site. Findings included the following: tissue blanching, decreased capillary refill, and severely restricted active/passive motion of the affected extremity. Peripheral pulses were present in all patients. Compartment pressure elevation (>30 mm Hg) was confirmed prior to operative intervention by a slit catheter system. Fasciotomy was required in the hand and forearm of 2 patients, and of the thigh, leg, and foot in 1 patient. Each infant recovered full use of the extremity. CONCLUSIONS: The reason that these pumps failed to detect the dangerously elevated pressures is unclear, but may be related to a combination of fluid dynamics and pump engineering. Routine nursing evaluation remains the gold standard for detection of these events. PMID- 21301290 TI - Suicide by burning: epidemiological and clinical profiles. AB - Self-immolation constitutes a rare form of suicide in developed countries, though it accounts for unique injury characteristics in the burn intensive care unit. The aim of this study was to present the epidemiological and clinical features of patients burned during a suicidal attempt seen in a North Rhine-Westphalia burn intensive care unit (BICU). To address this aim, we undertook a 21-year retrospective study involving patients with thermal injuries admitted to the largest burn unit in Germany. A total of 125 suicide-related burn victims were identified in the study period (9.4%). Comparing the self-immolation group with the rest burn patient cohort, suicide victims were more likely to be single and to act under the influence of alcohol. The suicidal group had a larger extent of burns, higher incidence of inhalation injury, required more surgical procedures, catecholamines, blood transfusions, and a longer BICU stay. Their clinical course was complicated by prolonged intubation period, higher rate of multiple drug resistant bacteria acquisition and sepsis, leading to a higher mortality rate. Although the proportion of self-immolation victims among all burned patients is not high, the markedly higher severity of their burns and their poorer quality of outcomes makes them an important clinical subgroup for further study. PMID- 21301291 TI - Combined first dorsal metacarpal artery flap and dorsal transposition flap for correction of extensive first web space contracture: a case report and literature review. AB - First web space contracture is a common sequela after hand trauma and exerts tremendously negative effects on hand function. To restore hand function, it is mandatory to release contracted first web structures, which usually results in a large skin defect. Dorsal transposition flaps sometimes are not sufficient to cover the whole defect. Microvascular flaps provide abundant soft tissue, but they are lengthy procedures and exhibit risks of complete flap failure. In this study, we present an alternative approach to address this difficult clinical problem. A 25-year-old man developed extensive contracture over the first web space after trauma. After release of the contracted structures, the extensive skin defect was covered by a dorsal transposition flap with an extension to the territory of the first dorsal metacarpal artery flap. The functional and cosmetic results were excellent, without recurrence of contracture postoperatively. The combined first dorsal metacarpal artery flap and dorsal transposition flap appeared to be an effective and relatively simple method for the reconstruction of severe first web space contracture. PMID- 21301292 TI - Congenital nasal cartilage deformities. AB - A unique case of congenital nasal septal deformity is reported with a chronological summary of literature pertaining to congenital nasal defects. PMID- 21301293 TI - Prefabricated osteocutaneous neural island flap model. AB - Neural-based flaps are an interesting clinical choice particularly in difficult cases that may not be reconstructed with known techniques. Their popularity is gradually increasing because these flaps offer the advantage of preservation of major extremity arteries and avoidance of microsurgical techniques. Our aim was to explore the feasibility of prefabrication of an osteocutaneous neural island flap model in this study. A peripheral nerve of the rat was implanted into the subcutaneous tissue of a skin flap that was connected to a segment of bone by a soft-tissue bridge, to prefabricate an osteocutaneous flap that was supplied only by the intrinsic vasculature of that nerve after a preliminary delay period. At the end of this study, based on direct observation, microangiographic findings, and additionally, a detailed histologic analysis consisting of both qualitative and quantitative assessments, we have proved that it was possible to prefabricate an osteocutaneous composite flap based on the vascularity of a peripheral nerve after a 2-step delay period. We believe that the clinical application of this new flap will gradually develop based on further experimental studies. PMID- 21301294 TI - Lower back defect coverage using a free-style gluteal perforator flap. AB - Lower back defects remain a major challenge for reconstructive surgeons. Advances in perforator flap techniques now make it possible to repair lower back defects using a gluteal perforator flap based on the free-style flap design. We used a free-style gluteal perforator flap in 10 patients with lower back defects due to skin cancer treatment (6 patients) or infection following spine surgery (4 patients). V-Y advancement flaps were used for defects <6 cm in length, and rotation flaps for defects >6 cm. Perforators were detected at the upper parasacral area, and the flap design was drawn on the skin of the upper gluteal region. Coverage was successful and donor sites were closed primarily in all cases. There were 4 complicated cases: 1 of partial flap loss that led to delay of the wound closure, 2 of initial venous congestion, and 1 of hematoma. These complications resolved, and there was no case of flap loss during a 12 to 62 months follow-up (mean, 32.4 months). The present series indicated that the free style gluteal perforator flap provides a safe, effective, and relatively easy option for lower back defect reconstruction. PMID- 21301295 TI - Use of porous high-density polyethylene (Medpor) for spreader or extended septal graft in rhinoplasty: aesthetics, functional outcomes, and long-term complications. AB - In this study, 29 patients with porous high-density polyethylene (group A) and 29 patients with septal cartilage (group B) were enrolled for either spreader or extended septal graft. By questionnaire or telephone survey, the authors evaluated patients' cosmetic satisfaction and complications. The authors also used postoperative photographs to evaluate cosmetic results. For the functional analysis, the change of visual analog scale of nasal obstruction and change of minimal cross-sectional area using acoustic rhinometry were compared. Of 29 patients in group A, 27 were totally satisfied with the results. There was no complication except for 2 cases of extrusion during 5.3 +/- 1.8 years. The patients in group A showed more decrease of nasal obstruction by visual analog scale and more improvement of minimal cross-sectional area as compared with those in group B. Therefore, porous high-density polyethylene is an ideal alloplastic material for spreader or extended septal graft in rhinoplasty in both cosmetic and functional aspects. And it is also safe and stable over a long-term period. PMID- 21301296 TI - Free calvarial periosteum graft vascularized by an omental flap in a rat model. AB - Because omental flaps are useful for flap prefabrication and the cambium layer of the periosteum can be osteogenic, we examined whether calvarial periosteum grafted onto greater omentum of rats was osteogenic and suitable for a flap. Distal omentum was wrapped with calvarial periosteum and so the cambium faced the omentum. Grafted omentum was harvested at 1 to 9 days. In other rats, grafted omentum was elevated as a pedicled flap and moved to the abdominal subcutis, to be harvested later at 1 to 5 months after the initial surgery. Bone formation was evaluated histologically, histochemically, and radiographically. On day 3, osteoid had formed. From day 4, calvarial periosteum was revascularized by omentum and bone was forming. New bone was maintained after grafting to subcutis for 5 months. Thus, bone formed by periosteum on the omentum could be used to reconstruct defects of the bone. PMID- 21301297 TI - Vascularized fibular flaps enhance histological repair in pasteurized autogenous bone graft. AB - The healing process of structural pasteurized autogenous bone graft has not been studied in detail. The purpose of this investigation was to assess the reparative process of pasteurized bone graft histologically, and clarify the factors influencing the outcome. From among 51 cases using pasteurized autogenous bone graft since 1992, 10 specimens were retrieved after lower extremity reconstruction of tibia or femur with or without simultaneous fibula flap, and subjected to the analysis. Regeneration of the grafted bone was assessed as the ratio of the number of viable cells to that of whole cells. Pasteurized bone combined with a vascularized fibula showed markedly better repair. Long duration from implantation to retrieval was associated with a better reparative process with vascularized fibula (P = 0.03), whereas other factors had no significant impact. This study demonstrated that pasteurized autogenous bone graft remained structurally stable for many years, although facilitators such as the combined use of a vascularized fibula are required to promote regeneration of the graft. PMID- 21301298 TI - The usefulness of oncoplastic volume displacement techniques in the superiorly located breast cancers for Korean patients with small to moderate-sized breasts. AB - Because the average breast size of Korean women is not as large as that of western women, it is not so easy to apply the oncoplastic volume displacement technique. However, we have tried to use volume displacement techniques that work well with small-breasted women. In this study, we report the usefulness of displacement techniques in the superiorly located cancers with small- to moderate sized breasts. Between September 2006 and August 2009, 58 women were treated for superiorly located cancers. All patients who were selected had small- to moderate sized breasts and small to moderate breast defects. They were divided into 3 groups. The groups were split based on the distance from the nipple-areolar complex, which are as follows: near, intermediate, and far. Their mean age was 46 and the average follow-up interval was 21 months. Median weight of the specimen on the tumor side was 84 g (range, 29-140 g). The various surgical techniques used were the "round block" technique (n = 8) and "batwing mastopexy" (n = 4) for near lesions; "tennis racket" method (n = 32) and "rotational flap" (n = 8) for intermediate lesions; and "parallelogram mastopexy lumpectomy" (n = 6) for far lesions. There were 4 complications (nipple-areolar complex partial necrosis, radiation burn, and 2 wound dehiscence). No local recurrences have been observed and a majority of the patients were satisfied with cosmetic results. Oncoplastic volume displacement techniques in superiorly located breast cancers for Korean patients with small- to moderate-sized breast are reliable and should be considered in the case of breast conserving surgery (BCS). PMID- 21301299 TI - Perforator flap breast reconstruction after unsatisfactory implant reconstruction. AB - In 2009, 86,424 breast reconstructions were performed in the United States, with 76% being implant-based procedures. Capsular contracture and infection are the 2 most cited indications for implant explantation, resulting in a reconstruction failure. However, several patients are dissatisfied with implant reconstruction even without the aforementioned complications. We hypothesize that microvascular autologous tissue transfer with perforator free-flap breast reconstruction provides an excellent salvage modality in the face of an unsatisfactory implant reconstruction, resulting in an improved cosmetic and functional outcome, with low risk of complications. We retrospectively reviewed the charts of patients in the senior author's practice who underwent perforator flap breast reconstruction between the years 1998 through 2008, and identified all patients who had prior implant reconstruction. Indications for implant explantation, medical history, operative procedure, and postoperative complications were reviewed. During the study period, 1846 perforator flaps were performed. We found 191 patients who underwent autologous breast reconstruction after implant reconstruction with a total of 284 flaps (15.4%). The most frequent patient complaint was unnatural appearance and feel of the implants (Baker I or Baker II), and the majority of patients had not undergone radiation. Most patients were reconstructed using abdominal flaps with 164 deep inferior epigastric perforators, 50 superior gluteal artery perforators, 30 superficial inferior epigastric arteries, 35 inferior gluteal artery perforators, and 5 transverse upper gracilis. The total complication rate was 7.4%, with most complications related to wound healing at the donor site. There were 3 flap losses (1%), all of which were later successfully reconstructed with another perforator flap. Implant failures are traditionally thought to be in patients with Baker grade III/IV capsular contractures and in patients status post radiation therapy. However, in our study, the majority of patients seeking perforator flap reconstruction after implant reconstruction complained of an unnatural feel and appearance of their breasts, and did not have a severe capsular contracture deformity (Baker III/IV), nor had they undergone radiation. This suggests that implant reconstruction can lead to patient dissatisfaction severe enough to warrant removal even with Baker I/II results, and not in the setting of postradiation changes. PMID- 21301300 TI - Abdominal contouring in super obese patients: a single-surgeon review of 22 cases. AB - BACKGROUND: It is generally believed that increasing obesity is a predictor of postoperative complications after abdominal contouring procedures such as abdominoplasty and panniculectomy. The purpose of this study is to review the complication rate for abdominal contouring in the level 3 obesity category (body mass index [BMI], >40 kg/m2) and to examine the safety of this procedure when performed in this select patient population. METHODS: Between 2003 and 2008, an institutional review board-approved, single-surgeon, single-institution retrospective review was conducted for all patients presenting for abdominal contouring. In all, 100 patients with precontouring BMI <40 kg/m2 were excluded, resulting in 22 patients who met the criteria for Level 3 obesity category, which are also referred as "super obese." To date, this is the largest series that has reported pertaining to this category and procedures. RESULTS: In this series, 77% (17/22) had prior bariatric surgery. The mean hospitalization was 2.8 days and mean length of follow-up was 202 days. The major complication rate was 4.5% (1/22). CONCLUSIONS: Abdominal contouring can be performed safely, effectively, and with minimal morbidity in the super obese. Only one patient required readmission after developing an infected seroma and all patients progressed to a well-healed wound. BMI >40 kg/m2 should not preclude patients from undergoing this functional and beneficial surgical procedure. PMID- 21301301 TI - Transposition technique for correction of a malpositioned nipple-areola complex after reconstruction following a nipple-sparing mastectomy: a case report. AB - We developed a novel transposition technique for the correction of an asymmetric nipple-areola complex (NAC) due to breast mound reconstruction after a nipple sparing mastectomy. The technique was composed of a rotation flap and an advancement flap. In this study, we describe a case of a 35-year-old woman with a malpositioned NAC located at the upper lateral position with a vertical scar in the lateral area of the breast treated by this technique, with a follow-up period of 12 years. In this case, established techniques were difficult to apply as there were thin underlying subcutaneous tissue and scars near the NAC. This technique may be useful in such a case and is an additional option in the correction of a malpositioned NAC from the upper lateral position to the ideal position on a breast mound. PMID- 21301302 TI - Repair of severe composite tissue defects in the lower leg using two different cross-leg free composite tissue flaps. AB - This article reports 2 cross-leg free composite tissue flaps for repairing the severe composite tissue defects in lower leg without suitable adjacent recipient vasculature for microvascular anastomosis. The osseous myocutaneous flap of ilium and tensor fascia lata pedicled with ascending branch of lateral femoral circumflex vessels and the osseous muscle flap of scapula and latissimus dorsi pedicled with subscapular vessels were performed, respectively, to reconstruct the bone and soft-tissue defects in the lower leg of 2 patients. Both donor vessels were the posterior tibial artery and great saphenous vein from the contralateral lower leg. The legs and the bone flaps were immobilized by an external fixator. The periods of pedicle division were 43 and 67 days, respectively, after transplantation. Both flaps survived after pedicle division and the patients regained the ability to walk. There were no such complications as joint stiffness or donor site morbidity except for a linear scar. The 2 cross leg free composite tissue flaps were optional methods for salvaging limbs that were otherwise nonreconstructable. But the indication for cross-leg free-tissue flap should be limited strictly. PMID- 21301303 TI - Occurrence of fat embolism after liposuction surgery with or without lipografting: an experimental study. AB - BACKGROUND: Liposuction in plastic surgery consists of the removal of excess fatty tissue in healthy individuals. In recent decades, this procedure has become more common worldwide. Associated with liposuction, lipografting has also been used for improving body contours, and has become known as liposculpture. Liposuction sometimes causes complications, including fat embolism, as described in the medical literature. The present study aims at ascertaining whether there is intravascular mobilization of fat after mechanical liposuction surgery and/or fat graft when carried out using one of the most common specific procedures used for liposuction, the superwet technique. METHODS: A total of 30 Wistar rats were included in this study. Before the surgery, the animals were placed in the supine position and anesthetized with thiopental for 50 to 60 minutes, as it is generally performed in clinical practice. The animals were divided in the following 3 groups. Group A, consisting of 10 rats, served as controls, and were only anesthetized. Group B consisted of 10 rats, which underwent only liposuction. Group C also comprised 10 rats, which were liposuctioned and then lipografted in the dorsal region. Blood was collected just before and again, 48 hours after the procedure. After 48 hours, the animals were killed, and the lungs, kidneys, liver, and brain were histologically examined. RESULTS: All the collected samples were analyzed microscopically with 2 different stains, namely, hematoxylin and eosin, and Sudan black. Fat particles were found in the lungs of 3 animals in group B (those that underwent only liposuction) and in 6 animals of group C (liposuction and lipografting). No fat particles were found in any organ of the control group. CONCLUSIONS: With this experiment, the authors showed that there is a risk of systemic mobilization of fat after liposuction surgery and that this risk is even higher when fat grafts are also carried out. PMID- 21301304 TI - Correction of syndactyly using a dorsal separated V-Y advancement flap and a volar triangular flap in adults. AB - Skin grafts and local flaps are conventional methods of repair for congenital syndactyly, but the results obtained are not always as functional and aesthetic as desired and frequently leave postoperative scars and residual syndactyly. In this article, we describe a new surgical technique for web reconstruction in the correction of simple, incomplete syndactyly. The technique consists of a dorsal separated V-Y advancement flap and a volar triangular flap to cover the newly created web space, thus avoiding skin graft in this space. In all, 15 web spaces in 10 patients were treated using this method. A follow-up period of 6 months to 2 years showed neither recurrence of the deformity nor web creep of any degree. The technique is rapid, safe, easily performed, and reproducible and requires a single surgical procedure. It uses donor tissue identical in color, texture, and thickness, which renders acceptable cosmesis in cases of simple, incomplete syndactyly, therefore, avoiding the use of skin grafts and resulting postoperative scar contracture in the web space. PMID- 21301305 TI - Medial plantar artery perforator flap for soft-tissue reconstruction of the heel. AB - Soft-tissue wounds of the foot and especially the heel are challenging problems for reconstructive surgeons. An important principle that guides heel reconstruction is to provide sensate skin with a similar thickness to resurface the weight-bearing heel and avoid late flap ulceration. Among various techniques to achieve this result, the sensate medial plantar perforator flap is an excellent option, which provides durability to friction, a cushioning effect, and sensation. An anatomic study was performed to clarify the anatomy of the cutaneous perforators of the medial plantar artery and to determine the optimal method of medial plantar artery perforator flap harvest. Fifteen cases of heel reconstruction with the sensate medial plantar perforator flap are presented. The outcome of surgery at a mean follow-up of 12 months is reported. The indications for surgery, operative procedures, advantages and disadvantages, and results are presented. Satisfactory results were obtained with a good color and texture match for heel repair and a good sensory recovery. No functional deficit was found at the donor site. PMID- 21301307 TI - Outcome analysis of immediate and delayed conservative breast surgery reconstruction with mastopexy and reduction mammaplasty techniques. AB - BACKGROUND: Bilateral mammaplasty or mastopexy is frequently used for oncoplastic objectives. However, little information has been available regarding outcome following immediate and delayed reconstruction. METHOD: Patients were divided into Group I (immediate reconstruction) and Group II (delayed reconstruction). Retrospective review was performed to compare complications, length of hospital stay, revision surgeries, and satisfaction. The associations between the complications with potential risk factors (timing, age, body mass index, smoking, and comorbid medical conditions) were analyzed. RESULTS: There were a total of 144 patients with a mean follow-up of 47 months. Of the 106 patients in Group I, complications occurred in 24 (22.6%), skin necrosis was observed in 7.5%, fat necrosis in 5.6%, and 6.6% patients developed local recurrence. Mean period of hospitalization was 1.89 days. Of the 38 patients of the Group II, complications occurred in 12 (31.5%), skin necrosis was observed in 7 (18.4%), fat necrosis in 4 (10.5%), and 5.2% patients developed local recurrence. Mean period of hospitalization was 1.35 days. Increased length of hospital stay greater than 1 day (P < 0.001) and the number of revision surgeries (P = 0.043) were associated with the timing of the reconstruction. In univariate analysis, no difference between groups was found with respect to complication incidence (P = 0.275); however, after adjusting for other risk factors, the probability of complications tend to be higher for Group II (OR = 2.65; 95% confidence interval = 1.01-7.00; P = 0.049). CONCLUSIONS: On the basis of the results of our study, the probability of complications tends to be higher for delayed reconstructions, and it is demonstrated that obesity and smoking are risk factors for complications. Ultimately, these data may facilitate the provision of individualized risk information for shared medical decision-making. PMID- 21301308 TI - Ideal anthropomorphic values of the female breast: correlation of pluralistic aesthetic evaluations with objective measurements. AB - BACKGROUND: In determining ideal anthropomorphic values of the female breast, previous studies relied on the aesthetic judgments of 1 plastic surgeon alone or conveyed no aesthetic judgment. METHODS: Anthropomorphic measurements were recorded from the breasts of 109 female volunteers. Images of their breasts were arranged into a computerized survey, and plastic surgeons, cosmetic breast surgery patients, and reconstructive breast surgery patients were interviewed for aesthetic feedback. RESULTS: In all, 252 plastic surgeons, 15 cosmetic patients, and 25 reconstructive patients submitted 4446 evaluations. The ideal sternal notch to nipple distance was 21 to 21.5 cm, the ideal nipple to base distance was 6 cm, and the ideal base to inframammary fold distance was 2 cm. These and other ideal anthropomorphic measurements were calculated and compared with previously published values. Among cosmetic patients, insufficient cleavage had the most negative effect on aesthetic value, and among reconstructive patients, severe asymmetry had the most negative effect. CONCLUSIONS: Ideal anthropomorphic values were similar among plastic surgeons and patients, and these values will be useful in achieving quantitative breast surgery. In cosmetic patients, operative planning should focus more on superomedial fullness of the breast to create cleavage, and in reconstructive patients, postoperative asymmetry should be minimized. PMID- 21301309 TI - Closure of large myelomeningocele defects using dorsal intercostal artery perforator flap. AB - Small meningomylocele defects can be closed primarily. Other repair techniques are required for closure of meningomyelocele defects of >5 cm. In this anomaly, in which random or musculocutaneous flaps are usually used, the technique for skin defect closure should have the following criteria: a safely harvested flap with good blood supply; minimal morbidity in the donor site; closure with adequate thickness to protect the underlying neural structure; and a repair to prevent leakage of cerebrospinal fluid. The dorsal intercostal artery perforator flap is a new perforator flap with a large skin island that can be used safely in the dorsal region. In this article, repair of large skin defects due to myelomeningocele has been attempted using a dorsal intercostal artery perforator flap, and the results are discussed. PMID- 21301310 TI - Macrostomia: a report of three cases. AB - Transverse facial clefts (macrostomia) are rare disorders that result when the embryonic mandibular and maxillary processes of the first branchial arch fail to fuse properly to form the corners of the mouth. Macrostomia may be seen alone or in association with other anomalies. It may be unilateral, extending along a line from the commissure to the tragus. It is usually partial, but rarely complete. Transverse facial clefts are more common in males, and commoner on the left when unilateral. We report on 3 patients with macrostomia managed in our unit. There were 2 girls with a bilateral transverse facial cleft and a boy with a left unilateral transverse facial cleft. All had a 3 layered repair of their clefts with Z-plasty repair of the skin. The longest duration of follow-up was 2 weeks. Strict adherence to the principles of surgical reconstruction is advised in the repair of macrostomia to prevent a poor treatment outcome. PMID- 21301311 TI - Does hyperbaric oxygen administration before or after irradiation decrease side effects of irradiation on implant sites? AB - BACKGROUND: One of the main limitations of implant-based breast reconstruction is the high rate of complications such as capsular contracture and poor aesthetic outcome, due to adjuvant radiotherapy. Hyperbaric oxygen treatment (HBOT) has been used to assist wound healing in the prevention and treatment of the side effects of irradiation. We aimed to investigate this effect of HBOT on the capsule reaction and skin, applied before and after irradiation, following the placement of an implant under the dorsal skin of the rat. METHODS: Fifteen Wistar rats were randomly divided into 3 groups. A 18-mL smooth testicular implant was introduced into a subcutaneous pocket located on the dorsum of each rat. A single dose of 17-Gy irradiation was given to the implanted area of each rat at the third week. HBOT which lasted 3 weeks was administered to group I before irradiation, group II after irradiation. The control group did not receive HBOT. All of the rats were killed at the ninth week (6 weeks after irradiation). The dorsal skin with the capsule overlying the implant were excised for histopathological processing. The thickness of the capsule reaction of each group was evaluated statistically. RESULTS: Our histopathological examination revealed changes due to radiation in the control group. Many of these findings were found to be more subtle in group I and nearly absent in the group II. There was not any statistical difference between the thickness of the capsule reactions of the control group and group I, or group I and group II, but the capsular thickness of the control group was statistically higher than group II. CONCLUSION: It can be predicted that the use of HBOT following irradiation is an effective tool to reduce the capsule reaction of the implanted area and the tissue damage seen in radiodermatitis. PMID- 21301312 TI - A cadaver study of the vascular territories of dominant and nondominant internal mammary artery perforators. AB - The perfusion territory of the pedicled internal mammary artery perforator flap has been described, but the number of perforators to be included in the flap's pedicle is controversial. We studied the vascular territory of the dominant perforator and the contribution of additional nondominant perforators to it. Therefore, the dominant perforators in 9 fresh cadavers and the nondominant perforators in 4 of these, were injected with water-based ink. The dominant perforator vascularized a territory extending from the superior border of the clavicle to the xiphoid, and from midsternal to the anterior axial fold, with a mean craniocaudal length of 19.4 cm (range, 17.0-24.0) and a mean mediolateral width of 18.6 cm (range, 16.0-22.5). Additional injection of nondominant perforators did not lead to any substantial enlargement of this territory. One single dominant perforator vascularizes a large part of the hemithorax, allowing for various flap designs. Nondominant perforators do not have to be included in the vascular pedicle of the internal mammary artery perforator flap, which leads to less donor-site morbidity. PMID- 21301313 TI - Congenital entropion. AB - Entropion is a malposition of the eyelid causing an abnormal inversion of the eyelid margin. This results in symptomatic contact of the eyelashes with the surface of the globe, resulting in corneal irritation. Symptoms primarily arise from irritation of the ocular surface. Corneal abrasions and scarring can occur. Although common in many canine breeds, it is rare in the pediatric congenital form and rarely reported in the literature. Success in treatment depends on diagnosing the appropriate cause and selecting a surgical procedure that adequately addresses the underlying abnormality. The authors describe a pediatric patient with congenital entropion and review the nature of the problem and its treatment options. PMID- 21301314 TI - Prophylactic flap reconstruction of the knee prior to total knee arthroplasty in high-risk patients. AB - Insufficient soft-tissue coverage following total knee arthroplasty (TKA) may threaten prosthesis retention or compromise joint function. A retrospective review was conducted of all patients who underwent prophylactic flap reconstruction of the knee prior to TKA or salvage flap reconstruction over a 6 year period. Twenty-three patients underwent prophylactic flap reconstruction. Complications at the time of flap transfer were common (48%), however, all flaps survived. All 23 successfully completed subsequent TKA with no wound complications occurring at the time of TKA. Complications in the salvage group were also frequent (44%) and 3 required above knee amputation. Postoperative range of motion was significantly better in the prophylactic group, as well as when cutaneous flaps were chosen. Prophylactic flap reconstruction of the knee prior to TKA in high-risk patients is an excellent option in this small subset of patients, many of whom would not be offered TKA without addressing the compromised soft-tissue envelope first. PMID- 21301315 TI - Comparisons of the postoperative rectus abdominis muscle thickness and the biomechanical properties of donor sites among different subtypes of muscle sparing transverse rectus abdominis myocutaneous flaps (MS0, MS1, MS2, MS3): a rat model. AB - BACKGROUND: The primary presumed advantages of the deep inferior epigastric perforator flap over the other muscle-sparing (MS) transverse rectus abdominis myocutaneous flaps are the improved functional rectus abdominis muscle outcomes and decreased abdominal contour morbidities. The purpose of this study was to verify this viewpoint objectively and quantitatively using an animal model. METHODS: Six rats were used in the pilot study and 40 rats were equally divided into a control group and 4 experimental groups (MS0, MS1, MS2, and MS3) according to the amount of rectus abdominis muscles harvested. At 3 and 6 weeks, 4 rats in each group were killed, then, the percentage of residual rectus abdominis muscle thickness compared with the control side and the ultimate load at failure of the abdominal wall were recorded and compared. RESULTS: All of the flaps survived completely without complications. Regarding the percentage of residual rectus abdominis muscle thickness compared with the control side, the results suggested MS3 > MS2 ~ MS1 > MS0; concerning the ultimate load at failure of the abdominal wall, the results showed MS3 ~ MS2 > MS1 > MS0. (~: P > 0.05; >: P < 0.05). CONCLUSIONS: According to the findings of this study, we advocate the use of the deep inferior epigastric perforator flap when possible, and the MS2-transverse rectus abdominis myocutaneous flap can serve as a backup when the perforator anatomy does not meet the flap safety criteria for preservation of rectus abdominis muscle function. PMID- 21301316 TI - Autologous breast augmentation with the deepithelialized fasciocutaneous infragluteal free flap: a 10-year experience. AB - INTRODUCTION: Breast augmentation with silicone implants is frequently performed, a daily procedure in plastic surgery. Nevertheless, there are well-known risks of capsular formation and contraction leading to pain, displacement, and rupture after breast augmentation. Thus, the frequency of augmentation with autologous tissue is increasing. Most frequently used are the transverse rectus abdominis muscle flap, the deep inferior epigastric artery perforator flap, and the gracilis free flap, but in some cases, these flaps are not the first choice. Therefore, we present our experience with the free fasciocutaneous infragluteal (FCI) flap. METHODS: The FCI flap is based on a constant end artery of the inferior gluteal artery and has frequently been used for various indications at our department for many years. Since 1998, 17 patients suffering from breast hypoplasia, congenital breast asymmetry, or consecutive capsular fibrosis were treated with 25 FCI flaps. RESULTS: In this series, no complete or partial flap loss was clinically detected. The only complaint was a discomfort at the donor site in the early postoperative period. As revealed by a final questionnaire, all patients were satisfied with the result. CONCLUSION: Our results suggest that the FCI flap should be considered as a worthy alternative for autologous breast augmentation, especially in thin patients suffering from breast hypoplasia, congenital asymmetry, or consecutive capsular formations. PMID- 21301317 TI - Radiosensitizing agents for the management of rectal cancer. PMID- 21301318 TI - Chemotherapy-induced cardiotoxicity: role of the tissue Doppler in the early diagnosis of left ventricular dysfunction. AB - Cardiotoxicity is a common complication of chemotherapy. The aim of this study was to assess the cardiotoxicity of anticancer drugs using tissue Doppler imaging. A prospective study was carried out using patients with early breast cancer (72 women, median age: 57 +/- 12 year) and other inclusion and exclusion criteria. Inclusion criteria were treatment with epirubicin, trastuzumab, fluorouracil, cyclophosphamide, taxotere, and taxolo; left ventricular ejection fraction (LVEF) of more than 50%; and absence of important pathologies. Exclusion criteria were presence of known heart disease, earlier exposure to mediastinal irradiation, and earlier chemotherapy. On the basis of treatment, patients were divided into five groups: A=fluorouracil-epirubicin-cyclophosphamide (FEC), B = FEC + trastuzumab, C = trastuzumab, D = FEC + taxotere, and E = FEC + taxol + trastuzumab. Cardiological evaluation including electrocardiogram and echocardiogram was carried out at baseline, 3 months, and 6 months after the start of chemotherapy in all patients. The Doppler patterns were integrated with other echo parameters (tissue Doppler). Significant changes (P < 0.05) in the echo parameters of the tissue Doppler were observed in treated patients during follow-up but not in LVEF. In conclusion, the tissue Doppler is more sensitive than standard Doppler in the study of diastolic function and LVEF in the study of systolic function. The tissue Doppler should integrate conventional echocardiography in the study of left ventricular function in patients treated with anticancer drugs. It is very important to reduce the risk of cardiovascular complications, especially heart failure, in breast cancer survivors. PMID- 21301319 TI - Temsirolimus in advanced leiomyosarcomas: patterns of response and correlation with the activation of the mammalian target of rapamycin pathway. AB - Preclinical data have indicated that alteration of PTEN and activation of the mammalian target of rapamycin (mTOR) pathway play a crucial role in the oncogenesis of leiomyosarcoma. The objective of this exploratory study was to assess the clinical role of mTOR inhibition in patients with advanced leiomyosarcoma refractory to standard chemotherapy. Patients with advanced leiomyosarcoma were treated with temsirolimus and consented to retrospective collection of data from their medical records and analysis of archival tumor specimens. Tumor response was determined according to the response evaluation criteria in solid tumor (RECIST) and Choi criteria. Tumors were assessed for immunohistochemical evidence of PTEN loss of expression and mTOR activation. Six patients participated in the study. According to the RECIST, three patients had stable disease and three patients had progressive disease. The three patients with RECIST stable disease had partial response according to the Choi criteria. Partial response according to the Choi criteria was associated with clinical improvement and biological signs of temsirolimus antitumor activity. The immunohistochemical status of PTEN and phosphorylated S6 ribosomal protein was not predictive of the outcome. This exploratory study indicates antitumor activity of temsirolimus in leiomyosarcoma, possibly through a mechanism involving aberration of the PTEN gene. Further investigations of the phosphoinositide 3-kinases/PTEN/Akt/mTOR pathway are needed to explore the role of mTOR inhibitors, either alone or in combination, in patients with advanced sarcoma. PMID- 21301320 TI - Evolution of 5-fluorouracil-based chemoradiation in the management of rectal cancer. AB - 5-Fluorouracil (5-FU) is the most widely used agent for the management of colorectal cancer. Capecitabine is metabolized by three enzymatic actions, the last of which is mediated by thymidine phosphorylase, to produce 5-FU. Given the oral bioavailability of capecitabine as well as in-vitro and in-vivo findings showing higher expression of thymidine phosphorylase in tumor cells and xenografts compared with normal tissue, capecitabine is an evolving candidate in the management of colorectal cancer with antimetabolite-based therapy. An ideal radiosensitizing agent must balance oncological outcomes with adverse effects and feasibility of administration. This discussion addresses the evolving role of 5 FU in the management of rectal cancer in the neoadjuvant setting in combination with ionizing radiation. PMID- 21301321 TI - The influence of cyclooxygenase-1 expression on the efficacy of cyclooxygenase-2 inhibition in head and neck squamous cell carcinoma cell lines. AB - We have previously observed that cyclooxygenase-2 (COX-2) inhibition blocked the production of vascular endothelial growth factor (VEGF) in some head and neck squamous cell carcinoma (HNSCC) cells. However, as some HNSCC cells showed little response to COX-2 inhibition, although they highly expressed COX-2 and prostaglandin E2, we set out to elucidate what made this difference between them and focused on the possibility of the differential expression of COX-1. In western blotting, we found that COX-1 was expressed in SNU-1041 and SNU-1066, but not in SNU-1076 and PCI-50. Only in those cell lines without expression of COX-1 was VEGF production blocked meaningfully by small interfering RNA of COX-2. However, by cotreating with small interfering RNAs of COX-2 and COX-1, VEGF synthesis and prostaglandin E2 were inhibited in SNU-1041 and SNU-1066, similarly in SNU-1076 and PCI-50 with high expression of only COX-2. We also found that there was no difference in the pattern of prostaglandin synthesis between COX-2 and COX-1 through enzyme-linked immunosorbent assay for various prostaglandins. Our study suggests that, as COX-1 and COX-2 express and affect VEGF synthesis in HNSCC cells, we should check COX-1 expression in investigations on cancer treatment by inhibiting COX-2-induced prostaglandins. PMID- 21301323 TI - Evaluation of the anxiolytic-like effects of clomipramine in two rat strains with different anxiety vulnerability (Wistar and Wistar-Kyoto rats): participation of 5-HT1A receptors. AB - The main aim of this study was to evaluate the anxiolytic-like effects of the serotonergic antidepressant, clomipramine (0.6-5.0 mg/kg), and the 5-HT1A agonist, (+/-)8-hydroxy-2-(di-n)-propil-aminotetraline hydrobromide (8-OH-DPAT; 0.01-0.5 mg/kg), in two strains of rat with different anxiety vulnerability: Wistar-Kyoto (WKY; with trait anxiety) and Wistar rats (control strain). The anxiety model used was the burying behavior test; decreases in burying, grooming of the snout, and freezing were interpreted as a reduction of anxiety-like levels. A second objective was to explore the participation of 5-HT1A receptors in the effects of clomipramine and 8-OH-DPAT. Behavior in the burying behavior test was strain dependent. In addition to the burying behavior, WKY rats showed high levels of freezing and grooming of the snout. Clomipramine and 8-OH-DPAT decreased the burying behavior in both strains of rats through a direct interaction with the 5-HT1A receptor. 8-OH-DPAT decreased freezing behavior in both strains through a mechanism that was not related to 5-HT1A receptors. Finally, clomipramine was able to block freezing and grooming behaviors only in WKY rats. In conclusion, strains with different anxiety vulnerability express different behavioral responses toward the same aversive stimulus, and the anxiolytic-like effects of clomipramine and 8-OH-DPAT are both behavior and strain dependent. PMID- 21301322 TI - Effects of 5-HT6 antagonists, Ro-4368554 and SB-258585, in tests used for the detection of cognitive enhancement and antipsychotic-like activity. AB - 5-Hydroxytryptamine 6 (5-HT6) receptors are involved in learning and memory processes and are discussed as promising targets for the treatment of cognitive impairment in central nervous system disorders. A number of 5-HT6 antagonists are currently in the clinical development for schizophrenia and Alzheimer's disease (AD). There is some discrepancy regarding cognitive efficacy in subjects, and only limited data are available on the role of the 5-HT6 receptor in animal models of psychosis. The aim of this study was to investigate the efficacy of the selective 5-HT6 antagonists, Ro-4368554 (1-10 mg/kg, intraperitoneally) and SB 258585 (3-30 mg/kg, intraperitoneally), in animal models for schizophrenia and AD. Both compounds showed cognition-enhancing effects in object recognition, whereas only SB-258585 was able to prevent the scopolamine-induced deficit in the Morris water-maze test. Neither Ro-4368554 nor SB-258585 prevented scopolamine induced impairment in contextual fear conditioning. Similarly, both compounds were ineffective on MK-801-induced deficits in contextual fear conditioning and spatial working memory. Ro-4368554, but not SB-258585 reversed the apomorphine induced deficit in prepulse inhibition. Amphetamine-induced hyperlocomotion was not affected by either compound. Taken together, the overall efficacy of Ro 4368554 and SB-258585 in animal models for AD and schizophrenia is rather limited. These data show moderate efficacy in some models for AD but do not support the therapeutic potential of 5-HT6 antagonists for schizophrenia. PMID- 21301324 TI - Modest abuse-related subjective effects of zolpidem in drug-naive volunteers. AB - Recent case reports suggest that the short-acting benzodiazepine-like hypnotic, zolpidem, may have abuse potential among individuals who have no personal history of abusing drugs or alcohol, particularly at doses higher than those recommended for treating insomnia. This study recruited drug-naive volunteers to assess the subjective effects of multiple doses of zolpidem (0, 5, 10, or 20 mg) administered in a within-subject double-blind design. Participants (n=11) answered computerized questionnaires (Addiction Research Center Inventory, visual analog scales, and a hypothetical Drug versus Money Choice) to address the hypothesis that a supratherapeutic dose (20 mg) would increase ratings of abuse related subjective effects, while lower therapeutic doses (5 and 10 mg) would not. Although participants rated some effects as negative at 10 and 20 mg, the highest dose engendered predominantly positive abuse-like effects such as 'High', 'Like', and 'Good Effects'. However, no dose of zolpidem was chosen over money ($0.35-$10) when participants made hypothetical choices between them. Results suggest that although individuals without a drug abuse history are not inclined to choose zolpidem when presented with an alternative reinforcer such as money, it may possess moderate abuse potential that limits its clinical utility. PMID- 21301325 TI - D-amphetamine, nicotine, and haloperidol produce similar disruptions in spatial and nonspatial temporal discrimination procedures. AB - Two different and generally noncomplimentary disruptions of timing by pharmacological agents have been found. One is a lateral shift of the psychophysical curve for time, indicating a subjective shortening or lengthening of time, whereas the other is a flattening of the curve and decrease in temporal accuracy. This study assessed the role of a methodological variation in producing this discrepancy. The procedure used required pigeons to classify stimulus duration intervals as short or long, using response alternatives that were defined either by the location of response keys (spatial), or by their color (nonspatial). D-amphetamine was used to replicate earlier findings, whereas nicotine and haloperidol extended the research to different drug classes. Dose dependent decreases in the accuracy of classifying temporal intervals and a flattening of the psychophysical curve were found across drug classes for both spatial and nonspatial procedural variations. Procedural variations, under these conditions, could not explain the discrepancy. However, the results from this study added to the mounting body of literature showing decrements in temporal accuracy and a flattening of the psychophysical curve because of a number of diverse pharmacological and nonpharmacological disruptors. PMID- 21301326 TI - MK-7128, a novel CB1 receptor inverse agonist, improves scopolamine-induced learning and memory deficits in mice. AB - Cannabinoid receptors (CBRs) play an important role in a variety of physiological functions and have been considered drug targets for obesity and psychiatric disorders. In particular, the CB1R is highly expressed in brain regions crucial to learning and memory processes, and several lines of evidence indicate that pharmacological blockade of this receptor could have therapeutic applications in the treatment of cognitive disorders. In this study, we investigated whether MK 7128 (0.1, 0.3, and 1 mg/kg, orally), a novel and selective CB1R inverse agonist, could improve learning and memory deficits induced by scopolamine (1 mg/kg, subcutaneously) in mice. The investigators also assessed CB1R occupancy in the brain to ensure target engagement of MK-7128, and showed that MK-7128 significantly improved both Y-maze spontaneous alternation and object habituation performance in scopolamine-treated mice and inhibits the binding of radioiodinated AM251 in murine cortex and hippocampus. These data indicate that MK-7128 improves cognitive performance in a model of cholinergic hypofunction and suggest that efficacy is achieved at relatively low levels of CB1R occupancy in the brain. Our results extend earlier findings suggesting a role of CB1Rs in the modulation of memory processes and a potential therapeutic application for CB1R inverse agonists in cognitive disorders. PMID- 21301327 TI - Intravenous immunoglobulins are a therapeutic option in the treatment of multiple sclerosis relapse. AB - OBJECTIVE: The objective of the study is to evaluate the efficacy and tolerability of intravenous immunoglobulin (IVIG) monotherapy in the treatment of multiple sclerosis (MS) relapse. BACKGROUND: High-dose intravenous methylprednisolone (IVMP) and plasmapheresis have been shown to shorten the recovery period of an MS relapse. Options for those who have contraindications for or are unresponsive to these treatments are very limited. Intravenous immunoglobulin has been used experimentally in these situations, even though there are no previous studies on its efficacy as monotherapy in MS relapse. SUBJECTS AND METHODS: Twelve consecutive MS patients with acute MS relapse were treated with IVIG 0.4 g/kg per day for 5 days, and the next 5 patients received IVMP 1000 mg/d for 3 days. Volumetric brain magnetic resonance imaging (MRI) and clinical evaluation using expanded disability status scale (EDSS) were performed at baseline and at 3 weeks after treatment. EDSS score after 1 year of the treatment was collected from the patient records. MRI evaluation was performed blindly but not the clinical examination and EDSS scoring. RESULTS: A significant reduction in the volumes of T2-, fluid-attenuated inversion recovery-, and gadolinium-enhanced lesions was detected in the IVIG-treated group, but not in the IVMP-treated patients. The difference between the groups did not reach statistical significance. The EDSS score improved equally in both groups. CONCLUSIONS: Intravenous immunoglobulin did not show inferiority compared with IVMP in the treatment of an acute MS relapse evaluated clinically and radiologically. Therefore, we suggest that IVIG may be tried as a therapy in acute MS relapse, especially in case of contraindications to IVMP and plasmapheresis. PMID- 21301328 TI - Innate Th2-type immune responses and the natural helper cell, a newly identified lymphocyte population. AB - PURPOSE OF REVIEW: We discuss recent progress in the understanding of Th2 cytokines derived from innate cells involved in the pathophysiology of various allergic diseases. RECENT FINDINGS: Recent studies have identified a previously unrecognized lymphocyte population capable of producing Th2 cytokines in response to IL-25 and/or IL-33 independently of T or B cells. SUMMARY: Newly identified cells responsive to IL-25 and/or IL-33 include natural helper cells, MPP, nuocytes and innate helper type 2 cells. These cells produce large amounts of Th2 cytokines, most notably IL-5 and IL-13, leading to eosinophilia and goblet cell hyperplasia and are critical for antihelminth reactions. IL-5 and IL-13 also play a role in pathophysiology of allergic diseases such as asthma and allergic diarrhea. There are similarities and differences between these newly identified cell populations. MPP cells can potentially differentiate to other myeloid cells, making this cell type distinct from the others. Natural helper cells constitutively produce Th2 cytokines, support the self-renewal of B1 cells and enhance IgA production. Unlike other innate Th2 producers, natural helper cells are present in fat-associated lymphoid clusters and likely play additional roles in the regulation of homeostasis in adipose tissues. PMID- 21301329 TI - WHO universal definition of severe asthma. AB - PURPOSE OF REVIEW: In 2009, an expert panel met to propose a WHO definition of asthma severity and control, and criteria for describing exacerbations and their severity, which would be globally applicable. This review addresses their findings in the context of recent literature, and assesses the usefulness of these definitions in children in particular. RECENT FINDINGS: Severe asthma was defined by the level of current clinical control and risks as: 'Uncontrolled asthma which can result in risk of frequent severe exacerbations (or death) and/or adverse reactions to medications and/or chronic morbidity (including impaired lung function or reduced lung growth in children)'. Severe asthma includes three groups, with different public health messages and challenges: untreated severe asthma, due to undiagnosed asthma or unavailability of therapy, difficult-to-treat severe asthma (due to adherence issues, inappropriate or incorrect use of medicines, environmental triggers or co-morbidity), and treatment-resistant severe asthma, including asthma for which control is not achieved despite the highest level of recommended treatment or asthma which is controlled only with the highest level of recommended treatment. SUMMARY: These definitions will enable more precise measurement of the burden of severe childhood asthma globally. International collaborations in epidemiological and mechanistic studies, and randomized controlled trials of treatment, will be facilitated. However, both pathophysiology and severity are influenced by a number of factors with wide global variation; international comparisons should be interpreted with caution. PMID- 21301330 TI - The indoor environment and its effects on childhood asthma. AB - PURPOSE OF REVIEW: Indoor pollutants and allergens cause asthma symptoms and exacerbations and influence the risk of developing asthma. We review recent studies regarding the effects of the indoor environment on childhood asthma. RECENT FINDINGS: Exposure to some indoor allergens and second hand smoke are causally related to the development of asthma in children. Many recent studies have demonstrated an association between exposure to indoor pollutants and allergens and airways inflammation, asthma symptoms, and increased healthcare utilization among individuals with established asthma. Genetic polymorphisms conferring susceptibility to some indoor exposures have also been identified, and recent findings support the notion that environmental exposures may influence gene expression through epigenetic modification. Recent studies also support the efficacy of multifaceted environmental interventions in childhood asthma. SUMMARY: Studies have provided significant evidence of the association between many indoor pollutants and allergens and asthma morbidity, and have also demonstrated the efficacy of multifaceted indoor environmental interventions in childhood asthma. There is also a growing body of evidence suggesting that some indoor pollutants and allergens may increase the risk of developing asthma. Future studies should examine mechanisms whereby environmental exposures may influence asthma pathogenesis and expand the current knowledge of susceptibility factors for indoor exposures. PMID- 21301331 TI - Recent developments in asthma education. AB - PURPOSE OF REVIEW: Asthma education is a key component of the National Heart, Lung, and Blood Institute (NHLBI) asthma guidelines. Although the benefits and importance of asthma patient education are well documented, there are still many open questions regarding how to best provide asthma education. The following review highlights recent developments in this topic. RECENT FINDINGS: Recent innovations have applied asthma education in a variety of settings. Ensuring that health professionals within a community provide consistent educational messages about asthma can create synergy and leverage limited healthcare resources to improve outcomes. In addition, children seem to have greater responsibility for self-management of asthma at younger ages. SUMMARY: Further work is needed to understand how clinicians can best educate and give parents anticipatory guidance about how to best teach and transfer asthma self-management skills to young children. By developing teaching and mastering self-management skills at an early age, children may be able to carry such skills into adulthood. Finally, given the prevalence of healthcare disparities, there is a continued need for rigorously evaluated programs that are culturally appropriate and effective. PMID- 21301332 TI - Traumatic brain injury in modern war. AB - PURPOSE OF REVIEW: To review the emerging literature on traumatic brain injury (TBI) caused by explosive blast. RECENT FINDINGS: Efforts are underway to understand how explosive blast injures brain, what is the clinical presentation and how best to manage it. A major way blast injures brain is from detonation pressure waves coupling to a victim's head leading to brain deformation. The effect of other explosion-related elements is unknown. Because scientific insights take time to develop but injuries are occurring now, the military adopts existing civilian standard of care practices developed for similar diseases, such as the Guidelines for the Management of Severe Traumatic Brain Injury developed mainly for closed head TBI. When these do not exist, the military creates them, such as the Veterans Administration and Department of Defense Clinical Practice Guidelines for Concussion/Mild TBI. Another treatment advance is the creation of the first large system-wide approach to diagnosis and clinical management of TBI, which begins at the site of injury and extends through both the military and the Veterans' Administration medical care systems. SUMMARY: Explosive blast TBI is being addressed at all levels - basic research through clinical care. New clinical practice guidelines are being used in a standardized system-wide approach. PMID- 21301333 TI - Managing ICU delirium. AB - PURPOSE OF REVIEW: ICU delirium is a common and serious acute brain dysfunction with adverse outcome and high risk of mortality. The awareness of ICU delirium as a problem, which immediately requires therapeutic intervention, has been increased in the past years. This article aims to provide information in order to increasingly modify the management of this severe problem, that is, its detection, prevention, and treatment toward algorithm-based and protocol-driven procedures. RECENT FINDINGS: The bundle of target-controlled and protocol-driven management of sedation, analgesia, and delirium and its monitoring included in this work offer the opportunity to improve the outcome of ICU patients based on the best evidence available to date. Moreover, the knowledge about precipitating and predisposing factors to prevent ICU delirium is essential and is represented in this review. Unresolved seems the pharmacological therapy of delirium because of the contradictory results of research published so far, especially regarding neuroleptics and cholinesterase inhibitors. SUMMARY: The management of ICU delirium must be a key aspect to improve the outcome of critically ill patients. The development of pharmacological treatment strategies and deeper understanding of the underlying pathophysiology will require further research. PMID- 21301334 TI - Why should we measure bacterial load when treating community-acquired pneumonia? AB - PURPOSE OF REVIEW: We focus on a number of studies in the past 2 years that herald a dramatic shift in how we treat patients with not just community-acquired pneumonia (CAP), but potentially all sepsis. RECENT FINDINGS: Recent studies report that high bacterial load, and specifically pneumococcal load in CAP, appears to be significantly associated with worse outcomes. These findings change the sepsis paradigm. Bacterial load may identify potential candidates for adjunctive therapy, ICU admission and more aggressive management. SUMMARY: Whereas we all acknowledge the importance of the virulence of the pathogen in the outcome of CAP, microbiological tests currently play little role in management of patients. Whereas molecular tests such as polymerase chain reaction have promised to deliver accurate results in a clinically useful period of time, apart from a few niche situations they have yet to enter routine practice. In particular the ability to calculate the bacterial load in blood, and specifically pneumococcal load in CAP, appears to have significant clinical utility. Not only does bacterial load predict clinical outcome, the data so far available challenge some of our fundamental assumptions about optimal antibiotic therapy and the pathogenesis of severe sepsis. PMID- 21301335 TI - Amphotericin B in neonates: deoxycholate or lipid formulation as first-line therapy - is there a 'right' choice? AB - PURPOSE OF REVIEW: The aim is to compare the available evidence on the efficacy and safety of deoxycholate and lipid amphotericin B formulations (AMBF) in the treatment of invasive fungal disease (IFD) in neonates. The review also aims to summarize current practices and recommendations. RECENT FINDINGS: To date most AMBF studies on neonates consist of retrospective reports and case series. The reviewed reports show that both amphotericin B deoxycholate (DAMB) and lipid formulations appear to have equal efficacy in treating IFD in neonates. The adverse effects of DAMB in neonates are considerably less than those in older children and adults. There is a trend of more nephrotoxicity reported with DAMB than with lipid formulations; however, the range reported is very wide (0-70%). Neonates with normal baseline renal function appeared to tolerate DAMB relatively well. A sodium intake of 4 mEq/kg/day may significantly reduce DAMB nephrotoxicity. SUMMARY: Deoxycholate amphotericin B is inexpensive and effective in treating neonatal IFD. It appears to be safe for use as first-line therapy if the underlying risk for nephrotoxicity is low and renal function and potassium are monitored closely. PMID- 21301336 TI - The pathogenesis of IgA nephropathy. AB - PURPOSE OF REVIEW: This review will analyze contemporary information concerning the possible pathogenetic mechanisms involved in IgA nephropathy, emphasizing studies in humans rather than experimental animals. RECENT FINDINGS: Deposition of IgA in the glomeruli, the hallmark of IgA nephropathy, may be a quite common phenomenon. Aberrant O-linked galactosylation of IgA subclass (IgA1) appears to play a central role and 'auto-immunity' to a conformational epitope related to glycans at the hinge region of IgA1 is apparently required. Both a circulating immune complex and an in-situ immune complex mechanism have been advanced. Mediator systems, such as complement activation and engagement of innate immune system, also play prominent roles in determining the clinical onset and severity of disease. Genetic influences are evident but the fine details of genetic predisposition and its impact on outcomes still need to be further elucidated. SUMMARY: Progress in understanding the details of the pathogenesis of IgA nephropathy will lead to a better means of diagnosis (including noninvasive tests for diagnosis), more accurate individualized prognosis and personalized treatment regimens for this globally distributed and very common primary glomerular disease. PMID- 21301337 TI - Signaling pathways for the vascular effects of hydrogen sulfide. AB - PURPOSE OF REVIEW: The physiological and pathophysiological importance of endogenous hydrogen sulfide to cardiovascular health has been recognized in recent years. The signaling mechanisms underlying the multifaceted vascular effects of H2S, on the contrary, have been unclear. This article reviews recent literature on cellular and molecular events triggered or modulated by H2S in the vascular system over the period of 2009-2010. RECENT FINDINGS: H2S causes protein S-sulfhydration. The activation of ATP-sensitive K channels (KATP channels) by H2S likely occurs as the result of specific cysteine residues of KATP channel proteins being S-sulfhydrated. Produced in endothelial cells and inducing smooth muscle hyperpolarization, H2S appears to functioning as an endothelium-derived hyperpolarizing factor. The inhibition of phosphodiesterases by endogenous H2S is an additional exciting discovery, which offers answers for the differential vascular effects of this gasotransmitter due to the tissue-specific distribution of different isozymes of phosphodiesterases. Furthermore, endothelial cells and smooth muscle cells have opposite growth responses to H2S stimulation, involving the same sets of signaling molecules. SUMMARY: An array of signaling pathways in vascular tissues is enlisted by endogenous H2S. An insightful understanding of these signaling mechanisms would help elucidate the pathogenesis of selective cardiovascular diseases and develop related therapeutic interventions by targeting H2S metabolism. PMID- 21301338 TI - New and forthcoming anti-epileptic drugs. AB - PURPOSE OF REVIEW: There is a need for newer anti-epileptic drugs (AEDs) with improved efficacy and tolerability. This article reviews AEDs introduced since 2007 and investigational compounds in clinical development. RECENT FINDINGS: Two recently introduced AEDs, stiripentol and rufinamide, have been licensed exclusively for orphan indications, that is severe myoclonic epilepsy of infancy (stiripentol, Europe) and Lennox-Gastaut syndrome (rufinamide, Europe and the USA). This signals a welcome new trend to explore novel treatments in specific pediatric syndromes for which there are high therapeutic needs. Two additional AEDs, lacosamide and eslicarbazepine acetate, have been licensed recently for a more traditional indication, refractory partial-onset seizures. Although newly introduced agents given as adjunctive therapy have been found to be superior to placebo in reducing seizure frequency, the ultimate goal of sustained seizure freedom is rarely achieved. Therefore, the search for better agents should continue. Several investigational compounds are currently in various stages of clinical development. SUMMARY: The recent introduction of newer AEDs has enlarged the armamentarium against epilepsy. However, newer agents had only a modest impact on the probability of achieving long-term remission. Novel strategies for the discovery and development of truly innovative AEDs are sorely needed. PMID- 21301340 TI - Racial/ethnic disparities in preterm birth: clues from environmental exposures. AB - PURPOSE OF REVIEW: Despite advances in medical care, preterm birth and its associated racial/ethnic disparities remain major public health issues. Environmental exposures may contribute to racial disparities in preterm birth. RECENT FINDINGS: Recent work in Iran demonstrated lead levels less than 10 MUg/dl to be associated with preterm birth and premature rupture of membranes. Data on air pollution are mixed. A study in California found exposure to nitric oxide species to be associated with preterm birth. However, results from large birth cohorts in the Netherlands found no association. Interestingly, a study in South Korea recently demonstrated that socioeconomic status modifies the association between air pollution and preterm birth. A recent promising study randomized minority pregnant women in Washington, District of Columbia, to cognitive behavioral therapy vs. usual care to decrease exposure to environmental tobacco smoke (ETS). The investigators reported reductions in ETS exposure and the risk of very preterm birth. SUMMARY: Clues about potential mechanisms underlying disparities in preterm birth can be gained from exploring differences in environmental exposures. Investigators should include environmental variables when studying birth outcomes. Such efforts should result in targeted interventions to decrease the incidence of preterm birth and its disparities. PMID- 21301339 TI - Mechanisms of neurocognitive dysfunction and therapeutic considerations in tuberous sclerosis complex. AB - PURPOSE OF REVIEW: Mendelian disorders that affect cognition provide a unique opportunity to study the mechanisms of neurodevelopmental disorders through the examination of genetic defects in animals and development of hypotheses that can be tested in human beings. Tuberous sclerosis complex (TSC) is a genetic disease that presents with epilepsy, autism, and intellectual disability. Here we review recent advances in our understanding of TSC pathogenesis and signaling pathways that may be modulated to treat the neurological symptoms. RECENT FINDINGS: Accumulating evidence suggests that TSC patients have nontuber abnormalities that contribute to the development of the neurological phenotype- in particular, disorganization of axon tracts and deficient myelination. TSC mouse models have failed to replicate the human neuropathology entirely, but have shed light on the cellular abnormalities and the neurobehavioral phenotypes. Most importantly, cell culture and animal models have identified the mTORC1 pathway as a therapeutic target in this disease. SUMMARY: Preclinical data strongly suggest that TSC is a disease of abnormal neuronal connectivity. The high incidence of neurodevelopmental deficits, early detection of the disease in very young ages, and availability of mTORC1 inhibitors make TSC a model for other Mendelian disorders of neurocognition and an avenue for the mechanism-based treatment trials of neurodevelopmental disorders. PMID- 21301341 TI - Contemporary role of prostate cancer gene 3 in the management of prostate cancer. AB - PURPOSE OF REVIEW: With increasing evidence that prostate-specific antigen (PSA) based screening can reduce disease-specific mortality but coincides with unacceptable levels of unnecessary testing and the diagnosis of potentially nonlife-threatening disease, the need for new, more specific biomarkers is urgent. Within this context the role of the prostate cancer gene 3 (PCA3) test is evaluated. RECENT FINDINGS: Studies investigating the value of PCA3 as a diagnostic test virtually all show a beneficial effect as compared to PSA with respect to specificity. Beside the fact that most of these studies are subject to potential bias, the observed increased specificity was accompanied by relatively low sensitivities. Two studies, attempting to avoid selection bias as much as possible, show a marginal beneficial effect of the PCA3 test. Data on PCA3 as a staging tool for prostate cancer remain inconclusive. SUMMARY: The PCA3 test is not capable of replacing the PSA test in clinical practice and an appropriate cut off level with acceptable performance characteristics is hard to define. Its value as a first-line diagnostic test is limited. The addition of PCA3 to risk assessment tools leads to an increase in predictive capability. Data relating to the accuracy of PCA3 on prostate cancer staging are contradictory and PCA3 as prognostic test should be subject of future studies. PMID- 21301343 TI - Infertility, ovulation, induced ovulation, and female cancers. PMID- 21301344 TI - A case-control study on the rs3130932 single nucleotide polymorphism in the OCT4B translation initiation codon in association with cancer state. AB - A previously characterized single nucleotide polymorphism (rs3130932) in the translation initiation codon of the OCT4B isoform of the human OCT4 gene, ATG -> AGG, is expected to hamper its expression in individuals carrying the AGG genotype. A case-control association study was conducted to validate the AGG genotype as a risk factor for tumour development. Blood samples were collected from 221 female patients with breast cancer, 100 female patients with ovarian cancer, 109 male patients with lung cancer and 553 age-matched and sex-matched healthy individuals. DNA was tested by restriction fragment length polymorphism PCR for the presence of rs3130932. Statistical association studies were carried out to investigate any association between hOCT4 genotypes and the onset of cancer. Genotypic and allelic statistical analyses led to no significant case control differences at a P value of less than 0.05 in all different types of cancer, thus showing no significant correlation of the hOCT4 genotypes tested with breast, ovarian or lung cancer risk. The AGG genotype in rs3130932 is not associated with increased (or decreased) cancer risk in homozygous individuals. Research focusing on the elucidation of the biological roles of each OCT4 isoform is further warranted. PMID- 21301345 TI - Effectiveness of repeated screening using the fecal occult blood test and its impact on reducing false-negative cancer cases. AB - Screening using the fecal occult blood test (FOBT) has been shown to reduce mortality from colorectal cancer. However, the impact of repeated screening on the detection of colorectal cancer and on false-negative results is unclear. Thus, we conducted a case-control study. Male patients with colorectal cancer, adenoma with high-grade dysplasia (polyp cancer) or adenomatous polyps, detected through screening using the FOBT between January 1996 and December 2007, were identified and their screening history was obtained. Patients with interval cancer, diagnosed within 1 year of the most recent FOBT, were also included. We identified 27 patients with interval cancer, 156 with colorectal cancer, 266 with polyp cancer, and 3566 with adenomatous polyps. Three controls for each patient with colorectal or interval cancer were selected randomly from patients with adenomatous polyp and polyp cancer, matched by diagnosis year and birth year. Odds ratios (ORs) for the diagnosis of colorectal cancer or interval cancer were estimated based on the frequency of screening. There was no apparent difference in the frequency of screening between the patients with colorectal cancer and the controls (polyp cancer and patients with adenomatous polyp). The OR (95% confidence interval) for being diagnosed with interval cancer after three or more screenings compared with a single screening was 0.07 (0.02-0.32), and the OR was 0.18 (0.05-0.66) compared with two screenings. The results of this study showed that repeated screening reduces the risk of being diagnosed with interval cancer. PMID- 21301346 TI - Distribution of overnight corneal swelling across subjects with 4 different silicone hydrogel lenses. AB - PURPOSE: To determine distribution of central corneal swelling (CCS) across subjects after 8 hr of sleep in eyes wearing silicone hydrogel lenses with various oxygen transmissibility (Dk/t) values and in eyes without lenses. METHODS: Twenty-nine neophytes wore lotrafilcon A (Dk, 140), balafilcon A (Dk, 91), galyfilcon A (Dk, 60), and senofilcon A (Dk, 103) lenses in powers -3.00, 10.00, and +6.00 diopters on separate nights, in random order, and on 1 eye only. The contralateral eye (no lens) served as the control. Central corneal thickness was measured using a digital optical pachometer before lens insertion and immediately after lens removal on waking. RESULTS: The average difference between the mean (7%) and the median (6.8%) CCS of all lenses was only 0.2%, suggesting a normal distribution. There was no correlation between the mean and the range of the CCS (r=0.058, P=0.766). Normal CCS distributions were also found with each lens-wearing eye and the control eye (P>0.20 for all). There was a significant correlation between lens-wearing eye and control eye (r=0.895, P<0.001) and between lotrafilcon A and each of the other 3 lenses for mean CCS across the study participants (P<0.001 for all). CONCLUSIONS: Distribution of corneal swelling in both lens-wearing eye and control eye followed a normal curve. An individual's corneal swelling response seems to be independent of lens type. PMID- 21301347 TI - On the use of NIH image J for objective assessment of conjunctival cell and nucleus dimensions of impression cytology samples. AB - BACKGROUND: To assess the use of a public domain software Image J (NIH Image, Bethesda, MD) to make dimensional measures of human bulbar conjunctival cells. METHODS: Impression cytology samples were obtained from the nasal bulbar conjunctiva, and color images were taken at 200* magnification and projected and an overlay prepared or the image uploaded into Image J. The final image magnification for the overlays was approximately 2* that on the computer screen. For either overlays or screen images, linear measures were made from 30 or 25 cells of the cell longest dimension (LONG) and of the longest dimension of the nucleus (NUCLONG). The predicted variability in measures, from the calculated average values for any particular image, was systematically assessed, and the overall average results were compared. RESULTS: Image J measures were within +/ 2% agreement with overlays, with LONG and NUCLONG measures increasing with the grade of squamous metaplasia. The net difference in LONG measures was within 2.65 to + 2.93 MUm, and NUCLONG measures were within -0.87 and +1.39 MUm. There was a slight tendency for NUCLONG measures to be systematically overestimated on smaller nuclei when using Image J on the color images. CONCLUSIONS: The manual use of Image J on on-screen images can provide reasonably accurate objective measures of bulbar conjunctival cells, as compared with a higher magnification manual overlay technique. This should be suitable for comparisons between samples and to assess the effects of any disease-related changes or any interventions. PMID- 21301348 TI - External ocular surface and lens microbiota in contact lens wearers with corneal infiltrates during extended wear of hydrogel lenses. AB - OBJECTIVES: To determine whether carriage of microbes on the contact lens or ocular surfaces during extended wear (EW) with soft hydroxyethyl methacrylate (HEMA)-based contact lenses predisposes the wearer to adverse events. METHODS: Participants (non-contact lens wearers) were enrolled in a clinical study involving wear of HEMA-based hydrogel lenses on a six night EW basis with weekly replacement. Type and number of bacteria colonizing the lower lid margins, upper bulbar conjunctiva, and contact lenses during EW after one night, 1 week, 1 month, and thereafter every 3 months for 3.5 years were determined. The association of bacteria with adverse responses was compared between carriers (defined as having significant microbes cultured from two or more samples with 1 year) and noncarriers, and the strength of the association was estimated using multivariate logistic regression. RESULTS: Carriers of gram-positive bacteria on lenses (particularly coagulase negative staphylococci or Corynebacterium spp.) were approximately three and eight times more likely to develop contact lens induced peripheral ulcers (CLPUs) and asymptomatic infiltrates (AIs), respectively. Staphylococcus aureus was most frequently isolated from lenses during CLPU. Carriers of gram-negative bacteria on lenses were five times more likely to develop contact lens-induced acute red eye (CLARE). Haemophilus influenzae was isolated most frequently from lenses during CLARE and AI events. CONCLUSIONS: Bacterial carriage on contact lenses during EW predisposes the wearer to the development of corneal inflammatory events including CLARE, CLPU, and AI. PMID- 21301349 TI - Relationship between conjunctivochalasis and refractive error. AB - OBJECTIVES: To assess the relation between the prevalence and grade of conjunctivochalasis and refractive error and to compare the grade of conjunctivochalasis between myopic and hyperopic patients. METHODS: Consecutive patients aged from 3 to 94 years were chosen for this study. Exclusion criteria included a history of using contact lenses, ocular surgeries, infectious conjunctivitis, or corneal diseases. The age, gender, medical history, ocular history, the grade and other parameters of inferior conjunctivochalasis classified into three locations (nasal, middle, and temporal), and refractive error were determined in all subjects. Patients were divided into three groups as follows: a hyperopic group (>=0.0 D), an emmetropic group (<0.0 and >=-2.0 D), and a myopic group (<-2.0 D). They were also divided into 10 groups according to age. One-way analysis of variance and the Scheffe multiple comparison test were used to compare the mean values among three groups. Relations among the variables were investigated by calculating Pearson correlation coefficients and partial correlation coefficients. RESULTS: A total of 1,110 patients were included in the study. In each age group, the mean grade of conjunctivochalasis was higher in hyperopic patients than in myopic patients. There were no significant differences in both the downward gaze- and digital pressure-dependent changes of conjunctivochalasis between the myopic and hyperopic groups. The severity of conjunctivochalasis affecting the nasal and temporal bulbar conjunctiva, and parameters such as the changes of conjunctivochalasis caused by downward gaze or digital pressure, were correlated with the refractive error, especially in patients over 40 years old (P<0.05). CONCLUSIONS: This was the first assessment of the relationship between refractive error and the grade of conjunctivochalasis in a large consecutive series of patients. Our results suggest that the prevalence and grade of conjunctivochalasis are dependent on refractive error, with hyperopia being an important risk factor for conjunctivochalasis. PMID- 21301350 TI - Spontaneous wound dehiscence after early suture removal after deep anterior lamellar keratoplasty. AB - PURPOSE: To describe a case of spontaneous wound dehiscence (WD) after complete suture removal in a patient with macular dystrophy who underwent deep anterior lamellar keratoplasty (DALK). METHODS: A 47-year-old man with macular corneal dystrophy underwent DALK. Intraoperative Descemet membrane perforation was noted. The postoperative period was complicated by corneal edema and high astigmatism. Videokeratography-guided suture removal was carried out, and all sutures were removed by the end of 5 months after which the patient developed spontaneous 270 degrees WD within 6 days. Visual acuity at the time of presentation in the affected eye was counting fingers, anterior chamber was formed, and intraocular pressure was normal. The wound was resutured with 17 interrupted sutures using 10 0 monofilament nylon under topical anesthesia. RESULTS: Three months after resuturing, the best-corrected visual acuity was 6/9, and the graft-host junction was well apposed. CONCLUSIONS: A spontaneous WD can be seen after complete removal of nonabsorbable suture during early months after DALK. Timely management can give good visual results. PMID- 21301351 TI - Central corneal thickness measured with three optical devices and ultrasound pachometry. AB - PURPOSE: To evaluate the reliability of three noninvasive pachometry methods against the ultrasound pachometer considered the gold standard. METHODS: Central corneal thickness (CCT) was measured using a Paxis ultrasound (US) pachometer, Orbscan II, Pentacam, and Topcon SP-3000 specular microscope in 22 right eyes of 22 healthy adults (7 men, 15 women). Three repeated measures were obtained and then compared to obtain the repeatability of each instrument and the agreement between pachometers. RESULTS: Pentacam is the optical system that renders values of CCT closer to those obtained with US pachometry. Conversely, a specular microscope shows a poorer agreement with US measures, and differences depend on the thickness being measured. The Orbscan system shows a consistent trend toward underestimation of CCT compared with US and Pentacam irrespective of the value measured. CONCLUSION: Different optical methods used to measure CCT showed significantly different results compared with US pachometry except for the Pentacam system. Clinicians should take into account the fact that specular microscopy might either underestimate or overestimate values of CCT, whereas Orbscan systematically overestimates CCT compared with US and Pentacam. PMID- 21301352 TI - Impact of mild stroke on the quality of life of spouses. AB - Clients with mild stroke may present subtle deficits that have an impact on complex activities and roles. The purpose of this study was to explore the perceived quality of life of spouses, 3 months after the client with stroke was discharged to go home from acute care. A qalitative design based on a constructivist paradigm was used. Interviews were conducted with family members of the clients with mild stroke, 3 months after discharge. An interview guide was used and the audio content was transcribed, followed by a content analysis. In this study, eight interviews were conducted (mean age 56.9+/-9.2 years; men=2/8), and six essential themes emerged from the data. According to the participants, clients with mild stroke present sequelae that interfere with complex tasks (patient), increasing the burden on other family members who have to limit their personal activities (daily living). Sometimes, spouses were reported to act like a parent, which caused tensions in the relationship (conjugal relationship). Anxiety is related to the risk of stroke recurrence (relapse) and some family members present physical symptoms and a lack of energy (health). However, family members do not have access to services despite support from their relatives (services). The results of this exploratory study strongly suggest that even a 'mild' stroke has an impact on the daily lives of spouses and affects their quality of life. PMID- 21301353 TI - Social cognitive correlates of physical activity in inactive adults with multiple sclerosis. AB - Persons with multiple sclerosis (MS) are often physically inactive. This observation has prompted the search for modifiable constructs derived from established theories that act as correlates of physical activity. This study investigated self efficacy, outcome expectations, impediments, and goal setting as correlates of physical activity in inactive persons with MS. Participants (n=54) completed a battery of measures as part of baseline data collection from an ongoing Internet intervention for increasing physical activity in inactive persons with MS. Bivariate correlation analysis indicated that physical activity was significantly correlated with outcome expectations (r=0.29), functional limitations (r=0.28), and goal setting (r=0.31), but not self efficacy (r=0.13). Multiple linear regression analysis indicated that only goal setting was significantly associated with physical activity (beta=0.31). Such results suggest that goal setting may be a primary correlate of physical activity in inactive persons with MS. PMID- 21301354 TI - Usefulness of multiple biomarkers for the prediction of significant fibrosis in chronic hepatitis B. AB - BACKGROUND/AIMS: It has not been explicitly addressed whether new biomarkers, in addition to readily available clinical data, make a contribution to the prediction of liver fibrosis. METHODS: A total of 209 patients with chronic hepatitis B who underwent liver biopsy were recruited. The Clinical Score (CS) model using only routine clinical data and the Biomarker Score (BS) model using 7 putative biomarkers were derived from the derivation set (n=105), and these models were applied to a separate patients group (n=104) to investigate whether the addition of BS improved the diagnostic accuracy in predicting significant fibrosis beyond an assessment based solely on CS. RESULTS: The most informative biomarkers for predicting significant fibrosis were hyaluronic acid and matrix metalloproteinase-2. The BS was an independent predictive factor for significant fibrosis even after accounting for CS in both sets. Among the derivation set, the incorporation of the BS into the CS model did not significantly increase the receiver operating characteristic area, with only a small improvement of about 2% (P=0.11). Similarly, in the validation set, a combined model with CS and BS showed no superior diagnostic accuracy over the CS model alone, with an improvement of approximately 2% [0.83 (0.75 to 0.92) vs. 0.81 (0.70 to 0.91); P=0.16]. CONCLUSIONS: The simultaneous addition of several biomarkers adds only modestly to clinical predictive factors for risk assessment of individual patients. These results highlight the need for the models to be validated in another cohort with a broader distribution of fibrosis severity. PMID- 21301355 TI - Cascade colorectal cancer screening guidelines: a global conceptual model. AB - BACKGROUND: Guidelines should be a catalyst toward achieving, as a universal standard, the most effective possible care. However, guidelines mainly use evidence of effectiveness as the basis for recommendations. This approach may not be the most appropriate for all healthcare settings because of differing levels of available medical and financial resources. This report from the Guidelines Committee of the World Gastroenterology Organization presents a new conceptual model of cascade colorectal cancer screening guidelines that is also evidence based but resource driven. The emphasis in this variation of the model is on colonoscopy resources at the top of the cascade for a screening goal of prevention by finding and removing the colorectal cancer precursor lesions, the adenoma, as well as early detection. This is a concept study for consideration in the development of future guidelines. Various tests can be reordered within the framework of this model. The cascade concept says, "do what you can with what you have," rather than, "do it this way or no way." METHODS: A systematic review of colorectal cancer screening was performed and an evidence-based cascade (hierarchical recommendations) developed that could apply to healthcare settings having different levels of medical (primarily colonoscopy in this version of the model) resources. A review team representing both developed and developing countries examined published data and provided expert opinion. Cascade guidelines were prepared and reviewed by the team. RESULTS: A set of 4 resource levels were delineated based on available data: colonoscopy, sigmoidoscopy, different sensitivity fecal occult blood tests, and recommendations for colorectal cancer screening were made based on each level, from high to low resources for average risk men and women. The major resource considered was endoscopic in this version of the model. CONCLUSIONS: Each country, region, or healthcare setting needs to determine whether colorectal cancer screening is a legitimate consideration based on other healthcare priorities. Where there is a major burden of colorectal cancer and sufficient resources to mount a screening program, the cascade colorectal cancer screening guidelines model can assist in decisions regarding screening methods. This version is based mainly on available endoscopic resources. These guidelines are evidence based but resource driven. Each healthcare setting needs to determine its resource level as a basis for selecting the screening approach that is most applicable and therefore most likely to succeed. This concept study provides a model that can be adapted to a variety of evidence-based options with consideration of available resources. Its goal is to enhance colorectal cancer screening worldwide, especially in developing countries where the colorectal cancer incidence and mortality is rising rapidly. PMID- 21301356 TI - Importance of diarrhea in evaluating constipation in irritable bowel syndrome clinical studies. AB - BACKGROUND: Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder characterized by alterations in bowel function, abdominal discomfort, and bloating. The symptoms of IBS vary widely between constipation and diarrhea predominance. In this study, we examine "constipation minus diarrhea" score (C-D) to account for the contribution of diarrhea and to create a reliable method for predicting constipation predominance in IBS. METHODS: A nested study was conducted in participants with IBS by Rome I criteria. After consent, they completed a daily stool diary for 1 week. This included recording frequency of bowel movements and describing consistency of stool using the Bristol stool scale. After submitting their diaries, participants rated their bowel symptoms using a visual analog score (VAS) scale from 0 to 100 mm, with 100 mm representing maximum severity. VAS scores for C, D, and C-D were subsequently compared with the true stool events of the previous week by stool diary to validate the potential usefulness of the simple C-D method. RESULTS: Eighty-four participants with IBS completed stool diaries and VAS surveys for bowel symptoms, from which C-D scores were compiled. By correcting for the predominance of constipation compared with diarrhea, C-D scores predicted constipation based on the frequency of bowel movements and Bristol stool score. Furthermore, a second method was used to validate the C-D technique by comparing the mean C-D score in participants with constipation (<=3 d with bowel movement in previous week). In this case, the mean C-D score was 74.1 +/- 3.8 compared with -3.0 +/- 5.9 for patients with >3 days with bowel movement in that week (P<0.001). Although the constipation severity alone also distinguished these 2 groups, the difference was less impressive (P<0.01). In participants with mean Bristol stool scores of <=2 in the preceding week, the C-D mean score was 25.4 +/ 6.1 compared with participants having mean Bristol stool score of >2 where the C D was -11.1 +/- 5.9 (P<0.01). Using constipation severity by VAS alone, there was no significant difference between these same 2 Bristol stool categories (P=0.29). CONCLUSIONS: IBS patients' self-assessment of constipation and diarrhea severity using the C-D score is an effective predictor of C-IBS and constipation severity. The C-D score may be a useful tool in future IBS constipation trials, as it seems to predict constipation and it correlates well with stool diaries. PMID- 21301357 TI - Multidisciplinary management of early and locally advanced esophageal cancer. AB - Clinical management of esophageal cancer is a multidisciplinary challenge. Diagnosis is associated with a high mortality and approximately 40% of patients have locally advanced disease at clinical presentation. Surgery remains one of the fundamental parts of treatment, but multimodal approaches including chemotherapy and radiation are associated with improved outcomes. This comprehensive review addresses the multidisciplinary management of early and locally advanced esophageal cancer. PMID- 21301358 TI - A randomized, double-blind, placebo-controlled multicenter trial of saccharomyces boulardii in irritable bowel syndrome: effect on quality of life. AB - BACKGROUND: Probiotics confer health benefits to the host. However, its clinical effect on irritable bowel syndrome (IBS) is controversial. AIMS: This study was aimed to evaluate the effects of Saccharomyces boulardii on quality of life (QOL) and symptoms in patients with diarrhea-predominant IBS or mixed-type IBS. METHODS: Sixty-seven patients with IBS were randomized either to receive S. boulardii at 2*10 live cells as a daily dose (n=34), or placebo (n=33) for 4 weeks. IBS-QOL was assessed at the beginning and end of the treatment phase. IBS related symptoms, bowel movement frequency, and stool consistency were recorded on a daily basis and assessed each week. RESULTS: The overall improvement in IBS QOL was higher in S. boulardii group than placebo (15.4% vs 7.0%; P<0.05). All eight domains of IBS-QOL were significantly improved in S. boulardii group; however, placebo group only showed improvements in dysphoria and health worry. Composite scores for IBS symptoms were significantly reduced in both groups to a similar extent. Bowel frequency and stool consistency did not change in either group. CONCLUSIONS: S. boulardii improved IBS-QOL better than placebo but was not superior for individual symptoms in patients with diarrhea-predominant IBS or mixed-type IBS. PMID- 21301359 TI - Endoscopic ultrasound and endoscopic retrograde cholangiopancreatography for obstructing pancreas head masses: combined or separate procedures? AB - BACKGROUND: Endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) are complementary procedures in the evaluation of obstructive jaundice. GOALS: To determine the feasibility, accuracy, and safety of the combined performance of EUS-guided fine needle aspiration (FNA) and ERCP with biliary stenting in patients with obstructive jaundice. STUDY: Retrospectively reviewed data from consecutive patients presenting with obstructive jaundice due to a pancreas mass at a tertiary referral hospital between April 2002 and November 2007 who underwent combined (under the same sedation and in the same room) or separate EUS and ERCP. Procedure duration, amount of sedative medication administered, ability to achieve biliary stent placement, and the diagnostic yield of EUS-FNA were evaluated. RESULTS: A total of 47 patients were evaluated: 29 patients underwent combined EUS and ERCP and 18 had separate procedures (median of 5 d between procedures). Stent placement at ERCP was successful in 72% combined procedures versus 88% separate ERCP. EUS-FNA diagnosis of malignancy was positive in 91.6% combined versus 87.5% separate. The only complication was self-limited melena after a combined procedure in 1 patient. The median time for combined procedures was 75 minutes versus 50 minutes for separate EUS and 50 minutes for ERCP. CONCLUSIONS: Combined EUS and ERCP can be performed under the same sedation with a median 25 minute greater procedure length and similarly high yields for diagnostic EUS-FNA. A nonsignificant trend toward lower biliary stent placement success rates with combined ERCP procedures merits further study. Benefits of a combined procedure may include expedited patient evaluation and the avoidance of repeated sedation. PMID- 21301360 TI - Comparison of transjugular intrahepatic portosystemic shunt (TIPS) alone versus TIPS combined with embolotherapy in advanced cirrhosis: a retrospective study. AB - OBJECTIVE: This study was designed to determine whether a transjugular intrahepatic portosystemic shunt (TIPS) combined with embolotherapy was superior to TIPS alone. METHODS: Seventy-nine patients were included in the study (43 in the TIPS and embolotherapy group and 36 in the TIPS alone group). Embolotherapy was performed after TIPS using coils and a tissue adhesive agent. The portosystemic pressure gradient (PPG) after TIPS was lower than 12 mm Hg in all patients. Multivariate analyses were performed using a Cox regression model, and the probabilities of survival and rebleeding were estimated with the Kaplan-Meier method. RESULTS: Baseline patient survey data showed similar distributions in both groups. The mean follow-up time was 45.6 months (range: 1 to 85.6 mo). There were no significant differences in the incidences of rebleeding (P=0.889), stent revision (P=0.728), encephalopathy (P=0.728), the cumulative survival rate (P=0.552), or the probability of being free of rebleeding (P=0.806) between the 2 groups. Of 9 patients with rebleeding after TIPS plus embolotherapy, 7 had a history of esophageal variceal bleeding and 2 had gastric variceal bleeding. Of 8 patients with rebleeding after TIPS alone, 4 had a history of esophageal variceal bleeding and 4 had gastric variceal bleeding (P=0.247). Multivariate analysis showed that PPG after TIPS was an independent predictor of rebleeding (P=0.036). Age and Model of End-stage Liver Disease score were independent predictors of survival (P=0.048 and 0.037). CONCLUSIONS: The results suggest that TIPS with embolotherapy cannot reduce the risk of rebleeding if PPG is less than 12 mm Hg after TIPS. PPG after TIPS is an independent predictor of rebleeding. PMID- 21301361 TI - Effect-site concentration of propofol target-controlled infusion at loss of consciousness in intractable epilepsy patients receiving long-term antiepileptic drug therapy. AB - BACKGROUND: Propofol dose requirement for loss of consciousness (LOC) in epilepsy patients would be probably affected by increasing factors [development of tolerance, up-regulated gamma-aminobutyric acid (GABAA) receptors, or antiepileptic activity of propofol] and reducing factors [synergistic interaction between propofol and antiepileptic drugs (AEDs) or reduced neuronal mass in cortex] in complex and counteracting ways. Therefore, we determined the effect site concentration (Ce) of propofol for LOC in intractable epilepsy patients receiving chronic AEDs in comparison with non-epilepsy patients. METHODS: Nineteen epilepsy patients receiving long-term AEDs therapy and 20 non-epilepsy patients, with the age of 20 to 65 years, were enrolled. The epilepsy patients took their prescribed AEDs until the morning of the operation. Ce of propofol for LOC was determined with isotonic regression method with bootstrapping approach following Dixon's up-and-down allocation. The study was carried out before surgical stimulation. RESULTS: Isotonic regression showed that estimated Ce50 and Ce95 of propofol for LOC were lower in epilepsy group [2.88 MUg/mL (83% confidence interval, 2.82-3.13 MUg/mL) and [3.43 MUg/mL (95% confidence interval, 3.28-3.47 MUg/mL)] than in non-epilepsy group [3.38 MUg/mL (83% confidence interval, 3.17-3.63 MUg/mL) and 3.92 MUg/mL (95% confidence interval, 3.80-3.97 MUg/mL)] with bootstrapping approach. Mean Ce50 of propofol of epilepsy group was also lower than that of non-epilepsy group without statistical significance (2.8240.19 MUg/mL vs 3.16+/-0.38 MUg/mL, P=0.056). CONCLUSIONS: For anesthetic induction of epilepsy patients with propofol target-controlled infusion, Ce may need to be reduced by 10% to 15% compared with non-epilepsy patients. PMID- 21301363 TI - Perioperative severe hypernatremia in a patient with central diabetes insipidus. PMID- 21301364 TI - Skeptical thinking series: an introduction to skeptical thinking in the evaluation of claims. AB - The aim of this study is to introduce the concept of skeptical thinking to evaluate a claim using the six component (Falsifiability, Logic, Comprehensiveness, Honesty, Replicability, and Sufficiency) FiLCHeRS method. These six rules were used to assess whether claims should be accepted or rejected. As this is an introductory study, there are no concrete results to report, although the conclusion is that the method of skeptical thinking using the FiLCHeRS method is a suitable and logical approach to evaluate a claim. PMID- 21301365 TI - Anterior dislocation of the sacroiliac joint in children: a new technique for pelvic fixation. AB - Pelvic injuries in children and especially sacroiliac anterior dislocation are uncommon lesions. In this study, we present an original technique for the fixation of such lesions by a custom-made frame through a single posterior approach. The case of a 12-year-old girl is reported here and advantages of this technique are described. At final follow-up, healing of the lesion was achieved with favourable clinical and radiological outcomes. PMID- 21301366 TI - Onset of developmental dysplasia of the hip during clubfoot treatment: report of two cases and review of patients with both deformities followed at a single institution. AB - Developmental dysplasia of the hip and idiopathic clubfoot are common musculoskeletal conditions in the pediatric orthopedic population. Although ultrasound or radiographic screening is generally recommended to rule out occult hip dysplasia, it has been suggested that children with clubfoot should no longer be screened. We report two cases of newborns with unilateral clubfoot and bilaterally stable hips that developed unilateral hip dysplasia on the same side as the foot deformity during clubfoot treatment. All cases previously reported in the literature are reviewed. We recommend systematic hip ultrasound screening in patients with idiopathic clubfoot. A second hip ultrasound or a pelvis radiograph, if the ossific nucleus has appeared, should be performed after completion of the clubfoot treatment if clinical examination is abnormal. PMID- 21301367 TI - How to make market competition work in healthcare. PMID- 21301368 TI - Vulnerability of health to market forces. AB - OBJECTIVES: This article reviews adverse influences of for-profit enterprises on health care and public health, and examines significance for public policy. RESEARCH DESIGN: Narrative review. RESULTS: For-profit health-care industries may increase costs and reduce quality, leading to market failure and contributing to the USA's unflattering position in international comparisons of health-care efficiency. Drug and device corporations use strategies such as making biased inferences, influencing scientists and physicians, marketing rather than informing the public, and lobbying to control their own industry regulations to create market advantage. Successful marketing leads to the increased use of costly profit-making drugs and procedures over cheaper, nonpatented therapies. Because resources are limited, the overuse of costly modalities contributes to expensive health care, which presents a challenge to universal coverage. The free market also fosters the proliferation of industries, such as tobacco, food, and chemicals, which externalize costs to maximize profits, seek to unduly influence research by paying experts and universities, and attempt to control the media and regulatory agencies. Most vulnerable to the cumulative harm of these tactics are children, the poor, the sick, and the least educated. CONCLUSIONS: The free market can harm health and health care. The corporate obligation to increase profits and ensure a return to shareholders affects public health. Such excesses of capitalism pose formidable challenges to social justice and public health. The recognition of the health risks entailed by corporation-controlled markets has important implications for public policy. Reforms are required to limit the power of corporations. PMID- 21301369 TI - Deployment and the citizen soldier: need and resilience. AB - BACKGROUND: The wars in Iraq and Afghanistan have made unprecedented demands on the nation's citizen soldiers, the National Guard and Reserve. A major concern involves the repeated deployment of these forces overseas. OBJECTIVES: Using data from the Department of Defense Survey of Health Related Behaviors among the Guard and Reserve Force, we examined the effects of deployment on 6 health outcomes. SUBJECTS: The Department of Defense Survey of Health Related Behaviors among the Guard and Reserve Force is a sample (n = 17,754) of all Reserve component personnel (including full time and/or activated Guard and Reservists) serving in all pay grades throughout the world. RESEARCH DESIGN: We relied on inverse probability of treatment weights to adjust for observed confounders and used sensitivity analyses to examine the sensitivity of our findings to potential unobserved confounding. RESULTS: Observed confounders explain much of the apparent effect of deployment. For men, the adjusted relationships could very well reflect further confounding involving unobserved factors. However, for women, effects of deployment on marijuana use, symptoms of post-traumatic stress disorder, and suicidal ideation are robust to adjustments for multiple testing and possible unobserved confounding. CONCLUSIONS: These effects are large in practical terms and troubling but suggest that media reports of the harm caused by deployment may be overstated. Such exaggerations run the risk of stigmatizing those who serve. PMID- 21301370 TI - Predicting the risk of 1-year mortality in incident dialysis patients: accounting for case-mix severity in studies using administrative data. AB - BACKGROUND: Administrative databases are increasingly being used to study the incident dialysis population and have important advantages. However, traditional methods of risk adjustment have limitations in this patient population. OBJECTIVE: Our objective was to develop a prognostic index for 1-year mortality in incident dialysis patients using administrative data that was applicable to ambulatory patients, used objective definitions of candidate predictor variables, and was easily replicated in other environments. RESEARCH DESIGN: Anonymized, administrative health data housed at the Institute for Clinical Evaluative Sciences in Toronto, Canada were used to identify a population-based sample of 16,205 patients who initiated dialysis between July 1, 1998 and March 31, 2005. The cohort was divided into derivation, validation, and testing samples and 4 different strategies were used to derive candidate logistic regression models for 1-year mortality. The final risk prediction model was selected based on discriminatory ability (as measured by the c-statistic) and a risk prediction score was derived using methods adopted from the Framingham Heart Study. Calibration of the predictive model was assessed graphically. RESULTS: The risk of death during the first year of dialysis therapy was 16.4% in the derivation sample. The final model had a c-statistic of 0.765, 0.763, and 0.756 in the derivation, validation, and testing samples, respectively. Plots of actual versus predicted risk of death at 1-year showed good calibration. CONCLUSION: The prognostic index and summary risk score accurately predict 1-year mortality in incident dialysis patients and can be used for the purposes of risk adjustment. PMID- 21301371 TI - Effect of copayments on use of outpatient mental health services among elderly managed care enrollees. AB - BACKGROUND: Recent parity legislation will require many insurers and the federal Medicare program to reduce mental health copayments, so that they are equivalent to copayments for other covered services. The effect of changes in mental health cost sharing has not been well studied, particularly among elderly populations. OBJECTIVE: To examine the consequences of increasing and decreasing copayments on the use of outpatient mental health services among the elderly. RESEARCH DESIGN: Difference-in-differences (DID) design comparing the use of outpatient mental health care in Medicare plans that changed mental health copayments compared with concurrent trends in matched control plans with unchanged copayments. STUDY POPULATION: A total of 1,147,916 enrollees aged 65 years and older in 14 Medicare plans that increased copayments by >= 25%, 3 plans that decreased copayments by >= 25%, and 17 matched control plans with unchanged copayments. RESULTS: In 14 plans that increased mental health copayments from a mean of $14.43 to $21.07, the proportion of enrollees who used mental health services remained at 2.2% in the year before and year after the increase (adjusted DID, 0.1 percentage points; 95% confidence interval, 0.0-0.1). Among 3 plans that decreased copayments from a mean of $25.00 to $8.33, utilization rates were 1.2% before and after the decrease (adjusted DID, 0.1 percentage points; 95% confidence interval, -0.2 to 0.3). Stratified analyses by age, gender, race, and presence of a disability yielded similar results. CONCLUSIONS: Few older adults in managed care plans used outpatient mental health services. Among this population, increasing or decreasing mental health copayments had negligible effects on the likelihood of using outpatient mental health care. PMID- 21301373 TI - Age, hormone therapy use, coronary heart disease, and mortality. PMID- 21301374 TI - Severe atrophic vaginitis causing vaginal synechiae and hematocolpos at menopause. AB - OBJECTIVE: Vaginal atrophy caused by decreased levels of ovarian estrogen production is common at menopause. Atrophic vaginitis severe enough to result in vaginal stricture of the upper two thirds of the vagina and subsequent hematocolpos is unusual. METHODS: A 53-year-old woman presented with nonvisualization of the cervix at the time of her annual examination. RESULTS: Pelvic ultrasound reported a "vaginal cyst," and the final diagnosis of hematocolpos was made by magnetic resonance imaging. The woman was managed with surgical excision of vaginal synechiae followed by local vaginal estrogen therapy and dilators, with satisfactory results. CONCLUSIONS: Untreated severe atrophic vaginitis at menopause can result in a shortened vagina and hematocolpos. Magnetic resonance imaging is useful to characterize vaginal pathology in postmenopausal women. PMID- 21301375 TI - Utility of postsurgical renal scintigraphy to predict one-year outcome of renal transplants in patients with delayed graft function. AB - OBJECTIVE: Delayed graft function is a frequent complication after kidney transplantation impacting aversely on graft survival. The aim of this study was to assess the prognostic value of quantitative scintigraphic parameters immediately after transplantation in this population. METHODS: One hundred patients with renal transplants suffering from delayed graft function were included in this study. All patients underwent Tc-mercaptoacetyltriglycine renal scintigraphy within 72 h of transplantation and were followed for 1 year. Various isotopic parameters were evaluated based on time-activity curves for angiographic and tubular phases. Threshold values for each parameter were derived from receiver operating characteristic curves to study their predictive values for transplant success at 1 year. RESULTS: Mean values of the Kirchner index, tubular function slope, graft/aorta perfusion ratio, or graft uptake/perfusion ratio were significantly higher in successfully grafted patients (P<0.05). The Kirchner index yielded the largest area under the receiver operating characteristic curves (0.75). The tubular function slope (odds ratio>1.4) was found to be an independent prognostic factor for 1-year renal graft failure. CONCLUSION: Our study confirms the prognostic value of vascular parameters in renal transplants, especially the Kirchner index whose negative predictive value was more than 90% for kidney transplantation 1-year success. In addition, isotopic parameters assessing the nephronic functional mass or the functional renal reserve seemed to be relevant prognostic tools with respect to 1-year outcomes. Therefore, the assessment of vascularization and renal function using an early Tc mercaptoacetyltriglycine renal scintigraphy seems to be a powerful tool in establishing 1-year prognosis of renal allografts. PMID- 21301376 TI - A prospective diagnostic accuracy study of F-18 fluorodeoxyglucose-positron emission tomography/computed tomography in the evaluation of indeterminate renal masses. AB - PURPOSE: We evaluated the efficacy of fluorine-18 fluorodeoxyglucose (F-18 FDG) positron emission tomography (PET)/computerized tomography (CT; F-18 FDG-PET/CT) in the detection of renal cell carcinoma (RCC) in patients with indeterminate renal masses. MATERIALS AND METHODS: Between December 2008 and June 2010, 18 patients with suspicious primary renal masses detected by conventional imaging underwent FDG PET/CT imaging. All patients underwent nephrectomy or surgical resection of the renal mass and the final diagnoses were based on histopathology. RESULTS: Fifteen patients had RCC (14 clear-cell RCC, one papillary RCC). Three renal tumors were benign, corresponding to two renal cortical cysts and one oncocytoma. FDG PET/CT accurately detected seven malignant lesions and yielded false-negative results in eight patients. FDG PET/CT was true negative in two patients with a renal cortical cyst and false positive in a patient with oncocytoma. PET showed a sensitivity of 46.6%, specificity of 66.6%, and accuracy of 50% for primary RCC tumors. The median size of visualized tumors was greater than the median size of nonvisualized tumors, and the average Fuhrman grade of the patients with FDG-positive malignant lesions were higher than that of the patients with FDG-negative lesions. In malignant tumors, the change between early and delayed imaging for average standardized uptake values and maximum SUVs were not statistically significant. CONCLUSION: FDG PET/CT is not a reliable modality in the diagnosis of RCC with its low sensitivity, but it is effective in the detection of distant metastases and can be used as a complementary tool when conventional imaging studies yield equivocal results. PMID- 21301377 TI - Can positron emission tomography work in the African tuberculosis epidemic? PMID- 21301378 TI - Re-evaluation of the new Jodal-Brochner-Mortensen equation for one-pool correction of slope-intercept measurement of glomerular filtration rate. AB - BACKGROUND: In their new one-pool correction equation (the JBM equation) for slope-intercept measurement of glomerular filtration rate (GFR), Jodal and Brochner-Mortensen (JBM) assumed that immediate tracer distribution volume (Vo) is the plasma volume. Derivation of the correction factor, f, required the measurement of plasma volume and the area, a, 'missing' in the slope-intercept technique. However, this study shows that any tracer distribution volume can be substituted for Vo to measure f. METHODS: Extracellular fluid volume (ECFV) and GFR were measured in 69 childhood patients and 101 renal transplant donors using chromium-51 (Cr-51)-EDTA. Data from 20 normal volunteers, in whom ECFV was measured with iohexol and GFR with Cr-51-EDTA, were used to measure a. Lean body mass and ECFV (ECFVBird) were estimated from equations based on height and weight described by Boer and Bird et al., respectively. Body surface area (BSA) was estimated from Haycock's formula. RESULTS: In children and donors, ln ECFV correlated closely with ln BSA [ECFV (millilitre) = 6080 * BSA; R = 0.943]. In normal volunteers, a was 18.6 (SD 5.5) min, resulting in f = 0.00308 * BSA min/ml, similar to the value of f in the JBM equation (0.0032 * BSA min/ml). BSA correlated closely with lean body mass (R = 0.80 in women and 0.98 in men). ECFVBird was almost identical to 6080 * BSA. GFR scaled to BSA correlated with BSA, but GFR scaled to BSA did not. CONCLUSION: Any distribution volume proportional to Vo can be used to calculate f in the JBM equation. The unsuitability of BSA for scaling GFR as a result of their nonlinear relationship is shown. PMID- 21301379 TI - Methodological quality in pharmacogenetic studies with binary assessment of treatment response: a review. AB - OBJECTIVE: To evaluate the reporting of critical design issues and methods of statistical analysis in pharmacogenetic studies published in the medical literature. STUDY DESIGN AND SETTINGS: Systematic review of 65 original pharmacogenetic studies published in the literature over the last 15 years. RESULTS: The sample size determination and the planned sample size were lacking in 63 papers. The study design characterization was lacking in 43 papers. The number of patients analyzed ranged from 36 to 1400 (median=161 and interquartile range of 119-250). The Pearson's chi2 test and the Fisher's test were the most common forms of analysis. Multiple statistical testing was relevant to 59 papers, but only 11 addressed the issue of multiplicity (Bonferroni correction). Sources of multiplicity were multiple association assessment (45 papers), analysis of both genotype and allelic frequencies (44), and multiple analysis methods (unadjusted and adjusted). Hardy-Weinberg equilibrium was tested in 12 of 45 papers performing allelic analysis and was fully reported in four of them. The results of association analyses were commonly reported as P values but rarely as estimates of an association measure (odds ratio or relative risk) and its accuracy. CONCLUSIONS: These results show that there is considerable room for improvement in the current standards of design, analysis, and reporting of pharmacogenetic research. PMID- 21301380 TI - Positive and negative associations of HLA class I alleles with allopurinol induced SCARs in Koreans. AB - Recent investigations suggest genetic susceptibility of allopurinol-induced severe cutaneous adverse reactions (SCARs). However, the strength of association was variable according to phenotypes and ethnic backgrounds. To explore genetic markers for allopurinol-induced SCARs in Koreans, we genotyped human leukocyte antigen (HLA) class I alleles of 25 cases of allopurinol-induced SCARs (20 cases of drug-induced hypersensitivity syndrome and five cases of Stevens-Johnson syndrome/toxic epidermal necrolysis) and 57 patients tolerant to allopurinol. Frequencies of B*5801 [92.0 vs. 10.5%, P(c)=2.45*10(-11), odds ratio (OR)=97.8], Cw*0302 (92.0 vs. 12.3%, P(c)=9.39*10(-11), OR=82.1), and A*3303 (88.0 vs. 26.3%, P(c)=3.31*10(-6), OR=20.5) were significantly higher in SCARs compared with tolerant controls. In contrast, A*0201 was not found in SCARs patients despite relatively high frequency in tolerant controls (29.8%). We found strong positive association of HLA-B*5801 and negative association of HLA-A*0201 with the development of allopurinol-induced SCARs in the Korean population. PMID- 21301381 TI - Light-emitting diode technology in vitreoretinal surgery. AB - BACKGROUND: Systems for vitreoretinal illumination during surgery usually consist of an external light source and a light fiber. We introduce a new illumination system for vitreoretinal surgery based on the light-emitting diode technology, with an embedded light source in the handle of the light fiber, making a separate light source unnecessary. METHODS: A prototype of a new illumination system for vitreoretinal surgery (ocuLED; Geuder, Heidelberg, Germany) was tested. This system consists of a handle with a built-in light-emitting diode, supported by an external power source. The OcuLED was analyzed in regards to wavelength, maximum radiant power, and maximum irradiance and was compared with three commercially available vitreoretinal illumination systems. Furthermore, the first intraoperative application and handling were evaluated. RESULTS: The ocuLED system works with a cool white or a neutral white light-emitting diode and is powered externally. The wavelength spectrum shows a maximum at 565 nm and a second peak at 455 nm. Compared with other light sources, the proportion of potentially harmful blue light is low. Maximum radiant power and irradiance are in line with xenon and mercury vapor light sources. The intrasurgical light is bright and offers good visibility. The handle of ocuLED is slightly wider than commonly used light fiber handles, which do not affect its use during surgery. CONCLUSION: Technical progress in light-emitting diode technology allows minimizing the equipment for vitreoretinal illumination. The OcuLED provides bright illumination without an external light source. Wavelength spectrum, maximum radiant power, and irradiance are safe from the risk of phototoxic damage. Intrasurgical handling is identical to conventional light fibers. PMID- 21301382 TI - Role of intravitreal bevacizumab in Eales disease with dense vitreous hemorrhage: a prospective randomized control study. AB - PURPOSE: To investigate the role of intravitreal bevacizumab in Eales disease with dense vitreous hemorrhage. METHODS: This is a prospective randomized control trial. Twenty eyes of 20 patients with dense vitreous hemorrhage because of Eales disease were randomly distributed in Group 1 (n = 10) and Group 2 (n = 10). Group 1 eyes received intravitreal injection of bevacizumab (1.25 mg/0.05 mL) every 4 weeks, and Group 2 eyes were observed. Patients of both groups were followed-up every 2 weeks. Vitrectomy was performed in case of nonresolving vitreous hemorrhage Grade 2 or more after 3 months of enrollment or immediately if retinal detachment was detected. Intraoperative difficulties while performing surgery and excessive bleeding were noted. The primary outcome measures were reduction in the grade of vitreous hemorrhage and the need for vitrectomy. RESULTS: Only 1 eye from Group 1 and 2 eyes from Group 2 showed decrease in vitreous hemorrhage to Grade 2 (P = 0.531, 95% confidence interval). But all three eyes required vitrectomy because of persisting poor vision. Postoperative mean vision +/- SD in Group 1 was 1.2 +/- 0.57 in logarithm of the minimum angle of resolution units, and in Group 2, it was 0.78 +/- 0.41 in logarithm of the minimum angle of resolution units (P = 0.086, 95% confidence interval). Three eyes (30%) in Group 1 had tractional retinal detachment after a single bevacizumab injection, while none of the Group 2 eyes had tractional retinal detachment (P = 0.060, 95% confidence interval). Vitrectomy was performed in all three eyes and had poor visual outcome after surgery. No intraoperative difficulties were noted in either group. CONCLUSION: Our study showed that repeated intravitreal bevacizumab in patients with Eales disease with dense vitreous hemorrhage may not hasten the resolution of vitreous hemorrhage or reduce the need for vitrectomy. Moreover, tractional retinal detachment may be a serious complication of therapy and hence should be closely monitored because it entails a poor visual prognosis. PMID- 21301384 TI - A qualitative study of patients' use of expedited partner therapy. AB - BACKGROUND: In randomized controlled trials of expedited partner therapy (EPT), among patients in the EPT arm, the proportion of partners believed to have taken the medication ranged from 56% to 85%. Little is known about the content of successful and unsuccessful EPT negotiations between patients and their partners. The aim of this study was to describe how patients made decisions about EPT and what they did with the EPT medication packs dispensed to them. METHODS: We performed a qualitative study at the Baltimore City Health Department sexually transmitted disease clinics, which instituted an EPT pilot program in 2007. In depth interviews were conducted with 31 patients, 1 week to 3 months after they had accepted EPT to bring to their partners. Taped interviews were transcribed verbatim and coded using ATLAS.ti 6 qualitative software. Codes were further combined into more comprehensive themes that were mapped onto the study's main aim. RESULTS: Participants were innovative about how to get medication to their partners and indicated a deep sense of concern and responsibility for their partners' health. On the other hand, participants reported of being anxious about the interaction and sometimes felt that they lacked the words to talk with their partners about EPT. Some participants used EPT in unexpected ways, such as giving it to people other than their sex partners or taking it themselves. CONCLUSIONS: Enhancing the counseling that accompanies EPT may improve patients' success in delivering it to their partners. PMID- 21301383 TI - Sexual partnership patterns in malawi: implications for HIV/STI transmission. AB - BACKGROUND: Concurrent sexual partnerships are believed to play an important role in HIV transmission in sub-Saharan Africa, but the contributions of concurrency to HIV and sexually transmitted infection (STI) spread depend on the details of infectious periods and relationship patterns. To contribute to the understanding of sexual partnership patterns in this region, we estimated partnership lengths, temporal gaps between partners, and periods of overlap across partners at an STI clinic in Lilongwe, Malawi. METHODS: Participants underwent physical examinations and HIV tests, and responded to questionnaires about demographics and risk behaviors, including detailed questions about a maximum of 3 sexual partners in the previous 2 months. We calculated partnership length as the time between the first and most recent sexual contact with a partner, and gap length as the time between the most recent contact with 1 partner and the first contact with the next. We defined concurrent and consecutive partnerships as gap length <=0 days and gap length >0 days, respectively. RESULTS: In the study population (n = 183), 86% reported 0 or 1 partner, 5% reported multiple consecutive partnerships, and 9% reported concurrency. The mean partnership length was 858 days (median = 176 days). Gaps between consecutive partnerships were short (mean = 21 days), and overlaps across concurrent partners tended to be long (mean = 246 days). CONCLUSIONS: Multiple sexual partnerships were uncommon, and partnerships were long on average. Among those reporting multiple recent partners, both long-term concurrency and narrowly spaced consecutive partnerships could present substantial risk for efficient transmission of HIV and classical STIs. PMID- 21301385 TI - Extracts of Canadian first nations medicinal plants, used as natural products, inhibit neisseria gonorrhoeae isolates with different antibiotic resistance profiles. AB - BACKGROUND: Neisseria gonorrhoeae (Ng) has developed resistance to most antimicrobial agents and the antibiotics recommended for therapy are restricted, for the most part, to third generation cephalosporins. In order to investigate new potential sources of antimicrobial agents, the antibacterial properties of 14 Canadian plants used in traditional First Nations' medicine were tested against Ng isolates having differing antimicrobial susceptibility profiles. METHODS: Ethanolic extracts of 14 Canadian botanicals, analyzed by high-performance liquid chromatography, were tested for their antimicrobial activity (disc diffusion and/or agar dilution assays) against susceptible Ng reference strains and a panel of 28 Ng isolates with various antimicrobial resistance profiles. RESULTS: Extracts of Arctostaphylos uva ursi (kinnikinnick or bearberry), Hydrastis canadensis (goldenseal), Prunus serotina (black cherry), and Rhodiola rosea (roseroot) inhibited the growth of all Ng isolates with minimum inhibitory concentrations of 32 MUg/mL, 4 to 32 MUg/mL, 16 to >32 MUg/mL, and 32 to 64 MUg/mL, respectively. Extracts of Acorus americanus (sweet flag), Berberis vulgaris (barberry), Cimicifuga racemosa (black cohosh), Equisetum arvense (field horsetail), Gaultheria procumbens (wintergreen), Ledum groenlandicum (Labrador tea), Ledum palustre (marsh Labrador tea), Oenothera biennis (common evening primrose), Sambucus nigra (elderberry), and Zanthoxylum americanum (prickly ash) had weak or no antimicrobial activity against the Ng isolates with minimum inhibitory concentrations >=256 MUg/mL. The phytochemical berberine from H. canadensis inhibited the growth of all Ng isolates. The phytochemicals, salidroside and rosavin, present in R. rosea, also showed inhibitory activity against Ng strains. CONCLUSION: Canadian botanicals represent a potential source of novel compounds which inhibit Ng, including isolates resistant to antibiotics. PMID- 21301386 TI - Disentangling screening and diagnostic Chlamydia test positivity among females testing at title x-funded and adolescent health clinics, san francisco 2009. AB - By using a reason-for-test code, we compared positivity for female chlamydia and gonorrhea. At family planning clinics, there were no statistically significant differences in screening versus diagnostic positivity for either chlamydia or gonorrhea among women. However, at adolescent health clinics, diagnostic positivity was higher than screening positivity for chlamydia and gonorrhea. PMID- 21301387 TI - HPV vaccination to prevent HIV infection: time for randomized controlled trials. PMID- 21301388 TI - Multilocus sequence typing of urogenital Chlamydia trachomatis from patients with different degrees of clinical symptoms. AB - BACKGROUND: In the past, contradictory results have been obtained linking Chlamydia trachomatis serovars (ompA gene) to different clinical courses of infection. METHODS: A high resolution multilocus sequence typing (MLST) system was used to genotype 6 genetic regions, including ompA, in 70 Dutch urogenital C. trachomatis strains from patients with different degrees of defined clinical symptoms (asymptomatic, symptomatic, and lower abdominal pain), to determine if MLST genotypes correlated with clinical manifestations of infection. RESULTS AND CONCLUSIONS: We identified 46 MLST types, with only a small overlap to Swedish MLST types. This study found no correlation between MLST profiles and symptomatology. To understand the clinical course of infection, future studies should not only consider bacterial factors but also look on the immunogenetics of the host. PMID- 21301389 TI - Clinical evaluation of the BD ProbeTecTM Chlamydia trachomatis Qx amplified DNA assay on the BD ViperTM system with XTRTM technology. AB - BACKGROUND: This study evaluated the performance of the BD ProbeTec Chlamydia trachomatis Q (CTQ) Amplified DNA Assay on the BD Viper System with XTR Technology in a multicenter study. METHODS: Specimens were collected at 7 geographically diverse clinical sites from 1538 women and men attending sexually transmitted disease, family planning, and obstetrics and gynecology clinics. There were 1465 evaluable participants, 993 women and 472 men. CTQ assay results from female endocervical, self-collected vaginal, male urethral swab specimens, and male and female neat (unpreserved) urine specimens as well as those obtained using the Urine Preservative Transport (UPT) tube for the CTQ assay were compared with patient-infected status (PIS). PIS was determined based on the combined results from Aptima Combo 2 and BD ProbeTec ET CT Amplified DNA Assay. RESULTS: The sensitivity versus PIS for endocervical, vaginal, and both female urine samples was 91.3%, 96.5%, and 93.0%, respectively. The specificity for the same specimen types was 98.3%, 99.2%, and 99.4% (urine neat) and 99.2% (UPT), respectively. The sensitivity versus PIS for male urethral swabs and both male neat and UPT urine were 92.1% and 98%, respectively, with specificities of 98.4%, 99.2%, and 98.1%, respectively. CONCLUSIONS: The CTQ assay demonstrated performance characteristics comparable with other commercially available nucleic acid-based tests such as Aptima Combo 2 and BD ProbeTec ET CT-Amplified DNA assay. Vaginal swabs and male urine specimens, the sample types recommended by the Centers for Disease Control for chlamydia screening, both performed at least as well as other sample types evaluated. PMID- 21301390 TI - Incidence and predictors of human papillomavirus-6, -11, -16, and -18 infection in young norwegian women. AB - BACKGROUND: Natural history data on human papillomavirus (HPV) incidence and its risk factors have not been reported on from young women in Norway. We report on incidence and predictors of HPV-6, 11, 16, and 18; 6 or 11; 16 or 18; or all 4. METHODS: A 48-month prospective study enrolled 898 women aged 16 to 24 between 1998 and 2000. HPV DNA polymerase chain reaction testing of genital tract specimens was performed and risk data collected every 6 months and HPV serology and genital Chlamydia trachomatis testing performed every 12 months. Cumulative incidence was estimated using the Kaplan-Meier method and covariates evaluated in Cox models. RESULTS: Among the women who were HPV DNA- and serology-negative at entry, 48-month cumulative incidences (95% confidence interval) were as follows: HPV-6: 20.0% (17.1-23.4), HPV-11: 2.2% (1.3-3.5), HPV-16: 25.0% (21.7-28.8), HPV 18: 13.6% (11.3-16.4), HPV-6 or -11: 21.5% (18.5-25.0), HPV-16 or -18: 30.4% (26.7-34.5), and HPV-6, -11, -16, or -18: 37.8% (33.6-42.3). Younger age at first intercourse, being single, having no regular partner, reporting new partners, and genital C. trachomatis infection were independent risk factors of incident HPV. CONCLUSIONS: Proxies measuring new partnerships and genital C. trachomatis infection predicted incident HPV-6, -11, -16, or -18. Incidence of HPV-6, -11, 16, or -18 in young Norwegian women is high, with more than one-third becoming infected over 48 months. PMID- 21301391 TI - Comparative safety of simultaneous and staged anterior and posterior spinal surgery. AB - STUDY DESIGN: Analysis of population-based national hospital discharge data collected for the Nationwide Inpatient Sample. OBJECTIVE: To study perioperative outcomes of circumferential spine surgery performed on either the same or different days of the same hospitalization. SUMMARY OF BACKGROUND DATA: Circumferential spine fusion surgery has been linked to an increased adjusted risk in perioperative morbidity and mortality compared with procedures involving only 1 site. To minimize these risks, some surgeons elect to perform the 2 components of this procedure in separate sessions during the same hospitalization. The value of this approach is uncertain. METHODS: Data collected between 1998 and 2006 for the Nationwide Inpatient Sample were analyzed. Hospitalizations during which a circumferential noncervical spine fusion was performed were identified. Patients were divided into those who had their anterior and posterior portion performed on the same and those performed on different days of the same hospitalization. The prevalence of patient and health care system-related demographics was evaluated. Frequencies of procedure-related complications and mortality were determined. Multivariate regression models were created to identify whether timing of procedures was associated with an independent increase in risk for adverse events. RESULTS: We identified a total of 11,265 entries for circumferential spine fusion. Of those, 71.2% (8022) were operated in 1 session. Complications were more frequent among staged- versus same day surgery patients (28.4% vs. 21.7%, P < 0.0001). The incidence of venous thrombosis and adult respiratory distress syndrome also increased among staged candidates, while the trend toward higher mortality (0.5% vs. 0.4%) did not reach significance. In the regression model, staged circumferential spine fusions were associated with a 29% increase in the odds morbidity and mortality compared with same-day procedures. CONCLUSION: Staging circumferential spine surgery procedures during the same hospitalization offers no mortality benefit and may even expose patients to increased morbidity. PMID- 21301392 TI - Dynamic change of dural sac cross-sectional area in axial loaded magnetic resonance imaging correlates with the severity of clinical symptoms in patients with lumbar spinal canal stenosis. AB - STUDY DESIGN: Cross-sectional registry and imaging cohort study. OBJECTIVE.: To examine whether the dural sac cross-sectional area (DCSA) in axial loaded magnetic resonance imaging (MRI) correlates with the severity of clinical symptoms in patients with lumbar spinal canal stenosis (LSCS). SUMMARY OF BACKGROUND DATA: Many studies have analyzed the relationship between DCSA on conventional MRI and the severity of symptoms in LSCS, but the link is still uncertain. Recently, axial loaded MRI, which can stimulate the spinal canal of patients in the upright position, has been developed. Axial loaded MRI demonstrates significant reduction of DCSA and provides valuable radiologic findings in the assessment of LSCS. However, there has been no study of the correlation between DCSA in axial loaded MRI and the severity of symptoms in LSCS. METHODS: In 88 patients with LSCS, DCSA in conventional MRI, axial loaded MRI, and changes in the DCSA were determined at the single most constricted intervertebral level. The severity of symptoms was evaluated on the basis of the duration of symptoms, walking distance, visual analogue scale of leg pain/numbness, and Japanese Orthopaedic Association score. Spearman correlations of the DCSA in conventional MRI, axial loaded MRI, and changes in the DCSA with the severity of symptoms were analyzed. In addition, the severity of symptoms and DCSA in conventional and axial loaded MRI were compared, respectively, between patients with and without significant (>15 mm) changes in the DCSA. RESULTS: The DCSA in axial loaded MRI had good correlations with walking distance and Japanese Orthopaedic Association score (rs = 0.46 and 0.45, respectively; P < 0.001). In addition, the change in the DCSA significantly correlated to walking distance, visual analogue scale of leg numbness, and Japanese Orthopaedic Association score (rs = 0.59, 0.44, and 0.54, respectively; P < 0.001). Furthermore, the symptoms were significantly worse in patients with more than 15 mm change in the DCSA (P < 0.001). Axial loaded MRI, but not conventional MRI, showed a significantly smaller DCSA in patients with more than 15 mm change in the DCSA (P < 0.05). CONCLUSION: DCSA in axial loaded MRI significantly correlated with the severity of symptoms. Axial loaded MRI demonstrated that changes in the DCSA significantly correlated with the severity of symptoms, which conventional MRI could not detect. Thus, MRI with axial loading provides more valuable information than the conventional MRI for assessing patients with LSCS. PMID- 21301393 TI - Bilateral discal cysts managed by partial hemilaminectomy and microscopic resection of hemilateral cyst. AB - STUDY DESIGN: A case report. OBJECTIVE: The objective of this article was to report a case of bilateral lumbar discal cysts and discuss the clinical, radiological, and surgical findings. SUMMARY OF BACKGROUND DATA: Discal cysts are rare lesions and to our knowledge there has been no report on multiple discal cysts at one disc level. METHODS: The patient's history, clinical examination, imaging findings, and treatment were reported. RESULTS: We reported on the case of a 33-year-old woman with left lower back and lower extremity pain. Neurological imagings demonstrated bilateral cysts at the L4-L5 disc level. She underwent left partial hemilaminectomy at the L4-L5 level and microscopic resection of the left cyst. The cyst contained bloody serous fluid. A connection between the cyst wall and the L4-L5 intervertebral disc and a small laceration in the annulus fibrosus were identified. Histologic examination revealed a cyst lined by fibrous connective tissue without synovium. Her symptoms improved remarkably immediately after surgery. Follow-up imaging 3 months after the operation showed that the bilateral cysts had completely disappeared. CONCLUSION: This is the first reported case of bilateral discal cysts at one disc level. Magnetic resonance images demonstrated rounded cysts on both sides of the posterior longitudinal ligament, which suggests that the discal cysts in our case were unlikely to have developed from an epidural hematoma. Partial hemilaminectomy and microscopic resection of the left cyst lead to complete regression of the bilateral cysts. This suggests that there was a communication between the two cysts via the intervertebral disc and that the content of the right cyst passed from the cyst to the disc. PMID- 21301394 TI - Geographic variation in the surgical treatment of degenerative cervical disc disease: American Board of Orthopedic Surgery Quality Improvement Initiative; part II candidates. AB - STUDY DESIGN: Retrospective case series. OBJECTIVE: To examine and document the change in rates and the geographic variation in procedure type and utilization of plating by orthopedic surgeons for anterior cervical discectomy-fusion. SUMMARY OF BACKGROUND: Age- and sex-adjusted rates of cervical spine surgery have not increased, but the rate of cervical spinal fusion has, accounting for 41% of all fusion procedures in 2004. METHODS: Records were selected from the American Board of Orthopedic Surgeons part II examination from 1999 to 2008. Current Procedural Terminology (CPT) and International Classification of Diseases, 9th Revision, Clinical Modification (ICDM-9-CM) codes were used to determine utilization of structural allograft, autograft/interbody devices, and anterior cervical plating over time and within geographic region. Main outcome measures were physician workforce, and rates and variation of procedure types. RESULTS: From 1999 to 2008, the number of self-declared orthopedic spine surgeon candidates increased 24%. Over this period, the annual number of discectomies with fusions for degenerative cervical disc disease increased by 67%, whereas the number of such operations per surgeon operating on at least 1 such case increased 48% (P = 0.018). Interbody device (0%-31%; P < 0.0001), anterior cervical plating (39% 79%; P < 0.0001), and allograft (14%-59%; P < 0.0001) use increased, whereas autograft use decreased (86%-10%; P < 0.0001). The Southwest and Southeast were more likely than the Midwest to use interbody devices (OR: 2.42 and 1.66, respectively). The Southwest and Northeast were more likely than the Midwest to use autograft (OR: 1.55 and 1.49). The Southwest, Northeast, and Southeast were less likely to use allograft than the Midwest (OR: 0.408, 0.742, and 0.770). The Northeast was less likely and the Southeast more likely than the Midwest to utilize anterior cervical plating (OR: 0.67 and 1.33). Surgical complications were more often associated with autograft compared with allograft (OR: 1.61). CONCLUSION: From 1999 to 2008, the number of orthopedic surgeon candidates performing spine surgery has increased. These surgeons are performing more fusions and utilizing more structural allografts, interbody devices, and/or anterior cervical plates. Regional variations also remain in the types of constructs utilized. PMID- 21301395 TI - "Can't walk nor raise arms to head": Harvey Cushing's surgical treatment of poliomyelitis. AB - STUDY DESIGN: This study was a retrospective chart review for patients undergoing operative treatment by Dr. Harvey Cushing at the Johns Hopkins Hospital between 1896 and 1912. OBJECTIVE: To illustrate the early use of peripheral nerve anastomoses for the treatment of postpoliomyelitis paralysis. SUMMARY OF BACKGROUND DATA: At the turn of the 20th century, poliomyelitis was recognized as a disease of neurons; neurological surgeons sought to find a surgical cure for the paralysis occurring after the disease onset. Peripheral nerve anastomoses were an attractive option employed during this time. METHODS: Following IRB approval, and through the courtesy of the Alan Mason Chesney Archives, the surgical records of the Johns Hopkins Hospital from 1896 to 1912 were reviewed. A single case of peripheral nerve anastomosis for the treatment of postpoliomyelitis paralysis was selected for further analysis. RESULTS: Cushing performed a multiple peripheral nerve anastomoses in a 3-year-old girl. Although the patient experienced no postoperative complications, there was no improvement in her function at the time of discharge from the hospital, and no long-term follow-up was available. CONCLUSION: While unsuccessful, Cushing's use of peripheral nerve anastomoses to restore motor function in the pediatric patient described here demonstrates his commitment to pushing the boundaries of neurological surgery at the turn of the 20th century. PMID- 21301396 TI - ISSLS prize winner: Adaptations to the multifidus muscle in response to experimentally induced intervertebral disc degeneration. AB - STUDY DESIGN: Basic science study of the rabbit multifidus muscle response to intervertebral disc degeneration. OBJECTIVE: To assess changes in passive mechanical properties, associated protein structure, and histology of multifidus in response to disc degeneration produced by experimental needle puncture. SUMMARY OF BACKGROUND DATA: Relationships have been reported between muscle dysfunction and low back injury; however, little is known about the cause and effect of such relationships. METHODS: Twelve rabbits were studied; 4 in each of 3 groups: control, 4-weeks postintervertebral disc injury (4-week disc degeneration), and 12-weeks postintervertebral disc injury (12-week disc degeneration). Single multifidus fibers and bundles of fibers were isolated and tested for slack sarcomere length and elastic modulus. Titin isoform mass, myosin heavy chain distribution, and muscle histology were also examined. RESULTS: Compared to control, individual muscle fibers were 34% stiffer and fiber bundles 107% stiffer in the 12-week disc degeneration group. No changes were detected at 4-week disc degeneration. No statistically significant change was found for MHC distribution in the 12-week disc degeneration group when compared to control, whereas titin isoforms were larger (P < 0.05) in the 12-week disc degeneration group. Histology revealed select regions of multifidus, at 12-week disc degeneration, with increased space between bundles of fibers, which in some instances was partly occupied by adipose tissue. CONCLUSION: Multifidus becomes stiffer, both in individual fibers and fiber bundles, in response to experimentally induced intervertebral disc degeneration. This cannot be explained by change in fiber-type due to reduced muscle use, nor by the increased size of the protein titin (which would reduce stiffness). We hypothesize that fiber bundles become stiffer by proliferation and/or reorganization of collagen content within the muscle but the basis for fiber stiffening is not known. PMID- 21301397 TI - Maximal pulmonary recovery after spinal fusion for adolescent idiopathic scoliosis: how do anterior approaches compare? AB - STUDY DESIGN: Retrospective analysis of prospectively collected data. OBJECTIVE: To compare the relative rates of pulmonary recovery and maximal pulmonary function with surgical approach. SUMMARY OF BACKGROUND DATA: Anterior versus posterior spinal fusion (ASF, PSF) for the treatment of adolescent idiopathic scoliosis (AIS) has been debated. Although procedures that violate the chest wall may compromise pulmonary function, lung function continues to improve after surgery at variable rates depending upon surgical approach. METHODS: We reviewed the medical records from one hundred fifty nine AIS patients (age 15.6+/-2.2; 113 women; 46 men) treated with spinal fusion from 2003 to 2007 by a single surgeon. Forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and radiographic measurements were evaluated before surgery and at 1, 3, 6, 12, and 24-months follow-up on average. Four surgical groups were compared: PSF, ASF (open thoracoabdominal approach for thoracolumbar curvature), video-assisted thoracoscopic surgical release with instrumentation (VATS-I), and VATS with PSF. FEV1 and FVC were fitted to model to evaluate the immediate postoperative pulmonary function (Yo), maximal recovery (Plateau), and rate (K) of pulmonary improvement. RESULTS: Patients in each surgical subgroup were as follows: PSF (Lenke 1: n=50, Lenke 2,3: n=20), ASF (Lenke 5, n=35), VATS-I (Lenke 1=31, Lenke 3=1), and VATS+PSF (Lenke1: n=9, Lenke 2-6: n=13). Early postoperative pulmonary function was higher with ASF and PSF as compared to both VATS groups (P<0.05). Comparing all curve types, VATS-I showed a small decline of absolute FEV1 compared to PSF at 2-years follow-up. Comparing thoracic curves, however, no differences in FEV1 or FVC were noted at 6 to 12 months until 2-years follow-up. The rate of recovery (K) was equivalent for all surgical approaches and curve types. CONCLUSION: Compared to ASF or PSF, VATS procedures showed an initial decline in pulmonary function, which resolved fully by 6- to 12-months follow-up. Modest declines in maximal pulmonary function with VATS-I were seen when comparing all curve types together but not when comparing Lenke 1 curves alone. VATS procedures for thoracic scoliosis and open approaches for thoracolumbar curve types were associated with minimal to no permanent deficits. PMID- 21301398 TI - Early reexploration for suspected thrombosis after pancreas transplantation. AB - BACKGROUND: Graft thrombosis is the most common cause of early graft loss after pancreas transplantation. Early reexploration may permit salvage or timely removal of the thrombosed graft. METHODS: This was a retrospective review of 345 pancreas transplants performed at a single center between January 2003 and December 2009. Early reexploration was defined as within 1 week of pancreas transplantation. RESULTS: Of the 345 transplants, there were 35 early reexplorations. The graft was compromised in 20 cases (57%): 10 venous thromboses, 3 arterial thromboses, 2 combined arterial and venous thrombosis, 2 thromboses secondary to allograft pancreatitis, and 3 cases of positional ischemia without thrombosis. Of these allografts, three reperfused once repositioned and six were successfully thrombectomized for a graft salvage rate of 45%. One of the thrombectomized grafts remained perfused but never functioned and was removed at retransplantation. The 10 remaining compromised grafts that were deemed unsalvageable and required allograft pancreatectomy. Nine of these recipients were retransplanted (eight within 2 weeks) and one was not a retransplantation candidate. CONCLUSIONS: Reexploration for suspected graft thrombosis after pancreas transplantation resulted in a negative laparotomy rate of 43%, but permitted graft salvage in 45% of compromised grafts. PMID- 21301399 TI - Trends in renal transplantation in patients with human immunodeficiency virus infection: an analysis of the United States renal data system. AB - BACKGROUND: We examined the United States Renal Data System registry to analyze trends in renal transplantation in patients with human immunodeficiency virus (HIV) infection. METHODS: A retrospective cohort study was performed using the United States Renal Data System, analyzing patients receiving renal transplants from January 1, 1995, to September 29, 2006. Factors independently associated with transplantation in HIV-infected patients with end-stage renal disease were identified. RESULTS: There was a significant increase in renal transplant recipients who were HIV seropositive who received renal transplants from 2001 to 2006 (n=208, 0.26%) versus 1995 to 2000 era (n=43, 0.06%, P<0.001). Before 2001, only 18 states performed renal transplants in HIV-infected patients, whereas most states transplanted HIV-infected patients in the second era. There were more African American recipients with HIV infection from 2001 to 2006 compared with the earlier cohort (n=118 vs. 8, P<0.001). Patients with HIV infection were more likely to have received induction therapy (n=121 vs. 37, P<0.001) and tacrolimus maintenance suppression (n=105 vs. 13, P<0.001) in the latter era. There were also more deceased donor transplants from 2001 to 2006 (n=143 vs. 25, P<0.001). In logistic regression analysis, when adjusted for multiple factors including recipient and donor age, race, gender, and donor type, patients with HIV infection were more likely to have been transplanted after 2001 (adjusted odds ratio, 2.21; 95% confidence interval=1.49-3.28). In analysis adjusted for multiple factors including hepatitis C virus coinfection, HIV infection was not significantly associated with all-cause graft loss. CONCLUSIONS: There has been a dramatic increase in the number of transplants among HIV-infected patients. These findings suggest improved access to transplant wait listing and better management of immunosuppression, especially among African American patients. PMID- 21301400 TI - Bladder augmentation using tissue-engineered autologous oral mucosal epithelial cell sheets grafted on demucosalized gastric flaps. AB - BACKGROUND: At present, autologous intestinal segments are often used for bladder reconstruction. However, the gastrointestinal mucosa often causes various complications. METHODS: Oral mucosal tissues were obtained from the buccal cavity of beagle dogs. Primary oral mucosal epithelial cells were cultured on temperature-responsive culture dishes with a mitomycin C-treated 3T3 feeder layer for 2 weeks. Cultured epithelial cells were harvested as contiguous sheets by reducing the temperature to 20 degrees C. The study consisted of three groups. In group 1, oral mucosal epithelial cell sheets were autografted on demucosalized gastric flaps. Next, the gastric flaps with the oral mucosal epithelial cell sheets were used for bladder reconstruction. Bladder reconstruction was once immediately and then 5 days after epithelial cell sheet grafting in groups 2 and 3, respectively. Three weeks after bladder reconstruction, the gastric flaps with the oral mucosal epithelial cell sheets were examined by immunohistology. RESULTS: Flaps grafted with oral mucosal epithelial cell sheets showed epithelial regeneration in groups 1 and 3. Regenerated epithelia were stratified and similar to native oral mucosa. However, the regenerated epithelium was absent from the reconstructive segment, and urothelial ingrowth was observed in group 2. Macroscopically, all reconstructive segments showed contracture. CONCLUSIONS: We successfully performed a bladder reconstruction using oral mucosal epithelial cell sheet-grafted flaps that exhibited epithelial regeneration. Further study should consider shrinkage prevention. PMID- 21301401 TI - Cardiovascular disease medications after renal transplantation: results from the Patient Outcomes in Renal Transplantation study. AB - BACKGROUND: Cardiovascular disease (CVD) is the most common cause of death after kidney transplantation. Nevertheless, the use of potentially protective CVD medications has not been examined in a large international cohort of kidney transplant patients. METHODS: Using the Patient Outcomes in Renal Transplantation database, we retrospectively examined CVD medication use in 14,236 kidney transplant patients from 10 centers worldwide at 4 and 12 months posttransplant. RESULTS: Use of CVD medications posttransplant increased between 1990 to 1994 and 2000 to 2006, with a 12-fold increase in the use of statins (odds ratio [OR] 12.28, 95% confidence interval [CI] 10.18-14.80). Use of beta-blockers also increased (OR 3.74, 95% CI 3.20-4.38), as did use of angiotensin converting enzyme inhibitors or angiotensin II receptor blockers (OR 3.68, 95% CI 3.07-4.40) and antiplatelet agents (OR 1.93, 95% CI 1.66-2.24). Use of most CVD medications was not higher in patients with diabetes than in patients without diabetes, despite a higher risk of CVD among patients with diabetes. Although use of several CVD medications was higher in patients with previous CVD events than in patients with no previous CVD, less than 75% of patients with previous CVD were using a statin or antiplatelet agent. CONCLUSION: Although use of CVD medications after kidney transplant has increased in recent years, use of potentially cardioprotective medications may be suboptimal given the high CVD risk in kidney transplant patients. PMID- 21301402 TI - Mammogram confusion. Questions about breast cancer screening continue. PMID- 21301404 TI - Hip replacement for women. Exploring your options. PMID- 21301403 TI - Combination hormone therapy tied to slight increase in breast cancer deaths. PMID- 21301406 TI - Exercise intensity. Working out in the right range. PMID- 21301405 TI - Mayo Clinic office visit. Palliative care. An interview with Edward Creagan, M.D., F.A.A.H.P.M. PMID- 21301407 TI - I recently learned I have a hiatal hernia. What's the treatment? PMID- 21301408 TI - How do you know if you have food poisoning? PMID- 21301409 TI - Hypertension. The importance of blood pressure awareness, control. PMID- 21301410 TI - Effects of rutin and hesperidin and their Al(III) and Cu(II) complexes on in vitro plasma coagulation assays. AB - Two flavonoids, rutin and hesperidin, were investigated in vitro for anticoagulant activity through coagulation tests: activated partial thromboplastin time (aPTT), prothrombin time (PT) and thrombin time (TT). Only an ethanolic solution of rutin at the concentration of 830 uM prolonged aPTT, while TT and PT were unaffected. In order to evaluate whether the prolongation of aPTT was due to the decrease of coagulation factors, the experiment with deficient plasma was performed, showing the effects on factors VIII and IX. Since pharmacological activity of flavonoids is believed to increase when they are coordinated with metal ions, complexes of these flavonoids with Al(III) and Cu(II) ions were also tested. The results showed that complexes significantly prolonged aPTT and had no effects on PT and TT. Assay with deficient plasma (plasma having the investigated factor at less then 1%) revealed that complexes could bind to the coagulation factors, what may lead to a non-specific inhibition and aPTT prolongation. An effort was made to correlate stability of complexes with their anticoagulant properties. PMID- 21301411 TI - New hydrophilic/lipophilic tetra-alpha-(4-carboxyphenoxy) phthalocyanine zinc mediated photodynamic therapy inhibits the proliferation of human hepatocellular carcinoma Bel-7402 cells by triggering apoptosis and arresting cell cycle. AB - Photodynamic therapy (PDT) is a novel and promising antitumor treatment. Phthalocyanine-mediated PDT has shown antitumor activity in some tumor cells, but the effect of new hydrophilic/lipophilic tetra-alpha-(4 carboxyphenoxy)phthalocyanine zinc (TalphaPcZn)-mediated PDT (TalphaPcZn-PDT) on human hepatocellular carcinoma Bel-7402 cells and underlying mechanisms have not been clarified. In the present study, therefore, the ultraviolet-visible (UV-vis) absorption spectrum and cellular localization of TalphaPcZn, and effect of TalphaPcZn-PDT on the proliferation, apoptosis, cell cycle, Bcl-2 and Fas in Bel 7402 cells were investigated by spectrophotometry, inverted microscope, 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay, electron microscopy, annexinV-FITC/propidium iodide double staining, DNA content and immunoblot assay, respectively. We found that an intense absorption in UV-vis absorption spectrum of TalphaPcZn was in the red visible region at 650-680 nm, where light penetration in tissue is efficient, that green TalphaPcZn localized to both plasma membrane and nuclear membrane of Bel-7402 cells, signifying that there was a selective uptake of TalphaPcZn in Bel-7402 cells and TalphaPcZn-PDT would be expected to directly damage DNA, and that TalphaPcZn-PDT significantly resulted in the proliferation inhibition, apoptosis induction, S cell cycle arrest, and down-regulation of Bcl-2 and Fas. Taken together, we conclude that TalphaPcZn-PDT inhibits the proliferation of Bel-7402 cells by triggering apoptosis and arresting the cell cycle. PMID- 21301412 TI - Two new phenols from Scutellaria barbata. AB - Two new phenols, 2(S)-2',7-dihydroxy-5,8-dimethoxyflavanone and (S)-2-(4 hydroxyphenyl)-6-methyl-2,3-dihydro-4H-pyran-4-one, were isolated from the ethanol extract of Scutellaria barbata. Their structures were elucidated on the basis of spectroscopic analysis. PMID- 21301414 TI - China calling. PMID- 21301415 TI - Testing times for gene test regulators. PMID- 21301416 TI - Industry gives cautious welcome to NIH translational center. PMID- 21301418 TI - RNAi momentum fizzles as pharma shifts priorities. PMID- 21301419 TI - ReNeuron and StemCells get green light for neural stem cell trials. PMID- 21301413 TI - Pitavastatin-induced angiogenesis and arteriogenesis is mediated by Notch1 in a murine hindlimb ischemia model without induction of VEGF. AB - Notch signaling is reported to regulate angiogenesis, interacting with vascular endothelial growth factor (VEGF) signaling. HMG CoA reductase inhibitors (statins) also alter Notch signaling in vascular cells, but the mechanism and involvement of Notch and VEGF signaling in statin-mediated angiogenesis remain unclear. Here, we examined how statins activate the endothelial Notch1, and promote angiogenesis and arteriogenesis. We examined blood flow recovery after hindlimb ischemia in wild-type (WT) and Notch1 mutant mice treated with or without pitavastatin (3 mg/kg/day, p.o.). Although VEGF induction was not altered in ischemic limbs, pitavastatin promoted blood flow recovery in ischemic limbs in control mice but not in Notch1 mutant mice. Furthermore, pitavastatin induced endothelial ephrinB2 downstream of Notch1 and increased the density of both capillaries and arterioles in the ischemic limbs of WT but not of Notch1 mutant mice. Pitavastatin (100 nmol/l) rapidly activated gamma-secretase and Notch1 in human umbilical vein endothelial cells without VEGF induction, which was suppressed by pharmacological inhibition and knockdown of Akt. Pitavastatin also augmented endothelial proliferation and tube formation on Matrigel, which were suppressed by either gamma-secretase inhibition or knockdown of Notch1. Pitavastatin-induced microvascular sprouting was also impaired in Notch1 mutant aortic explants. Taken together, pitavastatin activates Notch1 through Akt dependent stimulation of gamma-secretase in endothelial cells, and thereby increases vasculogenesis without VEGF induction. PMID- 21301423 TI - Cephalon splashes out on mesenchymal stem cells. PMID- 21301424 TI - Trade secrets in balance as agencies issue new transparency rules. PMID- 21301428 TI - 2010--bumper year for big biotech. PMID- 21301427 TI - Drug pipeline: Q410. PMID- 21301429 TI - Natural-born eaters. AB - With information on the Deepwater Horizon oil spill in the Gulf of Mexico still coming in, more is being learned about the role of indigenous bacteria in cleaning the spill. Meanwhile, efforts are under way to enlist new genomic technologies to improve outcomes. Jeffrey L. Fox reports. PMID- 21301430 TI - Something new under the skin. AB - One-size-fits-all intravenous delivery of biologics may be giving way to alternate delivery routes that enable safer and more efficient drug administration. Michael Eisenstein reports. PMID- 21301431 TI - The 2010 Eurobarometer on the life sciences. PMID- 21301432 TI - Balancing open source stem cell science with commercialization. PMID- 21301433 TI - MutaDATABASE: a centralized and standardized DNA variation database. PMID- 21301435 TI - Gene therapy finds its niche. AB - Gene therapy is finally poised to make a contribution to the treatment of debilitating, highly penetrant genetic diseases that have proved intractable to other regimens. PMID- 21301436 TI - The 'real world' utility of miRNA patents: lessons learned from expressed sequence tags. AB - Strategies are needed for drafting miRNA patent applications, in light of the existing patent landscape and genomic patent strategies of the past decades. PMID- 21301438 TI - TALEs of genome targeting. PMID- 21301439 TI - A mucosal gateway for vaccines. PMID- 21301440 TI - Sequencing for the cream of the crop. PMID- 21301443 TI - Fourth-quarter biotech job picture. PMID- 21301442 TI - David Roos. Interview by H. Craig Mak. AB - Reflecting on the growth of bioinformatics over the past decade, the University of Pennsylvania's David Roos highlights the increasing diversity of large-scale data sets, changing paradigms for data release and the emergence of new career opportunities. PMID- 21301446 TI - Federal funding for endoscopic research in the United States: 2003-2008. AB - OBJECTIVES: Endoscopic research is underfunded compared with other areas of research. In 2003 we evaluated trends in National Institutes of Health (NIH) funding for endoscopic research from 1972 through 2002. Here, we update those trends for 2003-2008. METHODS: We calculated the number of federally funded endoscopic research grants and classified them as primary or secondary. Endoscopy funding was compared with other funding for the same period. RESULTS: From 2003 through 2008, the NIH funded 76 primary and 114 secondary endoscopy grants. R01 grants accounted for 25% of these. Colorectal cancer research and imaging and advanced optical technology received most of the grants. More primary endoscopic grants were funded than Helicobacter pylori research grants or cardiac catheterization grants. The number of funded endoscopic grants was not different between the periods 1972-2002 and 2003-2008. CONCLUSIONS: Endoscopic research remains underfunded compared with other areas of research. PMID- 21301447 TI - Reflux monitoring: on or off therapy? AB - The role of esophageal pH (or impedance) monitoring in diagnosing gastroesophageal reflux disease (GERD) has evolved over the years. In the era of empiric therapy with potent acid-suppressive agents such as proton pump inhibitors (PPIs), esophageal reflux monitoring is often reserved for patients with PPI-refractory symptoms (1, 2). Given the complexity of patient presentations, technological advancement, and emerging data in the field of GERD, two essential questions need to be addressed: (i) What are the indications for esophageal pH testing in patients suspected to have GERD? (ii) If patients do not respond to aggressive acid suppression, what is the likelihood that they still have reflux; and should the testing be performed at baseline (i.e., off therapy), or is it more important to know whether there is continued reflux despite therapy (i.e., on therapy)? PMID- 21301448 TI - Screening and diagnosis of prostate cancer in patients with ileal pouch-anal anastomosis: consensus from an expert panel. AB - Screening for prostate cancer after restorative proctocolectomy with ileal pouch anal anastomosis can be challenging. Diagnostic biopsy for an elevated level of prostate-specific antigen may present difficulties as well. No guidelines have been issued regarding the value and accuracy of digital examination and the best route to obtain prostate biopsy specimens. A screening and diagnostic algorithm for prostate cancer was developed by an expert consensus panel. PMID- 21301451 TI - Editorial: consensus guidelines: method or madness? AB - Consensus development methodologies are used to develop evidence-based guidelines and include the Delphi process, the nominal group technique, and the National Institutes of Health (NIH) consensus process. Attention to methodology improves the outcomes of the consensus process and better guidelines. PMID- 21301454 TI - Editorial: should women with heartburn undergo screening upper endoscopy for prevention of cancer? AB - Esophageal adenocarcinoma (EAC) is a rare disease which is much more common in men than in women. For any given age, women with gastroesophageal reflux disease (GERD) symptoms actually have a lower risk of EAC than men without GERD symptoms. The cause of the difference in incidence rates between men and women is unclear and not accounted for by differential distribution of known risk factors. Despite the long-recognized difference in incidence between men and women, neither societal guidelines nor physician practice take into account this difference, leading to illogical use of health-care resources. Given the epidemiology of EAC, the yield of endoscopic screening examinations in those under 50, and in women, regardless of age or GERD symptoms, is exceedingly low, and may approximate the low risk of the endoscopic procedure itself. Recommending organizations should consider the epidemiology of EAC when making screening recommendations. PMID- 21301455 TI - Editorial: rifaximin and minimal hepatic encephalopathy. AB - Minimal hepatic encephalopathy (MHE) occurs in up to 70% of patients with cirrhosis and has a clear impact on health-related quality of life (HRQOL) in these patients. Antibiotics leading to reductions in circulating ammonia have been used in the past for the treatment of MHE. However, serious adverse effects such as nephrotoxicity, ototoxicity, and peripheral neuropathy limit their use to relatively short time periods. In this issue of the American Journal of Gastroenterology, an article by Sidhu et al. demonstrates unequivocally that the antibiotic rifaximin, a minimally absorbed antibiotic with broad spectrum activity, improves psychometric test performance scores and concomitantly improves HRQOL in patients with MHE (the RIME Trial). Rifaximin was well tolerated. Results of the RIME Trial represent an important step in the establishment of this antibiotic as an effective and safe treatment for MHE. PMID- 21301456 TI - Editorial: toll-like receptor expression in irritable bowel syndrome: on the alert for a microbial threat? AB - Evidence suggests that mucosal and luminal factors, including low-grade immune activation, increased mucosal permeability and altered host-microbiota interactions, contribute to IBS pathophysiology. In this issue of the American Journal of Gastroenterology, Brint and colleagues provide the first evidence of increased expression of toll-like receptors (TLRs) in patients with IBS. TLRs are known to be involved in the translation of bacterial signals into anti-bacterial innate immune responses. These results hold promise for a better understanding of the role of microbiota and immune activation in the pathophysiology of IBS and also provide novel pharmacological targets for this common troublesome disorder. PMID- 21301457 TI - Ischemic colitis: important differences between kaiser and montefiore reports. PMID- 21301458 TI - Is fecal incontinence a risk factor for institutionalization in the elderly? PMID- 21301460 TI - It is difficult to discontinue PPI treatment in patients with GERD. PMID- 21301463 TI - Double-contrast ultrasound: a novel surveillance tool for hepatocellular carcinoma. PMID- 21301464 TI - Appropriate response to influenza A (H1N1) virus vaccination in patients with inflammatory bowel disease on maintenance immunomodulator and/or biological therapy. PMID- 21301465 TI - Incidence reduction following colonoscopic polypectomy. PMID- 21301466 TI - Toward a successful strategy for publication of medical articles. PMID- 21301470 TI - Neurogenic heterotopic ossification of the hands in a patient with spinal cord injury: a case report. AB - STUDY DESIGN: The study was designed as a case report. OBJECTIVE: The objective of this study was to report an unusual case of bilateral neurogenic heterotopic ossification of the hands in a patient with spinal cord injury. SETTING: Physical Medicine and Rehabilitation department in Sale, Morocco. METHODS: A 47-year-old male patient with C5 quadriparesis was admitted in our department for rehabilitation. He had severe spasticity, characterized by extensors predominance in the upper extremities, and an aspect of pudgy fingers at the proximal phalanges in both hands. RESULTS: A plain radiograph of hands demonstrated ossification parallel to the proximal phalanx of the third and fourth digits on the right and of the second and third digits on the left. Serum alkaline phosphatase rate was increased. The diagnosis of heterotopic ossification of hands was retained. CONCLUSION: Neurogenic heterotopic ossification of hands can occur in quadriplegic patients. Finger extensors spasticity might help toward its development. PMID- 21301471 TI - Big data, but are we ready? PMID- 21301472 TI - The sociobiology of molecular systems. AB - It is often assumed that molecular systems are designed to maximize the competitive ability of the organism that carries them. In reality, natural selection acts on both cooperative and competitive phenotypes, across multiple scales of biological organization. Here I ask how the potential for social effects in evolution has influenced molecular systems. I discuss a range of phenotypes, from the selfish genetic elements that disrupt genomes, through metabolism, multicellularity and cancer, to behaviour and the organization of animal societies. I argue that the balance between cooperative and competitive evolution has shaped both form and function at the molecular scale. PMID- 21301474 TI - Cloud and heterogeneous computing solutions exist today for the emerging big data problems in biology. PMID- 21301473 TI - The importance of phase information for human genomics. AB - Contemporary sequencing studies often ignore the diploid nature of the human genome because they do not routinely separate or 'phase' maternally and paternally derived sequence information. However, many findings - both from recent studies and in the more established medical genetics literature - indicate that relationships between human DNA sequence and phenotype, including disease, can be more fully understood with phase information. Thus, the existing technological impediments to obtaining phase information must be overcome if human genomics is to reach its full potential. PMID- 21301476 TI - From vaccine practice to vaccine science: the contribution of human immunology to the prevention of infectious disease. AB - Over the past 50 years, the practice of vaccination has reached the important goal of reducing many of the diseases that afflicted humanity in past centuries. A better understanding of immunological mechanisms underlying the induction of immune protection and the advent of new technology led to improved vaccine preparations based on purified microbial antigens and new adjuvants able to boost both humoral and cellular immune responses. Despite these tremendous advances, much remains to be done. The emergence of new pathogens, the spread of strains resistant to antibiotics and the enormous increase in latent infections are urgently demanding more and more effective vaccines. Understanding the immunological mechanisms that mediate resistance against infections would certainly provide valuable information for the design of new candidate vaccines. PMID- 21301475 TI - Sex-chromosome evolution: recent progress and the influence of male and female heterogamety. AB - It is now clear that sex chromosomes differ from autosomes in many aspects of genome biology, such as organization, gene content and gene expression. Moreover, sex linkage has numerous evolutionary genetic implications. Here, I provide a coherent overview of sex-chromosome evolution and function based on recent data. Heteromorphic sex chromosomes are almost as widespread across the animal and plant kingdoms as sexual reproduction itself and an accumulating body of genetic data reveals interesting similarities, as well as dissimilarities, between organisms with XY or ZW sex-determination systems. Therefore, I discuss how patterns and processes associated with sex linkage in male- and female heterogametic systems offer a useful contrast in the study of sex-chromosome evolution. PMID- 21301478 TI - The structural bases of direct T-cell allorecognition: implications for T-cell mediated transplant rejection. AB - alphabeta T-cell receptors (TCRs), which can engage a broad array of foreign peptide-laden major histocompatibility complex (pMHC) landscapes, have an essential role in protective immunity. TCRs are selected by pMHC molecules in the thymus and in the periphery, and so are restricted to recognizing 'self'-major histocompatibility complex (MHC) molecules. Accordingly, T cells are inherently cross-reactive, and although the versatility and specificity of this MHC restricted response are the hallmarks of adaptive immunity, 'unwanted' TCR interactions, such as those observed in T-cell alloreactivity, often occur. Recent data have shown that direct T-cell alloreactivity can arise from peptide dependent molecular mimicry, as well as distinct pMHC-binding modes. Here we review recent advances in the field, focusing on structural data pertaining to alloreactivity, and discuss the implications for T-cell-mediated transplant rejection. PMID- 21301479 TI - Bias in the alphabeta T-cell repertoire: implications for disease pathogenesis and vaccination. AB - The naive T-cell repertoire is vast, containing millions of unique T-cell receptor (TCR) structures. Faced with such diversity, the mobilization of TCR structures from this enormous pool was once thought to be a stochastic, even chaotic, process. However, steady and systematic dissection over the last 20 years has revealed that this is not the case. Instead, the TCR repertoire deployed against individual antigens is routinely ordered and biased. Often, identical and near-identical TCR repertoires can be observed across different individuals, suggesting that the system encompasses an element of predictability. This review provides a catalog of alphabeta TCR bias by disease and by species, and discusses the mechanisms that govern this inherent and widespread phenomenon. PMID- 21301477 TI - Exploiting T cells specific for human minor histocompatibility antigens for therapy of leukemia. AB - Minor histocompatibility (H) antigens are major targets of a graft-versus leukemia (GVL) effect mediated by donor CD8(+) and CD4(+) T cells following allogeneic hematopoietic cell transplantation (HCT) between human leukocyte antigen identical individuals. In the 15 years since the first molecular characterization of human minor H antigens, significant strides in minor H antigen discovery have been made as a consequence of advances in cellular, genetic and molecular techniques. Much has been learned about the mechanisms of minor H antigen immunogenicity, their expression on normal and malignant cells, and their role in GVL responses. T cells specific for minor H antigens expressed on leukemic cells, including leukemic stem cells, can be isolated and expanded in vitro and infused into allogeneic HCT recipients to augment the GVL effect to prevent and treat relapse. The first report of the adoptive transfer of minor H antigen-specific T-cell clones to patients with leukemic relapse in 2010 illustrates the potential for the manipulation of alloreactivity for therapeutic benefit. This review describes the recent developments in T-cell recognition of human minor H antigens, and efforts to translate these discoveries to reduce leukemia relapse after allogeneic HCT. PMID- 21301480 TI - Human FoxP3(+)CD4(+) regulatory T cells: their knowns and unknowns. AB - Human regulatory T cells (Tregs) expressing the transcription factor FoxP3 play indispensable roles for the maintenance of immunological self-tolerance and immune homeostasis. In this review, we discuss immunological characteristics of human FoxP3(+) Tregs and to what extent they are similar to or different from the murine counterparts. We also discuss important issues that remain to be addressed in the field to better understand the pathophysiology of autoimmune disease and to build solid basis for immunotherapies targeting FoxP3(+) Tregs. PMID- 21301481 TI - Understanding human T-cell-mediated immunoregulation through herpesviruses. AB - Human herpesviruses have coevolved with humans over millions of years, and adaptation of latent infection within the cells of the immune system is a unique characteristic of many of these viruses. Following primary infection, these herpesviruses establish an asymptomatic-persistent infection in healthy individuals that is strictly controlled by virus-specific CD8(+) and CD4(+) T cells. Here, we provide a brief overview of how the human immune system interacts with these latent viruses and regulates the lifelong host-virus relationship in healthy virus carriers. Extensive studies on T-cell-mediated immune regulation over the last decade has allowed researchers to successfully translate these findings into the clinical setting to treat various herpesvirus-associated diseases in transplant patients and individuals with virus-associated malignancies. It is highly likely that these newly emerging T-cell-based therapeutic and diagnostic technologies will revolutionize the clinical management of patients with herpesvirus-associated diseases. PMID- 21301482 TI - Insights into human CD8(+) T-cell memory using the yellow fever and smallpox vaccines. AB - Live virus vaccines provide a unique opportunity to study human CD8(+) T-cell memory in the context of a controlled, primary acute viral infection. Yellow fever virus-17D and Dryvax are two such live-virus vaccines that are highly efficacious, used worldwide and provide long-term immunity against yellow fever and smallpox respectively. In this review, we describe the properties of virus specific memory CD8(+) T cells generated in smallpox and yellow fever vaccinees. We address fundamental questions regarding magnitude, functional quality and longevity of the CD8(+) T-cell response, which are otherwise challenging to address in humans. These findings provide insights into the attributes of the human immune system as well as provide a benchmark for the optimal quality of a CD8(+) T-cell response that can be used to evaluate novel candidate vaccines. PMID- 21301483 TI - Exploiting human herpesvirus immune evasion for therapeutic gain: potential and pitfalls. AB - Herpesviruses stand out for their capacity to establish lifelong infections of immunocompetent hosts, generally without causing overt symptoms. Herpesviruses are equipped with sophisticated immune evasion strategies, allowing these viruses to persist for life despite the presence of a strong antiviral immune response. Although viral evasion tactics appear to target virtually any stage of the innate and adaptive host immune response, detailed knowledge is now available on the molecular mechanisms underlying herpesvirus obstruction of MHC class I-restricted antigen presentation to T cells. This opens the way for clinical application. Here, we review and discuss recent efforts to exploit human herpesvirus MHC class I evasion strategies for the rational design of novel strategies for vaccine development, cancer treatment, transplant protection and gene therapy. PMID- 21301485 TI - Prevention of T1DM: feeding the ultimate goal. PMID- 21301484 TI - Mice with human immune system components as in vivo models for infections with human pathogens. AB - Many pathogens relevant to human disease do not infect other animal species. Therefore, animal models that reconstitute or harbor human tissues are explored as hosts for these. In this review, we will summarize recent advances to utilize mice with human immune system components, reconstituted from hematopoietic progenitor cells in vivo. Such mice can be used to study human pathogens that replicate in leukocytes. In addition to studying the replication of these pathogens, the reconstituted human immune system components can also be analyzed for initiating immune responses and control against these infections. Moreover, these new animal models of human infectious disease should replicate the reactivity of the human immune system to vaccine candidates and, especially, the adjuvants contained in them, more faithfully. PMID- 21301486 TI - Type 2 diabetes mellitus--current therapies and the emergence of surgical options. AB - Patients with type 2 diabetes mellitus (T2DM) are usually treated with pharmacologic agents in combination with lifestyle modification. The development of new antidiabetic agents, such as insulin analogs and incretin-based therapies, has led to treatment strategies that enable many patients with T2DM to achieve target HbA(1c) levels (<=7.0%). However, many factors-including those related to the patient or the health-care provider, drug inadequacies and adverse effects can interfere with the ability of some patients to reach metabolic targets. Clinical data from the USA indicate that HbA(1c) concentration, blood pressure and serum levels of lipids in patients with T2DM are progressively decreasing toward the target goals set by the American Diabetes Association. These improvements in metabolic regulation have led to a 30-40% decrease in reported microvascular and macrovascular complications of diabetes mellitus in the USA. Gastric bypass surgery in morbidly obese individuals with T2DM leads to remission of the diabetes mellitus in the majority of patients and improvement in the rest. A major contributor to this improvement is an alteration in gastrointestinal hormone secretions. Interventional surgery might, therefore, be considered a reasonable therapeutic alternative for overweight and obese (BMI <35 kg/m2) patients with T2DM who do not respond to medical therapy. PMID- 21301487 TI - Management of Cushing disease. AB - Cushing disease is caused by a corticotroph tumor of the pituitary gland. Patients with Cushing disease are usually treated with transsphenoidal surgery, as this approach leads to remission in 70-90% of cases and is associated with low morbidity when performed by experienced pituitary gland surgeons. Nonetheless, among patients in postoperative remission, the risk of recurrence of Cushing disease could reach 20-25% at 10 years after surgery. Patients with persistent or recurrent Cushing disease might, therefore, benefit from a second pituitary operation (which leads to remission in 50-70% of cases), radiation therapy to the pituitary gland or bilateral adrenalectomy. Remission after radiation therapy occurs in ~85% of patients with Cushing disease after a considerable latency period. Interim medical therapy is generally advisable after patients receive radiation therapy because of the long latency period. Bilateral adrenalectomy might be considered in patients who do not improve following transsphenoidal surgery, particularly patients who are very ill and require rapid control of hypercortisolism, or those wishing to avoid the risk of hypopituitarism associated with radiation therapy. Adrenalectomized patients require lifelong adrenal hormone replacement and are at risk of Nelson syndrome. The development of medical therapies with improved efficacy might influence the management of this challenging condition. PMID- 21301489 TI - Do fibrates truly preserve kidney function? PMID- 21301488 TI - The TSH upper reference limit: where are we at? AB - The diagnosis of subclinical hypothyroidism--serum TSH levels above and T(4) levels within the laboratory reference ranges--depends critically on the upper limit of the TSH reference interval. Calls have been made to lower the current upper TSH reference limit of 4.0 mU/l to 2.5 mU/l to exclude patients with occult hypothyroidism. However, data from population studies do not indicate that the distribution of TSH is altered owing to inclusion of such individuals. The opposite suggestion has also been put forward; the TSH upper reference limit is often too low, especially in the elderly, in women and in white individuals, which may lead to unnecessary or even harmful therapy. Studies in elderly individuals have shown that although aging may be associated with increased TSH levels, paradoxically, overt hypothyroidism in this population may be associated with a less robust TSH response than in young individuals. This Review highlights the interindividual and intraindividual variability of TSH levels and discusses the current controversy that surrounds the appropriateness of reference ranges defined on the basis of age, race, sex and amount of iodine intake. Moreover, the current evidence on lowering or increasing the upper limit of the TSH reference interval is reviewed and the need to individualize levothyroxine treatment in patients with elevated TSH levels is discussed. PMID- 21301490 TI - G protein-coupled receptors: mutations and endocrine diseases. AB - Over the past 20 years, naturally occurring mutations that affect G protein coupled receptors (GPCRs) have been identified, mainly in patients with endocrine diseases. The study of loss-of-function or gain-of-function mutations has contributed to our understanding of the pathophysiology of several diseases with classic hypophenotypes or hyperphenotypes of the target endocrine organs, respectively. Simultaneously, study of the mutant receptors ex vivo was instrumental in delineating the relationships between the structure and function of these important physiological and pharmacological molecules. Now that access to the crystallographic structure of a few GPCRs is available, the mechanics of these receptors can be studied at the atomic level. Progress in the fields of cell biology, molecular pharmacology and proteomics has also widened our view of GPCR functions. Initially considered simply as guanine nucleotide exchange factors capable of activating G protein-dependent regulatory cascades, GPCRs are now known to display several additional characteristics, each susceptible to alterations by disease-causing mutations. These characteristics include functionally important basal activity of the receptor; differential activation of various G proteins; differential activation of G protein-dependent and independent effects (biased agonism); interaction with proteins that modify receptor function; dimerization-dependent effects; and interaction with allosteric modulators. This Review attempts to illustrate how natural mutations of GPCR could contribute to our understanding of these novel facets of GPCR biology. PMID- 21301491 TI - Bone scintigraphy after osteochondral autograft transplantation in the knee: 13 patients followed for 4 years. AB - BACKGROUND AND PURPOSE: Autologous osteochondral transplantation (OCT) is an established method of treating articular cartilage defects in the knee. However, the potential for donor site morbidity remains a concern. Both the restoration of the original cartilage defect and the evolution of the donor site defects can be evaluated by bone scintigraphy. Thus, we performed a prospective bone scintigraphic evaluation in patients who were treated with OCT. PATIENTS AND METHODS: In 13 patients with a symptomatic articular cartilage defect, bone scintigraphies were obtained preoperatively, 1 year after osteochondral transplantation, and finally at an average follow-up of 4 (2.5-5.5) years. The evolution of scintigraphic activity was evaluated for both the recipient and the donor site. Parallel, clinical scoring was performed using the Lysholm knee scoring scale, the Cincinnati knee rating system, and the Tegner activity score. RESULTS: The bone scintigraphic uptake was elevated at the involved femoral condyle preoperatively, and gradually decreased to normal levels in 7 of 11 cases. The originally normal uptake at the trochlea increased 1 year after transplantation. Then, a gradual decrease in uptake occurred again at this donor site to remain elevated at the final scintigraphy. A correlation was found between elevated scintigraphic activity and the presence of retropatellar crepitus. The mean Lysholm and Cincinnati scores had increased 1 year after transplantation. The mean Tegner score had increased 3 years after transplantation. INTERPRETATION: Elevated bone scintigraphic activity from an osteochondral lesion in the knee can be restored with OCT. However, increased scintigraphic activity is introduced at the donor site, which becomes reduced with longer follow-up. The use of fairly large osteochondral plugs appears to correlate with retropatellar crepitus and increased scintigraphic activity, and is not therefore recommended. PMID- 21301492 TI - The 'old disease'. AB - Those over 65 in our society are a new lost generation. A homeostasis which has been established for 50 years is traumatically unbalanced, causing an endemic morbidity in senior citizens. This is reflected by the increased utilization of medical services and medications. Only an individual program for retirement will result in an equitable place in a healthy society for those who are now forced into involuntary retirement. PMID- 21301493 TI - Coping with change in retirement. AB - Retirement is a poorly understood life event which often signals the onset of old age. Adjustment may be difficult for many reasons, but there is little empirical support for the view that retirement results in premature physical and/or psychological deterioration. Flexible individuals who have derived satisfaction from many sources throughout life will do best in retirement. People who are rigid and for whom work provides an identity may be expected to experience difficulties. A knowledge of crisis theory and of stages in the process of retirement may be helpful in dealing with increasing numbers of older patients. PMID- 21301494 TI - An epidemiologist looks at retirement. AB - In projecting future needs in health and social services, one needs not only a knowledge of disease processes and demography, but also social and political factors which may influence the make up and disposition of the population. This article is a look at some of the trends which will influence our handling of the aging population. PMID- 21301495 TI - Can we slow the aging process? AB - Little can be done to slow biological aging. However, some measures can be taken to minimize the effects of certain diseases and conditions associated with aging. These measures include dietary and drug manipulations and changes in lifestyle. For many conditions, early changes in lifestyle would be far more effective than remedial efforts for end-stage disease. In the broader arena, greater attention to housing design and living arrangements, and revision of retirement policies are urgently needed, if our older citizens are to enjoy meaningful later years. PMID- 21301496 TI - Family doctors and their records: a survey in southern alberta. AB - A questionnaire about their approach to keeping office records was completed by 82 randomly selected family physicians in southern Alberta. The results suggest that although there were few manifestly inadequate recordkeepers, there were many areas for legitimate concern, especially the following:1. Extremely brief notes2. Limited attention to psychosocial data3. Underutilization of the more efficient filing techniques4. Poorly organized charts5. Failure to exploit fully innovations which had been introduced into the records system6. Inadequate protection of the records.There is reason to believe that the standard of record keeping in family practice is improving. A few small, simple changes in our record-keeping habits could effect a considerable acceleration of this process. PMID- 21301497 TI - As it happened: a problem case presentation in three episodes. AB - This presentation demonstrates that familiarity with patients' problems, as experienced in family practice, can be a double edged sword. The reader is invited to participate in solving the case; the diagnosis is therefore not revealed until the end of the presentation. PMID- 21301498 TI - Skin manifestations of internal malignancy. AB - Although some of the skin manifestations of internal malignancy are relatively rare, their identification may often be made at a crucial time, when intervention may save a life. This article classifies such signs and describes those which may be seen in family practice. PMID- 21301499 TI - [Not Available]. PMID- 21301500 TI - Scabies in babies. AB - The incidence of scabies has been progressively increasing during the last decade. The contrast of clinical manifestations seen in children and adults can make the diagnosis difficult in infants. Up-to-date treatment regimes described provide effective results and should be provided for all family members and close contacts. Only through such an epidemiological approach can 'ping pong' reinfestation be avoided, thus reducing the rate of spread and incidence of scabies in our society. PMID- 21301501 TI - Skin problems after ostomy surgery. AB - For many years people with colostomies, ileostomies and urinary diversions have had to live in a shadow due to ill-fitting appliances. This has lead to odor problems, skin excoriation, depression, and even withdrawal from society.Dr. Rupert Turnbull from the Cleveland Clinic in Ohio saw the need for an enterostomal therapy service some ten years ago. Patients rehabilitated in self care by an enterostomal therapist, pre and post-operatively, now rarely have any skin problems.During the last ten years new and better appliances have been developed, and with a well constructed stoma in a suitable site, any ostomate can return to a normal life. PMID- 21301502 TI - Self evaluation program. PMID- 21301503 TI - Cutaneous nontuberculous mycobacterial infections. AB - Nine patients exhibiting the characteristic clinical patterns in cutaneous atypical mycobacterial infections are presented. The verrucous plaque, sporotrichoid, ulcerated abscess, and scrophulous presentations are illustrated. The history, clinical appearance and treatment of cutaneous 'atypical' mycobacterial infections are reviewed. PMID- 21301504 TI - Are Canada's MDs Treated Fairly By The Tax Department? PMID- 21301505 TI - Pneumoconioses and their prevention. AB - This article classifies the types of occupational lung disease, details the known hazards of several substances and looks at prevention, both in terms of host factors and improvement of working environment. Current screening procedures are evaluated. PMID- 21301506 TI - [Not Available]. AB - The importance and advantages of organizing an occupational health service are demonstrated. A practical three point health program is described. The family physician is shown to be ideally prepared to head the health team. A brief description of the physical resources follows. PMID- 21301507 TI - Occupational dermatitis. AB - This article attempts to define the term 'occupational dermatitis'. A step by step approach to the management of possible occupational dermatitis is outlined under the following headings: Suspicion, Identification, Elimination or Reduction, and Treatment.Many other factors, in addition to the identification of occupational hazards, play a role in causation of occupational dermatitis and if not kept in mind may confuse or mislead the physician in his diagnosis and management. PMID- 21301508 TI - Family practice residency: was it worth it? PMID- 21301509 TI - Predicting the exercise catastrophe in the post-coronary patient. AB - A total of 230 patients attending an exercise-centred rehabilitation program have been divided into those engaged in physical activity and those inactive, at the time of their first infarction. The two groups have identical physical characteristics, initial fitness levels, and responses to laboratory exercise; the only distinguishing features of the 'active' group is a somewhat longer and more sharply localized pain during infarction and a greater response to exercise training. Since the potential victim of the exercise catastrophe cannot be identified, prevention rests upon careful counselling of all 'post-coronary' patients. Excessive and unusual exertion should be avoided, particularly when this is associated with competition and emotional excitement. Patients should also learn to recognize the symptoms associated with dysrhythmia and angina, and should moderate their physical activity schedule if they sense ischemial prodromata, mental tension or depression.Despite the large size of the exercise class, a good training response (13%-21% gain of aerobic power in one year) is being sustained. Despite objective evidence of effective cardiorespiratory training, systemic blood pressures remain unchanged, both at rest and during standard laboratory exercise. PMID- 21301510 TI - Is diabetes mellitus preventable? AB - The etiology of diabetes has so far defied complete description. Although it is a familial disorder, recent evidence has shown that the pattern of inheritance may be due to a number of factors. Diabetes is not a single disease but a syndrome of carbohydrate intolerance following altered beta cell function. A practical method of genetic counselling is presented, based on known rather than predicted incidence. PMID- 21301511 TI - The adolescent diabetic. AB - Adolescent diabetics present a challange to the attending physician. This is related to the type of diabetes they have, the usual turbulence of this time of life, and their reaction to a chronic condition which imposes certain restrictions. Successful management requires a good physician/patient/family relationship with some firm setting of limits, but avoidance of insistence on control so rigid that frequent hypoglycemia results. The goals of normal growth and activity, as well as a healthy emotional adjustment, should be sought. PMID- 21301513 TI - Self evaluation program. PMID- 21301512 TI - Who is a diabetic? AB - The question 'who is a diabetic?' involves those individuals who present with classical symptoms of diabetes mellitus, those who have no symptoms but glucose intolerance with or without fasting hyperglycemia and those who are sought by investigators searching for diabetes associated with other diseases or disease 'markers' such as particular HLA antigens. Classical juvenile onset diabetics (JODs) have hyperglycemia and acid-base disturbance to a degree which necessitates insulin therapy. Maturity-onset diabetics (MODs) can often control their hyperglycemia by weight reduction. Oral hyperglycemic agents have only a minor role in their management. Maturity-onset diabetes of the young (MODY) can also be treated by dietary manipulation. When the oral glucose tolerance test is used to diagnose diabetes three zones should be recognized: normal, gray zone, and diabetic. Criteria for each are presented. PMID- 21301514 TI - As it happened: a problem case presentation. AB - This presentation, in addition to the diagnostic challenge, brings into focus two problems associated with the practice of medicine. The first is: How far is far enough to go in search of a diagnosis? The second concerns the physician's dilemma when he disagrees with his consultants. As is customary in a mystery case, the diagnosis is not revealed in advance. PMID- 21301515 TI - Suggested core library list for family medicine centres, 1978. PMID- 21301516 TI - What are the real issues in occupational health? PMID- 21301517 TI - An educative approach to the pelvic examination in young women. AB - An educative approach to pelvic examination is described, in which a woman is taught to take part in her own examination. The reason for making this change is discussed as a personal view. PMID- 21301518 TI - [Not Available]. PMID- 21301519 TI - Getting it all together: the pregnancy box. AB - As an attempt to coordinate necessary materials and to facilitate office procedure, the author devised the 'Pregnancy Box' and the 'Baby Box', to be used by both doctor and nurse. The patient was included when books and cartoons were added. PMID- 21301520 TI - Clinical examination of the breast: a simplified technique for busy doctors. AB - A quick efficient method of clinical examination of the presumptively normal breast is outlined. Since most of the early cancers are discovered as small masses identified at the time of such a routine clinical examination, it is logical to expect that competent breast self examination will be even more fruitful. Consequently the teaching of BSE has been completely incorporated into the method. PMID- 21301521 TI - Goiter: an approach to management. AB - The incidence of goiter (any swelling of the thyroid, either diffuse or localized) varies from five to ten percent in the adult population. Carcinoma of the thyroid is rare, occurring in approximately 2.5 per 100,000 population. The prognosis is generally good. Clinically patients usually present in one of four ways: goiter alone, goiter with pain, hyperthyroidism or hypothyroidism. An approach to the management of this problem is presented, keeping these facts in mind. PMID- 21301522 TI - Sexual counselling: use and abuse. AB - Masters and Johnson state that 50 percent of all marriages in North America have some form of sexual dysfunction. If all physicians in North America were to do nothing but sexual counselling 24 hours a day, 365 days a year, there would still not be enough physicians to look after all the problems. This article represents one therapy team's approach to sexual and marital counselling. PMID- 21301523 TI - Assessment of prostatism. AB - Prostatism is a syndrome associated with outlet obstruction at the bladder neck and the commonest cause is benign prostatic hypertrophy. The main indications for investigation and treatment are these symptoms (especially nocturia). The diagnosis should then be confirmed by the physical signs such as an enlarged gland or palpable bladder. If other causes of these symptoms are eliminated, the patient should be referred to a urologist to confirm, through cystoscopy, signs of an obstructing prostate and bladder trabeculation. The surgery (TUR or open) for benign disease leaves the capsules behind and the patient should still be followed with routine rectal examinations for early detection of malignancy. PMID- 21301524 TI - [Not Available]. PMID- 21301525 TI - Renal stones and their medical management. AB - Renal stones are common; in North America calcific stones far exceed uric acid and cystine stones in number. Patients with recurrent, complicated, or bilateral stones merit thoughtful investigation which should take into account what is known about the causes of stone.This review gives an outline of investigation and therapy for cystine and uric acid stones on the assumption that they can be dissolved and recurrences prevented. The challenge of calcific stones is faced and the use of thiazide and allopurinol is discussed as a potentially useful approach to treatment. PMID- 21301526 TI - Male urethritis: gonococcal or not? AB - Differentiation between gonococcal and nongonococcal urethritis may be suspected on clinical grounds but must be proven by the absence of gonococci on smear and culture of the discharge. Chlamydia may be the most common etiological agent in NGU but other causative factors are still unclear. Tetracycline hydrochloride is effective treatment in most instances of GU and NGU. PMID- 21301527 TI - The Nurse Practitioner's Role In Private Practice. AB - The role of the nurse practitioner in private medical practice has been inadequately defined. In order to determine the potential of this role, the authors have examined the activities of one nurse practitioner in an independent pediatric practice in Toronto.The activities have been documented for the first year of the practice and categorized for purposes of this article into functional areas. Each activity is discussed in relation to its effect on medical management and office efficiency. PMID- 21301528 TI - Computers and kidneys: a need that must be filled. PMID- 21301529 TI - Concerns from afar. PMID- 21301530 TI - Memory AIDS in practice. AB - Checklists and other memory joggers are particularly useful to busy people, which certainly describes the average Canadian family physician. As part of an organized record system, they serve a useful function during the office visit. In addition, a variety of techniques can be employed to remind patients to make return visits for a range of medically valid reasons.The techniques for dealing with both these groups vary from the use of plain cards to the use of sophisticated computer technology. The choice of any of these alternatives depend on the specific needs of each practice and the initiative of the physician and office staff. PMID- 21301531 TI - [Relaxation techniques in the treatment of asthma]. PMID- 21301532 TI - Long term home care or institutionalization? AB - Patients, debilitated by chronic illness, do not necessarily have to be cared for in an institution. This study shows that with coordinated home care to provide support services in the community, many patients can remain in their own homes, and even become totally independent. PMID- 21301533 TI - Self evaluation program. PMID- 21301534 TI - From big city to small town: contrasts, comments, conclusions. PMID- 21301535 TI - Hypertension: The Family Physician's Role. AB - A review of a typical Canadian urban family practice over a ten year period, 1965 1974, has revealed that control of hypertension was achieved in 67% of cases. A statistically significant fall in mortality from stroke and congestive heart failure resulted. From these favorable results we suggest that the family physician is the ideal clinician to detect, evaluate, manage and control hypertension, and that he/she could use some assistance from secondary and tertiary care consultants, lay groups and the Ministry of Health in dealing with this problem. PMID- 21301537 TI - What Should Be The Role Of The College's New 'Academic Section'? PMID- 21301536 TI - Residents evaluate their training in family practice. AB - Family practice residents at McMaster University expressed concern about their training because of the diversity of clinical settings to which they were assigned. We found significant differences between units in patient volume, age and sex characteristics of practices and diagnoses. These differences have significant implications for resident training. While highly motivated residents can evaluate their training, faculty cooperation is required for implementation of change in the program. PMID- 21301538 TI - Helping patients cope with stressful life events. AB - Patients frequently present with stress-related symptoms which are associated with common life experiences. This article describes how the physician, or another health-care professional, may assess the stress patients are experiencing and the coping behaviors which they manifest. It also focuses on what the physician may do to help patients deal with certain life stresses. PMID- 21301539 TI - Anxiety States in childhood. AB - The up-to-date prevention and management of anxiety states in childhood is discussed with particular reference to the different presentations of anxiety and the ways in which preventive measures may be used. Anxiety creating developmental lag, mimicking other conditions, and appearing in very specific forms is mentioned. Techniques for handling are introduced together with some suggestions on the responsibility of the family doctor in this whole area of psychological medicine. In this article, the child is seen as part of a family setting; the effect of disturbances in the family constellation resulting in anxiety for the child is described. Some suggestions for ways in which the physician may be involved in patient and parent education are put forward. PMID- 21301540 TI - Therapy can be fun. AB - Many patients have difficulty with some aspects of their lives. Psychotropic medication often has little more than a "Bandaid" effect, but certain psychotherapeutic techniques can be effective alternatives. Three case histories illustrate basic principles. PMID- 21301543 TI - Self evaluation program. PMID- 21301542 TI - [Not Available]. PMID- 21301541 TI - Tension headaches: a challenge to the family physician. AB - Tension headache is a frequently encountered symptom. The skills of the family physician make him or her ideally suited to assess and manage the patient with this problem. Diagnosis depends on a thorough understanding of the nature and 'life-history' of the headache as well as knowledge of the patient as an individual and as part of his or her family and social environment. Management requires a holistic ongoing approach, employing a judicious combination of medication and physical therapy. Above all, the physician must help the patient develop different ways of dealing with anxiety and conflict. PMID- 21301544 TI - Depression in the geriatric patient. AB - This article gives the physician a general overview of depression in the elderly. It indicates a number of general parameters which may help the physician gain a greater understanding of depressive illness and to recognize and help the depressed geriatric patient more effectively. PMID- 21301545 TI - The epidemiology of psychotropic drug use in Canada. AB - The problems and limitations of the two primary methods of assessing prescription drug consumption are discussed. The latest available consumption data on tranquillizers and/or psychotropics from Ontario, Quebec, and Saskatchewan are presented. Total per capita consumption of all drugs has risen steadily while the proportion of all prescriptions accounted for by psychotropic drugs has remained quite consistent. Studies concerned with the patterns of psychotropic drug use are discussed. These identify the high-risk populations as the chronically ill, the elderly, women and the institutionalized. PMID- 21301546 TI - Should Advertising Restrictions On MDs Be Relaxed? PMID- 21301547 TI - CME in the Soviet Union. AB - This article documents the system of continuing medical education in the Soviet Union, as seen through the eyes of a visiting Canadian physician. The information was not easily obtained, since the visit was fraught with administrative difficulties, but the experience was highly educational, giving particular insight into the advantages and disadvantages of an educational system which is totally government funded. PMID- 21301549 TI - Diarrhea and vomiting in infancy. AB - Diarrhea and vomiting in infancy are not common complaints in the life of a busy Canadian family practitioner, but when they do occur the person caring for the infant is usually apprehensive, frustrated and concerned, deserving one's immediate attention. Although the condition is usually acute and self-limiting, its serious consequences make it imperative that investigation be adequate and surveillance strictly followed. Most children with this complaint can be managed at home. Prevention through parental education should be stressed. PMID- 21301548 TI - Epidemiology of gastrointestinal disorders. AB - Irritable bowel syndrome occurs most frequently in young adults in response to emotional and other factors. The 20th century western epidemic of diverticular disease may be linked to low dietary fiber intake. Peptic ulceration is determined by genetic and environmental factors including tobacco and coffee. Aspirin specifically predisposes to gastric ulcer. The incidence of peptic ulcer is declining. Crohn's disease is increasing in frequency although the incidence of ulcerative colitis is fairly steady. Gastrointestinal cancer is closely related to dietary factors including ingested procarcinogens, excessive carbohydrate, fat and animal protein. There is potential for control of some intestinal cancers. PMID- 21301550 TI - Diagnosing hiatus hernia. AB - Symptomatic gastroesophageal reflux is a common and important clinical problem, often keeping company with a radiologically demonstrable hiatus hernia. Recent advances in understanding of the pathophysiology provide a foundation for more rational medical and surgical therapy. A brief discussion of current concepts of gastroesophageal reflux follows. PMID- 21301551 TI - Constipation in the elderly. AB - Constipation is common in the elderly, although apparently no more so than in the general population. Constipation is not a consequence of normal aging. The definition and causes of constipation are discussed. A common-sense approach to investigation at the primary care level is outlined. Available laxative preparations are reviewed. A step-wise approach to the treatment of chronic constipation includes ensuring adequate fluid intake, maximizing activity and providing adequate bulk. A program of bowel training for use in resistant cases is described. Use of oral laxatives is de-emphasized. PMID- 21301552 TI - Inflammatory bowel disease: a practical experience. AB - Dealing with Inflammatory Bowel Disease (IBD) in family practice presents both challenges and satisfactions. A series of case reports taken from practice demonstrates that the family doctor can play an integral part in both the recognition of this disease and its management. One must be aware of the possibility of this condition and be willing to persevere in following and investigating cases where this diagnosis is suspected. One must also be prepared to play a central role in the ongoing care, in working with a group of consultants, and in providing the necessary emotional support to the patient and his family. PMID- 21301553 TI - Pill-induced liver disease. AB - On the ever increasing list of complications and risks associated with oral contraceptive use, those involving the hepatobiliary system are less well known. Four of these entities are reviewed: benign cholestasis, gallstones, hepatic vein occlusion and liver tumors. Some comments are made about the general risk-benefit ratio of pill use. PMID- 21301554 TI - What's New In Hip Surgery? AB - The problems of late loosening of conventional total hip replacements in young people with one joint disease have spurred the development of alternative designs of hip replacement. Two such developments have reached the stage of clinical application.In the double cup arthroplasty, only the damaged joint surfaces are replaced. This makes revision surgery, if required, very much simpler. In porous metal hip replacement, the stems of the prosthesis are porous coated to allow bone ingrowth which locks the implant firmly in place. This dispenses with the use of polymethylmethacrylate, which is the weakest part of the conventional total hip replacement system. PMID- 21301555 TI - ASA-Induced Hypoprothrombinemia: A Case Report. AB - An elderly man suffered a gastrointestinal bleed associated with prolonged prothrombin time while convalescing from surgical treatment of a fractured hip. He had been taking ASA for 19 days prior to the GI bleed.The prothrombin time was restored to normal within 24 hours following administration of Vitamin K. The bleeding stopped and did not recur. No bleeding site was identified, but the patient did have a previous history of duodenal ulceration.Hypoprothrombinemia as a consequence of ASA therapy is a rare cause of bleeding but should be considered in appropriate cases, since it is readily reversible. PMID- 21301556 TI - Maternal-infant bonding. AB - Maternal-infant bonding is a vital process which begins in early infancy and continues over the next few years. The bonding process has tremendous implications for both mother and child and is affected by many factors. Bonding problems occur and the family practitioner can identify these potential problems before pregnancy, during pregnancy, and in the postpartum period, and arrange assistance so the bonding process can unfold normally. PMID- 21301557 TI - The place of prenatal clases. AB - The past 20 years has shown an exponential rise in both obstetrical intervention and family centred maternity care. Prenatal classes, although not as yet fully integrated into prenatal care, fill a vital role in teaching couples the information, skills, and attitudes required to participate actively in their reproductive care, and to recognize both their rights and their responsibilities. PMID- 21301558 TI - The current status of amniocentesis in obstetrics. AB - Amniocentesis can now be used for in utero diagnosis of several conditions. This article summarizes its current uses and outlines indications for the procedure. PMID- 21301559 TI - Coping with obstetric hemorrhage. AB - Intrapartum hemorrhage can be life threatening at worst; at best it is an obstetrical emergency. This article outlines the main causes-uterine atony, lacerations, retained placental fragment, abruptio placentae and placenta previa together with the steps to take in managing these acute conditions. PMID- 21301560 TI - What is adequate prenatal care? AB - In this article, the role of the family physician in providing a high level of antenatal care is examined. Emphasis is placed on the early identification of the high risk pregnancy, either at the first visit or at subsequent visits so that this small but important group of patients, who account for most of our current perinatal mortality and morbidity, can receive the benefits which modern perinatology has to offer. Included in this paper is a survey of the various elements of antenatal care which are now considered of fundamental importance, and a practical outline of how they may be provided. PMID- 21301561 TI - [Not Available]. PMID- 21301562 TI - Prenatal high risk scoring: how family doctors do it. AB - Assessment of risk factors is an integral part of family medicine and of prenatal care. A strong positive relationship has been demonstrated between a high risk score and higher incidence of maternal or perinatal morbidity and mortality. The family physician, because of his previous knowledge of the patient, and his familiarity with a broad range of normals, is in a good position to use his clinical judgement in high risk scoring in pregnancy. We must also be cautious that high risk scoring does not become a self fulfilling prophecy. Risk scoring is simply risk scoring, not a plan of management and intervention. PMID- 21301563 TI - The role of diagnostic ultrasound in obstetrics. AB - Ultrasound has important uses in each trimester of pregnancy. This article outlines what information can be gained from ultrasound in each trimester, and which conditions can be detected by it. PMID- 21301564 TI - Self evaluation program. PMID- 21301565 TI - Gentle birth. AB - No delivery of a baby is routine-each birth is a special event. For the large percentage of normal deliveries, a more human, personal approach can be taken, providing this is what the couple and the doctor feel comfortable with. This article outlines one approach based on the LeBoyer method of slow delivery in a darkened room. PMID- 21301566 TI - Sexual adjustment of postpartum couples. AB - This study of 20 couples who were from six to eight months postpartum indicates that parturition leads to many changes in the sexual relationships of both women and men. On the whole, women reported a decrease in frequency, desire and satisfaction with their sexual relationships as compared to before pregnancy. Men noted decreased frequency of coitus, little change in desire and increased satisfaction. Fatigue and physical discomfort contributed to the women's reduction in sexual feelings and behavior. Men reported that their wives' disinterest was the major determinant of the decrease in frequency of coitus; a feeling of better family relationships led to their increased satisfaction. The data indicate that couples are not discussing these changes, and health professionals are not offering counselling. Important areas which require counselling are identified. PMID- 21301567 TI - Adult Onset Still's Disease Presenting as Fever Of Unknown Origin. AB - This paper describes a case of an adult female with most of the reported manifestations of Still's disease who presented with a fever of unknown origin. The diagnosis is clinical, with some laboratory support. Fever may precede joint pain by weeks or months. Management consists of ASA, but the combination of steroids plus ibuprofen has been found more therapeutic. PMID- 21301568 TI - Teaching through one-way glass. AB - The one-way glass or mirror is an acknowledged teaching tool in academic family practice. Most teaching units use this device. The authors contend that despite its widespread use, standards are incompletely developed and 'contracts' between trainees, patients and teachers are often not specific. However, it can be used creatively to enhance the relationship between the patient, trainee and teacher or preceptor.This article raises questions which should be directly faced by family practice teaching units. The unique way in which each unit will solve these questions or problems will determine a good part of not only the character, but the effectiveness of teaching in general within the unit. PMID- 21301569 TI - What are the implications of in vitro fertilization? PMID- 21301570 TI - Backwards and forwards: the college in 1979. PMID- 21301571 TI - [Not Available]. PMID- 21301572 TI - [Not Available]. PMID- 21301573 TI - Cow's milk. PMID- 21301574 TI - Dr. Parker replies. PMID- 21301575 TI - Laxatives. PMID- 21301576 TI - URIs in children. PMID- 21301577 TI - Dysmenorrhea. PMID- 21301578 TI - Casts applied with controlled pressure. PMID- 21301580 TI - Strength in study: an informal history of the college of family physicians. PMID- 21301579 TI - 25 years of family practice. AB - It is difficult to assess and analyze current history. A selected number of the important events that have occurred in Canadian medicine during the past 25 years are analyzed from the point of view of their impact on and revelance to family practice. Many of the events and advances that will have further impact in the next 25 years have been omitted, such as developments in computer technology and space age medicine. To date, these have had little effect on the majority of family physicians. The opinions expressed are those of the author. PMID- 21301582 TI - Family medicine training: what it takes and what it gives. AB - The needs of a credible residency training program are sufficient patients, a mix of community and academic teachers, cooperative consultants and money. In turn, the program must consider the needs of the community, the needs of the various services on which its residents work, and the needs of the patients. Criticisms often levelled at residency programs relate to their credibility in comparison to "the real world". If the above needs are met, a flexible, well trained physician can be the result. PMID- 21301581 TI - Tuberculosis: past, present and future. AB - Observation and statistics are offered on treatment of tuberculosis in sanatoria during the lifespan of those institutions with special reference to one where the first author's medical life was mainly spent as patient, physician, surgeon and superintendent.Despite the rapid decrease in morbidity and mortality of tuberculosis, the change in direction, and the change in treatment programs, vigilance is still required. It is only because of the commitment of those involved over the many years in the treatment of tuberculosis that we are now at this enviable position. PMID- 21301583 TI - Family medicine: the discipline, 1979. AB - In order for any discipline to remain current, and therefore to grow, it must constantly be aware of its own definition. From this definition will come the need for constant revision, exclusion of outdated or inappropriate material and inclusion of new knowledge. This article examines the principles by which family medicine can perform these functions. PMID- 21301585 TI - Self evaluation program. PMID- 21301584 TI - Acknowledgment of difference. AB - The practice profile of the family physician in 25 years will include far more chronic care, rehabilitation, prevention, education and measurement than at present. Medical schools and continuing medical education programs will have to respond to the challenge of teaching the necessary skills; there will be a necessary move by the College of Family Physicians of Canada to change its stance to one of primary care, encompassing emergency care, occupational health, geriatrics etc. in addition to the core of family physicians. These changes are contingent upon acknowlegement of differences in skills as they exist at present, and the willingness of society to reward prevention and adjustment to disease. PMID- 21301586 TI - The 'Organic' vs. The 'Functional': A Problem Case Presentation. AB - This presentation focuses on the difficulties encountered in trying to judge the impact of psychosocial factors on a major medical problem. The final diagnosis was a surprise to all concerned in the management of a very difficult patient. PMID- 21301587 TI - Training for health care. AB - As primary health care professionals, family physicians can be in the forefront of the emerging field of preventive health counselling. Thus far the emphasis has been on the screening and treatment of disease. Consideration of lifestyle factors like family communication, nutrition, exercise and degree of stress receive little attention.This article describes a family practice which functions as a health maintenance program. The influence of the family practice residency on the concept formation is described, and the difficulties and challenge of putting the concepts into practice are shown. PMID- 21301588 TI - The disparity of health facilities in an urban area discourages proposed treatment application in inoperable lung cancer patients. AB - OBJECTIVES: Patients with a newly diagnosed non-small cell lung cancer (NSCLC) stage IIIB are offered chemoradiotherapy, as proposed by the current guidelines. This combination treatment is facilitated by the coexistence of corresponding departments in the same establishment. The geographical disparity of these health facilities influences patients' willingness to be treated and may influence their survival. This is an observational study that compares the survival of two groups of patients with NSCLC stage IIIB: those treated with chemoradiotherapy versus those treated only with chemotherapy. These two comparable groups were formed exclusively by patients' and/or their families' decisions. METHODS: One hundred fifteen consecutive NSCLC stage IIIB patients were included in the study. All were hospitalized in the biggest Chest Disease Hospital in Athens and were offered sequential chemoradiotherapy. Only 54 patients opted for the proposed treatment, while 61 decided to be treated with chemotherapy only, denying continuing their treatment in another health care unit (radiotherapy). Their survival and related factors were analyzed. RESULTS: Mean overall survival was estimated 10 months (95% confidence interval [CI]: 7.96-12.04). Patients treated with chemoradiotherapy had almost double overall survival compared to those under chemotherapy (P = 0.001): 13.6 months (95% CI: 12.3-14.9) versus 7.5 (95% CI: 6.1 8.9). Patients aged <= 65 years (P < 0.001), smokers (P < 0.001), and those without a cancer history (P < 0.001) survived longer. CONCLUSIONS: The lack of a radiotherapy department in a hospital providing chemotherapy impedes the application of current guidelines advocating combined radiochemotherapy. When recommended radiotherapy after six chemo cycles, half of the patients are unwilling to be displaced and do not follow the recommendations. This has an impact on patient survival. PMID- 21301590 TI - Efficacy and safety of fentanyl buccal for cancer pain management by administration through a soluble film: an update. AB - More than half of patients receiving prescription medicine for cancer pain have been reported to experience inadequate pain relief or breakthrough pain. Buccal administration can deliver lipophilic opioids rapidly to the systemic circulation through the buccal mucosa, limiting gastrointestinal motility and first-pass metabolism. This review updates the safety and efficacy of fentanyl buccal soluble film (FBSF) in patients with cancer pain. Literature was identified through searches of Medline (PubMed). Search terms included combinations of the following: cancer pain, fentanyl, fentanyl buccal soluble film, pharmacology, kinetics, safety, efficacy and toxicity. FBSF is an oral transmucosal form of fentanyl citrate developed as a treatment of breakthrough pain in opioid-tolerant patients with cancer. Studies have shown that it is well tolerated in the oral cavity, with adequate bioavailability and safety in cancer patients. Further studies are warranted to evaluate, in comparison with other short-acting opioids, its efficacy in the management of breakthrough cancer pain, its addictive potential and its economic impact in cancer patients. PMID- 21301589 TI - Cancer chemotherapy: targeting folic acid synthesis. AB - Antifolates are structural analogs of folates, essential one-carbon donors in the synthesis of DNA in mammalian cells. Antifolates are inhibitors of key enzymes in folate metabolism, namely dihydrofolate reductase, beta-glycinamide ribonucleotide transformylase, 5'-amino-4'-imidazolecarboxamide ribonucleotide transformylase, and thymidylate synthetase. Methotrexate is one of the earliest anticancer drugs and is extensively used in lymphoma, acute lymphoblastic leukemia, and osteosarcoma, among others. Pemetrexed has been approved in combination with cisplatin as first-line treatment for advanced non-squamous-cell lung cancer, as a single agent for relapsed non-small-cell lung cancer after platinum-containing chemotherapy, and in combination with cisplatin for the treatment of pleural mesothelioma. Raltitrexed is approved in many countries (except in the United States) for advanced colorectal cancer, but its utilization is mainly limited to patients intolerant to 5-fluorouracil. Pralatrexate has recently been approved in the United States for relapsed or refractory peripheral T-cell lymphoma. This article gives an overview of the cellular mechanism, pharmacology, and clinical use of classical and newer antifolates and discusses some of the main resistance mechanisms to antifolate drugs. PMID- 21301591 TI - A discrete choice experiment evaluation of patients' preferences for different risk, benefit, and delivery attributes of insulin therapy for diabetes management. AB - OBJECTIVE: To evaluate patients' preferences for various attributes of insulin treatment, including route of insulin delivery. METHODS: We used a discrete choice experiment (DCE) to quantify patients' preferences. The attributes (and levels) included in the DCE questionnaire were: glucose control, frequency of hypoglycemic events, weight gain, route of administration for the long-acting and the short-acting insulin, and out-of-pocket cost. Data were analyzed using conditional logit regression and segmented models were also developed to evaluate differences in preferences between subgroups. RESULTS: Two hundred and seventy four questionnaires were completed. The mean age (SD) of participants was 56.7 (12.9) years. Forty-nine percent of participants were insulin users, and 17% had type 1 diabetes. Overall, patients' ideal insulin treatment would provide better glucose control, result in fewer adverse reactions, have the lowest cost, and be administered orally. Overall, there was a strong positive preference for better glucose control relative to the other attributes. Segmented analyses by insulin use and type of diabetes suggest that there may be an important psychosocial barrier to initiating insulin therapy but that patients tend to adjust to subcutaneous administration once they initiate therapy. CONCLUSIONS: This study illustrates the importance that patients with diabetes place on glucose control and how preferences for insulin therapy differ between subgroups. Specifically, efforts need to be made to overcome the psychosocial barriers to initiating insulin therapy which may lead to improved control through improved treatment acceptance and ultimately improve patients' quality of life and reduce the economic burden of the disease. PMID- 21301592 TI - Clinical management of smoking cessation: patient factors affecting a reward based approach. AB - Although the majority of current smokers indicate they would like to quit, only about half of smokers make a quit attempt each year. Of those who attempt to quit, only about 5% are successful. Many effective products and programs are available to assist in smoking cessation; however those interested in quitting often do not make use of these resources. To increase use of cessation products in order to improve successful cessation rates, the Consumer Demand Roundtable has argued that smokers need to be viewed as consumers of cessation products rather than as patients needing treatment. With this consumer-based approach in mind, the current review examines how participant characteristics, perceptions, and behavior influence, and are influenced by, contingency management (CM) paradigms in various settings. Findings suggest that participant factors associated with success in these programs include demographic characteristics (eg, gender, marital status), self-efficacy, motivation to quit, and impulsivity. Overall, participants perceive incentives for successful cessation as motivating. However, such programs may involve greater withdrawal symptoms (eg, craving for cigarettes) initially, but these symptoms tend to decrease at a greater rate over time compared with nonincentive group participants. CM programs have also been shown to be successful across a number of settings (eg, communities, schools), including settings in which smokers are often considered difficult to treat (eg, substance abuse treatment centers). Overall, CM programs are perceived positively by participants and can increase rates of successful cessation. Furthermore, CM interventions have the flexibility to adapt to individual preferences and needs, leading to greater participation and likelihood of successful cessation. Thus, CM provides an important framework for addressing the need for consumer-focused smoking cessation interventions. PMID- 21301593 TI - Practice characteristics of bachelor of science and doctor of pharmacy degreed pharmacists based on the 2009 National Workforce Survey. AB - OBJECTIVE: To compare practice settings and activities of pharmacists with bachelor of science (BS) in pharmacy and doctor of pharmacy (PharmD) degrees. METHODS: Data from the 2009 National Pharmacist Workforce Survey instrument were analyzed. Multivariate regression was used to examine the association of the PharmD degree with time spent in dispensing and patient care. RESULTS: The survey response rate by pharmacists was 52%, and 562 usable responses met our inclusion criteria. Sixty-three percent of BS and 39% of PharmD pharmacists were employed in community pharmacies, compared with 21% of BS and 38% of PharmD pharmacists employed in hospital pharmacy settings. Practicing in a community setting had the strongest influence on time spent in dispensing and time spent in patient care. Among respondents with PharmD degrees, a residency was associated with less time in dispensing and more time in patient care. CONCLUSION: Time spent in dispensing and patient care were influenced more by practice setting than by educational degree and residency training. PMID- 21301594 TI - Comparing team-based and mixed active-learning methods in an ambulatory care elective course. AB - OBJECTIVES: To assess students' performance and perceptions of team-based and mixed active-learning methods in 2 ambulatory care elective courses, and to describe faculty members' perceptions of team-based learning. METHODS: Using the 2 teaching methods, students' grades were compared. Students' perceptions were assessed through 2 anonymous course evaluation instruments. Faculty members who taught courses using the team-based learning method were surveyed regarding their impressions of team-based learning. RESULTS: The ambulatory care course was offered to 64 students using team-based learning (n = 37) and mixed active learning (n = 27) formats. The mean quality points earned were 3.7 (team-based learning) and 3.3 (mixed active learning), p < 0.001. Course evaluations for both courses were favorable. All faculty members who used the team-based learning method reported that they would consider using team-based learning in another course. CONCLUSIONS: Students were satisfied with both teaching methods; however, student grades were significantly higher in the team-based learning course. Faculty members recognized team-based learning as an effective teaching strategy for small-group active learning. PMID- 21301595 TI - Factors affecting prepharmacy students' perceptions of the professional role of pharmacists. AB - OBJECTIVE: To assess prepharmacy students' perceptions of the professional role of pharmacists prior to enrollment in pharmacy school, and the association between perceptions and student demographics. METHODS: A 58-question survey instrument regarding pharmacists' roles, work experiences, and demographics was developed and administered to students (N = 127) enrolled in an organic chemistry laboratory experience at Purdue University. RESULTS: Theory of planned behavior subscales (attitude, subjective norm, perceived behavioral control) were influenced by students' grade point average, gender, and application to pharmacy school, while unpaid work experience affected professional commitment. Students evaluated work experience related to their pharmacy studies more positively than non-pharmacy-related areas in the theory of planned behavior subscales. CONCLUSIONS: Evaluating students' perceptions may be beneficial in helping pharmacy educators design their curricula, as well as allowing admissions committees to select the most qualified students to promote the development of positive perceptions toward the professional role of pharmacists. Grade point average (GPA) and application to pharmacy school were associated with significant differences for the theory of planned behavior and professional commitment subscales. PMID- 21301596 TI - A 20-year perspective on preparation strategies and career planning of pharmacy deans. AB - OBJECTIVE: To provide a longitudinal description of the variety of career paths and preparation strategies of pharmacy deans. METHODS: A descriptive cross sectional study design using survey research methodology was used. Chief executive officer (CEO) deans at every full and associate member institution of the American Association of Colleges of Pharmacy (AACP) in the United States as of May 1, 2009, were potential subjects. RESULTS: The database housed 90.3% (N = 93) of all current (excluding interim/acting) CEO deans. Of the 4 cohorts across time (1991, 1996, 2002, and 2009 snapshots), the 2009 cohort had the highest percentage of deans following either the hierarchical or nontraditional career paths. CONCLUSIONS: Deans named since 2002 have spent less time collectively in the professoriate than cohorts before them. One reason for this is the increase in the number of deans that followed nontraditional career paths and who spent little or no time in the professoriate prior to their first deanship. This also could be due to the increased demand for individuals to serve as dean due to retirements and the creation of new institutions. PMID- 21301597 TI - Psychiatric pharmacy residency training. AB - The role of the psychiatric pharmacist in the care of the mentally ill has continually evolved since the late 1960s and early 1970s. Pharmacists in the field of psychiatric pharmacy work to improve the health, safety, and welfare of those impacted by one or more psychiatric conditions. Specialty residency training programs are accredited to establish minimum training standards and a board-certification process ensures that individuals provide a high level of quality of care. It is the position of the College of Psychiatric and Neurologic Pharmacists (CPNP) that Psychiatric Pharmacy residency programs obtain American Society of Health-System Pharmacy (ASHP) accreditation and help the profession move forward as a recognized specialty. PMID- 21301598 TI - Recognition of teaching excellence. AB - The 2008-2009 Task Force for the Recognition of Teaching Excellence was charged by the AACP Council of Faculties Leadership to examine teaching excellence by collecting best practices from colleges and schools of pharmacy, evaluating the literature to identify evidence-based criteria for excellent teaching, and recommending appropriate means to acknowledge and reward teaching excellence. This report defines teaching excellence and discusses a variety of ways to assess it, including student, alumni, peer, and self-assessment. The task force identifies important considerations that colleges and schools must address when establishing teaching recognition programs including the purpose, criteria, number and mix of awards, frequency, type of award, and method of nominating and determining awardees. The report concludes with recommendations for the academy to consider when establishing and revising teaching award programs. PMID- 21301599 TI - The influence of an elective introductory clinical research course on pharmacy student interest in pursuing research-based careers. AB - OBJECTIVE: To assess the impact of an elective clinical research course on second and third-year pharmacy students' knowledge of clinical research methods, training programs, career options, and interest in pursuing postgraduate training. DESIGN: A 2-credit hour elective course in clinical research was designed that included lectures, discussions, workshops, and in-class presentations related to study design and implementation, protocol synthesis, research evaluation, ethical and legal considerations, data analysis, and professional opportunities involving clinical research. Learner knowledge of these topics was assessed using several methods, including 3 assignments related to research protocol, ethical documentation, and presentation. ASSESSMENT: A survey instrument designed to evaluate the effect the course had on pharmacy students' knowledge of clinical research methods and interest in pursuing postgraduate training in clinical research was administered. Students who completed the elective had a greater level of familiarity with research-related topics, training options, and career opportunities (p < 0.05) and a greater interest in pursuing a career in clinical research (p < 0.05) than did students in a matched control group. CONCLUSION: Taking a 2-credit hour elective course in clinical research increased pharmacy students' interest in pursuing a career in clinical research. PMID- 21301600 TI - Influences on Malaysian pharmacy students' career preferences. AB - OBJECTIVES: To identify and evaluate factors affecting the career preferences of fourth-year bachelor of pharmacy (BPharm) students in Malaysia in the presence of a 4-year period of mandatory government service. METHODS: A validated self administered questionnaire was used in this cross-sectional study to collect data from final-year BPharm students enrolled at 3 government-funded universities and 1 private university in Malaysia. Both descriptive and inferential statistics were used for data analysis. RESULTS: Three hundred fourteen students responded (213 from public universities and 101 from the private university). Approximately 32% of public university students and 37% of private university students ranked their own interest in pharmacy as the reason for undertaking pharmacy degree studies; 40.4% of public and 19.8% of private university respondents stated that they would enter a nonpharmacy-related career upon graduation if given the choice. Public university students ranked hospital pharmacy as their choice of first career setting (4.39, p = 0.001), while private students ranked community pharmacy first (4.1, p = 0.002). On a scale of 1 to 5, salary received the highest mean score (3.9 and 4.0, p = 0.854) as the extrinsic factor most influencing their career choice. CONCLUSIONS: Final-year students at Malaysian public universities were most interested in hospital pharmacy practice as their first career step upon graduation, while private university students were most interested in community pharmacy. The top 3 extrinsic factors rated as significant in selecting a career destination were salary, benefits, and geographical location. PMID- 21301601 TI - Consumer-led mental health education for pharmacy students. AB - OBJECTIVE: To evaluate a consumer-led teaching intervention to reduce pharmacy students' stigma towards depression and schizophrenia, and improve attitudes toward providing pharmaceutical care for consumers with mental illness. DESIGN: Third-year bachelor of pharmacy degree students were given a series of mental health lectures, undertook supervised weekly placements in the community pharmacy setting, and attended a tutorial led by trained mental health consumer educators. ASSESSMENT: A previously validated 26-item survey instrument was administered at baseline, 6 weeks postintervention, and 12 months postintervention, and 3 focus groups were conducted. Survey instruments were completed by 225 students at baseline, 230 students postintervention, and 228 students at 12 months. Students' stigma decreased (p < 0.05) and their attitudes toward the provision of pharmaceutical services to consumers with a mental illness showed significant improvements (p < 0.05). These improvements were maintained at the 12-month follow-up. Four themes emerged from the focus groups: knowledge and experience of mental illness, mental health stigma, impacts on attitudes and self-reported behavior, and the role of the pharmacist in mental healthcare. CONCLUSIONS: Consumer-led education for pharmacy students may provide a sustainable reduction in stigma and improve attitudes towards providing pharmaceutical services to consumers with a mental illness. PMID- 21301602 TI - Pharmacists' role in targeted cancer therapy in Australia and implications for pharmacy education. AB - OBJECTIVES: To investigate the pharmacists' role in providing targeted therapies to patients and its implications for pharmacy education. METHODS: Nine pharmacy faculty members, 12 clinical pharmacists, and 4 oncologists from across Australia and New Zealand participated in semistructured interviews, which were analysed using the framework method. RESULTS: Education about targeted therapies was seen as being important, although content about pharmacodiagnostic tests was taught inconsistently among 7 universities. Issues including funding, clinical and diagnostic validity of tests, and time taken for turnaround of tests were perceived as impediments to the acceptance by clinicians of the utility of pharmacodiagnostic tests. CONCLUSIONS: Pharmacists may be the ideal professionals to interpret test results and provide counselling for patients to assist them in compliance with targeted cancer therapies. Pharmacy education in cancer therapies is critical to training pharmacists who can assist patients in the correct use of these therapies. PMID- 21301603 TI - High-fidelity patient simulation series to supplement introductory pharmacy practice experiences. AB - OBJECTIVE: To introduce a high-fidelity simulation series into a 5-year doctor of pharmacy (PharmD) curriculum to demonstrate a hybrid model for introductory pharmacy practice experience (IPPE) delivery. DESIGN: Fourth-year pharmacy students at a satellite campus participated in a 6-week high-fidelity patient simulation series in which small groups of students worked with members of a patient care team to care for patients in the following scenarios: asthma exacerbation, acute decompensated heart failure, and infective endocarditis with a subsequent anaphylactic reaction to the antibiotic. Fourth-year pharmacy students at the main campus who did not participate in the simulation served as a comparator group. ASSESSMENT: Students' scores on a knowledge-based post simulation quiz were significantly higher than scores on the presimulation quiz (p < 0.05). Knowledge retention was significantly higher among the simulation participants than students in the comparator group (p = 0.004). The majority (76%) of students felt more confident "making clinical recommendations to a healthcare provider" after completing the simulation series (p = 0.01). CONCLUSION: High-fidelity patient simulation is an effective active-learning strategy to augment IPPEs that allows students to apply clinical skills in a realistic but low-risk patient care setting. PMID- 21301604 TI - Transforming a large-class lecture course to a smaller-group interactive course. AB - OBJECTIVE: To transition a large pharmacokinetics course that was delivered using a traditional lecture format into a smaller-group course with a discussion format. DESIGN: An e-book and Web-based multimedia learning modules were utilized to facilitate students' independent learning which allowed the number of classes they were required to attend to be reduced from 3 to 1 per week. Students were assigned randomly to 1 of 3 weekly class sessions. The majority of lecture time was replaced with active-learning activities including discussion, problem solving, and case studies to encourage higher-order learning. ASSESSMENT: Changes in course delivery were assessed over a 4-year period by comparing students' grades and satisfaction ratings on course evaluations. Although student satisfaction with the course did not improve significantly, students preferred the smaller-group setting to a large lecture-based class. The resources and activities designed to shift responsibility for learning to the students did not affect examination grades even though a larger portion of examination questions focused on higher orders of learning (eg, application) in the smaller-group format. CONCLUSIONS: Transitioning to a smaller-group discussion format is possible in a pharmacokinetics course by increasing student accountability for acquiring factual content outside of the classroom. Students favored the smaller class format over a large lecture-based class. PMID- 21301605 TI - A standardized rubric to evaluate student presentations. AB - OBJECTIVE: To design, implement, and assess a rubric to evaluate student presentations in a capstone doctor of pharmacy (PharmD) course. DESIGN: A 20-item rubric was designed and used to evaluate student presentations in a capstone fourth-year course in 2007-2008, and then revised and expanded to 25 items and used to evaluate student presentations for the same course in 2008-2009. Two faculty members evaluated each presentation. ASSESSMENT: The Many-Facets Rasch Model (MFRM) was used to determine the rubric's reliability, quantify the contribution of evaluator harshness/leniency in scoring, and assess grading validity by comparing the current grading method with a criterion-referenced grading scheme. In 2007-2008, rubric reliability was 0.98, with a separation of 7.1 and 4 rating scale categories. In 2008-2009, MFRM analysis suggested 2 of 98 grades be adjusted to eliminate evaluator leniency, while a further criterion referenced MFRM analysis suggested 10 of 98 grades should be adjusted. CONCLUSION: The evaluation rubric was reliable and evaluator leniency appeared minimal. However, a criterion-referenced re-analysis suggested a need for further revisions to the rubric and evaluation process. PMID- 21301606 TI - A distance education course in statistics. AB - OBJECTIVES: To evaluate the learning outcomes of an online, distance education course in statistics for doctor of pharmacy (PharmD) students. DESIGN: Lectures for the course were produced by the course faculty, converted into digital format (mp4), placed within the college's course management system, and video streamed to students. The course required students to interact with the course content using workbooks and simulations and with the instructor via VoIP examination reviews. ASSESSMENT: A quasi-experimental study involving 4 groups of students was conducted. Second-year (P2) students were assigned randomly to 1 of 3 groups and asked to complete a precourse survey that contained: demographic information only (group 1); demographic items plus 10 items assessing statistics knowledge (group 2); or demographic items plus 20 items assessing statistics knowledge (group 3). At the end of the course, all students were given the same 20 items on the final examination (postcourse survey instrument). A control group consisting of randomly selected first-year (P1) students completed the 20-item precourse survey instrument. P1 and P2 students' scores on the 20-item precourse survey were not significantly different. Students who had taken a statistics course before entering the PharmD program scored higher on the precourse survey. P2 students in all 3 study groups had similar scores on the final examination (postcourse survey) (p = 0.43). CONCLUSIONS: Students can be taught the basic principles of statistics and how to use statistics to read the pharmacy and medical literature entirely online. This study has significant implications for how classes traditionally taught in the classroom might be taught at a distance using innovative instructional technologies. PMID- 21301607 TI - A model for self-directed problem-based learning for renal therapeutics. AB - OBJECTIVE: To introduce a new approach to problem-based learning (PBL) for self directed learning in renal therapeutics. DESIGN: This 5-week course, designed for large student cohorts using minimal teaching resources, was based on a series of case studies and subsequent pharmaceutical care plans, followed by intensive and regular feedback from the instructor. ASSESSMENT: Assessment of achievement of the learning outcomes was based on weekly-graded care plans and peer review assessment, allowing each student to judge the contributions of each group member and their own, along with a written case-study based examination. The pharmaceutical care plan template, designed using a "tick-box" system, significantly reduced staff time for feedback and scoring. CONCLUSION: The proposed instructional model achieved the desired learning outcomes with appropriate student feedback, while promoting skills that are essential for the students' future careers as health care professionals. PMID- 21301608 TI - Reflections on a decade of progress in pharmacy education: reasons for celebration. PMID- 21301609 TI - Poliomyelitis: the ghastly continuation of a global public health menace. PMID- 21301610 TI - Pharmacy students' exposure to a culture of safety and their communication of medication errors. PMID- 21301612 TI - The National Association of Boards of Pharmacy response to "Pharmacist licensure: time to step it up?". PMID- 21301614 TI - When preceptors fail their students. PMID- 21301615 TI - Legal issues in pharmacy education: making the case for engaging university counsel. PMID- 21301616 TI - Critical considerations in pharmacy curriculum development in South Asian and Southeast Asian developing nations. PMID- 21301617 TI - Cardiologists in training: be prepared for exams!: The only good is knowledge, the only evil is ignorance (Socrates). PMID- 21301618 TI - The role of echocardiography in patient selection for CRT: the switch from motion to understanding regional ventricular function. PMID- 21301619 TI - Peak longitudinal strain delay is superior to TDI in the selection of patients for resynchronisation therapy. AB - BACKGROUND: Mechanical dyssynchrony has proven to be superior to QRS duration in predicting response to cardiac resynchronisation therapy (CRT). Whether time to peak longitudinal strain delay between the mid-septum and mid-lateral left ventricular wall better predicts CRT response than tissue Doppler imaging (TDI) is unclear. This study compares the value of the two methods for the assessment of mechanical dyssynchrony and prediction of CRT responders. METHODS: 66 clinical responders and 17 nonresponders to CRT with severe systolic heart failure (LVEF <35%), New York Heart Association classification III or IV and a wide QRS >130 ms with left bundle branch block were evaluated by peak longitudinal strain and TDI. Doppler echocardiograms and electromechanical time delay (EMD) intervals were acquired before and after pacemaker implantation. RESULTS: In all responders EMD measured by peak longitudinal strain was >60 ms before implantation, compared with 76% of the patients measured by TDI. Nonresponders had EMD <60 ms measured by both techniques. Only peak longitudinal strain delay showed shortened values in every responder postimplantation and demonstrated the most significant reduction and could predict responders to CRT. However, EMD measured by TDI did not diminish in 30% of the positive clinical responders. Nonresponders showed worsening of the EMD with peak longitudinal strain, but not with TDI. CONCLUSIONS: Responders to CRT can be excellently predicted if EMD before implantation determined by peak longitudinal strain delay is >60 ms. Peak longitudinal strain delay appears to be superior to TDI to predict the response to CRT. (Neth Heart J 2010;18:574-82.). PMID- 21301620 TI - Recurrent and founder mutations in the Netherlands : Plakophilin-2 p.Arg79X mutation causing arrhythmogenic right ventricular cardiomyopathy/dysplasia. AB - BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited cardiac disease with reduced penetrance and a highly variable expression. Mutations in the gene encoding the plakophilin-2 gene (PKP2) are detected in about 50% of ARVC/D patients. The p.Arg79X mutation in PKP2 has been identified in Europe and North America and has been functionally characterised. We evaluated the prevalence of the p.Arg79X mutation in PKP2 in the Dutch population. METHODS: Twelve index patients and 41 family members were evaluated in three university hospitals in the Netherlands. The diagnosis of ARVC/D was established according to the recently revised Task Force Criteria. Segregation of the p.Arg79X mutation was studied and haplotypes were reconstructed to determine whether the p.Arg79X mutation was a recurrent or a founder mutation. RESULTS: The p.Arg79X mutation in PKP2 was identified in 12 index patients. Haplotype analysis revealed a shared haplotype among Dutch p.Arg79X mutation carriers, indicating a common founder. Six index patients (50%) had a first- or second-degree relative who had died of sudden cardiac death below 40 years of age. At age 60, only 60% of the mutation carriers had experienced any symptoms. There was no significant difference in symptom-free survival and event-free survival between men and women. CONCLUSION: We have identified the largest series of patients with the same desmosome gene mutation in ARVC/D reported to date. This p.Arg79X mutation in PKP2 is a founder mutation in the Dutch population. The phenotypes of PKP2 p.Arg79X mutation carriers illustrate the clinical variability and reduced penetrance often seen in ARVC/D. (Neth Heart J 2010;18:583-91.). PMID- 21301621 TI - A comparison between upfront high-dose tirofiban versus provisional use in the real-world of non-selected STEMI patients undergoing primary PCI: Insights from the Zwolle acute myocardial infarction registry. AB - BACKGROUND: Despite the proven benefit of glycoprotein IIb/IIIa blockers in patients with acute ST-segment elevation myocardial infarction (STEMI), there is still debate on the timing of administration of these drugs and whether all or only a selection of patients should be treated. We evaluated the effect of routine upfront versus provisional use of high-dose tirofiban (HDT) in a large real-world population of non-selected STEMI patients. METHODS: Consecutive STEMI patients were registered in a single-centre dedicated database. Patients with upfront HDT therapy before first balloon inflation were compared with patients who received the drug on a provisional basis, after first balloon inflation. Initial TIMI flow of the infarct-related vessel and enzymatic infarct size and 30 day clinical outcome were assessed. RESULTS: Out of 2679 primary PCI patients HDT was given upfront in 885 (33.0%) and provisionally in 812 (45.3%). Upfront as compared with provisional HDT showed higher initial patency (22.3 vs. 17.9%, p=0.006), smaller infarct size (1401 IU/l (IQR 609 to 2948) vs. 1620 (753 to 3132), p=0.03) and a lower incidence of death or recurrent MI at 30 days (3.3 vs. 5.1%, p=0.04) without an increase in TIMI bleeding (p=0.24). Upfront HDT independently predicted initial patency (odds ratio (OR) 1.47, 95% confidence interval (CI) 1.15 to 1.88, p=0.02), enzymatic infarct size (OR 0.70, 95% CI 0.56 to 0.86, p=0.001) and 30-day death or recurrent MI (OR 0.59, 95% CI 0.37 to 0.95, p=0.03). CONCLUSION: Our findings support the use of upfront potent antiplatelet and antithrombotic therapy in STEMI patients and encourage further clinical investigations in this field. (Neth Heart J 2010;18:592-7.). PMID- 21301623 TI - Left ventricular dysfunction due to right ventricular stimulation: is biventricular upgrade really necessary? AB - Left ventricular (LV) dysfunction can occur due to chronic right ventricular apical pacing. Upgrading of the pacemaker to biventricular pacing is an option to reverse LV dysfunction but reprogramming of the atrioventricular (AV) timing can also be favourable. In this case report we describe the effect of AV-time reprogramming in a patient with LV function deterioration that emerged two years after implantation of a dual chamber system for sick sinus syndrome. Echocardiographc studies demonstrated a tremendous improvement in LV function during two years follow-up whereas the percentage of right ventricular pacing diminished dramatically. Careful analysis of the cause of LV deterioration can avoid unnecessary upgrading to biventricular pacing. (Neth Heart J 2010;18:604 5.). PMID- 21301622 TI - Gender differences in coronary heart disease. AB - Cardiovascular disease develops 7 to 10 years later in women than in men and is still the major cause of death in women. The risk of heart disease in women is often underestimated due to the misperception that females are 'protected' against cardiovascular disease. The under-recognition of heart disease and differences in clinical presentation in women lead to less aggressive treatment strategies and a lower representation of women in clinical trials. Furthermore, self-awareness in women and identification of their cardiovascular risk factors needs more attention, which should result in a better prevention of cardiovascular events. In this review we summarise the major issues that are important in the diagnosis and treatment of coronary heart disease in women. (Neth Heart J 2010;18:598-603.). PMID- 21301624 TI - Immediate reduction of mitral regurgitation by percutaneous mitral valve repair with the MitraClip(r). PMID- 21301626 TI - Gastro-hep news. PMID- 21301625 TI - Cardiac gene expression profiling - the quest for an atrium-specific biomarker. AB - Biomarkers are gaining increasing interest to predict risk but also to aid in diagnostics. Tissue-specific biomarkers are of utmost importance to detect diseases of respective organs. As of yet there are no atrium-specific biomarkers for risk stratification of atrial disease, such as atrial fibrillation. Bioinformatics such as mRNA microarrays can help to detect tissue-enriched and possibly tissue-specific expressed genes that can be targets for biomarkers. We describe an approach to identify genes preferably expressed in atrial cardiomyocytes compared with ventricular cardiomyocytes by RNA microarray and confirmed by quantitative real-time polymerase chain reaction. By this approach we identified several atrium-enriched genes but also ventricle-enriched genes. As expected atrial natriuretic peptide (ANP) mRNA showed higher expression in atrial cardiomyocytes while with adrenergic stimulation expression was almost as high in ventricular as in atrial cells. Brain-type natriuretic peptide (BNP), however, was not different between atrial and ventricular cells giving a possible explanation for increased levels of NT-proBNP in atrial fibrillation patients. Interesting identified candidates are serpine1 and ltbp2 as atrium-enriched genes whereas alpha-adrenergic receptor subtype 1b and S100A1 expression was significantly higher in ventricular cells. The identified genes need to be confirmed in human tissue and might ultimately be tested as potential biomarkers for atrial stress. (Neth Heart J 2010;18:610-4.). PMID- 21301627 TI - Using CT and MR Enterography to Diagnose and Monitor IBD. PMID- 21301628 TI - Needle-knife papillotomy. PMID- 21301629 TI - Advances in diagnosis and treatment of cholangiocarcinomas. PMID- 21301630 TI - Management of total obstruction of the pharynx and upper esophagus. PMID- 21301631 TI - Mast cells in gastrointestinal disease. AB - The function of mast cells in allergic inflammatory reactions is well documented in the literature. Mast cells also play an important role in the regulation of gastrointestinal visceral sensitivity and vascular permeability. Several studies have noted an increased number of mast cells in the mucosa of patients with gastrointestinal diseases such as irritable bowel syndrome, mastocytic enterocolitis, and systemic mastocytosis. The role of mast cells in the symptomatology of these and other diseases has only recently been fully appreciated and could provide avenues for new therapeutic opportunities. This paper examines studies that have evaluated the role of mast cells in various gastrointestinal diseases. PMID- 21301633 TI - A foreign body larger than the overtube diameter: a case of a large cow foot bone causing esophageal impaction. PMID- 21301634 TI - The importance of preparation and innovation in the endoscopic management of esophageal foreign bodies. PMID- 21301632 TI - The obesity epidemic: challenges, health initiatives, and implications for gastroenterologists. AB - Obesity is the next major epidemiologic challenge facing today's doctors, with the annual allocation of healthcare resources for the disease and related comorbidities projected to exceed $150 billion in the United States. The incidence of obesity has risen in the United States over the past 30 years; 60% of adults are currently either obese or overweight. Obesity is associated with a higher incidence of a number of diseases, including diabetes, cardiovascular disease, and cancer. Consumption of fast food, trans fatty acids (TFAs), and fructose-combined with increasing portion sizes and decreased physical activity has been implicated as a potential contributing factor in the obesity crisis. The use of body mass index (BMI) alone is of limited utility for predicting adverse cardiovascular outcomes, but the utility of this measure may be strengthened when combined with waist circumference and other anthropomorphic measurements. Certain public health initiatives have helped to identify and reduce some of the factors contributing to obesity. In New York City and Denmark, for example, such initiatives have succeeded in passing legislation to reduce or remove TFAs from residents' diets. The obesity epidemic will likely change practice for gastroenterologists, as shifts will be seen in the incidence of obesity-related gastrointestinal disorders, disease severity, and the nature of comorbidities. The experience gained with previous epidemiologic problems such as smoking should help involved parties to expand needed health initiatives and increase the likelihood of preventing future generations from suffering the consequences of obesity. PMID- 21301635 TI - Magnetoacoustic imaging of human liver tumor with magnetic induction. AB - Magnetoacoustic tomography with magnetic induction (MAT-MI) is an imaging technique under development to achieve imaging of electrical impedance contrast in biological tissues with spatial resolution close to ultrasound imaging. However, previously reported MAT-MI experimental results are obtained either from low salinity gel phantoms, or from normal animal tissue samples. In this study, we report the experimental study on the performance of the MAT-MI imaging method for imaging in vitro human liver tumor tissue. The present promising experimental results suggest the feasibility of MAT-MI to image electrical impedance contrast between the cancerous tissue and its surrounding normal tissues. PMID- 21301636 TI - Droplet charging regimes for ultrasonic atomization of a liquid electrolyte in an external electric field. AB - Distinct regimes of droplet charging, determined by the dominant charge transport process, are identified for an ultrasonic droplet ejector using electrohydrodynamic computational simulations, a fundamental scale analysis, and experimental measurements. The regimes of droplet charging are determined by the relative magnitudes of the dimensionless Strouhal and electric Reynolds numbers, which are a function of the process (pressure forcing), advection, and charge relaxation time scales for charge transport. Optimal (net maximum) droplet charging has been identified to exist for conditions in which the electric Reynolds number is of the order of the inverse Strouhal number, i.e., the charge relaxation time is on the order of the pressure forcing (droplet formation) time scale. The conditions necessary for optimal droplet charging have been identified as a function of the dimensionless Debye number (i.e., liquid conductivity), external electric field (magnitude and duration), and atomization drive signal (frequency and amplitude). The specific regime of droplet charging also determines the functional relationship between droplet charge and charging electric field strength. The commonly expected linear relationship between droplet charge and external electric field strength is only found when either the inverse of the Strouhal number is less than the electric Reynolds number, i.e., the charge relaxation is slower than both the advection and external pressure forcing, or in the electrostatic limit, i.e., when charge relaxation is much faster than all other processes. The analysis provides a basic understanding of the dominant physics of droplet charging with implications to many important applications, such as electrospray mass spectrometry, ink jet printing, and drop on-demand manufacturing. PMID- 21301637 TI - Fourier-based magnetic induction tomography for mapping resistivity. AB - Magnetic induction tomography is used as an experimental tool for mapping the passive electromagnetic properties of conductors, with the potential for imaging biological tissues. Our numerical approach to solving the inverse problem is to obtain a Fourier expansion of the resistivity and the stream functions of the magnetic fields and eddy current density. Thus, we are able to solve the inverse problem of determining the resistivity from the applied and measured magnetic fields for a two-dimensional conducting plane. When we add noise to the measured magnetic field, we find the fidelity of the measured to the true resistivity is quite robust for increasing levels of noise and increasing distances of the applied and measured field coils from the conducting plane, when properly filtered. We conclude that Fourier methods provide a reliable alternative for solving the inverse problem. PMID- 21301638 TI - Problem with baby's hearing? An intervention checklist. PMID- 21301639 TI - Locked, loaded--and lethal. PMID- 21301640 TI - Texting tendinitis in a teenager. PMID- 21301641 TI - Warfarin therapy: tips and tools for better control. PMID- 21301642 TI - Which OC would you choose? Test your skills with these 3 cases. PMID- 21301643 TI - Clinical inquiries. Which medications benefit patients with diastolic heart failure? PMID- 21301644 TI - How I solved my e-prescribing dilemma. PMID- 21301645 TI - PURLs: Help for recurrent bacterial vaginosis. PMID- 21301646 TI - Alopecia with perifollicular papules and pustules. PMID- 21301647 TI - Clinical inquiries. Which nutritional therapies are safe and effective for depression? PMID- 21301648 TI - Clinical inquiries. What is the most effective treatment for acne rosacea? PMID- 21301649 TI - Quotes to remember... AB - At the GP10 conference, themed 'Shape our future', last month in Cairns, several of the workshops and presentations looked at minimising error in clinical practice. People are bound to make mistakes, but it is crucial that we learn from these and develop techniques to minimise their impact. Cicero once said, "To err is human, but to persevere in error is only the act of a fool." Our focus articles this month are based on the concept of 'traps for the unwary', and provide clinical topics that explore the issues of near misses, errors in practice, and gaining experience and expertise. PMID- 21301650 TI - General practice - engaging the online social networking revolution. AB - Current Australian health, hospital and primary care reforms, emphasise e-health strategies, including online communities and the electronic Person Controlled Health Record (ePCHR), as a means to improving patient support and self management of chronic disease. However, the benefits and risks of these tools to general practice are poorly understood. PMID- 21301651 TI - TIAs - management in general practice. AB - From April 2005 to March 2010 in the BEACH (Bettering the Evaluation and Care of Health) program, transient ischaemic attack (TIA) was managed in general practice at a rate of 2 per 1000 encounters, about 170,000 times per year nationally. PMID- 21301652 TI - Does it matter if I'm 'just' pregnant? AB - BACKGROUND: The time before a woman has confirmed her pregnancy is an important time for both the woman and her unborn baby's wellbeing. With the period of organogenesis largely occurring between the third and eighth week of development, early pregnancy is a time when a woman may have problems related to the pregnancy itself, or where diseases have a higher risk of morbidity in the woman or the fetus. Yet, the woman and her doctor, may be unaware of the pregnancy. OBJECTIVE: This article outlines presenting complaints where a doctor should specifically explore the possibility of early pregnancy in a woman in her reproductive years, as pregnancy may have an impact on the management, and ultimately the wellbeing, of both the woman and the fetus. DISCUSSION: Identification and appropriate management of the coexisting pregnancy and presenting condition allows the general practitioner to provide the most appropriate care in this clinical situation. PMID- 21301653 TI - Transient ischaemic attacks - assessment and management. AB - BACKGROUND: Transient ischaemic attacks (TIAs) can be challenging to diagnose, but early assessment and effective management can reduce the subsequent risk of stroke. OBJECTIVE: This article reviews the assessment and management of TIAs for general practitioners. DISCUSSION: Transient ischaemic attacks can be a trap for the unwary, with difficulty in making a diagnosis and varied assessment and management pathways. There is a significant risk of subsequent stroke. Early assessment and initiation of treatment, which can take place in the general practice setting, could lower the risk of stroke. Liaising with regional stroke care centres is required to establish an optimal pathway of care. PMID- 21301654 TI - Small dose... big poison. AB - BACKGROUND: It is not possible to identify all toxic substances in a single journal article. However, there are some exposures that in small doses are potentially fatal. Many of these exposures are particularly toxic to children. Using data from poison control centres, it is possible to recognise this group of exposures. OBJECTIVE: This article provides information to assist the general practitioner to identify potential toxic substance exposures in children. DISCUSSION: In this article the authors report the signs and symptoms of toxic exposures and identify the time of onset. Where clear recommendations on the period of observation and known fatal dose are available, these are provided. We do not discuss management or disposition, and advise readers to contact the Poison Information Service or a toxicologist for this advice. PMID- 21301655 TI - Addison disease - diagnosis and initial management. AB - BACKGROUND: Adrenal insufficiency is a rare disease caused by either primary adrenal failure (Addison disease) or by impairment of the hypothalamic-pituitary adrenal axis. Steroid replacement therapy normalises quality of life, however, adherence can be problematic. OBJECTIVE: This article provides information on adrenal insufficiency focusing on awareness of initial symptoms and on risk scenarios, emergency management and baseline investigations, complete investigations and long term management. DISCUSSION: Early recognition of adrenal insufficiency is essential to avoid associated morbidity and mortality. Initial diagnosis and decision to treat are based on history and physical examination. Appropriate management includes emergency resuscitation and steroid administration. Initial investigations can include sodium, potassium and blood glucose levels. However, complete investigations can be deferred. Specialist advice should be obtained and long term management includes a Team Care Arrangement. For patients, an emergency plan and emergency identification are essential. PMID- 21301656 TI - Intravenous iron replacement - management in general practice. AB - BACKGROUND: Iron deficiency is one of the most common nutritional deficiencies in Australia, and remains one of the most underdiagnosed conditions in general practice. The consequences of this condition can be subtle and the cause is often multifactorial. OBJECTIVE: The aim of this article is to review the safety of parenteral iron replacement therapy, and specifically intravenous infusion, in the general practice setting. The results of a recent clinical evaluation of 43 consecutive adult patients are reported. DISCUSSION: Intravenous iron polymaltose infusions are commonly used in the hospital setting with low rates of reported adverse reactions (including low rates of anaphylaxis and anaphylactoid reactions). In a primary care setting, patients were given low dose intravenous iron polymaltose as a slow injection diluted with normal saline, following a diagnosis of iron deficiency or iron depletion, with or without anaemia. Injections were given at intervals no more frequently than weekly. Serum ferritin levels were monitored following treatment, and as routine follow up. A total of 89 injections of intravenous iron were used in 43 patients. No serious adverse reactions occurred. The administration of low dose parenteral iron polymaltose in the primary care setting is well tolerated and is potentially a cost effective alternative to specialist care and hospital admissions. PMID- 21301657 TI - Patients living with cancer - the role of rehabilitation. AB - BACKGROUND: Patients are surviving longer with cancer due to early detection and improvements in treatment. With longer survival, quality of life becomes very important. While improvements in treatment add years to the life of patients diagnosed with cancer, rehabilitation can add life to those years. OBJECTIVE: This article highlights the role rehabilitation can play in enhancing the quality of life for patients living with cancer. DISCUSSION: There are an increasing number of cancer survivors, creating the imperative to look beyond just survival. Potentially remediable problems may include pain, deconditioning and functional impairments. Patients with cancers of the breast, head and neck, musculoskeletal, central nervous system and peripheral nervous system, prostate, and metastatic cancer of the spine may particularly benefit from rehabilitation. Active engagement of oncologists, palliative medicine, general practitioners and rehabilitation specialists can be useful to assist in the rehabilitation needs of patients. In appropriate situations, patients with cancer should be offered rehabilitation services if they are likely to benefit. PMID- 21301658 TI - Typhoid and paratyphoid fever - prevention in travellers. AB - This article forms part of our travel medicine series for 2010, providing a summary of prevention strategies and vaccinations for infections that may be acquired by travellers. The series aims to provide practical strategies to assist general practitioners in giving travel advice, as a synthesis of multiple information sources which must otherwise be consulted. BACKGROUND: Typhoid and paratyphoid (enteric) fever, a potentially severe systemic febrile illness endemic in developing countries, is associated with poor sanitation, reduced access to treated drinking water and poor food hygiene. It is one of the leading causes of infectious disease in the developing world. OBJECTIVE: This article discusses the clinical features and prevention opportunities for typhoid and paratyphoid fever. DISCUSSION: Travellers to developing countries are at risk of infection. This risk varies from 1:30 000 for prolonged stays in endemic regions to 1:3000 in high endemicity areas such as the Indian subcontinent, where risk is highest. The mainstay of prevention is hygiene and food and water precautions. Vaccines against typhoid fever are discussed. However, when used alone they provide incomplete protection. Treatment and future developments in typhoid fever diagnostics and vaccines are also briefly discussed to provide a general overview of typhoid fever and its prevention for use in travel related consultations in general practice. PMID- 21301659 TI - General practice as a fortress - occupational violence and general practice receptionists. AB - BACKGROUND: Occupational violence is well documented among general practice receptionists, who are singularly vulnerable because they are placed in the general practice 'frontline'. One response to this threat has been to physically isolate reception staff from waiting room patients by having a perspex shield at the reception desk and a locked door between waiting room and staff areas. METHOD: A qualitative study employing semistructured interviews, an inductive approach and a thematic analysis. The study explored the experiences and perceptions of three receptionists who work in a practice with a perspex and lockdown system, and 16 who work in practices without these. RESULTS: Receptionists were universally positive about the safety measures for reducing risk. But there was also a view that these safety measures potentially compromise the feeling of a practice being patient centred by alienating patients from staff and, paradoxically, increasing levels of patient violence and staff fearfulness. DISCUSSION: These safety measures, while viewed positively by receptionists, may have adverse effects on patient-staff relationships and exacerbate violence and increase staff fearfulness. PMID- 21301660 TI - Establishing the Victorian Primary Care Practice Based Research Network. AB - BACKGROUND: Practice based research networks comprise research academics and primary care practitioners who have the mutual goal of supporting the development and implementation of research that is necessary to build the evidence base that informs both primary healthcare practitioners and policy makers. This article describes the establishment of the Victorian Primary Care Practice Based Research Network (VicReN), which was established in 2007 and has grown to over 100 members. METHOD: The aim of this article is to discuss the key factors in the development of the organisational structure of VicReN, and to describe the outcome measures used to evaluate the network. RESULTS: VicReN has a diverse primary care membership. Members' different research needs have been addressed through numerous capacity building activities. The absence of core funding beyond the development phase has led to an innovative funding model. DISCUSSION: This article outlines a viable and sustainable background practice based research network model in the Australian environment that may assist other academic departments of general practice and rural health interested in establishing a practice based research network. PMID- 21301661 TI - Predicting central sensitisation - whiplash patients. AB - BACKGROUND: Central sensitisation is associated with chronic pain in whiplash patients. Predicting which patients will develop central sensitisation is difficult but patient expectations of recovery predict a variety of outcomes in whiplash patients. METHOD: Ninety-one whiplash patients were assessed within 1 week of their collision in order to ascertain their expectations of recovery and were then re-examined 3 months later with the Brachial Plexus Provocation Test (BPPT) as a sign of central sensitisation. RESULTS: Adjusting for a number of predictors, patient expectation of recovery was found to predict the results of the BPPT. Subjects who expected 'to get better soon' had a BPPT angle that was 42 degrees less (ie. closer to normal or full range) than any of the subjects who had poor recovery expectations. DISCUSSION: Whiplash patients who expect 'never to get better' or 'don't know' have a much higher likelihood of developing at least one sign of central sensitisation 3 months after their collision. PMID- 21301662 TI - Failure to diagnose: diabetic ketoacidosis. AB - A recent coronial inquest examined the death of a patient, 17 years of age, from fulminant diabetic ketoacidosis.1 The patient's presentation with diabetic ketoacidosis was the first manifestation of the onset of type 1 diabetes. This article examines the Coroner's findings and recommendations. PMID- 21301663 TI - Linking the RACGP curriculum to vocational education. AB - Regional training providers face many challenges in delivering vocational training to general practice registrars across Australia. They need to be able to respond to new learning theories and the ever expanding volume of medical knowledge, as well as the changing medical workforce. In 2008, the Victorian Metropolitan Alliance (VMA) embarked on a project to map the new Royal Australian College of General Practitioners curriculum to the VMA program. The aim of this article is to describe the processes through which the VMA created a curriculum guide for peer learning workshops, supervisors and registrars, designed to be adaptable to various Australian curricula and to be flexible and robust, as well as accessible to the intended users. PMID- 21301664 TI - Take heart general practice. AB - There has been recent passionate email discussion by members of the Australian Association for Academic Primary Care about the 'invisibility' of general practice research. PMID- 21301665 TI - The healthcare reform agenda - a key role for GPs. AB - Despite successive 'top down' reform initiatives, healthcare in Australia continues to be conducted as a series of silos with separate control and regulatory processes, and funding streams, which reflects that isolated high level change is ineffective in addressing current and future challenges in healthcare delivery. Questions are raised about which approaches might help deliver reform imperatives. As the first point of contact general practitioners are healthcare 'gatekeepers', and how they perceive change is fundamental to delivering comprehensive, coordinated and continuing healthcare strategy. PMID- 21301666 TI - Chronic heart failure - management in general practice. AB - From April 2005 to March 2010 in BEACH (Bettering the Evaluation and Care of Health), chronic heart failure (CHF) was managed at a rate of 0.7 per 100 encounters, suggesting it was managed by general practitioners about 717,000 times per year nationally. PMID- 21301667 TI - Heart failure management - a team based approach. AB - BACKGROUND: Chronic heart failure (CHF) is an important condition that requires complex treatment and management. OBJECTIVE: This article outlines the key benefits of a team based approach to CHF management and the role of the different health professionals involved, including a central role for the patient's general practitioner. DISCUSSION: Specific management programs are designed to improve CHF related outcomes such as reducing hospitalisation rates and prolonging survival. There are many components to these programs and a team based approach is arguably the most important. Programs that apply multidisciplinary care (either via dedicated CHF clinics or community based teams) are consistently superior to those supplied by an individual. PMID- 21301668 TI - Chronic heart failure - improving life with modern therapies. AB - BACKGROUND: Chronic heart failure (CHF) is an increasingly common condition with increasing prevalence in the aging population. It has a significant mortality and is associated with a high incidence of hospitalisation and morbidity. OBJECTIVE: This article describes the aspects of modern therapy that can improve survival, reduce hospitalisation and improve quality of life for CHF patients. DISCUSSION: A careful history, physical examination and judicious investigation (including chest X-ray, electrocardiogram, complete blood profile and echocardiogram) can often identify the cause of CHF, the severity of CHF and help guide management. Treatments which have been shown to be of significant benefit include angiotensin converting enzyme inhibitors, beta-blockers, aldosterone antagonists and angiotensin receptor blockers. Loop diuretics, nitrates, digoxin, hydralazine and amiodarone may be used when patients do not respond to initial therapy. Review by a cardiologist is often useful to exclude myocardial ischaemia and to perform echocardiography which is a key investigation in assessment of CHF patients. Ongoing regular review with uptitration of medications to achieve target blood pressure and pulse and exclude exacerbating conditions can lead to improvements in care and facilitate successful outcomes in CHF patients who are often very unwell. PMID- 21301669 TI - Echocardiography in heart failure - a guide for general practice. AB - BACKGROUND: Echocardiography is an essential investigation in patients with suspected heart failure. An echocardiogram provides assessment of cardiac chamber size and structure, ventricular function, valvular function and key haemodynamic parameters. OBJECTIVE: This article explains the principles of echocardiography and how general practitioners can use echocardiograms to manage patients with heart failure. DISCUSSION: Echocardiography can provide diagnostic information about the cause of heart failure, and may indicate what further investigations are required and what therapy is indicated. It may also provide important prognostic information. It can be used for noninvasive quantitative monitoring. Identification of impaired systolic function is important as there is evidence based therapy which can improve prognosis in this condition. PMID- 21301670 TI - Acute pulmonary oedema - management in general practice. AB - BACKGROUND: Acute pulmonary oedema is a life threatening emergency that requires immediate intervention with a management plan and an evidence based treatment protocol. OBJECTIVE: This article describes the features, causes, prevalence and prognosis of heart failure and the management of acute pulmonary oedema. DISCUSSION: Presentations of acute pulmonary oedema and acute heart failure to general practice require a coordinated and urgent response. Initial assessment, management and monitoring should occur concurrently and must be modified in response to clinical changes. PMID- 21301671 TI - End stage heart failure patients - palliative care in general practice. AB - BACKGROUND: Chronic heart failure is common, particularly in older individuals, and comorbidities are frequent. Patients with end stage heart failure can be highly symptomatic and require careful monitoring and treatment adjustment to improve symptoms. OBJECTIVE: This article summarises the fundamentals of implementing palliative care in general practice and provides guidelines on caring for chronic heart failure patients at the end of life. DISCUSSION: The high mortality in chronic heart failure underscores the importance of effective communication, symptom management and advanced care planning. The unpredictability and uncertainty around the timing of death mean that individuals, and their families, may be less likely to have an understanding of their prognosis or have access to supportive and palliative care. Ideally, patients with symptomatic chronic heart failure should be managed in collaboration with a multidisciplinary heart failure program. Symptom management can be achieved by additive therapies and access to specialist palliative care services should be considered when the symptom burden is high. PMID- 21301672 TI - Hepatitis A - prevention in travellers. AB - BACKGROUND: Hepatitis A is the second most common vaccine preventable infection in travellers. Highly effective vaccines exist for its prevention for travellers from 12 months of age, including last minute travellers and those in special risk groups. OBJECTIVE: Information about hepatitis A infection, its epidemiology and existing vaccine options is presented for use in travel related consultations in general practice. DISCUSSION: Most travellers at risk of hepatitis A should be vaccinated, as the vaccine is a safe and effective means of prevention. Combination vaccines - hepatitis A/hepatitis B and hepatitis A/typhoid - aim to facilitate the vaccination process for travellers, who are often also at risk of exposure to hepatitis B and typhoid fever. PMID- 21301673 TI - Manning up for men's mental illness. AB - Depression is often positioned as a woman's disease, in part due to the recognition of a lower incidence of depression among men compared to women. However, downstream indicators including men's self harm and suicide suggest that depression may be less often diagnosed because men tend to deny illness, self monitor and treat symptoms, and avoid health services or have difficulty engaging care providers. As a result, men's depression, including how to identify and treat it, is poorly understood. This case study highlights some of the more common features of depression in men. PMID- 21301674 TI - Treating common warts - options and evidence. AB - BACKGROUND: Nongenital warts are a common condition seen in general practice, affecting patients of all ages. There are many treatment options and patients often self medicate with remedies from folklore or tradition before presenting to their doctor. OBJECTIVE: This article attempts to summarise the quality of different treatments and to provide recommendations and a quick reference for treating common warts. DISCUSSION: Many common warts will resolve spontaneously but others are recalcitrant and often require ongoing treatment beyond first line measures. Without definite guidelines for treating recalcitrant warts, it is important for the general practitioner to consider the available evidence for efficacy and contraindication of the various treatment options. PMID- 21301675 TI - Hereditary haemochromatosis - diagnosis and management. AB - BACKGROUND: Hereditary haemochromatosis is a common inherited disorder in which excessive iron is absorbed and which, over time, may cause organ damage. Genetic predisposition leads to disease in some but not all cases. OBJECTIVE: This article discusses the presentation, testing, treatment and management of hereditary haemochromatosis. DISCUSSION: Hereditary haemochromatosis is autosomal recessive and is more common in people of Celtic or northern European descent. Although more than 90% of cases of hereditary haemochromatosis are due to C282Y homozygosity (carrying two copies of the C282Y gene) not all C282Y homozygous individuals will progress through all stages of disease development. Clinical disease is less common in females due to physiological blood loss from menstruation and pregnancy. Most importantly, early diagnosis and treatment of hereditary haemochromatosis prevents complications and results in a normal life expectancy. Venesection is a simple and effective way to both prevent and manage the potential sequelae of iron overload, which include severe fatigue, arthritis, impotence, raised alanine aminotransferase/aspartate aminotransferase, fibrosis or cirrhosis, diabetes, and cardiomyopathy. PMID- 21301676 TI - A persistent sore throat. PMID- 21301677 TI - Complementary medicine in general practice - a national survey of GP attitudes and knowledge. AB - BACKGROUND: Integrative medicine is a holistic approach to patient care that utilises both conventional and complementary therapy. This article compares the demographics of Australian general practitioners who do, and those who do not, practise integrative medicine, and their perceptions and knowledge about complementary medicines. METHODS: A postal survey sent to a random sample of 4032 Australian GPs. RESULTS: Data from 1178 GPs was analysed. While GPs who practise integrative medicine were more knowledgeable about complementary medicine and more aware of potential adverse reactions, there were significant knowledge gaps for both groups. DISCUSSION: Many GPs incorporate complementary medicines into their practice, whether or not they identify with the 'integrative medicine' label. General practitioners need to be well informed about the evidence base for, and potential risks of, complementary medicines to ensure effective decision making. Use of available resources and inclusion of complementary medicine in education programs may assist this. PMID- 21301678 TI - Lifestyle risk factors in general practice - routine assessment and management. AB - BACKGROUND: Evidence based guidelines recommend that adults be assessed for modifiable lifestyle risk factors: smoking, nutrition, alcohol and physical activity (SNAP) regularly. This article discusses the routine practices of GPs regarding assessment and management of these risk factors. OBJECTIVE: General practitioners participating in two randomised controlled trials completed questionnaires about their assessment and management of SNAP risk factors. RESULTS: Over half of the GPs usually assessed smoking and alcohol, and assessed a patient's readiness to change before offering advice. Diet and activity were assessed less frequently, with only 22% usually assessing diet and 28% usually assessing activity. Referral rates were low, with less than 10% of GPs reporting that they usually referred patients to programs. Less than 20% of GPs reported having difficulty referring to programs. DISCUSSION: Chronic disease risk factors are common in the Australian population, and GPs are ideally placed to offer assessment, advice and referral to services and programs. Recent changes to Medicare rebates for prevention activity may encourage a greater focus on prevention. PMID- 21301679 TI - Cardiovascular absolute risk assessment and management - engagement and outcomes in general practice patients. AB - Despite a decline in recent decades, cardiovascular disease (CVD) remains the major cause of death and disability in Australia. To improve primary prevention of CVD, many clinical guidelines recommend using cardiovascular absolute risk (CVAR) assessment to guide risk factor management. Cardiovascular absolute risk assessment predicts the overall risk of a cardiovascular event over a given time period (usually 5 or 10 years). However, use of CVAR is limited and has not been incorporated well in routine general practice. There has been little research on CVAR implementation and an effective implementation strategy has been lacking. PMID- 21301680 TI - Mailing GP reply letters after psychiatric assessment - a pilot randomised controlled trial. AB - BACKGROUND: Patients are not always fully aware of the details of their assessment and management plan detailed in the letter sent from the specialist to the general practitioner following referral. One approach to solving this problem is for the specialist to copy the GP reply letter to the patient. OBJECTIVE: To determine whether receiving a copy of the GP reply letter improves outcomes in patients referred by their GP for a psychiatric assessment. METHODS: A single blinded randomised control trial comparing outcomes following a one-off consultation for a depressive and/or anxiety disorder in patients who received the GP reply letter sent from a community mental health service, to patients who did not. RESULTS: Data was collected for 21 letter recipients and 18 control participants. A significant group by time interaction found total DASS-21 scores improved to a greater extent for the letter recipient group, no significant difference in adherence was found. PMID- 21301681 TI - Fostering registrar research - a model to overcome barriers. AB - BACKGROUND: Research and critical thinking are essential skills for general practitioners. However, evidence indicates that GPs tend to lack confidence in their research ability. Regional training providers can address this by integrating primary care research education and skills development into their general practice training programs. OBJECTIVE: The Adelaide to Outback GP Training Program developed a model that aims to overcome existing barriers to GP research and to promote a research culture across the organisation. It includes a research and critical thinking program for all registrars, a support structure for registrars wanting to extend their research expertise, and an organisational structure to promote and support research for registrars as well as throughout the organisation. DISCUSSION: Since the implementation of the model there has been an increase in the frequency and quality of research outcomes at the Adelaide to Outback GP Training Program. PMID- 21301682 TI - Healthcare teams - a practical framework for integration. AB - BACKGROUND: Delivering integrated team care is a major priority for many countries. In Australia this is a component of the GP Super Clinic Program but it is also a focus of the broader primary care sector. Explicit consideration of human dynamics and team process is often absent from the move to integrated team care. OBJECTIVE: To provide a practical framework that will inform the development and evaluation of integrated healthcare teams. DISCUSSION: The Team Focused and Clinical Content Framework is an approach to building integrated teams. This has the potential to be used to monitor and evaluate team development and functioning. Both the framework and clinical pathways provide practical tools for clinics to address the need to build integration into teams. PMID- 21301683 TI - GPs with special interests - impacting on complex diabetes care. AB - BACKGROUND: The growing prevalence and impact of type 2 diabetes mellitus is of international concern. OBJECTIVE: This article describes an innovative model of complex diabetes care, delivered by advanced skill general practitioners supported by an endocrinologist and diabetes educator within a general practice setting. DISCUSSION: Initial evaluation suggests a trend to better glycaemic control compared with the alternative available hospital outpatient care at a reduced delivery cost. A futuristic, integrated community/specialist model, delivered within a general practice setting, can deliver significant gains for Australians who have complex type 2 diabetes mellitus. PMID- 21301684 TI - Gaps, holes and change. AB - The start of a new year can be a time for reflection of the past and consideration of the future. Whether or not you are a fan of new year resolutions, there is usually something that you want to change. This issue of Australian Family Physician considers gaps in practice. Sometimes as general practitioners we know that there is a gap; sometimes our patients know that there is a gap; and sometimes there is a gap but no-one recognises that one exists. Sometimes we go along thinking that what we are doing is evidence based, and then get an unpleasant surprise when asked to justify 'what we always do'! PMID- 21301685 TI - Adaptability - building an academic workforce with GPs. AB - The University of Wollongong Graduate School of Medicine (UWGSM) opened in 2007. This is one of a new wave of medical schools to enable the more than doubling of the number of medical students graduating in the period from 2006-2014. However, this rapid expansion has exposed a relative paucity of experienced medical academics and the regional medical schools especially have found difficulty immediately attracting a full complement of academic staff. These schools have therefore sought to recruit locally and train staff who vary widely in previous experience in teaching. PMID- 21301686 TI - General practice - workforce gaps now and in 2020. AB - BACKGROUND: The general practice workforce required for Australia in the future will depend on many factors, including geographic areas and patient utilisation of general practice services. OBJECTIVE: This article examines the current and future general practice workforce requirements by way of an analysis of geographic areas accounting for differing patient utilisation. DISCUSSION: The results showed that, compared with major cities, inner regional areas had 24.4% higher expected patient general practice utilisation per general practitioner, outer regional 33.2%, and remote/very remote 21.4%. Balanced distribution would mean 1129 fewer GPs in major cities: 639 more in inner regional, 423 more in outer regional and 66 more in remote/very remote. With the population projected to increase 18.6-26.1% by 2020, expected general practice utilisation will increase by 27.0-33.1%. Initiatives addressing general practice workforce shortages should account for increasing general practice utilisation due to the aging population, or risk exacerbating the unequal distribution of general practice services. PMID- 21301687 TI - Indigenous health - a role for private general practice. AB - BACKGROUND: The Aboriginal and Torres Strait Islander life expectancy gap is associated with lower primary care usage by Indigenous Australians. Many Indigenous Australians regard private general practitioners as their usual source of healthcare. However, a range of barriers results in relatively low access to primary care, with subsequent inadequate prevention and management of chronic disease. Indigenous primary care requires development of a set of attributes by the GP. Clinician autonomy may need to be tempered to be responsive to the needs of local indigenous communities. OBJECTIVE: A partnership between an urban indigenous community and a private general practice is described. DISCUSSION: Over a period of 1 year, registered indigenous patients at the private general practice clinic increased from 10 to 147; monthly attendance increased from five to 40 (p<0.001). Local engagement between private practices and indigenous communities may be implemented widely to reduce the primary care gap. PMID- 21301688 TI - Appointments - getting it right. AB - BACKGROUND: Only 36% of sick Australians report being able to get an appointment on the day they need it, which is poor by international standards. This delay in care may impact on practice team morale, practice profitability and patient care. The Australian Primary Care Collaboratives Program aims to find better ways to provide primary healthcare services to patients through shared learning, peer support, training, education and support systems. OBJECTIVE: This article shares lessons from the Australian Primary Care Collaboratives Program that can help practices improve appointment scheduling. We describe steps to improving control of your practice scheduling - and your life - by measuring your practice demand, capacity and delay. DISCUSSION: Demand for appointments is finite, predictable and can be shaped. Delay is waste and the enemy of good healthcare. Where delay can be eliminated it should be. By measuring practice demand and capacity, improvements can be designed which will result in reduction in measured delay and patient unmet needs, and increased patient satisfaction. PMID- 21301689 TI - Why haven't I changed that? Therapeutic inertia in general practice. AB - BACKGROUND: There are multiple gaps between evidence and practice in our health system. The relatively new concept of 'therapeutic inertia' is useful to understand why these gaps persist. It is defined as 'failure of healthcare providers to initiate or intensify therapy when indicated' and 'recognition of the problem, but failure to act'. OBJECTIVE: This article explores the development of therapeutic inertia and its causes, and other concepts useful in closing gaps in general practice, including addressing emotional decisional making by doctors. DISCUSSION: Clinical inertia is the original term used to describe gaps in practice; and therapeutic inertia is now used interchangeably with it. The author illustrates his practice's approach to overcoming therapeutic inertia. The National Institute for Clinical Studies was set up in Australia to get the best available evidence from health and medical research into everyday practice to help close these gaps. PMID- 21301690 TI - Peer review - a safety and quality improvement initiative in a general practice. AB - BACKGROUND: A general practice in inner city Melbourne (Victoria), committed to ensuring quality standards of clinical care, developed a process for peer review of their doctors' performance. The aim was to ensure that there was a robust and fair process for evaluation of doctor performance from both a safety point of view, and from the perspective of contribution to team based practice. OBJECTIVE: This article describes the process and outcomes of this appraisal process. DISCUSSION: From the springboard of weekly clinical meetings which address critical incidents and near misses, the practice doctors developed an annual process of formal performance review incorporating hard and soft indicators of clinical performance and compliance with professional and practice standards. This type of activity falls within the scope of quality improvement in general practice. PMID- 21301691 TI - Management of severe asthma in children. AB - BACKGROUND: Asthma is the most common chronic disease of childhood and the leading cause of childhood morbidity from chronic disease. When uncontrolled, asthma can place significant limits on daily life, and is sometimes fatal. OBJECTIVE: This article describes the initial assessment and management of status asthmaticus in children. DISCUSSION: Status asthmaticus is a medical emergency in which asthma symptoms are refractory to initial bronchodilator therapy. Patients may report chest tightness, rapidly progressive shortness of breath, dry cough and wheezing. Typically, patients present a few days after the onset of a viral respiratory illness, following exposure to potent allergens or irritants, or after exercise in a cold environment, however, they can also present with sudden onset of symptoms with an unknown trigger. Early recognition and initiation of therapy is vital in preventing severe complications such as respiratory failure. Aggressive treatment with beta-agonists, anticholinergics and corticosteroids remains the gold standard for this condition. PMID- 21301692 TI - Recalcitrant nongenital warts. AB - Nongenital warts are a common presentation in general practice. Despite treatment according to evidence based guidelines, a significant proportion of common warts fail to resolve, becoming recalcitrant. This poses a problem in clinical management. The recommendations for treating recalcitrant warts are unclear and there is a wide range of second line treatments available. This article reviews the available methods of treatment for recalcitrant nongenital warts as described in the medical literature. PMID- 21301693 TI - Dual energy X-ray absorptiometry. AB - This article forms part of our 'Tests and results' series for 2011 which aims to provide information about common tests that general practitioners order regularly. It considers areas such as indications, what to tell the patient, what the test can and cannot tell you, and interpretation of results. Dual energy X ray absorptiometry (DXA) is the gold standard for diagnosing osteoporosis (OP). It uses X-rays at two energy levels and works on the principle that, as X-rays pass through body tissues they are attenuated to a different extent in different tissue types. The result - the bone mineral density (BMD) - can be reported at a number of sites. The most clinically useful are the lumbar spine, femoral neck and total hip (also termed the 'proximal femur'). PMID- 21301694 TI - Bone density testing. Patient information. PMID- 21301695 TI - Mallet finger - management and patient compliance. AB - BACKGROUND: Mallet finger is a flexion deformity of the finger resulting from injury to the extensor mechanism at the base of the distal phalanx. OBJECTIVE: This article discusses the current clinical assessment and appropriate management of mallet finger injuries. DISCUSSION: Mallet finger usually results from forced flexion of an extended finger. Treatment can be difficult as patient compliance is essential, and if not treated appropriately the injury can lead to permanent deformity. Patients will present with a flexion deformity of, and inability to actively extend, the distal interphalangeal joint. Closed mallet finger injuries are managed in a strict extension or hyperextension immobilisation splint for 8 weeks. Surgery is reserved for injuries involving fracture to greater than 30% of the articular surface, volar subluxation of the distal phalanx, avulsed fragments that fail reduction, injuries failing conservative management, and absence of full passive extension of the joint. Early referral is recommended if there is any concern. PMID- 21301696 TI - Making a difference - are you game? AB - Many 'bag carrying' general practitioners believe there is a gulf between the ivory tower of academia and the coalface of every day general practice. However, there are ways to share common ground. Many GPs are searching for an extra rewarding dimension to clinical work. They see things happening in their practice, have opinions, make changes and like to have a forum to discuss these thoughts with other like-minded GPs and primary care academics. PMID- 21301697 TI - Procedural skills in general practice vocational training - what should be taught? AB - BACKGROUND: A list of procedural skills is an important component of a curriculum for general practice vocational training. This study aimed to establish an up-to date list of core procedural skills that doctors undergoing general practice vocational training should be taught. METHOD: A Delphi process was used to rank the importance of 185 general practice procedures. In 2009, 31 general practitioners took part in a two round Delphi process. A 4-point Likert scale was used to rate the importance of each procedure in vocational training. RESULTS: Mean rating scores for all the procedural items listed were determined, and a core list of 112 procedures was agreed on the basis of the relative importance of procedures determined by the Delphi participants. DISCUSSION: The ranked list of clinical procedures provides a resource to form the basis of a procedures training curriculum which can be adapted to different general practice training contexts. PMID- 21301698 TI - Screening for physical inactivity in general practice - a test of diagnostic accuracy. AB - BACKGROUND: It is unclear what is the best method of accurately identifying physically inactive patients in general practice. This study aimed to compare the performance of different methods of assessing patient physical activity levels in general practice. OBJECTIVE: Thirteen general practitioners were randomly allocated to perform either their usual assessment, or this with a Lifescripts tool, on consecutive patients. The authors measured patients' physical activity by accelerometer over 1 week, including steps per day, then calculated agreement, kappa specificity, sensitivity, positive and negative predictive value (PV) and ROC characteristics for each assessment method (GPs' usual assessment, Lifescripts tool and steps per day) against the reference standard of accelerometer classification. RESULTS: Data from 29 patients was included. Agreement between subjective assessments was highest for GPs' usual assessment (agreement 73%; kappa 0.47; p=0.03), which also gave the highest area under the ROC curve (0.75, 95% CI: 0.52-0.98). However, this still had low specificity (67%) and positive PV (63%). Using a cut-off of 7500 steps/day maximised the area under the ROC curve at 0.91 (95% CI: 0.82-1.00), 19.2% greater than GPs' usual assessment. CONCLUSION: Measuring steps per day may be a feasible and more effective way to screen for physically inactive patients than self report. A large scale study to confirm these results is necessary. PMID- 21301699 TI - Teaching procedural skills in general practice. AB - BACKGROUND: General practitioners need the skills to perform a core set of procedures. The increase in community based medical education gives GPs more opportunity and responsibility to facilitate medical students and junior doctors' acquisition of these core skills. OBJECTIVE: This article summarises how procedural skills are learned and describes a practical framework for constructing a supportive learning environment that is safe for patients and learners. DISCUSSION: Procedural skills are learned in stages starting with a 'big picture' concept of the skill and its place in clinical care. Next the skill becomes fixed through deliberate practice with specific, constructive feedback based on observation. Autonomous practice is reached after further practice and exposure to increased complexity. General practitioners can facilitate skill development by using a staged learning cycle, building on their learner's prior knowledge and skill. PMID- 21301700 TI - Sickness certification. AB - This article forms part of our 'Paperwork' series for 2011, providing information about a range of paperwork that general practitioners complete regularly. The aim of the series is to provide information on the purpose of the paperwork, and hints on how to complete it accurately. This will allow the GP to be more efficient and the patient to have an accurately completed piece of paperwork for the purpose required. Sickness certificates are legal documents. Medical boards receive numerous complaints each year from patients, employers, insurers and other parties about the quality and accuracy of sickness certificates. General practitioners who deliberately issue a false, misleading or inaccurate certificate could face disciplinary action, or even a charge of fraud. This article provides some guidance for GPs about writing certificates certifying illness, and discusses common medicolegal issues associated with sickness certificates. PMID- 21301701 TI - Communities of practice - quality improvement or research in general practice. AB - BACKGROUND: A 'communities of practice' (CoP) approach has the potential to address quality improvement issues and facilitate research in general practice by engaging those most intimately involved in delivering services - the health professionals. OBJECTIVE: This article outlines the CoP approach and discusses some of the challenges involved in using this approach to raise standards in general practice and how these challenges might be addressed. DISCUSSION: General practitioner insight needs to be harnessed in order to develop solutions that are conceived in, and informed by, clinical practice. A CoP approach provides control to the practitioners over selection of the most relevant research question and outcome measure. However, the method is challenging as it requires a focus that is suitable, that motivates the participants, and effective management strategies and resources to support the CoP. PMID- 21301702 TI - Determination of coordination modes and estimation of the 31P-31P distances in heterogeneous catalyst by solid state double quantum filtered 31P NMR spectroscopy. AB - To overcome the separation difficulty of the palladium-based homogeneous catalyst, the palladium complex can be anchored on various supports such as silica. However, it is difficult to determine the amounts of the two coordination modes of the Pd nucleus, that is, Pd coordinates with one phosphorus atom and Pd coordinates with two phosphorus atoms. Here a (31)P double-quantum filtered (DQ filtered) method in solid-state NMR is introduced for the palladium-based heterogenous catalyst system. With the DQ-filtered method, we can not only determine the amounts of the two different kinds of palladium coordination modes, we can also estimate the interatomic distance of two (31)P nuclei bonded to a palladium nucleus. With the help of this method, we can quickly estimate interatomic distances in our designed system and accurately re-design the palladium system to accommodate either one (31)P or two (31)P. PMID- 21301703 TI - 99mTc(CO)3-labeled pamidronate and alendronate for bone imaging. AB - Bone scintigraphy with (99m)Technetium-methylenediphosphonate ((99m)Tc-MDP) or (99m)Technetium-hydroxymethylenediphosphonate ((99m)Tc-HMDP) presents several limitations, namely low specificity, uncertainty in the radiopharmaceutical's molecular structure and long acquisition time after injection. Aiming to find bone-seeking radiotracers based on the core fac-[(99m)Tc(CO)(3)](+) with improved chemical and biological properties, we synthesized new conjugates (pz-PAM and pz ALN), comprising a pyrazolyl-diamine chelating unit (pz: N,N,N donor atom set) for metal stabilization and a pendant pamidronate (PAM) or alendronate (ALN) moiety for bone targeting. The reaction of the conjugates with fac [(99m)Tc(CO)(3)](+) yielded (> 95%) the stable complexes fac-[(99m)Tc(CO)(3)(pz PAM)](-) (2a) and fac-[(99m)Tc(CO)(3)(pz-ALN)](-) (3a), which have been characterized by comparing their HPLC gamma-traces with the UV-vis traces of the Re surrogates 2 and 3, respectively. 2a and 3a bind strongly onto hydroxyapatite. The biodistribution studies in Balb-c mice have shown that 2a and 3a presented an high bone uptake (2a 18.3 +/- 0.6% I.D./g, 3a 17.3 +/- 6.1% I.D./g, at 1 h post injection), similar to (99m)Tc-MDP (17.1 +/- 2.4% I.D./g, at 1 h post injection), with comparable clearance from most tissues and increased total excretion (2a 66% I.D., 3a 67% I.D. and (99m)Tc-MDP 49% I.D., at 1 h post injection). The bone-to blood (2a 86.2, 3a 74.7) and the bone-to-muscle ratios (2a 77.7, 3a 79.0) are higher than the ones found for (99m)Tc-MDP (70.9, 47.9), at 4 h post injection. Planar whole-body gamma camera images of the rats injected with the (99m)Tc(CO)(3)-labeled pamidronate (2a) and alendronate (3a) confirmed the overall adequate biological profile of the new radiotracers for bone imaging. PMID- 21301705 TI - Polyethylenimine-carbon nanotube nanohybrids for siRNA-mediated gene silencing at cellular level. AB - Carbon nanotubes (CNTs) covalently modified with low molecular weight polyethylenimine (PEI) are able to bind and deliver siRNA to cells with higher efficacy than a reference lipidic carrier. The performances of the nanohybrid are rationalized by the combination of the cell penetration and endosomal escape properties of CNTs and PEI, respectively. PMID- 21301704 TI - No time to lose--high throughput screening to assess nanomaterial safety. AB - Nanomaterials hold great promise for medical, technological and economical benefits. Knowledge concerning the toxicological properties of these novel materials is typically lacking. At the same time, it is becoming evident that some nanomaterials could have a toxic potential in humans and the environment. Animal based systems lack the needed capacity to cope with the abundance of novel nanomaterials being produced, and thus we have to employ in vitro methods with high throughput to manage the rush logistically and use high content readouts wherever needed in order to gain more depth of information. Towards this end, high throughput screening (HTS) and high content screening (HCS) approaches can be used to speed up the safety analysis on a scale that commensurate with the rate of expansion of new materials and new properties. The insights gained from HTS/HCS should aid in our understanding of the tenets of nanomaterial hazard at biological level as well as assist the development of safe-by-design approaches. This review aims to provide a comprehensive introduction to the HTS/HCS methodology employed for safety assessment of engineered nanomaterials (ENMs), including data analysis and prediction of potentially hazardous material properties. Given the current pace of nanomaterial development, HTS/HCS is a potentially effective means of keeping up with the rapid progress in this field- we have literally no time to lose. PMID- 21301706 TI - Synthesis and characterization of titania hollow fiber and its application to the microextraction of trace metals. AB - A titania hollow fiber membrane was successfully synthesized in a macro range via a template method coupled with a sol-gel process. Thermal gravimetric and differential thermal analysis (TG-DTA) was employed to study the effect of heat treatment on the synthesized hollow fiber, and the crystal forms of the titania hollow fiber membranes at different temperatures were studied by X-ray diffraction (XRD). The pore structure of the prepared titania hollow fiber was characterized by scanning electron micrograph (SEM) and nitrogen adsorption/desorption measurements. The prepared titania hollow fiber membrane was explored as a new adsorption material for trace metals for the first time and a new method of titania hollow fiber membrane solid phase microextraction (MSPME) online coupled to inductively coupled plasma mass spectrometry (ICP-MS) was developed for the determination of trace amount of Cd, Co, V and Ni in human serum samples. In order to validate the developed method, two certified reference materials of NIES.No.10-b rice flour and BCR No.184 bovine muscle were analyzed and the determined values were in good agreement with the certified values. PMID- 21301707 TI - Molecular dynamics of zigzag single walled carbon nanotube immersion in water. AB - The results of enthalpy of immersion in water for finite single-walled carbon nanotubes are reported. Using molecular dynamics simulation, we discuss the relation between the value of this enthalpy and tube diameters showing that the obtained plot can be divided into three regions. The structure of water inside tubes in all three regions is discussed and it is shown that the existence of the strong maximum of enthalpy observed for tube diameter ca. 1.17 nm is due to freezing of water under confinement. The calculations of hydrogen bond statistics and water density profiles inside tubes are additionally reported to confirm the obtained results. Next, we show the results of calculation for the same tubes but containing surface carbonyl oxygen groups at pore entrances. A remarkable rise in the value of enthalpy of immersion in comparison to the initial tubes is observed. We also discuss the influence of charge distribution between oxygen and carbon atom forming surface carbonyls on the structure of confined water. It is concluded for the first time that the presence of surface oxygen atoms at the pore entrances remarkably influences the structure and stability of ice created inside nanotubes, and surface carbonyls appear to be chaotropic (i.e. structure breaking) for confined water. This effect is explained by the pore blocking leading to a decrease (compared to initial structure) in the number of confined water molecules after introduction of surface oxygen groups at pore entrances. PMID- 21301708 TI - Controlled assembly of Fe3O4 magnetic nanoparticles on graphene oxide. AB - We describe a facile approach to controllable assembly of monodisperse Fe(3)O(4) nanoparticles (NPs) on chemically reduced graphene oxide (rGO). First, reduction and functionalization of GO by polyetheylenimine (PEI) were achieved simultaneously by simply heating the PEI and GO mixture at 60 degrees C for 12 h. The process is environmentally friendly and convenient compared with previously reported methods. Meso-2,3-dimercaptosuccinnic acid (DMSA)-modified Fe(3)O(4) NPs were then conjugated to the PEI moiety which is located on the periphery of the GO sheets via formation of amide bonds between COOH groups of DMSA molecules bound on the surface of the Fe(3)O(4) NPs and amine groups of PEI. The magnetic GO composites were characterized by means of TEM, AFM, UV-vis, FTIR, Raman, TGA, and VSM measurements. Finally, preliminary results of using the Fe(3)O(4)-rGO composites for efficient removal of tetracycline, an antibiotic that is often found as a contaminant in the environment, are reported. PMID- 21301709 TI - Chiral inorganic nanoparticles: origin, optical properties and bioapplications. AB - Chirality of inorganic nanoparticles (NPs) is an emerging and hot topic in nanoresearch in the past several years. Many novel and interesting properties of chiral NPs have been explored and studied, which highlight their importance in both fundamental research and potential applications. This review summarizes recent progress in the study of origins, optical properties and bioapplications of chiral NPs, and future developments in this research area are also discussed. PMID- 21301710 TI - The design, synthesis and photochemical study of a biomimetic cyclodextrin model of photoactive yellow protein (PYP). AB - The design, synthesis and study of the photophysical and photochemical properties of the first biomimetic cyclodextrin (CD) model of photoactive yellow protein (PYP) are described. This model bears a deprotonated trans-p-coumaric acid chromophore, covalently linked via a cysteine moiety to a permethylated 6 monoamino beta-CD. NMR and UV/Visible spectroscopy studies showed the formation of strong self-inclusion complexes in water at basic pH. Steady-state photolysis demonstrated that, unlike the free chromophore in solution, excitation of the model molecule leads to the formation of a photoproduct identified as the cis isomer by NMR spectroscopy. These observations provide evidence that the restricted CD cavity offers a promising framework for the design of biomimetic models of the PYP hydrophobic pocket. PMID- 21301711 TI - Optimization of silver nanoparticles for surface enhanced Raman spectroscopy of structurally diverse analytes using visible and near-infrared excitation. AB - Several experimental parameters affecting surface enhanced Raman (SER) signals using 488, 785 and 1064 nm excitation for eight diverse analytes are reported. Citrate reduced silver colloids having average diameters ranging from 40 +/- 10 to 100 +/- 20 nm were synthesized. The nanoparticles were characterized by transmission electron microscopy, dynamic light scattering and absorbance spectrophotometry before and after inducing nanoparticle aggregation with 0.99% v/v 0.5 M magnesium chloride. The nanoparticle aggregates and SERS signal were stable between 30 and 90 minutes after inducing aggregation. For the analytes 4 mercaptopyridine, 4-methylthiobenzoic acid and the dipeptide phenylalanine cysteine using all three excitation wavelengths, the highest surface area adjusted SER signal was obtained using 70 +/- 20 nm nanoparticles, which generated 290 +/- 40 nm aggregates with the addition of magnesium chloride. The decrease in the SER signal using non-optimum colloids was 12 to 42% using 488 nm excitation and larger decreases in signal, up to 92%, were observed using near infrared excitation wavelengths. In contrast, pyridine, benzoic acid, and phenylalanine required 220 +/- 30 nm aggregates for the highest SER signal with 785 or 1064 nm excitation, but larger aggregates (290 +/- 40 nm) were required with 488 nm excitation. The optimum experimental conditions measured with the small molecule analytes held for a 10 amino acid peptide and hemoglobin. Reproducible SERS measurements with 2 to 9% RSD have been obtained by considering nanoparticle size, aggregation conditions, excitation wavelength and the nature of the analyte-silver interaction. PMID- 21301712 TI - All chemically deposited, annealing and mesoporous metal oxide free CdSe solar cells. AB - A facile, all chemical bath deposition process to fabricate CdSe (quantum dots) solar cells is presented, which is free from mesoporous metal oxides, high temperature annealing and ligand encapsulation, showing great perspective in cost effectiveness, reproducibility and flexibility. PMID- 21301713 TI - EPR parameters of amino acid radicals in P. eryngii versatile peroxidase and its W164Y variant computed at the QM/MM level. AB - Quantum mechanics/molecular mechanics (QM/MM) methods, employing density functional theory (DFT), have been used to compute the electron paramagnetic resonance (EPR) parameters of tryptophan and tyrosyl radical intermediates involved in the catalytic cycle of Pleurotus eryngii versatile peroxidase (VP) and its W164Y variant, respectively. These radicals have been previously experimentally detected and characterized both in the two-electron and one electron activated forms of the enzymes. In this work, the well-studied W164 radical in VP has been chosen for calibration purposes because its spectroscopic properties have been extensively studied by multifrequency EPR and ENDOR spectroscopies. Using a B3LYP/CHARMM procedure, appropriately accounting for electrostatic, such as hydrogen bonding, and steric environmental interactions, a good agreement between the calculated and measured EPR parameters for both radicals has been achieved; g-tensors, hyperfine coupling constants (hfcc) and Mulliken spin densities have been correlated to changes in geometries, hydrogen bond networks and electrostatic environment, with the aim of understanding the influence of the protein surroundings on EPR properties. In addition, the present calculations demonstrate, for VP, the formation of a neutral tryptophan radical, hydrogen bonded to the nearby E243, via a stepwise electron and proton transfer with earlier involvement of a short-lived tryptophan cationic species. Instead, for W164Y, the QM/MM dynamics simulation shows that the tyrosine oxidation proceeds via a concerted electron and proton transfer and is accompanied by a significant reorganization of residues and water molecules surrounding the tyrosyl radical. PMID- 21301714 TI - Reaction of elemental chalcogens with imidazolium acetates to yield imidazole-2 chalcogenones: direct evidence for ionic liquids as proto-carbenes. AB - Mechanistic analysis of the reaction between elemental sulfur or selenium and 1,3 dialkylimidazolium acetate ionic liquids, in the absence of an external base or solvent, affords evidence for the equilibrium presence of carbene species in these ionic liquids. It demonstrates the potential to control, through anion selection, the concentration of carbene in stable ionic liquids. PMID- 21301715 TI - Synthesis of foam-like freestanding Co3O4 nanosheets with enhanced electrochemical activities. AB - We report a facile and simple strategy to synthesize freestanding Co(3)O(4) nanosheets on conductive substrates. The as-prepared product shows two dimensional hexagons in morphology with mesoporous inside architecture. PMID- 21301716 TI - PEGylated liposome coated QDs/mesoporous silica core-shell nanoparticles for molecular imaging. AB - This paper describes the synthesis and application of PEGylated liposome-coated quantum dots (QDs)/mesoporous silica core-shell nanoparticles (NPs) for molecular imaging. This system increases biocompatibility and stability of QDs, thus improving the imaging effects in labeling of cancer cells. PMID- 21301717 TI - Acene-linked conjugated polymers with ratiometric fluorescent response to 1O2. AB - This communication describes new conjugated polymers that bear diarylanthracene or diaryltetracene pendants and respond to singlet oxygen by interrupting energy transfer resulting in blue-shifted fluorescence. PMID- 21301722 TI - Do all ionic liquids need organic cations? Characterisation of [AlCl2.nAmide]+ AlCl4(-) and comparison with imidazolium based systems. AB - The addition of a simple amide to AlCl(3) causes the formation of a liquid of the form [AlCl(2).nAmide](+) AlCl(4)(-). The material thus produced is liquid over a wide temperature range, is relatively insensitive to water and has the properties of an ionic liquid. This ionic liquid is shown to be a suitable medium for the acetylation of ferrocene and the electrodeposition of aluminium and demonstrated that quaternary ammonium cations are not always needed to form ionic liquids. PMID- 21301724 TI - Azepiphthalocyanine--an unprecedented large twist of a pi-conjugation system upon core-modification with a seven-membered ring unit. AB - Aromatic dicarbonitrile bearing cyano groups in a 1,4-relationship was utilized for a phthalocyanine synthesis to give azepiphthalocyanine having a seven membered ring unit instead of a five-membered ring unit. This molecule exhibits a significantly twisted structure and large splitting of the Q band absorption, indicative of its azachlorin-like conjugation system. PMID- 21301723 TI - First one-pot stereoselective synthesis of cis-2,3-dihydro-4-perfluoroalkyl-1H 1,5-benzodiazepines via a catalyst-free three-component reaction. AB - cis-2,3-Dihydro-4-perfluoroalkyl-1H-1,5-benzodiazepines were stereoselectively synthesized using a one-pot, catalyst-free, three-component reaction. This novel, efficient and convenient approach was used to synthesize 22 related products in moderate to excellent yields, demonstrating the scope and potential economic impact of the reaction. PMID- 21301725 TI - Stereoselective synthesis of oxazino[4,3-a]indoles employing the oxa-Pictet Spengler reaction of indoles bearing N-tethered vinylogous carbonate. AB - A one-pot, sequential 2,3-bis-functionalization of indoles bearing N-tethered vinylogous carbonates employing an intramolecular oxa-Pictet-Spengler reaction followed by electrophilic substitution is developed for the stereoselective synthesis of oxazino[4,3-a]indoles. PMID- 21301726 TI - Decarboxylative biaryl synthesis in a continuous flow reactor. AB - A practical protocol was developed that allows performing decarboxylative cross coupling reactions in continuous flow reactors. Various biaryls were thus synthesized from aromatic carboxylic acids and aryl triflates using a Cu/Pd catalyst system. PMID- 21301727 TI - Chemistry in human telomere biology: structure, function and targeting of telomere DNA/RNA. AB - Telomeres are present at the ends of all eukaryotic chromosomes. Human telomeres play an important role in critical processes underlying genome stability, cancer, and aging, and their importance was recognized via the award of the 2009 Nobel Prize in Physiology or Medicine. Chemistry has made vast and almost unparalleled contributions to telomere biology. This critical review highlights the contributions of chemistry in human telomeres and summarizes the significant development of human telomere biology. First, I provide an overview of the advances in understanding of the structures and functions of human telomeres. Second, I focus on the current efforts on developing various chemical approaches to targeting human telomeres and telomerase for the treatment of cancer. Third, studies on a newly discovered telomeric repeat-containing RNA are discussed in detail. Last, future challenges in the field are outlined, including perspectives of both chemistry and biology (412 references). PMID- 21301728 TI - Complexes of copper(II) with 3-(ortho-substituted phenylhydrazo)pentane-2,4 diones: syntheses, properties and catalytic activity for cyclohexane oxidation. AB - Reactions of copper(II) with 3-phenylhydrazopentane-2,4-diones X-2-C(6)H(4) NHN=C{C(=O)CH(3)}(2) bearing a substituent in the ortho-position [X = OH (H(2)L(1)) 1, AsO(3)H(2) (H(3)L(2)) 2, Cl (HL(3)) 3, SO(3)H (H(2)L(4)) 4, COOCH(3) (HL(5)) 5, COOH (H(2)L(6)) 6, NO(2) (HL(7)) 7 or H (HL(8)) 8] lead to a variety of complexes including the monomeric [CuL(4)(H(2)O)(2)].H(2)O 10, [CuL(4)(H(2)O)(2)] 11 and [Cu(HL(4))(2)(H(2)O)(4)] 12, the dimeric [Cu(2)(H(2)O)(2)(MU-HL(2))(2)] 9 and the polymeric [Cu(MU-L(6))](n)] 13 ones, often bearing two fused six-membered metallacycles. Complexes 10-12 can interconvert, depending on pH and temperature, whereas the Cu(II) reactions with 4 in the presence of cyanoguanidine or imidazole (im) afford the monomeric compound [Cu(H(2)O)(4){NCNC(NH(2))(2)}(2)](HL(4))(2).6H(2)O 14 and the heteroligand polymer [Cu(MU-L(4))(im)](n)15, respectively. The compounds were characterized by single crystal X-ray diffraction (complexes), electrochemical and thermogravimetric studies, as well as elemental analysis, IR, (1)H and (13)C NMR spectroscopies (diones) and ESI-MS. The effects of the substituents in 1-8 on the HOMO-LUMO gap and the relative stability of the model compounds [Cu(OH)(L(8))(H(2)O)].H(2)O, [Cu(L(1))(H(2)O)(2)].H(2)O and [Cu(L(4))(H(2)O)(2)].H(2)O are discussed on the basis of DFT calculations that show the stabilization follows the order: two fused 6-membered > two fused 6 membered/5-membered > one 6-membered metallacycles. Complexes 9, 10, 12 and 13 act as catalyst precursors for the peroxidative oxidation (with H(2)O(2)) of cyclohexane to cyclohexanol and cyclohexanone, in MeCN/H(2)O (total yields of ca. 20% with TONs up to 566), under mild conditions. PMID- 21301729 TI - Microfluidics and complex fluids. AB - In this paper, we describe four experimental studies we carried out over the last four years in the MMN lab, regarding the dynamical behaviour of complex fluids in microfluidic systems. The topics are: (1) Polymer breakup in microfluidic systems. (2) Flows of polymer solutions in microchannels close to a smooth wall. (3) Shear banding flows in microchannels (rheology, instabilities). (4) Flows of concentrated solutions of microgel particles through microchannels. Depending on the situation, we exploit the duality low Reynolds numbers/high Weissenberg numbers (for instance, by working at high shear rates without generating turbulence), use visualization windows naturally offered by the microfluidic environment or take advantage of the integration of various functionalities on the chip. In all cases, new information, hardly accessible to non-miniaturized approaches, could be obtained by using microfluidic technology. PMID- 21301730 TI - Silicate glass coated microchannels through a phase conversion process for glass like electrokinetic performance. AB - The surface modified polydimethylsiloxane (PDMS) microchannels show a much more inferior performance to the durable and reproducible glass chip. In this paper, a facile approach to preparing a silicate glass modified PDMS microchannel for glass-like performance is presented. This glass-like performance is made possible by a phase conversion of a preceramic polymer--allylhydridopolycarbosilane (AHPCS). The, several hundred nanometer thick, polymer that coats the PDMS channel is hydrolyzed to form hydrophilic silicate glass via phase conversion under an aqueous alkali condition. It is characterized by XPS, FTIR-ATR, AFM, and contact angle measurements. The silicate glass coated PDMS channel from AHPCS has an excellent solvent resistance, delivers a high electroosmotic flow (EOF) that is stable in the long-term (4.9+/-0.1*10(-4) cm(2) V(-1) s(-1)) and a reliable capillary electrophoresis (CE), which are comparable to those of native glass channels. Moreover, the silicate glass PDMS channel allows easy regeneration of the electrokinetic behavior, just as in a glass channel, by a simple treatment with alkali solution. This coating approach can be applied to other polymer substrates such as polyimide (PI). PMID- 21301733 TI - Effective oxidation of benzylic and alkane C-H bonds catalyzed by sodium o iodobenzenesulfonate with Oxone as a terminal oxidant under phase-transfer conditions. AB - Catalytic oxidation of benzylic C-H bonds could be efficiently realized using IBS as a catalyst which was generated in situ from the oxidation of sodium 2 iodobenzenesulfonate (1b) by Oxone in the presence of a phase-transfer catalyst, tetra-n-butylammonium hydrogen sulfate, in anhydrous acetonitrile at 60 degrees C. Various alkylbenzenes, including toluenes and ethylbenzenes, several oxygen containing functionalities substituted alkylbenzenes, and a cyclic benzyl ether could be efficiently oxidized. And, the same reagent system of cat. 1b/Oxone/cat. n-Bu(4)NHSO(4) could be applied to the effective oxidation of alkanes as well. PMID- 21301731 TI - An algorithm for three-dimensional Monte-Carlo simulation of charge distribution at biofunctionalized surfaces. AB - In this work, a Monte-Carlo algorithm in the constant-voltage ensemble for the calculation of 3d charge concentrations at charged surfaces functionalized with biomolecules is presented. The motivation for this work is the theoretical understanding of biofunctionalized surfaces in nanowire field-effect biosensors (BioFETs). This work provides the simulation capability for the boundary layer that is crucial in the detection mechanism of these sensors; slight changes in the charge concentration in the boundary layer upon binding of analyte molecules modulate the conductance of nanowire transducers. The simulation of biofunctionalized surfaces poses special requirements on the Monte-Carlo simulations and these are addressed by the algorithm. The constant-voltage ensemble enables us to include the right boundary conditions; the dna strands can be rotated with respect to the surface; and several molecules can be placed in a single simulation box to achieve good statistics in the case of low ionic concentrations relevant in experiments. Simulation results are presented for the leading example of surfaces functionalized with pna and with single- and double stranded dna in a sodium-chloride electrolyte. These quantitative results make it possible to quantify the screening of the biomolecule charge due to the counter ions around the biomolecules and the electrical double layer. The resulting concentration profiles show a three-layer structure and non-trivial interactions between the electric double layer and the counter-ions. The numerical results are also important as a reference for the development of simpler screening models. PMID- 21301738 TI - Synthesis and structural characterization of mixed-metal complexes of Cu(I) with MOS3 cores (M = Mo, W) and of an unusual polymeric AgI/mercaptoimidazole complex with five different Ag(I) coordination environments. AB - Reaction of (NH(4))(2)[MO(2)S(2)] (M = Mo or W) with KI, CuCl and 1,3-diazepane-2 thione (Diap) in acetone affords air- and moisture-stable mixed-metal cluster compounds [MOS(3)(CuDiap)(3)]I (1 and 2). Attempts to produce [WS(4)Ag(2)(Mim(Ph))(4)] (Mim(Ph) = 2-mercapto-1-phenylimidazole) led to the unexpected polymeric compound [Ag(5)I(5)(Mim(Ph))(4)](n) (4), subsequently obtained from a rational direct reaction between AgI and Mim(Ph) in chloroform. The complexes have been characterized by IR, (1)H and (13)C NMR spectroscopy, and single-crystal diffraction. 1 and 2 have crystallographic threefold rotation symmetry, with an incomplete distorted cube MS(3)Cu(3) core bearing terminal oxo and Diap ligands on M and Cu, respectively. The cube vertex opposite M is empty, giving an overall +1 cationic cluster and a separate I(-) anion too distant from the three Cu atoms to be considered as covalently bonded and resulting in discrete ion pairs in the crystal structures. This arrangement is different from previously reported related OMS(3)(CuL)(3)X complexes (L = monodentate ligand, X = halide), in which X, when present, is directly bonded to one, two or three Cu atoms. 4 has a one-dimensional polymeric chain structure in which silver displays five different approximately tetrahedral coordination environments, iodide ions serve as MU(2), MU(3) and MU(4) bridges, and the thione ligands are each either terminal or bridging. This unusually complex structure for a relatively simple chemical formula represents only the fifth example of a complex (AgI)(n)L(m) in which L is a neutral S-donor ligand, and the five structures display a wide range of individual features. In all three of the new structures, N-H...S and/or N H...I hydrogen bonds are found. PMID- 21301739 TI - Recent advances in particle and droplet manipulation for lab-on-a-chip devices based on surface acoustic waves. AB - Manipulation of microscale particles and fluid liquid droplets is an important task for lab-on-a-chip devices for numerous biological researches and applications, such as cell detection and tissue engineering. Particle manipulation techniques based on surface acoustic waves (SAWs) appear effective for lab-on-a-chip devices because they are non-invasive, compatible with soft lithography micromachining, have high energy density, and work for nearly any type of microscale particles. Here we review the most recent research and development of the past two years in SAW based particle and liquid droplet manipulation for lab-on-a-chip devices including particle focusing and separation, particle alignment and patterning, particle directing, and liquid droplet delivery. PMID- 21301740 TI - A novel cross-H-channel interface for flow injection-capillary electrophoresis to reduce sample requirement and improve sensitivity. AB - In this study, a cross-H-channel interface was constructed for coupling flow injection with capillary electrophoresis (FI-CE) to reduce sample requirement and sensitivity loss in the typical FI-CE. Based on this cross-H-channel interface, a new FI-CE system was established, in which sample introduction was performed by directly injecting sample solution along a thin capillary (50 MUm, i.d.) to the interface from an injection syringe. The sample requirement was reduced distinctly and usual sample dilution in the sample transport process was obviously decreased, thereby spontaneously enhancing the sensitivity. Moreover, because of the unique construction of the cross-H-channel interface, field amplified sample stacking (FASS) and high-speed CE were skillfully combined to further improve the sensitivity and to shorten separation time. The versatility of this new FI-CE was demonstrated by determination of ephedrine (E) and pseudoephedrine (PE) in human urine. Up to 45 repeated injections per hour and clearly baseline separation of E and PE in less than 1 min were achieved, giving limits of detection (LODs) of 0.23 and 0.21 MUg mL(-1) for E and PE, respectively, and yielding relative standard deviation (RSD) values of the migration time and the peak height (n=5) of 2.6% and 3.1% for E, 2.3% and 3.3% for PE, respectively. In contrast to typical FI-CE, approximately 8-250-fold decreases in sample volume requirement, 7-fold shortening in separation time and 50-fold improvements in sensitivity were obtained. PMID- 21301741 TI - Piezochromic fluorescence in liquid crystalline conjugated polymers. AB - Liquid crystalline diphenylacetylene polymer derivatives showed piezochromic fluorescence via order-to-disorder phase transition. PMID- 21301742 TI - Panchromatic light harvesting in single wall carbon nanotube hybrids immobilization of porphyrin-phthalocyanine conjugates. AB - We report on immobilizing H(2)/Zn-porphyrin-Zn-phthalocyanine conjugates onto single wall carbon nanotubes and by using the excellent stability of the resulting suspensions we were able to demonstrate for the first time the sequence of energy transfer-electron transfer in SWNT donor-acceptor conjugates. PMID- 21301743 TI - Photo-crosslinked and pH sensitive polymersomes for triggering the loading and release of cargo. AB - Crosslinkable and pH-sensitive amphiphilic block copolymers are promising candidates to establish pH-stable and permeable vesicles for synthetic biology. Here, we report the fabrication of crosslinked and pH-stable polymersomes as swellable vesicles for the pH-dependent loading and release of small dye molecules. PMID- 21301744 TI - Pd-catalyzed coupling of beta-hydroxy alpha-diazocarbonyl compounds with aryl iodides: a migratory insertion/beta-hydroxy elimination sequence. AB - The coupling of beta-hydroxy alpha-diazocarbonyl compounds with aryl halides is described, which proceeds through a Pd-catalyzed migratory insertion/beta-OH elimination sequence. This reaction provides a new route to the synthesis of tetrasubstituted olefins. PMID- 21301745 TI - Chemical mechanism of the high solubility pathway for the carbon dioxide free production of iron. AB - We determine the fundamental iron oxide high solubility mechanism that drives a new electrolytic pathway to iron production, and eliminates a major CO(2) emission source, for example it is produced using wind and solar energy, in a molten carbonate electrolyte, at a high rate and a low electrolysis energy. PMID- 21301746 TI - Gene delivery with polycationic fullerene hexakis-adducts. AB - Polyplexes prepared from DNA and globular compact polycationic derivatives constructed around a fullerene hexakis-adduct core have shown remarkable gene delivery capabilities. PMID- 21301747 TI - Proteomics and renaissance: accounts of the V Italian Proteomics Association Congress, Florence 2010. PMID- 21301752 TI - The first chemical synthesis of boronic acid-modified DNA through a copper-free click reaction. AB - The first chemical incorporation of the boronic acid group into DNA using a copper-free click reagent was reported. Compared with the PCR-based method, this approach allows for site-specific incorporation and synthesis on a larger scale. PMID- 21301753 TI - In vivo trapping of polyketide intermediates from an assembly line synthase using malonyl carba(dethia)-N-acetyl cysteamines. AB - Early-stage intermediates in the biosynthesis of erythromycin A by Saccharopolyspora erythraea were intercepted by malonyl carba(dethia)-N-acetyl cysteamines, generated in vivo from the hydrolysis of the corresponding methyl esters. PMID- 21301754 TI - Guiding the nitrogen nucleophile to the middle: palladium-catalyzed decarboxylative cyclopropanation of 2-alkylidenetrimethylene carbonates with isocyanates. AB - A palladium-catalyzed decarboxylative cyclopropanation of 2 alkylidenetrimethylene carbonates with isocyanates is described to form oxazolidinones of (1-aminocyclopropyl)methanols with high selectivity. The site of nucleophilic attack is directed by connecting the two reaction components and by employing an electron-deficient triarylphosphine ligand. PMID- 21301755 TI - The decision of do not resuscitate in pediatric practice. AB - Cardiopulmonary resuscitation (CPR) is now routinely performed on any hospitalized patients who suffer cardiac, or respiratory arrest. Children with irreversible, or progressive terminal illness may benefit temporarily from CPR, only to deteriorate later on. Painful and invasive procedures may be performed unnecessarily, and the child could be left in a poorer condition. A do not resuscitate (DNR) order indicates that the treating team has decided not to have CPR attempted in the event of cardiac or pulmonary arrest. While there is relatively ample literature on this topic in general, there is comparatively little focus on DNR orders as they pertain to pediatric patients. In this paper, various aspects related to the DNR decision making in children will be discussed, and a summary of the published guidelines by the Royal College of Pediatrics & Child Health and the American Academy of Pediatrics will be presented. PMID- 21301756 TI - Evaluation of direct detection of Mycobacterium tuberculosis in clinical samples using the BD ProbeTec ET system. AB - OBJECTIVE: To evaluate the performance of the semi-automated BD ProbeTec ET system for the direct detection of Mycobacterium tuberculosis complex (MTBC) in comparison with microscopy, and culture for respiratory and non-respiratory specimens. METHODS: The study was conducted in the Maternity and Children's Hospital, Madina, Saudi Arabia from October 2008 to October 2009. A single center prospective study of 70 suspected tuberculosis samples were subjected to microscopy, culture (solid and liquid), and the DB ProbeTec ET system. RESULTS: A total of 70 specimens were studied; 47 respiratory, and 23 non-respiratory. Twelve (92.3%) ProbeTec positive results were obtained from 13 MTBC isolates from culture, while one specimen was BD ProbeTec ET positive, but yielded no growth on culture. Two samples gave anomalous results (false negative and positive results). The evaluated system showed sensitivity of 92.3%, specificity of 98%, positive predictive value of 92.3%, and negative predictive value of 98% for all specimens, while 88% sensitivity, 100% specificity, 100% positive predictive value, and 97.3% negative predictive value in cases of respiratory specimens, and 100% sensitivity, 93.3% specificity, 80% positive predictive value, and 100% negative predictive value in cases of non-respiratory specimens. CONCLUSION: The ProbeTec ET is a rapid and specific method for direct detection of MTBC in clinical specimens compared with the gold standard of culture, especially in patients with smear-negative non-respiratory specimens. PMID- 21301757 TI - Low serum concentration facilitates the differentiation of hepatic progenitor cells. AB - OBJECTIVE: To investigate the effect of serum culture conditions on the differentiation of hepatic progenitor cells (HPCs) in vitro. METHODS: This study was conducted at the Stem Cell Biology and Therapy Laboratory, The Children's Hospital of Chongqing Medical University, Chongqing, China from August 2009 to June 2010. Differentiation of HPCs was induced with dexamethasone, hepatic growth factor, and fibroblast growth factor-4 in 10% fetal bovine serum (FBS), 2% FBS, 2% horse serum (HS) conditions. First, we investigated the indirect synthesis of albumin by the albumin promoter-driven Gaussia luciferase assay, and cell proliferation by cell counting. Then, we performed reverse transcriptase polymerase chain reaction and immunofluorescence to detect hepatic related markers Delta-like protein (DLK), cytokeratin 18 (CK18), tyrosine aminotransferase (TAT), albumin (ALB), a-fetoprotein (AFP), and glucuronosyltransferase 1A (UGT1A). Lastly, we used indocyanine green (ICG) uptake assay and periodic acid-Schiff (PAS) staining to determine the function of induced hepatocytes. RESULTS: The proliferation of HPCs was inhibited in 2% serum culture. Induced HPCs in 2% serum exhibited higher expression of ALB, CK18, UGT1A, and TAT, whereas lower expression of DLK and AFP, compared with 10% FBS. Interestingly, 2% serum culture improved ICG uptake function, but repressed PAS staining of induced HPCs. Generally, 2% HS was better at inducing mature hepatic markers and the function of HPCs than 2% FBS. CONCLUSION: Two percent low serum concentration conditions, especially 2% HS, improve the hepatic differentiation of HPCs, and PAS staining may not be used in induction testing of low serum concentrations. PMID- 21301758 TI - Quantitative DNA analysis of very low-level hepatitis B viremic patients reporting to the gastroenterology clinic. AB - OBJECTIVE: To examine data on very low-level viremic hepatitis B virus (HBV) infections in patients reporting to a gastroenterology clinic, and to investigate methods to improve analysis to avoid missing follow-up data and improve the management of HBV infection, and minimize morbidity and mortality outcomes. METHODS: A total of 104 patients with very low-level viremic HBV whom reported to the gastroenterology clinic at Al-Hada Armed Forces Hospital, Taif, Saudi Arabia and had a reading of <12 IU/mL on the real time (RT) polymerase chain reaction (PCR) detection system were enrolled in this study. For serological testing (for example, hepatitis B surface antigen [HBsAg]), we examined patients' results recorded in the laboratory information system since early 2007. Liver enzymes, alanine aminotransferase, and aspartate aminotransferase were assessed in some cases. RESULTS: After analyzing the data collected from 1,178 patients, we found 104 (8.83%) cases that fit the criteria for our study, including a reading of <12 IU/mL. We formed 6 groups of participants based on HBsAg reactivity and very low, elevated, or no viremia, and found 4 cases of continuous occult hepatitis B infection. CONCLUSION: The very low levels of DNA found had a diagnostic impact on the management of HBI and yielded several suggestions for clinicians regarding follow-up with patients. It is important to use a sensitive RT PCR to monitor the course of HBV infection. PMID- 21301759 TI - Detection of human papillomavirus in the saliva of women with concurrent human papillomavirus related genital lesions. AB - OBJECTIVE: To determine the association of the human papillomavirus (HPV) subtypes in the saliva of women and HPV-related genital lesions. METHODS: In a cross-sectional study, 104 women with documented genital HPV-related lesions and known HPV status were selected. These cases were examined for the HPV subtypes in their salivary specimens from July 2006 to August 2009 at the Gynecologic Clinics of Alzahra Teaching Hospital, Tabriz, Iran. To detect HPV DNA subtypes of 16, 18, 31, 33, 6, and 11,HPV was genotyped by polymerase chain reaction assay. RESULTS: Type 16 HPV was the most frequently detected subtype in the saliva (29.8%), and cervix (24%). In addition, there was a significant association between the saliva and cervix with co-infection (p=0.009), and between the viral types of salivary and cervical+vulvar samples (p=0.00), and salivary and vulvar samples (p=0.001). On the other hand, there was a significant difference between the cervical and vulvar samples for the viral subtypes (p=0.000). CONCLUSION: The high risk HPV 16 is the most common simultaneous HPV subtype in the saliva and cervix of the cases. Identifying the HPV subtypes in saliva may facilitate recognizing persistent genital infections. PMID- 21301760 TI - Open 3-step local anesthesia technique is a more applicable method as compared with spinal anesthesia in inguinofemoral hernia repair. AB - OBJECTIVE: To compare the effects of spinal anesthesia with those of the open 3 step local anesthesia (TSLA) technique under visual control. METHODS: Between January 2005 and August 2006, the data of 55 patients undergoing groin hernia repair with either the TSLA technique or spinal anesthesia (SA) were collected via retrospective case note review at the General Surgical Unit of the Ardahan Military Hospital, Ardahan, Turkey. Patient characteristics, preoperative and postoperative measurements prior to discharge, average pain, and nausea during the postoperative hospital stay were recorded. RESULTS: While there was no preoperative preparation time for the induction of anesthesia in the TSLA method, it was found that a preparation time of 24.56+/-8.85 minutes was required for the SA preoperatively. The evaluation of the visual analogue scores of both groups yielded no significant differences between the eighth and twenty-fourth hours. When the postoperative complications in both groups were considered, 3 patients had headache whereas 2 had nausea, and 5 had complications of urinary retention in the SA group. CONCLUSION: Except for the negative factors such as patient refusal, allergic reaction history, previous vaso-vagal episode, or fainting during local anesthesia, incooperability caused by psychiatric disorder or language barriers, the results of the present study indicate that the TSLA is a safe, effective, and appropriate anesthetic technique in the adult age group. PMID- 21301761 TI - Pain management of children and adolescents with sickle cell disease presenting to the emergency department. AB - OBJECTIVE: To show and characterize our practice in the initial management of children and adolescents with sickle cell disease (SCD) presenting in acute painful crises, and to identify if there is a delay in patients getting the initial analgesics compared with standard guidelines. METHODS: This retrospective cohort study was conducted at the Emergency Department (ED) of King Abdulaziz Hospital, Al-Ahsa, Kingdom of Saudi Arabia. The study participants were patients who visited the ED with acute painful crises related to SCD between July 2006 and July 2007. Exclusion criteria included age younger than 5 years and those older than 18 years old. A structured medical records review was used to abstract the data. The data was then computed using the Statistical Package for Social Sciences (SPSS, Chicago, IL, USA) for Windows version 16. RESULTS: There were 270 patient visits made by 43 patients. The time to administration of initial analgesic drugs was 42.2 +/- 20.4 minutes. Two hundred thirty-seven (87.7%) visits were discharged from ED after an average length of stay of 183.9 +/- 129.3 minutes. The 3 most common initial analgesics used were morphine sulphate, voltaren, and paracetamol. The routes frequently used were intravenous, oral, and intramuscular. CONCLUSION: There was a delay in the administration of the initial analgesic and approximately a fifth of patients received their analgesics via an unrecommended intramuscular route. PMID- 21301762 TI - Botulinum Toxin A in bruxers. One year experience. AB - OBJECTIVE: To review and assess the benefits, outcome, and side effects of using Botulinum Toxin A (BTxA) in the treatment of bruxism. METHODS: From January 2009 to January 2010, 120 bruxers were treated; no special examinations were carried out, since the exact diagnoses were made beforehand. All were treated with BTxA in the masseter muscle with standardized doses and injection sites. A follow-up examination was made 15 days post-procedure, and all patients responded to a short satisfaction questionnaire. Twenty-three patients were re-injected with additional doses of BTxA for insufficient results. Subjective results and side effects were assessed. RESULTS: All patients have declared a good/very good improvement in symptoms. No significant side effects were seen. At the study's conclusion, 36 patients (30%) declared a fair result, 79 (65.8%) good, and 5 (4.2%) excellent. CONCLUSION: Botulinum Toxin A is a simple method of treatment of bruxism, without side effects and appreciated by patients. The technique needs further studies to assess long-term outcome on target structures, especially on teeth. PMID- 21301763 TI - Meningitis and seasonal influenza vaccination coverage among military personnel in central Saudi Arabia. AB - OBJECTIVE: To determine the meningitis and influenza vaccination coverage rates among Saudi military personnel in Riyadh (Central Military Region [CMR]), Kingdom of Saudi Arabia, (KSA) and the socio-demographic factors that influence vaccination. METHODS: This cross-sectional descriptive study was carried out on a sample of 2286 military personnel from different army forces and different military ranks in CMR in KSA selected by a 2-stage stratified random sampling technique. A self-administered questionnaire designed for the National Military Health Survey was used with a section added for assessment of vaccination status. Data collection was carried out from May to August 2009. RESULTS: The response rate was 97.6%. The vaccination coverage was higher for meningitis (51.7%) compared with influenza (17.8%). A high percentage lacked awareness of their vaccination status. Vaccination rates were higher in the Land Forces, and increased with more years of education, and lower crowding index. CONCLUSION: The proportion of vaccination coverage among military personnel in CMR of KSA is low, especially for influenza, along with their awareness of their vaccination status. A vaccination program that includes awareness promotion of vaccine-preventable diseases is recommended, with changes in the policies to mandate vaccination against meningitis and influenza. PMID- 21301764 TI - Pregnancy outcomes of mothers aged 17 years or less. AB - OBJECTIVE: To study the obstetric complications of women who become pregnant at aged 17 years old or less. METHODS: A retrospective study was performed from January to December 2009 at Al-Thawra General Hospital, Sana'a, Yemen. We included all women aged 17 years or less who delivered in the hospital with singleton births after 24 weeks gestational age. The study group comprised 239 patients, and a control group (n=240) was chosen from women aged between 20-24 years. Data were retrieved from the hospital records. RESULTS: Pregnancy in women 17 years old or less was associated with higher frequency of low birth weight than the control group (21.3% versus 12%, p=0.0091). Anemia was higher in the study group (17.5% versus 7%, p=0.0008). Preterm labor was 11.6% in the study group, and 5.4% in the control group. In the study group, 7.9% had preeclampsia compared to 5% in the control group. The cesarean section rate in the study group was higher than the control group (6.3% versus 2%, p=0.0331). CONCLUSION: Pregnant women 17 years old or less were more likely to have maternal and neonatal morbidity, and were more likely to have abdominal deliveries. PMID- 21301765 TI - Potential adverse reactions to herbal medicines in patients attending a nephrology clinic in Abu Dhabi, United Arab Emirates. AB - OBJECTIVE: To provide data on herbal medicine (HM) use and safety in patients attending a nephrology clinic at Sheikh Khalifa Medical City (SKMC), Abu Dhabi, United Arab Emirates (UAE). METHODS: A prospective, 3-month study between June and September 2007, investigated all patients presenting to the Nephrology Clinic of the Sheikh Khalifa Medical center (SKMC) in Abu Dhabi, UAE. A structured questionnaire determined previous and current HM use, and descriptions of associated adverse reactions. Corroborating evidence was sought from the patient's medical records. Causality was assessed by consensus from an expert panel using the Naranjo algorithm. RESULTS: The HM use was widespread (468 of 688; 68%). Over two-thirds (69%) reported currently taking 3 or more herbal preparations. Patients reported using over 100 different HMs, many of them compounded mixtures; 35% could not identify a single ingredient of these mixtures, and 70% had not informed the clinic doctors that they were taking HMs. Just 2 patients had HM use recorded in their medical record. Twenty-eight HM related adverse reactions were identified in 26 (5.6%) patients; 12 probably and 16 possibly related to HMs. Seven involved HMs alone and 21, a HM/prescription medication (PM) interaction. CONCLUSION: The use of HMs in patients with underlying kidney problems was extensive and contributed additional pathology to the underlying renal disease, either alone or in combination with PMs. The reluctance of patients to inform their healthcare providers of concurrent use highlights a need to take a thorough drug history on clinic registration. PMID- 21301766 TI - House dust mites in pediatric atopic dermatitis. AB - OBJECTIVE: To evaluate hypersensitivity to Dermatophagoides pteronyssinus (D. pteronyssinus) and D. farinae in pediatric patients with atopic dermatitis (AD), and to assess the therapeutic value of using acaricides with other environmental anti house dust mites (HDM) measures. METHODS: Ninety-eight children with AD were chosen randomly from the Pediatric Allergy Clinic in Al-Noor Hospital, Khalifa branch, Abu Dhabi, United Arab Emirates during the period between January 2008 to January 2009 and were evaluated for severity and chronicity. They were subjected to skin prick test (SPT) including D. pteronyssinus and D. farinae antigens and were also assessed for the therapeutic value of acaricides and environmental anti HDM measures. RESULTS: We found that 74.5% of patients were sensitive to one or both strains of HDM. A highly significant association was found between the severity of the symptoms of AD and its persistence with hypersensitivity to HDM (p=0.001). Acaricides and environmental anti HDM measures can improve patients with mild AD. CONCLUSION: Hypersensitivity to HDM is an important factor for the more acute, more chronic, and more severe AD. Anti HDM measures including the use of acaricides can help control mild AD. We recommend SPT as a part of the work up of patients with AD. The HDM sensitive patients can benefit from anti HDM measures. PMID- 21301767 TI - An intervention study for viral hepatitis. Peer-led health education among high school students. AB - OBJECTIVE: To check the effectiveness of peer-led education in improving the knowledge, attitudes, and behavior of high school students regarding viral hepatitis (VH). METHODS: This study was conducted at 29 high schools in Erzurum city center, Turkey between February and May 2007. The study design is a prospective before-and-after intervention trial. In this study, 2930 students from 29 different schools were included. A total of 559 volunteer students were trained as peer educators. These students applied a standard education to their peers. RESULTS: The total knowledge scores of peer educators before was 7.99 +/- 2.73, and 13.91 +/- 3.85 after peer-training (p=0.000). The total knowledge scores of other students increased from 7.27 +/- 2.85 to 11.20 +/- 4.21 (p=0.000). There was an increase in all correct answers to the knowledge questions after the intervention (p=0.000). Response to the questions exploring attitude of students towards people infected with hepatitis virus significantly changed after the training (p=0.002). There was also a significant positive change in the behaviors after the intervention (p=0.000). CONCLUSION: The significant increase in the knowledge of students trained by their peers proves this method is effective to be utilized in the prevention strategies regarding VH infections. Further studies with long term follow-up would be useful to demonstrate the long term value of peer education. PMID- 21301768 TI - Laparoscopic duodenojejunostomy omega loop with braun anastomosis as a treatment for superior mesenteric artery syndrome. AB - Superior mesenteric artery (SMA) syndrome is a rare clinical phenomenon caused by compression of the third portion of the duodenum by the overlying SMA, and can be easily misdiagnosed. We report a case of SMA syndrome treated with laparoscopic duodenojejunostomy omega loop with Braun anastomosis. A 24-year-old women with body mass index of 14.9 presented with a 4-year history of vague abdominal pain mainly at the epigastric region, radiating to the back associated with heartburn, repeated vomiting, and significant loss of weight during the previous 6 months. The case was misdiagnosed as acute pancreatitis. The SMA syndrome was diagnosed using CT-scan and fluoroscopy. Laparoscopic omega loop with Braun anastomosis was preformed. She did well postoperatively, and Gastrografin study showed no leak and a patent anastomosis. She was subsequently discharged on regular diet. PMID- 21301769 TI - Post pubertal behavioral changes in rats with neonatal lesions of the ventral hippocampus. PMID- 21301770 TI - Congenital heart disease in south-west Saudi Arabia. PMID- 21301771 TI - Antibiotic prescribing in a pediatric emergency setting in central Saudi Arabia. PMID- 21301772 TI - A child with congenital longitudinal radial deficiency. Congenital radial club hand. PMID- 21301773 TI - Recurrent visits and admissions of children with asthma in central Saudi Arabia. PMID- 21301774 TI - Carnitine-acylcarnitine translocase deficiency. Clinical course of 3 Saudi children with a severe phenotype. PMID- 21301775 TI - Medical conditions associated with a positive anti-double-stranded deoxyribonucleic acid. PMID- 21301776 TI - Impaired platelet function and peripartum bleeding in women with Gaucher disease. AB - The risk of bleeding during delivery may be increased in women with Gaucher disease. We aimed to evaluate potential predictors for peripartum haemorrhage (PPH) during childbirth in these patients, while focusing upon coagulation tests and platelet function assays. Women with type 1 Gaucher disease who gave birth at Sheba Medical Center between 1999-2009 comprised the study cohort. Data collected included disease history, enzyme treatment, platelet counts, delivery and pregnancy outcome. PPH was defined as excessive bleeding during or immediately following delivery. Coagulation studies and platelet function tests, including aggregometry and cone and platelet (CPA) analyses, were performed on all women. We compared women with PPH (bleeders) and non-bleeders. Furthermore, women with abnormal CPA platelet function tests were compared with those with normal CPA platelet function with regards to the risk for PPH in at least one pregnancy. Forty-five pregnancies of 20 women were studied. Six women received enzyme replacement therapy during pregnancy. Mean platelet count prior to delivery was 83,000/MUl +/- 35,000/MUl. Fourteen out of 45 (31%) deliveries were complicated by PPH. Neither thrombocytopenia nor enzyme therapy predicted PPH. Twelve out of 13 women with PPH (92.3%) versus 2/7 non-bleeders (28.6%) had impaired platelet aggregation (less than the 3rd percentile of normal average aggregate size values), when tested by CPA, (odds ratio [OR] 17.8, 95% confidence interval [CI] 2.5; 126.2; p=0.007). Notably, 78.6% of women with impaired CPA aggregation developed PPH during at least one delivery, as opposed to 16.7% of those with normal CPA platelet function tests (OR 11.6, 95% CI 1.7-77.7, p=0.018). In conclusion, women with type 1 Gaucher disease who have abnormal platelet function tests may have an increased risk of PPH. PMID- 21301777 TI - Frequency of platelet type versus type 2B von Willebrand disease. An international registry-based study. AB - Less than 50 patients are reported with platelet type von Willebrand disease (PT VWD) worldwide. Several reports have discussed the diagnostic challenge of this disease versus the closely similar disorder type 2B VWD. However, no systematic study has evaluated this dilemma globally. Over three years, a total of 110 samples/data from eight countries were analysed. A molecular approach was utilised, analysing exon 28 of the von Willebrand factor (VWF) gene, and in mutation negative cases the platelet GP1BA gene. Our results show that 48 cases initially diagnosed as putative type 2B/PT-VWD carried exon 28 mutations consistent with type 2B VWD, 17 carried GP1BA mutations consistent with a PT-VWD diagnosis, three had other VWD types (2A and 2M) and five expressed three non previously published exon 28 mutations. Excluding 10 unaffected family members and one acquired VWD, 26 cases did not have mutations in either genes. Based on our study, the percentage of type 2B VWD diagnosis is 44% while the percentage of misdiagnosis of PT-VWD is 15%. This is the first large international study to investigate the occurrence of PT-VWD and type 2B VWD worldwide and to evaluate DNA analysis as a diagnostic tool for a large cohort of patients. The study highlights the diagnostic limitations due to unavailability/poor application of RIPA and related tests in some centres and proposes genetic analysis as a suitable tool for the discrimination of the two disorders worldwide. Cases that are negative for both VWF and GP1BA gene mutations require further evaluation for alternative diagnoses. PMID- 21301778 TI - Diagnostic test combinations associated with thrombosis in lupus anticoagulant positive patients. PMID- 21301779 TI - An improved method for specific and quantitative determination of the clopidogrel active metabolite isomers in human plasma. AB - Pharmacokinetic analyses of clopidogrel are hampered by the existence of multiple active metabolite isomers (H1 to H4) and their instability in blood. We sought to retest the pharmacodynamic activities of the four individual active metabolite isomers in vitro, with the ultimate aim of determining the isomers responsible for clopidogrel activity in vivo. In vitro activity was evaluated by measuring binding of [33P]-2-methylthio-ADP on P2Y12-expressing Chinese hamster ovary (CHO) cells and human platelets in platelet-rich plasma (PRP). A stereoselective method that used reverse-phase ultra high-performance liquid chromatography (UHPLC) and tandem mass spectrometry (MS) was developed to measure individual concentrations of the stable 3'-methoxyacetophenone (MP) derivatives of H1-H4. The new method was used to analyze plasma samples from clopidogrel-treated subjects enrolled in a phase I clinical trial. In vitro binding assays confirmed the previously observed biological activity of H4 (IC50: CHO-P2Y12: 0.12 MUM; PRP: 0.97 MUM) and inactivity of H3, and demonstrated that H1 was also inactive. Furthermore, H2 demonstrated approximately half of the biological activity in vitro compared with H4. Optimisation of UHPLC conditions and MS collision parameters allowed the resolution and detection of the four derivatised active metabolite isomers (MP-H1 to MP-H4). The stereoselective assay was extensively validated, and was accurate and precise over the concentration range 0.5-250 ng/ml. Only MP-H3 and MP-H4 were quantifiable in incurred clinical samples. Based on in vitro pharmacodynamic data and found concentrations, the active metabolite isomer H4 is the only diastereoisomer of clinical relevance for documenting the pharmacokinetic profile of the active metabolite of clopidogrel. PMID- 21301780 TI - Long-term secondary prophylaxis in children, adolescents and young adults with von Willebrand disease. Results of a cohort study. AB - In patients with von Willebrand disease (VWD) replacement therapy with factor VIII/von Willebrand (VWF) concentrates is increasingly applied as prophylactic regimen. Since 2000, 82 consecutively enrolled patients with clinically relevant bleeding episodes (spontaneous, peri- or postoperative) were diagnosed with VWD [type 1: 42/82; type 2: 24/82; type 3: 13/82; acquired: 3/82]. In all patients, decision for initiating prophylaxis was based on a bleeding score > 2 prior to diagnosis, concomitant with recurrent bleeds associated with anaemia in patients with on-demand VWD therapy. We report results on secondary prophylactic VWF replacement therapy applied in 32 patients [children n=13; adolescents n=7; adults n=12] with VWD [type 1: 4; type 2: 15; type 3: 13], 15 of which were females, and nine of these at the reproductive period. Eight patients were treated with Humate P(r) or Wilate(r) (n=24). Median [min-max] dose [vWF:RCo] was 40 [20-47] IU/kg, 23 patients were given substitution therapy twice weekly, seven patients three times a week, and two children four times per week. Within a 12 month-period haemoglobin concentrations returned to normal values. Median duration of prophylaxis was three years. Recurrent bleeding episodes stopped in 31 of 32 patients, whereas inhibitors developed in one. Following a 12-month observation period the monthly bleeding frequency and the bleeding score was significantly reduced [3 vs. 0.07; 3 vs. 0: p< 0.001], compared to the pre prophylaxis/pre-diagnostic values. The use of secondary prophylactic VWF replacement therapy is an effective tolerated treatment modality, highly beneficial for patients with VWD, who present with recurrent bleeding events during on-demand therapy. PMID- 21301781 TI - The value of 64-detector row computed tomography for the exclusion of pulmonary embolism. AB - Recently, a diagnostic strategy using a clinical decision rule, D-dimer testing and spiral computed tomography (CT) was found to be effective in the evaluation of patients with clinically suspected pulmonary embolism (PE). However, the rate of venous thromboembolic complications in the three-month follow-up of patients with negative CT was still substantial and included fatal events. It was the objective to evaluate the safety of withholding anticoagulants after a normal 64 detector row CT (64-DCT) scan from a cohort of patients with suspected PE. A total of 545 consecutive patients with clinically suspected first episode of PE and either likely pre-test probability of PE (using the simplified Wells score) or unlikely pre-test probability in combination with a positive D-dimer underwent a 64-DCT. 64-DCT scanning was inconclusive in nine patients (1.6%), confirmed the presence of PE in 169 (31%), and ruled out the diagnosis in the remaining 367. During the three-month follow-up of the 367 patients one developed symptomatic distal deep-vein thrombosis (0.27%; 95%CI, 0.0 to 1.51%) and none developed PE (0 %; 95%CI, 0 to 1.0%). We conclude that 64-DCT scanning has the potential to safely exclude the presence of PE virtually in all patients presenting with clinical suspicion of this clinical disorder. PMID- 21301782 TI - Urokinase-type plasminogen activator contributes to heterogeneity of macrophages at the border of damaged site during liver repair in mice. AB - Urokinase-type plasminogen activator (u-PA) plays an important role in tissue remodelling through the activation of plasminogen in the liver, but its mechanisms are less well known. Here, we investigated the involvement of u-PA in the accumulation and phenotypic heterogeneity of macrophages at the damaged site during liver repair. After induction of liver injury by photochemical reaction in mice, the subsequent pathological responses and expression of phenotypic markers in activated macrophages were analysed histologically. Fibrinolytic activity at the damaged site was also examined by fibrin zymography. In wild-type mice, the extent of damage decreased gradually until day 14 and was associated with an accumulation of macrophages at the border of the damaged site. In addition, the macrophages that accumulated near the damaged tissue expressed CD206, a marker of highly phagocytic macrophages, on day 7. Further, macrophages that were adjacent to CD206-positive cells expressed inducible nitric oxide synthase (iNOS), a pro inflammatory marker. u-PA activity increased at the damaged site on days 4 and 7, which distributed primarily at the border region. In contrast, in u-PA-deficient mice, the decrease in damage size and the accumulation of macrophages were impaired. Further, neither CD206 nor iNOS was expressed in the macrophages that accumulated at the border region in u-PA-deficient mice. Mice deficient for the gene encoding either u-PA receptor (u-PAR) or tissue-type plasminogen activator experienced normal recovery during liver repair. These data indicate that u-PA mediates the accumulation of macrophages and their phenotypic heterogeneity at the border of damaged sites through u-PAR-independent mechanisms. PMID- 21301783 TI - Increased platelet aggregation and in vivo platelet activation after granulocyte colony-stimulating factor administration. A randomised controlled trial. AB - Granulocyte colony-stimulating factor (G-CSF) stimulates the bone marrow to produce granulocytes and stem cells and is widely used to accelerate neutrophil recovery after chemotherapy. Interestingly, specific G-CSF receptors have been demonstrated not only on myeloid cells, but also on platelets. Data on the effects of G-CSF on platelet function are limited and partly conflicting. The objective of this study was to determine the effect of G-CSF on platelet aggregation and in vivo platelet activation. Seventy-eight, healthy volunteers were enrolled into this randomised, placebo-controlled trial. Subjects received 5 MUg/kg methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF, filgrastim) or placebo subcutaneously for four days. We determined platelet aggregation with a whole blood impedance aggregometer with various, clinically relevant platelet agonists (adenosine diphosphate [ADP], collagen, arachidonic acid [AA], ristocetin and thrombin receptor activating peptide 6 [TRAP]). Filgrastim injection significantly enhanced ADP (+40%), collagen (+60%) and AA (+75%)-induced platelet aggregation (all p<0.01 as compared to placebo and p<0.001 as compared to baseline). In addition, G-CSF enhanced ristocetin-induced platelet aggregation (+18%) whereas TRAP-induced platelet aggregation decreased slightly (-14%) in response to filgrastim. While baseline aggregation with all agonists was only slightly but insignificantly higher in women than in men, this sex difference was enhanced by G-CSF treatment, and became most pronounced for ADP after five days (p<0.001). Enhanced platelet aggregation translated into a 75% increase in platelet activation as measured by circulating soluble P selectin. G-CSF enhances platelet aggregation and activation in humans. This may put patients suffering from cardiovascular disease and cancer at risk for thrombotic events. PMID- 21301784 TI - Residual cyclooxygenase-1 activity and epinephrine reduce the antiplatelet effect of aspirin in patients with acute myocardial infarction. AB - Aspirin treatment is essential in patients with acute myocardial infarction (AMI) to block platelet thromboxane (TXA)2 synthesis. Epinephrine is known to enhance platelet reactivity induced by other agonists and to be elevated in patients with AMI due to stress. Our objective was to study the influence of epinephrine on platelet TXA2 synthesis in patients treated with aspirin for AMI at early onset (within 48 hours) and the potential biochemical mechanisms involved in the functional response. Washed platelets from 45 patients with AMI and 10 aspirin free controls were stimulated with arachidonic acid (AA) or AA + epinephrine, and aggregation and TXA2 synthesis were evaluated. Full platelet aggregation was recorded in 8/45 patients (18%) with a partial TXA2 inhibition (86%) vs. the aspirin-free controls. Platelets from the remaining 37 patients did not aggregate to AA and had TXA2 inhibition >95%. However, when platelets were simultaneously stimulated with AA + epinephrine, in 25/37 patients a large intensity of aggregation (73%) was observed and a 5.5-fold increase in TXA2 synthesis, although this remained residual (<5% of aspirin-free controls). This residual TXA2 was critical in the functional response, as demonstrated by the complete inhibition by TXA2 receptor blockade or additional aspirin in vitro. The phosphatidylinositol-3-kinase activity and the cytosolic calcium levels participated in this platelet response elicited by a receptor cooperation mechanism, while the Rho/p160(ROCK) pathway or the blockade of the ADP receptors (P2Y1, P2Y12) were without effect. Residual-cyclooxygenase -1 activity and epinephrine enhance TXA2-dependent platelet function, which may reduce the clinical benefit of aspirin in patients with AMI. PMID- 21301785 TI - Comparative assessment of drug-eluting balloons in an advanced porcine model of coronary restenosis. AB - The advent of drug-eluting balloon (DEB) therapy has represented an important development in interventional cardiology. Nevertheless, preclinical data with this technology remain scant, and comparative studies have not previously been published. Bare metal stents were implanted in the coronary arteries of 15 pigs followed by balloon angioplasty. Animals were allocated to treatment with a 60 second inflation of one of four different balloon catheters: a conventional untreated plain angioplasty balloon (PBA, Biotronik AG), the Pantera Lux DEB (3.0 MUg/mm2 paclitaxel; BTHC excipient, Biotronik AG), the Elutax DEB (2.0 MUg/mm2 paclitaxel; no excipient; Aachen Resonance), or the SeQuent Please DEB (3.0 MUg/mm2 paclitaxel; iopromide excipient: B. Braun). Twenty-eight days following balloon deployment, animals underwent repeat angiography for quantitative coronary angiography analysis and euthanasia for histopathologic assessment. By histology, the mean neointimal thickness was 0.44 +/- 0.19 mm with PBA, 0.35 +/- 0.13 mm with Pantera Lux , 0.61 +/- 0.20 mm with Elutax , and 0.47 +/- 0.21 mm with SeQuent Please DEB (p=0.02). In comparison with PBA, deployment of the Pantera Lux or the SeQuent Please DEB resulted in delayed healing characterised by significant increases in fibrin, neointimal cell vacuity and delayed re endothelialisation. In conclusion, investigation of comparative DEB performance in a porcine model of advanced coronary restenosis reveals significant heterogeneity of neointimal suppression between the devices tested with numerically lowest values seen in the Pantera Lux group. On the other hand, evidence of delayed healing was observed in the most effective DEB groups. PMID- 21301786 TI - Ischaemic cardiovascular mortality in patients with non-valvular atrial fibrillation according to CHADS2 score. AB - The CHADS2 score predicts the risk of ischaemic stroke in patients with non valvular atrial fibrillation (NVAF). Most components of the CHADS2 score are also risk factors of atherosclerosis, and clustering of these risk factors is associated with increased risk of cardiovascular disease, including ischaemic heart disease. The aim of this study was to investigate whether the CHADS2 score and CHA2DS2-VASc score are predictive of fatal ischaemic heart disease as well as fatal ischaemic stroke. Among 5,268 stroke patients admitted between August 1994 and December 2008, 770 stroke patients with NVAF were enroled in this study. The relationship between CHADS2 score or CHA2DS2-VASc score and the fatal ischaemic events was examined using a Cox regression model. During the follow-up period of 1156.0 +/- 1205.0 days (median 729.5, interquartile range 179.0-1751.0), 321 patients died (41.7%). The CHADS2 score or CHA2DS2-VASc score was positively correlated with fatal ischaemic heart disease as well as with fatal ischaemic stroke. After adjustment for all potential confounders, the occurrence of fatal ischaemic heart disease was independently associated with CHADS2 score or CHA2DS2 VASc score, and previous history of ischaemic heart disease. The CHADS2 and CHA2DS2-VASc scores provide valuable information for identifying high-risk individuals for fatal ischaemic heart and brain diseases among stroke patients with NVAF. PMID- 21301787 TI - Characterisation of factor IX with a glycine-to-valine missense mutation at residue 190 in a patient with severe haemophilia B. AB - A patient with severe haemophilia B with a glycine-to-valine missense mutation at residue 190 (c25, chymotrypsin numbering) in factor IX (FIX; FIX-G190V or FIX FuChou) had <1% of normal FIX clotting activity and 36% of normal FIX antigen levels (cross-reacting material- reduced, CRMr). Residue 190 in the C-terminal protease domain of human FIX is highly conserved in mammalian species and the serine protease family, suggesting that it has an indispensable role in protein function. To explore the pathological mechanism by which this mutation contributes to dysfunction of the FIX molecule, we functionally characterised FIX G190V in vitro and in vivo. Liver-specific FIX-G190V gene expression following hydrodynamic plasmid delivery into haemophilia B mice revealed a 5.7-fold reduction in specific clotting activity compared with FIX-WT (wild type) and a two-fold decrease in plasma FIX-G190V concentration. Pulse-chase analysis demonstrated that FIX-G190V was secreted at a significantly slower rate than was FIX-WT. Purified FIX-G190V and FIX-WT displayed normal calcium-dependent conformational changes as shown by intrinsic fluorescence quenching. The in vivo half-lives of FIX-G190V and FIX-WT were indistinguishable. FIX-G190V was, however, more readily degraded than FIX-WT, especially after being activated by the active form of FXI. The vulnerable sites were mapped to the peptide bonds at Arg116-Leu117, Lys265-Tyr266, Arg327-Val328, and Arg338-Ser339, which are in the exposed loops of the FIX molecule. Also, failure of FXIa-activated FIX-G190V to bind p-aminobenzamidine indicated an abnormal conformation of the active-site pocket. Thus, the mutation at residue 190 of FIX may result in protein misfolding that affects secretion, clotting function, and hydrolysis. PMID- 21301788 TI - A novel missense mutation in the FGB g. 3354 T>A (p. Y41N), fibrinogen Caracas VIII. AB - A novel dysfibrinogenaemia with a replacement of Tyr by Asn at Bbeta41 has been discovered (fibrinogen Caracas VIII). An asymptomatic 39-year-old male was diagnosed as having dysfibrinogenaemia due to a mildly prolonged thrombin time (+ 5.8 seconds); his fibrinogen concentration was in the low normal range, both by Clauss and gravimetric determination, 1.9 g/l and 2.1 g/l, respectively. The plasma polymerization process was slightly impaired, characterised by a mildly prolonged lag time and a slightly increased final turbidity. Permeation through the patients' clots was dramatically increased, with the Darcy constant around four times greater than that of the control (22 +/- 2 x 10(-9) cm2 compared to 6 +/- 0.5 x 10(-9) cm2 in controls). The plasma fibrin structure of the patient, by scanning electron microscopy, featured a mesh composed of thick fibres (148 +/- 50 nm vs. 120 +/- 31 nm in controls, p<0.05) and larger pores than those of the control fibrin clot. The viscoelastic properties of the clot from the patient were also altered, as the storage modulus (G', 310 +/- 30) was much lower than in the control (831 +/- 111) (p <=0.005). The interaction of the fibrin clot with a monolayer of human microvascular endothelial cells, by confocal laser microscopy, revealed that the patients' fibrin network had less interaction with the cells. These results demonstrate the significance of the amino terminal end of the beta chain of fibrin in the polymerisation process and its consequences on the clot organisation on the surface of endothelial cells. PMID- 21301789 TI - Comparison of research case definitions for carpal tunnel syndrome. AB - OBJECTIVE: The aim of this study was to assess agreement between different case definitions of carpal tunnel syndrome (CTS) for epidemiological studies. METHODS: We performed a literature search for papers suggesting case definitions for use in epidemiological studies of CTS. Using data elements based on symptom questionnaires, hand diagrams, physical examinations, and nerve conduction studies collected from 1107 newly-hired workers, each subject in the study was classified according to each of the case definitions selected from the literature. We compared each case definition to every other case definition, using the Kappa statistic to measure pair-wise agreement on whether each subject met the case definition. RESULTS: We found six unique papers in a 20-year period suggesting a case definition of CTS for use in population-based studies. We extracted seven case definitions. Definitions included different parameters: (i) symptoms only, (ii) symptoms and physical examination, (iii) symptoms and either physical examination or median nerve conduction study, and (iv) symptoms and nerve conduction study. When applied to our study population, the prevalence of CTS using different case definitions ranged from 2.5-11.0%. The percentage of misclassification was between 1-10%, with generally acceptable levels of agreement (kappa values ranged from 0.30-0.85). CONCLUSIONS: Different case definitions resulted in widely varying prevalences of CTS. Agreement between case definitions was generally good, particularly between those that required very specific symptoms or the combination of symptoms and physical examination or nerve conduction. The agreement observed between different case definitions suggests that the results can be compared across different research studies of risk factors for CTS. PMID- 21301790 TI - Causes of moderate to large pericardial effusion requiring pericardiocentesis in 140 Han Chinese patients. AB - BACKGROUND: Causes of pericardial effusion requiring pericardiocentesis are very complex; a summary of 140 patients, especially those having iatrogenic pericardial effusion, is rare. METHODS: We prospectively analyzed the clinical data and etiology of moderate to large pericardial effusion requiring pericardiocentesis and drainage in 140 consecutive Han Chinese patients from January 2007 to December 2009. RESULTS: Pericardiocentesis was successfully performed and effective in all patients. There were 9 cases with transudates, while the remaining 131 cases were diagnosed with exudates (neoplastic in 54 patients, tuberculous in 40 patients, 9 cases of connective tissue diseases, 12 cases undergoing cardiac catheterization, and 8 cases of acute myocardial infarction). Among the 54 malignancies, 30 patients had lung cancer, 7 had breast cancer, and 4 had liver cancer. No differences in the clinical characteristics and the results of routine and biochemistry studies in the pericardial fluid between tuberculous and malignant groups were found. Of the 12 patients undergoing cardiac catheterization, 6 cases had undergone catheter ablation for tachycardia and 4 cases had undergone percutaneous coronary intervention. The 6 patients undergoing catheter ablation were women and the ratio of pericardial effusion was higher in women (6/436) than in men (0/462; p<0.05). Pericardiocentesis and drainage was effective in the 6 patients who underwent catheter ablation, and the remaining 6 patients underwent surgical intervention after pericardiocentesis and drainage. All 8 patients with acute myocardial infarction died during hospitalization. CONCLUSION: In China, most moderate to large pericardial effusions requiring pericardiocentesis and drainage were exudates and bloody, which were mainly caused by malignancy and tuberculosis. However, the incidence of iatrogenic pericardial effusion has been increasing and should not be ignored. Pericardiocentesis and drainage were effective. PMID- 21301791 TI - [Psychosomatic aspects of chronic heart failure. Nothing but depression?]. AB - Psychosocial factors are bi-directionally associated with the pathophysiology, symptoms, and prognosis observed in heart failure. Cardiac symptom severity is both dependent on psychological appraisal processes and causally related to feelings of exhaustion and distress. Distress and depression have been shown to affect physiological processes involved in the pathogenesis and course of chronic heart failure as well as illness behaviors. Conversely, physiological consequences of heart failure such as inflammatory activation may lead to sickness behavior and depression. However, there are some indications that the secretion of natriuretic peptides observed in response to cardiac overload may also have beneficial psychological effects (e.g., anxiolysis). Quality of life is typically reduced in heart failure but functional impairment and psychological maladjustment seem to be more important for quality of life than cardiac severity markers such as systolic or diastolic function per se. Current guidelines therefore recommend complementing optimal medical care with good communication, the creation of a trustful physician-patient relationship, patient education and partnership building, as well as specialized mental health care in cases of severe or enduring mental disorders or inappropriate illness behavior. While the evidence for antidepressant drug treatment in heart failure appears inconclusive, behavioral treatments such as exercise and psychotherapy may be more promising in treating comorbid anxiety and depression. PMID- 21301792 TI - The Gretchen question in autosomal-dominant polycystic kidney disease research. PMID- 21301793 TI - A return to cancer metabolism. PMID- 21301794 TI - Glutamine: pleiotropic roles in tumor growth and stress resistance. AB - Tumors and tumor cell lines rapidly consume the amino acid glutamine (Gln) and use it to supply metabolic pathways that support cell growth and proliferation. Much of the research regarding the relationship between glutamine metabolism and cancer is based on the premise that this abundant nutrient represents an important driver of tumor cell anabolism. However, Gln's influence in cell biology and cancer extends far beyond its use as a carbon and nitrogen source for the structural components of dividing cells. Gln is truly a multipurpose nutrient, feeding many additional pathways that boost the ability of cells to communicate with each other and to cope with stress by oncogenic signaling and by the tumor microenvironment. A number of recent reports have highlighted these "non-anabolic" functions of Gln metabolism in regulating cell survival, oxidative stress resistance, signal transduction, and autophagy. Here, we review some of these findings and discuss their relevance to tumor biology and the potential for cancer therapy. PMID- 21301795 TI - Therapeutic targeting of cancer cell metabolism. AB - In 1927, Otto Warburg and coworkers reported the increased uptake of glucose and production of lactate by tumors in vivo as compared with normal tissues. This phenomenon, now known as the Warburg effect, was recapitulated in vitro with cancer tissue slices exhibiting excessive lactate production even with adequate oxygen. Warburg's in vivo studies of tumors further suggest that the dependency of tumors in vivo on glucose could be exploited for therapy, because reduction of arterial glucose by half resulted in a four-fold reduction in tumor fermentation. Recent work in cancer metabolism indicates that the Warburg effect or aerobic glycolysis contributes to redox balance and lipid synthesis, but glycolysis is insufficient to sustain a growing and dividing cancer cell. In this regard, glutamine, which contributes its carbons to the tricarboxylic acid (TCA) cycle, has been re-discovered as an essential bioenergetic and anabolic substrate for many cancer cell types. Could alterations in cancer metabolism be exploited for therapy? Here, we address this question by reviewing current concepts of normal metabolism and altered metabolism in cancer cells with specific emphasis on molecular targets involved directly in glycolysis or glutamine metabolism. PMID- 21301796 TI - Inborn and acquired metabolic defects in cancer. AB - The observation that altered metabolism is the fundamental cause of cancer was made by Otto Warburg nearly a century ago. However, the subsequent identification of oncogenes and tumor suppressor genes has displaced Warburg's theory pointing towards genetic aberrations as the underlining cause of cancer. Nevertheless, in the last decade, cancer-associated mutations have been identified in genes coding for tricarboxylic acid cycle (TCA cycle, also known as Krebs cycle) and closely related enzymes that have essential roles in cellular metabolism. These observations have revived interest in Warburg's hypothesis and prompted a flurry of functional studies in the hope of gaining mechanistic insight into the links between mitochondrial dysfunction, metabolic alterations, and cancer. In this review, we discuss the potential pro-oncogenic signaling role of some TCA cycle metabolites and their derivatives (oncometabolites). In particular, we focus on their effects on dioxygenases, a family of oxygen and alpha-ketoglutarate dependent enzymes that control, among other things, the levels and activity of the hypoxia-inducible transcription factors and the activity of DNA and histone demethylases. PMID- 21301797 TI - mTOR links oncogenic signaling to tumor cell metabolism. AB - As a key regulator of cell growth and proliferation, the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) has been the subject of intense investigation for its role in tumor development and progression. This research has revealed a signaling network of oncogenes and tumor suppressors lying upstream of mTORC1, and oncogenic perturbations to this network result in the aberrant activation of this kinase complex in the majority of human cancers. However, the molecular events downstream of mTORC1 contributing to tumor cell growth and proliferation are just coming to light. In addition to its better-known functions in promoting protein synthesis and suppressing autophagy, mTORC1 has emerged as a key regulator of cellular metabolism. Recent studies have found that mTORC1 activation is sufficient to stimulate an increase in glucose uptake, glycolysis, and de novo lipid biosynthesis, which are considered metabolic hallmarks of cancer, as well as the pentose phosphate pathway. Here, we focus on the molecular mechanisms of metabolic regulation by mTORC1 and the potential consequences for anabolic tumor growth and therapeutic strategies. PMID- 21301798 TI - Development of S/MAR minicircles for enhanced and persistent transgene expression in the mouse liver. AB - We have previously described the development of a scaffold/matrix attachment region (S/MAR) episomal vector system for in vivo application and demonstrated its utility to sustain transgene expression in the mouse liver for at least 6 months following a single administration. Subsequently, we observed that transgene expression is sustained for the lifetime of the animal. The level of expression, however, does drop appreciably over time. We hypothesised that by eliminating the bacterial components in our vectors, we could improve their performance since bacterial sequences have been shown to be responsible for the immunotoxicity of the vector and the silencing of its expression when applied in vivo. We describe here the development of a minimally sized S/MAR vector, which is devoid of extraneous bacterial sequences. This minicircle vector comprises an expression cassette and an S/MAR moiety, providing higher and more sustained transgene expression for several months in the absence of selection, both in vitro and in vivo. In contrast to the expression of our original S/MAR plasmid vector, the novel S/MAR minicircle vectors mediate increased transgene expression, which becomes sustained at about twice the levels observed immediately after administration. These promising results demonstrate the utility of minimally sized S/MAR vectors for persistent, atoxic gene expression. PMID- 21301799 TI - hSMG-1 is a granzyme B-associated stress-responsive protein kinase. AB - Granzyme B plays a key role in cell-mediated programmed cell death. We previously demonstrated that p53 is a functional determinant in the granzyme B-induced cytotoxic T-lymphocyte response. However, the pathways leading to activation of p53 by granzyme B remain incompletely understood. We now demonstrate that granzyme B-induced DNA damage signaling as revealed by histone H2AX phosphorylation and subsequent activation of the stress kinase CHK2. Confocal microscopy analysis indicates that granzyme B treatment of tumor cells induced an early translocation of endonuclease caspase-activated DNase. DNA microarray-based global transcriptional profiling and RT-PCR indeed revealed genes related to DNA damage. Among these genes, hSMG-1, a genotoxic stress-activated protein, was constantly upregulated in tumor cells following granzyme B treatment. Knockdown of the hSMG-1 gene in T1 tumor target cell line resulted in a significant inhibition of granzyme B- and CTL-induced killing. Our data suggest that granzyme B may exert cell death through DNA damage signaling and uncover a novel molecular link between the DNA damage pathway and granzyme B-induced cell death. PMID- 21301800 TI - [Psychiatric disorders associated with imminent deportation. Results of a retrospective study in a group of immigrants]. AB - BACKGROUND: The aim of this study was to investigate characteristics of migrants facing imminent deportation in comparison with migrants with guaranteed residence status. The occurrence of psychoreactive disorders in both groups was examined. PATIENTS AND METHODS: In a case-control study 82 migrants recorded as inpatients facing imminent deportation were compared to a control group of 93 migrants with guaranteed residence status. RESULTS: Migrants facing imminent deportation more frequently suffered from psychoreactive disorders, compared to migrants with guaranteed residence status. In this subgroup psychoreactive disorders were associated with reported traumatisations. Imminent deportation within the next month was associated with the diagnosis of psychoreactive disorder as well. CONCLUSION: Psychoreactive disorders appeared more frequently in immigrant inpatients facing imminent deportation. Additionally a history of traumatisations is associated with the progression of psychoreactive disorders. PMID- 21301801 TI - [On the differential diagnostics of depersonalization experiences]. AB - Depersonalization represents an unspecific symptom which is to be found across the entire spectrum of psychiatric nosology. Delineating the historical lines of development of the depersonalization concept and reviewing existing psychopathological experiential knowledge reveals that depersonalization is underpinned by highly diverse modes of experience. In terms of differential diagnostics at the symptom level, a distinction can be made between depersonalization as a neurotic phenomenon on the one hand and a psychotic form occurring in schizophrenia and melancholia on the other. The reference points defined here extend beyond current descriptive classifications and open up the diagnostic process to allow an inclusion of etiological and therapeutic aspects. PMID- 21301802 TI - Phylogenetic relationship of a new class of LMW-GS genes in the M genome of Aegilops comosa. AB - A new class of low molecular weight glutenin subunit (LMW-GS) genes was isolated and characterized from Aegilops comosa (2n = 2x = 14, MM). Although their DNA structure displayed high similarity to LMW-i type genes, there are some key differences. The deduced amino acid sequences of their mature proteins showed that the first amino acid residue of each gene was leucine and therefore they were designated as LMW-l type subunits. An extra cysteine residue was present in the signal peptide and the first cysteine residue of mature proteins located at the end of repetitive domain. Additionally, a long insertion of 10-22 residues (LGQQPQ(5-17)) occurred in the end of the C-terminal II. Comparative analysis demonstrated that LMW-l type glutenin genes possessed a great number of single nucleotide polymorphisms and insertions/deletions. A new classification system was proposed according to the gene structure and phylogenetic analysis. In this new system, LMW-GS is classified into two major classes, LMW-M and LMW-I, with each including two subclasses. The former included LMW-m and LMW-s types while the latter contained LMW-l and LMW-i types. Analysis of their evolutionary origin showed that the LMW-l genes diverged from the group 2 of LMW-m type genes at about 12-14 million years ago (MYA) while LMW-i type evolved from LMW-l type at approximately 8-12 MYA. The LMW-s type was a variant form of group 1 of LMW-m type and their divergence occurred about 4-6 MYA. In addition to homologous recombination, non-homologous illegitimate recombination could be an important molecular mechanism for the origin and evolution of LMW-GS gene family. The secondary structure prediction suggested that the novel LMW-l type subunits, such as AcLMW-L1 and AcLMW-L2, may have positive effects on dough properties. PMID- 21301803 TI - Delineation of interspecific epistasis on fiber quality traits in Gossypium hirsutum by ADAA analysis of intermated G. barbadense chromosome substitution lines. AB - Genetic diversity is the foundation of any crop improvement program, but the most cultivated Upland cotton [Gossypium hirsutum L., 2n = 52, genomic formula 2(AD)(1)] has a very narrow gene pool resulting from its evolutionary origin and domestication history. Cultivars of this cotton species (G. hirsutum L.) are prized for their combination of exceptional yield, other agronomic traits, and good fiber properties, whereas the other cultivated 52-chromosome species, G. barbadense L. [2n = 52, genomic formula 2(AD)(2)], is widely regarded as having the opposite attributes. It has exceptionally good fiber qualities, but generally lower yield and less desirable agronomic traits. Breeders have long aspired to combine the best attributes of G. hirsutum and G. barbadense, but have had limited success. F(1) hybrids are readily created and largely fertile, so the limited success may be due to cryptic biological and technical challenges associated with the conventional methods of interspecific introgression. We have developed a complementary alternative approach for introgression based on chromosome substitution line, followed by increasingly sophisticated genetic analyses of chromosome-derived families to describe the inheritance and breeding values of the chromosome substitution lines. Here, we analyze fiber quality traits of progeny families from a partial diallel crossing scheme among selected chromosome substitution lines (CS-B lines). The results provide a more detailed and precise QTL dissection of fiber traits, and an opportunity to examine allelic interaction effects between two substituted chromosomes versus one substituted chromosome. This approach creates new germplasm based on pair wise combinations of quasi-isogenic chromosome substitutions. The relative genetic simplicity of two-chromosome interactions departs significantly from complex or RIL-based populations, in which huge numbers of loci are segregating in all 26 chromosome pairs. Data were analyzed according to the ADAA genetic model, which revealed significant additive, dominance, and additive-by-additive epistasis effects on all of the fiber quality traits associated with the substituted chromosome or chromosome arm of CS-B lines. Fiber of line 3-79, the donor parent for the substituted chromosomes, had the highest Upper Half Mean length (UHM), uniformity ratio, strength, elongation, and lowest micronaire among all parents and hybrids. CS-B16 and CS-B25 had significant additive effects for all fiber traits. Assuming a uniform genetic background of the CS-B lines, the comparative analysis of the double-heterozygous hybrid combinations (CS-B * CS-B) versus their respective single heterozygous combinations (CS-B * TM-1) demonstrated that interspecific epistatic effects between the genes in the chromosomes played a major role in most of the fiber quality traits. Results showed that fiber of several hybrids including CS-B16 * CS-B22Lo, CS-B16 * CS-B25 and CS-B16 * TM-1 had significantly greater dominance effects for elongation and hybrid CS-B16 * CS-B17 had higher fiber strength than their parental lines. Multiple antagonistic genetic effects were also present for fiber quality traits associated with most of the substituted chromosomes and chromosome arms. Results from this study highlight the vital importance of epistasis in fiber quality traits and detected novel effects of some cryptic beneficial alleles affecting fiber quality on the 3-79 chromosomes, whose effects were not detected in the 3-79 parental lines. PMID- 21301804 TI - Calcium/calmodulin-dependent kinase IV controls glucose-induced Irs2 expression in mouse beta cells via activation of cAMP response element-binding protein. AB - AIMS/HYPOTHESIS: Irs2, which is upregulated by glucose, is important for beta cell plasticity. Cyclic AMP response element-binding protein (CREB) stimulates beta cell Irs2 expression and is a major calcium/calmodulin-dependent kinase (CaMK)(IV) target in neurons. We therefore hypothesised that CaMK(IV) mediates glucose-induced Irs2 expression in beta cells via CREB activation. METHODS: The functions of CaMK(IV) and CREB were investigated in MIN6 beta cells and mouse islets using the CaMK inhibitor KN62, the calcium chelator bapta-(AM) and the voltage-dependent calcium channel inhibitor nifedipine. Small interfering RNAs were used to silence endogenous CaMK(IV) production and expression vectors to overproduce constitutively active and dominant negative forms of CaMK(IV) and CREB. Irs1 and Irs2 expression were determined by quantitative PCR and Western blotting, and the role of CREB was also investigated by assessing its phosphorylation on serine 133. RESULTS: Increasing the glucose concentration from 2.5 to 25 mmol/l stimulated CREB phosphorylation on serine 133 and specifically stimulated Irs2 but not Irs1 expression. Similarly, overproduction of a constitutively active form of CaMK(IV) promoted sustained CREB phosphorylation and a significant increase in Irs2 but not Irs1 expression. In contrast, these stimulatory effects of glucose were all suppressed by overproducing an inactive CaMK(IV) mutant. Inhibition of glucose-induced calcium influx with nifedipine or chelation of intracellular calcium with bapta-(AM), as well as silencing of CaMK(IV) or inhibition of its activity with KN62 resulted in similar observations. Finally, overproduction of a dominant negative form of CREB completely suppressed glucose and CaMK(IV) stimulation of Irs2 expression. CONCLUSIONS/INTERPRETATION: Our results suggest that the Ca(2+)/CaMK(IV)/CREB cascade plays a critical role in the regulation of Irs2 expression in beta cells. PMID- 21301805 TI - Bioremediation of PAH by Streptomyces sp. AB - An actinobacterium designated as PAH-13 was isolated from bitumen (heavy crude oil) soil collected from Mathura refinery, India. The isolate was screened for its ability to degrade 3-4 ring PAH compounds (anthracene, fluorene, phenanthrene and pyrene) in minimal medium supplemented with 0.1% yeast extract as a co substrate. The isolate was found to degrade four PAHs between 28%-92% within 15 days at 100 ppm level. In addition, the strain showed good extracellular production of biosurfactant measured as emulsification index (55%) in the presence of glucose as co-metabolic source. The isolate PAH-13 was identified as Streptomyces rochei by phylogenetic analysis of 16S rDNA sequence. The above findings indicated the potential of S.rochei for bioremediation of PAHs. This is first report confirming the involvement of S.rochei in PAHs degradation. PMID- 21301806 TI - Intestinal parasite Acanthocephalus lucii (Acanthocephala) from European perch (Perca fluviatilis) as a bioindicator for lead pollution in the stream "Jevansky potok" near Prague, Czech Republic. AB - Lead concentrations in the tissues of perch and its parasites were determined as mg/kg dw. Lead was found at higher concentrations in the acanthocephalans (11.56) than in different tissues (liver, gonads and muscle with skin and bone) of perch. With respect to fish tissues, the highest concentrations of lead were present in the liver (1.24), followed by the gonads (0.57) whereas the lowest concentrations were in the muscle with skin and bone (0.21). The bioconcentration factors for lead indicated that parasites accumulate metals to a higher degree than fish tissues--lead concentrations in acanthocephalans were 9.32, 19.27 and 55.05 higher than in liver, gonads and muscles of host, respectively. PMID- 21301807 TI - Ibuprofen metabolism in the liver and gill of rainbow trout, Oncorhynchus mykiss. AB - The presence of pharmaceuticals in the environment has become an important topic of discussion with respect to pharmaceutical absorption, metabolism and elimination in fish. This study investigates the metabolism of ibuprofen by rainbow trout (Oncorhynchus mykiss). In vitro metabolic loss of parent compound was measured in gill and liver S9 and microsomal fractions. Metabolite analysis found 2-hydroxy-ibuprofen as the major metabolite in uninduced S9 fractions. Supplementing S9 fractions with UDPGA did not significantly enhance metabolism. Additionally, assays involving the induction and inhibition of specific CYP isozymes support CYP1A2 as a possible metabolic pathway in fish. PMID- 21301808 TI - [State of the art of lumbar intervertebral disc replacement]. AB - Lumbar intervertebral total disc replacement is becoming more commonly employed for patients with degenerative disc disease as an alternative to spinal arthrodesis. Postulated advantages for the patients are motion preservation and height restoration in the affected segment, preventing adjacent level degeneration. Although studies show short and mid-term results which are comparable to spinal fusion, to date the long-term outcome is not clear. The different types of artificial discs and the current status of lumbar disc replacement are described. PMID- 21301809 TI - [Submuscular approach to the lumbar spine and extraforaminal cage implantation]. AB - The posterior median approach to the lumbar spine may cause significant injury to the erector spinae muscles (ESM) which is minimized using the paralateral approach suggested by Ray. We have adopted this approach and have extended it into the disc space to allow cage implantation from outside the foramen (EPLIF - extraforaminal posterior lumbar interbody fusion). The initial exposure of the posterior vertebral elements between the ESM and the deep lumbar fascia is sufficient to attain the entry points of pedicle screws. The intervertebral foramen and posterior annulus fibrosus are then exposed after which distant lateral disc herniations may be removed, the foramen/lateral recess may be decompressed or an EPLIF performed following clearing and vertical distraction of the disc space. This is followed by ipsilateral transpedicular fixation (TpF), contralateral fixation (second approach) by TpF or translaminar screws. Indications are given for foraminal and extraforaminal disc herniation, stenosis of the foramen and/or of the lateral recess, posterolateral fusion, TpF and EPLIF. The submuscular approach and EPLIF have proven to be valuable alternatives to standard techniques. PMID- 21301810 TI - Prepulse inhibition of the startle reflex and response to antipsychotic treatments in two outbred mouse strains in comparison to the inbred DBA/2 mouse. AB - RATIONALE: Naturally low prepulse inhibition (PPI) in DBA/2 mice is increased by marketed antipsychotics and compounds acting at novel targets relevant to schizophrenia. Whether other mouse strains with naturally low PPI respond similarly and could be translational models of schizophrenia is unknown. OBJECTIVE: Baseline levels of PPI were determined in outbred CF-1 and Black Swiss mice. CF-1 and Black Swiss mice were then compared to DBA/2 mice for their responses to typical (haloperidol) and atypical (clozapine) antipsychotics and to compounds with potential antipsychotic activity, a histamine H(3) receptor antagonist (thioperamide) and a glycine transporter-1 inhibitor (SSR504734). RESULTS: CF-1 and Black Swiss mice had naturally low PPI, similar to the level in C57BL/6 mice, but higher than that in DBA/2 mice. Haloperidol (0.3-1 mg/kg) increased PPI in DBA/2, CF-1, and Black Swiss mice. Clozapine (3 mg/kg) increased PPI in DBA/2 and CF-1 mice, but not in Black Swiss mice. Thioperamide (10-30 mg/kg) and SSR504734 (30 mg/kg) increased PPI only in DBA/2 mice. Strain differences in PPI responsiveness were not due to differences in brain concentrations of the tested compounds. CONCLUSIONS: CF-1 mice with naturally low PPI may be useful for testing typical and atypical antipsychotics while Black Swiss mice only responded to a typical antipsychotic. DBA/2 mice remain the only strain with naturally low PPI that responds to marketed antipsychotics, as well as to compounds with novel mechanisms of action. Thus, DBA/2 mice may be the strain of choice for screening novel chemical entities for their ability to increase PPI. PMID- 21301811 TI - Divergent effects of two different doses of intranasal oxytocin on facial affect discrimination in schizophrenic patients with and without polydipsia. AB - RATIONALE: Hyponatremia and dexamethasone resistance in polydipsic schizophrenic patients are attributable to changes in hippocampal-modulated antidiuretic and stress hormone activity, respectively. The relationship of the neuroendocrine findings to the psychiatric illness, however, is unknown. An impaired ability to identify facial emotions has been linked to core features of schizophrenia and to diminished levels of the closely related hormone, oxytocin, in the polydipsic subset. Intranasal oxytocin enhances facial affect discrimination in healthy subjects. OBJECTIVE: The aim of this study is to explore if oxytocin reverses impaired facial affect discrimination in schizophrenic patients with, relative to that in patients without, polydipsia. METHODS: Intranasal oxytocin (10 or 20 IU) and placebo were administered on three occasions to five polydipsic schizophrenic patients, eight nonpolydipsic patients, and 11 healthy controls. Subsequently, subjects rated the presence and intensity of six facial emotions. RESULTS: Emotion recognition fell in both patient groups following 10 IU of oxytocin due to an increased propensity to identify all emotions regardless of whether they were displayed. By contrast, emotion recognition improved following 20 IU in polydipsic relative to nonpolydipsic patients due primarily to divergent effects on the bias to identify fear in nonfearful faces. CONCLUSION: The effects of 20 IU oxytocin support the hypothesis that altered neuroendocrine function in polydipsic patients contributes to their psychiatric illness. Further studies are warranted to confirm these findings and assess if oxytocin treatment improves social functioning in this subset. This is the first psychopharmacologic study to compare different doses of oxytocin in the same subject, thus the significance of the opposing responses is unclear. PMID- 21301812 TI - A randomised placebo-controlled trial of oral hydrocortisone for treating tobacco withdrawal symptoms. AB - RATIONALE: Many smokers experience a decline in cortisol to sub-normal levels during the first days of smoking cessation. A greater decline in cortisol is associated with more intense cigarette withdrawal symptoms, urge to smoke and relapse to smoking. Findings from an uncontrolled study suggest that glucocorticoids could ameliorate cigarette withdrawal. OBJECTIVES: We investigated whether taking oral hydrocortisone would reduce withdrawal symptoms and the desire to smoke on the first day of temporary smoking abstinence compared with placebo. METHODS: Using a double-blind within-subject randomised crossover design, 48 smokers took a single dose of 40 mg hydrocortisone, 20 mg hydrocortisone or placebo following overnight smoking abstinence. Abstinence was maintained through the afternoon, and withdrawal symptoms and the desire to smoke were rated across the morning. Salivary cortisol was assessed in the afternoon prior to abstinence (baseline) and while abstinent after each treatment. RESULTS: There was a significant dose-response relation between dose of hydrocortisone and reduction in depression and anxiety ratings while abstinent, but there were no other statistically significant associations with dose. Overall, the decline in cortisol following smoking cessation (placebo only) was not significant. Cortisol level on the afternoon of smoking abstinence was not significantly associated with symptom ratings. CONCLUSIONS: Supplements of hydrocortisone do not reduce the desire to smoke but may ameliorate withdrawal-related depression and anxiety, although the clinical benefit is slight. PMID- 21301813 TI - Fluoxetine regulates the expression of neurotrophic/growth factors and glucose metabolism in astrocytes. AB - RATIONALE: The pharmacological actions of most antidepressants are ascribed to the modulation of serotonergic and/or noradrenergic transmission in the brain. During therapeutic treatment for major depression, fluoxetine, one of the most commonly prescribed selective serotonin reuptake inhibitor (SSRI) antidepressants, accumulates in the brain, suggesting that fluoxetine may interact with additional targets. In this context, there is increasing evidence that astrocytes are involved in the pathophysiology of major depression. OBJECTIVES: The aim of this study was to examine the effects of fluoxetine on the expression of neurotrophic/growth factors that have antidepressant properties and on glucose metabolism in cultured cortical astrocytes. RESULTS: Treatment of astrocytes with fluoxetine and paroxetine, another SSRI antidepressant, upregulated brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and VGF mRNA expression. In contrast, the tricyclic antidepressants desipramine and imipramine did not affect the expression of these neurotrophic/growth factors. Analysis of the effects of fluoxetine on glucose metabolism revealed that fluoxetine reduces glycogen levels and increases glucose utilization and lactate release by astrocytes. Similar data were obtained with paroxetine, whereas imipramine and desipramine did not regulate glucose metabolism in this glial cell population. Our results also indicate that the effects of fluoxetine and paroxetine on glucose utilization, lactate release, and expression of BDNF, VEGF, and VGF are not mediated by serotonin-dependent mechanisms. CONCLUSIONS: These data suggest that, by increasing the expression of specific astrocyte-derived neurotrophic factors and lactate release from astrocytes, fluoxetine may contribute to normalize the trophic and metabolic support to neurons in major depression. PMID- 21301814 TI - A role for glutamate in subjective response to smoking and its action on inhibitory control. AB - RATIONALE: Our previous study using memantine in smokers suggests that there may be a differential role for N-methyl-D-aspartate (NMDA) receptors in the subjective and cognitive effects of smoking. OBJECTIVES: This study was designed to investigate if D-cycloserine (DCS) would modulate the subjective and cognitive effects of limited smoking. METHODS: Forty-eight habitual smokers abstinent for a minimum of 2 h were randomly allocated to receive either placebo or 50 mg DCS (double-blind) and were subsequently required either to smoke half of one cigarette or to remain abstinent. Subjective and physiological effects of DCS were measured at baseline, 90 min postcapsule, and again after the partial smoking manipulation, while the effects on sustained attention (rapid visual information processing test--RVIP) and cognitive flexibility (intra-extra dimensional set-shift test--IED) were evaluated only after the partial-smoking manipulation. RESULTS: DCS alone did not produce significant subjective effects other than an increase in ratings of "Stimulated". In combination with partial smoking, however, DCS blocked the smoking-induced increase in "Stimulated" and the decrease in "Relaxed" ratings. Furthermore, in combination with smoking, DCS reduced the number of false alarms during the RVIP test (an index of inhibitory control) and produced a small increase in diastolic blood pressure. DCS failed to modulate IED performance. CONCLUSIONS: These findings provide further evidence of a role for glutamate release in the subjective effects of smoking but not the effects on attention and cognitive flexibility. Furthermore, our results indicate that glutamate release may also be involved in the effect of smoking on inhibitory control. PMID- 21301815 TI - Sex difference in QTc prolongation in chronic institutionalized patients with schizophrenia on long-term treatment with typical and atypical antipsychotics. AB - OBJECTIVE: The rate-corrected electrocardiographic QT (QTc) interval may significantly increase in patients with schizophrenia taking antipsychotics. The objective of this naturalistic study was to assess the prevalence of prolonged QTc interval in a large population of inpatients with chronic schizophrenia and to explore QTc relationship with demographic variables and prescribed treatments. MATERIALS AND METHODS: Electrocardiograms were obtained from age- and sex-matched 456 controls and 1,006 inpatients with schizophrenia (male/female = 689/317) taking antipsychotics. QTc prolongation was defined as a mean value of two standard deviations above the controls. The adjusted relative risk was calculated using logistic regression analysis. RESULTS: QTc prolongation was present in 45 (4.5%) of 1,006 patients overall. Fewer men (3.2%, 22 of 689) than women (7.3%, 23 of 317) displayed QTc prolongation (p < 0.004). Moreover, QTc intervals were shorter in male (391 +/- 31 ms) than female subjects (400 +/- 37 ms) (p < 0.001). Clozapine was found to produce a longer QTc intervals compared to risperidone and typical antipsychotics. Furthermore, multiple regression analysis showed that significant predictors for QTc prolongation were comorbid cardiovascular disease, antipsychotic types, sex, and age (all p < 0.01). CONCLUSION: Our present findings suggest that there are sex differences in the prevalence of QTc prolongation and QTc lengthening in schizophrenia. Antipsychotic types are risk factors for QTc prolongation, and risks are substantially higher for clozapine. PMID- 21301816 TI - Responding during signaled availability and nonavailability of iv cocaine and food in rats: age and sex differences. AB - RATIONALE: Research suggests that age and sex are vulnerability factors for drug abuse. However, few studies have systematically examined their interaction. OBJECTIVE: The purpose of the present study was to examine male and female, adult and adolescent rats under a procedure that measures responding during periods of signaled availability and nonavailability of iv cocaine and food reinforcers. METHODS: Adolescent and adult rats lever pressed for iv infusions of cocaine or food pellets under a procedure with three components of signaled availability of the reinforcer alternating with two components of signaled nonavailability. Adolescent rats were removed and then later retested under the same conditions as adults, and a group of adult rats was also removed and retested after a similar number of days. A subset of rats earning cocaine infusions under the initial test was later retested with food pellets under the same behavioral task to assess the influence of prior cocaine exposure on subsequent responding for a nondrug reinforcer. RESULTS: Adolescents (vs. adults) made more responses during periods of signaled iv cocaine availability and nonavailabiltiy, and adult females responded more than adult males during these periods. Responding during periods of signaled nonavailability of iv cocaine and food did not differ between the initial and subsequent retest conditions in adult rats. Further, adult males and females exposed to cocaine during adolescence responded more during periods of food availability compared to cocaine-naive adults. CONCLUSION: These results indicate that sex and age are vulnerability factors in cocaine abuse, and cocaine exposure during critical developmental stages can have long-lasting effects. PMID- 21301817 TI - Prospective memory functioning among ecstasy/polydrug users: evidence from the Cambridge Prospective Memory Test (CAMPROMPT). AB - RATIONALE: Prospective memory (PM) deficits in recreational drug users have been documented in recent years. However, the assessment of PM has largely been restricted to self-reported measures that fail to capture the distinction between event-based and time-based PM. The aim of the present study is to address this limitation. OBJECTIVES: Extending our previous research, we augmented the range laboratory measures of PM by employing the CAMPROMPT test battery to investigate the impact of illicit drug use on prospective remembering in a sample of cannabis only, ecstasy/polydrug and non-users of illicit drugs, separating event and time based PM performance. We also administered measures of executive function and retrospective memory in order to establish whether ecstasy/polydrug deficits in PM were mediated by group differences in these processes. RESULTS: Ecstasy/polydrug users performed significantly worse on both event and time-based prospective memory tasks in comparison to both cannabis only and non-user groups. Furthermore, it was found that across the whole sample, better retrospective memory and executive functioning was associated with superior PM performance. Nevertheless, this association did not mediate the drug-related effects that were observed. Consistent with our previous study, recreational use of cocaine was linked to PM deficits. CONCLUSIONS: PM deficits have again been found among ecstasy/polydrug users, which appear to be unrelated to group differences in executive function and retrospective memory. However, the possibility that these are attributable to cocaine use cannot be excluded. PMID- 21301819 TI - Effect of a novel histamine subtype-3 receptor inverse agonist and modafinil on EEG power spectra during sleep deprivation and recovery sleep in male volunteers. AB - RATIONALE: Histamine and dopamine contribute to the maintenance of wakefulness. OBJECTIVE: This study aims to conduct an exploratory analysis of the effects of 10 and 50 mg of MK-0249, a novel histamine subtype-3 receptor inverse agonist, and 200 mg of modafinil, a presumed dopaminergic compound, on EEG power spectra during sleep deprivation and subsequent recovery sleep. METHODS: A total of 25 healthy men were recruited to a double-blind, placebo-controlled cross-over design. EEG power spectra, an electrophysiological marker of changes in sleepiness and vigilance, were obtained at the beginning of wake maintenance tests at two-hourly intervals throughout a night and day of sleep deprivation, which is an established model of excessive sleepiness. RESULTS: After placebo, sleep deprivation was associated with enhancements in delta and theta and reductions in alpha and beta activity. Following dosing at 02:00 h, MK-0249 and modafinil reduced delta and theta activity and enhanced alpha and beta activity, compared to placebo. During recovery sleep initiated at 21:00 h, latency to sleep onset and number of awakenings were not different from placebo for any of the active treatments. Wake after sleep onset and stage 1% was increased and total sleep time, SWS% and REM% were reduced after both doses of MK-0249. Compared to placebo, MK-0249, the 50-mg dose in particular, reduced activity in some delta and theta/alpha frequencies and enhanced beta activity during NREM sleep and REM sleep. After modafinil, no changes were observed for power spectra during sleep. CONCLUSION: Both MK-0249 and modafinil exert effects on the EEG which are consistent with wake promotion. PMID- 21301818 TI - The role of impulsivity in the aetiology of drug dependence: reward sensitivity versus automaticity. AB - RATIONALE: Impulsivity has long been known as a risk factor for drug dependence, but the mechanisms underpinning this association are unclear. Impulsivity may confer hypersensitivity to drug reinforcement which establishes higher rates of instrumental drug-seeking and drug-taking behaviour, or may confer a propensity for automatic (non-intentional) control over drug-seeking/taking and thus intransigence to clinical intervention. METHOD: The current study sought to distinguish these two accounts by measuring Barratt Impulsivity and craving to smoke in 100 smokers prior to their completion of an instrumental concurrent choice task for tobacco (to measure the rate of drug-seeking) and an ad libitum smoking test (to measure the rate of drug-taking-number of puffs consumed). RESULTS: The results showed that impulsivity was not associated with higher rates of drug-seeking/taking, but individual differences in smoking uptake and craving were. Rather, nonplanning impulsivity moderated (decreased) the relationship between craving and drug-taking, but not drug-seeking. CONCLUSIONS: These data suggest that whereas the uptake of drug use is mediated by hypervaluation of the drug as an instrumental goal, the orthogonal trait nonplanning impulsivity confers a propensity for automatic control over well-practiced drug-taking behaviour. PMID- 21301821 TI - Metabolite profiling of sucrose effect on the metabolism of Melissa officinalis by gas chromatography-mass spectrometry. AB - The effect of sugar on plant metabolism, which is known to be similar to hormone like signaling, was metabolomically studied using Melissa officinalis (lemon balm). The metabolite profiles of M. officinalis treated with sucrose were analyzed by gas chromatography-mass spectrometry (GC-MS) and principal component analysis (PCA). A total of 64 metabolites from various chemical classes including alcohols, amines, amino acids, fatty acids, inorganic acids, organic acids, phosphates, and sugars were identified by GC-MS. Three groups treated with different sucrose concentrations were clearly separated by PCA of their metabolite profiles, indicating changes in the levels of many metabolites depending on the sucrose concentration. Metabolite profiling revealed that treatment with a higher sucrose level caused an increase in the levels of metabolites such as sugars, sugar alcohols, and sugar phosphates, which are related to the glycolytic pathway of M. officinalis. Furthermore, proline and succinic acid, which are associated with the proline-linked pentose phosphate pathway, the shikimic acid pathway, and the biosynthesis of phenylpropanoids, also increased with increasing sucrose concentration. Therefore, these metabolic changes induced by sucrose ultimately led to the increased production of flavonoids such as caffeic acid via the biosynthetic pathway of phenylpropanoids. This study demonstrated that the abundance changes in some primary and secondary metabolites were somewhat interlocked with each other in response to sucrose. PMID- 21301820 TI - Triacylglycerol/phospholipid molecular species profiling of fatty livers and regenerated non-fatty livers in cystathionine beta-synthase-deficient mice, an animal model for homocysteinemia/homocystinuria. AB - Fatty liver is one of the typical manifestations in homocysteinemia/homocystinuria patients and their genetic animal model, mice lacking cystathionine beta-synthase (Cbs(-/-)). The vast majority of Cbs(-/-) die within 4 weeks after birth via yet unknown mechanisms, whereas a small portion survive to adulthood, escaping fatty degeneration of the liver during lactation periods, through regeneration. To investigate the molecular basis of such fatty changes, we analyzed lipid components in fatty livers of 2-week-old Cbs(-/-) and regenerated non-fatty livers of 8-week-old Cbs(-/-) survivors using a chip-based nanoESI (electrospray ionization)-MS system, which allows quantitative detection of triacylglycerol/phospholipid molecular species. Hepatic levels of all major triacylglycerol species were much higher in Cbs(-/-) than in wild-type mice at 2 weeks, although not at 8 weeks. Levels of some phospholipid species were either up- or downregulated in 2-week-old Cbs(-/-); e.g. saturated (16:0 and 18:0) or mono-unsaturated (16:1 and 18:1) fatty acids-containing phosphatidylcholine/phosphatidylethanolamine species were upregulated, while poly unsaturated fatty acids-containing phosphatidylcholine (18:2-18:2 and 18:2-20:5), phosphatidylethanolamine (18:1-20:4), and phosphatidylinositol (18:0-20:4) were downregulated. Capillary electrophoresis-MS analysis identified high-level accumulation of S-adenosylmethionine and S-adenosylhomocysteine in fatty livers of 2-week-old Cbs(-/-) but much less in non-fatty livers of 8-week-old Cbs(-/-). Although hepatic S-adenosylmethionine/S-adenosylhomocysteine ratios were comparable between 2-week-old Cbs(-/-) and wild-type, global protein arginine methylation was disturbed in fatty livers of Cbs(-/-). Our results suggest that cellular signaling mediated by altered phospholipid contents might be involved in pathogenesis of fatty liver in Cbs(-/-). PMID- 21301822 TI - Impact of hair-care products on FAEE hair concentrations in substance abuse monitoring. AB - Previous studies have indicated that the use of high-ethanol-content (>65%) hair care products may elevate fatty acid ethyl ester (FAEE) concentrations in hair. In this case series, nine individuals were identified by FAEE analysis to be chronic alcohol abusers in the context of child-welfare substance abuse monitoring. Based on patient claims of moderate or no alcohol consumption, the presence of ethanol in the patients' hair-care regimens was investigated. Samples were additionally tested for the presence of ethyl glucuronide (EtG). From a total of nine patients, 12 hair samples were submitted for analysis. Patient histories were obtained as well as Material Safety Data Sheets (MSDS) listing hair-care product ethanol content. Hair samples were pre-washed to remove external contamination and analyzed for FAEE and EtG by GC-MS. According to the Society of Hair Testing consensus guidelines, FAEE levels exceeding 0.50 ng/mg and/or EtG levels exceeding 30 pg/mg indicate chronic excessive alcohol consumption. Upon initial analysis, the nine samples exhibited positive FAEE findings ranging from 0.496 to 4.984 ng/mg. MSDS review revealed the presence of ethanol from 10% to 95% by volume in at least one hair-care product used by each individual. Results of the EtG analysis ranged from 1.9 to 23.5 pg/mg. These findings indicate that regular use of products with ethanol content as low as 10% can impact FAEE results. EtG analysis should be used to confirm FAEE findings and appears to be unaffected by hair-care products, likely due to alternative mechanisms of incorporation. PMID- 21301823 TI - QCM gas phase detection with ceramic materials--VOCs and oil vapors. AB - Titanate sol-gel layers imprinted with carbonic acids were used as sensitive layers on quartz crystal microbalance. These functionalized ceramics enable us detection of volatile organic compounds such as ethanol, n-propanol, n-butanol, n hexane, n-heptane, n-/iso-octane, and n-decane. Variation of the precursors (i.e., tetrabutoxy titanium, tetrapropoxy titanium, tetraethoxy titanium) allows us to tune the sensitivity of the material by a factor of 7. Sensitivity as a function of precursors leads to selective inclusion of n-butanol vapors down to 1 ppm. The selectivity of materials is optimized to differentiate between isomers, e.g., n- and iso-octane. The results can be rationalized by correlating the sensor effects of hydrocarbons with the Wiener index. A mass-sensitive sensor based on titanate layer was also developed for monitoring emanation of degraded engine oil. Heating the sensor by a meander avoids vapor condensation. Thus, a continuously working oil quality sensor was designed. PMID- 21301824 TI - A novel approach for an automated liquid/liquid extraction system--principle and application for the determination of several trace contaminants in highly alloyed steels and base alloys. AB - A novel automated liquid/liquid extraction system was developed for the determination of trace contaminants in unalloyed, alloyed and highly alloyed steels and super alloys. In the presented batch extraction system the aqueous phase and the non-water miscible organic phase were brought into close phase contact by high-speed stirring with a magnetic stir bar. Iodide complexes of Ag, Bi, Cd, Pb, Sb, Sn, Tl, and Zn were extracted from aqueous steel digests into 4 methylpentan-2-one (MIBK) containing 20 g L(-1) trioctylphosphine oxide. Ag, Bi, Cd, Pb, and Tl were extracted quantitatively whereas the extraction yields of Sb, Sn, and Zn were 83%, 61% and 75% respectively. Using high resolution continuum source flame AAS (HR-CS-FAAS) for analyte quantification the method was validated using 21 certified steel reference materials (CRMs). PMID- 21301825 TI - Innovative study design for paediatric clinical trials. AB - PURPOSE: Despite representing a fundamental step towards the efficacious and safe utilisation of drugs in the paediatric population, the conduct of clinical trials in children poses several problems. Methodological issues and ethical concerns represent the major obstacles that have traditionally limited paediatric research. The randomised clinical trial, mainstay of clinical studies to assess the effects of any therapeutic intervention, shows some weaknesses that make it scarcely applicable to the paediatric population. Alternative and innovative approaches to clinical trial design in small populations have been developed in the last few decades with the aim of overcoming the limits related to small samples and to the acceptability of the trial. METHODS: This systematic review describes a variety of alternative designs to assess efficacy and safety in the paediatric population, including their applicability, advantages, disadvantages and real case examples. Approaches include sequential and adaptive designs, Bayesian methods and other innovative approaches. RESULTS: By limiting the sample size and increasing acceptability, these methods may rationally limit the amount of experimentation in children to what is achievable, necessary and ethical CONCLUSION: Thanks to their features, these methods represent a reliable way of ultimately improving paediatric care. PMID- 21301826 TI - Variability in imaging utilization in U.S. pediatric hospitals. AB - BACKGROUND: Use of medical imaging is under scrutiny because of rising costs and radiation exposure. We compare imaging utilization and costs across pediatric hospitals to determine their variability and potential determinants. MATERIALS AND METHODS: Data were extracted from the Pediatric Health Information System (PHIS) database for all inpatient encounters from 40 U.S. children's hospitals. Imaging utilization and costs were compared by insurance type, geographical region, hospital size, severity of illness, length of stay and type of imaging, all among specific diagnoses. RESULTS: The hospital with the highest utilization performed more than twice as many imaging studies per patient as the hospital with the lowest utilization. Similarly, imaging costs ranged from $154 to $671/patient. Median imaging-utilization rate was 1.7 exams/patient on the ward and increased significantly in the PICU (11.8 exams/patient) and in the NICU (17.7 exams per patient, (P < 0.001). Considerable variability in imaging utilization persisted despite adjustment for case mix index (CMI, range in variation 16.6-25%). We found a significant correlation between imaging utilization and both CMI and length of stay, P < 0.0001). However, only 36% of the variation in imaging utilization could be explained by CMI. CONCLUSION: Diagnostic imaging utilization and costs vary widely in pediatric hospitals. PMID- 21301827 TI - Haplotypes of the bovine IgG2 heavy gamma chain in tick-resistant and tick susceptible breeds of cattle. AB - Bovines present contrasting, heritable phenotypes of infestations with the cattle tick, Rhipicephalus (Boophilus) microplus. Tick salivary glands produce IgG binding proteins (IGBPs) as a mechanism for escaping from host antibodies that these ectoparasites ingest during blood meals. Allotypes that occur in the constant region of IgG may differ in their capacity to bind with tick IGBPs; this may be reflected by the distribution of distinct allotypes according to phenotypes of tick infestations. In order to test this hypothesis, we investigated the frequency of haplotypes of bovine IgG2 among tick-resistant and tick-susceptible breeds of bovines. Sequencing of the gene coding for the heavy chain of IgG2 from 114 tick-resistant (Bos taurus indicus, Nelore breed) and tick susceptible (B. t. taurus, Holstein breed) bovines revealed SNPs that generated 13 different haplotypes, of which 11 were novel and 5 were exclusive of Holstein and 3 of Nelore breeds. Alignment and modeling of coded haplotypes for hinge regions of the bovine IgG2 showed that they differ in the distribution of polar and hydrophobic amino acids and in shape according to the distribution of these amino acids. We also found that there was an association between genotypes of the constant region of the IgG2 heavy chain with phenotypes of tick infestations. These findings open the possibility of investigating if certain IgG allotypes hinder the function of tick IGBPs. If so, they may be markers for breeding for resistance against tick infestations. PMID- 21301828 TI - Monoaxial versus polyaxial locking systems: a biomechanical analysis of different locking systems for the fixation of proximal humeral fractures. AB - OBJECTIVE: The development of locking plate systems has led to polyaxial screws and new plate designs. This study compares monoaxial head locking screws (PHILOS(c) by Synthes) and a new generation of polyaxial locking screws (NCB LE(c) by Zimmer) with respect to biomechanical stability. METHODS: On nine pairs of randomised formalin fixed humerus specimens, standardised osteotomies and osteosyntheses with nine monoaxial (group A) und nine polyaxial (group B) plate/screw systems were performed. A material testing machine by Instron (M-10 14961-DE) was used for cyclic stress tests and crash tests until defined breakup criteria as endpoints were reached. RESULTS: After axial cyclic stress 200 times at 90 N, plastic deformation was 1.02 mm in group A and 1.25 mm in group B. After the next cycle using 180 N the additional deformation averaged 0.23 mm in group A and 0.39 mm in group B. The deformation using 450 N was 0.72 mm in group A compared to 0.92 mm in group B. The final full power test resulted in a deformation average of 0.49 mm in group A and 0.63 mm in group B after 2,000 cycles using 450 N. When reaching the breakup criteria the plastic deformation of the NCB plate was 9.04 mm on average. The PHILOS plate was similarly deformed by 9.00 mm. As a result of the crash test, in group A the screws pulled out of the humeral head four times whereas the shaft broke one time and another time the implant was ripped out. The gap was closed four times. In group B, there were three cases of screw cut-through, four shaft fractures/screw avulsions from the shaft and two cases of gap closure. CONCLUSION: The two systems resist the cyclic duration tests and the increasing force tests in a similar manner. The considerable clinical benefits of the polyaxial system are enhanced by equal biomechanical performance. PMID- 21301830 TI - Unipolar hemiarthroplasty versus bipolar hemiarthroplasty in the most elderly patients with displaced femoral neck fractures: a randomised, controlled trial. AB - PURPOSE: Hemiarthroplasty (HA) is generally considered to be the treatment of choice in the most elderly patients with a displaced fracture of the femoral neck. However, there is inadequate evidence to support the choice between unipolar HA or bipolar HA. The primary aim of this study was to analyse the outcome regarding hip function and health-related quality of life (HRQoL) in patients randomised to either a unipolar or bipolar HA. The secondary aim was to analyse the degree of acetabular erosion and its influence upon outcome. METHODS: One hundred twenty patients with a mean age of 86 years and an acute displaced fracture of the femoral neck were randomly allocated to treatment by either unipolar or bipolar HA. Outcome measurements included hip function (Harris Hip Score, HHS), HRQoL (EQ-5D) and acetabular erosion. The patients were summoned at four and 12 months for follow-up. RESULTS: There were no significant differences between the groups regarding complications. The HHS scores were equal at both follow-ups, but there was a trend towards better HRQoL in the bipolar HA group at four months, EQ-5D (index) score 0.62 vs 0.54 (p = 0.06). Twenty percent of the patients in the unipolar HA group displayed acetabular erosion at the 12-month follow-up compared to 5% in the bipolar HA group (p = 0.03), and there were trends towards worse hip function and HRQoL among patients with acetabular erosion compared to those without: HHS scores 70.4 and 79.3, respectively (p = 0.09), and EQ-5D (index) scores 0.48 and 0.63, respectively (p = 0.13). CONCLUSION: Unipolar HA and bipolar HA appeared to produce equivalent clinical outcomes after one year, but the significantly higher incidence of acetabular erosion in the unipolar HA group may imply that bipolar HA should be the preferred treatment. PMID- 21301831 TI - Cervicofacial rhytidoplasty: more does not mean better. AB - BACKGROUND: Aesthetic correction of cervicofacial flaccidity has undergone numerous modifications over time, including extent and depth of dissection. We present our experience with this type of surgery, passing through different stages and procedures to achieve optimal and highly satisfactory results. METHODS: From January 1995 to December 2009, 576 patients (498 females and 78 males, age range = 34-78 years, mean = 47) underwent cervicofacial rhytidoplasty. During the first 6 years of the study period, cervicofacial tissue was managed with six different types of plications, according to the needs of each patient, requiring extensive supra-SMAS undermining. During the last 9 years, undermining was significantly limited and only three of the six plications were used, adding different surgical procedures to achieve the surgical objectives. RESULTS: During the first period, 220 patients were operated on and 164 patients required additional procedures (74%). Seventy-nine patients (36%) needed 6 plications, 90 patients (41%) required 5 plications, and 51 patients (23%) only 4 plications. During the second period, 356 patients were operated on, needing only 3 plications, but 336 (94%) required additional procedures. The percentage of complications during the first period was 2.2% hematomas, 2.7% superficial necrosis, and 0.45% deep necrosis compared with 0.84, 0.56, and 0%, respectively, in the second period. A greater disability rate than expected from edema and/or prolonged ecchymosis occurred in 25 and 12% of the patients in the first and second periods, respectively. A similar degree of patient satisfaction was obtained in both periods, 93 and 92%, respectively. CONCLUSION: Our approach to cervicofacial rhytidoplasty has varied substantially by limiting undermining, which has produced a lower complication rate and has accelerated the recovery process. However, to acquire similar results, we have had to implement additional procedures, with which we have obtained the same degree of satisfaction but with a lower rate of postsurgical morbidity. PMID- 21301833 TI - Pressure indicators of wood resource use in an Atlantic forest area, northeastern Brazil. AB - Wood resources are often used to support the needs of the local population. In order to protect biodiversity and resources, conservation strategies need to consider what types of wood use have the strongest impacts on forested areas. This study aimed to identify the use categories that put higher pressure on an Atlantic forest region located in the municipality of Igarassu in Pernambuco, northeastern Brazil. To conduct the study, we measured the volume of all wood products in 62 surveyed residences and registered the average replacement time for such products. The fuelwood category was most important locally and accounted for 92% of annual wood consumption. However, the construction category harvests more destructively and concentrates on the consumption of a few wood species. Therefore we recommend the fuelwood category to be the main focus of conservation effforts. In addition, the most important species for construction purposes (e.g., Eschweilera ovata (Cambess.) Miers, Apuleia leiocarpa (Vogel) J.F. Macbr. and Pogonophora schomburgkiana Miers ex Benth) should also be considered as a priority for conservation. PMID- 21301834 TI - Clinical, ultrasonographic, and pathologic characteristics of patients with chronic right-lower-quadrant abdominal pain that may benefit from appendectomy. AB - BACKGROUND: Chronic pains of the right lower quadrant of the abdomen (RLQA) remain a challenging problem worldwide, especially in areas with limited technical background; chronic appendicitis is still a subject of controversy. The aim of this study was to analyze the clinical and paraclinical data of patients with chronic pains of RLQA who had an appendectomy performed. METHODS: During a period of 4 years, all patients presenting with a chronic pain of the RLQA were selected for our study and underwent clinical assessment and systematic ultrasonography of the abdomen; these served as a basis of selecting candidates for appendectomy. The intraoperative findings, histology results, and outcome after appendectomy were analyzed. RESULTS: Three hundred nineteen patients presented with chronic pains of the RLQA of which 213 could be finally analyzed; their mean age was 15.3 years; 192 patients were females. They had pains for 2-8 years. Echography showed a heterogeneous lesion in the RLQA in 87% of the cases. The operative findings displayed adhesions and other signs of chronic inflammation in 182 cases. Pathological analysis frequently revealed fibrosis and lymphoplasmocytic infiltration indicative of chronic inflammation. Eighty-seven percent of the patients were cured by appendectomy. CONCLUSIONS: There is a chronic process involving the appendix that occurs in the RLQA of patients with chronic pains, typically the adolescent female. Appendectomy usually solves the problem. The criteria for selection of candidates still need to be identified, but in the absence of laparoscopic facilities, we recommend appendectomy when no other cause for the pain has been identified. PMID- 21301835 TI - Prognostic role of carcinoembryonic antigen is influenced by microsatellite instability genotype and stage in locally advanced colorectal cancers. AB - BACKGROUND: Carcinoembryonic antigen (CEA) is the most frequently used marker for colorectal cancer (CRC). Influence of genetic instability on tumor marker expression is not known. The aim of this study was to investigate microsatellite instability (MSI) of CEA serum levels in locally advanced CRC. METHODS: The observational cohort consisted of stage II-III CRC patients (n = 131) 75 years old or youngerwho underwent surgery with curative intent. CEA serum levels were measured before (preCEA) and immediately after surgery (postCEA). DNA from the extracted tumors was investigated for MSI. Survival was analyzed in univariate and multivariate analyses. RESULTS: The median preCEA was 3 U/ml (IQR = 1-3, range = 1-136 U/ml). Stage III cancers with MSI had an elevated preCEA more often than those without MSI (25% vs. 0%; p = 0.026). A preCEA >10 U/ml was significantly associated with elevated postCEA (CEA >1 U/ml; odds ratio [OR] = 5.4, 95% CI = 2.1-14.2; p < 0.001). Survival wasnot significantly different between those with postCEA <10 U/ml vs. postCEA >= 10 U/ml or when stratified by MSI status. A cutoff of postCEA <= 1 U/ml conferred significantly improved survival compared to higher CEA levels. Stratified for MSI status, this difference was significant for microsatellite stable (MSS) cancers only (p = 0.021). In multivariate analysis, postCEA >1 U/ml (hazard ratio [HR] = 3.5, 95% CI = 1.7-7.3, p = 0.001) and stage III (HR = 6.7, 95% CI = 3.0-14.9; p < 0.001) were predictors of decreased survival. CONCLUSIONS: Preoperative CEA levels were significantly higher in stage III cancers with the MSI genotype, and high preoperative CEA was associated with increased postoperative CEA. Absent postoperative CEA in serum conferred improved long-term survival. PMID- 21301836 TI - Challenges in the treatment of gastroesophageal junction cancer. PMID- 21301837 TI - Comparison of major hepatectomy performed under intermittent Pringle maneuver versus continuous Pringle maneuver coupled with in situ hypothermic perfusion. AB - BACKGROUND: The Pringle maneuver (hepatic inflow occlusion), applied intermittently or continuously, carries the risk of inducing ischemic and reperfusion injury. The risk of damage is higher in the latter procedure. Studies have shown that continuous Pringle maneuver coupled with in situ hypothermic perfusion (CPM-HP) circumvents such adversity. However, reports comparing this technique with the intermittent Pringle maneuver (IPM) are lacking. We therefore report our experience with the use of CPM-HP and compare its outcome with that of IPM. METHODS: We evaluated the outcome of similar sets of patients who had major hepatic resections performed under IPM and CPM-HP. Variables including short-term survival rate (>90 days), complications, operative time, transection time, intraoperative blood loss, postoperative liver functions, and postoperative hospital stay were used to compare the two groups. RESULTS: Eighteen major hepatectomies were performed with CPM-HP and 16 with IPM. CPM-HP was safely performed in patients with chronic liver disease. Lowering the liver's temperature extends the clamping period to 140 min. Perioperative outcomes including operative time (383.9 +/- 89.4 vs. 351.9 +/- 70.3 min, p = 0.252), blood loss (225.6 +/- 48.4 vs. 351.9 +/- 70.3 ml, p = 0.057), postoperative hospital stay, morbidity rate, and the rate of liver functions following resections were comparable for the CPM-HP and IPM groups. There was no mortality. Parenchymal transection time was significantly longer in the CPM-HP group (104.1 +/- 20.2 vs. 85.0 +/- 15.4 min, p = 0.004) CONCLUSION: Our findings did not show there to be a significant advantage of CPM-HP over IPM. PMID- 21301838 TI - Medical student surgery elective in rural Haiti: a novel approach to satisfying clerkship requirements while providing surgical care to an underserved population. AB - BACKGROUND: The addition of global health programs to medical school training results in graduates with enhanced clinical skills and increased sensitivity to cost issues. Funding from U.S. medical schools has been unable to meet student demand, and therefore it is often a critical limiting factor to the lack of development of these programs. We describe an alternative approach for global health surgical training for medical students. METHODS: Emory University medical students and faculty, in collaboration with Project Medishare for Haiti, planned, raised funds, and executed a successful short-term surgical camp to supplement available surgical services in rural Haiti. Learning objectives that satisfied Emory University School of Medicine surgery clerkship requirements were crafted, and third-year students received medical school credit for the trip. RESULTS: In the absence of house staff and placed in an under-resourced, foreign clinical environment, the surgical elective described here succeeded in meeting learning objectives for a typical third-year surgical clerkship. Objectives were met through a determined effort to ensure that home institution requirements were aligned properly with learning activities while students were abroad and through a close collaboration between medical students, faculty members, and the administration. CONCLUSIONS: Emory University's international surgery elective for medical students demonstrates that opportunities for supervised, independent student-learning and global health service can be integrated into a traditional surgical clerkship. These opportunities can be organized to meet the requirements and expectations for third-year surgery clerkships at other medical colleges. This work also identifies how such trips can be planned and executed in a manner that does not burden strained academic budgets with further demands on resources. PMID- 21301840 TI - Regarding renal artery stenting. PMID- 21301841 TI - Re: Renal artery stenting is no longer indicated after ASTRAL: pros and cons. PMID- 21301842 TI - "Re: Renal artery stenting is no longer indicated after ASTRAL: pros and cons". PMID- 21301843 TI - Carotid artery stenosis at MSCT: is there a threshold in millimeters that determines clinical significance? AB - PURPOSE: The purpose of this work was to determine whether it is possible to identify a reliable carotid stenosis threshold--measured in millimeters (mm)- that is associated with cerebrovascular symptoms. METHODS: Written, informed consent was obtained for each patient; 149 consecutive patients (98 men; median age, 68 years) were studied for suspected pathology of the carotid arteries by using MDCTA. In each patient, carotid artery stenosis was quantified using the mm method. Continuous data were described as the mean value +/- standard deviation (SD), and they were compared by using the Student's t test. A ROC curve was calculated to test the study hypothesis and identify a specific mm-stenosis threshold. Logistic regression analysis was performed to include other MDCTA findings, such as plaque type and ulcerations. A P value < 0.05 was considered to indicate statistical significance. RESULTS: Twenty-six patients were excluded. Of those remaining, 75 patients suffered cerebrovascular symptoms (61%). There was a statistically significant difference (P = 0.0046) in the mm-carotid stenosis between patients with symptoms (1.31 +/- 0.64 mm SD) and without symptoms (1.68 +/- 0.79 mm SD). Multiple logistic regression analysis confirmed that symptoms were associated with increased luminal stenosis (P = 0.013) and with the presence of fatty plaques (P = 0.0491). Moreover, the ROC curve (Az = 0.669; +/-0.051 SD; P = 0.0009) indicated that a threshold of 1.6 mm stenosis was associated with a sensitivity to symptoms of 76%. CONCLUSIONS: The results of our study suggest an association between luminal stenosis (measure in mm) and the presence of cerebrovascular symptoms. Luminal stenosis of 1.6 mm is associated, with a sensitivity of 76%, with cerebrovascular symptoms. PMID- 21301844 TI - Voice matters: late presentation of an iatrogenic vertebral arteriovenous fistula after liver transplantation in early childhood with successful endovascular treatment. PMID- 21301845 TI - Stent-assisted coil embolization of a traumatic wide-necked renal segmental artery pseudoaneurysm. AB - We present the case of an Afghan woman with a renal segmental artery false aneurysm of the right kidney due to a shell splinter injury. Stent-assisted coil embolization of the aneurysm is described in detail. PMID- 21301846 TI - Percutaneous management of postoperative bile leaks after upper gastrointestinal surgery. AB - PURPOSE: This study was designed to investigate the benefit of percutaneous interventional management of patients with postoperative bile leak on clinical outcome. Primary study endpoints were closure of the bile leak and duration of percutaneous transhepatic biliary drainage (PTBD) treatment. Secondary study endpoints were necessity of additional CT-guided drainage catheter placement, course of serum CRP level as parameter for inflammation, and patients' survival. METHODS: Between January 2004 and April 2008, all patients who underwent PTBD placement after upper gastrointestinal surgery were analyzed regarding site of bile leak and previous attempt of operative bile leak repair, interval between initial surgery and PTBD placement, procedural interventional management, course of inflammation parameters, duration of PTBD therapy, PTBD-related complications, and patients' survival. RESULTS: Thirty patients underwent PTBD placement for treatment of postoperative bile leaks. In 12 patients (40%), PTBD was performed secondary to a surgical attempt of bile leak repair. Additional percutaneous drainage of bilomas was performed in 14 patients (47%). CRP serum level decreased from 138.1 +/- 73.4 mg/l before PTBD placement to 43.5 +/- 33.4 mg/l 30 days after PTBD placement. The mean duration of PTBD treatment was 55.2 +/- 32.5 days in the surviving patients. In one patient, a delayed stenosis of the bile duct required balloon dilation. Two PTBD-related complications (portobiliary fistula, hepatic artery aneurysm) occurred, which were successfully treated by embolization. Overall survival was 73% (22 patients). CONCLUSIONS: PTBD treatment is an effective therapy. PTBD treatment and additional CT-guided drainage of bilomas helped to reduce intraabdominal inflammation, as shown by reduction of inflammation parameters. PMID- 21301847 TI - British Society of Interventional Radiology: Biliary Drainage and Stenting Registry (BDSR). AB - OBJECTIVES: This study was designed to audit current practice in percutaneous biliary drainage and stenting in the United Kingdom. METHODS: In 2006, the British Society of Interventional Radiology set up the first web-based Biliary Drainage and Stenting Registry (BDSR). This consisted of a series of tick sheets, which were completed online. Data collection included technical and clinical success of the procedures and outcomes at discharge with a separate form for any follow-up visits. Two months before data analysis, all contributors were asked via email to complete any outstanding data. This paper reports on data collected between November 1, 2006 and August 18, 2009. RESULTS: A total of 833 procedures were recorded and were entered by 62 operators from 44 institutions within the United Kingdom. There were 455 men and 378 women with a median age of 69 (range 20-101) years.The majority of procedures were performed by a consultant. Successful drainage of the biliary tree was achieved in 98.7%. Partial or complete relief of symptoms was seen in 65% of patients. Minor complications, predominantly pain (14.3%), were seen in 26% and major complications, predominantly sepsis (3.5%), were seen in 7.9% of patients. CONCLUSIONS: These figures provide an essential benchmark for both audit and patient information. Identifying areas of good practice and those that require improvement will ultimately result in better patient care. PMID- 21301848 TI - Comparison of liposomal cisplatin versus cisplatin in non-squamous cell non-small cell lung cancer. AB - PURPOSE: Liposomal cisplatin was developed to reduce the systemic toxicity of cisplatin, particularly the nephrotoxicity, and it has been used in combination with other agents in pancreatic and head and neck cancers and non-small-cell lung cancer (NSCLC). Our objective was to compare the effectiveness of lipoplatin combined with paclitaxel versus cisplatin with paclitaxel in advanced non squamous NSCLC. METHODS: During 2007-2010, 202 patients with non-squamous NSCLC (stage IIIB and IV) were recruited from the two participating institutions and divided into two arms: Arm A was treated with liposomal cisplatin 200 mg/m(2) combined with paclitaxel 135 mg/m(2) and Arm B with cisplatin 75 mg/m(2) in combination with paclitaxel 135 mg/m(2), repeated every 2 weeks. The number of cycles administered was 632 (Arm A) and 640 (Arm B), totaling 1,272. RESULTS: A partial response was achieved by 59.22% of Arm A patients versus 42.42% of Arm B, and the difference was statistically significant (P 0.036). The median survival time in months was 10 for Arm A and 8 for Arm B (P 0.1551). After 18 months, the number of surviving patients was double for Arm A versus Arm B. CONCLUSION: Liposomal cisplatin in combination with paclitaxel produces a statistically significantly higher response rate than cisplatin combined with paclitaxel in non squamous NSCLC. PMID- 21301849 TI - Budgeted Nature Reserve Selection with diversity feature loss and arbitrary split systems. AB - Arising in the context of biodiversity conservation, the Budgeted Nature Reserve Selection (BNRS) problem is to select, subject to budgetary constraints, a set of regions to conserve so that the phylogenetic diversity (PD) of the set of species contained within those regions is maximized. Here PD is measured across either a single rooted tree or a single unrooted tree. Nevertheless, in both settings, this problem is NP-hard. However, it was recently shown that, for each setting, there is a polynomial-time [Formula: see text] -approximation algorithm for it and that this algorithm is tight. In the first part of the paper, we consider two extensions of BNRS. In the rooted setting we additionally allow for the disappearance of features, for varying survival probabilities across species, and for PD to be measured across multiple trees. In the unrooted setting, we extend to arbitrary split systems. We show that, despite these additional allowances, there remains a polynomial-time (1 - 1/e)-approximation algorithm for each extension. In the second part of the paper, we resolve a complexity problem on computing PD across an arbitrary split system left open by Spillner et al. PMID- 21301850 TI - [Infections in organ transplantations]. AB - Infections play a crucial role in organ transplantations as possible complications. Viruses, bacteria, fungi and parasites are potential agents. The relevance of individual diseases depends on the organ transplanted. Morphology of the inflammatory reaction is given by the agent involved, but often several reactions can be caused by the same agent and different agents can also lead to the same reaction. Histology therefore provides concrete identification of the causal agent only in some cases, such that additional microbiological diagnostics are necessary. Results from these investigations should be transferred to the pathologist to distinguish between infection-associated changes and transplant rejection. PMID- 21301851 TI - Histochemical and immunohistochemical identification of laticifer cells in callus cultures derived from anthers of Hevea brasiliensis. AB - Laticifers are highly specialized cells present in over 20 plant families. They are well defined in planta. In vitro development of laticifers was also observed in some plants, but uncertain in the callus cultures of rubber tree, one of the most economically important latex producing plants. In the present study, we provide evidence that laticifer cells present in the callus cultures of rubber tree by histochemical and immunohistochemical studies. They present in the callus mainly as separate non-elongated form, a novel morphology different from the morphology of laticifer cells in planta, excluding their origin from explants. The occurring frequency of laticifer cells in the callus was genotype-dependent and negatively correlated with the somatic embryogenetic ability, suggesting that the presence of laticifer cells in the callus inhibit somatic embryogenesis in tissue culture of rubber tree. The genotypes PR107, RRIM600, Reyan8-79, and Reyan7-33-97 with lower embryogenetic ability compared to Haiken 2 had more laticifer cells, and laticifer clusters were only observed in these genotypes. PMID- 21301852 TI - Mapping of the genes for dioecism and monoecism in Spinacia oleracea L.: evidence that both genes are closely linked. AB - Spinach is basically a dioecious species, with occasional monoecious plants in some populations. Sexual dimorphism in dioecious spinach plants is controlled by an allelic pair termed X and Y located on the short arm of the longest chromosome (x = 6). Ten AFLP markers, closely linked to the X/Y locus, were identified using bulked segregant analysis, four of which were revealed to co-segregate with Y in the present mapping population. We mapped the AFLP markers and two known male specific DNAs to a 13.4 cM region encompassing the locus. These markers will be the basis for positional cloning of the sex-determination gene. We also showed that a single, incompletely dominant gene is responsible for the highly staminate monoecious character. The gene was found to be located at a distance of 4.3 cM from microsatellite marker SO4, which mapped 1.6 cM from the X/Y locus. This indicates that the monoecious gene seems not to be allelic to but closely linked to the X/Y gene pair. SO4 will enable breeders to efficiently select highly male monoecious plants for preferential use as the pollen parent for hybrid seed production. PMID- 21301853 TI - Selection of reliable reference genes for expression studies by reverse transcription quantitative real-time PCR in litchi under different experimental conditions. AB - Reverse transcription quantitative real-time PCR (RT-qPCR), a sensitive technique for quantifying gene expression, depends on the stability of the reference gene(s) used for data normalization. Only a few studies on reference genes have been done in fruit trees and none in litchi. In the present study, seven frequently used candidate reference genes, including actin (ACTIN), glyceraldehyde-3-phosphate-dehydrogenase (GADPH), elongation factor 1-alpha (EF 1alpha), poly ubiquitin enzyme (UBQ), alpha-tubulin (TUA), beta-tubulin (TUB) and RNA polymerase-II transcription factor (RPII), were evaluated for their expression stability in litchi. A total of 78 samples, including different varieties, tissues, organs, developmental stages and treatments, such as NAA, shading and girdling plus defoliation, were addressed in this analysis. Our results showed that GAPDH was the most suitable reference gene among all the tested samples, different organs and NAA treatment. ACTIN was stably expressed in varieties and fruit developmental stages. RPII and UBQ exhibited better expression stability in tissues. EF-1alpha was the most stable gene in shading and girdling plus defoliation treatments. Moreover, using combination of two genes as reference genes might improve the reliability of gene expression by RT qPCR in litchi. A better combination was GAPDH + EF-1alpha or GAPDH + ACTIN for all the examined samples. In addition, the validated reference genes were further relied on to quantify the expression of an interested gene, LcARF13 under different experimental conditions. These results first provide guidelines for reference genes selection under different experimental conditions and also a foundation for more accurate and widespread use of RT-qPCR in litchi. PMID- 21301855 TI - Low-dose lithium uptake promotes longevity in humans and metazoans. AB - PURPOSE: Lithium is a nutritionally essential trace element predominantly contained in vegetables, plant-derived foods, and drinking water. Environmental lithium exposure and concurrent nutritional intake vary considerably in different regions. We here have analyzed the possibility that low-dose lithium exposure may affect mortality in both metazoans and mammals. METHODS: Based on a large Japanese observational cohort, we have used weighted regression analysis to identify putative effects of tap water-derived lithium uptake on overall mortality. Independently, we have exposed Caenorhabditis elegans, a small roundworm commonly used for anti-aging studies, to comparable concentrations of lithium, and have quantified mortality during this intervention. RESULTS: In humans, we find here an inverse correlation between drinking water lithium concentrations and all-cause mortality in 18 neighboring Japanese municipalities with a total of 1,206,174 individuals (beta = -0.661, p = 0.003). Consistently, we find that exposure to a comparably low concentration of lithium chloride extends life span of C. elegans (p = 0.047). CONCLUSIONS: Taken together, these findings indicate that long-term low-dose exposure to lithium may exert anti aging capabilities and unambiguously decreases mortality in evolutionary distinct species. PMID- 21301856 TI - Erythrocyte membrane phospholipid polyunsaturated fatty acids are related to plasma C-reactive protein and adiponectin in middle-aged German women and men. AB - PURPOSE: Modulation of circulating inflammatory markers and adiponectin may link PUFA to risk of diabetes and cardiovascular diseases. We investigated erythrocyte n-6 and n-3 PUFA in relation to plasma C-reactive protein (CRP) and adiponectin, and whether the Pro12Ala polymorphism in the PPARgamma2 gene (PPARG2) modified these associations. METHODS: We conducted a cross-sectional analysis among 1,222 women and 758 men participating in the EPIC-Potsdam study. RESULTS: Most notably, in both sexes, higher linoleic acid (LA) was related to lower CRP (geometric mean outcome [mg/L], quintile 1, quintile 5, p for trend <= 0.01 unless otherwise stated: 0.95, 0.61 [women], 0.67, 0.51 [men]) and higher adiponectin (7.9, 9.1 [women], 5.3, 6.1 [men]), whereas higher gamma-linolenic acid (GLA) and dihomo gamma-linolenic acid (DGLA) were related to higher CRP (GLA: 0.63, 0.92 [women], 0.55, 0.70, p = 0.08 [men], DGLA: 0.55, 1.07 [women], 0.52, 0.76 [men]) and lower adiponectin (GLA: 8.6, 8.0 [women], 5.8, 5.4, p = 0.08 [men], DGLA: 9.2, 7.9 [women], 5.9, 5.4, p = 0.08 [men]) adjusting for age and lifestyle. The associations mostly did neither strongly nor significantly vary by PPARG2 genotype. In women, Pro12Ala appeared to interact with arachidonic acid on CRP (p = 0.04), as well as with docosatetraenoic acid on CRP (p = 0.08) and adiponectin (p = 0.02). CONCLUSIONS: Our findings suggest that erythrocyte PUFA, particularly LA and n-6 higher unsaturated fatty acids, are related to circulating CRP and adiponectin. They do not indicate that PUFA strongly interact with the PPARG2 Pro12Ala variant on these risk markers. PMID- 21301857 TI - Glutaminyl cyclase contributes to the formation of focal and diffuse pyroglutamate (pGlu)-Abeta deposits in hippocampus via distinct cellular mechanisms. AB - In the hippocampal formation of Alzheimer's disease (AD) patients, both focal and diffuse deposits of Abeta peptides appear in a subregion- and layer-specific manner. Recently, pyroglutamate (pGlu or pE)-modified Abeta peptides were identified as a highly pathogenic and seeding Abeta peptide species. Since the pE modification is catalyzed by glutaminyl cyclase (QC) this enzyme emerged as a novel pharmacological target for AD therapy. Here, we reveal the role of QC in the formation of different types of hippocampal pE-Abeta aggregates. First, we demonstrate that both, focal and diffuse pE-Abeta deposits are present in defined layers of the AD hippocampus. While the focal type of pE-Abeta aggregates was found to be associated with the somata of QC-expressing interneurons, the diffuse type was not. To address this discrepancy, the hippocampus of amyloid precursor protein transgenic mice was analysed. Similar to observations made in AD, focal (i.e. core-containing) pE-Abeta deposits originating from QC-positive neurons and diffuse pE-Abeta deposits not associated with QC were detected in Tg2576 mouse hippocampus. The hippocampal layers harbouring diffuse pE-Abeta deposits receive multiple afferents from QC-rich neuronal populations of the entorhinal cortex and locus coeruleus. This might point towards a mechanism in which pE-Abeta and/or QC are being released from projection neurons at hippocampal synapses. Indeed, there are a number of reports demonstrating the reduction of diffuse, but not of focal, Abeta deposits in hippocampus after deafferentation experiments. Moreover, we demonstrate in neurons by live cell imaging and by enzymatic activity assays that QC is secreted in a constitutive and regulated manner. Thus, it is concluded that hippocampal pE-Abeta plaques may develop through at least two different mechanisms: intracellularly at sites of somatic QC activity as well as extracellularly through seeding at terminal fields of QC expressing projection neurons. PMID- 21301858 TI - Buprenorphine and norbuprenorphine findings in hair during constant maintenance dosage. AB - It is still a matter of debate whether a positive correlation between the dose and the amount of drug in the hair exists. Drugs such as buprenorphine (BUP) used under controlled conditions present an opportunity to prove a possible relationship. Due to discrepant findings of BUP/norbuprenorphine (NBUP) ratios in hair, in vitro degradation of both analytes in diluted acid was also investigated. The levels of BUP and NBUP in proximal hair sections from 18 subjects participating in a maintenance program were determined by liquid chromatography/tandem mass spectrometry following incubation with methanol and subsequent liquid/liquid extraction. BUP and NBUP were incubated in diluted hydrochloric acid at 60 degrees C for up to 24 h. The alleged rearrangement products were simultaneously monitored. All hair samples tested positive for BUP (lower limit of detection-0.238 ng/mg hair) and NBUP (0.043-0.961 ng/mg hair). The concentration of NBUP in hair was consistently higher than that of BUP except for a single specimen. Degradation of BUP and NBUP was dependent on time; hydrolysis of NBUP occurred faster than that of BUP. The concentration of BUP and NBUP will be underestimated if analytes are recovered by acidic procedures. NBUP should be monitored in hair samples besides BUP for the sum of both BUP and NBUP may provide an estimate of BUP exposure following long-term administration of the drug. PMID- 21301859 TI - Genetic analysis of two Japanese families with progressive external ophthalmoplegia and parkinsonism. AB - Mutations in the progressive external ophthalmoplegia 1 (PEO1), adenine nucleotide translocator 1 (ANT1) and DNA polymerase gamma (POLG) genes were reported in patients with progressive external ophthalmoplegia and parkinsonism. However, the genotype-phenotype correlation and pathophysiology of these syndromes are still unknown. In order to define the molecular basis of progressive external ophthalmoplegia and parkinsonism, we screened for mutations in PEO1, ANT1, POLG genes and the whole mitochondrial genome in two families. In results, we identified a compound heterozygous POLG substitutions, c.830A>T (p.H277L) and c.2827C>T (p.R943C) in one of the families. These two mutations in the coding region of POLG alter conserved amino acids in the exonuclease and polymerase domains, respectively, of the POLG protein. Neither of these substitutions was found in the 100 chromosomes of ethnically matched control subjects. In the other family, no mutations were detected in any of the three genes and the whole mitochondrial genome in the blood sample, although mitochondrial DNA deletions were observed in the muscle biopsy sample. Progressive external ophthalmoplegia and parkinsonism are genetically heterogenous disorders, and part of this syndrome may be caused by mutations in other, unknown genes. PMID- 21301860 TI - Adjustment in patients with asystole during strabismus surgery. AB - PURPOSE: To investigate whether patients who developed asystole during strabismus surgery under general anesthesia also develop asystole during adjustment, and whether adjustment can safely be performed under topical anesthesia in these patients. DESIGN: Retrospective, noncomparative interventional case series. METHODS: Adjustment was performed with topical anesthesia in four patients aged 28, 32, 50, and 53 years who exhibited asystole during strabismus surgery under general anesthesia. Blood pressure and electrocardiogram were monitored during the adjustment. RESULTS: Adjustment was successfully completed in all patients without asystole. Two patients showed oculocardiac reflex (OCR), with a reduction in heart rate (HR) >20% of the baseline value. One of these patients exhibited severe OCR that developed when the patient's posture was changed from the supine to the sitting position for measurement of the angle of strabismus after adjustment, and again during conjunctival manipulation after conjunctival closure. No patient required atropine. CONCLUSIONS: Adjustment can safely be performed under topical anesthesia in patients who developed asystole during strabismus surgery under general anesthesia. PMID- 21301861 TI - Gastroduodenal artery-preserving pancreaticoduodenectomy after subtotal esophagectomy and gastric pull-up. AB - PURPOSE: Division of the gastroduodenal artery is commonly performed during pancreaticoduodenectomy for both malignant and benign disease. We describe here a technical modification of pylorus preserving pancreaticoduodenectomy with gastroduodenal artery preservation performed in a patient who previously underwent subtotal esophagectomy with gastric pull-up discussing advantages and drawbacks of the technique. METHODS: A 73-year-old man with a previous history of right nephrectomy and lower esophagectomy for cancer was referred to our center for the treatment of a 5-cm tumor of the pancreatic head. Following the preliminary steps of a standard pancreaticoduodenectomy, the gastroduodenal artery was isolated at its origin from the common hepatic artery. The entire length of the gastroduodenal artery was dissected after having sectioned the posterior-superior pancreaticoduodenal artery. The right gastroepiploic vessels were preserved along with the gastroduodenal artery. Digestive reconstruction was completed just as for pylorus-preserving pancreaticoduodenectomy. RESULTS: The preservation of the gastroduodenal artery along with the gastroepiloic vessels was safely performed with an operative time of 300 min and minimal blood loss. Pathology showed a solitary 5-cm renal cell carcinoma metastasis. CONCLUSIONS: Gastroduodenal artery preserving pancreaticoduodenectomy can serve as an additional option in the armamentarium of a pancreatic surgeon. This technique constitutes an interesting technical option that ensures optimal vascular supply to the gastric remnant after previous esophagectomy. Its clinical application remains limited to selected indications and deserves further experience and comparison with standard techniques. PMID- 21301862 TI - Role of autocrine/paracrine mechanisms in response to myocardial strain. AB - Myocardial strain triggers an autocrine/paracrine mechanism known to participate in myocardial hypertrophy development. After the onset of stretch, there is a rapid augmentation in developed tension due to an increase in myofilament calcium sensitivity (the Frank Starling mechanism) followed by a gradual increase in tension over the next 10-15 min. This second phase is called the slow force response (SFR) to stretch and is known to be the result of an increase in calcium transient amplitude. In the present review, we will discuss what is known thus far about the SFR, which is the in vitro equivalent of the Anrep effect and the mechanical counterpart of the autocrine/paracrine mechanism elicited by myocardial stretch. The chain of events triggered by myocardial stretch comprises: (1) release of angiotensin II, (2) release/formation of endothelin, (3) NADPH oxidase activation and transactivation of the EGFR, (4) mitochondrial reactive oxygen species production, (5) activation of redox-sensitive kinases, (6) NHE-1 hyperactivity, (7) increase in intracellular Na(+) concentration, and (8) increase in Ca(2+) transient amplitude through the Na(+)/Ca(2+) exchanger. The evidence for each step of the intracellular signaling pathway leading to the development of SFR and their relationship with the mechanisms proposed for cardiac hypertrophy development will be analyzed. PMID- 21301863 TI - Cysteine residue 911 in C-terminal tail of human BK(Ca)alpha channel subunit is crucial for its activation by carbon monoxide. AB - The large conductance, voltage- and calcium-activated potassium channel, BK(Ca), is a known target for the gasotransmitter, carbon monoxide (CO). Activation of BK(Ca) by CO modulates cellular excitability and contributes to the physiology of a diverse array of processes, including vascular tone and oxygen-sensing. Currently, there is no consensus regarding the molecular mechanisms underpinning reception of CO by the BK(Ca). Here, employing voltage-clamped, inside-out patches from HEK293 cells expressing single, double and triple cysteine mutations in the BK(Ca) alpha-subunit, we test the hypothesis that CO regulation is conferred upon the channel by interactions with cysteine residues within the RCK2 domain. In physiological [Ca(2+)](i), all mutants carrying a cysteine substitution at position 911 (C911G) demonstrated significantly reduced CO sensitivity; the C911G mutant did not express altered Ca(2+)-sensitivity. In contrast, histidine residues in RCK1 domain, previously shown to ablate CO activation in low [Ca(2+)](i), actually increased CO sensitivity when [Ca(2+)](i) was in the physiological range. Importantly, cyanide, employed here as a substituent for CO at potential metal centres, occluded activation by CO; this effect was freely reversible. Taken together, these data suggest that a specific cysteine residue in the C-terminal domain, which is close to the Ca(2+) bowl but which is not involved in Ca(2+) activation, confers significant CO sensitivity to BK(Ca) channels. The rapid reversibility of CO and cyanide binding, coupled to information garnered from other CO-binding proteins, suggests that C911 may be involved in formation of a transition metal cluster which can bind and, thereafter, activate BK(Ca). PMID- 21301864 TI - Ductal plates in hepatic ductular reactions. Hypothesis and implications. III. Implications for liver pathology. AB - This article discusses on the basis of the ductal plate hypothesis the implication of the concept for several liver abnormalities. The occurrence of ductal plates (DP) during liver growth in childhood would explain the paraportal and parenchymal localizations of von Meyenburg complexes in postnatally developed parts of the liver, and their higher incidence in adulthood versus childhood. It partly clarifies the lack of postnatal intrahepatic bile duct development in Alagille syndrome and the reduced number of portal tracts in this disease. Ductular reactions (DRs) in DP configuration are the predominant type of progenitor cell reaction in fulminant necro-inflammatory liver disease, when lack of sufficient parenchymal regeneration results in liver failure. The concept of dissecting DRs explains the micronodular pattern of advanced biliary and alcoholic cirrhosis. The concept explains the DP patterns of bile ducts in several cases of biliary atresia, with implications for diagnosis and prognosis. The hypothesis also has an impact on concepts about stem/progenitor cells and their niche. PMID- 21301865 TI - Altered expression of UPIa, UPIb, UPII, and UPIIIa during urothelial carcinogenesis induced by N-butyl-N-(4-hydroxybutyl)nitrosamine in rats. AB - In normal urothelium, superficial umbrella cells express four major integral membrane proteins, uroplakins UPIa, UPIb, UPII, and UPIIIa, which compose urothelial plaques. In the apical plasma membrane, urothelial plaques form microridges. During neoplastic changes, microridges are replaced by microvilli, while uroplakin expression is retained. We correlated individual uroplakin expression with apical plasma membrane structure, cytokeratin 20 expression, and urothelial cell proliferation (Ki-67). Male Wistar rats were treated with 0.05% N butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in drinking water, which caused flat hyperplasia with mild dysplasia, low-grade papillary urothelial carcinoma, invasive low- and high-grade papillary urothelial carcinoma and invasive squamous cell carcinoma with extensive keratinization, grade 2. During urothelial carcinogenesis, UPII expression was the most decreased in all urothelial lesions, while UPIa, UPIb, and UPIIIa expression was differently altered in different types of lesions. Superficial cells were covered with microvilli and ropy ridges, while microridges were disappearing. The expression of cytokeratin 20 was decreased and limited to superficial urothelial cells. Proliferation indices were increased, except for invasive squamous cell carcinoma with extensive keratinization. Our results indicate that during urothelial carcinogenesis the expression of UPII is diminished, suggesting that UPIb/UPIIIa heterodimer can still be formed, while heterodimer UPIa/UPII formation is disrupted. Correlation between decreased level of UPII expression and changed apical plasma membrane structure suggests that diminished expression of UPII hinders the urothelial plaque formation. PMID- 21301867 TI - The diagnosis of brain tuberculoma by (1)H-magnetic resonance spectroscopy. AB - Toddlers are more prone to develop severe and extrapulmonary tuberculosis (TB) than older children. This is partially explained by differences in the immune response. Early and specific diagnosis is essential to start adequate treatment, especially if the central nervous system (CNS) is involved. The lack of sputum production and inherent dangers or impossibility of sampling CNS lesions may delay diagnosis. In addition, the magnetic resonance imaging (MRI) features of TB abscesses are non-specific and may mimic abscesses of other infectious etiology. (1)H-magnetic resonance spectroscopy ((1)H-MRS) may increase specificity of diagnosis by identifying lipids within the lesions that are considered characteristic for TB. Therefore, we studied four children with presumable CNS-TB with MRI and (1)H-MRS. In vivo and in vitro (1)H-MRS showed elevated lipid peaks within the TB lesions. CONCLUSION: (1)H-MRS allows to non-invasively identifying TB with high specificity and may allow early installment of targeted antimicrobial treatment. PMID- 21301866 TI - Apnea of prematurity: from cause to treatment. AB - Apnea of prematurity (AOP) is a common problem affecting premature infants, likely secondary to a "physiologic" immaturity of respiratory control that may be exacerbated by neonatal disease. These include altered ventilatory responses to hypoxia, hypercapnia, and altered sleep states, while the roles of gastroesophageal reflux and anemia remain controversial. Standard clinical management of the obstructive subtype of AOP includes prone positioning and continuous positive or nasal intermittent positive pressure ventilation to prevent pharyngeal collapse and alveolar atelectasis, while methylxanthine therapy is a mainstay of treatment of central apnea by stimulating the central nervous system and respiratory muscle function. Other therapies, including kangaroo care, red blood cell transfusions, and CO(2) inhalation, require further study. The physiology and pathophysiology behind AOP are discussed, including the laryngeal chemoreflex and sensitivity to inhibitory neurotransmitters, as are the mechanisms by which different therapies may work and the potential long-term neurodevelopmental consequences of AOP and its treatment. PMID- 21301868 TI - Clinical practice: the treatment of acute convulsive seizures in children. AB - An adequate early treatment of a long-lasting convulsive seizure is critical in reducing potential morbidity, and in particular, brain damage. In pre-hospital settings the use of benzodiazepines should become standard. Nowadays, rectal diazepam is used frequently, but midazoloam and lorazepam are becoming more popular, both being given either intranasally or orally. The buccal route is to be preferred because of its easy use and high efficacy. A generally accepted policy for early treatment of convulsive seizures is a crucial issue in the elaboration of an overall treatment plan for the child with epilepsy. Such a plan should include instruction and education of the parents and the caregivers surrounding the child. PMID- 21301869 TI - A reminder on superior herniation of normal mediastinal thymus. PMID- 21301870 TI - Chemical composition, larvicidal evaluation, and adult repellency of endemic Greek Thymus essential oils against the mosquito vector of West Nile virus. AB - The volatile metabolites of Greek wild growing Thymus leucospermus and Thymus teucrioides subsp. candilicus were determined by gas chromatography and gas chromatography-mass spectrometry. The monoterpene hydrocarbon p-cymene (64.2%) dominated T. leucospermus oil, followed by gamma-terpinene (7.9%), thymol (4.8%), and borneol (4.7%), whereas the most abundant constituents in T. teucrioides subsp. candilicus oil were p-cymene (25.5%), gamma-terpinene (19.0%), thymol (18.8%), borneol (5.7%), and alpha-pinene (5.7%). The larvicidal and repellent activities of the analyzed essential oils were tested on Culex pipiens larvae and adults, respectively. Additionally, the main metabolite of the essential oils, p cymene was tested against C. pipiens adults in order to define the affiliation between p-cymene and the repellent properties of the oil. The essential oils of T. leucospermus and T. teucrioides subsp. candilicus provided repellency 78.1% and 72.9%, respectively, statistically equal to the reference product icaridin. The compound p-cymene showed almost no repellent activity. The essential oil of T. leucospermus presented lower larvicidal activity (LC(50) = 34.26 mgl(-1)) against C. pipiens third-fourth instar larvae while T. teucrioides subsp. candilicus was the most active with an estimated LC(50) value of 23.17 mgl(-1). PMID- 21301871 TI - Differential miRNA expression in the mouse jejunum during garlic treatment of Eimeria papillata infections. AB - Accumulating evidence indicates a critical role of microRNAs (miRNAs) in the outcome of diseases. Here, we investigate the effect of garlic on the intestinal miRNA signature of male Balb/c mice during infections with Eimeria papillata. Garlic decreases the intracellular development as evidenced by a lowered fecal output of E. papillata oocysts from 3,150 +/- 410 to approximately 1,750 +/- 390 oocysts per gram feces on day 4 postinoculation. This anti-coccidial activity of garlic is associated with an inhibition of the E. papillata-induced increases of interferon gamma, inducible nitric oxide synthase, nitrite/nitrate, and malondialdehyde and decrease in glutathione. Moreover, garlic downregulates the E. papillata-induced increases in the expression of the miRNAs miR-1959, miR-203, and miR-21, and it upregulates the expression of the 11 miRNA species miR-142-5P, miR-15A, miR-10A, miR-29B, miR-1902, miR-125A-5P, let-7E, miR-148A, miR-130A, miR 10B, and miR-93, respectively, as revealed by miRXplore microarray technology. Real-time PCR confirms these effects of garlic in the jejunum of E. papillata infected mice. Our data indicate that the anti-coccidial activity of garlic is associated with specific changes in the miRNA signature of the mouse jejunum, the target site of E. papillata. These changes may reflect an involvement of miRNAs in garlic-activated pathways to reduce and/or to repair E. papillata-induced tissue injuries. PMID- 21301872 TI - Phylogeography of Ascaris lumbricoides and A. suum from China. AB - In order to obtain further understanding of genetic structure and evolutionary relationship of Ascaris from humans and pigs, phylogeography study on 12 populations from six endemic regions in China was conducted using mitochondrial DNA markers (cytochrome c oxidase subunit 1 (COX1) and NAD1) and the software programs of DnaSP 5.0, Arlequin 3.0, MEGA 4.0, and NETWORK 4.5.1.6. Results showed that (a) genetic diversity of Ascaris varied with hosts and locations, but no distinct geographical distribution pattern was found, (b) a higher level of genetic diversity and differentiation was found in pig-derived populations in contrast to human-derived ones, and in populations of human-derived Ascaris from the southern regions in comparison to that from the middle and northern locations, but similar geographical difference was not observed within pig derived populations, (c) historical population expanding was detected from a large part of human-derived Ascaris populations but not in pig-derived Ascaris, (d) a high level of gene flow was detected between human- and pig-derived Ascaris and also among human-derived populations, and (e) network analysis from haplotype of COX1 indicated an ancestral haplotype from human-derived Ascaris. In conclusion, the present study revealed new information on Ascaris on the aspects of genetic diversity, population differentiation and historical demographic patterns, gene flow, phylogenesis reconstruction, and haplotype network, discussed the results with historical demographic migration of humans and domestication of wild boar in China, and raised a different assumption about the evolutionary relationship of the two roundworms. This study should have certain enlightenment for the epidemiology and the evolutionary and taxonomy relationship of Ascaris from humans and pigs. PMID- 21301873 TI - Epidemiology and history of human parasitic diseases in Romania. AB - Intestinal parasitic diseases such as enterobiasis, giardiasis, and ascariasis are detected most frequently in Romania, but their importance is definitely surpassed by trichinellosis, cystic echinococcosis, and toxoplasmosis. Malaria was common until its eradication in 1963, and only imported cases are reported nowadays. The aim of this review was to bring together essential data on the epidemiology and history of human parasitoses in Romania. Information on 43 parasitic diseases was collected from numerous sources, most of them unavailable abroad or inaccessible to the international scientific community. Over time, Romanian people of all ages have paid a significant tribute to the pathogenic influences exerted by the parasites. Sanitary and socio-economical consequences of the parasites diseases have great negative impact on the quality of life of affected individuals and the overall well-being of the population. Implementation of efficient public health measures and informative campaigns for the masses as well as changing the inadequate habits that are deeply rooted in the population are mandatory for cutting successfully this Gordian knot. PMID- 21301875 TI - Evaluation of erythrocyte antioxidant mechanisms: antioxidant enzymes, lipid peroxidation, and serum trace elements associated with progressive anemia in ovine malignant theileriosis. AB - Ovine malignant theileriosis is a fatal disease that is characterized by severe progressive anemia. In order to elucidate the underlying mechanisms involved in anemia, this study was designed to assess the antioxidant status and erythrocyte oxidative injuries in Iranian fat-tailed sheep that suffered from malignant theileriosis. The infected animals (infected group), composed of 50 Iranian sheep about 1-2 years old, naturally infected with Theileria sp., were divided into three subgroups according to parasitemia rates (<1%, 1-3%, 3-5%), and ten non infected animals were also selected as the control group. Blood samples were taken and hematological parameters, the activities of antioxidant enzymes including superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase, erythrocyte osmotic fragility, and serum concentrations of some trace elements (copper, iron, zinc, manganese, and selenium), were measured. As an index of lipid peroxidation, the level of malondialdehyde (MDA) was also determined. According to the results, a significant decrease in red blood cell (RBC) count, packed cell volume, the activities of SOD, GPX, and catalase (P <0.001), and also serum concentrations of Cu, Zn, Mn, and Se (P < 0.05) were evident in the infected sheep. In contrast, significantly increased levels of MDA and erythrocyte osmotic fragility (P < 0.001) as well as serum concentration of iron (P < 0.05) were recorded in the infected animals. The significant decrease in antioxidant enzyme activities and substantial elevated levels of lipid peroxidation and erythrocyte osmotic fragility associated with the increase in parasitemia indicate increased exposure of RBCs to oxidative damage. Also, it appears that disturbed antioxidant defense mechanisms can promote the development of anemia in ovine theileriosis. PMID- 21301874 TI - Epidemiological survey of Angiostrongylus cantonensis in the west-central region of Guangdong Province, China. AB - The study was to understand the Angiostrongylus cantonensis infectious situation of rodent definitive host, snail intermediate host, and local residents in the west-central region of Guangdong Province in China. The snails Achatina fulica and Pomacea canaliculata collected from the survey place were digested with artificial gastric juice, and the third-stage larvae of A. cantonensis in the snails were examined under microscope. The heart and lung of rats captured from the survey place were taken to check the adult of A. cantonensis. The questionnaire surveys related to the infection of A. cantonensis were taken in local residents randomly selected, and the IgG antibody against A. cantonensis was tested in those residents with enzyme-linked immunosorbent assay (ELISA). A total of 1,391 rats including eight kinds of rats, such as Rattus norvegicus, Rattus flavipectus, Bandicota indica, Rattus sladeni, Mus musculus, Rattus rattoides, Suncus Murinus, and Rattus confucianus, were examined and 132 of them were infected by A. cantonensis, with an average infection rate of 9.49% and a mean intensity of A. cantonensis in infected rats was 9.39. A total of 3,184 snails A. fulica and 3,723 snails P. canaliculata were detected. The average infection rates of them were 25.03% (797/3,184) and 6.50% (242/3,723), respectively. There were 180 positive samples of IgG antibody against A. cantonensis in 1,800 serum samples of the residents, with a positive rate of 10.00%. The west-central region of Guangdong Province is the natural focus of A. cantonensis. In comparison with the investigation results in other regions of China, the infection rate of rat definitive host is at the middle level; in the intermediate host, the infection rate of snail A. fulica is above the middle level, and the infection rate of snail Pomacea canaliculata is below the middle level. Some local residents had already been infected by A. cantonensis or at the risk of being infected. PMID- 21301876 TI - Morphology and SSU rDNA sequences of Ortholinea orientalis (Shul'man and Shul'man Albova, 1953) (Myxozoa, Ortholineidae) from Clupea harengus and Sprattus sprattus (Clupeidae) from Denmark. AB - Ortholinea orientalis (Shul'man and Shul'man-Albova 1953) Shul'man 1956 is redescribed from Clupea harengus L. and Sprattus sprattus (L.) (Teleostei, Clupeidae) from the northern Oresund, Denmark. S. sprattus is a new host record. Polysporic plasmodia and most myxospores were found in the ureters of both hosts. The myxospores have external valvular ridges, which were not observed in the original description. The presence of this character causes us to consider Ortholinea clupeidae Aseeva 2000 as a likely synonym of O. orientalis. Ortholinea antipae Moshu and Trombitsky, 2006 from a Black Sea clupeid is also similar and represent a possible synonym. Sequence comparisons and phylogenetic analysis of partial SSU rDNA sequences of O. orientalis reveal closest affinity (82-86% identity) to members of the 'Freshwater Urinary Bladder Clade' sensu Fiala (2006), a clade among the Platysporina containing members of the myxosporean genera Myxobilatus, Hoferellus, Myxidium, Zschokkella and Chloromyxum from freshwater fishes. PMID- 21301877 TI - Root fungal symbionts interact with mammalian herbivory, soil nutrient availability and specific habitat conditions. AB - Herbivory, competition and soil fertility interactively shape plant communities and exhibit an important role in modifying conditions for host-dependent fungal symbionts. However, field studies on the combined impacts of natural herbivory, competition and soil fertility on root fungal symbionts are rare. We asked how mammalian herbivory, fertilization, liming and plant-plant competition affect the root colonization of arbuscular mycorrhizal fungi (AMF) and dark septate endophytic (DSE) fungi of the dicot herb, Solidago virgaurea. The 2-year full factorial experiment was conducted in two contrasting habitats: non-acidic and acidic mountain tundra. We found that herbivory increased arbuscular colonization (i.e. the site of resource exchange) at fertile non-acidic sites, where vegetation was rich in species having AMF symbionts, whereas at infertile acidic sites, where plants having AMF symbiont are scarce, the response was the opposite. Herbivory of the host plant negatively affected DSE hyphal and sclerotial colonization in unfertilized plots, possibly due to reduced carbon flow from the host plant while there was no effect of herbivory in fertilized plots. DSE colonization was highest in unfertilized exclosures where soil nutrient concentrations were also lowest. Liming had a negative effect on DSE hyphal colonization, and its effect also interacted with herbivory and the habitat. Biomass removal of the neighboring plants did not affect the root colonization percent of either arbuscules or DSE. Our results show that the impacts of aboveground mammalian herbivory, soil nutrient availability and specific habitat conditions on belowground root fungal symbionts are highly dependent on each other. Arbuscule response to herbivory appeared to be regulated by specific habitat conditions possibly caused by differences in the AMF availability in the soil while DSE response was associated with availability of host-derived carbon. Our result of the relationship between herbivory and soil nutrients suggests an important role of DSE in ecosystem processes. PMID- 21301878 TI - The carotenoid conundrum: improved nutrition boosts plasma carotenoid levels but not immune benefits of carotenoid supplementation. AB - Carotenoids are widely heralded as central to honest signaling due to their dual roles as pigments and antioxidants/immunostimulants. The aim of this study is to test if diet quality and carotenoids alone or in an interaction influence condition, carotenoid availability in plasma and immune responsiveness. Therefore, a diet experiment during the moult of great tits, Parus major, was performed. In a two-way design, we manipulated general quality (digestibility, protein and vitamin content) as well as carotenoid (lutein) content of semi synthetic diets. Higher quality diet improved individual condition since birds had greater body mass, and to a lesser extent, higher hematocrit. In addition to the expected positive effect of carotenoid supplementation and individual lutein consumption on circulating lutein, there was a positive effect of enhanced diet quality on plasma carotenoid levels. Carotenoid supplementation, but not diet quality, improved the local inflammatory response and maintenance of body mass during a humoral immune reaction. The enhancement of circulating carotenoid levels by improved general quality of the diet or individual condition could provide a testable, mechanistic explanation for the variation in effects of carotenoid supplementation studies. PMID- 21301879 TI - Mediastinal lymphadenopathy: assessing clinical utility of EUS-FNA. PMID- 21301880 TI - Laparoscopic left colectomy combined with natural orifice access: operative technique and initial results. AB - BACKGROUND: Minimally invasive surgery for colon resection has improved patient outcome, but a minilaparotomy still is necessary to extract the specimen and place the anvil of the circular stapler into the proximal colon. This wound can cause postoperative pain, wound infection, and hernia. This report describes a new approach that combine classical laparoscopic left colon resection and natural orifice access using an operating rectoscope, with the aim to minimize abdominal wall trauma. METHODS: Laparoscopic left colon dissection for diverticular disease or small tumors was performed using a standard four-port technique. An operating rectoscope was transanally inserted into the rectum to remove the specimen and to pass the anvil of the circular stapler into the abdominal cavity. A straight needle was tied to the rod of the anvil to simplify its placement into the proximal colon so that a double-stapled anastomosis could be performed in the usual manner. Outcome parameters such as complications, conversions, operative time, and postoperative pain were prospectively recorded in a database. RESULTS: Surgery was performed for 15 patients with diverticular disease or small tumors. No intraoperative complications or conversions occurred. The median operating time was 145 min. The postoperative pain level was low, and only 3 of 15 patients needed opioid analgesia on postoperative day 1. The median postoperative hospital stay was 7 days. Blood oozing from the anastomotic site in one patient was the only recorded adverse event. For malignancies, tissue margins and lymphadenectomy were oncologically adequate. The 4-week follow-up period was uneventful. CONCLUSION: The described technique, a combination of laparoscopic and natural orifice surgery, has the potential to avoid incision-related morbidity of the minilaparotomy in laparoscopic left colon resections. PMID- 21301881 TI - Are blood group and save samples needed for cholecystectomy? AB - BACKGROUND: Cholecystectomy is a common, safe procedure. This study aimed to determine whether a blood group and save approach still is required for primary cholecystectomy. METHODS: A retrospective regional analysis of all cholecystectomy patients identified from pathology records between January 1998 and February 2005 was undertaken. The study excluded from further analysis patients for whom cholecystectomy was not the primary operation or for whom the data were incomplete. RESULTS: A total of 4,652 patients were identified. Of these patients, 19 were excluded due to incomplete data and 171 were excluded because the cholecystectomy was secondary to another procedure. Of the remaining 4,462 patients, 2,916 (65.4%) had a blood sample sent to the blood transfusion service. The 2,916 patients were subdivided into blood group and save samples (2461/4462, 55.2%) and blood cross-matched samples (455/4462, 10.2%). Blood transfusion was required by 48 patients (48/4462, 1.1%). Subanalysis of the transfused group showed that 27 patients received a blood transfusion due to complications of the index operation, with 18 (18/27, 66.7%) undergoing transfusion while in the operating theater. The indication for transfusion in the remaining 21 patients was secondary to a reoperation for complications of laparoscopic cholecystectomy (n = 8), related to primary hematologic malignancy (n = 6), or not documented (n = 7). CONCLUSION: The use of routine blood group and save is not justified. A targeted approach will reduce the demand on blood transfusion service without detriment to those undergoing cholecystectomy. There is no substitute for adequate vigilance for bleeding as a complication with any surgical procedure. PMID- 21301882 TI - Novel method of the double-loop slip-knot: preknotting on the laparoscopic forceps enables easy and secure intracorporeal ligation. AB - BACKGROUND: Laparoscopic ligation is a difficult and advanced technique because of the limited movement of forceps under two-dimensional videoscopic view. Currently, single-port surgery is widely used and a simple method for intracorporeal ligation is required. We describe an intracorporeal slip-knot with a double-loop strand that can be used to provide security and present the experimental results obtained. METHODS: A modified Eskimo bowline with a 4-0 absorbable monofilament was placed on a needle driver, and the forceps was used to grip both ends of the thread. Another forceps was used to pass the line under vessels in the abdominal cavity. The line was withdrawn from the gripping point through the preknot on the rod after it was gripped at the same point. The slip knot was tightened, and a pushing forceps and a needle driver were used to push the knot and complete the ligation. RESULTS: The double-loop slip-knot has a high bursting pressure compatible with that of a conventional square-to-slip knot, which is significantly higher than that of any other slip-knot. In an experimental evaluation on animal laparoscopy, residents performed complete ligations of gastric and colonic arteries and veins within 30 s after a short explanation of the procedure. CONCLUSION: This novel slip-knot with a double strand loop could provide easy and secure intracorporeal ligation. This type of slip-knot has great potential for wide use in open surgery using laparoscopy. Further evaluation is required to determine its clinical applicability. PMID- 21301883 TI - Experimental model of laparoscopic gastric ischemic preconditioning prior to transhiatal esophagectomy. AB - BACKGROUND: Cervical esophagogastric anastomotic disruption following transhiatal esophagectomy (THE) is a significant problem. Gastric tip ischemia is a primary cause of anastomotic failure. We examined gastric tip blood flow when laparoscopic "ischemic preconditioning" was attempted by selectively ligating the short gastric (SG) vessels or both the left and short gastric (LG/SG) vessels prior to THE. METHODS: Seventeen (25 kg) mongrel dogs underwent laparoscopy followed 3 weeks later by THE. Three groups were studied: control group = laparoscopy only, no preconditioning (n = 6); SG group = laparoscopic ligation of SG vessels only (n = 5); and LG/SG group = laparoscopic ligation of LG and SG vessels (n = 6). Tissue blood flow was assessed using the fluorescent microsphere method. The initial microsphere injections occurred prior to pneumoperitoneum and upon completion of the laparoscopy. At the second operation, transhiatal esophagectomy was performed and microsphere blood flow assessment occurred after induction of anesthesia, after mobilization of the stomach, and after completion of the cervical esophagogastric anastomosis. The animals were euthanized and regional gastric tissue was analyzed for microsphere estimates of blood flow. Differences in blood flow were evaluated using Student's t test. RESULTS: The mean baseline gastric blood flow was 0.58 ml/min/g. After THE, the proximal gastric blood flow fell to 16% of baseline in control and 22% in SG, but was reduced to only 60% of baseline in LG/SG. This relative preservation of blood flow among the LG/SG group approached significance compared with the laparoscopy only (control) group (P = 0.07). Ligation of SG vessels alone provided no preservation of proximal gastric blood flow following THE. CONCLUSION: Preoperative "ischemic preconditioning" through ligation of both the short and left gastric vessels may achieve preservation of blood flow to the gastric tip. Preconditioning during laparoscopic staging of esophageal carcinoma may be considered to reduce anastomotic complications following esophagectomy. PMID- 21301884 TI - Female population perception of conventional laparoscopy, transumbilical LESS, and transvaginal NOTES for cholecystectomy. AB - BACKGROUND: Recent population survey has shown a preference for transumbilical laparoendoscopic single-site surgery (U-LESS) compared with natural orifice transluminal endoscopic surgery (NOTES) for cholecystectomy, assuming similar surgical risk. This study was designed to evaluate the perception and preference of women regarding conventional laparoscopy, U-LESS, and transvaginal NOTES (TV NOTES) with particular interest to access perception. METHODS: An anonymous questionnaire on laparoscopic, U-LESS, and TV-NOTES cholecystectomy, without regards to risks or advantages, was given to female medical/paramedical staff (n=100), patients (n=100), and the general population (n=100). Women participants (median age, 35 (range, 16-79) years) were queried about preference, perception of the different accesses, and personal informations. Of the respondents, 54% had children, 79% had stable relationships, and 96% were sexually active (vaginal intercourse). RESULTS: With similar operative risk, 87% preferred U-LESS, 4% TV NOTES and 8% laparoscopy. LESS/NOTES choice was influenced by a desire of improved cosmetics (82%) and lower pain (44%). 96% had worries regarding transvaginal access, among them: dyspareunia (68%), decreased sensibility during intercourse (43%), refuse of short-term sexual abstinence (40%), and infertility (23%). Transumbilical access evocated worries in 35%: umbilical pain (19%), postoperative umbilical sensibility (15%), and incisional hernia (11%). Postoperative intercourse abstinence after TV-NOTES evocated worries in 76% (defined as 3 weeks in survey): feel less attractive (40%), less feminine (32%), tension with their intimate (35%), lover non-acceptation (20%), possible abortion of new relationship (26%), and feel less comfortable socially (16%). CONCLUSIONS: The high acceptation rate for U-LESS approach compared with TV-NOTES may be related to fears regarding postoperative sexuality and fertility. The importance of temporary postoperative sexual abstinence (vaginal intercourse) is high and may be difficult to influence. Future research on TV-NOTES should focus on the access risk to be able to scientifically reassure our patients. For now, U-LESS seems to be favor compared with TV-NOTES for cholecystectomy in female patients. PMID- 21301885 TI - Endoscopic resection of bladder cancer in patients receiving double platelet antiaggregant therapy. AB - BACKGROUND: Approximately 5% of patients who have undergone coronary artery stenting require noncardiac surgery within a year of their cardiac intervention. European cardiological guidelines and recommendations from the U.S. Food and Drug Administration on platelet antiaggregant therapy following coronary artery stenting are for dual treatment with acetylsalicylic acid and clopidogrel, which should be continued for at least 12 months. The aim of this study was to evaluate the clinical course in patients receiving double platelet antiaggregant therapy who underwent transurethral resection of bladder cancer. METHODS: Between September 2007 and April 2010, twelve patients receiving double antithrombotic therapy (clopidogrel+acetylsalicylic acid) underwent transurethral resection of bladder cancer. In two cases the operation was "urgent". The mean age of the patients was 71.25 years (range, 52-83 years). In nine cases the bladder cancer was newly diagnosed. RESULTS: The patients' preoperative mean hemoglobin concentration was 11.4 g/dl (range=5.2-13.4 g/dl), and on the first postoperative day it was 10.2 g/dl (range=9.6-12.6 g/dl). The mean duration of the intervention was 32 min (range=20-60 min). There were no cardiac complications in either the perioperative or the postoperative period. No patient required reintervention for hemostatic purposes. Three episodes of clot-related acute urinary retention occurred after removal of the bladder catheter, all of which were resolved with replacement of the catheter without needing reintervention. CONCLUSION: Despite the high number of complications related to cardiac problems that suspension of these drugs causes, this urological intervention, carried out during dual antithrombotic therapy, was feasible and without major complications. Given the high proportion of complications due to clot-related urinary retention, it is advisable to leave the urinary catheter in place for a longer period. PMID- 21301887 TI - A patient with polyuria and hydronephrosis: question. PMID- 21301888 TI - Microalbuminuria: causes and implications. AB - Management strategies are increasingly focused on tackling the increasing burden of cardiovascular disease worldwide. Microalbuminuria is a powerful predictor of cardiovascular disease and mortality in adults. This holds true in the general adult population but is particularly recognized in those with diabetes, where it identifies those likely to develop progressive atherosclerotic vascular disease and renal impairment. The atherosclerotic process begins in childhood with likely consequences in later life. In-depth understanding of the mechanisms through which microalbuminuria occurs holds promise for designing therapies to arrest its development in the future. Microalbuminuria arises from increased leakage of albumin through the complex glomerular sieve known as the glomerular filtration barrier. This requires changes in the physio-chemical properties of components of this barrier. However, the increased glomerular permeability confirmed in disease does not necessarily correlate with recognized histological changes in the glomerulus, suggesting that perhaps more subtle ultrastructural changes may be relevant. The epidemiology of microalbuminuria reveals a close association between systemic endothelial dysfunction and vascular disease, also implicating glomerular endothelial dysfunction in microalbuminuria. This review discusses the mechanisms of microalbuminuria in disease, particularly the emerging role of the glomerular endothelium and its glycocalyx, and examines its implications for cardiovascular disease in the pediatric population. PMID- 21301889 TI - Influence of air pressure, humidity, solar radiation, temperature, and wind speed on ambulatory visits due to chronic obstructive pulmonary disease in Bavaria, Germany. AB - Chronic obstructive pulmonary disease (COPD) is one of the most important causes of morbidity and mortality in the world. The disease is often aggravated by periods of increased symptoms requiring medical attention. Among the possible triggers for these exacerbations, meteorological factors are under consideration. The objective of this study was to assess the influence of various meteorological factors on the health status of patients with COPD. For this purpose, the daily number of ambulatory care visits due to COPD was analysed in Bavaria, Germany, for the years 2006 and 2007. The meteorological factors were provided by the model at the European Centre for Medium Range Weather Forecast (ECMWF). For the multivariate analysis, a generalised linear model was used. In Bavaria, an increase of 1% of daily consultations (about 103 visits per day) was found to be associated with a change of 0.72 K temperature, 209.55 of log air surface pressure in Pa, and a decrease of 1% of daily consultations with 1,453,763 Ws m(2) of solar radiation. There also seem to be regional differences between north and south Bavaria; for instance, the effect of wind speed and specific humidity with a lag of 1 day were only significant in the north. This study could contribute to a tool for the prevention of exacerbations. It also serves as a model for the further evaluation of the impact of meteorological factors on health, and could easily be applied to other diseases or other regions. PMID- 21301891 TI - The effect of one-lung ventilation upon pulmonary inflammatory responses during lung resection. AB - PURPOSE: One-lung ventilation (OLV) is commonly used during thoracic surgery. Clinical studies using bronchoalveolar lavage fluid analysis have demonstrated that OLV induces pulmonary inflammatory reactions in the ventilated dependent lung. However, few clinical studies have investigated such inflammatory reactions in the dependent lung compared with the collapsed nondependent lung. Here we used a bronchoscopic microsampling method to obtain epithelial lining fluid (ELF) from each lung, and then compared the inflammatory reactions in the dependent lung and the nondependent lung during thoracic surgery. METHODS: Twenty adult patients were studied. All patients underwent thoracic surgery using OLV. Propofol and remifentanil were used for total intravenous anesthesia. A double-lumen endotracheal tube was used to perform OLV. ELF was obtained from each lung using the bronchoscopic microsampling method. ELF levels of inflammatory mediators, tumor necrosis factor alpha, interleukin (IL)-1beta, IL-6, IL-8, IL-10, and IL 12p70 were measured using ELISA before and after OLV. RESULTS: ELF levels of IL 1beta, IL-6, and IL-8 were significantly increased in the dependent lung and the nondependent lung at the end of surgery compared with their baseline levels (p < 0.05). ELF level of IL-6 was significantly higher in the dependent lung than in the nondependent lung at the end of surgery (p = 0.019). CONCLUSIONS: One-lung ventilation induced inflammatory responses of the bronchial epithelia in the dependent lung and the nondependent lung during thoracic surgery. In addition, these inflammatory responses were more augmented in the dependent lung than in the nondependent lung. PMID- 21301892 TI - Common environmental factors explain both ectomycorrhizal species diversity and pine regeneration variability in a post-fire Mediterranean forest. AB - Natural seedling regeneration and establishment after stand replacing wildfires is influenced by a series of environmental and biological constraints. In this study, we characterized the diversity and structure of the ectomycorrhizal (ECM) fungal community associated with post-fire naturally regenerated maritime pine saplings, and individuate the environmental factors responsible for fungal species distribution. We also identify the main environmental factors responsible for maritime pine regeneration variability and assessed the relation between saplings performance and ECM fungal diversity indices. Fungal species were identified by direct sequencing of internal transcribed spacer regions. Five years after the disturbance event, a total of 30 taxa colonized the pine saplings. The ECM fungal community was dominated by ruderal species of the genus Rhizopogon (present in almost half of the samples). Almost one third of the identified ECM fungal species belonged to the family Thelephoraceae. Typical k selected species like Amanita pantherina, Boletus aestivalis, Lactarius chrysorrheus, and Russula densifolia were found on pine saplings collected in proximity of unburnt pine trees, in correspondence with low erosion extents. Pine regeneration varied throughout the study areas and was enhanced at higher elevations, in correspondence with moderate slopes, shallower soils, and a reduced cover of ericaceous shrubs and bare ground. These conditions were found in close proximity to patches of pine trees that survived the disturbance event and were previously characterized by a higher pre-fire pine biomass. Even though no correlations were found between saplings performance and ECM fungal diversity indices, common environmental factors (i.e., ericaceous shrub cover, extent of erosion, slope, and soil depth) were responsible for shaping the ECM fungal distribution and for describing most of the explained regeneration variability. PMID- 21301893 TI - Kinematic evaluation of the adjacent segments after lumbar instrumented surgery: a comparison between rigid fusion and dynamic non-fusion stabilization. AB - The aim of the current study was to evaluate changes in lumbar kinematics after lumbar monosegmental instrumented surgery with rigid fusion and dynamic non fusion stabilization. A total of 77 lumbar spinal stenosis patients with L4 degenerative spondylolisthesis underwent L4-5 monosegmental posterior instrumented surgery. Of these, 36 patients were treated with rigid fusion (transforaminal lumbar interbody fusion) and 41 with dynamic stabilization [segmental spinal correction system (SSCS)]. Lumbar kinematics was evaluated with functional radiographs preoperatively and at final follow-up postoperatively. We defined the contribution of each segmental mobility to the total lumbar mobility as the percent segmental mobility [(sagittal angular motion of each segment in degrees)/(total sagittal angular motion in degrees) * 100]. Magnetic resonance imaging was performed on all patients preoperatively and at final follow-up postoperatively. The discs were classified into five grades based on the previously reported system. We defined the progress of disc degeneration as (grade at final follow-up) - (grade at preoperatively). No significant kinematical differences were shown at any of the lumbar segments preoperatively; however, significant differences were observed at the L2-3, L4-5, and L5-S1 segments postoperatively between the groups. At final follow-up, all of the lumbar segments with rigid fusion demonstrated significantly greater disc degeneration than those with dynamic stabilization. Our results suggest that the SSCS preserved 14% of the kinematical operations at the instrumented segment. The SSCS may prevent excessive effects on adjacent segmental kinematics and may prevent the incidence of adjacent segment disorder. PMID- 21301894 TI - Electrophysiological characterization of NSCs after differentiation induced by OEC conditioned medium. AB - PURPOSE: We induced neural stem cells (NSCs) to neurons by olfactory ensheathing cell (OEC) conditioned medium and characterized their electrophysiological properties after neuronal differentiation. METHODS: Fetal NSCs and OECs were cultured from embryonic day 14 SD rats and the conditioned medium was collected and stored at -20 degrees C when the cell number was up to 80% of the culture flasks. The experiment groups were divided into a control group (cultured with DMEM/F12 without FBS) and an OECs induction group (cultured with OEC conditioned medium and DMEM/F12 without FBS). Immunocytochemistry staining was carried out to identify the neurons derived from NSCs and their electrophysiological properties were characterized after neuronal differentiation using a patch-clamp technique. RESULTS: The NSCs divided rapidly in the expansion medium, forming small proliferating spheres after 7 days. The OECs induction group presented an evident neuron-like type 7 days after adding OEC conditioned medium, and the nestin immunochemistry staining was positive. The electrophysiological characterization showed that the derived neurons presented a transient inward sodium current and slow outward potassium current under proper electric stimulus, which were blocked by tetrodotoxin (TTX) and tetraethylammonium (TEA). CONCLUSION: OEC conditioned medium can induce NSCs to form neurons, and electrophysiological characterization demonstrated that the derived neurons presented active electrophysiological properties which are essential for nervous excitation. PMID- 21301896 TI - Asymptomatic carotid stenosis: intervention or just stick to medical therapy--the case for medical therapy. AB - Asymptomatic significant (>=50%) carotid stenosis (ASCS) is a frequent finding in the aging population. The prevalence of moderate stenosis (50-70%) increases from 3.6% for those <70 years to 9.3% in those >=70 years. The (additional) prevalence of severe (70-99%) stenosis is 1.7%. The natural history of ASCS is quite benign. The overall risk of stroke is around 2% per year and within the group higher degrees of stenosis are associated with higher risks. Yet this stroke risk also includes "unrelated" strokes (i.e., lacunar and cardioembolic), and similarly, it is more of a marker for identifying high-risk group of patients at risk of cardiovascular morbidity and mortality (as revealed by many studies)! Carotid endarterectomy (CEA) has been evaluated in several studies; mainly ACAS and ACST. An overall modest benefit of about 1% risk reduction (per year) was found for CEA (with a peri-operative risk of <3%) versus medical treatment, over a 5-year period. Basically these two studies recruited similar patients with >=60% stenosis based on carotid duplex. However, the similar favorable results differ: while ACAS (published in 1995) found the risk for ipsilateral stroke in the medical group to be 11% over a 5-year period, the 11.8% risk observed in ACST (published in 2004) was for any strokes--showing a better "natural history" for patients with ASCS in the recent study. This observation adds to other reports suggesting a better outcome for patients with ASCS in the recent years, probably because of better medical treatment, mainly due to the significant increase in the use of statins. The suggested guideline that results from the above-mentioned studies is that CEA should be considered in every patient with significant (>=60%?, >=70%?) stenosis who has a life expectancy of more than 5 years (and is <75 years?). Taking this advice as such, would mean that we should screen for ASCS and operate on all appropriate candidates. This will result in a surge of CEA's! Such a recommendation is not in place, because the observed benefit of CEA by numbers needed to treat (NNT) per year to prevent any stroke is more than one hundred! (for symptomatic patients NNT is <10). This high-figure (i.e., low yield) results from failure of these studies to identify specific risk-factors (including the degree of stenosis within the wide range [60-99%] allowed in the studies) in patients with ASCS. Some studies are underway. Therefore, at present, it seems that for most patients, best (intensive) medical treatment is the best option. Alternately, they should join studies that will help to identify patients with the highest risk--those who will clearly benefit from carotid intervention. PMID- 21301897 TI - Mice with genetic deletion of the heparin-binding growth factor midkine exhibit early preclinical features of Parkinson's disease. AB - There is considerable evidence showing that the neurodegenerative processes that lead to sporadic Parkinson's disease (PD) begin many years before the appearance of the characteristic motor symptoms and that impairments in olfactory, cognitive and motor functions are associated with time-dependent disruption of dopaminergic neurotransmission in different brain areas. Midkine is a 13-kDa retinoic acid induced heparin-binding growth factor involved in many biological processes in the central nervous system such as cell migration, neurogenesis and tissue repair. The abnormal midkine expression may be associated with neurochemical dysfunction in the dopaminergic system and cognitive impairments in rodents. Here, we employed adult midkine knockout mice (Mdk(-/-)) to further investigate the relevance of midkine in dopaminergic neurotransmission and in olfactory, cognitive and motor functions. Mdk(/-) mice displayed pronounced impairments in their olfactory discrimination ability and short-term social recognition memory with no gross motor alterations. Moreover, the genetic deletion of midkine decreased the expression of the enzyme tyrosine hydroxylase in the substantia nigra reducing partially the levels of dopamine and its metabolites in the olfactory bulb and striatum of mice. These findings indicate that the genetic deletion of midkine causes a partial loss of dopaminergic neurons and depletion of dopamine, resulting in olfactory and memory deficits with no major motor impairments. Therefore, Mdk(-/-) mice may represent a promising animal model for the study of the early stages of PD and for testing new therapeutic strategies to restore sensorial and cognitive processes in PD. PMID- 21301898 TI - Recent progress in bone imaging for osteoporosis research. AB - Advances in bone imaging techniques have provided tools for analyzing bone structure at the macro-, micro- and nano-level. Quantitative assessment of macrostructure can be achieved using dual X-ray absorptiometry (DXA) and quantitative computed tomography (QCT), particularly volumetric quantitative CT (vQCT). In vivo quantitative techniques for assessing the microstructure of trabecular bone non-invasively and non-destructively include high-resolution CT (HR-CT) and high-resolution magnetic resonance (HR-MR). Compared with MR imaging, CT-based techniques have the advantage of directly visualizing the bone in the axial skeleton, with high spatial resolution, but the disadvantage of delivering a considerable radiation dose. Micro-CT (MUCT), which provides a higher resolution of the microstructure and is principally applicable in vitro, has undergone technological advances such that it is now able to elucidate the physiological skeletal change mechanisms associated with aging and determine the effects of therapeutic intervention on the bone microstructure. In particular, synchrotron MUCT (SR-CT) provides a more detailed view of trabecular structure at the nano-level. For the assessment of hip geometry, DXA-based hip structure analysis (HSA) and CT-based HSA have been developed. DXA-based HSA is a convenient tool for analyzing biomechanical properties and for assuming cross sectional hip geometry based on two-dimensional (2D) data, whereas CT-based HSA provides these parameters three-dimensionally in robust relationship with biomechanical properties, at the cost of greater radiation exposure and the lengthy time required for the analytical procedure. Further progress in bone imaging technology is promising to bring new aspects of bone structure in relation to bone strength to light, and to establish a means for analyzing bone structural properties in the everyday clinical setting. PMID- 21301899 TI - The prognostic factors of recurrent GCT: a cooperative study by the Eastern Asian Musculoskeletal Oncology Group. AB - BACKGROUND: Giant-cell tumor (GCT) of bone is a common primary benign tumor with high local recurrence and potential distant metastasis or malignant transformation. We have investigated the clinical behavior of recurrent GCT of bone in the extremities. METHODS: We retrospectively reviewed 110 patients with recurrent GCTs of bone in the extremities treated by the Eastern Asian Musculoskeletal Oncology Group. The factors that affected the number of recurrences and distant metastasis were analyzed. RESULTS: The median interval between initial surgery and the first recurrence of GCT was 16 months (2-180 months). All patients received additional surgery for first recurrence. Twenty five patients had a second recurrence and 6 patients had a third recurrence. The mean interval between the initial surgery and the first recurrence correlated with the eventual number of recurrences-14.1 months for the repeated recurrence groups (two and three recurrences) and 28.3 months for the single recurrence group (p = 0.016). Campanacci grade did not correlate with repeated recurrence (p = 0. 446). The venue of the initial surgery did not correlate with recurrence but did affect preservation of the adjacent joint (chi-squared test; p = 0.046). Campanacci grade II and III also correlated with sacrifice of the adjacent joint (p = 0.020). The incidence of lung metastasis and malignant transformation were 7.5% (8 out of 107 patients) and 2.7% (3 out of 110 patients), respectively. Repeat recurrence was associated with lung metastasis (p = 0.018). CONCLUSIONS: Early local recurrence of GCT is a risk factor for repeat recurrence. Repeat recurrence also correlates with lung metastasis. Recurettage with meticulous adjuvant treatment to completely preclude recurrent lesions is a reasonable method for preserving the adjacent joint. However, a continuous careful follow-up is mandatory. PMID- 21301900 TI - Salmonella septic arthritis following total knee arthroplasty for rheumatoid arthritis in a patient receiving etanercept. PMID- 21301901 TI - Splintered pathologic fracture of the patella secondary to gout tophi treated by total patellectomy. PMID- 21301902 TI - Oral soft tissue alterations in patients with neurofibromatosis. AB - Our aim was to characterize the type and frequency of oral soft tissue alterations in neurofibromatosis. A total of 103 patients with neurofibromatosis 1 (NF1) and three patients with neurofibromatosis 2 (NF2) were clinically evaluated for their oral soft tissue alterations. Disturbing growths were removed from nine patients with NF1 and from one patient with NF2. The specimens were analyzed using routine histological methods and with immunohistochemistry using antibodies to S100, type IV collagen, CD34, neurofilament, and neuron-specific tubulin (TUBB3). Alterations including oral tumors, overgrowths of gingival soft tissue, and enlarged papillae of the tongue were discovered in 74% of NF1 patients. The results showed that three tumors clinically classified as plexiform neurofibromas and five out of six discrete mucosal tumors displayed histology and immunohistology consistent with that of neurofibroma. The histology of one palatal lesion resembled that of a scar, and the lesion removed from the patient with NF2 was classified as an amyloid tumor. To conclude, oral soft tissue growths are common findings in NF1, but most lesions do not require treatment and the patients may even not be aware of these alterations. Collagen IV, S100, and CD34 are useful biomarkers in the analysis of NF1-related oral soft tissue tumors. The clinicians should recognize that oral soft tissue alterations are relatively common in NF1. Some of the growths are disturbing, and plexiform neurofibromas may bear a risk of malignant transformation. PMID- 21301903 TI - Biomechanical analysis of alveolar bone stress around implants with different thread designs and pitches in the mandibular molar area. AB - Threaded implants have been shown to play an important role in increasing mechanical osseointegration. The aim of this study was to determine bone stress distribution when using different types of implant thread pitches and designs. Five 3D finite element models were constructed to simulate bone stresses induced in implant bodies with two types of thread form: triangular ("Tri" prefix) and trapezoidal ("Trap" prefix). The former had thread pitches of 0.8, 1.2, and 1.6 mm, while the latter had thread pitches of 1.2 and 1.6 mm. A biting load of 143 N was applied vertically and obliquely to the occlusal central fossa of the crown. The main effects of each level of the three factors investigated (loading type, pitch, and thread form) in terms of the stress value were computed for all models. Results indicated that the loading type was the main factor of influence on the peak compressive stress of the alveolar bone. Optimal thread pitch was 1.2 mm for a triangular-thread implant, and a trapezoidal-threaded implant with thread pitch of 1.6 mm had the lowest stress value among trapezoidal-threaded implants. This study concluded that each thread form has its unique optimal thread pitch with regard to lower concentration of bone stress. Clinically, this study suggests that in biomechanical consideration, thread pitch exceeding 0.8 mm is more appropriate for a screwed implant. For clinical cases that require greater bone-implant interface, trapezoidal-threaded implants with thread pitch of 1.6 mm provide greater primary stability and lower concentration of bone stress under different loading directions. PMID- 21301904 TI - The structure of percolated polymer systems: a computer simulation study. AB - We studied the percolation process in a system consisting of long flexible polymer chains and solvent molecules. The polymer chains were approximated by linear sequences of beads on a two-dimensional triangular lattice. The system was athermal and the excluded volume was the only potential. The properties of the model system across the entire range of polymer concentrations were determined by Monte Carlo simulations employing a cooperative motion algorithm (CMA). The scaling behavior and the structure of the percolation clusters are presented and discussed. PMID- 21301905 TI - In silico screening for antibiotic escort molecules to overcome efflux. AB - Resistance to antibiotics is a growing problem worldwide and occurs in part due to the overexpression of efflux pumps responsible for the removal of antibiotics from bacterial cells. The current study examines complex formation between efflux pump substrates and escort molecules as a criterion for an in silico screening method for molecules that are able to potentiate antibiotic activities. Initially, the SUPERDRUG database was queried to select molecules that were similar to known multidrug resistance (MDR) modulators. Molecular interaction fields generated by GRID and the docking module GLUE were used to calculate the interaction energies between the selected molecules and the antibiotic norfloxacin. Ten compounds forming the most stable complexes with favourable changes to the norfloxacin molecular properties were tested for their potentiation ability by efflux pump modulation assays. Encouragingly, two molecules were proven to act as efflux pump modulators, and hence provide evidence that complex formation between a substrate and a drug can be used for in silico screening for novel escort molecules. PMID- 21301906 TI - Systematic assessment of accuracy of comparative model of proteins belonging to different structural fold classes. AB - In the absence of experimental structures, comparative modeling continues to be the chosen method for retrieving structural information on target proteins. However, models lack the accuracy of experimental structures. Alignment error and structural divergence (between target and template) influence model accuracy the most. Here, we examine the potential additional impact of backbone geometry, as our previous studies have suggested that the structural class (all-alpha, alphabeta, all-beta) of a protein may influence the accuracy of its model. In the twilight zone (sequence identity <= 30%) and at a similar level of target template divergence, the accuracy of protein models does indeed follow the trend all-alpha > alphabeta > all-beta. This is mainly because the alignment accuracy follows the same trend (all-alpha > alphabeta > all-beta), with backbone geometry playing only a minor role. Differences in the diversity of sequences belonging to different structural classes leads to the observed accuracy differences, thus enabling the accuracy of alignments/models to be estimated a priori in a class dependent manner. This study provides a systematic description of and quantifies the structural class-dependent effect in comparative modeling. The study also suggests that datasets for large-scale sequence/structure analyses should have equal representations of different structural classes to avoid class-dependent bias. PMID- 21301907 TI - Analysis of clinically relevant substrates of CYP2B6 enzyme by computational methods. AB - Mounting evidence thus far indicates that human cytochrome P450 2B6 (CYP2B6), an enzyme expressed at a relatively low level functionally, is primarily responsible for the metabolism of several clinically relevant drugs, including propofol, efavirenz, bupropion, mephobarbital, and the propofol analog 2,6-di-sec-butyl phenol. We used molecular dynamics and molecular docking methods to predict such interactions and to compare with experimentally measured metabolisms. Insight II and Discover Studio 2.5 were used to carry out the docking of these substrates into CYP2B6 to explore the critical residues and interaction energies of the complexes. Phe297, Glu301, Thr302 and Val367 were identified as major drug binding residues, which is consistent with previous data on site-directed mutagenesis, crystallography structure, and from modeling and docking studies. In addition, our docking results suggest that nonpolar amino acid clusters and heme also participate in binding to mediate drug oxidative metabolism. The binding modes of the five clinically relevant substrates mentioned above for metabolism on CYP2B6 are presented. PMID- 21301908 TI - Hydrogen bonds determine the structures of the ternary heterocyclic complexes C2H4O...2HF, C2H5N...2HF and C2H4S...2HF: density functional theory and topological calculations. AB - A theoretical study of structural, electronic, topological and vibrational parameters of the ternary hydrogen-bonded complexes C(2)H(4)O...2HF, C(2)H(5)N...2HF and C(2)H(4)S...2HF is presented here. Different from binary systems with a single proton donor, the tricomplexes have the property of forming multiple hydrogen bonds, which are analyzed from a structural and vibrational point of view, but verified only by means of the quantum theory of atoms in molecules (QTAIM). As traditionally done in the hydrogen bond theory, the charge transfer between proton donors and acceptors was computed using the CHELPG calculations, which also revealed agreement with dipole moment variation and a cooperative effect on the tricomplexes. Furthermore, redshift events on proton donor bonds were satisfactorily identified, although, in this case, an absence of experimental data led to the use of a theoretical argument to interpret these spectroscopic shifts. It was therefore the use of the QTAIM parameters that enabled all intermolecular vibrational modes to be validated. The most stable tricomplex in terms of energy was identified via the strength of the hydrogen bonds, which were modeled as directional and bifurcated. PMID- 21301909 TI - A high-penetrance form of late-onset torsion dystonia maps to a novel locus (DYT21) on chromosome 2q14.3-q21.3. AB - The primary dystonias are a genetically heterogeneous group of disorders that can be subdivided in pure dystonias, dystonia-plus syndromes, and paroxymal dystonia. Four pure autosomal dominant dystonia loci have been mapped to date, DYT1, 6, 7, and 13, with varying penetrance. We report the mapping of a novel locus for a late-onset form of pure torsion dystonia in a family from northern Sweden. The disease is inherited in an autosomal dominant manner with a penetrance that may be as high as 90%. The torsion dystonia locus in this family was mapped to chromosome 2q14.3-q21.3 using an Illumina linkage panel. We also confirmed the linkage, using ten tightly linked microsatellite markers in the region, giving a maximum LOD score of 5.59 for marker D2S1260. The disease-critical region is 3.6 8.9 Mb depending on the disease status of one individual carrying a centromeric recombination. Mutational analysis was performed on 22 genes in the disease critical region, including all known and hypothetical genes in the smaller, 3.6 Mb region, but no disease-specific mutations were identified. Copy number variation analysis of the region did not reveal any deletions or duplications. In order to increase the chances of finding the disease gene, fine-mapping may be necessary to decrease the region of interest. This report will hopefully result in the identification of additional dystonia families with linkage to the same locus, and thereby, refinement of the disease critical region. PMID- 21301910 TI - In vitro effects of Cyberknife-driven intermittent irradiation on glioblastoma cell lines. AB - Radiosurgery is used increasingly upon recurrence of high-grade gliomas to deliver a high dose of focused radiation to a defined target. The purpose of our study was to compare intermittent irradiation (IIR) by using a CyberKnife (CK) with continuous irradiation (CIR) by using a conventional linear accelerator (LINAC). A significant decrease in surviving fraction was observed after IIR irradiation compared with after CIR at a dose of 8 Gy. Three hours after irradiation, most of the DNA damage was repaired in U87. Slightly higher basal levels of Ku70/80 mRNA were found in U87 compared with A172, while radiation treatment induced only minor regulation of Ku70/80 and Rad51 transcription in either cell lines. IIR treatment using CK significantly decreased the survival in U87 and A172 compared with CIR. Although the two cell lines differed in DNA repair capability, the role of Ku70/80 and Rad51 in the cell line radiosensitivity seemed marginal. PMID- 21301911 TI - The differentiation of the newborn nerve cells in oculomotor nuclear after oculomotor nerve injury. AB - Oculomotor nerve injury is a common complication of cranial trauma and craniotomy. For a long time, it has been generally considered that the oculomotor nerve is unable to regenerate and recover functionally after injury. With the development of neuroradiology, microsurgery and neurohistology, it has been reported that the injured oculomotor nerve could be repaired by operation. However, the mechanisms of neural regeneration of the injured oculomotor nerve remain obscure. Therefore, by investigating the differentiation of the newborn nerve cells in oculomotor nuclear after oculomotor nerve injury, the mechanisms of the neural regeneration of the injured oculomotor nerve was studied in the present paper. After animal model establishment, we found that the function of the injured oculomotor nerve could recover at some degree without treatment, at fourth week after the nerve injury. This result confirms that the injured oculomotor nerve per se has the potential to regenerate and repair. At the present study, by BredU stain, BrdU labeling cells were observed in oculomotor nuclear at the fourth week post-operatively. It indicated that the oculomotor nuclear per se has the ability of generating the cells, which will regenerate and differentiate after the nerve injury, without stimulation by exogenous agents. Immunofluorescence double staining was used in this study to show the differentiation of the newborn cells in oculomotor nuclear after oculomotor nerve injury. It is found that they could differentiate into neural progenitor cells, neuronal cells and neuroglial cells. It is suggested that the different differentiation of cells may play a role in the nerve regeneration procedure. PMID- 21301912 TI - Influence of tracheostomy on the incidence of catheter-related bloodstream infection in the catheterization of jugular vein by posterior access. AB - There are no data about the influence of tracheostomy in the incidence of catheter-related bloodstream infection (CRBSI) on the catheterization of the jugular vein by posterior access and there are no recommendations relating to this circumstance in the guidelines of the Centers for Disease Control and Prevention (CDC) and of Healthcare Epidemiology of America/Infectious Diseases Society of America (SHEA/IDSA) for the prevention of CRBSI. The novel finding of this observational study was that there was a higher incidence of CRBSI in the catheterization of jugular vein by posterior access in patients with tracheostomy than without it (13.24 vs 0 episodes of CRBSI per 1,000 catheter-day; odds ratio = 23.92; 95% CI = 1.86-infinite; p = 0.008). Thus, the presence of tracheostomy is a risk factor of CRBSI on the catheterization of jugular vein by posterior access. PMID- 21301913 TI - Congenital craniocervical anomalies pose a vulnerability to spinal cord injury without radiographic abnormality (SCIWORA). PMID- 21301915 TI - Evaluation of surgical microscope-integrated intraoperative near-infrared indocyanine green videoangiography during aneurysm surgery. AB - The primary aim of this study is to assess the value of intraoperative near infrared indocyanine green videoangiography (ICGA) during intracranial aneurysm surgery. Altogether, 129 patients harboring 152 intracranial aneurysms were recruited in this study between March 2007 and December 2008 and the clinical data were retrospectively analyzed. Intraoperative ICGA was performed to examine the completeness of the aneurysm clipping and the patency of the parent arteries in all cases. The intraoperative findings were compared with that of postoperative digital subtraction angiography (DSA). On all of the patients, 276 successful ICGA investigations were performed intraoperatively. The image quality and resolution were excellent, allowing real-time assessment of the cerebral circulation. Indocyanine green (ICG) angiographic results could be divided into arterial, capillary, and venous phases, comparable to those observed with postoperative DSA. In all cases, the postoperative angiographic results corresponded to the intraoperative ICGA findings. In three cases, the information provided by intraoperative ICG angiography significantly changed the surgical procedure. Intraoperative ICG videoangiography may be a useful tool in real-time evaluation of the aneurysm clipping. Its simplicity and easy reproducibility all suggest it to be carried out as a routine procedure during aneurysm surgery. PMID- 21301914 TI - Prognostic factors for patients with gliomatosis cerebri: retrospective analysis of 17 consecutive cases. AB - Gliomatosis cerebri (GC) is a rare fatal glial neoplasm of the central nervous system. Neuroimaging, histological, and clinical outcome data were reviewed of 17 consecutive patients, 8 males and 9 females aged 15-68 years (median, 37 years), treated for GC between April 1992 and October 2007. All patients received cranial irradiation to include the hyperintense area on T2-weighted magnetic resonance imaging. The total dose of the radiotherapy was 50-72 Gy (median, 60). Intravenous nimustine hydrochloride was administered in all patients, combined with temozolomide in four patients. The median survival time was 23.3 months, with a median follow-up of 23.3 months. Kaplan-Meier analysis demonstrated the overall survival rate which was 70.6% for 1 year, 23.5% for 3 years, and 17.7% for 5 years. Spinal enhanced lesions and nodular malignant transformation to glioblastoma were observed during follow-up in two patients each. Poor survival showed correlation with higher Ki-67 labeling index, higher choline/N acetylaspartate ratio on magnetic resonance spectroscopy, tumor volumes, lower Karnofsky performance status on admission, cognitive/behavioral deterioration, poor response to the initial radiochemotherapy, and emergence of paraventricular enhanced lesions during the clinical course. The prognosis for patients with GC is unfavorable, but radiochemotherapy may prolong survival. PMID- 21301916 TI - Neurosurgery and elderly: analysis through the years. AB - The aging of the population in westernized countries constitutes an important issue for the health systems struggling with limited resources and increasing costs. Morbidity and mortality rates reported for neurosurgical procedures in the elderly vary widely. The lack of data on risk benefit ratios may result in challenging clinical decisions in this expanding group of patients. The aim of this paper is to analyze the elderly patients cohort undergoing neurosurgical procedures and any trend variations over time. The medical records of elderly patients (defined as an individual of 70 years of age and over) admitted to the Neurosurgical and Neuro-ICU Departments of a major University Hospital in Paris over a 25-year period were retrospectively reviewed. The analysis included: (1) number of admissions, (2) percentage of surgically treated patients, (3) type of procedures performed, (4) length of hospital stay, and (5) mortality. The analysis showed a progressive and significant increase in the proportion of elderly presenting for neurosurgical elective and/or emergency procedures over the last 25 years. The number of procedures on patients over 70 years of age increased significantly whereas the mortality dropped. Though the length of hospital stay was reduced, it remained significantly higher than the average stay. The types of procedures also changed over time with more craniotomies and endovascular procedures being performed. Age should not be considered as a contraindication for complex procedures in neurosurgery. However, downstream structures for postoperative elderly patients must be further developed to reduce the mean hospital stay in neurosurgical departments because this trend is likely to continue to grow. PMID- 21301917 TI - Primary squamous cell carcinoma associated with ovarian endometriosis: a case report and literature review. AB - Primary squamous cell carcinoma (SCC) associated with ovarian endometriosis is extremely rare and has a poor prognosis due to insufficient information on the optimal postoperative treatment. Here, we describe the response of this tumor to the administration of paclitaxel-carboplatin. A 45-year-old woman diagnosed with stage IIIc primary SCC of the ovary associated with endometriosis underwent optimal surgery followed by six courses of chemotherapy at 3-week intervals with paclitaxel and carboplatin. She tolerated the chemotherapy well and remained without evidence of disease during first-line chemotherapy. Two months later, she was readmitted with recurrence of a pelvic tumor. Although she was treated with chemotherapy (weekly paclitaxel and chemotherapeutic regimen of irinotecan + mitomycin C), the tumor was resistant to second-line and third-line chemotherapy and she died 15 months after surgery. Paclitaxel-carboplatin administration may be an effective treatment for primary SCC of the ovary but further studies are required to investigate it true efficacy in the treatment of this disease. PMID- 21301918 TI - Retrospective analysis of prognostic outcome of gastric cancer in young patients. AB - BACKGROUND: It has been suggested that gastric cancer in young patients has a worse prognosis than in older patients, but this is controversial. This retrospective investigation was undertaken to understand the clinicopathological features and identify the prognostic factors of gastric cancer in young patients. METHODS: Patients included in this study were those treated and followed up for gastric cancer from 1989 to 2005. Operative records, clinical, pathological, and follow-up data were reviewed. The critical age cut-off value for obtaining distinctive prognoses was 34 years. RESULTS: Of 1730 gastric cancer patients whose records were reviewed, 27 were less than 34 years old (YGC group). The YGC group contained significantly higher percentages of females, stage IV, macroscopic type 4 tumors, poorly differentiated histology, peritoneal dissemination, and epigastric pain symptoms than the gastric cancer group aged 34 years or more (OGC group). Survival in the YGC group was significantly worse than in the OGC group (p = 0.0363). Ten-year survival was 68.5% in the YGC group and 81.8% in the OGC group. Survival in the YGC group was poorer for the stage IV patients, compared with OGC patients, especially for the stage IV patients with peritoneal dissemination and without liver metastases (H0P1 patients) (p = 0.049). CONCLUSIONS: Age in gastric cancer affects the prognosis, which in gastric cancer patients less than 34 years old was significantly poorer than for older patients, because of the high incidence of stage IV cancer with peritoneal dissemination in gastric cancer patients less than 34 years old. PMID- 21301919 TI - Influence of erythropoietin-stimulating agent treatment on glycated hemoglobin values in diabetic patients with chronic kidney disease. PMID- 21301920 TI - Steroids and azathioprine in the treatment of IgA nephropathy. AB - AIM: IgA nephropathy (IgAN) is a very common glomerulonephritis among young adults, but the best therapeutic approach has not been fully elucidated. This study evaluated the effect of two different treatment regimes in IgAN, steroids alone or in combination with azathioprine. METHODS: Among 122 patients with primary IgA nephropathy diagnosed in the 2000-2007 period, 22 fulfilled the inclusion criteria for the study: estimated glomerular filtration rate (eGRF) >=30 ml/min/1.73 m(2), urine protein (Upr) >=1 g/24 h, blood pressure (BP) <130/80 mmHg, and previous treatment with renin-angiotensin system inhibitors (RAASi) and polyunsaturated fatty acids (PFA) for at least 6 months. Patients were randomized to receive either methylprednisolone alone (MP group) or MP in combination with azathioprine (MP + Aza group) for 12 months, while treatment with RAASi + PFA continued unchanged in both groups. RESULTS: At the completion of the trial, renal function in the MP group remained stable, eGFR from 52 +/- 26.7 to 53.6 +/- 27.3 ml/min/1.73 m(2), p = NS, and Upr decreased from 2.4 +/- 0.9 to 0.8 +/- 0.5 g/24 h, p < 0.001. In the MP + Aza group, eGFR slightly increased from 57.4 +/- 28.7 to 66 +/- 31 ml/min/1.73 m(2), p = NS, and Upr decreased from 2.4 +/- 1 to 0.7 +/- 0.7 g/24 h, p < 0.001. Four patients from the MP group with partial remission at the end of the trial had a complete response when converted to Aza. Eleven patients (5 from the MP and 6 from the MP + Aza group) relapsed after stopping treatment and were restarted on lower doses. CONCLUSIONS: Both, steroid treatment alone and steroids in combination with azathioprine seem to be effective in reducing the severity of proteinuria and stabilizing renal function in IgAN. Patients who do not respond to steroids may have a better response with the combination of steroids and azathioprine. PMID- 21301921 TI - Association between blood pressure measures and recurrent headache in adolescents: cross-sectional data from the HUNT-Youth study. AB - The relationship between blood pressure and headache in youth has not been explored and the objective of the present study was to provide data on this association in an adolescent population. Cross-sectional data from a large population-based survey, the Young-HUNT study, on 5,847 adolescents were used to evaluate the association between blood pressure (systolic, diastolic, mean arterial and pulse pressure) and recurrent headache, including migraine and tension-type headache. Increasing pulse pressure was inversely related to recurrent headache prevalence, and both tension-type headache and migraine. For systolic blood pressure such an inverse relationship was present for recurrent headache and tension-type headache prevalence. For migraine, the results were not significant, although there was a tendency in the same direction (p = 0.05). High pulse pressure has previously been found to be inversely related to the prevalence of migraine and tension-type headache in an adult population. This inverse relationship has now been demonstrated to be present among adolescents also, supporting the results from a previous study in adults, that blood pressure regulation may be linked to the pathophysiology of headache. PMID- 21301922 TI - Does visual cortex lactate increase following photic stimulation in migraine without aura patients? A functional (1)H-MRS study. AB - Proton magnetic resonance spectroscopy ((1)H-MRS) has been used in a number of studies to assess noninvasively the temporal changes of lactate (Lac) in the activated human brain. Migraine neurobiology involves lack of cortical habituation to repetitive stimuli and a mitochondrial component has been put forward. Our group has recently demonstrated a reduction in the high-energy phosphates adenosine triphosphate (ATP) and phosphocreatine (PCr) in the occipital lobe of migraine without aura (MwoA) patients, at least in a subgroup, in a phosphorus MRS ((31)P-MRS) study. In previous studies, basal Lac levels or photic stimulation (PS)-induced Lac levels were found to be increased in patients with migraine with aura (MwA) and migraine patients with visual symptoms and paraesthesia, paresia and/or dysphasia, respectively. The aim of this study was to perform functional (1)H-MRS at 3 T in 20 MwoA patients and 20 control subjects. Repetitive visual stimulation was applied using MR-compatible goggles with 8 Hz checkerboard stimulation during 12 min. We did not observe any significant differences in signal integrals, ratios and absolute metabolite concentrations, including Lac, between MwoA patients and controls before PS. Lac also did not increase significantly during and following PS, both for MwoA patients and controls. Subtle Lac changes, smaller than the sensitivity threshold (i.e. estimated at 0.1-0.2 MUmol/g at 3 T), cannot be detected by MRS. Our study does, however, argue against a significant switch to non-aerobic glucose metabolism during long-lasting PS of the visual cortex in MwoA patients. PMID- 21301923 TI - Five levels of PACS modularity: integrating 3D and other advanced visualization tools. AB - The current array of PACS products and 3D visualization tools presents a wide range of options for applying advanced visualization methods in clinical radiology. The emergence of server-based rendering techniques creates new opportunities for raising the level of clinical image review. However, best-of breed implementations of core PACS technology, volumetric image navigation, and application-specific 3D packages will, in general, be supplied by different vendors. Integration issues should be carefully considered before deploying such systems. This work presents a classification scheme describing five tiers of PACS modularity and integration with advanced visualization tools, with the goals of characterizing current options for such integration, providing an approach for evaluating such systems, and discussing possible future architectures. These five levels of increasing PACS modularity begin with what was until recently the dominant model for integrating advanced visualization into the clinical radiologist's workflow, consisting of a dedicated stand-alone post-processing workstation in the reading room. Introduction of context-sharing, thin clients using server-based rendering, archive integration, and user-level application hosting at successive levels of the hierarchy lead to a modularized imaging architecture, which promotes user interface integration, resource efficiency, system performance, supportability, and flexibility. These technical factors and system metrics are discussed in the context of the proposed five-level classification scheme. PMID- 21301925 TI - Bullous cellulitis with Cryptococcus neoformans. PMID- 21301926 TI - Role of CFTR expressed by neutrophils in modulating acute lung inflammation and injury in mice. AB - OBJECTIVE AND DESIGN: Cystic fibrosis transmembrane conductance regulator (CFTR) regulates infection and inflammation. In this study, we investigated whether a lack of functional CFTR in neutrophils would promote lipopolysaccharide (LPS) induced lung inflammation and injury. MATERIALS AND METHODS: CFTR-inhibited or F508del-CFTR-mutated neutrophils were stimulated with LPS and cultured to evaluate production of cytokines and NF-kappaB activation. Wild-type mice were reconstituted with F508del neutrophils or bone marrow and then intratracheally challenged with LPS to observe lung inflammatory response. RESULTS: Pharmacologic inhibition and genetic mutation of CFTR in neutrophils activated NF-kappaB and facilitated macrophage inflammatory protein-2 (MIP-2) and tumor necrosis factor alpha (TNF-alpha) production. Wild-type mice reconstituted with F508del neutrophils and bone marrow had more severe lung inflammation and injury after LPS challenge compared to wild-type mice receiving wild-type neutrophils or bone marrow reconstitution. CONCLUSIONS: Lack of functional CFTR in neutrophils can promote LPS-induced acute lung inflammation and injury. PMID- 21301928 TI - A beautiful death. PMID- 21301927 TI - Expression of metallocarboxypeptidase inhibitors in Escherichia coli: effect of cysteine content and protein size in the secretory production of disulfide bridged proteins. AB - Metallocarboxypeptidase inhibitors are proteins with possible applications in biomedicine given their properties as anticoagulant and antitumoral factors. They are small, eukaryotic polypeptides comprising several disulfide bridges, which makes them hard to express in inexpensive bacterial hosts. In this work, three of them were produced in high-cell-density cultures of Escherichia coli: PCI (39 residues and three bridges), LCI (66 residues and four bridges) and TCI (75 residues and six bridges). The genes coding for the mentioned inhibitors were cloned in an arabinose-inducible plasmid fused to the signal peptide of DsbA in order to have them secreted and grant the formation of the bridges. The trigger factor defective strain KTD101 was used as the expression host. The resulting recombinant strains were cultured in fed-batch mode employing minimal media and an exponential feed profile, keeping the specific growth rate at MU = 0.1 h(-1) by limitation of the fed carbon source (glycerol). Between 380 and 540 mg l(-1) of active inhibitors were obtained in both the periplasmic extracts and extracellular media of the cultures. Later on, excretion was enhanced using a cell permeabilization treatment, allowing the recovery of over 80% of the products from the extracellular fraction. Protein yields were found to be inversely proportional to cysteine content of the inhibitor, whereas protein excretion rates were inversely proportional to the protein size. Overall, these results offer insight into the secretory production of active disulfide-bridged proteins in high-cell-density cultures of E. coli. PMID- 21301929 TI - Management of axitinib (AG-013736)-induced fatigue and thyroid dysfunction, and predictive biomarkers of axitinib exposure: results from phase I studies in Japanese patients. AB - BACKGROUND: Axitinib is an oral, potent and selective inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2 and 3. We report on data obtained from 18 Japanese patients with advanced solid tumors in two phase I trials that evaluated the safety, pharmacokinetics and antitumor activity of axitinib and also examined potential biomarkers. METHODS: Six patients received a single 5-mg dose of axitinib followed by 5 mg twice daily (BID), and an additional six patients received axitinib 5 mg BID only. Another six patients received axitinib at 5-mg, 7-mg and 10-mg single doses followed by 5 mg BID. RESULTS: Plasma pharmacokinetics following single doses of axitinib was generally linear. Common treatment-related adverse events were fatigue (83%), anorexia (72%), diarrhea (67%), hand-foot syndrome (67%) and hypertension (61%). Sixteen patients (89%) experienced thyroid-stimulating hormone (TSH) elevation. Grade 3/4 toxicities included hypertension (33%) and fatigue (28%). No grade 3/4 fatigue occurred in patients who started thyroid hormone replacement therapy when TSH was elevated. Thyroglobulin elevation was observed in all patients who continued treatment with axitinib for >=3 months. Abnormal TSH correlated with exposure to axitinib (r = 0.72). Decrease in soluble (s) VEGFR-2 levels significantly correlated with exposure to axitinib (r = -0.94). Axitinib showed antitumor activity across multiple tumor types. CONCLUSIONS: Axitinib-related thyroid dysfunction could be due to a direct effect on the thyroid gland. Grade 3/4 fatigue and hypothyroidism appear to be controllable with use of thyroid hormone replacement therapy. sVEGFR-2 and TSH may act as biomarkers of axitinib plasma exposure. PMID- 21301930 TI - Bacterial transport of sulfate, molybdate, and related oxyanions. AB - Sulfur is an essential element for microorganisms and it can be obtained from varied compounds, sulfate being the preferred source. The first step for sulfate assimilation, sulfate uptake, has been studied in several bacterial species. This article reviews the properties of different bacterial (and archaeal) transporters for sulfate, molybdate, and related oxyanions. Sulfate uptake is carried out by sulfate permeases that belong to the SulT (CysPTWA), SulP, CysP/(PiT), and CysZ families. The oxyanions molybdate, tungstate, selenate and chromate are structurally related to sulfate. Molybdate is transported mainly by the high affinity ModABC system and tungstate by the TupABC and WtpABC systems. CysPTWA, ModABC, TupABC, and WtpABC are homologous ATP-binding cassette (ABC)-type transporters with similar organization and properties. Uptake of selenate and chromate oxyanions occurs mainly through sulfate permeases. PMID- 21301931 TI - Sex steroids influence glucose oxidation through modulation of insulin receptor expression and IRS-1 serine phosphorylation in target tissues of adult male rat. AB - Skeletal muscle, liver, and adipose tissue are major insulin responsive target organs that also express androgen receptor. Testosterone (T) plays a role in maintaining normal insulin sensitivity in men but its effects on insulin target tissues are not fully understood. Our previous study showed that orchidectomy impairs glucose oxidation through decreased insulin receptor (IR) mRNA expression in skeletal muscles, liver, and adipose tissue of male rat. Furthermore, T replacement restored IR mRNA expression in skeletal muscles and liver, but did not have any effect in adipose tissue. In the present study, orchidectomy decreased IR mRNA and protein levels in muscle, liver, and adipose tissue. Treatment with a combination of T plus estradiol (E) was necessary to restore the IR mRNA and protein to control levels in adipose tissue. T or E treatment alone had no effect on IR mRNA levels in adipose tissue. T alone also had no effect on the IR protein, whereas E alone had a stimulatory effect. In comparison, in muscle and liver, T or T plus E restored the IR mRNA and protein to control levels. In muscle and liver, E alone had no effect on IR mRNA expression but restored the IR protein. In addition, orchidectomy was seen to have a stimulatory effect on IRS-1 Serine(636/639) phosphorylation in the three tissues studied. Following T, E or combined supplementation to castrated rats, the pattern of IRS 1 serine phosphorylation was restored to normal control levels. Furthermore, orchidectomy decreased serum insulin and glucose oxidation in all three tissues, and this was restored by T and its combination with E replacement, whereas E alone had no effect. It is concluded from the present study that sex steroid deficiency induces impaired glucose oxidation in insulin responsive tissues, which is mediated through reduced IR expression, and increased IRS-1 serine phosphorylation. PMID- 21301932 TI - Salivary glands of Amblyomma cajennense (Acari: Ixodidae): a histological and an ultrastructural overview. AB - The present study on the salivary glands of semi-engorged Amblyomma cajennense females has identified the various cell types present in this tissue and allowed its morphohistochemical characterization. Marking techniques were applied to detect polysaccharides (PAS), proteins (bromophenol blue), lipids (Nile blue) and calcium (von Kossa), as well as those of scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The results obtained by TEM showed and confirmed that these individuals' glands are also formed by round acini that are connected to the common excretory duct through acinar and intermediate ducts. Histological data as well as ultrastructural ones showed that the glands are formed by types I, II and III acini. In this study with salivary glands polysaccharides, proteins, lipids and calcium were observed in the cytoplasm and/or cell secretion granules-both free or forming complexes, as the intensity of the marking varied according to the cell as well as the type of acini analyzed, showing the structural and functional complexity of the tick salivary glands, characteristics that give the multifunctional character to this organ. PMID- 21301933 TI - A new approach to explore the impact of freeze-thaw cycling on protein structure: hydrogen/deuterium exchange mass spectrometry (HX-MS). AB - PURPOSE: The impact of freeze-thaw (F/T) on structure integrity of protein therapeutics is poorly understood, partially due to lack of methods to detect protein structural perturbations during F/T processing in the frozen state. METHODS: A new approach of hydrogen/deuterium exchange was developed to separate and distinguish the specific impact of single freezing and F/T cycling on protein structure, using lactate dehydrogenase (LDH) as model system. RESULTS: In the freezing process, a fraction of LDH molecules that was inversely dependent on protein concentration was observed to partially denature its structure. Local structural perturbations were localized by peptide level HX analysis to the surface residues in segments 91-132, 170-237 and 288-331. In contrast, F/T cycling led to irreversible LDH aggregation with global structural unfolding. Residual solvent-protected structure was only detected in the aggregates for three segments, 13-31, 109-117 and 133-143, that were coincident with the consensus aggregation hotspots predicted by four different algorithms. CONCLUSIONS: Results indicate freezing preferentially disturbs local structure at the surface residues, consistent with ice-solution interface-mediated denaturation mechanism. F/T-induced aggregation begins as partial denaturation during freezing, but is accompanied by more comprehensive structural rearrangement during F/T cycling. PMID- 21301935 TI - Diclofenac enables prolonged delivery of naltrexone through microneedle-treated skin. AB - PURPOSE: The purpose of this study was to determine if non-specific COX inhibition could extend pore lifetime in hairless guinea pigs following microneedle treatment. METHODS: Hairless guinea pigs were treated with microneedle arrays +/- daily application of Solaraze(r) gel (3% diclofenac sodium (non-specific COX inhibitor) and 2.5% hyaluronic acid); transepidermal water loss was utilized to evaluate pore lifetime. To examine the permeation of naltrexone, additional guinea pigs were treated with microneedles +/- daily Solaraze(r) gel followed by application of a 16% transdermal naltrexone patch; pharmacokinetic analysis of plasma naltrexone levels was performed. Histological analysis was employed to visualize morphological changes following microneedle and Solaraze(r) treatment. RESULTS: Animals treated with microneedles + Solaraze(r) displayed extended pore lifetime (determined by transepidermal water loss measurements) for up to 7 days. Enhanced naltrexone permeation was also observed for an extended amount of time in animals treated with microneedles + Solaraze(r). No morphological changes resulting from microneedle treatment or COX inhibition were noted. CONCLUSIONS: Non-specific COX inhibition is an effective means of extending pore lifetime following microneedle treatment in hairless guinea pigs. This may have clinical implications for extending transdermal patch wear time and therefore increasing patient compliance with therapy. PMID- 21301934 TI - Antibody-mediated "universal" osteoclast targeting platform using calcitonin as a model drug. AB - PURPOSE: To generate and characterize a specific monoclonal antibody (mAb) against recombinant human RANK receptor and to develop an antiresorptive strategy using this mAb as an osteoclast-targeting platform that selectively targets osteoclast cells whilst delivering an attached (i.e. chemically conjugated) active drug cargo. METHODS: Using hybridoma technology, we generated a specific monoclonal antibody (mAb) against recombinant human RANK receptor and characterized by SDS PAGE, ELISA, Western Blot and immunocytochemistry, then synthesized osteoclast-targeting bioconjugates of salmon calcitonin (sCT) using this antibody by generating thiol groups on mAb using 2-Iminothiolane and subsequently reacting them with sCT-PEG-MAL synthesised from sCT and NHS-PEG-MAL. To test the efficacy of the conjugate in vitro, osteoclasts were generated from precursor RAW 264.7 cells by dosing with the cytokines macrophage-colony stimulating factor (M-CSF), and RANK Ligand (RANKL) and TRAP activity assay, Resorption Pit Assay, TRAP staining were performed. Cytotoxicity of the mAb-sCT conjugate was also evaluated in RAW 264.7 cells; sCT bioactivity and CTR binding potential were evaluated by in vitro intracellular cAMP stimulation assay in human T47D breast cancer cells. RESULTS: Generation of antibody against human RANK receptor was confirmed by SDS PAGE, ELISA and Western Blot. Immunocytochemistry confirmed the osteoclast targeting potential of the antibody. Successful conjugation of the antibody with sCT was confirmed by SDS PAGE and ELISA.Multinucleated osteoclast formation was confirmed by staining for tartrate resistant acid phosphatase (TRAP). Conjugate functionality was confirmed by TRAP activity and Resorption Pit assay, showing the inhibitory effect on osteoclast differentiation. cAMP assay confirmed the retention of calcitonin bioactivity after conjugation. CONCLUSIONS: Our strategy offers the potential for a "universal" osteoclast-targeting platform--one that targets the RANK receptor on osteoclast cells by simply altering the conjugated cargo in order to affect the specific regulation of osteoclast cells. PMID- 21301936 TI - Development of a bayesian forecasting method for warfarin dose individualization. AB - PURPOSE: The aim of this study was to develop a Bayesian dose individualization tool for warfarin. This was incorporated into the freely available software TCIWorks ( www.tciworks.info ) for use in the clinic. METHODS: All pharmacokinetic and pharmacodynamic (PKPD) models for warfarin in the medical literature were identified and evaluated against two warfarin datasets. The model with the best external validity was used to develop an optimal design for Bayesian parameter control. The performance of this design was evaluated using simulation-estimation techniques. Finally, the model was implemented in TCIWorks. RESULTS: A recently published warfarin KPD model was found to provide the best fit for the two external datasets. Optimal sampling days within the first 14 days of therapy were found to be days 3, 4, 5, 11, 12, 13 and 14. Simulations and parameter estimations suggested that the design will provide stable estimates of warfarin clearance and EC50. A single patient example showed the potential clinical utility of the method in TCIWorks. CONCLUSIONS: A Bayesian dose individualization tool for warfarin was developed. Future research to assess the predictive performance of the tool in warfarin patients is required. PMID- 21301937 TI - Glucose and glucose esters in the larval secretion of Chrysomela lapponica; selectivity of the glucoside import system from host plant leaves. AB - Larvae of Chrysomela lapponica (Coleoptera: Chrysomelidae) sequester characteristic O-glucosides from the leaves of their food plants, namely Betula and/or Salix The present study focuses on birch-feeding larvae of C. lapponica from the Altai region in East Kazakhstan. As in other sequestering leaf beetle larvae, the compounds are transported intact via different membrane barriers into the defensive system, followed by glucoside cleavage and subsequent transformations of the plant-derived aglycones. Unlike previous studies with model compounds, we studied the sequestration of phytogenic precursors by analyzing the complex pattern of glucosides present in food plant Betula rotundifolia (39 compounds) and compared this composition with the aglycones present as butyrate esters in the defensive secretion. In addition to the analytic approach, the insect's ability, to transport individual glucosides was tested by using hydrolysis-resistant thioglucoside analogs, applied onto the leaf surface. The test compounds reach the defensive system intact and without intermediate transformation. No significant difference of the transport capacity and selectivity was observed between larvae of birch-feeding population from Kazakhstan, and previous results for larvae of birch-feeding population from the Czech Republic or willow-feeding populations. Overall, the transport of the phytogenic glucosides is highly selective and highly efficient, since only minor compounds of the spectrum of phytogenic glucoside precursors contribute to the limited number of aglycones utilized in the defensive secretion. Interestingly, salicortin 44 and tremulacin 60 were found in the leaves, but no aldehyde or esters of salicylalcohol. Surprisingly, we observed large amounts of free glucose, together with small amounts of 6-O-butyrate esters of glucose (27a/b and 28a/b). PMID- 21301938 TI - Arylbenzo[h][1, 6]naphthyridine derivatives: synthesis and photophysical properties. AB - Suzuki-Miyaura cross coupling was successfully used for C5-arylation in 4-amino-2 chloroquinoline-3-carbaldehyde using arylbornic acid and tetrakistriphenylphosphine palladium catalyst in water. Friedlander condensation reaction on 4-amino-2-chloro/2-arylquinoline-3-carbaldehyde and aromatic ketones gave novel aryl and diarylbenzo[h] [1, 6]naphthyridines in good yields. Fluorescence quantum yields were increased by introducing C2 and C5 pi donor aryl benzo[h][1, 6]naphthyridines derivatives. PMID- 21301939 TI - Awareness of the importance of public health nursing activities in Japan. AB - The purpose of this study was to clarify the importance of public health nurses (PHNs) in Japan assigned to the targets and methods of public health nursing activities. Subjects were PHNs who had 10 years or more of work experience. A cross-sectional written survey was used to collect data from 1,967 PHNs (42% response rate). Survey items sought opinions on trends in community health and welfare activities (TCHWA), and the importance of public health nursing activities. TCHWA responses indicated that 70% or more of participants recognized the expansion of public responsibility, and the importance of the individual level of practice and policy-making. Surveyed PHNs found coordinating an organization (83.6%) to be important. Correlation of responses regarding TCHWA and the importance of public health nursing activities highlighted the importance of policy-making and indicated a significantly high awareness of the importance of activities. PHNs regarded support at both the individual/family and population/community levels to be important in terms of public health nursing activities. Currently, regarding public health nursing activities, it is necessary to promote the role of safety nets for protecting citizens' health, and effective public health nursing activities from which all citizens can equitably resource. PMID- 21301940 TI - Hearing loss and older adults' perceptions of access to care. AB - We investigated whether hard-of-hearing older adults were more likely to report difficulties and delays in accessing care and decreased satisfaction with healthcare access than those without hearing loss. The Wisconsin Longitudinal Study (2003-2006 wave, N = 6,524) surveyed respondents regarding hearing, difficulties/delays in accessing care, satisfaction with healthcare access, socio demographics, chronic conditions, self-rated health, depression, and length of relationship with provider/site. We used multivariate regression to compare access difficulties/delays and satisfaction by respondents' hearing status (hard of-hearing or not). Hard-of-hearing individuals comprised 18% of the sample. Compared to those not hard-of-hearing, hard-of-hearing individuals were significantly more likely to be older, male and separated/divorced. They had a higher mean number of chronic conditions, including atherosclerotic vascular disease, diabetes and depression. After adjustment for potential confounders, hard-of-hearing individuals were more likely to report difficulties in accessing healthcare (Odds Ratio 1.85; 95% Confidence Interval 1.19-2.88). Satisfaction with healthcare access was similar in both groups. Our findings suggest healthcare access difficulties will be heightened for more of the population because of the increasing prevalence of hearing loss. The prevalence of hearing loss in this data is low and our findings from a telephone survey likely underestimate the magnitude of access difficulties experienced by hard-of-hearing older adults. Further research which incorporates accessible surveys is needed. In the meantime, clinicians should pay particular attention to assessing barriers in healthcare access for hard-of-hearing individuals. Resources should be made available to proactively address these issues for those who are hard-of-hearing and to educate providers about the specific needs of this population. PMID- 21301941 TI - Arabidopsis thaliana uncoupling proteins (AtUCPs): insights into gene expression during development and stress response and epigenetic regulation. AB - Mitochondrial inner membrane uncoupling proteins (UCP) catalyze a proton conductance that dissipates the proton electrochemical gradient established by the respiratory chain, thus affecting the yield of ATP synthesis. UCPs are involved in mitochondrial energy flow regulation and have been implicated in oxidative stress tolerance. Based on the global gene expression profiling datasets available for Arabidopsis thaliana, in this review we discuss the regulation of UCP gene expression during development and in response to stress, and provide interesting insights on the possible existence of epigenetic regulation of UCP expression. PMID- 21301942 TI - On the mechanisms involved in biological heme crystallization. AB - Blood-feeding organisms digest hemoglobin, releasing large quantities of heme inside their digestive tracts. Free heme is very toxic, and these organisms have evolved several mechanisms to protect against its deleterious effects. One of these adaptations is the crystallization of heme into the dark-brown pigment hemozoin (Hz). Here we review the process of Hz formation, focusing on organisms other than Plasmodium that have contributed to a better understanding of heme crystallization. Hemozoin has been found in several distinct classes of organisms including protozoa, helminths and insects and Hz formation is the predominant form of heme detoxification. The available evidence indicates that amphiphilic structures such as phospholipid membranes and lipid droplets accompanied by specific proteins play a major role in heme crystallization. Because this process is specific to a number of blood-feeding organisms and absent in their hosts, Hz formation is an attractive target for the development of novel drugs to control illnesses associated with these hematophagous organisms. PMID- 21301944 TI - Routine prenatal HIV testing: women's concerns and their strategies for addressing concerns. AB - The purpose of this exploratory study was to solicit women's opinions about the process of routine prenatal HIV testing to identify strategies for routine testing that will address women's concerns, increase their level of comfort with testing, and support universal prenatal HIV testing. A convenience sample of English-speaking women between 18 and 45 years of age who were HIV-negative or of unknown HIV status were recruited for focus groups at four diverse community sites in four states. Focus group discussion questions addressed health care provider approaches and actions that would make a woman feel more comfortable with the process of routine prenatal HIV testing. Twenty-five women agreed to participate; most women (64%) were of Black, non-Hispanic race/ethnicity; 44% were 25-34 years of age. Thematic analysis of women's concerns about routine prenatal HIV testing fell into the following categories: fear, protecting the baby, protecting the woman, confidentiality, and stigma. Women's strategies for addressing these concerns were related to themes of education and information, normalizing HIV testing, patient-provider relationships, systems, and private communication. Participants offered numerous insightful and practical suggestions for addressing their concerns thereby supporting universal routine prenatal HIV testing. The themes that arose in this study support the conclusion that women will be more comfortable with routine prenatal HIV testing if they are fully informed and knowledgeable about the rationale for HIV testing during pregnancy and their right to decline, and if testing is carried out in a confidential and supportive health care environment. PMID- 21301945 TI - Social inequalities in the organization of pregnancy care in a universally funded public health care system. AB - To examine the social organization of pregnancy care and the extent to which socioeconomic factors affect women's experience of care. We consider these data in the global discussion on taking action to reduce health inequalities. This study draws on cross-sectional data from a large population-based survey of Australian women 6 months after giving birth. Only those women reporting to attend publically-funded models of antenatal care (i.e., public clinic, midwife clinic, shared care, primary medical care, primary midwife care) were included in analyses. Results showed a social patterning in the organization and experience of care with clear links between model of care attended in pregnancy and a number of individual-level indicators of social disadvantage. Our findings show model of care is a salient feature in how women view their care. How women from socially disadvantaged backgrounds navigate available care options are important considerations. Pregnancy care is recognized as an opportunity to intervene to give children 'the best start in life.' Our data show the current system of universally accessible pregnancy care in Australia is failing to support the most vulnerable women and families. This information can inform actions to reduce social disparities during this critical period. PMID- 21301946 TI - Brief report: excellent agreement between two brief autism scales (Checklist for Autism Spectrum Disorder and Social Responsiveness Scale) completed independently by parents and the Autism Diagnostic Interview-Revised. AB - Agreement between the Autism Diagnostic Interview-Revised (ADI-R) and two brief scales completed by parents was 93.1% for the Checklist for Autism Spectrum Disorder (CASD) and 89.7% for the Social Responsiveness Scale (SRS) in a sample of adolescents with suspected autism spectrum disorders. Our study is consistent with others showing that brief scales like the CASD and SRS have strong psychometric support and compare favorably with the ADI-R. The CASD and SRS are each completed and scored in 15 min, whereas the ADI-R takes over 2 h to administer and score. The CASD and SRS offer a valid and cost effective alternative to lengthy and expensive measures and, by virtue of their brevity and simplicity, could facilitate diagnosis, access to treatment, and research. PMID- 21301947 TI - Religion and healthy lifestyle behaviors among postmenopausal women: the women's health initiative. AB - Worship attendance has been associated with longer survival in prospective cohort studies. A possible explanation is that religious involvement may promote healthier lifestyle choices. Therefore, we examined whether attendance is associated with healthy behaviors, i.e. use of preventive medicine services, non smoking, moderate drinking, exercising regularly, and with healthy dietary habits. The population included 71,689 post-menopausal women enrolled in the Women's Health Initiative observational study free of chronic diseases at baseline. Attendance and lifestyle behaviors information was collected at baseline using self-administered questionnaires. Healthy behaviors were modeled as a function of attendance using logistic regression. After adjustment for confounders, worship attendance (less than weekly, weekly, and more than weekly vs. never) was positively associated with use of preventive services [OR for mammograms: 1.34 (1.19, 1.51), 1.41 (1.26, 1.57), 1.33 (1.17, 1.52); breast self exams: 1.14 (1.02, 1.27), 1.33 (1.21, 1.48), 1.25 (1.1, 1.43); PAP smears: 1.22 (1.01, 1.47-weekly vs. none)]; non-smoking: [1.41 (1.35, 1.48), 1.76 (1.69, 1.84), 2.27 (2.15, 2.39)]; moderate drinking [1.35 (1.27, 1.45), 1.60 (1.52, 1.7), 2.19 (2.0, 2.4)]; and fiber intake [1.08 (1.03, 1.14), 1.16 (1.11, 1.22), 1.31 (1.23, 1.39), respectively], but not with regular exercise or with lower saturated fat and caloric intake. These findings suggest that worship attendance is associated with certain, but not all, healthy behaviors. Further research is needed to get a deeper understanding of the relationship between religious involvement and healthy lifestyle behaviors and of the inconsistent patterns in this association. PMID- 21301949 TI - Preventing human immunodeficiency virus infection among sexual assault survivors in Cape Town, South Africa: an observational study. AB - We describe 131 South African sexual assault survivors offered HIV post-exposure prophylaxis (PEP). While the median days completed was 27 (IQR 27, 28), 34% stopped PEP or missed doses. Controlling for baseline symptoms, PEP was not associated with symptoms (OR = 1.30, 95% CI = 0.66, 2.64). Factors associated with unprotected sex included prior unprotected sex (OR = 6.46, 95% CI = 3.04, 13.74), time since the assault (OR = 1.33, 95% CI = 1.12, 1.57) and age (OR = 1.30, 95% CI = 1.08, 1.57). Trauma counseling was protective (OR = 0.18, 95% CI = 0.05, 0.58). Four instances of seroconversion were observed by 6 months (risk = 3.7%, 95% CI = 1.0, 9.1). Proactive follow-up is necessary to increase the likelihood of PEP completion and address the mental health and HIV risk needs of survivors. Adherence interventions and targeted risk reduction counseling should be provided to minimize HIV acquisition. PMID- 21301948 TI - A randomized controlled trial of a culturally congruent intervention to increase condom use and HIV testing among heterosexually active immigrant Latino men. AB - This randomized controlled trial tested the efficacy of an HIV prevention intervention to increase condom use and HIV testing among Spanish-speaking, heterosexually active immigrant Latino men. A community-based participatory research partnership developed the intervention and selected the study design. Following baseline data collection, 142 immigrant Latino men were randomized to the HIV prevention intervention or the cancer education intervention. Three-month follow-up data were collected from 139 participants, for a 98% retention rate. Mean age of participants was 31.6 years and 60% reported being from Mexico. Adjusting for baseline behaviors, relative to their peers in the cancer education comparison, participants in the HIV prevention intervention were more likely to report consistent condom use and receiving an HIV test. Community-based interventions for immigrant Latino men that are built on state of the art prevention science and developed in partnership with community members can greatly enhance preventive behaviors and may reduce HIV infection. PMID- 21301950 TI - Provider beliefs and practices relating to tobacco use in patients living with HIV/AIDS: a national survey. AB - The entire online HIV Medical Association US registry was invited to complete a questionnaire regarding beliefs and practices related to smoking in persons living with HIV/AIDS (PLWHAs). 363/486 returned completed questionnaires. Respondents from 43 states reported caring for 76,570 PLWHAs. Only 22.9% had ever received formal tobacco treatment training. Respondents generally agreed that smoking is an important issue in PLWHAs, but reported low levels of cessation promoting activities. Providers with larger patient panels, "primarily HIV" practices, and formal cessation training had higher questionnaire scores, indicating stronger beliefs in the harms of smoking, benefits of quitting, and effectiveness of cessation strategies. PMID- 21301951 TI - Psychiatric symptom typology in a sample of youth receiving substance abuse treatment services: associations with self-reported child maltreatment and sexual risk behaviors. AB - Latent profile analysis (LPA) was used to classify 394 adolescents undergoing substance use treatment, based on past year psychiatric symptoms. Relations between profile membership and (a) self-reported childhood maltreatment experiences and (b) current sexual risk behavior were examined. LPA generated three psychiatric symptom profiles: Low-, High- Alcohol-, and High- Internalizing Symptoms profiles. Analyses identified significant associations between profile membership and childhood sexual abuse and emotional neglect ratings, as well as co-occurring sex with substance use and unprotected intercourse. Profiles with elevated psychiatric symptom scores (e.g., internalizing problems, alcohol abuse and dependence symptoms) and more severe maltreatment histories reported higher scores for behavioral risk factors for HIV/STI exposure. Heterogeneity in psychiatric symptom patterns among youth receiving substance use treatment services, and prior histories of childhood maltreatment, have significant implications for the design and delivery of HIV/STI prevention programs to this population. PMID- 21301952 TI - Trajectories of symptom reduction during treatment for behavior problems in pediatric primary-care settings. AB - We examined trajectories of symptom reduction during the course of on-site treatment for behavior problems in pediatric primary-care settings for a subset of children from a larger clinical trial. Participants (N = 80) were children (ages 6-11) referred for treatment due to moderate elevations (>=75th percentile) on the externalizing subscale of the Pediatric Symptom Checklist (PSC-17). The sample was recruited from six pediatric practices in an urban setting. The treatment (Protocol for an Office-based Nurse-administered Intervention; PONI) was administered on-site by trained nurses over the course of 3-6 months. Overall, symptom reduction from the first session to last session was moderate (ES = 0.61) and gradual. Roughly two-thirds (72%) of symptom reduction took place over the first 8 weeks of treatment. The average trajectory of symptom reduction was characterized by a negative slope that flattened over time, consistent with a quadratic growth model. Initial symptom severity predicted final symptom severity (r = .36, P < .01), even though patients with greater initial symptom severity remained in treatment for a significantly greater number of sessions (r = .24, P < .05). The implications of these findings for enhancing the efficiency and effectiveness of treatment are discussed. PMID- 21301953 TI - Behavioral inhibition and anxiety: the moderating roles of inhibitory control and attention shifting. AB - Behavioral inhibition (BI), a temperament identified in early childhood, is associated with social reticence in childhood and an increased risk for anxiety problems in adolescence and adulthood. However, not all behaviorally inhibited children remain reticent or develop an anxiety disorder. One possible mechanism accounting for the variability in the developmental trajectories of BI is a child's ability to successfully recruit cognitive processes involved in the regulation of negative reactivity. However, separate cognitive processes may differentially moderate the association between BI and later anxiety problems. The goal of the current study was to examine how two cognitive processes attention shifting and inhibitory control-laboratory assessed at 48 months of age moderated the association between 24-month BI and anxiety symptoms in the preschool years. Results revealed that high levels of attention shifting decreased the risk for anxiety problems in children with high levels of BI, whereas high levels of inhibitory control increased this risk for anxiety symptoms. These findings suggest that different cognitive processes may influence relative levels of risk or adaptation depending upon a child's temperamental reactivity. PMID- 21301954 TI - Lower frequency of antidepressant use in patients on renin-angiotensin aldosterone system modifying medications. AB - Both hypertension and depression are common disorders which may both involve components of the hypothalamic-pituitary-adrenal axis system and the Renin Angiotensin-Aldosterone System (RAAS). These observations, coupled with growing evidence that RAAS-active drugs may have anti-depressant properties prompted us to study the frequency of anti-depressant medication usage in the patients receiving RAAS-active agents. A chart review was performed on 378 patients who were seen during a 3-month period in a primary care clinic and who were diagnosed with hypertension. Demographic information and data on the rates of co administration of antihypertensive and anti-depressant medications was collected. Overall, 23.7% of the sample was on an antidepressant. 20% of the patients taking a RAAS-modifying medication were on an antidepressant, compared to 34% of those not taking a RAAS-modifying medication (Chi(2) = 8.88, P = 0.003). The patients taking a beta-blocker alone had the highest rate of antidepressant usage (40%). The use of RAAS-modifying medications was associated with an even lower rate of anti-depressant usage in males compared with females. It was also observed that the patients taking an additional diuretic had a significantly lower rate of antidepressant use (17.6%, Chi(2) = 5.81, P = 0.016) compared with the patients not taking a diuretic. The patients being treated with an ACE inhibitor or ARB showed significantly lower rates of antidepressant usage. The data is supportive of the hypothesis that these agents may possess anti-depressant effects. PMID- 21301955 TI - Mothers' resolution of their young children's psychiatric diagnoses: associations with child, parent, and relationship characteristics. AB - Maternal resolution of a child's diagnosis relates to sensitive caregiving and healthy attachment. Failure to resolve is associated with maternal distress, high caregiving burden, and the quality of marital and social support. This study examined maternal resolution of diagnosis in a child psychiatric population utilizing the Reaction to Diagnosis paradigm. Thirty-three mothers of children ages 2-7 years with psychiatric disorders were interviewed using the Reaction to Diagnosis Interview. Slightly over half of the sample was classified as resolved. Associations between maternal resolution status, maternal depression, childrearing stress, and child functioning were examined and a predictive model for maternal resolution status was tested. Specific findings included a significant association between childrearing stress and maternal resolution status with support for some additional predictive power for maternal depression on resolution status. Child functioning was not significantly associated with resolution status, and may exert influence indirectly through its association with childrearing stress. There were no significant associations between maternal or child demographic characteristics and maternal resolution status. Clinical and research implications are discussed. PMID- 21301956 TI - Biomarkers of PARP inhibitor sensitivity. PMID- 21301958 TI - New land-based method for surveying sandy shores and extracting DEMs: the INSHORE system. AB - The INSHORE system (INtegrated System for High Operational REsolution in shore monitoring) is a land-base survey system designed and developed for the specific task of monitoring the evolution in time of sandy shores. This system was developed with two main objectives: (1) to produce highly accurate 3D coordinates of surface points (in the order of 0.02 to 0.03 m); and (2) to be extremely efficient in surveying a beach stretch of several kilometres. Previous tests have demonstrated that INSHORE systems fulfil such objectives. Now, the usefulness of the INSHORE system as a survey tool for the production of Digital Elevation Models (DEMs) of sandy shores is demonstrated. For this purpose, the comparison of DEMs obtained with the INSHORE system and with other relevant survey techniques is presented. This comparison focuses on the final DEM accuracy and also on the survey efficiency and its impact on the costs associated with regular monitoring programmes. The field survey method of the INSHORE system, based on profile networks, has a productivity of about 30 to 40 ha/h, depending on the beach surface characteristics. The final DEM precision, after interpolation of the global positioning system profile network, is approximately 0.08 to 0.12 m (RMS), depending on the profile network's density. Thus, this is a useful method for 3D representation of sandy shore surfaces and can permit, after interpolation, reliable calculations of volume and other physical parameters. PMID- 21301957 TI - Breast cancers in U.S. residing Indian-Pakistani versus non-Hispanic White women: comparative analysis of clinical-pathologic features, treatment, and survival. AB - South Asians from India and Pakistan represent one of the fastest growing immigrant populations in the US, yet there are limited data assessing breast cancers for this distinct ethnic sub-group. The aim of this study was to analyze clinical-pathologic, treatment and outcome characteristics of U.S.-residing Indian-Pakistani (IP) versus non-Hispanic white (NHW) female breast cancer patients to assess if any differences/disparities exist. The study cohort consisted of 2,393 IP and 555,832 NHW women (diagnosed 1988-2006) in the SEER database. Differences between the two populations were analyzed using chi-squared and multivariate regression analysis. Age-adjusted incidence, mortality, and relative survival rates were calculated for the two groups. Significant differences in the characteristics of the IP cohort's invasive disease included: younger median age at presentation; larger tumor size; higher stage, higher grade, more involved lymph-nodes, and more hormone receptor negative disease (all P < 0.01). The age-adjusted incidence and breast cancer mortality were lower in IP women. The relative survival at 5 years was statistically significant at 84% for IP versus 89% for NHW women, but was not significantly different on multivariate analysis (P > 0.05). Within each stage (Tis, I, II), there were no disparities in the rate of breast conservation surgery (BCS) or in the percentage of patients receiving adjuvant radiation after BCS for the 2 cohorts. Post mastectomy radiation was delivered significantly more often in stage I/II IP patients undergoing mastectomy. In conclusion, this analysis suggests that while there appear to be significant differences in the features of breast cancers of US-residing IP women, no disparities were noted in the rates of breast conserving surgery or adjuvant radiation, as seen in some other ethnicities. The more aggressive clinical-pathologic features stage-for-stage in IP women may partially explain the more frequent use of post-mastectomy RT in this patient population. These findings warrant further investigation. PMID- 21301959 TI - Management and monitoring of haemodynamic complications in acute heart failure. AB - The pathophysiology of acute heart failure syndromes (AHFS), defined as a change or worsening in heart failure symptoms and signs, is complex. The variety of adverse neurohormonal adaptations includes increased levels of plasma renin, aldosterone and angiotensin II, all responsible for cardio-renal dysfunction. In fact, such alterations result in an array of clinical changes that include abnormal haemodynamics, altered ventricular filling pressures, pathological neurohormonal responses, leading to fluid overload, congestion and ultimately heart failure symptoms. Clinical pictures can be various: in spite of a usual improvement in dyspnoea, little weight change and significant morbidity are generally observed during hospitalization. Short-term outcomes are characterized by a high 60-day re-hospitalization and high mortality rates; apparently, both can be predicted from pre-discharge characteristics. The most frequently used treatments for AHF care include diuretics, inotropic agents, and vasodilator/vasoactive agents; however, the final therapeutic strategy is often individualized. Diuretics are currently the most used agents, but resistance to diuretic therapy is common. In addition, several studies have demonstrated that aggressive diuresis can contribute to reduced renal function, and high doses of diuretics have been associated with increased morbidity and mortality. Many patients with AHFS also suffer from acute or from chronic renal dysfunction (cardio-renal syndromes type 1 and 2, respectively), which further complicate the outcomes and treatment strategies. A personalized patient evaluation of the combined heart and kidney functions is advised to implement the best possible multidisciplinary diagnostic and therapeutic approach. PMID- 21301960 TI - Complex interaction between symptoms, social factors, and gender in social functioning in a community-dwelling sample of schizophrenia. AB - Social functioning (SF) is the ultimate target aimed in treatment plans in schizophrenia, thus it is critical to know what are the factors that determine SF. Gender is a well-established variable influencing SF, yet it is not known how social variables and symptoms interact in schizophrenia patients. Furthermore, it remains unclear whether the interaction between social variables and symptoms is different in men compared to women. Our aim is to test whether social variables are better predictors of SF in community-dwelled individuals with schizophrenia, and whether men and women differ in how symptoms and social variables interact to impact SF. Community-dwelling individuals with schizophrenia (N = 231) were randomly selected from a register. Participants were assessed with symptom measures (PANSS), performance-based social scale (LSP), objective social and demographic variables. Stratification by gender and stepwise multivariate regression analyses by gender were used to find the best-fitting models that predict SF in both gender. Men had poorer SF than women in spite of showing similar symptom scores. On stepwise regression analyses, gender was the main variable explaining SF, with a significant contribution by disorganized and excitatory symptoms. Age of onset made a less marked, yet significant, contribution to explain SF. When the sample was stratified by gender, disorganized symptoms and 'Income' variable entered the model and accounted for a 30.8% of the SF variance in women. On the other hand, positive and disorganized symptoms entered the model and accounted for a 36.1% of the SF variance in men. Community-dwelling men and women with schizophrenia differ in the constellation of variables associated with SF. Symptom scores still account for most of the variance in SF in both genders. PMID- 21301961 TI - Whole-body Cerenkov luminescence tomography with the finite element SP(3) method. AB - Generation of an accurate Cerenkov luminescence imaging model is a current issue of nuclear tomography with optical techniques. The article takes a pro-active approach toward whole-body Cerenkov luminescence tomography. The finite element framework employs the equation of radiative transfer via the third-order simplified spherical harmonics approximation to model Cerenkov photon propagation in a small animal. After this forward model is performed on a digital mouse with optical property heterogeneity and compared with the Monte Carlo method, we investigated the whole body reconstruction algorithm along a regularization path via coordinate descent. The endpoint of the follow-up study is the in vivo application, which provides three-dimensional biodistribution of the radiotracer uptake in the mouse from measured partial boundary currents. The combination of the forward and inverse model with elastic-net penalties is not only validated by numerical simulation, but it also effectively demonstrates in vivo imaging in small animals. Our exact reconstruction method enables optical molecular imaging to best utilize Cerenkov radiation emission from the decay of medical isotopes in tissues. PMID- 21301962 TI - Are residents willing to discuss spirituality with patients? AB - Family medicine is redefining itself in the wake of the Future of Family Medicine Project, the move to the Patient-Centered Medical Home, and the 2010 Patient Protection and Affordable Care Act's emphasis on primary care. This effort has included representing family doctors as physicians who "care for the whole person" and who "specialize in you." Many patients believe that whole person care involves attention to spirituality and wish to share their beliefs in the medical encounter. This national survey investigated whether a random sample of family medicine residents were willing to address spirituality upon patient request. With varying degrees of willingness, most doctors said that they would discuss patient beliefs if asked. Denominational preference, residency training in addressing spirituality, and self-rated spirituality were all predictive of the strength of reported willingness. These results indicate that training in addressing spirituality may create residents more likely to discuss the topic in clinical practice. PMID- 21301963 TI - Is evidence able to persuade physicians to discuss spirituality with patients? AB - Patients believe that spirituality informs health; frequently, they wish to share their beliefs with physicians. Although a large number of physicians believe it their responsibility to be aware of patient beliefs, many do not address spirituality because they do not believe it their role to do so. These physicians would perhaps feel differently if presented with evidence that associated spirituality with positive health outcomes. This national sample of family medicine residents were asked if, presented with evidence that spirituality was associated with improved outcomes, they would be more likely to initiate discussions of spirituality with patients. To varying degrees, most residents agreed that they would be more willing to initiate spirituality discussions if presented with good evidence. Geographic region of training, religious preference, and Spiritual Well-Being Scale quartile predicted both strength of agreement and whether a resident would be as responsive to spirituality oriented research as to investigations of traditional therapeutic modalities. Although residents indicated that they would be more responsive to publications on traditional medical therapies, familiarity with the spirituality literature as part of a residency educational curriculum may help break down barriers to addressing this issue with patients. PMID- 21301964 TI - UK experience of liver transplantation for erythropoietic protoporphyria. AB - Erythropoietic protoporphyria (EPP) is characterised by excess production of free protoporphyrin from the bone marrow, most commonly due to deficiency of the enzyme ferrochelatase. Excess protoporphyrin gives rise to the cutaneous photosensitivity characteristic of the disease, and in a minority of patients leads to end-stage liver disease necessitating liver transplantation (LT). There is limited information regarding the timing, impact and long-term outcome of LT in such patients, thus we aimed to identify the indications and outcomes of all transplants performed for EPP in the UK using data from the UK Transplant Registry. Between 1987 and 2009, five patients underwent LT for EPP liver disease. Median follow-up was 60 months, and there were two deaths at 44 and 95 months from causes unrelated to liver disease. The remaining recipients are alive at 22.4 years, 61 months and 55 months after transplant. A high rate of postoperative biliary stricturing requiring multiple biliary interventions was observed. Recurrent EPP-liver disease occurred in 4/5 (80%) of patients but graft failure has not been observed. Given the role of biliary obstruction in inducing EPP-mediated liver damage, we suggest that consideration should be given for construction of a Roux loop at the time of transplant. Thus we demonstrate that although EPP liver transplant recipients have a good long-term survival, comparable to patients undergoing LT for other indications, biliary complications and disease recurrence are almost universal, and bone marrow transplantation should be considered where possible. PMID- 21301965 TI - Novel multi-sided, microelectrode arrays for implantable neural applications. AB - A new parylene-based microfabrication process is presented for neural recording and drug delivery applications. We introduce a large design space for electrode placement and structural flexibility with a six mask process. By using chemical mechanical polishing, electrode sites may be created top-side, back-side, or on the edge of the device having three exposed sides. Added surface area was achieved on the exposed edge through electroplating. Poly(3,4 ethylenedioxythiophene) (PEDOT) modified edge electrodes having an 85-MUm(2) footprint resulted in an impedance of 200 kOmega at 1 kHz. Edge electrodes were able to successfully record single unit activity in acute animal studies. A finite element model of planar and edge electrodes relative to neuron position reveals that edge electrodes should be beneficial for increasing the volume of tissue being sampled in recording applications. PMID- 21301966 TI - Objective assessment of thirst recovery in patients with adipsic diabetes insipidus. AB - Adipsic diabetes insipidus (ADI) is characterised by impaired thirst and defective AVP secretion. We have assessed the thirst response to graded osmotic stimulation using a visual analog scale (VAS) in patients with a history of ADI following surgery for a craniopharyngioma. The patients were thought to be regaining their thirst response but we wanted to confirm that this was the case objectively before relaxing their strict fluid balance regimen. Three patients with adipisa in the presence of hypernatremia following surgery for a craniopharyngioma are described. Their median age at surgery was 13 years (range 11-15 years). All patients had previously demonstrated no desire to drink despite a serum osmolality in excess of 300 mOsmol/kg. Fluid balance was maintained postoperatively with a regimen involving a fixed daily fluid intake and DDAVP dose together with daily weights and regular assessment of capillary sodium concentrations. Patients were thought to be regaining thirst sensation and so were assessed by hypertonic saline infusion (HSI) with thirst measured using a VAS. Patients underwent a HSI test 4, 6 and 9 months post surgery. All had abnormally low AVP production at raised plasma osmolalities but the visual analogue scale confirmed partial or complete thirst recovery. The intensive regimen used to maintain stable serum sodium concentrations was relaxed without the patients subsequently developing a significant hyperosmolar state. We have shown objective recovery of thirst perception in patients with adipsia within 9 months of surgery, despite persistence of cranial diabetes insipidus. These observations indicate that both osmoreceptors regulating thirst and their efferent pathways demonstrate more plasticity than those regulating AVP production. The HSI and thirst VAS are an objective way of assessing patients known to have ADI who are thought to be recovering thirst perception. PMID- 21301967 TI - High prevalence of radiological vertebral fractures in women with prolactin secreting pituitary adenomas. AB - Hyperprolactinemia may cause bone loss but data on fractures are scanty. The aim of this study was to evaluate the prevalence of vertebral fractures in women with prolactin (PRL)-secreting adenoma. In this cross-sectional study, 78 women (median age 45.5 years, range: 20-81) with PRL-secreting pituitary adenoma (66 with microadenoma and 12 with macroadenoma) and 156 control subjects, with normal PRL values and with comparable age to patients with hyperprolactinemia, were evaluated for vertebral fractures by a morphometric approach and for bone mineral density (BMD) by a dual-energy X-ray absorptiometry at lumbar spine. Vertebral fractures were shown in 25 patients with PRL-secreting adenoma (32.6%) and in 20 controls (12.8%, P < 0.001). Fractured patients were significantly older (P < 0.001) and had lower BMD T-score (P < 0.001), longer duration of disease (P < 0.001), higher serum PRL (P = 0.004) and lower serum IGF-I (P < 0.001) values as compared to patients who did not fracture. The prevalence of vertebral fractures was significantly (P < 0.001) higher in post-menopausal women with PRL-secreting adenoma as compared to pre-menopausal patients. Fractures occurred more frequently (P = 0.01) in patients with untreated hyperprolactinemia versus patients treated with cabergoline. Logistic regression analysis demonstrated that duration of disease maintained a significant correlation with vertebral fractures (odds ratio 1.16, C.I. 95% 1.02-1.33) even after correction for age, menopausal status, treatment with cabergoline, BMD, serum IGF-I and serum PRL values. Hyperprolactinemia is associated with high prevalence of radiological vertebral fractures in women with PRL-secreting adenoma. PMID- 21301968 TI - One-step nucleic acid amplification (OSNA) for the application of sentinel node concept in gastric cancer. AB - PURPOSE: This study was designed to apply safely the sentinel node navigation surgery (SNNS) to the malignancies, an accurate and prompt intraoperative diagnosis of SN is essential, and micrometastasis has been frequently missed by conventional frozen sections. Recently, a novel molecular-based rapid diagnosis for the lymph node (LN) metastases has been developed using (OSNA) in breast cancer, which takes approximately 30 min to obtain a final result. We evaluated the efficacy of OSNA in terms of the intraoperative diagnosis of LN metastasis in patients with gastric cancer. METHODS: A total of 162 LNs dissected from 32 patients with gastric cancer was included in this study; 45 LNs were pathologically diagnosed as metastatic LNs and 117 LNs were negative. The LNs were bisected; halves were examined with H&E stain, and the opposite halves were subjected to OSNA analyses of CK19 mRNA. The CK19 mRNA expression was examined in the positive or negative metastatic LNs, and the correlation between the tumor volume and CK19 mRNA expression in the metastatic LNs was examined. RESULTS: The CK19 mRNA expressions in the positive metastatic LNs were significantly higher than those of negative LNs. When 250 copies/MUl was set as a cutoff value, the concordance rate was 94.4%, the sensitivity was 88.9%, and the specificity was 96.6%. The OSNA expression was significantly correlated with the estimated tumor volumes in the metastatic LNs. CONCLUSIONS: The OSNA method is feasible and acceptable for detecting LN metastases in patients with gastric cancer. This should be applied for the intraoperative diagnosis in the SN-navigation surgery in gastric cancer. PMID- 21301969 TI - Magnetic resonance imaging and ultrasonography in predicting infiltrating residual disease after preoperative chemotherapy in stage II-III breast cancer. AB - BACKGROUND: This study was designed to evaluate the accuracy of breast magnetic resonance imaging (MRI) and ultrasonography (US) in predicting the extent of breast residual disease after preoperative chemotherapy. METHODS: Patients with stage II-III invasive breast tumors who received preoperative chemotherapy and were imaged with post-treatment MRI were included. Histopathological verification was available for all patients. The longest diameter of residual tumor measured with MRI and US has been compared with the infiltrating residual tumor size at pathologic evaluation. RESULTS: A total of 108 patients were enrolled: 59 were imaged with both MRI and US (MRI group), and 49 were imaged with US only (non-MRI group). The non-MRI group was enrolled as an external control to avoid possible bias in the selection of patients. In the MRI group, the means of the deltas between MRI residual tumor size and pathologic size and between US and pathologic size were 0.16 cm and -0.06 cm respectively (P = not significant). Overall, a discrepancy limited in the interval from -0.5 cm to +0.5 cm compared with the pathologic size was observed in 54% and 51% of the patients with MRI and US, respectively (P = not significant). The linear correlation between the radiological measurement and pathologic tumor size was r = 0.53 for MRI and r = 0.66 for breast US. In the non-MRI group, the mean of the deltas between US residual tumor size and pathologic size was 0.06 cm, and the linear correlation was r = 0.79. CONCLUSIONS: In this series of patients, MRI and US do not show significant differences in predicting the breast residual infiltrating tumor after preoperative chemotherapy. PMID- 21301970 TI - Water: a simple solution for tumor spillage. AB - BACKGROUND: Although often proposed as a means to reduce the harmful consequences of tumor spill, water lavage has yet to be systematically evaluated in relevant in vitro and in vivo models. This study evaluates the mechanisms and utility of a single water lavage to improve the sequelae of tumor spill during laparotomy. METHODS: Murine colorectal tumor cell susceptibility to water-induced osmotic lysis was characterized in vitro. A reproducible model of tumor spill was established to recapitulate water or saline lavage during laparotomy. Analyses of tumor volumes calculated from noninvasive imaging were performed. The tumor volumes and survival of mice treated with water, normal saline, or sham laparotomy were assessed. RESULTS: Significant osmotic lysis of cultured murine colorectal cancer cells was observed after a brief exposure to water. Compared to saline or sham laparotomy, water lavage demonstrated superior clinical outcomes with a decrease in tumor burden and concomitant improvement in survival. CONCLUSIONS: The use of water lavage during oncologic surgeries to reduce the sequelae of tumor spill is justified and strongly supported by our study. Data from our study raise several concerns regarding the mechanisms and efficacy of saline lavage. Clinically, the use of water lavage during laparotomy would be anticipated to reduce peritoneal disease burden with minimal toxicity or cost. PMID- 21301971 TI - Does previous head and neck irradiation increase the chance of multigland disease in patients with hyperparathyroidism? AB - BACKGROUND: Exposure to therapeutic radiation, whether used to treat lymphoma, breast cancer, or benign conditions, such as acne, is thought to cause an increased risk for thyroid and/or parathyroid neoplasia. We therefore investigated whether patients with a history of head/neck irradiation and hyperparathyroidism (HPT) had a higher incidence of multigland disease. METHODS: Between November 2000 and May 2010, 1,428 patients with HPT underwent parathyroidectomy at our institution. Of these cases, 39 patients (2.7%) had a history of radiation exposure (RADRX). These 39 cases were compared with the 1,389 cases without prior exposure (NO RAD RX). RESULTS: There were no significant differences in gender or age between the two groups. Whereas most laboratory values were similar, preoperative parathyroid hormone levels were higher in the NO RADRX patients (174 +/- 7 vs. 106 +/- 8 pg/ml; P < 0.001). Interestingly, the resected parathyroid glands were significantly smaller in the RADRX group compared with the NO RADRX group (511 +/- 70 vs. 790 +/- 37 mg; P = 0.001). No differences were noted in the recurrence rate (P = 0.392). Contrary to common belief, RADRX patients did not have a significantly higher incidence of multigland disease (P = 0.774). Of the 39 RADRX patients, 12 (31%) had multigland disease, whereas 398 of the 1,389 (28%) NO RADRX patients had multigland disease. CONCLUSIONS: Surgical outcomes are excellent in patients with a previous history of radiation and HPT who undergo parathyroidectomy. Previous radiation exposure does not appear to increase the likelihood of multigland disease in patients with HPT. PMID- 21301972 TI - Clinical significance of alpha-fetoprotein mRNA in peripheral blood in liver resection for hepatocellular carcinoma. AB - PURPOSE: Detection of AFP mRNA in peripheral blood is considered a useful predictor of HCC recurrence after resection. However, its interpretation and clinical significance remains to be determined. This study was designed to evaluate the clinical significance of detecting AFP mRNA positive cells in peripheral blood. METHODS: A total of 153 patients without macroscopic vascular invasion, who underwent liver resection, were prospectively enrolled in this study. The pattern of HCC recurrence was confirmed by image studies and divided into four types: (1) no recurrence (control group, n = 68); (2) intrahepatic single recurrence (SR group, n = 28); (3) intrahepatic multiple recurrences (MR group, n = 38); and (4) extrahepatic HCC recurrence (EX group, n = 19). RESULTS: HCC recurrence was identified in 85 (55.6%) patients during a follow-up of 8.6 +/ 6.7 (range, 0.7-36) months. Multivariate analysis identified preoperative AFP mRNA (HR = 2.54; P = 0.006) as an independent risk factor for HCC recurrence. Preoperative AFP mRNA expression was a significant predictor of HCC recurrence in the MR/EX group (P = 0.029) but not in the SR group (P = 0.467). CONCLUSIONS: Detection of AFP mRNA expression in peripheral blood before surgery for HCC is a useful predictor of multiple or extrahepatic HCC recurrences. PMID- 21301973 TI - Liver resection and ablation for metastatic adrenocortical carcinoma. AB - BACKGROUND: Adrenocortical carcinoma (ACC) is a rare disease without effective chemotherapy treated most appropriately with resection. The aim of this study was to evaluate our experience with liver resection for metastatic ACC. METHODS: This study is a retrospective review of patients who underwent liver resection or radiofrequency ablation (RFA) for ACC from 1979 to 2009. RESULTS: A total of 27 patients were identified. Of the 27, 19 underwent liver resection. Of the 19, 10 had a single liver lesion, and 18 of 19 were rendered free of disease in the liver, although only 11 of 19 were rendered completely free of disease because of extrahepatic disease (EHD). Of the 19, 13 had synchronous EHD. Also, 6 of 17 remained disease free in the liver at a median follow-up of 6.2 years (status of 2 of 19 was unknown). Of the 27 patients, 8 underwent RFA, 7 of 8 became free of disease in the liver, and 5 of 7 had EHD. No patients responded to prior chemotherapy. Median overall survival and survival of patients who underwent liver resection or RFA were both 1.9 years (0.2-12 + years); 5-year actuarial survivals were 29% and 29%, respectively. Disease-free interval (DFI) greater than 9 months from primary resection was associated with longer survival (median 4.1 vs 0.9 years; P = .013). CONCLUSIONS: This study is a tertiary institution series of liver resection and RFA for ACC. Given the lack of effective systemic treatment options and the safety of resection and ablation, liver resection or RFA may be considered in selected patients with ACC metastatic to the liver especially with a long DFI. PMID- 21301975 TI - Enzymatic basis for fungicide removal by Elodea canadensis. AB - PURPOSE: Plants can absorb a diversity of natural and man-made toxic compounds for which they have developed diverse detoxification mechanisms. Plants are able to metabolize and detoxify a wide array of xenobiotics by oxidation, sugar conjugation, glutathione conjugation, and more complex reactions. In this study, detoxification mechanisms of dimethomorph, a fungicide currently found in aquatic media were investigated in Elodea canadensis. METHODS: Cytochrome P450 (P450) activity was measured by an oxygen biosensor system, glucosyltransferases (GTs) by HPLC, glutathione S-transferases (GSTs), and ascorbate peroxidase (APOX) were assayed spectrophotometrically. RESULTS: Incubation of Elodea with dimethomorph induced an increase of the P450 activity. GST activity was not stimulated by dimethomorph suggesting that GST does not participate in dimethomorph detoxification. In plants exposed to dimethomorph, comparable responses were observed for GST and APOX activities showing that the GST was more likely to play a role in response to oxidative stress. Preincubation with dimethomorph induced a high activity of O- and N-GT, it is therefore likely that both enzymes participate in the phase II (conjugation) of dimethomorph detoxification process. CONCLUSIONS: For the first time in aquatic plants, P450 activity was shown to be induced by a fungicide suggesting a role in the metabolization of dimethomorph. Moreover, our finding is the first evidence of dimethomorph and isoproturon activation of cytochrome P450 multienzyme family in an aquatic plant, i.e., Elodea (isoproturon was taken here as a reference molecule). The detoxification of dimetomorph seems to proceed via hydroxylation, and subsequent glucosylation, and might yield soluble as well as cell wall bound residues. PMID- 21301976 TI - Development of a model to select plants with optimum metal phytoextraction potential. AB - PURPOSE: The aim of the present study is to propose a nonlinear model which provides an indicator for the maximum phytoextraction of metals to help in the decision-making process. Research into different species and strategies plays an important role in the application of phytoextraction techniques to the remediation of contaminated soil. Also, the convenience of species according to their biomass and pollutant accumulation capacities has gained important space in discussions regarding remediation strategies, whether to choose species with low accumulation capacities and high biomass or high accumulation capacities with low biomass. METHODS: The effects of heavy metals in soil on plant growth are studied by means of a nonlinear interaction model which relates the dynamics of the uptake of heavy metals by plants to heavy metal deposed in soil. RESULTS: The model, presented theoretically, provides an indicator for the maximum phytoextraction of metals which depends on adjustable parameters of both the plant and the environmental conditions. Finally, in order to clarify its applicability, a series of experimental results found in the literature are presented to show how the model performs consistently with real data. CONCLUSIONS: The inhibition of plant growth due to heavy metal concentration can be predicted by a simple kinetic model. The model proposed in this study makes it possible to characterize the nonlinear behaviour of the soil-plant interaction with heavy metal pollution in order to establish maximum uptake values for heavy metals in the harvestable part of plants. PMID- 21301977 TI - Natural dissolved humic substances increase the lifespan and promote transgenerational resistance to salt stress in the cladoceran Moina macrocopa. AB - PURPOSE: Evidence has accumulated that humic substances (HS) are not inert biogeochemicals. Rather, they cause stress symptoms and may modulate the life history of aquatic organisms. Nevertheless, it is still not clear how HS interact with additional stressors and if their effects are transgenerational. We tested the interactive effects of HS and salt to cladocerans, discussing their consequences for the persistence in fluctuating environments, such as coastal lagoons. METHODS: We used life-table experiments to test the effects of natural HS from a polyhumic coastal lagoon (0, 5, 10, 20, 50, and 100 mg dissolved organic carbon (DOC) L(-1)) on the life-history of the cladoceran Moina macrocopa. We further tested the effects of HS (10 mg DOC L(-1)), within and across generations, on the resistance of M. macrocopa to salt stress (5.5 g L( 1)). RESULTS: HS at 5-20 mg DOC L(-1) extended the mean lifespan of M. macrocopa by ~30%. HS also increased body length at maturity by ~4% at 5-50 mg DOC L(-1) and stimulated male offspring production at all tested concentrations. Exposure to HS (even maternal only) alleviated the salt-induced reduction of somatic growth. Co-exposure to HS increased body volume by 12-22% relative to salt-only treatments, while pre-exposure to HS increased body volume by 40-56% in treatments with salt presence, when compared to non-pre-exposed animals. CONCLUSIONS: HS at environmentally realistic concentrations, by acting as mild chemical stressors, modify crucial life-history traits of M. macrocopa, favoring its persistence in fluctuating environments. Some of the effects of HS are even transgenerational. PMID- 21301978 TI - Occurrence of perfluorinated organic acids in the North and Baltic seas. Part 1: distribution in sea water. AB - PURPOSE: Due to their high water solubilities and mobilities, persistent, polar perfluorinated compounds (PFCs) such as perfluorinated carboxylates and sulfonates are likely to end up in the oceans. In part 1 of this study, their distribution in North and Baltic Sea water is reported, being of special interest because these seas are surrounded by highly industrialized countries with high population densities. METHODS: A combination of solid-phase extraction and liquid chromatography coupled with tandem mass spectrometry was used after optimisation to determine nine PFCs with chain lengths of C(4) to C(10) in water samples at ultra-trace levels. RESULTS: The observed concentration distribution and gradients were explained by oceanographic mixing processes and currents. The big rivers were identified as major input sources. At the mouth of the river Elbe, concentrations of 9 ng/L were observed for perfluorooctanoate (PFOA), and 8 ng/L for perfluorooctylsulfonate (PFOS); all other PFC concentrations ranged from 0.6 to 1.7 ng/L. At coastal stations, concentrations decreased to 3.8 ng/L (PFOA) and 1.8 ng/L (PFOS), dropping to 0.13 and 0.09 ng/L, respectively, towards the open sea. Along the Dutch coast, high perfluorobutylsulfonate concentrations (3.9 ng/L) were observed as regional characteristics. In the Baltic Sea, fairly even PFC distributions with low gradients were observed. Again, PFOA and PFOS were the major compounds (up to 1.1 and 0.9 ng/L). CONCLUSION: The results underline the necessity to include PFCs in marine monitoring programs. Water was found to be a good matrix for monitoring environmental levels, sources, and transport pathways of PFCs. PMID- 21301979 TI - Active components from Siberian ginseng (Eleutherococcus senticosus) for protection of amyloid beta(25-35)-induced neuritic atrophy in cultured rat cortical neurons. AB - Not only neuronal death but also neuritic atrophy and synaptic loss underlie the pathogenesis of Alzheimer's disease as direct causes of the memory deficit. Extracts of Siberian ginseng (the rhizome of Eleutherococcus senticosus) were shown to have protective effects on the regeneration of neurites and the reconstruction of synapses in rat cultured cortical neurons damaged by amyloid beta (Abeta)(25-35), and eleutheroside B was one of the active constituents. In this study, a comprehensive evaluation of constituents was conducted to explore active components from Siberian ginseng which can protect against neuritic atrophy induced by Abeta(25-35) in cultured rat cortical neurons. The ethyl acetate, n-butanol and water fractions from the methanol extract of Siberian ginseng showed protective effects against Abeta-induced neuritic atrophy. Twelve compounds were isolated from the active fractions and identified. Among them, eleutheroside B, eleutheroside E and isofraxidin showed obvious protective effects against Abeta(25-35)-induced atrophies of axons and dendrites at 1 and 10 MUM. PMID- 21301980 TI - Production of monoclonal antibodies against antitumor cyclohexapeptide RA-VII from Rubia cordifolia and their characterization. AB - An immunoassay system was established for the estimation of the quantity of an antitumor cyclic hexapeptide RA-VII (1) from Rubia cordifolia L. and R. akane Nakai (Rubiaceae). First, 1 was converted into its hapten, which was then conjugated with a carrier protein to be used as an effective antigen to obtain its monoclonal antibody (MAb). In the resulting conjugate, the molecular ratio between 1 and the carrier protein as assayed by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) was about 5:1. Then, the splenocytes from the mouse immunized with the conjugate were fused with mouse myeloma cells to produce hybridoma, secreting MAb against 1. Two clones were isolated, one producing MAb IgG(1) and the other IgM, both having a kappa light chain. The sensitivity and cross-reactivity of the thus obtained MAb were also assayed. PMID- 21301981 TI - A first-passage-time theory for search and capture of chromosomes by microtubules in mitosis. AB - The mitotic spindle is an important intermediate structure in eukaryotic cell division, in which each of a pair of duplicated chromosomes is attached through microtubules to centrosomal bodies located close to the two poles of the dividing cell. Several mechanisms are at work toward the formation of the spindle, one of which is the 'capture' of chromosome pairs, held together by kinetochores, by randomly searching microtubules. Although the entire cell cycle can be up to 24 hours long, the mitotic phase typically takes only less than an hour. How does the cell keep the duration of mitosis within this limit? Previous theoretical studies have suggested that the chromosome search and capture is optimized by tuning the microtubule dynamic parameters to minimize the search time. In this paper, we examine this conjecture. We compute the mean search time for a single target by microtubules from a single nucleating site, using a systematic and rigorous theoretical approach, for arbitrary kinetic parameters. The result is extended to multiple targets and nucleating sites by physical arguments. Estimates of mitotic time scales are then obtained for different cells using experimental data. In yeast and mammalian cells, the observed changes in microtubule kinetics between interphase and mitosis are beneficial in reducing the search time. In Xenopus extracts, by contrast, the opposite effect is observed, in agreement with the current understanding that large cells use additional mechanisms to regulate the duration of the mitotic phase. PMID- 21301982 TI - From McCulloch-Pitts neurons toward biology. PMID- 21301983 TI - The impact of contraceptive counseling in primary care on contraceptive use. AB - BACKGROUND: Whether contraceptive counseling improves contraceptive use is unknown. OBJECTIVE: To evaluate the association between contraceptive counseling provided by primary care physicians and patients' contraceptive use. DESIGN/PARTICIPANTS: All women aged 18-50 who visited one of four primary care clinics between October 2008 and April 2010 were invited to complete surveys about their visit. Seven to 30 days post visit, participants completed a survey assessing pregnancy intentions, receipt of contraceptive counseling, and use of contraception at last sexual intercourse. Survey data were linked to medical record data regarding contraceptive prescriptions prior to and during the clinic visit. Women were classified as in need of contraceptive counseling if they were sexually active, were not pregnant or trying to get pregnant, and had no evidence of contraceptive use prior to their index clinic visit. KEY RESULTS: Fifty percent (n = 386) of women were in need of contraceptive counseling at the time of their visit. Those who received contraceptive counseling from a primary care provider were more likely to report use of hormonal contraception when they last had sex (unadjusted OR: 3.83, CI: 2.25-6.52), even after adjusting for age, race, education, income, marital status, pregnancy intentions, and prior pregnancy (adjusted OR: 2.68, CI: 1.48-4.87). Counseling regarding specific types of contraception was associated with an increased use of those methods. For example, counseling regarding hormonal contraceptives was associated with a greater likelihood of use of hormonal methods (adjusted OR: 4.78, CI: 2.51-9.12) and counseling regarding highly effective reversible methods was highly associated with use of those methods (adjusted OR: 18.45, CI: 4.88-69.84). These same relationships were observed for women with prior evidence of contraceptive use. CONCLUSIONS: Contraceptive counseling in primary care settings is associated with increased hormonal contraceptive use at last intercourse. Increasing provision of contraceptive counseling in primary care may reduce unintended pregnancy. PMID- 21301984 TI - A middle-aged woman with sudden onset dyspnea. PMID- 21301985 TI - Conducting high-value secondary dataset analysis: an introductory guide and resources. AB - Secondary analyses of large datasets provide a mechanism for researchers to address high impact questions that would otherwise be prohibitively expensive and time-consuming to study. This paper presents a guide to assist investigators interested in conducting secondary data analysis, including advice on the process of successful secondary data analysis as well as a brief summary of high-value datasets and online resources for researchers, including the SGIM dataset compendium ( www.sgim.org/go/datasets ). The same basic research principles that apply to primary data analysis apply to secondary data analysis, including the development of a clear and clinically relevant research question, study sample, appropriate measures, and a thoughtful analytic approach. A real-world case description illustrates key steps: (1) define your research topic and question; (2) select a dataset; (3) get to know your dataset; and (4) structure your analysis and presentation of findings in a way that is clinically meaningful. Secondary dataset analysis is a well-established methodology. Secondary analysis is particularly valuable for junior investigators, who have limited time and resources to demonstrate expertise and productivity. PMID- 21301986 TI - Resection of colorectal liver metastases. AB - INTRODUCTION: The gold-standard treatment for colorectal liver metastases (CLM) is liver resection. Advances in staging, surgical technique, perioperative care and systemic chemotherapy have contributed to steady improvement in oncologic outcomes for patients following surgery in this subset of patients with stage IV colorectal cancer. The limits of resection continue to expand to include patients with more, larger and bilateral CLM, yet outcomes continue to improve with 5-year overall survival exceeding 50% following resection. Chemotherapy is an important element of treatment for patients with CLM, and chemotherapy can be combined safely with surgery to improve outcomes further. METHODS: Tailored approaches to patients include major (anatomic) resection, minor (wedge) resection, liver volumetry, and preoperative enhancement of the volume and function of the planned future remnant liver using portal vein embolization. RESULTS: Assessment of response to chemotherapy, analysis of liver remnant volume changes following portal vein embolization, and consideration of the surgical recovery following multistage surgical resection of bilateral CLM enable remarkable survival even among properly selected patients with extensive disease. CONCLUSIONS: Until laboratory, pathologic, biologic, or genetic studies can define which patients will benefit most from surgical and other treatments, careful application of proven diagnostic and therapeutic approaches to patients with advanced disease will continue to allow surgeons to direct tailored, patient-centered treatment as part of a multidisciplinary team. PMID- 21301987 TI - Synergistic or antagonistic effect of MTE plus TF or icariin from Epimedium koreanum on the proliferation and differentiation of primary osteoblasts in vitro. AB - 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide test and alkaline phosphatase activity assay were employed to assess the effects of mixed trace elements including Zn(2+), Ca(2+), and Mn(2+) plus total flavonoids or icariin from Epimedium koreanum on the proliferation and differentiation of primary osteoblasts in vitro. The results indicated that icariin (0.1, 1, and 10 MUmol/L) and total flavonoids (0.06, 0.6, and 6 MUg/mL) inhibited the proliferation and promoted the differentiation of primary osteoblasts. Mixed trace elements including Zn(2+), Ca(2+), and Mn(2+) (0.1, 1, and 10 MUmol/L) inhibited the proliferation and promoted the differentiation at 0.1 and 1 MUmol/L, but inhibited the differentiation at 10 MUmol/L. The effects of mixed trace elements including Zn(2+), Ca(2+), and Mn(2+) plus total flavonoids or icariin from E. koreanum on the proliferation and differentiation of primary osteoblasts in vitro are complicated, and both synergistic and antagonistic effects are generated. The results suggest that there may be a potential cooperative action between flavonoids and trace metal elements on the proliferation and differentiation of primary osteoblasts by forming metal complexes. The combination model between flavonoids and trace metal elements is a pivotal factor for switching the biological effects from toxicity to activity, from damage to protection. PMID- 21301988 TI - Determination of trace elements in anti-influenza virus mushrooms. AB - We have determined the trace element composition of anti-influenza virus mushrooms using atomic absorption spectrophotometer. The elements present in greater concentration in Ganoderma lucidum samples are selenium, iron, and zinc, with selenium being the element with the highest concentration of all, at 416 +/- 38.5 mg/kg; in Cordyceps militaris samples are iron, selenium, and zinc, with iron being the element with the highest concentration of all, at 291 +/- 20.9 mg/kg; in Kuehneromyces mutabilis samples are selenium, iron, and manganese, with selenium being the element with the highest concentration of all, at 203 +/- 9.8 mg/kg; in Inonotus hispidus samples are zinc, selenium, and iron, with zinc being the element with the highest concentration of all, at 194 +/- 16.9mg/kg; in the Collybia maculata samples are iron, selenium, and zinc, with iron being the element with the highest concentration of all, at 274 +/- 22.2 mg/kg, respectively. The average metal concentrations in mushrooms decreases in the order: selenium > iron > zinc > chromium > manganese > copper > magnesium > lead. After the mice were administered (orally) with mushroom extracts for 8 weeks and inoculated intranasally with viral suspension, element levels in serum were also measured. Highly significantly increased values of Se, Zn, and Mg in the serum of mice supplemented with anti-influenza virus mushrooms were a characteristic finding. Se, Zn, and Mg present in mushrooms may play a direct or indirect role in their anti-influenza virus nature. They may provide prophylactic protection against influenza infection via stimulation of host innate immune response. PMID- 21301989 TI - Comparative metal distribution in scalp hair of Pakistani and Irish referents and hypertensive patients. AB - The abnormal metabolism of metal ions plays an important role in health and disease conditions, and studies about them have been attracting significant interest. The aim of our study was to assess the heavy metals (cadmium (Cd), nickel (Ni), lead (Pb), and zinc (Zn)) in scalp hair samples of 50 Irish and 78 Pakistani hypertensive patients of an urban population together with 50 Irish and 96 Pakistani non-hypertensive male subjects in the age group of 30-50 years. The concentrations of trace and toxic elements were measured by inductively coupled plasma-atomic emission spectrophotometer and atomic absorption spectrophotometer before microwave-assisted acid digestion. The validity and accuracy of the methodology were checked using certified reference materials, and by the conventional wet acid digestion method on the same certified reference materials and on real samples. The recovery of all the studied elements was found to be in the range of 97.5-99.7% in certified reference material. The results of this study showed that the mean values of cadmium, nickel, and lead were significantly higher in scalp hair samples of both Pakistani and Irish hypertensive patients than in referents (p < 0.001); whereas, the concentration of zinc was lower in the scalp hair samples of hypertensive patients of both genders. The deficiency of zinc and the high exposure of trace and toxic metals may be the risk factors associated with hypertension. PMID- 21301990 TI - Short-term evaluation of the impact of a food program on the micronutrient nutritional status of Argentinean children under the age of six. AB - This study was undertaken to evaluate the impact of Plan Mas Vida (PMV) on the micronutrient nutritional condition of children aged 1 to 6 years 1 year after PMV implementation. The food program was intended for low-income families from the province of Buenos Aires, Argentina and provided supplementary diets. A prospective, nonexperimental study was carried out. Children (472 at baseline and 474 after 1 year) were divided into two groups (1-2 and 2-6 years of age). Biochemical tests (hemogram, ferritin, zinc, vitamin A, and folic acid), anthropometric assessments (weight and height), and dietary surveys (24-h recall) were performed. Chronic growth retardation (-2 height/age Z-score) was present in 2.8% and 8.7% of 1-2- and 2-6-year-old children, respectively; 14.4% in the former and 8.8% in the latter group had overweight/obesity. No significant changes were recorded 1 year after PMV implementation. Whereas anemia values decreased (55.3% to 39.1%, p = 0.003) and serum zinc values increased in 1-2-year old children, the risk for vitamin A deficiency decreased significantly in both age groups. The evaluation of the early impact of PMV actions provided important nutritional data that should be used by provincial health authorities to conduct future evaluations. PMID- 21301991 TI - Impairment of erythrocytes incubated in glucose medium: a wavelet-information theory analysis. AB - This study investigates the effects produced by an increased concentration of glucose in a suspending medium on the erythrocytes Information Theory quantifiers. Erythrocytes, which were obtained from eight healthy volunteers, were washed and incubated in vitro with glucose solutions at different concentrations. The measured Wavelet-based Information Theory quantifiers include the Relative Wavelet Energy (RWE), the Normalized Total Wavelet Shannon Entropy (NTWS), MPR-Statistical Complexity Measure (SCM) and entropy-complexity plane. The results show that the increase in glucose concentration does not produce significant changes on the RWE, while significant ones on the NTSE, which combined with SCM values allow to identify different behaviour for all the different populations in the entropy-complexity plane. Modification in the hemorheological properties of cells could be clearly detected with these Wavelet based Information Theory quantifiers. PMID- 21301992 TI - Genetic polymorphisms of glutathione S-transferases are associated with ulcerative colitis in central China. AB - The present study aimed to investigate the association between genetic polymorphisms of glutathione S-transferases (GSTs) and susceptibility to ulcerative colitis (UC) in central China. The prevalence of GSTM1, GSTT1, and GSTP1 gene polymorphisms were examined using polymerase chain reaction methods in 270 consecutive UC patients and 623 age- and sex-matched healthy controls. The frequencies of the GSTM1(null) and GSTT1(null) as well as GSTP1 (Val/Val) genotypes were significantly higher in UC patients than in the controls (70.74% vs. 41.74%, P = 0.0001; 64.82% vs. 47.19%, P = 0.0001; and 48.89% vs. 34.35%, P = 0.0004, respectively). When the UC patients were stratified according to clinical features, we found that the frequencies of the GSTT1(null) and GSTP1 (Val/Val) genotypes but not the GSTM1(null) genotype were significantly higher in patients with distal colitis than in extensive colitis (P = 0.0007, P = 0.001, and P = 0.271, respectively). However, these variant GST genotypes were not significantly linked to severity of the disease (P > 0.05). GST variant genotypes are strongly correlated with prevalence and extent but not with severity of UC in the Hubei Han population in central China. PMID- 21301994 TI - Emergent, controlled lumbar drainage for intracranial pressure monitoring during orthotopic liver transplantation. AB - BACKGROUND: Measurement of intracranial pressure (ICP) is recommended in comatose acute liver failure (ALF) patients due to risk of rapid global cerebral edema. External ventricular drains (EVD) can be placed to drain cerebrospinal fluid and monitor ICP simultaneously although this remains controversial in the neurosurgical community given the risk of hemorrhagic complications. We describe a patient with ALF and global cerebral edema whose EVD failed immediately before orthotopic liver transplantation (OLT) in which a lumbar drain (LD) was used temporarily to monitor ICP. METHODS: We describe a 36 year old patient with ALF and brain edema from acetaminophen overdose who had an EVD placed for ICP monitoring and management. The EVD failed repeatedly (i.e., lost CSF drainage and ICP waveform) despite several saline irrigations and three doses intraventricular tissue plasminogen activator (1 mg) in the hours that immediately preceded her planned emergency OLT. An LD was placed emergently and controlled cerebrospinal fluid (CSF) drainage and ICP measurement was performed by setting the LD at 20 mmHg and leveling at the ear level (foramen of Monro). The LD was removed once the EVD flow was re-established post-OLT. RESULTS: The EVD and LD ICP measurements were reported to be the same just prior to removing the LD. CONCLUSIONS: Controlled CSF drainage using a lumbar drain can be used to monitor ICP when leveled at the foramen of Monro if EVD failure occurs perioperatively. The LD can temporarily guide ICP management until the EVD flow can be re established after OLT. PMID- 21301993 TI - A novel PrP partner HS-1 associated protein X-1 (HAX-1) protected the cultured cells against the challenge of H2O2. AB - Prion protein (PrP) is a ubiquitous conserved glycoprotein predominantly expressed in neurons of the central nervous system (CNS). To elucidate on its cellular function, we performed a yeast two-hybrid screen within an adult human brain cDNA library for potential PrP-binding molecules. A novel protein, HS-1 associated protein X-1 (HAX-1), was identified to be able to bind with PrP strongly. The interaction between the two proteins has been further verified by glutathione-S-transferase (GST) pull-down and immunoprecipitation assays. The minimal binding regions were mapped to the segments of residues aa 91-163 for PrP(C) and residues aa 38-129 for HAX-1. Immunofluorescent assays of co expressions of human PrP and HAX-1 in 293T and SHSY-5Y cells revealed marked co localizations of those two proteins in cytoplasm. Moreover, the co-expression of HAX-1 and wild-type PrP (PG5) was found to enhance the cellular resistance to the challenge of H2O2. Contrarily, co-transfection of HAX-1 did not reverse but aggravated the cytotoxicities of the genetic CJD (gCJD) associated PrP mutants with nine- (PG9) and fourteen-octarepeats (PG14). Our data provide for the first time a new PrP-interacting partner that may play role in cell oxidative stress and anti-apoptosis physiologically and cell damage pathologically. PMID- 21301995 TI - Necrotizing granulomatous hypophysitis presenting as a sellar mass. AB - We report the case of a 45-year-old Colombian female with a 3-month history of headache, anorexia, fatigue, and diplopia in addition to left facial nerve palsy 2 weeks prior to presentation. On examination, visual fields and fundi were normal, but left abducens and facial nerve palsies were noted. An MRI scan disclosed a sellar mass with suprasellar but neither parasellar nor retrosellar extension. The mass was interpreted as a pituitary tumor and resected via the transsphenoidal approach. Histologic examination revealed necrotizing granulomas in a background of normal pituitary gland tissue. The differential diagnosis includes tuberculosis, sarcoidosis, fungal infection, syphilis, granulomatous autoimmune hypophysitis, Langerhans cell histiocytosis, and Erdheim-Chester disease. Staining for tubercle bacilli (acid fast and fite) as well as for fungi (GMS) was negative and PCR for mycobacteria showed the same result. Postoperative empiric treatment with antituberculous medication resulted in resolution of the cranial nerve palsies within a 1 month. The diagnosis of inflammatory/infectious granulomatous hypophysitis can be difficult to diagnose preoperatively and occasionally even postoperatively. A high index of suspicion should be maintained especially in those patients with a history of a systemic granulomatous disease or in regions endemic in granulomatous infectious diseases. PMID- 21301996 TI - Metastatic desmoplastic small round cell tumor controlled by an anthracycline based regimen: review of the role of chemotherapy. AB - Desmoplastic small round cell tumors (DSRCT) are rare and aggressive malignant neoplasms that usually occur in young males. They usually present intraabdominally with widespread peritoneal involvement at diagnosis and are sometimes associated with lymphadenopathies and liver metastases. Intraabdominal DSRCT is usually disseminated; no curative outcome has yet been achieved. We report a case of metastatic intraabdominal DSRCT controlled by an anthracycline based regimen. A literature review of the treatment options, mainly chemotherapy, available for this unusual neoplasm, will be discussed. In patients with unresectable or metastatic disease, symptom control is most important because treatment modalities minimally impact survival. Palliative chemotherapy (mainly monotherapy) is preferable. PMID- 21301997 TI - Tracking the source of quantitative knowledge in neuroscience: a neuroinformatics role for computational models. PMID- 21301999 TI - Genetic variations in transcription factor 7-like 2 (TCF7L2) gene: association of TCF7L2 rs12255372(G/T) or rs7903146(C/T) with breast cancer risk and clinico pathological parameters. AB - The purpose of the present study was to evaluate the association between TCF7L2 rs12255372(G/T) or rs7903146(C/T) polymorphism and breast cancer risk, and clinico-pathologic characteristics of the patients. Genotyping of these polymorphisms was performed on 387 breast cancer patients and 252 normal and healthy women who had no history of any malignancy using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in a hospital based Malaysian population. The allele (P = 0.033) frequency of rs7903146 (T) polymorphism was significantly higher in the cancer patients than normal individuals. No significant association was demonstrated between CT (OR(adj) = 1.386; 95% CI, 0.985-1.949) or TT (OR(adj) = 1.579; 95% CI, 0.869-2.870) genotype and breast cancer risk. However, women who were carriers of T allele (OR(adj) = 1.316; 95% CI, 1.022-1.695) or T allele genotype (OR(adj) = 1.419; 95% CI, 1.027 1.960) showed significant increased risk of breast cancer. Women who were GT heterozygotes (OR(adj) = 1.329; 95% CI, 0.948-1.862) or TT homozygotes (OR(adj) = 1.574; 95% CI, 0.829-2.987), and carriers of T allele genotype (OR(adj) = 1.365; 95% CI, 0.989-1.883) or T allele (OR(adj) = 1.284; 95% CI, 0.995-1.657) were not associated with breast cancer risk. The rs7903146(T) allele genotype was significantly associated with nodal involvement (P = 0.003) but rs12255372 (T) allele genotype was not associated with the clinico-pathologic characteristics. In conclusion, our findings suggest that rs7903146 (T) variant may elevate the risk of breast cancer, thus could be a potential candidate for breast cancer susceptibility. The variant may also increase the metastatic potential of the tumor. PMID- 21301998 TI - Metformin and cancer: new applications for an old drug. AB - Metformin, one of most widely prescribed oral hypoglycemic agents, has recently received increased attention because of its potential antitumorigenic effects that are thought to be independent of its hypoglycemic effects. Several potential mechanisms have been suggested for the ability of metformin to suppress cancer growth in vitro and vivo: (1) activation of LKB1/AMPK pathway, (2) induction of cell cycle arrest and/or apoptosis, (3) inhibition of protein synthesis, (4) reduction in circulating insulin levels, (5) inhibition of the unfolded protein response (UPR), (6) activation of the immune system, and (7) eradication of cancer stem cells. There is also a growing number of evidence, mostly in the form of retrospective clinical studies that suggest that metformin may be associated with a decreased risk of developing cancer and with a better response to chemotherapy. There are currently several ongoing randomized clinical trials that incorporate metformin as an adjuvant to classic chemotherapy and aim to evaluate its potential benefits in this setting. This review highlights basic aspects of the molecular biology of metformin and summarizes new advances in basic science as well as intriguing results from recent clinical studies. PMID- 21302000 TI - Prognostic significance of kappaB-Ras1 expression in gliomas. AB - Nuclear factor (NF)-kappa-B is a pleiotropic transcriptional regulator that plays important roles in cell differentiation, growth, tumorigenesis, and apoptosis. Constitutive NF-kappa-B is overexpressed and activated in various tumors, including gliomas. Here, we investigated the expression of NF-kappa-B inhibitor interacting ras-like protein 1 (kappaB-Ras1), which is one of the most important negative modulators of NF-kappa-B, and a well-known proliferation biomarker survivin protein. We performed immunohistochemistry and western blot analysis on 154 glioma specimens and 3 non-neoplastic brain parenchyma specimens. Immunohistochemistry showed a strong-to-weak range of kappaB-Ras1 staining with increasing pathologic grade of glioma (P = 0.000). Immunoreactivity scores of kappaB-Ras1 were 8.15 +/- 0.72 in non-neoplastic brain parenchyma, 5.00 +/- 0.29 in low-grade gliomas, 3.89 +/- 0.30 in anaplasia astrocytomas, and 2.78 +/- 0.25 in glioblastomas. In contrast, the immunoreactivity of survivin increased with pathological grade in gliomas. The immunohistochemical data were in line with the results from western blot analysis. Moreover, a non-parametric analysis revealed that the attenuated kappaB-Ras1 expression was correlated with elevated survivin expression, large tumor diameter, frequent intra-tumor necrosis, and worse overall survival. These results indicated that kappaB-Ras1 was down-regulated in gliomas compared to non-neoplastic brain parenchyma, and the expression was even lower in glioblastomas. In addition, multivariate analysis showed that kappaB Ras1 expression and intra-tumor necrosis were two important prognostic factors identified by the Cox proportional hazards model. Taken together, our study suggests that glioma patients with lower kappaB-Ras1 expression have a worse prognosis, which is partly due to NF-kappa-B pathway-mediated aberrant proliferation of tumor cells. PMID- 21302001 TI - Comparison of overall survival between the early use and delayed use of Trastuzumab therapy groups: a retrospective analysis of 128 patients with HER-2 positive advanced breast cancer. AB - Trastuzumab has been the standard treatment in first-line treatment of HER-2 positive advanced breast cancer (H2ABC). This study explored whether the delayed and repeated use of trastuzumab could influence overall survival (OS). A total of 128 patients with H2ABC who had received at least one line of trastuzumab-based regimens were included. The primary endpoint was OS defined as from the date of first diagnosis of H2ABC to death. The median OS of initiating trastuzumab in first-line group (n = 56), in the second-line group (n = 32), and the third- or more-line group (n = 40) was 40.6 m, 39.5 m, and 38 m, respectively (P = 0.867). For patients who had received over one line of trastuzumab (n = 46), the median OS was 44 m, and for those receiving only one line (n = 67), it was 27.6 m (P = 0.059). The delayed use of trastuzumab has no negative effect on the OS of patients with H2ABC. There is a trend of improved OS over the repeated use of trastuzumab. PMID- 21302002 TI - True 'mirror image' lesions due to self-inflicted injury. PMID- 21302003 TI - Update on HDL receptors and cellular cholesterol transport. AB - Efflux is central to maintenance of tissue and whole body cholesterol homeostasis. The discovery of cell surface receptors that bind high-density lipoprotein (HDL) with high specificity and affinity to promote cholesterol release has significantly advanced our understanding of cholesterol efflux. We now know that 1) cells have several mechanisms to promote cholesterol release, including a passive mechanism that depends on the physico-chemical properties of cholesterol molecules and their interactions with phospholipids; 2) a variety of HDL particles can interact with receptors to promote cholesterol transport from tissues to the liver for excretion; and 3) interactions between HDL and receptors show functional synergy. Therefore, efflux efficiency depends both on the arrays of receptors on tissue cells and HDL particles in serum. PMID- 21302004 TI - The watery eye. AB - The surface of the eye needs to be wet constantly to ensure its integrity in maintaining ocular comfort, clear vision, and ocular health. This article presents new findings in the tear dynamics of the human eye, with an emphasis on the tear meniscus and tear film through the day and in response to punctual occlusion and wearing of contact lenses. Recent advances in imaging technique are briefly discussed. PMID- 21302005 TI - Advances in the surgical management of chronic sinusitis and nasal polyps. AB - Current research has only reinforced the belief that chronic rhinosinusitis is a multifactorial and idiosyncratic disease process. Most basic science research on the topic focuses on delineating the many proposed contributing factors and attempting to establish therapeutic targets. In patients whose symptoms do not respond to medical therapy, endoscopic sinus surgery may be offered. Several surgical techniques have been proposed, and it would appear that certain techniques are ideal for certain situations. Recent clinical research has focused on the introduction of new technology and new techniques. Additionally, investigators have looked for ways to optimize current techniques and to determine which patient populations may expect to benefit from which types of interventions. PMID- 21302006 TI - The Role of IgE Production in the Pathophysiology of Rhinitis and Rhinosinusitis. AB - A multitude of potential etiologies exist for rhinitis and rhinosinusitis. These sinonasal disorders are heterogeneous entities that are best understood by evaluating the causative factors in each individual patient. More precise diagnosis permits accurate and effective treatment. The association of allergy with sinonasal symptoms has been described for decades; however, the specific relationship between allergy, rhinitis, and rhinosinusitis is complex. Considering allergy in terms of a systemic atopic disorder, along with a local inflammatory process mediated by IgE production in sinonasal tissues, is helpful in unveiling the complex connection between allergy, rhinitis, and rhinosinusitis. This article reviews recent literature regarding local IgE and sinonasal inflammatory conditions. PMID- 21302008 TI - Need for standardization in defining parameters and success in clinical trials involving surgical treatment of urinary lithiasis. PMID- 21302007 TI - Mechanisms of IgE Inflammation. AB - The prevalence of diseases such as allergic asthma and rhinitis continues to increase in the United States, affecting millions of people. It is well established that allergy contributes to the pathogenesis of most asthma, especially in children and young adults. Despite current therapy (eg, inhaled corticosteroids, anti-leukotrienes, and bronchodilators), patients with moderate to severe asthma remain symptomatic and experience frequent exacerbations of disease requiring oral corticosteroids, emergency department treatments, and hospitalizations. Allergic diseases are traditionally referred to as immediate or type 1 hypersensitivity reactions, with IgE as a critical factor. IgE is involved in allergic inflammation, especially in early-phase response, but it may also be involved in the late-phase allergic response. A direct correlation between serum IgE levels and asthma exists. As logarithm IgE values increase, asthma prevalence increases linearly, even in patients who are categorized as having nonallergic asthma. In addition, there is a significant, although low association in allergic rhinitis with IgE levels and positive skin test reactivity to pollens. Recent advances in our understanding of the role of IgE in allergic inflammation have led to the development of a monoclonal antibody to IgE that reduces IgE levels, thereby reducing allergic inflammation. This review aims to provide an overview of the basic science of the IgE molecule and the clinical efficacy of anti-IgE therapy in allergic and asthmatic diseases. PMID- 21302009 TI - Prolonged intragastric drug delivery mediated by Eudragit(r) E-carrageenan polyelectrolyte matrix tablets. AB - Interpolyelectrolyte (IPE) complexation between carrageenan (CG) and Eudragit E (EE) was studied in 0.1 M HCl and was used to develop floating matrix tablets aimed to prolong gastric-residence time and sustain delivery of the loaded drug. The optimum EE/CG IPE complexation weight ratio (0.6) was determined in 0.1 M HCl using apparent viscosity measurements. The IPE complex was characterized by Fourier transform infrared spectroscopy and differential scanning calorimetry. Metronidazole matrix tablets were prepared by direct compression using EE, CG, or hybrid EE/CG with ratio optimal for IPE complexation. Corresponding effervescent tablets were prepared by including Na bicarbonate as an effervescent agent. Tablets were evaluated for in vitro buoyancy and drug release in 0.1 M HCl. Both CG and EE-CG effervescent matrices (1:2 drug to polymer weight ratio, 60 mg Na bicarbonate) achieved fast and prolonged floating with floating lag times less than 30 s and floating duration of more than 10 h. The corresponding EE effervescent matrices showed delayed floating and rapid drug release, and completely dissolved after 3 h of dissolution. CG matrices showed an initial burst drug release (48.3+/-5.0% at 1 h) followed by slow drug release over 8 h. EE-CG matrices exhibited sustained drug release in almost zero-order manner for 10 h (68.2+/-6.6%). The dissolution data of these matrices were fitted to different dissolution models. It was found that drug release followed zero-order kinetics and was controlled by the superposition of the diffusion and erosion. PMID- 21302010 TI - Prediction-corrected visual predictive checks for diagnosing nonlinear mixed effects models. AB - Informative diagnostic tools are vital to the development of useful mixed-effects models. The Visual Predictive Check (VPC) is a popular tool for evaluating the performance of population PK and PKPD models. Ideally, a VPC will diagnose both the fixed and random effects in a mixed-effects model. In many cases, this can be done by comparing different percentiles of the observed data to percentiles of simulated data, generally grouped together within bins of an independent variable. However, the diagnostic value of a VPC can be hampered by binning across a large variability in dose and/or influential covariates. VPCs can also be misleading if applied to data following adaptive designs such as dose adjustments. The prediction-corrected VPC (pcVPC) offers a solution to these problems while retaining the visual interpretation of the traditional VPC. In a pcVPC, the variability coming from binning across independent variables is removed by normalizing the observed and simulated dependent variable based on the typical population prediction for the median independent variable in the bin. The principal benefit with the pcVPC has been explored by application to both simulated and real examples of PK and PKPD models. The investigated examples demonstrate that pcVPCs have an enhanced ability to diagnose model misspecification especially with respect to random effects models in a range of situations. The pcVPC was in contrast to traditional VPCs shown to be readily applicable to data from studies with a priori and/or a posteriori dose adaptations. PMID- 21302011 TI - G-quadruplexes-novel mediators of gene function. AB - Since the famous double-helix model was proposed, chromosomal DNA has been regarded as a rigid molecule containing the genetic information of an organism. It is clear now that DNA can adopt many transient, complex structures that can perform different biological functions. The G4 DNA (also called DNA G-quadruplex or G-tetraplex), a four-stranded DNA structure composed of stacked G-tetrads (guanine tetrads), has attracted much attention during the past two decades due to its ability to adopt a variety of structures and its possible biological functions. This review gives a glimpse on the structural diversity and biophysical properties of these fascinating DNA structures. Common methods that are widely used in investigating biophysical properties and biological functions of G4 DNA are described briefly. Next, bioinformatics studies that indicate evidence of evolutionary selection and potential functions of G4 DNA are discussed. Finally, examples of various biological functions of different G4 DNA are given, and potential roles of G4 DNA in respect of cardiovascular science are discussed. PMID- 21302013 TI - Subvalvular hypertrophic calcification of the mitral annulus: [(18)F]FDG-PET-CT, MRI, and echocardiography findings. PMID- 21302014 TI - Myocardial perfusion imaging analysis in patients with regurgitant valvular heart disease. AB - BACKGROUND/AIM: We noticed that there was decreased correlation of the findings from myocardial perfusion imaging (MPI) and cardiac catheterization (CATH) in patients with mitral regurgitation (MR) and aortic regurgitation (AR) compared to patients without valve disease. METHODS: Through a systematic review of MPI records at the Harry S. Truman Memorial Veterans' Hospital between 1998 and 2008, we identified 58 patients with at least moderate MR or AR by echocardiogram who underwent cardiac catheterization within 6 months of the MPI study. A control group was formulated with 60 patients who did not have significant MR or AR on echocardiogram and who had both MPI and CATH. Correlation between MPI and CATH was graded as complete, partial, or absent. RESULTS: Correlation between MPI and CATH was lower in the valve disease patients (study group) when compared to controls. Correlation was complete in 76% of study patients and 90% of controls, partial in 15% of study patients and 5% of controls, and absent in 9% of study patients and 5% of controls. Differences between the groups were significant (P < .05). CONCLUSIONS: Patients with regurgitant valvular heart disease may have myocardial perfusion abnormalities that are not associated with angiographic critical coronary stenosis. PMID- 21302015 TI - The relationships between self-rated health and serum lipids across time. AB - BACKGROUND AND PURPOSE: We studied the hypothesized effects of changes in self rated health (SRH) on subsequently assessed changes in the levels of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, and triglycerides (TRI), separately for men and women. We also investigated the reverse causation hypothesis, expecting the initial changes in the levels of serum lipids to predict subsequently assessed changes in SRH levels. METHODS: We used a longitudinal design and controlled for possible confounders known to be precursors of both SRH and the above three serum lipids. Participants were apparently healthy men (N = 846) and women (N = 378) who underwent a routine health check at three points of time (T1, T2, and T3); T1 and T3 were on the average 40 and 44 months apart for the men and women, respectively. RESULTS AND CONCLUSIONS: For the men, relative to T1 SRH, an increase in T2 SRH was associated with an increase in the T3 HDL-C levels relative to T2 HDL-C and with a decrease in the T3 TRI levels relative to T2 TRI. For the women, initial changes in the SRH levels did not predict follow-up changes in either of the lipids. For both genders, the reverse causation hypothesis, expecting the T1-T2 change in each of the serum lipids to predict T2-T3 change in SRH, was not supported. For the men, there is support for the hypothesis that the effects of SRH on morbidity and mortality, found by past meta-analytic studies, could be mediated by serum lipids. PMID- 21302016 TI - A prehospital acute coronary syndrome in a cocaine user: an unstable clinical situation. AB - Chest pain is a common reason why cocaine-addicted patients call the emergency department, and acute coronary syndromes are difficult to diagnose in these situations. A 30-year-old cocaine-user patient contacts the Emergency Medical Assistance Service with constrictive chest pain. A doctor is sent out to the patient at home. The initial ECG is normal. No other aetiology of chest pain is revealed, except nicotine and cocaine addictions. First, a coronary artery spasm is suggested, caused by the injection of cocaine. During the journey, the patient indicates that the chest pain has returned. A 12-lead ECG shows repolarisation abnormality in the form of a subepicardial ischaemia. Fibrinolysis is not prescribed in view of the patient's history and of the proximity of the interventional cardiology team. The coronary angiogram enables the diagnosis of myocardial bridging in the middle anterior interventricular artery, and no significant lesion of the coronary arteries is noted. A particular feature of prehospital management in France is that medical care can be given in the early stages by a physician who is called by the patient. This case report discusses the specific care requirements of which the emergency physician needs to be aware in the context of this unstable clinical situation due to the urgency associated with the difficulties of ECG diagnosis of ST-segment elevation in cocaine users. PMID- 21302017 TI - Mass psychogenic illness: psychological predisposition and iatrogenic pseudo vocal cord dysfunction and pseudo-reactive airways disease syndrome. AB - A multidisciplinary team assessed five patients who alleged chronic medically unexplained multiorgan system symptoms described by idiopathic environmental intolerance allegedly triggered by exposure to solvents used in membrane roofing repair work on an office building. The event precipitated an incident of mass psychogenic illness (MPI). Treating physicians diagnosed irritant-associated vocal cord dysfunction (IVCD) and reactive airways disease syndrome (RADS) resulting from exposure. The authors conducted medical, psychological, and industrial hygiene evaluations. Air monitoring data for total volatile organic compounds obtained during the 2-day exposure period, measurements of emissions during membrane roofing repair at a similar site, mathematical modeling of air contaminant concentrations, and injection of tracer gas into the incident building revealed exposure levels well below those doses anticipated to cause clinical symptoms. There was no objective medical evidence validating symptoms. Review of the medical records indicated that the video laryngoscopy data, pulmonary function tests, and medical examinations relied upon by the treating physicians were inconsistent with published criteria for IVCD and RADS. Psychological evaluation identified defensiveness and self-serving misrepresentations of exaggerated health concerns associated with somatization and malingering. Each case had personality traits associated with at least one personality disorder. Social histories identified premorbid life events and stressors associated with distress. This is the first study to assess psychological predisposition, social interaction among the plaintiffs, and iatrogenic reinforcement of beliefs by diagnoses of pseudo-disorders associated with patient misrepresentation of exaggerated health concerns in an incident of MPI. PMID- 21302019 TI - Detection of HPV by in situ hybridization in thin-layer (ThinPrep) cervicovaginal samples. AB - We have studied an automated in situ hybridization (ISH) method as a possible alternative approach for detecting high-risk human papillomavirus (HPV) in monolayer (ThinPrep) cervico-vaginal samples, comparing the results with those obtained by polymerase chain reaction (PCR) using consensus primers and studying the relationship between the ISH staining pattern and the viral integration in HPV 16-positive cases. Eighty atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) cases were used for our purposes. The patients were monitored through periodic cytologies. ISH with was performed with an automated Ventana System, analysis by PCR was performed with consensus primers and integration of HPV16 was performed by realtime PCR analyzing E2 and E6 genes. Additionally, 27 HSIL cases were also studied to observe the ISH staining patterns. HPV infection was detected by ISH in 21.7% of the ASCUS cases and 55.8% of the LSIL cases. Two distinct staining patterns were observed: multipunctated (MP) and diffuse (DI). In some cases, a mixed pattern (MP + DI) was observed and these cases were considered as MP. The MP pattern increased with the degree of lesion and seemed to have a prognostic value in ASCUS/LSIL cases. The lesion in MP pattern cases persisted throughout the entire study in 77% of cases, whereas in cases with a DI staining pattern, only 41% of them showed persistence of the lesion (p <0.001). No correlation was found between HPV integration and the ISH staining pattern. Given the lower sensitivity and negative predictive value of ISH and its incapacity to demonstrate the integration of high-risk HPV in ASCUS and LSIL cases using liquid based cytology, we do not recommend this technique for the triage of ASCUS and LSIL cases. PMID- 21302021 TI - Recovery of subsampled dimensions and configurations derived from napping data by MFA and MDS. AB - Napping is a multivariate sensory method in which participants physically place stimuli on a large sheet of paper and orient them so that the distance between pairs represents a measure of dissimilarity. The two-dimensional nature of the task may be a limitation to the ability of this and similar methodologies to recover information about complex stimuli. In the first investigation, eight simulated three-dimensional stimuli were created with two different levels for each attribute. Simulated napping experiments had groups of participants attend to two of the dimensions with different probabilities. Multiple factor analysis (an analytical multivariate statistical procedure that can be thought of as a principle components analysis on the individuals) and MDS-INDSCAL (a variation on multidimensional scaling that finds a common configuration through reducing a stress measure associated with lack of fit) recovered full dimensionality from these data, although MFA had trouble when attention was the most unbalanced. In the second experiment, a human napping experiment was designed using custom three dimensional stimuli: shapes with two levels each of size, color, and shape attributes. This experiment confirmed the results of Experiment 1, as both MDS INDSCAL and MFA analyses again recovered the full dimensionality of the stimuli. PMID- 21302022 TI - Bayesian inference for the information gain model. AB - One of the most popular paradigms to use for studying human reasoning involves the Wason card selection task. In this task, the participant is presented with four cards and a conditional rule (e.g., "If there is an A on one side of the card, there is always a 2 on the other side"). Participants are asked which cards should be turned to verify whether or not the rule holds. In this simple task, participants consistently provide answers that are incorrect according to formal logic. To account for these errors, several models have been proposed, one of the most prominent being the information gain model (Oaksford & Chater, Psychological Review, 101, 608-631, 1994). This model is based on the assumption that people independently select cards based on the expected information gain of turning a particular card. In this article, we present two estimation methods to fit the information gain model: a maximum likelihood procedure (programmed in R) and a bayesian procedure (programmed in WinBUGS). We compare the two procedures and illustrate the flexibility of the bayesian hierarchical procedure by applying it to data from a meta-analysis of the Wason task (Oaksford & Chater, Psychological Review, 101, 608-631, 1994). We also show that the goodness of fit of the information gain model can be assessed by inspecting the posterior predictives of the model. These bayesian procedures make it easy to apply the information gain model to empirical data. Supplemental materials may be downloaded along with this article from www.springerlink.com. PMID- 21302020 TI - New allele of HvBRI1 gene encoding brassinosteroid receptor in barley. AB - The aim of these studies was to characterize nucleotide substitutions leading to the phenotype of brassinosteroid-insensitive, semi-dwarf barley mutant 093AR. Two substitutions in the sequence of barley HvBRI1 gene, encoding leucine-rich repeats receptor kinase (LRR-RK), which participates in brassinosteroid (BR) signalling, were identified in this chemically-induced barley mutant of the cv. Aramir. The LRR-RK is a transmembrane protein phosphorylating downstream components. The identified substitutions CC>AA at positions 1760 and 1761 in the HvBRI1 gene of this mutant led to a missense mutation, causing the Thr-573 to Lys 573 replacement in the protein sequence. The threonine residue is situated in the distal part of a 70-amino acids island responsible for binding of BR molecules. As this residue is conserved among BRI1 protein homologs in Arabidopsis thaliana, Lycopersicon esculentum, Oryza sativa and Hordeum vulgare, it was postulated that this residue is crucial for the protein function. The genetic analyses indicated that the mutant 093AR was allelic to the spontaneous, semi-dwarf mutant uzu which carries A>G substitution at position 2612 of the HvBRI1 gene (GenBank acc. no. AB088206). A comparison of the genomic sequence of HvBRI1 in the mutants uzu, 093AR and in the cv. 'Aramir' confirmed the presence of the single-nucleotide A>G substitution at position 2612 in the sequence encoding kinase domain of HvBRI1 polypeptide in uzu, but not in 093AR mutant, indicating that a new allele of the HvBRI1 gene was identified. PMID- 21302023 TI - A data-driven algorithm for offline pupil signal preprocessing and eyeblink detection in low-speed eye-tracking protocols. AB - Event detection is the conversion of raw eye-tracking data into events--such as fixations, saccades, glissades, blinks, and so forth--that are relevant for researchers. In eye-tracking studies, event detection algorithms can have a serious impact on higher level analyses, although most studies do not accurately report their settings. We developed a data-driven eyeblink detection algorithm (Identification-Artifact Correction [I-AC]) for 50-Hz eye-tracking protocols. I AC works by first correcting blink-related artifacts within pupil diameter values and then estimating blink onset and offset. Artifact correction is achieved with data-driven thresholds, and more reliable pupil data are output. Blink parameters are defined according to previous studies on blink-related visual suppression. Blink detection performance was tested with experimental data by visually checking the actual correspondence between I-AC output and participants' eye images, recorded by the eyetracker simultaneously with gaze data. Results showed a 97% correct detection percentage. PMID- 21302024 TI - Large-scale latent semantic analysis. AB - Latent semantic analysis (LSA) is a statistical technique for representing word meaning that has been widely used for making semantic similarity judgments between words, sentences, and documents. In order to perform an LSA analysis, an LSA space is created in a two-stage procedure, involving the construction of a word frequency matrix and the dimensionality reduction of that matrix through singular value decomposition (SVD). This article presents LANSE, an SVD algorithm specifically designed for LSA, which allows extremely large matrices to be processed using off-the-shelf computer hardware. PMID- 21302025 TI - A tutorial on a practical Bayesian alternative to null-hypothesis significance testing. AB - Null-hypothesis significance testing remains the standard inferential tool in cognitive science despite its serious disadvantages. Primary among these is the fact that the resulting probability value does not tell the researcher what he or she usually wants to know: How probable is a hypothesis, given the obtained data? Inspired by developments presented by Wagenmakers (Psychonomic Bulletin & Review, 14, 779-804, 2007), I provide a tutorial on a Bayesian model selection approach that requires only a simple transformation of sum-of-squares values generated by the standard analysis of variance. This approach generates a graded level of evidence regarding which model (e.g., effect absent [null hypothesis] vs. effect present [alternative hypothesis]) is more strongly supported by the data. This method also obviates admonitions never to speak of accepting the null hypothesis. An Excel worksheet for computing the Bayesian analysis is provided as supplemental material. PMID- 21302027 TI - Son preference in Indian families: absolute versus relative wealth effects. AB - The desire for male children is prevalent in India, where son preference has been shown to affect fertility behavior and intrahousehold allocation of resources. Economic theory predicts less gender discrimination in wealthier households, but demographers and sociologists have argued that wealth can exacerbate bias in the Indian context. I argue that these apparently conflicting theories can be reconciled and simultaneously tested if one considers that they are based on two different notions of wealth: one related to resource constraints (absolute wealth), and the other to notions of local status (relative wealth). Using cross sectional data from the 1998-1999 and 2005-2006 National Family and Health Surveys, I construct measures of absolute and relative wealth by using principal components analysis. A series of statistical models of son preference is estimated by using multilevel methods. Results consistently show that higher absolute wealth is strongly associated with lower son preference, and the effect is 20%-40% stronger when the household's community-specific wealth score is included in the regression. Coefficients on relative wealth are positive and significant although lower in magnitude. Results are robust to using different samples, alternative groupings of households in local areas, different estimation methods, and alternative dependent variables. PMID- 21302026 TI - Marked relationship between matrix metalloproteinase 7 and brain atrophy in HIV infection. AB - Circulating levels of matrix metalloproteinases (MMP-1 and 7) have been found to correlate with the severity of brain injury in HIV-infected subjects. This study used high-resolution neuroanatomic imaging and automated segmentation algorithms to clarify this relationship. Both metalloproteinases were significantly correlated with increased cerebrospinal fluid volume fraction. Comprehensive brain volumetric analysis revealed a more marked relationship with atrophy for MMP-7, which was significantly correlated with neural injury in multiple brain regions and nearly all ventricular measurements. MMP-7 was also correlated with measures of virologic and cognitive status. PMID- 21302028 TI - Parametric mapping of immunohistochemically stained tissue sections; a method to quantify the colocalization of tumor markers. AB - BACKGROUND: Automated analysis of immunohistochemically stained tissue sections is of great importance in cancer research to detect tumor-specific prognostic markers and make therapy decisions. Here, an automated quantitative analysis is presented to assess the colocalization of CAIX, a membrane-bound hypoxic marker and Ki-67, a nuclear proliferation marker. METHODS: Tissue sections of 104 biopsies from 89 patients were stained for CAIX and Ki-67 with diaminobenzidine and haematoxylin counterstain. Image scans of whole tumor sections were recorded and image maps were created with parametric mapping to quantify the markers and assess the colocalization. RESULTS: The fraction of CAIX showed a range of 0-93%. The interobserver correlation and the correlation between manual scores and automated analysis were both very strong (rs=0.96, p<0.0001, and rs=0.97, p<0.0001). The labelling index of Ki-67 exhibited a range of 0-42% with less strong interobserver and manual to automated analysis correlations (rs=0.90, p<0.0001, and rs=0.71, p<0.0008). The relative tumor area positive for both markers varied from 0-76%. CONCLUSION: Parametric mapping of immunohistochemically stained tumor sections is a reliable method to quantitatively analyze membrane-bound proteins and assess the colocalization of various tumor markers in different subcellular compartments. PMID- 21302029 TI - Photosynthetic carbon acquisition in Sargassum henslowianum (Fucales, Phaeophyta), with special reference to the comparison between the vegetative and reproductive tissues. AB - The photosynthetic oxygen evolution characteristics were examined in both vegetative (blade) and sexual reproductive (receptacle) tissues of Sargassum henslowianum (Fucales, Phaeophyta) from the Shenao bay of Nanao Island, China, to establish the mechanism of photosynthetic acquisition of inorganic carbon (Ci) in this species. In natural seawater (pH 8.1, ca. 2.2 mM Ci), irradiance-saturated net photosynthetic rate (NPR) was greater by 25.3% in blade than receptacle, whereas dark respiratory rate (DR) was 2-fold higher in receptacle than blade. NPR at pH 8.1 was nearly saturated with the 2.2 mM Ci for both blade and receptacle. However, the values of the half-saturation constant for Ci were sharply increased at pH 9.0. NPR was significantly affected, but DR was remained unchanged, with the variation of the pH values in seawater. The data from the final pH value derived from the pH-drift experiments and the comparison between the measured and theoretically estimated photosynthetic rates suggested that both blade and receptacle were capable of acquiring HCO(3)(-) in seawater. The inhibitors experiments showed that a HCO(3)(-) dehydration mechanism mediated by external carbonic anhydrase activity occurred in both the blade and receptacle tissues of S. henslowianum. The proton buffer TRIS had no inhibitory effect on NPR at normal pH value in natural seawater (pH 8.1), but it significantly depressed NPR at pH 9.0. This suggested that proton transport occurred at the outside of the plasma membrane facilitated the operation of the carbon acquisition at pH 9.0. It was proposed that the strategy of photosynthetic carbon acquisition at higher pH would prevent the alga from the damage of over excitation and photoinhibition in case of sunshine and calm water. We concluded that the blade and receptacle tissues of S. henslowianum have similar mechanism of acquisition of exogenous Ci from seawater to drive photosynthesis; yet they are differentiated more or less with the photosynthetic properties. PMID- 21302030 TI - Polyamines stimulate non-photochemical quenching of chlorophyll a fluorescence in Scenedesmus obliquus. AB - Polyamines (PAs) are small metabolites that are produced and oxidized in chloroplasts with an obscure mode of action. Recently, we showed that qE is stimulated by PAs in higher plants (Nicotiana tabacum) and in genetically modified plants with elevated thylakoid-associated PAs (Ioannidis and Kotzabasis Biochim Biophys Acta 1767:1371-1382, 2007; Ioannidis et al. Biochim Biophys Acta 1787:1215-1222, 2009). Here, we investigated further their quenching properties both in vivo in green algae and in vitro is isolated LHCII. In vivo spermine up regulates NPQ in Scenedesums obliquus about 30%. In vitro putrescine--the obligatory metabolic precursor of PAs--has a marginal quenching effect, while spermidine and spermine exhibit strong quenching abilities in isolated LHCII up to 40%. Based on available 3D models of LHCII we report a special cavity of about 600 A(3) and a near-by larger pocket in the trimeric LHCII that could be of importance for the stimulation of qE by amines. PMID- 21302031 TI - One-step plasmid construction for generation of knock-out mutants in cyanobacteria: studies of glycogen metabolism in Synechococcus sp. PCC 7002. AB - Genome sequences of microorganisms typically contain hundreds of genes with vaguely defined functions. Targeted gene inactivation and phenotypic characterization of the resulting mutant strains is a powerful strategy to investigate the function of these genes. We have adapted the recently reported uracil-specific excision reagent (USER) cloning method for targeted gene inactivation in cyanobacteria and used it to inactivate genes in glycogen metabolism in Synechococcus sp. PCC 7002. Knock-out plasmid constructs were made in a single cloning step, where transformation of E. coli yielded about 90% colonies with the correct construct. The two homologous regions were chosen independently of each other and of restriction sites in the target genome. Mutagenesis of Synechococcus sp. PCC 7002 was tested with four antibiotic resistance selection markers (spectinomycin, erythromycin, kanamycin, and gentamicin), and both single-locus and double-loci mutants were prepared. We found that Synechococcus sp. PCC 7002 contains two glycogen phosphorylases (A0481/glgP and A2139/agpA) and that both need to be genetically inactivated to eliminate glycogen phosphorylase activity in the cells. PMID- 21302032 TI - Expression of UDP-glucuronosyltransferase 1A4 in human placenta at term. AB - The placenta contains a large variety of metabolizing enzymes, among them UDP glucuronosyltransferase (UGT). Several UGT2B isozymes have so far been detected in human placenta, but little is known on placental expression of UGT1A isozymes. The antiepileptic drug lamotrigine (LTG) is a UGT1A4-substrate, and its serum concentration falls by over 50% during pregnancy, leading to impaired seizure control. The placenta may be involved in this. Microsomes from term placentas of 4 LTG-users and 10 healthy control subjects were prepared. Western blot analysis detected UGT1A proteins in all placentas. The presence of UGT1A4 in placenta from LTG users was confirmed with UGT1A4 commercial standard and a specific UGT1A4 primary antibody. Since LTG is primarily metabolized by UGT1A4 and this isozyme is shown to be present in placenta at term, it may be hypothesized that the placenta is involved in the fall of LTG serum concentrations during pregnancy. PMID- 21302033 TI - Pharmacokinetic interaction between zolpidem and ciprofloxacin in healthy volunteers. AB - Our objective was to evaluate a possible pharmacokinetic interaction between zolpidem and ciprofloxacin in healthy volunteers. The study consisted of two periods: Period 1 (reference), when each volunteer received a single dose of 5 mg zolpidem and Period 2 (test), when each volunteer received a single dose of 5 mg zolpidem and 500 mg ciprofloxacin. Between the two periods, the subjects were treated for 5 days with a single daily dose of 500 mg ciprofloxacin. Plasma concentrations of zolpidem were determined during a 12-hour period following drug administration. Pharmacokinetic parameters of zolpidem administered in each treatment period were calculated using non-compartmental analysis and the data from two periods were compared to determine statistically significant differences. In the two periods of treatments, the mean peak plasma concentrations (Cmax) were 75.73+/-28.34 ng/ml (zolpidem alone) and 80.58+/-22.40 ng/ml (zolpidem after pre-treatment with ciprofloxacin). The tmax, times taken to reach Cmax, were 0.91+/-0.42 and 1.44+/-0.61 h, respectively, and the total areas under the curve (AUC0-infinity) were 300.2+/-115.5 and 438.1+/-142.6 ng h/ml, respectively. The half-life of zolpidem was 2.39+/-0.53 h when administered alone and 3.34+/-0.87 h after pre-treatment with ciprofloxacin. These differences were statistically significant for Cmax, tmax, AUC0-infinity, half-life and mean residence time. Ciprofloxacin interacts with zolpidem in healthy volunteers, raising its bioavailability by about 46%. This magnitude of effect is likely to be clinically significant. PMID- 21302034 TI - Effects of antioxidants on drug absorption in in vivo intestinal ischemia/reperfusion. AB - Ischemia/reperfusion (I/R) injury must be overcome in order to succeed in small intestinal transplantation. Reactive oxygen species (ROS) are generated by I/R, and they induce lipid peroxidation which is one of the causes of mucosal lesion. We previously reported the protection effects of antioxidants to I/R injury in the in vitro study. In the present study, we examined the inhibitive effect of antioxidants on intestinal I/R injury in the in vivo study. Intestinal ischemia was induced in Wistar/ST rats using the spring scale and the surgical suture for 1 h, followed by reperfusion for 1 h. We used 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron), astaxanthin (ATX) and epigallocatechin gallate (EGCG) as antioxidants. The inhibitive effects on mucosal lesion, opening of TJ and decrease in protein expression level of P-gp by in vivo intestinal I/R were admitted by three kinds of antioxidant. Tiron and EGCG inhibited P-gp function but ATX did not. Therefore, for the use of P-gp substrate like immunosuppressants after the intestinal transplantation, ATX, which does not inhibit P-gp is considered to be effective for intestinal I/R injury. PMID- 21302035 TI - Pharmacokinetics and safety of a new bioengineered thrombolytic agent, human tissue urokinase type plasminogen activator in Chinese healthy volunteers. AB - The aim of our study was to investigate the pharmacokinetics and safety of human tissue urokinase type plasminogen activator (HTUPA) in healthy Chinese subjects after intravenous administration. Thirty-two subjects were given intravenous injection doses of 5-35 mg of HTUPA for safety evaluation. Twenty-four subjects were given 10, 20 or 30 mg HTUPA for pharmacokinetic assessment. Safety and tolerance were evaluated by monitoring adverse events, laboratory parameters, electrocardiography and vital signs. HTUPA concentration in human serum samples was determined by an enzyme-linked immunosorbent assay (ELISA) method. The main pharmacokinetic parameters were calculated by DAS software. HTUPA was generally well tolerated and in the whole study course no serious adverse events occurred. The main pharmacokinetic parameters were as follows: geometric mean [95% confidence interval, CI] for t1/2 were 1.5 (1.4, 1.6), 1.3 (1.2, 1.4), and 1.2 (1.2, 1.3) h, AUC0-t were 1.0 (0.7, 1.3), 2.1 (1.5, 2.7), and 5.6 (4.7, 6.6) mg h L(-1), AUC0-infinity were 1.1 (0.8, 1.3), 2.1 (1.5, 2.7), and 5.8 (4.7, 6.7) mg h L(-1) for 10, 20, and 30 mg group, respectively. The main pharmacokinetic parameters were not significantly different between males and females (P>0.05). No serious adverse events were reported by the subjects or revealed by clinical or laboratory examinations, suggesting the given doses were safe and well tolerated. PMID- 21302036 TI - The effects of an investigational antimalarial agent, NIPRD-AM1 on the single dose pharmacokinetics of metronidazole in healthy human volunteers. AB - The effect of concurrent administration of a novel phytomedicine, NIPRD-AM1 used for the treatment of malaria on the pharmacokinetics of metronidazole was investigated in healthy volunteers. The study was a completely randomized one, crossover involving administration of single dose metronidazole tablets (200 mg*2) concomitantly with NIPRD-AM1 capsules (250 mg*2) to 11 healthy volunteers. Blood samples were collected before and at pre-determined time intervals following administration of the drugs. Serum concentrations of the unchanged metronidazole were analyzed using a modified simple and sensitive reversed phase high performance liquid chromatography (HPLC) method. The method showed good precision for metronidazole with coefficient of variation less than 10%. The Pharmacokinetic parameters (AUC, Cmax, and Tmax) were generated using GraphPad Prism software version 2. The derived pharmacokinetic parameters (AUC, Cmax) following the administration of metronidazole alone and co-administration with NIPRD-AM1 were 76.12 MUg/ml per hour, 7.94 MUg/ml and 73.52 MUg/ml per hour, 7.83 MUg/ml, respectively. This differences were not statistically significant (P<0.05) and the relative bioavailability was found to be about 96%. The comparable relative bioavailabilty value obtained shows that there is little or no interaction between NIPRD-AM1 and metronidazole. The findings, therefore, showed that metronidazole can be administered with the phytomedicine NIPRD-AM1 without any significant effect on the pharmacokinetic profiles of metronidazole. PMID- 21302037 TI - Pharmacokinetics and tissue distribution of 25-hydroxyprotopanaxadiol, an anti cancer compound isolated from Panax ginseng, in athymic mice bearing xenografts of human pancreatic tumors. AB - To determine pharmacokinetics and tissue distribution of 25 hydroxyprotopanaxadiol [25-OH-PPD, 20(R)-dammarane-3beta,12beta,20,25-tetrol], a promising antitumor natural product isolated from the fruits of Panax ginseng, an analytical method involving liquid chromatography/tandem mass spectrometry in biological samples was developed and employed. After intravenous and oral administration to nude mice bearing xenografts of human pancreatic tumors at doses of 10 and 20 mg/kg body weight, respectively, 25-OH-PPD was rapidly absorbed and distributed in plasma and in all tissues examined, including the tumors, with all Cmax>2 MUg/ml or MUg/g and tmax<1 h. The absolute oral bioavailability of 25-OH-PPD was relatively high, compared with other ginsenosides. These results indicate that this novel anti-cancer ginsenoside has relatively favorable pharmacokinetic properties and provide a basis for further development of this compound as a chemotherapeutic agent. PMID- 21302038 TI - Plasma pharmacokinetics and tissue distribution of bufotalin in mice following single-bolus injection and constant-rate infusion of bufotalin solution. AB - Bufotalin is one of the active antitumor components in Ch'an Su which is a widely used traditional Chinese medicine. However, there is insufficient information on the biopharmaceutical properties of bufotalin based on pharmacokinetic studies. To investigate the pharmacokinetics and tissue distribution of bufotalin, single bolus injection and constant-rate infusion of bufotalin solution were performed in mice. After single intravenous administration, bufotalin was quickly distributed and eliminated from the plasma with a t1/2 of 28.6 min and an MRT of 14.7 min. Bufotalin concentrations in brain and lung were significantly higher than those in blood and other tissues at 30 min after dosing. The steady-state bufotalin plasma concentration and tissue distribution were determined using a novel constant-rate infusion device, and the distribution characteristics were similar to those of single-bolus injection. These results indicated that bufotalin could cross the blood-brain barrier and naturally target the lung. Bufotalin might be a promising antitumor candidate for lung cancer. PMID- 21302039 TI - Improved bioavailability of orally administered andrographolide from pH-sensitive nanoparticles. AB - Andrographolide, a major bioactive phytoconstituent derived from Androgaphis paniculata that is safe and beneficial in several ailments, was formulated into pH-sensitive nanoparticle suspension with a view of improving its oral bioavailability. The andrographolide-loaded pH-sensitive nanoparticles were prepared by nanoprecipitation technique using Eudragit(r) EPO (cationic poly methacrylate copolymer). The 3(2) factorial design was used to optimize the amount of polymer and stabilizer (Pluronic(r) F-68). The optimized batch obtained using 0.45% w/v of Eudragit(r) EPO and 0.6% w/v of Pluronic(r) F-68 showed high encapsulation efficiency of 93.8+/-0.67% with particle size of 255+/-9 nm and zeta potential of 29.3+/-3.4 mV. The bioavailability of andrographolide from optimized nanoparticles and pure andrographolide was assessed in male Wistar albino rats at a dose of 10 mg/kg. As compared to the pure andrographolide, almost 2.2 and 3.2-fold increase in AUC0-infinity, Cmax and 121.53% increase in relative bioavailability were observed for andrographolide from pH-sensitive nanoparticles (P<0.05). Shorter Tmax by about fourfold difference were observed with 2.2-fold decrease in Cl/F. The improved dissolution rate owing to its reduced particle size, increased surface area and reduced diffusion layer thickness may have contributed to oral bioavailability. The results clearly indicate the potential of pH-sensitive nanoparticles for oral delivery of low bioavailability phytoconstituents such as andrographolide. PMID- 21302040 TI - A rapid determination of drug candidate tyrosol galactoside in rat plasma by HPLC and its application to the pharmacokinetics study. AB - A simple and sensitive HPLC method has been developed and validated for the determination of tyrosol galactoside (TG) in rat plasma. After one-step protein precipitation with methanol, plasma samples were separated on an Ultimate AQ-C18 column (150 mm*4.6 mm, 5 MUm) using acetonitrile-water (7:93, v/v) as mobile phase at a flow rate of 1.2 mL/min. The ultraviolet detection wavelength was set at 275 nm. The lower limit of quantification was 1.140 MUg/mL. The calibration curve was linear over a concentration range of 1.140-228.0 MUg/mL. The assay accuracy and precision were within the range of 99.6-103.0 and 2.17-6.23%, respectively. The developed method was successfully applied to the pharmacokinetics study of TG in rats after intravenous and oral administration. The bioavailability of TG in rats is 27.9%. PMID- 21302041 TI - Determination of finasteride in human plasma by liquid chromatography electrospray ionization tandem mass spectrometry with flow rate gradient. AB - In this study, an attempt was made to describe and validate liquid chromatography electrospray ionization tandem mass spectrometry as a fast, sensitive and reproducible method for determining finasteride in human plasma. Finasteride and internal standard (pantoprazole) were extracted by liquid-liquid extraction using methyl tert-butyl ether. Separation was performed by using a flow rate gradient on a reverse phase C18 column at 25 degrees C. The mobile phase consisted of methanol-water (70:30, v/v) containing 0.5% anhydrous formic acid. The protonated analytes were quantitated in positive ionization by multiple reaction monitoring in mass spectrometry. The mass transitions are m/z 373.4->305.3 and 384.1->200.0 for finasteride and pantoprazole, respectively. The method had a run time of 3.6 min and a linear calibration curve at a range of 0.2-100 ng mL(-1) (r2=0.9958). The lower limit of quantification was 0.2 ng mL(-1). The extraction recoveries of finasteride from the biological matrix were more than 82.7%, and the intra- and inter-day precision of the assay at four concentrations were 2.4-8.0% with an accuracy of 94.3-105.8%. The developed method requires less plasma (0.1 mL), but has high sensitivity. The validated method has been successfully used to analyze human plasma samples in pharmacokinetic or bioequivalence studies. PMID- 21302042 TI - Quantification of pantoprazole in human plasma using LC-MS/MS for pharmacokinetics and bioequivalence study. AB - A highly sensitive and rapid method for the analysis of pantoprazole in human plasma using liquid chromatography coupled to tandem electrospray ionization mass spectrometry was developed. The procedure involves a simple protein precipitation method with methyl alcohol and separation by RP-HPLC. Detection was performed by positive ion electrospray ionization in multiple reaction monitoring mode, monitoring the transitions m/z 384.1->200.0 and m/z 346.1->198.0, for quantification of pantoprazole and IS, respectively. The standard calibration curves showed good linearity within the range of 5-5,000 ng mL(-1). The lower limit of quantitation (LLOQ) was about 5 ng mL(-1). The extractive recovery of pantoprazole from the biological matrix was more than 77.58% and the matrix effect was complied with relevant provision. The intra-day accuracy of the drug containing serum samples was more than 92.19% with a precision of 0.79-5.36%. The inter-day accuracy was 85.49% or more, with a precision of 0.91-12.67%. Intra and inter-day accuracy of the assay at four concentrations were 97.9-98.2% with a precision of 4.2-13.9%. This method offered good precision and accuracy and was successfully applied to the pharmacokinetic and bioequivalence studies of 40 mg of enteric-coated pantoprazole in 20 healthy Chinese volunteers. PMID- 21302043 TI - Extension and flexion torque variability in ACL deficiency. AB - PURPOSE: To evaluate possible differences in knee extension and flexion torque variability in the anterior cruciate ligament-deficient (ACLD) leg and their dependence on muscle length and visual feedback (VF). Although a knee extension torque deficit is found in the ACLD leg, there is no evidence that variability in submaximal isometric knee extension and flexion torque is affected in the ACLD leg or that it depends on VF. METHODS: All tests were performed using 13 untrained men with unilateral ACL rupture. Isometric knee extension torques at 90(o) and 120(o) and knee flexion torques at 90(o), 120(o) and 140(o) were evaluated in healthy and ACLD legs. Isometric torque variability at 20% of maximal force was evaluated with or without VF. The coefficients of variation (CV) and permutation entropies (PE) were used to calculate submaximal isometric torque variability. RESULTS: Healthy legs had significantly greater isometric torques at 90(o) and 120(o) knee angles during knee extension compared with ACLD legs. There were no differences between healthy and ACLD legs in torque variability in knee extension and flexion with or without VF. The PE of knee extension torque at knee angles of 90(o) and 120(o) was significantly (P < 0.05) greater in healthy legs. CONCLUSIONS: The effect of ACL deficiency on variability (CV) in submaximal isometric knee extension and flexion torque was not significant. However, PE of knee extension submaximal torque was significantly greater in the healthy leg than in the ACLD leg. When estimating ACL deficit, it is important to measure not only isometric maximal torque but also torque variability and complexity using nonlinear tool during submaximal isometric tasks. LEVEL OF EVIDENCE: III. PMID- 21302044 TI - The impact of a rectangular or trapezoidal flexion gap on the femoral component rotation in TKA. AB - PURPOSE: The influence of soft tissue balancing on femoral component rotation in the gap technique remains unclear. The present study therefore compared the reliability of femoral component rotation determined by rectangular and trapezoidal gaps in total knee arthroplasty (TKA) using a navigation-assisted gap balancing technique. The study also determined the correlation between femoral component rotation and gap measurement. METHODS: This prospective study included 99 patients (108 knees) who underwent postoperative CT after TKA with the navigation-assisted gap-balancing technique. A trapezoidal flexion or extension gap was defined as a >3 mm difference between the medial and lateral sides in 90 degrees flexion or extension. An outlier of femoral component rotation was defined as >3 degrees deviation from the transepicondylar axis. RESULTS: Postoperative CT showed that the femoral component had a tendency to rotate externally, with a mean 1.88 +/- 2.49 degrees from the surgical transepicondylar axis. Outliers and mean values of femoral component rotation were similar in the trapezoidal and rectangular flexion/extension gap groups. The medial flexion gap (r = -0.49, P = 0.007) and flexion gap differences (r = -0.59, P = 0.027) showed statistically significant negative correlations with the femoral component rotation. Multiple linear regression analysis also showed that the femoral component rotation was independently related to the flexion gap difference (beta = -0.27, P = 0.031). CONCLUSION: In the gap technique, the rotation of the femoral component is affected more by the flexion gap than by the extension gap. However, neither the trapezoidal nor rectangular flexion gap influenced femoral component rotation. PMID- 21302045 TI - Pseudoaneurysm of the superior medial genicular artery following knee arthroscopy. AB - We describe a case of a pseudoaneurysm of the superior medial genicular artery following arthroscopic knee surgery, which was diagnosed by means of computed tomography and arterial duplex ultrasound. The treatment consisted of surgical exploration with excision of the pseudoaneurysm, followed by ligation of the feeding artery. PMID- 21302046 TI - Anterior knee pain after total knee arthroplasty: does it correlate with patellar blood flow? AB - PURPOSE: Total knee arthroplasty (TKA) disturbs patellar blood flow, an unintended accompaniment to TKA that may be a cause of postoperative anterior knee pain. We examine whether disrupted patellar blood flow correlates with anterior knee pain following TKA. METHODS: In 50 patients (21 men, 29 women) undergoing TKA, we compared patellar blood flow at flexions 0 degrees to 30 degrees , 60 degrees , 90 degrees , and 110 degrees before and after medial parapatellar arthrotomy to pre- and postoperative anterior knee pain scores by means of a laser Doppler flowmeter (LDF) probe. Anterior knee pain was assessed using the pain intensity numeric rating scale (NRS) of 0-10 (0-no, 10-worst pain). Based on the NRS pain values, patients were divided into two main groups: group A (n = 34) with no pain or discomfort (NRS range 0-4) and group B (n = 16) with anterior knee pain (NRS range 5-10). RESULTS: Patients of group B demonstrated a significant decrease in blood flow before arthrotomy at flexions from 0 degrees to 90 degrees , and 110 degrees and from 0 degrees to 60 degrees , 90 degrees , and 110 degrees after arthrotomy. For group A, a significant decrease in blood flow was detected at flexions from 0 degrees to 90 degrees , and 110 degrees before and after arthrotomy. For both groups, medial arthrotomy did not have a statistically significant influence on patellar blood flow (margin of significance P < 0.05). Prior to TKA, 16 of the 50 patients of group B (32%) complained of anterior knee pain (mean NRS 7.1 +/- 1.7). At 2-year follow-up, pain significantly decreased (NRS 3.1 +/- 2.1) and only 4 of the 16 patients (25%) complained of moderate anterior pain (average NRS 5.7 +/- 0.5), while 8 of 16 (50%) patients reported discomfort (mean NRS 3.5 +/- 1.8) around the patella. Patients in group A also demonstrated a significant decrease in pain intensity (from NRS 1.5 +/- 1.4 preoperatively to NRS 0.4 +/- 1.5 at 2-year follow-up). Statistical analysis demonstrated no statistically significant correlation between pre-arthrotomy/post-arthrotomy patellar blood flow and the presence of preoperative and postoperative anterior knee pain. Only the degree of flexion had an influence on patellar blood flow. CONCLUSION: Medial arthrotomy had no direct significant effect on patellar blood flow, and the diminished blood flow did not correlate with postoperative anterior knee pain. However, a significant correlation was revealed between patellar blood flow and the degree of flexion: in almost a quarter of patients, blood flow dropped to zero at flexions of 100 degrees and above. PMID- 21302047 TI - Relationship between thickness of the anteromedial bundle and thickness of the posterolateral bundle in the normal ACL. AB - PURPOSE: Since the development of the anatomic double-bundle anterior cruciate ligament (ACL) reconstruction, many studies have focused on excursion and/or tension of each graft. However, no studies to date have adequately investigated thickness of the graft in anatomic double-bundle ACL reconstruction. To obtain basic knowledge from which an ideal graft thickness can be inferred, thicknesses of the anteromedial bundle (AMB) and posterolateral bundle (PLB) was measured in the normal ACL. METHODS: The right knees of 50 cadavers donated for anatomy instruction were studied. Each ACL was separated into the AMB and PLB, and circumferences at the mid-substance and cross-sectional area at the femoral and tibial footprints were measured in each. RESULTS: Cross-sectional areas of the AMB and PLB were 36 +/- 10 and 32.1 +/- 10.2 mm2 at the femoral footprint, and 60.9 +/- 21.8 and 52.2 +/- 17.3 mm2 at the tibial footprint, respectively. Circumferences at the mid-substance were 14.3 +/- 3.3 mm for the ALB and 10.8 +/- 3.1 mm for the PLB. A positive correlation was seen between AMB and PLB at each of the three sites. CONCLUSION: The AMB is thicker than the PLB, showing a constant correlation in the normal ACL. This suggests that the anteromedial graft must be thicker than the posterolateral graft at least in actual operations. PMID- 21302049 TI - Classification of trochlear dysplasia as predictor of clinical outcome after trochleoplasty. AB - PURPOSE: Sulcus-deepening trochleoplasty restores the trochlear groove in patients with patellofemoral instability and underlying trochlear dysplasia. There are types of dysplasia both with (B and D) and without (A and C) a supratrochlear spur. The aim of this study was to identify influencing factors for the clinical outcome following trochleoplasty. METHODS: Forty-four knees in 38 patients who underwent trochleoplasty for instability (type A in 9, B in 15, C in 9 and D in 11 knees) were assessed clinically with the Kujala score and radiologically with radiographs and MRI. The median follow-up was 4 (2-7.8) years. RESULTS: At follow-up, the median Kujala score had improved from 68 (29 84) to 90 (42-100) points (P < 0.001). Instability (P < 0.001) and pain (P = 0.027) decreased significantly, but in 3 knees, pain was worse postoperatively. Twenty-seven knees were ranked as excellent, 10 as good, 2 as fair and 5 as poor. Overall, dysplasia types B and D benefited more from surgery than types A and C. The postoperative MRI revealed no chondrolysis or subchondral necrosis, but deterioration of cartilage on the lateral trochlear facet was identified. CONCLUSION: Trochleoplasty is a useful and reliable surgical technique to improve patellofemoral instability in patients with a dysplastic trochlea. While improved stability is predictable, pain is less predictable and may even increase following surgery. The overall results were directly dependent on the type of the dysplasia, with a significantly better clinical outcome in type B and D. The clinical relevance of this study is that severe dysplasia can successfully be treated with trochleoplasty. LEVEL OF EVIDENCE: III. PMID- 21302050 TI - Possible palindromes in immunoglobulin heavy-chain genes: Their role in membrane attachment. AB - An analysis of mRNA structures as deduced from the amino acid sequences of immunoglobulin heavy chains reveals possible base-paired regions within the sequences coding for the 20 C-terminal amino acids of the human MU and alpha chains. The two regions are similar in structure and contain a palindrome which might serve as an enzyme recognition site. Although other base-paired regions can be predicted in the remainder of the constant regions of these heavy chains, they have no common features. These regions and the palindromes within them may be involved in the regulation of membrane and serum immunoglobulin synthesis. Two possible mechanisms for this are proposed. PMID- 21302051 TI - On the selective elimination of Y-bearing sperm. AB - The potential use of antibodies that selectively recognize either X-bearing or Y bearing sperm is self-evident. Thus our attention was directed to the fact that under optimal conditions, H-Y antibody lyses 50% of mouse spermatozoa. Accordingly, we asked whether expression of H-Y antigen is haploid in spermatozoa from XY male mice heterozygous for the autosomal dominantSxr gene, for if H-Y expression were haploid, H-Y antibody would be expected to kill 75% of spermatozoa derived from these XY,Sxr/- males. However, maximal lysis remained at the 50% level, which indicates that haploid expression of H-Y antigen and the potential immunoselection of Y-(or X-) bearing spermatozoa are unlikely. PMID- 21302052 TI - Genetic basis for unresponsiveness to lipopolysaccharide in C57BL/10Cr mice. AB - The unresponsiveness to LPS detected in C57BL/10Cr mice is inherited as a recessive trait and is determined by an autosomal gene linked to theMup-1 locus on chromosome 4. Since no complementation for LPS responsiveness was observed in F(1) hybrid mice between C3H/HeJ and C57BL/10Cr, we conclude that C57BL/10Cr mice carry a defective allele at the sameLps locus, previously identified by the mutation detected in the C3H/HeJ strain. PMID- 21302053 TI - Recombination between genes coding for immune response and the serologically determined antigens in the chickenB system. AB - Evidence is presented for a crossover between the genes coding for the serologically determined (SD) antigens on erythrocytes and an immune response gene (Ir-GAT) controlling immune response to the synthetic polypeptide GAT within theB complex, the MHC of chickens. TheIr-GAT (1) andIr-GAT (19) alleles control low and high immune response to GAT, respectively. Both low and high responders were recovered as recombinants fromB (1) B (1) andB (19) B (19) birds. The low responder haplotypes are homozygous for theIr-GAT (1) allele and the high responder haplotypes carry theIr-GAT (19) allele. Mortality forB (1) B (1) nonresponder birds was 39%, compared with 19% for theB (1) B (1) high responders; this suggests the possibility that genes located within the immune response region of theB complex exert some genetic control over viability and survival. PMID- 21302054 TI - The structure of immunoglobulin variable regions in the horned shark,Heterodontus francisci. AB - The heavy and light chains of pooled antibodies of the hybodont shark,Heterodontus francisci (horned shark), were subjected to amino acid sequence analysis. Yield determinations showed that more than 90% of the available polypeptides in the respective pools were sequenced. The heavy chains were homogeneous in the initial framework segment and showed a sequence homology of approximately 70% with the corresponding region of the more recently evolved nurse shark and a 45% homology with a human myeloma heavy chain. The light chains were less homogeneous and not identifiable as either kappa or lambda chains as known in higher species. The first half-cystine characteristics of the variable domain intrachain disulfide bridge of immunoglobulins was present in the same position (22 for heavy chains; 23 for light chains) in the horned shark as in mammalian species. The sequence analysis also suggested the presence of a hypervariable region in the horned shark light chains. The combined data imply that the antigen-binding function of immunoglobulins is mediated in much the same manner in this primitive shark as in more recently evolved species, including mammals. PMID- 21302055 TI - Genetic mapping and immunogenetic characterization of theH- 2(fb) mutation in the mouse. AB - Rejection of tailskin grafts exchanged between two male hybrids of the cross B10.M * B10.RIII(71NS) revealed a mutation in theH-2 ( f ) haplotype from the B10.M congenic line. Complementation studies with skin grafting and cell-mediated lympholysis showed the mutant, namedH-2 ( fb ), to be different from anotherH-2 ( f ) mutant,H-2 ( fa ), and further, that the HH-2 ( fb ) mutation occurred in theD end of theH-2 complex. Reciprocal skin grafts exchanged between mutant and normal mice were rejected. Hemagglutinating antibody reactive with B10.M cells was raised in the mutant mice. Mutant spleen cells responded weakly, but significantly, to wild-type cells in a mixed lymphocyte culture and in a graftversus-host assay, but no response was seen in the opposite direction. However, cytotoxic effector cells were generated against target cells in both directions in a cell-mediated lympholysis assay. PMID- 21302056 TI - Rapid murine mixed lymphocyte cultures assessed by emergence of T-cell insulin receptors. AB - Murine T lymphocytes incubated in a mixed lymphocyte culture with allogeneic lymphocytes incompatible for theH-2 region or subregions thereof rapidly develop insulin receptors. In contrast, T cells cultured with syngeneic orH-2- andMlslocus compatible cells do not develop insulin-binding sites. The emergence of insulin receptors is probably an early premitotic event. PMID- 21302057 TI - Split of HLA-DRw2 into subtypic specificities closely correlated to two HLA-D products. AB - Two B-lymphocyte-specific human alloantisera were studied, PA59 and 51.23. They identify two new HLA-DR alleles, which are both subtypic to HLA-DRw2. Moreover, they are closely correlated with two HLA-D products, Dw2 and tb24 (tb24 is a new specificity described by our group). Thus, DRw2 can be "split" into two subtypic specificities that have been named TO60 and TO61, which appear more strongly correlated with HLA-D antigens. Absorption studies demonstrated cytotoxicity negative, absorption-positive (CYNAP) reactions, and cross-reactive groups of antibodies. PMID- 21302058 TI - Strong and weak immune responses across the same major histocompatibility barrier in rats. AB - Inbred rat strains, Fischer 344 (F-344) and Lewis (LEW), share the serologicalAg Bl allele and react very weakly in mixed lymphocyte culture (MLC). Despite this apparent identity atAg-B, these strains differ markedly in their immune responses to anAg-B disparate third strain Marshall 520 (M-520) (Ag-B6). F-344 recipients allowed M-520 heart grafts an extended survival, whereas LEW recipients rejected them rapidly. F-344 and M-520 showed a weak response in MLC in contrast to a strong response for LEW and M-520. F-344 produced antisera in response to injection of M-520 cells that had a relatively high antibody titer but low cytotoxic activity. F-344 responded to another strain, Buffalo (BUF) (alsoAg-B6), in a similar fashion. F-344 apparently can produce a strong allogeneic response, as it was able to rapidly reject heart grafts from (LEW x Brown-Norway) F(1) donors (LBN) (Ag-B 1/3). The low response of F-344 to M-520 probably was not due to shared antigens between the two strains because M-520 heart grafts underwent rapid rejection in LEW hosts highly tolerant to F-344. To explain the contrasting response of F-344 and LEW to theAg-B6 disparity, we propose that it is controlled by an immune-response gene(s); that F-344 has a low-responding allele and LEW has a high-responding allele. The data do not reveal a location for this proposed gene. The high-responding allele appears to be dominant, as M-520 hearts were rejected rapidly by (F-344 x LEW) F(1) recipients. PMID- 21302059 TI - Host-determined T cell fine specificity for self-H-2 in radiation bone-marrow chimeras of standard C57BL/6 (H-2(b)) mutantHz1 (H-2 (ba)), and F (1) mice. AB - Reciprocal radiation bone-marrow chimeras were produced between the standard C57BL/6 (=B6) and the mutant B6.C-H-2 ( ba ) (=Hz1) strain. When infected with vaccinia virus, these chimeras, as well as an (Hz1 * B6)=-> Hz1 chimera, produced cytotoxic cells that killed vaccinia-infected H-2K(k)H-2D(b) target cells but failed to kill virus-infected H-2K(b)H-2D(d) cells. Virus-infected (Hz1 * B6)F(1) -> B6 chimeras, however, killed both types of target. These experiments demonstrate strict T-cell specificity capable of differentiating between two molecules that apparently differ by a single amino acid substitution. PMID- 21302060 TI - H-2 antigen expression: Loss in vitro, restoration in vivo, and correlation with cell-mediated cytotoxicity in a mouse lymphoma cell line. AB - The susceptibility to cell-mediated cytolysis of cells of the recently developed C57BL/Ka(H-2 ( b )) lymphoma cell line, BL/VL(3), was investigated in allogeneic assays with thymus-dependent lymphocytes (T cells). Compared to EL4, the widely used C57BL/6(H-2 ( b )) lymphoma cell line, BL/VL(3) cells were found to be insensitive to T-cell-mediated lysis as detected by the use of(51)Crrelease methods. When used as immunogens in alloreactive combinations with BALB/c(H-2 ( d )) splenocytes as responder cells, BL/VL(3) cells failed to elicit sensitization. Serological tests showed that this cell line had profoundly reduced levels of H 2(b) antigens on its surface. When BL/VL(3) cells were reinjected into C57BL/Ka and BALB/c mice, full recovery of H-2(b) antigen expression at the cell surface was observed in both syngeneic and allogeneic hosts after only 11 days of in vivo growth. Concomitantly, they acquired the ability to induce cytotoxic responses in allogeneic T cells and became susceptible to their lytic activity. The expression of H-2 antigens on the surface of BL/VL(3) cells is a reversibly modulated function that depends on in vivo growth conditions and is lost in vitro in the absence of immunoselective pressure. PMID- 21302061 TI - Serological and biochemical identification of theH-2K(p) (H 2.16) andH-2D (p) (H 2.22) gene products. PMID- 21302062 TI - Linkage for a locus of human complement C5 deficiency to the complement C6 structural locus. PMID- 21302063 TI - The genetics of teratocarcinoma transplantation: tumor formation in allogeneic hosts by the embryonal carcinoma cell lines F9 and PCC3. AB - Two cultured lines of murine embryonal carcinoma, F9 and PCC3, have been grafted to a variety of allogeneic hosts. The host strains have been classified by their resistance or sensitivity to these carcinomas. Resistance seems to be immunological in nature.Allograft rejection does not correlate withH-2 haplotype, and seems to be controlled by a limited number of recessive factors, presumably histocompatibility genes. We infer that these factors have limited polymorphism in the mouse species. Recombinational analysis of strain A/He has revealed the presence of a recessive factor linked to theH-2 locus. Tumor resistance of strains C57BL/6 and AKR appears to result from the interaction of dominant or semi-dominant factors in theH-2 region with other recessive elements in the genetic background.Though F(1) hybrids between resistant mouse strains and the syngeneic strain 129 are largely tumor-sensitive, a low level of hybrid resistance to F9 has been observed and shown to be eliminated by X-irradiation. PMID- 21302064 TI - Linkage between low-density lipoprotein and igk light-chain genes in rabbits. AB - The rabbit geneLpq, which codes for a low-density serum lipoprotein(2), is linked (34.6 +/- 5.3 centimorgans) to the Ig kappa light-chain gene (Ab). There is no evidence thatLpq is linked to another gene,Prt, that was previously found to be linked to theAb gene. This suggests that the gene order for the three genes isPrt Ab- Lpq. PMID- 21302065 TI - Immunogenetic studies of rhesus monkeys : X. The O, P, Q, R, and S blood group systems. AB - Five alloimmune blood typing reagents have been produced which define five new blood group systems in rhesus monkeys. Each of the five independent blood group loci is comprised of a detectable allele and a null allele. Using these new reagents and those previously described, we can potentially identify close to a million phenotypes in rhesus monkeys. PMID- 21302066 TI - Genetic control of igG2a production in the response to sheep erythrocytes. AB - A low IgG2a response in B10 mice during the primary response to sheep red blood cells (SRBC) is described. Analysis of the response in B10 * BALB/c hybrid progenies and in congenic strains indicates that this low response is a dominant phenotype placed under the control of a single Mendelian gene or a group of closely linked genes. This gene(s) is neither linked to CH allotypes orH2 haplotypes, nor is it sex-linked. It can be considered as an isotype- and antigenspecific regulatory gene of the immune response. PMID- 21302067 TI - Genetic Characterization of a new allele of the rabbit group b C(k) allotypes. AB - An inherited variant (b4(v)) of the rabbit kappa-chain allotype b4 is characterized by the presence of serine in place of alanine at position 121 and leucine in place of glutamine at position 124. The variant was traced through eight generations of a pedigreed rabbit family. Genetic analysis of this trait demonstrated that it is an allele of the other group b allotypes, and recent breedings have produced rabbits homozygous for this light-chain type. Two findings, other than the amino acid sequence differences, distinguish b4(v) from b4 in our colony. First, the level of expression of b4(v) in heterozygous rabbits is less than that of b4. For example, in b4b4(v) rabbits, approximately 30% of the preimmune IgG carries b4(v). In b4(v)b5 animals, 46% of the IgG carries the allotype b5, although in animals of allotype b4b5, 38% of the IgG is b5. Second, retrospective analysis of some litters revealed an abnormally low frequency of b4(v) in male heterozygotes. However, male b4(v)b4(v) homozygotes were found at the expected frequency in prospective crosses between b4(v)b5 rabbits. PMID- 21302068 TI - Dence for a gene in rats affecting lymphocyte responsiveness to PHA. AB - A gene controlling high responsiveness of lymphocytes to in vitro stimulation by PHA was transferred from the Lewis strain of rats to the BN background by ten generations of backcrossing. The high-responder phenotype was initially defined on the basis of incorporation of(3)H-thymidine, but we show that this trait also involves higher levels of mitotic activity than are observed with low responder lymphocytes. This gene is not closely linked to any histocompatibility locus which could be detected by skin grafting, and it does not appear to affect the proportion of T lymphocytes. PMID- 21302069 TI - Multi-Locus control of MLC reactions in rhesus monkeys. AB - The genetic basis for MLC reactivity in rhesus monkeys was further investigated. Cells from anintra-RhLA recombinant monkey were MLC reactive with those of an SD identical sib and with each of two sets of homozygous typing cells carrying either paternal haplotype. Also, cells from a pair ofRhLA- identical sibs reacted in MLC with each other, as well as with three genotypically different siblings. This excludes control of MLC reactivity by the conventionalD locus only. Thus the results selected for presentation provide formal evidence for the existence of at least one additional MLC locus, namedD'. The possibility thatD' exerts its influence on MLC reactivity only after alloimmunization is discussed. PMID- 21302070 TI - Production of congenic Anti-Lyt-3.1 sera. PMID- 21302071 TI - Differential mortality and lesion responses to reticuloendotheliosis virus infection in Marek's disease-resistant and susceptible chicken lines. PMID- 21302072 TI - Serological properties of anti-Ly-6.2 serum produced by a new immunization schedule. PMID- 21302074 TI - An Ly-like specificity with extensive nonlymphoid expression. AB - The characteristics of a strong mouse alloantigen with renal, bone marrow, and lymphoid expression were studied. This antigen is probably identical to that currently designated Ly-6.2. It was defined by the high-titered (1:1000) cytotoxic activity of three different antisera against peripheral lymphocyte target cells from DBA/2, DBA/1, and a variety of other strains. In the F(2) and four backcross generations the genetic control of this specificity segregated as a single autosomal dominant gene. In lymphoid tissues the predominant expression was on T cells but 10-30% of B cells were lysed by these antisera. The specificity was expressed strongly in kidney, as shown by sequential absorption, in amounts equal to or greater than the amount in lymphoid tissues. Comparison to the rate of absorption of H-2 by kidney indicated that this antigen may be expressed in amounts comparable to an H-2 antigen in kidney. Immunization with kidney tissue resulted in a strong cytotoxic antibody response. The number of bone marrow cells expressing this antigen (40-50%) was well beyond what could be accounted for by T lymphocytes in bone marrow. In addition, a nonlymphoid tumor, the P815Y mastocytoma, was positive by cytotoxicity and by absorption. The extensive nonlymphoid expression and antigenic strength of Ly-6.2 raises the possibility that this serologically defined lymphocyte alloantigen will have histocompatibility effects when allografts of the appropriate tissues are examined. PMID- 21302075 TI - Histocompatibility typing by cellular radioimmunoassay. AB - A quantitative cellular radioimmunoassay (CRIA) for histocompatibility typing is described. Chicken red blood cells (RBC) were incubated in microtiter plates with specific anti-MHC (B) alloantisera and the alloantibody bound measured indirectly by a second binding step with(125)I-labeled rabbit anti-chicken IgG. The assay is objective, highly consistent, and three to four orders of magnitude more sensitive than conventional hemagglutination assays. The new CRIA was used to detect minor subpopulations of cells in artificial cell mixtures; as few as 1% of relevant cells were easily detected. Erythrocyte chimerism was induced following the injection of B(2)/B(2) chicken embryos with B(15)/B(21) embryonic stem cells. Five weeks after hatching, erythrocyte chimerism was precisely quantitated by comparing the reaction of RBC from the putative chimeras with artificial cell mixtures using specific anti-B(15)/B(21) alloantisera. The percent varied from 13 40% in 13 chimeric animals. The new CRIA was also used for the sensitive detection of tumor-specific antigens on a T-cell lymphoma. An unexpected finding was that anti-B(15) alloantibody bound almost as well to B(15)/B(21) heterozygous RBC as to B(15)/B(15) homozygous cells, suggesting that either the concentration or the steric arrangement of B(15) alloantigen at the erythrocyte surface may not conform to conventional expectations. PMID- 21302076 TI - Immunoglobulin isoantigens (allotypes) in the mouse : V. Characterization of IgM allotypes. AB - Murine antisera raised against allogeneic lymphoid cells often contain antibodies to IgM allotypes. Rarely, allotypic antibodies to IgM have been found after immunization withB. pertussis anti-B. pertussis conjugates. Using both types of antibodies, we have defined a new constant-region locus for both secreted and membrane-bound MU chains. This locus,Ig-6, is closely linked to the previously described H-chain constant-region loci (Ig-1 throughIg-5) and is subject to allelic exclusion. We have identified three alleles and four antigenic specificities ofIg-6. PMID- 21302077 TI - Immune response gene(s) controlling the humoral antilysozyme response (Ir-Lys) linked to the major histocompatibility complexSL-A in the pig. AB - A genetic control of humoral immune response in pigs against hen egg-white lysozyme was shown to be linked to the major histocompatibility complexSLA. This control was detected when high antigen doses were used for immunization. It was more prominent with small immunizing doses of lysozyme. Under these latter conditions,SL- A heterozygous individuals exhibited a higher response than correspondingSL- A homozygous animals, suggesting a complementation phenomenon between several genes, at least one of which is linked to the porcine MHC,SL- A. PMID- 21302078 TI - The screening of non-H-2 congenic lines forSk loci. AB - Thirty-seven histocompatibility congenic lines of mice, including at least 27non- H-2 lines, developed by Bailey on the C57BL/6 background, were screened for loci determining Sk (skin-specific) histocompatibility antigens. Background strain hosts were inoculated with lymphoid cells from the congenic lines and subsequently challenged with skin test grafts from the same donors. Comparison of the survival times of these test grafts with those of first- and second-set skin grafts in the same donor-host combinations suggests that the lymphoid cells from 35 of the congenic lines apparently immunized or tolerized at least some of the hosts. Thus, the histocompatibility antigens involved were shared by lymphoid cells and skin, and by definition could not be Sk antigens. The tests were indecisive with two of the non-H-2 lines, but if Sk antigens were involved, their contribution to the immunogenicity of conventional skin allografts probably was negligible. Hence ifSk congenic lines are desired, they probably will have to be developed on their own by procedures specifically designed to select for Sk antigens of significant immunogenicity. PMID- 21302079 TI - The relationship between theH-2 loss mutations ofH-2(da) andH-2 (db) in the mouse. AB - The mouse strain B10.D2-H-2(da) carries the mutantH-2(da) allele, derived after chemical induction, and this has been shown to be a gain and loss mutation involving theH-2D(d) locus.BALB/c- H-2(db), derived spontaneously, is a loss mutation only, and appears not to involve theH-2D(d), but rather theH-2L(d) locus. The two mutations effectboth graft rejection and serologically detected H 2 specificities (Type II mutation). In the experiments described in this study, theloss mutations in theH-2(da) andH-2(db) mutants have been compared by skin grafting, and by direct and absorption serological techniques: (1) By skin grafting, using the well established complementation method, it has been shown thatH-2(da) andH-2(db) do not complement each other, i.e., the mutation in both occurred at the same 'locus.' However, by appropriate selection of donor and recipient, it has become clear thatH-2(da) had a greater loss than didH-2(db), althoughH-2(da) includes the loss found inH-2(db). (2) Serological studies have demonstrated that H-2D.4 was altered inH-2(da), but not inH-2(db); 'H-2.28' (detected by D-28b and D-29) was decreased or lost in both mutants;H-2(db) anti BALB/c failed to react withH-2(da); both mutants reacted similarly with D-28 sera. In addition, sera made usingH-2(da) as donor did not contain an anti-H 2.28 antibody. The loss mutation involvingH-2(da) therefore appears to have led also to the loss of H-2.28 as found inH-2(db). We conclude that theH-2(da) strain arose after a complex mutation or recombination event which involvedboth theH 2D(d) locus and the closely linkedH-2L(d) locus, whereasH-2(db) affects only theH 2L locus. PMID- 21302080 TI - The relationship between HLA antigens and Bermuda grass hayfever. PMID- 21302081 TI - Biochemical demonstration- of anti-Qa activity in an H-2.28 public specificity antiserum. PMID- 21302082 TI - Genetic control of responsiveness to the tumor-associated transplantation antigen of a chemically induced murine fibrosarcoma. PMID- 21302084 TI - The firstH- 2 mutant workshop. AB - CONCLUSION: The major accomplishment of the Workshop was probably the realization of many of its participants that most of the 21 availableH- 2 variants aretrue mutations very likely derived from single nucleotide substitutions. Any theory of the pleiotropic effect of theH- 2 genes must now take this fact into account; such theories must also consider the observation that a wide variety of immunological phenomena are affected byH- 2 mutations and thus, apparently, are controlled by a single gene. PMID- 21302085 TI - TheH-2L locus and the system of H-2 specificities. PMID- 21302086 TI - Location of theSas-1 locus on mouse chromosome 1. AB - Using three sets of recombinant inbred strains (BXD, BXH, and BXJ), we found the locus controlling an antigenic substance (Sas}-1) in murine serum to be closely linked to the Chromosome-1 marker,Dip-1. This linkage was confirmed by an analysis of backcross linkage. The BXD and backcross data suggest that the gene order isId-1-Dip-1-Sas-1-Mls. Data from the three sets of RI strains and the 32 backcross mice lead to the estimate that the recombination frequency betweenDip-1 andSas-1 is 0.030 +/-0.015. PMID- 21302087 TI - Detection of two allotype-(Ig-1)-linked minor histocompatibility loci by the use ofH-2-restricted cytotoxic lymphocytes in congenic mice. AB - Cytotoxic lymphocytes (CTL) were generated betweenIg-1-congenic strains BALB/c(H 2(d),Ig-1(a)) andC.B-17(H-2(d),Ig-1(b)) by cross-immunization in both directions and rechallenge in vitro. The effector cell populations specifically lysed target cells sharing both theH-2 haplotype and theIg-1 allele of the sensitizing strain. B- and T-cell blasts were equally good targets, suggesting thatH-2-restricted cytotoxic lymphocytes are not directed against serologically defined conventional allotypic determinants, but probably against minor histocompatibility antigens controlled by genes linked to theIg-1 complex. Competition experiments using cold target cells from a series ofIg-1(b)-congenic strains of the BALB/c background (BAB-14, C.B-17, C.B-26) revealed two not yet described minor histocompatibility loci linked to theIg-1 complex: We could demonstrate that BALB/c anti-C.B-17 effector cells recognize at least two distinct antigenic determinants on C.B-17 target cells, but only one on target cells from BAB-14, which carries a recombinantIg-1 complex. From these results we conclude that one of the minor histocompatibility antigens, designated as H(C(H)), is encoded by a gene linked to the heavy-chain constant-region (C(H)) genes, whereas the second minor histocompatibility antigen, designated as H(V(H)), is coded for by a gene linked to the heavy-chain variable-region (V(H)) genes. These two new genetic markers may be useful for further analysis of the mouseIg-1 complex because the analysis of the H(C(H)) and H(V(H)) genes may facilitate the search for recombinants in that chromosomal region. PMID- 21302088 TI - Relationship of F9 antigen and genes of theT/t complex. AB - Serological studies relating F9 antigen of embryonal carcinoma cells to[Formula: see text] at the murineT/t complex have been extended and confirm that only the lethal haplotype t(12)- and none of the other five lethal haplotypes-affects the quantitative expression of F9 antigen on sperm. Cytotoxicity tests on preimplantation embryos show that t(12) homozygotes are less susceptible to antiF9 serum than t(w5) homozygotes, and that using specific antimutant haplotype antisera prepared against sperm, t(12) antigen is detectable on morulae, whereas t(w5) antigen is not. PMID- 21302089 TI - Xenoantisera to human DR antigens: Serological and immunochemical characterization. AB - Antibodies to DR antigens were detected using serological and immunochemical tests in sera from rabbits and goats immunized with cultured human B-lymphoid cells mixed with an anti-T-cell xenoantiserum or with partially purified DR antigens. After absorption with human red blood cells, cultured melanoma cells, and/or T-lymphoid cells, DR xenoantisera become specifically cytotoxic to B lymphocytes. Three out of nine sera tested with a panel of T-depleted peripheral lymphocytes and chronic lymphocytic leukemia cells showed correlation with DR alloantisera submitted to the Seventh International Histocompatibility Workshop. Although the correlation coefficients were lower than those obtained with DR alloantisera, the results obtained suggest that DR xenoantisera may recognize allotypic specificities. PMID- 21302090 TI - Genetic differences unrelated toH-2 inH-2 congenic mice. PMID- 21302091 TI - Estimates of histocompatibility differences between inbred mouse strains. PMID- 21302093 TI - Matrix techniques applied to CML-typedH-2 mutants. AB - Techniques associated with the Labeled Reaction Matrix model are used to provide several assignments of discrete labels to some serologically identical, CML typedH-2 haplotypes. It is shown how this model can utilize the internal consistency of a labeling scheme to aid in making decisions on assigning values of 'positive' or 'negative' to reactions of questionable strength. A few examples of labeling schemes that may suggest further experimentation are derived. PMID- 21302094 TI - 'Hybrid resistance' against parental tumors: One or several genetic patterns? AB - A spectrum of lymphomas, sarcomas, and carcinomas were tested for F(1) hybrid resistance after s.c. inoculation of small numbers of cells into syngeneic and F(1) hybrid mice. Significant F(1) resistance was demonstrated against all tumors tested except one. Backcross and/or congenic inoculation tests showed significantH-2 linkage of hybrid resistance against all lymphomas and leukemias tested. There was no linkage betweenH-2 and hybrid resistance within the more limited group of carcinomas and sarcomas. DifferentH-2-linked resistance genes were shown to act against different lymphomas, including some that were induced by the same agent. Some lymphomas induced by different agents in the same strain were also found to differ in their sensitivity to the sameH-2-linked resistance factor. These data suggest the existence of a polymorphic system, probably pseudoallelic, rather than simply allelic in nature. PMID- 21302095 TI - Intra-H-2 recombination inH-2(b)/H-2 (t1) heterozygotes in the mouse : II. Characterization of recombinant haplotypesat2, at3, andat4. AB - Four cases of intra-H-2 recombination were detected during serological screening of 1066 backcross animals produced fromH-2(b)/H-2(t1) heterozygous mice. Three of the intra-H-2 recombinants received theK region fromH-2(t1) and theD region from theH-2(b) parental chromosome. The remaining recombinant received theK region from theH-2(b) parental chromosome and theD region fromH-2(t1). Three of the four recombinants have been developed into inbred lines TBR2, TBR3, and TBR4 and were assigned the haplotype designations at(2), at(3), and at(4). Ss typing revealed that TBR2 and TBR3 originated fromK- S interval crossover events, while the remaining two recombinants resulted from crossing over in theS- D interval. PMID- 21302096 TI - The alleles of theH-13 locus. AB - Seven congenic strains differing from C57BL/10Sn at theH-13 locus have been produced which define fourH-13 alleles. Isografting, exchanging of grafts between sublines, F(1) testing, and linkage testing demonstrate the presence of additionalH genes in four of these strains. The medial survival times (MSTs) of skin grafts fromH-13(a) to unimmunizedH-13(b) recipients ranged from 69 to 83 days. Rejection across all other barriers was extremely weak with most MSTs being > 100 days. Preinjection of donor strain thymocytes caused accelerated rejection of skin grafts fromH-13(a) toH-13(b) mice, but had only minimal effect on skin grafts across other barriers. Rejection ofH-13 incompatible grafts was significantly stronger when the donor and host areH-3(a) than when they wereH 3(b). PMID- 21302097 TI - Partial amino acid sequences of mouse transplantation antigens. AB - The partial N-terminal amino acid sequences of the K and D gene products from theH-2 ( q ) andH-2 ( s ) haplotypes are presented. These data in conjunction with data already published demonstrate striking homology relationships among the transplantation antigens of mouse and other species. Moreover, these new data support the presence of certain sequence patterns noted in earlier sequence studies (e. g. no Kness or Dness, species-associated residues, and complex allotypes). These patterns place interesting constraints on the genetic organization and evolutionary history of the genes encoding the transplantation antigens which are discussed in this report. PMID- 21302098 TI - The Biochemical characterization of syrian hamster cell-surface alloantigen : I. Analysis of allogeneic differences between recently wild and highly inbred hamsters. AB - The first alloantiserum to be described in Syrian hamsters has been characterized for its ability to react with externally and internally radiolabeled antigens derived from normal hamster lymphoid cells. Utilizing conventional biochemical techniques, radioiodinated and(3)H-leucine labeled cellular extracts have been prepared, partially purified by lentil lectin affinity chromatography, and indirectly immunoprecipitated with experimental alloantisera. Analysis of the precipitated radiolabeled antigens by polyacrylamide gel electrophoresis in SDS has identified two prominent cell-surface proteins at 39,000 (p39) and 29,000 daltons (p29) on 2-mercaptoethanol reduced gels. Further analysis of the radiolabeled extract has demonstrated the existence of hamster cell-surface proteins at 43,000 and 12,000 daltons which are immunoprecipitated by a xenoantiserum directed against human beta(2) microglobulin. Coelectrophoretic studies indicate the independent identity of these four species of hamster cellsurface proteins. These results suggest that between two hamster lines, derived from animals caught 40 years apart from different geographic locations in Syria, polymorphism of cell-surface antigens is restricted to p39 and p29 molecular species. PMID- 21302099 TI - H-2 Antigen variants in a cultured heterozygous mouse leukemia cell line : IV. Cell-Mediated cytolysis of wild type and variant cells. AB - H-2 antigen variants, derived from a heterozygous mouse Friend leukemia cell line by selection with anti-H-2 antisera and complement, were tested for susceptibility to cell-mediated cytolysis, using T-lymphocytes directed against individual H-2 antigens. The cytotoxic cells were generated in the BALB and B10 backgrounds by a combination of in vivo and in vitro immunizations. The phenotypes of the variants inferred from the patterns of resistance or susceptibility to CML were consistent with those presumed from earlier assays using antisera. The one exception was the variant cell line which was H-2D(d-) in assays using antisera, but was H-2D(d+) by CML. PMID- 21302100 TI - Expression of ia antigens by murine keratinizing epithelial langerhans cells. AB - Immunofluorescent and immunoelectron-microscopic staining methods were utilized to investigate the localization of Ia antigens in murine keratinizing epithelia. Approximately 3-5% of epidermal cells were shown to be Ia positive. Only dendritic Langerhans cells in the interfollicular epidermis and outer root sheaths were found to express Ia antigens. These Ia determinants were shown to be controlled by both theI- A andI- EC subregions of theH-2 complex. The results were confirmed by identifying positively stained cells containing Langerhans cell granules at the ultrastructural level. No staining was noted on the surface of keratinocytes, melanocytes, or immigrant lymphocytes. The results presented are in close agreement with those previously reported for Ia-bearing Langerhans cells in human and guinea pig epidermis. PMID- 21302101 TI - Defining specificities, genes, antigens, and antibodies- A matrix approach. AB - We study the consequences of assigning single letter symbols to operationally defined entities such as genes, antigens, specificities, and antibodies. If this is to be done and if reagents are not specific in recognizing the products of single genes or single antigens, then these entities must be defined by a 'definition matrix' to avoid mislabeling a matrix of data. A method is given whereby for a given matrix of data all possible definition matrices consistent with this data can be obtained. In particular, all the ways of labeling by the complex-complex code of Hirschfeld can be so obtained. PMID- 21302102 TI - The major histocompatibility complex of the rat,RT1 : I. serological characterization of the MNR haplotype (RT1 ( m )) in regard to the cross-reacting haplotypesRT1 ( a ),RT1 ( c ), andRT1 ( b ). AB - The antigenic determinants expressed on RBC and lymphocytes and coded for by the MHC, RT1,of the MNR (RT1 ( m )) rat strain were compared to those of the BN.DA(RT1 ( a )), ALB (RT1 ( b )), and AUG (RT1 ( c )) strains by direct cytotoxicity and absorption analysis with RT1 typing sera, sera produced against MNR cells, and sera produced in MNR responders against cells carrying thea, b, andc haplotype determinants. The results indicate that MNR shares major class I (A) antigens with DA, and major class II (B) determinants with AUG, but that MNR differs from DA and AUG with respect to both classes of determinant. It appears, therefore, that the MNR haplotype does not represent a simple composite of the two other haplotypes,RT1 ( a ) andRT1 ( c ), as reported earlier. PMID- 21302103 TI - The major histocompatibility complex of the rat,RT 1 : II. biochemical evidence for a complex genetic organization. AB - Recombinational analysis has shown that the rat MHC,RT1 is divided into two regions:RT1.A, which codes for class I (transplantation) antigens, andRT1.B, which controls the humoral immune response and proliferative response to allogeneic cells as well as the expression of class II (Ia) antigens. Serological and sequence studies suggest that there might be more than one antigen-coding locus within theRT1.A region. Results obtained by sequential immunoprecipitation reveal that both regions code for at least two gene products. By implication, theRT1 complex must therefore harbor at least four loci;RT1.A andD coding for class I glycoproteins (45,000 daltons); andRT1.B andE coding for class II (Ia) glycoproteins (35,000 and 28,000 daltons). PMID- 21302104 TI - Immunoglobulin levels in chickens with inherited muscular distrophy. AB - Blood serum levels of 7S Ig appear to be a highly heritable (h(2)=0.76) trait. A possibly weak association of high 7S Ig with the phenotype of inherited muscular dystrophy is noted. In contrast to a previous study (Sanders and Kline 1977), our survey of 4 comparisons in paired lines showed dystrophics with slightly elevated 7S Ig levels and no differences in IgM levels when compared to controls. PMID- 21302105 TI - Expression of Ly-6 on activated T and B cells: Possible identity with Ala-1. AB - The antigens Ala-1 and Ly-6 were first thought to be different on the grounds that Ala-1 was present only on activated T and B lymphocytes while Ly-6 was present only on post-thymic T lymphocytes. In this paper, it is shown that Ly-6 is expressed on activated B cells, including PFC and LPS blasts, and that after typing of several recombinant inbred lines,Ala-1 andLy-6 remain genetically inseparable. Based on available data, it is most likely that Ly-6 is in fact Ala 1, although further testing is required to confirm the absence of Ly-6 from nonactivated lymphocytes. PMID- 21302106 TI - Rat cell surface antigens: Nonidentity of the H-4 and Ag-F traits. AB - Animals partially congenic to Lewis have been bred that differ at the locus, linked to C., which controls the Ag-F antigenic trait. Skin grafts from these animals, placed on Lewis recipients, were not rejected. This result demonstrates that Ag-F does not mediate skin incompatibility and, thus, is distinct from H-4, which was defined based on a demonstrable incompatibility and which is also linked to C. PMID- 21302107 TI - Murine cytotoxic T-cell response to alphavirus is associated mainly withH- 2D ( k ). AB - A secondary in vitro response to alphaviruses Bebaru, Sindbis, and Semliki Forest is described. Optimum response appears at day 5-6 of culture. The cells responsible for lytic activity are nonadherent, Phi-positive, Ig(-), and mainly Ly-2.1 positive. Out of five haplotypes tested (H- 2 ( d ),H- 2 ( b ),H- 2 ( s ),H- 2 ( q ), andH- 2 ( k )) onlyH- 2 ( k ) was a responder. Genetic mapping of the response located it solely in theD region of theH- 2 complex. The other four haplotypes responded with a high antiself activity after a second stimulation with viruses. This antiself response also maps in theD region of theH- 2 complex. No complementation was observed in F(1) hybrids between responder and nonresponder strains. PMID- 21302110 TI - Relapsing thrombocytopenia leading to the diagnosis of pre-symptomatic Hashimoto's thyroiditis. PMID- 21302111 TI - Hemoglobin Lepore EF Bart's disease: a molecular, hematological, and diagnostic aspects. AB - We report the molecular basis and hematological phenotype associated with a hitherto undescribed interaction of hemoglobin (Hb) Lepore-Hollandia, Hb E and a deletion of three alpha-globin genes found in a 3-year-old Thai girl. She had mild anemia with Hb 10.9 g/dl and Hct 35.9% and had never received blood transfusion. Hb analysis revealed Hb E (22.1%) with a normal level of Hb A(2) (1.9%), unusually elevated Hb F (65.9%), Hb Lepore (4.0%), and 5.4% Hb Bart's. Globin gene analyses demonstrated that she carried the Hb Lepore-Hollandia mutation in trans to the Hb E and a compound heterozygosity for alpha(0) thalassemia (SEA deletion) and alpha(+)-thalassemia (3.7 kb deletion), leading to the Hb Lepore EF Bart's disease. Hematological data and diagnostics using combined Hb-HPLC, capillary electrophoresis, and PCR analysis of this condition were presented and compared with those of the patients with other forms of EF Bart's disease and EE Bart's disease in our series. PMID- 21302112 TI - CML with e6a2 BCR-ABL1 transcript: an aggressive entity? PMID- 21302113 TI - Hemolysis and methemoglobinemia due to hepatitis E virus infection in patient with G6PD deficiency. PMID- 21302114 TI - Primary effusion lymphoma of T-cell origin with t(7;8)(q32;q13) in an HIV negative patient with HCV-related liver cirrhosis and hepatocellular carcinoma positive for HHV6 and HHV8. PMID- 21302115 TI - Chronic nonspherocytic hemolytic anemia due to glucose-6-phosphate dehydrogenase deficiency: report of two families with novel mutations causing G6PD Bangkok and G6PD Bangkok Noi. AB - Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the most common hereditary enzymopathies worldwide. Mostly G6PD deficient cases are asymptomatic though they may have the risk of neonatal jaundice (NNJ) and acute intravascular hemolysis during oxidative stress. Chronic nonspherocytic hemolytic anemia (CNSHA) due to G6PD deficiency is rare. In Thailand, one case was reported 40 years ago and by biochemical study this G6PD was reported to be a new variant G6PD Bangkok. We, herein, report two families with CNSHA due to G6PD deficiency. In the first family, we have been following up the clinical course of the patient with G6PD Bangkok. In addition to chronic hemolysis, he had three acute hemolytic episodes requiring blood transfusions during childhood period. Multiple gallstones were detected at the age of 27. His two daughters who inherited G6PD Bangkok from him and G6PD Vanua Lava from his wife are asymptomatic. Both of them had NNJ and persistent evidences of compensated hemolysis. Molecular analysis revealed a novel missense mutation 825 G->C predicting 275 Lys->Asn causing G6PD Bangkok. In the second family, two male siblings are affected. They had NNJ and several hemolytic episodes which required blood transfusions. On follow-up they have been diagnosed with chronic hemolysis as evidenced by reticulocytosis and indirect hyperbilirubinemia. Molecular analysis revealed combined missense mutations in exons 12 and 13. The first mutation was 1376 G->T predicting 459 Arg >Leu (known as G6PD Canton) and the second one was 1502 T->G predicting 501 Phe >Cys. We designated the resulting novel G6PD variant, G6PD Bangkok Noi. PMID- 21302116 TI - Pleomorphic adenoma of the nasopharyngeal mucosal space with locally aggressive appearance (2010: 11b). AB - Pleomorphic adenoma arising from submucosal minor salivary gland tissue in the head and neck is well described in the published literature. Where associated bone changes are present, benign-appearing bone remodelling is the rule, reflecting the slow growth of this benign tumour. Aggressive-appearing bone destruction was observed in this case. This atypical appearance has not been widely described. PMID- 21302117 TI - Exfoliated malignant cells at the anastomosis site in colon cancer surgery: the impact of surgical bowel occlusion and intraluminal cleaning. AB - PURPOSE: Exfoliated malignant cells, present along staple lines of anastomosis, may be responsible for anastomotic recurrence of colon cancer. We aimed to assess the impact of surgical bowel occlusion around the tumor and intraluminal lavage on the presence of exfoliated malignant cells at anastomosis sites in patients with colon cancer. METHODS: In this prospective study, 32 patients with colon cancer, requiring right hemicolectomy between January 2007 and September 2008, were randomly assigned to a control group (no surgical bowel occlusion; 18 patients) and a "no-touch" group that underwent surgical bowel occlusion around the tumor before tumor manipulation (14 patients). The fluid used intraoperatively to irrigate the portion of the bowel clamped distal to the tumor was examined cytologically, and exfoliated cells of cytological classes IV and V were considered malignant. RESULTS: In the control group, 2 (11.1%) and 10 (55.6%) of 18 patients had exfoliated malignant cells at the terminal ileum and distal colon anastomosis sites, respectively; however, only 1 (7.1%) of the 14 patients in the no-touch group had exfoliated malignant cells at both the sites. The frequency of exfoliated malignant cells at the distal colon anastomosis site was significantly lower in the no-touch group (p = 0.0024). No exfoliated malignant cells were found upon saline irrigation of 400 ml or more in either group. CONCLUSION: Measures, such as surgical bowel occlusion around the tumor and intraluminal lavage, can prevent or eliminate exfoliated malignant cells at anastomotic sites in patients with colon cancer. PMID- 21302118 TI - Simultaneous massive low gastrointestinal bleeding and hemoperitoneum caused by a capillary hemangioma in ileocecal valve. PMID- 21302119 TI - Modeling trade-off between time-optimal and minimum energy in saccade main sequence. AB - Saccadic eye movement is highly stereotyped and commonly believed to be governed by an open-loop control mechanism. We propose a principle combining time-optimal and minimum control energy criteria to account for the saccade main sequence as observed from empirical data. The model prediction revealed that the weighting factor of the energy conservation becomes more dominant than the time-optimal when the saccade amplitude is large. We demonstrate that the proposed model is a general form synthesizing the time-optimum, minimum torque change, and minimum control effort models. In addition, we show the connection between our model and the stochastic minimum variance models from the aspect of optimization. PMID- 21302120 TI - Global daily dynamics of the pineal transcriptome. AB - Transcriptome profiling of the pineal gland has revealed night/day differences in the expression of a major fraction of the genes active in this tissue, with two thirds of these being nocturnal increases. A set of over 600 transcripts exhibit two-fold to >100-fold daily differences in abundance. These changes appear to be primarily attributable to adrenergic-cyclic-AMP-dependent mechanisms, which are controlled via a neural pathway that includes the suprachiasmatic nucleus, the master circadian oscillator. In addition to melatonin synthesis, night/day differences in gene expression impact genes associated with several specialized functions, including the immune/inflammation response, photo-transduction, and thyroid hormone/retinoic acid biology. The following nonspecialized cellular features are also affected: adhesion, cell cycle/cell death, cytoskeleton, DNA modification, endothelium, growth, RNA modification, small molecule biology, transcription factors, vesicle biology, signaling involving Ca(2+), cyclic nucleotides, phospholipids, mitogen-activated protein kinases, the Wnt signaling pathway, and protein phosphorylation. PMID- 21302122 TI - Different incubation temperatures affect viral polymerase activity and yields of low-pathogenic avian influenza viruses in embryonated chicken eggs. AB - Various incubation conditions (35 degrees C-38 degrees C, 2-7 days) have been used in surveillance studies of the prevalence of avian influenza viruses in wild birds. Here, we studied viral polymerase activity and virus growth kinetics of low-pathogenic avian influenza viruses (LPAIVs) isolated from field samples [A/duck/Hong Kong/365/1978 (H4N6) and A/duck/Nanchang/2-0480/2000 (H9N2)] during incubation at different temperatures (35 degrees C, 37 degrees C, and 39 degrees C) in the allantoic cavity of 10-day-old embryonated chicken eggs (ECE). The higher incubation temperatures (37 degrees C and 39 degrees C) resulted in a significantly higher rate of virus growth, which is most likely a result of increased viral polymerase activity (20%-60%), than was observed at 35 degrees C, and as much as a 100% greater virus yield (as measured by hemagglutination assay) was observed two days after inoculation. Our findings revealed that the optimal activity of the viral polymerase complex, resulting in the highest yield of LPAIV field isolates, could be obtained by incubation for two days in ECE at 37 degrees C and 39 degrees C. PMID- 21302123 TI - Genetic diversity of sweet potato begomoviruses in the United States and identification of a natural recombinant between sweet potato leaf curl virus and sweet potato leaf curl Georgia virus. AB - In the United States, two sweet potato begomoviruses, sweet potato leaf curl virus (SPLCV) and sweet potato leaf curl Georgia virus (SPLCGV), were previously identified in Louisiana. In recent years, at least seven additional sweet potato begomoviruses have been identified in other parts of the world. In an effort to determine the genetic diversity and distribution of sweet potato begomoviruses in the U.S., we focused our efforts on molecular characterization of field-collected begomovirus isolates in two states: Mississippi and South Carolina. Using rolling circle amplification, a total of 52 clones of the full genome were obtained. Initial inspection of alignments of the end sequences in these clones revealed a strong genetic diversity. Overall, 10 genotypes could be assigned. A majority of the isolates (50/52) in eight genotypes were shown to be closely related to SPLCV. A representative clone of each genotype was fully sequenced and analyzed. Among them, four genotypes from South Carolina with 91-92% sequence identity to the type member of SPLCV were considered a new strain, whereas four other genotypes from Mississippi with >95% sequence identity to SPLCV were considered variants. In addition, a member of a proposed new begomovirus species was identified after comparative sequence analysis of the isolate [US:SC:646B-9] from South Carolina with less than 89% sequence identity to any known begomovirus. Hence, the provisional name Sweet potato leaf curl South Carolina virus (SPLCSCV) is proposed. Moreover, a natural recombinant consisting of two distinct parental genomic sequences from SPLCV and SPLCGV was identified in the sample [US:MS:1B-3] from Mississippi. Two recombinant breakpoints were identified, one in the origin of replication and the other between C2 and C4. This knowledge about the genetic diversity of begomoviruses infecting sweet potato will likely have a major impact on PCR-based virus detection and on disease management practice through breeding for virus resistance. PMID- 21302121 TI - Impact of cigarette smoking on onset of nonalcoholic fatty liver disease over a 10-year period. AB - BACKGROUND: Metabolic syndrome, which includes obesity, hyperglycemia, dyslipidemia, and hypertension, is a major risk factor for the development of nonalcoholic fatty liver disease (NAFLD). Cigarette smoking is a well-known risk factor for metabolic syndrome, but the epidemiological impact of cigarette smoking on development of NAFLD is unclear. METHODS: In this retrospective study, 2,029 subjects underwent a complete medical health checkup in 1998 and again in 2008. Those who were positive for hepatitis B surface antigen or hepatitis C virus antibody, or had an alcohol intake of > 20 g/day as assessed by questionnaire, were excluded. Fatty liver was diagnosed by abdominal ultrasonography. Independent risk factors associated with the development of NAFLD were determined by multiple logistic regression analysis. Smoking status was expressed using the Brinkman index (BI), which was calculated as the number of cigarettes smoked per day multiplied by the number of years of smoking. RESULTS: Of 1,560 subjects without NAFLD in 1998, 266 (17.1%) were newly diagnosed with NAFLD in 2008. Multiple logistic analysis identified age [adjusted odds ratio (AOR) 0.95, 95% confidence interval (95% CI) 0.94-0.97], male sex (AOR 1.46, 95% CI 1.01-2.10), body mass index >= 25 (AOR 3.08, 95% CI 2.20-4.32), dyslipidemia (AOR 1.79, 95% CI 1.25-2.58) and cigarette smoking (AOR 1.91, 95% CI 1.34-2.72) as risk factors associated with the development of NAFLD. Smoking status at baseline was also associated with the development of NAFLD (BI 1-399: AOR 1.77, 95% CI 1.02-3.07, BI >= 400: AOR 2.04, 95% CI 1.37-3.03). CONCLUSION: Cigarette smoking is an independent risk factor for onset of NAFLD. PMID- 21302124 TI - Feline leukemia virus outbreak in the critically endangered Iberian lynx (Lynx pardinus): high-throughput sequencing of envelope variable region A and experimental transmission. AB - The Iberian lynx is the most endangered felid species. During winter/spring 2006/7, a feline leukemia virus (FeLV) outbreak of unexpected virulence killed about 2/3 of the infected Iberian lynxes. All FeLV-positive animals were co infected with feline hemoplasmas. To further characterize the Iberian lynx FeLV strain and evaluate its potential virulence, the FeLV envelope gene variable region A (VRA) mutant spectrum was analyzed using the Roche 454 sequencing technology, and an in vivo transmission study of lynx blood to specified-pathogen free cats was performed. VRA mutations indicated weak apolipoprotein B mRNA editing enzyme and catalytic polypeptide-like cytidine deaminase (APOBEC) restriction of FeLV replication, and variants characteristic of aggressive FeLV strains, such as FeLV-C or FeLV-A/61C, were not detected. Cats exposed to FeLV/Candidatus Mycoplasma haemominutum-positive lynx blood did not show a particularly severe outcome of infection. The results underscore the special susceptibility of Iberian lynxes to infectious diseases. PMID- 21302126 TI - Prevalence of hyperuricemia in Bangkok population. AB - To investigate the prevalence of hyperuricemia in general Thai population and to evaluate its association with metabolic syndrome. A total of 1,945 subjects who sought for routine annual health checkup in our hospital from 1 October 2009 to 31 March 2010 were enrolled into the study. Inclusion criteria were healthy individuals, aged >=35 years old, and lived in Bangkok for over 10 years. Data of general health status, age, gender, history of alcoholic consumption, body weight, height, and waist circumference were obtained by an interview-structured questionnaire. Fasting blood sample was collected from each subject early in the morning for uric acid, total cholesterol, high density lipoprotein cholesterol, triglycerides, and glucose levels. The prevalence of hyperuricemia in our study population was 24.4%, being significantly more common in men than women (59% vs. 11%, p < 0.001). The condition was also associated with various features of high body mass index or waist circumference, alcohol consumption, dyslipidemia, and high fasting blood glucose. Metabolic syndrome was found in 35% and 23% of men and women with hyperuricemia; direct relationship between level of uric acid and prevalence of metabolic syndrome was observed. Hyperuricemia is common among Bangkok population in our study. This disorder is frequently associated with metabolic syndrome. PMID- 21302127 TI - The first case of bloodstream infection by Candida intermedia in Japan: the importance of molecular identification. AB - A 65-year-old Chinese man with diabetes mellitus was admitted to our hospital complaining of bloody sputum, fever, and dyspnea. Despite antibiotic treatment, his condition deteriorated, necessitating mechanical ventilation. Diffuse alveolar hemorrhage was suspected, and steroid therapy was initiated. Although his condition improved and he was extubated, the fever recurred twice, and on both occasions blood cultures yielded yeasts. The yeasts were misidentified as Cryptococcus humicola with a commercially available phenotype test (API ID32C), which did not match the clinical profile, and molecular identification was then performed. The isolates were identified as Candida intermedia by molecular phylogenetic analyses of the chromosomal regions coding for the D1/D2 domain of the large-subunit 26S rRNA gene. The patient responded well to several antifungal agents and was discharged on the 34th hospital day. To our knowledge, this is the first case of C. intermedia infection reported in Japan, and the tenth case reported in the international medical literature. PMID- 21302125 TI - Characteristics of chronic fatigue syndrome in a Japanese community population : chronic fatigue syndrome in Japan. AB - This study seeks to estimate the prevalence of chronic fatigue syndrome (CFS) and assess the characteristics of CFS in a community population in Japan using laboratory tests and questionnaires for lifestyle, fatigue states, and depression states. The design of this study is a cross-sectional observational study. The setting of this study is a medical health checkup program in a general hospital. This study was conducted with 1,430 Japanese (867 men and 563 women), 20 to 78 years of age. We classified participants who complained of fatigue according to the case definition of CFS proposed by the Centers for Disease Control and Prevention in the USA in 1994. Alcohol, caffeine, catechin and total polyphenol consumption, smoking status, sleep duration, and physical activity were evaluated using questionnaires. The prevalence of CFS was 1.0% (95% CI 0.5-1.6%) of a community population in Japan. Although various lifestyle factors of the participants with CFS were similar to those without chronic fatigue, average sleep duration was significantly shorter among the participants with CFS (5.5 +/- 0.8 h) compared to those without chronic fatigue (6.3 +/- 0.9 h, P < 0.001). Proportion at subjects having average sleep duration of less than 6 h was 64.3% among the participants with CFS in contrast to only 15.0% in those without chronic fatigue (P < 0.001). Among the eight case-defining symptoms, "Unrefreshing sleep" had high sensitivity and high specificity for screening CFS in Japanese population (92.9% and 87.8%, respectively). The average sleep duration was notably shorter in Japanese suffering from CFS. Further longitudinal study is needed to evaluate the possibility of extreme short sleep duration as a major cause of CFS in Japan. PMID- 21302128 TI - Japanese guideline for clinical research of antimicrobial agents on urogenital infections: the first edition. PMID- 21302129 TI - Ethnic differences in diabetes-related mortality in the Brussels-Capital Region (2001-05): the role of socioeconomic position. AB - OBJECTIVES: To examine if and to what extent ethnic differences in diabetes related mortality are associated with differences in education and housing status. METHODS: The data consist of a cohort study linking the 2001 census to emigration and mortality data for the period 2001-05. The study population comprises all Belgian and North African inhabitants of the Brussels-Capital Region (BCR) aged 25-74. Age-standardized mortality rates (ASMRs) (direct standardization) and mortality rate ratios (MRRS) (Poisson regression) are computed. RESULTS: North Africans have a higher diabetes-related mortality compared to Belgians. The ASMRs for North African and Belgian women are 54.8 (95% confidence interval (CI) 31.5-78.2) and 23.8 (95% CI 20.3-27.3), respectively. These differences in diabetes-related mortality largely disappear when differences in education are taken into account. The MRRs for North African versus Belgian origin drop from 1.62 (95% CI 1.11-2.37) to 1.19 (95% CI 0.73 1.93) in men and from 3.35 (95% CI 2.08-5.41) to 1.88 (95% CI 0.95-3.69) in women. CONCLUSIONS: Differences in education play an important part in the excess diabetes-related mortality among North Africans in the BCR. PMID- 21302130 TI - Changing health inequalities in Germany from 1994 to 2008 between employed and unemployed adults. AB - OBJECTIVES: Unemployment is a major determinant of health. We investigate whether health inequalities with regards to employment status have changed in Germany. METHODS: We used longitudinal data for the years 1994-2008 from a representative panel study (GSOEP). The sample consisted of respondents aged 30-59 years (15 waves, 21,329 persons, 129,526 observations). We analyzed trends and determinants of self-rated health status by employment status using logistic regression and fixed-effects logistic panel models. RESULTS: Health inequalities by employment status increased significantly by 72% in men and by 16% in women after controlling covariates. The trends were partly mediated by consequences of unemployment such as income loss, income poverty, life satisfaction and economic sorrows. Using regression models for panel data we confirmed that the observed increases in health inequalities at the population level also exist at the individual level. DISCUSSION: Altogether, our findings indicate that health inequalities with regards to employment status increased among men between 1994 and 2008. This observation is in line with increasing income inequalities in Germany and with increasing health inequalities in other European countries. PMID- 21302131 TI - Production of beta-apo-10'-carotenal from beta-carotene by human beta-carotene 9',10'-oxygenase expressed in E. coli. AB - The gene encoding human beta-carotene-9',10'-oxygenase, which cleaves the 9',10' double bond in beta-carotene into beta-apo-10'-carotenal, was cloned and expressed in Escherichia coli. Under aqueous conditions, the optimum organic solvent for the formation of detergent micelles was toluene. The optimum pH, temperature, detergent type, and the optimum concentrations of detergent, substrate, and enzyme for beta-apo-10'-carotenal production were 8.0, 37 degrees C, Tween 40, 2.4%, 300 mg beta-carotene/l, and 0.25 U/ml, respectively. Under the optimum conditions, 43 mg beta-apo-10'-carotenal/l was produced after 21 h with a conversion of 14%. This is the first report to describe the enzymatic production of beta-apo-10'carotenal. PMID- 21302132 TI - Oral immunization of mice with Lactococcus lactis expressing the rotavirus VP8* protein. AB - The efficacy of recombinant Lactococcus lactis as a delivery vehicle for a rotavirus antigen was evaluated in a mouse model. The rotavirus VP8* protein was expressed intracellularly and extracellularly in L. lactis wild type and in an alr mutant deficient in alanine racemase activity, necessary for the synthesis of the cell-wall component D: -alanine. When the mucosal immune response was evaluated by measuring VP8*-specific IgA antibody in faeces, wild-type L. lactis triggered a low IgA synthesis only when the secreting strain was used. In contrast, VP8*-specific IgA was detected in faeces of both groups of mice orally given the alr mutant expressing extracellular VP8* and intracellular VP8*, which reached levels similar to that obtained with the wild type secreting strain. However, oral administration of the recombinant strains did not induce serum IgG or IgA responses. L. lactis cell-wall mutants may therefore provide certain advantages when low-antigenic proteins are expressed intracellularly. However, the low immune response obtained by using this antigen-bacterial host combination prompts to the use of new strains and vaccination protocols in order to develop acceptable rotavirus immunization levels. PMID- 21302133 TI - Nurses' views on electronic medical records (EMR) in Turkey: an analysis according to use, quality and user satisfaction. AB - Electronic medical records are generally used by nurses in hospitals. However, studies investigating views on and evaluations of electronic medical records by nurses are limited in Turkey and in other countries around the world. Thus, in this study, nurses' views on electronic medical record systems will be investigated in terms of use, quality and user satisfaction. Our goal was to investigate the views on electronic medical records used by nurses working at hospital clinics (inpatient care units). Moreover, in this study, we will examine whether there are relationships among the use, quality and user satisfaction of electronic medical records. This study is composed of field research conducted using questionnaires. To prepare the data-measuring instrument, the literature on electronic medical records was reviewed. In addition, during the pilot run of the questionnaire, some revisions were made to the measuring instrument to account for the views of nurse managers in the field. The questionnaire consists of 35 items: 12 items for use, 12 items for quality and 11 items for user satisfaction. A Likert scale type was used in this questionnaire. Responses for usage and quality were assigned a value of 1-5 ('never/almost never/not at all' to 'always/almost always') for each item. Responses for user satisfaction were assigned a value of 1-5 ('not at all', to 'very great') for each item. The study was planned and conducted on nurses working at inpatient care units at one public university hospital, one Turkish Ministry of Health hospital and one private hospital in Kocaeli. A sampling technique was not used because we aimed to conduct the questionnaire among all nurses. At the end of this study, the questionnaire had been conducted on 200 nurses. We found that the average score for the nurses' satisfaction with electronic medical records was 3.28, the average score for using electronic medical records was 1.96, and the average score for the quality of electronic medical records was 3.16. We also determined that there are significant relationships among the use, quality and user satisfaction of electronic medical records. This study revealed that there are significant differences among the mean quality scores for the EMR systems in the Ministry of health hospital, the university hospital and the private hospital. Interestingly, 59.0% of all participants in this study felt that EMR systems were not well integrated into their workflow. In addition, half of all respondents had not been trained in using EMR systems. PMID- 21302134 TI - Sphingosine-1-phosphate attenuates lung injury induced by intestinal ischemia/reperfusion in mice: role of inducible nitric-oxide synthase. AB - Multiple organ failure, including acute lung injury (ALI), is a common complication of intestinal ischemia/reperfusion (I/R) injuries and contributes to its high mortality rate. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that enhances vascular barrier function and has anti-inflammatory effects. In the current study, we investigated the effect of S1P on lung injury induced by intestinal I/R. Mice were randomly assigned to one of the following groups: (1) sham-operated mice, (2) mice exposed to superior mesenteric artery occlusion for 45 min followed by reperfusion for 6 h, or (3) mice exposed to I/R that received S1P (100 MUg/kg, administered by peritoneal injection). S1P markedly attenuated lung injury, manifested by the improvement of histological changes and significant decreases of lung water content. Moreover, S1P markedly reduced MDA levels and MPO activity in the lung tissues, and plasma levels of proinflammatory cytokines. In addition, S1P treatment significantly suppressed NO generation accompanied by down-regulation of iNOS expression. The results indicate that S1P has a protective effect on lung injury induced by I/R, which may be related to its suppression of iNOS-induced NO generation. S1P seems to be an effective therapeutic agent for intestinal I/R-related lung injury. PMID- 21302135 TI - Attenuation of hyperoxia-induced lung injury in rats by adrenomedullin. AB - Oxidative stress and inflammation are involved in the pathogenesis of acute lung injury (ALI). Adrenomedullin (AM) is an endogenous peptide with anti-inflammatory and antioxidant properties. This study investigated that whether AM treatment may ameliorate hyperoxia-induced ALI in rats via inhibition of oxidative stress and inflammation. Rats were randomized to receive continuous intravenous infusion of AM or saline through a microosmotic pump, and then ALI was induced by exposing the animals in sealed cages >95% oxygen for 72 h. Exposure to hyperoxia caused lung injury as increased infiltration of inflammatory cells and disruption of lung architecture. AM administration markedly improved these changes. Additionally, AM administration significantly increased glutathione peroxidase and superoxide dismutase activities. Meanwhile, hyperoxia-induced increase of lipid hydroperoxide level was markedly reduced by AM treatment. Moreover, nuclear factor-kappa B-DNA-binding activity, and production of the inflammatory mediators interleukin-6, keratinocyte-derived chemokine, and matrix metalloproteinase 9, were significantly inhibited by AM treatment. AM ameliorates hyperoxia-induced ALI in rats by suppression of oxidative stress and inflammation. PMID- 21302136 TI - Estrogen suppresses metastasis in rat hepatocellular carcinoma through decreasing interleukin-6 and hepatocyte growth factor expression. AB - Metastasis remains one of the major challenges before hepatocellular carcinoma (HCC) is finally conquered. Estrogen has recently emerged as a protective factor in the development and progression of HCC, but whether and how it reduces metastasis of HCC remain to be elucidated. We conducted an in vivo highly metastatic rat HCC model in female Sprague-Dawley rats induced by diethylnitrosamine and N-nitrosomorpholine to examine the effects of estrogen on HCC metastasis. Moreover, female rats were randomly distributed into four groups: ovariectomy (OVX), sham operation, ovariectomy followed by 30 MUg/kg body weight/day 17alpha-ethynylestradiol supplementation, and sexually intact control groups. Here, we show that, 60% lung metastasis was observed in the rats of OVX group, whereas 17-25% lung metastasis was found in rats of the other three groups. Furthermore, physiological doses of estrogen, no matter endogenous or exogenous, can suppress metastasis of HCC through decreasing interleukin-6 (IL-6) and hepatocyte growth factor (HGF) expression in the tumor microenvironment. In conclusion, the present study demonstrated that estrogen has the potential to inhibit lung metastasis from rat HCCs in vivo. Its mechanism of action may involve modulation of inflammatory tumor microenvironment by suppression of HGF and IL-6 production. PMID- 21302137 TI - Bleeding lesions within reach of conventional endoscopy in capsule endoscopy examinations for obscure gastrointestinal bleeding: is repeating endoscopy economically feasible? AB - BACKGROUND: Most tertiary gastroenterology centers currently offer an open-access capsule endoscopy (CE) service, including patients with obscure gastrointestinal bleeding. However, CE may identify lesions missed by conventional endoscopy. AIMS: To determine the incidence of bleeding lesions missed by the preceding gastroscopy/colonoscopy that were revealed by CE and compare potential differences in the rate of identifying such lesions in patients that we investigated as opposed to those investigated elsewhere. METHODS: We prospectively reviewed data from patients subjected to CE for obscure bleeding. We analyzed all cases where a source of bleeding was located in the stomach, duodenum, or colon. RESULTS: A total of 317 consecutive patients were subjected to CE for obscure gastrointestinal bleeding within 28 months. Prior to CE examination, 174 patients had gastroscopy and colonoscopy in our institutions and 143 were referrals, all with negative endoscopic investigation. We identified 11 (3.5%) cases where the source of bleeding was found in the stomach (n = 4) or the cecum (n = 7). There was a significant difference of extra small intestinal lesions diagnosed by CE between referrals (9/143, 6.3%) and endoscopic investigation performed in our institutions (2/174, 1.15%), (p = 0.026). The estimated cost of re-endoscoping in our institution all CE referrals would be 50,050 euro (143 patients * 350 euro), to avoid unnecessary CE examinations (9 patients * 600 euro = 5,400 euro). CONCLUSIONS: Reading the whole CE video is important, because small-bowel CE may identify lesions responsible for obscure bleeding missed by the preceding gastroscopy and colonoscopy. Repeating conventional endoscopy by experts before CE is not a cost-effective approach. PMID- 21302139 TI - Between the quack and the fanatic: movements in our self-belief. AB - Separate from the question of whether our patients believe us as doctors is the question of whether we ourselves believe in our healing 'performances'. Borrowing from Bernard Williams' model of truth based on the two irreducible virtues of sincerity and accuracy, this article describes a spectrum of states of self belief, from the quack who does not believe in his acts to the fanatic who does not 'dis-believe', with ranges of pious fraud and bad faith in between and on either side of a variable range of justified self-belief. I describe how as practitioners we move and are moved up and down this range throughout our careers and as a result of the behaviors of others. The model provides the basis for a critique of the marketing efforts of industries related to medical practice. PMID- 21302138 TI - Acid-suppressive effect of rabeprazole 5 mg and 10 mg once daily by 24-hour esophageal pH monitoring in patients with non-erosive reflux disease in Japan: a multicenter, randomized, parallel-group, double-blind pharmacodynamic study. AB - BACKGROUND: Acid suppression induced by rabeprazole 5 mg in patients with NERD has not been reported in the literature. AIMS: The objective of this study was to investigate gastroesophageal acid suppression in NERD patients by rabeprazole 5 mg and 10 mg/day. METHODS: Subjects were grade M (minimal changes) NERD patients. Twenty-two patients not responding to open label antacid therapy entered a double blind treatment phase in which rabeprazole 5 mg or 10 mg/day for four weeks were compared. Twenty-four-hour esophageal pH monitoring was performed before and on treatment (at week 4) to assess the pharmacodynamic effect of these doses of rabeprazole. RESULTS: The frequency of heartburn episodes and the number of acid reflux episodes in the esophagus corresponded well in grade M NERD patients (r=0.44, P=0.042). Median percentage of time at pH<4 was 4.3% before treatment and 1.1% on treatment with rabeprazole 5 mg (change from baseline; -2.5%), whereas the median percentage of time at pH<4 in the rabeprazole 10 mg group was 7.4% before treatment and 0.5% on treatment (change from baseline; -6.6%). Likewise, treatment-related changes of median number of reflux episodes were 18.0 with rabeprazole 5 mg and -44.0 with rabeprazole 10 mg. For each esophageal pH data, no significant differences were observed between the two groups (P=0.377, P=0.077). CONCLUSIONS: Administration of 5 mg and 10 mg rabeprazole sufficiently inhibited pathological gastroesophageal acid reflux and relieved heartburn episodes in NERD patients who did not respond to an antacid. Further investigation would be necessary to determine proper usage of the two doses. PMID- 21302140 TI - Comorbidity-related treatment outcomes among HIV-infected adults in the Bronx, NY. AB - Aging, HIV infection, and antiretroviral therapy have been associated with increasing rates of chronic comorbidities in patients with HIV. Urban minority populations in particular are affected by both the HIV/AIDS and chronic disease epidemics. Our objectives were to estimate the prevalence of and risk factors for hypertension, dyslipidemia, and diabetes among HIV-infected adults in the Bronx and describe comorbidity-related treatment outcomes. This was a cross-sectional study of 854 HIV-positive adults receiving care at 11 clinics which provide HIV primary care services; clinics were affiliated with a large urban academic medical center. Data on blood pressure (BP), cholesterol, and glycemic control were collected through standardized chart review of outpatient medical records. We found prevalence rates of 26%, 48%, and 13% for hypertension, dyslipidemia, and diabetes, respectively. Older age, obesity, family history, and current protease inhibitor use were consistently associated with comorbidity. Diabetes treatment goals were achieved less often than BP and lipid goals, and concurrent diabetes was a significant predictor for BP and lipid control. In conclusion, major cardiovascular-related comorbidities are prevalent among HIV-positive adults in the Bronx, especially older and obese individuals. Differences exist in comorbidity-related treatment outcomes, especially for patients with concurrent diabetes. Because cardiovascular risk is modifiable, effective treatment of related comorbidities may improve morbidity and mortality in HIV-infected patients. PMID- 21302141 TI - Appendix B: CAAC program resources. PMID- 21302142 TI - Recent progress on phospholipases: different sources, assay methods, industrial potential and pathogenicity. AB - Significant studies on phospholipases optimization, characterization, physiological role and industrial potential have been conducted worldwide. Some of them have been directed for biotechnological advances such as gene discovery and functional enhancement by protein engineering. Others reported phospholipases as virulence factor and major cause of pathophysiological effects. A general overview on phospholipase is needed for the identification of new reliable and efficient phospholipase, which would be potentially used in number of industrial and medical applications. Phospholipases catalyse the hydrolysis of one or more ester and phosphodiester bonds of glycerophospholipids. They vary in site of action on phospholipid which can be used industrially for modification/production of new phospholipids. Catalytically active phospholipase mainly use phosphatidylcholine as major substrate, but they can also show specificity with other phospholipids. Several accurate phospholipase assay methods are known, but a rapid and reliable method for high-throughput screening is still a challenge for efficient supply of superior phospholipases and their practical applications. Major application of phospholipase is in industries like oil refinery, health food manufacturing, dairy, cosmetics etc. All types of phospholipases can be involved as virulence factor. They can also be used as diagnostic markers for microbial infection. The importance of phospholipase in virulence is proven and inhibitors of the enzyme can be used as candidate for preventing the associated disease. PMID- 21302143 TI - Isolation, identification and optimization of a new extracellular lipase producing strain of Rhizopus sp. AB - A lipolytic mesophilic fungus which produces lipase extracellularly was isolated from soil. Based on ITS1-5.8S-ITS4 region sequences of ribosomal RNA, it was concluded that the isolate JK-1 belongs to genus Rhizopus and clades with Rhizopus oryzae. The present paper reports the screening, isolation, identification, and optimization of fermentation conditions for the production of lipase (EC 3.1.1.3). Culture conditions were optimized, and the highest lipase production was observed in basal medium with corn steep liquor as nitrogen source and glucose as carbon source. Maximum lipase production was observed at 72 h, which is about 870 U/ml. Optimization of fermentation conditions resulted in 16 fold enhancement in enzyme production. PMID- 21302144 TI - Protein refolding by N-alkylpyridinium and N-alkyl-N-methylpyrrolidinium ionic liquids. AB - An important property of ionic liquids consisting of cations and anions is that the chemical structures can be easily tuned. To expand the repertoire of effective ionic liquid-based refolding additives, we focused on this tunable property and investigated the effects of new candidates such as N-alkylpyridinium chlorides and N-alkyl-N-methylpyrrolidinium chlorides on protein refolding. Denatured lysozyme (30 mg/mL) was used as a model protein and refolded by 30-fold dilution with various refolding buffers containing different ionic liquids consisting of a systematic variety of alkyl chains. Compared with the refolding yield without additives (lower than 10%), less hydrophobic ionic liquids such as N-ethyl, N-butyl and N-hexylpyridinium chlorides, and N-butyl-N methylpyrrolidinium chloride were effective in enhancing the refolding yields (46 69%), because they primarily suppressed aggregation because of their chaotropic properties. N-alkylpyridinium cations were more hydrophobic than N-alkyl-N methylpyrrolidinium cations according to the calculated log P values and prevented aggregation at lower concentrations because of their hydrophobicity. The results provide a range of new effective ionic liquid-based additives for higher protein refolding yields and the knowledge of the effect of chemical structures of additives on protein refolding. PMID- 21302145 TI - Purification and properties of a psychrotrophic Trichoderma sp. xylanase and its gene sequence. AB - A psychrotrophic fungus identified as Trichoderma sp. SC9 produced 36.7 U/ml of xylanase when grown on a medium containing corncob xylan at 20 degrees C for 6 days. The xylanase was purified 37-fold with a recovery yield of 8.2%. The purified xylanase appeared as a single protein band on SDS-PAGE with a molecular mass of approximately 20.5 kDa. The enzyme had an optimal pH of 6.0, and was stable over pH 3.5-9.0. The optimal temperature of the xylanase was 42.5 degrees C and it was stable up to 35 degrees C at pH 6.0 for 30 min. The xylanase was thermolabile with a half-life of 23.9 min at 45 degrees C. The apparent K(m) values of the xylanase for birchwood, beechwood, and oat-spelt xylans were found to be 3, 2.1, and 16 mg/ml respectively. The xylanase hydrolyzed beechwood xylan and birchwood xylan to yield mainly xylobiose as end products. The enzyme hydrolysed xylotriose, xylotetraose, and xylopentose to produce xylobiose, but it hardly hydrolysed xylobiose. A xylanase gene (xynA) with an open reading frame of 669 nucleotide base pairs (bp), encoding 222 amino acids, from the strain was cloned and sequenced. The deduced amino acid sequence of XynA showed 85% homology with Xyn2 from a mesophilic strain of Trichoderma viride. PMID- 21302146 TI - Ethanol production from cashew apple bagasse: improvement of enzymatic hydrolysis by microwave-assisted alkali pretreatment. AB - In this work, the potential of microwave-assisted alkali pretreatment in order to improve the rupture of the recalcitrant structures of the cashew able bagasse (CAB), lignocellulosic by-product in Brazil with no commercial value, is obtained from cashew apple process to juice production, was studied. First, biomass composition of CAB was determined, and the percentage of glucan and lignin was 20.54 +/- 0.70% and 33.80 +/- 1.30%, respectively. CAB content in terms of cellulose, hemicelluloses, and lignin, 19.21 +/- 0.35%, 12.05 +/- 0.37%, and 38.11 +/- 0.08%, respectively, was also determined. Results showed that, after enzymatic hydrolysis, alkali concentration exerted influence on glucose formation, after pretreatment with 0.2 and 1.0 mo L(-1) of NaOH (372 +/- 12 and 355 +/- 37 mg g(glucan)(-1) ) when 2% (w/v) of cashew apple bagasse pretreated by microwave-assisted alkali pretreatment (CAB-M) was used. On the other hand, pretreatment time (15-30 min) and microwave power (600-900 W) exerted no significant effect on hydrolysis. On enzymatic hydrolysis step, improvement on solid percentage (16% w/v) and enzyme load (30 FPU g (CAB-M) (-1) ) increased glucose concentration to 15 g L(-1). The fermentation of the hydrolyzate by Saccharomyces cerevesiae resulted in ethanol concentration and productivity of 5.6 g L(-1) and 1.41 g L(-1) h(-1), respectively. PMID- 21302147 TI - Biosynthesis and characterization of poly (3-hydroxybutyrate-co-3-hydroxyvalerate co-4-hydroxybutyrate) terpolymer with various monomer compositions by Cupriavidus sp. USMAA2-4. AB - Poly(3-hydroxybutyrate-co-3-hydroxyvalerate-co-4-hydroxybutyrate) [P(3HB-co-3HV co-4HB)] terpolymer was produced using Cupriavidus sp. USMAA2-4 via one-step cultivation process through combination of various carbon sources such as 1,4 butanediol or gamma-butyrolactone with either 1-pentanol, valeric acid, or 1 propanol. Oleic acid was added to increase the biomass production. The composition of 3HV and 4HB monomers were greatly affected by the concentration of 1,4-butanediol and 1-pentanol. Terpolymers with 3HV and 4HB molar fractions ranging from 2 to 41 mol.% and 5 to 31 mol.%, respectively, were produced by varying the concentration of carbon precursors. The thermal and mechanical properties of the terpolymers containing different proportions of the constituent monomers were characterized using gel permeation chromatography (GPC), DSC, and tensile machine. GPC analysis showed that the molecular weights (M (w)) of the terpolymer produced were within the range of 346 to 1,710 kDa. The monomer compositions of 3HV and 4HB were also found to have great influences on the thermal and mechanical properties of the terpolymer P(3HB-co-3HV-co-4HB) produced. PMID- 21302148 TI - Citrate stimulates oligosaccharide synthesis in metabolically engineered Agrobacterium sp. AB - Agrobacterium sp. ATCC 31749 was previously shown to be an advantageous host for oligosaccharide production. Unexpectedly, the addition of citrate to the oligosaccharide synthesis reaction resulted in up to a sixfold improvement in the production N-aceytl-lactosamine, a disaccharide. The possible mechanisms for this citrate-induced stimulation of oligosaccharide production were investigated, including the consumption of citrate as a carbon and energy source, enhanced metal ion solubility from citrate chelation, and the ability of citrate to act as a buffer. The main mechanisms for the effect of citrate on oligosaccharide production were determined to be carbon and energy provision from citrate consumption and pH maintenance. ATCC 31749 was shown to co-metabolize citrate along with sucrose, a preferred carbon source, indicating the lack of a catabolite repression system in this Agrobacterium. Metabolic flux analysis suggested an increase in flux through TCA cycle for the citrate-containing reaction, which may provide additional energy supply to support enhanced oligosaccharide production. The citrate stimulation of oligosaccharide synthesis was shown to be unique to the Agrobacterium strain, as a similarly engineered Escherichia coli strain did not show significant improvement in oligosaccharide production with citrate addition. This work provides insight into the metabolism of Agrobacterium sp. ATCC 31749 and highlights important factors in whole-cell oligosaccharide synthesis. PMID- 21302149 TI - Fucoidans from brown seaweeds Sargassum hornery, Eclonia cava, Costaria costata: structural characteristics and anticancer activity. AB - Fucoidans were isolated by water extraction and ion-exchange chromatography from brown algae Eclonia cava, Sargassum hornery, and Costaria costata collected near of Korean coasts. The structures of fucoidans were investigated. Fucoidan from E. cava was mixture of sulfated rhamnogalactofucan and galactofucan. Fucoidan from C. costata was a sulfated galactofucan. Fucoidan isolated from S. hornery was separated into three fractions: a homofucan sulfate, a homofucan but without sulfate groups, and a sulfated rhamnofucan. The results clearly showed that fucoidans play an inhibitory role in colony formation in human melanoma and colon cancer cells and may be effective antitumor agents. PMID- 21302150 TI - Rapid and efficient isolation of high quality nucleic acids from plant tissues rich in polyphenols and polysaccharides. AB - Isolation of high quality nucleic acids from plant tissues rich in polysaccharides and polyphenols is often difficult. The presence of these substances can affect the quality and/or quantity of the nucleic acids isolated. Here, we describe a rapid and efficient nucleic acids extraction protocol that in contrast to other methods tested, effectively purify high quality nucleic acids from plant tissues rich in polysaccharides and polyphenolic compounds such as different grape tissues and fruit tissue of fruit trees. The nucleic acids isolated with this protocol were successfully used for many functional genomic based experiments including polymerase chain reaction, reverse transcription polymerase chain reaction (RT-PCR), cloning, and semiquantitative RT-PCR. PMID- 21302151 TI - The psychology of courage: modern research on an ancient virtue. AB - While drawing on a limited field of articles and chapters on courage, the editors of The Psychology of Courage: modern research on an ancient virtue have postulated a viable history of the evolution of courage in psychology and chosen a select set of articles which advocate the influence of some of the more modern approaches to psychological thought, while relying only slightly on the historical and alternative views of courage. An alternative view and application of courage presented here examines the impact of courage as a component of a dynamic system. This dynamic systems approach allows for courage to have an interactional impact on the individual regardless of cultural identity or label. PMID- 21302152 TI - Space cannot be cut-why self-identity naturally includes neighbourhood. AB - Psychology is not alone in its struggle with conceptualizing the dynamic relationship between space and individual or collective identity. This general epistemological issue haunts biology where it has a specific focus in evolutionary arguments. It arises because of the incompatibility between definitive logical systems of 'contradiction or unity', which can only apply to inert material systems, and natural evolutionary processes of cumulative energetic transformation. This incompatibility makes any attempt to apply definitive logic to evolutionary change unrealistic and paradoxical. It is important to recognise, because discrete perceptions of self and group, based on the supposition that any distinguishable identity can be completely cut free, as an 'independent singleness', from the space it inescapably includes and is included in, are a profound but unnecessary source of psychological, social and environmental conflict. These perceptions underlie Darwin's definition of 'natural selection' as 'the preservation of favoured races in the struggle for life'. They result in precedence being given to striving for homogeneous supremacy, through the competitive suppression of others, instead of seeking sustainable, co-creative evolutionary relationship in spatially and temporally heterogeneous communities. Here, I show how 'natural inclusion', a new, post dialectic understanding of evolutionary process, becomes possible through recognising space as a limitless, indivisible, receptive (non-resistive) 'intangible presence' vital for movement and communication, not as empty distance between one tangible thing and another. The fluid boundary logic of natural inclusion as the co-creative, fluid dynamic transformation of all through all in receptive spatial context, allows all form to be understood as flow-form, distinctive but dynamically continuous, not singularly discrete. This simple move from regarding space and boundaries as sources of discontinuity and discrete definition to sources of continuity and dynamic distinction correspondingly enables self-identity to be understood as a dynamic inclusion of neighbourhood, through the inclusion of space throughout and beyond all natural figural forms as configurations of energy. Fully to appreciate and communicate the significance of this move, it is necessary to widen the linguistic, mathematical and imaginative remit of conventional scientific argument and explication so as to include more poetic, fluid and artistic forms of expression. PMID- 21302153 TI - A call for standards on perioperative CO(2) regulation. PMID- 21302160 TI - Video observation of surface exploration in cyprids of Balanus amphitrite: the movements of antennular sensory setae. AB - Video microscopy of cyprids of Balanus amphitrite was used to monitor the action of antennular setae during the exploratory behaviour prior to attachment. In addition, SEM was used to provide a revised description of all antennular setae for that species. The videos describe if a particular seta touches the substratum and the area it can cover during surface exploration. On the fourth segment, the plumose terminal setae A and B are never in contact with the substratum, lack a terminal pore and it is argued that they sense hydrodynamic forces. The aesthetasc-like terminal seta D is likewise held free in the water at all times and it is speculated that it senses dissolved substances, but, since it contains a scolopale rod, it must also have a mechano-receptive function. All remaining antennular setae on the second, third and fourth segments have a terminal pore and it is argued that these are bimodal receptors with both chemo- and mechano receptive modalities. These setae are also at one time or another in contact with the substratum, except perhaps for the small preaxial seta 2 and terminal seta C. The first seta to contact the surface during a tentative step is radial seta 5, which is longer than all other radial setae. All other setae on the second and third segment are only in contact after a step is completed. When the attachment disc touches the surface (=a step completed) the long and curved postaxial seta 2 (on the second segment) and postaxial seta 3 on the third segment are both flexed to either side of the antennule. This lateral displacement ensures that these two setae can touch large surface areas to either side of the appendage. The four subterminal setae on the fourth segment contact the surface both immediately before and after a step has been completed, and the constant flicking of the segment significantly increases the surface area tested by both these chemoreceptors and by terminal seta E, which can sweep up to 60 MUm laterally from the attachment disc. The flicking of the fourth segment may also serve to dilute the boundary layer of chemoreceptors on the fourth segment such as the aesthetasc-like terminal seta D and thus facilitate the detection of new stimuli. PMID- 21302154 TI - Contextual conditioning in rats as an animal model for generalized anxiety disorder. AB - Animal models of psychiatric disorders are important translational tools for exploring new treatment options and gaining more insight into the disease. Thus far, there is no systematically validated animal model for generalized anxiety disorder (GAD), a severely impairing and difficult-to-treat disease. In this review, we propose contextual conditioning (CC) as an animal model for GAD. We argue that this model has sufficient face validity (there are several symptom similarities), predictive validity (it responds to clinically effective treatments), and construct validity (the underlying mechanisms are comparable). Although the refinement and validation of an animal model is a never-ending process, we want to give a concise overview of the currently available evidence. We suggest that the CC model might be a valuable preclinical tool to enhance the development of new treatment strategies and our understanding of GAD. PMID- 21302162 TI - A hybrid static optimisation method to estimate muscle forces during muscle co activation. AB - The general static optimisation (GSO) process is one of various muscle force estimation methods due to its low computational requirements. However, it can show biased muscle force estimation under muscle co-contraction. In the present study, we introduced a novel hybrid static optimisation (HSO) method to estimate reasonable muscle forces during muscle co-activation movements using more specific equality constraints, i.e. agonist and antagonist muscle moments predicted from a new correlation coefficient approach. The new method was evaluated for heel-rise movements. We found that the proposed method improved the potential of antagonist muscle force estimation in comparison to the GSO solutions. The proposed HSO method could be applied in biomechanics and rehabilitation, for example. PMID- 21302161 TI - Ketamine administration in healthy volunteers reproduces aberrant agency experiences associated with schizophrenia. AB - INTRODUCTION: Aberrant experience of agency is characteristic of schizophrenia. An understanding of the neurobiological basis of such experience is therefore of considerable importance for developing successful models of the disease. We aimed to characterise the effects of ketamine, a drug model for psychosis, on sense of agency (SoA). SoA is associated with a subjective compression of the temporal interval between an action and its effects: This is known as "intentional binding". This action-effect binding provides an indirect measure of SoA. Previous research has found that the magnitude of binding is exaggerated in patients with schizophrenia. We therefore investigated whether ketamine administration to otherwise healthy adults induced a similar pattern of binding. METHODS: 14 right-handed healthy participants (8 female; mean age 22.4 years) were given low-dose ketamine (100 ng/mL plasma) and completed the binding task. They also underwent structured clinical interviews. RESULTS: Ketamine mimicked the performance of schizophrenia patients on the intentional binding task, significantly increasing binding relative to placebo. The size of this effect also correlated with aberrant bodily experiences engendered by the drug. CONCLUSIONS: These data suggest that ketamine may be able to mimic certain aberrant agency experiences that characterise schizophrenia. The link to individual changes in bodily experience suggests that the fundamental change produced by the drug has wider consequences in terms of individuals' experiences of their bodies and movements. PMID- 21302163 TI - A full body musculoskeletal model based on flexible multibody simulation approach utilised in bone strain analysis during human locomotion. AB - Load-induced strains applied to bone can stimulate its development and adaptation. In order to quantify the incident strains within the skeleton, in vivo implementation of strain gauges on the surfaces of bone is typically used. However, in vivo strain measurements require invasive methodology that is challenging and limited to certain regions of superficial bones only such as the anterior surface of the tibia. Based on our previous study [Al Nazer et al. (2008) J Biomech. 41:1036-1043], an alternative numerical approach to analyse in vivo strains based on the flexible multibody simulation approach was proposed. The purpose of this study was to extend the idea of using the flexible multibody approach in the analysis of bone strains during physical activity through integrating the magnetic resonance imaging (MRI) technique within the framework. In order to investigate the reliability and validity of the proposed approach, a three-dimensional full body musculoskeletal model with a flexible tibia was used as a demonstration example. The model was used in a forward dynamics simulation in order to predict the tibial strains during walking on a level exercise. The flexible tibial model was developed using the actual geometry of human tibia, which was obtained from three-dimensional reconstruction of MRI. Motion capture data obtained from walking at constant velocity were used to drive the model during the inverse dynamics simulation in order to teach the muscles to reproduce the motion in the forward dynamics simulation. Based on the agreement between the literature-based in vivo strain measurements and the simulated strain results, it can be concluded that the flexible multibody approach enables reasonable predictions of bone strain in response to dynamic loading. The information obtained from the present approach can be useful in clinical applications including devising exercises to prevent bone fragility or to accelerate fracture healing. PMID- 21302164 TI - Finite element analysis of aortic root dilation: a new procedure to reproduce pathology based on experimental data. AB - Sinotubular junction dilation is one of the most frequent pathologies associated with aortic root incompetence. Hence, we create a finite element model considering the whole root geometry; then, starting from healthy valve models and referring to measures of pathological valves reported in the literature, we reproduce the pathology of the aortic root by imposing appropriate boundary conditions. After evaluating the virtual pathological process, we are able to correlate dimensions of non-functional valves with dimensions of competent valves. Such a relation could be helpful in recreating a competent aortic root and, in particular, it could provide useful information in advance in aortic valve sparing surgery. PMID- 21302165 TI - 3-D finite element modelling of facial soft tissue and preliminary application in orthodontics. AB - Prediction of soft tissue aesthetics is important for achieving an optimal outcome in orthodontic treatment planning. Previously, applicable procedures were mainly restricted to 2-D profile prediction. In this study, a generic 3-D finite element (FE) model of the craniofacial soft and hard tissue was constructed, and individualisation of the generic model based on cone beam CT data and mathematical transformation was investigated. The result indicated that patient specific 3-D facial FE model including different layers of soft tissue could be obtained through mathematical model transformation. Average deviation between the transformed model and the real reconstructed one was 0.47 +/- 0.77 mm and 0.75 +/ 0.84 mm in soft and hard tissue, respectively. With boundary condition defined according to treatment plan, such FE model could be used to predict the result of orthodontic treatment on facial soft tissue. PMID- 21302166 TI - Wear analysis in anatomical and reversed shoulder prostheses. AB - This paper describes the development of a computational model to calculate wear rates in total shoulder prostheses, for a 5-150 degrees arm abduction. Anatomical keeled and pegged prosthesis as well as reversed prosthesis were the studied implants. The bone models were built based on computed tomography (CT) images and using a computer aided design-based modelling pipeline. The finite element method was used to solve the contact problem between the surface of the polyethylene (PE) components and the corresponding articular component. The aim of this work was to determine linear and volumetric PE wear, for several radial mismatches, in conditions of pathological (rheumatoid arthritis) and non-pathological bone. Results showed that contact pressures and linear wear developed in anatomical prosthesis were higher than those visualised in reversed prosthesis. However, anatomical prosthesis exhibited a better volumetric wear performance. Moreover, our findings indicated higher values of volumetric wear in higher congruent models and on pathological bone conditions. PMID- 21302167 TI - Simulation of endovascular guidewire behaviour and experimental validation. AB - Guidewire manipulation is a core skill in endovascular interventional radiology procedures. Simulation-based training offers a valuable alternative for mastering these skills, but requires a faithful replication of complex guidewire behaviour inside the vasculature. This paper presents the integration of real flexural modulus (FM) measurements into our guidewire model that mimics the flexibility of standard guidewires. The variation of FM along the length of each wire was determined for seven commonly used guidewires using a three-point bending test for the main body and a two-point bending test for the flexible end. Guidewire FM values were then attributed to seven different models, each formed by a series of particles connected by links of variable FM and replicating the flexible end shape. The FM integration was done through a trial and error process matching real FM to virtual bending coefficient. This mass-spring representation captures the required range of behaviour and enables accurate deformation within virtual vasculature. PMID- 21302168 TI - Adapting an established measure of supervision for beach settings: is the parent supervision attributes profile questionnaire reliable? AB - The Parent Supervision Attributes Profile Questionnaire (PSAPQ), developed to measure aspects of caregiver supervision and protectiveness and previously applied within playgrounds and in the home, was modified for implementation in a beach setting. To assess the test-retest reliability of the PSAPQ beach modification (PSAPQ-BEACH), 20 caregivers completed the PSAPQ-BEACH twice, over a mean interval of 18 days (range 10-24). The test-retest reliability and internal consistency of the PSAPQ-BEACH scores were compared to those of the PSAPQ. All scores on the PSAPQ-BEACH were higher than the PSAPQ, providing evidence that the questionnaire remains reliable after its adaptation to beach settings. PMID- 21302169 TI - Mild cognitive impairment subcategories depend on the source of norms. AB - The diagnosis of mild cognitive impairment (MCI) entails evidence of objective cognitive loss using neuropsychological measures. In this study, we examined whether the presence and degree of objective cognitive impairment varied according to the use of published versus local norms. We also varied the cutoff scores at which impairment was recognized and examined whether this altered inclusion in MCI subcategories. We found that the use of different comparison normative groups altered the subcategory diagnoses, especially when the cutoff score for impairment was conservative. In general, local norms were more stringent than published norms. We discuss the implications of these results for MCI diagnosis and categorization. PMID- 21302170 TI - The Trail Making Test in prodromal Huntington disease: contributions of disease progression to test performance. AB - We examined the Trail Making Test (TMT) in a sample of 767 participants with prodromal Huntington disease (prodromal HD) and 217 healthy comparisons to determine the contributions of motor, psychiatric, and cognitive changes to TMT scores. Eight traditional and derived TMT scores were also evaluated for their ability to differentiate prodromal participants closer to estimated age of diagnosis from those farther away and prodromal individuals from healthy comparisons. Results indicate that motor signs only mildly affected Part A, and psychiatric symptoms did not affect either part. Tests of perceptual processing, visual scanning, and attention were primarily associated with Part A, and executive functioning (response inhibition, set-shifting), processing speed, and working memory were associated with Part B. Additionally, TMT scores differentiated between healthy comparisons and prodromal HD individuals as far as 9-15 years before estimated diagnosis. In participants manifesting prodromal motor signs and psychiatric symptoms, the TMT primarily measures cognition and is able to discriminate between groups based on health status and estimated time to diagnosis. PMID- 21302171 TI - Assessing executive functioning: on the validity, reliability, and sensitivity of a click/point random number generation task in healthy adults and patients with cognitive decline. AB - In random number generation (RNG) tasks, used to assess executive functioning, participants are asked to generate a random sequence of digits at a paced rate, either verbally or by writing. Some previous studies used an alternative format in which participants had to randomly press different response keys, assuming that this task version demands the same cognitive processes as those implied in the standard version. The present study examined the validity of this assumption. To this end, the construct validity, reliability, and sensitivity of a conceptually similar task version of the key-press task were examined. Participants had to randomly click on, or point to, the digits 1-9, laid out orderly in a 3 * 3 grid on a computer screen. Psychometric properties of this task were examined, based on the performance of 131 healthy participants and 80 patients with cognitive decline. The results suggest that the click/point RNG task version can be used as a reliable and valid substitute for standard task versions that use the same response set and response pacing rate as those used in the present study. This task might be a useful alternative, demanding no separate recording and recoding of responses, and being suitable for use with patients with speech or writing problems. PMID- 21302172 TI - Neuropsychological picture of 33 spinocerebellar ataxia cases. AB - We administered a large battery of neuropsychological tests to an heterogeneous cohort of genetically defined spinocerebellar ataxia (SCA) patients in order to assess their cognitive profile and to compare cognitive impairment among different SCA genotypes, particularly between SCA with the classical pattern of olivo-ponto-cerebellar atrophy (SCA1 and SCA2) and those with a relatively "pure" olivo-cerebellar atrophy (SCA6 and SCA8). Our data revealed a neuropsychological picture characterized by fronto-parietal involvement with mnestic, linguistic, visuospatial, attentional, executive, and mood changes, in agreement with the cerebellar cognitive affective syndrome definition. We found a homogeneous neuropsychological profile among SCA subgroups with a prominent role of frontal dysfunction--particularly, attention, memory, and executive functions. We analyzed the possible interactions between neuropsychological pattern and clinical, demographical, and genetic variables. We found the presence of a cognitive impairment at the early stages of the disease, without visuospatial alterations, which appeared later. Age and education represented the most important demographic factors to predict the neuropsychological performance in SCA and in controls, but their effect in patients had definitely more impact. In our sample education could represent a protective factor and a marker of an enriched environment or a better developmental cognitive differentiation. We demonstrated that in our patients there was a distinct subgroup of high functional subjects and that triplet repeats modulated the effect of aging on cognition and progression of motor disability. PMID- 21302173 TI - Integrated connection to neighborhood storytelling network, education, and chronic disease knowledge among African Americans and Latinos in Los Angeles. AB - Combining key ideas from the knowledge-gap hypothesis and communication infrastructure theory, the present study aimed to explain the relations among individuals' education, access to community-based communication resources, and knowledge of chronic diseases (diabetes, hypertension, breast cancer, and prostate cancer) among African Americans and Latinos in Los Angeles. Rather than explore the effect of isolated communication resources, this study explored the effect of an integrated connection to community-based storytellers on chronic disease knowledge. The authors hypothesized that individuals' access to a community-based communication infrastructure for obtaining and sharing information functions as an intervening step in the process where social inequality factors such as education lead to chronic disease knowledge gaps in a local community context. With random samples of African Americans and Latinos in Los Angeles, the authors found that access to community-based communication resources plays a mediating role in the case of breast cancer and diabetes knowledge, but not in hypertension and prostate cancer knowledge. The authors discussed these findings on the basis of communication infrastructure theory and knowledge-gap hypothesis. PMID- 21302174 TI - Principles of part-whole selective perception by dynamic touch extend to the torso. AB - The haptic subsystem of dynamic touch expresses a novel form of part-whole selective perception. When wielding a nonvisible rod grasped at some intermediate point along its length, an individual can attend to and report the length of a part of the rod (e.g., the segment forward of the hand) or the length of the whole rod. Both perceptions relate to the rod's mass moments about the point of grasp but in systematically different ways. Previous demonstrations of this part whole selectivity have been in respect to rods grasped by hand or attached to a foot. The authors demonstrated the part-whole selectivity for nonvisible rods attached to the shoulder girdle and wielded primarily by movements of the trunk with benchmark performance provided by the same rods grasped and wielded by hand. Their results suggest that part-whole selectivity is a haptic capability general to the body. PMID- 21302175 TI - The relationship between sex guilt and sexual desire in a community sample of Chinese and Euro-Canadian women. AB - Many studies have documented significant differences in sexual desire between individuals of European and Chinese descent, but few have examined the mechanisms that underlie these differences. A recent study of university students found that sex guilt is one mechanism by which culture influences sexual desire among Chinese and Euro-Canadian women. The goal of this study was to examine whether sex guilt also mediates the relationship between ethnicity and sexual desire in a sample that is more representative of women in the general population. Euro Canadian (n = 78; mean age = 42.1 years) and Chinese (n = 87; mean age = 42.8 years) women were recruited from the community. Euro-Canadian women reported greater sexual desire and less sex guilt. In the entire sample, sex guilt mediated the relationship between ethnicity and sexual desire such that the Chinese women reported greater sex guilt, which, in turn, was associated with lower sexual desire. Among the Chinese women, sex guilt mediated the relationship between mainstream acculturation (degree of Westernization) and sexual desire such that more Westernized Chinese women reported less sex guilt, which, in turn, was associated with greater sexual desire. These results support recent findings and further suggest that sex guilt may be one mechanism by which ethnicity affects sexual desire. PMID- 21302176 TI - Quercetin inhibits diethylnitrosamine-induced hepatic preneoplastic lesions in rats. AB - Quercetin is an antioxidant flavonoid, found ubiquitously in nature and extensively used in herbal medicines and food additives. This study aimed to investigate the effect of quercetin on diethylnitrosamine-induced preneoplastic lesions, using the medium-term rat liver bioassay. The gamma-benzene hexachloride was used as promoter at the doses of 0.1, 1.0, and 10.0 mg/kg against a single dose of diethylnitrosamine (200 mg/kg) in male Sprague-Dawley rats. All the rats were subjected to 70% partial hepatectomy at Week 4. The protective effect of quercetin (5 and 25 mg/kg) was examined against the highest dose of gamma-benzene hexachloride (10 mg/kg). A significant increase in the number as well as the mean area of glutathione S-transferase placental form (GST-P) positive foci, p53 positive hepatocytes, and the percentage of apoptotic cells were observed in the diethylnitrosamine-treated group. In the present investigation, both doses of QC (5 and 25 mg/kg) led to a significant decrease in the number as well as the mean area of GST-P positive foci, TUNEL positive apoptotic cells, p53 positive hepatocytes, and restoration of cellular morphology. These results clearly indicate that quercetin inhibits diethylnitrosamine-induced hepatic preneoplastic lesions in medium-term rat liver bioassay. PMID- 21302178 TI - A new paradigm for long-term recovery. PMID- 21302177 TI - Modulation of glioma risk and progression by dietary nutrients and antiinflammatory agents. AB - Gliomas are tumors of glial origin formed in the central nervous system and exhibit profound morphological and genetic heterogeneity. The etiology of this heterogeneity involves an interaction between genetic alterations and environmental risk factors. Scientific evidence suggests that certain natural dietary components, such as phytoestrogens, flavonoids, polyunsaturated fatty acids, and vitamins, may exert a protective effect against gliomas by changing the nature of the interaction between genetics and environment. Similarly, certain antiinflammatory drugs and dietary modifications, such as methionine restriction and the adoption of low-calorie or ketogenic diets, may take advantage of glioma and normal glial cells' differential requirements for glucose, methionine, and ketone bodies and may, therefore, be effective as part of preventive or treatment strategies for gliomas. Treatment trials of glioma patients and chemoprevention trials of individuals with a known genetic predisposition to glioma using the most promising of these agents, such as the antiinflammatory drugs curcumin and gamma-linolenic acid, are needed to validate or refute these agents' putative role in gliomas. PMID- 21302179 TI - Substance abuse treatment for older adults in private centers. AB - By 2020, an estimated 4.4 million older adults will require substance abuse treatment compared to 1.7 million in 2000-01. This study examined the availability of special services for older adults, adoption of recommended treatment approaches, and organizational characteristics of centers that offer special services. Data were collected via face-to-face interviews with administrators and/or clinical directors from a nationally representative sample of 346 private treatment centers participating in the 2006-07 National Treatment Center Study. Results indicated that only 18% provided special services for older adults; age-specific recommendations were generally adopted; more older adult specialty centers offered prescription drug addiction treatment, primary medical care, and housing assistance. The proportion of patients with Medicare payment predicted availability of special services. As more older adults will seek help with a myriad of substance use disorders (SUDs) over the next decade, treatment centers need to get ready for a plethora of challenges as well as unique opportunities for growth. PMID- 21302180 TI - Testing an optimized community-based human immunodeficiency virus (HIV) risk reduction and antiretroviral adherence intervention for HIV-infected injection drug users. AB - The authors conducted a preliminary study of the 4-session Holistic Health for HIV (3H+), which was adapted from a 12-session evidence-based risk reduction and antiretroviral adherence intervention. Improvements were found in the behavioral skills required to properly adhere to HIV medication regimens. Enhancements were found in all measured aspects of sex-risk reduction outcomes, including HIV knowledge, motivation to reduce sex-risk behavior, behavioral skills related to engaging in reduced sexual risk, and reduced risk behavior. Improvements in drug use outcomes included enhancements in risk reduction skills as well as reduced heroin and cocaine use. Intervention effects also showed durability from post intervention to the follow-up assessment point. Females responded particularly well in terms of improvements in risk reduction skills and risk behavior. This study suggests that an evidence-based behavioral intervention may be successfully adapted for use in community-based clinical settings where HIV-infected drug users can be more efficiently reached. PMID- 21302181 TI - Substance use attitudes and behaviors at three pharmacy colleges. AB - The objective of this study was to profile and compare alcohol and other drug (AOD) use attitudes and behaviors in three pharmacy colleges. Student surveys of AOD use attitudes and behaviors were conducted at one southwestern and two midwestern pharmacy colleges. Response was 86.5% (566/654). Reported past-year use included alcohol 82.8%, tobacco 25.4%, and marijuana 6.9%. Past-year AOD associated events included blackouts 18.2%, class or work under influence 7.8%, patient care under influence 1.4%, lowered grades or job evaluations 5.8%, legal charges 2.7%, and heavy drinking 29.0%. Family histories of alcohol or drug problems were reported by 35.5% and 13.1%, respectively. A number of significant differences in AOD use attitudes and behaviors between the three colleges were identified. Pharmacy students reported a number of risky drug-use attitudes and behaviors in this survey. Student AOD prevention, assistance, and education should be proactively addressed by pharmacy colleges. PMID- 21302182 TI - Alcoholics Anonymous and the Minnesota Model of treatment in Iceland. AB - This study was undertaken to provide an initial characterization of the current status of patients admitted to an alcoholism treatment program in Iceland. Consistent with the Minnesota Model, 12-step facilitation has been a central component of the program since its inception. Of the 94 patients assessed in this study, 67% were male and 40% had attended over 90 AA meetings prior to admission. The mean number of drinking days during the month prior to admission was 15.51 days and the mean length of hospital stay was 12.32 days. At time of hospital discharge, 39% were referred to residential treatment. Significant predictors of referral to residential treatment included having attended less than 90 AA meetings prior to admission and length of stay. PMID- 21302184 TI - Snake bite as a novel form of substance abuse: personality profiles and cultural perspectives. PMID- 21302186 TI - Observation and physical practice: coding of simple motor sequences. AB - An experiment was conducted to determine the coordinate system used in the development of movement codes during observation and utilized on later physical practice performance of a simple spatial-temporal movement sequence. The task was to reproduce a 1.3-s spatial-temporal pattern of elbow flexions and extensions. An intermanual transfer paradigm with a retention test and two transfer tests was used: a mirror transfer test where the same pattern of muscle activation and limb joint angles was required and a nonmirror transfer test where the visual-spatial pattern of the sequence was reinstated on the transfer test. The results indicated a strong advantage for participants in the physical practice condition when transferred to the mirror condition in which the motor coordinates (e.g., pattern of muscle activation and joint angles) were reinstated relative to transfer performance when the visual-spatial coordinates were reinstated (visual and spatial location of the target waveform). The observation group, however, demonstrated an advantage when the visual-spatial coordinates were reinstated. These results demonstrate that codes based in motor coordinates can be developed relatively quickly for simple rapid movement sequences when participants are provided physical practice, but observational practice limits the system to the development of codes based in visual-spatial coordinates. Performances of control participants, who were not permitted to practise or observe the task, were quite poor on all tests. PMID- 21302187 TI - The transnasal transclival approach for clivus chordoma. AB - BACKGROUND: We present our experience using a standardized transnasal transclival approach (TTA) for endoscopic removal of chordomas of the clivus. PATIENTS: 13 patients with clival chordoma (CC) underwent tumor resection. Patients were operated by a surgical team consisting of a rhinosurgeon and a neurosurgeon. All patients underwent postoperative proton radiotherapy. Residual tumor was left in situations where radical removal would have entailed an increased risk of neurological deficits. RESULTS: Radical or near total removal of CC was accomplished in 12/13 patients. Intraoperative MRI (IMRI) was used in 4/13 CC patients. A watertight dural seal presented as the main challenge specifically for tumor extensions resulting in large dural defects. CONCLUSION: The TTA provides an elegant alternative to classical approaches to clival lesions especially for midline tumor locations. For large tumors iMRI is of significant help. Dural reconstruction of large defects emerged as the greatest challenge of this technique even for experienced endoscopic surgeons. PMID- 21302188 TI - Balancing the shortcomings of microscope and endoscope: endoscope-assisted technique in microsurgical removal of recurrent epidermoid cysts in the posterior fossa. AB - BACKGROUND: We report about endoscope-assisted surgery of epidermoid cysts in the posterior fossa focusing on the application of neuro-endoscopy and the clinical outcome in cases of recurrent epidermoid cysts. MATERIAL AND METHODS: 25 consecutively operated patients with an epidermoid cyst in the posterior fossa were retrospectively analysed. Surgeries were performed both with an operating microscope (OPMI Pentero or NC 4, Zeiss Company, Oberkochen, Germany) and endoscopic equipment (4 mm rigid endoscopes with 30 degrees and 70 degrees optics; Karl Storz Company, Tuttlingen, Germany) under continuous intraoperative monitoring. Surgical reports and DVD-recordings were evaluated for identification of adhesion areas and surgical details. RESULTS: 7 (28%) of the 25 patients were recurrences of previously operated epidermoid cysts. Mean time to recurrence was 17 years (8-22 years). In 5 cases the endoscope was used as an adjunctive tool for inspection/endoscope-assisted removal of remnants. The effective time of use of the endoscope was limited to the end stage of the procedure, but was very effective. CONCLUSION: In a modern operative setting and with the necessary surgical experience recurrent epidermoid cysts may be removed with excellent clinical results. The combined use of microscope and endoscope offers relevant advantages in demanding anatomic situations. PMID- 21302189 TI - X-knife stereotactic radiosurgery on the trigeminal ganglion to treat trigeminal neuralgia: a preliminary study. AB - BACKGROUND: Stereotactic radiosurgery is an attractive option for elderly patients and those who do not tolerate the more invasive surgical procedures available for trigeminal neuralgia (TN). In the majority of the studies, the target location was designated as the proximal nerve at the root entry zone (REZ). The purpose of this article was to evaluate the efficacy of and complications associated with X-knife stereotactic radiosurgery on the trigeminal ganglion (TG) for TN. PATIENTS AND METHODS: 40 patients with typical idiopathic TN were treated with X-knife. The maximum radiation dose was 70 Gy. A 4-mm collimator and a 9-arc technique were employed. Treatment was focused at the TG. RESULTS: At the last follow-up (mean follow-up period: 7.9 months, range: 1-19 months), pain relief for all patients was excellent in 16 (40%), good in 17 (42.5%), for a total success rate of 82.8%. The mean time to initial relief was 12.5 days ranging from immediate in onset (<24 h) to 2 months. One patient (3.0%) experienced some recurrent pain. 3 patients (7.5%) experienced noticeable subjective facial numbness. Hearing impairment was found in 1 patient (2.5%), and ulceration of the temporal skin was seen in 2 patients (5%). CONCLUSION: Similar to other TN radiosurgery reports, X-knife stereotactic radiosurgery for TN provides effective pain relief with a low complication rate. PMID- 21302190 TI - Minimally invasive technique reduces secondary brain collapse following a frontal interhemispheric approach to midline tumors with accentuated brain shift phenomena. AB - BACKGROUND: The aim of this study was to assess the influence of minimal invasive techniques (MIT) on secondary brain collapse (BC) following a frontal inter hemispheric approach to midline tumors with accentuated preoperative brain shift phenomena. METHODS: We reviewed the results obtained in our department during the last 10 years in 24 treated patients with such tumors. Some of these patients underwent traditional surgical approaches using brain retractors (BR) and more recently alternative MIT including the creation of a narrow surgical corridor without brain retractors and the reinforcement and reinsertion from bridging veins. The patient's postoperative condition (consciousness recovery, respirator dependence, ICU-patient's stay and outcome) as well as the volume of the postoperative skull/brain space as a measurable indicator of BC and the ventricular index were assessed in all cases. All data were compared using the Chi square test, the 2-tailed Pearson correlation and t-test. RESULTS: 24 patients (11 operated with BR and 13 with MIT) were analyzed. The comparison between both techniques revealed a significant reduction of the postoperatively assessed skull/brain space (P<0.001), time for consciousness recovery (P<0.05), respirator dependence (P<0.001) and intensive care unit stay (P<0.005) for patients treated with MIT. A significant correlation was observed between radiological and clinical data (respirator dependence, consciousness recovery and ICU stay) from P<0.01, P<0.05 and P<0.01 respectively. CONCLUSIONS: In our study MIT allow the patients to recover consciousness in a shorter period of time, reducing the needs for prolonged mechanical ventilation and ICU stay. In these patients, such clinical advantages are related with a radiologically assessed postoperative reduced brain collapse. PMID- 21302191 TI - Minimally invasive spinal surgery using nucleoplasty and the Dekompressor tool: a comparison of two methods in a one year follow-up. AB - OBJECT: The Disc Dekompressor and Nucleoplasty are 2 different, minimally invasive, percutaneous methods in the therapy for chronic discogenic low back pain. The aim of this study is to compare the effectiveness of both methods concerning the outcome one year after surgery. METHODS: We included patients with MRI-proven disc protrusion suffering from low back pain and/or radiating pain in the lower extremities. The pain perception of the patients was documented using the visual analogue pain scale (VAS). Furthermore, the patients were queried about analgesic consumption, disability in daily life and ability to work. Percutaneous minimally invasive nucleotomy using the Nucleoplasty or the Disc Dekompressor was carried out under fluoroscopic and CT-guidance. We carried out a follow-up examination at 6 and 12 months after the operation. RESULTS: From April 2005 to November 2007 a total of 126 patients underwent percutaneous minimally invasive nucleotomy using Nucleoplasty (April 2005 - December 2006) or the Disk Dekompressor (February 2006 - November 2007) and were followed up after 6 and 12 months. In the Nucleoplasty group the mean age of the 27 females (39%) and 42 males (61%) was 42 years (range: 18-74). In the Disc Dekompressor group the mean age of the 22 females (39%) and 35 males (61%) was 44 years (range: 16-76). The mean duration of symptoms in the Nucleoplasty group was 30.5 months (range: 1 120), and in the Disc Dekompressor group 16.3 months (range: 1-72). Statistically significant postoperative improvement concerning the VAS score was evident in both groups. Whereas the VAS score slightly increased in the Nucleoplasty group comparing the early postoperative score and the score after 12 months, the VAS score stayed on a low level in the Disc Dekompressor group. A statistically significant reduction in analgesic consumption, disability and occupational incapacitation was observed in the Nuceloplasty group and the Disc Dekompressor group. CONCLUSIONS: Both Nucleoplasty and Disc Dekompressor are effective therapies for chronic, discogenic back pain. Regardless of the different mechanism no significant differences in the outcomes were found. Both techniques result in significant reductions in levels of disability and incapacity for work as well as decreased analgesic consumption. PMID- 21302192 TI - Endovascular treatment of vertebral artery dissection using stents and coils: its pitfall and technical considerations. AB - OBJECTIVE: There are various options for the treatment of vertebral artery dissection aneurysms (VADA). Treatment with stents may be an effective method to treat VADA involving the posterior inferior cerebellar artery (PICA) and dissection of the dominant vertebral artery (VA). In this article, our personal experience of the treatment of VADAs by using stents and coils is reported. METHODS: Since 1998, 26 cases of VADA have been treated by endovascular surgery by the first author. Of these cases, 6 cases were treated using stents, 3 of which were treated using stent and coils, 2 patients were treated using double overlapping stents, and the remaining one patient was treated using a single stent. RESULTS: In all patients, dissection aneurysms were successfully covered by stents. There was one complication: an intraprocedural rupture during additional coil insertion without neurological deterioration. Follow-up angiography was performed in all 5 surviving patients except for one patient who died due to the severity of his original subarachnoid hemorrhage (mean duration of follow-up angiography 22.8 months, range 15-57 months). Total or subtotal disappearance of the VADA was achieved in all 5 cases. At one year after the treatment, all 5 surviving patients remained clinically stable without any neurological deficit. CONCLUSIONS: Treatment using stents is an effective alternative for the treatment of VA dissecting aneurysms, especially for lesions of the dominant VA or involving the PICA. However, additional coil insertion should be performed very carefully and may be avoided if stagnation of contrast material is achieved after overlapping stenting. PMID- 21302193 TI - Frequency and risk factors for sepsis resulting from neuroendovascular treatment. AB - OBJECTIVE: Endovascular treatments are minimally invasive and rarely cause complicating infections. Although cases complicated by device infections have been reported, we could not find any studies evaluating infections following neuroendovascular treatment in particular. Therefore, we assessed the frequency of sepsis and other associated risk factors. METHODS: From September 2006 to May 2008, we investigated 256 prospective neuroendovascular treatment cases at our facility. We examined the frequency of sepsis and other associated risk factors as well as organisms and the early detection tests such as various cultures and serodiagnoses. RESULTS: The rate of sepsis due to complications was 8.6% in the aggregate and 5.7% in 193 procedures without a central venous catheter and hemodialysis. All sepsis cases were successfully treated with antibiotics. However, in 2 cases, the patients developed methicillin-resistant STAPHYLOCOCCUS AUREUS infections, which were intractable. The highest risk factors for sepsis were a large sheath size [>7 F; OR =5.03; P =0.01; 95% confidence interval (CI) 1.29-19.47] and meningioma embolization (OR =13.25; P =0.04; 95% CI 1.07-163.56). The degree to which experienced staff (OR =0.09; P =0.05; 95% CI 0.09-0.97) affected the incidence of sepsis was less significant. Microorganisms were isolated from half the operating field, and the risk factor, in this case, depended on inexperienced surgical staff (OR =1.98; P =0.03; 95% CI 1.07-3.67). Although we were unable to find a means to predict sepsis, we presumed antibiotic prophylaxis would be useful. CONCLUSIONS: The frequency of sepsis following neuroendovascular treatment is high. We should pay particular attention to the sterilization process and the operating field when undertaking neuroendovascular treatment that requires the use of a large-size sheath in patients with serious conditions. PMID- 21302194 TI - Endoscopic transnasal transmaxillary transpterygoid approach to the parapharyngeal space: an anatomic study. AB - BACKGROUND: The aim of this study was to assess the feasibility of an endoscopic approach to the parapharyngeal space through a transnasal route. For this purpose, an anatomic study was conducted. MATERIAL AND METHODS: The target area was studied separately on each side in 4 adult cadaver heads. To simulate actual endoscopic surgery, the dissection was performed thoroughly under the rigid endoscope. The surgical steps and extent of surrounding tissue resection necessary for the approach were evaluated. RESULTS: Both the pre- and poststyloid compartments could be exposed with restricted sacrifice of the surrounding tissue around the pterygoid process. Adding a wide sphenoidotomy and subpetrous bone resection, the surgical exposure could be extended at the medial temporal skull base including the medial infratemporal fossa. CONCLUSION: Although its usefulness has to be further verified in the clinical setting, the present results of the anatomic dissection indicate the potential of the approach to become a novel technique for treatment of a lesion in the parapharyngeal space. PMID- 21302195 TI - Endoscopic transnasal anatomy of the infratemporal fossa and upper parapharyngeal regions: correlations with traditional perspectives and surgical implications. AB - BACKGROUND: The aim of this study was to illustrate the endoscopic surgical anatomy of the infratemporal fossa (ITF) and upper parapharyngeal space and to provide useful landmarks by comparing transnasal perspectives with external ones. MATERIALS AND METHODS: 6 fresh double injected heads were dissected. External lateral dissection was performed through a pre-auricular skin incision while external anterior dissection started with a modified Weber-Ferguson incision. External medial to lateral dissection was performed starting from the rhinopharyngeal and pterygoid regions, after cutting the specimen in 2 halves passing through the nose. Endoscopic dissection was performed through an endonasal approach (0 degrees and 45 degrees scopes). RESULTS: Among all the structures identified during the dissection, the most useful landmark when dissecting the ITF in a lateral to medial direction is the lateral pterygoid muscle. In anterior approaches (mostly endoscopic) the role of the lateral pterygoid muscle is less important and the Eustachian tube (ET) represents the most important landmark to point out the upper portion of the parapharyngeal internal carotid artery (ICA). The role of the ET, in lateral dissection is, on the contrary, by far less important given the fact that it is very deep in the surgical field and that the ICA is encountered earlier during surgical approaches. Another crucial landmark during anterior endoscopic surgery is the vidian nerve because it points to the anterior genu of the internal carotid artery. CONCLUSION: The complex 3-dimensionality of the ITF and the upper parapharyngeal space needs a sound knowledge of the surgical anatomy. The role of the same landmarks changed in different approaches. The ability to orientate oneself in this complex area is related to an accurate knowledge of its anatomy through comparison of endoscopic and external perspectives. PMID- 21302196 TI - Uncontrollable high-frequency tachypnea: a rare and nearly fatal complication of endoscopic third ventriculostomy: case report and literature review. AB - BACKGROUND: Endoscopic third ventriculostomy (ETV) is considered a safe procedure although it carries its rate of risks and complications that may occasionally be life-threatening. CASE REPORT: This is a report about a 48-year-old woman presenting with progressive gait unsteadiness, weakness of the lower extremities and cognitive impairment due to tri-ventricular hydrocephalus. This was treated with standard ETV. In the immediate post-operative period the patient developed a severe and uncontrollable tachypnea requiring sedation, intubation and mechanical ventilation. CONCLUSION: Tachypnea may be an early complication after standard ETV and although its mechanism remains yet unclear, we speculate that it may be related to excessive traction and/or surgical manipulation of the floor of the third ventricle. Supportive care with mechanical ventilation is the mainstay of treatment until spontaneous normalization of the respiratory mechanism occurs. PMID- 21302197 TI - Hemorrhagic colloid cyst with sudden coma. AB - BACKGROUND: Third ventricle colloid cysts are regarded as benign lesions. They may, however, present with dramatic and rapidly deteriorating neurological signs, leading to sudden death. Although the exact cause of this clinical course is unknown, acute hydrocephalus caused by occlusion of Monro's foramina has been suggested. This, in turn, may be the result of acute cyst swelling, which can exceptionally be due to an intralesional hemorrhage. CASE REPORT: This report illustrates the case of a young patient who deteriorated to sudden coma and was found to have a hemorrhagic colloid cyst of the third ventricle. This was removed via a purely endoscopic technique. Although the radiological results were excellent, the clinical outcome was poor. CONCLUSIONS: This case suggests once again the importance of the early recognition of colloid cysts of the third ventricle for appropriate treatment before potentially irreversible neurological deterioration sets in. PMID- 21302198 TI - Minimally invasive decompression and stabilisation for extensive haemangiomas of lumbar spine. AB - INTRODUCTION: Vertebral haemangiomas are a common incidental finding and are largely asymptomatic. Extensive haemangiomas of the spine causing neurological deficits are exceedingly rare. Traditional open surgical approaches in these cases can be complicated by life-threatening blood loss. PATIENT CASE HISTORY: We describe 2 patients (ages 27 and 53 years) who presented with severe back pain and lower limb weakness. Radiological investigations revealed very extensive lesions of the L1 and L4 vertebral bodies, respectively, with severe narrowing of the lumbar canal. After selective embolisation of the spinal arterial feeders, both patients underwent a posterior decompression, vertebroplasty, and bilateral pedicle screw fixation in a minimally invasive fashion. Blood loss was minimal and a rapid clinical recovery was seen. CONCLUSIONS: Combinations of embolisation, vertebroplasty and minimally invasive posterolateral instrumentation are treatment strategies that can be used to treat extensive vertebral haemangiomas presenting with neurological deficits. PMID- 21302199 TI - A new tool for the navigated placement of intracerebral chemotherapy catheters. AB - OBJECTIVE: The aim of this report is to illustrate a method for the precise placement of chemotherapeutic delivery catheters with the aid of computer assisted navigation systems. MATERIALS AND METHODS: We have developed a cannula which can be referenced to our navigation system (BrainLab ((r))) to advance and position catheters. The cannula has a length of 10 cm. In the case of a ventricular puncture, CSF will drain through holes at the tip and a side port of the cannula to caution the surgeon. The cannula is fixed to the BrainLab ((r)) adapter ML and navigated with a BrainLab ((r)) vector vision ((r)) system. Using the puncture software, the placement is planned and executed. After placing the cannula as planned, the mandrin is removed and the primed catheter moved forward. When resistance is felt the cannula is withdrawn over the catheter. Further catheters can be placed similarly. RESULTS: Initial phantom tests showed a good target accuracy. Clinically we have used the cannula in 7 cases with good accuracy. CONCLUSION: This newly designed tool is easy to handle and well integrated into the navigation system. It provides the means to place catheters precisely to the planned position. Potentially it can be combined with every navigation system using adaptable reference systems. PMID- 21302200 TI - Concurrent stenting of multiple cerebrovascular stenotic lesions: technical note. AB - INTRODUCTION: Until recently, the treatment of intracranial atherosclerosis has remained limited. Due to advances in endovascular technology and technique, angioplasty and stenting has become an accepted treatment for medically refractory intracranial atherosclerosis. Patients with intracranial atherosclerosis frequently have multiple lesions, however, the clinical significance of each individual lesion is not always evident. In these instances the treating physician must decide which lesions should be managed conservatively, and which should be treated. TECHNIQUE: Emphasizing decision making, we describe a patient in whom 3 separate atherosclerotic lesions in the same vascular territory underwent endovascular treatment in one treatment session. Each of the lesions was treated with angioplasty and stent placement. CONCLUSION: This may be a relatively safe and efficacious technique that allows for the treatment of multiple lesions without the risks associated with multiple cerebral angiograms. PMID- 21302201 TI - Animal model for endoscopic neurosurgical training: technical note. AB - OBJECTIVE: The learning curve for endonasal endoscopic and neuroendoscopic port surgery is long and often associated with an increase in complication rates as surgeons gain experience. We present an animal model for laboratory training aiming to encourage the young generation of neurosurgeons to pursue proficiency in endoscopic neurosurgical techniques. METHODS: 20 Wistar rats were used as models. The animals were introduced into a physical trainer with multiple ports to carry out fully endoscopic microsurgical procedures. The vertical and horizontal dimensions of the paired ports (simulated nostrils) were: 35*20 mm, 35*15 mm, 25*15 mm, and 25*10 mm. 2 additional single 11.5 mm endoscopic ports were added. Surgical depth varied as desired between 8 and 15 cm. The cervical and abdominal regions were the focus of the endoscopic microsurgical exercises. RESULTS: The different endoscopic neurosurgical techniques were effectively trained at the millimetric dimension. Levels of progressive surgical difficulty depending upon the endoneurosurgical skills set needed for a particular surgical exercise were distinguished. LEVEL 1 is soft-tissue microdissection (exposure of cervical muscular plane and retroperitoneal space); LEVEL 2 is soft-tissue vascular and vascular-capsule microdissection (aorto-cava exposure, carotid sheath opening, external jugular vein isolation); LEVEL 3 is artery-nerve microdissection (carotid-vagal separation); LEVEL 4 is artery-vein microdissection (aorto-cava separation); LEVEL 5 is vascular repair and microsuturing (aortic rupture), which verified the lack of current proper instrumentation. CONCLUSION: The animal training model presented here has the potential to shorten the length of the learning curve in endonasal endoscopic and neuroendoscopic port surgery and reduce the incidence of training-related surgical complications. PMID- 21302203 TI - [Endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) as primary diagnostic tool for unclear lesions in the upper gastrointestinal tract]. AB - BACKGROUND: Endoscopic Ultrasound (EUS) and the EUS guided fine-needle Aspiration (EUS-FNA) increasingly plays an important role in the diagnostic evaluation of lesions or lymph nodes in the mediastinum and upper gastrointestinal tract of unknown origin. The objective of this study was to assess safety and accuracy of EUS-FNA in two secondary and tertiary health care providers. METHODS: Prospectively, from Mai 2003 to June 2007, all patients underwent EUS with devices from Pentax (FG38UX, EC3830UT) with EUS-FNA (Cook or Mediglobe) at Johannes Gutenberg University and Catholic Hospital in Mainz. In all cases, cytology and extracted cells were histological examined by the same pathologists. In case of negative EUS results, patients were observed for at least 12 months after initial diagnosis later by reanalysis, CT-scan and follow-up clinical data to confirm the diagnosis. RESULTS: In total, 776 patients with EUS and 167 EUS FNA (21.5 %) could be evaluated. Median age was 62 years, 68 % of patients were male. Patients underwent EUS-FNA in the mediastinum (n = 54), pancreas (73), stomach (13), liver, adrenal glands and rectum (n = 6). The complication rate of EUS-FNA was very low with only 0.6 %, mainly consistent of one minor haemorrhage at the aspiration site. A clear histological diagnosis could not be achieved in 12.5 % (21/167). Statistical analyses of all EUS-FNA revealed a sensitivity of 77.8 % (95 %CI 67,2 - 86,3) and a specificity of 98.5 % (95 % CI 92,2 - 100), with a positive and negative predictive value of 98.4 % and of 78.1 %, respectively. The overall accuracy was 87 % (95 %CI 80,4 - 92,0). CONCLUSION: EUS combined with FNA is a safe tool for first histological evaluation of unidentified lesions or lymph nodes in the mediastinum and upper gastrointestinal tract, indicative for gastrointestinal cancers. PMID- 21302204 TI - [Furuncles on the scalp after a trip to Brazil]. AB - HISTORY AND CLINICAL FINDINGS: A 68-year-old woman suffered for six weeks from four skin eruptions on her head after returning from Brazil. The skin manifestations resembled furuncles, grew continually in size until they were about 2 cm in diameter and [corrected] she finally developed intermittent sharp pain on her head. On presentation she had a mild lymphadenopathy on her neck but no other systemic complaints. INVESTIGATIONS: Each skin eruption had a central porus with seropurulent discharge and on examination within the central opening a whitish, tender moving mass could be detected. TREATMENT, COURSE AND DIAGNOSIS: We cautiously infiltrated each skin eruption with lidocaine. Immediately after infiltration a whitish maggot appeared from each nodule and could be easily extracted with a forceps. The maggots were identified as Dermatobia hominis larvae. After extraction a local antiseptic dressing was applied and the wounds healed without complications. CONCLUSION: Dermatobia hominis is a common cause of myiasis in Central- and South-America and should be taken into account in furuncular skin eruptions of returning travelers. The typical appearance of the skin eruption with a central porus, seropurulent discharge and a whitish, tender moving mass within the nodule is quite characteristic for myiasis. The patients often have [corrected] intermittent sharp pain in the area of the affected skin and report continuing growth of the nodules and a sensation of slight movement within the skin eruption. Extraction is accomplished with a forceps after lidocaine infiltration, alternatively an occlusive dressing could be applied by means of which the larvae can be removed easily from the cavity. PMID- 21302205 TI - [Progressive dyspnea of bronchial asthma]. PMID- 21302206 TI - [Epileptic seizures: effects on cardiac function]. AB - Sudden loss of consciousness can be caused by syncope or epileptic seizure, which therefore requires a diagnostic work-up including cardiological and neurological examinations. Thus, in clinical practice cooperation of these two medical specialties is common and of high relevance. Seizures may lead to cardiac arrhythmia or ictal asystole, and "sudden unexpected death in epilepsy" (SUDEP) is an important field of epilepsy research. Cardiac channelopathies such as long QT syndrome may be associated with seizures, suggesting a possible link between cardiac and cerebral channelopathy. We here review in detail cardiac effects due to epileptic seizures as well as possible pathogenetic correlations between cardiac and epileptic diseases. PMID- 21302207 TI - [Protective role of HLA-B27 in HIV and hepatitis C virus infection]. AB - The human leukocyte antigen (HLA) B27 has been linked to rheumatic diseases such as ankylosing spondylitis nearly 40 years ago, but its role in pathogenesis remains unclear. Apart from this association, HLA-B27 has a positive effect in two of the most threatening human viral infections: in HIV infection, HLA-B27 positive patients have low viral loads, CD4+ T cell counts decline slowly and AIDS progresses slowly. In acute hepatitis C virus (HCV) infection, HLA-B27 is associated with a very high rate of spontaneous viral clearance. The mechanisms of protection by HLA-B27 in HIV and HCV infection have been characterized in the recent years and will be discussed in this article. PMID- 21302208 TI - [Treating the symptoms in nephrotic syndrome: which therapeutic strategies are evidence based in the treatment of proteinuria?]. AB - Glomerular diseases are among the most common renal pathologies leading frequently to end-stage renal disease. Clinical disease can be divided into five different groups the features of which are determined by the underlying pathophysiology. One of these five clinical syndromes is the nephrotic syndrome, which is characterized by proteinuria > 3.5 g/day accompanied by hypalbuminemia, hyperlipoproteinemia and pronounced edema. The nephrotic syndrome may be the clinical manifestation of a row of underlying diseases. The pathophysiological basics had remained elusive for decades, yet recently significant progress which allows for establishing new therapeutic strategies has been made. A major breakthrough in understanding the function of the glomerular filter unit has been possible in the last years through both genetic and cell biological studies, which have revealed a crucial role for the visceral epithelial cells of the glomerulus - the podocytes. By now various factors have been found causing podocyte damage, such as toxines, immunological phenomena or systemic disease like diabetes mellitus. PMID- 21302210 TI - [Arthritis of the atlanto-axial joint with inflammatory neck pain as a primary manifestation of seronegative rheumatoid arthritis]. PMID- 21302211 TI - [Postoperative complications after recrossectomy of the saphenofemoral junction]. AB - The surgical procedure for recurrences at the saphenofemoral junction represents a great challenge for the surgeon due to the complex anatomic variability, the broad range of causes and the mostly extreme scar tissue. The incidences of postsurgical minor and major complications after recrossectomy in the groin area are determined and the clinical outcomes are analysed in this article. After specific and precise presurgical clinical and sonographical diagnoses having been undertaken a cutaneous incision is performed in the groin with the aid of tumescent local anaesthesia combined with total intravenous anaesthesia. From the proximal site any scar tissue exsisting is meticulously removed, the femoral vein is set free and the still remaining stump of the long saphenous vein or of the neovasculate as well as all left over varicose side branches of the saphenofemoral junction are removed. Within this special surgical procedure the stump of the long saphenous vein or the neovasculate are completely removed and, thereafter, a continuous longitudinal suture of the femoral vein is performed. Uncomplicated minor bleeding complications (haematoma in large extension or disseminated) appear quite frequently, lymphatic minor complications (conservatively treatable lymph oedema, lymphatic fistulae or lymphatic cysts) occur from time to time; major complications such as bleeding complications with the necessity of surgical reintervention occur only in sporadic cases and can be avoided by exact presurgical diagnosis, by meticulous special surgical technique matching the operation site as well as by regular and frequent postsurgical follow-ups. Absolute preconditions to achieve the very best results in the long run are the exact procedures of diagnosis and surgical technique. Performed by experienced phlebosurgeons or vascular surgeons, the recrossectomy of the saphenofemoral junction represents a low-risk surgery for the patient and is a singular and possibly time-consuming challenge for the surgeon. PMID- 21302212 TI - [Traumatic retroperitoneal perforation of a juxtapapillary duodenal diverticulum]. PMID- 21302213 TI - Estimating input original waveform from catheter-manometer system output waveform -an experimental study with pulmonary artery catheter. AB - The present study was performed to investigate the precision of and problems in arithmetic operations for synthesis/estimation of the input waveform from the output waveform of a pulmonary artery catheter (PAC) manometer system, by imposing arterial pressure waveform as an input pressure waveform. When a PAC manometer system is regarded as a second-order system, the input waveform can be synthesized/estimated from the output waveform by determining the natural frequency (fn), and damping coefficient (zeta) of the said system. The precision of synthesis/estimation diminished with the decreasing fn of the PAC manometer system. An attempt was thus made to explore the cause of the reduction in precision of estimation due to decreases in fn by constructing a second-order system equivalent circuit and a differentiation arithmetic circuit on the circuit simulator. The results demonstrated that correct synthesis/estimation of input waveform were attainable only when the set of fn and zeta for the arithmetic circuit coincided with that of the PAC manometer system. Decreases in fn correspond to such instances where the PAC manometer system can no longer be regarded as a second-order system, thus nullifying the measured fn and zeta. This accounts for the reduction in precision. PMID- 21302214 TI - Hepatocellular carcinoma metastatic to the orbit: a case report. AB - Hepatocellular carcinoma rarely metastasizes to the orbit. We report on a 72-year old man with a past history of resection for hepatocellular carcinoma and recurrent HCC, who presented with diplopia and left painful proptosis. Head scans revealed a large and irregular mass in the left orbit that caused destruction of the orbital bone superiorly and posterolaterally. A biopsy specimens of the orbital tumor showed features of metastatic foci of hepatocellular carcinoma. The tumor was surgically excised and histological findings revealed moderately differentiated hepatocellular carcinoma, resembling hepatocytes with a tendency to form trabeculae. Immunohistochemically, the tumor cells showed positive reaction against low-molecular-weight keratin and alpha-fetoprotein. There have been only 12 previous cases of hepatocellular carcinoma metastatic to the orbit cited in the literature. We presented here a rare case of hepatocellular carcinoma metastatic to the orbit. PMID- 21302215 TI - Less-invasive method for microsphere delivery to coronary circulation and evaluation of myocardial ischemic change in small animals. AB - We developed a less-invasive method for semi-selective administration of drugs into coronary arteries in small animals. With this method, we created microvascular myocardial ischemia in rabbits by microsphere injection. A 4F catheter was inserted into the left ventricle via the right common carotid artery and a balloon catheter into the descending thoracic aorta. Microspheres were administered into the left ventricle with temporary occlusion of the descending aorta and carotid arteries. In these conditions, regional blood flow in the heart was 10.8-times as much as in the kidney. Seventeen days after microsphere injection, the contractile function of the heart muscle deteriorated and the left ventricular endodiastolic pressure was increased. Patchy NADH-fluorescence was observed all over the left ventricular myocardium. Myocardial lactate concentration was higher than the normal standard animals. Histological analysis revealed that microscopic patchy necrosis was noted only in the myocardium but not in other organs. Semi-selective delivery of recombinant adenovirus expressing lacZ using the same method induced a gene expression in the heart. Thus, a unique model for microvascular myocardial ischemia was created by semi-selective delivery of microspheres into the coronary artery without special technique or equipment. The present model is also applicable to semi-selective gene transfer to the heart. PMID- 21302216 TI - Detection of individual over-smoking using conventional laboratory tests. AB - OBJECTIVE: The present study was designed to find useful markers for detecting the severity of smoking effects on the human body from conventional laboratory tests used in community health check-ups. METHODS: The subjects were 18,576 persons who visited Tokai University Hospital Health Check Clinic between January 5, 2000, and December 28, 2000. The data on their life-style information and laboratory tests were analyzed by multiple regression analysis and logistic analysis. RESULTS: White blood cell counts (WBC), the numbers of lymphocytes (Ly), hemoglobin concentration (Hb), mean corpuscular volume of red blood cells (MCV), and carcinoembriogenic antigen (CEA) were positively correlated with numbers of cigarettes consumed, while high density lipoprotein cholesterol (HDL C) was negatively correlated, with statistically significant difference. Although the relationship between the grade of smoking habit and MCV, HDL-C and CEA was affected by alcohol intake, the WBC, MCV, HDL-C and CEA were shown to be the grading index for smoking effect regardless of drinking habit. Logistic analysis indicated that an accumulation of these marker abnormalities was not useful for differentiating smokers from non-smokers as compared with a single marker abnormality. CONCLUSION: WBC, MCV, HDL-C and CEA can be the grading index for smoking effect. Abnormalities in one or some of those values observed in healthy smokers indicate some effects of smoking on their bodies. PMID- 21302217 TI - A newly developed assessment scale for attentional disturbance based on behavioral problems: Behavioral Assessment of Attentional Disturbance (BAAD). AB - Attentional disturbance following brain damage has been commonly evaluated by having the patients perform neuropsychological tasks. In rehabilitation settings, however, the primary concern is not task performance, but functional real-world behaviors. The aim of this study was to investigate the reliability and validity of a newly developed system for rating attentional behavior (Behavior Assessment of Attentional Disturbance, BAAD). The subjects included 183 patients with various types of brain damage. The initial form of BAAD consisted of 12 items to be completed by each patient's occupational therapist. Each item was rated based on the frequency with which the problem behaviors appeared during daily sessions of occupational therapy in the course of a week. A principle component analysis (factor analysis) with varimax rotation identified three principle factors which together explained 69.2% of the total variance. These components were regarded as related to "arousal", "sustained attention", and "selective attention". A final version of the BAAD scale with six items was developed by excluding all items with no significant relation to the aforementioned factors. The scale had a Cronbach's alpha coefficient of 0.81. The intraclass correlations for intra- and inter-rater reliability were 0.94 and 0.84, respectively. The BAAD score was significantly correlated with the patients' performance on the neuropsychological tests. The results indicate that the BAAD has good reliability and validity. PMID- 21302218 TI - Increased dosage of propofol in anesthesia induction cannot control the patient's responses to insertion of a laryngeal mask airway. AB - An increased dosage of propofol is frequently administered to reduce responses to insertion of the laryngeal mask airway (LMA). However, its clinical effect remains unknown. We investigated whether an increased dosage of propofol reduces responses to LMA insertion. Sixty adult patients were divided into 3 groups according to induction dosage of propofol (2.0 mg/kg, 2.5 mg/kg and 3.0 mg/kg). The patient's responses including body movement and the upper airway reflex were observed. The bispectral index (BIS) score as the index of the sedation level was monitored. There were no significant differences among the three groups in responses to LMA insertion, and no correlation was seen between the BIS score and the responses. These results suggest that propofol alone at clinical dosage levels does not completely control responses to LMA insertion. It is also suggested that the monitoring of BIS score is not effective in predicting responses to LMA insertion. Combination of propofol and analgesics such as fentanyl may be useful in reducing responses to LMA insertion. PMID- 21302219 TI - The surgical repair of a cyclodialysis cleft caused by a BB pellet. AB - We report our surgical technique to repair a cyclodialysis cleft in a young patient with hypotony maculopathy and decreasing visual acuity in his left eye for approximately seven weeks following ocular trauma caused by a BB pellet. The technique was introduced for suturing a cyclodialysis cleft in which sutures are placed on the corneal limbus to restore the cleft using a long curved needle with 10-0 polypropylene thread, in order to apply tension to the ciliary body which has been relaxed by dialysis. One year after surgery, the patient's visual acuity had improved, the hypotony showed recovery, and optic disc swelling had also improved. However, choroidal rupture persisted. This surgical technique is suitable for restoration of the traumatic cyclodialysis cleft associated with hypotony maculopathy. The technique in this report also makes it possible to spare the lens. PMID- 21302220 TI - A case of acute spinal epidural hematoma after abdominal aortic aneurysm operation. AB - A 76-year-old man who had an abdominal aortic aneurysm underwent vascular replacement, and an acute spinal epidural hematoma developed postoperatively despite the absence of abnormal preoperative laboratory data other than hypertension. General anesthesia was induced using nitrous oxide, oxygen, and sevoflurane (GOS), and epidural anesthesia was also performed at the intervertebral space between Th10 and Th11. At 5 days after operation, an emergency operation was carried out to remove the epidural hematoma, which was noted at the Th5-Th9 vertebral level. The patient's clinical course was relatively favorable, and he was eventually able to walk with a stick. The cause of this acute hematoma remains unclear, but the following important factors might have been involved in its development: a transient bleeding tendency caused by intraoperative use of heparin as well as adverse effects to the epidural blood vessels due to an increased venous pressure following the surgical procedures. Our patient, fortunately, had no significant sequelae. However, when performing epidural anesthesia, it is necessary to keep in mind that epidural hematoma, though observed very rarely, may develop, particularly in patients with a tendency for bleeding. PMID- 21302221 TI - Efficient preparation of cationized gelatin for gene transduction. AB - We previously reported gene therapy using cationized gelatin microspheres of phi20-32 MUm, prepared from pig skin, as a transducing agent, but although the gelatin offered various advantages, its yield was extremely low (only 0.1%). In this study, we markedly improved the yield of phi20-32 MUm cationized gelatin microspheres and prepared a newly less than phi20 MUm cationized gelatin. Conventionally, cationized gelatin is prepared by cationization, particulation by agitation, and cross-linking. The yield is determined by the particulation step, for which we had used a three-necked distillation flask of 500 mL and an agitation speed of 420 rpm. The yield was significantly increased from 0.13 +/- 0.02% to 8.80 +/- 1.90% by using a smaller flask of 300 mL and an agitation speed of 25000 rpm (p < 0.01). We could also prepare cationized gelatin of less than phi20 MUm, which had not been possible previously. We confirmed that efficient gene introduction into peritoneal macrophages could be achieved with the new cationized gelatin. PMID- 21302222 TI - A case of superficial angiomyxoma. AB - We report a case of a 19-year-old man who showed a brownish, elastic-soft, multilocular, pedunculated, solid tumor (10 * 6 * 6 cm), with scale crust and erosion, on the medial side of the right thigh. The histopathology of a specimen removed completely revealed a tumor that was located between the middle layer of the dermis and the subcutaneous fatty tissue, was filled with a mucoid material, and was surrounded by a fibrous tissue. The tumor consisted of small thin-walled blood vessels and spindle-shaped or stellate tumor cells without cytological atypia in addition to the mucoid material. Immunohistochemistory revealed that the tumor cells express the vimentin stain. Based on these clinical and histologic findings, we diagnosed the skin condition as superficial angiomyxoma. PMID- 21302223 TI - A case report of papillary fibroelastoma attached to chorda tendineae of mitral valve. AB - The case was a Japanese man of 62 years old. A bulbar mass attached to mitral valve anterior leaflet was discovered in an echocardiography within detailed examination of ischemic heart disease accidentally. We diagnosed him as ischemic heart disease and doubt of heart tumor. We thought about the danger of future embolism, surgical treatment was decided. We dissected the tumor together with one chorda tendineae of mitral valve, and a performed aorta - coronary bypass surgery. We diagnosed the tumor as papillary fibroelastoma by pathological diagnosis. Papillary fibroelastoma is extremely rare with 7-9% of benign tumor of heart primary. Most of the papillary fibroelastoma is incidentally discovered by echocardiography or autopsy. Or it is discovered for systemic embolism. The tumor is benign, but there is a problem to cause embolism. Therefore, when we discovered papillary fibroelastoma, surgical resection of the tumor is the first line therapy. A problem on surgical therapy is the range of resection area. Papillary fibroelastoma is benign tumor, but the pathological characteristic is still unidentified. Further epidemiological and pathological studies are necessary to determine the extent of surgical excision in associated with characteristics of papillary fibroelastoma. PMID- 21302224 TI - Evaluation of 25 years of Uterine Cervical Cancer Screening at Tokai University Hospital Health Evaluation and Promotion Center. AB - The total number of persons who underwent uterine cervical cancer screening at the Tokai University Hospital Health Evaluation and Promotion Center during the 25-year period from January 1976 to March 2001 was 30,173 (gross number: 111,181). Since 1995, more than 6,500 females have visited the center annually, and more than 70% were 40-59 years of age. Among these females, 849 exhibited atypical changes higher than class IIIa in the cytological examination (class IIIa: 779, IIIb: 43. IV: 14 and V: 13), and the detection rate was 0.76%. In examining the relationship between the age and number of visits to the center and the detection rate of atypical changes observed in the cytological examination, patients in their 40s exhibited the highest detection rate (1.31%), and the rate at the first screening was 1.19%. Analysis of the age distribution for the detection rate of atypical changes in the cytological examination before 1989 and after 1990 showed that persons in their 40s and 50s had high rates (1.62% and 1.69%, respectively) before 1989, but since 1990 persons in their 20s, 30s and 40s exhibited high rates (2.86%, 2.16% and 2.61%, respectively) (p < 0.001). This suggests a lowering of the age at which atypical changes are observed in the cytological examination. PMID- 21302226 TI - Successful treatment of severe reflux esophagitis with erythromycin in a patient with progressive systemic sclerosis and proximal gastrectomy. AB - A case of severe reflux esophagitis related to progressive systemic sclerosis (PSS) and proximal gastrectomy was successfully treated with oral erythromycin (EM). A 53-year-old woman was troubled with severe heartburn related to PSS for a long period and had undergone proximal gastrectomy for a gastric cancer a few months before. She was not readily made free from heartburn by any anti-ulcer drugs and she could barely eat. Therefore she underwent continuous intravenous hyperalimentation (IVH). She was referred to our hospital for IVH. Nine months after the proximal gastrectomy, we gave oral erythromycin to her in expectation of improvement of the heartburn. Gradually she recovered from the heartburn and became able to eat small amounts. EM is an agonist of motilin which is a gastrointestinal hormone. EM acts on the stomach and intestine not through the autonomic nervous system but through the circulation system of the blood. This is the reason why EM is effective in the residual stomach and intestine. In the case of severe esophagitis which is related to PSS and/or proximal gastrectomy and which resists anti-ulcer drugs, oral EM should be considered as a second therapy. PMID- 21302225 TI - Life-saving treatment by fluid resuscitation and a thoracotomy in a case of deep pulmonary laceration. AB - CASE: A 41-year-old man survived deep pulmonary and hepatic lacerations by treatment with fluid resuscitation, blood transfusion, thoracotomy, and transcatheter hepatic artery embolization. The patient was transferred to our hospital 46 minutes after his motorbike struck a station wagon from behind. Hemorrhagic shock with systolic blood pressure of 68 mmHg was observed. He showed nonresponse to 20-minute intravenous infusion of 1,500 mL of lactated Ringer's solution. The initial plain chest radiograph showed mediastinal deviation to the left, radio-opacity of the right lower lobe, and decreased radiolucency of the right thorax. Rapid drainage of 800 mL of blood through a right chest tube led to a diagnosis of a deep pulmonary laceration of the right lower lobe. Abdominal computed tomography revealed another deep laceration affecting 40% of the liver. A right lower lobectomy of the lung was performed at 169 minutes after arrival. After the thoracotomy,transcatheter arterial embolization of the right hepatic artery was performed. The patient was discharged on hospital day 57. CONCLUSION: Prompt diagnosis and appropriate treatment are necessary to save patients with multiple, severe blunt injuries. Advanced Trauma Life Support (ATLS) guidelines should be adhered to for appropriate early treatment of patients with severe trauma. PMID- 21302227 TI - The selective action of D2 dopamine receptor antisense oligodeoxynucleotide on the expression of the dopamine receptor subtype mRNA in rat striatum. AB - We have evaluated the effect of the D2 dopamine receptor antisense oligodeoxynucleotide (D2 AS ODN) on the gene expression of all five dopamine receptor subtypes including D1, D2, D3, D4 and D5 dopamine receptor in the rat striatum. The levels of D2 dopamine receptor mRNA are significantly decreased at 6, 12, 24 h after the last injection of three time injections of D2 AS ODN, although D1, D3, D4 and D5 subtype mRNA levels did not significantly reduced at any time. The present study is the first to demonstrate the selective effect of D2 AS ODN on D2 dopamine receptor mRNA among all five dopamine receptor subtypes and the effectiveness of D2 AS ODN without 6-hydroxydopamine. PMID- 21302228 TI - Rehabilitative intervention and social participation of a case with Balint's syndrome and aphasia. AB - Balint's syndrome is characterized by three major disorders of spatial analysis: fixed gaze or psychic paralysis, simultagnosia, and optic ataxia or misreaching. Most patients with Balint's syndrome generally do not show all three of these signs. The authors herein reported the more than four-year clinical course of a case (a 43-year-old man) with Balint's syndrome presenting these three disorders. The patient also had a mild type of conduction aphasia, but his attentional, intellectual and memory functions were well preserved. SPECT showed cerebral hypoperfusion in the bilateral parieto-occipital areas. Whereas rehabilitative intervention with process specific approach for the impaired visual cognition seemed to be significantly ineffective, a functional adaptation approach successfully promoted the patient's social participation. However, the present patient could not help having to resign from his job. Additionally, double impairment of visual (including optic ataxia) and language functions made it impossible for him to obtain a new work. Like the present case, those who have a higher brain dysfunction, but retain good physical ability can hardly receive the benefit of the social welfare system in Japan. Legislation addressing this problem is a matter of great urgency. PMID- 21302229 TI - Aortic root reconstruction in two patients with chronic aortic dissection by aortic valve-sparing procedures using a new aortic root conduit with the sinuses of valsalva (De Paulis Valsalva graft). AB - The durability of the aortic valve after aortic root reconstruction by an aortic valve-sparing procedure is of particular concern because of the absence of the sinuses of Valsalva in the David type-I reimplantation method. Various improvements have been made to the David-I method. In particular, a new aortic root conduit with the sinuses of Valsalva was developed recently and is expected to improve the long-term follow-up results of the aortic valve-sparing procedures. We used a Valsalva graft in two patients with aortic root dilation accompanied by aortic regurgitation and obtained good short-term results. PMID- 21302230 TI - A resectable case of gastrointestinal stromal tumor derived from the rectal wall after oral targeted molecular therapy with imatinib mesylate. AB - We performed targeted molecular therapy in a patient with a non-resectable pelvic gastrointestinal stromal tumor (GIST). Imatinib mesylate was administered at 400 600 mg/day for 6 months, and the tumor became resectable. The patient was a 58 year-old female who visited a gynecologic hospital with the chief complaint of a swollen feeling in the lower abdomen. A pelvic tumor was found by imaging, and the patient was referred to our hospital. Laparotomy was performed, but it was found that the tumor arose from the intestinal serous membrane, rather than from the uterus, and complete excision was difficult. A portion of the tumor tissue was excised, and the abdomen was closed. GIST was diagnosed on postoperative pathological examination, and the tissue was positive for c-kit protein on immunostaining. The tumor had markedly shrunk after oral administration of imatinib mesylate for 6 months, and excision by laparotomy became possible. PMID- 21302231 TI - A case of pulmonary semi-invasive aspergillosis developing fatal acute exacerbation. AB - A 80-year-old male was referred for detailed examination of left apical fibrotic changes in the chest radiograph. Six years later, several cavitary lesions with thickening of the pleura developed. Anti tuberculosis therapy had no effects. Despite intravenous administration of antibiotics, the cavities became larger and the infiltrates progressed to the left lower lobe. The air crescent was observed in one of the cavities. Repeated sputum examinations revealed Aspergillus niger only. With administration of anti fungal drug, infiltrates were faded. Four months after the cessation of antifungal drug high fever associated with new infiltrates developed. Sputum culture showed Aspergillus flavus. Infiltrates over the entire left lung field and in the right upper lobe were observed. On CT film necrotic lung tissue was strongly suggested in the cavity. The patients died of respiratory failure. Although initial course of the presented case was compatible with semi-invasive pulmonary aspergillosis (SIPA), fluminant and fatal exacerbations which may be very unusual in SIPA, developed in later. The mycetoma like ball may be occasionally made of necrotic lung parenchyma instead of fungal mycelia in SIPA. PMID- 21302232 TI - Clinical significance of serum matrix metalloproteinases and tissue inhibitors of metalloproteinases in chronic liver disease. AB - OBJECTIVE: We have attempted to determine serum levels of type IV collagen (IV C), laminin (LM), prolylhydroxylase (PH), metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) in chronic liver disease to elucidate the clinical significance of MMPs and TIMPs in the process of hepatic fibrosis. METHODS: Serum samples were collected from 60 patients with chronic liver disease caused by hepatitis B or C. Serum levels of IV-C, LM, PH, MMP-1, 2 and 3, and TIMP-1 and 2 were measured by a one-step sandwich enzyme immunoassay using monoclonal antibodies. The values were correlated with Histology Activity Index (HAI) scores of liver biopsy specimens. RESULTS: LM and IV-C levels markedly increased in parallel with the progression of the chronic liver disease. The MMP 2 and MMP-3 levels tended to increase in chronic active hepatitis (CAH), and significantly elevated in liver cirrhosis (LC). There was a positive correlation between the IV-C and MMP-2 levels, and the ratio of IV-C to MMP-2 levels was significantly elevated in LC. Both TIMP-1 and TIMP-2 levels were markedly increased in LC. The HAI scores were positively correlated with the serum IV-C and MMP-2 levels. CONCLUSIONS: Serum IV-C and MMP-2 levels may be useful diagnostic markers for hepatic fibrosis, since they increased in parallel with the progression of chronic liver disease. In addition, the imbalances between IV C, LM, and TIMP-1 and 2 as fibrogenic factors and MMP-2 and 3 as fibrolytic factors may lead to fibrosis in chronic viral liver disease, especially in cirrhosis. PMID- 21302233 TI - Predictors of short-term functional outcome following proximal tibial fractures: AO classification type C. AB - OBJECTIVE: Proximal tibial fractures are often difficult to treat and secondary osteoarthritis due to residual malalignment or irregularity of the articular surface is a common problem, especially in patients with comminuted fractures. The purpose of this retrospective study was to assess the relationship between the functional outcome and certain anatomical parameters as predictors for the prognosis in patients with AO type C fractures. METHODS: Clinical and functional data were collected on 24 AO type C fractures of the proximal tibia in 23 patients. The following factors were evaluated: the anatomical outcome, the tibial angle, the femoro-tibial angle, the medial and lateral tibial plateau angles, residual irregularity of the tibial plateau articular surface, and the functional outcome. The length of the follow-up period was 12 to 72 months. RESULTS: A large tibial angle and a small medial tibial plateau angle were associated with a worse functional outcome. All of the knees with residual irregularity of the medial tibial plateau articular surface had a worse functional outcome, while lateral irregularity was associated with various outcomes. CONCLUSION: These findings suggested that the medial compartment of the knee joint is more important than the lateral compartment for the short-term functional outcome. PMID- 21302234 TI - Aortic root reconstruction by aortic valve-sparing operation (David type I reimplantation) in Marfan syndrome accompanied by annuloaortic ectasia and acute type-A aortic dissection. AB - To reconstruct the aortic root for aneurysm of the ascending aorta accompanied by aortic regurgitation, annuloaortic ectasia (AAE) and acute type-A dissection with root destruction, the Bentall operation using a prosthetic valve still is the standard procedure today. Valve-sparing procedures have actively been used for aortic root lesions, and have also been attempted in aortic root reconstruction for Marfan syndrome which may have abnormalities in the valve leaflets. We conducted a valve-sparing procedure in a female patient with Marfan syndrome who had AAE accompanied by type-A acute aortic dissection. The patient was a 37-year old woman complaining of severe pain from the chest to the back. The limbs were long, and funnel breast was observed. Diastolic murmurs were heard. On chest computed tomography, a dissection cavity was present from the ascending aorta to the left common iliac artery, and the root dilated to 55 mm. Grade II aortic regurgitation was observed on ultrasound cardiography. Regarding her family history, her father had died suddenly at 54 years of age. She was diagnosed with type-A acute dissection concurrent with Marfan syndrome and AAE. The structure of the aortic valve was normal, and root reconstruction by a valve-sparing operation and total replacement of the aortic arch was conducted. On postoperative ultrasound cardiography, the aortic regurgitation was within the allowable range, and the shortterm postoperative results were good. PMID- 21302235 TI - Recent surgical outcomes of acute type-A aortic dissection. AB - The aim of this study is to assess the early outcome of the surgical treatment of acute type-A aortic dissection using recent improvements in antegrade selective cerebral perfusion. This study included 38 patients who had undergone surgery for acute type-A aortic dissection from October 2003 through March 2006. The surgery results were evaluated in 2 groups: group A was composed of those who had undergone the surgery before the procedures of antegrade selective cerebral perfusion was changed in December 2004, and group B consisted of those who had the surgery after the change. Operations were performed with hypothermic cardiopulmonary bypass, antegrade selective cerebral perfusion during the arch repair, and open distal anastomosis. Times to awakening after the surgery were 27.6+/-26.2 hours in group A and 19.8+/-22.3 hours in group B (p= 0.5). Intubation times were 8.55+/-7.09 days in group A and 5.11+/-2.56 days in group B (p=0.06). Permanent neurologic dysfunction was observed in 3 patients in group A and 1 in group B (p=0.6). Transient neurologic dysfunction was observed in 4 patients each in groups A and B (p=1). Mortality rates were 21.1% in group A and 10.5% in group B (p=0.65). There were no significant differences in mortality or morbidity between the two groups, but the intubation time tended to be shorter in group B. PMID- 21302236 TI - Surgical treatment of chronic atrial fibrillation: Report of 8 cases. AB - Since February 2003, we have conducted surgical treatment on 8 patients complicated with chronic atrial fibrillation during cardiac surgery. A radial procedure was conducted on 7 patients, and pulmonary vein isolation was conducted on 1 patient. Underlying diseases included mitral regurgitation (MR) in 5 patients, mitral stenosis (MS) in 1 patient, aortic stenosis (AS) + MS in 1 patient and chronic type A dissociation in 1 patient. Simultaneous procedures included mitral valve plasty (MVP) in 3 patients, mitral valve replacement (MVR) in 3 patients, aortic valve replacement (AVR) + MVR in 1 patient, and aortic root reconstruction by reimplantation procedure + total arch replacement in 1 patient. The operation time was 320 to 840 minutes and 458.1+/- 171.1 minutes on average. The cardiopulmonary bypass time was 204 to 404 minutes and 266.7 +/- 62.7 minutes on average. The aortic cross-clamp time was 142 to 271 minutes and 171+/- 41.5 minutes on average. One patient died in hospital. Six patients returned to sinus rhythm, and 1 patient required pacemaker implantation. The follow-up period was 2 to 37 months and 13.6 +/- 15 months on average. When cryoablation was changed to radiofrequency ablation to assist preparation of the block line, a tendency toward shortening of the aortic clamping time was observed. PMID- 21302237 TI - Surgical outcome of stentless aortic valve replacement for calcified aortic stenosis. AB - We have conducted aortic valve replacement (AVR) using a stentless bioprosthesis (Medtronic Freestyle valve) on 10 patients with calcified aortic stenosis since March 2004. There were 64-84 years of age and 75 +/- 5.5 years old on average, and included 4 males. Implantation was conducted by a modified subcoronary method in all the patients. The preoperative New York Heart Association class was class II in 80% of the patients. The preoperative left ventricular mass and the left ventricular mass index (LVMI) were 193.1-524.1 g and 144.1-299.5 g/m2 and, on average 328.4 +/- 104.7 g and 217.3 +/- 55.7 g/m2, respectively. The annulus dimension was 18-24 mm and, on average, 20.3 +/- 1.7 mm. The size of implanted valve was 19-25 mm and, on average, 21 +/- 2.2 mm. The maximum pressure gradient of the aortic valve remained at 14.2-46.5 mmHg, 25.2 +/- 10.2 mmHg on average, 1 or 2 months after surgery, but the LVMI significantly improved to 153.2 +/- 33.9 g/m2 (p = 0.018). The hospitalization period were 24.7 +/- 16.9 days for all the patients and 19.3 +/- 5.1 days for patients undergoing the AVR alone. These results show that LVMI is significantly reduced by using a stentless bioprosthesis in the early phase after surgery, and early discharge from hospital can be expected by concurrently using minimally invasive cardiac surgery. PMID- 21302238 TI - Predictive factors for the response to lamivudine in HBV-infected patients with chronic hepatitis and cirrhosis. AB - OBJECTIVE: To determine predictors for virological response to lamivudine, a retrospective-cohort study was designed. METHODS: Seventy HBV positive patients who received lamivudine were classified according to virological response into responders and non-responders. Background conditions and normalization and flare up of hepatitis were compared using student-t test and chi-square test. Logistic regression analysis was performed to determine the effect of explanatory variables, age, sex, ALT, HBV-DNA, hepatic fibrosisi, presence of absence of HBeAg, former IF non-response on the response to lamivudine. RESULTS: There were no difference in gender, age, observed period, ALT level, liver fibrosis, former response to Interferon in background but viral titer and rate of HBeAg (+) was higher in non-responders. Hepatitis normalization rates were not different but flare-up rates were significantly higher in non-responders. Multivariate analysis showed HBeAg is the relevant factor for the response to lamivudine. CONCLUSIONS: The presence of HBeAg was a risk for non-response to lamivudine therapy. PMID- 21302239 TI - Functional residual capacity and airway resistance in rats of COPD model induced by systemic hyaluronidase. AB - Chronic obstructive pulmonary disease (COPD) is characterized by obstructive bronchiolitis and parenchymal destruction. In animal models, air space enlargement induced by intratracheal elastase is augmented by prior depletion of lung hyaluronan by hyaluronisase. Recently our colleagues reported that intravenous hyaluronisaein in the absence of elastase produced emphysema-like alveolar dilation [1]. In this study we measured functional residual capacity (FRC) and airway resistance (Raw) in the rats with hyaluronidaseinduced experimental COPD. MATERIALS AND METHODS: Hyaruonidase (20 mg/kg) was administered from the caudal vein of 19 male Wistar rats (COPD rats). Two weeks after the injection, FRC and Raw were measured with bodyplethysmogarph. RESULTS: Thickness or inflammatory cell infiltrations were not apparent in the bronchus of the COPD rat while alveolar distension was obvious. The mean FRC of the COPD rats (6.22 +/- 1.00 ml, mean +/- SD) was significantly larger than that of Control rats (5.48 +/- 0.85 ml). There was no statistical significance between the mean Raw of the COPD rats (0.28 +/- 0.08 cmH2O/ml/s) and that of the control rats (0.28 +/- 0.13 cmH2O/ml/s). CONCLUSION: Systemic administration of hyaluronidase produced pulmonary overinflation but did not bronchial constriction. We speculate that hyaluonidase-induced COPD simulates panlobular emphysema. PMID- 21302240 TI - Search for appropriate experimental methods to create stable hind-limb ischemia in mouse. AB - OBJECTIVE: Stable animal models for refractory peripheral arterial disease are not established. A standardized animal model of hind-limb ischemia is required upon searching effective treatment for this condition. The aim of the study is to verify previously used hind-limb ischemia models to find a standard method. METHODS: Using Balb/ca mice six various methods of inducing hind-limb ischemia were applied and two weeks after operation degree of ischemic damage were examined. Six methods include V group, A group, AV group, A-strip group, AV-strip group and Prox-A group (refer the text). RESULTS: Degree of ischemia was evaluated macroscopically by judging toes, foot, knee, and total hind-limb necrosis. We found that severity of damage was markedly different among different methods. Furthermore the severity of necrosis was not uniform even in the same method group. CONCLUSIONS: The A-strip group in which the femoral artery from the bifurcation of the deep femoral artery to the saphenous artery was stripped appears to be suitable as a stable severe ischemia model. The A group in which the femoral artery were cut just below the bifurcation of the deep femoral artery appears to be suitable as a chronic mild ischemia model. PMID- 21302241 TI - Traumatic fracture of the stapes and perilymph fistula: report of a case. AB - We herein report a case of traumatic fracture of the stapes accompanying vestibular window rupture with perilymph fistula, and its diagnosis and surgical procedure were discussed. In the present case, a direct force through the external auditory canal damaged not only the ossicular chain but also the vestibular window. On the exploratory tympanotomy, the complete dislocation and fracture of the stapes with a relatively huge rupture was confirmed. Perilymph fistula was repaired with a connective tissue graft, which was inserted between disrupted vestibular window and the long process of the incus. Vestibular dysfunctions disappeared within 3 days, and a satisfactory audiologic result was obtained one month after surgery. PMID- 21302242 TI - Histologic and photonic evaluation of a pulsed Nd:YAG laser for ablation of subcutaneous adipose tissue. AB - Although various lasers are available, few of them are applicable in liposculpture. Laser interaction with fat tissue has not also been well documented. The aim of our study was to gather basic data on laser absorption in fat tissue and to analyze the relationship between laser energy and lipolysis for development of a more effective laser system. The transmittance rate in human fat specimens was measured by a spectrophotometer to determine the optimum wavelength. The absorption coefficient was used to evaluate laser absorption at a wavelength of 1064 nm. Areas of heat degeneration and evaporation were measured by scanning electron microscopy. The relation between laser energy and the areas was analyzed statistically among low-power and high-power groups and controls. Energy dispersion at the fiber tip was investigated and analyzed statistically using the far field pattern. A graph of the absorption rate at wavelengths from 400 to 2400 nm showed a peak near 1700 nm and increases at wavelengths over 2000 nm. The formula gave as an absorption coefficient of 0.4 cm(-1), and involvement of the photo-acoustic effect and non-linear effect with short-pulse and high-peak energy was suggested. Findings of tissue evaporation, destruction, heat coagulation, and rupture of cell membrane were more frequently seen in irradiated specimens than in controls in scanning electron microscopy. The destroyed area in the low-power irradiated groups was significantly larger than that of controls in the statistical analysis. The affected area in the high-power irradiated groups was significantly larger than that of low-power specimens. Energy was concentrated at the tip with laser coherency. Energy at the oblique-cut tip was statistically lower than that at the normal tip, revealing that durability and maintenance of the fiber tip is essential to maintain energy levels in clinical practice. This study is the first to demonstrate the histologic and photonic relationship of energy absorption and lipolysis using a pulsed Nd:YAG laser. The results will be useful for research and development of a more effective laser system for liposculpture. PMID- 21302243 TI - Progression of 189 women diagnosed with uterine cervical dysplasia based on abnormal results in mass screening. AB - During the five-year period from January 1997 to December 2001, cytological abnormalities in the uterine cervix were confirmed in 189 women (class IIIa: 172, class IIIb: 9, class IV: 7, and class V: 1) who underwent cytology screening of the uterine cervix at the Tokai University Health Evaluation and Promotion Center. Biopsy samples from the uterine cervix showed that the 172 women categorized into class IIIa based on cytology included 28 with no atypical lesions, 53 with mild dysplasia, 24 with moderate dysplasia, 3 with severe dysplasia; and the 9 women in class IIIb included 2 with mild dysplasia, 5 with moderate dysplasia, 1 with carcinoma in situ, and 1 with invasive carcinoma. The conformity rates between the cytology data and the biopsy samples were 71.3% and 11.1% in class IIIa and class IIIb, respectively. A three-year followup survey of the class IIIa and class IIIb subjects confirmed progression (PRO) in 8 (4.7%), continuous (CON) symptoms in 48 (27.9%), and regression (REG) in 116 (67.4%) in class IIIa, and PRO, CON and REG in 3 (33.3%), 4 (44.4%), and 2 (22.2%), respectively, in class IIIb; the percentage of subjects in the CON+REG group was significantly higher than in the PRO group (p = 0.0052). Twelve subjects underwent resection because uterine carcinoma was suspected in the punch biopsy; these subjects have remained under observation and have now made a complete recovery. Our results suggest that patients with uterine abnormal cells should undergo regular cytology and colposcopy for detection of high-risk patients and to allow treatment at an early stage. PMID- 21302245 TI - Laparoscopic treatment of intestinal intussusception in Peutz-Jeghers syndrome: case report and review of literature. AB - A 47-year-old woman presented with an abdominal mass and nausea. Abdominal ultrasound and computed tomography (CT) showed a sausage-shaped mass with invagination. One polyp that appeared to exceed 3 cm was found in the sigmoid colon. Laparoscopy confirmed an intussusception mass, and the intussusception was dissected by hand-assisted laparoscopy (HALS). The sigmoid colon was also mobilized to the site of the small incision and resected. Generally, we believe enterectomy including polyps should be avoided as much as possible in Peutz Jeghers syndrome (PJS) because poly-surgery may lead to short bowel syndrome. In addition, PJS patients often undergo multiple surgery, and therefore dense intra abdominal adhesions are seen at subsequent laparotomy, which makes surgery increasingly difficult with repeated operations. Laparoscopic-assisted surgery seems beneficial, as in the present case. PMID- 21302244 TI - Esophagogastrostomy before proximal gastrectomy in patients with early gastric cancers in the upper third of the stomach. AB - OBJECTIVE: This study was designed to assess the outcome of esophagogastrostomy before proximal gastrectomy in patients with early gastric cancers in the upper third of the stomach. METHODS: From 1997 through 2004, we studied 10 consecutive patients. A stapler was introduced into the stomach, and an esophagogastrostomy was performed before proximal gastrectomy. Hill's posterior gastropexy and Dor's anterior fundic wrap were performed to prevent reflux esophagitis. RESULTS: The operation time was 171 +/- 44 minutes, and the intraoperative bleeding volume was 294 +/- 228 mL. There was no anastomotic leakage. Anastomotic stenosis, occurring in 40% of the patients, required endoscopic balloon dilatation. Symptoms of reflux esophagitis, occurring in 40% of the patients, resolved within 2 years after operation. As compared with the preoperative value, body mass index was significantly decreased 1 and 2 years after operation, but was similar at 3 to 5 years. The percent decrease in body weight after operation fluctuated between 6% and 8% between 2 and 5 years. Postoperative weight loss was thus mild. CONCLUSIONS: Esophagogastrostomy before proximal gastrectomy may be less invasive, simpler, and produce better outcomes than conventional procedures for the surgical treatment of early gastric cancer in the upper third of the stomach. PMID- 21302246 TI - Successful second autologous peripheral blood stem cell transplantation conditioned with total body irradiation for progressive neuroblastoma after recurrence. AB - A girl with recurrent neuroblastoma was successfully treated with second autologous stem cell transplantation (SCT) conditioned with total body irradiation (TBI). This patient was diagnosed as stage IV neuroblastoma at the age of 18 months. Pathological finding was stroma-poor unfavorable histology and amplification of MYCN gene was extremely high (153 copies). In spite of autologous SCT with non-TBI regimen in the status of disease-free, neuroblastoma relapsed at the primary site 6 months later. Second autologous SCT conditioned with TBI and melphalan was performed although the tumor was progressive. Over 3 years after second SCT, she has been well with no evidence of further recurrence of neuroblastoma, but she was complicated with permanent atrophy of left kidney. TBI might be effective for relapsed neuroblastoma who previously received SCT with non-TBI regimen. PMID- 21302247 TI - Video-assisted thoracoscopic surgery in treatment of stabbing chest injuries. AB - Since 1994, we have performed video-assisted thoracoscopic surgery in order to treat thoracic trauma. In general, emergency surgery is performed for trauma injuries incurred by knives. Between 1994 and 2005, we performed thoracoscopic surgery on eighteen cases of thoracic stab wounds. Among these eighteen cases, two were characterized by wounds to the internal thoracic artery, and they had to be switched over to open thoracotomy due to excessive bleeding. In conclusion, open thoracotomy should be performed in cases in which the patient is in a state of shock due to severe intrathoracic bleeding; however, in cases in which the vital signs are stable, thoracoscopic surgery may be carried out to stop intrathoracic bleeding, to repair the lung injury by suturing, as well as by performing a partial resection of the lung. PMID- 21302248 TI - The lipid and lipoprotein profiles of apo B-carrying particles in remnant-like lipoproteins isolated from plasma in sudden cardiac death cases. AB - OBJECTIVE: Remnant-like lipoprotein particles (RLP) are known as a subset of TG rich lipoproteins which possess proatherogenic properties. In this study we have elucidated the characteristics of apoB carrying lipoprotein particles in RLP isolated from plasma in sudden cardiac death (SCD) cases and in coronary artery disease (CAD) patients. METHODS: Lipids and lipoproteins, especially apoB-48 and apoB-100, were analyzed in plasma and in RLP from SCD and CAD cases with full stomach. RESULTS: SDS-PAGE and ELISA showed the predominance of apoB-100 in RLP compared with apoB-48. The main peak of RLP fractionated by HPLC and monitored by TC and TG revealed the particle size at VLDL or IDL, similar to those from CAD patients. The main peak of RLP monitored by apoB-48 revealed the particle size smaller than those monitored by apoB-100 in both cases. RLP-TG/total TG ratio was shown to be significantly higher in SCD cases than in control death cases (P < 0.001) in spite of the same fatty acid composition in RLP between the cases. CONCLUSION: These results suggested that the major subset of apoB particles in RLP isolated from plasma in SCD cases was apoB-100 carrying VLDL remnants, not apoB-48 CM remnants, which was identical with RLP in CAD patients. PMID- 21302249 TI - A case report of advanced thoracic esophageal cancer with severe malignant stricture. AB - We experienced one case with locally advanced esophageal cancer that he gained a good result by the multidisciplinary treatment including the operation followed by chemoradiation. The case was a 74-year old man with the middle thoracic esophageal cancer accompanied by severe malignant stricture. He couldn't take any water, and his general condition was poor, because he lost 5 kg of his weight. By the clinical examinations, his cancer had no apparent invasion to adjacent organ. So, we planned the operation gone ahead the chemoradiation for him to take water and meals earlier, and to prevent pneumonia. The esophagectomy through right thoracotomy was done, and the pathological findings were type 3, well differentiated squamous cell carcinoma, pT3 N0, pStageII. Two months later after the operation, he took the chemoradiotherapy. 50 gray radiation therapy was done with chemotherapy including Cisplatin (10 mg/a time/week) and Tegafur (200 mg/day). About one and half a year after the operation, he sends good daily life with no recurrence. Recently, chemoradiotherapy is the first choice of the treatment for the locally advanced esophageal cancer. But in cases without apparent invasion to adjacent organ, it might be advisable that the operation goes ahead the chemoradiotherapy in the multidisciplinary treatment. PMID- 21302251 TI - Stem cells in biology and disease - ESTOOLS International Symposium. AB - ESTOOLS was the first EU-funded project entirely devoted to the study of human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). The final meeting of the consortium took place in Lisbon from 26 to 28 May 2010 and gathered 298 researchers from 27 countries. A dense programme of scientific sessions and outreach activities and an ethics workshop gave an all-round overview of the challenges, perspectives and ethical issues of this exciting field. The ESTOOLS consortium was launched in 2006 as a 4-year EU-funded 6th Framework (FP6) project, with a total funding of 12 million euro. The project has been the largest European consortium devoted to the study of human ESCs, teaming up 21 research groups in 10 countries. After the discovery of human induced pluripotent stem cells (iPSCs) by Shinya Yamanaka and James Thomson in 2007, the consortium opened a new workpackage dedicated to this groundbreaking field, and became the first to devote EU funding to study human iPSCs. The Lisbon meeting marked the end of the consortiums funding cycle, but it was more than a wrap-up of its overall work and achievements, providing a showcase of cutting-edge research in human pluripotent stem cells, with the participation of international leaders in the field. PMID- 21302252 TI - Cajal's achievements in the field of the development of dendritic arbors. AB - In 1909, Cajal published an up-dated version in French (Cajal, 1909-1911) of his main work Texture of the Nervous System of Man and Vertebrates (Cajal, 1899 1904), considered the most important book devoted to the nervous system. Owing that last year was the centenary of this publication, we decided to produce an article focused on Cajals description of the morphological changes that dendritic trees undergo during development. We will emphasize his brilliant hypotheses explaining the modelling of dendritic trees (the neurotropic hypothesis and the role of neuronal activity in the patterning of the dendritic trees), and the status of this topic in present day Neuroscience. Here, we will show original photographs taken from a selected collection of Cajals slides housed in the Cajal Museum (Instituto Cajal, CSIC, Madrid, Spain) illustrating the principal changes in neuronal morphology at different stages of development of the spinal cord, cerebellum and cerebral cortex. We will also discuss Cajals initial proposals regarding the influence of neurotropic substances (chemotactic hypothesis) and neural activity in the modelling of the dendritic tree, as well as the evidence that later confirmed these theories. PMID- 21302253 TI - Drosophila morgue influences cell numbers and positions in the embryonic nervous system. AB - Morgue is a unique multi-domain protein that contains a zinc finger motif, an F box, and a variant E2 conjugase domain. The presence of these domains suggests potentially complex and novel functions for Morgue in ubiquitination pathways. Morgue was originally identified via its gain-of-function enhancement of eye cell death phenotypes in Drosophila and ectopic expression of Morgue also influences circadian rhythms. However, there is as yet little known about Morgues normal developmental or physiological functions. To address this issue, we generated several morgue loss-of-function mutants via P element excision mutagenesis and analyzed the mutant phenotypes during the fly life cycle. These studies revealed that morgue null mutants are viable, though approximately 10% of the mutants exhibit defects in pupal spiracle eversion and malformations in the adult abdominal cuticle. In addition, a similar subset of morgue mutant embryos exhibited alterations in the normal number, position, or morphology of specific neurons and glia. Analysis of Morgue protein localization was addressed through generation of a transgenic fly strain that expresses a GFP::Morgue fusion protein. Use of this strain revealed Morgue protein localization in multiple cellular compartments, including nuclei, cytoplasm and membranes. Taken together, these diverse phenotypes and distribution patterns suggest pleiotropic functions for Morgue. PMID- 21302254 TI - Transplantation of Xenopus laevis ears reveals the ability to form afferent and efferent connections with the spinal cord. AB - Previous comparative and developmental studies have suggested that the cholinergic inner ear efferent system derives from developmentally redirected facial branchial motor neurons that innervate the vertebrate ear hair cells instead of striated muscle fibers. Transplantation of Xenopus laevis ears into the path of spinal motor neuron axons could show whether spinal motor neurons could reroute to innervate the hair cells as efferent fibers. Such transplantations could also reveal whether ear development could occur in a novel location including afferent and efferent connections with the spinal cord. Ears from stage 24-26 embryos were transplanted from the head to the trunk and allowed to mature to stage 46. Of 109 transplanted ears, 73 developed with otoconia. The presence of hair cells was confirmed by specific markers and by general histology of the ear, including TEM. Injections of dyes ventral to the spinal cord revealed motor innervation of hair cells. This was confirmed by immunohistochemistry and by electron microscopy structural analysis, suggesting that some motor neurons rerouted to innervate the ear. Also, injection of dyes into the spinal cord labeled vestibular ganglion cells in transplanted ears indicating that these ganglion cells connected to the spinal cord. These nerves ran together with spinal nerves innervating the muscles, suggesting that fasciculation with existing fibers is necessary. Furthermore, ear removal had little effect on development of cranial and lateral line nerves. These results indicate that the ear can develop normally, in terms of histology, in a new location, complete with efferent and afferent innervations to and from the spinal cord. PMID- 21302255 TI - Six1 is indispensable for production of functional progenitor cells during olfactory epithelial development. AB - The rodent olfactory epithelium (OE) is a good model system for studying the principles of stem and progenitor cell biology, because of its capacity for continuous neurogenesis throughout life and relatively well-characterized neuronal lineage. The development of mouse OE is divided into two stages, early and established neurogenesis. In established neurogenesis, which starts at embryonic day (E) 12.5, sustentacular cells and olfactory receptor neurons (ORNs) are produced from apical and basal progenitors, respectively. We previously reported that Six1(-/-) shows a lack of mature ORNs throughout development and disorganization of OE after E12.5. However, the molecular bases for these defects have not been addressed. Here, we show that Six1 is expressed in both apical and basal progenitors. In Six1(-/-) mice, apical proliferating cells were absent and no morphologically identifiable sustentacular cells were observed. Consistently, the expression of Notch2 and Jagged1 in the apical layer was absent in Six1(-/-) mice. On the other hand, basal proliferating cells were observed in Six1(-/-) animals, but the expression of Ngn1, NeuroD, Notch1, and Jagged2 in the basal layer was absent. The expression of Mash1, the determination gene for ORNs, and Hes genes was enhanced in Six1(-/-) mice. The present findings suggest that Six1 regulates production of functional apical and basal progenitors during OE development, through the regulation of various genes, such as neuronal basic helix-loop-helix (bHLH), neuronal repressor bHLH, and genes involved in the Notch signaling pathway. PMID- 21302256 TI - A novel mutant allele of Ncx1: a single amino acid substitution leads to cardiac dysfunction. AB - The biological role and structure-function relationship of the Na(+)Ca(2+) exchanger NCX1 have been the subject of much investigation. Subtle mutagenesis to study the function of a protein seems only feasible in in vitro systems, but genetic forward screens have the potential to provide in vivo models to study single amino acid substitutions. In a genetic screen in mouse, we have isolated a mutant line carrying a novel mutant allele of the mouse Ncx1 gene. In this allele, a point mutation causes the substitution of a highly conserved asparagine residue (N874) with lysine. Accepted models for NCX1 structure propose that the affected amino acid is located in one of the reentrant membrane loops and experiments in vitro have identified N874 as critical for the ion transport function of NCX1. We found severe circulation defects and defective placentation in homozygous Ncx1(N87K4) mutant embryos, making the phenotype essentially indistinguishable from those of previously described null mutants. By ex vivo analysis, we demonstrated intrinsic functional abnormalities of cardiomyocytes. Western blot analysis and immunohistochemistry demonstrated normal levels and subcellular localization of the altered protein, ruling out the possibility that the abnormalities are a mere consequence of a major disturbance of protein structure. This study confirms and extends studies in vitro indicating the significance of amino acid N874 for the function of the NCX1 protein. It provides an in vivo model for this mutation and demonstrates the potential of forward genetic screens in a mammalian system. PMID- 21302257 TI - Isolation of teleost primordial germ cells using flow cytometry. AB - Primordial germ cells (PGCs) generate gametes, the only cells that can transmit genetic information to the next generation. A previous report demonstrated that a fusion construct of green fluorescent protein (gfp) and zebrafish nos 1 3UTR mRNA could be used to label PGCs in a number of fish species. Here, we sought to exploit this labeling strategy to isolate teleost PGCs by flow cytometry (FCM), and to use these isolated PGCs to examine germ cell migration to the gonadal region. In zebrafish, medaka and goldfish, the PGCs were labeled by injecting the gfp-nos1 3UTR mRNA into 1- 4 cell embryos. When the embryos had developed to the somitogenesis or later stages, they were enzymatically disaggregated and GFP positive cells isolated using FCM. PGCs in the different species clustered in the same segments of the FCM scatter diagrams for total embryonic cells produced by plotting the forward scatter intensity against GFP intensity. In situ hybridization showed that the sorted zebrafish cells expressed vasa RNA in their cytoplasm, suggesting that they were PGCs. When the migration ability of the sorted cells from zebrafish was examined in an in vivo transplantation experiment, approximately 30% moved to the gonadal region of host embryos. These observations demonstrate that PGCs can be isolated without use of transgenic fishes and that the isolated PGCs retain the ability to migrate. Our data indicate that this technique will be of value for isolating PGCs from a range of fish species. PMID- 21302258 TI - Generation of germ-line chimera zebrafish using primordial germ cells isolated from cultured blastomeres and cryopreserved embryoids. AB - Primordial germ cells (PGCs) are the only cells in developing embryos with the potential to transmit genetic information to the next generation. In our previous study, a single PGC transplanted into a host differentiated into fertile gametes and produced germ-line chimeras of cyprinid fish, including zebrafish. In this study, we aimed to induce germ-line chimeras by transplanting donor PGCs from various sources (normal embryos at different stages, dissociated blastomeres, embryoids, or embryoids cryopreserved by vitrification) into host blastulae, and compare the migration rates of the PGCs towards the gonadal ridge. Isolated, cultured blastomeres not subject to mesodermal induction were able to differentiate into PGCs that retained their motility. Moreover, these PGCs successfully migrated towards the gonadal ridge of the host and formed viable gametes. Motility depended on developmental stage and culture duration: PGCs obtained at earlier developmental stages and with shorter cultivation periods showed an increased rate of migration to the gonadal ridge. Offspring were obtained from natural spawning between normal females and chimeric males. These results provide the basis for new methods of gene preservation in zebrafish. PMID- 21302259 TI - Expression pattern of iodotyrosine dehalogenase 1 (DEHAL1) during chick ontogeny. AB - The iodotyrosine dehalogenase1 (DEHAL1) enzyme is a transmembrane protein that belongs to the nitroreductase family and shows a highly conserved N-terminal domain. DEHAL1 is present in the liver, kidney and thyroid of mammals. DEHAL1 is known to act on diiodotyrosine (DIT) and monoiodotyrosine (MIT), and is involved in iodine recycling in relation to thyroglobulin. Here, we show the distribution of DEHAL1 during gastrulation to neurulation in developing chick. Immunocytochemistry using an anti-serum directed against the N-terminal domain (met(27)-trp(180) fragment) of human DEHAL1 revealed labelled cells in the embryonic ectoderm, embryonic endoderm, neural plate and in the yolk platelets of the chick embryo at gastrulation stage. Distinct DEHAL1 positive cells were located in the presumptive head ectoderm, presumptive neural crest, head mesenchymal cells and in the dorsal, lateral and ventral parts of neural tube during neurulation. Some cells located at the margin of the developing notochord and somites were also DEHAL1-positive. While the functional significance of this observation is not known, it is likely that DEHAL1 might serve as an agent that regulates cell specific deiodination of MIT and DIT before the onset of thyroidal secretion. The presence of DEHAL1 in different components of the chick embryo suggests its involvement in iodine turnover prior to the formation of functional thyroid. PMID- 21302260 TI - Comprehensive analysis of fibroblast growth factor receptor expression patterns during chick forelimb development. AB - Specific interactions between fibroblast growth factors (Fgf1-22) and their tyrosine kinase receptors (FgfR1-4) activate different signalling pathways that are responsible for the biological processes in which Fgf signalling is implicated during embryonic development. In the chick, several Fgf ligands (Fgf2, 4, 8, 9, 10, 12, 13 and 18) and the four FgfRs (FgfR 1, 2, 3 and 4) have been reported to be expressed in the developing limb. The precise spatial and temporal expression of these transcripts is important to guide the limb bud to develop into a wing/leg. In this paper, we present a detailed and systematic analysis of the expression patterns of FgfR1, 2, 3 and 4 throughout chick wing development, by in situ hybridisation on whole mounts and sections. Moreover, we characterize for the first time the different isoforms of FGFR1-3 by analysing their differential expression in limb ectoderm and mesodermal tissues, using RT-PCR and in situ hybridisation on sections. Finally, isoform-specific sequences for FgfR1IIIb, FgfR1IIIc, FgfR3IIIb and FgfR3IIIc were determined and deposited in GenBank with the following accession numbers: GU053725, GU065444, GU053726, GU065445, respectively. PMID- 21302261 TI - Digit ratio (2D:4D) and rowing ergometer performance in males and females. AB - Fetal and adult testosterone may be vital in the establishment and maintenance of sex-dependent abilities associated with male physical competitiveness. It has been shown that digit ratio (2D:4D) is negatively associated with prenatal testosterone, and it is also negatively associated with ability in sports such as football, skiing, middle distance running, and endurance running, which are dependent upon an efficient cardiovascular system. The relationship between digit ratio and sports requiring high power (physical strength) output in addition to well-developed cardiovascular systems has not been defined. This study investigated this association in male and female young adult rowers. Participants (77 male and 70 female) were student rowers encompassing a range of abilities from the University of Cambridge. Bilateral digit measurements were taken blind from each subject using Mitutoyo vernier calipers. Rowing performance over 2,000 m was assessed using the Concept 2 rowing ergometer. Significant negative correlations were observed between 2,000 m ergometer performance and male digit ratios, which persisted following adjustment for rowing experience and height. However, no such significant association was found in females despite a comparable sample size. Our data indicate that digit ratio is a predictor of ability in rowing, a sport which requires both cardiovascular efficiency and high power output, in males but not females. This in turn suggests that fetal testosterone exposure has long-term effects on traits associated with physical power in males but not females, suggesting a sex-difference in the capacity to respond to such exposures. PMID- 21302262 TI - Comparison of dental measurement systems for taxonomic assignment of first molars. AB - Morphometrics of the molar crown is based traditionally on diameter measurements but is nowadays more often based on 2D image analysis of crown outlines. An alternative approach involves measurements at the level of the cervical line. We compare the information content of the two options in a three-dimensional (3D) digital sample of lower and upper first molars (M(1) and M(1) ) of modern human and Neanderthal teeth. The cervical outline for each tooth was created by digitizing the cervical line and then sectioning the tooth with a best fit plane. The crown outline was projected onto this same plane. The curves were analyzed by direct extraction of diameters, diagonals, and area and also by principal component analysis either of the residuals obtained by regressing out these measurements from the radii (shape information) or directly by the radii (size and shape information). For M(1) , the crown and cervical outline radii allow us to discriminate between Neanderthals and modern humans with 90% and 95% accuracy, respectively. Fairly good discrimination between the groups (80-82.5%) was also obtained using cervical measurements. With respect to M(1) , general overlap of the two groups was obtained by both crown and cervical measurements; however, the two taxa were differentiable by crown outline residuals (90-97%). Accordingly, while crown diameters or crown radii should be used for taxonomic analysis of unworn or slightly worn M(1) s, the crown outline, after regressing out size information, could be promising for taxonomic assignment of lower M1s. PMID- 21302263 TI - Behavioral thermoregulation in a gregarious lemur, Eulemur collaris: effects of climatic and dietary-related factors. AB - Primates deal with fluctuations of the thermal environment by both physiological and behavioral mechanisms of thermoregulation. In this article we focus on non hibernating lemurs, which are hypometabolic and have to cope with a seasonal environment. Behavioral thermoregulation has received little attention compared with specific physiological adaptations to seasonality, i.e., hibernation and torpor, which characterize a number of lemurs. We investigated the role of seasonality and dietary-related factors in determining frequencies of resting, social and postural thermoregulation, and microhabitat selection in collared lemurs, Eulemur collaris. We observed two groups of collared lemurs over a 14 month period in the littoral forest of Sainte Luce, Southern Madagascar. Frequencies of total resting and time spent in huddling, prone, and curled postures were collected via 5-min instantaneous sampling. Microhabitat selection was evaluated as the proportion of time spent in the upper canopy as compared with other layers. Climatic variables were recorded by automatic data loggers, while dietary variables were derived from phenological data and nutritional analyses of the ingested food items. We weighted the combined effects of climatic and dietary variables on the different types of behavioral thermoregulation by means of canonical correlation analysis. The model with the strongest canonical correlation included a first root representing mainly feeding time, day length, and ambient temperature and a second root representing diet quality and height of feeding trees. The output indicated that collared lemurs adapt to thermal and dietary-related metabolic stress by adjusting resting time, social, and postural thermoregulation. PMID- 21302264 TI - A partial hominoid humerus from the middle miocene of Castell de Barbera (Valles Penedes Basin, Catalonia, Spain). AB - The hominoid right partial humerus IPS4334, from the middle Miocene (MN 8) of Castell de Barbera (Valles-Penedes Basin, Catalonia, Spain), is described. It preserves the mid-distal portion of the shaft until the proximal margins of the radial and coronoid fossae, as well as the proximal portion of the olecranon fossa; the capitulum, the trochlea and the two epicondyles are missing. Although morphological comparisons are restricted, available evidence indicates that IPS4334 is more derived towards the modern hominoid condition than the Klein Hadersdorf specimen attributed to Griphopithecus (ca. 13-14 Ma), thus being most similar (except for its larger size and greater robusticity) to the presumably juvenile specimen of Dryopithecus fontani from Saint Gaudens in France (ca. 11-12 Ma). On the basis of shaft measurements and allometric regressions derived for extant hominoids, a body mass estimate around 50 kg is derived for IPS4334. Morphological similarities with the Saint Gaudens specimen, together with the large body mass estimate, suggest a tentative attribution of IPS4334 to cf. D. fontani, which is the largest hominoid taxon so far recorded from the Valles Penedes Basin. The larger size and higher robusticity of IPS4334 as compared to the Saint Gaudens specimen might be explained by the juvenile status of the latter and/or sexual dimorphism. When both specimens are considered together with a partial femur from Abocador de Can Mata, D. fontani emerges as a less suspensory ape than the late Miocene Hispanopithecus, the locomotor repertoire of the former emphasizing climbing, but still displaying a significant quadrupedal component. PMID- 21302265 TI - Allometry and apparent paradoxes in human limb proportions: Implications for scaling factors. AB - It has been consistently demonstrated that human proximal limb elements exhibit negative allometry, while distal elements scale with positive allometry. Such scaling implies that longer limbs will have higher intralimb indices, a phenomenon not borne out by empirical analyses. This, therefore, creates a paradox within the limb allometry literature. This study shows that these apparently conflicting results are the product of two separate phenomena. First, the use of the geometric mean of limb elements produces allometry coefficients that are not independent, and that when using ordinary least squares regression must yield an average slope of one. This phenomenon argues against using the geometric mean as a size variable when examining limb allometry. While the employment of relevant dimensions independent of those under analysis to calculate the geometric mean--as suggested by Coleman (Am J Phys Anthropol 135 (2008) 404-415)--may be a partial method for resolving the problem, an empirically determined, independent and biologically relevant size variable is advocated. If stature is used instead of the geometric mean as an independent size variable, all major limb elements scale with positive allometry. Second, while limb allometry coefficients do indicate differential allometry in limb elements, and thus should lead to some intralimb index allometry, this pattern appears to be attenuated by other sources of limb element length variation. PMID- 21302266 TI - Comparative microcomputed tomography and histological study of maxillary pneumatization in four species of new world monkeys: the perinatal period. AB - In anthropoid primates, it has been hypothesized that the magnitude of maxillary sinus growth is influenced by adjacent dental and soft tissue matrices. Relatively, little comparative evidence exists for the perinatal period when secondary pneumatization is at its earliest stages in some primates. Here, dental and midfacial variables were studied in a perinatal sample of four anthropoid primates, including three callitrichines (Leontopithecus, Saguinus, and Callithrix) and Saimiri boliviensis. In the latter species, the maxillary recess (the ontogenetic precursor to a "true" maxillary sinus) does not undergo secondary pneumatization. Using histological methods and micro-computed tomography, midfacial and dental dimensions and radiographic hydroxyapatite density of tooth cusps were measured. The distribution of osteoclasts and osteoblasts was also documented. Kruskal-Wallis's one-way analysis of variance tests indicates significant (P < 0.05) differences among groups for dental and midfacial measurements. In particular, the posterior maxillary dentition is relatively larger and more mineralized in Saimiri compared to the callitrichines. At posterior dental levels, Saimiri has the lowest palatonasal index [interdental (palatal) width/width of the nasal cavity] and highest bizygomatic-interorbital index. Distribution of osteoclasts indicates that the inferomedial surfaces of the orbits are resorptive in perinatal Saimiri, whereas, in all callitrichines, these surfaces are depository. Taken together, these findings suggest that pneumatization in Saimiri is suppressed by an inward growth trajectory of the orbits, relatively large posterior dentition, and a correspondingly compressed nasal region. PMID- 21302267 TI - Talon cusp from two archaic period cemeteries in North America: implications for comparative evolutionary morphology. AB - Talon cusps are rare morphological features of the anterior dentition that represent a spectrum of lingual cingulum diversity. In this paper, talon cusp prevalence is described in two Archaic period North American samples, Windover Pond (Florida) and Buckeye Knoll (Texas). Given the early date of these cemeteries (~7500 BP), these specimens represent the oldest reported cases of lingual talon cusp in the New World, and perhaps globally. Windover preserves three cases of talon cusp (representing three different individuals) affecting the permanent maxillary lateral incisors. The sample frequencies were 1.8% and 3.1% for the left and right maxillary lateral incisors, respectively. Buckeye Knoll preserves four cases of talon cusp representing three individuals. Talon cusps at this site were distributed throughout the maxillary anterior dentition, including a permanent maxillary central incisor, bilateral permanent maxillary lateral incisors, and a deciduous maxillary lateral incisor. The multicomponent nature of this site complicates sample frequency calculation with by-tooth estimates ranging from 3.6% to 25%. This paper discusses the difficulties with comparative frequency estimation, resulting from a proliferation of terminology that is discipline-specific. Understanding the evolutionary basis and significance of dental morphological variation requires an inclusive approach to the comparative literature that focuses on homology within the context of odontogenetic process. PMID- 21302268 TI - Reduced stiffness of alveolar bone in the colobine mandible. AB - Alveolar bone has several mechanical functions, including tooth support and accommodation of occlusal and other masticatory forces. Its unique functional mechanical environment is reflected by its structural characteristics, but whether alveolar bone is materially distinct from bone elsewhere in the primate facial skeleton is uncertain. This uncertainty is attributable not only to a limited amount of data but also to conflicting findings among these data. We evaluated elastic modulus variation in the mandibular corpus of eight adult specimens of the monkeys Procolobus badius and Colobus polykomos via microindentation to evaluate whether alveolar bone is more compliant than basal bone and to quantify patterns of variation between sexes and species. We sampled Vickers hardness from six serial transverse sections and one coronal section from both the alveolar process and the basal corpus. Hardness values were converted to elastic modulus via regressions specific for bone tissue. Analysis of variance reveals that a plurality of variation is found on a regional scale; i.e., alveolar bone is more compliant than adjacent basal bone. Species affiliation and sex are not significant sources of variation. These findings support a hypothesis that compliance of alveolar bone represents a material solution for avoiding large stress concentrations arising from occlusal loads. Other comparative data suggest important differences between colobine and cercopithecine mandibles in terms of bone stiffness, both overall and in terms of relative stiffness of alveolar and basal cortical bone. PMID- 21302269 TI - Admixed ancestry and stratification of Quebec regional populations. AB - Population stratification results from unequal, nonrandom genetic contribution of ancestors and should be reflected in the underlying genealogies. In Quebec, the distribution of Mendelian diseases points to local founder effects suggesting stratification of the contemporary French Canadian gene pool. Here we characterize the population structure through the analysis of the genetic contribution of 7,798 immigrant founders identified in the genealogies of 2,221 subjects partitioned in eight regions. In all but one region, about 90% of gene pools were contributed by early French founders. In the eastern region where this contribution was 76%, we observed higher contributions of Acadians, British and American Loyalists. To detect population stratification from genealogical data, we propose an approach based on principal component analysis (PCA) of immigrant founders' genetic contributions. This analysis was compared with a multidimensional scaling of pairwise kinship coefficients. Both methods showed evidence of a distinct identity of the northeastern and eastern regions and stratification of the regional populations correlated with geographical location along the St-Lawrence River. In addition, we observed a West-East decreasing gradient of diversity. Analysis of PC-correlated founders illustrates the differential impact of early versus latter founders consistent with specific regional genetic patterns. These results highlight the importance of considering the geographic origin of samples in the design of genetic epidemiology studies conducted in Quebec. Moreover, our results demonstrate that the study of deep ascending genealogies can accurately reveal population structure. PMID- 21302270 TI - Paleoamerican morphology in the context of European and East Asian late Pleistocene variation: implications for human dispersion into the New World. AB - Early American crania show a different morphological pattern from the one shared by late Native Americans. Although the origin of the diachronic morphological diversity seen on the continents is still debated, the distinct morphology of early Americans is well documented and widely dispersed. This morphology has been described extensively for South America, where larger samples are available. Here we test the hypotheses that the morphology of Early Americans results from retention of the morphological pattern of Late Pleistocene modern humans and that the occupation of the New World precedes the morphological differentiation that gave rise to recent Eurasian and American morphology. We compare Early American samples with European Upper Paleolithic skulls, the East Asian Zhoukoudian Upper Cave specimens and a series of 20 modern human reference crania. Canonical Analysis and Minimum Spanning Tree were used to assess the morphological affinities among the series, while Mantel and Dow-Cheverud tests based on Mahalanobis Squared Distances were used to test different evolutionary scenarios. Our results show strong morphological affinities among the early series irrespective of geographical origin, which together with the matrix analyses results favor the scenario of a late morphological differentiation of modern humans. We conclude that the geographic differentiation of modern human morphology is a late phenomenon that occurred after the initial settlement of the Americas. PMID- 21302271 TI - Evolutionary perspectives on mother-infant sleep proximity and breastfeeding in a laboratory setting. AB - Human maternal and infant biology likely coevolved in a context of close physical contact and some approximation of frequent, "infant-initiated" breastfeeding. Still, mothers and infants commonly sleep apart from one another in many western societies, indicating a possible "mismatch" between cultural norms and infant biology. Here we present data from a 3-night laboratory-based study that examines differences in mother-infant sleep physiology and behavior when mothers and infants sleep together on the same surface (bedsharing) and apart in separate rooms (solitary). We analyze breastfeeding frequency and interval data from the first laboratory night (FN) for 52 complementary breastfeeding mothers and infants (26 total mother-infant pairs), of which 12 pairs were routine bedsharers (RB) and 14 were routine solitary sleepers (RS). RB infants were 12.0 +/- 2.7 (SD) weeks old; RS infants were 13.0 +/- 2.4 weeks old. On the FN, RB mother infant pairs (while bedsharing) engaged in a greater number of feeds per night compared to RS (while sleeping alone) (P < 0.001). RB also showed lower intervals (min) between feeds relative to RS (P < 0.05). When we evaluated data from all three laboratory nights (n = 36), post hoc, RB breastfed significantly more often (P < 0.01) and showed a trend towards lower intervals between feeds (P < 0.10). Given the widely known risks associated with little or no breastfeeding, the demonstrated mutually regulatory relationship between bedsharing and breastfeeding should be considered in future studies evaluating determinants of breastfeeding outcomes. PMID- 21302272 TI - Environmental effects on skeletal versus dental development II: further testing of a basic assumption in human osteological research. AB - This study further tests the general assumption that skeletal development is more sensitive to socioeconomic factors than dental development in a sample of modern immature Portuguese skeletons (N = 41) of known sex, age, and socioeconomic background. Skeletal development was assessed from skeletal maturation of the knee and dental development was assessed from schedules of tooth formation. Discrepancies between physiological age (skeletal and dental age) and chronological age were used as a measure of developmental status. A positive score indicates that physiological age is in advance of chronological age, whereas a negative score indicates the reverse. Two socioeconomic groups, one of low and the other of high socioeconomic status, were created based on the occupation of the father and on the place of residence, and developmental status was compared between the two socioeconomic groups. Results confirm previous studies by showing that dental development is less affected by environmental insults than skeletal maturation. While socioeconomic differences in skeletal maturation range from 1.20 to 1.22 years (15-18% of chronological age), socioeconomic differences in dental maturation range from 0.51 to 0.53 years (4 9% of chronological age). Compared to a previous study, results also suggest that skeletal maturation is more affected than skeletal growth. Additionally, an adaptation of the radiographic atlas of skeletal development of the knee is proposed for use with dry skeletal material. PMID- 21302273 TI - Male ancestry structure and interethnic admixture in African-descent communities from the Amazon as revealed by Y-chromosome Strs. AB - Some genetic markers on both the Y chromosome and mtDNA are highly polymorphic and population-specific in humans, representing useful tools for reconstructing the past history of populations with poor historical records. Such lack of information is usually true in the case of recent African-descent populations of the New World founded by fugitive slaves throughout the slavery period in the Americas, particularly in Brazil, where those communities are known as quilombos. Aiming to recover male-derived ethnic structure of nine quilombos from the Brazilian Amazon, a total of 300 individuals, belonging to Mazagao Velho (N = 24), Curiau (N = 48), Mazagao (N = 36), Trombetas (N = 20), Itacoa (N = 22), Saracura (N = 46), Marajo (N = 58), Pitimandeua (N = 26), and Pontal (N = 20), were investigated for nine Y-STRs (DYS393, DYS19, DYS390, DYS389 I, DYS389 II, DYS392, DYS391, DYS385 I/II). From the 169 distinct haplotypes obtained, 120 were singletons. The results suggest the West African coast as the main origin of slaves brought to Brazil (54% of male contribution); the European contribution was high (41%), while the Amerindian's was low (5%). Those results contrast with previous mtDNA data that showed high Amerindian female contribution (46.6%) in African-descent populations. AMOVA suggests that the genetic differentiation among the quilombos is mainly influenced by admixture with European. However, when restricting AMOVA to African-specific haplotypes, low differentiation was detected, suggesting great genetic homogeneity of the African founding populations and/or a later homogenization by intense slave trade inside Brazil. PMID- 21302274 TI - Brief communication: developmental dysplasia of the hip in medieval London. AB - Developmental dysplasia of the hip (DDH) is a spectrum of disease starting in childhood and in many cases persisting into adulthood. The spectrum ranges from acetabular dysplasia, through hip subluxation to dislocation. The aim of this research was to determine the prevalence and pathoanatomy of acetabular dysplasia and subluxation in excavated human skeletal remains, to complement past research on dislocation in DDH. The material under study was the medieval cemetery of St. Mary Spital in London, in use from c.1100 to 1539 AD. A series of 572 adults with both hips preserved were analyzed. Acetabular dysplasia was indicated by a shallow acetabulum with upward sloping roof. Subluxation was suggested by degenerative change along the margin of the acetabulum suggestive of labral tears, and degenerative change in the outer part of the acetabular roof suggestive of osteoarthritis. The prevalence of DDH (acetabular dysplasia, subluxation, or dislocation) was 1.7%. Because this a congenital musculoskeletal disorder of relatively high frequency, with significant variation in prevalence between populations around the world, it is a topic that warrants targeted research from physical anthropologists studying past populations. PMID- 21302275 TI - Brief communication: Ancient nuclear DNA and kinship analysis: the case of a medieval burial in San Esteban Church in Cuellar (Segovia, Central Spain). AB - The aim of this work was to investigate a very common situation in the archaeological and anthropological context: the study of a burial site containing several individuals, probably related genetically, using ancient DNA techniques. We used available ancient DNA and forensic protocols to obtain reliable results on archaeological material. The results also enabled molecular sex determination to be compared with osteological data. Specifically, a modified ancient DNA extraction method combined with the amplification of nuclear markers with the AmpFlSTR(r)MiniFilerTM kit(Applied Biosystems) was used. Seven medieval individuals buried in four niches dated in the 15th Century at San Esteban Church in Cuellar (Segovia, Central Spain) were analyzed by the proposed method, and four of seven provided complete autosomal short tandem repeat (STRs) profiles. Kinship analyses comprising paternity and sibship relations were carried out with pedigree-specific software used in forensic casework. A 99.98% paternity probability was established between two individuals, although lower percentages (68%) were obtained in other cases, and some hypothetical kinship relations were excluded. The overall results could eventually provide evidence for reconstructing the historical record. PMID- 21302276 TI - Brief communication: Y-chromosome haplogroup analysis indicates that Chinese Tuvans share distinctive affinity with Siberian Tuvans. AB - Tuvans are mainly distributed in Siberia (the Republic of Tuva), Mongolia, and China. The genetic origin of Chinese Tuvans remains controversial. The Tuvans in China were classified as Mongolians in the early 1950s by the National Ethnic Affairs Commission of China, but they defined themselves as a separate group. To resolve this dispute and determine their genetic relationships with the peoples in Central Asia, we randomly selected 150 male subjects from the Tuvans in the Altai region of Xinjiang Uygur Autonomous Region in China. Fourteen Y chromosomal markers were genotyped using the RFLP method or direct sequencing. These haplogroup data were combined with public data for 15 populations in South Siberia and Central Asia. Tuvans in both China and the Republic of Tuva had the highest frequencies of haplogroups K-M9 and Q-M242. Principal component analysis demonstrated that the Tuvans in China were of a distinct cluster, separated from their neighbors, the Mongolians and Kazakhs, which finding was consistent with the Analysis of Molecular Variances. Further population tree analysis revealed that Tuvans were on a far-separated cluster from their neighbors. Based on these results, we propose that the Tuvans (in both China and the Republic of Tuva) constitute a group distinct from Mongolians and from other Central Asia populations. However, the genetic results might be the consequence of some evolutionary forces like genetic drift and founder effect, and do not necessarily reflect their ultimate origin. PMID- 21302277 TI - Response to Deane and Kremer's comment: 3D, or not to 3D. PMID- 21302278 TI - Evidence of specific characteristics and osteogenic potentiality in bone cells from tibia. AB - Human bone cells used for in vitro studies are mainly derived from bone marrow (BM) or trabecular bone (TB). There are no specific markers or procedures for isolation and growth of these cells. To validate the potentiality of these cells, we isolated human mesenchymal stromal cells (MSCs) and osteoblasts (OBs) from the tibial plateau of the same subject, grown in two different media (alpha-MEM and DMEM/F12) and analyzed for cell growth, proliferation, phenotype and osteogenic potential. We found that OBs grew well in both media tested, but MSCs were able to grow only in alpha-MEM medium. OBs in DMEM/F12 showed reduced proliferation capability and expressed a low level of alkaline phosphatase (AP), RUNX-2, osteocalcin (OC), bone sialoprotein (BSP), collagen type I (Col.I) compared with OBs in alpha-MEM but high level of collagen type XV (Col.XV). Compared with MSCs in alpha-MEM, OBs have an increased ability to proliferate and express more OC and BSP at molecular level but less AP, RUNX-2 and Col.I than MSCs. Time-course experiments to analyze the osteogenic potential of these cells showed that OBs were more efficient than MSCs. However, these cells obtained from tibial plateau showed a different trend of AP, OC and Col.I osteogenic markers compared to control MSCs from the iliac crest. This study shows that bone-adherent OBs grown in alpha-MEM medium are more efficient for osteogenic differentiation than BM MSCs and contribute to defining their phenotypic and functional characteristics, so providing a rationale for their use in bone tissue engineering or therapeutic purposes. PMID- 21302280 TI - Enzymatic activity of sperm proprotein convertase is important for mammalian fertilization. AB - Proprotein convertase subtilisin/kexin 4 (PCSK4) is implicated for sperm fertilizing ability, based on studies using Pcsk4-null mice. Herein we demonstrated proprotein convertase (PC) activity in intact sperm and acrosomal vesicles. To determine whether this activity was important for sperm fertilizing ability, a peptide inhibitor was designed based on PCSK4 prodomain sequence (proPC4(75-90)), which contains its primary autocatalytic cleavage site. ProPC4(75-90) inhibited recombinant PCSK4's activity with a K(i) value of 5.4 uM, and at 500 uM, it inhibited sperm PC activity almost completely. Treatment of sperm with proPC4(75-90) inhibited their egg fertilizing ability in a dose dependent manner. Correlation between sperm PC activity and fertilizing ability showed a high co-efficient value (>0.9), indicating the importance of sperm PC activity in fertilization. In particular, sperm PC activity was important for capacitation and zona pellucida (ZP)-induced acrosome reaction, since proPC4(75 90) -treated sperm showed markedly decreased rates in these two events. These results were opposite to those observed in Pcsk4-null sperm, which contained higher PC activity than wild type sperm, possibly due to overcompensation by PCSK7, the other PCSK enzyme found in sperm. ADAM2 (45 kDa), a sperm plasma membrane protein, involved in sperm-egg plasma membrane interaction, was also processed into a smaller form (27 kDa) during capacitation at a much reduced level in proPC4(75-90) -treated sperm. This result suggested that ADAM2 may be a natural substrate of sperm PCSK4 and its cleavage by the enzyme during acrosome reaction may be relevant to the fertilization process. PMID- 21302279 TI - Knock-down of amphiregulin inhibits cellular invasion in inflammatory breast cancer. AB - We have previously shown that SUM-149 human breast cancer cells require an amphiregulin (AREG) autocrine loop for cell proliferation. We also demonstrated that AREG can increase epidermal growth factor receptor (EGFR) stability and promote EGFR localization to the plasma membrane. In the present studies we successfully knocked-down AREG expression in SUM-149 cells by lentiviral infection of AREG shRNA. In the absence of AREG expression, SUM-149 cell growth was slowed, but not completely inhibited. Furthermore, cells infected with AREG shRNA constructs showed an increase in EGFR protein expression by Western blot. Immunofluorescence and confocal microscopy showed that following AREG knock-down, EGFR continued to localize to the cell surface. Soft agar assays demonstrated that AREG knock-down cells retain anchorage-independent growth capacity. Additionally mammosphere forming assays and Adefluor staining analysis showed that knock-down of AREG expression did not affect the expression of stem cell phenotypes. However, following AREG knock-down, SUM-149 cells demonstrated a dramatic decrease in their ability to invade a Matrigel matrix. Consistent with this observation, microarray analysis comparing cells infected with a non silencing vector to the AREG knock-down cells, identified genes associated with the invasive phenotype such as RHOB and DKK1, and networks associated with cell motility such as integrin-linked kinase signaling, and focal adhesion kinase signaling. AREG was also found to modulate WNT and Notch signaling in these cells. Thus, AREG functions in regulating the invasive phenotype, and we propose that this regulation may be through altered signaling that occurs when AREG activates plasma membrane localized EGFR. PMID- 21302281 TI - Hyperosmotic stress strongly potentiates serum response factor (SRF)-dependent transcriptional activity in Ehrlich Lettre Ascites cells through a mechanism involving p38 mitogen-activated protein kinase. AB - Long-term osmotic stress results in altered gene transcription, however, with the exception of the TonE/TonEBP system, the underlying mechanisms are poorly understood. We previously showed that upon osmotic shrinkage of Ehrlich Lettre Ascites (ELA) fibroblasts, the MEK1-ERK1/2 pathway is transiently inhibited while p38 MAPK is activated, in turn impacting on cell survival (Pedersen et al., 2007, Cell Physiol Biochem 20: 735-750). Here, we show that downstream of these kinases, two transcription factors with major roles in control of cell proliferation and death, serum response factor (SRF) and cAMP response element binding protein (CREB) are differentially regulated in ELA cells. SRF Ser(103) phosphorylation and SRF-dependent transcriptional activity were strongly augmented 5-30 min and 24 h, respectively, after hyperosmotic stress (50% increase in extracellular ionic strength), in a p38 MAPK-dependent manner. In contrast, CREB Ser(133) was transiently dephosphorylated upon osmotic shrinkage. The ERK1/2 effector ribosomal S kinase (RSK) and the ERK1/2- and p38 MAPK effector mitogen- stress-activated protein kinase 1 (MSK1) both phosphorylate CREB at Ser(133) . RSK and MSK1 were dephosphorylated within 5 min of shrinkage. MSK1 phosphorylation recovered within 30 min in a p38-MAPK-dependent manner. CREB was transiently dephosphorylated after shrinkage in a manner exacerbated by p38 MAPK inhibition or MSK1 knockdown, but unaffected by inhibition of RSK. In conclusion, in ELA cells, hyperosmotic stress activates SRF in a p38 MAPK dependent manner and transiently inactivates CREB, likely due to MSK1 inactivation. We suggest that these events contribute to shrinkage-induced changes in gene transcription and death/survival balance. PMID- 21302282 TI - Characterization of the differential response of endothelial cells exposed to normal and elevated laminar shear stress. AB - Most acute coronary events occur in the upstream region of stenotic atherosclerotic plaques that experience laminar shear stress (LSS) elevated above normal physiological levels. Many studies have described the atheroprotective effect on endothelial behavior of normal physiological LSS (approximately 15 dynes/cm(2)) compared to static or oscillatory shear stress (OSS), but it is unknown whether the levels of elevated shear stress imposed by a stenotic plaque would preserve, enhance or reverse this effect. Therefore we used transcriptomics and related functional analyses to compare human endothelial cells exposed to laminar shear stress of 15 (LSS15-normal) or 75 dynes/cm(2) (LSS75-elevated). LSS75 upregulated expression of 145 and downregulated expression of 158 genes more than twofold relative to LSS15. Modulation of the metallothioneins (MT1-G, M, -X) and NADPH oxidase subunits (NOX2, NOX4, NOX5, and p67phox) accompanied suppression of reactive oxygen species production at LSS75. Shear induced changes in dual specificity phosphatases (DUSPs 1, 5, 8, and 16 increasing and DUSPs 6 and 23 decreasing) were observed as well as reduced ERK1/2 but increased p38 MAP kinase phosphorylation. Amongst vasoactive substances, endothelin-1 expression decreased whereas vasoactive intestinal peptide (VIP) and prostacyclin expression increased, despite which intracellular cAMP levels were reduced. Promoter analysis by rVISTA identified a significant over representation of ATF and Nrf2 transcription factor binding sites in genes upregulated by LSS75 compared to LSS15. In summary, LSS75 induced a specific change in behavior, modifying gene expression, reducing ROS levels, altering MAP kinase signaling and reducing cAMP levels, opening multiple avenues for future study. PMID- 21302283 TI - LPA(1) -induced migration requires nonmuscle myosin II light chain phosphorylation in breast cancer cells. AB - The enhanced migration found in tumor cells is often caused by external stimuli and the sequential participation of cytoskeleton-related signaling molecules. However, until now, the molecular connection between the lysophosphatidic acid (LPA) receptor and nonmuscle myosin II (NM II) has not been analyzed in detail for LPA-induced migration. Here, we demonstrate that LPA induces migration by activating the LPA(1) receptor which promotes phosphorylation of the 20 kDa NM II light chain through activation of Rho kinase (ROCK). We show that LPA-induced migration is insensitive to pertussis toxin (PTX) but does require the LPA(1) receptor as determined by siRNA and receptor antagonists. LPA activates ROCK and also increases GTP-bound RhoA activity, concomitant with the enhanced membrane recruitment of RhoA. LPA-induced migration and invasion are attenuated by specific inhibitors including C3 cell-permeable transferase and Y-27632. We demonstrate that NM II plays an important role in LPA-induced migration and invasion by inhibiting its cellular function with blebbistatin and shRNA lentivirus directed against NM II-A or II-B. Inhibition or loss of either NM II-A or NM II-B in 4T1 cells results in a decrease in migration and invasion. Restoration of the expression of NM II-A or NM II-B also rescued LPA-induced migration. Taken together, these results suggest defined pathways for signaling through the LPA(1) receptor to promote LPA-mediated NM II activation and subsequent cell migration in 4T1 breast cancer cells. PMID- 21302284 TI - Regulation of apoptosis and autophagy by sphingosylphosphorylcholine in vascular endothelial cells. AB - Sphingosylphosphorylcholine (SPC), an important cardiovascular mediator derived from sphingomyelin that has atheroprotective effects via actions on vascular endothelial cells (VECs) at normal levels in vivo. However, the underlying mechanism is not well known. To clarify this question, we first investigated the effect of SPC on VEC apoptosis and autophagy induced by deprivation of serum and fibroblast growth factor 2 (FGF-2). SPC at 5-20 uM inhibited apoptosis and induced autophagy in vitro. To understand the underlying mechanism, we investigated the role of integrin beta4 in SPC-induced autophagy in VECs. SPC significantly decreased the level of integrin beta4, whereas overexpression of integrin beta4 inhibited SPC-induced autophagy. Moreover, knockdown of integrin beta4 promoted VEC autophagy. To understand the downstream factors of integrin beta4 in this process, we observed the effects of SPC on phosphatidylcholine specific phospholipase C (PC-PLC) activity and level of p53. PC-PLC activity and p53 level in cytoplasm was decreased during autophagy induced by SPC, and knockdown of integrin beta4 inhibited the activity of PC-PLC and the cytoplasmic level of p53. SPC may promote autophagy via integrin beta4. Moreover, PC-PLC and p53 may be the downstream factors of integrin beta4 in autophagy of VECs deprived of serum and FGF-2. PMID- 21302285 TI - Bone marrow-derived stem cells contribute skin regeneration in skin and soft tissue expansion. AB - Skin and soft tissue expansion stimulates the proliferation of skin epidermal basal cells and increase the dermal collagen deposition and angiogenesis. To explore the contribution of bone marrow-derived stem cells (BMSCs) to the generation of "new" skin during the expansion, we used a chimeric mouse model in which the donor C57BL mice were engrafted with the bone marrow of enhanced green fluorescent protein (EGFP) transgenic mice. BMSCs were collected from the tibia and femur of EGFP(+) transgenic mice, and then injected into normal C57BL mice via the tail vein (chimeric mice). Skin was obtained at different times (days 0, 7, 14, 21, 28, and 35). Skin stromal-derived factor-1 (SDF-1) expression was evaluated. The number, distribution, and phenotype changes of EGFP(+) cells in the skin were also evaluated by means of fluorescent microscopy. EGFP(+) cells were present stably in the normal skin. The number of EGFP(+) cells of the Group A mice changed with the tension, and reached the peak on day 21(17.1 +/- 6.7%), as compared with either Group B (5.5 +/- 1.0%) or Group C (5.1 +/- 0.9%). The SDF 1 expression in the expanded skin was significant increased (~11-fold, P < 0.01) compared to non-expanded skin on day 21. Immunofluorescence showed EGFP(+) cells were converted into vascular endothelial cells, epidermal cells, and spindle shaped dermal fibroblasts. Strain can promote the expression of SDF-1 and facilitate the differentiation and proliferation of BMSCs in the expanded skin. PMID- 21302286 TI - Insulin-stimulated L-arginine transport requires SLC7A1 gene expression and is associated with human umbilical vein relaxation. AB - Insulin causes endothelium-derived nitric oxide (NO)-dependent vascular relaxation, and increases L-arginine transport via cationic amino acid transporter 1 (hCAT-1) and endothelial NO synthase (eNOS) expression and activity in human umbilical vein endothelium (HUVEC). We studied insulin effect on SLC7A1 gene (hCAT-1) expression and hCAT-transport activity role in insulin-modulated human fetal vascular reactivity. HUVEC were used for L-arginine transport and L [(3) H]citrulline formation (NOS activity) assays in absence or presence of N ethylmaleimide (NEM) or L-lysine (L-arginine transport inhibitors). hCAT-1 protein abundance was estimated by Western blot, mRNA quantification by real time PCR, and SLC7A1 promoter activity by Luciferase activity (-1,606 and -650 bp promoter fragments from ATG). Specific protein 1 (Sp1), and total or phosphorylated eNOS protein was determined by Western blot. Sp1 activity (at four sites between -177 and -105 bp from ATG) was assayed by chromatin immunoprecipitation (ChIP) and vascular reactivity in umbilical vein rings. Insulin increased hCATs-L-arginine transport, maximal transport capacity (V(max) /K(m) ), and hCAT-1 expression. NEM and L-lysine blocked L-arginine transport. In addition, it was trans-stimulated (~7.8-fold) by L-lysine in absence of insulin, but unaltered (~1.4-fold) in presence of insulin. Sp1 nuclear protein abundance and binding to DNA, and SLC7A1 promoter activity was increased by insulin. Insulin increased NO synthesis and caused endothelium-dependent vessel relaxation and reduced U46619-induced contraction, effects blocked by NEM and L-lysine, and dependent on extracellular L-arginine. We suggest that insulin induces human umbilical vein relaxation by increasing HUVEC L-arginine transport via hCATs (likely hCAT-1) most likely requiring Sp1-activated SLC7A1 expression. PMID- 21302287 TI - Unexpectedly low mutation rates in beta-myosin heavy chain and cardiac myosin binding protein genes in Italian patients with hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease. Fourteen sarcomeric and sarcomere-related genes have been implicated in HCM etiology, those encoding beta-myosin heavy chain (MYH7) and cardiac myosin binding protein C (MYBPC3) reported as the most frequently mutated: in fact, these account for around 50% of all cases related to sarcomeric gene mutations, which are collectively responsible for approximately 70% of all HCM cases. Here, we used denaturing high-performance liquid chromatography followed by bidirectional sequencing to screen the coding regions of MYH7 and MYBPC3 in a cohort (n = 125) of Italian patients presenting with HCM. We found 6 MHY7 mutations in 9/125 patients and 18 MYBPC3 mutations in 19/125 patients. Of the three novel MYH7 mutations found, two were missense, and one was a silent mutation; of the eight novel MYBPC3 mutations, one was a substitution, three were stop codons, and four were missense mutations. Thus, our cohort of Italian HCM patients did not harbor the high frequency of mutations usually found in MYH7 and MYBPC3. This finding, coupled to the clinical diversity of our cohort, emphasizes the complexity of HCM and the need for more inclusive investigative approaches in order to fully understand the pathogenesis of this disease. PMID- 21302288 TI - Importance of serum source for the in vitro replicative senescence of human bone marrow derived mesenchymal stem cells. AB - Human mesenchymal stem cells (hMSCs) may be used for therapeutic applications. Culture conditions such as the serum source may impact on cell quality and the onset of replicative senescence. We have examined the effect of culturing hMSCs in autologous serum (AS) versus fetal bovine serum (FBS) on factors involved in in vitro replicative senescence. hMSCs from four donors were cultured in 10% FBS or 10% AS until they reached senescence. Cells were harvested at early passage and near senescence to study factors known to be involved in cellular senescence. The number of population doublings till senescence was similar for cells cultured in FBS, but varied greatly for hMSCs cultured in AS. FBS cells accumulated in S phase of cell cycle. This could not be explained by increased expression of cell cycle inhibitor proteins. Heat shock proteins were upregulated in AS compared to FBS cells. Reactive oxygen species and nitric oxide were upregulated in senescent FBS cells. Telomeres were shorter in senescent cells, more significantly in FBS cells. The source of serum was a determinant for the time till senescence in cultured hMSC. Serum source affected aspects of cell cycle regulation and the levels of heat shock proteins. Several mechanisms are likely to be responsible for replicative senescence in hMSC. Insight into the molecular details of how serum factors impacts on these mechanisms is important for the safe use of hMSCs in clinical applications. PMID- 21302289 TI - HAX-1: a family of apoptotic regulators in health and disease. AB - HAX-1 comprises a family of ubiquitously expressed proteins that play important roles in the regulation of programmed cell death. Herein, we provide a comprehensive review of the expression profile of HAX-1 and its functional implications during health and disease, highlighting its direct involvement in the development of congenital neutropenia and neural abnormalities, when absent, and its contribution to the progression of psoriasis and cancer, when overexpressed. Moreover, we provide new information on the differential expression of the HAX-1 subfamily in three distinct types of epithelial cancers, including breast, skin, and colon. Our results demonstrate a significant up regulation of the anti-apoptotic HAX-1 variant 001 in skin and colon, but not in breast and cancer cells, indicating tissue-specific differences in its expression pattern and properties during cancer formation and progression. Our findings further reveal a considerable down-regulation, if not abrogation, of three distinct, yet to be characterized, HAX-1 isoforms in breast cancer cells, suggesting that they may function in an opposite manner to the anti-apoptotic variant 001. This study aims to summarize our current knowledge on the physiological implications of the expression profile of the HAX-1 subfamily in health and disease, and provide new information on the differential expression and activities of HAX-1 members in three distinct types of cancer. PMID- 21302290 TI - Comparison of bone morphogenetic protein-2 and osteoactivin for mesenchymal cell differentiation: effects of bolus and continuous administration. AB - Current osteoinductive protein therapy utilizes bolus administration of large doses of bone morphogenetic proteins (BMPs), which is costly, and may not replicate normal bone healing. The limited in vivo biologic activity of BMPs requires the investigation of growth factors that may enhance this activity. In this study, we utilized the C3H10T1/2 murine mesenchymal stem cell line to test the hypotheses that osteoactivin (OA) has comparable osteoinductive effects to bone morphogenetic protein-2 (BMP-2), and that sustained administration of either growth factor would result in increased osteoblastic differentiation as compared to bolus administration. Sustained release biodegradable hydrogels were designed, and C3H10T1/2 cells were grown on hydrogels loaded with BMP-2 or OA. Controls were grown on unloaded hydrogels, and positive controls were exposed to bolus growth factor administration. Cells were harvested at several time points to assess osteoblastic differentiation. Alkaline phosphatase (ALP) staining and activity, and gene expression of ALP and osteocalcin were assessed. Treatment with OA or BMP-2 resulted in comparable effects on osteoblastic marker expression. However, cells grown on hydrogels demonstrated osteoblastic differentiation that was not as robust as cells treated with bolus administration. This study shows that OA has comparable effects to BMP-2 on osteoblastic differentiation using both bolus administration and continuous release, and that bolus administration of OA has a more profound effect than administration using hydrogels for sustained release. This study will lead to a better understanding of appropriate delivery methods of osteogenic growth factors like OA for repair of fractures and segmental bone defects. PMID- 21302291 TI - Hypoxia-inducible factor 1 mediates increased expression of NADPH oxidase-2 in response to intermittent hypoxia. AB - Sleep-disordered breathing with recurrent apnea is associated with intermittent hypoxia (IH). Cardiovascular morbidities caused by IH are triggered by increased generation of reactive oxygen species (ROS) by pro-oxidant enzymes, especially NADPH oxidase-2 (Nox2). Previous studies showed that (i) IH activates hypoxia inducible factor 1 (HIF-1) in a ROS-dependent manner and (ii) HIF-1 is required for IH-induced ROS generation, indicating the existence of a feed-forward mechanism. In the present study, using multiple pharmacological and genetic approaches, we investigated whether IH-induced expression of Nox2 is mediated by HIF-1 in the central and peripheral nervous system of mice as well as in cultured cells. IH increased Nox2 mRNA, protein, and enzyme activity in PC12 pheochromocytoma cells as well as in wild-type mouse embryonic fibroblasts (MEFs). This effect was abolished or attenuated by blocking HIF-1 activity through RNA interference or pharmacologic inhibition (digoxin or YC-1) or by genetic knockout of HIF-1alpha in MEFs. Increasing HIF-1alpha expression by treating PC 12 cells with the iron chelator deferoxamine for 20 h or by transfecting them with HIF-1alpha expression vector increased Nox2 expression and enzyme activity. Exposure of wild-type mice to IH (8 h/day for 10 days) up regulated Nox2 mRNA expression in brain cortex, brain stem, and carotid body but not in cerebellum. IH did not induce Nox2 expression in cortex, brainstem, carotid body, or cerebellum of Hif1a(+/-) mice, which do not manifest increased ROS or cardiovascular morbidities in response to IH. These results establish a pathogenic mechanism linking HIF-1, ROS generation, and cardiovascular pathology in response to IH. PMID- 21302292 TI - Exposure to 50 Hz electromagnetic field raises the levels of the anti-apoptotic protein BAG3 in melanoma cells. AB - The expression of the anti-apoptotic protein BAG3 is induced in several cell types by exposure to high temperature, oxidants, and other stressful agents. We investigated whether exposure to 50 Hz electromagnetic fields raised BAG3 levels in the human melanoma cell line M14, in vitro and in orthotopic xenografts. Exposure of cultured cells or xenografts for 6 h or 4 weeks, respectively, produced a significant (P < 0.01) increase in BAG3 protein amounts. Interestingly, at the same times, we could not detect any significant variation in the levels of HSP70/72 protein or cell apoptosis. These results confirm the stressful effect of exposure to ELF in human cells, by identifying BAG3 protein as a marker of ELF-induced stress. Furthermore, they suggest that BAG3 induction by ELF may contribute to melanoma cell survival and/or resistance to therapy. PMID- 21302293 TI - Negative regulation of osteoblastogenesis through downregulation of runt-related transcription factor-2 in osteoblastic MC3T3-E1 cells with stable overexpression of the cystine/glutamate antiporter xCT subunit. AB - We have previously demonstrated that glutamate (Glu) suppresses cellular proliferation toward self-renewal through a mechanism associated with intracellular GSH depletion mediated by the bidirectional cystine/Glu antiporter in osteoblastic MC3T3-E1 cells cultured in the absence of differentiation inducers. To further evaluate the possible role of the antiporter in osteoblastogenesis, in this study, we have established stable transfectants of the xCT subunit of the antiporter in MC3T3-E1 cells. Stable overexpression led to a significant facilitation of cellular proliferation determined by different indices with increased GSH levels and decreased ROS generation in addition to promoted [(14)C]cystine incorporation, while Glu failed to significantly inhibit cellular proliferation in stable xCT transfectants. In stable transfectants cultured under differentiation conditions, drastic decreases were invariably seen in Ca(2+) accumulation, alkaline phosphatase activity and several osteoblastic marker gene expressions, in addition to downregulation of mRNA and corresponding protein for runt-related transcription factor-2 (Runx2). Runx2 promoter activity was significantly promoted by the introduction of Runx2 expression vector in a manner sensitive to the prevention by the co-introduction of xCT expression vector in MC3T3-E1 cells. In both MC3T3-E1 cells and murine calvarial osteoblasts cultured with differentiation inducers, transient transfection with xCT siRNA significantly increased Runx2 protein expression along with decreases in xCT mRNA expression and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide reduction. These results suggest that the cystine/Glu antiporter plays a pivotal role in cellular differentiation through a mechanism related to the regulation of transactivation of Runx2 essential for osteoblastogenesis toward maturation in osteoblastic cells. PMID- 21302294 TI - Involvement of L-type calcium channel and SERCA2a in myocardial dysfunction induced by obesity. AB - Obesity has been shown to impair myocardial performance. Nevertheless, the mechanisms underlying the participation of calcium (Ca(2+) ) handling on cardiac dysfunction in obesity models remain unknown. L-type Ca(2+) channels and sarcoplasmic reticulum (SR) Ca(2+) -ATPase (SERCA2a), may contribute to the cardiac dysfunction induced by obesity. The purpose of this study was to investigate whether myocardial dysfunction in obese rats is related to decreased activity and/or expression of L-type Ca(2+) channels and SERCA2a. Male 30-day-old Wistar rats were fed standard (C) and alternately four palatable high-fat diets (Ob) for 15 weeks. Obesity was determined by adiposity index and comorbidities were evaluated. Myocardial function was evaluated in isolated left ventricle papillary muscles under basal conditions and after inotropic and lusitropic maneuvers. L-type Ca(2+) channels and SERCA2a activity were determined using specific blockers, while changes in the amount of channels were evaluated by Western blot analysis. Phospholamban (PLB) protein expression and the SERCA2a/PLB ratio were also determined. Compared with C rats, the Ob rats had increased body fat, adiposity index and several comorbidities. The Ob muscles developed similar baseline data, but myocardial responsiveness to post-rest contraction stimulus and increased extracellular Ca(2+) was compromised. The diltiazem promoted higher inhibition on developed tension in obese rats. In addition, there were no changes in the L-type Ca(2+) channel protein content and SERCA2a behavior (activity and expression). In conclusion, the myocardial dysfunction caused by obesity is related to L-type Ca(2+) channel activity impairment without significant changes in SERCA2a expression and function as well as L-type Ca(2+) protein levels. PMID- 21302295 TI - Tiam1 is recruited to beta1-integrin complexes by 14-3-3zeta where it mediates integrin-induced Rac1 activation and motility. AB - 14-3-3 is an adaptor protein that localizes to the leading edge of spreading cells, returning to the cytoplasm as spreading ceases. Previously, we showed that integrin-induced Rac1 activation and spreading were inhibited by sequestration of 14-3-3zeta and restored by its overexpression. Here, we determined whether 14-3-3 mediates integrin signaling by localizing a guanine nucleotide exchange factor (GEF) to Rac1-activating integrin complexes. We showed that GST-14-3-3zeta recruited the Rac1-GEF, Tiam1, from cell lysates through Tiam1 residues 1-182 (N(1-182) Tiam1). The physiological relevance of this interaction was examined in serum-starved Hela cells plated on fibronectin. Both Tiam1 and N(1-182) Tiam1 were recruited to 14-3-3-containing beta1-integrin complexes, as shown by co localization and co-immunoprecipitation. Integrin-induced Rac1 activation was inhibited when Tiam1 was depleted with siRNA or by overexpression of catalytically inactive N(1-182) Tiam1, which was incorporated into 14-3-3/beta1 integrin complexes and inhibited spreading in a manner that was overcome by constitutively active Rac1. Integrin-induced Rac1 activation, spreading, and migration were also inhibited by overexpression of 14-3-3zeta S58D, which was unable to recruit Tiam1 from lysates, co-immunoprecipitate with Tiam1, or mediate its incorporation into beta1-integrin complexes. Taken together, these findings suggest a previously unrecognized mechanism of integrin-induced Rac1 activation in which 14-3-3 dimers localize Tiam1 to integrin complexes, where it mediates integrin-dependent Rac1 activation, thus initiating motility-inducing pathways. Moreover, since Tiam1 is recruited to other sites of localized Rac1 activation through its PH-CC-EX domain, the present findings show that a mechanism involving its N-terminal 182 residues is utilized to recruit Tiam1 to motility-inducing integrin complexes. PMID- 21302296 TI - Interplay between steroid receptors and neoplastic progression in sarcoma tumors. AB - Steroid hormones are expressed at low levels in mesenchymal cells and are highly expressed in soft tissue sarcoma. In human soft tissue fibrosarcoma cell line (HT 1080), the epidermal growth factor (EGF) stimulates the express of matrix metal (MMPs) expression through a Src-dependent mechanism. In human fibrosarcomas, increased expression of MMPs correlates with the metastatic progression. Our recent data in human breast cancer cell line MCF-7, demonstrates that EGF stimulates estradiol receptor (ER) phosphorylation on tyrosine at position 537 thereby promoting the association of a complex among EGF receptor (EGFR), androgen receptor (AR), ER, and Src that activates EGF-dependent signaling pathway. In the present study, we demonstrate that, in HT-1080 cells, the Src kinase activity is involved in EGFR phosphorylation and this activity is regulated by an interplay between Src, steroid receptors, and EGFR. In these cells, estradiol (E(2) )/ER and synthetic androgen (R1881)/AR trans-activate EGFR leading to the downstream signaling and to ERK activation. Indeed, the association between ER/AR and EGFR enhances metastatic progression of fibrosarcoma tumors. A population pilot study performed on 16 patients with soft tissue neoplasias highlights that MMPs expression correlates with progression of anaplastic sarcoma as well as overexpression of EGFR. These findings suggest that there is a crosstalk among AR, ER, and EGFR that lead to src activation also in fibrosarcoma cells. PMID- 21302297 TI - Therapeutic resistance resulting from mutations in Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR signaling pathways. AB - Chemotherapy remains a commonly used therapeutic approach for many cancers. Indeed chemotherapy is relatively effective for treatment of certain cancers and it may be the only therapy (besides radiotherapy) that is appropriate for certain cancers. However, a common problem with chemotherapy is the development of drug resistance. Many studies on the mechanisms of drug resistance concentrated on the expression of membrane transporters and how they could be aberrantly regulated in drug resistant cells. Attempts were made to isolate specific inhibitors which could be used to treat drug resistant patients. Unfortunately most of these drug transporter inhibitors have not proven effective for therapy. Recently the possibilities of more specific, targeted therapies have sparked the interest of clinical and basic researchers as approaches to kill cancer cells. However, there are also problems associated with these targeted therapies. Two key signaling pathways involved in the regulation of cell growth are the Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways. Dysregulated signaling through these pathways is often the result of genetic alterations in critical components in these pathways as well as mutations in upstream growth factor receptors. Furthermore, these pathways may be activated by chemotherapeutic drugs and ionizing radiation. This review documents how their abnormal expression can contribute to drug resistance as well as resistance to targeted therapy. This review will discuss in detail PTEN regulation as this is a critical tumor suppressor gene frequently dysregulated in human cancer which contributes to therapy resistance. Controlling the expression of these pathways could improve cancer therapy and ameliorate human health. PMID- 21302299 TI - Neuregulin induces HaCaT keratinocyte migration via Rac1-mediated NADPH-oxidase activation. AB - Neuregulin (NRG), a member of the epidermal growth factor family, plays important roles in the development of the nervous system and heart, and in cancer progression. Recent reports have suggested that NRG is involved in wound healing in keratinocytes, although the cellular mechanisms remain unclear. Here, we showed that NRG treatment increased slingshot-1L (SSH-1L)-mediated cofilin dephosphorylation and activation in HaCaT keratinocytes. Additionally, Rac1 activation and NADPH-oxidase (Nox)-dependent reactive oxygen species (ROS) generation, both known to be upstream regulators of the SSH-cofilin pathway, were increased in NRG-stimulated HaCaT cells. Inhibition of Rac1 or Nox activity blocked NRG-induced cofilin activation and cell migration by HaCaT cells. Moreover, the effects of Rac1 on cofilin activation were dependent on Nox activity. These findings indicate that NRG-induced HaCaT cell migration via the ROS-SSH-1L-cofilin pathway is activated as a consequence of Rac1 and Nox activation. PMID- 21302298 TI - TGFbeta- and bleomycin-induced extracellular matrix synthesis is mediated through Akt and mammalian target of rapamycin (mTOR). AB - A number of pro-fibrogenic stimuli, such as growth factors, cytokines, and extracellular matrix (ECM) proteins, involve Akt and its downstream substrates in mediating their effects. We previously reported that absence of Akt1, which is the predominant isoform of the three gene Akt family in vascular cells, resulted in impaired ECM remodeling in skin and vasculature. In the current study, we investigated the importance of Akt1 in TGFbeta- and bleomycin-induced synthesis and secretion of ECM proteins by fibroblasts. We observed that both TGFbeta and bleomycin stimulated the synthesis of ECM proteins in a dose- and time-dependent manner. Treatment with TGFbeta and bleomycin also resulted in increased phosphorylation of Akt, mammalian target of rapamycin (mTOR) and their downstream signaling partners, p70S6 Kinase, Ribosomal S6 protein and 4E-BP1, resulting in the activation of this pathway. The effects of TGFbeta and bleomycin on ECM synthesis were blunted by pre-treatment with an mTOR inhibitor rapamycin. Whereas mTOR is responsible for the transcriptional regulation of a number of ECM proteins, adhesion molecules and matrix metalloproteases (MMPs), synthesis of major ECM proteins such as fibronectin and collagens (types I, II and V) by fibroblasts in response to TGFbeta and bleomycin is regulated by mTOR at the translational level. These findings indicate the importance of the Akt-mTOR signaling pathway in TGF-mediated fibrogenic events in vivo. PMID- 21302300 TI - Normal atmospheric oxygen tension and the use of antioxidants improve hepatocyte spheroid viability and function. AB - Hepatocyte spheroids have been proposed for drug metabolism studies and in bioartificial liver devices. However, the optimal conditions required to meet the aerobic demands of mitochondria-rich hepatocyte spheroids is not well studied. We hypothesized that an optimal concentration of oxygen could be identified and that the health of hepatocyte spheroids might be further improved by antioxidant therapy. Rat hepatocyte spheroids were maintained in suspension culture for 7 days under a mixture of 5% CO(2) plus O(2):N(2) to achieve fractional oxygen contents of 6%(C1), 21%(C2), 58%(C3), and 95%(C4). Spheroid health was assessed under each condition by vital staining, TEM, oxygen consumption, and mitochondrial counts. Hepatocyte differentiation was assessed by expression of 10 liver-related genes (HNF4a, HNF6, Cyp1A1, albumin, Nags, Cps1, Otc, Ass, Asl, Arg1). Functional markers (albumin and urea) were measured. The influence of oxygen tension and antioxidant treatment on the production of reactive oxygen species (ROS) was assessed by confocal microscopy. We observed that the hepatocyte spheroids were healthiest under normal atmospheric (C2) conditions with antioxidants ascorbic acid and L-carnitine. Cell death and reduced functionality of hepatocyte spheroids correlated with the formation of ROS. Normal atmospheric conditions provided the optimal oxygen tension for suspension culture of hepatocyte spheroids. The formation and deleterious effects of ROS were further reduced by adding antioxidants to the culture medium. These findings have direct application to development of the spheroid reservoir bioartificial liver and the use of hepatocyte spheroids in drug metabolism studies. PMID- 21302301 TI - C/EBPbeta binds the P1 promoter of the Runx2 gene and up-regulates Runx2 transcription in osteoblastic cells. AB - The Runx2 factor is an essential component of the regulatory mechanisms that control transcription during skeletogenesis. Runx2/p57 expression in osteoblastic cells is controlled by the P1 promoter, which is recognized by key regulators of osteoblast differentiation including homeodomain factors and Wnt- and BMP signaling mediators. Here, we report that the transcription factor C/EBPbeta up regulates Runx2/p57 expression by directly binding to the Runx2 P1 promoter in mesenchymal, pre-osteoblastic, and osteoblastic cells. This C/EBPbeta-mediated up regulation is principally dependent on C/EBP site II that is located within the first 180 bp of the proximal P1 promoter region and is highly conserved among mouse, rat, and human Runx2 genes. Our studies reveal how the C/EBPbeta factor, known to have a key role during osteogenesis, contributes to regulating the expression of Runx2, the master regulator of osteoblast differentiation. PMID- 21302302 TI - Role of interleukin-23 circulating levels increase in resected colorectal cancer before and after chemotherapy: preliminary data and future perspectives. AB - Expression of IL-23, a heterodimeric cytokine involved in the induction of Th17 cells, is increased in human tumors. Although the endogenous IL-23 expression has been reported to promote tumor development and growth, the studies using local and systemic administration of IL-23 have shown that its application at the excessive amount induces antitumor immune responses. IL-23 is, today, considered the key driver of intestinal inflammation and its role in inflammatory responses is tissue-specific. The aim of this study was to investigate the role of circulating levels of IL-23 in patients with resected colorectal cancer (CRC) before and after chemotherapy, respect to healthy controls. Twenty-five patients were enrolled between June 2007 and January 2009, and followed through 2010. All patients underwent chemotherapy, mostly FOLFOX4. Twenty-sex and age-matched healthy donors were recruited as controls. IL-23 serum concentrations, measured by a quantitative enzyme immunoassay technique, were significantly higher in patients with resected CRC (26.02 +/- 28.63 pg/ml versus 7.1 +/- 6.4 pg/ml, P < 0.001) and after chemotherapy respect to controls (21.74 +/- 23.82 pg/ml versus 7.17 +/- 6.43 pg/ml, P < 0.001). An increase was documented also before chemotherapy (26.02 +/- 28.63 pg/ml versus 21.74 +/- 23.82 pg/ml, P = 0.7) but not statistically significant. This work investigated, for the first time, the role of IL-23 in CRC resection and chemotherapy, showing no correlation with the severity of disease, tumor removal, and chemotherapeutic treatment. However, other works are needed to better clarify if IL-23 could be considered a key molecule in human CRC and a target for tumor treatment. PMID- 21302303 TI - Activity of different anthracycline formulations in hormone-refractory prostate cancer cell lines: role of Golgi apparatus. AB - The efficacy of therapy for hormone-refractory prostate cancer (HRPC) is still unsatisfactory and new agents and therapeutic modalities are needed. The aims of the present work were to examine the in vitro activity and mechanisms of action of doxorubicin (DX), pegylated liposomal DX (PLDX), and non-pegylated liposomal DX (NPLDX) in DU145 and taxane-resistant DU145-R HRPC cell lines. Drug activity and incorporation, apoptosis, and expression of cell death-related markers were evaluated by SRB test, cytofluorimetric assays, and Western blot, respectively. Among the different DX formulations, NPLDX showed the highest cytotoxic activity in both cell lines, with more than 50% of apoptotic cells at only 1/10 of the plasma peak concentration after 72 h exposure. Anthracyclines, in particular NPLDX, were highly concentrated in the Golgi apparatus. Moreover, a significant increase was observed in the expression of CD95 receptor, GD3 ganglioside and, caspase-2 and -8 active forms in both cell lines followed by caspase-3 activation and mitochondrial membrane depolarization. The Golgi apparatus, probably acting as a stress sensor, intensified the conventional apoptotic mechanism induced by anthracyclines. Our data support the hypothesis that organelle-dependent initiation of cell death other than that induced by mitochondria and nucleus is a research area worthy of pursuing and suggest that the Golgi apparatus could be an ideal target for anti-cancer therapy. Of note, the activity of NLPDX in taxane resistant DU145-R cells warrants further evaluation as second-line treatment of advanced HRPC after taxane failure. PMID- 21302304 TI - Stabilization of brain microvascular endothelial barrier function by shear stress involves VE-cadherin signaling leading to modulation of pTyr-occludin levels. AB - Blood-brain barrier (BBB) regulation involves the coordinated interaction of intercellular adherens and tight junctions in response to stimuli. One such stimulus, shear stress, has been shown to upregulate brain microvascular endothelial cell (BMvEC) barrier function, although our knowledge of the signaling mechanisms involved is limited. In this article, we examined the hypothesis that VE-cadherin can transmit shear signals to tight junction occludin with consequences for pTyr-occludin and barrier function. In initial studies, chronic shear enhanced membrane localization of ZO-1 and claudin-5, decreased pTyr-occludin (in part via a dephostatin-sensitive mechanism), and reduced BMvEC permeability, with flow reduction in pre-sheared BMvECs having converse effects. In further studies, VE-cadherin inhibition (VE-cad DeltaEXD) blocked shear induced Rac1 activation, pTyr-occludin reduction, and barrier upregulation, consistent with an upstream role for VE-cadherin in transmitting shear signals to tight junctions through Rac1. As VE-cadherin is known to mediate Rac1 activation via Tiam1 recruitment, we subsequently confirmed that Tiam1 inhibition (Tiam1 C580) could elicit effects similar to VE-cad DeltaEXD. Finally, the observed attenuation of shear-induced changes in pTyr-occludin level and barrier phenotype following Rac1 inhibition (NSC23766, T17N) establishes a downstream role for Rac1 in this pathway. In summary, we describe for the first time in BMvECs a role for VE-cadherin in the transmission of physiological shear signals to tight junction occludin through engagement of Tiam1/Rac1 leading to barrier stabilization. A downstream role is also strongly indicated for a protein tyrosine phosphatase in pTyr-occludin modulation. Importantly, these findings suggest an important route of inter-junctional signaling cross-talk during BBB response to flow. PMID- 21302305 TI - New players in ovarian cancer. AB - Ovarian cancer is the leading cause of gynecologic cancer mortality worldwide. The aim of this review is to highlight the most recent studies regarding ovarian cancer pathogenesis and the new therapeutic approaches against this insidious disease. We focus on the relevance of some cell cycle genes, transcription factors, and microRNAs in the carcinogenesis of ovarian cancer as well as on a new hypothesis for therapy using histone deacetylase inhibitors. We also report recent studies regarding some mechanisms of chemoresistance, a major obstacle in the treatment of ovarian cancer. Together these studies can improve our knowledge of ovarian cancer tumorigenesis and diagnosis providing new tools to hopefully defeat this deadly disease. PMID- 21302307 TI - Human salivary gland acinar cells spontaneously form three-dimensional structures and change the protein expression patterns. AB - Applying tissue engineering principles to design an auto-secretory device is a potential solution for patients suffering loss of salivary gland function. However, the largest challenge in implementing this solution is the primary culture of human salivary gland cells, because the cells are highly differentiated and difficult to expand in vitro. This situation leads to the lack of reports on the in vitro cell biology and physiology of human salivary gland cells. This study used a low-calcium culture system to selectively cultivate human parotid gland acinar (PGAC) cells from tissues with high purity in cell composition. This condition enables PGAC cells to continuously proliferate and retain the phenotypes of epithelial acinar cells to express secreting products (alpha-amylase) and function-related proteins (aquaporin-3, aquaporin-5, and ZO 1). Notably, when the cells reached confluence, three-dimensional (3D) cell aggregates were observed in crowded regions. These self-formed cell spheres were termed post-confluence structures (PCSs). Unexpectedly, despite being cultured in the same media, cells in PCSs exhibited higher expression levels and different expression patterns of function-related proteins compared to the two-dimensional (2D) cells. Translocation of aquoporin-3 from cytosolic to alongside the cell boundaries, and of ZO-1 molecules to the boundary of the PCSs were also observed. These observations suggest that when PGAC cells cultured on the 2D substrate would form PCSs without the help of 3D scaffolds and retain certain differentiation and polarity. This phenomenon implies that it is possible to introduce 2D substrates instead of 3D scaffolds into artificial salivary gland tissue engineering. PMID- 21302306 TI - Regulation of non-classical FGF1 release and FGF-dependent cell transformation by CBF1-mediated notch signaling. AB - FGF1, a widely expressed proangiogenic factor involved in tissue repair and carcinogenesis, is released from cells through a non-classical pathway independent of endoplasmic reticulum and Golgi. Although several proteins participating in FGF1 export were identified, genetic mechanisms regulating this process remained obscure. We found that FGF1 export and expression are regulated through Notch signaling mediated by transcription factor CBF1 and its partner MAML. The expression of a dominant negative (dn) form of CBF1 in 3T3 cells induces transcription of FGF1 and sphingosine kinase 1 (SphK1), which is a component of FGF1 export pathway. dnCBF1 expression stimulates the stress independent release of transduced FGF1 from NIH 3T3 cells and endogenous FGF1 from A375 melanoma cells. NIH 3T3 cells transfected with dnCBF1 form colonies in soft agar and produce rapidly growing highly angiogenic tumors in nude mice. The transformed phenotype of dnCBF1 transfected cells is efficiently blocked by dn forms of FGF receptor 1 and S100A13, which is a component of FGF1 export pathway. FGF1 export and acceleration of cell growth induced by dnCBF1 depend on SphK1. Similar to dnCBF1, dnMAML transfection induces FGF1 expression and release, and accelerates cell proliferation. The latter effect is strongly decreased in FGF1 null cells. We suggest that the regulation of FGF1 expression and release by CBF1 mediated Notch signaling can play an important role in tumor formation. PMID- 21302308 TI - Apoptosis induced clustering of IP(3)R1 in nuclei of non-differentiated PC12 cells. AB - Inositol 1,4,5-trisphosphate (IP(3)) receptors are emerging as key sites for regulation by pro- and anti-apoptotic factors. Induction of apoptosis for 3 h increased mRNA and protein levels of type 1 IP(3) receptors in non-differentiated (ND), but not in differentiated (D) PC12 cells. Inhibitors of the IP(3) R's calcium release-2-aminoethoxydiphenyl borate (2-APB) and xestospongin-completely prevented Bax and caspase-3 mRNA increase after treatment with the apoptosis inducer set (AIK), and this reinforces the importance of IP(3) R1 in the apoptosis of ND PC12 cells. Apoptosis induction not only increases the IP(3) R1 protein, but it also causes formation of IP(3) R1 clusters in the nucleus which most likely result from fusion of the nucleoplasmic reticulum and/or IP(3) R1 translocation to the nucleus. This is quite similar to the observations noted after overexpression of IP(3) R1 in PC12 cells. The amount of IP(3) induced calcium release was higher in control than in AIK-treated cells. From our results we propose that after the apoptosis induction the amount of intranuclear calcium decreased dramatically due to the increase of calcium permeability of the nuclear calcium store vesicles. Therefore, increase of the calcium permeability may result from IP(3) receptors translocation to nuclei that can boost the calcium transport through IP(3) receptors. PMID- 21302309 TI - Paracrine regulation of fibroblast aminopeptidase N/CD13 expression by keratinocyte-releasable stratifin. AB - As wound healing proceeds into the tissue remodeling phase, cellular interactions become dominated by the interplay of keratinocytes with fibroblasts in the skin, which is largely mediated through paracrine signaling and greatly affects the molecular constitution of the extracellular matrix. We have recently identified aminopeptidase N (APN)/CD13 as a potential fibroblast receptor for 14-3-3 sigma (also known as stratifin), a keratinocyte-releasable protein with potent matrix metalloproteinase 1 (MMP1) stimulatory activity. The present study demonstrates that the expression of APN on dermal fibroblasts is regulated through paracrine signaling by keratinocyte-derived soluble factors. By using an in vitro keratinocyte-fibroblast co-culture system, we showed that APN expression in dermal fibroblasts is induced in the presence of keratinocytes or in response to keratinocyte-conditioned medium. Conditioned medium collected from differentiated keratinocytes further increases APN protein production, suggesting an amplified stimulatory effect by keratinocyte differentiation. Recombinant stratifin potently induces APN synthesis in a dose-dependent manner. A consistent correlation between the protein expression levels of APN and MMP1 was also observed. These results confirm paracrine regulation of APN expression in dermal fibroblasts by keratinocyte-derived stimuli, in particular stratifin, and provide evidence that APN may serve as a target in the regulation of MMP1 expression in epidermal-mesenchymal communication. PMID- 21302310 TI - Alternative splicing of CARMA2/CARD14 transcripts generates protein variants with differential effect on NF-kappaB activation and endoplasmic reticulum stress induced cell death. AB - The caspase recruitment domain (CARD)-containing proteins CARMA1-3 share high degree of sequence, structure and functional homology. Whereas CARMA1 and CARMA3 have been identified as crucial components of signal transduction pathways that lead to activation of NF-kappaB transcription factor, little is known about the function of CARMA2. Here we report the identification of two splice variants of CARMA2. One transcript, named CARMA2short (CARMA2sh), is predicted to encode for a CARMA2 polypeptide containing the CARD, coiled coil, and a PDZ domains, but lacking the SH3 and the GuK domains. The second variant, CARMA2cardless (CARMA2cl), encodes for a polypeptide lacking the CARD domain and containing only a portion of the coiled coil domain and a linker region. Expression analysis confirmed the presence of the CARMA2 alternatively spliced transcripts in both human cell lines and tissues. Fluorescence microscopy data show that both splice variants localize in the cytosol. Biochemical experiments indicate that CARMA2sh interacts with TRAF2 and activates NF-kappaB in a TRAF2-dependent manner. Finally, CARMA2sh variant protects cells from apoptosis induced by different stimuli. Taken together, these results demonstrate that multiple transcripts encoding several CARMA2 isoforms exist in vivo and regulate NF-kappaB activation and apoptosis. PMID- 21302312 TI - Postharvest technology for developing countries: challenges and opportunities in research, outreach and advocacy. AB - This article discusses the needs and challenges of developing good, science based, simple methods for postharvest handling that can be made available in developing countries. Some of the traditional challenges have been successfully met (i.e. identifying causes and sources of losses for key crops, identifying many potential postharvest technologies of practical use for reducing losses), but many challenges remain. These include the characterization of indigenous crops in terms of their unique postharvest physiology (e.g. respiration rate, susceptibility to water loss, chilling sensitivity, ethylene sensitivity), ascertaining the differences between handling recommendations made for well-known varieties and the needs of local varieties of crops, and determining cost effectiveness of scale-appropriate postharvest technologies in each locale and for each crop. Key issues include building capacity at the local level in postharvest science, university teaching and extension, and continued adaptive research efforts to match emerging postharvest technologies to local needs as these continue to change over time. Development of appropriate postharvest technology relies upon many disciplines that are relevant to the overall success of horticulture, i.e. plant biology, engineering, agricultural economics, food processing, nutrition, food safety, and environmental conservation. The expanding pool of new information derived from postharvest research and outreach efforts in these areas can lead in many directions which are likely to have an impact on relieving poverty in developing countries. PMID- 21302313 TI - Antioxidant activity of hard wheat flour, dough and bread prepared using various processes with the addition of different phenolic acids. AB - BACKGROUND: The purpose of this study was to evaluate the effect of baking process on the antioxidant activity of different phenolic acids. Antioxidant potential was determined using the beta-carotene-bleaching activity assay, and free phenolic acid levels were determined by high-performance liquid chromatography. Four phenolic acids, caffeic acid, ferulic acid, syringic acid and gallic acid, were mixed with wheat flour at a concentration of 4.44 umol/g of flour. RESULTS: Type of phenolic acid and processing affected antioxidant activity. Of the phenolic acids, caffeic acid had the most pronounced antioxidant effect. The ranking of phenolic acids in terms of their antioxidant activity in fermented dough and bread was similar to that before processing, i.e. syringic acid < gallic acid < ferulic acid < caffeic acid. The content of ferulic acid was greater than that of the other phenolic acids after baking. Antioxidant activity and free phenolic acid content were reduced by mixing but recovered after fermentation and baking. Phenolic acid recovery after baking was 74-80%. CONCLUSION: Phenolic acids retain their antioxidant activity after the baking process, which has potential health benefits for consumers. Elucidation of interactions between the baking process and phenolic acids is important for the development of functional foods. PMID- 21302311 TI - The suppression of myosin light chain (MLC) phosphorylation during the response to lipopolysaccharide (LPS): beneficial or detrimental to endothelial barrier? AB - Sepsis-induced vascular leakage is a major underlying cause of the respiratory dysfunction seen in severe sepsis. Here, we studied the role of MLC phosphorylation in LPS-induced endothelial hyperpermeability and assessed how the changes in phospho-MLC distribution affect LPS-induced barrier dysfunction. We demonstrated that the changes in human lung microvascular endothelial permeability are preceded by the increase in intracellular calcium level, and increase in MYPT and MLC phosphorylation. Using the siRNA approach, we showed that both LPS-induced barrier dysfunction and MLC phosphorylation are attenuated by the depletion of the smooth muscle isoform of MLC kinase (MLCK) and Rho kinase 2 (ROCK2). Surprisingly, pharmacological inhibition of both ROCK1 and 2 with Y 27632 exacerbated LPS-induced drop in transendothelial resistance, although significantly decreasing MLC phosphorylation level. We next studied the involvement of protein kinase A (PKA)-dependent pathways in LPS-induced barrier dysfunction. We showed that LPS decreased the level of PKA-dependent phosphorylation in endothelial cells; and the pretreatment with forskolin or PKA activator bnz-cAMP counteracted this effect. Forskolin and bnz-cAMP also attenuated LPS-induced increase in MLC phosphorylation level. As we have shown earlier (Bogatcheva et al., 2009), forskolin and bnz-cAMP provide protection from LPS-induced barrier dysfunction. We compared the effects of bnz-cAMP and Y-27632 on phospho-MLC distribution and observed that while bnz-cAMP increased the association of the phospho-MLC signal with the cortical structures, Y-27632 decreased this association. These data indicate that an overall decrease in MLC phosphorylation could be either beneficial or detrimental to endothelial barrier, depending on the intracellular locale of major phospho-MLC changes. PMID- 21302314 TI - Ripening of salted anchovy (Engraulis anchoita): development of lipid oxidation, colour and other sensorial characteristics. AB - BACKGROUND: Changes in lipids are in general associated with quality deterioration, though earlier studies in anchovy indicate that the volatile compounds of importance to the characteristic flavour could be generated by lipid oxidation. The aim of the present paper was to study the changes in the fatty acid composition and the lipid oxidation of Engraulis anchoita during ripening and their relationship with the development of the typical sensorial characteristics. RESULTS: As a result of ripening, polyunsaturated fatty acids decrease from 4.27 to 2.42 and 2.00 g kg(-1) fatty acids in gutted fish and fillet, respectively. The most affected class of fatty acids was the n-3 fatty acids, especially docosahexaenoic acid. Moreover, saturated fatty acids were the most stable to the process. 2-Thiobarbituric acid reactive substances (TBARS) increased throughout ripening, and the use of fillets instead of gutted fish reduced this value. The a value was the parameter most modified, showing a marked increase which correlates with the acquisition of a uniform pink colour. Sensory analysis did not show development of off-odour or undesirable changes in colour during ripening. CONCLUSION: As a result of ripening, the fatty acid profile was modified and an increment of TBARS was observed. However, these changes did not lead to deterioration in the quality of the product. PMID- 21302316 TI - Wheat gluten-based materials plasticised with glycerol and water by thermoplastic mixing and thermomoulding. AB - BACKGROUND: Gluten has been investigated as a source for biodegradable polymeric materials because it is a renewable, available and low-cost raw material. The aim of this study was to evaluate the influence of some variables involved in the two stages of protein/plasticiser thermo-mechanical processing, where a mixture of glycerol and water was used as the plasticiser. RESULTS: Gluten/glycerol/water blends mixed under different thermal conditions (adiabatic starting at 25 degrees C and isothermal at 60 and 90 degrees C) exhibited shear thinning capillary flow behaviour, where a marked increase in flow properties was obtained at the highest temperature. Two thermal events, glass transitions related to the plasticiser blend and gluten, were detected by Modulated Differential Scanning Calorimetry (MDSC) and Dynamic Mechanical Analysis (DMA) tests. Moderate moulding temperature led to less resistant materials showing higher ductility, whereas higher mixing and moulding temperatures led to bioplastics with higher mechanical properties. CONCLUSION: A moulding temperature of 130 degrees C (close to the denaturation temperature) was found to be suitable for the thermomoulding process. In addition, the use of moderate mixing temperature seems to be convenient for those applications that required materials exhibiting high water absorption behaviour and suitable mechanical properties. Protein extractability results reflect the benefits of combining high shear and high temperature during processing to improve cross-linking reactions. PMID- 21302317 TI - Effect of irradiation, active and modified atmosphere packaging, container oxygen barrier and storage conditions on the physicochemical and sensory properties of raw unpeeled almond kernels (Prunus dulcis). AB - BACKGROUND: The present study investigated the effect of irradiation, active and modified atmosphere packaging, and storage conditions on quality retention of raw, whole, unpeeled almonds. Almond kernels were packaged in barrier and high barrier pouches, under N(2) or with an O(2) absorber and stored either under fluorescent lighting or in the dark at 20 degrees C for 12 months. Quality parameters monitored were peroxide value, hexanal content, colour, fatty acid composition and volatile compounds. Of the sensory attributes colour, texture, odour and taste were evaluated. RESULTS: Peroxide value and hexanal increased with dose of irradiation and storage time. Irradiation resulted in a decrease of polyunsaturated and monounsaturated fatty acids during storage with a parallel increase of saturated fatty acids. Volatile compounds were not affected by irradiation but increased with storage time indicating enhanced lipid oxidation. Colour parameters of samples remained unaffected immediately after irradiation. For samples packaged under a N(2) , atmosphere L and b values decreased during storage with a parallel increase of value a resulting to gradual product darkening especially in irradiated samples. CONCLUSION: Non-irradiated almonds retained acceptable quality for ca. 12 months stored at 20 degrees C with the O(2) absorber irrespective of lighting conditions and packaging material oxygen barrier. The respective shelf life for samples irradiated at 1.0 kGy was 12 months packaged in PET-SiOx//LDPE irrespective of lighting conditions and 12 months for samples irradiated at 3 kGy packaged in PET-SiOx//LDPE stored in the dark. PMID- 21302318 TI - Expression of genes associated with ethylene-signalling pathway in harvested banana fruit in response to temperature and 1-MCP treatment. AB - BACKGROUND: Little attention has been paid to characterising the ethylene signalling pathway genes in relation to abnormal ripening of harvested banana fruit during storage at high temperature. The aim of the present study was to investigate banana fruit abnormal ripening and the expression of ten genes associated with the ethylene-signalling pathway, namely MaACS1, MaACO1, MaERS1-4 and MaEIL1-4, at high temperature. Changes in these parameters of banana fruit at high temperature in response to 1-MCP pretreatment were also investigated. RESULTS: High temperature accelerated the decline in fruit firmness, increased ethylene production and inhibited degreening in banana fruit, resulting in fruit abnormal ripening. In addition, the expression of MaACS1, MaACO1, MaERS2, MaERS3, MaERS4, MaEIL1, MaEIL3 and MaEIL4 was enhanced in banana fruit stored at high temperature. However, application of 1-MCP prior to high temperature storage delayed fruit abnormal ripening and simultaneously suppressed the expression of MaACS1, MaERS2, MaERS3, MaEIL1, MaEIL3 and MaEIL4. CONCLUSION: The findings of this study suggested that the expression of genes associated with the ethylene signalling pathway might be involved in banana fruit abnormal ripening at high temperature. Application of 1-MCP suppressed the expression of genes associated with the ethylene-signalling pathway, which may be attributed at least partially to 1-MCP delaying fruit abnormal ripening at high temperature. PMID- 21302320 TI - Preharvest bagging with wavelength-selective materials enhances development and quality of mango (Mangifera indica L.) cv. Nam Dok Mai #4. AB - BACKGROUND: Preharvest bagging has been shown to improve development and quality of fruits. Different light transmittance bags showed different effects on fruit quality. This study presents the benefits of using newly developed plastic bagging materials with different wavelength-selective characteristics for mangoes (cv. Nam Dok Mai #4). Mangoes were bagged at 45 days after full bloom (DAFB) and randomly harvested at 65, 75, 85, 95, and 105 DAFB. The bags were removed on the harvest days. The wavelength-selective bags (no pigment, yellow, red, blue/violet, blue) were compared with the Kraft paper bag with black paper liner, which is currently used commercially for several fruits, and with non-bagging as a control. RESULTS: Bagging significantly (p?0.05) reduced diseases and blemishes. Mango weight at 95 DAFB was increased approximately 15% by VM and V plastic bagging, as compared to paper bagging and control. Plastic bagging accelerated mango ripening as well as growth. Plastic-bagged mangoes reached maturity stage at 95 DAFB, while non-bagged mangoes reached maturity stage at 105 DAFB. Paper bagging resulted in a pale-yellow peel beginning at 65 DAFB, while plastic bagging improved peel glossiness. CONCLUSION: Preharvest bagging with different wavelength-selective materials affected mango development and quality. Bagging mangoes with VM and V materials could reduce peel defects and diseases, increase weight, size, and sphericity, improve peel appearance, and shorten the development periods of mangoes. The results suggest a favorable practice using the newly developed VM and V plastic bags in the production of mangoes, and possibly other fruits as well. PMID- 21302322 TI - Effects of water-saving superabsorbent polymer on antioxidant enzyme activities and lipid peroxidation in oat (Avena sativa L.) under drought stress. AB - BACKGROUND: Drought stress significantly limits oat (Avena sativa L.) growth and productivity. Thus an efficient management of soil moisture and study of metabolic changes in response to drought are important for improved production of oat. The objective was to gain a better understanding of drought tolerance mechanisms and improve soil water management strategies using water-saving superabsorbent polymer (SAP) at 60 kg ha(-1) under three irrigation levels (adequate, moderate and deficit) using a new type of hydraulic pressure controlled auto irrigator. RESULTS: The results showed that the relative water content and leaf water potential (psi(1) ) were much higher in oats treated with SAP. Although the SAP had little effect on plant biomass accumulation under adequate and moderate irrigation, it significantly increased the biomass by 52.7% under deficit irrigation. Plants treated with SAP under deficit irrigation showed a significant decrease in superoxide dismutase, catalase, peroxidase, ascorbate peroxidase and glutathione reductase activities in leaves compared with control plants. CONCLUSION: Our results suggested that drought stress leads to production of oxygen radicals, which results in increased lipid peroxidation and oxidative stress in the plant, and the application of SAP could conserve soil water, making same available to plants for increased biomass accumulation and reduced oxidative stress especially under severe water stress. PMID- 21302323 TI - Effects of rice dreg protein and its hydrolysate on growth performance and small intestine morphology of early-weaned rats. AB - BACKGROUND: Protein hydrolysate has more efficient peptide absorption and less hypertonic protein absorption. This study aims to investigate the influences of rice dreg (RD) protein and its hydrolysate on growth and somatropic axis in early weaned Sprague-Dawley rats in comparison with soybean (SB) protein. RESULTS: Compared with a SB diet control, a rice dregs protein hydrolysate (RD-H) diet decreased average daily feed intake and feed/gain in weeks 1 (P < 0.01) and 2 (P < 0.05), while an RD diet decreased average daily feed intake and feed/gain in week 1 (P < 0.01). Average daily body gain exhibited no significant differences between either treatment during the 28-day period. After 28 d, villus height and lamina propria depth of jejunum and duodenum were greater in the RD-H treatment than in RD and control treatments (P < 0.01), while serum urea nitrogen concentration was lower in RD and RD-H treatments than in the control (P < 0.05). There were no differences in serum growth hormone concentration, hepatic and muscle insulin-like growth factor-1 expression, and muscle growth hormone receptor expression at 7 and 28 d (P > 0.05), but hepatic growth hormone receptor expression was higher in RD-H treatment than in RD and control treatments after 7 d (P < 0.05). CONCLUSION: Results showed that RD and RD-H diets improved feed utilisation efficiency in the first 2 weeks post-weaning and small intestine morphology at 28 d post-weaning for an early-weaned mammal compared with a SB diet. PMID- 21302324 TI - Schisandrin enhances dendrite outgrowth and synaptogenesis in primary cultured hippocampal neurons. AB - BACKGROUND: Schisandra chinensis, commonly used in Asia for tea material and traditional Chinese medicine, is presumed to enhance mental and intellectual functions. In this study, the effects and signalling mechanisms of a purified compound schisandrin, one of the lignan of Schisandra chinensis, on primary cultured hippocampal neurons were investigated. RESULTS: Schisandrin treatment enhanced total dendritic length and branching complexity, both of which were significantly suppressed in the presence of specific blockers for calmodulin dependent kinase II (CaMKII), protein kinase C epsilon (PKCepsilon), and mitogen activated protein kinase kinase (MEK). Moreover, schisandrin induced calcium influx, and phosphorylation of CaMKII, PKCepsilon, and MEK. Inhibition of CAMKII and PKCepsilon attenuated the schisandrin-induced phosphorylation of PKCepsilon and MEK, and the phosphorylation of MEK, respectively. Moreover, schisandrin also stimulated the phosphorylation of cyclic AMP responsive-element binding protein (CREB) at Ser-133, an effect that was blocked by KN93. In addition to its neuritogenic effects, schisandrin increased the numbers of postsynaptic density 95-positive and FM1-43-positive puncta in dendrites and synaptic boutons, respectively. CONCLUSION: In hippocampal neurons, schisandrin exhibits neurotrophic properties that are mediated by the CaMKII-PKCepsilon-MEK pathway. PMID- 21302326 TI - Contribution of sulfur-containing compounds to the colour-inhibiting effect and improved antioxidant activity of Maillard reaction products of soybean protein hydrolysates. AB - BACKGROUND: Light-coloured and savoury-tasting flavour enhancers are attractive to both consumers and food producers. The aim of this study was to investigate the colour-inhibiting effect of L-cysteine and thiamine during the Maillard reaction of soybean peptide and D-xylose. The correlation between volatile compounds and antioxidant activity of the corresponding products was also studied. RESULTS: Colour formation was markedly suppressed by cysteine. Compared with peptide/xylose (PX), the taste profile of Maillard reaction products (MRPs) derived from peptide/xylose/cysteine (PXC) and peptide/xylose/cysteine/thiamine (PXCT) was stronger, including umami, mouthfulness, continuity, meaty and overall acceptance. PXC and PXCT also exihibited distinctly higher antioxidant activity. Principal component analysis was applied to investigate the correlation between antioxidant activity and volatile compounds. Of 88 volatile compounds identified, 55 were significantly correlated with antioxidant activity by two principal components (accounting for 85.05% of the total variance). CONCLUSION: Effective colour control of the Maillard reaction by L-cysteine may allow the production of healthier (higher antioxidant activity) and tastier foods to satisfy consumers' and food producers' demands. Light-coloured products might be used as functional flavour enhancers in various food systems. PMID- 21302327 TI - Effect of free or protein-associated soy isoflavones on the antioxidant status in rats. AB - BACKGROUND: The objective of this study was to investigate the effect of chronic ingestion of free and protein-associated soy isoflavones on the antioxidant status in male Wistar rats. Free isoflavone (iso), protein-associated soy isoflavone (iso + prot) and soy protein (prot) extracts were administered for 30 days by gavage to the rats at a dosage of 1 mg aglycone isoflavones per 200 g body weight, adjusted daily, and the prot group was given the same concentration of soy protein received by the iso + prot group. Antioxidant capacity of plasma, thiobarbituric acid-reactive substance (TBARS) and glutathione (GSH) levels and catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities in plasma, erythrocytes and tissues and gene expression levels in liver and kidney were evaluated. RESULTS: Chronic ingestion of free but not of protein-associated soy isoflavones nor of solely soy protein increased plasma antioxidant capacity and GPx activity in erythrocytes. Soy protein increased CAT activity and gene expression in liver. SOD activity in erythrocytes was increased by all treatments. CONCLUSION: The overall results confirm that dietary soy isoflavones have a positive effect on antioxidant status, enhancing antioxidant capacity of plasma and antioxidant enzymes in various tissues, but the effects are dependent on the form of administration and on a complex mechanism of antioxidant status balance on the organism. PMID- 21302330 TI - Dry matter content and fruit size affect flavour and texture of novel Actinidia deliciosa genotypes. AB - BACKGROUND: Previous studies with commercial kiwifruit cultivars have demonstrated that the taste of fruit with higher dry matter content (DM) is more liked by consumers. A unique replicated trial of kiwifruit genotypes (10 high/low DM * small/large-fruited genotypes) has provided an opportunity to consider how the genetic propensity for a kiwifruit to accumulate DM affects fruit flavour and texture. In the present study, eating-ripe fruit from each of the genotypes were assessed using a trained sensory panel and the relationships between these sensory attributes and fresh weight, DM, flesh firmness and soluble solids content (SSC) were explored. RESULTS: The genotypes provided a diversity of flavour and texture attributes, each of which varied in perceived intensity of the sensory experience. High-DM genotypes had higher SSC and were perceived as sweeter than low-DM genotypes. Sweet taste was closely associated with the perception of the tropical flavour and high-DM genotypes were found to have more tropical notes. Fruit size was associated with fruit texture, and small fruit were characterised by a firmer and more fibrous core. Large high-DM fruit were perceived as juicier than those of all other genotypes. CONCLUSIONS: Genotypes were perceived differently from one another, and differences in fruit size and DM content were reflected in fruit sensorial properties. This study is unique in demonstrating interactions between fruit size, DM and sensory properties. These findings could be relevant not only to kiwifruit but to fruiting crop breeders in general, because of the demonstrated potential for effects of fruit size and DM content on sweetness, flavour and fruit texture. PMID- 21302331 TI - Influence of shriveling on berry composition and antioxidant activity of Cabernet Sauvignon grapes from Shanxi vineyards. AB - BACKGROUND: Berry shrivel (BS), a berry development disorder, appears soon after veraison. It occurs worldwide and affects the quality of grape berries and wine. However, it had not been reported in China until recently. This study aimed to investigate the changes in berry composition and antioxidant activity of Cabernet Sauvignon grapes from Xiangning Valley, Shanxi Province, China, during BS. RESULTS: Shrinkage contributed to an increase in the concentration of basic grape ingredients such as sugar and acid. An appropriate degree of shrinkage was apparently helpful in improving the phenolic content and increasing the antioxidant activity, but the berries that continued to shrivel showed a low antioxidant activity. Further, the results indicated distinct differences between the berries harvested from the southern side of the canopy and those harvested from the northern side, presumably due to variations in sunlight exposure. CONCLUSION: Moderate BS was beneficial since it increased berry quality and antioxidant activity of Cabernet Sauvignon grapes from Shanxi vineyards. PMID- 21302332 TI - Effects of molecular characteristics of on konjac glucomannan glass transitions of potato amylose, amylopection and their mixtures. AB - BACKGROUND: The purpose of this study was to explore further the functions of konjac glucomannan (KGM) in starch-based foods. Experiments were carried out using the mixed amylose/amylopectin/KGM system as a model. High-speed differential scanning calorimetry (hyper-DSC) with the support of high performance size exclusion chromatography (HPSEC) equipped with multi-angle laser light scattering (MALLS) and differential refractive index (RI), X-ray diffractometry (XRD) and viscosimetry was used to investigate the effects of KGM on glass transition temperatures (T(g) s) of mixtures with different amylose/amylopectin ratios. RESULTS: Hyper-DSC results showed that the T(g) s of amylose, amylopection and their mixtures decreased with increasing concentration of KGM. Based on the molecular characteristics of KGM, HPSEC-MALLS-RI, viscosimetry and XRD results showed that the molar masses of KGM ranged from 1.023 * 10(6) to 1.329 * 10(6) g mol(-1) ; the root mean square (RMS) radii were distributed from 110.5 to 129.6 nm, and M(w) /M(n) was 1.017. KGM was a linear molecule with random-coil conformation in solution and the crystallinity was 0.00%. CONCLUSION: It is suggested that the addition of KGM has plasticizing effects on the structures of amylose and amylopectin, which can increase free volume and molecular movement of amylose and amylopectin chains, resulting in a decrease in their T(g) s. PMID- 21302334 TI - Studies on the antioxygenic activity of bitter gourd (Momordica charantia) and its fractions using various in vitro models. AB - BACKGROUND: A study was undertaken to evaluate the antioxygenic activity of bitter gourd pulp and seed powders as well as their various solvent extracts using different methods and to minimise the oxidative deterioration of lipids by natural antioxidants. RESULTS: Bitter gourd pulp and seed powders at 20 g kg(-1) and their ethanol/water extracts exhibited stronger antioxygenic activity than other solvent extracts. Bitter gourd pulp and its extracts showed slightly higher antioxygenic activity than bitter gourd seed and its extracts. This may be attributed to the presence of higher amounts of phenolics and flavonoids, which have been reported as potential antioxidants. The seed portion of bitter gourd contained higher levels of total protein (188.3 g kg(-1) ), total fat (238.9 g kg(-1) ) and crude fibre (350.2 g kg(-1) ) than the pulp portion. Fatty acid analysis of bitter gourd seed oil indicated the presence of alpha-eleostearic acid, an isomer of conjugated linolenic acid, as a major fatty acid, but this acid was absent in the pulp. CONCLUSION: The results of this study confirmed the presence of antioxygenic compounds in both bitter gourd pulp and seed. In particular, their ethanol/water extracts showed great potential as natural antioxidants to inhibit lipid peroxidation in foods. PMID- 21302335 TI - Demographic differences in Down syndrome livebirths in the US from 1989 to 2006. AB - OBJECTIVE: To explore demographic differences in Down syndrome livebirths in the United States. METHODS: Using National Center for Health Statistics (NCHS) birth certificate data from 1989 to 2006 we analyzed Down syndrome livebirths after correcting for under-reporting. We created six subsets based on maternal age (15 34 and 35-49 years old); US regions, that is, Northeast, Midwest, South and West; marital status, (married, unmarried); education, ( <= 12 years, >= 13 years); race, (white, black); and Hispanic ethnicity, (non-Hispanic, Hispanic). We estimated expected Down syndrome livebirths assuming no change in birth certificate reporting. The percentage of expected Down syndrome livebirths actually born was calculated by year. RESULTS: There were 72 613 424 livebirths from 1989 to 2006. There were 122 519 Down syndrome livebirths expected and 65 492 were actually born. The Midwest had the most expected Down syndrome livebirths actually born (67.6%); the West was lowest (44.4%). More expected Down syndrome livebirths were born to women who were 15 to 34 years old (61 vs 43.8%) and to those with <= 12 years education (60.4 vs 46.9%), white race (56.6 vs 37%), unmarried (56.0 vs 52.5%), and of Hispanic ethnicity (55.0 vs 53.3%). CONCLUSION: The percentage of expected Down syndrome livebirths actually born varies by demographics. PMID- 21302336 TI - An Acardiac twin with a documented heart beat at 6 + 5 weeks and TRAP diagnosed at 8 + 5 weeks-insights into possible pathophysiology. PMID- 21302337 TI - Comment on "Organometallic complexes for nonlinear optics. 45. Dispersion of the third-order nonlinear optical properties of triphenylamine-cored alkynylruthenium dendrimers" - increasing the nonlinear optical response by two orders of magnitude. PMID- 21302338 TI - In vivo and in vitro antimalarial activity of 4-nerolidylcatechol. AB - 4-Nerolidylcatechol (4-NC) isolated from Piper peltatum L. (Piperaceae) was evaluated for in vitro antiplasmodial activity against Plasmodium falciparum (cultures of both standard CQR (K1) and CQS (3D7) strains and two Amazonian field isolates) and for in vivo antimalarial activity using the Plasmodium berghei murine model. 4-NC exhibits significant in vitro and moderate in vivo antiplasmodial activity. 4-NC administered orally and subcutaneously at doses of 200, 400 and 600 mg/kg/day suppressed the growth of P. berghei by up to 63% after four daily treatments (days 1-4). Also, 4-NC exhibited important in vitro antiplasmodial activity against both standard and field P. falciparum strains in which 50% inhibition of parasite growth (IC(50) ) was produced at concentrations of 0.05-2.11 MUg/mL and depended upon the parasite strain. Interestingly, healthy (non-infected) mice that received 4-NC orally presented (denatured) blood plasma which exhibited significant in vitro activity against P. falciparum. This is evidence that mouse metabolism allows 4-NC or active metabolites to enter the blood. Further chemical and pharmacological studies are necessary to confirm the potential of 4-NC as a new antimalarial prototype. PMID- 21302339 TI - Ultrafast vibrational population transfer dynamics in 2-acetylcyclopentanone studied by 2D IR spectroscopy. AB - 2-Acetylcyclopentanone (2-ACP), which is a beta-dicarbonyl compound, undergoes keto-enol isomerization, and its enol tautomers are stabilized by a cyclic intramolecular hydrogen bond. 2-ACP (keto form) has symmetric and asymmetric vibrational modes of the two carbonyl groups at 1748 and 1715 cm(-1) , respectively, which are well separated from the carbonyl modes of its enol tautomers in the FTIR spectrum. We have investigated 2-ACP dissolved in carbon tetrachloride by 2D IR spectroscopy and IR pump-probe spectroscopy. Vibrational population transfer dynamics between the two carbonyl modes were observed by 2D IR spectroscopy. To extract the population exchange dynamics (i.e., the down- and uphill population transfer rate constants), we used the normalized volumes of the cross-peaks with respect to the diagonal peaks at the same emission frequency and the survival and conditional probability functions. As expected, the downhill population transfer time constant (3.2 ps) was measured to be smaller than the uphill population transfer time constant (3.8 ps). In addition, the vibrational population relaxation dynamics of the two carbonyl modes were observed to be the same within the experimental error and were found to be much slower than vibrational population transfer between two carbonyl modes. PMID- 21302340 TI - Copy number variation characteristics in subpopulations of patients with autism spectrum disorders. AB - Autism spectrum disorders (ASDs) are a heterogeneous group of disorders with a complex genetic etiology. We used high-resolution whole genome array-based comparative genomic hybridization (array-CGH) to screen 223 ASD patients for gene dose alterations associated with susceptibility for autism. Clinically significant copy number variations (CNVs) were identified in 18 individuals (8%), of which 9 cases (4%) had de novo aberrations. In addition, 20 individuals (9%) were shown to have CNVs of unclear clinical relevance. Among these, 13 cases carried rare but inherited CNVs that may increase the risk for developing ASDs, while parental samples were unavailable in the remaining seven cases. Classification of all patients into different phenotypic and inheritance pattern groups indicated the presence of different CNV patterns in different patient groups. Clinically relevant CNVs were more common in syndromic cases compared to non-syndromic cases. Rare inherited CNVs were present in a higher proportion of ASD cases having first- or second-degree relatives with an ASD-related neuropsychiatric phenotype in comparison with cases without reported heredity (P = 0.0096). We conclude that rare CNVs, encompassing potential candidate regions for ASDs, increase the susceptibility for the development of ASDs and related neuropsychiatric disorders giving us further insight into the complex genetics underlying ASDs. PMID- 21302341 TI - "Replicated" genome wide association for dependence on illegal substances: genomic regions identified by overlapping clusters of nominally positive SNPs. AB - Declaring "replication" from results of genome wide association (GWA) studies is straightforward when major gene effects provide genome-wide significance for association of the same allele of the same SNP in each of multiple independent samples. However, such unambiguous replication may be unlikely when phenotypes display polygenic genetic architecture, allelic heterogeneity, locus heterogeneity, and when different samples display linkage disequilibria with different fine structures. We seek chromosomal regions that are tagged by clustered SNPs that display nominally significant association in each of several independent samples. This approach provides one "nontemplate" approach to identifying overall replication of groups of GWA results in the face of difficult genetic architectures. We apply this strategy to 1 million (1M) SNP Affymetrix and Illumina GWA results for dependence on illegal substances. This approach provides high confidence in rejecting the null hypothesis that chance alone accounts for the extent to which clustered, nominally significant SNPs from samples of the same racial/ethnic background identify the same chromosomal regions. There is more modest confidence in: (a) identification of individual chromosomal regions and genes and (b) overlap between results from samples of different racial/ethnic backgrounds. The strong overlap identified among the samples with similar racial/ethnic backgrounds, together with prior work that identified overlapping results in samples of different racial/ethnic backgrounds, support contributions to individual differences in vulnerability to addictions that come from both relatively older allelic variants that are common in many current human populations and newer allelic variants that are common in fewer current human populations. PMID- 21302342 TI - Parent-of-origin effects of the serotonin transporter gene associated with autism. AB - A promoter-linked insertion/deletion polymorphism of the serotonin transporter gene (SLC6A4) has been implicated in autism spectrum disorders (ASDs) in numerous family based association studies. However, the results of these investigations have been inconsistent in that both the long and short alleles have been shown to be over-transmitted to affected offspring. In order to further elucidate the relationship between the 5-HTTLPR variant and autism risk, we undertook a thorough study of parent-of-origin effects, maternal genotype effects, and offspring genotype effects in a sample of affected offspring from the Autism Genetic Resource Exchange (AGRE). Both the overall autism phenotype and measures of autism behaviors from the Autism Diagnostic Interview-Revised [Lord et al. (1994); J Autism Dev Disord 24(5): 659-685] were considered. We found evidence of over-transmission (risk allele short, P = 0.012), maternal effects (risk allele long, P = 0.035), and parent-of-origin effects (risk allele short from mother, P = 0.018) of the 5-HTTLPR variant in the AGRE sample. Population- and gender specific effects were also explored as associations may be heterogeneous across populations and sexes. Parent-of-origin effects of the variant were associated with maternally inherited copies of the short allele that resulted in more impaired overall level of language (P = 0.04). Our study was conducted to further investigate the 5-HTTLPR risk variants by identifying allelic associations that may be population-specific, phenotype-specific, or conferred by maternal or parent-of-origin effects. In light of conflicting observations from previous studies, these are just a few of the possible explanations that deserve attention. PMID- 21302343 TI - The ATXN1 and TRIM31 genes are related to intelligence in an ADHD background: evidence from a large collaborative study totaling 4,963 subjects. AB - Intelligence is a highly heritable trait for which it has proven difficult to identify the actual genes. In the past decade, five whole-genome linkage scans have suggested genomic regions important to human intelligence; however, so far none of the responsible genes or variants in those regions have been identified. Apart from these regions, a handful of candidate genes have been identified, although most of these are in need of replication. The recent growth in publicly available data sets that contain both whole genome association data and a wealth of phenotypic data, serves as an excellent resource for fine mapping and candidate gene replication. We used the publicly available data of 947 families participating in the International Multi-Centre ADHD Genetics (IMAGE) study to conduct an in silico fine mapping study of previously associated genomic locations, and to attempt replication of previously reported candidate genes for intelligence. Although this sample was ascertained for attention deficit/hyperactivity disorder (ADHD), intelligence quotient (IQ) scores were distributed normally. We tested 667 single nucleotide polymorphisms (SNPs) within 15 previously reported candidate genes for intelligence and 29451 SNPs in five genomic loci previously identified through whole genome linkage and association analyses. Significant SNPs were tested in four independent samples (4,357 subjects), one ascertained for ADHD, and three population-based samples. Associations between intelligence and SNPs in the ATXN1 and TRIM31 genes and in three genomic locations showed replicated association, but only in the samples ascertained for ADHD, suggesting that these genetic variants become particularly relevant to IQ on the background of a psychiatric disorder. PMID- 21302344 TI - Cognitive effects of genetic variation in monoamine neurotransmitter systems: a population-based study of COMT, MAOA, and 5HTTLPR. AB - Individual differences in cognitive function are highly heritable and most likely driven by multiple genes of small effect. Well-characterized common functional polymorphisms in the genes MAOA, COMT, and 5HTTLPR each have predictable effects on the availability of the monoamine neurotransmitters dopamine, noradrenaline, and serotonin. We hypothesized that 5HTTLPR genotype would show little association with prefrontal cognitive performance, but that COMT and MAOA would have interacting effects on cognition through their shared influence on prefrontal catecholamine availability. We assessed the individual and epistatic effects of functional polymorphisms in COMT, MAOA, and 5HTTLPR on children's prefrontal cognitive function in nearly 6,000 children from the population-based Avon Longitudinal Study of Parents and Children (ALSPAC). Neither MAOA nor 5HTTLPR polymorphisms showed significant effects on cognitive function. In boys but not girls, there was a modest but statistically significant interaction between MAOA and COMT genotypes such that increased prefrontal catecholamine availability was associated with better working memory. These results suggest that assessment of multiple genes within functionally related systems may improve our understanding of the genetic basis of cognition. PMID- 21302346 TI - Genetic association and sequencing of the insulin-like growth factor 1 gene in bipolar affective disorder. AB - Insulin-like growth factor 1 (IGF1) has been shown to have an important role in brain development and function. Studies of IGF1 administration in rodents have shown that it has an anxiolytic and antidepressant effect. A genome-wide association study (GWAS) of the first University College London (UCL) cohort of 506 bipolar affective disorder subjects and 510 controls was carried out. The exons and flanking regions of IGF1 were resequenced, any new polymorphisms found were genotyped in an enlarged UCL sample of 937 cases and 941 controls. GWAS data gave good evidence of allelic and haplotypic association between multiple IGF1 SNP's and bipolar disorder (BD). New polymorphisms were found by resequencing IGF1 region. Data from GWAS and the new markers showed that twelve out of 43 SNPs showed association with BD with the four most significant SNPs having values of 3.7 * 10(-5) , 8.4 * 10(-4) , 2.6 * 10(-4) , and 2.5 * 10(-4) . A 5' promoter microsatellite polymorphism previously correlated with plasma lipoprotein concentration was also associated with BD (P = 0.013). Haplotypic association confirmed association with BD with significance values similar to the single marker SNP values. The marker rs12426318 has also been found to be associated with BD in a second sample. A test of gene wide significance with permutation testing for all markers genotyped at IGF1 was also significant. These data implicate IGF1 as a candidate gene to cause genetic susceptibility to BD. PMID- 21302345 TI - Fine mapping of candidate regions for bipolar disorder provides strong evidence for susceptibility loci on chromosomes 7q. AB - Genomewide scans of bipolar disorder (BP) have not produced consistent linkage findings. Follow-up studies using enlarged samples and enhanced marker density can bolster or refute claims of linkage and pave the way to gene discovery. We conducted linkage and association analyses, using a ~3-cM density map of 10 candidate regions, in a large BP pedigree sample (865 individuals from 56 pedigrees). The candidate regions were identified in a previous 10-cM genome-wide scan using a subset of this sample (373 individuals from 40 pedigrees). The present sample consists of the expanded original pedigrees ("core" pedigrees) and 16 additional pedigrees. We obtained experiment-wide significant linkage on chromosome 7q34 (LOD score 3.53, P < 0.001), substantially stronger than that observed in the genome-wide scan. Support for linkage was sustained on chromosomes 2p13, 4q31, 8q13, 13q32, 14q21, and 17q11, though at a more modest level. Family-based association analysis was consistent with the linkage results at all regions with linkage evidence, except 4q an 8q, but the results fell short of statistical significance. Three of the previously implicated regions-9q31, 10q21 and 10q24-showed substantial reduction in evidence of linkage. Our results strongly support 7q34 as a region harboring susceptibility locus for BP. Somewhat lesser, yet notable support was obtained for 2p13, 4q31, 8q13, 13q32, 14q21, and 17q11. These regions could be considered prime candidates for future gene finding efforts. PMID- 21302347 TI - Linkage and association on 8p21.2-p21.1 in schizophrenia. AB - In the past decade, we and others have consistently reported linkage to a schizophrenia (SZ) susceptibility region on chromosome 8p21. Most recently, in the largest SZ linkage sample to date, a multi-site international collaboration performed a SNP-based linkage scan (~6,000 SNPs; 831 pedigrees; 121 from Johns Hopkins (JHU)), that showed the strongest evidence for linkage in a 1 Mb region of chr 8p21 from rs1561817 to rs9797 (Z(max) = 3.22, P = 0.0004) [Holmans et al. 2009. Mol Psychiatry]. We have investigated this 8p21 peak region further in two ways: first by linkage and family-based association in 106 8p-linked European Caucasian (EUC) JHU pedigrees using 1,402 SNPs across a 4.4 Mb region surrounding the peak; second, by an independent case-control association study in the genetically more homogeneous Ashkenazim (AJ) (709 cases, 1,547 controls) using 970 SNPs in a further narrowed 2.8 Mb region. Family-based association analyses in EUC pedigrees and case-control analyses in AJ samples reveal significant associations for SNPs in and around DPYSL2 and ADRA1A, candidate genes previously associated with SZ in our work and others. Further, several independent gene expression studies have shown that DPYSL2 is differentially expressed in SZ brains [Beasley et al. 2006. Proteomics 6(11):3414-3425; Edgar et al. 2000. Mol Psychiatry 5(1):85-90; Johnston-Wilson et al. 2000. Mol Psychiatry 5(2):142-149] or in response to psychosis-inducing pharmaceuticals [Iwazaki et al. 2007. Proteomics 7(7):1131-1139; Paulson et al. 2004. Proteomics 4(3):819-825]. Taken together, this work further supports DPYSL2 and the surrounding genomic region as a susceptibility locus for SZ. PMID- 21302348 TI - Evaluation of risk loci for schizophrenia derived from genome-wide association studies in a German population. AB - In the genome-wide association study (GWAS) on schizophrenia [O'Donovan et al. (2008); Nat Genet 40:1053-1055] a UK-sample of 479 cases with DSM-IV schizophrenia was genotyped in comparison to control subjects with follow up of 12 putative loci in international replication sets of approximately 15,000 cases and controls. In these cohorts and a combined bipolar and schizophrenia UK sample, six single nucleotide polymorphisms (SNPs) supported association, with the strongest evidence for SNP-marker rs1344706 at the zinc finger ZNF804A locus on chromosome 2q32.1 (P = 1.61 * 10-7). We attempted replication of these findings in a German population of 2,154 individuals (632 with affective disorders, 937 with schizophrenia, and 585 controls), but found none of the GWAS risk alleles significantly associated with psychosis. Particularly rs1344706, initially surpassing the genome-wide significance level in an extended phenotype of schizophrenia and affective disorder, produced consistently negative results. At the ZNF804A locus estimated Odds ratios reached 1.08 (0.93-1.26 95% CI) for the schizophrenia sample and 1.04 (0.90-1.20 95% CI) for the combined set of cases with schizophrenia and affective disorder. The main limitation of our study may be the reduced power of the sample size, but our data may be useful for future meta-analysis of GWA data sets. Although GWAS have proven extraordinary successful in identifying susceptibility genes for complex genetic disorders, the hypothesis of common genetic variants in the complex group of the schizophrenic psychoses with small effect size but relatively high frequency is still put to further scrutiny. PMID- 21302349 TI - Inherited balanced translocation t(9;17)(q33.2;q25.3) concomitant with a 16p13.1 duplication in a patient with schizophrenia. AB - We report two rare genetic aberrations in a schizophrenia patient that may act together to confer disease susceptibility. A previously unreported balanced t(9;17)(q33.2;q25.3) translocation was observed in two schizophrenia-affected members of a small family with diverse psychiatric disorders. The proband also carried a 1.5 Mbp microduplication at 16p13.1 that could not be investigated in other family members. The duplication has been reported to predispose to schizophrenia, autism and mental retardation, with incomplete penetrance and variable expressivity. The t(9;17) (q33.2;q25.3) translocation breakpoint occurs within the open reading frames of KIAA1618 on 17q25.3, and TTLL11 (tyrosine tubulin ligase like 11) on 9q33.2, causing no change in the expression level of KIAA1618 but leading to loss of expression of one TTLL11 allele. TTLL11 belongs to a family of enzymes catalyzing polyglutamylation, an unusual neuron-specific post-translational modification of microtubule proteins, which modulates microtubule development and dynamics. The 16p13.1 duplication resulted in increased expression of NDE1, encoding a DISC1 protein partner mediating DISC1 functions in microtubule dynamics. We hypothesize that concomitant TTLL11-NDE1 deregulation may increase mutation load, among others, also on the DISC1 pathway, which could contribute to disease pathogenesis through multiple effects on neuronal development, synaptic plasticity, and neurotransmission. Our data illustrate the difficulties in interpreting the contribution of multiple potentially pathogenic changes likely to emerge in future next-generation sequencing studies, where access to extended families will be increasingly important. PMID- 21302350 TI - Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and age of onset in schizophrenia: a combined analysis of independent samples. AB - Methylenetetrahydrofolate reductase (MTHFR) is involved in the one-carbon cycle, which is of importance for nucleotide synthesis and methylation of DNA, membranes, proteins and lipids. The MTHFR gene includes two common polymorphisms (rs1801133 or C677T; rs1801131 or A1298C) which both alter enzyme activity. The T allele of the C677T polymorphism has recently been associated with earlier age at onset of schizophrenia. In the present study we examined the association between the MTHFR C677T and A1298C polymorphisms and age at onset of schizophrenia in twelve samples consisting of 3,213 unrelated schizophrenia patients, including the original Scandinavian sample. There was no consistent relationship between MTHFR C677T, A1298C or combined 677T/1298C carriers and age of onset in schizophrenia when the results of each study were combined using meta-analysis. The present results suggest that the investigated MTHFR polymorphisms do not influence age of onset in schizophrenia. PMID- 21302351 TI - Intra-family phenotypic heterogeneity of 16p11.2 deletion carriers in a three generation Chinese family. AB - The 16p11.2 deletion is a recurrent genomic event and a significant risk factor for autism spectrum disorders (ASD). This genomic disorder also exhibits extensive phenotypic variability and diverse clinical phenotypes. The full extent of phenotypic heterogeneity associated with the 16p11.2 deletion disorder and the factors that modify the clinical phenotypes are currently unknown. Multiplex families with deletion offer unique opportunities for exploring the degree of heterogeneity and implicating modifiers. Here we reported the clinical and genomic characteristics of three 16p11.2 deletion carriers in a Chinese family. The father carries a de novo 16p11.2 deletion, and it was transmitted to the proband and sib. The proband presented with ASD, intellectual disability, learning difficulty, congenital malformations such as atrial septal defect, scoliosis. His dysmorphic features included myopia and strabismus, flat and broad nasal bridge, etc. While the father shared same neurodevelopmental problems as the proband, the younger brother did not show many of the proband's phenotypes. The possible unmasked mutation of TBX6 and MVP gene in this deleted region and the differential distribution of other genomic CNVs were explored to explain the phenotypic heterogeneity in these carriers. This report demonstrated the different developmental trajectory and discordant phenotypes among family members with the same 16p11.2 deletion, thus further illustrated the phenotypic complexity and heterogeneity of the 16p11.2 deletion. PMID- 21302352 TI - Common genetic variation in the GAD1 gene and the entire family of DLX homeobox genes and autism spectrum disorders. AB - Biological and positional evidence supports the involvement of the GAD1 and distal-less homeobox genes (DLXs) in the etiology of autism. We investigated 42 single nucleotide polymorphisms in these genes as risk factors for autism spectrum disorders (ASD) in a large family-based association study of 715 nuclear families. No single marker showed significant association after correction for multiple testing. A rare haplotype in the DLX1 promoter was associated with ASD (P-value = 0.001). Given the importance of rare variants to the etiology of autism revealed in recent studies, the observed rare haplotype may be relevant to future investigations. Our observations, when taken together with previous findings, suggest that common genetic variation in the GAD1 and DLX genes is unlikely to play a critical role in ASD susceptibility. PMID- 21302353 TI - Genome-wide association study of hoarding traits. PMID- 21302354 TI - Narrowing the critical deletion region for autism spectrum disorders on 16p11.2. PMID- 21302355 TI - Engineering, characterization and directional self-assembly of anisotropically modified nanocolloids. AB - Along with traditional attributes such as the size, shape, and chemical structure of polymeric micro-objects, control over material distribution, or selective compartmentalization, appears to be increasingly important for maximizing the functionality and efficacy of biomaterials. The fabrication of tri- and tetracompartmental colloids made from biodegradable poly(lactide-co-glycolide) polymers via electrohydrodynamic co-jetting is demonstrated. The presence of three compartments is confirmed via flow cytometry. Additional chemical functionality is introduced via the incorporation of acetylene-functionalized polymers into individual compartments of the particles. Direct visualization of the spatioselective distribution of acetylene groups is demonstrated by confocal Raman microscopy as well as by reaction of the acetylene groups with azide-biotin via 'click chemistry'. Biotin-streptavidin binding is then utilized for the controlled assembly and orientation of bicompartmental particles onto functionalized, micropatterned substrates prepared via chemical vapor deposition polymerization. PMID- 21302356 TI - Interaction of spherical silica nanoparticles with neuronal cells: size-dependent toxicity and perturbation of calcium homeostasis. AB - The effects of Stober silica nanoparticles on neuronal survival, proliferation, and on the underlying perturbations in calcium homeostasis are investigated on the well-differentiated neuronal cell line GT1-7. The responses to nanoparticles 50 and 200 nm in diameter are compared. The 50-nm silica affects neuronal survival/proliferation in a dose-dependent way, by stimulating apoptotic processes. In contrast, the 200-nm silica does not show any toxic effect even at relatively high concentrations (292 MUg mL-1). To identify the mechanisms underlying these effects, the changes in intracellular calcium concentration elicited by acute and chronic administration of the two silica nanoparticles are analyzed. The 50-nm silica at toxic concentrations generates huge and long lasting increases in intracellular calcium, whereas the 200-nm silica only induces transient signals of much lower amplitude. These findings provide the first evidence that silica nanoparticles can induce toxic effects on neuronal cells in a size-dependent way, and that these effects are related to the degree of perturbation of calcium homeostasis. PMID- 21302357 TI - Affibody-functionalized gold-silica nanoparticles for Raman molecular imaging of the epidermal growth factor receptor. AB - The affibody functionalization of fluorescent surface-enhanced Raman scattering gold-silica nanoparticles as multimodal contrast agents for molecular imaging specific to epidermal growth factor receptor (EGFR) is reported. This nanoparticle bioconjugate reports EGFR-positive A431 tumors with a signal nearly 35-fold higher than EGFR-negative MDA-435S tumors. The low-level EGFR expression in adjacent healthy tissue is 7-fold lower than in the positive tumors. Validation via competitive inhibition reduces the signal by a factor of six, and independent measurement of EGFR via flow cytometry correlates at R(2) = 0.92. PMID- 21302358 TI - Enhanced field emission and improved supercapacitor obtained from plasma-modified bucky paper. AB - The surface morphology of bucky papers (BPs) made from single-walled carbon nanotubes (CNTs) is modified by plasma treatment resulting in the formation of vertical microstructures on the surface. The shapes of these structures are either pillarlike or conelike depending on whether the gas used during plasma treatment is Ar or CH(4) . A complex interplay between different factors, such as the electric field within the plasma sheath, polarization of the CNT, intertubular cohesive forces, and ion bombardment, result in the formation of these structures. The roles played by these factors are quantitatively and qualitatively analyzed. The final material is flexible, substrate-free, composite free, made only of CNTs, and has discrete vertically aligned structures on its surface. It shows enhanced field emission and electrochemical charge-storage capabilities. The field enhancement factor is increased by 6.8 times, and the turn-on field drops by 3.5 times from an initial value of 0.35 to 0.1 V MUm(-1) as a result of the treatment. The increase in Brunauer-Emmett-Teller surface area results in about a fourfold improvement in the specific capacitance of the BP electrodes. Capacitance values before and after the treatments are 75 and 290 F g(-1) , respectively. It is predicted that this controlled surface modification technique could be put to good use in several applications based on macroscopic CNT films. PMID- 21302360 TI - Comparison of a pair of synthetic tea-catechin-derived epimers: synthesis, antifolate activity, and tyrosinase-mediated activation in melanoma. AB - Despite bioavailability issues, tea catechins have emerged as promising chemopreventive agents because of their efficacy in various animal models. We synthesized two catechin-derived compounds, 3-O-(3,4,5-trimethoxybenzoyl)-(-) catechin (TMCG) and 3-O-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin (TMECG), in an attempt to improve the stability and cellular absorption of tea polyphenols. The antiproliferative and pro-apoptotic activities of both compounds were analyzed with various cancer cell systems, and TMCG, which was easily synthesized in excellent yield, was more active than TMECG in both melanoma and non-melanoma cell lines. TMCG was also a better inhibitor of dihydrofolate reductase and was more efficiently oxidized by tyrosinase, potentially explaining the difference in activity between these epimers. PMID- 21302361 TI - Aurones as modulators of ABCG2 and ABCB1: synthesis and structure-activity relationships. AB - The ability of aurones to modulate the efflux activities of ABCG2 and ABCB1 was investigated by quantifying their effects on the accumulation of pheophorbide A (PhA) in ABCG2-overexpressing MDA-MB-231/R cells and calcein AM in ABCB1 overexpressing MDCKII/MDR1 cells. Key structural features for interactions at both ABCG2 and ABCB1 are a methoxylated ring A, an intact exocyclic double bond, and the location of the carbonyl bond on ring C. Modifications on rings B and C were less critical and served primarily to moderate activity and selectivity for one or both transporters. These SAR trends were quantified by Free-Wilson analyses and are reflected in a pharmacophore model for PhA accumulation. Several compounds were found to be equipotent with fumitremorgin C (FTC) in promoting PhA accumulation, and they also demonstrated strong affinities for ABCB1. These compounds were disubstituted on ring B with methoxy or a combination of methoxy and hydroxy groups. Taken together, our findings highlight the versatility of the aurone template as a lead scaffold for the design of dual-targeting ABCG2 and ABCB1 modulators. PMID- 21302359 TI - Synthesis, receptor binding, and CNS pharmacological studies of new thyrotropin releasing hormone (TRH) analogues. AB - As part of our search for selective and CNS-active thyrotropin-releasing hormone (TRH) analogues, we synthesized a set of 44 new analogues in which His and pGlu residues were modified or replaced. The analogues were evaluated as agonists at TRH-R1 and TRH-R2 in cells in vitro, and in vivo in mice for analeptic and anticonvulsant activities. Several analogues bound to TRH-R1 and TRH-R2 with good to moderate affinities, and are full agonists at both receptor subtypes. Specifically, analogue 21 a (R=CH3) exhibited binding affinities (Ki values) of 0.17 MUM for TRH-R1 and 0.016 MUM for TRH-R2; it is 10-fold less potent than TRH in binding to TRH-R1 and equipotent with TRH in binding to TRH-R2. Compound 21 a, the most selective agonist, activated TRH-R2 with a potency (EC50 value) of 0.0021 MUM, but activated TRH-R1 at EC50=0.05 MUM, and exhibited 24-fold selectivity for TRH-R2 over TRH-R1. The newly synthesized TRH analogues were also evaluated in vivo to assess their potencies in antagonism of barbiturate-induced sleeping time, and several analogues displayed potent analeptic activity. Specifically, analogues 21 a,b and 22 a,b decreased sleeping time by nearly 50% more than TRH. These analogues also displayed potent anticonvulsant activity and provided significant protection against PTZ-induced seizures, but failed to provide any protection in MES-induced seizures at 10 MUmol kg(-1). The results of this study provide evidence that TRH analogues that show selectivity for TRH-R2 over TRH-R1 possess potent CNS activity. PMID- 21302362 TI - The medicinal potential of promising marine macrolides with anticancer activity. AB - Marine natural products have become a major source of new chemical entities in the discovery of potential anticancer agents that potently suppress various molecular targets. In particular, the marine macrolides, which include an array of novel biomolecules endowed with outstanding cytotoxic and/or antiproliferative activities, are a prominent class of marine natural products that offer continued promise for breakthroughs in anticancer research. Herein we highlight some recent studies of promising marine macrolides, paying particular attention to their discovery, anticancer activities, mechanisms of action, chemical synthesis, and representative analogues. PMID- 21302363 TI - Continuous synthesis of tert-butyl peroxypivalate using a single-channel microreactor equipped with orifices as emulsification units. AB - The two-step synthesis of tert-butyl peroxypivalate is performed in a single channel microreactor. The first step, the deprotonation of tert-butyl hydroperoxide, is done in a simple mixer tube setup. The residence time section for the second reaction step is equipped with orifices for interfacial area renewal, needed for ensuring mass transfer between the two immiscible phases. The strong dependence of the reaction performance on the size of the interfacial area is demonstrated by using a setup with 4 orifices (distance of 52 cm), giving a HPLC yield of 71% at a residence time of 8 s and a reaction temperature of 23 degrees C. A further shortening of orifice distances helped to shorten the residence time down to 1.5 s and 0.5 s (using 9 orifices and 3 orifices with a distance of 5 cm). When using these setups, the produced heat could not be removed from the system sufficiently quickly (DeltaT=38 K). The achieved yields (ca. 70% by HPLC) are close to the state of the art (cascaded batch processing) and provide an indication that the tert-butyl peroxypivalate synthesis can be performed at higher temperatures or at least, a more flexible process control can be allowed compared to high-volume batch reactors. Processing at higher reaction temperatures up to 70 degrees C shows a slight optimum at reaction temperatures between 40 degrees C to 50 degrees C, depending on the setup used. Knowing this novel process window as well as the optimum orifice geometry and distance will allow for tailored design of the microreactor. For the processing in the single channel microreactor setup using 9 orifices (distance of 5 cm) and a reaction temperature of 40 degrees C a space-time-yield of 420,000 g L(-1) h(-1) was reached which is higher than the space-time-yield for the industrial 3 cascaded batch reactor process (190 g L(-1) h(-1)). PMID- 21302364 TI - Carbon nanotubes as nanotexturing agents for high power supercapacitors based on seaweed carbons. AB - The advantages provided by multiwalled carbon nanotubes (CNTs) as backbones for composite supercapacitor electrodes are discussed. This paper particularly highlights the electrochemical properties of carbon composites obtained by pyrolysis of seaweed/CNTs blends. Due to the nanotexturing effect of CNTs, supercapacitors fabricated with electrodes from these composites exhibit enhanced electrochemical performances compared with CNT-free carbons. The cell resistance is dramatically reduced by the excellent conductivity of CNTs and by the good propagation of ions favored by the presence of opened mesopores. As a consequence, the specific power of supercapacitors based on these nanocomposites is very high. Another advantage related to the presence of CNTs is a better life cycle of the systems. The composite electrodes are resilient during the charge/discharge of capacitors; these are able to perfectly accommodate the dimensional changes appearing in the active material without mechanical damages. PMID- 21302365 TI - Improved particle counting and size distribution determination of aggregated virus populations by asymmetric flow field-flow fractionation and multiangle light scattering techniques. AB - A method using a combination of asymmetric flow field-flow fractionation (AFFFF) and multiangle light scattering (MALS) techniques has been shown to improve the estimation of virus particle counts and the amount of aggregated virus in laboratory samples. The method is based on the spherical particle counting approach given by Wyatt and Weida in 2004, with additional modifications. The new method was tested by analyzing polystyrene beads and adenovirus samples, both having a well-characterized particle size and concentration. Influenza virus samples were analyzed by the new AFFFF-MALS technique, and particle size and aggregate state were compared with results from atomic force microscopy analysis. The limitations and source of possible errors for the new AFFFF-MALS analysis are discussed. PMID- 21302366 TI - Spatial and temporal resolution of shear in an orbiting petri dish. AB - It is well documented that physiological and morphological properties of anchored cells are influenced by fluid shear stress. Common orbital shakers provide a means of simultaneously applying shear stress to cells for tens to hundreds of cases by loading the shaker with multiple dishes. However, the complex flow in orbiting dishes is amenable to analytical solution for resolving shear created by the fluid motion only for simplified conditions. The only existing quantification of shear in this flow is an equation that estimates a constant scalar value of shear for the entire surface of the dish. In practice, wall shear stress (WSS) will be oscillatory rather than steady due to the travelling waveform and will vary across the surface of the dish at any instant in time. This article presents a computational model that provides complete spatial and temporal resolution of WSS over the bottom surface of a dish throughout the orbital cycle. The model is reasonably well validated by the analytical solution, with resultant WSS magnitudes that are within 0.99 +/- 0.42 dyne/cm(2) . The model results were compared to tangential WSS magnitudes obtained using one-dimensional optical velocimetry at discreet locations on the bottom of an orbiting dish. The experimental minimum and maximum WSS at 1 mm from the center of the dish were 6 and 7 dyne/cm(2) , respectively, whereas WSS generated from the computational model ranged from 0.5 to 8.5 dyne/cm(2) . The experimental minimum and maximum WSS at 12 mm from the center of the dish were 6 and 16 dyne/cm(2) , respectively, whereas WSS generated from the computational model ranged from 0.5 to 14 dyne/cm(2) . Discrepancies between the experimental and computational data may be attributed to a sparse sampling rate for the experimental probe, a sharp gradient at the sample area which could cause the unidirectional probe to be inaccurate if its location were not precise, and too few particles to track and a scattering of the signal by the free surface when the liquid is shallow. PMID- 21302367 TI - Transcription factors as tools to engineer enhanced drought stress tolerance in plants. AB - Plant growth and productivity are greatly affected by abiotic stresses such as drought, salinity, and temperature. Drought stress is one of the major limitations to crop productivity worldwide due to its multigene nature, making the production of transgenic crops a challenging prospect. To develop crop plant with enhanced tolerance of drought stress, a basic understanding of physiological, biochemical, and gene regulatory networks is essential. In the signal transduction network that leads from the perception of stress signals to the expression of stress-responsive genes, transcription factors (TFs) play an essential role. Because TFs, as opposed to most structural genes, tend to control multiple pathways steps, they have emerged as powerful tools for the manipulation of complex metabolic pathways in plants. One such class of TFs is DREB/CBF that binds to drought responsive cis-acting elements. Transgenic plants have been developed with enhanced stress tolerance by manipulating the expression of DREB/CBF. Recently the functions of an increasing number of plant TFs are being elucidated and increased understanding of these factors in controlling drought stress response has lead to practical approaches for engineering stress tolerance in plants. The utility of the various TFs in plant stress research we review is illustrated by several published examples. The manipulation of native plant regularity networks therefore represents a new era for genetically modified crops. This review focuses on the recent understanding, latest advancements related to TFs and present status of their deployment in developing stress tolerant transgenic plants. PMID- 21302368 TI - Acyl cystamine: small-molecular foldase mimics accelerating oxidative refolding of disulfide-containing proteins. AB - Based on the structural characteristic of Protein disulfide isomerases and DsbA that have hydrophobic regions around the active sites, hydrophobic alkyl tails are linked to cystamine to create new small molecular foldase mimics, acyl cystamine. Both the oxidizing power and oxidation specificity of cystamine are enhanced by n-octanoyl or n-hexanoyl tail. N-octanoyl and n-hexanoyl cystamine are very effective to facilitate oxidative protein refolding at strong reducing environments. In the presence of 0.42 mM DTT, the activity recovery of lysozyme is over 90% by 90-min refolding with 0.1 mM n-octanoyl cystamine and 0.1 mM cystamine as oxidant, while almost no activity is recovered with 0.2 mM GSSG by 160-min refolding. For the refolding of 0.2 mg/mL lysozyme, with 0.6 mM n hexanoyl cystamine and 1.12 mM residual DTT as redox agents, the activity recovery reaches as high as 93% after refolding for only 20 min. For ribonuclease A (RNase A) refolding, with 0.4 mM n-hexanoyl cystamine and 1.30 mM DTT, the recovery of activity reaches as high as 90% within 3 h. Thus, with n-octanoyl or n-hexanoyl cystamine as the oxidants, the necessity to remove excess DTT in the reduced and denatured protein solutions can be greatly alleviated. With a moderate hydrophobicity, n-hexanoyl cystamine is promising for application in oxidative protein refolding at an extensive concentration range. It is observed that in the oxidative refolding of 0.2 mg/mL lysozyme and RNase A, only about half of n-hexanoyl cystamine is needed when compared to cystamine to achieve the same kinetic effect. PMID- 21302369 TI - Screening for enzyme activity in turbid suspensions with scattered light. AB - New screening techniques for improved enzyme variants in turbid media are urgently required in many industries such as the detergent and food industry. Here, a new method is presented to measure enzyme activity in different types of substrate suspensions. This method allows a semiquantitative determination of protease activity using native protein substrates. Unlike conventional techniques for measurement of enzyme activity, the BioLector technology enables online monitoring of scattered light intensity and fluorescence signals during the continuous shaking of samples in microtiter plates. The BioLector technique is hereby used to monitor the hydrolysis of an insoluble protein substrate by measuring the decrease of scattered light. The kinetic parameters for the enzyme reaction (V(max,app) and K(m,app)) are determined from the scattered light curves. Moreover, the influence of pH on the protease activity is investigated. The optimal pH value for protease activity was determined to be between pH 8 to 11 and the activities of five subtilisin serine proteases with variations in the amino acid sequence were compared. The presented method enables proteases from genetically modified strains to be easily characterized and compared. Moreover, this method can be applied to other enzyme systems that catalyze various reactions such as cellulose decomposition. PMID- 21302370 TI - Protease digestion from wheat stillage within a dry grind ethanol facility. AB - As the current starch based ethanol market increases at its rapid pace, finding new markets for the primary coproduct, distiller's grains, has gained considerable interest. One possibility is to isolate the protein-rich fraction for use as precursors to biochemicals and bioplastics, further decreasing fossil fuel consumption. This research focuses on enzymatic extraction of protein peptides from wheat heavy stillage using commercially available proteases. The energy saved due to this process ranged from ~ 1.5 to 3.0 GJ/ton wheat stillage compared to fossil fuel-based chemicals. Using Protex 6L (Genencor), ~ 57% of the protein in the stillage was soluble 24 h after protease addition at 0.1% w/w loading. Of these proteins, ~ 32% were already soluble, indicating the importance of using wet heavy stillage as the feedstock rather than dried distiller's grains. Peptide size was less than 6 kDa. Further improvements in protein removal may be obtained through a fed batch addition of protease and improved protease cocktails. PMID- 21302371 TI - Protein and solute distribution in drug substance containers during frozen storage and post-thawing: a tool to understand and define freezing-thawing parameters in biotechnology process development. AB - Active pharmaceutical ingredient for biotechnology-based drugs, commonly known as drug substance (DS), is often stored frozen for longer shelf-life. Freezing DS enhances stability by slowing down reaction rates that lead to protein instability, minimizes the risk of microbial growth, and eliminates the risk of transport-related stress. High density polyethylene bottles are commonly used for storing monoclonal antibody DS due to good mechanical stress/strain resistant properties even at low temperatures. Despite the aforementioned advantages for frozen storage of DS, this is not devoid of risks. Proteins are known to undergo ice-water surface denaturation, cryoconcentration, and cold denaturation during freezing. A systematic investigation was performed to better understand the protein and solute distribution along with potential of aggregate formation during freeze and thaw process. A significant solute and protein concentration gradient was observed for both frozen and thawed DS bottles. In case of thawed DS, cryoconcentration was localized in the bottom layer and a linear increase in concentration as a function of liquid depth was observed. On the other hand, for frozen DS, a "bell shaped" cryoconcentration distribution was observed between the bottom layers and centre position. A cryoconcentration of almost three-fold was observed for frozen DS in the most concentrated part when freezing was conducted at -20 and -40 degrees C and 2.5-fold cryoconcentration was observed in the thawed DS before mixing. The information obtained in this study is critical to design freeze thaw experiments, storage condition determination, and process improvement in manufacturing environment. PMID- 21302372 TI - [Can the occupational health physician promote work as a health factor?]. AB - This report answers the question: "In carrying out his/her institutional tasks, can the Occupational Health Physician (MC--medico competente--in Italian) promote work as a health factor?" The answer is in the affirmative, with identification of the social and regulatory framework within which the occupational health physician operates, examples of professional activities directed towards this aim and stressing the fact that the physician requires clinical skills so that he/she can work actively in the process of diagnosis-treatment-rehabilitation of the sick worker. Furthermore technological and organizational knowledge of the enterprise is required together with knowledge of the "social safeguards", that are useful for both the worker and the enterprise that employs him/her. In the current social and regulatory context the occupational health physician can promote work as a health factor both through cooperation in the process of improvement of the workplace, and by actively participating in the most appropriate placement of "frail" workers' (elderly people, disease sufferers, the disabled). It is necessary for the occupational health physician to develop a close working cooperation with the business system to achieve these aims. PMID- 21302373 TI - [Atopic eczema]. PMID- 21302377 TI - [Tobacco smoking cessation as covered cost for COPD patients? Therapy goal: smoking cessation without relapse]. PMID- 21302378 TI - Evidence-based guideline update: Determining brain death in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology. PMID- 21302379 TI - "The case for boosting infant male circumcision in the face of rising heterosexual transmission of HIV" ... and now the case against. Comment. PMID- 21302380 TI - "The case for boosting infant male circumcision in the face of rising heterosexual transmission of HIV" ... and now the case against. Comment. PMID- 21302381 TI - "The case for boosting infant male circumcision in the face of rising heterosexual transmission of HIV" ... and now the case against. Comment. PMID- 21302382 TI - "The case for boosting infant male circumcision in the face of rising heterosexual transmission of HIV" ... and now the case against. Comment. PMID- 21302383 TI - Medicine and management: will we ever cross the divide? PMID- 21302384 TI - Outbreak news. Yellow fever, Uganda. PMID- 21302385 TI - Leptospirosis: an emerging public health problem. PMID- 21302386 TI - Community-based model for speech therapy in Thailand: implementation. AB - OBJECTIVES: To establish a Community-Based Model for Speech Therapy in Thailand and to implement it. MATERIALS AND METHOD: The development of a Community-Based Model for Speech Therapy was based on the principles of primary healthcare, community-based rehabilitation and institutional sharing. Workshops for speech and language pathologists (SLPs), including "Training for Trainers" and six "Smart Smile & Speech" workshops were held. We held 1) a workshop for training SLPs in how to manage speech and language problems in cleft lip and palate (CLP); 2) a workshop for training healthcare providers who are not speech and language pathologists (para-speech and language pathologists: para-SLPs) how to identify speech, language and hearing problems in CLP and undertake early intervention; and, 3) four speech camps for continuing education via life demonstration and practice. RESULTS: Standard guidelines were produced for SLPs to remedy speech and language disorders in children with CLP in Thailand and para-SLP manuals for speech and language intervention for CLP were developed. Para-SLPs will be better equipped to identify and then provide early intervention for individuals with CLP, as well as to refer children with CLP and complicated speech and language disorders to speech clinics for the further management. Percentage of agreement among SLP, audiologists and para-SLPs ranged 50-93.33 while the Kappa coefficients ranged -0.07 to 0.86. CONCLUSION: The Community-Based Model for Speech Therapy for Children with CLP was an appropriate approach for coming up with solutions for the lack of speech services for children with CLP in Thailand. PMID- 21302387 TI - Thai speech and language norms for children 2 1/2 to 4 years of age. AB - OBJECTIVE: To create a Thai speech and language assessment tool and norms for children between 2 1/2 and 4 years of age (TSLT21/2-4). MATERIAL AND METHOD: The Thai speech and language assessment tool was created for children between 2 1/2 and 4 years of age using existing Thai and English speech and language development theory, research results and tests. In order to validate the norms, the speech and language skills were prospectively assessed in 4,169 normal children representing the five regions of Thailand. Language quotients, percentiles and Conbrach's Alpha coefficients were calculated for use as a reference for Thai language development norms. RESULTS: Speech and language norms for children age 2 1/2-4 years were presented. Most of the Cronbach's Alpha coefficients were good (equal or more than 70%). CONCLUSION: The Thai speech and language assessment tools and norms are useful for the assessment of speech and language for children with risk for delayed speech and language development (e.g., individuals with cleft lip and palate, global development delay, autism) in Thailand. The norms can also provide the guideline for "intervention planning". PMID- 21302388 TI - Development and reliability of the THAICLEFT Quality of Life Questionnaire for children with cleft lip/palate and families. AB - OBJECTIVE: The objective of this study was to develop and test the reliability of the THAICLEFT Quality of Life (QoL) questionnaire for families of children coping with the problems associated with cleft lip/palate (CLP). MATERIAL AND METHOD: After reviewing the literature on QoL measurements, the THAICLEFT QoL questionnaire was developed. The 27 families registered with the Tawanchai CLP service registry completed the questionnaire. RESULTS: The Cronbach's alpha, i.e., the internal consistency and reliability, of 24 Quality of Life questionnaires was calculated. Values > 0.7 are considered acceptable and the value of the THAICLEFT QoL questionnaire was 0.861. CONCLUSION: Using the THAICLEFT QoL questionnaire can help the healthcare provider to support parents and understand whether they are able to care for the patients and their psycho economic needs. PMID- 21302389 TI - Primary bilateral cleft lip-nose repair: the Tawanchai Cleft Center's integrated and functional reconstruction. AB - BACKGROUND: The repair of a bilateral cleft is more difficult than a unilateral repair because of numerous anatomical challenges, such as difficulty of repairing the skin and muscle overlying the protruded premaxilla and bilateral nasal reconstruction with shortening of the columella. An optimum outcome is achieved when all of the deformities of the primary cleft palate, the problems of scar and secondary deformities have been addressed. OBJECTIVES: To propose an integrated and functional reconstruction of the primary bilateral cleft lip-nose repair and to present the preliminary outcomes of this technique and its advantages. MATERIAL AND METHOD: An integrated, functional reconstruction process includes: 1) analysis of the bilateral cleft deformities; 2) interdisciplinary management and use of Tawanchai Center's protocol for cleft lip and palate care; 3) pre surgical orthopedic treatments; and, 4) integrated primary cleft lip-nose repair and post-operative management. This approach to repair includes: 1) design of a prolabial flap and a modified, rotation advancement technique for skin surgery; 2) functional muscle reconstruction; 3) correction of nasal deformities and columella lengthening; 4) reconstruction of the vermillion; and, 5) final skin closure. RESULTS: Between 2002 and 2010, this technique was performed and evaluated on 42 patients who received primary bilateral cleft lip-nose repair, including 31complete, 6 incomplete and 5 right complete and left incomplete, 27 males and 15 females. Six parameters (scar, Cupid's bow symmetry, vermillion border symmetry, philtrum anatomic fidelity, muscle function and nasal symmetry) were used for evaluating the results, based on 4 scales (0-3) by 2 plastic surgeons. Among the mean scores better rating scales were achieved in philtrum anatomic fidelity (0.69) and Cupid' bow symmetry (0.76) while the mean of the less satisfactory rating scale was found in scar (1.13) and nasal asymmetry (0.96). These preliminary outcomes showed satisfactory results. Secondary reconstruction is less difficult and may be performed at the age of 4-6 years if indicated. DISCUSSION AND CONCLUSION: The authors introduced the Tawanchai Center's integrated concepts and functional reconstruction technique for bilateral cleft lip-nose repair. The technique offers the advantages of an integrated assessment for all of the deformities of the primary cleft palate, the design of an integrated technique together with proper peri-operative care, presurgical orthodontic treatment, and a well-coordinated, holistic, interdisciplinary management. A satisfactory preliminary outcome was demonstrated but more improvement of the outcome can be achieved by: 1) continuing assessment of this group of patients until they reach maturity; 2) refining techniques; 3) improving interdisciplinary care; and, 4) setting benchmarks for the outcome. PMID- 21302390 TI - Application of Geographic Information System (GIS) for management of cleft lip palate care at the Tawanchai Cleft Center. AB - OBJECTIVE: To use a Geographic Information System (GIS) approach to study the distribution and statistics of patients with cleft lip/palate in Thailand's Northeast region who get treatment at Srinagarind Hospital, Khon Kaen University. MATERIAL AND METHOD: Using a GIS approach, the researchers reviewed every case with cleft lip/palate treated at Srinagarind Hospital between 1984 and 2007 to study the distribution of cleft lip/palate in Northeast Thailand. RESULTS: Of the 1,950 patients, there were more male patients (56.3%) with cleft lip/palate than females (43.7%). One-third (31.8%) of the patients had cleft lip only, while 22.5% had cleft palate only and 45.7% had both cleft lip and cleft palate. Most of the patients (55.1%) lived in Khon Kaen, 24.9% in Mahasarakam and 16.9% in Kalasin provinces. Since 2002, more patients have had surgical treatment at the ages and intervals recommended by our centre's protocol. DISCUSSION AND CONCLUSION: Most of the patients who have got treatment at The Tawanchai Center lived in central and northern Northeast Thailand: most lived in Khon Kaen province. More of the patients tended to get surgery on time, according to the establishment of The Tawanchai Center's interdisciplinary protocol for cleft lip and cleft palate care; however some were still getting the surgery late. The GIS data was very useful for the Cleft Center for planning outreach, community-based interdisciplinary treatment, referrals, preparing a schedule for follow-up and follow-on treatments; thus, improving care for the patients with cleft lip/palate. PMID- 21302391 TI - The promotion of exclusive breastfeeding in infants with complete cleft lip and palate during the first 6 months after childbirth at Srinagarind Hospital, Khon Kaen Province, Thailand. AB - BACKGROUND: Breastfeeding is especially important for infants with cleft lip and/or cleft palate because it helps prevent nasal septum irritation, decreases the number of ear infections, and provides a sort of psychologically support for the postpartum mothers. It is difficult for a baby born with a cleft lip and/or cleft palate to suck milk out of the breast or bottle. OBJECTIVE: This study aimed to 1) promote exclusive breast-feeding in infants with CL-CP during their first 6 months after delivery and 2) examine risk factors related to the success of exclusive breastfeeding. MATERIAL AND METHOD: A counseling session provided by a special trained nurse is arranged for the parents of these infants as the earliest after birth. The mothers were advised that the best breastfeeding position either cross cradle or football position. The mothers were instructed to support their breasts with four fingers underneath and press their thumb on top to squeeze breast milk to help the babies with CL-CP get enough milk. The breast squeezing should be related to baby's sucking, swallowing and breathing rhythm. The infant weight gain after birth, their comfort, 6-8 urine per day, and 1 - 2 stool per day were used as the indications of breastfeeding success. RESULTS: Twenty infants were included in this study. A follow up after hospital discharge was set at 1 week 1, 2, 3, 4 and 6 months to provide continuously breastfeeding support for the mothers. After the 6-month period, we found that 2 infants were exclusively breastfed for 6 months and continued to have breast milk until 15 and 18 months of age, 2 infants had breastfeed for less than 2 months, and 16 infants for 3-4 months. Employment status played an important factor for the breastfeeding success among the mothers of CL-CP infants. The only 2 mothers able to provide 6 months exclusive breastfeeding did not work while the mothers who could not continue their breastfeeding reported that they felt very exhausted having to go to work and breastfeed their babies when they returned back home. CONCLUSION: This study revealed that exclusive breastfeeding for CL-CP infants can be achieved when the relationship between infants, parents and their families were established. PMID- 21302392 TI - Distraction osteogenesis treatment of maxillary deficiency for cleft patient using internal distraction device: a case report. AB - A case of severe maxillary hypoplasia in a 21 years old male Thai patient with a complete unilateral cleft of primary and secondary palates treated by internal distraction osteogenesis for maxillary advancement is presented. Initial evaluation showed Class III malocclusion with total crossbite and Class III skeletal malrelationship. Two intraoral distractors were placed following a Le Fort I osteotomy. A maxillary advancement of 8 mms was obtained with 1 mm overjet. Following distraction, Class III elastics were used to increase the overjet until an overjet of 3 mms was obtained. Both acceptable skeletal and soft tissue relationships and satisfactory occlusion have been produced. After 20 months of postoperative follow-up, the occlusal result is stable and skeletal relapse can not be detected. PMID- 21302393 TI - The assessment of treatment outcome by evaluation of dental arch relationships in cleft lip/palate. AB - Cleft lip/palate (CLP) patients need an interdisciplinary team approach for optimal treatment, care and results. Evaluation of the treatment outcomes is essential to allow for identification and implementation of the highest possible standard of care. The aim of this paper is to present the less invasive methods of assessment of treatment outcomes by evaluation of dental arch relationships in both unilateral and bilateral CLP. PMID- 21302394 TI - Effect of curcumin on vascular endothelial growth factor expression in diabetic mice kidney induced by streptozotocin. AB - OBJECTIVE: To localize and demonstrate the effect of curcumin on vascular endothelial growth factor in diabetic mice kidney induced by streptozotocin. MATERIAL AND METHOD: Diabetic mice were induced by streptozotocin (60 mg/kg BW). Male mice were divided into three groups, control mice, diabetic mice (DM) and diabetic mice treated with curcumin (DMC) (200 mg/kg BW). At 4 and 8 weeks, animals were sacrificed and kidneys were processed by immunohistochemistry technique. RESULTS: At the end of 4 and 8 week experiments, glomeruli were slightly enlarged and showed diffuse thickening of the glomerular capillary walls in diabetic mice. Administration with curcumin presented the better improvement and recovery of cells and tissues compared with diabetic mice. Immunohistochemical staining for vascular endothelial growth factor (VEGF) demonstrated that VEGF was mainly detected in the podocytes and renal tubules. There was an increase in VEGF expression in diabetic mice as compared to control. Treatment with curcumin significantly inhibited the expression of VEGF in the kidney tissue of diabetic mice in both 4 and 8 weeks. Comparing the diabetic mice between 4 and 8 week experiments, the expression of VEGF in the podocytes and renal tubules at 8 week were significantly stronger than at 4 week which represented time-dependent change. Nevertheless, the intensity of VEGF was not different in DMC mice when it was compared between 4 and 8 weeks. CONCLUSION: VEGF immunoreactivity of the podocytes and the renal tubules at 4 and 8 weeks in DM mice showed strong intensity more than in control mice. However, the intensity of VEGF in DMC mice was less when it was compared with DM mice. Moreover, VEGF was a key modulator of angiogenesis and a potent mitogen for endothelial cells. These results demonstrated the potential use of antiangiogenic curcumin as a novel therapeutic agent in diabetic mellitus and maintain normal structure of the kidney. PMID- 21302395 TI - Blepharoptosis repaired by frontalis-orbicularis oculi flap: a new technique. AB - BACKGROUND: The treatment of blepharoptosis depends on the degree of ptosis and the function of the levator muscle. In cases of severe blepharoptosis, however, the levator muscle is essentially nonfunctional, thus frontal sling procedure, a static correction method, is usually performed. Recently the orbicularis oculi flap has become popular but lagopthalmos is still a bothersome problem. A new technique has been introduced in order to reduce the lagopthalmos. MATERIAL AND METHOD: Our technique is modified from a technique using double breast frontalis orbicularis oculi muscle flap. The technique enhances mobility and amount of the pretarsal orbicularis oculi muscle and is devoid of vertical cutting of the flap and orbital septum involvement. RESULTS: The technique was performed in 8 patients (12 lids) between 2007 and 2008. All patients were congenital and had severe ptosis. All of them were able to close their eyelids completely by 2 weeks. There was no complication in the series. CONCLUSION: This novel technique yields an excellent result in cases of severe blepharoptosis. The technique is superior to the technique using frontalis muscle flap because there is only one incision, no forehead depression and no neurovascular injury. In addition, this technique also reduced period of lagopthalmos compared with the original technique. PMID- 21302396 TI - A whole blood lymphocyte proliferation assay in healthy Thais: comparison of heparinized blood and acid citrate dextrose blood. AB - The lymphocyte proliferation assay (LPA) is a technique to determine T-lymphocyte functions in vitro. The standard LPA using peripheral blood mononuclear cells (PBMC) separated from heparinized blood requires a large blood sample, time consuming and expensive. It is more useful if acid citrate dextrose (ACD) blood could be used not only for LPA but also for other purposes. To determine whether whole blood composing between heparinized blood and ACD blood could be substituted for standard LPA using PBMC. Heparinized and ACD blood of 35 healthy Thai blood donors were studied herein. PBMC separated by density gradient centrifugation and diluted heparinized and ACD blood were used to test and compare for lymphoproliferative responses to phytohemagglutinin (PHA), pokeweed mitogen (PWM), and tetanus toxoid. A stimulation index (SI) for each mitogen or antigen was calculated. All Thai blood donors demonstrated positive proliferative responses to PHA and PWM by using PBMC and whole blood culture assays from both heparinized and ACD blood. However, the difference in the frequency of positive proliferative responses to tetanus toxoid by using PBMC and whole blood culture assays was significant. Nevertheless, no significant difference in frequency of positive responses to tetanus toxoid between heparinized and ACD blood was observed. This results suggested that no significant difference between using heparinized and ACD blood in standard LPA using PBMC. However, the whole blood LPA for measuring mitogen induced lymphoproliferation could be substituted for standard LPA from heparinized andACD blood. Whole blood LPA is easy, rapid, and more cost effective than PBMC culture assay. Thus, it would be applicable in a clinical laboratory as well as in research setting. PMID- 21302397 TI - Prevalence of overweight and obesity among school children in suburb Thailand defined by the International Obesity Task Force Standard. [corrected]. AB - BACKGROUND: Overweight and obesity is an emerging problem among children worldwide. Body mass index (BMI) is widely used to define overweight and obesity as it correlates well with high accuracy to measure body fatness. OBJECTIVE: Aim of the present study is to determine the prevalence of obesity in Thai school children by using the International Obesity Task Force (IOTF) standard. MATERIAL AND METHOD: The school based cross-sectional study was conducted in 1,140 children aged 6-15 years in Ongkharak, Thailand. Anthropometric measurements including weight and height were obtained to determine BMI. The results were analyzed statistically by applying student t-test, and Chi-square test. RESULTS: The prevalence of overweight and obesity among school children in suburb Thailand was 12.8% and 9.4%, respectively. There were no significant differences in prevalence of overweight and obesity between gender splits and between age specific groups. CONCLUSION: The prevalence of overweight and obesity has been dramatically increasing among Thai children. Further long-term follow-up studies are required to determine the growth pattern of children with higher BMI for age and to survey for obesity-related co-morbid condition in Thai children. PMID- 21302398 TI - Development of a medical expert system for the diagnosis of ectopic pregnancy. AB - OBJECTIVE: To developed a software-based medical expert system for supporting in the diagnosis of ectopic pregnancy. MATERIAL AND METHOD: This system was developed to facilitate the knowledge creation and inference engine. The diagnostic process used the interactive backward chaining inference algorithm. The medical knowledge base was represented as production rules which performed in tree structure. The system designed to interact with users in question information form. After that, the clinical data from medical records of patients were applied to the system by physician retrospectively. RESULTS: Thirty-two medical records of women who diagnosed ectopic pregnancy were reviewed. The mean patients' age was 27.7 years. The majority of the patients were multigravida gestation. There were twenty-one patients who did not have any risk factors of ectopic pregnancy. 31 of patients' clinical data applied to the system successfully. All of them had correspondent diagnosis with established ectopic pregnancy. CONCLUSION: This medical expert system was found to be a good tool to facilitate the decision making in the diagnosis of ectopic pregnancy. PMID- 21302399 TI - The results of ankle arthrodesis with screws for end stage ankle arthrosis. AB - Aim of this study was to evaluate the results of ankle arthrodesis with screws in patients with ankle arthrosis. The author studied 19 patients (20 feet) who had been treated by ankle arthrodesis with screws from 2003 to 2008. Ten patients were men (11 feet) and nine (9 feet) were women. Their mean age was 56 years (30 to 65), and the average duration of follow-up was four years (2 to 6). Two compression screws were used in all feet. Union was achieved in 19 of the 20 feet (95%). Average scores for pain and clinical condition are increase after operation. One re-operation was performed for nonunion. Author conclude that ankle arthrodesis with screws was effective treatment for ankle arthrosis. PMID- 21302400 TI - Comparative study of two central corneal thickness measurements in glaucoma patients. AB - BACKGROUND: Goldmann applanation tonometry (GAT) has been the gold standard for IOP measurements in glaucoma patients. The accuracy of GAT measurements is dependent on many factors, particularly the central corneal thickness (CCT) has been shown to have effect on IOP measurements. OBJECTIVE: To compare of two central corneal thickness measurements in glaucoma patients. MATERIAL AND METHOD: Forty-five right eyes of 45 patients were enrolled. All patients underwent a complete ophthalmologic examination. CCT measurements were performed with an ultrasound pachymeter on two different visits. Patients presenting Diabetes Mellitus (DM), previous history of intraocular surgery and laser were excluded. Antiglaucoma medications were allowed to use during the study. For statistical analysis, paired t-test was used. RESULTS: In the present study, the mean age of patients was 59.18 years. (range 40-91 years). Twenty-one patients (46.7%) were male and twenty-four patiens (53.3%) were female. The interval between two measurement periods was 8.42 weeks (range 2-24 weeks). The mean CCT values were not significantly different between the two visit (521.29 micron SD 32.52 micron and 518.76 micron SD 33.26 micron; p = 0.15). CONCLUSION: In the present study which excluded patients with DM, previous history of intraocular surgery and laser treatment was shown that there was no statistically significant difference in CCT measurements on different occasions. PMID- 21302401 TI - Influence of capsicum extract and capsaicin on endothelial health. AB - OBJECTIVE: To examine the effect of Capsicum spp extract (CEX) and capsaicin (CAP) on endothelial nitric oxide release and protection against lipopolysaccharide (LPS)-induced cellular apoptosis. MATERIAL AND METHOD: Human umbilical vein endothelial cells (HUVEC) were isolated from newborn cords. Evaluation of cytotoxicity was performed by MTT assay. Endothelial nitric oxide (NO) production was evaluated by Griess reaction. Alteration in eNOS expression was detected by westernblot analysis. To induce oxidative stress and apoptosis, lipopolysaccharide (LPS) was coincubated with HUVEC in the presence or absence of CEX or CAP, and the vanilloid receptor blocker capsazepine (CZP). Hoechst nuclear staining was used to determine percent apoptotic nuclei. RESULTS: The highest concentrations of CEX (1000 microg/mL) and CAP (25 microM) used in the study did not induce cytotoxicity in HUVEC. Significant increase in NO release was observed when cells were incubated with CEX (100 microg/mL) and CAP (25 microM) and this effect was inhibited by CZP only in CAP treatment group. Despite enhanced NO generation was observed, western blot analysis indicated no change in eNOS expression. Interestingly, endothelial cells incubated with L-arginine (L-ARG, 1000 microg/mL) alone significantly showed increased NO production while L-ARG co incubation abrogated CEX or CAP effects on endothelialNO generation. CEX (10 microg/mL) and CAP (1 microM) decreased apoptotic nuclei in HUVEC treated with LPS. CONCLUSION: CEX and CAP improved endothelial function and protected against LPS-induced apoptosis. Regular consumption of Capsicum spp. may promote endothelial health and reduce cardiovascular disease risk. PMID- 21302402 TI - The prevalence of snoring in Thai pregnant women. AB - OBJECTIVE: To determine the prevalence of snoring in Thai, pregnant women. MATERIAL AND METHOD: This study was carried out from April 2008 through August 2008 at the antenatal clinic, HRH Princess Maha Chakri Sirindhorn Medical Center Nakorn Nayok province. Two hundred and thirty-eight pregnant women were enrolled. All subjects answered the Berlin questionnaire; this include information on age, weight, height, gravid health status, gestational age, witnessed incidences of snoring, and symptoms associated with sleep apnea. The description of snoring as frequency, volume, complaints from other people and bouts of sleep apnea were recorded and analyzed. RESULTS: The prevalence of snoring in pregnancy was 35.29%. The snoring volume, recorded as slightly louder than breathing, in this group was 91.67%. One-fourth of the cases presented with snoring approximately 3 4 times a week with complaints of snoring bothering other people. The incidence of sleep apnea was found in 5.95% of this group. CONCLUSION: The prevalence of snoring was found in approximately one-third of the pregnant women screened. PMID- 21302403 TI - Psychological problems and overweight in medical students compared to students from Faculty of Humanities, Srinakharinwirot University, Thailand. AB - BACKGROUND: Medical students have a high prevalence of stress, depression, daytime sleepiness, sleep deprivation and overweight. The students from the social sciences such as Faculty of Humanities, may have different problems. The aim of this study was to compare the epidemiology of stress, depression, daytime sleepiness, sleep deprivation and overweight of medical students with students from Faculty of Humanities, Srinakharinwirot University. MATERIAL AND METHOD: Total of 646 students from Faculty of Medicine and 103 students from Division of Children's Literature, Faculty of Humanity from Srinakharinwirot University were selected; the response rate was 75% and 83.5%, respectively. The design was cross sectional study. Each participant was evaluated by Health-Related Self-Reported (HRSR) Scale from Psychological Department, Ministry of Public Health, Suanprung stress test from Suanprung Hospital, Thailand, and Epworth sleepiness scale during February, 11th 2008 to March, 4th 2008. Categorical variables were analyzed using the Chi-square test or Fisher exact test and p-value less than 0.05 was considered significant. RESULTS: The prevalence of depression in medical students was 11.5% and the prevalence of depression in students from Faculty of Humanities was 12.2%. Medical students in clinical class had high to severe stress more than medical students in pre-clinical class and had the most sleep deprivation on class 6. Male medical students had sleep deprivation and overweight more than female. Medical students with underlying diseases had high to severe stress, but students from Faculty of Humanities had depression. Medical students had odds ratio of stress and sleep deprivation 0.61 and 0.39, respectively compared to the students from Faculty of Humanities. CONCLUSION: The students from Faculty of Humanities had high to severe stress and sleep deprivation more than medical students but they were the same as depression, excessive daytime sleepiness and overweight. The administrators of each faculty should adjust the curriculum and train the advisors to support their students. PMID- 21302404 TI - Middle cerebral artery peak systolic velocity in fetuses with homozygous alpha thalassemia-1: case series. AB - OBJECTIVES: The objective of this study is to evaluate the potential usefulness of middle cerebral artery peak systolic velocity (MCA-PSV) as a non-invasive means of detecting an anemic fetus from homozygous alpha-thalassemia-1. MATERIAL AND METHOD: We observed four cases of referrals with complicated pregnancies in which the fetuses were suspected with homozygous alpha-thalassemia-1. Three out of four cases involved hydrop fetalis, detected through previous ultrasounds, while the remaining case was referred for prenatal diagnosis. Subsequently, we performed a detailed ultrasound and fetal MCA-PSV in all cases, and to confirm the diagnosis, we also performed cordocentesis. RESULTS: With all the four cases having the gestational age range from 18 to 27 weeks, three showed hydrop fetalis. The remaining case, the 18-week gestational age fetus referred for prenatal diagnosis, showed an increase in the cardiothoracic ratio without other signs of hydrop fetalis. MCA-PSV suggested the presence of fetal anemia in all cases (with the velocity ranging from 37.3 to 62.2 cm/sec). The results obtained from cordocentesis confirmed fetal anemia and homozygous alpha-thalassemia-1 in all cases. CONCLUSION: Peak systolic velocity of fetal middle cerebral artery can predict anemia in fetus affected with homozygous alpha-thalassemia-1 disease. PMID- 21302405 TI - An exploratory study on association between family relationship and relapse among methamphetamine users in Compulsory Treatment System of Khon Kaen and Yasothon Provinces. AB - BACKGROUND: It was estimated that 3.5 million Thais have ever used "Yaba (methamphetamine)" at least once in their entire life. The Northeastern region had the highest number of Yaba users with a high relapse rate after treatment. OBJECTIVE: The authors aimed to explore the association between relapse, among methamphetamine users in the Compulsory Treatment System of Khon Kaen and Yasothon Provinces, and family relationship as well as other contextual factors. MATERIAL AND METHOD: An exploratory study was conducted from all cases of post treatment methamphetamine users in the databases of Khon Kaen Drug Dependence Treatment Center and Yasothorn Provincial Probation Office during October 2007 and February 2008. Interviews and observations were done for data collection. Double data entry was applied. Pearson Chi-square, Fisher's exact test and odds ratio were used to assess the associations. RESULTS: Sixty-five users were found (13 relapses and 52 abstainers). Family relationship revealed no significant association with relapse of the methamphetamine users. Other contextual factors, however, did. They were social acceptance [acceptance by community leader (p = 0.006), acceptance for working or studying (p = 0.049)], risky community situations [using Yaba of close friend, existence of Yaba users and Yaba trading in community (p = 0.014, p < 0.001 and p = 0.038 respectively)] and risky personal behaviors [ever selling or being a Yaba agent and drinking of alcohol to reduce Yaba desire (p = 0.012 and p = 0.013)]. CONCLUSION: Effect of family relationship on relapse among post-treatment methamphetamine users could not be demonstrated in the present study. But several contextual factors had significant relationship with the relapse. PMID- 21302406 TI - Health behaviors in the development and maintenance process of homosexual identity. AB - BACKGROUND: Health behaviors of men who have sex with men (MSM) affect their health status in many aspects. Rate of HIV infection among Thai male prostitutes in 2005 was 15.4%. Among these, 28.3% were MSM. Thirty percent of youth suicides were conducted by gays and lesbians. OBJECTIVE: To explore the health behaviors related to the development and maintenance process of men who have sex with men. MATERIAL AND METHOD: This was a qualitative study. The study population was MSM in Mukdahan province. The subjects were recruited gradually, by snowball sampling, until the required data were saturated. In-depth interviews and participant observations were performed over a period of 17 months. A triangulation technique was applied to check reliability of the data. Data were analyzed by content analysis and compared with the Troiden's stages of development and maintenance process of homosexual identity. RESULTS: Eleven Thai MSM were recruited and followed up. Health behaviors of them were different according to the stages of development and maintenance process regarding Troiden's theory. Physical, psychological, social and sexual aspects of health behaviors were identified in various stages. It was found that many factors affect health behaviors of MSM. These include health promoting and undermining factors. CONCLUSION: Health behaviors of MSM varied in each stage of development and maintenance of homosexual identity. Health promotion campaigns and policies for MSM should be designed accordingly. PMID- 21302407 TI - Relationship between the ability to change from a supine to a sitting position at admission and mobility outcomes after stroke rehabilitation. AB - BACKGROUND: Regarding observations, stroke patients able to change their basic body position from supine to sitting at admission usually could walk by the end of rehabilitation. However, there was not yet supported by any research evidence. OBJECTIVE: To study the relationship between the patient's ability at admission to change basic body position from a supine to a sitting position and the mobility outcome after stroke rehabilitation. MATERIAL AND METHOD: Data were gathered and analyzed from the case record forms (including the Barthel ADL Index assessment sheets) of 327 stroke patients in nine tertiary in-patient rehabilitation settings in Thailand between March and December 2006. RESULTS: On admission, 58.7% of the patients were able to change their basic position from supine to sitting. At the end of rehabilitation, the group which was able to sit had a higher mobility sub-score (OR = 6.15; 95% CI 3.24 -11.67) and total Barthel ADL index score (OR = 9.64; 95% CI 5.74-16.18) than the group which was unable to sit. CONCLUSION: The ability at admission to change from a supine to a sitting position was significantly related to a better mobility outcome after stroke rehabilitation. PMID- 21302408 TI - Comparative study for the detection of C4d in paraffin-embedded renal allograft biopsies by immunohistochemical techniques. AB - BACKGROUND: Peritubular capillary complement C4d deposition is one of the criteria for diagnosis of acute humoral rejection in kidney allografts. Little information is provided for the effective technique to stain C4d protein. OBJECTIVE: To compare C4d staining results by using indirect immunofluorescence detection (IF) with immunoperoxidase methods (IP) in formalin-fixed, paraffin embedded renal allograft tissue. MATERIAL AND METHOD: C4d protein was detected in renal allograft tissues by IF and IP methods. The antigen unmarking procedures were used including (i) heating with 0.05% citraconic anhydride in a water bath plus proteinase K digestion, (ii) heating with 10 mM citrate buffer in a microwave and (iii) digesting with proteinase K for comparing the deposition of C4d in paraffin-embedded tissues. RESULTS: The results showed that the unmarking solution containing 0.05% citraconic anhydride pH 7.4 and heating in a water bath revealed a signal enhancement in the IP method whereas the solution containing 0.05% citraconic anhydride pH 7.4 and heating in a water bath plus proteinase K digestion showed a greatly enhanced signal in the IF method. The prevalence of C4d staining detected in peritubular capillaries was 68% (17/25) and the results observed for both methods were similar. CONCLUSION: 0.05% citraconic anhydride in a water bath with or without proteinase K digestion is useful for unmasking C4d deposition in peritubular capillaries of renal allografts performed by IP and IF methods. PMID- 21302409 TI - Monitoring coral reefs, seagrasses and mangroves in Costa Rica (CARICOMP). AB - The coral reefs, seagrasses and mangroves from the Costa Rican Caribbean coast have been monitored since 1999 using the CARICOMP protocol. Live coral cover at Meager Shoal reef bank (7 to 10 m depth) at the Parque Nacional Cahuita (National Park), increased from 13.3% in 1999, to 28.2% in 2003, but decreased during the next 5 years to around 17.5%. Algal cover increased significantly since 2003 from 36.6% to 61.3% in 2008. The density of Diadema antillarum oscillated between 2 and 7ind/m2, while Echinometra viridis decreased significantly from 20 to 0.6ind/m2. Compared to other CARICOMP sites, live coral cover, fish diversity and density, and sea urchin density were low, and algal cover was intermediate. The seagrass site, also in the Parque Nacional Cahuita, is dominated by Thalassia testudinum and showed an intermediate productivity (2.7 +/- 1.15 g/m2/d) and biomass (822.8 +/- 391.84 g/m2) compared to other CARICOMP sites. Coral reefs and seagrasses at the Parque Nacional Cahuita continue to be impacted by high sediment loads from terrestrial origin. The mangrove forest at Gandoca, within the Refugio Nacional de Vida Silvestre Gandoca-Manzanillo (National Wildlife Refuge), surrounds a lagoon and it is dominated by the red mangrove, Rhizophora mangle. Productivity and flower production peak was in July. Biomass (14 kg/m2) and density (9.0 +/- 0.58 trees/100 m2) in Gandoca were relatively low compared to other CARICOMP sites, while productivity in July in Costa Rica (4 g/m2/d) was intermediate, similar to most CARICOMP sites. This mangrove is expanding and has low human impact thus far. Management actions should be taken to protect and preserve these important coastal ecosystems. PMID- 21302410 TI - Temporal and spatial distribution patterns of echinoderm larvae in La Parguera, Puerto Rico. AB - This study describes temporal and spatial abundance patterns of echinoderm larvae in La Parguera, Puerto Rico. For the temporal study, larvae were sampled by a series of monthly tows taken with a 64 microm mesh net between the new and full moon from April 2005 to July 2006, September 2006 and August 2007. In order to measure spatial variation of echinoderm larval abundances, oblique tows were taken with 64 and 202 microm mesh nets at seven different sites within the shelf, at the shelf-edge, and at a nearby oceanic stations during August 2007. Overall, Echinoidea (sea urchin) exhibited the highest abundance with a total of 11 921 larvae, representing 52.5% of the total collection. Ophiuroidea (brittle star) ranked second in abundance with 45.6% of the total larvae. Holothuroidea (sea cucumber) and Asteroidea larvae (sea star) accounted for less than 2% of the total echinoderm larval collection. Early larval stages (2-8 day old) of Diadema antillarum represented 20% of the total Echinoidea larvae. There was no marked seasonal trend of echinoderm larval abundance; Echinoidea and Ophiuroidea larvae were present in all monthly samples indicating that reproduction occurs year round. Peak abundances of later-stage Echinoidea larvae were observed during January, July and October and of later-stage Ophiuroidea larvae during June, August and October. The observed peaks of later-stage larval abundances may be indicative of higher recruitment activity during these months. There was a significant difference of echinoderm larval abundance between spatial stations, with higher abundances collected at the shelf-edge. Later-stage (approximately 24 day old) D. antillarum larvae were mostly collected at shelf-edge and oceanic locations. In addition, the 64 microm mesh net was more efficient for collection of echinoderm larvae than the 202 microm mesh net. PMID- 21302411 TI - Prevention of acute acoustic trauma by earmuffs during military training. AB - BACKGROUND: Impulse noise produced from firearms can potentially damage hearing organs resulting in sensorineural hearing loss (SNHL). In Chiang Mai during 1997, Detphithak et al reported a prevalence of acute acoustic trauma (AAT) in 22% of new military privates using an H.K.33 for shooting practice without hearing protection. The H.K.33 renders an average sound pressure level of 128 dBA. Earmuffs are claimed by their manufacturing company to attenuate noise 27 dB, and they have been recently introduced in Chiang Mai to prevent AAT. OBJECTIVE: To study the outcomes of hearing protection against AAT using earmuffs during shooting training (H.K.33) in the Military Reserve Officer Training Corps (MROTC). MATERIAL AND METHOD: A quasi - experiment study was conducted among 267 normal hearing MROTCs in the Reserve Officers Student Training Center (ROSTC) of the 33rd Military Circle, Chiang Mai, Thailand. Their condition of hearing was examined by an otolaryngologist and an audiologist using pure tone audiometry (PTA) before shooting practice, within 2 hours after the practice, 3 days after the practice at the ROSTC; and 1 month later at Fort Kawila Hospital, Chiang Mai, Thailand. RESULTS: All 267 MROTCs used earmuffs during shooting practice. Their mean age was 17.95 years. Average sound pressure level of an HK.33 was 127 dBA (range; 126.5-130 dBA). AAT was found in 4 persons (1.5%) within two hours after shooting. Repeat testing 3 days later revealed that only one person (0.37%) still had SNHL. Fortunately, this case reached complete recovery within 1 month. When comparing these findings with those of 1997, earmuffs can reduce AAT by 15 times (95% confidence interval 5.3-40.5, p-value < 0.0001) to a negligible level. CONCLUSION: Shooting training with an H.K. 33 produces a dangerous sound pressure level at the shooting site, resulting in a possible high risk of acute acoustic trauma. Earmuffs can effectively reduce this risk by approximately 15 times, and they should be widely used in all shooting training. PMID- 21302412 TI - Quality of working life: perceptions of professional nurses at Phramongkutklao Hospital. AB - BACKGROUND AND OBJECTIVE: The 10th National Economic and Social Developmental Plan considered quality of human. Quality of human life was affected by quality of working life (QWL). Professional nurses had responsibility for patients' quality of life. Thus, professional nurses should have a quality of working life more effectively before they could help patients. Personal factors have relationships with the quality of working life. Thus, the present study was to describe the level of the QWL, to examine the relationships between job characteristics, organizational climate, organizational commitment, and job satisfaction with the QWL and to predict the QWL among professional nurses at Phramongkutklao Hospital. MATERIAL AND METHOD: Two hundred and thirty-one professional nurses, who had worked for at least 3 years, were selected by stratified random sampling from 12 departments at Phramongkutklao Hospital. The questionnaires were developed, consisting of personal factors, job characteristics, organizational climate and commitment, job satisfaction and QWL. Content validity was examined by 9 experts. Reliability was obtained at 0.97 by means of Cronbach's alpha coefficient. RESULTS: The over all mean score of the level of quality of working life among professional nurses was at a moderate level (mean = 3.412, SD = 0.459). Personal factors were age, status, education, position, experience, salary and wards were no relationships with the QWL. Job satisfaction was positive and related at a high level, while organizational commitment, organizational climate, and job characteristics were positive and related at a moderate level to the QWL significantly at 0.001 level (r = 0.724, 0.694, 0.640, and 0.334). Multiple regression analysis factors affecting QWL indicated that professional nurses associated negative factors with job characteristics and positive factors with job satisfaction, organizational commitment, and organizational climate at 62.10 percent (R2 = 0.621). QWL = 0.762 + 0.336 Job satisfaction + 0.265 Organizational climate + 0.250 Organizational commitment - 0.118 Job characteristics. CONCLUSION: In order to develop the QWL among professional nurses at Phramongkutklao hospital, nursing administrators should promote their job satisfaction, organizational commitment, organizational climate, and job characteristics. Professional nurses who have better QWL, are more likely to stay in their positions and provide better nursing care. PMID- 21302413 TI - Incidence of rickettsial infection in patients with acute fever in provincial Thai army hospitals. AB - Scrub typhus is common among patients with acute fever in rural areas of Thailand. The authors prospectively recruited patients with acute fever from provincial Thai army hospitals. Dot-ELISA test for scrub typhus was done in hospitals and then compared with standard immunofluorescent assay for diagnosis of scrub typhus. Among 178 patients, scrub typhus was diagnosed by immunofluorescent assay in 10 patients (5.61%). The incidence was high in the northeastern and northern regions. Dot-ELISA gave positive results in 4 of 115 patients, while immunofluorescent assay gave positive results in 6 patients (sensitivity = 66.7%). No false positive results of Dot-ELISA were found among 109 patients (specificity = 100%). All patients gave negative results for murine typhus and Thai tick typhus using immunofluorescent assay. Regarding this present study, Dot-ELISA for scrub typhus has a good sensitivity and specificity and can be used in rural hospitals. This test could be useful for diagnosis of scrub typhus in hospitals where immunofluorescent assay is not available. PMID- 21302414 TI - Prevalence of intestinal parasitic infections in military personnel and military dogs, Thailand. AB - OBJECTIVE: To determine the prevalence of intestinal parasitic infections and risk factors among military personnel and military dogs at the Military Dog Center, Veterinary and Remount Department, Royal Thai Army, Thailand. MATERIAL AND METHOD: A cross-sectional study was conducted in January 2006 to examine intestinal parasitic infections using wet preparation and, formalin-ethyl acetate concentration. Modified acid fast and gram-chromotrope stains were used to identify Cryptosporidium spp. and microsporidia, respectively. Culture for Blastocystis was performed using Jone's medium. Genotypic characterization of Blastocystis and Giardia duodenalis were also determined using PCR-RFLP. To determine the risk factors and outcomes of intestinal parasitic infections, standardized questionnaires were used in the present study. RESULTS: Of 317 military personnel, the prevalence of intestinal parasitic infections was 22.4%. Blastocystis was the most predominant intestinal protozoa infection of 14.5% while G. duodenalis was only 1.3%. The prevalence of other helminthic infections were 4.8% which were Strongyloides stercoralis (2.5%), Hookworm (1.0%), Opisthorchis viverrini (1.0%), and Taenia spp. (0.3%), respectively. Blastocystis subtype 1 was identified in 25 positive culture specimens while all 4 positive of G. duodenalis were analyzed as Assemblage B, subgenotype IV. The presented data could not indicate that intestinal parasitic infections and blastocystosis in this army population were significantly linked to risk association among groups with regard to rank, age group, working unit, area of residence, animal contact, source and treatment of drinking water. Of 189 military dogs, the prevalence of intestinal parasitic infections was only 3.7% which was Blastocystis sp. (2.6%), S. stercoralis (0.5%), and Entamoeba coli (0.5%), respectively. CONCLUSION: The predominant intestinal parasites found in this population, such as Blastocystis sp. and G duodenalis transmit to humans via fecal-oral route so that improvement of sanitation and personal hygiene should be emphasized. PMID- 21302415 TI - The prevalence of common mental disorders among outpatient Thai army personnel. AB - BACKGROUND: The purpose of the present study was to determine the prevalence of common mental disorders among Thai army personnel who attended the outpatient clinic, Department of Psychiatry and Neurology, Phramongkutklao Hospital in 2005. MATERIAL AND METHOD: The authors retrospectively reviewed and analyzed all outpatient medical records in 2005 of Thai army personnel who received treatment at the outpatient clinic, Department of Psychiatry and Neurology, Phramongkutklao Hospital from January 2005 to December 2005. RESULTS: Altogether 1,729 Thai army personnel were enrolled in the present study. They were 1,546 males and 183 females. The most common age range was 41-50 years (27.8%) and most of them were married. The prevalence of the first ten rank of mental disorders among Thai army personnel were schizophrenia (30.5%), alcohol dependence (18.21%), major depressive disorder (10.75%), generalized anxiety disorder (6.88%), panic disorder (6.13%), acute stress reaction (4.22%), adjustment disorder (4.1%), dysthymia (3.12%), insomnia (3%) and bipolar disorder (2.48%), respectively. CONCLUSION: The three most common prevalence of mental disorders among Thai army personnel who attended in the year 2005 were schizophrenia, alcohol dependence, and major depressive disorder. PMID- 21302416 TI - Prevalence of chronic diseases risk factors among persons attending six administrative courses in the Army Training Command area in 2006. AB - BACKGROUND: The chronic diseases prevalence tends to increase worldwide and the risk factors are identified and reduced. OBJECTIVE: To survey the prevalence of chronic diseases risk factors among persons attending 6 administrative courses in the Army Training Command area in 2006 and compare with results of the former study. MATERIAL AND METHOD: All persons attending the 6 courses were asked to answer the questionnaires. The SPSS for Windows version 10 computer program was used for data analysis. RESULTS: There were 445 respondents. Most of them were men (87.2%), married (75.9%), finished a bachelor degree or higher (93.9%), military personnel (97.5%) and the average age was 43.7 +/- 5.6 years. The prevalence percentages of smoking, alcohol drinking, physical inactivity, preferred high fat food, preferred sweet food, preferred salty food, obesity, hypertension, dyslipidemia, diabetes and hyperstress was 18.7, 13.5, 56.6, 41.9, 20.9, 11.0, 35.4, 14.4, 38.5, 4.3 and 18.7, respectively. Most of the prevalence of risk factors, except smoking, was not decreased when compared to the former study in the similar group of persons in 2004. CONCLUSION: The prevalence of chronic diseases risk factors in this group was high and seemed difficult to reduce. There should be appropriate surveillance and intervention programs to reduce these risks to prevent disease in this special group. PMID- 21302417 TI - Prevalence and patterns of alcohol consumption among Royal Thai Army personnel. AB - OBJECTIVE: To determine the prevalence and patterns of alcohol consumption among the army personnel. MATERIAL AND METHOD: A cross-sectional study was carried out during the annual health examination between 2000 and 2001 in two army units located in the central region of Thailand. A total of 843 active duty army personnel participated in the present study. Data on demographic characteristics, smoking status and alcohol consumption were collected using a self-rating questionnaire. Drinking patterns during the past year were measured in the following aspects: frequency, quantity, binge drinking and beverage preference. RESULTS: Eight hundred and thirty-one (98.6%) studied personnel provided complete information and were included in the analysis. All were males with the mean age of 37.2 +/- 7.7 years. Five hundred and ninety-three (71.4%) study personnel were current drinkers. The majority of 57.5% drank at least five drinks per drinking day. With regard to the frequency of drinking, 10.7% reported that they drank as often as daily or nearly every day. Additionally, 22.7% had five drinks or more per drinking day at least weekly. Up to 28.2% had binge drinking or episodic heavy drinking practices. The most common type of alcoholic beverage for drinkers was mixed spirit and beer (30.7%). Only three (0.4%) personnel reported drinking wine. CONCLUSION: The results suggest that alcohol abuse becomes a significant problem among the army personnel. Most drinking patterns established among the army personnel are more likely to be harmful and unsafe to their health than beneficial effects. Thus, there is an urgent need to initiate appropriate action to prevent the harm from alcohol use and to protect the military performance and readiness. PMID- 21302418 TI - Role of the Student Affairs Division, Phramongkutklao College of Medicine in assessing medical cadets. AB - OBJECTIVE: To evaluate the role of the Student Affairs Division: Phramongkutklao College of Medicine in assessing medical cadets and determine the problems and obstacles in assessing. MATERIAL AND METHOD: Qualitative study using focus group discussion was conducted in staff and medical cadets to determine functions, problems and obstacles of the Student Affairs Division, Phramongkutklao College of Medicine. Questionnaire was used to determine the agreement to ten domains: main educational programs, aims and missions, teaching methods, organizational culture, key requirements and expectation for programs, related units relationships and communication mechanisms, role of staff for student assessment, discipline, leadership assessment, problems and obstacles for student assessment and related units of student assessment, respectively. RESULTS: The present study indicated that majority of the subjects agreed with the curriculum of the Student Affairs Division, especially the military subjects. However, a leadership subject should be added. Majority of the subjects supported the organizational culture of the Student Affairs Division. CONCLUSION: This study showed that most of the subjects supported the vital role of the Student Affairs Division: Phramongkutklao College of Medicine in assessing medical students. However, improving the current assessment system regarding the leadership, is needed. PMID- 21302419 TI - Personality and social adjustment of medical cadets, Phramongkutklao College of Medicine. AB - OBJECTIVE: To determine personality and ability of social adjustment of medical cadets, Phramongkutkao College of Medicine. In addition, the factors influencing social adjustment in these medical cadets were evaluated. MATERIAL AND METHOD: The study population consisted of 45 medical cadets in their second year of a 6 year medical curriculum of Phramongkutkao College of Medicine. All study medical cadets gave written informed consent. The medical cadets completed a baseline assessment including a standardized questionnaire for general information and social adjustment. Personality traits were determined by a standard personality test, the 16 Personality Factor Questionnaire (16PF). RESULTS: The personalities of medical cadets were in between reserved and outgoing socially aware, concerns, shrewd and practical. The ability of social adjustment in these medical cadets was high. Social adjustment was significantly different between medical cadets who received different scholarships. Social adjustment of the medical cadets was positively correlated with personalities: factor C (emotionally stable), factor I (sensitivity), factor G (group conformity), factor H (social boldness), and factor Q3 (self-control), but negatively correlated with factor M (abstractedness), and factor Q2 (self-sufficiency). CONCLUSION: This study presents the unique personalities of medical cadets. Social adjustment is significantly different between medical cadets with different source of scholarships. Longitudinal study of the influence of personality and social adjustment on academic performance needs to be performed. PMID- 21302420 TI - Key themes in research on the demography of aging. PMID- 21302421 TI - Biodemography: new approaches to understanding trends and differences in population health and mortality. AB - The incorporation of biological information in large population surveys has expanded demographic analysis to clarify the meaning of observed trends and differences in population health and mortality. Levels of measured biological risk in the population were reduced in recent years largely because of the expanded use of prescription drugs. The increased use of antihypertensives and, to a lesser extent, lipid-lowering drugs was a likely cause of significant mortality reduction. Blacks and persons with lower educational attainment experience higher levels of biological risk factors, more diseases, and more frailty; these differences are the sources of higher mortality for these groups. Hispanics are less likely to have a higher prevalence of risk factors and diseases than the non-Hispanic population, providing further understanding of the "Hispanic paradox." Almost every examined indicator of biological risk, disease, and frailty is related to higher mortality, indicating how incorporation of this information provides a fuller understanding of the morbidity process. PMID- 21302423 TI - Facilitating longer working lives: international evidence on why and how. AB - The article advances the view that social and economic choices in societies can reasonably adjust as the age structure of the population changes; in particular, some of the bounty of longer lives can reasonably be allocated to prolonging the labor force participation of older workers. Data on reductions in mortality and, in some countries, declines in disability are presented in ways that help to clarify that prolonged working lives may be a natural concomitant of living longer. The article reviews the problems inherent in the combination of living longer and reducing labor force participation at older ages. It discusses two ways to facilitate longer working lives: (1) eliminating penalties on work at older ages--inherent in the provisions of the social security programs in many countries--that induce older persons to leave the labor force at younger ages; and (2) correcting a false rationale--the "boxed economy" view of the labor market--that is often used to support retention of the provisions that induce older persons to leave the labor force. PMID- 21302422 TI - Families, social life, and well-being at older ages. AB - As people age, many aspects of their lives tend to change, including the constellation of people with whom they are connected, their social context, their families, and their health--changes that are often interrelated. Wave I of the National Social Life, Health, and Aging Project (NSHAP) has yielded rich information on intimate ties, especially dyads and families, and on social connections generally. Combined with extensive biological and other health measures, NSHAP enables researchers to address key questions on health and aging. We begin with recent findings on intimate dyads, then move to social participation, and finally to elder mistreatment. Among dyads, we find that whereas sexual activity drops sharply with age for both women and men, gender differences in partner loss as well as psychosocial and normative pressures constrain women's sex more than men's. However, surviving partnerships tend to be emotionally and physically satisfying and are marked by relatively frequent sex. In contrast to sex, nonsexual intimacy is highly prevalent at older ages, especially among women. Older adults are also socially resilient--adapting to the loss of social ties by increasing involvement with community and kin networks. Despite these social assets, older adults remain vulnerable to mistreatment. Overall, these findings yield a mixed picture of gender-differentiated vulnerabilities balanced by proactive adaptation and maintenance of social and dyadic assets. PMID- 21302424 TI - The potential impact of comparative effectiveness research on U.S. health care expenditures. AB - Comparative effectiveness research (CER) has the potential to slow health care spending growth by focusing resources on health interventions that provide the most value. In this article, we discuss issues surrounding CER and its implementation and apply these methods to a salient clinical example: treatment of prostate cancer. Physicians have several options for treating patients recently diagnosed with localized disease, including removal of the prostate (radical prostatectomy), treatment with radioactive seeds (brachytherapy), radiation therapy (IMRT), or--if none of these are pursued--active surveillance. Using a commercial health insurance claims database and after adjustment for comorbid conditions, we estimate that the additional cost of treatment with radical prostatectomy is $7,300, while other alternatives are more expensive- $19,000 for brachytherapy and $46,900 for IMRT. However a review of the clinical literature uncovers no evidence that justifies the use of these more expensive approaches. These results imply that if patient management strategies were shifted to those supported by CER-based criteria, an estimated $1.7 to $3.0 billion (2009 present value) could be saved each year. PMID- 21302425 TI - Disease prevalence, disease incidence, and mortality in the United States and in England. AB - We find that both disease incidence and disease prevalence are higher among Americans in age groups 55-64 and 70-80, indicating that Americans suffer from higher past cumulative disease risk and experience higher immediate risk of new disease onset compared with the English. In contrast, age-specific mortality rates are similar in the two countries, with an even higher risk among the English after age 65. We also examine reasons for the large financial gradients in mortality in the two countries. Among 55- to 64-year-olds, we estimate similar health gradients in income and wealth in both countries, but for 70- to 80-year olds, we find no income gradient in the United Kingdom. Standard behavioral risk factors (work, marriage, obesity, exercise, and smoking) almost fully explain income gradients among those aged 55-64 in both countries and a significant part among Americans 70-80 years old. The most likely explanation of the absence of an English income gradient relates to the English income benefit system: below the median, retirement benefits are largely flat and independent of past income, and hence past health, during the working years. Finally, we report evidence using a long panel of American respondents that their subsequent mortality is not related to large changes in wealth experienced during the prior 10-year period. PMID- 21302426 TI - Evidence-based guideline update: Determining brain death in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology. PMID- 21302427 TI - Prologue: research on the demography and economics of aging. PMID- 21302428 TI - Trends in health of older adults in the United States: past, present, future. AB - The decline in late-life disability prevalence in the United States was one of the most important developments in the well-being of older Americans in the 1980s and 1990s, but there is no guarantee that it will continue into the future. We review the past literature on trends in disability and other health indicators and then estimate the most recent trends in biomarkers and limitations for both the population aged 65 and older and those aged 40 to 64, the future elderly. We then investigate the extent to which trends in education, smoking, and obesity can account for recent trends in limitations and discuss how these three factors might influence future prospects for late-life health. We find that improvements in the health of the older population generally have continued into the first decade of the twenty-first century. The recent increase in the proportion of the younger population needing help with activities of daily living is concerning, as is the doubling of obesity in the last few decades. However the increase in obesity has recently paused, and favorable trends in education and smoking are encouraging. PMID- 21302429 TI - Causes and consequences of early-life health. AB - We examine the consequences of child health for economic and health outcomes in adulthood, using height as a marker of childhood health. After reviewing previous evidence, we present a conceptual framework that highlights data limitations and methodological problems that complicate the study of this topic. We then present estimates of the associations between height and a range of outcomes--including schooling, employment, earnings, health, and cognitive ability--measured in five data sets from early to late adulthood. These results indicate that, on average, taller individuals attain higher levels of education. Height is also positively associated with better economic, health, and cognitive outcomes. These associations are only partially explained by the higher average educational attainment of taller individuals. We then use data from the National Longitudinal Survey of Youth 1979 Children and Young Adults survey to document the associations between health, cognitive development, and growth in childhood. Even among children with the same mother, taller siblings score better on cognitive tests and progress through school more quickly. Part of the differences found between siblings arises from differences in their birth weights and lengths attributable to mother's behaviors while pregnant. Taken together, these results support the hypothesis that childhood health influences health and economic status throughout adulthood. PMID- 21302430 TI - Recent developments in longitudinal studies of aging in the United States. AB - We review recent developments in longitudinal studies of aging, focusing on the Wisconsin Longitudinal Study (WLS) and the Health and Retirement Study (HRS). Both studies are part of a trend toward biosocial surveys in which biological measurement is joined with traditional survey techniques, and a related trend toward greater harmonization across studies. Both studies have collected DNA samples and are working toward genotyping that would allow broadly based association studies. Increased attention to psychological measurement of personality and of cognitive ability using adaptive testing structures has also been shared across the studies. The HRS has expanded its economic measurement to longitudinal studies of consumption and to broader-based measurement of pension and Social Security wealth. It has added biomarkers of cardiovascular risk. The WLS has developed an integrated approach to the study of death and bereavement and an innovative use of high school yearbook photographs to capture information about health in early life of its participants. PMID- 21302431 TI - Some macroeconomic aspects of global population aging. AB - Across the demographic transition, declining mortality followed by declining fertility produces decades of rising support ratios as child dependency falls. These improving support ratios raise per capita consumption, other things equal, but eventually deteriorate as the population ages. Population aging and the forces leading to it can produce not only frightening declines in support ratios but also very substantial increases in productivity and per capita income by raising investment in physical and human capital. Longer life, lower fertility, and population aging all raise the demand for wealth needed to provide for old age consumption. This leads to increased capital per worker even as aggregate saving rates fall. However, capital per worker may not rise if the increased demand for wealth is satisfied by increased familial or public pension transfers to the elderly. Thus, institutions and policies matter for the consequences of population aging. The accumulation of human capital also varies across the transition. Lower fertility and mortality are associated with higher human capital investment per child, also raising labor productivity. Together, the positive changes due to human and physical capital accumulation will likely outweigh the problems of declining support ratios. We draw on estimates and analyses from the National Transfer Accounts project to illustrate and quantify these points. PMID- 21302432 TI - What can we learn from (and about) global aging? AB - Although aging is a global phenomenon, there are large differences across countries in both the speed of aging and the current age composition. Furthermore, countries adopt vastly different policies. This creates a natural laboratory that scientists can use to understand how policies affect outcomes. I discuss under what circumstances data from different countries can be used for inference about policy effects. Although comparable health and retirement data are currently being collected in some 25 countries, the use of such data requires careful modeling of differences in institutions and in response styles across countries. PMID- 21302433 TI - [Quercetin permeability across blood-brain barrier and its effect on the viability of U251 cells]. AB - OBJECTIVE: To investigate the permeability of quercetin across blood-brain barrier (BBB) and its impact on the proliferation and apoptosis of U251 cells. METHODS: The BBB model was established through culture of primary brain microvessel endothelial cells (BMVEC) and primary astroglia cells (AC), which was confirmed by transmission electron microscopy (TEM) and trans epithelial electric resistance (TEER). High pressure liquid chromatography (HPLC) was performed to determine quercetin permeability across BBB. U251 cells were exposed to quercetin. MTT assay, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), single-cell gel electrophoresis (SCGE) and flow cytometry (FCM) were performed to analyze cell proliferation, apoptosis, DNA damage and cell cycle distribution. RESULTS: The BBB was constructed successfully. Up to 65.54% of quercetin permeated across the BBB. Quercetin attenuated the proliferation of U251 and induced apoptosis. The FCM revealed that the U251 cells were inhibited at the G2/M point. CONCLUSION: Quercetin can permeate across the BBB effectively, restraining the proliferation of U251 cells and inducing apoptosis. PMID- 21302434 TI - [Inhibitory effect and molecular mechanism of silencing S100A4 gene on the growth of transplanted tumor of human esophageal carcinoma EC-1 cells in nude mice]. AB - OBJECTIVE: To study the effect of S100A4siRNA on tumor growth of xenografted human esophageal squamous cell carcinoma (ESCC) cell line EC1 in nude mice and explore its related molecular mechanism. METHODS: The xenografted tumor model was established in nude mice, and S100A4siRNA chemically synthesized was used to transfect the xenografted nude mice. The tumor growth was observed. The mRNA and protein expressions of S100A4, MMP-2 and E-cadherin in tumor after transfection with S100A4siRNA were detected by RT-PCR and immunohistochemistry. RESULTS: The tumor volume of S100A4siRNA transfection group was lower than that of nonsense siRNA transfection group and blank control group (P < 0.05), and tumor inhibitive ratio of S100A4siRNA group was higher than that of nonsense siRNA transfection group (P < 0.05). Furthermore, the mRNA and protein expressions of S100A4, MMP-2 in S100A4siRNA group were lower than those in nonsense siRNA group and control group (P < 0.05), the mRNA and protein expressions of E-cadherin in S100A4siRNA group were higher than those in nonsense siRNA group and control group (P < 0.05). CONCLUSION: S100A4siRNA could effectively lead to growth inhibition of xenografted human esophageal tumor in nude mice, with down regulation of MMP-2 and up regulation of E-cadherin, which provides theoretical basis for molecular therapy of ESCC. PMID- 21302435 TI - [Construction and expression of recombinant plasmid pET28alpha-Sj26GST of Schistosoma japonicum in Escherichia coli BL21]. AB - OBJECTIVE: To construct and express recombinant plasmid pET28a-Sj26GST of Schistosoma japonicum (Sj) in Escherichia coli BL21 (DE3). METHODS: The total RNA was extracted from Sj adult worms by ultrasound-breaking. The Sj26GST antigen gene was amplified by RT-PCR from the total RNA, and then cloned into prokaryotic expression plasmid pET28alpha and transformed into E. coli BL2 (DE3). The BL21(pET28a-Sj26GST) was induced with isopropyl-beta-D-thiogalactopyranosid (IPTG), and the expressed products were analyzed and identified with SDS-PAGE and Western blot. RESULTS: The 676 bp Sj26GST gene was successfully amplified by RT PCR and cloned into pET28alpha. The recombinant plasmid pET28a-Sj26GST was successfully constructed, with a relative molecular weight of expressed recombinant protein at approximately 36 x 10(3) as determined by SDS-PAGE. The amount of the expressed protein comprised 26% of the total bacterial proteins. The fusion protein could be recognized by the sera of rabbits infected with Sj. CONCLUSION: The recombinant plasmid pET28alpha-Sj26GST is successfully constructed and highly expressed in E. coli in a fused form with His-tag. The expressed fusion protein shows specific antigenicity. PMID- 21302436 TI - [Dynamic observation on splenocyte subsets in mice immunized with recombinant Bb Eg95-EgA31 vaccine of Echinococcus granulosus]. AB - OBJECTIVE: To dynamically observe changes of subsets of splenocytes in mice immunized with recombinant Bifidobacteria bifidum (Bb)-Eg95-EgA31 vaccine of Echinococcus granulosus (Eg). METHODS: BALB/c mice were vaccinated by 5 x 10(8) colony forming unit (CFU) orally and 5 x 10(5) CFU intranasally respectively. Mice were killed on week 0, 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20 after immunization respectively, and spleens were separated for cell preparation. CD4+ and CD8+ T cells were determined by flow cytometry (FCM), with MRS as control. RESULTS: In the oral immunization group, CD4+ cells showed a significant increase during the 4th-10th week after vaccination, and reached the highest level on the 6th week, whereas no obvious changes in CD8+ cells numbers were observed. In the intranasal immunization group, CD4+ cells showed an obvious increase during the 4th-8th week after vaccination, and reached the highest level on the 6th week, CD8+ subsets had no obvious changes. CONCLUSION: CD4+ T cell cells may play a key role in immune response in mice immunized with the recombinant Bb-Eg95-EgA31 vaccine of Echinococcus granulosus. PMID- 21302437 TI - [Vasodilatory effects of CNP on aortic arteries of rabbits]. AB - OBJECTIVE: To investigate the mechanism of vasodilatory effects of C-type natriuretic peptide (CNP). METHODS: Tension changes in aortic rings of rabbits were recorded with the presence of CNP or C-type natriuretic peptide receptor (NPR-C) agonist (cANF4-23) after pretreatment with epinephrine (NE) or 60 mmol/L KCl. The vasodilatory effects of four types of potassium channel blocker and NPR C antagonist (cANF4-28) were also tested. RESULTS: A maximal vasorelaxant effects of (33.5 +/- 5.9) % and (38.4 +/- 10.6)% were recorded in the presence of 1 micromol/L CNP and cANF4-23, respectively, cANF4-28 attenuated the action of CNP [(19.8 +/- 8.3)%]. The vasorelaxant effects of CNP and cANF4-23 decreased significantly after pretreatment with 60 mmol/L KCl (P < 0.01). Glibenclamide and BaCl2 also attenuated the relaxant activities of CNP (P < 0.05). But only BaClZ decreased the vasodilatory action of cANF4-23 (P < 0.05). CONCLUSION: The relaxant activity of CNP is mediated through three paths: NPR-B/KATP, NPR-C/KIR and NPR-C/calcium channels. PMID- 21302438 TI - [Directed migration and morphological changes of cultured trophoblast cells in small electric fields]. AB - OBJECTIVE: To study the effect of physiological direct current electric fields (dcEF) on the migration and morphology of trophoblast cells. METHODS: The trophoblast cells (HTR8) were exposed to dcEF at 100 mV/mm and 200 mV/mm for 5 and 24 hours. The cell images were recorded and analyzed by image analyzer. RESULTS: Trophoblast cells cultured in medium containing 20% calf serum showed significant galvanotropism, including directed migration and orientation in the electric fields with a field strength of 100 mV/mm and 200 mV/mm. The cells showed obvious anode migration and enhanced migration rates compared with the non EF stimulated cells. The directed migration was serum dependent. No significant cell migration occurred in the serum free medium under dcEF stimulation. The trophoblast cells showed morphological changes such as elongation under dcEF stimulation. CONCLUSION: Physiological direct current electrical fields may induce directed migration of trophoblast cells and this response is serum dependent. The morphological change featured with elongation is evident under dcEF stimulation. PMID- 21302439 TI - [Effects of adiponectin gene SNP45T/G on changes of serum lipid ratios induced by high-carbohydrate/low-fat diet in healthy Chinese youth]. AB - OBJECTIVE: To investigate the effects of adiponectin gene (APM1) SNP45T/G on serum lipid ratios and their responses to high-carbohydrate/low-fat (HC/LF) diet in healthy young Chinese. METHODS: Fifty-six healthy young subjects were given two consecutive diets. The first was control diet (54% carbohydrate, 15% protein, and 31% fat) for 7 days, and the second was HC/LF diet (70% carbohydrate, 15% protein, and 15% fat) for 6 days. Before and after each diet, serum lipids and SNP45T/G were analyzed. The ratios of TG/HDL-C, log (TG/HDL-C), TC/HDL-C, and LDL C/HDL-C were calculated. RESULTS: There was no significant difference of baseline lipid ratios between subjects with TT genotype and subjects carrying G allele (G carriers) in the whole population or in the males and females separately. The G allele was associated with significantly higher TC/HDL-C after HC/LF diet in the males (P < 0.05); and the males with TT genotype had significant decreases of LDL C/HDL-C (P < 0.05) and TC/HDL-C (P < 0.05) after HC/LF diet compared with those before the diet, while G carriers only experienced significant decrease of TC/HDL C (P < 0.01). In the females, TT genotype was associated with significantly higher TG/HDL-C (P < 0.05) and log (TG/HDL-C) (P < 0.05) both before and after the HC/LF diet. When compared with those before HC/LF diet, elevated TG/HDL-C (P < 0.05) and log (TG/ HDL-C) (P < 0.05) and declined TC/HDL-C (P < 0.01) were observed in the subjects with TT genotype after the diet. In the female subjects of G carriers, LDL-C/HDL-C (P < 0.05) and TC/HDL-C (P < 0.01) decreased significantly after the HC/LF diet. CONCLUSION: G allele of APM1 45T/G could inhibit increase of TG/HDL-C and log (TG/HDL-C) and promote the decrease of LDL C/HDL-C induced by HC/LF diet in healthy young females. But in the healthy young males, it might eliminate the decline of LDL-C/HDL-C induced by HC/LF diet and increase TC/HDL-C. PMID- 21302440 TI - [KeLuoXin medicated serum extract inhibits high glucose-induced proliferation and phosphorylation of ERK1/2 in rat mesangial cell]. AB - OBJECTIVE: To investigate the effects and mechanism of KeLuoXin (KLX) capsule on rat mesangial cell proliferation induced by high glucose. METHODS: Rat mesangial cells (HBZY-1) were cultured in vitro and stimulated with high glucose(30 mmol/L glucose) for different time after the treatment with or without KLX medicated serum extract, the proliferation was assessed by cell counting Kit-8 (CCK-8) and the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) was detected by Western blot. RESULTS: KLX could significantly inhibit HBZY-1 cell proliferation induced by high glucose (P < 0.05). In addition, KLX could reduce the increase of the phosphorylation level of ERK1/2 (P < 0.01), which was induced by high glucose in HBZY-1 cells. CONCLUSION: KLX can inhibit rat mesangial cell proliferation, and the mechanisms may relate to the interruption of ERK1/2 Mitogen-activated protein kinase (MAPK) pathway. PMID- 21302441 TI - [Effects of high glucose on expression of core binding factor alpha1 and osteocalcin in vascular smooth muscle cells]. AB - OBJECTIVE: To investigate the effects of high glucose on expression of core binding factor alpha1 (cbfalpha-1) and osteocalcin (OC) in vascular smooth muscle cells (VSMCs), and discuss the mechanism of small vessels calcification induced by high glucose (GS) in vitro. METHODS: The primary cultured VSMCs from rats' aortic segments were divided into three groups, including normal control group (5 mmol/L D-glucose), high glucose group (25 mmol/L D-glucose) and mannitol group (5 mmol/L D-glucose plus 25 mmol/L mannitol). We measured quantitatively the calcium deposition in VSMCs and investigated the calcium extent of VSMCs by alizarin red stain in each group. The mRNA levels of cbfalpha-1 and OC were measured by real time PCR, and the protein expression levels of cbfalpha-1 and OC were examined by Western blot. The activity of alkaline phosphatase was measured by alkaline phosphatase activity testing kit, and the protein level of alpha-smooth muscle actin (a-SMA) was detected by immunohistochemistry. RESULTS: When compared with the normal group and mannitol group, the high glucose group showed that the calcium deposition and calcium extent of VSMCs increased obviously, the mRNA and protein levels of cbfalpha-1 and OC also increased significantly (P < 0.05), while the protein level of alpha-SMA decreased (P < 0.05), which were in a dose dependent manner. The level of alkaline phosphatase activity of VSMCs was approximately doubled in high glucose group. CONCLUSION: The mechanism of high glucose induced calcification in VSMCs may be due to the increased expression of cbfalpha-1 and OC. High glucose decrease the expression of alpha-SMA in VSMCs, which could induce the transdifferentiation from RVSMCs to osteoblast-like cells. PMID- 21302442 TI - [Effects of bortezomib combined with daunorubicin on proliferation and apoptosis in primary adult acute leukemia]. AB - OBJECTIVE: To assess effects of proteasome inhibitor Bortezomib (Bor) in combination with Daunorubicin (DNR) on proliferation, apoptosis and the expression of Bcl-2 mRNA in primary leukemia cells in vitro. METHODS: Primary leukemia cells were isolated from bone marrow of adult acute leukemia patients using Ficoll liquid, then the primary leukemia cells were treated with different concentration of these two drugs (Bor 5, 10, 20, 50 nmol/L, DNR 50, 100, 200, 500 nmol/L, and Bor 5, 10 nmol/L combined with DNR 50, 100, 200, 500 nmol/L respectively ). Cells proliferation, IC50 and CDI were analyzed by MTT assay, cellular apoptosis was observed by flow cytometry, Bcl-2 mRNA was analyzed by RT PCR. RESULTS: Growth inhibition ratio of all the types of acute leukemia cells were increased with the treatment of DNR and Bor in dose-dependent manner. Combined with Bor (5, 10 nmol/L),the IC50 of DNR decreased from (102 +/- 27) nmol/L to (73 +/- 26), (55 +/- 22) nmol/L respectively. DNR 200 nmol/L combined with Bor 10 nmol/L showed a better synergism (CDI = 0. 17). Compared with control group and single drug (DNR or Bor) group, there were obvious increase of apoptosis ratio and obvious decrease of Bcl-2 in the group of DNR 100 nmol/L combined with Bor 20 nmol/L after 24 h or 48 h cultivation (P < 0.05). CONCLUSION: Bor combined with DNR shows synergetic effect in promoting the apoptosis of adult acute leukemia primary cells as well as inhibitory effect on the proliferation of leukemia cells. PMID- 21302443 TI - [The anti-leukemic effects of imatinib, daunorubicin and bortezomib on two leukemia cell lines with Ph(+)]. AB - OBJECTIVE: To study the proliferative inhibition effects of imatinib, daunorubicin and bortezomib on two leukemia cell lines with Ph(+), chronic myelogenous leukemia cell line K562 expressing P210 protein and acute lymphoblastic leukemia cell line SUP-B15 expressing P190 protein. METHODS: (1) The cells of the two cell lines treated with imatinib, daunorubicin and bortezomib for 72 hours were analyzed by MTT assay for proliferation. The proliferative activity was displayed by growth curve and IC50 value. (2) The bcr abl transcriptant in the cells treated with imatinib (final concentration at 0, 0.35, 1 micromol/L) for 48 hours was detected by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: (1) The IC50 values of K562 and SUP-B15 cell lines treated with imatinib, daunorubicin and bortezomib for 72 hours were respectively (0.286 +/- 0.060) micromol/L, (0.303 +/- 0.009) micromol/L, (22.127 +/- 3.592) nmol/L and (1.387 +/- 0.180) micromol/L, (0.117 +/- 0.017) micromol/L, (12.350 +/- 0.740) nmol/L. (2) There was no change of bcr-abl expression level in both cell lines after the treatment of imatinib. CONCLUSION: Imatinib, daunorubicin and bortezomib showed anti-cancer effects on Ph(+) leukemia cells in vitro. K562 cells were more sensitive to imatinib than the other two drugs, whereas SUP-B15 cells are more sensitive to daunorubicin and bortezomib. The short time intervention of imatinib has no effect on the expression of bcr-abl in Ph (+) leukemia cell lines. PMID- 21302444 TI - [Effects and mechanisms of recombinant human erythropoietin in treating multiple myeloma in murine mice]. AB - OBJECTIVE: To test the effects and to identify appropriate dosage and possible mechanisms of recombinant human erythropoietin (rHuEPO) in treating MPC-11 myeloma in the BALB/c murine models. METHODS: A total of 420 BALB/c mice were divided into five groups. 410 of which were injected with 10(4) MPC-11 cells. The 10 mice without myeloma cell inoculation served as normal controls. On the fifth day after inoculation, 50 tumor-bearing mice were arbitrarily assigned into the placebo group, while the other 360 mice were randomly allocated into three experimental groups. Each experimental group had 120 mice and received 10, 20 and 30 units subcutaneous injection of rHuEPO, respectively. A daily injection was administered for 14 days, followed by three injections per week. The mice in the placebo group were administered with saline following the same scheme. Dynamic monitoring of serum M-protein and hemoglobin levels of the mice were performed after myeloma cell inoculation. The subcutaneous nodules were sent for pathological biopsy to ascertain the successful establishment of the murine models. The mice were randomly chosen from each group to be tested for the levels of monoclonal IgG and kappa light chain in their sera (immunofixation electrophoresis and ELISA), counts of CD4 and CD8 positive cells in whole blood (flow cytometry), microvessel density (by marking CD31) and cell apoptosis (TdT mediated dUTP-biotin nick end labeling, TUNEL) of tumor tissues, as well as the levels of cytokines such as IL-6 and TNF-alpha in sera (ELISA) at each month after the injection of rHuEPO. RESULTS: The serum monoclonal immunoglobulin appeared on the 22nd day after inoculation of MPC-11 cells. rHuEPO increased Hb level and survival time of the mice with multiple myeloma. The serum levels of IL 6, IgG and kappa light chain decreased significantly in the mice in the treatment groups compared with those in the placebo group. The overall survival time showed a positive correlation with the Hb level (P = 0.000), and a negative correlation with the serum levels of IL-6 (P = 0.009). CONCLUSION: rHuEPO increases Hb levels and survival time and reduces serum IL-6 and M-protein of the mice with multiple myeloma. PMID- 21302445 TI - [Effects of pretreatment regimen on mice liver injury in hematopoietic stem cell transplantation]. AB - OBJECTIVE: To investigate the effects of conditioning regimen on mice liver injury during hematopoietic stem cell transplantation. METHODS: Forty healthy 8 10 weeks old female BALB/c mice were randomly divided into control group, non myeloablative total body irradiation group, myeloablative total body irradiation group, busulfan group and cyclophosphamide group with 8 mice each. The general condition of each mouse was continuously observed. Peripheral white blood cells were counted and pathological changes of liver were examined by hematoxylin and eosin stain under microscope. The ultrastructure changes of hepatocyte and liver vascular endothelium were detected under transmission electron microscope. RESULTS: Compared to control group, each experimental group showed that the count of white blood cells was decreased significantly after conditioning pretreatments (P < 0.05). The conditioning regimen had injury effects on the mice liver in each experimental group. There were various degrees of damage to the hepatocyte and liver vascular endothelium. CONCLUSION: Total body irradiation, Busulfan and Cyclophosphamide all led to the damage of liver vascular endothelium in hematopoietic stem cell transplantation, and may be the important triggers of hepatic veno-occlusive disease. PMID- 21302446 TI - [5-HT descending expressing in the dorsal horn of cat spinal cord after deafferentation]. AB - OBJECTIVE: To investigate the Serotonin (5-HT) expression in dorsal horn of cat spinal cord and the atypical complex terminal (ACT) after complete dorsal rhizotomy. METHODS: Ten male adult cats were divided into 2 groups after carrying out the complete dorsal rhizotomy: acute group, which survived 2 weeks; chronic group, which survived 2 months. At maturity, all cats were perfused after anaesthesia, the L6 segments of the spinal cord were removed and prepared for light and electron microscopy of 5-HT immunohistochemistry for observing of ACT. RESULTS: 5-HT immuno-reactivity was demonstrated in dorsal horn especially in laminal II both in operation and control sides in acute group. In chronic group, the 5-HT positive stain in operation sides was stronger than that of control sides. The immuno-positive ACTs were founded in the lamina II of chronic operation side beside some 5-HT immuno-positive simple terminals; they were round or ellipse in shape and usually form flat or convex two synapse with two post compounds. ACTs mainly contain clear or dense core vesicles. CONCLUSION: The descending 5-HT express in operation side after complete dorsal rhizotomy is mainly on the in lamina II. The 5-HT immuno-positive ACT may imply the mechanism of descending spinal cord plasticity. PMID- 21302447 TI - [Ultrastructure of unfertilized human oocytes and undivided human zygoytes]. AB - OBJECTIVE: To study the ultrastructure of unfertilized human oocytes and undivided human zygoytes. METHODS: Unfertilized human oocytes and undivided human zygoytes were collected during in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), and then observed under transmission electron microscope (TEM) after fixation, dehydration, embedding, and ultrashing. RESULTS: The unfertilized oocytes from conventional IVF showed (1) normal zona pellucida (ZP) but without cortical granules (CG) beneath oolemma, condensed sperm nuclei, and disappearance of mitochondria and smooth endoplasmic reticulum (SER), (2) abnormal dense in ZP, lack of other organelles [SER tubuli (SER-T),SER vesicles (SER-V)] besides CG and mitochondria, and intact acrosome that penetrated the ZP. The unfertilized oocytes from ICSI showed (1) normal cortex containing one row of dense cortical granules beneath oolemma, SER-T and SER-V associated with mitochondria, some injected spermatozoon with lost nuclear envelope, and some decondensed chromatin, (2) little or scattered cortical granules, which dispersed beneath oolemma, scarce mitochondria and SER-T or isolated mitochondria. The undivided zygotes showed cortical granules contents free in the perivitelline space, little mitochondria, some second lysosomes filled with droplets, and large clumps of annulate lamellae (AL). CONCLUSION: Appearance of organelles in abnormal position is related to oocytes cytoplasmic maturation, which leads to failure in fertilization. Absence of aerosome reaction and abnormal dense of zona pellucida are associated with failed fertilization in conventional IVF. Absence of oocyte activation is associated with failed fertilization in ICSI. The presence of lipofuscin body and abnormal assembly of annulate lamellae are associated with fertilization arrest at the pronuclear stage of human zygotic development. PMID- 21302448 TI - [Vasohibin and VEGF protein levels in placentae from pregnancies complicated by severe pre-eclampsia]. AB - OBJECTIVE: To study the expression of vasohibin and vascular endothelial growth factor (VEGF) in placentae from normal pregnancies and pregnancies complicated by severe pre-eclampsia. METHODS: Placental tissues were obtained by caesarean section for 30 cases of pregnancy with severe pre-eclampsia and 30 cases of matched normal pregnancies. Protein levels of vasohibin and VEGF in placental tissue were quantified by Western blot analysis. Immunohistochemistry was used to determine the localization of the vasohibin protein in placental tissue. RESULTS: The mean value of vasohibin in normal pregnant women was 0.91 +/- 0.12, and in women with severe pre-eclampsia was 0.58 +/- 0.09. These values were statistically different between the two groups (P < 0.05). Moreover, VEGF expression was also significantly reduced in the patients compared with the controls (0.65 +/- 0.20 vs. 0.24 +/- 0.13, P < 0.05). There was a significant positive correlation between vasohibin and VEGF levels (r = 0.262, P < 0.05). Immunolocalization of vasohibin in normal term villous placenta was specifically expressed in the vascular endothelial cells, and no positive staining of other cell types such as syncytiotrophoblast cells, cytotrophoblast cells, and chorionic villi interstitial cells was found. CONCLUSION: These results suggest that reduced vasohibin and VEGF expression may be responsible, at least in part, for the impaired vascular development which occurs in the pre-eclampsia. PMID- 21302449 TI - [Tumor microvascular density detected by anti-CD105 and anti-CD34 in hepatocellular carcinoma patients and its predictive value of tumor recurrence after liver transplantation]. AB - OBJECTIVE: To investigate the clinical significance of tumor microvascular density (MVD) detected by anti-CD105 and anti-CD34 as a predictor of recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT). METHODS: One hundred and twelve (100 with adjacent nontumorous area) patients with HCC who underwent LT between Jan. 2001 and Dec. 2006 were included in this retrospective study. Paraffin blocks of tumor tissue and adjacent nontumorous tissue were used for immunohistochemical study. MVD of HCC was evaluated by anti-CD105 monoclonal antibody and anti-CD34 monoclonal antibody. RESULTS: The immunohistochemich staining showed CD34 strongly positive expressed in the tumor area with tumor mature vasculature, and CD105 strongly positive expressed in adjacent nontumorous area with tumor newly formed vessels. Univariate analysis using chi-square test showed portal vein tumor thrombus (PVTT), pTNM stage, MVD-CD105 expression in adjacent nontumorous area, tumor size and serum AFP level were significantly associated with HCC recurrence after LT (P < 0.05). Multivariate analysis by Cox's regression model showed MVD-CD105 expression in adjacent nontumorous area and PVTT still remained significant correlation with recurrence of HCC after LT (P < 0.05), and MVD-CD105 in adjacent nontumorous area was significantly correlated with PVTT (r(s) = 0.257, P = 0.01), pTNM stage (r(s) = 0.350, P = 0.000), as well as serum AFP level (r(s) = 0.208, P = 0.038). CONCLUSION: The anti-CD105 mAb is an ideal tool to quantify new microvessels in HCC. MVD-CD105 expression in adjacent nontumorous area may be used as an additional factor for the identification of patients at risk for post-transplant recurrence. PMID- 21302451 TI - [The relationship between esp and the ability of biofilm formation in enterococci from the intestinal tract of normal people]. AB - OBJECTIVE: To investigate the biofilm formation of Enterococci from the intestinal tract of normal people, to study the relationship between esp and the ability of biofilm formation in Enterococci. METHODS: PCR was applied to detect the esp gene in 84 isolates. And the biofilm formation was performed in 96 well polystyrene plates. RESULTS: The detection rate of esp in Enterococci was 14.3%, the rate of biofilm formation was 25.0%, the rate of biofilm formation of esp positive isolates was 83.3%, and that of esp negative isolates was 15.3%. CONCLUSION: Biofilm formation is not very common in Enterococci from the intestinal tract of normal people, esp is an important factor of biofilm formation, and the ability of biofilm formation is not limited to the esp positive isolates. PMID- 21302450 TI - [Expressions of APC and c-Myc and its implication on non-small cell lung cancer]. AB - OBJECTIVE: To investigate the expressions of adenomatous polyposis coli (APC) protein and c-Myc protein in non-small cell lung cancer (NSCLC) and their lymph node metastases. METHODS: APC and c-Myc proteins were detected in 270 cases of primary NSCLC, 55 cases of lymph node metastatic tissues and 46 cases of adjacent normal lung tissues by EliVision and EnVision methods of immunohistochemical staining. RESULTS: Higher rates of the expressions of both APC and c-Myc proteins in NSCLC primary foci were found compared with those in lymph node metastases (P < 0.05). Furthermore, the expressions of APC and c-Myc proteins varied with histological types, TNM stagings and metastasis of the NSCLC (P < 0.05). The Spearman correlation analysis showed that the expressions of APC and c-Myc proteins were positively correlated (r(s) = 0.376, P = 0.000). The Kaplan-Meier survival analysis revealed that the survival rate was lower in patients with positive expressions of APC and c-Myc proteins than in patients with negative expressions (P < 0.05). Histological type, pathologic grading, metastasis and c Myc were identified as independent risk factors with related to the prognosis of NSCLC patients in the multivariate Cox regression model (P < 0.05). CONCLUSION: APC and c-Myc may play an important role in the progression of NSCLC. PMID- 21302452 TI - [Influence of mutation of -1997G-->T of COL I A1 gene on the biochemical function of osteoblast]. AB - OBJECTIVE: To study the influence of mutation of -1997G-->T of COL I A1 gene on the biochemical function of osteoblast, and the pathomechanism of BMD. METHODS: Spongy bones were obtained to culture osteoblast primarily during total hip or knee replacements. The genotype of osteoblast was identified with PCR-RFLP. The amount of mRNA of COL I A1 and collagen type I were determined by RT-PCR and ELISA. The growth of osteoblast, the activity of bone ALP, and the amount of calcium in cell matrix and calcium nodus were measured. RESULTS: Three genotypes GG, GT and TT in osteoblast were successfully identified. Compared with GG and GT genotypes, lower expression of mRNA of COL I A1 gene, lesser collagen type I, calcium in cell matrix, and calcium nodus were found in the cells with TT genotype (P < 0.01). No significant differences were found between GG and GT genotype (P > 0.05). There were no significant differences in age, growth of osteoblast, and activity of bone ALP among the three genotypes (P > 0.05). CONCLUSION: Cells with TT genotype have low expression of mRNA of COL I A1 gene and less collagen type I , calcium in cell matrix and calcium nodus. The lower amount of collagen type I synthesized by osteoblast can decrease the matrix outside the bone cells and result in insufficient site for calcium deposition. This may be the cause of lower BMD in patients with TT genotype. PMID- 21302453 TI - [The effects of NKG2D mAb on the survival of allogeneic transplanted islets in spontaneous diabetic nonobese diabetic mice]. AB - OBJECTIVE: To investigate the effects of NKG2D mAb on the survival of allogeneic transplanted islets nonobese diabetic (NOD) mice, and to find if CD154 mAb has synergistic effects. METHODS: Spontaneous diabetic NOD mice transplanted with allogeneic islets of BALB/c mice were divided into 4 groups. Group A was control group, Group B were treated with anti-NKG2D monoclonal antibody (mAb), Group C were treated with CD154 mAb (MR1), Group D were treated with NKG2D mAb and MR1. Glucose levels were monitored at regular intervals through caudal vein, and islet function was evaluated by glycemia. Histological study was performed at graft rejection or at day 120. Spleen cell suspension was prepared for mixed lymphocyte cultivation. The kidneys hosting the islet graft were prepared with HE staining and immuno-histochemistry staining of CD3, CD4 and CD8 was performed. RESULTS: MR1 therapy alone significantly prolonged the survival of islet grafts when compared to NKG2D mAb group and the control group: median graft survival was 41 days versus 8 days (P < 0.05) and 8 days (P < 0.05), respectively. Combination therapy with NKG2D mAb and MR1 prolonged islet grafts survival when compared to MR1 therapy alone: median graft survival was 51 days versus 41 days (P > 0.05). CONCLUSION: NKG2D mAb alone did not result in the prolongation of islet graft survival, whereas CD154 mAb increased graft survival. When both antibodies were administered, a synergistic effect was obtained, but did not provide permanent protection from diabetes recurrence. PMID- 21302454 TI - [Preparation of zoledronic-acid-loaded collagen membrane]. AB - OBJECTIVE: To develop a new local delivery system, osteoclastic-inhibitor-loaded collagen membrane, and to evaluate its drug loading and drug release properties. METHODS: Efforts were made to develop the drug-loaded membranes by combining two commercially available collagen barrier membranes (Bio-Gide and BME-10X) with zoledronic acid (ZA). The physicochemical and pharmacological properties of resulting materials were determined using SEM, EDS, FTIR, and HPLC. RESULTS: After ZA loading, the micropores between the thin collagen fibers in the Bio-Gide disappeared, whereas crystalloid powders appeared on the surface of pore walls in BME-10X. Phosphorus was detected on both drug-loaded membranes. The Amides shifted. With the same drug solution, Bio-Gide presented larger amount of ZA loading and slower ZA release than BME-10X. ZA loading did not affect the 3D fiber network and the degradation of membranes. CONCLUSION: Both collagen membranes load ZA successfully and delay drug release. But Bio-Gide shows higher loading values and slower release than BME-10X. PMID- 21302455 TI - [Role of enamel organic matrix in the remineralization of initial demineralized enamel and artificial hydroxylapatite treated with Galla chinensis]. AB - OBJECTIVE: To observe the remineralization of initial demineralized enamel and artificial hydroxylapatite treated with Galla chinensis in vitro, and to assess the effect of enamel organic matrix on the potential of Galla chinensis to promote the remineralization of initial enamel carious lesions, further to elucidate the mechanism of Galla chinensis in promoting the remineralization of initial enamel carious lesion. METHODS: Bovine sound enamel blocks, non-organic enamel blocks and artificial hydroxylapatite blocks were demineralized and exposed to a pH-cycling. During the pH-cycling, the specimens were randomly treated with 1 g/L NaF, 4 g/L Galla chinensis extract (GCE) or double deionized water (DDW). Surface microhardness of all the samples was measured before and after the pH-cycling, and percentage surface microhardness recovery (% SMHR) was calculated. The surface morphology was observed by scanning electron microscopy. RESULTS: A significant increase in microhardness (P < 0.05) with many irregular deposits and prominences on GCE treated regular enamel blocks were observed. No significant increase in that of the regular enamel treated with DDW, enamel disposed of its organic matrix or artificial hydroxylapatite treated with GCE were observed (P > 0.05). No obvious changes in the SEM images of regular enamel treated with DDW, enamel disposed of its organic matrix or artificial hydroxylapatite treated with GCE compared to those of them before pH-cycling. CONCLUSION: Galla chinensis enhances the remineralization of initial enamel carious lesions in vitro. The organic matrix of enamel was shown to play a substantial role in the observed mechanism. PMID- 21302456 TI - [Condylar position of post-orthodontic patients with class II malocclusion]. AB - OBJECTIVE: To study the condylar position of post-orthodontic patients with class II malocclusion. METHODS: Forty four patients with class II malocclusion were recruited, among whom 22 were given orthodontic treatment and 22 without any treatment as controls. The condylar distractions between centric relation (CR) and centric occlusion (CO) were measured by an Panadent articulator with Measurement of Condylar Displacement (MCD). RESULTS: There was no significant difference in condylar position between the two groups. Most condylar distractions happened to the posterior-inferior direction and were clinically acceptable. The amount of distractions was not correlated with Class II elastics. CONCLUSION: There is no enough evidence to show that traditional orthodontic treatment impacts the condylar position in patients with Class II malocclusion. However, attention still needs to be paid to condylar position in order to achieve a functional occlusion. PMID- 21302457 TI - [The effect on angiogenesis of endometrium after transcervical resection of polyp]. AB - OBJECTIVE To investigate angiogenesis of endometrium after transcervical resection of endometrial polyp. METHODS: Twenty five patients were chosen whose final diagnosises are EP. They all conceived the treatment of transcervical resection of polyp in 5-7 days after the end of menstruation. The tissue of EP were resected in the operation were collected as the first group. The second group included 20 patients who conceived the treatment of transcervical resection of polyp, in the 1-3 months after the operation,we collected their endometrium located in the extent of rescection samely in one day of 5-7 days after the ending of their menstruations. 25 endometrium in proliferative stage were collected as the third group. expression of vascular endothelial growth factor (VEGF) and CD34 were detected by immunohistochemical methods. We counted the microvessel density (MVD) depending on microscope, and detected integrated optical density (IOD) of VEGF by using special image analysis software (image pro plus 4.5). RESULTS: IOD of VEGF expression and MVD of the first group were significantly higher than that of the second and the third group (P > 0.05). IOD of VEGF expression and MVD were both same in the second and third group (P > 0.05). CONCLUSION: Significance of the angiogenesis in the formation of EP was obvious. Expression of VEGF and MVD could be degraded in someone's local endometrium after they conceived the treatment of TCRP. These results were the molecular mechanisms how TCRP could cure EP successfully. PMID- 21302458 TI - [Isoflurance-based intravenous and inhalation combined anesthesia versus low-dose ketamine-based total intravenous anesthesia for valvuloplasty in minipigs]. AB - OBJECTIVE: To compare the effectiveness of anesthesia between Isoflurane-based intravenous and inhalant combined approach and low-dose-ketamine-based total intravenous approach for valvuloplasty in minipigs. METHODS: Twenty four minipigs were given 3-5 mg/kg ketamine intramuscularly and 15-20 mg/kg pentobarbital intravenously for anesthetic induction and intubation. They were then randomly divided into two groups, each with 12 minipigs. In group I (isoflurane), the minipigs received isoflurane 1.0-2.0 minimum alveolar concentration (MAC), fentanyl 20-25 microg/(kg x h), midazolam 0.1-0.2 mg/(kg x h) and pipecuronium 0.10-0.15 mg/(kg x h) for maintenance. In group K (ketamine), the minipigs were given ketamine 3-5 mg/(kg x h), pentobarbital 8-10 mg/(kg x h) and pipecuronium 0. 10-0.15 mg/(kg x h) intravenously. The general peri-operation characteristics were recorded. Hemodynamics, blood gas and respirations were monitored. Anesthetic complications were observed. RESULTS: Two minipigs died from causes other than anesthesia. The minipigs in group I had lower mean aortic pressure (MAP) than those in group K during cardiopulmonary bypass (CPB), but without a statistical significance. The minipigs in group I had significantly lower levels of lactic acid than those in group K after CPB cessation (P < 0.05). The times on analepsia were (21.6 +/- 4.1) min and (67.8 +/- 8.5) min for group I and group K, respectively. The times on ventilator were (281.3 +/- 34.7) min and (330.4 +/- 27.0) min for group I and group K, respectively. The differences were significant (P < 0.05). One minipig in group K was intubated for espiratory depression after surgery. CONCLUSION: The isoflurane-based intravenous and inhalant combined anesthesia was preferable for valvular reparation in minipigs. However, low-dose ketamine-based total intravenous anesthesia is also a good choice in the circumstance of limited resources. PMID- 21302459 TI - [The sedative and hypnotic effects and safety of oral emulsified isoflurane in rats]. AB - OBJECTIVE: To investigate the sedative and hypnotic effects and safety of oral emulsified isoflurane in rats. METHODS: Thirty healthy Sprague-Dawley (SD) rats were randomly divided into three groups. The rats in the emulsified isoflurane group were orally administered with emulsified isoflurane with the sequential method, while the rats in the normal sodium group and the intralipid group were orally administered with sodium and intralipid respectively. The rats in the emulsified isoflurane group received 2.15 mL/100 g of 8% emulsified isoflurane, a dosage calculated with an increase of a common ratio (r = 0.8) on the basis of median effective dose (ED50). Similarly, 2.15 mL/100 g of normal sodium and 2.15 mL/100 g of 30% intralipid were given to the rats in the normal sodium group and the intralipid group, respectively. The neurobehaviors of the rats were assessed, and the interval of disappearance and recovery of the righting reflex were recorded. RESULTS: Oral emulsified isoflurane reduced the autonomic activity time and induced the loss of righting reflex. The ED50 of the loss of righting reflex was 1.72 mL/100 g. The rats orally administered with 2.15 mL/100 g of 8% emulsified isoflurane had 90% of loss of righting reflex, with a sleeping latency of 15-20 min and up to 60 min of sleeping duration. CONCLUSION: Oral emulsified isoflurane has obvious sedative and hypnotic effects. PMID- 21302460 TI - [A photographic scale for evaluating facial pores and analysis of factors associated with pore widening in Chengdu]. AB - OBJECTIVE: To develop a photographic scale for grading widening of pores, and to identify the factors associated with pore widening. METHODS: People with widened pores were recruited, with photographs taken on their nasal tips, nasal alas and cheeks. A questionnaire survey was undertaken by dermatologists to assess the severity of pore widening. A Cumulative Logit Model was established to identify factors that were associated with pore widening. RESULTS: A total of 115 people participated in the study and 562 photographs were taken. The photographic scale was highly consistent with the clinical judgment. Another 1011 residents aged from 18 to 70 years old in Chengdu were surveyed. The logit model revealed that facial pore widening were associated with gender, age, oily skin, sun protection and anti-aging cosmetic. CONCLUSION: The photographic scale is reliable and easy to use. Gender, age and oily skin are risk factors, and sun protection and anti aging cosmetic are protective factors with related to pore widening. PMID- 21302461 TI - [Separation, culture and purification of rat brain microendothelial cell]. AB - OBJECTIVE: To develop a separation method for brain microendothelial cells with the comparison of other ones. METHODS: Twice enzymatic digestion and twice gradient centrifugation were applied to separate rat brain microendothelial cells. Then, immunomagnetic beads and Thy1.1 antibody were used respectively to purify the cultured cells. RESULTS: Twice enzymatic digestion and twice gradient centrifugation could separate the cell successfully. High purification but low cell yield was obtained with immunomagnetic beads. The cells handled with Thy1.1 antibody had both higher purify coefficient and higher yield. CONCLUSION: The developed method could separate the brain microendothelial cells successfully. PMID- 21302462 TI - [Simultaneous determination of five illegal drugs in weight control foods with solid phase extraction-high performance liquid chromatography]. AB - OBJECTIVE: To develop a method for simultaneous determination of hydrochlorothiazide, furosemide, clopamide, bumetanide and sibutramine hydrochloride in weight control foods with solid phase extraction-high performance liquid chromatography. METHODS: The analytes in the samples were extracted with 2% phosphoric acid-methanol (1:1, V/V) solution ultrasonically and centrifuged. The extracts were clean-up with Osis MCX SPE columns, concentrated under weak N2 stream, and reconstituted with 2% phosphoric acid-methanol (1:1, V/V) solution, vortex mixing and centrifugation at 12,000 r/min. The high performance liquid chromatography was performed with Phenomenex C18 (250 x 4.60 mm, 5 microm) as separation column, 0.02 mol/L acetonitrile potassium dihydrogen phosphate buffer as mobile phase, gradient elution of 1.0 mL/min for the flow rate, and 40 degrees C for the column temperature. The standard curve method was used for the quantitative analysis. RESULTS: A good linear range appeared for the five analytes from 0.25 to 100 microg/mL (r > or = 0.999). The detection limits were 5.2-108 microg/kg. The average recoveries were 86.5%-113.1%, with the relative standard deviations of 1.6%-8.9%. CONCLUSION: The proposed method is a reliable method with high selectivity and high sensitivity for the detection of the five illegal chemicals in the weight control foods. PMID- 21302463 TI - [Determination of dimethyl sulphate in environmental samples with GC-ECD]. AB - OBJECTIVE: To develop an gas chromatography-electrophoretic capture detection (GC ECD)method for determining dimethyl sulphate (DMS) in environmental samples. METHODS: The environmental samples were dissolved with acetone and the DMS was reacted with KI. The reaction product of methyl iodide was extracted with Hexane and determined by GC-ECD, with HP-5 (30.0 m x 0.32 mm x 0.25 microm) as column, high purity nitrogen as carries, 60 degrees C for column temperature and 240 degrees C for ECD and injector temperature, and 5:1 for split ratio. RESULTS: The linear range appeared from 0.05 microg/mL to 2.0 microg/mL. The detection limit was 0.0011 microg/mL. The precision [measured by relative standard deviation (RSD)] of peak area and reserved time for the standard solution was 4.95% and 0.15% respectively for intra-day detections, and 5.99% and 0.83% respectively for inter-day detections. Satisfactory results were obtained for the analysis of environmental samples. The RSD for the water and soil samples were 9.6% and 7.5% respectively and the recoveries were 76.0%-85.0% and 82.0%-110.0% respectively. CONCLUSION: The method was simple, accurate, sensitive and applicable for DMS analysis in environmental samples. PMID- 21302464 TI - [Nonenhanced renal artery MR angiography with time spatial labeling inversion pulse technology and its clinical values]. AB - OBJECTIVE: To evaluate the feasibility of nonenhanced renal artery MR angiography (MRA) with respiratory-gated time spatial labeling inversion pulse (time-slip) and its clinical application. METHODS: Thirty-two consecutive patients underwent the 1.5 T MRI (TOSHIBA EXCELART Vantage) examination to visualize renal artery with contrast-enhanced MRA (CEMRA) and the examination with time-slip technology. Signal to noise ratio (SNR) and contrast to noise ratio (CNR) were measured on CEMRA and Time-slip images, respectively. Two experienced radiologists assessed the imaging quality of renal artery MRA on 3D-MIPs reconstructed images. RESULTS: Sixty-four renal arteries and 3 accessory renal arteries in 32 patients were visualized on both time-slip and CEMRA. SNR values on Time-slip and CEMRA were 102.7 +/- 16.2 and 83.9 +/- 17.7 (t = -4.625, P < 0.001); CNR were 97.8 +/- 16.1 and 78.8 +/- 18.3 (t = -4.554, P < 0.001), respectively. Time-slip MIP images obtained higher quality than CEMRA did (Z = -2.318, P = 0.02), and venous contamination was sharply reduced on Time-slip technology when compared with CEMRA (Z = -4.895, P = 0.001). CONCLUSION: Non-enhanced renal artery MRA with respiratory-gated time-slip technology can provide higher SNR images of renal artery than conventional CEMRA, which can provide more information for clinical decision-making. PMID- 21302465 TI - [Clinical features and treatment of seventh day syndrome following living donor liver transplantation]. AB - OBJECTIVE: To investigate the clinic features and treatment of seventh day syndrome (7DS) following living donor liver transplantation (LDLT). METHODS: From January 2002 to March 2009, 8 patients were diagnosed with 7DS following LDLT. A retrospective analysis was made on the clinical data containing liver and renal functions, coagulation function, sonographic and histological features and effectiveness of the treatments. RESULTS: Rapid deterioration of liver function happened 1-2 weeks after operations, followed by renal dysfunction. There was a reduction of velocity or bidirectional blood flow in the portal vein. Massive coagulative necrosis with disruption of lobular architecture occurred in 3.3% of cases, with a mortality of 87.5%. The steroid pulse and OKT3 (anti-CD3 antibody) therapy showed minimal effects. Prolonged application of i.v. methylprednisolone may be helpful with the delay of 7DS. CONCLUSION: The 7DS may be an immune mediated graft failure. The prevention and control of 7DS is difficult due to lack of research evidence. PMID- 21302466 TI - [Travel medicine: an emerging discipline in medicine]. PMID- 21302467 TI - [The profile of Israeli travelers to developing countries: perspectives of a travel clinic]. AB - BACKGROUND: The number of Israeli travelers is increasing, including the number of travelers to developing countries. AIM: This study aimed to characterize the profile of Israeli travelers to developing countries. METHODS: Data regarding demographics, travel destinations, trip duration and the purpose of travel were collected on travelers attending the pre-travel clinic at the Sheba Medical Center during a period of 9 years. RESULTS: Between the dates 1/1/1999 and 31/12/2007, 42,771 travelers presented for consultation at the Sheba Medical Center pre-travel clinic. The average age was 30.8 +/- 13.4 years and 54% of the travelers were males. The female proportion increased from 42% in 1999 to 49% in 2006. There was a steady increase in the number of travelers attending our clinic, except in 2003 (coinciding with the SARS epidemic). Post-army backpackers (20-25 year-old age group) were only 43% of the travelers. Children (<18 years), and elderly (>60 years) comprised 4.4% and 4.6% of the travelers, respectively. The favorite destinations were Asia (55%), followed by Latin America (27%) and Africa (13%). The distribution of travel destinations varied significantly during the study period. Of note is the sharp decline in travel to Africa following the terrorist attack in Mombassa, Kenya (November 2002). The median trip duration changed during the study period, from 30 to 45 days, between 1999-2004 and 2005 2007 respectively. The majority (87%) of voyagers traveled for pleasure, 6% went for business, and 7% were representatives of governmental organizations. CONCLUSION: This study found an increasing diversity in the traveler population (more women, more children and older travelers) and more diversity in travel destinations. Disease outbreaks and terrorist attacks had transient negative impacts on the number of travelers. PMID- 21302468 TI - [Morbidity of Israeli travelers after traveling to developing countries]. AB - BACKGROUND: International tourism, including traveling to developing countries, has become increasingly popular. The number of Israeli travelers to developing countries is estimated at approximately 170,000 annually. AIM: This study aims to analyze the morbidity among returning Israeli travelers. METHODS: A retrospective evaluation was conducted of patient files for those attending the Tropical Disease clinic at the Sheba Medical Center between 1994-2004. RESULTS: A total of 842 patients attended the clinic during this period, with 1126 different diagnoses, including 20.9% of patients who were hospitalized in Israel and 6.2% abroad. Slightly more than half (56.7%) were male, 70% were in the 20-29 year age group. Most of the patients attended the clinic shortly after returning from traveling, but some attended the clinic more than 1 year later. The main destinations were Asia (49.2%), Latin America (23.4%) and Africa (23.2%). The most common diagnoses were gastrointestinal disease (41%), fatigue (25.8%), dermatological conditions (23.4%) and febrile diseases (22.7%). The typical diagnoses in travelers returning from Asia were chronic diarrhea and dengue fever. Dermatological conditions including leishmaniasis were prominent in travelers returning from Latin America, and in travelers returning from Africa- malaria, and schistosomiasis. In addition, there were gender differences; males acquired malaria, leishmaniasis and schistosomiasis more often, while females had more gastrointestinal complaints and fatigue. CONCLUSIONS: Travelers acquired different health problems in different continents. This must be taken into consideration when patients seek medical advice either before or after their journey. Furthermore, physicians must be aware of the importance of having a thorough travel history of their patients, since medical problems acquired during travel may manifest long after returning home. PMID- 21302469 TI - [The awareness of malaria in primary care medicine]. AB - BACKGROUND: Malaria is still one of the most prevalent infectious diseases worldwide. It is the most common specific cause of fever in returning travelers. Western countries, Israel amongst them, are no longer endemic for the disease. Nonetheless, morbidity is increasing due to the importation of malaria by travelers to endemic regions. METHODS: In this study the authors observed the diagnostic process that 22 malaria patients underwent prior to their hospitalization at the Sheba Medical Center. RESULTS AND CONCLUSIONS: The results of the study were disturbing and showed underdiagnosis of malaria at a rate of 78% by primary care physicians and 28% by physicians in the emergency rooms. These rates are comparable to reports from other western countries and may be the result of a variety of reasons. The major reasons are the non-specific presentation of the disease, lack of awareness of the possibility of malaria and misinterpretation of laboratory results. PMID- 21302470 TI - [Rickettsia africae infection among participants in a women's safari to South Africa]. AB - PREFACE: In recent years infections with Rickettsia africae (African tick bite fever) have become a common and important cause of febrile illness among travelers returning from Sub-Saharan Africa, primarily from South Africa. METHODS: A prospective observational study, involving 671 participants in safaris to South Africa during 2008. RESULTS: Nine participants (1.34%) were diagnosed with African tick bite fever. The symptoms included fever, headache, muscle pain, lymphadenopathy, vesicular rash, and an eschar. Lack of familiarity with the disease led to an incorrect diagnosis and delayed treatment with doxycycline in a number of cases. CONCLUSIONS: African tick bite fever is frequent among Israeli travelers to Sub-Saharan Africa. Travelers should be counseled on tick bite prevention. Increased awareness of the disease among Israeli physicians may prevent diagnostic delays. PMID- 21302471 TI - [Neurocysticercosis in Israel]. AB - BACKGROUND: Neurocysticercosis is the most common cause of adult onset seizures in developing countries. In recent years, with the rise in the number of immigrants to developed countries and travelers to endemic areas, neurocysticercosis is increasingly diagnosed in non-endemic countries. AIMS OF THE STUDY: The authors describe the clinical and epidemiologic characteristics of patients diagnosed with neurocysticercosis acquired in Israel or in immigrants to Israel from endemic countries. METHODS: A retrospective national survey of patients diagnosed with neurocysticercosis during 1994-2009 was conducted. Clinical and epidemiologic data were recorded. Case definition consisted of roentgenologic, serologic and pathologic features. RESULTS: In all, 17 cases of neurocysticercosis were diagnosed in Israel during the study period. Nine (53%) cases were diagnosed in travelers to endemic areas, and six (35%) in immigrants from endemic areas. Two cases were native Israelis who had never traveled to an endemic area. Most immigrants suffered from multiple brain lesions. Two immigrants underwent brain biopsy. CONCLUSIONS: This is the first report of the clinical and epidemiologic characteristics of patients diagnosed with neurocysticercosis acquired in Israel or diagnosed in immigrants to Israel. Neurocysticercosis must be included in the differential diagnosis of seizures, headache or neurologic deficit with single or multiple brain lesions, especially in immigrants from endemic countries. Invasive procedures may be obviated by appropriate clinical diagnosis, imaging and serology. PMID- 21302472 TI - [Acute respiratory distress syndrome (ARDS) as a complication of malaria P.vivax]. AB - The authors review a case of an Indian tourist couple both presenting a clinical picture of intermittent fever, thrombocytopenia and relative leukopenia several days after their arrival to israel. The diagnosis of Plasmodium vivax (P.vivax) malaria was established in both patients and antimalarial treatment with chloroquine was initiated. Shortly after initiating the treatment, the husband developed clinical acute respiratory distress syndrome (ARDS). With symptomatic treatment, the patient recovered within few days. The diagnosis of P. vivax was confirmed by PCR, and was shown to be a single infection with no Plasmodium falciparum as co-infection. Although P. vivax is considered as having a benign course, in contrast to P. falciparum infections, in recent years there have been an increased number of reports of complicated P. vivax malaria, mainly ARDS. Physicians should be aware of the possible complicated course of P. vivax malaria. PMID- 21302473 TI - [Polymorphism at the MDR1 locus as a cause of mefloquine-induced psychosis]. AB - The use of mefloquine for malaria prophylaxis has been hampered by the drug's adverse effects. Foremost among the latter are neuropsychiatric adverse effects such as dizziness, vivid dreams, epilepsy and psychosis. Recent evidence from studies in mice has implicated the lack of P-glycoprotein at the blood-brain barrier as the cause of these adverse effects. The authors present the case of a 60 year-old man who was hospitalized for psychosis following ingestion of mefloquine for malaria prophylaxis. Genetic studies have found polymorphism at the MDR1 gene with genotypes 3435TT and 2677TT which underlie high levels of mefloquine in the brain. PMID- 21302474 TI - [Laboratory tests for parasitic diseases in Israel]. AB - Microscopic examination is still considered the gold standard for the diagnosis of parasitic diseases. In many clinical laboratories in hospitals and in health maintenance organizations ("Kupot Holim"), an excellent microscopic identification of parasites is performed. Microscopic examinations using wet mount preparations are performed for the detection of protozoan trophozoites and helmintic ova or larvae. Specific concentration techniques, including flotation and sedimentation procedures are further performed for the diagnosis of parasitic diseases. However, microscopic examinations are time-consuming, non-sensitive and not always reliable. Furthermore, the diagnosis of certain infections is not always possible by searching for the parasites in host tissues or excreta since risky invasive techniques might be necessary to locate the parasites. Detection of antibodies can be very useful as an indication for infection with a specific parasite, especially in individuals with no exposure to the parasite prior to recent travel in a disease-endemic area. In addition to serology, there are other tests of high sensitivity which can be integrated with microscopy, such as antigen detection in stool and blood samples as well as the use of other molecular diagnosis methods. There are two main laboratories in Israel where parasitic diagnosis is available by integration of microscopy, serology, antigen detection and molecular methods: The Reference Laboratory for Parasitology in Jerusalem at the Central Laboratories of the Ministry of Health (MOH) and the Laboratory of Parasitology at Soroka University Medical Center, Beer Sheva (SOR). There are also two special diagnostic units, one responsible for the identification of toxopLasma: Reference Laboratory for Toxoplasmosis, Public Health Laboratory, Ministry of Health, Tel Aviv (Tox), and the other for the identification of Leishmaniasis: Kuvin Center, Faculty of Medicine, Hebrew University of Jerusalem (Kuv). This article summarizes the tests which are currently available for the diagnosis of parasites in Israel and specifies the laboratories in which they can be performed. PMID- 21302475 TI - [Vaccinations for travelers--a review of current recommendations]. AB - The number of travelers abroad rises every year. Concurrently, the age and health conditions of the travelers are becoming increasingly varied as are their destinations and the degree of risk involved. In the face of this complexity, it is recommended that travelers seek medical advice at specializing travel medicine clinics before leaving for their trip. The object of the consultation is to fit the general guidelines regarding preventative behavior and vaccinations to the specific traveler. Several sources of information are available for receiving updated vaccination recommendations for travelers. Usually these sources provide similar recommendations but occasionally different instructions can be found. In this review, the authors discuss vaccination recommendations for travelers while pointing out the similarities and differences among the various information sources. The different recommendations for travelers groups and types are noted. The available vaccinations are reviewed, detailing the indications and contraindications as well as side effects. PMID- 21302476 TI - [Personal protection measures against blood-sucking insects and ticks]. AB - Blood-sucking arthropods are major vectors of various pathogens like viruses, bacteria, protozoa and nematodes. Preventing exposure to the vector is imperative especially when vaccine and prophylactic treatments are not available. Personal protection measures (PPM) are essential and often the only means available when dealing with blood-sucking disease transmitting arthropods. Awareness of the risk in the specific areas of travel is the first step to be taken before and while traveling. PPM include preventive personal behavior, suitable clothing, application of insect repellents to the skin, the use of space repellents, impregnation of clothing, camping gear and bed nets and, when necessary, ground spraying of insecticides. The registered and recommended active ingredients for skin application are Deet, picaridin (icaridin), p-menthane-3,8-diol (PMD) and IR3535. Volatile pyrethrins are used as space repellents while pyrethroids, especially permethrin, are employed for impregnation and for ground spraying. It is recommended to purchase only products registered in Israel or other developed countries. These products should have a detailed label specifying the concentration of the active ingredient, application instructions and the duration of protection. PMID- 21302477 TI - [Fever in returned travelers]. AB - Fever is one of the most common complaints in returned travelers and accounts for about 25% of cases seeking medical care. Fever is one of the most challenging conditions since fever may be the manifestation of a self-limited, trivial infection, or on the other hand, can be the presenting sign of an infection that could be rapidly progressive and lethal. The list of infections that should be considered includes common, worldwide (cosmopolitan) infections as well as unique tropical diseases, related to specific regions (malaria, dengue fever, enteric fever, schistosomiasis, leptospirosis, rickettsia). Many febrile infections are associated with focal signs and symptoms, which help to limit the differential diagnosis. However, returning travelers with undifferentiated fever are the largest group of those with febrile infection and among these patients, malaria is the most common specific pathogen. The approach to patients must include consideration of the geographic area visited, the estimated incubation period, mode of exposure and impact of pre-travel vaccination. A routine laboratory work up may offer important clues to the final diagnosis. Initial attention should focus urgently on infections that are treatable, transmissible, and that cause serious sequelae or death. Finally, malaria must be ruled out in any febrile traveler returning from endemic regions. PMID- 21302478 TI - [Protracted rheumatologic manifestations in travelers]. AB - Protracted rheumatological manifestations especially arthralgia and or polyarthritis may occur as a consequence of a wide range of pathogens including viral, bacterial and parasites. Few pathogenetic mechanisms leading to these clinical presentations have been suggested including a direct invasion of the synovial cells by the pathogens, immune complex formation, and others. The natural history of infectious arthritis/arthralgia is altogether benign, with full recovery and without sequelae, albeit sometimes very long. Diagnosis of infections-related arthralgia/arthritis is important since these diseases have a better prognosis, and can relieve anxiety among patients who are afraid of developing a chronic rheumatic disease. Since many patients will seek medical advice with these chronic complaints a long time after travel, physicians should be aware of the possible association between these complaints and remote travel. Thus, travel history should be mandatory, even in a rheumatologic setting. PMID- 21302479 TI - [Dr. Sarah Ben Ami Solodar: a pioneer in the fight against malaria in the moshavot in the Upper Galilee]. AB - Eretz Israel medical history considers Dr. Sarah Ben Ami Solodar, a pioneer in the fight against malaria, as the first woman doctor in the moshavot (villages) of the Upper Galilee. In spite of her undisputed place in the historical account, information about her is extremely meager and the historical sources, surveying the development of medicine in Eretz Israel, ignore her achievements. This article portrays this fine doctor, a young educated woman, a fervent Zionist who had immigrated from Odessa, her dream being to fulfill her commitment to Zionism by working as a doctor in Eretz Israel. The article aims to tell the story of her exciting life and describes her medical-educational activities in the health services in the moshavot of the Upper Galilee during the period 1913 to 1919, against the background of life in the moshavot during the final years of the Ottoman period. She fought malaria in Yesod Hama'alah and in Mishmar Hayarden under the guidance of Dr. Hillel Yaffe. She deserves to be remembered as the first woman doctor working in the Upper Galilee moshavot and as a pioneer in her field, who contributed to the development of the medical system in the country and in particular in the Upper Galilee, during the first years of settlement in Eretz Israel. PMID- 21302480 TI - [Integrative medical intervention strategies for recurrent angina after coronary revascularization]. AB - Coronary revascularization (CRV), mainly by means of percutaneous coronary intervention or coronary artery bypass graft surgery, has been developed nowadays to rescue patients with myocardial ischemia. Nevertheless, the recurrent angina after coronary revascularization (RACR) remains a concernful problem in clinical practice, its management is still a real challenge to physicians. Therefore, the prevention and treatment of RACR become vital for keeping the benefits of CRV. The common causes of RACR and the adoptable integrative medical approaches for its diagnosis and treatment were discussed in this paper. PMID- 21302481 TI - [Application of pragmatic clinical trials in clinical evaluation of Chinese medicine]. AB - Since the evidence-based medicine (EBM) being evoked widely, to seek out the best evidence is becoming the pivotal step for the development of Chinese medicine (CM), and randomized controlled trial (RCT, at most times, it means explanatory clinical trial--ECT) has been accepted as the general golden standard for the evaluation of clinical intervention. However, it is noted that the traditional RCT (ECT) is unsuitable for the special characteristics of individual treatment in CM. The formation and development of CM theory is found on large amount of clinical experiences, and to evaluate its clinical efficacy and safety is the most primary task. Because the CM intervention measures are complex and individualized, the clinical effectiveness of CM is embodied as a complex system, which impacted greatly by the environment factors. It is deemed that the pragmatic clinical trial (PCT) has the character just fitting for the evaluation. The feasibility of PCT in CM clinical evaluation is discussed in this paper in order to raise a new issue for the evaluation of CM effectiveness. PMID- 21302482 TI - [Relationships of blood stasis syndrome, CYP2C19 gene polymorphism with clopidogrel resistance and post-PCI prognosis]. AB - OBJECTIVE: To study the relationships of blood stasis syndrome (BSS), CYP2C19 gene polymorphism with clopidogrel resistance (CR) and post-PCI prognosis. METHODS: Materials of 415 patients (Han nationality) with coronary atherosclerotic heart disease (CAHD) hospitalized between January 2008 and July 2009 were collected. The CYP2C19*2 gene distribution in patients with different degrees of BBS was observed, and the relationships of BSS, CYP2C19*2 with the laboratory CR [LCR, percentage of patients with ADP-induced maximal platelet aggregation (MPA) rate reduced for < or = 10% after a 10-day clopidogrel treatment] were analyzed. Besides, an assay on the relations of maximal platelet aggregation suppressive rate (MPAS), LCR, recurrent cardiovascular events (RCEs) with BSS and CYP2C19*2 gene mutation was performed in a 7-month (in median) follow-up study on 180 post-PCI patients who received conventional treatment by clopidogrel and aspirin. RESULTS: (1) The frequency of 681G>A mutation in patients with severe BSS and in those who received PCI was higher than that in those with mild BSS (P<0.01); (2) After clopidogrel treatment, LCR was 45.06% (187/415) in total patients, 61.63% (143/232) in patients with severe BSS, 53.24% (115/216) in patients carrying 681A allele; (3) The MPA was less decreased and the LCR was higher in patients with severe BSS than in those with mild BSS (P<0.01); (4) After clopidogrel treatment, the MPA was less decreased and the LCR was higher in carrying CYP2C19 681A allele than in those carrying 681 GG type gene (P<0.01); (5) Follow-up study showed that not only the MPA suppressive rate was lower, LCR was higher in patients with severe BSS or those carrying CYP2C19 681A allele, but a higher RCEs was also shown in them (P<0.01). Moreover, after the various risk factors had been adjusted, the RCEs in patients with severe BSS or carrying CYP2C19 681A allele was higher than in those with mild BSS (OR: 4.01; 95% CI: 1.79-8.99) or carrying GG type gene (OR: 6.89; 95% CI: 2.97-15.97). CONCLUSION: Severe BSS and CYP2C19*2 gene mutation are associated with LCR, and could increase the risk of post-PCI cardiovascular events recurrence in patients with CAHD. PMID- 21302483 TI - [Effect of rhodiola on serum troponin 1, cardiac integral backscatter and left ventricle ejective fraction of patients who received epirubicin-contained chemotherapy]. AB - OBJECTIVE: To investigate the myocardial protective effect of Rhodiola on patients who received epidoxorubicin (EPI) treatment. METHODS: Forty-two patients with myocardial damage who received 3 courses of EPI-contained chemotherapy were randomly and equally assigned to two groups, the Rhodiola treated group and the control group. After 1-month treatment, the changes in serum troponin I (cTnI) level, cardiac integral backscatter (IBS), and left ventricle ejective fraction (LVEF) in patients were observed and compared between groups. RESULTS: Levels of cTnI in the treated group and control group were (0.54 +/- 0.05) mg/L and (0.98 +/- 0.03) mg/L respectively, IBS were 55.23 +/- 5.72 scores and 61.23 +/- 5.96 scores, and LVEF (%) were 68 +/- 3 and 57 +/- 2 respectively, all showed significant differences between groups (P<0.05). CONCLUSION: Rhodiola can improve cardiac function, and suppress the increase of serum cTnI level and IBS in patients who received EPI treatment. PMID- 21302484 TI - [Effect of post-remission therapy mainly with compound huangdai tablet on long term survival of patients with acute promyelocytic leukemia]. AB - OBJECTIVE: To investigate the effect of post-remission therapy mainly with Compound Huangdai Tablet (CHDT) on long-term survival of patients with acute promyelocytic leukemia (APL). METHODS: One hundred and twelve APL patients were treated after remission mainly with CHDT administered alternately with chemotherapeutic projects such as HACP, HAOP, HAEP and HAMP. The relapse rate and relapse-free survival (RFS) rate in them were estimated by bone marrow examination. RESULTS: The total relapse rate was 14.29% (16/112), and the median time of relapse was 12.5 (4-67) months. Patients were followed up for 1-72 months, the median follow-up time being 59 months. The actual RFS rate of 1-, 2-, 3-, 4-, 5- and 6-year was 92.86%, 89.29%, 88.39%, 87.50%, 86.61% and 85.71%, respectively, while the estimated RFS rate (%) of corresponding year was 92.45 +/ 2.57, 88.25 +/- 3.20, 87.09 +/- 3.36, 85.89 +/- 3.52, 84.44 +/- 3.75 and 82.78 +/- 4.03 respectively; the relapse rate in patients who received treatment after complete response for <10 courses group was 34.29%, while in those treated for > or = 10 courses was 5.19%; and the RFS rate in them was 65.71% and 94.81% respectively, the difference between groups was statistically significant (P<0.01). CONCLUSION: The post-remission therapy mainly with CHDT is an effective and feasible program for the treatment of APL. PMID- 21302485 TI - [Clinical observation on treatment of major depressive disorder by paroxetine combined with chaihu xiaoyao mixture]. AB - OBJECTIVE: To evaluate the efficacy and safety of Chaihu Xiaoyao Mixture (CXM) for the treatment of major depressive disorder (MDD). METHODS: One hundred and ninety patients with MDD were randomly assigned to two groups, the test group and the control group. They were treated by paroxetine combined with CXM or placebo for 8 weeks. The therapeutic efficacy was evaluated at the end of the 2nd, 4th and 8th week by scoring according Hamilton Rating Scale for Depression (HAMD-17) and Clinical Global Impression (CGI) scale, and the adverse reaction was scaled by Treatment Emergent Symptoms Scale (TESS). RESULTS: Follow-up study was completed in 89/92 patients in the test group, and 93/98 patients in the control group, with 3 and 5 cases dropping, respectively. The effective rate in the two groups was 84.8% and 71.4%, and the cure rate was 69.6% and 55.1%, respectively, which were significantly higher in the test group than in the control group (chi2=4.92, P<0.05; chi2=4.22, P<0.05). As compared with the baseline, significant differences in HAMD-17 total score and scores of its various factors as well as the CGI score were shown in both groups after 2, 4 and 8's week treatment (P<0.01). Comparison between groups showed that significant differences presented in HAMD-17 total score and CGI score at the end of the 8th week (P<0.01), while comparison of adverse reactions between groups showed insignificantly statistical difference (P>0.05). CONCLUSION: Combined treatment of CXM and paroxetine is more effective than that with paroxetine alone in treating MDD, and it could enhance the clinical efficacy with higher safety. PMID- 21302486 TI - [Efficacy of integrative medicine for the treatment of rheumatoid arthritis and its effect on glucocorticoid receptor expression]. AB - OBJECTIVE: To investigate the efficacy and mechanism of Fengshikang (FSK) in treating rheumatoid arthritis (RA). METHODS: Thirty-eight patients with RA of damp-heat block syndrome type in Chinese medicine (CM), were randomized into two groups. They all received glucocorticoid therapy for 1 month, but FSK was administered to the 20 patients in the CM group in addition, while to the 18 in the WM group, MTX was given. Besides, a normal control group with 20 healthy subjects was set up. Blood levels of RA related indices were measured and compared. RESULTS: After treatment, the levels of rheumatoid factor (RF) and C reactive protein (CRP) were significantly reduced in both groups (P<0.05), but the reduction was more significant in the CM group (P<0.05). No significant change was found in the level of ESR after treatment and showed no significant difference between groups (P>0.05). Both hGRalpha mRNA and hGRbeta mRNA expressions were significantly higher in the patients than in the normal controls (P<0.01), they were lowered after treatment in the CM group (P<0.01), but significant reduction could only be found in level of hGRbeta mRNA in the control group (P<0.01). CONCLUSION: FSK combined with glucocorticoid can effectively control the inflammatory reaction, decrease the level of hGRalpha and hGRbeta expressions and enhance the clinical efficacy in treating RA. PMID- 21302487 TI - [Effect of compound danshen dripping pill on arterial intima-media thickness in patients with newly diagnosed type 2 diabetes mellitus]. AB - OBJECTIVE: To investigate the effect of compound Danshen Dripping Pill (CDDP) on peripheral arterial intima-media thickness (IMT) in patients newly diagnosed as type 2 diabetes mellitus. METHODS: One hundred and eight patients were equally randomized into 3 groups, in addition to the basic hypoglycemic, hypotensive and lipid-regulation treatment, they were administered orally with aspirin (0.1 g, once daily), vitamin E (0.1 g, twice daily) and CDDP (10 pills, thrice daily) for 18 months, respectively. The conventional cardiovascular risk factors, such as hyperglycemia, lipids profile, and homeostasis model assessment of insulin resistance (HOMA-IR) as well as ultrasound measurement of peripheral arterial IMT before and after treatment were compared. RESULTS: In the group treated with CDDP after treatment, the levels of HbA1c, serum total cholesterol and low density lipoprotein cholesterol (LDL-C) were significantly lower (all P<0.01), HOMA-IR was higher than those in the other two groups; while IMTs of carotid, iliac and femoral arteries were insignificantly different among them (P>0.05); however, the increment of carotid IMT in the CDDP treated group was less than that in the aspirin treated group (P<0.05), and that of femoral IMT was less than both the aspirin and vitamin E treated groups (P<0.05). CONCLUSION: For the patients with newly diagnosed type 2 diabetes, additional administration of CDDP to the conventional treatment could exert beneficial effects on blood glucose controling, and lipid profile improvement and delay of arterial intima-media proliferation. PMID- 21302488 TI - [Study on somato-type distribution and its correlations with body mass index, blood lipids and hepato-enzymes in 1 163 patients with non-alcoholic fatty liver disease]. AB - OBJECTIVE: To investigate the distribution of somato-types in Chinese medicine and its correlations with body mass index (BMI), blood lipids and hepato-enzymes in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: From January 2008 to December 2008, the somato-types of 1 163 NAFLD patients were categorized, and its correlations with BMI, blood lipids and hepato-enzymes were analyzed. RESULTS: Among the 1 163 patients, 401 were categorized as qi-deficiency type and 371 as phlegm-dampness type, accounting for 66.38%. Levels of BMI, blood lipids (TC, TG, LDL) and hepato-enzymes (ALT, AST, GGT) in patients of phlegm-dampness type were higher than those in patients of other types, the differences were statistically significant (P<0.05). CONCLUSIONS: Qi-deficiency type and phlegm dampness type are the dominant pathogenetic somsto-types in patients with NAFLD; abnormal BMI, blood lipids and hepato-enzymes may present in those of phlegm dampness type more frequently. PMID- 21302489 TI - [Clinical observation on effect of shaogen decoction for the prevention and treatment of acute radiation esophagitis]. AB - OBJECTIVE: To observe the effect of Shaogen Decoction (SGD) for the prevention and treatment of acute radiation esophagitis (ARE). METHODS: Sixty patients with breast tumor receiving chemo/radiotherapy were assigned to two groups, the SGD group and the control group. The patients in the SGD group were administered with SGD, a Chinese preparation consisted of Radix Sophorae tonkinensis 10 g, Radix Paeoniae Alba 30 g, Radix Scrophulariae 15 g, Rhizoma Bletillae 15 g, Radix Notoginseng 3 g, etc., starting from the initial day of radiotherapy, 10 mL, thrice a day, while in case of 2nd or over 2nd grade ARE occurred, it was changed to 10 mL, every 2 h, medicated by keeping in mouth and slowly swallowed followed with 5-min forbiddance of food and water. The patients in the control group were treated, in case of 2nd or over 2nd grade ARE occurred, with antibiotic drugs (such as cefuroxime 4.5 g) and hormone (dexamethasone 5 mg) by intravenous infusion for 7 days. The incidence, happening time, and retaining time of ARE, therapeutic effect on it, as well as the proportion of patients for whom antibiotics and hormone were used in the two groups were observed. RESULTS: The incidence of 2nd or over 2nd grade ARE in the SGD group and the control group was 33.33% and 63.33%, respectively, that in the former was significantly lower (chi2 = 5.406, P<0.05). Different degrees of acute esophageal toxic response occurred in both groups, initially presenting at 19.8 +/- 7.4 days in the SGD group and at 20.2 +/- 9.6 days in the control group after radiotherapy, that was delayed in the former (t=2.130, P<0.05). Clinical symptom of ARE retained for 56.4 +/- 19.5 days and 58.2 +/- 15.0 days in the two groups, respectively, it was shorter in the SGD groups (t=2.441, P<0.05). Moreover, the proportion of patients for whom antibiotics and hormone were used in the SGD group was less. CONCLUSION: SGD acted, in coordinating with chemo-radiotherapy, to reduce the incidence, retard the happening and shorten the retaining time of 2nd or over 2nd grade ARE, and reduce the proportion of patients needing antibiotics and hormone treatment as well, showing equivalent efficacy in treating ARE as Western drugs. PMID- 21302490 TI - [Clinical observation on treatment of infantile rotavirus enteritis by umbilical application of lunxieting paste]. AB - OBJECTIVE: To observe the clinical effect of umbilical application with Lunxieting Paste (LXT) for the treatment of infantile rotavirus enteritis (IRE). METHODS: One hundred and ninety infants with IRE were randomly assigned into three groups, 55 in Group A, 60 in Group B and 75 in Group C. All were treated with conventional therapy, mainly the dehydration and acidosis correcting, rehydration salt and antiviral therapy; but to patients in Groups B and C, an additional medication of Smecta 1.5 g, thrice a day. for infants below 1 year and 3 g, thrice a day. for those between 1-2 years old, by orally taken with 0.05 L of warm water and umbilical application with LXT (one dose per day, containing 6.0 g of crude drug) was given respectively. RESULTS: The total effective rate was 69.1% in Group A, 75% in Group B and 92% in Group C, respectively, showing significant difference (P<0.05) in comparing Group C with Groups A and B. Moreover, serum levels of TNF-alpha were decreased and IFN-gamma increased in Group C after treatment, all showed statistical significance as compared with those in the other two groups (P<0.05). No significant adverse reactions were observed in all patients. CONCLUSION: Umbilical application of LXT could effectively alleviate the diarrhea symptom in IRE patients, accelerate the negative inversion of rotavirus, and reduce the injury of intestinal membrane, showing a therapeutic efficacy more effective and quicker than that of conventional treatment with more convenience for use. PMID- 21302491 TI - [Effects of xiongshao capsule combined with ischemic postconditioning on monocyte chemoattractant protein-1 and tumor necrosis factor-alpha in rat myocardium with ischemic reperfusion injury]. AB - OBJECTIVE: To investigate effect of Xiongshao Capsule (XSC) combined with ischemic postconditioning (IPoC) on tumor necrosis factor-alpha (TNF-alpha) and monocyte chemoattractant protein-1 (MCP-1) contents as well as inflammatory cell infiltration (ICI) in myocardium of rat with ischemic reperfusion (I/R) injury. METHODS: Seventy-five Sprague-Dawley rats were equally randomized into 5 groups, the sham-operated group (A), the I/R group (B), the IPoC group (C), the fosinopril sodium plus IPoC group (D), and the XSC plus IPoC group (E). Excepting rats in Group A, all animals received I/R injury through a 30-min occlusion of left anterior descending artery followed by 1-h reperfusion. Additionally, IPoC (3 cycles of 10 s reperfusion/10 s of ischemia) was applied on rats in Group C before 1 h of reperfusion; while rats in Groups D and E were pretreated for 14 days with 0.9 mg/kg fosinopril sodium and 0.135 g/kg XSC respectively via gastrogavage, and the I/R injury with IPoC applied 2 h after the final gavage. Serum creatine kinase-MB (CK-MB) and cardiac troponin T (cTnT) levels were detected by colorimetric method, myocardial infarction size was measured by nitro blue tetrazolium chloride (NBT) staining, MCP-1 and TNF-alpha contents in myocardial tissue were examined by enzyme-linked immunosorbent assay (ELISA), and ICI was detected by HE staining. RESULTS: Compared with Group B, myocardial enzymes and infarction size were significantly decreased (P<0.01), contents of MCP-1, TNF-alpha and ICI in myocardial tissue were significantly decreased (P<0.05, P<0.01) in Group C. Compared with Group C, further reduced infarction size and release of myocardial enzyme CK-MB (P<0.01) were seen in Group E, and contents of MCP-1 and TNF-alpha as well as ICI in myocardial tissue in Group E were also significantly lower (P<0.05, P<0.01). CONCLUSION: XSC could enhance the protective effect of IPoC on rat with myocardial I/R injury, and the mechanism may be related to its inhibition on MCP-1 and TNF-alpha expressions as well as ICI suppression. PMID- 21302492 TI - [Effects of shexiang baoxin pill on angiogenesis in atherosclerosis plaque and ischemic myocardium]. AB - OBJECTIVE: To investigate the effects of Shexiang Baoxin Pill (SBP) in intervening atherosclerosis and myocardial infarction (AS-MI) in experimental animals, and inspect its influences on angiogenesis. METHODS: Twenty male New Zealand rabbits were made into AS-MI model, and randomly divided into 2 groups equally. Group A was fed with high-fat diet for control; Group B was fed with high-fat diet but intervened with SBP. The cardiac function and the positive area of plaque were determined. The CD34 positive response intensity at infarcted marginal zone and aorta vessel wall, and the capillary density of myocardium were measured by immunohistochemical staining. In addition, the protein expressions of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor-2 (VEGFR-2) were detected by Western blot. RESULTS: Compared to Group A, the cardiac function was obviously improved (P<0.05) and the plaque positive area (%) was significantly decreased in Group B (45.82 +/- 3.68 vs 82.56 +/- 4.97, P<0.01). The CD34 positive response intensity and the capillary density as well as VEGF and VEGFR-2 expressions in infarcted marginal zone in Group A were higher than those in Group B (P<0.01); but these parameters at aorta vessel walls were lower in Group A than in Group B (P<0.01). CONCLUSION: SBP could advance the angiogenesis in the marginal zone of infarction, improve heart function, and embarrass angiogenesis in atherosclerotic plaque. PMID- 21302493 TI - [Effect of feiliuping ointment and its disassembled prescriptions on dendritic cell of mice with transplanted Lewis lung cancer]. AB - OBJECTIVE: To explore the possible immuno-regulating mechanism of action of Chinese drugs in different combinations (assembled depending different therapeutic principles) through observing the effects of Feiliuping ointment (FLP) and its disassembled prescriptions on dendritic cells (DC) in blood, spleen and tumor in mice with transplanted Lewis lung cancer (LLC). METHODS: Percentages of DC in blood, spleen and tumor of mice with transplanted LLC treated by FLP and its disassembled prescriptions were estimated, and the S-100 protein expression in tumor tissue was detected by immunohistochemical method. RESULTS: The percentage of DC (per thousand) in tumor bearing mice was 0.43 +/- 0.26 in peripheral blood, and 0.32 +/- 0.16 in spleen, significantly lower than those in normal mice 4.68 +/- 0.90 and 3.68 +/- 1.58, P<0.01); and S-100 protein expression in tumor was weakened. After FLP treatment, the percentages of DC (per thousand) in tumor bearing mice were increased to 2.55 +/- 0.29 in peripheral blood and 2.70 +/- 0.63 in spleen (P<0.01), with the S-100 protein expression in tumor tissue up-regulated significantly (P<0.01). Study on different assembled prescriptions of FLP showed that the qi supplementing components of FLP displayed the optimal actions. CONCLUSION: FLP, a Chinese herbal prescription made depending on Chinese medicine therapeutic principle of strengthening body resistance and consolidating constitution, has an obvious anti-tumor effect, to improve the immunological anti-tumor function of organism by promoting the amount and expression of DC might be the possible intrinsic mechanism. PMID- 21302494 TI - [Experimental study on suppressive effect of zilongjin on growth of human breast cancer cell line MCF-7 in vitro and in vivo]. AB - OBJECTIVE: To investigate the suppressive effect and mechanism of action of Zilongjin (ZLJ, a composite Chinese drug) on the growth of human breast carcinoma cell line MCF-7 in vivo and in vivo. METHODS: The cell survival rate and clone forming efficiency were observed by direct cell counting with trypan blue staining and double layers soft agar test; the p-ERK 1/2 expression was analyzed using Western blotting; 17-beta-estrogen pellet embedding was adopted to make the subcutaneous transplanted tumor MCF-7 cell in BALB/c nude mice for detecting the tumor growth suppressive effect of ZLJ (20 g crude drug/kg). RESULTS: The survival rate of MCF-7 cell was obviously decreased by ZLJ in a time and dose dependent manner; only few and small clones on soft agar could be found after treated with ZLJ, the inhibition rates of clone formation(%) for 0.75, 1.5, 3, 6 mg/mL of ZLJ were 12.66 +/- 1.54, 88.83 +/- 2.13, 100 and 100, respectively, as compared with that of non-treated. The expression of p-ERK 1/2 was suppressed and the ability of the tumorigenicity in nude mice was reduced effectively by ZLJ. The mean volumes and weights of tumor in the test group and the control group were (0.73 +/- 0.58) cm3 vs (1.36 +/- 0.64) cm3 and (1.02 +/- 0.25) g vs (1.66 +/ 0.09) g respectively, showing significant difference (P<0.05), and the tumor inhibition rate of ZLJ was 38.55%. CONCLUSION: ZLJ shows obviously suppressive actions on malignant proliferation, transformation and tumorigenicity of human breast carcinoma cell line MCF-7; the down-regulation of p-ERK 1/2 protein may involve in these effects. PMID- 21302495 TI - [Effects of jiaotai pill and its single components on ectopic fat accumulation in rats with type 2 diabetes mellitus]. AB - OBJECTIVE: To study the effects of Jiaotai Pill (JTP) and its single components on ectopic fat accumulation in rats with type 2 diabetes mellitus (T2DM). METHODS: The T2DM model of rat was established by injection of streptozotocin from tail vein and high fat-caloric diet feeding. Model rats were randomly divided into the model group and four treated groups were treated respectively with JTP and its single components, Rhizoma Coptidis, Cinnamon and metformin, via gastric perfusion. Meanwhile, a normal control group was also set up. Body weight (BW), liver index (LI), levels of fasting plasma glucose (FPG), fasting serum insulin (FINS) and insulin resistance index (HOMA-IR), plasma activities of liver associated enzymes (LAE), triglyceride (TG) contents and pathological changes of liver, heart and muscle were determined before and after a 8-week treatment. RESULTS: As compared with the normal rats, BW, LI, LAE activities, HOMA-IR, TG contents of the liver, heart and muscle were all increased in the model rats (P<0.05 or P<0.01), with pathologic appearance of fatty degeneration in different degrees. Compared with the model group, LI, LAE, HOMA-IR, and TG contents in the liver, heart and muscle tissues were decreased in different extents in the four treated groups (P<0.05 or P<0.01), and the histology of tissues in them was restored to near normal. Compared with the metformin treated group, the hepatic and muscular TG contents decreased in the JTP treated group (P<0.01), and the muscular TG content in the Rhizoma Coptidis treated group were lower (P<0.05). And the gamma-GT level in the JTP treated group was the lowest in the three Chinese drugs treated groups (P<0.01). CONCLUSIONS: The disturbances of glucose and lipid metabolism and abnormality of liver function in T2DM rats could be improved by JTP and its single components. The mechanism might be related to their effects in improving insulin resistance and reducing ectopic fat accumulation. PMID- 21302496 TI - [Effect of baicalin on protease-activated receptor-1 expression and cell apoptosis in brain of rat with intracerebral hemorrhage]. AB - OBJECTIVE: To investigate the protective effect and mechanism of baicalin on nerve tissue in rat with intracerebral hemorrhage (ICH). METHODS: Rats were randomly divided into five groups: the sham-operated group, the ICH model group, and the three baicalin treated groups treated respectively with small, medium and large doses of baicalin. ICH rat model was established by injecting collagenase VII into caudate nucleus. Baicalin was given by peritoneal injection to the baicalin treated groups, and saline was given to the other two groups once a day started from 2 h after modeling. Animals were sacrificed in batches on the 1st, 3rd, 5th and 10th day of treatment to take their brains for detecting protease activated receptor-1 (PAR-1) expression and cell apoptosis in brain tissue surrounding hematoma by Western blot and TUNEL method, respectively. And the water content of brain was estimated by dry-wet weight method. RESULTS: Compared with the model group, the PAR-1 expression and TUNEL-positive cells were significantly reduced in the baicalin treated groups; and brain edema was also significantly reduced (P<0.01). CONCLUSIONS: The up-regulated PAR-1 expression after ICH in rats might play an important role in inducing cell apoptosis and brain edema. Baicalin shows significant protective effect on ICH rats, which may be related to its effects in inhibiting PAR-1 expression and decreasing apoptosis cells, so as to reduce brain edema. PMID- 21302497 TI - [Effects of three Chinese herbal antidotes (Herba artemisiae annuae, Herba hedyotis diffusae and Rhizoma cimicifugae) and their different combinations on regulated on activation normal T cell expressed and secreated expression in MRL/lpr mice]. AB - OBJECTIVE: To explore the effects of three Chinese herbal antidotes, i.e. Herba Artemisiae annuae (A), Herba Hedyotis diffusae (H) and Rhizoma Cimicifugae (C), all were ingredients of Jiedu Quyu Ziyin Recipe, for adjusting the regulated on activation normal T cell expressed and secreated (RANTES), gene expression in serum and renal tissue of MRL/lpr mice. METHODS: Fifty-four MRL/lpr mice were randomized into 9 groups, with 6 in each, and intragastrically infused with A, H, C, A+H, H+C, A+C, A+H+C (all in dosage-form of decoction), prednisone suspension and physiological saline, respectively for 12 weeks. RANTES expression in serum and renal tissue of animals were detected with ELISA and RT-PCR at the end of the study. RESULTS: Levels of RANTES expression was significantly reduced in the prednisone treated group after treatment. Excepting no significant change being observed in the groups treated with A and C, the changes in the other groups were all milder than those in the group treated with A+H+C. CONCLUSION: Chinese herbal antidotes A, H and C in combination can significantly inhibit the RANTES expression in serum and renal tissue of MRL/lpr mice. PMID- 21302498 TI - [Thinking on the prevention and treatment of myocardial ischemia/reperfusion injury by Chinese medicine therapy of activating blood circulation and removing stasis]. AB - In this paper, the theoretical and experimental researches concerning the prevention and treatment of myocardial ischemia/reperfusion (I/R) injury by Chinese medicine (CM) therapy of activating blood circulation and removing stasis in recent five years were reviewed, and the mechanisms were summarized. Thereby, based upon the current development of molecular biology and application of new technology, the authors offered their suggestions on the emphasized points and methods of present CM study in this scope. PMID- 21302499 TI - [About the mutual compensation between advantages of Chinese and Western medical subjective indices for measurement and evaluation]. AB - Upon the background of new medical model being formed, to make measurement/evaluation with subjective indices (SIM/E) has become a new hot-spot in Western medical researches and much methodological achievements have been made, but difficulties in comprehensive evaluation and result interpretation are still encountered. SIM/E has played important guideline roles in Chinese medicine (CM) clinical practice, and since it is characterized by holism and syndrome differentiation, it showed great advantage in comprehensive evaluation and result interpretation, though further standardization is yet required. To analyze the related tools and scientific regulations of SIM/E in Western medicine, and establish the concept, domain and conceptual framework of a SIM/E system based on the CM syndrome theory should be feasible to realize the mutual compensation between advantages of the two medical sciences, and promote the progress of SIM/E. PMID- 21302500 TI - [Exploration on current clinical management of cardiovascular diseases]. AB - Dramatic advances in the treatment of cardiovascular disease were witnessed in recent years, however, there are still some problems needed to be explored. The related issues in terms of coronary heart disease, atrial fibrillation and chronic heart failure were discussed in this paper, and the latest progress of integrative medical treatment on them were reviewed as well. PMID- 21302501 TI - [Progress on research of salviae and salvianolic acid B in treating myocardial infarction with myocardial cell orientating differentiation of bone marrow mesenchymal stem cell]. PMID- 21302502 TI - [Candida biofilm formation on Provox 2 and Provox Acti Valve voice prosthesis]. AB - INTRODUCTION: Patients who underwent laryngectomy due to larynx cancer have a possibility to regain ability to speak with the use of silicone voice prosthesis. However, the lifetime of the device is limited, and last for approximately 3-6 months, mainly due to bacterial and fungal biofilm formation, that subsequently causes deterioration of the prosthesis and malfunction of the valve mechanisms. Moreover, the biofilm can be reservoir for chronic and systemic infections. AIM: The aim of the following study was to investigate Candida biofilm formation on silicone voice prosthesis. MATERIAL AND METHODS: Experiments were performed using C. albicans and C. krusei fungal strains with Provox 2 and Provox Acti Valve voice prosthesis. Fungal biofilms were examined under various magnifications using SEM technique. RESULTS: Scanning electron microscopy revealed that Candida biofilms formed on voice prosthesis had highly heterogeneous structure and were composed of blastospores, pseudohyphae, hyphae and ,,germ tubes" encased in an extracellular material. Noticeable differences in biofilms structure depended on Candida species and type of voice prosthesis. CONCLUSIONS: Presented data throws light on problems concerned fungal colonization on indwelled medical devices. PMID- 21302503 TI - [Osteomas and exostoses of external auditory canal in material of Otolaryngology Department Medical University of Gdansk]. AB - INTRODUCTION: Osteomas and exostoses of the external auditory canal are benign tumours arising in bones, leading to its obstruction and causing hearing loss. The treatment of these entities may present a therapeutic dilemma. AIM OF THE STUDY: To assess epidemiological and clinical data and surgical treatment effectiveness. SUBJECTS AND METHODS: The study group consisted of 21 patients (14 men and 7 women) between 18 to 63 years of age, treated in the Otorhinolaryngology Department of Medical University of Gdansk from 1995 to 2009. The results of audiometric, radiological and histopathological examination were taken into consideration. RESULTS: Unilateral osteomas developing in tympanosquamous suture in 5 patients, in tympanomastoid suture in 4. Bilateral exostoses occured in 12 patients in anterior, posterior and inferior wall of the external auditory canal. In all patients: conductive hearing loss ranged from 15 to 30 dB (average 29.9 dB), in 6 patients with concomitant sensorineural component. Osteomas were removed via intrauricular approach according to Mawson Goodhill's method. Exostoses were removed via intrauricular, intracanal or postauricular approach. Histological examination confirmed benign overgrowth of compact and trabecular bone. The auditory canal was successfully reamed, the hearing improved in all patients. CONCLUSIONS: Osteomas are benign tumours leading to obstruction of the external auditory canal. Exostosis is the overgrowth of the external auditory canal's compact bone in adults. Osteomas and exostoses may lead to hearing loss. Indications to surgical treatment are ear pain, progressive hearing loss and recurrent otitis external. PMID- 21302504 TI - [Sialendoscopy as a non-invasive treatment method of sialolithiasis and non inflammatory processes causing salivary gland swelling]. AB - Inflammatory and non-neoplastic diseases of salivary glands affect approximately 5% of patients in every day laryngology practice. Sialolithiasis is the most common cause of obstructive diseases in salivary glands and is supposed to affect 1,2% of population. Other, non inflammatory reasons of glandular swelling are sialodochitis (acute ductal inflammation), stenosis of the duct, and chronic, obstructive changes in the ductal epithelium found in patients with chronic recurrent (juvenile) parotitis. Sialendoscopy is a minimal invasive technique aiming to visualize the lumen of the salivary ducts and their pathologies. It could be used for diagnostic reasons, in case of sialolithiasis extraction of stones and in case of stenosis dilatation is performed (interventional sialendoscopy). In ENT Department Medical University in Poznan, in the period 2008 XII between 2010 IV, 46 sialendoscopies were performed. Sialolithiasis was observed in 29 patients, stenosis of main duct in 16 patients. In 1 case any changes in ductal system were observed. In group with sialolithiasis, in 19 cases stones were removed endoscopically, in 4 patients papillotomy was performed to extraction of the stone. In 3 patients with big stones and an extreme posterior location, bilateral (external and endoscopical) approach was used. Any postoperative complications were observed. PMID- 21302505 TI - [Clinical and pathological features of cholesteatoma in young children]. AB - INTRODUCTION: Children cholesteatoma have been shown to demonstrate aggressive growth with greater extension and higher rates residual and recurrent disease compared with adults, due to anatomic and physiologic differences. AIM: This study aimed to determine the clinical and pathological features of cholesteatoma in young children less than 7 years of age. MATERIAL AND METHODS: Retrospective review of a group of 23 children (24 ears) who had cholesteatoma surgery between 1996 and 2004. Patients ages ranged from 1.8 to 7 years, follow up from 3.5 to 12 years (mean 7.4). Medical history (previous otorrhea, hearing loss) and contralateral ear status was analyzed. The extent of cholesteatoma and ossicular destruction for attic, pars tensa I and pars tensa II type and congenital of cholesteatoma was graded using of Saleh and Mills classification. Residual and recurrent disease depending on type of cholesteatoma, extent of the disease, type of surgery and contalateral ear status was assessed. RESULTS: Otorrhea and hearing loos are the most common clinical symptoms observed in 90% and 59% children. 70% of treated children had otitis media with effusion and/or its sequel in contralateral ear. 60% of acquired cholesteatomas were classified as S3 and S4 extension during surgery with ossicular destruction in 46% of attic cholestatoma. 75% operated ears had a signs of mucosa inflammation during surgery. Residual cholesteatoma was observed in 38.5% ears with attic cholesteatoma and in 25% with pars tensa I cholesteatoma. CONCLUSION: Acquired cholesteatoma in young children are diagnosed in the advanced stages with ossicular chain destruction. High rate of recidivism after surgery, particularly in attic cholesteatomas is observed. Most of operated ears have symptoms of inflammation of middle era mucosa during surgery and otitis media with effusion in contralateral ear and because of that need long-term follow up and constant observation. PMID- 21302506 TI - [Binaural asymmetric sensorineural hearing loss in audiological practice]. AB - OBJECTIVES: To estimate binaural asymmetric sensorineural hearing loss in own material of patients treated in Dept. of Phoniatrics and Audiology. MATERIAL & METHODS: The retrospective analysis was performed on the group of 1816 patients hospitalized in 2008 due to hearing disorders. Asymmetry of hearing loss was classified on Margolis and Saly criteria in PTA, and in ABR results in children. CONCLUSIONS: Binaural asymmetric sensorineural hearing loss was found in 70 patients (3.9%). In a group of 46 differences of inter-aural threshold level in PTA were estimated on 21 to 30 dB. After audiological examination 14% of this patients were qualified for MRI investigation, in 2 (3%) of them acoustic neurinoma was found. The hearing aids fitting were performed in 44% of a group of 70 patients. PMID- 21302507 TI - [Combined tumor of ceruminous gland origin in the external auditory canal--a histopathological and immunohistochemical study]. AB - OBJECTIVES: We present a case of a combined tumor consisting of solid tubular gland adenoma (TA) and syringocystadenoma papilliferum (SCAP) of the external auditory canal and review of the literature on this subject. METHODS: Tumour of the external auditory canal was removed by retroauricular approach with good clinical outcome. Histopathological and immunohistochemical study was performed. RESULTS: In the histopathological assessment tumour revealed an extraordinary combination of syringocystadenoma papilliferum and ceruminous tubular gland adenoma pattern. It was positive for epithelial markers with presence of basal type cytokeratins. The proliferative index was low within the neoplastic cells. CONCLUSIONS: Tubular gland adenoma and syringocystadenoma papilliferum are benign tumors originating from ceruminous glands of the skin, characterized by very rare occurrence especially in the skin of the external auditory canal. Their histogenesis is still controversial. Every tumor arising from the external auditory canal should be examined histologically and immunohistochemically in order to choose the best treatment option. PMID- 21302508 TI - [Propranolol for treatment of subglottic hemangioma]. AB - Subglottic hemangiomas are extremely dangerous due to its location and rapid growth during the proliferative phase. Many different treatments are described but these methods are still not satisfactory. Recently propranolol has been used as a new option in hemangioma therapy. We describe a case of 6-week infant with subglottic hemangioma discovered direct laryngoscopy, presented with dyspnoea and inspiratory stridor. After oral propranolol administration all baseline airway symptoms had resolved and endoscopic examination demonstrated significant regression of the hemangioma. We suggest that the propranolol should be used as a first-line treatment in subglottic hemangiomas in children. PMID- 21302509 TI - [Neurootological symptoms in Bruns' syndrome]. AB - The aim of the study was to present clinical neurootological symptoms in the case of early stage of the fourth ventricle tumor diagnosed finally on the base of MRI. Visual-oculomotor, vestibular-oculomotor, vestibulo-spinal and other electrophysiological signs of the vestibular damage of the brainstem were: paresis of the sixth nerve unilaterally, prolonged latency of III-V waves on brain stem audiological responses (BERA), asymmetry of the fusion limit of optokinetic nystagmus, bilateral areflexia of the caloric and kinetic labyrinth reaction, abnormal Unterberger's test in craniocorpography, the presence of gaze nystagmus. The study stressed the value of the widen and careful neurootological examination in such cases. PMID- 21302510 TI - [Rare case of upper respiratory tract obstruction secondary to massive hematoma of pharynx, larynx and trachea]. AB - The rare case of 75-years-old female patient was presented in this paper. She reported hoarseness in addition to pharyngeal pain, dysphagia and medium level dyspnea. Her exploration revealed a wide hematoma of the left lateral wall of orohypopharynx spreading to the left aryepiglottic fold, left aryepiglottic cartilage, false and true vocal fold and later to left lateral and posterior tracheal wall. The patient did not require a control of airway by intubation or tracheotomy according to quick relief after pharmacological treatment. PMID- 21302511 TI - [Gene expression profile in laryngeal cancer in vivo by high-density oligonucleotide microarrays analysis]. PMID- 21302512 TI - [Carcinoma of the larynx in region of Warmia and Mazury (1998-2007): epidemiological and clinical analysis and assessment of treatment results]. PMID- 21302513 TI - [Summary of 2010. From the technical to the clinical]. PMID- 21302514 TI - [Fish and chips]. AB - Academic hospital laboratories should offer patients the possibility to have the most accurate diagnosis by the development of new analyses, such as molecular biology tests including FISH (Fluorescent In Situ Hybridization) and chips (microarrays,...). The purpose of this article is to describe the principles and the potential applications of these techniques. PMID- 21302516 TI - [Image guided stereotactic treatment with CyberKnife yields surgical precision]. AB - The field of radiation oncology is rapidly evolving especially thanks to the tremendous progress in robotics and computer sciences. One of the consequences is the implementation of a technique like the CyberKnife. This particular radiation therapy modality allows the use of "ablative" radiation doses, a concept which is not even conceivable with conventional approaches. This has been made possible by major changes in the ways target and margins around are defined and the way radiation therapy is fractionated. The result of these changes is for some tumours a doubling of the radiobiological effect of the ionizing irradiation. In order to cover the target with the highest possible conformality, without harming surrounding healthy tissues, optimized definition of the target is key. It is not only important to get information on the extent of the target with the highest possible resolution, but it is also important to assess the content, i.e., metabolic heterogeneity. The developments made in the field of diagnostic and functional radiology and nuclear medicine do allow to take advantage of the numerical information to individualize and adapt treatment prescription, even consider modification throughout the course of irradiation. PMID- 21302515 TI - [Endobronchial ultrasonography: a novel technique for investigation of the mediastinum]. AB - Mediastin pathology includes primary lesion and lymph node invasion. The exploration of this anatomical region remains difficult and even hazardous, particularly to obtain histological biopsies. No invasive diagnostic exploration (thorax tomodensitometry and positron emission tomography) allows a histological precision, so mediastinoscopy remains the gold standard in the mediastinum investigation. However, it is not deprived of risk. Recently, guided biopsies and real-time transbronchial needle aspiration by endobronchial ultrasonography (EBUS) have been shown to increase the diagnostic yield over conventional bronchoscopic techniques. Therefore, EBUS is a suitable alternative to mediastinoscopy in the diagnosis of pulmonary or extra-thoracic malignancy, in the staging of mediastinal lymphadenopathy, and in the evaluation of mediastinal response after induction therapy. In the present paper, we present this new diagnostic approach and clarify the current indications of EBUS. PMID- 21302517 TI - [Extracorporeal membrane oxygenation (ECMO) in ICU patients suffering from cardiogenic shock, refractory hypoxemia or cardiac arrest]. AB - ExtraCorporeal Membrane Oxygenation (ECMO) is a cardiopulmonary assistance device able to support patients in cardiac arrest, refractory cardiogenic shock or refractory hypoxemia otherwise sentenced to death. Recent technical progresses, early indication decision, bedside multidisciplinary implant, specific complications screening and echocardiographic weaning testing are crucial points to allow success of this exceptional technique. PMID- 21302518 TI - [MALDI-TOF mass spectrometry in clinical bacteriology or how to identify a bacteria within one minute]. AB - The major application of MALDI-TOF mass spectrometry in clinical microbiology is the bacterial identification based on the analysis of all their proteins (ribosomal and membrane-associated proteins). This technology allows the identification of most of bacteria within a few minutes. The method is fast, accurate, reliable and cost-effective by comparison to conventional phenotypic techniques. Other applications of MALDI-TOF mass spectrometry are still under development, as the detection of bacterial toxins or resistance mechanisms to antimicrobial agents. PMID- 21302519 TI - [The anatomical laboratory: a tool for the trial of the new therapeutic procedures]. AB - Since September 2009, the new anatomical department is located on the CHU building. This modern anatomical laboratory is an effective tool to design the new therapeutic procedures and to teach these procedures to practitioners. PMID- 21302520 TI - [Organizational well-being in public health. Climate survey in a Piedmont public health organization]. AB - INTRODUCTION: More and more Italian and European directives refers to organizational health promotion in work placements. As a matter of fact, organization well-being implies important benefits for individuals and improves business efficiency/efficacy. Improving factors involve listening tools aimed to analyze critical situations and needs, focus on working teams and communication development. In this respect, in a public health organization in Piedmont a research was devised for planning interventions of organizational health promotion and improvement, relying on climate analysis. The research process was supported by General Direction and involved the head of physicians and the departments CPSE (Coordinatore Professionale Sanitario Esperto: Professional Health Coordinator). METHODS: The survey was carried out on the organizational population, focusing on teambuilding, which is the core of daily work life. Team Climate Inventory Questionnaire (TCI) was employed and administered on-line. Beyond the 5 original factorial scales, 6 item groups related to the individuals feeling in working team and consistent with the research interests were identified. 75.42% (n=1264) of employees answered the provided questionnaire. RESULTS: The data highlighted average scores--expressing organizational climate- over other public health organization data. The subjects also showed a good organizational climate perception. Elderly workers appeared more satisfied than the young ones. Furthermore, higher educated subjects took more advantage of technical and organizational supports. PMID- 21302521 TI - [Job satisfaction and psychological wellbeing in bio-medical researchers]. AB - INTRODUCTION: The aim of the study was to assess job satisfaction and risk of depression/anxiety in researchers of a Research Institute in Rome. METHODS: The personnel was invited to participate in a survey filling in the General Health Questionnaire (GHQ.12) for the screening of depression/anxiety disorders and the evaluation of psychological stress, and a validated satisfaction questionnaire. RESULTS: A descriptive analysis was conducted and logistic regressions were performed examining the following outcomes in separate models: being positive at the GHQ and being satisfied. The response rate was 52%. Among participants 15.1% were at risk of depression/anxiety, 77.4% were stressed and 66% were dissatisfied. Major determinants for dissatisfaction were "job opportunities" "communication between units", "judgment about spaces" "economic rewards", "participation in the organization of the unit". CONCLUSIONS: Dissatisfaction with "economic rewards" was predictive of depression, independently of sex, age and job duration. Areas of possible intervention were identified. PMID- 21302522 TI - [International Classification of Functioning, Disability and Health (ICF) and quality of life in cancer patients in a terminal condition]. AB - INTRODUCTION: Quality of life (QoL) preservation for the patient with cancer in a terminal condition is a central goal in palliative care. Aim of the present study is to assess QoL and to verify the additive value of the ICF in a sample of cancer inpatients of a palliative care unit. Method. 32 terminal palliative care inpatients were evaluated by means of traditional assessment tools: Karnofsky Performance Status (KPS), Palliative Prognostic Index (PPI), Barthel Index (BI), SF-12, EuroQol VAS (today and last 30 days) and ICF checklist. Results. Among the 32 patients (age 70.4 +/- 10.2), 17 male (53.1%) and 15 female (49.6%), 8 were alive at the end of the study (24 deceased: survival days 41.0 +/- 46.4). As to the traditional assessment instruments, patients resulted severely impaired: KPS 30.0 +/- 10.4; PPI 5.7 +/- 2.7; BI 35.6 +/- 22.2; EuroQol-VAS today 46.5 +/- 19.7; EuroQol-VAS last 30 days 29.0 +/- 22.5; SF-12: PCS 29.2 +/- 8.1 e MCS 39.7 +/- 11.8. As to the ICF Activity and Participation categories 21 out of 42 (with equipment aids only) and 12 out of 42 (with equipment aids and with a person's help) resulted at least mildly impaired in > or =50% of patients. Delta values of the former scores (caregiver's impact) were calculated: in 10 categories the median value was > or =1 (caregiver as a positive disability modulator) and in 32 the median value was 0 (neutral role of the caregiver). Environmental Factors were mainly facilitators. Conclusions. Traditional QoL assessment highlights the severity of this condition. Whereas the ICF Checklist shows a more diversified situation, where some aspects of daily life are maintained, safeguarding personal dignity and family role. An integrated use of these instruments may grant an overall assessment, showing both difficulties and resources, confirming the importance of a unique interdisciplinary approach with patients at end of life. PMID- 21302523 TI - [Levels of burden of Alzheimer disease caregivers]. AB - INTRODUCTION: Our aim was to investigate the caregiver burden by means of scales to quantify the perceived burden, and the anxiety and depression levels. METHODS: Seventy-seven caregivers of patients with Alzheimer disease or other kinds of dementia (19 males and 58 females) admitted to the Alzheimer Evaluation Unit of Milan Niguarda Ca'Granda Hospital, were enrolled and filled in Caregiver Burden Inventory (CBI) and the short form of the Anxiety and Depression scale (AD-R). The statistical analysis demonstrates that caregiver with relatives affected by more severe cognitive impairment (patients) show significant levels of burden and anxiety. RESULTS: The most relevant burden dimensions are: Time-Dependence Burden, Developmental Burden and Physical Burden. Time-Dependence Burden and Social Burden significantly correlate with cognitive (p = 0.01, p = 0.05) and functional rates of patients (p = 0.01, p = 0.05), whereas Developmental Burden only correlates with cognitive rates (p = 0.01). The more prolonged patients' disease the higher the caregivers'anxiety level (p < 0.05). There is nota significant correlation between the Developmental Burden, Physical Burden and Depression, observed in the caregivers' sample, and the cognitive and functional state of patients. CONCLUSIONS: Alzheimer disease caregivers need an increase of their personal time anda specific intervention aimed to reduce the perceived feeling of social isolation, the physical distress and the anxious and depressive symptoms. PMID- 21302524 TI - [Family presence during cardiopulmonary resuscitation and other invasive procedures]. AB - INTRODUCTION: Family presence during patient cardiopulmonary resuscitation and other invasive procedures has been discussed and debated since the early 1990s. Although family presence was nor a well-practiced phenomenon, nor generally accepted, since the early to mid 1990s many American professional organizations have endorsed the idea of family presence. The aim of this study is to identify the policies, preferences, and practices of critical care and emergency personnel for having patients' families present during medical procedures and cardiopulmonary resuscitation. METHODS: A total of 378 nurses and medical workers filled out a 10-item survey. RESULTS: Among the respondents, nurses tended to disagree more with family presence in comparison to physician. Critical care unit personnel tended to disagree more with family presence in comparison to emergency department personnel and especially pre-hospital care personnel. While 83% of participants disagree with family presence during cardiopulmonary resuscitation, 67% of participant endorse the view that family presence may foster collaboration between family members and staff members. Overall, 92% of participants worked on units without written policies allowing family presence. CONCLUSIONS: Training programs aimed at disseminating knowledge about the relational aspects of health care and the development of written policies or guidelines for family presence during medical procedures are recommended. PMID- 21302525 TI - [A critical review of Italian Children's Depression Scale]. AB - INTRODUCTION: In the present paper we investigate the factor structure of the Italian version of the Children's Depression Scales (CDS). METHODS: We analyzed the responses at the questionnaires of 592 subjects (9-16 years old) and we studied three factor structures previous considered in literature. As a first step, we replicated an exploratory factor analyses and, then, a two and three factor solutions analyzed by a confirmatory factorial analysis. Finally, we modified the models introducing the parameter estimation of correlation between errors when paired item were present (e.g., two similar item but one referred to mother and the other one to father). Results showed the two-factor model interpretation has to be preferred when we administer the CDS Italian version; indeed there are important differences in the factor structure between the Italian and the original English version. CONCLUSIONS: Findings should be considered for further studies on the factor structure of the CDS. Finally, it seems to us not easy to consider these results entirely coherent with Lang & Tisher theory both for how they define the latent trait (i.e., depression), and how they measure it using the CDS. PMID- 21302526 TI - [From Eysenck to Costa and McCrae: a proposal for a change in CBA--Schedule 5]. AB - This study is an explorative research aiming to revise Schedule 5 of Cognitive Behavioural Assessment 2.0 (CBA), that is a reduced version of the Eysenck Personality Questionnaire (EPQ-R). The main goal of this work is to adapt this inventory to the Big Five model by adding new items with good psychometric characteristics, according to the up-to-date Five-Factor personality model. METHODS: These items were chosen on the basis of correlations between the scales of three personality inventories: EPQ-R, Neo Personality Inventory-Revised (NEO PI-R) and International Personality Item Pool (IPIP) test. The questionnaires have been submitted to a sample of 159 subjects, aged 35 to 65. RESULTS: First results confirm good indicators for the dimensions extraversion and Neuroticism, while Psychoticism did not exhibit significant correlations. Moreover, three dimensions in the NEO PI-R and IPIP test (Openness to Experience, Agreeableness, Conscientiousness) showed good psychometric characteristics. CONCLUSIONS: To obtain a new revised form of CBA 2.0 Schedule 5, we suggest the substitution of Psychoticism with three more consistent dimensions belonging to both the NEO PI-R and IPIP test: Openness to experience, agreeableness, conscientiousness. We also propose the new items for these dimensions to be selected from the short form of the NEO PI-R, the NEO Five Factor Inventory (NEO-FFI), as such selection has been already validated. PMID- 21302527 TI - [Psychometric properties of the Italian version of the reduced form of the Oral Health Impact Profile (OHIP-14)]. AB - Aim of this study was to perform a comprehensive psychometric analysis of the Italian version of the Oral Health Impact Profile short-form (OHIP-14)--a questionnaire analysing the oral health-related quality of life--using both classical test theory and Rasch analysis. Eighty-five subjects, residents in a long-term nursing home, were analysed using the OHIP-14, Geriatric Oral Health Assessment Instrument (GOHAI) and a global clinical judgement. Two of the five rating categories (1 = almost never; 3 = quite often) did not comply with the Rasch criteria for category functioning. After collapsing rating categories into a three-level rating scale (0 = never; 1 = sometimes; 2 = often), the new model met the set criteria. Item 12 ('difficulty doing usual jobs') was slightly underfitting. At the principal component analysis on the standardized residuals, item 9 ('difficulty to relax') and 11 ('irritable with other people') showed a high correlation (r = 0.66). This indicates that they may not be locally independent. Rasch analysis showed both the substantial unidimensionality of OHIP 14, and the possibility of simplifying the structure of its rating scale. Further studies are needed to confirm the stability of these findings in different testing situations. PMID- 21302528 TI - [Heavy metal distribution in superficial sedimenta ta Saco, Gulf of Cariaco, Sucre, Venezuela]. AB - The Gulf of Cariaco is a marine ecosystem with high primary productivity, which gives it an ecological and socioeconomic importance. Nevertheless, anthropogenic activities around the Gulf produce wastes that are deposited directly or by runoff into the sediments, and consequently, increases concentrations of metals in this ecosystem. The objective of this study was to determine the distribution of cadmium, copper, lead, manganese, nickel and zinc in geochemical fractions of surface sediments, using modified BCR sequential extraction procedure. The concentrations were measured using flame atomic absorption spectroscopy. In addition, the contents of soluble and exchangeable metals associated to carbonate fractions, determined by BCR, were compared with those determined by the method of Campanella. Samples were collected in 12 stations during June 2007. The applied methodologies were evaluated with a certified reference material of marine sediments (HISS-1) and the results indicated that these methods provide adequate accuracy and precision for the extraction of metals. The total metal concentrations (microg g(-1)) were, Cd: < limit of detection (LD)-5.0; Pb: 1.79 60.41; Cu: no detected (ND)-42.18; Zn: 25.13-104.57; Mn: 66.31-80.29 and Ni: 3.29 24.58. Cd, Cu, Ni and Pb at several stations, exceeded the Canadian Sediment Quality Guidelines of the Lowest Effect Levels (LEL). Cadmium was identified as being the most mobile of the elements, having the highest concentrations in soluble and exchangeable cations and carbonates. However, Pb, Cu, Mn and Zn levels were found highly associated to organic matter and sulfide fractions. The methods did not show significant statistical differences for the extraction of soluble and exchangeable cations and the metals associated to carbonate fraction. There are several significant correlations between heavy metals, which suggest their common origin. PMID- 21302529 TI - [Ichthyofauna associated to a shallow reef in Morrocoy National Park, Venezuela]. AB - Ichthyofauna associated to a shallow reef in Morrocoy National Park, Venezuela. Morrocoy National Park is one of the most studied coastal marine environments in Venezuela; however, efforts have been concentrated in south zone. In this study we select a shallow reef located in the north zone, characterized the benthic community and the structure of the fish community was studied using visual censuses. The benthic community was dominated by dead coral covered by algae (31%) and the live coral coverage was 12%. A total of 65 fish species belonging to 24 families were recorded, being Pomacentridae (43%), Scaridae (19%) and Haemulidae (15%) the most abundant families. Significant differences in the fish species abundances were found along the depth gradient, which could be related to the habitat characteristics, nevertheless herbivorous species dominance was evident at all depth strata. There seems to be a trend towards greater richness and density in the south zone reefs, and these differences may be related to the presence of extensive seagrass meadows and mangrove forests in that area or to differences in the recruitment patterns. PMID- 21302530 TI - [Sponges (porifera) distribution along a depth gradient in a coral reef, Parque Nacional San Esteban, Carabobo, Venezuela]. AB - Sponges constitute one of the most diverse and abundant animal groups in the marine tropical benthos especially in coral reefs, though poorly studied to species level. The aim of this study is to characterize the sponge community along a depth gradient at Isla Larga (Parque Nacional San Esteban, Venezuela) fringe reef. Net and total sedimentation, roughness index, sponge species richness, density and proportion of the bottom covered by sponges, were evaluated at seven depths (1, 3, 6, 9, 12, 15, 18 m), 17 species were identified grouped in 10 demosponges families. The highest densities and coverage corresponded to 6 m of depth (6.03ind/m2; 11%), that coincides with the lowest net sedimentation and highest substrate heterogeneity. Most abundant species were Desmapsamma anchorata, Amphimedon erina and Scopalina rueztleri. Principal component analysis divided this community in three zones according to depth. The shallow zone of the reef (1 and 3 m), where wave force and high irradiance exert a constant stress sponges, shows the lowest density and coverage by sponges. In contrast, medium depth (6, 9 y 12 m) and deep zone (15 y 18 m) with lower light and sedimentation levels seem to enhance sponge growth and survival that are reflected on the higher densities and coverage of sponges. PMID- 21302531 TI - [Abundance and richness of mollusks and crustaceans associated to the submerged roots of red mangrove (Rhizophora mangle) at Bocaripo Lagoon, Sucre, Venezuela]. AB - Mangrove roots are important habitats for many species. The abundance and richness of mollusks and crustaceans associated with the roots demerged of Rhizophora mangle was studied. The samples were gathered between February 2005 and January 2006, in Bocaripo lagoon, north coast of Sucre state, Venezuela. Five stations were established inside the lagoon; on every station two roots were chosen at random, put in plastic bags and scraped. The associated organisms were separated by taxa and fixed in 10% formaldehyde. One thousand ninety two specimens of mollusks, distributed in two classes: Bivalve and Gastropod were collected. Bivalve was the most abundant with 943 individuals. The most representative family was Mytilidae with 6 species, being Musculus lateralis the dominant species. The crustaceans were represented by 372 organisms, belonging to the class Malacostraca, where Panopeus herbstii (169 ind.) was the most abundant species. The families Panopeidae, Porcellanidae and Majidae had the highest number of species. Maximum abundance was in February (224 ind.), with a richness of 25 species and the minimums in November (45 ind.) and a richness of 12 species. The stations 1 and 5 presented the major abundance and richness of organisms, which could be related to environmental conditions favorable, as the major availability of microhabitats and nourishing offer; on the contrary the station 4, presented a more inhospitable environment, due to the high values in the salinity and temperature, which contributes with the minor abundance and richness of the present species. PMID- 21302532 TI - In this issue: clinical decision support. PMID- 21302533 TI - Klinefelter syndrome (KS). Foreword. PMID- 21302535 TI - Abstracts of the Intensive Care Annual Scientific Meeting of the Australian and New Zealand Intensive Care Society and Australian College of Critical Care Nurses. October 14-16, 2010, Melbourne, Victoria, Australia. PMID- 21302534 TI - Proceedings of the Seventh Multidisciplinary Conference on Drug Research. May 10 12, 2010. Zakopane, Poland. PMID- 21302536 TI - Abstracts from the 60th Czech-Slovack Pharmacological Days, September 15-17, 2010, Hradec Kralove, Czech Republic. PMID- 21302537 TI - Adolescent health. Abstracts of the Annual Medical Research Day, October 25, 2008, Harare, Zimbabwe. PMID- 21302538 TI - [Research and cure: knowledge and prophylaxis of endemic goiter in Argentina (1916-1958).]. AB - The present paper focuses on the reconstruction of the historical circumstances of knowledge production as well as and the debates about endemic goiter disease during the period 1916-1955 in Argentina. Taking into account the social, political and material dimensions, this text explores the re-signification of scientific and medical knowledge oriented to the prevention and health treatment, through the positioning of several social actors engaged all along the period, and the diverse historical and institutional contexts. PMID- 21302539 TI - [To treat or not to treat? Scientific controversy about the treatment for chronic Chagas' disease patients.]. AB - Chagas disease is one of the main endemic illnesses in Latin America. Since 1969 up to the present, the treatment of chronic Chagas patients has been the object of a scientific-medical controversy mobilizing several bodies of knowledge and actors. The resolution of the controversy has direct effects on the health of patients; however, they have been systematically excluded of public debates. In this paper we identified and specified four different steps of the controversy, showing the different positions adopted by the actors implicated, analyzing their statements, the scientific knowledge mobilized during the debates and the consequences for the establishment of norms for the treatment. We conclude showing that what makes up the central issue of the controversy is not what the actors implicated explicitly state as it but the criteria (technical and cognitive) through which are measured and defined "illness" and "cure" states. This research is about a case study in Argentina. PMID- 21302540 TI - The significance of trace constituents in the solar system. AB - Trace or minor constituents are key to the origin, maintenance, and the eventual fate of atmospheres of solar system objects. In this Introductory Paper, I illustrate this point by discussing certain cross cutting themes, including the chemistry of the formation and stability of a nitrogen atmosphere on Titan and the Earth, the chemical and biochemical origin of methane on the terrestrial planets and Titan, production and role of photochemical haze and aerosols, especially on Titan, and the significance of electro-photochemistry for habitability of Mars. PMID- 21302541 TI - Formation of NH3 and CH2NH in Titan's upper atmosphere. AB - The large abundance of NH3 in Titan's upper atmosphere is a consequence of coupled ion and neutral chemistry. The density of NH3 is inferred from the measured abundance of NH4+. NH3 is produced primarily through reaction of NH2 with H2CN, a process neglected in previous models. NH2 is produced by several reactions including electron recombination of CH2NH2+. The density of CH2NH2+ is closely linked to the density of CH2NH through proton exchange reactions and recombination. CH2NH is produced by reaction of N(2D) and NH with ambient hydrocarbons. Thus, production of NH3 is the result of a chain of reactions involving non-nitrile functional groups and the large density of NH3 implies large densities for these associated molecules. This suggests that amine and imine functional groups may be incorporated as well in other, more complex organic molecules. PMID- 21302542 TI - Mapping Titan's HCN in the far infra-red: implications for photochemistry. AB - Observations of Titan's far infra-red spectra by the Cassini orbiter's Composite InfraRed Spectrometer have been used to determine the latitude distribution of HCN at 1 mbar by fitting the HCN and CO rotational lines in the 18-60 cm(-1) (160 550 microm) spectral range. Results confirm the north polar HCN enrichment previously observed using mid-IR data and support the conclusion that Titan's nitrile species are significantly more enriched than hydrocarbons species with similar predicted photochemical lifetimes. This suggests Titan's photochemical cycle includes an additional sink for nitrogen bearing species. The abundance of CO was also determined, and had a mean value of 55 +/- 6 ppm at 20 mbar. However, it was not possible to reliably determine the CO latitude variation due to unconstrained temperatures in the north polar lower stratosphere. PMID- 21302543 TI - Upper limits for undetected trace species in the stratosphere of Titan. AB - In this paper we describe the first quantitative search for several molecules in Titan's stratosphere in Cassini CIRS infrared spectra. These are: ammonia (NH3), methanol (CH3OH), formaldehyde (H2CO), and acetonitrile (CH3CN), all of which are predicted by photochemical models but only the last of which has been observed, and not in the infrared. We find non-detections in all cases, but derive upper limits on the abundances from low-noise observations at 25 degrees S and 75 degrees N. Comparing these constraints to model predictions, we conclude that CIRS is highly unlikely to see NH3 or CH3OH emissions. However, CH3CN and H2CO are closer to CIRS detectability, and we suggest ways in which the sensitivity threshold may be lowered towards this goal. PMID- 21302544 TI - On the abundance of non-cometary HCN on Jupiter. AB - Using one-dimensional thermochemical/photochemical kinetics and transport models, we examine the chemistry of nitrogen-bearing species in the Jovian troposphere in an attempt to explain the low observational upper limit for HCN. We track the dominant mechanisms for interconversion of N2-NH3 and HCN-NH3 in the deep, high temperature troposphere and predict the rate-limiting step for the quenching of HCN at cooler tropospheric altitudes. Consistent with some other investigations that were based solely on time-scale arguments, our models suggest that transport induced quenching of thermochemically derived HCN leads to very small predicted mole fractions of hydrogen cyanide in Jupiter's upper troposphere. By the same token, photochemical production of HCN is ineffective in Jupiter's troposphere: CH4-NH3 coupling is inhibited by the physical separation of the CH4 photolysis region in the upper stratosphere from the NH3 photolysis and condensation region in the troposphere, and C2H2-NH3 coupling is inhibited by the low tropospheric abundance of C2H2. The upper limits from infrared and submillimetre observations can be used to place constraints on the production of HCN and other species from lightning and thundershock sources. PMID- 21302545 TI - Photochemical modeling of Titan atmosphere at the "10 percent uncertainty horizon". AB - Titan's atmospheric chemistry modeling is presently limited by the lack of knowledge about many reaction rate coefficients at low temperature (50-200 K). Considering the difficulty of measuring such data, the only way to improve this situation is to identify key reactions as the ones for which better estimations of reaction rates is guaranteed to have a strong influence on the precision of model predictions. This is a slow iterative process, the limit of which has never been clearly defined in terms of model precision. The fact is that this limit is not a fully deterministic simulation, since one should not expect all reaction rate coefficients ever to become available with null uncertainty. The present study considers a quite optimistic scenario, in which all reaction rate coefficients in the chemical model are assumed to be known with a 10% relative uncertainty. The implications for chemical growth modeling are discussed. PMID- 21302546 TI - Experimental measurements of low temperature rate coefficients for neutral neutral reactions of interest for atmospheric chemistry of Titan, Pluto and Triton: reactions of the CN radical. AB - The kinetics of the reactions of cyano radical, CN (X2sigma+) with three hydrocarbons, propane (CH3CH2CH3), propene (CH3CH=CH2) and 1-butyne (CH[triple band]CCH2CH3) have been studied over the temperature range of 23-298 K using a CRESU (Cinetique de Reaction en Ecoulement Supersonique Uniforme or Reaction Kinetics in Uniform Supersonic Flow) apparatus combined with the pulsed laser photolysis-laser induced fluorescence technique. These reactions are of interest for the cold atmospheres of Titan, Pluto and Triton, as they might participate in the formation of nitrogen and carbon bearing molecules, including nitriles, that are thought to play an important role in the formation of hazes and biological molecules. All three reactions are rapid with rate coefficients in excess of 10( 10) cm3 molecule(-1) s(-1) at the lowest temperatures of this study and show behaviour characteristic of barrierless reactions. Temperature dependences, different for each reaction, are compared to those used in the most recent photochemical models of Titan's atmosphere. PMID- 21302547 TI - An experimental and theoretical investigation of the competition between chemical reaction and relaxation for the reactions of 1CH2 with acetylene and ethene: implications for the chemistry of the giant planets. AB - The temperature dependence of the branching ratios for H atom production from the reactions of the first excited state of methylene (a1A1 1CH2) with acetylene and ethene have been measured at approximately 1 Torr total pressure and temperatures of 195, 250 and 298 K by monitoring the production of H atoms using laser induced fluorescence, comparing the signal to that observed from a calibration reaction. For the reaction with acetylene the yield of H increases from 0.28 (195 K) to 0.53 (250 K) to 0.88 at 298 K. The H atom yield from the reaction of 1CH2 with ethene shows similar behaviour, the yields being 0.35 (195 K), 0.51 (250 K) and 0.71 (298 K). The co-products, propargyl (C3H3) and allyl (C3H5) are formed from the dissociation of chemically activated C3H4 and C3H6 intermediates respectively, and are important species in the formation of higher hydrocarbons, including benzene, in the atmospheres of the outer planets and Titan. H atom production is in competition with electronic relaxation to form ground state methylene (X3B1, 3CH2) and collisional stabilization to form C3H4 and C3H6. Master equation calculations have been carried out to demonstrate that for the reaction of 1CH2 with acetylene, collisional stabilization is insignificant under experimental conditions and hence the balance of reaction is due to electronic relaxation. Non-adiabatic transition state theory has been applied to the reaction of 1CH2 with acetylene. The calculations show reasonable agreement with experiment, generally being within the combined errors, and reproduce the negative temperature dependence for electronic relaxation. The implications of the temperature dependence of the absolute rate coefficients for 1CH2 reactions with inert gases, hydrogen, acetylene and ethene and of the branching ratios between chemical reaction and electronic relaxation are discussed. PMID- 21302548 TI - Formation of nitriles and imines in the atmosphere of Titan: combined crossed beam and theoretical studies on the reaction dynamics of excited nitrogen atoms N(2D) with ethane. AB - The dynamics of the H-displacement channels in the reaction N(2D) + C2H6 have been investigated by the crossed molecular beam technique with mass spectrometric detection and time-of-flight analysis at two different collision energies (18.0 and 31.4 kJ mol(-1)). From the derived center-of-mass product angular and translational energy distributions the reaction micromechanisms and the product energy partitioning have been obtained. The interpretation of the scattering results is assisted by new ab initio electronic structure calculations of stationary points and product energetics for the C2H6N ground state doublet potential energy surface. C-C bond breaking and NH production channels have been theoretically characterized and the statistical branching ratio derived at the temperatures relevant for the atmosphere of Titan. Methanimine plus CH3 and ethanimine plus H are the main reaction channels. Implications for the atmospheric chemistry of Titan are discussed. PMID- 21302549 TI - Structural and spectroscopic characterization of mixed planetary ices. AB - Mixed ices play a central role in characterizing the origin, evolution, stability and chemistry of planetary ice surfaces. Examples include the polar areas of Mars, the crust of the Jupiter moon Europa, or atmospheres of planets and their satellites, particularly in the outer solar system. Atomistic simulations using accurate representations of the interaction potentials have recently shown to be suitable to quantitatively describe both, the mid- and the far-infrared spectrum of mixed H2O/CO amorphous ices. In this work, molecular dynamics simulations are used to investigate structural and spectroscopic properties of mixed and crystalline ices containing H2O, CO and CO2. Particular findings include: (a) the sensitivity of the water bending mode to the local environment of the water molecules which, together with structural insights from MD simulations, provides a detailed picture for the relationship between spectroscopy and structure; and (b) the sensitivity of the low-frequency spectrum to the structure of the mixed CO2/H2O ice. Specifically, for mixed H2O/CO2 ices with low water contents isolated water molecules are found which give rise to a band shifted by only 12 cm(-1) from the gas-phase value whereas for increasing water concentration (for a 1 : 1 mixture) the band progressively shifts to higher frequency because water clusters can form. More generally it is found that changes in the ice structure due to the presence of CO2 are larger compared to changes induced by the presence of CO and that this difference is reflected in the shape of the water bending vibration. Thus, the water bending vibration appears to be a suitable diagnostic for structural and chemical aspects of mixed ices. PMID- 21302550 TI - Isomer specific spectroscopy of C10Hn, n = 8-12: exploring pathways to naphthalene in Titan's atmosphere. AB - Laboratory investigations of the isomer-specific spectroscopy of several C10Hn isomers with n = 8-12 are described, focusing on structures of relevance to the formation or subsequent reaction of naphthalene. The photochemical models of Titan's atmosphere have now progressed to the point that further development of the large-molecule end of the model must recognize and explicitly incorporate the unique spectroscopy, photochemistry, and reactivity of structural isomers. Mass resolved, resonant two-photon ionization (R2PI) was used to record ultraviolet spectra of specific C10Hn composition, while hole-burning methods were used to resolve the spectra of different structural and conformational isomers under jet cooled conditions. The R2PI spectrum of a new C10H8 isomer, 1-phenyl-1-butyne-3 ene, is described and contrasted with other C10H8 isomers. The anticipated role for resonance-stabilized radicals is illustrated by studies of the visible spectroscopy of two hydronaphthyl radical isomers, 1-C10H9 and 2-C10H9, and the trihydronaphthyl radical 1,2,3-C10H11. Conformation-specific spectra of an anticipated C10H12 recombination product of benzyl and allyl radicals is also reported. A reaction scheme that fleshes out the experimental data surrounding naphthalene and its hydrogenated radicals and ions is proposed as a basis for future modeling under Titan's conditions. PMID- 21302551 TI - H3+ cooling in planetary atmospheres. AB - We review the role of H3+ in planetary atmospheres, with a particular emphasis on its effect in cooling and stabilising, an effect that has been termed the "H3+ thermostat" (see Miller et al., Philos. Trans. R. Soc. London, Ser. A, 2000, 58, 2485). In the course of our analysis of this effect, we found that cooling functions that make use of the partition function, Q(T) based on the calculated H3+ energy levels of Neale and Tennyson (Astrophys. J., 1995, 454, L169) may underestimate just how much energy this ion is radiating to space. So we present a new fit to the calculated values of Q(T) that is accurate to within 2% for the range 100 K to 10 000 K, a very significant improvement on the fit originally provided by Neale and Tennyson themselves. We also present a fit to Q(T) calculated from only those values Neale and Tennyson computed from first principles, which may be more appropriate for planetary scientists wishing to calculate the amount of atmospheric cooling from the H3+ ion. PMID- 21302552 TI - Negative ions at Titan and Enceladus: recent results. AB - The detection of heavy negative ions (up to 13 800 amu) in Titan's ionosphere is one of the tantalizing new results from the Cassini mission. These heavy ions indicate for the first time the existence of heavy hydrocarbon and nitrile molecules in this primitive Earth-like atmosphere. These ions were suggested to be precursors of aerosols in Titan's atmosphere and may precipitate to the surface as tholins. We present the evidence for and the analysis of these heavy negative ions at Titan. In addition we examine the variation of the maximum mass of the Titan negative ions with altitude and latitude for the relevant encounters so far, and we discuss the implications for the negative ion formation process. We present data from a recent set of encounters where the latitude was varied between encounters, with other parameters fixed. Models are beginning to explain the low mass negative ions, but the formation process for the higher mass ions is still not understood. It is possible that the structures may be chains, rings or even fullerenes. Negative ions, mainly water clusters in this case, were seen during Cassini's recent close flybys of Enceladus. We present mass spectra from the Enceladus plume, showing water clusters and additional species. As at Titan, the negative ions indicate chemical complexities which were unknown before the Cassini encounters, and are indicative of a complex balance between neutrals and positively and negatively charged ions. PMID- 21302553 TI - Chemical origins of the Mars ultraviolet dayglow. AB - Airglow optical emissions from planetary atmospheres provide remotely observable signatures of atmospheric composition, energy deposition processes, and the resulting chemical reactions. We may one day be able to detect airglow emissions from extrasolar planets. Reliable interpretation requires quantitative understanding of the energy sources and chemical mechanisms that produce them. The ultraviolet dayglow observations by the Mariner 6 and 7 (1969) and Mariner 9 (1971-72) motivated numerous modeling studies and laboratory experiments. The most obvious source reaction is photodissociation and photoionization of ambient CO2, which is known in the laboratory to produce the four strong dayglow emitting states: hv + CO2 --> O(1S), CO(a3pi), CO2(+)(A2pi(u) & B2sigma u(+)). (1) If this simplest of models were sufficient, then the high altitude dayglow emissions would all share the same scale height, which would be that of CO2. The few Mariner dayglow observations provide weak statistics. Addition of 4 months of Mars Express dayglow data, and including radio occultation and mass spectrometry data from other missions, have made the analyses and conclusions more robust. The CO(a3pi) and CO2+(B2sigma u(+)) dayglow altitude profiles are consistent with Reaction (1). In contrast, the O(1S) dayglow scale heights are much larger and are consistent with source Reaction (2): O2(+) + e(-) --> O(1S) (2). Both sets of scale heights change with respect to solar activity roughly as suggested by modeling studies. PMID- 21302554 TI - Laboratory chemistry relevant to understanding and modeling the ionosphere of Titan. AB - Laboratory data have a dual and critical role in interpreting information obtained from the Cassini spacecraft in its passes through the Titan ionosphere. Firstly, in situ mass spectra are obtained by Cassini and their conversion into atmospheric molecular composition requires chemical modeling to create agreement between the observed mass spectra and those determined from the models. Secondly, once agreement is obtained, then the chemical model can be considered to represent the evolution of the Titan atmosphere. As a contribution to these endeavors in the past, laboratory measurements have been made in the Selected Ion Flow Tube (SIFT) of the reactions of a series of ring molecules with the important ionospheric ion CH3+. These reactions showed that a dominant reaction channel is association. In the present study, this work has been extended to reactions of another important Titan ion C3H3+. These ion-molecule reactions have also been studied at room temperature using a SIFT. Reactions have been studied in detail with benzene, toluene and pyridine and show again that association is very important. The loss of ionization in the ionosphere is then controlled by electron-ion dissociative recombination of the association ions and their progeny. The recombination reactions have been studied as a function of temperature (300 to 550 K) using a flowing afterglow. These combined data have been used to develop a subset of the chemistry and test its viability. They have indicated that association of the important Titan ions with the abundant nitrogen, followed by switching of the nitrogen for the ring compounds, can build up larger species, perhaps resulting in multi-rings. Recombination of such species can affect the ionization balance and provide species which can contribute to the parallel neutral chemistry. Species are suggested that should be looked for in the in situ mass spectra. PMID- 21302555 TI - Fast ion-molecule reactions in planetary atmospheres: a semiempirical capture approach. AB - The description of planetary and interstellar chemistry relies strongly on ion molecule reaction rate data collected at room temperature or above. However, the temperature in the ionospheres of planets and in the interstellar medium can decrease down to 100 K and 10 K, respectively. We present here a simple semiempirical method to extend available measurements towards those temperatures. Our approach is based on the long-range capture theory combined with room temperature data. Results are presented for cation-molecule and anion-molecule reactions. An overall good agreement is observed between our model and various experimental data in the temperature range 20-295 K. Deviations larger than a factor of 2 are found, however, with ion trap measurements below approximately 50 K. Predictions are also made for reactions of carbon chain and hydrocarbon ions with atomic hydrogen, of particular importance in Titan's atmosphere and in interstellar clouds. PMID- 21302556 TI - Meteoric ion layers in the Martian atmosphere. AB - Low-lying plasma layers have been observed sporadically in the Martian atmosphere by radio occultation measurements from spacecraft such as the Mars Express Orbiter and the Mars Global Surveyor. These layers are just a few km wide, and tend to occur around 90 km. It has been proposed that the layers consist of metallic ions, for two reasons: they occur in the aerobraking region of the planet where meteoroids ablate; and they resemble sporadic E layers in the terrestrial atmosphere which are known to be composed principally of Fe+ and Mg+ ions. This paper addresses the problem of how metallic ions can persist in a CO2 rich atmosphere, where the ions should be neutralized rapidly by formation of metal-CO2 cluster ions followed by dissociative electron recombination. Laboratory studies using the pulsed laser photolysis/laser induced fluorescence and flow tube/mass spectrometer techniques were used to measure the following rate coefficients: k (Mg+ + CO2 (+ CO2) --> Mg+ x CO2, 190-403 K) = (5.3 +/- 0.7) x 10(-29) (T/300 K)(-1.86 +/- 0.03) cm6 molecule --> 2 s(-1); k(Mg+ x CO2 + O2 - > MgO2(+) + CO2, 297 K) = (2.2 +/- 0.8) x 10(-11) cm3 molecule(-1) s(-1); k(MgO2(+) + O --> MgO(+) + O2, 297 K) = (6.5 +/- 1.8) x 10(-10) cm3 molecule(-1) s(-1); and k(MgO(+) + O --> Mg(+) + O2, 297 K) = (5.9 +/- 2.4) x 10(-10) cm3 molecule(-1) s(-1). A model of magnesium and iron chemistry in the Martian atmosphere was then constructed, which includes meteoric differential ablation rates calculated with the Leeds CABMOD model, photo-ionization, and gas-phase ion molecule and neutral chemistry. The model shows that nearly all the metallic ions between 70 and 110 km should be Mg+, because the reactions of MgO2+ and MgO+ with atomic O are fast enough to prevent these molecular ions undergoing dissociative electron recombination (unlike the analogous Fe species). There are enough Mg+ ions to form sporadic layers of the observed plasma density, and the layers can have a lifetime against neutralization in excess of 20 h. PMID- 21302557 TI - Exploring extrasolar worlds: from gas giants to terrestrial habitable planets. AB - Almost 500 extrasolar planets have been found since the discovery of 51 Peg b by Mayor and Queloz in 1995. The traditional field of planetology has thus expanded its frontiers to include planetary environments not represented in our Solar System. We expect that in the next five years space missions (Corot, Kepler and GAIA) or ground-based detection techniques will both increase exponentially the number of new planets discovered and lower the present limit of a approximately 1.9 Earth-mass object [e.g. Mayor et al., Astron. Astrophys., 2009, 507, 487]. While the search for an Earth-twin orbiting a Sun-twin has been one of the major goals pursued by the exoplanet community in the past years, the possibility of sounding the atmospheric composition and structure of an increasing sample of exoplanets with current telescopes has opened new opportunities, unthinkable just a few years ago. As a result, it is possible now not only to determine the orbital characteristics of the new bodies, but moreover to study the exotic environments that lie tens of parsecs away from us. The analysis of the starlight not intercepted by the thin atmospheric limb of its planetary companion (transit spectroscopy), or of the light emitted/reflected by the exoplanet itself, will guide our understanding of the atmospheres and the surfaces of these extrasolar worlds in the next few years. Preliminary results obtained by interpreting current atmospheric observations of transiting gas giants and Neptunes are presented. While the full characterisation of an Earth-twin might requires a technological leap, our understanding of large terrestrial planets (so called super-Earths) orbiting bright, later-type stars is within reach by current space and ground telescopes. PMID- 21302558 TI - Titan and habitable planets around M-dwarfs. AB - The Cassini-Huygens mission discovered an active "hydrologic cycle" on Saturn's giant moon Titan, in which methane takes the place of water. Shrouded by a dense nitrogen-methane atmosphere, Titan's surface is blanketed in the equatorial regions by dunes composed of solid organics, sculpted by wind and fluvial erosion, and dotted at the poles with lakes and seas of liquid methane and ethane. The underlying crust is almost certainly water ice, possibly in the form of gas hydrates (clathrate hydrates) dominated by methane as the included species. The processes that work the surface of Titan resemble in their overall balance no other moon in the solar system; instead, they are most like that of the Earth. The presence of methane in place of water, however, means that in any particular planetary system, a body like Titan will always be outside the orbit of an Earth-type planet. Around M-dwarfs, planets with a Titan-like climate will sit at 1 AU--a far more stable environment than the approximately 0.1 AU where Earth-like planets sit. However, an observable Titan-like exoplanet might have to be much larger than Titan itself to be observable, increasing the ratio of heat contributed to the surface atmosphere system from internal (geologic) processes versus photons from the parent star. PMID- 21302559 TI - The fate of aerosols on the surface of Titan. AB - A laboratory study based on the chemical transformation that Titan's aerosol analogues suffer when placed under putative surface conditions of the satellite was performed. In order to understand the role that aqueous ammonia may play on the chemical transformation of atmospheric aerosols once they reach the surface, we synthesized laboratory analogues of Titan's aerosols from an N2 : CH4 (98 : 2) mixture irradiated at low temperatures under a continuous flow regime by a cold plasma discharge of 180 W. The analogues were recovered, partitioned in several 10.0 mg samples and placed inside different ammonia concentrations during 10 weeks at temperatures as low as those reported for Titan's surface. After a derivatization process performed to the aerosols' refractory phase with MTBSTFA in DMF, the products were identified and quantified using a GC-MS system. We found derived residues related to amino acids as well as urea. The simplest amino acids aminoethanoic acid (glycine) and 2-aminopropanoic acid (alanine) as well as diaminomethanal (urea), are found regardless of the ammonia concentration and temperature value to which the aerosol analogues were exposed. Our results have important astrobiological implications to Titan's environment particularly if the existence of the suggested subsurface water-ammonia mixture and its deposition on the satellite's surface is validated. PMID- 21302560 TI - Untangling the chemical evolution of Titan's atmosphere and surface--from homogeneous to heterogeneous chemistry. AB - In this article, we first explored the chemical dynamics of simple diatomic radicals (dicarbon, methylidyne) utilizing the crossed molecular beams method. This versatile experimental technique can be applied to study reactions relevant to the atmospheres of planets and their moons as long as intense and stable supersonic beam sources of the reactant species exist. By focusing on reactions of dicarbon with hydrogen cyanide, we untangled the contribution of dicarbon in its singlet ground and first excited triplet states. These results were applied to understand and re-analyze the data of crossed beam reactions of the isoelectronic dicarbon plus acetylene reaction. Further, we investigated the interaction of ionizing radiation in form of energetic electrons with organic molecules ethane and propane sequestered on Titan's surface. These experiments presented compelling evidence that even at irradiation exposures equivalent to about 44 years on Titan's surface, aliphatic like organic residues can be produced on Titan's surface with thicknesses up to 1.5 m. Finally, we investigated how Titan's nascent chemical inventory can be altered by an external influx of matter as supplied by (micro)meteorites and possibly comets. For this, we simulated the ablation process in Titan's atmosphere, which can lead to ground and electronically excited atoms of, for instance, the principal constituents of silicates like iron, silicon, and magnesium, in laboratory experiments. By ablating silicon species and seeding the ablated species in acetylene carrier gas, which also acts as a reactant, we produced organo silicon species, which were then photoionized utilizing tunable VUV radiation from the Advanced Light Source. In combination with electronic structure calculations, the structures and ionization energies of distinct organo-silicon species were elucidated. PMID- 21302561 TI - Mechanisms of formation of nitrogen-containing polycyclic aromatic compounds in low-temperature environments of planetary atmospheres: a theoretical study. AB - Polycyclic aromatic hydrocarbons (PAHs) are believed to be responsible for the formation of organic haze layers in Titan's atmosphere, but the nature of PAHs on Titan and their formation and growth mechanisms are not well understood. Considering the high abundance of nitrogen in Titan's atmosphere, it is likely that the haze layers hold not only pure hydrocarbon PAHs but also their nitrogenated analogs, N-containing polycyclic aromatic compounds (N-PACs) with 'hetero' N atoms in aromatic rings. Laboratory studies of Titan's tholins also support the hypothesis that, together with pure PAHs and their cations, N-PACs may be the fundamental building blocks of microphysical tholin particles. In the present work, we carried out ab initio quantum chemical calculations of potential energy surfaces for various reaction mechanisms of incorporation of nitrogen atoms into aromatic rings of polycyclic aromatic compounds, which may lead to the formation of N-PACs under the low-temperature and low-pressure conditions of Titan's atmosphere. This includes mechanisms analogous to the Ethynyl Addition Mechanism (EAM) recently proposed by us for the growth of PAH by sequential C2H additions to benzene. We consider consecutive C2H and CN additions to C6H6, C6H6 + CN --> C6H5CN + H, C6HCN + C2H --> C6H4(CN)(C2H) + H, C6H5CN + CN --> C6H4(CN)2 + H, C6H4(CN)(C2H) + C2H --> 2-aza-4-ethynyl-1-naphthyl/2-aza-1-ethynyl-4 naphthyl, C6H4(CN)2 + C2H --> C6H4(CN)(NCCCH), and C6H4(CN)(NCCCH) + C2H --> 1,4 diethynylphthalazine. Although these reactions are found to be barrierless and exothermic and therefore feasible at low temperatures, the steps leading to the aza-ethynyl-naphthyl radicals, C6H4(CN)(NCCCH), and 1,4-diethynylphthalazine can give N-PACs as final products only upon their collisional or radiational stabilization. Alternatively, an N-PAC can be synthesized via the reaction of 2 methyleneaminobenzonitrile with C2H, producing 4-ethynyl-quinoline + H without an entrance barrier via a three-step sequence including C2H addition to C of CN, ring closure, and H elimination. 2-Methyleneaminobenzonitrile itself can be formed in the reaction of methyleneaminobenzene with cyano radical, C6H5(NCH2) + CN --> C6H5(NCH2)(CN) --> C6H4(NCH2)(CN) + H, which also does not have any entrance barrier. Methyleneaminobenzene can be produced through recombination of phenyl and methylene-amidogen radicals followed by collisional stabilization of the product, via the barrierless C6Hs + CH3N --> C6Hs(NCH3) --> C6H5(NCH2) + H reaction, or in the reaction of phenyl with methyleneimine, C6H5 + CH2NH --> C6Hs(NHCH3) --> C6H5(NCH2) + H. The latter would be slow at low-temperature conditions owing to the barriers of 4.5 and 2.8 kcal mol(-1) relative to the initial reactants, but feasible if the reactants possess sufficient internal energy to overcome these barriers. We anticipate that the presented mechanisms are viable to form N-PACs in hydrocarbon and nitrogen rich, low temperature atmospheres of planets and their moons such as Titan. PMID- 21302562 TI - Very high resolution mass spectrometry of HCN polymers and tholins. AB - HCN polymers are complex organic solids resulting from the polymerization of hydrogen cyanide (HCN) molecules. They have been suspected to contribute to the refractory carbonaceous component of comets as well as the distributed CN sources in cometary atmospheres. Titan's tholins are also organic compounds produced in a laboratory setting but result from the complex chemistry between N2 and CH4 induced by UV radiation or electric discharges. Some of these compounds have optical properties in the visible range fairly similar to those of Titan's aerosols or those of the reddish surfaces of many icy satellites and small bodies. It has been proposed that HCN polymers are constituents of tholins but this statement has never received any clear demonstration. We report here on the comparative analysis of tholins and HCN polymers in order to definitely establish if the molecules identified in the HCN polymers are present in the tholins as well. First, we present a global comparison of HCN polymers with three kinds of tholins, using elemental analysis measurements, infrared spectroscopy and very high resolution mass spectrometry of their soluble fraction. We show that the chemical composition of the HCN polymers is definitely simpler than that of any of the tholins studied. Second, we focus on six ions representative of the composition of HCN polymers and using mass spectrometry (HRMS and MS/HRMS), we determine that these tholins contain at best a minor fraction of this kind of HCN polymers. PMID- 21302563 TI - Volatile inventories in clathrate hydrates formed in the primordial nebula. AB - The examination of ambient thermodynamic conditions suggests that clathrate hydrates could exist in the Martian permafrost, on the surface and in the interior of Titan, as well as in other icy satellites. Clathrate hydrates are probably formed in a significant fraction of planetesimals in the solar system. Thus, these crystalline solids may have been accreted in comets, in the forming giant planets and in their surrounding satellite systems. In this work, we use a statistical thermodynamic model to investigate the composition of clathrate hydrates that may have formed in the primordial nebula. In our approach, we consider the formation sequence of the different ices occurring during the cooling of the nebula, a reasonable idealization of the process by which volatiles are trapped in planetesimals. We then determine the fractional occupancies of guests in each clathrate hydrate formed at a given temperature. The major ingredient of our model is the description of the guest-clathrate hydrate interaction by a spherically averaged Kihara potential with a nominal set of parameters, most of which are fitted to experimental equilibrium data. Our model allows us to find that Kr, Ar and N2 can be efficiently encaged in clathrate hydrates formed at temperatures higher than approximately 48.5 K in the primitive nebula, instead of forming pure condensates below 30 K. However, we find at the same time that the determination of the relative abundances of guest species incorporated in these clathrate hydrates strongly depends on the choice of the parameters of the Kihara potential and also on the adopted size of cages. Indeed, by testing different potential parameters, we have noted that even minor dispersions between the different existing sets can lead to non-negligible variations in the determination of the volatiles trapped in clathrate hydrates formed in the primordial nebula. However, these variations are not found to be strong enough to reverse the relative abundances between the different volatiles in the clathrate hydrates themselves. On the other hand, if contraction or expansion of the cages due to temperature variations are imposed in our model, the Ar and Kr mole fractions can be modified up to several orders of magnitude in clathrate hydrates. Moreover, mole fractions of other molecules such as N2 or CO are also subject to strong changes with the variation of the size of the cages. Our results may affect the predictions of the composition of the planetesimals formed in the outer solar system. In particular, the volatile abundances calculated in the giant planets' atmospheres should be altered because these quantities are proportional to the mass of accreted and vaporized icy planetesimals. For similar reasons, the estimates of the volatile budgets accreted by icy satellites and comets may also be altered by our calculations. For instance, under some conditions, our calculations predict that the abundance of argon in the atmosphere of Titan should be higher than the value measured by Huygens. Moreover, the Ar abundance in comets could be higher than the value predicted by models invoking the incorporation of volatiles in the form of clathrate hydrates in these bodies. PMID- 21302565 TI - Impact factor: an achievement? PMID- 21302564 TI - Closing remarks. PMID- 21302566 TI - Asymptomatic enlargement of the clavicle: a review of underlying aetiologies. AB - An asymptomatic enlargement of the medial clavicle is a condition that is often both missed and misdiagnosed. We review the most common causes of an isolated and asymptomatic enlargement of the medial clavicle. Underlying aetiologies include osteoarthritis of the sternoclavicular joint, condensing osteitis, spontaneous dislocation of the sternoclavicular joint, and sternocostoclavicular hyperostosis. Key points in the history and physical examination as well as characteristic radiographic findings are sufficient for correct diagnoses. Treatment is conservative. PMID- 21302567 TI - Is there still a place for arthrodesis in the surgical treatment of basal joint osteoarthritis of the thumb? AB - Despite the obvious success of arthroplasty trapeziectomy with or without interposition and prosthesis--in the treatment for trapeziometacarpal osteoarthritis, one may question the value of an arthrodesis in particular situations. In most reported series the outcome is reasonably successful, but when comparing the results of arthrodesis with arthroplasty, there is convincing evidence that the latter gives better outcomes. Considering the overall complication rate, and more specifically the incidence of nonunion after trapeziometacarpal fusion, it can be reasonably concluded that the latter should be reserved for specific indications. PMID- 21302568 TI - Clavicle non-union: autologous bone graft is not a necessary augment to internal fixation. AB - Most series of patients undergoing open reduction and internal fixation (ORIF) of clavicular non-union utilise distant autologous bone graft. We aimed to report the outcomes of a series of patients who had undergone ORIF for clavicular non union without the use of distant bone graft. All patients undergoing ORIF of a clavicular nonunion were identified on the hospital database. Records were reviewed to determine basic demographics, operative findings, and radiological outcome. Patients were contacted and details about initial injury and treatment, and return to work and sport, were recorded. Disabilities of Arm, Shoulder and Hand (DASH) questionnaires for both operated and non-operated shoulders were completed. Fifteen patients with at least 6 months follow-up (average 12A) were identified. Their average age was 39 years. All patients were initially treated in a broad arm sling. All fractures were fixed with a pre-contoured locking plate and all went on to achieve clinical and radiological union. The average DASH score was 14.5 on the operated side and 4.2 on the contralateral side. All patients had returned to work and regular sport activities. One patient required plate removal due to local irritation. The results of this small series suggest that use of distant bone graft is not necessary when performing ORIF for symptomatic non-union of the clavicle with appropriate preparation of fracture ends and adequate fixation. PMID- 21302569 TI - Patient related functional outcome of glenoid rim fractures treated with open reduction and internal fixation. AB - The aim of this study was to evaluate patient related outcome and shoulder stability following open reduction and internal fixation (ORIF) in patients with glenoid rim fractures. After a median follow-up of four years, 14 patients completed the Rowe Shoulder Stability Score and Quick DASH questionnaire. The median Rowe score was 90 (Q1: 88, Q3: 100). Results were graded excellent in 11 patients and good in three. The median DASH score was 4.6 (Q1: 0, Q3: 32). In conclusion this study showed that ORIF of type la and 2 glenoid rim fractures provided satisfactory results with respect to prevention of instability. However, patient reported functional outcome was disappointing in 21% of the patients. PMID- 21302570 TI - Operative treatment of humeral shaft fractures. Comparison of plating and intramedullary nailing. AB - Plate and screw fixation (PSF) has always been the more common surgical treatment of humeral shaft fractures. However, intramedullary nailing (IMN) of the humerus has gained in popularity over the last two decades. The purpose of this retrospective study was to evaluate the clinical outcome of plate fixation versus intramedullary nailing of midshaft humeral fractures. The study included 91 patients treated at the department of Trauma Surgery of the University hospital of Leuven; 42 fractures had been treated by plate fixation and 49 by IM nailing. Union, functional outcome, possible complications and the need for additional surgery were compared between the IMN and PSF group. No significant difference in terms of fracture union and functional recovery was noted between the two groups. There were four cases of postoperative radial nerve palsy in the PSF group, versus two in the IMN group (non significant difference). A significantly larger number of patients with restrictive pain and/or functional hindrance in the shoulder or elbow was noted in the IMN group (p = 0.0053). Problems with osteosynthesis material occurred as often in the PSF group as in the IMN group. One patient developed wound infection at the shoulder after antegrade nailing. A significantly larger number of complications was seen in the IMN group than in the PSF group (p = 0.05). A reoperation was necessary in 143% of the PSF patients and 163% of the IMN patients (non significant difference). In this retrospective study, IMN did not achieve better results than PSF of humeral midshaft fractures and was associated with more postoperative complications. Based on these findings, we suggest that plating of humeral shaft fractures should be considered as the primary treatment for all surgical indications, except for some open fractures requiring temporary external fixation, pathological fractures, humeral shaft fractures in morbidly obese and osteopenic patients, and large segmental fractures of the humerus. PMID- 21302571 TI - Effect of patient age on malunion of operatively treated distal radius fractures. AB - Radiological outcomes of 200 distal radius fractures following surgical treatment were retrospectively assessed to investigate whether malunion was more frequent in older patients. Malunited fractures were classified into four types: malunion with dorsal or palmar displacement, malunion with incongruity of the radiocarpal joint and malunion with radial shortening. Most fractures were treated with percutaneous K-wire fixation (n=139) and volar plates (n=50). Thirty-five percent of fractures were found to be malunited. In patients over 65 years of age, malunion was present in 54 % of the cases. Mean age of patients with malunion was 60 and without malunion 51 years. Patients with dorsal displacement and radial shortening were older than those with palmar displacement and radiocarpal incongruity. PMID- 21302572 TI - Single retrograde intramedullary wire fixation of metacarpal shaft fractures. AB - From 1993 to present day, 110 metacarpal fractures in 89 patients were stabilised using a method of inserting a percutaneous intramedullary wire. This allowed for early unimpeded movement in wrist and hand together with ease of wire removal in clinic. Reduction was maintained in all patients until fracture healing, and there were no malunions. One was re-done owing to inadequate reduction intra operatively, which thereafter united. One re-fractured and was subsequently treated non-operatively. There were two superficial infections. One patient was lost to follow-up at 4 weeks; the rest regained a full range of pain-free movement. In a final assessment of 62 patients, the mean DASH score was 4.6. We recommend this technique for metacarpal fractures that are: transverse and off ended; angulated transverse or short oblique; multiple transverse or short oblique. We do not recommend this technique for long oblique or rotationally malaligned fractures. PMID- 21302573 TI - Primary metal-on-metal total hip arthroplasty with large-diameter femoral heads: a clinical trial of 59 hips. AB - Large-diameter femoral heads with nearly anatomical sizes became available for metal-on-metal total hip arthroplasty after recent advances in metal-on-metal technology. We retrospectively studied the clinical and radiological results in 59 hips of 54 patients (32 women and 22 men, mean age 54.4 years) who underwent cementless metal-on-metal total hip arthroplasty with large-diameter heads. Patients were followed for a mean of 48.6 months. Range of motion improved significantly after surgery (p = 0.001). Harris hip scores improved from 38.5 points to 903 points at latest follow-up. We found no gender-related differences in Harris hip scores, whereas there was a correlation between age and Harris hip scores (p < 0.001), with excellent results being observed predominantly in younger patients. Mean acetabular inclination of the acetabular cup was 42.2 degrees (range: 37-51 degrees). Radiologically, a 1 mm thick radiolucency was detected in three acetabula, which were asymptomatic. One acetabulum was revised because of displacement. Three patients reported squeaking within their hips, which however disappeared in a short time. We did not observe any dislocation, deep infection or loosening. Grade 1 heterotopic ossification was detected in one hip. Although the inherent stability and the functional results of large anatomical heads are encouraging, longer follow-up data and larger series are essential to evaluate the real advantages of this type of prosthesis over conventional femoral heads. PMID- 21302574 TI - Revision hip arthroplasty in nonagenarians. AB - The results of a series of revision hip arthroplasties in nonagenarians performed at a single institution over an 8 year period are presented. All data was collected prospectively. The indications for surgery, ASA grade, co-morbid medical conditions, post operative complications, blood transfusion requirements, length of in-patient stay, and discharge deposition, were recorded. Thirty day, one year and current mortality rates were calculated. Fifteen patients were identified with a mean follow-up of 3 years. There were 14 single-stage and 1 two stage revisions. The mean age at the time of surgery was 92 years. The mean ASA grade was 2. The average inpatient stay was 14 days. Sixty three percent of patients required a period of further rehabilitation. The rate of complications was high (63%) as was the need for blood transfusion (75%). Mortality at 30 days was 7% (1/15),at 1 year 20% (3/15), and at 3 years 33% (5/15). If indicated, revision hip arthroplasty can still be considered in very elderly patients; however, a higher than usual complication rate is to be expected. PMID- 21302575 TI - No effect of PMMA bone cement on thrombocyte levels after total hip arthroplasty. AB - Thrombocytopenia has been reported to occur after total hip arthroplasty (THA). Several in vitro studies have investigated whether polymethylmethacrylate (PMMA) bone cement could be a possible origin for toxic agents that interfere with platelet function and survival. The aim of this study was to screen patient data for postoperative thrombocytopenia and the level of platelet concentrations in relation with the fixation method of THA. A consecutive series of 499 THAs was studied (24.6% fully cemented, 45.5% hybrid and 29.9% uncemented). Pre- and postoperative thrombocyte levels were recorded. Patient data were reviewed for age, indication, BMI, blood cell count, and thromboembolic events. Patients in the noncemented group were significantly younger and their thrombocyte levels were higher. There were no statistically significant differences in platelet loss between groups at any point in time following THA. Platelet concentrations had fully recovered at the time of discharge from hospital. Power analysis revealed that the cohort was large enough to show even small effect sizes. The use of PMMA cement in THA does not appear to affect postoperative platelet concentrations to any significant extent. PMID- 21302576 TI - Subtrochanteric fracture: a rare but severe complication after screw fixation of femoral neck fractures in the elderly. AB - Cannulated screw fixation is a minimal invasive technique to treat undisplaced femoral neck fractures. It is the preferred method in elderly patients who often suffer co-morbidities. There is scarce literature on subtrochanteric femoral fracture as a complication of cannulated screw fixation of a femoral neck fracture. This complication occurred, without an adequate trauma, in two of 35 patients (5.7%) in this retrospective study of patients older than 65 years (mean age: 77 years) who were treated with cannulated screws for an undisplaced femoral neck fracture between 2004 and 2009. We reviewed the literature for the incidence of this complication and possible predisposing factors. The overall incidence reported in literature is 2.4-4.4% (mean: 2.97%). Despite a broad use of this type of osteosynthesis, the literature does not provide clear biomechanical or clinical indications for optimal screw placement to avoid this complication. Considering the literature and our personal results, surgeons should be aware of this severe complication; they may opt for a different implant in the very old, osteoporotic patient with an undisplaced femoral neck fracture. PMID- 21302577 TI - Early primary total knee replacement for complex proximal tibia fractures in elderly and osteoarthritic patients. AB - Complex intra-articular fractures of the proximal tibia are difficult to treat, especially in the elderly osteoporotic patient. Pre-existing osteoarthritis, cartilage damage during trauma, suboptimal reduction and fixation due to poor bone stock and/or secondary displacement frequently lead to poor outcome. After osteosynthesis rehabilitation is cumbersome as patients have been non-weight bearing for long periods of time and secondary total knee arthroplasty can be challenging. For these reasons, we investigated the possibility to perform a total knee arthroplasty with or without adjuvant osteosynthesis as a primary treatment in elderly and/or osteoarthritic patients with complex tibial plateau fractures. Between 2002 and 2009, 12 patients (mean age: 73 years (58-81)) with an AO-41 fracture type B1 (1), B3 (8) and C3 (3) were treated with a primary total knee arthroplasty within three weeks from their trauma. Most patients (7/12) were allowed early full-weight bearing. One patient died due to an unrelated cause; the remaining eleven were reviewed at a mean follow-up period of 31 months (5 w-81 m). At final follow-up the median knee score was 78 (50-100) and the function score 58 (0-100): 7/11 patients had an excellent result, while 1/11 had a fair and 3/11 a poor result. Fair and poor results were mostly related to pre-existing poor general condition and/or concomitant disease. Most patients were satisfied and only minor short- and long-term complications were noted. There was no need for revision surgery. Our limited series of well-selected elderly and/or osteoarthritic patients with a complex tibial plateau fracture treated with primary total knee arthroplasty yielded encouraging results. PMID- 21302578 TI - Are clinical photographs appropriate to determine the maximal range of motion of the knee? AB - Goniometry is a commonly used method for the clinical assessment of range of motion (ROM) of the knee. A digital photograph of the knee in maximal flexion and extension could provide a more objective way to assess the ROM. The aim of our study was to investigate the reliability of the use of digital photographs as a method for measuring the ROM of the knee. Four observers examined 49 patients. Digital photographs of the knee in maximal flexion and extension were compared with standard clinical goniometric measurements in the same position. We observed higher intra-observer reliability for the digital method in flexion (p < 0.0001) and extension (p = 0.005) compared to goniometry. The extension results were numerically lower when using goniometry compared to the digital method (p < 0.001). For both methods, the intra-observer reliability for extension was lower compared to flexion. The intraobserver standard error of measurement (SEM) of the digital method was smaller than the goniometric SEM; the digital method thus appeared more reliable. Measuring maximal flexion and extension on digital photographs is more reliable for both extension and flexion compared to standard goniometric measurements. PMID- 21302579 TI - Influence of patellar subluxation on ligament balancing in total knee arthroplasty through a subvastus approach. An in vivo study. AB - Post-operative joint stability and ligament balance are crucial factors in the longevity of the prosthesis after total knee arthroplasty (TKA). The influence of patellar position on the balance of the knee is controversial. We studied the influence of patellar subluxation on tibiofemoral pressure distribution in vivo, in 32 knees undergoing TKA through a subvastus approach. We used the e-LIBRA Dynamic Knee Balancing System (Synvasive Technology, El Dorado Hills, CA, USA). This is a device that measures the pressures in the medial and lateral compartment independently. After balancing the knee in flexion with the patella in place, we demonstrated a significant rise in pressure in the medial compartment with subluxation of the patella (p < 0.0001). Our findings give a new insight on the role of the patellar position while balancing a total knee arthroplasty. Surgeons should be aware of this effect when choosing their surgical technique for this operative procedure. PMID- 21302580 TI - En bloc resection of osteosarcoma of the proximal fibula. An analysis of 8 cases. AB - Osteosarcoma of the proximal fibula is a rare entity that poses a surgical challenge. Limb salvage is the goal of treatment, and this entails sacrifice of the common peroneal nerve as well as the anterior tibial artery. Also the loss of the lateral collateral ligament and biceps attachment leads to unavoidable knee instability which requires special reconstructive procedures. From 2002 to 2008, eight patients with osteosarcoma of the fibular head were treated in our institution with Malawer type II resection. Seven of these patients are still alive without evidence of disease. Our results indicate that the sacrifice of the common peroneal nerve ensures a wide margin of resection which in turn correlates with long-term survival. Furthermore, our technique of reconstruction of lateral knee structures has produced good functional outcome without significant postoperative knee instability. PMID- 21302581 TI - Management of massive posttraumatic bone defects in the lower limb with the Ilizarov technique. AB - Massive bone defects have been treated by various methods with variable success rates. The Ilizarov technique has been advocated as a preferred method for treatment of large segmental defects. Twenty five patients with massive post traumatic bone defects of the lower limb (22 tibiae, 3 femurs) were treated using Ilizarov's technique. After radiological evaluation, the patients were subjected to bone transport. Bifocal osteosynthesis was performed in all except those needing >12 cm of bone transport. Distraction was started between day 4 and 7 at the rate of 1 mm per day in four increments. All were males with a mean gap of 8.9 cm (range: 5-17 cm), mean age of 28.24 years (16-40) and having undergone a mean of 2.6 previous surgeries. Mean time in Ilizarov frame was 8.8 months and external fixator index was 0.98 months. Mean duration of follow-up after frame removal was 23.5 months. Union was achieved in 23 (92%) cases. Bone grafting was required in 9 (36%) According to ASAMI criteria, bone results were excellent in 13, good in 1, and poor in 11 patients. Functional results were excellent in 6 patients, good in 9, fair in 4, and poor in 6 patients. A total of 72 complications occurred (2.88 complications per patient). Union was achieved in all except two patients. The Ilizarov external fixator offers a limb salvage solution even in large bone defects but the surgeon should set realistic goals both for himself and his patients while offering this method of treatment. PMID- 21302582 TI - Management of diabetic neuropathic ankle arthropathy by arthrodesis using an Ilizarov frame. AB - Charcot neuroarthropathy is a peripheral and autonomic neuropathy that typically presents as a hyperaemic event (e.g., a red, swollen foot). The diabetic Charcot ankle and foot is a potentially limb-threatening disorder that is being recognized with increasing frequency in persons with longstanding diabetes and concomitant peripheral sensory neuropathy. While considered a rare complication of diabetes, it can be a devastating complication requiring months of treatment to arrest its progression. The main problems encountered in this process are osteopenia, fragmentation of the bones of the foot and ankle, joint subluxation or even dislocation, ulceration of the skin and the development of deep sepsis. Arthrodesis using an Ilizarov external fixator is regarded as an optimal choice for the treatment of Charcot arthropathy. PMID- 21302583 TI - A simple cost effective technique for soft tissue protection during intramedullary nailing of the tibia. AB - Intramedullary nailing has revolutionized the management of tibial diaphyseal fractures. However, anterior knee pain remains a common complication. Although knee pain causes are still largely unknown, there is evidence to suggest that adhesions resulting from soft tissue damage may contribute to it. We describe a simple cost-effective technique that utilises a syringe to protect the patellar ligament and Hoffa's fat pad during intramedullary nailing of the tibia. PMID- 21302584 TI - Stabilization of chronic proximal tibiofibular joint instability with a semitendinosus graft. AB - Although chronic proximal tibiofibular joint instability is a rare condition, it is associated with marked functional impairment. Various surgical options have been reported in literature, all associated with several problems and limitations. We describe a new technique of reconstruction of the proximal tibiofibular joint using the semitendinosus tendon. The key steps of the procedure are the preparation of a proximally released semitendinosus tendon, and its guidance through two transtibial tunnels and one transfibular tunnel. The semitendinosus tendon acts as a soft tissue sling and does not interfere with mobility at the proximal or distal tibiofibular joints as noted after fibular head resection or arthrodesis of the proximal tibiofibular joint. Further advantages are the easy accessibility of the semitendinosus graft and the small surgical scar with better cosmetic results as compared to ligamentous reconstructive procedures using a split biceps femoris tendon or a strip of the iliotibial band. PMID- 21302585 TI - Delayed migration of a metal suture anchor into the glenohumeral joint. AB - Intra-articular migration is a known complication of poorly placed metallic suture anchors in rotator cuff repair and labral reconstruction. We report a case of intra-articular migration of a metallic suture anchor seven years after open labral reconstruction. Despite the fact that the patient remained asymptomatic for seven years, presence of an extra-osseous anchor was already noted postoperatively. In an era where the use of suture anchors has become common practice, surgeons should always be aware of possible anchor migration, especially when patients complain of sudden sharp pain, persistent pain, a catching sensation and loss of mobility. PMID- 21302586 TI - Fatigue stress fractures of the pelvis: a rare cause of low back pain in female athletes. AB - Stress fracture of the pelvis represents one rare differential diagnosis among the manifold causes of low back pain in female athletes. We report a case of fatigue stress fracture of the pelvis in a 24-year-old female athlete as an unusual differential diagnosis of low back pain that should be taken into consideration. According to the literature the incidence of low back pain in athletes ranges from 1% to 30% and is influenced by sport type, gender, training intensity, training frequency and technique. In some cases, no specific pain generator is found, which makes diagnosis and treatment difficult. The frequency of the injury and the treatment options are discussed, based on published studies. PMID- 21302587 TI - Extra-skeletal Ewing's sarcoma in adults: presentation of two cases. AB - Extraosseous Ewing's sarcoma represents about 5% of the Ewing family of tumours. Two cases in adult patients are presented, emphasizing the complexity of a multi modality treatment approach of this tumour. Clinical presentation, chemotherapeutical, surgical and radiotherapeutical approaches are discussed. A thorough literature search was done to correlate our therapeutic attitude with current knowledge of this very rare disease. PMID- 21302588 TI - Rickets in the Benelux. A case report of two Indian immigrants. AB - The last decades showed a resurgence of rickets and osteomalacia in the developed countries. In this report, we present two cases of dietary rickets in Indian teenage brothers who migrated to Europe. Supplementation of calcium and vitamin D3 to their diet resulted in rapid relief of musculoskeletal symptoms. PMID- 21302589 TI - Analysis of pharmaceutical product diversion and the gray market: cheaper drugs, but at what cost? PMID- 21302590 TI - Preliminary study of the fibrin structure in hypertensive, dyslipidemic and type 2 diabetic patients. AB - Individuals with hypertension, dyslipidemia or diabetes are at a higher risk to suffer cardiovascular disease than other people; while impaired fibrin structure/function may contribute to further raise the cardiovascular risk in the former. The purpose of this work was to study the fibrin network and fibrin degradation properties in hypertensive (HT) patients, pharmacologically treated, 124 +/- 11 mmHg, systolic blood pressure, and 70 +/- 10 mmHg, diastolic blood pressure, n = 12; metabolic dyslipidemic patients (DL), cholesterol: 5.7 +/- 1.5 mmol/L, n = 10; patients with type 2 diabetes mellitus (T2D), fasting plasma glucose: 8.8 +/- 2.2 mmol/L, n = 10; and a control group of healthy individuals, n = 9. The fibrinogen concentration was determined by the gravimetric method. Fibrin network formation and porosity were assessed by turbidity and permeation techniques, respectively; fibrin elastic properties were evaluated by compaction and fibrin lysis, by turbidity after addition of external tPA prior to plasma clotting. Fibrinogen concentration was significantly higher only in T2D patients (p = 0.004), compared to the control group. The fibrin polymerization and lysis processes were similar for all patient and control groups. Permeation was significantly slower in DL and T2D patients, p = 0.022 and 0.0002, respectively, whereas the compaction coefficient was significantly smaller in T2D patients, p = 0.0015. Our results suggest that the fibrin structure was altered in DL and T2D patients, probably due to the increased cholesterol and glycation, respectively. PMID- 21302591 TI - Hemoglobin S/hemoglobin City of Hope compound heterozygote with a SubSaharan genetic background and severe bone marrow hypoplasia. AB - Hemoglobin City of Hope (Hb CH) (HBB: c.208G>A, beta 69 (E13)Gly>Ser) is a rare, anomalous change. Seven independent carriers reported so far, had not displayed any hematological manifestations. The ethnic origin of the known instances is presumably heterogeneous, although they are mainly Mediterraneans or equatorial West Africans. We describe the case of a compound heterozygote in trans for Hb S (Glu6Val) and Hb City of Hope (Gly69Ser) in an anemic two year-old boy with a severe immune-deficient phenotype and fatal chronic parvovirus B19 infection. Haplotype with the Hb S was Bantu; while it was a mixed atypical Benin/Cameroon for Hb CH. Remote ancestral origin of the City of Hope mutation in this family seems to be SubSaharan African. The compound heterozygosis in trans for hemoglobins S and City of Hope, jointly with an unfavorable HBB control region background and a viral chronic infection, seemed the cause of the fatal outcome in the patient. When accompanied by other Hb deleterious mutations in trans, Hb CH should not be considered any longer as an innocuous or functionally silent variant. PMID- 21302592 TI - Autism associated to a deficiency of complexes III and IV of the mitochondrial respiratory chain. AB - Autism is the prototype of generalized developmental disorders or what today are called autism spectrum disorders. In most cases it is impossible to detect a specific etiology. It is estimated that a causative diagnosis may be shown in approximately 10-37% of the cases, including, congenital rubella, tuberous sclerosis, chromosome abnormalities such as fragile X syndrome and 22q13.3 deletion syndrome, Angelman, Williams, Smith-Magenis, Sotos, Cornelia de Lange, Mobius, Joubert and Goldenhar syndromes, Ito's hypomelanosis, as well as certain cerebral malformations and several inherited metabolic disorders. The case of a 3 year old girl is described, who was considered as autistic according to the criteria established by the DSM-IV manual for psychiatric disorders. She showed a delay in psychomotor development since she was 18 months old; she pronounces very few words (10), points to some objects, does not look up and it is hard to establish eye contact with her. She has paradoxical deafness and therefore, does not respond when called or when she is given orders, she is beginning to walk. She has not convulsions. Laboratory tests showed an anion gap of 31.6 mEq/L, lactate: 2.55: mmol/L, pyruvate: 0.06 mmol/L, and elevated lactate to/pyruvate ratio: 42.5. Under optical microscopy a muscular biopsy showed a reduction of the diameter of muscular fibers. The study of energy metabolism showed a partial deficiency of complexes III and IV of the respiratory chain, which allowed us to conclude that this was a mitochondrial dysfunction with an autistic clinical spectrum. PMID- 21302593 TI - LABAs and asthma: from the SMART study to the SMART approach. PMID- 21302594 TI - Risk of pneumonia with use of inhaled corticosteroids in patients with chronic obstructive pulmonary disease. PMID- 21302595 TI - Outpatient pulmonary rehabilitation in severe chronic obstructive pulmonary disease. AB - OBJECTIVES: An outpatient programme for rehabilitation of patients with severe ventilatory impairment due to chronic obstructive pulmonary disease (COPD) was conducted. Its main purpose was to assess the feasibility of the programme for COPD patients. METHODS: Initial assessment included a shuttle walking test, administration of the chronic respiratory disease questionnaire (CRDQ), assessment of the hospital anxiety and depression scale (HAD) and sickness impact profile (SIP). The patients were entered into a 6-week outpatient programme between January 2007 to July 2007 during which they attended twice weekly for a 2 1/2 hour session. Assessment was repeated on completion of the study at three months and later at six months. RESULTS: The study included 44 (28 males) patients with COPD with a mean age 66 years. All patients had severe ventilatory impairment as defined by a forced expiratory volume in one second (FEV1) of less than 40% of predicted. The shuttle walking distance improved significantly and was maintained at the improved level for six months. The improvement in all four dimensions of the CRDQ was statistically significant (p < 0.05) and reached clinical significance for fatigue and for mastery. On entry, a notable level of depression was found in 32% of patients, and anxiety in 40 percent. There was a significant reduction in both of these that was maintained at six months (p < 0.05). There was no improvement in the SIP at three months, but significant improvement was found at six months (p < 0.05). CONCLUSIONS: This study shows that a successful outpatient programme can be conducted in patients with severe ventilatory impairment, and that benefits in physical ability and in health related quality of life (HRQOL) can be achieved. The improvements were maintained at six months. PMID- 21302596 TI - Factors associated with hospital admission in patients with acute exacerbation of chronic obstructive pulmonary disease. AB - BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (AE COPD) impair quality of life (QOL), accelerate the decline in lung function and often require hospitalisation, and thus, leading to increased healthcare burden. By identifying factors that may be associated with AE-COPD and managing them rationally, not only the hospital admissions could be avoided but progression of the disease may also be slowed. Objective. The aim of the present study was to determine the factors associated with hospital admissions among adults with AE COPD. METHODS: Seventy-three patients admitted with AE-COPD were administered a structured questionnaire during their hospital stay. Data on body mass index (BMI), smoking, symptoms, co-morbidities course of the disease, spirometry management and outcomes during the hospitalisation were obtained. Factors associated with hospital admissions were analysed. RESULTS: The hospitalisation due to AE-COPD was significantly associated with the reduced forced expiratory volume in one second (FEV1), and peak expiratory flow rates, increasing sputum purulence, number of hospitalisations during previous year for COPD and presence of co-morbidities. CONCLUSIONS: The study shows that both disease and healthcare related factors are predictors for hospitalisation. Identification of risk factors and appropriate management may reduce hospitalisation due to AE-COPD. PMID- 21302597 TI - Retrospective study of interstitial lung disease in a tertiary care centre in India. AB - BACKGROUND: There has been a recent surge in the recognition of interstitial lung disease (ILD) in India. METHODS: We conducted a retrospective study based on the available medical records of 274 patients with biopsy proven ILD seen during the period 1994-2001 at our tertiary care referral hospital. RESULTS: Idiopathic pulmonary fibrosis (43%), sarcoidosis (22%), ILDs secondary to collagen vascular disease (19%) and extrinsic allergic alveolitis, among others, were the most common aetiological causes of ILD. The diagnostic yield from transbronchial lung biopsy (TBLB) was high (96%). CONCLUSIONS: Interstitial lung diseases (ILDs) appear to be under-reported from India. Lack of recognition and inadequate availability of diagnostic facilities, like high resolution computed tomography (HRCT) of the chest may be some of the reasons for this. The diagnostic yield from TBLB in our study was high at 96 percent. The TBLB may be used as the initial, cost-effective and safe tool for confirmation of aetiological diagnosis in most patients with diffuse parenchymal lung diseases. PMID- 21302598 TI - Spirometry and diffusion studies in patients with type-2 diabetes mellitus and their association with microvascular complications. AB - BACKGROUND: Diabetes is a systemic disease with-well known complications involving eyes, kidneys and nerves. The presence of an extensive pulmonary microvascular circulation and abundant connective tissue raises the possibility that lung may also be a target organ in diabetes. METHODS: A total of 45 subjects were included in the study. All patients were evaluated for diabetic microangiopathies: nephropathy (by 24-hour protein excretion), retinopathy (by direct ophthalmoscopy) and neuropathy (by clinical examination). The patients were divided into following three groups: Group A: patients with type-2 diabetes mellitus (DM) with evidence of microangiopathy (n=15); Group B: patients with type-2 DM without any evidence of microangiopathy (n=15); Group C: non-diabetic subjects (n=15) as controls. Glycosylated haemoglobin (HbA1C) was measured as an indicator of glycemic control. Spirometry and single-breath diffusion capacity for carbon-monoxide (DLCO) were performed on all patients using Elite Series Body Plethysmograph machine. RESULTS: A significant reduction of diffusion capacity corrected for alveolar volume (%DL/VA) was observed in group A (p < 0.001), as compared to the other groups. There were no differences among the three groups for other pulmonary functions. There was a significant correlation between DL/VA percent predicted and albuminuria (r= -0.975, p < 0.001), and DL/VA percent predicted and the retinopathy (r = -0.550, p < 0.05). CONCLUSION: This study shows a mild reduction in diffusing capacity in patients with type-2 DM with microangiopathy. PMID- 21302599 TI - Identification of IgE-mediated food allergy and allergens in older children and adults with asthma and allergic rhinitis. AB - BACKGROUND AND OBJECTIVE: Prevalence of immunoglobulin (Ig) E-mediated food allergy is primarily reported for certain pediatric populations and adults. The present study was aimed to investigate the relative prevalence of food allergy and allergens in older children and adults with asthma and allergic rhinitis. METHODS: Patients (12-62 years) were screened using standard questionnaire and skin prick-test (SPT) with common foods and aeroallergens. Specific IgE level was determined by enzyme linked immunosorbent assay (ELISA) and allergy was established by blinded food challenges. RESULTS: Of 1860 patients screened, 1097 (58.9%) gave history of food allergy. Of the history positive patients skin tested (n=470), 138 (29.3%) showed a marked positive reaction to food extracts. Rice elicited positive SPT reaction in maximum number of cases 29 (6.2%) followed by blackgram 28 (5.9%), lentil 26 (5.5%), citrus fruits 25 (5.3%), pea 18 (3.8%), maize 18 (3.8%) and banana 17 (3.6%). The SPT positive patients showed elevated specific IgE levels (range: 0.8-79 IU/mL) against respective food allergens than normal controls (0.73 IU/mL, mean +/- 2 SD). Food allergy was confirmed in 21/45 (46.6%) of the patients by blinded controlled food challenges. The prevalence of food allergy was estimated to be 4.5% (2.6%-6.34%) at 95% confidence interval (95% CI) in test population (n=470). Sensitisation to food was significantly associated with asthma (p = 0.0065) while aeroallergens were strongly related to rhinitis (p < 0.01). CONCLUSIONS: Food allergy is estimated to be 4.5% in adolescents and adults with asthma, rhinitis or both. Rice, citrus fruits, blackgram and banana are identified as major allergens for inducing allergic symptoms. PMID- 21302600 TI - Coexistent chronic obstructive pulmonary disease-heart failure: mechanisms, diagnostic and therapeutic dilemmas. AB - Mortality in chronic obstructive pulmonary disease (COPD) is more often due to cardiac rather than respiratory causes. The coexistence of heart failure (HF) and COPD is frequent but remains under-diagnosed. Both conditions share several similarities including the age of the population affected, a common risk factor in smoking and symptoms of exertional dyspnoea. There is also a strong possibility of COPD promoting atherosclerotic vascular disease through systemic inflammation. Both the conditions are punctuated by episodes of acute exacerbations of symptoms from time to time where differentiation between these two can be especially challenging. Although coexistence of the two is common, more often, only one of the two is diagnosed resulting in under-treatment and unsatisfactory response. Awareness of co-occurrence is essential among both pulmonologists and cardiologists and a high index of suspicion should be maintained. The coexistence of the COPD and HF also poses several challenges in management. Active search for the second disease using clinical examination supplemented with specialised investigations including plasma natriuretic peptides, lung function testing and echocardiography should be carried out followed by appropriate management. Issues such as adverse effects of drugs on cardiac or pulmonary function need to be sorted out by studies in coexistent COPD HF patients. Caution is advised with use of beta2-agonists in COPD when HF is also present, more so in acute exacerbations. On current evidence, the beneficial effects of selective beta1-blockers should not be denied in stable patients who have coexistent COPD-HF. The prognosis of coexistent COPD and HF is poorer than that in either disease alone. A favourable response in the patient with coexistent COPD and HF depends on proper evaluation of the severity of each of the two and appropriate management with judicious use of medication. PMID- 21302601 TI - Hydatid ruptured into the bronchus. PMID- 21302602 TI - Primary carcinoid of posterior mediastinum: truth or myth! AB - Mediastinal masses present challenging problems in thoracic practice. Most of them remain asymptomatic for long and by the time the pressure symptoms develop, these are quite advanced. Carcinoids arising from the mediastinum are invariably related to thymus. Non-thymic origin of mediastinal carcinoids is rare, especially in the posterior mediastinum. Only two cases of posterior mediastinal carcinoids have been reported so far. These were assumed to be arising from ectopic thymus tissue. We report a case of a 45-year-old woman who presented with dyspnoea and dry cough due to giant carcinoid tumour of the mediastinum, the pedicle originating from the posterior mediastinum, not related to thymus. She underwent thoracotomy and resection that provided relief. The immunochemical studies revealed positive reaction to cytokeratin, chromogranins and synaptophysin, and negative reaction to S100, CD99 (MIC2) confirming the tumour being neuroendocrine in nature. PMID- 21302603 TI - Mediastinal hydatid disease: an unusual presentation. AB - Hydatid disease is a significant health problem in endemic areas. While occurrence of the cysts in the liver and lung is common, mediastinal localisation is extremely rare. We report the case of a 35-year-old male who presented with a painless swelling on the right side of the neck and features of superior vena caval obstruction. Chest radiography and computed tomography (CT) suggested a cyst in the right upper lobe, extending into the right supraclavicular region as well as another cyst in the left lung. Thoracotomy revealed that the right-sided cyst was actually mediastinal in location and had herniated through the thoracic inlet compressing the superior vena cava (SVC). Both cysts were removed in two separate operations and symptoms of SVC compression subsided after removal of the right-sided cyst. Histopathology was consistent with a hydatid disease. PMID- 21302604 TI - Hantavirus pulmonary syndrome coexistent with Dengue. AB - Dengue is an arthropod-borne disease caused by viruses of Flaviviridae family. It poses a major public health burden in tropical and sub-tropical regions. Clinical features of dengue vary from a mild flu-like disease and rash, to a potentially lethal haemorrhagic fever or shock syndrome. Hantavirus pulmonary syndrome is a rodent-born disease emerging in the American continent and is caused by viruses of the Bunyaviridae family. Potential reservoirs of these agents were described in Brazilian Central Plateau. Dengue infection is transmitted by mosquitoes, while hantaviruses are acquired by contact or inhalation of aerosolised excreta of infected rodents. Dengue and hantavirus infections have also been considered as emerging public health problems in some Indian areas; moreover, other infections mixed with dengue have been documented. The case of a Brazilian patient with hantavirus pulmonary syndrome and serologic evidence of dengue infection is described. PMID- 21302605 TI - Role of T-cells in delayed hypersensitivity reactions in patients of allergic diseases. PMID- 21302606 TI - Molecular oncogenesis of prostate adenocarcinoma: role of the human epidermal growth factor receptor 2 (HER-2/neu). AB - The potential mechanisms involving the genesis and growth of androgen-independent prostate cancer include super-expression of the androgen receptor (AR), in an attempt to compensate for the low androgenic plasma levels and mutations of this specific receptor, which could determine resistance to anti-androgenic therapy. However, most advanced prostate tumors have no mutations or amplifications of the AR, suggesting a potential role of non-androgenic growth factors, including epidermal growth factor (EGF), transforming growth factor alpha, insulin-like growth factor (IGF-1) and fibroblast growth factor. More specifically, these factors, and their receptors like EGFR (HER-1) and HER-2/neu, through paracrine and autocrine mechanisms, may contribute to the proliferation and growth of prostate cancer. PMID- 21302607 TI - Treatment of glioblastoma in elderly patients: an overview of current treatments and future perspective. AB - Current treatment of glioblastoma in the elderly includes surgery, radiotherapy and chemotherapy, but the prognosis remains extremely poor, and its optimal management is still debated. Longer survival after extensive resection compared with biopsy only has been reported, although the survival advantage remains modest. Radiation in the form of standard (60 Gy in 30 fractions over 6 weeks) and abbreviated courses of radiotherapy (30-50 Gy in 6-20 fractions over 2-4 weeks) has been employed in elderly patients with glioblastoma, showing survival benefits compared with supportive care alone. Temozolomide is an alkylating agent recently employed in older patients with newly diagnosed glioblastoma. The addition of concomitant and/or adjuvant chemotherapy with temozolomide to radiotherapy, which is currently the standard treatment in adults with glioblastoma, is emerging as an effective therapeutic option for older patients with favorable prognostic factors. The potential benefits on survival, improvement in quality of life and toxicity of different schedules of radiotherapy plus temozolomide need to be addressed in future randomized studies. PMID- 21302608 TI - The transforming growth factor beta 1/SMAD signaling pathway involved in human chronic myeloid leukemia. AB - Transforming growth factor beta 1 (TGF-beta1) is the prototypic member of a large family of structurally related pleiotropic-secreted cytokines. The TGF-beta1/SMAD signaling pathway usually participates in a wide range of cellular processes such as growth, proliferation, differentiation and apoptosis. Upon binding on TGF beta1, the dimerized TGF-beta type II receptors recruit and phosphorylate the TGF beta type I receptors, which phosphorylate the receptor-regulated SMAD (SMAD2 and SMAD3) presented by the SMAD anchor for receptor activation. The phosphorylated receptor-regulated SMAD form heterologous complexes with the common-mediator SMAD (SMAD4) and subsequently translocate into the nucleus, where they interact with other transcription factors to regulate the expression of target genes. This multi-functional signaling pathway modulated by various elements with complex mechanisms at different levels is also inevitably involved in cancer. We herein present data on the role of the TGF-beta1/SMAD signaling pathway in human chronic myeloid leukemia and explain the potent biological effects of TGF-beta1 on leukemia cells. The paper is based on a review of articles selected from Cancerline and Medline data bases. The constitutively active tyrosine kinase produced by the specific Bcr-Abl fusion gene on the Philadelphia chromosome can enhance the resistance of malignant cells to TGF-beta1-induced growth inhibition and apoptosis, which contributes to enhancement of proteasomal degradation of p27. However, overexpression of the EVI1 gene, which is also caused by Bcr-Abl, can recruit the C-terminal binding protein and histone deacetylase to prevent the MH2 domain on SMAD3. The later is essential for transcription activation on target genes and leads to blockage of the TGF-beta1/SMAD signaling pathway. Some studies have indicated that certain therapeutic agents applied in clinical treatment can inhibit proliferation and promote differentiation of leukemia cells by way of modulation of the TGF-beta1/SMAD signal pathway. For example, arsenic trioxide can promote specific degradation of the AML1/MDS1/EVI1 oncoprotein and inhibit the proliferation of leukemia cells. However, specific histone deacetylase inhibitors can interrupt the effect of histone deacetylase to alleviate EVI1-mediated suppression of TGF-beta1/SMAD signaling. The tyrosine kinase inhibitor in the target therapy of chronic myeloid leukemia can effectively inhibit the tyrosine kinase activity of Bcr-Abl and induce suppression on the TGF-beta1/SMAD signaling pathway. The TGF-beta1/SMAD signaling pathway plays an important role in chronic myeloid leukemia cells and leads the leukemia cells to growth inhibition, differentiation and apoptosis. The positive influence of the TGF-beta1/SMAD signaling pathway in chronic myeloid leukemia is fairly significant, and its potential effects in clinical treatment will bring about definite benefits. Since it is a complex signaling pathway widely involved in many aspects of cellular activities, further study and comprehensive analysis of the TGF-beta1/SMAD signaling pathway are imperative and will have a guiding significance in research and clinical applications. It is an exciting area for future research. PMID- 21302609 TI - No implication of Simian virus 40 in pathogenesis of malignant pleural mesothelioma in Slovenia. AB - BACKGROUND AND AIM: Malignant mesothelioma is predominantly caused by asbestos exposure, although the association of Simian virus 40 in its pathogenesis is currently still under debate. Simian virus 40, a DNA rhesus monkey virus with oncogenic properties, accidentally contaminated early batches of polio vaccine in the 1960s. In the 1990s, viral sequences and proteins were discovered in several human tumors, which triggered research to find a link between Simian virus 40 and human cancers, especially malignant mesothelioma. The aim of our study was to establish an effective laboratory procedure for Simian virus 40 detection and to investigate the presence of Simian virus 40 DNA and small t antigen in mesothelioma samples from Slovenian patients. METHODS AND STUDY DESIGN: Paraffin embedded malignant pleural mesothelioma specimens from 103 Slovenian patients were collected and used for total DNA isolation and real-time polymerase chain reaction for Simian virus 40 small t and large T DNA analysis. Special attention was devoted to primer design, good laboratory practice and polymerase chain reaction contamination prevention. Polymerase chain reaction products were sequenced and BLAST aligned. One 5 microm thick paraffin section from each patient's tissue block was stained with hematoxylin and eosin for histological typing and one for immunohistochemical detection of Simian virus 40 small t antigen using a monoclonal antibody against Simian virus 40 (Pab280). SV40 expressing Wi-38 cells were used as positive control in both PCR and immunohistochemistry. RESULTS: In real-time polymerase chain reaction analyses, only 4 samples gave products with primer pairs amplifying small t antigen and were inconsistent and poorly reproducible. BLAST alignment showed no homology with any deposited SV40 sequences. No immunopositive staining for SV40 small t antigen was found in any of the samples. CONCLUSIONS: We found no evidence of SV40 presence in tissue samples from 103 Slovenian patients with malignant pleural mesothelioma. Asbestos exposure remains the main risk factor for malignant pleural mesothelioma in Slovenia. PMID- 21302610 TI - Characteristics of upper urothelial carcinoma in an area of Balkan endemic nephropathy in south Serbia. A fifty-year retrospective study. AB - AIMS AND BACKGROUND: Upper urinary tract transitional cell carcinoma, a relatively rare tumor, is up to 100 times more frequent in regions with Balkan endemic nephropathy. Characteristics of transitional cell carcinoma in the endemic South Morava Region in Serbia in the previous 50 years were evaluated. PATIENTS: We analyzed 477 cases with pathologically confirmed transitional cell carcinoma who underwent surgery from 1957 to 2006: 91 from endemic, 106 from adjacent and 280 from control settlements. Cases in the study came from 10 endemic villages, 46 adjacent villages, 51 control villages and the city of Nis. RESULTS: The increase in number of transitional cell carcinoma from 1957 was followed by a peak between 1967 and 1978 (yearly incidence 21.9 per 100,000) and a slow decrease thereafter to 7.4 (1997-2006). In the control settlements, the increase was steady. Reduced kidney function at surgery was found in 58% of patients from endemic and in 20% from control settlements. Age at surgery has significantly increased from 52.3 and 51.5 (1957-1966) to 70.9 and 66.1 (1997 2006) for endemic and control settlements, respectively. The female sex was predominant in endemic and adjacent settlements and the male sex in control settlements. Transitional cell carcinoma from endemic settlements was of a lower grade in the period from 1957-1986, but in the period from 1987-2006 they were predominantly high grade. Low tumor stage (pTa-pT1) predominated in transitional cell carcinoma from the endemic and adjacent but not the control settlements in the period from 1957 to 1986. However, in the last 20 years, upper urinary tract transitional cell carcinoma stage increased, the highest in the period from 1997 to 2006 in all settlements studied. Conservative surgery was advocated for transitional cell carcinoma in Balkan endemic nephropathy areas up to 1996. Transitional cell carcinoma are now more malignant and more advanced than before, and a less aggressive approach is used only for absolute indications. CONCLUSIONS: An increased number of transitional cell carcinoma in endemic settlements was observed, markedly decreasing in the last decade. An increasing age and a shorter survival were recorded in patients both from Balkan endemic nephropathy and control settlements. Sporadic cases upper urinary tract transitional cell carcinoma in settlements adjacent to endemic settlements were demonstrated. PMID- 21302611 TI - Lung cancer mortality trend by birth cohort in men, Tuscany, 1971-2006. AB - AIMS AND BACKGROUND: In Tuscany, lung cancer mortality in men has shown a decreasing geographical trend over the last 3 decades from the most industrialized north-western coastal areas (Massa-Carrara, Viareggio) to the south-eastern areas (Arezzo, Siena), following the path of the development of industrial activities. The aim of the study was to evaluate lung cancer mortality in males by birth cohort in order to verify whether there was also a decreasing birth cohort trend in male lung cancer mortality rates between north-western and south-eastern Tuscan areas. METHODS: Lung cancer deaths that occurred in men resident in Tuscany, 1971-2006, were analyzed by birth cohort, age group and local health authority area. RESULTS: Rates in men >65 years were significantly higher in Viareggio and Massa-Carrara than in the south-eastern areas for all generations, in particular for men born in 1896-1926. Rates for men aged 55-64 years were higher in Massa-Carrara and Viareggio than in south-eastern areas for men born before 1926, whereas for younger generations the rates leveled off. For men aged 45-54 years, rates were similar in all areas only for younger generations (men born around 1951 and 1956), whereas for men aged 35-44 years, rates were similar in all areas for all generations considered. CONCLUSIONS: The higher lung cancer mortality rates in men aged >65 years and born in 1896-1926 in the north-western areas than in those born in the south-eastern areas may indicate that the tobacco epidemic spread earlier in the north-western areas of Tuscany, following the path of industrialization. However, the higher mortality rates in north-western than in south-eastern areas are at least in part attributable to the high occupational risks for lung cancer experienced by workers in these areas during the first half of 20th century. PMID- 21302612 TI - Neuroblastoma in patients over 12 years old: a 20-year experience at the Istituto Nazionale Tumori of Milan. AB - AIMS AND BACKGROUND: Neuroblastoma is the most common solid extracranial tumor in children. The median age of onset is 2 years, with more than 95% of patients younger than 10 years at diagnosis. As neuroblastoma is rare in adolescents and exceedingly rare in adults, few series are reported in the literature. In the present study, we analyzed the outcomes and clinical characteristics of a mono institutional series. METHODS: We describe 27 consecutive patients over 12 years of age (range, 12-69) with previously untreated neuroblastoma treated at our Institution between 1982 and 2001. RESULTS: Overall survival at 5 and 10 years was 40% and 20%, respectively, and progression-free survival at 5 and 10 years was 18%. In the present series, there was a long interval between the onset of signs/symptoms and diagnosis, and between recurrence/progression and death. None had MYCN amplification. CONCLUSIONS: The passive course of the disease in most of our patients did not reflect a more favorable outcome compared with younger patients, thus suggesting a possible genetically different subset of neuroblastoma in older patients. PMID- 21302613 TI - Central venous catheter-associated thrombosis in the perioperative period: a frequent complication in cancer patients that can be detected early with doppler examination. AB - AIMS AND BACKGROUND: The aim of the study was to determine the incidence of venous thrombosis in cancer patients with central venous catheters inserted perioperatively. METHODS AND STUDY DESIGN: A prospective analysis was performed with 68 patients in whom central venous catheters were placed perioperatively. Cancer patients with planned central venous catheters had prophylaxis with low molecular-weight heparin. Patient characteristics, procedure-related complications and venous thrombosis related to central venous catheters were recorded. In order to detect the venous thrombosis, color Doppler sonography was used after removal of the central venous catheter. RESULTS: The median age of the 68 patients was 55 years (range, 24-83). The median duration of catheter placement in patients was 9 days (range, 1-24). Venous thrombosis was detected in 45 (66.2%) patients: at the superficial veins (jugular and subclavian veins) in 27 patients, stretching from superficial veins into the vena cava in 8 cases, in the vena cava in 2 cases, in the right atrium in 2 cases, and at more then one place in 6 patients. Total thrombosis was detected only in 3 patients. CONCLUSIONS: Cancer patients have a high central venous catheter-related thrombosis risk perioperatively despite prophylactic anticoagulation. Color Doppler sonography is a rapid and noninvasive technique and it is accurate in the diagnosis of venous thrombosis. Early detection of venous thrombosis is important to prevent the systemic and fatal complication of the thrombosis. PMID- 21302614 TI - Tumor laterality in early ovarian cancer: influence on left-right asymmetry of pelvic lymph nodes. AB - AIM AND BACKGROUND.:To determine whether left-right asymmetry was present in cases of early ovarian cancer and whether or not the difference between number of removed lymph nodes on both sides of the pelvis is associated with tumor laterality. METHODS AND STUDY DESIGN: We extracted from the medical data base cases of early ovarian cancer with lymphadenectomy who had been treated between 1994 and 2008. The sample was divided in three groups according to the left-right laterality of the tumor in the pelvis (bilateral, left sided, right sided). For each case, we subtracted the number of dissected lymph nodes on the left side from the number of dissected lymph nodes on the right side of the pelvis (N(Right side) - N(Left side)). We used one sample t test to determine whether the mean of differences for each group was different from zero. Results. We extracted 48 cases with early ovarian cancer who had undergone lymphadenectomy. The average number of dissected lymph nodes was 24 (SD, 12). In 3 cases, we confirmed the presence of lymph node metastasis (6.3%). In 2 of the upstaged cases, tumor and involved lymph nodes were on the right side of the pelvis. In the third case, the tumor was on the left side, whereas involved lymph nodes were on both sides of the pelvis. For bilateral tumors, tumors on the left, and those on the right side of the pelvis, the mean difference was -0.5 (95% CI, -9.9 to 8.9; t, -0.137; P = 0.90), 0.32 (95% CI, -3.8 to 4.5; t, 0.16; P = 0.87) and 3.5 (95% CI, 0.03 to 7.01; t, 2.09; P = 0.048), respectively. CONCLUSIONS: When the tumor was on the left or on both sides of the pelvis, there was no significant difference in the number of removed lymph nodes. In contrast, when the tumor was on the right side, the number of removed lymph nodes was significantly higher on the right hemipelvis than on the left hemipelvis. PMID- 21302615 TI - Influence of stage discrepancy on outcome in patients treated with radical cystectomy. AB - AIMS AND BACKGROUND: To evaluate the influence of stage discrepancy on clinical outcome in patients with bladder cancer who have undergone radical cystectomy. METHODS AND STUDY DESIGN: We reviewed the records of 155 patients who had undergone radical cystectomy. Of the 155 patients (128 males, 27 females), 68 had clinical nonmuscle invasive disease and 87 had muscle invasive disease. Follow-up ranged from 1.0 to 162.4 months (median, 34.3). RESULTS: There was no significant difference in overall survival according to clinical T stage (P = 0.483). However, the actuarial overall survival rate of the pathological muscle invasive disease group was significantly less than that in the pathological nonmuscle invasive disease group (P < 0.001). Multivariate analysis with the Cox regression model revealed that lymphovascular invasion (P = 0.001, relative risk [RR] = 2.463) and pathological T stage (P = 0.003, RR = 3.148) were strongly associated with overall survival. There was no difference in cancer-specific survival according to clinical T stage (P = 0.455). However, cancer-specific survival rate of the pathological muscle invasive disease group was significantly less than that in the pathological nonmuscle invasive disease group (P < 0.001). Multivariate Cox proportional hazards model analysis showed that lymphovascular invasion (P = 0.001, RR = 2.545) and pathological T stage (P = 0.002, RR = 3.823) were independent predictors of cancer-specific survival. CONCLUSIONS: Our findings indicate that clinical stage determined by transurethral resection is not predictive of clinical outcome after radical cystectomy in patients with bladder cancer. PMID- 21302616 TI - Laparoscopic resection of colorectal cancer in elderly patients. AB - AIMS AND BACKGROUND: Aging of the population and a longer life expectancy have led to an increased number of elderly patients presenting with colorectal cancer and searching for treatment. The aim of the study was to assess the effects of age on the outcome of laparoscopic colorectal surgery for cancer at a single department. METHODS: Perioperative outcome of patients > or =75 years old undergoing laparoscopic colorectal surgery between June 2005 and January 2009 for colorectal cancer were compared with findings in younger patients. RESULTS: The analysis considered 134 patients <75 years and 82 patients > or =75 years of age. There was a significant difference in perioperative risk factors, as reflected by different ASA scores and a significantly higher postoperative 'medical' morbidity, but 'surgical' morbidity was similar in the two groups and remained low. DISCUSSION: Surgical morbidity rate was not affected by age. Cardiovascular and pulmonary comorbid conditions were mainly responsible for the higher morbidity rate reported in the elderly patients, although advanced age, per se, should not be considered a contraindication to laparoscopic colorectal surgery for cancer. PMID- 21302617 TI - Preoperative radiotherapy and concurrent chemotherapy with bolus 5-fluorouracil for rectal cancer: a prospective analysis of 98 patients. AB - AIMS AND BACKGROUND: Surgical resection of rectal cancer is associated with a high pelvic recurrence rate. Preoperative large-fraction radiotherapy (RT) with a short interval after local excision has been associated with a significant improvement in locoregional recurrence rates and overall survival, but with high rates of toxicity. We here present the results of our combined-modality treatment protocol for patients with locally advanced rectal cancer. METHODS: Between September 1999 and June 2005, 98 patients were prospectively entered into the protocol. Eligibility criteria included any of the following: cT3-4 disease, clinically positive lymph nodes, or tumor located less than 6 cm from the anal verge. RT was delivered with a three-field technique to a dose of 45 Gy, plus an optional 5.4-9 Gy boost. Chemotherapy, administered concomitantly with RT, consisted of bolus 5-fluorouracil (5-FU) 500 mg days 1-5 followed by 5-FU 600 mg/m2 and leucovorin 50 mg on days 16, 23, 30 and 37. Surgery was performed 6-8 weeks after RT completion and was followed by 8 courses of 5-FU 900 mg/m2 and leucovorin 100 mg/m2 every 14 days. RESULTS: Low anterior resection was performed in 64.5% of the patients and in 38.8% of those with tumors located less than 6 cm from the anal verge. All patients except one had clear pathological margins, 68.8% had negative nodes, and pathological complete response was seen in 13.5%. With a median follow-up of 31.5 months, 3 patients (3.0%) had locoregional recurrence, 19 (19.3%) developed distant metastasis, and 10 patients (10.1%) died. The estimated median disease-free survival was 70.6 months. Grade 3 or 4 gastrointestinal toxicity was seen in 24.5% of the patients and 3.0% had neutropenic fever. One fatal toxicity occurred during treatment. CONCLUSIONS: Our results suggest that our combined-modality treatment protocol is well tolerated and achieves high locoregional control in this unselected population. The overall survival results are also encouraging. Further studies are required to confirm the toxicity profile and survival results of this regimen. PMID- 21302618 TI - Combination effect of cetuximab with radiation in colorectal cancer cells. AB - AIMS AND BACKGROUND: Colorectal cancer (CRC) is one of the commonest malignant disorders and frequently associated with high expression of epidermal growth factor receptor (EGFR), resulting in advanced disease and a poor prognosis. In this study, we investigated the radiosensitizing effects of the selective EGFR inhibitor cetuximab in human CRC cell lines. METHODS: Four human CRC cell lines, CaCo-2, HCT-8, LoVo, and WiDr, were treated with cetuximab and/or radiation. The effects on cell proliferation and viability were measured by MTT and annexin-V staining, and clonogenic survival assay. The in vivo effect on the growth of CRC xenografts was assessed in athymic nude mice. RESULTS: Cetuximab in combination with radiation significantly inhibited the in vitro proliferation of CRC cells, with a concomitant increase in cell death, except in WiDr cells. Clonogenic survival assay confirmed that cetuximab worked as a radiosensitizer in three cetuximab-sensitivie CRC cells. However, no correlations were found between the radiosensitivity and EGFR expression level or mutation status of EGFR signaling molecules. In nude mice bearing CRC cell xenografts, cetuximab plus radiation significantly inhibited the tumor growth over either agent alone. Interestingly, the WiDr xenograft was also sensitive to cetuximab and/or radiation in vivo, suggesting host-mediated effects of cetuximab. CONCLUSIONS: Cetuximab enhanced the radiosensitivity of CRC cells in vitro and efficiently inhibited xenograft tumor growth. This study provided a rationale for the clinical application of the selective EGFR inhibitor cetuximab in combination with radiation in CRC. PMID- 21302619 TI - Research trends for early cancer biomarker detection in Italy: an integrated program in oncology (PIO) survey. AB - AIMS AND BACKGROUND: In 2007, an Italian Research Network proposed to the Ministry of Health a concerted action aimed at developing a specific pathway for the analytical and clinical validation of new biomarkers for early cancer diagnosis. The action, funded by the Italian Ministry of Health within the Integrated Program in Oncology (PIO) and coordinated by the National Cancer Institute of Bari, started in 2008 involving 37 national research teams. METHODS: To monitor the methodological and analytical needs of the studies proposed by the research teams of PIO as well as to explore the plausibility of planning external quality assessment programs for early cancer biomarker detection, the coordinating team developed an ad hoc questionnaire that was submitted to each research team. RESULTS: From the collected data it emerged that about 70% of the biomarkers under investigation were analyzed according to nonroutine laboratory practices. The biological material utilized for biomarker assessment consisted of solid tissue (normal or pathological) in 31% of studies, serum in 21%, urine in 15%, plasma in 15%, and whole blood in 11%. Specific training of personnel directly involved in the program was reported by 18% of the teams. In 2008, only 6% of laboratories involved in PIO participated in both external quality assessment and internal quality control schemes specifically designed for the biomarkers under consideration. Standard operating procedures for the determination of about half (52%) of the biomarkers proved to be lacking in at least one phase of the biomarker assessment process. CONCLUSIONS: On the basis of these results, we decided to give priority to the application of a four-phase process for the analytical validation of new potential biomarkers by setting up and applying standard operating procedures and developing external quality assessment and internal quality control schemes as specific steps of the workflow. PMID- 21302620 TI - Promoter methylation of p16, Runx3, DAPK and CHFR genes is frequent in gastric carcinoma. AB - AIMS AND BACKGROUND: Transcriptional silencing induced by hypermethylation of CpG islands in the promoter regions of genes is believed to be an important mechanism of carcinogenesis in human cancers including gastric cancer. A number of reports on methylation of various genes in gastric cancer have been published, but most of these studies focused on cancer tissues or only a single gene. In this study, we determined the promoter hypermethylation status and mRNA expression of 4 genes: p16, Runx3, DAPK and CHFR. METHODS: Methylation-specific polymerase chain reaction (MSP) was used to determine the methylation status of p16, Runx3, DAPK and CHFR gene promoters in cancer and adjacent normal gastric mucosa specimens from 70 patients with gastric cancer, as well as normal gastric biopsy samples from 30 people without cancer serving as controls. In addition, the mRNA expression of p16, Runx3, DAPK and CHFR was investigated in 34 gastric cancer patients by RT-PCR. Bisulfite DNA sequence analysis was applied to check the positive samples detected by MSP. RESULTS: When carcinoma specimens were compared with adjacent normal gastric mucosa samples, a significant increase in promoter methylation of p16, Runx3, DAPK and CHFR was observed, while all 30 histologically normal gastric specimens were methylation free for all 4 genes. The methylation rate of the 4 genes increased from normal stomach tissue to tumor adjacent gastric mucosa to gastric cancer tissue. Concurrent methylation in 2 or more genes was found in 22.9% of tumor-adjacent normal gastric mucosa and 75.7% of cancer tissues. No correlation was found between hypermethylation and other clinicopathological parameters such as sex, age, and tumor location. However, the frequency of DAPK and CHFR methylation in cancer tissues was significantly associated with the extent of differentiation and lymph node metastasis (P < 0.05) and the frequency of Runx3 methylation was significantly associated with tumor size (P < 0.05). Weak expression and loss of expression of the 4 genes was observed in cancer tissues and was significantly associated with promoter hypermethylation (P < 0.05). CONCLUSIONS: Promoter hypermethylation of p16, Runx3, DAPK and CHFR is frequent in gastric cancer. DAPK and CHFR promoter hypermethylation may be an important help in evaluating the differentiation grade and lymph node status of gastric cancer. Weak gene expression and loss of gene expression due to promoter hypermethylation may be a cancer-specific event. PMID- 21302621 TI - Caveolin-1 and VEGF-C promote lymph node metastasis in the absence of intratumoral lymphangiogenesis in non-small cell lung cancer. AB - AIMS AND BACKGROUND: Caveolin-1 is a key component of membrane caveolae which plays an important role in cell transformation, cell migration, metastasis and angiogenesis. The mechanism of caveolin-1 and VEGF-C in lymphatic metastasis of nonsmall cell lung cancer (NSCLC) is still unclear. This study aimed to define the caveolin-1 and VEGF-C expression and lymph vessel density in NSCLC and look for correlations with clinicopathological features in NSCLC. METHODS: Caveolin-1, VEGF-C, and D2-40 protein expression were assessed by immunohistochemistry in a tissue microarray constructed from 70 NSCLCs and 12 normal lungs. RESULTS: Caveolin-1 expression was detected in 31 of 70 (44.3%) NSCLCs, which was significantly lower than its expression in normal lungs (9 of 12, 75%; P = 0.049). Expression ofVEGF-C was detected in 49 of 70 (70%) NSCLCs and 4 of 12 (33.3%) normal lungs (P = 0.022). Both caveolin-1 and VEGF-C expression were correlated with lymph node metastasis of NSCLC (P = 0.001; P = 0.028). Moreover, caveolin-1 expression was correlated with tumor stage, histological type, and differentiation grade (P = 0.012; P = 0.038; P = 0.002). VEGF-C expression was correlated only with histological type (P = 0.020). There was no correlation between intratumoral lymph vessel density and any clinicopathological parameters including lymph node status. Furthermore, there was no correlation between caveolin-1 expression, VEGF-C expression, and lymph vessel density. CONCLUSIONS: These findings indicated a reduction of caveolin- 1 expression in NSCLC and suggested that caveolin-1 as well as VEGF-C might be involved in lymph node metastasis of NSCLC. The role of caveolin-1 in lymphatic metastasis and intratumoral lymphangiogenesis in NSCLC needs further study. Free full text available at www. tumorionline.it PMID- 21302622 TI - Suppression of TSPAN1 by RNA interference inhibits proliferation and invasion of colon cancer cells in vitro. AB - AIMS AND BACKGROUND: To investigate effect ofTSPAN1 downregulation by RNA interference (RNAi) on proliferation and invasion of human colon cancer cells in vitro. METHODS AND STUDY DESIGN: RNAi was performed using the vector (pU6H1-GFP) based small-interfering RNA (siRNA) plasmid gene silencing system to specifically knock down TSPAN1 expression in a colon cancer cell line, HCT-8. The expression of TSPAN1 mRNA was detected by reverse-transcription polymerase chain reaction. TSPAN1 protein expression was observed using Western blots and immunofluorescent microscopy. Cell proliferation and cell cycle assay were measured using methyl thiazolyl tetrazolium (MTT) and flow cytometry, respectively. The invasive ability of HCT-8 cells was examined using a duel culture chamber separated by polycarbonate membranes coated with Matrigel (8.0-microm pore size). RESULTS: After transfection with the TSPAN1 siRNA plasmid, TSPAN1 mRNA and protein expression was significantly decreased. The decrease in mRNA and protein was associated with a significant decrease in TSPAN1 fluorescent staining and a decrease in cell proliferation due to cell cycle arrest in the G1/G0 phase. A significant decrease in the number of invading HCT-8 cells was associated with these changes. CONCLUSION: RNAi-mediated downregulation of TSPAN1 expression significantly inhibits the proliferation and invasion of colon cancer cells in vitro. This finding suggests that TSPAN1 plays an important role in colon cancer progression, and RNAi targeting of TSPAN1 may be a potential therapeutic strategy for the treatment of colon cancer. PMID- 21302623 TI - Effect of microRNA-206 on cytoskeleton remodelling by downregulating Cdc42 in MDA MB-231 cells. AB - AIMS AND BACKGROUND: MicroRNAs are small, noncoding, single-stranded RNAs that regulate gene expression post-transcriptionally. miR-206 is known to play an important role in breast cancer metastasis. When we sought to predict the target of miR-206 by Targetscan, Pictar and miRanda, we found Cdc42 was a potential one. In this study, we transfected miR-206 into MDA-MB-231 cells and examined Cdc42 protein expression as well as MMP-2 and MMP-9, which are also associated with metastasis of breast cancer. Since Cdc42 is involved in filopodia and invadopodia formation, we examined the morphological changes of MDA-MB-231 cells. METHODS AND STUDY DESIGN: miR-206 mimics were transfected into MDA-MB-231 cells using LipofectamineTM 2000. Protein expression was detected by Western blot. Cells were stained with FITC-phalloidin to visualize F-actin. Invasive ability and migratory ability were examined by invasion assay and migration assay in vitro. RESULTS: Cdc42, MMP-2 and MMP-9 were downregulated on the protein level. The formation of filopodia, which requires Cdc42, was inhibited in miR-206 transfected cells, even under the stimulation of EGF. The invasion and migration of MDA-MB-231 cells in vitro was inhibited by miR-206 too. CONCLUSIONS: The results suggest that miR-206 may suppress invasion and migration of MDA-MB-231 cells in vitro partly via regulating actin cytoskeleton remodelling such as filopodia formation. PMID- 21302624 TI - Polymorphisms in the microsomal epoxide hydrolase gene: role in lung cancer susceptibility and prognosis. AB - AIMS AND BACKGROUND: The aim of this study was to investigate the relationship between EPHXI exon 3 Tyr113His and exon 4 His139Arg polymorphisms, predicted microsomal epoxide hydrolase (mEH) activity, and lung cancer development. mEH is a protective enzyme involved in oxidative defences against a number of environmental chemicals and pollutants, but it is also responsible for the xenobiotic activation of carcinogens. METHODS: We investigated the two polymorphisms of the mEH gene (EPHX1) in 58 lung cancer patients and 41 controls using polymerase chain reaction-restriction fragment length polymorphism (PCR RFLP). RESULTS: The exon 3 Tyr113His polymorphism was associated with lung cancer (P < 0.001). The frequency of the His113His homozygote genotype in exon 3 was significantly increased in patients compared with controls (P < 0.001). In contrast, there was no significant difference in exon 4 polymorphisms between patients and controls. When the exon 3 and 4 polymorphisms were considered together, the combined EPHX1 His113His113/His139His139 genotype (very low predicted enzyme activity) was found to be associated with an increased risk of lung cancer (P = 0.044, OR = 3.063, CI = 0.932-10.069). We observed that patients with T3 + T4 tumors had an approximately 3-fold higher risk of the Tyr113/His113 genotype than patients with T1 + T2 tumors. Lung cancer patients carrying a heterozygote Tyr113/His 113 genotype had a 2-fold increased risk of lymph node metastases (P = 0.051). CONCLUSION: These findings suggest that the exon 3 Tyr113His and exon 4 His139Arg polymorphisms of EPHXI may be associated with a increased risk of lung cancer and a worse prognosis. PMID- 21302625 TI - Metastatic pancreatic cancer response to treatment with cetuximab and gemcitabine plus capecitabine: a case report and review of the literature. AB - The treatment of pancreatic cancer remains a formidable challenge to clinicians. Here we describe the case of a 57-year-old man with metastatic pancreatic cancer who received combination treatment with cetuximab and capecitabine plus gemcitabine for four cycles. Repeat CT scan showed that the size of both the primary tumor in the pancreas and the metastatic lesions in the liver had shrunk significantly. Rapid reduction of the serum CA19-9 level was observed, and no serious toxic events occurred. The patient had a progression-free survival of eight months at the time we wrote this paper. The combination of cetuximab and capecitabine plus gemcitabine may be a useful therapy in metastatic pancreatic cancer. PMID- 21302626 TI - Long-lasting response with metronomic capecitabine in advanced hepatocellular carcinoma. AB - Effective and safe systemic treatment for advanced hepatocellular carcinoma (HCC) with severe underlying cirrhosis is not yet available. Sorafenib, an oral multikinase inhibitor, has proved to be effective in the treatment of patients affected by HCC with Child-Pugh class A liver function. For patients with cirrhosis-associated HCC having Child-Pugh class B and C liver function, no systemic treatments of documented efficacy and safety exist. We report a case of metastatic HCC associated with Child-Pugh class B cirrhosis that was treated with low, "metronomic" doses of capecitabine (1000 mg/day continuously). This treatment was effective and well tolerated and the response was maintained for 18 months. Metronomic capecitabine may represent a possible alternative in the treatment of those patients with advanced cirrhosis-associated HCC who cannot be treated with sorafenib. PMID- 21302627 TI - Chemopotentiation by ultrafractionated radiotherapy in glioblastoma resistant to conventional therapy. AB - INTRODUCTION: Induced radiation resistance (IRR) and hyper-radiosensitivity (HRS) are well-described phenomena in basic literature, yet few reports have been published in which such phenomena are exploited clinically for the benefit of patients. Glioblastoma is a prime example. CASE AND METHODS: The case of an 82 year-old woman is described whose resected frontoparietal glioblastoma progressed through treatment administered according to standard methods. With review board and patient approval, we continued her treatment using radiotherapy and temozolomide, but drastically modified the radiotherapy fractionation, administering 50 cGy twice daily on each of the first 5 days of a 14-day cycle. Temozolomide was administered on the first 4 days of each cycle. We use the term "ultrafractionated radiotherapy" to refer to the extremely low doses of radiation used in this case. RESULTS: This modified regimen resulted in regression of the contrast-enhancing areas of disease recurrence identified on MRI, and the patient survived approximately 6 months following recurrence of her disease, having received 5 cycles of additional therapy after prior full-dose treatment. CONCLUSIONS: Ultrafractionated radiotherapy and concurrent temozolomide were efficacious and tolerable in this patient whose glioblastoma previously progressed through conventional treatment. Additional studies of this approach are warranted. PMID- 21302628 TI - Image-guided-radiotherapy retreatment of spine metastasis: a case report and radiobiological evaluation. AB - AIMS AND BACKGROUND: The present case report describes vertebral metastasis retreatment using kilovoltage cone-beam computed tomography (CBCT) for setup error correction, in order to improve target irradiation and prevent spinal cord toxicity. We evaluated the feasibility of the second radiation therapy course on the overlapping treatment volume. METHODS AND STUDY DESIGN: A patient with metastatic kidney cancer, previously treated to the tenth dorsal vertebra with conventional radiation planning (21 Gy; 3 x 7 Gy), underwent retreatment. In order to deliver 30 Gy (15 x 2 Gy) to the target volume with the second irradiation, we evaluated the residual dose that could be received by the spinal cord. We calculated the biologically effective dose according to the linear quadratic model, using an alpha/beta ratio of 2 Gy. A 3-dimensional conformal plan was generated; CBCT imaging was used to ensure accurate repositioning. RESULTS: A total of 15 CBCT scans were performed; the mean setup corrections in the lateral, longitudinal and vertical directions were 3.38 mm (SD 2.09; range, 0.2 mm division by 7.6 mm), 2.13 mm (SD 3.38; range, -5.9 mm divison by 6 mm), and -1.28 mm (SD 2.02; range, -7.1 mm division by 0.3 mm), respectively. CONCLUSION: Image-guided radiotherapy is an alternative approach for the retreatment of spine tumors; it ensures accurate patient setup correction and high-precision treatment delivery, which are required for target volumes very close to critical structures. PMID- 21302629 TI - Small cell/neuroendocrine tumors of the esophagus: presentation of two cases and review of the literature. AB - Small cell cancers of the gastrointestinal tract are part of a family of extrapulmonary small cell carcinomas. These tumors can occur anywhere in the body and generally carry a poor prognosis. Treatment usually consists of a combination of chemotherapy and radiation therapy. We present two cases illustrating diagnostic and treatment issues and review the literature on the treatment of this uncommon but aggressive family of tumors. PMID- 21302630 TI - Isolated splenic metastasis of ovarian cancer 20 years after operation: a case report and literature review. AB - Splenic metastasis reflecting multiple metastases of cancer is often observed in the terminal stage, although solitary splenic metastasis is extremely rare. In addition, late recurrence even after 20 years of operation is very unusual. We report the case of a 52-year-old woman who was admitted to our department with a splenic tumor. She had a past history of total abdominal hysterectomy with bilateral sapingo-oophorectomy for ovarian cancer 20 years ago. Abdominal CT scan revealed a huge mass of 12 x 8 x 5.5 cm between the spleen and the left kidney. Splenectomy was performed with a diagnosis of splenic tumor. Microscopically, the tumor was a poorly differentiated adenocarcinoma including components of poorly differentiated ovarian cancer, and was diagnosed as an ovarian cancer metastasis. The patient showed no evidence of recurrence until 5 years postoperatively. Splenic metastasis is considered a terminal stage of cancer. However, when the lesion is solitary, surgical treatment is recommended. PMID- 21302631 TI - Quadruple primary malignancies of liver, bladder, lung and stomach in one patient. AB - Multiple primary malignancies are defined as two or more malignancies in an individual without any relationship between the tumors. Because of advances in the early detection, treatment, and supportive care for cancer, the number of cancer survivors has been gradually increasing, and this has led to an increase in the possible occurrence of subsequent malignancies. Recently, there have been reports that smoking is associated with a specific genetic mutation (the tumor suppressor gene TP53), and this genetic predisposition may be related to the development of multiple primary malignancies. Here we present a rare case of quadruple primary malignancies of the liver, bladder, lung and stomach, some of which possibly linked to smoking-related TP53 mutation. Because of its extreme rarity and the clear relationship between multiple primary malignancies and smoking-related TP53 mutation, we report this case along with a review of the relevant literature. PMID- 21302632 TI - Reirradiation: hopes and concerns of the radiation oncologist. PMID- 21302633 TI - Is it possible to optimize the use of targeted therapies in the treatment of renal cell carcinoma? PMID- 21302634 TI - Neuroendocrine tumors (NETs): historical overview and epidemiology. AB - Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms which take origin from the neuroendocrine cell system and are characterized by embryological, biological and histopathological differences. Traditionally considered as a rare and "niche" pathology, over the last decades they have gained significant attention from the scientific community, even because of their increasing incidence and prevalence probably imputable to the availability of more sensitive diagnostic tools and to the development of higher awareness among clinicians. This paper retraces the key events that led to the discovery, characterization and classification of NETs as well as to the development of adequate treatment strategies. Incidence and epidemiology are also addressed. PMID- 21302635 TI - Somatostatin and dopamine receptors. AB - The discovery of the new properties of SSRs and DRs has led to a renewed interest in agents targeting these receptors and has opened new perspectives for medical treatment of patients with pituitary and neuroendocrine tumors resistant to the "classical", currently available analogs. Moreover, SSRs and DRs crosstalk at membrane level may trigger alternative intracellular pathways or enhance the signalling for the control of cell growth. New somatostatin analogs and hybrid molecules, which display a broader and different spectrum of activities compared to conventional analogs, seem to be a promising therapeutic alternative for the control of hormone secretion and, hopefully, to reduce tumor burden. Receptor profile characterization is crucial for the accurate selection of patients potentially responsive to a given therapy. PMID- 21302636 TI - The ENETS guidelines: the new TNM classification system. AB - The WHO definition of the 3 classes of well differentiated endocrine tumor, well differentiated endocrine carcinoma and poorly differentiated carcinoma, allows an efficient general classification of GEP NETs fitting European Union (EU) current clinical use. The ENETS grading and TNM staging systems are complementary tools allowing to improve patients' stratification, and their adoption is strongly recommended. However, the prognostic value of these tools is still under investigation and more data are needed to support their usefulness at all gut sites and in perspective series. Similarly, the four classes system adopted by the WHO for the endocrine tumors of the lung allows a prognostically effective stratification of patients. A common grading system is advocated for lung and GEP NETS. PMID- 21302637 TI - Pathological diagnosis and tumor markers. AB - Pulmonary and digestive neuroendocrine tumors (NETs) are a group of neoplasms whose incidence and prevalence has been constantly increasing over the last years thanks to the significant improvements in instrumental diagnostic techniques. Because NETs are extremely heterogeneous a correct histopathological diagnosis is essential for appropriate treatment. More specifically, the histopathological diagnosis of NETs can be regarded as a multistep: identification of the neuroendocrine nature of the neoplasm, determination of tumor grading; identification of unknown primary. Laboratory biomarkers for the study of gastroenteropancreatic neuroendocrine tumors include both specific markers and non-specific or general markers. At the moment, chromogranin A is the best available and most frequently used biomarker for the diagnosis of NETs, offering the highest overall sensitivity. CgA has also demonstrated some utility in the assessment of response to treatment and as indicator of tumor recurrence. PMID- 21302638 TI - Imaging techniques in diagnostic approaches. AB - Despite the considerable technological advances in imaging modalities which have occurred over the last years, EUS remains one of the most reliable and accurate technique for the study of gastroenteropancreatic neuroendocrine tumors. More specifically, EUS can detect very small lesions, assess the local extent and lymph node involvement and biopsy the lesion for cytophatological confirmation (EUS-FNA). In addition, nuclear medicine imaging has a relevant role in the evaluation of NET. However, its performance depends on series of patient-specific features (lesion size and uptake, depth and other anatomic features; metabolic activity, receptor expression, affinity and vacancy, tissue specificity) and technical features (choice of tracer, administered dose, and physical half-life; instrument sensitivity, acquisition technique, reader experience). In particular, current data show that PET/CT has greater intrinsic resolution and sensitivity than SPECT or SPECT/CT images resulting in improved tumor detection. However, the PET tracer of choice has not yet been identified. 18F-FDG has proved to be useful as indicator of tumor aggressiveness rather than detection of extent of disease, and 68Ga-DOTA-TOC has demonstrated good results in clinical trials. 11C-5HTP has performed well in limited trials, but the 20-min half life of 11C precludes widespread availability. Better information concerning biodistribution and further comparative data of these agent in larger clinical trials are warranted. PMID- 21302639 TI - MEN syndromes. AB - MEN1 and MEN2 are rare inherited cancer syndromes which express a variety of endocrine and nonendocrine tumors. The improved knowledge of molecular and clinical physiopathology of MEN syndromes, together with the availability of genetic testing, have led to earlier detection and intervention, with consequent reduction of mortality and morbidity for MEN-associated tumors. Genetic testing has gained a key role in the detection of asymptomatic patients harbouring mutations responsible for these syndrome, and allows institution of early and tailored intervention with a positive impact on the course of disease. PMID- 21302640 TI - False positives and false negatives in neuroendocrine tumors diagnosis: clinical reports. AB - Differential diagnosis NETs may be highly challenging. In order to exclude conditions that may mimic a neuroendocrine neoplasms, a deep knowledge of all the aspects of the disease, together with an adequate capacity to interpret clinical data and imaging findings and to put them in right correlation, are strongly warranted. Patients which suspected neuroendocrine neoplasms should be referred to reference centers to receive optimal multidisciplinary care. PMID- 21302641 TI - Multidisciplinary approach for the treatment of neuroendocrine tumors. PMID- 21302644 TI - Defence anaesthesia--look back, look forward. PMID- 21302643 TI - Perspectives in the development of novel treatment approaches. PMID- 21302642 TI - Pharmacological therapy of neuroendocrine tumors. PMID- 21302645 TI - Pre-hospital anaesthesia. AB - This review presents the history of pre-hospital anaesthesia, it's evidence base, required training and examines current arguments focusing on best practice such as who should undertake the procedure and how identifying appropriate patients, utilizing new techniques and drugs may benefit the Pre-hospital practitioner in optimum delivery of this important procedure. PMID- 21302646 TI - Prehospital analgesia: systematic review of evidence. AB - The purpose of this systematic review is to investigate current evidence for analgesic use in the prehospital environment using expert military and civilian opinion to determine the important clinical questions. There was a high degree of agreement that pain should be no worse than mild, that pain relief be rapid (within 10 minutes), that patients should respond to verbal stimuli and not require ventilatory support, and that major adverse events should be avoided. Twenty-one studies provided information about 6212 patients; the majority reported most of the outcomes of interest. With opioids 60-70% of patients still had pain levels above 30/100 mm on a Visual Analogue Scale after 10 minutes, falling to about 30% by 30-40 minutes. Fascia iliaca blocks demonstrated some efficacy for femoral fractures. No patient on opioids required ventilatory support; two required naloxone; sedation was rare. Cardiovascular instability was uncommon. Main adverse events were dizziness or giddiness, and pruritus with opioids. There was little evidence regarding the prehospital use ofketamine. PMID- 21302647 TI - Total intravenous anaesthesia for war surgery. AB - Total intravenous anaesthesia (TIVA) and target-controlled infusion (TCI) of anaesthesia are techniques that have benefited from recent advances in microprocessor technology and drug design. Though dependant on technology, they offer significant clinical benefits and logistic advantages. Manipulation of complex data derived from population pharmacokinetics has enabled greater understanding of drug handling models, thus enabling individual patient titration of anaesthesia. This has also informed manual techniques of intravenous anaesthesia. These approaches constitute a useful and logical alternative in the field, both in austere circumstances as well as the more established deployed setting. The pharmacodynamics and pharmacokinetics of potent intravenous anaesthesia agents in the complex combat trauma patient require continued examination. PMID- 21302648 TI - Anaesthesia at Role 4. AB - The contribution of anaesthesia to the care of injured military personnel at Role 4 is described with particular emphasis on the working relationship between the Royal Centre for Defence Medicine and the civilian department of anaesthesia. The implications for operating theatre activity are discussed. PMID- 21302649 TI - Field intensive care--weaning and extubation. AB - Injury following ballistic trauma is the most prevalent indication for providing organ system support within an ICU in the field. Following damage control surgery, postoperative ventilatory support may be required, but multiple factors may influence the indications for and duration of invasive mechanical ventilation. Ballistic trauma and surgery may trigger the systemic inflammatory response syndrome (SIRS) and are important causative factors in the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). However, their pathophysiological effect on the respiratory system is unpredictable and variable. Invasive mechanical ventilation is associated with numerous complications and the return to spontaneous ventilation has many physiological benefits. Following trauma, shorter periods of ICU sedation-amnesia and a protocol for early weaning and extubation, may minimize complications and have a beneficial effect on their psychological recovery. In the presence of stable respiratory function, appropriate analgesia and favourable operational and transfer criteria, we believe that the prompt restoration of spontaneous ventilation and early tracheal extubation should be a clinical objective for casualties within the field ICU. PMID- 21302650 TI - Traumatic pneumorrhachis. AB - Pneumorrhachis or intraspinal air is an increasingly encountered phenomenon in the management of severe trauma. The case of a 23-year-old soldier, who sustained a gunshot wound to the chest, is presented and the subsequent discussion illustrates that while often benign this phenomenon may indicate serious occult injury. PMID- 21302651 TI - Paediatric anaesthesia in Afghanistan: a review of the current experience. AB - This paper describes the author's experience of the paediatric patient load on the U.K. medical services in Afghanistan. Over a 3 month period there was a mean of 2.9 paediatric trauma admissions per week, mean age was 6.8 years with gunshot wound or explosive injury being the mechanisms of injury in 77% of the trauma admissions. Overall these children represented 10.8% of the surgical workload. Some of the issues of paediatric anaesthesia in this environment are discussed including paediatric equipment, resuscitation for paediatric massive haemorrhage and regional anaesthesia. The need to formally recognise the problem in training and equipping deployed medical personnel to deal with this challenge is examined. PMID- 21302652 TI - Toxicology and military anaesthesia. AB - The combination of trauma and poisoning is a situation likely to be faced by a deployed force at some point. This article provides practical advice on how to deal with poisoned patients without deviating from the concept of damage control resuscitation. The constraints of limited diagnostics, both at the scene and clinically, and lack of antidotal therapy are fundamental to the practice of clinical toxicology. Some of the specific therapies such as atropine and oximes were not evaluated prior to their introduction and there are few randomised controlled trials of poisoned patients. Most of the diagnoses will be made on clinical grounds and most of the therapy will be supportive; this article aims to reassure military anaesthetists in the process of dealing with the poisoned trauma patient. PMID- 21302653 TI - Operational anaesthesia for the management of traumatic brain injury. AB - The primary brain insult that occurs at the time of head injury, is determined by the degree of neuronal damage or death and so cannot be influenced by further treatment. The focus of immediate and ongoing care from the point of wounding to intensive care management at Role 4 should be to reduce or prevent any secondary brain injury. The interventions and triage decisions must be reassessed at every stage of the process, but should focus on appropriate airway management, maintenance of oxygenation and carbon dioxide levels and maintenance of adequate cerebral perfusion pressure. Early identification of raised intracranial pressure and appropriate surgical intervention are imperative. Concurrent injuries must also be managed appropriately. Attention to detail at every stage of the evacuation chain should allow the head-injured patient the best chance of recovery. PMID- 21302654 TI - Critical care at Role 4. AB - This descriptive paper focuses on the sequence of events that occur during the admission and ongoing management of the Military Polytrauma patient to Critical Care, Area B, Queen Elizabeth Hospital Birmingham (QEHB). It is intended to inform new clinical staff, the wider DMS, and potentially other NHS intensive care units which may be called upon to manage such patients during a military surge or following a U.K. domestic major incident. PMID- 21302655 TI - Maritime anaesthesia. PMID- 21302656 TI - Creating airway management guidelines for casualties with penetrating airway injuries. AB - Anaesthetists in the Defence Medical Services (DMS) are currently dealing with casualties who have an increased prevalence of injuries due to blast, fragmentation and gunshot wounds. Despite guidelines already existing for unanticipated difficult tracheal intubation these have been designed for a civilian population and might not be relevant for the anticipated difficult airway experienced in the deployed field hospital. In order to establish an overview of current practice, three methods of investigation were undertaken; a literature review, a survey of DMS Anaesthetists and a search of the UKJoint Theatre Trauma Database. Results are discussed in terms of anatomical site, bleeding in the airway, facial distortion, patient positioning and an anaesthetic approach. There are certain key principles that should be considered in all cases and these are considered. Potential pitfalls are discussed and our initial proposed guidelines for use in the deployed field hospital are presented. PMID- 21302657 TI - The paediatric transfusion challenge on deployed operations. AB - This paper briefly touches on the problem of dealing with the severely injured child requiring massive transfusion and produces a guide on the management of this based on the current Surgeon General's Operational Policy Letter. There are no known UK guidelines on massive transfusion in trauma in the paediatric population although many specialist centres have guidance for dealing with cases in theatre during elective surgery. It is hoped that these guidelines will be used by deployed military anaesthetists to aid in their management of these difficult cases, not normally seen in the U.K. PMID- 21302658 TI - Simulation, human factors and defence anaesthesia. AB - Simulation in healthcare has come a long way since it's beginnings in the 1960s. Not only has the sophistication of simulator design increased, but the educational concepts of simulation have become much clearer. One particularly important area is that of non-technical skills (NTS) which has been developed from similar concepts in the aviation and nuclear industries. NTS models have been developed for anaesthetists and more recently for surgeons too. This has clear value for surgical team working and the recently developed Military Operational Surgical Training (MOST) course uses simulation and NTS to improve such team working. The scope for simulation in Defence medicine and anaesthesia does not stop here. Uses of simulation include pre-deployment training of hospital teams as well as Medical Emergency Response Team (MERT) and Critical Care Air Support Team (CCAST) staff. Future projects include developing Role 1 pre-deployment training. There is enormous scope for development in this important growth area of education and training. PMID- 21302659 TI - Use of transoesophageal echocardiography during the peri-operative period for trauma patients. AB - The medical facility at Camp Bastion continues to evolve as a consequence of the increased throughput of battlefield trauma patients. There is a requirement for rapid and accurate diagnosis of haemodynamic instability and continued haemodynamic monitoring throughout the peri-operative period. Transoesophageal echocardiography (TOE) has been used for this purpose in the arena of cardiac anaesthesia since the mid 1980s. It is being introduced to other peri-operative settings where severe haemodynamic instability is expected. The old proverb: 'There are none so blind as those who cannot see' (Jeremiah 5:21) is applicable to this topic, in that TOE is proven to be a rapid, portable, safe and effective tool in the assessment of the haemodynamically unstable patient. This paper explores the application of TOE for the assessment of the major causes of haemodynamic instability in the trauma population. PMID- 21302660 TI - The Triservice Anaesthetic Apparatus: a review. AB - The Triservice Anaesthetic Apparatus was designed around 30 years ago as a robust and highly portable anaesthesia delivery system for medical support to airborne operations and it has been the core anaesthesia system for the Defence Medical Services since then. Over this period there have been a number of equipment changes but issues remain which are in part mitigated by recent training developments. This article reviews these changes and developments and considers the future of this equipment. PMID- 21302661 TI - Vascular access on the 21st century military battlefield. AB - Timely and appropriate access to the vascular circulation is critical in the management of 21st century battlefield trauma. It allows the administration of emergency drugs, analgesics and rapid replacement of blood volume. Methods used to gain access can include; the cannulation of peripheral and central veins, venous cut-down and intraosseus devices. This article reviews the current literature on the benefits and complications of each vascular access method. We conclude that intraosseus devices are best for quick access to the circulation, with central venous access via the subclavian route for large volume resuscitation and low complication rates. Military clinicians involved with the care of trauma patients either in Role 2 and 3 or as part of the medical emergency response team (MERT), must have the skill set to use these vascular access techniques by incorporating them into their core medical training. PMID- 21302662 TI - Current epidural practice--results of a survey of military anaesthetists. AB - OBJECTIVES: As epidurals are now used for pain relief on deployment a survey was conducted to look at the current epidural practice of U.K. military anaesthetists. The aim was to identify any potential issues with regard to equipment and training to allow future development ofpre-deployment training. METHODS: An Internet based survey was carriedout. All military anaesthetistswere sent an e-mail containing a link to the survey and the results of those who responded were analysed. RESULTS: A total of 49 surveys were completed. 78% of respondents carried out epidurals more than once a month, in a wide range of specialities. There was considerable variation in methods of securing epidurals and in drug choice amongst respondents. CONCLUSIONS: The results of this survey show that whilst epidurals are commonly carried out amongst military anaesthetists during their U.K. practice, there is significant variation within the practice. Areas have been identified for development of educational courses, for example methods of securing epidurals, and these have already been acted upon. PMID- 21302663 TI - Evolution of the role 4 U.K. military pain service. AB - The early development of the U.K. Role 4 pain service has already been described. This article will describe developments up to October 2010, and present the results of projects used in assessing the effect of this service. PMID- 21302664 TI - Statistics at a glance. AB - I still remember my first book on statistics: "Elementary statistics with applications in medicine and the biological sciences" by Frederick E. Croxton. For me, it has been the start of pursuing understanding statistics in daily life and in medical practice. It was the first volume in a long row of books. In his introduction, Croxton pretends that"nearly everyone involved in any aspect of medicine needs to have some knowledge of statistics". The reality is that for many clinicians, statistics are limited to a "P < 0.05 = ok". I do not blame my colleagues who omit the paragraph on statistical methods. They have never had the opportunity to learn concise and clear descriptions of the key features. I have experienced how some authors can describe difficult methods in a well understandable language. Others fail completely. As a teacher, I tell my students that life is impossible without a basic knowledge of statistics. This feeling has resulted in an annual seminar of 90 minutes. This tutorial is the summary of this seminar. It is a summary and a transcription of the best pages I have detected. PMID- 21302665 TI - Pattern of acute myocardial infarction in an African country. AB - OBJECTIVE: The objective of this study was to describe the pattern of acute myocardial infarction in an African country. These data are important for prevention strategies but are scarce from sub-Saharan African countries and altogether absent from Kenya. METHODS AND RESULTS: This was a retrospective study done at Kenyatta National Hospital, Kenya. Cases of acute myocardial infarction admitted to the hospital between January 2000 and December 2009 were examined for mode of diagnosis, age, gender, risk factors, and outcome. Only those with confirmed diagnosis were included. Results were analysed by SPSS version 13.0 for Windows, and are presented in tables and bar charts. One hundred twenty cases (80 men; 40 women) were analysed. Clinical diagnosis had been confirmed by electrocardiography and cardiac enzymes (87.5%), angiography (8.3%) and echocardiography (4.2%). Mean age was 56.8 years and male:female ratio 2:1. Common risk factors were hypertension (35%), diabetes mellitus (20.8%), smoking and infection 12.5% each and alcohol (10.8%). The majority (50.8%) of the patients recovered, 44.2% developed congestive cardiac failure and only 5% died. CONCLUSION: Acute myocardial infarction is not uncommon in Kenya. Over 30% of the patients are 50 years and younger and it carries a high morbidity from heart failure. Risk factors comprise a combination of non-communicable diseases, namely hypertension and diabetes mellitus, coexisting with infections. Control measures targeting both categories are recommended. PMID- 21302666 TI - Searching the seat of the soul in Ancient Greek and Byzantine medical literature. AB - OBJECTIVE: The objective of this paper was to examine the ancient and medieval concepts about the seat of the mental functions, as exposed in Greek texts from Antiquity to Byzantine times. METHODS: The review of the philosophical and medical literature from the original ancient Greek language from the Homeric epics to the Holy Fathers of Christianity, as the problem of the seat of the soul remained without a certain answer through the centuries. RESULTS: Primitive concepts attributed great significance to the soul and dictated cannibal behaviours for the possession and eating of the defeated enemy's heart. Mental functions, such as thinking, feeling and mainly those related to affective manifestations, were attributed to the heart and to some other internal organs (liver, diaphragm) from the times of Greek mythology. Philosophy and empirical medicine had underestimated the brain probably because it is a 'silent' organ, contrary to the palpitating heart, with its obvious participations in the emotional reactions. The role of the brain as the mental organ and the seat of emotions has been gradually recognized. CONCLUSION: The permanent question of the seat of the soul had been for many centuries a critical dispute and the contribution of Greek philosophical and medical thought was decisive for the contemporary transformation of the whole concept. PMID- 21302667 TI - Coronary wall characteristics after myocardial infarction without significant coronary angiographic lesion: an intravascular ultrasound study. AB - AIM: Coronary of angiography may be normal or without significant lesion after myocardial infarction (MI) in about 10% of cases. Our aim was to evaluate intravascular ultrasound (IVUS) findings, mainly remodelling, in patients with normal or near normal angiography early after MI. METHODS AND RESULTS: We prospectively included 17 patients, admitted for STEMI or non-STEMI with no lesion > 30% (QCA) on early coronary angiography. Culprit vessel was defined by evidence of a thrombus in a proximal segment, distal embolization or focal akinesia of the left ventricle. Negative remodelling (NR) was defined as a remodelling index (lesion/reference external elastic membrane cross sectional area [CSA]) < 0.95, no remodelling as between 0.95-1.05, and positive remodelling (PR) as > 1.05. IVUS could identify a short, single, minor, eccentric and hypoechogenic lesion in all patients, of proximal location in 76.4% cases. PR was observed in only 1 patient (5.9%). CONCLUSION: A discrete lesion was observed in all patients with apparently normal arteries. Although previous reports have shown an association between PR and vulnerability, in our study PR was unusual. Our study supports the hypothesis that in some patients, vulnerability may appear very early in the natural history of coronary artery disease before any vessel remodelling. PMID- 21302668 TI - Chronotropic incompetence and coronary artery disease. AB - OBJECTIVE: Although chronotropic incompetence (CI) represents an independent predictor of mortality and incidence of coronary artery disease, its pathophysiological mechanisms remain unknown. The purpose of this investigation was to evaluate wall motion abnormalities of the left ventricle and location of coronary arterial lesions in patients with and without CI. METHODS: After exclusion of confounding factors, 610 patients (mean age of 58.4 +/- 11 years; 275 men) with ischaemia who underwent exercise echocardiography were studied. Based on heart rate (HR) reached in treadmill testing, patients were divided into two groups: Chl (97 patients who did not reach 85% of maximum HR recommended for age) and ChC (513 patients who achieved 85% of the maximum age-predicted HR). RESULTS: There was a higher frequency of dyspnoea (5.2% vs. 0.6%, P = 0.003), systemic hypertension (69.1% vs. 57.3%, P = 0.031) and obesity (38.1% vs. 22.6%, P = 0.001), and a lower tolerance to effort (dyspnoea as limitation of physical effort: 36.1% vs. 8.0%, P < 0.0001; duration of treadmill test: 4.4 +/- 2.2 vs. 7.2 +/- 2.8, P < 0.0001; METs: 6.0 +/- 2.6 vs. 8.4 +/- 2.9, P = 0.002) in Chl compared to ChC. The wall motion score index (WMSI) was higher in Chl than in ChC, both at rest (1.15 +/- 0.29 vs. 1.07 +/- 0.19, P = 0.011) and after exercise (1.24 +/- 0.29 vs. 1.15 +/- 0.19, P = 0.002). Systolic function, which was evaluated in peak exercise through WMSI, was significantly more altered in the Chl group. The presence of severe injuries in right coronary was independently associated with CI (adjusted OR = 3.57, CI 95%: 1.86-6.87). CONCLUSION: Chronotropic incompetence is associated with ventricular dysfunction in peak exercise and critical right coronary artery lesions. PMID- 21302669 TI - Myocardial ischaemic and diazoxide preconditioning both increase PGC-1alpha and reduce mitochondrial damage. AB - OBJECTIVES: Pretreatment with diazoxide, a mitochondrial ATP-sensitive potassium channel (mito KATP) opener, was found to protect the rat heart against ischaemia reperfusion (I/R) injury by mimicking ischaemic preconditioning (IPC). However, the protection mechanisms have not been fully clarified yet.We hypothesize that molecular regulation of mitochondrial energetics is integral to this cardioprotective programme. We explored the involvement of peroxisome proliferator-activated receptor gamma coactivator-1-1alpha (PGC-1alpha) in the effect of IPC and diazoxide preconditioning (DPC) with regard to its role in protection against I/R injury. METHODS: 30 Wistar rats were used to establish the Langendorff isolated perfused heart model. Rats were randomly divided into 5 groups, 6 in each group: (1) the I/R group: after 30 min of equilibration perfusion, the heart was subjected to 30 min of ischaemia and 1 h of reperfusion; (2) the IPC group: after 10 min of equilibration perfusion, the heart was subjected to two times 5 min ischaemia and 5 min of reperfusion, followed by 30 min of ischaemia and 1 h of reperfusion; (3) the DPC group: after 10 min of equilibration perfusion, the heart was given two times a K-H perfusion solution containing diazoxide (100 micromol/l) for 5 min then a non-diazoxide K-H perfusion solution for 5 min, followed by 30 min of ischaemia and 1 h of reperfusion; (4) a blank control group: an equal amount of saline was used instead of diazoxide. The perfusion procedure was the same as in the DPC group; (5) the dimethyl sulfoxide (DMSO) group: DMSO was applied instead of diazoxide, and the perfusion procedure was the same as in the DPC group. Cardiac apex muscle was cut for frozen section. Immunohistochemistry staining of PGC-1alpha was performed and average absorbance was calculated. An electron microscope was used for Flameng scoring of the myocardial mitochondria. RESULTS: The average absorbance values of PGC-1alpha were: I/R group (3.88 +/- 1.72), IPC group (10.94 +/- 5.23), DPC group (8.40 +/- 3.64), blank control group (3.55 +/- 1.56) and DMSO group (4.16 +/- 0.52), respectively. The expression of PGC- 1alpha was significantly increased in the IPC and DPC groups and the differences were statistically significant compared to the I/R, blank control and DMSO groups, i.e., P < 0.01 for IPC group and P < 0.05 for DPC group. However, there was no significant difference between the IPC and DPC groups (P > 0.05). Flameng score: IPC group (0.44 +/- 0.13), DPC group (0.47 +/- 0.10), I/R group (1.78 +/- 0.14), blank control group (1.70 +/- 0.03) and DMSO group (1.68 +/- 0.06). The Flameng score of the IPC and DPC groups was statistically significantly different as compared to the I/R group, blank control group and DMSO group (P < 0.01), but no significant difference was detected between the IPC and DPC groups (P > 0.05). CONCLUSION: IPC and DPC have a protective effect on myocardial mitochondria, and their mechanism of action may be related to activation and over-expression of PGC 1alpha. PMID- 21302670 TI - Effectiveness of invasive reperfusion therapy and standard medical treatment in AMI. AB - OBJECTIVE: Coronary revascularization methods are among the most common major medical procedures performed in industrialized countries. The short- and long term comparative effectiveness of different techniques remains undetermined. METHODS AND RESULTS: The study population included all adult patients (94,864 subjects) admitted for acute myocardial infarction (AMI) in 2004 in Italy, as recorded in the National Hospital Discharge Records. Invasive reperfusion therapy (coronary artery bypass graft, percutaneous coronary intervention), and standard medical treatments were compared. End points were short-term (30-day) in-hospital mortality and any combination of new revascularizations, re-AMI, stroke, or death (MACCE) occurring within 6 and 12 months from initial treatment. Risk factors and comorbidities were used to define patients' health status. The Cox model was applied to evaluate risk-adjusted hazard ratios (HR) for different approaches. Medical treatment was used as the reference category. Propensity score matching was performed to evaluate selection bias in the allocation to CABG or percutaneous coronary intervention (PCI). Both short-term mortality and 6- and 12 month MACCE risk for invasive reperfusion therapy was significantly lower than the reference (HR: 0.50, P < 0.001; 0.54, P < 0.001; 0.64, P < 0.001, respectively). In the matched population, while short-term mortality was significantly lower for PCI (HR 0.36, P < 0.001), long-term MACCE risk was lower for CABG (6-month HR 2.93, P < 0.001; 12-month HR 3.01, P < 0.001). CONCLUSIONS: In spite of adjustments for patients' health status, medical treatment resulted in a higher mortality and increased MACCE risk. While PCI gave the best short term results, after 1 year the risk of re-interventions or further events was significantly lower for patients undergoing CABG. PMID- 21302671 TI - Metabolic syndrome does not impose greater atrial fibrillation risk in elderly hypertensive patients. AB - OBJECTIVE: Metabolic syndrome (MS) increases the risk of atrial fibrillation (AF). It is not clear if MS imposes a greater risk of AF in elderly hypertensive patients. METHODS: The data were gathered from surveys of 3,775 patients participating in the LIFE survey from November 2005 to July 2006. From this database there were 2,055 patients with MS, and 125 patients were diagnosed with AF. RESULTS: The prevalence of AF was not different between the MS and non-MS group. With an increasing number of MS components, the prevalence of AF did not change. Univariate analysis revealed that AF patients were older, male predominant, and had more left ventricular hypertrophy (LVH), heart failure, and coronary artery disease. There were higher levels of uric acid and creatinine in AF patients. AF patients were prescribed antihypertensive drugs, especially diuretics, but less frequently statins. Upon multivariate analysis, age, LVH, heart failure, use of diuretics, and use of statins were the independent predictors of AF. None of the MS components could predict AF attack. CONCLUSIONS: MS does not impose more AF risk in elderly hypertensive patients. Aging, heart failure, LVH, and drugs used may play more important roles. PMID- 21302672 TI - Effect of primary percutaneous coronary intervention on serum collagen biomarkers following acute myocardial infarction. AB - OBJECTIVE: The aim of this study was to investigate the effect of primary percutaneous coronary intervention (PCI) on serum collagen biomarkers following acute myocardial infarction (AMI). METHODS AND RESULTS: Thirty-eight patients were enrolled into a primary PCI (n = 16) and a control (n = 22) group. The PCI group received successful PCI within 6 h of MI, whereas the control group received no PCI or thrombolytic therapy. Serum type I procollagen (PICP) and type III procollagen (PIIINP) were measured by enzyme-linked immunosorbent assay (ELISA). The baseline characteristics were similar between the PCI and control groups. There was no significant difference in left ventricular end-systolic, end diastolic volume or ejection fraction between the two groups 30 min after MI (P > 0.05). A significant increase in PICP and PIIINP was noted in both groups 3 days after MI (P < 0.01). PICP and PIIINP in the PCI group declined overtime to the pre-PCI level, whereas they remained high in the control group. In the PCI group, the mean serum PICP and PIIINP on day 7, 14 and 30 was lower than in the control group (P < 0.01). CONCLUSIONS: AMI is associated with an increase in serum biomarkers of collagen synthesis. Early and successful PCI is associated with a reduction in serum collagen biomarkers. PMID- 21302673 TI - Pulmonary veins branching pattern, assessed by magnetic resonance, does not affect transcatheter atrial fibrillation ablation outcome. AB - AIM: The aim of the present study is to provide, in a large cohort of patients, a description of the left atrium (LA) and pulmonary veins (PV) anatomy in relation to ablation outcome. BACKGROUND: The role of LA imaging, assessed before transcatheter ablation of atrial fibrillation (AF), is unknown. METHODS: 330 patients referred for transcatheter ablation of AF (paroxysmal 62.7%; persistent 25.5%; long-standing 11.8%) underwent contrast-enhanced magnetic resonance imaging (MRI) before the procedure. Transcatheter ablation was performed aiming to AF interruption and/or absence of inducibility. Patients were followed clinically, by ECG, and 24-hour Holter ECG at 1-3-6-12-18-24 months. RESULTS: The MRI preceding the procedure depicted a typical PV branching pattern, two left and two right, in 130 (39.4%) patients; 117 (35.4%) presented common left trunk (short and long) and 75 (22.7%) at least one accessory PV. Mean atrial volume was 142.0 +/- 48.5 ml. The ablation procedure resulted successful, after 15.6 +/- 7.2 months follow-up, in 174 (52.7%) patients. PV branching pattern did not relate (P = 0.304) to ablation outcome. A multiple Cox proportional hazard model, adjusted for potential confounders, proved that only LA volume was independently related to ablation outcome (HR 1.007, 95% CI 1.003-1.011; P = 0.001). A LA cut-off volume of 135 ml emerged as a significant predictor of ablation failure (ROC curve area 0.651, 95% CI 0.591-0.710; P < 0.001). CONCLUSIONS: Less than half of the patients referred for transcatheter AF ablation present a typical PV branching pattern; the PV branching pattern, however, does not affect ablation outcome. LA volume strongly predicts AF ablation outcome. PMID- 21302674 TI - No evidence for increased intraoperative bleeding in aortic-valve stenosis: a comparative analysis of haemotherapy in 136 patients undergoing aortic-valve replacement. AB - OBJECTIVE: An association of aortic-valve stenosis and abnormal bleeding, particularly from gastrointestinal angiodysplasia, has been reported. In this setting, high-shear stress generated by the transvalvular gradient leads to a conformational change of plasmic von Willebrand factor, making this adhesive protein more susceptible for proteolytic cleavage. Consequently, highest molecular weight multimers of the von Willebrand factor are degraded through a von Willebrand factor specific protease leading to impaired platelet-related haemostasis. METHODS AND RESULTS: To assess the role of aortic-valve stenosis as a factor predicting abnormal intraoperative bleeding in patients suffering from aortic-valve stenosis, we compared the number of intraoperatively administered blood components during aortic-valve replacement for aortic-valve stenosis (n = 50), aortic-valve insufficiency (n = 19) and combined aortic-valve defects (n = 67). As a result, the three subgroups did not differ significantly regarding the mean number of transfused red-blood cell units (0.94 +/- 1.36, 0.4 +/- 0.9, or 0.86 +/- 1.3, respectively) and plasma units (0.04 +/- 0.28, 0.21 +/- 0.71, or 0.15 +/- 0.61, respectively). None of the patients received platelet concentrates. A multivariate logistic regression model adjusted for age and gender did not show an influence of the presence and severity of aortic-valve stenosis on intraoperatively applied haemotherapy. CONCLUSION: Along with our findings, the presence or severity of aortic-valve stenosis does not predict an increased need for intraoperative transfusion of blood components. Thus, this cardiac defect does not seem to represent a major risk determinant for intraoperative bleeding despite the high prevalence of shear-stress induced von Willebrand factor abnormalities in this setting. PMID- 21302675 TI - Paraoxonase 1 polymorphisms as the risk factor of coronary heart disease in a Thai population. AB - OBJECTIVE: Two common polymorphisms of the paraoxonase (PON1) gene, L55M and Q192R, were proven to mitigate atherosclerosis pathogenesis by protecting lipoproteins against peroxidation. This study was to evaluate the associations between both PON1 gene polymorphisms in Thai hyperlipidaemia with and without coronary heart disease (CHD). METHODS: Both PON1 genotypes were determined using PCR-RFLP in 103 healthy control subjects, 103 primary hyperlipidaemia without history of such diseases and 106 angiographically documented CHD patients. RESULTS: The frequencies of PON1 192R allele and 192RR genotype were significantly higher in CHD patients than in normal control subjects (P = 0.009 and 0.037, respectively). The significantly higher frequencies of 55M allele and 55LM genotype were also observed in CHD patients (P = 0.037 and P = 0.034, respectively). The frequencies of both PON1 polymorphisms were not different in primary hyperlipidaemia as compared to the normal control subjects. The odds ratio (OR) of 192RR genotype and 192R allele for CHD were 2.84 (1.17-6.99, P = 0.011) and 1.70 (1.11-2.61, P = 0.009), respectively. The age-adjusted OR for CHD was 2.72 (1.25-5.94, P = 0.012). These frequencies of both PON1 alleles were similar to those seen in other Asian populations. CONCLUSIONS: The association between PON1 polymorphisms and CHD risk was demonstrated in aThai population. These new data underscore the essence of ethnic variations in the interpretation of CHD associated with PON1 polymorphism. PMID- 21302676 TI - Ulnar and cerebellar embolization from an ulcerative subclavian artery lesion. PMID- 21302677 TI - Glycoprotein IIIa gene polymorphism in children with a family history of premature coronary artery disease. PMID- 21302678 TI - Percutaneous closure of a coronary artery fistula in a 70-year-old woman. AB - This case report is about a 70-year-old woman who was diagnosed with a symptomatic coronary fistula from the circumflex artery to the vena cava superior. Because of the steal effect on a dobutamine stress test, the fistula was closed percutaneously. PMID- 21302679 TI - Cardiac tamponade after mitral valvuloplasty in a pregnant woman. AB - Mitral stenosis during pregnancy poses a substantial risk, both to the mother and foetus. Percutaneous mitral valvuloplasty performed during pregnancy has been associated with an excellent short-term outcome, with reduction of both maternal and foetal complications. We report a case of percutaneous mitral valvuloplasty in a pregnant woman with severe rheumatic mitral stenosis and impending pulmonary oedema. The procedure was performed through a right femoral vein approach, employing the multitrack technique, using 2 balloons (20 and 18 mm). Inadvertently, the procedure was complicated by cardiac tamponade. Despite a stable haemodynamic condition, and absence of echocardiographic signs of chamber collapse, haemodynamic monitoring revealed an equal value for right atrial, left atrial and left ventricular end-diastolic pressure. Immediately, adequate pericardiocentesis was performed and post-procedural echocardiography revealed a mitral valve area of 2.0 cm2, with no mitral regurgitation. Eventually, the pregnancy was continued and ultimately, the patient gave birth to a healthy full term baby. PMID- 21302680 TI - Ortner's syndrome, presentation of two cases with cardiovocal hoarseness. AB - We present two cases of Ortner's syndrome, a syndrome with hoarseness caused by unilateral left recurrent laryngeal nerve palsy as a complication of cardiovascular diseases. In the first case, aneurysmatic dilatation of the aorta and in the second case a dilated pulmonary trunk was thought to be the cause. PMID- 21302681 TI - A young man with chest pain and fever. AB - A young man with an unremarkable medical history was diagnosed with meningococcal endocarditis and was treated with penicillin and gentamycin. Further history was complicated by a fistulisation between the left ventricle and right atrium and aortic and tricuspid valve insufficiency. Aortic valve replacement, correction of the fistulisation and annuloplasty of the tricuspid valve were performed with good results. A search of the literature revealed only ten cases of meningococcal endocarditis without any report concerning the tricuspid valve. PMID- 21302682 TI - An unusual cause of carcinoid heart disease. AB - Carcinoid heart disease (CHD) is a rare form of valvular heart disease characterized by right-sided heart valve dysfunction. Carcinoid heart disease occurs most frequently when carcinoid tumour cells metastasize from a primary site in the gut to the liver, so that vasoactive substances produced by the tumour are able to reach the systemic circulation. By contrast, in ovarian carcinoid tumours carcinoid heart disease develops in the absence of liver metastasis, because vasoactive substances can be released directly into the systemic circulation, bypassing the first-pass metabolism of the liver. There are only a few case reports in the world literature of carcinoid heart disease caused by ovarian carcinoid tumour. We report a case of an 85-year-old woman with carcinoid heart disease caused by a bilateral ovarian carcinoid tumour metastasized from a primary ileal site. PMID- 21302683 TI - Successful anticoagulation for treatment of a giant left atrial thrombus. AB - We report the discovery at transthoracic echocardiography of a very large, sessile formation in the left atrium in a 77-year-old woman with permanent non valvular atrial fibrillation who did not receive anticoagulant therapy. After six weeks of anticoagulation by subcutaneous low-molecular-weight heparin, a control echocardiogram demonstrated an almost complete resolution of the mass without systemic embolisation. This case highlights the success, without complications, of a medical anticoagulant therapy for giant left atrial thrombus. PMID- 21302684 TI - Antibiotic use and doctor visits are reduced after adenotonsillectomy. AB - OBJECTIVE: A tonsillectomy, with or without an adenotomy ((A)TE), is a common surgical procedure in children. The most important indications are recurrent tonsillitis and upper airway obstruction secondary to adenotonsillar hypertrophy. The aim of this study was to investigate whether the current (A)TE practice in Belgium reduced the need for medical care. STUDY DESIGN AND METHODS: The database of the Christelijke Mutualiteit, one of the most important health insurance organizations in Belgium, provided data on approximately 11,000 (A)TE's in children aged 0 to 15 years, performed by different ENT-specialists from Jan 1st 2002 to Sept 30th 2003. We compared the use of antibiotics during the 12 months before and the 12 months after (A)TE. We also compared the number of visits to pediatricians and general practitioners during the 12 months before and the 12 months after surgery. RESULTS: The median antibiotic use dropped from 4 boxes in the year before the operation to 1 box in the year after the operation. The median number of doctor visits also dropped from 7 visits in the year before to 4 visits in the year after (A)TE. CONCLUSION: Although there are no generally accepted guidelines on the indications for (A)TE in Belgium, the current practice effectively reduced the need for medical care. PMID- 21302685 TI - Outpatient cold knife tonsillectomy in toddlers with sleep disordered breathing. AB - PROBLEM: Tonsillectomy performed as day surgery has become popular over the last fifteen years. However, there are conflicting opinions regarding the safety of this practice, especially in children of very young age. We sought to determine the safety of outpatient tonsillectomy in children aged three years old and younger. METHODOLOGY: A retrospective study of all tonsillectomies performed in a major pediatric hospital during a two-year period was conducted. Age, gender, indication for tonsillectomy, other procedures performed simultaneously, seniority of operating surgeon, and reasons for hospital admissions during the first post-operative week were recorded. Patients with inappropriate records for the analysis were excluded. A total of 1058 patients were studied. Tonsillectomized children were divided into two age groups: greater than 3 years old (n = 951) and 3 years old or younger (n = 107). RESULTS: Male gender, obstructed sleep disordered breathing as indication for surgery, seniority of the operating surgeon, and age of 3 years old or younger were not associated with post-operative complications. CONCLUSIONS: Outpatient tonsillectomy can be managed safely regardless of age, as long as specific factors, such as good recovery room supervision, exist. PMID- 21302686 TI - Thermal welding technique versus cold dissection for adult tonsillectomy. AB - OBJECTIVES: To compare the thermal welding technique (TWT) with cold dissection (CD) for adult tonsillectomy. METHODOLOGY: A prospective, double-blind, non randomised study was planned for 20 adult patients undergoing tonsillectomy; a total of 16 patients were included for evaluation. In all patients, the right tonsil was removed by TWT, the left tonsil by CD. Indications included chronic tonsillitis with or without upper airway obstruction. Patients with peritonsillar abscess history or bleeding disorders were excluded from analysis. Age, gender, dissection and hemostasis time, intra-operative hemostasis method, post-operative pain using a visual analogue scale, and extent of healing of the tonsillar fossa on the tenth post-operative day were evaluated. RESULTS: TWT was significantly superior to CD with regard to intra-operative hemostasis (p = 0.029). There were statistically significant differences between the two techniques in a post operative pain score (p = 0.001). There were no statistically significant differences between the two techniques in dissection and hemostasis time (p = 0.321), nor in the healing of the tonsillar fossae on the tenth day of the surgery (p = 0.285). CONCLUSION: Compared with CD, TWT provides sufficient hemostasis and lower post-operative pain, as assessed in a limited number of adult tonsillectomy cases. PMID- 21302687 TI - Lidocaine spray versus tetracaine solution for monopolar submucosal diathermy for inferior turbinate hypertrophy. AB - OBJECTIVE: To compare the efficacy of lidocaine spray 10% to tetracaine 2% solution, as a local anaesthetic for patients undergoing monopolar submucosal diathermy of the inferior turbinate. METHODS: A prospective study was conducted on 48 patients undergoing submucosal diathermy of the inferior turbinate. Patients were randomly assigned to receive tetracaine 2% solution (24 patients) or to receive lidocaine spray 10% (24 patients). Patients were asked to evaluate the severity of pain during the procedure using a visual analogue scale. Patient data, pain scores, and potential complications were assessed statistically. RESULTS: The tetracaine group had significantly lower mean pain scores compared to the lidocaine group: 2.29 vs. 3.04 (p < 0.001). There were no complications or side effects from tetracaine. CONCLUSION: Tetracaine 2% solution applied locally is an easy, safe, inexpensive, and effective analgesia for submucosal diathermy for inferior turbinate hypertrophy. PMID- 21302688 TI - New surgical technique for endoscopic management of anterior glottic web. AB - OBJECTIVES: In this study we report a new endoscopic technique for the management of anterior glottic web (AGW). Previously, various procedures with endoscopic or open surgical approaches have been described for the treatment of symptomatic AGW. We present an original, highly effective endoscopic technique that seems to have several advantages over traditional approaches. METHODS: We used this novel technique in a preliminary series of four patients. Using a CO2 laser, a curvilinear mucosal flap based on the web is elevated from the superior surface of one vocal chord. The web is divided, and the flap is sutured at the inferior surface of the opposite vocal chord, ensuring that no raw surfaces will be left exposed on this side of the larynx. We accurately describe the technique, displaying diagrams of the surgical steps. RESULTS: In three cases, a restoration of the laryngeal airway, with complete resolution of the AGW, was achieved. A limited residual web persisted close to the anterior commissure in the fourth patient. CONCLUSIONS: The new endoscopic technique utilized in our preliminary series of patients is a simple, repeatable, and effective surgical procedure for managing AGW. PMID- 21302689 TI - A pre-paid newborn hearing screening programme: a community-based study. AB - OBJECTIVES: To help obstetric hospitals and clinics to implement newborn hearing screening and to test the feasibility of a pre-paid model for screening. PATIENTS AND METHODS: From July 2005 to August 2008, we organised a coordinated newborn hearing screening team with portable automated auditory brainstem response (AABR) to provide in-patient screening after delivery and out-patient re-screening at one month of age in birthing facilities throughout Changhua County, Taiwan. This was a community-based study organised by otolaryngologists at a tertiary referral centre. RESULTS: Ten medical facilities participated in our screening programme. 7,139 out of 12,901 neonates delivered in these facilities during the period were screened for hearing loss. 105 (1.47%) babies who did not pass the in-patient screening were re-screened at one month old. Forty (0.56%) babies referred from the re-screening were sent for diagnostic work-up and six of them failed to show up. The overall follow-up rate was 94.3% (99/105). Eleven babies with bilateral hearing loss and eight babies with unilateral hearing loss were diagnosed. The incidence of bilateral hearing loss in our programme was 1.5/1000. The screening rate descended from medical centre to clinic (p < 0.0001). There was no significant difference between the referral rates for different levels of birthing facilities (p = 0.5611). CONCLUSIONS: Our study demonstrates that a pre paid model using AABR is feasible at all three levels of medical facilities. Pre paid community-based screening might be an option for developing countries in the implementation of universal newborn hearing screening. PMID- 21302690 TI - Effects of subjective tinnitus on sleep quality and Mini Mental Status Examination scores. AB - OBJECTIVES: We investigated the effects of subjective tinnitus on sleep quality and Mini Mental Status Examination (MMSE) scores of participants. METHODS: The study group consisted of 15 patients, including 21 ears with tinnitus (6 bilateral, 9 unilateral). The control group consisted of 8 healthy patients with normal hearing and no tinnitus (16 ears). We assessed sleep quality using the Mini Sleep Questionnaire (MSQ) and mental health using the MMSE. RESULTS: Sleep delay (SD) was significantly higher in tinnitus patients (5.28 +/- 2.23) compared to controls (3.25 +/- 2.56) (p = 0.018). Subjective tinnitus loudness level (STLL) scores were higher and sleep quality was impaired in females, older patients, and patients with lower MMSE scores. Sleep quality was also worse in patients with longer tinnitus duration. In younger and well educated patients, MMSE scores were higher. Higher STLL scores and shorter tinnitus duration were associated with lower MMSE scores. Patients with newly developed tinnitus reported more disturbances and showed greater effects on mental and cognitive functioning. CONCLUSION: In subjective tinnitus patients, sleep delay values increased. Long tinnitus duration and high STLL scores may affects patients' cognitive functions as shown by decreased MMSE scores. Furthermore, mental status changes in tinnitus patients were frequently overlooked. PMID- 21302691 TI - Schwannoma of the auricle. AB - OBJECTIVES: We report an extremely rare case of schwannoma of the auricle. METHODOLOGY: A case report and review of the world literature concerning schwannoma of the auricle are presented. RESULTS: Schwannoma is a benign, encapsulated, slow-growing neoplasm. Approximately 25-45% of all schwannomas occur in the head and neck, whereas schwannomas of the external ear are extremely uncommon, with only nine cases reported in the English literature since the first report in 1977. In this report, we describe the case of a 47-year-old male patient who presented with a 2-year history of a slow-growing mass in the left auricle, which was managed by wide surgical excision. We believe this case to be the second case of schwannoma of the auricle reported. CONCLUSIONS: To our knowledge, this is the second report in the world literature of auricle schwannoma. Schwannoma should be considered in the evaluation of any tumour of the auricle. PMID- 21302692 TI - Laryngeal Kaposi sarcoma: case report and literature review. AB - PROBLEM/OBJECTIVE: Kaposi sarcoma is the most frequently-occurring neoplasm in AIDS patients. Laryngeal localization is infrequent. We discuss the management options for laryngeal Kaposi sarcoma based on a literature review. CASE REPORT: A 42 year old, HIV-positive male receiving HAART therapy presented with mild hoarseness and sore throat. Fiberoptic laryngeal examination identified a small purple lesion in the right ventricular fold. He underwent biopsy under general anaesthesia. The lesion was histologically diagnosed as a Kaposi sarcoma. Systemic treatment was pursued, but 6 weeks later the patient developed severe dysphagia and acute airway obstruction when the lesion became glotto-supraglottic and obstruced the airway. Transoral tumour vaporization with a CO2 laser was performed in the emergency department. Post-operative chemotherapy was administered. Three months later, the patient was completely asymptomatic and the laryngeal examination was normal. CONCLUSION: Transoral CO2 laser vaporization combined with chemotherapy is a valid option for managing obstructive laryngeal Kaposi sarcoma. PMID- 21302693 TI - Localisation of Mediterranean Kaposi's sarcoma in Morgagni's ventricle. AB - OBJECTIVE: Head and neck involvement in Kaposi's Sarcoma (KS) is not unusual. However, laryngeal involvement is a relatively infrequent manifestation and ENT specialists should consider it in differential diagnosis in laryngeal lesions of AIDS patients and/or subjects from the Mediterranean area. METHODS: Case report and review of the literature in English. CLINICAL CASE: Male patient presenting with a three-month history of cough and acute dyspnoea. Laryngoscopy identified a laryngeal mass occluding the glottic plane. Tracheotomy was then performed and the laryngeal lesion was removed. Histopathology showed neoplastic spindle cells that were positive to immunostain with CD-31 and CD-34, and immunoreactivity for HHV-8 was present. A diagnosis of KS was then suspected and confirmed after dermatological inspection. CONCLUSION: Purple vascular mass lesions should lead in ENT to a high index of suspicion to exclude systemic diseases. Laryngeal KS must be included in the differential diagnosis of pigmented laryngeal lesions to plan correct management. PMID- 21302694 TI - Post-rhinoplasty mucous cyst formation of the nasal dorsum. AB - PROBLEM: Formation of a mucous cyst of the nasal dorsum after rhinoplasty is a rare complication, and a limited number of cases has been reported. Located subcutaneously, mucous cysts are thought to arise from traumatically displaced mucosal remnants. This may well be the result of inadequate surgical technique, and preservation of the mucosal lining, whenever possible, is therefore advocated when performing a rhinoplasty procedure. METHODOLOGY: We report a well-documented case of a patient with a mucous cyst of the nasal dorsum, which developed 40 years after the initial surgery. RESULTS: The cyst was excised through an external rhinoplasty approach. A thin-walled cyst, firmly attached to the bony pyramid, was easily removed from the overlying skin. CONCLUSIONS: Histopathological confirmation of such cysts is emphasized, as well as consideration of the technical aspects of prior surgery, since this may provide insight into risk factors involved. PMID- 21302695 TI - Maxillary sinusitis caused by the migration of a silastic implant used for an orbital floor reconstruction: a case report. AB - OBJECTIVE: The authors report on a patient whose unilateral chronic maxillary sinusitis was caused by the migration of a silastic implant used for orbital floor repair. CASE REPORT: A 32-year-old woman presented with a three-year history of right-sided maxillary discomfort that was associated with a purulent discharge. Her medical history included chronic allergic rhinitis and the placement of a silastic implant after a right orbital floor fracture at the age of 14. The silastic implant was then removed endoscopically in a right maxillary sinus meatotomy. The symptoms improved within three weeks after surgery. CONCLUSION: Orbital implant migration is a rare cause of chronic unilateral sinusitis, and it must be suspected on the basis of a careful anamnesis, appropriate clinical examination, and sinus computed tomography. Misdiagnosing such a condition may increase patient morbidity by leading to inappropriate treatment. PMID- 21302696 TI - Nasal septal abscess complicating isolated acute sphenoiditis: case report and literature review. AB - This report presents an extremely rare case of nasal septal abscess complicating acute sphenoiditis in a non-immunocompromised adult patient. A 56-year-old woman came to our emergency service with a 2 wk history of nasal obstruction, headache, and facial pain. A nontraumatic nasal septal abscess complicating acute isolated sphenoiditis was diagnosed. Under general anaesthesia, we drained the septal abscess and performed an endoscopic transnasal sphenoidotomy. Bacteriological cultures revealed viridans streptococci in the septal abscess and sphenoid cavity. We discuss the patient's diagnosis, possible complications, and treatment. There are limited reports in the literature on this subject. Our report emphasizes the need to determine whether an infection is associated with a non-traumatic nasal septal abscess. The incidence of severe complications is directly related to delays in diagnosis and treatment. Therefore, a prompt and correct diagnosis immediately followed by appropriate treatment is necessary. PMID- 21302697 TI - A historical vignette (20). A royal otitis. AB - A royal otitis. The young king of France, Francis II, the eldest son of Henry II and Catherine de Medici, died in Orleans from the effects of the complications of a chronic otitis on 6 December 1560. Based on texts of the time, the paper discusses the nature of the illness, the treatment, and the medical and political entourage of the king. PMID- 21302698 TI - Benedictine monastery on the Island of Rab hides the mystery of sunlight influence on development of macular degeneration (AMD). Is a harmful sunlight, risk factor or cause of macular degeneration? AB - Benedictine Monastery of St. Andrew is probably the oldest existing Benedictine monastery in this area. According to hundreds of years of legend, it was founded in 1018 year. In clinical examination about the possibility of the macular degeneration occurrence in 15 Benedictine sisters, we found the age-related macular degeneration (AMD) in two cases only. In 13 other sisters aging 27, 60, 67years, the fundus picture was like in a baby, vision, visual field and meridian thresholds were normal. What is the explanation for this phenomenon? Two sisters with AMD work and live as the farm workers, but the other sisters live in closed monastery with very low natural sunlight, approximately 300-500 lx. In conclusion, the earlier author's experimental and clinical works follow the consequence that without exposure of eyes to harmful higher doses of sunlight, it is not possible to develop AMD. The harmful cumulative dose of sunlight is not the risk factor but the cause, including the inheritance, for AMD development. PMID- 21302699 TI - Skin changes in the elderly people--how strong is the influence of the UV radiation on skin aging? AB - Just like every other part of the organism, the skin ages as a result of the passage of time. That process is called chronologic or intrinsic aging. However, skin is also exposed to external insults, such as UV radiation, which is the most influential extrinsic factor in skin aging, causing so called photoaging or extrinsic skin aging. Photoaging is a cumulative process which depends on the degree of UV exposure and the skin type. It is much more visible in individuals with skin types I and II and, less prominent in dark-skinned population. Chronic sun exposure can result in numerous changes in human skin, particularly on the face, nape, and arms. Keratinocytes, melanocytes, fibroblasts, and endothelial cells are altered by UV radiation. Therefore, changes in photoaging include wrinkling, elastosis, actinic keratoses, irregular pigmentation, telangiectases, and the development of malignant skin tumours. In the last decades, important progress has been made in understanding molecular mechanisms of photoaging. It is a complex process in which UV radiation has effects on numerous molecular processes that damage the skin, especially connective tissue of the skin. These processes include cell surface receptors, certain signal transduction pathways, transcription factors and, various enzymes involved in the synthesis and degradation of the dermal elements. Initial process in the activation of this process is UV-induced generation of the reactive oxygen species, which can also directly damage cell's DNA, membrane and proteins. Most of alterations found on the photoaged skin had formerly been considered to be caused by UVB wavelengths. However, a number of recent studies have demonstrated that UVA can also cause burning, elastosis, and skin cancer. PMID- 21302700 TI - Progression of age related maculopathy in phakic versus pseudophakic eyes. AB - Age-related maculopathy (ARM) is one of the leading causes of central visual acuity loss in older western population. Many factors are responsible for the fast development of ARM. One of this is significant increases of optical radiations through artificial lens after removal of the catarctous lens. The aim of this study was to compare progression of ARM in phakic and pseudophakic patients and to calculate the possibility ofpseudophakia as a risk factor for faster progression of ARM. Medical records of 76 patients, older than 60 years (32 male and 44 female) with early forms of ARM were randomly evaluated. They had undergone cataract removal by phacoemulsification with intraocular lens implantation from January 2002 to December 2006 at the Department of Ophthalmology, Rijeka University Hospital, Croatia. Patients were examined two weeks after the surgery and followed up for two years. The control group consisted of 48 patients (21 males and 27 females) with also early forms of ARM, older than 60 years, examined at the Policlinic Department from January 2006 to December 2006 and followed up at least for two years without any cataract surgery. Comparing progression of ARM in these two groups, a total of 19 patients (25%) in pseudophakic group showed progression to late forms of ARM, but only 6 patients (12.5 %) in the control group developed these aggressive ARM forms. More aggressive forms of ARM in pseudophakic group indicate that pseudophakia should be considered as a risk factor for development of ARM. PMID- 21302701 TI - Epidemiology and quality of life of patients with age-related macular degeneration. AB - It is well known that age-related macular degeneration (AMD), besides glaucoma and diabetic retinopathy, represents a major cause of low vision and blindness throughout the world. In this study, specific causal factors of AMD are analyzed, emphasizing the causal role and effects of sunlight, no matter which part of its spectrum, in a longer exposition through life. The accent is also put on the influence of lifestyle as well as vitamin and antioxidants supplementation in development or prevention of AMD. PMID- 21302703 TI - Epidemiological study of sun exposure and visual field damage in children in Primorsko-Goranska County--the risk factors of earlier development of macular degeneration. AB - The aim of this study was to examine the possible harmful effects of solar exposure on visual field damage in children living in Primorsko-Goranska County. Our previous work has shown noxious influence on visual field in children with anamnesis long term exposure to sunlight. This is an extended study, including children in Novi Vinodolski and Gorski kotar. We measured possible defect in isopteric visual field and macular-meridian thresholds. In the area of island of Rab these changes were the biggest, subsequently is Novi Vinodolski and at least Gorski kotar with the smallest range of eye complicates according to exposure to sunlight. These damages correlate with the areas of great solar emission. Damages in periphery isopters of visual field have shown the characteristics of periphery defect invagination, while increased macular thresholds in complete visual field was from 5 to 15Asb. We can conclude that there is direct connection between increased sunlight and long-term exposure to sunlight on one side, and on the other side, damages of retinal perception. Increased sun exposure may represent very important factors in early occurrence and develop of Age-Related Macular Degeneration (AMD). It is recommended the children protection in summer months, as well as taking derivates of vitamin A and antioxidants. Nowadays, AMD is one of the most important causes of damaged visual field, pretend to be national problem if we don't use the adequate prevention. World Health Organization has to begin with prevention of AMD, including these risk factors. PMID- 21302702 TI - Giant pseudocyst of the rectus femoris muscle--repetitive strain injury in recreational soccer player. AB - We report a case of a traumatic pseudocyst, in a recreational soccer player, after rupture of rectus femoris muscle. 37-year-old male, with history of repetitive painful accidents, was examined because of a double fist-sized mass in the anterior thigh. Ultrasound examination revealed a cystic mass in the rectus femoris muscle. Surgical removal of the mass and proximal remnant of muscle was done. Primary healing and functional recovery was achieved. Histological analysis revealed pseudocyst filled with degenerating clot and surrounded with thick fibrous capsule. The repetitive strain muscle injury, with prolonged period of healing, can occur like pseudocyst. PMID- 21302704 TI - The circulatory influence on development of age-related macular degeneration and hearing and equilibrium impairments. AB - This study attempts to answer the question if any level of head and neck circulation takes a part in development of Age-Related Macular Degeneration (ARMD) and hearing and equilibrium impairments. Condition of large blood vessels was examined by Color-Doppler ultrasound, and carotid and ophthalmic arteries were included. The microcirculatory changes were examined directly by fundus photography and fluorescein angiography and indirectly testing hearing and equilibrium. The study group included 40 patients (21 females, 19 males) aging from 53 to 84 years with different stages of ARMD. The control group included 40 patients (18 females, 22 males) aging from 51 to 82 years without ARMD. Patients were inhabitants of Primorsko-Goranska County. There was no relationship between ARMD and condition of large blood vessels because significant stenosis of carotid arteries was found in 2 patients (5%) in study group and 3 patients (7.5%) in the control group (p > 0.05). On the contrary, we found correlation between ARMD and hearing (p = 0.0127) and equilibrium impairments (p = 0.0242). Fluorescein angiograms shows raised number of ischemic retinal capillaries in patients with ARMD (p = 0.0053). Results lead to conclusion that circulatory disorders on microcirculatory level take a great part in development of ARMD and hearing and equilibrium impairments in the elderly. The key is damage of sensory cells of the retina and inner ear caused by microcirculatory disorders. Interesting data was noticed that 9 patients with more serious ARMD on one side of head had greater hearing loss on the same side. If we find a new treatment for microcirculatory disorders, maybe we can treat both sensory impairments in earlier stage. PMID- 21302705 TI - Penetrating keratoplasty and Verisyse iris-claw lens--is it safe for corneal graft? AB - The loss of the corneal endothelial cells, especially in a first postoperative year, has been observed in patients who underwent penetrating keratoplasty (PK). The implantation of new generation of "iris claw" phakic IOL (Verisyse) in refractive cases has been shown to cause clinicaly insignificant endothelial cell loss. In our prospective case series we investigated the endothelial cell loss and clinical outcome in patients that either underwent PK and implantation of PCIOL or PK and implantation of Verisyse IOL. In the first group of 9 patients scheduled for PK, implantation of Verisyse was performed due to the absence of the posterior capsule support. 2 of these patients had angle supported ACIOL, 4 patients were aphakic and 3 had posttraumatic cataract with ruptured posterior capsule. The second group of 12 patients had standard "triple" procedure (PK + ECCE + PCIOL). BCVA of both groups of patients prior the operation was hand movement in 12 patients, light perception in 7 patients and 0.05 in 3 patients. The preoperative endothelial cell count of the donor grafts obtained from the eye bank was 2800 cells/mm2 on average. The follow up was 6-10 months. Six months after the operation all "Verysise" patients maintained transparent graft. Postoperative visual acuity improvement was recorded in 18 out of 21 eyes (85.7%). Best spectacle corrected visual acuity of > or = 0.3 was achived in 55.5% in the Verisyse group and in 50.0% of "triple procedure" group. The endothelial cell count and morphology were estimated on the specular microscope on a monthly basis. Mean endothelial cells loss in patients with PK and Verysise was 40 +/- 8% and in patients with "triple" procedure was 42 +/- 12% at 10 postoperative months. There was no significant difference in the endothelial cell loss and clinical outcome between the group of patients who had PK and Verysise as compared to those with implanted PCIOL. PMID- 21302706 TI - Histomorphological analysis of the osteophytic appositions in patients with lumbar lateral recess syndrome. AB - Patients with lumbar lateral recess syndrome (LRS) can be successfully cured by removing osseous excrescences that grow on the peripheral edge of articular surface of the facet joint. They cause narrowing of the lateral recess and compress a root of the spinal nerve. Their appearance is related to the instability of respective dynamic vertebral segment. The aim of this study was to analyze the osteophytic composition morphohistochemically and elucidate cellular processes that lead to this new formation appearance. It is necessary to find a possible causative-consequential relation between the osteophyte and instability. The ideal object to explore was the osteophyte in the lateral recess because it had to be removed during operative treatment. The group of 30 patients with clinical feature of LRS was chosen. Each patient had clinically verified LRS with consequential radiculopathy. Bony outgrowths were removed surgically and analyzed by histological and immunohistochemical methods: toluidine blue, Goldner trichrome, TRAP, indirect peroxidase with antibodies against BMP 3 and BMP 7. The outgrowths that caused lateral recess stenosis were composed of fibrous and hyaline cartilage and cancellous bone. The changes in cartilage and bone, and occurrence of intramembranous bone formation in sense of enlargement of trabeculae, leads to the conclusion that marginal osteophytic formations could be an adaptation to changed conditions in the dynamic vertebral segment and an attempt to stabilize this segment by enlargement of articular surface. PMID- 21302707 TI - Senile lentigo--cosmetic or medical issue of the elderly population. AB - Senile lentigo or age spots are hyperpigmented macules of skin that occur in irregular shapes, appearing most commonly in the sun-exposed areas of the skin such as on the face and back of the hands. Senile lentigo is a common component of photoaged skin and is seen most commonly after the age of 50. There are many disscusions on whether senile lentigo represents a melanoma precursor, namely lentigo maligna melanoma and, if there is a need for a regular follow up in cases of multiple lesions. Clinical observations sometimes report that in the location of the newly diagnosed melanoma, such lesion preexsisted. On contrary, some authors believe that senile lentigo represents a precursor of seborrheic keratosis, which does not require a serious medical treatment. However, the observation of the possible association of senile lentigo with the melanoma development makes us cautious in the assessment of this lesion. Histologically, there are elongated rete ridges with increased melanin at the tips, and the number of melanocytes is not increased. The dermatoscopic features are also distinctive. If the lesion becomes inflammed it may evolve into benign lichenoid keratosis. Cryotherapy and laser treatment are common therapeutic approaches. Sun protection creams may be useful in early lesions. PMID- 21302708 TI - Comparison of different presbyopia treatments: refractive lens exchange with multifocal intraocular lens implantation versus LASIK monovision. AB - There are several methods for presbyopia treatment. Refractive lens exchange (RLE) followed by multifocal intraocular lens (MFIOL) implantation enables high rate of spectacle independence but have some visual disturbances. Laser in Situ Keratomileusis (LASIK) monovision gives patient ability to have good distant vision with dominant eye and good near vision with nondominant eye. In this prospective randomized study we wanted to compare clinical outcomes in patients who underwent either of the mentioned procedures. The first group included 50 patients (N = 100 eyes) who underwent RLE with MFIOL implantation and the second group included 50 patients (N = 100 eyes) who underwent LASIK monovision as presbyopia treatment. Uncorrected distant, near and intermediate visual acuity, patient's subjective satisfaction and visual disturbances were measured. Follow up was 6 months. Patients in RLE group had better near uncorrected visual acuity (UCVA) and patients in LASIK monovision group had better distant and intermediate vision. Patients in RLE group reported visual disturbances (halo, glare). Patients satisfaction and spectacle independence was high in both groups. Refractive lens exchange with multifocal intraocular lens implantation and LASIK monovision are effective methods for presbyopia treatment. LASIK monovision with 0.50D - 1.25D of residual dioptry at nondominant eye in patients under 50 years enables good vision at all distances without affecting stereovision. Patient selection and preoperative counseling are key to success. PMID- 21302709 TI - Distribution of age-related macular degeneration in Primorsko-Goranska County. AB - The aim of this study is to show what part of our County has the most population with age-related macular degeneration (ARMD) and how some types frequently appear in same parts. The County includes 3 different geographic areas: Gorski Kotar, Coast and Islands. ARMD is the leading cause of visual impairment and blindness in developed countries. There are two categories of ARMD: atrophic or "dry" ARMD and exudative or"wet" ARMD. Our epidemiological study group includes 60 patients (33 females, 27 males) with both types of ARMD and they mostly spent their life times in our County. Patients were examined and treated in our Clinic during 2008 and 2009. We also examined which contribution factor (age, genetics, UV-exposure, diet, iris and macular pigment) is more common and found a links with occupation, residence and habits. Our study shows that ARMD in our County is most frequent in interval of 61-80 years. Incidence of ARMD is mild increased in female (55%). Significant incidence of ARMD is connected with patients who work outdoor more than 5 hours daily (70 %). There were no significant difference between patients in different areas[-Gorski Kotar and Coast (p = 0.9260), Gorshi Kotar and Islands (p = 0.8382) and Coast and Islands (p = 0.8546) connected with occupations. Regions Coast and Islands had more cases of ARMD than Gorski Kotar, but in Gorski Kotar patients had greater percent of "wet" type. Difference is statistically significant between areas Gorski Kotar and Islands (chi2 = 4.675, p = 0.0306). Also, there were statistically significant difference in nutrition between Gorski Kotar and Islands (chi2 = 4.17, p = 0.0411). Incidence of ARMD is related with less iris and macular pigment--47 patients (77%). There was an increased risk for exudative type in Trsce and Cabar in Gorski Kotar PMID- 21302710 TI - Role of bone morphogenetic proteins in human prostate cancer pathogenesis and development of bone metastases: immunohistochemical study. AB - Bone morphogenetic proteins (BMP) have the ability to induce ectopic bone formation. The findings of their expression in prostate cancers have been linked with specifically tumor progression to bone and development of osteosclerotic metastases. We investigated the expression pattern of BMP-2/4, -6 and -7 and the receptors BMPR-IA,-IB and -II in normal human prostate, organ-localized and metastatic prostate cancers. The expression we also examined in skeletal metastases caused by prostate cancer. In localized prostate cancers we found increased expression of BMP-6 and decreased expression of BMP-2/4 and -7. In metastatic prostate cancers the expression of examined BMPs decreased. The expression of BMPRs showed the tendency to be lower with progression of prostate cancer but the expression of BMPR-II was completely absent in metastatic prostate cancers. In bone metastases caused by prostate cancer we found high expression of BMP-2/4, -6 and -7. Decreased expression of BMPs and lose of BMPR-II expression, could suggest that the influence of BMPs on prostate cancer cells is inhibited and plays an important role in prostate cancer pathogenesis. High expression of osteogenic BMPs in prostate cancer bone metastases could explain their osteosclerotic properties. PMID- 21302711 TI - Solar spectral lines ("solar halo")--healing or harmful for the retina? AB - The sungazing method has been known for thousands of years as healing method based on chromotherapeutic principle. Our examinations on the island of Rab show that it is acceptable only if applied 10 min before the sunset. Gazing has to be directed towards the green-yellow part of the spectrum, since the remaining part of the sun halo contains harmful energy. However, authors suggest that it would be preferable to use spectacles with medical filters transmitting wavelight of green-yellow colour, especially for treatment of macular degeneration. PMID- 21302712 TI - Multiple primary melanoma: epidemiological and prognostic implications; analysis of 36 cases. AB - Patients who are already diagnosed with cutaneous melanoma are at increased risk of developing another primary melanoma. The occurrence of multiple primary melanoma is a rare phenomenon, varying in frequency, with an estimated incidence ranging from 0.2% to 8.6%. The authors are presenting data on the patients with multiple primary melanoma from the Croatian Referral Melanoma Centre. The clinical, histological and epidemiological characteristics of 36 (3.6%) patients, identified from 991 patients with histologically confirmed melanoma, are analyzed in this study. Twenty-eight of the patients (78%) had two primary melanomas, six had three melanomas (16.7%) and two (5,6%) had four melanomas. Diagnosis was established synchronously in 11 patients (30%) and, in the rest of the patients, time interval between the diagnosis of the first and second melanoma varied from 1 month to the longest interval of 16 years. However, the majority of subsequent melanomas were removed within 2 years of the initial operation. The mean Breslow's thickness of the first melanoma was significantly higher than the mean Breslow's thickness of the second primary melanoma. The proportion of in situ to invasive melanomas was greater for the second melanomas compared with the first melanomas. Therefore, we emphasize the importance of regular follow-up as well as the education in regular self--skin examinations in melanoma patients in order to detect subsequent primary melanomas in the early phase. PMID- 21302713 TI - Increased bone turnover markers after renal transplantation. AB - Bone remodeling is a process that occurs continuously in a seemingly inactive tissue like bone. Because of decreased vitamin D synthesis, phosphorus retention and decreased calcium blood concentration, patients with chronic renal failure (CRF) develop secondary hyperparathyroidism. Elevated PTH levels shifts balance between osteoblast and osteoclast activity in favor of osteoclast activity and, therefore, bone resorption. Bone metabolic disorder that affects patients with CRF is called renal osteodystrophy (ROD). We presume that renal transplantation reverses bone metabolism disorder and our goal was to establish whether osteoblast and osteoclast activity returns to the levels of healthy individuals. PMID- 21302714 TI - Expression of bone morphogenetic protein-7, its receptors and Smad1/5/8 in normal human kidney and renal cell cancer. AB - Bone morphogenetic proteins (BMPs) are cytokines which are important for kidney homeostasis but also have role in the some renal diseases and renal cell carcinoma (RCC). In the last three decades incidence of RCC was constantly increased and the role of different molecular biomarkers in RCC is explored'. We analyzed expression of BMP-7, their receptors (BMPR-IA, BMPR-IB, BMPR-II) and proteins of their signaling pathway (pSmad1/5/8) in sixteen renal cancer samples and paired normal tissue. Tissue samples were analyzed by immunohistochemistry and Western blot. BMP-7, BMP receptors and pSmad1/5/8 were expressed in all structures of normal kidney but dominantly in the proximal tubular cells. In the cancer samples their expression was also noticed. Comparison of BMPs between different tissue showed increased expression of BMPR-IB and pSmad 1/5/8 and decreased expression of BMP-7 and BMPR-II in RCC compared to normal kidney. BMPR IA was detected with immunohistochemistry but with Western blot attenuated signal was presented. BMP-7, BMP receptors and pSmad1/5/8 were showed in normal kidney and RCC. Detected alterations of BMP-7, BMP receptors and pSmad expression in RCC suggested their possible role in tumorigenesis of kidney cancer. PMID- 21302715 TI - Diet quality of middle age and older women from Primorsko-Goranska County evaluated by healthy eating index and association with body mass index. AB - Accorded dietary habits provide adequate nutrient intakes, especially important for quality aging. Adequate nutrition for older persons has vital influence on maintaining good health and social functioning. Therefore, using simple tool for evaluation of diet of older population in relation to overweight and obesity is of public health importance. Among many factor that influence quality of aging has obesity, where in Croatia the prevalence of obesity is greater in older women than men. Our aim was to evaluate diet quality of middle age and older women from Primorsko-Goranska County by Healthy Eating Index (HEI) and to see the association of HEI to overweight and obesity. Diet quality of 124 women with average age 59.91 +/- 5.31 years was graded with 10 component HEI score, ranging from 0 to 100, where HEI score less than 51 implies "poor" diet. Overweight and obesity was classified according to WHO classification. The majority of women had diet that "needs improvement" (66.1%), and only 3.2% had "good" diet. Older women had better HEI score than middle-aged women, while overweight was statistically significant positively related to better HEI score (P = 0.26, p = 0.048). Older women better scored for meat, dairy, cholesterol and dietary variety. "Poor" diet mostly had women with normal weight and middle-aged. Age did not influenced overall HEI score, neither its components. Obese women had lower achievements for almost all recommended HEI components. Women having "poor" diet quality could raise a chance for overweight and obesity for almost two times ([OR] = 1.67, 95% [CI] = 1.072-2.59, p = 0.023; [OR] = 1.51, 95% [CI] = 1.08-2.10, p = 0.015, respectively). The provided results showed that with age, women tended to have better diet. These could be because of that with aging are higher disease incidences that essentially need diet improvements; so older women tended to improve their diet to reduce disease discomforts. Being obese influenced the diet quality of our sample of women, therefore, for quality aging, the importance of public health nutrition programs are strongly needed. HEI score is a good assessment for diet quality, but further investigation of influence on other sociodemographic and health characteristics is required. PMID- 21302716 TI - Bone quality assessment in individuals of different age, gender and body constitution. AB - The concept of bone quality describes the sets of the characteristics of the osseous tissue that influence bone strength. The aim was to explore the influence of anthropometric parameters and age on the parameters of the bone architecture and bone mineral properties in the lumbar vertebral bone of men and women. Vertebral bone samples underwent bone histomorphometry, bone densitometry and atomic absorption spectrometry. Men have greater values of the bone volume and thicker bone trabeculae in relation to women, which indicates that vertebral bone architecture is better preserved in men than in women. Age is the best predictor of changes that affect bone architecture and bone mineral properties. Bone mineral density value and calcium concentration are both negatively predicted by age, but positively predicted by body mass index. Such result supports the opinion that low body mass index is associated with conditions of bone deficit such are osteopenia and osteoporosis. PMID- 21302717 TI - Immunohistochemical analysis of the human psoas major muscle with regards to the body side and aging. AB - The aim of our study was to explore the age related changes of the fibre type composition of the human psoas major muscle. Moreover, we wanted to compare the fibre type composition of the left and right muscle. Muscle samples were collected from 15 young and 15 old males. Type I, IIA and IIX muscle fibres were typed using myosin heavy chain identification. The serial transverse sections were analysed using a light microscope. Results of our study showed that the age related atrophy affected all three fibre types. Type IIA fibres were affected most profoundly while type I fibres were affected most weakly. The percentage of the different fibre types did not change during aging. There were no differences in the fibre type composition between the left and right muscle. Human psoas major muscle undergoes normal aging changes with the atrophy of all three fibre types, whereas atrophy most profoundly affects type IIA fibres. No differences in the fibre type composition between the left and right muscle point to the equal engagement of both legs in normal everyday activities of human. PMID- 21302718 TI - Influence of UV radiation on immunological system and occurrence of autoimmune diseases. AB - During the last three decades scientists worldwide have investigated how ultraviolet radiation (UVR) influences the immune system. The vast majority of the researchers was primarily focused on the local immunomodulatory role of UVR. But today evidence is increasing in favor of plural immune activation and systemic reaction of the organism. Most of the attention is directed toward the regulatory T lymphocytes which are responsible for the local and systemic immunosuppressive response under the impact of sunlight. The role of regulatory T cells in autoimmune diseases is well studied on patients with systemic lupus erythematosus (SLE). Epidemiological research shows a proportional interdependence of latitude and prevalence of autoimmune diseases such as multiple sclerosis (MS), insulin-dependent diabetes mellitus (IDDM) and rheumatoid arthritis (RA). There is evidence that UVR has direct influence on the level of antibodies against the SNF2-superfamily helicase (Mi-2), distinctive for dermatomyositis (DM). On this basis a hypothesis is established that UVR is a risk factor for DM. A Croatian epidemiologic study o f systemic sclerosis (SSc) gave results consistent with the hypothesis that there is a higher prevalence of SSc in the Mediterranean regions of Croatia. Such discoveries encouraged further studies that found that not only regulatory T cells are responsible for a systemic immunosuppressive response, but that there is a complex interactive network of immune cells and mediators such as cytokines, neuropeptides, and chromophores like urocanic acid involved. Present findings require continued research on the importance of UVR on autoimmune disease prevalence and immunopathophysiology. Finally, it is necessary to distinguish whether UVR is a protective factor for some autoimmune diseases or a risk factor for their induction. PMID- 21302719 TI - UV clothing and skin cancer. AB - Skin cancer incidence in Croatia is steadily increasing in spite of public and governmental permanently measurements. It is clear that will soon become a major public health problem. The primary cause of skin cancer is believed to be a long exposure to solar ultraviolet (UV) radiation. The future designers of UV protective materials should be able to block totally the ultraviolet radiation. The aim of this paper is to present results of measurements concerning UV protecting ability of garments and sun-screening textiles using transmission spectrophotometer Cary 50 Solarscreen (Varian) according to AS/NZS 4399:1996; to show that standard clothing materials are not always adequate to prevent effect of UV radiation to the human skin; and to suggest the possibilities for its improvement for this purpose. PMID- 21302720 TI - Amaurosis fugax is in the first place, during attack, medical emergency for ophthalmologist's practice. AB - This paper is focused on disease Amaurosis Fugax (AF), indicating the necessary urgent therapy in attack of illnesses. In attack, the patient represents ophthalmic case, because of vision lost, but primary process and cause exists even earlier and very often is of chronical character. Authors emphasize sequencing in therapy of AF and accentuate that in 24 hours the cause of the disease may be defined. AF is a syndrome with very different etiopathogenesis, including also big complexity in diagnosis and therapy. PMID- 21302721 TI - Modified extensive anterior vaginal wall repair for cystocoele. AB - We describe a new transvaginal technique for cystocoele repair. We prospectively evaluated patients with moderate and high-grade cystocoele who underwent repair with the new transvaginal repair between 2000 and June 2009. Preoperative evaluation included history and physical examination using the Pelvic Organ Prolapse Quantification, urine culture, residual urine measurement, urodinamycs and cystoscopy. We performed the repair in 76 patients with a mean age of 65.24 years (range, 36 to 84 years), wit anatomical cure in 72 (95%) patients. Four (5%) patients had recurrent cystocoele, 3 (4%) patients claimed residual sensory urgency and 4 (5%) stress urinary incontinence (SUI) after the operation. The operation is safe, simple, and provides good anatomic results with minimal complications. PMID- 21302722 TI - Specular microscopy in glaucoma patients. AB - The endothelial cells are one of the most important structures in a donor cornea. Morphology and concentration of endothelial cells must be carefully evaluated with a specular microscope before transplantation. The aim of this study is to evaluate the status of corneal endothelium in glaucoma patients. Prospective study included 50 patients suffering from glaucoma and 50 patients in control group. Patients had no corneal disease, ocular inflammation, previous trauma or ocular surgery. Patients were not contact lens wearers. They were also analyzed in groups according to type of glaucoma. Specular microscopy was performed on central corneas. This study showed that patients with glaucoma have lower central corneal endothelial cell density than those without glaucoma of the same age group. Also, patients with pseudoexfoliative glaucoma had lower values of central endothelial cell density comparing to patients with open angle or angle closure glaucoma. PMID- 21302723 TI - Pseudoexfoliative syndrome and pseudoexfoliative glaucoma in Primorsko-Goranska County. AB - The aim of this study is to evaluate pseudoexfoliative glaucoma (PEX) in Primorsko-Goranska County, Croatia, and its characteristics comparing to primary open angle glaucoma (POAG). In the study a hundred patients with open angle glaucoma were examined, twenty six of them had a pseudoexfoliative glaucoma diagnosed. We were following intraocular pressure (IOP) values, visual acuities, visual fields and optical nerve head changes retrospectively. Comparing to primary open angle glaucoma pseudoexfoliative glaucoma in Primorsko-Goranska County has less good prognosis because the IOP is usually higher and more difficult to control, we found progressive loss of retinal ganglion cells and visual field loss develop more rapidly. Because of that pseudoexfoliative glaucoma requires special treatment and following. PMID- 21302724 TI - Is mitral valve repair safe procedure in elderly patients? AB - The aim of this randomized, prospective, study was to evaluate postoperative hospital mortality and morbidity after mitral valve repair by comparing two surgical techniques for resolving mitral valve insufficiency in elderly patients. In comparison were: mitral valve repair vs. mitral valve replacement in patients older than 70 years. In period from January 1st 2006 until August 30th 2009. Eighty patients with mitral valve disease, isolated or associated with other comorbidities, were scheduled for mitral valve repair or mitral valve replacement in our institution. Patients were randomized in two groups, one scheduled for mitral valve repair and another one for mitral valve replacement using the envelope method with random numbers. Results show no difference in hospital mortality and morbidity postoperatively in both groups. In group undergoing valve replacement we had one significant complication of ventricle rupture in emphatically calcified posterior part of mitral valve annulus. In conclusion we found no distinction in postoperative hospital mortality and morbidity after using one of two surgical techniques. PMID- 21302725 TI - Pediatric idiopathic intracranial hypertension: clinical and demographic features. AB - Idiopathic intracranial hypertension (IIH) is a clinical condition characterized by elevated intracranial pressure and absence of clinical, laboratory or radiographic evidence of central nervous system infection, vascular malformation, intracranial space occupying lesion or hydrocephalus. In the last years the raising understanding of pediatric IIH, especially concerning its demographics and epidemiology, has brought up to a redefinition of diagnostic criteria and reevaluation of pathogenesis and treatment. The authors reviewed the records of nineteen consecutive children with newly diagnosed IIH in order to compare demographic characteristics, clinical pictures and ophthalmologic aspects as optic disc evaluation and visual field evaluation, as well as treatment modalities and follow up. Beside obesity and female gender, potential alternative risk factors remains to be investigated, which need a good collaboration between neuro-ophthalmologists and pediatric neurologists. PMID- 21302726 TI - Radical surgical treatment of the urinary bladder cancer in patients over the age of 60--our experiences. AB - The goal of the paper was the analysis of patients over the age of 60 suffering from the urinary bladder cancer that underwent radical surgical treatment of the urinary bladder and establishing urine derivation. In the 1972-2008 period 2405 patients with the urinary bladder cancer were treated, 296 (12.3%) of whom underwent radical surgical treatment. The average age was between 60 and 80 years -in 207 (70%) patients. In our patients there were 190 patients (91.6%) with transitional cell cancers. According to TNM classification, T3 stage in 92 (44.4%) patients and T2 stage in 85 (41%) patients were predominant in our study. According to histological criteria, the most common stage was G3 stage--in 151 (73%) patients. Radical cystectomy or combined with urethrectomy was performed in 178 (86%) patients. Unfortunately, in 12% of them (T3 and T4 stages) the inner iliac blood vessels were tied off due to a progressive cancer. The outer supravesical urine derivation (Bricker, U-tubing nephrostomy, and ureterocutaneostomy) was done in 163 (78.7%) patients. The inner derivation (Coffey, ureteroileosigmoidostomy, Mainz-Pouch II) was performed in 17 (8.2%) patients and neovesica (Hautmann, Studer) in 24 (11.5%)patients. There were 74 (35.7%) patients with early postoperative complications. Among them the most dominant were the surgical complications--in 28 (13.5%) patients and distant organ complications--in 22 (10.6%) patients. In 75 (36%)patients with negative nodes the survival rate was 55% after five years. In 73 (35%) patients with positive nodes the survival rate was 27% after five years. PMID- 21302727 TI - Acute skin sun damage in children and its consequences in adults. AB - Children spend more time outdoors than adults and there is compelling evidence that childhood is a particularly vulnerable time for the photocarcinogenic effects of the sun. The negative effects of solar radiation are accumulated during the entire lifetime; however 80% of total lifetime sun exposure is taking place before the age of 18 years. Child skin is more sensitive than adult skin because natural defense mechanisms are not fully developed. A short exposure to midday sun will result in sunburns. Epidemiologic studies show a higher incidence of malignant melanoma in persons with a history of sunburns during childhood and adolescence. Sun exposure among infants and pre-school children is largely dependent on the discretion of adult care providers. Sun protective habits of mothers may predict the level of sun exposure in children. It is very important to transfer the knowledge and positive habits of proper sun protection to children. The purpose of sun-safety behavior is not to avoid outdoor activities, but rather to protect the skin from detrimental sun effects. Proper sun protection of children includes protection from excessive sun exposure, sunburns and other forms of skin damage caused by sun, which may lead to the future development of skin cancers. This paper reviews acute skin reactivity to sun in childhood and adolescence that causes damage in skin structure and function and produces undesirable chronic changes in adults. PMID- 21302728 TI - Obtaining the child testimony in the criminal proceedings. AB - Children fall under the special category of vulnerable witnesses. Children's vulnerability is the reason that we must approach obtaining the child's testimony in the criminal proceedings with special attention. It is important to take the child's testimony as soon as possible and to avoid the repetition of interrogation. The criminal proceedings law and the juvenile court law enable children interrogation through the professional person without the presence of other parties in the procedure and enable the recording of such interrogation by audio-video link which considerably diminish the secondary victimization. The professionals who obtain the testimony must be well acquainted with children's psychological development. Knowledge of psychological development is of major importance in order to make the quality arrangements for interrogation and to interrogate the child and to achieve positive social contact between the examiner and the examinee and it is also of great importance for the credibility evaluation of the child's testimony. The adequate way of children interrogation will enable the child to say the correct information and to recognize the perpetrator. The forensic interview is well elaborated and child adapted technique of interrogation. Respecting the rules of forensic interview will enable the child's testimony on court to be relevant evidence. PMID- 21302729 TI - New option in photoprotection. AB - All the people are exposed to solar ultraviolet radiation. Exposure to sun with living in an oxygen-rich atmosphere causes unwanted photodemage. Sunburned skin is a leading risk factor for melanoma and non-melanoma cancers. UV exposure causes immunosuppression via multiple mechanisms in the skin. In this review the main topic is to mention new or alternative ways of photoprotection. Sunscreens are commonly used as protection against sun damage. They reduce the penetration of damaging solar UV wavelengths in skin by reflecting or absorbing them. Sunscreens are very valuable, but they have limitations. They have to be used properly to gain the full effect (application a little while before UV exposure, at frequent time points and in adequate amounts). Also, they have the problem of photoinactivation, which is the degeneration of the UV-filter due to exposure to UV rays resulting in the loss of absorbing capacity. Products with immune protection factor contain DNA-repair enzymes and antioxidants that may reduce mutations and enable the immune system to combat photodamage. The use of antioxidants and polyphenols may exert an anti-aging effect by preventing and even reversing sun damage. Adequate photoprotection is essential to control photocarcinogenesis and photoaging. PMID- 21302730 TI - Photosensitivity skin disorders in childhood. AB - Photosensitivity in childhood is caused by a diverse group of diseases. A specific sensitivity of a child's skin to ultraviolet light is often the first manifestation or a clinical symptom of photodermatosis. It might indicate a serious underlying systemic disease such as lupus erythematosus or dermatomyositis, or a rare group of genetic skin disorders like Xeroderma pigmentosum, Cockayne syndrome, Trichothyodystrophy, Bloom syndrome, Rothmund Thomson and Kindler syndrome as well as metabolic disorders and cutaneous porphyria. Photosensitivity secondary to topical or systemic agents may also cause photosensitivity in children. Early recognition and prompt diagnosis may prevent complications associated with unprotected exposure to sunlight and avoid actinic injuries that can lead to malignant skin changes. PMID- 21302731 TI - Trichophyton Spp. fungal keratitis in 22 years old female contact lenses wearer. AB - Fungal keratitis represents one of the most difficult forms of microbial keratitis to diagnose and treat successfully. It is difficult to obtain correct diagnosis and topical antifungal preparations. Fungi can cause severe stromal necrosis and enter the anterior chamber by penetrating an intact Descemet membrane. The most common pathogens are filamentous fungi (Aspergillus and Fusarium spp.) and Candida albicans. The incidence of Trichophyton spp. keratitis is 5%. A 22 years old female contact lenses wearer after keratitis developed corneal melting syndrome, spontaneous perforation of the cornea and complicated cataract of the left eye. Conjunctival swab was sterile as well as first sample of corneal tissue and sample from the anterior chamber. Urgent therapeutic perforating keratoplasty (PK), was performed together with extracapsular cataract extraction and the implantation of the intraocular lens in the posterior chamber. The patient was treated with ciprofloxacin and diflucan (systemic therapy); with dexamethason and atropin (subconjunctivaly) and chlorhexidine, brolene, levofloxacin, polimyxin B, and dexamethason/neomycin (topically). Microbiology evaluation was performed once again following excisional biopsy of the intracameral portion of the lesion. The presence of Trichophyton spp. was finally confirmed. Itraconazole and garamycin were included in the systemic therapy. Corneal graft was clear for 17 days but decompensated 28 days after the PK. After two weeks microorganisms invaded the vitreous and caused endophthalmitis. Despite urgent pars plana vitrectomy patient developed endophthalmitis, lost light sensation and developed phthysis. Evisceration and the implantation of silicon prosthesis was done. Perforating keratoplasty is a method of choice in treating severe infectious keratitis unresponsive to conservative treatment but without the eradication of microorganisms it cannot restore the vision or save the eye. Trichophyton spp. may cause a severe disease of the anterior and posterior part of the eye which may finish with the lost of vision/eye. Prompt diagnosis and treatment of Trichophyton spp. keratitis are essential for a good visual outcome. PMID- 21302732 TI - Selective laser trabeculoplasty in the treatment of pseudoexfoliation glaucoma in patients allergic to all anti-glaucoma drops. AB - Secondary chronic open-angle glaucoma associated with pseudoexfoliation (PEX) syndrome accounts for approximately 25% of all glaucomas and represents the most common identifiable cause of glaucoma overall. Selective laser trabeculoplasty (SLT) is effective in reducing intraocular pressure (IOP) in glaucomatous patients and has the advantage of preserving surrounding structures. We report here SLT treatment of a 82 year old female with a secondary developed open-angle pseudoexfoliation glaucoma allergic to all anti glaucoma eye drops especially those which contain bensalconium chloridum as preservative. Since patient was allergic also to methyl-cellulose, we performed SLT with water as a mediator. Patient had PEX syndrome for 10 years, immature cataracts on both eyes, and best corrected visual acuity (BCVA) 0.7 on the right and 0.2 on the left eye. We have monitored intraocular pressure (IOP), the changes in the visual field and optic nerve. Preoperative IOP was 28 mmHg on the right and 30 mmHg on the left eye. The follow up period was 24 months with time points for measured parameters every 3 months. After 18 months IOP remained in the normal values (average 17 mmHg) on the right eye, but on the left eye it increased up to 28 mmHg. SLT re-treatment was carried out on the left eye and the IOP stabilized again on the values between 16-18mmHg. There were no significant change in the visual field and optic nerve configuration before and after SLT (C/D value for right eye: 0.3-0.4; C/D left eye: 0.5). Based on this case report, SLT seems to be very effective treatment for maintaining regular IOP in patient with PEX who is allergic to all types of medications. PMID- 21302733 TI - The role of apoptosis in the pathogenesis of malignant melanoma. AB - Malignant melanoma genesis is a very complex process that involves a sequence of pathogenetic cellular events. Mutation of various genes and numerous other cellular mechanisms play an important role in the course of malignant melanocyte alteration and their malignant transformation from naevi into melanoma. Apoptosis is an active, genetically controlled process of programmed cell death, which leads to cell destruction and cell death without involvement of surrounding cells or inflammatory response. In this process, disrupted mechanisms of cell regulation and apoptosis take place in malignant melanoma cells, thus leading to their uncontrolled proliferation and melanocyte growth. Apoptosis is a process that involves two major pathways, the intrinsic and extrinsic apoptotic pathway, which interlace at certain points and ultimately result in apoptosis. It can be said that molecular events regulating cell survival, normal growth arrest, apoptosis and cell differentiation, contribute to the overall pathogenesis of malignant cell growth. It is presumed that in the future, understanding of molecular aberrations and cellular processes, such as cell signaling, cell cycle regulation and cell apoptosis, will be essential for better patient monitoring and rational design of effective treatment. PMID- 21302734 TI - Standard oral rehydration solution as a new storage medium for avulsed teeth. AB - OBJECTIVES: Immediate tooth replantation is the choice of treatment in tooth avulsion. When it is impossible to replant immediately an appropriate medium must be used to maintain periodontal ligament (PDL) cell viability. The purpose of this study was to investigate the effect of standard Oral Rehydration Solution (ORS) as a new storage medium for the preservation of PDL cell viability. METHODS: 75 young adult premolar teeth without periodontal disease were used (25 teeth for each medium). Teeth were placed in the experimental media including standard ORS, HBSS and tap water for intended incubation periods. After that, PDL cells were separated and cell viability was determined by Trypan blue staining. The results were analysed by one way ANOVA. RESULTS: There was no significant difference between HBSS and Standard ORS in supporting the maintenance of PDL cell viability. A significant difference between the effect of Standard ORS and water and HBSS and water was observed in maintaining PDL cell viability. CONCLUSIONS: Standard ORS is a suitable transport medium to support the maintenance of PDL cell viability. Regarding its inexpensiveness and availability, standard ORS has preference over some other approved transport media like HBSS. PMID- 21302735 TI - Smoking prevalence and attitude toward anti-smoking activities among Korean dentists. AB - AIMS: To investigate the smoking habits and attitudes toward anti-smoking activities of Korean dentists according to their smoking status. METHODS: A questionnaire was mailed to a random sample of 2500 currently active Korean dentists in 2008. After 20% of the 1680 returned surveys (response rate 67.2%) were excluded due to missing data, 1443 surveys were analysed. RESULTS: Among the 1443 respondents, most were male (81.8%) and age 40-49 was the most prevalent age group (41.6%). Approximately half of participating dentists were never-smokers, 24.6% were current smokers, and 29% were ex-smokers. Women (95.8%) were significantly more likely to have never smoked than men (35.4%). Prevalence of cigarette smoking of Korean male and female dentists was much lower than that of male and female Korean adults, respectively. Ex-smokers were significantly more likely to show a positive attitude about anti-smoking activities, compared to current smokers (p < .0001). CONCLUSIONS: A majority of respondents agreed dentists should encourage their patients to stop smoking. Further effort is needed to encourage smoking cessation among male Korean dentists who smoke so they benefit from a healthier lifestyle and will subsequently be more likely to provide recommendations for smoking prevention and cessation for their patients. PMID- 21302736 TI - A cross-sectional survey investigating the care of the primary dentition by general dental practitioners working in Japan and England. AB - OBJECTIVE: To compare treatment decisions about primary dentistry made by Japanese and English general dental practitioners (GDPs). METHOD: Four clinical scenarios were used to ascertain the clinical opinions of GDPs about what treatment to offer a 6-year-old boy with a carious molar. The first and second scenarios were a single distal and a distalocclusal cavity in a vital tooth without pain. The third was a large distal-occlusal cavity in a non-vital tooth without pain. The fourth was large distal-occlusal cavity in a non-vital tooth with pain. The participants were 234 GDPs in Japan and 322 GDPs in England. RESULTS: In the first scenario, 62.2% of Japanese GDPs preferred traditional restorative care compared with 34.7% of English GDPs. In the second scenario, Japanese participants were less likely to offer atraumatic treatment (16.5% vs. 34.9%). In the third scenario, Japanese dentists displayed a greater tendency to open the pulp chamber (55.2% vs. 7.6%). In the final scenario, 71% of Japanese GDPs would open the pulp chamber, whereas 50.3% of English GDPs favoured extraction. CONCLUSION: Japanese and English GDPs differed substantially in their views about the best treatment for a young child with a carious molar. PMID- 21302737 TI - Healthy mind and body in a healthy work environment. AB - OBJECTIVES: To assess the relationship between psychological distress and physical somatic symptoms as well as work environment conditions in the diverse population of dentists based in the Canary Islands (Spain). METHODS: 203 dentists officially registered with the local General Dental Councils, returned the questionnaire delivered by mail. Participants provided information on demographic characteristics, self-constructed questions like self-perceived environmental working conditions (location, access, temperature, humidity and pollution). They also completed the Spanish versions of the 12-item General Health Questionnaire (GHQ-12) and the revised version of the Symptom Checklist (SCL-90-R). The GHQ-12 was used to assess psychological distress and the somatic physical symptoms were assessed with the 12-item somatic subscale extracted from the SCL-90-R. Three different linear regression models were constructed. RESULTS: Psychological distress was positively related to somatic symptoms in all the models even after adjusting for sex and age. This association also remained significant for self perceived environmental working conditions in the two final models. 23% of the dentists had psychological distress. The mean score for the SCL-90-R somatic subscale was 0.55 points (Standard Deviation: 0.50). CONCLUSIONS: Self-perceived environmental working conditions were also associated with the strong relationship found between psychological distress and physical somatic symptoms among dentists. PMID- 21302738 TI - Illegal oral care: more than a legal issue. AB - Affordable, safe and appropriate oral care, including preventive services, is not available for large parts of the world's population. In many low- and middle income countries patients have to rely on a range of illegal oral care providers who are often socially accepted and part of the cultural context. Although filling a gap in service provision for poor populations, illegal provision of oral care is a serious public health problem, resulting in situations of low quality care and risks for patients. It is a complex phenomenon going far beyond the legal context. It should be seen as a symptom of underlying health system and society deficits, ranging from lack of access to care and health inequities to problems of governance and law-enforcement. This paper analyses the problem based on the country case of Guyana, explores the public health, legal, professional, social, economical and ethical dimensions of the problem and proposes a differential view on illegal practice by grouping illegal oral care situations in four broad categories; each of them requiring different solutions to tackle underlying issues leading to the problem of illegal oral care. PMID- 21302739 TI - Endemic fluorosis among 14-year-old Yemeni adolescents: an exploratory survey. AB - OBJECTIVE: To assess the extent of fluorosis in a representative sample of 14 year-old Yemeni adolescents. METHODS: A random sample of 2400 14-year-old Yemeni adolescents, equally distributed by gender, zone and locations, participated in the study. Fluorosis was identified using photographs for measuring Dean's Fluorosis Index. Water samples were taken and analysed for fluoride concentration using the ion selective electrode method at the Oral Biology laboratory, University of Malaya. RESULTS: Fluorosis was found to be present in 30.8% of all subjects examined. Slightly more males (32.3%) than females (29.3%) were observed to have varying degrees of fluorosis. There were more cases with fluorosis among children in rural areas (31.9%) than urban children (29.7%). Adolescents in the south (46.9%) or east (49%) Yemen were found to have almost two times or more children with fluorosis than all other zones (North 15.2%, Central 20%, West 22.9%), the differences were significant at p = 0.0001. Fluoride concentration in natural drinking water in the study locations was found to be between 0.5-3.8 ppmF. CONCLUSION: Findings found fluorosis to be significant among Yemeni adolescents. PMID- 21302740 TI - Risk of suicide amongst dentists: myth or reality? AB - OBJECTIVES: To analyse the scientific weight of the studies about reports of suicide rates in dentistry and decide the possible stressors caused by dental clinical activity, their consequences and their treatment. DISCUSSION: The previous literature treats the high suicide rate associated with the dental profession in different ways: myth for some, important statistical data which needs further research for others. The possible errors repeated in the literature as a result of not introducing certain indispensable variables are analysed and a report given of the main stressors linked to the profession. The results showed that the absence of treatment of the disorders arising from these stressors by qualified professionals along with the lack of preventative measures developed by universities and clinicians to be one of the main problems. CONCLUSIONS: In the literature we find systematically a suicide rate among dentists higher than those of other occupations. These studies lack the correct scientific weight and new studies are required that introduce the demographic variables, the psiquiatric morbidity previous to the development of the profession, the opportunity factor, the stressors not related to work and the relative emphasis to these are necessary to for the profession to decrease the risk of suicide. PMID- 21302741 TI - Effect of whitening toothpastes on tooth staining using two different colour measuring devices--a 12-week clinical trial. AB - AIM: To evaluate the potential of two whitening toothpastes on stain removal, using two different spectrophotometeric devices. DESIGN: In a randomised, double blind clinical trial, 150 participants with tooth discolouration were assigned to use one of three toothpastes containing: hydroxyapatite, calcium peroxide and no active ingredient (placebo). They were examined at baseline and after 4, 8 and 12 weeks. MEASURES: Two methods of colour measurement were used: Vita Easyshade (Vita 3D-master scale) and Degudent Shadepilot (Classical Vitashade scale). RESULTS: No significant improvement was observed after using the two spectrophotometeric methods. However, a subjective lighter tooth colour and less staining were perceived by the participants in all three groups (not significant). Moreover, there was a significant improvement in the gingival and plaque index in all three groups after the 12 weeks. CONCLUSIONS: The toothpaste containing hydroxyapatite or calcium peroxide did not produce any reduction in tooth staining compared with a placebo fluoride toothpaste. PMID- 21302743 TI - On the sidelines with an NFL doc. PMID- 21302742 TI - NFL concussions and common sense. A recipe for medical errors and a lesson for physician leaders. PMID- 21302744 TI - Community hospital to community health system: A blueprint for continuum of care. PMID- 21302745 TI - The rapid growth of MD/MBA programs: are they worth it. PMID- 21302746 TI - Applying lessons from Hollywood to heatlh care: managing the intimidating star. PMID- 21302747 TI - Improving seniors access to care: the preceptor model. PMID- 21302748 TI - Lean Six Sigma, innovation, and the change acceleration process can work together. PMID- 21302749 TI - Sustaining Lean Six Sigma projects in health care. PMID- 21302750 TI - One year as chief medical officer: challenges encountered and lessons learned. PMID- 21302751 TI - Good networking/bad networking. PMID- 21302752 TI - Leadership and governance for IT projects. PMID- 21302753 TI - Retirees may consider non-clinical "encore" career. PMID- 21302754 TI - Readiness for change. PMID- 21302755 TI - Putting your best foot forward: tips for terrific interviews. PMID- 21302756 TI - Comparison of sampling methods, culture, acid-fast stain, and polymerase chain reaction assay for the diagnosis of mycobacteriosis in ring-neck doves (Streptopelia risoria). AB - Even when different diagnostic modalities are available, mycobacteriosis is difficult to diagnose in a live bird. To investigate the diagnostic value of sampling different tissues and using different diagnostic methods, we evaluated results of mycobacterial culture, Ziehl-Neelsen (ZN) staining, and single amplification polymerase chain reaction assay (PCR) of 18 ring-neck doves (Streptopelia risoria) with confirmed natural infection with Mycobacterium avium avium. Results of testing liver biopsy, duodenal aspirate, and bone marrow aspirate samples and liver and spleen samples collected at necropsy were compared. Results showed the use of one single technique did not allow identification of all infected birds. In liver biopsy and bone marrow aspirate samples, culture had the highest sensitivity, whereas PCR assay and ZN staining had low sensitivity, and their combination was less sensitive than culture alone. Examination of ZN staining of the intestinal aspirate samples failed to detect infection in most birds. More splenic lesions contained acid-fast organisms than did liver lesions, suggesting that splenic biopsy may have the greatest potential for diagnosis of mycobacterial infection antemortem. Sensitivity was higher for postmortem examination of multiple liver sections than of a single biopsy section; therefore, obtaining multiple liver biopsy sections may increase detection of mycobacteria. Examination of multiple tissues and the use of several different diagnostic techniques significantly increases the probability of diagnosis of mycobacteriosis. PMID- 21302757 TI - Evaluation of a pediatric blood filter for whole blood transfusions in domestic chickens (Gallus gallus). AB - Blood filters that prevent clots, microaggregates, and other debris from being passed from the donor blood into the recipient are an essential component of blood transfusions in mammalian species but have not been consistently recommended in avian transfusions. To evaluate the hemolytic effect of an 18 microm filter in chickens, 9 mL of blood was collected from each of 30 chickens (Gallus gallus) into a syringe containing 1 mL of citrate phosphate dextrose adenine (CPDA-1) to obtain a 1:9 dilution of CPDA-1 to blood. One half of each sample was then run through a pediatric blood filter before separating the plasma. The level of hemolysis in both filtered and unfiltered portions was determined by measuring the concentration of free hemoglobin in the plasma. All samples had low hemoglobin concentrations (less than 30 mg/dL) with no significant difference between the unfiltered and filtered portions. Based on these results, an 18-microm blood filter can be used safely for blood transfusions in domestic chickens as it does not cause significant hemolysis. PMID- 21302758 TI - Lead poisoning of bald (Haliaeetus leucocephalus) and golden (Aquila chrysaetos) eagles in the U.S. inland Pacific northwest region--an 18-year retrospective study: 1991-2008. AB - To determine risk factors and seasonal trends of lead poisoning in bald (Haliaeetus leucocephalus) and golden (Aquila chrysaetos) eagles, blood lead levels were evaluated in eagles admitted from the inland Pacific Northwest region of the United States to the Raptor Rehabilitation Program, College of Veterinary Medicine at Washington State University from 1991 to 2008. Admissions were from Washington (32 bald eagles, 27 golden eagles), northern Idaho (21 bald eagles, 25 golden eagles), northeastern Oregon (5 bald eagles, 6 golden eagles), Montana (2 bald eagles), Alaska (1 bald eagle), and unrecorded (6 bald eagles, 5 golden eagles). In these birds, 48% (22/46) of bald and 62% (31/50) of golden eagles tested had blood lead levels considered toxic by current standards. Of the bald and golden eagles with toxic lead levels, 91% (20/22) and 58% (18/31) respectively, were admitted after the end of the general deer and elk hunting seasons in December. Coyote hunting intensifies with the end of the large game hunting seasons and coyote carcasses left in the field and contaminated with lead bullet fragments become readily available food sources, exposing scavenging bald and golden eagles to high risk of acute lead poisoning. PMID- 21302759 TI - Health and nutritional status of wild Australian psittacine birds: an evaluation of plasma and hepatic mineral levels, plasma biochemical values, and fecal microflora. AB - To evaluate the health and nutritional status of 3 wild Australian psittacine species, plasma and hepatic mineral concentrations and plasma biochemical values were measured in wild-caught galahs (Eolophus roseicapilla), long-billed corellas (Cacatua tenuirostris), and sulphur-crested cockatoos (Cacatua galerita). No correlations were found between hepatic and plasma mineral levels. Mean plasma calcium (1.79 mmol/L [7.16 mg/dL]) and sodium (103 mmol/ L [103 mEq/L]) concentrations were lower, whereas mean total phosphorus (6.53 mmol/L [20.22 mg/dL]) and potassium (8.87 mmol/L [8.87 mEq/L]) concentrations were higher than values for captive counterparts. Plasma iron levels were higher than those reported for captive counterparts, with evidence of interspecific (sulphur crested cockatoos, 109 micromol/L [609 microg/dL]; corellas, 57 micromol/L [318 microg/dL]; galahs, 90 micromol/L [503 microg/dL]) and temporal variation (galahs: May, 107 micromol/L [598 microg/dL]; July, 59 micromol/L [330 microg/dL]). Hepatic iron concentrations were as high as 1030 mg/kg. Interspecific variation was minimal in mean plasma selenium (11.8 micromol/L [929 microg/L]) and zinc (31.2 micromol/L [204 microg/dL]) concentrations. Plasma biochemical values varied significantly from reported reference ranges. Ranges for total protein, albumin, and bile acid concentrations were lower, whereas uric acid, glutamate dehydrogenase, amylase, and cholesterol concentrations were higher than those previously reported for these species, and interspecific variation was evident. Variation in measures of mineral status or plasma biochemical values between males and females were negligible. An evaluation of fecal microflora showed a distinct absence of gram-negative bacteria or budding yeast. Results of this study show that analyte values used to determine health and nutritional status of wild birds differ from those published for captive counterparts. Although analyte values appear to vary minimally by sex, distinct taxonomic and some temporal differences exist in values from wild birds of these 3 species. PMID- 21302760 TI - Radiation therapy of a malignant melanoma in a thick-billed parrot (Rhynchopsitta pachyrhyncha). AB - A male thick-billed parrot (Rhynchopsitta pachyrhyncha) was diagnosed with a malignant melanoma of the mandibular beak (gnathotheca). Surgical excision was impossible because of the location of the lesion; a combination of radiation therapy and oral antitumor drugs were used to treat the neoplasm. A whole-body computed tomographic scan showed evidence of metastasis in the lungs; the bird, therefore, was considered to have stage IV disease. Throughout the treatment period, the bird showed no clinical evidence of systemic disease. The bird was given 20 treatments of localized radiation therapy of 2.5 Gray (Gy) for a cumulative dose of 50 Gy. The bird was also treated with piroxicam and cimetidine orally from the time of diagnosis, throughout radiation therapy, and until its death. By the completion of radiation therapy, the initial lesion had decreased considerably in size. The bird survived 2.5 months after radiation therapy was completed but died of complications related to metastatic disease. Necropsy results revealed metastases throughout the body, including lesions in the lungs and liver. To our knowledge, this is the first report of localized radiation therapy and oral antitumor drugs being used to treat malignant melanoma in an avian patient. The radiation therapy did produce tumor response in the form of a reduction in size of the visible tumor. PMID- 21302761 TI - Use of a portable tower and remote-controlled launcher to improve physical conditioning in a rehabilitating wild mallard (Anas platyrhynchos). AB - Prerelease reconditioning improves the chance of survival of rehabilitating raptors. Reconditioning may also help to rehabilitate waterfowl, including those that are threatened or endangered, especially if the birds are released during periods of migration. A flying harness, creance, remote-controlled launcher, and portable tower were used to create a means of reconditioning a rehabilitating 5 month-old female wild mallard duck (Anas platyrhynchos) that had been housed in a rehabilitation center for 7 weeks while recovering from an injury. Pre- and postflight serum lactate levels, body condition index scores, and controlled flight distances were used to assess the bird's degree of conditioning. Postflight serum lactate levels never returned to preflight levels and were not deemed a reliable indicator of physical fitness. However, the mallard showed an increase in endurance and strength as well as improved body condition index scores over the course of the reconditioning program. PMID- 21302762 TI - Mixed infection with reovirus and Chlamydophila in a flock of budgerigars (Melopsittacus undulatus). AB - Eleven budgerigars (Melopsittacus undulatus) from a zoological collection presented at necropsy with emaciation and splenomegaly or hepatomegaly or both. Polymerase chain reaction assays performed on liver and spleen samples were positive for Chlamydophila psittaci in 2 of 3 birds tested, and histologic findings in 2 additional birds were compatible with chlamydiosis. The aviary was subsequently closed to the public, and a 45-day treatment regimen with doxycycline in the seeds was initiated. No further deaths of birds with hepatomegaly or splenomegaly were observed after the first day of treatment. Further investigation of birds that died during the outbreak with emaciation and with hepatic and splenic enlargement revealed severe necrosis of the spleen and liver suggestive of reovirus infection, which was supported with polymerase chain reaction analysis from paraffin-embedded tissue. This reovirus was sequenced and had 100% homology with a reovirus previously identified in an African grey parrot (Psittacus erithacus). The outbreak did not affect cockatiels (Nymphicus hollandicus) and blue quail (Coturnix chinensis) kept in the same aviary. A group of budgerigars added to the collection soon before the opening of the aviary may have introduced reovirus and Chlamydophila into the collection. PMID- 21302763 TI - Multiple tracheal resections and anastomoses in a blue and gold macaw (Ara ararauna). AB - A 1.5-year-old, male blue and gold macaw (Ara ararauna) was anesthetized for a health examination and blood collection. The following day it was returned for episodes of coughing. The bird was presented again 13 days after the initial presentation with severe dyspnea. A tracheal stenosis was diagnosed by endoscopy and treated by surgical resection of 5 tracheal rings and tracheal anastomosis. The bird was discharged but returned 2 days later with a recurrent stenosis. Bougienage and balloon dilation of the stenotic area were performed separately; each resulted in less than 48 hours' improvement in clinical signs after treatment. A second tracheal resection and anastomosis was performed, during which an additional 10 tracheal rings were removed. This second anastomosis was significantly more difficult to complete given the marked variation in diameter of the proximal and distal tracheal segments. The macaw recovered without complication and has had no recurrence of respiratory abnormalities 2 years after the second surgery. This report describes the longest total tracheal segment to be resected, followed by tracheal anastomosis, in a psittacine bird. The positive outcome in this case suggests that, when surgical therapy is elected, an aggressive approach is necessary to prevent recurrence of tracheal stenosis. In addition, macaws can recover well even after significant lengths of the trachea are resected. PMID- 21302764 TI - Long-term treatment of chronic lymphocytic leukemia in a green-winged macaw (Ara chloroptera). AB - A 32-year-old green-winged macaw (Ara chloroptera) was diagnosed with chronic lymphocytic leukemia based on progressive lymphocytosis and the presence of a monomorphic population of well-differentiated lymphocytes in the bone marrow of a clinically normal bird. Chemotherapy was initiated because of rapidly increasing peripheral lymphocyte counts. In addition to oral prednisone (1 mg/kg once daily), oral chlorambucil (1 mg/kg twice weekly) was initiated but was discontinued after 6 weeks because of thrombocytopenia. The leukocyte count was stabilized for 29 weeks with the concurrent use of oral cyclophosphamide (5 mg/kg 4 d/wk) and daily prednisone, and the bird exhibited a good quality of life. The bird died shortly after the chemotherapy was inadvertently discontinued. The neoplastic cells from this macaw stained positive for CD-3 antibody and negative for Bla.36, suggesting the leukemia was of T-cell origin. This is the first report of long-term treatment of a macaw with cyclophosphamide and documents thrombocytopenia in a macaw secondary to chlorambucil treatment. PMID- 21302765 TI - Birds and exotic pets: not just for veterinarians. PMID- 21302766 TI - What is your diagnosis? Gastrointestinal tract obstruction. PMID- 21302767 TI - Point/counterpoint. Co-60 tomotherapy is the treatment modality of choice for developing countries in transition toward IMRT. PMID- 21302768 TI - Target tracking using DMLC for volumetric modulated arc therapy: a simulation study. AB - PURPOSE: Target tracking using dynamic multileaf collimator (DMLC) is a promising approach for intrafraction motion management in radiation therapy. The purpose of this work is to develop a DMLC tracking algorithm capable of delivering volumetric-modulated arc therapy (VMAT) to the targets that experience two dimensional (2D) rigid motion in the beam's eye view. METHODS: The problem of VMAT delivery to moving targets is formulated as a control problem with constraints. The relationships between gantry speed, gantry acceleration, MLC leaf-velocity, dose rate, and target motion are derived. An iterative search algorithm is developed to find numerical solutions for efficient delivery of a specific VMAT plan to the moving target using 2D DMLC tracking. The delivery of five VMAT lung plans is simulated. The planned and delivered fluence maps in the target-reference frame are calculated and compared. RESULTS: The simulation demonstrates that the 2D tracking algorithm is capable of delivering the VMAT plan to a moving target fast and accurately without violating the machine constraints and the integrity of the treatment plan. The average delivery time is only 29 s longer than that of no-tracking delivery, 101 versus 72 s, respectively. The fluence maps are normalized to 200 MU and the average root-mean square error between the desired and the delivered fluence is 2.1 MU, compared to 14.8 MU for no-tracking and 3.6 MU for one-dimensional tracking. CONCLUSIONS: A locally optimal MLC tracking algorithm for VMAT delivery is proposed, aiming at shortest delivery time while maintaining treatment plan invariant. The inconsequential increase of treatment time due to DMLC tracking is clinically desirable, which makes VMAT with DMLC tracking attractive in treating moving tumors. PMID- 21302769 TI - An iterative method for tomographic x-ray perfusion estimation in a decomposition model-based approach. AB - PURPOSE: X-ray based tomographic blood perfusion imaging requires recovery of contrast time-attenuation-curves from dynamic projection data. When using slowly rotating imaging systems, this task is challenging due to nonsimultaneous projection acquisition. A dynamic reconstruction method is proposed that aims at compensating the lack of simultaneously acquired information by incorporating prior knowledge about the expected temporal contrast dynamics. METHODS: A decomposition model using temporal basis functions to approximate time attenuation-curves is integrated into an iterative tomographic reconstruction method. The computationally efficient implementation of the proposed approach makes use of standard forward-projections and backprojections, as well as scalar products in image space. The critical issue of projection noise propagation is tackled by the application of regularization which is realized by the early stopping of iteration cycles and by the proper selection of smooth temporal basis functions. The performance of the proposed dynamic reconstruction approach is evaluated in a simulation study concerning various aspects: Noise propagation and regularization, specification of the temporal model, and type of acquisition mode. RESULTS: The evaluation based on dynamic phantom data indicates that tomographic recovery of contrast time-attenuation-curves in tissue can be achieved with an average range of accuracy of approximately 2% (with respect to dynamic peak attenuation) under ideal noise-free conditions. The relative estimation error for arterial time-attenuation-curves is in the range of 8%, which is due to faster contrast dynamics in the artery. In general, performance depends on the level of acquired information contained in the projection data, which is mainly influenced by the type of rotational acquisition mode; restrictions in angular range and speed can lead to limited accuracy. The analysis of propagated projection noise in a statistical bias-variance framework reveals relative noise levels in estimated time-attenuation-curves of 3%-4% in tissue regions and below 1% in vessels when using optimized settings for regularization. Here, the effect of noise suppression depends on the interrelation between the number of iteration cycles and the constraints imposed by the temporal decomposition model. CONCLUSIONS: For usage with slowly rotating imaging systems, the presented model-based iterative dynamic reconstruction method is capable of recovering contrast time-attenuation-curves related to tissue perfusion. The proposed regularization framework is an effective means to limit the impact of projection noise, which is a factor dominating estimation accuracy in tissue regions. PMID- 21302770 TI - Multiscale entropy of laser Doppler flowmetry signals in healthy human subjects. AB - PURPOSE: The cardiovascular system (CVS) regulation can be studied from a central viewpoint, through heart rate variability (HRV) data, and from a peripheral viewpoint, through laser Doppler flowmetry (LDF) signals. Both the central and peripheral CVSs are regulated by several interacting mechanisms, each having its own temporal scale. The central CVS has been the subject of many multiscale studies. By contrast, these studies at the level of the peripheral CVS are very recent. Among the multiscale studies performed on the central CVS data, multiscale entropy has been proven to give interesting physiological information for diagnostic purposes. However, no multiscale entropy analysis has been performed on LDF signals. The authors' goal is therefore to propose a first multiscale entropy study of LDF data recorded in healthy subjects. METHODS: The LDF signals recorded in the forearm of seven healthy subjects are processed. Their period sampling is T=50 ms, and coarse-graining scales from T to 23T are studied. Also, for validation, the algorithm is first tested on synthetic signals of known theoretical multiscale entropy. RESULTS: The results reveal nonmonotonic evolution of the multiscale entropy of LDF signals, with a maximum at small scales around 7T and a minimum at longer scales around 18T, singling out in this way two distinctive scales where the LDF signals undergo specific changes from high to low complexity. This also marks a strong contrast with the HRV signals that usually display a monotonic increase in the evolution of the multiscale entropy. CONCLUSIONS: Multiscale entropy of LDF signals in healthy subjects shows variation with scales. Moreover, as the variation pattern observed appears similar for all the tested signals, multiscale entropy could potentially be a useful stationary signature for LDF signals, which otherwise are probe-position and subject dependent. Further work could now be conducted to evaluate possible diagnostic purposes of the multiscale entropy of LDF signals. PMID- 21302771 TI - High-rate x-ray spectroscopy in mammography with a CdTe detector: a digital pulse processing approach. AB - PURPOSE: Direct measurement of mammographic x-ray spectra under clinical conditions is a difficult task due to the high fluence rate of the x-ray beams as well as the limits in the development of high resolution detection systems in a high counting rate environment. In this work we present a detection system, based on a CdTe detector and an innovative digital pulse processing (DPP) system, for high-rate x-ray spectroscopy in mammography. METHODS: The DPP system performs a digital pile-up inspection and a digital pulse height analysis of the detector signals, digitized through a 14-bit, 100 MHz digitizer, for x-ray spectroscopy even at high photon counting rates. We investigated on the response of the digital detection system both at low (150 cps) and at high photon counting rates (up to 500 kcps) by using monoenergetic x-ray sources and a nonclinical molybdenum anode x-ray tube. Clinical molybdenum x-ray spectrum measurements were also performed by using a pinhole collimator and a custom alignment device. RESULTS: The detection system shows excellent performance up to 512 kcps with an energy resolution of 4.08% FWHM at 22.1 keV. Despite the high photon counting rate (up to 453 kcps), the molybdenum x-ray spectra, measured under clinical conditions, are characterized by a low number of pile-up events. The agreement between the attenuation curves and the half value layer values, obtained from the measured spectra, simulated spectra, and from the exposure values directly measured with an ionization chamber, also shows the accuracy of the measurements. CONCLUSIONS: These results make the proposed detection system a very attractive tool for both laboratory research and advanced quality controls in mammography. PMID- 21302772 TI - Quantitative breast tomosynthesis: from detectability to estimability. AB - PURPOSE: This work aimed to extend Fourier-based imaging metrics for modeling and predicting quantitative imaging performance. The new methodology was applied to the platform of breast tomosynthesis for investigating the influence of acquisition parameters (e.g., acquisition angle and dose) on quantitative imaging performance. METHODS: Two quantitative imaging tasks were considered: Area estimation and volume estimation of a 4 mm diameter spherical target. The maximum likelihood estimator yielded training data to generate a size estimation task function, which was combined with the MTF and NPS to predict estimation performance by computing an "estimability index" analogous to the detectability index. Estimation performance for the two tasks was computed as a function of acquisition angle and dose. The results were used for system optimization in terms of quantitation performance and further compared to the detectability index for the detection of the same spherical target. RESULTS: The estimability index computed with the size estimation tasks correlated well with precision measurements for area and volume estimation over a broad range of imaging conditions and provided a meaningful figure of merit for quantitative imaging performance and optimization. The results highlighted that optimal breast tomosynthesis acquisition parameters depend significantly on imaging task and dose. At nominal dose (1.5 mGy), mass detection was optimal at an acquisition angle of 85 degrees, while area and volume estimation for the same mass were optimal at approximately 125 degrees and 164 degrees acquisition angles, respectively. CONCLUSIONS: These findings provide an initial validation that the Fourier-based metrics extended to estimation tasks can represent a meaningful metric and predictor of quantitative imaging performance. The optimization framework also revealed trade-off between anatomical noise and system noise in volumetric imaging systems potentially identifying different optimal acquisition parameters than currently used in breast tomosynthesis and CT. PMID- 21302773 TI - Reduction of dental filling metallic artifacts in CT-based attenuation correction of PET data using weighted virtual sinograms optimized by a genetic algorithm. AB - PURPOSE: The presence of metallic dental fillings is prevalent in head and neck PET/CT imaging and generates bright and dark streaking artifacts in reconstructed CT images. The resulting artifacts would propagate to the corresponding PET images following CT-based attenuation correction (CTAC). This would cause over- and/or underestimation of tracer uptake in corresponding regions thus leading to inaccurate quantification of tracer uptake. The purpose of this study is to improve our recently proposed metal artifact reduction (MAR) approach and to assess its performance in a clinical setting. METHODS: The proposed MAR algorithm is performed in the virtual sinogram space to overcome the challenges associated with manipulating raw CT data. The corresponding bins of the virtual sinogram affected by metallic objects are obtained by forward projection of segmented metallic objects in the original CT image. These bins are then substituted by weighted values of three estimates: the affected bins in the original sinogram, the bins in the corrected sinogram using spline interpolation, and the sinogram bins in the neighboring column of the sinogram matrix. The optimized weighting factors (alpha, beta, and gamma) were estimated using a genetic algorithm (GA). The optimized combination of weighting coefficients was obtained using the GA applied to 24 clinical CT data sets. The proposed MAR method was then applied to 12 clinical head and neck PET/CT data sets containing dental artifacts. Analysis of the results was performed using Bland and Altman plots and a method allowing analysis in the absence of gold standard called regression without truth (RWT). The proposed method was also compared to an image-based MAR method. RESULTS: Optimization of the weighting coefficients using the GA resulted in an optimum combination of parameters of alpha=0.26, beta=0.67, and gamma=0.07. According to Bland and Altman plots generated for both CT and PET images of the clinical data, the proposed MAR algorithm is efficient for reduction of streak artifacts in CT images and such reduce the over- and/or underestimation o tracer uptake. The RWT method also confirmed the effectiveness of the proposed MAR method. The obtained figures of merit revealed that attenuation corrected PET data corrected using CTAC after applying the MAR algorithm are more similar to the assumed gold standard. Comparison with the knowledge-based method revealed that the proposed method mainly corrects the artifactual regions without modifying the unaffected regions. The knowledge-based method globally modifies the images including those that do not include metallic artifacts. CONCLUSIONS: The proposed MAR algorithm improves the quality and quantitative accuracy of clinical head and neck PET/CT images and could be easily integrated in clinical setting. PMID- 21302774 TI - A comparison of the respiratory signals acquired by different respiratory monitoring systems used in respiratory gated radiotherapy. AB - PURPOSE: Respiratory monitoring systems are used to detect the respiratory phase of patients during the planning and administration of respiratory gated radiotherapy by using four-dimensional computed tomography (4DCT) or 4D positron emission tomography/CT (4DPET/CT) and the linear accelerator (linac), respectively. Generally, identical respiratory monitoring systems are used for 4DCT, 4DPET/CT, and linac. However, different systems are sometimes used in combination because the accessibility of the respiratory monitoring systems may differ by manufacturer. The combined use of different respiratory monitoring systems in phase-based gating is of concern because the differences in the timing of tags (end-respiration signals algorithmically determined by the respiratory monitoring system), defined by the two systems, may result in phase differences, The purpose of this study is to estimate this difference and evaluate its effect on 4DCT data. METHODS: Ten patients (seven men and three women) with a median age of 75 yr (range: 57-84 yr) were treated by gated stereotactic body radiation therapy between April and December 2009. Two types of respiratory monitoring systems--RPM (Varian Medical Systems) and AZ-733V (Anzai MEDICAL)--were placed on the abdominal surface of the patients, and the respiratory signals were acquired by both systems. The relationship between the amplitude peak and the tag obtained by each respiratory system was analyzed for each patient. Further, the 4DCT images were reconstructed by using the signals obtained from both the RPM and the AZ-733V systems, and the tumor volumes and the tumor centroid positions in the craniocaudal plane were analyzed for each patient. RESULTS: The correlation factor between the respiratory signals from the RPM system and AZ-733V system was 0.990 (range: 0.940-0.994). The amplitude peak of the RPM system corresponded well with that of the AZ-733V system. The median +/- standard deviation of the phase difference for all the patients ranged from -4.3 +/- 7.1% to 3.5 +/- 2.2%. In the case of some patients, differences were noted between the two systems in the estimation of the tumor centroid position and tumor shape. CONCLUSIONS: The estimation of the position of the tumor centroid and tumor shape may vary with the use of different respiratory monitoring systems. This implies that it is preferable to use the same respiratory monitoring system with 4DCT, 4DPET-CT, and linac. PMID- 21302775 TI - Comparison of radiation exposure and associated radiation-induced cancer risks from mammography and molecular imaging of the breast. AB - PURPOSE: Recent studies have raised concerns about exposure to low-dose ionizing radiation from medical imaging procedures. Little has been published regarding the relative exposure and risks associated with breast imaging techniques such as breast specific gamma imaging (BSGI), molecular breast imaging (MBI), or positron emission mammography (PEM). The purpose of this article was to estimate and compare the risks of radiation-induced cancer from mammography and techniques such as PEM, BSGI, and MBI in a screening environment. METHODS: The authors used a common scheme for all estimates of cancer incidence and mortality based on the excess absolute risk model from the BEIR VII report. The lifetime attributable risk model was used to estimate the lifetime risk of radiation-induced breast cancer incidence and mortality. All estimates of cancer incidence and mortality were based on a population of 100 000 females followed from birth to age 80 and adjusted for the fraction that survives to various ages between 0 and 80. Assuming annual screening from ages 40 to 80 and from ages 50 to 80, the cumulative cancer incidence and mortality attributed to digital mammography, screen-film mammography, MBI, BSGI, and PEM was calculated. The corresponding cancer incidence and mortality from natural background radiation was calculated as a useful reference. Assuming a 15%-32% reduction in mortality from screening, the benefit/risk ratio for the different imaging modalities was evaluated. RESULTS: Using conventional doses of 925 MBq Tc-99m sestamibi for MBI and BSGI and 370 MBq F-18 FDG for PEM, the cumulative cancer incidence and mortality were found to be 15-30 times higher than digital mammography. The benefit/risk ratio for annual digital mammography was >50:1 for both the 40-80 and 50-80 screening groups, but dropped to 3:1 for the 40-49 age group. If the primary use of MBI, BSGI, and PEM is in women with dense breast tissue, then the administered doses need to be in the range 75-150 MBq for Tc-99m sestamibi and 35 MBq-70 MBq for F 18 FDG in order to obtain benefit/risk ratios comparable to those of mammography in these age groups. These dose ranges should be achievable with enhancements to current technology while maintaining a reasonable examination time. CONCLUSIONS: The results of the dose estimates in this study clearly indicate that if molecular imaging techniques are to be of value in screening for breast cancer, then the administered doses need to be substantially reduced to better match the effective doses of mammography. PMID- 21302776 TI - Monte Carlo calculation of imaging doses from diagnostic multidetector CT and kilovoltage cone-beam CT as part of prostate cancer treatment plans. AB - PURPOSE: To calculate imaging doses to the rectum, bladder, and femoral heads as part of a prostate cancer treatment plans, assuming an image guided radiation therapy (IGRT) procedure involving either the multidetector CT (MDCT) or kilovoltage cone-beam CT (kV CBCT). METHODS: This study considered an IGRT treatment plan for a prostate carcinoma patient involving 50.4 Gy from 28 initial fractions and a boost of 28.8 Gy from 16 fractions. A total of 45 CT imaging procedures, each involving a MDCT or a kV CBCT scan procedure, were carefully modeled using the MCNPX code version 2.5.0. The MDCT scanner model is based on the GE LightSpeed 16-MDCT scanner and the kV CBCT scanner model is based on the Varian On-Board Imager using parameters reported by the CT manufacturers and literatures. A patient-specific treatment planning CT data set was used to construct the phantom for the dose calculation. The target, organs-at-risk (OARs), and background voxels in the CT data set were categorized into six tissue types according to CT numbers for Monte Carlo calculations. RESULTS: For a total of 45 imaging procedures, it was found that the rectum received 78.4 and 76.7 cGy from MDCT and kV CBCT, respectively. The bladder received slightly greater doses of 82.4 and 77.9 cGy, while the femoral heads received much higher doses of 182.3 and 141.3 cGy from MDCT and kV CBCT, respectively. To investigate the impact of these imaging doses on treatment planning, OAR doses from MDCT or kV CBCT imaging procedures were added to the corresponding dose matrix reported by the original treatment plans to construct dose volume histograms. It was found that after the imaging dose is added, the rectum volumes irradiated to 75 and 70 Gy increased from 13.9% and 21.2%, respectively, in the original plan to 14.8% and 21.8%. The bladder volumes receiving 80 Gy increased to 4.6% from 4.1% in the original plan and the volume receiving 75 Gy increased to 7.9% from 7.5%. All values remained within the tolerance levels: V70<25%, V75 <15% for rectum and V75 < 25%, V80 < 15% for bladder. The irradiation of femoral heads was also acceptable with no volume receiving >45 Gy. CONCLUSIONS: IGRT procedures can irradiate the OARs to an imaging dose level that is great enough to require careful evaluation and perhaps even adjustment of original treatment planning in order to still satisfy the dose constraints. This study only considered one patient CT because the CT x rays cover a relatively larger volume of the body and the dose distribution is considerably more uniform than those associated with the therapeutic beams. As a result, the dose to an organ from CT imaging doses does not vary much from one patient to the other for the same CT settings. One factor that would potentially affect such CT dose level is the size of the patient body. More studies are needed to develop accurate and convenient methods of accounting for the imaging doses as part of treatment planning. PMID- 21302777 TI - The role of x-ray Swank factor in energy-resolving photon-counting imaging. AB - PURPOSE: Energy-resolved x-ray imaging has the potential to improve contrast-to noise ratio by measuring the energy of each interacting photon and applying optimal weighting factors. The success of energy-resolving photon-counting (EPC) detectors relies on the ability of an x-ray detector to accurately measure the energy of each interacting photon. However, the escape of characteristic emissions and Compton scatter degrades spectral information. This article makes the theoretical connection between accuracy and imprecision in energy measurements with the x-ray Swank factor for a-Se, Si, CdZnTe, and HgI2-based detectors. METHODS: For a detector that implements adaptive binning to sum all elements in which x-ray energy is deposited for a single interaction, energy imprecision is shown to depend on the Swank factor for a large element with x rays incident at the center. The response function for each converter material is determined using Monte Carlo methods and used to determine energy accuracy, Swank factor, and relative energy imprecision in photon-energy measurements. RESULTS: For each material, at energies below the respective K edges, accuracy is close to unity and imprecision is only a few percent. Above the K-edge energies, characteristic emission results in a drop in accuracy and precision that depends on escape probability. In Si, and to some extent a-Se, Compton-scatter escape also degrades energy precision with increasing energy. The influence of converter thickness on energy accuracy and imprecision is modest for low-Z materials but becomes important when using high-Z materials at energies greater than the K-edge energies. CONCLUSIONS: Accuracy and precision in energy measurements by EPC detectors are determined largely by the energy-dependent x-ray Swank factor. Modest decreases in the Swank factor (5%-15%) result in large increases in relative imprecision (30%-40%). PMID- 21302778 TI - Reconstruction of a cone-beam CT image via forward iterative projection matching. AB - PURPOSE: To demonstrate the feasibility of reconstructing a cone-beam CT (CBCT) image by deformably altering a prior fan-beam CT (FBCT) image such that it matches the anatomy portrayed in the CBCT projection data set. METHODS: A prior FBCT image of the patient is assumed to be available as a source image. A CBCT projection data set is obtained and used as a target image set. A parametrized deformation model is applied to the source FBCT image, digitally reconstructed radiographs (DRRs) that emulate the CBCT projection image geometry are calculated and compared to the target CBCT projection data, and the deformation model parameters are adjusted iteratively until the DRRs optimally match the CBCT projection data set. The resulting deformed FBCT image is hypothesized to be an accurate representation of the patient's anatomy imaged by the CBCT system. The process is demonstrated via numerical simulation. A known deformation is applied to a prior FBCT image and used to create a synthetic set of CBCT target projections. The iterative projection matching process is then applied to reconstruct the deformation represented in the synthetic target projections; the reconstructed deformation is then compared to the known deformation. The sensitivity of the process to the number of projections and the DRR/CBCT projection mismatch is explored by systematically adding noise to and perturbing the contrast of the target projections relative to the iterated source DRRs and by reducing the number of projections. RESULTS: When there is no noise or contrast mismatch in the CBCT projection images, a set of 64 projections allows the known deformed CT image to be reconstructed to within a nRMS error of 1% and the known deformation to within a nRMS error of 7%. A CT image nRMS error of less than 4% is maintained at noise levels up to 3% of the mean projection intensity, at which the deformation error is 13%. At 1% noise level, the number of projections can be reduced to 8 while maintaining CT image and deformation errors of less than 4% and 13%, respectively. The method is sensitive to contrast mismatch between the simulated projections and the target projections when the soft-tissue contrast in the projections is low. CONCLUSIONS: By using prior knowledge available in a FBCT image, the authors show that a CBCT image can be iteratively reconstructed from a comparatively small number of projection images, thus saving acquisition time and reducing imaging dose. This will enable more frequent daily imaging during radiation therapy. Because the process preserves the CT numbers of the FBCT image, the resulting 3D image intensities will be more accurate than a CBCT image reconstructed via conventional backprojection methods. Reconstruction errors are insensitive to noise at levels beyond what would typically be found in CBCT projection data, but are sensitive to contrast mismatch errors between the CBCT projection data and the DRRs. PMID- 21302780 TI - A novel off-axis scanning method for an enlarged ellipse cone-beam computed tomography field of view. AB - PURPOSE: Current on-board imaging systems commonly used by modern linear accelerators (LINACs) have a limited field of view (FOV) for a cone-beam CT (CBCT) scan, which is typically less than 50 cm. Consequently, truncation artifacts often occur for large patients. The goal of this work is to investigate a novel method to increase the FOV for current on-board CBCT systems. METHODS: When a large patient is scanned with CBCT, any region outside the FOV is only partially sampled within a short range of projection angles, and at other angles no x-ray beams may pass through that region. To increase the sampling rate for the region outside the FOV, we have designed a new source trajectory by shifting the center of rotation during a CBCT scan. This resulted in a reduced sampling rate at the central area and increased sampling rate at the edges. The tradeoff led to a more balanced sampling for an enlarged FOV. An iterative algorithm was also developed to reconstruct the CT image under the new sampling scheme using a compressed sensing technique. RESULTS: The method was validated by numerical simulations mimicking a Varian Trilogy CBCT system, and it was found that artifact-free images could be obtained with the FOV as large as 80 cm. CONCLUSIONS: The new CT scanning trajectory can be easily realized under current clinical setup with little modification of the control system, and this can be useful for treating obese patients. PMID- 21302779 TI - Joint correction of respiratory motion artifact and partial volume effect in lung/thoracic PET/CT imaging. AB - PURPOSE: Respiratory motion artifacts and partial volume effects (PVEs) are two degrading factors that affect the accuracy of image quantification in PET/CT imaging. In this article, the authors propose a joint motion and PVE correction approach (JMPC) to improve PET quantification by simultaneously correcting for respiratory motion artifacts and PVE in patients with lung/thoracic cancer. The objective of this article is to describe this approach and evaluate its performance using phantom and patient studies. METHODS: The proposed joint correction approach incorporates a model of motion blurring, PVE, and object size/shape. A motion blurring kernel (MBK) is then estimated from the deconvolution of the joint model, while the activity concentration (AC) of the tumor is estimated from the normalization of the derived MBK. To evaluate the performance of this approach, two phantom studies and eight patient studies were performed. In the phantom studies, two motion waveforms-a linear sinusoidal and a circular motion-were used to control the motion of a sphere, while in the patient studies, all participants were instructed to breathe regularly. For the phantom studies, the resultant MBK was compared to the true MBK by measuring a correlation coefficient between the two kernels. The measured sphere AC derived from the proposed method was compared to the true AC as well as the ACs in images exhibiting PVE only and images exhibiting both PVE and motion blurring. For the patient studies, the resultant MBK was compared to the motion extent derived from a 4D-CT study, while the measured tumor AC was compared to the AC in images exhibiting both PVE and motion blurring. RESULTS: For the phantom studies, the estimated MBK approximated the true MBK with an average correlation coefficient of 0.91. The tumor ACs following the joint correction technique were similar to the true AC with an average difference of 2%. Furthermore, the tumor ACs on the PVE only images and images with both motion blur and PVE effects were, on average, 75% and 47.5% (10%) of the true AC, respectively, for the linear (circular) motion phantom study. For the patient studies, the maximum and mean AC/SUV on the PET images following the joint correction are, on average, increased by 125.9% and 371.6%, respectively, when compared to the PET images with both PVE and motion. The motion extents measured from the derived MBK and 4D CT exhibited an average difference of 1.9 mm. CONCLUSIONS: The proposed joint correction approach can improve the accuracy of PET quantification by simultaneously compensating for the respiratory motion artifacts and PVE in lung/thoracic PET/CT imaging. PMID- 21302781 TI - ACCOMP: Augmented cell competition algorithm for breast lesion demarcation in sonography. AB - PURPOSE: Fully automatic and high-quality demarcation of sonographical breast lesions remains a far-reaching goal. This article aims to develop an image segmentation algorithm that provides quality delineation of breast lesions in sonography with a simple and friendly semiautomatic scheme. METHODS: A data driven image segmentation algorithm, named as augmented cell competition (ACCOMP) algorithm, is developed to delineate breast lesion boundaries in ultrasound images. Inspired by visual perceptual experience and Gestalt principles, the ACCOMP algorithm is constituted of two major processes, i.e., cell competition and cell-based contour grouping. The cell competition process drives cells, i.e., the catchment basins generated by a two-pass watershed transformation, to merge and split into prominent components. A prominent component is defined as a relatively large and homogeneous region circumscribed by a perceivable boundary. Based on the prominent component tessellation, cell-based contour grouping process seeks the best closed subsets of edges in the prominent component structure as the desirable boundary candidates. Finally, five boundary candidates with respect to five devised boundary cost functions are suggested by the ACCOMP algorithm for user selection. To evaluate the efficacy of the ACCOMP algorithm on breast lesions with complicated echogenicity and shapes, 324 breast sonograms, including 199 benign and 125 malignant lesions, are adopted as testing data. The boundaries generated by the ACCOMP algorithm are compared to manual delineations, which were confirmed by four experienced medical doctors. Four assessment metrics, including the modified Williams index, percentage statistic, overlapping ratio, and difference ratio, are employed to see if the ACCOMP-generated boundaries are comparable to manual delineations. A comparative study is also conducted by implementing two pixel-based segmentation algorithms. The same four assessment metrics are employed to evaluate the boundaries generated by two conventional pixel-based algorithms based on the same set of manual delineations. RESULTS: The ACCOMP-generated boundaries are shown to be comparable to the manual delineations. Particularly, the modified Williams indices of the boundaries generated by the ACCOMP algorithm and the first and second pixel-based algorithms are 1.069 +/- 0.024, 0.935 +/- 0.024, and 0.579 +/- 0.013, respectively. If the modified Williams index is greater than or equal to 1, the average distance between the computer-generated boundaries and manual delineations is deemed to be comparable to that between the manual delineations. CONCLUSIONS: The boundaries derived by the ACCOMP algorithm are shown to reasonably demarcate sonographic breast lesions, especially for the cases with complicated echogenicity and shapes. It suggests that the ACCOMP-generated boundaries can potentially serve as the basis for further morphological or quantitative analysis. PMID- 21302783 TI - A comprehensive study of the Gafchromic EBT2 radiochromic film. A comparison with EBT. AB - PURPOSE: Radiochromic film has become an important tool to assess complex dose distributions. In particular, EBT was accepted by the scientific community as a reference two-dimensional detector. Recently, Gafchromic EBT2 has replaced old film, providing new improvements in both accuracy and handling. METHODS: This work presents a dosimetric study of the new Gafchromic EBT2 using an Epson 10000XL flatbed scanner, also comparing the results with EBT film as reference when necessary. The most important film characteristics have been studied, such as ambient light sensitivity, different possibilities of the three RGB color channels, postirradiation development, high dose behavior, exposition at temperatures similar to the human body, and dependence on orientation during the scanning process. RESULTS: The results obtained confirm a considerably lower sensitivity to ambient light of EBT2, as well as a fast stabilization of the film within 2 h. It has also been found that the green channel has a better behavior at high dose levels up to 35 Gy, in addition to good behavior of the red channel at doses below 10 Gy. Other features, such as temperature independence and scanning orientation dependence, have also been shown. CONCLUSIONS: Gafchromic EBT2 can be used for clinical practice in the same way as the old EBT film. However, a much easier handling as the result of all new enhancements improves film behavior, expanding in this way the potential applications of radiochromic film dosimetry. PMID- 21302782 TI - A statistical, task-based evaluation method for three-dimensional x-ray breast imaging systems using variable-background phantoms. AB - PURPOSE: For the last few years, development and optimization of three dimensional (3D) x-ray breast imaging systems, such as digital breast tomosynthesis (DBT) and computed tomography, have drawn much attention from the medical imaging community, either academia or industry. However, there is still much room for understanding how to best optimize and evaluate the devices over a large space of many different system parameters and geometries. Current evaluation methods, which work well for 2D systems, do not incorporate the depth information from the 3D imaging systems. Therefore, it is critical to develop a statistically sound evaluation method to investigate the usefulness of inclusion of depth and background-variability information into the assessment and optimization of the 3D systems. METHODS: In this paper, we present a mathematical framework for a statistical assessment of planar and 3D x-ray breast imaging systems. Our method is based on statistical decision theory, in particular, making use of the ideal linear observer called the Hotelling observer. We also present a physical phantom that consists of spheres of different sizes and materials for producing an ensemble of randomly varying backgrounds to be imaged for a given patient class. Lastly, we demonstrate our evaluation method in comparing laboratory mammography and three-angle DBT systems for signal detection tasks using the phantom's projection data. We compare the variable phantom case to that of a phantom of the same dimensions filled with water, which we call the uniform phantom, based on the performance of the Hotelling observer as a function of signal size and intensity. RESULTS: Detectability trends calculated using the variable and uniform phantom methods are different from each other for both mammography and DBT systems. CONCLUSIONS: Our results indicate that measuring the system's detection performance with consideration of background variability may lead to differences in system performance estimates and comparisons. For the assessment of 3D systems, to accurately determine trade offs between image quality and radiation dose, it is critical to incorporate randomness arising from the imaging chain including background variability into system performance calculations. PMID- 21302784 TI - Evaluation of a multi-atlas based method for segmentation of cardiac CTA data: a large-scale, multicenter, and multivendor study. AB - PURPOSE: Computed tomography angiography (CTA) is increasingly used for the diagnosis of coronary artery disease (CAD). However, CTA is not commonly used for the assessment of ventricular and atrial function, although functional information extracted from CTA data is expected to improve the diagnostic value of the examination. In clinical practice, the extraction of ventricular and atrial functional information, such as stroke volume and ejection fraction, requires accurate delineation of cardiac chambers. In this paper, we investigated the accuracy and robustness of cardiac chamber delineation using a multiatlas based segmentation method on multicenter and multivendor CTA data. METHODS: A fully automatic multiatlas based method for segmenting the whole heart (i.e., the outer surface of the pericardium) and cardiac chambers from CTA data is presented and evaluated. In the segmentation approach, eight atlas images are registered to a new patient's CTA scan. The eight corresponding manually labeled images are then propagated and combined using a per voxel majority voting procedure, to obtain a cardiac segmentation. RESULTS: The method was evaluated on a multicenter/multivendor database, consisting of (1) a set of 1380 Siemens scans from 795 patients and (2) a set of 60 multivendor scans (Siemens, Philips, and GE) from different patients, acquired in six different institutions worldwide. A leave-one-out 3D quantitative validation was carried out on the eight atlas images; we obtained a mean surface-to-surface error of 0.94 +/- 1.12 mm and an average Dice coefficient of 0.93 was achieved. A 2D quantitative evaluation was performed on the 60 multivendor data sets. Here, we observed a mean surface-to surface error of 1.26 +/- 1.25 mm and an average Dice coefficient of 0.91 was achieved. In addition to this quantitative evaluation, a large-scale 2D and 3D qualitative evaluation was performed on 1380 and 140 images, respectively. Experts evaluated that 49% of the 1380 images were very accurately segmented (below 1 mm error) and that 29% were accurately segmented (error between 1 and 3 mm), which demonstrates the robustness of the presented method. CONCLUSIONS: A fully automatic method for whole heart and cardiac chamber segmentation was presented and evaluated using multicenter/multivendor CTA data. The accuracy and robustness of the method were demonstrated by successfully applying the method to 1420 multicenter/ multivendor data sets. PMID- 21302785 TI - Alanine/EPR dosimetry applied to the verification of a total body irradiation protocol and treatment planning dose calculation using a humanoid phantom. AB - PURPOSE: To avoid complications in total body irradiation (TBI), it is important to achieve a homogeneous dose distribution throughout the body and to deliver a correct dose to the lung which is an organ at risk. The purpose of this work was to validate the TBI dose protocol and to check the accuracy of the 3D dose calculations of the treatment planning system. METHODS: Dosimetry based on alanine/electron paramagnetic resonance (EPR) was used to measure dose at numerous locations within an anthropomorphic phantom (Alderson) that was irradiated in a clinical TBI beam setup. The alanine EPR dosimetry system was calibrated against water calorimetry in a Co-60 beam and the absorbed dose was determined by the use of "dose-normalized amplitudes" A(D). The dose rate of the TBI beam was checked against a Farmer ionization chamber. The phantom measurements were compared to 3D dose calculations from a treatment planning system (Pinnacle) modeled for standard dose calculations. RESULTS: Alanine dosimetry allowed accurate measurements which were in accordance with ionization chamber measurements. The combined relative standard measurement uncertainty in the Alderson phantom was U(r)(A(D))=0.6%. The humanoid phantom was irradiated to a reference dose of 10 Gy, limiting the lung dose to 7.5 Gy. The ratio of the average measured dose midplane in the craniocaudal direction to the reference dose was 1.001 with a spread of +/- 4.7% (1 sd). Dose to the lung was measured in 26 locations and found, in average, 1.8% lower than expected. Lung dose was homogeneous in the ventral-dorsal direction but a dose gradient of 0.10 Gy cm(-1) was observed in the craniocaudal direction midline within the lung lobe. 3D dose calculations (Pinnacle) were found, in average, 2% lower compared to dose measurements on the body axis and 3% lower for the lungs. CONCLUSIONS: The alanine/EPR dosimetry system allowed accurate dose measurements which enabled the authors to validate their TBI dose protocol. Dose calculations based on a collapsed cone convolution dose algorithm modeled for regular treatments are accurate within 3% and can further be improved when the algorithm is modeled for TBI. PMID- 21302786 TI - Correction of breathing-induced errors in magnetic resonance thermometry of hyperthermia using multiecho field fitting techniques. AB - PURPOSE: Breathing motion can create large errors when performing magnetic resonance (MR) thermometry of the breast. Breath holds can be used to minimize these errors, but not eliminate them. Between breath holds, the referenceless method can be used to further reduce errors by relying on regions of nonheated fatty tissue surrounding the heated region. When the surrounding tissue is heated (i.e., for a hyperthermia treatment), errors can result due to phase changes of the small amounts of water in the tissue. Therefore, an extension of the referenceless method is proposed which fits for the field in fatty tissue independent of temperature change and extrapolates it to the water-rich regions. METHODS: Nonheating experiments were performed with male volunteers performing breath holds on top of a phantom mimicking a breast with a tumor. Heating experiments were also conducted with the same phantom while mechanically simulated breath holds were performed. A nonheating experiment was also performed with a healthy female breast. For each experiment, a nonlinear fitting algorithm was used to fit for temperature change and B0 field inside of the fatty tissue. The field changes were then extrapolated into water-rich (tumor) portions of the image using a least-squares fit to a fifth-order equation, to correct for field changes due to breath hold changes. Similar results were calculated using the image phase, to mimic the use of the referenceless method. RESULTS: Phantom results showed large reduction of mean error and standard deviation. In the non heating experiments, the traditional referenceless method and our extended method both corrected by similar amounts. However, in the heating experiments, the average deviation of the temperature calculated with the extended method from a fiber optic probe temperature was approximately 50% less than the deviation with the referenceless method. The in vivo breast results demonstrated reduced standard deviation and mean. CONCLUSIONS: In this paper, we have developed an extension of the referenceless method to correct for breathing errors using multiecho fitting methods to fit for the B0 field in the fatty tissue and using measured field changes as references to extrapolate field corrections into a water-only (tumor) region. This technique has been validated in a number of situations, and in all cases, the correction method has been shown to greatly reduce temperature error in water-rich regions. The method has also been shown to be an improvement over similar methods that use image phase changes instead of field changes, particularly when temperature changes are induced. PMID- 21302787 TI - Commissioning Siemens Virtual Wedges in the Oncentra MasterPlan treatment planning system using Gafchromic EBT film. AB - PURPOSE: Virtual Wedges were introduced in Siemens LINACs to improve the treatment workflow. The aim of the present work is the validation of dose calculation by MasterPlan-Oncentra treatment planning system for virtual wedged beams. METHODS: The Oncor Siemens accelerator installed in the authors' department produces 6 and 15 MV photon beams. At first, the consistency of VW LINAC production was tested and the EBT film measuring method was verified. This method is based on the scanner uniformity correction and absolute dose calibration as reported in literature. Then, the measured and calculated wedge factors and beam profiles are compared. For 15 degrees, 30 degrees, 45 degrees, and 60 degrees wedge angles, the wedge factors for different field sizes were measured by an ionization chamber and the dose profiles were acquired by Gafchromic EBT film. Both types of measurements were collected in isocentric condition. RESULTS: The comparison between measured and calculated VW factors shows discrepancies that increase with field size and angle. The OTP Enhanced algorithm produces better agreement with measurements than the Classic one, with improvement overall visible for large angles. The agreement between measured and planned beam profiles is within limits reported by the ESTRO Booklet No. 7 in terms of confidence limits. CONCLUSIONS: The MasterPlan-Oncentra treatment planning system determines wedge factors and VW profiles within the requested accuracy in the majority of treatment conditions. For big field dimensions and wedge angle, wedge factor accordance was worse, but it may be increased with an improvement of the LINAC dosimetric board calibration. PMID- 21302788 TI - Direct three-dimensional coherently scattered x-ray microtomography. AB - PURPOSE: It has been shown that coherently scattered x rays can be used to discriminate and identify specific components in a mixture of low atomic weight materials. The authors demonstrated a new method of doing coherently scattered x ray tomography with a thin sheet of x ray. METHODS: A collimated x-ray fan-beam, a parallel polycapillary collimator, and a phantom consisting of several biocompatible materials of low attenuation-based contrast were used to investigate the feasibility of the method. Because of the particular experimental setup, only the phantom translation perpendicular to the x-ray beam is needed and, thus, there is no need of Radon-type tomographic reconstruction, except for the correction of the attenuation to the primary and scattered x rays, which was performed by using a conventional attenuation-based tomographic image data set. The coherent scatter image contrast changes with momentum transfer among component materials in the specimen were investigated with multiple x-ray sources with narrow bandwidth spectra generated with anode and filter combinations of Cu/Ni (8 keV), Mo/Zr (18 keV), and Ag/Pd (22 keV) and at multiple scatter angles by orienting the detector and polycapillary collimator at different angles to the illuminating x ray. RESULTS: The contrast among different materials changes with the x-ray source energy and the angle at which the image was measured. The coherent scatter profiles obtained from the coherent scatter images are consistent with the published results. CONCLUSIONS: This method can be used to directly generate the three-dimensional coherent scatter images of small animal, biopsies, or other small objects with low atomic weight biological or similar synthetic materials with low attenuation contrast. With equipment optimized, submillimeter spatial resolution may be achieved. PMID- 21302789 TI - Computerized quantitative evaluation of mammographic accreditation phantom images. AB - PURPOSE: The objective was to develop and investigate an automated scoring scheme of the American College of Radiology (ACR) mammographic accreditation phantom (RMI 156, Middleton, WI) images. METHODS: The developed method consisted of background subtraction, determination of region of interest, classification of fiber and mass objects by Mahalanobis distance, detection of specks by template matching, and rule-based scoring. Fifty-one phantom images were collected from 51 facilities for this study (one facility provided one image). A medical physicist and two radiologic technologists also scored the images. The human and computerized scores were compared. RESULTS: In terms of meeting the ACR's criteria, the accuracies of the developed method for computerized evaluation of fiber, mass, and speck were 90%, 80%, and 98%, respectively. Contingency table analysis revealed significant association between observer and computer scores for microcalcifications (p<5%) but not for masses and fibers. CONCLUSIONS: The developed method may achieve a stable assessment of visibility for test objects in mammographic accreditation phantom image in whether the phantom image meets the ACR's criteria in the evaluation test, although there is room left for improvement in the approach for fiber and mass objects. PMID- 21302790 TI - Optimal shielding design for bunkers of compact cyclotrons used in the production of medical radionuclides. AB - PURPOSE: There are several options to consider in the design of a vault that will house a cyclotron for radioisotopes production with regards to the door entrance. Alternatives are a direct-shielded door, a simple maze, or a double-legged maze. In this work, the impact of the neutron and photon doses at the vault entrance was evaluated for these options. METHODS: Monte Carlo simulations were carried out in order to assess photon and neutron ambient dose equivalents. Simulations results were compared to experimental measurements taken inside a vault with a direct-shielded door. RESULTS: The double-legged maze is the configuration that provides the higher degree of radiological protection at the vault entrance. In addition, the fact of the location of the cyclotron target plays an important role in the ambient dose equivalents. CONCLUSIONS: The comparison performed between measurements and results of MCNP simulations confirmed a favorable agreement; maze legs reduce the neutron energies at the entrances of the vault. However, a degree of dose reduction similar to the one obtained for a two-legged maze can be achieved with the addition of shielding against neutrons in the inner maze entrance to act as a second door. A choice of a vault design is more evident by comparing the results of this study. PMID- 21302791 TI - Combining registration and active shape models for the automatic segmentation of the lymph node regions in head and neck CT images. AB - PURPOSE: Intensity-modulated radiation therapy (IMRT) is the state of the art technique for head and neck cancer treatment. It requires precise delineation of the target to be treated and structures to be spared, which is currently done manually. The process is a time-consuming task of which the delineation of lymph node regions is often the longest step. Atlas-based delineation has been proposed as an alternative, but, in the authors' experience, this approach is not accurate enough for routine clinical use. Here, the authors improve atlas-based segmentation results obtained for level II-IV lymph node regions using an active shape model (ASM) approach. METHODS: An average image volume was first created from a set of head and neck patient images with minimally enlarged nodes. The average image volume was then registered using affine, global, and local nonrigid transformations to the other volumes to establish a correspondence between surface points in the atlas and surface points in each of the other volumes. Once the correspondence was established, the ASMs were created for each node level. The models were then used to first constrain the results obtained with an atlas based approach and then to iteratively refine the solution. RESULTS: The method was evaluated through a leave-one-out experiment. The ASM- and atlas-based segmentations were compared to manual delineations via the Dice similarity coefficient (DSC) for volume overlap and the Euclidean distance between manual and automatic 3D surfaces. The mean DSC value obtained with the ASM-based approach is 10.7% higher than with the atlas-based approach; the mean and median surface errors were decreased by 13.6% and 12.0%, respectively. CONCLUSIONS: The ASM approach is effective in reducing segmentation errors in areas of low CT contrast where purely atlas-based methods are challenged. Statistical analysis shows that the improvements brought by this approach are significant. PMID- 21302792 TI - Acoustic radiation force contrast in MRI: detection of calcifications in tissue mimicking phantoms. AB - PURPOSE: Mammography is a widely used tool for the screening of breast cancer, and calcifications are a common finding in most mammograms. The location, size, number, morphology, and distribution of calcifications are an important information to differentiate a benign lesion from probably malignant pathologies. Calcifications are not detectable with a standard dynamic contrast enhanced breast MRI. The authors present a novel method for the detection and imaging of calcifications in breast tissue without ionizing radiation or contrast agents. METHODS: Measurements of localized tissue displacement in phantoms due to applied acoustic radiation force were performed. This displacement was imaged with a displacement sensitive spin-echo MRI sequence. Pieces of eggshell that represent calcifications were embedded in tissue-mimicking agarose phantoms. The sizes of the calcifications were 0.8 x 0.8 x 0.4, 1.5 x 1.5 x 0.4, and 2 x 3 x 0.4 mm3. The calcifications were scanned with ultrasound (U.S.) at 2.5 MHz and intensities up to I(spta) =7.18 W/cm2. The U.S. beam was moved inside the phantom by a computer-controlled three-dimensional hydraulic positioning system. The U.S. beam was scanned over the two smaller calcifications with the displacement sensitivity of the MRI sequence parallel to the U.S. beam path. Grayscale coded maps of the displacement scans are presented. For the 0.8 x 0.8 x 0.4 mm3 calcification, the U.S. intensities were varied. Finite element simulations were performed to verify if the experiments complied with theory. RESULTS: The authors found that the displacement caused by the U.S. is increased at the position of the calcification. The area of increased displacement is at least twice as large as the calcification itself. The simulations show this increase in displacement and area at the position of the calcification. When changing the displacement sensitivity direction to perpendicular to the U.S. beam, a crossed black and white four-leaf clover is visible at the position of the calcification. CONCLUSIONS: The U.S. is scattered and reflected by the calcifications. This leads to the increased displacement which is transmitted to the surrounding material because of the elastic coupling between the calcification and the agarose material. Due to the high differences in acoustic impedance and elastic properties between the surrounding tissue and the calcification, even the detection of pieces smaller than the resolution of the MRI scanner is possible. The acoustic radiation force contrast in MR phase-difference images offers a positive signal for calcifications from a smooth background in phantoms. This method offers a possibility of differentiating qualitatively and quantitatively hard calcifications from stiffer inclusions such as tumors. PMID- 21302793 TI - Telerobotic system concept for real-time soft-tissue imaging during radiotherapy beam delivery. AB - PURPOSE: The curative potential of external beam radiation therapy is critically dependent on having the ability to accurately aim radiation beams at intended targets while avoiding surrounding healthy tissues. However, existing technologies are incapable of real-time, volumetric, soft-tissue imaging during radiation beam delivery, when accurate target tracking is most critical. The authors address this challenge in the development and evaluation of a novel, minimally interfering, telerobotic ultrasound (U.S.) imaging system that can be integrated with existing medical linear accelerators (LINACs) for therapy guidance. METHODS: A customized human-safe robotic manipulator was designed and built to control the pressure and pitch of an abdominal U.S. transducer while avoiding LINAC gantry collisions. A haptic device was integrated to remotely control the robotic manipulator motion and U.S. image acquisition outside the LINAC room. The ability of the system to continuously maintain high quality prostate images was evaluated in volunteers over extended time periods. Treatment feasibility was assessed by comparing a clinically deployed prostate treatment plan to an alternative plan in which beam directions were restricted to sectors that did not interfere with the transabdominal U.S. transducer. To demonstrate imaging capability concurrent with delivery, robot performance and U.S. target tracking in a phantom were tested with a 15 MV radiation beam active. RESULTS: Remote image acquisition and maintenance of image quality with the haptic interface was successfully demonstrated over 10 min periods in representative treatment setups of volunteers. Furthermore, the robot's ability to maintain a constant probe force and desired pitch angle was unaffected by the LINAC beam. For a representative prostate patient, the dose-volume histogram (DVH) for a plan with restricted sectors remained virtually identical to the DVH of a clinically deployed plan. With reduced margins, as would be enabled by real-time imaging, gross tumor volume coverage was identical while notable reductions of bladder and rectal volumes exposed to large doses were possible. The quality of U.S. images obtained during beam operation was not appreciably degraded by radiofrequency interference and 2D tracking of a phantom object in U.S. images obtained with the beam on/off yielded no significant differences. CONCLUSIONS: Remotely controlled robotic U.S. imaging is feasible in the radiotherapy environment and for the first time may offer real-time volumetric soft-tissue guidance concurrent with radiotherapy delivery. PMID- 21302794 TI - An eight-channel transmit/receive multipurpose coil for musculoskeletal MR imaging at 7 T. AB - PURPOSE: MRI plays a leading diagnostic role in assessing the musculoskeletal (MSK) system and is well established for most questions at clinically used field strengths (up to 3 T). However, there are still limitations in imaging early stages of cartilage degeneration, very fine tendons and ligaments, or in locating nerve lesions, for example. 7 T MRI of the knee has already received increasing attention in the current published literature, but there is a strong need to develop new radiofrequency (RF) coils to assess more regions of the MSK system. In this work, an eight-channel transmit/receive RF array was built as a multipurpose coil for imaging some of the thus far neglected regions. An extensive coil characterization protocol and first in vivo results of the human wrist, shoulder, elbow, knee, and ankle imaged at 7 T will be presented. METHODS: Eight surface loop coils with a dimension of 6 x 7 cm2 were machined from FR4 circuit board material. To facilitate easy positioning, two coil clusters, each with four loop elements, were combined to one RF transmit/receive array. An overlapped and shifted arrangement of the coil elements was chosen to reduce the mutual inductance between neighboring coils. A phantom made of body-simulating liquid was used for tuning and matching on the bench. Afterward, the S-parameters were verified on a human wrist, elbow, and shoulder. For safety validation, a detailed compliance test was performed including full wave simulations of the RF field distribution and the corresponding specific absorption rate (SAR) for all joints. In vivo images of four volunteers were assessed with gradient echo and spin echo sequences modified to obtain optimal image contrast, full anatomic coverage, and the highest spatial resolution within a reasonable acquisition time. The performance of the RF coil was additionally evaluated by in vivo B1 mapping. RESULTS: A comparison of B1 per unit power, flip angle distribution, and anatomic images showed a fairly homogeneous excitation for the smaller joints (elbow, wrist, and ankle), while for the larger joints, the shoulder and especially the knee, B1 inhomogeneities and limited penetration depth were more pronounced. However, the greater part of the shoulder joint could be imaged. In vivo images rendered very fine anatomic details such as fascicles of the median nerve and the branching of the nerve bundles. High-resolution images of cartilage, labrum, and tendons could be acquired. Additionally, turbo spin echo (TSE) and inversion recovery sequences performed very well. CONCLUSIONS: This study demonstrates that the concept of two four-channel transmit/receive RF arrays can be used as a multipurpose coil for high-resolution in vivo MR imaging of the musculoskeletal system at 7 T. Not only gradient echo but also typical clinical and SAR-intensive sequences such as STIR and TSE performed well. Imaging of small structures and peripheral nerves could in particular benefit from this technique. PMID- 21302795 TI - Three-dimensional tracking of cardiac catheters using an inverse geometry x-ray fluoroscopy system. AB - PURPOSE: Scanning beam digital x-ray (SBDX) is an inverse geometry fluoroscopic system with high dose efficiency and the ability to perform continuous real-time tomosynthesis at multiple planes. This study describes a tomosynthesis-based method for 3D tracking of high-contrast objects and present the first experimental investigation of cardiac catheter tracking using a prototype SBDX system. METHODS: The 3D tracking algorithm utilizes the stack of regularly spaced tomosynthetic planes that are generated by SBDX after each frame period (15 frames/s). Gradient-filtered versions of the image planes are generated, the filtered images are segmented into object regions, and then a 3D coordinate is calculated for each object region. Two phantom studies of tracking performance were conducted. In the first study, an ablation catheter in a chest phantom was imaged as it was pulled along a 3D trajectory defined by a catheter sheath (10, 25, and 50 mm/s pullback speeds). SBDX tip tracking coordinates were compared to the 3D trajectory of the sheath as determined from a CT scan of the phantom after the registration of the SBDX and CT coordinate systems. In the second study, frame-to-frame tracking precision was measured for six different catheter configurations as a function of image noise level (662-7625 photons/mm2 mean detected x-ray fluence at isocenter). RESULTS: During catheter pullbacks, the 3D distance between the tracked catheter tip and the sheath centerline was 1.0 +/- 0.8 mm (mean +/- one standard deviation). The electrode to centerline distances were comparable to the diameter of the catheter tip (2.3 mm), the confining sheath (4 mm outside diameter), and the estimated SBDX-to-CT registration error (+/- 0.7 mm). The tip position was localized for all 332 image frames analyzed and 83% of tracked positions were inside the 3D sheath volume derived from CT. The pullback speeds derived from the catheter trajectories were within 5% of the programed pullback speeds. The tracking precision of ablation and diagnostic catheter tips ranged from +/- 0.2 mm at the highest image fluence to +/- 0.9 mm at the lowest fluence. Tracking precision depended on image fluence, the size of the tracked catheter electrode, and the contrast of the electrode. CONCLUSIONS: High speed multiplanar tomosynthesis with an inverse geometry x-ray fluoroscopy system enables 3D tracking of multiple high-contrast objects at the rate of fluoroscopic imaging. The SBDX system is capable of tracking electrodes in standard cardiac catheters with approximately 1 mm accuracy and precision. PMID- 21302796 TI - Automatic anatomy recognition via multiobject oriented active shape models. AB - PURPOSE: This paper studies the feasibility of developing an automatic anatomy recognition (AAR) system in clinical radiology and demonstrates its operation on clinical 2D images. METHODS: The anatomy recognition method described here consists of two main components: (a) multiobject generalization of OASM and (b) object recognition strategies. The OASM algorithm is generalized to multiple objects by including a model for each object and assigning a cost structure specific to each object in the spirit of live wire. The delineation of multiobject boundaries is done in MOASM via a three level dynamic programming algorithm, wherein the first level is at pixel level which aims to find optimal oriented boundary segments between successive landmarks, the second level is at landmark level which aims to find optimal location for the landmarks, and the third level is at the object level which aims to find optimal arrangement of object boundaries over all objects. The object recognition strategy attempts to find that pose vector (consisting of translation, rotation, and scale component) for the multiobject model that yields the smallest total boundary cost for all objects. The delineation and recognition accuracies were evaluated separately utilizing routine clinical chest CT, abdominal CT, and foot MRI data sets. The delineation accuracy was evaluated in terms of true and false positive volume fractions (TPVF and FPVF). The recognition accuracy was assessed (1) in terms of the size of the space of the pose vectors for the model assembly that yielded high delineation accuracy, (2) as a function of the number of objects and objects' distribution and size in the model, (3) in terms of the interdependence between delineation and recognition, and (4) in terms of the closeness of the optimum recognition result to the global optimum. RESULTS: When multiple objects are included in the model, the delineation accuracy in terms of TPVF can be improved to 97%-98% with a low FPVF of 0.1%-0.2%. Typically, a recognition accuracy of > or = 90% yielded a TPVF > or = 95% and FPVF < or = 0.5%. Over the three data sets and over all tested objects, in 97% of the cases, the optimal solutions found by the proposed method constituted the true global optimum. CONCLUSIONS: The experimental results showed the feasibility and efficacy of the proposed automatic anatomy recognition system. Increasing the number of objects in the model can significantly improve both recognition and delineation accuracy. More spread out arrangement of objects in the model can lead to improved recognition and delineation accuracy. Including larger objects in the model also improved recognition and delineation. The proposed method almost always finds globally optimum solutions. PMID- 21302797 TI - An automatic and accurate x-ray tube focal spot/grid alignment system for mobile radiography: system description and alignment accuracy. AB - PURPOSE: A mobile radiography automatic grid alignment system (AGAS) has been developed by modifying a commercially available mobile unit. The objectives of this article are to describe the modifications and operation and to report on the accuracy with which the focal spot is aligned to the grid and the time required to achieve the alignment. METHODS: The modifications include an optical target arm attached to the grid tunnel, a video camera attached to the collimator, a motion control system with six degrees of freedom to position the collimator and x-ray tube, and a computer to control the system. The video camera and computer determine the grid position, and then the motion control system drives the x-ray focal spot to the center of the grid focal axis. The accuracy of the alignment of the focal spot with the grid and the time required to achieve alignment were measured both in laboratory tests and in clinical use. RESULTS: For a typical exam, the modified unit automatically aligns the focal spot with the grid in less than 10 s, with an accuracy of better than 4 mm. The results of the speed and accuracy tests in clinical use were similar to the results in laboratory tests. Comparison patient chest images are presented--one obtained with a standard mobile radiographic unit without a grid and the other obtained with the modified unit and a 15:1 grid. The 15:1 grid images demonstrate a marked improvement in image quality compared to the nongrid images with no increase in patient dose. CONCLUSIONS: The mobile radiography AGAS produces images of significantly improved quality compared to nongrid images with alignment times of less than 10 s and no increase in patient dose. PMID- 21302798 TI - A method of estimating conceptus doses resulting from multidetector CT examinations during all stages of gestation. AB - PURPOSE: Current methods for the estimation of conceptus dose from multidetector CT (MDCT) examinations performed on the mother provide dose data for typical protocols with a fixed scan length. However, modified low-dose imaging protocols are frequently used during pregnancy. The purpose of the current study was to develop a method for the estimation of conceptus dose from any MDCT examination of the trunk performed during all stages of gestation. METHODS: The Monte Carlo N Particle (MCNP) radiation transport code was employed in this study to model the Siemens Sensation 16 and Sensation 64 MDCT scanners. Four mathematical phantoms were used, simulating women at 0, 3, 6, and 9 months of gestation. The contribution to the conceptus dose from single simulated scans was obtained at various positions across the phantoms. To investigate the effect of maternal body size and conceptus depth on conceptus dose, phantoms of different sizes were produced by adding layers of adipose tissue around the trunk of the mathematical phantoms. To verify MCNP results, conceptus dose measurements were carried out by means of three physical anthropomorphic phantoms, simulating pregnancy at 0, 3, and 6 months of gestation and thermoluminescence dosimetry (TLD) crystals. RESULTS: The results consist of Monte Carlo-generated normalized conceptus dose coefficients for single scans across the four mathematical phantoms. These coefficients were defined as the conceptus dose contribution from a single scan divided by the CTDI free-in-air measured with identical scanning parameters. Data have been produced to take into account the effect of maternal body size and conceptus position variations on conceptus dose. Conceptus doses measured with TLD crystals showed a difference of up to 19% compared to those estimated by mathematical simulations. CONCLUSIONS: Estimation of conceptus doses from MDCT examinations of the trunk performed on pregnant patients during all stages of gestation can be made using the method developed in the current study. PMID- 21302799 TI - In vivo small animal imaging: current status and future prospects. AB - The use of small animal models in basic and preclinical sciences constitutes an integral part of testing new pharmaceutical agents prior to commercial translation to clinical practice. Whole-body small animal imaging is a particularly elegant and cost-effective experimental platform for the timely validation and commercialization of novel agents from the bench to the bedside. Biomedical imaging is now listed along with genomics, proteomics, and metabolomics as an integral part of biological and medical sciences. Miniaturized versions of clinical diagnostic modalities, including but not limited to microcomputed tomography, micromagnetic resonance tomography, microsingle-photon emission tomography, micropositron-emission tomography, optical imaging, digital angiography, and ultrasound, have all greatly improved our investigative abilities to longitudinally study various experimental models of human disease in mice and rodents. After an exhaustive literature search, the authors present a concise and critical review of in vivo small animal imaging, focusing on currently available modalities as well as emerging imaging technologies on one side and molecularly targeted contrast agents on the other. Aforementioned scientific topics are analyzed in the context of cancer angiogenesis and innovative antiangiogenic strategies under-the-way to the clinic. Proposed hybrid approaches for diagnosis and targeted site-specific therapy are highlighted to offer an intriguing glimpse of the future. PMID- 21302800 TI - An algorithm for fast beam angle selection in intensity modulated radiotherapy. AB - PURPOSE: This article aims to introduce a novel algorithm for fast beam angle selection in intensity modulated radiotherapy (IMRT). METHODS: The algorithm models the optimization problem as a beam angle ranking problem and chooses suitable beam angles according to their rank. A new parameter called "beam intensity profile perturbation score (BIPPS)" is used for ranking the beam angles. The BIPPS-based beam angle ranking implicitly accounts for the dose volume effects of the involved structures. A simulated phantom case with obvious optimal beam angles is used to verify the validity of the presented technique. In addition, the efficiency of the algorithm was examined in three clinical cases (prostate, pancreas, and head and neck) in terms of DVH and dose distribution. In all cases, the judgment of the algorithm's efficiency was based on the comparison between plans with equidistant beams (equal-angle-plan) and plans with beams obtained using the algorithm (suitable-angle-plan). RESULTS: It is observed from the study that the beam angle ranking function over BIPPS instantly picks up a suitable set of beam angles for a specific case. It takes only about 15 min for choosing the suitable beam angles even for the most complicated cases. The DVHs and dose distributions confirm that the proposed algorithm can efficiently reduce the mean or maximum dose to OARs, while guaranteeing the target coverage and dose uniformity. On the average, about 17% reduction in the mean dose to critical organs, such as rectum, bladder, kidneys and parotids, is observed. Also, about 12% (averaged) reduction in the maximum dose to critical organs (spinal cord) is observed in the clinical cases presented in this study. CONCLUSIONS: This study demonstrates that the algorithm can be effectively applied to IMRT scenarios to get fast and case specific beam angle configurations. PMID- 21302801 TI - Estimation and correction of cardiac respiratory motion in SPECT in the presence of limited-angle effects due to irregular respiration. AB - PURPOSE: One issue with amplitude binning list-mode studies in SPECT for respiratory motion correction is that variation in the patient's respiratory pattern will result in binned motion states with little or no counts at various projection angles. The reduced counts result in limited-angle reconstruction artifacts which can impact the accuracy of the necessary motion estimation needed to correct the images. In this work, the authors investigate a method to overcome the effect of limited-angle reconstruction artifacts in SPECT when estimating respiratory motion. METHODS: In the first pass of the reconstruction method, only the projection angles with significant counts in common between the binned respiratory states are used in order to better estimate the motion between them. After motion estimation, the estimates are used to correct for motion within iterative reconstruction using all of the acquired projection data. RESULTS: Using simulated SPECT studies based on the NCAT phantom, the authors demonstrate the problem caused by having data available for only a limited number of angles when estimating motion and the utility of the proposed method in diminishing this error. For NCAT data sets with a clinically appropriate level of Poisson noise, the average registration error for motion with the proposed method was always less with the use of their algorithm, the reduction being statistically significant (p<0.05) in the majority of cases. The authors illustrate the ability of their method to correct the degradations caused by respiratory motion in short axis slices and polar maps of the NCAT phantom for cases with 1 and 2 cm amplitudes of respiratory motion. In four cardiac-perfusion patients acquired on the same day, the authors demonstrate the large variability of the number of counts in the amplitude-binned projections. Finally, the authors demonstrate a visual improvement in the slices and polar maps of patient studies with the algorithm for respiratory motion correction. CONCLUSIONS: The authors' method shows promise in reducing errors in respiratory motion estimation despite the presence of limited-angle reconstruction effects due to irregularity in respiration. Improvements in image quality were observed in both simulated and clinical studies. PMID- 21302802 TI - Failure mode and effect analysis-based quality assurance for dynamic MLC tracking systems. AB - PURPOSE: To develop and implement a failure mode and effect analysis (FMEA)-based commissioning and quality assurance framework for dynamic multileaf collimator (DMLC) tumor tracking systems. METHODS: A systematic failure mode and effect analysis was performed for a prototype real-time tumor tracking system that uses implanted electromagnetic transponders for tumor position monitoring and a DMLC for real-time beam adaptation. A detailed process tree of DMLC tracking delivery was created and potential tracking-specific failure modes were identified. For each failure mode, a risk probability number (RPN) was calculated from the product of the probability of occurrence, the severity of effect, and the detectibility of the failure. Based on the insights obtained from the FMEA, commissioning and QA procedures were developed to check (i) the accuracy of coordinate system transformation, (ii) system latency, (iii) spatial and dosimetric delivery accuracy, (iv) delivery efficiency, and (v) accuracy and consistency of system response to error conditions. The frequency of testing for each failure mode was determined from the RPN value. RESULTS: Failures modes with RPN > or = 125 were recommended to be tested monthly. Failure modes with RPN < 125 were assigned to be tested during comprehensive evaluations, e.g., during commissioning, annual quality assurance, and after major software/hardware upgrades. System latency was determined to be approximately 193 ms. The system showed consistent and accurate response to erroneous conditions. Tracking accuracy was within 3%-3 mm gamma (100% pass rate) for sinusoidal as well as a wide variety of patient-derived respiratory motions. The total time taken for monthly QA was approximately 35 min, while that taken for comprehensive testing was approximately 3.5 h. CONCLUSIONS: FMEA proved to be a powerful and flexible tool to develop and implement a quality management (QM) framework for DMLC tracking. The authors conclude that the use of FMEA-based QM ensures efficient allocation of clinical resources because the most critical failure modes receive the most attention. It is expected that the set of guidelines proposed here will serve as a living document that is updated with the accumulation of progressively more intrainstitutional and interinstitutional experience with DMLC tracking. PMID- 21302803 TI - A comparative analysis of OTF, NPS, and DQE in energy integrating and photon counting digital x-ray detectors. AB - PURPOSE: One of the benefits of photon counting (PC) detectors over energy integrating (EI) detectors is the absence of many additive noise sources, such as electronic noise and secondary quantum noise. The purpose of this work is to demonstrate that thresholding voltage gains to detect individual x rays actually generates an unexpected source of white noise in photon counters. METHODS: To distinguish the two detector types, their point spread function (PSF) is interpreted differently. The PSF of the energy integrating detector is treated as a weighting function for counting x rays, while the PSF of the photon counting detector is interpreted as a probability. Although this model ignores some subtleties of real imaging systems, such as scatter and the energy-dependent amplification of secondary quanta in indirect-converting detectors, it is useful for demonstrating fundamental differences between the two detector types. From first principles, the optical transfer function (OTF) is calculated as the continuous Fourier transform of the PSF, the noise power spectra (NPS) is determined by the discrete space Fourier transform (DSFT) of the autocovariance of signal intensity, and the detective quantum efficiency (DQE) is found from combined knowledge of the OTF and NPS. To illustrate the calculation of the transfer functions, the PSF is modeled as the convolution of a Gaussian with the product of rect functions. The Gaussian reflects the blurring of the x-ray converter, while the rect functions model the sampling of the detector. RESULTS: The transfer functions are first calculated assuming outside noise sources such as electronic noise and secondary quantum noise are negligible. It is demonstrated that while OTF is the same for two detector types possessing an equivalent PSF, a frequency-independent (i.e., "white") difference in their NPS exists such that NPS(PC) > or = NPS(EI) and hence DQE(PC) < or = DQE(EI). The necessary and sufficient condition for equality is that the PSF is a binary function given as zero or unity everywhere. In analyzing the model detector with Gaussian blurring, the difference in NPS and DQE between the two detector types is found to increase with the blurring of the x-ray converter. Ultimately, the expression for the additive white noise of the photon counter is compared against the expression for electronic noise and secondary quantum noise in an energy integrator. Thus, a method is provided to determine the average secondary quanta that the energy integrator must produce for each x ray to have superior DQE to a photon counter with the same PSF. CONCLUSIONS: This article develops analytical models of OTF, NPS, and DQE for energy integrating and photon counting digital x ray detectors. While many subtleties of real imaging systems have not been modeled, this work is illustrative in demonstrating an additive source of white noise in photon counting detectors which has not yet been described in the literature. One benefit of this analysis is a framework for determining the average secondary quanta that an energy integrating detector must produce for each x ray to have superior DQE to competing photon counting technology. PMID- 21302804 TI - Comment on "A gamma dose distribution evaluation technique using the k-d tree for nearest neighbor searching" [Med. Phys. 37, 4868-4873 (2010)]. PMID- 21302805 TI - Comment on "On the insensitivity of single field planar dosimetry to IMRT inaccuracies" [Med. Phys. 37, 2516-2524 (2010)]. PMID- 21302806 TI - Cancer: a novel "no-nonsense" approach to treatment. AB - Nonsense mutations, which lead to premature termination codons, are prevalent in a wide variety of cancers and many studies highlight clear evidence of functions. Based on these observations, a strategy is proposed for using various natural and synthetic derivatives based on aminoglycosides and their conjugates that have the unique property of read-through of nonsense mutations. The results and current status of this group of drugs are presented to show their effectiveness in treating other nonsense-codon-mediated diseases unrelated to cancer such as cystic fibrosis, thalassaemia, and muscular dystrophy. Concluding remarks indicate that this novel approach to cancer treatment with relatively low toxicity and reversibility of drug action as well as potential good patient acceptance and compliance ought to be now trialed for use in treating a wide variety of cancers. PMID- 21302807 TI - Hepatoma-derived growth factor regulates the bad-mediated apoptotic pathway and induction of vascular endothelial growth factor in stomach cancer cells. AB - Hepatoma-derived growth factor (HDGF) is highly expressed in tumor cells and may play an important role in the development and progression of carcinomas. However, the molecular mechanism by which HDGF participates in gastric carcinomatosis requires further analysis. In this study, we determined the role of HDGF in tumorigenesis and elucidated the mechanisms of action. To determine aggressive biological behavior, we knocked down HDGF expression with HDGF-specific shRNA in two gastric cancer cell lines. First, using cDNA microarrary, we showed that hepatocyte growth factor (HGF) induced HDGF and confirmed this by Western blotting. HGF increased HDGF in a dose-dependent manner. We also determined whether HDGF induces angiogenic factor, and found the vascular endothelial growth factor (VEGF) was induced by HDGF. Downregulation of HDGF resulted in a decrement of VEGF. HDGF knock-down was found to induce the expression of the proapoptotic protein, Bad, and also inactivate ERK, which in turn led to dephosphorylation of Bad at ser112 and ser136, and induced apoptosis. Transfection with HDGF-siRNA resulted in a decrement of cell proliferation, as determined with a MMT assay. In an in vitro invasion assay, significantly fewer cells transfected with HDGF-siRNA than control cells were able to invade across a Matrigel membrane barrier. Our results suggest that HDGF is involved in cell growth, cell invasion, and apoptosis. These qualities may contribute to the HDGF-associated aggressive biological behavior of gastric cancer and thus serve as a potential target for cancer therapy. PMID- 21302808 TI - Downregulation of protein kinase Calpha was involved in selenite-induced apoptosis of NB4 cells. AB - We revealed in our previous research that sodium selenite induced obvious apoptosis of human leukemia NB4 cells, with reactive oxygen species (ROS), mitochondrial apoptosis pathway, and endoplasmic reticulum stress (ER stress) involved. In the present study, we revealed protein kinase Ca (PKCalpha) was dramatically downregulated in selenite-induced apoptosis, which was mediated by ROS. Besides, we confirmed PKCalpha played an antiapoptotic role through its effects on ERK1/2 and Akt, while its downregulation was attributed to caspase-3 and PP2Ac under the regulation of ROS. In summary, we speculated that in apoptosis of NB4 cells induced by selenite, PKCalpha functioned to counteract apoptosis, thus its downregulation seemed a mechanism aggravating apoptosis. PMID- 21302809 TI - Invadopodia formation by bladder tumor cells. AB - A major cause of death in patients with bladder tumors is recurrence with metastasis. Bladder tumor metastasis is largely dependent upon the invasive capacity of tumor cells. Tumor cell invasion is mainly mediated by actin-rich protrusive membrane structures called invadopodia. The formation of invadopodia was observed in various types of invasive tumors such as breast cancer and melanomas. However, invadopodia formation so far has not been described in bladder tumor cells. We here report that human bladder tumor cells form functionally active invadopodia. By using a confocal laser scanning microscope, we demonstrated that invasive bladder tumor cell lines, YTS-1 and T24, with high Matrigel degradation activity form invadopodia but that noninvasive bladder tumor cell lines, RT4 and KK-47, form no detectable invadopodia. Invadopodia formed by YTS-1 cells had the ability to secrete matrix metalloproteases and degrade extracellular matrix to invade surrounding areas. Moreover, we observed that primary tumor cells obtained from patients with invasive bladder tumors also form invadopodia, validating the results from bladder tumor cell lines. Our results provide evidence that invasive human bladder tumor cells form invadopodia for tumor invasion. PMID- 21302810 TI - Tumor MET expression may not predict the risk of venous thromboembolism in cancer patients. AB - Venous thromboembolism (VTE) occurs at an increased incidence in cancer patients. A cancer-related hypercoagulable state has been considered to play role in this phenomenon. Preclinical data suggest an association between tumor expression of MET proto-oncogene (MET) and a hypercoagulable state, resulting in VTE. We investigated this association in this retrospective study. Thirty-five cancer patients with documented VTE and no relevant predisposing factors were compared with 35 matched cancer patients without VTE who served as controls. Pathology specimens of all patients and controls were stained by immunohistochemistry (IHC) for MET protein. Intensity of reactivity to the MET antibody was read as 0 (negative), 1+ (equivocal), and 2+ (positive). The pathologists were blinded to the patient VTE status. The MET reactivity in tissue sections were compared between the two cohorts. No significant difference was observed between the two groups for MET expression. This study's findings indicate no association between the reactivity for MET protein as measured through an immunohistochemical technique, and the incidence of VTE in cancer patients. PMID- 21302811 TI - Mutations in the HD and PEST domain of Notch-1 receptor in T-cell acute lymphoblastic leukemia: report of novel mutations from Indian population. AB - Notch-1 is a transmembrane receptor protein that directs T-cell differentiation. Gain-of-function mutations in Notch-1 have been reported in more than 50% of human T-cell acute lymphoblastic leukemia (T-ALL). The current study was undertaken to characterize mutations in the heterodimerization (HD) domain and proline, glutamic acid, serine, threonine-rich (PEST) domain of the Notch-1 receptor. RNA was isolated from peripheral blood/bone marrow of 15 de novo T-ALL subjects; the Notch-1 HD and PEST regions were amplified and sequenced. Overall six patients (40%) had at least one Notch-1 mutation, 2/15 (13%) in the HD and 4/15 (27%) in the PEST domain. None of the samples showed simultaneous mutations in HD and PEST domains. Mutations were seen in 4/10 adult patients (40%); in the pediatric cohort 2/5 (40%) had mutations both of which were in the PEST domain. Of the different mutations, two have been previously reported and the other four are novel. A high incidence of Notch-1 mutations has been seen; unlike other studies, a higher frequency of mutations was found in PEST domain. The current study also served to identify four novel mutants that add new insights into the genetic heterogeneity of T-ALL. More ongoing larger studies are warranted to elucidate the molecular pathogenesis of T-ALL that arises in this part of the world. PMID- 21302812 TI - Frequency, not relative abundance, of temperate tree species varies along climate gradients in eastern North America. AB - There have been many attempts to model the impacts of climate change on the distributions of temperate tree species, but empirical analyses of the effects of climate on the distribution and abundance of tree species have lagged far behind the models. Here, we used forest inventory data to characterize variation in adult tree abundance along climate gradients for the 24 most common tree species in the northeastern United States. The two components of our measure of species abundance--local frequency vs. relative abundance--showed dramatically different patterns of variation along gradients of mean annual temperature and precipitation. Local frequency (i.e., the percentage of plots in a given climate in which a species occurred) varied strongly for all 24 species, particularly as a function of temperature. Relative abundance when present in a plot, on the other hand, was effectively constant for most species right up to their estimated climatic range limits. Although the range limits for both temperature and precipitation were quite broad for all of the species, the range of climates within which a species was common (i.e., high frequency) was much narrower. Because frequency in sites within a given climate shows a strong sensitivity to temperature, at least, this suggests that the processes determining canopy tree recruitment on new sites also vary strongly with climate. PMID- 21302813 TI - Community composition and consumer identity determine the effect of resource species diversity on rates of consumption. AB - The effect of species diversity on ecosystem function is commonly studied within a single trophic level, but less is known about how resource diversity affects species interactions between trophic levels. We conducted a grazing experiment to determine how resource species diversity affects rates of consumption by three species of freshwater zooplankton consumers. We measured the effect of resource diversity on rates of consumption for several resource community compositions. These compositions varied in terms of palatability for the consumers. The effect of resource diversity on consumption rates depended on the diet breadth of the consumer species (from specialist to generalist) and the community composition of resources. Overall, high resource diversity commonly caused a decline in consumption rates of consumers. The most selective grazer showed reduced consumption for nearly all community compositions, whereas the most generalist grazer showed accelerated consumption when all resource species were palatable. Our results demonstrate that resource species diversity can modulate rates of consumption through the action of multiple different mechanisms. PMID- 21302814 TI - Ecological boundary detection using Bayesian areal wombling. AB - The study of ecological boundaries and their dynamics is of fundamental importance to much of ecology, biogeography, and evolution. Over the past two decades, boundary analysis (of which wombling is a subfield) has received considerable research attention, resulting in multiple approaches for the quantification of ecological boundaries. Nonetheless, few methods have been developed that can simultaneously (1) analyze spatially homogenized data sets (i.e., areal data in the form of polygons rather than point-reference data); (2) account for spatial structure in these data and uncertainty associated with them; and (3) objectively assign probabilities to boundaries once detected. Here we describe the application of a Bayesian hierarchical framework for boundary detection developed in public health, which addresses these issues but which has seen limited application in ecology. As examples, we analyze simulated spread data and the historic pattern of spread of an invasive species, the hemlock woolly adelgid (Adelges tsugae), using county-level summaries of the year of first reported infestation and several covariates potentially important to influencing the observed spread dynamics. Bayesian areal wombling is a promising approach for analyzing ecological boundaries and dynamics related to changes in the distributions of native and invasive species. PMID- 21302815 TI - Nitrogen turnover in the leaf litter and fine roots of sugar maple. AB - In order to better understand the nitrogen (N) cycle, a pulse of 15NO3- was applied in 1998 to a sugar maple (Acer saccharum) dominated northern hardwood forest receiving long-term (1994-2008) simulated atmospheric N deposition. Sugar maple leaf litter and live fine-root 15N were quantified for four years prior to labeling and for 11 subsequent years. Continuous sampling of 15N following addition of the tracer enabled calculation of leaf litter and fine-root N pool turnover utilizing an exponential decay function. Fine-root 15N recovery peaked at 3.7% +/- 1.7% the year the tracer was applied, while leaf litter 15N recovery peaked in the two years following tracer application at approximately 8%. These results suggest shoots are primarily constructed from N taken up in previous years, while fine roots are constructed from new N. The residence time of N was 6.5 years in leaf litter and 3.1 years in fine roots. The longer residence time and higher recovery rate are evidence that leaves were a stronger sink for labeled N than fine roots, but the relatively short residence time of tracer N in both pools suggests that there is not tight intra-ecosystem cycling of N in this mature forest. PMID- 21302816 TI - Consistent effects of nitrogen fertilization on soil bacterial communities in contrasting systems. AB - Ecosystems worldwide are receiving increasing amounts of reactive nitrogen (N) through anthropogenic activities. Although the effects of increased N inputs on plant communities have been reasonably well studied, few comparable studies have examined impacts on whole soil bacterial communities, though they play critical roles in ecosystem functioning. We sampled soils from two long-term ecological research (LTER) experimental N gradients, both of which have been amended with NH4NO3; a grassland at Cedar Creek (27 years of N additions) and an agricultural field at Kellogg Biological Station (8 years of N additions). By examining shifts in bacterial communities across these contrasting ecosystem types, we could test competing hypotheses about the direct and indirect factors that might drive bacterial responses to elevated N inputs. Bacterial community structure was highly responsive to N additions. We observed predictable and consistent changes in the structure of the bacterial communities across both ecosystem types. Our results suggest that bacterial communities across these gradients are more structured by N and/or soil carbon availability than by shifts in the plant community or soil pH associated with the elevated nitrogen inputs. In contrast to the pronounced shifts in bacterial community composition and in direct contrast to the patterns often observed in plant communities, increases in N availability did not have consistent effects on the richness and diversity of soil bacterial communities. PMID- 21302817 TI - The Robert H. MacArthur Award Lecture. Timescales, dynamics, and ecological understanding. AB - Explicit consideration of timescales and dynamics is required for an understanding of fundamental issues in ecology. Endogenous dynamics can lead to transient states where asymptotic behavior is very different from dynamics on short timescales. The causes of these kinds of transients can be placed in one of three classes: linear systems with different timescales embedded or exhibiting reactive behavior, the potentially long times to reach synchrony across space for oscillating systems, and the complex dynamics of systems with strong density dependent (nonlinear) interactions. It is also important to include the potentially disparate timescales inherent in ecological systems when determining the endogenous dynamics. I argue that the dynamics of ecological systems can best be understood as the response, which may include transient dynamics, to exogenous influences leading to the observed dynamics on ecologically relevant timescales. This view of ecosystem behavior as responses of ecological systems governed by endogenous dynamics to exogenous influences provides a synthetic way to unify different approaches to population dynamics, to understand mechanisms that determine the distribution and abundance of species, and to manage ecosystems on appropriate timescales. There are implications for theoretical approaches, empirical approaches, and the statistical approaches that bridge theory and observation. PMID- 21302818 TI - Does pyrogenicity protect burning plants? AB - Pyrogenic plants dominate many fire-prone ecosystems. Their prevalence suggests some advantage to their enhanced flammability, but researchers have had difficulty tying pyrogenicity to individual-level advantages. Based on our review, we propose that enhanced flammability in fire-prone ecosystems should protect the belowground organs and nearby propagules of certain individual plants during fires. We base this hypothesis on five points: (1) organs and propagules by which many fire-adapted plants survive fires are vulnerable to elevated soil temperatures during fires; (2) the degree to which burning plant fuels heat the soil depends mainly on residence times of fires and on fuel location relative to the soil; (3) fires and fire effects are locally heterogeneous, meaning that individual plants can affect local soil heating via their fuels; (4) how a plant burns can thus affect its fitness; and (5) in many cases, natural selection in fire-prone habitats should therefore favor plants that burn rapidly and retain fuels off the ground. We predict an advantage of enhanced flammability for plants whose fuels influence local fire characteristics and whose regenerative tissues or propagules are affected by local variation in fires. Our "pyrogenicity as protection" hypothesis has the potential to apply to a range of life histories. We discuss implications for ecological and evolutionary theory and suggest considerations for testing the hypothesis. PMID- 21302819 TI - Living dangerously with big fancy models. PMID- 21302820 TI - Advances in modeling highlight a tension between analytical accuracy and accessibility. PMID- 21302821 TI - Model complexity and information in the data: could it be a house built on sand? PMID- 21302822 TI - Are exercises like this a good use of anybody's time? PMID- 21302823 TI - Bridging gaps between statistical and mathematical modeling in ecology. PMID- 21302824 TI - Food availability at birth limited reproductive success in historical humans. AB - Environmental conditions in early life can profoundly affect individual development and have consequences for reproductive success. Limited food availability may be one of the reasons for this, but direct evidence linking variation in early-life nutrition to reproductive performance in adulthood in natural populations is sparse. We combined historical agricultural data with detailed demographic church records to investigate the effect of food availability around the time of birth on the reproductive success of 927 men and women born in 18th-century Finland. Our study population exhibits natural mortality and fertility rates typical of many preindustrial societies, and individuals experienced differing access to resources due to social stratification. We found that among both men and women born into landless families (i.e., with low access to resources), marital prospects, probability of reproduction, and offspring viability were all positively related to local crop yield during the birth year. Such effects were generally absent among those born into landowning families. Among landless individuals born when yields of the two main crops, rye and barley, were both below median, only 50% of adult males and 55% of adult females gained any reproductive success in their lifetime, whereas 97% and 95% of those born when both yields were above the median did so. Our results suggest that maternal investment in offspring in prenatal or early postnatal life may have profound implications for the evolutionary fitness of human offspring, particularly among those for which resources are more limiting. Our study adds support to the idea that early nutrition can limit reproductive success in natural animal populations, and provides the most direct evidence to date that this process applies to humans. PMID- 21302825 TI - High connectivity among locally adapted populations of a marine fish (Menidia menidia). AB - Patterns of connectivity are important in understanding the geographic scale of local adaptation in marine populations. While natural selection can lead to local adaptation, high connectivity can diminish the potential for such adaptation to occur. Connectivity, defined as the exchange of individuals among subpopulations, is presumed to be significant in most marine species due to life histories that include widely dispersive stages. However, evidence of local adaptation in marine species, such the Atlantic silverside, Menidia menidia, raises questions concerning the degree of connectivity. We examined geochemical signatures in the otoliths, or ear bones, of adult Atlantic silversides collected in 11 locations along the northeastern coast of the United States from New Jersey to Maine in 2004 and eight locations in 2005 using laser ablation inductively coupled plasma mass spectrometry (ICP-MS) and isotope ratio monitoring mass spectrometry (irm MS). These signatures were then compared to baseline signatures of juvenile fish of known origin to determine natal origin of these adult fish. We then estimated migration distances and the degree of mixing from these data. In both years, fish generally had the highest probability of originating from the same location in which they were captured (0.01-0.80), but evidence of mixing throughout the sample area was present. Furthermore, adult M. menidia exhibit highly dispersive behavior with some fish migrating over 700 km. The probability of adult fish returning to natal areas differed between years, with the probability being, on average, 0.2 higher in the second year. These findings demonstrate that marine species with largely open populations are capable of local adaptation despite apparently high gene flow. PMID- 21302826 TI - Indirect effects of a key ecosystem engineer alter survival and growth of foundation coral species. AB - Stegastes nigricans, a "farmerfish" that cultivates algal turf and defends territories from grazers and other intruders, can affect coral indirectly due to increased competition with farmed algal turf and/or reduced predation resulting from territorial aggression directed at corallivores. To investigate the indirect effects of this key ecosystem engineer on coral mortality and growth, we transplanted caged and exposed fragments of four coral species to patch reefs in French Polynesia on which we manipulated the presence of S. nigricans and turf, and to reefs naturally devoid of S. nigricans. Reef access was two to four times higher for herbivorous fishes, and two times higher for corallivorous fishes, when S. nigricans was removed, indicating that reef access is reduced for two important guilds of fishes when S. nigricans is present. Stegastes' territoriality indirectly benefited delicate acroporids (Montipora floweri and Acropora striata), yielding a twofold to fivefold reduction in skeletal loss due to lower predation frequencies in the presence of S. nigricans. Three corals, A. striata, M. floweri, and especially Porites australiensis, suffered mortality due to overgrowth significantly more frequently in the presence of farmed turf, but Pocillopora verrucosa did not. Algal abundance predicted the frequency of overgrowth for only A. striata and P. australiensis. M. floweri were more likely to be overgrown when exposed (uncaged) in the presence of S. nigricans, suggesting an interaction modification, in this case that initial predation increased susceptibility to competition with turf. In this community, the presence of S. nigricans may increase algal overgrowth of massive Porites by facilitating its turf competitors and simultaneously reduce predation of branching corals through territorial exclusion of corallivores. These indirect interactions may underlie previously documented community transitions from disturbance-resistant massive coral to recovering branching corals within S. nigricans territories. PMID- 21302827 TI - Bioengineers and their associated fauna respond differently to the effects of biogeography and upwelling. AB - Temperature and primary production (often linked to nutrient supply) are two of the few factors influencing species diversity and abundances across mesoscale gradients, while at smaller scales the habitat complexity offered by bioengineers is important. Previous studies have illustrated effects of upwelling and biogeography on intertidal bioengineers, but it is not known if these processes influence assemblages associated with those bioengineers in a similar way. We examined the habitat structure offered by two species of mussels and their associated fauna in five regions across 3000 km and three biogeographic provinces of the South African coast, replicating upwelling and non-upwelling areas within each region. Upwelling and region influenced the structure of mussel beds (the density and size of mussels). In contrast, upwelling did not influence mesoscale differences in composition, abundance, and numbers of species of crustaceans, mollusks, or polychaetes in mussel beds. Regardless of trophic level or mode of reproduction, mussel bed fauna were influenced only by region. Regional differences were strongly influenced by biogeography. The associated fauna was, however, also strongly correlated with the structure of the habitats created by mussels. Our results support the importance of upwelling to a critical ecosystem engineer, but show that these effects do not extend directly to the assemblages of associated fauna, which are more influenced by regional-scale effects and biogeography. We suggest that mesoscale patterns in the associated fauna of this bioengineered habitat are driven by the direct effects of biogeography, combined with the influence of biogeography and upwelling on mussel bed structure. PMID- 21302828 TI - Field evidence for pervasive indirect effects of fishing on prey foraging behavior. AB - The indirect, ecosystem-level consequences of ocean fishing, and particularly the mechanisms driving them, are poorly understood. Most studies focus on density mediated trophic cascades, where removal of predators alternately causes increases and decreases in abundances of lower trophic levels. However, cascades could also be driven by where and when prey forage rather than solely by prey abundance. Over a large gradient of fishing intensity in the central Pacific's remote northern Line Islands, including a nearly pristine, baseline coral reef system, we found that changes in predation risk elicit strong behavioral responses in foraging patterns across multiple prey fish species. These responses were observed as a function of both short-term ("acute") risk and longer-term ("chronic") risk, as well as when prey were exposed to model predators to isolate the effect of perceived predation risk from other potentially confounding factors. Compared to numerical prey responses, antipredator behavioral responses such as these can potentially have far greater net impacts (by occurring over entire assemblages) and operate over shorter temporal scales (with potentially instantaneous response times) in transmitting top-down effects. A rich body of literature exists on both the direct effects of human removal of predators from ecosystems and predators' effects on prey behavior. Our results draw together these lines of research and provide the first empirical evidence that large-scale human removal of predators from a natural ecosystem indirectly alters prey behavior. These behavioral changes may, in turn, drive previously unsuspected alterations in reef food webs. PMID- 21302829 TI - Estimating dispersal potential for marine larvae: dynamic models applied to scleractinian corals. AB - Dispersal influences ecological dynamics, evolution, biogeography, and biodiversity conservation, but models of larval dispersal in marine organisms make simplifying assumptions that are likely to approximate poorly the temporal dynamics of larval survival and capacity for settlement. In particular, larval mortality rates are typically assumed to be constant throughout larval life; and all larvae are frequently assumed to acquire and lose competence at the same time. To improve upon these assumptions, we here develop simple models of dispersal potential that incorporate rates of mortality, and acquisition and loss of settlement competence. We fit these models to empirical competence and survival data for five scleractinian coral species, to test the models' ability to characterize empirical survival and competence patterns, and to estimate the dispersal potential implied by those patterns. The models fit the data well, incorporating qualitative features of competence and survival that traditional approaches to modeling dispersal do not, with important implications for dispersal potential. Most notably, there was high within-cohort variation in the duration of the competent period in all species, and this variation increases both self-recruitment and long-distance dispersal compared with models assuming a fixed competent period. These findings help to explain the seeming paradox of high genetic population structure, coupled with large geographic range size, observed in many coral species. More broadly, our approach offers a way to parsimoniously account for variation in competence dynamics in dispersal models, a phenomenon that our results suggest has important effects on patterns of connectivity in marine metapopulations. PMID- 21302830 TI - Trophic cascades result in large-scale coralline algae loss through differential grazer effects. AB - Removal of predators can have strong indirect effects on primary producers through trophic cascades. Crustose coralline algae (CCA) are major primary producers worldwide that may be influenced by predator removal through changes in grazer composition and biomass. CCA have been most widely studied in Caribbean and temperate reefs, where cover increases with increasing grazer biomass due to removal of competitive fleshy algae. However, each of these systems has one dominant grazer type, herbivorous fishes or sea urchins, which may not be functionally equivalent. Where fishes and sea urchins co-occur, fishing can result in a phase shift in the grazing community with subsequent effects on CCA and other substrata. Kenyan reefs have herbivorous fishes and sea urchins, providing an opportunity to determine the relative impacts of each grazer type and evaluate potential human-induced trophic cascades. We hypothesized that fish benefit CCA, abundant sea urchins erode CCA, and that fishing indirectly reduces CCA cover by removing sea urchin predators. We used closures and fished reefs as a large-scale, long-term natural experiment to assess how fishing and resultant changes in communities affect CCA abundance. We used a short-term caging experiment to directly test the effects of grazing on CCA. CCA cover declined with increasing fish and sea urchin abundance, but the negative impact of sea urchin grazing was much stronger than that of fishes. Abundant sea urchins reduced the CCA growth rate to almost zero and prevented CCA accumulation. A warming event (El Nino Southern Oscillation, ENSO) occurred during the 18-year study and had a strong but short-term positive effect on CCA cover. However, the effect of the ENSO on CCA was lower in magnitude than the effect of sea urchin grazing. We compare our results with worldwide literature on bioerosion by fishes and sea urchins. Grazer influence depends on whether benefits of fleshy algae removal outweigh costs of grazer-induced bioerosion. However, the cost-benefit ratio for CCA appears to change with grazer type, grazer abundance, and environment. In Kenya, predator removal leads to a trophic cascade that is expected to reduce net calcification of reefs and therefore reduce reef stability, growth, and resilience. PMID- 21302831 TI - Bigger is not always better: offspring size does not predict growth or survival for seven ascidian species. AB - The presumed trade-off between offspring size and quality predicted by life history theory is often invoked to explain the wide range of propagule sizes observed in animals and plants. This trade-off is broadly supported by intraspecific studies but has been difficult to test in an interspecific context, particularly in animals. We tested the fitness consequences of offspring size both intra- and interspecifically for seven species of ascidians (sessile, suspension-feeding, marine invertebrates) whose offspring volumes varied over three orders of magnitude. We measured two major components of fitness, juvenile growth rates and survival, in laboratory and field experiments encompassing several food conditions. Contrary to the predictions of life history theory, larger offspring size did not result in higher rates of growth or survival, and large offspring did not perform better under nutritional stress, either intraspecifically or interspecifically. In fact, two of the four species with small offspring grew rapidly enough to catch up in size to the species with large offspring in as little as eight weeks, under wild-type food conditions. Trade offs between growth potential and defense may overwhelm and obscure any trade offs between offspring size and survival or growth rate. While large initial size may still confer a competitive advantage, we failed to detect any consequences of interspecific variation in initial size. This implies that larger offspring in these species, far from being inherently superior in growth or survival, require compensation in other aspects of life history if reproductive effort is to be efficient. Our results suggest that the importance of initial offspring size is context dependent and often overestimated relative to other life history traits. PMID- 21302832 TI - Climate change effects on an endemic-rich edaphic flora: resurveying Robert H. Whittaker's Siskiyou sites (Oregon, USA). AB - Species with relatively narrow niches, such as plants restricted (endemic) to particular soils, may be especially vulnerable to extinction under a changing climate due to the enhanced difficulty they face in migrating to suitable new sites. To test for community-level effects of climate change, and to compare such effects in a highly endemic-rich flora on unproductive serpentine soils vs. the flora of normal (diorite) soils, in 2007 we resampled as closely as possible 108 sites originally studied by ecologist Robert H. Whittaker from 1949 to 1951 in the Siskiyou Mountains of southern Oregon, USA. We found sharp declines in herb cover and richness on both serpentine and diorite soils. Declines were strongest in species of northern biogeographic affinity, species endemic to the region (in serpentine communities only), and species endemic to serpentine soils. Consistent with climatic warming, herb communities have shifted from 1949-1951 to 2007 to more closely resemble communities found on xeric (warm, dry) south-facing slopes. The changes found in the Siskiyou herb flora suggest that biotas rich in narrowly distributed endemics may be particularly susceptible to the effects of a warming climate. PMID- 21302833 TI - Recovery of plant diversity following N cessation: effects of recruitment, litter, and elevated N cycling. AB - Plant species richness has declined and composition shifted in response to elevated atmospheric deposition of biologically active nitrogen over much of the industrialized world. Litter thickness, litter nitrogen (N) content, and soil N mineralization rates often remain elevated long after inputs cease, clouding the prospects that plant community diversity and composition would recover should N inputs be reduced. Here we determined how N cycling, litter accumulation, and recruitment limitation influenced community recovery following cessation of long term N inputs to prairie-like grasslands. We alleviated each of these potential inhibitors through a two-year full-factorial experiment involving organic carbon addition, litter removal, and seed addition. Seed addition had the largest effect on increasing seedling and species numbers and may be necessary to overcome long term burial of seeds of target perennial grassland species. Litter removal increased light availability and bare sites for colonization, though it had little effect on reducing the biomass of competing neighbors or altering extractable soil N. Nonetheless, these positive influences were enough to lead to small increases in species richness within one year. We found that, although C addition quickly altered many factors assumed favorable for the target community (decreased N availability and biomass of nearby competitors, increased light and site availability), these changes were insufficient to positively impact species richness or seedling numbers over the experimental duration. However, only carbon addition had species-specific effects on the existing plant community, suggesting that its apparent limited utility may be more a result of slow recovery under ambient recruitment rather than from a lack of a restorative effect. There were dramatic interactions among treatments, with the positive effects of litter removal largely negated by carbon addition, and the positive effects of seed addition generally amplified by litter removal. It remains unclear whether each mechanism explored here will induce community recovery, but over different temporal scales. Long-term monitoring will help resolve these remaining questions. Regardless, our results suggest that reversal of species loss and compositional shifts from N deposition in prairies may be more inhibited by habitat fragmentation, recruitment limitation, and long-term suppression of fire than from continued effects of elevated N. PMID- 21302834 TI - Evidence of dispersal limitation in soil microorganisms: isolation reduces species richness on mycorrhizal tree islands. AB - Dispersal limitation plays an important role in a number of equilibrium and nonequilibrium theories about community ecology. In this study we use the framework of island biogeography to look for evidence of dispersal limitation in ectomycorrhizal fungal assemblages on "tree islands," patches of host trees located in a non-host vegetation matrix. Because of the potentially strong effects of island area on species richness and immigration, we chose to control island size by sampling tree islands consisting of a single host individual. Richness on tree islands was high, with estimates ranging up to 42 species of ectomycorrhizal fungi associating with a single host individual. Species richness decreased significantly with increasing isolation of tree islands, with our regression predicting a 50% decrease in species richness when tree islands are located distances of approximately 1 km from large patches of contiguous forests. Despite the fact that fungal fruit bodies produce large numbers of spores with high potential for long-distance travel, these results suggest that dispersal limitation is significant in ectomycorrhizal assemblages. There were no discernible effects of isolation or environment on the species identity of tree island fungal colonists. In contrast to the highly predictable patterns of tree island colonization we observed in a previous study on early successional forests, we suggest that over longer time periods the community assembly process becomes more dominated by stochastic immigration and local extinction events. PMID- 21302835 TI - Untangling positive and negative biotic interactions: views from above and below ground in a forest ecosystem. AB - In ecological communities, the outcome of plant-plant interactions represents the net effect of positive and negative interactions occurring above and below ground. Untangling these complex relationships can provide a better understanding of mechanisms that underlie plant-plant interactions and enhance our ability to predict population, community, and ecosystem effects of biotic interactions. In forested ecosystems, tree seedlings interact with established vegetation, but the mechanisms and outcomes of these interactions are not well understood. To explore such mechanisms, we manipulated above- and belowground interactions among tree seedlings, shrubs, and trees and monitored seedling survival and growth of six species (Pinus banksiana, Betula papyrifera, P. resinosa, Quercus rubra, P. strobus, and Acer rubrum) in mature pine-dominated forest in northern Minnesota, USA. The forest had a moderately open canopy and sandy soils. Understory manipulations were implemented in the forest interior and in large gaps and included removal of shrubs (no interactions), tieback of shrubs (belowground), removal of shrubs with addition of shade (aboveground), and unmanipulated shrubs (both below- and aboveground). We found that shrubs either suppressed or facilitated seedling survival and growth depending on the seedling species, source of interaction (e.g., above- or belowground), and ecological context (e.g., gap or forest interior). In general, shrubs strongly influenced survival and growth in gaps, with more modest effects in the forest interior. In gaps, the presence of shrub roots markedly decreased seedling growth and survival, supporting the idea that belowground competition may be more important in dry, nutrient-poor sites. Shrub shade effects were neutral for three species and facilitative for the other three. Facilitation was more likely for shade-tolerant species. In the forest interior, shrub shade negatively affected seedling survival for the most shade-intolerant species. For several species the net effect of shrubs masked the existence of both positive and negative interactions above and below ground. Our results highlight the complexity of plant-plant interactions, demonstrate that outcomes of these interactions vary with the nature of resource limitation and the ecophysiology of the species involved, and suggest that ecological theory that rests on particular notions of plant-plant interactions (e.g., competition) should consider simultaneous positive and negative interactions occurring above and below ground. PMID- 21302836 TI - Neighborhood phylodiversity affects plant performance. AB - Facilitation and competition are ecological interactions that are crucial for the organization of plant communities. Facilitative interactions tend to occur among distantly related species, while the strength of competition tends to decrease with phylogenetic distance. The balance between both types of interactions will ultimately determine the specific composition of multispecies associations. Although multispecies patches are the arena in which coexistence develops among different phylogenetic groups within communities, the specific processes that occur across life stages have not been explored. Here we study how different species, in composing discrete patches in central Mexico, exert competitive or facilitative effects on seeds and seedlings. We relate these interactions to phylogenetic relationships among nurse species and beneficiary species, and among members of the patches. Survivorship and growth rates of the columnar cactus Neobuxbaumia mezcalaensis were highly positively related to increasing phylogenetic distance to different nurse species, to the presence of related species in patches, and to mean phylogenetic distances to the rest of the species in the patch. Each of these three elements influenced N. mezcalaensis differently, with different nurse species varying substantially in their early effects on emergence, and the nearest relatives and species composition of patches varying in their late effects on survival and growth. Our results emphasize that evolutionary relationships among co-occurring species in vegetation clumps exert direct and indirect effects on plants, affecting individual performance and species coexistence. PMID- 21302837 TI - Functional traits and the growth-mortality trade-off in tropical trees. AB - A trade-off between growth and mortality rates characterizes tree species in closed canopy forests. This trade-off is maintained by inherent differences among species and spatial variation in light availability caused by canopy-opening disturbances. We evaluated conditions under which the trade-off is expressed and relationships with four key functional traits for 103 tree species from Barro Colorado Island, Panama. The trade-off is strongest for saplings for growth rates of the fastest growing individuals and mortality rates of the slowest growing individuals (r2 = 0.69), intermediate for saplings for average growth rates and overall mortality rates (r2 = 0.46), and much weaker for large trees (r2 < or = 0.10). This parallels likely levels of spatial variation in light availability, which is greatest for fast- vs. slow-growing saplings and least for large trees with foliage in the forest canopy. Inherent attributes of species contributing to the trade-off include abilities to disperse, acquire resources, grow rapidly, and tolerate shade and other stresses. There is growing interest in the possibility that functional traits might provide insight into such ecological differences and a growing consensus that seed mass (SM), leaf mass per area (LMA), wood density (WD), and maximum height (H(max)) are key traits among forest trees. Seed mass, LMA, WD, and H(max) are predicted to be small for light-demanding species with rapid growth and mortality and large for shade-tolerant species with slow growth and mortality. Six of these trait-demographic rate predictions were realized for saplings; however, with the exception of WD, the relationships were weak (r2 < 0.1 for three and r2 < 0.2 for five of the six remaining relationships). The four traits together explained 43-44% of interspecific variation in species positions on the growth-mortality trade-off; however, WD alone accounted for > 80% of the explained variation and, after WD was included, LMA and H(max) made insignificant contributions. Virtually the full range of values of SM, LMA, and H(max) occurred at all positions on the growth-mortality trade-off. Although WD provides a promising start, a successful trait-based ecology of tropical forest trees will require consideration of additional traits. PMID- 21302838 TI - Widespread density-dependent seedling mortality promotes species coexistence in a highly diverse Amazonian rain forest. AB - Negative density-dependent mortality can promote species coexistence through a spacing mechanism that prevents species from becoming too locally abundant. Negative density-dependent seedling mortality can be caused by interactions among seedlings or between seedlings and neighboring adults if the density of neighbors affects the strength of competition or facilitates the attack of natural enemies. We investigated the effects of seedling and adult neighborhoods on the survival of newly recruited seedlings for multiple cohorts of known age from 163 species in Yasuni National Park, Ecuador, an ever-wet, hyper-diverse lowland Amazonian rain forest. At local scales, we found a strong negative impact on first-year survival of conspecific seedling densities and adult abundance in multiple neighborhood sizes and a beneficial effect of a local tree neighborhood that is distantly related to the focal seedling. Once seedlings have survived their first year, they also benefit from a more phylogenetically dispersed seedling neighborhood. Across species, we did not find evidence that rare species have an advantage relative to more common species, or a community compensatory trend. These results suggest that the local biotic neighborhood is a strong influence on early seedling survival for species that range widely in their abundance and life history. These patterns in seedling survival demonstrate the role of density dependent seedling dynamics in promoting and maintaining diversity in understory seedling assemblages. The assemblage-wide impacts of species abundance distributions may multiply with repeated cycles of recruitment and density dependent seedling mortality and impact forest diversity or the abundance of individual species over longer time scales. PMID- 21302839 TI - The trait contribution to wood decomposition rates of 15 Neotropical tree species. AB - The decomposition of dead wood is a critical uncertainty in models of the global carbon cycle. Despite this, relatively few studies have focused on dead wood decomposition, with a strong bias to higher latitudes. Especially the effect of interspecific variation in species traits on differences in wood decomposition rates remains unknown. In order to fill these gaps, we applied a novel method to study long-term wood decomposition of 15 tree species in a Bolivian semi evergreen tropical moist forest. We hypothesized that interspecific differences in species traits are important drivers of variation in wood decomposition rates. Wood decomposition rates (fractional mass loss) varied between 0.01 and 0.31 yr( 1). We measured 10 different chemical, anatomical, and morphological traits for all species. The species' average traits were useful predictors of wood decomposition rates, particularly the average diameter (dbh) of the tree species (R2 = 0.41). Lignin concentration further increased the proportion of explained inter-specific variation in wood decomposition (both negative relations, cumulative R2 = 0.55), although it did not significantly explain variation in wood decomposition rates if considered alone. When dbh values of the actual dead trees sampled for decomposition rate determination were used as a predictor variable, the final model (including dead tree dbh and lignin concentration) explained even more variation in wood decomposition rates (R2 = 0.71), underlining the importance of dbh in wood decomposition. Other traits, including wood density, wood anatomical traits, macronutrient concentrations, and the amount of phenolic extractives could not significantly explain the variation in wood decomposition rates. The surprising results of this multi-species study, in which for the first time a large set of traits is explicitly linked to wood decomposition rates, merits further testing in other forest ecosystems. PMID- 21302840 TI - Modeling spatial aggregation of finite populations. AB - Accurate description of spatial distribution of species is essential for correctly modeling macroecological patterns and thus to infer mechanisms of species coexistence. The Poisson and negative binomial distribution (NBD) are most widely used to respectively model random and aggregated distributions of species in infinitely large areas. As a finite version of the Poisson distribution, the binomial distribution is used to model random distribution of species populations in finite areas. Despite that spatial aggregation is the most widespread pattern and no species in nature are distributed in infinitely large areas, no model is currently available to describe spatial aggregation for species distributed in finite areas. Here we develop a finite counterpart of the NBD to model aggregated species in finite landscapes. Similar to the NBD, this new model also has a parameter k measuring spatial aggregation. When k --> infinity, this model becomes the binomial distribution; when study area approaches infinite, it becomes the NBD. This model was extensively evaluated against the distributions of over 300 tree species in a 50-ha stem-mapping plot from Barro Colorado Island, Panama. The results show that when sampling area is small (relative to the study area), the new model and the NBD are of little difference. But the former correctly models spatial distribution at the finite limit at which the NBD fails. We reveal serious theoretical pathologies by using infinite models to approximate finite distribution and show the theoretical and practical advantages for using the new finite model for modeling species-area relationships, species occupancy and spatial distribution of rare species. PMID- 21302841 TI - Herbivores on a dominant understory shrub increase local plant diversity in rain forest communities. AB - Indirect effects of trophic interactions on biodiversity can be large and common, even in complex communities. Previous experiments with dominant understory Piper shrubs in a Costa Rican rain forest revealed that increases in herbivore densities on these shrubs caused widespread seedling mortality as a result of herbivores moving from Piper to seedlings of many different plant genera. We tested components of the Janzen-Connell hypothesis by conducting focused studies on the effects of specialist and generalist Piper herbivores on local seedling diversity. Whereas specialist herbivores are predicted to increase mortality to neighboring seedlings that are closely related to the source plant, true generalists moving from source plants may cause density-dependent mortality of many species, and possibly increase richness if new species replace abundant species that have been thinned by herbivores. Therefore, we hypothesized that seedling richness would be greater in understory control plots created in patches of Piper that had normal densities of generalist herbivores compared to plots from which we removed generalist herbivores manually from all Piper shrubs. After 15 months, generalist-herbivore-removal plots had > 40% fewer seedlings, > 40% fewer species, and 40% greater seedling evenness, on average, than control plots with generalist herbivores intact. Using a complementary approach in unmanipulated plots in four forests, we used path analysis to test for a positive association between seedling diversity and herbivore damage on Piper species. In unmanipulated plots, for both generalist and specialist herbivores, our data were significant fits to the causal model that Piper herbivores decrease evenness and increase plant species richness, corroborating the experimental results. Because herbivores changed how individuals were apportioned among the species and families present (lower evenness), one interpretation of these associations between herbivores on Piper shrubs and local seedling richness is that high seedling mortality in dominant families allowed the colonization or survival of less common species. If interspecific or apparent competition allowed for a relative increase in species richness, then the Janzen-Connell hypothesis may extend its predictions to generalist seedling predators. We speculate that apparent competition may explain some of the deviations from neutral model predictions, especially at small scales. PMID- 21302842 TI - Counterintuitive effects of large-scale predator removal on a midlatitude rodent community. AB - Historically, small mammals have been focal organisms for studying predator-prey dynamics, principally because of interest in explaining the drivers of the cyclical dynamics exhibited by northern vole, lemming, and hare populations. However, many small-mammal species occur at relatively low and fairly stable densities at temperate latitudes, and our understanding of how complex predator assemblages influence the abundance and dynamics of these species is surprisingly limited. In an intact grassland ecosystem in western Montana, USA, we examined the abundance and dynamics of Columbian ground squirrels (Spermophilus columbianus), deer mice (Peromyscus maniculatus), and montane voles (Microtus montanus) on 1-ha plots where we excluded mammalian and avian predators and ungulates, excluded ungulates alone, or allowed predators and ungulates full access. Our goal was to determine whether the relatively low population abundance and moderate population fluctuations of these rodents were due to population suppression by predators. Our predator-exclusion treatment was divided into two phases: a phase where we excluded all predators except weasels (Mustela spp.; 2002-2005), and a phase where all predators including weasels were excluded (2006 2009). Across the entire duration of the experiment, predator and/or ungulate exclusion had no effect on the abundance or overall dynamics of ground squirrels and deer mice. Ground squirrel survival (the only species abundant enough to accurately estimate survival) was also unaffected by our experimental treatments. Prior to weasel exclusion, predators also had no impacts on montane vole abundance or dynamics. However, after weasel exclusion, vole populations reached greater population peaks, and there was greater recruitment of young animals on predator-exclusion plots compared to plots open to predators during peak years. These results suggest that the impacts of predators cannot be generalized across all rodents in an assemblage. Furthermore, they suggest that specialist predators can play an important role in suppressing vole abundance even in lower-latitude vole populations that occur at relatively low densities. PMID- 21302843 TI - Deviations from predictions of the metabolic theory of ecology can be explained by violations of assumptions. AB - The metabolic theory of ecology (MTE) is based on models derived from the first principles of thermodynamics and biochemical kinetics. The MTE predicts that the relationship between temperature and species richness of ectotherms should show a specific slope. Testing the validity of this model, however, depends on whether empirical data do not violate assumptions and are obtained within contour conditions. When dealing with richness gradients, the MTE must be empirically tested only for ectothermic organisms at high organization levels and when their body size as well as abundance does not vary with temperature gradients. Here we evaluate whether the magnitude of the deviations in slope expected from the MTE to empirical data for New World amphibians is due to the violations of model assumptions and to lack of generality due to restricting contour conditions. We found that the MTE correctly predicted biodiversity patterns only at higher levels of organization and when assumptions of the basic model were not violated. Approximately 60% of the deviations from the MTE-predicted slope across amphibian families were due to violations of the model assumptions. The hypothesis that richness patterns are a function of environmental temperature is too restrictive and does not take complex environmental and ecological processes into account. However, our results suggest that it may be possible to obtain multiple derivations of the MTE equation if idiosyncrasies in spatial and biological/ecological issues that are essential to understanding biodiversity patterns are considered. PMID- 21302844 TI - Is the patch size distribution of vegetation a suitable indicator of desertification processes? Comment. PMID- 21302845 TI - Autism in the U.S.: social movement and legal change. AB - The social movement surrounding autism in the U.S. has been rightly defined a ray of light in the history of social progress. The movement is inspired by a true understanding of neuro-diversity and is capable of bringing about desirable change in political discourse. At several points along the way, however, the legal reforms prompted by the autism movement have been grafted onto preexisting patterns of inequality in the allocation of welfare, education, and medical services. In a context most recently complicated by economic recession, autism driven change bears the mark of political and legal fragmentation. Distributively, it yields ambivalent results that have not yet received systemic attention. This article aims to fill this analytical vacuum by offering, first, a synoptic view of the several legal transformations brought about or advocated for by the autism movement and, second, a framework for investigating their distributive consequences. PMID- 21302846 TI - Can we handle the truth? Legal fictions in the determination of death. AB - Advances in life-saving technologies in the past few decades have challenged our traditional understandings of death. People can be maintained on life-support even after permanently losing the ability to breathe spontaneously and remaining unconscious and unable to interact meaningfully with others. In part because this group of people could help fulfill the growing need for organ donation, there has been a great deal of pressure on the way we determine death. The determination of death has been modified from the old way of understanding death as occurring when a person stops breathing, her heart stops beating, and she is cold to the touch. Today, physicians determine death by relying on a diagnosis of total brain failure or by waiting a short while after circulation stops. Evidence has emerged that the conceptual bases for these approaches to determining death are fundamentally flawed and depart substantially from our biological and common sense understandings of death. We argue that the current approach to determining death consists of two different types of unacknowledged legal fictions. These legal fictions were developed for practices that are largely ethically legitimate but need to be reconciled with the law. However, the considerable debate over the determination of death in the medical and scientific literature has not informed the public of the fact that our current determinations of death do not adequately establish that a person has died. It seems unlikely that this information can remain hidden for long. Given the instability of the status quo and the difficulty of making the substantial legal changes required by complete transparency, we argue for a second-best policy solution of acknowledging the legal fictions involved in determining death. This move in the direction of greater transparency may someday result in allowing us to face squarely these issues and effect the legal changes necessary to permit ethically appropriate vital organ transplantation. Finally, this paper also provides the beginnings of a taxonomy of legal fictions, concluding that a more systematic theoretical treatment of legal fictions is warranted to understand their advantages and disadvantages across a variety of legal domains. PMID- 21302847 TI - Patient data: property, privacy & the public interest. PMID- 21302848 TI - Prometheus and Bilski: pushing the bounds of patentable subject matter in medical diagnostic techniques with the machine-or-transformation test. PMID- 21302849 TI - A reasonable time, place and manner restriction: Medicare reimbursement law should require pharmacists to fill prescriptions regardless of personal belief. PMID- 21302850 TI - Preface. Sleep and sleep disorders in adolescents. PMID- 21302851 TI - Physiology of normal sleep in adolescents. AB - Among the many behavioral changes associated with adolescent development are later bedtimes and less sleep. This article presents an overview of healthy adolescent sleep in humans along with a review of the maturation of homeostatic (process S) and circadian (process C) processes regulating sleep. We propose that maturational changes to the homeostatic and circadian processes push adolescents toward later bedtimes, while societal demands, such as early school start times, result in a pattern of insufficient and ill-timed sleep. The implications of sleep curtailment during this developmental period are discussed. PMID- 21302852 TI - The effects of media on sleep. AB - The media are an important part of young people's lives, but television, computer games, Internet use, cellular phone use, and even book reading threaten healthy sleep. Adults do not fully comprehend the ways in which young people use various media. Media use is a type of behavior that may displace sleep time or shorten it. Media content may lead to overexcitement or cause recurring nightmares. The cellular telephone is a particular threat. Parents may also use media excessively, establishing an unhealthy environment that may lead to sleep dysfunction in children and adolescents. Therefore, anticipatory guidance for healthy behavioral changes should be focused on the family. PMID- 21302853 TI - Etiologies and evaluation of sleep disturbances in adolescence. AB - The etiologies of sleep disturbances in adolescents are varied and include biological, environmental, and sociocultural factors. Health care practitioners need to have a basic understanding of normal sleep development in adolescents and the risk factors for inadequate sleep, as well as an appreciation for the myriad potential consequences of insufficient sleep (ie, mood dysregulation, academic failure, and obesity). This chapter provides a systematic approach to screening and evaluating adolescent sleep complaints in the clinical setting and provides suggestions for anticipatory guidance regarding healthy sleep, which should be part of standard adolescent health care. PMID- 21302854 TI - Sleep and headaches during adolescence. AB - Adolescence is a complex period of life with hormonal, physiologic, and psychological modifications that affect headache and sleep. Because of the well documented association between sleep and headache, it is reasonable to expect that changes in sleep would be reflected in the onset, duration, and frequency of headache. The sleep structure changes and the presence of poor sleep hygiene in adolescence could be responsible for the appearance of headache in adolescents or could contribute to the increased chronicity of headaches. It is essential in adolescence to perform a careful analysis of sleep habits, patterns, and disturbances to develop adequate treatment methods for both sleep and headache. PMID- 21302855 TI - Diagnosis and treatment of sleep apnea in adolescents. AB - Sleep-disordered breathing is very common and is associated with poor health and cognitive outcomes in children and adolescents. Its prevalence is between 2% and 4% of the population this group. Problems such as life-threatening events, failure to thrive, cardiovascular insult, poor cognition, poor school performance, and psychiatric/behavioral problems have been reported. This chapter will outline how to diagnose and treat adolescents with sleep apnea. PMID- 21302856 TI - The obesity epidemic and disordered sleep during childhood and adolescence. AB - The obesity pandemic is claiming its presence even among youngest of children and is clearly on the rise. Although the extent and implications of this massive increase in the prevalence of overweight and obese children are unclear, they are anticipated to be deleterious to global health outcomes and life expectancy. The potential interrelationships between sleep and obesity have gained recent attention. In this chapter, we initially examine the critical evidence supporting or refuting such proposed associations. In addition, the potential reciprocal roles of obesity and obstructive sleep apnea in the facilitation of their pathophysiology are also reviewed, along with their amplificatory effects on their respective morbidities. PMID- 21302857 TI - Impact of inadequate sleep on unintentional injuries in adolescents. AB - Excessive daytime sleepiness is a growing societal problem in adolescents. Empirical evidence demonstrates that adolescents experience significant sleepiness as a result of inadequate or disrupted sleep. Although the functional impairment caused by sleepiness in the pediatric population is less studied, children and adolescents do experience changes in behavior and a decline in performance as seen in the adult population. The end result is functional impairment in adolescents, which then places them at higher risk for unintentional injury. PMID- 21302858 TI - Pharmacotherapy in pediatric sleep disorders. AB - Sleep disorders are highly prevalent during childhood and adolescence. It is known that if left untreated, these problems can have significant impact on daytime function, including learning, memory, attention, and behavior. The approach to the treatment of these disorders (whether with or without pharmacotherapy) is dependent on a thorough evaluation of the sleep complaint and determination of an accurate diagnosis. Many pediatric sleep problems are due to insomnia. There is good evidence that young children with behaviorally based insomnia respond to appropriate behavioral interventions. There is less research evidence of the efficacy of these interventions in children who are either school age or adolescents; however, nonpharmacologic strategies are usually indicated initially in the approach to treatment. The indication for the use of pharmacotherapy in pediatric insomnia is not well understood; however, some general principles are described when medications may be considered. There are specific sleep disorders (other than insomnia) for which pharmacotherapy plus behavioral strategies are warranted. The research regarding pharmacotherapy in pediatric sleep disorders is limited; often, medications are used "off label" based on data extrapolated from adult studies. Clinicians who suggest over-the counter treatments or prescribe medications for pediatric patients with sleep disorders should have an understanding of the classification of sleep disorders and the role of pharmacotherapy in the treatment of these disorders. In this chapter, the emphasis is on the pharmacologic treatment of sleep disorders in typically developing children and adolescents. PMID- 21302859 TI - Sleep and academic success: mechanisms, empirical evidence, and interventional strategies. AB - Mounting evidence indicates that sleep is beneficial for learning, memory, attention, and academic success. However, the importance of sleep in these contexts has rarely been addressed in programs aimed at optimizing academic performance. This review aims to describe the role that sleep plays in processes pertaining to academic achievement. We first describe the basic sleep processes and their role with respect to cognitive and behavioral/emotional systems important for academic performance. We next review studies conducted to assess the association between sleep and academic performance, concluding by describing interventional programs being used to optimize sleep in the context of academic success. PMID- 21302860 TI - Narcolepsy in adolescents. AB - Narcolepsy is a disorder of children and adolescence, but until recently it was often not identified until adulthood, with a reported time from onset to diagnosis of about a decade. This disorder affects approximately 0.05% of the population and starts in childhood and adolescence about half of the time. With narcolepsy, the boundaries between wake, sleep, and dreams are blurred. The cardinal features of narcolepsy-cataplexy are daytime somnolence, cataplexy (sometimes occurring long after onset of sleepiness), sleep paralysis, and hypnagogic hallucinations. Weight gain, disturbed nocturnal sleep, and social/school functional changes are common; reactive substance use to maintain wakefulness during the day may also be seen. Males and females are equally affected. It is classically associated with HLA DQB1*0602, the most specific genetic marker for narcolepsy across all ethnic groups. CSF hypocretin has recently been found to be depleted in this disorder, and late-breaking data support that the disease is caused by autoimmune destruction of hypocretin producing neurons in the hypothalamus. There is no known cure for narcolepsy. Therapies include behavioral/ scheduling modification, medications to combat daytime sleepiness and cataplexy, and treatment of concomitant disorders leading to daytime sleepiness. The differential diagnosis for this disorder should include other disorders of excessive daytime sleepiness with a proclivity toward onset in adolescence, such as delayed sleep phase syndrome, obstructive sleep apnea, and insufficient sleep time; substance use; and less commonly neurologic disorders such as Klein Levin syndrome, Prader-Willi syndrome, and others. Immunomodulator therapy and hypocretin replacement are proposed therapies that hold promise for the future. PMID- 21302861 TI - Case report: Patient with ketoacidosis and impaired insulin secretion. PMID- 21302863 TI - Yes: treatment of moderately elevated triglycerides is supported by the evidence. PMID- 21302864 TI - No: reducing moderately elevated triglycerides is not proven to improve patient outcomes. PMID- 21302865 TI - A home visit. PMID- 21302866 TI - Management options for early incomplete miscarriage. PMID- 21302867 TI - Clozapine vs. other atypical antipsychotics for schizophrenia. PMID- 21302868 TI - Treatment of acute migraine headache. AB - Migraine headache is a common and potentially debilitating disorder often treated by family physicians. Before diagnosing migraine, serious intracranial pathology must be ruled out. Treating acute migraine is challenging because of substantial rates of nonresponse to medications and difficulty in predicting individual response to a specific agent or dose. Data comparing different drug classes are relatively scarce. Abortive therapy should be used as early as possible after the onset of symptoms. Effective first-line therapies for mild to moderate migraine are nonprescription nonsteroidal anti-inflammatory drugs and combination analgesics containing acetaminophen, aspirin, and caffeine. Triptans are first line therapies for moderate to severe migraine, or mild to moderate migraine that has not responded to adequate doses of simple analgesics. Triptans should be avoided in patients with vascular disease, uncontrolled hypertension, or hemiplegic migraine. Intravenous antiemetics, with or without intravenous dihydroergotamine, are effective therapies in an emergency department setting. Dexamethasone may be a useful adjunct to standard therapy in preventing short term headache recurrence. Intranasal lidocaine may also have a role in relief of acute migraine. Isometheptene-containing compounds and intranasal dihydroergotamine are also reasonable therapeutic options. Medications containing opiates or barbiturates should be avoided for acute migraine. During pregnancy, migraine may be treated with acetaminophen or nonsteroidal anti-inflammatory drugs (prior to third trimester), or opiates in refractory cases. Acetaminophen, ibuprofen, intranasal sumatriptan, and intranasal zolmitriptan seem to be effective in children and adolescents, although data in these age groups are limited. PMID- 21302869 TI - Osteochondrosis: common causes of pain in growing bones. AB - Osteochondrosis is a term used to describe a group of disorders that affect the growing skeleton. These disorders result from abnormal growth, injury, or overuse of the developing growth plate and surrounding ossification centers. The exact etiology of these disorders is unknown, but genetic causes, repetitive trauma, vascular abnormalities, mechanical factors, and hormonal imbalances may all play a role. Legg-Calve-Perthes disease is a hip disorder that causes hip pain, an atraumatic limp, and knee pain. Osgood-Schlatter and Sinding-Larsen-Johannson diseases are common causes of anterior knee pain that is aggravated by jumping activities and kneeling. Sever disease causes heel pain that is exacerbated by activity and wearing cleats. It often mimics Achilles tendinitis and is treated with activity and shoe modifications, heel cups, and calf stretches. Freiberg disease and Kohler bone disease often cause foot pain and are disorders of the metatarsal head and navicular bone, respectively. Radiographs show sclerosis, flattening, and fragmentation of bone in both diseases. Elbow pain can be caused by medial epicondyle apophysitis or Panner disease. Medial epicondyle apophysitis is exacerbated by frequent throwing and is treated with throwing cessation and acetaminophen or nonsteroidal anti-inflammatory drugs. Panner disease is the most common cause of lateral-sided elbow pain in children younger than 10 years. It may or may not be associated with frequent throwing, and it resolves spontaneously. Scheuermann disease causes back pain and a humpback deformity from vertebral bone anterior wedging. PMID- 21302870 TI - Recurrent venous thromboembolism. AB - A previous venous thromboembolism is the most important risk factor for predicting recurrence of the condition. Several studies have shown that routine testing for inherited thrombophilias is not helpful in predicting the risk of recurrence or altering treatment decisions, and therefore is not cost-effective. Updated practice guidelines from the American College of Chest Physicians shift the focus away from laboratory testing and place stronger emphasis on identifying clinical factors when making treatment decisions. The major determinants for treatment duration are whether the deep venous thrombosis was located in a distal or proximal vein, whether the thrombotic episode was an initial or recurrent event, and whether transient risk factors were present. Persistent elevations on the D-dimer test or the presence of residual thrombosis may provide further information to predict recurrence risk and determine treatment duration. Screening for antiphospholipid syndrome and/or malignancy should be considered in patients presenting with arterial thrombosis, thrombosis at an unusual site, or recurrent pregnancy loss. Patients with venous thromboembolism and a known malignancy should be treated with low-molecular-weight heparin rather than oral anticoagulation as long as the cancer is active. All patients with recurrent, unprovoked venous thromboembolism should be considered for long-term treatment. PMID- 21302871 TI - VTE: What are the risks? PMID- 21302872 TI - Erythematous, annular, scaling patches on the skin. Erythema annulare centrifugum. PMID- 21302874 TI - A microcosm of the health care 'system'. PMID- 21302876 TI - "Refills" for schedule II controlled substances? PMID- 21302877 TI - PCMH, ACOs and health care "systems". PMID- 21302878 TI - CPT update for 2011: immunizations, observations and more. PMID- 21302879 TI - Should your practice participate in a quality-reporting program? PMID- 21302881 TI - Integrating a behavioral health specialist into your practice. PMID- 21302882 TI - What you need to know about the Medicare preventive services expansion. PMID- 21302892 TI - The efficiencies of meandering. PMID- 21302893 TI - Protective effects of anthocyanins against amyloid beta-peptide-induced damage in neuro-2A cells. AB - Alzheimer's disease is neuropathologically characterized by amyloid beta-protein (Abeta) deposition, resulting in neurotoxicity. Herein, we focused on the prevention of anthocyanins from amyloid-mediated neurodysfunction. The data demonstrated that combined exposure of Abeta(1-40) and Abeta(25-35) to Neuro-2A cells resulted in reactive oxygen species (ROS) production and perturbation of calcium homeostasis. The expressions of LXRalpha, ApoE, ABCA1, and seladin-1 genes were significantly down-regulated upon Abeta challenge. beta-Secretase, the rate-limiting enzyme that catalyzes amyloid precursor protein transform to Abeta, was up-regulated by Abeta treatment. For the duration of Abeta stimulation, malvidin (Mal) or oenin (Oen; malvidin-3-O-glucoside) was added, and the protective effects were observed. Mal and Oen showed protective effects against Abeta-induced neurotoxicity through blocking ROS formation, preserving Ca(2+) homeostasis, and preventing Abeta-mediated perturbation of certain genes involved in Abeta metabolism and cellular defense. The present study implicates anthocyanin as a potential therapeutic candidate for the prevention of amyloid mediated neurodysfunction. PMID- 21302894 TI - Display of Fibrobacter succinogenes beta-glucanase on the cell surface of Lactobacillus reuteri. AB - The aim of this study was to display a rumen bacterial beta-glucanase on the cell surface of a probiotic Lactobacillus reuteri strain. The beta-glucan degrading ability and the adhesion capability of the genetically modified strain were evaluated. The beta-glucanase (Glu) from Fibrobacter succinogenes was fused to the C-terminus of collagen-binding protein (Cnb) from L. reuteri and then expressed by L. reuteri Pg4 as a recombinant Cnb-Glu-His(6) fusion protein. Confocal immunofluorescence microscopy and flow cytometric analysis of the transformed strain L. reuteri pNZ-cnb/glu demonstrated that Cnb-Glu-His(6) fusion protein was displayed on its cell surface. In addition, L. reuteri pNZ-cnb/glu acquired the capacity to break down barley beta-glucan and showed higher adhesion capability, in comparison with the parental strain L. reuteri Pg4. To the best of the authors' knowledge, this is the first report of successful display of fibrolytic enzymes on the cell surface of intestinal lactobacilli. PMID- 21302895 TI - Selectivity in Garratt-Braverman cyclization: an experimental and computational study. AB - Bispropargyl sulfones equipped with aromatic rings of dissimilar nature were synthesized. Under basic conditions, these sulfones isomerized to the bisallenic sulfones, creating a competitive scenario between two alternate Garratt-Braverman (GB) cyclization pathways. The observed product distribution ruled out the involvement of any ionic intermediate and supported the diradical mechanism with greater involvement of the electron-rich aromatic ring via the more nucleophilic radical. DFT-based calculations supported the diradical mechanism along with the observed selectivity. PMID- 21302896 TI - Enantioselective haloetherification by asymmetric opening of meso-halonium ions. AB - A new approach to enantioselective haloetherification reactions via desymmetrization of in situ-generated meso-halonium ions is described. The combination of N-haloamides as a halogen source and sodium salts of chiral phosphoric acids as catalysts can be used for the cyclization of symmetrical ene diol substrates, yielding the haloetherification products under practical conditions in enantioenriched form. PMID- 21302897 TI - The reversible consecutive mechanism for the reaction of trinitroanisole with methoxide ion. AB - Although the competitive mechanism for Meisenheimer complex formation during the reaction of 2,4,6-trinitroanisole with methoxide ion in methanol is generally accepted, no kinetic evidence has been presented to rule out a reversible consecutive mechanism. Simulation of the competitive mechanism revealed that a fractional order in [MeO(-)] is predicted by the latter. Conventional pseudo first-order analysis of the kinetics resulted in cleanly first-order in [MeO(-)], which rules out the competitive mechanism. The kinetic data are consistent with the reversible consecutive mechanism, which is proposed for this important reaction. An intermediate is required for this mechanism, and we propose that a dianion complex (III) is formed reversibly from the initial 1,3-sigma complex (I). The trimethoxy complex (III), the (1)H NMR spectrum of which was observed earlier by Servis (Servis, K. L. J. Am. Chem. Soc. 1965, 87, 5495; 1967, 89, 1508), then eliminates methoxide ion reversibly to form the 1,1-sigma complex product (II). PMID- 21302898 TI - Chemosynthesis of poly(epsilon-lysine)-analogous polymers by microwave-assisted click polymerization. AB - Poly(epsilon-lysine) (epsilon-PL)-analogous click polypeptides with not only similar alpha-amino side groups but also similar main chain to epsilon-PL were chemically synthesized for the first time through click polymerization from aspartic (or glutamic)-acid-based dialkyne and diazide monomers. With microwave assisting, the reaction time of click polymerization was compressed into 30 min. The polymers were fully characterized by NMR, ATR-FTIR, and SEC-MALLS analysis. The deprotected click polypeptides had similar pK(a) value (7.5) and relatively low cytotoxicity as epsilon-PL and could be used as substitutes of epsilon-PL in biomedical applications, especially in endotoxin selective removal. Poly(ethylene glycol) (PEG)-containing alternating copolymers with alpha-amino groups were also synthesized and characterized. After deprotection, the polymers could be used as functional gene vector with PEG shadowing system and NCA initiator to get amphiphilic graft polymers. PMID- 21302899 TI - Colorimetric chiral recognition of enantiomers using the nucleotide-capped silver nanoparticles. AB - Chiral recognition is among the important and special modes of molecular recognition. It is highly desirable to develop a simple, rapid, sensitive, and high-throughput routine assay for chiral recognition. In this study, we demonstrate that nucleotide-capped Ag nanoparticles (AgNPs) can be used as an ultrahigh efficiency enantioseparation and detection platform for D- and L cysteine. The aggregation of AgNPs is selectively induced by an enantiomer of cysteine, which allowed the rapid colorimetric enantiodiscrimination of cysteine without any prior derivatization and specific instruments and left an excess of the other enantiomer in the solution, thus resulting in enantioseparation. This is the first application of a nucleotide-capped AgNP-based biosensing platform for chiral recognition and opens new opportunities for design of more novel enantiosensing strategies and enantiospecific adsorbents and expansion of its application in different fields. PMID- 21302900 TI - Asymmetric synthesis of alpha-aryl amino acids; aryne-mediated diastereoselective arylation. AB - An aryne-mediated alpha-arylation reaction of Schollkopf's bis-lactim ether is described. Arynes were generated via an ortho-lithiation approach, affording syn arylated products in up to 94:6 dr with moderate to good yields and excellent regioselectivities. Hydrolysis provided a variety of substituted arylglycines containing a range of functional groups without racemization. PMID- 21302901 TI - Enantioselective, biocatalytic reduction of 3-substituted cyclopentenones: application to the asymmetric synthesis of an hNK-1 receptor antagonist. AB - A convergent and enantioselective route to the hNK-1 receptor antagonist (1) is described, which sets all six stereogenic centers with high diastereoselectivity and delivers 1 in only 11 steps and 23% overall yield. The process was enabled by the development of the enantioselective enzymatic reduction of 3-functionalized cyclopentenones and stereospecific Pd-catalyzed etherification coupling of fragments 6 and 7. PMID- 21302902 TI - Implementation of a statistically supported heuristic approach to alternating current voltammetric harmonic component analysis: re-evaluation of the macrodisk glassy carbon electrode kinetics for oxidation of ferrocene in acetonitrile. AB - Sinusoidal large amplitude ac voltammetric techniques gene-rate very large data sets. When analyzed in the frequency domain, using a Fourier transform (FT)-band filtering- inverse FT sequence, the data may be resolved into the aperiodic dc, fundamental, second, and higher order ac harmonics. Each of these components exhibit a different level of sensitivity to electrode kinetics, uncompensated resistance and capacitance. Detailed simulations illustrate how the heuristic approach for evaluation of each data subset may be implemented and exploited in the assessment of the electrode kinetics for the fast Fc [symbol:see text] Fc(+) + e (Fc = ferrocene) oxidation process at a glassy carbon macrodisk electrode. The simulations presented in this study are based on the Butler-Volmer model and incorporate consideration of the uncompensated resistance (R(u)), double-layer capacitance (C(dl)), rate constant (k(0)), and charge transfer coefficient (alpha). Error analysis of the heuristically evaluated simulation-experiment comparison is used to assist in establishing the best fit of data for each harmonic. The result of the heuristic pattern recognition type approach for analysis of the oxidation of ferrocene (0.499, 0.999, and 5.00 mM) at a glassy carbon macrodisk electrode in acetonitrile (0.1 M Bu(4)NPF(6)) implies that k(0) >= 0.25 cm s(-1) on the basis of analysis of the first 4 harmonics and plausibly lies in the range of 0.25-0.5 cm s(-1) with alpha = 0.25-0.75 when analysis of the next four harmonics is undertaken. The k(0) value is significantly faster then indicated in most literature reports based on use of dc cyclic voltammetry under transient conditions at glassy carbon macrodisk electrode. The data analysis with a sinusoidal amplitude of 80 mV is conducted at very low frequency experiments of 9 Hz to minimize contribution from electrode heterogeneity, frequency dispersion, and adsorption, all of which can complicate the response for the oxidation of Fc in acetonitrile at a glassy carbon electrode. PMID- 21302903 TI - N-acylsulfonamide assisted tandem C-H olefination/annulation: synthesis of isoindolinones. AB - A tandem C-H olefination/annulation sequence directed by N-acylsulfonamides affords a variety of isoindolinones. This transformation is compatible with aliphatic alkenes as well as conjugated alkenes. Notably, molecular oxygen can be used as the sole, eco-friendly oxidant. PMID- 21302904 TI - Theoretical study on the gas phase reaction of sulfuric acid with hydroxyl radical in the presence of water. AB - The reactions of H2SO4 with the OH radical without water and with water are investigated employing the quantum chemical calculations at the B3LYP/6 311+G(2df,2p) and MP2/aug-cc-pv(T+d)z levels of theory, respectively. The calculated results show that the reaction of H2SO4 with OH and H2O is a very complex mechanism because of the formation of the prereactive complex prior to the transition state and product. There are two prereactive complexes with stabilization energies being -20.28 and -20.67 kcal/mol, respectively. In addition, the single water can lower the energy barriers of the hydrogen abstraction and the proton transfer to 7.51 and 6.37 kcal/mol, respectively from 13.79 and 8.82 kcal/mol with respect to the corresponding prereactive complex. The computed rate constants indicate that the water-assisted reaction of sulfuric acid with OH radical is of greater importance than the reaction of the naked sulfuric acid with the OH radical because the rate constant of the water-assisted process is about 10(3) faster than that of the reaction sulfuric acid with OH. Therefore, the conclusion is obtained that the water-assisted process plays an important role in the sink for the gaseous sulfuric acid in the clean area. PMID- 21302905 TI - Molecule-ion interaction and its effect on coordination interaction. AB - The present work revealed the presence of the molecule-ion interaction between ethylenediaminetetraacetic acid disodium salt (Na(2)H(2)EDTA) and beta cyclodextrin (CD) on the basis of observable changes in crystal patterns and thermal behaviors before and after interaction. Results from electric conductivity measurements confirmed this presence and showed that the extent of the molecule-ion interaction was associated with the concentration of beta-CD. More importantly, the molecule-ion interaction led to a decreased coordination interaction of Na(2)H(2)EDTA and copper chloride, and this decrease exhibited a concentration dependence of beta-CD. Similar phenomena were also observed in the case of several analogs of Na(2)H(2)EDTA by UV-vis spectroscopy. A possible explanation was proposed on the basis of the hypothesis that there was a competitive relationship between the molecule-ion interaction and the coordination interaction. Further, nuclear magnetic resonance measurements provided important information on the difference in interaction modes of beta-CD with H(2)EDTA(2-) and [Cu(EDTA)](2-). We are of the opinion that the results would provide a significant bridge between coordination chemistry and supramolecular chemistry and help us further understand factors related to different interactions in multicomponent systems. PMID- 21302906 TI - Stepwise 1D growth of luminescent Au(I)-Ag(I) phosphine-alkynyl clusters: synthesis, photophysical, and theoretical studies. AB - Reactions between the diphosphino-gold cationic complexes [Au(2)(PPh(2)-C(2) (C(6)H(4))(n)-C(2)-PPh(2))(2)](2+) (n = 0, 1, 2, 3) and polymeric acetylides (AuC(2)Ph)(n) and (AgC(2)Ph)(n) lead to the formation of a new family of heterometallic clusters with the general formula [Au(8+2n)Ag(6+2n)(C(2)Ph)(8+4n)(PPh(2)C(2)(C(6)H(4))(n)C(2)PPh(2))(2)](2+), n = 0 (1), 1 (2), 2 (3), 3 (4). Compounds 1-4 were characterized in detail by NMR and ESI-MS spectroscopy. Complex 1 (n = 0) crystallizes in two forms (orange (1a) and yellow (1b)), one of which (1a) has been analyzed by X-ray crystallography. The luminescence behavior of 1-4 has been studied. Compounds 2 and 3 exhibited orange red phosphorescence with quantitative quantum efficiency in both aerated and degassed CH(2)Cl(2), implying O(2)-independent phosphorescence due to efficient protection of the emitting chromophore center by the organic ligands. Complex 3 exhibits reasonable two-photon absorption (TPA) property with a cross section of sigma ~ 45 GM (800 nm), which is comparable to the value of commercially available TPA dyes such as coumarin 151. Computational studies have been performed to correlate the structural and photophysical features of the complexes studied. The metal-centered triplet emission within the heterometallic core is suggested to play a key role in the observed phosphorescence. The luminescence spectrum of 1 in CH(2)Cl(2) shows dual phosphorescence maximized at 575 nm (the P(1) band) and 770 nm (the P(2) band). Both P(1) and P(2) bands possess identical excitation spectra, i.e., the same ground-state origin, and the same relaxation dynamics throughout the temperature range of 298-200 K. The dual emission of 1 arises from fast structural fluctuation upon excitation, perhaps forming two geometry isomers, which exhibit distinctly different P(1) and P(2) bands. The scrambling dynamics might require large-amplitude motion and, hence, is hampered in rigid media, as evidenced by the single emission for 1a (610 nm) and 1b (570 nm) observed in solid. PMID- 21302907 TI - Comparative proteomic analysis of blood eosinophils reveals redox signaling modifications in patients with FIP1L1-PDGFRA-associated chronic eosinophilic leukemia. AB - The FIP1L1-PDGFRA (F/P) fusion gene, which was identified as a recurrent molecular finding in hypereosinophilic syndrome (HES), lead to a constitutively increased tyrosine kinase activity of the fusion protein. Despite data obtained in animals or cell lines models, the mechanisms underlying the predominant eosinophil lineage targeting and the cytotoxicity of eosinophils in this leukemia remain unclear. To define more precisely intrinsic molecular events associated with F/P gene, we performed a proteomic analysis comparing F/P+ eosinophils (F/P Eos) and eosinophils from healthy donors (C-Eos). Using 2D-DIGE and mass spectrometry techniques, we identified 41 proteins significantly overexpressed between F/P-Eos and C-Eos. Among them, 17.8% belonged to the oxidoreductase family. We further observed a down-expression of peroxiredoxin-2 (PRX-2) and an overexpression of src-homology-2 domain containing tyrosine phosphatase (SHP-1), enzymes regulating PDGFR downstream pathways, and especially intracellular reactive oxygen species (ROS) production. This profile, confirmed in immunoblot analysis, appears specific to F/P-Eos compared to controls and patients with idiopathic HES. In this clonal disorder possibly involving a pluripotent hematopoietic stem cell, we postulate that the well documented relationships between PDGFRA downstream signals and intracellular ROS levels might influence the phenotype of this leukemia. PMID- 21302908 TI - Porous anionic, cationic, and neutral metal-carboxylate frameworks constructed from flexible tetrapodal ligands: syntheses, structures, ion-exchanges, and magnetic properties. AB - A series of coordination polymers with anionic, cationic, and neutral metal carboxylate frameworks have been synthesized by using a flexible tetrapodal ligand tetrakis[4-(carboxyphenyl)oxamethyl] methane acid (H(4)X). The reactions between divalent transition-metal ions and H(4)X ligands gave [M(3)X(2)].[NH(2)(CH(3))(2)](2).8DMA (M = Co (1), Mn (2), Cd(3)) which have anionic metal-carboxylate frameworks with NH(2)(CH(3))(2)(+) cations filled in channels. The reactions of trivalent metal ions Y(III), Dy(III), and In(III) with H(4)X ligands afforded cationic metal-carboxylate frameworks [M(3)X(2).(NO(3)).(DMA)(2).(H(2)O)].5DMA.2H(2)O (M = Y(4), Dy(5)) and [In(2)X.(OH)(2)].3DMA.6H(2)O (6) with the NO(3)(-) and OH(-) serving as counterions, respectively. Moreover, a neutral metal-carboxylate framework [Pb(2)X.(DMA)(2)].2DMA (7) can also be isolated from reaction of Pb(II) and H(4)X ligands. The charged metal-carboxylate frameworks 1-5 have selectivity for specific counterions in the reaction system, and compounds 1 and 2 display ion exchange behavior. Moreover, magnetic property measurements on compounds 1, 2, and 5 indicate that there exists weak antiferromagnetic interactions between magnetic centers in the three compounds. PMID- 21302909 TI - Electric field-driven acid-base chemistry: proton transfer from acid (HCl) to base (NH3/H2O). AB - It is well-known that single H3N-HCl and H2O-HCl acid-base pairs do not react to form the ion pairs, H4N(+)Cl(-) and H3O(+)Cl(-), in isolation. On the basis of ab initio method, we propose a physical method of external electric field (Eext) to drive the proton transfer from acid (HCl) to base (NH3/H2O). Our results show that when Eext along the proton-transfer direction achieves or exceeds the critical electric field (Ec), the proton transfer occurs, such as, the Ec values of proton transfer for H3N-HCl and H2O-HCl are 54 * 10(-4) and 210 * 10(-4) au, respectively. And the degree of the proton transfer can be controlled by modulating the strength of Eext. Furthermore, we estimate the inductive strength of an excess electron (Ee) equivalent to the Eext = 125 * 10(-4) au, which is greater than the Ec (54 * 10(-4) au) of NH3-HCl but less than the Ec (210 * 10( 4) au) of H2O-HCl. This explains well the anion photoelectron spectroscopy [Eustis et al. Science 2008, 319, 936] that an excess electron can trigger the proton transfer for H3N-HCl but not for H2O-HCl. On the basis of the above estimation, we also predict that two excess electrons can induce H2O-HCl to undergo the proton transfer and form the ion pair H3O(+)Cl(-). PMID- 21302910 TI - Cavitation in metastable fluids confined to linear mesopores. AB - We study the adsorption process of nitrogen (at 77.4 and 51.3 K) and argon (at 60 K) in porous silicon duplex layers, Si/A/B and Si/B/A, where the pores of A are on average narrower than the pores of B. We compare the experimental isotherms to that calculated from elemental isotherms measured in layers A and B supported by or detached from the silicon substrate. This allows us to confirm our previous studies which show that the relaxation of the substrate constraint modifies the adsorption strains and leads to a decrease of the adsorbed amount before condensation and consequently increases the condensation pressure. In the so called ink-bottle Si/B/A configuration, layer B empties while layer A remains filled which proves that layer B empties via cavitation. The vapor pressure at which cavitation occurs in layer B in Si/B/A configuration is close to the pressure at which the same layer empties when it is in direct contact with the gas reservoir (Si/A/B configuration) which indicates that layer B contains all the ingredients necessary for cavitation to occur. The absolute value of the liquid pressure at which cavitation occurs is much lower than the value predicted by the theory of homogeneous nucleation. Nucleation of gas bubbles thus takes place on the surface of the pore walls. This is the crucial point of the paper. A receding meniscus with a contact angle lower than pi/2 inside a pore and a gas bubble with a contact angle higher than pi/2 are thus mutually exclusive. A receding meniscus cannot enter a pore. This has nothing to do with a pore blocking effect; this is related to the physical parameters which define the contact angle inside the pores, that is, the surface energies at the solid liquid, solid-vapor, and liquid-vapor interfaces. For argon at 60 K in the Si/B/A duplex layer, cavitation in layer B activates the emptying of a fraction of pores of layer A which constitutes a direct observation of metastable states. PMID- 21302911 TI - Preparation of a [Ru(bpy)2(dppz)]2+-intercalated DNA cast film using a self standing method and its luminescence tuning by Cu2+ ions and EDTA. AB - In this correspondence, we report on the first preparation of [Ru(bpy)(2)(dppz)](2+)-intercalated (bpy = 2,2'-bipyridine; dppz = dipyrido[3,2 a:2',3'-c]phenazine) DNA films on an indium-tin oxide surface via a solution based self-standing strategy, carried out by the direct mixing of aqueous solutions of both anionic DNA and cationic metallointercalator at a molar ratio of 5:6. The luminescence of a [Ru(bpy)(2)(dppz)](2+)-intercalated DNA cast film is studied and found to show excellent tunable characteristics by Cu(2+) ions and ethylenediaminetetraacetic acid addition. PMID- 21302912 TI - Surface activation of electrocatalysis at oxide electrodes. Concerted electron proton transfer. AB - Dramatic rate enhancements are observed for the oxidation of phenols, including tyrosine, at indium-tin oxide electrodes modified by the addition of the electron transfer relays [M(II)(bpy)(2)(4,4'-(HO)(2)P(O)CH(2))(2)bpy)](2+) (M = Ru, Os) with clear evidence for the importance of proton-coupled electron transfer and concerted electron-proton transfer. PMID- 21302913 TI - Phthalocyanine-peptide conjugates via palladium-catalyzed cross-coupling reactions. AB - Phthalocyanines (Pc) were conjugated with peptide moieties to improve their target selectivity for potential use as fluorescence and/or positron emission tomography (PET) probes in medical imaging. Three synthetic methods based on palladium-catalyzed cross-coupling reactions (Sonogashira, Buchwald-Hartwig, and Suzuki-Miyaura) were investigated. Using these methods, a series of peptides monofunctionalized with Pc at the N/C-terminal position or on a phenylalanine side chain was obtained in good yields and characterized. PMID- 21302914 TI - Chemically cross-linked thin poly(vinylidene fluoride-co-trifluoroethylene)films for nonvolatile ferroelectric polymer memory. AB - Both chemically and electrically robust ferroelectric poly(vinylidene fluoride-co trifluoro ethylene) (PVDF-TrFE) films were developed by spin-coating and subsequent thermal annealing with the thermal cross-linking agent 2,4,4-trimethyl 1,6-hexanediamine (THDA). Well-defined ferroelectric beta crystalline domains were developed with THDA up to approximately 50 wt %, with respect to polymer concentration, resulting in characteristic ferroelectric hysteresis polarization voltage loops in metal/cross-linked ferroelectric layer/metal capacitors with remnant polarization of approximately 4 MUC/cm(2). Our chemically networked film allowed for facile stacking of a solution-processable organic semiconductor on top of the film, leading to a bottom-gate ferroelectric field effect transistor (FeFET). A low-voltage operating FeFET was realized with a networked PVDF-TrFE film, which had significantly reduced gate leakage current between the drain and gate electrodes. A solution-processed single crystalline tri isopropylsilylethynyl pentacene FeFET with a chemically cross-linked PVDF-TrFE film showed reliable I-V hysteresis with source-drain ON/OFF current bistablility of 1 * 10(3) at a sweeping gate voltage of +/-20 V. Furthermore, both thermal micro/nanoimprinting and transfer printing techniques were conveniently combined for micro/nanopatterning of chemically resistant cross-linked PVDF-TrFE films. PMID- 21302915 TI - Six new metal-organic frameworks based on polycarboxylate acids and V-shaped imidazole-based synthon: syntheses, crystal structures, and properties. AB - Solvothermal reactions of 4,4'-bis(imidazol-1-yl)diphenyl ether (BIDPE) with deprotonated 5-hydroxy-isophthalic acid (5-OH-H(2)bdc), and benzene-1,3,5 tricarboxylic acid (H(3)btc) in the presence of cadmium(II), zinc(II), cobalt(II), nickel(II), and manganese(II) salts in H(2)O or H(2)O/DMF produced six new complexes, namely, [Cd(BIDPE)(5-OH-bdc).H(2)O](n) (1), [Co(BIDPE)(5-OH bdc).H(2)O](n) (2), [Zn(3)(BIDPE)(3)(5-OH-bdc)(3).4H(2)O](n) (3), [Ni(BIDPE)(2)(5 OH-bdc)(H(2)O).3H(2)O](n) (4), {[Mn(2)(BIDPE)(2)(5-OH-bdc)(2)](n) (5), and [Ni(BIDPE)(2)(Hbtc)(H(2)O)](n) (6). These complexes were characterized by elemental analysis, IR spectroscopy, and X-ray single-crystal diffraction. Compounds 1 and 2 reveal the same two-dimensional (2D) sheets with a 32-membered [(Cd/Co)(2)(BIDPE)(2)] metallocyclic ring constructed from BIDPE and 5-OH-H(2)bdc with Cd or Co salts. For compound 3, six identical 2D sheets are polycatenated in parallel to form a rare 2D -> 2D framework; it displays ferroelectric behavior with a remnant electric polarization (P(r)) of 0.033 MUC/cm(2) and an electric coercive field (E(c)) of 11.15 kV/cm. In compounds 4 and 6, only one carboxyl group coordinated to the Ni atom from 5-OH-H(2)bdc or H(3)btc. Compound 5 exists as binuclear Mn clusters, which are linked by BIDPE and 5-OH-H(2)bdc to generate a 2D sheet and displays weak antiferromagnetic character. In addition, the thermal stabilities and photochemical properties of these new complexes have been studied. PMID- 21302916 TI - Fluorous monolith specificity: the effects of polymer density and secondary interactions on column performance and amenability to biological samples. AB - Continuing from the foundation laid by our previous work in the field, we present here an examination of the effects of monolith density and overall composition on the efficacy of performance in the realm of fluorous separations. By variation of the proportions of monomer and cross-linking agent relative to a static porogenic solvent composition, it was found that a composition of 30% polymer-forming material provides the optimal results in terms of resolution and peak shape for fluorous chromatography of a mixture of similarly labeled benzylamines. The presence of so-called "secondary interactions" that can compete with fluorous specificity in columns of this type were also examined and discussed, with similar results to those observed for commercial fluorous columns being noted. We suggest that these effects may actually be positive if they can be properly harnessed, as the ability to provide a second dimension for fluorous separations based on polarity may allow more complex analyses of labeled proteomic samples to be effectively undertaken. Finally, we present some initial results on the effectiveness of our optimized fluorous monoliths in a series of tagging and separation experiments using a custom-synthesized peptide. With successful resolution of labeled biological samples from their nonfluorous counterparts achieved, we discuss the potential expansion and further applicability of fluorous monoliths of this type in proteomic avenues, as well as their amenability to the greater analytical community. PMID- 21302917 TI - In situ, real-time identification of biological tissues by ultraviolet and infrared laser desorption ionization mass spectrometry. AB - Laser desorption ionization-mass spectrometric (LDI-MS) analysis of vital biological tissues and native, ex vivo tissue specimens is described. It was found that LDI-MS analysis yields tissue specific data using lasers both in the ultraviolet and far-infrared wavelength regimes, while visible and near IR lasers did not produce informative MS data. LDI mass spectra feature predominantly phospholipid-type molecular ions both in positive and negative ion modes, similar to other desorption ionization methods. Spectra were practically identical to rapid evaporative ionization MS (REIMS) spectra of corresponding tissues, indicating a similar ion formation mechanism. LDI-MS analysis of intact tissues was characterized in detail. The effect of laser fluence on the spectral characteristics (intensity and pattern) was investigated in the case of both continuous wave and pulsed lasers at various wavelengths. Since lasers are utilized in various fields of surgery, a surgical laser system was combined with a mass spectrometer in order to develop an intraoperative tissue identification device. A surgical CO(2) laser was found to yield sufficiently high ion current during normal use. The principal component analysis-based real-time data analysis method was developed for the quasi real-time identification of mass spectra. Performance of the system was demonstrated in the case of various malignant tumors of the gastrointestinal tract. PMID- 21302918 TI - Molecular layer deposition of functional thin films for advanced lithographic patterning. AB - Photoresist materials comprise one of the main challenges faced by lithography to meet the requirements of electronic device size scaling. Here we report for the first time the use of molecular layer deposition (MLD) to produce photoresist materials with controllable placement of functional moieties. Polyurea resists films are deposited by MLD using urea coupling reactions between 1,4-phenylene diisocyanate (PDIC) and ethylenediamine (ED) or 2,2'-(propane-2,2 diylbis(oxy))diethanamine (PDDE) monomers in a layer-by-layer fashion with a linear growth rate, allowing acid-labile groups to be incorporated into the film at well-controlled positions. The films are deposited with stoichiometric compositions and have highly uniform surface morphology as investigated using atomic force microscopy. We show that acid treatment can cleave the backbone of the polyurea film at positions where the acid-labile groups are embedded. We further show that after soaking the polyurea film with photoacid generator (PAG), it acts as a photoresist material and we present several UV patterning demonstrations. This approach presents a new way to make molecularly designed resist films for lithography. PMID- 21302919 TI - Quantitative chemical state analysis of supported vanadium oxide catalysts by high resolution vanadium Kalpha spectroscopy. AB - Oxidation states of vanadium species on Al(2)O(3), SiO(2), and TiO(2) were quantitatively analyzed by least-squares fitting of V Kalpha spectra recorded with a two-crystal X-ray fluorescence spectrometer. Uncertainties of analytical results by the normalization procedure, and coefficient of validation and the reduction behavior of vanadium species by X-ray irradiation were discussed. The V(5+)/V(4+)/V(3+) ratios on Al(2)O(3), SiO(2), and TiO(2) calcined at 773 K in air were determined to be ca. 6/3/1, 3/6/1, and 5/4/1, respectively. The possible chemical states of vanadium species on supports were proposed. PMID- 21302920 TI - Bronsted base-assisted boronic acid catalysis for the dehydrative intramolecular condensation of dicarboxylic acids. AB - Bronsted base-assisted boronic acid catalysis for the dehydrative self condensation of carboxylic acids is described. Arylboronic acid bearing bulky (N,N-dialkylamino)methyl groups at the 2,6-positions can catalyze the intramolecular dehydrative condensation of di- and tetracarboxylic acids. This is the first successful method for the catalytic dehydrative self-condensation of carboxylic acids. PMID- 21302921 TI - Construction of a photoactivatable profluorescent enzyme via propinquity labeling. AB - A strategy for the construction of a profluorescent caged enzyme is described. An active site-directed peptide-based affinity label was designed, synthesized, and employed to covalently label a nonactive site residue in the cAMP-dependent protein kinase. The modified kinase displays minimal catalytic activity and low fluorescence. Photolysis results in partial cleavage of the enzyme-bound affinity label, restoration of enzymatic activity (60-80%) and a strong fluorescent response (10-20 fold). The caged kinase displays analogous behavior in living cells, inducing a light-dependent loss of stress fibers that is characteristic of cAMP action. This strategy furnishes molecularly engineered enzymes that can be remotely controlled in time, space, and total activity. PMID- 21302922 TI - A metal-insulator transition in R2O2Bi with an unusual Bi2- square net (R = rare earth or Y). AB - A series of tetragonal ThCr(2)Si(2)-type compounds, R(2)O(2)Bi (R = rare earth or Y), are synthesized in which an unusual Bi(2-) anion forms a square net layer that is sandwiched between (R(2)O(2))(2+) fluorite layers. Two-dimensional (2D) electronic bands around the Fermi energy are predominantly composed of 6p(x)6p(y) orbitals in the Bi(2-) square net, which contains a positive hole per Bi(2-) ion. The decrease in the size of the square net caused by reducing the size of the R ion enhances the electrical conductivity because of the hole, resulting in a "chemical pressure"-induced metal-insulator transition. PMID- 21302923 TI - Computational study of the effect of confinement within microporous structures on the activity and selectivity of metallocene catalysts for ethylene oligomerization. AB - The effect of confinement within some zeolitic structures on the activity and selectivity of metallocene catalysts for the ethylene oligomerization has been investigated using grand canonical Monte Carlo simulations (GCMC). The following zeolite (host) frameworks displaying different pore sizes, have been studied as solid hosts: mazzite (MAZ), AIPO-8 (AET), UTD-1F (DON), faujasite (FAU), and VPI 5 (VFI). Intermediates and transition states involved in the ethylene trimerization reaction catalyzed by a Ti-based catalyst [(eta(5) C(5)H(4)CMe(2)C(6)H(5))TiCl(3)/MAO] have been used as sorbates (guests). We have demonstrated linear correlations with slope a(H,j) between the adsorption enthalpy and the molecular volume V(m) of the sorbates, each holding for a given microporous host below a host-specific threshold V(mmax,j). Beyond this maximal molecular volume, the adsorption vanishes due to steric exclusion. a(H,j) increases, and V(mmax,j) decreases with decreasing host pore size, in line with the confinement concept. We moreover showed that, in the limit of vanishing loading (Henry regime), the enthalpies and entropies of adsorption in a given host are linearly correlated. We have defined a host-specific confinement compensation temperature a(j), which refers to a temperature where the stabilizing adsorption enthalpic interactions are canceled out against the loss in entropy. However, calculated a(j) are much larger than the operating temperatures. With a setup microkinetic model, we predict that the activity and selectivity of the confined Ti-catalyst in ethylene oligomerization can be significantly altered with respect to homogeneous phase conditions, since the adsorption free energies of transition states and intermediates also become functions of a(H,j) and V(m). We have applied this theory to predict the optimum host pore size to get maximum alpha-octene production, instead of alpha-hexene, which is primarily produced in the homogeneous phase. We also predict a significantly increased activity for confined catalysts. PMID- 21302924 TI - Nonradiative deactivation of excited hemicyanines studied with submolecular spatial resolution by time-resolved surface second harmonic generation at liquid liquid interfaces. AB - The excited-state dynamics of aminostilbazolium dyes is known to be dominated by nonradiative deactivation through large-amplitude motion. In order to identify the coordinate(s) responsible for this process, the excited-state lifetimes of two dialkylaminostyryl-methylpyridinium iodides have been measured at liquid liquid interfaces using time-resolved surface second harmonic generation. We found that the decay time of the excited-states of both compounds was increasing with the viscosity of the apolar phase, consisting of n-alkanes of varying length, but was unaffected by that of the polar phase, made of water/glycerol mixtures. This indicates that the nonradiative deactivation is associated with the twist of the dialkylaniline group, which is located in the apolar part of the molecule. PMID- 21302925 TI - Stabilization of electrocatalytic metal nanoparticles at metal-metal oxide graphene triple junction points. AB - Carbon-supported precious metal catalysts are widely used in heterogeneous catalysis and electrocatalysis, and enhancement of catalyst dispersion and stability by controlling the interfacial structure is highly desired. Here we report a new method to deposit metal oxides and metal nanoparticles on graphene and form stable metal-metal oxide-graphene triple junctions for electrocatalysis applications. We first synthesize indium tin oxide (ITO) nanocrystals directly on functionalized graphene sheets, forming an ITO-graphene hybrid. Platinum nanoparticles are then deposited, forming a unique triple-junction structure (Pt ITO-graphene). Our experimental work and periodic density functional theory (DFT) calculations show that the supported Pt nanoparticles are more stable at the Pt ITO-graphene triple junctions. Furthermore, DFT calculations suggest that the defects and functional groups on graphene also play an important role in stabilizing the catalysts. These new catalyst materials were tested for oxygen reduction for potential applications in polymer electrolyte membrane fuel cells, and they exhibited greatly enhanced stability and activity. PMID- 21302926 TI - The formal combination of three singlet biradicaloid entities to a singlet hexaradicaloid metalloid Ge14[Si(SiMe3)3]5[Li(THF)2]3 cluster. AB - The reaction of GeBr with LiSi(SiMe(3))(3) leads to the metalloid cluster compound [(THF)(2)Li](3)Ge(14)[Si(SiMe(3))(3)](5) (1). After the introduction of a first cluster of this type, in which 14 germanium atoms form an empty polyhedron, [(THF)(2)Li](3)Ge(14)[Ge(SiMe(3))(3)](5) (2), we present here further investigations on 1 to obtain preliminary insight into its chemical and bonding properties. The molecular structure of 1 is determined via X-ray crystal structure solution using synchrotron radiation. The electronic structure of the Ge(14) polyhedron is further examined by quantum chemical calculations, which indicate that three singlet biradicaloid entities formally combine to yield the singlet hexaradicaloid character of 1. Moreover, the initial reactions of 1 after elimination of the [Li(THF)(2)](+) groups by chelating ligands (e.g., TMEDA or 12 crown-4) are presented. Collision induced dissociation experiments in the gas phase, employing FT-ICR mass spectrometry, lead to the elimination of the singlet biradicaloid Ge(5)H(2)[Si(SiMe(3))(3)](2) cluster. The unique multiradicaloid bonding character of the metalloid cluster 1 might be used as a model for reactions and properties in the field of surface science and nanotechnology. PMID- 21302927 TI - High-spin cobalt(II) ions in square planar coordination: structures and magnetism of the oxysulfides Sr2CoO2Cu2S2 and Ba2CoO2Cu2S2 and their solid solution. AB - The antiferromagnetic structures of the layered oxychalcogenides (Sr(1 x)Ba(x))(2)CoO(2)Cu(2)S(2) (0 <= x <= 1) have been determined by powder neutron diffraction. In these compounds Co(2+) is coordinated by four oxide ions in a square plane and two sulfide ions at the apexes of an extremely tetragonally elongated octahedron; the polyhedra share oxide vertexes. The magnetic reflections present in the diffraction patterns can in all cases be indexed using a ?2a * ?2a * c expansion of the nuclear cell, and nearest-neighbor Co(2+) moments couple antiferromagnetically within the CoO(2) planes. The ordered magnetic moment of Co(2+) in Sr(2)CoO(2)Cu(2)S(2) (x = 0) is 3.8(1) MU(B) at 5 K, consistent with high-spin Co(2+) ions carrying three unpaired electrons and with an additional significant unquenched orbital component. Exposure of this compound to moist air is shown to result in copper deficiency and a decrease in the size of the ordered moment to about 2.5 MU(B); there is a strong correlation between the size of the long-range ordered moment and the occupancy of the Cu site. Both the tetragonal elongation of the CoO(4)S(2) polyhedron and the ordered moment in (Sr(1-x)Ba(x))(2)CoO(2)Cu(2)S(2) increase with increasing Ba content, and in Ba(2)CoO(2)Cu(2)S(2), which has Co(2+) in an environment that is close to purely square planar, the ordered moment of 4.5(1) MU(B) at 5 K is over 0.7 MU(B) larger than that in Sr(2)CoO(2)Cu(2)S(2), so the unquenched orbital component in this case is even larger than that observed in octahedral Co(2+) systems such as CoO. The experimental observations of antiferromagnetic ground states and the changes in properties resulting from replacement of Sr by Ba are supported by ab initio calculations on Sr(2)CoO(2)Cu(2)S(2) and Ba(2)CoO(2)Cu(2)S(2). The large orbital moments in these systems apparently result from spin-orbit mixing of the unequally populated d(xz), d(yz), and d(z(2)) orbitals, which are reckoned to be almost degenerate when the CoO(4)S(2) polyhedron reaches its maximum elongation. The magnitudes of the ordered moments in high-spin Co(2+) oxide, oxychalcogenide, and oxyhalide systems are shown to correlate well with the tetragonal elongation of the coordination environment. The large orbital moments lead to an apparently magnetostrictive distortion of the crystal structures below the Neel temperature, with the symmetry lowered from tetragonal I4/mmm to orthorhombic Immm and the size of the distortion correlating well with the size of the long-range ordered moment for all compositions and for temperature-dependent data gathered on Ba(2)CoO(2)Cu(2)S(2). PMID- 21302928 TI - Time dependence and signs of the shift of the surface plasmon resonance frequency in nanocages elucidate the nanocatalysis mechanism in hollow nanoparticles. AB - Surface plasmon resonance (SPR) wavelength of plasmonic nanoparticles is sensitive to changes in the dielectric function of its exposed surface to the medium. Gold nanocages (AuNCs) have two surfaces (inner and outer) and thus two plasmon fields., When the dielectric of the medium changes around the outer surface only, the SPR shifts to different extent from that observed when the dielectric constant of the medium changes around both surfaces. This property of plasmonic AuNCs was used to elucidate the mechanism of the catalytic reduction of 4-nitro to 4-amino phenol, whether it is occurring within the cavity or on the exterior surface of the nanocages. For this purpose two types of nanocages were prepared, one with two plasmonic surfaces and the other with Au/Pt shell-shell nanocages, where only the external surface is plasmonic as gold is outside and Pt is inside. By following the time dependence of the plasmonic band shift resulting from the addition of the reactants and comparing the reaction kinetic parameters for two types of nanocages with those of the pure single metallic nanocages, it was concluded that the catalysis is taking place within the cavity in both types of hollow nanoparticles. PMID- 21302929 TI - Polymer-incarcerated gold-palladium nanoclusters with boron on carbon: a mild and efficient catalyst for the sequential aerobic oxidation-Michael addition of 1,3 dicarbonyl compounds to allylic alcohols. AB - We have developed a polymer-incarcerated bimetallic Au-Pd nanocluster and boron as a catalyst for the sequential oxidation-addition reaction of 1,3-dicarbonyl compounds with allylic alcohols. The desired tandem reaction products were obtained in good to excellent yields under mild conditions with broad substrate scope. In the course of our studies, we discovered that the excess reducing agent, sodium borohydride, reacts with the polymer backbone to generate an immobilized tetravalent boron catalyst for the Michael reaction. In addition, we found bimetallic Au-Pd nanoclusters to be particularly effective for the aerobic oxidation of allylic alcohols under base- and water-free conditions. The ability to conduct the reaction under relatively neutral and anhydrous conditions proved to be key in maintaining good catalyst activity during recovery and reuse of the catalyst. Structural characterization (STEM, EDS, SEM, and N(2) absorption/desorption isotherm) of the newly prepared PI/CB-Au/Pd/B was performed and compared to PI/CB-Au/Pd. We found that while boron was important for the Michael addition reaction, it was found to alter the structural profile of the polymer-carbon black composite material to negatively affect the allylic oxidation reaction. PMID- 21302930 TI - 8-Azatetracyclines: synthesis and evaluation of a novel class of tetracycline antibacterial agents. AB - A novel series of fully synthetic 8-azatetracyclines was prepared and evaluated for antibacterial activity. Compounds were identified that overcome both efflux (tet(K)) and ribosomal protection (tet(M)) tetracycline resistance mechanisms and are active against Gram-positive and Gram-negative organisms. Two compounds were identified that exhibit comparable efficacy to marketed tetracyclines in in vivo models of bacterial infection. PMID- 21302931 TI - Broad-spectrum enhancement of polymer composite dielectric constant at ultralow volume fractions of silica-supported copper nanoparticles. AB - A new strategy for the synthesis of high permittivity polymer composites is demonstrated based on well-defined spatial distribution of ultralow amounts of conductive nanoparticles. The spatial distribution was realized by immobilizing Cu nanoparticles within the pore system of silica microspheres, preventing direct contact between individual Cu particles. Both Cu-loaded and unloaded silica microspheres were then used as fillers in polymer composites prepared with thermoplastic SEBS rubber as the matrix. With a metallic Cu content of about 0.10 vol % [corrected] in the composite, a relative increase of 94% in real permittivity was obtained. No Cu-induced relaxations were observed in the dielectric spectrum within the studied frequency range of 0.1 Hz to 1 MHz. When related to the amount of conductive nanoparticles, the obtained composites achieve the highest broad-spectrum enhancement of permittivity ever reported for a polymer-based composite. PMID- 21302932 TI - Photoluminescence imaging of focused ion beam induced individual quantum dots. AB - We report on scanning microphotoluminescence measurements that spectrally and spatially resolve emission from individual InAs quantum dots that were induced by focused ion beam patterning. Multilayers of quantum dots were spaced 2 MUm apart, with a minimum single dot emission line width of 160 MUeV, indicating good optical quality for dots patterned using this technique. Mapping 16 array sites, at least 65% were occupied by optically active dots and the spectral inhomogeneity was within 30 meV. PMID- 21302933 TI - Fluorescence spectroscopy as a probe of the effect of phosphorylation at serine 40 of tyrosine hydroxylase on the conformation of its regulatory domain. AB - Phosphorylation of Ser40 in the regulatory domain of tyrosine hydroxylase activates the enzyme by increasing the rate constant for dissociation of inhibitory catecholamines from the active site by 3 orders of magnitude. To probe the changes in the structure of the N-terminal domain upon phosphorylation, individual phenylalanine residues at positions 14, 34, and 74 were replaced with tryptophan in a form of the protein in which the endogenous tryptophans had all been mutated to phenylalanine (W(3)F TyrH). The steady-state fluorescence anisotropy of F74W W(3)F TyrH was unaffected by phosphorylation, but the anisotropies of both F14W and F34W W(3)F TyrH increased significantly upon phosphorylation. The fluorescence of the single tryptophan residue at position 74 was less readily quenched by acrylamide than those at the other two positions; fluorescence increased the rate constant for quenching of the residues at positions 14 and 34 but did not affect that for the residue at position 74. Frequency domain analyses were consistent with phosphorylation having no effect on the amplitude of the rotational motion of the indole ring at position 74, resulting in a small increase in the rotational motion of the residue at position 14 and resulting in a larger increase in the rotational motion of the residue at position 34. These results are consistent with the local environment at position 74 being unaffected by phosphorylation, that at position 34 becoming much more flexible upon phosphorylation, and that at position 14 becoming slightly more flexible upon phosphorylation. The results support a model in which phosphorylation at Ser40 at the N-terminus of the regulatory domain causes a conformational change to a more open conformation in which the N-terminus of the protein no longer inhibits dissociation of a bound catecholamine from the active site. PMID- 21302934 TI - Physical characterization of icosahedral virus ultra structure, stability, and integrity using electrospray differential mobility analysis. AB - We present a rapid and quantitative method to physically characterize the structure and stability of viruses. Electrospray differential mobility analysis (ES-DMA) is used to determine the size of capsomers (i.e., hexons) and complete capsids. We demonstrate how to convert the measured mobility size into the icosahedral dimensions of a virus, which for PR772 become 68.4 nm for vertex-to vertex, 54.4 nm for facet-to-facet, and 58.2 nm for edge-to-edge lengths, in reasonable agreement with dimensions from transmission electron microscopy for other members of the family Tectiviridae (e.g., PRD1). These results indicate ES DMA's mobility diameter most closely approximates the edge-to-edge length. Using PR772's edge length (36.0 nm) and the size of the major capsid hexon (~8.4 nm) from ES-DMA with icosahedral geometry, PR772's T = 25 symmetry is confirmed and the number of proteins in the capsid shell is determined. We also demonstrate the use of ES-DMA to monitor the temporal disintegration of PR772, the thermal degradation of PP7, and the appearance of degradation products, essential to viral stability assays. These results lay groundwork essential for the use of ES DMA for a variety of applications including monitoring of vaccine and gene therapy vector products, confirmation of viral inactivation, and theoretical studies of self-assembling macromolecular structures. PMID- 21302935 TI - Technical updates to the bacterial method for nitrate isotopic analyses. AB - The bacterial conversion of aqueous nitrate (NO(3)(-)) to nitrous oxide (N(2)O) for isotopic analysis has found widespread use since its introduction (Sigman, D. M.; Casciotti, K. L.; Andreani, M.; Galanter, M.; Bohlke, J. K. Anal. Chem.2001, 73, 4145-4153; Casciotti, K. L.; Sigman, D. M.; Galanter Hastings, M.; Bohlke, J. K.; Hilkert, A. Anal. Chem.2002, 74, 4905-4912). The bacterial strain Pseudomonas aureofaciens (ATTC no. 13985) was shown to convert NO(3)(-) to N(2)O while retaining both N and O isotopic signatures, and automation of the isotopic analysis of N(2)O greatly increased the throughput of the method (Casciotti, K. L.; Sigman, D. M.; Galanter Hastings, M.; Bohlke, J. K.; Hilkert, A. Anal. Chem.2002, 74, 4905-4912). Continued development of the denitrifier method has led to increased precision and throughput of NO(3)(-) isotopic analysis. Presented here are several recent procedural modifications and the demonstration of their effectiveness. PMID- 21302936 TI - pH-dependent equilibrium isotope fractionation associated with the compound specific nitrogen and carbon isotope analysis of substituted anilines by SPME GC/IRMS. AB - Solid-phase microextraction (SPME) coupled to gas chromatography/isotope ratio mass spectrometry (GC/IRMS) was used to elucidate the effects of N-atom protonation on the analysis of N and C isotope signatures of selected aromatic amines. Precise and accurate isotope ratios were measured using polydimethylsiloxane/divinylbenzene (PDMS/DVB) as the SPME fiber material at solution pH-values that exceeded the pK(a) of the substituted aniline's conjugate acid by two pH-units. Deviations of delta(15)N and delta(13)C-values from reference measurements by elemental analyzer IRMS were small (<0.90/00) and within the typical uncertainties of isotope ratio measurements by SPME-GC/IRMS. Under these conditions, the detection limits for accurate isotope ratio measurements were between 0.64 and 2.1 mg L(-1) for delta(15)N and between 0.13 and 0.54 mg L(-1) for delta(13)C, respectively. Substantial inverse N isotope fractionation was observed by SPME-GC/IRMS as the fraction of protonated species increased with decreasing pH leading to deviations of -200/00 while the corresponding delta(13)C-values were largely invariant. From isotope ratio analysis at different solution pHs and theoretical calculations by density functional theory, we derived equilibrium isotope effects, EIEs, pertinent to aromatic amine protonation of 0.980 and 1.001 for N and C, respectively, which were very similar for all compounds investigated. Our work shows that N-atom protonation can compromise accurate compound-specific N isotope analysis of aromatic amines. PMID- 21302937 TI - Rapid discovery of death ligands with one-bead-two-compound combinatorial library methods. AB - The one-bead-one-compound (OBOC) technology enables one to generate thousands to millions of chemical molecules on resin beads (90 MUm diameter) such that each bead displays 10(13) copies of the same chemical entity. Whole-cell binding assays have been developed to screen OBOC combinatorial libraries for ligands that bind to specific cell surface receptors. While very powerful, this screening method does not address the downstream cell signaling properties of the binding ligand. We have modified the OBOC technology by introducing a fixed known cell adhesion ligand to the outer layer of each bead. This one-bead-two-compound (OB2C) library configuration allows the bound cells to interact with the random immobilized chemical molecules on each bead. The bound cells can then be probed for specific cellular responses such as apoptosis and activation or inhibition of a specific cell signaling pathway. To validate this concept, an OB2C combinatorial library was created such that a random hexapeptide plus a high affinity lymphoma targeting ligand LLP2A were displayed on each bead. This LLP2A X(6) OB2C library was then screened with human T-cell leukemia cells (Molt-4) for cell death responses. After 5 days of incubation, propidium iodide was added to the bead library to stain dead cells. Beads coated by red fluorescent cells were isolated for sequence analysis. Two ligands identified by this method, when added to the lymphoid cancer cells, were able to induce cell death. PMID- 21302938 TI - Electrorotation of metallic microspheres. AB - Electrorotation (ER) experiments of gold-coated micrometer-sized spheres suspended in an electrolyte are presented for three different ionic conductivities over the frequency range of 100 Hz to 40 MHz. The direction of rotation was observed to be counter-field (opposite to the rotating field vector) with a single rotation peak. The maximum in rotation occurs for a frequency on the order of the reciprocal RC time constant for charging the double layer at the gold surface. Dielectrophoresis (DEP) experiments showed that the gold-coated particles undergo negative DEP at low frequencies and positive DEP at high frequencies with the same relaxation frequency as electrorotation. No induced charge electrophoresis was noticeable in ER or DEP experiments. PMID- 21302939 TI - Comprehensive sensomics analysis of hop-derived bitter compounds during storage of beer. AB - For the first time, quantitative LC-MS/MS profiling of 56 hop-derived sensometabolites contributing to the bitter taste of beer revealed a comprehensive insight into the transformation of individual bitter compounds during storage of beer. The proton-catalyzed cyclization of trans-iso-alpha-acids was identified to be the quantitatively predominant reaction leading to lingering, harsh bitter tasting tri- and tetracyclic compounds such as, e.g. the cocongeners tricyclocohumol, tricyclocohumene, isotricyclocohumene, tetracyclocohumol, and epitetracyclocohumol, accumulating in beer during storage with increasing time and temperature. The key role of these transformation products in storage-induced trans-iso-alpha-acid degradation was verified for the first time by multivariate statistics and hierarchical cluster analysis of the sensomics data obtained for a series of commercial beer samples stored under controlled conditions. The present study offers the scientific basis for a knowledge-based extension of the shelf life of the desirable beer's bitter taste and the delay of the onset of the less preferred harsh bitter aftertaste by controlling the initial pH value of the beer and by keeping the temperature as low as possible during storage of the final beverage. PMID- 21302940 TI - Simultaneous Determination of Furostanol, Pennogenyl, and Diosgenyl Glycosides in Taiwanese Rhizoma Paridis ( Paris formosana Hayata) by high-performance liquid chromatography with evaporative light scattering detection. AB - A high-performance liquid chromatographic method with an evaporative light scattering detector (HPLC-ELSD) was developed to simultaneously determine 10 steroidal saponins, including 3 furostanol glycosides, 3 pennogenyl glycosides, and 4 diosgenyl glycosides in Taiwanese rhizoma paridis ( Paris formosana Hayata). The condition was a Cosmosil C18 column kept at 35 degrees C and a step gradient solvent system consisting of acetonitrile and water (25:75, v/v) in the first 30 min, 45:55 (v/v) from 31 to 45 min, and 50:50 (v/v) from 45 to 65 min, at a flow rate of 1 mL/min. The separation factors (alpha) and resolutions (Rs) were better than 1, and the limits of detection (LODs) and limits of quantification (LOQs) were 0.01-0.27 and 0.04-0.90 MUg, respectively, for these saponins. Moreover, 203 nm UV detection was also used for comparison. The saponins in P. formosana Hayata gathered from various areas of Taiwan were determined by applying the established method. PMID- 21302941 TI - Kinetics of heat-induced polymerization of gliadin. AB - The kinetics of heat-induced polymerization of gliadin, that is, a mixture of monomeric wheat storage proteins, was studied using a model system. Samples were heated at pH 6.0 and 8.0 at 110, 120, and 130 degrees C for up to 240 min, and their extractabilities were compared under nonreducing and reducing (with 1% dithiothreitol) conditions. Extraction media were sodium dodecyl sulfate (SDS) containing buffer (pH 6.8, SDS buffer) and/or 70% ethanol. Gliadin cross-linking mainly resulted from intermolecular disulfide (SS) bond formation. At higher temperatures and, preferably, alkaline pH, intramolecular SS bonds in gliadin underwent beta-elimination reactions, leading to the formation of dehydroalanine (DHA) and free sulfhydryl (SH) groups. The latter interchanged rapidly with SS bonds, leading to intermolecular SS bonds and gliadin extractability loss. When free SH groups had been formed, gliadin extractability in SDS buffer decreased following first-order reaction kinetics, the reaction rate constant of which increased with temperature and pH. Furthermore, the extractabilities of alpha- and gamma-gliadin in 70% ethanol decreased according to first-order reaction kinetics. omega-Gliadin extractability was much less affected. Under the experimental conditions, gliadin polymerization through SH-SS interchange occurred much more rapidly than beta-elimination of cystine. PMID- 21302942 TI - Comparison of metabolic profiling of cyanidin-3-O-galactoside and extracts from blueberry in aged mice. AB - The metabonomics changes of plasma and brain tissue after dietary supplementation with blueberry extracts (BBE) and cyanidin-3-O-galactoside from blueberry (BBM) in aged mice were investigated by (1)H NMR technique. The mice received intragastric administration of BBE (200 mg/kg/day), BBM (50 mg/kg/day), and saline water (0.9%) for 6 weeks, respectively, in the BBE, BBM, and control groups. At the end of the experiment, plasma and brain samples were collected for NMR analysis. The results demonstrated that the level of choline in plasma from BBE and BBM groups were obviously elevated relative to the control group, whereas the levels of lactate and phosphocholine in plasma were remarkably reduced. Compared with those in the control group, the levels of choline and GABA in the brain from the BBE group were obviously increased, whereas glutamate and phosphocholine in the BBE group were significantly decreased. The level of taurine in the brain from the BBM group was particularly higher than that in the control group. These results indicated supplementation with BBE or BBM might induce similar changes of endogenous plasma and brain metabolic profiles in aged mice. PMID- 21302944 TI - Dynamic combinatorial donor-acceptor catenanes in water: access to unconventional and unexpected structures. AB - We describe here the assembly of new types of donor-acceptor [2]catenanes from dynamic combinatorial libraries (DCL) in water. These new catenanes contain both the donor and acceptor components in at least one of the interlocked rings, thereby possessing unusual and unexpected DAAD or DADD stacking sequences of the pi units in their structures. The efficiency of the catenane assembly process can be enhanced by manipulating the DCL equilibrium in a variety of ways: adding a guest, changing the building block stoichiometries, or increasing the library concentration or the ionic strength of the solvent. The formation of catenanes and their constitutions are found to be dependent on subtle differences in the geometry, dimension, and flexibility of the donor building blocks. PMID- 21302945 TI - Unique assembly of charged polymers at the oil-water interface. AB - Understanding the interfacial adsorption of polymers has become increasingly important because a wide range of scientific disciplines utilize these macromolecular structures to facilitate processes such as nanoparticle assembly, environmental remediation, electrical multilayer assembly, and surfactant adsorption. Structure and adsorption characteristics for poly(acrylic acid) at the oil-water interface have been studied using vibrational sum frequency spectroscopy and interfacial tension to increase the comprehension of polyelectrolyte structure at interfaces. The adsorption of poly(acrylic acid) to the oil-water interface from the aqueous phase is found to be highly pH dependent and occurs in a multistep process, with the initial polymer adsorption displaying a high degree of conformational ordering. PMID- 21302943 TI - Genetic requirement for mutagenesis of the G[8,5-Me]T cross-link in Escherichia coli: DNA polymerases IV and V compete for error-prone bypass. AB - gamma-Radiation generates a variety of complex lesions in DNA, including the G[8,5-Me]T intrastrand cross-link in which C8 of guanine is covalently linked to the 5-methyl group of the 3'-thymine. We have investigated the toxicity and mutagenesis of this lesion by replicating a G[8,5-Me]T-modified plasmid in Escherichia coli with specific DNA polymerase knockouts. Viability was very low in a strain lacking pol II, pol IV, and pol V, the three SOS-inducible DNA polymerases, indicating that translesion synthesis is conducted primarily by these DNA polymerases. In the single-polymerase knockout strains, viability was the lowest in a pol V-deficient strain, which suggests that pol V is most efficient in bypassing this lesion. Most mutations were single-base substitutions or deletions, though a small population of mutants carrying two point mutations at or near the G[8,5-Me]T cross-link was also detected. Mutations in the progeny occurred at the cross-linked bases as well as at bases near the lesion site, but the mutational spectrum varied on the basis of the identity of the DNA polymerase that was knocked out. Mutation frequency was the lowest in a strain that lacked the three SOS DNA polymerases. We determined that pol V is required for most targeted G -> T transversions, whereas pol IV is required for the targeted T deletions. Our results suggest that pol V and pol IV compete to carry out error prone bypass of the G[8,5-Me]T cross-link. PMID- 21302946 TI - Adsorption and desorption of DNA on graphene oxide studied by fluorescently labeled oligonucleotides. AB - Being the newest member of the carbon materials family, graphene possesses many unique physical properties resulting is a wide range of applications. Recently, it was discovered that graphene oxide can effectively adsorb DNA, and at the same time, it can completely quench adsorbed fluorophores. These properties make it possible to prepare DNA-based optical sensors using graphene oxide. While practical analytical applications are being demonstrated, the fundamental understanding of binding between graphene oxide and DNA in solution received relatively less attention. In this work, we report that the adsorption of 12-, 18 , 24-, and 36-mer single-stranded DNA on graphene oxide is affected by several factors. For example, shorter DNAs are adsorbed more rapidly and bind more tightly to the surface of graphene. The adsorption is favored by a lower pH and a higher ionic strength. The presence of organic solvents such as ethanol can either increase or decrease adsorption depending on the ionic strength of the solution. By adding the cDNA, close to 100% desorption of the absorbed DNA on graphene can be achieved. On the other hand, if temperature is increased, only a small percentage of DNA is desorbed. Further, the adsorbed DNA can also be exchanged by free DNA in solution. These findings are important for further understanding of the interactions between DNA and graphene and for the optimization of DNA and graphene-based devices and sensors. PMID- 21302947 TI - Precision AFM measurements of dynamic interactions between deformable drops in aqueous surfactant and surfactant-free solutions. AB - The atomic force microscope (AFM) has provided unprecedented opportunities to study velocity-dependent interactions between deformable drops and bubbles under a range of solution conditions. The challenge is to design an experimental system that enables accurate force spectroscopy of the interaction between deformable drops and thus the extraction of accurate quantitative information about the physically important force-separation relation. This step requires very precise control and knowledge of the interfacial properties of the interacting drops, the drive conditions of the force-sensing cantilever, the disposition of the interacting drops on the substrate and on the cantilever, and transducer calibrations of the instrument in order to quantify the effects of approach velocities and interfacial deformation. This article examines and quantifies in detail all experimental conditions that are necessary to facilitate accurate processing of dynamic force spectroscopy data from the AFM using the well-defined system of tetradecane drops in aqueous solutions under surfactant and surfactant free conditions over a range of force magnitudes that has not been attained before. The ability of drops to deform and increase the effective area of interaction instead of decreasing the distance of closest approach when disjoining pressure exceeds the Laplace pressure means that the DLVO paradigm of colloidal stability as being determined by a balance of kinetic energy against the height of the primary maximum is no longer valid. The range of interfacially active species present in alkane-aqueous systems investigated provides insight into the applicability of the tangentially immobile boundary condition in colloidal interactions. PMID- 21302948 TI - Interplay between hydration water and headgroup dynamics in lipid bilayers. AB - In this study, the interplay between water and lipid dynamics has been investigated by broadband dielectric spectroscopy and modulated differential scanning calorimetry (MDSC). The multilamellar lipid bilayer system 1,2 dimyristoyl-sn-glycero-3-phosphocholine (DMPC) has been studied over a broad temperature range at three different water contents: about 3, 6, and 9 water molecules per lipid molecule. The results from the dielectric relaxation measurements show that at temperatures <250 K the lipid headgroup rotation is described by a super-Arrhenius temperature dependence at the lowest hydration level and by the Arrhenius law at the highest hydration level. This difference in the temperature dependence of the lipid headgroup rotation can be explained by the increasing interaction between the headgroups with decreasing water content, which causes their rotational motion to be more cooperative in character. The main water relaxation shows an anomalous dependence on the water content in the supercooled and glassy regime. In contrast to the general behavior of interfacial water, the water dynamics is fastest in the driest sample and its temperature dependence is best described by a super-Arrhenius temperature dependence. The best explanation for this anomalous behavior is that the water relaxation becomes more determined by fast local lipid motions than by the intrinsic water dynamics at low water contents. In support for this interpretation is the finding that the relaxation time of the main water process is faster than that in most other host systems at temperatures below 180 K. Thus, the dielectric relaxation data show clearly the strong interplay between water and lipid dynamics; the water influences the lipid dynamics and vice versa. In the MDSC data, we observe a weak enthalpy relaxation at 203 K for the driest sample and at 179 K for the most hydrated sample, attributed to the freezing-in of the lipid headgroup rotation observed in the dielectric data, since this motion reaches a time scale of about 100 s at about the same temperatures. PMID- 21302949 TI - Kinetic analysis of complex solid-state reactions. A new deconvolution procedure. AB - The kinetic analysis of complex solid-state reactions that involve simultaneous overlapping processes is challenging. A method that involves the deconvolution of the individual processes from the overall differential kinetic curves obtained under linear heating rate conditions, followed by the kinetic analysis of the discrete processes using combined kinetic analysis, is proposed. Different conventional mathematical fitting functions have been tested for deconvolution, paying special attention to the shape analysis of the kinetic curves. It has been shown that many conventional mathematical curves such as the Gaussian and Lorentzian ones fit kinetic curves inaccurately and the subsequent kinetic analysis yields incorrect kinetic parameters. Alternatively, other fitting functions such as the Fraser-Suzuki one properly fit the kinetic curves independently of the kinetic model followed by the reaction and their kinetic parameters, and moreover, the subsequent kinetic analysis yields the correct kinetic parameters. The method has been tested with the kinetic analysis of complex processes, both simulated and experimental. PMID- 21302950 TI - Structure and mechanical properties of wet-spun fibers made from natural cellulose nanofibers. AB - Cellulose nanofibers were prepared by TEMPO-mediated oxidation of wood pulp and tunicate cellulose. The cellulose nanofiber suspension in water was spun into an acetone coagulation bath. The spinning rate was varied from 0.1 to 100 m/min to align the nanofibers to the spun fibers. The fibers spun from the wood nanofibers had a hollow structure at spinning rates of >10 m/min, whereas the fibers spun from tunicate nanofibers were porous. Wide-angle X-ray diffraction analysis revealed that the wood and tunicate nanofibers were aligned to the fiber direction of the spun fibers at higher spinning rates. The wood spun fibers at 100 m/min had a Young's modulus of 23.6 GPa, tensile strength of 321 MPa, and elongation at break of 2.2%. The Young's modulus of the wood spun fibers increased with an increase in the spinning rate because of the nanofiber orientation effect. PMID- 21302951 TI - Graft polymerization of native chicken feathers for thermoplastic applications. AB - Inexpensive and biodegradable thermoplastics were developed through graft polymerization of native chicken feather with methyl acrylate as a potential substitute for petroleum products. Poultry feathers are available in large quantities at a low price. However, natural chicken feathers have poor thermoplasticity, cannot be used to develop thermoplastic products, have very limited industrial applications, and are often considered as solid wastes. In this research, the effects of graft polymerization conditions, such as molar ratio of NaHSO(3) to K(2)S(2)O(8), initiator and monomer concentrations, pH, temperature and time of polymerization, on grafting parameters, that is, the conversion of monomer to polymer, grafting percentage, and grafting efficiency were evaluated. Methyl acrylate was found to be successfully grafted onto functional groups on the surfaces of the chicken feathers, and optimal graft polymerization conditions were also obtained. The feather-g-poly(methyl acrylate) developed showed good thermoplasticity, and feather films had substantially higher tensile properties than soy protein isolate and starch acetate films. PMID- 21302952 TI - Aziridinofullerene: a versatile platform for functionalized fullerenes. AB - An aziridine moiety on the fullerene core can serve as an acid-triggered reacting template for the controlled synthesis of a range of functionalized fullerenes that are otherwise difficult to synthesize in an efficient and selective manner. A copper-catalyzed aziridination of C(60) for the practical synthesis of aziridinofullerene 1 and acid-catalyzed reactions of 1 with mono- and bifunctional nucleophiles as well as alkynes are described. The rapid generation of structural diversity in a single chemical operation using the common platform 1 is notable. PMID- 21302953 TI - Discovery of potent inhibitors of soluble epoxide hydrolase by combinatorial library design and structure-based virtual screening. AB - Structure-based virtual screening was applied to design combinatorial libraries to discover novel and potent soluble epoxide hydrolase (sEH) inhibitors. X-ray crystal structures revealed unique interactions for a benzoxazole template in addition to the conserved hydrogen bonds with the catalytic machinery of sEH. By exploitation of the favorable binding elements, two iterations of library design based on amide coupling were employed, guided principally by the docking results of the enumerated virtual products. Biological screening of the libraries demonstrated as high as 90% hit rate, of which over two dozen compounds were single digit nanomolar sEH inhibitors by IC(50) determination. In total the library design and synthesis produced more than 300 submicromolar sEH inhibitors. In cellular systems consistent activities were demonstrated with biochemical measurements. The SAR understanding of the benzoxazole template provides valuable insights into discovery of novel sEH inhibitors as therapeutic agents. PMID- 21302954 TI - Ag@poly(m-phenylenediamine) core-shell nanoparticles for highly selective, multiplex nucleic acid detection. AB - In this letter, we report on the one-step synthesis of Ag@poly(m phenylenediamine) core-shell nanoparticles (APCSNPs), carried out by direct mixing of aqueous silver nitrate and m-phenylenediamine solutions at room temperature. We further demonstrate the use of APCSNP as a novel fluorescent sensing platform for nucleic acid detection. In this regard, the detection of DNA is accomplished in two steps. First, APCSNP absorbs and quenches the fluorescence of dye-labeled single-stranded DNA (ssDNA) as a probe. Second, hybridizing of the probe with its target produces a double-stranded DNA (dsDNA) that detaches from APCSNP, resulting in the recovery of dye fluorescence. It suggests that this sensing system has a high selectivity down to single-base mismatch, and the results exhibit good reproducibility. Furthermore, we also demonstrate its application for the multiplex detection of nucleic acid sequences. PMID- 21302956 TI - Kinetics and mechanism of the electrochemical formation of iron oxidation products on steel immersed in sour acid media. AB - From electrochemical techniques (cyclic voltammetry, potential steps, and EIS), XRD, and SEM-EDX, the kinetics and mechanism of anodic film formation applying anodic potential steps on steel immersed in sour acid media was determined. It was found, from a thermodynamic analysis, based on equilibrium phase diagrams of the system considered in this work, that iron oxidation may produce different new solid phases, depending on the applied potential, the first being the iron oxidation associated with formation of FeS((c)) species, which in turn can be reoxidized to FeS(2(c)) or even to Fe(2)O(3(c)) at higher potential values. From analysis of the corresponding experimental potentiostatic current density transients, it was concluded that the electrochemical anodic film formation involves an E(1)CE(2) mechanism, whereby the first of the two simultaneous processes were the Fe electrochemical oxidation (E(1)) followed by FeS precipitation (C) that occurs by 3D nucleation and growth limited by mass transfer reaction and FeS oxidation (E(2)) forming a mix of different stoichiometry iron sulphides and oxides. From EIS measurements, it was revealed that the anodic film's charge transfer resistance diminishes as the potential applied for its formation becomes more anodic, thus behaving poorly against corrosion. PMID- 21302955 TI - Structures of beta-hairpin antimicrobial protegrin peptides in lipopolysaccharide membranes: mechanism of gram selectivity obtained from solid-state nuclear magnetic resonance. AB - The structural basis for the gram selectivity of two disulfide-bonded beta hairpin antimicrobial peptides (AMPs) is investigated using solid-state nuclear magnetic resonance (NMR) spectroscopy. The hexa-arginine PG-1 exhibits potent activities against both gram-positive and gram-negative bacteria, while a mutant of PG-1 with only three cationic residues maintains gram-positive activity but is 30-fold less active against gram-negative bacteria. We determined the topological structure and lipid interactions of these two peptides in a lipopolysaccharide (LPS)-rich membrane that mimics the outer membrane of gram-negative bacteria and in the POPE/POPG membrane, which mimics the membrane of gram-positive bacteria. (31)P NMR line shapes indicate that both peptides cause less orientational disorder in the LPS-rich membrane than in the POPE/POPG membrane. (13)C chemical shifts and (13)C-(1)H dipolar couplings show that both peptides maintain their beta-hairpin conformation in these membranes and are largely immobilized, but the mutant exhibits noticeable intermediate-time scale motion in the LPS membrane at physiological temperature, suggesting shallow insertion. Indeed, (1)H spin diffusion from lipid chains to the peptides shows that PG-1 fully inserts into the LPS-rich membrane whereas the mutant does not. The (13)C-(31)P distances between the most hydrophobically embedded Arg of PG-1 and the lipid (31)P are significantly longer in the LPS membrane than in the POPE/POPG membrane, indicating that PG-1 does not cause toroidal pore defects in the LPS membrane, in contrast to its behavior in the POPE/POPG membrane. Taken together, these data indicate that PG-1 causes transmembrane pores of the barrel-stave type in the LPS membrane, thus allowing further translocation of the peptide into the inner membrane of gram-negative bacteria to kill the cells. In comparison, the less cationic mutant cannot fully cross the LPS membrane because of weaker electrostatic attractions, thus causing weaker antimicrobial activities. Therefore, strong electrostatic attraction between the peptide and the membrane surface, ensured by having a sufficient number of Arg residues, is essential for potent antimicrobial activities against gram-negative bacteria. The data provide a rational basis for controlling gram selectivity of AMPs by adjusting the charge densities. PMID- 21302959 TI - Structure-based design of a heptavalent anthrax toxin inhibitor. AB - The design of polyvalent molecules, consisting of multiple copies of a biospecific ligand attached to a suitable scaffold, represents a promising approach to inhibit pathogens and oligomeric microbial toxins. Despite the increasing interest in structure-based drug design, few polyvalent inhibitors based on this approach have shown efficacy in vivo. Here we demonstrate the structure-based design of potent biospecific heptavalent inhibitors of anthrax lethal toxin. Specifically, we illustrate the ability to design potent polyvalent ligands by matching the pattern of binding sites on the biological target. We used a combination of experimental studies based on mutagenesis and computational docking studies to identify the binding site for an inhibitory peptide on the heptameric subunit of anthrax toxin. We developed an approach based on copper catalyzed azide-alkyne cycloaddition (click-chemistry) to facilitate the attachment of seven copies of the inhibitory peptide to a beta-cyclodextrin core via a polyethylene glycol linker of an appropriate length. The resulting heptavalent inhibitors neutralized anthrax lethal toxin both in vitro and in vivo and showed appreciable stability in serum. Given the inherent biocompatibility of cyclodextrin and polyethylene glycol, these potent well-defined heptavalent inhibitors show considerable promise as anthrax antitoxins. PMID- 21302960 TI - Pectin-based injectable biomaterials for bone tissue engineering. AB - A variety of natural polymers and proteins are considered to be 3D cell culture structures able to mimic the extracellular matrix (ECM) to promote bone tissue regeneration. Pectin, a natural polysaccharide extracted from the plant cell walls and having a chemical structure similar to alginate, provides interesting properties as artificial ECM. In this work, for the first time, pectin, modified with an RGD-containing oligopeptide or not, is used as an ECM alternative to immobilize cells for bone tissue regeneration. The viability, metabolic activity, morphology, and osteogenic differentiation of immobilized MC3T3-E1 preosteoblats demonstrate the potential of this polysaccharide to keep immobilized cells viable and differentiating. Preosteoblasts immobilized in both types of pectin microspheres maintained a constant viability up to 29 days and were able to differentiate. The grafting of the RGD peptide on pectin backbone induced improved cell adhesion and proliferation within the microspheres. Furthermore, not only did cells grow inside but also they were able to spread out from the microspheres and to organize themselves in 3D structures producing a mineralized extracellular matrix. These promising results suggest that pectin can be proposed as an injectable cell vehicle for bone tissue regeneration. PMID- 21302961 TI - Organocatalytic functionalization of carboxylic acids: isothiourea-catalyzed asymmetric intra- and intermolecular Michael addition--lactonizations. AB - Tetramisole promotes the catalytic asymmetric intramolecular Michael addition lactonization of a variety of enone acids, giving carbo- and heterocyclic products with high diastereo- and enantiocontrol (up to 99:1 dr, up to 99% ee) that are readily derivatized to afford functionalized indene and dihydrobenzofuran carboxylates. Chiral isothioureas also promote the catalytic asymmetric intermolecular Michael addition-lactonization of arylacetic acids and alpha-keto-beta,gamma-unsaturated esters, giving anti-dihydropyranones with high diastereo- and enantiocontrol (up to 98:2 dr, up to 99% ee). PMID- 21302963 TI - Protein micro- and nanopatterning using aminosilanes with protein-resistant photolabile protecting groups. AB - An approach to the integration of nanolithography with synthetic chemical methodology is described, in which near-field optical techniques are used to selectively deprotect films formed by the adsorption of aminosilanes protected by modified 2-nitrophenylethoxycarbonyl (NPEOC) groups. The NPEOC groups are functionalized at the m- or p-position with either a tetraethyleneglycol or a heptaethylene glycol adduct. We describe the synthesis of these bioresistant aminosilanes and the characterization of the resulting photoreactive films. Photodeprotection by exposure to UV light (lambda = 325 nm) yielded the amine with high efficiency, at a similar rate for all four adsorbates, and was complete after an exposure of 2.24 J cm(-2). Following photodeprotection, derivatization by trifluoroacetic anhydride was carried out with high efficiency. Micropatterned samples, formed using a mask, were derivatized with aldehyde-functionalized polymer nanoparticles and, following derivatization with biotin, were used to form patterns of avidin-coated polymer particles. Fluorescence microscopy and atomic force microscopy data demonstrated that the intact protecting groups conferred excellent resistance to nonspecific adsorption. Nanometer-scale patterns were created using scanning near-field photolithography and were derivatized with biotin. Subsequent conjugation with avidin-functionalized polymer nanoparticles yielded clear fluorescence images that indicated dense attachment to the nanostructures and excellent protein resistance on the surrounding surface. These simple photocleavable protecting group strategies, combined with the use of near-field exposure, offer excellent prospects for the control of surface reactivity at nanometer resolution in biological systems and offer promise for integrating the top-down and bottom-up molecular fabrication paradigms. PMID- 21302962 TI - Biodegradable and biocompatible synthetic saccharide-Peptide hydrogels for three dimensional stem cell culture. AB - Saccharide-peptide hydrogels have been developed in our laboratory as new synthetic extracellular matrices for regenerative medicine applications. In this work, we have expanded on our previously reported system and applied copolymerization of cysteine (Cys) and vinyl sulfone (VS)-functionalized saccharide-peptide polymers via Michael-type addition for encapsulation and 3D culture of cells. Specifically, our aims were to (1) develop a novel hydrogel platform, which could be applied for encapsulating and culturing mesenchymal stem cells (MSCs) in a 3D environment, (2) characterize the tunable properties of the hydrogel, specifically, degradation, mechanical, and gel network properties, and (3) determine the biocompatibility of the saccharide-peptide hydrogel material with MSCs. Hydrogel mechanical properties were tunable by varying the VS:Cys ratio (= 0.5, 1, or 2) as well as the pH (6, 7, or 8) of the cross-linking components. Stiffer gels were formed at VS:Cys = 1 and pH 6 or 7. Gels formed at pH 8 or with excess Cys (VS:Cys = 0.5) or VS (VS:Cys = 2) were significantly softer. Cross-linking pH and VS:Cys ratio also had an effect on the degradation behavior of the VS:Cys gels, with higher cross-linking pH resulting in an accelerated loss of mass. On the basis of environmental scanning electron microscopy (ESEM) analysis and fluorescence microscopy, all hydrogels appeared to exhibit porous gel networks. MSCs cultured in monolayer and exposed to soluble Cys or VS copolymers (0.1-5 mg/mL) did not exhibit measurable cytotoxicity. In addition, MSCs were cultured in 3D for up to 14 days in vitro without deleterious effects on cell viability. In summary, we have established and characterized a tunable 3D saccharide-peptide hybrid copolymer hydrogel platform for culturing MSCs. Future studies will focus on utilizing the hydrogel system for controlling the differentiation of MSCs. PMID- 21302964 TI - Claurailas A-D, cytotoxic carbazole alkaloids from the roots of Clausena harmandiana. AB - Four new carbazole alkaloids, claurailas A-D (1-4), as well as 12 known carbazoles and three known coumarins were isolated from the roots of Clausena harmandiana. Heptaphylline (6) and 7-methoxyheptaphylline (7) showed strong cytotoxicity against NCI-H187 and KB cell lines with IC(50) values ranging from 1.3 to 2.7 MUM. Compound 7 showed no cytotoxicity against Vero cells. PMID- 21302965 TI - Pestaloquinols A and B, isoprenylated epoxyquinols from Pestalotiopsis sp. AB - Two new isoprenylated epoxyquinol derivatives, pestaloquinols A (2) and B (3), and their putative biosynthetic precursor, cytosporin D (1), were isolated from the crude extract of the plant endophytic fungus Pestalotiopsis sp. The structures of these compounds were elucidated primarily by NMR experiments. Pestaloquinols A (2) and B (3) possess a previously undescribed nonacyclic ring system and showed cytotoxicity against HeLa cells. PMID- 21302966 TI - Phosphine- and nitrogen-containing Lewis base catalyzed highly regioselective and geometric selective cyclization of isatin derived electron-deficient alkenes with ethyl 2,3-butadienoate. AB - An interesting phosphine-containing Lewis base catalyzed highly regioselective [3 + 2] cycloaddition and a novel nitrogen-containing Lewis base catalyzed highly geometric selective [4 + 2] cycloaddition of isatin derived alpha,beta unsaturated diesters with alpha-allenic ester have been disclosed to give the corresponding cyclic products in good to excellent yields under mild conditions. A plausible reaction mechanism has also been proposed on the basis of previous literature and our own investigation. PMID- 21302967 TI - Blockade of IL-6 secretion pathway by the sesquiterpenoid atractylenolide III. AB - Atractylenolide III (1) is the major bioactive component of Atractylodes lancea. The aim of this study was to analyze the effect on the regulation of interleukin (IL)-6 secretion pathway caused by 1. This sesquiterpenoid inhibited the secretion and expression of IL-6 in phorbol 12-myristate 13-acetate- and calcium ionophore A23187-stimulated human mast cells (HMC)-1. In addition, 1 inhibited histamine release in stimulated HMC-1 cells. In stimulated HMC-1 cells, 1 suppressed activation of p38 mitogen-activated protein kinase, C-Jun-N-terminal protein kinase, and nuclear factor-kappaB. In addition, 1 suppressed the activation of caspase-1 and the expression of receptor interacting protein-2. These results provide new insights that atractylenolide III (1) may control immunological reactions by regulating the cellular functions of IL-6 in mast cells. PMID- 21302968 TI - Unusual formal [4 + 2] cycloaddition of ethyl allenoate with arylidenoxindoles: synthesis of dihydropyran-fused indoles. AB - An unusual DABCO-catalyzed formal [4 + 2] cycloaddition of ethyl allenoate, as a surrogate of a "1,2-dipole", with various arylidenoxindoles has been developed for the synthesis of dihydropyran-fused indoles. The DFT mechanistic study indicates that the cycloaddition takes place stepwise and the essential role of the catalyst is to raise the HOMO of allenoate. PMID- 21302969 TI - Design, synthesis, and evaluation of a helicenoidal DMAP Lewis base catalyst. AB - The design, synthesis, and study of a helical dialkylaminopyridine Lewis base catalyst is reported. Helical DMAP analogue 4 is based upon a helicenoid structure and displays good to excellent levels of selectivity (S <= 116) in the kinetic resolution of chiral secondary alcohols. Catalyst 4 displays excellent reactivity with exceptionally low loadings of 0.05 mol % effecting practical levels of selectivity in kinetic resolutions. PMID- 21302970 TI - Comparison of MALDI-TOF-MS and HPLC-ESI-MS/MS for endopeptidase activity-based quantification of Anthrax lethal factor in serum. AB - Diagnosing and treating anthrax at the earliest stage of disease is critical. We developed a method to diagnose anthrax at early stages of infection by detecting anthrax lethal factor (LF) at the attomol/mL level in plasma or serum. This method uses antibody capture and quantification of LF endoproteinase activity by isotope dilution matrix-assisted laser-desorption ionization (MALDI) time-of flight (TOF) mass spectrometry (MS). Many public health laboratories do not use MALDI-TOF-MS; thus, we have adapted the LF method for detection by electrospray ionization (ESI) tandem MS (MS/MS), which allowed comparison of both MS platforms for LF quantification. Calibration curves were linear from 0.05-2.5 ng/mL when measured after 2 h and from 0.005-1.0 ng/mL after 18 h incubation time. The limit of detection was 0.005 ng/mL using a 200 MUL sample. The coefficient of variation for quality control samples was 6-12% for both MS platforms. Samples used to perform cross-validation included 158 serum samples from a study in rabbits exposed to anthrax spores by inhalation. Some were treated with anthrax immune globulin before exposure. Concentrations measured by ESI-MS/MS matched those by MALDI-TOF-MS with p = 0.99 (r(2) = 0.997) and -0.25% mean relative difference (+/ 9% standard deviation). This study shows that isotope dilution MALDI-TOF-MS is a robust and precise quantitative MS platform. PMID- 21302971 TI - Preface to the Supramolecular chemistry at interfaces special issue. PMID- 21302972 TI - NMR profiling of histone deacetylase and acetyl-transferase activities in real time. AB - Histone deacetylases (HDACs) and histone acetyl-transferases (HATs) are universal regulators of eukaryotic transcriptional activity and emerging therapeutic targets for human diseases. Here we describe the generation of isotope-labeled deacetylation and acetylation reporters for simultaneous NMR readouts of multiple deacetylation and acetylation reactions at different histone H4 sites. The site preferences of two prototypic histone deacetylases (Sir2.1 and HDAC8) and two acetyl-transferases (HAT1 and p300/CBP) were studied in intramolecular competition assays. We identify a previously ill-defined acetylation site, lysine 20 of histone H4, as a preferred target of three of theses enzymes. In situ analyses of endogenous deacetylation reactions at H4 sites in HeLa nuclear extracts point to abundant HDAC activities in human cellular environments. PMID- 21302974 TI - Nickel-catalyzed cycloaddition of anthranilic acid derivatives to alkynes. AB - A nickel-catalyzed cycloaddition has been developed where readily available anthranilic acid derivatives react with alkynes to afford substituted indoles. The reaction involves oxidative addition of Ni(0) to an ester moiety, which allows intermolecular addition to alkynes via decarbonylation and 1,3-acyl migration. PMID- 21302973 TI - Nanoimprint lithography for high-efficiency thin-film silicon solar cells. AB - We demonstrate high-efficiency thin-film silicon solar cells with transparent nanotextured front electrodes fabricated via ultraviolet nanoimprint lithography on glass substrates. By replicating the morphology of state-of-the-art nanotextured zinc oxide front electrodes known for their exceptional light trapping properties, conversion efficiencies of up to 12.0% are achieved for micromorph tandem junction cells. Excellent light incoupling results in a remarkable summed short-circuit current density of 25.9 mA/cm(2) for amorphous top cell and microcrystalline bottom cell thicknesses of only 250 and 1100 nm, respectively. As efforts to maximize light harvesting continue, our study validates nanoimprinting as a versatile tool to investigate nanophotonic effects of a large variety of nanostructures directly on device performance. PMID- 21302975 TI - Perceptual assimilation of Dutch vowels by Peruvian Spanish listeners. AB - Many cross-language and L2 speech perception studies have been conducted on English sounds and a limited number of speakers or synthetic tokens have been used for auditory stimuli. The Spanish listeners of the present study were presented with natural tokens of Dutch vowels produced by males and females selected from the corpus reported in Adank et al. [(2004) J. Acoust. Soc. Am. 116, 1729-1738]. The results show that single category assimilations are common and that certain Dutch vowels frequently assimilate to Spanish diphthongs. Predictions are made for Spanish learners' initial stage in the acquisition of the Dutch vowel system. PMID- 21302976 TI - Lateralization produced by interaural intensitive disparities appears to be larger for high- vs low-frequency stimuli. AB - The purpose of this communication is to report the results of a study indicating that a given magnitude of interaural intensitive disparity (IID) produced a larger extent of laterality, as measured via an acoustic pointer, for stimuli centered at 4 kHz than for stimuli centered at 500 Hz. The data and their analysis, taken together, suggest that the findings reflect true across-frequency differences rather than being manifestations of response-related factors. PMID- 21302977 TI - Noise tolerance in human frequency-following responses to voice pitch. AB - Speech communication usually occurs in the presence of background noise. This study examined noise tolerance in the brainstem's processing of voice pitch, as reflected by the scalp-recorded frequency-following response (FFR) from 12 normal hearing adults. By systematically manipulating signal-to-noise ratio (SNR) across three different stimulus intensities, the results indicated that Frequency Error, Slope Error, and Tracking Accuracy remained relatively stable until SNR was degraded to 0 dB or lower (i.e., a turning point). This turning point not only provided physiological evidence supporting pitch tolerance of noise but also allowed recommendation of a minimal SNR when evaluating pitch processing in difficult-to-test patients. PMID- 21302978 TI - Investigations on the balloon as an impulse source. AB - Measurements of impulses produced by bursting balloons are presented. Various sizes of balloons were popped with a mechanical device in an anechoic chamber and recorded with a spherical microphone array. The power responses and directivity of the balloons are analyzed. Results indicate that power responses have two emphasized frequencies which depend on balloon size and inflation level. Larger balloons radiated more energy and higher inflation levels resulted in stronger high frequency content. Balloon directivity patterns are stable over repetitions. However, balloons do not radiate omnidirectionally. The degree of omnidirectionality improves with balloon size and for midrange frequencies. PMID- 21302979 TI - A method for evaluating the relation between sound source segregation and masking. AB - Sound source segregation refers to the ability to hear as separate entities two or more sound sources comprising a mixture. Masking refers to the ability of one sound to make another sound difficult to hear. Often in studies, masking is assumed to result from a failure of segregation, but this assumption may not always be correct. Here a method is offered to identify the relation between masking and sound source segregation in studies and an example is given of its application. PMID- 21302980 TI - Experimental implementation of reverse time migration for nondestructive evaluation applications. AB - Reverse time migration (RTM) is a commonly employed imaging technique in seismic applications (e.g., to image reservoirs of oil). Its standard implementation cannot account for multiple scattering/reverberation. For this reason it has not yet found application in nondestructive evaluation (NDE). This paper applies RTM imaging to NDE applications in bounded samples, where reverberation is always present. This paper presents a fully experimental implementation of RTM, whereas in seismic applications, only part of the procedure is done experimentally. A modified RTM imaging condition is able to localize scatterers and locations of disbonding. Experiments are conducted on aluminum samples with controlled scatterers. PMID- 21302981 TI - Frequency discrimination duration effects for Huggins pitch and narrowband noise (L). AB - Frequency difference limens (FDLs) were measured for Huggins pitch (HP) stimuli, consisting of a 30-Hz wide band of interaurally decorrelated noise in a diotic low-pass noise and for 30-Hz wide bands of diotic narrowband noise presented in a diotic low-pass noise background. FDLs at a 400-ms duration for the two stimulus types were equated by adjusting the level of the narrowband noise relative to the background. The effects of duration on the FDLs were then measured for center frequencies of 300, 600, and 900 Hz. Although the results were compromised by floor effects at 900 Hz, at 300 and 600 Hz, the duration effects were very similar for the HP and narrowband noise stimuli, with a large improvement in performance between 100 and 400 ms. In contrast to previous results for pure tones, the effect of duration was independent of frequency. The results suggest that: (1) Binaural and monaural pitches may be processed using a common mechanism; (2) discrimination performance for HP and low-sensation-level narrowband noise stimuli is not determined by the number of waveform periods. PMID- 21302982 TI - Higher mode sound transmission from a point source through a rectangular aperture. AB - This paper considers the higher-order scattered and transmitted wave fields that result when an acoustic wave from a point source impinges at an arbitrary angle on a rectangular aperture in a rigid, thick wall. In this analysis, it is assumed that free field conditions exist on both sides of the aperture. Although the full scattered and transmitted pressure fields contain both modal sum and modal coupling effects, the modal coupling effects of the higher-order modes are ignored such that an approximate analytical solution to the uncoupled analysis can be utilized. Experiments have been undertaken to measure the sound pressure levels in the transmitted field that result when sound from a point source impinges on the opposite side of a rectangular aperture. Measurements were made with the source located at the required position to drive a particular in aperture higher-order mode. The source was also located at positions that did not directly excite any in-aperture higher-order mode at a cut-on frequency. These results indicate that the approximate analysis developed here gives accurate solutions whether or not any mode of the aperture is driven at cut-on. Thus, the method can be used for any relative location of a source from a rectangular aperture of any dimensions. PMID- 21302983 TI - Acoustical scattering by multilayer spherical elastic scatterer containing electrorheological layer. AB - A computational procedure for analyzing acoustical scattering by multilayer concentric spherical scatterers having an arbitrary mixture of acoustic and elastic materials is proposed. The procedure is then used to analyze the scattering by a spherical scatterer consisting of a solid shell and a solid core encasing an electrorheological (ER) fluid layer, and the tunability in the scattering characteristics afforded by the ER layer is explored numerically. Tunable scatterers with two different ER fluids are analyzed. One, corn starch in peanut oil, shows that a significant increase in scattering cross-section is possible in moderate frequencies. Another, fine poly-methyl methacrylate (PMMA) beads in dodecane, shows only slight change in scattering cross-sections overall. But, when the shell is thin, a noticeable local resonance peak can appear near ka=1, and this resonance can be turned on or off by the external electric field. PMID- 21302984 TI - Green's function of radial inhomogeneous spheres excited by internal sources. AB - Green's function in the interior of penetrable bodies with inhomogeneous compressibility by sources placed inside them is evaluated through a Schwinger Lippmann volume integral equation. In the case of a radial inhomogeneous sphere, the radial part of the unknown Green's function can be expanded in a double Dini's series, which allows analytical evaluation of the involved cumbersome integrals. The simple case treated here can be extended to more difficult situations involving inhomogeneous density as well as to the corresponding electromagnetic or elastic problem. Finally, numerical results are given for various inhomogeneous compressibility distributions. PMID- 21302985 TI - Evaluation of a wave-vector-frequency-domain method for nonlinear wave propagation. AB - A wave-vector-frequency-domain method is presented to describe one-directional forward or backward acoustic wave propagation in a nonlinear homogeneous medium. Starting from a frequency-domain representation of the second-order nonlinear acoustic wave equation, an implicit solution for the nonlinear term is proposed by employing the Green's function. Its approximation, which is more suitable for numerical implementation, is used. An error study is carried out to test the efficiency of the model by comparing the results with the Fubini solution. It is shown that the error grows as the propagation distance and step-size increase. However, for the specific case tested, even at a step size as large as one wavelength, sufficient accuracy for plane-wave propagation is observed. A two dimensional steered transducer problem is explored to verify the nonlinear acoustic field directional independence of the model. A three-dimensional single element transducer problem is solved to verify the forward model by comparing it with an existing nonlinear wave propagation code. Finally, backward-projection behavior is examined. The sound field over a plane in an absorptive medium is backward projected to the source and compared with the initial field, where good agreement is observed. PMID- 21302986 TI - Aspects of ground effect modeling. AB - A recently published one-parameter ground model based on Darcy's law is here generalized into a two-parameter model which depends on an effective flow resistivity and an effective layer depth. Extensive field measurements of the acoustic impedance of various ground types have been carried out for frequencies in the range from 200 Hz to 2.5 kHz. The model based on Darcy's law gives an improved fit to the measurements compared to the Delany-Bazley model. It is, in addition, argued on purely theoretical grounds that the suggested model is preferable. In contrast to the Delany-Bazley model it corresponds to a proper causal time-domain model. This is particularly relevant for extrapolation of the models to lower frequencies and for the recently developed harmonized methods intended for use in the implementation of the European Union directive on the assessment and management of environmental noise. The harmonized methods include frequencies down to the 25 Hz third octave band and have the Delany-Bazley ground impedance model as the default choice. The arguments presented here suggest that this default choice should be replaced by the more physically based model from the law of Darcy. PMID- 21302987 TI - Interpretation of multi-frequency acoustic data: effects of fish orientation. AB - One goal of fisheries acoustics is to develop objective classification or identification methods to automate allocation of acoustic backscatter to species. Classification schemes rely on consistent relationships for successful apportionment of acoustic backscatter to species. A method is developed that compares frequency-dependent volume backscatter from an acoustical survey of Atlantic herring (Clupea harengus) to investigate the potential for classifying herring. Predicted backscattering patterns by a Kirchhoff-ray approximation are used to explain the observed relationships and evaluate the potential for classification of multi-frequency data. Combining predicted backscatter with observations of the frequency-dependent volume backscatter gave approximately 40% classification success, which is not sufficient for survey purposes. However, this method highlighted potential consequences that fish orientation may have on classification schemes and density and abundance estimates. This method of comparing multi-frequency volume backscatter appears to be beneficial for detecting behavioral changes by groups of fish, which may be used to select target strength values for density or abundance estimates. Utilizing predicted target strengths from numerical or analytical solutions or approximations, appropriate target strengths could be selected and would provide more accurate estimates of fish density and abundance. PMID- 21302988 TI - Wind-generated ambient noise in a topographically isolated basin: a pre industrial era proxy. AB - During the mid-1980s, calibrated measurements of ambient noise and wind speed were made in the Tongue of the Ocean in the Bahamas to quantify the spectra and statistics of wind-generated noise. This deep basin is topographically isolated from the Atlantic Ocean and, therefore, largely acoustically decoupled from the Atlantic Ocean deep sound channel. The quantitative effects of contaminating (non surface wind-generated) noise sources within the basin were eliminated by careful measurement and robust statistical analysis methodologies. Above 500 Hz, the spectral slopes are approximately -5 dB per octave and independent of wind speed. Below 500 Hz, the ambient noise is no longer a linear function of wind speed. Below 100 Hz and for wind speeds greater than 18.5 knots (kt), the ambient noise is independent of frequency. The minimum observed ambient noise level falls 13 dB below Urick's "light shipping" level at 30 Hz and 2-5 dB below Wenz's sea state zero level through the wind-dominated portion of the spectrum. The basin's geographical isolation and the rigorous measurement and analysis methodologies employed make this two-decade-old data set a reasonable and justified proxy for pre-industrial era ocean noise levels in the 20 Hz to 20 kHz frequency band. PMID- 21302989 TI - The effect of coupling on bubble fragmentation acoustics. AB - Understanding the formation and evolution of bubble populations is important in a wide range of situations, including industrial processes, medical applications, and ocean science. Passive acoustical techniques can be used to track changes in the population, since each bubble formation or fragmentation event is likely to produce sound. This sound potentially contains a wealth of information about the fragmentation process and the products, but to fully exploit these data it is necessary to understand the physical processes that determine its characteristics. The focus of this paper is binary fragmentation, when turbulence causes one bubble to split into two. Specifically, the effect that bubble-bubble coupling has on the sound produced is examined. A numerical simulation of the acoustical excitation of fragmenting bubbles is used to generate model acoustic signals, which are compared with experimental data. A frequency range with a suppressed acoustic output which is observed in the experimental data can be explained when coupling is taken into account. In addition, although the driving mechanism of neck collapse is always consistent with the data for the larger bubble of the newly formed pair, a different mechanism must be driving the smaller bubble in some situations. PMID- 21302990 TI - Target detection and localization in shallow water: an experimental demonstration of the acoustic barrier problem at the laboratory scale. AB - This study demonstrates experimentally at the laboratory scale the detection and localization of a wavelength-sized target in a shallow ultrasonic waveguide between two source-receiver arrays at 3 MHz. In the framework of the acoustic barrier problem, at the 1/1000 scale, the waveguide represents a 1.1-km-long, 52 m-deep ocean acoustic channel in the kilohertz frequency range. The two coplanar arrays record in the time-domain the transfer matrix of the waveguide between each pair of source-receiver transducers. Invoking the reciprocity principle, a time-domain double-beamforming algorithm is simultaneously performed on the source and receiver arrays. This array processing projects the multireverberated acoustic echoes into an equivalent set of eigenrays, which are defined by their launch and arrival angles. Comparison is made between the intensity of each eigenray without and with a target for detection in the waveguide. Localization is performed through tomography inversion of the acoustic impedance of the target, using all of the eigenrays extracted from double beamforming. The use of the diffraction-based sensitivity kernel for each eigenray provides both the localization and the signature of the target. Experimental results are shown in the presence of surface waves, and methodological issues are discussed for detection and localization. PMID- 21302991 TI - Fluctuating arrivals of short-range acoustic data. AB - Geoacoustic inversion using fluctuating signal observations can be challenging. The origin of these fluctuations needs to be understood so the signals can be used appropriately. A set of experiments [Tang et al., Oceanogr. 20(4), 156-167 (2007)] was carried out in shallow water near the New Jersey shelf break in summer 2006. Significant fluctuations in the direct path and surface-reflected arrivals of short-range chirp transmissions (1.1-2.9 kHz) were observed on a vertical line array. This paper explains the origin of these signal fluctuations through analysis of the arrival amplitudes. It is shown that the strong thermocline combined with an oscillating source motion due to ocean surface waves results in the signal fluctuations. PMID- 21302992 TI - Multiple scattering by cylinders immersed in fluid: high order approximations for the effective wavenumbers. AB - Acoustic wave propagation in a fluid with a random assortment of identical cylindrical scatterers is considered. While the leading order correction to the effective wavenumber of the coherent wave is well established at dilute areal density (n0) of scatterers, in this paper the higher order dependence of the coherent wavenumber on n0 is developed in several directions. Starting from the quasi-crystalline approximation (QCA) a consistent method is described for continuing the Linton and Martin formula, which is second order in n0, to higher orders. Explicit formulas are provided for corrections to the effective wavenumber up to O (n0(4)). Then, using the QCA theory as a basis, generalized self-consistent schemes are developed and compared with self-consistent schemes using other dynamic effective medium theories. It is shown that the Linton and Martin formula provides a closed self-consistent scheme, unlike other approaches. PMID- 21302993 TI - Comparison between maximum radial expansion of ultrasound contrast agents and experimental postexcitation signal results. AB - Experimental postexcitation signal data of collapsing Definity microbubbles are compared with the Marmottant theoretical model for large amplitude oscillations of ultrasound contrast agents (UCAs). After taking into account the insonifying pulse characteristics and size distribution of the population of UCAs, a good comparison between simulated results and previously measured experimental data is obtained by determining a threshold maximum radial expansion (Rmax) to indicate the onset of postexcitation. This threshold Rmax is found to range from 3.4 to 8.0 times the initial bubble radius, R0, depending on insonification frequency. These values are well above the typical free bubble inertial cavitation threshold commonly chosen at 2R0. The close agreement between the experiment and models suggests that lipid-shelled UCAs behave as unshelled bubbles during most of a large amplitude cavitation cycle, as proposed in the Marmottant equation. PMID- 21302994 TI - Liquid compressibility effects during the collapse of a single cavitating bubble. AB - The effect of liquid compressibility on the dynamics of a single, spherical cavitating bubble is studied. While it is known that compressibility damps the amplitude of bubble rebounds, the extent to which this effect is accurately captured by weakly compressible versions of the Rayleigh-Plesset equation is unclear. To clarify this issue, partial differential equations governing conservation of mass, momentum, and energy are numerically solved both inside the bubble and in the surrounding compressible liquid. Radiated pressure waves originating at the unsteady bubble interface are directly captured. Results obtained with Rayleigh-Plesset type equations accounting for compressibility effects, proposed by Keller and Miksis [J. Acoust. Soc. Am. 68, 628-633 (1980)], Gilmore, and Tomita and Shima [Bull. JSME 20, 1453-1460 (1977)], are compared with those resulting from the full model. For strong collapses, the solution of the latter reveals that an important part of the energy concentrated during the collapse is used to generate an outgoing pressure wave. For the examples considered in this research, peak pressures are larger than those predicted by Rayleigh-Plesset type equations, whereas the amplitudes of the rebounds are smaller. PMID- 21302995 TI - Acoustical power amplification and damping by temperature gradients. AB - Ceperley proposed a concept of a traveling wave heat engine ["A pistonless Stirling engine-The traveling wave heat engine," J. Acoust. Soc. Am. 66, 1508 1513 (1979).] that provided a starting point of thermoacoustics today. This paper verifies experimentally his idea through observation of amplification and strong damping of a plane acoustic traveling wave as it passes through axial temperature gradients. The acoustic power gain is shown to obey a universal curve specified by a dimensionless parameter omegataualpha; omega is the angular frequency and taualpha is the relaxation time for the gas to thermally equilibrate with channel walls. As an application of his idea, a three-stage acoustic power amplifier is developed, which attains the gain up to 10 with a moderate temperature ratio of 2.3. PMID- 21302996 TI - Material selection for acoustic radiators that are light and stiff. AB - The headmass is a key element in tonpilz transducer design. As an acoustic radiator, a successful headmass must be built from a material that is both light and stiff. To assess the suitability of ceramics for this application, the authors used the mechanical properties of candidate materials to perform a theoretical comparison based on the flexural behavior of square plates. Although not a comprehensive metric for identifying the best headmass materials, the headmass flexure may be usefully employed as a first-level selection criteria. A software routine based on thin plate and thick plate theory was created to evaluate the flexural behavior in candidate materials. PMID- 21302997 TI - A synthesis approach for reproducing the response of aircraft panels to a turbulent boundary layer excitation. AB - Random wall-pressure fluctuations due to the turbulent boundary layer (TBL) are a feature of the air flow over an aircraft fuselage under cruise conditions, creating undesirable effects such as cabin noise annoyance. In order to test potential solutions to reduce the TBL-induced noise, a cost-efficient alternative to in-flight or wind-tunnel measurements involves the laboratory simulation of the response of aircraft sidewalls to high-speed subsonic TBL excitation. Previously published work has shown that TBL simulation using a near-field array of loudspeakers is only feasible in the low frequency range due to the rapid decay of the spanwise correlation length with frequency. This paper demonstrates through theoretical criteria how the wavenumber filtering capabilities of the radiating panel reduces the number of sources required, thus dramatically enlarging the frequency range over which the response of the TBL-excited panel is accurately reproduced. Experimental synthesis of the panel response to high-speed TBL excitation is found to be feasible over the hydrodynamic coincidence frequency range using a reduced set of near-field loudspeakers driven by optimal signals. Effective methodologies are proposed for an accurate reproduction of the TBL-induced sound power radiated by the panel into a free-field and when coupled to a cavity. PMID- 21302998 TI - Experimental study of a smart foam sound absorber. AB - This article presents the experimental implementation and results of a hybrid passive/active absorber (smart foam) made up from the combination of a passive absorbent (foam) and a curved polyvinylidene fluoride (PVDF) film actuator bonded to the rear surface of the foam. Various smart foam prototypes were built and tested in active absorption experiments conducted in an impedance tube under plane wave propagation condition at frequencies between 100 and 1500 Hz. Three control cases were tested. The first case used a fixed controller derived in the frequency domain from estimations of the primary disturbance at a directive microphone position in the tube and the transfer function between the control PVDF and the directive microphone. The two other cases used an adaptive time domain feedforward controller to absorb either a single-frequency incident wave or a broadband incident wave. The non-linearity of the smart foams and the causality constraint were identified to be important factors influencing active control performance. The effectiveness of the various smart foam prototypes is discussed in terms of the active and passive absorption coefficients as well as the control voltage of the PVDF actuator normalized by the incident sound pressure. PMID- 21302999 TI - Mathematically trivial control of sound using a parametric beam focusing source. AB - By exploiting a case regarded as trivial, this paper presents global active noise control using a parametric beam focusing source (PBFS). As with a dipole model, one is used for a primary sound source and the other for a control sound source, the control effect for minimizing a total acoustic power depends on the distance between the two. When the distance becomes zero, the total acoustic power becomes null, hence nothing less than a trivial case. Because of the constraints in practice, there exist difficulties in placing a control source close enough to a primary source. However, by projecting a sound beam of a parametric array loudspeaker onto the target sound source (primary source), a virtual sound source may be created on the target sound source, thereby enabling the collocation of the sources. In order to further ensure feasibility of the trivial case, a PBFS is then introduced in an effort to meet the size of the two sources. Reflected sound wave of the PBFS, which is tantamount to the virtual sound source output, aims to suppress the primary sound. Finally, a numerical analysis as well as an experiment is conducted, verifying the validity of the proposed methodology. PMID- 21303000 TI - On the stability of adaptation process in active noise control systems. AB - The stability analysis of the adaptation process, performed by the filtered-x least mean square algorithm on weights of active noise controllers, has not been fully investigated. The main contribution of this paper is conducting a theoretical stability analysis for this process without utilizing commonly used simplifying assumptions regarding the secondary electro-acoustic channel. The core of this analysis is based on the root locus theory. The general rules for constructing the root locus plot of the adaptation process are derived by obtaining root locus parameters, including start points, end points, asymptote lines, and breakaway points. The conducted analysis leads to the derivation of a general upper-bound for the adaptation step-size beyond which the mean weight vector of the active noise controller becomes unstable. Also, this analysis yields the optimum step-size for which the adaptive active noise controller has its fastest dynamic performance. The proposed upper-bound and optimum values apply to general secondary electro-acoustic channels, unlike the commonly used ones which apply to only pure delay channels. The results are found to agree very well with those obtained from numerical analyses and computer simulation experiments. PMID- 21303001 TI - Aircraft noise: accounting for changes in air traffic with time of day. AB - Aircraft noise contours are estimated using model calculations and, due to their impact on land use planning, they need to be highly accurate. During night time, not only the number and dominant types of aircraft may differ from daytime but also the flight paths flown may differ. To determine to which detail these variations in flight paths need to be considered, calculations were performed exemplarily for two airports using all available radar data over 1 year, taking into account their changes over the day. The results of this approach were compared with results of a simpler approach which does not consider such changes. While both calculations yielded similar results for the day and close to the airport, differences increased with distance as well as with the period of day (dayn transition energy and solvatochromic shift are in good agreement with other theoretical results. PMID- 21303097 TI - Maximum likelihood-based analysis of single-molecule photon arrival trajectories. AB - In this work we explore the statistical properties of the maximum likelihood based analysis of one-color photon arrival trajectories. This approach does not involve binning and, therefore, all of the information contained in an observed photon strajectory is used. We study the accuracy and precision of parameter estimates and the efficiency of the Akaike information criterion and the Bayesian information criterion (BIC) in selecting the true kinetic model. We focus on the low excitation regime where photon trajectories can be modeled as realizations of Markov modulated Poisson processes. The number of observed photons is the key parameter in determining model selection and parameter estimation. For example, the BIC can select the true three-state model from competing two-, three-, and four-state kinetic models even for relatively short trajectories made up of 2 * 10(3) photons. When the intensity levels are well-separated and 10(4) photons are observed, the two-state model parameters can be estimated with about 10% precision and those for a three-state model with about 20% precision. PMID- 21303098 TI - Explicitly time-dependent coupled cluster singles doubles calculations of laser driven many-electron dynamics. AB - We report explicitly time-dependent coupled cluster singles doubles (TD-CCSD) calculations, which simulate the laser-driven correlated many-electron dynamics in molecular systems. Small molecules, i.e., HF, H(2)O, NH(3), and CH(4), are treated mostly with polarized valence double zeta basis sets. We determine the coupled cluster ground states by imaginary time propagation for these molecules. Excited state energies are obtained from the Fourier transform of the time dependent dipole moment after an ultrashort, broadband laser excitation. The time dependent expectation values are calculated from the complex cluster amplitudes using the corresponding configuration interaction singles doubles wave functions. Also resonant laser excitations of these excited states are simulated, in order to explore the limits for the numerical stability of our current TD-CCSD implementation, which uses time-independent molecular orbitals to form excited configurations. PMID- 21303099 TI - A water-swap reaction coordinate for the calculation of absolute protein-ligand binding free energies. AB - The accurate prediction of absolute protein-ligand binding free energies is one of the grand challenge problems of computational science. Binding free energy measures the strength of binding between a ligand and a protein, and an algorithm that would allow its accurate prediction would be a powerful tool for rational drug design. Here we present the development of a new method that allows for the absolute binding free energy of a protein-ligand complex to be calculated from first principles, using a single simulation. Our method involves the use of a novel reaction coordinate that swaps a ligand bound to a protein with an equivalent volume of bulk water. This water-swap reaction coordinate is built using an identity constraint, which identifies a cluster of water molecules from bulk water that occupies the same volume as the ligand in the protein active site. A dual topology algorithm is then used to swap the ligand from the active site with the identified water cluster from bulk water. The free energy is then calculated using replica exchange thermodynamic integration. This returns the free energy change of simultaneously transferring the ligand to bulk water, as an equivalent volume of bulk water is transferred back to the protein active site. This, directly, is the absolute binding free energy. It should be noted that while this reaction coordinate models the binding process directly, an accurate force field and sufficient sampling are still required to allow for the binding free energy to be predicted correctly. In this paper we present the details and development of this method, and demonstrate how the potential of mean force along the water-swap coordinate can be improved by calibrating the soft-core Coulomb and Lennard-Jones parameters used for the dual topology calculation. The optimal parameters were applied to calculations of protein-ligand binding free energies of a neuraminidase inhibitor (oseltamivir), with these results compared to experiment. These results demonstrate that the water-swap coordinate provides a viable and potentially powerful new route for the prediction of protein-ligand binding free energies. PMID- 21303100 TI - Variational second order density matrix study of F3-: importance of subspace constraints for size-consistency. AB - Variational second order density matrix theory under "two-positivity" constraints tends to dissociate molecules into unphysical fractionally charged products with too low energies. We aim to construct a qualitatively correct potential energy surface for F(3)(-) by applying subspace energy constraints on mono- and diatomic subspaces of the molecular basis space. Monoatomic subspace constraints do not guarantee correct dissociation: the constraints are thus geometry dependent. Furthermore, the number of subspace constraints needed for correct dissociation does not grow linearly with the number of atoms. The subspace constraints do impose correct chemical properties in the dissociation limit and size consistency, but the structure of the resulting second order density matrix method does not exactly correspond to a system of noninteracting units. PMID- 21303101 TI - Efficient time-dependent density functional theory approximations for hybrid density functionals: analytical gradients and parallelization. AB - In this paper, we present the implementation of efficient approximations to time dependent density functional theory (TDDFT) within the Tamm-Dancoff approximation (TDA) for hybrid density functionals. For the calculation of the TDDFT/TDA excitation energies and analytical gradients, we combine the resolution of identity (RI-J) algorithm for the computation of the Coulomb terms and the recently introduced "chain of spheres exchange" (COSX) algorithm for the calculation of the exchange terms. It is shown that for extended basis sets, the RIJCOSX approximation leads to speedups of up to 2 orders of magnitude compared to traditional methods, as demonstrated for hydrocarbon chains. The accuracy of the adiabatic transition energies, excited state structures, and vibrational frequencies is assessed on a set of 27 excited states for 25 molecules with the configuration interaction singles and hybrid TDDFT/TDA methods using various basis sets. Compared to the canonical values, the typical error in transition energies is of the order of 0.01 eV. Similar to the ground-state results, excited state equilibrium geometries differ by less than 0.3 pm in the bond distances and 0.5 degrees in the bond angles from the canonical values. The typical error in the calculated excited state normal coordinate displacements is of the order of 0.01, and relative error in the calculated excited state vibrational frequencies is less than 1%. The errors introduced by the RIJCOSX approximation are, thus, insignificant compared to the errors related to the approximate nature of the TDDFT methods and basis set truncation. For TDDFT/TDA energy and gradient calculations on Ag-TB2-helicate (156 atoms, 2732 basis functions), it is demonstrated that the COSX algorithm parallelizes almost perfectly (speedup ~26 29 for 30 processors). The exchange-correlation terms also parallelize well (speedup ~27-29 for 30 processors). The solution of the Z-vector equations shows a speedup of ~24 on 30 processors. The parallelization efficiency for the Coulomb terms can be somewhat smaller (speedup ~15-25 for 30 processors), but their contribution to the total calculation time is small. Thus, the parallel program completes a Becke3-Lee-Yang-Parr energy and gradient calculation on the Ag-TB2 helicate in less than 4 h on 30 processors. We also present the necessary extension of the Lagrangian formalism, which enables the calculation of the TDDFT excited state properties in the frozen-core approximation. The algorithms described in this work are implemented into the ORCA electronic structure system. PMID- 21303102 TI - A quantum propagator for path-integral simulations of rigid molecules. AB - The expression for the quantum propagator for rigid tops, proposed by Muser and Berne [Phys. Rev. Lett. 77, 2638 (1996)], has been extended to asymmetric tops. Path-integral Monte Carlo simulations are provided that show that the quantum propagator proposed in this work exactly reproduces the rotational energy of free asymmetric tops as evaluated from the partition function. This propagator can subsequently be used in path-integral simulations of condensed phases if a rigid molecular model is used. PMID- 21303103 TI - Tensor decomposition in post-Hartree-Fock methods. I. Two-electron integrals and MP2. AB - A new approximation for post-Hartree-Fock (HF) methods is presented applying tensor decomposition techniques in the canonical product tensor format. In this ansatz, multidimensional tensors like integrals or wavefunction parameters are processed as an expansion in one-dimensional representing vectors. This approach has the potential to decrease the computational effort and the storage requirements of conventional algorithms drastically while allowing for rigorous truncation and error estimation. For post-HF ab initio methods, for example, storage is reduced to O(d.R.n) with d being the number of dimensions of the full tensor, R being the expansion length (rank) of the tensor decomposition, and n being the number of entries in each dimension (i.e., the orbital index). If all tensors are expressed in the canonical format, the computational effort for any subsequent tensor contraction can be reduced to O(R(2).n). We discuss details of the implementation, especially the decomposition of the two-electron integrals, the AO-MO transformation, the Moller-Plesset perturbation theory (MP2) energy expression and the perspective for coupled cluster methods. An algorithm for rank reduction is presented that parallelizes trivially. For a set of representative examples, the scaling of the decomposition rank with system and basis set size is found to be O(N(1.8)) for the AO integrals, O(N(1.4)) for the MO integrals, and O(N(1.2)) for the MP2 t(2)-amplitudes (N denotes a measure of system size) if the upper bound of the error in the l(2)-norm is chosen as epsilon = 10(-2). This leads to an error in the MP2 energy in the order of mHartree. PMID- 21303104 TI - Vibrational coupled cluster response theory: a general implementation. AB - The calculation of vibrational contributions to molecular properties using vibrational coupled cluster (VCC) response theory is discussed. General expressions are given for expectation values, linear response functions, and transition moments. It is shown how these expressions can be evaluated for arbitrary levels of excitation in the wave function parameterization as well as for arbitrary coupling levels in the potential and property surfaces. The convergence of the method is assessed by benchmark calculations on formaldehyde. Furthermore, excitation energies and infrared intensities are calculated for the fundamental vibrations of furan using VCC limited to up to two-mode and up to three-mode excitations, VCC[2] and VCC[3], as well as VCC with full two-mode and approximate three-mode couplings, VCC[2pt3]. PMID- 21303105 TI - Freezing of Lennard-Jones-type fluids. AB - We put forward an approximate method to locate the fluid-solid (freezing) phase transition in systems of classical particles interacting via a wide range of Lennard-Jones-type potentials. This method is based on the constancy of the properly normalized second derivative of the interaction potential (freezing indicator) along the freezing curve. As demonstrated recently it yields remarkably good agreement with previous numerical simulation studies of the conventional 12-6 Lennard-Jones (LJ) fluid [S.A.Khrapak, M.Chaudhuri, G.E.Morfill, Phys. Rev. B 134, 052101 (2010)]. In this paper, we test this approach using a wide range of the LJ-type potentials, including LJ n-6 and exp-6 models, and find that it remains sufficiently accurate and reliable in reproducing the corresponding freezing curves, down to the triple-point temperatures. One of the possible application of the method--estimation of the freezing conditions in complex (dusty) plasmas with "tunable" interactions--is briefly discussed. PMID- 21303106 TI - Transition from patchlike to clusterlike inhomogeneity arising from hydrogen bonding in water. AB - Assembling of water molecules via hydrogen bonding has been studied by molecular dynamics simulations using flexible potential model. The relationship between the number of H-bonds per molecule, n(HB), the size of H-bonded nets, k, and the size of patches of four-bonded molecules, k(4), has been examined for several thermodynamic states of water ranging from ambient to supercritical conditions. Two kinds of structural inhomogeneity have been found: the patchlike associated with the mean n(HB)> 2.0 and the clusterlike for n(HB)< 1.9. In compressed water up to ~473 K patches coexist with less ordered nets, both constituting the gel like H-bonded network. The size of patches steeply decreases with the increasing temperature and the decreasing density of water. The inhomogeneity resulting from the presence of patches disappears above 473 K. This feature is associated with the rapid increase in the fraction of unbound molecules and with the breakage of the gel-like network into a variety of H-bonded clusters leading to the clusterlike structural inhomogeneity. In contrast to the patchlike inhomogeneity an increase in temperature and a decrease in density make this kind of inhomogeneity more pronounced. A degree of connectivity of H-bonds has been characterized by a parameter P(g) defined as the total fraction of molecules belonging to the H-bonded clusters of size k >= 5. The simulation-derived values of P(g) agree well with the predictions of the random bond theory giving the explicit expression for P(g) as a function of the mean n(HB). Going from ambient to supercritical conditions, we have found that the patchlike inhomogeneity is connected with the very slight reduction in P(g), whereas the clusterlike inhomogeneity generates a steep linear decrease of P(g) with the decreasing mean n(HB). The self-diffusion coefficient calculated for the thermodynamic states of water showing the clusterlike inhomogeneity has occurred to be inversely proportional to the density. We have also found that the clusterlike inhomogeneity is associated with the linear correlation between P(g) and the macroscopic properties of water: the static dielectric constant, the viscosity, and the density. The provided relationships allow one to estimate the degree of connectivity of hydrogen bonds from the measured macroscopic quantities. PMID- 21303107 TI - The spin-free analogue of Mukherjee's state-specific multireference coupled cluster theory. AB - In this paper, we develop a rigorously spin-adapted version of Mukherjee's state specific multireference coupled cluster theory (SS-MRCC, also known as Mk-MRCC) [U. S. Mahapatra, B. Datta, and D. Mukherjee, J. Chem. Phys. 110, 6171 (1999)] for reference spaces comprising open-shell configurations. The principal features of our approach are as follows: (1) The wave operator Omega is written as Omega = ?(MU)Omega(MU)|phi(MU)>c(MU), where {phi(MU)} is the set of configuration state functions spanning a complete active space. (2) In contrast to the Jeziorski Monkhorst Ansatz in spin-orbital basis, we write Omega(MU) as a power series expansion of cluster operators R(MU) defined in terms of spin-free unitary generators. (3) The operators R(MU) are either closed-shell-like n hole-n particle excitations (denoted as T(MU)) or they involve valence (active) destruction operators (denoted as S(MU)); these latter type of operators can have active-active scatterings, which can also carry the same active orbital labels (such S(MU)'s are called to have spectator excitations). (4) To simulate multiple excitations involving powers of cluster operators, we allow the S(MU)'s carrying the same active orbital labels to contract among themselves. (5) We exclude S(MU)'s with direct spectator scatterings. (6) Most crucially, the factors associated with contracted composites are chosen as the inverse of the number of ways the S(MU)'s can be joined among one another leading to the same excitation. The factors introduced in (6) have been called the automorphic factors by us. One principal thrust of this paper is to show that the use of the automorphic factors imparts a remarkable simplicity to the final amplitude equations: the equations consist of terms that are at most quartic in cluster amplitudes, barring only a few. In close analogy to the Mk-MRCC theory, the inherent linear dependence of the cluster amplitudes leading to redundancy is resolved by invoking sufficiency conditions, which are exact spin-free analogues of the spin-orbital based Mk-MRCC theory. This leads to manifest size-extensivity and an intruder-free formulation. Our formalism provides a relaxed description of the nondynamical correlation in presence of dynamical correlation. Pilot numerical applications to doublet systems, e.g., potential energy surfaces for the first two excited (2)A' states of asymmetric H(2)S(+) ion and the ground (2)Sigma(+)state of BeH radical are presented to assess the viability of our formalism over an wide range of nuclear geometries and the manifest avoidance of intruder state problem. PMID- 21303108 TI - Calculation of spin-current densities using gauge-including atomic orbitals. AB - The gauge-including magnetically induced current method for calculating the components of the current-density tensor using gauge-including atomic orbitals has been extended to treating open-shell molecules. The applicability of the method is demonstrated by calculations of first-order induced current densities on cyclobutadiene, Al(3), and B(3) at correlated ab initio levels of theory. For comparison, current-density calculations were also performed on the lowest closed shell singlet state of cyclobutadiene as well on the closed-shell Al(3)(-) and B(3)(-) anions. The ring-current susceptibilities of the open-shell species are computed at the Hartree-Fock self-consistent-field, second-order Moller-Plesset perturbation theory, and coupled-cluster singles and doubles levels, whereas for the closed-shell systems also density functional theory calculations were employed. Explicit values for the current strengths caused by alpha and beta electrons as well as the difference, representing the spin current, were obtained by numerical integration of the current-density contributions passing a plane perpendicular to the molecular ring. Comparisons of the present results to those recently obtained for the lowest triplet state of biphenyl emphasize that electron correlation effects must be considered for obtaining an accurate description of spin-current densities. PMID- 21303109 TI - Statistical approaches to forcefield calibration and prediction uncertainty in molecular simulation. AB - Calibration of forcefields for molecular simulation should account for the measurement uncertainty of the reference dataset and for the model inadequacy, i.e., the inability of the force-field/simulation pair to reproduce experimental data within their uncertainty range. In all rigour, the resulting uncertainty of calibrated force-field parameters is a source of uncertainty for simulation predictions. Various calibration strategies and calibration models within the Bayesian calibration/prediction framework are explored in the present article. In the case of Lennard-Jones potential for Argon, we show that prediction uncertainty for thermodynamical and transport properties, albeit very small, is larger than statistical simulation uncertainty. PMID- 21303110 TI - A regionally contracted multireference configuration interaction method: general theory and results of an incremental version. AB - This work proposes to take benefit of the localizability of both occupied and virtual inactive molecular orbitals (MOs) in the context of complete active space singles and doubles configuration interaction (CAS-SDCI). The doubly occupied MOs are partitioned into blocks, or regions, corresponding to a subset of adjacent bonds and lone pairs. The localized virtual MOs are attributed to these regions from a spatial criterion. Then a series of limited post-CAS-CI calculations is performed, using the same reference space, one for each block, and then one per pair of blocks. From these independent CI calculations contracted external functions are defined for each block or for each pair of blocks, and for each state. A general multistate formalism is proposed, the CI matrix being expressed in the space defined by the CAS and the contracted functions. Preliminary numerical studies, resting on the evaluation of single-block and two-block contributions to the dynamical correlation energy of each state, are presented. Provided that size-consistency corrections are taken into account the results of the procedure are shown to be in excellent agreement with those of the nonpartitioned post-CAS-CI. The computational benefits of this evidently parallelizable procedure are underlined. PMID- 21303111 TI - Using nonproduct quadrature grids to solve the vibrational Schrodinger equation in 12D. AB - In this paper we propose a new quadrature scheme for computing vibrational spectra and apply it, using a Lanczos algorithm, to CH(3)CN. All 12 coordinates are treated explicitly. We need only 157'419'523 quadrature points. It would not be possible to use a product Gauss grid because 33 853 318 889 472 product Gauss points would be required. The nonproduct quadrature we use is based on ideas of Smolyak, but they are extended so that they can be applied when one retains basis functions theta(n(1))(r(1))...theta(n(D))(r(D)) that satisfy the condition alpha(1)n(1) + ... + alpha(D)n(D) <= b, where the alpha(k) are integers. We demonstrate that it is possible to exploit the structure of the grid to efficiently evaluate the matrix-vector products required to use the Lanczos algorithm. PMID- 21303112 TI - Adaptive temperature-accelerated dynamics. AB - We present three adaptive methods for optimizing the high temperature T(high) on the-fly in temperature-accelerated dynamics (TAD) simulations. In all three methods, the high temperature is adjusted periodically in order to maximize the performance. While in the first two methods the adjustment depends on the number of observed events, the third method depends on the minimum activation barrier observed so far and requires an a priori knowledge of the optimal high temperature T(high)(opt)(E(a)) as a function of the activation barrier E(a) for each accepted event. In order to determine the functional form of T(high)(opt)(E(a)), we have carried out extensive simulations of submonolayer annealing on the (100) surface for a variety of metals (Ag, Cu, Ni, Pd, and Au). While the results for all five metals are different, when they are scaled with the melting temperature T(m), we find that they all lie on a single scaling curve. Similar results have also been obtained for (111) surfaces although in this case the scaling function is slightly different. In order to test the performance of all three methods, we have also carried out adaptive TAD simulations of Ag/Ag(100) annealing and growth at T = 80 K and compared with fixed high-temperature TAD simulations for different values of T(high). We find that the performance of all three adaptive methods is typically as good as or better than that obtained in fixed high-temperature TAD simulations carried out using the effective optimal fixed high temperature. In addition, we find that the final high temperatures obtained in our adaptive TAD simulations are very close to our results for T(high)(opt)(E(a)). The applicability of the adaptive methods to a variety of TAD simulations is also briefly discussed. PMID- 21303113 TI - Assessment of the DeltaSCF density functional theory approach for electronic excitations in organic dyes. AB - This paper assesses the accuracy of the DeltaSCF method for computing low-lying HOMO->LUMO transitions in organic dye molecules. For a test set of vertical excitation energies of 16 chromophores, surprisingly similar accuracy is observed for time-dependent density functional theory and for DeltaSCF density functional theory. In light of this performance, we reconsider the ad hoc DeltaSCF prescription and demonstrate that it formally obtains the exact stationary density within the adiabatic approximation, partially justifying its use. The relative merits and future prospects of DeltaSCF for simulating individual excited states are discussed. PMID- 21303114 TI - Chloroacetone photodissociation at 193 nm and the subsequent dynamics of the CH3C(O)CH2 radical--an intermediate formed in the OH + allene reaction en route to CH3 + ketene. AB - We use a combination of crossed laser-molecular beam experiments and velocity map imaging experiments to investigate the primary photofission channels of chloroacetone at 193 nm; we also probe the dissociation dynamics of the nascent CH(3)C(O)CH(2) radicals formed from C-Cl bond fission. In addition to the C-Cl bond fission primary photodissociation channel, the data evidence another photodissociation channel of the precursor, C-C bond fission to produce CH(3)CO and CH(2)Cl. The CH(3)C(O)CH(2) radical formed from C-Cl bond fission is one of the intermediates in the OH + allene reaction en route to CH(3) + ketene. The 193 nm photodissociation laser allows us to produce these CH(3)C(O)CH(2) radicals with enough internal energy to span the dissociation barrier leading to the CH(3) + ketene asymptote. Therefore, some of the vibrationally excited CH(3)C(O)CH(2) radicals undergo subsequent dissociation to CH(3) + ketene products; we are able to measure the velocities of these products using both the imaging and scattering apparatuses. The results rule out the presence of a significant contribution from a C-C bond photofission channel that produces CH(3) and COCH(2)Cl fragments. The CH(3)C(O)CH(2) radicals are formed with a considerable amount of energy partitioned into rotation; we use an impulsive model to explicitly characterize the internal energy distribution. The data are better fit by using the C-Cl bond fission transition state on the S(1) surface of chloroacetone as the geometry at which the impulsive force acts, not the Franck-Condon geometry. Our data suggest that, even under atmospheric conditions, the reaction of OH with allene could produce a small branching to CH(3) + ketene products, rather than solely producing inelastically stabilized adducts. This additional channel offers a different pathway for the OH-initiated oxidation of such unsaturated volatile organic compounds, those containing a C=C=C moiety, than is currently included in atmospheric models. PMID- 21303115 TI - Computational studies of the x-ray scattering properties of laser aligned stilbene. AB - The enhancement of the x-ray scattering signal from partially aligned molecular samples is investigated. The alignment properties of the studied molecular system are modeled based on the method of laser alignment. With the advances in the area of laser alignment of molecules, the application of this sample manipulation technique promises a great potential for x-ray scattering measurements. Preferential alignment of molecules in an otherwise amorphous sample leads to constructive interference and thus increases the scattering intensity. This enhances the structural information encoded in the scattering images and enables improved resolution in studies of reaction dynamics, as in this work is shown for the example of the photo-isomerization of stilbene. We demonstrate that the scattering signal is strongly influenced by the alignment axis. Even the most basic one-dimensional alignment offers significant improvement compared to the structural information provided by a randomly oriented sample. Although the signal is sensitive to the uncertainty in the alignment angle, it offers encouraging results even at realistic alignment uncertainties. PMID- 21303116 TI - Highly accurate determination of the electron affinity of SF6 and analysis of structure and photodetachment spectrum of SF6-. AB - The title system is thoroughly investigated by high-level electronic structure techniques and nuclear quantum dynamics calculations. Equilibrium geometries and harmonic frequencies are determined by coupled-cluster singles doubles [CCSD(T)] calculations with large AO basis sets. A C(4v) distorted geometry is found for the anion in contrast to previous assumptions. This is explained by the bonding situation in the electronic ground state and possible vibronic interactions with higher electronic states. The computed adiabatic electron affinity of 0.73 eV is considerably lower than the currently recommended value. Analysis of the electronic states of the anion shows that the sigma* ground state at equilibrium position corresponds to a highly excited state at the neutral's geometry where the ground state is either a very weakly bound or scattering state. If the electron is captured by this latter state, a nonadiabatic transition to the sigma* state followed by internal vibrational redistribution could explain the formation of a stable anion. The C(4v) distortion of the equilibrium geometry is essential for the explanation of recently measured photodetachment spectra. Since the distortion leads to six equivalent minima with very low barriers, an anharmonic potential energy surface (PES) of the four relevant vibrational modes is constructed and fitted to CCSD(T) computed energies. The remaining 11 modes are treated as harmonic oscillators. The vibrational dynamics of the anion is studied by diagonalization of the Hamiltonian in the basis of the neutral's eigenstates. The computed photoelectron spectra are in good agreement with recent experiments and demonstrate the quality of the PES and that C(4v) distortion is responsible for the observed irregularities. However, thermal effects play a significant role for the shape of the spectra because many low-lying initial states are populated. PMID- 21303117 TI - Electric deflection of rotating molecules. AB - We provide a theory of the deflection of polar and nonpolar rotating molecules by inhomogeneous static electric field. Rainbowlike features in the angular distribution of the scattered molecules are analyzed in detail. Furthermore, we demonstrate that one may efficiently control the deflection process with the help of short and strong femtosecond laser pulses. In particular, the deflection process may be turned off by a proper excitation, and the angular dispersion of the deflected molecules can be substantially reduced. We study the problem both classically and quantum mechanically, taking into account the effects of strong deflecting field on the molecular rotations. In both treatments we arrive at the same conclusions. The suggested control scheme paves the way for many applications involving molecular focusing, guiding, and trapping by inhomogeneous fields. PMID- 21303118 TI - Bond dissociation of the dipeptide dialanine and its derivative alanine anhydride induced by low energy electrons. AB - Dissociative electron attachment to dialanine and alanine anhydride has been studied in the gas phase utilizing a double focusing two sector field mass spectrometer. We show that low-energy electrons (i.e., electrons with kinetic energies from near zero up to 13 eV) attach to these molecules and subsequently dissociate to form a number of anionic fragments. Anion efficiency curves are recorded for the most abundant anions by measuring the ion yield as a function of the incident electron energy. The present experiments show that as for single amino acids (M), e.g., glycine, alanine, valine, and proline, the dehydrogenated closed shell anion (M-H)(-) is the most dominant reaction product. The interpretation of the experiments is aided by quantum chemical calculations based on density functional theory, by which the electrostatic potential and molecular orbitals are calculated and the initial electron attachment process prior to dissociation is investigated. PMID- 21303119 TI - Structure evolution of gold cluster anions between the planar and cage structures by isoelectronic substitution: Au(n)- (n = 13-15) and MAu(n)- (n = 12-14; M = Ag, Cu). AB - The structural and electronic effects of isoelectronic substitution by Ag and Cu atoms on gold cluster anions in the size range between 13 and 15 atoms are studied using a combination of photoelectron spectroscopy and first-principles density functional calculations. The most stable structures of the doped clusters are compared with those of the undoped Au clusters in the same size range. The joint experimental and theoretical study reveals a new C(3v) symmetric isomer for Au(13)(-), which is present in the experiment, but has hitherto not been recognized. The global minima of Au(14)(-) and Au(15)(-) are resolved on the basis of comparison between experiment and newly computed photoelectron spectra that include spin-orbit effects. The coexistence of two isomers for Au(15)(-) is firmly established with convincing experimental evidence and theoretical calculations. The overall effect of the isoelectronic substitution is minor on the structures relative to those of the undoped clusters, except that the dopant atoms tend to lower the symmetries of the doped clusters. PMID- 21303120 TI - Ab initio chemical kinetics for reactions of ClO with Cl2O2 isomers. AB - The mechanisms for the reactions of ClO with ClOClO, ClOOCl, and ClClO(2) have been investigated at the CCSD(T)/6-311+G(3df)//PW91PW91/6-311+G(3df) level of theory. The rate constants for their low energy channels have been calculated by statistical theory. The results show that the main products for the reaction of ClO with ClOClO are ClOCl + ClOO, which can be produced readily by ClO abstracting the terminal O atom from ClOClO. This process occurs without an intrinsic barrier, with the predicted rate constant: k (ClO + ClOClO) = 7.26 * 10(-10) T(-0.15) * exp (-40/T) cm(3)molecule(-1)s(-1) for 200-1500 K. For the reactions of ClO + ClOOCl and ClClO(2), the lowest abstraction barriers are 7.2 and 7.3 kcal/mol, respectively, suggesting that these two reactions are kinetically unimportant in the Earth's stratosphere as their rate constants are less than 10(-14) cm(3)molecule(-1)s(-1) below 700 K. At T = 200-1500 K, the computed rate constants can be represented by k (ClO+ ClOOCl) = 1.11 * 10 (-14) T (0.87) exp (-3576/T) and k (ClO+ ClClO(2)) = 4.61 * 10(-14) T(0.53) exp (-3588/T) cm(3)molecule(-1)s(-1). For these systems, no experimental or theoretical kinetic data are available for comparison. PMID- 21303121 TI - Photoelectron spectroscopic study of the E?e Jahn-Teller effect in the presence of a tunable spin-orbit interaction. I. Photoionization dynamics of methyl iodide and rotational fine structure of CH3I+ and CD3I+. AB - The high-resolution single-photon pulsed-field-ionization zero-kinetic-energy photoelectron spectra of the X(+) (2)E(3/2)<-X(1)A(1) transition of CH(3)I and CD(3)I have been recorded. The spectral resolution of better than 0.15 cm(-1) enabled the observation of the rotational structure. CH(3)I(+) and CD(3)I(+) are subject to a weak E?e Jahn-Teller effect and strong spin-orbit coupling. The treatment of the rovibronic structure of the photoelectron spectra in the corresponding spin double group, C(3v)(2)(M), including the effects of the spin orbit interaction and the vibrational angular momentum, allowed the reproduction of the experimentally observed transitions with spectroscopic accuracy. The relevant spin-orbit and linear Jahn-Teller coupling parameters of the X(+) ground state were derived from the analysis of the spectra of the two isotopomers, and improved values were obtained for the adiabatic ionization energies [E(I)(CH(3)I)/hc=76931.35(20) cm(-1) and E(I)(CD(3)I)/hc=76957.40(20) cm(-1)] and the rotational constants of the cations. Rovibronic photoionization selection rules were derived for transitions connecting neutral states following Hund's case-(b)-type angular momentum coupling and ionic states following Hund's-case (a)-type coupling. The selection rules, expressed in terms of the angular momentum projection quantum number P, account for all observed transitions and provide an explanation for the nonobservation of several rotational sub-bands in the mass-analyzed threshold-ionization spectra of CH(3)I and CD(3)I reported recently by Lee et al. [J. Chem. Phys. 128, 044310 (2008)]. PMID- 21303122 TI - Spectral identification of diffuse resonances in H2 above the n = 2 dissociation limit. AB - The resonance structure in molecular hydrogen above the n = 2 dissociation limit is experimentally investigated in a 1 XUV + 1 VIS coherent two-step laser excitation process, with subsequent ionization of H(n = 2) products. Diffuse spectral features exhibiting widths of several cm(-1) in the excitation range of 118,500-120,500 cm(-1) are probed. Information on angular momentum selection rules for parallel and crossed polarizations, combination differences, the para ortho distinction, extrapolation from rovibrational structure in the bound region below the n = 2 threshold, and mass-selective detection of H(2)(+) parent and H(+) daughter fragments is used as input. This allows for an assignment of the diffuse resonances observed in terms of (1)Sigma(g)(+), (1)Pi(g), and (1)Delta(g) states, specified with vibrational and rotational quantum numbers. PMID- 21303123 TI - Infrared spectroscopy of ionized corannulene in the gas phase. AB - The gas-phase infrared spectra of radical cationic and protonated corannulene were recorded by infrared multiple-photon dissociation (IRMPD) spectroscopy using the IR free electron laser for infrared experiments. Electrospray ionization was used to generate protonated corannulene and an IRMPD spectrum was recorded in a Fourier-transform ion cyclotron resonance mass spectrometer monitoring H-loss as a function of IR frequency. The radical cation was produced by 193-nm UV photoionization of the vapor of corannulene in a 3D quadrupole trap and IR irradiation produces H, H(2), and C(2)H(x) losses. Summing the spectral response of the three fragmentation channels yields the IRMPD spectrum of the radical cation. The spectra were analyzed with the aid of quantum-chemical calculations carried out at various levels of theory. The good agreement of theoretical and experimental spectra for protonated corannulene indicates that protonation occurs on one of the peripheral C-atoms, forming an sp(3) hybridized carbon. The spectrum of the radical cation was examined taking into account distortions of the C(5v) geometry induced by the Jahn-Teller effect as a consequence of the degenerate (2)E(1) ground electronic state. As indicated by the calculations, the five equivalent C(s) minima are separated by marginal barriers, giving rise to a dynamically distorted system. Although in general the character of the various computed vibrational bands appears to be in order, only a qualitative match to the experimental spectrum is found. Along with a general redshift of the calculated frequencies, the IR intensities of modes in the 1000-1250 cm(-1) region show the largest discrepancy with the harmonic predictions. In addition to CH "in-plane" bending vibrations, these modes also exhibit substantial deformation of the pentagonal inner ring, which may relate directly to the vibronic interaction in the radical cation. PMID- 21303124 TI - Theoretical studies of the N2O van der Waals dimer: ab initio potential energy surface, intermolecular vibrations and rotational transition frequencies. AB - Theoretical studies of the potential energy surface and bound states were performed for the N(2)O dimer. A four-dimensional intermolecular potential energy surface (PES) was constructed at the CCSD(T) level with aug-cc-pVTZ basis set supplemented with bond functions. Three co-planar local minima were found on this surface. They correspond to a nonpolar isomer with slipped-antiparallel planar structure and two equivalent polar isomers with slipped-parallel planar structures. The nonpolar isomer is energetically more stable than the polar ones by 162 cm(-1). To assign the fundamental vibrational frequencies for both isomers, more than 150 vibrational bound states were calculated based on this PES. The orientation of the nodal surface of the wave functions plays an important role in the assignment of disrotation and conrotation vibrational modes. The calculated vibrational frequencies are in good agreement with the available experimental data. We have also found a quantum tunneling effect between the two equivalent polar structures in the higher vibrational excited states. Rotational transition frequencies of the polar structure were also calculated. The accuracy of the PES is validated by the good agreement between theoretical and experimental results for the transition frequencies and spectroscopic parameters. PMID- 21303125 TI - NO+ formation pathways in dissociation of N2O+ ions at the C2Sigma+ state revealed from threshold photoelectron-photoion coincidence velocity imaging. AB - Using the novel threshold photoelectron-photoion coincidence (TPEPICO) velocity imaging technique, the dissociative photoionization of N(2)O molecule via the C(2)Sigma(+) ionic state has been investigated. Four fragment ions, NO(+), N(2)(+), O(+), and N(+), are observed, respectively, and the NO(+) and N(+) ions are always dominant in the whole excitation energy range of the C(2)Sigma(+) ionic state. Subsequently, the TPEPICO three-dimensional time-sliced velocity images of NO(+) dissociated from the vibrational state-selected N(2)O(+)(C(2)Sigma(+)) ions have been recorded. Thus the kinetic and internal energy distributions of the NO(+) fragments have been obtained directly as the bimodal distributions, suggesting that the NO(+) fragments are formed via both NO(+)(X(1)Sigma(+)) + N((2)P) and NO(+)(X(1)Sigma(+)) + N((2)D) dissociation channels. Almost the same vibrational population reversions are identified for both dissociation pathways. Interestingly, the obtained branching ratios of the two channels exhibit some dependence on the excited vibrational mode for N(2)O(+)(C(2)Sigma(+)), in which the excited asymmetrical stretching potentially promotes dissociation possibility along the NO(+)(X(1)Sigma(+)) + N((2)D) pathway. In addition, the measured anisotropic parameters of NO(+) are close to 0.5, indicating that the C(2)Sigma(+) state of N(2)O(+) is fully predissociative, indeed, with a tendency of parallel dissociation, and therefore, the corresponding predissociation mechanisms for the N(2)O(+)(C(2)Sigma(+)) ions are depicted. PMID- 21303126 TI - Conformationally selective photodissociation dynamics of propanal cation. AB - We have previously reported experimental evidence for conformationally selective dissociation of propanal cation that was interpreted, on the basis of ab initio multiple spawning calculations, as arising from distinct dynamics in the excited state manifold of the cation. Two conical intersections (CIs) are accessible from Franck-Condon points on the dark state; however, different conformers prefer different CIs and quench to different regions on the ground state. In this paper, we extend our initial report to include experimental results for the partially deuterated propanal cation as well as detailed characterization of the ground state potential energy surface and statistical calculations of the ground state dissociation dynamics. The DC slice imaging experiments show a bimodal velocity distribution for H elimination with the observed branching ratio of the two channels different for the cis and gauche conformers. H(D)-elimination experiments from deuterated propanal cation support the dissociation mechanism proposed in the earlier report. We further investigate reaction rates on the ground state using Rice-Ramsperger-Kassel-Marcus theory. We find that the experimental results are consistent with a mechanistic picture where the ground state dissociation is statistical, and conformer specificity of the dissociation products arises because of the different populations in distinct ground state isomers after photoexcitation due to ultrafast quenching to the ground state. PMID- 21303127 TI - Mg2H2: new insight on the Mg-Mg bonding and spectroscopic study. AB - The six dimensional potential energy surface of the electronic ground state X(1)Sigma(g)(+) of Mg(2)H(2) has been generated by the coupled-cluster approach with single, double and perturbative triple excitations [CCSD(T)] combined with the aug-cc-pCVTZ basis set for Mg atoms and the aug-cc-pVTZ basis set for the H atoms. The analytical representation of this surface was used in variational calculations of the rovibrational energies of Mg(2)H(2), Mg(2)D(2), and HMg(2)D for J = 0 and 1. For Mg(2)H(2), the rotational constant B(0) is computed to be 0.1438 cm(-1), and the fundamental anharmonic wavenumbers are calculated to be nu(1) = 1527.3 cm(-1) (Sigma(g)(+)), nu(2) = 275.3 cm(-1) (Sigma(g)(+)), nu(3) = 1503.6 cm(-1) (Sigma(u)(+)), nu(4) = 312.9 cm(-1) (Pi(g)), and nu(5) = 256.5 cm( 1) (Pi(u)). In addition, the electronic ground states of Mg(2)H, MgH(2), Mg(2), and MgH have been investigated in order to compute the bonding energies of Mg(2)H(2) and to explain the strength of the Mg-Mg bond in this tetra-atomic molecule. The nature of the low-lying excited states of Mg(2)H(2) is also studied. PMID- 21303128 TI - Dynamic (hyper)polarizabilities of the ozone molecule: coupled cluster calculations including vibrational corrections. AB - In this work, we present results for dynamical (hyper)polarizabilities of the ozone molecule with inclusion of vibrational corrections. Electronic contributions for dynamic properties were computed analytically at the single and double coupled cluster level through response theories for the frequencies 0, 0.0239, 0.0428, and 0.0656 hartree. In the static limit, the electronic contributions were also computed at the single and double coupled cluster with perturbative correction of connected triple excitations level by means of the finite-field method. It was found that the inclusion of connected triple excitations is important, especially for a reliable description of the hyperpolarizabilities. Vibrational corrections were calculated by means of the perturbation theoretical method. The zero-point vibrational average correction was found to be relevant only for the linear polarizability, representing approximately 8% of the corresponding electronic contribution. Results also showed that the pure vibrational correction is relevant for the dc-Pockels effect, dc-second harmonic generation, intensity dependent refractive index, and dc-Kerr effect nonlinear optical processes. The double-harmonic approximation is in general suitable to compute this correction, the anharmonicity being small for the dc-Kerr effect and negligible for the other processes. PMID- 21303129 TI - Unraveling the spectroscopy of coupled intramolecular tunneling modes: a study of double proton transfer in the formic-acetic acid complex. AB - The rotational spectrum of the hetero dimer comprising doubly hydrogen-bonded formic acid and acetic acid has been recorded between 4 and 18 GHz using a pulsed nozzle Fourier transform microwave spectrometer. Each rigid-molecule rotational transition is split into four as a result of two concurrently ongoing tunneling motions, one being proton transfer between the two acid molecules, and the other the torsion/rotation of the methyl group within the acetyl part. We present a full assignment of the spectrum J = 1 to J = 6 for the ground vibronic states. The transitions are fitted to within a few kilohertz of the observed frequencies using a molecule-fixed effective rotational Hamiltonian for the separate A and E vibrational species of the G(12) permutation-inversion symmetry group. Interpretation of the motion problem uses an internal-vibration and overall rotation angular momentum coupling scheme and full sets of rotational and centrifugal distortion constants are determined. The tunneling frequencies of the proton-transfer motion are measured for the ground A and E methyl rotation states as 250.4442(12) and -136.1673(30) MHz, respectively. The slight deviation of the latter tunneling frequency from being one half of the former, as simple theory otherwise predicts, is due to different degrees of mixing in wavefunctions between the ground and excited states. PMID- 21303130 TI - Hydrogen bond and halogen bond inside the carbon nanotube. AB - The hydrogen bond and halogen bond inside the open-ended single-walled carbon nanotubes have been investigated theoretically employing the newly developed density functional M06 with the suitable basis set and the natural bond orbital analysis. Comparing with the hydrogen or halogen bond in the gas phase, we find that the strength of the hydrogen or halogen bond inside the carbon nanotube will become weaker if there is a larger intramolecular electron-density transfer from the electron-rich region of the hydrogen or halogen atom donor to the antibonding orbital of the X-H or X-Hal bond involved in the formation of the hydrogen or halogen bond and will become stronger if there is a larger intermolecular electron-density transfer from the electron-rich region of the hydrogen or halogen atom acceptor to the antibonding orbital of the X-H or X-Hal bond. According to the analysis of the molecular electrostatic potential of the carbon nanotube, the driving force for the electron-density transfer is found to be the negative electric field formed in the carbon nanotube inner phase. Our results also show that the X-H bond involved in the formation of the hydrogen bond and the X-Hal bond involved in the formation of the halogen bond are all elongated when encapsulating the hydrogen bond and halogen bond within the carbon nanotube, so the carbon nanotube confinement may change the blue-shifting hydrogen bond and the blue-shifting halogen bond into the red-shifting hydrogen bond and the red shifting halogen bond. The possibility to replace the all electron nanotube confined calculation by the simple polarizable continuum model is also evaluated. PMID- 21303131 TI - Photoelectron and computational studies of the copper-nucleoside anionic complexes, Cu(-)(cytidine) and Cu(-)(uridine). AB - The copper-nucleoside anions, Cu(-)(cytidine) and Cu(-)(uridine), have been generated in the gas phase and studied by both experimental (anion photoelectron spectroscopy) and theoretical (density functional calculations) methods. The photoelectron spectra of both systems are dominated by single, intense, and relatively narrow peaks. These peaks are centered at 2.63 and 2.71 eV for Cu( )(cytidine) and Cu(-)(uridine), respectively. According to our calculations, Cu( )(cytidine) and Cu(-)(uridine) species with these peak center [vertical detachment energy (VDE)] values correspond to structures in which copper atomic anions are bound to the sugar portions of their corresponding nucleosides largely through electrostatic interactions; the observed species are anion-molecule complexes. The combination of experiment and theory also reveal the presence of a slightly higher energy, anion-molecule complex isomer in the case of the Cu( )(cytidine). Furthermore, our calculations found that chemically bond isomers of these species are much more stable than their anion-molecule complex counterparts, but since their calculated VDE values are larger than the photon energy used in these experiments, they were not observed. PMID- 21303132 TI - Ultrafast spectroscopy and coherent acoustic phonons of Au-Ag core-shell nanorods. AB - We performed the first investigations of coherent acoustic phonons in Au-Ag core shell nanorods, which were compared with the results of parental Au nanorods. Both breathing and extensional modes were observed in Au-Ag core-shell nanorods with ~11 nm Ag shell while only extensional modes were detected in other core shell nanorods with 4-7 nm Ag shell. Young's modulus estimated from the oscillation period of extensional modes was found to be larger for Au-Ag core shell nanorods with ~4 nm Ag shell, as compared with that of Au nanorods. The value of Young's modulus decreases with the increase of the Ag shell thickness and finally becomes smaller than that of Au nanorods. This phenomenon is interpreted in terms of the surface effects and the existence of grain boundaries in the lattice structure of Ag shell. PMID- 21303133 TI - Generalizations of the Fuoss approximation for ion pairing. AB - An elementary statistical observation identifies generalizations of the Fuoss approximation for the probability distribution function that describes ion clustering in electrolyte solutions. The simplest generalization, equivalent to a Poisson distribution model for inner-shell occupancy, exploits measurable interionic correlation functions, and is correct at the closest pair distances whether primitive electrolyte solutions models or molecularly detailed models are considered, and for low electrolyte concentrations in all cases. With detailed models, these generalizations include nonionic interactions and solvation effects. These generalizations are relevant for computational analysis of bimolecular reactive processes in solution. Comparisons with direct numerical simulation results show that the simplest generalization is accurate for a slightly supersaturated solution of tetraethylammonium tetrafluoroborate in propylene carbonate ([tea][BF(4)]/PC), and also for a primitive model associated with the [tea][BF(4)]/PC results. For [tea][BF(4)]/PC, the atomically detailed results identify solvent-separated nearest-neighbor ion-pairs. This generalization is examined also for the ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF(4)]) where the simplest implementation is less accurate. In this more challenging situation an augmented maximum entropy procedure is satisfactory, and explains the more varied near-neighbor distributions observed in that case. PMID- 21303134 TI - Electronic structure of three-dimensional isotropic quantum dots by four component relativistic coupled cluster methods. AB - Quantum dots with three-dimensional isotropic harmonic confining potentials and up to 60 electrons are studied. The Dirac-Coulomb Hamiltonian serves as a framework, so that relativistic effects are included, and electron correlation is treated at a high level by the Fock-space coupled cluster method, with single and double excitations summed to all orders. Large basis sets composed of spherical Gaussian functions are used. Energies of ground and excited states are calculated. The orbital order is 1s, 2p, 3d, 3s, 4f, 4p, 5g, ... , and closed shell structures appear for 2, 8, 18, 20, 34, 40, and 58 electrons. Relativistic effects are negligible for low strengths of the harmonic potential and increase rapidly for stronger potentials. Breit contributions, coming from the lowest order relativistic correction to the interelectronic repulsion terms, are also studied. Correlation effects are significant for these systems, in particular for weak confining potentials and for small systems, where they constitute up to 6% of the total energies. Their relative weight goes down (although they increase in absolute value) for larger systems or confining potentials. Planned applications to quantum dots with impurities are discussed briefly. PMID- 21303135 TI - Equilibrium equation of state of a hard sphere binary mixture at very large densities using replica exchange Monte Carlo simulations. AB - We use replica exchange Monte Carlo simulations to measure the equilibrium equation of state of the disordered fluid state for a binary hard sphere mixture up to very large densities where standard Monte Carlo simulations do not easily reach thermal equilibrium. For the moderate system sizes we use (up to N = 100), we find no sign of a pressure discontinuity near the location of dynamic glass singularities extrapolated using either algebraic or simple exponential divergences, suggesting they do not correspond to genuine thermodynamic glass transitions. Several scenarios are proposed for the fate of the fluid state in the thermodynamic limit. PMID- 21303136 TI - Dynamics of hard sphere suspensions using dynamic light scattering and X-ray photon correlation spectroscopy: dynamics and scaling of the intermediate scattering function. AB - Intermediate scattering functions are measured for colloidal hard sphere systems using both dynamic light scattering and x-ray photon correlation spectroscopy. We compare the techniques, and discuss the advantages and disadvantages of each. Both techniques agree in the overlapping range of scattering vectors. We investigate the scaling behavior found by Segre and Pusey [Phys. Rev. Lett. 77, 771 (1996)] but challenged by Lurio et al. [Phys. Rev. Lett. 84, 785 (2000)]. We observe a scaling behavior over several decades in time but not in the long-time regime. Moreover, we do not observe long-time diffusive regimes at scattering vectors away from the peak of the structure factor and so question the existence of long-time diffusion coefficients at these scattering vectors. PMID- 21303137 TI - Experimental and computational study of crystalline formic acid composed of the higher-energy conformer. AB - Crystalline formic acid (FA) is studied experimentally and by first-principles simulations in order to identify a bulk solid structure composed of the higher energy (cis) conformer. In the experiments, deuterated FA (HCOOD) was deposited in a Ne matrix and transformed to the cis conformer by vibrational excitation of the ground state (trans) form. Evaporation of the Ne host above 13 K prepared FA in a bulk solid state mainly composed of cis-FA. Infrared absorption spectroscopy at 4.3 K shows that the obtained solid differs from that composed of trans-FA molecules and that the state persists up to the annealing temperature of at least 110 K. The first-principles simulations reveal various energetically stable periodic chain structures containing cis-FA conformers. These chain structures contain either purely cis or both cis and trans forms. The vibrational frequencies of the calculated structures were compared to the experiment and a tentative assignment is given for a novel solid composed of cis-FA. PMID- 21303138 TI - Interaction potential and infrared absorption of endohedral H2 in C60. AB - We have measured the temperature dependence of the infrared spectra of a hydrogen molecule trapped inside a C(60) cage, H(2)@C(60), in the temperature range from 6 to 300 K and analyzed the excitation spectrum by using a five-dimensional model of a vibrating rotor in a spherical potential. The electric dipole moment is induced by the translational motion of endohedral H(2) and gives rise to an infrared absorption process where one translational quantum is created or annihilated, DeltaN = +/-1. Some fundamental transitions, DeltaN = 0, are observed as well. The rotation of endohedral H(2) is unhindered but coupled to the translational motion. The isotropic and translation-rotation coupling part of the potential are anharmonic and different in the ground and excited vibrational states of H(2). The vibrational frequency and the rotational constant of endohedral H(2) are smaller than those of H(2) in the gas phase. The assignment of lines to ortho- and para-H(2) is confirmed by measuring spectra of a para enriched sample of H(2)@C(60) and is consistent with the earlier interpretation of the low temperature infrared spectra [Mamone et al., J. Chem. Phys. 130, 081103 (2009)]. PMID- 21303139 TI - Effect of polarization on the solubility of gases in molten salts. AB - The solubility of noble gases and water in molten salts is predicted by developing an analytical parameter-free description in terms of polarizable hard sphere (the gas particle) in a medium composed of charged hard spheres of comparable size (the salt). The chemical potential of solute contains contributions from excluded volume, polarization, and dispersion forces. The polarization of the gas particle is calculated explicitly within the framework of the mean spherical approximation for the ion-dipole mixture. An additional contribution originating from the polarization of the salt is proposed. This effect has been overlooked in previous theoretical studies. Its magnitude is estimated in an approximate way. The description is found to give predictions that are in good agreement with experimental solubility data for noble gases and water in molten KCl and RbCl. The results suggest that volume exclusion and salt polarization may constitute the main two opposing factors affecting this phenomenon. PMID- 21303140 TI - Ground state of small mixed helium and spin-polarized tritium clusters: a quantum Monte Carlo study. AB - We report results for the ground-state energy and structural properties of small (4)He-T? clusters consisting of up to four T? and eight (4)He atoms. These results have been obtained using very well-known (4)He-(4)He and T?- T? interaction potentials and several models for the (4)He- T? interatomic potential. All the calculations have been performed with variational and diffusion Monte Carlo methods. It takes at least three atoms to form a mixed bound state. In particular, for small clusters the binding energies are significantly affected by the precise form of the (4)He- T? interatomic potential but the stability limits remain unchanged. The only exception is the (4)He(2)T? trimer whose stability in the case of the weakest (4)He- T? interaction potential is uncertain while it seems stable for other potentials. The mixed trimer (4)He(T?)(2), a candidate for the Borromean state, is not bound. All other studied clusters are stable. Some of the weakest bound clusters can be classified as quantum halo as a consequence of having high probability of being in a classically forbidden region. PMID- 21303141 TI - Beyond quantum microcanonical statistics. AB - Descriptions of molecular systems usually refer to two distinct theoretical frameworks. On the one hand the quantum pure state, i.e., the wavefunction, of an isolated system is determined to calculate molecular properties and their time evolution according to the unitary Schrodinger equation. On the other hand a mixed state, i.e., a statistical density matrix, is the standard formalism to account for thermal equilibrium, as postulated in the microcanonical quantum statistics. In the present paper an alternative treatment relying on a statistical analysis of the possible wavefunctions of an isolated system is presented. In analogy with the classical ergodic theory, the time evolution of the wavefunction determines the probability distribution in the phase space pertaining to an isolated system. However, this alone cannot account for a well defined thermodynamical description of the system in the macroscopic limit, unless a suitable probability distribution for the quantum constants of motion is introduced. We present a workable formalism assuring the emergence of typical values of thermodynamic functions, such as the internal energy and the entropy, in the large size limit of the system. This allows the identification of macroscopic properties independently of the specific realization of the quantum state. A description of material systems in agreement with equilibrium thermodynamics is then derived without constraints on the physical constituents and interactions of the system. Furthermore, the canonical statistics is recovered in all generality for the reduced density matrix of a subsystem. PMID- 21303142 TI - Thermodynamic analysis of nucleation in confined space: generalized Gibbs approach. AB - A general thermodynamic analysis of nucleation-growth processes in confined space in initially metastable states of the ambient phase is performed based on the generalized Gibbs approach to the description of heterogeneous systems. In particular, it is shown analytically how the parameters of critical clusters and clusters in stable equilibrium with the ambient phase depend on the volume of the system for initially fixed intensive state parameters of the ambient phase. Qualitatively, the results are shown to be similar independent on the boundary conditions employed. It is demonstrated further that the behavior of systems in confined space is directly related to the kinetics of phase transformation processes in spatially extended systems, when ensembles of clusters are formed. The results of the thermodynamic analysis of cluster formation and growth in a confined space are employed then, in particular, to the derivation of kinetic equations for the description of the process of coarsening or Ostwald ripening. In the analysis of both the nucleation in confined space and the description of Ostwald ripening, no specific assumptions concerning the equations of state of the system under consideration and the number of components both in the ambient and newly evolving phases are made. Consequently, the results are of very general nature and hold always as far as the necessary condition for the possibility of a phase transformation is fulfilled. PMID- 21303143 TI - Water dynamics in small reverse micelles in two solvents: two-dimensional infrared vibrational echoes with two-dimensional background subtraction. AB - Water dynamics as reflected by the spectral diffusion of the water hydroxyl stretch were measured in w(0) = 2 (1.7 nm diameter) Aerosol-OT (AOT)/water reverse micelles in carbon tetrachloride and in isooctane solvents using ultrafast 2D IR vibrational echo spectroscopy. Orientational relaxation and population relaxation are observed for w(0) = 2, 4, and 7.5 in both solvents using IR pump-probe measurements. It is found that the pump-probe observables are sensitive to w(0), but not to the solvent. However, initial analysis of the vibrational echo data from the water nanopool in the reverse micelles in the isooctane solvent seems to yield different dynamics than the CCl(4) system in spite of the fact that the spectra, vibrational lifetimes, and orientational relaxation are the same in the two systems. It is found that there are beat patterns in the interferograms with isooctane as the solvent. The beats are observed from a signal generated by the AOT/isooctane system even when there is no water in the system. A beat subtraction data processing procedure does a reasonable job of removing the distortions in the isooctane data, showing that the reverse micelle dynamics are the same within experimental error regardless of whether isooctane or carbon tetrachloride is used as the organic phase. Two time scales are observed in the vibrational echo data, ~1 and ~10 ps. The slower component contains a significant amount of the total inhomogeneous broadening. Physical arguments indicate that there is a much slower component of spectral diffusion that is too slow to observe within the experimental window, which is limited by the OD stretch vibrational lifetime. PMID- 21303144 TI - Orientational correlations in two-dimensional liquid crystals studied by molecular dynamics simulation. AB - Orientational correlations in Langmuir monolayers of nematic and smectic-C liquid crystal (LC) phases are investigated by molecular dynamics simulation. In both phases, the orientational correlation functions decay algebraically yet with the different exponents of 1.9 and 0.2 for the nematic and the smectic-C monolayers, respectively. The power law decay, i.e., the absence of long-range orientational order, means the both monolayers should be the ideal 2D system with a continuous symmetry, whereas the large difference in the exponents of power law gives rise to the crucial difference in their optical properties; the nematic monolayer is optically isotropic while the smectic-C monolayer exhibits an anisotropy on the length scale of visible light. Since the exponent is inversely proportional to the molecular exchange energy, the averaged molecular interaction in the nematic monolayer should be an order of magnitude smaller than that in the smectic-C monolayer, which is ascribed to the low molecular density and the weak molecular dipole due to the water molecule. The relation between the molecular interaction and the orientational correlation calculated for the 2D LC system offers much information not only about the 2D LCs but also on the bulk system. PMID- 21303145 TI - Self-consistent equations governing the dynamics of nonequilibrium colloidal systems. AB - A self-consistent theoretical procedure is proposed to derive the governing equations for the dynamic properties of nonequilibrium colloidal systems within the framework of the probability theory. Unlike alternative methods in the literature, the self-consistent procedure completely decouples dynamic variables from thermodynamic functions introduced for equilibrium systems. The intrinsic characteristics of a nonequilibrium system is described by the one-body temporal- and spatial-dependent dynamic variables, including the particle density profile, the local momentum, the kinetic energy or dynamic temperature, and by various forms of the two-body position and momentum correlation functions. Within appropriate constraints related to the initial/boundary conditions of a nonequilibrium system, the governing equations for the time evolution of these dynamic functions are obtained by maximizing the information entropy, i.e., the time-evolution equations for the dynamic variables correspond to a probability distribution in the reduced phase space that best represents the known information. It is shown that the dynamic equations are in parallel to and fully consistent with the statistical description of equilibrium systems. With certain assumptions, the self-consistent procedure can be reduced to various conventional theories of nonequilibrium processes. PMID- 21303146 TI - Photoemission study of praseodymia in its highest oxidation state: the necessity of in situ plasma treatment. AB - A cold radio frequency oxygen plasma treatment is demonstrated as a successful route to prepare clean, well-ordered, and stoichiometric PrO(2) layers on silicon. High structural quality of these layers is shown by x-ray diffraction. So far unobserved spectral characteristics in Pr 3d x-ray photoelectron (XP) spectra of PrO(2) are presented as a fingerprint for praseodymia in its highest oxidized state. They provide insight in the electronic ground state and the special role of praseodymia among the rare earth oxides. They also reveal that former XP studies suffered from a significant reduction at the surface. PMID- 21303147 TI - A molecular dynamics study of ethanol-water hydrogen bonding in binary structure I clathrate hydrate with CO2. AB - Guest-host hydrogen bonding in clathrate hydrates occurs when in addition to the hydrophilic moiety which causes the molecule to form hydrates under high pressure low temperature conditions, the guests contain a hydrophilic, hydrogen bonding functional group. In the presence of carbon dioxide, ethanol clathrate hydrate has been synthesized with 10% of large structure I (sI) cages occupied by ethanol. In this work, we use molecular dynamics simulations to study hydrogen bonding structure and dynamics in this binary sI clathrate hydrate in the temperature range of 100-250 K. We observe that ethanol forms long-lived (>500 ps) proton-donating and accepting hydrogen bonds with cage water molecules from both hexagonal and pentagonal faces of the large cages while maintaining the general cage integrity of the sI clathrate hydrate. The presence of the nondipolar CO(2) molecules stabilizes the hydrate phase, despite the strong and prevalent alcohol-water hydrogen bonding. The distortions of the large cages from the ideal form, the radial distribution functions of the guest-host interactions, and the ethanol guest dynamics are characterized in this study. In previous work through dielectric and NMR relaxation time studies, single crystal x-ray diffraction, and molecular dynamics simulations we have observed guest-water hydrogen bonding in structure II and structure H clathrate hydrates. The present work extends the observation of hydrogen bonding to structure I hydrates. PMID- 21303148 TI - The role of temperature in nucleation processes. AB - Heat and mass transfers are coupled processes, also in nucleation. In principle, a nucleating cluster would have a different temperature compared to the surrounding supersaturated old phase because of the heat release involved with attaching molecules to the cluster. In turn a difference in temperature across the cluster surface is a driving force for the mass transfer to and from the cluster. This coupling of forces in nonisothermal nucleation is described using mesoscopic nonequilibrium thermodynamics, emphasizing measurable heat effects. An expression was obtained for the nonisothermal nucleation rate in a one-component system, in the case where a temperature difference exists between a cluster distribution and the condensed phase. The temperature is chosen as a function of the cluster size only, while the temperature of the condensed phase is held constant by a bath. The generally accepted expression for isothermal stationary nucleation is contained as a limiting case of the nonisothermal stationary nucleation rate. The equations for heat and mass transport were solved for stationary nucleation with the given cluster distribution and with the temperature controlled at the boundaries. A factor was defined for these conditions, determined by the heat conductivity of the surrounding phase and the phase transition enthalpy, to predict the deviation between isothermal and nonisothermal nucleation. For the stationary state described, the factor appears to give small deviations, even for primary nucleation of droplets in vapor, making the nonisothermal rate smaller than the isothermal one. The set of equations may lead to larger and different thermal effects under different boundary conditions, however. PMID- 21303149 TI - Catalytic activity of Pd ensembles over Au(111) surface for CO oxidation: a first principles study. AB - Employing the first-principles pseudopotential plane-wave methods and nudged elastic-band simulations, we studied the reaction of CO oxidation on Pd-decorated Au(111) surface. We found that the contiguous Pd ensembles are required for the CO + O(2) reaction. Interestingly, Pd dimer is an active site for the two-step reaction of CO+O(2)->OOCO->CO(2)+O, and a low energy barrier (0.29 eV) is found for the formation of the intermediate metastable state (OOCO) compared to the barrier of 0.69 eV on Pd trimer. Furthermore, the residual atomic O in the CO + O(2) reaction can be removed by another CO on Pd dimer with the barrier of 0.56 eV close to the value of 0.52 eV on Pd monomer via Langmuir-Hinshelwood mechanism. The higher energy barriers (0.96 and 0.64 eV) are also found for the CO + O reaction on Pd trimers. The calculated results indicate Pd dimer is highly reactive for CO oxidation by O(2) via association mechanism on Pd-decorated Au(111) surface. PMID- 21303150 TI - Charge transfer dynamics of model charge transfer centers of a multicenter water splitting dye complex on rutile TiO2(110). AB - Charge transfer dynamics between an adsorbed molecule and a rutile TiO(2)(110) surface have been investigated in three organometallic dyes related to multicenter water splitting dye complexes: Ru 535 (cis bis(isothiocyanato)bis(2,2'-bipyridyl-4,4'-dicarboxylato)-ruthenium(II)), Ru 455 (cis-bis(2,2'-bipyridyl)-(2,2'-bipyridyl-4,4'-dicarboxylic acid)-ruthenium(II)), and Ru 470 (tris(2,2'-bipyridyl-4,4'-dicarboxylic acid)-ruthenium(II)). The adsorption of the dye molecules on the rutile TiO(2)(110) surface has been studied using core-level and valence photoemission. Dye molecules were deposited in situ using ultrahigh vacuum electrospray deposition. Core-level photoemission spectra reveal that each complex bonds to the surface via deprotonation of two carboxylic groups. All three dye complexes show evidence of ultrafast charge transfer to the TiO(2) substrate using the core-hole clock implementation of resonant photoemission spectroscopy. PMID- 21303151 TI - Charge regulation and ionic screening of patchy surfaces. AB - The properties of surfaces with charge-regulated patches are studied using nonlinear Poisson-Boltzmann theory. Using a mode expansion to solve the nonlinear problem efficiently, we reveal the charging behavior of Debye-length sized patches. We find that the patches charge up to higher charge densities if their size is relatively small and if they are well separated. The numerical results are used to construct a basic analytical model which predicts the average surface charge density on surfaces with patchy chargeable groups. PMID- 21303152 TI - In situ optical microspectroscopy approach for the study of metal transport in dielectrics via temperature- and time-dependent plasmonics: Ag nanoparticles in SiO2 films. AB - This study proposes in situ optical microspectroscopy as a means for the investigation of particle growth and metal transport in nanocomposite systems based on the temperature- and time-dependent optical response of the material. The technique has been successfully employed for the real-time monitoring of the growth of Ag nanoparticles (NPs) in SiO(2) films deposited on soda-lime glass during thermal processing in nitrogen atmosphere. By fitting the surface plasmon resonance (SPR) profiles with spectra calculated by Mie theory in the quasi static regime, the time variation in effective Ag particle size was determined and subsequently analyzed in the context of crystal growth theory. The Ag NPs were indicated to grow first through a diffusion-based process and subsequently via Ostwald ripening. The experimental determination of the activation energies associated with each one of the particle growth mechanisms was carried out based on the time evolution of the SPR of Ag NPs. Arrhenius-type analyses of a set of time-dependent isotherms allowed for estimating the activation energies at 2.3 eV for the diffusion-based growth and 2.8 eV for the ripening stage. PMID- 21303153 TI - Bias effects on the electronic spectrum of a molecular bridge. AB - In this paper the effect of bias and geometric symmetry breaking on the electronic spectrum of a model molecular system is studied. Geometric symmetry breaking can either enhance the dissipative effect of the bias, where spectral peaks are disabled, or enable new excitations that are absent under zero bias conditions. The spectral analysis is performed on a simple model system by solving for the electronic response to an instantaneously impulsive perturbation in the dipole approximation. The dynamical response is extracted from the electronic equations of motion as expressed by the Keldysh formalism. This expression provides for the accurate treatment of the electronic structure of a bulk-coupled system at the chosen model Hamiltonian electronic structure level. PMID- 21303154 TI - Theoretical study on tethered polymers with explicit grafting points in Theta solvent. AB - Systematic studies on the polymers chemically grafted onto a solid substrate with various grafting densities are presented based on the self-consistent mean-field theory (SCMFT). The distribution of the grafting points is explicitly included and all the three coordinates of each grafting point are fixed during the calculations. The existence of solvent molecules is also explicitly considered in the model and the case of Theta-solvent is investigated. The structure of the system is derived by solving the SCMFT equations in three-dimensional space. For the cases of low grafting density, the system is highly inhomogeneous and typical mushroom-like structures are derived. On the other hand, when the grafting density is high enough, the system is nearly homogeneous along the substrate and the polymer concentration profile is consistent with the numerical results of one dimensional SCMFT calculations. The crossover between "mushroom" regime and polymer brush is obtained by tuning the grafting density. In addition, in brush limit, while the root-mean-squared thickness of the brush is linearly dependent on the degree of polymerization, its dependency on the grafting density is in general more complicated than a simple power law. PMID- 21303155 TI - Nonequilibrium simulations of filled polymer networks: searching for the origins of reinforcement and nonlinearity. AB - We present nonequilibrium dissipative particle dynamics (DPD) simulations of cross-linked elastomers containing solid filler particles at 30% volume fraction. We study systematically the effect of the morphology (dispersed or aggregated particles) and of the effective particle-particle interactions. In addition, we have experimented by replacing the standard harmonic DPD bonds with other potential functions, conceived to deal with the finite extensibility of the polymer chains and the possibility of a slow equilibrium between strongly and weakly adsorbed chains at the rubber-filler interface. The simulation results shed some light on the basic mechanisms of rubber reinforcement, including the nonlinearity and history dependence commonly known as "Payne effect" and "Mullins effect." PMID- 21303156 TI - Spin-filter and Fano antiresonant effect in conductance through a zigzaglike polymer device: nonequilibrium Green's function approach. AB - Electronic transport through a quasi-one-dimensional zigzaglike polymer device is theoretically studied by means of the nonequilibrium Green's function approach. In this system, the main zigzag chain consists of carbon atoms and is attached with side radicals at its next-near-neighbor sites. The results show that a zero point of the linear conductance spectrum occurs due to the Fano antiresonance induced by the electron hoppings between the main chain and the side radicals, which leads to the fact that the linear conductance spectrum displays an insulating band around the antiresonant point. The increase in the polymer size makes both edges of the insulating band to become steep rapidly, which makes the insulating band approach to be a well-defined one. The formation of the dimer along the main chain enhances the insulating band width but much suppresses the electronic transport through the device. Moreover, if the many-body effect due to the electron interaction is taken into account, the antiresonance effect and the well-defined insulating band remain. As a result, a well spin-polarized window appears as the spin splitting occurred by applying an external magnetic field. These results strongly propose that there is a new way for the organic polymer to be applied as a spin-filter. PMID- 21303157 TI - Study of the structure and dynamics of poly(vinyl pyrrolidone) by molecular dynamics simulations validated by quasielastic neutron scattering and x-ray diffraction experiments. AB - Quasielastic neutron scattering, x-ray diffraction measurements, and fully atomistic molecular dynamics simulations have been performed on poly(vinylpyrrolidone) homopolymer above its glass transition temperature. A "prepeak" appears in the x-ray diffraction pattern that shows the typical features of a first amorphous halo. From an effective description of the experimentally accessed incoherent scattering function of hydrogens in terms of a stretched exponential function, we observe enhanced stretching and a momentum transfer dependence of the characteristic time different from that usually reported for more simple polymers (main-chain polymers or polymers with small side groups). The comparison with both kinds of experimental results has validated the simulations. The analysis of the simulated structure factor points to a nanosegregation of side groups (SG) and main-chains (MC). The detailed insight provided by the simulations on the atomic trajectories reveals a partial and spatially localized decoupling of MC and SG dynamics at length scales between the average SG-SG distance and the characteristic length of the backbone interchain correlations. Anomalous behavior in correlators calculated for the SG subsystem are found, like e.g., logarithmiclike decays of the density-density correlation function. They might be a consequence of the existing large dynamic asymmetry between SG and MC subsystems. Our results suggest that, as the SGs are spatially extended and chemically different from the backbone, they form transient nanosegregated domains. The dynamics of these domains show similar behavior to that found in other systems displaying large dynamic asymmetry. PMID- 21303158 TI - Charged colloid-polymer mixtures: a study on electrostatic depletion attraction. AB - In this work, light scattering methods have been used to study the effect of adding charged polymer chains on the structural and dynamic properties of a charged colloidal system. The experimental measurements of the static structure factor S(cc)(q) show that as the polymer concentration increases, the main peak moves to higher q-values, which is interpreted in terms of the electrostatically enhanced depletion attraction induced by the polymer. Moreover, we found that the shift of the peak depends on the interplay between two relevant length scales, the polymer radius of gyration, R(g), and the Debye length, kappa(-1). To reach these conclusions, the polymer reference interaction site model has been employed to explain the experimental results and to study how the effective depletion attraction depends on the polymer concentration, R(g) and kappa(-1). Additionally, the measurements of the dynamic structure factor f(q, tau) indicate that the colloidal diffusion increases with the polymer concentration. Both static and dynamic analysis point out that the repulsion between colloids becomes weaker as the charged polymer is added. PMID- 21303159 TI - Mesophase formation in two-component cylindrical bottlebrush polymers. AB - When two types of side chains (A,B) are densely grafted to a (stiff) backbone and the resulting bottlebrush polymer is in a solution under poor solvent conditions, an incompatibility between A and B leads to microphase separation in the resulting cylindrical brush. The possible types of ordering are reminiscent of the ordering of block copolymers in cylindrical confinement. Starting from this analogy, Leibler's theory of microphase separation in block copolymer melts is generalized to derive a description of the system in the weak segregation limit. Also molecular dynamics simulation results of a corresponding coarse-grained bead spring model are presented. Using side chain lengths up to N = 50 effective monomers, the ratio of the Lennard-Jones energy parameter between unlike monomers (epsilon(AB)) and monomers of the same kind (epsilon(AA) = epsilon(BB)) is varied. Various correlation functions are analyzed to study the conditions when (local) Janus-cylinder-type ordering and when (local) microphase separation in the direction along the cylinder axis occurs. Both the analytical theory and the simulations give evidence for short-range order due to a tendency toward microphase separation in the axial direction, with a wavelength proportional to the side chain gyration radius, irrespective of temperature and grafting density, for a wide range of these parameters. PMID- 21303160 TI - Vibronic line shapes of PTCDA oligomers in helium nanodroplets. AB - Oligomers of the organic semiconductor 3,4,9,10-perylene-tetracarboxylic dianhydride, C(24)H(8)O(6) (PTCDA) are studied by means of helium nanodroplet isolation spectroscopy. In contrast to the monomer absorption spectrum, which exhibits clearly separated, very sharp absorption lines, it is found that the oligomer spectrum consists of three main peaks having an apparent width orders of magnitude larger than the width of the monomer lines. Using a simple theoretical model for the oligomer, in which a Frenkel exciton couples to internal vibrational modes of the monomers, these experimental findings are nicely reproduced. The three peaks present in the oligomer spectrum can already be obtained taking only one effective vibrational mode of the PTCDA molecule into account. The inclusion of more vibrational modes leads to quasicontinuous spectra, resembling the broad oligomer spectra. PMID- 21303161 TI - Solvent-free coarse-grained lipid model for large-scale simulations. AB - A coarse-grained molecular model, which consists of a spherical particle and an orientation vector, is proposed to simulate lipid membrane on a large length scale. The solvent is implicitly represented by an effective attractive interaction between particles. A bilayer structure is formed by orientation dependent (tilt and bending) potentials. In this model, the membrane properties (bending rigidity, line tension of membrane edge, area compression modulus, lateral diffusion coefficient, and flip-flop rate) can be varied over broad ranges. The stability of the bilayer membrane is investigated via droplet-vesicle transition. The rupture of the bilayer and worm-like micelle formation can be induced by an increase in the spontaneous curvature of the monolayer membrane. PMID- 21303162 TI - Analyzing the components of the free-energy landscape in a calcium selective ion channel by Widom's particle insertion method. AB - The selectivity filter of the L-type calcium channel works as a Ca(2+) binding site with a very large affinity for Ca(2+) versus Na(+). Ca(2+) replaces half of the Na(+) ions in the filter even when these ions are present in 1 MUM and 30 mM concentrations in the bath, respectively. The energetics of this strong selectivity is analyzed in this paper. We use Widom's particle insertion method to compute the space-dependent profiles of excess chemical potential in our grand canonical Monte Carlo simulations. These profiles define the free-energy landscape for the various ions. Following Gillespie [Biophys. J. 94, 1169 (2008)], the difference of the excess chemical potentials for the two competing ions defines the advantage that one of the ions has over the other in the competition for space in the crowded selectivity filter. These advantages depend on ionic bath concentrations: the ion that is present in the bath in larger quantity (Na(+)) has the "number" advantage which is balanced by the free-energy advantage of the other ion (Ca(2+)). The excess chemical potentials are decomposed into hard sphere exclusion and electrostatic components. The electrostatic terms correspond to interactions with the mean electric field produced by ions and induced charges as well to ionic correlations beyond the mean field description. Dielectrics are needed to produce micromolar Ca(2+) versus Na(+) selectivity in the L-type channel. We study the behavior of these terms with changes in bath concentrations of ions, charges, and diameters of ions, as well as geometrical parameters such as radius of the pore and the dielectric constant of the protein. Ion selectivity in calcium binding proteins probably has a similar mechanism. PMID- 21303163 TI - Hydration of hydrophobic biological porphyrins. AB - Explicit solvent, single solute molecular dynamics simulations of protoporphyrin IX and its Fe(2+) complex (heme) in water were performed. The relation of solute solvent was examined through the spatial distribution functions of water molecules around the centroid of the porphyrin ring. A detailed description of the time-averaged structure of water surrounding the solutes as well as of its fluctuations is presented. PMID- 21303164 TI - Hydrophobic hydration of tert-butyl alcohol studied by Brillouin light and inelastic ultraviolet scattering. AB - The longitudinal viscosity of diluted water-tert-butyl alcohol solutions in the 10 GHz frequency region has been measured by means of Brillouin light scattering and inelastic ultraviolet scattering. The main advantage of our hypersonic investigation compared to more traditional ultrasonic measurements is that in the gigahertz frequency range slow relaxation processes involving the alcohol dynamics are completely unrelaxed, so that the measured viscosity mainly originates from the hydrogen bond restructuring of water. In contrast with previous determinations, we estimate an activation energy which is independent from the alcohol mole fraction up to X = 0.1, and comparable to that of bulk water. A simple two-component model is used to describe the steep increase of viscosity with increasing alcohol mole fraction, and a retardation factor 1.7 +/- 0.2 is found between the relaxation times of hydration and bulk water. These findings endorse a dynamic scenario where the slowing down of hydration water is mainly due to a reduction of configurational entropy and does not involve an arrested, icelike, dynamics. PMID- 21303165 TI - Entropy and enthalpy convergence of hydrophobic solvation beyond the hard-sphere limit. AB - The experimentally well-known convergence of solvation entropies and enthalpies of different small hydrophobic solutes at universal temperatures seems to indicate that hydrophobic solvation is dominated by universal water features and not so much by solute specifics. The reported convergence of the denaturing entropy of a group of different proteins at roughly the same temperature as hydrophobic solutes was consequently argued to indicate that the denaturing entropy of proteins is dominated by the hydrophobic effect and used to estimate the hydrophobic contribution to protein stability. However, this appealing picture was subsequently questioned since the initially claimed universal convergence of denaturing entropies holds only for a small subset of proteins; for a larger data collection no convergence is seen. We report extensive simulation results for the solvation of small spherical solutes in explicit water with varying solute-water potentials. We show that convergence of solvation properties for solutes of different radii exists but that the convergence temperatures depend sensitively on solute-water potential features such as stiffness of the repulsive part and attraction strength, not so much on the attraction range. Accordingly, convergence of solvation properties is only expected for solutes of a homologous series that differ in the number of one species of subunits (which attests to the additivity of solvation properties) or solutes that are characterized by similar solute-water interaction potentials. In contrast, for peptides that arguably consist of multiple groups with widely disperse interactions with water, it means that thermodynamic convergence at a universal temperature cannot be expected, in general, in agreement with experimental results. PMID- 21303166 TI - Domain formation in membranes with quenched protein obstacles: lateral heterogeneity and the connection to universality classes. AB - We show that lateral fluidity in membranes containing quenched protein obstacles belongs to the universality class of the two-dimensional random-field Ising model. The main feature of this class is the absence of a phase transition: there is no critical point and macroscopic domain formation does not occur. Instead there is only one phase. This phase is highly heterogeneous with a structure consisting of microdomains. The presence of quenched protein obstacles thus provides a mechanism to stabilize lipid rafts in equilibrium. Crucial for two dimensional random-field Ising universality is that the obstacles are randomly distributed and have a preferred affinity to one of the lipid species. When these conditions are not met standard Ising or diluted Ising universality applies. In these cases a critical point does exist which then marks the onset toward macroscopic demixing. PMID- 21303167 TI - Protein folding in a reverse micelle environment: the role of confinement and dehydration. AB - Characterization of the molecular interactions that stabilize the folded state of proteins including hydrogen bond formation, solvation, molecular crowding, and interaction with membrane environments is a fundamental goal of theoretical biophysics. Inspired by recent experimental studies by Gai and co-workers, we have used molecular dynamics simulations to explore the structure and dynamics of the alanine-rich AKA(2) peptide in bulk solution and in a reverse micelle environment. The simulated structure of the reverse micelle shows substantial deviations from a spherical geometry. The AKA(2) peptide is observed to (1) remain in a helical conformation within a spherically constrained reverse micelle and (2) partially unfold when simulated in an unconstrained reverse micelle environment, in agreement with experiment. While aqueous solvation is found to stabilize the N- and C-termini random coil portions of the peptide, the helical core region is stabilized by significant interaction between the nonpolar surface of the helix and the aliphatic chains of the AOT surfactant. The results suggest an important role for nonpolar peptide-surfactant and peptide-lipid interactions in stabilizing helical geometries of peptides in reverse micelle environments. PMID- 21303168 TI - Clusters in strong polyelectrolyte solutions in the condensation theory approach. AB - The interaction free energy of parallel clusters of like-charged rod polyelectrolytes in solution is calculated in the framework of the extended condensation theory. For sufficiently high linear charge density of the polyelectrolyte, clustering takes place. The greater is the number of polyelectrolytes participating to the cluster, the smaller is the equilibrium interpolyelectrolyte distance, and the deeper is the corresponding free energy minimum. It is a counterintuitive organization due to the increasing of the counterion condensed charge and condensation volume, taking place as the polyelectyrolytes approach each other. PMID- 21303169 TI - On the proper calculation of electrostatic interactions in solid-supported bilayer systems. AB - Modeling systems that are not inherently isotropic, e.g., extended bilayers, using molecular simulation techniques poses a potential problem. Since these methods rely on a finite number of atoms and molecules to describe the system, periodic boundary conditions are implemented to avoid edge effects and capture long-range electrostatic interactions. Systems consisting of a solvated bilayer adsorbed on a solid surface and exposed to an air/vacuum interface occur in many experimental settings and present some unique challenges in this respect. Here, we investigated the effects of implementing different electrostatic boundary conditions on the structural and electrostatic properties of a quartz/water/vacuum interface and a similar quartz-supported hydrated lipid bilayer exposed to vacuum. Since these interfacial systems have a net polarization, implementing the standard Ewald summation with the conducting boundary condition for the electrostatic long-range interactions introduced an artificial periodicity in the out-of-plane dimension. In particular, abnormal orientational polarizations of water were observed with the conducting boundary condition. Implementing the Ewald summation technique with the planar vacuum boundary condition and calculating electrostatic properties compatible with the implemented electrostatic boundary condition removed these inconsistencies. This formulation is generally applicable to similar interfacial systems in bulk solution. PMID- 21303170 TI - Human aquaporin 4 gating dynamics in dc and ac electric fields: a molecular dynamics study. AB - Water self-diffusion within human aquaporin 4 has been studied using molecular dynamics (MD) simulations in the absence and presence of external ac and dc electric fields. The computed diffusive (p(d)) and osmotic (p(f)) permeabilities under zero-field conditions are (0.718 +/- 0.24) * 10(-14) cm(3) s(-1) and (2.94 +/- 0.47) * 10(-14) cm(3) s(-1), respectively; our p(f) agrees with the experimental value of (1.50 +/- 0.6) * 10(-14) cm(3) s(-1). A gating mechanism has been proposed in which side-chain dynamics of residue H201, located in the selectivity filter, play an essential role. In addition, for nonequilibrium MD in external fields, it was found that water dipole orientation within the constriction region of the channel is affected by electric fields (e-fields) and that this governs the permeability. It was also found that the rate of side-chain flipping motion of residue H201 is increased in the presence of e-fields, which influences water conductivity further. PMID- 21303171 TI - Note: A simple picture of subdiffusive polymer motion from stochastic simulations. PMID- 21303172 TI - Comment on "Neutron scattering study of the dynamics of the polymer melt under nanoscopic confinement" [J. Chem. Phys. 131, 174901 (2009)]. PMID- 21303177 TI - A stochastic collocation method for uncertainty quantification and propagation in cardiovascular simulations. AB - Simulations of blood flow in both healthy and diseased vascular models can be used to compute a range of hemodynamic parameters including velocities, time varying wall shear stress, pressure drops, and energy losses. The confidence in the data output from cardiovascular simulations depends directly on our level of certainty in simulation input parameters. In this work, we develop a general set of tools to evaluate the sensitivity of output parameters to input uncertainties in cardiovascular simulations. Uncertainties can arise from boundary conditions, geometrical parameters, or clinical data. These uncertainties result in a range of possible outputs which are quantified using probability density functions (PDFs). The objective is to systemically model the input uncertainties and quantify the confidence in the output of hemodynamic simulations. Input uncertainties are quantified and mapped to the stochastic space using the stochastic collocation technique. We develop an adaptive collocation algorithm for Gauss-Lobatto-Chebyshev grid points that significantly reduces computational cost. This analysis is performed on two idealized problems--an abdominal aortic aneurysm and a carotid artery bifurcation, and one patient specific problem--a Fontan procedure for congenital heart defects. In each case, relevant hemodynamic features are extracted and their uncertainty is quantified. Uncertainty quantification of the hemodynamic simulations is done using (a) stochastic space representations, (b) PDFs, and (c) the confidence intervals for a specified level of confidence in each problem. PMID- 21303178 TI - Evaluation of different projectiles in matched experimental eye impact simulations. AB - Eye trauma results in 30,000 cases of blindness each year in the United States and is the second leading cause of monocular visual impairment. Eye injury is caused by a wide variety of projectile impacts and loading scenarios with common sources of trauma being motor vehicle crashes, military operations, and sporting impacts. For the current study, 79 experimental eye impact tests in literature were computationally modeled to analyze global and localized responses of the eye to a variety of blunt projectile impacts. Simulations were run with eight different projectiles (airsoft pellets, baseball, air gun pellets commonly known as BBs, blunt impactor, paintball, aluminum, foam, and plastic rods) to characterize effects of the projectile size, mass, geometry, material properties, and velocity on eye response. This study presents a matched comparison of experimental test results and computational model outputs including stress, energy, and pressure used to evaluate risk of eye injury. In general, the computational results agreed with the experimental results. A receiver operating characteristic curve analysis was used to establish the stress and pressure thresholds that best discriminated for globe rupture in the matched experimental tests. Globe rupture is predicted by the computational simulations when the corneoscleral stress exceeds 17.21 MPa or the vitreous pressure exceeds 1.01 MPa. Peak stresses were located at the apex of the cornea, the limbus, or the equator depending on the type of projectile impacting the eye. A multivariate correlation analysis revealed that area-normalized kinetic energy was the best single predictor of peak stress and pressure. Additional incorporation of a relative size parameter that relates the projectile area to the area of the eye reduced stress response variability and may be of importance in eye injury prediction. The modeling efforts shed light on the injury response of the eye when subjected to a variety of blunt projectile impacts and further validate the eye model's ability to predict globe rupture. Results of this study are relevant to the design and regulation of safety systems and equipment to protect against eye injury. PMID- 21303179 TI - Comparative analysis of methods for estimating arm segment parameters and joint torques from inverse dynamics. AB - A common problem in the analyses of upper limb unfettered reaching movements is the estimation of joint torques using inverse dynamics. The inaccuracy in the estimation of joint torques can be caused by the inaccuracy in the acquisition of kinematic variables, body segment parameters (BSPs), and approximation in the biomechanical models. The effect of uncertainty in the estimation of body segment parameters can be especially important in the analysis of movements with high acceleration. A sensitivity analysis was performed to assess the relevance of different sources of inaccuracy in inverse dynamics analysis of a planar arm movement. Eight regression models and one water immersion method for the estimation of BSPs were used to quantify the influence of inertial models on the calculation of joint torques during numerical analysis of unfettered forward arm reaching movements. Thirteen subjects performed 72 forward planar reaches between two targets located on the horizontal plane and aligned with the median plane. Using a planar, double link model for the arm with a floating shoulder, we calculated the normalized joint torque peak and a normalized root mean square (rms) of torque at the shoulder and elbow joints. Statistical analyses quantified the influence of different BSP models on the kinetic variable variance for given uncertainty on the estimation of joint kinematics and biomechanical modeling errors. Our analysis revealed that the choice of BSP estimation method had a particular influence on the normalized rms of joint torques. Moreover, the normalization of kinetic variables to BSPs for a comparison among subjects showed that the interaction between the BSP estimation method and the subject specific somatotype and movement kinematics was a significant source of variance in the kinetic variables. The normalized joint torque peak and the normalized root mean square of joint torque represented valuable parameters to compare the effect of BSP estimation methods on the variance in the population of kinetic variables calculated across a group of subjects with different body types. We found that the variance of the arm segment parameter estimation had more influence on the calculated joint torques than the variance of the kinematics variables. This is due to the low moments of inertia of the upper limb, especially when compared with the leg. Therefore, the results of the inverse dynamics of arm movements are influenced by the choice of BSP estimation method to a greater extent than the results of gait analysis. PMID- 21303180 TI - A mathematical simulation of the ureter: effects of the model parameters on ureteral pressure/flow relations. AB - Ureteral peristaltic mechanism facilitates urine transport from the kidney to the bladder. Numerical analysis of the peristaltic flow in the ureter aims to further our understanding of the reflux phenomenon and other ureteral abnormalities. Fluid-structure interaction (FSI) plays an important role in accuracy of this approach and the arbitrary Lagrangian-Eulerian (ALE) formulation is a strong method to analyze the coupled fluid-structure interaction between the compliant wall and the surrounding fluid. This formulation, however, was not used in previous studies of peristalsis in living organisms. In the present investigation, a numerical simulation is introduced and solved through ALE formulation to perform the ureteral flow and stress analysis. The incompressible Navier-Stokes equations are used as the governing equations for the fluid, and a linear elastic model is utilized for the compliant wall. The wall stimulation is modeled by nonlinear contact analysis using a rigid contact surface since an appropriate model for simulation of ureteral peristalsis needs to contain cell-to cell wall stimulation. In contrast to previous studies, the wall displacements are not predetermined in the presented model of this finite-length compliant tube, neither the peristalsis needs to be periodic. Moreover, the temporal changes of ureteral wall intraluminal shear stress during peristalsis are included in our study. Iterative computing of two-way coupling is used to solve the governing equations. Two phases of nonperistaltic and peristaltic transport of urine in the ureter are discussed. Results are obtained following an analysis of the effects of the ureteral wall compliance, the pressure difference between the ureteral inlet and outlet, the maximum height of the contraction wave, the contraction wave velocity, and the number of contraction waves on the ureteral outlet flow. The results indicate that the proximal part of the ureter is prone to a higher shear stress during peristalsis compared with its middle and distal parts. It is also shown that the peristalsis is more efficient as the maximum height of the contraction wave increases. Finally, it is concluded that improper function of ureteropelvic junction results in the passage of part of urine back flow even in the case of slow start-up of the peristaltic contraction wave. PMID- 21303181 TI - Influence of clinically relevant factors on the immediate biomechanical surrounding for a series of dental implant designs. AB - The objective of the present study was to assess the influence of various clinically relevant scenarios on the strain distribution in the biomechanical surrounding of five different dental implant macrogeometries. The biomechanical environment surrounding an implant, i.e., the cortical and trabecular bone, was modeled along with the implant. These models included two different values of the study parameters including loading conditions, trabecular bone elastic modulus, cortical/trabecular bone thickness ratio, and bone loss for five implant designs. Finite element analysis was conducted on the models and strain in the bones surrounding the implant was calculated. Bone volumes having strains in four different windows of 0-200 MUepsilon, 200-1000 MUepsilon, 1000-3000 MUepsilon, and > 3000 MUepsilon were measured and the effect of each biomechanical variable and their two-way interactions were statistically analyzed using the analysis of variance method. This study showed that all the parameters included in this study had an effect on the volume of bones in all strain windows, except the implant design, which affected only the 0-200 MUepsilon and >3000 MUepsilon windows. The two-way interaction results showed that interactions existed between implant design and bone loss, and loading condition, bone loss in the 200-1000 MUepsilon window, and between implant design and loading condition in the 0-200 MUepsilon window. Within the limitations of the present methodology, it can be concluded that although some unfavorable clinical scenarios demonstrated a higher volume of bone in deleterious strain levels, a tendency toward the biomechanical equilibrium was evidenced regardless of the implant design. PMID- 21303182 TI - Simulation of LV pacemaker lead in marginal vein: potential risk factors for acute dislodgement. AB - Although left ventricular (LV) coronary sinus lead dislodgement remains a problem, the risk factors for dislodgement have not been clearly defined. In order to identify potential risk factors for acute lead dislodgement, we conducted dynamic finite element simulations of pacemaker lead dislodgement in marginal LV vein. We considered factors such as mismatch in lead and vein diameters, velocity of myocardial motion, branch angle between the insertion vein and the coronary sinus, degree of slack, and depth of insertion. The results show that large lead-to-vein diameter mismatch, rapid myocardial motion, and superficial insertion are potential risk factors for lead dislodgement. In addition, the degree of slack presents either a positive or negative effect on dislodgement risk depending on the branch angle. The prevention of acute lead dislodgment can be enforced by inducing as much static friction force as possible at the lead-vein interface, while reducing the external force. If the latter exceeds the former, dislodgement will occur. The present findings underscore the major risk factors for lead dislodgment, which may improve implantation criterion and future lead design. PMID- 21303185 TI - Nonlinear smooth orthogonal decomposition of kinematic features of sawing reconstructs muscle fatigue evolution as indicated by electromyography. AB - Tracking or predicting physiological fatigue is important for developing more robust training protocols and better energy supplements and/or reducing muscle injuries. Current methodologies are usually impractical and/or invasive and may not be realizable outside of laboratory settings. It was recently demonstrated that smooth orthogonal decomposition (SOD) of phase space warping (PSW) features of motion kinematics can identify fatigue in individual muscle groups. We hypothesize that a nonlinear extension of SOD will identify more optimal fatigue coordinates and provide a lower-dimensional reconstruction of local fatigue dynamics than the linear SOD. Both linear and nonlinear SODs were applied to PSW features estimated from measured kinematics to reconstruct muscle fatigue dynamics in subjects performing a sawing motion. Ten healthy young right-handed subjects pushed a weighted handle back and forth until voluntary exhaustion. Three sets of joint kinematic angles were measured from the right upper extremity in addition to surface electromyography (EMG) recordings. The SOD coordinates of kinematic PSW features were compared against independently measured fatigue markers (i.e., mean and median EMG spectrum frequencies of individual muscle groups). This comparison was based on a least-squares linear fit of a fixed number of the dominant SOD coordinates to the appropriate local fatigue markers. Between subject variability showed that at most four to five nonlinear SOD coordinates were needed to reconstruct fatigue in local muscle groups, while on average 15 coordinates were needed for the linear SOD. Thus, the nonlinear coordinates provided a one-order-of-magnitude improvement over the linear ones. PMID- 21303184 TI - Effect of supraspinatus tendon repair technique on the infraspinatus tendon. AB - Supraspinatus tendon tears are common and often propagate into larger tears that include the infraspinatus tendon, resulting in loss of function and increased pain. Previously, we showed that the supraspinatus and infraspinatus tendons mechanically interact through a range of rotation angles, potentially shielding the torn supraspinatus tendon from further injury while subjecting the infraspinatus tendon to increased risk of injury. Surgical repair of torn supraspinatus tendons is common, yet the effect of the repair on the infraspinatus tendon is unknown. Since we have established a relationship between strain in the supraspinatus and infraspinatus tendons the success of a supraspinatus tendon repair depends on its effect on the loading environment in the infraspinatus tendon. More specifically, the effect of transosseous supraspinatus tendon repair in comparison to one that utilizes suture anchors, as is commonly done with arthroscopic repairs, on this interaction through these joint positions will be evaluated. We hypothesize that at all joint positions evaluated, both repairs will restore the interaction between the two tendons. For both repairs, (1) increasing supraspinatus tendon load will increase infraspinatus tendon strain and (2) altering the rotation angle from internal to external will increase strain in the infraspinatus tendon. Strains were measured in the infraspinatus tendon insertion through a range of joint rotation angles and supraspinatus tendon loads, for the intact, transosseous, and suture anchor repaired supraspinatus tendons. Images corresponding to specific supraspinatus tendon loads were isolated for the infraspinatus tendon insertion for analysis. The effect of supraspinatus tendon repair on infraspinatus tendon strain differed with joint position. Altering the joint rotation did not change strain in the infraspinatus tendon for any supraspinatus tendon condition. Finally, increasing supraspinatus tendon load resulted in an increase in average maximum and decrease in average minimum principal strain in the infraspinatus tendon. There is a significant difference in infraspinatus tendon strain between the intact and arthroscopically (but not transosseous) repaired supraspinatus tendons that increases with greater loads. Results suggest that at low loads neither supraspinatus tendon repair technique subjects the infraspinatus tendon to potentially detrimental loads; however, at high loads, transosseous repairs may be more advantageous over arthroscopic repairs for the health of the infraspinatus tendon. Results emphasize the importance of limiting loading of the repaired supraspinatus tendon and that at low loads, both repair techniques restore the interaction to the intact supraspinatus tendon case. PMID- 21303183 TI - Experimentally validated microstructural 3D constitutive model of coronary arterial media. AB - Accurate modeling of arterial response to physiological or pathological loads may shed light on the processes leading to initiation and progression of a number of vascular diseases and may serve as a tool for prediction and diagnosis. In this study, a microstructure based hyperelastic constitutive model is developed for passive media of porcine coronary arteries. The most general model contains 12 independent parameters representing the three-dimensional inner fibrous structure of the media and includes the effects of residual stresses and osmotic swelling. Parameter estimation and model validation were based on mechanical data of porcine left anterior descending (LAD) media under radial inflation, axial extension, and twist tests. The results show that a reduced four parameter model is sufficient to reliably predict the passive mechanical properties. These parameters represent the stiffness and the helical orientation of each lamellae fiber and the stiffness of the interlamellar struts interconnecting these lamellae. Other structural features, such as orientational distribution of helical fibers and anisotropy of the interlamellar network, as well as possible transmural distribution of structural features, were found to have little effect on the global media mechanical response. It is shown that the model provides good predictions of the LAD media twist response based on parameters estimated from only biaxial tests of inflation and extension. In addition, good predictive capabilities are demonstrated for the model behavior at high axial stretch ratio based on data of law stretches. PMID- 21303186 TI - Lumen irregularity dominates the relationship between mechanical stress condition, fibrous-cap thickness, and lumen curvature in carotid atherosclerotic plaque. AB - High mechanical stress condition over the fibrous cap (FC) has been widely accepted as a contributor to plaque rupture. The relationships between the stress, lumen curvature, and FC thickness have not been explored in detail. In this study, we investigate lumen irregularity-dependent relationships between mechanical stress conditions, local FC thickness (LT(FC)), and lumen curvature (LC(lumen)). Magnetic resonance imaging slices of carotid plaque from 100 patients with delineated atherosclerotic components were used. Two-dimensional structure-only finite element simulations were performed for the mechanical analysis, and maximum principal stress (stress-P1) at all integral nodes along the lumen was obtained. LT(FC) and LC(lumen) were computed using the segmented contour. The lumen irregularity (L-deltair) was defined as the difference between the largest and the smallest lumen curvature. The results indicated that the relationship between stress-P1, LT(FC), and LC(lumen) is largely dependent on L deltair. When L-deltair >= .31 (irregular lumen), stress-P1 strongly correlated with lumen curvature and had a weak/no correlation with local FC thickness, and in 73.4% of magnetic resonance (MR) slices, the critical stress (maximum of stress-P1 over the diseased region) was found at the site where the lumen curvature was large. When L-deltair <= 0.28 (relatively round lumen), stress-P1 showed a strong correlation with local FC thickness but weak/no correlation with lumen curvature, and in 71.7% of MR slices, the critical stress was located at the site of minimum FC thickness. Using lumen irregularity as a method of identifying vulnerable plaque sites by referring to the lumen shape is a novel and simple method, which can be used for mechanics-based plaque vulnerability assessment. PMID- 21303188 TI - Technically assisted rehabilitation. PMID- 21303189 TI - Complementary limb motion estimation for the control of active knee prostheses. AB - To restore walking after transfemoral amputation, various actuated exoprostheses have been developed, which control the knee torque actively or via variable damping. In both cases, an important issue is to find the appropriate control that enables user-dominated gait. Recently, we suggested a generic method to deduce intended motion of impaired or amputated limbs from residual human body motion. Based on interjoint coordination in physiological gait, statistical regression is used to estimate missing motion. In a pilot study, this complementary limb motion estimation (CLME) strategy is applied to control an active knee exoprosthesis. A motor-driven prosthetic knee with one degree of freedom has been realized, and one above-knee amputee has used it with CLME. Performed tasks are walking on a treadmill and alternating stair ascent and descent. The subject was able to walk on the treadmill at varying speeds, but needed assistance with the stairs, especially to descend. The promising results with CLME are compared with the subject's performance with her own prosthesis, the C-Leg from Otto Bock. PMID- 21303190 TI - Acupuncture treatment as breastfeeding support: preliminary data. AB - OBJECTIVES: This article investigates the efficacy of acupuncture for the maintenance of breastfeeding during the first 3 months of a newborn's life. SUBJECTS AND INTERVENTIONS: After written informed consent was obtained, 90 women were randomly divided into two groups: acupuncture treatment or observation. Acupuncture sessions were performed twice weekly for 3 weeks (total six sessions). The control group made weekly visits to the clinic and the midwife observed their breastfeeding, giving routine care. In both groups, a semistructured clinical assessment of breastfeeding quality was carried out by the midwife at enrollment and after 3 weeks. Moreover, in both groups a telephone interview was conducted by the midwife at the third month of the infants' lives, regarding the continuation of breastfeeding. RESULTS: No significant difference in the exclusive breastfeeding rate before treatment was observed between acupuncture and observation groups (51.2% versus 48.8%). However, at 3 weeks post enrollment, exclusive breastfeeding was significantly lower in the observation group than in the acupuncture group (60% versus 100%; p < 0.03). At the third month of the newborns' lives, breastfeeding was reported in 35% of the acupuncture group, compared to 15% of the observation group (p < 0.03). CONCLUSIONS: Such preliminary data suggest that 3 weeks of acupuncture treatment were more effective than observation alone in maintaining breastfeeding until the third month of the newborns' lives. PMID- 21303191 TI - On the meaning of change in a clinician's routine measure of outcome. PMID- 21303192 TI - Amphetamine availability and admissions for psychosis in New South Wales, 2001 2009. AB - OBJECTIVE: Clinicians have raised concerns about the impact of amphetamines on demand for mental health services. However, evidence for this link is limited. This study explores whether changes in the availability of amphetamines in NSW in the last decade have been associated with variations in admission to mental health units for amphetamine related conditions and for psychoses more generally. METHOD: The study examined admissions from community settings to NSW acute mental health units from 2000 to 2009. Quarterly rates of hospital admission with primary or comorbid diagnoses of stimulant use disorders, stimulant-induced psychoses and non-drug-related psychoses were compared to quarterly rates of criminal incidents of amphetamine possession and use, which provide an indirect measure of the community availability of amphetamines. Analysis was confounded by increases in mental health beds over the period. Linear regression predicted admission rates on the basis of amphetamine availability, adjusting for changing mental health bed numbers. RESULTS: Amphetamine availability and admissions for psychoses increased steadily from 2000 to a peak in early 2007, but have declined since. Regression models including both amphetamine availability and bed numbers predicted 34% of variation in stimulant use disorders admission rates and 50% of variation in stimulant induced psychoses admission rates. There was no significant effect of amphetamine availability on admissions for schizophrenia and other non-drug-induced psychoses after controlling for changing bed numbers. CONCLUSIONS: Increased amphetamine availability appears to have been one factor increasing demand for mental health admission in NSW over the last decade. However, there appears to have been a recent downward trend in both amphetamine availability and amphetamine-related admissions. Policies which reduce the community availability of amphetamines may result in reduced admissions for amphetamine-related mental health conditions, including amphetamine-induced psychoses. Further research is needed regarding effects of amphetamine availability on admissions for schizophrenia. PMID- 21303193 TI - Mental health of newly arrived Burmese refugees in Australia: contributions of pre-migration and post-migration experience. AB - OBJECTIVE: This study documents the mental health status of people from Burmese refugee backgrounds recently arrived in Australia, then examines the contributions of gender, pre-migration and post-migration factors in predicting mental health. METHOD: Structured interviews, including a demographic questionnaire, the Harvard Trauma Questionnaire, the Post-migration Living Difficulties Checklist and Hopkins Symptom Checklist assessed pre-migration trauma, post-migration living difficulties, depression, anxiety, somatization and traumatization symptoms in a sample of 70 adults across five Burmese ethnic groups. RESULTS: Substantial proportions of participants reported psychological distress in symptomatic ranges including: post-traumatic stress disorder (9%), anxiety (20%) and depression (36%), as well as significant symptoms of somatization (37%). Participants reported multiple and severe pre-migration traumas. Post-migration living difficulties of greatest concern included communication problems and worry about family not in Australia. Gender did not predict mental health. Level of exposure to traumatic events and post-migration living difficulties each made unique and relatively equal contributions to traumatization symptoms. Post-migration living difficulties made unique contributions to depression, anxiety and somatization symptoms. CONCLUSIONS: While exposure to traumatic events impacted on participants' mental well-being, post-migration living difficulties had greater salience in predicting mental health outcomes of people from Burmese refugee backgrounds. Reported rates of post-traumatic stress disorder symptoms were consistent with a large review of adults across seven western countries. High levels of somatization point to a nuanced expression of distress. Findings have implications for service provision in terms of implementing appropriate interventions to effectively meet the needs of this newly arrived group in Australia. PMID- 21303194 TI - Subjective experiences and psychopathology of schizophrenia: phenomenology lost in translation? PMID- 21303195 TI - Efficacy and tolerability of oral lactoferrin supplementation in mild to moderate acne vulgaris: an exploratory study. AB - OBJECTIVE: Lactoferrin, an innate defense iron-binding protein, possesses antimicrobial and anti-inflammatory activities. Beneficial systemic effects on inflammatory diseases have been proposed. The aim of the present study was to explore the efficacy and tolerability of oral bovine lactoferrin supplementation in subjects with mild to moderate facial acne vulgaris. METHODS: In this open label, single-arm study, 43 adolescents and young adults were enrolled to take a chewable tablet formulation of bovine lactoferrin twice daily for 8 weeks. The primary efficacy endpoint was the improvement in acne lesion counts compared with baseline. Tolerability was evaluated on the basis of adverse event frequencies. RESULTS: Thirty-nine subjects, aged 17.5 +/- 3.8 years, completed the study per protocol. At the end of the study (week 8), a mean reduction in inflammatory lesion count of 20.2% (-2.2 +/- 7.0, p = 0.054), in non-inflammatory lesion count of 23.5% (-6.2 +/- 9.8, p < 0.001), and in total lesion count of 22.5% (-8.4 +/- 13.1, p < 0.001) was observed as compared with baseline. At study conclusion, 76.9% (30 of 39) of subjects showed a reduction in total lesion count. The results for inflammatory acne lesions were variable over the study course. None of the subjects experienced a lactoferrin-related adverse event during the trial. CONCLUSION: Despite the limitations of an uncontrolled, open-label study, the results from this study indicate that lactoferrin in mild to moderate acne vulgaris is well tolerated and may lead to an overall improvement in acne lesion counts in the majority of affected adolescents and young adults when administered as a dietary supplement on a twice daily regimen. Further randomized, placebo controlled trials of longer duration appear warranted. PMID- 21303196 TI - Medication adherence and healthcare costs among patients with diabetic peripheral neuropathic pain initiating duloxetine versus pregabalin. AB - OBJECTIVE: To examine the impact of medication choice between duloxetine or pregabalin on medication adherence and direct healthcare costs among patients with diabetic peripheral neuropathic pain (DPNP). METHODS: A retrospective cohort study design was used with a large US national administrative claims database. Commercially-insured DPNP patients aged 18-64 years who initiated duloxetine or pregabalin in 2006 were selected, with the first initiation date as the index date. All selected patients had 12 months continuous enrollment in the pre- and post-index periods, and were grouped into the duloxetine or pregabalin cohort based on the index agent. The duloxetine and pregabalin cohorts were constructed via propensity score stratification with similar demographics, co-morbid medical conditions, pre-index healthcare utilization and costs, and prior treatment patterns. Medication possession ratio (MPR), proportion of patients with MPR >= 0.8 and healthcare costs over the 12-month post-index period were compared between cohorts. RESULTS: Both the duloxetine (n = 794) and pregabalin (n = 1779) cohorts had a mean age of 56 years, and 58% of female. Common co-morbid conditions among duloxetine and pregabalin patients were cardiovascular disease (82.5 vs. 82.2%), neuropathic pain other than DPNP (71.1 vs. 72.7%), osteoarthritis (39.0 vs. 41.3%), and low back pain (29.4 vs. 30.5%). More than 73% of the patients had opioid use prior to the initiation of duloxetine or pregabalin. Among patients with similar demographic, clinical and economic characteristics, and prior treatment patterns, duloxetine-treated patients had significantly higher MPR (0.34 vs. 0.13), higher proportion of patients with MPR >= 0.8 (15.5 vs. 0.7%), and significantly lower total healthcare costs ($34,146 vs. 34,897) over the 12-month post-index period than pregabalin-treated patients (all p < 0.05). CONCLUSIONS: Commercially-insured DPNP patients initiating duloxetine had significantly higher medication adherence and lower healthcare costs than those initiating pregabalin. PMID- 21303197 TI - Neurofeedback-enhanced gamma brainwaves from the prefrontal cortical region of meditators and non-meditators and associated subjective experiences. AB - OBJECTIVES: This study had two aims: (1) to explore the inner experiences associated with increased production of gamma brainwaves in an initial neurofeedback experience; and (2) to measure and compare neurofeedback-enhanced increased output from the prefrontal cortical region of meditators and non meditators, using the Peak Brain Happiness Trainer(TM) neurofeedback system. DESIGN: This was a controlled pilot study; it involved a single session per subject. SETTING: The research was conducted in a nonprofit laboratory in the United States. SUBJECTS: There were 12 adults in 2 groups (N = 12): 6 practitioners of Transcendental Meditation(TM) and six controls. MEASURES: The measures were self-assessed inner experiences and measurements of clarified gamma output at the prefrontal cortical region. RESULTS: (1) Self-assessed descriptions were comparable for both groups; (2) the associations of 16 supplied descriptors with the initial neurofeedback experience were comparable for both groups and showed highest scores for "happy" (p < 0.0001) and "loving" (p < 0.0001), and lowest scores for "stressed" (p < 0.0001) and "disappointed" (p < 0.0001); (3) baseline measures were comparable for both groups; (4) both groups were able to increase gamma brainwaves using neurofeedback (p < 0.01); and (5) meditators produced greater increases over controls (p = 0.02). CONCLUSIONS: The inner experience associated with increased clarified gamma amplitude from the prefrontal cortex apparently involves positive emotions of happiness and love, along with reduced stress. Meditators achieved greater increases in the gamma band from the prefrontal cortical region over controls during an initial neurofeedback session. PMID- 21303198 TI - Linking health and health-related information to the ICF: a systematic review of the literature from 2001 to 2008. AB - INTRODUCTION: In 1976, the World Health Organization (WHO) estimated worldwide disability prevalence at 10%; recent evidence suggests the prevalence is even higher. Given the extent of disability around the world, it is essential for researchers and policy makers to have a uniform language for describing and discussing disability. The International Classification of Functioning, Disability and Health (ICF) is WHO's attempt to provide that standard language. Linking rules were published in 2002 and 2005 suggesting a method for standardising the process of connecting outcome measures to the ICF classification. The objective of this study is to study the extent to which the linking rules have been used by researchers to link health and health-related information to the ICF and collect the feedback about the current practices, applications and areas to improve the linking method. METHOD: Using a systematic review of health-based literature between 2001 and February 2008, we (1) determined research areas where the linking method is applied, (2) examined the characteristics of studies that linked information to the ICF and (3) described current practices and issues related to the process of linking health and health related information to the ICF both quantitatively and qualitatively. RESULTS: The systematic review yielded 109 articles from 58 journals that linked health information to the ICF and 58 of the articles employed published linking rules. The majority of articles were descriptive in nature, used linking for connecting content of health instruments to the ICF and linked English health content. Quality controls such as reliability checks, multiple raters and iterative linking processes were found frequently among users of the linking rules. Qualitative analysis created themes about: preparing units of information, who links to the ICF, reliability, matching or translating concepts from text to ICF categories, information unable or difficult to capture, quantitative reporting standards and overall linking process. DISCUSSION: This review also shows that the linking process is a useful way to apply the ICF classification in research. With over 100 articles published in 58 peer-reviewed journals across 50 focus areas, linking health and health-related information to the ICF has been shown to be a useful tool for describing, comparing and contrasting information from outcome measures used to collect quantitative data, qualitative research results and clinical patient reports across diagnoses, settings, languages and countries. PMID- 21303199 TI - Detection of elevated antibody against calreticulin by ELISA in aged cynomolgus monkey plasma. AB - Calreticulin (Crt) is a molecular chaperone ubiquitously present in the endoplasmic reticulum. In non-human primates, age-related occurrence of anti-Crt antibody has not been reported. We developed an ELISA assay for an anti-Crt antibody and determined the age-related increase in the levels of anti-Crt antibody in three groups of cynomolgus monkeys: juvenile (1.5 yr), young adults (5-10 yr) and aged adults (20-34 yr). Mean +/- SD auto-antibody levels at 450 nm in juvenile, young adults and aged groups were 0.23 +/- 0.18, 0.30 +/- 0.28, and 0.55 +/- 0.33, respectively. Statistically significant differences were noted in the autoantibody levels to Crt among the aged group and juvenile or young adults. This is the first report to demonstrate the expression of anti-Crt autoantibody in aged monkeys and indicates that cynomologous monkeys may serve as an appropriate nonhuman primate model for studies of age-related alteration of immune function in elderly humans. Though preliminary, this finding merits further investigation to determine the relationship between immunosenescence and expression of antibodies to Crt. PMID- 21303200 TI - Phylogenetic relationships among bisexual and unisexual lineages of the weevil Scepticus insularis (Coleoptera: Curculionidae) on Hokkaido, Northern Japan. AB - We examined the geographic distributions and phylogenetic relationships of bisexual and unisexual (parthenogenetic) forms of the weevil Scepticus insularis on Hokkaido Island, northern Japan. Unisexual beetles were widespread throughout Hokkaido, whereas bisexuals were found only in three remote areas. Bisexuals (females and males) and unisexual females occurred sympatrically in two areas. We determined nucleotide sequences for part of the mitochondrial NADH dehydrogenase subunit 2 (ND2; 633 bp) gene for 104 individuals, and for part of the nuclear internal transcribed spacer region 2 (ITS2; 360 bp) for 91 individuals. In an ND2 gene tree, haplotypes of S. insularis fell into two distinct clades (A and B), which were genetically differentiated from one another by 9.1% nucleotide sequence divergence. Haplotypes of females identified as unisexual were all in clade A, whereas those of females identified as bisexual belonged to clade B. Haplotypes of males were in clade B, except for two males having a clade-A haplotype. Circumstantial evidence suggests that these two males were produced by unisexual females. The ND2 tree suggests that the current unisexual form of S. insularis on Hokkaido was of a single origin. In contrast, a gene tree for ITS2 haplotypes show no clear divergence between the two modes of reproduction, with two major haplotypes shared by unisexual females, bisexual females, and males. This incongruence between the nuclear and mitochondrial phylogenies may be attributable to occasional gene flow between the unisexual and bisexual lineages through males occasionally produced by unisexual females, but our results do not exclude the possibility that the two lineages share polymorphic ancestral ITS2 haplotypes. PMID- 21303201 TI - Copulation type affects parturition in the guppy. AB - In some animals, females are often compelled to mate with less desirable males due to the males' alternative mating tactics. Male guppies, Poecilia reticulata, exhibit courtship displays and cooperatively copulate with females. However, they also exhibit sneaking behaviors and coercively copulate with females. To examine the consequences of these two mating patterns, we investigated the influence of copulation type, i.e., cooperative or coercive, on parturition and brood size of females. A single female was allowed to freely contact and copulate with a single male only once. Males that cooperatively copulated with females had larger orange spot areas (an important criterion of female mate choice) than males that copulated coercively. Most females that were coerced into copulation did not give birth to offspring within 100 days after mating. The probability of parturition was high when females copulated cooperatively, and when their mates exhibited frequent postcopulatory jerking behavior. However, the results suggest that copulation type did not affect brood size. Brood size was positively influenced by both female body size and male orange spot area. These results suggest that parturient success is low when females are coerced into mating by less desirable males, whereas brood size is independent of copulation type. PMID- 21303202 TI - Evaluation of stored body fat in nuisance-killed Japanese black bears (Ursus thibetanus japonicus). AB - We evaluated the stored body fat of Japanese black bears (Ursus thibetanus japonicus) killed as nuisances in Gifu and Fukushima prefectures, Japan, during 2005-2007. We employed femur marrow fat (FMF), modified kidney fat index (mKFI), and abdominal subcutaneous fat (ASF) as indices for quantitative evaluation. We examined the basic characteristics of these indices, such as seasonality, age and sex dependency, and the quantitative relationship among them. mKFI and ASF increased towards the beginning of the denning period (December), while FMF was relatively stable throughout the sampling period (July-December). In cubs, all indices showed significantly lower values than in the older age classes. There seemed to be a catabolizing order between FMF and mKFI, but not between mKFI and ASF. We also evaluated the yearly change in the indices, and discussed its relevance to the incidence of bear intrusion into human residential areas. Bears nuisance-killed in summer (July-September) 2006 had a significantly larger amount of stored body fat than those killed in summer 2007, although the number of nuisance kills was larger in 2006 than in 2007. This suggests that poor nutritional condition is not a direct cause of bear intrusion. PMID- 21303203 TI - Molecular cloning of novel antimicrobial peptide genes from the skin of the Chinese brown frog, Rana chensinensis. AB - One species of the Chinese brown frog, Rana chensinensis, is widely distributed in north-central China. In this study, a cDNA library was constructed to clone the antimicrobial peptides' genes from the skin of R. chensinensis. Twenty-three prepropeptide cDNA sequences encoding twelve novel mature antimicrobial peptides were isolated and characterized. Six peptides belonged to three known families previously identified from other Ranid frogs: temporin (4 peptides), brevinin-2 (1 peptide), and palustrin-2 (1 peptide). The other six peptides showed little similarity to known antimicrobial peptides. According to the amino acid sequences, with or without alpha-helix structure, and either hydrophilic or hydrophobic, these were organized into four new families: chensinin-1 (3 peptides), chensinin-2 (1 peptide), chensinin-3 (1 peptide), and chensinin-4 (1 peptide). Five peptides from different families were chemically synthesized, and their antimicrobial, cytolytic, and hemolytic activities were evaluated. Of these, brevinin-2CE showed strongest antimicrobial activities against both the Gram-positive and Gram-negative bacteria with a slight hemolysis. Temporin-1CEe and palustrin-2CE also displayed a slight hemolysis, but they had different activities to prokaryotic cells. Temporin-1CEe showed higher antimicrobial activity against Gram-positive bacteria than Gram-negative bacteria, whereas it was contrary to palustrin-2CE. Chensinin-1 CEb and chensinin-3CE only had moderate antimicrobial activity against microorganisms. In addition, the brevinin 2 peptides from different brown frogs were analyzed to reveal the taxonomy and phylogenetic relationships of R. chensinensis. PMID- 21303204 TI - The postbranchial digestive tract of the ascidian, Polyandrocarpa misakiensis (Tunicata: Ascidiacea). 1. Oesophagus. AB - The organization of the oesophagus in the budding styelid ascidian, Polyandrocarpa misakiensis, is described. The oesophagus consists of external and internal epithelium, and there are loose connective tissue, blood sinuses, and a muscular layer between them. The internal epithelium is simple columnar, except for the bottom of three folds. The external epithelium is simple squamous. The internal epithelium contains four cell types, i.e., ciliated mucous cells, band cells, endocrine cells, and undifferentiated cells. The ciliated mucous cells have apical cilia and microvilli, and two types of mucous vesicle. The band cells also have apical cilia and electron-dense granules in the apical cytoplasm. The endocrine cells are bottle-shaped, and have electron-dense granules both above and below the nucleus. The undifferentiated cells form pseudostratified epithelium at the bottom of each fold, and they have nuclei with prominent nucleoli. One type of coelomic cell, which has retractile cytoplasm, often migrates in the internal epithelium. Near the stomach, there are many darkly stained round cells clustered around the posterior end of the oesophagus. These two types of coelomic cells may be involved in the defense mechanism against the invasion of foreign organisms. The basic organization of the oesophagus of P. misakiensis is similar to those of other ascidians. However, the presence of three folds is a characteristic of a solitary species, rather than of a colonial species. Although ascidians are chordate invertebrates, the organization of their oesophagus is not very complex, which might reflect their life style. PMID- 21303205 TI - Molecular identification of novel alpha- and gammaherpesviruses from cetaceans stranded on Japanese coasts. AB - Herpesviral infections have been documented in some cetaceans; however, they have not yet been identified in species in the western North Pacific. In the present study, 178 tissue samples from 76 stranded cetacean individuals were tested for the presence of herpesviruses. Herpesvirus genomic DNA fragments surrounding the DNA polymerase gene were amplified in samples from four individuals. TA cloning and direct sequencing of these DNA fragments revealed the presence of two novel alphaherpesviruses, and two novel gammaherpesviruses in the four cetacean individuals. The alphaherpesviruses were associated with the lung tissue of a false killer whale (Pseudorca crassidens), and with the mucus of a melon-headed whale (Peponocephala electra). The gammaherpesviruses were found in the lymph tissues of a Stejneger's beaked whale (Mesoplodon stejnegeri) and a sperm whale (Physeter macrocephalus). The phylogenetic tree using amino acid sequences of the DNA polymerase gene supported the inclusion of the novel viruses identified here in a single monophyletic group containing alphaherpesviruses from other Atlantic cetacean species. Conversely, the novel gammaherpesviruses formed an independent clade distant from other known cetacean gammaherpesviruses. PMID- 21303206 TI - Cribrimorph and other Cauloramphus species (Bryozoa: Cheilostomata) from the Northwestern Pacific. AB - We provide original descriptions for nine new species in the cheilostome bryozoan genus Cauloramphus (C. gracilis, C. Ordinarius, C. amphidisjunctus, C. cheliferoides, C. oshurkovi, C. infensus, C. parvus, C. peltatus, and C. ascofer) and a redescription of C. disjunctus Canu and Bassler, 1929 . We delineate a group of eight species, here termed the 'C. disjunctus clade,' that have the opesial spine joints calcified to a greater or lesser extent in mature zooids; most also have paired, hypertrophied avicularia. This group includes C. amphidisjunctus, C. cheliferoides, C. infensus, C. parvus, C. peltatus, and C. ascofer in the Aleutian Islands, Alaska; C. oshurkovi in the Commander Islands; and C. disjunctus in Japan. High levels of apparent endemism in two unrelated bryozoan genera (Cauloramphus and Monoporella), and geographical population differentiation in C. ascofer indicating ongoing allopatric speciation, suggest high speciation rates for deep benthic bryozoans in the western Aleutians. A phylogenetic hypothesis for the C. disjunctus clade indicates that populations of Cauloramphus dispersed between the Aleutians and Asia on at least three separate occasions, and that the polarity of at least two of these dispersal events was from the Aleutians to Asia. PMID- 21303207 TI - A taxonomic review of the genus Astrocharis Koehler (Echinodermata: Ophiuroidea: Asteroschematidae), with a description of a new species. AB - A revision of the genus Astrocharis Koehler (Echinodermata: Ophiuroidea: Asteroschematidae) is based on 41 specimens, including three syntypes of Astrocharis virgo Koehler, one syntype of Astrocharis ijimai Matsumoto and the holotype of Astrocharis gracilis Mortensen. Astrocharis gracilis is a junior subjective synonym of A. ijimai. A. virgo and A. ijimai are redescribed. A new species, Astrocharis monospinosa is described from southwestern Japan. A tabular key to the three species of the genus Astrocharis is provided. PMID- 21303208 TI - Acheilognathus changtingensis sp. nov., a new species of the cyprinid genus Acheilognathus (Teleostei: Cyprinidae) from Southeastern China based on morphological and molecular evidence. AB - A new species of the bitterling genus Acheilognathus, Acheilognathus changtingensis sp. nov., was recently discovered from Changting County in Hanjiang River, Fujian Province, Southeastern China. It can be diagnosed by the following combination of characters: dorsal fin with three simple and 15 (occasionally 14) branched fin rays, anal fin with three simple and 12 (occasionally 11) branched fin rays; dorsal fin pale and anal fin slightly pale; white spots on anal-fin rays forming a transverse band, and anal fin margined with white band in males. Its unique characters are the many dispersed black spots on the dorsal, anal, pelvic, caudal fins, and on the head. Using the mitochondrial cytochrome Jb gene as a molecular marker, we reconstructed phylogenetic trees of A. changtingensis sp. nov. and other species in Acheilognathus to confirm its taxonomic status and study its speciation. Analyses of both morphological and molecular data consistently indicated the taxonomic status of the present new species. The results also show that A. changtingensis sp. nov. and Acheilognathus macropterus are sister species that diverged about 14.50 MYA by geographical isolation. PMID- 21303209 TI - Found in translation: high-throughput chemical screening in Arabidopsis thaliana identifies small molecules that reduce Fusarium head blight disease in wheat. AB - Despite the tremendous economic impact of cereal crop pathogens such as the fungus Fusarium graminearum, the development of strategies for enhanced crop protection is hampered by complex host genetics and difficulties in performing high-throughput analyses. To bypass these challenges, we have developed an assay in which the interaction between F. graminearum and the model plant Arabidopsis thaliana is monitored in liquid media in 96-well plates. In this assay, fungal infection is associated with the development of dark lesion-like spots on the cotyledons of Arabidopsis seedlings by 4 days postinoculation. These symptoms can be alleviated by the application of known defense-activating small molecules and in previously described resistant host genetic backgrounds. Based on this infection phenotype, we conducted a small-scale chemical screen to identify small molecules that protect Arabidopsis seedlings from infection by F. graminearum. We identified sulfamethoxazole and the indole alkaloid gramine as compounds with strong protective activity in the liquid assay. Remarkably, these two chemicals also significantly reduced the severity of F. graminearum infection in wheat. As such, the Arabidopsis-based liquid assay represents a biologically relevant surrogate system for high-throughput studies of agriculturally important plant pathogen interactions. PMID- 21303210 TI - Genetic analysis of the resistance to eight anthracnose races in the common bean differential cultivar Kaboon. AB - Resistance to the eight races (3, 7, 19, 31, 81, 449, 453, and 1545) of the pathogenic fungus Colletotrichum lindemuthianum (anthracnose) was evaluated in F(3) families derived from the cross between the anthracnose differential bean cultivars Kaboon and Michelite. Molecular marker analyses were carried out in the F(2) individuals in order to map and characterize the anthracnose resistance genes or gene clusters present in Kaboon. The analysis of the combined segregations indicates that the resistance present in Kaboon against these eight anthracnose races is determined by 13 different race-specific genes grouped in three clusters. One of these clusters, corresponding to locus Co-1 in linkage group (LG) 1, carries two dominant genes conferring specific resistance to races 81 and 1545, respectively, and a gene necessary (dominant complementary gene) for the specific resistance to race 31. A second cluster, corresponding to locus Co 3/9 in LG 4, carries six dominant genes conferring specific resistance to races 3, 7, 19, 449, 453, and 1545, respectively, and the second dominant complementary gene for the specific resistance to race 31. A third cluster of unknown location carries three dominant genes conferring specific resistance to races 449, 453, and 1545, respectively. This is the first time that two anthracnose resistance genes with a complementary mode of action have been mapped in common bean and their relationship with previously known Co- resistance genes established. PMID- 21303211 TI - Analysis of the resistance-breaking ability of different beet necrotic yellow vein virus isolates loaded into a single Polymyxa betae population in soil. AB - The genome of most Beet necrotic yellow vein virus (BNYVV) isolates is comprised of four RNAs. The ability of certain isolates to overcome Rz1-mediated resistance in sugar beet grown in the United States and Europe is associated with point mutations in the pathogenicity factor P25. When the virus is inoculated mechanically into sugar beet roots at high density, the ability depends on an alanine to valine substitution at P25 position 67. Increased aggressiveness is shown by BNYVV P type isolates, which carry an additional RNA species that encodes a second pathogenicity factor, P26. Direct comparison of aggressive isolates transmitted by the vector, Polymyxa betae, has been impossible due to varying population densities of the vector and other soilborne pathogens that interfere with BNYVV infection. Mechanical root inoculation and subsequent cultivation in soil that carried a virus-free P. betae population was used to load P. betae with three BNYVV isolates: a European A type isolate, an American A type isolate, and a P type isolate. Resistance tests demonstrated that changes in viral aggressiveness towards Rz1 cultivars were independent of the vector population. This method can be applied to the study of the synergism of BNYVV with other P. betae-transmitted viruses. PMID- 21303212 TI - Genetic differentiation of Puccinia triticina populations in the Middle East and genetic similarity with populations in Central Asia. AB - Leaf rust of wheat, caused by Puccinia triticina, is a common and widespread disease in the Middle East. The objective of this study was to determine whether genetically differentiated groups of P. triticina are present in the Middle East region and to compare the population from the Middle East with the previously characterized population from Central Asia to determine whether genetically similar groups of isolates are found in the two regions. In total, 118 isolates of P. triticina collected from common wheat and durum wheat in Egypt, Israel, Turkey, Ethiopia, and Kenya were tested for virulence on 20 lines of wheat with single genes for leaf rust resistance and for molecular genotypes with 23 simple sequence repeat (SSR) markers. After removal of isolates with identical virulence and SSR genotype in each country, 103 isolates were retained for further analysis. Clustering of SSR genotypes based on two-dimensional principal coordinates and virulence to wheat differential lines grouped the isolates into four Middle East (ME) groups. The two largest ME groups had virulence phenotypes typical of isolates collected from common wheat and two smaller ME groups had virulence typical of isolates collected from durum wheat. All pairs of ME groups were significantly differentiated for SSR genotype based on R(ST) and F(ST) statistics, and for virulence phenotype based on Phi(PT). All ME groups had observed values of heterozygosity greater than expected and significant fixation indices that indicated the clonal reproduction of urediniospores in the overall population. Linkage disequilibria for SSR genotypes was high across the entire population. The overall values of R(ST) and F(ST) were lower when isolates were grouped by country of origin that indicated the likely migration of isolates within the region. Although the two ME groups with virulence typical of isolates from common wheat were not differentiated for SSR genotype from groups of isolates from Central Asia based on R(ST), there was no direct evidence for migration between the two regions because all ME isolates differed from the Central Asia isolates for SSR genotypes. PMID- 21303213 TI - Sclerotinia blight resistance in Virginia-type peanut transformed with a barley oxalate oxidase gene. AB - Transgenic peanut lines expressing oxalate oxidase, a novel enzyme to peanut, were evaluated for resistance to Sclerotinia blight in naturally infested fields over a 5-year period. Area under the disease progress curve (AUDPC) for transgenic lines in single rows planted with seed from single-plant selections averaged 78, 83, and 90% lower than nontransgenic parents in 2004, 2005, and 2006, respectively. In addition, AUDPC in 14 transgenic lines planted with bulked seed in two-row plots averaged 81% lower compared with nontransgenic parents in 2005 and 86% lower in 16 transgenic lines in 2006. Six transgenic lines yielded 488 to 1,260 kg/ha greater than nontransgenic parents in 2005, and 10 lines yielded 537 to 2,490 kg/ha greater in 2006. Fluazinam (0.58 kg a.i./ha) fungicide sprays in 2008 and 2009 reduced AUDPC in transgenic and nontransgenic lines but AUDPC was lowest in transgenic lines. Without fluazinam, yields of transgenic lines averaged 1,133 to 1,578 kg/ha greater than nontransgenic lines in 2008 and 1,670 to 2,755 kg/ha greater in 2009. These results demonstrated that the insertion of barley oxalate oxidase in peanut conveyed a high level of resistance to Sclerotinia blight, and negated the need for costly fungicide sprays. PMID- 21303214 TI - Satisfaction rates amongst elderly amputees provided with a static prosthetic foot. AB - AIM: Persons in Israel losing a lower limb owing to disease and have an ambulatory potential are provided with an artificial limb financed by the Ministry of Health. The choice of foot provided depends upon the physicians' assessment of the amputees' ambulatory potential. The present study investigates the patients' satisfaction with the provided limb. METHOD: A telephone survey was carried out and patients were asked to reply to a number of relevant questions. RESULTS: The less disabled patients', who received their prosthesis early, were the most satisfied. Increasing patient disability correlated with less prosthetic usage and hence greater dis-satisfaction. CONCLUSIONS: Solid ankle cushion heel (SACH) feet, which are cheap, are adequate for amputees with limited walking ability. Just over 10% of the patients who received an artificial limb could not continue using it and further studies should be conducted to investigate whether any predictive features can be found in order to minimise the financial waste. PMID- 21303215 TI - Magnetic resonance imaging of the cervix in women at high risk for preterm delivery. AB - OBJECTIVES: To assess whether changes in signal intensity of cervical stroma layers on magnetic resonance imaging (MRI) are associated with spontaneous preterm delivery. METHODS: Prospective cohort study of women admitted for threatened late miscarriage or preterm delivery between 18 and 34 weeks of gestation. We performed T2-weighted low-field MRI of the uterine cervix among 100 women. Cervical stromal differentiation, defined as the contrast between signal intensities of the inner and outer cervical layers, was classified as high, intermediate, or low by a radiologist blinded to the participant's clinical report. The main outcome measure was the proportion of spontaneous preterm delivery. RESULTS: Thirty-six women had a spontaneous preterm delivery. The proportion of spontaneous preterm delivery for high, intermediate, and low stromal differentiation was 7/24 (29%), 21/64 (33%; risk ratio 1.1; 95% confidence interval [CI]: 0.6-2.3), and 8/12 (67%; risk ratio 2.3; 95% CI: 1.1 4.8), respectively. The risk of delivering within 7 days increased when stromal differentiation decreased, although the difference was not statistically significant. CONCLUSIONS: The risk of spontaneous preterm delivery is increased in women with low cervical stromal differentiation on MRI. This risk is also associated with short cervical length, a measurement easier and less costly to obtain by transvaginal ultrasound. PMID- 21303216 TI - Evaluation of normal values of reactive oxygen species and total antioxidant defenses on cord blood of full-term healthy infants with a bedside method. AB - AIM: We measured in parallel and with a bedside equipment, the reference values of reactive oxygen species (ROS) and of total antioxidant defenses (TAD) in healthy full-term infants at birth on cord blood. TYPE OF STUDY: Population study of consecutive patients. PATIENTS AND METHODS: One hundred infants with gestational age 37-42 wks without signs of fetal distress or perinatal asphyxia. ROS and TAD were measured on cord blood - together with blood gas analysis - immediately after birth with a bedside equipment (FORM plus, Callegari 1930, Italy). RESULTS: The average time to the end of the exams was 19 min (5-55 min). After outliers' exclusion, ROS resulted meanly 117 +/- 58.2 U.F. and TAD 1.31 +/- 0.45 mmol/l Trol.eq., being the ROS' value lower and that of TAD in the same range than those of adult people. No relationship was found between cesarean and vaginal delivery and between male and female sex. CONCLUSION: The normal full-term infants present low values of ROS but normal values of TAD when compared to adult people. We speculate this is a defensive mechanism, a sort of preparation of the fetus to face the partial pressure of oxygen of the room-air, increased with respect to that present in the womb. PMID- 21303217 TI - Antioxidative properties of curcumin in the protection of blood platelets against oxidative stress in vitro. AB - The present in vitro study was designed to estimate the antioxidative activity of curcumin in the protection of human blood platelets and plasma against peroxynitrite (ONOO(-))-induced oxidative stress. The effects of curcumin (12.5 50 ug/ml) on ONOO(-)-induced damage of proteins and lipids were determined by the estimation of protein carbonyl groups, 3-nitrotyrosine formation, and thiobarbituric acid reactive substance (TBARS) generation. Exposure of blood platelets and plasma to 100 uM ONOO(-) resulted in an increased level of carbonyl groups, nitration of protein tyrosine residues, and enhanced lipid peroxidation. Curcumin inhibited carbonyl group formation in plasma and in platelet proteins. The highest dose of curcumin (50 ug/ml) reduced blood platelet protein carbonylation by approximately 40%. In the protection of blood plasma protein, the lower doses of curcumin (12.5 and 25 ug/ml) were more effective. Curcumin partially prevented 3-nitrotyrosine formation in plasma proteins; the effect of curcumin was only statistically significant in blood platelets at the highest dose (50 ug/ml). The antioxidative action of curcumin in the protection against lipid peroxidation caused by ONOO(-) was also observed. Curcumin suppressed the formation of TBARS both in blood platelets and in plasma samples. The highest concentration of curcumin (50 ug/ml) decreased the TBARS level by approximately 35% in both blood platelets and plasma samples. In conclusion, the present study demonstrates the antioxidative properties of curcumin and its protective effects against oxidative/nitrative changes of blood platelets and plasma components, especially proteins and lipids. PMID- 21303218 TI - Aerobic physical activity improves endothelial function in the middle-aged patients with erectile dysfunction. AB - OBJECTIVE: Physical activity (PhA) has proven to be a protective factor for normal erectile function. The aim of this study was to evaluate the effects of a standard protocol of aerobic PhA on quality of erectile dysfunction (ED) in patients with arterial ED. MATERIALS AND METHODS: Fifty patients (48-62 years) were selected and underwent to standard protocol of aerobic PhA: 150 min of moderate intensity aerobic activity per week (group A). Twenty patients, matched aged, with vascular ED who did not accept to undergo the standard PhA's protocol, represented the control group. All patients were evaluated, by IIEF-5 questionnaire administration, penile eco color doppler and flow-cytometric analysis for detection of serum concentrations of original immunophenotype endothelial progenitor cells (EPCs) = CD45neg/CD34pos/CD144pos and endothelial microparticles (EMPs) = CD45neg/CD34neg/CD144pos. RESULTS: After 3 months, group A showed IIEF 5 score and peak systolic velocity significantly higher (p < 0.05) compared to controls, and significantly lower values (p < 0.05) of acceleration time, in addition serum concentrations of EPCs and EMPs were significantly lower (p < 0.05) in group A compared to controls. CONCLUSIONS: PhA improves quality of arterial ED, without other pharmacological approach, probably by reduced endothelial apoptosis. This study characterises the study of endothelial dysfunction by new cell circulating markers. PMID- 21303219 TI - Resistance to antibiotics and characterization of Helicobacter pylori strains isolated from antrum and body from adults in Mexico. AB - BACKGROUND AND AIMS: Resistance to antibiotics is common in patients with Helicobacter pylori infection in more than one anatomic stomach site. We assessed whether the antibiotic resistance varies according to virulence factors of the bacteria as well as to the age and gender of individuals infected in two anatomic sites. METHODS: H. pylori strains were isolated from an antral and corpus biopsy from 90 patients with gastric ambulatory who had not received any previous therapy. Susceptibility to metronidazole and clarithromycin was assessed by E test, and vacA and cagA genotypes were determined by polymerase chain reaction. RESULTS: Dual resistance to metronidazole and clarithromycin was 3.3% in antrum and 4.4% in the corpus; heteroresistance was 19% and 5.5% for metronidazole and clarithromycin, respectively. Clarithromycin resistance significantly increased with age. Women showed a twofold increased risk for metronidazole-resistant strains in antrum (odds ratio = 2.85, 95% confidence interval 1.09 to 7.42). Virulence factors were not associated with antimicrobial resistance. CONCLUSION: Prevalence of resistance to clarithromycin may be increasing in this country. Antimicrobial susceptibility tests from different biopsy sites deserve attention. PMID- 21303221 TI - Glutathione transferase zeta: discovery, polymorphic variants, catalysis, inactivation, and properties of Gstz1-/- mice. AB - Glutathione transferase zeta (GSTZ1) is a member of the GST superfamily of proteins that catalyze the reaction of glutathione with endo- and xenobiotics. GSTZ1-1 was discovered by a bioinformatics strategy that searched the human expressed sequence-tag database with a sequence that matched a putative plant GST. A sequence that was found was expressed and termed GSTZ1-1. In common with other GSTs, GSTZ1-1 showed some peroxidase activity, but lacked activity with most known GST substrates. GSTZ1-1 was also found to be identical with maleylacetoacetate isomerase, which catalyzes the penultimate step in the tyrosine-degradation pathway. Further studies showed that dichloroacetate (DCA) and a range of alpha-haloalkanoates and alpha,alpha-dihaloalkanoates were substrates. A subsequent search of the human-expressed sequence-tag database showed the presence of four polymorphic alleles: 1a, 1b, 1c, and 1d; GSTZ1c was the most common and was designated as the wild-type gene. DCA was shown to be a k(cat) inactivator of human, rat, and mouse GSTZ1-1; human GSTZ1-1 was more resistant to inactivation than mouse or rat GSTZ1-1. Proteomic analysis showed that hGSTZ1-1 was inactivated when Cys-16 was modified by glutathione and the carbon skeleton of DCA. The polymorphic variants of hGSTZ1-1 differ in their susceptibility to inactivation, with 1a-1a being more resistant to inactivation than the other variants. The targeted deletion of GSTZ1 yielded mice that were not phenotypically distinctive. Phenylalanine proved, however, to be toxic to Gstz1(-/-) mice, and these mice showed evidence of organ damage and leucopenia. PMID- 21303220 TI - Indentation versus tensile measurements of Young's modulus for soft biological tissues. AB - In this review, we compare the reported values of Young's modulus (YM) obtained from indentation and tensile deformations of soft biological tissues. When the method of deformation is ignored, YM values for any given tissue typically span several orders of magnitude. If the method of deformation is considered, then a consistent and less ambiguous result emerges. On average, YM values for soft tissues are consistently lower when obtained by indentation deformations. We discuss the implications and potential impact of this finding. PMID- 21303222 TI - Elastic liposomes as carriers for oral delivery and the brain distribution of (+) catechin. AB - The aim of this work was to investigate whether the oral bioavailability and brain regional distribution of (+)-catechin could be improved by utilizing elastic liposomes. Liposomes containing soy phosphatidylcholine, cholesterol, and Tween 80 in the presence of 15% ethanol were prepared by a thin-film method and subsequent sonication and extrusion. The size, zeta potential, and stability of the liposomes in simulated gastrointestinal (GI) media were characterized. The mean size of liposomes was 35-70 nm, which decreased with an increase in the Tween 80 concentration. The zeta potential of the system was about-15 mV. More than 80% of the (+)-catechin was entrapped in the aqueous core of liposomes produced with 1% Tween 80. Liposomes entrapping (+)-catechin remained stable in the presence of GI fluids, especially in simulated intestinal fluid. The liposomes showed suppressed and sustained release of (+)-catechin compared with that from an aqueous solution. The aqueous control and liposomes were orally administered to rats. The blood level of liposomal (+)-catechin was enhanced at a later stage after administration compared with the free control. In the experiment on the brain distribution, liposomes with elastic properties showed 2.9- and 2.7-fold higher (+)-catechin accumulations compared with the aqueous solution in the cerebral cortex and hippocampus, respectively. Greater compound accumulations with liposomes were also detected in the striatum and thalamus. The experimental results suggest that elastic liposomes may offer a promising strategy for improving (+)-catechin delivery via oral ingestion. PMID- 21303223 TI - Plasma netrin-1 is a diagnostic biomarker of human cancers. AB - CONTEXT: The axon guidance cues netrin-1 is a secreted protein overexpressed in many different cancer tissues. OBJECTIVES: To determine whether plasma netrin-1 can be used as a diagnostic biomarker of human cancer. MATERIALS AND METHODS: A total of 300 cancer plasma samples from breast, renal, prostate, liver, meningioma, pituitary adenoma, glioblastoma, lung, pancreatic and colon cancer patients were compared against 138 control plasma samples. Netrin-1 levels were quantified by ELISA and immunohistochemistry. RESULTS: Plasma netrin-1 levels were significantly increased in breast, renal, prostate, liver, meningioma, pituitary adenoma, and glioblastoma cancers as compared to control samples. DISCUSSION AND CONCLUSION: Our results suggest that plasma netrin-1 can be used as a diagnostic biomarker for many human cancers. PMID- 21303225 TI - Cholinesterase modulations in patients with acute bacterial meningitis. AB - BACKGROUND: The circulating cholinesterases acetyl- and butyrylcholinesterase may be suppressed and subsequently released from the brain in acute bacterial meningitis. METHODS: We report serum activities of acetylcholinesterase and butyrylcholinesterase in paired arterial and jugular venous samples from seven patients with acute bacterial meningitis and eight healthy controls. Paraoxonase 1, which protects these enzymes from oxidative inactivation, was also measured. FINDINGS AND CONCLUSION: Acetyl- and butyrylcholinesterase activities were lower in patients, independently of changes in paraoxonase 1. Arterial and jugular venous enzyme activities were similar both in patients and controls, suggesting that no cerebral release was present. PMID- 21303224 TI - Platelet depletion, platelet activation and coagulation during treatment with hemodialysis. AB - Bioincompatibility is the total of side effects during hemodialysis (HD) including, amongst others, changes in platelet (PLT) level. Deviations in PLT count, immature PLT count, PLT morphology, CD62p expression, Platelet Factor 4 (PF4), beta-Thromboglobulin (beta-TG), serotonin, Thrombin-Antithrombin III (TAT) and Prothrombin Fragment 1+2 (F1+2) are monitored before and during treatment with HD in order to elucidate the interaction between modifications in PLT morphology, PLT activation and markers concerning activation of coagulation. Different patterns with time indicate that there is no correlation between an increased amount of depleted PLTs and increased amounts of PLT activation markers such as CD62p, PF4, beta-TG and serotonin. A statistically significant correlation between increased PLT activation markers and markers for increased activation of coagulation such as TAT and F1+2 has not been established. Only a weak correlation is demonstrated between the increase of markers for activation of coagulation and the decrease in PLT counts, immature PLT counts and depleted PLTs during HD treatment. The change in the extracorporeal circuit during HD is probably a more critical factor in the mechanism leading to activation of the coagulation pathway than the modifications in PLT morphology. PMID- 21303226 TI - Hypoxia preconditioning of tissue-engineered mucosa enhances its angiogenic capacity in vitro. AB - Improving vascularization of tissue-engineered oral mucosa (TEM) is a major challenge in the field of plastic surgery. Hypoxia is a stimulator of angiogenesis through a number of mechanisms. Therefore, hypoxia is a critical parameter that can be controlled in an effort to improve angiogenesis. In the present study we studied the secretion of a number of angiogenic factors during hypoxia exposure and evaluated the effect of TEM conditioned medium on endothelial cells. TEM was constructed by seeding human oral mucosa keratinocytes and fibroblasts on acellular human donor skin. TEM was exposed to hypoxia during 6, 12, and 24 h. Cellular hypoxia was assessed by immunolocalization of the hypoxia-inducible factor-1alpha. Secretion of vascular endothelial growth factor, placental growth factor (PlGF), tissue inhibitors of matrix metalloproteinases-1 and -2, and the activity of matrix metalloproteinase-9 significantly increased during hypoxia exposure. Moreover, conditioned medium from hypoxic TEM strongly enhanced endothelial cell proliferation and migration. In vitro exposure of TEM to hypoxia improves its capacity to support endothelial cell proliferation and migration, which suggests that hypoxia preconditioning of TEM potentially improves angiogenic responses for in vivo implantation. PMID- 21303227 TI - An adaptive clinical test of temporal resolution: within-channel and across channel gap detection. AB - OBJECTIVE: Several methods exist to measure temporal resolution in a clinical setting. The Adaptive Tests of Temporal Resolution (ATTR(c)) are unique in that they incorporate an adaptive psychophysical procedure to present stimuli via computer sound card. The purpose of this study was to determine if ATTR gap detection thresholds (GDTs) were stable across presentation levels (80 dB SPL, listener-selected level) and sound cards (high-end, inexpensive). DESIGN: GDTs were measured using three conditions of the ATTR: broad-band noise within-channel (BBN-WC), narrowband noise within-channel (NBN-WC), and narrowband noise across channel (NBN-AC). Analysis of the acoustical properties of ATTR stimuli was made by measuring the electrical signals produced by each sound card. STUDY SAMPLE: Participants were 30 young adults with normal hearing. RESULTS: The ATTR GDTs did not differ between presentation levels for all three stimulus conditions. Also, neither ATTR stimuli nor ATTR GDTs differed between sound cards for all conditions. CONCLUSIONS: The ATTR may be used in a clinical setting with a relatively inexpensive sound card and listener-selected levels. Normative performance values for each ATTR condition are provided. PMID- 21303228 TI - Relationship between self-reported hearing and measured hearing impairment in an elderly population in Finland. AB - OBJECTIVE: The objective of this study was to evaluate the usefulness of the Finnish version of the Hearing Handicap Inventory for Elderly Screening (HHIE-S) questionnaire and a simple single-question method in detecting hearing loss. DESIGN: We compared the HHIE-S score and the single question with audiometry results. By analysing the receiver operating characteristic (ROC) curves of the HHIE-S scores we estimated the appropriate cut-off points for the different degrees of hearing loss. STUDY SAMPLE: 164 home-dwelling subjects in the age cohorts of 70, 75, 80 and 85 years in an industrialized town in Finland filled in the questionnaire, and attended the audiometry. RESULTS: For the detection of moderate or worse hearing loss (i.e., pure tone average at 0.5-4 kHz frequencies >40 dB), the HHIE-S cut-off score of >8 had a sensitivity of 100% and a specificity of 59.7%. The single question had a sensitivity of 100% and a specificity of 70.7%. Thus, the single question was equally sensitive and more specific in detecting moderate or worse hearing loss than the HHIE-S score. However, for the detection of mild hearing loss (i.e., pure tone average >25 dB), the HHIE-S was more sensitive but less specific than the single question. PMID- 21303229 TI - Bilateral macular ischemia and severe visual loss following trastuzumab therapy. PMID- 21303230 TI - Limited impact on patient experience of access of a pay for performance scheme in England in the first year. AB - BACKGROUND: Improvement of access to general practice is a priority in England. In 2006/07 an annual national survey of patient experience of access was introduced, with financial incentives to practices based on the findings of the survey among their own patients. OBJECTIVES: To describe changes in patient experience of access over the first two years of the survey and incentive scheme, and identify respondent and practice characteristics associated with patient experience of access. DESIGN AND METHODS: The study included 222 general practices in the east of England, which had completed the access survey in 2006/07 and 2007/08. We compared proportions of patients reporting satisfaction with different aspects of access in each year. In explanatory regression models, we investigated the associations between improvement of reported access and respondent and practice characteristics. RESULTS: There were some small improvements in reported access between the two surveys, although satisfaction with opening hours declined marginally. The explanatory analysis showed that larger practices, a higher proportion of respondents from ethnic minority groups, and higher deprivation were associated with patient reports of worse access. These variables and practice response rates did not explain the amount of change between the two years. CONCLUSIONS: The launch of the incentive scheme was not followed by convincing improvements in patient experience of access. Practices with deprived populations or with a high proportion of ethnic minority survey respondents are perceived as offering worse access, were not more likely to achieve improvements, and additional support should be considered to help these practices. PMID- 21303231 TI - Enhancement of matrix production and cell proliferation in human annulus cells under bioreactor culture. AB - Tissue engineering is a promising approach for treatment of disc degeneration. Herein, we evaluated effects of rotating bioreactor culture on the extracellular matrix production and proliferation of human annulus fibrosus (AF) cells. AF cells were embedded into alginate beads, and then cultured up to 3 weeks in a rotating wall vessel bioreactor or a static vessel. By real-time reverse transcription-polymerase chain reaction, expression of aggrecan, collagen type I and type II, and collagen prolyl 4-hydroxylase II was remarkably elevated, whereas expression of matrix metalloproteinase 3 and a disintegrin and metalloproteinase with thrombospondin motifs 5 was significantly decreased under bioreactor. Biochemical analysis revealed that the levels of the whole cell associated proteoglycan and collagen were approximately five- and twofolds in rotating bioreactor, respectively, compared to those in static culture. Moreover, AF cell proliferation was augmented in rotating bioreactor. DNA contents were threefolds higher in rotating bioreactor than that in static culture. Expression of the proliferating cell nuclear antigen was robustly enhanced in rotating bioreactor as early as 1 week. Our findings suggested that rotating bioreactor culture would be an effective technique for expansion of human annulus cells for tissue engineering driven treatment of disc degeneration. PMID- 21303232 TI - Introduction: The New York HIV-drug use epidemic: lessons learned and unresolved issues. PMID- 21303233 TI - HIV among drug users at Beth Israel Medical Center, New York City, the first 25 years. AB - New York City experienced the first and largest HIV epidemic among injecting drug users (IDUs). Using data collected from IDUs entering the Beth Israel drug detoxification program, we trace the history of this epidemic from the mid-1970s through the early 2000s. The epidemic can best be described in terms of successive stages: (1) introduction and rapid transmission of HIV in the IDU population; (2) stabilization of HIV prevalence at a high level (over 50%); (3) a decline in incidence and prevalence, following large-scale implementation of syringe exchange programs; and (4) a sexual transmission phase, in which HIV prevalence is approximately equal among injecting and noninjecting heroin and cocaine users, and sexual transmission is more important than injecting-related transmission among IDUs. Given the current spread of HIV among IDUs in many places in the world, New York City provides a very strong example for implementation of large-scale comprehensive syringe exchange programs as early as possible in HIV epidemics among IDUs. PMID- 21303234 TI - Access to sterile syringes for injecting drug users in New York City: politics and perception (1984-2010). AB - In the United States, political and social environments have shaped public health response to injecting drug use, and New York City represents a salient example. The history of "harm reduction" in New York City is characterized within changing historical periods and in relation to the actions of stakeholders. The expansion is traced over four periods: (i) 1984-1989: emergence, activism, and science; (ii) 1990-1994 reckoning: syringe exchange legislation and consolidation; (iii) 1995-1999: bureaucratization, opposition, and challenges to institutional control; and (iv) 2000-2010 revitalization: expansion of syringe access and harm reduction. It is clear from this review that the leadership of activism and the work of advocates catalyzed syringe access policy and practice. Without this "push," it is unlikely that New York City would have experienced the dramatic decline in HIV infection among drug injectors in the 1990s. Second, successful arguments for expanding syringe access in New York City were based on the high HIV/AIDS infection rates. Thus, program developments were advocated as HIV prevention interventions, rather than as expanded services for addressing broader health and social issues of injecting drug use. PMID- 21303235 TI - The transformation of drug markets and its impact on HIV outreach to injection drug users in New York City, 1987-2008. AB - This oral history describes three periods of street outreach to injection drug users at risk for HIV in New York City: outreach in an era of public drug markets (1987-1993), outreach in an era of private markets (1993-2006), and network driven outreach (2006-present). Individual interviews with administrators and supervisors of outreach workers are combined with field notes from the ethnographic research experiences of the first two authors to contextualize, compare, and contrast these distinct periods. The combination and triangulation of these sources of data allow for an analysis of both the specific and the wider social and cultural contexts in which outreach intervention efforts were situated. Through these lenses, the article examines some of the reasons why they were or were not successful and discusses prospects for the future. PMID- 21303236 TI - HIV in the epicenter of the epicenter: HIV and drug use among criminal justice populations in New York City, 1980-2007. AB - During the 1990s, some of the highest rates of HIV infection in the United States were found among inmates in the New York City jail and prisons systems. This article traces the history of drug use and HIV infection among populations incarcerated in New York City jails and New York State prisons between 1980 and 2007. It describes and analyzes the policies and programs that were initiated to respond to these epidemics and assesses the lessons learned from almost three decades of experience with HIV among populations in New York's correctional facilities. PMID- 21303237 TI - Addressing the HIV-related needs of substance misusers in New York State: the benefits and barriers to implementing a "one-stop shopping" model. AB - Substance misusers are at risk for contracting HIV/AIDS, and substance user treatment programs (SUTPs) are uniquely situated to address their HIV-related needs. In New York State, some SUTPs have implemented a centralized model of substance user treatment and HIV care. We synthesize past literature and use data from semistructured interviews with SUTP staff, analyzed with qualitative software, to describe implementation barriers. These interviews were conducted in 2003-2004 at three SUTPs in Texas and New York as part of a study funded by the National Institutes of Health. With study limitations noted, main implications include a need for a combined medical-addiction treatment philosophy to facilitate multidisciplinary care. PMID- 21303238 TI - Comparison of HIV risk by duration of injection drug use. AB - Early studies documented an inverse association between the HIV risk and duration of injection among injection drug users (IDUs). Results from subsequent studies have been inconsistent. To examine this issue, we conducted interviews with 395 street-recruited active IDUs from 38 neighborhoods in New York City during 2005 and 2008. We observed no significant differences in drug or risky sex behaviors by duration of drug use among these IDUs. Despite this, continuing to tailor HIV prevention programs for these recent-onset IDUs is prudent. The study's limitations are noted. PMID- 21303240 TI - Sexual risk and HIV infection among drug users in New York City: a pilot study. AB - Measures of sexual health were assessed during 2008-2009 in a New York City sample of 102 injection and noninjection users of heroin, cocaine, or crack. There was considerable overlap and transitioning between crack smoking and injecting. Crack users were also significantly more likely to be gay, lesbian, or bisexual than other drug users. In multivariate analysis, HIV infection was independently associated with crack use and with being gay or bisexual. In New York City, HIV prevention for drug users has focused on syringe access, safe injection, and drug user treatment, but further progress in HIV control will require strategies to address sexual health among people who use drugs. The study's limitations are noted. PMID- 21303239 TI - Continuing HIV risk in New York City injection drug users: the association of syringe source and syringe sharing. AB - Sterile syringe access is an important means to reduce HIV risk, but many injection drug users (IDU) who obtain syringes from sterile sources continue to share syringes. We examined the factors associated with continuing syringe sharing in New York City. We recruited 500 active IDU in 2005 through respondent driven sampling. In multiple logistic regression, not obtaining all syringes in the past year exclusively from sterile sources was associated with increased syringe sharing. Ensuring adequate syringe availability as well as engaging and retaining nonusers and inconsistent users in sterile syringe services may increase sterile syringe access and decrease syringe sharing. PMID- 21303241 TI - HIV heterosexual sexual risk from injecting drug users among HIV-seronegative noninjecting heroin users. AB - Noninjecting heroin users (NIUs) were recruited in New York City during 1996 2003. Cumulative logistic regression was used to analyze the correlates of HIV sexual risk from injecting drug users (IDUs) among HIV seronegative NIUs engaging in heterosexual vaginal or anal sex in the past 30 days (N = 347). Participants were 67% male and 70% African American or Latino, with a mean age of 32.6 years. Hierarchical categories of IDU partner sexual risk included (1) no unprotected sex and no IDU sex partners (21%), (2) unprotected sex but not with IDUs (55%), (3) IDU sex partners but no unprotected sex with them (6%), and (4) unprotected sex with IDUs (17%). Independent correlates (p < .05) of HIV sexual risk from IDU partners included female versus male gender (adjusted odds ratio [AOR] = 2.01), ex-IDU versus never IDU (AOR = 1.90), and lower versus higher perceived social distance from IDUs (AOR = 1.60). Interventions should target female NIUs, ex IDUs, and NIU members of IDU social and sexual networks. The study's limitations are noted. PMID- 21303243 TI - Trends related to aging and co-occurring disorders in HIV-infected drug users. AB - Drug users with HIV infection successfully treated with highly active antiretroviral therapy are now living to older ages. As persons with HIV infection age, they become at risk for comorbidities that occur in any group of aging individuals. However, some of these conditions occur at increased rates, with increasing severity, or pose special problems in older persons with HIV infection. This article discusses the epidemiology of HIV infection in aging drug users, and hormonal, cardiovascular, liver, renal, bone, and cognitive disorders and depression and cancer in these individuals, as well as problems related to taking multiple medications and HIV disease progression. PMID- 21303244 TI - Excess mortality among injection drug users with AIDS, New York City (1999-2004). AB - We calculated proportions and trends in contributing causes of death among persons with AIDS (PWA) and a history of injection drug use (IDU) in New York City and compared the proportions with those among PWA with a transmission risk of high-risk heterosexual sex (HRH) and men who have sex with men (MSM). We included all 10,575 injection drug user, HRH, and MSM residents aged 13+ years with AIDS reported by September 30, 2006 , who died from 1999 through 2004. Accidental drug overdose was the most frequent contributing cause of death among IDUs (20.5%). Overdose prevention initiatives may greatly and immediately reduce deaths among PWA. PMID- 21303242 TI - Strategies to improve access to and utilization of health care services and adherence to antiretroviral therapy among HIV-infected drug users. AB - We review five innovative strategies to improve access, utilization, and adherence for HIV-infected drug users and suggest areas that need further attention. In addition, we highlight two innovative programs. The first increases access and utilization through integrated HIV and opioid addiction treatment with buprenorphine in a community health center, and the second incorporates adherence counseling for antiretroviral therapy in methadone programs. Preliminary evaluations demonstrated that these strategies may improve both HIV and opioid addiction outcomes and may be appropriate for wider dissemination. Further refinement and expansion of strategies to improve outcomes of HIV-infected drug users is warranted. PMID- 21303245 TI - HIV risk and prevention among Hispanic immigrants in New York: the salience of diversity. AB - The importance of identifying differences in HIV risk between Hispanic subgroups is the focus of this article. Data are drawn from two New York?based HIV-related studies: among Puerto Rican drug users and among new immigrants from Central America, the Dominican Republic, and Mexico. Results indicated that intercultural individuals (i.e., those involved in both Puerto Rican and mainland cultures) were less risky in terms of injection- and sex-related risk behaviors and that geographic and other contextual factors, along with cultural norms, influence risk behaviors for immigrants. Both studies indicate the need to differentiate subgroup factors affecting HIV risk and prevention behaviors to develop appropriate and effective community-based interventions. The study's limitations are noted. PMID- 21303246 TI - Substance use in the MSM population of New York City during the era of HIV/AIDS. AB - This literature review considers the historical significance, emergence of, and interplay between the HIV and illicit drug use epidemics among gay, bisexual, and other men who have sex with men (MSM) in New York City (NYC). The continual rise in HIV infections in recent years among MSM, particularly among young MSM (YMSM), commands a need for the examination of the effectiveness of current HIV prevention strategies and a more comprehensive understanding of the complex biopsychosocial influences that place YMSM at risk. A chronological perspective of both the HIV and illicit drug use epidemics affecting NYC MSM is presented, followed by a review of the existing research on the synergistic relation between the two. Special consideration is given to the patterns and interconnectivity between HIV, substance use, and housing instability specific to YMSM, as they represent the demographic currently at greatest risk for HIV transmission in NYC. Thereafter, an overview of treatment research is provided. We conclude by offering recommendations for future research and best practices as we move forward in an attempt to reduce the incidence of HIV transmission. PMID- 21303247 TI - HIV risk behaviors among young drug using women who have sex with women (WSWs) in New York City. AB - Previous research has suggested that multiple stressors may work in tandem to affect the health of women who have sex with women (WSWs). WSWs have been a part of the HIV epidemic in New York City since the beginning, making it an ideal setting to further explore these women's risk. Among a sample of 375 heroin, crack and/or cocaine using women recruited from economically disadvantaged communities in New York City, we examined HIV seroprevalence and risk behaviors among WSWs as compared to women who have sex with men only (WSMOs). We also explore differences between WSWs and WSMOs with respect to potential stressors (i.e., decreased access to resources and health care utilization and violence victimization) that might contribute overall HIV risk. The study's limitations are noted. PMID- 21303248 TI - Overview of HIV among injection drug users in New York City: critical next steps to eliminate racial/ethnic disparities. AB - At the start of the HIV epidemic, 50% of new infections were among injection drug users (IDUs) in New York City. While HIV has declined among IDUs since the mid 1990s, parenteral transmission continues to overburden Blacks/Hispanic IDUs. Individual risk behaviors do not explain the distribution of HIV/AIDS among IDUs. Social and/or structural factors are likely fueling racial disparities creating a high-risk socioenvironmental context. While increased access to structural interventions (i.e., syringe exchange and pharmacy syringe access) is needed, it may not be sufficient to eliminate HIV/AIDS disparities among IDUs. Research on incorporating structural factors into intervention strategies is needed. PMID- 21303249 TI - Intimate partner violence and HIV among drug-involved women: contexts linking these two epidemics--challenges and implications for prevention and treatment. AB - Intimate partner violence (IPV) and HIV are two serious overlapping public health epidemics that disproportionately affect drug-involved women. This article reviews research that has identified a number of contexts that may explain the links between IPV and HIV transmission risks. These contexts include sexual coercion, fear of violence, negotiation of condom use, extradyadic relationships, disclosure of sexually transmitted infections or HIV seropositivity to intimate partners, drug involvement of women and their male partners, low social status of drug-involved women, relationship dependencies, and sex ratio imbalances. The article focuses on how the bidirectional relationship between IPV and HIV risks may be mediated by a history of childhood sexual abuse and post-traumatic stress disorder. Also addressed are the challenges that substance user treatment programs face in dealing with female clients who experience IPV and the implications for HIV prevention. PMID- 21303250 TI - Symbiotic goals and the prevention of blood-borne viruses among injection drug users. AB - A positive-deviance control-case life history study of injection drug users (IDUs) in New York City who had injected drugs for 8-15 years compared 21 IDUs who were antibody negative for both HIV and hepatitis C with 3 infected with both viruses and 11 infected with hepatitis C virus but not HIV. Eligible subjects were referred from other research studies and from community organizations that conduct testing for HIV and hepatitis C virus. Data were collected during 2005 2008 and were analyzed using life history and grounded theory approaches. They support grounded hypotheses that IDUs who are able to attain symbiotic goals like avoiding withdrawal and maintaining social support are assisted thereby in remaining uninfected with HIV or hepatitis C. These hypotheses should be tested using cohort studies and prevention trials to see if helping IDUs attain symbiotic goals reduces infection risk. The study's limitations are noted. PMID- 21303251 TI - Current and emerging research needs in studying the NYC HIV-drug use epidemic. AB - As we begin the fourth decade of the epidemic, it is clear that, as demonstrated by the articles in this Special Issue, much has been learned about factors contributing to the decline in HIV prevalence among drug users in New York. However, there are a number of outstanding research questions that remain or are emerging. Following is a summary of some of the topics requiring further research. While this summary does not represent a comprehensive list, it is based on many of the questions raised in the articles in this Special Issue and identifies some of the directions to be investigated during the next decade. PMID- 21303253 TI - Comorbid psychiatric diagnoses among individuals presenting to an addiction treatment program for alcohol dependence. AB - A retrospective patient record review was conducted to examine comorbid psychiatric diagnoses, and comorbid substance use, among 465 patients below 45 years of age, presenting to a national alcohol addiction treatment unit in Dublin, between 1995 and 2006. Rates were high for depressive disorder (25.3%) particularly among females (35.4%). Lifetime reported use of substances other than alcohol was 39.2%, and further analysis showed significantly higher rates of deliberate self-harm among this group. Lifetime reported use of ecstasy was also significantly associated with depression in this alcohol-dependent population using logistic regression analysis. Implications and limitations of the findings are discussed. PMID- 21303254 TI - Drug use among prisoners: by any definition, it's a big problem. AB - According to several studies, the prevalence of drug use (1) among prisoners is manyfold compared to general population. However, comparisons across studies are hampered by the use of a variety of mutually noncomparable methodologies. We report substance use among Finnish prisoners using three methods and analyze these differences. The material consisted of 610 Finnish prisoners in 2006 and represents all Finnish prisoners. The subjects participated in a comprehensive field study including a standardized psychiatric interview (SCID-I). Alcohol abuse/dependence was diagnosed in 68% (SCID-I) and 72% (ICD-10) among men and 70% (both SCID-I and ICD-10) among women. Drug abuse/dependence was diagnosed in 62% (SCID-I) and 69% (ICD-10) among men and 64% (SCID-I) and 70% (ICD-10) among women prisoners. Interview data revealed that the majority had at least tried most substances. Both alcohol and drug abuse/dependence were vastly more common among Finnish prisoners than reported elsewhere. The DSM-IV-based SCID-I produced slightly lower prevalence estimates than an ICD-10 clinical examination, but overall SCID/ICD agreement was very good. It seems that physicians use information other than that captured by standardized structured clinical interview when placing a diagnosis. Nonclinical interview-based prevalence figures may overestimate harmful use of drugs unless known risk patterns of use (e.g., intravenous use) are specifically addressed. PMID- 21303256 TI - Metabolic control through hepatocyte and adipose tissue cross-talk in a multicompartmental modular bioreactor. AB - Physiological processes involve a complex network of signaling molecules that act through paracrinal or endocrinal pathways; however, traditional in vitro models cannot mimic these interactions because of the lack of a dynamic cross-talk between cells belonging to different tissues. The multicompartmental modular bioreactor is a novel cell culture system where hepatocytes and adipose tissue are shown to interact in a more physiological manner. In the multicompartmental modular bioreactor, cells and tissues can be cultured in a common medium, which flows through the system acting as the bloodstream. Primary rat hepatocytes and adipose tissue were cultured separately and together in conventional conditions and in the bioreactor. Urea synthesis, albumin secretion, glycerol, free fatty acid, and glucose concentrations were analyzed and compared. The dynamic connected culture of adipose tissue and hepatocytes led to a significant enhancement of hepatic function in terms of increase of albumin and urea production with respect to conventional cultures. Interestingly, the glycerol gradually released from adipose tissue was buffered in the dynamic connected culture, manifesting a homeostatic-like control. These data show that the dynamic culture not only improves hepatocyte function, but also allows a cross-talk between tissues, leading to enhanced metabolic regulation in vitro. PMID- 21303258 TI - Noninvasive multimodal evaluation of bioengineered cartilage constructs combining time-resolved fluorescence and ultrasound imaging. AB - A multimodal diagnostic system that integrates time-resolved fluorescence spectroscopy, fluorescence lifetime imaging microscopy, and ultrasound backscatter microscopy is evaluated here as a potential tool for assessing changes in engineered tissue composition and microstructure nondestructively and noninvasively. The development of techniques capable of monitoring the quality of engineered tissue, determined by extracellular matrix (ECM) content, before implantation would alleviate the need for destructive assays over multiple time points and advance the widespread development and clinical application of engineered tissues. Using a prototype system combining time-resolved fluorescence spectroscopy, FLIM, and UBM, we measured changes in ECM content occurring during chondrogenic differentiation of equine adipose stem cells on 3D biodegradable matrices. The optical and ultrasound results were validated against those acquired via conventional techniques, including collagen II immunohistochemistry, picrosirius red staining, and measurement of construct stiffness. Current results confirm the ability of this multimodal approach to follow the progression of tissue maturation along the chondrogenic lineage by monitoring ECM production (namely, collagen type II) and by detecting resulting changes in mechanical properties of tissue constructs. Although this study was directed toward monitoring chondrogenic tissue maturation, these data demonstrate the feasibility of this approach for multiple applications toward engineering other tissues, including bone and vascular grafts. PMID- 21303259 TI - Genistein mediates the anti-adipogenic actions of Sophora japonica L. extracts. AB - Previous studies showed that feeding diets containing the mature fruits of Sophora japonica L. prevented body weight gain and reduced fat mass in high-fat diet-induced obese mice. This observation has led to the hypothesis that extracts from S. japonica L. may inhibit adipocyte differentiation of preadipocytes. To elucidate the possible mechanisms for the anti-obesity action of S. japonica L., its effects on adipocyte differentiation were investigated in C3H10T1/2 mesenchymal stem cells and 3T3-L1 preadipocyte cells. The mature fruit of S. japonica L. was partitioned with ethanol, hexane, dichloromethane, ethyl acetate (EtOAc), and butanol to identify the active fractions. The EtOAc fraction extracts inhibited morphological differentiation and lipid accumulation in the C3H10T1/2 and 3T3-L1 preadipocytes. Molecular studies indicated that the EtOAc fraction extracts also reduced the expression of peroxisome proliferator activated receptor gamma and other adipocyte markers. Furthermore, among the fractions, the EtOAc fraction extracts had the highest total phenolic contents, suggesting that the polyphenols in the EtOAc fractions mediated the anti adipogenic effects. Finally, high-performance liquid chromatography identified genistein, a known anti-adipogenic compound, as the probable mediator of the anti adipogenic effects of the EtOAc fractions. This work validates the beneficial roles of S. japonica L. in controlling body weight and obesity-related metabolic diseases. PMID- 21303257 TI - Knockdown of Akt1 promotes Akt2 upregulation and resistance to oxidative-stress induced apoptosis through control of multiple signaling pathways. AB - The Akt signaling pathway plays a key role in promoting the survival of various types of cells from stress-induced apoptosis, and different members of the Akt family display distinct physiological roles. Previous studies have shown that in response to UV irradiation, Akt2 is sensitized to counteract the induced apoptosis. However, in response to oxidative stress such as hydrogen peroxide, it remains to be elucidated what member of the Akt family would be activated to initiate the signaling cascades leading to resistance of the induced apoptosis. In the present study, we present the first evidence that knockdown of Akt1 enhances cell survival under exposure to 50 MUM H(2)O(2). This survival is derived from selective upregulation and activation of Akt2 but not Akt3, which initiates 3 major signaling cascades. First, murine double minute 2 (MDM2) is hyperphosphorylated, which promotes p53 degradation and attenuates its Ser-15 phosphorylation, significantly attenuating Bcl-2 homologous antagonist killer (Bak) upregulation. Second, Akt2 activation inactivates glycogen synthase kinase 3 beta (GSK-3beta) to promote stability of myeloid leukemia cell differentiation protein 1 (MCL-1). Finally, Akt2 activation promotes phosphorylation of FOXO3A toward cytosolic export and thus downregulates Bim expression. Overexpression of Bim enhances H(2)O(2)-induced apoptosis. Together, our results demonstrate that among the Akt family members, Akt2 is an essential kinase in counteracting oxidative-stress-induced apoptosis through multiple signaling pathways. PMID- 21303260 TI - Phenethyl isothiocyanate inhibits 12-O-tetradecanoylphorbol-13-acetate-induced inflammatory responses in mouse skin. AB - Phenethyl isothiocyanate (PITC) is the hydrolysis product of the glucosinolate gluconasturtiin in cruciferous vegetables. This study was conducted to determine whether PITC inhibits 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation in the mouse ear. Topical application of 5 nmol of TPA to mouse ears markedly increased the ear weight, expression of the inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 protein, and phosphorylation of the inhibitor of kappaB (IkappaB) alpha, AKT, and extracellular signal-regulated protein kinase (ERK) 1/2 and reduced IkappaBalpha protein levels. Pretreatment with PITC (150-450 nmol) significantly suppressed these TPA-induced inflammatory responses. We also determined whether low concentrations of PITC (0.5-5 MUmol/L) inhibited lipopolysaccharide (LPS)-stimulated inflammatory responses in Raw264.7 cells. PITC dose-dependently reduced the LPS-induced secretion of nitric oxide, prostaglandin E(2), interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF) alpha, as well as COX-2 and iNOS protein expression. PITC also attenuated LPS induced increases in iNOS, COX-2, IL- 6, IL-1beta, and TNF-alpha mRNA levels, as well as the promoter-dependent transcriptional activation of the genes for iNOS and COX-2. PITC inhibited LPS-induced IkappaBalpha phosphorylation and degradation and subsequently reduced LPS-induced p65 nuclear translocation and the transcriptional activity of nuclear factor-kappaB (NF-kappaB), which was accompanied by a reduction in ERK1/2 and AKT phosphorylation. The results of this study demonstrated that PITC effectively inhibits inflammatory responses in vivo and in vitro, which may be mediated via the inhibition of AKT and ERK1/2 activation, leading to subsequent inhibition of the transcriptional activity of NF-kappaB. PMID- 21303261 TI - Stimulation of activity and expression of antioxidant enzymes by solvent fractions and isolated compound from Cedrela sinensis leaves in HepG2 cells. AB - Cedrela sinensis has been widely used in traditional Oriental medicine to treat a variety of diseases. However, little is known about the cellular actions by which this plant mediates its antioxidant effects. In this study, activity-guided fractionations of C. sinensis leaves were performed using column chromatographic techniques as well as biological assays with HepG2 cells. The ethanol (95%) extract of C. sinensis leaves was sequentially extracted with hexane, chloroform, ethyl acetate (EtOAc), butanol, and water, and the fractions were screened for their antioxidant potentials for scavenging radicals as well as inducing antioxidant enzyme activity and expression. The most potent antioxidant EtOAc fraction was further separated using chromatographic techniques including open column and high-performance liquid chromatography. Compound 1 from the EtOAc fraction showed strong radical scavenging activity with a 50% scavenging concentration value close to that of ascorbic acid and induced both the activity and expressions of antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase. Inhibitory effects on the phosphorylations of upstream mitogen-activated protein kinases such as c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38 were also observed after treatments with compound 1. Compound 1 was identified as quercitrin by (1)H- and (13)C-nuclear magnetic resonance techniques. Taken together, our findings demonstrated for the first time that C. sinensis leaves appear to be a useful source of a cytoprotective and chemopreventive agent that can stimulate the activity and expression of crucial antioxidant enzymes in cells. PMID- 21303262 TI - A combination of green tea extract and l-theanine improves memory and attention in subjects with mild cognitive impairment: a double-blind placebo-controlled study. AB - A combination of green tea extract and l-theanine (LGNC-07) has been reported to have beneficial effects on cognition in animal studies. In this randomized, double-blind, placebo-controlled study, the effect of LGNC-07 on memory and attention in subjects with mild cognitive impairment (MCI) was investigated. Ninety-one MCI subjects whose Mini Mental State Examination-K (MMSE-K) scores were between 21 and 26 and who were in either stage 2 or 3 on the Global Deterioration Scale were enrolled in this study. The treatment group (13 men, 32 women; 57.58 +/- 9.45 years) took 1,680 mg of LGNC-07, and the placebo group (12 men, 34 women; 56.28 +/- 9.92 years) received an equivalent amount of maltodextrin and lactose for 16 weeks. Neuropsychological tests (Rey-Kim memory test and Stroop color-word test) and electroencephalography were conducted to evaluate the effect of LGNC-07 on memory and attention. Further analyses were stratified by baseline severity to evaluate treatment response on the degree of impairment (MMSE-K 21-23 and 24-26). LGNC-07 led to improvements in memory by marginally increasing delayed recognition in the Rey-Kim memory test (P = .0572). Stratified analyses showed that LGNC-07 improved memory and selective attention by significantly increasing the Rey-Kim memory quotient and word reading in the subjects with MMSE-K scores of 21-23 (LGNC-07, n = 11; placebo, n = 9). Electroencephalograms were recorded in 24 randomly selected subjects hourly for 3 hours in eye-open, eye-closed, and reading states after a single dose of LGNC-07 (LGNC-07, n = 12; placebo, n = 12). Brain theta waves, an indicator of cognitive alertness, were increased significantly in the temporal, frontal, parietal, and occipital areas after 3 hours in the eye-open and reading states. Therefore, this study suggests that LGNC-07 has potential as an intervention for cognitive improvement. PMID- 21303263 TI - Application of low-level laser irradiation (LLLI) and rhBMP-2 in critical bone defect of ovariectomized rats: histomorphometric evaluation. AB - OBJECTIVES: The aim of this study was to evaluate the osteogenic potential of recombinant human bone morphogenetic protein-2 (rhBMP-2) and low-level laser irradiation (LLLI), isolated or combined in critical bone defects (5 mm) in parietal bone using ovariectomized female rats as an experimental animal model. MATERIALS AND METHODS: Forty-nine female Wistar rats, bilaterally ovariectomized (OVX), were divided into seven treatment groups of seven animals each: (I) laser in a single application, (II) 7 MUg of pure rhBMP-2, (III) laser and 7 MUg of pure rhBMP-2, (IV) 7 MUg of rhBMP-2/monoolein gel, (V) laser and 7 MUg of rhBMP 2/monoolein gel, (VI) laser and pure monoolein gel, and (VII) critical bone defect controls. The low-level laser source used was a gallium aluminum arsenide semiconductor diode laser device (lambda = 780 nm, D = 120 J/cm(2)). RESULTS: Groups II and III presented higher levels of newly formed bone than all other groups with levels of 40.57% and 40.39%, respectively (p < 0.05). The levels of newly formed bone of groups I, IV, V, and VI were similar with levels of 29.67%, 25.75%, 27.75%, and 30.64%, respectively (p > 0.05). The area of new bone formation in group VII was 20.96%, which is significantly lower than groups I, II, III, and VI. CONCLUSIONS: It was concluded that pure rhBMP-2 and a single dose of laser application stimulated new bone formation, but the new bone formation area was significantly increased when only rhBMP-2 was used. Additionally, the laser application in combination with other treatments did not influence the bone formation area. PMID- 21303264 TI - Incidence of cleft pathology in Greater New Orleans before and after Hurricane Katrina. AB - BACKGROUND: Reports after the 2005 Hurricane Katrina have documented an increase in stress reactions and environmental teratogens (arsenic, mold, alcohol). OBJECTIVE: To assess the incidence of cleft pathology before and after the hurricane, and the distribution of cleft cases by gender and race. METHODS: Retrospective chart review of cleft lip with or without cleft palate (CL/P) and cleft palate (CP) cases registered with the Cleft and Craniofacial Team at Children's Hospital of New Orleans, the surgical center that treated cleft cases in Greater New Orleans between 2004 and 2007. Live birth data were obtained from the Louisiana State Center for Health Statistics. RESULTS: The incidence of cleft cases, beginning 9 months after the hurricane (i.e., June 1, 2006) was significantly higher compared with the period before the hurricane (0.80 versus 1.42; p = .008). Within racial group comparisons showed a higher incidence among African Americans versus whites (0.42 versus 1.22; p = .01). The distribution of CL/P and CP cases by gender was significant (p = .05). CONCLUSION: The increase in the incidence of cleft cases after the hurricane may be attributable to increased stress and teratogenic factors associated with the hurricane. The increase among African Americans may have been due to comparatively higher exposure to environmental risk factors. These findings warrant further investigation to replicate the results elsewhere in the Gulf to determine whether there is a causal relationship between environmental risk factors and increased cleft pathology. PMID- 21303265 TI - Flood, disaster, and turmoil: social issues in cleft and craniofacial care and crisis relief. AB - OBJECTIVE: To examine social issues in the conduct of cleft and craniofacial care through relief programs in disrupted crisis contexts. METHOD: Social, health policy, and ethical analyses. RESULTS: At best, craniofacial team care is multidisciplinary, coordinated, and sustained, requiring a long-term relationship between team members, patients, and families. Disasters and societal turmoil interrupt such relationships, causing craniofacial care to become a secondary concern. Providing craniofacial team care in a crisis setting requires rebuilding disrupted coordination and communication. Crisis relief care involves a complex set of expectations and responsibilities and raises issues such as (1) quality assurance, infection control, appropriate standards of care, and follow-up care/continuity; (2) equity of access to services and clinical ethics in the context of war and/or deprivation; (3) training of visitors in the local nation or site; (4) disciplinary composition of teams, interprofessional communication/rivalry, and credentials of clinicians; (5) ownership of the site and local visitor relations; (6) fundraising and marketing strategies; and (7) ethical issues in the doctor-patient relationship. CONCLUSIONS: Specific ethical standards for international cleft and craniofacial care delivery also apply to domestic and global crisis relief contexts. Guidance on issues related to professional experience, informed consent, and continuity of care will help care providers address social and ethical issues raised in crisis relief programs. This paper proposes that the Position Paper of the American Cleft Palate Craniofacial Association (ACPA) on International Treatment Programs should be used as a template to develop and disseminate a set of standards that apply to crisis relief. PMID- 21303266 TI - Safety of intravenous infusion of human adipose tissue-derived mesenchymal stem cells in animals and humans. AB - Adipose tissue-derived mesenchymal stem cells (AdMSCs) represent an attractive and ethical cell source for stem cell therapy. With the recent demonstration of MSC homing properties, intravenous applications of MSCs to cell-damaged diseases have increased. In the present study, the toxicity and tumorigenicity of human AdMSCs (hAdMSCs) were investigated for clinical application. Culture-expanded hAdMSCs showed the typical appearance, immunophenotype, and differentiation capacity of MSCs, and were genetically stable at least 12 passages in culture. Cells suspended in physiological saline maintained their MSC properties in a cold storage condition for at least 3 days. To test the toxicity of hAdMSCs, different doses of hAdMSCs were injected intravenously into immunodeficient mice, and the mice were observed for 13 weeks. Even at the highest cell dose (2.5*10(8) cells/kg body weight), the SCID mice were viable and had no side effects. A tumorigenicity test was performed in Balb/c-nu nude mice for 26 weeks. Even at the highest cell dose (2*10(8) MSCs/kg), no evidence of tumor development was found. In a human clinical trial, 8 male patients who had suffered a spinal cord injury >12 months previous were intravenously administered autologous hAdMSCs (4*10(8) cells) one time. None of the patients developed any serious adverse events related to hAdMSC transplantation during the 3-month follow-up. In conclusion, the systemic transplantation of hAdMSCs appears to be safe and does not induce tumor development. PMID- 21303268 TI - The complexities of home visitation for children with asthma in underserved communities. PMID- 21303267 TI - Single-walled carbon nanotubes chemically functionalized with polyethylene glycol promote tissue repair in a rat model of spinal cord injury. AB - Traumatic spinal cord injury (SCI) induces tissue damage and results in the formation of a cavity that inhibits axonal regrowth. Filling this cavity with a growth-permissive substrate would likely promote regeneration and repair. Single walled carbon nanotubes functionalized with polyethylene glycol (SWNT-PEG) have been shown to increase the length of selected neurites in vitro. We hypothesized that administration of SWNT-PEG after experimental SCI will promote regeneration of axons into the lesion cavity and functional recovery of the hindlimbs. To evaluate this hypothesis, complete transection SCI was induced at the T9 vertebral level in adult female rats. One week after transection, the epicenter of the lesion was injected with 25??L of either vehicle (saline), or 1??g/mL, 10??g/mL, or 100??g/mL of SWNT-PEG. Behavioral analysis was conducted before injury, before treatment, and once every 7 days for 28 days after treatment. At 28 days post-injection the rats were euthanized and spinal cord tissue was extracted. Immunohistochemistry was used to detect the area of the cyst, the extent of the glial scar, and axonal morphology. We found that post-SCI administration of SWNT-PEG decreased lesion volume, increased neurofilament positive fibers and corticospinal tract fibers in the lesion, and did not increase reactive gliosis. Additionally, post-SCI administration of SWNT-PEG induced a modest improvement in hindlimb locomotor recovery without inducing hyperalgesia. These data suggest that SWNT-PEG may be an effective material to promote axonal repair and regeneration after SCI. PMID- 21303269 TI - Autologous cell therapy for cardiac repair. AB - INTRODUCTION: While new therapies have improved the prognosis of patients post acute myocardial infarction, many patients still suffer from irreversible damage and live with the debilitating consequences. However, with the advent of stem cell-based therapies, future treatments may enable us to harness the potential of autologous stem cells to prevent and even reverse heart damage. AREAS COVERED: We outline the results of the early clinical trials using autologous cell therapy and highlight the hurdles and limitations that still need to be addressed. We also discuss new approaches that hold promise for developing the next generations of autologous cell therapy by exploring strategies to enhance their regenerative activity using biomaterials, genetic modification, optimal cell types and small molecule preconditioning. EXPERT OPINION: Autologous cell therapy may be on the cusp of being widely adopted for the treatment of patients with large areas of myocardial damage. Techniques to enhance the activity and retention of autologous cell products may represent the next generation of this therapy. PMID- 21303270 TI - Macaque cytochromes P450: nomenclature, transcript, gene, genomic structure, and function. AB - Monkeys, especially macaques, including cynomolgus (Macaca fascicularis) and rhesus monkeys (Macaca mulatta), are frequently used in drug metabolism studies due to their evolutionary closeness to humans. Recently, numerous cytochrome P450 (P450 or CYP) cDNAs have been identified and characterized in cynomolgus and rhesus monkeys and were named by the P450 Nomenclature Committee. However, recent advances in genome analysis of cynomolgus and rhesus monkeys revealed that some monkey P450s are apparently orthologous to human P450s and thus need to be renamed corresponding to their human orthologs. In this review, we focus on the P450s identified in cynomolgus and rhesus monkeys and present an overview of the identity and functional characteristics of each P450 cDNA in the CYP1-4 families. Information on the Japanese monkey (Macaca fuscata), African green monkey (Cercopithecus aethiops), and marmoset (Callithrix jacchus), primate species used in some drug metabolism studies, are also included. We compared the genomic structure of the macaque P450 genes to those of human and rat P450 genes in the CYP1-4 families. Based on sequence identity, phylogeny, and genomic organization of monkey P450s, we determined orthologous relationships of monkey P450s and, in this article, propose a revised nomenclature: CYP2B17/CYP2B30 to CYP2B6, CYP2C20/CYP2C74 to CYP2C8, CYP2C43/CYP2C83 to CYP2C9, CYP2C75 to CYP2C19, CYP2F6 to CYP2F1, CYP3A8/CYP3A21/CYP3A64 to CYP3A4, CYP3A66 to CYP3A5, and CYP4F45 to CYP4F2. The information presented in this review is expected to promote a better understanding of monkey P450 genes through comparative genomics and thereby make it more feasible to use monkeys in drug metabolism studies. PMID- 21303271 TI - 21st century mental health care: what it looks like and how to achieve it. PMID- 21303272 TI - The suicides of The Metamorphoses. AB - AIM: The aim of this paper was to explore the attitude toward and motives for suicide recorded in Ovid's The Metamorphoses, a document that has influenced Western culture. METHOD: The translation by Horace Gregory was examined. RESULTS: Twenty-five mentions of suicidal thoughts or actions were identified, mainly by humans but also by a god, a nymph and a centaur. Fifteen suicides by humans were identified. The motives were predicaments including the loss of a loved individual or status and the threat of murder or plague. There was one instance of intolerable physical pain and one of defiance in the face of intimidation. While there are mentions of madness, there is no mention of madness leading to suicide. There was no censure of suicide. CONCLUSION: Suicide in Western culture appears to have roots in ancient times. PMID- 21303273 TI - Chronic suicidal thoughts and implicit memory: hypothesis and practical implications. AB - OBJECTIVE: This paper outlines a hypothesis linking the development of implicit memory in infants and chronic suicidal thoughts in adults. In order to do this, the developmental trajectory of memory is reviewed, as well as how attachment experiences are encoded in implicit memory. The cognitive/emotional capacity of infants is then compared to the subjective experience of the chronically suicidal patient. This is used to develop the hypothesis that chronic suicidal thoughts are located in implicit memory, encoded very early in life. This idea is then used to explain why common responses by mental health workers to the chronically suicidal patient may inadvertently reinforce suicidal thoughts. Finally, understanding these concepts helps us to understand how psychotherapy can change chronic suicidal ideation. CONCLUSION: A hypothesis is proposed to link infant memory systems with adult chronic suicidal thoughts, and is used to understand helpful responses for patients who suffer with chronic suicidal ideation. PMID- 21303274 TI - In conversation with Allan Schore. Interview by George Halasz. PMID- 21303275 TI - Overview of the national mental health benchmarking project. AB - OBJECTIVE: This paper provides an overview of the National Mental Health Benchmarking Project (NMHBP) which explored the value of benchmarking within the four main program areas of public sector mental health (general adult, child and adolescent, older persons and forensic). The NMHBP involved a series of forums which enabled participating organizations to benchmark themselves against each other, with a view to understanding variability in performance against a range of key performance indicators (KPIs). METHOD: Twenty-three mental health organizations took part in the NMHBP. The forums culminated in each mental health organization documenting its performance against relevant KPIs. The processes, impacts and outcomes of the NMHBP were evaluated via a multi-methods evaluation. RESULTS: There was considerable variability across program streams for many of the KPIs, much of which could be explained by contextual factors. Within program streams there was considerable intra-organization variability. Participants found the examination of intra-organization variability on particular indicators to be useful. CONCLUSIONS: The NMHBP has shown that benchmarking is possible. Managers and clinical leaders will need to champion benchmarking and highlight its utility in relation to quality improvement and service development if the accountability goals of the Fourth National Mental Health Plan are to be realized. PMID- 21303276 TI - Benchmarking older persons mental health organizations. AB - OBJECTIVE: This paper offers a reflection about the outcomes of the older persons benchmarking forums that formed part of the National Mental Health Benchmarking Project (NMHBP). METHOD: Seven older persons mental health organizations took part in the NMHBP. Representatives from these organizations attended eight benchmarking forums at which they documented their performance against relevant key performance indicators (KPIs). In order to better understand the differential performance of organizations on particular KPIs, participants gathered additional contextual data. This included organization-level data, data on the local catchment area, and data with which to profile the consumers accessing services through the given organization. RESULTS: Participants' average performance on some indicators was stable over time, while the average performance on others demonstrated fluctuations. Perhaps more importantly, the inter-organization range for almost all of the indicators was substantial. CONCLUSIONS: The older persons benchmarking forums provided an opportunity for participants to gauge the performance of their own organizations on a range of KPIs, come to understand some of the reasons for their own organization's performance and that of their counterparts, consider which of these reasons may be within their control, and reflect upon opportunities for quality improvement within their own organizations. PMID- 21303277 TI - A community mental health service delivery model: integrating the evidence base within existing clinical models. AB - OBJECTIVES: A model of care for community mental health services was developed by reviewing the available literature, surveying ?best practice? and evaluating the performance of existing services in a metropolitan area mental health service servicing a population of approximately 1.1 million people. METHODS: A review of relevant academic literature and recognized ?good practice? service delivery models was undertaken in conjunction with a review of local activity data and consultation with key stakeholders (not addressed in this paper). A model was developed identifying the core functions of community mental health service delivery. RESULTS: The components of a comprehensive, integrated model of community mental health service (CMHS) are outlined. The essential components of a comprehensive, integrated model of CMHSs include: acute and emergency response, community continuing care services, assertive rehabilitation teams, partnerships with general practitioners and other human services agencies. CONCLUSIONS: We propose a comprehensive integrated model of community mental health service. Clarity of role, required outputs and expected outcomes will assist the development of effective and appropriate community mental health services. Outreach to the community is a key success factor for these services and their associated inpatient services. Gap analysis can assist in the planning and costing of community mental health services. PMID- 21303278 TI - An intensive community team in aged persons mental health. AB - OBJECTIVE: The aim of this paper was to describe an intensive community team (ICT) in aged persons' mental health. The rationale for setting up the team, the principles, service activity and findings from the evaluation of the service are discussed. CONCLUSIONS: The program was found to provide substantial support and benefit for patients. ICT does not replace the need for acute inpatient beds but it does provide an opportunity for some patients, who otherwise would have been admitted, to be managed in their homes. It also has the potential of reducing the length of stay for a number of patients. PMID- 21303279 TI - Temporal trends in self harm and aggression on a paediatric mental health ward. AB - OBJECTIVE: The aim of this paper is to describe trends in aggression and self harm on a mental health inpatient unit for children and adolescents between January 2006 and August 2009. Various ward interventions and the ward milieu were evaluated as possible explanatory factors for trends. METHOD: This was a retrospective study whereby incidents of aggression, self harm and seclusion were obtained from a computerized Incident Information Management System (IIMS) database. Trends in incidents were analysed using linear regression analyses. RESULTS: Over a 44-month period, 292 incidents of aggression and 139 incidents of self harm were reported. The use of seclusion and the number of aggressive incidents both significantly decreased over time. Trends suggested a positive relationship between the introduction of restraint training, changes in leadership and full staff complement, and a reduction in aggression and seclusion. CONCLUSIONS: Although the findings are limited by their retrospective nature and reliance on formal records, this study suggests that different factors can contribute to decrease the incidence of adverse events on a psychiatric ward. Future prospective research is needed to assess the effectiveness of different interventions in both the prevention and management of self harm, aggression and seclusion in child and adolescent inpatient units. PMID- 21303280 TI - How acceptable are one-off consultations for consumers? Further information on Item 291. AB - OBJECTIVE: The aim of this paper is to evaluate consumer and carer views of one off psychiatric assessments, Item 291 in the Australian Medicare system. METHOD: Following general practitioner referral to a psychiatrist, consumers were invited to enroll in this study and provide: demographic data; a one-off face-to-face recorded interview 6-8 weeks following psychiatric assessment; and longitudinal assessment of their mental health, using the DASS, K10 and WHOQoL (prior to psychiatric assessment, 6-8 weeks after assessment and 3-4 months later). RESULTS: Consumer and carer enrollment were very difficult to obtain. Sufficient consumers (8) enrolled to provide meaningful qualitative data. Most had good mental health literacy, had severe and chronic mental health problems, and appreciated the opportunity to access a mental health expert and receive a management plan. Overall, GPs had appropriately informed consumers of the process. Following assessment, the GP and consumer were implementing the suggested management plan. Negative statements included instances of failure to improve, insufficient appointments with the psychiatrist, and concern with GP follow-up. CONCLUSION: One-off psychiatric assessments using Item 291 appear highly acceptable to referred consumers. Qualitative outcomes showed trends towards an improvement in mental health, in an appropriate target group. PMID- 21303281 TI - Consumer strategies for coping with antipsychotic medication side effects. AB - OBJECTIVE: This study was designed to investigate the strategies employed by consumers to manage the common side effects associated with antipsychotic medication use. METHOD: Focus group discussions and individual interviews involving 238 consumers, 25 carers and 16 mental health staff were employed to identify key side effects and a range of consumer coping strategies for managing these adverse effects. RESULTS: Nine side effects were selected from a total pool of 32 proposed in the group discussions. Strategies that were perceived by the participants to be useful in coping with the selected side effects were then identified. CONCLUSIONS: While the strategies proposed for each side effect differed, common themes included the maintenance of a balanced lifestyle, healthy eating and sleeping routines, and fostering a positive outlook on life. Understanding the strategies employed by consumers to deal with the adverse effects of their medications may help clinicians to engage more effectively with consumers in the discussion and management of side effects. PMID- 21303282 TI - Supported employment can reduce social exclusion and improve schizophrenia. AB - OBJECTIVE: There are significant mental health benefits in schizophrenia associated with integration into society and the workplace. This case examines factors contributing to such reintegration. CONCLUSIONS: A hostel team, an employment officer from an employment agency for the disabled and a community clinic collaborated to foster reintegration into the community through supported employment, improved supported accommodation and family support. PMID- 21303286 TI - NSW law, ECT and DBS. PMID- 21303287 TI - Code of ethics: the time-bomb of clause 3.13. PMID- 21303288 TI - The language and purpose of medico-legal reports. PMID- 21303289 TI - Calling a spade a spade. PMID- 21303290 TI - Fear of the yawning mother: a case study of misophonia. PMID- 21303295 TI - Thyroxin overdose due to rheumatoid factor interferences in thyroid-stimulating hormone assays. AB - BACKGROUND: Immunoassays are susceptible to interferences by anti-hormone antibodies, heterophilic antibodies or rheumatoid factor (RF). METHODS: We report a case of levothyroxin overdose because of gross overestimation of thyroid stimulating hormone (TSH) by chemiluminescent and IRMA assays. Alternate assays were performed and heterophilic antibodies blocking tubes were used. RESULTS: Analytical investigations revealed: i) non-linear concentrations of TSH after serum dilutions, ii) decreased TSH concentrations after removal of heterophilic antibodies, iii) appropriately decreased TSH concentrations in alternate TSH assays and iv) identification of increased concentrations of RF. CONCLUSIONS: The presence of RF may be responsible for false determination of TSH concentrations preventing monitoring of TSH. PMID- 21303296 TI - Implementation of computerized add-on testing for hospitalized patients in a large academic medical center. AB - BACKGROUND: Physician requests for additional testing on an existing laboratory specimen (add-ons) are resource intensive and generally require a phone call to the laboratory. Verbal orders such as these have been noted to be associated with errors in accuracy. The aim of this study was to compare a novel computerized system for add-on requests to the prior verbal system. METHOD: We compare the computerized add-on request system to the verbal system with respect to order completeness and workflow. RESULTS: We demonstrate that the computerized add-on system resulted in the complete in-laboratory documentation of the add-on request 100% of the time, compared to 58% with the verbal add-on system. In addition, we show that documentation of a verbal add-on request in the electronic medical record (EMR) occurred for 4% of requests, while in the computerized system EMR documentation occurred 100% of the time. We further demonstrate that the computerized add-on request process was well accepted by providers and did not significantly change the test mix of the add-on requests. CONCLUSIONS: In computerized physician order entry (CPOE) implementations, add-on order functionality should be considered so these orders are documented in the EMR. PMID- 21303297 TI - CSF biomarkers in neurodegenerative diseases. AB - Neurodegenerative diseases are major world wide causes of morbidity and mortality. They form a heterogeneous group of diseases, ranging from rare monogenic inherited errors of metabolism to common multi-factorial dementias. Major research efforts focus on the development of disease modifying drugs for neurodegenerative diseases. As a result, there follows a need for reliable tools for diagnosis, prognosis and monitoring of therapy. Processes in the brain can be monitored by analysis of cerebrospinal fluid (CSF). Several CSF biomarkers of pathological processes in the brain are now available. Such biomarkers may be used for both research and in the clinical setting. However, several difficult problems remain to be solved. More intensive collaboration between academia, industry and government is likely needed to develop treatments and biomarkers for neurodegenerative diseases. This article reviews the definitions, usage and current limitations of CSF biomarkers in this field. PMID- 21303298 TI - High frequency of inadequate test requests for antiphospholipid antibodies in daily clinical practice. AB - BACKGROUND: We have empirically noted that many physicians routinely request anti phospholipid antibodies (aPL) without a correct clinical indication. The aim of this study was to evaluate retrospectively whether aPL testing at our Thrombosis Centre was justified. METHODS: Medical records from 520 subjects for aPL screening tests for various clinical conditions were reviewed. The aPL screening tests were: lupus anticoagulant (LA), anti-cardiolipin antibodies (aCL) and anti beta(2) glycoptotein I (abeta(2) GPI). Requests for aPL screening were divided into justified, potentially justified or not adequately justified. RESULTS: aPL testing requests were considered justified in 358 (69%) patients, potentially justified in 66 (12.6%) and not adequately justified in 96 (18.4%). LA was positive in 65 (18%) of justified requests and in only one (1%) of the 96 potentially justified requests. None of the 66 not adequately justified for aPL testing was positive for LA. abeta(2) GPI was positive in 63 (17.6%) of the 358 justified, in four (6%) of the 66 potentially justified and in five (5.2%) of the 96 not adequately justified requests; aCL IgG were positive in 59 (16.4%) of the 358 justified and in five (7.5%) and six (6.2%) of the potentially justified and not adequately justified requests, respectively. The presence of the triple aPL positivity was found exclusively in the justified requests. CONCLUSIONS: This study suggests that requests for aPL tests should be addressed more adequately. This work could be an example of how to focus attention on requests for laboratory tests especially on the basis of valid clinical criteria before the analyte is measured. PMID- 21303299 TI - S100B protein in neurodegenerative disorders. AB - "Classic" neurodegenerative disorders, such as Alzheimer's disease and amyotrophic lateral sclerosis share common pathophysiological features and involve progressive loss of specific neuronal populations, axonal or synaptic loss and dysfunction, reactive astrogliosis, and reduction in myelin. Furthermore, despite the absence of astrogliosis, impaired expression of astrocyte- and oligodendrocyte-related genes has been observed in patients with major psychiatric disorders, including schizophrenia and mood disorders. Because S100B is expressed in astrocytes and oligodendrocytes, its concentration in cerebrospinal fluid (CSF) or serum has been considered a suitable surrogate marker for the diagnostic or prognostic assessment of neurodegeneration. This review summarizes previous postmortem, CSF and serum studies regarding the role of S100B in this context. A general drawback is that only small single-center studies have been performed. Many potential confounding factors exist because of the wide extra-astrocytic and extracerebral expression of S100B. Due to lack of disease specificity, reliance on S100B concentrations for differential diagnostic purposes in cases of suspected neurodegenerative disorders is not recommended. Moreover, there is no consistent evidence for a correlation between disease severity and concentrations of S100B in CSF or serum. Therefore, S100B has limited usefulness for monitoring disease progression. PMID- 21303300 TI - Biomarkers in Alzheimer's disease. AB - Dementia is a growing public health concern because of the lack of effective curative treatment options and a rising global prevalence. Alzheimer's disease (AD) is the most common type of dementia, affecting 60%-70% of all patients with dementia. The main pathological features of Alzheimer's dementia are neurofibrillary tangles and senile plaques caused by progressive deposition of beta-amyloid in the brain, but its underlying pathological basis is unclear. In common late onset AD sporadic forms (95% of all AD cases), a major genetic risk factor is the apolipoproteinE-E4 (ApoE-E4) alleles, and other genetic determinants have also been proposed to play causative role. This review focuses on biomarkers and subsequent changes in continuous measurement of cognitive and functional abilities in patients with mild cognitive impairment (MCI) and AD that aim to achieve a higher diagnostic accuracy for AD along with clinical assessment, neuropsychological testing and neuroimaging. PMID- 21303301 TI - Non-invasive prenatal diagnosis of trisomy 21 by reverse transcriptase multiplex ligation-dependent probe amplification. AB - BACKGROUND: Obtaining fetal DNA or RNA by either chorionic villus sampling (CVS) or amniocentesis is currently, the gold standard prenatal diagnosis. However, these invasive procedures carry risk of miscarriage. A reliable method for non invasive prenatal diagnosis (NIPD) has long been sought to reduce the risk of miscarriage. METHODS: Cell-free fetal RNA was extracted from the plasma of peripheral blood from 121 women 9-20 weeks of pregnancy. Five single nucleotide polymorphism (SNP) loci in PLAC4 gene were analyzed by reverse transcriptase multiplex ligation-dependent probe amplification (RT-MLPA), followed by capillary electrophoresis. Karyotype analysis was used for confirmation of prenatal diagnosis of trisomy 21. RESULTS: Of 121 samples, 23 were diagnosed with trisomy 21, 87 with normal ploidy, nine had all five SNP loci homozygous and two had one heterozygous SNP locus. Comparing with karyotype analysis, the diagnostic sensitivity and specificity of RT-MLPA were 92% and 100%, respectively. CONCLUSIONS: RT-MLPA is a convenient and reliable method for the diagnosis of trisomy 21. We have shown that this method has good specificity, high sensitivity, and high throughput, making this technique applicable for NIPD in clinical practice. PMID- 21303302 TI - Inflammatory markers in childhood asthma. AB - The major characteristic of asthma is persistent airway inflammation that fails to resolve spontaneously. Dysregulation of pro- and anti-inflammatory mechanisms is responsible for the development of chronic inflammation. The inflammatory reaction is mediated by numerous cells and their mediators. Detection and quantification of airway inflammation in children are subject to many requirements, e.g., use of biologic samples obtained in a non-invasive way; use of standardized analytical methods to determine biomarkers that can identify inflammation processes (inflammation itself, oxidative stress, apoptosis and remodelling); determining the role of systemic inflammation; assessment of correlation of various biomarkers of inflammation with clinical parameters and their diagnostic efficacy; providing a tool(s) to monitor diseases, and to evaluate adequacy of therapy; and predicting the clinical course of inflammation and prognosis of asthma. Using standardized analyses, it is now possible to determine direct markers of local inflammation, i.e., fractional nitric oxide (marker of oxidative stress) in exhaled breath, pH (marker of acid stress) in breath condensate, and indirect markers in blood/serum, i.e., eosinophil granulocytes (indicating migration), eosinophil cationic protein (marker of activated eosinophil granulocytes) and C-reactive protein (marker of systemic inflammation). However, none of these biomarkers are specific for asthma. Further standardization of the known pulmonary biomarkers of local inflammation and identification of new ones will allow for longitudinal follow-up of inflammation in children with asthma. PMID- 21303303 TI - Role of unique basic residues in cytotoxic, antibacterial and antiparasitic activities of human eosinophil cationic protein. AB - Eosinophil granule proteins, eosinophil cationic protein (ECP) and eosinophil derived neurotoxin are members of the RNase A superfamily, which play a crucial role in host defense against various pathogens as they are endowed with several biological activities. Some of the biological activities possessed by ECP have been attributed to its strong basic character. In the current study, we have investigated the role of five unique basic residues, Arg22, Arg34, Arg61, Arg77 and His64 of ECP in its catalytic, cytotoxic, antibacterial and antiparasitic activities. These residues were changed to alanine to generate single and double mutants. None of the selected residues was found to be involved in the RNase activity of ECP. The substitution of all five residues individually was detrimental for the cytotoxic, antibacterial and antiparasitic activities of ECP; however, mutation of Arg22 and Arg34 resulted in the most significant effects. The double mutants also had reduced biological activities. All ECP mutants that had significantly reduced toxicity also had reduced membrane destabilization activity. Our study demonstrates that Arg22, Arg34, Arg61, Arg77 and His64 of ECP are crucial for its membrane destabilization activity, which appears to be the underlying mechanism of its cytotoxic, antibacterial and antiparasitic activities. PMID- 21303304 TI - Opinion & hypothesis could early aspirin prophylaxis prevent against preterm birth? AB - A growing body of evidence suggests that defective placentation may play a major role in the genesis of preterm birth, indicating that preeclampsia, intra-uterine growth restriction (IUGR), and spontaneous preterm birth can share a similar mechanism of disease. A recent meta-analysis of low-dose aspirin trials for the prevention of preeclampsia and IUGR in high-risk women demonstrated that, when started early in gestation, aspirin could prevent more than half of preeclampsia and IUGR cases but was also linked with a significant decrease of preterm births (relative risk 0.22, 95% confidence interval: 0.10-0.49). Unfortunately, most studies did not report specific data on the cause of preterm deliveries and, therefore, we could not estimate the proportion of this effect that could be related to spontaneous preterm births. Therefore, we hypothesize that low-dose aspirin could become an additional weapon in the prevention of preterm births and we suggest that further studies should be performed in this area of research. PMID- 21303308 TI - Cystic fibrosis transmembrane regulator potentiators as promising cystic fibrosis therapies. AB - INTRODUCTION: Several types of mutations in the cystic fibrosis transmembrane regulator (CFTR) gene lead to abnormal CFTR protein and alterations of chloride and sodium transmembrane transportation in cystic fibrosis (CF). Some investigational compounds such as VX-770 can improve CFTR protein function. AREAS COVERED: This paper discusses the results of a Phase II study investigating the safety and efficacy of VX-770 in patients with CF. EXPERT OPINION: VX-770 is able to improve chloride and sodium transportation and has a good safety profile. Although such compounds have limited therapeutic targeting potential, preliminary results show great promise in the context of CF therapy. PMID- 21303309 TI - Mifepristone followed by home administration of buccal misoprostol for medical abortion up to 70 days of amenorrhoea in a general practice in Curacao. AB - OBJECTIVE: To evaluate the efficacy and safety of home administration of buccal misoprostol after mifepristone for medical abortion up to 70 days' gestation in a general practice in Curacao, where induced abortion is severely restricted by law. METHODS: In a prospective study 330 women received 200 mg mifepristone and were instructed to take four tablets (800 MUg) of misoprostol via the buccal route 24-36 h later, at home. One week later, follow-up took place. RESULTS: The outcome could be evaluated in 307 of the 330 women. The efficacy of the mifepristone-buccal misoprostol procedure was 97.7% (300/307). In seven women vacuum aspirations for continuing pregnancy or incomplete abortion following treatment were required. Success rates at 64-70 days' gestation were the same as for gestations of less than 64 days duration. The main adverse effects were nausea and diarrhoea. CONCLUSION: Home administration of buccal misoprostol 24-36 h after mifepristone is a safe and effective method of medical abortion up to 70 days. It could be applied in a general practice in Curacao, where induced abortion is legally restricted. PMID- 21303310 TI - [Our experience in nasal reconstruction with local nasal and regional flaps]. AB - OBJECTIVES: In this study, we evaluated the patients, who underwent nasal reconstruction with local nasal or regional flaps and compared our approach with the algorithms of nasal reconstruction in literature. PATIENTS AND METHODS: Twenty-seven patients (15 males, 12 females; mean age 68.7 years; range 42 to 86 years) who underwent nasal reconstruction with local nasal or regional flaps due to excision of skin cancers on the nose, between November 2007 and December 2009 were included in this study. The demographic data (age, sex and occupation), the location, histopathologic type, subtype and size of the tumor, the size and thickness of the defect area, the reconstruction technique and complications were recorded. All patients were photo-documented pre-, intra- and postoperatively, and were followed up at regular intervals. RESULTS: Basal cell carcinoma was detected in 23 patients and squamous cell carcinoma was detected in four patients. The tumors were most frequently located on the nasal dorsum (n=8, 29%) and the side walls (n=6, 22%). The tumor size was >15 mm in 14 (52%) patients. The size of the nasal defect was >20 mm in 18 (66%) patients. Reconstruction was performed with local nasal flaps in 10 patients and with regional flaps in 17 patients. CONCLUSION: The surgical flaps for nasal reconstruction should be selected individually. The ideal technique of nasal reconstruction should be determined based on the location, size, and thickness of the nasal defects, the preferences of the patients and the surgeon's experience. PMID- 21303311 TI - [Evaluation of the effect of intranasal corticosteroid sprays on radiofrequency tissue ablation in the treatment of hypertrophied inferior turbinate]. AB - OBJECTIVES: This study aims to evaluate the effect of combining the confidingly preferred modality of radiofrequency (RF) application with intranasal corticosteroid spray treatment on the efficacy of RF and on the number of sessions in patients with hypertrophy of inferior turbinate. PATIENTS AND METHODS: Fifty patients (37 males, 13 females; mean age 42.9 years; range 15 to 74 years) who admitted with the complaint of nasal obstruction and were detected to have hypertrophied inferior turbinate by nasal endoscopy were enrolled in the study. The patients were divided into two groups, each consisting of 25 patients. Before the treatment, the severity of nasal obstruction was evaluated and scored by a visual analogue scale (VAS). Radiofrequency was applied to every patient. Control group received no medical treatment following RF application. Drug group received mometasone furoate nasal spray (MFNS) at a dose of 200 mcg once daily into both nasal passages for eight weeks following surgery. All patients were asked to return for a control visit at week eight after treatment. Radiofrequency application was repeated in patients who continued to have complaints of nasal blockage. At the end of treatment, patients were reevaluated and VAS scores were recorded. RESULTS: The improvement in VAS scores following treatment was statistically significant in both groups (p<0.05). When the two groups were compared, there was no statistical difference between the two groups before treatment; however there was an improvement in the post-treatment corticostreoid group (p<0.05). The mean session number was calculated to be 1.16 in the control group and 1.08 in the corticosteroid treatment group. The difference between the two groups was not statistically significant (p>0.05). CONCLUSION: We recommend the use of intranasal corticosteroids with RF applications to increase the efficacy of radiofrequency. PMID- 21303312 TI - The reliability of SleepStrip as a screening test in obstructive sleep apnea syndrome. AB - OBJECTIVES: This study aims to assess the reliability of SleepStrip as a screening test in obstructive sleep apnea syndrome (OSAS). PATIENTS AND METHODS: Seventy-two patients (50 males, 22 females; mean age 51.4+/-11.1 years; range 20 to 74 years) with OSAS were included in this prospective, non-randomized double blinded single cohort study between May 2008 and February 2009. Patients who underwent an attended overnight polysomnography (PSG) and consented to participate in the study were asked to use SleepStrip device within the week following PSG recording. The apnea-hypopnea index (AHI) was compared with the SleepStrip score (Sscore). RESULTS: The mean body mass index of patients was 31.1+/-4.3. Both AHI and Sscore were obtained in 64 patients. There was a strong correlation between Sscore and AHI (r=0.76, p<0.001). The sensitivity and specificity of the SleepStrip were 94.4% and 93.5% when used to diagnose cases with AHI = or >40. The sensitivity and specificity of the SleepStrip was reduced to 80% and 87.2% when AHI threshold was chosen as = or >25 and 83.3% and 76.5% for AHI = or >15 respectively. CONCLUSION: There is a strong correlation between SleepStrip and AHI. SleepStrip was found to be effective in diagnosing severe OSAS with AHI = or >40, however, its diagnostic capability was reduced in patients with lower AHI's who constitute the main target of screening. PMID- 21303313 TI - [Evaluation of swallowing function with surface electromyography before and after tonsillectomy]. AB - OBJECTIVES: In this study, we evaluated the swallowing function with surface electromyography before and after tonsillectomy. PATIENTS AND METHODS: Twenty patients (12 males, 8 females; mean age 23.8 years; range 17 to 30 years) who had tonsillectomy indication as study group, and 10 healthy individuals (8 males, 2 females; mean age 26 years; range 18 to 35 years) as control group were included in this prospective study between October 2008 and February 2009. Due to their significant role on oral and faringeal phases of swallowing; the surface electromyography prosedure is performed on the masseter muscle, the submental submandibular muscle group and the infrahyoid muscles to measure their electrical activity and duration of contraction. For this purpose, single swallow and continuous drinking of 100 cc water tests were applied to each patient preoperatively and; in the postoperative 1st week and the 1st month. RESULTS: The preoperative duration of drinking periods were significanly longer in the study group compared to the control group (p<0.05). At the end of the first postoperative week the duration of drinking 100 cc water test was significantly longer than the preoperative mean of the study group (p<0.05). After one month single- swallow durations of study group were significantly shorter then the preoperative mean (p<0.05). The electrical activity of the masseter and infrahyoid muscles were significantly higher in study group compared with control group (p<0.05). CONCLUSION: The close proximity of the surgical area to the muscles affects swallowing after tonsillectomy. The surface electromyography is a simple, non-invasive and reliable method for postoperative evaluation of the swallowing functions of the throat muscles and thereby allows monitoring of the recovery and functional improvement of these muscles. PMID- 21303314 TI - A "modified-flying wing" procedure for the treatment of saddle nose and supratip pathologies. AB - OBJECTIVES: In this report, we present the usage of a "modified flying wing" procedure for different indications such as correction of primary supratip depression and saddle nose deformity due to prior septal surgery or prior trauma, and also for prevention of possible supratip deformity. PATIENTS AND METHODS: Between April 2004 and January 2008, the "modified flying wing" procedure was used in a total of 11 patients; for the correction of primary supratip depression deformities in three patients, for the saddle nose deformities due to prior trauma or septal surgery in four patients, and for the prevention of future supratip deformity in four patients (3 males, 8 females; mean age 25.3 years; range 19 to 35 years). The "modified-flying wing" procedure was performed as described by Jugo. Hump removal and medial or lateral osteotomy were considered based on patient status. In all patients a symmetric, balanced nose was achieved with an adequately projected tip and an esthetically satisfactory dorsum extending from the brows to the tip of the nose. No patient required a secondary rhinoplasty. RESULTS: In all patients the postoperative periods were without any complication and the long-term results were satisfactory. CONCLUSION: Using a "modified flying wing" procedure for the correction of saddle nose deformity avoids some disadvantages of autografts, such as the tendency of the autograft to warp and curl. Use of this procedure for primary rhinoplasty patients with a risk of developing future supratip deformity prevents this deformity. This combination approach in selected primary rhinoplasty cases provides an esthetically pleasing nose while preventing some complications of classical reduction rhinoplasty. We performed this procedure in 11 patients with good long-term functional and esthetic results. PMID- 21303315 TI - [Effect of propolis against radiation-induced oral mucositis in rats]. AB - OBJECTIVES: This study aims to investigate whether propolis has a protective role in oral mucosal damage induced by radiotherapy applied to head-neck region, using quantitative, biochemical and histopathological approaches. MATERIALS AND METHODS: Forty eight Wistar-Albino adult female rats at eight weeks of age and weighing 213+/-27 grams were included in this study and randomly divided into six groups: Group 1: control, group 2: only irradiated rats, group 3: irradiated rats with propolis administration at 50 mg/kg/day, group 4: irradiated rats with propolis administration at 100 mg/kg/day, group 5: only propolis administration at 50 mg/kg/day, group 6: only propolis administration at 100 mg/kg/day. The first dose of propolis was administered before 30 minutes irradiation and the other doses after irradiation once daily for seven days by topical application. Radiotherapy was applied to the total cranium by single fraction at a dose of 18 Gy. The mucositis degrees and body weights of the animals were measured throughout the experiment. On the 7th day of study, blood samples were taken from the rats under ketamine anesthesia and then the rats were sacrificed and tongue tissues samples were taken. Complete blood count and biochemical and antioxidant activities were analysed in the blood samples. The tongue samples were microscopically examined. RESULTS: Radiotherapy group had a decrease in body weight and neutrophil count, and an increase in oral mucositis as compared with the control group (p<0.001). Moreover, an increase in plasma malondialdehyde concentrations (p<0.001) and significant decreases in catalase and superoxide dismutase activities (p<0.001) were observed in irradiation-alone group when compared to the control group. Propolis administered irradiated rat groups showed a dose-dependent normalization in quantitative, biochemical and histopathological parameters when compared with the irradiation-alone group. CONCLUSION: The results showed that propolis is effective in reducing the severity of oral mucositis induced by head-and-neck irradiation. PMID- 21303316 TI - Bilateral acquired external auditory canal stenosis with squamous papilloma: a case report. AB - Acquired external auditory canal (EAC) stenosis is described as resulting from a number of different causes such as infection, trauma, neoplasia, inflammation and radiotherapy. Human papilloma virus (HPV) type 6, a deoxyribonucleic acid (DNA) virus, is considered to cause squamous papilloma of the EAC. In this article, we report a case of a 56-year-old male with warty lesions in the left external ear and a totally stenotic right external ear which had similar lesions one year before the involvement of his left ear. On computed tomography of the temporal bone, there was soft tissue obstruction of the right EAC, and thickening in the skin of the left EAC. The middle ear structures were normal on both sides. Biopsy was performed from the lesion in the left ear, and revealed squamous papilloma. We presented this case because squamous papilloma related bilateral acquired EAC stenosis is a rare entity. PMID- 21303317 TI - A rare case of fistula: nasocutaneous fistula. AB - A three-year-old male patient was brought to our clinic by his family with the complaint of a non-healing wound with discharge on his forehead and the nasal region. He had a history of a fall one-year ago. The patient had recurrent complaints of swelling and hyperemia following this trauma. He had undergone an operation with the pre-diagnosis of foreign body in soft tissue six months ago. However, no foreign body had been detected and the inflamed tissue had been excised and closed again. The swelling and purulent discharge in the region between nose and eye continued after this surgery. The patient underwent an operation and a circular defect 0.5 cm in diameter was detected on the dorsum of the nasal bone and a fistula tract was found to have developed between this defect and the skin between the nose and the eye. A subcutaneous forehead flap without skin tissue was removed including the periosteum from the left part of forehead after excision of the fistula tract. The flap was transferred to the nasal dorsum and the component of the forehead flap including the periosteum was used for reconstruction of the nasal mucosa. The wound healed without any problems and no fistula or infection developed again during the six-month follow up. PMID- 21303318 TI - [Sphingomonas paucimobilis infection with underlying submandibular sialolithiasis]. AB - Sphingomonas paucimobilis (S. paucimobilis), is a gram-negative, aerobic, non fermentative, oxidase (+) and catalase (+) bacterium. Although S. paucimobilis is isolated very rarely, it can cause both nosocomial and community-acquired infections. A patient admitted to our clinic had a complaint of swelling in the right mandibular region and pain increasing while eating for the previous week. Bimanual palpation revealed a painful swelling of 1x1x1 cm in size inside the right Wharton's duct. Via massage over the right submandibular gland, a purulent drainage came up from the opening of the Wharton's duct and it was cultivated and S. paucimobilis was isolated. There was no ultrasonographic evidence of calculi in the duct or in the gland, but during the right submandibular gland massage, two stones came out through the Wharton's duct. The infection was observed to be eradicated with a 14-day ampicillin-sulbactam treatment. In the control examination after six months, there were no pathological signs or symptoms and the ultrasonogram was normal. As far as we know, this is the first sialadenitis case with underlying sialolithiasis where S. paucimobilis was isolated. PMID- 21303320 TI - Radiofrequency treatment for inferior turbinate hypertrophy. AB - Radiofrequency ablation (RFA) is a technique which causes a reduction in tissue amount using ablation by high-frequency current. Beside other surgical tools, RFA has become quite popular over the past decade. Hypertrophy of the inferior turbinate is a common cause of chronic nasal obstruction. There is no agreement on how to deal with this problem. An ideal procedure for turbinate reduction should be performed with minimal discomfort or adverse reactions and should preserve the physiologic function of the turbinate, such as regulation of humidification and temperature of inspired air. All the current techniques have potential short and long-term complications such as bleeding and atrophic rhinitis. No technique is perfect, and the main goal of turbinate surgery should be the preservation of mucosal surfaces with reduction of submucosal tissue. The variety of surgical techniques available indicates the lack of consensus on the optimal technique. Radiofrequency tissue reduction is a surgical procedure that uses radiofrequency heating to induce submucosal tissue destruction, leading to the reduction of tissue volume. This energy induces ion agitation within the tissue, which increases the local temperature and causes a thermal lesion that should occur in the deep mucosa without damaging the surface. The healing process secondarily induces fibrosis with wound contraction, leading to tissue volume reduction. Radiofrequency ablation is an efficient, easily applicable technique, which does not lead to serious complications in the treatment of the nasal obstruction caused by inferior turbinate hypertrophy. PMID- 21303319 TI - Inappropriate use of foreign materials in temporomandibular joint ankylosis surgery: report of two cases. AB - Gap and interpositional arthroplasties are the most commonly used methods in the treatment of temporomandibular joint ankylosis. Complete resection of ankylotic segments, fibrotic band release and creating gap between the condyle and the glenoid fossa have great importance. Two patients were admitted to our clinic with complaints of difficulty in opening mouth and joint pain. In physical examination, maximum mouth opening values were recorded as 7 mm in one patient and 9 mm in another. An operation was planned due the presence of radiological grade 4 bilateral bony ankylosis. During the operation, foreign materials were found in the joint spaces of the patients. The first patient had a piece of nylon bag in the joint space, whereas the second patient had a silicon sheath used for wound therapy. Following removal of these materials, as a result of the recreation of joint spaces and the placement of suitable silicon blocks, 32 and 34 mm of mouth openings were noted during follow-up. In conclusion, recreated temporomandibular joint spaces after ankylosis surgery may be filled with a variety of autogenous or non-autogenously materials. However, the use of wrong materials inevitably causes recurrence and even worsens the primary condition. PMID- 21303321 TI - Responding to change: thermo- and photo-responsive polymers as unique biomaterials. AB - Responsive polymer systems that react to thermal and light stimuli have been a focus in the biomaterials literature because they have the potential to be less invasive than currently available materials and may perform well in the in vivo environment. Natural and synthetic polymer systems created to exhibit a temperature-sensitive phase transition lead to in situ forming hydrogels that can be degradable or non-degradable. These systems typically yield physical gels whose properties can be manipulated to accommodate specific applications while requiring no additional solvents or cross-linkers. Photo-responsive isomerization, dimerization, degradation, and triggered processes that are reversible and irreversible may be used to create unique gel, micelle, liposome, and surface-modified polymer systems. Unique wavelengths induce photo-chemical reactions of polymer-bound chromophores to alter the bulk properties of polymer systems. The properties of both thermo- and photo-responsive polymer systems may be taken advantage of to control drug delivery, protein binding, and tissue scaffold architectures. Systems that respond to both thermo- and photo-stimuli will also be discussed because their multi-responsive properties hold the potential to create unique biomaterials. PMID- 21303322 TI - Ablation of chronic total occlusions using kilohertz-frequency mechanical vibrations in minimally invasive angioplasty procedures. AB - Certain minimally invasive cardiology procedures, such as balloon angioplasty and stent implantation, critically require that the site of an arterial blockage be crossed by an intraluminal guidewire. Plaques resulting in near or totally occluded arteries are known as chronic total occlusions, and crossing them with conventional guidewires is a significant challenge. Among the most promising proposed solutions is the delivery of high-power, low-frequency ultrasonic vibrations to the occlusion site via an intraluminal wire waveguide. The vibrating distal tip of the ultrasound wire waveguide is used to transmit energy to the surrounding plaques, tissues, and fluids to ablate or weaken atherosclerotic plaque. Potential mechanisms of interaction with the plaque and adjacent fluids identified in the literature include: (i) direct contact with the waveguide distal tip, (ii) subcavitational acoustic fluid pressure fluctuations, (iii) cavitation, and (iv) acoustic streaming. We summarize developments in this area over more than two decades, describing experimental methods for device performance characterization, preclinical tests, early clinical investigations, and, later, full clinical trials. The article also reviews theoretical foundations and numerical models suitable for device design and analysis. Finally, important issues for future research and for the development of this technology will be considered. PMID- 21303323 TI - Mathematical foundations of biomechanics. AB - The aim of biomechanics is the analysis of the structure and function of humans, animals, and plants by means of the methods of mechanics. Its foundations are in particular embedded in mathematics, physics, and informatics. Due to the inherent multidisciplinary character deriving from its aim, biomechanics has numerous connections and overlapping areas with biology, biochemistry, physiology, and pathophysiology, along with clinical medicine, so its range is enormously wide. This treatise is mainly meant to serve as an introduction and overview for readers and students who intend to acquire a basic understanding of the mathematical principles and mechanics that constitute the foundation of biomechanics; accordingly, its contents are limited to basic theoretical principles of general validity and long-range significance. Selected examples are included that are representative for the problems treated in biomechanics. Although ultimate mathematical generality is not in the foreground, an attempt is made to derive the theory from basic principles. A concise and systematic formulation is thereby intended with the aim that the reader is provided with a working knowledge. It is assumed that he or she is familiar with the principles of calculus, vector analysis, and linear algebra. PMID- 21303324 TI - Influence of Rosemarinus officinalis extract on radiation-induced intestinal injury in mice. AB - The radioprotective effect of Rosemarinus officinalis extract (ROE) was studied in mice exposed to 3 Gy gamma radiation. Crypt survival, villus length, apoptotic cells, mitotic figures and goblet cells in intestine were studied at different autopsy intervals i.e. 12 hrs to 30 days after irradiation. Maximum changes in all the intestinal parameters were observed on day 3 after irradiation. Irradiated animals with ROE pretreatment exhibited a significant increase in the number of crypt cells, mitotic figures and villus length; whereas a significant decrease in the counts of apoptotic and goblet cells showed a significant decrease respective controls at all the autopsy intervals. Irradiation of animals resulted an elevation in lipid peroxidation and a reduction in glutathione concentration in the intestine at 1 hour post-irradiation. In contrast, ROE treatment before irradiation caused a significant depletion in lipid peroxidation and elevation in glutathione levels. PMID- 21303325 TI - Residual urinary volume and urinary tract infection, a life threatening illness: a case report. AB - Multiple Sclerosis (MS) is an inflammatory disease that demyelinates the central nervous system causing progressive disability. The urodynamics of MS patients is an important consideration because these patients are susceptible to acute urinary bladder retention associated with a high fever. Treatment should include irrigation using a Foley catheter and an irrigation syringe to remove residual urine and sediment from the neurogenic bladder, intravenous fluid resuscitation, bacteriological analysis of the residual urine, and admission to an Intensive Care Unit for further evaluation by a urologist. After discharge, suprapubic cystostomy should be a consideration for patients who have chronic urinary tract infections associated with acute urinary bladder retention, as well as limited mobility to perform self catheterization, or limited personal care assistants trained to perform a urethral clean intermittent catheterization. PMID- 21303326 TI - Protective effects of a by-product of the pecan nut industry (Carya illinoensis) on the toxicity induced by cyclophosphamide in rats Carya illinoensis protects against cyclophosphamide-induced toxicity. AB - This study investigated the antioxidant effects of pecan nut (Carya illinoensis) shell aqueous extract (AE) on toxicity induced by cyclophosphamide (CP) in the heart, kidney, liver, bladder, plasma and erythrocytes of rats. Rats were treated with water or pecan shell AE (5%) ad libitum, replacing drinking water for 37 days up to the end of the experiment. On day 30, half of each group received a single administration of vehicle or CP 200 mg/kg-ip. After 7 days, the organs were removed. Rats treated with CP showed an increase in lipid peroxidation (LP) and decrease in reduced glutathione (GSH) levels in all structures. Catalase (CAT) activity was increased in the heart and decreased in liver and kidney. Besides, CP treatment decreased plasmatic vitamin C (VIT C) levels and induced bladder macroscopical and microscopical damages. In contrast, co-treatment with pecan shell AE prevented the LP development and the GSH depletion in all structures, except in the heart and plasma, respectively. CAT activity in the heart and liver as well as the plasmatic VIT C levels remained unchanged. Finally, AE prevented CP-induced bladder injury. These findings revealed the protective role of pecan shell AE in CP-induced multiple organ toxicity. PMID- 21303327 TI - Protective role of perillic acid against radiation-induced oxidative stress, cytokine profile, DNA damage, and intestinal toxicity in mice. AB - The radioprotective effect of perillic acid was studied using an in vivo mouse model. Whole-body exposure of Swiss albino mice to gamma-rays (6 Gy) reduced the total white blood cell count to 1035 +/- 378 cells/mm3 on the 9th day, which was significantly elevated to 2196 +/- 382 cells/mm3 by the administration of perillic acid (50 MUmoles/kg body weight, intraperitoneally) on the same day. The number of bone marrow cells and alpha-esterase positive cells in control animals after 11 days of irradiation was reduced to 12.5 +/- 0.8 * 106 cells/femur and 674 +/- 45.2/4000 cells, respectively. In perillic acid treated animals, bone marrow cellularity was increased to 14.8 +/- 1.8 * 106 cells/femur and alpha esterase positive cells were 941 +/- 56.5 /4000 cells, similar to normal level (935 +/- 51.4/4000 cells). Administration of perillic acid could reduce the radiation-induced elevated levels of alkaline phosphatase (ALP), glutathione pyruvate transferase (GPT) and lipid peroxidation (LPO) in both serum and liver of irradiated animals. Perillic acid could significantly enhance the glutathione (GSH) content in liver and intestinal mucosa of irradiated animals. Histopathological analysis of small intestine also suggests that perillic acid could reduce the radiation-induced intestinal damage. The level of proinflammatory cytokines such as IL-1beta, TNF-alpha and CRP, which were elevated during irradiation, was significantly reduced by the Perillic acid administration. Perillic acid treatment could also stimulate the production of other cytokines such as GM-CSF and IFN-gamma in animals exposed to whole-body gamma irradiation. Agarose gel electrophoresis of DNA isolated from bone marrow of mice exposed to gamma radiation showed heavy damage that was reduced by treatment with perillic acid. PMID- 21303328 TI - Molecular characterization of isocyanate-induced male germ-line genomic instability. AB - Male reproductive health is exquisitely sensitive to environmental insults as evidenced by the rising incidence of testicular cancers and low and probably declining semen quality. Isocyanates, such as methyl isocyanate (MIC), with their wide industrial applications, are known to exert severe ill health effects. The present study was performed to find out the pathophysiological implications of isocyanate exposure on the male germ line. The investigations were performed in the cultured mouse spermatogonial GC-1 spg cell line using N-succinimidyl N methylcarbamate, a surrogate chemical to MIC. DNA damage, oxidative stress and apoptosis response parameters increased with time of exposure and dose after treatment. Treated cells also displayed elevated levels of inflammatory cytokines as well as morphological transformation and stress-responsive senescence. Chromosomal aberrations, telomere anomaly, aneuploidy and variable amplification of microsatellite repeats additionally indicated induced genomic instability. This was accompanied by evidence of a deregulation of cell cycle progression, such as substantial fold-changes in the expression of proliferating cell nuclear antigen, Cyclin D1, Bcl-2 and Bax genes; and aberrant expression of p53, cyclin A, cyclin E, CDK-2 and aurora kinase-B proteins. Our results demonstrate that MIC in the form of N-succinimidyl N-methylcarbamate promotes germ-line genomic instability in vitro. We envisage that understanding the interplay between environmental toxin-induced signaling and predisposition to testicular cancers would spur identification of meaningful targets for useful therapeutic translational modalities. PMID- 21303329 TI - A pilot study of male breast cancer in the Veterans Affairs healthcare system. AB - BACKGROUND: We report our findings on a hospital-based retrospective pilot cohort with case-controls study, which we carried out to examine genetic, environmental, and occupational risk factors in men with breast cancer. METHODS: 86 men with breast cancer were diagnosed in eight VA medical centers that agreed to collaborate on this project. A case-control analysis was conducted on a subset of the male breast cancer cases (n = 44) and age- and ethnicity-matched controls (n = 77). We compared host characteristics, comorbidities, and medications intake between cases and controls by using Chi-square analysis and Fisher's exact test. RESULTS: The descriptive analysis showed that the majority of veterans with male breast cancer were non-Hispanic white (60%), older than 65 years at diagnosis (56%), and more likely estrogen receptor positive (45%). World War II veterans represented the largest group (22%), followed by the Vietnam era veterans (10%). Thirty-three percent reported a positive family history of cancer, while 18% had another primary cancer diagnosis. Prior alcohol (43%) and tobacco use (56%) was substantial among these patients. Twenty percent of patients were overweight or obese and 55% had comorbid diseases with heart disease being the most prevalent, followed by diabetes mellitus. The case-control analysis yielded a significantly greater proportion of cases with gynecomastia (p < 0.0001), a positive family history of cancer (p = 0.0028), history of antibiotic use (p = 0.0112), and history of tobacco use (p = 0.0143) compared to controls. CONCLUSION: The findings of this hospital-based pilot study indicate case-control differences in gynecomastia and family history of cancer. The pilot study lacked sufficient power to determine a true association between the variables of interest and warrants a large-scale collaborative study between the VA medical centers. PMID- 21303330 TI - Maternal intake of N-nitroso compounds from cured meat and the risk of pediatric brain tumors: a review. AB - Experimental investigations conducted over the last several decades suggest that transplacental exposure of offspring to certain N-nitroso compounds (NOCs) results in the development of brain tumors in laboratory animals. Dietary cured meats are a recognized source of such exposures in humans, which raises the possibility that maternal consumption of cured meat products during pregnancy could increase the risk of childhood brain tumors. This hypothesis was first suggested by an observational study conducted by Preston-Martin et al. in 1982 supporting such a role in human disease. Since that time, additional epidemiological analyses have been performed addressing this hypothesis although results are inconsistent across studies. Due to the possible impact of bias and confounding in the available observational studies, the relatively weak effect seen in some observational analyses is of questionable validity. Nonetheless, since the association of transplacental NOC exposure and brain tumor risk is biologically plausible, the suspected association cannot be unequivocally dismissed. This paper reviews the current epidemiological evidence dealing with the maternal cured meat intake/childhood brain tumor association and suggests further avenues for research. PMID- 21303331 TI - Chemopreventive action of diclofenac in dimethybenzanthracene induced lung cancer in female Wistar rat. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to be effective antineoplastic agents that block prostaglandin formation by inhibiting the enzyme cyclooxygenase (COX), which exists in two isoforms, COX-1 and COX-2. COX-2 is over expressed in lung cancer. The present study evaluates the chemopreventive efficiency of diclofenac, which is a preferentially selective COX-2 inhibitor in lung cancer. Female Wistar rats were divided into 4 groups. Group 1 served as control and received saline intratracheally, once. In group 2 lung cancer was induced by a single intratracheal instillation of dimethybenz(a)anthracene (DMBA) (20 mg/kg body weight). Group 3 was given the intervention of diclofenac (8 mg/kg body weight) daily by oral gavage, in addition to DMBA. Group 4 received diclofenac alone. After 18 weeks of treatment, animals were sacrificed and various studies done. COX-2 expression as seen by western immunoblot and immunohistochemistry (IHC) was increased in the DMBA group, while diclofenac intervention was able to bring down the levels of the enzyme. Apoptosis studies by DNA fragmentation, TUNEL and fluorescent dyes reveal the lowered number of apoptotic cells in group 2. The levels were restored by diclofenac treatment in group 3. There was also a significant reduction in tumor incidence in DMBA+Diclofenac treated animals. All these results indicate that diclofenac acts as an effective chemopreventive agent that mediates its effects by the induction of apoptosis in cancer tissue and suppression of COX-2 enzyme. PMID- 21303332 TI - Antidiabetic agents in patients with chronic kidney disease and end-stage renal disease on dialysis: metabolism and clinical practice. AB - Numerous drugs with different mechanisms of action and different pharmacologic profiles are being used with the aim of improving glycemic control in patients with type 2 diabetes. Therapeutic options for patients with type 2 diabetes and chronic kidney disease (CKD) are limited because a reduced glomerular filtration rate results in the accumulation of certain drugs and/or their metabolites. Conventional oral hypoglycemic agents, such as sulfonylurea (SU), are not suitable due to the risk of prolonged hypoglycemia; furthermore, metformin is contraindicated for moderate to advanced CKD. Therefore, in order to achieve good glycemic control, insulin injection therapy remains the mainstay of treatment in diabetic patients with moderate to advanced CKD, particularly in those receiving dialysis therapy. However, some agents have been used even in patients with CKD. Repaglinide and mitiglinide are rapid- and short-acting insulinotropic SU receptor ligands. They are rarely accompanied by hypoglycemia, and are attractive therapeutic options even in the dialysis population. In addition, alpha glucosidase inhibitors are rarely accompanied by hypoglycemia and are administered without dose adjustments in dialysis patients. However, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines recommended that alpha-glucosidase inhibitors should be avoided in patients with advanced stage CKD and on dialysis. Furthermore, mitiglinide is not currently used in the US. Thus, recommended oral antidiabetic agents differ between countries. Moreover, dipeptidyl peptidase-4 inhibitors and incretin mimetics are new antihyperglycemic agents, which may be used more frequently in the future in patients with type 2 diabetes and CKD. Here, we describe the pharmacokinetics, metabolism, clinical efficacy, and safety of oral Antidiabetic agents for patients with CKD, including those receiving dialysis. PMID- 21303333 TI - Reprogramming of normal and cancer stem cells. PMID- 21303335 TI - Epidemiology and management of infectious complications of contemporary management of chronic leukemias. AB - This is a review of the epidemiology and management of infectious complications of contemporary management of chronic leukemias. Patients with chronic leukemias typically are affected by nuisance infections due to the underlying hematologic condition, particularly hypogammaglobulinemia in CLL patients. With active treatment, particularly those agents that cause defects in cell-mediated immunity, the incidence of opportunistic infections increases although endogenous bacterial, mycobacterial, and fungal infections also occur. Exogenous treatment with immunoglobulin and antimicrobial prophylaxis, particularly anti-Pneumocystis prophylaxis, may be indicated in select patients. Routine vaccinations should be maintained in these patients and vaccination early in the course of treatment may result in improve protection. PMID- 21303336 TI - Epidemiology and prevention of bacterial infections in patients with hematologic malignancies. AB - Bacterial infections are a serious complication of hematologic malignancies and the therapies used to treat them. Neutropenia can result from the malignancy itself or develop as a complication of chemotherapy and remains a major risk factor for the development of infections in these patients. In addition, the mechanical and chemotherapeutic interventions applied to patients with hematologic malignancies impose additional challenges to host defenses against bacterial invasion. The bacteria responsible for most infections in this patient population have continued to evolve as different therapeutic, preventive, and preemptive strategies are introduced into the armamentarium for leukemias, lymphomas, and myelomas. Both Gram-negative and Gram-positive pathogens have become increasingly resistant to available antimicrobial agents, in part due to the increasing use of agents, especially the fluoroquinolones, to prevent bacterial infections. This review addresses recent clinical developments in the epidemiology and prevention of bacterial infections in these unique populations of patients. PMID- 21303337 TI - Challenges and advances in infection control of hematopoietic stem cell transplant recipients. AB - Hematopoietic Stem Cell Transplantation (HSCT) has revolutionized the outcome of many malignant and non-malignant disorders; however, infection still accounts for a substantial number of deaths after both allogeneic and autologous transplants. Hospital-acquired infections (HAI) such as bloodstream infections, pneumonias, and diarrhea are common in this population and account for significant morbidity and cost of care. Also, there is renewed focus on epidemiologically important organisms as the cause of HAI, most notably methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, multi-drug resistant gram-negative bacilli, and Clostridium difficile. We review the infectious risks of HSCT, including those due to HAI as well as measures to decrease these infectious complications. This includes discussion of measures to implement prior to transplant and measures to implement during the pre-engraftment phase, post engraftment phase, and late phase after transplantation. Additionally, general infection control measures related to healthcare worker behavior as well as environmental control are reviewed. Despite the marked advances in the field of HSCT, challenges remain for clinicians and researchers to conduct properly designed studies to better describe the epidemiology of, risks for, and measures for prevention of transplant related infections. PMID- 21303338 TI - Epidemiology and prevention of viral infections in patients with hematologic malignancies. AB - Viral infections are some of the most frequent complications in patients with hematologic malignancies are viral infections. Infections caused by cytomegalovirus, herpes simplex virus, varicella zoster virus, hepatitis B virus and influenza virus are associated with high morbidity and mortality in this vulnerable population. Fortunately, a growing number of antiviral medications and vaccines are allowing for more effective prophylaxis against these pathogens. This article reviews the epidemiology and prophylactic strategies available for these opportunistic viral pathogens. PMID- 21303339 TI - Epidemiology, prevention, and management of influenza in patients with hematologic malignancy. AB - Influenza results in annual epidemics of respiratory viral illness during the winter; when a novel virus enters the human population, a pandemic may result with a larger proportion of the population sickened. Unlike the mild and typically self-limited disease seen in immunocompetent patients, immunocompromised patients frequently have a more severe course. These individuals shed virus for a prolonged period of time, have a high rate of viral pneumonia, more frequently develop bacterial and fungal super-infections, and may develop late-onset airflow obstruction. Further, antiviral resistance develops more frequently in immunosuppressed patients. Although the cornerstone of prevention of influenza is vaccination, vaccine efficacy in patients with hematologic malignancies, particularly stem cell transplant recipients, is poor. Alternative preventative measures, such as seasonal antiviral prophylaxis can be considered. Lastly, there have been no prospective studies of antivirals in the management of influenza infections in these patients. As such, the optimal regimen and duration remains to be defined. Available evidence suggests that prolonged course are frequently needed. Patients who fail to response or have relapsed infections should be tested for emergence of antiviral resistance and alternative diagnoses should be investigated. PMID- 21303340 TI - Infection and anemia. AB - Anemia most frequently accompanies infection in varying degrees and in different forms. Anemia of inflammation is the most common and is due to over-expression of hepcidin. This is followed by hemolytic anemia, red cell aplasia and blood loss. The degree of anemia may not necessarily be proportional to the severity of the infection, nor is it specific for the type of infection. A clear understanding of these diverse causes and a recognition that they often occur in combination can be of enormous assistance in forming a proper diagnosis and an appropriate management plan. PMID- 21303341 TI - Approaches to minimize infection risk in blood banking and transfusion practice. AB - The use of blood donor history and state-of-the-art FDA-licensed serological and nucleic acid testing (NAT) assays have greatly reduced the "infectious window" for several transfusion-transmitted pathogens. Currently transmission of human immunodeficiency virus (HIV), Human T-cell Lymphotropic Virus (HTLV), hepatitis viruses and West Nile Virus are rare events. The seroprevalence of cytomegalovirus in the donor population is high and cytomegalovirus infection can cause significant complications for immunocompromised recipients of blood transfusion. Careful use of CMV seronegative blood resources and leukoreduction of blood products are able to prevent most CMV infections in these patients. Currently, bacterial contamination of platelet concentrates is the greatest remaining infectious disease risk in blood transfusion. Specialized donor collection procedures reduce the risk of bacterial contamination of blood products; blood culture and surrogate testing procedures are used to detect potential bacterially contaminated platelet products prior to transfusion. A rapid quantitative immunoassay is now available to test for the presence of lipotechoic acid and lipopolysaccharide bacterial products prior to platelet transfusion. Attention has now turned to emerging infectious diseases including variant Creutzfeldt-Jakob disease, dengue, babesiosis, Chagas' disease and malaria. Challenges are presented to identify and prevent transmission of these agents. Several methods are being used or in development to reduce infectivity of blood products, including solvent-detergent processing of plasma and nucleic acid cross-linking via photochemical reactions with methylene blue, riboflavin, psoralen and alkylating agents. Several opportunities exist to further improve blood safety through advances in infectious disease screening and pathogen inactivation methods. PMID- 21303342 TI - HIV-1 infected patients have antibodies recognizing folded Tat. AB - Tat is a regulatory viral protein known as transactivator of HIV-1 genes but Tat is also secreted in the blood from HIV-1 infected cells. Extra cellular Tat can cross cellular membranes to trigger apoptosis and might explain the incapacity of the cellular immunity to eliminate HIV-1 infected cells. There is a controversy regarding Tat structure with studies suggesting that Tat would be a naturally unfolded protein. Here, we show that synthetic Tat variants need to be folded to have a transactivation activity in a cellular assay but this folding is unstable regarding the buffers and/or pH used as solvent. We show also that the recognition of a Tat variant versus peptides, covering its sequence, was different. Using an indirect ELISA method with 40 sera from volunteer HIV-1 infected patients, we show that Tat was recognized by 19 human sera either exclusively (n=8) or with Tat peptides (n=11). Dot Blot showed that unfolded Tat was no longer detectable by sera of the first group (n=8) compared to folded Tat. As a conclusion, this study suggests that Tat could be a naturally folded protein in the blood of HIV infected patients. PMID- 21303343 TI - Development of anti-viral agents using molecular modeling and virtual screening techniques. AB - Computational chemistry has always played a key role in anti-viral drug development. The challenges and the quickly rising public interest when a virus is becoming a threat has significantly influenced computational drug discovery. The most obvious example is anti-AIDS research, where HIV protease and reverse transcriptase have triggered enormous efforts in developing and improving computational methods. Methods applied to anti-viral research include (i) ligand based approaches that rely on known active compounds to extrapolate biological activity, such as machine learning techniques or classical QSAR, (ii) structure based methods that rely on an experimentally determined 3D structure of the targets, such as molecular docking or molecular dynamics, and (iii) universal approaches that can be applied in a structure- or ligand-based way, such as 3D QSAR or 3D pharmacophore elucidation. In this review we summarize these molecular modeling approaches as they were applied to fight anti-viral diseases and highlight their importance for anti-viral research. We discuss the role of computational chemistry in the development of small molecules as agents against HIV integrase, HIV-1 protease, HIV-1 reverse transcriptase, the influenza virus M2 channel protein, influenza virus neuraminidase, the SARS coronavirus main proteinase and spike protein, thymidine kinases of herpes viruses, hepatitis c virus proteins and other flaviviruses as well as human rhinovirus coat protein and proteases, and other picornaviridae. We highlight how computational approaches have helped in discovering anti-viral activities of natural products and give an overview on polypharmacology approaches that help to optimize drugs against several viruses or help to optimize the metabolic profile of and anti viral drug. PMID- 21303344 TI - The diagnostic and therapeutic importance of human growth hormone isoforms. AB - The study of human growth hormone isoforms has conduced to the elaboration of patents related to very important items: codifying and regulatory sequences, production of the protein at large-scale, modifications to prolong half-life as monomer, dimer and fusion protein for treatments directed to growth-associated diseases. The designs to identification and quantification of hGH are besides the formers establishing very important basis of patented sources that can be used for a specific and opportune diagnosis and treatment of biological abnormalities or undesirable effects when these growth hormones are involved. PMID- 21303345 TI - Significance of P2X7 receptor variants to human health and disease. AB - The human P2X7 receptor is a trimeric ligand-gated cation channel coded by the P2XR7 gene located at chromosome position 12q24. P2X7 is expressed in a wide variety of normal and disease-associated cell types. Activation of this receptor by extracellular adenosine 5'-triphosphate results in numerous downstream events including the release of pro-inflammatory mediators, cell proliferation or death, and killing of intracellular pathogens. As a result, P2X7 plays important roles in inflammation, immunity, bone homeostasis, neurological function and neoplasia. The P2XR7 gene encodes a P2X7 subunit 595 amino acids in length, however splice isoforms that can alter receptor expression and function, and modify the signaling properties downstream of receptor activation also exist. Moreover, the relative amount of P2X7 function varies between human individuals due to numerous single nucleotide polymorphisms resulting in either loss- or gain-of-function. Combinations of these polymorphisms give rise to various haplotypes that can also modify P2X7 function. Collectively, P2X7, and its splice and polymorphic variants are attracting considerable interest in relation to human health and disease, including the development and publication of a number of patents. PMID- 21303346 TI - Human DNA extraction methods: patents and applications. AB - Since the pioneer experiments conducted by Friedrich Miescher in 1861, extraordinary advances have been achieved in the field of DNA handling. Today nucleic acids can be extracted from any type of biological material such as tissues, cells and viruses. Moreover, increasing knowledge of human genome is paving the way to an effective employment of pharmacogenomics and genetic-based predictive tests in medicine. In this context, the recovery of DNA from different sources of biological samples (e.g. archived formalin-fixed autopsy tissues, dried blood spots, frozen serum or plasma, long-term stored whole blood) is also an emerging field in genetic epidemiology studies. Thus, given the crucial role played by DNA in bio-medical research and in its related applications, here we review the main relevant issued patents and recently published advances in the field of DNA extraction and purification from human specimens. PMID- 21303347 TI - Neutral sphingomyelinase 2 (nSMase2) is the primary neutral sphingomyelinase isoform activated by tumour necrosis factor-alpha in MCF-7 cells. AB - Activation of N-SMase (neutral sphingomyelinase) is an established part of the response of cytokines such as TNF (tumour necrosis factor)-alpha. However, it remains unclear which of the currently cloned N-SMase isoforms (nSMase1, nSMase2 and nSMase3) are responsible for this activity. In MCF-7 cells, we found that TNF alpha induces late, but not early, increases in N-SMase activity, and that nSMase2 is the primary isoform activated, most likely through post transcriptional mechanisms. Surprisingly, overexpression of tagged or untagged nSMase3 in multiple cell lines had no significant effect on in vitro N-SMase activity. Moreover, only overexpression of nSMase2, but not nSMase1 or nSMase3, had significant effects on cellular sphingolipid levels, increasing ceramide and decreasing sphingomyelin. Additionally, only siRNA (small interfering RNA) knockdown of nSMase1 significantly decreased basal in vitro N-SMase activity of MCF-7 cells, whereas nSMase2 but not nSMase3 siRNA inhibited TNF-alpha-induced activity. Taken together, these results identify nSMase2 as the major TNF-alpha responsive N-SMase in MCF-7 cells. Moreover, the results suggest that nSMase3 may not possess in vitro N-SMase activity and does not affect cellular sphingolipid levels in the cell lines evaluated. On the other hand, nSMase1 contributes to in vitro N-SMase activity, but does not affect cellular sphingolipids much. PMID- 21303348 TI - Intraventricular thrombolysis with rt-PA in patients with intraventricular hemorrhage. AB - OBJECTIVES: To evaluate safety, clinical feasibility, and outcome of intraventricular (IVen) administration of recombinant tissue plasminogen activator (rt-PA) in patients with intraventricular hemorrhage (IVH). MATERIALS AND METHODS: Forty-eight patients with IVH who received IVen rt-PA were compared with 49 age-, sex-, Glasgow Coma Scale score-, and Intracerebral Hemorrhage score matched control patients. Patients with IVH of aneurysmal or arteriovenous malformation origin were excluded. External ventricular drainage was inserted as soon as baseline CT was performed and rt-PA was administered within 12 +/- 1 h after the ictal onset. RESULTS: The outcome after 3 months was evaluated using the modified Rankin Scale (mRS). In addition, Glasgow Outcome Scale (GOS) and mortality were assessed. A good outcome, defined as mRS 0-3, was detected in 27% of patients from the control group vs 58% of patients in the IVen group; P = 0.003. GOS as other outcome scale yielded a significant difference between groups: 20% in the control group, vs 54% in the IVen group; P = 0.001. A statistically significant decrease in mortality was observed in the IVen group: 30% in the control vs 10% in IVen group; P = 0.003. No one patient died because of a complication which could be directly attributed to the IVen thrombolytic therapy. CONCLUSIONS: IVen administration of rt-PA seems to be safe in cases of IVH. This pilot study shows that it may be associated with better outcomes. Further studies and clinical randomized trials are needed to establish indications and IVen administration protocols. PMID- 21303349 TI - Lipid peroxidation in Alzheimer's disease: emphasis on metal-mediated neurotoxicity. AB - Despite the crucial role of redox active metals like copper and iron in central biological reactions, their elevated levels are involved in the pathogenesis of Alzheimer's Disease (AD). Similarly reactive oxygen/nitrogen species (ROS/RNS) produced during normal metabolic activities, specifically oxidative phosphorylation of the cell, are scavenged by antioxidant enzymes like superoxide dismutase (SOD), catalase but impaired metabolic pathways tend to generate elevated levels of these ROS/RNS. Iron, copper, and zinc are some of the metals, which intensify this process and contribute for the pathogenesis of AD. This review summarizes the mechanism of ROS/RNS production and their role in lipid peroxidation. The factors, which make brain vulnerable for lipid peroxidation, have been discussed. It also focuses on possible treatment options and future directions. PMID- 21303350 TI - European neuroborreliosis: quality of life 30 months after treatment. AB - OBJECTIVES: The prognosis after Lyme neuroborreliosis (LNB) is debated. The aim of this study was to assess health-related Quality of Life (QoL) and neurological symptoms 30 months after treatment in European patients with LNB. MATERIALS AND METHODS: In a prospective case-control designed study, we investigated 50 well characterized patients with LNB who had participated in a treatment trial for LNB 30 months earlier and 50 matched control persons with the health QoL questionnaire Short-Form 36 (SF-36), the Fatigue Severity Scale (FSS), the Montgomery and Asberg Depression Rating Scale (MADRS), the Starkstein Apathy Scale (SAS), and the Mini Mental State (MMS). Clinical and demographic data were collected by semi-structured interviews and clinical neurological examination. RESULTS: Lyme neuroborreliosis-treated patients scored lower than control persons in the SF-36 domains physical component summary (PCS) (44 vs 51 P < 0.001) and mental component summary (MCS) (49 vs 54 P = 0.010). They also scored lower than control persons in all the SF-36 subscales, except for bodily pain, and on FSS (3.5 vs 2.1 P < 0.001), but not on MMS (28 vs 29 P = 0.106). There was a difference in MADRS (3.1 vs 0. 8 P = 0.003) and SAS (13 vs 11 P = 0.016), but the scores were low in both groups. Fatigue was the most frequently reported symptom among LNB-treated patients (50%). Patients who reported complete recovery (56%) after LNB had similar QoL scores as the controls. CONCLUSION: European persons treated for LNB have poorer health-related QoL and have more fatigue than persons without LNB. PMID- 21303351 TI - Cognitive impairment using education-based cutoff points for CMMSE scores in elderly Chinese people of agricultural and rural Shanghai China. AB - OBJECTIVES: To evaluate cognitive impairment (CI) in rural China using the Chinese version of the Mini-Mental Status Examination (CMMSE) and compare the prevalence of CI using two different cutoff points. MATERIALS & METHODS: A population-based survey was conducted of 2809 people aged 60 years and above in a community of two towns (Huaxin and Xujing) in the Qingpu district, located in the western suburb of Shanghai. Face-to-face interviews were carried out to collect relevant information with questionnaires. The Chinese version of the Mini-Mental State Examination with either a 23/24 cutoff point or a cutoff point varying according to education level (AEL) was used to screen subjects for CI. RESULTS: Among these subjects, the mean age was 70.6 years (SD = 6.6) and ranged from 60 to 92 years and included 1010 (36.0%) men and 1799 (64.0%) women. The mean age was 70.7 years (SD = 6.4) for men and 70.5 years (SD = 6.7) for women. Of the 2809 subjects, 2010 (71.5%) had no formal education, 607 (21.6%) completed 1-6 years of education, and 173 (6.2%) completed more than 6 years of school education. The prevalence of CI was 35.6% (95% CI: 33.8-37.4) for both genders when the cutoff point of 23/24 was used. However, when the cutoff point was altered with respect to different education levels, the prevalence of CI was 7.0%. For each item of the CMMSE, increased years of education correlated with a higher item score, with the exception of the 'Naming' item score. CONCLUSIONS: This study demonstrates that screening of CI using the AEL cutoff scores is feasible in a low-education population. Determining whether the 23/24 cutoff point is suitable for the Chinese people requires future prospective studies in a large Chinese population. PMID- 21303352 TI - The Creutzfeldt-Jakob disease (CJD) neurological status scale: a new tool for evaluation of disease severity and progression. AB - OBJECTIVES: To develop a scale sensitive for the neurological manifestations of Creutzfeldt-Jakob disease (CJD). METHODS: A 26-item CJD neurological status scale (CJD-NS) was created based on characteristic disease manifestations. Each sign was assigned to one of eight neurological systems to calculate a total scale score (TSS) and a system involvement score (SIS). The scale was administered to 37 CJD patients, 101 healthy first-degree relatives of the patients and 14 elderly patients with Parkinson's disease (PD). RESULTS: The mean TSS (+/-SD) was significantly higher in patients with CJD (13.19 +/- 5.63) compared with normal controls (0.41 +/- 0.78) and PD patients (9.71 +/- 3.05). The mean SIS was also significantly different between the CJD (5.19 +/- 1.22) and PD (2.78 +/- 1.18 P <= 0.01) groups reflecting the disseminated nature of neurological involvement in CJD. Using a cutoff of TSS > 4 yielded a sensitivity of 97% for CJD, and specificity of 100% against healthy controls. All individual items showed excellent specificity against healthy subjects, but sensitivity was highly variable. Repeat assessments of CJD patients over 3-9 months revealed a time dependent increase in both the TSS and the SIS reflecting the scale's ability to track disease progression. CONCLUSIONS: The CJD-NS scale is sensitive to neurological signs and their progression in CJD patients. PMID- 21303354 TI - B-cell receptor, clinical course and prognosis in chronic lymphocytic leukaemia: the growing saga of the IGHV3 subgroup gene usage. AB - The immunoglobulin heavy chain variable gene (IGHV) mutational status has been recognized as an important predictor of prognosis in chronic lymphocytic leukaemia (CLL) since 1999. More recently, other features of the B-cell receptor, such as stereotypy, have been identified as capable of refining the prognostic potential of IGHV status in the clinical assessment of CLL patients. In this context, different genes belonging to the IGHV3 subgroup, the most frequently used subgroup in CLL, have been shown to denote disease subsets that either display a bad prognosis (i.e. IGHV3-21, IGHV3-23) or are associated with particularly good clinical outcomes, including a highly stable/indolent clinical course, even prone to spontaneous regression (i.e. IGHV3-72, IGHV3-30). The present review focuses on the molecular and biological features of CLL-expressing specific genes belonging to the IGHV3 subgroup that are known to mark disease subsets with completely different clinical courses, and may be possibly related to CLL pathogenesis via antigen and/or superantigen involvement. PMID- 21303353 TI - Hypertension and incident dementia in community-dwelling elderly Yoruba Nigerians. AB - OBJECTIVES: To investigate the relationship between hypertension and dementia incidence in community-dwelling elderly Yoruba (aged 70 years and above) because of sparse information on dementia and its risk factors in developing countries. MATERIALS AND METHODS: Community-based, prospective study of consenting elderly Yoruba using two-stage design. Blood pressure was measured during the baseline evaluation at 2001 and hypertension was defined as BP >= 140/90 mmHg. Diagnosis of dementia and normal cognition was by consensus using standard criteria. Non demented subjects from the 2001 evaluation wave were re-evaluated during the 2004 and 2007 waves for dementia. Logistic regression was used to examine the association of baseline hypertension and incident dementia, after adjusting for age, gender, education, and histories of stroke and smoking. P-values <0.05 were considered significant. RESULTS: During the 6-year follow-up, 120 individuals developed dementia, while 1633 remained non-demented. The frequency of hypertension in the demented group was significantly higher than in the non demented (70.0% vs 60.2%, P = 0.034). Baseline hypertension was a significant risk factor for dementia (OR = 1.52; 95% CI 1.01-2.30). Higher systolic, diastolic or pulse pressure was associated with increased risk (P < 0.05). Participants with diastolic BP >= 90 mmHg were at a significantly greater risk than those with readings below 70 mmHg (OR = 1.65; 95% CI 1.01-2.69). CONCLUSIONS: Hypertension was associated with increased risk of dementia in elderly Yoruba and its appropriate treatment may lower the risk. PMID- 21303355 TI - Microparticles, malignancy and thrombosis. AB - Microparticles (MPs) are considered to be important biological effectors of several different physiological and pathological processes. There is increasing evidence of their role in haemostasis and thrombosis, and also of their importance in cancer cell survival, invasiveness and metastasis. The level of circulating MPs has been assessed in many different disease states, and there are reports that patients with malignancy and patients with thrombosis have increased levels of circulating MPs and MP-dependent thrombogenic potential. Research into the function and effect of MPs is currently hampered by a lack of standardization in the methods used to identify and quantify them. As these methods improve it is likely that MP assays will be of use both diagnostically and therapeutically in the future. PMID- 21303356 TI - Advances in understanding the pathogenesis of familial thrombocythaemia. AB - Familial thrombocytosis can be divided into two broad categories. The first includes inherited syndromes that affect only the megakaryocytic lineage with Mendelian inheritance, high penetrance and polyclonal haematopoiesis. The second category includes inherited predisposition to true Philadelphia-negative myeloproliferative neoplasms (MPN) and is characterized by low penetrance, clonal haematopoiesis and presence of somatic mutations such as JAK2 V617F. It must be underlined that these two categories represent two well separate entities, with different patterns of proliferation and different transmission modalities. This review will focus on the molecular pathogenesis of hereditary thrombocytosis, underlining those clinical pictures that are specifically associated with mutations in the genes of thrombopoietin or in its receptor. Moreover, we propose an approach for the diagnosis and therapy of these syndromes. PMID- 21303357 TI - Familial haemophagocytic lymphohistiocytosis: advances in the genetic basis, diagnosis and management. AB - Familial haemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive disorder of immune dysregulation associated with uncontrolled T cell and macrophage activation and hypercytokinaemia. The incidence of FHL is 0.12/100.000 children born per year, with a male to female ratio of 1:1. The disease is classified into six different types based on genetic linkage analysis and chromosomal localization; five specific genetic defects have been identified, which account for approximately 90% of all patients. Type 1 is due to an as yet unidentified gene defect located on chromosome nine. Type 2 is caused by mutations in the perforin (PRF1) gene, type 3 by mutations in the Munc-13-4 (UNC13D) gene, type 4 by mutations in the syntaxin 11 (STX11) gene and the recently described type 5 due to mutations in the gene encoding syntaxin binding protein 2 (STXBP-2). The incidence of the five types varies in different ethnic groups. The most common presenting features are pyrexia of unknown origin, pronounced hepatosplenomegaly and cytopenias. Neurological features tend to present later and are associated with poor prognosis. Absent or decreased lymphocyte cytotoxicity is the cellular hallmark of FHL. Biochemical features such as hyperferritinaemia, hypertriglyceridaemia and hypofibrinogenaemia are usually present, along with high levels of soluble interleukin 2 receptor in the blood and cerebrospinal fluid. Bone marrow aspirate may demonstrate the characteristic haemophagocytes, but initially is non-diagnostic in two-thirds of patients. Established international clinical, haematological and biochemical criteria now facilitate accurate clinical diagnosis. The disease is fatal unless a haematopoietic stem cell transplant (HSCT) is performed. The introduction of HSCT has dramatically improved the prognosis of the disease. However, the mortality of the disease is still significantly high and a number of challenges remain to be addressed. Active disease at the time of the transplant is the major significant poor prognostic factor. Delayed diagnosis, after irreversible organ damage has occurred, especially neurological damage, disease reoccurrence and pre transplant mortality, remain a concern. PMID- 21303358 TI - Allogeneic haematopoietic stem cell transplantation in patients with human immunodeficiency virus: the experiences of more than 25 years. AB - For treatment of several malignancies, transplantation of allogeneic haematopoietic stem cells (HSCT) derived from bone marrow or peripheral blood has been used as a therapeutic procedure for decades. In the past, HSCT has been suggested as a treatment option for infection with the human immunodeficiency virus type 1 (HIV-1), but these attempts were mostly unsuccessful. Today, after the introduction of an active anti-retroviral therapy, the lifetime expectancy of HIV-infected patients has improved substantially, but nevertheless the incidence rate of malignancies in these patients has increased considerably. Therefore, it can be assumed that there will be a rising necessity for HIV-1-infected patients with malignancies for allogeneic HSCT. At the same time, there is increasing interest in treatment methods which might target the HIV-1 reservoir more effectively, and the question has been raised as to whether allogeneic HSCT could be linked to such strategies. In this paper the data of more than 25 years experience with allogeneic HSCT in patients with HIV-1 are reviewed and analysed. PMID- 21303359 TI - Expression and function of the autoimmune regulator (Aire) gene in non-thymic tissue. AB - Educational immune tolerance to self-antigens is induced primarily in the thymus where tissue-restricted antigens (TRAs) are presented to T lymphocytes by cells of the thymic stroma - a process known as central tolerance. The expression of these TRAs is controlled in part by a transcription factor encoded by the autoimmune regulatory (Aire) gene. Patients with a mutation of this gene develop a condition known as autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), characterized by autoimmune destruction of endocrine organs, fungal infection and dental abnormalities. There is now evidence for TRA expression and for mechanisms of functional tolerance outside the thymus. This has led to a number of studies examining Aire expression and function at these extra-thymic sites. These investigations have been conducted across different animal models using different techniques and have often shown discrepant results. Here we review the studies of extra thymic Aire and discuss the evidence for its expression and function in both human and murine systems. PMID- 21303360 TI - Distinct cytokine and regulatory T cell profile at pleural sites of dual HIV/tuberculosis infection compared to that in the systemic circulation. AB - Pleural tuberculosis (TB) remains a common presentation of Mycobacterium tuberculosis (MTB) infection in HIV/TB dually infected subjects, and both cellular and acellular components of the pleural milieu promote HIV-1 replication; however, they remain uncharacterized. Using cytokine array of pleural fluid and real-time reverse transcription-polymerase chain reaction (RT PCR) and immunophenotype analysis, pleural fluid mononuclear cells (PFMC) were compared to systemic counterparts [i.e. plasma and peripheral blood mononuclear cells (PBMC)]. Significant increases in pleural fluid cytokines compared to plasma were limited to interleukin (IL)-6, IL-8, interferon (IFN)-gamma and transforming growth factor (TGF)-beta, and did not include other T helper type 1 (Th1) (IL-2, IL-15), Th2 or Th17 cytokines. Patterns and levels of cytokines were indistinguishable between pleural fluid from HIV/TB and TB patients. Forkhead box P3 (FoxP3) mRNA in PFMC was increased significantly and correlated highly with levels of IL-6 and IL-8, less with TGF-beta, and not with IFN-gamma. Among CD4 T cells, FoxP3-reactive CD25(hi) were increased in HIV/TB dually infected subjects compared to their PBMC, and up to 15% of FoxP3(+) CD25(hi) CD4 T cells were positive for IL-8 by intracellular staining. These data implicate a dominant effect of MTB infection (compared to HIV-1) at pleural sites of dual HIV/TB infection on the local infectious milieu, that include IL-6, IL-8, IFN-gamma and TGF-beta and regulatory T cells (T(reg) ). A correlation in expansion of T(reg) with proinflammatory cytokines (IL-6 and IL-8) in pleural fluid was shown. T(reg) themselves may promote the inflammatory cytokine milieu through IL-8. PMID- 21303361 TI - Raised tryptase without anaphylaxis or mastocytosis: heterophilic antibody interference in the serum tryptase assay. AB - Mast cell tryptase (MCT) is a key diagnostic test for mastocytosis and anaphylaxis. High serum tryptase levels are also one of the risk factors for adverse reaction in venom immunotherapy, yet occasional patients are seen with raised levels in the absence of either diagnosis. False positive results can be due to assay interference by heterophilic antibodies such as rheumatoid factor (RF) and human anti-mouse antibodies (HAMA). We therefore investigated heterophilic antibody interference by rheumatoid factor activity and HAMA as a cause of raised MCT results in the Phadia tryptase assay. Serum samples from 83 patients were assayed for MCT and rheumatoid factor before and after the use of heterophilic antibody blocking tubes (HBT). Samples with more than 17% reduction in MCT with detectable RF were then assayed for HAMA. Fourteen (17%) of the 83 samples with positive RF showed a >17% decrease in mast cell tryptase after HBT blocking. Post-HBT, eight of 14 (57%) reverted from elevated to normal range values with falls of up to 98%. RF levels were also decreased significantly (up to 75%). Only one of the 83 tested was apparently affected by HAMA in the absence of detectable IgM RF. In conclusion, any suspicious MCT result should be checked for heterophilic antibodies to evaluate possible interference. False positive MCT levels can be caused by rheumatoid factor. We suggest a strategy for identifying assay interference, and show that it is essential to incorporate this caveat into guidance for interpretation of MCT results. PMID- 21303362 TI - Elevated blood levels of inflammatory monocytes (CD14+ CD16+ ) in patients with complex regional pain syndrome. AB - Complex regional pain syndrome (CRPS) is a chronic pain disorder. Although its pathophysiology is not completely understood, neurogenic inflammation is thought to play a significant role. Microglia and astrocytes are activated following tissue injury or inflammation and have been reported to be both necessary and sufficient for enhanced nociception. Blood-borne monocytes/macrophages can infiltrate the central nervous system (CNS) and differentiate into microglia resulting in hypersensitivity and chronic pain. The primary aim of this study was to evaluate the proportion of the proinflammatory CD14(+) CD16(+) monocytes as well as plasma cytokine levels in blood from CRPS patients compared to age- and gender-matched healthy control individuals. Forty-six subjects (25 CRPS, 21 controls) were recruited for this study. The percentage of monocytes, T, B or natural killer (NK) cells did not differ between CRPS and controls. However, the percentage of the CD14(+) CD16(+) monocyte/macrophage subgroup was elevated significantly (P<0.01) in CRPS compared to controls. Individuals with high percentage of CD14(+) CD16(+) demonstrated significantly lower (P<0.05) plasma levels on the anti-inflammatory cytokine interleukin (IL)-10. Our data cannot determine whether CD14(+) CD16(+) monocytes became elevated prior to or after developing CRPS. In either case, the elevation of blood proinflammatoty monocytes prior to the initiating event may predispose individuals for developing the syndrome whereas the elevation of blood proinflammatory monocytes following the development of CRPS may be relevant for its maintenance. Further evaluation of the role the immune system plays in the pathogenesis of CRPS may aid in elucidating disease mechanisms as well as the development of novel therapies for its treatment. PMID- 21303363 TI - Smoking and periodontal disease: discrimination of antibody responses to pathogenic and commensal oral bacteria. AB - Smoking is an independent risk factor for the initiation, extent and severity of periodontal disease. This study examined the ability of the host immune system to discriminate commensal oral bacteria from pathogens at mucosal surfaces, i.e. oral cavity. Serum immunoglobulin (Ig)G antibody reactive with three pathogenic and five commensal oral bacteria in 301 current smokers (age range 21-66 years) were examined by enzyme-linked immunosorbent assay. Clinical features of periodontal health were used as measures of periodontitis. Antibody to the pathogens and salivary cotinine levels were related positively to disease severity; however, the antibody levels were best described by the clinical disease unrelated to the amount of smoking. The data showed a greater immune response to pathogens than commensals that was related specifically to disease extent, and most noted in black males. Significant correlations in individual patient responses to the pathogens and commensals were lost with an increasing extent of periodontitis and serum antibody to the pathogens. Antibody to Porphyromonas gingivalis was particularly distinct with respect to the discriminatory nature of the immune responses in recognizing the pathogens. Antibody responses to selected pathogenic and commensal oral microorganisms differed among racial groups and genders. The antibody response to the pathogens was related to disease severity. The level of antibody to the pathogens, and in particular P. gingivalis, was correlated with disease severity in black and male subsets of patients. The amount of smoking did not appear to impact directly serum antibody levels to these oral bacteria. PMID- 21303365 TI - Host characteristics and environmental factors differentially drive the burden and pathogenicity of an ectoparasite: a multilevel causal analysis. AB - 1. Understanding the ecological factors driving the burden and pathogenicity of parasites is challenging. Indeed, the dynamics of host-parasite interactions is driven by factors organized across nested hierarchical levels (e.g. hosts, localities), and indirect effects are expected owing to interactions between levels. 2. In this study, we combined Bayesian multilevel models, path analyses and a model selection procedure to account for these complexities and to decipher the relative effects of host- and environment-related factors on the burden and the pathogenicity of an ectoparasite (Tracheliastes polycolpus) on its fish host (Leuciscus leuciscus). We also tested the year-to-year consistency of the relationships linking these factors to the burden and the pathogenic effects of T. polycolpus. 3. We found significant relationships between the parasite burden and host-related factors: body length and age were positively related to parasite burden and heterozygous hosts displayed a higher parasite burden. In contrast, both host- and environment-related factors were linked to pathogenic effects. Pathogenicity was correlated negatively with host body length and positively with age; this illustrates that some factors (e.g. body length) showed inverse relationships with parasite burden and pathogenicity. Pathogenic effects were stronger in cooler upstream sites and where host density was lower. Path analyses revealed that these relationships between environment-related factors and pathogenic effects were direct and were not indirect relationships mediated by the host characteristics. Finally, we found that the strength and the shape of certain relationships were consistent across years, while they were clearly not for some others. 4. Our study illustrates that considering conjointly causal relationships among factors and the hierarchical structure of host-parasite interactions is appropriate for dissecting the complex links between hosts, parasites and their common environment. PMID- 21303364 TI - Programmed death ligand 2 regulates arginase induction and modifies Trypanosoma cruzi survival in macrophages during murine experimental infection. AB - The programmed death ligands 1 (PD-L1) and 2 (PD-L2) that bind to programmed death 1 (PD-1) have been involved in peripheral tolerance and in the immune escape mechanisms during chronic viral infections and cancer. However, there are no reports about the role of these molecules during Trypanosoma cruzi infection. We have studied the role of PD-L1 and PD-L2 in T. cruzi infection and their importance in arginase/inducible nitric oxide synthase (iNOS) balance in the immunomodulatory properties of macrophages (Mphi). In this work, we have demonstrated that expression of the PD-1/PD-L pathway is modified during T. cruzi infection on Mphis obtained from peritoneal cavity. The Mphis from T. cruzi infected mice suppressed T-cell proliferation and this was restored when anti-PD 1 and anti-PD-L1 antibodies were added. Nevertheless, anti-PD-L2 antibody treatment did not re-establish T-cell proliferation. PD-L2 blockade on peritoneal cells from infected mice showed an increase in arginase expression and activity and a decrease in iNOS expression and in nitric oxide (NO) production. Additionally, interleukin-10 production increased whereas interferon-gamma production was reduced. As a result, this microenvironment enhanced parasite proliferation. In contrast, PD-1 and PD-L1 blockage increased iNOS expression and NO production on peritoneal Mphis from T. cruzi-infected mice. Besides, PD-L2 knockout infected mice showed an increased in parasitaemia as well as in arginase activity, and a reduction in NO production. Taken together, our results demonstrate that PD-L2 is involved in the arginase/iNOS balance during T. cruzi infection having a protective role in the immune response against the parasite. PMID- 21303366 TI - Enhancing blood donation intentions using multimedia donor education materials. AB - BACKGROUND: Prior research has shown that education materials that directly address prospective donor concerns and provide specific coping suggestions are particularly effective at enhancing donation attitudes and intentions to give blood. This study compared the effect of donor coping materials, provided in written and audiovisual formats, as potential tools to enhance recruitment of prospective blood donors. The role of initial attitudes toward blood donation on responses to these materials was also considered. STUDY DESIGN AND METHODS: Young adults (62% female; mean [SD] age=19.1 [1.4]; mean [range] prior blood donations=1.32 [0-13]) were randomly assigned to 1) read a brochure addressing common blood donor concerns and suggesting specific coping strategies, 2) view a video addressing blood donor concerns and illustrating coping techniques, 3) read the brochure and view the video, or 4) read a control brochure on healthy eating and exercise. Measures of blood donation attitudes, anxiety, confidence, and intentions to give blood were completed before and after the intervention. RESULTS: Relative to the control brochure, all the intervention groups showed larger reductions in anxiety, more positive changes in attitude, and greater increases in donation confidence and intentions. The combination of the brochure and video outperformed either intervention alone in further improving donation attitudes among participants with high initial donation attitudes. CONCLUSION: Blood donation coping materials, presented in either written or audiovisual formats, significantly enhance willingness to donate blood among young adults regardless of their initial attitudes toward blood donation. PMID- 21303367 TI - Modeling transfusion reactions and predicting in vivo cell survival with kodecytes. AB - BACKGROUND: The availability of suitable animal models is a limitation in research on transfusion reactions. KODE technology allows for the artificial attachment of incompatible blood group antigens, plus visualization and recovery constructs onto red blood cells (RBCs), making them potentially suitable to study both transfusion reactions and determine in vivo cell survival. STUDY DESIGN AND METHODS: Function-spacer-lipid (FSL) constructs representing blood group A antigen (FSL-A) and biotin (FSL-biotin) together with FSL-GB3 as a benign antigen were used to create a range of murine kodecytes. Compatible and incompatible kodecytes were transfused into naive or anti-A hyperimmune mice. FSL-biotin constructs simultaneously included in the same RBC were visualized with avidin Alexa Fluor 488 and fluorescence microscopy to determine circulating cell survival or to demonstrate recovery of kodecytes. RESULTS: Using fluorescence microscopy of blood films, biotin, and GB3+biotin kodecyte transfusions, all showed similar survival and were present in the circulation at more than 72 hours in naive and anti-A-immunized mice. A+ biotin kodecytes were also present in the circulation at more than 72 hours in naive mice but were mostly cleared within 6 minutes in anti-A-immunized mice. Avidin agarose beads in gel cards were used to demonstrate recovery of A+ biotin kodecytes from blood samples. CONCLUSIONS: KODE technology not only enables the creation of artificial transfusion reactions in animal models, but also has the potential to be used clinically in man to determine 24-hour cell survival. The ability to recover the kodecytes for further analysis has valuable research and diagnostic potential. PMID- 21303368 TI - Distribution of parvovirus B19 DNA in blood compartments and persistence of virus in blood donors. AB - BACKGROUND: Because the receptor for parvovirus B19 (B19V) is on red blood cells (RBCs), we investigated B19V distribution in blood by in vitro spiking experiments and evaluated viral compartmentalization and persistence in natural infection. STUDY DESIGN AND METHODS: Two whole blood (WB) protocols (ultracentrifugation and a rapid RBC lysis and removal protocol) were evaluated using quantitative real-time polymerase chain reaction. WB was spiked with known concentrations of B19V and recovery in various blood fractions was determined. The rapid RBC lysis and removal protocol was then used to compare B19V concentrations in 104 paired WB and plasma samples collected longitudinally from 43 B19V-infected donors with frozen specimens in the REDS Allogeneic Donor and Recipient Repository (RADAR). RESULTS: In B19V spiking experiments, approximately one-third of viral DNA was recovered in plasma and two-thirds was loosely bound to RBCs. In the immunoglobulin (Ig)M-positive stage of infection in blood donors when plasma B19V DNA concentrations were greater than 100 IU/mL, median DNA concentrations were approximately 30-fold higher in WB than in plasma. In contrast, when IgM was absent and when the B19V DNA concentration was lower, the median WB-to-plasma ratio was approximately 1. Analysis of longitudinal samples demonstrated persistent detection of B19V in WB but declining ratios of WB to plasma B19V with declining plasma viral load levels and loss of IgM reactivity. CONCLUSIONS: The WB-to-plasma B19V DNA ratio varies by stage of infection, with 30-fold higher concentrations of B19V DNA in WB relative to plasma during the IgM positive stage of infection followed by comparable levels during persistent infection when only IgG is present. Further study is required to determine if this is related to the presence of circulating DNA-positive RBCs derived from B19V-infected erythroblasts, B19V-specific IgM-mediated binding of virus to cells, or other factors. PMID- 21303369 TI - Effect on the quality of blood components after simulated blood transfusions using volumetric infusion pumps. AB - BACKGROUND: It is unknown whether the use of volumetric infusion pumps for the transfusion of red blood cells (RBCs) or platelet (PLT) concentrates (PCs) affects the quality of the blood components. We therefore investigated the in vitro quality of these components after use of infusion pumps. STUDY DESIGN AND METHODS: Ten different volumetric infusion pumps were used to simulate transfusion with RBCs and PCs. To prevent donor-dependent differences multiple units were pooled and divided into equal portions. The storage time of RBCs was 30 to 35 days (n=10 experiments), and for PCs, either 2 (n=5) or 7 days (n=5). For RBCs an infusion rate of 100 or 300mL/hr was used, and for PCs, 600mL/hr. Transfusions without an infusion pump served as a reference. RESULTS: None of the infusion pumps induced an increase of free hemoglobin, annexin A5 binding, or formation of echinocytes in RBCs compared to reference units. In 2- and 7-day-old PCs no effect was shown on PLT concentration, annexin A5 binding, mean PLT volume, and morphology score compared to the reference. The CD62P expression of 2 day-old PCs was significantly lower after transfusion compared to the reference, that is, 11.7+/-2.1% versus 8.1+/-1.3% (p<0.01). CONCLUSION: There was no adverse effect on the in vitro quality of RBCs or PCs after simulated transfusion using volumetric infusion pumps. A decrease in PLT activation was observed, which can probably be explained by capturing of activated or damaged PLTs in the 200-um filter present in the infusion system. PMID- 21303370 TI - A comprehensive program to minimize platelet outdating. AB - BACKGROUND: Platelet (PLT) transfusions are essential for patients who are bleeding or have an increased risk of bleeding due to a decreased number or abnormal function of circulating PLTs. A shelf life of 5 days for PLT products presents an inventory management challenge. In 2006, greater than 10% of apheresis PLTs made in the United States outdated. It is imperative to have a sufficient number of products for patients requiring transfusion, but outdating PLTs is a financial burden and a waste of a resource. STUDY DESIGN AND METHODS: We present the approach used in our institution to anticipate inventory needs based on current patient census and usage. Strategies to predict usage and to identify changes in anticipated usage are examined. Annual outdating is reviewed for a 10-year period from 2000 through 2009. RESULTS: From January 1, 2000, through December 2009, there were 128,207 PLT transfusions given to 15,265 patients. The methods used to anticipate usage and adjust inventory resulted in an annual outdate rate of approximately 1% for the 10-year period reviewed. In addition we have not faced situations where inventory was inadequate to meet the needs of the patients requiring transfusions. CONCLUSION: We have identified three elements of our transfusion service that can minimize outdate: a knowledgeable proactive staff dedicated to PLT management, a comprehensive computer-based transfusion history for each patient, and a strong two-way relationship with the primary product supplier. Through our comprehensive program, based on the principles of providing optimal patient care, we have minimized PLT outdating for more than 10 years. PMID- 21303371 TI - Fukuoka-1 strain of transmissible spongiform encephalopathy agent infects murine bone marrow-derived cells with features of mesenchymal stem cells. AB - BACKGROUND: The possible risk of iatrogenic transmissible spongiform encephalopathies (TSEs, prion diseases) from transplantation of marrow-derived mesenchymal stem cells (MSCs) is uncertain. While most cell lines resist infection, a few propagate TSE agents. STUDY DESIGN AND METHODS: We generated MSC like (MSC-L) cell cultures from bone marrow (BM) of mice inoculated with the human-derived Fukuoka-1 (Fu) strain of TSE agent. Cultured cells were characterized for various markers and cellular prion protein (PrP(C) ) by fluorescence-activated cell sorting and for PrP(C) and its pathologic TSE associated form (PrP(TSE) ) by Western blotting (WB). Cell cultures were tested for their susceptibility to infection with Fu in vitro. The infectivity of one Fu infected cell culture was assayed in mice. RESULTS: BM cells from Fu-infected mice expressed neither PrP(C) nor PrP(TSE) after 3 days in culture as demonstrated by WB. Cells adherent to plastic and maintained under two different culture conditions became spontaneously immortalized and began to express PrP(C) at about the same time. One culture became transformed shortly after exposure to Fu in vitro and remained persistently infected, continuously generating PrP(TSE) through multiple passages; the infectivity of cultured cells was confirmed by intracerebral inoculation of lysates into mice. Both persistently TSE-infected and uninfected cells expressed a number of typical MSC markers. CONCLUSION: BM derived MSC-L cells of mice became persistently infected with the Fu agent under certain conditions in culture-conditions that differ substantially from those currently used to develop investigational human stem cell therapies. PMID- 21303372 TI - Antibodies to oxaliplatin, a chemotherapeutic, are found in plasma of healthy blood donors. AB - BACKGROUND: Oxaliplatin is one of the platinum chemotherapeutics that includes cisplatin and carboplatin. Antibodies to all three drugs have caused immune hemolytic anemia (IHA). In an investigation of oxaliplatin-induced IHA, the negative plasma control agglutinated oxaliplatin-coated red blood cells (RBCs). Previous preparations of this control had not agglutinated oxaliplatin- or cisplatin-coated RBCs. STUDY DESIGN AND METHODS: Drug-coated RBCs, prepared by incubating 1/10th volume of RBCs with 1 mg/mL drug in phosphate-buffered saline for 1 hour at 37 degrees C, were incubated with plasma from random blood donors and patients. Plasma was treated with dithiothreitol to determine the immunoglobulin class. Hapten inhibition was performed by incubating plasma with solutions of oxaliplatin or cisplatin. RESULTS: Nineteen of 121 (16%) donors' plasma samples agglutinated oxaliplatin-coated RBCs; 7 of 102 (7%) donors' plasma samples agglutinated cisplatin-coated RBCs. Two of 50 (4%) patients' samples agglutinated oxaliplatin-coated RBCs. The agglutinin was immunoglobulin M and inhibited by oxaliplatin and cisplatin. CONCLUSION: An agglutinin reactive with oxaliplatin-coated RBCs was found in 16% of donors' and 4% of patients' samples. Inhibition by oxaliplatin and cisplatin indicates the antibody may be directed to platinum. The presence of this antibody in healthy individuals may be related to the increasing environmental presence of platinum in air and soil as a byproduct of automobile catalytic converters and pharmaceuticals in our water and food chain. This antibody in individuals without IHA suggests that testing untreated and enzyme-treated RBCs in the presence of a solution of drug may be the best method to investigate IHA caused by drugs in the platinum family. PMID- 21303373 TI - Nonleukemic myeloid dendritic cells obtained from autologous stem cell products elicit antileukemia responses in patients with acute myeloid leukemia. AB - BACKGROUND: Dendritic cell (DC)-based immunotherapeutic protocols are being developed to treat acute myeloid leukemia (AML). So far, DCs for clinical use are obtained from leukemic blasts or from monocytes, after 6 to 10 days of ex vivo culture. However, DC precursors are easily driven to DCs in short-term culture. We tested if DC precursors contained in peripheral blood stem cell (PBSC) products obtained from AML patients can be used to induce antileukemia responses. STUDY DESIGN AND METHODS: PBSCs obtained from 30 consecutive AML patients were tested. Myeloid DCs (MDCs) were purified by immunomagnetic selection and screened for cytogenetic and/or molecular abnormalities by fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR) assays. MDCs were matured and pulsed with autologous blast lysates and tested for stimulatory capability against AML cells. RESULTS: A median of 0.62 * 10(6) MDCs (range, 0.04-3.25)/mL were quantified in PBSC products. Isolated MDC expressed Class I and II HLA but CD86, CD54, and CCR5 partially. By FISH or PCR assay, these MDCs lacked cytogenetic or molecular abnormalities detected in leukemia cells at diagnosis. MDCs achieved a maturated stage (mature-MDCs) after 24-hour ex vivo culture with tumor necrosis factor-alpha and autologous blast lysates. These mature-MDCs were capable of stimulating autologous peripheral blood effectors to exert cytotoxicity against autologous leukemia cells and HL-60 cell line. CONCLUSION: We conclude that PBSCs obtained for autologous stem cell transplantation can constitute a novel source of MDCs to design feasible vaccination trials. PMID- 21303374 TI - Characteristics of post donation information donors and comparison with appropriately deferred donors. AB - BACKGROUND: Post donation information (PDI) is the most frequently reported biological product deviation (BPD) related to donor suitability and the health history screening process. PDI occurs when a deferrable health history known by the donor is not disclosed, but is subsequently disclosed at a future donation. STUDY DESIGN AND METHODS: PDI and appropriately deferred (AD) donors were identified at six US blood centers from July 1, 2006, to June 30, 2007. PDI and AD donors were categorized according to travel, medical, blood disease or exposure, and high-risk-sexual and high-risk-nonsexual deferrals. Information was obtained from BPD reports and blood center records. Predictors of PDI were identified using an adjusted logistic regression model controlling for select characteristics. RESULTS: There were 2059 PDI and 36,512 AD donors. PDI donors were significantly more likely to be male, older, and more educated than AD donors. Medical and high-risk-sexual PDI donors were more likely to have more than six intervening donations before disclosure of deferrable history. PDI donors with a deferral reason due to high-risk behaviors (both sexual and nonsexual) were 2.3 and 2.6 times more likely to be PDI than the reference group (travel PDI donors). CONCLUSIONS: No previous studies have described the characteristics of PDI donors or examined how PDI donors are different from AD donors for the same deferral reasons. We found that PDIs are more likely in older, male donors with higher levels of education when compared to AD donors. PMID- 21303375 TI - Drug re-challenges in cutaneous adverse drug reactions: information and effectiveness in the long-term management of patients. AB - BACKGROUND: In patients with cutaneous adverse drug reactions (CADR), drug skin tests and re-challenge under hospital surveillance (RCH) are helpful. The aim of this study was to determine if patients with negative drug RCH can tolerate subsequent treatments with the same drugs. PATIENTS AND METHODS: Patients with a negative RCH in the last 10 years answered a telephone questionnaire which was delivered by the same investigator in order to determine if subsequently the patients were able to tolerate the drug with which they had a negative RCH and also to study the reasons why the drugs were not taken again. RESULTS: Six hundred and thirty-seven RCH were analyzed (349 patients, mean age 47 years), 134 drugs were taken again (group A) and 359 were not (group B). In group A, 12 reactions occurred in 10 patients (9%). In group B, drugs were not taken again because 76% of the patients evaluated for an intolerance to antibiotics or radiocontrast media did not require a new course of these products or because their general practitioner (GP) did not want to prescribe these drugs. DISCUSSION: Ninety percent of the RCH (88.5% of the patients) with a CADR followed by investigations and a RCH have a good tolerance to subsequent treatment with the RC drug. The mechanisms involved in this intolerance despite negative RCH are discussed. CONCLUSION: The provocation test procedure, considered as useful by 88% of the patients, has a good negative predictive value. Furthermore, these investigations need to be accompanied by clear information on the patient and his GP. PMID- 21303376 TI - Occupational rhinitis in bell pepper greenhouse workers: determinants of leaving work and the effects of subsequent allergen avoidance on health-related quality of life. AB - BACKGROUND: Avoidance of occupational allergens or reduction in exposure has been advocated as the mainstay of the management of occupational rhinitis. Sparse data to the effect of allergen avoidance are available. OBJECTIVE: To identify factors that may lead to leaving work and to address the effect of subsequent allergen avoidance on quality of life. METHODS: A survey to the prevalence of occupational allergy to bell pepper performed in 1999 comprised 472 employees, of which 254 had work-related rhinitis and 228 completed the Rhinitis-related Quality of Life Questionnaire. After 8-year follow-up in 2007, 91 workers with rhinitis in 1999 were available to fill out the questionnaire again and were used to evaluate the course of nasal disease in terms of perceived severity and impact on daily life. RESULTS: Workers with rhinitis at baseline were more likely to leave their job in bell pepper cultivation for another job (OR = 1.62, 95% CI 0.95-2.75). Among the 91 workers, 58 subjects were still at work, whereas 33 subjects had left work. The subjects who left jobs reported substantial improvement in quality of life. The magnitude of the changes ranged from -0.31 to -1. The effect of quitting work on the mean quality of life score amounted -0.76 +/- 0.15. CONCLUSIONS: The current study is the first large longitudinal studies showing that leaving work and subsequent occupational allergen avoidance have a beneficial effect on rhinitis-related quality of life. The study suggests that occupational rhinitis can be a reason to leave work. PMID- 21303377 TI - Efficacy of a 2-dose regimen of a sustained release ceftiofur suspension in horses with Streptococcus equi subsp. zooepidemicus bronchopneumonia. AB - The efficacy and safety of sustained release ceftiofur administered twice, 4 days apart, for treatment of horses with naturally acquired Streptococcus equi subsp. zooepidemicus (Strep. zoo.) pneumonia was evaluated in a multicenter, placebo controlled, double-blinded, randomized clinical trial. The study included 373 horses (278 treated and 95 placebos) with naturally acquired pneumonia. Inclusion in the statistical analyses for treatment efficacy for Strep. zoo. required recovery of >=10(4) CFU/mL of Strep. zoo. on the primary isolation plate which resulted in 201 cases (145 treated and 56 placebos) with confirmed Strep. zoo. pneumonia evaluable for treatment success. Therapeutic success was defined by clinical improvement of lower respiratory tract infection at 4 and 9 days after initial dosing, resolution of clinical signs by 15 days, and no recurrence by 25 days. Of the 278 treated horses, 239 (85.9%) completed the 25 day study without additional therapy compared to 50 of the 95 (53.6%) placebo horses. In confirmed Strep. zoo. cases, a clinical cure was achieved in 66.9% of 145 treated horses compared to 32.1% of 56 placebo horses (P = 0.0286). Two doses of sustained release ceftiofur suspension were effective and safe in the treatment of naturally acquired lower respiratory tract infection associated with Strep. zoo. in horses under field use conditions. PMID- 21303378 TI - Effect of intravenous sodium salicylate administration prior to castration on plasma cortisol and electroencephalography parameters in calves. AB - Nociception is an unavoidable consequence of many routine management procedures such as castration in cattle. This study investigated electroencephalography (EEG) parameters and cortisol levels in calves receiving intravenous sodium salicylate in response to a castration model. Twelve Holstein calves were randomly assigned to the following groups: (i) castrated, untreated controls, (ii) 50 mg/kg sodium salicylate IV precastration, were blood sampled at 0, 5, 10, 20, 30, 45, 60, 90, 120, 150, 180, 240, 360, and 480 min postcastration. The EEG recording included baseline, castration, immediate recovery (0-5 min after castration), middle recovery (5-10 min after castration), and late recovery (10 20 min after castration). Samples were analyzed by competitive chemiluminescent immunoassay and fluorescence polarization immunoassay for cortisol and salicylate, respectively. EEG visual inspection and spectral analysis were performed. Statistical analyses included anova repeated measures and correlations between response variable. No treatment effect was noted between the two groups for cortisol and EEG measurements, namely an attenuation of acute cortisol response and EEG desynchronization in sodium salicylate group. Time effects were noted for EEG measurements, cortisol and salicylates levels. Significant correlations between cortisol and EEG parameters were noted. These findings have implications for designing effective analgesic regimens, and they suggest that EEG can be useful to monitor pain attributable to castration. PMID- 21303379 TI - The N-terminal amino acid of apolipoprotein D is putatively covalently bound to 3 hydroxy-3-methyl hexanoic acid, a key odour compound in axillary sweat. AB - Axillary sweat is odourless when freshly collected at the surface of human skin, but it contains non-odoriferous precursors, which can be transformed into odorous substances by bacteria. E-3-methyl-2-hexanoic acid (3M2H) is one of the key odorous substances, but there are two contradictory reports about its precursor form. One report states that 3M2H linked non-covalently to apolipoprotein D (apoD) is the precursor, while a second report states that 3M2H-Gln identified in human axillary sweat is the precursor. Recently, 3-hydroxy-3-methyl hexanoic acid (HMHA) and 3-methyl-3-sulfanylhexane-1-ol (3M3T) have also been identified and reported as characteristic components found in apocrine sweat. To better understand the formation of axillary odours and the structural relationships between these compounds and apoD, we characterized the linkage between odorous substances and apoD in human axillary secretions. ApoD was purified from human axillary secretions collected from 50 healthy female volunteers and was then digested by trypsin and analysed by MALDI-TOF mass spectrometry. A Mascot search showed that 8 peaks identified in the trypsin-digested samples correspond to the masses calculated for theoretically digested apoD sequences and the purified protein was assigned as a precursor of apoD [Homo sapiens]. One spectrum corresponded to the theoretical peak of HMHA linked covalently to the N-terminal fragment of apoD. In contrast, no spectrum corresponded to the theoretical peak of a 3M2H adduct or to an unmodified N-terminal fragment of apoD. These results indicate a possibility that HMHA binds covalently to the N-terminal amino acid of apoD in human axillary secretions. PMID- 21303380 TI - Molecular pathogenesis of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the major causes of death among cirrhotic patients, being viral hepatitis and alcohol abuse, the main risk factors for its development. The introduction of highly sophisticated genomic technologies has spurred extensive research on the molecular pathogenesis of this devastating disease. Several signaling cascades have been consistently found dysregulated in HCC (e.g., WNT-beta-catenin, PI3K/AKT/MTOR, RAS/MAPK, IGF, HGF/MET, VEGF, EGFR, and PDGF). In addition, there have been numerous molecular classifications proposed for this disease, what provides an additional hint about its genomic complexity. The importance of knowing the molecular drivers of HCC is underscored by the positive results of a molecular targeted agent, sorafenib, able to improve survival in patients with advanced disease. This review will briefly outline key concepts in alcohol-related hepatocarcinogenesis, and provide some insight regarding current trends in translating HCC genomics into clinical management of the disease. PMID- 21303381 TI - Genetics and alcohol: a lethal combination in pancreatic disease? AB - An association between alcohol consumption and pancreatic diseases has been recognized for decades, but the absolute risk for pancreatic disease for individuals who drink alcohol is low. Other than smoking, few additional environmental factors have been identified, which suggests that genetic risk factors may be important. Studies in our laboratory using the Lieber-DeCarli feeding technique demonstrate that alcohol causes oxidative stress and mitochondrial damage and alters neruohormonal regulation of the pancreas after a threshold dose is exceeded, which makes the pancreas susceptible to withdrawal hypersensitivity and acute pancreatitis. Alcohol also shifts cell death from apoptosis to necrosis and promotes fibrosis through anti-inflammatory immune mechanisms. Others have demonstrated that alcohol lowers the threshold for trypsin activation in acinar cells, which increases sensitivity to triggering pancreatitis. In addition, we used the Lieber-DeCarli diet plus recurrent acute pancreatitis insults to develop the first animal model of chronic pancreatitis that mimics human disease. Finally, our North American Pancreatitis Study 2 (NAPS2), which was built on insights from animal studies, confirmed the threshold effect predicted by Charles Lieber (>5 drinks per day and >35 drinks/week). These studies and others also defined distinctive roles of alcohol and genetics in the etiology and progression of chronic pancreatitis. PMID- 21303382 TI - High-dose baclofen for suppression of alcohol dependence. PMID- 21303383 TI - Baclofen effect related to liver damage. PMID- 21303385 TI - L-cysteine prevents ethanol-induced stimulation of mesolimbic dopamine transmission. AB - BACKGROUND: Acetaldehyde (ACD), the first metabolite of ethanol (EtOH) appears to be involved in many of the psychoactive effects of its parent compound, including EtOH-induced activation of the mesolimbic dopamine (DA) system, thereby suggesting that ACD may participate in EtOH motivational properties. l-cysteine (Lcys), a thiol compound sequestering ACD, is able to prevent the behavioral effect of EtOH and ACD. Here we show that the stimulatory effect of both EtOH and ACD on the mesolimbic DA system is prevented by Lcys pretreatment. METHODS: Male Wistar rats were implanted with a microdialysis probe in the nucleus accumbens shell (NAccs), and pretreated intraperitoneally with Lcys (30 mg/kg) before intragastric administration of EtOH (1 g/kg) or ACD (20 mg/kg) or before intraperitoneal administration of morphine (2.5 mg/kg). RESULTS: Pretreatment with Lcys prevented both EtOH and ACD-induced DA release in the NAccs without influencing morphine-induced DA release, suggesting that Lcys specifically affects EtOH-induced DA release possibly through ACD sequestering. CONCLUSIONS: Our results underscore the role of ACD on EtOH-induced stimulation of DA mesoaccumbens system and support the notion that thiol compounds such as Lcys, by modulating EtOH-derived ACD bioavailability, would blunt EtOH rewarding properties. PMID- 21303384 TI - Inter-hemispheric functional connectivity disruption in children with prenatal alcohol exposure. AB - BACKGROUND: MRI studies, including recent diffusion tensor imaging (DTI) studies, have shown corpus callosum abnormalities in children prenatally exposed to alcohol, especially in the posterior regions. These abnormalities appear across the range of fetal alcohol spectrum disorders (FASD). Several studies have demonstrated cognitive correlates of callosal abnormalities in FASD including deficits in visual-motor skill, verbal learning, and executive functioning. The goal of this study was to determine whether inter-hemispheric structural connectivity abnormalities in FASD are associated with disrupted inter hemispheric functional connectivity and disrupted cognition. METHODS: Twenty-one children with FASD and 23 matched controls underwent a 6-minute resting-state functional MRI scan as well as anatomical imaging and DTI. Using a semi-automated method, we parsed the corpus callosum and delineated 7 inter-hemispheric white matter tracts with DTI tractography. Cortical regions of interest (ROIs) at the distal ends of these tracts were identified. Right-left correlations in resting fMRI signal were computed for these sets of ROIs, and group comparisons were made. Correlations with facial dysmorphology, cognition, and DTI measures were computed. RESULTS: A significant group difference in inter-hemispheric functional connectivity was seen in a posterior set of ROIs, the para-central region. Children with FASD had functional connectivity that was 12% lower than in controls in this region. Subgroup analyses were not possible owing to small sample size, but the data suggest that there were effects across the FASD spectrum. No significant association with facial dysmorphology was found. Para central functional connectivity was significantly correlated with DTI mean diffusivity, a measure of microstructural integrity, in posterior callosal tracts in controls but not in FASD. Significant correlations were seen between these structural and functional measures, and Wechsler perceptual reasoning ability. CONCLUSIONS: Inter-hemispheric functional connectivity disturbances were observed in children with FASD relative to controls. The disruption was measured in medial parietal regions (para-central) that are connected by posterior callosal fiber projections. We have previously shown microstructural abnormalities in these same posterior callosal regions, and the current study suggests a possible relationship between the two. These measures have clinical relevance as they are associated with cognitive functioning. PMID- 21303386 TI - Alcohol-metabolizing enzyme gene polymorphisms in the Basque Country, Morocco, and Ecuador. AB - BACKGROUND: Genes ADH1B and ADH1C have certain functional SNPs that are related to alcoholism. The frequencies of these polymorphisms vary between populations, so studying them in populations made up of groups with different phylogeographic origins requires an individualized analysis of each group. In the Basque Country, various recently arrived foreign groups live side by side with the original Southern European population, particularly North Africans from Morocco and Hispanics from Ecuador. This study sets out to examine the distribution of the frequencies of alleles that encode alcohol dehydrogenase with different metabolization rates, as higher rates make for greater susceptibility to alcoholism. METHODS: Four SNPs: rs1229984, rs2066702, rs698, and rs1693482 using Taqman technology with a Rt-PCR were studied in a sample of 114 European individuals originating from the Basque Country, 100 North Africans from Morocco, and 109 Hispanics from Ecuador. The allele and genotype frequencies were calculated using Genepop v4.0. The most frequent haplotypes were estimated using the ELB algorithm with Arlequin v3.01. A breakdown of the complete disequilibrium commonly observed between the 2 missense polymorphisms that distinguish the common ADH1C alleles rs698 and rs1693482 was observed and confirmed by sequencing in 2 individuals from the Basque Country. RESULTS: A higher frequency of protective allele ADH1C*1 was found in the North African population group. Haplotype combinations are also studied, and the rare association of alleles ADH1B*2-ADH1C*2 was observed in the Southern European group in the Basque Country, along with an allele not hitherto described in the ADH1C locus. CONCLUSIONS: This study provides the first data published on the allele and genotype frequencies of the ADH1C locus in the Moroccan population and on the ADH1B and ADH1C loci in the Ecuadorian population. The study shows differences in the distribution of the frequency of allele ADH1C*1 between the Basque Country and Moroccan populations, and a new allele not described to date. PMID- 21303387 TI - High ventricular lead impedance of a DDD pacemaker after cranial magnetic resonance imaging. AB - Management of electromagnetic interference in the form of magnetic resonance imaging (MRI) in patients with pacemakers (PMs) may be challenging. Serious consequences, especially in PM-dependent patients, may be encountered. Changes in device programming, asynchronous pacing, heating of the lead tip(s), and increased thresholds or even device dislocation may be experienced. We report of a patient with a DDD PM who underwent an emergent MRI, after which there was an increase in ventricular impedance as well as increased cardiac biomarkers. PMID- 21303388 TI - Ajmaline challenge in young individuals with suspected Brugada syndrome. AB - BACKGROUND: The clinical characteristics and the results of ajmaline challenge in young individuals with suspected Brugada syndrome (BS) have not been systematically investigated. METHODS: Among a larger series of patients included in the BS database of our Department, 179 patients undergoing ajmaline challenge were included in the study and categorized in two groups according to age: group 1 (<18 years old) and group 2 (>=18 years old). Clinical features and results of the ajmaline challenge of each group were compared. RESULTS: Young individuals were more often asymptomatic compared to adult patients (P = 0.002). They showed a higher number of normal ECGs (P = 0.023), a lower percentage of Brugada type II electrocardiographic pattern compared to the adult population (P = 0.011), and a comparable amount of spontaneous Brugada type III electrocardiographic pattern (P = 0.695). Ajmaline provoked a higher degree of intraventricular conduction delay (P = 0.002) and higher degree of prolongation of the ventricular repolarization phase (P = 0.013) in young individuals but its pro-arrhythmic risk was comparable in the two groups (P = 0.684). Furthermore, inducibility of ventricular arrhythmias in young patients with a positive ajmaline test was comparable to that of the adults with a positive ajmaline test (P = 0.694). CONCLUSIONS: The present study demonstrates the low-risk profile of the ajmaline test in young patients when performed by experienced physicians and nurses in an appropriate environment. PMID- 21303389 TI - Incidence and significance of pacemaker and implantable cardioverter defibrillator lead masses discovered during transesophageal echocardiography. AB - BACKGROUND: Pacemaker and implantable cardioverter-defibrillator device infections are feared complications. The finding of a lead-associated mass on transesophageal echocardiogram (TEE) raises concern for endocarditis. However, the incidence and clinical importance of lead masses is not currently known. METHODS: Consecutive patients with transvenous leads undergoing TEE from July 1, 2003, to June 30, 2005, were identified and assessed for a clinical diagnosis of endocarditis. An echocardiographer blinded to clinical information reviewed all TEEs. RESULTS: Of 177 TEEs performed on 153 patients, a visible mass on a device lead was observed in 25 (14%), including 11 TEEs showing a lead vegetation, 13 TEEs showing lead strands, and one study showing both. Seventeen patients were adjudicated to have endocarditis, of which eight had a mass seen on a lead during TEE. Thus, 72% of patients (18 of 25) with a lead-associated mass did not have evidence of an infection. In TEEs performed for indications other than to rule out endocarditis, lead masses were seen in 13 of 136 studies (10%), with only one patient adjudicated to clinically have an infected device. CONCLUSION: During this 2-year study of consecutive patients with a tranvenous lead undergoing TEE, lead-associated masses were found in 14% of patients. In 72% of patients, the mass did not prove to be secondary to infectious causes. Thus, masses attached to a device lead should be interpreted in the overall clinical context and, in the absence of concomitant evidence of endocarditis, should not mandate device and lead removal. PMID- 21303390 TI - Prevalence of asymptomatic upper extremity venous obstruction in 302 patients undergoing first implantation of cardioverter defibrillator. AB - BACKGROUND: Little is known about the prevalence of upper extremity vein obstruction or anomalies in patients before first implantation of implantable cardioverter defibrillator (ICD). It remains unclear in which patients contrast venography is warranted before implantation procedure. METHODS: Results of clinical data and contrast venography of 302 consecutive patients scheduled for first ICD implantation were analyzed. RESULTS: Prevalence of upper vein obstruction was 6.6% (20/302 patients) in a typical patient population undergoing first ICD implantation. Age, left ventricular ejection fraction, underlying heart disease, prior open-heart surgery, or cardiopulmonary resuscitation were not predictors of obstruction. Patients with previous cardiac pacemaker implantation had a higher rate of obstruction, though this was not statistically significant (20% vs 15.7%, P = 0.54). Persistent left vena cava was found in 0.7%. CONCLUSION: There is no clinical parameter sufficient enough to predict upper extremity venous obstruction. Contrast venography may be considered in patients with previous pacemaker placement but should not be a routine diagnostic tool in unselected patients prior to first ICD-implantation procedure. PMID- 21303391 TI - ICD and neuromodulation devices: is peaceful coexistence possible? AB - AIM: The aim of this study was to investigate the potential cross-talk between implantable cardioverter defibrillator device (ICD) and implantable neuromodulation device (IND) during the implantation procedure and the ventricular fibrillation induction test and in daily life. METHODS: We present two cases of patients with an IND who underwent ICD implantation and one case of a patient implanted with a biventricular ICD who received an IND 6 months later. Two of these patients had a spinal cord stimulator (SCS), while the other had a sacral neuromodulator. RESULTS: No cross-talk was recorded in the patient with the sacral neuromodulator and the ICD. Temporary damage to one of the SCSs was observed after multiple ICD shocks. CONCLUSIONS: When implanted contemporarily with sacral or spinal neurostimulators, cardiac devices appear to be safe, as confirmed by the appropriate detection and interruption of arrhythmic episodes. On the other hand, neuromodulation devices could be temporarily or permanently damaged by multiple ICD discharges. It is recommended that the neurostimulator be interrogated after an ICD shock, in order to check the state of the device. PMID- 21303392 TI - Programming ICDs in the Modern Era beyond Out-of-the Box Settings. AB - Implantable cardioverter-defibrillators (ICDs) improve survival when used as primary or secondary prevention therapy in patients with a broad spectrum of disorders associated with a high risk of sudden death. As indications continue to be refined, attention has increasingly turned to ICD-related complications and their impact on quality of life. Foremost among these complications are inappropriate shocks. This issue remains a major challenge, despite technological advances with sophisticated recording capabilities and detection algorithms. While pharmacological and catheter-based interventions represent important adjunctive tools for the reduction of inappropriate shocks, this contemporary review focuses on customizing and optimizing ICD programming. Studies addressing ICD programming beyond "out the box" settings are reviewed for each device manufacturer and special circumstances are considered. We discuss the benefits and pitfalls of strategies such as high cutoff rates, longer detections times, antitachycardia pacing, and discriminators in reducing the incidence of inappropriate shocks and offer practical programming tips. PMID- 21303394 TI - Multiresistant Gram-negative bacteria: the role of high-risk clones in the dissemination of antibiotic resistance. AB - Multilocus sequence typing reveals that many bacterial species have a clonal structure and that some clones are widespread. This underlying phylogeny was not revealed by pulsed-field gel electrophoresis, a method better suited to short term outbreak investigation. Some global clones are multiresistant and it is easy to assume that these have disseminated from single foci. Such conclusions need caution, however, unless there is a clear epidemiological trail, as with KPC carbapenemase-positive Klebsiella pneumoniae ST258 from Greece to northwest Europe. Elsewhere, established clones may have repeatedly and independently acquired resistance. Thus, the global ST131 Escherichia coli clone most often has CTX-M-15 extended-spectrum beta-lactamase (ESBL), but also occurs without ESBLs and as a host of many other ESBL types. We explore this interaction of clone and resistance for E. coli, K. pneumoniae, Acinetobacter baumannii- a species where three global lineages dominate--and Pseudomonas aeruginosa, which shows clonal diversity, but includes the relatively 'tight' serotype O12/Burst Group 4 cluster that has proved adept at acquiring resistances--from PSE-1 to VIM-1 beta lactamases--for over 20 years. In summary, 'high-risk clones' play a major role in the spread of resistance, with the risk lying in their tenacity--deriving from poorly understood survival traits--and a flexible ability to accumulate and switch resistance, rather than to constant resistance batteries. PMID- 21303393 TI - Phosphoethanolamine methyltransferases in phosphocholine biosynthesis: functions and potential for antiparasite therapy. AB - S-adenosyl-L-methionine (SAM)-dependent methyltransferases represent a diverse group of enzymes that catalyze the transfer of a methyl group from a methyl donor SAM to nitrogen, oxygen, sulfur or carbon atoms of a large number of biologically active large and small molecules. These modifications play a major role in the regulation of various biological functions such as gene expression, signaling, nuclear division and metabolism. The three-step SAM-dependent methylation of phosphoethanolamine to form phosphocholine catalyzed by phosphoethanolamine N methyltransferases (PMTs) has emerged as an important biochemical step in the synthesis of the major phospholipid, phosphatidylcholine, in some eukaryotes. PMTs have been identified in nematodes, plants, African clawed frogs, zebrafish, the Florida lancelet, Proteobacteria and human malaria parasites. Data accumulated thus far suggest an important role for these enzymes in growth and development. This review summarizes published studies on the biochemical and genetic characterization of these enzymes, and discusses their evolution and their suitability as targets for the development of therapies against parasitic infections, as well as in bioengineering for the development of nutritional and stress-resistant plants. PMID- 21303395 TI - Shifts in coastal Antarctic marine microbial communities during and after melt water-related surface stratification. AB - Antarctic coastal waters undergo major physical alterations during summer. Increased temperatures induce sea-ice melting and glacial melt water input, leading to strong stratification of the upper water column. We investigated the composition of micro-eukaryotic and bacterial communities in Ryder Bay, Antarctic Peninsula, during and after summertime melt water stratification, applying community fingerprinting (denaturing gradient gel electrophoresis) and sequencing analysis of partial 18S and 16S rRNA genes. Community fingerprinting of the eukaryotic community revealed two major patterns, coinciding with a period of melt water stratification, followed by a period characterized by regular wind induced breakdown of surface stratification. During the first stratified period, we observed depth-related differences in eukaryotic fingerprints while differences in bacterial fingerprints were weak. Wind-induced breakdown of the melt water layer caused a shift in the eukaryotic community from an Actinocyclus sp.- to a Thalassiosira sp.-dominated community. In addition, a distinct transition in the bacterial community was found, but with a few days' delay, suggesting a response to the changes in the eukaryotic community rather than to the mixing event itself. Sequence analysis revealed a shift from an Alpha- and Gammaproteobacteria to a Cytophaga-Flavobacterium-Bacteroides-dominated community under mixed conditions. Our results show that melt water stratification and the transition to nonstabilized Antarctic surface waters may have an impact not only on micro-eukaryotic but also bacterial community composition. PMID- 21303396 TI - Diversity of endophytic bacteria within nodules of the Sphaerophysa salsula in different regions of Loess Plateau in China. AB - A total of 115 endophytic bacteria were isolated from root nodules of the wild legume Sphaerophysa salsula grown in two ecological regions of Loess Plateau in China. The genetic diversity and phylogeny of the strains were revealed by restriction fragment length polymorphism and sequencing of 16S rRNA gene and enterobacterial repetitive intergenic consensus-PCR. Their symbiotic capacity was checked by nodulation tests and analysis of nifH gene sequence. This is the first systematic study on endophytic bacteria associated with S. salsula root nodules. Fifty of the strains found were symbiotic bacteria belonging to eight putative species in the genera Mesorhizobium, Rhizobium and Sinorhizobium, harboring similar nifH genes; Mesorhizobium gobiense was the main group and 65 strains were nonsymbiotic bacteria related to 17 species in the genera Paracoccus, Sphingomonas, Inquilinus, Pseudomonas, Serratia, Mycobacterium, Nocardia, Streptomyces, Paenibacillus, Brevibacillus, Staphylococcus, Lysinibacillus and Bacillus, which were universally coexistent with symbiotic bacteria in the nodules. Differing from other similar studies, the present study is the first time that symbiotic and nonsymbiotic bacteria have been simultaneously isolated from the same root nodules, offering the possibility to accurately reveal the correlation between these two kinds of bacteria. These results provide valuable information about the interactions among the symbiotic bacteria, nonsymbiotic bacteria and their habitats. PMID- 21303397 TI - Genetic diversity of nodulating and non-nodulating rhizobia associated with wild soybean (Glycine soja Sieb. & Zucc.) in different ecoregions of China. AB - A total of 99 bacterial isolates that originated from root nodules of Glycine soja were characterized with restriction analyses of amplified 16S ribosomal DNA and 16S-23S rDNA intergenic spacers (ITS), and sequence analyses of 16S rRNA, rpoB, atpD, recA and nodC genes. When tested for nodulation of G. soja, 72 of the isolates were effective symbionts, and these belonged to five species: Bradyrhizobium japonicum, Bradyrhizobium elkanii, Bradyrhizobium yuanmingense, Bradyrhizobium liaoningense and Sinorhizobium fredii. All of these, except some B. yuanmingense strains, also formed effective nodules on the domesticated soybean Glycine max. The remaining 27 isolates did not nodulate either host, but were identified as Rhizobium. Phylogeny nodC in the G. soja symbionts suggested that this symbiosis gene was mainly maintained by vertical gene transfer. Different nodC sublineages and rrs-ITS clusters reflected the geographic origins of isolates in this study. PMID- 21303398 TI - Growth and symbiotic effectiveness of an arbuscular mycorrhizal fungus in organic matter in competition with soil bacteria. AB - Arbuscular mycorrhizal (AM) fungi can enhance the rate of decomposition of organic material, and can acquire nitrogen (N) from organic sources, although they are not saprotrophs. These fungi may instead indirectly influence decomposition through interactions with other soil microorganisms. We investigated the impact of both AM hyphae and a bacterial filtrate on N capture by a host plant from sterilized organic material (Lolium perenne shoots dual labelled with (15) N and (13) C), using compartmented microcosms. The addition of a bacterial filtrate considerably suppressed AM hyphal growth in the patch and reduced the root phosphorus content, demonstrating that bacterial populations can reduce symbiotic effectiveness. In contrast, AM hyphae had only a limited impact on bacterial community structure. Uptake of (15) N greatly exceeded that of (13) C, demonstrating that fungi acquired N in an inorganic form. We also examined the ability of AM fungi in gnotobiotic hairy root culture to acquire N directly from organic materials of varying complexities (glutamic acid, urea, bacterial lysate and L. perenne shoots). AM colonization did not enhance root N capture from these materials, although the bacterial lysate reduced both total AM colonization and arbuscule frequency. Collectively, these data demonstrate antagonistic interactions between AM fungi and bacteria that reflect resource competition for decomposition products. PMID- 21303399 TI - Review article: the pathophysiology, differential diagnosis and management of rumination syndrome. AB - BACKGROUND: Rumination syndrome, characterised by the effortless, often repetitive, regurgitation of recently ingested food into the mouth, was originally described in children and in the developmentally disabled. It is now well-recognised that rumination syndrome occurs in patients of all ages and cognitive abilities. AIM: To review a scholarly review on our current understanding of the rumination syndrome. METHODS: The review was conducted on the basis of a medline search to identify relevant publications pertaining to the pathophysiology, clinical diagnosis and management of rumination syndrome. RESULTS: The Rome III consensus established diagnostic criteria for rumination syndrome in adults, children and infants. A typical history can be highly suggestive but oesophageal (high resolution) manometry/impedance with ingestion of a meal may help to distinguish rumination syndrome from other belching/regurgitation disorders. The pathophysiology is incompletely understood, but involves a rise in intra-gastric pressure, generated by a voluntary, but often unintentional, contraction of the abdominal wall musculature, at a time of low pressure in the lower oesophageal sphincter, causing retrograde movement of gastric contents into the oesophagus. To date, controlled trials in the treatment rumination syndrome are lacking. The mainstay of treatment for rumination syndrome is explanation and behavioural treatment which consists of habit reversal techniques that compete with the urge to regurgitate. Chewing gum, prokinetics, baclofen and even antireflux surgery have been proposed as adjunctive therapies, but high quality studies are generally lacking. CONCLUSIONS: Rumination is an under-recognised condition with incompletely understood pathophysiology. Behavioural therapy seems effective, but controlled treatment trials are lacking. PMID- 21303400 TI - Review article: proton pump inhibitors with clopidogrel--evidence for and against a clinically-important interaction. AB - BACKGROUND: The treatment of acute coronary syndromes involves a combination of antiplatelet therapies. Proton pump inhibitors are frequently recommended for patients receiving clopidogrel in addition to aspirin, to minimise the risk of bleeding. Several studies have shown that proton pump inhibitors can affect the platelet inhibitory effects of clopidogrel. However, the data on whether this has an effect on clinical outcomes are conflicting and a definitive answer is still awaited. AIM: To provide an overview of the evidence for the pharmacological interaction between proton pump inhibitors and clopidogrel and to discuss whether this interaction translates into adverse clinical outcomes. Despite recent developments, clear consensus is lacking. METHODS: A search of the published literature combined with the authors' knowledge of the field. RESULTS: There is evidence to show that proton pump inhibitors can influence the pharmacodynamics of clopidogrel, but the data suggesting clinical effects are weak and conflicting. Supporting a clinically important interaction are four retrospective studies including over 11,000 patients prescribed both clopidogrel and a proton pump inhibitor. Evidence against a clinically important interaction is derived from over 18,000 patients from seven studies, including the only prospective trial to examine the potential interaction. Confounding variables are relevant and prospective clinical evidence is lacking. CONCLUSIONS: Proton pump inhibitors offer clear protection and the concern over clinically relevant interactions with clopidogrel is biologically plausible, but not yet proven. PMID- 21303401 TI - Economics of disaster risk, social vulnerability, and mental health resilience. AB - We investigate the relationship between exposure to Hurricanes Katrina and/or Rita and mental health resilience by vulnerability status, with particular focus on the mental health outcomes of single mothers versus the general public. We advance a measurable notion of mental health resilience to disaster events. We also calculate the economic costs of poor mental health days added by natural disaster exposure. Negative binomial analyses show that hurricane exposure increases the expected count of poor mental health days for all persons by 18.7% (95% confidence interval [CI], 7.44-31.14%), and by 71.88% (95% CI, 39.48 211.82%) for single females with children. Monthly time-series show that single mothers have lower event resilience, experiencing higher added mental stress. Results also show that the count of poor mental health days is sensitive to hurricane intensity, increasing by a factor of 1.06 (95% CI, 1.02-1.10) for every billion (U.S.$) dollars of damage added for all exposed persons, and by a factor of 1.08 (95% CI, 1.03-1.14) for single mothers. We estimate that single mothers, as a group, suffered over $130 million in productivity loss from added postdisaster stress and disability. Results illustrate the measurability of mental health resilience as a two-dimensional concept of resistance capacity and recovery time. Overall, we show that natural disasters regressively tax disadvantaged population strata. PMID- 21303402 TI - Clinical and radiographic outcomes of the modified minimally invasive surgical technique with and without regenerative materials: a randomized-controlled trial in intra-bony defects. AB - AIMS: This three-arm study compared the clinical and radiographic efficacy of the modified minimally invasive surgical technique (M-MIST) alone and combined with enamel matrix derivative (EMD) or EMD plus bone mineral derived xenograph (BMDX), in the treatment of isolated, inter-dental intra-bony defects. MATERIALS AND METHODS: Forty-five deep isolated intra-bony defects in 45 patients were included, accessed with the M-MIST and randomly assigned to three balanced experimental groups. The M-MIST consisted of a small buccal flap without elevation of the defect-associated papilla. After removal of the granulation tissue by sharp dissection and root instrumentation the regenerative material was applied, when indicated, before obtaining primary closure with a single internal modified mattress suture. Surgery was performed with the aid of an operating microscope and microsurgical instruments. Outcomes were evaluated as pocket depth reduction, attachment level gain, radiographic bone fill and patient-related outcomes. RESULTS: Primary wound closure was maintained in all treated sites with the exception of one M-MIST EMD+BMDX site. No patient reported intra-operative or post-operative pain. Within group differences between baseline and 1 year were statistically significant in the three groups in terms of probing pocket depth reduction, clinical attachment level (CAL) gain and bone fill (p<0.0001). Comparisons among the thre groups showed no statistically significant difference in any of the measured clinical outcomes. In particular, CAL gains of 4.1+/-1.4mm were observed in the M-MIST control group, 4.1+/-1.2mm in the EMD group and 3.7+/ 1.3mm in the EMD+BMDX one. The percentage radiographic bone fill of the intra bony component was 77+/-19% in the M-MIST control group, 71+/-18% in the EMD group and 78+/-27% in the EMD+BMDX group. CONCLUSIONS: M-MIST with or without regenerative materials resulted in significant clinical and radiographic improvements. While this initial study did not have sufficient power to detect inter-group CAL differences <0.96mm, the observed outcomes were remarkably similar and warrant further investigations. PMID- 21303403 TI - Impact of systemic antimicrobials combined with anti-infective mechanical debridement on the microbiota of generalized aggressive periodontitis: a 6-month RCT. AB - AIM: To compare the effects of systemic amoxicillin (AMX) plus metronidazole (MET) or placebos combined with anti-infective mechanical debridement on the sub gingival microbiota of generalized aggressive periodontitis (GAP). MATERIAL AND METHODS: The study was a 6-month randomized, double-blinded, placebo-controlled clinical trial. Thirty-one subjects received full-mouth ultrasonic debridement followed by scaling and root planing with chlorhexidine rinsing, brushing and irrigation. During mechanical therapy, subjects received systemic AMX (500mg)+MET (250mg) or placebo, t.i.d. for 10 days. Sub-gingival samples were obtained from each patient and analysed for their composition by checkerboard at baseline, 3 and 6 months post-therapy. Significant differences between groups over time were examined by General Linear Model of Repeated Measures. RESULTS: High levels of periodontal pathogens, as well as some "non-periodontal" species were observed. Most of the periodontal pathogens decreased significantly over time (p<0.05), whereas "non-periodontal" bacteria tended to increase in both groups. Sites that showed attachment loss and probing depth increase harboured higher levels of Dialister pneumosintes, Campylobacter rectus, Fusobacterium necrophorum, Prevotella tannerea and Peptostreptococcus anaerobius than sites that improved after both therapies (p<0.05). CONCLUSIONS: Systemic AMX+MET or placebos adjunctive to anti-infective mechanical debridement were comparable in lowering periodontal pathogens up to 6 months after treatment. Species not commonly associated with GAP were less affected by both therapies. PMID- 21303404 TI - Factitious self-manipulation of the external insulin pump in adolescents with Type 1 diabetes. PMID- 21303405 TI - Response to Matthews and Matthews. Type 2 diabetes as an 'infectious' disease: is this the 'Black Death' of the 21st century? PMID- 21303406 TI - Prebiotic treatment in experimental colitis reduces the risk of colitic cancer. AB - BACKGROUND AND AIM: Germinated barley foodstuff (GBF) is a prebiotic product that reduces colonic mucosal inflammation and the clinical symptoms observed in ulcerative colitis (UC). The risk of contracting colorectal cancer is higher in patients with UC than in that of the general population. The aim of this study is to apply this prebiotic approach to control chronic colitis and to reduce the incidence of colitic cancer. METHODS: Repeated and intermitted dextran sulfate sodium administration to male Sprague-Dawley rats was used for the chronic and subacute colitis models. GBF was added as the diet (10% w/v). The incidence of adenomatous high-grade dysplasia, and pathophysiological observations, including the proliferative cell nuclear antigen (PCNA) labeling index, and clinical score, cecal organic acid profile, and the accompanying beta-glucosidase activity were determined. RESULTS: In the chronic phase, the incidence of adenomatous dysplasia was only confirmed in the control group, and the GBF group had no dysplasia in the entire colon; the stratified squamous epithelium area of GBF was significantly lower than that of the controls. GBF treatment significantly lowered the cecal succinate content and significantly increased beta-glucosidase activity compared to the controls. In addition, colonic mucosal inflammatory damage was comparable between the two groups, while the PCNA labeling index of the colonic mucosa in the GBF group was significantly lower than that of the control group. However, in the subacute phase, the mucosal damage score of GBF was significantly attenuated, and the PCNA labeling index of the colonic mucosa in the GBF group was significantly higher than that of the control group. CONCLUSION: This preliminary study demonstrated that GBF effectively prevents colitis-related dysplasia and inflammatory change in chronic and subacute colitis models by modulating the intestinal environment as a prebiotic. This prebiotic might contribute to the prevention of mucosal damage, to show different proliferative effects on the epithelium in the regeneration and steady states. PMID- 21303407 TI - Genetic background is different between sentinel and recurrent acute pancreatitis. AB - BACKGROUND AND AIM: Previous studies have shown an association of variants in trypsin-associated genes, such as cationic trypsinogen (PRSS1) and serine protease inhibitor, Kazal type-1 (SPINK1) with pancreatitis. However, whether these genetic variants are associated with acute pancreatitis (AP) remains largely unknown, especially when the first attack is separated from recurrent attacks. METHODS: A total of 261 patients with AP (174 with a sentinel attack, and 87 with recurrent attacks) and healthy controls were genotyped for the p.R122H mutation in the PRSS1 gene, p.N34S and IVS3 + 2T > C variants in the SPINK1 gene, the p.G191R variant in the anionic trypsinogen gene, the p.E32del variant in the mesotrypsinogen (PRSS3) gene, and the -2518G > A variant in the monocyte chemoattractant protein-1 gene by polymerase chain reaction-restriction enzyme digestion and direct sequencing. RESULTS: Patients with recurrent attacks were younger. The proportions of biliary pancreatitis and severe cases were lower, and that of idiopathic pancreatitis was higher in patients with a sentinel attack than in those with recurrent attacks. The frequencies of the genetic variants examined did not differ between controls and patients with sentinel pancreatitis. The frequencies of the PRSS1 p.R122H mutation, SPINK1 p.N34S variant, and PRSS3 p.E32del variant, but not other genetic variants, were higher in patients with recurrent attacks than in controls or those with a sentinel attack. CONCLUSIONS: The PRSS1 p.R122H mutation, SPINK1 p.N34S, and PRSS3 p.E32del variants were associated with recurrent, but not sentinel AP. The genetic background could possibly be different between sentinel and recurrent AP. PMID- 21303408 TI - Serum pepsinogen II: a neglected but useful biomarker to differentiate between diseased and normal stomachs. AB - BACKGROUND AND AIM: Serum pepsinogen II (sPGII) is underutilized and considered an inconspicuous biomarker in clinical practice. We refocused on this neglected but novel biomarker and conducted the present study, aiming to elucidate the normal level of sPGII in healthy Chinese patients and to investigate the clinical utility of sPGII for gastric disease screening. METHODS: In 2008-2009, a total of 2022 participants from northern China were selected and enrolled in the study. sPGII and Helicobacter pylori (H. pylori)-immunoglobulin G were measured with ELISA. RESULTS: sPGII showed a normal value of 6.6 microg/L in a total of 466 patients with endoscopically- and histologically-normal stomachs. A small sex difference was observed: the average value of sPGII was 7 microg/L and 6 microg/L in males and females, respectively (P < 0.001). In the differentiation between healthy and diseased (endoscopically-diseased stomach or gastritis/atrophic gastritis in endoscopic biopsies) stomach mucosae, the best sPGII cut-off value was 8.25 microg/L (sensitivity 70.6%, specificity 70.8%). In screening the H. pylori seropositivity, the optimum cut-off sPGII value was 10.25 microg/L (sensitivity 71.6%, specificity 70.1%). CONCLUSIONS: We demonstrated that the mean values of sPGII in a healthy Chinese population are 7 microg/L and 6 microg/L for males and females, respectively. sPGII significantly increases in diseased and H. pylori-infected stomach, and the best sPGII cut-off value is 8.25 microg/L in the differentiation between patients with healthy and diseased stomach mucosae. Furthermore, Chinese patients with sPGII greater than 10.25 microg/L are at greater risk of various H. pylori-related gastropathies, and are therefore prior candidates for gastro-protection therapy. PMID- 21303409 TI - LMP2/LMP7 gene variant: a risk factor for intestinal Mycobacterium tuberculosis infection in the Chinese population. AB - BACKGROUND AND AIMS: Low molecular mass protein-2 (LMP2) and low molecular mass protein-7 (LMP7) genes play a critical role in foreign antigen processing on the major histocompatibility complex-I CD8(+) cytotoxic T-lymphocyte pathway. This study was designed to investigate whether the sequence variants in the LMP2/LMP7 coding region were associated with intestinal Mycobacterium tuberculosis (M. tuberculosis) infection or with the co-infection of pulmonary tuberculosis. METHODS: A total of 168 patients with intestinal tuberculosis and 235 normal controls were recruited for this study. Two polymorphisms of LMP2 (Arg60-His) and LMP7 (Gln145-Lys) were identified by polymerase chain reaction-restriction fragment length polymorphism method. The associations of the LMP2/LMP7 genotype and haplotype with intestinal M. tuberculosis infection were assessed by using logistic regression analysis. RESULTS: The results revealed that LMP7 position codon 145 Lys/Lys and Gln/Lys alleles in the coding region were associated with the infection of intestinal M. tuberculosis (P=0.003, odds ratio [OR]= 3.86 and P < 0.001, OR = 2.28, respectively). Meanwhile, the Arg-Lys and Cys-Lys haplotypes exhibited significant relation to the intestinal M. tuberculosis infection (P= 0.006, OR=1.87; P=0.021, OR=1.83, respectively). No significant associations were observed for any of the single-nucleotide polymorphism genotypes or haplotypes with the co-infection of pulmonary tuberculosis (P > 0.05). CONCLUSIONS: The results indicated that the genetic variant within the LMP2/LMP7 gene would increase the risk of intestinal M. tuberculosis infection. PMID- 21303410 TI - Inferior vena cava filter migration to the right ventricle. AB - Inferior vena cava (IVC) filter placement is recommended for acute proximal deep venous thrombosis if anticoagulation is contraindicated. A 52-year-old man presented with weakness, dyspnea, syncope, and renal failure 8 months after IVC filter placement. Imaging revealed migration of the IVC filter to the right ventricle. Endovascular retrieval was not feasible, thus surgical extraction and tricuspid valve repair was performed. IVC filter migration to the heart is a rare, but a potentially life-threatening complication. Retrieval can be accomplished using endovascular or open surgical technique. PMID- 21303411 TI - Assessment of EuroSCORE in patients undergoing aortic valve replacement. AB - AIMS: The logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation) is a risk stratification system used to predict the operative risk in patients undergoing surgical aortic valve replacement (AVR). The aim of this study is to investigate how accurate this system is, and how it compares to the observed risk. METHODS AND RESULTS: From January 1, 2004 through December 31, 2009, 1389 patients underwent AVR +/- coronary artery bypass grafting (CABG) (865 primary isolated AVR and 524 AVR + CABG) at the New Royal Infirmary Edinburgh. The logistic EuroSCORE was calculated for each patient and summed up for expected in-hospital mortality. Expected and observed mortalities were compared. On the whole, the in-hospital mortality was 3% and was overestimated by the logistic EuroSCORE that predicted 7.2% mortality (p = 0.05). This discrepancy was even more pronounced in high-risk patients, where the in-hospital mortality was 8%, while the logistic EuroSCORE predicted 19.5% (p = 0.03). CONCLUSION: The logistic EuroSCORE overestimates the risks for AVR. Therefore, it should not be used to deny high-risk patients a surgical AVR. PMID- 21303412 TI - Surgical and transcatheter closure of right pulmonary artery to left atrial fistula. AB - BACKGROUND AND AIM OF THE STUDY: Right pulmonary artery to left atrium fistula is a very rare cardiac malformation. We sought to describe our experience with surgical and transcatheter treatment of this defect in three cases. MATERIAL AND METHODS: Between October 2000 and October 2009, three patients with right pulmonary artery to left atrial fistula were treated at our institute. They were all males and aged 23, 7, and 14, respectively. They presented with cyanosis with clubbing of fingers and toes in three cases, and exertional dyspnea in two. Laboratory tests showed elevated hemoglobin and decreased systemic arterial oxygen saturation. Preoperative diagnosis was made by echocardiography and cardioangiography. The fistula was closed surgically in two patients either by simple ligation without cardiopulmonary bypass or by suture of the fistula from inside the right pulmonary artery lumen under cardiopulmonary bypass. In the third patient, the fistula was occluded with an 18-mm Amplatzer septal occluder (AGA Medical, Plymouth, MN, USA). RESULTS: The systemic oxygen saturation rose up to above 96% immediately after the procedures. No operative or procedural complication and late deaths occurred. All three patients were asymptomatic on follow-up. CONCLUSIONS: Both surgical and transcatheter closure are safe and reliable treatment for patients with right pulmonary artery to left atrial fistula. The treatment should be individualized and performed as soon as the diagnosis is made. PMID- 21303413 TI - Serum phosphate and outcome at one year after deceased donor renal transplantation. AB - Traditional risk factors do not adequately explain the increased prevalence of cardiovascular disease in renal patients. This study considered a "non traditional" risk factor, serum phosphate and outcome in renal transplant recipients. Data from 377 patients who received a first deceased donor renal transplant between January 1, 1999, and December 31, 2008, were recorded; 10% (n=38) had diabetes, 16.7% (n=63) were smokers, and 18.8% (n=71) had a history of vascular disease. Three hundred and thirty-three patients were alive at the time of the analysis. Survivors were significantly younger, less likely to be smokers or diabetic, and had a higher estimated glomerular filtration rate at one yr post transplantation. Serum phosphate was significantly lower in these patients (0.95 +/- 0.23 vs. 1.04 +/- 0.26, p = 0.031). Analysis of recipient survival, stratified by serum phosphate at one yr post-transplant, revealed that serum phosphate > 1.11 mMol/L was a significant predictor of all-cause mortality (p=0.006). Serum phosphate between 0.9 and 1.11 mMol/L afforded the best outcome. In multivariate analysis, serum phosphate remained a significant predictor of mortality (p=0.016). Serum phosphate at one yr after transplant seems to have a J shaped relationship with mortality, and this effect is independent of traditional cardiovascular risk factors. PMID- 21303414 TI - Donor risk score and baseline biopsy CADI value predict kidney graft outcome. AB - Different donor parameters and baseline biopsy have been used to assess the quality of donor organs. There is, however, no consensus which risk factors and chronic changes in the donor kidney can be accepted for transplantation. The study included 481 deceased organ donors and their 829 kidney recipients transplanted during 1995-2005. The biopsies were re-evaluated according to the Banff 97 classification. The prognostic significance of donor risk factors and Chronic Allograft Damage Index (CADI) was analyzed. We propose a new donor risk score, calculated as the count of positive risk factors from a defined set of factors in the medical history of the donor. This donor risk score predicts histological quality of the kidney, graft function, and survival. Transplantations from donors with donor risk score >4 had significantly decreased graft survival compared to those with donor risk scores 0-4; the five-yr death censored graft survivals were 83% vs. 93%, respectively. High donor CADI score (>3) was associated with worse graft function and survival. Three-yr glomerular filtration rate declined from 82 to 49 mL/min with donor CADI increase from 0 to >=4. Our results show that high donor risk score and CADI value reflect low functional reserve and risk for poor graft outcome. PMID- 21303415 TI - Extended criteria donors in liver transplant candidates with hepatorenal syndrome. AB - Hepatorenal syndrome (HRS) is a complication of cirrhosis with a poor prognosis without transplantation. The aim of this study is to analyze the influence of extended criteria donors (ECD) on the postoperative outcome of recipients with HRS. The last 498 patients were divided according to pre-transplant type 1 or 2 HRS. Sixty-six (13.25%) recipients fulfilled HRS criteria. Three-month graft survival was 84% with at-listing recipient serum creatinine ranging from 0-0.8 mg/dL; 80% with s-creatinine = 0.9-1.5 mg/dL; 79% with s-creatinine = 1.6-2.5 mg/dL; and 58% with s-creatinine >2.6 mg/dL (log-rank = 18.039; p = 0.001). Recipients with HRS presented higher levels of pre-transplant creatinine and lower levels of sodium, more episodes of hemodialysis and ascitis, and higher model of end-stage liver disease-scores. Three-month graft survival in recipients with HRS relative to ECD-variables showed differences in univariate analysis according to graft steatosis (85% in absent steatosis = 0-10%; 78% in mild steatosis = 10-30%; 76% in moderate steatosis = 30-60%; and 49% when severe steatosis >60%; log-rank = 5.146; p = 0.023). Cox-proportional-hazard-model revealed that graft macrosteatosis per-30%-increments (p = 0.000; HR = 1.303 [1.24-1.33] per-30%-increment) and donors >65 yr (p = 0.089; HR = 1.622 [1.17 1.94]) were independent predictors of graft loss in recipients with HRS. In conclusion, the use of ECD in recipients with cirrhosis and HRS is a good option. However, grafts from moderate-to-severe steatosis and those from aged donors must be carefully allocated in candidates with HRS. PMID- 21303416 TI - Surveillance of megakaryocytic function by measurement of CD61-exposing microparticles in allogeneic hematopoietic stem cell recipients. AB - Increasing evidence suggests that circulating microparticles (MP) exposing CD61 originate predominantly from megakaryocytes. Dramatic changes in megakaryocytic homeostasis are regularly observed following allogeneic hematopoietic stem cell transplantation (HSCT) and associated with transplantation-associated complications. We studied MP plasma levels prospectively in healthy subjects (n = 10) and allogeneic HSCT recipients (n = 19) twice weekly from the start of conditioning therapy up to day 30. A total of 224 measurement points were evaluated. MP were isolated, double-stained with annexin V and anti-CD61, and analyzed by flow cytometry. In uncomplicated HSCT, we found a correlation between platelet and CD61-exposing MP count, which resulted in a constant ratio of MP per platelet. The ratio was increased in patients with active hematological malignancies before transplantation and normalized during conditioning therapy. After take, the MP ratio increased, whereas infections and microangiopathic hemolytic anemia did not affect the ratio. In patients with GvHD, a decreased MP ratio was observed depending on the grade of GvHD, possibly indicating megakaryocytic damage. The MP ratio was able to discriminate between toxic, septic, and GvHD-induced hyperbilirubinemia. We first describe CD61+ MP levels during allogeneic HSCT and postulate that the MP ratio might be a useful biomarker for the surveillance of megakaryocytes during HSCT. PMID- 21303417 TI - Long-term effects on renal function of dose-reduced calcineurin inhibitor and sirolimus in cardiac transplant patients. AB - Calcineurin inhibitor (CNI)-associated renal insufficiency is common after cardiac transplantation (CTX); however, the addition of sirolimus allows for CNI dose reduction and this strategy may limit CNI renal toxicity. This study examines the long-term effects of such a strategy. METHODS: Patients from a single center who had CTX from 1990 to 2007 and who were converted to sirolimus and a dose-reduced CNI were compared to group-matched controls maintained on CNI and an antiproliferative agent. RESULTS: One hundred and fifty-five patients (79 sirolimus and 76 controls) were included and had similar baseline characteristics. Sirolimus was started a mean of 1429 d post-CTX and maintained for a mean of 823 d. Reason for conversion to sirolimus was renal insufficiency (34%), vasculopathy (29%), recurrent rejection (19%), and other (18%). The eGFR was not different between groups at baseline (44.7 mL/min/1.73 m(2) vs. 46.0, p = 0.64) or at any point during follow-up: 90 d, 180 d, 1 yr, 2 yr, and 3 yr. conclusion: Patients converted to a regimen of sirolimus and a dosed-reduced CNI have stable renal function over the following three yr, but do not have an improvement in renal outcomes compared to patients maintained on full dose CNI. PMID- 21303418 TI - Enhancing bone formation by transplantation of a scaffold-free tissue-engineered periosteum in a rabbit model. AB - OBJECTIVES: The periosteum plays an important role in bone regeneration. However, the harvesting of autogenous periosteum is associated with disadvantages such as donor site morbidity and limited donor sources. This study uses an osteogenic predifferentiated cell sheet to fabricate a scaffold-free tissue-engineered periosteum (TEP). MATERIAL AND METHODS: We generated an osteogenic predifferentiated cell sheet from rabbit bone marrow stromal cells (BMSCs) using a continuous culture system and harvested it using a scraping technique. Then, the in vitro characterization of the sheet was investigated using microscopy investigation, quantitative analysis of alkaline phosphatase (ALP) activity, and RT-PCR. Next, we demonstrated the in vivo osteogenic potential of the engineered sheet in ectopic sites together with a porous beta-tricalcium phosphate ceramic. Finally, we evaluated its efficiency in treating delayed fracture healing after wrapping the cell sheet around the mandible in a rabbit model. RESULTS: The engineered periosteum showed sporadic mineralized nodules, elevated ALP activity, and up-regulated gene expression of osteogenic markers. After implantation in the subcutaneous pockets of the donor rabbits, the in vivo bone-forming capability of the engineered periosteum was confirmed by histological examinations. Additionally, when wrapping the engineered periosteum around a mandibular fracture gap, we observed improved bone healing and reduced amounts of fibrous tissue at the fracture site. CONCLUSION: The osteogenic predifferentiated BMSC sheet can act as a scaffold-free TEP to facilitate bone regeneration. Hence, our study provides a promising strategy for enhancing bone regeneration in clinical settings. PMID- 21303419 TI - Assessment of mini-implant displacement using cone beam computed tomography. AB - OBJECTIVES: To assess, through cone beam computed tomography (CBCT), the mini implants' stability and behaviour when submitted to orthodontic force during upper molars' intrusion. MATERIAL AND METHODS: Forty-one mini-implants were divided into two groups: 30 in the buccal and palatal mini-implants group (BPMI), inserted into buccal and palatal sides, and 11 in the midpalatal mini-implants group (MPMI), inserted into midpalatal suture. One day after insertion, a 200 gf was applied on the mini-implants during a 5-month period. CBCT was performed twice: before force application (CBCT 1) and 5 months later (CBCT 2). For mini implant displacement assessment, the distance of mini-implants' head (HMI) and tail (TMI) to coronal, sagittal and axial planes was measured at CBCT 1 and 2. RESULTS: For the BPMI group, the displacement rate was statistically significant (P<0.05) in all three dimensions for both the head and the tail. For the MPMI group, the displacement rate was statistically significant (P<0.05) only in the antero-posterior (head and tail) and vertical (head) dimensions. CONCLUSIONS: Buccal, palatal and midpalatal mini-implants showed some displacement (mean value <=0.78) when submitted to force, although they are aimed to provide stable skeletal anchorage. PMID- 21303420 TI - The effect of SLActive surface in guided bone formation in osteoporotic-like conditions. AB - OBJECTIVES: The aim of the study was to evaluate new bone formation under etched titanium (SLA) and modified-etched hydrophilic titanium (modSLA) domes placed on the calvarium of healthy, osteoporotic and osteoporotic treated with bisphosphonates rabbits. METHODS: Experimental osteoporosis was induced by ovariectomy (OV) and calcium-deficient diet in 24 New Zealand female rabbits. Twelve OV rabbits were treated with weekly dozes of alendronate (Fosamax((r))) (B) while 12 OV rabbits received no treatment (O). Another 12 rabbits were sham operated and used as healthy controls (C). At 6 weeks following OV, one modSLA and one SLA titanium dome were placed in the parietal bones of each rabbit. The animals were sacrificed at 30 and 120 days following the dome placement. Various histomorphometric measurements were performed in the most central of the undecalcified sections produced. RESULTS: After 30 days of healing, in the C group, the total bone (TB) area was 37.6% and 37.0% under the modSLA and SLA domes, respectively. In the O group, the TB was 35.7% and 24.8%. In the B group, TB was 37.0% and 32.1%, respectively. After 120 days of healing, in the C group TB was 40.1% and 36.4%, respectively. In the O group, TB was 29.6% and 27.9%, respectively. In the B group, TB was 49.7% and 42.5%, respectively. Hierarchical analysis of variance showed that the type of titanium dome significantly influenced new bone and the amount of new bone being in contact with inner surface of the dome (BIC) independently of the observation period and group (P<0.05). The administration of bisphosphonates influenced the BIC (P<0.05). CONCLUSION: The use of modSLA surface may promote bone healing and osseointegration in osteoporotic rabbits, whereas administration of bisphosphonates may compromise the osseointegration of the newly formed bone at the early healing period. PMID- 21303421 TI - Effects of ginseng on Pseudomonas aeruginosa motility and biofilm formation. AB - Biofilm-associated chronic Pseudomonas aeruginosa lung infections in patients with cystic fibrosis are virtually impossible to eradicate with antibiotics because biofilm-growing bacteria are highly tolerant to antibiotics and host defense mechanisms. Previously, we found that ginseng treatments protected animal models from developing chronic lung infection by P. aeruginosa. In the present study, the effects of ginseng on the formation of P. aeruginosa biofilms were further investigated in vitro and in vivo. Ginseng aqueous extract at concentrations of 0.5-2.0% did not inhibit the growth of P. aeruginosa, but significantly prevented P. aeruginosa from forming biofilm. Exposure to 0.5% ginseng aqueous extract for 24 h destroyed most 7-day-old mature biofilms formed by both mucoid and nonmucoid P. aeruginosa strains. Ginseng treatment enhanced swimming and twitching motility, but reduced swarming of P. aeruginosa at concentrations as low as 0.25%. Oral administration of ginseng extracts in mice promoted phagocytosis of P. aeruginosa PAO1 by airway phagocytes, but did not affect phagocytosis of a PAO1-filM mutant. Our study suggests that ginseng treatment may help to eradicate the biofilm-associated chronic infections caused by P. aeruginosa. PMID- 21303422 TI - Effects of the presence of hypertension on the relationship between obstructive sleep apnoea and sleepiness. AB - Obstructive sleep apnoea (OSA) plays a significant role in increasing blood pressure. Significant decreases were reported in blood pressure of hypertensive OSA patients with sleepiness who underwent continuous positive airway pressure (CPAP) treatment, but not in non-sleepy hypertensive OSA patients. More recently, however, significant decreases in blood pressure in non-sleepy hypertensive OSA patients following CPAP were shown. Effects of sleepiness on hypertension in OSA patients have been investigated, but not the effects of hypertension on sleepiness in OSA patients. We investigated the relationships between hypertension and sleepiness in patients with OSA. We analysed data on 275 middle aged male subjects from a cross-sectional epidemiological health survey. We measured blood pressure and sleep duration objectively using an actigraph for 7 days and the respiratory disturbance index (RDI) with a type 3 portable device for 2 nights, and assessed sleepiness using the Epworth Sleepiness Scale (ESS). The RDI correlated significantly with ESS scores in the 88 hypertensive subjects (r = 0.33, P = 0.0024), but not in the 187 non-hypertensive subjects (r = -0.01, P = 0.91). Short sleep duration correlated significantly with ESS scores in both groups. Both the RDI and short sleep duration were related independently to sleepiness in only hypertensive subjects. Furthermore, the RDI was related negatively significantly to sleep duration in hypertensive subjects. Although short sleep duration was related significantly to sleepiness in both groups, hypertension may be important for the sleepiness in OSA patients. Detailed mechanisms of the difference in the relationship between sleepiness and the severity of OSA with or without hypertension should be studied further. PMID- 21303423 TI - Management of asymptomatic hyperuricaemia in patients with chronic kidney disease by Japanese nephrologists: a questionnaire survey. AB - AIM: Hyperuricaemia is associated with chronic kidney disease (CKD) progression and cardiovascular events (CVE). In a US study, only 4% of rheumatologists initiated urate-lowering therapy in patients with asymptomatic hyperuricaemia (AHU). The present study aimed to clarify how Japanese board-certified nephrologists manage AHU in CKD patients. METHODS: Questionnaires on management of AHU in CKD stage 3 or more were mailed to 1500 Japanese board-certified nephrologists, excluding paediatricians and urologists, randomly selected from the directory of the Japanese Society of Nephrology (n = 2976). RESULTS: Five hundred and ninety-five nephrologists (40%) responded. Most nephrologists (84 89%) recommended that AHU in patients in CKD stages 3-5 should be treated, but fewer nephrologists (63%) recommended that AHU in patients of CKD stage 5D should be treated. The serum urate level to start urate-lowering therapy and the target serum urate level to be achieved (mg/dL) were 8.2 +/- 0.9 and 6.9 +/- 0.9, 8.4 +/ 0.9 and 7.0 +/- 1.0, 8.6 +/- 1.0 and 7.3 +/- 1.1, and 9.1 +/- 1.2 and 7.8 +/- 1.3 at stages 3, 4, 5 and 5D, respectively. The most frequently used maximal dosage of allopurinol was 100 mg/day at each stage. Benzbromarone was used in 52% of patients at stage 3, but only in 29%, 13% and 5% of patients at stages 4, 5 and 5D, respectively. The most important reasons to treat AHU at CKD stages 3-5 were prevention of CKD progression (45%), CVE (33%), gout (18%) and urolithiasis (3%). CONCLUSION: Most Japanese nephrologists treat AHU in pre-dialysis CKD with an aim to prevent CKD progression or CVE mainly by allopurinol. PMID- 21303424 TI - Renoprotective efficacy of valsartan in chronic non-diabetic proteinuric nephropathies with renin-angiotensin system gene polymorphisms. AB - AIM: The renoprotective effects of angiotensin receptor blockers vary considerably among individuals. We investigated the renoprotective effects of valsartan according to polymorphisms of the renin-angiotensin system and transforming growth factor-b1 (TGFB1) genes in patients with chronic non-diabetic proteinuric nephropathies. METHODS: Two hundred and thirty-nine non-diabetic patients with proteinuria of at least 1 g/day were enrolled. Patients received 80 g of valsartan daily, followed by 160 mg/day after 6 weeks. The follow-up period was 18 months. The status of the angiotensin-converting enzyme (ACE) insertion/deletion, angiotensinogen (AGT) M235T, type 1 angiotensin II receptor (ATR1) A1166C, and TGFB1 C509 and T869C polymorphisms was determined in 162 patients. RESULTS: Valsartan treatment caused a significant reduction in proteinuria from baseline throughout the study in patients with each genotype of the ACE, AGT and TGFB1 genes. However, patients with the ATR1 AC genotype had no significant reduction in proteinuria from baseline throughout the study course. The median reductions in proteinuria after 6 months were 45.7% and 10.8% in the patients with the ATR1 AA and AC genotypes, respectively (P = 0.034). The annual change in the estimated glomerular filtration rate did not differ significantly among the genotypes for each gene. On multiple regression analysis, the change in proteinuria after 6 months of treatment was independently associated with the ATR1 genotype and the change in blood pressure (P = 0.005 and 0.019, respectively). CONCLUSION: Valsartan treatment significantly reduced the blood pressure and urinary protein excretion of patients with chronic non-diabetic proteinuric nephropathies. Interindividual differences in the anti-proteinuric effect of valsartan may be related partly to the ATR1 A1166C polymorphism. PMID- 21303425 TI - Gene expression of TWEAK/Fn14 and IP-10/CXCR3 in glomerulus and tubulointerstitium of patients with lupus nephritis. AB - AIM: The role of the tumour necrosis factor-like weak inducer of apoptosis (TWEAK)/Fn14 and interferon-inducible protein (IP-10)/CXCR3 axis in the pathogenesis of lupus nephritis were studied. METHODS: The mRNA expression of TWEAK, Fn14, IP-10 and CXCR3 were quantified in the glomerulus and tubulointerstitium of 42 patients with lupus nephritis (LN group) and 10 healthy controls. RESULTS: As compared to controls, LN patients had higher glomerular expression of TWEAK and Fn14, but glomerular CXCR3 expression was lower in the LN group. Similarly, the LN group had higher tubulointerstitial expression of TWEAK and Fn14, but lower tubulointerstitial expression of CXCR3, than controls. Glomerular TWEAK expression of class V nephritis was significantly higher than class IV nephritis. Glomerular expression of CXCR3 significantly correlated with proteinuria (r = -0.532; P = 0.019), whereas tubulointerstitial CXCR3 significantly correlated with serum creatinine (r = -0.447; P = 0.029). CONCLUSION: In patients with lupus nephritis, there is an increase in intra-renal expression of TWEAK and Fn14, and a decrease in CXCR3 expression. Intra-renal expression of CXCR3 correlates with proteinuria and renal function. Our findings suggest that the TWEAK/Fn14 and IP-10/CXCR3 axis may contribute to the pathogenesis of lupus nephritis. PMID- 21303426 TI - Genetic predisposition to diffuse panbronchiolitis. AB - Diffuse panbronchiolitis is characterized by chronic inflammation in respiratory bronchioles and sinobronchial infection. The pathophysiology accompanying the persistent bacterial infection is noteworthy for the accumulation of lymphocytes and foamy macrophages around the small airways, for mucus hypersecretion, and for the number of neutrophils in the large airways. Until the establishment of long term macrolide therapy, the prognosis was generally poor. Case studies of diffuse panbronchiolitis in East Asians, including Japanese, Koreans and Chinese, have frequently been reported, and genetic predisposition to the disease has been assumed in Asians. Immunogenetic studies revealed a strong association with human leukocyte antigen (HLA)-B54 in Japanese, whereas an association with HLA-A11 was reported in Koreans. These findings imply that a major susceptibility gene may be located between the HLA-A and HLA-B loci on the short arm of human chromosome 6. We have recently cloned novel mucin-like genes in this candidate region. In addition to accumulated knowledge of classical HLA genes and mucin genes, further analysis of newly identified genes may provide insights into the pathogenesis of the disease. PMID- 21303427 TI - Galanin receptor 3--a potential target for acute pancreatitis therapy. AB - BACKGROUND: Galanin participates in the pathogenesis of acute pancreatitis (AP). The galanin receptor (GALR) sub-types involved, however, are unclear. We aimed to determine GALRs messenger RNA (mRNA) expression in mouse pancreas, describe their localization, and ascertain if GALR2 and GALR3 are involved in AP. METHODS: Galanin receptor expression in murine whole pancreas, acinar, and islet cells was quantified by polymerase chain reaction amplification of reverse-transcribed RNA for mRNA, Western blot analysis for protein and in situ hybridization for GALR localization. Isolated acinar cells were used to determine galanin's effect on amylase secretion. Acute pancreatitis was induced in mice by caerulein injections. Mice, with and without AP, were treated with the highly selective GALR2 antagonist M871, or the specific GALR3 antagonist SNAP-37889. Indices of AP were measured at 12 h. KEY RESULTS: Murine pancreas expresses mRNA for GALRs. In islets the expression of all GALR are comparable, whereas in acinar cells GALR3 is predominantly expressed. Western blot analysis confirmed that the GALR proteins are expressed by acinar cells. In situ hybridization analysis confirmed that GALR3 mRNA is present in islet and acinar cells, while mRNA for GALR1 and 2 is confined to islets. Galanin did not influence basal and caerulein-stimulated amylase release from acinar cells. M871 treatment reduced some, whereas SNAP 37889 treatment reduced all indices of AP (by 40-80%). CONCLUSIONS & INFERENCES: Galanin receptor mRNA and protein are expressed in mouse pancreas, with GALR3 mRNA predominating. GALR3 antagonism reduced the severity of AP whereas GALR2 antagonism was less effective. GALR3 is a potential target for treatment of AP. PMID- 21303428 TI - The microbiome-gut-brain axis: from bowel to behavior. AB - The ability of gut microbiota to communicate with the brain and thus modulate behavior is emerging as an exciting concept in health and disease. The enteric microbiota interacts with the host to form essential relationships that govern homeostasis. Despite the unique enteric bacterial fingerprint of each individual, there appears to be a certain balance that confers health benefits. It is, therefore, reasonable to note that a decrease in the desirable gastrointestinal bacteria will lead to deterioration in gastrointestinal, neuroendocrine or immune relationships and ultimately disease. Therefore, studies focusing on the impact of enteric microbiota on the host and in particular on the central nervous system are essential to our understanding of the influence of this system. Recent studies published in this Journal demonstrate that germ-free mice display alterations in stress-responsivity, central neurochemistry and behavior indicative of a reduction in anxiety in comparison to conventional mice. Such data offer the enticing proposition that specific modulation of the enteric microbiota may be a useful strategy for stress-related disorders and for modulating the co-morbid aspects of gastrointestinal disorders such as irritable bowel syndrome and inflammatory bowel disease. PMID- 21303429 TI - Effect of motilin on gastric distension sensitive neurons in arcuate nucleus and gastric motility in rat. AB - BACKGROUND: Intestinal motilin is known to stimulate gastrointestinal (GI) motility and the arcuate nucleus (Arc) of hypothalamus is shown to be involved in the regulation of GI motility. METHODS: Single unit discharges in the Arc were recorded extracellularly by implantation of a force transducer into the stomach in rats, to evaluate the effect of motilin on gastric motility. Projection of nerve fiber and expression of motilin were observed by retrograde tracer deposits of Fluoro-Gold (FG) and fluo-immunohistochemistry staining. KEY RESULTS: 65.5% of neurons in Arc responded to gastric distension (GD), 55.6% of which showed excitation (GD-E), and 44.4% showed inhibition (GD-I). After GD, the firing rate of GD-E neurons significantly increased (P<0.01), but decreased for GD-I neurons (P<0.01). Most of both GD-E and GD-I neurons were activated by motilin (P<0.05). The frequency and amplitude of gastric contractions significantly increased by administration of motilin in Arc with a dose dependent manner (P<0.05-0.01). However, pretreatment with GM109 could abolish the responses of neurons and excitatory effect of gastric motility induced by motilin. Motilin immunoreactive neurons were increased in Arc via gastric distention (P<0.05). Motilin/FG-labeled neurons were detected in hypothalamus paraventricular nucleus (PVN). CONCLUSIONS & INFERENCES: Our findings suggest that motilin neurons in Arc may accept peripheral somatosensory afferent inputs from gastric mechanoreceptors of the stomach, and also may acts as a stimulatory factor in Arc to regulate gastric motility via some inferior nucleus relay pathway. The results provide insight into the role of Arc in the control of digestion mediated via motilin. PMID- 21303430 TI - Efficacy and safety of oral lubiprostone in constipated patients with or without irritable bowel syndrome: a randomized, placebo-controlled and dose-finding study. AB - BACKGROUND: Lubiprostone is a prostone analog with a novel mechanism of action involving type-2 chloride channel activation. The aim of this work was to perform a dose-finding study for lubiprostone for the treatment of constipation with or without irritable bowel syndrome (IBS) in Japan. METHODS: A total of 170 patients (128 without IBS and 42 with IBS) with chronic idiopathic constipation (CIC) randomly received a placebo (n=42) or 16MUg (n=41), 32MUg (n=43), or 48MUg (n=44) of lubiprostone daily for 2weeks. KEY RESULTS: There was a statistically significant and dose-dependent increase in change from baseline in the weekly average number of spontaneous bowel movements at week 1 (placebo: 1.5+/-0.4; 16MUg: 2.3+/-0.4, 32MUg: 3.5+/-0.5; and 48MUg: 6.8+/-1.1, per week, mean+/-SE; P<0.0001). These primary endpoint results were significant on stratified analysis when patients were limited to those without IBS (P<0.0001). The primary endpoint in patients with IBS treated with 48MUg of lubiprostone was significantly better than those given placebo (P=0.0086). Dose dependency was also seen for the secondary efficacy endpoints. Lubiprostone produced no serious side effects. CONCLUSIONS & INFERENCES: Our results suggest that lubiprostone produced a steady and effective improvement in the symptoms of CIC with or without IBS in a dose dependent manner with a good safety profile and tolerability in a Japanese population. PMID- 21303431 TI - High-resolution manometric characteristics help differentiate types of distal esophageal obstruction in patients with peristalsis. AB - BACKGROUND: High-resolution manometry (HRM) can identify obstructive motor features at the esophagogastric junction and abnormalities in esophageal bolus transit. We sought to determine if HRM patterns can differentiate functional from organic mechanical lower esophageal sphincter (LES) obstruction. METHODS: Segmental characteristics of peristalsis were examined using HRM in symptomatic subjects with elevated postdeglutitive residual pressure gradients across the LES (>=5mmHg). Sixteen consecutive patients with non-achalasic mechanical fixed obstruction were compared with 13 patients with elevated pressure gradients yet no mechanical obstruction and 14 asymptomatic controls. Pressure volumes were determined in mmHg cm s for peristaltic segments defined on HRM Clouse plots using an on-screen pressure volume measurement tool. KEY RESULTS: Residual pressure gradients were similarly elevated in both patient groups. A visually conspicuous and distinctive shift in the proportionate pressure strengths of the second and third peristaltic segments was apparent across groups. Whereas the ratios of peak pressures and pressure volumes between second and third segments approached 1 in controls (0.92, 0.98), pressures shifted to the second segment in mechanical obstruction (peak pressure ratio: 1.2+/-0.4; pressure volume ratio: 1.8+/-0.9) and to the third segment in functional obstruction (peak ratio: 0.7+/ 0.2; volume ratio: 0.5+/-0.2; P<0.02 for any comparison of either group with controls). A threshold volume ratio of 1.0 correctly segregated 93% of obstruction (P<0.0001); visual pattern inspection was equally effective. CONCLUSIONS & INFERENCES: When elevated residual pressure gradients are present in non-achalasic patients, topographic characteristics of peristalsis can differentiate fixed mechanical obstruction from functional obstruction. PMID- 21303433 TI - Novel model of peripheral tissue trauma-induced inflammation and gastrointestinal dysmotility. AB - BACKGROUND: Trauma is a leading cause of death and although the gut is recognized as the 'motor' of post-traumatic systemic inflammatory response syndrome and multiple organ failure, studies on the gastrointestinal (GI) tract are few. Our objectives were to create a precisely controllable tissue injury model in which GI motility, systemic inflammation and wound fluid can be analyzed. METHODS: A non-narcotic murine trauma model was developed by the subcutaneous dorsal trans implantation of a devitalized donor syngeneic harvested tissue-bone matrix (TBX), which was precisely adjusted to % total body weight and studied after 21 h. Gastrointestinal transit histograms were plotted after the oral administration of non-digestible FITC-dextran and geometric centers calculated. Organ bath evaluated jejunal circular muscle contractility. Multiplex electrochemiluminescence measurements of serum and TBX wound fluid inflammatory mediators were performed. KEY RESULTS: Increasing TBX amounts progressively delayed transit, whereas TBX heat denaturation or decellularization prevented ileus and death. In the TBX(17.5%) model, jejunal muscle contractility was suppressed and a systemic inflammatory response developed as significant serum elevations in IL-6, keratinocyte cytokine and IL-10 compared to sham. In addition, inflammatory responses within the wound fluid showed elevated levels of preformed IL-1beta and TNF-alpha, whereas, 21 h after implantation IL-1beta, IL-6 and keratinocyte cytokine were significantly increased in the wound. CONCLUSIONS & INFERENCES: A novel donor tissue-bone matrix trauma model was developed that is precisely adjustable and recapitulates important clinical phenomena. The non narcotic model demonstrated that increasing tissue injury progressively caused ileus, initiated a systemic inflammatory response and developed inflammatory changes within the wound. PMID- 21303432 TI - Intestinal glucose-induced calcium-calmodulin kinase signaling in the gut-brain axis in awake rats. AB - BACKGROUND: Lumenal glucose initiates changes in gastrointestinal (GI) function, including inhibition of gastric emptying, stimulation of pancreatic exocrine and endocrine secretion, and intestinal fluid secretion. Glucose stimulates the release of GI hormones and 5-hydroxytryptamine (5-HT), and activates intrinsic and extrinsic neuronal pathways to initiate changes in GI function. The precise mechanisms involved in luminal glucose-sensing are not clear; studying gut endocrine cells is difficult due to their sparse and irregular localization within the epithelium. METHODS: Here we show a technique to determine activation of gut epithelial cells and the gut-brain pathway in vivo in rats using immunohistochemical detection of the activated, phosphorylated, form of calcium calmodulin kinase II (pCaMKII). KEY RESULTS: Perfusion of the gut with glucose (60 mg) increased pCaMKII immunoreactivity in 5-HT-expressing enterochromaffin (EC) cells, cytokeratin-18 immunopositive brush cells, but not in enterocytes or cholecystokinin-expressing cells. Lumenal glucose increased pCaMKII in neurons in the myenteric plexus and nodose ganglion, nucleus of the solitary tract, dorsal motor nucleus of the vagus and the arcuate nucleus. pCaMKII expression in neurons, but not in EC cells, was significantly attenuated by pretreatment with the 5-HT(3) R antagonist ondansetron. Deoxynojirimycin, a selective agonist for the putative glucose sensor, sodium-glucose cotransporter-3 (SGLT-3), mimicked the effects of glucose with increased pCaMKII in ECs and neurons; galactose had no effect. CONCLUSIONS & INFERENCES: The data suggest that native EC cells in situ respond to glucose, possibly via SGLT-3, to activate intrinsic and extrinsic neurons and thereby regulate GI function. PMID- 21303434 TI - Cannabinoid-induced delayed gastric emptying is selectively increased upon intermittent administration in the rat: role of CB1 receptors. AB - BACKGROUND: Cannabinoids acutely administered depress central, cardiovascular and gastrointestinal functions. These effects might be modified upon repeated administration. Compared to the effects induced by daily administration, those induced by intermittent administration are less known. The effect of intermittent treatment with the CB1/CB2 cannabinoid agonist WIN55,212-2 (WIN) was studied in the rat. METHODS: Male rats received saline, vehicle or WIN at 0.5 (low-WIN) or 5 (high-WIN) mg kg(-1) week(-1) for 4 weeks. WIN effects on the central nervous system (cannabinoid tetrad tests), cardiovascular function and gastrointestinal motor function were evaluated after the first and last doses, and, where appropriate, 1 week after the last dose. To determine the involvement of CB1 receptors in the chronic effect of WIN, the CB1 receptor antagonist/inverse agonist AM251 (1 mg kg(-1)) was used. KEY RESULTS: High- (but not low-) WIN induced the four signs of the cannabinoid tetrad, and reduced gastrointestinal motility, but did not alter cardiovascular parameters. Upon chronic intermittent administration, tolerance did not clearly develop to WIN effects. Quite the opposite, depression of gastric emptying was intensified. No effect was long lasting. Repeated administration of AM251 was more efficacious than single administration to block WIN chronic central effects, but the opposite occurred regarding lower intestinal motility. CONCLUSIONS & INFERENCES: Upon intermittent administration, hypersensitization may develop to some effects (particularly delayed gastric emptying) induced by cannabinoid agonists. CB1 antagonists/inverse agonists may show different efficacy upon repeated or single administration to block cannabinoid-induced central and gastrointestinal effects. Thus, cannabinoid effects are dependent on the pattern of drug administration. PMID- 21303435 TI - Clinical results and issues of acute myeloid leukemia in elderly patients aged 75 years and older. AB - AIM: Clinical outcomes of acute myeloid leukemia (AML) in elderly patients still remain unsatisfactory and the optimal treatment has yet to be clearly established. This report describes the results of a retrospective study of clinical outcomes and prognostic factors of AML in patients aged 75 years and older. In addition, we aimed to elucidate the situation of patients with AML accompanied by dementia, which has been largely ignored in previous studies. METHODS: The subjects consisted of 31 patients with untreated AML (including previous myelodysplastic syndrome: AML/MDS). All patients underwent chemotherapy, with 25 undergoing conventional therapy and six undergoing low-intensity therapy. RESULTS: Complete remission was obtained in 16 of the 31 cases (51.6%), with a 3 year survival rate of 11.5%. However, in seven cases, Alzheimer's disease (AD) was observed. Although we were able to perform induction therapy in each of these cases, consolidation therapy was difficult in cases of moderate AD. CONCLUSION: The results of this study suggest that even very elderly patients can benefit from chemotherapy. However, it is thought that the treatment selection for cases which are complicated by moderate to severe dementia should be determined carefully while considering the patient's quality of life. PMID- 21303436 TI - Partitioning global patterns of freshwater fish beta diversity reveals contrasting signatures of past climate changes. AB - Here, we employ an additive partitioning framework to disentangle the contribution of spatial turnover and nestedness to beta diversity patterns in the global freshwater fish fauna. We find that spatial turnover and nestedness differ geographically in their contribution to freshwater fish beta diversity, a pattern that results from contrasting influences of Quaternary climate changes. Differences in fish faunas characterized by nestedness are greater in drainage basins that experienced larger amplitudes of Quaternary climate oscillations. Conversely, higher levels of spatial turnover are found in historically unglaciated drainage basins with high topographic relief, these having experienced greater Quaternary climate stability. Such an historical climate signature is not clearly detected when considering the overall level of beta diversity. Quantifying the relative roles of historical and ecological factors in explaining present-day patterns of beta diversity hence requires considering the different processes generating these patterns and not solely the overall level of beta diversity. PMID- 21303439 TI - Modulating effects of acepromazine on the reactive oxygen species production by stimulated equine neutrophils. AB - OBJECTIVE: To investigate the effect of acepromazine (ACP) on reactive oxygen species (ROS) production by stimulated equine neutrophils. STUDY DESIGN: Ex vivo biochemical experiments. ANIMALS: Isolated neutrophils from healthy untreated horses. METHODS: Neutrophils were incubated with ACP at concentrations of 10(-4), 10(-5) or 10(-6) M and then stimulated with phorbol-myristate-acetate (PMA) before measurement of lucigenin-enhanced chemiluminescence (CL). In a second experiment neutrophils were incubated in the presence of alpha-keto-gamma methylthiobutyric acid (KMB) and treated with ACP at concentrations of 10(-4), 10(-5) or 10(-6) M. Subsequent PMA stimulation lead to neutrophilic ROS production and decomposition of KMB to ethylene, which is measured by gas chromatography. Electron paramagnetic resonance-spin trapping (EPR) analysis was performed with PMA-stimulated neutrophils in the presence of ACP (10(-4), 10(-5) or 10(-6) M) directly added to the cell suspension. In the second experiment, the same concentrations of ACP were pre-incubated with neutrophils, then centrifuged to eliminate the excess of ACP and re-suspended in phosphate buffer before stimulation with PMA. In all experiments, the results of ACP-treated and ACP untreated stimulated neutrophils were compared. RESULTS: Overall, results obtained with lucigenin-enhanced CL and KMB oxidation were in agreement with those seen in electron paramagnetic resonance spectroscopy. Acepromazine induced a dose-dependent inhibitory effect on neutrophilic ROS production. Electron paramagnetic resonance also showed, at high ACP concentration, the appearance of a cation radical derived from ACP. In contrast, electron paramagnetic resonance study performed with pre-incubated neutrophils showed an important dose-dependent inhibitory effect of ACP. CONCLUSION: The results indicate that ACP can neutralize O.-2 or its by-products during the stimulation of neutrophils. CLINICAL RELEVANCE: These findings may have a therapeutic relevance when phenothiazines are used in horses suffering from inflammatory diseases in which neutrophil activation and ROS production are implicated. PMID- 21303437 TI - Increases in the flux of carbon belowground stimulate nitrogen uptake and sustain the long-term enhancement of forest productivity under elevated CO2. AB - The earth's future climate state is highly dependent upon changes in terrestrial C storage in response to rising concentrations of atmospheric CO2. Here we show that consistently enhanced rates of net primary production (NPP) are sustained by a C-cascade through the root-microbe-soil system; increases in the flux of C belowground under elevated CO2 stimulated microbial activity, accelerated the rate of soil organic matter decomposition and stimulated tree uptake of N bound to this SOM. This process set into motion a positive feedback maintaining greater C gain under elevated CO2 as a result of increases in canopy N content and higher photosynthetic N-use efficiency. The ecosystem-level consequence of the enhanced requirement for N and the exchange of plant C for N belowground is the dominance of C storage in tree biomass but the preclusion of a large C sink in the soil. PMID- 21303440 TI - Effects of 6% hetastarch (600/0.75) or lactated Ringer's solution on hemostatic variables and clinical bleeding in healthy dogs anesthetized for orthopedic surgery. AB - OBJECTIVE: To evaluate and compare hemostatic variables and clinical bleeding following the administration of 6% hetastarch (600/0.75) or lactated Ringer's solution (LRS) to dogs anesthetized for orthopedic surgery. STUDY DESIGN: Randomized blinded prospective study. ANIMALS: Fourteen, healthy adult mixed breed hound dogs of either sex, aged 11-13 months, and weighing 20.8+/-1.2 kg. METHODS: The dogs were randomly assigned to receive a 10 mL kg(-1) intravenous (i.v.) bolus of either 6% hetastarch (600/0.75) or LRS over 20 minutes followed by a maintenance infusion of LRS (10 mL kg(-1) hour(-1)) during anesthesia. Before (Baseline) and at 1 and 24 hours after bolus administration, packed cell volume (PCV), total protein concentration (TP), prothrombin time (PT), activated partial thromboplastin time (APTT), von Willebrand's factor antigen concentration (vWF:Ag), factor VIII coagulant activity (F VIII:C), platelet count, platelet aggregation, colloid osmotic pressure (COP) and buccal mucosal bleeding time (BMBT) were measured. In addition a surgeon who was blinded to the treatments assessed bleeding from the incision site during the procedure and at 1 and 24 hours after the bolus administration. RESULTS: Following hetastarch or LRS administration, the PCV and TP decreased significantly 1-hour post-infusion. APTT did not change significantly compared to baseline in either treatment group, but the PT was significantly longer at 1-hour post-infusion than at 24 hours in both groups. No significant change was detected for vWF:Ag, FVIII:C, platelet aggregation or clinical bleeding in either group. The BMBT increased while platelet count decreased significantly at 1-hour post-infusion in both groups. The COP decreased significantly in both treatment groups 1-hour post-infusion but was significantly higher 1-hour post-infusion in the hetastarch group compared to the LRS group. CONCLUSIONS AND CLINICAL RELEVANCE: At the doses administered, both hetastarch and LRS can alter hemostatic variables in healthy dogs. However, in these dogs undergoing orthopedic surgery, neither fluid was associated with increased clinical bleeding. PMID- 21303441 TI - Evaluation of medetomidine-ketamine and dexmedetomidine-ketamine in Chinese water deer (Hydropotes inermis). AB - OBJECTIVE: To investigate physiological and sedative/immobilization effects of medetomidine or dexmedetomidine combined with ketamine in free-ranging Chinese water deer (CWD). STUDY DESIGN: Prospective clinical trial. ANIMALS: 10 free ranging adult Chinese water deer (11.0+/-2.6 kg). METHODS: Animals were darted intramuscularly with 0.08+/-0.004 mg kg(-1) medetomidine and 3.2+/-0.2 mg kg(-1) ketamine (MK) or 0.04+/-0.01 mg kg(-1) dexmedetomidine and 2.9+/-0.1 mg kg(-1) ketamine (DMK). If the animal was still laterally recumbent after 60 minutes of immobilization, atipamezole was administered intravenously (MK: 0.4+/-0.02 mg kg( 1), DMK: 0.2+/-0.03 mg kg(-1)). Heart rate (HR) respiratory rate (f(R)) and temperature were recorded at 5-minute intervals. Arterial blood was taken 15 and 45 minutes after initial injection. Statistical analysis was performed using Student's t-test or ANOVA. p<0.05 was considered significant. RESULTS: Animals became recumbent rapidly in both groups. Most had involuntary ear twitches, but there was no response to external stimuli. There were no statistical differences in mean HR (MK: 75+/-14 beats minute(-1); DMK: 85+/-21 beats minute(-1)), f(R) (MK: 51+/-35 breaths minute(-1); DMK; 36+/-9 breaths minute(-1)), temperature (MK: 38.1+/-0.7 degrees C; DMK: 38.4+/-0.5 degrees C), blood gas values (MK: PaO(2) 63+/-6 mmHg, PaCO(2) 49.6+/-2.6 mmHg, HCO(3)(-) 30.8+/-4.5 mmol L(-1); DMK: PaO(2) 77+/-35 mmHg, PaCO(2) 45.9+/-11.5 mmHg, HCO(3)(-) 31.0+/-4.5 mmol L( 1)) and biochemical values between groups but temperature decreased in both groups. All animals needed antagonism of immobilization after 60 minutes. Recovery was quick and uneventful. There were no adverse effects after recovery. CONCLUSION AND CLINICAL RELEVANCE: Both anaesthetic protocols provided satisfactory immobilisation. There was no clear preference for either protocol and both appear suitable for CWD. PMID- 21303442 TI - Successful treatment of hyperkalaemic periodic paralysis in a horse during isoflurane anaesthesia. AB - HISTORY: A 3-year-old, 400 kg, gelding Quarter Horse was presented for investigation of epistaxis. PHYSICAL EXAMINATION: The horse was bright, alert and responsive with rectal temperature, heart rate and respiration rate within normal limits. MANAGEMENT: During a second general anaesthetic for surgical treatment of guttural pouch mycosis by balloon-tipped catheter occlusion of the right major palatine artery and ligation of the right external carotid artery, signs consistent with hyperkalaemic periodic paralysis (HYPP) were exhibited. These included concurrent hyperkalaemia, hypercapnoea, sinus tachycardia, and muscle fasciculations in the presence of normothermia. Stress associated with an acute haemorrhage pre-operatively, and intra-operative hypercapnoea may have precipitated the episode. There were no signs of HYPP during a general anaesthetic, 1 week earlier, when an initial attempt at surgical treatment of guttural pouch mycosis was performed. Treatment consisted of fluid therapy and administration of calcium gluconate (0.1-0.2 mg kg(-1) minute(-1)), dextrose 5% (5 mL kg(-1) hour(-1)) and insulin (0.05 IU kg(-1)). Treatment resulted in the resolution of clinical signs and an uneventful recovery. FOLLOW-UP: The diagnosis of HYPP was confirmed by DNA analysis post-operatively. CONCLUSIONS: Clinical cases of intra-operative HYPP can present despite a previous history of uneventful general anaesthesia. Rapid diagnosis and treatment can result in the successful management of HYPP. This report documents an unusual presentation of HYPP, a disease that remains present in the Quarter Horse population. PMID- 21303443 TI - Effects of epidural morphine on gastrointestinal transit in unmedicated horses. AB - OBJECTIVE: To evaluate the effect of epidural morphine on gastrointestinal (GI) motility in horses. STUDY DESIGN: Randomly ordered crossover design. ANIMALS: Six healthy adult horses weighing 585+/- 48 kg (mean+/-SD). METHODS: Horses were randomly assigned to receive either 0.2 mg kg(-1) morphine or an equal volume (0.04 mL kg(-1)) of saline epidurally (the first inter coccygeal space) with 2 weeks between treatments. The horses were stabled, fed a standardized diet and allowed water ad libitum throughout the duration of the study. Radiopaque spheres were administered by stomach tube. Xylazine 0.2 mg kg(-1) intravenously was administered prior to epidural injection. Heart rate, respiratory rate, GI sounds score and behavior score were recorded before drug administration and after epidural injection at 4, 8, 12, 18, 24 hours and every 12 hours thereafter for 6 days. Feces were weighed, radiographed and the number of spheres counted. Data were analyzed using a mixed effect model. RESULTS: At no time did horses exhibit signs of colic or show significant differences between treatments regarding heart rate, respiratory rate, GI sounds score, behavior score, or cumulative number of spheres. The concentration of spheres per kg of feces was significantly lower (p<0.05) for the morphine group at 18 and 24 hours. Using the centroid of the curves (spheres kg(-1) plotted versus time) the average transit time after saline epidural was 38 hours and after morphine it was 43 hours. The weight of feces hour(-1) was significantly lower (p<0.05) at only 4 and 8 hours after morphine. CONCLUSIONS AND CLINICAL RELEVANCE: Epidural morphine, at a dose of 0.2 mg kg(-1) , temporarily reduced GI motility but did not cause ileus or colic in this small group of healthy unfasted horses. Care should be taken when extrapolating these data to situations in which other factors may also affect GI motility. PMID- 21303444 TI - Comparison of the cytotoxic effects of bupivacaine, lidocaine, and mepivacaine in equine articular chondrocytes. AB - OBJECTIVE: To compare the chondrotoxicity of bupivacaine, lidocaine, and mepivacaine in equine articular chondrocytes in vitro. STUDY DESIGN: Prospective, experimental study. STUDY MATERIAL: Equine articular chondrocytes. METHODS: Primary cultured equine chondrocytes were exposed to 0.5% bupivacaine, 2% lidocaine, or 2% mepivacaine for 30 or 60 minutes. After treatment, cell viability was evaluated by trypan blue exclusion and the 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay in a dose dependent manner. Apoptosis and necrosis of chondrocytes were analyzed with the double staining of Hoechst 33258 and propidium iodide using fluorescence microscopy, and the results were confirmed using flow cytometry. RESULTS: After 30-minute exposure, trypan blue exclusion assay revealed that cell viability of 0.5% bupivacaine group was 28.73+/-8.44%, and those of 2% lidocaine and 2% mepivacaine were 66.85+/-6.03% and 86.27+/-2.00%, respectively. The viability of chondrocytes after saline treatment was 95.95+/-2.75%. The results of MTT assay and fluorescence microscopy had similar tendency with trypan blue assay. Each result showed that bupivacaine was the most toxic of the three local anaesthetics. Mepivacaine was less toxic than lidocaine. The results of the viability test suggest that bupivacaine and lidocaine exhibit a marked chondrotoxicity, and that this is mainly due to necrosis rather than apoptosis. CONCLUSIONS AND CLINICAL RELEVANCE: Bupivacaine may induce detrimental chondrotoxicity when administered intra-articularly, especially in patients with joint disease, and we suggest that it should be used cautiously in equine practice. Mepivacaine may be an alternative to both bupivacaine and lidocaine. PMID- 21303445 TI - Do psychological and physiological stressors alter the acute pain response to castration and tail docking in lambs? AB - OBJECTIVE: To investigate whether events that may be stressful to young lambs, including simulated infection or social isolation, modulate pain experienced by lambs following castration and tail docking (C/D). STUDY DESIGN: Randomised, controlled, prospective study. ANIMALS: Fifty male lambs born to 46 second-parity Mule ewes. METHODS: Lambs were allocated randomly to one of four groups, experiencing either a potential stressor or handling on day 2 after birth, followed by C/D or handling only on day 3. Quantitative sensory testing (QST) data [mechanical nociceptive thresholds (MNT), Semmes Weinstein filaments (SW), response to cold] and serum cortisol concentration were measured at time points after application of treatments to lambs on days 2 and 3 after birth. The treatment groups were LPS, injection of bacterial lipopolysaccharide IV on day 2, C/D on day 3; ISOL, isolation from the dam for 10 minutes on day 2, C/D on day 3; CAST, handling only on day 2, C/D on day 3; CONT, handled only on days 2 and 3. RESULTS: Castration and tail docking caused transient hypoalgesia as measured by MNT and SW. Simulated infection and isolation caused hyperalgesia 3 hours after application, indicated by a reduction in MNT, however they did not alter the pain response to C/D compared to lambs in the CAST group. Injection of LPS and C/D caused increased serum cortisol concentration. The magnitude of the cortisol response to C/D was not altered by prior exposure to either LPS or isolation. CONCLUSIONS AND CLINICAL RELEVANCE: LPS and isolation did not modulate the response to C/D but did cause hyperalgesia. This highlights the importance of flock health management and husbandry techniques to reduce the incidence of either systemic infection or psychological stressors in young lambs. PMID- 21303446 TI - Cardiovascular effects of epidural administration of methadone, ropivacaine 0.75% and their combination in isoflurane anaesthetized dogs. AB - OBJECTIVE: To compare the cardiovascular effects of four epidural treatments in isoflurane anaesthetised dogs. STUDY DESIGN: Prospective, randomized. experimental study. ANIMALS: Six female, neutered Beagle dogs (13.3+/-1.0 kg), aged 3.6+/-0.1 years. METHODS: Anaesthesia was induced with propofol (8.3+/-1.1 mg kg(-1)) and maintained with isoflurane in a mixture of oxygen and air [inspiratory fraction of oxygen (FiO(2))=40%], using intermittent positive pressure ventilation. Using a cross-over model, NaCl 0.9% (P); methadone 1% 0.1 mg kg(-1) (M); ropivacaine 0.75% 1.65 mg kg(-1) (R) or methadone 1% 0.1 mg kg(-1) + ropivacaine 0.75% 1.65 mg kg(-1) (RM) in equal volumes (0.23 mL kg(-1)) using NaCl 0.9%, was administered epidurally at the level of the lumbosacral space. Treatment P was administered to five dogs only. Cardiovascular and respiratory variables, blood gases, and oesophageal temperature were recorded at T-15 and for 60 minutes after epidural injection (T0). RESULTS: Mean overall heart rate (HR in beats minute(-1)) was significantly lower after treatment M (119+/-16) (p=0.0019), R (110+/-18) (p< 0.0001) and RM (109+/-13) (p<0.0001), compared to treatment P (135+/-21). Additionally, a significant difference in HR between treatments RM and M was found (p=0.04). After both ropivacaine treatments, systemic arterial pressures (sAP) were significantly lower compared to other treatments. No significant overall differences between treatments were present for central venous pressure, cardiac output, stroke volume, systemic vascular resistance, oxygen delivery and arterial oxygen content (CaO(2)). Heart rate and sAP significantly increased after treatment P and M compared to baseline (T-15). With all treatments significant reductions from baseline were observed in oesophageal temperature, packed cell volume and CaO(2) . A transient unilateral Horner's syndrome occurred in one dog after treatment R. CONCLUSIONS AND CLINICAL RELEVANCE: Clinically important low sAPs were observed after the ropivacaine epidural treatments in isoflurane anaesthetised dogs. Systemic arterial pressures were clinically acceptable when using epidural methadone. PMID- 21303447 TI - An unusual complication of endotracheal intubation. PMID- 21303448 TI - Transgenic maize plants expressing the Totivirus antifungal protein, KP4, are highly resistant to corn smut. AB - The corn smut fungus, Ustilago maydis, is a global pathogen responsible for extensive agricultural losses. Control of corn smut using traditional breeding has met with limited success because natural resistance to U. maydis is organ specific and involves numerous maize genes. Here, we present a transgenic approach by constitutively expressing the Totivirus antifungal protein KP4, in maize. Transgenic maize plants expressed high levels of KP4 with no apparent negative impact on plant development and displayed robust resistance to U. maydis challenges to both the stem and ear tissues in the greenhouse. More broadly, these results demonstrate that a high level of organ independent fungal resistance can be afforded by transgenic expression of this family of antifungal proteins. PMID- 21303450 TI - Comparative aspects of the proliferation marker thymidine kinase 1 in human and canine tumour diseases. AB - As cell proliferation is one of the hallmarks of cancer, various types of proliferation markers are used as important tools in diagnosis, prognosis, treatment decision-making and follow-up in clinical oncology. The S phase specific protein thymidine kinase 1 (TK1) can be used in immunohistochemistry for RNA/protein expression in tissue specimens and for activity or protein/peptide levels in serum from patients. TK1 has been used mainly in haematologic malignancies in humans, but also found beneficial in canine malignancies. As the protein sequence homology is high between humans and dogs, findings in canine models will have a high comparative value in further human research as well. In the present review, we will focus on the recent results concerning TK1's S phase correlated expression, increased serum levels of TK1 in patients with malignancies and the relevance for veterinary and comparative oncology. Finally, the benefit of recently developed specific anti-TK1 antibodies suitable for immunologic assay is discussed. PMID- 21303451 TI - Hypoxia-inducible factors--regulation, role and comparative aspects in tumourigenesis. AB - Hypoxia-inducible factors (HIFs) play a key role in the cellular response experienced in hypoxic tumours, mediating adaptive responses that allow hypoxic cells to survive in the hostile environment. Identification and understanding of tumour hypoxia and the influence on cellular processes carries important prognostic information and may help identify potential hypoxia circumventing and targeting strategies. This review summarizes current knowledge on HIF regulation and function in tumour cells and discusses the aspects of using companion animals as comparative spontaneous cancer models. Spontaneous tumours in companion animals hold a great research potential for the evaluation and understanding of tumour hypoxia and in the development of hypoxia-targeting therapeutics. PMID- 21303452 TI - CHOP chemotherapy for the treatment of canine multicentric T-cell lymphoma. AB - Dogs with multicentric T-cell lymphoma are commonly treated with CHOP chemotherapy protocols that include cyclophosphamide, doxorubicin, vincristine and prednisone. The purpose of this study was to evaluate the use of CHOP chemotherapy for dogs with multicentric T-cell lymphoma. Identification of prognostic factors in this specific subset of dogs was of secondary interest. Twenty-three out of 24 dogs responded to CHOP chemotherapy and these dogs remained on the protocol for a median of 146 days. No variable was associated with progression free survival (PFS) including stage, substage, hypercalcemia or radiographic evidence of a cranial mediastinal mass. The median overall survival time (OST) for all dogs was 235 days. Dogs that were thrombocytopenic at presentation experienced a significantly longer OST (323 versus 212 days, P=0.01). PMID- 21303453 TI - Breed differences in the proportional morbidity of testicular tumours and distribution of histopathologic types in a population-based canine cancer registry. AB - Histologically verified tumours submitted to the Norwegian Canine Cancer Register from 1990 to 1998 were studied (n=14,401). The proportion of testicular tumours (n=345) was 2.4%, and the breakdown of histological tumour diagnoses is presented. The frequency of the most common histopathological types was 33% interstitial (Leydig), 26.4% Sertoli and 33.9% seminomas/germ cell tumours. The average age at diagnosis was 10 years, but was significantly lower for Sertoli cell tumours (8.6 years) than for the other tumour types. Following a histopathological re-evaluation, 22.5% of the original tumor diagnoses were modified. Proportional morbidity ratios were calculated and individuals from the breeds Shetland sheepdog and Collie were five times more likely to have testicular tumours than the overall average for the registry. Breed differences in the distribution of histopathologic types were observed. Shetland sheepdog and Collie were most commonly diagnosed with Sertoli cell tumours, while all tumours from Norwegian elkhound in this material were seminomas. PMID- 21303454 TI - Increased monocyte chemotactic protein-1 concentration and monocyte count independently associate with a poor prognosis in dogs with lymphoma. AB - Overexpression of the chemokine monocyte chemotactic protein-1 (MCP-1) has been associated with a poor prognosis in many human cancers. Increased MCP-1 concentrations may promote tumour progression by increasing mobilization of myeloid derived suppressor cells such as immature monocytes and neutrophils. We hypothesized that increased numbers of peripheral neutrophils or monocytes and increased MCP-1 concentrations would predict a worse outcome in dogs with multicentric lymphoma. In this retrospective study involving 26 client-owned dogs diagnosed with lymphoma, we show that peripheral neutrophil and monocyte counts as well as serum MCP-1 concentrations were significantly elevated relative to healthy control animals, and that such increases were associated with a decreased disease-free interval in dogs treated with chemotherapy based on cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP). To our knowledge, this is the first study showing that pretreatment evaluation of monocyte and neutrophil counts can provide important prognostic information in dogs with lymphoma. The mechanisms underlying these observations remain to be determined. PMID- 21303455 TI - Characterization of beta-catenin expression in canine osteosarcoma. AB - Osteosarcoma (OSA) is the most frequently occurring malignant primary bone tumour in dogs and children and arises from cells of the osteoblast lineage. Inappropriate Wnt signalling activity has been implicated in human OSA. Altered expression of beta-catenin, an integral member of the Wnt signalling pathway, has been associated with numerous human cancers, including OSA. In this study, 30 of the 37 primary canine OSA tissues and 2 of the 3 metastatic OSAs were positive for beta-catenin expression as determined by immunohistochemistry, whereas 2 normal bones stained negative for beta-catenin. No mutations were identified in exon 3 of beta-catenin in the three OSA cases in which DNA sequencing was performed. Finally, there was no relationship between beta-catenin expression and overall survival time or disease-free interval. Our results indicate beta-catenin is frequently expressed within the cytoplasm of neoplastic cells in canine OSA but contains no detectable mutations in exon 3, similar to human OSA. PMID- 21303456 TI - The clinical efficacy of two semi-quantitative wound-swabbing techniques in identifying the causative organism(s) in infected cutaneous wounds. AB - A prospective randomised controlled trial of two paired wound-swabbing techniques (Levine versus Z) was conducted to establish which method was more effective in determining the presence of bacteria in clinically infected wounds. The Levine technique involves rotating the wound swab over a 1-cm(2) area of the wound; the Z technique involves rotating the swab between the fingers in a zigzag fashion across the wound without touching the wound edge. Fifty patients were recruited into the study with acute (42%) and chronic wounds (58%). Overall, the Levine technique detected significantly more organisms than the Z technique (P<= 0. 001). When acute and chronic wounds were analysed separately, the Levine technique again detected more organisms in both acute (P<= 0. 001) and chronic wounds (P<= 0. 001). We conclude that the Levine technique is superior to the Z technique and this result may be because of the Levine technique's ability to express fluid from the wound bed and thereby sampling a greater concentration of microorganisms from both the surface and slightly below the surface of the wound. PMID- 21303457 TI - Guest Editorial: The essence of expertise in care for older people - nurses, doctors and teamwork. PMID- 21303458 TI - Guest editorial: culture change - challenges, opportunities and questions. PMID- 21303459 TI - A concept analysis of home and its meaning in the lives of three older adults. AB - AIM: To identify and define the concept of home and its meaning in the lives of three older women. BACKGROUND: For many older adults home is the centre of daily life and increasingly important as a place where health care is delivered. Yet, as a concept, home remains theoretically and empirically underdeveloped. METHODS: The Hybrid Model of Concept Development was used to interface theoretical analysis and empirical observation with a focus on definition. A comprehensive, interdisciplinary literature review, semi-structured interviews with three older women and case and cross-case analysis were completed. RESULTS: Interviewees spoke of childhood, community, residential, church and heavenly homes. Feelings of comfort and security were associated with residential homes, peace and quiet with church homes, safety and pleasure with heavenly homes. The experience of home as being taken for granted, unselfconscious and unrecognized, became obvious when one woman tried to consciously establish a sense of being at home in her new residence. CONCLUSION: No single comprehensive and measurable definition was found. However, three major components were identified (place, relationship and experience) and used to define home as a place to which one is attached, feels comfortable and secure and has the experience of dwelling. RELEVANCE TO CLINICAL PRACTICE: Every day assumptions about the meaning of home and home as just another place where health care is provided are called into question. Increased awareness and dialogue is needed among health-care providers working with older adults in their homes. Future research needs to explore the impact of home care on the older adult's meaning of home and its potential impact on recovery. PMID- 21303460 TI - Focus on communication: increasing the opportunity for successful staff-patient interactions. AB - OBJECTIVES: This study reports on a pilot study examining the feasibility of a Patient-Centred Communication Intervention. Aims of this study include: assessing the implementation of the communication care plans; identifying staff perceptions of the intervention; exploring changes in patients' perceptions of care and psychosocial functioning; and exploring changes in nurses' knowledge of and attitude towards communication with patients. BACKGROUND: More than 50% of stroke survivors have speech and language impairments. Many nurses lack the specialized skills to effectively communicate with patients and therefore have difficulties understanding the patients' needs. DESIGN: A one-group pre- post test design supplemented with a focus group session with nursing staff was used. The intervention consisted of developing individualized communication plans; attending at a workshop; and implementing a system to support nurses when using the plans. The plans were used over a 2-month period. Focus groups were held with seven nurses. RESULTS: The pilot study demonstrated feasibility. There was an excellent response rate and nurses adhered to the intervention. CONCLUSION: The Patient-Centred Communication Intervention is feasible and has demonstrated potential for a larger-scale study. RELEVANCE TO CLINICAL PRACTICE: Providing tailored approaches to communication-enhancement education may be necessary for changes in practice to occur. PMID- 21303461 TI - Sense of security - searching for its meaning by using stories: a Participatory Action Research study in health and social care in Sweden. AB - AIM: The aim of this study was to make sense of the Swedish concept 'trygghet' by using stories from daily life in a Participatory Action Research project. BACKGROUND: In Sweden, attempts to implement core values to ensure high quality health and social care for older people are given high priority and concepts such as security and dignity are often used. As concepts are abstract they are difficult to transform into practical work. DESIGN: One group of six assistant nurses and one group of five Registered Nurses working in a municipality participated in Story Dialogue Method and four older women were interviewed. RESULT: 'Trygghet' was found to be an internal sense - an intrinsic state based on faith and trust in oneself and others called Sense of security. External factors that strengthened Sense of security were to be part of a community, to recognize and be familiar with things and situations and to use various kinds of aids. CONCLUSION AND RELEVANCE TO CLINICAL PRACTICE: A prerequisite for the professionals being able to support the care receivers adequately is that they have a sense of security themselves, and that they are allowed to operate in a system that facilitates for the care receivers to maintain trustworthy and reliable relations over time. PMID- 21303462 TI - Collaborative relationship in preventive home visits to older people. AB - AIM: To describe what characterizes preventive home visits with collaborative relationships among non-disabled home-dwelling older people in Japan. BACKGROUND: Preventive home visits have the potential to result in improved health outcomes among older people. Collaboration, mutual understanding and trust between visitor and the visited person seem to work as a vehicle, but little is known about which part of the encounters contributes to a collaborative relationship. METHODS: We performed a retrospective qualitative analysis of visiting records written by preventive home visitors immediately after the visits were made. A collaborative relationship was predefined as a favourable change in behaviour seen in the visited person during the study period. Visitor characteristics were analysed from 248 records where 37 cases of collaborative relationships were documented. RESULTS: The three most important elements associated with a collaborative relationship were (i) visitor communication skills i.e. mastering 'enhancing motivation' and 'having patience and coping with frustrations' in difficult and problematic situations, (ii) professionalism, which includes 'professional instruction and guidance' based on documented knowledge in health and social domains combined with an overall 'caring approach' and (iii) practical actions which imply an 'immediate concrete response to identified needs or problems' and 'individually tailored advice' to suit the older person's daily life. CONCLUSIONS: Preventive home visitor communication skills and professionalism, and practical actions after the visits characterized cases, where favourable changes in behaviour were obtained in non-disabled home-dwelling older people in Japan. RELEVANCE TO CLINICAL PRACTICE: Education should be emphasized, because preventive home visitor competence may be the most important element of proactive assessment schemes to obtain beneficial outcomes. PMID- 21303463 TI - Hidden treasures within the use of innovative approaches to treat individuals with dignity, compassion and respect - policy commentary on McLafferty et al. (2009) 'using gaming workshops to prepare nursing students for caring for older people in clinical practice'. International Journal of Older People Nursing 5, 51 60. PMID- 21303464 TI - Editorial: optimising medication use in nursing homes: problems, solutions and future challenges. PMID- 21303465 TI - Prescribing for older people in nursing homes: a review of the key issues. AB - Prescribing of medication is one of the most common interventions that residents in nursing homes will experience. There is little doubt that medication has greatly contributed to improvements in symptom control, long-term management of medical conditions and greater longevity. However, the quality of prescribing has also been criticised and this paper outlines the issues that have proved to be most problematic and have been repeatedly highlighted in the literature. There have been numerous reports of over-use of inappropriate medicines for which there is no clinical indication or for which there is little evidence of effectiveness, and under-use of medicines that would be indicated for residents with certain medical conditions. Residents may also suffer from adverse drug events and enforced or erratic compliance. Some of these problems may arise because of the difficulties encountered by staff or a breakdown in communication when residents move from one setting to another (e.g. hospital to nursing home or vice versa). PMID- 21303466 TI - Prescribing for older people in nursing homes: strategies to improve prescribing and medicines use in nursing homes. AB - Interventions to improve prescribing in the nursing home environment are many and varied. The critical literature review presented in Paper 1 (Parsons et al., 2011, International Journal of Older People Nursing 6, 45-54) in this series discussed the main issues repeatedly identified as problematic, and this paper summarises the main approaches which have been used to attempt to improve prescribing. These include national legislation which demands documented justification for the prescribing of medicines, medication review, approaches to reducing medication errors, improving communication across care boundaries and assessment teams and alternative service models. It is difficult to make global recommendations as some of these approaches are country specific or have been delivered in different ways, involving different professionals. However, a series of prompt questions have been provided which may assist nursing home staff in deciding whether prescribing is optimal in a resident or if an intervention is required which may lead to an overall improvement in outcomes. PMID- 21303467 TI - Prescribing for older people in nursing homes: challenges for the future. AB - As the population continues to age, long-term care for older people will be required, although the setting and method of delivery may differ depending on people's needs. We anticipate that nursing homes will continue to be part of the overall long-term care delivery model, but will face a number of challenges if they are to be considered as much sought-after places. This paper highlights three issues in relation to prescribing that have been largely ignored to date, but which need to be considered by practitioners, policy makers and researchers alike: culture; resident-centred decision-making and care at the end of life. There has been growing interest in culture within organisations and how this may influence behaviour and performance. In this paper, we will consider how culture may influence prescribing. Culture is important in how it contributes to resident centred care and this leads to a consideration on how residents may be involved in decision-making, specifically in the area of medicines. Finally, care at the end of life in nursing homes, particularly in those with dementia, has been shown to be poor in quality, and this also encompasses the medicines that are prescribed. Palliative services need to be developed to meet the requirements of some of the most vulnerable residents in this care setting. PMID- 21303468 TI - Rehabilitation interventions for improving physical and psychosocial functioning after hip fracture in older people. PMID- 21303469 TI - Hydroxychloroquine-induced ototoxicity in a child with systemic lupus erythematosus. PMID- 21303470 TI - Bilateral knee lipoma arborescence diagnosed by ultrasound. PMID- 21303471 TI - Development of multiple myeloma in a case of longstanding ankylosing spondylitis: more than a coincidence? PMID- 21303472 TI - Rituximab and lupus interstitial lung disease: friend or foe? PMID- 21303473 TI - Portal vein thrombosis in systemic lupus erythematosus associated with anticardiolipin antibodies. PMID- 21303474 TI - Vaccination as a triggering agent for the development of rheumatoid arthritis. PMID- 21303475 TI - Clinical research in systemic lupus erythematosus: immediate relevance to clinical practice. AB - Systemic lupus erythematosus remains a challenge because of its diverse presentations, variable natural history, and lack of uniform response to treatment. True remission is very rare. Reliance on corticosteroid treatment leads to unwanted long-term toxicity. Great advances have been made in the early detection of lupus nephritis and in treatment. Greater appreciation of cognitive impairment and of lupus myelitis is now possible. Pregnancy risks are better characterized. However, the greatest unmet challenge remains atherosclerosis. PMID- 21303476 TI - The use of opioids in fibromyalgia. AB - Fibromyalgia syndrome (FMS) is a chronic disorder of widespread pain with high personal and societal burdens. Although targeted pharmacotherapies have become available in recent years, it remains a challenging condition to treat. Despite no randomized controlled trials addressing the short- or long-term use of opioids in FMS, their use remains prevalent. In this article we discuss the role of opioids and other analgesics in the management of FMS, with particular focus on problems associated with their use. We review aspects of the pathophysiology of FMS and consider how specific factors may contribute to the lack of efficacy of opioids in this condition. Finally, we discuss drugs with combined opioid and anti-opioid action and their roles in FMS. There is insufficient evidence to recommend the routine use of opioids in FMS. As well as having a significant adverse effect profile, their inefficacy may be due to their inability to target the pathophysiologic processes involved in this central sensitization syndrome. PMID- 21303477 TI - The prevalence of rheumatoid factor isotypes and anti-cyclic citrullinated peptides in Malaysian rheumatoid arthritis patients. AB - AIM: The purpose of this study is to compare the prevalence of rheumatoid factor (RF) isotypes and second generation anti-cyclic citrullinated peptides (anti-CCP) in Malaysian rheumatoid arthritis (RA) patients. METHODS: In this cross-sectional study, 147 established RA patients from three ethnic groups were recruited from a major rheumatology clinic in Malaysia. Enzyme-linked immunosorbent assays (ELISA) for serum RF isotypes IgA, IgG and IgM as well as second-generation anti-CCP were performed and the prevalence of each auto-antibody was compared in the three ethnic groups. RESULTS: The anti-CCP was the most prevalent auto-antibody in each of the ethnic groups, followed closely by RF IgM and RF IgG. Rheumatoid factor IgA was the least prevalent across all three ethnic groups. The anti-CCP-RF IgM combination provided the best test sensitivity. Seroprevalence of anti-CCP was strongly associated with the presence of each of the RF isotypes. The seroprevalence of RF and anti-CCP did not increase or decrease with advancing age, age at onset and disease duration. CONCLUSION: When used alone, anti-CCP provides a diagnostic advantage over RF IgM on the basis of test sensitivity. Considering the high cost of the anti-CCP assay, step-wise serum testing with IgM RF followed by anti-CCP may provide a more economically sensible option to optimize test sensitivity for RA. PMID- 21303478 TI - A cross-sectional study of diastolic dysfunction in rheumatoid arthritis and its association with disease activity. AB - AIMS: The aim of this study was to evaluate the left ventricular (LV) diastolic dysfunction in rheumatoid arthritis (RA) patients without clinically evident cardiovascular manifestations and to estimate whether there is any correlation between RA disease severity and disability and LV diastolic dysfunction. METHODS: The study was a cross-sectional study involving 53 patients (47 female and 6 male) with RA without clinically evident heart disease and 53 healthy subjects (47 female and 6 male) who served as a control group. Both groups were matched for age and sex. Echocardiographic and Doppler studies were conducted in all patients with RA and control subjects. RESULTS: Of 17 cardiac parameters assessed, only two were abnormal. None of the specific cardiac diastolic dysfunction parameters were significantly different in RA patients compared to the control group. There was no significant correlation between diastolic function values in RA patients and value of Disease Activity Score 28 (DAS-28) and value of Health Assessment Questionnaires Disability Index (HAQDI). Atrial (A) wave velocity was greater in RA patients compared to the control group (0.71 [0.58-0.83] vs. 0.61 [0.51-0.71]; P < 0.04). However, interventricular relaxation time (IVRT) ([73.08 +/- 9.92 vs. 70.74 +/- 9.02], P = 0.207), lower E/A ratio (1.27 [1.02-1.56] vs. 1.42 [1.20-1.68], P = 0.102), diastolic dysfunction parameters according to Redfield Classification (25 [47.2%] vs. 27 [50.9%] P = 0.56), diastolic dysfunction using E/A (P = 0.321) and tissue doppler imaging (E/E') (P = 0.148) were not different. CONCLUSION: Prevalence of diastolic dysfunction in the rheumatoid arthritis group (47.2%) was not different from controls (50.9%). LV diastolic function had no significant correlation with RA disease severity and duration of disease. PMID- 21303479 TI - Clinical factors related to the efficacy and complications of orthopedic surgery for rheumatoid arthritis with infliximab. AB - AIMS: To determine what clinical factors relating to efficacy besides complications of orthopedic surgery for patients treated with anti-tumor necrosis factor (TNF)-alpha therapy (infliximab), we analyzed the clinical data of 52 cases of orthopedic surgery, such as total hip arthroplasy (THA), total knee arthroplasty (TKA), total shoulder arthroplasy (TSA), total elbow arthroplasty (TEA), arthroscopic synovectomy, foot arthroplasty, spine surgery, hand surgery and fracture. METHODS: We analyzed clinical factors including age, disease duration, preoperative C-reactive protein (CRP), disease activity score (DAS)-28, matrix metalloproteinase (MMP)-3, and rheumatoid arthritis particle-agglutination (RAPA) in 52 cases of rheumatoid arthritis (RA) undergoing orthopedic surgery. For complications of orthopedic surgery, signs of postoperative infection were recorded, including rubor, discharge, systemic infection and frequencies of wound dehiscence, as well as the incidence of any surgical complication requiring a secondary revision procedure were measured. RESULTS: Signs of infection or surgical complications occurred in two of 52 patients (3.8%). There is significant correlation between RAPA and improvement of CRP 3 months after surgery; however, there is no correlation between infection and clinical factors including age, disease duration, preoperative CRP, MMP-3, RAPA and the period until surgery after infliximab infusion. CONCLUSION: Infliximab did not increase the risk of either infections or surgical complications occurring in patients with RA within 1 year of orthopedic surgery. Improvement of CRP after surgery is likely to be due to infliximab for high RAPA in RA patients. PMID- 21303480 TI - Clinical and psychosocial factors associated with depression and anxiety in Singaporean patients with rheumatoid arthritis. AB - AIM: To assess the frequency of, and factors associated with, depression and anxiety in Singaporean patients with rheumatoid arthritis (RA). METHOD: One hundred RA patients were recruited in a cross-sectional study. Socio demographics, severity of anxiety and depression, disease activity, levels of serological markers and health-related quality of life were analyzed. RESULTS: Twenty-six percent presented with anxiety, 15% with depression and 11% with both. Univariate regression showed that age (P = 0.039), Disease Activity Scale (DAS 28) (P < 0.001), number of medications (P < 0.001) and rheumatoid factor (RF) (P < 0.001) were positively associated with severity of depression, while income (P = 0.001), education (P = 0.029), self-perceived social support (P = 0.007), Short form 12 (SF-12) physical health (P < 0.001) and SF-12 mental health (P < 0.001) were negatively associated with severity of depression. After adjustment for confounding factors in multivariate regression, income (beta = -0.347, P = 0.018), RF (beta = 0.304, P = 0.043) and SF-12 mental health (beta = -0.501 P = 0.001) remained significantly associated with depression. Univariate regression showed that DAS-28 (P = 0.009), number of medications (P = 0.004) and RF (P = 0.043) were positively associated with anxiety, while income (P = 0.022), self perceived social support (P = 0.04), SF-12 physical health (P < 0.001) and SF-12 mental health (P < 0.001) were negatively associated with anxiety. After adjustment for confounding factors, no factors remained significantly associated with anxiety. CONCLUSION: Low income, high levels of RF and poor mental health were associated with depression in RA. Our findings may help to formulate depression screening strategies. Further research is required to identify the role of RF in depression. PMID- 21303481 TI - Leflunomide in Pakistani patients with rheumatoid arthritis: prospective study in daily rheumatology practice. AB - INTRODUCTION: Leflunomide is a disease-modifying anti-rheumatic drug (DMARD) for rheumatoid arthritis (RA). It has been widely studied in the West but there is no available local Pakistani data. OBJECTIVE: To evaluate the efficacy and safety profile of leflunomide in Pakistani patients with RA, either alone or in combination with methotrexate. MATERIALS AND METHODS: A prospective, non comparator, open-label study in a setting of 'care as usual' was performed. In this study, 63 consecutive RA patients on leflunomide were enrolled. Leflunomide dose was started with full loading in 5 (8%), half loading in 39 (62%) and without loading in 19 (30%) patients. Methotrexate was also used in 20 (32%) patients. Primary end-point was 20% improvement in American College of Rheumatology response criteria (ACR-20). Safety was assessed by adverse events and abnormalities in laboratory parameters. RESULTS: Out of 63 patients, 54 (85.7%) were female. Mean age was 46 +/- 12.6 years. Mean disease duration was 5.1 +/- 4.5 years. Fifty-two (86.6%) patients achieved ACR-20 response at 6 months; 32 (53%) achieved ACR-50 response at 6 months; 20% experienced at least one adverse event, which resolved by reducing leflunomide dose. Only seven (11%) had raised liver enzymes from baseline. CONCLUSION: This prospective study conducted in the setting of a daily rheumatology practice shows that leflunomide is an effective and safe DMARD in treatment of RA in Pakistani patients. PMID- 21303482 TI - Rheumatic-musculoskeletal manifestations in type 2 diabetes mellitus patients in south India. AB - AIM: To determine the prevalence of rheumatic musculoskeletal disorders (RMSD) in type 2 diabetes mellitus (T2DM) and study their risk factors. METHODS: Diagnosed patients of T2DM attending the diabetic clinic in a premier teaching institution in south India were interviewed and requested to mark their RMS pain sites on a mannequin and intensity of pain on a visual analogue scale (VAS). A complete RMS examination was done and diagnoses were noted. These RMSDs were compared with those in age- and sex-matched, non-diabetic individuals from the general population. Association of RMSD with variables was determined using Chi-square test and multiple logistic regression models for risk factors were created using SPSS 17.0 software. RESULTS: Prevalence of RMSD in 310 cases and controls was 42.58%; 95% CI: 37.08-48.08 and 31.61%; 95% CI: 26.43-36.79, respectively. RMS pain was marked by 194 individuals. Knee was the most common site of pain (33.4%). Prevalence of common RMSD was osteoarthritis knee (20.64%; 95% CI 16.14 25.16), frozen shoulder (16.45%; 95% CI: 12.32-20.58), diffuse idiopathic skeletal hyperostosis (14.52%; 95% CI: 10.6-18.44) and limited joint mobility (8.06%; 95% CI: 5.03-11.09). Age (P = 0.046), duration of T2DM (P < 0.001) and glycosylated hemoglobin (P < 0.001) were found to have significant associations with RMSD. In logistic regression analysis, duration (OR: 1.467; 95% CI: 1.210 1.779) and severity (OR: 1.354; 95% CI: 1.169-1.569) of T2DM were identified as the risk factors. CONCLUSION: Thorough RMS examination should be included as an integral part of care in T2DM patients. PMID- 21303483 TI - Coping and disability: evidence from a developing country. AB - AIM: In view of the increasing burden of musculoskeletal-related disability, the growing number of older persons and the scarcity of research on musculoskeletal conditions in the Eastern Mediterranean region, coping with musculoskeletal problems deserves special attention. This paper examines how good coping links to musculoskeletal-related disability among Lebanese citizens aged 15 years and older. METHODS: The sample included 200 people living in southern Lebanon and who participated in the Community Oriented Program for Control of Rheumatic Diseases (COPCORD) survey. Disability and coping were assessed using self-reported questions. Covariates included demographics, musculoskeletal pain variables, and body mass index (BMI). RESULTS: Around one-third of the sample had lifetime functional disability due to musculoskeletal problems and 62% were coping well with their problems. Adjusted data showed that the odds of musculoskeletal related disability among individuals who were not coping well was 2.35 times the odds of disability among individuals who were coping well with 95% CI = 1.10 5.02. CONCLUSION: This study provides evidence of the importance of complementing pharmacological treatment with a cognitive-behavioral approach for management of musculoskeletal problems. PMID- 21303484 TI - Bone mineral density in young males with ankylosing spondylitis. AB - OBJECTIVE: To assess bone mineral density (BMD) abnormalities in young Indian males with ankylosing spondylitis (AS) and factors influencing this. METHODS: Eighty AS male subjects were compared with 160 age/sex matched controls for BMD of lumbar spine and proximal femur. AS subjects were evaluated and followed up every 3 months for disease activity. BMD was estimated at spine and proximal femur using the dual-energy X-ray absorptiometry (DXA) technique. RESULTS: All subjects were males with mean age of 32.9 +/- 8.3 years and mean duration of disease was 8.1 +/- 5.8 years. AS subjects had significantly lower BMD at the spine and femur as compared with controls (both P < 0.001). Using WHO standards, osteoporosis (OP) in spine and femur neck was seen in 28.75% (controls: 1.84%, P < 0.001) and 11.54% (controls: 1.23%, P < 0.001), respectively. No statistically significant difference in prevalence of OP was seen with disease duration, C reactive protein levels and disease activity indices (all P > 0.05). Syndesmophytes were seen in 22.5% (n = 18) of AS subjects. There was no significant difference between BMD values at spine in AS subjects with or without syndesmophytes (0.91 + 0.16 g/cm(2) vs. 0.90 + 0.14 g/cm(2), P = 0.79). CONCLUSION: OP is a significant complication in AS even in young males with early disease, and more prevalent in the spine compared to femur. In our study, BMD was not influenced by disease activity indices, inflammatory markers or total disease duration. Spinal BMD is the most sensitive site for defining OP in AS. PMID- 21303485 TI - Development of the Japanese version of the Fibromyalgia Impact Questionnaire (JFIQ): psychometric assessments of reliability and validity. AB - AIM: To perform a psychometric assessment of the Japanese version of the Fibromyalgia Impact Questionnaire (JFIQ). METHODS: Data for the psychometric assessment were collected from Japanese fibromyalgia (FM) patients who visited a clinic. Analyses were performed to examine the reliability and validity of the JFIQ. RESULTS: A total of 56 patients were included in the analysis. There was no remarkable floor or ceiling effect for the JFIQ item or total scores. In the analysis of reproducibility, the interclass correlation coefficients of each item score and total score ranged from 0.61 to 0.95. Cronbach's alpha coefficient was 0.92. For the concurrent validity, the total score and most of the item scores correlated to every domain of Short Form-36 or Beck Depression Inventory-II to a moderate or great extent. The results of the known-group comparisons indicated that the total score tended to increase with the increase in severity of FM and pain (P-values for trend < 0.05). CONCLUSION: This psychometric assessment demonstrated good reliability and validity of the JFIQ for use with Japanese FM patients. In the future, we expect that this questionnaire will be used in clinical studies and medical practice, and will be beneficial in the development of new therapies as well as for the comprehensive evaluation of patients' conditions in Japan. PMID- 21303486 TI - Impact of C1q deficiency on the severity and outcome of childhood systemic lupus erythematosus. AB - OBJECTIVE: To delineate the clinical and laboratory features of systemic lupus erythematosus (SLE) in C1q-deficient Saudi children and to compare them with sporadic SLE patients with respect to their clinical and laboratory features and disease outcome. METHODS: The C1q-deficient SLE patient group comprised 14 patients, while the comparative group comprised 11 patients selected by systemic sampling from our pediatric lupus clinic database. The two groups were compared with respect to: demographic, clinical and laboratory variables and outcome. RESULTS: The C1q-deficient SLE patients had an earlier age of onset of disease (P = 0.003); 43% had familial SLE and none of the comparative group had family histories of SLE. The two groups were comparable with respect to gender, disease duration and follow-up. Scarring alopecia, discoid rash and nail changes were more frequent in the C1q-deficient SLE patient group. However, there were no significant differences. The mean white blood cell count was lower (P = 0.04) and the level of anti-Sm and anti-phospholipid antibodies were higher (P = 0.04) in the C1q-deficient SLE patients. Other variables did not show significant differences. Two patients from the C1q-deficient SLE patient group died due to infection. All patients from the control group are alive. Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index mean was higher in the C1q-deficient SLE patients group but was not statistically significant. CONCLUSION: C1q-deficient SLE patients tend to be younger and more likely to have familial disease with severe cutaneous manifestations. The mortality among them is more frequent, which may reflect disease severity. PMID- 21303487 TI - Importance of serine727 phosphorylated STAT1 in IFNgamma-induced signaling and apoptosis of human salivary gland cells. AB - AIM: It is reported that in salivary glands of Sjogren's syndrome (SS), interferon gamma (IFNgamma) and IFNgamma-inducible genes containing signal transducers and activators of transcription 1 (STAT1) are upregulated and play a crucial role in the pathogenesis of SS. The aim of this study is to clarify which phosphorylation of STAT1, serine727 (Ser(727)) or tyrosine701 (Tyr(701)) of STAT1, is important for IFNgamma signaling and IFNgamma-induced apoptosis in salivary gland cells. METHODS: We established STAT1 Tyr(701) variant (tyrosine to phenylalanine; Y701F) and STAT1 Ser(727) variant (serine to alanine; S727A), which were transfected into human salivary gland (HSG) cells. HSG cells transfected with these mutant-STAT1 were analyzed on the expression of IFNgamma inducible genes and apoptosis after stimulation with IFNgamma. RESULTS: In Y701F mutant-STAT1 transfected HSG cells (Ser(727)-dominant HSG cells), IFNgamma inducible genes such as IP10, IRF1, and Fas expression were increased after stimulation with IFNgamma. In Ser(727)-dominant HSG cells, the induction of apoptosis after stimulation with IFNgamma was also increased compared with S727A mutant-STAT1 transfected HSG cells (Tyr(701)-dominant HSG cells). CONCLUSION: Phosphorylation of Ser(727) in STAT1 might be more important in IFNgamma signaling and the induction of apoptosis in HSG cells than phosphorylation of Tyr(701). Accordingly, we propose that phosphorylation of Ser(727) in STAT1 could be a potentially suitable new therapeutic target for SS patients to prevent the destruction of salivary glands. PMID- 21303488 TI - Radiographic findings of Wistar rats fed with T-2 toxin and Kashin-Beck disease affected diet. AB - OBJECTIVE: To characterize the features of radiographic abnormalities of the tibial bone in Wistar rats which have been fed T-2 toxin and Kashin-Beck disease (KBD) epidemic district food. METHODS: Ninety Wistar rats were divided into five groups. Group A was fed with a normal diet as control; group B was fed with a normal diet and T-2 toxin; group C was fed with a low-nutrition diet and T-2 toxin; group D was fed with a low-nutrition diet; and group E was fed with a KBD affected diet. At 4, 8 and 12 weeks, six rats from each group were radiographed. After radiographic examination, samples of left knees were harvested and stained with hematoxylin and eosin. RESULTS: At 8 and 12 weeks, there were radiological changes in the epiphyseal plate. Abnormal radiological signs of blurring, thinning and irregularity were seen in groups C and E rats, and the length of tibial bones showed significant difference in the KBD-fed rats and low-nutrition diet combined T-2 toxin rats, compared to the control group rats (P < 0.05). The epiphyseal plates showed more obvious necrosis of chondrocytes in groups C and E. CONCLUSIONS: A rat model of KBD can be established by a KBD-affected diet; proximal epiphyseal plate and metaphyseal bone of the tibia abnormalities on radiographs and histopathology were present in KBD model rats. A low nutrition diet may be involved the aetiology of KBD, and determination of this should be studied in the future. PMID- 21303489 TI - Acute abdomen in SLE. AB - Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune connective tissue disease with protean manifestations. Most often it presents with mucocutaneous, musculoskeletal or renal involvement. In comparison, gastrointestinal (GI) manifestations of SLE are far less common. The case presented here highlights the differential diagnosis of GI manifestations of SLE that range from non-life-threatening to serious life-threatening complications, including some of the complications of on-going drug treatments. While some of them present as 'acute abdomen', others are more subacute or chronic, yet serious enough to be life-threatening. The serious GI manifestations of SLE include mesenteric vasculitis causing perforation or hemorrhage with peritonitis, acute pancreatitis and intestinal pseudo-obstruction. The patient in this paper had clinical features, imaging findings and laboratory parameters that helped the treating physician to narrow down the diagnostic possibilities and finally, in making the diagnosis of lupus-pancreatitis. She was treated with intravenous 'bolus' (i.v.-pulse) methylprednisolone for 3 days, i.v.-pulse cyclophosphamide 750 mg (one dose) along with oral methylprednisolone and other supportive measures including blood transfusions. This led to prompt and complete recovery. PMID- 21303490 TI - Tophaceous gout of the odontoid process causing glossopharyngeal, vagus, and hypoglossal nerve palsies. AB - Gout affecting the axial joints is uncommon; however, its involvement may be complicated by neurological symptoms associated with spinal compression at the affected level. Specific involvement of the odontoid process is even rarer. We report the first case of gout involving the odontoid process with resultant glossopharyngeal (CN IX), vagus (CN X) and hypoglossal (CN XII) nerve palsies. PMID- 21303492 TI - Classical swine fever (hog cholera): review of aspects relevant to control. AB - Classical swine fever (CSF) has the ability to spread over large distances when human intervention such as illegal swill feeding facilitates its movement. This was apparent during 2005 when CSF appeared in South Africa (SA) after an absence of 87 years. In this review, various newly published developments in terms of the diagnosis of the disease and vaccination are described and applied to situations similar to SA. The role of wildlife such as feral pigs and European wild boar in the dissemination and maintenance of CSF virus are discussed, and the dearth of knowledge on the potential of other wild pig species prevalent on southern Africa noted. The modes of spread and control measures to prevent introduction as well as during outbreaks are discussed. PMID- 21303493 TI - Type I interferon in organ-targeted autoimmune and inflammatory diseases. AB - A significant role for IFNalpha in the pathogenesis of systemic lupus erythematosus is well supported, and clinical trials of anti-IFNalpha monoclonal antibodies are in progress in this disease. In other autoimmune diseases characterized by substantial inflammation and tissue destruction, the role of type I interferons is less clear. Gene expression analysis of peripheral blood cells from patients with rheumatoid arthritis and multiple sclerosis demonstrate an interferon signature similar to but less intense than that seen in patients with lupus. In both of those diseases, presence of the interferon signature has been associated with more significant clinical manifestations. At the same time, evidence supports an anti-inflammatory and beneficial role of IFNbeta locally in the joints of patients with rheumatoid arthritis and in murine arthritis models, and many patients with multiple sclerosis show a clinical response to recombinant IFNbeta. As can also be proposed for type I diabetes mellitus, type I interferon appears to contribute to the development of autoimmunity and disease progression in multiple autoimmune diseases, while maintaining some capacity to control established disease - particularly at local sites of inflammation. Recent studies in both rheumatoid arthritis and multiple sclerosis suggest that quantification of type I interferon activity or target gene expression might be informative in predicting responses to distinct classes of therapeutic agents. PMID- 21303494 TI - Protection from avian influenza H5N1 virus infection with antibody-impregnated filters. AB - There is worldwide concern over the possibility of a new influenza pandemic originating from the highly pathogenic avian H5N1 influenza viruses. We herein demonstrate that functional air filters impregnated with ostrich antibodies against the hemagglutinin of the H5N1 virus protect chickens from death by H5N1 transmission. These results suggest that the use of ostrich antibody-impregnated filters might be a powerful way to prevent the transmission of H5N1. PMID- 21303495 TI - Interferon-gamma, a valuable surrogate marker of Plasmodium falciparum pre erythrocytic stages protective immunity. AB - Immunity against the pre-erythrocytic stages of malaria is the most promising, as it is strong and fully sterilizing. Yet, the underlying immune effectors against the human Plasmodium falciparum pre-erythrocytic stages remain surprisingly poorly known and have been little explored, which in turn prevents any rational vaccine progress. Evidence that has been gathered in vitro and in vivo, in higher primates and in humans, is reviewed here, emphasizing the significant role of IFN gamma, either as a critical immune mediator or at least as a valuable surrogate marker of protection. One may hope that these results will trigger investigations in volunteers immunized either by optimally irradiated or over-irradiated sporozoites, to quickly delineate better surrogates of protection, which are essential for the development of a successful malaria vaccine. PMID- 21303496 TI - Improvement of a synthetic lure for Anopheles gambiae using compounds produced by human skin microbiota. AB - BACKGROUND: Anopheles gambiae sensu stricto is considered to be highly anthropophilic and volatiles of human origin provide essential cues during its host-seeking behaviour. A synthetic blend of three human-derived volatiles, ammonia, lactic acid and tetradecanoic acid, attracts A. gambiae. In addition, volatiles produced by human skin bacteria are attractive to this mosquito species. The purpose of the current study was to test the effect of ten compounds present in the headspace of human bacteria on the host-seeking process of A. gambiae. The effect of each of the ten compounds on the attractiveness of a basic blend of ammonia, lactic and tetradecanoic acid to A. gambiae was examined. METHODS: The host-seeking response of A. gambiae was evaluated in a laboratory set-up using a dual-port olfactometer and in a semi-field facility in Kenya using MM-X traps. Odorants were released from LDPE sachets and placed inside the olfactometer as well as in the MM-X traps. Carbon dioxide was added in the semi field experiments, provided from pressurized cylinders or fermenting yeast. RESULTS: The olfactometer and semi-field set-up allowed for high-throughput testing of the compounds in blends and in multiple concentrations. Compounds with an attractive or inhibitory effect were identified in both bioassays. 3-Methyl-1 butanol was the best attractant in both set-ups and increased the attractiveness of the basic blend up to three times. 2-Phenylethanol reduced the attractiveness of the basic blend in both bioassays by more than 50%. CONCLUSIONS: Identification of volatiles released by human skin bacteria led to the discovery of compounds that have an impact on the host-seeking behaviour of A. gambiae. 3 Methyl-1-butanol may be used to increase mosquito trap catches, whereas 2 phenylethanol has potential as a spatial repellent. These two compounds could be applied in push-pull strategies to reduce mosquito numbers in malaria endemic areas. PMID- 21303497 TI - Concomitant influence of helminth infection and landscape on the distribution of Puumala hantavirus in its reservoir, Myodes glareolus. AB - BACKGROUND: Puumala virus, the agent of nephropathia epidemica (NE), is the most prevalent hantavirus in Europe. The risk for human infection seems to be strongly correlated with the prevalence of Puumala virus (PUUV) in populations of its reservoir host species, the bank vole Myodes glareolus. In humans, the infection risks of major viral diseases are affected by the presence of helminth infections. We therefore proposed to analyse the influence of both helminth community and landscape on the prevalence of PUUV among bank vole populations in the Ardennes, a PUUV endemic area in France. RESULTS: Among the 313 voles analysed, 37 had anti-PUUV antibodies. Twelve gastro-intestinal helminth species were recorded among all voles sampled. We showed that PUUV seroprevalence strongly increased with age or sexual maturity, especially in the northern forests (massif des Ardennes). The helminth community structure significantly differed between this part and the woods or hedgerows of the southern cretes pre ardennaises. Using PUUV RNA quantification, we identified significant coinfections between PUUV and gastro-intestinal helminths in the northern forests only. More specifically, PUUV infection was positively associated with the presence of Heligmosomum mixtum, and in a lesser extent, Aonchotheca muris sylvatici. The viral load of PUUV infected individuals tended to be higher in voles coinfected with H. mixtum. It was significantly lower in voles coinfected with A. muris-sylvatici, reflecting the influence of age on these latter infections. CONCLUSIONS: This is the first study to emphasize hantavirus- helminth coinfections in natural populations. It also highlights the importance to consider landscape when searching for such associations. We have shown that landscape characteristics strongly influence helminth community structure as well as PUUV distribution. False associations might therefore be evidenced if geographic patterns of helminths or PUUV repartition are not previously identified. Moreover, our work revealed that interactions between helminths and landscape enhance/deplete the occurrence of coinfections between PUUV and H. mixtum or A. muris-sylvatici. Further experimental analyses and long-term individual surveys are now required to confirm these correlative results, and to ascertain the causal links between helminth and PUUV infection risks. PMID- 21303498 TI - Malaria infection by sporozoite challenge induces high functional antibody titres against blood stage antigens after a DNA prime, poxvirus boost vaccination strategy in Rhesus macaques. AB - BACKGROUND: A DNA prime, poxvirus (COPAK) boost vaccination regime with four antigens, i.e. a combination of two Plasmodium knowlesi sporozoite (csp/ssp2) and two blood stage (ama1/msp142) genes, leads to self-limited parasitaemia in 60% of rhesus monkeys and survival from an otherwise lethal infection with P. knowlesi. In the present study, the role of the blood stage antigens in protection was studied in depth, focusing on antibody formation against the blood stage antigens and the functionality thereof. METHODS: Rhesus macaques were immunized with the four-component vaccine and subsequently challenged i.v. with 100 P. knowlesi sporozoites. During immunization and challenge, antibody titres against the two blood stage antigens were determined, as well as the in vitro growth inhibition capacity of those antibodies. Antigen reversal experiments were performed to determine the relative contribution of antibodies against each of the two blood stage antigens to the inhibition. RESULTS: After vaccination, PkAMA1 and PkMSP119 antibody titres in vaccinated animals were low, which was reflected in low levels of inhibition by these antibodies as determined by in vitro inhibition assays. Interestingly, after sporozoite challenge antibody titres against blood stage antigens were boosted over 30-fold in both protected and not protected animals. The in vitro inhibition levels increased to high levels (median inhibitions of 59% and 56% at 6 mg/mL total IgG, respectively). As growth inhibition levels were not significantly different between protected and not protected animals, the ability to control infection appeared cannot be explained by GIA levels. Judged by in vitro antigen reversal growth inhibition assays, over 85% of the inhibitory activity of these antibodies was directed against PkAMA1. CONCLUSIONS: This is the first report that demonstrates that a DNA prime/poxvirus boost vaccination regimen induces low levels of malaria parasite growth inhibitory antibodies, which are boosted to high levels upon challenge. No association could, however, be established between the levels of inhibitory capacity in vitro and protection, either after vaccination or after challenge. PMID- 21303499 TI - Promiscuous prediction and conservancy analysis of CTL binding epitopes of HCV 3a viral proteome from Punjab Pakistan: an in silico approach. AB - BACKGROUND: HCV is a positive sense RNA virus affecting approximately 180 million people world wide and about 10 million Pakistani populations. HCV genotype 3a is the major cause of infection in Pakistani population. One of the major problems of HCV infection especially in the developing countries that limits the limits the antiviral therapy is the long term treatment, high dosage and side effects. Studies of antigenic epitopes of viral sequences of a specific origin can provide an effective way to overcome the mutation rate and to determine the promiscuous binders to be used for epitope based subunit vaccine design. An in silico approach was applied for the analysis of entire HCV proteome of Pakistani origin, aimed to identify the viral epitopes and their conservancy in HCV genotypes 1, 2 and 3 of diverse origin. RESULTS: Immunoinformatic tools were applied for the predictive analysis of HCV 3a antigenic epitopes of Pakistani origin. All the predicted epitopes were then subjected for their conservancy analysis in HCV genotypes 1, 2 and 3 of diverse origin (worldwide). Using freely available web servers, 150 MHC II epitopes were predicted as promiscuous binders against 51 subjected alleles. E2 protein represented the 20% of all the predicted MHC II epitopes. 75.33% of the predicted MHC II epitopes were (77-100%) conserve in genotype 3; 47.33% and 40.66% in genotype 1 and 2 respectively. 69 MHC I epitopes were predicted as promiscuous binders against 47 subjected alleles. NS4b represented 26% of all the MHC I predicted epitopes. Significantly higher epitope conservancy was represented by genotype 3 i.e. 78.26% and 21.05% for genotype 1 and 2. CONCLUSIONS: The study revealed comprehensive catalogue of potential HCV derived CTL epitopes from viral proteome of Pakistan origin. A considerable number of predicted epitopes were found to be conserved in different HCV genotype. However, the number of conserved epitopes in HCV genotype 3 was significantly higher in contrast to its conservancy in HCV genotype 1 and 2. Despite of the lower conservancy in genotype 1 and 2, all the predicted epitopes have important implications in diagnostics as well as CTL-based rational vaccine design, effective for most population of the world and especially the Pakistani population. PMID- 21303500 TI - Cost-effectiveness of three malaria treatment strategies in rural Tigray, Ethiopia where both Plasmodium falciparum and Plasmodium vivax co-dominate. AB - BACKGROUND: Malaria transmission in Ethiopia is unstable and the disease is a major public health problem. Both, p.falciparum (60%) and p.vivax (40%) co dominantly exist. The national guideline recommends three different diagnosis and treatment strategies at health post level: i) the use of a p.falciparum/vivax specific RDT as diagnosis tool and to treat with artemether-lumefantrine (AL), chloroquine (CQ) or referral if the patient was diagnosed with p.falciparum, p.vivax or no malaria, respectively (parascreen pan/pf based strategy); ii) the use of a p.falciparum specific RDT and AL for p.falciparum cases and CQ for the rest (paracheck pf based strategy); and iii) the use of AL for all cases diagnosed presumptively as malaria (presumptive based strategy). This study aimed to assess the cost-effectiveness of the recommended three diagnosis and treatment strategies in the Tigray region of Ethiopia. METHODS: The study was conducted under a routine health service delivery following the national malaria diagnosis and treatment guideline. Every suspected malaria case, who presented to a health extension worker either at a village or health post, was included. Costing, from the provider's perspective, only included diagnosis and antimalarial drugs. Effectiveness was measured by the number of correctly treated cases (CTC) and average and incremental cost-effectiveness calculated. One-way and two-way sensitivity analyses were conducted for selected parameters. RESULTS: In total 2,422 subjects and 35 health posts were enrolled in the study. The average cost effectiveness ratio showed that the parascreen pan/pf based strategy was more cost-effective (US$1.69/CTC) than both the paracheck pf (US$4.66/CTC) and the presumptive (US$11.08/CTC) based strategies. The incremental cost for the parascreen pan/pf based strategy was US$0.59/CTC to manage 65% more cases. The sensitivity analysis also confirmed parascreen pan/pf based strategy as the most cost-effective. CONCLUSION: This study showed that the parascreen pan/pf based strategy should be the preferred option to be used at health post level in rural Tigray. This finding is relevant nationwide as the entire country's malaria epidemiology is similar to the study area. PMID- 21303501 TI - FCR (Fludarabine, Cyclophosphamide, Rituximab) regimen followed by 90Yttrium ibritumomab tiuxetan consolidation for the treatment of relapsed grades 1 and 2 follicular lymphoma: a report of 9 cases. AB - BACKGROUND: This retrospective analysis is focused on the efficacy and safety of radioimmunotherapy (RIT) with Zevalin(r) in nine patients with recurrent follicular lymphoma (FL) who were treated in a consolidation setting after having achieved complete remission or partial remission with FCR. METHODS: The median age was 63 yrs (range 46-77), all patients were relapsed with histologically confirmed CD20-positive (grade 1 or 2) FL, at relapse they received FCR every 28 days: F (25 mg/m2x 3 days), C (1 gr/m2 day 1) and R (375 mg/m2 day 4) for 4 cycles. Who achieved at least a partial remission, with < 25% bone marrow involvement, was treated with 90Yttrium Ibritumomab Tiuxetan 11.1 or 14.8 MBq/Kg up to a maximum dose 1184 MBq, at 3 months after the completion of FCR. The patients underwent a further restaging at 12 weeks after 90Y-RIT with total body CT scan, FDG-PET/CT and bilateral bone marrow biopsy. RESULTS: Nine patients have completed the treatment: FCR followed by 90Y-RIT (6 patients at 14.8 MBq/Kg, 3 patients at 11.1 MBq/Kg). After FCR 7 patients obtained CR and 2 PR; after 90Y RIT two patients in PR converted to CR 12 weeks later. With median follow up of 34 months (range 13-50) the current analysis has shown that overall survival (OS) is 89% at 2 years, 76% at 3 years and 61% at 4 years. The most common grade 3 or 4 adverse events were hematologic, one patient developed herpes zoster infection after 8 months following valacyclovir discontinuation; another patient developed fungal infection. CONCLUSIONS: Our experience indicate feasibility, tolerability and efficacy of FCR regimen followed by 90Y-RIT in patients relapsed with grades 1 and 2 FL with no unexpected toxicities. A longer follow up and a larger number of patients with relapsed grades 1 and 2 FL are required to determine the impact of this regimen on long-term duration of response and PFS. PMID- 21303502 TI - Prevention of pulmonary complications of pneumoperitoneum in rats. AB - BACKGROUND: Carbon dioxide (CO2) pneumoperitoneum facilitates the visualization of abdominal organs during laparoscopic surgery. However, the associated increase in intra-abdominal pressure causes oxidative stress, which contributes to tissue injury. OBJECTIVE: We investigated the ability of the antioxidant and anti inflammatory drug Erdosteine to prevent CO2 pneumoperitoneum-induced oxidative stress and inflammatory reactions in a rat model. METHODS: Fourteen female adult Wistar albino rats were divided into a control group (Group A, n = 7) and an Erdosteine group (Group B, n = 7). Group A received 0.5 cc/day 0.9% NaCl, and Group B received 10 mg/kg/day Erdosteine was administered by gavage, and maintained for 7 days prior to the operation. During the surgical procedure, the rats were exposed to CO2 pneumoperitoneum with an intra-abdominal pressure of 15 mmHg for 30 min. The peritoneal gas was then desufflated. The rats were sacrificed following 3 h of insufflation. Their lungs were removed, histologically evaluated, and scored for intra-alveolar hemorrhage, alveolar edema, congestion, and leukocyte infiltration. The results were statistically analyzed. A value of P < 0.05 was considered statistically significant. RESULTS: Significant differences were detected in intra-alveolar hemorrhage (P < 0.05), congestion (P < 0.001), and leukocyte infiltration (P < 0.001) in Group A compared with Group B. However, the differences in alveolar edema were not statistically significant (P = 0.698). CONCLUSIONS: CO2 pneumoperitoneum results in oxidative injury to lung tissue, and administration of Erdosteine reduces the severity of pathological changes. Therefore, Erdosteine may be a useful preventive and therapeutic agent for CO2 pneumoperitoneum-induced oxidative stress in laparoscopic surgery. PMID- 21303503 TI - Integrative taxonomy: Combining morphological, molecular and chemical data for species delineation in the parthenogenetic Trhypochthonius tectorum complex (Acari, Oribatida, Trhypochthoniidae). AB - BACKGROUND: There is a long-standing controversial about how parthenogenetic species can be defined in absence of a generally accepted species concept for this reproductive mode. An integrative approach was suggested, combining molecular and morphological data to identify distinct monophyletic entities. Using this approach, speciation of parthenogenetic lineages was recently demonstrated for groups of bdelloid rotifers and oribatid mites. Trhypochthonius tectorum, an oribatid mite from the entirely parthenogenetic desmonomatan family Trhypochthoniidae, is traditionally treated as a single species in Central Europe. However, two new morphological lineages were recently proposed for some Austrian populations of T. tectorum, and were described as novel subspecies (T. silvestris europaeus) or form (T. japonicus forma occidentalis). We used the morphological and morphometrical data which led to this separation, and added mitochondrial and nuclear DNA sequences and the chemical composition of complex exocrine oil gland secretions to test this taxonomical hypothesis. This is the first attempt to combine these three types of data for integrative taxonomical investigations of oribatid mites. RESULTS: We show that the previous European species T. tectorum represents a species complex consisting of three distinct lineages in Austria (T.tectorum, T. silvestris europaeus and T. japonicus forma occidentalis), each clearly separated by morphology, oil gland secretion profiles and mitochondrial cox1 sequences. This diversification happened in the last ten million years. In contrast to these results, no variation among the lineages was found in the nuclear 18S rDNA. CONCLUSIONS: Our approach combined morphological, molecular and chemical data to investigate diversity and species delineation in a parthenogenetic oribatid mite species complex. To date, hypotheses of a general oribatid mite phylogeny are manifold, and mostly based on single-method approaches. Probably, the integrative approach proposed here can be used to uncover further hidden biodiversity of glandulate Oribatida and help to build up more stable phylogenetic hypotheses in the future. PMID- 21303504 TI - The ethical and legal aspects of palliative sedation in severely brain-injured patients: a French perspective. AB - To fulfill their crucial duty of relieving suffering in their patients, physicians may have to administer palliative sedation when they implement treatment-limitation decisions such as the withdrawal of life-supporting interventions in patients with poor prognosis chronic severe brain injury. The issue of palliative sedation deserves particular attention in adults with serious brain injuries and in neonates with severe and irreversible brain lesions, who are unable to express pain or to state their wishes. In France, treatment limitation decisions for these patients are left to the physicians. Treatment limitation decisions are made collegially, based on the presence of irreversible brain lesions responsible for chronic severe disorders of consciousness. Before these decisions are implemented, they are communicated to the relatives. Because the presence and severity of pain cannot be assessed in these patients, palliative analgesia and/or sedation should be administered. However, palliative sedation is a complex strategy that requires safeguards to prevent a drift toward hastening death or performing covert euthanasia. In addition to the law on patients' rights at the end of life passed in France on April 22, 2005, a recent revision of Article 37 of the French code of medical ethics both acknowledges that treatment-limitation decisions and palliative sedation may be required in patients with severe brain injuries and provides legal and ethical safeguards against a shift towards euthanasia. This legislation may hold value as a model for other countries where euthanasia is illegal and for countries such as Belgium and Netherlands where euthanasia is legal but not allowed in patients incapable of asking for euthanasia but in whom a treatment limitation decision has been made. PMID- 21303505 TI - Short-term outcomes of community-based adolescent weight management: The Loozit(r) Study. AB - BACKGROUND: The Loozit((r)) Study is a randomised controlled trial investigating extended support in a 24 month community-based weight management program for overweight to moderately obese, but otherwise healthy, 13 to 16 year olds. METHODS: This pre-post study examines the two month outcomes of the initial Loozit((r)) group intervention received by both study arms. Adolescents (n = 151; 48% male) and their parents separately attended seven weekly group sessions focused on lifestyle modification. At baseline and two months, adolescents' anthropometry, blood pressure, and fasted blood sample were assessed. Primary outcomes were two month changes in body mass index (BMI) z-score and waist-to height-ratio (WHtR). Secondary outcomes included changes in metabolic profile, self-reported dietary intake/patterns, physical and sedentary activities, psychological characteristics and social status. Changes in outcome measures were assessed using paired samples t-tests for continuous variables or McNemar's test for dichotomous categorical variables. RESULTS: Of the 151 adolescents who enrolled, 130 (86%) completed the two month program. Among these 130 adolescents (47% male), there was a statistically significant (P < 0.01) reduction in mean [95% CI] BMI (0.27 kg/m2 [0.41, 0.13]), BMI z-score (0.05 [0.06, 0.03]), WHtR (0.02 [0.03, 0.01]), total cholesterol (0.14 mmol/L [0.24, 0.05]) and low-density lipoprotein cholesterol (0.12 mmol/L [0.21, 0.04]). There were improvements in all psychological measures, the majority of the dietary intake measures, and some physical activities (P < 0.05). Time spent watching TV and participating in non screen sedentary activities decreased (P < 0.05). CONCLUSIONS: The Loozit((r)) program may be a promising option for stabilizing overweight and improving various metabolic factors, psychological functioning and lifestyle behaviors in overweight adolescents in a community setting. TRIAL REGISTRATION: Australian New Zealand Clinical Trials RegistryACTRNO12606000175572. PMID- 21303506 TI - Protein kinase A type I activates a CRE-element more efficiently than protein kinase A type II regardless of C subunit isoform. AB - BACKGROUND: Protein kinase A type I (PKAI) and PKAII are expressed in most of the eukaryotic cells examined. PKA is a major receptor for cAMP and specificity is achieved partly through tissue-dependent expression and subcellular localization of subunits with different biochemical properties. In addition posttranslational modifications help fine tune PKA activity, distribution and interaction in the cell. In spite of this the functional significance of two forms of PKA in one cell has not been fully determined. Here we have tested the ability of PKAI and PKAII formed by expression of the regulatory (R) subunits RIalpha or RIIalpha in conjunction with Calpha1 or Cbeta2 to activate a co-transfected luciferace reporter gene, controlled by the cyclic AMP responsive element-binding protein (CREB) in vivo. RESULTS: We show that PKAI when expressed at equal levels as PKAII was significantly (p < 0.01) more efficient in inducing Cre-luciferace activity at saturating concentrations of cAMP. This result was obtained regardless of catalytic subunit identity. CONCLUSION: We suggest that differential effects of PKAI and PKAII in inducing Cre-luciferace activity depend on R and not C subunit identity. PMID- 21303507 TI - A novel approach to the clustering of microarray data via nonparametric density estimation. AB - BACKGROUND: Cluster analysis is a crucial tool in several biological and medical studies dealing with microarray data. Such studies pose challenging statistical problems due to dimensionality issues, since the number of variables can be much higher than the number of observations. RESULTS: Here, we present a general framework to deal with the clustering of microarray data, based on a three-step procedure: (i) gene filtering; (ii) dimensionality reduction; (iii) clustering of observations in the reduced space. Via a nonparametric model-based clustering approach we obtain promising results both in simulated and real data. CONCLUSIONS: The proposed algorithm is a simple and effective tool for the clustering of microarray data, in an unsupervised setting. PMID- 21303508 TI - Gene gain and loss events in Rickettsia and Orientia species. AB - BACKGROUND: Genome degradation is an ongoing process in all members of the Rickettsiales order, which makes these bacterial species an excellent model for studying reductive evolution through interspecies variation in genome size and gene content. In this study, we evaluated the degree to which gene loss shaped the content of some Rickettsiales genomes. We shed light on the role played by horizontal gene transfers in the genome evolution of Rickettsiales. RESULTS: Our phylogenomic tree, based on whole-genome content, presented a topology distinct from that of the whole core gene concatenated phylogenetic tree, suggesting that the gene repertoires involved have different evolutionary histories. Indeed, we present evidence for 3 possible horizontal gene transfer events from various organisms to Orientia and 6 to Rickettsia spp., while we also identified 3 possible horizontal gene transfer events from Rickettsia and Orientia to other bacteria. We found 17 putative genes in Rickettsia spp. that are probably the result of de novo gene creation; 2 of these genes appear to be functional. On the basis of these results, we were able to reconstruct the gene repertoires of "proto-Rickettsiales" and "proto-Rickettsiaceae", which correspond to the ancestors of Rickettsiales and Rickettsiaceae, respectively. Finally, we found that 2,135 genes were lost during the evolution of the Rickettsiaceae to an intracellular lifestyle. CONCLUSIONS: Our phylogenetic analysis allowed us to track the gene gain and loss events occurring in bacterial genomes during their evolution from a free-living to an intracellular lifestyle. We have shown that the primary mechanism of evolution and specialization in strictly intracellular bacteria is gene loss. Despite the intracellular habitat, we found several horizontal gene transfers between Rickettsiales species and various prokaryotic, viral and eukaryotic species. OPEN PEER REVIEW: Reviewed by Arcady Mushegian, Eugene V. Koonin and Patrick Forterre. For the full reviews please go to the Reviewers' comments section. PMID- 21303509 TI - Follistatin-like protein 1 is elevated in systemic autoimmune diseases and correlated with disease activity in patients with rheumatoid arthritis. AB - INTRODUCTION: Follistatin-like protein 1 (FSTL1) is a proinflammation mediator implicated in arthritis in rodent animal models. The present study is aimed at assessing FSTL1 levels in systemic autoimmune diseases and correlating them with disease activity in patients with rheumatoid arthritis (RA). METHODS: Serum FSTL1 levels from 487 patients with systemic autoimmune diseases and 69 healthy individuals were measured by enzyme-linked immunosorbent assay (ELISA). FSTL1 expression in synovial fluid (SF) and synovial tissues (STs) was determined by ELISA, immunohistochemistry, real-time polymerase chain reaction (RT-PCR) and western blot analysis in RA patients and trauma controls. FSTL1 levels in fibroblast-like synoviocytes (FLSs) from RA patients were determined by real-time PCR and western blot analysis. RESULTS: Serum FSTL1 levels were significantly elevated in patients with RA, ulcerative colitis, systemic lupus erythematosus, Sjogren's syndrome (SS), systemic sclerosis and polymyositis/dermatomyositis. Serum FSTL1 levels in the RA and secondary SS patients were substantially higher than those in other patients. Serum FSTL1 levels were increased in early RA, rheumatoid factor (RF)- and anti-cyclic citrullinated peptide antibody (ACPA) negative patients compared to healthy controls. Moreover, serum FSTL1 concentrations were significantly higher in long-standing RA patients than in early RA patients and in the RF- and ACPA-positive RA patients than in RF- and ACPA-negative RA patients. Elevated FSTL1 levels in the STs and SF of RA patients were also observed. FSTL1 levels in serum were markedly higher than those in SF in RA patients. The strongest FSTL1 staining was detected in the cytoplasm of synovial and capillary endothelial cells from RA synovium. Furthermore, FSTL1 was induced in FLSs by inflammatory mediators. Importantly, serum FSTL1 levels were correlated with several important biologic and clinical markers of disease activity, including erythrocyte sedimentation rate, C-reactive protein, RF, ACPA, swollen joint count, patient global visual analogue scale score and Disease Activity Score 28 in the adult RA patient population. Notably, serum FSTL1 levels were significantly diminished following successful treatment and clinical improvement. CONCLUSIONS: Elevated FSTL1 levels reflect not only joint diseases but also inflammation and tissue degradation in systemic autoimmune diseases. Serum FSTL1 levels may thus serve as a serological inflammatory marker of disease activity in RA patients. PMID- 21303510 TI - EMS-physicians' self reported airway management training and expertise; a descriptive study from the Central Region of Denmark. AB - BACKGROUND: Prehospital advanced airway management, including prehospital endotracheal intubation is challenging and recent papers have addressed the need for proper training, skill maintenance and quality control for emergency medical service personnel. The aim of this study was to provide data regarding airway management-training and expertise from the regional physician-staffed emergency medical service (EMS). METHODS: The EMS in this part of The Central Region of Denmark is a two tiered system. The second tier comprises physician staffed Mobile Emergency Care Units. The medical directors of the programs supplied system data. A questionnaire addressing airway management experience, training and knowledge was sent to the EMS-physicians. RESULTS: There are no specific guidelines, standard operating procedures or standardised program for obtaining and maintaining skills regarding prehospital advanced airway management in the schemes covered by this study. 53/67 physicians responded; 98,1% were specialists in anesthesiology, with an average of 17,6 years of experience in anesthesiology, and 7,2 years experience as EMS-physicians. 84,9% reported having attended life support course(s), 64,2% an advanced airway management course. 24,5% fulfilled the curriculum suggested for Danish EMS physicians. 47,2% had encountered a difficult or impossible PHETI, most commonly in a patient in cardiac arrest or a trauma patient. Only 20,8% of the physicians were completely familiar with what back-up devices were available for airway management. CONCLUSIONS: In this, the first Danish study of prehospital advanced airway management, we found a high degree of experience, education and training among the EMS-physicians, but their equipment awareness was limited. Check-outs, guidelines, standard operating procedures and other quality control measures may be needed. PMID- 21303511 TI - The dilemma of widal test - which brand to use? a study of four different widal brands: a cross sectional comparative study. AB - BACKGROUND: Serodiagnosis of typhoid fever by Widal test based on demonstrating the presence of agglutinins (antibodies) in the serum of an infected patient, against the H (flagellar) and O (somatic) antigens of Salmonella enterica serotype Typhi has been associated with many debates. This is why the aim of this study was to: (i) Compare the diagnostic accuracy of four different commercial kits used to perform Widal test (Remel, BioSystems, Dialab and Biotec). (ii) Compare the sensitivity and specificity of both anti-O and anti-H antibodies. (iii) Compare the validity of single versus paired serum samples with a rising titer for the diagnosis of typhoid fever. METHODS: Duplicate serum samples were obtained from 150 patients clinically diagnosed as typhoid fever patients. Moreover, single serum samples were obtained from 25 patients with febrile diseases other than typhoid fever. All samples were tested using the four different Widal brands and Salmonella Typhi IgM anti-LPS ELISA. RESULTS: -The results of Widal tests differed markedly using the four Widal brands in terms of sensitivity and specificity at three cut-off values of 1/80, 1/160 and 1/320. Remel brand gave the highest sensitivities and the lowest specificities and Dialab brand gave the highest specificities and the lowest sensitivities for both anti-O and anti-H antibodies at the three cut-off values.-Four fold rise in the antibodies titer was not demonstrable among clinically diagnosed typhoid fever patients-H agglutinins were less sensitive and less specific than O agglutinins CONCLUSIONS: -Widal test results showed marked discrepancies using different Widal brands. None of the serum samples of the typhoid fever patients showed four fold rise in the antibody titers. Raised O agglutinins were of slightly greater diagnostic value than raised H agglutinins. SIGNIFICANCE AND IMPACT OF STUDY: Widal test done sequentially using two brands could be of value in typhoid fever diagnosis. Single serum sample could be used for typhoid fever diagnosis relying on anti O titer. PMID- 21303512 TI - Genetic diversity of Actinobacillus lignieresii isolates from different hosts. AB - Genetic diversity detected by analysis of amplified fragment length polymorphisms (AFLPs) of 54 Actinobacillus lignieresii isolates from different hosts and geographic localities is described. On the basis of variances in AFLP profiles, the strains were grouped in two major clusters; one comprising strains isolated from horses and infected wounds of humans bitten by horses and another consisting of strains isolated from bovine and ovine hosts. The present data indicate a comparatively higher degree of genetic diversity among strains isolated from equine hosts and confirm the existence of a separate genomospecies for A. lignieresi-like isolates from horses. Among the isolates from bovine and ovine hosts some clonal lines appear to be genetically stable over time and could be detected at very distant geographic localities. Although all ovine strains investigated grouped in a single cluster, the existence of distinct genetic lineages that have evolved specificity for ovine hosts is not obvious and needs to be confirmed in other studies. PMID- 21303513 TI - Neuropathologic features in the hippocampus and cerebellum of three older men with fragile X syndrome. AB - BACKGROUND: Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, and is the most common single-gene disorder known to be associated with autism. Despite recent advances in functional neuroimaging and our understanding of the molecular pathogenesis, only limited neuropathologic information on FXS is available. METHODS: Neuropathologic examinations were performed on post-mortem brain tissue from three older men (aged 57, 64 and 78 years) who had received a clinical or genetic diagnosis of FXS. In each case, physical and cognitive features were typical of FXS, and one man was also diagnosed with autism. Guided by reports of clinical and neuroimaging abnormalities of the limbic system and cerebellum of individuals with FXS, the current analysis focused on neuropathologic features present in the hippocampus and the cerebellar vermis. RESULTS: Histologic and immunologic staining revealed abnormalities in both the hippocampus and cerebellar vermis. Focal thickening of hippocampal CA1 and irregularities in the appearance of the dentate gyrus were identified. All lobules of the cerebellar vermis and the lateral cortex of the posterior lobe of the cerebellum had decreased numbers of Purkinje cells, which were occasionally misplaced, and often lacked proper orientation. There were mild, albeit excessive, undulations of the internal granular cell layer, with patchy foliar white matter axonal and astrocytic abnormalities. Quantitative analysis documented panfoliar atrophy of both the anterior and posterior lobes of the vermis, with preferential atrophy of the posterior lobule (VI to VII) compared with age-matched normal controls. CONCLUSIONS: Significant morphologic changes in the hippocampus and cerebellum in three adult men with FXS were identified. This pattern of pathologic features supports the idea that primary defects in neuronal migration, neurogenesis and aging may underlie the neuropathology reported in FXS. PMID- 21303514 TI - Pulmonary artery injury during mediastinoscopy controlled without gauze packing. AB - The most serious complication that can occur during mediastinoscopy is hemorrhage from large vessels in the mediastinum, whereas there are few articles relating to injury to major vessels. We describe a case of 77-year-old male with mediastinal lymphadenopathy, who underwent a mediastinoscopy procedure. When the pretracheal lymph nodes adjoining the right pulmonary artery were biopsied, a massive amount of bleeding spilled out through the scope. Immediately, the scope was removed from the body and the bleeding was controlled with digital compression at the skin incision. Then we closed the incision in a three-layer manner without any gauze packing in the mediastinum. Although some reports recommended gauze packing for massive bleeding during mediastinoscopy, we believe not all cases need gauze packing because bleeding from a low-pressure circulation system component into closed compartment, such as mediastinum, would cease without resulting in a large hematoma or pseudoaneurysm. PMID- 21303516 TI - Genetic diversity of Imjin virus in the Ussuri white-toothed shrew (Crocidura lasiura) in the Republic of Korea, 2004-2010. AB - Recently, Imjin virus (MJNV), a genetically distinct hantavirus, was isolated from lung tissues of the Ussuri white-toothed shrew (Crocidura lasiura) captured near the demilitarized zone in the Republic of Korea. To clarify the genetic diversity of MJNV, partial M- and L-segment sequences were amplified from lung tissues of 12 of 37 (32.4%) anti-MJNV IgG antibody-positive Ussuri white-toothed shrews captured between 2004 and 2010. A 531-nucleotide region of the M segment (coordinates 2,255 to 2,785) revealed that the 12 MJNV strains differed by 0 12.2% and 0-2.3% at the nucleotide and amino acid levels, respectively. A similar degree of nucleotide (0.2-11.9%) and amino acid (0-3.8%) difference was found in a 632-nucleotide length of the L segment (coordinates 962 to 1,593) of nine MJNV strains. Phylogenetic analyses, based on the partial M and L segments of MJNV strains generated by the neighbor-joining and maximum likelihood methods, showed geographic-specific clustering, akin to the phylogeography of rodent-borne hantaviruses. PMID- 21303515 TI - Hand-suture versus stapling for closure of loop ileostomy: HASTA-Trial: a study rationale and design for a randomized controlled trial. AB - BACKGROUND: Colorectal cancer is the second most common tumor in developed countries, with a lifetime prevalence of 5%. About one third of these tumors are located in the rectum. Surgery in terms of low anterior resection with mesorectal excision is the central element in the treatment of rectal cancer being the only option for definite cure. Creating a protective diverting stoma prevents complications like anastomotic failure and meanwhile is the standard procedure. Bowel obstruction is one of the main and the clinically and economically most relevant complication following closure of loop ileostomy. The best surgical technique for closure of loop ileostomy has not been defined yet. METHODS/DESIGN: A study protocol was developed on the basis of the only randomized controlled mono-center trial to solve clinical equipoise concerning the optimal surgical technique for closure of loop ileostomy after low anterior resection due to rectal cancer.The HASTA trial is a multi-center pragmatic randomized controlled surgical trial with two parallel groups to compare hand-suture versus stapling for closure of loop ileostomy. It will include 334 randomized patients undergoing closure of loop ileostomy after low anterior resection with protective ileostomy due to rectal cancer in approximately 20 centers consisting of German hospitals of all level of health care. The primary endpoint is the rate of bowel obstruction within 30 days after ileostomy closure. In addition, a set of surgical and general variables including quality of life will be analyzed with a follow-up of 12 months. An investigators meeting with a practical session will help to minimize performance bias and enforce protocol adherence. Centers are monitored centrally as well as on-site before and during recruitment phase to assure inclusion, treatment and follow up according to the protocol. DISCUSSION: Aim of the HASTA trial is to evaluate the efficacy of hand-suture versus stapling for closure of loop ileostomy in patients with rectal cancer. TRIAL REGISTRATION: German Clinical Trial Register Number: DRKS00000040. PMID- 21303517 TI - Dysregulated expression of MIG/CXCL9, IP-10/CXCL10 and CXCL16 and their receptors in systemic sclerosis. AB - INTRODUCTION: Systemic sclerosis (SSc) is characterized by fibrosis and microvascular abnormalities including dysregulated angiogenesis. Chemokines, in addition to their chemoattractant properties, have the ability to modulate angiogenesis. Chemokines lacking the enzyme-linked receptor (ELR) motif, such as monokine induced by interferon-gamma (IFN-gamma) (MIG/CXCL9) and IFN-inducible protein 10 (IP-10/CXCL10), inhibit angiogenesis by binding CXCR3. In addition, CXCL16 promotes angiogenesis by binding its unique receptor CXCR6. In this study, we determined the expression of these chemokines and receptors in SSc skin and serum. METHODS: Immunohistology and enzyme-linked immunosorbent assays (ELISAs) were used to determine chemokine and chemokine receptor expression in the skin and serum, respectively, of SSc and normal patients. Endothelial cells (ECs) were isolated from SSc skin biopsies and chemokine and chemokine receptor expression was determined by quantitative PCR and immunofluorescence staining. RESULTS: Antiangiogenic IP-10/CXCL10 and MIG/CXCL9 were elevated in SSc serum and highly expressed in SSc skin. However, CXCR3, the receptor for these chemokines, was decreased on ECs in SSc vs. normal skin. CXCL16 was elevated in SSc serum and increased in SSc patients with early disease, pulmonary arterial hypertension, and those that died during the 36 months of the study. In addition, its receptor CXCR6 was overexpressed on ECs in SSc skin. At the mRNA and protein levels, CXCR3 was decreased while CXCR6 was increased on SSc ECs vs. human microvascular endothelial cells (HMVECs). CONCLUSIONS: These results show that while the expression of MIG/CXCL9 and IP-10/CXCL10 are elevated in SSc serum, the expression of CXCR3 is downregulated on SSc dermal ECs. In contrast, CXCL16 and CXCR6 are elevated in SSc serum and on SSc dermal ECs, respectively. In all, these findings suggest angiogenic chemokine receptor expression is likely regulated in an effort to promote angiogenesis in SSc skin. PMID- 21303518 TI - The bioenergetic signature of isogenic colon cancer cells predicts the cell death response to treatment with 3-bromopyruvate, iodoacetate or 5-fluorouracil. AB - BACKGROUND: Metabolic reprogramming resulting in enhanced glycolysis is a phenotypic trait of cancer cells, which is imposed by the tumor microenvironment and is linked to the down-regulation of the catalytic subunit of the mitochondrial H+-ATPase (beta-F1-ATPase). The bioenergetic signature is a protein ratio (beta-F1-ATPase/GAPDH), which provides an estimate of glucose metabolism in tumors and serves as a prognostic indicator for cancer patients. Targeting energetic metabolism could be a viable alternative to conventional anticancer chemotherapies. Herein, we document that the bioenergetic signature of isogenic colon cancer cells provides a gauge to predict the cell-death response to the metabolic inhibitors, 3-bromopyruvate (3BrP) and iodoacetate (IA), and the anti metabolite, 5-fluorouracil (5-FU). METHODS: The bioenergetic signature of the cells was determined by western blotting. Aerobic glycolysis was determined from lactate production rates. The cell death was analyzed by fluorescence microscopy and flow cytometry. Cellular ATP concentrations were determined using bioluminiscence. Pearson's correlation coefficient was applied to assess the relationship between the bioenergetic signature and the cell death response. In vivo tumor regression activities of the compounds were assessed using a xenograft mouse model injected with the highly glycolytic HCT116 colocarcinoma cells. RESULTS: We demonstrate that the bioenergetic signature of isogenic HCT116 cancer cells inversely correlates with the potential to execute necrosis in response to 3BrP or IA treatment. Conversely, the bioenergetic signature directly correlates with the potential to execute apoptosis in response to 5-FU treatment in the same cells. However, despite the large differences observed in the in vitro cell-death responses associated with 3BrP, IA and 5-FU, the in vivo tumor regression activities of these agents were comparable. CONCLUSIONS: Overall, we suggest that the determination of the bioenergetic signature of colon carcinomas could provide a tool for predicting the therapeutic response to various chemotherapeutic strategies aimed at combating tumor progression. PMID- 21303519 TI - Consistent phenological shifts in the making of a biodiversity hotspot: the Cape flora. AB - BACKGROUND: The best documented survival responses of organisms to past climate change on short (glacial-interglacial) timescales are distributional shifts. Despite ample evidence on such timescales for local adaptations of populations at specific sites, the long-term impacts of such changes on evolutionary significant units in response to past climatic change have been little documented. Here we use phylogenies to reconstruct changes in distribution and flowering ecology of the Cape flora--South Africa's biodiversity hotspot--through a period of past (Neogene and Quaternary) changes in the seasonality of rainfall over a timescale of several million years. RESULTS: Forty-three distributional and phenological shifts consistent with past climatic change occur across the flora, and a comparable number of clades underwent adaptive changes in their flowering phenology (9 clades; half of the clades investigated) as underwent distributional shifts (12 clades; two thirds of the clades investigated). Of extant Cape angiosperm species, 14-41% have been contributed by lineages that show distributional shifts consistent with past climate change, yet a similar proportion (14-55%) arose from lineages that shifted flowering phenology. CONCLUSIONS: Adaptive changes in ecology at the scale we uncover in the Cape and consistent with past climatic change have not been documented for other floras. Shifts in climate tolerance appear to have been more important in this flora than is currently appreciated, and lineages that underwent such shifts went on to contribute a high proportion of the flora's extant species diversity. That shifts in phenology, on an evolutionary timescale and on such a scale, have not yet been detected for other floras is likely a result of the method used; shifts in flowering phenology cannot be detected in the fossil record. PMID- 21303520 TI - Evidence for validity and reliability of a French version of the FAAM. AB - BACKGROUND: The Foot and Ankle Ability Measure (FAAM) is a self reported questionnaire for patients with foot and ankle disorders available in English, German, and Persian. This study plans to translate the FAAM from English to French (FAAM-F) and assess the validity and reliability of this new version. METHODS: The FAAM-F Activities of Daily Living (ADL) and sports subscales were completed by 105 French-speaking patients (average age 50.5 years) presenting various chronic foot and ankle disorders. Convergent and divergent validity was assessed by Pearson's correlation coefficients between the FAAM-F subscales and the SF-36 scales: Physical Functioning (PF), Physical Component Summary (PCS), Mental Health (MH) and Mental Component Summary (MCS). Internal consistency was calculated by Cronbach's Alpha (CA). To assess test re-test reliability, 22 patients filled out the questionnaire a second time to estimate minimal detectable changes (MDC) and intraclass correlation coefficients (ICC). RESULTS: Correlations for FAAM-F ADL subscale were 0.85 with PF, 0.81 with PCS, 0.26 with MH, 0.37 with MCS. Correlations for FAAM-F Sports subscale were 0.72 with PF, 0.72 with PCS, 0.21 with MH, 0.29 with MCS. CA estimates were 0.97 for both subscales. Respectively for the ADL and Sports subscales, ICC were 0.97 and 0.94, errors for a single measure were 8 and 10 points at 95% confidence and the MDC values at 95% confidence were 7 and 18 points. CONCLUSION: The FAAM-F is valid and reliable for the self-assessment of physical function in French-speaking patients with a wide range of chronic foot and ankle disorders. PMID- 21303521 TI - Molecular cytogenetic analysis and clinical manifestations of a case with de novo mosaic ring chromosome 7. AB - AIM: Clinical and molecular cytogenetic investigations of a newborn girl exhibiting facial dysmorphism with developmental delay. METHODS: Phenotypic evaluation was first applied to examine the proband's developmental status. Computed tomography and colour transcranial Doppler were used then to investigate her brain structure and function. Subsequently, chromosomal abnormalities were examined by karyotyping and fluorescent in situ hybridization was performed to investigate size of fragments lost at the two distal ends of the ring chromosome 7. In addition, multicolour banding was applied to rule out structural rearrangement occurs in between the ring chromosome 7. RESULTS: The proband was born with mosaic supernumerary ring chromosome 7, without a normal karyotype detected in the peripheral blood lymphocytes. The distal arm of chromosome 7p (at least 255 kb from the telomere) was part of an extra ring chromosome 7. In addition, the distal arm of 7q, at least 8 kb from the telomere, was missing. There was no other chromosomal rearrangement detected by multicolour banding. INTERPRETATION: This is the 19th reported case of complete ring chromosome 7 mosaicism and the first survived case with mosaic supernumerary ring 7 without a normal karyotype detected in the peripheral lymphocytes. PMID- 21303522 TI - Differential relationships of family drinking with alcohol expectancy among urban school children. AB - BACKGROUND: Positive alcohol outcome expectancy has consistently been linked with problematic drinking, but there is little population-based evidence on its role on early stages of drinking in childhood. The present study seeks to understand the extent to which drinking of family members is differentially associated with the endorsement of alcohol expectancy in late childhood. METHODS: A representative sample of 4th and 6th graders (N = 2455) drawn from 28 public schools in an urban region of Taiwan completed a self-administered paper-and pencil questionnaire. Each student provided information on alcohol expectancy, drinking experiences, and individual and family attributes. Complex survey analyses were performed to evaluate the relationship, with stratification by children's alcohol drinking history. RESULTS: An estimated 29% of the 4th graders and 43% of the 6th graders had initiated alcohol consumption (over 40% of them had drank on three or more occasions). Alcohol drinking-related differences appear in both the endorsement and the correlates of alcohol expectancy. Positive alcohol expectancy was strongly associated with family drinking, particularly the dimension of "enhanced social behaviors"; negative alcohol expectancy was inversely associated with drinking frequency. Among alcohol naive children, significant connections appear between paternal drinking and three dimensions of positive alcohol expectancy (i.e., enhanced social behaviors:betawt = 0.15, promoting relaxation or tension reduction:betawt = 0.18, and global positive transformation:betawt = 0.22). CONCLUSIONS: Individual tailored strategies that address family influences on alcohol expectancy may be needed in prevention programs targeting drinking behaviors in children. PMID- 21303523 TI - Climate for evidence-informed health systems: A print media analysis in 44 low- and middle-income countries that host knowledge-translation platforms. AB - BACKGROUND: We conducted a print media analysis in 44 countries in Africa, the Americas, Asia, and the Eastern Mediterranean in order to understand one dimension of the climate for evidence-informed health systems and to provide a baseline for an evaluation of knowledge-translation platforms. Our focus was whether and how policymakers, stakeholders, and researchers talk in the media about three topics: policy priorities in the health sector, health research evidence, and policy dialogues regarding health issues. METHODS: We developed a search strategy consisting of three progressively more delimited phases. For each jurisdiction, we searched Major World Publications in LexisNexis Academic News for articles published in 2007, selected relevant articles using one set of general criteria and three sets of concept-specific criteria, and coded the selected articles to identify common themes. Second raters took part in the analysis of Lebanon and Malaysia to assess inter-rater reliability for article selection and coding. RESULTS: We identified approximately 5.5 and 5 times more articles describing health research evidence compared to the number of articles describing policy priorities and policy dialogues, respectively. Few articles describing health research evidence discussed systematic reviews (2%) or health systems research (2%), and few of the policy dialogue articles discussed researcher involvement (9%). News coverage of these concepts was highly concentrated in several countries like China and Uganda, while few articles were found for many other jurisdictions. Kappa scores were acceptable and consistently greater than 0.60. CONCLUSIONS: In many countries the print media, at least as captured in a global database, are largely silent about three topics central to evidence-informed health systems. These findings suggest the need for proactive media engagement strategies. PMID- 21303524 TI - Under-reporting of foetal alcohol spectrum disorders: an analysis of hospital episode statistics. AB - BACKGROUND: Internationally, 0.97 per 1,000 live births are affected by foetal alcohol syndrome (FAS). However, prevalence intelligence has been limited in the UK, hindering the development of appropriate services. This analysis compares hospital admissions over time, between regions and with alcohol-related admissions for adult females to assess whether established patterns (such as the North experiencing elevated harms) can be identified. METHODS: A retrospective analysis of hospital admissions data (April 2002 to March 2008) for foetal alcohol spectrum disorder (FASD)-related conditions: foetal alcohol syndrome (dysmorphic) (n = 457); foetus and newborn affected by maternal use of alcohol (n = 157); maternal care for (suspected) damage to foetus from alcohol (n = 285); and 322,161 women admitted due to alcohol-related conditions. RESULTS: Whilst the rate of admission for alcohol-related conditions in women aged 15-44 years increased significantly by 41% between 2002/03 and 2007/08 (p < 0.0001), no such increases were seen in the numbers of FASD-related conditions (all p < 0.05). Established regional rates of admission for alcohol-related conditions in women aged 15-44 years old were not associated with admission for FASD-related conditions. CONCLUSIONS: It would be expected that the North West and North East regions, known to have higher levels of alcohol harm would have higher levels of FASD-related conditions. However, this was not reflected in the incidence of such conditions, suggesting under-reporting. With incomplete datasets, intelligence systems are severely limited, hampering efforts to develop targeted interventions. Improvements to intelligence systems, practitioner awareness and screening are essential in tackling this. PMID- 21303525 TI - A single-tube allele specific-polymerase chain reaction to detect T315I resistant mutation in chronic myeloid leukemia patients. AB - BACKGROUND: BCR-ABL kinase domain (KD) mutation is the major mechanism contributing to suboptimal response to tyrosine kinase inhibitors (TKI) in BCR ABL-positive chronic myeloid leukemia (CML) patients. T315I mutation, as one of the most frequent KD mutations, has been shown to be strongly associated with TKI resistance and subsequent therapeutic failure. A simple and sensitive method is thus required to detect T315I mutation at the earliest stage. METHODS: A single tube allele specific-polymerase chain reaction (AS-PCR) method was developed to detect T315I mutation in a mixture of normal and mutant alleles of varying dilutions. Denaturing high performance liquid chromatography (DHPLC) and direct sequencing were performed as a comparison to AS-PCR. RESULTS: T315I mutant bands were observed in the mixtures containing as low as 0.5-1% of mutant alleles by AS PCR. The detection sensitivity of DHPLC was around 1.5-3% dilution whereas sequencing analysis was unable to detect below 6.25% dilution. CONCLUSION: A single-tube AS-PCR is a rapid and sensitive screening method for T315I mutation. Detection of the most resistant leukemic clone in CML patients undergoing TKI therapy should be feasible with this simple and inexpensive method. PMID- 21303526 TI - Regulation of cardiac microRNAs by serum response factor. AB - Serum response factor (SRF) regulates certain microRNAs that play a role in cardiac and skeletal muscle development. However, the role of SRF in the regulation of microRNA expression and microRNA biogenesis in cardiac hypertrophy has not been well established. In this report, we employed two distinct transgenic mouse models to study the impact of SRF on cardiac microRNA expression and microRNA biogenesis. Cardiac-specific overexpression of SRF (SRF-Tg) led to altered expression of a number of microRNAs. Interestingly, downregulation of miR 1, miR-133a and upregulation of miR-21 occurred by 7 days of age in these mice, long before the onset of cardiac hypertrophy, suggesting that SRF overexpression impacted the expression of microRNAs which contribute to cardiac hypertrophy. Reducing cardiac SRF level using the antisense-SRF transgenic approach (Anti-SRF Tg) resulted in the expression of miR-1, miR-133a and miR-21 in the opposite direction. Furthermore, we observed that SRF regulates microRNA biogenesis, specifically the transcription of pri-microRNA, thereby affecting the mature microRNA level. The mir-21 promoter sequence is conserved among mouse, rat and human; one SRF binding site was found to be in the mir-21 proximal promoter region of all three species. The mir-21 gene is regulated by SRF and its cofactors, including myocardin and p49/Strap. Our study demonstrates that the downregulation of miR-1, miR-133a, and upregulation of miR-21 can be reversed by one single upstream regulator, SRF. These results may help to develop novel therapeutic interventions targeting microRNA biogenesis. PMID- 21303527 TI - Bostrycin inhibits proliferation of human lung carcinoma A549 cells via downregulation of the PI3K/Akt pathway. AB - BACKGROUND: Bostrycin is a novel compound isolated from marine fungi that inhibits proliferation of many cancer cells. However, the inhibitory effect of bostrycin on lung cancers has not been reported. This study is to investigate the inhibitory effects and mechanism of bostrycin on human lung cancer cells in vitro. METHODS: We used MTT assay, flow cytometry, microarray, real time PCR, and Western blotting to detect the effect of bostrycin on A549 human pulmonary adenocarcinoma cells. RESULTS: We showed a significant inhibition of cell proliferation and induction of apoptosis in bostrycin-treated lung adenocarcinoma cells. Bostrycin treatment caused cell cycle arrest in the G0/G1 phase. We also found the upregulation of microRNA-638 and microRNA-923 in bostrycin-treated cells. further, we found the downregulation of p110alpha and p-Akt/PKB proteins and increased activity of p27 protein after bostrycin treatment in A549 cells. CONCLUSIONS: Our study indicated that bostrycin had a significant inhibitory effect on proliferation of A549 cells. It is possible that upregulation of microRNA-638 and microRNA-923 and downregulation of the PI3K/AKT pathway proteins played a role in induction of cell cycle arrest and apoptosis in bostrycin treated cells. PMID- 21303528 TI - Blood transfer devices for malaria rapid diagnostic tests: evaluation of accuracy, safety and ease of use. AB - BACKGROUND: Malaria rapid diagnostic tests (RDTs) are increasingly used by remote health personnel with minimal training in laboratory techniques. RDTs must, therefore, be as simple, safe and reliable as possible. Transfer of blood from the patient to the RDT is critical to safety and accuracy, and poses a significant challenge to many users. Blood transfer devices were evaluated for accuracy and precision of volume transferred, safety and ease of use, to identify the most appropriate devices for use with RDTs in routine clinical care. METHODS: Five devices, a loop, straw-pipette, calibrated pipette, glass capillary tube, and a new inverted cup device, were evaluated in Nigeria, the Philippines and Uganda. The 227 participating health workers used each device to transfer blood from a simulated finger-prick site to filter paper. For each transfer, the number of attempts required to collect and deposit blood and any spilling of blood during transfer were recorded. Perceptions of ease of use and safety of each device were recorded for each participant. Blood volume transferred was calculated from the area of blood spots deposited on filter paper. RESULTS: The overall mean volumes transferred by devices differed significantly from the target volume of 5 microliters (p < 0.001). The inverted cup (4.6 microliters) most closely approximated the target volume. The glass capillary was excluded from volume analysis as the estimation method used is not compatible with this device. The calibrated pipette accounted for the largest proportion of blood exposures (23/225, 10%); exposures ranged from 2% to 6% for the other four devices. The inverted cup was considered easiest to use in blood collection (206/226, 91%); the straw-pipette and calibrated pipette were rated lowest (143/225 [64%] and 135/225 [60%] respectively). Overall, the inverted cup was the most preferred device (72%, 163/227), followed by the loop (61%, 138/227). CONCLUSIONS: The performance of blood transfer devices varied in this evaluation of accuracy, blood safety, ease of use, and user preference. The inverted cup design achieved the highest overall performance, while the loop also performed well. These findings have relevance for any point-of-care diagnostics that require blood sampling. PMID- 21303529 TI - A randomised controlled trial of preventive spinal manipulation with and without a home exercise program for patients with chronic neck pain. AB - BACKGROUND: Evidence indicates that supervised home exercises, combined or not with manual therapy, can be beneficial for patients with non-specific chronic neck pain (NCNP). The objective of the study is to investigate the efficacy of preventive spinal manipulative therapy (SMT) compared to a no treatment group in NCNP patients. Another objective is to assess the efficacy of SMT with and without a home exercise program. METHODS: Ninety-eight patients underwent a short symptomatic phase of treatment before being randomly allocated to either an attention-group (n = 29), a SMT group (n = 36) or a SMT + exercise group (n = 33). The preventive phase of treatment, which lasted for 10 months, consisted of meeting with a chiropractor every two months to evaluate and discuss symptoms (attention-control group), 1 monthly SMT session (SMT group) or 1 monthly SMT session combined with a home exercise program (SMT + exercise group). The primary and secondary outcome measures were represented by scores on a 10-cm visual analog scale (VAS), active cervical ranges of motion (cROM), the neck disability index (NDI) and the Bournemouth questionnaire (BQ). Exploratory outcome measures were scored on the Fear-avoidance Behaviour Questionnaire (FABQ) and the SF-12 Questionnaire. RESULTS: Our results show that, in the preventive phase of the trial, all 3 groups showed primary and secondary outcomes scores similar to those obtain following the non-randomised, symptomatic phase. No group difference was observed for the primary, secondary and exploratory variables. Significant improvements in FABQ scores were noted in all groups during the preventive phase of the trial. However, no significant change in health related quality of life (HRQL) was associated with the preventive phase. CONCLUSIONS: This study hypothesised that participants in the combined intervention group would have less pain and disability and better function than participants from the 2 other groups during the preventive phase of the trial. This hypothesis was not supported by the study results. Lack of a treatment specific effect is discussed in relation to the placebo and patient provider interactions in manual therapies. Further research is needed to delineate the specific and non-specific effects of treatment modalities to prevent unnecessary disability and to minimise morbidity related to NCNP. Additional investigation is also required to identify the best strategies for secondary and tertiary prevention of NCNP. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00566930. PMID- 21303530 TI - Why are anopheline mosquitoes not present in the Seychelles? AB - BACKGROUND: Species of anopheline mosquitoes are largely distributed over emerged lands around the world and, within the tropics, few areas are without these insects, which are vectors of malaria parasites. Among the exceptions is the Seychelles archipelago in the western Indian Ocean. However, in the Aldabra island group, located in the extreme western portion of the archipelago, Anopheles gambiae s.l. was introduced, leading to massive proliferation and then elimination, with the most recent autochthonous malaria cases recorded in 1931. METHODS: In order to re-examine the absence of anopheline mosquitoes in the Seychelles, an entomological field survey was conducted in December 2008 at 17 sites on four granitic islands, including Mahe and Praslin, and ten sites on coralline atolls in the extreme west, including Aldabra. RESULTS: No evidence of larval or adult anophelines was found at the surveyed sites, which supports their absence in the Seychelles. CONCLUSIONS: In the granitic islands of the Seychelles, the climate is favourable for anophelines. However, these islands are protected by their remoteness and prevailing seasonal winds. In addition, stagnant freshwater, required in anopheline larval development, is relatively uncommon on the granitic islands because of the steep slopes. In the southwestern atolls (Aldabra and Providence-Farquhar groups), the presence of a long dry season of up to nine months and the total absence of permanent natural freshwater prevents the breeding of anophelines and their successful colonization. The Seychelles does not have any native land mammals and like in other parts of the world (Antarctica, Iceland, New Caledonia, Central Pacific islands) their absence is associated with the lack of anophelines. This suggests an obligatory relationship for anophelines to feed on terrestrial mammals, without alternative for blood-feeding sources, such as bats, birds and reptiles. PMID- 21303531 TI - Heart failure therapy in diabetic patients-comparison with the recent ESC/EASD guideline. AB - BACKGROUND: To assess heart failure therapies in diabetic patients with preserved as compared to impaired systolic ventricular function. METHODS: 3304 patients with heart failure from 9 different studies were included (mean age 63 +/- 14 years); out of these, 711 subjects had preserved left ventricular ejection fraction (>= 50%) and 994 patients in the whole cohort suffered from diabetes. RESULTS: The majority (>90%) of heart failure patients with reduced ejection fraction (SHF) and diabetes were treated with an ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB) or with beta-blockers. By contrast, patients with diabetes and preserved ejection fraction (HFNEF) were less likely to receive these substance classes (p < 0.001) and had a worse blood pressure control (p < 0.001). In comparison to patients without diabetes, the probability to receive these therapies was increased in diabetic HFNEF patients (p < 0.001), but not in diabetic SHF patients. Aldosterone receptor blockers were given more often to diabetic patients with reduced ejection fraction (p < 0.001), and the presence and severity of diabetes decreased the probability to receive this substance class, irrespective of renal function. CONCLUSIONS: Diabetic patients with HFNEF received less heart failure medication and showed a poorer control of blood pressure as compared to diabetic patients with SHF. SHF patients with diabetes were less likely to receive aldosterone receptor blocker therapy, irrespective of renal function. PMID- 21303532 TI - Hypothyroidism causing paralytic ileus and acute kidney injury - case report. AB - We present a patient with severe hypothyroidism complicated by paralytic ileus and acute kidney injury. A 65 year old male patient, diagnosed with hypothyroidism one year ago was transferred to our unit in a state of drowsiness and confusion. He was severely hypothyroid and had paralytic ileus and impaired renal function at the time of transfer. Hypokalaemia was present, and was likely to have contributed to the paralytic ileus and this together with dehydration was likely to have contributed to renal injury. Nonetheless, hypothyroidism is very likely to have been the principal precipitant of both these complications, and both paralytic ileus and acute kidney injury improved with thyroxine replacement. Unfortunately, the patient died unexpectedly eight days after admission to the unit.Hypothyroidism may induce de novo acute kidney injury or it may exacerbate ongoing chronic kidney disease. This rare complication is assumed to be due to the hypodynamic circulatory state created by thyroid hormone deficiency. Paralytic ileus is an even rarer fatal manifestation of hypothyroidism and is thought to be due to an autonomic neuropathy affecting the intestines that is reversible with thyroxine replacement. To our knowledge, both these complications have not been observed in a single patient so far.It is important that clinicians are aware of these rare manifestations of hypothyroidism as in most occasions, thyroxine deficiency may be missed, and treatment can reverse the complications. PMID- 21303533 TI - SFRP1 reduction results in an increased sensitivity to TGF-beta signaling. AB - BACKGROUND: Transforming growth factor (TGF)-beta plays a dual role during mammary gland development and tumorigenesis and has been shown to stimulate epithelial-mesenchymal transition (EMT) as well as cellular migration. The Wnt/beta-catenin pathway is also implicated in EMT and inappropriate activation of the Wnt/beta-catenin signaling pathway leads to the development of several human cancers, including breast cancer. Secreted frizzled-related protein 1 (SFRP1) antagonizes this pathway and loss of SFRP1 expression is frequently observed in breast tumors and breast cancer cell lines. We previously showed that when SFRP1 is knocked down in immortalized non-malignant mammary epithelial cells, the cells (TERT-siSFRP1) acquire characteristics associated with breast tumor initiating cells. The phenotypic and genotypic changes that occur in response to SFRP1 loss are consistent with EMT, including a substantial increase in the expression of ZEB2. Considering that ZEB2 has been shown to interact with mediators of TGF-beta signaling, we sought to determine whether TGF-beta signaling is altered in TERT-siSFRP1 cells. METHODS: Luciferase reporter assays and real-time PCR analysis were employed to measure TGF-beta transcriptional targets. Western blot analysis was used to evaluate TGF-beta-mediated ERK1/2 phosphorylation. Migration chamber assays were utilized to quantify cellular migration. TERT-siSFRP1 cells were transfected with Stealth RNAiTM siRNA in order to knock-down the expression of ZEB2. RESULTS: TERT-siSFRP1 cells exhibit a significant increase in both TGF-beta-mediated luciferase activity as well as TGF beta transcriptional targets, including Integrin beta3 and PAI-1. Phosphorylation of ERK1/2 is increased in TERT-siSFRP1 cells in response to enhanced TGF-beta signaling. Furthermore, when the TGF-beta pathway is blocked with a TGF-betaR antagonist (LY364947), cellular migration is significantly hindered. Finally, we found that when ZEB2 is knocked-down, there is a significant reduction in the expression of exogeneous and endogenous TGF-beta transcriptional targets and cellular migration is impeded. CONCLUSIONS: We demonstrate that down-regulation of SFRP1 renders mammary epithelial cells more sensitive to TGF-beta signaling which can be partially ameliorated by blocking the expression of ZEB2. PMID- 21303534 TI - Effect of nitric oxide on mitochondrial activity of human synovial cells. AB - BACKGROUND: Nitric oxide (NO) is a messenger implicated in the destruction and inflammation of joint tissues. Cartilage and synovial membrane from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) have high levels of NO. NO is known to modulate various cellular pathways and, thus, inhibit the activity of the mitochondrial respiratory chain (MRC) of chondrocytes and induce the generation of reactive oxygen species (ROS) and cell death in multiple cell types. For these reasons, and because of the importance of the synovial membrane in development of OA pathology, we investigated the effects of NO on survival, mitochondrial function, and activity of fibroblastic human OA synovial cells. METHODS: Human OA synovia were obtained from eight patients undergoing hip joint replacement. Sodium nitroprusside (SNP) was used as a NO donor compound and cell viability was evaluated by MTT assays. Mitochondrial function was evaluated by analyzing the mitochondrial membrane potential (Deltapsim) with flow cytometry using the fluorofore DePsipher. ATP levels were measured by luminescence assays, and the activities of the respiratory chain complexes (complex I: NADH CoQ1 reductase, complex II: succinate dehydrogenase, complex III: ubiquinol-cytochrome c reductase, complex IV: cytochrome c oxidase) and citrate synthase (CS) were measured by enzymatic assay. Protein expression analyses were performed by western blot. RESULTS: SNP at a concentration of 0.5 mM induced cell death, shown by the MTT method at different time points. The percentages of viable cells at 24, 48 and 72 hours were 86.11 +/- 4.9%, 74.31 +/- 3.35%, and 43.88 +/- 1.43%, respectively, compared to the basal level of 100% (*p < 0.05). SNP at 0.5 mM induced depolarization of the mitochondrial membrane at 12 hours with a decrease in the ratio of polarized cells (basal = 2.48 +/- 0.28; SNP 0.5 mM = 1.57 +/- 0.11; *p < 0.01). The time course analyses of treatment with SNP at 0.5 mM demonstrated that treatment reliably and significantly reduced intracellular ATP production (68.34 +/- 14.3% vs. basal = 100% at 6 hours; *p < 0.05). The analysis of the MRC at 48 hours showed that SNP at 0.5 mM increased the activity of complexes I (basal = 36.47 +/- 3.92 mol/min/mg protein, SNP 0.5 mM = 58.08 +/- 6.46 mol/min/mg protein; *p < 0.05) and III (basal = 63.87 +/- 6.93 mol/min/mg protein, SNP 0.5 mM = 109.15 +/- 30.37 mol/min/mg protein; *p < 0.05) but reduced CS activity (basal = 105.06 +/- 10.72 mol/min/mg protein, SNP at 0.5 mM = 66.88 +/- 6.08 mol/min/mg protein.; *p < 0.05), indicating a decrease in mitochondrial mass. Finally, SNP regulated the expression of proteins related to the cellular cycle; the NO donor decreased bcl-2, mcl-1 and procaspase-3 protein expression. CONCLUSIONS: This study suggests that NO reduces the survival of OA synoviocytes by regulating mitochondrial functionality, as well as the proteins controlling the cell cycle. PMID- 21303535 TI - Improving Salmonella vector with rec mutation to stabilize the DNA cargoes. AB - BACKGROUND: Salmonella has been employed to deliver therapeutic molecules against cancer and infectious diseases. As the carrier for target gene(s), the cargo plasmid should be stable in the bacterial vector. Plasmid recombination has been reduced in E. coli by mutating several genes including the recA, recE, recF and recJ. However, to our knowledge, there have been no published studies of the effect of these or any other genes that play a role in plasmid recombination in Salmonella enterica. RESULTS: The effect of recA, recF and recJ deletions on DNA recombination was examined in three serotypes of Salmonella enterica. We found that (1) intraplasmid recombination between direct duplications was RecF independent in Typhimurium and Paratyphi A, but could be significantly reduced in Typhi by a DeltarecA or DeltarecF mutation; (2) in all three Salmonella serotypes, both DeltarecA and DeltarecF mutations reduced intraplasmid recombination when a 1041 bp intervening sequence was present between the duplications; (3) DeltarecA and DeltarecF mutations resulted in lower frequencies of interplasmid recombination in Typhimurium and Paratyphi A, but not in Typhi; (4) in some cases, a DeltarecJ mutation could reduce plasmid recombination but was less effective than DeltarecA and DeltarecF mutations. We also examined chromosome-related recombination. The frequencies of intrachromosomal recombination and plasmid integration into the chromosome were 2 and 3 logs lower than plasmid recombination frequencies in Rec+ strains. A DeltarecA mutation reduced both intrachromosomal recombination and plasmid integration frequencies. CONCLUSIONS: The DeltarecA and DeltarecF mutations can reduce plasmid recombination frequencies in Salmonella enterica, but the effect can vary between serovars. This information will be useful for developing Salmonella delivery vectors able to stably maintain plasmid cargoes for vaccine development and gene therapy. PMID- 21303536 TI - First aid skill retention of first responders within the workplace. AB - BACKGROUND: Recent literature states that many necessary skills of CPR and first aid are forgotten shortly after certification. The purpose of this study was to determine the skill and knowledge decay in first aid in those who are paid to respond to emergency situations within a workplace. METHODS: Using a choking victim scenario, the sequence and accuracy of events were observed and recorded in 257 participants paid to act as first responders in large industrial or service industry settings. A multiple choice exam was also written to determine knowledge retention. RESULTS: First aid knowledge was higher in those who were trained at a higher level, and did not significantly decline over time. Those who had renewed their certificate one or more times performed better than those who had learned the information only once. During the choking scenario many skills were performed poorly, regardless of days since last training, such as hand placement and abdominal thrusts. Compressions following the victim becoming unconscious also showed classic signs of skill deterioration after 30 days. CONCLUSIONS: As many skills deteriorate rapidly over the course of the first 90 days, changing frequency of certification is not necessarily the most obvious choice to increase retention of skill and knowledge. Alternatively, methods of regularly "refreshing" a skill should be explored that could be delivered at a high frequency - such as every 90 days. PMID- 21303537 TI - De novo characterization of the gametophyte transcriptome in bracken fern, Pteridium aquilinum. AB - BACKGROUND: Because of their phylogenetic position and unique characteristics of their biology and life cycle, ferns represent an important lineage for studying the evolution of land plants. Large and complex genomes in ferns combined with the absence of economically important species have been a barrier to the development of genomic resources. However, high throughput sequencing technologies are now being widely applied to non-model species. We leveraged the Roche 454 GS-FLX Titanium pyrosequencing platform in sequencing the gametophyte transcriptome of bracken fern (Pteridium aquilinum) to develop genomic resources for evolutionary studies. RESULTS: 681,722 quality and adapter trimmed reads totaling 254 Mbp were assembled de novo into 56,256 unique sequences (i.e. unigenes) with a mean length of 547.2 bp and a total assembly size of 30.8 Mbp with an average read-depth coverage of 7.0*. We estimate that 87% of the complete transcriptome has been sequenced and that all transcripts have been tagged. 61.8% of the unigenes had blastx hits in the NCBI nr protein database, representing 22,596 unique best hits. The longest open reading frame in 52.2% of the unigenes had positive domain matches in InterProScan searches. We assigned 46.2% of the unigenes with a GO functional annotation and 16.0% with an enzyme code annotation. Enzyme codes were used to retrieve and color KEGG pathway maps. A comparative genomics approach revealed a substantial proportion of genes expressed in bracken gametophytes to be shared across the genomes of Arabidopsis, Selaginella and Physcomitrella, and identified a substantial number of potentially novel fern genes. By comparing the list of Arabidopsis genes identified by blast with a list of gametophyte-specific Arabidopsis genes taken from the literature, we identified a set of potentially conserved gametophyte specific genes. We screened unigenes for repetitive sequences to identify 548 potentially-amplifiable simple sequence repeat loci and 689 expressed transposable elements. CONCLUSIONS: This study is the first comprehensive transcriptome analysis for a fern and represents an important scientific resource for comparative evolutionary and functional genomics studies in land plants. We demonstrate the utility of high-throughput sequencing of a normalized cDNA library for de novo transcriptome characterization and gene discovery in a non model plant. PMID- 21303538 TI - Seasonal and geographic differences in treatment-seeking and household cost of febrile illness among children in Malawi. AB - BACKGROUND: Households in malaria endemic countries experience considerable costs in accessing formal health facilities because of childhood malaria. The Ministry of Health in Malawi has defined certain villages as hard-to-reach on the basis of either their distance from health facilities or inaccessibility. Some of these villages have been assigned a community health worker, responsible for referring febrile children to a health facility. Health facility utilization and household costs of attending a health facility were compared between individuals living near the district hospital and those in hard-to-reach villages. METHODS: Two cross-sectional household surveys were conducted in the Chikhwawa district of Malawi; one during each of the wet and dry seasons. Half the participating villages were located near the hospital, the others were in areas defined as hard to-reach. Data were collected on attendance to formal health facilities and economic costs incurred due to recent childhood febrile illness. RESULTS: Those living in hard-to-reach villages were less likely to attend a formal health facility compared to those living near the hospital (Dry season: OR 0.35, 95%CI0.18-0.67; Wet season: OR 0.46, 95%CI0.27-0.80). Analyses including community health workers (CHW) as a source of formal health-care decreased the strength of this relationship, and suggested that consulting a CHW may reduce attendance at health facilities, even if indicated. Although those in hard-to reach villages were still less likely to attend in both the dry (OR 0.53, 95%CI 0.25-1.11) and wet (OR 0.60, 95%CI 0.37-0.98) seasons. Household costs for those who attended a health facility were greater for those in HTR villages (Dry: USD5.24; Wet: USD5.60) than for those living near the district hospital (Dry: USD3.45; Wet: USD4.46). CONCLUSION: Those living in hard-to-reach areas were less likely to attend a health facility for a childhood febrile event and experienced greater associated household costs. Consulting CHWs was infrequent, but appeared to reduce attendance at a health facility, even when indicated. Health service planners must consider geographic and financial barriers to accessing public health facilities in designing appropriate interventions. PMID- 21303539 TI - Stereoscopic motion analysis in densely packed clusters: 3D analysis of the shimmering behaviour in Giant honey bees. AB - BACKGROUND: The detailed interpretation of mass phenomena such as human escape panic or swarm behaviour in birds, fish and insects requires detailed analysis of the 3D movements of individual participants. Here, we describe the adaptation of a 3D stereoscopic imaging method to measure the positional coordinates of individual agents in densely packed clusters. The method was applied to study behavioural aspects of shimmering in Giant honeybees, a collective defence behaviour that deters predatory wasps by visual cues, whereby individual bees flip their abdomen upwards in a split second, producing Mexican wave-like patterns. RESULTS: Stereoscopic imaging provided non-invasive, automated, simultaneous, in-situ 3D measurements of hundreds of bees on the nest surface regarding their thoracic position and orientation of the body length axis. Segmentation was the basis for the stereo matching, which defined correspondences of individual bees in pairs of stereo images. Stereo-matched "agent bees" were re identified in subsequent frames by the tracking procedure and triangulated into real-world coordinates. These algorithms were required to calculate the three spatial motion components (dx: horizontal, dy: vertical and dz: towards and from the comb) of individual bees over time. CONCLUSIONS: The method enables the assessment of the 3D positions of individual Giant honeybees, which is not possible with single-view cameras. The method can be applied to distinguish at the individual bee level active movements of the thoraces produced by abdominal flipping from passive motions generated by the moving bee curtain. The data provide evidence that the z-deflections of thoraces are potential cues for colony intrinsic communication. The method helps to understand the phenomenon of collective decision-making through mechanoceptive synchronization and to associate shimmering with the principles of wave propagation. With further, minor modifications, the method could be used to study aspects of other mass phenomena that involve active and passive movements of individual agents in densely packed clusters. PMID- 21303540 TI - Anti-allergic and anti-inflammatory effects of butanol extract from Arctium Lappa L. AB - BACKGROUND: Atopic dermatitis is a chronic, allergic inflammatory skin disease that is accompanied by markedly increased levels of inflammatory cells, including eosinophils, mast cells, and T cells. Arctium lappa L. is a traditional medicine in Asia. This study examined whether a butanol extract of A. lappa (ALBE) had previously unreported anti-allergic or anti-inflammatory effects. METHODS: This study examined the effect of ALBE on the release of beta-hexosaminidase in antigen-stimulated-RBL-2H3 cells. We also evaluated the ConA-induced expression of IL-4, IL-5, mitogen-activated protein kinases (MAPKs), and nuclear factor (NF) kappaB using RT-PCR, Western blotting, and ELISA in mouse splenocytes after ALBE treatment. RESULTS: We observed significant inhibition of beta-hexosaminidase release in RBL-2H3 cells and suppressed mRNA expression and protein secretion of IL-4 and IL-5 induced by ConA-treated primary murine splenocytes after ALBE treatment. Additionally, ALBE (100 MUg/mL) suppressed not only the transcriptional activation of NF-kappaB, but also the phosphorylation of MAPKs in ConA-treated primary splenocytes. CONCLUSIONS: These results suggest that ALBE inhibits the expression of IL-4 and IL-5 by downregulating MAPKs and NF-kappaB activation in ConA-treated splenocytes and supports the hypothesis that ALBE may have beneficial effects in the treatment of allergic diseases, including atopic dermatitis. PMID- 21303541 TI - Diagnostic properties of metabolic perturbations in rheumatoid arthritis. AB - INTRODUCTION: The aim of this study was to assess the feasibility of diagnosing early rheumatoid arthritis (RA) by measuring selected metabolic biomarkers. METHODS: We compared the metabolic profile of patients with RA with that of healthy controls and patients with psoriatic arthritis (PsoA). The metabolites were measured using two different chromatography-mass spectrometry platforms, thereby giving a broad overview of serum metabolites. The metabolic profiles of patient and control groups were compared using multivariate statistical analysis. The findings were validated in a follow-up study of RA patients and healthy volunteers. RESULTS: RA patients were diagnosed with a sensitivity of 93% and a specificity of 70% in a validation study using detection of 52 metabolites. Patients with RA or PsoA could be distinguished with a sensitivity of 90% and a specificity of 94%. Glyceric acid, D-ribofuranose and hypoxanthine were increased in RA patients, whereas histidine, threonic acid, methionine, cholesterol, asparagine and threonine were all decreased compared with healthy controls. CONCLUSIONS: Metabolite profiling (metabolomics) is a potentially useful technique for diagnosing RA. The predictive value was without regard to the presence of antibodies against cyclic citrullinated peptides. PMID- 21303542 TI - Mutational profiling reveals PIK3CA mutations in gallbladder carcinoma. AB - BACKGROUND: The genetics of advanced biliary tract cancers (BTC), which encompass intra- and extra-hepatic cholangiocarcinomas as well as gallbladder carcinomas, are heterogeneous and remain to be fully defined. METHODS: To better characterize mutations in established known oncogenes and tumor suppressor genes we tested a mass spectrometric based platform to interrogate common cancer associated mutations across a panel of 77 formalin fixed paraffin embedded archived BTC cases. RESULTS: Mutations among three genes, KRAS, NRAS and PIK3CA were confirmed in this cohort. Activating mutations in PIK3CA were identified exclusively in GBC (4/32, 12.5%). KRAS mutations were identified in 3 (13%) intra-hepatic cholangiocarcinomas and 1 (33%) perihillar cholangiocarcinoma but were not identified in gallbladder carcinomas and extra-hepatic cholangiocarcinoma. CONCLUSIONS: The presence of activating mutations in PIK3CA specifically in GBC has clinical implications in both the diagnosis of this cancer type, as well as the potential utility of targeted therapies such as PI3 kinase inhibitors. PMID- 21303544 TI - Retinal specific measurement of dark-adapted visual function: validation of a modified microperimeter. AB - BACKGROUND: Scotopic function is an important marker of many retinal diseases and is increasingly used as an outcome measure in clinical trials, such as those investigating gene therapy for Lebers congenital amaurosis. Scotopic visual function has traditionally been measured using an adapted perimetry system such as the Humphrey field analyser (HFA). However this system does not control for fixation errors or poor fixation stability. Here we evaluate the use of an adapted microperimeter to measure visual function at defined retinal regions under scotopic conditions. METHODS: A MP-1 microperimeter (Nidek Technologies, Italy) was modified by adding a 1 log unit Neutral Density filter and a 530 nm shortpass filter within the optical path of the instrument. Stray light was shielded. Fine matrix mapping perimetry was performed on five younger (< 35 years) and five older (> 65 years) subjects with no eye disease and good vision. All subjects were fully dark adapted before testing and pupils were dilated with 1% tropicamide. Tests was performed once on the modified MP-1 microperimeter and once using a modified HFA, in a counterbalanced order. RESULTS: A foveal scotopic scotoma with a sensitivity reduction of >1 log unit was found using each instrument. In addition, the MP-1 system showed the retinal location of the foveal scotoma. Mean test time was 25 minutes for the MP-1 and 32 minutes for the HFA. DISCUSSION: A modified MP-1 microperimeter can be used to measure scotopic retinal function, creating results which are comparable to the modified Humphrey field analyser. Advantages of the MP-1 system include the ability to track the retina through testing, retinal localisation of the scotoma and a faster test time. PMID- 21303545 TI - Integration of lipidomics and transcriptomics data towards a systems biology model of sphingolipid metabolism. AB - BACKGROUND: Sphingolipids play important roles in cell structure and function as well as in the pathophysiology of many diseases. Many of the intermediates of sphingolipid biosynthesis are highly bioactive and sometimes have antagonistic activities, for example, ceramide promotes apoptosis whereas sphingosine-1 phosphate can inhibit apoptosis and induce cell growth; therefore, quantification of the metabolites and modeling of the sphingolipid network is imperative for an understanding of sphingolipid biology. RESULTS: In this direction, the LIPID MAPS Consortium is developing methods to quantitate the sphingolipid metabolites in mammalian cells and is investigating their application to studies of the activation of the RAW264.7 macrophage cell by a chemically defined endotoxin, Kdo2-Lipid A. Herein, we describe a model for the C16-branch of sphingolipid metabolism (i.e., for ceramides with palmitate as the N-acyl-linked fatty acid, which is selected because it is a major subspecies for all categories of complex sphingolipids in RAW264.7 cells) integrating lipidomics and transcriptomics data and using a two-step matrix-based approach to estimate the rate constants from experimental data. The rate constants obtained from the first step are further refined using generalized constrained nonlinear optimization. The resulting model fits the experimental data for all species. The robustness of the model is validated through parametric sensitivity analysis. CONCLUSIONS: A quantitative model of the sphigolipid pathway is developed by integrating metabolomics and transcriptomics data with legacy knowledge. The model could be used to design experimental studies of how genetic and pharmacological perturbations alter the flux through this important lipid biosynthetic pathway. PMID- 21303543 TI - An EST-based analysis identifies new genes and reveals distinctive gene expression features of Coffea arabica and Coffea canephora. AB - BACKGROUND: Coffee is one of the world's most important crops; it is consumed worldwide and plays a significant role in the economy of producing countries. Coffea arabica and C. canephora are responsible for 70 and 30% of commercial production, respectively. C. arabica is an allotetraploid from a recent hybridization of the diploid species, C. canephora and C. eugenioides. C. arabica has lower genetic diversity and results in a higher quality beverage than C. canephora. Research initiatives have been launched to produce genomic and transcriptomic data about Coffea spp. as a strategy to improve breeding efficiency. RESULTS: Assembling the expressed sequence tags (ESTs) of C. arabica and C. canephora produced by the Brazilian Coffee Genome Project and the Nestle Cornell Consortium revealed 32,007 clusters of C. arabica and 16,665 clusters of C. canephora. We detected different GC3 profiles between these species that are related to their genome structure and mating system. BLAST analysis revealed similarities between coffee and grape (Vitis vinifera) genes. Using KA/KS analysis, we identified coffee genes under purifying and positive selection. Protein domain and gene ontology analyses suggested differences between Coffea spp. data, mainly in relation to complex sugar synthases and nucleotide binding proteins. OrthoMCL was used to identify specific and prevalent coffee protein families when compared to five other plant species. Among the interesting families annotated are new cystatins, glycine-rich proteins and RALF-like peptides. Hierarchical clustering was used to independently group C. arabica and C. canephora expression clusters according to expression data extracted from EST libraries, resulting in the identification of differentially expressed genes. Based on these results, we emphasize gene annotation and discuss plant defenses, abiotic stress and cup quality-related functional categories. CONCLUSION: We present the first comprehensive genome-wide transcript profile study of C. arabica and C. canephora, which can be freely assessed by the scientific community at http://www.lge.ibi.unicamp.br/coffea. Our data reveal the presence of species-specific/prevalent genes in coffee that may help to explain particular characteristics of these two crops. The identification of differentially expressed transcripts offers a starting point for the correlation between gene expression profiles and Coffea spp. developmental traits, providing valuable insights for coffee breeding and biotechnology, especially concerning sugar metabolism and stress tolerance. PMID- 21303546 TI - Challenges associated with the targeted delivery of gelonin to claudin-expressing cancer cells with the use of activatable cell penetrating peptides to enhance potency. AB - BACKGROUND: Treatment of tumors with macromolecular toxins directed to cytoplasmic targets requires selective endocytosis followed by release of intact toxin from the endosomal/lysosomal compartment. The latter step remains a particular challenge. Claudins 3 and 4 are tight junction proteins that are over expressed in many types of tumors. This study utilized the C-terminal 30 amino acid fragment of C. perfringens enterotoxin (CPE), which binds to claudins 3 and 4, to deliver a toxin in the form of recombinant gelonin (rGel) to the cytoplasm of the human ovarian carcinoma cell line 2008. RESULTS: CPE was fused to rGel at its N-terminal end via a flexible G4S linker. This CPE-G4S-rGel molecule was internalized into vesicles from which location it produced little cytotoxicity. To enhance release from the endosomal/lysosomal compartment a poly-arginine sequence (R9) was introduced between the CPE and the rGel. CPE-R9-rGel was 10 fold more cytotoxic but selectivity for claudin-expressing cells was lost. The addition of a poly-glutamic acid sequence (E9) through a G4S linker to R9-rGel (E9-G4S-R9-rGel) largely neutralized the non-selective cell membrane penetrating activity of the R9 motif. However, introduction of CPE to the E9-G4S-R9-rGel fusion protein (CPE-E9-G4S-R9-rGel) further reduced its cytotoxic effect. Treatment with the endosomolytic reagent chloroquine increased the cytotoxicity of CPE-E9-G4S-R9-rGel. Several types of linkers susceptible to cleavage by furin and endosomal cathepsin B were tested for their ability to enhance R9-rGel release but none of these modifications further enhanced the cytotoxicity of CPE E9-G4S-R9-rGel. CONCLUSION: We conclude that while a claudin-3 and -4 ligand serves to deliver rGel into 2008 cells the delivered molecules were entrapped in intracellular vesicles. Incorporation of R9 non-specifically increased rGel cytotoxicity and this effect could be masked by inclusion of an E9 sequence. However, the putative protease cleavable sequences tested were inadequate for release of R9-rGel from CPE-E9-G4S-R9-rGel. PMID- 21303547 TI - Gene expression profiling of oxidative stress response of C. elegans aging defective AMPK mutants using massively parallel transcriptome sequencing. AB - BACKGROUND: A strong association between stress resistance and longevity in multicellular organisms has been established as many mutations that extend lifespan also show increased resistance to stress. AAK-2, the C. elegans homolog of an alpha subunit of AMP-activated protein kinase (AMPK) is an intracellular fuel sensor that regulates cellular energy homeostasis and functions in stress resistance and lifespan extension. FINDINGS: Here, we investigated global transcriptional responses of aak-2 mutants to oxidative stress and in turn identified potential downstream targets of AAK-2 involved in stress resistance in C. elegans. We employed massively parallel Illumina sequencing technology and performed comprehensive comparative transcriptome analysis. Specifically, we compared the transcriptomes of aak-2 and wild type animals under normal conditions and conditions of induced oxidative stress. This research has presented a snapshot of genome-wide transcriptional activities that take place in C. elegans in response to oxidative stress both in the presence and absence of AAK-2. CONCLUSIONS: The analysis presented in this study has enabled us to identify potential genes involved in stress resistance that may be either directly or indirectly under the control of AAK-2. Furthermore, we have extended our current knowledge of general defense responses of C. elegans against oxidative stress supporting the function for AAK-2 in inhibition of biosynthetic processes, especially lipid synthesis, under oxidative stress and transcriptional regulation of genes involved in reproductive processes. PMID- 21303549 TI - Effective detection of human adenovirus in Hawaiian waters using enhanced PCR methods. AB - BACKGROUND: The current criteria for recreational water quality evaluation are primarily based on measurements of fecal indicator bacteria growth. However, these criteria often fail to predict the presence of waterborne human pathogenic viruses. To explore the possibility of direct use of human enteric viruses as improved human fecal contamination indicators, human adenovirus (HAdV) was tested as a model in this study. FINDINGS: In order to establish a highly sensitive protocol for effective detection of HAdV in aquatic environments, sixteen published PCR primer sets were re-optimized and comparatively evaluated. Primer sets nehex3deg/nehex4deg, ADV-F/ADV-R, and nested PCR primer sets hex1deg/hex2deg and nehex3deg/nehex4deg were identified to be the most sensitive ones, with up to 1,000 fold higher detection sensitivity compared to other published assays. These three PCR protocols were successfully employed to detect HAdV in both treated and untreated urban wastewaters, and also in 6 of 16 recreational water samples collected around the island of Oahu, Hawaii. CONCLUSIONS: Findings from this study support the possible use of enteric viruses for aquatic environmental monitoring, specifically for the essential routine monitoring of Hawaiian beach waters using the optimized PCR protocol to detect HAdV at certain water sites to ensure a safe use of recreational waters. PMID- 21303548 TI - Adherence and virologic suppression during the first 24 weeks on antiretroviral therapy among women in Johannesburg, South Africa - a prospective cohort study. AB - BACKGROUND: Adherence is a necessary part of successful antiretroviral treatment (ART). We assessed risk factors for incomplete adherence among a cohort of HIV infected women initiating ART and examined associations between adherence and virologic response to ART. METHODS: A secondary data analysis was conducted on a cohort of 154 women initiating non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART at a single site in Johannesburg, South Africa. Ninety women had been enrolled in a prevention of mother-to-child transmission (pMTCT) program and were exposed to single-dose nevirapine (sdNVP) >18 months earlier. Women were interviewed pre-treatment and clinical, virologic and adherence data were collected during follow-up to 24 weeks. Incomplete adherence to ART was defined as returning >5% of medications, estimated by pill counts at scheduled visits. Multivariable logistic regression analysis and unadjusted odds ratio (95%CI) were performed, using STATA/SE (ver 10.1). RESULTS: About half of the women (53%) were <30 years of age, 63% had <11 years of schooling, 69% were unemployed and 37% lived in a shack. Seven percent of women had a viral load >400 copies/ml at 24 weeks and 37% had incomplete adherence at one or more visits. Incomplete adherence was associated with less education (p = 0.01) and lack of financial support from a partner (p = 0.02) after adjustment for confounders. Only when adherence levels dropped below 80% was there a significant association with viremia in the group overall (p = 0.02) although adherence <95% was associated with viremia in the sdNVP-exposed group (p = 0.03). The main reasons for incomplete adherence were being away from home, busy with other things and forgetting to take their medication. CONCLUSION: Virologic response to NNRTI treatment in the cohort was excellent. However, women who received sdNVP were at greater risk of virologic failure when adherence was <95%. Women exposed to sdNVP, and those with less education and less social support may benefit from additional adherence counseling to ensure the long-term success of ART. More than 80% adherence may be sufficient to maintain virologic suppression on NNRTI-based regimens in the short-term, however complete adherence should be encouraged. PMID- 21303550 TI - The multiple personalities of Watson and Crick strands. AB - BACKGROUND: In genetics it is customary to refer to double-stranded DNA as containing a "Watson strand" and a "Crick strand." However, there seems to be no consensus in the literature on the exact meaning of these two terms, and the many usages contradict one another as well as the original definition. Here, we review the history of the terminology and suggest retaining a single sense that is currently the most useful and consistent. PROPOSAL: The Saccharomyces Genome Database defines the Watson strand as the strand which has its 5'-end at the short-arm telomere and the Crick strand as its complement. The Watson strand is always used as the reference strand in their database. Using this as the basis of our standard, we recommend that Watson and Crick strand terminology only be used in the context of genomics. When possible, the centromere or other genomic feature should be used as a reference point, dividing the chromosome into two arms of unequal lengths. Under our proposal, the Watson strand is standardized as the strand whose 5'-end is on the short arm of the chromosome, and the Crick strand as the one whose 5'-end is on the long arm. Furthermore, the Watson strand should be retained as the reference (plus) strand in a genomic database. This usage not only makes the determination of Watson and Crick unambiguous, but also allows unambiguous selection of reference stands for genomics. REVIEWERS: This article was reviewed by John M. Logsdon, Igor B. Rogozin (nominated by Andrey Rzhetsky), and William Martin. PMID- 21303551 TI - The association between bullying and early stages of suicidal ideation in late adolescents in Greece. AB - BACKGROUND: Bullying in schools has been associated with suicidal ideation but the confounding effect of psychiatric morbidity has not always been taken into account. Our main aim was to test the association between bullying behavior and early stages of suicidal ideation in a sample of Greek adolescents and to examine whether this is independent of the presence of psychiatric morbidity, including sub-threshold symptoms. METHODS: 5614 pupils 16-18 years old and attending 25 senior high schools were screened in the first phase and a stratified random sample of 2431 were selected for a detailed interview at the second phase. Psychiatric morbidity and suicidal ideation were assessed with the revised Clinical Interview Schedule (CIS-R) while bullying was assessed with the revised Olweus bully/victim questionnaire. RESULTS: Victims of bullying behavior were more likely to express suicidal ideation. This association was particularly strong for those who were bullied on a weekly basis and it was independent of the presence of psychiatric morbidity (Odds Ratio: 7.78; 95% Confidence Interval: 3.05 - 19.90). In contrast, being a perpetrator ("bullying others") was not associated with this type of ideation after adjustment. These findings were similar in both boys and girls, although the population impact of victimization in the prevalence of suicidal ideation was potentially higher for boys. CONCLUSIONS: The strong cross-sectional association between frequent victimization and suicidal ideation in late adolescence offers an opportunity for identifying pupils in the school setting that are in a higher risk for exhibiting suicidal ideation. PMID- 21303553 TI - Rapid analysis of seed size in Arabidopsis for mutant and QTL discovery. AB - BACKGROUND: Arabidopsis thaliana is a useful model organism for deciphering the genetic determinants of seed size; however the small size of its seeds makes measurements difficult. Bulk seed weights are often used as an indicator of average seed size, but details of individual seed is obscured. Analysis of seed images is possible but issues arise from variations in seed pigmentation and shadowing making analysis laborious. We therefore investigated the use of a consumer level scanner to facilitate seed size measurements in conjunction with open source image-processing software. RESULTS: By using the transmitted light from the slide scanning function of a flatbed scanner and particle analysis of the resulting images, we have developed a method for the rapid and high throughput analysis of seed size and seed size distribution. The technical variation due to the approach was negligible enabling us to identify aspects of maternal plant growth that contribute to biological variation in seed size. By controlling for these factors, differences in seed size caused by altered parental genome dosage and mutation were easily detected. The method has high reproducibility and sensitivity, such that a mutant with a 10% reduction in seed size was identified in a screen of endosperm-expressed genes. Our study also generated average seed size data for 91 Arabidopsis accessions and identified a number of quantitative trait loci from two recombinant inbred line populations, generated from Cape Verde Islands and Burren accessions crossed with Columbia. CONCLUSIONS: This study describes a sensitive, high-throughput approach for measuring seed size and seed size distribution. The method provides a low cost and robust solution that can be easily implemented into the workflow of studies relating to various aspects of seed development. PMID- 21303552 TI - Clearance of fear memory from the hippocampus through neurogenesis by omega-3 fatty acids: a novel preventive strategy for posttraumatic stress disorder? AB - Not only has accidental injury been shown to account for a significant health burden on all populations, regardless of age, sex and geographic region, but patients with accidental injury frequently present with the psychiatric condition of posttraumatic stress disorder (PTSD). Prevention of accident-related PTSD thus represents a potentially important goal. Physicians in the field of psychosomatic medicine and critical care medicine have the opportunity to see injured patients in the immediate aftermath of an accident. This article first briefly reviews the prevalence and associated factors of accident-related PTSD, then focuses on a conceptual model of fear memory and proposes a new, rationally hypothesized translational preventive intervention for PTSD through promoting hippocampal neurogenesis by omega-3 fatty acid supplementation. The results of an open-label pilot trial of injured patients admitted to the intensive care unit suggest that omega-3 fatty acid supplementation immediately after accidental injury can reduce subsequent PTSD symptoms. PMID- 21303554 TI - Differences in the epigenetic regulation of MT-3 gene expression between parental and Cd+2 or As+3 transformed human urothelial cells. AB - BACKGROUND: Studies have shown that metallothionein 3 (MT-3) is not expressed in normal urothelium or in the UROtsa cell line, but is expressed in urothelial cancer and in tumors generated from the UROtsa cells that have been transformed by cadmium (Cd+2) or arsenite (As+3).The present study had two major goals. One, to determine if epigenetic modifications control urothelial MT-3 gene expression and if regulation is altered by malignant transformation by Cd+2 or As+3. Two, to determine if MT-3 expression might translate clinically as a biomarker for malignant urothelial cells released into the urine. RESULTS: The histone deacetylase inhibitor MS-275 induced MT-3 mRNA expression in both parental UROtsa cells and their transformed counterparts. The demethylating agent, 5-Aza-2' deoxycytidine (5-AZC) had no effect on MT-3 mRNA expression. ChIP analysis showed that metal-responsive transformation factor-1 (MTF-1) binding to metal response elements (MRE) elements of the MT-3 promoter was restricted in parental UROtsa cells, but MTF-1 binding to the MREs was unrestricted in the transformed cell lines. Histone modifications at acetyl H4, trimethyl H3K4, trimethyl H3K27, and trimethyl H3K9 were compared between the parental and transformed cell lines in the presence and absence of MS-275. The pattern of histone modifications suggested that the MT-3 promoter in the Cd+2 and As+3 transformed cells has gained bivalent chromatin structure, having elements of being "transcriptionally repressed" and "transcription ready", when compared to parental cells. An analysis of MT-3 staining in urinary cytologies showed that a subset of both active and non-active patients with urothelial cancer shed positive cells in their urine, but that control patients only rarely shed MT-3 positive cells. CONCLUSION: The MT-3 gene is silenced in non-transformed urothelial cells by a mechanism involving histone modification of the MT-3 promoter. In contrast, transformation of the urothelial cells with either Cd+2 or As+3 modified the chromatin of the MT-3 promoter to a bivalent state of promoter readiness. Urinary cytology for MT-3 positive cells would not improve the diagnosis of urothelial cancer, but might have potential as a biomarker for tumor progression. PMID- 21303555 TI - Genetic diversity of Phytophthora infestans in the Northern Andean region. AB - BACKGROUND: Phytophthora infestans (Mont.) de Bary, the causal agent of potato late blight, is responsible for tremendous crop losses worldwide. Countries in the northern part of the Andes dedicate a large proportion of the highlands to the production of potato, and more recently, solanaceous fruits such as cape gooseberry (Physalis peruviana) and tree tomato (Solanum betaceum), all of which are hosts of this oomycete. In the Andean region, P. infestans populations have been well characterized in Ecuador and Peru, but are poorly understood in Colombia and Venezuela. To understand the P. infestans population structure in the Northern part of the Andes, four nuclear regions (ITS, Ras, beta-tubulin and Avr3a) and one mitochondrial (Cox1) region were analyzed in isolates of P. infestans sampled from different hosts in Colombia and Venezuela. RESULTS: Low genetic diversity was found within this sample of P. infestans isolates from crops within several regions of Colombia and Venezuela, revealing the presence of clonal populations of the pathogen in this region. We detected low frequency heterozygotes, and their distribution patterns might be a consequence of a high migration rate among populations with poor effective gene flow. Consistent genetic differentiation exists among isolates from different regions. CONCLUSIONS: The results here suggest that in the Northern Andean region P. infestans is a clonal population with some within-clone variation. P. infestans populations in Venezuela reflect historic isolation that is being reinforced by a recent self-sufficiency of potato seeds. In summary, the P. infestans population is mainly shaped by migration and probably by the appearance of variants of key effectors such as Avr3a. PMID- 21303556 TI - Generation and analysis of expressed sequence tags (ESTs) for marker development in yam (Dioscorea alata L.). AB - BACKGROUND: Anthracnose (Colletotrichum gloeosporioides) is a major limiting factor in the production of yam (Dioscorea spp.) worldwide. Availability of high quality sequence information is necessary for designing molecular markers associated with resistance. However, very limited sequence information pertaining to yam is available at public genome databases. Therefore, this collaborative project was developed for genetic improvement and germplasm characterization of yams using molecular markers. The current investigation is focused on studying gene expression, by large scale generation of ESTs, from one susceptible (TDa 95 0310) and two resistant yam genotypes (TDa 87-01091, TDa 95-0328) challenged with the fungus. Total RNA was isolated from young leaves of resistant and susceptible genotypes and cDNA libraries were sequenced using Roche 454 technology. RESULTS: A total of 44,757 EST sequences were generated from the cDNA libraries of the resistant and susceptible genotypes. Greater than 56% of ESTs were annotated using MapMan Mercator tool and Blast2GO search tools. Gene annotations were used to characterize the transcriptome in yam and also perform a differential gene expression analysis between the resistant and susceptible EST datasets. Mining for SSRs in the ESTs revealed 1702 unique sequences containing SSRs and 1705 SSR markers were designed using those sequences. CONCLUSION: We have developed a comprehensive annotated transcriptome data set in yam to enrich the EST information in public databases. cDNA libraries were constructed from anthracnose fungus challenged leaf tissues for transcriptome characterization, and differential gene expression analysis. Thus, it helped in identifying unique transcripts in each library for disease resistance. These EST resources provide the basis for future microarray development, marker validation, genetic linkage mapping and QTL analysis in Dioscorea species. PMID- 21303557 TI - Need for continual education about disaster medicine for health professionals in China--a pilot study. AB - BACKGROUND: Disaster Medicine training is not included in medical education curriculum in China, even though the country has suffered various disasters annually. We intended to assess the need for continual education regarding disaster management for health professionals in China. METHODS: A survey was conducted among 324 health professionals who participated in the response to the Wenchuan earthquake medical relief and public health assessment in October, 2008. RESULTS: The most of participants (67.3%) received informal disaster medicine training, and only a few (12.7%) participated in disaster drills. Most of the participants wanted to get continual education about disaster medicine training (89.8%), but prefer on-line training course for the flexibility of time scheduling and travel through China. CONCLUSION: The need for continual disaster medicine training is high; health professionals should be equipped with knowledge and skills for disaster management. PMID- 21303558 TI - A framework for automatic heart sound analysis without segmentation. AB - BACKGROUND: A new framework for heart sound analysis is proposed. One of the most difficult processes in heart sound analysis is segmentation, due to interference form murmurs. METHOD: Equal number of cardiac cycles were extracted from heart sounds with different heart rates using information from envelopes of autocorrelation functions without the need to label individual fundamental heart sounds (FHS). The complete method consists of envelope detection, calculation of cardiac cycle lengths using auto-correlation of envelope signals, features extraction using discrete wavelet transform, principal component analysis, and classification using neural network bagging predictors. RESULT: The proposed method was tested on a set of heart sounds obtained from several on-line databases and recorded with an electronic stethoscope. Geometric mean was used as performance index. Average classification performance using ten-fold cross validation was 0.92 for noise free case, 0.90 under white noise with 10 dB signal to-noise ratio (SNR), and 0.90 under impulse noise up to 0.3 s duration. CONCLUSION: The proposed method showed promising results and high noise robustness to a wide range of heart sounds. However, more tests are needed to address any bias that may have been introduced by different sources of heart sounds in the current training set, and to concretely validate the method. Further work include building a new training set recorded from actual patients, then further evaluate the method based on this new training set. PMID- 21303559 TI - Dr. PIAS: an integrative system for assessing the druggability of protein-protein interactions. AB - BACKGROUND: The amount of data on protein-protein interactions (PPIs) available in public databases and in the literature has rapidly expanded in recent years. PPI data can provide useful information for researchers in pharmacology and medicine as well as those in interactome studies. There is urgent need for a novel methodology or software allowing the efficient utilization of PPI data in pharmacology and medicine. RESULTS: To address this need, we have developed the 'Druggable Protein-protein Interaction Assessment System' (Dr. PIAS). Dr. PIAS has a meta-database that stores various types of information (tertiary structures, drugs/chemicals, and biological functions associated with PPIs) retrieved from public sources. By integrating this information, Dr. PIAS assesses whether a PPI is druggable as a target for small chemical ligands by using a supervised machine-learning method, support vector machine (SVM). Dr. PIAS holds not only known druggable PPIs but also all PPIs of human, mouse, rat, and human immunodeficiency virus (HIV) proteins identified to date. CONCLUSIONS: The design concept of Dr. PIAS is distinct from other published PPI databases in that it focuses on selecting the PPIs most likely to make good drug targets, rather than merely collecting PPI data. PMID- 21303560 TI - Multimodal microscopy for automated histologic analysis of prostate cancer. AB - BACKGROUND: Prostate cancer is the single most prevalent cancer in US men whose gold standard of diagnosis is histologic assessment of biopsies. Manual assessment of stained tissue of all biopsies limits speed and accuracy in clinical practice and research of prostate cancer diagnosis. We sought to develop a fully-automated multimodal microscopy method to distinguish cancerous from non cancerous tissue samples. METHODS: We recorded chemical data from an unstained tissue microarray (TMA) using Fourier transform infrared (FT-IR) spectroscopic imaging. Using pattern recognition, we identified epithelial cells without user input. We fused the cell type information with the corresponding stained images commonly used in clinical practice. Extracted morphological features, optimized by two-stage feature selection method using a minimum-redundancy-maximal relevance (mRMR) criterion and sequential floating forward selection (SFFS), were applied to classify tissue samples as cancer or non-cancer. RESULTS: We achieved high accuracy (area under ROC curve (AUC) >0.97) in cross-validations on each of two data sets that were stained under different conditions. When the classifier was trained on one data set and tested on the other data set, an AUC value of ~0.95 was observed. In the absence of IR data, the performance of the same classification system dropped for both data sets and between data sets. CONCLUSIONS: We were able to achieve very effective fusion of the information from two different images that provide very different types of data with different characteristics. The method is entirely transparent to a user and does not involve any adjustment or decision-making based on spectral data. By combining the IR and optical data, we achieved high accurate classification. PMID- 21303561 TI - Association and haplotype analysis of candidate genes in five genomic regions linked to sow maternal infanticide in a white Duroc * Erhualian resource population. AB - BACKGROUND: Maternal infanticide is an extreme and failed maternal behavior, which is defined as an active attack on piglets using the jaws, resulting in serious or fatal bite wounds. It brings big economic loss to the pig industry and severe problems to piglets' welfare. But little is known about the genetic background of this behavior. Quantitative trait loci (QTL) for maternal infanticide were identified in a White Duroc * Erhualian intercross by a non parametric linkage analysis (NPL) in our previous study. In this study, associations of 194 microsatellite markers used in NPL analysis with maternal infanticide behavior were further analyzed by transmission-disequilibrium test (TDT). On this basis, seven genes (ESR2, EAAT2, BDNF, OXTR, 5-HTR2C, DRD1 and GABRA6) at five genomic regions were selected and further analyzed. Associations of single nucleotide polymorphisms (SNPs) and haplotypes in each gene with maternal infanticide behavior were evaluated. RESULTS: Microsatellite markers on pig chromosome (SSC) 2, 13, 15, and X displayed significance at P < 0.05 by both TDT and NPL. Of the seven candidate genes, three ESR2 SNPs had nominal evidence for association (P < 0.05). Allele A at EAAT2 g. 233G > A and allele T at DRD1 g.1013C > G > T also showed evidence of overtransmission to infanticidal sows. In the overall tests of association of haplotypes, candidate genes of ESR2, EAAT2 and DRD1 achieved overall significance level (P < 0.05). Haplotype [A; A; G], [G; A; G], [A; G; G] and [C; C], respectively, from ESR2, EAAT2 and DRD1 showed higher frequencies to infanticidal sows (P < 0.05). Alleles among haplotypes and SNPs which showed an overtransmission to infanticidal sows were from White Duroc. CONCLUSIONS: From association tests of SNPs and haplotypes, ESR2, EAAT2 and DRD1 showed significant associations with maternal infanticide. This result supported the existence of QTL for maternal infanticide behavior on SSC1, SSC2 and SSC16. PMID- 21303563 TI - Prevalence of Hepatitis B surface antigen (HBsAg) among visitors of Shashemene General Hospital voluntary counseling and testing center. AB - BACKGROUND: Hepatitis B virus (HBV) infection is significant health problem, as it can lead to chronic hepatitis, liver cirrhosis, and hepatic carcinoma. Due to shared routes of transmission, HBV and human immunodeficiency virus (HIV) co infection is common and is an emerging concern in the clinical management of patients because of increased mortality, accelerated hepatic disease progression, and the frequent hepatotoxicity caused by anti-retroviral therapy. The aim of this study was to determine the prevalence of Hepatitis B surface antigen (HBsAg) and its risk factors, among individuals visiting Shashemene General Hospital VCT center. FINDINGS: Institution based cross-sectional study was performed from November 3, 2008 to December 29, 2008 and 384 voluntary counseling and testing (VCT) clients were investigated. Data on socio demographic and HBV risk factors was collected using structured questionnaires. Blood samples were collected and screened for hepatitis B surface antigen (HBsAg) and HIV by commercially available rapid test kits. The prevalence of HBsAg in this study group was 5.7%. Fourteen percent of HIV positive subjects (8/57) and 4.3% (14/327) of HIV negative subjects were positive for HBsAg. Significantly high prevalence of HBsAg was observed among individuals who had history of invasive procedures, like tooth extraction, abortion and ear piercing; history of hospital admission, history of unsafe inject and HIV positives. CONCLUSIONS: Although HBsAg prevalence is much higher among subjects who are HIV positive (14.0% versus 4.3%), the prevalence of HBsAg in HIV negative subjects is high enough to warrant a recommendation to screen all clients at VCT centers irrespective of HIV status. PMID- 21303562 TI - The association of dimethylarginine dimethylaminohydrolase 1 gene polymorphism with type 2 diabetes: a cohort study. AB - BACKGROUND: Elevated plasma levels of asymmetric dimethylarginine (ADMA) has been reported to be associated with insulin resistance and micro/macrovascular diabetic complications, and may predict cardiovascular events in type 2 diabetic patients. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is the major enzyme eliminating ADMA in humans, but the effect of genetic variations in DDAH1 on type 2 diabetes and its long-term outcome are unknown. METHODS: From July 2006 to June 2009, we assessed the association between polymorphisms in DDAH1 and type 2 diabetes in 814 consecutive unrelated subjects, including 309 type 2 diabetic patients and 505 non-diabetic individuals. Six single nucleotide polymorphisms (SNPs) in DDAH1, rs233112, rs1498373, rs1498374, rs587843, rs1403956, and rs1241321 were analyzed. Plasma ADMA levels were determined by high performance liquid chromatography. Insulin sensitivity was assessed by the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: Among the 6 SNPs, only rs1241321 was significantly associated with a decreased risk of type 2 diabetes (AA vs GG+AG, OR = 0.64, 95% CI 0.47-0.86, p = 0.004). The association remained unchanged after adjustment for plasma ADMA level. The fasting plasma glucose and log HOMA-IR tended to be lower in subjects carrying the homozygous AA genotype of rs1241321 compared with the GG+AG genotypes. Over a median follow-up period of 28.2 months, there were 44 all-cause mortality and 50 major adverse cardiovascular events (MACE, including cardiovascular death, non-fatal myocardial infarction and stroke). Compared with the GG and AG genotypes, the AA genotype of rs1241321 was associated with reduced risk of MACE (HR = 0.31, 95% CI: 0.11-0.90, p = 0.03) and all-cause mortality (HR = 0.18, 95% CI: 0.04-0.80, p = 0.02) only in subgroup with type 2 diabetes. One common haplotype (GGCAGC) was found to be significantly associated with a decreased risk of type 2 diabetes (OR = 0.67, 95% CI = 0.46-0.98, p = 0.04). CONCLUSIONS: Our results provide the first evidence that SNP rs1241321 in DDAH1 is associated with type 2 diabetes and its long-term outcome. PMID- 21303564 TI - The Happy Life ClubTM study protocol: a cluster randomised controlled trial of a type 2 diabetes health coach intervention. AB - BACKGROUND: The Happy Life ClubTM is an intervention that utilises health coaches trained in behavioural change and motivational interviewing techniques to assist with the management of type 2 diabetes mellitus (T2DM) in primary care settings in China. Health coaches will support participants to improve modifiable risk factors and adhere to effective self-management treatments associated with T2DM. METHODS/DESIGN: A cluster randomised controlled trial involving 22 Community Health Centres (CHCs) in Fengtai District of Beijing, China. CHCs will be randomised into a control or intervention group, facilitating recruitment of at least 1320 individual participants with T2DM into the study. Participants in the intervention group will receive a combination of both telephone and face-to-face health coaching over 18 months, in addition to usual care received by the control group. Health coaching will be performed by CHC doctors and nurses certified in coach-assisted chronic disease management. Outcomes will be assessed at baseline and again at 6, 12 and 18 months by means of a clinical health check and self administered questionnaire. The primary outcome measure is HbA1c level. Secondary outcomes include metabolic, physiological and psychological variables. DISCUSSION: This cluster RCT has been developed to suit the Chinese health care system and will contribute to the evidence base for the management of patients with T2DM. With a strong focus on self-management and health coach support, the study has the potential to be adapted to other chronic diseases, as well as other regions of China. TRIAL REGISTRATION: Current Controlled Trials ISRCTN01010526. PMID- 21303565 TI - Leukocyte count affects expression of reference genes in canine whole blood samples. AB - BACKGROUND: The dog is frequently used as a model for hematologic human diseases. In this study the suitability of nine potential reference genes for quantitative RT-PCR studies in canine whole blood was investigated. FINDINGS: The expression of these genes was measured in whole blood samples of 263 individual dogs, representing 73 different breeds and a group of 40 mixed breed dogs, categorized into healthy dogs and dogs with internal and hematological diseases, and dogs that underwent a surgical procedure. GeNorm analysis revealed that a combination of 5 to 6 of the most stably expressed genes constituted a stable normalizing factor. Evaluation of the expression revealed different ranking of reference genes in Normfinder and GeNorm. The disease category and the white blood cell count significantly affected reference gene expression. CONCLUSIONS: The discrepancy between the ranking of reference genes in this study by Normfinder and Genorm can be explained by differences between the experimental groups such as "disease category" and "WBC count". This stresses the importance of assessing the expression stability of potential reference genes for gene experiments in canine whole blood anew for each specific experimental condition. PMID- 21303566 TI - Deep transcranial magnetic stimulation for the treatment of auditory hallucinations: a preliminary open-label study. AB - BACKGROUND: Schizophrenia is a chronic and disabling disease that presents with delusions and hallucinations. Auditory hallucinations are usually expressed as voices speaking to or about the patient. Previous studies have examined the effect of repetitive transcranial magnetic stimulation (TMS) over the temporoparietal cortex on auditory hallucinations in schizophrenic patients. Our aim was to explore the potential effect of deep TMS, using the H coil over the same brain region on auditory hallucinations. PATIENTS AND METHODS: Eight schizophrenic patients with refractory auditory hallucinations were recruited, mainly from Beer Ya'akov Mental Health Institution (Tel Aviv university, Israel) ambulatory clinics, as well as from other hospitals outpatient populations. Low frequency deep TMS was applied for 10 min (600 pulses per session) to the left temporoparietal cortex for either 10 or 20 sessions. Deep TMS was applied using Brainsway's H1 coil apparatus. Patients were evaluated using the Auditory Hallucinations Rating Scale (AHRS) as well as the Scale for the Assessment of Positive Symptoms scores (SAPS), Clinical Global Impressions (CGI) scale, and the Scale for Assessment of Negative Symptoms (SANS). RESULTS: This preliminary study demonstrated a significant improvement in AHRS score (an average reduction of 31.7% +/- 32.2%) and to a lesser extent improvement in SAPS results (an average reduction of 16.5% +/- 20.3%). CONCLUSIONS: In this study, we have demonstrated the potential of deep TMS treatment over the temporoparietal cortex as an add-on treatment for chronic auditory hallucinations in schizophrenic patients. Larger samples in a double-blind sham-controlled design are now being preformed to evaluate the effectiveness of deep TMS treatment for auditory hallucinations. TRIAL REGISTRATION: This trial is registered with clinicaltrials.gov (identifier: NCT00564096). PMID- 21303567 TI - Abstracts of the 2011 SCMR (Society for Cardiovascular Magnetic Resonance) /Euro CMR Joint Scientific Sessions. Nice, France. February 3-6, 2011. PMID- 21303568 TI - Diversity and metabolic impact of intestinal Lactobacillus species in healthy adults and the elderly. AB - The present study aimed at assessing the counts and species distribution of intestinal lactobacilli and exploring if the data are associated with BMI and blood glucose level in healthy adults and elderly persons. The BMI (P < 0.01), the level of fasting blood glucose (P < 0.001) and the total counts of lactobacilli (P < 0.01 by bacteriology; P < 0.001 by real-time PCR) were higher in the elderly. The number of species in adults was lower (P < 0.05), who were more often colonised with Lactobacillus acidophilus (P = 0.031) and L. helveticus (P < 0.001). In contrast, L. plantarum (P = 0.035), L. paracasei (P < 0.001) and L. reuteri (P = 0.031) were more prevalent in the elderly. L. rhamnosus was detected in adults (P < 0.001), but not in any elderly person. BMI was associated with counts of lactobacilli, adjusted for age and sex (P = 0.008). The higher BMI in both groups of persons was associated with the presence of obligate homofermentative lactobacilli and L. sakei, both adjusted for age and sex. Plasma glucose values were positively correlated with BMI and negatively correlated with colonisation with L. paracasei (P = 0.0238) in adults and on the borderline with L. fermentum (P = 0.052) in the elderly. Thus, the species-specific PCR analysis of Lactobacillus sp. combined with viable plating data indicates substantial age related structural differences in the intestinal lactobacilli communities. The higher counts of intestinal Lactobacillus sp. are associated with higher BMI and blood glucose content, while their specific fermentative groups and species of lactobacilli appear at different glucose levels both in adults and in the elderly. PMID- 21303570 TI - Iron absorption in hepcidin1 knockout mice. AB - Hepcidin, the Fe-regulatory peptide, has been shown to inhibit Fe absorption and reticuloendothelial Fe recycling. The present study was conducted to explore the mechanism of in vivo Fe regulation through genetic disruption of hepcidin1 and acute effects of hepcidin treatment in hepcidin1 knockout (Hepc1-/-) and heterozygous mice. Hepcidin1 disruption resulted in significantly increased intestinal Fe uptake. Hepcidin injection inhibited Fe absorption in both genotypes, but the effects were more evident in the knockout mice. Hepcidin administration was also associated with decreased membrane localisation of ferroportin in the duodenum, liver and, most significantly, in the spleen of Hepc1-/- mice. Hypoferraemia was induced in heterozygous mice by hepcidin treatment, but not in Hepc1-/- mice, 4 h after injection. Interestingly, Fe absorption and serum Fe levels in Hepc1-/- and heterozygous mice fed a low-Fe diet were not affected by hepcidin injection. The present study demonstrates that hepcidin deficiency causes increased Fe absorption. The effects of hepcidin were abolished by dietary Fe deficiency, indicating that the response to hepcidin may be influenced by dietary Fe level or Fe status. PMID- 21303569 TI - Efficacy of a microencapsulated iron pyrophosphate-fortified fruit juice: a randomised, double-blind, placebo-controlled study in Spanish iron-deficient women. AB - Fe-deficiency anaemia is a worldwide health problem. We studied the influence of consuming an Fe-fortified fruit juice on Fe status in menstruating women. A randomised, double-blind, placebo-controlled study of 16 weeks of duration was performed. Subjects were randomised into two groups: the P group (n 58) or the F group (n 64), and consumed, as a supplement to their usual diet, 500 ml/d of a placebo fruit juice or an Fe-fortified fruit juice, respectively. The Fe fortified fruit juice, containing microencapsulated iron pyrophosphate, provided 18 mg Fe/d (100 % of the RDA). At baseline and monthly, dietary intake, body weight and Fe parameters were determined: total erythrocytes, haematocrit, mean corpuscular volume (MCV), red blood cell distribution width (RDW), Hb, serum Fe, serum ferritin, serum transferrin, transferrin saturation, soluble transferrin receptor (sTfR) and zinc protoporphyrin (ZnPP). The fruit juice consumption involved increased intake of carbohydrates and vitamin C, and increased BMI within normal limits. Ferritin was higher in the F group after week 4 (P < 0.05) and became 80 % higher than in the P group after week 16 (P < 0.001), and transferrin decreased in the F group compared with the P group after week 4 (P < 0.001). RDW was higher at weeks 4 and 8 in the F group compared with the P group (P < 0.05). Transferrin saturation increased after week 8, and haematocrit, MCV and Hb increased after week 12, in the F group compared with the P group. Serum Fe did not change. sTfR and ZnPP decreased in the F group at week 16 (P < 0.05). Iron pyrophosphate-fortified fruit juice improves Fe status and may be used to prevent Fe-deficiency anaemia. PMID- 21303571 TI - Flavonoid intake in relation to cognitive function in later life in the Lothian Birth Cohort 1936. AB - Previous studies have suggested a link between flavonoid intake and better cognitive function in later life but have not been able to control for possible confounding by prior intelligence quotient (IQ). The aim of the present study was to address this issue in a cross-sectional survey of 1091 men and women born in 1936, in whom IQ was measured at age 11 years. At the age of 70 years, participants carried out various neuropsychological tests and completed a FFQ. Associations between test scores and nutrient intake were assessed by linear regression with adjustment for potentially confounding variables. Total fruit, citrus fruits, apple and tea intakes were initially found to be associated with better scores in a variety of cognitive tests, but the associations were no longer statistically significant after adjusting for confounding factors, including childhood IQ. Flavanone intake was initially found to be associated with better scores in verbal fluency (P = 0.003, with standardised regression coefficient 0.10), but, again, the association was no longer statistically significant after adjusting for confounding factors. These findings do not support a role for flavonoids in the prevention of cognitive decline in later life. Studies of diet and cognitive function should include measurement of potential confounding variables, including prior IQ wherever possible. PMID- 21303572 TI - Effect of feeding Atlantic salmon (Salmo salar L.) a diet enriched with stearidonic acid from parr to smolt on growth and n-3 long-chain PUFA biosynthesis. AB - Vegetable oils (VO) have become the predominant substitute for fish oil (FO) in aquafeeds; however, the resultant lower content of n-3 long-chain ( >= C20) PUFA (n-3 LC-PUFA) in fish has put their use under scrutiny. The need to investigate new oil sources exists. The present study tested the hypothesis that in Atlantic salmon (Salmo salar L.), a high intake of stearidonic acid (SDA) from Echium oil (EO) would result in increased n-3 LC-PUFA biosynthesis due to a lower requirement for Delta6 desaturase. Comparisons were made with fish fed on diets containing rapeseed oil (RO) and FO in freshwater for 112 d followed by 96 d in seawater. EO fish had higher whole-carcass SDA and eicosatetraenoic acid (ETA) in freshwater and prolonged feeding on the EO diet in seawater resulted in higher SDA, ETA, EPA and docosapentaenoic acid (DPA) compared with RO fish. Fatty acid mass balance of freshwater fish indicated higher biosynthesis of ETA and EPA in EO fish compared with fish fed on the other diets and a twofold increase in n-3 LC-PUFA synthesis compared with RO fish. In seawater, n-3 biosynthetic activity was low, with higher biosynthesis of ETA in EO fish and appearance of all desaturated and elongated products along the n-3 pathway. SDA-enriched VO are more suitable substitutes than conventional VO from a human consumer perspective due to the resulting higher SDA content, higher total n-3 and improved n-3:n-6 ratio obtained in fish, although both VO were not as effective as FO in maintaining EPA and DHA content in Atlantic salmon. PMID- 21303573 TI - Intestinal barrier function and absorption in pigs after weaning: a review. AB - Under commercial conditions, weaning of piglets is associated with social, environmental and dietary stress. Consequently, small-intestinal barrier and absorptive functions deteriorate within a short time after weaning. Most studies that have assessed small-intestinal permeability in pigs after weaning used either Ussing chambers or orally administered marker probes. Paracellular barrier function and active absorption decrease when pigs are weaned at 3 weeks of age or earlier. However, when weaned at 4 weeks of age or later, the barrier function is less affected, and active absorption is not affected or is increased. Weaning stress is a critical factor in relation to the compromised paracellular barrier function after weaning. Adequate feed intake levels after weaning prevent the loss of the intestinal barrier function. Transcellular transport of macromolecules and passive transcellular absorption decrease after weaning. This may reflect a natural intestinal maturation process that is enhanced by the weaning process and prevents the pig from an antigen overload. It seems that passive and active absorption after weaning adapt accurately to the new environment when pigs are weaned after 3 weeks of age. However, when weaned at 3 weeks of age or earlier, the decrease in active absorption indicates that pigs are unable to sufficiently adapt to the new environment. To improve weaning strategies, future studies should distinguish whether the effect of feed intake on barrier function can be directed to a lack of a specific nutrient, i.e. energy or protein. PMID- 21303575 TI - Adherence to a Mediterranean diet and plasma fatty acids: data from the Bordeaux sample of the Three-City study. AB - Higher adherence to a Mediterranean diet (MeDi) and n-3 PUFA may both contribute to decreased dementia risk, but the association between MeDi adherence and lipid status is unclear. The aim of the present study was to analyse the relationship between plasma fatty acids and MeDi adherence in French elderly community dwellers. The study population (mean age 75.9 years) consisted of 1050 subjects from Bordeaux (France) included in the Three-City cohort. Adherence to the MeDi (scored as 0-9) was computed from a FFQ and 24 h recall. The proportion of each plasma fatty acid was determined. Cross-sectional analysis of the association between plasma fatty acids and MeDi adherence was performed by multi-linear regression. After adjusting for age, sex, energy intake, physical activity, smoking status, BMI, plasma TAG and apoE-E4 genotype, plasma palmitoleic acid was significantly inversely associated with MeDi adherence, whereas plasma DHA, the EPA+DHA index and total n-3 PUFA were positively associated with MeDi adherence. The n-6:n-3 PUFA, arachidonic acid (AA):EPA, AA:DHA and AA:(EPA+DHA) ratios were significantly inversely associated with MeDi adherence. Plasma EPA was positively associated with MeDi adherence only in apoE-E4 non-carriers. There was no association between MeDi adherence and SFA and total MUFA. The present results suggest that the protective effect of the MeDi on cognitive functions might be mediated by higher plasma DHA and lower n-6:n-3 PUFA ratios. PMID- 21303576 TI - A whey-based glutathione-enhancing diet decreases allergen-induced airway contraction in a guinea-pig model of asthma. AB - Since an allergen-induced early asthmatic reaction is likely to be accompanied by oxidative stress and since levels of the endogenous antioxidant glutathione can be enhanced by a whey-based diet (undenatured whey protein concentrate, UWPC), it was investigated whether UWPC could alleviate allergen-induced lung contractions. Guinea pigs were fed water or UWPC twice a day starting at day - 3 up to day 20. The animals were sensitised to ovalbumin or received saline on day 0. Serum samples were taken at several days after sensitisation to measure allergen specific IgG. On day 20, lungs were isolated and perfused with buffer containing the allergen ovalbumin. Airway contractions were assessed, and mediators and indicators for oxidative stress were measured in the lung effluent. Moreover, glutathione levels were determined in the liver. The indicator of oxidative stress and airway contractile mediator, 8-iso-PGF(2alpha), was increased upon ovalbumin challenge in ovalbumin-sensitised groups. Furthermore, thiobarbituric acid-reactive substances (TBARS) were increased as well. Sensitisation with ovalbumin increased IgG levels from day 12 up to day 20, which were not influenced by the UWPC diet. In contrast, the UWPC diet significantly enhanced glutathione levels in the liver. Moreover, the UWPC diet significantly reduced the ovalbumin-induced anaphylactic response by 45 % and decreased PGE2 levels by 55 % in the effluent fluid. We show for the first time that during anaphylaxis, there is acute oxidative stress in the respiratory tract. The UWPC diet did not influence the sensitisation response to the allergen but did increase endogenous glutathione levels. The UWPC diet profoundly reduces allergen-induced airway constrictions, which opens new avenues for dietary management of allergic diseases. PMID- 21303577 TI - The pressure wire as a diagnostic tool in patients with congenital cardiac disease. AB - The pressure wire has emerged as a useful tool to assess the clinical severity of moderate coronary artery lesions. We report a novel use of the pressure wire in adult patients with complex congenital cardiac disease in whom it was used in assessing pressures beyond the stenosis in the distal pulmonary artery, aorto pulmonary collaterals, and across prosthetic tricuspid valves, where conventional catheters were unable to reach. We used this in three of our patients for assessment of pulmonary artery pressures and in two patients for assessment of pressures across a prosthetic St Jude(r) valve. Out of the three patients referred for assessment, only two had significantly raised distal pulmonary pressures enabling them to receive appropriate therapy. Out of the two patients with a prosthetic tricuspid valve, only one required surgery based on this assessment. We describe a novel use of the pressure wire in the functional assessment of adults with congenital cardiac disease in whom conventional catheter techniques may not be able to provide adequate data. It can be a guide to provide appropriate therapy and avoid unnecessary interventions in this patient group. PMID- 21303578 TI - Markers of susceptibility to acute rheumatic fever: the B-cell antigen D8/17 is not robust as a marker in South Africa. AB - BACKGROUND: Acute rheumatic fever and its chronic sequelae, rheumatic cardiac disease, and neuropsychiatric movement disorders, remain major public health problems in South Africa. Early identification and treatment of streptococcal pharyngitis in susceptible individuals would prevent rheumatic cardiac disease. The B-cell antigen D8/17 is a marker of susceptibility to rheumatic fever in some populations. METHODS AND RESULTS: We assessed the significance of the D8/17 marker in a group of South Africans. Blood was collected from 107 individuals; 40 patients had previous confirmed rheumatic fever, 20 were first-degree relatives, and 47 were controls. The expression of D8/17 in each sample was analysed by flow cytometry. The mean proportion of B-cells that were D8/17 positive was 0.5% in the index cases, 0.47% in their relatives, and 0.27% in the controls. There was a significant difference between the index cases and the controls, p = 0.03, but the mean percentage positive in each group was very low. CONCLUSIONS: Patients with a history of rheumatic fever had statistically increased expression of the D8/17 marker. However, the actual percentages in this observational study were markedly lower than in other populations, ranging from 0.14%-1.53% compared to 11.6%-39.3%. The D8/17 marker would be an impractical screening tool in the South African population. PMID- 21303579 TI - Early extubation in tetralogy of Fallot patients after complete repair. AB - AIM: To document the feasibility of early extubation and to know the effect of age, weight, and post-operative right ventricle/left ventricle ratio in early extubation in intracardiac repair for tetralogy of Fallot. MATERIALS AND METHODS: This is a prospective study of 76 consecutive patients undergoing intracardiac repair between January, 2010 and April, 2010. The patients were compared between duration of ventilation with age, weight, and post-operative left ventricle/right ventricle ratio. RESULTS: In the age group less than 10 years, 47 patients were extubated within 4 hours and 12 after 4 hours. In the age group of 10-20 years, eight patients were extubated within 4 hours and seven patients after 4 hours. In the more than 20 years category, one patient was extubated within 4 hours and the other after 4 hours. In the weight category less than 10 kilograms, 17 patients were extubated within 4 hours and seven patients after 4 hours. In the 10-20 kilogram category, 27 patients were extubated before 4 hours and four patients after 4 hours. In the more than 20-kilogram category, 12 patients were extubated before 4 hours and nine patients after 4 hours. Where the ratio was less than 0.5, 47 patients were extubated within 4 hours and 14 patients after 4 hours. Where the ratio was greater than 0.5, nine patients were extubated within 4 hours and six patients after 4 hours. CONCLUSION: There was no correlation between duration of ventilation with age, weight, and right ventricle/left ventricle ratio. Early extubation in patients after intracardiac repair in tetralogy of Fallot is safe and effective. PMID- 21303581 TI - Ongoing inflammation in children with rheumatic heart disease. AB - AIM OF THE WORK: To elucidate the hypothesis of ongoing inflammation in children with chronic rheumatic heart disease, and its possible consequences. SUBJECTS AND METHODS: This study was conducted on 36 patients with a mean age of 12.63 years: six with acute rheumatic carditis, and 30 with chronic rheumatic heart disease. There were 15 age- and sex-matched children who served as a control group. All subjects underwent echocardiographic assessment of valvular involvement and left ventricular function. Laboratory investigations comprised lipid profile, high sensitivity C-reactive protein, and homocysteine assay. RESULTS: High-sensitivity C-reactive protein was significantly elevated in patients with acute rheumatic carditis and in patients with chronic rheumatic heart disease (mean and standard deviation of 78.33, 156 micrograms per millilitre and 78.33, 23.17 micrograms per millilitre, respectively) as compared to the control group (mean and standard deviation of 5.83 and 2.79 micrograms per millilitre). High-sensitivity C reactive protein correlated with the grade of mitral regurgitation (p less than 0.05). Homocysteine was significantly elevated in patients with acute carditis and patients with rheumatic heart disease as compared to the control group (their mean and standard deviation were 2.96, 0.476 nanograms per decilitre, 2.99, 1.48 nanograms per decilitre, and 1.717, 0.733 nanograms per decilitre, respectively), but did not show significant difference between the two studied groups of patients. Neither C-reactive protein nor homocysteine correlated with any of the studied parameters of lipid profile. CONCLUSION: There is evidence of ongoing inflammation in children with rheumatic heart disease, which correlates with the degree of valvular involvement. This ongoing inflammation may put those children at risk for premature atherosclerosis. PMID- 21303582 TI - Is traditional contraceptive use in Moldova associated with poverty and isolation? AB - This study investigates the correlates of traditional contraceptive use in Moldova, a poor country in Europe with one of the highest proportions of traditional contraceptive method users. The high reliance on traditional methods, particularly in the context of sub-replacement level fertility rate, has not been systematically evaluated in demographic research. Using cross-sectional data on a sub-sample of 6039 sexually experienced women from the 2005 Moldovan Demographic and Health Survey, this study hypothesizes that (a) economic and spatial disadvantages increase the likelihood of traditional method use, and (b) high exposure to family planning/reproductive health (FP/RH) programmes increases the propensity to modern method use. Multilevel multinomial models are used to examine the correlates of traditional method use controlling for exposure to sexual activity, socioeconomic and demographic characteristics and data structure. The results show that economic disadvantage increases the probability of traditional method use, but the overall effect is small. Although higher family planning media exposure decreases the reliance on traditional methods among younger women, it has only a marginal effect in increasing modern method use among older women. Family planning programmes designed to encourage women to switch from traditional to modern methods have some success--although the effect is considerably reduced in regions outside of the capital Chisinau. The study concludes that FP/RH efforts directed towards the poorest may have limited impact, but interventions targeted at older women could reduce the burden of unwanted pregnancies and abortions. Addressing differentials in accessing modern methods could improve uptake in rural areas. PMID- 21303580 TI - Plasma proteomic alterations in non-human primates and humans after chronic alcohol self-administration. AB - Objective diagnostics of excessive alcohol use are valuable tools in the identification and monitoring of subjects with alcohol use disorders. A number of potential biomarkers of alcohol intake have been proposed, but none have reached widespread clinical usage, often due to limited diagnostic sensitivity and specificity. In order to identify novel potential biomarkers, we performed proteomic biomarker target discovery in plasma samples from non-human primates that chronically self-administer high levels of ethanol. Two-dimensional difference in-gel electrophoresis (2D-DIGE) was used to quantify plasma proteins from within-subject samples collected before exposure to ethanol and after 3 months of excessive ethanol self-administration. Highly abundant plasma proteins were depleted from plasma samples to increase proteomic coverage. Altered plasma levels of serum amyloid A4 (SAA4), retinol-binding protein, inter-alpha inhibitor H4, clusterin, and fibronectin, identified by 2D-DIGE analysis, were confirmed in unmanipulated, whole plasma from these animals by immunoblotting. Examination of these target plasma proteins in human subjects with excessive alcohol consumption (and control subjects) revealed increased levels of SAA4 and clusterin and decreased levels of fibronectin compared to controls. These proteins not only serve as targets for further development as biomarker candidates or components of biomarker panels, but also add to the growing understanding of dysregulated immune function and lipoprotein metabolism with chronic, excessive alcohol consumption. PMID- 21303583 TI - Post-thaw culture in presence of insulin-like growth factor I improves the quality of cattle cryopreserved embryos. AB - The goal of this study was to examine the effect of insulin-like growth factor I (IGF-I; added during post-thaw culture (48 h)) on the preimplantation viability and quality of cryopreserved bovine in vivo recovered embryos. The morula stage embryos, non-surgically recovered from superovulated dairy cows of Czech Fleckvieh cattle breed, had previously been cryopreserved by a slow freezing technique and stored in liquid nitrogen since 1989-1990. Following thawing, the embryos were cultured for 48 h either alone (no IGF-I) or in the presence of IGF I (10 or 100 ng/ml); non-cultured embryos served as a control. Thereafter, the embryos were analyzed for cleavage to the blastocyst stage, apoptosis (TUNEL), embryo cell number and quality of actin cytoskeleton. Following post-thaw culture 41% of embryos developed to advanced blastocysts. IGF-I increased this per cent and, at a higher dose, essentially reduced the per cent of degenerated embryos. In cultured embryos, IGF-I at both doses elevated the cell number compared with non-cultured embryos. However, in comparison with embryos cultured without IGF-I, only the higher IGF-I dose resulted in elevating the embryo cell number. The TUNEL index was significantly lowered by IGF-I treatment. Thawed embryos were mostly of the grade III actin type and fewer (12%) had grade II actin, whilst no grade I actin embryos were noted. The addition of IGF-I resulted in the appearance of grade I actin embryos (8.33 and 6.9% for 10 and 100 ng/ml, respectively). These observations indicate that the addition of IGF-I during post thaw culture can improve the quality of bovine cryopreserved embryos. PMID- 21303585 TI - Production of transgenic canine embryos using interspecies somatic cell nuclear transfer. AB - Somatic cell nuclear transfer (SCNT) has emerged as an important tool for producing transgenic animals and deriving transgenic embryonic stem cells. The process of SCNT involves fusion of in vitro matured oocytes with somatic cells to make embryos that are transgenic when the nuclear donor somatic cells carry 'foreign' DNA and are clones when all the donor cells are genetically identical. However, in canines, it is difficult to obtain enough mature oocytes for successful SCNT due to the very low efficiency of in vitro oocyte maturation in this species that hinders canine transgenic cloning. One solution is to use oocytes from a different species or even a different genus, such as bovine oocytes, that can be matured easily in vitro. Accordingly, the aim of this study was: (1) to establish a canine fetal fibroblast line transfected with the green fluorescent protein (GFP) gene; and (2) to investigate in vitro embryonic development of canine cloned embryos derived from transgenic and non-transgenic cell lines using bovine in vitro matured oocytes. Canine fetal fibroblasts were transfected with constructs containing the GFP and puromycin resistance genes using FuGENE 6(r). Viability levels of these cells were determined by the MTT [3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay. Interspecies SCNT (iSCNT) embryos from normal or transfected cells were produced and cultured in vitro. The MTT measurement of GFP-transfected fetal fibroblasts (mean OD = 0.25) was not significantly different from non-transfected fetal fibroblasts (mean OD = 0.35). There was no difference between transgenic iSCNT versus non transgenic iSCNT embryos in terms of fusion rates (73.1% and 75.7%, respectively), cleavage rates (69.7% vs. 73.8%) and development to the 8-16-cell stage (40.1% vs. 42.7%). Embryos derived from the transfected cells completely expressed GFP at the 2-cell, 4-cell, and 8-16-cell stages without mosaicism. In summary, our results demonstrated that, following successful isolation of canine transgenic cells, iSCNT embryos developed to early pre-implantation stages in vitro, showing stable GFP expression. These canine-bovine iSCNT embryos can be used for further in vitro analysis of canine transgenic cells and will contribute to the production of various transgenic dogs for use as specific human disease models. PMID- 21303584 TI - Increased blastocyst formation of cloned porcine embryos produced with donor cells pre-treated with Xenopus egg extract and/or digitonin. AB - Pre-treating donor cells before somatic cell nuclear transfer (SCNT, 'cloning') may improve the efficiency of the technology. The aim of this study was to evaluate the early development of cloned embryos produced with porcine fibroblasts pre-treated with a permeabilizing agent and extract from Xenopus laevis eggs. In Experiment 1, fetal fibroblasts were permeabilized by digitonin, incubated in egg extract and, after re-sealing of cell membranes, cultured for 3 or 5 days before use as donor cells in handmade cloning (HMC). Controls were produced by HMC with non-treated donor cells. The blastocyst rate for reconstructed embryos increased significantly when digitonin-permeabilized, extract-treated cells were used after 5 days of culture after re-sealing. In Experiment 2, fetal and adult fibroblasts were treated with digitonin alone before re-sealing the cell membranes, then cultured for 3 or 5 days and used as donor cells in HMC. Treatment with digitonin alone increased the blastocyst rate, but only when fetal, and not adult fibroblasts, were used as donor cells, and only after 3 days of culture. In conclusion, we find a time window for increased efficiency of porcine SCNT using donor cells after pre-treatment with permeabilization/re-sealing and Xenopus egg extract. Interestingly, we observe a similar increase in cloning efficiency by permeabilization/re-sealing of donor cells without extract treatment that seems to depend on choice of donor cell type. Thus, pre-treatment of donor cells using permeabilizing treatment followed by re-sealing and in vitro culture for few days could be a simple way to improve the efficiency of porcine cloning. PMID- 21303586 TI - Insulin-transferrin-selenium (ITS) improves maturation of porcine oocytes in vitro. AB - The objective of this study was to determine if insulin-transferrin-selenium (ITS) promoted a nuclear and cytoplasmic maturation of porcine oocytes that better supports subsequent embryonic development. The rate of oocyte in vitro maturation (IVM) in an experimental group treated with hormones for 42 h was significantly increased compared with that in a control group without hormone treatment (47.8% vs. 11.7%, respectively, p < 0.05). Following reduction of the hormone treatment period from 42 h to 21 h, which included both the first 21 h period of hormones treatment (45.4%) and the second 21 h period of hormone treatment (44.8%), the rate of oocyte IVM was still higher than that of the control group (p < 0.05). To improve porcine oocyte nuclear maturation, 1% ITS was added to medium supplemented with hormones. The rate of nuclear maturation in the ITS-treated group was significantly higher than in the ITS-untreated group (78.6% vs. 54.4%, respectively, p < 0.05). ITS treatment also significantly reduced the per cent of oocytes with type I and type III cortical granule (CG) distribution, respectively, and significantly increased the per cent of oocytes with type II CG distribution (85.3%). These observations indicated that the synchronization rates of nuclear and ooplasmic maturation reached 67.04% (78.56 * 85.33%). In conclusion, the combination of modified Tissue Culture Medium-199 (mM199) + 10 ng/ml epidermal growth factor (EGF) + 10 IU/ml pregnant mare serum gonadotrophin (PMSG) + 10 IU/ml human chorion gonadotrophin (hCG) + 2.5 IU/ml follicle stimulating hormone (FSH) + 1% ITS is suitable for culturing porcine oocytes in vitro, and effectively enhances porcine oocyte nuclear and cytoplasmic maturation. PMID- 21303587 TI - Anaesthetic and post-operative management of a modified Norwood operation for hypoplastic left heart syndrome: a retrospective series of 11 cases. AB - OBJECTIVE: This study aimed to describe the pre-operative and operative findings, as well as the post-operative haemodynamics of patients operated on for hypoplastic left heart. The findings of patients who survived or did not survive were also compared to anticipate the risk factors for mortality. METHODS: We retrospectively reviewed the anaesthetic and intensive care records of 11 (seven male and four female) patients who underwent a modified Norwood operation as neonates. There were eight patients who survived, while three did not survive after the operation. Haemodynamics, oxygenation, and medications of patients were recorded for the pre-operative and post-operative conditions for 2 days, and compared between groups of patients who survived and those who did not. RESULTS: The normalised modified Blalock-Taussig shunt area was 3.28, 0.57 square millimetres per kilogram (mean, standard deviation) for the group of patients who survived and 3.55, 1.4 square millimetres per kilogram for the group of patients who did not survive (p = 0.51). The group of patients who survived had a significantly larger normalised aortic annulus area (3.3, 0.89 square millimetres per kilogram versus 1.68, 0.21 square millimetres per kilogram, p = 0.01), lower median age (5.57 (3-8) days versus 46.67 (4-90) days, p = 0.02), and lower weight (2.95, 0.46 kilograms versus 3.85, 0.56 kilograms, p = 0.03) than the group of patients who did not survive. Furthermore, the group of patients who did not survive had a significantly worse pre-operative condition, lower systemic venous and arterial oxygen saturation, and need for a high dose of drugs in the pre operative and post-operative periods (p was less than 0.05 for each variable). CONCLUSION: The pre-operative, operative, and post-operative findings may be related to mortality early after the modified Norwood operation for hypoplastic left heart syndrome. PMID- 21303588 TI - Exploratory and recruitment phases in soldier-mediated foraging activities in the termite, Coptotermes intermedius Silvestri (Rhinotermitidae: Coptotermitinae). AB - Coptotermes intermedius is a damp-wood subterranean termite, which attacks timber and other woody materials with heavy losses in the southern part of Nigeria. The process leading to search for wood and eventual damage was investigated, with focus on how this search is initiated and by which of the termite castes. Results showed that minor soldiers initiate the exploratory phase of search, while the workers are involved in the eventual recruitment process. Under appropriate soldier-worker caste ratio or percentages, exploratory activities in C. intermedius may be regulated. PMID- 21303589 TI - A hierarchical model for real-time monitoring of variation in risk of non specific gastrointestinal infections. AB - The AEGISS (Ascertainment and Enhancement of Disease Surveillance and Statistics) project uses spatio-temporal statistical methods to identify anomalies in the incidence of gastrointestinal infections in the UK. The focus of this paper is the modelling of temporal variation in incidence using data from the Southampton area in southern England. We identified and fitted a hierarchical stochastic model for the time series of daily incident cases to enable probabilistic prediction of temporal variation in risk, and demonstrated the resulting gains in predictive accuracy by comparison with a conventional analysis based on an over dispersed Poisson log-linear regression model. We used Bayesian methods of inference in order to incorporate parameter uncertainty in our predictive inference of risk. Incorporation of our model in the overall spatio-temporal model, will contribute to the accurate and timely prediction of unusually high food-poisoning incidence, and thus to the identification and prevention of future outbreaks. PMID- 21303590 TI - Changes in antibiotic usage and susceptibility in nosocomial Enterobacteriaceae and Pseudomonas isolates following the introduction of ertapenem to hospital formulary. AB - There is concern that widespread usage of ertapenem may promote cross-resistance to other carbapenems. To analyse the impact that adding ertapenem to our hospital formulary had on usage of other broad-spectrum agents and on susceptibilities of nosocomial Enterobacteriaceae and Pseudomonas isolates, we performed interrupted time-series analyses to determine the change in linear trend in antibiotic usage and change in mean proportion and linear trend of susceptibility pre- (March 2004 June 2005) and post- (July 2005-December 2008) ertapenem introduction. Usage of piperacillin-tazobactam (P=0.0013) and ampicillin-sulbactam (P=0.035) declined post-ertapenem introduction. For Enterobacteriaceae, the mean proportion susceptible to ciprofloxacin (P=0.016) and piperacillin-tazobactam (P=0.038) increased, while the linear trend in susceptibility significantly increased for cefepime (P=0.012) but declined for ceftriaxone (P=0.0032). For Pseudomonas, the mean proportion susceptible to cefepime (P=0.011) and piperacillin-tazobactam (P=0.028) increased, as did the linear trend in susceptibility to ciprofloxacin (P=0.028). Notably, no significant changes in carbapenem susceptibility were observed. PMID- 21303591 TI - Under full sail. PMID- 21303592 TI - Mandibular pseudoepitheliomatous hyperplasia following treatment for oral squamous cell carcinoma. PMID- 21303593 TI - Stepwise regional and distant progression of recurrent pleomorphic adenoma. PMID- 21303594 TI - From fragments to the whole: a comparison between cochlear implant users and normal-hearing listeners in music perception and enjoyment. AB - BACKGROUND: Cochlear implants (CIs) allow many profoundly deaf individuals to regain speech understanding. However, the ability to understand speech does not necessarily guarantee music enjoyment. Enabling a CI user to recover the ability to perceive and enjoy the complexity of music remains a challenge determined by many factors. OBJECTIVES: (1) To construct a novel, attention-based, diagnostic software tool (Music EAR) for the assessment of music enjoyment and perception and (2) to compare the results among three listener groups. METHODS: Thirty-six subjects completed the Music EAR assessment tool: 12 normal-hearing musicians (NHMs), 12 normal-hearing nonmusicians (NHnMs), and 12 CI listeners. Subjects were required to (1) rate enjoyment of musical excerpts at three complexity levels; (2) differentiate five instrumental timbres; (3) recognize pitch pattern variation; and (4) identify target musical patterns embedded holistically in a melody. RESULTS: Enjoyment scores for CI users were comparable to those for NHMs and superior to those for NHnMs and revealed that implantees enjoyed classical music most. CI users performed significantly poorer in all categories of music perception compared to normal-hearing listeners. Overall CI user scores were lowest in those tasks requiring increased attention. Two high-performing subjects matched or outperformed NHnMs in pitch and timbre perception tasks. CONCLUSIONS: The Music EAR assessment tool provides a unique approach to the measurement of music perception and enjoyment in CI users. Together with auditory training evidence, the results provide considerable hope for further recovery of music appreciation through methodical rehabilitation. PMID- 21303596 TI - Comparison of two approaches to the surgical management of juvenile nasopharyngeal angiofibroma stages I and II. AB - OBJECTIVE: Our study was designed to compare two surgical approaches that are currently employed in the treatment of nasopharyngeal angiofibroma stages I and II. STUDY DESIGN: Retrospective chart review to compare outcomes in 11 patients who underwent endoscopic resection with outcomes of transpalatal excision in 13 patients with juvenile nasopharyngeal angiofibroma (JNA) at our department between 1992 and 2008. SETTING: Academic otorhinolaryngologic referral centre. SUBJECTS AND METHOD: Twenty-four patients were divided into two groups according to the surgical technique used. The transpalatal approach was followed for 13 patients, whereas the transnasal endoscopic approach was adhered to for 11. The outcome variables of intraoperative blood loss, length of hospital stay, complications, and rate of recurrence were analyzed. RESULTS: Compared to the transpalatal surgery group, the transnasal endoscopic group had less intraoperative blood loss (375 +/- 27 mL vs 635 +/- 41 mL), the mean duration of surgery was significantly shorter (115.7 +/- 7.6 minutes vs 141.5 +/- 9.8 minutes), and there was a lower occurrence of complications (1 patient vs 6 patients) and a shorter length of hospital stay (4 +/- 1.0 days vs 6 +/- 1.5 days), but there was no significant difference in the rate of recurrence. CONCLUSION: In JNA stages I and II, the transnasal endoscopic approach is clearly a good alternative to the transpalatal approach. PMID- 21303595 TI - Effectiveness of the heat-activated nitinol smart piston stapes prosthesis in stapedectomy surgery. AB - OBJECTIVE: To compare the SMart piston stapes prosthesis to a standard manual crimp prosthesis on operative time and air-bone gap (ABG) closure in stapedectomy. DESIGN: Retrospective chart review. SETTING: Tertiary referral centre. METHODS: The charts of patients undergoing stapedectomy for otosclerosis were analyzed. We compared the results of 76 patients (80 ears) who received the autocrimping SMart piston prosthesis to those of 21 patients (21 ears) who received the conventional manual crimp Fisch-type prosthesis. Data were analyzed using t-test, chi-square, or two-way analysis of variance where appropriate. MAIN OUTCOME MEASURE: Operative time with ABG closure as a secondary outcome measure. RESULTS: There was a significant difference in operative time between the Fisch type prosthesis and the SMart piston prosthesis groups. The operation required 28.9 +/- 3.2 minutes when using the Fisch-type prosthesis, whereas 21.2 +/- 2.4 minutes were needed when using the SMart piston (p < .001). There was a significant improvement in postoperative ABG for both the Fisch-type piston (28.1 +/- 3.1 to 9.0 +/- 1.4, p < .001) and the SMart piston (25.1 +/- 3.7 to 8.2 +/- 2.5, p < .001) groups. CONCLUSIONS: Use of the SMart piston prosthesis results in ABG closure similar to that of the traditional Fisch-type prosthesis but offers the added advantage of reduced operative time. PMID- 21303597 TI - Lingual thyroid in adults: management algorithm based on swallowing outcomes. AB - OBJECTIVE: To review the presentation, workup, and functional outcomes of adult patients diagnosed with lingual thyroid treated by transoral subtotal excision. These results were then used to formulate a management algorithm. DESIGN: Retrospective chart review (2001-2008). SETTING: Tertiary care academic hospital. PATIENTS: All patients diagnosed with a lingual thyroid as an adult were identified in the University of Alberta's head and neck mass database. Charts were reviewed for initial presentation, diagnostic methods, radiographic findings, and treatment and follow-up results. INTERVENTION: Transoral subtotal excision of lingual thyroid tissue. MAIN OUTCOME MEASURE: Postoperative swallowing function as measured by pharyngeal residue and aspiration on videofluoroscopic swallowing studies. RESULTS: Five patients with lingual thyroids meeting the study criteria were identified. All were females aged 29 to 58 years (mean 44 years). Presentations ranged from asymptomatic to acute airway obstruction. Diagnosis was made with flexible nasopharyngoscopy, thyroid scintigraphy, and computed tomography. All patients underwent transoral subtotal excision of their thyroids with either a CO2 laser or electrocautery. Two patients complained of residual symptoms and received adjunctive 131I, which led to symptom resolution. Pathologic evaluation revealed benign thyroid tissue. Swallowing function remained efficacious and safe in all patients, as shown by a lack of aspiration and low pharyngeal residue scores. These results were used to propose a management algorithm for the spectrum of adult-diagnosed lingual thyroid presentations. CONCLUSIONS: Transoral subtotal excision of lingual thyroid glands provides adequate resection of the lesion with good postoperative swallowing function. When appropriate, this is advocated as the treatment modality of choice. PMID- 21303599 TI - Adenocarcinoma of the nasal cavity and paranasal sinuses: single-institution review of diagnosis, histology, and outcome. AB - OBJECTIVE: To study the incidence, treatment, and outcomes of adenocarcinomas of the nose and paranasal sinuses over the last 15 years. DESIGN: Retrospective chart review of 20 patients identified and treated at the otolaryngology clinic of Zurich University Hospital between 1992 and 2007. MAIN OUTCOME MEASURES: Recurrence- and disease-free survival were the most important outcomes of interest. RESULTS: Twenty patients (16 men) with sinonasal adenocarcinoma were found. The average age was 64 years. At the time of diagnosis, usually more than one sinus was involved and nasal obstruction was the most common symptom. In 57.9% of patients, the initial treatment was endoscopic surgery. Two-year recurrence-free survival was 48.5%, and 5-year disease-specific survival was 77.8%. CONCLUSIONS: Surgical resection is difficult owing to anatomic restraints, and adjuvant therapy must be considered in most patients. Endoscopic surgery was performed in a majority of patients, with outcomes comparable to those in the general literature. SIGNIFICANCE: Adenocarcinoma of the paranasal sinuses was found to have almost 80% 5-year survival if adequately treated surgically and with adjuvant intensity-modulated radiotherapy. PMID- 21303598 TI - Incidence of parathyroid tissue in level VI neck dissection. AB - BACKGROUND: Level VI central neck dissections are commonly completed with thyroidectomy. This procedure involves risk of damage to, or incidental excision of, one or more of the parathyroid glands. METHODS: This study examined the pathology reports of patients undergoing thyroid surgery to determine the incidence of parathyroid tissue associated with level VI neck dissections and the risk factors associated with incidental parathyroidectomy. RESULTS: Ninety pathology specimens were analyzed. The incidence of parathyroid tissue associated with level VI neck dissections was 41.4%. We discovered that a higher frequency of incidental parathyroid tissue was located in level VI neck dissections among patients discovered to have malignant thyroid disease. There was no significant association between incidental parathyroidectomy and the sex of the patient, the age of the patient, the type of thyroid surgery, or transient or permanent hypoparathyroidism. CONCLUSION: A large percentage of level VI neck dissections in thyroid surgery were associated with incidental parathyroid tissue. A more detailed examination of surgical specimens may decrease this possibly preventable surgical complication. PMID- 21303600 TI - Comparison of speech and aesthetic outcomes in patients with maxillary reconstruction versus maxillary obturators after maxillectomy. AB - BACKGROUND: Two options exist for restoring structure and function after maxillectomy. Prosthodontic rehabilitation requires that an obturator be constructed to address the oronasal communication that exists after resection of the maxilla. Surgical reconstruction of the defect is another option, often accomplished with the use of bone-containing flaps. OBJECTIVE: To determine whether prosthetic rehabilitation or surgical reconstruction of the maxilla provides better speech and facial aesthetic outcomes after maxillectomy. DESIGN, PARTICIPANTS, AND MEASURES: Fifty-nine patients in three groups were included: 23 patients with maxillary obturators, 16 patients with maxillary reconstruction, and 20 patients without any maxillary defects but who were diagnosed with nasopharyngeal cancer and who served as a control group. Using digitized photographs, facial attractiveness was rated on a 10-point scale by eight judges who were blinded to treatment group. Speech outcomes included nasalance, velopharyngeal orifice opening, and speech intelligibility. RESULTS AND CONCLUSIONS: There were no significant between-group differences found for facial attractiveness ratings. However, patients in either group who had involvement of the orbital rim or the orbital rim and zygoma were rated as significantly less attractive than those without such involvement. With respect to speech outcomes, the control group (ie, nasopharynx) had smaller velopharyngeal orifice areas than the obturator group; however, this was not clinically significant as scores in both groups were within normal limits. In conclusion, this study found no differences between surgical reconstruction or prosthodontic intervention of maxillary defects when facial attractiveness was assessed by naive raters and speech outcomes were assessed using objective measurements. PMID- 21303601 TI - Cost-effectiveness of simultaneous versus sequential surgery in head and neck reconstruction. AB - OBJECTIVE: To determine whether simultaneous (ablation and reconstruction overlaps by two teams) head and neck reconstruction is cost effective compared to sequentially (ablation followed by reconstruction) performed surgery. STUDY DESIGN: Case-controlled study. SETTING: Tertiary care hospital. SUBJECTS: Oncology patients undergoing free flap reconstruction of the head and neck. METHODS: A match paired comparison study was performed with a retrospective chart review examining the total time of surgery for sequential and simultaneous surgery. Nine patients were selected for both the sequential and simultaneous groups. Sequential head and neck reconstruction patients were pair matched with patients who had undergone similar oncologic ablative or reconstructive procedures performed in a simultaneous fashion. A detailed cost analysis using the microcosting method was then undertaken looking at the direct costs of the surgeons, anesthesiologist, operating room, and nursing. RESULTS: On average, simultaneous surgery required 3 hours 15 minutes less operating time, leading to a cost savings of approximately $1200/case when compared to sequential surgery. This represents approximately a 15% reduction in the cost of the entire operation. CONCLUSION: Simultaneous head and neck reconstruction is more cost effective when compared to sequential surgery. PMID- 21303602 TI - A new approach in open rhinoplasty: new alar rim raising technique. AB - BACKGROUND: The relationship of the alar rim to the columella and its contour has great aesthetic importance, and correcting its deformities is sometimes challenging, especially if it is hanging, asymmetrical, or sigmoid--especially in the African or Asian nose. METHODS: The new method of alar rim incision is described here. This new approach combines the alar rim incision and incisions necessary for external rhinoplasty (modified external approach). RESULTS: All 24 patients noticed improvement and were satisfied with the results. Alar function was preserved in all cases. There were no complications, but two cases had asymmetrical alar width. CONCLUSION: Our new incision for alar rim excision not only decreases incision lines in the limited area of the nose, resulting in decreased risk of tissue compromise, but also provides a controlled method to remove excessive skins of the rim. PMID- 21303603 TI - Nasal polyps: heredity, allergies, and environmental and occupational exposure. AB - OBJECTIVE: To determine the role of heredity, allergies, smoking, and environmental and occupational exposure in the epidemiology of nasal polyposis. STUDY DESIGN: A case-control study comprising 100 patients with nasal polyps admitted to three Athens hospitals and 102 controls from the general population. Gender, educational level, family history, allergies, smoking, occupational activities, and environmental exposure were examined as eventual determinants. The prevalence of each determinant was compared between cases and controls using multiple logistic regression, and odds ratios (ORs) were estimated. RESULTS: A total of 13.3% of the patients and none of the controls had a history of polyps in the family. According to multiple logistic regression, the OR for certain allergies was 19.1 and for probable allergy was 9.0, with the prevalence among patients being 64% and 12%, respectively. The OR for certain environmental exposures was 15.0 and for occupational exposures was 21.4. Occupational exposure to chemicals was a predominant factor among patients. No significant difference was found between nasal polyps and educational level or smoking habits. CONCLUSIONS: The development of nasal polyps seems to be strongly related to family history and a history of allergies, but the role of smoking remains controversial. Occupational and environmental exposures probably enhance the appearance of the disease on the basis of genetic predisposition. PMID- 21303604 TI - Expression and role of acidic mammalian chitinase and eotaxin-3 in chronic rhinosinusitis with nasal polyps. AB - OBJECTIVE: Acidic mammalian chitinase (AMCase) has been found to play an important role in allergy and asthma. Chronic rhinosinusitis with nasal polyps (CRSwNPs) is chronic inflammation with eosinophilic infiltration, which is similar to asthmatic inflammation. The role of AMCase in CRSwNPs has been less studied. Eotaxin-3 is a potent eosinophil attractant and can induce eosinophil recruitment and activation in the airways of asthmatics. The expression and role of eotaxin-3 messenger ribonucleic acid (mRNA) and its relationship to AMCase in CRSwNPs have not been studied previously. SUBJECTS AND METHODS: Twenty-three subjects with nasal polyps and nine subjects with nasal septum deviation were included in the study. The polyps and inferior turbinate mucosa were obtained as the tissue samples. Real-time reverse transcriptase-polymerase chain reaction was used to analyze and compare the expression levels of AMCase and eotaxin-3 in nasal polyps and inferior turbinate tissues (ITTs). RESULTS: AMCase and eotaxin-3 were detected in all nasal polyps and ITTs. The expression ratio of AMCase mRNA was 123.90 +/- 30.60 in nasal polyps and 2.38 +/- 0.41 in ITTs. The expression ratio of eotaxin-3 mRNA was 43.58 +/- 15.15 and 0.84 +/- 0.30, respectively. The expression of AMCase and eotaxin-3 mRNA was significantly higher in nasal polyps than in ITTs (p < .01). CONCLUSIONS: Our results reveal that AMCase and eotaxin-3 may be important mediators in the pathogenesis of nasal polyps. The increased AMCase and eotaxin-3 might lead to nasal polyp formation and growth. Future studies are needed to determine the potential of AMCase and eotaxin-3 as therapeutic targets in CRSwNPs. PMID- 21303605 TI - Drainage of the maxillary sinus: a comparative anatomy study in humans and goats. AB - OBJECTIVE: The maxillary sinuses are the most frequently infected paranasal sinuses in humans. It has been suggested that infection occurs relatively commonly in the maxillary sinuses owing to the position of their ostia high on their superomedial walls, which may be suboptimal for natural drainage. This may represent evolutionary lag, whereby the ostia remained in a quadrupedal position as bipedal humans evolved from their primate ancestors. This study examined the hypothesis that drainage of the maxillary sinus is optimal in the quadrupedal position. DESIGN: The drainage of the human maxillary sinus and an analogous quadruped, the goat, was examined and compared in the upright, quadrupedal, and intermediate positions. SETTING: Department of Anatomy, King's College London. METHODS: Cadaveric human and goat maxillary sinuses were filled with saline in each position and the volume at which saline overflowed through the ostia was noted. MAIN OUTCOME MEASURE: Volume at which spontaneous drainage occurred through ostia. RESULTS: The volume of saline instilled before drainage was maximal in the upright position and reduced with each increase in anterior tilt, with drainage occurring most easily at 90 degrees for both human and goat sinuses. Drainage was significantly better in the quadrupedal head position than upright in both species (p < .01). CONCLUSIONS: This study demonstrated that human maxillary sinuses exhibit better passive drainage through their ostia when tilted anteriorly to mimic a quadrupedal head position. This may be an example of an evolutionary lag phenomenon and could be one etiologic factor in the prevalence of maxillary sinusitis in humans. PMID- 21303606 TI - Accuracy and reproducibility of automatic versus manual registration using a cone beam CT image guidance system. AB - INTRODUCTION: Intraoperative imaging reveals morphologic changes and resolves anatomic uncertainties during surgery. The automatic registration (AR) approach provides registered intraoperative images for real-time tracking within seconds of acquisition. PURPOSE: (1) To design an AR device for clinical use integrated with cone-beam computed tomography, (2) to compare the accuracy and reproducibility of manual and automatic registration, and (3) to evaluate the robustness of the AR system. METHODS: An AR device consisting of an acrylic face shield with fiducials mounted on an adjustable arm was designed. Eight surface and five internal divot markers were placed with bony fixation to a cadaveric head. Internal markers were localized on the image representing the "true" location. This was compared to the positions localized using a navigational system when both manual registration and AR were applied. A series of surgical tasks and variation of the AR device height above the surgical field was performed, and target registration error (TRE) was measured. RESULTS: The mean fiducial registration error (FRE) for manual and automatic registration was 0.72 mm +/- 0.03 and 0.41 mm +/- 0.01, respectively. The mean TRE for manual and automatic registration was 0.89 mm +/- 0.26 and 0.91 mm +/- 0.25, respectively. CONCLUSIONS: AR offers a more accurate and reproducible FRE and a TRE equally comparable to that of manual registration. This system also demonstrates robustness with comparable accuracy and reproducibility throughout different surgical tasks and variation of AR device height up to 9 cm above the surgical field. This system is currently being translated into clinical trials. PMID- 21303608 TI - Modified intraoral approach for removal of an elongated styloid process. AB - OBJECTIVE: To decrease the postoperative pain and the probability of intraoperative complications during intraoral removal of an elongated styloid process. STUDY DESIGN: A prospective, clinical trial. METHODS: Twenty-seven patients with 45 elongated styloid processes underwent surgery. There were 24 females and 3 males, with a mean age of 47.1 years. A simple visual analogue scale was used to assess pre- and postoperative pain. The length and medial and anterior angulation of each process were measured on lateral skull and Towne projection. During the surgery, after tonsillectomy was performed, the styloid process was identified and the process was stripped off proximally using a ring curette. The muscles and ligaments were in continuity with the periosteum, and attachments to the periostem were not disrupted. RESULTS: No intraoperative complications were seen. Only 2 of 45 procedures did not result in a decrease in pain, and a success rate of 95.6% was achieved by this modified surgical method. CONCLUSIONS: Excision of the styloid process without disturbing the attachments of the muscles and ligaments to the periosteum of the process is an important factor in relieving postoperative pain and complications. PMID- 21303607 TI - Global health initiatives and electives: a survey of interest among Canadian otolaryngology residents. AB - OBJECTIVE: To determine the level of interest among Canadian otolaryngology residents in global health initiatives (GHIs) and international health electives (IHEs) and the barriers to participation in such initiatives. METHODS: A Web based survey was developed and sent to all Canadian otolaryngology residents. Questions were posed on demographics, the level of interest in GHIs and IHEs, past experiences in this field, real and perceived barriers in pursuing GHIs and IHEs, previous global health experience, and, finally, the current infrastructure that exists in Canadian postsecondary institutions and otolaryngology programs to encourage participation. RESULTS: The level of interest among Canadian otolaryngology residents in GHIs and IHEs is at least 32%. The greatest barriers to pursuing this interest are cost, lack of infrastructure, lack of mentors, and lack of elective time. To contribute to an important cause was the top reason (79%) cited by respondents for their interest in global health. This was followed by personal growth and to learn about medicine in low- and middle-income countries, respectively. CONCLUSION: At least 32% of Canadian otolaryngology residents showed interest in participating in a GHI or IHE. We must devise means of overcoming barriers to participation in GHIs and IHEs and facilitate the clear and substantial resident interest in GHIs and IHEs. By supporting these endeavours, we will expose a cross section of physicians to global issues and give them an important and meaningful context in our increasingly interconnected world. PMID- 21303609 TI - A standardized approach for photography of radial forearm free flap donor site scars. PMID- 21303610 TI - Nanomedicine explored at molecular imaging summit. PMID- 21303611 TI - Inorganic nanoparticles for multimodal molecular imaging. AB - Multimodal molecular imaging can offer a synergistic improvement of diagnostic ability over a single imaging modality. Recent development of hybrid imaging systems has profoundly impacted the pool of available multimodal imaging probes. In particular, much interest has been focused on biocompatible, inorganic nanoparticle-based multimodal probes. Inorganic nanoparticles offer exceptional advantages to the field of multimodal imaging owing to their unique characteristics, such as nanometer dimensions, tunable imaging properties, and multifunctionality. Nanoparticles mainly based on iron oxide, quantum dots, gold, and silica have been applied to various imaging modalities to characterize and image specific biologic processes on a molecular level. A combination of nanoparticles and other materials such as biomolecules, polymers, and radiometals continue to increase functionality for in vivo multimodal imaging and therapeutic agents. In this review, we discuss the unique concepts, characteristics, and applications of the various multimodal imaging probes based on inorganic nanoparticles. PMID- 21303612 TI - Emerging nanomaterial governance systems: the state of play. AB - Domestic laws, their implementing regulations and policies, and government and private-party governance programs are now being carefully reviewed and revised to enhance their utility to manage the potential risks posed by nanoscale materials. Whether existing laws and their implementing programs are adequate to address such risks will continue to inspire debate and legislative and regulatory initiatives for years to come. This article reviews existing legal and governance oversight systems and analyzes their strengths and deficiencies in addressing the potential risks posed by nanoscale materials and in fostering nanotechnology's promise. Particular attention is devoted to emerging regulatory approaches the US Environmental Protection Agency is taking under the Toxic Substances Control Act and the Federal Insecticide, Fungicide, and Rodenticide Act, the two domestic chemical product laws primarily responsible for ensuring the safety of chemical substances and mixtures. PMID- 21303613 TI - Multifunctional synthetic poly(L-glutamic acid)-based cancer therapeutic and imaging agents. AB - Modern polymer chemistry has led to the generation of a number of biocompatible synthetic polymers that have been increasingly studied as efficient carriers for drugs and imaging agents. Synthetic biocompatible polymers have been used to improve the efficacy of both small-molecular-weight therapeutics and imaging agents. Furthermore, multiple targeted anticancer agents and/or imaging reporters can be attached to a single polymer chain, allowing multifunctional and/or multimodality therapy and molecular imaging. Having both an anticancer drug and an imaging reporter in a single polymer chain allows noninvasive real-time visualization of the pharmacokinetics of polymeric drug delivery systems, which can uncover and explain the complicated mechanisms of in vivo drug delivery and their correlation to pharmacodynamics. This review examines the use of the synthetic biocompatible polymer poly(L-glutamic acid) (PG) as an efficient carrier of cancer therapeutics and imaging agents. This review summarizes and updates our recent research on the use of PG as a platform for drug delivery and molecular imaging, including recent clinical findings with respect to PG paclitaxel (PG-TXL), the combination of PG-TXL with radiotherapy, mechanisms of action of PG-TXL, and noninvasive visualization of in vivo delivery of polymeric conjugates with contrast-enhanced magnetic resonance imaging, optical imaging, and multimodality imaging. PMID- 21303614 TI - Proteomic analysis of serum opsonins impacting biodistribution and cellular association of porous silicon microparticles. AB - Mass transport of drug delivery vehicles is guided by particle properties, such as size, shape, composition, and surface chemistry, as well as biomolecules and serum proteins that adsorb to the particle surface. In an attempt to identify serum proteins influencing cellular associations and biodistribution of intravascularly injected particles, we used two-dimensional gel electrophoresis and mass spectrometry to identify proteins eluted from the surface of cationic and anionic silicon microparticles. Cationic microparticles displayed a 25-fold greater abundance of Ig light variable chain, fibrinogen, and complement component 1 compared to their anionic counterparts. Anionic microparticles were found to accumulate in equal abundance in murine liver and spleen, whereas cationic microparticles showed preferential accumulation in the spleen. Immunohistochemistry supported macrophage uptake of both anionic and cationic microparticles in the liver, as well as evidence of association of cationic microparticles with hepatic endothelial cells. Furthermore, scanning electron micrographs supported cellular competition for cationic microparticles by endothelial cells and macrophages. Despite high macrophage content in the lungs and tumor, microparticle uptake by these cells was minimal, supporting differences in the repertoire of surface receptors expressed by tissue-specific macrophages. In summary, particle surface chemistry drives selective binding of serum components impacting cellular interactions and biodistribution. PMID- 21303615 TI - Near-infrared imaging method for the in vivo assessment of the biodistribution of nanoporous silicon particles. AB - In the development of new nanoparticle-based technologies for therapeutic and diagnostic purposes, understanding the fate of nanoparticles in the body is crucial. We recently developed a multistage vector delivery system comprising biodegradable and biocompatible nanoporous silicon particles (first-stage microparticles [S1MPs]) able to host, protect, and deliver second-stage therapeutic and diagnostic nanoparticles (S2NPs) on intravenous injection. This delivery system aims at sequentially overcoming the biologic barriers en route to the target delivery site by separating and assigning tasks to the coordinated logic-embedded vectors constituting it. In this work, by conjugating a near infrared dye on the surface of the S1MP without compromising the porous structure and potential loading of S2NPs, we were able to monitor the in vivo distribution of S1MPs in healthy mice using an optical imaging system. It was observed that particles predominantly accumulated in the liver and spleen at the end of 24 hours. Further quantification of S1MPs in the major organs of the animals by elemental analysis of silicon using inductively coupled plasma-atomic electron spectroscopy verified the accuracy of in vivo near-infrared imaging as a tool for evaluation of nanovector biodistribution. PMID- 21303618 TI - Hospital diabetes: why quality of care matters to both patients and hospitals. PMID- 21303616 TI - Glypican-3 targeting of liver cancer cells using multifunctional nanoparticles. AB - Imaging is essential in accurately detecting, staging, and treating primary liver cancer (hepatocellular carcinoma [HCC]), one of the most prevalent and lethal malignancies. We developed a novel multifunctional nanoparticle (NP) specifically targeting glypican-3 (GPC3), a proteoglycan implicated in promotion of cell growth that is overexpressed in most HCCs. Quantitative real-time polymerase chain reaction was performed to confirm the differential GPC3 expression in two human HCC cells, Hep G2 (high) and HLF (negligible). These cells were treated with biotin-conjugated GPC3 monoclonal antibody (alphaGPC3) and subsequently targeted using superparamagnetic iron oxide NPs conjugated to streptavidin and Alexa Fluor 647. Flow cytometry demonstrated that only GPC3-expressing Hep G2 cells were specifically targeted using this alphaGPC3-NP conjugate (fourfold mean fluorescence over nontargeted NP), and magnetic resonance imaging (MRI) experiments showed similar findings (threefold R2 relaxivity). Confocal fluorescence microscopy localized the alphaGPC3 NPs only to the cell surface of GPC3-expressing Hep G2 cells. Further characterization of this construct demonstrated a negatively charged, monodisperse, 50 nm NP, ideally suited for tumor targeting. This GPC3-specific NP system, with dual-modality imaging capability, may enhance pretreatment MRI, enable refined intraoperative HCC visualization by near-infrared fluorescence, and be potentially used as a carrier for delivery of tumor-targeted therapies, improving patient outcomes. PMID- 21303619 TI - How continuous monitoring changes the interaction of patients with a mobile telemedicine system. AB - BACKGROUND: The combination of telemedicine systems integrating mobile technologies with the use of continuous glucose monitors improves patients' glycemic control but demands a higher interaction with information technology tools that must be assessed. In this article, we analyze patients' behavior from the use-of-the-system point of view, identifying how continuous monitoring may change the interaction of patients with the mobile telemedicine system. METHODS: Patients' behavior were evaluated in a clinical experiment consisting of a 2 month crossover randomized study with 10 type 1 diabetes patients. During the entire experiment, patients used the DIABTel telemedicine system, and during the intervention phase, they wore a continuous glucose monitor. Throughout the experiment, all user actions were automatically registered. This article analyzes the occurrence of events and the behavior patterns in blood glucose (BG) self monitoring and insulin adjustments. A subjective evaluation was also performed based on the answers of the patients to a questionnaire delivered at the end of the study. RESULTS: The number of sessions established with the mobile Smart Assistant was considerably higher during the intervention period than in the control period (29.0 versus 18.8, p < .05), and it was also higher than the number of Web sessions (29.0 versus 22.2, p < .01). The number of daily boluses was higher during the intervention period than in the control period (5.27 versus 4.40, p < .01). The number of daily BG measurements was also higher during the intervention period (4.68 versus 4.05, p < .05) and, in percentage, patients increased the BG measurements not associated to meals while decreasing the percentage of preprandial measurements. The subjective evaluation shows that patients would recommend the use of DIABTel in routine care. CONCLUSIONS: The use of a continuous glucose monitor changes the way patients manage their diabetes, as observed in the increased number of daily insulin bolus, the increased number of daily BG measurements, and the differences in the distribution of BG measurements throughout the day. Continuous monitoring also increases the interaction of patients with the information system and modifies their patterns of use. We can conclude that mobile technologies are especially useful in scenarios of tight monitoring in diabetes, and they are well accepted by patients. PMID- 21303620 TI - The Karlsburg Diabetes Management System: translation from research to eHealth application. AB - BACKGROUND: Several telemedicine-based eHealth programs exist, but patient focused personalized decision support (PDS) is usually lacking. We evaluated the acceptance, efficiency, and cost-effectiveness of telemedicine-assisted PDS in routine outpatient diabetes care. METHODS: Data are derived from the Diabetiva(r) program of the German health insurance company BKK TAUNUS. Diabetiva offers telemedicine-based outpatient health care in combination with PDS generated by the Karlsburg Diabetes Management System, KADIS(r). This retrospective analysis is based on data from the first year of running KADIS-based PDS in routine diabetes care. Participants were insured persons diagnosed with diabetes and cardiovascular diseases. For final analysis, patients were grouped retrospectively as users or nonusers according to physician acceptance or not (based on questionnaires) of the KADIS-based PDS. RESULTS: A total of 538 patients participated for more than one year in the Diabetiva program. Of these patients, 289 had complete data sets (two continuous glucose monitoring measurements, two or more hemoglobin A1c (HbA1c) values, and a signed questionnaire) and were included in the final data analysis. Of the physicians, 74% accepted KADIS-based PDS, a rate that was clearly related to HbA1c at the beginning of the observation. If KADIS-based PDS was accepted, HbA1c decreased by 0.4% (7.1% to 6.7%). In contrast, rejection of KADIS-based PDS resulted in an HbA1c increase of 0.5% (6.8% to 7.3%). The insurance company revealed an annual cost reduction of about 900 ? per participant in the Diabetiva program. CONCLUSIONS: KADIS-based PDS in combination with telemedicine has high potential to improve the outcome of routine outpatient diabetes care. PMID- 21303622 TI - Implementing a web-based home monitoring system within an academic health care network: barriers and facilitators to innovation diffusion. AB - The practice of outpatient type 2 diabetes management is gradually moving from the traditional visit-based, fee-for-service model to a new, health information communication technology (ICT)-supported model that can enable non-visit-based diabetes care. To date, adoption of innovative health ICT tools for diabetes management has been slowed by numerous barriers, such as capital investment costs, lack of reliable reimbursement mechanisms, design defects that have made some systems time-consuming and inefficient to use, and the need to integrate new ICT tools into a system not primarily designed for their use. Effective implementation of innovative diabetes health ICT interventions must address local practice heterogeneity and the interaction of this heterogeneity with clinical care delivery. The Center for Connected Health at Partners Healthcare has implemented a new ICT intervention, Diabetes Connect (DC), a Web-based glucose home monitoring and clinical messaging system. Using the framework of the diffusion of innovation theory, we review the implementation and examine lessons learned as we continue to deploy DC across the health care network. PMID- 21303621 TI - DrishtiCare: a telescreening platform for diabetic retinopathy powered with fundus image analysis. AB - OBJECTIVE: Diabetic retinopathy is the leading cause of blindness in urban populations. Early diagnosis through regular screening and timely treatment has been shown to prevent visual loss and blindness. It is very difficult to cater to this vast set of diabetes patients, primarily because of high costs in reaching out to patients and a scarcity of skilled personnel. Telescreening offers a cost effective solution to reach out to patients but is still inadequate due to an insufficient number of experts who serve the diabetes population. Developments toward fundus image analysis have shown promise in addressing the scarcity of skilled personnel for large-scale screening. This article aims at addressing the underlying issues in traditional telescreening to develop a solution that leverages the developments carried out in fundus image analysis. METHOD: We propose a novel Web-based telescreening solution (called DrishtiCare) integrating various value-added fundus image analysis components. A Web-based platform on the software as a service (SaaS) delivery model is chosen to make the service cost effective, easy to use, and scalable. A server-based prescreening system is employed to scrutinize the fundus images of patients and to refer them to the experts. An automatic quality assessment module ensures transfer of fundus images that meet grading standards. An easy-to-use interface, enabled with new visualization features, is designed for case examination by experts. RESULTS: Three local primary eye hospitals have participated and used DrishtiCare's telescreening service. A preliminary evaluation of the proposed platform is performed on a set of 119 patients, of which 23% are identified with the sight threatening retinopathy. Currently, evaluation at a larger scale is under process, and a total of 450 patients have been enrolled. CONCLUSION: The proposed approach provides an innovative way of integrating automated fundus image analysis in the telescreening framework to address well-known challenges in large scale disease screening. It offers a low-cost, effective, and easily adoptable screening solution to primary care providers. PMID- 21303623 TI - Creating a place for caregivers in personal health: the iHealthSpace copilot program and diabetes care. AB - BACKGROUND: As America's baby boom generation reaches retirement, the number of elders, and, in turn, the number of lay individuals who support them, will continue to increase. With the important services caregivers provide, it is critical that we recognize and provide assistance to the informal caregivers who play this important role in our society. The network of support provisioned by relatives, partners, friends, and neighbors suggests that the dyadic, unidirectional caregiver-care recipient relationship assumed by caregiver research so far and by resources deployed to assist caregivers may be insufficient to ascertain and meet the needs of the care community. METHODS: In this article, we describe the extension of a Web-based personal health record system, iHealthSpace, for explicitly and openly incorporating caregivers into the care community. RESULTS: Using this portal, a set of business rules was implemented to support the creation of custodial accounts. These business rules will be used to create modules that support diabetes care in an adult population. CONCLUSIONS: We successfully extended an existing patient portal to accommodate the creation of custodial accounts. We will use this portal to assess the impact of custodial access in the care of older patients with diabetes. PMID- 21303624 TI - Helping high-risk youth move through high-risk periods: personally controlled health records for improving social and health care transitions. AB - BACKGROUND: New patient-centered information technologies are needed to address risks associated with health care transitions for adolescents and young adults with diabetes, including systems that support individual and structural impediments to self- and clinical-care. METHODS: We describe the personally controlled health record (PCHR) system platform and its key structural capabilities and assess its alignment with tenets of the chronic care model (CCM) and the social-behavioral and health care ecologies within which adolescents and young adults with diabetes mature. RESULTS: Configured as Web-based platforms, PCHRs can support a new class of patient-facing applications that serve as monitoring and support systems for adolescents navigating complex social, developmental, and health care transitions. The approach can enable supportive interventions tailored to individual patient needs to boost adherence, self management, and monitoring. CONCLUSIONS: The PCHR platform is a paradigm shift for the organization of health information systems and is consistent with the CCM and conceptualizations of patient- and family-centered care for diabetes. Advancing the approach augers well for improvement around health care transitions for youth and also requires that we address (i) structural barriers impacting diabetes care for maturing youth; (ii) challenges around health and technology literacy; (iii) privacy and confidentiality issues, including sharing of health information within family and institutional systems; and (iv) needs for evaluation around uptake, impacts, and outcomes. PMID- 21303625 TI - Utilizing information technologies for lifelong monitoring in diabetes patients. AB - BACKGROUND: Information and communication technologies have long been acknowledged to support information sharing along the whole chain of care, from the clinic to the homes of patients and their relatives. Thus they are increasingly being considered for improving the delivery of health care services also in light of clinical and technological achievements that propose new treatments requiring a tighter interaction among patients and physicians. METHODS: The multiagent paradigm has been utilized within an architecture for delivering telemedicine services to chronic outpatients at their domiciles and enforcing cooperation among patients, caregivers, and different members of the health care staff. The architecture sees each communication device such as a palmtop, smart phone, or personal digital assistant as a separate agent upon which different services are deployed, including telemetry, reminders, notifications, and alarms. Decoupling services from agents account for a highly configurable environment applicable to almost any context that can be customized as needed. RESULTS: The architecture has been used for designing and implementing a prototypical software infrastructure, called LifePhone, that runs on several communication devices. A basic set of services has been devised with which we were able to configure two different applications that address long-term and short-term monitoring scenarios for diabetes patients. The long-term scenario encompasses telemetry and reminder services for patients undergoing peritoneal dialysis, which is a treatment for chronic renal failure, a diabetes complication. The short-term scenario incorporates telemetry and remote alarms and is applicable for training patients to use an artificial pancreas. CONCLUSIONS: Our experiments proved that an infrastructure such as LifePhone can be used successfully for bridging the interaction gap that exists among all the components of a health care delivery process, improving the quality of service and possibly reducing the overall costs of health care. Furthermore, the modularity of services allows for more complex scenarios encompassing data analysis or even involving actors at multiple institutions in order to better support the overall health care organization. PMID- 21303626 TI - Smart telemedicine support for continuous glucose monitoring: the embryo of a future global agent for diabetes care. AB - Although current systems for continuous glucose monitoring (CGM) are the result of progressive technological improvement, and although a beneficial effect on glucose control has been demonstrated, few patients are using them. Something similar has happened to telemedicine (TM); in spite of the long-term experience, which began in the early 1980s, no TM system has been widely adopted, and presential visits are still almost the only way diabetologists and patients communicate. The hypothesis developed in this article is that neither CGM nor TM will ever be routinely implemented separately, and their consideration as essential elements for standard diabetes care will one day come from their integration as parts of a telemedical monitoring platform. This platform, which should include artificial intelligence for giving decision support to patients and physicians, will represent the core of a more complex global agent for diabetes care, which will provide control algorithms and risk analysis among other essential functions. PMID- 21303627 TI - The design and development of fluorescent nano-optodes for in vivo glucose monitoring. AB - BACKGROUND: The advent of fluorescent nanosensors has enabled intracellular monitoring of several physiological analytes, which was previously not possible with molecular dyes or other invasive techniques. We have extended the capability of these sensors to include the detection of small molecules with the development of glucose-sensitive nano-optodes. Herein, we discuss the design and development of glucose-sensitive nano-optodes, which have been proven functional both in vitro and in vivo. METHODS: Throughout the design process, each of the sensor formulations was evaluated based on their response to changes in glucose levels. The percent change in signal, sensor reversibility, and the overall fluorescence intensity were the specific parameters used to assess each formulation. RESULTS: A hydrophobic boronic acid was selected that yielded a fully reversible fluorescence response to glucose in accordance with the sensor mechanism. The change in fluorescence signal in response to glucose was approximately 11%. The use of different additives or chromophores did not improve the response; however, modifications to the plasticized polymeric membrane extended sensor lifetime. CONCLUSIONS: Sensors were developed that yielded a dynamic response to glucose and through further modification of the components, sensor lifetime was improved. By following specific design criteria for the macrosensors, the sensors were miniaturized into nano-optodes that track changes in glucose levels in vivo. PMID- 21303628 TI - "Smart tattoo" glucose biosensors and effect of coencapsulated anti-inflammatory agents. AB - BACKGROUND: Minimally invasive glucose biosensors with increased functional longevity form one of the most promising techniques for continuous glucose monitoring. In the present study, we developed a novel nanoengineered microsphere formulation comprising alginate microsphere glucose sensors and anti-inflammatory drug-loaded alginate microspheres. METHODS: The formulation was prepared and characterized for size, shape, in vitro drug release, biocompatibility, and in vivo acceptability. Glucose oxidase (GOx)- and Apo-GOx-based glucose sensors were prepared and characterized. Sensing was performed both in distilled water and simulated interstitial body fluid. Layer-by-layer self-assembly techniques were used for preventing drug and sensing chemistry release. Finally, in vivo studies, involving histopathologic examination of subcutaneous tissue surrounding the implanted sensors using Sprague-Dawley rats, were performed to test the suppression of inflammation and fibrosis associated with glucose sensor implantation. RESULTS: The drug formulation showed 100% drug release with in 30 days with zero-order release kinetics. The GOx-based sensors showed good enzyme retention and enzyme activity over a period of 1 month. Apo-GOx-based visible and near-infrared sensors showed good sensitivity and analytical response range of 0 50 mM glucose, with linear range up to 12 mM glucose concentration. In vitro cell line studies proved biocompatibility of the material used. Finally, both anti inflammatory drugs were successful in controlling the implant-tissue interface by suppressing inflammation at the implant site. CONCLUSION: The incorporation of anti-inflammatory drug with glucose biosensors shows promise in improving sensor biocompatibility, thereby suggesting potential application of alginate microspheres as "smart tattoo" glucose sensors with increased functional longevity. PMID- 21303629 TI - No relevant relationship between glucose variability and oxidative stress in well regulated type 2 diabetes patients. AB - BACKGROUND: A strong relationship between glycemic variability and oxidative stress in poorly regulated type 2 diabetes (T2DM) on oral medication has been reported. However, this relationship was not seen in type 1 diabetes. The purpose of this study is to reexamine the relation between glycemic variability and oxidative stress in a cohort of T2DM patients on oral medication. METHODS: Twenty four patients with T2DM on oral glucose lowering treatment underwent 48 hours of continuous glucose monitoring (CGMS(r) System GoldTM, Medtronic MiniMed) and simultaneous collection of two consecutive 24-hour urine samples for determination of 15(S)-8-iso-prostaglandin F2alpha (PGF2alpha) using high performance liquid chromatography tandem mass spectrometry. Standard deviation (SD) and mean amplitude of glycemic excursions (MAGE) were calculated as markers of glycemic variability. RESULTS: Included in the study were 66.7% males with a mean age (range) of 59 (36-76) years and a mean (SD) HbA1c of 6.9% (0.7). Median [interquartile range (IQR)] urinary 15(S)-8-iso-PGF2alpha excretion was 176.1 (113.6-235.8) pg/mg creatinine. Median (IQR) SD was 31 (23-40) mg/dl and MAGE 85 (56-106) mg/dl. Spearman correlation did not show a significant relation for SD (rho = 0.15, p = .49) or MAGE (rho = 0.23, p = .29) with 15(S)-8-iso-PGF2alpha excretion. Multivariate regression analysis adjusted for age, sex, HbA1c, and exercise did not alter this observation. CONCLUSIONS: We did not find a relevant relationship between glucose variability and 15(S)-8-iso-PGF2alpha excretions in T2DM patients well-regulated with oral medication that would support an interaction between hyperglycemia and glucose variability with respect to the formation of reactive oxygen species. PMID- 21303630 TI - Use of a continuous glucose sensor in an extracorporeal life support circuit. AB - BACKGROUND: Standard care for infants on extracorporeal life support (ECLS) relies on intermittent measurement of blood glucose (BG); however, this can lead to significant changes in BG that go unrecognized for several hours. The present study was designed to assess performance and clinical applicability of a subcutaneous glucose sensor technology modified for use as a blood-contacting sensor within the ECLS circuit. METHODS: Twelve children, aged 3 years or less, requiring ECLS support were studied. Three continuous glucose sensors (Medtronic MiniMed) were inserted into hubs placed in line with the ECLS circuit. Blood glucose was assessed with a laboratory analyzer (BG(LAB); Bayer Rapidlab 860) approximately every 5 h (mean 4.9 +/- 3.3 h) with more frequent samples obtained with a bedside monitor (HemoCue) as needed. Sensor current (I(SIG)) was transmitted to a laptop computer and retrospectively calibrated using BGLAB. Sensor performance was assessed by mean absolute relative difference (MARD), linear regression slope and intercept, and correlation, all with BGLAB as reference. RESULTS: The BGLAB averaged 107.6 +/- 36.4 mg/dl (mean +/- standard deviation) ranging from 58 to 366 mg/dl. The MARD was 11.4%, with linear regression slope (0.86 +/- 0.030) and intercept (9.0 +/- 3.2 mg/dl) different from 1 and 0, respectively (p < .05), and correlation (r2 = 0.76; p < .001). The system was not associated with any adverse events, and placement and removal into the hubs was easily accomplished. Instances in which more frequent BG values were obtained using a bedside HemoCue (BGHEMO) monitor showed the sensor to respond rapidly to changes. CONCLUSIONS: We conclude that continuous sensors can be adapted for use in an ECLS circuit with accuracy similar to or better than that achieved with the subcutaneous site. Continuous glucose monitoring in this population can rapidly detect changes in BG that would not otherwise be observed. Further studies will be needed to assess the benefit of continuous glucose monitoring in this population. PMID- 21303631 TI - FreeStyle Navigator Continuous Glucose Monitoring System with TRUstart algorithm, a 1-hour warm-up time. AB - BACKGROUND: The first-generation FreeStyle Navigator(r) Continuous Glucose Monitoring System (FreeStyle Navigator CGM) requires a 10 h warm-up period to avoid inaccurate glucose readings caused by sensor insertion trauma and wound healing processes. The performance of a second-generation FreeStyle Navigator CGM that begins reporting glucose 1 h after sensor insertion is described. METHODS: Second-generation FreeStyle Navigator CGM performance was evaluated in an in clinic study using the YSI Model 2300 STATPlus Glucose Analyzer as reference with 47 subjects with type 1 diabetes. The reference readings were taken at 15 min intervals, and the study was designed to emphasize the first 10 h of use. RESULTS: The second-generation FreeStyle Navigator CGM exhibited continuous glucose error grid analysis ratings of 93.7% "clinically accurate," 3.6% "benign errors," and 2.8% "clinical errors" and a mean and median absolute relative difference of 14.5% and 10.7%, respectively. The second-generation algorithm detected signal instability in the first 10 h of use and suspended the reporting of 14.1% of first day continuous glucose readings. The clinical accuracy of the second-generation FreeStyle Navigator CGM was similar for the first 10 h versus subsequent hours, with 92.6% and 94.2% "clinically accurate" readings, respectively. CONCLUSION: The warm-up period for the second-generation FreeStyle Navigator CGM was reduced from 10 to 1 h, with minimal interruption of glucose reporting and without sacrificing clinical performance. PMID- 21303632 TI - Self-monitoring of cardiac autonomic function at home is feasible. AB - BACKGROUND: Cardiovascular autonomic neuropathy (CAN) is associated with diabetes and may be related to the development of hypertension, ischemic stroke, and a number of other late complications. The earliest sign of CAN is a reduction of heart rate variability (HRV). Standard HRV tests for CAN include expiration-to inspiration ratio, response to active standing (30:15), and the Valsalva maneuver. Because of the technical requirements for these tests, they are limited to the point-of-care office or a clinical laboratory setting. It is unknown if a "white-coat" phenomenon exists in autonomic neuropathy testing and if home testing is feasible. The aims of this study were (1) to evaluate the reproducibility of CAN testing in a clinical setting, (2) to evaluate the feasibility of self-monitoring of cardiovascular autonomic function at home, and (3) report possible differences in measurements taken at the hospital versus those taken at home. METHOD: Ten healthy subjects were included. Participants underwent in-hospital testing for CAN before and after home monitoring. For 6 consecutive days, participants measured autonomic function once a day at home. The intra- and interindividual reproducibility was determined by coefficient of variation (CV) and the reproducibility coefficient (RC). Agreement between hospital and home testing was analyzed using Pearson r, mean difference, and Bland-Altman analysis with Pitman's test of difference in variance. RESULTS: Pitman's test showed no significant difference in variance between hospital and home measurements, indicating suitable agreement between the two measurements. Reproducibility was moderate to high in all measures, with RC ranging from 66-94% and CV ranging from 5-10%. CONCLUSIONS: Home testing of CAN is feasible. The evaluations showed no significant systematic error of in-hospital testing compared with self-monitoring at home. In this study, we were not able to demonstrate the presses of "white coat" effect in standard cardiovascular reflex tests. PMID- 21303633 TI - Enhanced absorption of NasulinTM, an ultrarapid-acting intranasal insulin formulation, using single nostril administration in normal subjects. AB - BACKGROUND: This pharmacokinetic (PK) study was designed to investigate the maximum intranasal insulin dose that could be achieved by repeated doses in a single nostril of a nasal spray of recombinant regular human insulin 1% in combination with cyclopentadecalactone (CPE-215) 2%, a compound that enhances absorption of molecules across mucous membranes (NasulinTM, CPEX Pharmaceuticals, Inc.). METHOD: A nine-period crossover study of 8 healthy, nonsmoking subjects (ages 18-50, body mass index <33 kg/m2, weight >70 kg) were studied. In a fasted state, subjects were randomly given 25, 50, and 75 U in a single nostril on the first day and randomly given 50, 75, and 100 U doses utilizing both nostrils on two subsequent days. After a 45-minute PK assessment, subjects were given a meal. To determine the mechanism of enhanced absorption in a single nostril, a second study utilizing 24 subjects under similar conditions received 25 U, placebo (P) that included CPE-215 plus 25 U, and 50 U in a single nostril. RESULTS: Single nostril administration revealed enhanced absorption with maximum concentrations (C(max)) of 13, 65, and 96 uU/ml for the 25, 50, and 75 U doses, respectively. Dual nostril administration in two cohorts resulted in C(max) of 31/42, 65/52, and 88/79 uU/ml for the 50, 75, and 100 U, respectively. In the second cohort, C(max) was 23, 19, 56 uU/ml for the 25, P + 25, and 50 U doses, respectively. CONCLUSIONS: Repeated dosing in a single nostril resulted in enhanced absorption; this was not due to the increased CPE-215 but to the increased insulin administered. PMID- 21303634 TI - Explorative study of pharmacokinetics and pharmacodynamics after change in basal insulin infusion rate. AB - BACKGROUND: The use of insulin pumps is rapidly increasing and new, technologically more advanced pumps are continuously being developed. It is of interest to assess the clinical relevance of the many technical features of these pumps, e.g., the effect on pharmacokinetics and pharmacodynamics with change in infusion rate. METHOD: The aim of this study was to explore the sequence of pharmacokinetic and pharmacodynamic changes after dose doubling of the basal insulin infusion rate with subcutaneous bolus insulin injections once an hour, continuous subcutaneous insulin infusion, and continuous intravenous insulin infusion. Ten type 1 diabetes mellitus patients were included. The insulin doses were calculated based on the habitual insulin doses. The study was designed as an open-labeled, single-center, randomized, crossover exploratory trial. RESULTS: Dose doubling of the basal insulin infusion rate with the three different administration protocols did not result in any clinically relevant differences in the time courses of the pharmacokinetic and pharmacodynamic parameters. With all three administration protocols, we observed a time interval of more than 6 hours before a new steady state of insulin was achieved. CONCLUSIONS: Our results indicate that frequent changes in basal subcutaneous insulin infusion rates are not of significant clinical relevance on a 24-hour basis. Regarding technological features of subcutaneous insulin pumps, no discernable advantages of increasing pump stroke frequency were found. This indicates that pump stroke frequency sophistication might not be of clinical relevance in pumps used for basal subcutaneous insulin infusion. PMID- 21303635 TI - Guidelines for optimal bolus calculator settings in adults. AB - Bolus insulin calculators (BCs) became available in insulin pumps in 2002 and are being integrated into glucose meters and portable device applets for use with multiple daily injections. A retrospective analysis of continuous subcutaneous insulin infusion data from the Actual Pump Practices (APP) study is used in this article to generate formulas for more precise BC settings. A well-designed BC determines accurate bolus doses for carbohydrate intake and for correcting elevated glucose levels. It should also provide the logic necessary to track residual bolus insulin and reduce bolus recommendations to minimize insulin stacking. To provide appropriate bolus doses, a BC requires accurate settings for the carbohydrate factor or insulin:carbohydrate ratio, glucose correction factor, duration of insulin action, and correction target. We provide guidelines to select BC settings from the user's current total daily dose (TDD) of insulin and to determine more appropriate BC settings from an improved TDD based on the mean glucose level. PMID- 21303636 TI - Do different body colors and labels of insulin pens enhance a patient's ability to correctly identify pens for injecting long-acting versus short-acting insulins? AB - BACKGROUND: The objective of this study was to characterize how successfully patients with diabetes are able to distinguish between pens of the same pen type containing long- and short-acting insulins. METHODS: Structured one-on-one interviews were conducted with 400 patients with diabetes in the United States, using either a differentiated (n = 100) or undifferentiated (n = 100) SoloSTAR(r) (insulin glargine vs insulin glulisine) or (n = 200) FlexPen(r) (insulin detemir vs insulin aspart). A pair of each pen type was presented simultaneously, and participants were asked to identify the pen that they would use to (1) inject at lunch, (2) inject once daily, and (3) inject at breakfast and how they differentiated between pens. The short-acting insulin pen was then presented, and the interviewer asked whether this was the correct pen to administer insulin once or thrice daily. RESULTS: More patients successfully identified the correct SoloSTAR pen across the tests vs FlexPen, and the error rate (incorrect selection/inability to select) was significantly lower, respectively [2.7% (n = 8) vs 16.3% (n = 98)]. The most common reason cited for correct responses among all patients was color (of the label/pen, according to pen type). CONCLUSIONS: This study suggests that the full pen body color used on SoloSTAR pens enhances the patient's ability to differentiate between the pens for long- and short acting insulin and is a notable improvement compared with the standard approach of differing label color. PMID- 21303637 TI - Injection force of SoloSTAR(r) compared with other disposable insulin pen devices at constant volume flow rates. AB - BACKGROUND: Injection force is a particularly important practical aspect of therapy for patients with diabetes, especially those who have dexterity problems. This laboratory-based study compared the injection force of the SoloSTAR(r) insulin pen (SoloSTAR; sanofi-aventis) versus other available disposable pens at injection speeds based on the delivered volume of insulin released at the needle. METHOD: Four different prefilled disposable pens were tested: SoloSTAR containing insulin glargine; FlexPen(r) and the Next Generation FlexPen(r) (NGFP) (Novo Nordisk), both containing insulin detemir; and KwikPen(r) containing insulin lispro (Eli Lilly). All pens were investigated using the maximum dispense volume for each pen type [80 units (U) for SoloSTAR; 60 U for the other pens], from the free needle tip dispensing into a beaker. Twenty pens of each type were fitted with the recommended needles and tested at two dose speeds (6 and 10 U/s); each pen was tested twice. RESULTS: Mean plateau injection force and maximum injection force were consistently lower with SoloSTAR compared with FlexPen, NGFP, and KwikPen at both injection speeds tested. An injection speed of 10 U/s was associated with higher injection force compared with 6 U/s for all the pens tested (p < .001). CONCLUSIONS: SoloSTAR stands out because of its low injection force, even when compared with newer insulin pen devices such as the KwikPen and NGFP. This may enable patients, especially those with dexterity problems, to administer insulin more easily and improve management of their diabetes. PMID- 21303638 TI - Analysis of the injection force of solostar(r) compared with other disposable insulin pen devices at constant volume flow rates. AB - Insulin pen devices have greatly enhanced the portability and accessibility to insulin therapy for millions of people with diabetes. Comparison research data should be reviewed thoroughly. In this issue of Journal of Diabetes Science and Technology, the study presented by Thomas van der Burg is balanced in number of samples tested, same tensile meter, and identical units per second delivery rate into an open beaker. Mean plateau force of SoloSTAR(r) and KwikPenTM were significantly lower. KwikPen and SoloSTAR utilized 5-mm length 31-gauge (G) needles vs 6-mm 31G needles for FlexPen(r) and Next Generation FlexPen(r), perhaps skewing results in favor of shorter needles instead of device design. Individual understanding of correct insulin use, appropriate self-monitoring of blood glucose, vision and dexterity capability, and affordability of therapy must be considered first. SoloSTAR holds one unique market advantage, delivery of up to 80 units of insulin per injection. PMID- 21303639 TI - Evaluation of dexterity in insulin-treated patients with type 1 and type 2 diabetes mellitus. AB - BACKGROUND: Daily routine for insulin-treated patients with diabetes mellitus requires correct performance of self-monitoring of blood glucose and insulin injections several times a day. Dexterity skills may play an important role in the performance efficacy of these procedures. METHODS: We collected data of insulin-treated (>10 years) patients with different age ranges [healthy controls, 14 female/11 male, age (mean +/- standard deviation) 55 +/- 7 years; type 1 diabetes mellitus (T1DM) patients, 12/13, 45 +/- 9 years, disease duration 23.9 +/- 6.5 years; T2DM patients, 8/17, 64 +/- 6 years, 16.2 +/- 6.9 years; T2DM patients (>70 years of age), 9/16, 75 +/- 4 years, 19.7 +/- 7.0 years]. After assessment of neuropathy (temperature, pain, and vibration perception), the patients participated in two dexterity test batteries [Jebsen-Taylor hand function test (JHFT) and motoric performance series (MPS)]. RESULTS: Patients with type 2 diabetes showed disturbed vibration perception as compared to the other groups. The dexterity results were influenced by age to a large extent. Older T2DM patients performed worst in the majority of the subtests (e.g., JHFT, writing nondominant hand: control, 40.8 +/- 11.7 s; T1DM, 46.3 +/- 50.9 s, not significant versus control; old T2DM, 68.1 +/- 29.5 s, p < .05; young T2DM, 52.5 +/- 26.2 s, p < .05). Patients with type 1 diabetes showed similar JHFT and MPS results than the 10-year-older control subjects and performed outside of the age dependent normal reference range. CONCLUSIONS: Manual skills and dexterity differed between the groups, and age-corrected reduced skills were common in both T1DM and T2DM patients in this study. Our findings underline the importance of considering dexterity and manual skills when designing medical devices for patients with diabetes mellitus. PMID- 21303640 TI - Noninvasive diagnostic devices for diabetes through measuring tear glucose. AB - This article reviews the development of a noninvasive diagnostic for diabetes by detecting ocular glucose. Early diagnosis and daily management are very important to diabetes patients to ensure a healthy life. Commercial blood glucose sensors have been used since the 1970s. Millions of diabetes patients have to prick their finger for a drop of blood 4-5 times a day to check blood glucose levels--almost 1800 times annually. There is a strong need to have a noninvasive device to help patients to manage the disease easily and painlessly. Instead of detecting the glucose in blood, monitoring the glucose level in other body fluids may provide a feasible approach for noninvasive diagnosis and diabetes control. Tear glucose has been studied for several decades. This article reviews studies on ocular glucose and its monitoring methods. Attempts to continuously monitor the concentration of tear glucose by using contact lens-based sensors are discussed as well as our current development of a nanostructured lens-based sensor for diabetes. This disposable biosensor for the detection of tear glucose may provide an alternative method to help patients manage the disease conveniently. PMID- 21303641 TI - Blood glucose testing in the hospital: error sources and risk management. AB - Glucose testing in the hospital with point-of-care devices presents multiple opportunities for error. Any device can fail under the right conditions. For glucose monitoring in the hospital, with thousands of operators, hundreds of devices, and dozens of locations involved, there is ample opportunity for errors that can impact the quality of test results. Errors can occur in any phase of the testing process: preanalytic, analytic, or postanalytic. Common sources of meter error include patient or methodology interferences, operator mistakes, environmental exposure, and device malfunction. Early models of glucose meters had few internal checks or capability to warn the operator of meter problems. The latest generation of glucose monitors has a number of internal checks and controls engineered into the testing process to prevent serious errors or warn the operator by suppressing test results. Some of these control processes are built into the software and data management system of the meters, others require the hospital to do something, such as regularly clean the meter or analyze control samples of known glucose concentration, to verify meter performance. Hospitals need to be aware of the potential for errors by understanding weaknesses in the testing process that could lead to erroneous results and take steps to prevent errors from occurring or to minimize the harm to patients when errors do occur. The reliability of a glucose result will depend on the balance of internal control features available from manufacturers in conjunction with the liquid control analysis and other control processes (operator training, device validation, and maintenance) utilized by the hospitals. PMID- 21303642 TI - H.E.A.L.T.H.: efficacy of an internet/population-based behavioral weight management program for the U.S. Army. AB - BACKGROUND: A significant number of soldiers exceed the maximum allowable weight standards or have body weights approaching the maximum allowable weight standards. This mandates development of scalable approaches to improve compliance with military weight standards. METHODS: We developed an intervention that included two components: (1) an Internet-based weight management program (Web site) and (2) a promotion program designed to promote and sustain usage of the Web site. The Web site remained online for 37 months, with the Web site promotion program ending after 25 months. RESULTS: Soldiers' demographics were as follows: mean age, 32 years; body mass index (BMI), 28 kg/m2; 31% female; and 58% Caucasian. Civilian demographics were as follows: mean age, 38 years; BMI, 30 kg/m2; 84% female; and 55% Caucasian. Results indicated that 2417 soldiers and 2147 civilians (N = 4564) registered on the Web site. In the first 25 months (phase 1) of the study, new participants enrolled on the Web site at a rate of 88 (soldiers) and 80 (civilians) per month. After the promotion program was removed (phase 2), new participants enrolled at a rate of 18 (soldiers) and 13 (civilians) per month. Utilization of the Web site was associated with self reported weight loss (p < .0001). Participants who utilized the Web site more frequently lost more weight (p < .0001). Participants reported satisfaction with the Web site. CONCLUSIONS: The Web site and accompanying promotion program, when implemented at a military base, received satisfactory ratings and benefited a subset of participants in promoting weight loss. This justifies further examination of effectiveness in a randomized trial setting. PMID- 21303643 TI - Integration of remote blood glucose meter upload technology into a clinical pharmacist medication therapy management service. AB - A pharmacist-delivered, outpatient-focused medication therapy management (MTM) program is using a remote blood glucose (BG) meter upload device to provide better care and to improve outcomes for its patients with diabetes. Sharing uploaded BG meter data, presented in easily comprehensible graphs and charts, enables patients, caregivers, and the medical team to better understand how the patients' diabetes care is progressing. Pharmacists are becoming increasingly more active in helping to manage patients' complex medication regimens in an effort to help detect and avoid medication-related problems. Working together with patients and their physicians as part of an interdisciplinary health care team, pharmacists are helping to improve medication outcomes. This article focuses on two case studies highlighting the Diabetes Monitoring Program, one component of the Meridian Pharmacology Institute MTM service, and discusses the clinical application of a unique BG meter upload device. PMID- 21303644 TI - Diabetes and biomarkers. AB - Biomarkers play an integral part in conducting clinical trials and treating patients. In most instances, they help medical practitioners, researchers, and regulatory officials make well-informed, scientifically sound decisions. However, in clinical studies, there is often uncertainty in how much weight to place on biomarker results versus clinical outcomes. This uncertainty emanates from opposing goals of the drug approval process. On one hand, the process must ensure that all therapeutics tested are safe and that the benefits outweigh the risks. On the other hand, the process should allow therapies to be accessible to patients as quickly as reasonably possible. Judicious use of biomarkers in the drug development process can bring these goals into alignment. More efficient discovery and use of biomarkers in the development of antidiabetes drugs will depend on advancing our understanding of the pathogenesis of diabetes and especially its macrovascular complications. PMID- 21303645 TI - Performance of the CONTOUR(r) TS Blood Glucose Monitoring System. AB - BACKGROUND: Self-monitoring of blood glucose (SMBG) remains an important component of diabetes management, engendering a need for affordable blood glucose (BG) meters that are accurate, precise, and convenient. The CONTOUR(r) TS is a BG meter that endeavors to meet this need. It uses glucose dehydrogenase/flavin dinucleotide chemistry, automatic test strip calibration, and autocompensation for hematocrit along with the ease of use that has come to be expected of a modern meter. The objective of this clinical trial was to determine whether the CONTOUR TS system met these criteria. METHODS: The system was evaluated at a single clinical site with 106 subjects with type 1 or type 2 diabetes. Blood glucose values ranged from 60 to 333 mg/dl over all subjects. Both lay users and health care professionals (HCPs) tested the meters, with test strips from three different lots. Results were compared to a reference analyzer of verified precision and accuracy. Forty-nine of the subjects also participated in a home study of the meter. Lay users learned to use the system without assistance and were surveyed on its use at the end of the study. RESULTS: When used with capillary blood, both subjects and HCPs obtained results that exceeded the International Organization for Standardization 15197:2003 criteria, (i.e., >=95% of values fell within 20% or 15 mg/dl of the laboratory value for BG levels greater than or less than 75 mg/dl, respectively). Specifically, lay users achieved 97.9% and HCPs 98.6%. When used with venous blood, 99.8% of measurements were within the criteria. All measurements for both capillary and venous blood fell into zones A or B of the Parkes error grid, deemed clinically accurate. Hematocrit was found to have no influence on BG measurements. A large majority of the subjects found the system easy to learn and to use. CONCLUSIONS: The CONTOUR TS BG meter system gave accurate and reproducible results with both capillary and venous blood; subjects learned to use the meter system by following the user guide and quick reference guide. PMID- 21303646 TI - Analysis of the performance of the CONTOUR(r) TS Blood Glucose Monitoring System: when regulatory performance criteria are met, should we have confidence to use a medical device with all patients? AB - The article entitled, Performance of the CONTOUR(r) TS Blood Glucose Monitoring System, by Frank and colleagues in this issue of Journal of Diabetes Science and Technology, demonstrates that the CONTOUR(r) TS glucose meter exceeds current regulatory expectations for glucose meter performance. However, the appropriateness of current regulatory expectations, such as International Organization for Standardization (ISO) 15197:2003, is being reevaluated because of increasing concern regarding the reliability of glucose meters in ambulatory and hospitalized environments. Between 2004 and 2008, 12,673 serious adverse events with glucose meters that met the ISO 15197 expectations were reported in the Food and Drug Administration-Manufacturer and User Facility Device Experience surveillance database. Should different glucose meter performance criteria be applied to ambulatory versus critical care patients? PMID- 21303647 TI - Sulfur signaling: is the agent sulfide or sulfane? PMID- 21303648 TI - Simultaneous gas chromatography-tandem mass spectrometry quantification of symmetric and asymmetric dimethylarginine in human urine. AB - Previously, we demonstrated the utility of a gas chromatography-tandem mass spectrometry (GC-MS/MS) method for the quantitative determination of asymmetric dimethylarginine (ADMA) in biological samples. Here we report the extension of this method to symmetric dimethylarginine (SDMA) in human urine. SDMA and ADMA were simultaneously quantitated in urine by using their in situ prepared trideuteromethyl esters as internal standards. The GC-MS/MS method was validated for SDMA and ADMA in spot urine samples of 19 healthy adults. In these samples, the creatinine-corrected excretion rate was 3.23+/-0.63 MUmol/mmol for SDMA and 3.14+/-0.98 MUmol/mmol for ADMA. PMID- 21303649 TI - Identification of holocarboxylase synthetase chromatin binding sites in human mammary cell lines using the DNA adenine methyltransferase identification technology. AB - Holocarboxylase synthetase (HCS) is a chromatin protein that is essential for mediating the covalent binding of biotin to histones. Biotinylation of histones plays crucial roles in the repression of genes and repeats in the human genome. We tested the feasibility of DNA adenine methyltransferase identification (DamID) technology to map HCS binding sites in human mammary cell lines. Full-length HCS was fused to DNA adenine methyltransferase (Dam) for subsequent transfection into breast cancer (MCF-7) and normal breast (MCF-10A) cells. HCS docking sites in chromatin were identified by using the unique adenine methylation sites established by Dam in the fusion construct; docking sites were unambiguously identified using methylation-sensitive digestion, cloning, and sequencing. In total, 15 novel HCS binding sites were identified in the two cell lines, and the following 4 of the 15 overlapped between MCF-7 and MCF-10A cells: inositol polyphosphate-5-phosphatase A, corticotropin hormone precursor, ribosome biogenesis regulatory protein, and leptin precursor. We conclude that DamID is a useful technology to map HCS binding sites in human chromatin and propose that the entire set of HCS binding sites could be mapped by combining DamID with microarray technology. PMID- 21303650 TI - Fluorogenic polymerase, endonuclease, and ligase assays based on DNA substrates labeled with a single fluorophore. AB - This paper describes the development of homogeneous, fluorogenic polymerase, restriction endonuclease, and ligase assays based on the use of DNA substrate molecules labeled with a single fluorophore. All three enzymatic assays are based on the same observed phenomenon whereby the fluorescence intensity of hairpin type oligonucleotides with a 5'single-stranded extension, labeled with a single fluorophore, changes when the distance of the dye from the 3' end of the molecule is altered as a result of the enzymatic transformation (i.e., polymerase extension, endonuclease hydrolysis, or ligation). The magnitudes of the observed fluorescence intensity changes range from 1.2-fold to 3.9-fold, and they are dependent on the type of dye used, its position within the substrate and product molecules, and the base composition surrounding the labeling site. PMID- 21303652 TI - Analysis of global DNA methylation by hydrophilic interaction ultra high-pressure liquid chromatography tandem mass spectrometry. AB - We developed and validated a rapid, sensitive, and specific liquid chromatography tandem mass spectrometry (LC-MS/MS) method for determination of global DNA methylation in tissue. DNA was extracted by phenol-chloroform, hydrolyzed using 88% formic acid at 140 degrees C, spiked with cytosine-2,4-(13)C(15)N(2) as internal standard, evaporated under nitrogen, reconstituted in methanol, and analyzed by LC-MS/MS in multiple reaction monitoring mode to reflect the global DNA methylation of the tissue. The method was linear throughout the range of clinical interest and had good sensitivity, with a limit of quantification of 0.5pg for both cytosine (Cyt) and 5-methylcytosine (5mCyt). The linear range of calibration curve was 1-50 and 1-100ng/ml for 5mCyt and Cyt, respectively, with a correlation coefficient higher than 0.99. The relative standard deviation (RSD) was 0.70-4.09% and 0.60-4.81% for Cyt and 5mCyt, respectively. The intraday precision expressed as RSD ranged from 1.86% to 4.67%, whereas the interday values ranged from 3.72% to 4.68%. The recovery of the method varied from 86.52% to 105.14%. This yielded a simple and reliable LC-MS/MS assay for detection of Cyt and 5mCyt, thereby enabling the evaluation of global DNA methylation. PMID- 21303651 TI - Development of a dispersive liquid-liquid microextraction method for spectrophotometric determination of barbituric acid in pharmaceutical formulation and biological samples. AB - In this paper, a novel and simple method for the determination of trace amounts of barbituric acid in water and biological samples was developed by using dispersive liquid-liquid microextraction (DLLME) techniques combined with spectrophotometric analysis. The procedure is based on color reaction of barbituric acid with p-dimethylaminobenzaldehyde and extraction of the color product using the DLLME technique. Some important parameters such as reaction conditions and the type and volume of extraction and dispersive solvents as well as the extraction time were investigated and optimized in detail. Under the optimum conditions, the calibration graphs were linear over the range of 5.0 to 200 ng ml(-1) with limit of detection of 2.0 ng ml(-1). Relative standard deviation for five replicate determinations of barbituric acid at 50 ng ml(-1) concentration level was calculated to be 1.64%. Average recoveries for spiked samples were determined to be between 94% and 105%. The proposed method was applied for the determination of barbituric acid in pharmaceutical formulation and biological samples. PMID- 21303653 TI - Bovine Serum Albumin protofibril-like aggregates formation: solo but not simple mechanism. AB - We report an experimental study on the model protein Bovine Serum Albumin (BSA), with the aim of elucidating the mechanisms by which a fully folded globular protein undergoes different aggregation pathways leading to the formation of amyloid fibrils or amorphous aggregates. We observe thermally induced formation of fibrillar structures at pH far from the protein isoelectric point. The increase of electrostatic repulsion results in protein destabilization and in modifications of inter and intra-molecular interactions leading to the growth of fibril-like aggregates stabilized by inter-molecular-beta sheets. The aggregation kinetics is studied by means of fluorescence techniques, light scattering, Circular Dichroism (CD), infrared spectroscopy (FTIR) and Atomic Force Microscopy (AFM). Changes in protein secondary structures turn out to be the driving mechanism of the observed aggregation and they progress in parallel with the growth of Thioflavin T emission intensity and scattering signal. This concurrent behavior suggests a mutual stabilization of elongated protofibril-like structures and of protein conformational and structural changes, which lead to a more rigid and ordered structures. Our results give new insights on BSA self-assembly process in alkaline conditions clearly providing new pieces of evidences of the interplay of several and interconnected mechanisms occurring on different time and length scales. PMID- 21303654 TI - Nrf2 regulates ferroportin 1-mediated iron efflux and counteracts lipopolysaccharide-induced ferroportin 1 mRNA suppression in macrophages. AB - Iron is an essential element of hemoglobin, and efficient iron recycling from senescent erythrocytes by splenic macrophages is required for erythrocyte hemoglobin synthesis during erythropoiesis. Ferroportin 1 (Fpn1) is the sole iron exporter in mammals, and it also regulates iron reutilization. In this study, we demonstrated genetically that a redox-sensitive transcription factor, Nrf2, regulates Fpn1 mRNA expression in macrophages. Nrf2 activation by several electrophilic compounds commonly resulted in the upregulation of Fpn1 mRNA in bone marrow-derived and peritoneal macrophages obtained from wild-type mice but not from Nrf2 knockout mice. Further, Nrf2 activation enhanced iron release from the J774.1 murine macrophage cell line. Previous studies showed that inflammatory stimuli, such as LPS, downregulates macrophage Fpn1 by transcriptional and hepcidin-mediated post-translational mechanisms leading to iron sequestration by macrophages. We showed that two Nrf2 activators, diethyl maleate and sulforaphane (SFN; a natural Nrf2 activator found in broccoli), restored the LPS-induced suppression of Fpn1 mRNA in human and mouse macrophages, respectively. Furthermore, SFN counteracted the LPS-induced increase of Hepcidin mRNA by an Nrf2-independent mechanism in mouse peritoneal macrophages. These results demonstrate that Nrf2 regulates iron efflux from macrophages through Fpn1 gene transcription and suggest that Nrf2 may control iron metabolism during inflammation. PMID- 21303656 TI - Functional bitter taste receptors are expressed in brain cells. AB - Humans are capable of sensing five basic tastes which are sweet, sour, salt, umami and bitter. Of these, bitter taste perception provides protection against ingestion of potentially toxic substances. Bitter taste is sensed by bitter taste receptors (T2Rs) that belong to the G-protein coupled receptors (GPCRs) superfamily. Humans have 25 T2Rs that are expressed in the oral cavity, gastrointestinal (GI) neuroendocrine cells and airway cells. Electrophysiological studies of the brain neurons show that the neurons are able to respond to different tastants. However, the presence of bitter taste receptors in brain cells has not been elucidated. In this report using RT-PCR, and immunohistochemistry analysis we show that T2Rs are expressed in multiple regions of the rat brain. RT-PCR analysis revealed the presence of T2R4, T2R107 and T2R38 transcripts in the brain stem, cerebellum, cortex and nucleus accumbens. The bitter receptor T2R4 was selected for further analysis at the transcript level by quantitative real time PCR and at the protein level by immunohistochemistry. To elucidate if the T2R4 expressed in these cells is functional, assays involving G protein mediated calcium signaling were carried out. The functional assays showed an increase in intracellular calcium levels after the application of exogenous ligands for T2R4, denatonium benzoate and quinine to these cultured cells, suggesting that endogenous T2R4 expressed in these cells is functional. We discuss our results in terms of the physiological relevance of bitter receptor expression in the brain. PMID- 21303655 TI - On the chemical mechanism of succinic semialdehyde dehydrogenase (GabD1) from Mycobacterium tuberculosis. AB - Succinic semialdehyde dehydrogenases (SSADHs) are ubiquitous enzymes that catalyze the NAD(P)+-coupled oxidation of succinic semialdehyde (SSA) to succinate, the last step of the gamma-aminobutyrate shunt. Mycobacterium tuberculosis encodes two paralogous SSADHs (gabD1 and gabD2). Here, we describe the first mechanistic characterization of GabD1, using steady-state kinetics, pH rate profiles, 1H NMR, and kinetic isotope effects. Our results confirmed SSA and NADP+ as substrates and demonstrated that a divalent metal, such as Mg2+, linearizes the time course. pH-rate studies failed to identify any ionizable groups with pK(a) between 5.5 and 10 involved in substrate binding or rate limiting chemistry. Primary deuterium, solvent and multiple kinetic isotope effects revealed that nucleophilic addition to SSA is very fast, followed by a modestly rate-limiting hydride transfer and fast thioester hydrolysis. Proton inventory studies revealed that a single proton is associated with the solvent sensitive rate-limiting step. Together, these results suggest that product dissociation and/or conformational changes linked to it are rate-limiting. Using structural information for the human homolog enzyme and 1H NMR, we further established that nucleophilic attack takes place at the Si face of SSA, generating a thiohemiacetal with S stereochemistry. Deuteride transfer to the Pro R position in NADP+ generates the thioester intermediate and [4A-2H, 4B-1H] NADPH. A chemical mechanism based on these data and the structural information available is proposed. PMID- 21303657 TI - Increased tissue kallikrein amidase activity in urine of patients with type 1 diabetes under insulin therapy, and in those with gestational diabetes mellitus not under insulin therapy. AB - Human tissue kallikrein (hK1) is reduced in hypertension, cardiovascular and renal diseases. There is little information on the participation of hK1 in type 1 diabetes mellitus (DM), type 2 DM, and gestational diabetes mellitus (GDM), respectively. The aim of this study was to evaluate the roles of insulin and hyperglycemia on urinary hK1 activity in type 1 DM and in GDM. Forty-three type 1 DM patients (5-35 years, disease duration <= 5years, receiving insulin, HbA(1c)>7.6%) were selected. Forty-three healthy individuals, paired according to gender and age, were used as controls. Thirty GDM patients (18-42 years, between the 24th and 37th week of pregnancy, recently diagnosed, not under insulin therapy) were also selected. Thirty healthy pregnant (18-42years, between the 24th and 37th week of pregnancy) and 30 healthy non-pregnant women (18-42years) were selected as controls. Random midstream urine was used. hK1 amidase activity was estimated with D-Val-Leu-Arg-Nan substrate. Creatinine was determined by Jaffe's method. hK1 specific amidase activity was expressed as MUM/(minmg creatinine) to correct for differences in urine flow rate. hK1 specific amidase activity was significantly higher in the urine of type 1 DM than in controls, and in the urine of GDM patients than in healthy pregnant women and healthy non pregnant women, respectively. The data suggest that hyperglycemia, rather than insulin, is involved in the mechanism of increased hK1 specific amidase activity in both type 1 DM and GDM patients, respectively. PMID- 21303659 TI - The size distribution of protein families within different types of folds. AB - It is well known that the structure is currently available only for a small fraction of known protein sequences. It is urgent to discover the important features of known protein sequences based on present protein structures. Here, we report a study on the size distribution of protein families within different types of folds. The fold of a protein means the global arrangement of its main secondary structures, both in terms of their relative orientations and their topological connections, which specify a certain biochemical and biophysical aspect. We first search protein families in the structural database SCOP against the sequence-based database Pfam, and acquire a pool of corresponding Pfam families whose structures can be deemed as known. This pool of Pfam families is called the sample space for short. Then the size distributions of protein families involving the sample space, the Pfam database and the SCOP database are obtained. The results indicate that the size distributions of protein families under different kinds of folds abide by similar power-law. Specially, the largest families scatter evenly in different kinds of folds. This may help better understand the relationship of protein sequence, structure and function. We also show that the total of proteins with known structures can be considered a random sample from the whole space of protein sequences, which is an essential but unsettled assumption for related predictions, such as, estimating the number of protein folds in nature. Finally we conclude that about 2957 folds are needed to cover the total Pfam families by a simple method. PMID- 21303658 TI - 2-BFI attenuates experimental autoimmune encephalomyelitis-induced spinal cord injury with enhanced B-CK, CaATPase, but reduced calpain activity. AB - The lack of disease-modifying pharmacological agents for effective treatment of multiple sclerosis (MS) still represents a large and urgent unmet medical need. Our previous studies showed that ligands to type 2 imidazoline receptors (I(2)R) were effective in protecting spinal cord injury caused by experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. In this study, we further examined the protective property of a very selective ligand of I(2)R, 2-(2-benzofuranyl) 2 imidazoline (2-BFI) against EAE. Importantly, a mechanism of 2-BFI-mediated protection was investigated which possibly involves an I(2)R binding protein, brain-creatine kinase (B-CK), as well as CaATPase and calpain. The enzymatic activity of B-CK and CaATPase was significantly reduced in EAE injured spinal cord. Reduction of B-CK activity in EAE spinal cord may lead to energy reduction and dysfunction in cellular calcium homeostasis. Increased intracellular calcium evokes elevation of calpain activity occurring in EAE spinal cord which causes further tissue damage. Indeed, EAE injured spinal cord showed significant reduction in CaATPase and increase calpain activities. Remarkably, spinal cord tissue from mice treated daily with 2-BFI during the progression of EAE significantly restored B-CK and CaATPase enzymatic activities and showed no induction in calpain activity. Moreover, EAE spinal cord from 2-BFI treated mice also demonstrated better preservation of myelin; reduced axonal injury, as evidenced by the lower level of beta-APP expression, and above all, highly improved neurobehavioral scores (p<0.01; n=10). These findings suggest that 2-BFI can be further developed as a therapeutic drug for MS treatment. PMID- 21303660 TI - TIM-1 signaling in B cells regulates antibody production. AB - Members of the T cell Ig and mucin (TIM) family have recently been implicated in the control of T cell-mediated immune responses. In this study, we found TIM-1 expression on anti-IgM- or anti-CD40-stimulated splenic B cells, which was further up-regulated by the combination of anti-IgM and anti-CD40 Abs. On the other hand, TIM-1 ligand was constitutively expressed on B cells and inducible on anti-CD3(+) anti-CD28-stimulated CD4(+) T cells. In vitro stimulation of activated B cells by anti-TIM-1 mAb enhanced proliferation and expression of a plasma cell marker syndecan-1 (CD138). We further examined the effect of TIM-1 signaling on antibody production in vitro and in vivo. Higher levels of IgG2b and IgG3 secretion were detected in the culture supernatants of the anti-TIM-1 stimulated B cells as compared with the control IgG-stimulated B cells. When immunized with T-independent antigen TNP-Ficoll, TNP-specific IgG1, IgG2b, and IgG3 Abs were slightly increased in the anti-TIM-1-treated mice. When immunized with T-dependent antigen OVA, serum levels of OVA-specific IgG2b, IgG3, and IgE Abs were significantly increased in the anti-TIM-1-treated mice as compared with the control IgG-treated mice. These results suggest that TIM-1 signaling in B cells augments antibody production by enhancing B cell proliferation and differentiation. PMID- 21303661 TI - Acerogenin A, a natural compound isolated from Acer nikoense Maxim, stimulates osteoblast differentiation through bone morphogenetic protein action. AB - We investigated the effects of acerogenin A, a natural compound isolated from Acer nikoense Maxim, on osteoblast differentiation by using osteoblastic cells. Acerogenin A stimulated the cell proliferation of MC3T3-E1 osteoblastic cells and RD-C6 osteoblastic cells (Runx2-deficient cell line). It also increased alkaline phosphatase activity in MC3T3-E1 and RD-C6 cells and calvarial osteoblastic cells isolated from the calvariae of newborn mice. Acerogenin A also increased the expression of mRNAs related to osteoblast differentiation, including Osteocalcin, Osterix and Runx2 in MC3T3-E1 cells and primary osteoblasts: it also stimulated Osteocalcin and Osterix mRNA expression in RD-C6 cells. The acerogenin A treatment for 3days increased Bmp-2, Bmp-4, and Bmp-7 mRNA expression levels in MC3T3-E1 cells. Adding noggin, a BMP specific-antagonist, inhibited the acerogenin A-induced increase in the Osteocalcin, Osterix and Runx2 mRNA expression levels. These results indicated that acerogenin A stimulates osteoblast differentiation through BMP action, which is mediated by Runx2 dependent and Runx2-independent pathways. PMID- 21303662 TI - Mechanistic distinction between activation and inhibition of (Na(+)+K(+))-ATPase mediated Ca2+ influx in cardiomyocytes. AB - (Na(+)+K(+))-ATPase (NKA) mediates positive inotropy in the heart. Extensive studies have demonstrated that the reverse-mode Na(+)/Ca(2+)-exchanger (NCX) plays a critical role in increasing intracellular Ca(2+) concentration through the inhibition of NKA-induced positive inotropy by cardiac glycosides. Little is known about the nature of the NCX functional mode in the activation of NKA induced positive inotropy. Here, we examined the effect of an NKA activator SSA412 antibody on (45)Ca influx in isolated rat myocytes and found that KB R7943, a NCX reverse-mode inhibitor, fails to inhibit the activation of NKA induced (45)Ca influx, suggesting that the Ca(2+) influx via the reverse-mode NCX does not mediate this process. Nifedipine, an L-type Ca(2+) channel (LTCC) inhibitor, completely blocks the activation of NKA-induced (45)Ca influx, suggesting that the LTCC is responsible for the moderate increase in intracellular Ca(2+). In contrast, the inhibition of NKA by ouabain induces 4.7 fold (45)Ca influx compared with the condition of activation of NKA. Moreover, approximately 70% of ouabain-induced (45)Ca influx was obstructed by KB-R7943 and only 30% was impeded by nifedipine, indicating that both the LTCC and the NCX contribute to the rise in intracellular Ca(2+) and that the NCX reverse-mode is the major source for the (45)Ca influx induced by the inhibition of NKA. This study provides direct evidence to demonstrate that the activation of NKA-induced Ca(2+) increase is independent of the reverse-mode NCX and pinpoints a mechanistic distinction between the activation and inhibition of the NKA-mediated Ca(2+) influx path ways in cardiomyocytes. PMID- 21303663 TI - GalNAcbeta1,3-linked paragloboside carries the epitope of a sperm maturation related glycoprotein that is recognized by the monoclonal antibody MC121. AB - The functional maturation of spermatozoa during epididymal transit in mammals accompanies the changes in their plasma membrane due to the binding or removal of proteins or interactions with the proteases, glycosidases and glycosyltransferases present in the epididymis. In order to study the surface changes in spermatozoa during their maturation in the epididymis, we previously established several monoclonal antibodies against the 54kDa sialoglycoprotein of mouse cauda epididymal spermatozoa, which gradually increased the expression of antigenic determinants during epididymal transit. One of these monoclonal antibodies, MC121, reacted with mouse sperm glycoproteins on a polyvinylidene fluoride membrane after desialylation of the glycoproteins, and the treatment of the desialylated sperm glycoproteins with beta-N-acetylhexosaminidase greatly decreased the expression of the antigenic determinants. In addition to reacting with mouse cauda epididymal spermatozoa, MC121 reacted with human red blood cells (hRBCs). MC121 induced agglutination of sialidase-treated hRBCs and stained hRBCs fixed with formalin vapor much more heavily than it stained hRBCs fixed with methanol. The thin layer chromatography (TLC) immunostaining of the sialidase treated lipids of hRBCs with MC121 suggested that the epitope-bearing molecule is a glycosphingolipids (GSL), and that MC121 reacts with a pentaose-GSL. Analysis of sialidase-treated GSLs by TLC-Blot-Matrix Assisted Laser Desorption Ionization Time-of-Flight mass spectrometry (MALDI TOF MS) revealed that the GSL bound by MC121 was [HexNAc][HexNAc+Hex][Hex][Hex]-Cer. The lipid band stained with mAb TH2, which is specific for a GSL, GalNAcbeta1-3Galbeta1-4GlcNAcbeta1-3Galbeta1 4Glcbeta1-ceramide. These results indicated that the epitope to which MC121 binds is present in a neolacto-series GSL, IV3GalNAcbeta-nLc4Cer2 sequence. PMID- 21303664 TI - Local administration of TGFbeta-1/VEGF165 gene-transduced bone mesenchymal stem cells for Achilles allograft replacement of the anterior cruciate ligament in rabbits. AB - Graft remodeling following anterior cruciate ligament (ACL) reconstruction requires a long period of recovery before it is capable of withstanding physiological loads. Graft revascularization is extremely important in the remodeling process. In ACL reconstruction, the local administration of vascular endothelial growth factor (VEGF) significantly increased revascularization of the graft, but did not significantly affect the mechanical properties of the graft after implantation (Ju et al., 2006; Yoshikawa, et al., 2006). Our previous studies showed that transforming growth factor-beta1 (TGFbeta1) could promote improvements in mechanical strength in Achilles tendon regeneration, by regulating collagen type I and type III synthesis, cross-link formation, and matrix-remodeling (Hou et al., 2009). The current study aims to investigate whether the co-expression of TGFbeta1/VEGF(165) could beneficially affect the remodeling of ACL grafts. Bone marrow-derived mesenchymal stem cells (BMSCs), transfected with an adenoviral vector encoding TGFbeta1, VEGF(165) or TGFbeta1/VEGF(165), were surgically implanted into experimental ACL grafts, with non-transfected cells as a control. HE and toluidine blue staining, vascular number, and biomechanical features were analyzed at 3, 6, 12, and 24 weeks after surgery. The results suggest that TGFbeta1 expression, in the TGFbeta1/VEGF(165) transfected BMSCs, could accelerate the remodeling of the reconstructed ligament. The cross-talk between TGFbeta1 and VEGF(165) has positive consequences, as TGFbeta1/VEGF(165)-transfected BMSCs significantly promoted angiogenesis of the reconstructed ligament at 3, 6, 12 weeks, with the best mechanical properties being achieved at 24 weeks. Furthermore, co-expression of these genes is more powerful and efficient than single gene therapy. PMID- 21303665 TI - EphB4 is developmentally and differentially regulated in blood vessels throughout the forebrain neurogenic niche in the mouse brain: Implications for vascular remodeling. AB - Neurogenesis is a process influenced by environmental cues that create highly specific functional niches. Recently, the role of blood vessels in the maintenance and functioning of neurogenic niches during development and in adult life has been hallmarked. In addition to their trophic support for the highly demanding neurogenic process, blood vessels regulate neuroblast differentiation and migration and define functional domains. Since neurogenesis along the forebrain neurogenic niche (FNN) is a multistage process, in which neuroblast proliferation, differentiation and migration are spatially restricted to specific locations; we evaluated the structural features of vascular beds that support these processes during critical time points in their development. Additionally, we studied the molecular identity of the endothelial components of vascular beds using the expression of the venous marker EphB4. Our results show that blood vessels along the FNN: 1) are present very early in development; 2) define the borders of the FNN since early developmental stages; 3) experience constant remodeling until achieving their mature structure; 4) show venous features during perinatal developmental times; and 5) down-regulate their EphB4 expression as development proceeds. Collectively, our results describe the formation of the intricate vascular network that may support neurogenesis along the FNN and show that blood vessels along this neurogenic niche are dynamic entities that experience significant structural and molecular remodeling throughout development. PMID- 21303666 TI - Cellular and laminar expression of Dab-1 during the postnatal critical period in cat visual cortex and the effects of dark rearing. AB - This study describes postnatal critical period changes in cellular and laminar expression of Dab-1, a gene shown to play a role in controlling neuronal positioning during embryonic brain development, in cat visual cortex and the effects of dark rearing (DR). At 1week, there is dense cellular staining which is uniform across cortical layers and very light neuropil staining. At the peak of the critical period (5weeks), dense cell staining is largely restricted to large pyramidal cells of deep layer III and layer V, there is faint cell body staining throughout all cortical layers, neuropil staining is markedly increased and uniform in layers III to VI. This dramatic change in laminar and cellular labeling is independent of visual input, since immunostaining is similar in 5 week DR cats. By 10weeks, the mature laminar and cellular staining pattern is established and the major subsequent change is a further reduction in the density of cellular staining in all cortical layers. Neuropil staining is pronounced and uniform across cortical layers. These developmental changes are altered by DR. Quantification by cell counts indicated that age and DR interact such that differences in cellular expression are opposite in direction between 5- and 20 week-old cats. This bidirectional regulation of cellular expression is the same in all cortical laminae. The bidirectional regulation of cellular expression matches the effects of age and DR on physiological plasticity during the critical period as assessed by ocular dominance shifts in response to monocular deprivation. PMID- 21303667 TI - Altered adult hippocampal neuronal maturation in a rat model of fetal alcohol syndrome. AB - Exposure to ethanol during pregnancy can be devastating to the developing nervous system, leading to significant central nervous system dysfunction. The hippocampus, one of the two brain regions where neurogenesis persists into adulthood, is particularly sensitive to the teratogenic effects of ethanol. In the present study, we tested a rat model of fetal alcohol syndrome (FAS) with ethanol administered via gavage throughout all three trimester equivalents. Subsequently, we assessed cell proliferation, as well as neuronal survival, and differentiation in the dentate gyrus of the hippocampus of adolescent (35 days old), young adult (60 days old) and adult (90 days old) Sprague-Dawley rats. Using both extrinsic (bromodeoxyuridine) and intrinsic (Ki-67) markers, we observed no significant alterations in cell proliferation and survival in ethanol exposed animals when compared with their pair-fed and ad libitum controls. However, we detected a significant increase in the number of new immature neurons in animals that were exposed to ethanol throughout all three trimester equivalents. This result might reflect a compensatory mechanism to counteract the deleterious effects of prenatal ethanol exposure or an ethanol-induced arrest of the neurogenic process at the early neuronal maturation stages. Taken together these results indicate that exposure to ethanol during the period of brain development causes a long-lasting dysregulation of the neurogenic process, a mechanism that might contribute, at least in part, to the hippocampal deficits that have been reported in rodent models of FAS. PMID- 21303668 TI - Central substance P NK1 receptors are involved in fever induced by LPS but not by IL-1beta and CCL3/MIP-1alpha in rats. AB - Substance P (SP) is a neuropeptide that can modulate inflammatory mediator release through activation of NK(1) receptors (NK(1)R). Some studies have also suggested the involvement of SP in lipopolysaccharide (LPS)-induced fever. However, the precise contribution of this neuropeptide to the pathways activated during fever is unknown. In this study we investigated the effect of a selective NK(1)R antagonist, SR140333B, on the febrile response induced by LPS and cytokines. Our results show that the systemic injection of SR140333B did not modify the fever induced by LPS at a dose that is able to reduce protein extravasation induced by SP in the skin. On the other hand, intracerebroventricular administration of SR140333B significantly reduced the fever induced by peripheral injection of LPS. These data emphasize an important role for SP in the central nervous system during the febrile response to LPS, and are reinforced by the fact that intracerebroventricular injection of SP also induced fever in a dose-dependent manner in captopril-treated rats. Considering that the febrile response can result from the generation of several endogenous pyrogens, among them interleukin (IL)-1beta and macrophage inflammatory protein 1alpha (CCL3/MIP-1alpha), we also examined the effect of SR140333B on the fever induced by these cytokines which act through prostaglandin-dependent and independent mechanisms, respectively. Surprisingly, SR140333B did not modify the febrile response to IL-1beta or CCL3/MIP-1alpha. Altogether these data suggest that the central action of SP is essential for LPS-, but not for IL-1beta- or CCL3/MIP-1alpha-induced fever. PMID- 21303670 TI - Do two models of acute and chronic stress stimulation influence the amount of nerve growth factor (NGF) and its receptor TrkA in the hippocampal neurons of middle aged rats? AB - Our study aimed to explore the influence of two different stressors: acute (once for 15 min) and chronic (15 min daily for 21 days) exposure to high light open field (HL-OF) or forced swim (FS) on the density of nerve growth factor (NGF) and tyrosine kinase A (TrkA) immunoreactive neurons in the hippocampal CA1 and CA3 pyramidal cell layers and dentate gyrus (DG) granule cell layer in middle aged (360 days old; P360; P, postnatal day) rats. In contrast to non-stressed animals, acute HL-OF stimulation resulted in an increase (p<0.001) in the density of NGF ir cells in CA1, CA3, DG, whereas chronic HL-OF produced no changes in all hippocampal regions. The rats which underwent acute and chronic FS tests showed no statistically significant differences in the density of NGF-ir containing cells in the CA1, CA3, and DG subfields compared with control rats. Except for DG, where after 21 days of FS the density of TrkA-ir neurons was found to increase (p<0.05) in comparison to unstressed rats, no changes were noted in the density of TrkA-ir in the studied hippocampal structures as a result of acute and chronic HL-OF or FS exposure. These results indicate that acute HL-OF stress stimulation was the only factor inducing changes in the density of NGF-ir containing neurons in the hippocampal CA1, CA3, and DG of middle aged rats. In respect of the density of NGF-ir and TrkA-ir cells in the hippocampal structures, prolonged exposure to HL-OF or FS stressors did not constitute an aggravating factor for rats in the studied ontogenetic period. PMID- 21303669 TI - Effects of lipoic acid on antiapoptotic genes in control and ethanol-treated fetal rhombencephalic neurons. AB - This laboratory showed that ethanol augments apoptosis in fetal rhombencephalic neurons and co-treatment with alpha-lipoic acid (LA) or one of several other antioxidants prevents ethanol-associated apoptosis. Because ethanol increases oxidative stress, which causes apoptosis, it is likely that some of the neuroprotective effects of LA and other antioxidants involve classical antioxidant actions. Considering the reported link of LA with pro-survival cell signaling, it is also possible that LA's neuroprotective effects involve additional mechanisms. The present study investigated the effects of LA on ethanol-treated fetal rhombencephalic neurons with regard to oxidative stress and up-regulation of the pro-survival genes Xiap and Bcl-2. We included parallel gene expression studies with N-acetyl cysteine (NAC) to determine whether LA's effects on Xiap and Bcl-2 were shared by other antioxidants. We also used enzyme inhibitors to determine which signaling pathway(s) might be involved with the effects of LA. The results of this investigation showed that LA treatment of ethanol-treated neurons exerted several pro-survival effects. LA blocked two pro apoptotic changes, i.e., the ethanol-associated rise in ROS and caspase-3. LA also up-regulated the expression genes that encode the anti-apoptotic proteins Bcl-2 and Xiap by a mechanism that involves NF-kappaB. NAC also up-regulated Bcl 2 and Xiap. Thus, the neuroprotective effects of LA and NAC could involve up regulation of pro-survival genes as well as their classical antioxidant actions. PMID- 21303671 TI - Vascular-endothelial growth factor and its high affinity receptor VEGFR-2 in the normal versus destructive lesions human forebrain during development: an immuno histochemical comparative study. AB - Vascular endothelial growth factor (VEGF) is an angiogenic inducer and neurotrophic factor both in adult and neonatal animal models. In the destructive lesions of the developing human brain, the role and expression of VEGF and of its mitogenic receptor VEGFR-2 have been hardly studied. The aim of the present work was to determine the immunohistochemical distribution of VEGF and VEGFR-2 in premature and full-term infants presenting with hypoxic/ischemic lesions, and to compare results with normal infant brains at similar developmental stages. Paraffin embedded brain tissue samples were assessed using anti-human VEGF and VEGFR-2 antibodies. In all undamaged forebrain areas, VEGF and VEGFR-2 displayed same expression patterns in control and pathologic brains, whatever the destructive lesion occurrence's time (before 25 weeks of gestation (WG), between 25 and 34WG, perinatal period and infancy). In the destructive lesions, VEGF was always expressed in neurons, astrocytes and in neovessel walls, contrary to VEGFR 2 which was only expressed in dispersed astrocytes. VEGF was expressed in oligodendrocytes of prenatally damaged brains, whereas VEGF was expressed in these cells in undamaged areas from birth only, similarly to control brains. These data suggest that VEGF plays specific roles and may not be mediated by VEGFR-2 in human forebrain structures exposed to ischemia. PMID- 21303672 TI - Urocortin I inhibits the effects of ghrelin and neuropeptide Y on feeding and energy substrate utilization. AB - The corticotropin releasing hormone-related ligand, urocortin-I (UcnI), suppresses food intake when injected into multiple hypothalamic and extrahypothalamic areas. UcnI also alters energy substrate utilization, specifically via enhanced fat oxidation as reflected in reductions in respiratory quotient (RQ). In the present study we compared the feeding and metabolic effects of ghrelin and NPY following pretreatment with UcnI. Direct PVN injections of NPY (50 pmol) and ghrelin (50 pmol) were orexigenic while UcnI (10-40 pmol) reliably suppressed food intake. Both ghrelin and NPY increased RQ, indicating enhanced utilization of carbohydrates and the preservation of fat stores. UcnI alone suppressed RQ responses. PVN UcnI attenuated the effects of both ghrelin and NPY on food intake and energy substrate utilization. While ghrelin (5 pmol) potentiated the effect of NPY (25 pmol) on RQ and food intake, these responses were inhibited by pretreatment with UcnI (10 pmol). In conclusion, PVN NPY and ghrelin stimulate eating and promote carbohydrate oxidation while inhibiting fat utilization. These effects are blocked by UcnI which alone suppresses appetite and promotes fat oxidation. Overall these findings are consistent with a possible interactive role of PVN NPY, ghrelin and urocortin in the modulation of appetite and energy metabolism. PMID- 21303673 TI - Evaluation of cell damage in organotypic hippocampal slice culture from adult mouse: a potential model system to study neuroprotection. AB - The use of organotypic hippocampal slice culture (OHSC) has become a powerful tool for studying cell damage in different neuropathological states, since it reproduces the basic morphological and functional properties of hippocampal neuronal network. However, the conventional OHSCs are established from postnatal animals rather than adult. Here we reevaluated the features of cell death in adult OHSC in detail and found potential utility for the study of neuroprotection. Organotypic culture of hippocampal slices from adult mice under conventional conditions led to a time-dependent and reproducible cell death. Around 6days in vitro (DIV), slices lost 50% of the cells, based on LDH release assessment. The cell death was greater than 90% after DIV 15. The cell loss was linearly correlated (r=0.944, P<0.01) with the time in culture. The electrophysiological responses to the stimulus in the cultured adult slices were accordingly reduced. The cell degeneration during adult OHSC might be utilized as a tool for studying neuroprotective effects in drug development. To illustrate this potential use, adult OHSCs were challenged with brain-derived neurotrophic factor (BDNF). We found that the continuous supplementation of 300ng/ml BDNF promoted cell survival of adult OHSC. Using immunohistochemistry and Western blot analyses of neuronal markers, we also demonstrated the pro-survival effects of BDNF on neurons in the adult OHSC system. It is suggested that OHSCs from adult mice might provide an alternative model system for neuronal degeneration, suitable for studying physiological factors and pharmacological compounds contributing to neuronal survival. PMID- 21303674 TI - Subthalamic deep brain stimulation increases pallidal firing rate and regularity. AB - While high-frequency stimulation of the subthalamic nucleus (STN-HFS) is highly effective in the treatment of Parkinson's disease (PD), the mechanisms underlying its therapeutic action remain unclear. Here, we report changes of single-neuron pallidal activity during STN-HFS in a parkinsonian patient. STN-HFS increased firing rate in both segments of the pallidum. Neurons displayed time-locked responses to stimulation pulses, with an early excitation followed by inhibition and late excitation. Finally, pallidal neurons fired more regularly during STN HFS. The time-locked responses and increased firing regularity may override abnormally patterned pallidal activity, and thereby significantly contribute to the clinical efficacy of STN-HFS in PD. PMID- 21303675 TI - Microscopic colitis. AB - Microscopic colitis is a common cause of chronic watery diarrhea, especially among older persons. Diagnosis requires histologic analysis of colon biopsy samples in the appropriate clinical setting. Recent studies have shown an increase in the incidence of microscopic colitis, and several have addressed potential mechanisms. We review recent findings about the clinical features, diagnosis, epidemiology, pathophysiology, and treatment of microscopic colitis. PMID- 21303676 TI - The influence of chronic eicosanoid biosynthesis inhibition on life history of the greater waxmoth, Galleria mellonella and its ectoparasitoid, Bracon hebetor. AB - Eicosanoids are oxygenated metabolites of three C20 polyunsaturated fatty acids, mainly arachidonic acid (AA; 20:4n-6), but also 20:3n-6 and 20:5n-3. Aside from their importance in biomedicine, eicosanoids act in invertebrate biology. Prostaglandins (PGs) influence salt and water transport physiology in insect rectal epithelia and in Malpighian tubules. PGs also influence a few insect behaviors, including releasing oviposition behavior and behavioral fever. Eicosanoids act in ovarian development and in insect immunity. Because eicosanoids act in several areas of insect biology, we posed the hypothesis that chronic inhibition of eicosanoid biosynthesis, in the absence of microbial challenge, can influence insect life table parameters, including developmental time, survival, adult longevity and parasitoid fecundity. Here we report that inhibiting eicosanoid biosynthesis throughout the larval life exerted minor influences on some life table parameters of the greater wax moth, Galleria mellonella and its ectoparasitoid, Bracon hebetor, however, the inhibitors strongly reduced the production and hatchability of the parasitoids' eggs. The significance of the work relates to the potentials of understanding and targeting eicosanoid systems as a platform for developing new technologies of insect pest management. As seen here, the impact of targeting eicosanoid systems is seen in crucial moments of insect life histories, such as reproduction or immune challenge rather than in overall larval development. PMID- 21303677 TI - Personal neglect-a disorder of body representation? AB - The cognitive mechanisms underlying personal neglect are not well known. One theory postulates that personal neglect is due to a disorder of contralesional body representation. In the present study, we have investigated whether personal neglect is best explained by impairments in the representation of the contralesional side of the body, in particular, or a dysfunction of the mental representation of the contralesional space in general. For this, 22 patients with right hemisphere cerebral lesions (7 with personal neglect, 15 without personal neglect) and 13 healthy controls have been studied using two experimental tasks measuring representation of the body and extrapersonal space. In the tasks, photographs of left and right hands as well as left and right rear-view mirrors presented from the front and the back had to be judged as left or right. Our results show that patients with personal neglect made more errors when asked to judge stimuli of left hands and left rear-view mirrors than either patients without personal neglect or healthy controls. Furthermore, regression analyses indicated that errors in interpreting left hands were the best predictor of personal neglect, while other variables such as extrapersonal neglect, somatosensory or motor impairments, or deficits in left extrapersonal space representation had no predictive value of personal neglect. These findings suggest that deficient body representation is the major mechanism underlying personal neglect. PMID- 21303678 TI - Novelty-seeking behavior predicts vulnerability in a rodent model of depression. AB - BACKGROUND: The onset of major depressive disorder is likely precipitated by a combination of heredity and life stress. The present study tested the hypothesis that rats selectively bred on a trait related to emotional reactivity would show differential susceptibility or resilience to the development of depression-like signs in response to chronic mild variable intermittent stress (CMS). METHODS: Male Sprague-Dawley rats that were bred based on the trait of either high or low locomotor activity in response to a novel environment were exposed to 4 weeks of CMS or control conditions. Changes in hedonic behavior were assessed using weekly sucrose preference tests and anxiety-like behavior was evaluated using the novelty-suppressed feeding test. RESULTS: During 4 weeks of CMS, bred low responder (bLR) rats became anhedonic at a faster rate and to a larger degree than bred high responder (bHR) rats, based on weekly sucrose preference tests. Measures of anxiety-like behavior in the novelty-suppressed feeding test were also significantly increased in the CMS-exposed bLR rats, though no differences were observed between CMS-exposed bHR rats and their unstressed controls. CONCLUSIONS: These findings present further evidence that increased emotional reactivity is an important factor in stress susceptibility and the etiology of mood disorders, and that bHR and bLR rats provide a model of resistance or vulnerability to stress-induced depression. Furthermore, exposing bHR and bLR rats to CMS provides an excellent way to study the interaction of genetic and environmental factors in the development of depression-like behavior. PMID- 21303679 TI - Comparative study of voltage-gated sodium channel alpha-subunits in non overlapping four neuronal populations in the rat dorsal root ganglion. AB - Voltage-gated sodium channel alpha-subunit (Nav) is the major determinant of neuronal electrophysiological characters. In order to compare the composition of Navs among neurochemically different neurons in the rat dorsal root ganglion (DRG), we examined the expression of Nav transcripts in four non-overlapping neuronal populations, with (+) or without (-) N52 immunoreactivity, a marker of neurons with myelinated axons, and TrkA mRNA identified by in situ hybridization histochemistry. Both N52-/TrkA+ and N52-/TrkA- populations had high levels of signals for Nav1.7, Nav1.8, and Nav1.9 mRNAs, but rarely expressed Nav1.1 or Nav1.6. There was no significant difference in these signals, suggesting that C fiber peptidergic and non-peptidergic neurons have similar electrophysiological characters with regard to sodium currents. N52+/TrkA+ neurons (putative A-fiber nociceptors) had similar high levels of signals for Nav1.7 and Nav1.8, but a significantly lower level of Nav1.9 signals, as compared to N52- neurons. Although, almost no N52+/TrkA- neurons had Nav1.8 or Nav1.9, half of this population expressed Nav1.7 at similar levels to other three populations and the other half completely lacked this channel. These data suggest that Nav1.8 is a common channel for both C- and A-fiber nociceptors, and Nav1.9 is rather selective for C-fiber nociceptors. Nav1.7 is the most universal channel while some functionally unknown N52+/TrkA- subpopulation selectively lacks it. PMID- 21303680 TI - Monocyte-mediated regulation of genes by the amyloid and prion peptides in SH SY5Y neuroblastoma cells. AB - Alzheimer's disease as well as prion-related encephalopathies are neurodegenerative disorders of the central nervous system, which cause mental deterioration and progressive dementia. Both pathologies appear to be primarily associated with the pathological accumulation and deposit of beta-amyloid or prion peptides in the brain, and it has been even suggested that neurotoxicity induced by these peptides would be associated to essentially similar pathogenic mechanisms, in particular to those that follow the activation of microglial cells. To probe whether the neurotoxic effects induced by the beta-amyloid and prion peptides are actually mediated by similar glial-associated mechanisms, we have examined the differential expression of genes in SH-SY5Y neuroblastoma cells incubated with conditioned media from beta-amyloid or prion-stimulated THP-1 monocytic cells. According to microarray analysis, not many coincidences are observed and only four genes (Hint3, Psph, Daam1 and c-Jun) appear to be commonly upregulated by both peptides. Furthermore, c-Jun appears to be involved in the cell death mediated by both peptides. PMID- 21303681 TI - Anterior insular volume is larger in patients with obsessive-compulsive disorder. AB - There has been increasing evidence indicating gray matter abnormalities in patients with obsessive-compulsive disorder (OCD). Several voxel-based morphometry (VBM) studies have reported volume changes in the insular cortex. Although there are distinct differences in the connectivity and functions in the anterior and posterior insular cortices, these two regions have never been distinguished in previous VBM studies. In this study, we adopted a region of interest (ROI) method to measure insular volume separately. We investigated insular volume in 32 drug-free patients with OCD and in 34 healthy controls using magnetic resonance imaging (MRI). Repeated measures multivariate analysis of covariance (MANCOVA) was conducted to examine the difference between the patients and the controls. Compared with the healthy controls, the patients had a significantly larger gray matter volume in the anterior insular cortex bilaterally (post hoc test, p=0.036; left, p=0.047; right). This is the first volumetric MRI study to separately investigate the anterior and posterior insular cortex volumes in non-medicated patients with OCD. The results suggest that the anterior insular cortex may be related to the pathophysiology of OCD. PMID- 21303683 TI - Central administration of ghrelin alters emotional responses in rats: behavioural, electrophysiological and molecular evidence. AB - The orexigenic and pro-obesity hormone ghrelin targets key hypothalamic and mesolimbic circuits involved in energy balance, appetite and reward. Given that such circuits are closely integrated with those regulating mood and cognition, we sought to determine whether chronic (>2 weeks) CNS exposure to ghrelin alters anxiety- and depression-like behaviour in rats as well as some physiological correlates. Rats bearing chronically implanted i.c.v. catheters were treated with ghrelin (10 MUg/d) or vehicle for 4 weeks. Tests used to assess anxiety- and depression-like behaviour were undertaken during weeks 3-4 of the infusion. These revealed an increase in anxiety- and depression-like behaviour in the ghrelin treated rats relative to controls. At the end of the 4-week infusion, brains were removed and the amygdala dissected for subsequent qPCR analysis that revealed changes in expression of a number of genes representing key systems implicated in these behavioural changes. Finally, given the key role of the dorsal raphe serotonin system in emotional reactivity, we examined the electrophysiological response of dorsal raphe neurons after a ghrelin challenge, and found mainly inhibitory responses in this region. We demonstrate that the central ghrelin signalling system is involved in emotional reactivity in rats, eliciting pro anxiety and pro-depression effects and have begun to explore novel target systems for ghrelin that may be of importance for these effects. PMID- 21303684 TI - Interrelations and circadian changes of electroencephalogram frequencies under baseline conditions and constant sleep pressure in the rat. AB - Similar to the nap-protocols applied in humans, the repeated short-sleep deprivation protocol in rats stabilizes slow-wave activity (SWA, 0.5-4 Hz) in the non-rapid eye movement (NREM) sleep electroencephalogram (EEG), thus reflecting a constant sleep pressure or sleep homeostatic level, whereas higher frequencies (7 25 Hz) in these conditions preserve their daily rhythm, therefore demonstrating a strong input from an endogenous circadian clock. How different EEG frequencies in rapid eye movement (REM) sleep and waking respond to these constant conditions, how they interrelate to each other within the different vigilance states, and which component of sleep regulation (homeostatic or circadian) is involved, remain unknown. To answer these questions, we applied power spectral analysis and correlation analysis to 1 Hz bin EEG frequency data for different vigilance states in freely moving rats in constant darkness, under baseline conditions and during the repeated short-sleep deprivation protocol. Our analysis suggests that (1) 0.5-5 Hz frequencies in NREM sleep and higher frequencies in REM sleep (above 19 Hz) and waking (above 10 Hz) are sleep-dependent, and thus seem to be under control of the sleep homeostat, while (2) faster frequencies in the NREM sleep EEG (7-25 Hz) and 3-7 Hz activity in the REM sleep EEG are under strong influence of the endogenous circadian clock. Theta activity in waking (5-7 Hz) seems to reflect both circadian and behavior dependent influences. NREM sleep EEG frequencies between 9 and 14 Hz showed both homeostatic and circadian components in their behavior. Thus, frequencies in the EEG of the different vigilance states seem to represent circadian and homeostatic components of sleep regulatory mechanisms, where REM sleep and waking frequency ranges behave similarly to each other and differently from NREM sleep frequencies. PMID- 21303685 TI - Toll-like receptor signaling in amyotrophic lateral sclerosis spinal cord tissue. AB - Increasing evidence indicates that inflammatory responses could play a critical role in the pathogenesis of motor neuron injury in amyotrophic lateral sclerosis (ALS). Recent findings have underlined the role of Toll-like receptors (TLRs) and the receptor for advanced glycation endproducts (RAGE) in the regulation of both innate and adaptive immunity in different pathologies associated with neuroinflammation. In the present study we investigated the expression and cellular distribution of TLR2, TLR4, RAGE and their endogenous ligand high mobility group box 1 (HMGB1) in the spinal cord of control (n=6) and sporadic ALS (n=12) patients. The immunohistochemical analysis of TLR2, TLR4 and RAGE showed increased expression in reactive glial cells in both gray (ventral horn) and white matter of ALS spinal cord. TLR2 was predominantly detected in cells of the microglia/macrophage lineage, whereas the TLR4 and RAGE was strongly expressed in astrocytes. Real-time quantitative PCR analysis confirmed the increased expression of both TLR2 and TLR4 and HMGB1 mRNA level in ALS patients. In ALS spinal cord, HMGB1 signal is increased in the cytoplasm of reactive glia, indicating a possible release of this molecule from glial cells. Our findings show increased expression of TLR2, TLR4, RAGE and HMGB1 in reactive glia in human ALS spinal cord, suggesting activation of the TLR/RAGE signaling pathways. The activation of these pathways may contribute to the progression of inflammation, resulting in motor neuron injury. In this context, future studies, using animal models, will be important to achieve a better understanding of these signaling pathways in ALS in view of the development of new therapeutic strategies. PMID- 21303682 TI - Neuroimaging biomarkers of epileptogenesis. AB - Much progress has been made in the field studying the process of epileptogenesis via neuroimaging techniques. Conventional imaging methods include magnetic resonance imaging with morphometric analysis, magnetic resonance spectroscopy and positron emission tomography. Newer network-based methods such as diffusion tensor imaging and functional magnetic resonance imaging with resting functional connectivity are being developed and applied to clinical use. This review provides a brief summary of the major human and animal studies in both partial and generalized epilepsies that demonstrate the potential of these imaging modalities to serve as biomarkers of epileptogenesis. PMID- 21303686 TI - Yokukansan, a traditional Japanese medicine, ameliorates memory disturbance and abnormal social interaction with anti-aggregation effect of cerebral amyloid beta proteins in amyloid precursor protein transgenic mice. AB - The deposition of amyloid beta protein (Abeta) is a consistent pathological hallmark of Alzheimer's disease (AD) brains. Therefore, inhibition of Abeta aggregation in the brain is an attractive therapeutic and preventive strategy in the development of disease-modifying drugs for AD. An in vitro study demonstrated that yokukansan (YKS), a traditional Japanese medicine, inhibited Abeta aggregation in a concentration-dependent manner. An in vivo study demonstrated that YKS and Uncaria hook (UH), a constituent of YKS, prevented the accumulation of cerebral Abeta. YKS also improved the memory disturbance and abnormal social interaction such as increased aggressive behavior and decreased social behavior in amyloid precursor protein transgenic mice. These results suggest that YKS is likely to be a potent and novel therapeutic agent to prevent and/or treat AD, and that this may be attributed to UH. PMID- 21303687 TI - Effect of emodin on neuropathic pain transmission mediated by P2X2/3 receptor of primary sensory neurons. AB - Neuropathic pain is the most difficult type of pain to cure. The P2X(2/3) receptors play a crucial role in facilitating the transmission of pain at neuropathic pain states. Emodin is a natural anthraquinone in rhubarb. The present research investigated the effects of emodin on the pain transmission in neuropathic pain states that was mediated by P2X(2/3) receptor in primary sensory neurons. Chronic constriction injury (CCI) model was used as neuropathic pain model. Emodin was dissolved in 0.5% sodium carboxymethyl cellulose (CMC) as vehicle. Sprague-Dawley male rats had been randomly divided into Sham+vehicle group, CCI+emodin group, and CCI+vehicle group. Mechanical withdrawal threshold and thermal withdrawal latency were measured. P2X(2/3) expression in L4/L5 dorsal root ganglion (DRG) was detected by immunohistochemistry, in situ hybridization (ISH) and RT-PCR. The mechanical withdrawal threshold and thermal withdrawal latency in CCI+vehicle group were lower than those in Sham+vehicle group and CCI+emodin group (p<0.05), while P2X(2) and P2X(3) receptor expression of L4/L5 DRG in CCI+vehicle group was higher than those in the other two groups (p<0.05). The co-local staining of P2X(2) and P2X(3) in the DRG of CCI group appeared to be more intense than that in the DRG of the other two groups with double-label fluorescence immunohistochemistry. The results showed that the application of emodin alleviated the hyperalgesia of CCI rats and significantly decreased the P2X(2/3) expression of L4/L5 DRG in CCI+emodin group compared with that in CCI+vehicle group (p<0.05). The data of ISH and RT-PCR in P2X(2) and P2X(3) mRNA expression suggest that the pharmacologic mechanism of emodin is involved in the nucleic acid level. The results showed that emodin can inhibit the transmission of neuropathic pain mediated by P2X(2/3) receptor of primary sensory neurons to alleviate chronic neuropathic pain. PMID- 21303688 TI - Proteins responsible for lysogeny of deep-sea thermophilic bacteriophage GVE2 at high temperature. AB - The lytic and lysogenic life cycle switch of bacteriophages plays very important roles in virus-host interactions. However, the lysogeny of thermophilic bacteriophage infecting thermophile at high temperatures has not been addressed. In this study, two lysogeny-related genes encoding the CI protein and recombinase of GVE2, a thermophilic bacteriophage obtained from a deep-sea hydrothermal vent, were characterized. Temporal analyses showed that the two genes were expressed at early stages of GVE2 infection. Based on chromatin immunoprecipitation (ChIP) assay and electrophoretic mobility shift assay (EMSA), the GVE2 CI protein was bound with only one DNA fragment located at 24264-24036 bp in the GVE2 genome. This location might be the original transcription site and the lysis-lysogeny switch site, which was very different from mesophilic bacteriophages. The GVE2 CI and recombinase proteins could function only at high temperatures. Therefore our study improved our understanding of the lysogeny process of bacteriophages at high temperatures. PMID- 21303689 TI - Measurement of absolute auditory thresholds in the common marmoset (Callithrix jacchus). AB - The common marmoset is a small, arboreal, New World primate that has emerged as a promising non-human model system in auditory neuroscience. A complete understanding of the neuroethology of auditory processing in marmosets will include behavioral work examining how sounds are perceived by these animals. However, there have been few studies of the marmoset's hearing and perceptual abilities and the audiogram of this species has not been measured using modern psychophysical methods. The present experiment pairs psychophysics with an operant conditioning technique to examine perception of pure tone stimuli by marmosets using an active behavioral paradigm. Subjects were trained to lick at a feeding tube when they detected a sound. Correct responses provided access to a food reward. Pure tones of varying intensities were presented to subjects using the method of constant stimuli. Behavioral thresholds were calculated for each animal based on hit rate--threshold was defined by the tone intensity that the animal correctly identified 50% of the time. Results show that marmoset hearing is comparable to that of other New World monkeys, with a hearing range extending from about 125 Hz up to 36 kHz and a sensitivity peak around 7 kHz. PMID- 21303690 TI - Modification of the conformational skin structure by treatment with liposomal formulations and its correlation to the penetration depth of aciclovir. AB - The stratum corneum (SC), top layer of the epidermis, is comprised mostly of lipids that are responsible for the permeability properties of the SC and which protect the body from external agents. Changes in these skin microconstituents can be understood by instrumental methods such as attenuated total reflectance Fourier-transform infrared (ATR-FTIR) spectroscopy. The present work shows that different types of analyzed skin, dermatomed abdominal porcine skin, pig ear skin, and human heat separated skin, influenced both the shape and the intensity of recorded spectra. The typical FTIR spectral bands of the conformation of the lipid aliphatic chains in the skin samples were altered after treatment with pure DPPC liposomes and chitosan (CS) coated DPPC liposomes, but not with aqueous CS solution. The conformational change could be the reason for the variable permeability of the skin. This was confirmed by tape stripping on pig ear skin (imitating in vivo studies): the amount of aciclovir penetrating from polymer coated and polymer free liposomes was significantly higher under the skin surface in comparison with the aqueous CS-solution. Moreover, the addition of the polymer to liposomes induced a higher skin penetration than pure liposomes. One explanation might be the CS's stronger adhesion to the skin. PMID- 21303691 TI - A new approach for the evaluation of niosomes as effective transdermal drug delivery systems. AB - The central motivation for this study was to evaluate if the increased hydrophilic drug permeation across the skin, which is always observed in presence of vesicular systems, is dependent on the structural organization of niosomes, that are used to transport the active molecules, or if it is only dependent on the surfactant dual nature. To answer this question, non-ionic surfactants belonging to the class of Pluronic and sucrose esters were used both as components of niosomal systems or in the form of sub-micellar solutions. The obtained niosomes were characterized by their entrapment efficiency, size and morphology. The enhancing effect of niosomes on the ex vivo percutaneous penetration of a model drug was investigated using a Franz-type diffusion chamber and compared to that obtained by using sub-micellar solution of surfactant or achieving pretreatment of the skin with surfactants' sub-micellar solution or empty niosomes. The results suggest that the surfactants used in this study could be considered as percutaneous permeation enhancers only when they are in the form of drug-loaded vesicular systems: no percutaneous promotion was achieved by using sub-micellar solution containing free Sulfadiazine sodium salt or performing pretreatment with empty niosomes or sub-micellar solutions of the surfactant. In our experiments, only niosomes act as effective transdermal drug delivery systems. PMID- 21303692 TI - Edaravone-loaded liposomes for retinal protection against oxidative stress induced retinal damage. AB - To optimize the retinal protective effects of submicron-sized liposomes (ssLips) containing edaravone for intravitreal administration, we investigated the effects of liposomal formulation on the pharmacological effects. Loading of edaravone into ssLips of around 50% entrapment efficiency was achieved by a calcium acetate gradient method. The in vitro radical-scavenging capacity of edaravone-loaded ssLip based on egg phosphatidylcholine (EPC-ssLip) and L-alpha-distearoyl phosphatidylcholine (DSPC-ssLip) was determined in RGC-5, a neuronal precursor cell line that can be differentiated to resemble retinal ganglion cells. Edaravone-loaded EPC-ssLip scavenged intracellular H(2)O(2) radical more strongly than DSPC-ssLip, although there was only a small difference in cellular uptake of edaravone into RGC-5. An in vivo N-methyl-D-aspartate (NMDA)-induced disease model was used to investigate the retinal protective effects in mice. The edaravone-loaded EPC-ssLip significantly reduced NMDA-induced ganglion cell layer (GCL) cell death compared with free edaravone. Such protective effect was small in the case of DSPC-ssLip. These results may be related to the release profile of the edaravone from ssLips across the inner layers of the retina including GCL, indicating effective retinal protection of EPC-ssLip compared to that of DSPC ssLip. EPC-ssLip is a promising carrier for edaravone in treating oxidative stress-induced retinal diseases. PMID- 21303693 TI - Development and characterization of a novel lipid nanocapsule formulation of Sn38 for oral administration. AB - The purpose of this work was to encapsulate 7-Ethyl-10-hydroxy-camptothecin (Sn38) in lipid nanocapsules (LNCs) using phase inversion-based method in order to deliver Sn38 by oral route. LNCs were prepared by a low-energy emulsification method and were characterized for size, polydispersity index (PDI), surface charge, drug payload, in vitro drug release, and storage stability. Moreover, in view of an oral administration, in vitro stability in gastrointestinal fluid and permeability across Caco-2 cells were tested. Sn38-loaded LNCs with a mean particle size of 38+/-2 nm were obtained. The particles displayed a narrow size distribution and a drug payload of 0.40+/-0.07 mg/g of LNC dispersion. In vitro stability in simulated gastric and intestinal media was also observed. Finally, Sn38-loaded LNCs improved permeability of Sn38 across Caco-2 cells (5.69+/ 0.87*10(6) cm s(-1) at 6h vs 0.31+/-0.02*10(6) cm s(-1)) and intracellular concentration compared with free Sn38. In conclusion, Sn38 nanocarriers have been developed and display a strong potential for oral administration. PMID- 21303694 TI - Uptake of phenothiazines by the harvested chylomicrons ex vivo model: influence of self-nanoemulsifying formulation design. AB - The aim of this study was to examine the potential of self-nanoemulsifying drug delivery systems (SNEDDS) on the uptake of the lipophilic and poorly water soluble phenothiazines thioridazine and chlorpromazine with the isolated plasma derived chylomicron (CM) ex vivo model. The multi-component delivery systems were optimized by evaluating their ability to self-emulsify when introduced to an aqueous medium under gentle agitation. The uptake of phenothiazines by isolated plasma derived chylomicrons was investigated with short chain triglyceride (SCT) SNEDDS, medium chain triglyceride (MCT) SNEDDS, and long chain triglyceride (LCT) SNEDDS. SNEDDS were also evaluated for their stabilities, dispersibilities, percentage transmittances and by particle size analyses. For thioridazine a 5.6 fold and for chlorpromazine a 3.7-fold higher CM uptake could be observed using a LCT-SNEDDS formulation compared to the drugs without formulation. In contrast, ex vivo uptake by isolated CM was not significantly increased by SNEDDS formulations based on MCT and SCT. Compared with isolated CM, the CM sizes were increased 2.5 fold in LCT-SNEDDS, whereas in MCT-SNEDDS or SCT-SNEDDS only a small, non significant (P<0.05) increase in CM size was observed. These results show that distinct SNEDDS formulations containing phenothiazines are efficiently uptaken by plasma derived chylomicrons ex vivo. PMID- 21303696 TI - Ndrg1 in development and maintenance of the myelin sheath. AB - CMT4D disease is a severe autosomal recessive demyelinating neuropathy with extensive axonal loss leading to early disability, caused by mutations in the N myc downstream regulated gene 1 (NDRG1). NDRG1 is expressed at particularly high levels in the Schwann cell (SC), but its physiological function(s) are unknown. To help with their understanding, we characterise the phenotype of a new mouse model, stretcher (str), with total Ndrg1 deficiency, in comparison with the hypomorphic Ndrg1 knock-out (KO) mouse. While both models display normal initial myelination and a transition to overt pathology between weeks 3 and 5, the markedly more severe str phenotype suggests that even low Ndrg1 expression results in significant phenotype rescue. Neither model replicates fully the features of CMT4D: although axon damage is present, regenerative capacity is unimpaired and the mice do not display the early severe axonal loss typical of the human disease. The widespread large fibre demyelination coincides precisely with the period of rapid growth of the animals and the dramatic (160-500-fold) increase in myelin volume and length in large fibres. This is followed by stabilisation after week 10, while small fibres remain unaffected. Gene expression profiling of str peripheral nerve reveals non-specific secondary changes at weeks 5 and 10 and preliminary data point to normal proteasomal function. Our findings do not support the proposed roles of NDRG1 in growth arrest, terminal differentiation, gene expression regulation and proteasomal degradation. Impaired SC trafficking failing to meet the considerable demands of nerve growth, emerges as the likely pathogenetic mechanism in NDRG1 deficiency. PMID- 21303697 TI - Loss of amyloid precursor protein in a mouse model of Niemann-Pick type C disease exacerbates its phenotype and disrupts tau homeostasis. AB - Niemann-Pick type C disease (NPC) is a lysosomal storage disorder which, at the cellular level, shows amyloid Abeta and tau pathologies comparable to those seen in the AD brain. Here, we have investigated, in a mouse model of NPC, the impact of removing the source of Abeta, namely APP, on the disease phenotype and on the expression levels and phosphorylation patterns of tau. We reasoned that removing APP from the NPC brain might help to unveil its impact on the disease phenotype and shed light on the mechanisms governing the interaction, both physiological and pathological, between APP function and tau homeostasis, at least in NPC. We show that, unexpectedly, loss of APP in NPC mice leads to poorer neuromuscular coordination and cumulative survival rates; exacerbation of their cholesterol abnormalities; higher levels of astrocytosis and dysregulation of tau homeostasis. Our results are consistent with a mechanism of neurodegeneration in the NPC and AD brains in which cholesterol dysregulation is a key early pathogenic event affecting tau homeostasis in parallel with, and independently of, amyloid accumulation. PMID- 21303698 TI - Dopamine D2-receptor knockout mice are protected against dopaminergic neurotoxicity induced by methamphetamine or MDMA. AB - Methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA), amphetamine derivatives widely used as recreational drugs, induce similar neurotoxic effects in mice, including a marked loss of tyrosine hydroxylase (TH) and dopamine transporter (DAT) in the striatum. Although the role of dopamine in these neurotoxic effects is well established and pharmacological studies suggest involvement of a dopamine D2-like receptor, the specific dopamine receptor subtype involved has not been determined. In this study, we used dopamine D2 receptor knock-out mice (D2R(-/-)) to determine whether D2R is involved in METH- and MDMA-induced hyperthermia and neurotoxicity. In wild type animals, both drugs induced marked hyperthermia, decreased striatal dopamine content and TH- and DAT immunoreactivity and increased striatal GFAP and Mac-1 expression as well as iNOS and interleukin 15 at 1 and 7days after drug exposure. They also caused dopaminergic cell loss in the SNpc. Inactivation of D2R blocked all these effects. Remarkably, D2R inactivation prevented METH-induced loss of dopaminergic neurons in the SNpc. In addition, striatal dopamine overflow, measured by fast scan cyclic voltammetry in the presence of METH, was significantly reduced in D2R(-/-) mice. Pre-treatment with reserpine indicated that the neuroprotective effect of D2R inactivation cannot be explained solely by its ability to prevent METH-induced hyperthermia: reserpine lowered body temperature in both genotypes, and potentiated METH toxicity in WT, but not D2R(-/-) mice. Our results demonstrate that the D2R is necessary for METH and MDMA neurotoxicity and that the neuroprotective effect of D2R inactivation is independent of its effect on body temperature. PMID- 21303699 TI - Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission. AB - Alpha-synuclein aggregation plays a central role in Parkinson's disease pathology. Direct transmission of alpha-synuclein from pathologically affected to healthy unaffected neurons may be important in the anatomical spread of the disease through the nervous system. We have demonstrated that exosomes released from alpha-synuclein over-expressing SH-SY5Y cells contained alpha-synuclein and these exosomes were capable of efficiently transferring alpha-synuclein protein to normal SH-SY5Y cells. Moreover, the incubation of cells with ammonium chloride or bafilomycin A1 to produce the lysosomal dysfunction recently reported in Parkinson's disease led to an increase in the release of alpha-synuclein in exosomes and a concomitant increase in alpha-synuclein transmission to recipient cells. This study clearly demonstrates the importance of exosomes in both the release of alpha synuclein and its transmission between cells and suggests that factors associated with PD pathology accelerate this process. These mechanisms may play an important role in PD pathology and provide a suitable target for therapeutic intervention. PMID- 21303695 TI - The functional neuroanatomy of dystonia. AB - Dystonia is a neurological disorder characterized by involuntary twisting movements and postures. There are many different clinical manifestations, and many different causes. The neuroanatomical substrates for dystonia are only partly understood. Although the traditional view localizes dystonia to basal ganglia circuits, there is increasing recognition that this view is inadequate for accommodating a substantial portion of available clinical and experimental evidence. A model in which several brain regions play a role in a network better accommodates the evidence. This network model accommodates neuropathological and neuroimaging evidence that dystonia may be associated with abnormalities in multiple different brain regions. It also accommodates animal studies showing that dystonic movements arise with manipulations of different brain regions. It is consistent with neurophysiological evidence suggesting defects in neural inhibitory processes, sensorimotor integration, and maladaptive plasticity. Finally, it may explain neurosurgical experience showing that targeting the basal ganglia is effective only for certain subpopulations of dystonia. Most importantly, the network model provides many new and testable hypotheses with direct relevance for new treatment strategies that go beyond the basal ganglia. This article is part of a Special Issue entitled "Advances in dystonia". PMID- 21303700 TI - NADPH oxidase is involved in post-ischemic brain inflammation. AB - Nicotinamide adenine dinucleotide phosphate oxidase (NOX) is widely expressed in brain tissue including neurons, glia, and endothelia in neurovascular units. It is a major source of oxidants in the post-ischemic brain and significantly contributes to ischemic brain damage. Inflammation occurs after brain ischemia and is known to be associated with post-ischemic oxidative stress. Post-ischemic inflammation also causes progressive brain injury. In this study we investigated the role of NOX2 in post-ischemic cerebral inflammation using a transient middle cerebral artery occlusion model in mice. We demonstrate that mice with NOX2 subunit gp91(phox) knockout (gp91 KO) showed 35-44% less brain infarction at 1 and 3 days of reperfusion compared with wild-type (WT) mice. Minocycline further reduced brain damage in the gp91 KO mice at 3 days of reperfusion. The gp91 KO mice exhibited less severe post-ischemic inflammation in the brain, as evidenced by reduced microglial activation and decreased upregulation of inflammation mediators, including interleukin-1beta (IL-1beta), tumor necrosis factor-alpha, inducible nitric oxide synthases, CC-chemokine ligand 2, and CC-chemokine ligand 3. Finally, we demonstrated that an intraventricular injection of IL-1beta enhanced ischemia- and reperfusion-mediated brain damage in the WT mice (double the infarction volume), whereas, it failed to aggravate brain infarction in the gp91 KO mice. Taken together, these results demonstrate the involvement of NOX2 in post-ischemic neuroinflammation and that NOX2 inhibition provides neuroprotection against inflammatory cytokine-mediated brain damage. PMID- 21303701 TI - Different phospholipid transfer protein complexes contribute to the variation in plasma PLTP specific activity. AB - Phospholipid transfer protein (PLTP) facilitates the transfer of phospholipids among lipoproteins. Over half of the PLTP in human plasma has been found to have little phospholipid transfer activity (inactive PLTP). We recently observed that plasma PLTP specific activity is inversely correlated with high-density lipoprotein (HDL) level and particle size in healthy adults. The purpose of this study was to evaluate the factors that contribute to the variation in plasma PLTP specific activity. Analysis of the specific activity of PLTP complexes in nine plasma samples from healthy adults revealed two clusters of inactive PLTP complexes with mean molecular weights (MW) of 342kDa and 146kDa. The large and small inactive PLTP complexes represented 52+/-8% (range 39-63%) and 8+/-8% (range 1-28%) of the plasma PLTP, respectively. Active PLTP complexes had a mean MW of 207kDa and constituted 40+/-6% (range 33-50%) of the plasma PLTP. The specific activity of active PLTP varied from 16 to 32MUmol/MUg/h. These data demonstrate for the first time the existence of small inactive plasma PLTP complexes. Variation in the amount of the two clusters of inactive PLTP complexes and the specific activity of the active PLTP contribute to the variation in plasma PLTP specific activity. PMID- 21303703 TI - There is no evidence that mitochondria are the main source of reactive oxygen species in mammalian cells. AB - It is often assumed that mitochondria are the main source of reactive oxygen species (ROS) in mammalian cells, but there is no convincing experimental evidence for this in the literature. What evidence there is suggests mitochondria are a significant source for ROS, which may have physiological and pathological effects. But quantitatively, endoplasmic reticulum and peroxisomes have a greater capacity to produce ROS than mitochondria, at least in liver. In most cells and physiological or pathological conditions there is a lack of evidence for or against mitochondria being the main source of cellular ROS. Mitochondria can rapidly degrade ROS and thus are potential sinks for ROS, but whether mitochondria act as net sources or sinks within cells in particular conditions is unknown. PMID- 21303702 TI - Quality assessment of human mitochondrial DNA quantification: MITONAUTS, an international multicentre survey. AB - Mitochondrial DNA quantification by qPCR is used in the context of many diseases and toxicity studies but comparison of results between laboratories is challenging. Through two multigroup distributions of DNA samples from human cell lines, the MITONAUTS group anonymously compared mtDNA/nDNA quantification across nine laboratories involved in HIV research worldwide. Eight of the nine sites showed significant correlation between them (mean raw data R(2)=0.664; log(10) transformed data R(2)=0.844). Although mtDNA/nDNA values were well correlated between sites, the inter-site variability on the absolute measurements remained high with a mean (range) coefficient of variation of 71 (37-212) %. Some variability appeared cell line-specific, probably due to chromosomal alterations or pseudogenes affecting the quantification of certain genes, while within cell line variability was likely due to differences in calibration of the standard curves. The use of two mtDNA and two single copy nDNA genes with highly specific primers to quantify each genome would help address copy number variants. Our results indicate that sample shipment must be done frozen and that absolute mtDNA/nDNA ratio values cannot readily be compared between laboratories, especially if assessing cultured cell mtDNA content. However, within laboratory and relative mtDNA/nDNA comparisons between laboratories should be reliable. PMID- 21303704 TI - MERRF: Clinical features, muscle biopsy and molecular genetics in Brazilian patients. AB - Myoclonic epilepsy with ragged red fibers (MERRF) is a mitochondrial disease that is characterized by myoclonic epilepsy with ragged red fibers (RRF) in muscle biopsies. The aim of this study was to analyze Brazilian patients with MERRF. Six patients with MERRF were studied and correlations between clinical findings, laboratory data, electrophysiology, histology and molecular features were examined. We found that blood lactate was increased in four patients. Electroencephalogram studies revealed generalized epileptiform discharges in five patients and generalized photoparoxysmal responses during intermittent photic stimulation in two patients. Muscle biopsies showed RRF in all patients using modified Gomori-trichrome and succinate dehydrogenase stains. Cytochrome c oxidase (COX) stain analysis indicated deficient activity in five patients and subsarcolemmal accumulation in one patient. Molecular analysis of the tRNA(Lys) gene with PCR/RFLP and direct sequencing showed the A8344G mutation of mtDNA in five patients. The presence of RRFs and COX deficiencies in muscle biopsies often confirmed the MERRF diagnosis. We conclude that molecular analysis of the tRNA(Lys) gene is an important criterion to help confirm the MERRF diagnosis. Furthermore, based on the findings of this study, we suggest a revision of the main characteristics of this disease. PMID- 21303705 TI - Recommendations for the management of mixed cryoglobulinemia syndrome in hepatitis C virus-infected patients. AB - OBJECTIVE: The objective of this review was to define a core set of recommendations for the treatment of HCV-associated mixed cryoglobulinemia syndrome (MCS) by combining current evidence from clinical trials and expert opinion. METHODS: Expert physicians involved in studying and treating patients with MCS formulated statements after discussing the published data. Their attitudes to treatment approaches (particularly those insufficiently supported by published data) were collected before the consensus conference by means of a questionnaire, and were considered when formulating the statements. RESULTS: An attempt at viral eradication using pegylated interferon plus ribavirin should be considered the first-line therapeutic option in patients with mild-moderate HCV related MCS. Prolonged treatment (up to 72 weeks) may be considered in the case of virological non-responders showing clinical and laboratory improvements. Rituximab (RTX) should be considered in patients with severe vasculitis and/or skin ulcers, peripheral neuropathy or glomerulonephritis. High-dose pulsed glucocorticoid (GC) therapy is useful in severe conditions and, when necessary, can be considered in combination with RTX; on the contrary, the majority of conference participants discouraged the chronic use of low-medium GC doses. Apheresis remains the elective treatment for severe, life-threatening hyper viscosity syndrome; its use should be limited to patients who do not respond to (or who are ineligible for) other treatments, and emergency situations. Cyclophosphamide can be considered in combination with apheresis, but the data supporting its use are scarce. Despite the limited available data, colchicine is used by many of the conference participants, particularly in patients with mild moderate MCS refractory to other therapies. Careful monitoring of the side effects of each drug, and its effects on HCV replication and liver function tests is essential. A low-antigen-content diet can be considered as supportive treatment in all symptomatic MCS patients. Although there are no data from controlled trials, controlling pain should always be attempted by tailoring the treatment to individual patients on the basis of the guidelines used in other vasculitides. CONCLUSION: Although there are few controlled randomised trials of MCS treatment, increasing knowledge of its pathogenesis is opening up new frontiers. The recommendations provided may be useful as provisional guidelines for the management of MCS. PMID- 21303707 TI - Bovine lactoferrin improves bone status of ovariectomized mice via immune function modulation. AB - We have previously shown that bovine lactoferrin (bLF) supplementation can have a beneficial effect on postmenopausal bone loss by modulating bone formation and resorption. A direct effect of bLF on bone metabolism is support by its presence in mice blood. Moreover we know that LF plays a key role in innate immunity and recent studies have shown its ability to modulate adaptive immunity. In particular bLF ingestion prevents recruitment and activation of immune cells at inflammatory sites. We propose that LF through its ability to modulate maturation and differentiation of leucocytes can participate to abolish the deregulation induced by estrogen deficiency on T cells. This study evaluated the effects of bovine lactoferrin on immune function in ovariectomized mice. We investigated whether bLF ingestion could prevent bone loss via modulation of immune function. Three-month-old female C3H mice were either ovariectomized or sham-operated and fed for 1, 2 or 4 months with a control diet (AIN-93M) or the same diet including 10g bLF/kg diet. Bone mineral density was determined using a Lunar Piximus densitometer. The immune parameters were assessed by flow cytometry. In addition, Real-Time PCR was performed to quantify TNFalpha expression and plasma cytokines were measured at 4 months with Luminex. Ovariectomy induced significant changes on bone parameters and increased recruitment of macrophages, dendritic cells, and B and T cells associated with T lymphocyte activation in bone marrow. Compared to the control diet, ingestion of bLF-enriched diet for 2 months prevented T cell activation and restored dendritic and B cell populations in the bone micro environment in ovariectomized mice. Furthermore, TNFalpha expression in bone was decreased by bLF supplementation after 2 and 4 months. Similarly, a decreased plasma level of TNFalpha was observed concomitantly to an increase of IL-10 level. In conclusion, these experiments suggest that bLF can mediate the prevention of lymphocyte activation and cytokine release in the bone micro environment. Dietary bLF supplementation could have a beneficial effect on postmenopausal bone loss by modulating immune function. PMID- 21303706 TI - Protein folding at single-molecule resolution. AB - The protein folding reaction carries great significance for cellular function and hence continues to be the research focus of a large interdisciplinary protein science community. Single-molecule methods are providing new and powerful tools for dissecting the mechanisms of this complex process by virtue of their ability to provide views of protein structure and dynamics without associated ensemble averaging. This review briefly introduces common FRET and force methods, and then explores several areas of protein folding where single-molecule experiments have yielded insights. These include exciting new information about folding landscapes, dynamics, intermediates, unfolded ensembles, intrinsically disordered proteins, assisted folding and biomechanical unfolding. Emerging and future work is expected to include advances in single-molecule techniques aimed at such investigations, and increasing work on more complex systems from both the physics and biology standpoints, including folding and dynamics of systems of interacting proteins and of proteins in cells and organisms. This article is part of a Special Issue entitled: Protein Dynamics: Experimental and Computational Approaches. PMID- 21303708 TI - The virus-induced signaling adaptor molecule enhances DNA-raised immune protection against H5N1 influenza virus infection in mice. AB - As an adaptor molecule in the retinoic acid-inducible gene-I (RIG-I) signaling pathway, the virus-induced signaling adaptor (VISA) molecule activates NF-kappaB and IRF3 and thereby leads to the production of type I interferons (IFNs). To explore the potential of VISA as a genetic adjuvant for DNA vaccines, a eukaryotic expression plasmid, pVISA, was generated by cloning the VISA gene into the pVAX1vector. For comparison, the pTRIF plasmid was similarly constructed, encoding the known genetic adjuvant TRIF (TIR-domain-containing adapter-inducing interferon-beta), an adapter in the Toll-like receptor (TLR) signaling pathway. Mice were immunized with the chimeric DNA vaccine pHA/NP(147-155), which encodes the HA (hemagglutinin) fused with NP (nucleoprotein) CTL epitope (NP(147-155)) of H5N1 influenza virus, either alone or in combination with pVISA or pTRIF. Antigen specific immune responses were examined in immunized mice. Our results demonstrate that co-immunization of the pHA/NP(147-155) plasmid with the VISA adjuvant augmented DNA-raised cellular immune responses and provided protection against H5N1 influenza virus challenge in mice. In addition, our data suggest that VISA acts as a stronger adjuvant for DNA immunization than TRIF. We conclude that co-inoculation with a vector expressing the adaptor molecule VISA enhanced the protective immunity against H5N1 infection induced by pHA/NP(147-155) and that VISA could be developed as a novel genetic adjuvant for DNA vaccines. PMID- 21303709 TI - Immunogenicity and protective efficacy of a psoralen-inactivated dengue-1 virus vaccine candidate in Aotus nancymaae monkeys. AB - Psoralens are photoreactive compounds that cross-link pyrimidines after exposure to UVA radiation. In this experiment, we tested the protective efficacy of a psoralen-inactivated dengue vaccine candidate in non-human primates. Two groups of 7 Aotus nancymaae monkeys received either 10ng per dose of inactivated DENV1 plus alum adjuvant or alum alone (controls). Doses were injected intradermally on days 0, 14, and 28. Monkeys then received a challenge inoculation of 1.1 * 10(4)PFUs of WestPac 74 DENV-1 on day 132. At 62 days, only 1/7 vaccinated monkeys had detectable IgM, but IgG and neutralizing antibody remained detectable in 7/7. No IgM, IgG, or neutralizing antibody was detectable in control monkeys. DENV-1 viremia was detected after challenge in 3/7 vaccinated monkeys and 5/6 control monkeys (with one removed due to pregnancy) (p=0.27), but days of viremia were reduced from 3.67 days/animal among controls to 0.71 days/animal among vaccinated monkeys (p=0.051). Psoralen-inactivated DENV1 is immunogenic in Aotus nancymaae with a trend towards a reduction in days of viremia following experimental challenge. PMID- 21303710 TI - The 1258 G>A polymorphism in the neuropeptide Y gene is associated with greater alcohol consumption in a Mediterranean population. AB - Neuropeptide Y (NPY) is a neurotransmitter widely distributed in the central nervous system. Several studies have demonstrated that increases of NPY are associated with reduced alcohol intake and anxiety manifestations. The Leu7Pro polymorphism in the NPY has been associated with alcohol consumption, but evidence is scarce. In the Spanish Mediterranean population, this variant is not polymorphic. Thus, our aim is to identify novel functional variants in the NPY and to investigate the impact of these markers and others previously described on alcohol consumption in this population. A total of 911 subjects (321 men and 590 women) from the Spanish Mediterranean population were recruited. Alcohol consumption, and demographic and lifestyle variables were measured. Nucleotide sequence determination and SNP analyses were carried out. Only one exonic SNP was detected by direct sequencing (1258 G>A or rs9785023; allele frequency 0.47). From the intronic markers chosen (483 A>G or rs13235938, 2517 A>G or rs4722342, and 7065 A>G or rs4722343), only the two latter ones were polymorphic (allele frequencies 0.46 and 0.04, respectively), and none of them were associated with alcohol consumption. However, the 1258 G>A SNP was associated (recessive pattern) with higher alcohol intake. This association was particularly relevant in men with high alcohol intake (59.1+/-5.0 g/day in AA as opposed to 40.6+/-7.5 in the G carriers, P=.022) and women with moderate alcohol intake (7.3+/-5.5 g/day in AA as opposed to 4.6+/-3.9g/day in G carriers, P=.048). The 1258 G>A polymorphism in the NPY is associated with higher alcohol consumption in the Mediterranean population. PMID- 21303711 TI - I see what you're saying: the integration of complex speech and scenes during language comprehension. AB - The effect of language-driven eye movements in a visual scene with concurrent speech was examined using complex linguistic stimuli and complex scenes. The processing demands were manipulated using speech rate and the temporal distance between mentioned objects. This experiment differs from previous research by using complex photographic scenes, three-sentence utterances and mentioning four target objects. The main finding was that objects that are more slowly mentioned, more evenly placed and isolated in the speech stream are more likely to be fixated after having been mentioned and are fixated faster. Surprisingly, even objects mentioned in the most demanding conditions still show an effect of language-driven eye-movements. This supports research using concurrent speech and visual scenes, and shows that the behavior of matching visual and linguistic information is likely to generalize to language situations of high information load. PMID- 21303712 TI - How long to wait before reducing antipsychotic dosage in stabilized patients with schizophrenia? A retrospective chart review. AB - OBJECTIVE: Antipsychotic dose reduction is generally recommended to occur after six months of clinical stabilization despite inadequate evidence. This timing issue was addressed in this study. METHODS: This is an observational, retrospective and medical chart-based study. Inclusion criteria were (1) diagnosis of schizophrenia (DSM-IV), (2) being acutely psychotic at their first outpatient visit from May, 2002 to April, 2003, (3) having responded to antipsychotics and achieved clinical stabilization of acute symptoms, indexed as a fixation of regimen for four or more weeks, and (4) having one or more years of follow-up. Patients who had their antipsychotic doses reduced were then identified, and they were divided into two groups based on the waiting period before dose reduction: <24 weeks (Early Group) and >=24 weeks (Standard Group). The rate of dose escalation for >=20% during follow-up period was investigated as a proxy of clinical worsening. RESULTS: After excluding stable patients at baseline, 211 patients met inclusion criteria. The mean +/- SD waiting period before reducing antipsychotics was 122 +/- 102 days. The rates of patients needing dose escalation were not significantly different between patients whose dose was reduced (N = 83) and those who was not (N = 128) (57.8% vs. 59.4%), and between Early Group (N = 59) and Standard Group (N = 24) (61.0% vs. 50.0%) although the reduction rate in antipsychotic dosage was significantly greater in Early Group (58.7% vs. 43.3%, p < 0.05). CONCLUSION: These findings may indicate that timeline until antipsychotic reduction in stable patients with schizophrenia could be earlier than recommended, although caution is needed in interpreting our retrospective results. PMID- 21303713 TI - Chromium removal by combining the magnetic properties of iron oxide with adsorption properties of carbon nanotubes. AB - The adsorption features of multiwall carbon nanotubes (MWCNTs) with the magnetic properties of iron oxides have been combined in a composite to produce a magnetic adsorbent. Composites of MWCNT/nano-iron oxide were prepared, and were characterized by X-ray diffraction (XRD), field emission scanning electron microscope (FESEM) and Fourier transform infrared spectroscopy (FTIR). XRD suggests that the magnetic phase formed is maghemite and/or magnetite. FESEM image shows nano-iron oxides attached to a network of MWCNTs. The adsorption capability of the composites was tested in batch and fixed bed modes. The composites have demonstrated a superior adsorption capability to that of activated carbon. The results also show that the adsorptions of Cr(III) on the composites is strongly dependent on contact time, agitation speed and pH, in the batch mode; and on flow rate and the bed thickness in the fixed bed mode. Along with the high surface area of the MWCNTs, the advantage of the magnetic composite is that it can be used as adsorbent for contaminants in water and can be subsequently controlled and removed from the medium by a simple magnetic process. PMID- 21303714 TI - Sub-Saharan centralized biorepository for genetic and genomic research. AB - Quality-assessed biomedical samples are essential for academia- and industry driven research on human diseases. The etiologies and the molecular genetic factors relevant in African diseases, including both infections and complex degenerative diseases as well as cancer, need to be studied using well annotated and well-preserved biosamples acquired from native African ethnic groups and compare the results with non-African populations and/or with Afro-Americans. However, a number of difficulties negatively impact on the possibility to obtain clinically annotated biological samples in most Sub-Saharan African countries. This is mainly due to major organizational problems, lack of clinical centres that can dedicate resources to research, as well as lack of facilities in which biomaterials can be properly processed and safely stored. Harmonization of biosample acquisition, storage phenotyping schemes and biocomputer infrastructures are the principal objectives of biological resource centers (BRCs). BRCs comprise biobanks of different formats (collection of blood, DNA, tissues, etc., annotated with medical, environmental, life-style and follow up data) a fundamental tool for molecular epidemiological studies aiming to increase excellence and efficacy of biomedical results, drug development and public health. BRCs provide large and highly controlled biomolecular resources necessary to meet the "omics" scientific platforms. Sudan may be a candidate nation to host such infrastructure, in view of its strategic geographical position and the already existing simple biobanking experiences connected with research groups in Central Sudan. Here, we describe the potential role of biobanks in African genetic studies aiming to dissect the eziopathogenesis of complex diseases in relation to environmental and life-style factors. PMID- 21303715 TI - Copper addition by organic matter degradation in the freshwater reaches of a turbid estuary. AB - This study reports on the relationship between copper (Cu) behavior and organic matter (OM) transformation along the turbidity gradient in the freshwater reaches of the Gironde Estuary. During a one-year survey, surface water and suspended particulate matter (SPM) were sampled at least monthly at three sites along the Garonne Branch, representing the main fluvial branch of the Gironde Estuary. Additionally, a longitudinal high resolution profile was sampled along the Garonne Branch, covering the turbidity gradient from the river water endmember to the maximum turbidity zone (MTZ). Seasonal variability and spatial distribution of Cu in both the dissolved phases (<0.2 MUm, Cu(0.2) and <0.02 MUm, Cu(0.02)) and particulate Cu (Cu(P)) clearly suggested Cu(0.2) addition during summer, that increased the Cu(0.2) concentrations by a factor ~2, mainly manifested by an increase in the Cu(0.02) fraction. At the annual timescale (2004), this internal Cu reactivity increased Cu(0.02) fluxes in the Garonne Branch by ~20% (3.6 t year(-1)), with the equivalent of ~2.9 t year(-1) derived from the Cu(P) fraction and ~0.7 t year(-1) from the colloidal (0.02-0.2 MUm) fraction, without involving and/or affecting the Cu(C18) (hydrophobic metal-organic complexes) fraction. Combining data on Cu speciation with the results obtained by several independent techniques (DOC and POC measurements, 3D-fluorescence, and TEM) suggested close relationships between Cu behavior and OM transformation/restructuration along the turbidity gradient in the Garonne Branch. The observed Cu(0.02) addition was related to increasing humification (humification index HIX increased from 9 to 12, network formation) and labile OM degradation (Igamma/Ialpha ratio decreased from 0.70 to 0.44), going along with decreasing DOC and POC concentrations. Mass balances suggest that in the studied system, degradation of OM may account for the release of ~25 MUmol potentially bioaccessible Cu(0.02) per mole of particulate organic carbon mineralized. PMID- 21303716 TI - Understanding suicide among sexual minority youth in America: an ecological systems analysis. AB - This article examines major risk factors for suicide among sexual minority youth using Bronfenbrenner's ecological systems theory. Although suicidal behavior among sexual minority youth is a major public concern in the United States, understanding of this phenomenon has been limited since the majority of empirical research studies have addressed individual level characteristics without much consideration to the larger environmental contexts. This review integrates past and current empirical findings on suicidal behaviors of sexual minority youth within the context of micro-, meso-, exo-, macro-, and chrono-systems levels. Finally, it draws implications for assessment, prevention, and intervention strategies. PMID- 21303717 TI - Photosensitizer-conjugated magnetic nanoparticles for in vivo simultaneous magnetofluorescent imaging and targeting therapy. AB - A major challenge in nanotechnology and nanomedicine is to integrate tumor targeting, imaging, and selective therapy functions into a small single nanoparticle (<50 nm). Herein, photosensitizer-conjugated magnetic nanoparticles with ~20 nm in diameter were strategically designed and prepared for gastric cancer imaging and therapy. The second generation photosensitizer chlorin e6 (Ce6) was covalently anchored on the surface of magnetic nanoparticles with silane coupling agent. We found that the covalently incorporated Ce6 molecules retained their spectroscopic and functional properties for near-infrared (NIR) fluorescence imaging and photodynamic therapy (PDT), and the core magnetic nanoparticles offered the functions of magnetically guided drug delivery and magnetic resonance imaging (MRI). The as-prepared single particle platform is suitable for simultaneous targeting PDT and in vivo dual-mode NIR fluorescence imaging and MRI of nude mice loaded with gastric cancer or other tumors. PMID- 21303718 TI - Mechanical properties and in vivo behavior of a biodegradable synthetic polymer microfiber-extracellular matrix hydrogel biohybrid scaffold. AB - A biohybrid composite consisting of extracellular matrix (ECM) gel from porcine dermal tissue and biodegradable elastomeric fibers was generated and evaluated for soft tissue applications. ECM gel possesses attractive biocompatibility and bioactivity with weak mechanical properties and rapid degradation, while electrospun biodegradable poly(ester urethane)urea (PEUU) has good mechanical properties but limited cellular infiltration and tissue integration. A concurrent gel electrospray/polymer electrospinning method was employed to create ECM gel/PEUU fiber composites with attractive mechanical properties, including high flexibility and strength. Electron microscopy revealed a structure of interconnected fibrous layers embedded in ECM gel. Tensile mechanical properties could be tuned by altering the PEUU/ECM weight ratio. Scaffold tensile strengths for PEUU/ECM ratios of 67/33, 72/28 and 80/20 ranged from 80 to 187 kPa in the longitudinal axis (parallel to the collecting mandrel axis) and 41-91 kPa in the circumferential axis with 645-938% breaking strains. The 72/28 biohybrid composite and a control scaffold generated from electrospun PEUU alone were implanted into Lewis rats, replacing a full-thickness abdominal wall defect. At 4 wk, no infection or herniation was found at the implant site. Histological staining showed extensive cellular infiltration into the biohybrid scaffold with the newly developed tissue well integrated with the native periphery, while minimal cellular ingress into the electrospun PEUU scaffold was observed. Mechanical testing of explanted constructs showed evidence of substantial remodeling, with composite scaffolds adopting properties more comparable to the native abdominal wall. The described elastic biohybrid material imparts features of ECM gel bioactivity with PEUU strength and handling to provide a promising composite biomaterial for soft tissue repair and replacement. PMID- 21303719 TI - The effect of acetylcholine-like biomimetic polymers on neuronal growth. AB - Driven by clinical needs, nerve regeneration studies have recently become the focus of research and area of growth in tissue engineering. Biomimetic polymer synthesis and functional interface construction is a promising solution to induce neuritic sprouting and guide the regenerating nerve. However, few studies have been made on primary hippocampal neurons. In this study, a new type of acetylcholine-like biomimetic polymers for their potential in biomaterial modulated nerve regeneration application is synthesized using click chemistry and free radical polymerization. The structure of the synthesized polymers includes a "bioactive" unit (acetylcholine-like unit) and a "bioinert" unit [poly(ethylene glycol) unit]. To explore the effects of the bioactive unit and the bioinert unit on neuronal growth, different ratios of the two initial monomers poly(ethylene glycol) monomethyl ether-glycidyl methacrylate (MePEG-GMA) and dimethylaminoethyl methacrylate (DMAEMA) were employed and five different polymers were synthesized. Their chemical structures were characterized using (1)H nuclear magnetic resonance and Fourier-transform infrared spectroscopy, and their physical properties (including molecular weight, polydispersity, glass transition temperature, and melting point) were determined using gel permeation chromatography and differential scanning calorimetry. Culturing of the primary rat hippocampal neurons on the polymeric surfaces show that the ratio of the two initial monomers utilized for polymer synthesis significantly affects neuronal growth. Rat hippocampal neurons show different growth morphologies on different polymeric surfaces. The polymeric surface prepared with 1:60 (mol/mol) of MePEG GMA to DMAEMA induces neuronal regenerative responses similar to that on poly-l lysine, a very common benchmark material for nerve cell cultures. These results suggest that acetylcholine-like biomimetic polymers are potential biomaterials for neural engineering applications, particularly in modulating the growth of hippocampal neurons. PMID- 21303720 TI - Failure of Abeta(1-40) amyloid fibrils under tensile loading. AB - Amyloid fibrils and plaques are detected in the brain tissue of patients affected by Alzheimer's disease, but have also been found as part of normal physiological processes such as bacterial adhesion. Due to their highly organized structures, amyloid proteins have also been used for the development of nanomaterials, for a variety of applications including biomaterials for tissue engineering, nanolectronics, or optical devices. Past research on amyloid fibrils resulted in advances in identifying their mechanical properties, revealing a remarkable stiffness. However, the failure mechanism under tensile loading has not been elucidated yet, despite its importance for the understanding of key mechanical properties of amyloid fibrils and plaques as well as the growth and aggregation of amyloids into long fibers and plaques. Here we report a molecular level analysis of failure of amyloids under uniaxial tensile loading. Our molecular modeling results demonstrate that amyloid fibrils are extremely stiff with a Young's modulus in the range of 18-30 GPa, in good agreement with previous experimental and computational findings. The most important contribution of our study is our finding that amyloid fibrils fail at relatively small strains of 2.5%-4%, and at stress levels in the range of 1.02 to 0.64 GPa, in good agreement with experimental findings. Notably, we find that the strength properties of amyloid fibrils are extremely length dependent, and that longer amyloid fibrils show drastically smaller failure strains and failure stresses. As a result, longer fibrils in excess of hundreds of nanometers to micrometers have a greatly enhanced propensity towards spontaneous fragmentation and failure. We use a combination of simulation results and simple theoretical models to define critical fibril lengths where distinct failure mechanisms dominate. PMID- 21303721 TI - Review: Leptin gene expression in the placenta--regulation of a key hormone in trophoblast proliferation and survival. AB - Leptin is a 16000 MW protein originally described as an adipocyte-derived signaling molecule for the central control of metabolism. However, pleiotropic effects of leptin have been identified in reproduction and pregnancy. The leptin gene is expressed in placenta, where leptin promotes proliferation and survival of trophoblast cells. Study of the major signaling pathways known to be triggered by leptin receptor has revealed that leptin stimulates JAK/STAT, MAPK and PI3K pathways in placental cells. Leptin also exerts an antiapoptotic action in placenta and this effect is mediated by the MAPK pathway. Moreover, leptin stimulates protein synthesis by activating the translational machinery via both PI3K and MAPK pathways. Expression of leptin in placenta is highly regulated, suggesting that certain key pregnancy molecules participate in such regulation. An important hormone in reproduction, hCG, induces leptin expression in trophoblast cells and this effect involves the MAPK signal transduction pathway. Moreover, the cyclic nucleotide cAMP, which has profound actions upon human trophoblast function, also stimulates leptin expression and this effect seems to be mediated by crosstalk between the PKA and MAPK signaling pathways. Estrogens play a central role in reproduction. 17beta-estradiol upregulates leptin expression in placental cells through genomic and non-genomic actions, probably via crosstalk between estrogen receptor-alpha and the MAPK and PI3K signal transduction pathways. Taken together these findings give a better understanding of the function of leptin and the regulatory mechanisms of leptin expression in human placental trophoblast and further support the importance of leptin in the biology of reproduction. PMID- 21303722 TI - Differential appearance of placentomes and expression of prostaglandin H synthase type 2 in placentome subtypes after betamethasone treatment of sheep late in gestation. AB - Inappropriate fetal exposure to maternal glucocorticoid (GC) has been proposed as a mechanism for fetal programming where the effects of GC may be mediated by the placenta. However, the consequences of maternal GC on placental morphology and enzyme expression are unclear. OBJECTIVES: We used betamethasone (BET) to determine effects on placentome subtype distribution and expression of prostaglandin H synthase type 2 (PGHS-2) enzyme. METHODS: Pregnant sheep carrying male fetuses were randomized to receive injections of saline (n = 30) or one (104 days of gestation, (dG); n = 6), two (104, 111 dG; n = 6) or three (104, 111, 118 dG; n = 11) doses of BET (0.5 mg/kg). Placental tissue was collected prior to (75, 84, 101 dG), during (109, 116 dG) and after BET (122, 132, 146 dG). RESULTS: Total number of placentomes was not different between gestational ages. A- and B subtypes were most affected by prenatal BET exposure; numbers of A-subtypes were increased and numbers of B-subtypes were decreased compared to controls at 116 dG. At term numbers of A-subtypes were lower after BET, but the weight range distribution was similar to controls. In controls, placental PGHS-2 protein levels increased with gestational age and PGHS-2 localized primarily to uninuclear trophoblast cells. After BET, PGHS-2 protein in C-subtypes at term was significantly increased compared to A-subtypes. CONCLUSIONS: Maternal BET treatment in late gestation affects the proportions of placentome subtypes and their differential expression of PGHS-2. Our data do not support previous hypotheses that A-subtypes develop into B-, C- and D-subtypes over the course of gestation. PMID- 21303723 TI - AFLP variability, toxin production, and pathogenicity of Alternaria species from Argentinean tomato fruits and puree. AB - Large amounts of tomato fruits and derived products are produced in Argentina and may be contaminated by Alternaria toxins. Limited information is available on the genetic variability, toxigenicity, and pathogenicity of Alternaria strains occurring on tomato. We analyzed 65 Alternaria strains isolated in Argentina from tomato fruits affected by black mould and from tomato puree, using amplified fragment length polymorphisms (AFLPs) technique. AFLP analysis resolved the set of strains in 3 main clusters (DICE similarity values of 58 and 60%) corresponding to A. alternata/tenuissima (44 strains), A. arborescens (15 strains) and to an unknown group (6 strains). Most of the representative strains, belonging to each AFLP cluster, when cultured on rice, produced tenuazonic acid (up to 46,760 mg/kg), alternariol monomethyl ether (AME, up to 1860 mg/kg), and alternariol (up to 70 mg/kg). The toxin profile related to the strains was not related to any AFLP cluster, except for AME which was produced at lower level by A. arborescens. Most of strains were pathogenic on two types of commonly cultivated tomato fruits. These findings provide new information on the variability within the Alternaria species complex associated with tomato disease. PMID- 21303724 TI - Synthesis and anticonvulsant activity of 8-alkoxy-5,6-dihydro-4H [1,2,4]triazolo[4,3-a][1]benzazepin-1-one derivatives. AB - A series of novel 8-alkoxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1 one derivatives were synthesized and screened for their anticonvulsant activities by the maximal electroshock (MES) test, subcutaneous pentylenetetrazol (scPTZ) test, and their neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). The results of these tests demonstrated that 8-heptyloxy-5,6-dihydro-4H [1,2,4]triazolo[4,3-a][1]benzazepin-1-one (3f) and 8-hexyloxy -5,6-dihydro-4H [1,2,4]triazolo[4,3-a][1]benzazepin-1-one (3e) were the most promising compounds, with median effective dose (ED(50)) of 17.6 and 17.9 mg/kg, and protective index (PI) of greater than 63.4 and 62.4 in the MES test, respectively. These PI values were higher than the PI value of the prototype antiepileptic drug carbamazepine. The scPTZ test showed that 8-pentyloxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3 a][1]benzazepin-1-one (3d) was the most potent with ED(50) value of 38.0 mg/kg and PI value of greater than 29.4, which is much safer than marketed drug carbamazepine. The possible structure-activity relationship was discussed. PMID- 21303725 TI - A review of the factors influencing the development of intermuscular adipose tissue in the growing pig. AB - Compared with subcutaneous or abdominal fat depots of pig carcasses, intermuscular fat displays a number of original properties. It cannot be easily removed from fresh or processed meat delivered to consumers and has therefore an influence on consumer acceptability of pork. Particular compositional characteristics of intermuscular fat include low lipid content and small size of adipocytes. How age (or body weight), gender, castration, environmental temperature, feeding restriction, diet composition, as well as genetic factors affect intermuscular fat development and composition are surveyed in this review paper. Up to now, few studies have specifically dealt with the intermuscular compartment of body fat while very abundant information is available on the subcutaneous one. As a general rule, any factor, either genetic or non-genetic, which causes a decrease of whole carcass fat deposition generates a higher relative importance of the intermuscular fraction of total fat as well as an increased degree of unsaturation of constituent fatty acids. PMID- 21303726 TI - Determining the impact of varying levels of cherry powder and starter culture on quality and sensory attributes of indirectly cured, emulsified cooked sausages. AB - Indirect curing is a process that utilizes ingredients high in naturally occurring nitrate and a nitrate reducing bacterial starter culture (SC) to provide quality and sensory attributes similar to nitrite-added cured meats. The objective of this study was to determine the effects varying concentrations of starter culture and the addition of cherry powder (CP) had on improving quality and sensory attributes of indirectly cured sausages. Four treatments (TRTs) (TRT 1: low SC+no CP; TRT 2: low SC+CP; TRT 3: high SC+no CP; and TRT 4: high SC+CP) and a sodium nitrite-added (156 ppm) control were investigated. Residual nitrite levels throughout storage declined most rapidly in TRTs 2 and 4 (P<0.05). Few differences existed between TRTs and C for pH, objective color, or cured pigment concentrations. Consumer sensory panel scores revealed all treatment combinations were comparable (P>0.05) to the C for all sensory attributes. PMID- 21303727 TI - Efficacy and safety of antifungals in pediatric patients. AB - Invasive fungal infections (IFIs) constitute an important cause for morbidity and mortality in immunocompromised pediatric patients [1]. Despite substantial achievements, the prevention and treatment of IFIs are still limited by the facts that not all antifungal agents are approved in the pediatric population, the appropriate dosage of these drugs has not been established for all age groups, and postmarketing data providing information on the safety and efficacy of approved agents under real-life circumstances are scant. In this article, we 1) briefly review the principles of drug development, 2) discuss safety and approved indications of antifungal agents, and 3) provide a summary of current options for treatment of invasive fungal infections in pediatric patient populations. PMID- 21303728 TI - Medical and nursing care in post-operative period to the newborn with surgical problems and intestinal ostomy. PMID- 21303729 TI - Erythropoietin and retinopathy of prematurity. AB - Erythropoietin (EPO) is a glycoprotein that regulates many functions of an organism: It stimulates the production of red blood cells and it has angiogenic and neuroprotective properties in newborn infants. Retinopathy of prematurity (ROP) is a frequent cause of visual impairment in preterm newborn infants and it has two distinct phases in which hypoxia-induced angiogenic factors are involved. The relationship between EPO and ROP is derived from the observation of studies done on the haematopoietic effect of EPO. The first observations suggested that a precocious treatment with EPO increases the risk of ROP, while the most recent reports suggested that the late treatment with high doses of rhEPO can increase the risk of ROP. All these studies were not designed to demonstrate the relationship between EPO and ROP. Further studies specifically designed should be performed. New ongoing studies on the neuroprotective role of EPO should consider this objective. In the mean time the use of EPO in the neonatal period should be cautious, mainly in very low birth weight infants. PMID- 21303730 TI - Cross-sectional prevalence of metabolic syndrome in Korean patients with schizophrenia. PMID- 21303732 TI - Are stimulants effective in the treatment of executive function deficits? Results from a randomized double blind study of OROS-methylphenidate in adults with ADHD. AB - The objective of this study was to evaluate the association between executive function deficits (EFDs) and response to methylphenidate treatment in ADHD in adults. We conducted a 6-week, parallel design, randomized, placebo controlled study in adults with DSM-IV ADHD. Our psychometric index of executive function used standardized neuropsychological testing. We assessed behaviors reflective of EFDs using the Behavior Rating Inventory of Executive Function--Adult Version (BRIEF-A). Subjects with available measures of executive functioning (OROS-MPH N=40; Placebo N=47) were included for analysis. There was no difference in the percent of subjects completing the 6-week acute efficacy Phase I of the trial (100% (N=40) vs. 98% (N=46), p=0.4). The mean daily dose at Phase I endpoint was 84.6+/-31.6 mg (1.04+/-0.29 mg/kg) OROS-MPH and 100.5+/-21.9 mg (1.20+/-0.11 mg/kg) placebo (p=0.0007). Based on the neuropsychological testing at the baseline assessment, 40% of the ADHD subjects (N=35/87) were considered to have EFDs but 93% (N=81) of subjects had >= 2 BRIEF-A clinical scale T-scores > 65. Regardless of the definition used, however, EFDs did not impact the clinical response to OROS-MPH. This randomized clinical trial showed that executive function deficits do not moderate the response to methylphenidate and measures of executive function deficits are not associated with response to OROS-MPH. PMID- 21303731 TI - Deficits in GABA(B) receptor system in schizophrenia and mood disorders: a postmortem study. AB - Postmortem and genetic studies have clearly demonstrated changes in GABA(B) receptors in neuropsychiatric disorders such as autism, bipolar disorder, major depression, and schizophrenia. Moreover, a number of recent studies have stressed the importance of cerebellar dysfunction in these same disorders. In the current study, we examined protein levels of the two GABA(B) receptor subunits GABBR1 and GABBR2 in lateral cerebella from a well-characterized cohort of subjects with schizophrenia (n=15), bipolar disorder (n=14), major depression (n=13) and healthy controls (n=12). We found significant reductions in protein for both GABBR1 and GABBR2 in lateral cerebella from subjects with schizophrenia, bipolar disorder and major depression when compared with controls. These results provide further evidence of GABAergic dysfunction in these three disorders as well as identify potential targets for therapeutic intervention. PMID- 21303733 TI - Attenuated store-operated divalent cation entry and association between STIM1, Orai1, hTRPC1 and hTRPC6 in platelets from type 2 diabetic patients. AB - Agonist-evoked Ca(2+) entry has been reported to be enhanced in platelets from type 2 diabetic patients, which results in altered platelet responsiveness and cardiovascular complications. The present study is aimed to investigate whether store-operated divalent cation entry, a major Ca(2+) entry pathway, is altered in platelets from diabetic patients. Store-operated divalent cation entry was estimated by determination of Mn(2+) entry. Association between STIM1, Orai1, hTRPC1 and hTRPC6 was detected by co-immunoprecipitation and Western blotting. In the presence of specific purinergic and serotoninergic receptor antagonists Mn(2+) entry, induced by thapsigargin (TG), was reduced in platelets from diabetic donors as compared to healthy controls. Treatment with TG or the agonist thrombin enhanced co-immunoprecipitation of STIM1 with Orai1, hTRPC1 and hTRPC6 in platelets from healthy donors, a response that was significantly reduced in platelets from diabetic patients. Our results indicate that store-operated divalent cation entry is reduced in platelets from type 2 diabetic subjects, which is likely mediated by impairment of the association of STIM1 with the channel subunits Orai1, hTRPC1 and hTRPC6 and might be involved in the pathogenesis of the altered platelet responsiveness observed in diabetic patients. PMID- 21303734 TI - Novel splice site mutations and a large deletion in three patients with the cblF inborn error of vitamin B12 metabolism. AB - The cblF disorder, characterized by accumulation of internalized cobalamin in the lysosome, is caused by mutations in the LMBRD1 gene which encodes an integral lysosomal membrane protein. We describe novel mutations in LMBRD1 in three patients: two splice site mutations, c.916-1G>T and c.1339-1G>T, and a 6785 bp deletion encompassing exon 2, c.70-4298_246+2311del6785. The three patients are compound heterozygotes for one novel mutation and the common c.1056delG mutation. PMID- 21303735 TI - Association study of MC4R with complex obesity and replication of the rs17782313 association signal. AB - Recently, genome-wide association studies have discovered several single nucleotide polymorphisms (SNPs) involved in the etiology of complex obesity. A variant downstream from the melanocortin-4 receptor gene (MC4R), a gene known to be involved in monogenic obesity, was reported to be highly associated with BMI. In the present study, we performed a replication study with the previously reported SNP rs17782313. We also included 3 tagSNPs (rs8087522, rs11872992, and rs1943226) for the MC4R gene region in our study to understand the role of this gene in complex obesity. We genotyped all 4 SNPs in a population of 1049 obese cases (mean BMI=38.2+/-6.2) and 312 healthy lean individuals (mean BMI 22.0+/ 1.7). We could confirm that rs17782313 is highly associated with complex obesity in our population (odds ratio=1.42, 95% CI 1.14-1.77, P=0.002). Furthermore, we found this SNP to be associated with BMI (B=0.92, 95% CI 0.19-1.65, P=0.01) and body weight (B=2.44, 95% CI 0.28-4.60, P=0.03). In addition, we could also detect an association between rs11872992 and complex obesity (odds ratio=0.74, 95% CI 0.57-0.98, P=0.03). Through conditional analysis, we demonstrate that this effect is independent from the rs17782313 association signal. No associations with obesity could be found for rs8087522 and rs1943226. In conclusion, we could replicate the previously reported association between rs17782313 and complex obesity. Furthermore, our data do not support the hypothesis that a SNP in MC4R causes the rs17782313 association signal. PMID- 21303737 TI - Disorders of sex development. AB - Infants born with ambiguous genitalia represent a complex clinical challenge. A systematic clinical investigation aims at determining the hormone production and which anatomical structures are present in order to understand at what level the sex differentiation has been affected; chromosomal, gonadal or hormonal synthesis and action levels. The increased genetic knowledge in the field has opened up new diagnostic possibilities. Sex development requires the balanced and sequential activation of transcription factors, signaling molecules and hormones. It has recently been shown that not only testis but also normal ovarian development is an active process. Genes involved in gonadal disorders of sex development often act in a gene dosage-dependent manner, with different effects in XY or XX embryos. The management of patients with disorders of sex development, including decisions about sex of rearing, must be carried out by a specialized multidisciplinary team and include an extended genetic investigation as well as psychological considerations. PMID- 21303738 TI - Cardiac leiomyoma associated with advanced atrioventricular block in a young dog. AB - A 1 year old intact female Labrador retriever dog presented for evaluation of syncope caused by severe bradycardia. Advanced atrioventricular block was diagnosed. A mass infiltrating the interventricular septum and the tricuspid annulus was identified with echocardiography. Histopathological evaluation of the mass was consistent with cardiac leiomyoma, and immunohistochemical staining for smooth muscle actin confirmed the diagnosis. To the authors' knowledge, this is the first report of cardiac leiomyoma in the canine species. PMID- 21303739 TI - Subnanosecond electric pulses cause membrane permeabilization and cell death. AB - Subnanosecond electric pulses (200 ps) at electric field intensities on the order of 20 kV/cm cause the death of B16.F10 murine melanoma cells when applied for minutes with a pulse repetition rate of 10 kHz. The lethal effect of the ultrashort pulses is found to be caused by a combination of thermal effects and electrical effects. Studies on the cellular level show increased transport across the membrane at much lower exposure times or number of pulses. Exposed to 2000 pulses, NG108 cells exhibit an increase in membrane conductance, but only allow transmembrane currents to flow, if the medium is positively biased with respect to the cell interior. This means that the cell membrane behaves like a rectifying diode. This increase in membrane conductance is a nonthermal process, since the temperature rise due to the pulsing is negligible. PMID- 21303740 TI - Efficient computational methods for strongly coupled cardiac electromechanics. AB - Strongly coupled cardiac electromechanical models can further our understanding of the relative importance of feedback mechanisms in the heart, but computational challenges currently remain a major obstacle, which limit their widespread use. To address this issue, we present a set of efficient computational methods including an efficient adaptive cell model integration scheme and a solution method for the monodomain equations that maintains high conduction velocity for time steps greater than 0.1 ms. We also present a novel method for increasing the efficiency of simulating electromechanical coupling, which shows a significant reduction in computational cost of the mechanical component on a personalized left ventricular geometry with an active contraction cell model reparametrized for human cells. PMID- 21303741 TI - A probabilistic model for automatic segmentation of the esophagus in 3-D CT scans. AB - Being able to segment the esophagus without user interaction from 3-D CT data is of high value to radiologists during oncological examinations of the mediastinum. The segmentation can serve as a guideline and prevent confusion with pathological tissue. However, limited contrast to surrounding structures and versatile shape and appearance make segmentation a challenging problem. This paper presents a multistep method. First, a detector that is trained to learn a discriminative model of the appearance is combined with an explicit model of the distribution of respiratory and esophageal air. In the next step, prior shape knowledge is incorporated using a Markov chain model. We follow a "detect and connect" approach to obtain the maximum a posteriori estimate of the approximate esophagus shape from hypothesis about the esophagus contour in axial image slices. Finally, the surface of this approximation is nonrigidly deformed to better fit the boundary of the organ. The method is compared to an alternative approach that uses a particle filter instead of a Markov chain to infer the approximate esophagus shape, to the performance of a human observer and also to state of the art methods, which are all semiautomatic. Cross-validation on 144 CT scans showed that the Markov chain based approach clearly outperforms the particle filter. It segments the esophagus with a mean error of 1.80 mm in less than 16 s on a standard PC. This is only 1 mm above the interobserver variability and can compete with the results of previously published semiautomatic methods. PMID- 21303742 TI - Multiscale Adaptive Search. AB - We present a continuous-space multiscale adaptive search (MAS) algorithm for single or multiple searchers that finds a stationary target in the presence of uncertainty in sensor diameter. The considered uncertainty simulates the influence of the changing environment and terrain as well as adversarial actions that can occur in practical applications. When available, information about the foliage areas and a priori distribution of the target position is included in the MAS algorithm. By adapting to various uncertainties, MAS algorithm reduces the median search time to find the target with a probability of detection of at least PD and a probability of false alarm of at most PFA. We prove that MAS algorithm discovers the target with the desired performance bounds PD and PFA. The unique features of the MAS algorithm are realistic second-order dynamics of the mobile sensors that guarantees uniform coverage of the surveyed area and a two-step Neyman-Pearson-based decision-making process. Computer simulations show that MAS algorithm performs significantly better than lawnmower-type search and billiard type random search. Our tests suggest that the median search time in the MAS algorithm may be inversely proportional to the number of participating searchers. As opposed to lawnmower search, the median search time in the MAS algorithm depends only logarithmically on the magnitude of uncertainty. PMID- 21303743 TI - Microbiological evaluation of commercial probiotic products available in the USA in 2009. AB - Probiotics are widely used to prevent and treat several diseases. Many commercial products are available worldwide. However, there is no clear international or local legislation about them and previous studies showed that most of the tested products are not in conformity with international guidelines. The aim of this study was to determine if products available in the USA market in 2009 were correctly labeled in terms of quantity of viable bacteria, identification of species and cross contamination by species not on the label. Disturbingly, we found that only 4 of 13 products (31%) were in accordance with label claims. Our results suggest the need for adequate control of probiotic production as well as periodical screenings by competent organizations to monitor the effect of storage on product quality. PMID- 21303744 TI - Antimicrobial activity of tobramycin against respiratory cystic fibrosis Pseudomonas aeruginosa isolates from Bulgaria. AB - Tobramycin solution for inhalation (TSI) (Novartis pharmaceuticals) is indicated as chronic suppressive treatment for cystic fibrosis (CF) patients aged 6 years and older who are chronically infected by Pseudomonas aeruginosa . Inhaled administration of tobramycin assures high concentrations in the lungs of CF patients, improving the therapeutic ratio over that of parenteral tobramycin levels. Clinical and laboratory Standards institute (CLSI) breakpoints only consider parenteral levels and do not take into account these high antimicrobial concentrations. Therefore, the Spanish meNSURA Group has defined specific values for inhaled tobramycin when testing CF P. aeruginosa isolates (susceptible: minimal inhibitory concentration (MIC) <= 64 MUg/ml; resistant: >= 128 MUg/ml). In this study the antimicrobial activity of tobramycin against 120 respiratory CF P. aeruginosa isolates was determined by high-range etest strips (LIOFILCHEM). Applying MENSURA breakpoints, 95% of the strains were categorized as susceptible. With CLSI breakpoints, the susceptibility rate decreased to 92.5%. The activity against non-mucoid P. aeruginosa was higher than that against mucoid isolates (MIC(50)=0.75 and MIC(90)=2 MUg/ml vs. MIC(50)=1 and MIC(90)=4 MUg/ml). The isolates obtained from patients untreated with TSI were more susceptible to the drug than those from patients receiving maintenance therapy with TSI (MIC(50)=0.75 and MIC(90) =1.5 MUg/ml vs. MIC(50)=1.5 and MIC(90)=6 MUg/ml). The isolates from patients with long-term P. aeruginosa colonization (over 5 years) revealed the highest tobramycin MICs (MIC(50)=1.00 and MIC(90)>1024 MUg/ml). In conclusion, tobramycin has excellent in vitro activity against the studied CF isolates. Some factors such as isolate morphotype, pre-administration of TSI and duration of colonization influence its activity. Whenever TSI is considered for therapy, the CF P. aeruginosa strains categorized as intermediate or resistant to tobramycin according to the CLSI criteria should be recategorized by using the MENSURA interpretive criteria. PMID- 21303745 TI - Safety and efficacy of intravenous doripenem for the treatment of complicated urinary tract infections and pyelonephritis. AB - Doripenem was evaluated in adults with complicated urinary tract infections and pyelonephritis in two phase 3 studies. DORI-05, a randomized, double-blind study compared doripenem 500 mg every 8 hours with levofloxacin 250 mg every 24 hours. DORI-06 was a single-arm study designed to confirm the doripenem response in DORI 05. 799 received doripenem, 372 levofloxacin. Microbiological eradication rates in microbiologically evaluable populations were 82.8% for doripenem, 83.4% for levofloxacin (Delta: -0.6%; 95% confidence interval: -6.4, 5.2), and 80.9% and 78.2%, respectively (Delta: 2.7%; 95% confidence interval: -3.0, 8.3) in the co primary microbiologically modified intent-to-treat populations. Clinical cure rates in the clinically evaluable populations were 94.1% for doripenem, 90.2% for levofloxacin (Delta: 3.9%; 95% confidence interval: -0.5, 8.2). In subjects infected with levofloxacin- resistant Escherichia coli, outcomes were statistically significantly greater with doripenem. Genotyping data indicate persistent E. coli infections were often due to infection with new strains. Doripenem was generally found to be safe and well tolerated.ClinicalTrials.gov registration numbers: DORI-05 = NCT00229021, DORI-06 = NCT00210990. PMID- 21303746 TI - High frequency of Chlamydophila pneumoniae infections: patients with peripheral arterial disease and those with risk factors for cardiovascular diseases compared to normal subjects. AB - The role of bacterial infections, mainly Chlamydophila pneumoniae, on atherosclerotic processes as well as the therapeutic utility of additional antibiotic treatment is still an open question. In this study we compared the serological profiles of 160 patients (80 with peripheral arterial disease (PAD), diagnosed with an ankle/brachial index (ABI) <= 0.9 and 80 with risk factors for cardiovascular disease - CVD) with those of 80 healthy subjects, serum levels of specific C. pneumoniae antibodies using the microimmunofluorescence test. Our results show that PAD patients had a higher frequency of C. pneumoniae infection than those with risk factors for cardiovascular disease. This frequency was lower if compared to the previous two groups in controls. 44 out of the 80 (55%) patients with PAD and 34 out of the 80 (42.58%) subjects with risk factors for cardiovascular disease were seropositive while only 24 of the 80 (30%) healthy subjects showed seropositivity to C. pneumoniae. Furthermore, higher anticorpal titers were also found in patients with peripheral arterial disease and in patients with cardiovascular risk factors if compared to healthy subjects. On the basis of these results, we confirm that C. pneumoniae infection is frequent in peripheral arterial disease patients and we believe that it could be considered as an additional risk factor involved in the pathogenesis of this disease. PMID- 21303747 TI - Clinical experience of anidulafungin for the treatment of patients with documented candidemia. AB - Candida species are the most common causes of invasive fungal infections in humans, producing infections that range from mucocutaneous disorders to invasive disease that can involve any organ. Here we present our clinical experience with anidulafungin for the treatment of documented nosocomial candidaemia. From february 2009 through January 2010 all patients with documented candidemia treated with anidulafungin in three medical centers in italy were reviewed. Demographics, clinical and microbiological data, and outcome were collected for each patient. Twenty-four patients were included in the study. most patients had a central venous catheter (CVC) or a port-a-cath (100%), had a history of recent surgery (87.5%), or were receiving total parenteral nutrition (79%), broad spectrum antibiotics (83%), steroids or chemotherapy (45.8%). C. albicans (54%) was the most commonly isolated pathogen. CVC was the source of candidemia in 79% of cases. Six patients (25%) developed severe sepsis or septic shock, and five patients had unfavorable outcomes, with an overall mortality rate of 20%. No patients experienced side effects related to anidulafungin therapy. Anidulafungin was effective in the treatment of patients with documented candidemia arising from different sites, and no significant side effects were observed. PMID- 21303748 TI - Overexpression of vascular endothelial growth factor 165 (VEGF165) protects cardiomyocytes against doxorubicin-induced apoptosis. AB - Doxorubicin (Dox) has been employed in cancer chemotherapy for a few decades. However its clinical application became restricted because of dose-dependent cardiomyopathy. Recent studies suggest that Dox-induced cardiomyocyte apoptosis is a primary cause of cardiac damage. Vascular endothelial growth factor (VEGF) is a major factor for endothelial cell survival and angiogenesis. We have previously shown that VEGF165 significantly attenuates oxidative stress-induced cardiomyocytes apoptosis. We hypothesized that VEGF165 will protect the cardiomyocytes from Dox-induced apoptosis. to evaluate our hypothesis, we transfected cardiomyocytes H9c2 with adenovirus expressing VEGF165 24 hours before the cells were challenged with Dox at a concentration of 2 um. Cardiomyocyte apoptosis was evaluated by Annexin V-FITC staining and by Western blot detection of cleaved caspase-3. The hypothesis was confirmed, and the protective mechanisms involve the inhibition of death receptor-mediated apoptosis and up-regulation of the prosurvival Akt/Nf-kappab/bcl-2 signaling pathway. PMID- 21303749 TI - Enhanced cancer therapy with the combination of EGFR and VEGFR-2 targeting in an orthotopic glioblastoma model. AB - Using an orthotopic glioblastoma model, we investigated the activity of the combination of monoclonal antibody DC101 against vascular endothelial growth factor receptor-2 (VEGFR-2) and monoclonal antibody C225 against epidermal growth factor receptor (EGFR). Nude mice bearing intracerebral glioblastoma xenografts were administered either DC101 or C225, or the combination via intraperitoneal (i.p.) injection. Histopathological analysis of solid tumor volume, microvessel density, tumor cell proliferation and apoptosis were performed. In the DC101 treated group, solid tumor volume and microvessel density were reduced by 59.7% and 64%, respectively. The tumor cell proliferation level was reduced by 53.2% and tumor cell apoptosis was increased by 66.7% but there was enhanced tumor cell invasiveness. C225 alone reduced the invasiveness of tumor tissue, but had no effect on solid tumor growth, microvessel density, tumor cell proliferation or apoptosis. The combination cancer therapy with C225 and DC101 enhanced tumor treatment with reduced tumor volume, microvessel density, tumor cell proliferation level, and increased cancer cell apoptosis, while decreasing tumor cell invasiveness. PMID- 21303750 TI - High grade malignant peripheral nerve sheath tumors: outcome of 62 patients with localized disease and review of the literature. AB - Malignant peripheral nerve sheath tumours (MPNST) are rare sarcomas with one of the poorest prognoses of all the soft tissue sarcomas. Information about adjuvant treatment is scarce and not homogeneous for this diagnosis. We analyzed retrospectively the outcome of patients with localized high grade MPNST admitted to our institute from 1969 to 2008. A review of the literature is also reported. Of 62 evaluable patients, 23 were females and 39 males, median age 39 years (17 71), 22/62 had neurofibromatosis type I. Median follow-up was 54 months (range 12 194). A total of 22/62 are alive; 26 patients had surgery alone, 18 received radiation therapy, 12 received radiation therapy and chemotherapy, and 6 received only adjuvant chemotherapy. The 5-year disease-free survival was 30% and 5-year overall survival was 38%. A positive trend for adjuvant radiation, but not for chemotherapy was observed according to univariate analysis only for disease-free survival and overall survival. Multivariate analysis indicated that primary site, size and surgical margins remained significant for disease-free survival and only site and size were significant for overall survival. New drugs employed successfully in advanced mpNSt should be employed also in the adjuvant setting. PMID- 21303751 TI - Weekly regimen of paclitaxel and carboplatin as first-line chemotherapy in elderly patients with stage IIIB-IV non small cell lung cancer (NSCLC): results of a phase II study. AB - Single-agent chemotherapy is the preferred treatment option in chemonaive elderly patients with advanced nonsmall-cell lung cancer (NSCLC). The role of combination chemotherapy in this setting is uncertain although several studies report satisfactory efficacy and safety using weekly paclitaxel and carboplatin (AUC=6) as first-line chemotherapy in elderly patients. It is still unclear which schedule of this regimen which could offer the best therapeutic index. The aim of this study was to evaluate the activity and tolerability of concomitant weekly administration of paclitaxel and carboplatin in untreated elderly patients with advanced NSCLC. From february 2005 to April 2008 36 consecutive elderly patients with advanced NSCLC were enrolled. Median age was 74 years (range, 70-83 years) and median ECOG PS was 1 (range, 0-1). patients received carboplatin (AUC=2) and paclitaxel 80 mg/m2 on days 1,8 and 15 every 28 days. All patients were evaluable for efficacy and toxicity; a median of 4 cycles was administered. Twelve patients had partial response (33%; 95% C.I. 15,8-52,3%), 10 patients (28%) showed stable disease. The median time to progression (TTP) was 5.7 months (95% C.I. 3.1-8.6 months) with a median overall survival (MOS) of 9 months (95% C.I. 4.4-13.9 months). Toxicity was mild with no cases of febrile neutropenia; 5 patients (14%) developed grade 2 neuropathy. Our study confirms the substantial activity of weekly regimen of paclitaxel and carboplatin. Due to its favorable profile of toxicity this schedule could represent an interesting therapeutic option in selected chemonaive elderly patients with advanced NSCLC. PMID- 21303752 TI - Predictors of methicillin resistance in healthcare-associated Staphylococcus aureus bloodstream infections: the role of recent antibiotic use. PMID- 21303753 TI - Ventilator-associated pneumonia in patients with 2009 pandemic influenza A (H1N1) infection: an observational study. PMID- 21303754 TI - No impact of limited cephalosporin use on prevalence of methicillin-resistant Staphylococcus aureus in the intensive care unit. PMID- 21303755 TI - Salvarsan: Early days of a new chemotherapeutic drug. PMID- 21303756 TI - Administration interval and daptomycin toxicity: a case report of rhabdomyolysis. PMID- 21303757 TI - Long term survival in a patient with adenocarcinoma of the cystic duct. PMID- 21303758 TI - Prenatal echocardiographic diagnosis of cardiac right/left axis and malpositions according to standardized Cordes technique. AB - OBJECTIVE: The aim of this study was to evaluate distinguishing the right/left side of the fetus, cardiac axis and position according to the standardized Cordes technique in 20 cases with cardiac malposition. METHODS: We studied retrospectively 1536 cases whose fetal echocardiographic examinations were performed between 1999 and 2006 in prenatal cardiology unit. Among these, cardiac malpositions were determined in 20 cases. The cardiac axis and position were determined according to the Cordes technique. All cases were followed-up by serial fetal echocardiograms until birth or intrauterine death occurred. In cases of intrauterine death, an autopsy was performed. After birth, physical and echocardiographic examinations were done and prenatal and postnatal diagnoses were compared. RESULTS: Of 1536 fetal echocardiograms performed, 144 revealed congenital heart diseases (9.4%), among these cases 20 were diagnosed with cardiac malposition. Of cases with cardiac malposition, 16 had congenital heart disease, and four had extracardiac malformation. There were six cases of isolated dextrocardia, three cases of situs inversus totalis, six cases of situs ambiguous, and one case of situs inversus with isolated levocardia. Of four cases with extracardiac malformations, two cases had mesoposition, one had dextroposition, and one had extreme levoposition. In six cases the autopsy findings were the same as that their prenatal echocardiographic findings. When postnatal echocardiographic results of the remaining cases with cardiac malposition due to congenital heart disease were compared with prenatal diagnoses, the same echocardiographic findings were verified. CONCLUSION: The fetal right/left axis must be determined correctly for the accurate diagnosis of cardiac malpositions. Therefore, we recommend that Cordes technique provides a simple and reliable determination of the fetal right/left axis and fetal situs. PMID- 21303759 TI - Prevalence and distribution of structural heart diseases in high and low risk pregnancies. AB - OBJECTIVE: To establish and compare the frequency of intrauterine congenital heart defects in high-risk and low-risk pregnancies for congenital heart diseases. METHODS: Records of 3782 patients who underwent fetal echocardiography at the Pediatric Cardiology Unit were reviewed for reasons of referral and results of echocardiography retrospectively. The categorical variables between the groups were analyzed using a Chi-square test. RESULTS: Structural heart defects were found in 213 (5.6%) fetuses in both high and low risk groups. Most common defects were ventricular septal defect (36.2%) and atrioventricular septal defect (14.1%). Frequency of congenital heart diseases was 7.8% (169 fetuses) in high-risk group: 4.1% were complex, 2.3% significant and 1.4% were minor. In low risk group, the frequency was 2.7% (44 fetuses): 0.6% were complex, 0.8% significant and 1.3% were minor. In this group, rates of congenital defects were high regarding particular reasons: intrauterine fetal death in previous pregnancy (6.3%), abnormal first or second trimester screening tests (4.3%), and multiple gestations (3.4%). The sensitivity and specificity of fetal echocardiography according to transthoracic echocardiography were found to be 86% and 99%, respectively. CONCLUSION: Congenital heart diseases rate, as expected, was found to be higher in high-risk group. However, regarding intrauterine fetal death in previous pregnancy, abnormal first or second trimester screening tests and multiple gestation, no statistically significant difference was observed between low-risk and high-risk groups. Therefore, we suggest the routine use of fetal echocardiography in cases we have mentioned above if the staff and equipment of the pediatric cardiology clinic are eligible. PMID- 21303760 TI - Circadian blood pressure pattern and cardiac autonomic functions: different aspects of same pathophysiology. AB - Arterial blood pressure fluctuates with a pattern that follows a circadian rhythm, with a peak in the early morning hours and a trough during nighttime. Nocturnal dipping of arterial blood pressure is part of this normal circadian pattern, and its absence, which is called non-dipping is associated with more severe end-organ damage and increased risk of cardiovascular events, especially in hypertensive patients. Although pathologic mechanisms are still unclear, it has been suggested that non-dippers show impairment in the autonomic system functions that include abnormal parasympathetic and sympathetic activities. Several studies have examined the role of the autonomic nervous system in the non dipping phenomenon. In this paper, we aimed to review the studies evaluating the relationship between circadian arterial blood pressure pattern and indices of cardiac autonomic functions. PMID- 21303761 TI - Functional disability in adolescents with orthostatic intolerance and chronic pain. AB - A retrospective review identified 99 adolescents (79% female) referred to a tertiary care center to evaluate the relationship between symptoms of orthostatic intolerance and chronic pain. Regression analysis indicated that functional disability was strongly associated with pain intensity (P < .001) and depression (P = .024). The association between functional disability and number of symptoms of orthostatic intolerance trended toward significance (P = .057). Meeting a threshold heart rate increment of 30 beats per minute on head-up tilt was not associated with functional disability (P = .188). Separate regression analysis of female patients showed similar results to the full sample but with a stronger relationship between depression and functional disability and a weaker relationship between heart increment and functional disability. In this sample of adolescents with symptoms of orthostatic intolerance and chronic pain, pain intensity and depression were associated with functional status, but postural tachycardia was not. Further research is needed to clarify potential gender differences. PMID- 21303763 TI - Hoarding behaviors in children with learning disabilities. AB - Our objective was to describe the prevalence, comorbidity, and neuropsychological profiles of children with hoarding and learning disabilities. From 61 children with learning disabilities, 16.4% exhibited hoarding as a major clinical issue. Although children with learning disabilities and hoarding displayed greater rates of obsessive-compulsive disorder (30%) as compared to those with learning disabilities without hoarding (5.9%), the majority of patients belonging to the former group did not display obsessive-compulsive disorder diagnosis. When learning disability patients with hoarding were compared to age-, sex-, and IQ matched learning disability subjects without hoarding, hoarders exhibited a slower learning curve on word list-learning task. In conclusion, salient hoarding behaviors were found to be relatively common in a sample of children with learning disabilities and not necessarily associated with obsessive-compulsive disorder, supporting its nosological independence. It is unclear whether underlying cognitive features may play a major role in the development of hoarding behaviors in children with learning disabilities. PMID- 21303762 TI - Network analysis: applications for the developing brain. AB - Development of the human brain follows a complex trajectory of age-specific anatomical and physiological changes. The application of network analysis provides an illuminating perspective on the dynamic interregional and global properties of this intricate and complex system. Here, we provide a critical synopsis of methods of network analysis with a focus on developing brain networks. After discussing basic concepts and approaches to network analysis, we explore the primary events of anatomical cortical development from gestation through adolescence. Upon this framework, we describe early work revealing the evolution of age-specific functional brain networks in normal neurodevelopment. Finally, we review how these relationships can be altered in disease and perhaps even rectified with treatment. While this method of description and inquiry remains in early form, there is already substantial evidence that the application of network models and analysis to understanding normal and abnormal human neural development holds tremendous promise for future discovery. PMID- 21303764 TI - Anthropometric and fitness variables associated with bone mineral density and broadband ultrasound attenuation in ambulatory children with cerebral palsy. AB - We investigated anthropometric and fitness variables associated with areal bone mineral densities and broadband ultrasound attenuation in ambulatory children with cerebral palsy. Thirty-four children with cerebral palsy, aged 4-12 years, and 33 normal development children were collected. There were significant differences in femoral bone densities and calcaneus broadband ultrasound attenuation, but not in lumbar bone densities, between cerebral palsy and normal groups. Regression analysis revealed that different anthropometric and fitness variables were linked to bone densities of different skeletal regions in children with cerebral palsy (adjusted r(2) = .41-.67). Growth variables were mainly related to femoral and lumbar bone densities, while muscular endurance was mainly related to femoral and calcaneus bone densities. These findings suggest multiple complex variables can contribute to bone density variations among different skeleton areas in these children. These data can allow clinicians to identifying early these children at risk for low bone density. PMID- 21303765 TI - Rapid changes in gene expression: DNA determinants of promoter regulation by the concentration of the transcription initiating NTP in Bacillus subtilis. AB - In bacteria, rapid changes in gene expression can be achieved by affecting the activity of RNA polymerase with small molecule effectors during transcription initiation. An important small molecule effector is the initiating nucleoside triphosphate (iNTP). At some promoters, an increasing iNTP concentration stimulates promoter activity, while a decreasing concentration has the opposite effect. Ribosomal RNA (rRNA) promoters from Gram-positive Bacillus subtilis are regulated by the concentration of their iNTP. Yet, the sequences of these promoters do not emulate the sequence characteristics of [iNTP]-regulated rRNA promoters of Gram-negative Escherichia coli. Here, we identified the 3'-promoter region, corresponding to the transcription bubble, as key for B. subtilis rRNA promoter regulation via the concentration of the iNTP. Within this region, the conserved -5T (3 bp downstream from the -10 hexamer) is required for this regulation. Moreover, we identified a second class of [iNTP]-regulated promoters in B. subtilis where the sequence determinants are not limited to the transcription bubble region. Overall, it seems that various sequence combinations can result in promoter regulation by [iNTP] in B. subtilis. Finally, this study demonstrates how the same type of regulation can be achieved with strikingly different promoter sequences in phylogenetically distant species. PMID- 21303766 TI - Translational recoding as a feedback controller: systems approaches reveal polyamine-specific effects on the antizyme ribosomal frameshift. AB - The antizyme protein, Oaz1, regulates synthesis of the polyamines putrescine, spermidine and spermine by controlling stability of the polyamine biosynthetic enzyme, ornithine decarboxylase. Antizyme mRNA translation depends upon a polyamine-stimulated +1 ribosomal frameshift, forming a complex negative feedback system in which the translational frameshifting event may be viewed in engineering terms as a feedback controller for intracellular polyamine concentrations. In this article, we present the first systems level study of the characteristics of this feedback controller, using an integrated experimental and modeling approach. Quantitative analysis of mutant yeast strains in which polyamine synthesis and interconversion were blocked revealed marked variations in frameshift responses to the different polyamines. Putrescine and spermine, but not spermidine, showed evidence of co-operative stimulation of frameshifting and the existence of multiple ribosome binding sites. Combinatorial polyamine treatments showed polyamines compete for binding to common ribosome sites. Using concepts from enzyme kinetics and control engineering, a mathematical model of the translational controller was developed to describe these complex ribosomal responses to combinatorial polyamine effects. Each one of a range of model predictions was successfully validated against experimental frameshift frequencies measured in S-adenosylmethionine-decarboxylase and antizyme mutants, as well as in the wild-type genetic background. PMID- 21303767 TI - Evaluation of a preoperative team briefing: a new communication routine results in improved clinical practice. AB - BACKGROUND Suboptimal communication within healthcare teams can lead to adverse patient outcomes. Team briefings were previously associated with improved communication patterns, and we assessed the impact of briefings on clinical practice. To quantify the impact of the preoperative team briefing on direct patient care, we studied the timing of preoperative antibiotic administration as compared to accepted treatment guidelines. STUDY DESIGN A retrospective pre intervention/post-intervention study design assessed the impact of a checklist guided preoperative team briefing on prophylactic antibiotic administration timing in surgical cases (N=340 pre-intervention and N=340 post-intervention) across three institutions. chi(2) Analyses were performed to determine whether there was a significant difference in timely antibiotic administration between the study phases. RESULTS The process of collecting and analysing these data proved to be more complicated than expected due to great variability in documentation practices, both between study sites and between individual practitioners. In cases where the timing of antibiotics administration was documented unambiguously in the chart (n=259 pre-intervention and n=283 post intervention), antibiotic prophylaxis was on time for 77.6% of cases in the pre intervention phase of the study, and for 87.6% of cases in the post-intervention phase (p<0.01). CONCLUSIONS Use of a preoperative team checklist briefing was associated with improved physician compliance with antibiotic administration guidelines. Based on the results, recommendations to enhance timely antibiotic therapy are provided. PMID- 21303768 TI - An assessment of the quality and impact of NPSA medication safety outputs issued to the NHS in England and Wales. AB - OBJECTIVES: To assess the quality and impact of medication safety outputs issued by the National Patient Safety Agency (NPSA) to the NHS in England and Wales. METHODS: A multi-method study comprising (1) focus groups and interviews with NHS Chief Pharmacists and (2) an electronic survey of medical, nursing and clinical governance directors. RESULTS: Acute sector respondents agreed that the medication outputs had a major impact on patient safety. Pharmacists welcomed national support for medication safety improvement, despite the resulting workload. Medical Directors were much less likely to be aware of alerts and Rapid Response Reports (RRRs) than their nursing and clinical governance colleagues. One key finding was the inability of around half of NHS trusts to communicate effectively and reliably with their junior doctors. CONCLUSION: Medication alerts issued by the NPSA have stimulated significant work to improve medication safety and are believed to have had an important impact on patient safety. PMID- 21303769 TI - Quality of patient record keeping: an indicator of the quality of care? AB - BACKGROUND: Patient record review of hospitalised patients is by far the most applied method to assess adverse events (AEs) in hospitals. The diligence with which information is recorded may influence the visibility of AEs. On the other hand, poor quality of the information in patient records may be a cause or a consequence of poor quality of care and may thus be associated with higher rates of AEs. The objective of this study was to assess the relation between the quality of patient records and the occurrence of AEs. METHODS: In this study, 7926 hospital admissions of 21 Dutch hospitals were analysed with a structured record review method. The occurrence of AEs, the presence of patient information and the quality of the present information (completeness, readability and adequacy) were assessed. Their association was analysed using multilevel logistic regression analyses. RESULTS: The absence of record components was associated with lower rates of AEs, suggesting that missing record components lead to an underassessment of AEs in record-review studies. In contrast, poor quality of the information present in patient records was associated with higher rates of AEs, implying that the quality of the present patient information is a predictor of the quality of care. CONCLUSIONS: Evidence-based standards and a (electronic) format for record keeping are necessary for standardisation of recording patient information. This will improve the completeness, readability, accessibility, accuracy and exchange of patient information between healthcare providers and institutions. Better registration of patient information will benefit the quality of the healthcare process and will reduce the risk of AEs. PMID- 21303770 TI - Safety culture in healthcare: a review of concepts, dimensions, measures and progress. AB - BACKGROUND: A growing body of peer-reviewed studies demonstrate the importance of safety culture in healthcare safety improvement, but little attention has focused on developing a common set of definitions, dimensions and measures. OBJECTIVES: Specific objectives of this literature review include: summarising definitions of safety culture and safety climate, identifying theories, dimensions and measures of safety culture in healthcare, and reviewing progress in improving safety culture. METHODS: Peer-reviewed, English-language articles published from 1980 to 2009 pertaining to safety culture in healthcare were reviewed. One hundred and thirty-nine studies were included in this review. RESULTS: Results suggest that there is disagreement among researchers as to how safety culture should be defined, as well as whether or not safety culture is intrinsically diverse from the concept of safety climate. This variance extends into the dimensions and measurement of safety culture, and interventions to influence culture change. DISCUSSION: Most studies utilise quantitative surveys to measure safety culture, and propose improvements in safety by implementing multifaceted interventions targeting several dimensions. Conversely, very few studies made their theoretical underpinnings explicit. Moving forward, a common set of definitions and dimensions will enable researchers to better share information and strategies to improve safety culture in healthcare, building momentum in this rapidly expanding field. Advancing the measurement of safety culture to include both quantitative and qualitative methods should be further explored. Using the expertise of traditional culture experts, anthropologists, more in-depth observational and longitudinal research is needed to move research in this area forward. PMID- 21303771 TI - Development of quality of care indicators for patients undergoing total hip or total knee replacement. AB - OBJECTIVE: The objective of this study was to develop evidence-based quality indicators to measure key aspects of care that can be targeted to decrease variations in complication rates between surgeons performing total joint replacement. DESIGN: RAND/University of California, Los Angeles (UCLA) modified Delphi expert panel method. To accomplish this objective, a proposed set of quality of care indicators was developed through a comprehensive literature search and structured interviews with expert clinicians. An expert panel of orthopaedic surgeons was then convened to rate the validity of these quality indicators using the RAND/UCLA Appropriateness Method. Indicators were classified as valid by the panel based on the median panel rating and the amount of dispersion of panel ratings. RESULTS: There were 101 candidate indicators of quality identified in the six domains of preoperative processes of care, intraoperative processes, postoperative processes, implant selection and the use of new technology, privileging of hospitals and surgeons, and outcomes and comorbidity assessment. A total of 68 of the 101 indicators were rated as valid with statistical agreement. CONCLUSIONS: This study identifies measures of structure, process and outcome rated as valid quality indicators for hip and knee replacement. This project provides tools to measure and improve quality of care for patients undergoing total joint replacement. PMID- 21303772 TI - Elimination of central-venous-catheter-related bloodstream infections from the intensive care unit. AB - INTRODUCTION: Central-venous-catheter (CVC)-related bloodstream infection (CRBSI) is a complication of intensive care stay which can have important adverse consequences for both patient and institution. There are a number of evidence based interventions that reduce CRBSI, but it is recognised that consistently applying the best evidence every time is a challenge. METHODS: The authors set out to reduce CRBSI and introduced interventions in our intensive care unit (ICU) over a 4-year period using a quality improvement approach. In a setting supportive to change and improvement, the authors established infection surveillance and introduced bundles of care processes relating to insertion and maintenance of CVCs. The changes were supported by educational interventions. The authors measured care processes and outcomes, and used statistical process control charts to illustrate changes. The final 18 months of the work was performed in the context of a national safety improvement programme (The Scottish Patient Safety Programme). RESULTS: Following interventions, the annual CRBSI rate fell from 3.4 to 0/1000 patient days with zero episodes during the final 19 months of the study. CONCLUSIONS: The authors describe a significant reduction in CRBSI for the first time in a UK ICU. The authors summarised and simplified what to do, measured and provided feedback on outcomes, and improved expectations of performance standards for care processes. The authors believe that these approaches are worthy of serious consideration elsewhere. PMID- 21303774 TI - Not all critical laboratory values are equally urgent to physicians. PMID- 21303773 TI - Resident-initiated interventions to improve inpatient heart-failure management. AB - BACKGROUND: Third-year internal medicine residents participating in a quality improvement rotation identified gaps between the Joint Commission's ORYX quality guidelines and clinical practices for the inpatient management of heart failure (HF) at the William S. Middleton Memorial Veterans Hospital. Residents focused on the performance metrics associated with tobacco-cessation counselling documentation, ejection fraction assessment and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker prescriptions. METHODS: After analysing data collected by the External Peer Review Program, residents reviewed the institution's admissions and discharge processes with the aim of improving quality and compliance. In redesigning these processes, residents created an admissions template and a discharge face sheet, and compared specific ORYX measure compliance rates before and after institution-wide implementation. RESULTS: Following implementation of the tobacco-cessation admissions template, 100% of HF patients who used tobacco received documented cessation counselling, compared with 59% prior to intervention (p<0.01, n=32). Following implementation of the mandatory discharge face sheet, 97% of HF patients (compared with 92% preintervention, p>0.05) received comprehensive discharge instruction; LV function assessment went from 98% to 100% (p>0.05); and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker prescription for left ventricular systolic dysfunction at discharge (or documentation of a contra-indication) went from 82% to 100% (p<0.01, n=48). DISCUSSION: By implementing a standardised admissions template and a mandatory discharge face sheet, the hospital improved its processes of documentation and increased adherence to quality-performance measures. By strengthening residents' learning and commitment to quality improvement, the hospital created a foundation for future changes in the systems that affect patient care. PMID- 21303775 TI - Medical students' preferred style of learning patient safety. PMID- 21303776 TI - Dietary iron intake during early pregnancy and birth outcomes in a cohort of British women. AB - BACKGROUND Iron deficiency during pregnancy is associated with adverse birth outcomes, particularly, if present during early gestation. Iron supplements are widely recommended during pregnancy, but evidence of their benefit in relation to infant outcomes is not established. This study was performed in the UK, where iron supplements are not routinely recommended during pregnancy, to investigate the association between iron intake in pregnancy and size at birth. METHODS From a prospective cohort of 1274 pregnant women aged 18-45 years, dietary intake was reported in a 24-h recall administered by a research midwife at 12-week gestation. Dietary supplement intake was ascertained using dietary recall and three questionnaires in the first, second and third trimesters. RESULTS Of the cohort of pregnant women, 80% reported dietary iron intake below the UK Reference Nutrient Intake of 14.8 mg/day. Those reported taking iron-containing supplements in the first, second and third trimesters were 24, 15 and 8%, respectively. Women with dietary iron intake >14.8 mg/day were more likely to be older, have a higher socioeconomic profile and take supplements during the first trimester. Vegetarians were less likely to have low dietary iron intake [odds ratio = 0.5, 95% confidence interval (CI): 0.4, 0.8] and more likely to take supplements during the first and second trimesters. Total iron intake, but not iron intake from food only, was associated with birthweight centile (adjusted change = 2.5 centiles/10 mg increase in iron, 95% CI: 0.4, 4.6). This association was stronger in the high vitamin C intake group, but effect modification was not significant. CONCLUSION There was a positive relationship between total iron intake, from food and supplements, in early pregnancy and birthweight. Iron intake, both from diet and supplements, during the first trimester of pregnancy was higher in vegetarians and women with a better socioeconomic profile. PMID- 21303777 TI - Efficacy of oocyte vitrification combined with blastocyst stage transfer in an egg donation program. AB - BACKGROUND A successful oocyte vitrification program is important for women with various indications for assisted reproduction technology. The objective of this study was to report the outcome of vitrification of oocytes, obtained through an oocyte donation program, by evaluating the embryo development, pregnancy and implantation rates (IRs) after blastocyst transfer. METHODS A total of 1098 oocytes were obtained from 78 donors. There were 312 oocytes used in the study group (vitrified oocytes) and 786 used in the control group (fresh oocytes). There were 34 recipients who received blastocysts obtained from vitrified oocytes and 58 recipients who received blastocysts from fresh oocytes. The fertilization rate, cleavage rate, embryo quality, pregnancy rate (PR) and IR were compared between groups. RESULTS Vitrified oocytes showed a survival rate of 89.4%. There was no difference in the fertilization rate (76.1 and 87.5%), Day 2 cleavage rate (96.3 and 98.0%) or blastocyst formation rate (41.3 and 45.3%) for the study and control groups, respectively. PRs, IRs and miscarriages rates (MRs) were similar for the study group compared with the control group (PR: 61.8 versus 60.0%; IR: 43.9 versus 42.9%; MR: 9.5 versus 5.9%). CONCLUSIONS The developmental competence of embryos obtained from vitrified oocytes is not affected by the vitrification procedure, since they preserve the potential to be fertilized and to develop into high-quality blastocysts, similar to embryos from fresh oocytes. The successful clinical outcome indicates the use of this procedure for oocyte donation programs and for oocyte storage in general. PMID- 21303778 TI - Abnormal activation of Ras/Raf/MAPK and RhoA/ROCKII signalling pathways in eutopic endometrial stromal cells of patients with endometriosis. AB - BACKGROUND Enhanced proliferation and survival of eutopic endometrial cells from patients with endometriosis compared with healthy women is associated with abnormal activation of extra-cellular signal-regulated kinases 1 and 2 (ERK1/2). Given the role of Ras/Raf/mitogen-activated protein kinase (MAPK) and RhoA/ROCKII signalling pathways in the regulation of cell proliferation and migration, we analysed their possible roles in endometriosis. METHODS Primary eutopic endometrial stromal cells of patients with endometriosis (Eu-hESC, n= 16) and endometriosis-free controls (Co-hESC, n= 14) were harvested and subjected to proliferation and migration assays as well as kinase activity assays and immunoblot analysis of proteins from the Ras/Raf/MAPK and RhoA/ROCKII signalling pathways. Effects of ROCKII (Y-27632) and MAPK (U0126) inhibitors or siRNA knockdown of ROCKII, Raf-1 and B-Raf were analysed. RESULTS The proliferation rate of Eu-hESC was 54% higher than Co-hESC. Eu-hESC also displayed a 75% higher migration rate than Co-hESC. Eu-hESC displayed higher levels of ERK phosphorylation (83%) and p27 expression (61%) and lower levels of Raf-1 protein (47%) compared with controls. In addition to an inhibitory effect on cell proliferation, ROCKII knockdown led to significant down-regulation of cyclinD1 and p27 but did not affect ERK phosphorylation. Down-regulation of Raf-1 by siRNA was dispensable for cell proliferation control but led to an increase in ROCKII activity and a decrease in cell migration. B-Raf was shown to act as a regulator of hESC proliferation by modulating cellular ERK1/2 activity and cyclinD1 levels. Eu-hESC displayed 2.4-fold higher B-Raf activity compared with Co-hESC and therefore exhibit abnormally activated Ras/Raf/MAPK signalling. CONCLUSIONS We show that the same molecular mechanisms operate in Co- and Eu-hESC. The differences in cell proliferation and migration between both cell types are likely due to increased activation of Ras/Raf/MAPK and RhoA/ROCKII signalling pathways in cells from endometriosis patients. PMID- 21303779 TI - Elevated endocannabinoid plasma levels are associated with coronary circulatory dysfunction in obesity. AB - AIMS: Aim of this study was to evaluate a possible association between endocannabinoid (EC) plasma levels, such as anandamide (AEA) and 2 arachidonoylglycerol (2-AG), and coronary circulatory function in obesity. METHODS AND RESULTS: Myocardial blood flow (MBF) responses to cold pressor test (CPT) and during pharmacological vasodilation with dipyridamole were measured with (13)N-ammonia PET/CT. Study participants (n = 77) were divided into three groups based on their body mass index (BMI, kg/m(2)): control group 20 <= BMI <25 (n = 21); overweight group, 25 <= BMI <30 (n = 26); and obese group, BMI >= 30 (n = 30). Anandamide plasma levels, but not 2-AG plasma levels, were significantly elevated in obesity as compared with controls, respectively [0.68 (0.53, 0.78) vs. 0.56 (0.47, 0.66) ng/mL, P = 0.020, and 2.2 (1.21, 4.59) vs. 2.0 (0.80, 5.90) ng/mL, P = 0.806)]. The endothelium-related change in MBF during CPT from rest (DeltaMBF) progressively declined in overweight and obese when compared with control group [0.21 (0.10, 0.27) and 0.09 (-0.01, 0.15) vs. 0.26 (0.23, 0.39) mL/g/min; P = 0.010 and P = 0.0001, respectively). Compared with controls, hyperaemic MBFs were significantly lower in overweight and obese individuals [2.39 (1.97, 2.62) vs. 1.98 (1.69, 2.26) and 2.10 (1.76, 2.36); P = 0.007 and P = 0.042, respectively)]. In obese individuals, AEA and 2-AG plasma levels were inversely correlated with DeltaMBF to CPT (r = -0.37, P = 0.046 and r = -0.48, P = 0.008) and hyperaemic MBFs (r = -0.38, P = 0.052 and r = -0.45, P = 0.017), respectively. CONCLUSIONS: Increased EC plasma levels of AEA and 2-AG are associated with coronary circulatory dysfunction in obese individuals. This observation might suggest increases in EC plasma levels as a novel endogenous cardiovascular risk factor in obesity, but needing further investigations. PMID- 21303780 TI - When are pro-inflammatory cytokines SAFE in heart failure? AB - The cytokine hypothesis presently suggests that an excessive production of pro inflammatory cytokines, such as tumour necrosis factor alpha (TNF) and interleukin 6 (IL6), contributes to the pathogenesis of heart failure. The concept, successfully proved in genetically modified animal models, failed to translate to humans. Recently, accumulation of apparently paradoxical experimental data demonstrates that, under certain conditions, production of pro inflammatory cytokines can initiate the activation of a pro-survival cardioprotective signalling pathway. This novel path that involves the activation of a transcription factor, signal transducer and activator of transcription 3 (STAT3), has been termed the survival activating factor enhancement (SAFE) pathway. In this review, we will discuss whether targeting the SAFE pathway may be considered as a preventive and/or therapeutic measure for the treatment of heart failure. PMID- 21303781 TI - Right ventricular aneurysm and large coronary arteriovenous fistula in a 3100 g infant. PMID- 21303782 TI - Decreasing radiation doses in digital subtraction angiographies consecutively performed by trainees. AB - Digital subtraction angiography (DSA) performed by trainees may be related to increased radiation exposure. This study was aimed to investigate and quantify this learning effect, with fluoroscopy time and dose-area product (DAP) as parameters. We collected procedure data of the first to the fortieth cerebral DSA consecutively performed by 13 trainees in a training centre. DAP, procedure time, fluoroscopy time, number of cine-frames of the first 20 DSA procedures performed by these trainees were compared with that of the second 20 procedures. There was no significant difference concerning the procedure time between the first and the second 20 procedures (56.3 +/- 29.5 vs 51.5 +/- 20.2 min, p = 0.113). Numbers of cine-frames were very similar between the first and the second 20 procedures (750.7 +/- 290.3 vs 744.5 +/- 188.7, p = 0.830). Fluoroscopy time of the first 20 procedures was significantly longer than that of the second 20 procedures (17.8 +/- 15.4 vs 12.6 +/- 9.0, p = 0.001). DAP of the first 20 procedures was significantly higher than that of the second 20 procedures (6.4 +/- 4.9 vs 3.8 +/ 1.8, p < 0.001). DAP was correlated significantly with the performer's experience (R = -0.288, p < 0.001). There exists a learning effect of radiation exposure during cerebral DSA procedures performed by trainees. The learning effect is significant during the first 20 procedures, and becomes insignificant after 20 procedures. Insufficient catheter skills in novice trainees may be one reason for this effect. PMID- 21303783 TI - The shoot apical meristem of oil palm (Elaeis guineensis; Arecaceae): developmental progression and dynamics. AB - BACKGROUND AND AIMS: Oil palm, an unbranched perennial monocotyledon, possesses a single shoot apical meristem (SAM), which is responsible for the initiation of the entire above-ground structure of the plant. To compare the palm SAM structure with those of other monocots and to study variations in its structure throughout the life of the plant, its organization was characterized from the embryonic stage to that of the reproductive plant. METHODS: SAM structure was studied by a combination of stained histological sections, light and confocal microscopy, and serial section-based three-dimensional reconstructions. KEY RESULTS: The oil palm SAM is characterized by two developmental phases: a juvenile phase with a single tunica-corpus structure displaying a gradual increase in size; and a mature phase characterized by a stable size, a modified shape and an established histological zonation pattern. In mature plants, fluctuations in SAM shape and volume occur, mainly as a consequence of changes in the central zone, possibly in relation to leaf initiation. CONCLUSIONS: Development of the oil palm SAM is characterized by a juvenile to mature phase transition accompanied by establishment of a zonal pattern and modified shape. SAM zonation is dynamic during the plastochron period and displays distinct features compared with other monocots. PMID- 21303784 TI - Endozoochory by beetles: a novel seed dispersal mechanism. AB - BACKGROUND AND AIMS: Due in part to biophysical sized-related constraints, insects unlike vertebrates are seldom expected to act as primary seed dispersers via ingestion of fruits and seeds (endozoochory). The Mediterranean parasitic plant Cytinus hypocistis, however, possesses some characteristics that may facilitate endozoochory by beetles. By combining a long-term field study with experimental manipulation, we tested whether C. hypocistis seeds are endozoochorously dispersed by beetles. METHODS: Field studies were carried out over 4 years on six populations in southern Spain. We recorded the rate of natural fruit consumption by beetles, the extent of beetle movement, beetle behaviour and the relative importance of C. hypocistis fruits in beetle diet. KEY RESULTS: The tenebrionid beetle Pimelia costata was an important disperser of C. hypocistis seeds, consuming up to 17.5 % of fruits per population. Forty-six per cent of beetles captured in the field consumed C. hypocistis fruits, with up to 31 seeds found in individual beetle frass. An assessment of seeds following passage through the gut of beetles indicated that seeds remained intact and viable and that the proportion of viable seeds from beetle frass was not significantly different from that of seeds collected directly from fruits. CONCLUSIONS: A novel plant-animal interaction is revealed; endozoochory by beetles may facilitate the dispersal of viable seeds after passage through the gut away from the parent plant to potentially favourable underground sites offering a high probability of germination and establishment success. Such an ecological role has until now been attributed only to vertebrates. Future studies should consider more widely the putative role of fruit and seed ingestion by invertebrates as a dispersal mechanism, particularly for those plant species that possess small seeds. PMID- 21303785 TI - Partial mechanical stimulation facilitates the growth of the rhizomatous plant Leymus secalinus: modulation by clonal integration. AB - BACKGROUND AND AIMS: Mechanical stimulation (MS) often induces plants to undergo thigmomorphogenesis and to synthesize an array of signalling substances. In clonal plants, connected ramets often share resources and hormones. However, little is known about whether and how clonal integration influences the ability of clonal plants to withstand MS. We hypothesized that the effects of MS may be modulated by clonal integration. METHODS: We conducted an experiment in which ramet pairs of Leymus secalinus were subjected to three treatments: (1) connected ramet pairs under a homogeneous condition [i.e. the proximal (relatively old) and distal (relatively young) ramets were not mechanically stressed]; (2) connected ramet pairs under a heterogeneous condition (i.e. the proximal ramet was mechanically stressed but the distal ramet was not); and (3) disconnected ramet pairs under the same condition as in treatment 2. At the end of the experiment, we harvested all plants and determined their biomass and allocation. KEY RESULTS: Clonal integration had no significant influence on measured traits of distal L. secalinus ramets without MS. However, under MS, plants with distal ramets that were connected to a mother ramet produced more total plant biomass, below-ground biomass, ramets and total rhizome length than those that were not connected. Partial MS exerted local effects on stimulated ramets and remote effects on connected unstimulated ramets. Partial MS increased total biomass, root/shoot ratio, number of ramets and total rhizome length of stimulated proximal ramets, and increased total biomass, root weight ratio, number of ramets and total rhizome length of connected unstimulated ramets due to clonal integration. CONCLUSIONS: These findings suggest that thigmomorphogenesis may protect plants from the stresses caused by high winds or trampling and that thigmomorphogenesis can be strongly modulated by the degree of clonal integration. PMID- 21303786 TI - The selfing syndrome: a model for studying the genetic and evolutionary basis of morphological adaptation in plants. AB - BACKGROUND: In angiosperm evolution, autogamously selfing lineages have been derived from outbreeding ancestors multiple times, and this transition is regarded as one of the most common evolutionary tendencies in flowering plants. In most cases, it is accompanied by a characteristic set of morphological and functional changes to the flowers, together termed the selfing syndrome. Two major areas that have changed during evolution of the selfing syndrome are sex allocation to male vs. female function and flower morphology, in particular flower (mainly petal) size and the distance between anthers and stigma. SCOPE: A rich body of theoretical, taxonomic, ecological and genetic studies have addressed the evolutionary modification of these two trait complexes during or after the transition to selfing. Here, we review our current knowledge about the genetics and evolution of the selfing syndrome. CONCLUSIONS: We argue that because of its frequent parallel evolution, the selfing syndrome represents an ideal model for addressing basic questions about morphological evolution and adaptation in flowering plants, but that realizing this potential will require the molecular identification of more of the causal genes underlying relevant trait variation. PMID- 21303787 TI - Mainstream media and the social determinants of health in Canada: is it time to call it a day? AB - This article explores the dearth of coverage of the social determinants of health by the Canadian mainstream media. It is argued that this neglect is primarily a reflection of political and economic societal structures that has been associated with increasing corporate control of the mainstream media. Applying a critical political economy lens, it is argued that the barriers to having the Canadian mainstream media report on the social determinants of health are so numerous that it may indeed be 'time to call it a day' in regard to having them assist in the dissemination of social determinants of health findings. Recognizing this reality should spur the development of alternative means of communicating with the public in order to develop a citizens' movement to create health-promoting public policy. Recent dissemination efforts related to the Social Determinants of Health: The Canadian Facts provide an example of how this might be accomplished. PMID- 21303788 TI - Support for health promoting schools: a typology of supporting strategies in Austrian provinces. AB - Schools that want to implement health promotion (HP) are often confronted with obstacles that they cannot overcome by themselves and therefore need support from their environment. However, the issue of which kind of support is needed for HP implementation is complex. A systems approach suggests that the individual logic of each school be considered and that supporting strategies be flexible to specific needs. This article pursues the question which types of support for health promoting schools are offered on a provincial level in Austria. Using a grounded theory approach, 18 in-depth interviews with representatives of provincial organizations and 26 documents relevant for school HP were analysed. As a result, five different strategies of supporting health promoting schools have been identified in Austria: (i) organize exchange among schools, (ii) establish certification and quality control of school health efforts, (iii) offer consultation and information, (iv) carry out a specific HP programme and (v) coordinate HP actors and information. These strategies are usually combined and rarely occur in their pure form. It was also determined that the coordination of the different strategies and human resources for HP are missing for schools in Austria. It is argued that each of these supporting strategies has benefits and limitations for schools and the providers, and that they all have the potential to respond to the school as a complex social system. PMID- 21303789 TI - Prospective phase II study of FOLFIRI for mCRC in Japan, including the analysis of UGT1A1 28/6 polymorphisms. AB - OBJECTIVES: This is the first phase II study to evaluate the efficacy and tolerability of the first-line FOLFIRI, as well as the influence of uridine diphosphate glucuronosyl transferase 1, family polypeptide A1 gene (UGT1A1) 28/6 polymorphism, in Japanese metastatic colorectal cancer patients. METHODS: Fifty two patients were enrolled in this study and were administrated FOLFIRI (irinotecan; 150 mg/m(2)) as first-line chemotherapy. Thirty-nine patients accepted the evaluation of UGT1A1 genotypes. In patients with UGT1A1 28 homozygosity, the starting dose was reduced (100 mg/m(2)) according to the Food and Drug Administration recommendation and our previous phase I study. RESULTS: After a median follow-up period of 22 months, complete response was achieved in 1.9%, partial response in 38.5 %, stable disease in 51.9% and progressive disease in 3.9%. The overall response rate was 40.4%, the disease control rate was 92.3% and the median overall survival time was 22.3 months. The major toxicity was grade 3-4 neutropenia in 44.2%. There was no definite relation between UGT1A1 28, 6 polymorphisms and toxicity. However, homozygosity for UGT1A1 28 or UGT1A1 6 and double heterozygosity for both UGT1A1 28 and UGT1A1 6 were significantly associated with severe neutropenia in metastatic colorectal cancer patients (P< 0.001). CONCLUSIONS: FOLFIRI is effective and tolerable for Japanese metastatic colorectal cancer patients. Homozygosity for UGT1A1 28 or 6 and heterozygosity for both UGT1A1 28 and 6 are associated with severe neutropenia. PMID- 21303790 TI - Retrospective cohort study on the safety and efficacy of bevacizumab with chemotherapy for metastatic colorectal cancer patients: the HGCSG0801 study. AB - OBJECTIVE: After approval of bevacizumab in Japan, post-marketing surveillance studies reported on safety. However, few reports have shown the efficacy of bevacizumab as used in daily practice. We evaluated the efficacy and safety of bevacizumab for metastatic colorectal cancer patients in daily practice. METHODS: All unresectable metastatic colorectal cancer patients who began receiving bevacizumab in participating facilities from June 2007 to October 2008 were retrospectively analyzed for safety and efficacy. Adverse events were assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events. Response Evaluation in Solid Tumors criteria, version 1.0, was used for the tumor response rate. RESULTS: A total of 212 patients from 17 institutions were assessed. Grade 3 or higher adverse events related to bevacizumab included gastrointestinal perforation in 3, thrombosis in 7, hypertension in 30 and gastrointestinal bleeding in 2. Response rates were 62.5, 30.1 and 11.8% overall among patients receiving bevacizumab as first-, second- and third-line or greater therapy. Median progression-free survival was 14.4 [95% confidence interval (CI): 10.8-18.1], 7.8 (95% CI: 6.5-9.1) and 6.0 (95% CI: 4.6-7.3) months, and median overall survival was 32.5 (95% CI: 24.6-40.3), 16.4 (95% CI: 14.4-18.5) and 11.8 (95% CI: 8.6-15.0) months, respectively. CONCLUSIONS: The general cohort of patients in HGCSG0801 showed a similar efficacy and safety profile of bevacizumab as seen in clinical trials. Although the sample size was small and there were several study limitations, these results suggest that colorectal cancer patients in Japan might safely receive and benefit from bevacizumab in combination with chemotherapy in daily practice, as is seen in patients in other countries. PMID- 21303791 TI - Interstitial lung disease during chemotherapy combined with oxaliplatin and/or bevacizumab in advanced colorectal cancer patients. AB - OBJECTIVE: Interstitial lung disease in patients with colorectal cancer during chemotherapy combined with bevacizumab is rare. METHODS: We reviewed 104 colorectal cancer patients treated with standard chemotherapy with bevacizumab and examined the incidence of interstitial lung disease and its clinical features. RESULTS: We identified interstitial lung disease in four patients (3.85%). All patients were male. The median age was 64.5 years. Three of four patients had a history of smoking; median smoking index was 40 pack-years. Except one patient who had asymptomatic pulmonary fibrosis, chest computed tomography before chemotherapy showed no fibrotic changes. Pulmonary function test before chemotherapy showed normal values. All patients had received median 10 cycles (range 10-15 cycles) of FOLFOX before the onset of interstitial lung disease. Interstitial lung disease developed during FOLFOX + bevacizumab in two patients and during FOLFIRI + bevacizumab in two patients. The initial symptom of interstitial lung disease was fever in all patients. The median duration from the last chemotherapy to the onset of interstitial lung disease was 3.5 days (range 2 8 days). Three of four patients showed Grade 3 or more severity of interstitial lung disease according to Common Terminology Criteria for Adverse Events v3.0. High-dose steroid therapy was effective in all patients. CONCLUSIONS: Interstitial lung disease induced by standard chemotherapy with bevacizumab is rare, but rapidly progressed and were severe in our experience. PMID- 21303792 TI - General practitioners' conflicts of interest, the paramountcy principle and safeguarding children: a psychodynamic contribution. AB - Wainwright and Gallagher propose that when child protection concerns emerge significant difficulties arise for General Practitioners because of conflicts between the individual interests of children and parents who are their patients and the Paramountcy Principle. From a psychodynamic perspective their analysis does not give sufficient weight to the nature of personal as opposed to interpersonal conflict of a conscious or unconscious nature. When issues of major import arise, ordinary parenting inevitably involves parents in putting their children's needs first if competing possibilities occur. It is an over simplification to present this as a conflict between the interests of children and parents. Parents' own best interests are served by securing their children's safety and welfare. An appreciation of this is crucial in order to implement child protection procedures appropriately. Errors may occur because the complex emotions and relationships involved lead professionals to experience themselves as potential agents of harm rather than benefit. PMID- 21303793 TI - Healthcare scandals in the NHS: crime and punishment. AB - The Francis Report into failures of care at Mid Staffordshire NHS Foundation Trust Hospital documented a series of 'shocking' systematic failings in healthcare that left patients routinely neglected, humiliated and in pain as the Trust focused on cutting costs and hitting government targets. At present, the criminal law in England plays a limited role in calling healthcare professionals to account for failures in care. Normally, only if a gross error leads to death will a doctor or nurse face the prospect of prosecution. Doctors and nurses caring for patients under the Mental Health Act 1983 and the Mental Capacity Act 2005 may however be prosecuted for wilful neglect of a patient. In the light of the Francis Report, this article considers whether the criminal offence of wilful neglect should be extended to a broader healthcare setting and not confined to mental healthcare. PMID- 21303794 TI - Does the rejection of wrongful life claims rely on a conceptual error? AB - There are four major arguments raised against wrongful life claims: first, that it is impossible to establish harm in wrongful life claims; second, that wrongful life claims are illogical or incoherent; third, that life is inviolable and sacred no matter the quality; and fourth, that there are no rights and duties towards non-existent persons. In this paper, I will examine and evaluate critically the first two arguments. I will reject these objections against wrongful life claims and demonstrate that they rely on a conceptual error/mistake. In doing so, I will reject the logic of comparing existence with non-existence in wrongful life claims. Instead, I will maintain that recognition of the infant's cause of action and recognition of the infant's harmed condition need not imply any preference for non-existence over existence, and it need not to be so severe as to make life not worth living. I will conclude by briefly giving an account of what seems to me to be the right conception of what it is to be harmed. PMID- 21303795 TI - Estimation of atrial fibrillation recency of onset and safety of cardioversion using NTproBNP levels in patients with unknown time of onset. AB - OBJECTIVE: As shown previously in patients with new-onset atrial fibrillation (AF) without symptoms or signs of heart failure, N-terminal pro-brain natriuretic peptide (NTproBNP) increases rapidly, reaching a maximum within 24-36 h, and then decreases even if AF persists. A study was undertaken to use NTproBNP measurements in patients with AF of unknown time of onset to identify patients with presumed recent onset of the arrhythmia. DESIGN: Two-group open cross sectional study. SETTING: Hospitalised patients in cardiology departments of four hospitals. PATIENTS: Patients presenting with AF of unknown onset and no signs or symptoms of heart failure were separated into two groups: group A with NTproBNP above the cut-off level and group B with a low NTproBNP level. INTERVENTIONS: No therapeutic intervention. All patients underwent transoesophageal echocardiography (TEE). MAIN OUTCOME MEASURES: Presence of left atrial thrombus on TEE. RESULTS: In group A (N=43) only two patients (4.7%) were found to have an atrial thrombus on TEE (negative predictive value of raised NTproBNP levels 95.3%) compared with 13 of 43 patients in group B (30.2%; p=0.002). Patients with a higher CHA(2)DS(2)VASc score (p=0.002) and a larger left atrium (p<0.001) were more likely to have an atrial thrombus. In the multivariate analysis, NTproBNP below the cut-off level was the most powerful predictor of the presence of thrombus (OR 25.0; p=0.016). CONCLUSION: The reported strong correlation between raised NTproBNP levels and the absence of atrial thrombi on TEE suggests that the short-term increase in NTproBNP levels after AF onset might be used to assess the age of the arrhythmia and thus the safety of cardioversion in patients with AF of unknown onset and no heart failure. PMID- 21303796 TI - Fractal branching quantifies vascular changes and predicts survival in pulmonary hypertension: a proof of principle study. AB - OBJECTIVES: To develop a non-invasive method of assessing disease severity in pulmonary hypertension by quantifying the overall degree of vascular pruning using fractal geometry. DESIGN: A retrospective analysis of ECG-gated CT pulmonary angiograms. SETTING: A single national referral centre for the investigation and treatment of children with pulmonary hypertension. PATIENTS: Consecutive CT pulmonary angiograms in children and young adults (mean age 10.3 years, range 0.7-19.1) with pulmonary arterial hypertension assessed between January 2007 and April 2009. MAIN OUTCOME MEASURES: The fractal dimension (FD) of skeletonised CT pulmonary angiograms was calculated using the box counting method. The FD was compared with pulmonary vascular resistance, the percentage of predicted 6-min walk distance, WHO functional class and survival. RESULTS: Diagnostic plots confirmed that the pulmonary artery angiograms were all fractal. The FD correlated negatively with the pulmonary vascular resistance index (r= 0.55, p=0.01, n=21) and with WHO functional class (p<0.01, n=31) while it correlated positively with the percentage of predicted 6-min walk distance (r=0.43, p=0.04, n=24). A lower FD was associated with poorer survival (HR 5.6; 95% CI 1.2 to 25; p=0.027) for every SD reduction in FD. CONCLUSION: The FD derived from CT can be used to quantify vascular changes in pulmonary hypertension. This non-invasive technique may be useful in monitoring disease progression and response to therapy. PMID- 21303797 TI - Endogenous testosterone levels and cardiovascular disease in healthy men. PMID- 21303798 TI - Assessing healing of drug eluting stents. PMID- 21303799 TI - Response to influenza virus vaccination during chemotherapy in patients with breast cancer. AB - BACKGROUND: Patients receiving chemotherapy are at increased risk for influenza virus infection. Little is known about the preferred moment of vaccination during chemotherapy. PATIENTS AND METHODS: Breast cancer patients received influenza vaccination during FEC (5-fluorouracil, epirubicin and cyclophosphamide) containing chemotherapy regimens. Patients were randomised for early (day 4) or late (day 16) vaccination during the chemotherapy cycle. Influenza virus-specific antibody titres were determined before and 3 weeks after vaccination by haemagglutination inhibition. RESULTS: We included 38 breast cancer patients (20 in the early and 18 in the late group) and 21 healthy controls. The overall patient group had significant lower responses to the vaccine compared with healthy controls. Patients vaccinated at day 4 tended to have higher antibody titres as compared with patients vaccinated at day 16, although the difference in post-vaccination titres is not statistically significant. Geometric mean titres post-vaccination for day 4 versus day 16 were 63.7 versus 29.5 (H3N2), 28.2 versus 19.6 (H1N1) and 29.8 versus 16.0 (B/Brisbane), respectively. CONCLUSIONS: Patients on chemotherapy have significantly lower responses to influenza virus vaccination compared with healthy controls. Vaccination early during the chemotherapy cycle induces better responses than does vaccination at day 16 of the cycle. Follow-up studies are needed to confirm this effect. PMID- 21303800 TI - Immunochemotherapy with rituximab, methotrexate, procarbazine, and lomustine for primary CNS lymphoma (PCNSL) in the elderly. AB - BACKGROUND: Primary central nervous system lymphoma (PCNSL) is an aggressive extranodal non-Hodgkin lymphoma confined to the central nervous system. In this article, we report the results of a pilot trial adding rituximab to the established regimen consisting of methotrexate, procarbazine, and lomustine (R MCP). DESIGN AND METHODS: PCNSL patients >=65 years without Karnofsky performance score (KPS) limit were included. R-MCP regimen consisted of rituximab (375 mg/m(2) i.v. on days -6, 1, 15, and 29), methotrexate (3 g/m(2) i.v., days 2, 16, and 30) followed by folinic rescue, procarbazine (60 mg/m(2) orally, days 2-11), and lomustine (110 mg/m(2) orally, day 2). A maximum of three 43-day cycles were applied. Primary end point was response to treatment obtained by magnetic resonance imaging. Secondary end points were overall survival (OS) and progression-free survival (PFS). RESULTS: Twenty-eight patients were included (median age 75, median KPS 60%). Best documented response: complete remission in 18 of 28 (64%), partial remission in 5 of 28 (18%), stable disease in 1 of 28 (4%), and progressive disease in 2 of 28 (7%) patients. Response was not assessed in two patients. Two treatment-associated deaths were observed. After a median follow-up of 36 months, the 3-year PFS and OS was 31%. CONCLUSION: R-MCP regimen is well tolerated and active in elderly patients with newly diagnosed PCNSL. PMID- 21303801 TI - European cancer mortality predictions for the year 2011. AB - BACKGROUND: Mortality figures become available after some years. MATERIALS AND METHODS: Using the World Health Organization mortality and population data, we estimated numbers of deaths in 2011 from all cancers and selected sites for the European Union (EU) and six major countries, by fitting a joinpoint model to 5 year age-specific numbers of deaths. Age-standardized rates were computed using EUROSTAT population estimates. RESULTS: The predicted number of cancer deaths in the EU in 2011 was 1,281,436, with standardized rates of 143/100,000 men and 85/100,000 women. Poland had the highest rates, with smaller falls over recent periods. Declines in mortality for major sites including stomach, colorectum, breast, uterus, prostate and leukemias, plus male lung cancer, will continue until 2011, and a trend reversal or a leveling off is predicted where upward trends were previously observed. Female lung cancer rates are increasing in all major EU countries except the UK, where it is the first cause of cancer death, as now in Poland. The increasing pancreatic cancer trends in women observed up to 2004 have likely leveled off. CONCLUSIONS: Despite falls in rates, absolute numbers of cancer deaths are stable in Europe. The gap between Western and former nonmarket economy countries will likely persist. PMID- 21303803 TI - Hierarchical latency models for dose-time-response associations. AB - Exposure lagging and exposure-time window analysis are 2 widely used approaches to allow for induction and latency periods in analyses of exposure-disease associations. Exposure lagging implies a strong parametric assumption about the temporal evolution of the exposure-disease association. An exposure-time window analysis allows for a more flexible description of temporal variation in exposure effects but may result in unstable risk estimates that are sensitive to how windows are defined. The authors describe a hierarchical regression approach that combines time window analysis with a parametric latency model. They illustrate this approach using data from 2 occupational cohort studies: studies of lung cancer mortality among 1) asbestos textile workers and 2) uranium miners. For each cohort, an exposure-time window analysis was compared with a hierarchical regression analysis with shrinkage toward a simpler, second-stage parametric latency model. In each cohort analysis, there is substantial stability gained in time window-specific estimates of association by using a hierarchical regression approach. The proposed hierarchical regression model couples a time window analysis with a parametric latency model; this approach provides a way to stabilize risk estimates derived from a time window analysis and a way to reduce bias arising from misspecification of a parametric latency model. PMID- 21303804 TI - Re: "The emergence of translational epidemiology: from scientific discovery to population health impact". PMID- 21303806 TI - Short sleep duration and body mass index: a prospective longitudinal study in preadolescence. AB - Short sleep duration is associated with incidence of overweight and obesity in preadolescent children. The authors performed regression analyses on data from the Quebec Longitudinal Study of Kindergarten Children (1986-1987), a prospective cohort study comprising 1,916 preadolescent children in Canada. The aim was to assess associations between time spent in bed and body mass index reported by mothers after adjusting for numerous confounding factors, such as pubertal status. Time-in-bed and body mass index trajectories were computed using a semiparametric model mixture. Time-in-bed trajectories were classified as short (15% of the preadolescents), 10.5-hour (68%), and 11-hour (17%) sleep-duration trajectories, decreasing over time. Body mass index trajectories were classified as normal weight (68% of the preadolescents), overweight (27%), and obese (5%). The short sleep trajectory was associated with an increased odds ratio of being in the overweight body mass index trajectory (odds ratio (OR)=1.55, 95% confidence interval (CI): 1.39, 1.71) or in the obese body mass index trajectory (OR=3.26, 95% CI: 3.20, 3.29) compared with the 11-hour trajectory. One hour less of sleep per night at 10 years of age was associated with an increased odds ratio of being overweight (OR=1.51, 95% CI: 1.28, 1.76) or obese (OR=2.07; 95% CI: 1.51, 2.84) at 13 years of age. PMID- 21303805 TI - Usual physical activity and hip fracture in older men: an application of semiparametric methods to observational data. AB - Few studies have examined the relation between usual physical activity level and rate of hip fracture in older men or applied semiparametric methods from the causal inference literature that estimate associations without assuming a particular parametric model. Using the Physical Activity Scale for the Elderly, the authors measured usual physical activity level at baseline (2000-2002) in 5,682 US men >=65 years of age who were enrolled in the Osteoporotic Fractures in Men Study. Physical activity levels were classified as low (bottom quartile of Physical Activity Scale for the Elderly score), moderate (middle quartiles), or high (top quartile). Hip fractures were confirmed by central review. Marginal associations between physical activity and hip fracture were estimated with 3 estimation methods: inverse probability-of-treatment weighting, G-computation, and doubly robust targeted maximum likelihood estimation. During 6.5 years of follow-up, 95 men (1.7%) experienced a hip fracture. The unadjusted risk of hip fracture was lower in men with a high physical activity level versus those with a low physical activity level (relative risk = 0.51, 95% confidence interval: 0.28, 0.92). In semiparametric analyses that controlled confounding, hip fracture risk was not lower with moderate (e.g., targeted maximum likelihood estimation relative risk = 0.92, 95% confidence interval: 0.62, 1.44) or high (e.g., targeted maximum likelihood estimation relative risk = 0.88, 95% confidence interval: 0.53, 2.03) physical activity relative to low. This study does not support a protective effect of usual physical activity on hip fracture in older men. PMID- 21303807 TI - Occlusal asymmetries in children with congenital hip dislocation. AB - Developmental dysplasia of the hip (DDH) has been associated with other congenital postural deformities and associated with asymmetric features in the body. The aim of this study was to examine the associations between developmental DDH and malocclusions in preschool and school children. The subjects were 60 children (40 girls and 20 boys) born during 1997-2001 in Northern Ostrobothnia Hospital District and having developmental DDH and treated by Von Rosen method. The control group consisted of 71 Finnish children (46 girls and 25 boys) matched by age and gender. Children participated the cross-sectional study at the age of 5-10 years; the mean age of the DDH children was 8.0 (SD 1.4) and controls 7.9 (SD 1.4) years. Dental examinations, intra-oral photographs, and clinical examination including growth measurements were carried out. The DDH children had significantly more lateral crossbites than controls (30/9.9 per cent; P < 0.003). Overall, 77.8 per cent of cases were unilateral crossbites and found more on the right side (50 per cent) compared to the left side (22.2 per cent). Girls had more crossbite compared to boys (77.8/22.2 per cent; odds ratio 2.53). Children with congenital hip dislocation are more predisposed to the asymmetric growth of occlusion and the development of crossbite. The genetic and environmental factors including intrauterine conditions in addition to the splint therapy may be possible influencing factors. This study will give additional information of the development of occlusal asymmetries and the multifactorial nature of the aetiology of lateral malocclusions. PMID- 21303808 TI - Non-steroidal and steroidal anti-inflammatory use in the context of orthodontic movement. AB - The early phase of orthodontic tooth movement involves sterile acute inflammation of the periodontal ligament in response to biomechanical forces. Anti inflammatories are pharmacologic agents used in medical and dentistry clinics. The aim of the study was to analyse the bone remodelling during orthodontic movement under non-steroidal and steroidal treatment. Male Wistar rats (n = 90) were randomly divided into three groups: C (control), non-steroidal anti inflammatory drug (NSAID; potassium diclofenac), and steroidal anti-inflammatory drug (SAID; dexamethasone dissodium phosphate). The animals of the C group received 0.9 per cent saline solution, the NSAID group received potassium diclofenac CATAFLAM(r) (5 mg/kg), and the SAID group received dexamethasone dissodium phosphate DEXANIL(r) (2 mg/kg). Animals were sacrificed 3, 7, or 14 days after placement of the orthodontic appliance. The upper first molars were processed histologically; we quantified the blood vessels, Howship lacunae, and osteoclast-like cells present on the tension and compression sides of the periodontal ligament. Bone formation was evaluated under polarized light microscopy; 4.5 Image Pro-Plus(r) software calculated the percentage of immature/mature collagen present. The results showed that, in 3 and 7 days, NSAID and SAID groups presented fewer blood vessels, Howship lacunae, and osteoclast like cells when compared to the control group. On the 7th and 14th days, there was a lower percentage of mature collagen in the SAID group (P < 0.001). These data demonstrate that potassium diclofenac and dexamethasone inhibit bone resorption during the initial period of orthodontic movement and that dexamethasone delays the collagen maturation process in established bone matrix. PMID- 21303809 TI - The position of maxillary canine impactions and the influenced factors to adjacent root resorption in the Korean population. AB - The purpose of this study was to evaluate the position and aspects of maxillary canine impactions in the Korean population and investigate its comparison with the previous reports, while aiding in the establishment of diagnosis and treatment planning by revealing the influential factors of root resorption associated with such impactions. The subjects of this study consisted of 186 teeth from 148 patients, who had visited Seoul National University Dental Hospital due to impacted canines and had taken computerized tomographic images and panorama radiographic images. As a result, maxillary canine impaction in the Korean population occurred 1.5 times more often in females (F:M = 89:59) than males. Regarding the position of impaction, there were three times more buccal impactions (B:P = 140:46) than palatal impactions. The occurrence of root resorption was as high as 49.5 per cent. In evaluating the influential factors affecting adjacent root resorption, the significance of the impacted angulation was insufficient (P = 0.652). However, the buccopalatal position (P < 0.0001) and mesiodistal placement (P = 0.006, 0.037) of the impacted tooth were determined to be significant factors. Therefore, the adjacent root resorption caused by impacted maxillary canines can be stated to exhibit a greater amount of resorption as the positional proximity of the canine crown and lateral incisor root increases. PMID- 21303810 TI - Metal ion release from fixed orthodontic appliances--an in vivo study. AB - The aim of this study was to test the hypothesis that there is no difference in salivary metal ion content between subjects with fixed orthodontic appliances and their same-gender sister or brother without any orthodontic appliance. This retrospective study was carried out on 28 subjects (16 females and 12 males) who had undergone fixed orthodontic therapy for a duration of 12-18 months. In order to limit the effects of dietary and hygiene habits on salivary metal ion concentration, a same-gender brother or sister (total of 28 subjects) was selected as a control. Approximately 5 ml of saliva was collected from each subject, and the samples were analysed using an atomic absorption spectrophotometer. The detection limit of the method for sample solutions was 1 ng/ml. Since some variables were not normally distributed, non-parametric tests (Mann-Whitney U and Wilcoxon W) were used for statistical analysis. The mean salivary nickel (Ni) content in subjects with and without a fixed orthodontic appliance was 18.5 +/- 13.1 and 11.9 +/- 11.4 ng/ml, respectively. A statistically significant difference (P < 0.035) was found between the two groups. The mean salivary chromium (Cr) ion level recorded was 2.6 +/- 1.6 ng/ml in the study group and 2.2 +/- 1.6 ng/ml in the control group. The difference, however, was statistically insignificant. Within the limits of this in vivo study, it can be concluded that the presence of fixed orthodontic appliances leads to an increased concentration of metal ions in salivary secretions. PMID- 21303811 TI - A new approach of assessing sagittal dysplasia: the W angle. AB - In orthodontic diagnosis and treatment planning, an accurate antero-posterior measurement of jaw relationships is critically important. Previously described angular and linear measurements can be inaccurate because of their dependency on various factors. The purpose of this study was to introduce a new cephalometric measurement, named the W angle, to assess the sagittal relationship between maxilla and mandible with accuracy and reproducibility. This angle uses three skeletal landmarks--point S, point M, and point G--to measure an angle that indicates the severity and the type of skeletal dysplasia in the sagittal dimension. One hundred and forty-two pre-treatment cephalometric radiographs of patients between the age of 15 and 25 years were selected. They were again subdivided into Classes I, II, and III groups on the basis of Beta angle, Wits appraisal, and ANB angle. The W angle was measured between the perpendicular from point M on S-G line and the M-G line. The mean and the standard deviation for the W angle were calculated. After using the one-way analysis of variance and the Newman-Keuls test, receiver operating characteristics curves were obtained. Results showed that a patient with a W angle between 51 and 56 degrees can be considered to have a Class I skeletal pattern. With an angle less than 51 degrees, patients are considered to have a skeletal Class II relationship and with an angle greater than 56 degrees, patients have a skeletal Class III relationship. PMID- 21303812 TI - Turner syndrome isochromosome karyotype correlates with decreased dental crown width. AB - The aim of this project was to study possible influences of Turner syndrome (TS) karyotype and the number of X chromosomes with intact short arm (p-arm) on dental crown width. Primary and permanent mesio-distal crown width was measured on plaster casts from 112 TS females. The influence on crown width of four karyotypes: 1. monosomy (45,X), 2. mosaic (45,X/46,XX), 3. isochromosome, and 4. other, and the number of intact X chromosomal p-arms were investigated. In comparisons between karyotypes, statistically significant differences were found for isochromosome karyotype maxillary second premolars, canines, laterals, mandibular first premolars, and canines, indicating that this karyotype was the most divergent as shown by the most reduced crown width. When each karyotype group were compared versus controls, all teeth in the isochromosome group were significantly smaller than controls (P < 0.01-0.001). The 45,X/46,XX karyotype expressed fewer and smaller differences from controls, while 45,X individuals seemed to display an intermediate tooth width compared with 45,X/46,XX and isochromosomes. No significant difference in crown width was found comparing the groups with one or two intact X chromosomal p-arms. Both primary and permanent teeth proved to have a significantly smaller crown width in the entire group of TS females compared to healthy females. We conclude that the isochromosome group deviates most from other karyotypes and controls, exhibiting the smallest dental crown width, while individuals with 45,X/46,XX mosaicism seemed to have a less affected crown width. An influence of the number of intact p-arms on crown width could not be demonstrated in this study. PMID- 21303814 TI - Robust post-translocational N-glycosylation at the extreme C-terminus of membrane and secreted proteins in Xenopus laevis oocytes and HEK293 cells. AB - N-Glycosylation is normally a co-translational process that occurs as soon as a nascent and unfolded polypeptide chain has emerged ~12 residues into the lumen of the endoplasmic reticulum (ER). Here, we describe the efficient utilization of an N-glycosylation site engineered within the luminal extreme C-terminal residues of distinct integral membrane glycoproteins, a native ER resident protein and an engineered secreted protein. This N-glycan addition required that the acceptor asparagine within an Asn-Trp-Ser sequon be located at least four residues away from the C-terminus of the polypeptide and, in the case of membrane proteins, at least 13 residues away from the lumenal side of the transmembrane segment. Pulse chase assays revealed that the natural N-glycans of the proteins studied were attached co-translationally, whereas C-terminal N-glycosylation occurred post translocationally within a time frame of hours in Xenopus laevis oocytes and minutes in human embryonic kidney 293 (HEK293) cells. In oocyte and HEK cell expression systems, affinity tag-driven C-terminal N-glycosylation may facilitate the determination of orientation of the C-terminal tail of membrane proteins relative to the membrane. PMID- 21303815 TI - Structure of a lectin with antitumoral properties in king bolete (Boletus edulis) mushrooms. AB - A novel lectin has been isolated from the fruiting bodies of the common edible mushroom Boletus edulis (king bolete, penny bun, porcino or cep) by affinity chromatography on a chitin column. We propose for the lectin the name BEL (B. edulis lectin). BEL inhibits selectively the proliferation of several malignant cell lines and binds the neoplastic cell-specific T-antigen disaccharide, Galbeta1-3GalNAc. The lectin was structurally characterized: the molecule is a homotetramer and the 142-amino acid sequence of the chains was determined. The protein belongs to the saline-soluble family of mushroom fruiting body-specific lectins. BEL was also crystallized and its three-dimensional structure was determined by X-ray diffraction to 1.15 A resolution. The structure is similar to that of Agaricus bisporus lectin. Using the appropriate co-crystals, the interactions of BEL with specific mono- and disaccharides were also studied by X ray diffraction. The six structures of carbohydrate complexes reported here provide details of the interactions of the ligands with the lectin and shed light on the selectivity of the two distinct binding sites present in each protomer. PMID- 21303813 TI - Salicylate treatment improves age-associated vascular endothelial dysfunction: potential role of nuclear factor kappaB and forkhead Box O phosphorylation. AB - We hypothesized that I kappa B kinase (IKK)-mediated nuclear factor kappa B and forkhead BoxO3a phosphorylation will be associated with age-related endothelial dysfunction. Endothelium-dependent dilation and aortic protein expression/phosphorylation were determined in young and old male B6D2F1 mice and old mice treated with the IKK inhibitor, salicylate. IKK activation was greater in old mice and was associated with greater nitrotyrosine and cytokines. Endothelium-dependent dilation, nitric oxide (NO), and endothelial NO synthase phosphorylation were lower in old mice. Endothelium-dependent dilation and NO bioavailability were restored by a superoxide dismutase mimetic. Nuclear factor kappa B and forkhead BoxO3a phosphorylation were greater in old and were associated with increased expression/activity of nicotinamide adenine dinucleotide phosphate oxidase and lower manganese superoxide dismutase expression. Salicylate lowered IKK phosphorylation and reversed age-associated changes in nitrotyrosine, endothelium-dependent dilation, NO bioavailability, endothelial NO synthase, nuclear factor kappa B and forkhead BoxO3a phosphorylation, nicotinamide adenine dinucleotide phosphate oxidase, and manganese superoxide dismutase. Increased activation of IKK with advancing age stimulates nuclear factor kappa B and inactivates forkhead BoxO3a. This altered transcription factor activation contributes to a pro-inflammatory/pro-oxidative arterial phenotype that is characterized by increased cytokines and nicotinamide adenine dinucleotide phosphate oxidase and decreased manganese superoxide dismutase leading to oxidative stress-mediated endothelial dysfunction. PMID- 21303816 TI - Hard-to-reach? Using health access status as a way to more effectively target segments of the Latino audience. AB - Health issues disproportionately affect Latinos, but variations within this ethnic group may mean that some Latinos are harder to reach with health messages than others. This paper introduces a methodology grounded in communication infrastructure theory to better target 'hard-to-reach' audiences. A random digit dialing telephone survey of 739 Latinos living in two Los Angeles communities was conducted. The relationships between health access difficulties and connections to an integrated storytelling network as well as individual health communication source connections were explored. Findings suggest that Latinos who are connected to an integrated storytelling network report marginally greater ease finding healthcare, despite not being any more likely to have insurance or a regular place for healthcare. Latinos who have health access problems tended to rely more upon Spanish-language television for health information. In addition, those without healthcare access problems are more likely to indicate that they use health professionals, the Internet, mainstream TV and printed materials like health pamphlets for health information. The theoretical and methodological contributions of this work, its major findings, implications, limitations and policy guidelines are discussed. PMID- 21303817 TI - Characteristics of 'tween' participants and non-participants in the VERBTM summer scorecard physical activity promotion program. AB - Creating community-based opportunities for youth to be physically active is challenging for many municipalities. A Lexington, Kentucky community coalition designed and piloted a physical activity program, 'VERBTM summer scorecard (VSS)', leveraging the brand equity of the national VERBTM--It's What You Do! campaign. Key elements of VSS subsequently were adopted in Sarasota County, FL. This study identified characteristics of Sarasota's VSS participants and non participants. Students in Grades 5-8 from six randomly selected public schools completed a survey assessing VSS participation, physical activity level, psychosocial variables, parental support for physical activity and demographics. Logistic regression showed that VSS participants were more likely to be from Grades 5 to 6 versus Grades 7 and 8 [odds ratio (OR) = 6.055] and perceive high versus low parental support for physical activity (OR = 4.627). Moreover, for each unit rise in self-efficacy, the odds of VSS participation rose by 1.839. Chi squared automatic interaction detector (CHAID) analysis suggested an interaction effect between grade and school socioeconomic status (SES), with a large proportion of seventh and eighth graders from high SES schools being non participants (76.6%). A VSS-style program can be expected to be more effective with tweens who are younger, in a middle SES school, having high self-efficacy and high parental support for physical activity. PMID- 21303818 TI - How should we react to adverse drug reactions? PMID- 21303819 TI - Attitudes towards exercise in patients with chronic disease: the influence of comorbid factors on motivation and ability to exercise. AB - BACKGROUND: Exercise is an integral part of a healthy lifestyle. It has a well defined role in maintaining health in chronic illness. This study was undertaken to determine attitudes towards exercise in patients admitted to hospital with medical illnesses. METHODS: A questionnaire on attitudes to and extent of exercise was devised and administered to patients admitted to an acute medical unit of a large university teaching hospital in 2008. Data were analysed using SPSS. RESULTS: 107 patients participated, mean age 57 years (range 20-92): 79% had at least one chronic disease, 60% were overweight, 42% did little or no exercise, while 81% did not achieve moderate physical activity. Factors associated with reduced activity included increasing age, alcohol excess, lower education level, and unemployment. Approximately 50% of the patients blamed health problems while the other half cited lack of time or motivation as reasons for not exercising. Only 3% were aware of national or international exercise recommendations. CONCLUSIONS: Much greater awareness of the importance of exercise and its impact on health and longevity is needed. Healthcare providers have an important role in exercise education in patients with acute and chronic disease. PMID- 21303820 TI - Republished review: Tourette's syndrome and other tic disorders. AB - Tourette's syndrome is a neuropsychiatric disorder characterised by motor and phonic tics. Although tics are common in children, only about 1% of those affected meet the criteria for Tourette's syndrome, and many are not disabled by it. Associated problems such as attention deficit hyperactivity disorder and obsessive-compulsive disorders can often be more disabling than the tics themselves. People with Tourette's tend to be worst in their teenage years but improve in adulthood. The cause is unknown but there are strong genetic factors. Treatment should be aimed at minimising disability and includes social, psychological and biological approaches. PMID- 21303821 TI - Republished review: Mitral regurgitation in patients with aortic stenosis undergoing valve replacement. AB - Mitral regurgitation is a frequent finding in patients with aortic stenosis scheduled for aortic valve replacement. Detection of mitral regurgitation in such patients has important implications, as it can independently affect functional status and prognosis. When mitral regurgitation is moderate to severe, a decision to operate on both valves should only be made following a careful clinical and echocardiographic assessment. Indeed, double-valve surgery increases perioperative and postoperative risks, and mitral regurgitation may improve spontaneously after isolated aortic valve replacement. Better understanding of the determinants of these changes appears particularly crucial in the light of recent advances in percutaneous aortic valve replacement. PMID- 21303822 TI - Wistful thinking. PMID- 21303823 TI - Are transposable element insertions homoplasy free?: an examination using the avian tree of life. PMID- 21303824 TI - Taxon sampling and the optimal rates of evolution for phylogenetic inference. PMID- 21303825 TI - Differential responses to salt supplementation in adult male and female rat adrenal glands following intrauterine growth restriction. AB - In low sodium-induced intrauterine growth restricted (IUGR) rat, foetal adrenal steroidogenesis as well as the adult renin-angiotensin-aldosterone system (RAAS) is altered. The aim of the present study was to determine the expression of cytochrome P450 aldosterone synthase (P450aldo) and of angiotensin II receptor subtypes 1 (AT(1)R) and 2 (AT(2)R) in adult adrenal glands and whether this expression could be influenced by IUGR and by high-salt intake in a sex-specific manner. After 6 weeks of 0.9% NaCl supplementation, plasma renin activity, P450aldo expression and serum aldosterone levels were decreased in all groups. In males, IUGR induced an increase in AT(1)R, AT(2)R, and P450aldo levels, without changes in morphological appearance of the zona glomerulosa (ZG). By contrast, in females, IUGR had no effect on the expression of AT(1)R, but increased AT(2)R mRNA while decreasing protein expression of AT(2)R and P450aldo. In males, salt intake in IUGR rats reduced both AT(1)R mRNA and protein, while for AT(2)R, mRNA levels decreased whereas protein expression increased. In females, salt intake reduced ZG size in IUGR but had no affect on AT(1)R or AT(2)R expression in either group. These results indicate that, in response to IUGR and subsequently to salt intake, P450aldo, AT(1)R, and AT(2)R levels are differentially expressed in males and females. However, despite these adrenal changes, adult IUGR rats display adequate physiological and adrenal responses to high-salt intake, via RAAS inhibition, thus suggesting that extra-adrenal factors likely compensate for ZG alterations induced by IUGR. PMID- 21303827 TI - Immunoadsorption (IAS) for systemic lupus erythematosus. AB - Immunoadsorption (IAS) is used as a rescue therapy in severely ill SLE patients who are refractory to conventional therapies. This extracorporeal method aims at the rapid and extensive removal of pathogenic immunocomplexes (ICs) and (auto )antibodies (Abs). Although past data have shown short- to mid-term efficacy and biocompatibility of IAS in (renal) SLE, it is still an experimental and rather expensive procedure - and evidence from randomized controlled trials (RCTs) is lacking. Nevertheless, IAS is successfully used in life-threatening situations because of its fast mode of action and its acceptable safety profile. PMID- 21303826 TI - Selective deletion of long but not short Cypher isoforms leads to late-onset dilated cardiomyopathy. AB - Cypher long (CypherL) and short (CypherS) isoforms are distinguished from each other by the presence and absence of three C-terminal LIM domains, respectively. Cypher isoforms are developmentally regulated, and mutations affecting both long and short isoforms are linked to muscle disease in humans. Given these data, we hypothesized that various Cypher isoforms play overlapping and unique roles in striated muscle. To determine the specific role of Cypher isoforms in striated muscle, we generated two mouse lines in which either CypherS or CypherL isoforms were specifically deleted. Mice specifically, deficient in CypherS isoforms had no detectable muscle phenotype. In contrast, selective loss of CypherL isoforms resulted in partial neonatal lethality. Surviving mutants exhibited growth retardation and late-onset dilated cardiomyopathy, which was associated with cardiac fibrosis and calcification, leading to premature adult mortality. At a young age, preceding development of cardiomyopathy, hearts from these mutants exhibited defects in both Z-line ultrastructure and specific aberrations in calcineurin-NFAT and protein kinase C pathways. Earlier onset of cardiac dilation relative to control wild-type mice was observed in young CypherL isoform knockout mice consequent to pressure overload, suggesting a greater susceptibility to the disease. In summary, we have identified unique roles for CypherL isoforms in maintaining Z-line ultrastructure and signaling that are distinct from the roles of CypherS isoforms, while highlighting the contribution of mutations in the long isoforms to the development of dilated cardiomyopathy. PMID- 21303828 TI - IL-17-producing T cells in lupus nephritis. AB - Significant evidence implicates interleukin-17 (IL-17) in the pathogenesis of systemic lupus erythematosus (SLE), particularly in the development of tissue damage. IL-17 production and IL-17-producing CD4+ and CD3 + CD4-CD8- cells are increased in patients with SLE. IL-17-producing cells are present in the inflamed kidney tissues from patients with lupus nephritis. In lupus-prone mice, IL-17 production appears to be involved in the expression of disease pathology and pharmacologic or genetic manipulation of its production results in suppression of the disease. It becomes obvious that the use of biologics including humanized anti-IL-17 antibodies or decoy IL-17 receptors deserve clinical consideration. Similarly, the development of drugs that suppress the production of IL-17 is in order. PMID- 21303829 TI - Test-retest reliability of hand-held dynamometry and functional tests in systemic lupus erythematosus. AB - The aim of this study was to evaluate the test-retest reliability and determine the degree of measurement error of tests of isometric muscle strength and upper and lower limb function in women with systemic lupus erythematosus (SLE). Twelve women with SLE (age 39.8 +/- 10 years) were assessed on two occasions separated by a 7-10-day interval. Strength of six muscle groups was measured using a hand held dynamometer; function was measured by the 30-s sit to stand test and the 30 s 1 kg arm lift. Relative reliability was estimated using the intraclass correlation coefficient (ICC), model 2,1 (ICC2,1). Absolute reliability was estimated using standard error measurement and the minimal detectable difference was calculated. All ICCs were greater than 0.87. Muscle strength would need to increase by between 18% and 39% in women with SLE to be 95% confident of detecting real changes. The functional tests demonstrated a systematic bias between trials. This study demonstrates that hand-held dynamometry in SLE can be performed with excellent reliability. Further work needs to be completed to determine the number of trials necessary for both the 30-s sit to stand and 30-s 1 kg arm lift to decrease the systematic bias. PMID- 21303831 TI - Antiphospholipid antibodies and the brain: a consensus report. AB - This report discusses the difference between antiphospholipid antibodies (aPL) as a predictor for first and recurrent ischemic stroke, whether or not concomitant systemic lupus erythematosus (SLE) increases aPL-associated risk, and the association of aPL with other neurological manifestations. The neurological manifestations covered in this report were selected because they are among the most common, including cognitive dysfunction, headache, multiple sclerosis and seizures/epilepsy. Recommendations are made regarding further research that is needed to clarify remaining uncertainties. PMID- 21303832 TI - Report of the Obstetric APS Task Force: 13th International Congress on Antiphospholipid Antibodies, 13th April 2010. AB - The Obstetric APS Task Force of the 13th International Congress identified and discussed five general topics within 'Obstetric' Antiphospholipid Syndrome (APS) that contained areas of controversy or uncertainty: recurrent early miscarriage (REM), fetal death, delivery <34 weeks for severe preeclampsia or placental insufficiency, postpartum care, and long-term implications and care. The Task Force concluded that the frequency with which women with REM have a high titer of antiphospholipid antibodies (aPL) or lupus anticoagulant (LA) is somewhat controversial, especially with regard to the diagnostic titers required by the current international criteria for APS. Also, treatment trials involving heparin differ from one another with regard to the patients included and the outcomes achieved. Similarly, the frequency with which women with fetal death or delivery <34 weeks for severe preeclampsia or placental insufficiency have a high titer of aPL or LA is poorly defined, and there is no level I evidence to guide treatment in either group. Suggestions for future studies with regard to both REM and fetal death or delivery <34 weeks for severe preeclampsia or placental insufficiency were discussed and are outlined below. Postpartum and long-term care in women with APS diagnosed solely for obstetric criteria has been largely guided by expert opinion, and systematic evaluations of these populations would be welcome. PMID- 21303833 TI - Task Force on Catastrophic Antiphospholipid Syndrome (APS) and Non-criteria APS Manifestations (I): catastrophic APS, APS nephropathy and heart valve lesions. AB - The objectives of the 'Task Force on Catastrophic Antiphospholipid Syndrome (APS) and Non-criteria APS Manifestations' were to assess the clinical utility of the international consensus statement on classification criteria and treatment guidelines for the catastrophic APS, to identify and grade the studies that analyse the relationship between the antiphospholipid antibodies and the non criteria APS manifestations and to present the current evidence regarding the accuracy of these non-criteria APS manifestations for the detection of patients with APS. This article summarizes the studies analysed on the catastrophic APS, APS nephropathy and heart valve lesions, and presents the recommendations elaborated by the Task Force after this analysis. PMID- 21303834 TI - Task Force on Catastrophic Antiphospholipid Syndrome (APS) and Non-criteria APS Manifestations (II): thrombocytopenia and skin manifestations. AB - The objectives of the 'Task Force on Catastrophic Antiphospholipid Syndrome (APS) and Non-criteria APS Manifestations' were to assess the clinical utility of the international consensus statement on classification criteria and treatment guidelines for the catastrophic APS, to identify and grade the studies that analyze the relationship between the antiphospholipid antibodies and the non criteria APS manifestations, and to present the current evidence regarding the accuracy of these non-criteria APS manifestations for the detection of patients with APS. This article summarizes the studies analyzed on thrombocytopenia and skin manifestations, and presents the recommendations elaborated by the Task Force after this analysis. PMID- 21303835 TI - 'Criteria' aPL tests: report of a task force and preconference workshop at the 13th International Congress on Antiphospholipid Antibodies, Galveston, Texas, April 2010. AB - Current classification criteria for definite antiphospholipid syndrome (APS) mandate the use of one or more of three positive 'standardized' laboratory assays to detect antiphospholipid antibodies (aPL) (viz: anticardiolipin [aCL] IgG and IgM; anti-beta(2)glycoprotein I [anti-beta(2)GPI] antibodies IgG and IgM; and/or a lupus anticoagulant [LAC]), when at least one of the two major clinical manifestations (thrombosis or pregnancy losses) are present. Although, efforts of standardization for these 'criteria' aPL tests have been conducted over the last 27 years, reports of inconsistencies, inter-assay and inter-laboratory variation in the results of aCL, LAC, and anti-beta(2)GPI, and problems with the interpretation and the clinical value of the tests still exist, which affect the consistency of the diagnosis of APS. A Task Force of scientists and pioneers in the field from different countries, subdivided in three working groups, discussed and analyzed critical questions related to 'criteria' aPL tests in an evidence based manner, during the 13(th) International Congress on Antiphospholipid Antibodies (APLA 2010, April 13-16, 2010, Galveston, TX). These included: review of the standardization and the need for international consensus protocol for aCL and anti-beta(2)GPI tests; the use of monoclonal and/or polyclonal standards in the calibration curve of those tests; and the need for establishment of international units of measurement for anti-beta(2)GPI tests. The group also reviewed the recently updated guidelines for LAC testing, and analyzed and discussed the possibility of stratification of 'criteria' aPL tests as risk factors for APS, as well as the clinical value of single positive vs. multiple aPL positivity. The group members presented, discussed, analyzed data, updated and re-defined those critical questions at a preconference workshop that was open to congress attendees. This report summarizes the findings, conclusions, and recommendations of this Task Force. PMID- 21303836 TI - 'Non-criteria' aPL tests: report of a task force and preconference workshop at the 13th International Congress on Antiphospholipid Antibodies, Galveston, TX, USA, April 2010. AB - Abstract: Current classification criteria for definite APS recommend the use of one or more of three positive standardized laboratory assays, including anticardiolipin antibodies (aCL), lupus anticoagulant (LA), and antibodies directed to beta(2)glycoprotein I (anti-beta(2)GPI) to detect antiphospholipid antibodies (aPL) in the presence of at least one of the two major clinical manifestations (i.e., thrombosis or pregnancy morbidity) of the syndrome. Several other autoantibodies shown to be directed to phospholipids and/or their complexes with phospholipids and/or to proteins of the coagulation cascade, as well as a mechanistic test for resistance to annexin A5 anticoagulant activity, have been proposed to be relevant to APS. A task force of worldwide scientists in the field discussed and analyzed critical questions related to 'non-criteria' aPL tests in an evidence-based manner during the 13th International Congress on Antiphospholipid Antibodies (APLA 2010, 13-16 April 2010, Galveston, Texas, USA). This report summarizes the findings, conclusions, and recommendations of this task force. PMID- 21303837 TI - Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: report of a task force at the 13th International Congress on antiphospholipid antibodies. AB - The antiphospholipid syndrome (APS) is defined by the presence of thrombosis and/or pregnancy morbidity in combination with the persistent presence of circulating antiphospholipid antibodies: lupus anticoagulant, anticardiolipin antibodies and/or anti-beta2-glycoprotein I antibodies in medium to high titers. The management of thrombosis in patients with APS is a subject of controversy. This set of recommendations is the result of an effort to produce guidelines for therapy within a group of specialist physicians in Cardiology, Neurology, Hematology, Rheumatology and Internal Medicine, with a clinical and research focus on APS. PMID- 21303838 TI - Antiphospholipid Syndrome Clinical Research Task Force report. AB - The Antiphospholipid Syndrome (APS) Clinical Research Task Force (CRTF) was one of six Task Forces developed by the 13(th) International Congress on Antiphospholipid Antibodies (aPL) organization committee with the purpose of: a) evaluating the limitations of APS clinical research and developing guidelines for researchers to help improve the quality of APS research; and b) prioritizing the ideas for a well-designed multicenter clinical trial and discussing the pragmatics of getting such a trial done. Following a systematic working algorithm, the Task Force identified five major issues that impede APS clinical research and the ability to develop evidence-based recommendations for the management of aPL-positive patients: (1) aPL detection has been based on partially or non-standardized tests, and clinical (and basic) APS research studies have included patients with heterogeneous aPL profiles with different clinical event risks; (2) clinical (and basic) APS research studies have included a heterogeneous group of patients with different aPL-related manifestations (some controversial); (3) thrombosis and/or pregnancy risk stratification and quantification are rarely incorporated in APS clinical research; (4) most APS clinical studies include patients with single positive aPL results and/or low titer aPL ELISA results; furthermore, study designs are mostly retrospective and not population based, with limited number of prospective and/or controlled population studies; and (5) lack of the understanding the particular mechanisms of aPL-mediated clinical events limits the optimal clinical study design. The Task Force recommended that there is an urgent need for a truly international collaborative approach to design and conduct well-designed prospective large scale multi-center clinical trials of patients with persistent and clinically significant aPL profiles. An international collaborative meeting to formulate a good research question using 'FINER' (Feasible; Interesting; Novel; Ethical; and Relevant) criteria took place in November 2010. PMID- 21303839 TI - Zebrafish deficient for Muscleblind-like 2 exhibit features of myotonic dystrophy. AB - Myotonic dystrophy (DM; also known as dystrophia myotonica) is an autosomal dominant disorder that affects the heart, eyes, brain and endocrine system, but the predominant symptoms are neuromuscular, with progressive muscle weakness and wasting. DM presents in two forms, DM1 and DM2, both of which are caused by nucleotide repeat expansions: CTG in the DMPK gene for DM1 and CCTG in ZNF9 (CNBP) for DM2. Previous studies have shown that the mutant mRNAs containing the transcribed CUG or CCUG repeats are retained within the nuclei of cells from individuals with DM, where they bind and sequester the muscleblind-like proteins MBNL1, MBNL2 and MBNL3. It has been proposed that the sequestration of these proteins plays a key role in determining the classic features of DM. However, the functions of each of the three MBNL genes are not completely understood. We have generated a zebrafish knockdown model in which we demonstrate that a lack of mbnl2 function causes morphological abnormalities at the eye, heart, brain and muscle levels, supporting an essential role for mbnl2 during embryonic development. Major features of DM are replicated in our model, including muscle defects and splicing abnormalities. We found that the absence of mbnl2 causes disruption to the organization of myofibrils in skeletal and heart muscle of zebrafish embryos, and a reduction in the amount of both slow and fast muscle fibres. Notably, our findings included altered splicing patterns of two transcripts whose expression is also altered in DM patients: clcn1 and tnnt2. The studies described herein provide broader insight into the functions of MBNL2. They also lend support to the hypothesis that the sequestration of this protein is an important determinant in DM pathophysiology, and imply a direct role of MBNL2 in splicing regulation of specific transcripts, which, when altered, contributes to the DM phenotype. PMID- 21303840 TI - A Drosophila model for fetal alcohol syndrome disorders: role for the insulin pathway. AB - Prenatal exposure to ethanol in humans results in a wide range of developmental abnormalities, including growth deficiency, developmental delay, reduced brain size, permanent neurobehavioral abnormalities and fetal death. Here we describe the use of Drosophila melanogaster as a model for exploring the effects of ethanol exposure on development and behavior. We show that developmental ethanol exposure causes reduced viability, developmental delay and reduced adult body size. We find that flies reared on ethanol-containing food have smaller brains and imaginal discs, which is due to reduced cell division rather than increased apoptosis. Additionally, we show that, as in mammals, flies reared on ethanol have altered responses to ethanol vapor exposure as adults, including increased locomotor activation, resistance to the sedating effects of the drug and reduced tolerance development upon repeated ethanol exposure. We have found that the developmental and behavioral defects are largely due to the effects of ethanol on insulin signaling; specifically, a reduction in Drosophila insulin-like peptide (Dilp) and insulin receptor expression. Transgenic expression of Dilp proteins in the larval brain suppressed both the developmental and behavioral abnormalities displayed by ethanol-reared adult flies. Our results thus establish Drosophila as a useful model system to uncover the complex etiology of fetal alcohol syndrome. PMID- 21303841 TI - Dual targeting of a mitochondrial protein: the case study of cytochrome c1. AB - As a result of the endosymbiotic gene transfer, the majority of proteins of mitochondria and chloroplasts is encoded in the nucleus and synthesized in the cytosol as precursor molecules carrying N-terminal transit peptides for the transport into the respective target organelle. In most instances, transport takes place into either mitochondria or chloroplasts, although a few examples of dual targeting into both organelles have been described. Here, we show by a combination of three different experimental strategies that also cytochrome c(1) of potato, a component of the respiratory electron transport chain, is imported not only into mitochondria, but also into plastids. In organello import experiments with isolated mitochondria and chloroplasts, which were analyzed in both single and mixed organelle assays, demonstrate that the processing products accumulating after import within the two endosymbiotic organelles are different in size. Dual targeting of cytochrome c(1) is observed also in vivo, after biolistic transformation of leaf epidermal cells with suitable reporter constructions. Finally, Western analyses employing cytochrome c(1)-specific antiserum provide evidence that the protein accumulates in significant amounts in mitochondria and chloroplasts of both pea and spinach. The possible consequences of our findings on the relevance of the dual targeting phenomenon are discussed. PMID- 21303842 TI - ORS1, an H2O2-responsive NAC transcription factor, controls senescence in Arabidopsis thaliana. AB - We report here that ORS1, a previously uncharacterized member of the NAC transcription factor family, controls leaf senescence in Arabidopsis thaliana. Overexpression of ORS1 accelerates senescence in transgenic plants, whereas its inhibition delays it. Genes acting downstream of ORS1 were identified by global expression analysis using transgenic plants producing dexamethasone-inducible ORS1-GR fusion protein. Of the 42 up-regulated genes, 30 (~70%) were previously shown to be up-regulated during age-dependent senescence. We also observed that 32 (~76%) of the ORS1-dependent genes were induced by long-term (4 d), but not short-term (6 h) salinity stress (150 mM NaCl). Furthermore, expression of 16 and 24 genes, respectively, was induced after 1 and 5 h of treatment with hydrogen peroxide (H2O2), a reactive oxygen species known to accumulate during salinity stress. ORS1 itself was found to be rapidly and strongly induced by H2O2 treatment in both leaves and roots. Using in vitro binding site selection, we determined the preferred binding motif of ORS1 and found it to be present in half of the ORS1-dependent genes. ORS1 is a paralog of ORE1/ANAC092/AtNAC2, a previously reported regulator of leaf senescence. Phylogenetic footprinting revealed evolutionary conservation of the ORS1 and ORE1 promoter sequences in different Brassicaceae species, indicating strong positive selection acting on both genes. We conclude that ORS1, similarly to ORE1, triggers expression of senescence-associated genes through a regulatory network that may involve cross talk with salt- and H2O2-dependent signaling pathways. PMID- 21303843 TI - Antiplatelet therapy and vascular disease: an update. AB - Atherosclerosis is a diffuse, systemic disorder of the large and medium-sized arterial vessels, affecting the coronary, cerebral and peripheral circulation. Chronic inflammatory processes are the central pathophysiological mechanism largely driven by lipid accumulation, and provide the substrate for occlusive thrombus formation. The clinical sequelae of acute arterial thrombosis, heart attack and stroke, are the most common causes of morbidity and mortality in the industrialized world. Such acute events are characterized by rupture or erosion of the atherosclerotic plaque leading to acute thrombosis. The atherosclerotic process and associated thrombotic complications are collectively termed atherothrombosis. The platelet is a pivotal mediator of various endothelial, immune, thrombotic and inflammatory responses and therefore a key player in the initiation and progression of atherothrombosis. A robust evidence base supports the clear clinical benefits of antiplatelet agents in the primary and secondary therapy of atherothrombotic disorders. Percutaneous coronary and peripheral interventions have an established central role in the management of atherothrombotic disease and demand a greater understanding of platelet biology. In this article, we provide a clinically orientated overview of the pathophysiology of arterial thrombosis and the evidence supporting the use of the various established antiplatelet therapies, and discuss new and future agents. PMID- 21303845 TI - Asymmetric division of cyst stem cells in Drosophila testis is ensured by anaphase spindle repositioning. AB - Many stem cells divide asymmetrically to balance self-renewal and differentiation. In Drosophila testes, two stem cell populations, germline stem cells (GSCs) and somatic cyst stem cells (CySCs), cohere and regulate one another. Here, we report that CySCs divide asymmetrically through repositioning the mitotic spindle around anaphase. CySC spindle repositioning requires functional centrosomes, Dynein and the actin-membrane linker Moesin. Anaphase spindle repositioning is required to achieve high-fidelity asymmetric divisions in CySCs, thus maintaining both GSC and CySC numbers. We propose that dynamic spindle repositioning allows CySCs to divide asymmetrically while accommodating the structure of the GSCs they encapsulate. PMID- 21303846 TI - Mos limits the number of meiotic divisions in urochordate eggs. AB - Mos kinase is a universal mediator of oocyte meiotic maturation and is produced during oogenesis and destroyed after fertilization. The hallmark of maternal meiosis is that two successive M phases (meiosis I and II) drive two rounds of asymmetric cell division (ACD). However, how the egg limits the number of meioses to just two, thereby preventing gross aneuploidy, is poorly characterized. Here, in urochordate eggs, we show that loss of Mos/MAPK activity is necessary to prevent entry into meiosis III. Remarkably, maintaining the Mos/MAPK pathway active after fertilization at near physiological levels induces additional rounds of meiotic M phase (meiosis III, IV and V). During these additional rounds of meiosis, the spindle is positioned asymmetrically resulting in further rounds of ACD. In addition, inhibiting meiotic exit with Mos prevents pronuclear formation, cyclin A accumulation and maintains sperm-triggered Ca(2+) oscillations, all of which are hallmarks of the meiotic cell cycle in ascidians. It will be interesting to determine whether Mos availability in mammals can also control the number of meioses as it does in the urochordates. Our results demonstrate the power of urochordate eggs as a model to dissect the egg-to-embryo transition. PMID- 21303844 TI - Elaborating polarity: PAR proteins and the cytoskeleton. AB - Cell polarity is essential for cells to divide asymmetrically, form spatially restricted subcellular structures and participate in three-dimensional multicellular organization. PAR proteins are conserved polarity regulators that function by generating cortical landmarks that establish dynamic asymmetries in the distribution of effector proteins. Here, we review recent findings on the role of PAR proteins in cell polarity in C. elegans and Drosophila, and emphasize the links that exist between PAR networks and cytoskeletal proteins that both regulate PAR protein localization and act as downstream effectors to elaborate polarity within the cell. PMID- 21303847 TI - The control of foxN2/3 expression in sea urchin embryos and its function in the skeletogenic gene regulatory network. AB - Early development requires well-organized temporal and spatial regulation of transcription factors that are assembled into gene regulatory networks (GRNs). In the sea urchin, an endomesoderm GRN model explains much of the specification in the endoderm and mesoderm prior to gastrulation, yet some GRN connections remain incomplete. Here, we characterize FoxN2/3 in the primary mesenchyme cell (PMC) GRN state. Expression of foxN2/3 mRNA begins in micromeres at the hatched blastula stage and then is lost from micromeres at the mesenchyme blastula stage. foxN2/3 expression then shifts to the non-skeletogenic mesoderm and, later, to the endoderm. Here, we show that Pmar1, Ets1 and Tbr are necessary for activation of foxN2/3 in micromeres. The later endomesoderm expression of foxN2/3 is independent of the earlier expression of foxN2/3 in micromeres and is independent of signals from PMCs. FoxN2/3 is necessary for several steps in the formation of the larval skeleton. Early expression of genes for the skeletal matrix is dependent on FoxN2/3, but only until the mesenchyme blastula stage as foxN2/3 mRNA disappears from PMCs at that time and we assume that the protein is not abnormally long-lived. Knockdown of FoxN2/3 inhibits normal PMC ingression and foxN2/3 morphant PMCs do not organize in the blastocoel and fail to join the PMC syncytium. In addition, without FoxN2/3, the PMCs fail to repress the transfating of other mesodermal cells into the skeletogenic lineage. Thus, FoxN2/3 is necessary for normal ingression, for expression of several skeletal matrix genes, for preventing transfating and for fusion of the PMC syncytium. PMID- 21303848 TI - Characterization of a Dchs1 mutant mouse reveals requirements for Dchs1-Fat4 signaling during mammalian development. AB - The Drosophila Dachsous and Fat proteins function as ligand and receptor, respectively, for an intercellular signaling pathway that regulates Hippo signaling and planar cell polarity. Although gene-targeted mutations in two mammalian Fat genes have been described, whether mammals have a Fat signaling pathway equivalent to that in Drosophila, and what its biological functions might be, have remained unclear. Here, we describe a gene-targeted mutation in a murine Dachsous homolog, Dchs1. Analysis of the phenotypes of Dchs1 mutant mice and comparisons with Fat4 mutant mice identify requirements for these genes in multiple organs, including the ear, kidney, skeleton, intestine, heart and lung. Dchs1 and Fat4 single mutants and Dchs1 Fat4 double mutants have similar phenotypes throughout the body. In some cases, these phenotypes suggest that Dchs1-Fat4 signaling influences planar cell polarity. In addition to the appearance of cysts in newborn kidneys, we also identify and characterize a requirement for Dchs1 and Fat4 in growth, branching and cell survival during early kidney development. Dchs1 and Fat4 are predominantly expressed in mesenchymal cells in multiple organs, and mutation of either gene increases protein staining for the other. Our analysis implies that Dchs1 and Fat4 function as a ligand-receptor pair during murine development, and identifies novel requirements for Dchs1-Fat4 signaling in multiple organs. PMID- 21303849 TI - beta-catenin specifies the endomesoderm and defines the posterior organizer of the hemichordate Saccoglossus kowalevskii. AB - The canonical Wnt/beta-catenin pathway is a key regulator of body plan organization and axis formation in metazoans, being involved in germ layer specification, posterior growth and patterning of the anteroposterior axis. Results from animals spanning a wide phylogenetic range suggest that a unifying function of beta-catenin in metazoans is to define the posterior/vegetal part of the embryo. Although the specification of vegetal territories (endoderm) by beta catenin has been demonstrated in distantly related animals (cnidarians, a protostome, echinoderms and ascidians), the definition of the posterior part of the embryo is well supported only for vertebrates and planarians. To gain insights into beta-catenin functions during deuterostome evolution, we have studied the early development of the direct developing hemichordate Saccoglossus kowalevskii. We show that the zygote is polarized after fertilization along the animal-vegetal axis by cytoplasmic rearrangements resembling the ascidian vegetal contraction. This early asymmetry is translated into nuclear accumulation of beta catenin at the vegetal pole, which is necessary and sufficient to specify endomesoderm. We show that endomesoderm specification is crucial for anteroposterior axis establishment in the ectoderm. The endomesoderm secretes as yet unidentified signals that posteriorize the ectoderm, which would otherwise adopt an anterior fate. Our results point to a conserved function at the base of deuterostomes for beta-catenin in germ layer specification and to a causal link in the definition of the posterior part of the embryonic ectoderm by way of activating posteriorizing endomesodermal factors. Consequently, the definition of the vegetal and the posterior regions of the embryo by beta-catenin should be distinguished and carefully re-examined. PMID- 21303850 TI - Signaling through BMP receptors promotes respiratory identity in the foregut via repression of Sox2. AB - The mammalian foregut gives rise to the dorsally located esophagus and stomach and the ventrally located trachea and lung. Proper patterning and morphogenesis of the common foregut tube and its derived organs is essential for viability of the organism at birth. Here, we show that conditional inactivation of BMP type I receptor genes Bmpr1a and Bmpr1b (Bmpr1a;b) in the ventral endoderm leads to tracheal agenesis and ectopic primary bronchi. Molecular analyses of these mutants reveal a reduction of ventral endoderm marker NKX2-1 and an expansion of dorsal markers SOX2 and P63 into the prospective trachea and primary bronchi. Subsequent genetic experiments show that activation of canonical WNT signaling, previously shown to induce ectopic respiratory fate in otherwise wild-type mice, is incapable of promoting respiratory fate in the absence of Bmpr1a;b. Furthermore, we find that inactivation of Sox2 in Bmpr1a;b mutants does not suppress ectopic lung budding but does rescue trachea formation and NKX2-1 expression. Together, our data suggest that signaling through BMPR1A;B performs at least two roles in early respiratory development: first, it promotes tracheal formation through repression of Sox2; and second, it restricts the site of lung bud initiation. PMID- 21303851 TI - Concentric zones, cell migration and neuronal circuits in the Drosophila visual center. AB - The Drosophila optic lobe comprises a wide variety of neurons, which form laminar neuropiles with columnar units and topographic projections from the retina. The Drosophila optic lobe shares many structural characteristics with mammalian visual systems. However, little is known about the developmental mechanisms that produce neuronal diversity and organize the circuits in the primary region of the optic lobe, the medulla. Here, we describe the key features of the developing medulla and report novel phenomena that could accelerate our understanding of the Drosophila visual system. The identities of medulla neurons are pre-determined in the larval medulla primordium, which is subdivided into concentric zones characterized by the expression of four transcription factors: Drifter, Runt, Homothorax and Brain-specific homeobox (Bsh). The expression pattern of these factors correlates with the order of neuron production. Once the concentric zones are specified, the distribution of medulla neurons changes rapidly. Each type of medulla neuron exhibits an extensive but defined pattern of migration during pupal development. The results of clonal analysis suggest homothorax is required to specify the neuronal type by regulating various targets including Bsh and cell adhesion molecules such as N-cadherin, while drifter regulates a subset of morphological features of Drifter-positive neurons. Thus, genes that show the concentric zones may form a genetic hierarchy to establish neuronal circuits in the medulla. PMID- 21303852 TI - Neuronal subtype specification in the spinal cord of a protovertebrate. AB - The visceral ganglion (VG) comprises the basic motor pool of the swimming ascidian tadpole and has been proposed to be homologous to the spinal cord of vertebrates. Here, we use cis-regulatory modules, or enhancers, from transcription factor genes expressed in single VG neuronal precursors to label and identify morphologically distinct moto- and interneuron subtypes in the Ciona intestinalis tadpole larva. We also show that the transcription factor complement present in each differentiating neuron correlates with its unique morphology. Forced expression of putative interneuron markers Dmbx and Vsx results in ectopic interneuron-like cells at the expense of motoneurons. Furthermore, by perturbing upstream signaling events, we can change the transcription factor expression profile and subsequent identity of the different precursors. Perturbation of FGF signaling transforms the entire VG into Vsx+/Pitx+ putative cholinergic interneurons, while perturbation of Notch signaling results in duplication of Dmbx+ decussating interneurons. These experiments demonstrate the connection between transcriptional regulation and the neuronal subtype diversity underlying swimming behavior in a simple chordate. PMID- 21303853 TI - Cooperative activity of noggin and gremlin 1 in axial skeleton development. AB - Inductive signals from adjacent tissues initiate differentiation within the somite. In this study, we used mouse embryos mutant for the BMP antagonists noggin (Nog) and gremlin 1 (Grem1) to characterize the effects of BMP signaling on the specification of the sclerotome. We confirmed reduction of Pax1 and Pax9 expression in Nog mutants, but found that Nog;Grem1 double mutants completely fail to initiate sclerotome development. Furthermore, Nog mutants that also lack one allele of Grem1 exhibit a dramatic reduction in axial skeleton relative to animals mutant for Nog alone. By contrast, Pax3, Myf5 and Lbx1 expression indicates that dermomyotome induction occurs in Nog;Grem1 double mutants. Neither conditional Bmpr1a mutation nor treatment with the BMP type I receptor inhibitor dorsomorphin expands sclerotome marker expression, suggesting that BMP antagonists do not have an instructive function in sclerotome specification. Instead, we hypothesize that Nog- and Grem1-mediated inhibition of BMP is permissive for hedgehog (Hh) signal-mediated sclerotome specification. In support of this model, we found that culturing Nog;Grem1 double-mutant embryos with dorsomorphin restores sclerotome, whereas Pax1 expression in smoothened (Smo) mutants is not rescued, suggesting that inhibition of BMP is insufficient to induce sclerotome in the absence of Hh signaling. Confirming the dominant inhibitory effect of BMP signaling, Pax1 expression cannot be rescued in Nog;Grem1 double mutants by forced activation of Smo. We conclude that Nog and Grem1 cooperate to maintain a BMP signaling-free zone that is a crucial prerequisite for Hh-mediated sclerotome induction. PMID- 21303854 TI - Locomotion in stroke subjects: interactions between unaffected and affected sides. AB - The aim of this study was to evaluate the sensorimotor interactions between unaffected and affected sides of post-stroke subjects during locomotion. In healthy subjects, stimulation of the tibial nerve during the mid-stance phase is followed by electromyography responses not only in the ipsilateral tibialis anterior, but also in the proximal arm muscles of both sides, with larger amplitudes prior to swing over an obstacle compared with normal swing. In post stroke subjects, the electromyography responses were stronger on both sides when the tibial nerve of the unaffected leg was stimulated compared with stimulation of the affected leg. This difference was more pronounced when stimuli were applied prior to swing over an obstacle than prior to normal swing. This indicates an impaired processing of afferent input from the affected leg resulting in attenuated and little task-modulated reflex responses in the arm muscles on both sides. In contrast, an afferent volley from the unaffected leg resulted in larger electromyography responses, even in the muscles of the affected arm. Arm muscle activations were stronger during swing over an obstacle than during normal swing, with no difference in electromyography amplitudes between the unaffected and affected sides. It is concluded that the deficits of the affected arm are compensated for by influences from the unaffected side. These observations indicate strong mutual influences between unaffected and affected sides during locomotion of post-stroke subjects, which might be used to optimize rehabilitation approaches. PMID- 21303856 TI - Reply to Oluf Anderson's reply: Predicting a window of therapeutic opportunity in multiple sclerosis. PMID- 21303855 TI - The clinical and molecular genetic features of idiopathic infantile periodic alternating nystagmus. AB - Periodic alternating nystagmus consists of involuntary oscillations of the eyes with cyclical changes of nystagmus direction. It can occur during infancy (e.g. idiopathic infantile periodic alternating nystagmus) or later in life. Acquired forms are often associated with cerebellar dysfunction arising due to instability of the optokinetic-vestibular systems. Idiopathic infantile periodic alternating nystagmus can be familial or occur in isolation; however, very little is known about the clinical characteristics, genetic aetiology and neural substrates involved. Five loci (NYS1-5) have been identified for idiopathic infantile nystagmus; three are autosomal (NYS2, NYS3 and NYS4) and two are X-chromosomal (NYS1 and NYS5). We previously identified the FRMD7 gene on chromosome Xq26 (NYS1 locus); mutations of FRMD7 are causative of idiopathic infantile nystagmus influencing neuronal outgrowth and development. It is unclear whether the periodic alternating nystagmus phenotype is linked to NYS1, NYS5 (Xp11.4-p11.3) or a separate locus. From a cohort of 31 X-linked families and 14 singletons (70 patients) with idiopathic infantile nystagmus we identified 10 families and one singleton (21 patients) with periodic alternating nystagmus of which we describe clinical phenotype, genetic aetiology and neural substrates involved. Periodic alternating nystagmus was not detected clinically but only on eye movement recordings. The cycle duration varied from 90 to 280 s. Optokinetic reflex was not detectable horizontally. Mutations of the FRMD7 gene were found in all 10 families and the singleton (including three novel mutations). Periodic alternating nystagmus was predominantly associated with missense mutations within the FERM domain. There was significant sibship clustering of the phenotype although in some families not all affected members had periodic alternating nystagmus. In situ hybridization studies during mid-late human embryonic stages in normal tissue showed restricted FRMD7 expression in neuronal tissue with strong hybridization signals within the afferent arms of the vestibulo-ocular reflex consisting of the otic vesicle, cranial nerve VIII and vestibular ganglia. Similarly within the afferent arm of the optokinetic reflex we showed expression in the developing neural retina and ventricular zone of the optic stalk. Strong FRMD7 expression was seen in rhombomeres 1 to 4, which give rise to the cerebellum and the common integrator site for both these reflexes (vestibular nuclei). Based on the expression and phenotypic data, we hypothesize that periodic alternating nystagmus arises from instability of the optokinetic vestibular systems. This study shows for the first time that mutations in FRMD7 can cause idiopathic infantile periodic alternating nystagmus and may affect neuronal circuits that have been implicated in acquired forms. PMID- 21303857 TI - A new case of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids with initial normal magnetic resonance imaging. PMID- 21303858 TI - Neuronal networks in children with continuous spikes and waves during slow sleep. PMID- 21303859 TI - In vivo activation of endocannabinoid system in temporal lobe epilepsy with hippocampal sclerosis. AB - The endocannabinoid system modulates neuronal excitability, protects neurons against hyperexcitability and is involved in epileptogenesis in animal models of mesial temporal lobe epilepsy with hippocampal sclerosis. We performed in vivo positron emission tomography imaging of the type 1 cannabinoid receptor in patients with mesial temporal lobe epilepsy with hippocampal sclerosis. Twelve patients with refractory mesial temporal lobe epilepsy due to hippocampal sclerosis received a [(18)F]MK-9470 scan to assess type 1 cannabinoid receptor availability in vivo. Parametric modified standard uptake values were used as quantitative measure of type 1 cannabinoid receptor availability and images were spatially normalized to standard space. Voxel-based analysis was performed comparing patients with hippocampal sclerosis to controls and correlations between type 1 cannabinoid receptor status and seizure characteristics were done using volumes of interest. Type 1 cannabinoid receptor positron emission tomography was co-registered with subtraction ictal single photon emission computed tomography co-registered to magnetic resonance imaging of a complex partial seizure (n = 9). An increased type 1 cannabinoid receptor availability in the ipsilateral temporal lobe was observed, which correlated negatively with the latency since last seizure before scanning and positively to the number of seizures in the month before scanning. A decreased type 1 cannabinoid receptor availability was present in the superior insular cortex, ipsilateral more than contralateral. The ipsilateral insular region displayed a mild ictal hyperperfusion in the transition zone of subtraction ictal single photon emission computed tomography co-registered to magnetic resonance imaging temporal lobe hyperperfusion-frontal lobe hypoperfusion during complex partial seizures. Type 1 cannabinoid receptor availability showed opposite changes in different brain regions that are involved during complex partial seizures in refractory mesial temporal lobe epilepsy with hippocampal sclerosis. The increase in type 1 cannabinoid receptor availability at the seizure onset zone might be a protective mechanism of neurons against hyperexcitability and seizure activity, or contribute to the process of epileptogenesis, or both. The decreased type 1 cannabinoid receptor availability in the insula may play a role in surround inhibition and prevention of seizure propagation. PMID- 21303860 TI - Mouse models of dominant ACTA1 disease recapitulate human disease and provide insight into therapies. AB - Mutations in the skeletal muscle alpha-actin gene (ACTA1) cause a range of pathologically defined congenital myopathies. Most patients have dominant mutations and experience severe skeletal muscle weakness, dying within one year of birth. To determine mutant ACTA1 pathobiology, transgenic mice expressing ACTA1(D286G) were created. These Tg(ACTA1)(D286G) mice were less active than wild type individuals. Their skeletal muscles were significantly weaker by in vitro analyses and showed various pathological lesions reminiscent of human patients, however they had a normal lifespan. Mass spectrometry revealed skeletal muscles from Tg(ACTA1)(D286G) mice contained ~25% ACTA1(D286G) protein. Tg(ACTA1)(D286G) mice were crossed with hemizygous Acta1(+/-) knock-out mice to generate Tg(ACTA1)(D286G)(+/+).Acta1(+/-) offspring that were homozygous for the transgene and hemizygous for the endogenous skeletal muscle alpha-actin gene. Akin to most human patients, skeletal muscles from these offspring contained approximately equal proportions of ACTA1(D286G) and wild-type actin. Strikingly, the majority of these mice presented with severe immobility between postnatal Days 8 and 17, requiring euthanasia. Their skeletal muscles contained extensive structural abnormalities as identified in severely affected human patients, including nemaline bodies, actin accumulations and widespread sarcomeric disarray. Therefore we have created valuable mouse models, one of mild dominant ACTA1 disease [Tg(ACTA1)(D286G)], and the other of severe disease, with a dramatically shortened lifespan [Tg(ACTA1)(D286G)(+/+).Acta1(+/-)]. The correlation between mutant ACTA1 protein load and disease severity parallels effects in ACTA1 families and suggests altering this ratio in patient muscle may be a therapy for patients with dominant ACTA1 disease. Furthermore, ringbinden fibres were observed in these mouse models. The presence of such features suggests that perhaps patients with ringbinden of unknown genetic origin should be considered for ACTA1 mutation screening. This is the first experimental, as opposed to observational, evidence that mutant protein load determines the severity of ACTA1 disease. PMID- 21303861 TI - Smoking and two human leukocyte antigen genes interact to increase the risk for multiple sclerosis. AB - Both genetic and environmental factors display low or modest associations with multiple sclerosis. Hypothetically, gene-environment interactions may exert much stronger effects. In this study, we investigated potential interactions between genetic risk factors and smoking in relation to risk of developing multiple sclerosis. A population-based case-control study involving incident cases of multiple sclerosis (843 cases, 1209 controls) was performed in Sweden. Cases and controls were classified according to their smoking status and human leukocyte antigen DRB1 as well as human leukocyte antigen A genotypes. Subjects with different genotypes and smoking habits were compared with regard to incidence of multiple sclerosis, by calculating odds ratios with 95% confidence intervals employing logistic regression. The potential interaction between different genotypes, as well as between genotype and smoking, was evaluated by calculating attributable proportion due to interaction. A significant interaction between two genetic risk factors, carriage of human leukocyte antigen DRB1*15 and absence of human leukocyte antigen A*02, was observed among smokers whereas such an interaction was absent among non-smokers. There were considerable differences in odds ratios between the various groups. Compared with non-smokers with neither of the genetic risk factors, the odds ratio was 13.5 (8.1-22.6) for smokers with both genetic risk factors. The odds ratio for smokers without genetic risk was 1.4 (0.9-2.1) and the odds ratio for non-smokers with both genetic risk factors was 4.9 (3.6-6.6). Among those with both genetic risk factors, smoking increased the risk by a factor of 2.8 in comparison with a factor of 1.4 among those without the genetic risk factors. The risk of developing multiple sclerosis associated with human leukocyte antigen genotypes may be strongly influenced by smoking status. The findings are consistent with our hypothesis that priming of the immune response in the lungs may subsequently lead to multiple sclerosis in genetically susceptible people. PMID- 21303862 TI - SBML-PET-MPI: a parallel parameter estimation tool for Systems Biology Markup Language based models. AB - Parameter estimation is crucial for the modeling and dynamic analysis of biological systems. However, implementing parameter estimation is time consuming and computationally demanding. Here, we introduced a parallel parameter estimation tool for Systems Biology Markup Language (SBML)-based models (SBML-PET MPI). SBML-PET-MPI allows the user to perform parameter estimation and parameter uncertainty analysis by collectively fitting multiple experimental datasets. The tool is developed and parallelized using the message passing interface (MPI) protocol, which provides good scalability with the number of processors. AVAILABILITY: SBML-PET-MPI is freely available for non-commercial use at http://www.bioss.uni-freiburg.de/cms/sbml-pet-mpi.html or http://sites.google.com/site/sbmlpetmpi/. PMID- 21303863 TI - GeneTUKit: a software for document-level gene normalization. AB - MOTIVATION: Linking gene mentions in an article to entries of biological databases can facilitate indexing and querying biological literature greatly. Due to the high ambiguity of gene names, this task is particularly challenging. Manual annotation for this task is cost expensive, time consuming and labor intensive. Therefore, providing assistive tools to facilitate the task is of high value. RESULTS: We developed GeneTUKit, a document-level gene normalization software for full-text articles. This software employs both local context surrounding gene mentions and global context from the whole full-text document. It can normalize genes of different species simultaneously. When participating in BioCreAtIvE III, the system obtained good results among 37 runs: the system was ranked first, fourth and seventh in terms of TAP-20, TAP-10 and TAP-5, respectively on the 507 full-text test articles. AVAILABILITY AND IMPLEMENTATION: The software is available at http://www.qanswers.net/GeneTUKit/. PMID- 21303864 TI - Right mesothelial pericardial cyst determining intractable atrial arrhythmias. AB - Pericardial cysts are intrathoracic lesions usually considered to be congenital and less frequently to be acquired. They are normally found incidentally upon chest radiography, computed tomography (CT)-scan or echocardiography. They are usually asymptomatic and have a benign behavior although sometimes they can cause clinical symptoms and diagnosis can be uncertain. We present, herein, the case of a 51-year-old male with a history of atrial arrhythmia resistant to transcatheter ablation therapies with an accidental finding of a pericardial cyst adherent to the lateral wall of the right atrium at the emerging superior vena cava. The patient was studied with transesophageal echocardiography, CT-scan and cardiovascular magnetic resonance with the evidence of dimensional increasing of the cyst at seriate controls. Considering this, in the absence of a definitive diagnosis and suspecting a link between the mass and the arrhythmia, the cyst was surgically removed through median sternotomy, off-pump on a beating heart. Postoperative course was unremarkable. Histopathologic examination confirmed it was a mesothelial pericardial cyst. At 12 months of follow-up the patient is doing well and he is in sinus rhythm. In conclusion, we believe that, although the majority of pericardial cysts need only radiological and clinical follow-up, surgical resection should be performed when the patient is symptomatic and when diagnosis is uncertain. PMID- 21303865 TI - Extracorporeal membrane oxygenation for acute respiratory distress syndrome: is the configuration mode an important predictor for the outcome? AB - Extracorporeal membrane oxygenation (ECMO) is increasingly applied as rescue therapy for patients with severe acute respiratory distress syndrome (ARDS). Here, we evaluate the effect of different configuration strategies (venovenous vs. venoarterial vs. veno-venoarterial) on the outcome. From 2006 to 2008, 30 patients received ECMO for severe ARDS. Patients were divided into three groups according to the configuration: veno-venous (vv; n = 11), venoarterial (va; n=8) or veno-venoarterial (vva; n = 11). Data were prospectively collected and endpoint was 30-day mortality. To identify independent risk factors, univariate analysis was performed for clinical parameters, such as age, body mass index, gender, configuration, low-pH, oxygenation index (pO(2)/FiO(2)) and underlying disease. Thirty-day mortality was 53% (n = 16) for all comers: 63% (n = 7) died in the vv-group, 75% (n = 6) in the va-group and 27% (n = 3) in the vva-group. Although univariate analysis could not rule out a significant predictor for the outcome, there was a trend visible to decreased mortality in the vva-group when compared to vv- and va-groups (27% vs. 63% vs. 75%; P = 0.057). ECMO provides a survival benefit in patients when considering a predicted mortality rate of 80% in ARDS. The configuration mode appears to impact the outcome as the veno venoarterial appears to further improve the survival in this subset of patients. PMID- 21303866 TI - Thymic metastasis from lung carcinoma. AB - Primary thymic carcinomas are well known but thymic metastases are very rare. To our knowledge a thymic metastasis from lung carcinoma has never been reported. We report the case of a metastatic lung cancer to the thymus, five years after a lobectomy for a stage I lung adenocarcinoma. PMID- 21303867 TI - Aortic valve replacement normalizes left ventricular twist function. AB - The aim of this study was to assess the effect of aortic valve replacement (AVR) on left ventricular (LV) twist function. We studied 28 severe aortic stenosis (AS) patients with normal LV ejection fraction (EF) before and six months after AVR. LV long axis function was assessed using M-mode and tissue Doppler and twist function using speckle tracking echocardiography. The data were compared with 28 age and sex-matched normal controls. In patients, LVEF remained unchanged after AVR. LV long axis function was reduced before surgery but normalized after AVR. LV twist was increased before (19.7 +/- 5.7 degrees vs. 12.9 +/- 3.2 degrees , P<0.001) and normalized after AVR (14.4 +/- 5.2 degrees , P < 0.001). In normals, LV twist correlated with LV fractional shortening (r = 0.81, P<0.001) but not with EF. This relationship was reversed in patients before ( r= 0.52, P < 0.01) and after AVR (r = 0.34, P = ns). In patients with severe AS and normal EF, LV twist is exaggerated suggesting potential compensation for the reduced long axis function. These disturbances normalize within six months of AVR but lose their relationship with basal LV function. PMID- 21303868 TI - Anterior approach to the thoracic spine. AB - An anterior approach affords the spine surgeon excellent visualization and access to the anterior thoracic spine, the vertebral bodies, intervertebral disks, spinal canal, and nerve roots. This approach is currently used in the surgical treatment of thoracic disk disease, vertebral osteomyelitis or discitis, fractures and tumors of the vertebral bodies, allowing for proper decompression of neural elements and spine stabilization. Over a 10-year period in a single institution, a total of 142 patients with a mean age of 49.6 years underwent anterior thoracic exposure of the spine. The indication for surgery was trauma fracture in 20 patients, malignancy in 35, degenerative disease in 29 and correction of scoliosis in 58. Surgical approaches were determined based on the location and length of spinal involvement, including cervico-thoracic approach (15) thoracotomic approach (85) video-assisted thoracoscopy (10) and thoracolumbar exposure (32). Mean operative time was 334 min (range from 256 to 410 min). There was no perioperative mortality. Thirty-one patients (21.8%) developed postoperative complications. The anterior approach to the thoracic spine is safe and effective and even the presence of complications can be appropriately managed. An adequate preoperative evaluation stratifying the risk and instituting measures to reduce it, accurate surgical planning and careful surgical technique are key to yielding a good outcome and to reduce the risk of complications. PMID- 21303869 TI - Atypical tamponade hemodynamic in a patient with temporary left ventricular assist device. AB - Postoperative bleeding and tamponade are considered major complications after implantation of left ventricular assist devices. Firstly, 40% of patients supported by ventricular assist devices experience early postoperative bleeding, and 20% developed tamponade requiring re-exploration. Secondly, we present a case of a patient with tamponade, on temporary left ventricular assist device (LVAD) support with atypical hemodynamic and echocardiographic manifestations demonstrated with computed tomography (CT)-M mode, conventional Doppler, color Doppler and echo imaging. PMID- 21303870 TI - Postoperative paraplegia after resection of a giant posterior mediastinal tumour. Importance of the blood supply in the upper spinal cord. AB - A 10-cm diameter tumour was revealed in the left upper posterior mediastinum in a 15-year-old female. After exclusion of the possibility of a dumbbell tumour and confirmation of a ganglioneurinoma, an encapsulated, but vascularised tumour was removed via a left posterolateral thoracotomy from the level of the first-third costo-vertebral angle, without intraoperative complications. Following surgery, acute paraplegia was diagnosed, with a spinal cord lesion at the high thoracic level. Magnetic resonance imaging did not reveal any disorder in the spinal cord. In response to medical treatment, the patient's locomotor and sensation functions normalised within six months. On revising the preoperative computed tomography, we found dilated vessels passing through the tumour and the hypoplastic vertebral artery on the left side. This finding led us to suspect that the spinal cord circulation was partially supplied by the arteries passing through the tumour, which were clipped during surgery. Verification of the blood supply of the spinal cord is therefore highly recommended before resection of a giant tumour from the posterior mediastinum. PMID- 21303872 TI - Staging of patients after extrapleural pneumonectomy for malignant pleural mesothelioma--institutional review and current update. AB - Extrapleural pneumonectomy (EPP) has been established as a viable surgical option in the treatment of malignant pleural mesothelioma (MPM) for selected patients. A number of pathological staging systems have been developed to prognosticate survival outcomes. We assessed 91 patients with MPM who underwent EPP in our institution and evaluated the applicability of the most updated staging systems in the current literature. After a mean follow-up of 20 months, the median overall survival was 27.6 months. Postoperative pathological staging according to the International Mesothelioma Interest Group criteria (P = 0.026) and the Brigham and Women's Hospital criteria (P = 0.039) were both found to be significant prognostic factors. Adjuvant chemotherapy (P = 0.022) and radiotherapy (P = 0.008) were associated with improved survival outcomes. These findings are consistent with previous reports that demonstrated the usefulness of pathological staging systems as a prognostic tool in patients with MPM after undergoing EPP. However, preoperative clinical staging systems need to be developed to facilitate the patient selection process prior to surgery. PMID- 21303871 TI - Vulnerability of an equine pericardial roll graft to Gram-positive cocci after graft replacement for a ruptured infected abdominal aorta. AB - We describe the influence of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia on histopathological alteration of a glutaraldehyde-fixed equine pericardial roll (EPR) graft in a 77-year-old male who underwent in-situ EPR replacement of a ruptured infected abdominal aorta with concomitant repair of the perforated duodenum. The patient died of circulatory failure after septic shock due to MRSA infection and gastrointestinal bleeding on postoperative day (POD) 23. The autopsy revealed no perforation of the EPR graft or anastomotic disruption between the native abdominal aorta and EPR graft. Histological examination revealed that the inner layer of the EPR graft was colonized and damaged by Gram-positive cocci (MRSA suspected). We therefore suggest that the infection-resistant property of EPR grafts may be uncertain in patients with postoperative sustained MRSA bacteremia when these grafts are used for arterial reconstruction. PMID- 21303873 TI - Large thoracomyoplasty and negative pressure therapy for late postpneumonectomy empyema with a retrosternal abscess: a modern version of the Clagett procedure. AB - A 63-year-old male with a history of cancer, and who had undergone a left pneumonectomy seven years before, presented with deterioration in his general status and recent dyspnea [stage III (New York Heart Association) NYHA]. Imaging revealed a contralateral mediastinal shift and cardiac compression caused by pneumonectomy cavity enlargement and a retrosternal liquid mass. Late empyema associated with a retrosternal abscess caused by Propionibacterium acnes was diagnosed after thoracoscopy and an anterior mediastinotomy. Surgical treatment included an axillary open-window thoracostomy associated with negative pressure therapy (NPT), followed by a large thoracomyoplasty where part of the latissimus dorsi was harvested, and then guided healing. The chest was closed after eight months. This case is an unusual observation of a late post-pneumonectomy empyema with Propionibacterium acnes presenting like recurring cancer, but that was treated effectively using traditional (Clagett procedure) and newer (NPT) strategies. PMID- 21303874 TI - Development and validation of a quantitative assay based on tandem mass spectrometry. AB - Many routine hospital and clinical research assays have relied upon immunoassay procedures to achieve sensitive measurements of a range of important analytes. Some of the methods have been developed in-house but increasingly commercial kits and automated analysers have become commonplace. The accuracies of these methods are under question in health care. Mass spectrometry (MS) is potentially a more accurate technique with the ability to demonstrate specificity. An introduction of the basic analytical aspects of liquid chromatography (LC)-MS/MS leads on to the validation of the method before general use. LC coupled with MS and tandem mass spectrometry (MS(n)) is being adopted in a number of hospital laboratories for the quantitative analysis of a number of analytes from physiological matrices, but standards for development and validation of such assays are not easily available. Most assays can be regarded as in-house methods and herein may lay the failure so far for mass spectrometric methods to improve quality of results between laboratories for an analyte using the same technology. Manufacturers are taking on board the experience of clinical laboratories with kits containing all or most of the disposable items and reagents. A number of documents and guidelines have been consulted. These documents are expensive to purchase, are often very long and not easy to read. This review highlights the specific requirements for introduction of a tandem mass spectrometric test for small molecules into a routine hospital laboratory. A number of experiments need to be planned and executed in order to describe a new quantitative method in terms of selectivity, accuracy, imprecision, sensitivity and stability. The introduction of a quantitative method based on tandem MS requires careful validation. This review has distilled out important points from a number of key documents in order to provide a working validation guideline for clinical laboratories. In a supplementary file a working document for assembling the assay validation is proposed. PMID- 21303875 TI - Utility of the urine calcium-to-creatinine ratio to diagnose primary hyperparathyroidism in asymptomatic hypercalcaemic patients with vitamin D deficiency. AB - BACKGROUND: Primary hyperparathyroidism (PHP) is the most common cause of hypercalcaemia, and often requires surgical treatment. Familial hypocalciuric hypercalcaemia (FHH) has similar biochemical features to PHP, but requires no treatment. The most common biochemical method used to distinguish between PHP and FHH is the urine calcium-to-creatinine ratio (UCCR). Vitamin D deficiency may alter the renal excretion of calcium, but it is unclear how vitamin D deficiency affects the diagnostic performance of UCCR. AIM: To examine the reliability of UCCR to detect PHP in patients presenting with asymptomatic hypercalcaemia, in the presence or absence of vitamin D deficiency. METHODS: One hundred and eighteen UCCR measurements from 97 asymptomatic hypercalcaemic patients diagnosed with PHP presenting to a single specialist endocrine unit were analysed retrospectively. RESULTS: A significantly higher proportion of UCCR measurements were <0.010 in patients with serum vitamin D <25 nmol/L when compared with patients with serum vitamin D >25 nmol/L, thus incorrectly suggesting the presence of FHH (proportion of measurements with UCCR >0.010: 11/48 [22.9%], vitamin D <25 nmol/L; 4/70 [5.7%], vitamin D >25 nmol/L; P < 0.001). Urine calcium concentration was 26% lower and serum parathyroid hormone (PTH) was 27% higher in patients with vitamin D deficiency when compared with patients without vitamin D deficiency. CONCLUSIONS: These data suggest that the presence of vitamin D deficiency is associated with worsened PTH hypersecretion, impairment of urinary calcium excretion and reduced sensitivity of UCCR measurement with respect to the detection of PHP. These data have important clinical implications for the investigation and management of patients with asymptomatic hypercalcaemia. PMID- 21303877 TI - "Disruptive" doctors are often found to be perfectionists, agency reports. PMID- 21303879 TI - A qualitative study of the difficulties in reaching sustainable universal health insurance coverage in Iran. AB - OBJECTIVE To understand the Iranian health financing system and provide lessons for policy makers about achieving universal coverage. METHODS Twenty-five interviewees from seven major health insurance companies were selected for a qualitative study in 2007. Using a semi-structured interview, three main tasks of the health financing system (revenue collection, risk pooling and purchasing) were investigated. A framework method was applied for the data analysis. RESULTS The results of the study show the following seven major obstacles to universal coverage: unknown insured rate; regressive financing and non-transparent financial flow; fragmented and non-compulsory system; non-scientifically designed benefit package; non-health-oriented and expensive payment system; uncontrolled demands; and administrative deficiency. A long-term systematic plan is required to address the above problems. PMID- 21303880 TI - Postmarketing studies of drug safety. PMID- 21303882 TI - Pandemic influenza vaccines. PMID- 21303883 TI - Paediatric ENT surgery. Grommets and cholesteatoma. PMID- 21303884 TI - Publicity of NHS breast cancer screening programme is unfair. PMID- 21303885 TI - Laparoscopy complications. Understating under-reporting. PMID- 21303886 TI - Laparoscopy complications. Apply safety rule of thumb. PMID- 21303887 TI - Aviation and patient safety. Send in the marines? PMID- 21303888 TI - Aviation and patient safety. We cannot go too far in the pursuit of patient safety. PMID- 21303890 TI - MMR scare. Robust procedures for research conduct are needed. PMID- 21303891 TI - MMR scare. In the wake of Wakefield. PMID- 21303892 TI - MMR scare. Response from the UK Research Integrity Office. PMID- 21303893 TI - MMR scare. The BMJ's measly editorial policies. PMID- 21303894 TI - MMR scare. Are the GMC, news media, and BMJ the right tribunals? PMID- 21303896 TI - GMC's revalidation plans don't tackle problem of poorly performing doctors, MPs say. PMID- 21303898 TI - The physiology, signaling, and pharmacology of dopamine receptors. AB - G protein-coupled dopamine receptors (D1, D2, D3, D4, and D5) mediate all of the physiological functions of the catecholaminergic neurotransmitter dopamine, ranging from voluntary movement and reward to hormonal regulation and hypertension. Pharmacological agents targeting dopaminergic neurotransmission have been clinically used in the management of several neurological and psychiatric disorders, including Parkinson's disease, schizophrenia, bipolar disorder, Huntington's disease, attention deficit hyperactivity disorder (ADHD(1)), and Tourette's syndrome. Numerous advances have occurred in understanding the general structural, biochemical, and functional properties of dopamine receptors that have led to the development of multiple pharmacologically active compounds that directly target dopamine receptors, such as antiparkinson drugs and antipsychotics. Recent progress in understanding the complex biology of dopamine receptor-related signal transduction mechanisms has revealed that, in addition to their primary action on cAMP-mediated signaling, dopamine receptors can act through diverse signaling mechanisms that involve alternative G protein coupling or through G protein-independent mechanisms via interactions with ion channels or proteins that are characteristically implicated in receptor desensitization, such as beta-arrestins. One of the future directions in managing dopamine-related pathologic conditions may involve a transition from the approaches that directly affect receptor function to a precise targeting of postreceptor intracellular signaling modalities either directly or through ligand biased signaling pharmacology. In this comprehensive review, we discuss dopamine receptor classification, their basic structural and genetic organization, their distribution and functions in the brain and the periphery, and their regulation and signal transduction mechanisms. In addition, we discuss the abnormalities of dopamine receptor expression, function, and signaling that are documented in human disorders and the current pharmacology and emerging trends in the development of novel therapeutic agents that act at dopamine receptors and/or on related signaling events. PMID- 21303900 TI - Additional ablation of complex fractionated atrial electrograms after pulmonary vein isolation in patients with atrial fibrillation: a meta-analysis. AB - BACKGROUND: The efficacy of additional complex fractionated atrial electrogram (CFAE) ablation after pulmonary vein antrum isolation (PVAI) in patients with atrial fibrillation (AF) remains controversial. This meta-analysis was performed to assess the additional efficacy of CFAEs ablation after a single procedure without antiarrhythmic drugs. METHODS AND RESULTS: Trials were identified in MEDLINE, Cochrane Library, Embase, Google Scholar, reviews, and reference lists of relevant papers. Controlled cohort studies comparing the long-term efficacy of combined CFAEs plus PVAI ablation with PVAI alone were included. The primary end point was the maintenance of sinus rhythm without antiarrhythmic drugs. Seven controlled trials (9 comparisons) with a total of 622 participants (332 patients underwent PVAI plus CFAE ablation and 330 patients underwent PVAI alone) were included in the meta-analysis. In an overall pooled estimate, compared with PVI alone, long-term rates of sinus rhythm maintenance (relative risk, 1.17, 95% confidence interval, 1.03 to 1.33, P=0.019) were increased by additional CFAE ablation. Subgroup analysis demonstrated that additional CFAEs ablation increased rates of sinus rhythm maintenance in nonparoxysmal AF (relative risk, 1.35; 95% confidence interval, 1.04 to 1.75; P=0.022), whereas had no effect on patients with paroxysmal AF (relative risk, 1.04; 95% confidence interval, 0.92 to 1.18; P=0.528). CONCLUSIONS: Adjuvant CFAE ablation in addition to standard PVAI increases the rate of long-term sinus rhythm maintenance in nonparoxysmal AF patients after a single procedure without antiarrhythmic drugs but does not provide additional benefit to sinus rhythm maintenance in paroxysmal AF patients. PMID- 21303901 TI - Low-dose valproic acid enhances radiosensitivity of prostate cancer through acetylated p53-dependent modulation of mitochondrial membrane potential and apoptosis. AB - Histone deacetylase inhibitors (HDI) have shown promise as candidate radiosensitizers for many types of cancers, including prostate cancer. However, the mechanisms of action are not well understood. In this study, we show in prostate cancer cells that valproic acid (VPA) at low concentrations has minimal cytotoxic effects yet can significantly increase radiation-induced apoptosis. VPA seems to stabilize a specific acetyl modification (lysine 120) of the p53 tumor suppressor protein, resulting in an increase in its proapoptotic function at the mitochondrial membrane. These effects of VPA are independent of any action of the p53 protein as a transcription factor in the nucleus, since these effects were also observed in native and engineered prostate cancer cells containing mutant forms of p53 protein having no transcription factor activity. Transcription levels of p53-related or Bcl-2 family member proapoptotic proteins were not affected by VPA exposure. The results of this study suggest that, in addition to nuclear-based pathways previously reported, HDIs may also result in radiosensitization at lower concentrations via a specific p53 acetylation and its mitochondrial-based pathway(s). PMID- 21303899 TI - International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors--an update. AB - In the 10 years since our previous International Union of Basic and Clinical Pharmacology report on the nomenclature and classification of adenosine receptors, no developments have led to major changes in the recommendations. However, there have been so many other developments that an update is needed. The fact that the structure of one of the adenosine receptors has recently been solved has already led to new ways of in silico screening of ligands. The evidence that adenosine receptors can form homo- and heteromultimers has accumulated, but the functional significance of such complexes remains unclear. The availability of mice with genetic modification of all the adenosine receptors has led to a clarification of the functional roles of adenosine, and to excellent means to study the specificity of drugs. There are also interesting associations between disease and structural variants in one or more of the adenosine receptors. Several new selective agonists and antagonists have become available. They provide improved possibilities for receptor classification. There are also developments hinting at the usefulness of allosteric modulators. Many drugs targeting adenosine receptors are in clinical trials, but the established therapeutic use is still very limited. PMID- 21303902 TI - Dense genotyping of candidate gene loci identifies variants associated with high density lipoprotein cholesterol. AB - BACKGROUND: Plasma levels of high-density lipoprotein cholesterol (HDL-C) are known to be heritable, but only a fraction of the heritability is explained. We used a high-density genotyping array containing single-nucleotide polymorphisms (SNPs) from HDL-C candidate genes selected on known biology of HDL-C metabolism, mouse genetic studies, and human genetic association studies. SNP selection was based on tagging SNPs and included low-frequency nonsynonymous SNPs. METHODS AND RESULTS: Association analysis in a cohort containing extremes of HDL-C (case control, n=1733) provided a discovery phase, with replication in 3 additional populations for a total meta-analysis in 7857 individuals. We replicated the majority of loci identified through genome-wide association studies and present on the array (including ABCA1, APOA1/C3/A4/A5, APOB, APOE/C1/C2, CETP, CTCF PRMT8, FADS1/2/3, GALNT2, LCAT, LILRA3, LIPC, LIPG, LPL, LRP4, SCARB1, TRIB1, ZNF664) and provide evidence that suggests an association in several previously unreported candidate gene loci (including ABCG1, GPR109A/B/81, NFKB1, PON1/2/3/4). There was evidence for multiple, independent association signals in 5 loci, including association with low-frequency nonsynonymous variants. CONCLUSIONS: Genetic loci associated with HDL-C are likely to harbor multiple, independent causative variants, frequently with opposite effects on the HDL-C phenotype. Cohorts comprising subjects at the extremes of the HDL-C distribution may be efficiently used in a case-control discovery of quantitative traits. PMID- 21303903 TI - Potent and selective inhibitors of the inositol-requiring enzyme 1 endoribonuclease. AB - Inositol-requiring enzyme 1 (IRE1) is the most highly conserved signaling node of the unfolded protein response (UPR) and represents a potential therapeutic target for a number of diseases associated with endoplasmic reticulum stress. IRE1 activates the XBP-1 transcription factor by site-specific cleavage of two hairpin loops within its mRNA to facilitate its nonconventional splicing and alternative translation. We screened for inhibitors using a construct containing the unique cytosolic kinase and endoribonuclease domains of human IRE1alpha (hIRE1alpha cyto) and a mini-XBP-1 stem-loop RNA as the substrate. One class compounds was salicylaldehyde analogs from the hydrolyzed product of salicylaldimines in the library. Salicylaldehyde analogs were active in inhibiting the site-specific cleavage of several mini-XBP-1 stem-loop RNAs in a dose-dependent manner. Salicyaldehyde analogs were also active in inhibiting yeast Ire1 but had little activity inhibiting RNase L or the unrelated RNases A and T1. Kinetic analysis revealed that one potent salicylaldehyde analog, 3-ethoxy-5,6 dibromosalicylaldehyde, is a non-competitive inhibitor with respect to the XBP-1 RNA substrate. Surface plasmon resonance studies confirmed this compound bound to IRE1 in a specific, reversible and dose-dependent manner. Salicylaldehydes inhibited XBP-1 splicing induced pharmacologically in human cells. These compounds also blocked transcriptional up-regulation of known XBP-1 targets as well as mRNAs targeted for degradation by IRE1. Finally, the salicylaldehyde analog 3-methoxy-6-bromosalicylaldehyde strongly inhibited XBP-1 splicing in an in vivo model of acute endoplasmic reticulum stress. To our knowledge, salicylaldehyde analogs are the first reported specific IRE1 endoribonuclease inhibitors. PMID- 21303904 TI - Two pathways of sphingolipid biosynthesis are separated in the yeast Pichia pastoris. AB - Although the yeast Saccharomyces cerevisiae has only one sphingolipid class with a head group based on phosphoinositol, the yeast Pichia pastoris as well as many other fungi have a second class, glucosylceramide, which has a glucose head group. These two sphingolipid classes are in addition distinguished by a characteristic structure of their ceramide backbones. Here, we investigate the mechanisms controlling substrate entry into the glucosylceramide branch of the pathway. By a combination of enzymatic in vitro studies and lipid analysis of genetically engineered yeast strains, we show that the ceramide synthase Bar1p occupies a key branching point in sphingolipid biosynthesis in P. pastoris. By preferring dihydroxy sphingoid bases and C(16)/C(18) acyl-coenzyme A as substrates, Bar1p produces a structurally well defined group of ceramide species, which is the exclusive precursor for glucosylceramide biosynthesis. Correlating with the absence of glucosylceramide in this yeast, a gene encoding Bar1p is missing in S. cerevisiae. We could not successfully investigate the second ceramide synthase in P. pastoris that is orthologous to S. cerevisiae Lag1p/Lac1p. By analyzing the ceramide and glucosylceramide species in a collection of P. pastoris knock-out strains in which individual genes encoding enzymes involved in glucosylceramide biosynthesis were systematically deleted, we show that the ceramide species produced by Bar1p have to be modified by two additional enzymes, sphingolipid Delta4-desaturase and fatty acid alpha hydroxylase, before the final addition of the glucose head group by the glucosylceramide synthase. Together, this set of four enzymes specifically defines the pathway leading to glucosylceramide biosynthesis. PMID- 21303905 TI - Lantibiotic transporter requires cooperative functioning of the peptidase domain and the ATP binding domain. AB - Lantibiotics are ribosomally synthesized and post-translationally modified peptide antibiotics that contain unusual amino acids such as dehydro and lanthionine residues. Nukacin ISK-1 is a class II lantibiotic, whose precursor peptide (NukA) is modified by NukM to form modified NukA. ATP-binding cassette (ABC) transporter NukT is predicted to cleave off the N-terminal leader peptide of modified NukA and secrete the mature peptide. Multiple sequence alignments revealed that NukT has an N-terminal peptidase domain (PEP) and a C-terminal ATP binding domain (ABD). Previously, in vitro reconstitution of NukT has revealed that NukT peptidase activity depends on ATP hydrolysis. Here, we constructed a series of NukT mutants and investigated their transport activity in vivo and peptidase activity in vitro. Most of the mutations of the conserved residues of PEP or ABD resulted in failure of nukacin ISK-1 production and accumulation of modified NukA inside the cells. NukT(N106D) was found to be the only mutant capable of producing nukacin ISK-1. Asn(106) is conserved as Asp in other related ABC transporters. Additionally, an in vitro peptidase assay of NukT mutants demonstrated that PEP is on the cytosolic side and all of the ABD mutants as well as PEP (with the exception of NukT(N106D)) did not have peptidase activity in vitro. Taken together, these observations suggest that the leader peptide is cleaved off inside the cells before peptide secretion; both PEP and ABD are important for NukT peptidase activity, and cooperation between these two domains inside the cells is indispensable for proper functioning of NukT. PMID- 21303906 TI - Identification of a novel functional domain of ricin responsible for its potent toxicity. AB - Ribosome-inactivating proteins (RIPs) are toxic N-glycosidases that depurinate the universally conserved alpha-sarcin loop of large rRNAs. They have received attention in biological and biomedical research because of their unique biological activities toward animals and human cells as cell-killing agents. A better understanding of the depurination mechanism of RIPs could allow us to develop potent neutralizing antibodies and to design efficient immunotoxins for clinical use. Among these RIPs, ricin exhibited remarkable efficacy in depurination activity and highly conserved tertiary structure with other RIPs. It can be considered as a prototype to investigate the depurination mechanism of RIPs. In the present study, we successfully identified a novel functional domain responsible for controlling the depurination activity of ricin, which is located far from the enzymatic active site reported previously. Our study indicated that ricin A-chain mAbs binding to this domain (an alpha-helix comprising the residues 99-106) exhibited an unusual potent neutralizing ability against ricin in vivo. To further investigate the potential role of the alpha-helix in regulating the catalytic activity of ricin, ricin A-chain variants with different flexibility of the alpha-helix were rationally designed. Our data clearly demonstrated that the flexibility of the alpha-helix is responsible for controlling the depurination activity of ricin and determining the extent of protein synthesis inhibition, suggesting that the conserved alpha-helix might be considered as a potential target for the prevention and treatment of RIP poisoning. PMID- 21303907 TI - Identification of new batrachotoxin-sensing residues in segment IIIS6 of the sodium channel. AB - Ion permeation through voltage-gated sodium channels is modulated by various drugs and toxins. The atomistic mechanisms of action of many toxins are poorly understood. A steroidal alkaloid batrachotoxin (BTX) causes persistent channel activation by inhibiting inactivation and shifting the voltage dependence of activation to more negative potentials. Traditionally, BTX is considered to bind at the channel-lipid interface and allosterically modulate the ion permeation. However, amino acid residues critical for BTX action are found in the inner helices of all four repeats, suggesting that BTX binds in the pore. In the octapeptide segment IFGSFFTL in IIIS6 of a cockroach sodium channel BgNa(V), besides Ser_3i15 and Leu_3i19, which correspond to known BTX-sensing residues of mammalian sodium channels, we found that Gly_3i14 and Phe_3i16 are critical for BTX action. Using these data along with published data as distance constraints, we docked BTX in the Kv1.2-based homology model of the open BgNa(V) channel. We arrived at a model in which BTX adopts a horseshoe conformation with the horseshoe plane normal to the pore axis. The BTX ammonium group is engaged in cation-pi interactions with Phe_3i16 and BTX moieties interact with known BTX sensing residues in all four repeats. Oxygen atoms at the horseshoe inner surface constitute a transient binding site for permeating cations, whereas the bulky BTX molecule would resist the pore closure, thus causing persistent channel activation. Our study reinforces the concept that steroidal sodium channel agonists bind in the inner pore of sodium channels and elaborates the atomistic mechanism of BTX action. PMID- 21303908 TI - Interleukin-13 (IL-13)/IL-13 receptor alpha1 (IL-13Ralpha1) signaling regulates intestinal epithelial cystic fibrosis transmembrane conductance regulator channel dependent Cl- secretion. AB - Interleukin-13 (IL-13) has been linked to the pathogenesis of inflammatory diseases of the gastrointestinal tract. It is postulated that IL-13 drives inflammatory lesions through the modulation of both hematopoietic and nonhematopoietic cell function in the intestine. To delineate the relevant contribution of elevated levels of intestinal IL-13 to intestinal structure and function, we generated an intestinal IL-13 transgenic mouse (iIL-13Tg). We show that constitutive overexpression of IL-13 in the small bowel induces modification of intestinal epithelial architecture (villus blunting, goblet cell hyperplasia, and increased epithelial proliferation) and epithelial function (altered basolateral -> apical Cl(-) ion conductance). Pharmacological analyses in vitro and in vivo determined that elevated Cl(-) conductance is mediated by altered cystic fibrosis transmembrane conductance regulator expression and activity. Generation of iIL-13Tg/Il13ralpha1(-/-), iIL-13Tg/Il13ralpha2(-/-), and iIL 13Tg/Stat6(-/-) mice revealed that IL-13-mediated dysregulation of epithelial architecture and Cl(-) conductance is dependent on IL-13Ralpha1 and STAT-6. These observations demonstrate a central role for the IL-13/IL-13Ralpha1 pathway in the regulation of intestinal epithelial cell Cl(-) secretion via up-regulation of cystic fibrosis transmembrane conductance regulator, suggesting an important role for this pathway in secretory diarrhea. PMID- 21303909 TI - The intrinsically disordered nuclear localization signal and phosphorylation segments distinguish the membrane affinity of two cytidylyltransferase isoforms. AB - Membrane phosphatidylcholine homeostasis is maintained in part by a sensing device in the key regulatory enzyme, CTP:phosphocholine cytidylyltransferase (CCT). CCT responds to decreases in membrane phosphatidylcholine content by reversible membrane binding and activation. Two prominent isoforms, CCTalpha and beta2, have nearly identical catalytic domains and very similar membrane binding amphipathic helical (M) domains but have divergent and structurally disordered N terminal (N) and C-terminal phosphorylation (P) regions. We found that the binding affinity of purified CCTbeta2 for anionic membranes was weaker than CCTalpha by more than an order of magnitude. Using chimeric CCTs, insertion/deletion mutants, and truncated CCTs, we show that the stronger affinity of CCTalpha can be attributed in large part to the electrostatic membrane binding function of the polybasic nuclear localization signal (NLS) motif, present in the unstructured N-terminal segment of CCTalpha but lacking in CCTbeta2. The membrane partitioning of CCTbeta2 in cells enriched with the lipid activator, oleic acid, was also weaker than that of CCTalpha and was elevated by incorporation of the NLS motif. Thus, the polybasic NLS can function as a secondary membrane binding motif not only in vitro but in the context of cell membranes. A comparison of phosphorylated, dephosphorylated, and region P truncated forms showed that the in vitro membrane affinity of CCTbeta2 is more sensitive than CCTalpha to phosphorylation status, which antagonizes membrane binding of both isoforms. These data provide a model wherein the primary membrane binding motif, an amphipathic helical domain, works in collaboration with other intrinsically disordered segments that modulate membrane binding strength. The NLS reinforces, whereas the phosphorylated tail antagonizes the attraction of domain M for anionic membranes. PMID- 21303911 TI - Regarding the overestimation of serum kappa free light chains. PMID- 21303910 TI - Subunit organization of the human INO80 chromatin remodeling complex: an evolutionarily conserved core complex catalyzes ATP-dependent nucleosome remodeling. AB - We previously identified and purified a human ATP-dependent chromatin remodeling complex with similarity to the Saccharomyces cerevisiae INO80 complex (Jin, J., Cai, Y., Yao, T., Gottschalk, A. J., Florens, L., Swanson, S. K., Gutierrez, J. L., Coleman, M. K., Workman, J. L., Mushegian, A., Washburn, M. P., Conaway, R. C., and Conaway, J. W. (2005) J. Biol. Chem. 280, 41207-41212) and demonstrated that it is composed of (i) a Snf2 family ATPase (hIno80) related in sequence to the S. cerevisiae Ino80 ATPase; (ii) seven additional evolutionarily conserved subunits orthologous to yeast INO80 complex subunits; and (iii) six apparently metazoan-specific subunits. In this report, we present evidence that the human INO80 complex is composed of three modules that assemble with three distinct domains of the hIno80 ATPase. These modules include (i) one that is composed of the N terminus of the hIno80 protein and all of the metazoan-specific subunits and is not required for ATP-dependent nucleosome remodeling; (ii) a second that is composed of the hIno80 Snf2-like ATPase/helicase and helicase-SANT associated/post-HSA (HSA/PTH) domain, the actin-related proteins Arp4 and Arp8, and the GLI-Kruppel family transcription factor YY1; and (iii) a third that is composed of the hIno80 Snf2 ATPase domain, the Ies2 and Ies6 proteins, the AAA(+) ATPases Tip49a and Tip49b, and the actin-related protein Arp5. Through purification and characterization of hINO80 complex subassemblies, we demonstrate that ATP-dependent nucleosome remodeling by the hINO80 complex is catalyzed by a core complex comprising the hIno80 protein HSA/PTH and Snf2 ATPase domains acting in concert with YY1 and the complete set of its evolutionarily conserved subunits. Taken together, our findings shed new light on the structure and function of the INO80 chromatin-remodeling complex. PMID- 21303912 TI - Rectal epithelial cell mitosis and expression of macrophage migration inhibitory factor are increased 3 years after Roux-en-Y gastric bypass (RYGB) for morbid obesity: implications for long-term neoplastic risk following RYGB. AB - BACKGROUND: Rectal epithelial cell mitosis and crypt size, as well as expression of proinflammatory genes including macrophage migration inhibitory factor (MIF), are increased 6 months after Roux-en-Y gastric bypass (RYGB) in morbidly obese patients. Tests were carried out to determine whether these putative colorectal cancer risk biomarkers remained elevated long term after RYGB, and the mechanistic basis, as well as the functional consequences, of Mif upregulation in intestinal epithelial cells was investigated. METHODS: Rectal mucosa and blood were obtained a median of 3 years after RYGB from the original cohort of patients with RYGB (n = 19) for crypt microdissection, real-time PCR, immunohistochemistry for MIF and immunoassay of proinflammatory markers. Immunohistochemistry for Mif and bromodeoxyuridine labelling were performed on AhCre+ mouse and Apc(Min/+) mouse (with and without functional Mif alleles) intestine, respectively. RESULTS: Rectal epithelial cell mitosis and crypt size remained elevated 3 years after RYGB compared with preoperative values (1.7- and 1.5-fold, respectively; p < 0.05). There was a 40-fold (95% CI 13 to 125) increase in mucosal MIF transcript levels at 3 years associated with increased epithelial cell MIF protein levels. Conditional Apc loss in AhCre+ mice led to increased epithelial cell Mif content. Mif deficiency in Apc(Min/+) mice was associated with a combined defect in intestinal epithelial cell proliferation and migration, which was reflected by the longitudinal clinical data. CONCLUSIONS: Mucosal abnormalities persist 3 years after RYGB and include elevation of the protumorigenic cytokine MIF, which is upregulated following Apc loss and which contributes to intestinal epithelial cell homeostasis. These observations should prompt clinical studies of colorectal neoplastic risk after RYGB. PMID- 21303913 TI - TGFalpha-associated MUC2 and MUC3 expression of the gastric epithelium in Menetrier's disease during remission of ulcerative colitis. PMID- 21303914 TI - Interferon lambdas: the next cytokine storm. AB - For two decades the scientific community has sought to understand why some people clear hepatitis C virus (HCV) and others do not. Recently, several large genome wide association studies have identified single nucleotide polymorphisms (SNPs) linked to interferon lambda 3 (IFNlambda3) that are associated with the spontaneous resolution and successful treatment of HCV infection. These observations are generating intense research activity; the hope is that IFNlambda3 genetic variants may serve as important predictive biomarkers of treatment outcome and offer new insights into the biological pathways involved in viral control. A pharmacogenomic treatment approach for HCV can now be envisaged, with the incorporation of host genetic variants into a predictive treatment algorithm with other factors. The SNPs associated with the clinical outcome of HCV infection are located some distance from the IFNlambda3 gene itself, and causal genetic variants have yet to be clearly defined. Locating these causal variants, mapping in detail the IFNlambda3 signalling pathways and determining the downstream genetic signature so induced will clarify the role of IFNlambda3 in the pathogenesis of HCV. Clinical studies assessing safety and efficacy in the treatment of HCV with exogenous IFNlambda3 are currently underway. Early results suggest that IFNlambda3 treatment inhibits HCV replication and is associated with a limited side effect profile. However, hepatotoxicity in both healthy volunteers and HCV-infected patients has been described. This review discusses the genetic studies that link IFNlambda3 to both the spontaneous resolution and treatment induced clearance of HCV and the potential impact of this in clinical practice, the biology of IFNlambda3 as currently understood and how this may impact on HCV infection, and describes the early studies that assess the role of this cytokine in the treatment of patients with HCV. PMID- 21303915 TI - Management of achalasia: surgery or pneumatic dilation. AB - Achalasia is an esophageal motility disorder of unknown cause, characterised by aperistalsis of the esophageal body and impaired lower esophageal sphincter relaxation. Patients present at all ages, primarily with dysphagia for solids/liquids and bland regurgitation. The diagnosis is suggested by barium esophagram or endoscopy and confirmed by esophageal manometry. Achalasia cannot be cured. Instead, our goal is to relieve symptoms, improve esophageal emptying and prevent the development of megaesophagus. The most successful therapies are pneumatic dilation and surgical myotomy. The advantages of pneumatic dilation include an outpatient procedure, minimal pain, return to work the next day, mild if any GERD, and can be performed in any age group and even during pregnancy. Pneumatic dilation does not hinder future myotomy, and all cost analyses find it less expensive than Heller myotomy. Laparoscopic myotomy with a partial fundoplication has the advantage of being a single procedure, dysphagia relief is longer at the cost of more troubling heartburn, and a myotomy may be more effective treatment in adolescents and younger adults, especially men. Over a two year horizon, the clinical success of pneumatic dilation and laparoscopic myotomy are comparable in a recent large European randomised trial. The prognosis for achalasia patients to return to near-normal swallowing and good quality of life are excellent, but few are "cured" with a single treatment and intermittent "touch up" procedures may be required. PMID- 21303916 TI - Non-alcoholic fatty liver disease: what's new under the microscope? AB - Pathologist's observations have remained central to the evolution of the field of non-alcoholic fatty liver disease, even with the advent of increasingly effective non-invasive markers of advanced fibrosis. As the field matures, the role of pathology has also shifted from being largely descriptive to being confirmatory and diagnostic, as well as providing semi-quantitative evaluation of specific findings, particularly in therapeutic interventional trials. Some newly appreciated histopathological findings will be discussed in this review. PMID- 21303917 TI - A population-based comparison of the survival of patients with colorectal cancer in England, Norway and Sweden between 1996 and 2004. AB - OBJECTIVE: To examine differences in the relative survival and excess death rates of patients with colorectal cancer in Norway, Sweden and England. METHODS: All individuals diagnosed with colorectal cancer (ICD10 (International Classification of Diseases, 10th revision) C18-C20) between 1996 and 2004 in England, Norway and Sweden were included in this population-based study of patients with colorectal cancer. The main outcome measures were 5-year cumulative relative period of survival and excess death rates stratified by age and period of follow-up. RESULTS: The survival of English patients with colorectal cancer was significantly lower than was observed in both Norway and Sweden. Five-year age standardised colon cancer relative survival was 51.1% (95% CI 50.1% to 52.0%) in England compared with 57.9% (95% CI 55.2% to 60.5%) in Norway and 59.9% (95% CI 57.7% to 62.0%) in Sweden. Five-year rectal cancer survival was 52.3% (95% CI 51.1% to 53.5%) in England compared with 60.7% (95% CI 57.0% to 64.2%) and 59.8% (95% CI 56.9% to 62.6%) in Norway and Sweden, respectively. The lower survival for colon cancer in England was primarily due to a high number of excess deaths among older patients in the first 3 months after diagnosis. In patients with rectal cancer, excess deaths remained elevated until 2 years of follow-up. If the lower excess death rate in Norway applied in the English population, then 890 (13.6%) and 654 (16.8%) of the excess deaths in the colon and rectal cancer populations, respectively, could have been prevented at 5 years follow-up. Most of these avoidable deaths occurred shortly after diagnosis. CONCLUSIONS: There was significant variation in survival between the countries, with the English population experiencing a poorer outcome, primarily due to a relatively higher number of excess deaths in older patients in the short term after diagnosis. It seems likely, therefore, that in England a greater proportion of the population present with more rapidly fatal disease (especially in the older age groups) than in Norway or Sweden. PMID- 21303918 TI - Evaluation of oesophageal mucosa integrity by the intraluminal impedance technique. AB - BACKGROUND: Oesophageal intraluminal impedance is currently used for assessment of reflux in gastro-oesophageal reflux disease (GORD). Oesophageal mucosa integrity may have a key role in heartburn perception in non-erosive reflux disease (NERD). Severe erosive oesophagitis is associated with low impedance baseline. We hypothesised that impedance baseline measurements could be used to evaluate changes in oesophageal mucosa integrity in man. METHODS: We measured oesophageal impedance baseline before, during and after acid perfusion in rabbits and healthy subjects. Transepithelial resistance (TER) was determined and dilated intercellular spaces (DIS) were assessed in isolated rabbit oesophageal mucosa. Impedance baseline was measured retrospectively at different levels of the oesophagus in impedance-pH recordings from asymptomatic volunteers and patients with GORD. RESULTS: In healthy subjects and rabbits, impedance baseline dropped dramatically during perfusion of control solution (pH 7.2) but after perfusion, impedance recovered. In rabbits, after perfusion with saline pH 1.5 and 1.0 impedance values remained a 39.1 +/- 7.0% and 63.9 +/- 6.5% (p < 0.05) lower respectively. There was a positive correlation between in vivo basal impedance and in vitro TER values (r = 0.72, p = 0.0021). Tissue showed no erosions but both acidic solutions induced DIS. In healthy subjects, after perfusion with saline pH 2.0 and 1.0 the impedance baseline remained lower a 21.9 +/- 6.5% and 52.7 +/- 5.0%, (p < 0.0001) respectively. Patients with GORD have a lower impedance baseline than healthy volunteers at the distal oesophagus. CONCLUSIONS: Impedance baseline measurements might be used to evaluate the status of the oesophageal mucosa and to study the role of the impaired mucosal integrity in acid-induced heartburn in healthy volunteers and in patients with GORD. PMID- 21303920 TI - Chronic N-acetylcysteine during abstinence or extinction after cocaine self administration produces enduring reductions in drug seeking. AB - The cysteine prodrug N-acetylcysteine (NAC) has been shown to reduce reinstatement of cocaine seeking by normalization of glutamatergic tone. However, enduring inhibition of cocaine seeking produced by NAC has not been explored under different withdrawal conditions. Thus, the present study determined whether chronic NAC administered during daily extinction training or daily abstinence after withdrawal from cocaine self-administration would reduce cocaine seeking. Rats self-administered intravenous cocaine during daily 2-h sessions for 12 days, followed by daily extinction or abstinence sessions. During this period, rats received daily injections of saline or NAC (60 or 100 mg/kg). Subsequently, rats were tested for cocaine seeking via conditioned cue, cue + cocaine-primed, and context-induced relapse. Chronic NAC administration blunted cocaine seeking under multiple experimental protocols. Specifically, NAC attenuated responding during cue and cue + cocaine-primed reinstatement tests after extinction and context, cue, and cue + cocaine relapse tests after abstinence. Protection from relapse by NAC persisted well after treatment was discontinued, particularly when the high dose was combined with extinction trials. The finding that NAC reduced cocaine seeking after drug treatment was discontinued has important implications for the development of effective antirelapse medications. These results support recent preclinical and clinical findings that NAC may serve as an effective treatment for inhibiting relapse in cocaine addicts. PMID- 21303921 TI - Proteasome regulator marizomib (NPI-0052) exhibits prolonged inhibition, attenuated efflux, and greater cytotoxicity than its reversible analogs. AB - The present study was undertaken to compare the cellular transport characteristics of [(3)H]NPI-0052 (1R,4R,5S)-4-(2-chloroethyl)-1-((S)-((S) cyclohex-2-enyl)(hydroxy)methyl)-5-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7 dione (marizomib; salinosporamide A) and [(3)H]NPI-0047 (1R,4R, 5S)-1-((S)-((S) cyclohex-2-enyl)(hydroxy)methyl)-4-ethyl-5-methyl-6-oxa-2 azabicyclo[3.2.0]heptane-3,7-dione in RPMI 8226 multiple myeloma and PC-3 prostate adenocarcinoma cells to determine whether these properties explain differences in the cytotoxic potencies of these chemical analogs. The results indicate that marizomib, which possesses a chemical-leaving group, is more cytotoxic to both cell lines and inhibits proteasome activity more completely at lower concentrations than NPI-0047, a nonleaving-group analog. Moreover, it was found that both compounds accumulate in these cells by simple diffusion and the same carrier-mediated transport system. Although the rate of uptake is similar, the cellular efflux, which does not seem to be mediated by a major ATP-binding cassette (ABC)-efflux transporter, is more rapid for NPI-0047 than for marizomib. Experiments revealed that the irreversible binding of marizomib to the proteasome is responsible for its slower efflux, longer duration of action, and greater cytotoxicity compared with NPI-0047. The discovery that major ABC transporters of the multidrug resistance-associated protein family do not seem to be involved in the accumulation or removal of these agents suggests they may not be affected by multidrug resistance mechanisms during prolonged administration. PMID- 21303922 TI - Regulation of transforming growth factor-beta1-dependent integrin beta6 expression by p38 mitogen-activated protein kinase in bile duct epithelial cells. AB - Bile duct epithelial cells (BDECs) contribute to liver fibrosis by expressing alphaVbeta6 integrin, a critical activator of latent transforming growth factor beta (TGF-beta). beta6 integrin (Itgbeta6) mRNA induction and alphaVbeta6 integrin expression in BDECs are partially TGF-beta-dependent. However, the signaling pathways required for TGF-beta-dependent Itgbeta6 mRNA induction in BDECs are not known. We tested the hypothesis that the p38 mitogen-activated protein kinase (MAPK) signaling pathway contributes to TGF-beta1 induction of Itgbeta6 mRNA by activating SMAD and activator protein 1 (AP-1) transcription factors. Pretreatment of transformed human BDECs (MMNK-1 cells) with two different p38 MAPK inhibitors, but not a control compound, inhibited TGF-beta1 induction of Itgbeta6 mRNA. Inhibition of p38 also reduced TGF-beta1 activation of a SMAD-dependent reporter construct. Expression of a dominant-negative SMAD3 (SMAD3DeltaC) significantly reduced TGF-beta1-induced Itgbeta6 mRNA expression. Expression of JunB mRNA, but not other AP-1 proteins, increased in TGF-beta1 treated MMNK-1 cells, and induction of JunB expression was p38-dependent. Consistent with a requirement for de novo induction of JunB protein, cycloheximide pretreatment inhibited TGF-beta1 induction of Itgbeta6 mRNA. Expression of a dominant-negative AP-1 mutant (TAM67) also inhibited TGF-beta1 induction of Itgbeta6 mRNA. Overall, the results suggest that p38 contributes to TGF-beta1-induced Itgbeta6 mRNA expression in MMNK-1 cells by regulating activation of both SMAD and AP-1 transcription factors. PMID- 21303923 TI - Prediction of human drug clearance by multiple metabolic pathways: integration of hepatic and intestinal microsomal and cytosolic data. AB - The current study assesses hepatic and intestinal glucuronidation, sulfation, and cytochrome P450 (P450) metabolism of raloxifene, quercetin, salbutamol, and troglitazone using different in vitro systems. The fraction metabolized by conjugation and P450 metabolism was estimated in liver and intestine, and the importance of multiple metabolic pathways on accuracy of clearance prediction was assessed. In vitro intrinsic sulfation clearance (CL(int, SULT)) was determined in human intestinal and hepatic cytosol and compared with hepatic and intestinal microsomal glucuronidation (CL(int, UGT)) and P450 clearance (CL(int, CYP)) expressed per gram of tissue. Hepatic and intestinal cytosolic scaling factors of 80.7 mg/g liver and 18 mg/g intestine were estimated from published data. Scaled CL(int, SULT) ranged between 0.7 and 11.4 ml . min(-1) . g(-1) liver and 0.1 and 3.3 ml . min(-1) . g(-1) intestine (salbutamol and quercetin were the extremes). Salbutamol was the only compound with a high extent of sulfation (51 and 28% of total CL(int) for liver and intestine, respectively) and also significant renal clearance (26-57% of observed plasma clearance). In contrast, the clearance of quercetin was largely accounted for by glucuronidation. Drugs metabolized by multiple pathways (raloxifene and troglitazone) demonstrated improved prediction of intravenous clearance using data from all hepatic pathways (44-86% of observed clearance) compared with predictions based only on the primary pathway (22-36%). The assumption of no intestinal first pass resulted in underprediction of oral clearance for raloxifene, troglitazone, and quercetin (3-22% of observed, respectively). Accounting for the intestinal contribution to oral clearance via estimated intestinal availability improved prediction accuracy for raloxifene and troglitazone (within 2.5-fold of observed). Current findings emphasize the importance of both hepatic and intestinal conjugation for in vitro-in vivo extrapolation of metabolic clearance. PMID- 21303924 TI - Differential role of Toll-interleukin 1 receptor domain-containing adaptor protein in Toll-like receptor 2-mediated regulation of gene expression of hepatic cytokines and drug-metabolizing enzymes. AB - Pharmacological activities of drugs are impaired during inflammation because of reduced expression of hepatic drug-metabolizing enzyme genes (DMEs) and their regulatory nuclear receptors (NRs): pregnane X receptor (PXR), constitutive androstane receptor (CAR), and retinoid X receptor (RXRalpha). We have shown that a component of Gram-positive bacteria, lipoteichoic acid (LTA) induces proinflammatory cytokines and reduces gene expression of hepatic DMEs and NRs. LTA is a Toll-like receptor 2 (TLR2) ligand, which initiates signaling by recruitment of Toll-interleukin 1 receptor domain-containing adaptor protein (TIRAP) to the cytoplasmic TIR domain of TLR2. To determine the role of TIRAP in TLR2-mediated regulation of DME genes, TLR2(+/+), TLR2(-/-), TIRAP(+/+), and TIRAP(-/-) mice were given LTA injections. RNA levels of the DMEs (Cyp3a11, Cyp2b10, and sulfoaminotransferase), xenobiotic NRs (PXR and CAR), and nuclear protein levels of the central NR RXRalpha were reduced ~ 50 to 60% in LTA-treated TLR2(+/+) but not in TLR2(-/-) mice. Induction of hepatic cytokines (interleukin 1beta, tumor necrosis factor-alpha, and interleukin-6), c-Jun NH(2)-terminal kinase, and nuclear factor-kappaBeta was blocked in TLR2(-/-) mice. As expected, expression of hepatic DMEs and NRs was reduced by LTA in TIRAP(+/+) but not in TIRAP(-/-) mice. Of interest, cytokine RNA levels were induced in the livers of both the TIRAP(+/+) and TIRAP(-/-) mice, whereas LTA-mediated induction of serum cytokines was attenuated in TIRAP(-/-) mice. LTA-mediated down-regulation of DME genes was attenuated in hepatocytes from TLR2(-/-) or TIRAP(-/-) mice and in small interfering RNA-treated hepatocytes. Thus, the effect of TLR2 on DME genes in hepatocytes was mediated by TIRAP, whereas TIRAP was not involved in mediating the effects of TLR2 on cytokine expression in the liver. PMID- 21303925 TI - Electron tomography reveals a flared morphology on growing microtubule ends. AB - Microtubules (MTs) exhibit dynamic instability, alternating between phases of growth and shortening, mostly at their uncapped plus ends. Based on results from cryo-electron microscopy it was proposed that growing MTs display mainly curved sheets and blunt ends; during depolymerisation curled 'ramshorns' predominate. Observations of MTs in mitotic cells have suggested that the situation in vivo differs from that in vitro, but so far, a clear comparison between in vivo and in vitro results has not been possible because MT end structures could not be correlated directly with the dynamic state of that particular MT. Here we combine light microscopy and electron tomography (ET) to show that growing MT plus ends in the fission yeast Schizosaccharomyces pombe display predominantly a flared morphology. This indicates that MT polymerisation in vivo and in vitro can follow different paths. PMID- 21303926 TI - Proteomic analysis of endocytic vesicles: Rab1a regulates motility of early endocytic vesicles. AB - Texas-Red-asialoorosomucoid (ASOR) fluorescence-sorted early and late endocytic vesicles from rat liver were subjected to proteomic analysis with the aim of identifying functionally important proteins. Several Rab GTPases, including Rab1a, were found. The present study immunolocalized Rab1a to early and late endocytic vesicles and examined its potential role in endocytosis. Huh7 cells with stable knockdown of Rab1a exhibited reduced endocytic processing of ASOR. This correlated with the finding that Rab1a antibody reduced microtubule-based motility of rat-liver-derived early but not late endocytic vesicles in vitro. The inhibitory effect of Rab1a antibody was observed to be specifically towards minus end-directed motility. Total and minus-end-directed motility was also reduced in early endocytic vesicles prepared from Rab1a-knockdown cells. These results corresponded with virtual absence of the minus-end-directed kinesin Kifc1 from early endocytic vesicles in Rab1a knockdown cells and imply that Rab1a regulates minus-end-directed motility largely by recruiting Kifc1 to early endocytic vesicles. PMID- 21303927 TI - Differential endocytosis and signaling dynamics of insulin receptor variants IR-A and IR-B. AB - Insulin signaling comprises a complex cascade of events, playing a key role in the regulation of glucose metabolism and cellular growth. Impaired response to insulin is the hallmark of diabetes, whereas upregulated insulin activity occurs in many cancers. Two splice variants of the insulin receptor (IR) exist in mammals: IR-A, lacking exon 11, and full-length IR-B. Although considerable biochemical data exist on insulin binding and downstream signaling, little is known about the dynamics of the IR itself. We created functional IR transgenes fused with visible fluorescent proteins for use in combination with biotinamido caproyl insulin and streptavidin quantum dots. Using confocal and structured illumination microscopy, we visualized the endocytosis of both isoforms in living and fixed cells and demonstrated a higher rate of endocytosis of IR-A than IR-B. These differences correlated with higher and sustained activation of IR-A in response to insulin and with distinctive ERK1/2 activation profiles and gene transcription regulation. In addition, cells expressing IR-B showed higher AKT phosphorylation after insulin stimulation than cells expressing IR-A. Taken together, these results suggest that IR signaling is dependent on localization; internalized IRs regulate mitogenic activity, whereas metabolic balance signaling occurs at the cell membrane. PMID- 21303928 TI - Nesprin-3 augments peripheral nuclear localization of intermediate filaments in zebrafish. AB - The outer nuclear membrane protein nesprin-3 binds the cytoskeletal linker protein plectin, which are proposed to anchor the intermediate filaments to the nuclear envelope. To investigate the function of nesprin-3 in vivo, we used the zebrafish as a vertebrate model system. Zebrafish nesprin-3 is expressed at the nuclear envelope of epidermal and skeletal muscle cells during development. Unexpectedly, loss of nesprin-3 did not affect embryonic development, viability or fertility. However, nesprin-3-deficient zebrafish embryos showed a reduced concentration of intermediate filaments around the nucleus. Additional analysis revealed the presence of two nesprin-3 isoforms in zebrafish, nesprin-3alpha and nesprin-3beta. Nesprin-3beta is only expressed during early development and lacks seven amino acids in its first spectrin repeat that are crucial for plectin binding and recruitment to the nuclear envelope. These seven amino acids are highly conserved and we showed that residues R43 and L44 within this motif are required for plectin binding. Furthermore, several residues in the actin-binding domain of plectin that are crucial for binding to the integrin beta4 subunit are also important for the binding to nesprin-3alpha, indicating partial overlapping binding sequences for nesprin-3alpha and integrin beta4. All this shows that nesprin-3 is dispensable for normal development in zebrafish, but important for mediating the association of the intermediate filament system with the nucleus in vivo. PMID- 21303929 TI - Translocation dynamics of sorting nexin 27 in activated T cells. AB - Sorting nexin 27 (SNX27) belongs to the sorting nexin family of proteins, which participate in vesicular and protein trafficking. Similarly to all sorting nexin proteins, SNX27 has a functional PX domain that is important for endosome binding, but it is the only sorting nexin with a PDZ domain. We identified SNX27 as a partner of diacylglycerol kinase zeta (DGKzeta), a negative regulator of T cell function that metabolises diacylglycerol to yield phosphatidic acid. SNX27 interacts with the DGKzeta PDZ-binding motif in early/recycling endosomes in resting T cells; however, the dynamics and mechanisms underlying SNX27 subcellular localisation during T cell activation are unknown. We demonstrate that in T cells that encounter pulsed antigen-presenting cells, SNX27 in transit on early/recycling endosomes polarise to the immunological synapse. A fraction of SNX27 accumulates at the mature immunological synapse in a process that is dependent on vesicular trafficking, binding of the PX domain to phosphatidylinositol 3-phosphate and the presence of the PDZ region. Downmodulation of expression of either SNX27 or DGKzeta results in enhanced basal and antigen-triggered ERK phosphorylation. These results identify SNX27 as a PDZ containing component of the T cell immunological synapse, and demonstrate a role for this protein in the regulation of the Ras-ERK pathway, suggesting a functional relationship between SNX27 and DGKzeta. PMID- 21303930 TI - Identification of PTPsigma as an autophagic phosphatase. AB - Macroautophagy is a dynamic process whereby portions of the cytosol are encapsulated in double-membrane vesicles and delivered to the lysosome for degradation. Phosphatidylinositol-3-phosphate (PtdIns3P) is concentrated on autophagic vesicles and recruits effector proteins that are crucial for this process. The production of PtdIns3P by the class III phosphatidylinositol 3 kinase Vps34, has been well established; however, protein phosphatases that antagonize this early step in autophagy remain to be identified. To identify such enzymes, we screened human phosphatase genes by RNA interference and found that loss of PTPsigma, a dual-domain protein tyrosine phosphatase (PTP), increases levels of cellular PtdIns3P. The abundant PtdIns3P-positive vesicles conferred by loss of PTPsigma strikingly phenocopied those observed in cells starved of amino acids. Accordingly, we discovered that loss of PTPsigma hyperactivates both constitutive and induced autophagy. Finally, we found that PTPsigma localizes to PtdIns3P-positive membranes in cells, and this vesicular localization is enhanced during autophagy. We therefore describe a novel role for PTPsigma and provide insight into the regulation of autophagy. Mechanistic knowledge of this process is crucial for understanding and targeting therapies for several human diseases, including cancer and Alzheimer's disease, in which abnormal autophagy might be pathological. PMID- 21303931 TI - The F-actin cortical network is a major factor influencing the organization of the secretory machinery in chromaffin cells. AB - We have studied how the F-actin cytoskeleton is involved in establishing the heterogeneous intracellular Ca(2+) levels ([Ca(2+)](i)) and in the organization of the exocytotic machinery in cultured bovine chromaffin cells. Simultaneous confocal visualization of [Ca(2+)](i) and transmitted light studies of the cytoskeleton showed that, following cell stimulation, the maximal signal from the Ca(2+)-sensitive fluorescent dye Fluo-3 was in the empty cytosolic spaces left by cytoskeletal cages. This was mostly due to the accumulation of the dye in spaces devoid of cytoskeletal components, as shown by the use of alternative Ca(2+) insensitive fluorescent cytosolic markers. In addition to affecting the distribution of such compounds in the cytosol, the cytoskeleton influenced the location of L- and P-Q-type Ca(2+) channel clusters, which were associated with the borders of cytoskeletal cages in resting and stimulated cells. Indeed, syntaxin-1 and synaptotagmin-1, which are components of the secretory machinery, were present in the same location. Furthermore, granule exocytosis took place at these sites, indicating that the organization of the F-actin cytoskeletal cortex shapes the preferential sites for secretion by associating the secretory machinery with preferential sites for Ca(2+) entry. The influence of this cortical organization on the propagation of [Ca(2+)](i) can be modelled, illustrating how it serves to define rapid exocytosis. PMID- 21303933 TI - Alterations in hepatic one-carbon metabolism and related pathways following a high-fat dietary intervention. AB - Obesity frequently leads to insulin resistance and the development of hepatic steatosis. To characterize the molecular changes that promote hepatic steatosis, transcriptomics, proteomics, and metabolomics technologies were applied to liver samples from C57BL/6J mice obtained from two independent intervention trials. After 12 wk of high-fat feeding the animals became obese, hyperglycemic, and insulin resistant, had elevated levels of blood cholesterol and VLDL, and developed hepatic steatosis. Nutrigenomic analysis revealed alterations of key metabolites and enzyme transcript levels of hepatic one-carbon metabolism and related pathways. The hepatic oxidative capacity and the lipid milieu were significantly altered, which may play a key role in the development of insulin resistance. Additionally, high choline levels were observed after the high-fat diet. Previous studies have linked choline levels with insulin resistance and hepatic steatosis in conjunction with changes of certain metabolites and enzyme levels of one-carbon metabolism. The present results suggest that the coupling of high levels of choline and low levels of methionine plays an important role in the development of insulin resistance and liver steatosis. In conclusion, the complexities of the alterations induced by high-fat feeding are multifactorial, indicating that the interplay between several metabolic pathways is responsible for the pathological consequences. PMID- 21303932 TI - Serotonin transporter, sex, and hypoxia: microarray analysis in the pulmonary arteries of mice identifies genes with relevance to human PAH. AB - Pulmonary arterial hypertension (PAH) is up to threefold more prevalent in women than men. Female mice overexpressing the serotonin transporter (SERT; SERT+ mice) exhibit PAH and exaggerated hypoxia-induced PAH, whereas male SERT+ mice remain unaffected. To further investigate these sex differences, microarray analysis was performed in the pulmonary arteries of normoxic and chronically hypoxic female and male SERT+ mice. Quantitative RT-PCR analysis was employed for validation of the microarray data. In relevant groups, immunoblotting was performed for genes of interest (CEBPbeta, CYP1B1, and FOS). To translate clinical relevance to our findings, CEBPbeta, CYP1B1, and FOS mRNA and protein expression was assessed in pulmonary artery smooth muscle cells (PASMCs) derived from idiopathic PAH (IPAH) patients and controls. In female SERT+ mice, multiple pathways with relevance to PAH were altered. This was also observed in chronically hypoxic female SERT+ mice. We selected 10 genes of interest for qRT-PCR analysis (FOS, CEBPbeta, CYP1B1, MYL3, HAMP2, LTF, PLN, NPPA, UCP1, and C1S), and 100% concordance was reported. Protein expression of three selected genes, CEBPbeta, CYP1B1, FOS, was also upregulated in female SERT+ mice. Serotonin and 17beta-estradiol increased CEBPbeta, CYP1B1, and FOS protein expression in PASMCs. In addition, CEBPbeta, CYP1B1, and FOS mRNA and protein expression was also increased in PASMCs derived from IPAH patients. Here, we have identified a number of genes that may predispose female SERT+ mice to PAH, and these findings may also be relevant to human PAH. PMID- 21303934 TI - Use of videophones to deliver a cognitive-behavioural therapy to hospice caregivers. AB - We investigated the feasibility of videophones for the delivery of problem solving therapy (PST) for informal hospice caregivers. Informal hospice caregivers were randomly assigned to receive PST from researchers using videophones, instead of communicating in face-to-face sessions. Outcome measures included caregiver anxiety, quality of life and problem-solving abilities, technical quality of videosessions and satisfaction of participants (including both subjects and researchers). A total of 42 hospice caregivers were enrolled (mean age 62 years). A total of 112 videocall attempts were documented. Of these, 100 (89%) resulted in successful videocalls and 12 (11%) were cases in which a call was not established. The average videocall duration was 38 min (range 18-84 min). The overall technical quality of the videocalls was very good. Caregivers reported a slightly higher quality of life post-intervention than at baseline, although this was not significant. Caregivers reported lower levels of anxiety post-intervention than at baseline (P = 0.04). The subjects were generally satisfied with the videophones during their exit interviews. PMID- 21303935 TI - Use of telemedicine for haemodialysis in very remote areas: the Canadian First Nations. AB - We used a pre-post design to compare the health and care utilization of patients receiving telehaemodialysis services in two James Bay Cree communities. The Cree are an Amerindian First Nation living in the remote James Bay region. The same group of dialysed patients (n = 19) was followed longitudinally over a two-year period: 12 months pre and 12 months post. Analysis of variables measuring the patients' health conditions showed that the quality of care provided was well within recognized good practice guidelines. Repeated measures ANOVA on the variables measuring care utilization showed a significant decrease in the monthly number of medication changes over time (P < 0.01). Different telehaemodialysis models were used in the two communities (virtual patient rounds and telecase reviews with multidisciplinary teams), but they did not lead to differences in health condition or care utilization. This suggests that there is no single prescriptive model for the delivery of tele-expertise. PMID- 21303937 TI - Understanding ribosome assembly: the structure of in vivo assembled immature 30S subunits revealed by cryo-electron microscopy. AB - Four decades after early in vitro assembly studies demonstrated that ribosome assembly is a controlled process, our understanding of ribosome assembly is still incomplete. Just as structure determination has been so important to understanding ribosome function, so too will it be critical to sorting out the assembly process. Here, we used a viable deletion in the yjeQ gene, a recognized ribosome assembly factor, to isolate and structurally characterize immature 30S subunits assembled in vivo. These small ribosome subunits contained unprocessed 17S rRNA and lacked some late ribosomal proteins. Cryo-electron microscopy reconstructions revealed that the presence of precursor sequences in the rRNA induces a severe distortion in the 3' minor domain of the subunit involved in the decoding of mRNA and interaction with the large ribosome subunit. These findings suggest that rRNA processing events induce key local conformational changes directing the structure toward the mature assembly. We concluded that rRNA processing, folding, and the entry of tertiary r-proteins are interdependent events in the late stages of 30S subunit assembly. In addition, we demonstrate how studies of emerging assembly factors in ribosome biogenesis can help to elucidate the path of subunit assembly in vivo. PMID- 21303938 TI - The role of glucocorticoids in pregnancy, parturition, lactation, and nurturing in melanocortin receptor 2-deficient mice. AB - Maternal glucocorticoids are critical for fetal development, but overexpression can be deleterious. Previously we established a mouse line deficient in melanocortin receptor 2 (MC2R). MC2R(-/-) mice have undetectable levels of corticosterone despite high levels of ACTH and defects resembling those in patients with familial glucocorticoid deficiency. Here we analyzed the role of glucocorticoids in pregnancy, parturition, lactation, and nurturing in MC2R(-/-) mice. MC2R(-/-) mice were fertile and produced normal litters when crossed with MC2R(+/+) mice. However, MC2R(-/-) females crossed with MC2R(-/-) males had no live births, and approximately 20% of the embryos at d 18.5 of pregnancy were of normal body size but were dead when born. MC2R(-/-) pregnant females crossed with MC2R(+/+) males had detectable serum corticosterone levels, suggesting the transplacental passage of corticosterone from fetus to mother. MC2R(+/-) pups delivered from MC2R(-/-) females crossed with MC2R(+/+) males mice thrived poorly with MC2R(-/-) mothers but grew to adulthood when transferred to foster mothers after birth, suggesting that MC2R(-/-) females are poor mothers or cannot nurse. MC2R(-/-) females had normal alveoli, but penetration of mammary epithelium into fat pads and expression of milk proteins were reduced. Myoepithelial cells, which force milk out of the alveoli, were fully developed and differentiated. Pup retrieval behavior was normal in MC2R(-/-) mice. Exogenous corticosterone rescued expression of milk proteins in MC2R(-/-) mothers, and the pups of treated mothers grew to adulthood. Our results reveal the importance of glucocorticoids for fetal survival late in pregnancy, mammary gland development, and milk protein gene expression. PMID- 21303939 TI - GPR30 activation opposes estrogen-dependent uterine growth via inhibition of stromal ERK1/2 and estrogen receptor alpha (ERalpha) phosphorylation signals. AB - Although estradiol-17beta (E2)-regulated early and late phase uterine responses have been well defined, the molecular mechanisms linking the phases remain poorly understood. We have previously shown that E2-regulated early signals mediate cross talk with estrogen receptor (ER)-alpha to elicit uterine late growth responses. G protein-coupled receptor (GPR30) has been implicated in early nongenomic signaling mediated by E2, although its role in E2-dependent uterine biology is unclear. Using selective activation of GPR30 by G-1, we show here a new function of GPR30 in regulating early signaling events, including the inhibition of ERK1/2 and ERalpha (Ser118) phosphorylation signals and perturbation of growth regulation under the direction of E2 in the mouse uterus. We observed that GPR30 primarily localizes in the uterine epithelial cells, and its activation alters gene expression and mediates inhibition of ERK1/2 and ERalpha (Ser118) phosphorylation signals in the stromal compartment, suggesting a paracrine signaling is involved. Importantly, viral-driven manipulation of GPR30 or pharmacological inhibition of ERK1/2 activation effectively alters E2 dependent uterine growth responses. Overall, GPR30 is a negative regulator of ERalpha-dependent uterine growth in response to E2. Our work has uncovered a novel GPR30-regulated inhibitory event, which may be physiologically relevant in both normal and pathological situations to negatively balance ERalpha-dependent uterine growth regulatory functions induced by E2. PMID- 21303940 TI - Absence of melatonin induces night-time hepatic insulin resistance and increased gluconeogenesis due to stimulation of nocturnal unfolded protein response. AB - It is known that the circadian rhythm in hepatic phosphoenolpyruvate carboxykinase expression (a limiting catalytic step of gluconeogenesis) and hepatic glucose production is maintained by both daily oscillation in autonomic inputs to the liver and night feeding behavior. However, increased glycemia and reduced melatonin (Mel) levels have been recently shown to coexist in diabetic patients at the end of the night period. In parallel, pinealectomy (PINX) is known to cause glucose intolerance with increased basal glycemia exclusively at the end of the night. The mechanisms that underlie this metabolic feature are not completely understood. Here, we demonstrate that PINX rats show night-time hepatic insulin resistance characterized by reduced insulin-stimulated RAC-alpha serine/threonine-protein kinase phosphorylation and increased phosphoenolpyruvate carboxykinase expression. In addition, PINX rats display increased conversion of pyruvate into glucose at the end of the night. The regulatory mechanism suggests the participation of unfolded protein response (UPR), because PINX induces night time increase in activating transcription factor 6 expression and prompts a circadian fashion of immunoglobulin heavy chain-binding protein, activating transcription factor 4, and CCAAT/enhancer-binding protein-homologous protein expression with Zenith values at the dark period. PINX also caused a night-time increase in Tribble 3 and regulatory-associated protein of mammalian target of rapamycin; both were reduced in liver of PINX rats treated with Mel. Treatment of PINX rats with 4-phenyl butyric acid, an inhibitor of UPR, restored night-time hepatic insulin sensitivity and abrogated gluconeogenesis in PINX rats. Altogether, the present data show that a circadian oscillation of UPR occurs in the liver due to the absence of Mel. The nocturnal UPR activation is related with night-time hepatic insulin resistance and increased gluconeogenesis in PINX rats. PMID- 21303941 TI - DHEA suppresses longitudinal bone growth by acting directly at growth plate through estrogen receptors. AB - Dehydroepiandrosterone (DHEA) is produced by the adrenal cortex and is the most abundant steroid in humans. Although in some physiological and pathological conditions the increased secretion of DHEA and its sulfated form is associated with accelerated growth rate and skeletal maturation, it is unclear whether DHEA can affect longitudinal bone growth and skeletal maturation by acting directly at the growth plate. In our study, DHEA suppressed metatarsal growth, growth plate chondrocyte proliferation, and hypertrophy/differentiation. In addition, DHEA increased the number of apoptotic chondrocytes in the growth plate. In cultured chondrocytes, DHEA reduced chondrocyte proliferation and induced apoptosis. The DHEA-induced inhibition of metatarsal growth and growth plate chondrocyte proliferation and hypertrophy/differentiation was nullified by culturing metatarsals with DHEA in the presence of ICI 182,780, an inhibitor of estrogen receptor, but not in the presence of Casodex, an inhibitor of androgen receptor. Lastly, nuclear factor-kappaB DNA binding activity was inhibited by the addition of DHEA in the medium of cultured chondrocyte. Our findings indicate that DHEA suppressed bone growth by acting directly at growth plate through estrogen receptor. Such growth inhibition is mediated by decreased chondrocyte proliferation and hypertrophy/differentiation and by increased chondrocyte apoptosis. PMID- 21303942 TI - Modulation of PC1/3 activity by self-interaction and substrate binding. AB - Prohormone convertase (PC)1/3 is a eukaryotic serine protease in the subtilase family that participates in the proteolytic maturation of prohormone and neuropeptide precursors such as proinsulin and proopiomelanocortin. Despite the important role of this enzyme in peptide synthesis, how PC1/3 activity is regulated is still poorly understood. Using ion exchange chromatography and two dimensional gel electrophoresis we found that natural PC1/3 present in AtT-20 cells and bovine chromaffin granules, as well as recombinant PC1/3 secreted from overexpressing Chinese hamster ovary cells, exists as multiple ionic forms. Gel filtration and cross-linking studies revealed that protein oligomerization and aggregation contribute greatly to variability in surface charge. The most acidic forms of PC1/3 contained both inactive aggregates as well as oligomerized 87-kDa PC1/3 that exhibited stable activity which was partially latent and could be revealed by dilution. No such latency was observed for the more basic, 66/74-kDa forms of PC1/3. Fractions containing these species were stabilized by preincubation with micromolar concentrations of either fluorogenic substrate or peptides containing pairs of basic residues. In addition, the most active form of 87-kDa PC1/3, a probable homodimer, was activated by preincubation with these same peptides. Cleavage by PC1/3 is often the initiating step in the biosynthetic pathway for peptide hormones, implying that this is a natural step for regulation. Our data suggest that enzyme oligomerization and peptide stabilization represent important contributing factors for the control of PC1/3 activity within secretory granules. PMID- 21303943 TI - 17beta-Estradiol, aging, inflammation, and the stress response in the female heart. AB - Heat shock proteins (HSPs) are a cardioprotective class of proteins induced by stress and regulated by the transcription factor, heat shock factor (HSF)-1. 17beta-estradiol (E(2)) indirectly regulates HSP expression through rapid activation of nuclear factor-kappaB (NF-kappaB) and HSF-1 and protects against hypoxia. As males experience a loss of protective cellular responses in aging, we hypothesized that aged menopausal (old ovariectomized) rats would have an impaired HSP response, which could be prevented by immediate in vivo E(2) replacement. After measuring cardiac function in vivo, cardiac myocytes were isolated from ovariectomized adult and old rats with and without 9 weeks of E(2) replacement. Myocytes were treated with E(2) in vitro and analyzed for activation of NF-kappaB, HSF-1, and HSP expression. In addition, we measured inflammatory cytokine expression and susceptibility to hypoxia/reoxygenation injury. Cardiac contractility was reduced in old ovariectomized rats and could prevented by immediate E(2) replacement in vivo. Subsequent investigations in isolated cardiac myocytes found that in vitro E(2) activated NF-kappaB, HSF-1, and increased HSP 72 expression in adult but not old rats. In response to hypoxia/reoxygenation, myocytes from adult, but not old, rats had increased HSP 72 expression. In addition, expression of the inflammatory cytokines TNF-alpha and IL-1beta, as well as oxidative stress, were increased in myocytes from old ovariectomized rats; only the change in cytokine expression could be attenuated by in vivo E(2) replacement. This study demonstrates that while aging in female rats led to a loss of the cardioprotective HSP response, E(2) retains its protective cellular properties. PMID- 21303944 TI - Genetic identification of GnRH receptor neurons: a new model for studying neural circuits underlying reproductive physiology in the mouse brain. AB - GnRH signaling regulates reproductive physiology in vertebrates via the hypothalamic-pituitary-gonadal axis. In addition, GnRH signaling has been postulated to act on the brain. However, elucidating its functional role in the central nervous system has been hampered because of the difficulty in identifying direct GnRH signaling targets in live brain tissue. Here we used a binary genetic strategy to visualize GnRH receptor (GnRHR) neurons in the mouse brain and started to characterize these cells. First, we expressed different fluorescent proteins in GnRHR neurons and mapped their precise distribution throughout the brain. Remarkably, neuronal GnRHR expression was only initiated after postnatal day 16, suggesting peri- and postpubertal functions of GnRH signaling in this organ. GnRHR neurons were found in different brain areas. Many GnRHR neurons were identified in areas influencing sexual behaviors. Furthermore, GnRHR neurons were detected in brain areas that process olfactory and pheromonal cues, revealing one efferent pathway by which the neuroendocrine hypothalamus may influence the sensitivity towards chemosensory cues. Using confocal Ca(2+) imaging in brain slices, we show that GnRHR neurons respond reproducibly to extracellular application of GnRH or its analog [D-TRP(6)]-LH-RH, indicating that these neurons express functional GnRHR. Interestingly, the duration and shape of the Ca(2+) responses were similar within and different between brain areas, suggesting that GnRH signaling may differentially influence brain functions to affect reproductive success. Our new mouse model sets the stage to analyze the next level of GnRH signaling in reproductive physiology and behavior. PMID- 21303946 TI - Transcription factor AP-2alpha promotes EGF-dependent invasion of human trophoblast. AB - The basic helix-span-helix transcription factor activating protein (AP)-2alpha is critically involved in cell-specific hormone expression of syncytializing human trophoblasts. Its role in invasive trophoblast differentiation, however, remains largely elusive. Using RT-PCR, Western blotting, and immunofluorescence of first trimester placentae, we here show that AP-2alpha is expressed in extravillous trophoblasts (EVTs) both in situ and in vitro as well as in invasive trophoblast cell lines. Its protein expression was increased upon supplementation of epidermal growth factor (EGF) both in primary EVTs and trophoblastic SGHPL-5 cells. Gene silencing of AP-2alpha using small hairpin microRNA (shRNAmir) did not affect basal invasion of SGHPL-5 cells through Matrigel-coated filters but reduced EGF-stimulated invasion. Similarly, treatment of primary EVTs with AP 2alpha small interfering RNA decreased EGF-dependent invasion. Proliferation of SGHPL-5 cells and primary EVTs, measured by cumulative cell numbers and 5-bromo 2'-deoxyuridine labeling, respectively, were not affected on loss of AP-2alpha. EGF-dependent induction of matrix metalloproteinase (MMP)-2, pro- and active form of urokinase plasminogen activator, and chorionic gonadotropin (CG)-beta was noticed in shRNAmir-control cells, whereas these genes were suppressed in EGF treated shRNAmir-AP-2alpha cells. Similarly, EGF-stimulated MMP-2 and CGbeta protein expression was reduced in AP-2alpha small interfering RNA-treated primary EVTs. Knockdown of AP-2alpha also decreased luciferase activity of the CGbeta5 promoter in SGHPL-5 cells, which was compensated upon transient overexpression of AP-2alpha cDNA. In conclusion, we show that AP-2alpha expression positively affects human trophoblast invasion under EGF-stimulated conditions, likely by inducing critical invasion-promoting genes such MMP-2, urokinase plasminogen activator, and CG. PMID- 21303945 TI - ACTH-dependent ultradian rhythm of corticosterone secretion. AB - The activity of the hypothalamic-pituitary-adrenal axis is characterized by an ultradian pulsatile pattern of glucocorticoid secretion. Despite increasing evidence for the importance of pulsatility in regulating glucocorticoid responsive gene transcription, little is known about the mechanism underlying the pulsatility of glucocorticoid synthesis and release. We tested the hypothesis that pulsatile ACTH release is critical for optimal adrenocortical function. Hypothalamic-pituitary-adrenal activity was suppressed by oral methylprednisolone, and ACTH (4 ng/h) was infused for 24h either as a constant infusion or in 5-min pulses at hourly intervals. Control methylprednisolone treated rats had very low plasma corticosterone (CORT) levels with undetectable pulses and also had steroidogenic acute regulatory protein (StAR) and cytochrome P450 side-chain cleavage (P450scc) heteronuclear RNA levels reduced to approximately 50% of that seen in untreated animals. Pulsatile but not constant ACTH infusion restored pulsatile CORT secretion, and this was accompanied by parallel rises in StAR and P450scc heteronuclear RNA levels during the rising phase of the CORT pulse, which then fell during the falling phase. The pulsatile pattern of StAR and P450scc was paralleled by pulsatile transcription of the melanocortin 2 receptor accessory protein. Pulsatile ACTH activation of the adrenal cortex not only is critical for the secretion of CORT but also induces episodic transcription of the rate-limiting enzymes necessary for physiological steroidogenic responses. Because constant infusion of identical amounts of ACTH did not activate CORT secretion, pulsatility of ACTH provides a more effective signaling system for the activation of adrenocortical activity. PMID- 21303947 TI - Fragments of genomic DNA released by injured cells activate innate immunity and suppress endocrine function in the thyroid. AB - Activation of innate and acquired immune responses, which can be induced by infection, inflammation, or tissue injury, may impact the development of autoimmunity. Although stimulation of cells by double-stranded DNA (dsDNA) has been shown to activate immune responses, the role of self-genomic DNA fragments released in the context of sterile cellular injury is not well understood. Using cultured thyroid cells, we show that cell injury prompts the release of genomic DNA into the cytosol, which is associated with the production of type I interferons, inflammatory cytokines, and chemokines. Molecules necessary for antigen processing and presentation to lymphocytes are also induced in thyroid cells by injury. dsDNA strongly suppressed the expression of sodium/iodide symporter and radioiodine uptake. To identify molecules responsible for sensing cytosolic dsDNA, we directly identified the cellular proteins that bound a dsDNA Sepharose column by mass spectrometry. Our analysis identified histone H2B, which was previously demonstrated to be an essential factor that mediates the activation of innate immunity induced by dsDNA. Knockdown of histone H2B using specific small interfering RNA abolished cell injury-induced innate immune activation and increased sodium/iodide symporter expression. These results indicate that genomic DNA fragments released by cell injury are recognized by extrachromosomal histone H2B, which results in the activation of genes involved in both innate and acquired immune responses in thyroid cells and suppression of thyroid function. These results suggest that sterile thyroid injury, in the absence of infection, may be sufficient to trigger autoimmune reaction and to induce thyroid dysfunction. PMID- 21303948 TI - Increase of anteroventral periventricular kisspeptin neurons and generation of E2 induced LH-surge system in male rats exposed perinatally to environmental dose of bisphenol-A. AB - Perinatal exposure to environmental levels of bisphenol-A (BPA) impairs sexually dimorphic behaviors in rodents. Kisspeptin neurons in anteroventral periventricular nucleus (AVPV), which plays an important role in the activation of GnRH neurons and the initiation of LH-surge, have been suggested to be sexual dimorphism in rats. This study focused on exploring the influence of a perinatal exposure to an environmental dose of BPA on the development and maturation of male AVPV kisspeptin neurons and hypothalamus-pituitary-gonadal axis. Female rats were injected sc with 2 MUg BPA/kg.d from gestation d 10 through lactation d 7. Anatomical and functional changes in AVPV kisspeptin neurons and hypothalamus pituitary-gonadal axis were examined in prepubertal, pubertal, and adult male rats exposed perinatally to BPA (BPA-rats). Here, we show that in postnatal d (PND)30/50/90 BPA-rats, the number of AVPV kisspeptin-immunoreactive cells was persistently increased in comparison with age-matched control male rats. The number of GnRH-immunoreactive cells in PND30 BPA-rats declined approximately 40% compared with control male rats, whereas that in PND50/90 BPA-rats was increased in a G protein-coupled receptor 54-dependent manner. Estradiol could induce a stable LH-surge in PND90 BPA-rats and control female rats, which was sensitive to the G protein-coupled receptor 54 inhibitor. In PND30/50 BPA-rats, plasma level of LH was higher, but the level of testosterone was lower than control male rats. These findings provide evidence that perinatal exposure to an environmental dose of BPA causes a sustained increase in AVPV kisspeptin neurons in male rats, leading to the generation of estradiol-induced LH-surge system. PMID- 21303949 TI - Growth hormone-dependent pathogenesis of human hepatic steatosis in a novel mouse model bearing a human hepatocyte-repopulated liver. AB - Clinical studies have shown a close association between nonalcoholic fatty liver disease and adult-onset GH deficiency, but the relevant molecular mechanisms are still unclear. No mouse model has been suitable to study the etiological relationship of human nonalcoholic fatty liver disease and human adult-onset GH deficiency under conditions similar to the human liver in vivo. We generated human (h-)hepatocyte chimeric mice with livers that were predominantly repopulated with h-hepatocytes in a h-GH-deficient state. The chimeric mouse liver was mostly repopulated with h-hepatocytes about 50 d after transplantation and spontaneously became fatty in the h-hepatocyte regions after about 70 d. Infusion of the chimeric mouse with h-GH drastically decreased steatosis, showing the direct cause of h-GH deficiency in the generation of hepatic steatosis. Using microarray profiles aided by real-time quantitative RT-PCR, comparison between h hepatocytes from h-GH-untreated and -treated mice identified 14 GH-up-regulated and four GH-down-regulated genes, including IGF-I, SOCS2, NNMT, IGFLS, P4AH1, SLC16A1, SRD5A1, FADS1, and AKR1B10, respectively. These GH-up- and -down regulated genes were expressed in the chimeric mouse liver at lower and higher levels than in human livers, respectively. Treatment of the chimeric mice with h GH ameliorated their altered expression. h-Hepatocytes were separated from chimeric mouse livers for testing in vitro effects of h-GH or h-IGF-I on gene expression, and results showed that GH directly regulated the expression of IGF I, SOCS2, NNMT, IGFALS, P4AH1, FADS1, and AKR1B10. In conclusion, the chimeric mouse is a novel h-GH-deficient animal model for studying in vivo h-GH-dependent human liver dysfunctions. PMID- 21303950 TI - Lack of action of exogenously administered T3 on the fetal rat brain despite expression of the monocarboxylate transporter 8. AB - Mutations of the monocarboxylate transporter 8 gene (MCT8, SLC16A2) cause the Allan-Herndon-Dudley syndrome, an X-linked syndrome of severe intellectual deficit and neurological impairment. Mct8 transports thyroid hormones (T4 and T3), and the Allan-Herndon-Dudley syndrome is likely caused by lack of T3 transport to neurons during critical periods of fetal brain development. To evaluate the role of Mct8 in thyroid hormone action in the fetal brain we administered T4 or T3 to thyroidectomized pregnant dams treated with methyl mercapto-imidazol to produce maternal and fetal hypothyroidism. Gene expression was then measured in the fetal cerebral cortex. T4 increased Camk4, Sema3c, and Slc7a3 expression, but T3 was without effect. To investigate the cause for the lack of T3 action we analyzed the expression of organic anion transport polypeptide (Oatp14, Slco1c1), a T4 transporter, and Mct8 (Slc16a2), a T4 and T3 transporter, by confocal microscopy. Both proteins were present in the brain capillaries forming the blood-brain barrier and in the epithelial cells of the choroid plexus forming the blood-cerebrospinal fluid barrier. It is concluded that T4 from the maternal compartment influences gene expression in the fetal cerebral cortex, possibly after transport via organic anion transporter polypeptide and/or Mct8, and conversion to T3 in the astrocytes. On the other hand, T3 does not reach the target neurons despite the presence of Mct8. The data indicate that T4, through local deiodination, provides most T3 in the fetal rat brain. The role of Mct8 as a T3 transporter in the fetal rat brain is therefore uncertain. PMID- 21303951 TI - Overexpression of pregnancy-associated plasma protein-A in ovarian cancer cells promotes tumor growth in vivo. AB - Pregnancy-associated plasma protein-A (PAPP-A) is an important regulatory component of the IGF system. Through proteolysis of inhibitory IGF binding proteins (IGFBPs), PAPP-A acts as a positive modulator of local IGF signaling in a variety of biological systems. A role of IGF in the progression of several common forms of human cancer is now emerging, and therapeutic intervention of IGF receptor signaling is currently being explored. However, little is known about the activities of other components of the IGF system in relation to cancer. We hypothesized that PAPP-A acts to enhance tumor growth in vivo. To test this hypothesis, we overexpressed wild-type PAPP-A or a mutant PAPP-A with markedly reduced IGFBP protease activity in SKOV3 cells, a human ovarian carcinoma cell line with low tumorigenic potential. In vitro, SKOV3 clones with elevated PAPP-A expression (PAPP-A-1, PAPP-A-28) showed accelerated anchorage-independent growth in soft agar assays compared to clones overexpressing mutant PAPP-A (E483Q-1, E483Q-5) and vector controls. PAPP-A-28, with the highest PAPP-A expression and IGFBP proteolytic activity, also had markedly increased cell invasion through Matrigel. In vivo, we found significantly accelerated tumor growth rates of PAPP A-overexpressing SKOV3 clones compared with mutant PAPP-A and controls. Investigation of angiogenesis indicated that overexpression of PAPP-A favored development of mature tumor vasculature and that tumor precursors of PAPP-A-28 in particular had a significantly higher degree of vascularization months before obvious tumor development. In conclusion, our data show that PAPP-A proteolytic activity enhances the tumorigenic potential of ovarian cancer cells and establish a novel tumor growth-promoting role of PAPP-A. PMID- 21303952 TI - Maternal fructose intake during pregnancy and lactation alters placental growth and leads to sex-specific changes in fetal and neonatal endocrine function. AB - The effects of maternal fructose intake on offspring health remain largely unknown, despite the marked increase in consumption of sweetened beverages that has paralleled the obesity epidemic. The present study investigated the impact of maternal fructose intake on placental, fetal, and neonatal development. Female Wistar rats were time-mated and allocated to receive either water [control (CONT)] or fructose solution designed to provide 20% of caloric intake from fructose (FR). FR was administered from d 1 of pregnancy until postnatal day (P) 10. All dams had ad libitum access to standard laboratory chow and water. Dams and offspring were killed at embryonic day (E) 21 and P10. FR dams demonstrated increased total caloric intake and maternal hyperinsulinemia at E21 as well as increased maternal plasma fructose levels at E21 and P10. FR intake did not alter maternal blood glucose, beta-hydroxybutyrate (BHB), or electrolyte levels at either time point. Fetal weights at E21 were unchanged, although placental weights were reduced in FR female but not FR male fetuses. Plasma leptin, fructose, and blood glucose levels were increased and BHB levels decreased in FR female but not male fetuses. Plasma insulin levels were not different between CONT and FR groups. Male and female FR neonates had higher plasma fructose levels and were hypoinsulinemic but euglycemic at P10 compared with CONT. Blood BHB levels were increased in FR male neonates but not females at P10. P10 plasma leptin levels were not different between groups. Stomach content leptin levels were increased in all FR offspring at P10, but no differences in stomach content insulin or fructose levels were observed. This study reports for the first time that maternal FR intake resulted in sex-specific changes in offspring development, whereby females appear more vulnerable to metabolic compromise during neonatal life. Independent follow-up studies are essential to investigate the long-term consequences of maternal FR consumption on offspring health. PMID- 21303953 TI - Angiotensin III stimulates aldosterone secretion from adrenal gland partially via angiotensin II type 2 receptor but not angiotensin II type 1 receptor. AB - Angiotensin II (Ang II) and Ang III stimulate aldosterone secretion by adrenal glomerulosa, but the angiotensin receptor subtypes involved and the effects of Ang IV and Ang (1-7) are not clear. In vitro, different angiotensins were added to rat adrenal glomerulosa, and aldosterone concentration in the medium was measured. Ang II-induced aldosterone release was blocked (30.3 +/- 7.1%) by an Ang II type 2 receptor (AT2R) antagonist, PD123319. Candesartan, an Ang II type 1 receptor (AT1R) antagonist, also blocked Ang II-induced aldosterone release (42.9 +/- 4.8%). Coadministration of candesartan and PD123319 almost abolished the Ang II-induced aldosterone release. A selective AT2R agonist, CGP42112, was used to confirm the effects of AT2R. CGP42112 increased aldosterone secretion, which was almost completely inhibited by PD123319. In addition to Ang II, Ang III also induced aldosterone release, which was not blocked by candesartan. However, PD123319 blocked 22.4 +/- 10.5% of the Ang III-induced aldosterone secretion. Ang IV and Ang (1-7) did not induce adrenal aldosterone secretion. In vivo, both Ang II and Ang III infusion increased plasma aldosterone concentration, but only Ang II elevated blood pressure. Ang IV and Ang (1-7) infusion did not affect blood pressure or aldosterone concentration. In conclusion, this report showed for the first time that AT2R partially mediates Ang III-induced aldosterone release, but not AT1R. Also, over 60% of Ang III-induced aldosterone release may be independent of both AT1R and AT2R. Ang III and AT2R signaling may have a role in the pathophysiology of aldosterone breakthrough. PMID- 21303954 TI - Essential roles of androgen signaling in Wolffian duct stabilization and epididymal cell differentiation. AB - The epididymis is a male accessory organ and functions for sperm maturation and storage under the control of androgen. The development of the epididymis is also androgen dependent. The Wolffian duct (WD), anlagen of the epididymis, is formed in both male and female embryos; however, it is stabilized only in male embryos by testicular androgen. Androgen drives subsequent differentiation of the WD into the epididymis. Although the essential roles of androgen in WD masculinization and epididymal function have been established, little is known about cellular events regulated precisely by androgen signaling during these processes. It is also unclear whether androgen signaling, especially in the epithelia, has further function for epididymal epithelial cell differentiation. In this study we examined the cellular death and proliferation controlled by androgen signaling via the androgen receptor (AR) in WD stabilization. Analyses using AR knockout mice revealed that androgen signaling inhibits epithelial cell death in this process. Analysis of AP2alpha-Cre;AR(flox/Y) mice, in which AR function is deleted in the WD epithelium, revealed that epithelial AR is not required for the WD stabilization but is required for epithelial cell differentiation in the epididymis. Specifically, loss of epithelial AR significantly reduced expression of p63 that is essential for differentiation of basal cells in the epididymal epithelium. We also interrogated the possibility of regulation of the p63 gene (Trp63) by AR in vitro and found that p63 is a likely direct target of AR regulation. PMID- 21303956 TI - Insulin-like growth factor-I:vitronectin complex-induced changes in gene expression effect breast cell survival and migration. AB - Recent studies have demonstrated that IGF-I associates with vitronectin (VN) through IGF-binding proteins (IGFBP), which in turn modulate IGF-stimulated biological functions such as cell proliferation, attachment, and migration. Because IGFs play important roles in transformation and progression of breast tumors, we aimed to describe the effects of IGF-I:IGFBP:VN complexes on breast cell function and to dissect mechanisms underlying these responses. In this study we demonstrate that substrate-bound IGF-I:IGFBP:VN complexes are potent stimulators of MCF-7 breast cell survival, which is mediated by a transient activation of ERK/MAPK and sustained activation of phosphoinositide 3-kinase/AKT pathways. Furthermore, use of pharmacological inhibitors of the MAPK and phosphoinositide 3-kinase pathways confirms that both pathways are involved in IGF-I:IGFBP:VN complex-mediated increased cell survival. Microarray analysis of cells stimulated to migrate in response to IGF-I:IGFBP:VN complexes identified differential expression of genes with previously reported roles in migration, invasion, and survival (Ephrin-B2, Sharp-2, Tissue-factor, Stratifin, PAI-1, IRS 1). These changes were not detected when the IGF-I analogue ([L(24)][A(31)]-IGF I), which fails to bind to the IGF-I receptor, was substituted; confirming the IGF-I-dependent differential expression of genes associated with enhanced cell migration. Taken together, these studies have established that IGF-I:IGFBP:VN complexes enhance breast cell migration and survival, processes central to facilitating metastasis. This study highlights the interdependence of extracellular matrix and growth factor interactions in biological functions critical for metastasis and identifies potential novel therapeutic targets directed at preventing breast cancer progression. PMID- 21303955 TI - Transgenic overexpression of the extra-large Gsalpha variant XLalphas enhances Gsalpha-mediated responses in the mouse renal proximal tubule in vivo. AB - XLalphas, a variant of the stimulatory G protein alpha-subunit (Gsalpha), can mediate receptor-activated cAMP generation and, thus, mimic the actions of Gsalpha in transfected cells. However, it remains unknown whether XLalphas can act in a similar manner in vivo. We have now generated mice with ectopic transgenic expression of rat XLalphas in the renal proximal tubule (rptXLalphas mice), where Gsalpha mediates most actions of PTH. Western blots and quantitative RT-PCR showed that, while Gsalpha and type-1 PTH receptor levels were unaltered, protein kinase A activity and 25-hydroxyvitamin D 1-alpha-hydroxylase (Cyp27b1) mRNA levels were significantly higher in renal proximal tubules of rptXLalphas mice than wild-type littermates. Immunohistochemical analysis of kidney sections showed that the sodium-phosphate cotransporter type 2a was modestly reduced in brush border membranes of male rptXLalphas mice compared to gender-matched controls. Serum calcium, phosphorus, and 1,25 dihydroxyvitamin D were within the normal range, but serum PTH was ~30% lower in rptXLalphas mice than in controls (152 +/- 16 vs. 222 +/- 41 pg/ml; P < 0.05). After crossing the rptXLalphas mice to mice with ablation of maternal Gnas exon 1 (E1(m-/+)), male offspring carrying both the XLalphas transgene and maternal Gnas exon 1 ablation (rptXLalphas/E1(m /+)) were significantly less hypocalcemic than gender-matched E1(m-/+) littermates. Both E1(m-/+) and rptXLalphas/E1(m-/+) offspring had higher serum PTH than wild-type littermates, but the degree of secondary hyperparathyroidism tended to be lower in rptXLalphas/E1(m-/+) mice. Hence, transgenic XLalphas expression in the proximal tubule enhanced Gsalpha-mediated responses, indicating that XLalphas can mimic Gsalpha in vivo. PMID- 21303957 TI - Hyperphagia and central mechanisms for leptin resistance during pregnancy. AB - The purpose of this work was to study the central mechanisms involved in food intake regulation and leptin resistance during gestation in the rat. Sprague Dawley rats of 7, 13, and 18 d of pregnancy [days of gestation (G) 7, G13, and G18] were used and compared with nonpregnant animals in diestrus-1. Food intake was already increased in G7, before hyperleptinemia and central leptin resistance was established in midpregnancy. Leptin resistance was due to a reduction in leptin transport through the blood-brain barrier (BBB) and to alterations in leptin signaling within the hypothalamus based on an increase in suppressor of cytokine signaling 3 levels and a blockade of signal transducer and activator of transcription-3 phosphorylation (G13), followed by a decrease in LepRb and of Akt phosphorylation (G18). In early gestation (G7), no change in hypothalamic neuropeptide Y (NPY), agouti-related peptide (AgRP), or proopiomelanocortin (POMC) expression was shown. Nevertheless, an increase in NPY and AgRP and a decrease in POMC mRNA were observed in G13 and G18 rats, probably reflecting the leptin resistance. To investigate the effect of maternal vs. placental hormones on these mechanisms, we used a model of pseudogestation. Rats of 9 d of pseudogestation were hyperphagic, showing an increase in body and adipose tissue weight, normoleptinemia, and normal responses to iv/intracerebroventricular leptin on hypothalamic leptin signaling, food intake, and body weight. Leptin transport through the BBB, and hypothalamic NPY, AgRP and POMC expression were unchanged. Finally, the transport of leptin through the BBB was assessed using a double-chamber culture system of choroid plexus epithelial cells or brain microvascular endothelial cells. We found that sustained high levels of prolactin significantly reduced leptin translocation through the barrier, whereas progesterone and beta-estradiol did not show any effect. Our data demonstrate a dual mechanism of leptin resistance during mid/late-pregnancy, which is not due to maternal hormones and which allows the maintenance of hyperphagia in the presence of hyperleptinemia driven by an increase in NPY and AgRP and a decrease in POMC mRNA. By contrast, in early pregnancy maternal hormones induce hyperphagia without the regulation of hypothalamic NPY, AgRP, or POMC and in the absence of leptin resistance. PMID- 21303958 TI - Early-life exposure to testosterone programs the hypothalamic melanocortin system. AB - In mammals, males consume more food, which is considered a masculinized behavior, but the underlying mechanism of this sex-specific feeding behavior is unknown. In mice, neonatal testosterone (NT) is critical to masculinize the developing brain, leading to sex differences in reproductive physiology. The proopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus (ARC) are critical to suppress energy intake and POMC innervation of hypothalamic feeding circuits develops to a large extent neonatally. We hypothesized that NT programs the masculinization of energy intake by programming POMC neurons. We tested this hypothesis by comparing control females and control males (CMs) with female mice neonatally androgenized with testosterone (NTFs). We show that increased food intake in CMs is associated with reduced POMC expression and decreased intensity of neuronal projections from POMC neurons within the ARC compared with control females. We found that NTFs display a masculinized energy intake and ARC POMC expression and innervation as observed in CMs, which can be mimicked by neonatal exposure to the androgen receptor agonist dihydrotestosterone (DHT). NTFs also exhibit hyperleptinemia and a decreased ability of leptin to up-regulate POMC, suppress food intake, and prevent adipose tissue accumulation, independent of signal transducer and activator of transcription 3. However, this leptin resistance is specific to NTFs, is not a consequence of masculinization, and is reproduced by neonatal exposure to estrogen but not DHT. Thus, NT programs a sexual differentiation of POMC neurons in female mice via DHT but also predisposes to leptin resistance and obesity in an estrogen-dependent manner. PMID- 21303959 TI - Polyamines are implicated in the emergence of the embryo from obligate diapause. AB - Embryonic diapause is a poorly understood phenomenon of reversible arrest of embryo development prior to implantation. In many carnivores, such as the mink (Neovison vison), obligate diapause characterizes each gestation. Embryo reactivation is controlled by the uterus by mechanisms that remain elusive. Because polyamines are essential regulators of cell proliferation and growth, it was hypothesized that they trigger embryo reactivation. To test this, mated mink females were treated with alpha-difluoromethylornithine, an inhibitor of ornithine decarboxylase 1, the rate-limiting enzyme in polyamine biosynthesis, or saline as a control during the first 5 d of reactivation. This treatment induced polyamine deprivation with the consequence of rearrest in embryo cell proliferation. A mink trophoblast cell line in vitro subjected to alpha difluoromethylornithine treatment likewise displayed an arrest in cell proliferation, morphological changes, and intracellular translocation of ornithine decarboxylase 1 protein. The arrest in embryo development deferred implantation for a period consistent with the length of treatment. Successful implantation and parturition ensued. We conclude that polyamine deprivation brought about a reversible rearrest of embryo development, which returned the mink embryo to diapause and induced a second delay in embryo implantation. The results are the first demonstration of a factor essential to reactivation of embryos in obligate diapause. PMID- 21303960 TI - A promising culture model for analyzing the interaction between adipose tissue and cardiomyocytes. AB - The heart has epicardial adipose tissue that produces adipokines and mesenchymal stem cells. Systemic adipose tissue is involved in the pathophysiology of obesity related heart diseases. However, the method for analyzing the direct interaction between adipose tissue and cardiomyocytes has not been established. Here we show the novel model, using collagen gel coculture of adipose tissue fragments (ATFs) and HL-1 cardiomyocytes, and electron microscopy, immunohistochemistry, real-time RT-PCR, and ELISA. HL-1 cells formed a stratified layer on ATF-nonembedded gel, whereas they formed almost a monolayer on ATF-embedded gel. ATFs promoted the apoptosis, lipid accumulation, and fatty acid transport protein (FATP) expression of FATP4 and CD36 in HL-1 cells, whereas ATFs inhibited the growth and mRNA expression of myosin, troponin T, and atrial natriuretic peptide. Treatment of leptin (100 ng/ml) and adiponectin (10 MUg/ml) neither replicated nor abolished the ATF-induced morphology of HL-1 cells, whereas that of FATP4 and CD36 antibodies (25 MUg/ml) never abolished it. HL-1 cells prohibited the development of CD44+/CD105+ mesenchymal stem cell-like cells and lipid-laden preadipocytes from ATFs. HL-1 cells increased the production of adiponectin in ATFs, whereas they decreased that of leptin. The data indicate that our model actively creates adipose tissue-HL-1 cardiomyocyte interaction, suggesting first that ATFs may be related to the lipotoxiciy of HL-1 cells via unknown factors plus FATP4 and CD36 and second that HL-1 cells may help to retain the static state of ATFs, affecting adipokine secretion. Our model will serve to study adipose tissue-cardiomyocyte interaction and mechanisms of obesity-related lipotoxicity and heart diseases. PMID- 21303961 TI - Soluble CD40 ligand is predictive of combined cardiovascular morbidity and mortality in patients on haemodialysis at a relatively short-term follow-up. AB - BACKGROUND: We tested the hypothesis that soluble CD40 ligand (sCD40L), a biomarker of proatherogenic inflammation, may be predictive of cardiovascular (CV) events in a subgroup of patients from the RISCAVID study, an observational and prospective study in patients on haemodialysis (HD). METHODS: Plasma sCD40L levels were assessed at the time of the enrollment in 300 HD patients (mean age: 65 +/- 15 years), recruited in five different centres. During a follow-up of 24 months, overall mortality, CV mortality and CV major nonfatal events (acute myocardial infarction, congestive heart failure and stroke) were registered. Cox proportional hazards regression assessed adjusted differences in CV morbidity and mortality risk. RESULTS: Stratifying patients according to plasma sCD40L levels in those with levels lower or equal to (sCD40L-) and greater than (sCD40L+) the median value of 7.6 ng/mL, no significant difference was observed at baseline between the two groups in age, gender, blood pressure values and previous CV events. At 24-month follow-up, a significant (P < 0.01) lower incidence of the combined end point of CV morbidity and mortality was observed in the sCD40L- group (29%) as compared to the sCD40L+ group (36%). In the multivariate Cox proportional hazards regression model, the presence of sCD40L above the median value is associated with a significant increase in the risk of CV morbidity and mortality (hazard ratio: 1.61, 95% confidence interval 1.03-3.11). CONCLUSIONS: These observational results support the prognostic value of sCD40L in end-stage renal disease, thus providing a useful tool to better stratify CV prognosis in these patients. PMID- 21303962 TI - Renal interstitial fibrosis in children treated with FK506 for nephrotic syndrome. AB - BACKGROUND: Steroid-dependent, steroid-resistant or frequently relapsing nephrotic syndrome carries a poor prognosis, including progression to renal failure. There are a number of studies confirming the efficacy of FK506 in steroid-resistant or steroid-dependent nephrotic syndrome. Although the use of this medication is becoming more common, we know very little about the potential nephrotoxicity when used in nephrotic syndrome. METHOD: We retrospectively reviewed the characteristics and biopsy findings of 11 children with steroid dependent or frequently relapsing nephrotic syndrome treated with FK506. Two sequential biopsies were evaluated for the change in interstitial fibrosis, measured by a quantitative stereological method, and the change in arteriolar hyaline thickening, tubular atrophy and interstitial fibrosis, graded according to Banff criteria. RESULTS: There was an increase in interstitial fibrosis (P = 0.005), with a median absolute change in the per cent volume density between initial and follow-up biopsies of 1.8% [interquartile range (IQR) 3.9%]. Median percentage change in volume density of interstitial fibrosis, relative to volume density of interstitial fibrosis prior to initiating FK506, was 93% (IQR 138%). Banff scores for interstitial fibrosis and tubular atrophy also increased following tacrolimus therapy (P = 0.04 for both). Average FK506 trough level over the treatment period was significantly associated with change in fibrosis (Spearman's rho = 0.67 and P = 0.02). CONCLUSIONS: This is some of the first histological data concerning tacrolimus nephrotoxicity in childhood nephrotic syndrome. Although the role of the natural progression of the underlying disease in the observed change is not definitively clear, the changes seen are in keeping with the known nephrotoxic effects of FK506 demonstrated in renal transplant. This increase is small when presented as a median change. However, there were a number of children who had a larger change in fibrosis. The factors predictive of interstitial fibrosis while on FK506 are not well defined; the findings from this study suggest that FK506 level may be a factor. Given the observations and limitations of the few published studies, there is an obvious need for further study in a large multicenter prospective trial. PMID- 21303963 TI - Effects of argatroban as an anticoagulant for intermittent veno-venous hemofiltration (IVVH) in patients at high risk of bleeding. AB - BACKGROUND: The critically ill patients with acute renal failure (ARF) undergoing intermittent veno-venous hemofiltration (IVVH) are often at high risk of bleeding. No conventional anticoagulants can adequately achieve this task. Argatroban, a synthetic direct thrombin inhibitor, has been approved for the treatment of hemodialysis patients with antithrombin III deficiency and particularly for heparin-induced thrombocytopenia II patients. Therefore, the anticoagulating effect of argatroban in patients with a high risk of bleeding was investigated. METHODS: One hundred and one ARF patients at high risk of bleeding were treated with predilution IVVH, assigned to a nonheparin group (n = 44) and an argatroban group (n = 57). Venous blood was collected to monitor the change of coagulant parameters pre- and post-IVVH in both groups. Activated partial thromboplastin time (APTT) value was monitored in the argatroban group at different sites and time points to adjust the dosage during IVVH. RESULTS: All the patients in the argatroban group completed treatment successfully, whereas in the nonheparin group, clotting of the extracorporeal circuit occurred in 16.9% of patients. Furthermore, D-dimer increased slightly and platelet counts decreased post-hemofiltration in the nonheparin group. No change was found in platelet counts and coagulant parameters in the argatroban group pre- and post hemofiltration. Argatroban prolonged the APTT by 50% at the venous site after the initial bolus and the maintenance infusion at 2 and 4 h during the treatment with no change at the arterial site. No major bleeding episodes and serious side effects were found. CONCLUSIONS: In critically ill patients with a high risk of bleeding, argatroban is an effective and safe anticoagulant for IVVH. PMID- 21303964 TI - Risks for glomerular filtration rate decline in association with progression of albuminuria in type 2 diabetes. AB - BACKGROUND: The aim of this study was to investigate the annual rate of glomerular filtration rate (GFR) decline and risks for this decline in association with albuminuria progression in type 2 diabetes. METHODS: An observational 4-year cohort study was performed on 1002 subjects with preserved GFR (699 normoalbuminuric), and the predictive value of baseline variables on the GFR slope was investigated. GFR decliner and albuminuria progressor were defined as a GFR slope <-4.0%/year and changes in the geometric mean of urinary albumin from baseline to follow-up >150%, respectively. RESULTS: Annual rates of GFR decline (percent per year, median and interquartile range) were -2.58 (-4.70 to 0.48) in normoalbuminuria, -3.49 (-5.93 to -1.11) in microalbuminuria and -6.58 ( 10.64 to -3.53) in macroalbuminuria. Subjects cross-classified according to GFR decliner/albuminuria progressor consisted of 51% (-/-), 13% (-/+), 28% (+/-) and 8% (+/+). Common risks for GFR decline and albuminuria progression were retinopathy, neuropathy, hemoglobin A(1C) (HbA(1C)) and urinary albumin. Independent significant risks for GFR decline were baseline GFR, systolic blood pressure (SBP), total protein (TP) and hypertension. Proportions with progression to albuminuria were similar between GFR decliners and non-decliners. Multiple linear regression analysis indicated that GFR slope was predicted by baseline variables of urinary albumin, GFR, HbA(1C), SBP, plasma TP and retinopathy. These risks appeared variable according to high or low levels of urinary albumin and GFR. CONCLUSIONS: Urinary albumin excretion is only one risk factor for albuminuria progression and GFR decline, and other important factors were implicated as important for prevention of end-stage renal disease. PMID- 21303965 TI - The relative role of fibroblast growth factor 23 and parathyroid hormone in predicting future hypophosphatemia and hypercalcemia after living donor kidney transplantation: a 1-year prospective observational study. AB - BACKGROUND: Kidney transplantation (KTx) restores many of the disorders accompanying end-stage renal failure. However, hypercalcemia and hypophosphatemia are both common complications after renal transplantation. Prospective observation of these complications has not been well described and pre-transplant predictors also remain unknown. This prospective observational cohort study was carried out to clarify pre-transplant risk factors of persistent hypophosphatemia and/or hypercalcemia at 12 months after transplantation. METHODS: Consecutive living donor KTx recipients (n = 39) at Tokyo Women's Medical University were prospectively recruited. Parameters of bone and mineral metabolism including intact parathyroid hormone (iPTH) and full-length fibroblast growth factor (FGF) 23 were followed. RESULTS: FGF23 decreased to comparable levels for renal function while hyperparathyroidism persisted at 12 months after transplantation. Multivariate linear regression analysis revealed that pre-transplant iPTH correlated with hypercalcemia at 12 months and pre-transplant FGF23 was the best pre-transplant predictor of persistent hypophosphatemia at 12 months. CONCLUSIONS: It is intriguing that although FGF23 is not a causal factor for hypophosphatemia at 12 months post-transplantation, it is a significant predictor of this common complication. PMID- 21303966 TI - Low-level C-reactive protein levels exert cytoprotective actions on human podocytes. AB - BACKGROUND: Albuminuria and elevated C-reactive protein (CRP) levels are common manifestations of many inflammatory diseases. Cardiovascular-based drugs, with secondary anti-inflammatory actions, such as angiotensin-converting enzyme inhibitors are able to reduce both proteinuria and CRP levels, raising the question of whether CRP directly influences the processes that result in proteinuria. As proteinuria is thought to be induced as a result of podocyte dysfunction, we investigated whether there is a pathomechanistic link with CRP. METHODS: Podocytes were analysed for evidence of endogenous CRP production in response to inflammatory agents. In addition, they were incubated in the presence of various concentrations of exogenous CRP and analysed for evidence of a response to treatment. RESULTS: Our results demonstrated that inflammatory agents such as macrophage-conditioned medium and interleukin-1beta induced the expression of CRP messenger RNA in podocytes. However, they were unable to induce CRP protein. Stimulation of podocytes with exogenous CRP demonstrated that 10 MUg/mL CRP induced a low but significant level of interleukin-6 secretion. Tumour necrosis factor alpha, however, was not detected. CRP did up-regulate the expression of the slit diaphragm proteins nephrin and CD2AP, as well as the structural proteins ezrin and podocalyxin-like protein-1, proteins known to be involved in signalling via the phosphotidylinositol-3 (PI-3) kinase pathway. CRP exposure reduced caspase-3 enzyme activity and up-regulated the expression of the anti-apoptotic protein Bcl-2. In the presence of the PI-3 kinase inhibitor LY294002, the ability of CRP to suppress caspase-3 activity was significantly reduced. CONCLUSIONS: Taken together, these data suggest that rather than inducing podocyte damage, CRP may be a survival factor for podocytes by maintaining their structural integrity and initiating a survival cascade, which may facilitate podocyte recovery from injury. PMID- 21303967 TI - Organic anion transporters play an important role in the uptake of p-cresyl sulfate, a uremic toxin, in the kidney. AB - BACKGROUND: p-Cresyl sulfate (PCS), a recently identified anionic uremic toxin, is the main circulating metabolite of p-cresol. In cases of chronic kidney disease (CKD), it might be associated with cardiovascular outcomes and the progression of CKD. However, the renal excretion pathway of PCS is currently unknown. The objective of the present study was to determine whether organic anion transporters (OATs), which are renal tubular basolateral membrane transporters, play an important role in this process. METHODS: The uptake of PCS was investigated using rat renal cortical slices and human proximal tubular cells (HK-2). The active uptake velocity was calculated by subtracting the uptake velocity at 4 degrees C (nonspecific uptake) from that at 37 degrees C. RESULTS: As evidenced by renal cortical slice experiments, the uptake of PCS was saturable with a mean K(m) of 231.6 MUM, indicating that the active transport is involved in the basolateral uptake of PCS. Similar results were also observed in HK-2 cells. The active transport of PCS was significantly suppressed by inhibitors of OATs, such as probenecid, benzylpenicillin, p-aminohippuric acid and estrone sulfate. Similar inhibitions were observed in the presence of indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropionate, OATs substrates among uremic toxins. In contrast, digoxin and tetraethylammonium that did not interact with OATs had little inhibitory effect. CONCLUSIONS: The findings of the present study strongly suggest that PCS serves as a substrate for OATs, is preferentially recognized by OAT3 and plays a key role in the renal tubular secretion process. PMID- 21303968 TI - Dialysate sodium and sodium gradient in maintenance hemodialysis: a neglected sodium restriction approach? AB - BACKGROUND: A higher sodium gradient (dialysate sodium minus pre-dialysis plasma sodium) during hemodialysis (HD) has been associated with sodium loading; however, its role is not well studied. We hypothesized that a sodium dialysate prescription resulting in a higher sodium gradient is associated with increases in interdialytic weight gain (IDWG), blood pressure (BP) and thirst. METHODS: We conducted a cross-sectional study on 1084 clinically stable patients on HD. A descriptive analysis of the sodium prescription was performed and clinical associations with sodium gradient were analyzed. RESULTS: The dialysate sodium prescription varied widely across dialysis facilities, ranging from 136 to 149 mEq/L, with a median of 140 mEq/L. The mean pre-HD plasma sodium was 136.7 +/- 2.9 mEq/L, resulting in the majority of subjects (n = 904, 83%) being dialyzed against a positive sodium gradient, while the mean sodium gradient was 4.6 +/- 4.4 mEq/L. After HD, the plasma sodium increased in nearly all patients (91%), reaching a mean post-HD plasma sodium of 141.3 +/- 2.5 mEq/L. We found a direct correlation between IDWG and sodium gradient (r = 0.21, P < 0.0001). After adjustment for confounders and clustering by facilities, the sodium gradient was independently associated with IDWG (70 g/mEq/L, P < 0.0001). There were no significant associations among sodium gradient and BP, whether measured as pre-HD systolic (r = -0.02), diastolic (r = -0.06) or mean arterial pressure (r = 0.04). Post-HD thirst was directly correlated with sodium gradient (r = 0.11, P = 0.02). CONCLUSION: Sodium gradient is associated with statistically significant and clinically meaningful differences in IDWG in stable patients on HD. PMID- 21303969 TI - Lung cancer: New biological insights and recent therapeutic advances. AB - Approximately 1.6 million new cases of lung cancer are diagnosed each year throughout the world. In many countries, the mortality related to lung cancer continues to rise. The outcomes for patients with all stages of lung cancer have improved in recent years. The use of systemic therapy in conjunction with local therapy has led to improved cure rates in both resectable and unresectable patient groups. For patients with advanced stage disease, modest but real improvements in overall survival and quality of life have been achieved with systemic chemotherapy. A major focus of research has been the development of molecularly targeted agents and the identification of biomarkers for patient selection. Patients with non-small cell lung cancer with mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain achieve response rates of greater than 70% and superior progression-free survival when treated with an EGFR tyrosine kinase inhibitor compared with standard chemotherapy. This has now emerged as the preferred therapeutic approach for the subset of patients with a mutation in exons 19 or 21 of the EGFR. Another promising targeted approach involves the use of an anaplastic lymphoma kinase (ALK) inhibitor in patients with a translocation involving the echinoderm microtubule-associated protein-like 4 (EML4) and -ALK genes. Finally, a paradigm shift in favor of maintenance therapy for patients with advanced stage disease has gained strength from recent data. All of these advances have been made possible by developing a greater understanding of the biology, the discovery of novel anticancer agents, and improved supportive care measures. This article reviews the major strides made in the treatment of lung cancer in the recent past. PMID- 21303970 TI - Pten in the breast tumor microenvironment: modeling tumor-stroma coevolution. AB - Solid human tumors and their surrounding microenvironment are hypothesized to coevolve in a manner that promotes tumor growth, invasiveness, and spread. Mouse models of cancer have focused on genetic changes in the epithelial tumor cells and therefore have not robustly tested this hypothesis. We have recently developed a murine breast cancer model that ablates the PTEN tumor suppressor pathway in stromal fibroblasts. Remarkably, the model resembles human breast tumors both at morphologic and molecular levels. We propose that such models reflect subtypes of tumor-stromal coevolution relevant to human breast cancer, and will therefore be useful in defining the mechanisms that underpin tumor stroma cross-talk. Additionally, these models should also aid in molecularly classifying human breast tumors on the basis of both the microenvironment subtypes they contain as well as on the tumor subtype. PMID- 21303971 TI - PIPKIgamma regulates beta-catenin transcriptional activity downstream of growth factor receptor signaling. AB - Increased beta-catenin transcriptional activity downstream of the Wnt/Wingless signaling pathway has been observed in many human tumors, most notably colorectal carcinomas. However, beta-catenin activation is also observed in many human malignancies with no observable Wnt activity. Wnt-independent pathways that activate beta-catenin remain undefined, yet have the potential to play a significant role during tumorigenesis. Here, we report that phosphotidylinositol phosphate kinase Igamma (PIPKIgamma), an enzyme that generates phosphoinositide messengers in vivo, directly associates with beta-catenin and increases beta catenin activity downstream of growth factor stimulation. PIPKIgamma expression and kinase activity enhance beta-catenin phosphorylation on residues that promote nuclear importation and transcriptional activity. Lastly, we show that beta catenin is required for PIPKIgamma-dependent increased cell proliferation. These results reveal a novel mechanism in which PIPKIgamma expression and catalytic activity enhance beta-catenin nuclear translocation and expression of its target genes to promote tumorigenic phenotypes. PMID- 21303972 TI - Activation of the androgen receptor by intratumoral bioconversion of androstanediol to dihydrotestosterone in prostate cancer. AB - The androgen receptor (AR) mediates the growth of benign and malignant prostate in response to dihydrotestosterone (DHT). In patients undergoing androgen deprivation therapy for prostate cancer, AR drives prostate cancer growth despite low circulating levels of testicular androgen and normal levels of adrenal androgen. In this report, we demonstrate the extent of AR transactivation in the presence of 5alpha-androstane-3alpha,17beta-diol (androstanediol) in prostate derived cell lines parallels the bioconversion of androstanediol to DHT. AR transactivation in the presence of androstanediol in prostate cancer cell lines correlated mainly with mRNA and protein levels of 17beta-hydroxysteroid dehydrogenase 6 (17beta-HSD6), one of several enzymes required for the interconversion of androstanediol to DHT and the inactive metabolite androsterone. Levels of retinol dehydrogenase 5, and dehydrogenase/reductase short-chain dehydrogenase/reductase family member 9, which also convert androstanediol to DHT, were lower than 17beta-HSD6 in prostate-derived cell lines and higher in the castration-recurrent human prostate cancer xenograft. Measurements of tissue androstanediol using mass spectrometry demonstrated androstanediol metabolism to DHT and androsterone. Administration of androstanediol dipropionate to castration-recurrent CWR22R tumor-bearing athymic castrated male mice produced a 28-fold increase in intratumoral DHT levels. AR transactivation in prostate cancer cells in the presence of androstanediol resulted from the cell-specific conversion of androstanediol to DHT, and androstanediol increased LAPC-4 cell growth. The ability to convert androstanediol to DHT provides a mechanism for optimal utilization of androgen precursors and catabolites for DHT synthesis. PMID- 21303973 TI - MTGR1 is required for tumorigenesis in the murine AOM/DSS colitis-associated carcinoma model. AB - Myeloid Translocation Gene, Related-1 (MTGR1) CBFA2T2 is a member of the Myeloid Translocation Gene (MTG) family of transcriptional corepressors. The remaining two family members, MTG8 (RUNX1T1) and MTG16 (CBFA2T3) are identified as targets of chromosomal translocations in acute myeloid leukemia (AML). Mtgr1(-/-) mice have defects in intestinal lineage allocation and wound healing. Moreover, these mice show signs of impaired intestinal stem cell function. Based on these phenotypes, we hypothesized that MTGR1 may influence tumorigenesis arising in an inflammatory background. We report that Mtgr1(-/-) mice were protected from tumorigenesis when injected with azoxymethane (AOM) and then subjected to repeated cycles of dextran sodium sulfate (DSS). Tumor cell proliferation was comparable, but Mtgr1(-/-) tumors had significantly higher apoptosis rates. These phenotypes were dependent on epithelial injury, the resultant inflammation, or a combination of both as there was no difference in aberrant crypt foci (ACF) or tumor burden when animals were treated with AOM as the sole agent. Gene expression analysis indicated that Mtgr1(-/-) tumors had significant upregulation of inflammatory networks, and immunohistochemistry (IHC) for immune cell subsets revealed a marked multilineage increase in infiltrates, consisting predominately of CD3(+) and natural killer T (NKT) cells as well as macrophages. Transplantation of wild type (WT) bone marrow into Mtgr1(-/-) mice, and the reciprocal transplant, did not alter the phenotype, ruling out an MTGR1 hematopoietic cell-autonomous mechanism. Our findings indicate that MTGR1 is required for efficient inflammatory carcinogenesis in this model, and implicate its dysfunction in colitis-associated carcinoma. This represents the first report functionally linking MTGR1 to intestinal tumorigenesis. PMID- 21303974 TI - Polymalic acid-based nanobiopolymer provides efficient systemic breast cancer treatment by inhibiting both HER2/neu receptor synthesis and activity. AB - Biodegradable nanopolymers are believed to offer great potential in cancer therapy. Here, we report the characterization of a novel, targeted, nanobiopolymeric conjugate based on biodegradable, nontoxic, and nonimmunogenic PMLA [poly(beta-l-malic acid)]. The PMLA nanoplatform was synthesized for repetitive systemic treatments of HER2/neu-positive human breast tumors in a xenogeneic mouse model. Various moieties were covalently attached to PMLA, including a combination of morpholino antisense oligonucleotides (AON) directed against HER2/neu mRNA, to block new HER2/neu receptor synthesis; anti-HER2/neu antibody trastuzumab (Herceptin), to target breast cancer cells and inhibit receptor activity simultaneously; and transferrin receptor antibody, to target the tumor vasculature and mediate delivery of the nanobiopolymer through the host endothelial system. The results of the study showed that the lead drug tested significantly inhibited the growth of HER2/neu-positive breast cancer cells in vitro and in vivo by enhanced apoptosis and inhibition of HER2/neu receptor signaling with suppression of Akt phosphorylation. In vivo imaging analysis and confocal microscopy demonstrated selective accumulation of the nanodrug in tumor cells via an active delivery mechanism. Systemic treatment of human breast tumor bearing nude mice resulted in more than 90% inhibition of tumor growth and tumor regression, as compared with partial (50%) tumor growth inhibition in mice treated with trastuzumab or AON, either free or attached to PMLA. Our findings offer a preclinical proof of concept for use of the PMLA nanoplatform for combination cancer therapy. PMID- 21303975 TI - Raf kinase inhibitor protein RKIP enhances signaling by glycogen synthase kinase 3beta. AB - Raf kinase inhibitory protein (RKIP) is a physiologic inhibitor of c-RAF kinase and nuclear factor kappaB signaling that represses tumor invasion and metastasis. Glycogen synthase kinase-3beta (GSK3beta) suppresses tumor progression by downregulating multiple oncogenic pathways including Wnt signaling and cyclin D1 activation. Here, we show that RKIP binds GSK3 proteins and maintains GSK3beta protein levels and its active form. Depletion of RKIP augments oxidative stress mediated activation of the p38 mitogen activated protein kinase, which, in turn, inactivates GSK3beta by phosphorylating it at the inhibitory T390 residue. This pathway de-represses GSK3beta inhibition of oncogenic substrates causing stabilization of cyclin D, which induces cell-cycle progression and beta-catenin, SNAIL, and SLUG, which promote epithelial to mesenchymal transition. RKIP levels in human colorectal cancer positively correlate with GSK3beta expression. These findings reveal the RKIP/GSK3 axis as both a potential therapeutic target and a prognosis-based predictor of cancer progression. PMID- 21303976 TI - Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. AB - The tumor microenvironment includes a complex network of immune T-cell subpopulations. In this study, we systematically analyzed the balance between cytotoxic T cells and different subsets of helper T cells in human colorectal cancers and we correlated their impact on disease-free survival. A panel of immune related genes were analyzed in 125 frozen colorectal tumor specimens. Infiltrating cytotoxic T cells, Treg, Th1, and Th17 cells were also quantified in the center and the invasive margin of the tumors. By hierarchical clustering of a correlation matrix we identified functional clusters of genes associated with Th17 (RORC, IL17A), Th2 (IL4, IL5, IL13), Th1 (Tbet, IRF1, IL12Rb2, STAT4), and cytotoxicity (GNLY, GZMB, PRF1). Patients with high expression of the Th17 cluster had a poor prognosis, whereas patients with high expression of the Th1 cluster had prolonged disease-free survival. In contrast, none of the Th2 clusters were predictive of prognosis. Combined analysis of cytotoxic/Th1 and Th17 clusters improved the ability to discriminate relapse. In situ analysis of the density of IL17+ cells and CD8+ cells in tumor tissues confirmed the results. Our findings argue that functional Th1 and Th17 clusters yield opposite effects on patient survival in colorectal cancer, and they provide complementary information that may improve prognosis. PMID- 21303977 TI - Genome-wide significant association between a sequence variant at 15q15.2 and lung cancer risk. AB - Genome-wide association studies (GWAS) have identified 3 genomic regions, at 15q24-25.1, 5p15.33, and 6p21.33, which associate with the risk of lung cancer. Large meta-analyses of GWA data have failed to find additional associations of genome-wide significance. In this study, we sought to confirm 7 variants with suggestive association to lung cancer (P < 10(-5)) in a recently published meta analysis. In a GWA dataset of 1,447 lung cancer cases and 36,256 controls in Iceland, 3 correlated variants on 15q15.2 (rs504417, rs11853991, and rs748404) showed a significant association with lung cancer, whereas rs4254535 on 2p14, rs1530057 on 3p24.1, rs6438347 on 3q13.31, and rs1926203 on 10q23.31 did not. The most significant variant, rs748404, was genotyped in an additional 1,299 lung cancer cases and 4,102 controls from the Netherlands, Spain, and the United States and the results combined with published GWAS data. In this analysis, the T allele of rs748404 reached genome-wide significance (OR = 1.15, P = 1.1 * 10( 9)). Another variant at the same locus, rs12050604, showed association with lung cancer (OR = 1.09, 3.6 * 10(-6)) and remained significant after adjustment for rs748404 and vice versa. rs748404 is located 140 kb centromeric of the TP53BP1 gene that has been implicated in lung cancer risk. Two fully correlated, nonsynonymous coding variants in TP53BP1, rs2602141 (Q1136K) and rs560191 (E353D) showed association with lung cancer in our sample set; however, this association did not remain significant after adjustment for rs748404. Our data show that 1 or more lung cancer risk variants of genome-wide significance and distinct from the coding variants in TP53BP1 are located at 15q15.2. PMID- 21303978 TI - Tumor suppressor RARRES1 interacts with cytoplasmic carboxypeptidase AGBL2 to regulate the alpha-tubulin tyrosination cycle. AB - Even though it is among the most commonly methylated loci in multiple cancers, the retinoic acid-induced tumor suppressor retinoic acid receptor responder 1 (RARRES1) has no known function. We now show that RARRES1 is lost in many cancer cells, particularly those with a mesenchymal phenotype, and is a transmembrane carboxypeptidase inhibitor that interacts with ATP/GTP binding protein-like 2 (AGBL2), a cytoplasmic carboxypeptidase. Knockdown of AGBL2 results in a failure of the cell to detyrosinate the C-terminal EEY region of alpha-tubulin and indicates that it is a candidate for the long sought-after tubulin tyrosine carboxypeptidase important in the regulation of microtubule dynamics. In contrast, knockdown of RARRES1 increases the level of detyrosinated alpha-tubulin consistent with a role as the cognate inhibitor of AGBL2. We conclude that RARRES1, its interacting partners AGBL2, Eg5/KIF11, another EEY-bearing protein (EB1), and the microtubule tyrosination cycle are important in tumorigenesis and identify a novel area for therapeutic intervention. PMID- 21303979 TI - Altered TGF-beta signaling in a subpopulation of human stromal cells promotes prostatic carcinogenesis. AB - Carcinoma-associated fibroblasts (CAF) play a critical role in malignant progression. Loss of TGF-beta receptor II (TGFbetaR2) in the prostate stroma is correlated with prostatic tumorigenesis. To determine the mechanisms by which stromal heterogeneity because of loss of TGFbetaR2 might contribute to cancer progression, we attenuated transforming growth factor beta (TGF-beta) signaling in a subpopulation of immortalized human prostate fibroblasts in a model of tumor progression. In a tissue recombination model, loss of TGFbetaR2 function in 50% of the stromal cell population resulted in malignant transformation of the nontumorigenic human prostate epithelial cell line BPH1. Mixing fibroblasts expressing the empty vector and dominant negative TGFbetaR2 increased the expression of markers of myofibroblast differentiation [coexpression of vimentin and alpha smooth muscle actin (alphaSMA)] through elevation of TGF-beta1 and activation of the Akt pathway. In combination, these two populations of stromal cells recapitulated the tumor inductive activity of CAFs. TGFbetaR2 activity in mixed stromal cell populations cultured in vitro caused secretion of factors that are known to promote tumor progression, including TGF-beta1, SDF1/CXCL12, and members of the fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) families. In vivo, tissue recombination of fibroblasts overexpressing TGF beta1 and SDF1/CXCL12 not only induced transformation of BPH1 cells, but also promoted a robust growth of highly invasive cells, similar to effects produced by CAFs. While the precise nature and/or origin of the particular stromal cell populations in vivo remain unknown, these findings strongly link heterogeneity in TGF-beta signaling to tumor promotion by tumor stromal cells. PMID- 21303980 TI - Fusion between Intestinal epithelial cells and macrophages in a cancer context results in nuclear reprogramming. AB - The most deadly phase in cancer progression is attributed to the inappropriate acquisition of molecular machinery leading to metastatic transformation and spread of disease to distant organs. Although it is appreciated that metastasis involves epithelial-mesenchymal interplay, the underlying mechanism defining this process is poorly understood. Specifically, how cancer cells evade immune surveillance and gain the ability to navigate the circulatory system remains a focus. One possible mechanism underlying metastatic conversion is fusion between blood-derived immune cells and cancer cells. While this notion is a century old, in vivo evidence that cell fusion occurs within tumors and imparts genetic or physiologic changes remains controversial. We have previously demonstrated in vivo cell fusion between blood cells and intestinal epithelial cells in an injury setting. Here, we hypothesize that immune cells, such as macrophages, fuse with tumor cells imparting metastatic capabilities by transferring their cellular identity. We used parabiosis to introduce fluorescent-labeled bone marrow-derived cells to mice with intestinal tumors, finding that fusion between circulating blood-derived cells and tumor epithelium occurs during the natural course of tumorigenesis. Moreover, we identify the macrophage as a key cellular partner for this process. Interestingly, cell fusion hybrids retain a transcriptome identity characteristic of both parental derivatives, while also expressing a unique subset of transcripts. Our data supports the novel possibility that tumorigenic cell fusion may impart physical behavior attributed to migratory macrophages, including navigation of circulation and immune evasion. As such, cell fusion may represent a promising novel mechanism underlying the metastatic conversion of cancer cells. PMID- 21303981 TI - Small molecule kinase inhibitor screen identifies polo-like kinase 1 as a target for neuroblastoma tumor-initiating cells. AB - Neuroblastoma (NB) is an often fatal pediatric tumor of neural crest origin. We previously isolated NB tumor-initiating cells (NB TIC) from bone marrow metastases that resemble cancer stem cells and form metastatic NB in immunodeficient animals with as few as ten cells. To identify signaling pathways important for the survival and self-renewal of NB TICs and potential therapeutic targets, we screened a small molecule library of 143 protein kinase inhibitors, including 33 in clinical trials. Cytostatic or cytotoxic drugs were identified that targeted PI3K (phosphoinositide 3-kinase)/Akt, PKC (protein kinase C), Aurora, ErbB2, Trk, and Polo-like kinase 1 (PLK1). Treatment with PLK1 siRNA or low nanomolar concentrations of BI 2536 or BI 6727, PLK1 inhibitors in clinical trials for adult malignancies, were cytotoxic to TICs whereas only micromolar concentrations of the inhibitors were cytotoxic for normal pediatric neural stem cells. Furthermore, BI 2536 significantly inhibited TIC tumor growth in a therapeutic xenograft model, both as a single agent and in combination with irinotecan, an active agent for relapsed NB. Our findings identify candidate kinases that regulate TIC growth and survival and suggest that PLK1 inhibitors are an attractive candidate therapy for metastatic NB. PMID- 21303982 TI - Noncytotoxic differentiation treatment of renal cell cancer. AB - Current drug therapy for metastatic renal cell cancer (RCC) results in temporary disease control but not cure, necessitating continued investigation into alternative mechanistic approaches. Drugs that inhibit chromatin-modifying enzymes involved in transcription repression (chromatin-relaxing drugs) could have a role, by inducing apoptosis and/or through differentiation pathways. At low doses, the cytosine analogue decitabine (DAC) can be used to deplete DNA methyl-transferase 1 (DNMT1), modify chromatin, and alter differentiation without causing apoptosis (cytotoxicity). Noncytotoxic regimens of DAC were evaluated for in vitro and in vivo efficacy against RCC cell lines, including a p53-mutated RCC cell line developed from a patient with treatment-refractory metastatic RCC. The cell division-permissive mechanism of action-absence of early apoptosis or DNA damage, increase in expression of HNF4alpha (hepatocyte nuclear factor 4alpha), a key driver associated with the mesenchymal to epithelial transition, decrease in mesenchymal marker expression, increase in epithelial marker expression, and late increase in cyclin-dependent kinase inhibitor CDKN1B (p27) protein-was consistent with differentiation-mediated cell-cycle exit. In vivo blood counts and animal weights were consistent with minimal toxicity of therapy. The distinctive mechanism of action of a dose and schedule of DAC designed for noncytotoxic depletion of DNMT1 suggests a potential role in treating RCC. PMID- 21303984 TI - HIF-1alpha confers aggressive malignant traits on human tumor cells independent of its canonical transcriptional function. AB - Hypoxia is known to favor tumor survival and progression. Numerous studies have shown that hypoxia-inducible factor 1alpha (HIF-1alpha), an oxygen-sensitive transcription factor, is overexpressed in various types of human cancers and upregulates a battery of hypoxia-responsive genes for the growth and survival of cancer cells. Although tumor progression involves the acquisition of genetic and/or epigenetic changes that confer additional malignant traits, the underlying mechanisms of these changes remain obscure. We recently identified an alternative mechanism of HIF-1alpha function by which HIF-1alpha suppresses DNA repair by counteracting c-Myc transcriptional activity that maintains gene expression. Here, we show that this HIF-alpha-c-Myc pathway plays an essential role in mediating hypoxic effects on malignant progression via genetic alterations, resulting in the formation of malignant tumors with aggressive local invasion and epithelial-mesenchymal transition. We show an absolute requirement of the HIF alpha-c-Myc pathway for malignant progression, whereas the canonical transcription function of HIF-1alpha alone is insufficient and seemingly dispensable. This study indicates that HIF-1alpha induction of genetic alteration is the underlying cause of tumor progression, especially by the hypoxic microenvironment. PMID- 21303983 TI - Replication and functional genomic analyses of the breast cancer susceptibility locus at 6q25.1 generalize its importance in women of chinese, Japanese, and European ancestry. AB - We evaluated the generalizability of a single nucleotide polymorphism (SNP), rs2046210 (A/G allele), associated with breast cancer risk that was initially identified at 6q25.1 in a genome-wide association study conducted among Chinese women. In a pooled analysis of more than 31,000 women of East-Asian, European, and African ancestry, we found a positive association for rs2046210 and breast cancer risk in Chinese women [ORs (95% CI) = 1.30 (1.22-1.38) and 1.64 (1.50 1.80) for the AG and AA genotypes, respectively, P for trend = 1.54 * 10-30], Japanese women [ORs (95% CI) = 1.31 (1.13-1.52) and 1.37 (1.06-1.76), P for trend = 2.51 * 10-4], and European-ancestry American women [ORs (95% CI) = 1.07 (0.99 1.16) and 1.18 (1.04-1.34), P for trend = 0.0069]. No association with this SNP, however, was observed in African American women [ORs (95% CI) = 0.81 (0.63-1.06) and 0.85 (0.65-1.11) for the AG and AA genotypes, respectively, P for trend = 0.4027]. In vitro functional genomic studies identified a putative functional variant, rs6913578. This SNP is 1,440 bp downstream of rs2046210 and is in high linkage disequilibrium with rs2046210 in Chinese (r(2) = 0.91) and European ancestry (r2 = 0.83) populations, but not in Africans (r2 = 0.57). SNP rs6913578 was found to be associated with breast cancer risk in Chinese and European ancestry American women. After adjusting for rs2046210, the association of rs6913578 with breast cancer risk in African Americans approached borderline significance. Results from this large consortium study confirmed the association of rs2046210 with breast cancer risk among women of Chinese, Japanese, and European ancestry. This association may be explained in part by a putatively functional variant (rs6913578) identified in the region. PMID- 21303985 TI - Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria. AB - Excessive release of proinflammatory cytokines by innate immune cells is an important component of the pathogenic basis of malaria. Proinflammatory cytokines are a direct output of Toll-like receptor (TLR) activation during microbial infection. Thus, interference with TLR function is likely to render a better clinical outcome by preventing their aberrant activation and the excessive release of inflammatory mediators. Herein, we describe the protective effect and mechanism of action of E6446, a synthetic antagonist of nucleic acid-sensing TLRs, on experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA. We show that in vitro, low doses of E6446 specifically inhibited the activation of human and mouse TLR9. Tenfold higher concentrations of this compound also inhibited the human TLR8 response to single-stranded RNA. In vivo, therapy with E6446 diminished the activation of TLR9 and prevented the exacerbated cytokine response observed during acute Plasmodium infection. Furthermore, severe signs of ECM, such as limb paralysis, brain vascular leak, and death, were all prevented by oral treatment with E6446. Hence, we provide evidence that supports the involvement of nucleic acid-sensing TLRs in malaria pathogenesis and that interference with the activation of these receptors is a promising strategy to prevent deleterious inflammatory responses that mediate pathogenesis and severity of malaria. PMID- 21303987 TI - Efficacy of major general surgery performed by non-physician clinicians at a central hospital in Malawi. AB - In some sub-Saharan African countries non-physician clinicians have to perform major general surgery without medical officers and surgeons. The safety of this practice has not been established. The aim of this study was to evaluate the contribution of clinical officers (COs) to major general surgery at Zomba Central Hospital. We performed a retrospective five-year period study during 2003-2007. The perioperative outcome for three procedures was analysed. During the study 2931 major general surgical procedures were performed: 1437 (49%) by surgeons; 366 (12.5%) by COs assisted by surgeons; and 1128 (38.5%) by COs alone. COs performed 50% of prostatectomies, ventriculo-peritoneal-shuntings and strangulated hernia repairs with bowel resection alone. Baseline parameters and perioperative outcomes of the patients who underwent operations with surgeons present (as operator or assistant, 'surgeon group') or patients operated by COs alone ('CO group') were similar. COs can safely perform major general surgery when adequate training and supervision are provided. PMID- 21303986 TI - Local anesthetic inhibits hyperpolarization-activated cationic currents. AB - Systemic administration of local anesthetics has beneficial perioperative properties and an anesthetic-sparing and antiarrhythmic effect, although the detailed mechanisms of these actions remain unclear. In the present study, we investigated the effects of a local anesthetic, lidocaine, on hyperpolarization activated and cyclic nucleotide-gated (HCN) channels that contribute to the pacemaker currents in rhythmically oscillating cells of the heart and brain. Voltage-clamp recordings were used to examine the properties of cloned HCN subunit currents expressed in Xenopus laevis oocytes and human embryonic kidney (HEK) 293 cells under control condition and lidocaine administration. Lidocaine inhibited HCN1, HCN2, HCN1-HCN2, and HCN4 channel currents at 100 MUM in both oocytes and/or HEK 293 cells; it caused a decrease in both tonic and maximal current (~30-50% inhibition) and slowed current activation kinetics for all subunits. In addition, lidocaine evoked a hyperpolarizing shift in half activation voltage (DeltaV(1/2) of ~-10 to -14 mV), but only for HCN1 and HCN1 HCN2 channels. By fitting concentration-response data to logistic functions, we estimated half-maximal (EC(50)) concentrations of lidocaine of ~30 to 40 MUM for the shift in V(1/2) observed with HCN1 and HCN1-HCN2; for inhibition of current amplitude, calculated EC(50) values were ~50 to 70 MUM for HCN1, HCN2, and HCN1 HCN2 channels. A lidocaine metabolite, monoethylglycinexylidide (100 MUM), had similar inhibitory actions on HCN channels. These results indicate that lidocaine potently inhibits HCN channel subunits in dose-dependent manner over a concentration range relevant for systemic application. The ability of local anesthetics to modulate I(h) in central neurons may contribute to central nervous system depression, whereas effects on I(f) in cardiac pacemaker cells may contribute to the antiarrhythmic and/or cardiovascular toxic action. PMID- 21303988 TI - Snake bites in Moyen Chari district, Chad: a five-year experience. AB - Snake bites are of major public health importance in Africa as a cause of morbidity and mortality. Echis ocellatus is responsible for the majority of envenomation cases in West Africa. Antivenom immunotherapy is the only specific treatment available for envenomed patients. From January 1997 to December 2001, 325 patients suffering from snake bites were enrolled in a survey undertaken at Goundi Hospital, Chad. We analysed the percentage of envenomed patients, sex distribution, distribution along the year, lethality, hospital stay and recovery clotting time. Two hundred and ninety-eight patients showed signs of envenomation and were treated with antivenom immunotherapy with three different sera in consecutive periods. Young males were more frequently involved. The overall lethality was 8%. Lethality and hospital stay were significantly different in the differently treated patients. Most of the data in our series were similar to those from other sub-Saharan countries but, overall, the percentage of snake bite victims who were admitted to hospital was higher. PMID- 21303990 TI - Visual distortion of body size modulates pain perception. AB - Pain is a complex subjective experience that is shaped by numerous contextual factors. For example, simply viewing the body reduces the reported intensity of acute physical pain. In this study, we investigated whether this visually induced analgesia is modulated by the visual size of the stimulated body part. We measured contact heat-pain thresholds while participants viewed either their own hand or a neutral object in three size conditions: reduced, actual size, or enlarged. Vision of the body was analgesic, increasing heat-pain thresholds by an average of 3.2 degrees C. We further found that visual enlargement of the viewed hand enhanced analgesia, whereas visual reduction of the hand decreased analgesia. These results demonstrate that pain perception depends on multisensory representations of the body and that visual distortions of body size modulate sensory components of pain. PMID- 21303989 TI - Left ventricular assist device therapy in patients with restrictive and hypertrophic cardiomyopathy. AB - BACKGROUND: Left ventricular assist device (LVAD) is being increasingly used in patients with end-stage dilated and ischemic cardiomyopathy. There have been no clinical trials addressing the use of LVAD therapy in patients with end-stage heart failure caused by restrictive (RCM) or hypertrophic cardiomyopathy (HCM). The purpose of this study was therefore to analyze the outcome of LVAD therapy in these patients. METHODS AND RESULTS: Eighty-three patients received continuous axial flow LVAD (Heart mate II, Thoratec, Pleasanton, CA) from February 2007 to May 2010 at our institution. We analyzed the baseline characteristics and surgical and long-term impact of LVAD therapy in 8 patients with RCM or HCM and compared their outcomes with the 75 patients with dilated and ischemic cardiomyopathy. Compared with patients with ischemic or dilated cardiomyopathy, patients with RCM and HCM have significantly smaller left ventricular end diastolic dimensions (52.5+/-6 mm versus 68.6+/-8 mm; P<0.0001) and increased thickness of septal (16 [12, 19] mm versus 10[8.5, 11] mm, P=0.0003) and higher left ventricular ejection fraction (21 [20, 36]% versus 17 [15, 22]%; P=0.0009). We found no difference in early mortality (12.5% versus 9.3%, P=0.57) or length of hospital stay (11 [8, 45] days versus 18.5 [12.2, 27.7] days; P=0.51) between the 2 groups. The right atrial pressure was higher (18 [15, 20] mm Hg versus 12 [9, 15] mm Hg, P=0.03), and pump flow was lower (4.3 [3.8, 4.5] L versus 5.2 [4.7, 5.5] L, P=0.001) after LVAD implantation in patients with RCM and HCM. Central venous catheter related infections were more common in patients with RCM and HCM (87.5% versus 44.5%, P=0.006). There was no difference in the total number of blood units transfused. Median (min, max) follow-up duration after LVAD implantation was 166 [1, 1044] days. The 1-year actuarial survival rate was not different between the 2 groups (87.5% [95% confidence interval, 52.9% to 97.8%] versus 73.2 [95% confidence interval, 60% to 85%]; P=0.77). CONCLUSIONS: Our preliminary data show that patients with end-stage heart failure caused by RCM or HCM may benefit from continuous axial flow LVAD therapy. This small study suggests that mortality is comparable with those patients who have dilated or ischemic cardiomyopathy, but right heart failure, prolonged inotropic use, and central venous catheter infections are more common in patients with RCM and HCM who were treated with LVAD. Because of the small numbers the differences should be interpreted cautiously, and prospective clinical trials would be required to recommend this therapy for these patients as bridge to transplantation or destination treatment. PMID- 21303991 TI - Third parties, violence, and conflict resolution: the role of group size and collective action in the microregulation of violence. AB - Although researchers know much about the causes of aggression, they know surprisingly little about how aggression leads to violence or how violence is controlled. To explore the microregulation of violence, we conducted a systematic behavioral analysis of footage from closed-circuit television surveillance of public spaces. Using 42 incidents involving 312 people, we compared aggressive incidents that ended in violence with those that did not. Behaviors of antagonists and third parties were coded as either escalating or conciliatory acts. Results showed that third parties were more likely to take conciliatory actions than to escalate violence and that this tendency increased as group size increased. This analysis revealed a pattern of third-party behaviors that prevent aggression from becoming violent and showed that conciliatory behaviors are more successful when carried out by multiple third parties than when carried out by one person. We conclude by emphasizing the importance of collective third-party dynamics in understanding conflict resolution. PMID- 21303992 TI - Outsourcing self-regulation. AB - Three studies demonstrate a novel phenomenon--self-regulatory outsourcing--in which thinking about how other people can be instrumental (i.e., helpful) for a given goal undermines motivation to expend effort on that goal. In Experiment 1, participants who thought about how their partner helped them with health goals (as opposed to career goals) planned to spend less time and effort on health goals in the upcoming week. This pattern was stronger for depleted participants than for nondepleted participants. In Experiment 2, participants who thought about how their partner helped them with academic-achievement goals procrastinated more, leaving themselves less time for an academic task, than did participants in two control conditions. This pattern was stronger for participants who were told that procrastinating would drain their resources for the academic task than for participants who were told that procrastinating would not drain their resources for that task. In Experiment 3, participants who decreased their effort after thinking of an instrumental significant other reported higher relationship commitment to that individual than did participants who did not decrease their effort. The possibility for shared (or transactive) self-regulation is discussed. PMID- 21303993 TI - Eye tracking unconscious face-to-face confrontations: dominance motives prolong gaze to masked angry faces. AB - In primates, dominance/submission relationships are generally automatically and nonaggressively established in face-to-face confrontations. Researchers have argued that this process involves an explicit psychological stress-manipulation mechanism: Striding with a threatening expression, while keeping direct eye contact, outstresses rivals so that they submissively avert their gaze. In contrast, researchers have proposed a reflexive and implicit modulation of face to-face confrontation in humans, on the basis of evidence that dominant and submissive individuals exhibit vigilant and avoidant responses, respectively, to facial anger in masked emotional Stroop tasks. However, these tasks do not provide an ecologically valid index of gaze behavior. Therefore, we directly measured gaze responses to masked angry, happy, and neutral facial expressions with a saccade-latency paradigm and found that increased dominance traits predict a more prolonged gaze to (or reluctance to avert gaze from) masked anger. Furthermore, greater non-dominance-related reward sensitivity predicts more persistent gaze to masked happiness. These results strongly suggest that implicit and reflexive mechanisms underlie dominant and submissive gaze behavior in face to-face confrontations. PMID- 21303995 TI - Beyond sequencing: new diagnostic tests turn to pathways. PMID- 21303994 TI - Risk of birth abnormalities in the offspring of men with a history of cancer: a cohort study using Danish and Swedish national registries. AB - BACKGROUND: The potential mutagenic effects of cancer therapies and the growing number of young male cancer survivors have given rise to concern about the health of their offspring. METHODS: We identified all singleton children born alive in Denmark between 1994 and 2004 and in Sweden between 1994 and 2005 (n = 1,777,765). Of the 8670 children with a paternal history of cancer, 8162 were conceived naturally and 508 were conceived using assisted reproductive technologies (ARTs) (in vitro fertilization or intracytoplasmatic sperm injection). Of the 1,769,095 children without a paternal history of cancer, 25,926 were conceived using ARTs. Associations between paternal history of cancer and risk of adverse birth outcomes of children conceived naturally or by ARTs were investigated using log-linear binomial models, yielding risk ratios (RRs) with 95% confidence intervals (CIs). All statistical tests were two-sided. RESULTS: The offspring of male cancer survivors were more likely to have major congenital abnormalities than the offspring of fathers with no history of cancer (RR = 1.17, 95% CI = 1.05 to 1.31, P = .0043, 3.7% vs 3.2%). However, the mode of conception (natural conception or ARTs) did not modify the association between paternal history of cancer and risk of congenital abnormalities (natural conception, RR = 1.17, 95% CI = 1.04 to 1.31; ARTs, RR = 1.22, 95% CI = 0.80 to 1.87, P(interaction) = .84). CONCLUSION: We observed a statistically significant but modest increase in the risk of major congenital abnormalities among offspring of males with a history of cancer, independent of the mode of conception. PMID- 21303996 TI - Concerns about Provenge simmer as CMS ponders coverage. PMID- 21303997 TI - Proposed new clinical trial system at NCI gets mixed reviews. PMID- 21303998 TI - StatBite: States that require health plans to cover patient care costs in clinical trials. PMID- 21303999 TI - Congenital abnormalities: a legacy of cancer treatment? PMID- 21304000 TI - Markers of pancreatic cancer: working toward early detection. AB - Because early detection of pancreatic cancer is the best way to cure this disease, investigators continue to try to identify accurate markers of early pancreatic cancer. Because early-stage pancreatic cancer is generally asymptomatic, the only reliable way to detect it is by targeting individuals at increased risk for pancreatic screening. PMID- 21304001 TI - Phase I clinical study of Seneca Valley Virus (SVV-001), a replication-competent picornavirus, in advanced solid tumors with neuroendocrine features. AB - PURPOSE: Seneca Valley Virus (SVV-001) is a novel naturally occurring replication competent picornavirus with potent and selective tropism for neuroendocrine cancer cell types, including small cell lung cancer. We conducted a first-in human, first-in-class phase I clinical trial of this agent in patients with cancers with neuroendocrine features, including small cell lung cancer. EXPERIMENTAL DESIGN: Clinical evaluation of single intravenous doses in patients with cancers with neuroendocrine features was performed across five log increments from 10(7) to 10(11) vp/kg. Toxicity, viral titers and clearance, neutralizing antibody development, and tumor response were assessed. RESULTS: A total of 30 patients were treated with SVV-001, including six with small cell carcinoma at the lowest dose of 10(7) vp/kg. SVV-001 was well tolerated, with no dose-limiting toxicities observed in any dose cohort. Viral clearance was documented in all subjects and correlated temporally with development of antiviral antibodies. Evidence of in vivo intratumoral viral replication was observed among patients with small cell carcinoma, with peak viral titers estimated to be >10(3)-fold higher than the administered dose. One patient with previously progressive chemorefractory small cell lung cancer remained progression-free for 10 months after SVV-001 administration, and is alive over 3 years after treatment. CONCLUSIONS: Intravenous SVV-001 administration in patients is well tolerated at doses up to 10(11) vp/kg, with predictable viral clearance kinetics, intratumoral viral replication, and evidence of antitumor activity in patients with small cell lung cancer. Phase II clinical evaluation in small cell lung cancer is warranted, and has been initiated. PMID- 21304002 TI - Clinical validation of colorectal cancer biomarkers identified from bioinformatics analysis of public expression data. AB - PURPOSE: Identification of novel biomarkers of cancer is important for improved diagnosis, prognosis, and therapeutic intervention. This study aimed to identify marker genes of colorectal cancer (CRC) by combining bioinformatics analysis of gene expression data and validation experiments using patient samples and to examine the potential connection between validated markers and the established oncogenes such as c-Myc and K-ras. EXPERIMENTAL DESIGN: Publicly available data from GenBank and Oncomine were meta-analyzed leading to 34 candidate marker genes of CRC. Multiple case-matched normal and tumor tissues were examined by RT-PCR for differential expression, and 9 genes were validated as CRC biomarkers. Statistical analyses for correlation with major clinical parameters were carried out, and RNA interference was used to examine connection with major oncogenes. RESULTS: We show with high confidence that 9 (ECT2, ETV4, DDX21, RAN, S100A11, RPS4X, HSPD1, CKS2, and C9orf140) of the 34 candidate genes are expressed at significantly elevated levels in CRC tissues compared to normal tissues. Furthermore, high-level expression of RPS4X was associated with nonmucinous cancer cell type and that of ECT2 with lack of lymphatic invasion while upregulation of CKS2 was correlated with early tumor stage and lack of family history of CRC. We also demonstrate that RPS4X and DDX21 are regulatory targets of c-Myc and ETV4 is downstream to K-ras signaling. CONCLUSIONS: We have identified multiple novel biomarkers of CRC. Further analyses of their function and connection to signaling pathways may reveal potential value of these biomarkers in diagnosis, prognosis, and treatment of CRC. PMID- 21304003 TI - Radiation protection for an intra-operative X-ray device. AB - OBJECTIVES: Therapeutic partial breast irradiation can be delivered intra operatively using the Intrabeam 50 kVp compact X-ray device. Spherical applicators are added to the source to give an isotropic radiation dose. The low energy of this unit leads to rapid attenuation with distance, but dose rates are much greater than for diagnostic procedures. METHODS: To investigate the shielding requirements for this unit, attenuation measurements were carried out with manufacturer-provided tungsten-rubber sheets, lead, plasterboard and bricks. A prospective environmental dose rate survey was also conducted in the designated theatre. RESULTS: As a result of isotropic geometry, the scattered dose around shielding can be 1% of primary and thus often dominates measured dose rates compared with transmission. The absorbed dose rate of the unshielded source at 1 m was 11.6 mGy h(-1) but this was reduced by 95% with the shielding sheets. Measured values for the common shielding materials were similar to reference data for the attenuation of a 50 kVp diagnostic X-ray beam. Two lead screens were constructed to shield operators remaining in the theatre and an air vent into a service corridor. A lead apron would also provide suitable attenuation, although a screen allows greater flexibility for treatment operators. With these measures, staff doses were reduced to negligible quantities. Survey measurements taken during patient treatments confirmed no additional measures were required, but the theatre should be a controlled area and access restricted. CONCLUSION: Results from this study and reference data can be used for planning other facilities. PMID- 21304004 TI - A preliminary comparison of total skin electron treatment techniques to demonstrate the application of a mid-torso phantom for measurement of dose penetration. AB - OBJECTIVES: In the UK, the treatment of patients with mycosis fungoides using total skin electron (TSE) beam therapy is undertaken using a number of different irradiation techniques. As part of a review of these techniques, a comparative set of measurements would be useful to determine how the techniques differ in terms of dose distribution. A dose penetration intercomparison method that could be used as part of such a study is presented here. METHODS: The dose penetrations for six treatment techniques currently or recently used in four centres in the UK were measured. The variation of dose with skin depth was measured in a WT1 solid water mid-torso phantom. The phantom is portable and suitable to be used in all the techniques. It is designed to hold four small radiochromic film dosemeters to investigate the variation in dose around the mid-torso. For each treatment technique, the phantom was irradiated using the clinical set-up. RESULTS: The phantom performed well and was able to measure dose penetration and the uniformity of penetration for several treatment techniques. CONCLUSION: These preliminary results demonstrate that there is some variation in dose distribution between different TSE treatment techniques and that the phantom could be used in a more comprehensive intercomparison. The results are not intended to demonstrate comprehensively the range of penetration that can be achieved in clinical practice as, for one of the treatment techniques, the penetration is customised for the extent of the disease. PMID- 21304005 TI - Virtual reality, ultrasound-guided liver biopsy simulator: development and performance discrimination. AB - OBJECTIVES: The aim of this article was to identify and prospectively investigate simulated ultrasound-guided targeted liver biopsy performance metrics as differentiators between levels of expertise in interventional radiology. METHODS: Task analysis produced detailed procedural step documentation allowing identification of critical procedure steps and performance metrics for use in a virtual reality ultrasound-guided targeted liver biopsy procedure. Consultant (n=14; male=11, female=3) and trainee (n=26; male=19, female=7) scores on the performance metrics were compared. Ethical approval was granted by the Liverpool Research Ethics Committee (UK). Independent t-tests and analysis of variance (ANOVA) investigated differences between groups. RESULTS: Independent t-tests revealed significant differences between trainees and consultants on three performance metrics: targeting, p=0.018, t=-2.487 (-2.040 to -0.207); probe usage time, p = 0.040, t=2.132 (11.064 to 427.983); mean needle length in beam, p=0.029, t=-2.272 (-0.028 to -0.002). ANOVA reported significant differences across years of experience (0-1, 1-2, 3+ years) on seven performance metrics: no go area touched, p=0.012; targeting, p=0.025; length of session, p=0.024; probe usage time, p=0.025; total needle distance moved, p=0.038; number of skin contacts, p<0.001; total time in no-go area, p=0.008. More experienced participants consistently received better performance scores on all 19 performance metrics. CONCLUSION: It is possible to measure and monitor performance using simulation, with performance metrics providing feedback on skill level and differentiating levels of expertise. However, a transfer of training study is required. PMID- 21304006 TI - Hounsfield units upon PET/CT are useful in evaluating metastatic regional lymph nodes in patients with oesophageal squamous cell carcinoma. AB - OBJECTIVES: This study evaluated the usefulness of measurements of X-ray attenuation (in Hounsfield units) obtained from unenhanced CT images for attenuation correction of the positron emission tomography (PET) data from PET/CT in the assessment of regional lymph node metastasis in oesophageal squamous cell carcinoma. METHODS: 17 patients with oesophageal squamous cell carcinoma underwent surgery after evaluation with PET/CT. After the excised lymph nodes were reviewed, we compared the histopathology and PET/CT findings, and analysed the lymph node metastasis. When 18-F fludeoxyglucose (FDG) uptake in the lymph nodes was focally prominent in comparison with background mediastinal activity (regardless of lymph node size), the lymph nodes were considered to be positive for malignancy by PET/CT. The mean Hounsfield units of mediastinal lymph nodes showing abnormally increased FDG uptake in PET/CT was retrospectively evaluated using images from the unenhanced CT component of PET/CT. Receiver operating characteristic (ROC) curve analysis was applied to determine the optimal cut-off value of mean Hounsfield units for detecting individual lymph node metastases. RESULTS: For depiction of malignant nodal groups in each lymph node group, the sensitivity, specificity and accuracy of PET/CT based on increased FDG uptake were 58.8%, 74.5% and 70.8%, respectively. For patients with nodal groups that were positive for uptake by PET/CT, the mean attenuation in lymph nodes as measured by CT was 48 +/- 13 HU for malignant nodes and 75 +/- 18 HU for benign nodes. This difference was statistically significant (p<0.001). Using ROC curve analysis, we determined the cut-off as 71 HU. When we excluded lymph nodes with attenuation higher than 71 HU from the nodes determined as malignant by PET/CT, the specificity and accuracy for detecting metastatic lymph nodes improved to 90.9% and 83.3%, respectively. CONCLUSIONS: When interpreting lymph node metastasis in oesophageal squamous cell carcinoma using PET/CT, the assumption that any lymph node with mean HU>71 is benign can improve diagnostic accuracy. PMID- 21304008 TI - MRI features of serous oligocystic adenoma of the pancreas: differentiation from mucinous cystic neoplasm of the pancreas. AB - OBJECTIVES: The purpose of this study was to describe the MRI features of the benign pancreatic neoplasm serous oligocystic adenoma (SOA) that differ from those of mucinous cystic neoplasm (MCN), a neoplasm with the potential for malignant degeneration. METHODS: Seven patients with SOA (seven women; mean age 36.6 years) and eight patients with MCN (eight women: mean age 39.9 years) were included. Several imaging features were reviewed: mass size, location, shape, wall thickness, cyst configuration (Type I, unilocular; Type II, multiple clustered cyst; Type III, cyst with internal septation) and signal intensity of the lesion with heterogeneity. RESULTS: SOA lesions were smaller (3.4 cm) than those of MCN (9.3 cm) (p=0.023). The commonest lesion shape was lobulated (85.7%) for SOA, but oval (50.0%) or lobulated (37.5%) for MCN (p=0.015). The most common cyst configuration was Type II (85.7%) for SOA and Type III (75.0%) for MCN (p=0.008). Heterogeneity of each locule in T(1) weighted images was visible in all cases of MCN, but in no case for SOA (p=0.004). CONCLUSION: SOA could be differentiated from MCN by identifying the imaging features of lobulated contour with multiple clustered cyst configurations and homogeneity of each locule in T(1) weighted MR images. PMID- 21304007 TI - Post-operative radiochemotherapy in patients with gastric cancer: one department's experience of 56 patients. AB - OBJECTIVES: Prognosis in patients with locally advanced stomach cancer undergoing surgery alone is poor. High local failure rates in gastric cancer have been reported of up to 70%. When a relapse occurs, attempts at curative treatment are generally unsuccessful. A retrospective analysis was performed in order to determine whether post-operative radiochemotherapy improves treatment results in patients with locally advanced gastric cancer. METHODS: Between November 2004 and July 2008, 56 patients with clinical Stage IB-IV cancer of the stomach underwent curative gastrectomy and adjuvant radiochemotherapy. Patients with distant metastases were excluded from the analysis. The total radiation dose was 45.0 Gy. The chemotherapy regimen comprised a 5 day cycle of 5-fluorouracil at 425 mg m( 2) and leucovorin at 20 mg m(-2). Overall survival and disease-free survival, as well as toxicity, were estimated for all patients. RESULTS: Within the study group there were 7 (13%) local recurrences, 4 (7%) distant metastases and 8 (14%) local and distant relapses. The 2 year overall survival was 48%. A total of 19 (34%) patients developed Grade 3 gastrointestinal toxicity. There were no treatment-related deaths. CONCLUSION: Post-operative radiochemotherapy is an effective and safe regimen in patients with curatively resected locally advanced gastric cancer. PMID- 21304009 TI - Changing the referral criteria for bone scan in newly diagnosed prostate cancer patients. AB - OBJECTIVES: The aim of this study was to correlate the prostate-specific antigen (PSA) level and Gleason score with staging bone scan result in patients with a new diagnosis of prostate cancer in order to establish the feasibility of implementing the European Association Urology guidelines, which state that a bone scan may not be indicated when PSA <20 in well-moderately differentiated tumours. METHODS: We identified 633 patients retrospectively and 186 patients prospectively with a new diagnosis of prostate cancer undergoing a staging bone scan between March 2005 and January 2010. Patients were excluded if there was no Gleason score available or if the PSA level was checked over 3 months prior to bone scan. Bone scan results were analysed with respect to age, PSA level and Gleason score. In the case of an equivocal result, subsequent imaging was taken into consideration or the initial bone scan was re-reviewed. In persistently equivocal cases, all relevant imaging was assessed by a blinded panel of radiologists to allow a final decision to be made. RESULTS: Of 672 patients aged 39-93 years (median 71 years), who fulfilled the inclusion criteria, 54 (8%) had evidence of bony metastases. PSA level and Gleason score were both independent predictors of bone scan positivity and their predictive value was additive p<0.01. None of the 357 patients with a PSA level of <20 and a Gleason score of <8 had a positive bone scan. CONCLUSION: Staging bone scans in newly diagnosed prostate cancer patients with a PSA level of <20 and a Gleason score of <8 can be safely omitted, with these criteria having a negative predictive value of 100% in our series. PMID- 21304010 TI - Evaluation of CT coronary artery angiography with 320-row detector CT in a high risk population. AB - OBJECTIVES: The aim of this article was to prospectively evaluate the accuracy and radiation dose of 320-detector row dynamic volume CT (DVCT) for the detection of coronary artery disease (CAD) in a high-risk population. METHODS: 60 patients with a high risk of CAD underwent DVCT without preceding heart rate control and also underwent invasive coronary angiography (ICA), which served as the standard reference. RESULTS: On a per segment analysis, overall sensitivity was 95.3%, specificity was 97.6%, positive predictive value was 90.6%, negative predictive value was 98.8% and Youden index was 0.93. In both heart rate subgroups, diagnostic accuracy for the assessment of coronary artery stenosis was similar. The accuracy of the subgroup with an Agatston score >=100 was lower than that for patients with an Agatston score <100. However, the difference between DVCT and ICA results was not significant (p=0.08). The mean estimated effective dose of CT was 12.5 +/- 9.4 mSv. In those patients with heart rates less than 70 beats per minute (bpm), the mean radiation exposure of DVCT was 5.2 +/- 0.9 mSv. The effective radiation dose was significantly lower than that of ICA (14.1 +/- 5.9 mSv) (p<0.001). When the heart rate was >70 bpm, a significantly higher dose was delivered to patients with DVCT (22.6 +/- 5.2 mSv, p<0.001) than with ICA (15.0 +/- 5.3 mSv, p<0.001). CONCLUSION: DVCT reliably provides high diagnostic accuracy without heart rate/rhythm control. However, from a dosimetric point of view, it is recommended that heart rate should be controlled to <70 bpm to decrease radiation dose. PMID- 21304011 TI - Practical patient dosimetry for partial rotation cone beam CT. AB - OBJECTIVES: This work investigates the validity of estimating effective dose for cone beam CT (CBCT) exposures from the weighted CT dose index (CTDIW) and irradiated length. METHODS: Measurements were made within cylindrical poly(methyl methacrylate) (PMMA) phantoms measuring 14 cm and 28 cm in length and 32 cm in diameter for the 200 degrees DynaCT acquisition on the Siemens Artis zee fluoroscopy unit (Siemens Medical Solutions, Erlangen, Germany). An interpolated average dose was calculated to account for the partial rotation. Organ and effective doses were estimated by modelling projections in the Monte Carlo software programme PCXMC (STUK, Helsinki, Finland). RESULTS: The CTDIW was found to closely approximate the interpolated average dose if the positions of the measured doses reflected the X-ray beam rotation. The average dose was found to increase by 8% when the phantom length was increased from 14 to 28 cm. Using the interpolated average dose and the irradiated length for effective dose calculations gave similar values to PCXMC when a double-length (28-cm) CT dose index phantom was irradiated. Simplifying the estimation of effective dose with PCXMC by modelling just 4 projections around the abdomen gave effective doses that were only 7% different to those given when 41 projections were modelled. Calculated doses to key organs within the beam varied by as much as 27%. CONCLUSION: Estimating effective dose from the CTDIW and the irradiated length is sufficiently accurate for CBCT if the chamber positions are considered carefully. A conversion factor can be used only if a single CT dose index phantom is available. The estimation of organ doses requires a large number of modelled projections in PCXMC. PMID- 21304012 TI - Counterpoint: humans do not demonstrate selective brain cooling during hyperthermia. PMID- 21304013 TI - Rebuttal from Nybo and Secher. PMID- 21304014 TI - Rebuttal from White, Greiner, and McDonald. PMID- 21304015 TI - Comments on point:counterpoint: humans do/do not demonstrate selective brain cooling during hyperthermia. PMID- 21304018 TI - Doublet electrical stimulation enhances torque production in people with spinal cord injury. AB - BACKGROUND: Muscle fatigue prevents repetitive use of paralyzed muscle after spinal cord injury (SCI). OBJECTIVE: This study compared the effects of hybrid patterns of muscle stimulation in individuals with acute and chronic SCI. METHODS: Individuals with chronic (n = 11) or acute paralysis (n = 3) underwent soleus muscle activation with a constant (CT) or doublet (DT) stimulation train before and at various times after a fatigue protocol. RESULTS: The chronically paralyzed soleus was highly fatigable with a fatigue index (FI) of 19% +/- 6%, whereas the acutely paralyzed soleus was fatigue resistant (FI = 89% +/- 8%). For the chronically paralyzed group, the DT protocol caused less than 5% improvement in peak and mean force relative to the CT protocol before fatigue; however, after fatigue the DT protocol caused an increase in peak and mean force (>10%), compared with the CT protocol (P < .05). As the chronically paralyzed muscle developed low-frequency fatigue, the DT protocol became more effective than the CT protocol (P < .05). The DT protocol increased the rate of torque development before fatigue (42% +/- 78%), after fatigue (62% +/- 52%), and during recovery (87% +/- 54% to 101% +/- 56%; P < .05). The acutely paralyzed group showed minimal change in peak and mean torque with the DT protocol. CONCLUSIONS: Chronic reduced activity is associated with muscle adaptations (slow to fast) that render the muscle more amenable to force enhancement through doublet train activation after fatigue. These findings are applicable to patients using neuromuscular stimulation. PMID- 21304019 TI - Prediction of natural history of neuromuscular properties after stroke using Fugl Meyer scores at 1 month. AB - BACKGROUND: The link between spasticity and impaired voluntary movement after stroke remains unclear because of the lack of suitable tools characterizing properties of spastic muscles. Describing this relationship early poststroke can potentially help predict the extent and time course of recovery. OBJECTIVE: To describe the time course of changes in neuromuscular properties after stroke using the upper extremity Fugl-Meyer Assessment (FMA) at 1 month to predict recovery patterns over 1 year. METHODS: Using a parallel cascade system identification technique, this study characterized intrinsic and reflex behaviors for different mean elbow joint angles, at specified times poststroke. Then the "growth mixture" model was used to characterize recovery patterns over 1 year. Logistic regression analyses were applied to predict these patterns. The impact of patient characteristics was also investigated. RESULTS: In 21 stroke survivors, 14 had sustained hemorrhage and 7 had thromboses. The study observed several recovery classes, relating intrinsic and reflex stiffness magnitudes with changing elbow angle at different time points. The largest group (48%) showed progressive increase in reflex stiffness over time, but 33% showed declining reflex stiffness over the same period. A third class (19%) showed invariant reflex properties. These differences were linked to the initial reflex magnitudes. The FMA at 1 month showed an inverse relationship with key reflex patterns and proved to be a strong predictor of class membership. Stroke type was also influential. CONCLUSIONS: The logistical regression class may enable us to accurately predict reflex responses during the first year, allowing us to apportion impairment between central and peripheral mechanisms. PMID- 21304020 TI - Functional electrical stimulation therapy of voluntary grasping versus only conventional rehabilitation for patients with subacute incomplete tetraplegia: a randomized clinical trial. AB - BACKGROUND: Functional electrical stimulation therapy (FET) has a potential to improve voluntary grasping among individuals with tetraplegia secondary to traumatic spinal cord injury (SCI). OBJECTIVE: This single-site, randomized controlled trial examined the efficacy of 40 hours of FET with conventional occupational therapy (COT) compared with COT alone to improve grasping. METHODS: Twenty-four subjects with subacute traumatic incomplete SCI (C4-C7, AIS B-D) consented to participate in 40 hours of therapy over 8 weeks, beyond the conventional rehabilitation program. Subjects were randomized to receive FET + COT (n = 9) or COT (n = 12). The key outcomes were changes in Functional Independence Measure (FIM) self-care subscores, Spinal Cord Independence Measure (SCIM) self-care subscores, and Toronto Rehabilitation Institute Hand Function Test (TRI-HFT) performed at baseline and follow-up. RESULTS: At the end of the treatments, the change in mean FIM self-care subscore for the FET + COT group was 20.1 versus 10 (P = .015) for the COT group. Subjects randomized to FET + COT also had greater improvements in the SCIM and TRI-HFT. No longer term follow-up was feasible. CONCLUSION: FET significantly reduced disability and improved voluntary grasping beyond the effects of considerable conventional upper extremity therapy in individuals with tetraplegia. PMID- 21304021 TI - Adalimumab-Induced Disseminated Superficial Porokeratosis. PMID- 21304022 TI - Comment: Assessment of Changes in Utilization of Health-Care Services After Implementation of a Prior Authorization Policy for Atypical Antipsychotic Agents. PMID- 21304023 TI - Reply: To PMID 20388858. PMID- 21304024 TI - Impact of a Pharmacist-Directed Anticoagulation Service on the Quality and Safety of Heparin-Induced Thrombocytopenia Management. AB - BACKGROUND: The use of anticoagulant medications is complex and prone to error in the inpatient setting. Patients with heparin-induced thrombocytopenia (HIT) must receive treatment with alternative anticoagulant agents to ensure optimal patient outcomes. OBJECTIVE: To evaluate the impact of an inpatient pharmacist-directed anticoagulation service (PDAS) on the safety and efficiency of direct thrombin inhibitor use in patients with HIT. METHODS: This was a quasi-experimental pre/postintervention study comparing patients with HIT managed with usual care to patients managed with a focused inpatient anticoagulation service. The primary endpoints of the study were the percent of time that the activated partial thromboplastin time (aPTT) remained within the therapeutic range and time to achievement of a therapeutic aPTT. Bleeding and appropriateness of warfarin initiation were evaluated as secondary endpoints. RESULTS: A total of 193 patients were included in the study. Percent of time that aPTT was in the therapeutic range was 32% higher with the PDAS (p < 0.001) and time to therapeutic aPTT was shortened by approximately 12.5 hours in patients managed by the PDAS (p < 0.001). There was a trend for more bleeding events, regardless of severity, among control patients (p = 0.130). Rate of TIMI (Thrombolysis in Myocardial Infarction) major bleeding was lower in the PDAS group (p = 0.006), but there was no significant difference between groups in GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) moderate/severe bleeding (p = 0.679). Appropriateness of warfarin initiation was also similar between groups. CONCLUSIONS: Implementation of a focused inpatient PDAS was associated with improved efficiency of dosing, improved monitoring, and low bleeding risk. PMID- 21304025 TI - A Comparative Look at the Safety Profiles of Intravenous Iron Products Used in the Hemodialysis Population. AB - OBJECTIVE: To review clinical trials conducted in hemodialysis patients of the 4 intravenous iron products available in the US in an attempt to discern strengths and inferiorities between products and evaluate current safety data that can be used to assist the clinician in selecting the most appropriate agent. DATA SOURCES: Literature was accessed through PubMed (January 2000-October 2010). In some cases, reference citations from selected review articles were evaluated as well. STUDY SELECTION AND DATA EXTRACTION: Clinical trials published in the English language were selected using the search terms iron dextran, iron sucrose, sodium ferric gluconate, and ferumoxytol. Studies were further pared down to include only those enrolling hemodialysis patients. DATA SYNTHESIS: There are currently 4 intravenous iron formulations in the US used to treat iron-deficiency anemia in hemodialysis patients. Ferumoxytol has not yet been directly compared to the other 3 agents. Eight studies have been conducted in hemodialysis patients directly comparing iron dextran, iron sucrose, and/or sodium ferric gluconate. These studies were further categorized for evaluation based on iron products compared. Four studies directly compared iron dextran to iron sucrose, 1 study compared iron dextran to sodium ferric gluconate, 1 study compared iron sucrose to sodium ferric gluconate, and 2 studies compared all 3 agents. Of the 3 agents, iron dextran appears to have the least favorable safety profile, while iron sucrose appears most favorable. CONCLUSIONS: The newest intravenous iron product, ferumoxytol, has not been directly compared to the other 3 agents. Large well controlled studies of these products specifically in the hemodialysis population would further help clinicians determine appropriate therapy. Iron sucrose appears to offer the most favorable safety profile when compared to iron dextran and sodium ferric gluconate in treating hemodialysis patients. Oxidative stress and hypersensitivity reactions are common problems encountered when administering intravenous iron. PMID- 21304026 TI - Regional, Geographic, and Ethnic Differences in Medication Adherence Among Adults with Type 2 Diabetes. AB - BACKGROUND: Medication adherence, a critical component of glycemic control for patients with type 2 diabetes, differs by race/ethnicity. However, few studies have examined regional and rural/urban differences in medication adherence and whether racial/ethnic differences persist after controlling for these differences. OBJECTIVE: To examine regional, rural/urban, and racial/ethnic differences in medication adherence in a national sample of veterans with type 2 diabetes. METHODS: We performed a cohort study of a national sample of veterans with diabetes (N = 690,968) receiving prescriptions for insulin or oral hypoglycemic agents in 2002. Patients were followed until death, loss to follow up, or through December 2006. We calculated the annual medication possession ratio (MPR) for each veteran across 4 groups of medication users: individuals using (1) insulin only, (2) oral hypoglycemic agents only, (3) insulin combined with hypoglycemic agents, and (4) insulin or oral hypoglycemic agents (primary analysis). RESULTS: In longitudinal models for the primary analysis, adjusting for relevant covariates and time trends, MPR was significantly lower among non Hispanic blacks (NHBs), Hispanics, and individuals with other/missing/unknown race/ethnicity (6.07%, 1.76%, and 2.83% lower, respectively) relative to non Hispanic whites (NHWs). MPR was also 2.0% higher in rural versus urban veterans and 1.28% higher in the mid-Atlantic, 2.04% higher in the Midwest, and 0.76% lower in the West, relative to the South. There was a significant race/ethnicity and urban/rural interaction. In NHWs and NHBs, MPR was 1.91% and 2.00% higher, respectively, in rural versus urban veterans; in contrast, in Hispanics, MPR was 1.0% lower in rural veterans relative to urban veterans. CONCLUSIONS: In a national longitudinal cohort of veterans with type 2 diabetes, we found significant regional, rural/urban, and racial/ethnic differences in MPR. Rural/urban residence modified the effect of race/ethnicity on MPR. Recognition of these differences can enable clinicians to better allocate resources and target quality improvement programs. PMID- 21304027 TI - Strategies to Improve Medication Adherence Reported by Diabetes Patients and Caregivers: Results of a Taking Control of Your Diabetes Survey. AB - BACKGROUND: Published studies assessing specific methods that patients with diabetes and their caregivers perceive as helpful means of increasing medication adherence are lacking. OBJECTIVE: To determine methods that patients with diabetes and their caregivers have used to improve medication adherence, investigate the perceived helpfulness of these methods, and identify motivating factors and medication characteristics that may positively influence adherence. METHODS: A cross-sectional survey was distributed to patients with diabetes and caregivers of patients with diabetes at the 11th annual Taking Control of Your Diabetes conference in October 2005 at the San Diego Convention Center. Outcome measures were self-reported medication adherence, perceived helpfulness of methods employed to improve adherence, motivating factors that may improve adherence, and medication characteristics that may improve adherence. RESULTS: A total of 524 (40.5% response rate) questionnaires were included in the final analysis, 357 from patients with diabetes and 167 from caregivers. Taking medications as part of a daily routine and using pill boxes were the most frequently reported helpful methods for improving medication adherence. The 3 motivating factors most commonly identified as improving medication adherence were: knowing that diabetes medications work effectively to lower blood glucose, knowing how to manage medication adverse effects, and understanding medication benefits. Many participants thought that newer injectable diabetes medications resulting in weight loss or no additional blood glucose monitoring would be helpful in optimizing adherence. CONCLUSIONS: Participants in this study identified medication education as a key factor in improving adherence. To empower patients to overcome medication adherence barriers, pharmacists could perform more proactive and thorough counseling sessions that include education on indication, mechanism of action, and therapeutic effects of drugs. They could recommend that patients take medications concurrently with a daily routine and use a pill box, as these actions were reported to be likely to improve medication adherence. However, our results also remind us that motivating factors and tools that may improve adherence may be very patient specific and that pharmacists should incorporate an assessment of this variance in their counseling sessions. PMID- 21304028 TI - Comment: Assessment of Changes in Utilization of Health-Care Services After Implementation of a Prior Authorization Policy for Atypical Antipsychotic Agents. PMID- 21304029 TI - Clinical Course Following Supratherapeutic Teriparatide Dosing. PMID- 21304030 TI - Comment: Residency Requirement for Pharmacists Providing Direct Patient Care. PMID- 21304031 TI - Impact of Early Postoperative Hydrocortisone Administration in Cardiac Surgical Patients After Cardiopulmonary Bypass. AB - BACKGROUND: The usefulness of glucocorticoids after cardiac surgery with cardiopulmonary bypass has been a matter of debate for many years. Exposure to cardiopulmonary bypass evokes the systemic inflammatory response syndrome in patients undergoing cardiac surgery. Intravenous glucocorticoids have been used to reduce proinflammatory cytokine release, slow leukocyte migration, and decrease capillary leak associated with cardiopulmonary bypass. OBJECTIVE: To assess the impact of early postoperative hydrocortisone administration on duration of vasoactive medication administration and the incidence of postoperative atrial fibrillation in cardiac surgical patients after cardiopulmonary bypass. METHODS: A retrospective cohort study (between July 1, 2004, and June 30, 2008) was conducted at a large, university-affiliated, tertiary-care medical center. One-hundred forty-seven patients who underwent cardiac surgery with cardiopulmonary bypass, 72 of whom received at least 1 dose of hydrocortisone (treatment), and 75 similar patients who did not receive hydrocortisone (control), were randomly selected. RESULTS: Cardiopulmonary bypass and aortic cross-clamp times were similar between treatment and control groups (128 vs 124 minutes, p = 0.56; 103 vs 98 minutes, p = 0.39). Patients who received hydrocortisone had a significantly shorter time to discontinuation of all vasoactive medications (79.6 vs 21.1 hours, p < 0.001), and less postoperative atrial fibrillation (OR 0.28, 95% CI 0.14 to 0.56, p < 0.001). Patients in the treatment group experienced significantly more hyperglycemia (89 vs 71%, p = 0.006); however, major and minor bleeding or infection rates did not differ significantly between groups. CONCLUSIONS: Patients treated with hydrocortisone after cardiac surgery with cardiopulmonary bypass experienced a significantly shorter time to discontinuation of all vasoactive medications and less postoperative atrial fibrillation than patients not treated with hydrocortisone. These benefits came at the expense of significantly more hyperglycemia. PMID- 21304032 TI - Plasmapheresis and Intravenous Immune Globulin Improve Neurologic Outcome of Central Pontine Myelinolysis Occurring Post Orthotopic Liver Transplant. AB - OBJECTIVE: To report 2 cases of central pontine myelinolysis (CPM) post liver transplantation in which treatment with plasmapheresis and intravenous immune globulin improved expected neurologic outcome. CASE SUMMARY: Two patients who underwent orthotopic liver transplant developed CPM early in their postoperative course. Magnetic resonance imaging of the brain demonstrated severe demyelination of either the pons or the midbrain, respectively. Both patients developed significant neurologic abnormalities, including acute mental status changes, severe muscle weakness, spasticity, and/or prolonged paralysis. Pretransplant laboratory results indicated serum sodium levels fluctuating between 115 mEq/L and 152 mEq/L. Both patients received 6 days of plasmapheresis (PP) followed by 5 consecutive days of intravenous immune globulin (IVIG). Significant neurologic improvement was experienced at 2 and 4 weeks, respectively, after therapy was initiated. Complete resolution of neurologic symptoms was evident at 1 year follow-up. DISCUSSION: Currently, specific guidelines or recommendations for the treatment of CPM are practically nonexistent. CPM remains a neurologic complication that is difficult to treat and may result in permanent significant neurologic sequelae. The etiology and pathogenesis of this disease are unclear, although aggressive osmolar correction, particularly in the setting of hyponatremia, is the main risk factor. While patients may eventually show some improvement with supportive care, progress is often protracted, and complete resolution of symptoms is exceedingly rare. The severity of the midbrain lesions juxtaposed against the rapidity of symptom resolution in these 2 patients alludes to a potential therapeutic benefit after initiation of therapy with PP and IVIG. CONCLUSIONS: These cases suggest that prompt recognition of CPM and initiation of PP and IVIG may help modulate its progress and improve long-term neurologic outcome. PMID- 21304033 TI - Genetic Mechanisms of Antimicrobial Resistance of Acinetobacter baumannii. AB - OBJECTIVE: To summarize published data identifying known genetic mechanisms of antibiotic resistance in Acinetobacter baumannii and the correlating phenotypic expression of antibiotic resistance. DATA SOURCES: MEDLINE databases (1966-July 15, 2010) were searched to identify original reports of genetic mechanisms of antibiotic resistance in A. baumannii. DATA SYNTHESIS: Numerous genetic mechanisms of resistance to multiple classes of antibiotics are known to exist in A. baumannii, a gram-negative bacterium increasingly implicated in nosocomial infections. Mechanisms may be constitutive or acquired via plasmids, integrons, and transposons. Methods of resistance include enzymatic modification of antibiotic molecules, modification of antibiotic target sites, expression of efflux pumps, and downregulation of cell membrane porin channel expression. Resistance to beta-lactams appears to be primarily caused by beta-lactamase production, including extended spectrum beta-lactamases (b/aTEM, blaSHV, b/aTX M,b/aKPC), metallo-beta-lactamases (blaMP, blaVIM, bla, SIM), and most commonly, oxacillinases (blaOXA). Antibiotic target site alterations confer resistance to fluoroquinolones (gyrA, parC) and aminoglycosides (arm, rmt), and to a much lesser extent, beta-lactams. Efflux pumps (tet, ade, abe) contribute to resistance against beta-lactams, tetracyclines, fluoroquinolones, and aminoglycosides. Finally, porin channel deletion (carO, oprD) appears to contribute to beta-lactam resistance and may contribute to rarely seen polymyxin resistance. Of note, efflux pumps and porin deletions as solitary mechanisms may not render clinical resistance to A. baumannii. CONCLUSIONS: A. baumannii possesses copious genetic resistance mechanisms. Knowledge of local genotypes and expressed phenotypes for A. baumannii may aid clinicians more than phenotypic susceptibilities reported in large epidemiologic studies. PMID- 21304034 TI - The Pharmacogenetic Rescue of Side-Lined Anticancer Drugs to the Front-Line: Gefitinib as a Case Example. AB - OBJECTIVE: To illustrate the increasing importance of pharmacogenetics in drug development and clinical practice through a critical analysis of the validation and licensing of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, as a treatment for non-small cell lung cancer (NSCLC). DATA SOURCES: Journal articles and the "grey" literature were identified through a systematic search of MEDLINE (to June 2010) and the Web sites of the major drug regulators. References identified through the reference lists of major published reviews of gefitinib and Erb receptors, including EGFR, were also reviewed. STUDY SELECTION AND DATA EXTRACTION: A broad appraisal of the titles and abstracts of articles on gefitinib and tyrosine kinase inhibitors in lung cancer was undertaken to identify pertinent concepts and relevant publications for further analysis. Articles deemed particularly relevant were retrieved for detailed appraisal. Dossiers on the licensing of gefitinib from the Food and Drug Administration Web site and major published reviews were retrieved. Relevant pharmacogenetic issues were identified and the clinical studies addressing these were evaluated. DATA SYNTHESIS: Initial promising trial data for gefitinib in NSCLC led to its conditional marketing approval. When the drug's efficacy was not confirmed in a pivotal Phase 3 trial, its prescribing was restricted. Subsequent discovery of activating mutations in the tyrosine kinase domain of EGFR led to further retrospective and prospective evaluation of the drug in patients with those mutations. The new evidence was sufficiently robust to persuade the drug regulators to license the drug as first-line treatment for patients with locally advanced or metastatic NSCLC who test positive for those mutations. CONCLUSIONS: Pharmacogenetic evidence has played a key role in rescuing gefitinib for front line treatment of NSCLC. This case-example portends what will be increasingly likely scenarios in the regulation and clinical validation of targeted drug therapies. PMID- 21304035 TI - Epidemiologic Evaluation of Cardiovascular Risk in Patients Receiving Milnacipran, Venlafaxine, or Amitriptyline: Evidence from French Health Data. AB - BACKGROUND: Milnacipran, a selective serotonin and norepinephrine reuptake inhibitor, is approved by the Food and Drug Administration for the management of fibromyalgia. It has been available for many years in several countries outside the US for the treatment of depression. OBJECTIVE: To conduct population-based analyses comparing the risk of serious cardiovascular (CV) events (eg, acute myocardial infarction, stroke, congestive heart failure) associated with treatment with milnacipran compared with venlafaxine and amitriptyline, 2 other commonly prescribed drugs that also inhibit reuptake of norepinephrine and serotonin. METHODS: Information from the French Thales electronic health record database from 2001 to 2007 was used. Patients with 1 or more prescriptions for milnacipran, venlafaxine, or amitriptyline; 180 or more days of continuous eligibility prior to the first prescription; and no prior CV event diagnoses during the 180-day baseline period were included. A retrospective, matched-cohort design was employed. The incidence rates of CV events between cohorts receiving milnacipran, venlafaxine, and amitriptyline were compared using unadjusted incidence rate ratio (IRR) and adjusted conditional IRR based on Poisson regression. RESULTS: We identified 4452 milnacipran-venlafaxine and 3761 milnacipran-amitriptyline matched pairs. The matched cohorts had similar baseline characteristics. The unadjusted IRRs of any CV events, comparing milnacipran with venlafaxine or amitriptyline, were 1.02 (95% CI 0.73 to 1.44) and 1.30 (95% CI 0.90 to 1.89), respectively. Adjusted IRRs confirmed the statistical similarity in the CV event risk between milnacipran and venlafaxine (adjusted IRR = 1.29, 95% CI 0.76 to 2.17) or amitriptyline (adjusted IRR = 1.06, 95% CI 0.59 to 1.89). CONCLUSIONS: This French population-based study found that the risk of CV events was not significantly different for patients receiving milnacipran versus those receiving venlafaxine or amitriptyline. PMID- 21304036 TI - Impact of Mycophenolate Mofetil Dose Reduction on Allograft Outcomes in Kidney Transplant Recipients on Tacrolimus-Based Regimens: A Systematic Review. AB - OBJECTIVE: To systematically evaluate the clinical consequences of mycophenolate dose reduction in renal transplant recipients on tacrolimus-based regimens. DATA SOURCES: PubMed (1949-July 2010), EMBASE (1980-July 2010), Cochrane Database of Systematic Reviews, International Pharmaceutical Abstracts, and Web of Science were searched using the terms mycophenolate mofetil, tacrolimus, dose reduction, and kidney and/or renal transplant. References from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: Studies reporting on rejection rate, allograft survival, or renal function were included and ranked according to the US Preventive Services Task Force classification; excluded were studies that were dose-finding or used cyclosporine only, involved patients on enteric-coated mycophenolate sodium or those with multiorgan transplant, or provided no information on concomitant immunosuppressants. Data extracted were study design, sample size, immunosuppression regimen, type of transplant, and allograft outcomes. DATA SYNTHESIS: Of 13 studies included, 1 was level I evidence, 3 were level II-2, 6 were level II-3, and 3 were level III evidence. Three focused on tacrolimus-based regimens, whereas 7 included either cyclosporine or tacrolimus. The only prospective, randomized, multicenter trial demonstrated that early taper of mycophenolate dosage to 1 g/day can be utilized without increased risk of rejection, compared with late tapering, but the rejection rate was high (30-40%). Overall, we found conflicting evidence regarding the impact of mycophenolate dose reduction on rejection rate and allograft loss and that discontinuing mycophenolate led to an increased risk of graft loss as high as 8 fold. Allograft survival was lowest in patients with gastrointestinal complications and those in whom mycophenolate was discontinued, compared with patients with neither gastrointestinal complications nor mycophenolate discontinuation. CONCLUSIONS: Weak evidence suggests that mycophenolate dose modifications, either reduction or discontinuation, may increase rejection rate and graft loss; however, this is more apparent in cyclosporine-based regimens. Prospective, well-designed trials are necessary to definitively determine the impact of dose reduction in renal transplant recipients on tacrolimus-based regimens. PMID- 21304037 TI - Thienopyridines in Acute Coronary Syndrome. AB - OBJECTIVE: To evaluate the safety and efficacy of the thienopyridines in order to identify their current place in therapy for the treatment of acute coronary syndrome (ACS). DATA SOURCES: Literature was accessed through MEDLINE (1966 October 2010 week 1), EMBASE (1980-2010 week 40), and a bibliographic review of published articles using the search terms acute coronary syndrome, clopidogrel, and prasugrel. Articles were limited to clinical trials conducted in humans and published in the English language. STUDY SELECTION AND DATA EXTRACTION: Head-to head clinical trials evaluating the safety and efficacy of the thienopyridines in patients with ACS were critically reviewed. Trials evaluating ticlopidine were excluded due to its limited clinical use. DATA SYNTHESIS: Thienopyridines are an integral part of the treatment of ACS. Prior to the approval of prasugrel, clopidogrel was considered the agent of choice due to safety concerns associated with ticlopidine. A randomized controlled trial comparing prasugrel and clopidogrel has demonstrated superior efficacy with prasugrel, and post hoc analyses suggest additional benefit with prasugrel is derived in patients with ST segment elevation myocardial infarction and patients with diabetes. However, safety concerns exist linking prasugrel with an increased risk of bleeding, which diminishes its advantage in elderly patients, underweight patients, and those with a history of stroke. Pharmacokinetic and pharmacodynamic studies discussing differences in response variability, platelet inhibition, interactions with proton pump inhibitors, and genetic factors between the thienopyridines are numerous, although more clinical data are needed to determine clinical implications. CONCLUSIONS: Clinical trial data have suggested prasugrel is superior to clopidogrel at preventing ischemic events in patients with ACS undergoing percutaneous coronary intervention. However, this coincides with an increased risk of bleeding. Clinicians must carefully interpret the current evidence, including limitations in study design and pharmacologic differences between agents, in order to balance the risks and benefits as new data become available. PMID- 21304038 TI - Can Pharmacokinetic and Pharmacodynamic Principles Be Applied to the Treatment of Multidrug-Resistant Acinetobacter? AB - OBJECTIVE: To discuss treatment options that can be used for treatment of Acinetobac/erinfections. DATA SOURCES: A MEDLINE search (1966-November 2010) was conducted to identify English-language literature on pharmacotherapy of Acinetobacter and the bibliographies of pertinent articles. Programs and abstracts from infectious diseases meetings were also searched. Search terms included Acinetobacter, multidrug resistance, pharmacokinetics, pharmacodynamics, Monte Carlo simulation, nosocomial pneumonia, carbapenems, polymyxins, sulbactam, aminoglycosides, tetracyclines, tigecycline, rifampin, and fluoroquinolones. DATA SELECTION AND DATA EXTRACTION: All articles were critically evaluated and all pertinent information was included in this review. DATA SYNTHESIS: Multidrug resistant (MDR) Acinetobacter, defined as resistance to 3 or more antimicrobial classes, has increased over the past decade. The incidence of carbapenem resistant Acinetobacter is also increasing, leading to an increased use of dose optimization techniques and/or alternative antimicrobials, which is driven by local susceptibility patterns. However, Acinetobacter infections that are resistant to all commercially available antibiotics have been reported. General principles are available to guide dose optimization of aminoglycosides, beta lactams, fluoroquinolones, and tigecycline for infections due to gram-negative pathogens. Unfortunately, data specific to patients with Acinetobacter infections are limited. Recent pharmacokinetic-pharmacodynamic information has shed light on colistin dosing. The dilemma with colistin is its concentration-dependent killing, which makes once-daily dosing seem like an attractive option, but its short postantibiotic effect limits a clinician's ability to extend the dosing interval. Localized delivery of antimicrobials is also an attractive option due to the ability to increase drug concentration at the infection site while minimizing systemic adverse events, but more data are needed regarding this approach. CONCLUSIONS: Increased reliance on dosage optimization, combination therapy, and localized delivery of antimicrobials are methods to pursue positive clinical outcomes in MDR Acinetobacter infections since novel antimicrobials will not be available for several years. Well-designed clinical trials with MDR Acinetobacter are needed to define the best treatment options for these patients. PMID- 21304039 TI - Rhabdomyolysis in a Prostate Cancer Patient Taking Ketoconazole and Simvastatin: Case Report and Review of the Literature. AB - OBJECTIVE: To report a case of severe rhabdomyolysis resulting in acute renal failure caused by an interaction between ketoconazole and simvastatin in a patient with prostate cancer. CASE SUMMARY: A 64-year-old man who received ketoconazole for prostate cancer, along with simvastatin and fenofibrate for dyslipidemia, presented to our ambulatory clinic with complaints of blood in his urine and weakness following an increase in his ketoconazole dose. Two days after presentation, the patient was admitted with rhabdomyolysis and acute renal failure, as evidenced by elevated serum creatine kinase (>32,000 IU/L), serum myoglobin (20.6 ng/mL), and serum creatinine (4.2 mg/dL) as well as abnormal bone scintigraphy findings. Ketoconazole, fenofibrate, and simvastatin were discontinued. Renal function did not normalize with hydration, and intermittent hemodialysis was initiated; 10 days of hemodialysis resulted in normalization of electrolytes and creatine kinase. Symptom improvement and normalization of laboratory parameters were observed after prolonged hospitalization (24 days). DISCUSSION: Prostate cancer is the most common malignancy among men in the US. Androgen deprivation therapy is the standard initial treatment for biochemical recurrence or metastatic disease. Most patients experience progression to a castrate-resistant disease state, requiring the use of additional therapies. Ketoconazole is considered a secondary hormonal treatment option. We describe an interaction in a patient with prostate cancer between a 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor and ketoconazole resulting in rhabdomyolysis, requiring hemodialysis. An objective causality assessment using the Horn Drug Interaction Probability Scale revealed that the adverse drug reaction was a possible result of the interaction. CONCLUSIONS: The temporal fashion in which the episode occurred suggests that a possible simvastatin-ketoconazole interaction precipitated rhabdomyolysis in this patient. The use of ketoconazole for castrate-resistant prostate cancer can lead to drug drug interactions in patients taking simvastatin or other HMG-CoA reductase inhibitors. Clinicians should be aware of this severe adverse event and take steps to minimize its occurrence. PMID- 21304041 TI - Battlefield orthopaedic injuries cause the majority of long-term disabilities. AB - Extremity injuries make up 54% of combat wounds sustained in Operation Iraqi Freedom and Operation Enduring Freedom. In a cohort of war-wounded service members, we identified the conditions secondary to battle injury that result in disqualification from continued service. The Army Physical Evaluation Board records of 464 wounded service members who were injured between October 2001 and January 2005 were reviewed to determine the codes indicating unfitting conditions. Sixty-nine percent of these conditions were orthopaedic. Fifty-seven percent of the injured had unfitting conditions that were orthopaedic only. Of those evacuated from theater with a primary diagnosis of injury to the head, thorax, or abdomen and who suffered an orthopaedic injury as well, 76% had an orthopaedic diagnosis as the primary unfitting condition. Orthopaedic-related disability has a significant impact on the affected patient, the health care system, and, in the case of wounded service members, on military strength and readiness. PMID- 21304040 TI - Intestinal Necrosis Associated with Orally Administered Calcium Polystyrene Sulfonate Without Sorbitol. AB - OBJECTIVE: To describe a case of extensive intestinal necrosis with oral intake of calcium polystyrene sulfonate without sorbitol. CASE SUMMARY: A 73-year-old woman was admitted to the emergency department with abdominal pain. Abdominal computed tomography (CT) scan showed widespread dilatation of the bowel. The diagnosis of acute colonic pseudoobstruction was made. On day 3, her serum potassium level rose to 5.6 mEq/L. It was treated with hydrocortisone 100 mg/day and calcium polystyrene sulfonate 15 g/day via nasogastric tube from day 3 to day 6. On day 6, the severe abdominal pain recurred, with abdominal tenderness. CT scan showed pneumoperitoneum and peritoneal effusion. At surgery, 2 lenticular jejunal perforations and an ischemic cecum were found. Microscopic findings indicated that the transmural abscess contained massive inflammatory infiltrate and the cecal mucosa showed ulceration and inflammation with a fibrinous and purulent coating. Small gray-purple or blue angulated crystals were embedded in the cecal and most of the jejunal mucosal ulcers. On day 19, the patient died of multiple organ failure after her third laparotomy. DISCUSSION: Ion-exchanging resins are given orally or by retention enema for the treatment of hyperkalemia. The most commonly used and best-established resin is sodium polystyrene sulfonate. However, it is known to promote colonic necrosis when sorbitol is also given or especially in patients with renal failure or postoperative ileus. Calcium polystyrene sulfonate is another ion-exchange resin. There are few reports of adverse effects in the literature. Our case is interesting for 2 reasons: the resin given was calcium polystyrene sulfonate and sorbitol was not used. CONCLUSIONS: Like sodium polystyrene sulfonate, calcium polystyrene sulfonate is an ion-exchanging resin that can promote bowel necrosis. We believe that it should not be used with sorbitol or when bowel transit time is slowed. PMID- 21304042 TI - Moderators' summary: perceived performance differences. limb salvage versus amputation in the lower extremity (session II). AB - Severe extremity trauma is a significant cause of morbidity and disability; these injuries are often considered for amputation. Two studies have shown few differences between amputation and limb salvage outcomes. Functional limitations that result from loss of muscle needed to cover bone and provide limb function are a major factor in the decision to amputate a salvaged limb. Several studies have reported successful management of muscle loss with soft-tissue transfer. Extracellular matrix scaffolds and muscle regeneration using stem cells are promising technologies. However, no single strategy has proved to be effective in the management of limb pain following extremity trauma; a multimodal approach is required for best results. Additional knowledge gaps exist, such as the effect of occupational and physical therapy on the outcome of severe limb injury, factors such as peer visitation and social support networks, and the effect of sex, cultural differences, and patient personality. PMID- 21304043 TI - Painful sequelae following limb salvage: etiology and management. AB - Inadequately controlled pain is a significant problem during limb salvage and is associated with poor outcomes. This pain has several causes, and many management options exist. Chronic pain associated with limb salvage causes unnecessary suffering and negatively affects long-term function. Chronic pain and disability in this population may be prevented with early, aggressive, comprehensive treatment. Ongoing research into the cause and clinical course of limb salvage pain likely will lead to advances in pain management and functional improvement. PMID- 21304044 TI - Limb salvage with major nerve injury: current management and future directions. AB - Major peripheral nerve injuries are often associated with devastating functional deficits. Current management techniques fail to achieve adequate functional neural regeneration, and the development of adjunct therapies is necessary to improve outcomes. Recent efforts at enhancing the regeneration rate of peripheral nerves and developing axonal guidance channels or conduits have had limited success. The neuromuscular junction serves as the interface between the peripheral nerves and muscle. This critical area undergoes significant changes following peripheral nerve injury and induces end-organ atrophy after denervation, which limits the chance of true functional regeneration. Stabilization of the neuromuscular junction may be an important adjunct in peripheral nerve repair and should be explored as a method of managing major nerve injuries. PMID- 21304045 TI - Volumetric muscle loss. AB - Prevention of infection, as well as bone covering and healing, is paramount in the management of limb injury with associated muscle injury. Volumetric muscle loss (VML) is the traumatic or surgical loss of skeletal muscle with resultant functional impairment. No standardized evaluation protocol exists for the characterization and quantification of VML. Clinical photographs and video recordings, range of motion measurements, manual muscle strength testing, and isokinetic muscle function testing may prove to be useful in documenting VML. Current treatment options include functional free muscle transfer and the use of advanced bracing designs. Advances in powered bracing and regenerative medicine may one day provide additional therapeutic options. Further research on VML is warranted. PMID- 21304046 TI - New minimal immunosuppression strategies for composite tissue allograft transplantation: the cleveland clinic experience. AB - Clinical application of composite tissue allografts requires the introduction of new minimal immunosuppressive or tolerance-inducing protocols. We have established a protocol for tolerance induction under alpha/beta selective blocking antibody T-cell receptor combined with interleukin-2 blocker cyclosporin A therapy. Application of this therapy resulted in induction of tolerance in fully allogenic and semiallogenic limb allograft transplants. Based on this experience we have found that the bone marrow component of the allograft is essential for tolerance induction and have confirmed that injection of bone marrow of donor origin directly into the bone marrow compartment of allograft recipients resulted in higher chimerism levels. In addition, we have developed a system for isolation of chimeric cells, which are specific for both the donor and recipient, by using magnetic activated cell sorting technique and flow cytometry. These new, experimental approaches confirm that introducing minimal suppression to patients undergoing hand or face transplantation will likely be achieved in the near future. PMID- 21304047 TI - Congressionally directed research will improve outcomes through funding opportunities for orthopaedics. AB - The large funding opportunities created by the US Congress have allowed the military and civilian orthopaedic communities to collaborate to define clinical problems and develop solutions. It is believed that this research effort will be constructive in the short term because of emphasis placed on funding projects that used relevant populations and approaches that will benefit patients soon. The immediate results will define best practice guidelines. Additionally, new therapies will be fielded that will reduce complications and improve the outcomes of both injured service personnel and civilians. PMID- 21304048 TI - Partnered disaster preparedness: lessons learned from international events. AB - Military, governmental, and civilian agencies routinely respond to disasters around the world, including large-scale mass casualty events such as the earthquake in Pakistan in 2005, Hurricane Katrina in the United States in 2005, and the earthquake in Haiti in 2010. Potential exists for improved coordination of medical response between civilian and military sectors and for the creation of a planned and practiced interface. Disaster preparedness could be enhanced with more robust disaster education for civilian responders; creation of a database of precredentialed, precertified medical specialists; implementation of a communication bridge; and the establishment of agreements between military and civilian medical/surgical groups in advance of major catastrophic events. PMID- 21304049 TI - Diagnosis and management of chronic infection. AB - High-energy penetrating extremity injuries are often associated with severe open fractures that have varying degrees of soft-tissue contamination and tenuous soft tissue coverage. The result is a relatively high prevalence of chronic osteomyelitis compared with that in civilian trauma patients. Diagnosing chronic osteomyelitis requires a careful history and thorough physical and radiographic examinations. Cross-sectional imaging can help delineate the extent of bony involvement, and scintigraphy can be used as a diagnostic tool and to gauge response to treatment. Clinical staging also directs surgical management. Adequacy of debridement remains the most important clinical predictor of success; thus, adopting an oncologic approach to complete (ie, wide) excision is important. Reconstruction can be safely performed by a variety of methods; however, proper staging and patient selection remain critical to a successful outcome. Although systemic and depot delivery of antibiotics plays a supporting role in the treatment of chronic osteomyelitis, the ideal dosing regimens, and the duration of treatment, remain controversial. PMID- 21304050 TI - Extremity war injuries V: barriers to return of function and duty. PMID- 21304051 TI - 2'-hydroxyflavanone inhibits proliferation, tumor vascularization and promotes normal differentiation in VHL-mutant renal cell carcinoma. AB - Renal cell carcinoma (RCC) is one of the top ten cancers prevalent in USA. Loss of-function mutations in the von Hippel-Lindau (VHL) gene constitute an established risk factor contributing to 75% of total reported cases of RCC. Loss of-VHL leads to a highly vascularized phenotype of renal tumors. Intake of citrus fruits has been proven to reduce the risk of RCC in multicenter international studies. Hence, we studied the effect of 2'-hydroxyflavanone (2HF), an active anticancer compound from oranges, in RCC. Our in vitro investigations revealed that 2HF suppresses VHL-mutant RCC to a significantly greater extent than VHL wild-type RCC by inhibiting epidermal growth factor receptor signaling, which is increased due to VHL mutations in RCC. Our results also revealed for the first time, that 2HF inhibits glutathione S-transferase pi activity. 2HF reduced cyclin B1 and CDK4 levels and induced G2/M phase arrest in VHL-mutant RCC. Importantly, 2HF inhibited the angiogenesis in VHL-mutant RCC by decreasing vascular endothelial growth factor expression. Our in vivo studies in mice xenografts confirmed our in vitro results as evident by decreased levels of proliferation marker, Ki67 and angiogenic marker, CD31, in 2HF-treated mice xenografts of VHL mutant RCC. 2HF also increased the expression of E-cadherin in VHL-mutant RCC, which would be of significance in restoring normal epithelial phenotype. Collectively, our in vitro and in vivo results revealed the potent antiproliferative, anti-angiogenic and prodifferentiation properties of 2HF in VHL-mutant RCC, sparing normal cells, which could have significant implications not only in the specific management of VHL-mutant RCC but also towards other VHL syndromes. PMID- 21304052 TI - Estrogen-mediated epigenetic repression of the imprinted gene cyclin-dependent kinase inhibitor 1C in breast cancer cells. AB - While tumor suppressor genes frequently undergo epigenetic silencing in cancer, how the instructions directing this transcriptional repression are transmitted in cancer cells remain largely unclear. Expression of cyclin-dependent kinase inhibitor 1C (CDKN1C), an imprinted gene on chromosomal band 11 p15.5, is reduced or lost in the majority of breast cancers. Here, we report that CDKN1C is suppressed by estrogen through epigenetic mechanisms involving the chromatin interacting noncoding RNA KCNQ1OT1 and CCCTC-binding factor (CTCF). Activation of estrogen signaling reduced CDKN1C expression 3-fold (P < 0.001) and established repressive histone modifications at the 5' regulatory region of the locus. These events were concomitant with induction of KCNQ1OT1 expression as well as increased recruitment of CTCF to both the distal KCNQ1OT1 promoter-associated imprinting control region (ICR) and the CDKN1C locus. Transient depletion of CTCF by small interfering RNA increased CDKN1C expression and significantly reduced the estrogen-mediated repression of CDKN1C. Further studies in breast cancer cell lines indicated that the epigenetic silencing of CDKN1C occurs in part as the result of genetic loss of the inactive methylated 11p15.5 ICR allele (R(2) = 0.612, P < 0.001). We also found a novel cis-encoded antisense transcript, CDKN1C AS, which is induced by estrogen signaling following pharmacologic inhibition of DNA methyltransferase and histone deacetylase activity. Forced expression of CDKN1C-AS was capable of repressing endogenous CDKN1C in vivo. Our findings suggest that in addition to promoter hypermethylation, epigenetic repression of tumor suppressor genes by CTCF and noncoding RNA transcripts could be more common and important than previously understood. PMID- 21304053 TI - Th17 cells in cancer: help or hindrance? AB - The role of CD4+ T helper (Th) 17 cells in malignancy is currently under debate. However, upon closer scrutiny, it becomes apparent that this discussion includes not only evaluations of Th17 cells but also IL-17+ cells from other immune populations, the cytokine interleukin (IL)-17 itself (both endogenous and exogenous) and IL-23. Further complicating the matter are occasionally conflicting results of studies in humans versus those in mice and contradictory data from immunocompetent versus immunodeficient mice. To better understand the role of Th17 cells in the tumor-bearing host, we focus first upon those studies investigating Th17 cells in patients and then those in mice, all the while keeping in mind that variables such as tumor-initiating agents, a pre-existing inflammatory environment and the immune competence of the host may have direct effects upon this T-cell subset. In this review, we will describe the phenotype of tumor-associated Th17 cells, review those studies that have examined the population directly, and finally, briefly discuss the studies involving Th17 associated signature cytokines. PMID- 21304054 TI - Genetic polymorphisms in DNA double-strand break repair genes XRCC5, XRCC6 and susceptibility to hepatocellular carcinoma. AB - Environmental risk factors cause DNA damages. Imprecise DNA repair leads to chromosome aberrations, genome destabilization and hepatocarcinogenesis. Ku is a key DNA double-strand break repair protein. We hypothesized that the genetic variants in Ku subunits encoding genes, XRCC5/XRCC6, may contribute to hepatocellular carcinoma (HCC) susceptibility. We genotyped 13 common single nucleotide polymorphisms (SNPs) in XRCC5 and XRCC6 and evaluated their associations with HCC risk in 689 pathologically confirmed cases and 690 cancer free controls from a Chinese population. We found that a significantly reduced risk for HCC was associated with XRCC5 rs16855458 [odds ratio (OR)=0.59; 95% confidence interval (CI)=0.43-0.81; CA+AA versus CC] and a significantly increased risk for HCC was associated with XRCC5 rs9288516 (OR=2.02; 95% CI=1.42 2.86; TA+AA versus TT) even after Bonferroni correction (Pcorrected=0.026 and 0.002, respectively). The effects of rs16855458 (OR=0.57; 95% CI=0.37-0.86, P=0.008) and rs9288516 (OR=1.86; 95% CI=1.19-2.90, P=0.007) were more significant in hepatitis B surface antigen-infected subjects than non-infected subjects. The haplotype-based analysis revealed that in XRCC5, AA in block 1 (OR=0.63; 95% CI=0.48-0.83) and CGGTT in block 2 (OR=0.52; 95% CI=0.39-0.69) were associated with decreased HCC risk (Pcorrected=0.013 and <0.001, respectively). The aforementioned two SNPs exhibited a significant cumulative risk effect (Ptrend<0.001). Additionally, potential interaction among XRCC5 rs9288516 and rs2267437, rs5751131 in XRCC6 was indicated by the multifactor dimensionality reduction analysis. In conclusion, XRCC5 variants may play a role in determining individual's HCC susceptibility, which warranted validation in larger studies. PMID- 21304055 TI - Promoter methylation of Wnt antagonists DKK1 and SFRP1 is associated with opposing tumor subtypes in two large populations of colorectal cancer patients. AB - Aberrant activation of canonical Wnt signaling is a hallmark event in colorectal carcinogenesis. The Dickkopf-1 (DKK1) and Secreted Frizzled Related Protein 1 (SFRP1) genes encode extracellular inhibitors of Wnt signaling that are frequently silenced by promoter hypermethylation in colorectal cancer (CRC). These methylation events have been identified as prognostic markers of patient outcome and tumor subtype in several cancers but similar roles in CRC have not been comprehensively examined. In CRC, the microsatellite instability (MSI) subtype associates with favorable disease outcome but the molecular events that are responsible remain poorly understood. Consequently, we quantified promoter methylation status of the Wnt antagonist genes DKK1 and SFRP1 in a large population-based cohort of CRCs from Ontario (n = 549) and Newfoundland (n = 696) stratified by MSI status. We examined the association between methylation status and clinicopathological features including tumor MSI status and patient survival. DKK1 and SFRP1 were methylated in 13 and 95% of CRCs, respectively. In Ontario, DKK1 methylation was strongly associated with MSI tumors after adjustment for age, sex and tumor location [odds ratio (OR) = 13.7, 95% confidence interval (CI) = 7.8-24.2, P < 0.001]. Conversely, SFRP1 methylation was inversely associated with MSI tumors after these adjustments (OR = 0.3, 95% CI = 0.1-0.9, P = 0.009). Similar results were obtained in Newfoundland. There were no independent associations with recurrence-free survival. This is the first large study to identify associations between Wnt antagonist promoter hypermethylation and CRC MSI subtype. These events provide insight into subtype-specific epigenetic mediation of Wnt signaling in CRC. PMID- 21304056 TI - Is vitamin D deficiency associated with heart failure? A review of current evidence. AB - An estimated 1 billion people worldwide have deficient or insufficient levels of vitamin D. Even more alarming is the association of vitamin D deficiency with many types of diseases, particularly heart failure (HF). Hypovitaminosis D has been observed to be highly prevalent in the HF community with rates varying from approximately 80% to 95%. Higher rates of deficiency have been linked to winter months, in patients with protracted decompensated HF, darker skin pigmentation, and higher New York Heart Association (NYHA) classes. In fact, some data suggest vitamin D deficiency may even be an independent predictor of mortality in patients with HF. Traditionally obtained through UV exposure and activated in the liver and then the kidneys, vitamin D is classified as a vitamin but functions as a steroid hormone. The hormone acts through the vitamin D receptor (VDR), which is expressed in vascular smooth muscle cells, renal juxtaglomerular cells, and most interestingly, cardiac myocytes. Studies have shown that the association between vitamin D deficiency and HF often manifests in the structural components of cardiac myocytes and/or through alterations of the neurohormonal cascade. In addition, vitamin D may also act rapidly through intracellular nongenomic receptors that alter cardiac contractility. Unfortunately, prospective vitamin D supplementation trials show mixed results. In rat models, successful correction of deficiency was associated with reductions in ventricular hypertrophy. In humans, however, echocardiographic dimensions did not change significantly. These results bring into questions whether vitamin D is a risk factor for HF, a marker of HF disease severity, or has a true pathologic role. This article provides a thorough review of vitamin D deficiency etiology, prevalence, and possible pathophysiologic role in HF. Furthermore, we carefully review prospective trials on vitamin D therapy in HF. We believe more trials on vitamin D therapy in HF need to be conducted before any conclusions can be drawn. PMID- 21304057 TI - Losartan decreases cardiac muscle fibrosis and improves cardiac function in dystrophin-deficient mdx mice. AB - Recent studies showed that chronic administration of losartan, an angiotensin II type I receptor antagonist, improved skeletal muscle function in dystrophin deficient mdx mice. In this study, C57BL/10ScSn-Dmd(mdx)/J female mice were either untreated or treated with losartan (n = 15) in the drinking water at a dose of 600 mg/L over a 6-month period. Cardiac function was assessed via in vivo high frequency echocardiography and skeletal muscle function was assessed using grip strength testing, Digiscan monitoring, Rotarod timing, and in vitro force testing. Fibrosis was assessed using picrosirius red staining and Image J analysis. Gene expression was evaluated using real-time polymerized chain reaction (RT-PCR). Percentage shortening fraction was significantly decreased in untreated (26.9% +/- 3.5%) mice compared to losartan-treated (32.2% +/- 4.2%; P < .01) mice. Systolic blood pressure was significantly reduced in losartan-treated mice (56 +/- 6 vs 69 +/- 7 mm Hg; P < .0005). Percentage cardiac fibrosis was significantly reduced in losartan-treated hearts (P < .05) along with diaphragm (P < .01), extensor digitorum longus (P < .05), and gastrocnemius (P < .05) muscles compared to untreated mdx mice. There were no significant differences in skeletal muscle function between treated and untreated groups. Chronic treatment with losartan decreases cardiac and skeletal muscle fibrosis and improves cardiac systolic function in dystrophin-deficient mdx mice. PMID- 21304061 TI - Duodenal-jejunal bypass protects GK rats from {beta}-cell loss and aggravation of hyperglycemia and increases enteroendocrine cells coexpressing GIP and GLP-1. AB - Dramatic improvement of type 2 diabetes is commonly observed after bariatric surgery. However, the mechanisms behind the alterations in glucose homeostasis are still elusive. We examined the effect of duodenal-jejunal bypass (DJB), which maintains the gastric volume intact while bypassing the entire duodenum and the proximal jejunum, on glycemic control, beta-cell mass, islet morphology, and changes in enteroendocrine cell populations in nonobese diabetic Goto-Kakizaki (GK) rats and nondiabetic control Wistar rats. We performed DJB or sham surgery in GK and Wistar rats. Blood glucose levels and glucose tolerance were monitored, and the plasma insulin, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) levels were measured. beta-Cell area, islet fibrosis, intestinal morphology, and the density of enteroendocrine cells expressing GLP-1 and/or GIP were quantified. Improved postprandial glycemia was observed from 3 mo after DJB in diabetic GK rats, persisting until 12 mo after surgery. Compared with the sham-GK rats, the DJB-GK rats had an increased beta cell area and a decreased islet fibrosis, increased insulin secretion with increased GLP-1 secretion in response to a mixed meal, and an increased population of cells coexpressing GIP and GLP-1 in the jejunum anastomosed to the stomach. In contrast, DJB impaired glucose tolerance in nondiabetic Wistar rats. In conclusion, although DJB worsens glucose homeostasis in normal nondiabetic Wistar rats, it can prevent long-term aggravation of glucose homeostasis in diabetic GK rats in association with changes in intestinal enteroendocrine cell populations, increased GLP-1 production, and reduced beta-cell deterioration. PMID- 21304062 TI - Characterization of the reproductive effects of the anorexigenic VGF-derived peptide TLQP-21: in vivo and in vitro studies in male rats. AB - VGF (nonacronymic) is a 68-kDa protein encoded by the homonymous gene, which is expressed abundantly at the hypothalamus and has been involved in the control of metabolism and body weight homeostasis. Different active peptide fragments are generated from VGF, including TLQP-21. Circumstantial evidence has suggested that VGF might also participate in the control of reproduction. Yet its mechanisms of action and the eventual role of specific VGF-derived peptides on the hypothalamic pituitary-gonadal (HPG) axis remain unknown. Herein we report a series of studies on the reproductive effects of TLQP-21 as evaluated in male rats by a combination of in vivo and in vitro analyses. Central administration of TLQP-21 induced acute gonadotropin responses in pubertal and adult male rats, likely via stimulation of GnRH secretion, as documented by static incubations of hypothalamic tissue. In addition, in pubertal (but not adult) males, TLQP-21 stimulated LH secretion directly at the pituitary level. Repeated central administration of TLQP-21 to pubertal males subjected to chronic undernutrition was able to ameliorate the hypogonadotropic state induced by food deprivation. In contrast, chronic administration of TLQP-21 to fed males at puberty resulted in partial desensitization and puberty delay. Finally, in adult (but not pubertal) males, TLQP-21 enhanced hCG-stimulated testosterone secretion by testicular tissue in vitro. In summary, our data are the first to document a complex and multifaceted mode of action of TLQP-21 at different levels of the male HPG axis with predominant stimulatory effects, thus providing a tenable basis for the (direct) reproductive role of this VGF-derived peptide. PMID- 21304063 TI - Effect of diet-induced obesity and metabolic syndrome on skeletal muscles of Ossabaw miniature swine. AB - Ossabaw swine fed excess kilocalorie diet develop metabolic syndrome (MS) characterized by obesity, hypertension, insulin resistance, and glucose intolerance with/without dyslipidemia. The purpose of this study was to test the hypothesis that MS would have a detrimental effect on skeletal muscle structure and cause changes in the expression of myosin heavy chains (MHCs). Adult male Ossabaw swine were fed for 24 wk high-fructose or high-fat/cholesterol/fructose diets to induce normolipidemic MS (MetS) or dyslipidemic MS (DMetS), respectively, and were compared with the lean swine on control diet. MetS swine showed mild MS, lacking increases in total and low density lipoprotein (LDL) cholesterol, both of which were highly upregulated in DMetS swine. There was an ~1.2-fold increase in the cross-sectional areas of muscle fibers in MetS and DMetS groups compared with control for biceps femoris and plantaris muscles. In plantaris muscles, DMetS diet caused an ~2-fold decrease in slow MHC mRNA and protein expression and an ~1.2- to 1.8-fold increase in the number of intramyocellular lipid (IMCL) droplets without large changes in the size of the droplets. There was a trend to the decrease in slow MHC expression in muscles of swine on MetS diet. The number of IMCL droplets in muscle fibers of the MetS group was comparable to controls. These data correlate well with the data on total plasma cholesterol (control = 60, MetS = 70, and DMetS = 298 mg/dl) and LDL (control = 29, MetS = 30, and DMetS = 232 mg/dl). We conclude that structural changes observed in skeletal muscle of obese Ossabaw swine correlate with those previously reported for obese humans. PMID- 21304065 TI - An amino acid mixture improves glucose tolerance and insulin signaling in Sprague Dawley rats. AB - The aims of this investigation were to evaluate the effect of an amino acid supplement on the glucose response to an oral glucose challenge (experiment 1) and to evaluate whether differences in blood glucose response were associated with increased skeletal muscle glucose uptake (experimental 2). Experiment 1 rats were gavaged with either glucose (CHO), glucose plus an amino acid mixture (CHO AA-1), glucose plus an amino acid mixture with increased leucine concentration (CHO-AA-2), or water (PLA). CHO-AA-1 and CHO-AA-2 had reduced blood glucose responses compared with CHO, with no difference in insulin among these treatments. Experiment 2 rats were gavaged with either CHO or CHO-AA-1. Fifteen minutes after gavage, a bolus containing 2-[(3)H]deoxyglucose and [U (14)C]mannitol was infused via a tail vein. Blood glucose was significantly lower in CHO-AA-1 than in CHO, whereas insulin responses were similar. Muscle glucose uptake was higher in CHO-AA-1 compared with CHO in both fast-twitch red (8.36 +/- 1.3 vs. 5.27 +/- 0.7 MUmol.g(-1).h(-1)) and white muscle (1.85 +/- 0.3 vs. 1.11 +/- 0.2 MUmol.g(-1).h(-1)). There was no difference in Akt/PKB phosphorylation between treatment groups; however, the amino acid treatment resulted in increased AS160 phosphorylation in both muscle fiber types. Glycogen synthase phosphorylation was reduced in fast-twitch red muscle of CHO-AA-1 compared with CHO, whereas mTOR phosphorylation was increased. These differences were not noted in fast-twitch white muscle. These findings suggest that amino acid supplementation can improve glucose tolerance by increasing skeletal muscle glucose uptake and intracellular disposal through enhanced intracellular signaling. PMID- 21304064 TI - Gastric bypass surgery is associated with near-normal insulin suppression of lipolysis in nondiabetic individuals. AB - We hypothesized that individuals who have undergone gastric bypass have greater insulin sensitivity that obese subjects but less compared with lean. We measured free fatty acid (FFA) and glucose kinetics during a two-step, hyperinsulinemic euglycemic clamp in nondiabetic subjects who were 38 +/- 5 mo post-gastric bypass surgery (GB; n = 15), in lean subjects (L; n = 15), and in obese subjects (O; n = 16). Fasting FFAa were not significantly different between the three study groups but during both doses of insulin were significantly higher in O than in either GB or L. The effective insulin concentration resulting in half-maximal suppression of FFA was similar in L and GB and significantly less in both groups compared with O. Glucose infusion rates during low-dose insulin were not significantly different in GB compared with either L or O. During high-dose insulin, glucose infusion rates were significantly greater in GB than in O but less than in L. Endogenous glucose production in GB was significantly lower than O only during low dose of insulin. We conclude that gastric bypass is associated with improvements in adipose tissue insulin sensitivity to levels similar to lean, healthy persons and also with improvements in the response of glucose metabolism to insulin. These changes may be due to preferential reduction in visceral fat and decreased FFA availability. However, some differences in insulin sensitivity in GB remain compared with L. Residual insulin resistance may be related to excess total body fat or abnormal lipolysis and requires further study. PMID- 21304066 TI - Uterine signaling at the emergence of the embryo from obligate diapause. AB - Embryonic diapause is the reversible arrest of embryo development prior to implantation under a regime of uterine control that is not well understood. Our objective was to explore uterine modifications associated with the emergence of embryonic diapause in the mink, a species in which embryonic diapause characterizes every gestation. We investigated the uterine transcriptome at reactivation using the suppressive subtractive hybridization technique. A library of 123 differentially expressed genes between uteri with blastocysts in diapause and reactivated blastocysts was generated. Among those genes, 41.5% encode for potential secreted products that are implicated in regulation of cell proliferation (14%), homeostasis (14%), protein folding (11%), electron transport chain (8%), and innate immune response (8%), therefore suggesting that these biological processes are implicated in blastocyst reactivation. Two genes, the high-mobility group nucleosome binding domain 1 (HMGN1), a chromatin remodeling factor, and the secreted protein acidic and cystein-rich (SPARC), which is implicated in extracellular cell-cell interactions, were submitted to more detailed analysis of expression patterns in the mink uterus at blastocyst reactivation. Expression of both HMGN1 and SPARC was increased significantly in the uterus at embryo reactivation compared with diapause, principally in the endometrial epithelium and subepithelial stroma. These results provide new insight into uterine signaling at the emergence of the blastocyst from diapause and highlight the factors HMGN1 and SPARC as potential inductors of uterine environment modifications underlying uterine signaling during emergence of the embryo from embryonic diapause. PMID- 21304067 TI - Fenofibrate, a PPAR{alpha} agonist, decreases atrogenes and myostatin expression and improves arthritis-induced skeletal muscle atrophy. AB - Arthritis is a chronic inflammatory illness that induces cachexia, which has a direct impact on morbidity and mortality. Fenofibrate, a selective PPARalpha activator prescribed to treat human dyslipidemia, has been reported to decrease inflammation in rheumatoid arthritis patients. The aim of this study was to elucidate whether fenofibrate is able to ameliorate skeletal muscle wasting in adjuvant-induced arthritis, an experimental model of rheumatoid arthritis. On day 4 after adjuvant injection, control and arthritic rats were treated with 300 mg/kg fenofibrate until day 15, when all rats were euthanized. Fenofibrate decreased external signs of arthritis and liver TNFalpha and blocked arthritis induced decreased in PPARalpha expression in the gastrocnemius muscle. Arthritis decreased gastrocnemius weight, which results from a decrease in cross-section area and myofiber size, whereas fenofibrate administration to arthritic rats attenuated the decrease in both gastrocnemius weight and fast myofiber size. Fenofibrate treatment prevented arthritis-induced increase in atrogin-1 and MuRF1 expression in the gastrocnemius. Neither arthritis nor fenofibrate administration modify Akt-FoxO3 signaling. Myostatin expression was not modified by arthritis, but fenofibrate decreased myostatin expression in the gastrocnemius of arthritic rats. Arthritis increased muscle expression of MyoD, PCNA, and myogenin in the rats treated with vehicle but not in those treated with fenofibrate. The results indicate that, in experimental arthritis, fenofibrate decreases skeletal muscle atrophy through inhibition of the ubiquitin-proteasome system and myostatin. PMID- 21304068 TI - Switching from rosiglitazone: thinking outside the class. PMID- 21304069 TI - Perinatal care for incarcerated patients: a 25-year-old woman pregnant in jail. AB - More than 6 million men and 1 million women are under US correctional control, be it jail, prison, probation, or parole. On any given day, about 250,000 women and adolescent girls are behind bars, a number well in excess of those documented for all other sovereign nations. Moreover, women and girls represent the fastest growing segment of the prison and jail populations. Approximately 75% of these women are mothers of minor children (leaving 200,000 children "motherless") and as many as 10,000 may be pregnant. Primarily designed for male offenders, the US correctional system is struggling to meet the specialized needs of its female inmates. Although incarceration during pregnancy is both stressful and dehumanizing, most studies paradoxically document better outcomes for pregnancies managed behind bars than for women of similar socioeconomic status whose pregnancies are managed in the community. Using the case of Ms A as a springboard for discussion, the issues, benefits, and challenges of caring for an incarcerated pregnant woman are addressed, as is the importance of family planning services to those about to be released. PMID- 21304070 TI - Abdominal aortic aneurysm growth predicted by uptake of ultrasmall superparamagnetic particles of iron oxide: a pilot study. AB - BACKGROUND: Abdominal aortic aneurysms are a major cause of death. Prediction of aneurysm expansion and rupture is challenging and currently relies on the simple measure of aneurysm diameter. Using MRI, we aimed to assess whether areas of cellular inflammation correlated with the rate of abdominal aortic aneurysm expansion. METHODS AND RESULTS: Stable patients (n=29; 27 male; age, 70+/-5 years) with asymptomatic abdominal aortic aneurysms (4.0 to 6.6 cm) were recruited from a surveillance program and imaged using a 3-T MRI scanner before and 24 to 36 hours after administration of ultrasmall superparamagnetic particles of iron oxide (USPIO). The change in T2* value on T2*-weighted imaging was used to detect accumulation of USPIO within the abdominal aortic aneurysm. Histological examination of aneurysm tissue confirmed colocalization and uptake of USPIO in areas with macrophage infiltration. Patients with distinct mural uptake of USPIO had a 3-fold higher growth rate (n=11, 0.66 cm/y; P=0.020) than those with no (n=6, 0.22 cm/y) or nonspecific USPIO uptake (n=8, 0.24 cm/y) despite having similar aneurysm diameters (5.4+/-0.6, 5.1+/-0.5, and 5.0+/-0.5 cm, respectively; P>0.05). In 1 patient with an inflammatory aneurysm, there was a strong and widespread uptake of USPIO extending beyond the aortic wall. CONCLUSIONS: Uptake of USPIO in abdominal aortic aneurysms identifies cellular inflammation and appears to distinguish those patients with more rapidly progressive abdominal aortic aneurysm expansion. This technique holds major promise as a new method of risk-stratifying patients with abdominal aortic aneurysms that extends beyond the simple anatomic measure of aneurysm diameter. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00794092. PMID- 21304071 TI - The cover. Incense of a new church. PMID- 21304072 TI - A piece of my mind. Life imitates work. PMID- 21304073 TI - Electric pulses help with chemotherapy, may open new paths for other agents. PMID- 21304074 TI - Lifestyle changes key to cut stroke risk: guidelines place emergency physicians on front line. PMID- 21304075 TI - Stroke increase reported in HIV patients. PMID- 21304076 TI - Diet and physical activity interventions in severely obese adults. PMID- 21304077 TI - Diet and physical activity interventions in severely obese adults. PMID- 21304078 TI - KRAS genotypes and outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. PMID- 21304079 TI - KRAS genotypes and outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. PMID- 21304080 TI - KRAS genotypes and outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. PMID- 21304081 TI - Physicians on Twitter. PMID- 21304082 TI - Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. AB - CONTEXT: Sentinel lymph node dissection (SLND) accurately identifies nodal metastasis of early breast cancer, but it is not clear whether further nodal dissection affects survival. OBJECTIVE: To determine the effects of complete axillary lymph node dissection (ALND) on survival of patients with sentinel lymph node (SLN) metastasis of breast cancer. DESIGN, SETTING, AND PATIENTS: The American College of Surgeons Oncology Group Z0011 trial, a phase 3 noninferiority trial conducted at 115 sites and enrolling patients from May 1999 to December 2004. Patients were women with clinical T1-T2 invasive breast cancer, no palpable adenopathy, and 1 to 2 SLNs containing metastases identified by frozen section, touch preparation, or hematoxylin-eosin staining on permanent section. Targeted enrollment was 1900 women with final analysis after 500 deaths, but the trial closed early because mortality rate was lower than expected. INTERVENTIONS: All patients underwent lumpectomy and tangential whole-breast irradiation. Those with SLN metastases identified by SLND were randomized to undergo ALND or no further axillary treatment. Those randomized to ALND underwent dissection of 10 or more nodes. Systemic therapy was at the discretion of the treating physician. MAIN OUTCOME MEASURES: Overall survival was the primary end point, with a noninferiority margin of a 1-sided hazard ratio of less than 1.3 indicating that SLND alone is noninferior to ALND. Disease-free survival was a secondary end point. RESULTS: Clinical and tumor characteristics were similar between 445 patients randomized to ALND and 446 randomized to SLND alone. However, the median number of nodes removed was 17 with ALND and 2 with SLND alone. At a median follow-up of 6.3 years (last follow-up, March 4, 2010), 5-year overall survival was 91.8% (95% confidence interval [CI], 89.1%-94.5%) with ALND and 92.5% (95% CI, 90.0%-95.1%) with SLND alone; 5-year disease-free survival was 82.2% (95% CI, 78.3%-86.3%) with ALND and 83.9% (95% CI, 80.2%-87.9%) with SLND alone. The hazard ratio for treatment-related overall survival was 0.79 (90% CI, 0.56-1.11) without adjustment and 0.87 (90% CI, 0.62-1.23) after adjusting for age and adjuvant therapy. CONCLUSION: Among patients with limited SLN metastatic breast cancer treated with breast conservation and systemic therapy, the use of SLND alone compared with ALND did not result in inferior survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00003855. PMID- 21304083 TI - Maternal HIV infection and antibody responses against vaccine-preventable diseases in uninfected infants. AB - CONTEXT: Altered immune responses might contribute to the high morbidity and mortality observed in human immunodeficiency virus (HIV)-exposed uninfected infants. OBJECTIVE: To study the association of maternal HIV infection with maternal- and infant-specific antibody levels to Haemophilus influenzae type b (Hib), pneumococcus, Bordetella pertussis antigens, tetanus toxoid, and hepatitis B surface antigen. DESIGN, SETTING, AND PARTICIPANTS: A community-based cohort study in Khayelitsha, Western Cape Province, South Africa, between March 3, 2009, and April 28, 2010, of 109 HIV-infected and uninfected women and their infants. Serum samples from 104 women and 100 infants were collected at birth and samples from 93 infants were collected at 16 weeks. MAIN OUTCOME MEASURE: Level of specific antibody in mother-infant pairs at delivery and in infants at 16 weeks, determined by enzyme-linked immunosorbent assays. RESULTS: At birth, HIV-exposed uninfected infants (n = 46) had lower levels of specific antibodies than unexposed infants (n = 54) did to Hib (0.37 [interquartile range {IQR}, 0.22 0.67] mg/L vs 1.02 [IQR, 0.34-3.79] mg/L; P < .001), pertussis (16.07 [IQR, 8.87 30.43] Food and Drug Administration [FDA] U/mL vs 36.11 [IQR, 20.41-76.28] FDA U/mL; P < .001), pneumococcus (17.24 [IQR, 11.33-40.25] mg/L vs 31.97 [IQR, 18.58 61.80] mg/L; P = .02), and tetanus (0.08 [IQR, 0.03-0.39] IU/mL vs 0.24 [IQR, 0.08-0.92] IU/mL; P = .006). Compared with HIV-uninfected women (n = 58), HIV infected women (n = 46) had lower specific antibody levels to Hib (0.67 [IQR, 0.16-1.54] mg/L vs 1.34 [IQR, 0.15-4.82] mg/L; P = .009) and pneumococcus (33.47 [IQR, 4.03-69.43] mg/L vs 50.84 [IQR, 7.40-118.00] mg/L; P = .03); however, no differences were observed for antipertussis or antitetanus antibodies. HIV exposed uninfected infants (n = 38) compared with HIV-unexposed infants (n = 55) had robust antibody responses following vaccination, with higher antibody responses to pertussis (270.1 [IQR, 84.4-355.0] FDA U/mL vs 91.7 [IQR, 27.9 168.4] FDA U/mL; P = .006) and pneumococcus (47.32 [IQR, 32.56-77.80] mg/L vs 14.77 [IQR, 11.06-41.08] mg/L; P = .001). CONCLUSION: Among South African infants, antenatal HIV exposure was associated with lower specific antibody responses in exposed uninfected infants compared with unexposed infants at birth, but with robust responses following routine vaccination. PMID- 21304084 TI - Association of myocardial enzyme elevation and survival following coronary artery bypass graft surgery. AB - CONTEXT: Several small studies have suggested that cardiac enzyme elevation in the 24 hours following coronary artery bypass graft (CABG) surgery is associated with worse prognosis, but a definitive study is not available. Also, the long term prognostic impact of small increases of perioperative enzyme has not been reported. OBJECTIVE: To quantify the relationship between peak post-CABG elevation of biomarkers of myocardial damage and early, intermediate-, and long term mortality, including determining whether there is a threshold below which elevations lack prognostic significance. DATA SOURCES: Studies (randomized clinical trials or registries) of patients undergoing CABG surgery in which postprocedural biomarker and mortality data were collected and included. A search of the PubMed database was performed in July 2008 using the search terms coronary artery bypass, troponin, CK-MB, and mortality. STUDY SELECTION: Studies evaluating mortality and creatine kinase (CK-MB), troponin, or both were included. One study investigator declined to participate and 3 had insufficient data. DATA EXTRACTION: Two independent reviewers determined study eligibility. The principal investigator from each eligible study was contacted to request his/her participation. Once institutional review board approval for the use of these data for this purpose was obtained, we requested patient-level data from each source. Data were examined to ensure that cardiac markers had been measured within 24 hours after CABG surgery, key baseline covariates, and mortality were available. RESULTS: A total of 18,908 patients from 7 studies were included. Follow-up varied from 3 months to 5 years. Mortality was found to be a monotonically increasing function of the CK-MB ratio. The 30-day mortality rates by categories of CK-MB ratio were 0.63% (95% confidence interval [CI], 0.36% 1.02%) for 0 to <1, 0.86% (95% CI, 0.49%-1.40%) for 1 to <2, 0.95% (95% CI, 0.72% 1.22%) for 2 to <5, 2.09% (95% CI, 1.69%-2.57%) for 5 to <10, 2.78% (95% CI, 2.12%-3.58%) for 10 to <20, and 7.06% (95% CI, 5.46%-8.96%) for 20 to >=40. Of the variables considered, the CK-MB ratio was the strongest independent predictor of death to 30 days and remained significant even after adjusting for a wide range of baseline risk factors (chi(2) = 143, P < .001; hazard ratio [HR] for each 5 point-increment above the upper limits of normal [ULN] = 1.12; 95% CI, 1.10-1.14). This result was strongest at 30 days, but the adjusted association persisted from 30 days to 1 year (chi(2) = 24; P < .001; HR for each 5-point increment above ULN = 1.17; 95% CI, 1.10-1.24) and a trend was present from 1 year to 5 years (chi(2) = 2.8; P = .10; HR for each 5-point increment above ULN = 1.05; 95% CI, 0.99-1.11). Similar analyses using troponin as the marker of necrosis led to the same conclusions (chi(2) = 142 for 0-30 days and chi(2) = 40 for 30 days to 6 months, both P < .001; HR for each 50 points above the ULN = 1.28; 95% CI, 1.23-1.33 and 1.15; 95% CI, 1.10-1.21, respectively). CONCLUSIONS: Among patients who had undergone CABG surgery, elevation of CK-MB or troponin levels within the first 24 hours was independently associated with increased intermediate- and long-term risk of mortality. PMID- 21304085 TI - A cautious path forward on accountable care organizations. PMID- 21304086 TI - The clinical research enterprise: time to change course? PMID- 21304087 TI - Management of axillary lymph node metastasis in breast cancer: making progress. PMID- 21304090 TI - JAMA patient page. Kidney transplantation. PMID- 21304091 TI - The cost-effectiveness of percutaneous coronary intervention as a function of angina severity in patients with stable angina. AB - BACKGROUND: The COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial compared percutaneous coronary intervention (PCI) plus optimal medical therapy (OMT) to OMT alone in reducing the risk of cardiovascular events in 2287 patients with stable coronary disease. We examined the cost-effectiveness of PCI as a function of angina severity at the time of randomization. METHODS AND RESULTS: Angina severity was assessed with the Seattle Angina Questionnaire (SAQ). Patients were grouped into tertiles based on the distribution of baseline scores such that higher tertiles represented better health status. Clinically significant improvement from baseline within individual patients was defined as score increases of >8 for physical limitation, >20 for angina frequency, and >16 for quality-of-life domains. The incremental cost effectiveness ratio for PCI was calculated as the difference in costs divided by the difference in proportion of patients with clinically significant improvement. Improvement in angina severity was significantly greater for PCI patients in the lowest and middle tertiles. The number of patients needed to treat was much larger for the highest tertile. The added in-trial cost of PCI ranged from $7300 to $13 000. Incremental cost-effectiveness ratios ranged from $80 000 to $330 000 for the lowest and middle tertiles and from $520 000 to >$3 million for the highest tertile for 1 additional patient to achieve significant clinical improvement in health status. CONCLUSIONS: The incremental cost of PCI to provide meaningful clinical benefit above that achieved by OMT alone was lower for patients with severe angina than for those with mild or no angina. However, it is uncertain that at any level of angina severity that PCI as an initial strategy would achieve a socially acceptable cost threshold. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00007657. PMID- 21304092 TI - Trends in coronary revascularization in the United States from 2001 to 2009: recent declines in percutaneous coronary intervention volumes. AB - BACKGROUND: There is speculation that the volume of percutaneous coronary interventions (PCIs) has been decreasing over the past several years. Published studies of PCI volume have evaluated regional or hospital trends, but few have captured national data. This study describes the use of coronary angiography and revascularization methods in Medicare patients from 2001 to 2009. METHODS AND RESULTS: This retrospective study used data from the Centers for Medicare & Medicaid Services from 2001 to 2009. The annual number of coronary angiograms, PCI, intravascular ultrasound, fractional flow reserve, and coronary artery bypass graft (CABG) surgery procedures were determined from billing data and adjusted for the number of Medicare recipients. From 2001 to 2009, the average year-to-year increase for PCI was 1.3% per 1000 beneficiaries, whereas the mean annual decrease for CABG surgery was 5%. However, the increase in PCI volume occurred primarily from 2001 to 2004, as there was a mean annual rate of decline of 2.5% from 2004 to 2009; similar trends were seen with diagnostic angiography. The use of intravascular ultrasound and fractional flow reserve steadily increased over time. CONCLUSIONS: This study confirms recent speculation that PCI volume has begun to decrease. Although rates of CABG have waned for several decades, all forms of coronary revascularization have been declining since 2004. PMID- 21304093 TI - Use of a screening tool improves appropriate referral to an electrophysiologist for implantable cardioverter-defibrillators for primary prevention of sudden cardiac death. AB - BACKGROUND: Despite data showing the benefits of implantable cardioverter defibrillator (ICD) insertion for primary prevention in populations at risk for sudden death, professional society guidelines recommending primary prevention, and recognition by payers of the clinical value of ICDs in these populations, ICDs for primary prevention remain underused. We sought to determine whether implementing a screening tool would increase appropriate identification of patients showing clinical evidence of ICD benefit and prompt referral to an electrophysiologist for ICD implantation. METHODS AND RESULTS: Screening tools were affixed to medical records for patients seen in 2 outpatient cardiology offices that queried ejection fraction and whether referral to an electrophysiologist was made (N=6632). The number of appropriate referrals in the screening period were compared with analogous data collected before implementation of the screening tool (control period) through retrospective record review (n=3606). Significantly more eligible patients were offered referral during the screening period than during the control period at both sites, 80% (8/10 eligible) versus 33% (5/15) at site 1 (P<0.02) and 100% (44/44) versus 60% (21/35) at site 2 (P<0.001). Of all patients offered referral, 41% (32/78) accepted. CONCLUSIONS: The use of a screening tool increases referral to electrophysiology for patients in whom placement of an ICD confers the benefit of sudden cardiac death primary prevention. Barriers to referral include both physician and patient factors. Verification of these findings on a larger scale as well as studies defining the foundation of these barriers may further improve use of ICDs in patients for whom their mortality benefit is well described. PMID- 21304094 TI - The impact of postrandomization crossover of therapy in acute coronary syndromes care. AB - BACKGROUND: In the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) study, patients assigned enoxaparin or unfractionated heparin (UFH) were treated with alternative anticoagulant therapy after randomization at physician discretion, a practice made possible because the trial was open label. Using SYNERGY as an example, we demonstrate the difficulty of evaluating the effect of postrandomization events in clinical trials and discuss possible methodology. METHODS AND RESULTS: Patients with and without postrandomization crossovers were characterized and event rates analyzed. Statistical modeling was performed using inverse probability weighting and landmark analyses to evaluate the potential impact of postrandomization crossovers on event rates and treatment effect. Of 9978 SYNERGY patients, 9613 (96.3%) received at least 1 dose of randomized therapy and are included in these analyses. Of these, 740 (7.7%; 554 enoxaparin; 186 UFH) had postrandomization crossover. Crossover patients had higher unadjusted rates of 30 day death/myocardial infarction (MI) (18.9% versus 14.0%), thrombolysis in MI (TIMI) bleeding (16.9% versus 7.6%), Global Use of Strategies to Open Occluded Coronary Arteries bleeding (4.5% versus 2.3%), and transfusions (32.3% versus 15.2%). Adjustment for timing of crossover relative to the events attenuated the difference noted in death/MI but accentuated the association with TIMI bleeding. After adjustment using the inverse probability weighting technique, only a modest difference in the absolute treatment effect was observed between enoxaparin and UFH on death/MI (0.6% [unadjusted] versus 0.8% [adjusted]) and TIMI major bleeding (1.5% [unadjusted] versus 1.0% [adjusted]). The landmark analysis indicated a significant association between crossover from enoxaparin to UFH and TIMI bleeding but not in the other direction, and no crossover association was found in death/MI. CONCLUSIONS: Postrandomization events in clinical trials are accompanied by substantial confounders that require careful consideration. In SYNERGY, postrandomization crossovers occurred in nearly 10% of patients, abetted by the open-label trial design. These patients had increased incidence of bleeding and death/MI, but after adjustment using several modeling techniques, only a modest impact of postrandomization crossovers on treatment effect was observed. The usual methods of analyzing end points cannot adequately address biases in changing treatment in these patients. The potential biases of membership in a postrandomization subgroup, as well as the methods used to account for the biases, should be considered when weighing the strength of results. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00043784. PMID- 21304095 TI - Racial differences in incident heart failure during antihypertensive therapy. AB - BACKGROUND: Blacks have a higher prevalence of heart failure (HF) than nonblacks, possibly reflecting a greater burden of HF risk factors, including hypertension. Although HF incidence is significantly higher in blacks during long-term follow up of young adults, the relationship of incident HF to race in hypertensive patients undergoing treatment is unclear. METHODS AND RESULTS: Incident HF was evaluated in 497 black and 8199 nonblack hypertensive patients with no history of HF randomly assigned to losartan- or atenolol-based treatment. During 4.7+/-1.1 years mean follow-up, HF hospitalization occurred in 265 patients (3.0%); 5-year HF incidence was significantly greater in black than nonblack patients (7.0 versus 3.1%, P<0.001). In Cox multivariate analyses adjusting for randomized treatment, age, sex, the presence of the strain pattern on the baseline ECG, and other HF risk factors treated as standard covariates, and for incident myocardial infarction, in-treatment QRS duration, diastolic and systolic pressure, Cornell product, and Sokolow-Lyon voltage criteria for left ventricular hypertrophy (LVH) treated as time-varying covariates, black race remained associated with a 130% increased risk of developing new HF (hazard ratio 2.30, 95% confidence interval 1.24 to 4.28). CONCLUSIONS: Incident HF is substantially more common among black than nonblack hypertensive patients. The increased risk of developing new HF in blacks persists after adjusting for the higher prevalence of HF risk factors in blacks, for treatment effects and in-treatment blood pressure, and for the known predictive value of the ECG strain pattern and in-treatment ECG LVH and QRS duration for incident HF in this population. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00338260. PMID- 21304096 TI - Guideline-discordant periprocedural interruptions in warfarin therapy. AB - BACKGROUND: Periprocedural interruptions in warfarin therapy increase thromboembolic risks to patients and are not indicated for all procedures. We sought to determine the frequency and guideline concordance of periprocedural warfarin interruptions to inform a future educational intervention. METHODS AND RESULTS: In October and November of 2009, an anonymous postal survey was sent to all patients followed for more than 1 year by the University of Michigan Anticoagulation service. Patients were asked how many times in the prior year they were requested to interrupt warfarin therapy for a medical or dental procedure or test and the specific indication for the requested interruption in warfarin therapy. A total of 1686 of 2133 (79%) subjects responded. The mean age of respondents was 69 years (SD=14 years). The majority were men (56%) and white (93%). Atrial fibrillation was the most common indication for warfarin therapy (n=966, 57%). At least 1 request to interrupt warfarin therapy in the prior year was given by 819 of 1648 (50%) respondents, including 481 of the 947 (51%) respondents taking warfarin for atrial fibrillation. Forty-eight percent of requests to interrupt warfarin among all respondents and 50% of requests to interrupt warfarin among those taking warfarin, specifically for atrial fibrillation, were for indications not supported by guideline statements. CONCLUSIONS: Periprocedural requests to interrupt warfarin therapy are common and are often discordant with current guidelines. Educational interventions may decrease risk of periprocedural thromboembolic complications. PMID- 21304097 TI - Mortality implications of primary percutaneous coronary intervention treatment delays: insights from the Assessment of Pexelizumab in Acute Myocardial Infarction trial. AB - BACKGROUND: Prior studies demonstrate a direct relationship between treatment delays to primary percutaneous intervention and mortality in patients with ST segment elevation myocardial infarction (STEMI). This analysis compared the relationship of symptom onset-to-balloon time and door-to-balloon time on mortality in patients with STEMI. METHODS AND RESULTS: We analyzed different treatment delays (symptom onset-to-balloon time, door-to-balloon time) and mortality in 5745 STEMI patients. Baseline characteristics, flow grade, 90-day mortality, and clinical outcomes were compared in patients stratified by treatment delay. Multivariable logistic regression modeling was performed to assess the independent and relative effect of each treatment delay on 90-day mortality. Female sex, increased age, and worse thrombolysis in myocardial infarction flow grade were significantly associated with longer symptom onset-to balloon times and door-to-balloon times. Longer symptom onset-to-balloon time was significantly associated with worse 90-day mortality (3.7%, 4.2%, and 6.5% for time delays <3 hours, 3 to 5 hours, and >5 hours, respectively, P<0.0001). Similarly, longer door-to-balloon times were significantly associated with worse 90-day mortality (3.2%, 4.0%, 4.6%, and 5.3% for delays <60 minutes, 60 to 90 minutes, 90 to 120 minutes, and >=120 minutes respectively, P<0.0001). In a multivariate model of 90-day mortality, door-to-balloon time (chi(2) 6.0, P<0.014), and symptom onset-to-hospital arrival (chi(2) 9.8, P<0.007) remained independent determinants. CONCLUSIONS: Both symptom onset-to-balloon time and hospital door-to-balloon time are strongly associated with 90-day mortality following STEMI. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00091637. PMID- 21304098 TI - Extent of and reasons for nonuse of implantable cardioverter defibrillator devices in clinical practice among eligible patients with left ventricular systolic dysfunction. AB - BACKGROUND: Several studies that used claims and registry data have reported that 40% to 80% of patients eligible for an implantable cardioverter defibrillator (ICD) fail to receive one in clinical practice, and the rates are especially high among women and blacks. The extent and documented reasons for nonuse of ICDs among patients with left ventricular systolic dysfunction are unknown. METHODS AND RESULTS: Using hospital claims and clinical data, we identified patients hospitalized with a heart failure diagnosis and left ventricular ejection fraction <=30% between January 1, 2007, and August 30, 2007, at a tertiary-care center. Using claims data, we determined placement of an ICD or cardiac resynchronization therapy with defibrillation device at any time up to 1 year after hospitalization. Medical records for patients without an ICD were abstracted to determine reasons for nonuse. Patients with an ICD were compared with patients without an ICD and also with patients without an ICD who did not have any contraindication for an ICD as identified through chart abstraction. Of the 542 potentially eligible patients identified, 224 (41%) did not have an ICD. In the initial adjusted analysis, female sex (odds ratio=1.90; 95% CI, 1.28 to 2.81) and increasing age (odds ratio=1.07; 95% CI, 1.04 to 1.11) were associated with a higher likelihood of not having an ICD. After detailed chart review, of the 224 patients without an ICD, 117 (52%) were ineligible for the device and 38 (17%) patients refused the device, resulting in only 69 (13%) patients eligible for an ICD who failed to receive one. In this subsequent adjusted analysis, remaining factors associated with a higher likelihood of not having an ICD were absence of ventricular arrhythmias (odds ratio=4.93; 95% CI, 2.56 to 9.50), noncardiology hospital service (odds ratio=3.73; 95% CI, 1.98 to 7.04), and lack of health insurance (odds ratio=3.10; 95% CI, 1.48 to 6.46). CONCLUSIONS: On the basis of a detailed chart review, the true rate of ICD underuse may be substantially lower than previous estimates. In addition, after accounting for ICD eligibility criteria, patient sex and age disparities in ICD therapy were no longer present. PMID- 21304099 TI - Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. AB - More than any other cytokine family, the IL-1 family of ligands and receptors is primarily associated with acute and chronic inflammation. The cytosolic segment of each IL-1 receptor family member contains the Toll-IL-1-receptor domain. This domain is also present in each Toll-like receptor, the receptors that respond to microbial products and viruses. Since Toll-IL-1-receptor domains are functional for both receptor families, responses to the IL-1 family are fundamental to innate immunity. Of the 11 members of the IL-1 family, IL-1beta has emerged as a therapeutic target for an expanding number of systemic and local inflammatory conditions called autoinflammatory diseases. For these, neutralization of IL 1beta results in a rapid and sustained reduction in disease severity. Treatment for autoimmune diseases often includes immunosuppressive drugs whereas neutralization of IL-1beta is mostly anti-inflammatory. Although some autoinflammatory diseases are due to gain-of-function mutations for caspase-1 activity, common diseases such as gout, type 2 diabetes, heart failure, recurrent pericarditis, rheumatoid arthritis, and smoldering myeloma also are responsive to IL-1beta neutralization. This review summarizes acute and chronic inflammatory diseases that are treated by reducing IL-1beta activity and proposes that disease severity is affected by the anti-inflammatory members of the IL-1 family of ligands and receptors. PMID- 21304100 TI - Developmental differences in megakaryocytopoiesis are associated with up regulated TPO signaling through mTOR and elevated GATA-1 levels in neonatal megakaryocytes. AB - Multiple observations support the existence of developmental differences in megakaryocytopoiesis. We have previously shown that neonatal megakaryocyte (MK) progenitors are hyperproliferative and give rise to MKs smaller and of lower ploidy than adult MKs. Based on these characteristics, neonatal MKs have been considered immature. The molecular mechanisms underlying these differences are unclear, but contribute to the pathogenesis of disorders of neonatal megakaryocytopoiesis. In the present study, we demonstrate that low-ploidy neonatal MKs, contrary to traditional belief, are more mature than adult low ploidy MKs. These mature MKs are generated at a 10-fold higher rate than adult MKs, and result from a developmental uncoupling of proliferation, polyploidization, and terminal differentiation. This pattern is associated with up-regulated thrombopoietin (TPO) signaling through mammalian target of rapamycin (mTOR) and elevated levels of full-length GATA-1 and its targets. Blocking of mTOR with rapamycin suppressed the maturation of neonatal MKs without affecting ploidy, in contrast to the synchronous inhibition of polyploidization and cytoplasmic maturation in adult MKs. We propose that these mechanisms allow fetuses/neonates to populate their rapidly expanding bone marrow and intravascular spaces while maintaining normal platelet counts, but also set the stage for disorders restricted to fetal/neonatal MK progenitors, including the Down syndrome-transient myeloproliferative disorder and the thrombocytopenia absent radius syndrome. PMID- 21304101 TI - Development of an IL-15-autocrine CD8 T-cell leukemia in IL-15-transgenic mice requires the cis expression of IL-15Ralpha. AB - IL-15 has growth-promoting effects on select lymphoid subsets, including natural killer (NK) cells, NK T cells, intraepithelial lymphocytes (IELs), CD8 T cells, and gammadelta-T cells. Constitutive expression of murine IL-15 in IL-15 transgenic mice was reported to cause T-NK leukemia. We investigated whether IL 15 expression is sufficient for leukemic transformation using a human IL-15 transgenic (IL-15Tg) mouse model. We noted that 100% of the mice observed over a 2-year period (n > 150) developed fatal expansions of CD8 T cells with NK markers, and determined that these cells expressed IL-15 receptor alpha (IL 15Ralpha). The expression of IL-15Ralpha on CD8 T cells appears to be required for uncontrolled aggressive lymphoproliferation, because none of the IL-15Ralpha( /-)-IL-15Tg mice that we followed for more than 2 years developed the fatal disease despite controlled expansion of CD8 T cells. In addition, in contrast to IL-15Tg mice, in which leukemia-like CD8 T cells expressed IL-15Ralpha persistently, acutely activated normal CD8 T cells only transiently expressed IL 15Ralpha. Inhibition of DNA methylation enabled sustained IL-15Ralpha expression induced by activation. We present a scenario for IL-15Tg mice in which CD8 T cells that acquire constitutive persistent IL-15Ralpha expression are at a selective advantage and become founder cells, outgrow other lymphocytes, and lead to the establishment of a leukemia-like condition. PMID- 21304102 TI - Dendritic cells with lymphocyte-stimulating activity differentiate from human CD133 positive precursors. AB - CD133 is a hallmark of primitive myeloid progenitors. We have addressed whether human cord blood cells selected for CD133 can generate dendritic cells, and Langerhans cells in particular, in conditions that promote that generation from CD34(+) progenitors. Transforming growth factor-beta1 (TGF-beta1) and anti-TGF beta1 antibody, respectively, were added in some experiments. With TGF-beta, monocytoid cells were recognized after 7 days. Immunophenotypically immature dendritic cells were present at day 14. After 4 more days, the cells expressed CD54, CD80, CD83, and CD86 and were potent stimulators in mixed lymphocyte reaction; part of the cells expressed CD1a and langerin, but not Birbeck granules. Without TGF-beta, only a small fraction of cells acquired a dendritic shape and expressed the maturation-related antigens, and lymphocytes were poorly stimulated. With anti-TGF-beta, the cell growth was greatly hampered, CD54 and langerin were never expressed, and lymphocytes were stimulated weakly. In conclusion, CD133(+) progenitors can give rise in vitro, through definite steps, to mature, immunostimulatory dendritic cells with molecular features of Langerhans cells, although without Birbeck granules. Addition of TGF-beta1 helps to stimulate cell growth and promotes the acquisition of mature immunophenotypical and functional features. Neither langerin nor Birbeck granules proved indispensable for lymphocyte stimulation. PMID- 21304103 TI - T cells redirected against CD70 for the immunotherapy of CD70-positive malignancies. AB - T-cell therapy with genetically modified T cells targeting CD19 or CD20 holds promise for the immunotherapy of hematologic malignancies. These targets, however, are only present on B cell-derived malignancies, and because they are broadly expressed in the hematopoietic system, their targeting may have unwanted consequences. To expand T-cell therapies to hematologic malignancies that are not B cell-derived, we determined whether T cells can be redirected to CD70, an antigen expressed by limited subsets of normal lymphocytes and dendritic cells, but aberrantly expressed by a broad range of hematologic malignancies and some solid tumors. To generate CD70-specific T cells, we constructed a chimeric antigen receptor (CAR) consisting of the CD70 receptor (CD27) fused to the CD3 zeta chain. Stimulation of T cells expressing CD70-specific CARs resulted in CD27 costimulation and recognition of CD70-positive tumor cell lines and primary tumor cells, as shown by IFN-gamma and IL-2 secretion and by tumor cell killing. Adoptively transferred CD70-specific T cells induced sustained regression of established murine xenografts. Therefore, CD70-specific T cells may be a promising immunotherapeutic approach for CD70-positive malignancies. PMID- 21304104 TI - Is normal hematopoiesis maintained solely by long-term multipotent stem cells? AB - The understanding of the hierarchical organization of the human hematopoietic system is of major biologic and clinical significance. The validity of the conventional model in which hematopoiesis is solely maintained by a pool of multipotent long-term hematopoietic stem cells (LT-HSCs) has been recently challenged by several mouse studies. These new data point to the existence of a heterogeneous stem cell population that consists of distinct subsets of LT-HSCs, which include stem cells biased toward lineage-specific differentiation programs. This review attempts to discuss the balanced versus biased patterns of lineage output of human LT-HSCs gathered in 3 different gene therapy trials on the basis of vector integration site analysis by deep sequencing. The distribution of integration sites observed tends to support the validity of the revised model. PMID- 21304106 TI - Histidine-rich glycoprotein binds factor XIIa with high affinity and inhibits contact-initiated coagulation. AB - Histidine-rich glycoprotein (HRG) circulates in plasma at a concentration of 2MUM and binds plasminogen, fibrinogen, and thrombospondin. Despite these interactions, the physiologic role of HRG is unknown. Previous studies have shown that mice and humans deficient in HRG have shortened plasma clotting times. To better understand this phenomenon, we examined the effect of HRG on clotting tests. HRG prolongs the activated partial thromboplastin time in a concentration dependent fashion but has no effect on tissue factor-induced clotting, localizing its effect to the contact pathway. Plasma immunodepleted of HRG exhibits a shortened activated partial thromboplastin time that is restored to baseline with HRG replenishment. To explore how HRG affects the contact pathway, we examined its binding to factors XII, XIIa, XI, and XIa. HRG binds factor XIIa with high affinity, an interaction that is enhanced in the presence of Zn2(+), but does not bind factors XII, XI, or XIa. In addition, HRG inhibits autoactivation of factor XII and factor XIIa-mediated activation of factor XI. These results suggest that, by binding to factor XIIa, HRG modulates the intrinsic pathway of coagulation, particularly in the vicinity of a thrombus where platelet release of HRG and Zn2(+) will promote this interaction. PMID- 21304105 TI - Mechanisms of enhanced thrombus formation in cerebral microvessels of mice expressing hemoglobin-S. AB - The microvasculature assumes an inflammatory and procoagulant state in a variety of different diseases, including sickle cell disease (SCD), which may contribute to the high incidence of ischemic stroke in these patients. This study provides evidence for accelerated thrombus formation in arterioles and venules in the cerebral vasculature of mice that express hemoglobin-S (beta(s) mice). Enhanced microvascular thrombosis in beta(s) mice was blunted by immunologic or genetic interventions that target tissue factor, endothelial protein C receptor, activated protein C, or thrombin. Platelets from beta(s) mice also exhibited enhanced aggregation velocity after stimulation with thrombin but not ADP. Neutropenia also protected against the enhanced thrombosis response in beta(s) mice. These results indicate that the cerebral microvasculature is rendered vulnerable to thrombus formation in beta(s) mice via a neutrophil-dependent mechanism that is associated with an increased formation of and enhanced platelet sensitivity to thrombin. PMID- 21304108 TI - A possible case of minimal hepatic encephalopathy treated successfully with lactulose. PMID- 21304107 TI - Density enhanced phosphatase-1 down-regulates urokinase receptor surface expression in confluent endothelial cells. AB - VEGF(165), the major angiogenic growth factor, is known to activate various steps in proangiogenic endothelial cell behavior, such as endothelial cell migration and invasion, or endothelial cell survival. Thereby, the urokinase-type plasminogen activator (uPA) system has been shown to play an essential role not only by its proteolytic capacities, but also by induction of intracellular signal transduction. Therefore, expression of its cell surface receptor uPAR is thought to be an essential regulatory mechanism in angiogenesis. We found that uPAR expression on the surface of confluent endothelial cells was down-regulated compared with subconfluent proliferating endothelial cells. Regulation of uPAR expression was most probably affected by extracellular signal-regulated kinase 1/2 (ERK1/2) activation, a downstream signaling event of the VEGF/VEGF-receptor system. Consistently, the receptor-like protein tyrosine phosphatase DEP-1 (density enhanced phosphatase-1/CD148), which is abundantly expressed in confluent endothelial cells, inhibited the VEGF-dependent activation of ERK1/2, leading to down-regulation of uPAR expression. Overexpression of active ERK1 rescued the DEP-1 effect on uPAR. That DEP-1 plays a biologic role in angiogenic endothelial cell behavior was demonstrated in endothelial cell migration, proliferation, and capillary-like tube formation assays in vitro. PMID- 21304109 TI - Association of STAI and SDS scores with 8-hydroxydeoxyguanosine and serotonin levels in young women with depressive symptoms. PMID- 21304110 TI - Schizophrenia-like alcoholic dementia or dementia praecox. PMID- 21304111 TI - Significant increase in plasma thyroid-stimulating hormone during low-frequency repetitive transcranial magnetic stimulation. PMID- 21304112 TI - Neuroleptic malignant syndrome induced by blonanserin. PMID- 21304114 TI - Of postures, mirrors, and models in catatonia. PMID- 21304113 TI - Paliperidone-induced neuroleptic malignant syndrome. PMID- 21304115 TI - Voltage-gated sodium channel gating modifiers: valuable targets for multiple sclerosis treatment. PMID- 21304116 TI - Rapid control of manic symptoms during combination of electroconvulsive therapy and lithium. PMID- 21304117 TI - Sertraline-induced apathy syndrome. PMID- 21304118 TI - Pathological gambling in a bipolar patient treated with pramipexole. PMID- 21304119 TI - Manic symptoms associated with Hashimoto's encephalopathy: response to corticosteroid treatment. PMID- 21304120 TI - Valproate-induced encephalopathy related to concurrent antimanic medications. PMID- 21304121 TI - A case of nonfluent aphasia treated successfully with speech therapy and adjunctive mixed amphetamine salts. PMID- 21304122 TI - A case of paraneoplastic limbic encephalitis during the course of depression. PMID- 21304123 TI - Tourette's syndrome and type 2 bipolar disorder. PMID- 21304124 TI - A case of crying seizures. PMID- 21304125 TI - Catatonia as the initial presenting feature of subacute sclerosing panencephalitis. PMID- 21304126 TI - Lamotrigine reduces craving and depressive symptoms in cocaine dependence. PMID- 21304127 TI - Kleine-Levin syndrome and response to modafinil in a young woman. PMID- 21304128 TI - Trazodone ameliorates nightmares in major depressive disorder. PMID- 21304129 TI - Worsening mania associated with slow increase of quetiapine dose. PMID- 21304130 TI - Rapid weight gain during mirtazapine treatment. PMID- 21304131 TI - Impulsive cross-dressing in Parkinson's disease treated with ropinerole. PMID- 21304132 TI - The persistence of the "organic" problem. PMID- 21304133 TI - Developmental origins for neuropsychiatric illness. PMID- 21304134 TI - A review of the brain structure correlates of successful cognitive aging. AB - Unimpaired cognition is an important feature of successful aging. Differences in cognitive performance among healthy older adults may be related to differences in brain structure. The authors reviewed the literature to examine the relationship between brain-structure size and cognitive performance in older adults. Eighty three percent of studies found at least one positive relationship between these factors; however, findings were variable. Positive relationships emerged most consistently between the hippocampal formation and global cognition and memory and between frontal measures and executive function. Additional longitudinal study is needed to further evaluate structure-cognition relationships in older adulthood and across the adult lifespan. PMID- 21304135 TI - Does PTSD impair cognition beyond the effect of trauma? AB - This systematic review analyzed data from studies examining memory and cognitive function in subjects with posttraumatic stress disorder (PTSD), compared with subjects exposed to trauma (but without PTSD). Based on analysis of 21 articles published in English from 1968 to 2009, the conclusion is that individuals with PTSD, particularly veterans, show signs of cognitive impairment when tested with neuropsychological instruments, more so than individuals exposed to trauma who do not have PTSD. PMID- 21304136 TI - Anxiety disorders in children and adolescents in the first six months after traumatic brain injury. AB - The study's objective was to assess the nature, rate, predictive factors, and neuroimaging correlates of novel (new-onset) definite anxiety disorders and novel definite/subclinical anxiety disorders (in a broader group of children with at least subclinical anxiety disorders) after traumatic brain injury (TBI). Children with TBI from consecutive admissions to five trauma centers were enrolled and studied with psychiatric interviews soon after injury (baseline) and again 6 months post-injury. Novel definite anxiety disorder and novel definite/subclinical anxiety disorders were heterogeneous and occurred in 8.5% (N=12) and 17% (N=24) of participants, respectively, in the first 6 months after injury. Novel definite anxiety disorder was significantly associated with younger age at injury and tended to be associated with novel depressive disorder, as well as lesions of the superior frontal gyrus. Novel definite/subclinical anxiety disorder was significantly associated with concurrent psychiatric problems of personality change due to TBI and novel definite/subclinical depressive disorder, as well as with lesions of the superior frontal gyrus and a trend-association with frontal lobe white-matter lesions. These findings suggest that anxiety after childhood TBI may be part of a broader problem of affective dysregulation related to damaged dorsal frontal lobe and frontal white-matter systems, with younger children being at greatest risk for developing novel anxiety disorder after TBI. PMID- 21304137 TI - Repetitive transcranial magnetic stimulation and threat memory: selective reduction of combat threat memory p300 response after right frontal-lobe stimulation. AB - Using the event-related potential P3a component as a marker, the authors tested the efficacy of repetitive transcranial magnetic stimulation (rTMS) for reducing hyperarousability to specific threat stimuli in one Vietnam veteran with chronic posttraumatic stress disorder (PTSD), who exhibited an exaggerated P3a response to combat-related pictures. Twenty minutes of 1-Hz rTMS to the right prefrontal area effected a reduction in the P3a amplitude, whereas similar rTMS to the left prefrontal area did not. In addition to providing evidence for the effectiveness of right frontal rTMS for an exaggerated response to trauma-related stimuli, this study provides electrophysiological corroboration of subjective reports of PTSD symptoms. PMID- 21304138 TI - The parkinsonian personality and concomitant depression. AB - Parkinson's disease (PD) has been associated with a distinctive parkinsonian personality, characterized by conscientiousness, punctuality, industriousness, and reduced novelty-seeking, as compared with healthy elderly persons. Similar traits are identified in relation to depression. The objective of the study was to elucidate the relationship between the parkinsonian personality and depression. Thirty-two depressed and 86 nondepressed PD patients and 30 healthy control subjects completed the NEO-Personality Inventory Revised Short Version. PD patients with depression displayed a distinct personality profile, with increased Neuroticism and reduced Extroversion, as compared with nondepressed PD patients and control subjects. It seems plausible that a subgroup of PD patients possesses a distinct personality profile that renders them sensitive to development of depression, although the reverse might also be possible. PMID- 21304140 TI - SPECT imaging of dopamine transporters with (99m)Tc-TRODAT-1 in major depression and Parkinson's disease. AB - To investigate dopamine transporter in major depressive disorder and Parkinson's disease, the authors obtained single photon emission computed tomography (SPECT) brain images from 13 patients with major depression, 17 Parkinson's disease patients, and 10 healthy volunteers by using 99mTc-TRODAT-1. The authors found the 99mTc-TRODAT-1 radio signal in the striatum was reduced in the majority of patients with major depressive disorder, and this decrease was even more severe in patients with Parkinson's disease. The results support the hypothesis of dopamine hypofunction in major depressive disorder and suggest that deficient dopamine transporter may be involved in the etiology of severe major depressive disorder. PMID- 21304139 TI - Binge eating in Parkinson's disease: prevalence, correlates and the contribution of deep brain stimulation. AB - Of 96 Parkinson's disease patients surveyed at the University of Florida Movement Disorders Center, one (1%) met diagnostic criteria for binge-eating disorder. Eight (8.3%) exhibited subthreshold binge eating. Psychometric criteria classified problem gambling in 17.8%, hoarding in 8.3%, compulsive buying in 11.5%, hypersexuality in 1.0%, and mania in 1.0% of patients. More overeaters met psychometric criteria for at least one additional impulse-control disorder (67% versus 29%). No more overeaters than non-overeaters were taking a dopamine agonist (44% versus 41%). More overeaters had a history of subthalamic deep brain stimulation (DBS; 44% versus 14%). History of DBS was the only independent predictor of overeating. PMID- 21304141 TI - Soft neurological signs in drug-free people with schizophrenia with and without obsessive-compulsive symptoms. AB - Obsessive-compulsive (OC) symptoms are clinically important phenomena in people with schizophrenia. Schizophrenia and obsessive-compulsive disorder (OCD) are considered as neurodevelopmental disorders with dysfunctional frontal subcortical circuitry. In this cross-sectional study, the authors tested the hypothesis that people with schizophrenia with OC symptoms form a subtype with a distinct neurological substrate. Using the Neurological Evaluation Scale (NES), the authors assessed 65 people with ICD-10 criteria for schizophrenia, 21 of whom had OC symptoms, and who were drug-naive or had not received any antipsychotic or anti-obsessive drugs for the previous 3 months. People with schizophrenia and OC symptoms were better educated than those without OC symptoms and differed significantly in proportion to premorbid OC symptoms, but did not differ on measures of psychopathology. Total NES scores and subgroup scores did not differ significantly between people with schizophrenia with or without OC symptoms, but the groups did differ in motor coordination test scores for the left side. Total NES scores correlated significantly with Positive and Negative Symptom Scales negative symptoms scores in those with OC symptoms but not in those without OC symptoms; this correlation was not observed with Yale-Brown Obsessive-Compulsive Scale scores. These findings, if replicated, suggest that OC symptoms in people with schizophrenia are due to differences in frontocerebellar neurological circuitry from those without OC symptoms, with possible neuro-developmental origins. PMID- 21304143 TI - HIV and age do not substantially interact in HIV-associated neurocognitive impairment. AB - The authors investigated the combined age and HIV effects on cognitive functions in 146 individuals, 116 of whom had HIV infection. Forty-two percent had HIV associated neurocognitive disorder, and all were receiving highly active antiretroviral therapy. Using linear and nonlinear regression modeling, the authors found only a trending effect of the quadratic term HIV status * age, both including dementia cases (p=0.12) and excluding dementia cases (p<0.06). Our results suggest that either this early-2000 cohort is not old enough to detect a clear interactive age and HIV effect or that there may be a survivor bias for individuals with long-term infection. Further longitudinal studies are warranted. PMID- 21304142 TI - Social cognition, executive functioning, and neuroimaging correlates of empathic deficits in frontotemporal dementia. AB - The authors investigated aspects of interpersonal sensitivity and perspective taking in relation to empathy, social cognitions, and executive functioning in 26 frontotemporal dementia (FTD) patients. Behavioral-variant FTD (bvFTD) patients were significantly impaired on caregiver assessments of empathy, although self ratings were normal. Progressive nonfluent aphasia and semantic-dementia samples were rarely abnormal. In bvFTD, empathy ratings were found to be correlated with social cognition and executive functioning measures, but not depression. Voxel based morphometry revealed that reduced empathic perspective-taking was related to bifrontal and left anterior temporal atrophy, whereas empathic emotions were related to right medial frontal atrophy. Findings suggest that bvFTD causes multiple types of breakdown in empathy, social cognition, and executive resources, mediated by frontal and temporal disease. PMID- 21304144 TI - The emerging link between autoimmune disorders and neuropsychiatric disease. AB - Abnormal autoimmune activity has been implicated in a number of neuropsychiatric disorders. In this review, the authors discuss a newly recognized class of synaptic autoimmune encephalitides as well as behavioral and cognitive manifestations of systemic autoimmune diseases. PMID- 21304145 TI - Impact of playing American professional football on long-term brain function. AB - The authors recruited 100 active and former National Football League players, representing 27 teams and all positions. Players underwent a clinical history, brain SPECT imaging, qEEG, and multiple neuropsychological measures, including MicroCog. Relative to a healthy-comparison group, players showed global decreased perfusion, especially in the prefrontal, temporal, parietal, and occipital lobes, and cerebellar regions. Quantitative EEG findings were consistent, showing elevated slow waves in the frontal and temporal regions. Significant decreases from normal values were found in most neuropsychological tests. This is the first large-scale brain-imaging study to demonstrate significant differences consistent with a chronic brain trauma pattern in professional football players. PMID- 21304146 TI - Abnormal structural correlates of response perseveration in individuals with psychopathy. AB - Structural deficits in the frontotemporal network have been shown in individuals with psychopathy and are posited to contribute to neuropsychological impairments such as response perseveration. However, no study to date has examined structural correlates of response perseveration in individuals with psychopathy. In this structural MRI study, the authors found higher correlations between increased response perseveration and reduced cortical thickness in the orbitofrontal and anterior temporal regions in individuals with psychopathy than in healthy comparison subjects. The findings provide preliminary evidence suggesting potential contributions of frontotemporal structural deficits in neurocognitive impairment with perseveration in individuals with psychopathy. PMID- 21304147 TI - Frontal brain oscillatory coupling in children of parents with social phobia: a pilot study. AB - Spectral coupling between delta and beta oscillations has been related to anxiety. The authors provide preliminary evidence that frontal brain oscillatory coupling discriminates children born to socially phobic versus healthy parents, despite there being no difference in parental perceptions of their children's shyness. PMID- 21304148 TI - The efficacy and safety of fentanyl buccal tablet compared with immediate-release oxycodone for the management of breakthrough pain in opioid-tolerant patients with chronic pain. AB - BACKGROUND: Current clinical guidelines have identified the need for studies comparing the effect of different short-acting or rapid-onset opioids for the treatment of breakthrough pain (BTP). In this study we evaluated the efficacy and safety of treatment with fentanyl buccal tablet (FBT) in comparison with immediate-release oxycodone in alleviating BTP in opioid-tolerant patients with chronic pain. METHODS: In this cross-over design study, opioid-tolerant patients were randomized to open-label titration with FBT (200, 400, 600, 800 MUg) followed by oxycodone (15, 30, 45, 60 mg) or vice versa for the management of BTP. After titration to a successful dose of both study drugs, patients were rerandomized to double-blind treatment for 10 BTP episodes with 1 of the already identified successful doses of study drug followed by cross-over to double-blind treatment for 10 BTP episodes with the other study drug. The primary efficacy measure was the difference in pain intensity (based on an 11-point numerical scale) 15 minutes after administration of study drug (PID(15)). Other efficacy measures included PID at other time points postdose (5 through 60 minutes), the sum of pain intensity differences (SPID) at 30 and 60 minutes postdose, pain relief (5 through 60 minutes), proportion of BTP episodes for which patients experienced meaningful reduction in pain intensity, and patient preference for BTP medication. Adverse events were also recorded. RESULTS: Of the 323 patients enrolled, 203 achieved a successful dose of both study drugs, 191 completed the titration phase, and 180 completed the double-blind phase. PID(15) was significantly greater after FBT versus oxycodone (mean [SD], 0.82 [1.12] vs. 0.60 [0.88]; 95% confidence interval [CI] = 0.18, 0.29; P < 0.0001). Secondary efficacy measures favored FBT and showed differences versus oxycodone from 5 minutes postdose for PID and 10 minutes postdose for pain relief. SPID(30) and SPID(60) were greater with FBT than with oxycodone (P < 0.0001 for both measures). A >=33% improvement in pain intensity occurred in a larger proportion of FBT-treated episodes versus oxycodone beginning 15 through 45 minutes postdose (P < 0.05). FBT was preferred by 52% of patients, oxycodone by 33%. Adverse events with both study drugs were generally typical of opioids, and the majority occurred during titration. Two serious adverse events (pneumonia) were reported in 1 patient; both occurrences were considered unrelated to study drug. CONCLUSION: FBT resulted in more rapid onset of analgesia and was generally well tolerated in comparison with oxycodone for the treatment of BTP in opioid tolerant patients. PMID- 21304149 TI - A systematic review of third-generation hydroxyethyl starch (HES 130/0.4) in resuscitation: safety not adequately addressed. AB - BACKGROUND: Hydroxyethyl starches (HES) are widely used for intravascular volume therapy in surgical, emergency, and intensive care patients. There are safety concerns with regard to coagulopathy, renal failure, pruritus, tissue storage, and mortality. Third-generation HES 130/0.4 is considered to have an improved risk profile. A common rationale for the use of HES is the belief that 3 to 4 times more crystalloid than colloid volume is needed to achieve similar hemodynamic end points. Our goal was to assess whether published studies on HES 130/0.4 resuscitation are sufficiently well designed to draw conclusions about the safety of this compound. In addition, we wanted to assess crystalloid-to colloid fluid ratios in studies with goal-directed fluid regimen. METHODS: Systematic review of randomized controlled trials in which HES 130/0.4 is used for resuscitation. RESULTS: We identified 56 randomized controlled trials (RCTs) with HES 130/0.4 in. acute hypovolemia, mainly from the elective surgical setting (n = 45). Surgical studies were small-sized (median 25 patients in the HES groups, range 10 to 90) and of short duration (median 12 hours, range 0.5 to 144 hours). The median cumulative HES dose was 2465 mL (range 328 to 6229 mL), corresponding to 35 mL/kg in a 70-kg patient, the daily dose limit being 50 mL/kg. End points mostly addressed variable surrogate outcomes. Sixty percent of control fluids were other HES solutions, gelatins, or dextran, which have a similar risk profile. Without exception, these studies were not designed for clinically important safety outcomes, primarily because they were too small, used mostly inadequate control fluids, and had inappropriately short observation periods. Therefore, and also because of heterogeneity of patient groups and outcome definitions, results from these studies cannot be pooled. These studies do not allow any conclusion about the safety of HES 130/0.4. There is a common belief that 3 to 4 times more crystalloid than colloid volume is necessary to achieve similar hemodynamic effects. We found a considerably lower ratio in surgical studies (mean 1.8, SD 0.1). CONCLUSIONS: In summary, the extent of fluid load reduction that can be achieved by HES 130/0.4 is overestimated. Use of older HES solutions may be associated with serious side effects, and clinicians should be aware that there is no convincing evidence that third-generation HES 130/0.4 is safe in surgical, emergency, or intensive care patients despite publication of numerous clinical studies. PMID- 21304150 TI - Urine flow is a novel hemodynamic monitoring tool for the detection of hypovolemia. AB - BACKGROUND: Noticeable changes in vital signs indicating hypovolemia occur only after 15% of the blood volume is lost. More sensitive variables (e.g., cardiac output, systolic pressure variation and its Deltadown component) are invasive and difficult to obtain in the early phase of bleeding. Lately, a new technology for continuous optical measurements of minute-to-minute urine flow rates has become available. We performed a preliminary evaluation to determine whether urine flow can act as an early and sensitive warning of hypovolemia. METHODS: Eleven patients (ASA physical status I-II) undergoing posterior spine fusion surgery were studied prospectively. Study variables included heart rate, blood pressure (systolic and diastolic), systolic pressure variation and Deltadown, minute urinary flow, hemoglobin, blood and urinary sodium, and creatinine in the blood and urine. Urine flow rate was measured using URINFO 2000TM (FlowSense Medical, Misgav, Israel). After recording baseline variables, 10 mL/kg of the patient's blood was shed and a second set of variables was recorded. Subsequently, hypovolemia was reversed by infusing colloid solution (hetastarch 6%) followed by recording a third set of variables. These 3 observations were then compared. RESULTS: An average of 614 +/- 143 mL (mean +/- SD) of blood was shed. During phlebotomy, the mean urine flow rate decreased from 5.7 +/- 8 mL/min to 1.07 +/- 2.5 mL/min. Systolic blood pressure and hemoglobin also decreased. Deltadown increased. After rehydration, urine flow, blood pressure, and Deltadown values returned to baseline. The hemoglobin concentration decreased whereas other variables did not change significantly. CONCLUSION: Urine flow rate is a dynamic variable that seems to be a reliable indicator of changes in blood volume. These results justify further investigation. PMID- 21304151 TI - Challenging lung isolation secondary to aberrant tracheobronchial anatomy. AB - Aberrant tracheobronchial anatomy is reported at an incidence of approximately 10% and most frequently involves the segmental and subsegmental bronchi. The most relevant abnormality to the practice of anesthesiology is the presence of a tracheal bronchus. Although typically an asymptomatic finding during bronchoscopy, a tracheal bronchus has important implications for airway management and lung isolation. Coexisting abnormalities may further complicate lung isolation. We describe a patient with a tracheal bronchus, coexisting with a left-shifted carina and apically retracted left mainstem bronchus, presenting for right extrapleural pneumonectomy. Attempts to place a left-sided double-lumen endotracheal tube were unsuccessful. We discuss our solution, review the literature, and present potential solutions for lung isolation in patients with a tracheal bronchus. PMID- 21304152 TI - Mass in the left main coronary artery after aortic valve replacement. PMID- 21304153 TI - A comparison of the classic and a modified laryngeal mask airway (OPLACTM) in adult patients. AB - BACKGROUND: A modified disposable laryngeal mask airway (LMA) (Oro-Pharyngo Laryngeal Airway Cap, OPLACTM) was developed in our department. In this study, we compared the performance of the LMA ClassicTM with that of the OPLAC. METHODS: This was a randomized, single-blinded, crossover study involving 60 paralyzed, anesthetized adult patients. Both devices were inserted into each patient in different sequences after anesthesia had been induced. In 30 patients, the LMA was inserted first and in 30 patients, the OPLAC was inserted first. The success rate, insertion time, fiberoptic view, peak airway pressure, sealing pressure, incidence of gastric insufflations, trace of blood on the device, and incidence of postoperative sore throat were evaluated. RESULTS: The success rate of placement on the first attempt was high for both devices. The insertion time was significantly shorter and better engagement was noted on fiberoptic view with the OPLAC than with the LMA. The sealing pressure was significantly higher and the incidence of gastric insufflations was significantly lower with the OPLAC. The overall incidence of sore throat was 13.33%. CONCLUSIONS: Both devices have comparable airflow resistance and are easy to insert. The OPLAC requires less insertion time, has less variation on insertion time, fits better into the laryngopharynx, is less likely to cause gastric insufflations, and has a higher sealing pressure. PMID- 21304154 TI - The use of opioids and sedatives and time until death after withdrawing mechanical ventilation and vasoactive drugs in a dutch intensive care unit. AB - BACKGROUND: We studied the frequency of withdrawal of mechanical ventilation (MV) and/or vasoactive agents (VAs), the time until death, and dosages of opioids and sedatives in a Dutch academic intensive care unit (ICU), and compared these practices with international observations in this field. METHODS: Retrospective data were collected from the electronic and paper files of all patients who died after withdrawal of treatment in a Dutch ICU between October 2006 and February 2007. RESULTS: In this period, 471 patients were admitted to the ICU, of whom 88 died (18%). In 60 of these patients (68%), MV and/or VAs were withdrawn. This group represented 13% of the total ICU population. Of the 60 patients for whom MV and/or VAs were withdrawn, 54 (90%) died after withdrawal of MV (with or without VAs). Six (10%) died after withdrawal of VAs only, 33 (55%) after withdrawal of MV in combination with VAs, and 21 (35%) after withdrawal of MV only. Death occurred after withdrawal of MV in combination with VAs after a median of 30 minutes (interquartile range [IQR], 10-195 minutes). When only MV was discontinued, the median time until death was 50 minutes (IQR, 15-530 minutes). When only VAs were withdrawn, patients died after a median of 45 minutes (IQR, 20 715 minutes). Ten patients (17%) did not receive opioids or sedatives in their last hours. Fifty patients received opioids in their last hours. Fentanyl, with a median dosage at time of death of 100 MUg/h, was the most frequently used opioid. Forty (80%) of the 50 patients mentioned above received some kind of sedative until death. In the MV withdrawal group, 34 of the 54 patients (63%) received sedatives in the last hours of their lives: 16 (27%) received midazolam (median, 10 mg/h), 12 (22%) propofol (median, 160 mg/h), and 6 (11%) lorazepam (2.0 mg/h). Sedatives were administered to all patients in whom only VAs were withdrawn. CONCLUSIONS: Dutch patients who die in the ICU, or die after discharge from the ICU, die after MV and/or VAs are withdrawn. When treatments are withdrawn, death follows within 1 hour in most patients, which is a reflection of the severity of illnesses. At least 80% of patients receive opioids, and 67% receive sedatives until death. Fentanyl is the most used opioid, whereas midazolam is the most used sedative. Dosages of opioids and sedatives did not significantly exceed the ranges described as usual in the international literature. PMID- 21304155 TI - Equivalence and noninferiority testing in regression models and repeated-measures designs. AB - Equivalence and noninferiority designs are useful when the superiority of one intervention over another is neither expected nor required. Equivalence trials test whether a difference between groups falls within a prespecified equivalence region, whereas noninferiority trials test whether a preferred intervention is either better or at least not worse than the comparator, with worse being defined a priori. Special designs and analyses are needed because neither of these conclusions can be reached from a nonsignificant test for superiority. Using the data from a companion article, we demonstrate analyses of basic equivalence and noninferiority designs, along with more complex model-based methods. We first give an overview of methods for design and analysis of data from superiority, equivalence, and noninferiority trials, including how to analyze each type of design using linear regression models. We then show how the analogous hypotheses can be tested in a repeated-measures setting in which there are multiple outcomes per subject. We especially address interactions between the repeated factor, usually time, and treatment. Although we focus on the analysis of continuous outcomes, extensions to other data types as well as sample size consideration are discussed. PMID- 21304156 TI - The influence of age on bupivacaine cardiotoxicity. AB - BACKGROUND: The susceptibility of children and newborns to cardiotoxicity from racemic bupivacaine, RS(+/-)-bupivacaine, is controversial. Some studies indicate that newborns can sustain higher bupivacaine plasma levels than adults, without severe toxicity. In this study, we compared the influence of age on cardiotoxicity from RS(+/-)-bupivacaine and S(-)-bupivacaine in rats. The effects of these local anesthetics (LAs) on the regulation of intracellular Ca(2+) concentrations in cardiac fibers were also investigated. METHODS: The lethal dose was determined in ventilated male Wistar rats at 2, 4, 8, and 16 weeks of age by monitoring when cardiac electrical activity stopped after infusion of RS(+/-) bupivacaine and S(-)-bupivacaine (4 mg . kg(-1) . min(-1)). The effects on cardiac muscle contraction were investigated by in vitro measurement of papillary muscle twitches in the presence and absence of RS(+/-)-bupivacaine or S(-) bupivacaine. Skinned ventricular fibers were used to investigate the intracellular effects on Ca(2+) regulation induced by both LAs. RESULTS: The lethal dose for RS(+/-)-bupivacaine and S(-)-bupivacaine in 2-week-old animals (46.0 +/- 5.2 and 91.3 +/- 4.9 mg . kg(-1), respectively) was higher than in 16 week-old animals (22.7 +/- 1.3 and 22.0 +/- 2.7 mg . kg(-1), respectively). Papillary muscle twitches were reduced in a dose-dependent manner, with significant difference between young and adult hearts. In adults, the muscle twitches were reduced to 8.6% +/- 0.8% of control by RS(+/-)-bupivacaine, and to 18.1% +/- 2.7% of control by S(-)-bupivacaine (100 MUM). S(-)-bupivacaine had a positive inotropic effect at <10 MUM, but only in 2-week-old animals. In chemically skinned ventricular fibers, RS(+/-)-bupivacaine and S(-)-bupivacaine induced similar increases in Ca(2+) release from the sarcoplasmic reticulum (SR) preactivated with caffeine (1 mM), and this effect was greater in younger rats than adults. In 16-week-old rats, caffeine-induced tension was 53.9% +/- 1.7% of the maximal fiber response with RS(+/-)-bupivacaine, and 54.1% +/- 3.2% with S(-) bupivacaine. The caffeine response in 2-week-old rats was 81.1% +/- 3.7% of the maximal response with RS(+/-)-bupivacaine, and 78.1% +/- 4.5% with S(-) bupivacaine. The Ca(2+) sensitivity of contractile proteins was equally increased at both ages tested, with RS(+/-)-bupivacaine or S(-)-bupivacaine. Ca(2+) uptake from the SR was not altered by the LA or by age. CONCLUSIONS: Differences in the mechanisms for regulating intracellular SR Ca(2+) may contribute to the decreased susceptibility of young animals to cardiodepression induced by RS(+/-) bupivacaine and S(-)-bupivacaine. PMID- 21304157 TI - Galpha(q) and phospholipase C-beta: turn on, turn off, and do it fast. AB - Heterotrimeric G proteins and G protein-coupled receptors represent conserved protein families with origins in the prokaryotes, but the various G protein regulated effectors are heterogeneous in structure and function. The effectors apparently evolved ways to listen to G proteins late in their evolutionary histories. The structure of a complex between the effector protein phospholipase C-beta3 (PLC-beta3) and its activator, Galpha(q), suggests that several effectors independently evolved a structurally similar helix-turn-helix segment for G protein recognition. PLC-betas are also guanosine triphosphatase (GTPase) activating proteins (GAPs) for the G(q) that activates them. In a second example of convergent evolution, the GAP activity of these proteins depends on a flexible asparagine-containing loop that resembles the GAP site on RGS proteins, another family of G protein GAPs. Together, these two sites are proposed to cooperate to enable fast binding to activated Galpha(q), followed by fast deactivation. This cycle allows rapid sampling of the activation state of G(q)-coupled receptors while providing efficient signal transduction. PMID- 21304158 TI - How cells use pseudopods for persistent movement and navigation. AB - Pseudopods are cell extensions used for movement. The direction and trajectory of cell movement depend on how cells extend pseudopods. Experimental data show that new pseudopods are frequently formed by the splitting of an existing pseudopod, often as a series of left-right extensions. Here, these data on pseudopod extensions are discussed in the context of a theoretical model for pseudopod splitting. PMID- 21304159 TI - The crystal structure of a self-activating G protein alpha subunit reveals its distinct mechanism of signal initiation. AB - In animals, heterotrimeric guanine nucleotide-binding protein (G protein) signaling is initiated by G protein-coupled receptors (GPCRs), which activate G protein alpha subunits; however, the plant Arabidopsis thaliana lacks canonical GPCRs, and its G protein alpha subunit (AtGPA1) is self-activating. To investigate how AtGPA1 becomes activated, we determined its crystal structure. AtGPA1 is structurally similar to animal G protein alpha subunits, but our crystallographic and biophysical studies revealed that it had distinct properties. Notably, the helical domain of AtGPA1 displayed pronounced intrinsic disorder and a tendency to disengage from the Ras domain of the protein. Domain substitution experiments showed that the helical domain of AtGPA1 was necessary for self-activation and sufficient to confer self-activation to an animal G protein alpha subunit. These findings reveal the structural basis for a mechanism for G protein activation in Arabidopsis that is distinct from the well established mechanism found in animals. PMID- 21304160 TI - Innovation in hip arthroscopy: is hip arthritis preventable in the athlete? AB - INTRODUCTION: The hip is the second most common area for injury in collegiate athletes and may account for 2-5% of all sports injuries. Hip and groin pain in the athlete has long been associated with structural abnormalities of the femoral neck, acetabulum and labral pathology. REVIEW: The relationship between osteoarthritis and femoroacetabular impingement (FAI) is well established now with clinical studies, radiographic studies and computer simulations. TREATMENT: The successful treatment of the athlete with FAI and subsequent labral and chondral damage has been well documented. New techniques, such as labral reconstruction, are being developed to address the more complex injuries seen in athletes, while helping to protect the joint surfaces and decrease the risk of early onsite osteoarthritis. CONCLUSION: The athlete's painful hip, which is becoming an increasingly more common complaint, is being identified and treated with greater chances of returning to play without compromising long-term hip function and the progression of hip osteoarthritis. PMID- 21304161 TI - Surface EMG decomposition requires an appropriate validation. PMID- 21304163 TI - Polypillomania. PMID- 21304164 TI - Reducing NSAID-induced gastrointestinal complications. AB - Around 17 million items for non-steroidal anti-inflammatory drugs (NSAIDs) are prescribed annually in England alone.1 These drugs are associated with upper gastrointestinal complications.2 For example, each year, NSAIDs cause about 3,500 hospitalisations for, and 400 deaths from, ulcer bleeding in people aged 60 years or above.3 Aspirin, even in low doses, is also associated with gastrointestinal complications.4 5 Here we assess strategies for reducing gastrointestinal complications induced by NSAIDs, including aspirin and selective inhibitors of cyclo-oxygenase-2 (coxibs). PMID- 21304165 TI - Botox for chronic migraine. AB - Botulinum toxin A is used as treatment for various conditions involving muscle spasm and is available in several formulations. One of these (Botox) has recently been licensed in the UK for the prevention of headaches in adults with chronic migraine1 as regular injections into head and neck muscles. Here we discuss the efficacy and safety of this treatment. PMID- 21304166 TI - An insertion mutation that distorts antibody binding site architecture enhances function of a human antibody. AB - The structural and functional significance of somatic insertions and deletions in antibody chains is unclear. Here, we demonstrate that a naturally occurring three amino-acid insertion within the influenza virus-specific human monoclonal antibody 2D1 heavy-chain variable region reconfigures the antibody-combining site and contributes to its high potency against the 1918 and 2009 pandemic H1N1 influenza viruses. The insertion arose through a series of events, including a somatic point mutation in a predicted hot-spot motif, introduction of a new hot spot motif, a molecular duplication due to polymerase slippage, a deletion due to misalignment, and additional somatic point mutations. Atomic resolution structures of the wild-type antibody and a variant in which the insertion was removed revealed that the three-amino-acid insertion near the base of heavy-chain complementarity-determining region (CDR) H2 resulted in a bulge in that loop. This enlarged CDR H2 loop impinges on adjacent regions, causing distortion of the CDR H1 architecture and its displacement away from the antigen-combining site. Removal of the insertion restores the canonical structure of CDR H1 and CDR H2, but binding, neutralization activity, and in vivo activity were reduced markedly because of steric conflict of CDR H1 with the hemagglutinin antigen. PMID- 21304167 TI - Genome variation in Cryptococcus gattii, an emerging pathogen of immunocompetent hosts. AB - Cryptococcus gattii recently emerged as the causative agent of cryptococcosis in healthy individuals in western North America, despite previous characterization of the fungus as a pathogen in tropical or subtropical regions. As a foundation to study the genetics of virulence in this pathogen, we sequenced the genomes of a strain (WM276) representing the predominant global molecular type (VGI) and a clinical strain (R265) of the major genotype (VGIIa) causing disease in North America. We compared these C. gattii genomes with each other and with the genomes of representative strains of the two varieties of Cryptococcus neoformans that generally cause disease in immunocompromised people. Our comparisons included chromosome alignments, analysis of gene content and gene family evolution, and comparative genome hybridization (CGH). These studies revealed that the genomes of the two representative C. gattii strains (genotypes VGI and VGIIa) are colinear for the majority of chromosomes, with some minor rearrangements. However, multiortholog phylogenetic analysis and an evaluation of gene/sequence conservation support the existence of speciation within the C. gattii complex. More extensive chromosome rearrangements were observed upon comparison of the C. gattii and the C. neoformans genomes. Finally, CGH revealed considerable variation in clinical and environmental isolates as well as changes in chromosome copy numbers in C. gattii isolates displaying fluconazole heteroresistance. PMID- 21304168 TI - Evidence of a dominant lineage of Vibrio cholerae-specific lytic bacteriophages shed by cholera patients over a 10-year period in Dhaka, Bangladesh. AB - Lytic bacteriophages are hypothesized to contribute to the seasonality and duration of cholera epidemics in Bangladesh. However, the bacteriophages contributing to this phenomenon have yet to be characterized at a molecular genetic level. In this study, we isolated and sequenced the genomes of 15 bacteriophages from stool samples from cholera patients spanning a 10-year surveillance period in Dhaka, Bangladesh. Our results indicate that a single novel bacteriophage type, designated ICP1 (for the International Centre for Diarrhoeal Disease Research, Bangladesh cholera phage 1) is present in all stool samples from cholera patients, while two other bacteriophage types, one novel (ICP2) and one T7-like (ICP3), are transient. ICP1 is a member of the Myoviridae family and has a 126-kilobase genome comprising 230 open reading frames. Comparative sequence analysis of ICP1 and related isolates from this time period indicates a high level of genetic conservation. The ubiquitous presence of ICP1 in cholera patients and the finding that the O1 antigen of lipopolysaccharide (LPS) serves as the ICP1 receptor suggest that ICP1 is extremely well adapted to predation of human-pathogenic V. cholerae O1. PMID- 21304170 TI - The impact of stimulus complexity and frequency swapping on stabilization of binocular rivalry. AB - Binocular rivalry occurs when an image is presented to one eye while at the same time another, incongruent, image is presented to the other eye in the corresponding retinotopic location and conscious perception alternates spontaneously between the two monocular views. If a short blank period is inserted between intermittent presentations of rivaling stimuli, perception is stabilized and spontaneous alternations are drastically reduced. Whether the complexity of rivaling stimuli plays a role in stabilization is unknown. We replicated previous findings that swapping the stimuli between eyes across presentations abolishes stabilization for Gabors, but for more complex stimuli (a face and a house in our experiment), stabilization is eye-specific and not disrupted. Phase scrambling the rivaling face and house images did not change the stabilization pattern showing that the pattern can be observed without high-level perceptual content. We conclude that overlaps at low visual stages are the most likely cause of the eye-specific stabilization for both stimulus types. Additionally, we examined the impact of swapping the flicker frequency of the images and found a general impact on stabilization not specific to stimulus type. Taken together, the findings indicate that choice of stimulus features impact greatly on the results obtained in stabilization paradigms. PMID- 21304169 TI - Functional reorganization of promyelocytic leukemia nuclear bodies during BK virus infection. AB - BK virus (BKV) is the causative agent for polyomavirus-associated nephropathy, a severe disease found in renal transplant patients due to reactivation of a persistent BKV infection. BKV replication relies on the interactions of BKV with many nuclear components, and subnuclear structures such as promyelocytic leukemia nuclear bodies (PML-NBs) are known to play regulatory roles during a number of DNA virus infections. In this study, we investigated the relationship between PML NBs and BKV during infection of primary human renal proximal tubule epithelial (RPTE) cells. While the levels of the major PML-NB protein components remained unchanged, BKV infection of RPTE cells resulted in dramatic alterations in both the number and the size of PML-NBs. Furthermore, two normally constitutive components of PML-NBs, Sp100 and hDaxx, became dispersed from PML-NBs. To define the viral factors responsible for this reorganization, we examined the cellular localization of the BKV large tumor antigen (TAg) and viral DNA. TAg colocalized with PML-NBs during early infection, while a number of BKV chromosomes were adjacent to PML-NBs during late infection. We demonstrated that TAg alone was not sufficient to reorganize PML-NBs and that active viral DNA replication is required. Knockdown of PML protein did not dramatically affect BKV growth in culture. BKV infection, however, was able to rescue the growth of an ICP0-null herpes simplex virus 1 mutant whose growth defect was partially due to its inability to disrupt PML-NBs. We hypothesize that the antiviral functions of PML NBs are inactivated through reorganization during normal BKV infection. PMID- 21304171 TI - Visual acuity under combined astigmatism and coma: optical and neural adaptation effects. AB - Previous studies suggest that certain combinations of coma and astigmatism improve optical quality over astigmatism alone. We tested these theoretical predictions on 20 patients. Visual acuity (VA) was measured under best spherical correction for different conditions: low- and higher order aberrations corrected, in the presence of 0.5 D of induced astigmatism, and adding different amounts of coma to 0.5 D of astigmatism. Measurements were performed for different relative angles between coma and astigmatism and for selected conditions, also through focus. Adding coma (0.23 MUm for 6-mm pupil) to astigmatism resulted in a clear increase of VA in 6 subjects, consistently with theoretical optical predictions, while VA decreased when coma was added to astigmatism in 7 subjects. In addition, in the presence of astigmatism only, VA decreased more than 10% with respect to all aberrations corrected in 13 subjects, while VA was practically insensitive to the addition of astigmatism in 4 subjects. The effects were related to the presence of natural astigmatism and whether this was habitually corrected or uncorrected. The fact that the expected performance occurs mainly in eyes with no natural astigmatism suggests relevant neural adaptation effects in eyes normally exposed to astigmatic blur. PMID- 21304172 TI - Spatiotopic apparent motion reveals local variations in space constancy. AB - While participants made 10 degrees horizontal saccades, two dots were presented, one before and one after the saccade. Each dot was presented for 400 ms, the first turned off about 100 ms before, while the second turned on about 100 ms after the saccade. The two dots were separated vertically by 3 degrees , but because of the intervening eye movement, they were also separated horizontally on the retina by an additional 10 degrees . Participants nevertheless reported that the perceived motion was much more vertical than horizontal, suggesting that the trans-saccadic displacement was corrected, at least to some extent, for the retinal displacement caused by the eye movement. The corrections were not exact, however, showing significant biases that corresponded to about 5% of the saccade amplitude. The perceived motion between the probes was tested at 9 different locations and the biases, the deviations from accurate correction, varied significantly across locations. Two control experiments for judgments of position and of verticality of motion without eye movement confirmed that these biases are specific to the correction for the saccade. The local variations in the correction for saccades are consistent with physiological "remapping" proposals for space constancy that individually correct only a few attended targets but are not consistent with global mechanisms that predict the same correction at all locations. PMID- 21304173 TI - Tumor reversion holds promise. PMID- 21304174 TI - Addiction to B-MYB. PMID- 21304175 TI - The evolving picture of the glioblastoma genome. PMID- 21304176 TI - The anti-apoptotic members of the Bcl-2 family are attractive tumor-associated antigens. AB - Anti-apoptotic members of the Bcl-2 family (Bcl-2, Bcl-X(L) and Mcl-2) are pivotal regulators of apoptotic cell death. They are all highly overexpressed in cancers of different origin in which they enhance the survival of the cancer cells. Consequently, they represent prime candidates for anti-cancer therapy and specific antisense oligonucleotides or small molecule inhibitors have shown broad anti-cancer activities in pre-clinical models and are currently tested in clinical trials. In addition, immune-mediated tumor destruction is emerging as an interesting modality to treat cancer patients. Notably, spontaneous cellular immune responses against the Bcl-2 family proteins have been identified as frequent features in cancer patients underscoring that these proteins are natural targets for the immune system. Thus, Bcl-2 family may serve as an important and widely applicable target for anti-cancer immunotherapeutic strategies, alone or in the combination with conventional therapy. Here, we summarize the current knowledge of Bcl-2 family proteins as T-cell antigens, which has set the stage for the first explorative trial using these antigens in therapeutic vaccinations against cancer, and discuss future opportunities. PMID- 21304177 TI - A novel screen using the Reck tumor suppressor gene promoter detects both conventional and metastasis-suppressing anticancer drugs. AB - The membrane-anchored matrix metalloproteinase-regulator RECK is often downregulated in various types of cancers; the levels of residual RECK in resected tumors often correlate with better prognosis. Forced expression of RECK in cancer cells suppresses tumor angiogenesis, invasion, and metastasis in xenograft models. RECK is therefore a promising marker for benignancy and a potential effector in cancer therapy. We established a cell line containing two transgene systems: (1) the secreted alkaline phosphatase (SEAP) gene fused to Reck promoter and (2) the HRAS(12V) oncogene driven by the Tet-off promoter system. This cell line exhibits transformed phenotype in regular medium and flat morphology with increased SEAP activity in the presence of doxycycline, allowing the assessment of RECK-inducing activity of chemicals in the contexts of both transformed and untransformed cells. Our pilot experiments with 880 known bioactive compounds detected 34 compounds that activate RECK promoter; among these, 10 were authentic anticancer drugs. Four selected compounds up-regulated endogenous RECK protein in several human cancer cell lines. The top-ranking compound, disulfiram, strongly suppressed spontaneous lung-metastasis of human fibrosarcoma cells in nude mice. Our data demonstrate the value of this screen in discovering effective cancer therapeutics. PMID- 21304178 TI - Addiction of MYCN amplified tumours to B-MYB underscores a reciprocal regulatory loop. AB - MYCN is a member of the MYC family of oncoproteins frequently amplified or overexpressed in aggressive, paediatric tumours of the nervous system. In this study we have identified the gene B-MYB, encoding the transcription factor also known as MYBL2, as a downstream target of MYCN. Using multiple in silico databases we show that expression of B-MYB significantly correlates with that of MYCN in neuroblastoma patients. MYCN binds to and activates the B-MYB gene in vivo and in vitro. Blunting B-MYB expression by RNA interference causes reduced proliferation of MYCN amplified, but not MYCN-non amplified, neuroblastoma cell lines, indicating that tumour cells are addicted to B-MYB in a MYCN dependent manner. Notably, B-MYB binds in vivo to the MYCN amplicon and is required for its expression. We conclude that MYCN and B-MYB are engaged in a reciprocal regulatory loop whose pharmacological targeting could be beneficial to patients with the aggressive forms of cancer in which MYCN is amplified. PMID- 21304180 TI - The secretory small GTPase Rab27B as a marker for breast cancer progression. AB - In contemporary oncology practice, an urgent need remains to refine the prognostic assessment of breast cancer. It is still difficult to identify patients with early breast cancer who are likely to benefit from adjuvant chemotherapy. Although invasion of cancer cells is the main prognostic denominator in tumor malignancy, our molecular understanding and diagnosis are often inadequate to cope with this activity. Therefore, deciphering molecular pathways of how tumors invade and metastasize may help in the identification of a useful prognostic marker. We recently discovered that the secretory small GTPase Rab27B, a regulator of vesicle exocytosis, delivers proinvasive signals for increased invasiveness, tumor size, and metastasis of various estrogen receptor (ER)-positive breast cancer cell lines, both in vitro and in vivo. In human breast cancer specimens, the presence of Rab27B protein proved to be associated with a low degree of differentiation and the presence of lymph node metastasis in ER-positive breast cancer. PMID- 21304181 TI - MicroRNAs and senescence. PMID- 21304179 TI - p300- and Myc-mediated regulation of glioblastoma multiforme cell differentiation. AB - Tumorigenic potential of glioblastoma multiforme (GBM) cells is, in part, attributable to their undifferentiated (neural stem cell-like) phenotype. Astrocytic differentiation of GBM cells is associated with transcriptional induction of Glial Fibrillary Acidic Protein (GFAP) and repression of Nestin, whereas the reciprocal transcription program operates in undifferentiated GBM cells. The molecular mechanisms underlying the regulation of these transcription programs remain elusive. Here, we show that the transcriptional co-activator p300 was expressed in GBM tumors and cell lines and acted as an activator of the GFAP gene and a repressor of the Nestin gene. On the other hand, Myc (formerly known as c-Myc overrode these p300 functions by repressing the GFAP gene and inducing the Nestin gene in GBM cells. Moreover, RNAi-mediated inhibition of p300 expression significantly enhanced the invasion potential of GBM cells in vitro. Taken together, these data suggest that dedifferentiated/undifferentiated GBM cells are more invasive than differentiated GBM cells. Because invasion is a major cause of GBM morbidity, differentiation therapy may improve the clinical outcome. PMID- 21304182 TI - Soluble Abeta(1-40) peptide increases excitatory neurotransmission and induces epileptiform activity in hippocampal neurons. AB - It is believed that amyloid-beta peptide (Abeta), in its aggregated-oligomeric state, constitutes one of the neurotoxic factors involved in the pathogenesis of Alzheimer's disease. With the objective of studying a potential role of the peptide on synaptic transmission, we studied the effect of soluble Abeta(1-40) on synaptic transmission in rat hippocampal neurons. Neurons incubated with 500 nM of Abeta(1-40) peptide for 3 days presented higher levels of intracellular calcium transients, as evaluated by fluorimetric techniques. These effects of Abeta were time and concentration dependent and were accompanied by increases in glutamatergic (0.8+/-0.2 Hz to 2.9+/-0.6 Hz), but not GABAergic, transmission. The analysis of pharmacologically isolated currents in treated neurons showed increases in both AMPA- and NMDA-mediated currents as compared to control. The effects of the peptide on the frequency of synaptic currents correlated well with increases in the number of SV2 puncta and of FM1-43 destaining, suggesting a presynaptic locus for the peptide. The data also shows that application of either Abeta or bicuculline alone for 24 h was without effects on neurotransmission. However, their co-application induced an increase in synaptic transmission which was accompanied by synchronous discharges reminiscent to those produced by pro convulsive drugs, such as bicuculline. In conclusion, these results suggest that the soluble form of Abeta(1-40) participates in the regulation of synaptic transmission increasing excitability and producing a pre-epileptogenic state in hippocampal neurons. PMID- 21304183 TI - Elderly-onset essential tremor and mild cognitive impairment: a population-based study (NEDICES). AB - Mild cognitive impairment (MCI) is often considered to be a transitional stage between normal aging and dementia. Frontal-executive dysfunction, memory impairments, and dementia have been associated with essential tremor (ET). Yet the association between MCI and ET has only been examined in one prior study. We determined whether ET is associated with MCI. We identified all persons with MCI and ET in a dementia-free, population-based study in central Spain (NEDICES). MCI was diagnosed using consensus criteria of the International Working Group on MCI. Forty-two (20.3%) of 207 ET cases had MCI versus 399 (16.1%) of 2,472 non-ET subjects (controls) (odds ratio [OR] = 1.32, 95% Confidence Interval [CI] = 0.93 to 1.89, p = 0.12). In a model that adjusted for age, gender, educational level, smoking, hearing impairment, depressive symptoms or antidepressant use, and use of a medication that could potentially affect cognitive function, the OR was 1.28, 95% CI = 0.88 to 1.84, p = 0.19. In an adjusted model, ET cases with tremor onset after age 65 were 57% more likely to have MCI than controls (OR = 1.57, 95% CI = 1.03 to 2.38, p = 0.03), whereas ET cases with tremor onset prior to age 65 and controls were equally likely to have MCI (OR = 0.73, 95% CI = 0.34 to 1.57, p = 0.43). In this study, older-onset ET was associated with MCI. This finding supports the hypothesis that cognitive disturbances are one of the core non-motor symptoms of ET. PMID- 21304184 TI - Memory for names test provides a useful confrontational naming task for aging and continuum of dementia. AB - There is an increasing need to develop new neuropsychometric tools sensitive enough to detect subtle declines in cognitive performance during normal aging, as well as to distinguish between normal aging and the earliest stages of dementia. In this study, we report our findings regarding a new confrontational naming test, the Memory for Names test. We conducted evaluations utilizing a cohort of 234 elderly participants who comprised a spectrum of cognitive function ranging from normal for age (Uniform Data Set Overall Appraisal = 2, Clinical Dementia Rating = 0) to demented (Clinical Dementia Rating = 1-2, Mini Mental Status Examination Total Score <25). The Memory for Names test was found to measure the same cognitive construct as the Boston Naming Test. In conclusion, the Memory for Names test is a reliable and valid measure of age-related cognitive function that can discriminate between normal aging and mild cognitive impairment, and between mild cognitive impairment and dementia. PMID- 21304186 TI - Diagnostics for tuberculosis: time to usher in a new era. PMID- 21304187 TI - Burkholderia cepacia complex: beyond pseudomonas and acinetobacter. AB - Burkholderia cepacia complex (BCC) is an important nosocomial pathogen in hospitalised patients, particularly those with prior broad-spectrum antibacterial therapy. BCC causes infections that include bacteraemia, urinary tract infection, septic arthritis, peritonitis and respiratory tract infection. Due to high intrinsic resistance and being one of the most antimicrobial-resistant organisms encountered in the clinical laboratory, these infections can prove very difficult to treat and, in some cases, result in death. Patients with cystic fibrosis (CF) and those with chronic granulomatous disease are predisposed to infection by BCC bacteria. BCC survives and multiplies in aqueous hospital environments, including disinfectant agents and intravenous fluids, where it may persist for long periods. Outbreaks and pseudo-outbreaks of BCC septicaemia have been documented in intensive care units, oncology units and renal failure patients. BCC is phenotypically unremarkable, and the complex exhibits an extensive diversity of genotypes. BCC is of increasing importance for agriculture and bioremediation because of their antinematodal and antifungal properties as well as their capability to degrade a wide range of toxic compounds. It has always been a tedious task for a routine microbiological laboratory to identify the nonfermenting gram-negative bacilli, and poor laboratory proficiency in identification of this nonfermenter worldwide still prevails. In India, there are no precise reports of the prevalence of BCC infection, and in most cases, these bacteria have been ambiguously reported as nonfermenting gram-negative bacilli or simply Pseudomonas spp. The International Burkholderia cepacia Working Group is open to clinicians and scientists interested in advancing knowledge of BCC infection/colonisation in persons with CF through the collegial exchange of information and promotion of coordinated approaches to research. PMID- 21304188 TI - Pandemic influenza A (H1N1) 2009 vaccine: an update. AB - The world witnessed a the first influenza pandemic in this century and fourth overall since first flu pandemic was reported during the World War I. The past experiences with influenza viruses and this pandemic of H1N1 place a consider able strain on health services and resulted in serious illnesses and a large number of deaths. Develop-ing countries were declared more likely to be at risk from the pandemic effects, as they faced the dual problem of highly vulnerable populations and limited resources to respond H1N1. The public health experts agreed that vaccination is the most effective ways to mitigate the negative effects of the pandemic. The vaccines for H1N1 virus have been used in over 40 countries and administered to over 200 million people helped in a great way and on August 10, 2010, World Health Organization (WHO) announced H1N1 to be in postpandemic period. But based on knowledge about past pandemics, the H1N1 (2009) virus is expected to continue to circulate as a seasonal virus and may undergo some agenic-variation. As WHO strongly recommends vaccination, vigilance for regular updating of the composition of influenza vaccines, based on an assessment of the future impact of circulating viruses along with safety surveillance of the vaccines is necessary. This review has been done to take a stock of the currently available H1N1 vaccines and their possible use as public health intervention in the postpandemic period. PMID- 21304189 TI - BinaxNOW(r) - an immunochromatographic test for the diagnosis of human influenza viruses: comparison with viral culture and polymerase chain reaction. AB - PURPOSE: A rapid test for influenza viruses (Binax NOW(r) ) was evaluated. MATERIALS AND METHODS: In season-1, 35 respiratory samples were tested retrospectively; in season-2, 45 samples were tested prospectively [gold standard: viral culture in season-1, culture+ reverse transcriptase-polymerase chain reaction (RT-PCR) in season-2]. RESULTS: Sensitivity for Binax for influenza A was 59.3 and 0% in season-1 and -2, respectively. Sensitivity was low for influenza B (33.3% in season-1, 26.1% in season-2). Samples having low viral load were more likely to have a negative Binax test. Specificity of Binax was high (100 and 94.7% with influenza A and B, respectively). CONCLUSION: Sensitivity information provided in the kit insert does not always reflect post licensure performance in clinical settings. PMID- 21304190 TI - Multidrug-resistant Enterobacteriaceae including metallo-beta-lactamase producers are predominant pathogens of healthcare-associated infections in an Indian teaching hospital. AB - PURPOSE: A study was carried out in an Indian teaching hospital in 2009 to detect the rate of surgical site infections (SSI) and peripheral vascular access site infections. MATERIALS AND METHODS: The study was a point-prevalence study involving over 300 patients. The presence of infection was determined according to the CDC criteria. Swabs were taken from the infected sites and identification and sensitivity were carried out using VITEK(r) 2 automated system. Characterisation of beta-lactamase was carried out at ARRML, Colindale, London. RESULTS: The rate of SSI was 15% for the clean and clean-contaminated categories while that for the dirty contaminated category was 85% (NNIS risk index 0). Cultures yielded definite or probable pathogens from 64% (9/14) of the patients with SSI. In 1/3 rd of the cultures, Staphylococcus aureus was grown and the rest had Enterobacteriaceae, either extended-spectrum beta-lactamase (ESBL) producers or Amp-C hyperproducers and, alarmingly, three isolates were positive for newly recognised New Delhi metallo-beta-lactamase-1 (NDM-1). In medicine, 87% (n = 99) of the patients had a peripheral IV access device, 55% developed associated phlebitis/infection and, in seven, probable pathogens were isolated (Candida species and Escherichia coli producing ESBL and NDM-1, respectively, Staphylococcus aureus and Enterococcus faecium). All ESBL and metallo-beta lactamase producers were resistant to multiple classes of antimicrobials, the latter being sensitive only to colistin and tigecycline. The study also found that all post-operative patients were on antibiotics, 92% on IV [213 defined daily doses (DDD)/100 post-op patients] limited mainly to the third-generation cephalosporins (26%) and aminoglycosides (24%) and imidazole derivatives (30%). In medicine, 83% (n = 82) were on IV antibiotics (123 DDD/100 bed-days), limited mainly to the third-generation cephalosporins (74%). CONCLUSION: Indiscriminate use of antibiotics is a major problem predisposing patients to harm by multi resistant pathogens. Carbapenems were in little use in this hospital, but the selection pressure exerted by cephalosporins and other unrelated classes was sufficient to select NDM-1-producing strains due to co-selection, suggesting a role of single plasmid carrying resistance genes to multiple classes. PMID- 21304191 TI - Human leucocyte antigens and cytokine gene polymorphisms and tuberculosis. AB - PURPOSE: Several genes encoding different cytokines and human leucocyte antigens (HLA) may play crucial roles in host susceptibility to tuberculosis (TB). Our objective was to investigate whether these genes might be associated with protection from or susceptibility to TB. MATERIALS AND METHODS: Genomic DNA from patients with TB (n = 30) and ethnically matched controls (n = 30) was genotyped by using sequence-specific primers-polymerase chain reaction and sequence specific oligonucletid methods. RESULTS: Our results demonstrated that HLA CwFNx0101 [P = 0.05, odds ration (OR) (95% confidence interval) = 2.269 (1.702 3.027)] allele frequency was significantly more common in TB patients than in healthy controls, and HLA-CwFNx0101 may be associated with susceptibility to TB. Analysis of cytokine allele frequencies showed that interleukin (IL)-10, -819 C and -592 C alleles was significantly more common in TB patients than in controls (pc: 0.038 and 0.017, respectively). From the IL-10 cluster, a positive significant difference was found at positions -1082 and -592 C/C (pc: 0.027 and 0.054, respectively) genotypes. Although these differences could be explained by the highest frequency of C/C and G/G homozygous patients with TB, in contrast to the control group, statistically significant differences for the C/C genotype however were lost after Bonferroni correction of the P-values. CONCLUSION: Altogether, our results suggest that the polymorphisms in HLA (class I) and cytokine (IL-10) genes may affect the susceptibility to TB and increase the risk of developing the disease. PMID- 21304192 TI - Simultaneous and rapid differential diagnosis of Mycoplasma genitalium and Ureaplasma urealyticum based on a polymerase chain reaction-restriction fragment length polymorphism. AB - OBJECTIVES: The aim of this investigation was to simultaneously detect and differentiate Mycoplasma genitalium and Ureaplasma urealyticum in female patients suffering from genital complications by polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP). MATERIALS AND METHODS: Genital swabs were taken from 210 patients. They were transported to the laboratory in phosphate-buffered saline. For PCR, samples were analysed with genus-specific MyUu-R and MyUu-F primers. This primer set, which was originally designed in our laboratory, amplified a 465 bp fragment (M. genitalium) and a 559 bp fragment (U. urealyticum). Samples containing a band of the expected sizes for the Mycoplasma strains were subjected to digestion with a restriction endonuclease enzyme of TaqI and Cac8I. RESULTS: Of the 210 samples, a total of 100 (47.6%) samples were found to be positive for Mycoplasmas (seven M. genitalium isolates, 3.3%; and 89 U. urealyticum isolates, 42.4%), and coinfections with both species were detected in four samples (1.9%). The PCR-RFLP results showed that M. genitalium and U. urealyticum are different by enzyme patterns. CONCLUSION: PCR-RFLP offers a rapid and easily applicable protocol to simultaneous detection and differentiation of M. genitalium and U. urealyticum from clinical samples when specific primers and restriction enzymes are used. PMID- 21304193 TI - Pandemic Influenza A (H1N1) 2009 in India: duration of virus shedding in patients under antiviral treatment. AB - BACKGROUND: National Centre for Disease Control (NCDC), Delhi, is a national nodal centre for surveillance of pandemic Influenza A (H1N1) in India. The present study was undertaken to see the period of infectivity in positive cases undergoing antiviral therapy. OBJECTIVE: To assess the duration of virus shedding by real-time polymerase chain reaction (real-time PCR) in some of the positive patients taking Oseltamivir treatment. MATERIALS AND METHODS: Clinical samples (throat swabs, nasal swabs and nasopharyngeal swabs) collected by the clinicians from patients quarantined in government hospitals in different parts of India are being sent to the designated reference laboratory at Delhi for screening presence of pandemic Influenza virus. The samples are tested by Real-Time PCR using CDC recommended reagents and protocol for confirmation of the H1N1 novel influenza virus. In 150 of the positive cases, we requested the clinicians to send samples for 5 consecutive days after administration of antiviral therapy, to see the trend of therapy response on viral shedding. Samples for more than 5 days were received from patients till they showed no amplification for any of the three target genes (Influenza A, Swine Influenza A or Swine H1). RESULTS AND CONCLUSION: In 99.33% (149/150) cases, the influenza infection resolved within 10 days. Sixty-four percent (96/150) of the positive patients turned negative within 5 days of the start of antiviral treatment. Only one patient belonging to high risk group showed prolonged virus shedding (19 days). PMID- 21304194 TI - Comparison of four methods for rapid identification of Staphylococcus aureus directly from BACTEC 9240 blood culture system. AB - PURPOSE: Differentiation of Staphylococcus aureus (S. aureus) from coagulase negative staphylococci is very important in blood stream infections. Identification of S. aureus and coagulase-negative staphylococci (CoNS) from blood cultures takes generally 18-24 h after positive signaling on continuously monitored automated blood culture system. In this study, we evaluated the performance of tube coagulase test (TCT), slide agglutination test (Dry Spot Staphytect Plus), conventional polymerase chain reaction (PCR) and LightCycler Staphylococcus MGrade kit directly from blood culture bottles to achieve rapid identification of S. aureus by using the BACTEC 9240 blood culture system. MATERIALS AND METHODS: A total of 129 BACTEC 9240 bottles growing gram-positive cocci suggesting Staphylococci were tested directly from blood culture broths (BCBs) with TCT, Dry Spot Staphytect Plus, conventional PCR and LightCycler Staphylococcus MGrade kit for rapid identification of S. aureus. RESULTS: The sensitivities of the tests were 99, 68, 99 and 100%, respectively. CONCLUSION: Our results suggested that 2 h TCT was found to be simple and inexpensive method for the rapid identification of S. aureus directly from positive blood cultures. PMID- 21304195 TI - Nested polymerase chain reaction on blood clots for gene encoding 56 kDa antigen and serology for the diagnosis of scrub typhus. AB - PURPOSE: Scrub typhus is a zoonotic illness endemic in the Asia-Pacific region. Early diagnosis and appropriate management contribute significantly to preventing adverse outcomes including mortality. Serology is widely used for diagnosing scrub typhus. Recent reports suggest that polymerase chain reaction (PCR) could be a rapid and reliable alternative. This study assessed the utility of these tests for scrub typhus diagnosis. MATERIALS AND METHODS: Nested PCR to detect the 56 kDa antigen gene of O. tsutsugamushi was performed on blood clots from 87 individuals with clinically suspected scrub typhus. Weil-Felix test and scrub typhus IgM ELISA were performed on serum samples from the same patients. As a gold standard reference test was not available, latent class analysis (LCA) was used to assess the performance of the three tests. RESULTS: The LCA analysis showed the sensitivity of Weil-Felix test, IgM ELISA and PCR to be 59%, 100% and 58% respectively. The specificity of ELISA was only 73%, whereas those of the Weil-Felix test and PCR were 94% and 100% respectively. CONCLUSION: Nested PCR using blood clots while specific, lacked sensitivity as compared to IgM ELISA. In resource-poor settings Weil-Felix test still remains valuable despite its moderate sensitivity. PMID- 21304196 TI - Evaluation of a commercial Dengue NS1 enzyme-linked immunosorbent assay for early diagnosis of dengue infection. AB - PURPOSE: Dengue is one of the most serious mosquito-borne viral infections affecting tropical and subtropical countries in the world. Since there is no immunoprophylactic or specific antiviral therapy available, timely and rapid diagnosis plays a vital role in patient management and implementation of control measures. This paper evaluates a commercially available NS1 antigen capture ELISA vis-a-vis SD bioline Dengue NS1 antigen test for early detection of dengue virus. MATERIALS AND METHODS: To evaluate a commercial NS1 antigen detection kit vis-a vis SD bioline Dengue NS1 antigen test, a total of 91 clinical samples were tested. Virological investigations with regard to dengue virus, viz. NS1 antigen capture ELISA (Panbio, Australia), SD bioline Dengue NS1 antigen test, RT-PCR and virus isolation were performed. RESULTS: Out of 91 samples, 24 (26%) were positive by NS1 antigen capture ELISA, 15 (16%) by SD bioline Dengue NS1 antigen test and 11(12%) positive by RT-PCR analysis. The RT-PCR-positive samples were further subjected to virus isolation and resulted in three isolates. The results of the Panbio NS1 antigen capture ELISA, SD bioline Dengue NS1 antigen test, RT PCR and virus isolation were correlated among themselves. CONCLUSIONS: The present study comprehensively established the utility of NS1 antigen ELISA in early diagnosis of dengue infection. PMID- 21304197 TI - Cost-effective screening of pooled faecal specimens from patients with nosocomial diarrhoea for Clostridium perfringens enterotoxin. AB - PURPOSE: Clostridium perfringens is a significant cause of nosocomial AAD. The prevalence of C. perfringens enterotoxin (CPE)-positive stool specimens in hospitalised patients is very low in the Indian setting making the diagnostics very expensive. Therefore, a cost-effective diagnostic approach to screen faecal specimens for CPE was devised. MATERIALS AND METHODS: Faecal specimens from 540 hospitalised patients with various ailments and from 340 healthy subjects were investigated for CPE. An aliquot of pooled faecal supernatants was made by mixing 100 MUl each of 10 specimens to be tested. Each aliquot was investigated for the presence of CPE by an enzyme immunoassay. A repetition of the assay was done with individual specimens of the pooled aliquots from each positive well as seen visually by colour development. RESULTS: Of the 540 patient specimens tested, 405 (75%) patients were on antibiotics, the predominant ones being cephalosporins, penicillin, quinolones, aminoglycosides, etc. During the time of sampling, diarrhoea was present in 481 (89%), abdomen pain in 203 (37.6%) and fever in 242 (44.8%) patients. C. perfringens enterotoxin was positive in nine wells of the 540 pooled test specimens whereas all of the pooled 340 control samples were negative. Repeat of individual specimens comprising the nine wells with positive samples helped to identify the individual patients positive for CPE. CONCLUSION: Only two CPE kits were needed for a total of 880 faecal specimens tested. The cost-effective diagnostic approach to screen faecal specimens for CPE, as described herein will help to save institutional resources. PMID- 21304198 TI - Sepsis due to linezolid resistant Staphylococcus cohnii and Staphylococcus kloosii: first reports of linezolid resistance in coagulase negative staphylococci from India. AB - Linezolid, a viable alternative to vancomycin against methicillin resistant staphylococcal isolates, has been in use for a decade around the globe. However, resistance against staphylococci remains extremely rare and unreported from most of the Asian countries. Herein, we report two cases of linezolid resistant, coagulase negative staphylococcal sepsis for the first time from India. The first case was an 18-year-old burn patient, who, after a major graft surgery, landed in sepsis, and linezolid resistant Staphylococcus cohnii with an minimum inhibitory concentration (MIC) of >256 MUg/ml by both broth microdilution and Etest, was isolated from multiple blood cultures. The second patient was a 60-year-old male with an intracranial bleed and sepsis, from whose blood cultures, linezolid resistant Staphylococcus kloosii was repeatedly isolated. Linezolid MIC was >32 MUg/ml by broth microdilution and >16 MUg/ml by Etest. PMID- 21304199 TI - Tuberculosis of nose and palate with vanishing uvula. AB - During the past two decades, tuberculosis - both pulmonary and extrapulmonary - has re-emerged as a major health problem worldwide. Nasal tuberculosis - either primary or secondary to pulmonary tuberculosis or facial lupus - is rare, but it should be considered in the differential diagnosis of nasal granulomas. We describe a case of tuberculosis in an adult male who presented with palatal perforation with vanishing uvula and arch deformity of the palate. The diagnosis was based on histopathology and patient's successful response to antituberculous drug treatment. PMID- 21304200 TI - Bacteremia due to Rhodococcus equi in an immunocompetent infant. AB - Rhodococcus equi , previously known as Corynebacterium equi, is one of the most important causes of zoonotic infection in grazing animals. Increased cases of human infection with R. equi have been reported especially in immunocompromised patients. Infection in immunocompetent patients is extremely rare. We report a case of R. equi bacteremia in a 26-day-old immunocompetent infant with recurrent swellings on different parts of the body. To the best of our knowledge, this is the first ever report of R. equi bacteremia from an immunocompetent patient from Northern India. PMID- 21304201 TI - Nocardia brasiliensis primary pulmonary nocardiosis with subcutaneous involvement in an immunocompetent patient. AB - This is a report of an unusual case of Nocardia brasiliensis causing primary pulmonary nocardiosis with disseminated subcutaneous lesions in an immunocompetent patient. This case highlights the importance of considering nocardiosis as a differential diagnosis in patients with pulmonary and cutaneous lesions and the need for vigorous management for complete cure. PMID- 21304202 TI - Vancomycin-dependent Enterococcus. PMID- 21304203 TI - Testing Hepatitis A virus antibody in oral fluid among the prospective vaccinees foster the need of new oral HAV rapid test. PMID- 21304204 TI - Laboratory confirmed outbreak of meningococcal infections in Tripura. PMID- 21304205 TI - Extended spectrum beta-lactamase production in Shigella isolates - a matter of concern. PMID- 21304206 TI - First case of resistance to tigecycline by Klebsiella pneumoniae in a European University Hospital. PMID- 21304207 TI - Neonatal listeriosis: a case report from sub-Himalayas. PMID- 21304209 TI - Simultaneous visualization of 2 intracardiac masses in both atria on 3 dimensional transesophageal echocardiography. PMID- 21304208 TI - Acid-sensing ion channels in blood volume regulation. PMID- 21304210 TI - Combined measurements of cardiac troponin I and brain natriuretic peptide are useful for predicting adverse outcomes in hypertrophic cardiomyopathy. AB - BACKGROUND: Although serum cardiac troponin I (cTnI) and plasma brain natriuretic peptide (BNP) have become clinically important tools as diagnostic and prognostic markers for ischemic heart disease and heart failure, the usefulness of these biomarkers for risk stratification of hypertrophic cardiomyopathy (HCM) is not clear. METHODS AND RESULTS: We studied 167 patients with HCM, and cTnI and BNP were measured. During follow-up (38.5 months), 20 patients suffered from cardiovascular events: HCM-related deaths in 6, hospitalization for heart failure in 8, embolic stroke in 5 and 1 patient with spontaneous sustained ventricular tachycardia. Patients with high cTnI values (>=0.04 ng/ml) had more frequent cardiovascular events than did those with low cTnI values (P=0.008). Similarly, there were more frequent adverse events in the high BNP group (>=200 pg/ml) than in the low BNP group (P=0.002). When groups were allocated according to both cTnI and BNP measurements, serum cTnI used in conjunction with BNP further improved the prognostic value; patients with both high cTnI and BNP values had an 11.7 fold increased risk of cardiovascular events compared with those with both low cTnI and BNP values. CONCLUSIONS: CTnI and BNP are useful parameters for identifying patients at risk for clinical deteriorations, and combined measurements of these biomarkers further improves the prognostic value of increased cardiovascular events in HCM. PMID- 21304211 TI - Role of the acid-sensing ion channel 3 in blood volume control. AB - BACKGROUND: The mechanically sensitive volume receptors, primarily located in the venoatrial junction area, are essential for blood volume homeostasis. However, the molecular basis of the volume receptors is still unknown. METHODS AND RESULTS: We hypothesized that the acid-sensing ion channel 3 (ASIC3) might be a candidate for the mechanically sensitive molecules expressed in the volume receptors. We examined the effect of Asic3 null mutation (Asic3(-/-)) on blood volume expansion (BVE)-induced urine flow, neural activation, and atrial natriuretic peptide (ANP) release in mice. BVE-induced urine flow was lower in Asic3(-/-) mice than in wild-type littermates. In addition, the stretch-activated channel blocker GdCl(3) further reduced the BVE-induced urine flow in Asic3(-/-) mice. BVE increased phosphorylated extracellular signal-related kinase (pERK) immunoreactivity in nodose ganglia and many segments of dorsal root ganglia (DRG) in all mice, but pERK-positive neurons were fewer in Asic3(-/-) mice or mice pretreated with GdCl(3) than in wild-type mice. Asic3 knockout selectively decreased BVE-induced pERK-immunoreactive neurons in nodose ganglia, and in C8 and T2 DRG. Moreover, BVE increased the circulating ANP level, which was abolished in Asic3(-/-) mice and wild-type mice treated with GdCl(3). Asic3 knockout reduced the BVE-induced plasma ANP elevation in a GdCl(3)-independent manner. CONCLUSIONS: ASIC3 is a molecular substrate involved in detecting the vessel stretch caused by BVE. PMID- 21304212 TI - Alanine aminotransferase is associated with metabolic syndrome independently of insulin resistance. AB - BACKGROUND: Few studies have examined the effect of insulin resistance on the association between alanine aminotransferase (ALT) and metabolic syndrome. The association between ALT levels and metabolic syndrome were determined, independently of insulin resistance in Korean populations. METHODS AND RESULTS: The association between ALT and metabolic syndrome were examined in 28,456 subjects who visited 7 Health Promotion Centers at University Hospitals in Korea from 2006 to 2008. HOMA-IR index was used to represent insulin resistance index. ALT levels were found to be positively associated with metabolic syndrome after adjusting for age, alcohol intake, and smoking status. Furthermore, when additional adjustment was made for insulin resistance, this association between ALT and metabolic syndrome, although slightly attenuated, remained strongly significant. Subjects in the highest ALT quartile were found to have a higher risk of having metabolic syndrome than those in the lowest quartile (odds ratio (OR)=4.45, 95% confidence interval (CI)=3.96-4.99 for men and OR=3.51, 95%CI=2.73 4.52 for women). In addition, the association between ALT level and the risk of metabolic syndrome was significantly higher in the relatively low risk group. CONCLUSIONS: ALT levels were found to be significantly associated with metabolic syndrome independently of insulin resistance and with an interaction by age. Further cohort studies are needed to determine the usefulness of ALT levels for predicting the risk of metabolic syndrome. PMID- 21304213 TI - Guidelines for diagnosis and treatment of myocarditis (JCS 2009): digest version. PMID- 21304214 TI - A phase III, multicenter, collaborative, open-label clinical trial of sildenafil in Japanese patients with pulmonary arterial hypertension. AB - BACKGROUND: There is evidence that phosphodiesterase type-5 is effective for the treatment of pulmonary arterial hypertension (PAH). METHODS AND RESULTS: A phase III, multicenter, open-label clinical trial of sildenafil 20mg t.i.d. was conducted in 21 Japanese patients with PAH to examine its efficacy, safety, and pharmacokinetics. The present trial consisted of a screening period and 12-week treatment. Patients who were enrolled in the present trial increased their 6-min walking distance of administration increased at week 12 by 84.2m from baseline. Hemodynamic parameters (eg, mean pulmonary artery pressure and pulmonary vascular resistance), Borg dyspnea scores, and plasma brain natriuretic peptide concentrations also improved compared to baseline. Most patients improved or sustained WHO functional class. Seven subjects, who were examined for the pharmacokinetics of sildefanil, showed relatively large interindividual variations in the C(max), AUC(0-8), C(ss,av), and C(trough) of the drug. Any serious adverse events, severe adverse events, and deaths were not observed. Most of events of undeniable causality were mild or moderate in severity. Sildefanil was well tolerated by the subjects. CONCLUSIONS: Sildenafil 20mg t.i.d. was effective and safe for Japanese patients with PAH. PMID- 21304215 TI - Comparative study between high-dose fluvastatin and low-dose fluvastatin and ezetimibe with regard to the effect on endothelial function in diabetic patients. AB - It is well established that statins improve the prognosis of patients with coronary artery disease. However, it is still unclear whether the protective effects of statins relate to lipid lowering alone or whether other pleiotropic effects may contribute. Thus, we compared the endothelial function among two groups of diabetic patients treated with fluvastatin 60 mg (F60) or fluvastatin 20 mg combined with ezetimibe 10 mg (F20/E10). The endothelial function was evaluated by measuring flow-mediated vasodilatation (FMD) at baseline and follow up at 10 weeks. Similar improvements in FMD were observed in the two groups. The reduction in low-density lipoprotein cholesterol (LDL-C) was less pronounced in the F60 group, compared with the F20/E10 group. A significant reduction in remnant-like lipoprotein particles cholesterol (RLP-C) was observed in the F20/E10 group, but not in the F60 group. A correlation between the observed reduction in LDL-C or RLP-C and the improvement in FMD was observed in F20/E10 group. These results suggest that high-dose fluvastatin might have pleiotropic effects of potential clinical benefit, and that the combination of ezetimibe with a reduced dose of fluvastatin may also significantly improve endothelial function with reduction of LDL-C and RLP-C. PMID- 21304216 TI - A rapid and simple method to obtain canine peripheral blood-derived macrophages. AB - Macrophages play an important role in a variety of situations, including pathogen elimination, inflammation, and tissue repair. However, these cells are not fully studied in dogs, in part, due to the difficulty of efficiently isolating and culturing them in vitro. In this study, we cultured canine peripheral blood mononuclear cells (PBMCs) with 10 ng/ml of phorbol 12-myristate-13-acetate (PMA) for 5 days to obtain macrophages. A high number of round-adherent cells were obtained without the addition of any cytokine. These cells showed active phagocytic activity and a cell surface antigen profile different from dendritic cells. Our method facilitates a high yield of macrophages in a short cultivation period compared with previous studies. This method might be a powerful tool to study macrophage functions in dogs. PMID- 21304217 TI - Sitagliptin, a dipeptidyl peptidase-4 inhibitor, decreases systolic blood pressure in Japanese hypertensive patients with type 2 diabetes. AB - Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is a newly developed oral hypoglycemic agent. Sitagliptin increases the level of glucagon-like polypeptide (GLP)-1 that increases insulin secretion. In addition, GLP-1 decreases salt intake and increases urinary salt excretion. Therefore, the sitagliptin treatment might lower blood pressure in hypertensive patients with type 2 diabetes. It also remains to be examined whether the reduction in blood pressure with sitagliptin treatment is related to the blood glucose improvement and the body weight decrease. To identify beneficial effects of sitagliptin treatment, we administered sitagliptin (50 mg) on alternate days to seventeen type 2 diabetes outpatients with insufficient blood glucose control (8 males and 9 females; mean age of 67.1 years). The patients were also treated with oral hypoglycemic agents and antihypertensive drugs for six months before and during the sitagliptin administration. We measured the level of hemoglobin (Hb) A1c, systolic blood pressure (SBP), and body mass index (BMI) for up to six months thereafter. Their BMIs remained unchanged. The levels of HbA1c were dropped from 6.5 +/- 0.3% to 5.8 +/- 0.3%, while SBP was also dropped from 130.0 +/- 37.2 mmHg to 119.7 +/- 9.4 mmHg. However, the degree of the decrease in HbA1c levels was not significantly correlated with that of SBP (r = 0.24). In conclusion, the present findings suggest that sitagliptin lowers SBP without reducing BMI, independent of the blood glucose reduction. The hypotensive effect is apparent with the alternate-day regimen of sitagliptin at a lower dose compared to the everyday medication. PMID- 21304218 TI - Cyclooxygenase-2 polymorphisms and susceptibility to esophageal cancer: a meta analysis. AB - Esophageal cancer (EC) is one of the most common cancers worldwide with 5-year survival rate less than 10%. However, there is a lack of specific genetic markers that could help better understanding the mechanisms of esophageal carcinogenesis, improving the detection rate of EC, and distinguishing histological types. Cyclooxygenase-2 (COX-2) as an inducible enzyme in cancer development and progression is involved in esophageal carcinogenesis. A large number of studies have demonstrated a strong association between COX-2 polymorphisms and EC risk. However, the overall results are still controversial. This controversy may be partly due to the mix-up of esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC). The aim of this study was to investigate the association between COX-2 polymorphisms and susceptibility to ESCC or EAC by conducting a meta-analysis. Seven studies were retrieved reporting a total of 1450 ESCC patients, 523 EAC patients, and 2663 cancer-free control subjects. Five COX-2 polymorphisms were addressed, including -765G>C (rs20417), -1195G>A (rs689465), 1290A>G (rs689466), -8473T>C (rs5275) and -1759G>A (rs3218625). Meta-analysis results showed that the -765C allele is significantly associated with the susceptibility to both ESCC and EAC especially in Asian populations. In addition, there was a significant association between the -8473C allele and the susceptibility to EAC in Caucasian populations. In conclusion, our meta-analysis suggests that the -765C allele of the COX-2 gene might be a potential risk factor for both ESCC and EAC especially in Asian populations, while the -8473C allele might be a risk factor for EAC in Caucasian populations. PMID- 21304219 TI - Comparison of immunosorbent assays for the quantification of biomarkers for Alzheimer's disease in human cerebrospinal fluid. AB - BACKGROUND: The clinical diagnosis of Alzheimer's disease in early stages may be substantiated by the quantification of the biomarkers Abeta42, Abeta40 and total Tau (t-Tau) in cerebrospinal fluid (CSF). Different commercially available immunosorbent assays yield reliable results, yet the absolute values obtained may differ in between tests. METHODS: We used CSF samples from patients that reported to our memory clinic. Enzyme-linked immunosorbent assays obtained from Innogenetics were used for the quantification of Abeta42 and t-Tau, test kits from IBL International were used to determine Abeta42 and Abeta40 concentrations. The multiplex assay system obtained from Mesoscale Discovery (MSD) Systems was used for the quantification of all three biomarkers. RESULTS: For all biomarkers, the absolute values obtained with different test systems differ. However, the data sets highly correlate for all comparisons, with the MSD test system proving to be slightly more sensitive. Correlation coefficients (c) for the Abeta42 and Abeta40 quantifications lie between c = 0.80 and c = 0.87, and for the t-Tau quantifications we determined c = 0.99. CONCLUSION: We conclude that all assays evaluated give reliable results, yet absolute values obtained have to be assessed differently within the framework of diagnostic procedures, depending on the system used. PMID- 21304220 TI - Skeletal muscle metabolic gene expression is not affected by dichloroacetate mediated modulation of substrate utilisation. AB - AIM: This study investigated whether changing fuel use, by increasing pyruvate dehydrogenase complex (PDC) flux, independently of plasma substrate availability and insulin signalling, would alter metabolic gene expression. METHODS: The PDC activator, dichloroacetate (DCA), was administered as an intravenous infusion in healthy male subjects at a rate of 50 mg kg(-1) min(-1), for 90 min. Saline was infused as a control (CON) on a separate occasion in a randomised sequence. Muscle biopsies were taken from the vastus lateralis at 0 and 30 min into the infusion and 90 min after infusion. Gene expression was quantified using RT-qPCR, and immunoblotting was used to confirm that there were no changes in insulin signalling via the PI3K/Akt pathway. RESULTS: Blood glucose concentrations fell during both trials but 3 h after the start of the infusion they were lower in DCA (p < 0.05) than CON. Blood lactate concentrations also declined in both trials (p < 0.01), however, this decrease was also more pronounced in DCA than CON (p < 0.001). Carbohydrate oxidation was increased by DCA, 0.037 +/- 0.017 g min(-1) (p < 0.05) at 3 h with no change observed in CON. UCP3 and PGC1alpha mRNA expression were induced in CON (as a response to continued fasting) but this was attenuated by DCA. Akt phosphorylation and the expression of other metabolic genes and transcription factors were unchanged throughout the intervention. CONCLUSION: It is concluded that PDC flux can be increased independently of plasma substrate availability, without causing downstream alterations to metabolic gene expression in the short term. PMID- 21304221 TI - Insulin resistance: pathophysiology and rationale for treatment. AB - After binding to its receptor and activating the beta-subunit, insulin is faced with two divergent pathways: one is phosphatidylinositol 3-kinase (PI 3-K) dependent, while another is dependent upon activation of mitogen-activated protein kinase (MAP-K). The former is absolutely necessary for mediating most metabolic and antiapoptotic effects; the latter is linked to nonmetabolic, proliferative and mitogenic effects. In obese patients, especially with type 2 diabetes mellitus (DM2), only the PI 3-K, but not the MAP-K, is resistant to insulin stimulation: hence insulin resistance is better defined as metabolic insulin resistance. The resulting 'compensatory hyperinsulinemia' is an unsuccessful attempt to overcome the inhibition of the metabolic pathway at the price of unopposed stimulation of the MAP-K pathway, and the administration of exogenous insulin might worsen the metabolic dysfunction. As the preferential activation of the MAP-K pathway in insulin-resistant patients has atherogenic and mitogenic properties, this leads to atherosclerosis and cancer. Metformin may carry out direct protective action on human beta cells, inasmuch as it improves both primary and secondary endpoints through selective inhibition of fatty acyl oxidation. PMID- 21304222 TI - Long-term efficacy of Serenoa repens treatment in patients with mild and moderate symptomatic benign prostatic hyperplasia. AB - INTRODUCTION: The study aimed to evaluate the long-term efficacy of treatment with extract of Serenoa repens (Prostamol Uno) in patients with lower urinary tract symptoms (LUTS) induced by benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: We studied 120 patients with mild or moderate LUTS induced by BPH, maximal urinary flow (Q(max)) <15 ml with a voided volume >=150 ml, prostate specific antigen <4 ng/ml, and residual urinary volume <150 ml, treated daily for 24 months with one capsule of 320 mg ethanolic extract of Serenoa repens. RESULTS: Statistically significant improvements in the International Prostate Symptom Score (5.5 points), quality of life (QoL; 1.8 points), Q(max) (5.6 ml/s), International Index of Erectile Function (IIEF; 6.4 points) and reduction in residual urinary volume were observed during the study period. The mean prostate volume at 24 months was 36 ml, compared to 39.8 ml at baseline. CONCLUSIONS: Long term treatment with 320 mg ethanolic extract of Serenoa repens proved to be efficient in reducing urinary obstruction, improving symptomatology and QoL of BPH patients. It also had a positive effect on sexual function, demonstrated by the statistically significant increase in the IIEF. PMID- 21304223 TI - Bupivacaine induces reactive oxygen species production via activation of the AMP activated protein kinase-dependent pathway. AB - AIMS: It was our aim to investigate whether AMP-activated protein kinase (AMPK) mediates the considerable increase in reactive oxygen species (ROS) and cell apoptosis induced by bupivacaine in the human neuroblastoma cell line SH-SY5Y. METHODS: The recombinant plasmids pGPU6/GFP/Neo-shRNA AMPKalpha2 and pEGFP-N1 AMPKalpha2 were constructed and transfected into the SH-SY5Y cell line. The expression of AMPKalpha2 was determined by RT-PCR and Western blot after transfection. The SH-SY5Y cells transfected with recombinant plasmid were exposed to 1 mmol/l bupivacaine. Cell viability, intracellular ROS and apoptosis were determined. RESULTS: The plasmid pEGFP-N1-AMPKalpha2 can upregulate the expression of AMPKalpha2, and the pGPU6/GFP/Neo-shRNA AMPKalpha2 can downregulate the expression of AMPKalpha2 in cells. Inhibition of AMPKalpha2 expression attenuated ROS production and cell apoptosis, and overexpression of AMPKalpha2 promoted ROS production and cell apoptosis after bupivacaine treatment. CONCLUSION: AMPK probably mediated ROS production and cell apoptosis induced by bupivacaine. PMID- 21304224 TI - Correlation between serum immunoglobulin G and hearing threshold among elderly subjects with age-related hearing loss. AB - BACKGROUND AND PURPOSE: This study was based on the hypothesis that suboptimal immune response and low serum immunoglobulin G (IgG) may predispose to age related hearing loss (ARHL), and the objective was to determine the serum levels of IgG and hearing thresholds of apparently healthy elderly subjects and assess their correlation. METHOD: This prospective study involved 126 participants >= 60 years old who were found to be free of any medical conditions. Pure-tone averages for both the speech (500-2,000 Hz) and high frequencies (3,000-8,000 Hz) and serum IgG levels were determined. Using 30 dB as cut-off for hearing loss, the correlation with serum IgG was assessed. RESULTS: There were 59 males and 67 females with a mean age +/- SD of 67.0 +/- 2.7 years. Speech frequency hearing loss was seen in 30.2%, while high-frequency hearing loss accounted for 74.6%. In the speech frequencies, the mean +/- SD of serum IgG among subjects with normal hearing was 11.3 +/- 3.9 g/l, while among those with hearing loss it was 8.3 +/- 3.3 g/l (p = 0.01). In the high frequencies, the mean +/- SD values of serum IgG among the subjects with normal hearing was 11.1 +/- 2.3 g/l, while among those with hearing loss it was 8.7 +/- 1.9 g/l (p = 0.01). CONCLUSION: Low serum IgG may be a contributory factor to the development of ARHL among the elderly. However, a longitudinal study involving intervention with immunoglobulin supplementation may further confirm this role. PMID- 21304225 TI - Pituitary stalk dysgenesis-induced hypopituitarism in adult patients: prevalence, evolution of hormone dysfunction and genetic analysis. AB - OBJECTIVES: To investigate the prevalence of pituitary stalk dysgenesis (PSD) in adult hypopituitary patients by describing the chronology of hormone deficiencies and their potential correlation with traumatic delivery, mutations in genes required for pituitary development and function and pituitary stalk visibility on MRI. DESIGN: Retrospective and prospective study involving 231 hypopituitary patients, including 26 diagnosed with PSD. Clinical, biochemical and radiological studies were reviewed. Molecular analyses of HESX1, LHX4,PROP1 and POU1F1 genes were performed prospectively. RESULTS: PSD was present in 11.2% of hypopituitary patients. PSD was diagnosed before 14 years of age in 46.2% of cases, between 14 and 18 years of age in 23%, and in adulthood in 30.8%. Perinatal complications or gene mutations were present in 26.9 and 4.3% of patients, respectively. At first assessment, 92.3% of patients had growth hormone (GH) deficiency. 26.9% presented as combined pituitary deficiencies and 7.6% as panhypopituitarism. Hormone deficiencies were progressive during follow-up in 84.6%. 96% progressed to multiple deficiencies and 46% to panhypopituitarism. No significant association was found between hormonal dysfunction and previous perinatal damage or breech delivery (p = 0.17), PROP1 mutations (p = 0.26) or pituitary stalk visibility on MRI (p = 0.52). No mutations in POU1F1, HESX1 and LHX-4 genes were detected. CONCLUSION: In this study, PSD prevalence in adult hypopituitary patients was 11.2%. Typical clinical presentation includes isolated or combined pituitary hormone deficiencies during the pediatric age, which usually progress to combined or complete hypopituitarism in adulthood. Phenotype is highly variable depending on hormone profile and age at onset. PMID- 21304226 TI - New insight into the hypercoagulability of Cushing's syndrome. AB - BACKGROUND: Hypercoagulability and a tendency for thromboembolic complications are reported in Cushing's syndrome (CS). The hypercoagulability is due mainly to the cortisol-induced increase in von Willebrand factor (VWF) and factor VIII. This is not a constant feature of CS, however; it depends on particular single nucleotide polymorphism (SNP) haplotypes in the VWF gene promoter: haplotype 1 ( 3268G/-2709C/-2661A/-2527G) confers a greater risk of VWF upregulation by cortisol than haplotype 2 (-3268C/ -2709T/-2661G/-2527A). In healthy individuals these SNPs are in linkage disequilibrium with the -2144 (GT)(n) of the VWF promoter: haplotype 1 mainly segregates with short GT repeats (15-19, GTs), haplotype 2 with long repeats (GT >= 20, GT(L)). METHODS: We analyzed the (GT)(n) locus, the SNP haplotypes and their association with VWF levels in 80 CS patients in order to precisely define the cortisol-sensitive VWF promoter pattern. CS patients were divided into groups A (increased VWF) and B (normal VWF). RESULTS: Haplotype 1 and (GT)(S) were more frequent in group A patients, and conferred a 9 and 7.5-fold risk of developing high VWF levels, respectively. Haplotype 2 and (GT)(L) were more represented in group B. There was also an unexpected higher prevalence of recombinant SNP haplotypes in CS patients (6.2%) than in normals (0.9%), p = 0.002. CONCLUSIONS: Our results indicate that the cortisol-induced increase in VWF may be predicted by VWF promoter polymorphisms, haplotype 1 and (GT)(S) being the sensitive pattern. These represent new markers for defining the prothrombotic risk of CS. The clinical significance, if any, of the increased recombination rate in SNP haplotypes in the VWF promoter warrants further study. PMID- 21304227 TI - Antidepressants reverse short-photoperiod-induced, forced swim test depression like behavior in the diurnal fat sand rat: further support for the utilization of diurnal rodents for modeling affective disorders. AB - Recent findings demonstrate strong links between abnormalities in circadian rhythms and sleep and the etiology, pathophysiology and treatment of major affective disorders. Further exploration of these interactions requires the development, identification and utilization of good and predictive animal models. The biology and behavior related to circadian rhythms are significantly different in diurnal and nocturnal rodents. Accordingly, it is possible that exploring the interactions between these mechanisms and affective change in diurnal animals may be advantageous. Recent studies demonstrate that diurnal fat sand rats and Nile grass rats show depression-like behavior when maintained under short-photoperiod (SP) conditions compared with animals maintained under neutral photoperiod (NP) conditions. Moreover, these behaviors were ameliorated after treatment with bright light. The present study further explores the possible utility of sand rats as animal models by testing the effects of antidepressants on the SP-induced depression-like behaviors of sand rats. Sand rats maintained in SP or NP conditions for 3 weeks were treated subchronically (5 injections) with the clinically effective antidepressant bupropion, and their behavior was tested in a number of depression-related tests. Results show that antidepressant treatment reverses the effects of SP conditions in the forced swim test, but that neither SP conditions nor antidepressants influenced sweet solution preference. These results partly support the validity of the sand rat model, but suggest that not all tests that were validated in nocturnal laboratory rodents can be applied to other rodent species and that additional tests should be applied to further explore the validity of the model. PMID- 21304228 TI - P-glycoprotein influence on the brain uptake of a 5-HT(2A) ligand: [(18)F]MH.MZ. AB - BACKGROUND/AIMS: The serotonergic system, especially the 5-HT(2A) receptor, is involved in various diseases and conditions. We have recently developed a new [(18)F]-5-HT(2A) receptor ligand using an analogue, MDL 100907, as a basis for molecular imaging with positron emission tomography. This tracer, [(18)F]MH.MZ, has been shown to be an adequate tool to visualize the 5-HT(2A) receptors in vivo. However, [(18)F]altanserin, similar in chemical structure, is a substrate of efflux transporters, such as P-glycoprotein (P-gp), of the blood-brain barrier, thus limiting its availability in the central nervous system. The aim of this study was to determine whether transport by P-gp influences the distribution ratio of [(18)F]MH.MZ in the frontal cortex. METHODS: The approach was based on P gp knockout mice which were compared with wild-type mice under several conditions. In vivo pharmacokinetic and microPET investigations were carried out. RESULTS: All analyses showed that [(18)F]MH.MZ entered the brain and was sensitive to P-gp transport. In P-gp knockout mice, brain concentrations of MH.MZ were about 5-fold higher than in wild-type animals which is reflected by a 2-fold increase in standardized uptake values of [(18)F]MH.MZ in the frontal cortex of P gp knockout mice. CONCLUSION: Our results give evidence for a functional role of transport mechanisms at the blood-brain barrier, specifically of P-gp, and its subregional distribution. Investigation of these mechanisms will benefit the development of more efficient radioligands and drugs for molecular imaging and pharmacotherapy of the mentally ill. PMID- 21304229 TI - Gender effect of catechol-O-methyltransferase Val158Met polymorphism on suicidal behavior. AB - Genetic factors and catecholaminergic dysfunction have been suggested as the etiology of suicide. The catechol-O-methyltransferase (COMT) 158Val/Met polymorphism affects COMT activity; that is, the alleles encoding Val and Met are associated with relatively high and relatively low COMT activity, respectively. We aimed to identify the role of the COMT Val158Met polymorphism in suicidal attempt behavior. The COMT 158Val/Met polymorphisms were analyzed in 197 suicide attempters (male/female: 70/127), 170 control subjects (male/female: 85/85). All subjects were ethnic Korean. The Lethality Suicide Attempt Rating Scale (LSARS) and risk-rescue rating (RRR) system were explored. For the male subjects, there was a significant difference in genotype distributions and allele frequencies between control subjects and suicide attempters. That is, Val/Val genotype and Val carriers were more frequent in suicide attempters than in control subjects. For the female subjects, however, no significant difference was shown in genotype distributions and allele frequencies between control subjects and suicide attempters. There were no significant differences in LSARS and RRR according to the genotypes. The distribution of the COMT 158Val/Met polymorphism showed a biologically meaningful difference between control subjects and suicide attempters among the male subjects although selection bias should be considered. PMID- 21304231 TI - Population-based screening of children for specific speech and language impairment in Germany: a systematic review. AB - OBJECTIVE: The study was aimed at evaluating the effectiveness of a systematic population-based screening programme for specific language impairment (SLI) in preschool children in Germany. METHODS: The study question was divided into a review of (1) evidence from studies evaluating screening programmes, (2) diagnostic instruments in the German language, and (3) studies evaluating speech and language interventions. A systematic database search was conducted between June and October 2007 and was updated in January and again in May 2008. Relevant studies were identified by 2 independent reviewers based on screened titles/abstracts and full texts. RESULTS: 4,806 studies were screened. The only existing controlled screening study did not provide data for SLI. No diagnostic study met the inclusion criteria. Sixteen randomized intervention studies were included, 3 studies contributed to the appraisal of earlier against later initiation of treatment. Most studies were of limited quality. We found indications of short-term positive effects from language therapies in children with SLI. Long-term outcomes were not investigated. No evidence supporting the advantage of earlier treatment initiation was identified. CONCLUSIONS: The benefit of population-based language screening of preschool children with SLI is not proven. Controlled screening studies are therefore necessary. For Germany, the accuracy of existing diagnostic instruments has not yet been sufficiently examined. PMID- 21304230 TI - Woodhouse-Sakati syndrome in an Israeli-Arab family presenting with youth-onset diabetes mellitus and delayed puberty. AB - BACKGROUND AND OBJECTIVE: Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive disorder characterized by a combination of hypogonadism, alopecia, diabetes mellitus (DM), mental retardation and extrapyramidal signs, not described previously in Israel. Our aim was to study the clinical and genetic characteristics of the extended family of a 16-year-old female who presented with new-onset DM and had delayed puberty on physical examination. METHODS: The primary physician's medical charts of 9 members of the proband's consanguineous Israeli-Arab family were reviewed. Hormonal, metabolic and antibody profile, imaging studies and molecular analysis were performed in 4 phenotypically compatible members, including the proband. RESULTS: Four subjects, 2 females and 2 males, had DM, absent pubertal development and similar appearance. None had extrapyramidal signs. The patients were homozygous for a one-base deletion mutation (c.436delC) in the C2orf37 gene. CONCLUSION: We describe the first Israeli-Arab family with phenotype and genotype of WSS, imitating autoimmune DM with gonadal failure. PMID- 21304232 TI - Quality control for intravascular intrauterine transfusion using cumulative sum (CUSUM) analysis for the monitoring of individual performance. AB - INTRODUCTION: Intravascular intrauterine transfusion (IUT) is an effective and relatively safe method for the treatment of fetal anemia. Although implemented in centers all over the world in the 1980s, the length and strength of the learning curve for this procedure has never been studied. Cumulative sum (CUSUM) analysis has been increasingly used as a graphical and statistical tool for quality control and learning curve assessment in clinical medicine. We aimed to test the feasibility of CUSUM analysis for quality control in fetal therapy by using this method to monitor individual performance of IUT in the learning phase and over the long term. METHODS: IUTs performed in the Dutch referral center for fetal therapy from 1987 to 2009 were retrospectively classified as successful or failed. Failed was defined as no net transfusion or the occurrence of life threatening procedure-related complications. The CUSUM statistical method was used to estimate individual learning curves and to monitor long-term performance. Four operators who each performed at least 200 procedures were included. RESULTS: Individual CUSUM graphs were easily assessed. Both operators pioneering IUT in the late 1980s had long learning phases. The 2 operators learning IUT in later years in an experienced team performed acceptably from the start and reached a level of competence after 34 and 49 procedures. DISCUSSION: CUSUM analysis is a feasible method for quality control in fetal therapy. In an experienced setting, individual competence may be reached after 30 to 50 IUTs. Our data suggest that operators need at least 10 procedures per year to keep a level of competence. PMID- 21304233 TI - Peritoneal resorption capacity for lipopolysaccharide and interleukin-6 in acute zymosan-induced chemical peritonitis. AB - AIM: To evaluate peritoneal resorption capacity for lipopolysaccharide (LPS) and interleukin-6 (IL-6) in a model of chemical peritonitis. METHODS: Zymosan peritonitis was induced in anesthetized rats. LPS was injected intraperitoneally to different groups at 4 h (n = 10), 8 h (n = 9), 12 h (n = 9), and 24 h (n = 9) after peritonitis and to a control group (n = 8). Similarly, IL-6 was injected intraperitoneally to different groups at 4 h (n = 9), 8 h (n = 10), 12 h (n = 10), and 24 h (n = 10) after peritonitis, and to a control group (n = 10). Plasma levels of LPS or IL-6 were measured immediately after intraperitoneal injections of LPS or IL-6, respectively, and at 5, 15, 30, 45, and 60 min later. RESULTS: There was no change over time in plasma LPS levels in the groups receiving LPS intraperitoneally (p = 0.4). There was highly significant change over time in the IL-6 level in the studied time periods in the groups receiving IL-6 intraperitoneally (p < 0.0001). There was an increase in the plasma IL-6 level when sampled at 4 h after peritonitis. CONCLUSION: There was a reduction of resorption capacity of inflamed peritoneum for inflammatory mediators in acute chemical peritonitis. PMID- 21304234 TI - Parental divorce, adolescents' feelings toward parents and drunkenness in adolescents. AB - The aim of this study was to explore the association between parental divorce and adolescent drunkenness and the contribution of adolescents' feelings toward their parents to this association. Cross-sectional data on 3,694 elementary school students from several cities in Slovakia (mean age 14.3, 49.0% males; response rate 93%) were obtained. Respondents completed questionnaires on how often they had been drunk in the previous 4 weeks, whether their parents were divorced and a measure of their feelings toward their parents. Parental divorce was found to have an effect on adolescent drunkenness in the previous month, as were the high rates of negative and low rates of positive feelings toward both parents. The effect of divorce on drunkenness strongly decreased if adjusted for the affect of the adolescent toward the father, but not the mother. Our findings indicate that to keep the father positively involved after divorce might be a protective factor with regard to a higher probability of adolescent drunkenness in divorced families. PMID- 21304235 TI - High prevalence of vitamin D deficiency in Zahedan, southeast Iran. AB - BACKGROUND: Several studies show a high prevalence of vitamin D deficiency in Asia. Data regarding the prevalence of vitamin D deficiency in southeast Iran are inadequate. OBJECTIVES: The purpose of this study was to determine the prevalence of vitamin D deficiency in Zahedan, a sunny area in southeast Iran. SUBJECTS AND METHODS: This population-based cross-sectional study was performed on 993 apparently healthy subjects. Serum levels of 25-hydroxy vitamin D (25-OH vit D), parathyroid hormone, calcium, phosphate, and alkaline phosphatase activity were measured. RESULTS: Inadequate vitamin D status was diagnosed in 94.7% of the subjects (25-OH vit D <30 ng/ml). The frequencies of deficiency (<20 ng/ml), insufficiency (20-30 ng/ml), sufficiency (30-150 ng/ml), and toxicity (>150 ng/ml) were 85.2, 9.5, 5.3, and 0.0%, respectively. CONCLUSION: The results indicate that vitamin D deficiency is common in the population of Zahedan. Based on our results, fortification of milk and the use of supplements is suggested in this region. PMID- 21304236 TI - Novel endoscopic technique for the diagnosis of early gastric cancer: endoscopy with crystal violet staining. PMID- 21304237 TI - Steroid and ursodesoxycholic Acid combination therapy in severe drug-induced liver injury. AB - BACKGROUND: Drug-induced liver injury (DILI) is the leading cause of acute severe liver disease in Western countries. Treatment strategies for DILI are still not well defined. AIM: We studied the safety and outcomes of steroid/ursodesoxycholic acid (UDCA) combination therapy in DILI patients. PATIENTS, MATERIALS AND METHODS: 15 consecutive patients with severe DILI were analyzed for clinical, biochemical and histological data. Nine patients were treated with a steroid step down therapy with reduction of the daily dose over several weeks; 6 patients received a steroid pulse therapy for 3 days. UDCA was administered for several weeks in both groups. RESULTS: Patients without histological signs of preexistent liver damage (n = 10) showed the most favorable clinical course. Bilirubin and serum transaminases dropped to <50% of peak values within 2 weeks, and normalized within 4-8 weeks. In contrast, patients with positive autoimmune antibodies (anti nuclear antibodies and/or soluble liver antigen) and/or histological features of chronic hepatitis (n = 3) exhibited a slower reduction in bilirubin and serum transaminase levels. These patients were given immunosuppressants (steroids, azathioprine) for a further 6 months. CONCLUSION: Treatment of severe DILI with corticosteroids (both pulse and step-down therapy) and UDCA appears to be safe, and leads to a more rapid reduction in bilirubin and transaminases after DILI. PMID- 21304238 TI - Effect of proton-pump inhibitor therapy on serum chromogranin a level. AB - BACKGROUND: The neuroendocrine marker, chromogranin A (CgA) increases during medium- or long-term proton-pump inhibitor (PPI) treatment. AIMS: To analyze the effect of ultra-short-term and diverse dose of PPI therapy on serum CgA and gastrin levels and evaluate the effect of PPI treatment cessation. PATIENTS AND METHODS: Fasting serum CgA and gastrin were determined in newly diagnosed gastroesophageal reflux disease (GERD) patients (n = 54) treated with diverse doses of PPI during a 28-day period, in patients treated with PPIs for at least 6 months (n = 42), and in subjects where PPI treatment could be stopped (n = 11). RESULTS: A significant stepwise increase of CgA levels was observed after 5 days during the 28-day period treatment with all PPI doses. Gastrin increased significantly also in the standard and high-dose PPI subgroups. The most prominent increase of CgA was observed in the high-dose PPI subgroup. Serum CgA and gastrin were markedly elevated after 6 months of PPI treatment, and decreased significantly after 5 days of PPI discontinuation. CONCLUSIONS: Serum CgA increases significantly even after ultra-short-term (5 days) PPI therapy. After long-term treatment, 5-day cessation of PPI therapy is sufficient to decrease significantly both CgA and gastrin levels. PMID- 21304239 TI - Analysis of IL2/IL21 gene variants in cholestatic liver diseases reveals an association with primary sclerosing cholangitis. AB - BACKGROUND/AIMS: The chromosome 4q27 region harboring IL2 and IL21 is an established risk locus for ulcerative colitis (UC) and various other autoimmune diseases. Considering the strong coincidence of primary sclerosing cholangitis (PSC) with UC and the increased frequency of other autoimmune disorders in patients with primary biliary cirrhosis (PBC), we investigated whether genetic variation in the IL2/IL21 region may also modulate the susceptibility to these two rare cholestatic liver diseases. METHODS: Four strongly UC-associated single nucleotide polymorphisms (SNPs) within the KIAA1109/TENR/IL2/IL21 linkage disequilibrium block were genotyped in 124 PBC and 41 PSC patients. Control allele frequencies from 1,487 healthy, unrelated Caucasians were available from a previous UC association study. RESULTS: The minor alleles of all four markers were associated with a decreased susceptibility to PSC (rs13151961: p = 0.013, odds ratio (OR) 0.34; rs13119723: p = 0.023, OR 0.40; rs6822844: p = 0.031, OR 0.41; rs6840978: p = 0.043, OR 0.46). Moreover, a haplotype consisting of the four minor alleles also had a protective effect on PSC susceptibility (p = 0.0084, OR 0.28). A haplotype of the four major alleles was independently associated with PSC when excluding the patients with concomitant inflammatory bowel disease (p = 0.033, OR 4.18). CONCLUSION: The IL2/IL21 region may be one of the highly suggestive but so far rarely identified shared susceptibility loci for PSC and UC. PMID- 21304240 TI - Submucosal fibrosis and basic-fibroblast growth factor-positive neutrophils correlate with colonic stenosis in cases of ulcerative colitis. AB - BACKGROUND AND AIMS: The frequency of benign stenosis in ulcerative colitis (UC) is low, reported as being 3.2-11.2%, with fibrosis in the submucosa or deeper pointed out as one of the causes. The aim of the present study was to assess stenosis in UC cases using immunostaining and to analyze differences between stenotic and nonstenotic cases, focusing on basic-fibroblast growth factor (b FGF) expression and myofibroblasts. METHODS: Totals of 9 stenotic and 17 nonstenotic UC cases were histopathologically examined and immunohistochemically stained for b-FGF, alpha-smooth muscle actin (alpha-SMA), CD34, CD68 and IL-6. To identify b-FGF-positive cells, double immunostaining for b-FGF and myeloperoxidase or CD68 was performed. RESULTS: In addition to submucosal fibrosis, a significant increase of b-FGF-positive inflammatory cells and myofibroblasts was observed in stenotic portions. Most b-FGF-positive cells were also positive for myeloperoxidase, and a correlation between b-FGF-positive and total neutrophil counts was found. CONCLUSIONS: One of the major causes of stenosis in long-standing UC is fibrosis in the bowel wall, possibly induced by infiltrating inflammatory neutrophils producing b-FGF. PMID- 21304241 TI - Proton pump inhibitor dose-related healing rate of artificial ulcers after endoscopic submucosal dissection: a prospective randomized controlled trial. AB - BACKGROUND/AIMS: Two studies have reported on the superiority of a proton pump inhibitor (PPI) compared with a histamine-2-receptor antagonist for the treatment of artificial ulcers after endoscopic submucosal dissection (ESD), but the optimal dose of PPI remains to be defined. The aim of this study was to evaluate the possibility of reducing the dose of PPI. The authors thus compared 30 mg (standard-dose) and 15 mg (half-dose) lansoprazole in terms of ulcer healing, prevention of bleeding and quality of life. METHODS: 91 patients with gastric mucosal neoplasm were enrolled. All patients who underwent ESD were administered lansoprazole 30 mg daily during the first week, after which they were randomly assigned to either the standard-dose or half-dose group. RESULTS: One patient in each group developed hematemesis. The stage of ulcers, ulcer reduction ratios and scores on the Gastrointestinal Symptom Rating Scale did not differ at 28 and 56 days. The costs of PPI for the half-dose group and standard-dose group were 7,326.5 and 11,698.4 JPY, respectively, i.e. a difference of 471.9 JPY. CONCLUSIONS: A reduced dose of PPI after 1 week of ESD was equivalent in treatment performance to the standard dose and cheaper. PMID- 21304242 TI - Hypoxemia during moderate sedation for gastrointestinal endoscopy: causes and associations. AB - BACKGROUND/AIMS: Although prolonged hypoxemia (henceforth referred to as hypoxemia) is not uncommon during moderate sedation for endoscopy, there are only sparse data regarding its relationship with medications, endoscopic intubations and ventilation patterns. We aimed to study these relationships. METHODS: 123 patients enrolled in the control arm of a randomized trial of ventilation monitoring during endoscopy were analyzed. Hypoxemia was defined as oxygen saturation of <90% for >=15 s, and apnea as lack of respiratory activity for >=15 s. RESULTS: There were 132 hypoxemic events; 46 (35%) and 112 (85%) events occurred within 1 and 5 min of medication administration/endoscopic intubations, and conversely, 46/638 (7%) and 112/638 (18%) of all medication administration/endoscopic intubations led to hypoxemia in 1 and 5 min, respectively. Apnea, abnormal ventilation and normal ventilation were associated with 36, 30 and 34% of all hypoxemia events, respectively. However, only 101/268 (38%) apnea/abnormal ventilation events led to hypoxemia. Significant predictors of apnea were total dose of meperidine/fentanyl 1.3 (1.02-1.6) and total dose of midazolam 0.84 (0.71-0.99). CONCLUSIONS: Hypoxemia occurs typically within 5 min of medication administration or endoscope intubation and only one third of all apnea/abnormal ventilation events eventually lead to hypoxemia. PMID- 21304243 TI - Acute renal failure caused by imiquimod 5% cream in a renal transplant patient: review of the literature on side effects of imiquimod. AB - Imiquimod is an immunomodulator of the imidazoquinoline group which possesses antiviral and antitumour activities. Although its mechanism of action has not been entirely elucidated yet, imiquimod 5% cream has been shown to be an efficient, long-lasting and safe therapy for multiple actinic keratoses in non immunosuppressed patients and in transplant recipients. We report the case of a 44-year-old patient with a third renal transplant who developed an acute tubular necrosis confirmed by renal biopsy after the use of imiquimod 5% cream. The result of a literature search revealed a wide variety of side effects attributable to the use of imiquimod. PMID- 21304244 TI - Prevention and correction mechanisms behind anaphase synchrony: implications for the genesis of aneuploidy. AB - The perpetuation of the species' genomic identity strongly depends on the accurate maintenance of chromosome number through countless cell generations. The synchronous entry and progression of all chromosomes through anaphase is fundamental for the quality of mitosis and is guaranteed by error prevention and correction mechanisms that ultimately certify the bipolar attachment of chromosomes to the mitotic spindle, the uniform distribution of forces amongst different chromosomes, and the simultaneity of sister-chromatid separation. The existence of a kinetochore-attachment checkpoint (KAC; also known as spindle assembly checkpoint) ensures a delay in anaphase onset if any kinetochore remains unattached or devoid of a proper complement of microtubules. The stochastic nature of microtubule-kinetochore interactions predisposes the mitotic process to mistakes, but different molecular players cooperate by detecting and releasing incorrect attachments and thus delaying checkpoint satisfaction. Conversely, correct microtubule-kinetochore interactions become selectively stabilized. Once anaphase onset is triggered, the segregation velocities achieved by each chromosome should be similar, so that none of the chromosomes is lagged behind. This reflects the uniformity of forces acting on the different chromosomes and relies on a conspicuous mitotic spindle property known as microtubule poleward flux. Importantly, not all incorrect attachments are detected and resolved prior to anaphase leading to asynchronous chromosome segregation, but several mechanisms are in place to prevent aneuploidy. One of these mechanisms relies on anaphase spindle forces and another, known as the NoCut checkpoint, delays cell cleavage during cytokinesis until chromosomes can free the spindle mid-region. In this review we discuss how these different mechanisms act in concert to ensure the fidelity of the mitotic process. PMID- 21304245 TI - Aspirin dose and ticagrelor benefit in PLATO: fact or fiction? AB - OBJECTIVES: To summarize the available evidence regarding whether or not a higher aspirin maintenance dose inversely affects the ticagrelor benefit observed in the US cohort of the PLATO trial. BACKGROUND: In the recent PLATO trial, the daily aspirin dosages in the USA were split between 81 and 325 mg while the vast majority of dosing outside of the USA was 75 or 100 mg. The FDA conducted exhaustive analyses of the aspirin dosage in a framework of primary clinical efficacy. Considering the post hoc, not prespecified nature of such analyses as well as multiple confounding problems with biologic plausibility, sensitivity to reclassification of small numbers of cases regarding loading versus maintenance aspirin dosing, and the distribution of events in high-dose aspirin observed outside of the USA, the FDA documents clearly suggest that aspirin dosing does not explain the disparate outcome results. In addition, the Advisory Committee members found no evidence to establish a reasonable link, and they uniformly rejected the hypothesis that aspirin dose affects the heterogeneity of outcomes in PLATO. METHODS: Additional evidence driven from the FDA review on aspirin dose and PLATO outcomes is reassessed. RESULTS: The wide distribution of outcomes differing from country to country, and inconsistency in European data despite identical aspirin doses, preclude the acceptance of the hypothesis that aspirin affects PLATO outcomes in general or adversely impacts the benefit of ticagrelor in the US cohort in particular. Differences in primary site monitoring by the study sponsor in most countries versus a third-party CRO in the USA represent an alternative explanation and deserve further attention. CONCLUSIONS: There is no solid evidence that aspirin dose affects outcomes after ticagrelor. Reevaluation of the overall endpoint differences, especially focusing on mortality, driven from sponsor-monitored sites versus outcomes observed by independent CROs is neccessary. The practice of self-monitoring in pivotal indication-seeking clinical trials should be avoided in the future. PMID- 21304246 TI - Caloric restriction and antiaging effects. AB - Caloric restriction (CR) is widely used to study aging processes. It is a simple and highly reproducible method for delaying the aging process, preventing the onset of aging-related diseases and extending average or maximum lifespan. However, the mechanism underlying these effects of CR is still not clear. CR can inhibit growth, reduce body size and maintain a low body temperature. At the same time, there is a measurable decrease in the volume of adipose tissue, hyperglycemia and hyperinsulinemia, accompanied by modifications of lipid and energy metabolism and increased resistance to endogenous and extraneous stress. The metabolic changes induced by dietary restriction, the inhibition of fat deposition in nonadipose tissue and the effects on signal transduction are considered the most likely candidates for mechanisms underlying the effects of CR. PMID- 21304247 TI - The pig genome project has plenty to squeal about. AB - Significant progress on pig genetics and genomics research has been witnessed in recent years due to the integration of advanced molecular biology techniques, bioinformatics and computational biology, and the collaborative efforts of researchers in the swine genomics community. Progress on expanding the linkage map has slowed down, but the efforts have created a higher-resolution physical map integrating the clone map and BAC end sequence. The number of QTL mapped is still growing and most of the updated QTL mapping results are available through PigQTLdb. Additionally, expression studies using high-throughput microarrays and other gene expression techniques have made significant advancements. The number of identified non-coding RNAs is rapidly increasing and their exact regulatory functions are being explored. A publishable draft (build 10) of the swine genome sequence was available for the pig genomics community by the end of December 2010. Build 9 of the porcine genome is currently available with Ensembl annotation; manual annotation is ongoing. These drafts provide useful tools for such endeavors as comparative genomics and SNP scans for fine QTL mapping. A recent community-wide effort to create a 60K porcine SNP chip has greatly facilitated whole-genome association analyses, haplotype block construction and linkage disequilibrium mapping, which can contribute to whole-genome selection. The future 'systems biology' that integrates and optimizes the information from all research levels can enhance the pig community's understanding of the full complexity of the porcine genome. These recent technological advances and where they may lead are reviewed. PMID- 21304248 TI - Characterization of Eu- and heterochromatin of citrus with a focus on the condensation behavior of 45S rDNA chromatin. AB - To characterize the properties of eu- and heterochromatic regions in Citrus species, the chromosomal distribution of different histone H3 marks, DNA methylation sites (5mC) and 45S ribosomal DNA sites were determined for C. clementina, C. paradisi, C. sinensis, and for the hybrid Ortanique C. reticulata * C. sinensis. Our data show that in the relatively small genomes of investigated Citrus species (genome size ranges from 378-400 Mbp) the euchromatin is characterized by histone H3 lysine 4 mono-, di- and trimethylation (H3K4me1/ 2/3) and histone H3 lysine 9 trimethylation (H3K9me3). In contrast, histone H3 lysine 9 mono- and dimethylation (H3K9me1/2), histone H3 lysine 27 mono-, di- and trimethylation (H3K27me1/2/3) as well as 5-methylcytosine (5mC) were enriched at certain heterochromatin fractions. Whereas H3K9me1/2 and H3K27me1 were preferentially enriched at the chromomycin A(3)-bright (CMA(+)) heterochromatin, H3K27me2/3 showed a higher accumulation at the DAPI brightly-stained heterochromatin. 5mC signals were associated with most of the CMA(+) areas as well as with the DAPI strongly-stained heterochromatin fraction. Therefore, extensive methylation of DNA as well as of H3K9me1/2 and H3K27me1/2/3, and depletion of H3K4me1/2/3 and H3K9me3 appear to be specific features of heterochromatin in Citrus. Transcriptionally active decondensed 45S rDNA sites were found DNA hypomethylated, while the silenced condensed sites were strongly 5mC methylated. Although the number of chromosomal 45S rDNA sites differed between the species, the number of transcriptionally active rDNA sites remains constant. PMID- 21304249 TI - Intravenous pamidronate treatment improves growth in prepubertal osteogenesis imperfecta patients. AB - BACKGROUND/AIMS: Pamidronate is widely used to treat pediatric patients with osteogenesis imperfecta (OI). We aimed at delineating the effects of monthly pamidronate therapy on the growth of different body segments in prepubertal OI patients. METHODS: The study included 14 prepubertal patients (12 boys, 2 girls) with mild forms of OI (type I and IV). The mean age at treatment start was 7:8 years:months (3:7-11:0). Pamidronate was given as monthly intravenous infusions. The patients were measured 1 year before, at treatment start and 1 and 2 years after treatment start. RESULTS: Height standard deviation score (SDS) and sitting height SDS significantly increased (p < 0.05) during the first year of treatment when compared to the pre-treatment year. No further improvement was detected during the second year of treatment. However, when plotted on disease-specific growth charts (untreated patients with the same OI types), height gain was significant during the first (p < 0.001) and second (p < 0.05) years of treatment. All patients increased their bone mineral density throughout the follow-up. CONCLUSION: Monthly pamidronate improves the growth of prepubertal patients with mild OI, where the most prominent growth stimulation is seen in the upper body segment. PMID- 21304250 TI - Improvements in behaviour and self-esteem following growth hormone treatment in short prepubertal children. AB - BACKGROUND/AIMS: To evaluate effects of growth hormone (GH) treatment on behaviour and psychosocial characteristics in short-stature children. METHODS: 99 referred prepubertal non-familiar short-stature children (32 GH deficiency; 67 idiopathic short stature) aged 3-11 years, randomized to fixed or individual GH doses and their parents completed questionnaires (Child Behaviour Checklist, Birleson Depression Self-Report Scale, Abbreviated Parent-Teacher Questionnaire, I Think I Am, Well-Being Visual-Analogue Scales for Short-Stature Children) at baseline (BL) and after 3, 12, and 24 months. RESULTS: At BL, children showed higher levels of internalizing behaviour (p < 0.001), lower levels of externalizing behaviour (p < 0.006) and self-esteem (p < 0.001) compared to reference values. During GH treatment, behavioural measures (p < 0.001) and depression (p < 0.01) changed towards the mean of the population within the first 3 months and remained improved to 24 months. Self-esteem improved at all time points (p < 0.001), and in all subgroups, as did well-being dimensions stability and mood (p < 0.05). Multiple regression analysis showed that greater improvements were related to lower BL value, height gain, higher maximal GH value, being older, and being male. CONCLUSION: On GH treatment, prepubertal short children significantly improved on behavioural, depression, and psychosocial evaluations over a 2-year period of GH treatment. Most change occurred within the first 3 months, which highlights this short period as important not only for growth and metabolic changes but also for behaviour and psychosocial improvements following GH treatment. PMID- 21304251 TI - Differentiating between aphasic and nonaphasic stroke patients using semantic verbal fluency measures with administration time of 30 seconds. AB - Administration time of 1 min for semantic verbal fluency measures can be overly long and therefore bothersome for aphasic patients because they can often retrieve only a few items after a certain period of time. The purpose of this study was to determine whether an administration time of 30 s would be more efficient in differentiating among aphasics, nonaphasic stroke patients, and normal controls. The subjects were 53 stroke patients and 28 normal controls. They had to generate as many animal names as they could within a given time. The number of animal names is gradually diminished in three groups (p < 0.001) in each time frame, that is, during the entire 60 s, the initial 30 s, and the following 30 s. The reaction time (RT) measure indicated that the RT of the aphasic patients was significantly increased compared to those of the other two groups (p < 0.001). The most optimal cutoff scores that differentiated each group are presented. These results suggest that an administration time of 30 s has discriminative validity to differentiate between the two patient groups. This shorter administration time could make the test more efficient by reducing the burden on both examiners and aphasic patients. PMID- 21304252 TI - [Efficacy and safety of imidafenacin in female patients with urge and mixed urinary incontinence]. AB - The effect of imidafenacin for the treatment of overactive bladder (OAB), in female patients with urge and mixed urinary incontinence was examined. Prior to administration and at 1, 2, 3, 4, 6, 8, 10 and 12 weeks after administration, symptoms and quality of life were assessed using the overactive bladder symptom score (OABSS) and the international consultation on incontinence questionnaire short form (ICIQ-SF), respectively. After administration, OABSS and ICIQ-SF scores were improved significantly when compared to baseline values. The incidence of adverse events was 7. 9% and none were serious. Imidafenacin was effective in female patients with urge and mixed urinary incontinence. In addition, imidafenacin rapidly improved incontinence one week after administration. PMID- 21304253 TI - [Efficacy of naftopidil in patients with overactive bladder associated with benign prostatic hyperplasia: prospective randomized controlled study to compare differences in efficacy between morning and evening medication]. AB - A total of 100 patients with benign prostatic hyperplasia (BPH) and overactive bladder (OAB) symptoms (BPH/OAB), enrolled between June 2006 to March 2008, were randomly divided into 2 groups of morning medication (M) and evening medication (E) groups, then 50 mg of naftopidil was given once a day after breakfast or supper for 8 weeks. Data were available for efficacy analysis on 80 patients (M group ; 43, E group ; 37). Naftopidil significantly improved the overall international prostatic symptom score ; from 19.2+/-7.9 to 11.7+/-5.8 in the M group and from 19.4+/-6.4 to 12.3+/-6.8 in the E group (p<0.0001), QOL score from 4.9+/-0.8 to 3.2+/-1.4 in the M group and from 5.0+/-0.8 to 3.6+/-1.3 in the E group (p<0.0001), and OAB symptom score from 7.8+/-2.6 to 5.0+/-2.5 in the M group (p<0.0001) and from 8.6+/-2.9 to 5.8+/- 3.3 in the E group (p<0.0001). There was no significant difference in the incidence of adverse effects between the M group (6.1%) and E group (2.2%). These results suggest that naftopidil improves storage symptoms as well as voiding symptoms regardless of timing of administration. PMID- 21304254 TI - [The first case of adenine phosphoribosyltransferase deficiency with APRT Q0 (M1V) mutation in Japan]. AB - Adenine phosphoribosyltransferase (APRT) deficiency is an enzyme deficiency associated with purine metabolism, a hereditary disease that causes recurrent 2, 8-DHA stone formation due to a complete or partial APRT defect and slowly damages the renal function. Since APRT deficiency can be treated to prevent its progression to renal insufficiency, it is important to detect APRT gene mutations and make a definite diagnosis early. A 3.5-year-old girl presented with painful urination and dysuria, and was admitted to our hospital. The analysis of stones collected after spontaneous passage revealed 2, 8-dihydroxyadenine (DHA) urolithiasis. To make a definite diagnosis, we searched for the APRT gene mutations reported in Japanese. However, no APRT Q0 mutation was identified. Only a heterogeneous mutation, APRT J, was noted. Subsequently, we screened the gene mutation regions reported from Europe and the United States and identified a heterogeneous mutation at the start codon of APRT Q0 from methionine to valine. This is the first report of this mutation in Japan. She was diagnosed with APRT deficiency caused by a compound heterogeneous mutation : APRT Q0/(M1V) APRT J (M136T). We believe that the same gene mutation has been inherited among other Japanese. For the future genetic diagnosis of APRT deficiency, this is a valuable case. PMID- 21304255 TI - [A case report: small cell carcinoma of the ureter]. AB - An 82-year-old woman visited our hospital with right flank pain. Computed tomography showed a right ureteral tumor. Urine cytology was class IV and cystoscopy demonstrated no obvious lesion. We performed right total nephroureterectomy and histopathological diagnosis was small cell carcinoma of the ureter. The serum ProGRP was slightly elevated postoperatively. Positron emission tomography showed a distant metastasis to the third lumber vertebra. She received two courses of chemotherapy (cisplatin and etoposide) and radiation therapy (8 Gy), but the distant metastasis was progressive. She died 6 months postoperatively. PMID- 21304256 TI - [Two cases of congenital pelvic arteriovenous malformation in male]. AB - Congenital pelvic arteriovenous malformation(AVM) is extremely rare, especially in males. Herein we report two males with pelvic AVM. Computed tomography (CT) or magnetic resonance imaging (MRI) demonstrated markedly dilated, and tortuous vessels in the pelvis in both patients. The first patient, a 77- year-old male, presented with difficulty in voiding and weak urinary stream. He was scheduled to have a prostate biopsy for suspicion of prostate cancer with pelvic lymph node swelling. However, the mass was diagnosed as pelvic AVM with MRI, and the prostate biopsy was cancelled. He has been followed conservatively since then. The second patient, a 55-year-old male, presented with gross hematuria which caused severe hemorrhagic hypovolemic shock. He had pelvic AVM, and he was treated with transcatheter arterial embolization two times. When patients with this disease present with general urological symptoms, urological procedures, without attention to this disease, might cause severe complications such as serious hemorrhage. We discuss the clinical course and the treatment for AVM, and review the literature. PMID- 21304257 TI - [Dieulafoy lesion of the ileal conduit: a case report]. AB - Late side effects of ileal conduit are uncommon. Here we report a case of ileal conduit hemorrhage in a 78-year-old woman 8 years after radical cystectomy and ileal conduit diversion. The patient presented with gross hematuria and abdominal dynamic computed tomography showed extravasation of contrasts in ileal conduit and the patient was diagnosed with ileal conduit hemorrhage. Clipping hemostasis was performed under gastrointestinal endoscope and revealed that Dieulafoy's ulcer was the cause of ileal conduit hemorrhage. This is the first case of Dieulafoy's ulcer occurred in ileal conduit. Hemorrhage from ileal conduit is an important late side effect. PMID- 21304258 TI - [Change in concepts of urolithiasis: recent advances in pathogenesis, assessment, treatment and prophylaxis]. AB - A nationwide survey of urolithiasis in Japan conducted in 2005 disclosed its steady increase in incidence and the life-long risk was estimated to be 15% in men and 6% in women. The recurrence rate has also increased, to 70 -80% in the extracorporeal shock wave lithotripsy (ESWL) era from around 50% previously. Although urolithiasis is very common and highly recurrent, the impact and concern of stone disease are not necessarily as high as expected either medically or socially, because of its benign nature and easy accessibility to treatments by ESWL and/or endourological procedures. Dramatic progress is taking place both experimentally and clinically in this field, such as development of a simple method of measuring metastable limits using a microplate, clarifying altered oxalate metabolism due to insulin resistance and close relationship between stone disease and metabolic syndrome, elucidating the exact role of osteopontin in an experimental model at a molecular level, prophylaxis of stone disease by angiotensin II type I receptor blocker, and addition of a new modality of fiberscopic transurethral lithotripsy (f-TUL) to the conventional endourological treatments. We hope that "change and future perspective" in the field of urolithiasis will be discussed and clarified in this symposium. PMID- 21304259 TI - [Evolution of strategy to measure urinary supersaturation]. AB - Urinary stones have an estimated lifetime morbidity of 15.1% in males and 6.1% in females ; in other words, one out of seven males and one out of fifteen females are affected with this disease at least once in their life. Previously, we reported a simple and easy method using microplates to measure the metastable limit (ML), which indicate the upper limit of supersaturation dissolution. In this study, we examined the usability of this microplate method. We confirmed that ML is correlated with the urinary calcium concentration in healthy subjects, single stone formers (SF), and recurrent stone formers (RSF). There was no significant difference between healthy subjects and RSF in urinary magnesium concentration, and ML was found to be correlated with urinary the concentration of oxalate and citrate acid in healthy subjects only. These results suggest that ML is a simple and easy way to measure the urinary calcium level and that ML could be a useful test item in outpatient settings as a convenient indicator for preventing recurrence of urinary stones in the future. PMID- 21304260 TI - [Future perspective in the treatment of urolithiasis based on oxalate metabolism]. AB - Urinary excretion of oxalate is one of risk factors in urinary stone formation. Prevention of undesirable overflow into the production of oxalate definitely leads to a decrease of urolithiasis. The activity of serine : pyruvate/alanine : glyoxylate aminotransferase (SPT/AGT) or glyoxylate reductase/hydroxypyruvate reductase (GRHPR), the key enzyme of primary hyperoxlauria type 1 and 2, respectively, and their subcellular distribution highly affects the oxalate production. On the other hand, urolithiasis is tightly related to lifestyle disease, such as diabetes mellitus and insulin resistance. The hypothesis that insulin resistance induces mitochondria dysfunction, resulting in the decrease of mitochondria-related enzyme activity is a very attractive new treatment strategy of urolithiasis. Namely, the improvement of insulin resistance might prevent stone formation. PMID- 21304261 TI - [Metabolic syndrome and nephrolithiasis]. AB - Recent epidemiological studies revealed an association of obesity, diabetes mellitus, hypertension and metabolic syndrome (MetS) with kidney stone disease. We examined how these disorders cause kidney stones. A clinical study on 467 patients with nephrolithiasis at our institution revealed that clustering of MetS traits increased the risk of uric acid stone formation by decreasing urinary pH. A subsequent study analyzing detailed data from 30,448 patients enrolled in the 6th Nationwide Survey on Urolithiasis in Japan showed that clustering of MetS traits were associated with an increased severity of the kidney stone disease and elevated urinary excretion of calcium, uric acid and oxalate. Finally, the OLETF rats, an animal model of MetS, showed lower urinary pH, decreased citrate excretion, and increased uric acid and calcium excretion. In addition, the administration of pioglitazone, an agent that improves insulin resistance, significantly increased the urinary pH. These results indicate that MetS causes changes in urinary constituents, leading to an increased risk of both uric acid and calcium oxalate stone formation. We suggest that kidney stone disease should be considered as a component of MetS and that the improvement in insulin resistance by means of diet and lifestyle changes and medical therapy might help to prevent this disorder. PMID- 21304262 TI - [Multifunctional character of osteopontin and strategy for clinical applications]. AB - Osteopontin (OPN) is the major constituent of calcium-containing urinary stones and is involved in the inhibition of nucleation and aggregation of calcium oxalate (CaOx) crystals, promotion of the adherence of CaOx crystals to cultured renal epithelial cells, and regulation of inflammatory cells as chemokine. OPN has different effects (inhibitor and promoter) at each stage of stone formation in vitro and these multifunctional actions of OPN have not been fully elucidated. We developed a modified crystal method using collagen granules (CG) and immobilized OPN. OPN had strong inhibitory activity on the aggregation/growth of CaOx crystals, but the inhibitory activity decreased by use of OPN-immobilized CG. OPN is also a critical promoter of adherence for CaOx crystals to cultured renal epithelial cells in an in vitro experimental system. We examined the effect of OPN in vivo, by OPN siRNA transfection in rats. Hydrodynamic intravenous and renal subcapsular injections with lipofection were performed on days 1 and 8. The calcium concentration in the kidney was significantly lower and the frequency of CaOx crystal deposits in the tubules was lower in the OPN siRNA transfection group (drinking 1.5% ethylene glycol (EG)), than in the EG drinking group (sham operation) at day 15. We examined the effect of candesartan, an angiotensin II (Ang II) type 1 receptor blockers (ARB) in hyperoxaluric rats. ARB reduced crystal formation and calcium concentrations in the whole kidney. Hyperoxaluria leads to CaOx crystallization and the development of tubulointerstitial lesions in the kidney. AngII mediates OPN synthesis, which is involved in both macrophage recruitment and CaOx crystallization. OPN synthesis and production increased with hyperoxaluria but to a lesser extent in ARB-treated hyperoxaluric rats. These results show that oxalate can activate the renal renin-angiotensin system and that oxalate-induced upregulation of OPN is in part mediated via the renal renin angiotensin system. PMID- 21304263 TI - [Functional domains of osteopontin stimulate renal crystal formation: analysis of OPN-transgenic mice]. AB - Osteopontin (OPN) has been described to play a nonredundant role in the formation of renal crystals. This biological activity of OPN may be attributed to its characteristic structure, which includes 2 calcium binding sites, Arg-Gly-Asp (RGD) sequences. To test this hypothesis, we evaluated wild-type mice (WT group), OPN-knockout mice (KO group), and two types of transgenic mice : (1) one type carrying a transgene in which the sequences coding for the 2 calcium-binding sites of the OPN were deleted (CaX group) and (2) the other type carrying a transgene in which the sequence that codes for the RGD sequence of the OPN was modified to one that codes for Arg-Gly-Glu (RGE ; RGE group). Changes occurring after intraperitoneal injection of glyoxylate for 9 d were analyzed. The amount of crystals deposited was the greatest in mice of the WT group and the least in those of the KO group. The number of crystal deposits in mice of the RGE and KO groups was approximately the same. Microscopic observations revealed that the crystal nuclei in mice in the CaX group were stratified and exhibited a disordered pattern ; this pattern was dissimilar to that observed in the mice in the WT and RGE groups, wherein the crystal nuclei exhibited a rosette petal-like radial pattern. The results indicate the possibility that each domain contributes to the mechanism by which OPN stimulates crystal formation. PMID- 21304264 TI - [Changes of the surgical treatment for urinary caliculi]. AB - In the 1980s, the surgical treatment for urinary caliculi in Japan, changed from open surgery, which aims to remove the urinary calculi completely, to extracorporeal shock wave lithotripsy (ESWL), which aims only to crush the stone and the endoscopic procedure which aims mainly to crush and in some cases to remove the stone if possible. The residual stone fragments are considered to be a cause of reccurence, but these new treatments are less invasive. Recently, with the development of endoscopic instruments stone fragments can be removed completely with flexible ureteronephroscopes, thin laser fibers, and fine basket catheters. PMID- 21304266 TI - The intrinsic resistome of Pseudomonas aeruginosa to beta-lactams. AB - Pseudomonas aeruginosa is a relevant opportunistic pathogen particularly problematic due to its low intrinsic susceptibility to antibiotics. Intrinsic resistance has been traditionally attributed to the low permeability of cellular envelopes together with the presence of chromosomally-encoded detoxification systems such as multidrug efflux pumps or antibiotic inactivating enzymes. However, some recently published articles indicate that several other elements can contribute to the phenotype of intrinsic resistance of bacterial pathogens. In a recently published article, we explored the chromosomally-encoded determinants that contribute to the phenotype of susceptibility of P. aeruginosa to ceftazidime, imipenem and carbapenem. Using a comprehensive library of transposon-tagged insertion mutants, we found 37 loci in the chromosome of P. aeruginosa that contributed to its intrinsic resistance, because mutants in these loci were more susceptible to antibiotics than their parental strain. 41 further loci could potentially be involved in the acquisition of resistance, because mutants in these loci were less susceptible than their wild-type counterpart. These results indicate that the intrinsic resistome of P. aeruginosa involves several elements, belonging to different functional families and cannot be considered as a specific mechanism of adaptation to the recent usage of antibiotics as therapeutic agents. In the current article, we summarize the findings of the paper and discuss their implications for understanding the evolution of antibiotic resistance and for defining novel targets for the search of new antimicrobials. Finally, the validity of recent theories on the mechanisms of action of antibiotics is discussed taken into consideration the results of our paper and other recently published works on the mechanisms of intrinsic resistance to antibiotics of P. aeruginosa. PMID- 21304268 TI - Nuancing the proposed role of NKT cells in aging. PMID- 21304267 TI - The challenge of managing fusariosis. AB - Fusarium is the second most frequent mold involved in fungal infections and is particularly important among immunocompromised patients. Culture methods and microscopy are still routinely used in clinical laboratories to identify Fusarium spp, and more sophisticated, timely, and effective methods for detecting Fusarium spp. in laboratory samples could improve the outcome of the patient. These investigational diagnostic approaches include serological assays and specific nested PCR assays that can yield positive and negative predictive values of over 90%. Other assays in development, such as mass spectroscopy techniques, can provide accurate and consistent results. The treatment of fusariosis in immunocompromised patients remains a challenge and the prognosis of systemic fusariosis in this population remains poor. Successful treatment is highly dependent on the particular Fusarium species involved in the infection. High dose intravenous amphotericin B formulation is recommended as the first line of therapy in management of fusariosis in patients. Voriconazole is also effective in treating fusariosis. Intolerance, contraindication, or failure of the amphotericin B formulation warrants the use of voriconazole as an alternative agent, and posaconazole is licensed as salvage therapy against invasive fusariosis. Adjunctive therapies such as surgical debridement of infected tissue, granulocyte colony stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) infusions, or granulocyte transfusions are also tools for managing fusariosis. In conclusion, Fusarium infection is considered an emerging problem and should be suspected in immunocompromised patients experiencing systemic infection and should be treated accordingly. PMID- 21304269 TI - A homeodomain transcription factor regulates the DNA replication checkpoint in yeast. AB - Checkpoints monitor the successful completion of cell cycle processes, such as DNA replication, and also regulate the expression of cell cycle-dependent genes that are required for responses. In the model yeast Schizosaccharomyces pombe G 1/S phase-specific gene expression is regulated by the MBF (also known as DSC1) transcription factor complex and is also activated by the mammalian ATM/ATR related Rad3 DNA replication checkpoint. Here, we show that the Yox1 homeodomain transcription factor acts to co-ordinate the expression of MBF-regulated genes during the cell division cycle. Moreover, our data suggests that Yox1 is inactivated by the Rad3 DNA replication checkpoint via phosphorylation by the conserved Cds1 checkpoint kinase. Collectively, our data has implications for understanding the mechanisms underlying the coordination of cell cycle processes in eukaryotes. PMID- 21304270 TI - Administration of vitamin K does not counteract the ectopic mineralization of connective tissues in Abcc6 (-/-) mice, a model for pseudoxanthoma elasticum. AB - Pseudoxanthoma elasticum (PXE) is a heritable multisystem disorder manifesting with ectopic calcification of peripheral connective tissues, caused by mutations in the ABCC6 gene. Alterations in vitamin K metabolism have been suggested to contribute to the pathomechanisms of the mineralization process. In this study we administered vitamin K or its glutathione conjugate (K3-GSH) into Abcc6 (-/-) mice which recapitulate features of PXE. Oral administration of vitamin K2 in dosages, which vastly exceed the amounts in control diet or the recommended amounts for humans, did not alter the ectopic mineralization in Abcc6 (-/-) mice. Similarly, intravenous administration of K3-GSH did not alter the degree of mineralization. Testing of vitamin K2, K3 and K3-GSH in an in vitro calcification system provided no evidence of mineralization inhibition. Collectively, our data suggest that vitamin K deficiency in the peripheral tissues is not a simple explanation for development of mineral deposits in PXE. PMID- 21304272 TI - A tool for increasing the lifetime of chromatography resins. AB - There is a steadily increasing demand for speed, cost efficiency, and process understanding within biopharmaceutical process development. To match this, a high throughput method for screening of cleaning-in-place (CIP) conditions for chromatography resins has been developed. The methodology includes fouling of MabSelect SuRe chromatography resin in 96-well filter plates, cleaning of the fouled resin by incubation in different CIP agents, and finally, analysis of the residual impurities on the resin after cleaning. This article describes the improvements that transformed the method from low throughput and significant manual interference to a totally automated method with high throughput and good reproducibility. PMID- 21304271 TI - IBC's 21st Annual Antibody Engineering and 8th Annual Antibody Therapeutics International Conferences and 2010 Annual Meeting of the Antibody Society. December 5-9, 2010, San Diego, CA USA. AB - The 21st Annual Antibody Engineering and 8th Annual Antibody Therapeutics international conferences, and the 2010 Annual Meeting of The Antibody Society, organized by IBC Life Sciences with contributions from The Antibody Society and two Scientific Advisory Boards, were held December 5-9, 2010 in San Diego, CA. The conferences were organized with a focus on antibody engineering only on the first day and a joint engineering/therapeutics session on the last day. Delegates could select from presentations that occurred in two simultaneous sessions on days 2 and 3. Day 1 included presentations on neutralizing antibodies and the identification of vaccine targets, as well as a historical overview of 20 years of phage display utilization. Topics presented in the Antibody Engineering sessions on day 2 and 3 included antibody biosynthesis, structure and stability; antibodies in a complex environment; antibody half-life; and targeted nanoparticle therapeutics. In the Antibody Therapeutics sessions on days 2 and 3, preclinical and early stage development and clinical updates of antibody therapeutics, including TRX518, SYM004, MM111, PRO140, CVX-241, ASG-5ME, U3-1287 (AMG888), R1507 and trastuzumab emtansine, were discussed, and perspectives were provided on the development of biosimilar and biobetter antibodies, including coverage of regulatory and intellectual property issues. The joint engineering/therapeutics session on the last day focused on bispecific and next generation antibodies. PMID- 21304273 TI - Don't jump to rash conclusions. PMID- 21304274 TI - Formosanin C-inhibited pulmonary metastasis through repression of matrix metalloproteinases on mouse lung adenocarcinoma. AB - Formosanin C (FC) isolated from Rhizoma Paridis, showed pro-apoptosis and immunoregulation with antitumor activity in cultured cells and animal systems. However, there is no report about its anti-metastatic effect on cancer cells. This research used the wound healing and the migration assay to detect the anti invasive effect of FC on LA795 cells. Through the gelatin zymography assay and immunofluorescence analysis, FC showed suppression of enzyme activity of MMP-2 and MMP-9, and protein expression of MMP-1, -2, -3, -9 and -14 excreted from LA795 cells. Finally, FC exhibited much more effective inhibition of tumor growth and pulmonary metastasis in T739 mice than cisplatin did. Overall, the strong inhibition of MMP expression by FC might provide a potential therapeutic modality for lung tumors. PMID- 21304275 TI - NF-Y affects histone acetylation and H2A.Z deposition in cell cycle promoters. AB - Histones post-translational modifications (PTMs) are crucial for transcriptional control, defining positive and negative chromatin territories. We previously described an extensive methylation-acetylation switch on cell cycle promoters using a single nucleosome ChIP assay. A key issue is how PTMs are locally positioned. We report an analysis on the role of the NF-Y CCAAT transcription factor on histone acetylation. Whereas H3K9 and H3K14 acetylation in core promoters is not influenced by NF-Y, H3K18ac, H3K36ac and H3K27ac are increased in the absence of NF-Y. Interestingly, NF-Y affects H2B acetylation in an opposite way: H2BK16ac is decreased and Lysine 120 acetylation, which counter correlates with ubiquitination, increases dramatically upon NF-Y removal. KAT2A/KAT2B and subunits of the SAGA and ATAC complexes (SPT20 and ZZZ3) are differentially regulated. Finally, the deposition of H2A.Z, which maps around the TSS, is also NF-Y-dependent. In summary, NF-Y influences histone acetylation in different processes, including those involved in a methylation-acetylation switch and in the recruitment of histone variants. PMID- 21304276 TI - Comprehensive DNA methylation analysis of human peripheral blood leukocytes and lymphoblastoid cell lines. AB - DNA methylation is involved in development and in human diseases. Genomic DNA derived from lymphoblastoid cell lines (LCLs) is commonly used to study DNA methylation. There are potential confounding factors regarding the use of LCL derived DNA, however, such as Epstein-Barr (EB) viral infection and artifacts induced during cell culture. Recently, several groups compared the DNA methylation status of peripheral blood leukocytes (PBLs) and LCLs and concluded that the DNA methylation profiles between them might be consistent. To confirm and extend theses results, we performed a comprehensive DNA methylation analysis using both PBLs and LCLs derived from the same individuals. Using the luminometric methylation assay, we revealed that the global DNA methylation level was different between PBLs and LCLs. Furthermore, the direction of change was not consistent. Comparisons of genome-wide DNA methylation patterns of promoter regions revealed that methylation profiles were largely conserved between PBLs and LCLs. A preliminary analysis in a small number of samples suggested that the methylation status of an LCL may be better correlated with PBLs from the same individual than with LCLs from other individuals. Expectedly, DNA methylation in promoter regions overlapping with CpG islands was associated with gene silencing in both PBLs and LCLs. With regard to methylation differences, we found that hypermethylation was more predominant than hypomethylation in LCLs compared with PBLs. These findings suggest that LCLs should be used for DNA methylation studies with caution as the methylation patterns of promoter regions in LCLs are not always the same as those in PBLs. PMID- 21304277 TI - A model for neurorehabilitation after severe traumatic brain injury: facilitating patient participation and learning. AB - BACKGROUND: During intensive neurorehabilitation, it is a professional challenge that patients with severe traumatic brain injury may have changed abilities to learn. PURPOSE: To develop, initially test, and evaluate a model for neurorehabilitation aimed at systematizing and facilitating professionals' efforts of promoting patients' participation and learning. METHODS: Qualitative study inspired by action research. Empirical data were analyzed by a theoretical framework of "didactic relation model," "situated learning theory," and neurophysiologic/neuropsychological categories of learning premises. FINDINGS: Our findings indicate that the model for neurorehabilitation expands and systematizes the professional's reflections and interventions aimed at facilitating learning among patients with traumatic brain injury. PMID- 21304279 TI - Regarding recent publication, politics of nursing knowledge and education. PMID- 21304281 TI - An introduction to the multisystem model of knowledge integration and translation. AB - Many nurse researchers have designed strategies to assist health care practitioners to move evidence into practice. While many have been identified as "models," most do not have a conceptual framework. They are unidirectional, complex, and difficult for novice research users to understand. These models have focused on empirical knowledge and ignored the importance of practitioners' tacit knowledge. The Communities of Practice conceptual framework allows for the integration of tacit and explicit knowledge into practice. This article describes the development of a new translation model, the Multisystem Model of Knowledge Integration and Translation, supported by the Communities of Practice conceptual framework. PMID- 21304282 TI - Advancing nursing knowledge through complex holism. AB - This article presents how nursing worldviews, relationship, and holism have evolved differently according to the predominant mode of perception used to create them. Intensive and extensive modes of perception are both primarily and fundamentally different; neither mode of perception can be subsumed by the other. Nurses are susceptible to limiting their perception by practicing simple holism. An evolution to complex holism in both intensive and extensive modes of perception is advocated for effective leadership in shaping the future of health care and nursing practice. PMID- 21304283 TI - Wholeness and life patterning: unitary foundations for a healing praxis. AB - Unitary appreciative nursing is a healing praxis that is grounded in an evolving theory of wholeness and life patterning. The theory regards people as having the potential for transforming their health through participating knowingly in change focused on appreciating their wholeness and life patterning. In unitary appreciative nursing, people generate their own knowledge through appreciation and participation in the wholeness of life patterning. This knowledge facilitates and advances their flourishing and well-being in a healing praxis. The conceptual presuppositions and theoretical propositions that were generated or affirmed arising from a healing praxis are clarified and explicated with women who have experienced abuse and despair. PMID- 21304284 TI - Nursing theory-based independent nursing practice: a personal experience of closing the theory-practice gap. AB - The article presents a narrative and exemplar from an independent nursing practice underpinned by the theory of health as expanding consciousness. The journey illustrates the importance of developing personal and professional awareness of theories that are congruent with one's worldview. This enhances meaning in nursing practice and contributes to closing the theory-practice gap. The benefits of independent nursing practice to closing the gap are also discussed. PMID- 21304285 TI - A risk reduction model for late-onset preeclampsia: a theory for using low intensity exercises to enhance cardiac homeostasis in nursing research and practice. AB - Viewing late-onset preeclampsia as an autonomic dysregulation is a new approach. It is one that will provide nurses and other clinicians with theory-based prenatal care choices that focus on enhancing homeostasis rather than prediction. The dominant prediction model manages the disease based on one biomedical pathway even though the disease is believed to be heterogeneous. Unlike early-onset preeclampsia, which involves severe placental pathophysiology and thus should be left for medical research, late-onset preeclampsia--intact placenta with maternal cardiovascular dysregulation--may be prevented with a lifestyle intervention, in particular, low-intensity exercise. This article discusses a nursing approach to promote health and reduce risks even when the etiology of the disease remains unknown. PMID- 21304286 TI - Deer stand fatalities in Kentucky: two cases of reverse suspension and blunt force trauma. AB - Hunting many types of wild game is an avidly pursued outdoor activity that attracts all ages and both genders at various times of the year. Deer hunting is a popular sport in many regions of North America. A variety of weapons are used in the hunting, trapping, and killing of game. As a variety of different modalities are used, myriad types of injuries unique to the type of hunting can occur. Most deer hunting-related fatalities identified at the Office of the Chief Medical Examiner in Kentucky are accidental firearm injuries. Less commonly encountered are fatalities resulting from elevation of the hunter in a tree stand, often associated with poor design or construction of the perch. We present 2 tree stand-related deaths. One victim died of positional asphyxia due to reverse suspension from a hunting tree stand. The second victim died of multiple blunt force injuries sustained in a 20-foot fall from a tree stand. We summarize the features of morbidity and mortality related to deer hunting based on investigations by the Office of the Chief Medical Examiner. PMID- 21304288 TI - Simultaneous amniotic membrane patch in high-risk keratoplasty. AB - PURPOSE: To analyze the short- and intermediate-term results of simultaneous transplantation of amniotic membrane with high-risk keratoplasty. METHODS: Between January 2002 and February 2004, a simultaneous amniotic membrane patch was transplanted with penetrating keratoplasty in 16 eyes of 16 patients. In 13 eyes, a soft contact lens was applied afterward. Corneal perforation was present in 10 of 14 eyes with emergency keratoplasty. Five patients received systemic immunosuppressive medication for 4-6 months after penetrating keratoplasty. RESULTS: The amniotic membrane patch fell off after 8 +/- 3 (range: 4-14) days without residual tissue except in 1 case. In 15 of 16 eyes, the epithelium was completely closed after 10 +/- 8 (range: 4-30) days. In 3 eyes, recurrence of the epithelial defect occurred after 3-6 months. During a follow-up period of 18 +/- 6 months, 13 of 16 corneal grafts were clear. CONCLUSIONS: Simultaneous amniotic membrane transplantation and penetrating keratoplasty may improve the prognosis of corneal graft in eyes with risk of epithelial healing problems. PMID- 21304287 TI - Ocular herpes simplex virus type 1: is the cornea a reservoir for viral latency or a fast pit stop? AB - PURPOSE: To present a review supporting and refuting evidence from mouse, rabbit, nonhuman primate, and human studies of herpes simplex virus type 1 (HSV-1) concerning corneal latency. METHODS: More than 50 research articles on HSV-1 published in peer-reviewed journals were examined. RESULTS: Infectious HSV-1 has been found in mouse denervated tissues and in tissues with negative cultures from the corresponding ganglion. However, the different mouse strains have shown varied responses to different strains of HSV, making it difficult to relate such findings to humans. Rabbit studies provide excellent evidence for HSV-1 corneal latency including data on HSV-1 migration from the cornea into the corneoscleral rim and on the distribution of HSV-1 DNA in the cornea. However, the available methods for the detection of infectious HSV-1 may not be sensitive enough to detect low-level infection. Infectious HSV-1 has been successfully isolated from the tears of nonhuman primates in the absence of detectable corneal lesions. The recurrence of corneal ulcers in nonhuman primates before the appearance of infectious HSV-1 in tears suggests that the origin of the HSV-1 is the cornea, rather than the trigeminal ganglion. Human studies presented evidence of both ganglion and corneal latency. CONCLUSIONS: Understanding HSV-1 disease progression and the possibility of corneal latency could lead to more effective treatments for herpetic keratitis. However, it is unlikely that operational latency in the cornea will be definitively proven unless a new method with higher sensitivity for the detection of infectious virus is developed. PMID- 21304289 TI - Evaluation of posterior wound profile after penetrating keratoplasty using anterior segment optical coherence tomography. AB - PURPOSE: To study the wound configuration after penetrating keratoplasty (PKP) using anterior segment optical coherence tomography. METHODS: All post-PKP patients who were examined at the Cornea Services of the Royal Victorian Eye and Ear Hospital, Melbourne, between February and November 2008, were enrolled in the study. The wound profile was studied using anterior segment optical coherence tomography. RESULTS: A total of 159 graft-host sections from 29 eyes (24 patients, mean age 57 +/- 20 years) were analyzed. Cases with remaining sutures were excluded from the study. The majority of patients included were operated for keratoconus (16 eyes, 55%) followed by endothelial dysfunction (8 eyes, 27.6%). The anterior graft-host junction was smooth in all the scans. Internal graft-host aberrations were observed in the form of host "ledge" (100 scans, 62.9%) and graft-host "steps" (59 scans, 37.1%). Steps were identified by a change in the curvature of the posterior surface of graft-host junction. Ledges were defined by the presence of a rim of extra corneal tissue in any of the quadrants that were protruding into the anterior chamber. Patients with keratoconus (34 ledges and 22 steps) had more host ledges, whereas those transplanted for endothelial dysfunction (12 ledges and 33 steps) had more steps. Graft over sizing revealed an increased trend toward the occurrence of steps. Although statistically nonsignificant, cases with higher astigmatism seemed to have more steps (4.31 +/- 3.39 diopter) than ledges (1.75 +/- 1.87 diopter) (P = 0.36). CONCLUSIONS: After PKP, the posterior graft-host malapposition occurs commonly and may be related to the original corneal pathology. PMID- 21304290 TI - Comparative study of descemet stripping automated endothelial keratoplasty donor preparation by Moria CBm microkeratome, horizon microkeratome, and Intralase FS60. AB - PURPOSE: To evaluate the quality of stromal bed and the safety on endothelium in preparation of donor tissue for Descemet stripping automated endothelial keratoplasty in a masked fashion using 2 mechanical microkeratomes and a femtosecond laser. METHODS: Deep anterior lamellar dissection was performed on 15 donor corneas. Central endothelial cell density was calculated using specular microscopy before and after the dissection. One cornea from each of 5 donor pairs was cut with the Moria ALTK system with the CBm microkeratome using the 300-MUm head and the mate cut with the Horizon disposable 300-MUm microkeratome. Five additional donor corneas were cut with the Intralase 60-kHz FS laser. The donor corneas were then bisected with half of the cornea used for Live/Dead assay to study central endothelial viability. The other halves were sent for scanning electron microscopy of the stromal bed. Qualitative surface roughness of the scanning electron microscopy images was graded by 2 masked observers, and quantitative surface roughness was assessed using roughness evaluation software. RESULTS: The Horizon group showed a smoother stromal bed compared with the Moria or Intralase groups by 2 masked observers. However, the Moria group had the smoothest quantitative score of all the groups when assessed by roughness evaluation software. There was no statistically significant difference among the 3 groups in the percentage change in the central endothelial cell density or percentage of viable central endothelium by Live/Dead assay after the dissection. CONCLUSIONS: Both mechanical microkeratomes created smoother stromal bed dissections than the femtosecond laser. All systems provided good endothelial cell viability. PMID- 21304291 TI - Tear analysis and lens-tear interactions: part II. Ocular lipids-nature and fate of meibomian gland phospholipids. AB - PURPOSE: Published data indicate that the polar lipid content of human meibomian gland secretions (MGS) could be anything between 0.5% and 13% of the total lipid. The tear film phospholipid composition has not been studied in great detail and it has been understood that the relative proportions of lipids in MGS would be maintained in the tear film. The purpose of this work was to determine the concentration of phospholipids in the human tear film. METHODS: Liquid chromatography mass spectrometry (LCMS) and thin layer chromatography (TLC) were used to determine the concentration of phospholipid in the tear film. Additionally, an Amplex Red phosphatidylcholine-specific phospholipase C (PLC) assay kit was used for determination of the activity of PLC in the tear film. RESULTS: Phospholipids were not detected in any of the tested human tear samples with the low limit of detection being 1.3 MUg/mL for TLC and 4 MUg/mL for liquid chromatography mass spectrometry. TLC indicated that diacylglycerol (DAG) may be present in the tear film. PLC was in the tear film with an activity determined at approximately 15 mU/mL, equivalent to the removal of head groups from phosphatidylcholine at a rate of approximately 15 MUM/min. CONCLUSIONS: This work shows that phospholipid was not detected in any of the tested human tear samples (above the lower limits of detection as described) and suggests the presence of DAG in the tear film. DAG is known to be at low concentrations in MGS. These observations indicate that PLC may play a role in modulating the tear film phospholipid concentration. PMID- 21304292 TI - Bibliography--editors' selection of current word literature. PMID- 21304293 TI - Adjunctive pharmacologic therapy in percutaneous coronary intervention: part II anticoagulant therapy. AB - Pharmacological adjuvant therapies to protect against procedure-related thrombotic complication are indispensable during percutaneous coronary intervention. In addition to antiplatelet therapy, use of anticoagulants to prevent acute thrombotic complication during percutaneous coronary intervention is essential. Besides unfractionated heparin (UFH), new anticoagulants have been developed and compared with UFH. Low-molecular weight heparins, direct thrombin inhibitors (e.g. bivalirudin), and recently developed agents such as fondaparinux (a factor Xa inhibitor) provide new alternatives to conventional UFH. PMID- 21304294 TI - Twenty-three years of progress in the management of a rare disease. PMID- 21304295 TI - The impact of professionalism. PMID- 21304296 TI - A comparison of open and robotic total mesorectal excision for rectal adenocarcinoma. AB - PURPOSE: This retrospective study was designed to compare open with robot assisted total mesorectal excision for rectal adenocarcinoma. METHODS: With use of predefined exclusion criteria, all consecutive laparoscopic-assisted (51 patients) and robot-assisted (36 patients) rectal resections for adenocarcinoma from August 2005 to November 2009 at a single institution were considered. Hand assisted laparoscopy was used for splenic flexure mobilization in all cases. Patients were assigned into robotic and open groups on the basis of the technique used for total mesorectal excision. All 36 robot-assisted resections had the total mesorectal excision performed with robotic assistance and were included in the robotic group. Forty-six of the 51 patients who received a laparoscopic assisted procedure had the total mesorectal excision performed through the hand port using open surgical technique and were included in the open group. Both groups were compared with respect to patient demographics, perioperative outcomes, and pathology. RESULTS: The robotic and open groups were comparable in age, sex, body mass index, history of prior abdominal surgery, ASA class, number of patients receiving neoadjuvant chemoradiation, and tumor stage. There were more abdominoperineal resections (P = .019) and more low and mid rectal tumors (P = .007) in the robotic group. Total procedure time was longer in the robotic group (P = .003), but blood loss was less (P = .036). Lymph node yield, intraoperative and postoperative complications, and length of stay were all comparable. There were 3 positive circumferential margins in the open group vs none in the robotic group, but this did not reach statistical significance. CONCLUSIONS: Robotic total mesorectal excision is feasible and safe, and is comparable to open total mesorectal excision in terms of perioperative and pathological outcomes. The longer operative time associated with robotic total mesorectal excision could decrease as experience with this relatively new technique increases. Large randomized trials are necessary to validate the potential benefits of less blood loss and lower margin positivity rates observed in this study. PMID- 21304297 TI - Long-term follow-up after an initial episode of diverticulitis: what are the predictors of recurrence? AB - PURPOSE: The purpose of our study was to determine the clinical and CT predictors of recurrent disease after a first episode of diverticulitis that was successfully managed nonoperatively. METHODS: We retrospectively analyzed 954 consecutive patients who presented to our institution with diverticulitis from 2002 to 2008. Patients were identified with International Classification of Diseases, 9th Revision/Current Procedural Terminology codes. Patients were excluded if they had subsequent colectomy based on the first attack (n = 81), or if the attack they had between 2002 and 2008 was not their first attack (n = 201). We evaluated CT variables chosen by a panel of expert gastrointestinal radiologists. These radiologists reviewed the available published literature for CT imaging characteristics thought to predict diverticulitis severity. CT variables (n = 20) were determined by prospective reevaluation of scans by blinded study radiologists. Clinical variables (n = 43) were coded based on a retrospective chart review. Univariate analysis of variables in relation to recurrent disease was performed by a log-rank test of Kaplan-Meier estimates. Multivariate analysis was performed using Cox proportional hazards modeling. Variables with P < .2 on univariate analysis were included in a stepwise selection algorithm. RESULTS: The study population included 672 patients; mean age, 61 +/- 15 years; mean follow-up, 42.8 +/- 24 months. The index presentation of diverticulitis was most commonly located in the sigmoid colon (72%), followed by descending colon (33%), right colon (5%), and transverse colon (3%). Overall recurrence at 5 years was 36% by (95% CI 31.4%-40.6%) Kaplan-Meier estimate. Complicated recurrence (fistula, abscess, free perforation) occurred in 3.9% (95% CI 2.2%-5.6%) of patients at 5 years by Kaplan-Meier estimate. Family history of diverticulitis (HR 2.2, 95% CI 1.4-3.2), length of involved colon >5 cm (HR 1.7, 95% CI 1.3-2.3), and retroperitoneal abscess (HR 4.5, 95% CI 1.1-18.4) were associated with diverticulitis recurrence. Right colon disease (HR 0.27, 95% CI 0.09-0.86) was associated with freedom from recurrence. CONCLUSION: Although diverticulitis recurrence is common following an initial attack that has been managed medically, complicated recurrence is uncommon. Patients who present with a family history of diverticulitis, long segment of involved colon, and/or retroperitoneal abscess are at higher risk for recurrent disease. Patients who present with right-sided diverticulitis are at low risk for recurrent disease. These findings should be taken into consideration when counseling patients regarding the potential benefits of prophylactic colectomy. PMID- 21304298 TI - Early result of ligation of the intersphincteric fistula tract for fistula-in ano. AB - PURPOSE: The ligation of the intersphincteric fistula tract is a new surgical procedure without any use of biologic material. The purpose of this study is to present our early results with this novel technique. METHODS: A retrospective review of patients who underwent the procedure for high transsphincteric fistulas was analyzed. The procedure was performed by a single surgeon. Patient and fistula characteristics, complications, and recurrences were reviewed. RESULTS: Twenty-five patients underwent the ligation of intersphincteric fistula tract procedure. All the patients had transsphincteric fistulas that were not suitable for fistulotomy. All patients underwent the procedure on an outpatient basis with a median follow-up of 24 weeks (range, 8-52 wk). Of the 25 patients, 17 (68%) healed completely and did not require any further surgical treatment. Eight of the 25 patients had persistent symptoms: 5 patients had a clear tract with an internal opening, 2 patients had a draining sinus without an identifiable internal opening, and 1 patient presented with an intersphincteric fistula, which was at the site of the intersphincteric groove incision. There were no statistically significant differences in recurrence rates with regard to the presence of a seton at the time of surgery, history of previous operations such as mucosal advancement flap, or seton placement. CONCLUSION: The ligation of intersphincteric fistula is a promising sphincter-preserving procedure that is simple and safe, and it does not require expensive biologic material. Our early data confirm a low recurrence rate with a primary healing rate of 68%. PMID- 21304299 TI - Operative findings, early complications, and long-term survival in 456 patients with pseudomyxoma peritonei syndrome of appendiceal origin. AB - BACKGROUND: Pseudomyxoma peritonei syndrome is a clinical entity characterized by mucinous ascites usually originating from a perforated mucinous appendiceal tumor. Currently optimal therapy is considered complete macroscopic tumor removal (complete cytoreduction) combined with heated intraperitoneal chemotherapy. When complete cytoreduction is not achievable, major tumor debulking is undertaken. The long-term follow-up of patients undergoing surgery for perforated appendiceal tumors in a national pseudomyxoma center is reported. METHODS: Between March 1994 and July 2009, 456 patients with pseudomyxoma peritonei syndrome from perforated appendiceal tumors underwent surgery. The treatment strategy involved a combination of cytoreductve surgery aiming for macroscopic tumor removal, combined with hyperthermic intraperitoneal chemotherapy with mitomycin C. Where complete tumor removal was not possible, maximal tumor debulking was performed. Perioperative outcomes and predicted 5- and 10-year survival are reported. RESULTS: Overall 15 of 456 (3%) tumors were not resectable at laparotomy. Of the 441 patients who had resection, 289 (66%) had complete cytoreduction and 152 (34%) had major tumor debulking. Postoperative in-hospital mortality was 1.6% and grade 3/4 morbidity was 7%. The Kaplan-Meier method predicted 5- and 10-year overall survival of 69% and 57%, respectively. Five- and 10-year predicted survival was 87% and 74% for the 289 patients who had complete cytoreduction compared with 34% and 23% for the 152 who had major tumor debulking. CONCLUSION: Complete tumor removal was achieved in 289 of 441 (66%) patients with peritoneal dissemination from perforated appendiceal tumors with good long-term survival and probable cure in more than two-thirds. PMID- 21304300 TI - Sinus excision and primary closure versus laying open in pilonidal disease: a prospective randomized trial. AB - BACKGROUND: Surgical excision is the standard treatment for chronic pilonidal disease, but all excisional techniques are associated with tissue loss, risk of wound break down, and chronic healing problems. OBJECTIVE: The aim of the study was to compare sinus excision and primary closure vs a laying open technique in a prospective randomized trial. DESIGN, PATIENTS, AND INTERVENTIONS: Eighty patients were randomly assigned to sinus excision and primary closure (n = 39) or laying open (n = 41). Follow-up was performed 1, 3, and 12 months after surgery. MAIN OUTCOME MEASURE: The main outcome measure was the healing rate after 1 year. RESULTS: The healing rate was significantly higher after excision and closure than after laying open at 1 month (20 of 39 vs 8 of 41; P = .005) and 3 months (36 of 38 vs 28 of 39; P = .013) after surgery. At follow-up 12 months after surgery no difference was seen in healing rate between the treatment arms (33 of 37 vs 37 of 38; P = .198). CONCLUSIONS: This prospective randomized trial shows that sinus excision and primary closure results in faster healing than laying open does, but there is no difference in healing rate after 1 year. The laying open procedure is minimally invasive with small risks for the patient, and it might therefore be considered more frequently as the first choice of treatment (www.clinicaltrials.gov. Unique identifier: NCT00997048). PMID- 21304301 TI - Minimally invasive pouch surgery for ulcerative colitis: is there a benefit in staging? AB - BACKGROUND: With the introduction of biologic agents, medical and surgical management of ulcerative colitis has been associated with significant morbidity. A staged surgical approach is advocated to obviate the risks of infectious complication and consequent poor pouch function. OBJECTIVE: The aim of this study was to analyze the outcomes of our selective staged approaches in patients with ulcerative colitis who were undergoing laparoscopic pouch surgery. DESIGN: Consecutive patients with ulcerative colitis referred for laparoscopic surgical treatment between 2002 and 2008 were included in the study. Data were prospectively collected. Patients were divided into 2 groups: a 3-stage group, initial laparoscopic abdominal colectomy followed by pouch surgery with a diverting loop ileostomy, and a 2-stage group, laparoscopic pouch surgery with a diverting loop ileostomy at the initial operation. RESULTS: Of the 118 patients eligible for the study, 68 were in the 2-stage group and 50 were in the 3-stage group. Patients were more likely to have been receiving aggressive medical therapy in the 3-stage group than in the 2-stage group: 43% vs 16% (P = .01) receiving anti-tumor necrosis factor therapy and 96% vs 67% (P = .04) receiving systemic corticosteroids. Although overall complication rates were similar between groups (P = .4), infectious complications were higher in the 2-stage group (38.2% vs 21%, P < .05). CONCLUSIONS: In our practice, we have selectively applied a 3-stage laparoscopic surgical approach to restorative proctocolectomy in patients with ulcerative colitis who are receiving aggressive medical therapy in an attempt to minimize perioperative complications. This strategy appears efficacious, and short-term outcomes compare favorably with those following a 2 stage approach. PMID- 21304302 TI - Perioperative factors during ileal pouch-anal anastomosis predict pouchitis. AB - PURPOSE: Pouchitis is the most common complication of IPAA. Identifying factors predictive of pouchitis may improve outcomes by modifying contributing factors and enhancing patient selection. The most objective means for confirming pouchitis is by histology because the clinical and endoscopic diagnoses rely on more subjective assessments. The importance of histological pouchitis in the absence of clinical or endoscopic findings is unknown. METHODS: Prospectively collected data on patients with IPAA and pouch surveillance were evaluated. Patients who developed pouchitis, defined as symptoms of pouchitis confirmed by endoscopic biopsy (group B) were compared with those without any episode of clinical, endoscopic, or histological pouchitis (group A) for pre- and intraoperative factors and outcomes. Asymptomatic patients with histological pouchitis on surveillance biopsies (group C) were further compared with group A. Patients with Crohn's disease were excluded. RESULT: Of the 673 patients with pouch biopsies, 422 (62.7%) were in group A, 161 (23.9%) in group B, and 90 (13.4%) in group C. Mean follow-up was 9.8 (+/-5.1), 12.4 (+/-5.4), and 13. (+/ 4.7) years. Of the 43 preoperative factors evaluated, those associated with group B included leukocytosis (P < .001), rheumatologic extraintestinal disease (P < .001), disease proximal to splenic flexure (P = .001), pulmonary comorbidity (P = .004), prior steroid use (P = .006), and age at operation and diagnosis (P = .018 and .021). Of the 10 intraoperative factors evaluated, pouchitis was associated with S-pouch reconstruction (P < .001), transfusion (P < .001), and 2-stage instead of 3-stage operation (P = .05), all surrogates for operative complexity. On multivariate analysis, pulmonary comorbidity (OR 3.38, 95% CI 1.62-7.07), disease proximal to splenic flexure (OR 2.37, 95% CI 1.18-4.77), extraintestinal disease manifestations (OR 1.6, 95% CI 1.01-2.54), and S-pouch reconstruction (OR 1.59, 95% CI 0.99 - 2.54) were associated with pouchitis. Patients in group B had worse outcomes, including more strictures (P = .015), bowel obstructions (P = .019), fistulas (P = .18), and lower quality of life (P < .001). Group C patients had the same outcomes as those in group A and the finding was not predicted by the above-mentioned parameters. CONCLUSION: Patients with symptomatic, biopsy confirmed pouchitis have worse long-term outcomes than those without pouchitis. This complication is associated with specific pre- and intraoperative factors. Histological pouchitis incidentally found on surveillance biopsy in asymptomatic patients is of no clinical relevance and does not influence outcome. Identification of these preoperative factors associated with the subsequent development of pouchitis will strengthen patient counseling and may facilitate risk stratification. PMID- 21304303 TI - Relief of fecal incontinence by sacral nerve stimulation linked to focal brain activation. AB - OBJECTIVE: This study aimed to test the hypothesis that sacral nerve stimulation affects afferent vagal projections to the central nervous system associated with frontal cortex activation in patients with fecal incontinence. PATIENTS: Nine women and one man received temporary sacral nerve stimulation with permanent electrodes as a treatment for fecal incontinence. INTERVENTIONS: We used positron emission tomography to record indices of regional cerebral blood flow before and after 30 minutes of continuous stimulation. We repeated this procedure after 2 weeks of continued stimulation, before and 30 minutes after arrest of the stimulation. RESULTS: The initial stimulation activated a region of the contralateral frontal cortex that normally is active during focused attention. After 2 weeks of stimulation, this activation had been replaced by activity in parts of the ipsilateral caudate nucleus, a region of the brain thought to be specifically involved in learning and reward processing. CONCLUSIONS: Sacral nerve stimulation induces changes in cerebral activity consistent with an effect on afferent projections of the vagus. The initial activation of the frontal cortex may reflect focused attention, whereas the subsequent activation of the caudate nucleus may reflect recruitment of mechanisms involved in learning and reward processing. These changes may contribute to the improved continence, which is an acquired result of the stimulation. PMID- 21304304 TI - Sacral nerve stimulation: a novel treatment of chronic anal fissure. AB - OBJECTIVE: The purpose of this pilot study of 5 patients was to test the feasibility of a new treatment approach for chronic anal fissure utilizing minimally invasive sacral nerve stimulation before designing and conducting a larger prospective controlled study. MEASUREMENTS: The patients underwent uneventful placement of one temporary 8-electrode Octad lead for sacral nerve root stimulation. Stimulation was conducted for 20 minutes 3 times per day. The lead was removed after 3 weeks of stimulation. RESULTS: The patients experienced an immediate improvement in perineal pain after the initiation of sacral nerve stimulation. The pain relief effect lasted 10 to 12 hours, so stimulation was conducted for short episodes to ensure patient comfort and to extend the battery life of the external neurostimulator. For all patients, the chronic anal fissure healed by the end of the third week of temporary sacral nerve stimulation. There was no recurrence of anal fissure 1 year after treatment in all of the study participants. CONCLUSION: Sacral nerve stimulation offers an effective alternative treatment option for chronic anal fissure in patients who chose not to pursue more invasive surgical interventions. PMID- 21304305 TI - Postgraduate multidisciplinary development program: impact on the interpretation of pelvic MRI in patients with rectal cancer: a clinical audit in West Denmark. AB - BACKGROUND: Pelvic MRI in patients with rectal cancer is an accepted tool for the identification of patients with poor prognostic tumors who may benefit from neoadjuvant therapy. In Denmark, this examination has been mandatory in the workup on rectal cancer since 2002. OBJECTIVE: This study aimed to assess the impact of a multidisciplinary team course for doctors in West Denmark on the technical quality, reporting, and interpretation of pelvic MRI in rectal cancer. DESIGN: This study is interventional and observational. Two expert reviewers served as reference standard in the evaluation of consecutively performed pelvic MRI scans against which the evaluations from the participating centers were compared. SETTINGS: Five imaging centers in West Denmark performed pelvic MRI in rectal cancer from March 1 to December 31, 2007. PATIENTS: One hundred and eighty patients with newly diagnosed rectal cancer were enrolled. INTERVENTIONS: This study involved a multidisciplinary team course including on-site visits. MAIN OUTCOME MEASURES: The MR scans were evaluated concerning technical performance, reporting, interpretation, and the ability to correctly allocate patients to chemoirradiation based on imaging findings pre- and postcourse. RESULTS: Eighteen percent of the scans were of satisfying technical quality for staging rectal cancer before the course compared with 74% after (P < .001). After the course, the T-stage subclassification, the depth of extramural spread, the N stage, and the presence of extramural vascular invasion was reported significantly more frequently. Based on imaging findings, we observed no significant effect on the ability to perform correct treatment stratification according to Danish guidelines. LIMITATIONS: The evaluation process itself may have improved the performance of the participating centers. CONCLUSIONS: Performance and reporting of pelvic MRI in patients with rectal cancer can be improved significantly through multidisciplinary development courses and on-site visits, whereas improvements in image interpretation with regard to treatment stratification may demand more intensive efforts. PMID- 21304306 TI - Older patients and adjuvant therapy for colorectal cancer: surgeon knowledge, opinions, and practice. AB - BACKGROUND: Increasing patient age independently predicts nonreferral and nonreceipt of adjuvant therapy among patients with colorectal cancer. OBJECTIVE: This study aimed to identify factors affecting surgeons' decisions to refer older patients for adjuvant therapy. DESIGN/SETTINGS/PARTICIPANTS: A self-administered survey was sent to all Australian and New Zealand colorectal surgeons (n = 146). MAIN OUTCOME MEASURES: The survey consisted of 3 sections: 1) knowledge of research evidence, 2) opinions on evidence and adjuvant therapy in older patients, and 3) self-reported practice, or likelihood of patient referral in different scenarios. Demographic information was also obtained. RESULTS: Seventy percent of surgeons responded. Surgeons were significantly less likely to refer older patients than younger patients for adjuvant therapy in all scenarios (P < .001). The difference in referral recommendations was greatest when patients lived a long way from treatment, had a comorbid condition, or had little social support. There was greater variation in referral recommendations for older patients, and marked disagreement between surgeons in knowledge and opinion questions. Surgeon age was the only significant predictor of survey responses. Greater knowledge and more positive opinions predicted similar referral recommendations for older and younger patients (P = .02, P = .01). LIMITATIONS: Although decreased referral and receipt of adjuvant therapy among older patients is most likely multifactorial, this survey focused on the views of one physician group and a number of specific scenarios. CONCLUSIONS: Chronological age alone appears to impact colorectal surgeons' decisions to refer patients for adjuvant therapy. Sociodemographic and physiological factors further decrease the likelihood of referral of older patients. A lack of consensus among surgeons suggests that more research is needed both to predict how older patients with cancer will react to treatment, and to determine how information from emerging evidence can be best used to assist physicians' treatment decisions. PMID- 21304307 TI - Robotic versus laparoscopic rectopexy for complex rectocele: a prospective comparison of short-term outcomes. AB - PURPOSE: The role of robotic assistance in pelvic floor prolapse surgery is debatable. This study aims to report our early experience of robotic-assisted ventral mesh rectopexy in the treatment of complex rectocele and to compare this with the laparoscopic approach in terms of safety and short-term postoperative outcomes. METHODS: We analyzed a cohort of 63 consecutive patients operated on for complex rectocele from March 2008 to December 2009. A complex rectocele was defined as a rectocele that had one or more of the following features: larger than 3 cm in diameter, associated with an enterocele or internal rectal prolapse. The patients underwent either the robotic procedure or laparoscopic procedure, based only on the availability of the robotic system. Procedures involved either a single-mesh fixation for posterior-compartment prolapse (concurrent rectocele and enterocele) or a double-mesh fixation for a concurrent anterior compartment prolapse (with cystocele). A transvaginal tape was inserted at the same surgery in patients with urinary incontinence. RESULTS: All patients were female; 40 underwent the laparoscopic procedure and 23 underwent the robotic procedure. Both groups were similar in age (mean, 59 +/- 13 vs 61 +/- 11; P = .440), ASA status, and previous abdominal surgery, respectively. Patients undergoing the robotic procedure had a significantly higher body mass index (mean, 27 +/- 4 vs 24 +/- 4; P = .03), more frequent double-mesh implantation (17/23 vs 14/40; P = .003), and longer operative time (mean, 221 +/- 39 min vs 162 +/- 60 min; P = .0001). Patients undergoing a laparoscopic procedure had slightly more blood loss (mean, 45 +/- 91mL vs 6 +/- 23 mL, P = .05). The number of transvaginal-tape procedures performed (6/40 vs 3/23, P > .999), conversion rate (10% vs 5%; P = .747), and duration of hospitalization were similar (mean, 5 +/- 2 d vs 5 +/- 1.6 d; P = .872). There were no mortalities or recurrences at the 6-month postoperative review. CONCLUSION: In our experience, the robotic approach for the treatment of complex rectocele is as safe as the laparoscopic approach, with favorable short term results. PMID- 21304308 TI - Predictors of anal dysplasia in men who have sex with men with benign cytology. AB - PURPOSE: Anal cytology is used to screen patients for anal dysplasia. Anal pap smears are collected without direct visualization of the canal, whereas cervical cytology is obtained with direct visualization. Current screening guidelines dictate that patients with abnormal cytology are to be evaluated with high resolution anoscopy, and patients with benign anal cytology forgo high-resolution anoscopy. We routinely perform standard anoscopy after cytology collection. We endeavored to determine whether our standard procedure would reveal findings supporting high-resolution anoscopy even with benign cytology. METHODS: We performed a retrospective chart review of all anal cytology results from January 2008 to March 2009, identifying the patients with benign results who had undergone high-resolution anoscopy. Records were analyzed to determine the indication for high-resolution anoscopy and biopsy results. RESULTS: We identified 2084 patients with anal cytology results, including 613 (29%) patients who had benign results and 169 (28%) patients who had undergone high-resolution anoscopy. The main reasons for high-resolution anoscopy were high risk of recurrent dysplasia based on prior high-grade squamous intraepithelial lesion with cytology done concurrently in 77 (46%), and abnormal anoscopy findings thought to be indicative of dysplasia (plaque or nodule suspicious of dysplasia, internal or external condyloma, dysplastic appearing fissure) in 92 (54%). Of subjects with abnormal anoscopy findings indicative of dysplasia, 25 (27%) had high-grade and 39 (42%) had low-grade dysplasia. Of those undergoing cytology and high-resolution anoscopy simultaneously, 14 (18%) had high-grade and 12 (16%) had low-grade dysplasia. In total, 90 (53%) of those with benign cytology who had high-resolution anoscopy had abnormal pathology, and 39 (23%) had high-grade dysplasia. CONCLUSIONS: Men having sex with men can have significant dysplasia with benign cytology. Standard anoscopy identifies findings indicative of dysplasia that, if present, should lead to high-resolution anoscopy even with benign cytology. Standard anoscopy should become an integral part of anal dysplasia screening. Prior recent history of high-grade dysplasia should lead to high-resolution anoscopy even with benign cytology. PMID- 21304309 TI - The psychological impact of being screened for anal cancer in HIV-infected men who have sex with men. AB - BACKGROUND: Anal cancer screening may be considered in HIV-infected men who have sex with men because they are at increased risk. Cancer screening can provoke anxiety, which may lead to poorer screening compliance. OBJECTIVE: This study aimed to measure the psychological consequences of anal cancer screening in HIV infected men who have sex with men. DESIGN: This investigation is a prospective cohort study. SETTING: This study was conducted in primary and tertiary care HIV clinics in Toronto, Canada. PATIENTS: One hundred four HIV-infected men who have sex with men were studied. MAIN OUTCOME MEASURES: : Psychological impact was measured at 4 time points (before screening, after screening, after receiving results, and before follow-up) using the Impact of Events Scale, the Illness Intrusiveness Ratings Scale, and the Psychological Consequences Questionnaire. RESULTS: Median age was 44, 77% were receiving antiretroviral therapy, and 11% had high-grade anal dysplasia (anal intraepithelial neoplasia 2/3). Fifteen to 32% of the patients reported high levels of negative psychological consequences across the 4 time points; the highest levels occurred at time 2. Higher HIV symptom count and baseline level of negative impact were significantly associated with higher Impact of Events scores, whereas younger age and a higher baseline level of negative impact were significantly associated with higher scores with use of the Illness Intrusiveness Ratings Scale. CONCLUSIONS: Anal cancer screening is not associated with greater adverse psychological impact in most HIV infected men who have sex with men. Younger patients, those with more HIV-related symptoms and greater baseline psychological distress, are at risk for increased psychological distress during screening. PMID- 21304310 TI - Right colonic transposition technique: when the left colon is unavailable for achieving a pelvic anastomosis. AB - PURPOSE: On occasion, the left colon is not available for rectal or low pelvic anastomosis either because of synchronous pathology, previous resections, or inadequate blood supply. The short middle colic pedicle prevents use of the transverse colon for this purpose. In this situation, the right colon is a good anastomotic conduit. The aim of this video is to demonstrate the right colonic transposition technique. METHODS: Intraoperative footage was filmed and edited in a multimedia format. Operative details were as follows: the diseased left colon and transverse colon are excised; the right colon is fully mobilized and transposed 180 degrees anticlockwise around the axis of the ileocolic pedicle, so the hepatic flexure reaches into the pelvis without tension. The hepatic flexure is then used for anastomosis within the pelvis either to the residual rectum or anus (see Supplemental Digital Content, Videos 1-3, http://links.lww.com/DCR/A46, http://links.lww.com/DCR/A47, and http://links.lww.com/DCR/A48). Case notes were reviewed to analyze clinical outcome and bowel function. RESULTS: Three patients underwent the technique, 2 females and 1 male (median age, 45 (range, 30-55) years). Median operating time was 98 (range, 95-114) minutes. There were no anastomotic failures or other major complications. One patient had a superficial wound infection. The median in-hospital stay was 7 (range, 7-8) days. The median time to first bowel movement was 3 (range, 3-4) days; the median daily stool frequency was 4 (range, 3-4) on discharge, decreasing to 2 daily stools 12 months after surgery. Stoma formation and total colectomy were successfully avoided in each patient. CONCLUSIONS: Right colonic transposition is a useful technique to enable the construction of a tension-free rectal anastomosis with a good blood supply. The use of the right colon in these clinicopathological situations can be achieved with low morbidity and results in good short- and long-term bowel function in these patients. Careful preservation of the ileocolic pedicle and division of the right colic vessels are essential to facilitate successful anastomosis. PMID- 21304311 TI - Topic update: effects of colorectal cancer treatments on female fertility and potential methods for fertility preservation. AB - PURPOSE: Preservation of fertility in young females with a diagnosis of colorectal cancer is gaining increasing importance as survival rates of cancer increase. This review examines the effects of pelvic surgery, chemotherapy, and radiotherapy on fecundity. It also discusses the options available to patients including ovarian transposition, gonadotropin-releasing hormone analogs, embryo and ovarian cryopreservation, and ovarian tissue transplantation. METHODS: A search of MEDLINE, EMBASE, and the Cochrane library was performed using keywords and exploded Mesh search headings and the subsequent articles were reviewed. Relevant studies were included. RESULTS: There are no studies that examine the effect of surgery for colorectal cancer on female fertility, in particular, surgery below the peritoneal reflection for rectal cancer. However, patients with familial adenomatous polyposis have a similar fecundity before and after proctocolectomy with ileal pouch-anal anastomosis. These patients did significantly better than patients with ulcerative colitis who underwent the same procedure. There is conflicting evidence regarding the effects of open vs laparoscopic surgery on fertility. Oxaliplatin, an adjuvant therapy, has moderate gonadotoxic effects. Fluorouracil is considered to have almost no effect on human reproductive function. Gonadotropin-releasing hormone agonists are currently used to preserve female fecundity during chemotherapy. A recent update of patients treated for Hodgkin lymphoma showed that significantly fewer women treated with a gonadotropin-releasing hormone agonist during chemotherapy exhibited premature ovarian failure. Ovarian transposition reduces the radiation dose to approximately 5% to 10% of the dose to the ovaries in their normal position. Other options are available to women with cancer who wish to preserve their germ line, including embryo and oocyte cryopreservation and ovarian tissue cryopreservation. CONCLUSION: Significant advances are now allowing females to preserve their fertility after cancer treatment. It is essential that patients receive adequate fertility counseling before any intervention to give them an opportunity to consider fertility alternatives. PMID- 21304312 TI - Is "ischemic" colitis ischemic? AB - Ischemic colitis appears to be a collection of diseases rather than a single entity. On the one hand, there is the colitis that truly appears to be caused by a lack of blood flow and, on the other hand, there is the disease that is called "ischemic" for lack of a better diagnosis-the colitis that is more "idiopathic" than "ischemic." Four widely held tenets of "ischemic" colitis are wrong: 1) the colon is not particularly sensitive to ischemia; 2) ischemic colitis is rarely preceded by a period of global hypoperfusion; 3) the "watershed areas" are not disproportionately affected; and 4) colonoscopy with biopsy is not specific for the disease. The cause of "ischemic" colitis is unknown. Therefore it is, until proven otherwise, "acute idiopathic colitis." PMID- 21304314 TI - The evolving role of robotic colorectal surgery. PMID- 21304316 TI - European initiatives in colorectal cancer screening. PMID- 21304317 TI - Association of celiac disease and hereditary angioedema due to C1-inhibitor deficiency. Screening patients with hereditary angioedema for celiac disease: is it worth the effort? AB - OBJECTIVE: Hereditary angioedema due to C1-inhibitor deficiency is a life threatening condition, which manifests as edematous attacks involving subcutaneous tissues and/or the upper airway/gastrointestinal mucosa. Celiac disease is a gluten-sensitive small intestinal disorder that can lead to severe villous atrophy, malabsorption, and malignancy. Both hereditary angioedema and celiac disease may present with abdominal symptoms. Our aim was to study the occurrence of celiac disease in the hereditary angioedema population, as well as to analyze the clinical course of cases with both diseases. METHODS: One hundred and twenty-eight patients with hereditary angioedema were screened for celiac disease, using serological methods [antiendomysial antibodies-immunoglobulin A (IgA), antiendomysial antibodies-IgG and tissue transglutaminase-IgA, tissue transglutaminase-IgG]. Clinical data of a child with hereditary angioedema and celiac disease diagnosed earlier were added to the dataset to be analyzed. Thus, the total number of patients was 129, comprising 107 adults and 22 pediatric patients. In patients with celiac disease, molecular genetics analysis (human leukocyte antigen-DQA1, human leukocyte antigen-DQB1) was carried out along with the introduction of a gluten-free diet and regular follow-up. RESULTS: Four out of the 22 children were diagnosed with celiac disease in our hereditary angioedema population. The prevalence of celiac disease among our pediatric patients with hereditary angioedema (22 children) was higher than in the general population (18.1 vs. 1.2%). Switching from the wheat starch-containing tranexamic acid product to danazol and introducing a gluten-free diet mitigated abdominal symptoms of hereditary angioedema. CONCLUSION: Similarities between the symptoms of hereditary angioedema and celiac disease may cause difficulties in differential diagnosis, as well as in choosing the appropriate therapy. In our opinion, screening hereditary angioedema patients for celiac disease is warranted if abdominal attacks or neurological symptoms persist despite adequate management. Complement testing is recommended whenever abdominal symptoms persist despite the histological and serological remission of gluten-sensitive enteropathy after the introduction of a gluten-free diet. PMID- 21304318 TI - Oral medication adherence and disease severity in pediatric inflammatory bowel disease. AB - OBJECTIVE: The purpose of this study was to examine the relationship of oral medication adherence and perceived adherence barriers with disease severity in a sample of adolescents with inflammatory bowel disease (IBD). METHODS: Participants included 62 adolescents, aged 13-17 years, diagnosed with IBD, and their parents. Data on the measures of parent-rated and patient-rated oral medication adherence and related barriers, behavioral and emotional functioning per parent report and self-report, and disease severity per medical chart reported by a physician were obtained. RESULTS: Fifteen percent of the sample reported clinically elevated depressive symptoms and 24% reported clinically elevated internalizing behavioral problems. Number of reported adherence barriers was 2.6+/-1.5, and none of the participants reported zero barriers. Parental ratings of medication adherence (t = -2.11, P<0.05) and perceived barriers to adherence (t = 2.05, P<0.05) significantly predicted disease severity after statistically controlling for the contributions of behavioral and disease parameters to disease severity. CONCLUSION: Results suggest that the oral medication adherence and perceived adherence barriers are significantly related to disease severity in adolescents with IBD. These patients also may be at risk for increased behavioral and emotional problems, which may impact health outcomes as well. Clinicians should make particular efforts to attend to medication adherence issues with their patients. Working with patients and families to develop solutions for eliminating adherence barriers might result in better disease outcomes. PMID- 21304319 TI - Clinical impact of fluorodeoxyglucose-positron emission tomography scan/computed tomography in comparison with computed tomography on the detection of colorectal cancer recurrence. AB - BACKGROUND AND AIMS: Early detection is an essential prognostic factor in colorectal cancer (CRC) recurrence. Our aim was to evaluate diagnostic performances of (18)F-fluorodeoxyglucose-positron emission tomography ((18)F-FDG PET)/computed tomography (CT) as compared with CT in the detection of CRC recurrence. METHODS: Data of patients with suspected CRC recurrence and in whom both FDG-PET/CT and CT were performed were analyzed. All detected lesions were characterized according to their number, size, and localization. Positive histological or radiological follow-up was considered as the 'gold standard'. Diagnostic performances of FDG-PET/CT and CT were calculated by lesion, globally and with respect to the site of recurrence. RESULTS: One hundred and seventy-six true-positive lesions were identified in 71 patients. CT scan was positive in 58 (82%) patients and FDG-PET/CT in 70 (98%) patients. In per lesion analysis, the global accuracy of FDG-PET/CT in detection of lesions was of 88% (sensitivity = 95%, specificity = 54%), which was higher than that of CT (53%, sensitivity = 55%, specificity = 43%), particularly in case of lymph nodes metastases (100 vs. 35%) and locoregional lesions (100 vs. 39%) (P<0.0001). FDG-PET/CT modified the clinical management in 31 patients. CONCLUSIONS: FDG-PET/CT is more sensitive than CT for diagnosis of CRC recurrence and can modify the management in 40% of patients. PMID- 21304320 TI - Stevens-Johnson syndrome and cholestatic hepatitis induced by acute Epstein-Barr virus infection. PMID- 21304323 TI - Prevalence of gastrointestinal problems in occupations: a retrospective study. PMID- 21304324 TI - A basis for the pathological oscillations in basal ganglia: the crucial role of dopamine. PMID- 21304325 TI - The electrophysiological correlates of the size incongruity effect. AB - The size incongruity effect refers to an increase in response time when the physical size of the letters in which the name of an object is written conflicts with the actual size of the object named. The electrophysiological correlates of the size incongruity effect were investigated in 13 healthy individuals through event-related potentials in this study. Scalp event-related potential analysis revealed: the incongruent condition elicited two more negative components N200 400 and N500-700 than did the congruent condition. N200-400 is a critical sign of conflict detection in the early stage, whereas N500-700 mirrors the response conflict in the late stage. The results provided evidence for the dissociation between conflict detection and conflict resolution in the size incongruity effect. PMID- 21304326 TI - Attentional awakening, resource allocation and the focus of temporal attention. AB - Attentional awakening (AA) is an impairment in the identification of target stimuli that are presented early in a rapidly presented sequence of visual stimuli. Here we investigate whether AA is related to resource allocation, measured as amplitude of the P3 event-related potential and/or variance in the focus of temporal attention, measured as P3 phase distribution. We observed a relationship between P3 amplitude and AA that depended strongly on targets' a posteriori probabilities. Evidence was found for a link between performance and P3 phase distributions, but a relationship between AA and P3 phase distributions was not evident. These findings suggest that resource allocation is a relevant factor for AA whereas the variance in the focus of temporal attention contributes only little to AA. PMID- 21304327 TI - Counteractive effects of cannabinoid and nicotine-addictive behavior. AB - Our recent results suggest that cannabinoid exposure induces conditioned place preference (CPP) through facilitated induction of synaptic long-term depression at dopamine circuitry of the midbrain ventral tegmental area (VTA). Here, we show that chronic nicotine exposure also induces CPP, but facilitates the induction of synaptic long-term potentiation in the VTA. Coadministration of cannabinoid and nicotine leads to a blockade of facilitated long-term depression and long-term potentiation induction in these neurons and elimination of CPP. These findings point to counteractive effects of cannabinoid and nicotine-addictive behavior through opposite changes in synaptic plasticity of dopamine circuitry of the VTA. PMID- 21304328 TI - Increased regional homogeneity of blood oxygen level-dependent signals in occipital cortex of early blind individuals. AB - Although resting-state functional magnetic resonance imaging has shown altered functional connectivity between visual and other brain areas in the early blind individuals, it cannot answer which brain area's local activities are changed. In this study, regional homogeneity, a measure of the homogeneity of the local blood oxygen level-dependent signals, was used for the first time to investigate the changes in the resting-state brain activity in the early blind individuals. Compared with age-matched and sex-matched sighted individuals, the early blind individuals showed increased regional homogeneity only in the occipital areas, which might be explained by the abnormal cortical development and/or experience dependent plasticity, resulted from an early visual deprivation. PMID- 21304330 TI - Surgical view of the lumbar arteries and their branches: an anatomical study. AB - BACKGROUND: Although injury to the lumbar arteries during anterior spinal approaches is often encountered, there are few published articles regarding the relationship between the lumbar arteries and spinal cord ischemia. OBJECTIVE: To examine the morphology of the lumbar arteries and to emphasize their clinical importance. METHODS: With the aid of a surgical microscope, 80 lumbar arteries in 10 formalin-fixed male cadavers were studied. Measurements of these structures were made and relationships observed. RESULTS: The spinal artery was usually the first branch of the lumbar artery. The greatest lumbar artery diameter was at L4 and had a mean diameter of 3.25 mm; the smallest diameter was identified at L2 and had a mean diameter of 2.05 mm. The largest spinal artery diameter was at L3 (mean, 0.56 mm) and the smallest at L1 (mean, 0.42 mm). The largest anastomotic artery diameter was at L4 (mean, 0.42 mm) and the smallest at L1 (mean, 0.32 mm). For the right and left sides, the mean greatest distance between the origin of the lumbar artery and the tendinous arch was at L4 (mean, 40.9 and 31.8 mm, respectively) and the least at L1 (mean, 31.8 and 22.5 mm, respectively). The mean of the greatest distance between the anastomotic branch and the base of the transverse process of the lumbar vertebrae was at L4 (mean, 4.41 and 4.35 mm, respectively) and the smallest at L1 (mean, 4.04 and 4.08 mm, respectively). CONCLUSION: These anatomic findings of the lumbar segmental arteries would be useful for emphasizing their surgical importance. PMID- 21304331 TI - A computed tomography-based localizer to determine the entry site of the ventricular end of a parietal ventriculoperitoneal shunt. AB - BACKGROUND: One of the major principles of shunt insertion into the brain involves choosing an entry site that avoids eloquent cortex. OBJECTIVE: We describe a novel tool to accurately locate the burr hole for insertion of the ventricular end of a catheter during parietal ventriculoperitoneal shunt surgery. METHODS: Computed tomography (CT)-based measurements in 2 dimensions were used to mark the entry point with the help of an indigenously designed Vellore burr hole localizer (VL). Patients underwent surgery with either the conventional method to localize the burr hole (Keen point; group A; n = 28) or the VL (group B; n = 28). An independent observer determined the accuracy of shunt placement on postoperative CT scans. The VL is designed with a fixed horizontal arm that can be aligned with the CT or magnetic resonance reference plane and a vertical arm with a flexible sliding horizontal arm that is attached to it with an adjustable screw. By manipulating the flexible arm along the contour of the skull and using the scale provided on both the vertical and horizontal arms, we can mark the burr hole site for placement of a parietal ventriculoperitoneal shunt. RESULTS: Overall accuracy in group A was 32.1%, whereas in group B, an accuracy of 82.1% could be achieved (P < .01). CONCLUSION: Placement of a burr hole guided by the VL increases the accuracy of the desired entry point of the ventricular catheter. PMID- 21304332 TI - Presurgical simulation with advanced 3-dimensional multifusion volumetric imaging in patients with skull base tumors. AB - BACKGROUND: Despite recent diagnostic and technical advancements in the field of neurosurgery, surgical treatment for tumors in the skull base region, ie, skull base tumors (SBTs), remains a challenge. OBJECTIVE: To validate the utility of presurgical simulation for the treatment of SBTs by 3-dimensional multifusion volumetric imaging (3D MFVI), including volume rendering and image fusion, to combine data from various imaging modalities. METHODS: We performed presurgical simulation using 3D MFVI for 21 SBTs (acoustic neurinomas, jugular neurinomas, meningiomas, chordomas, and others) in 20 patients. We collected targeted data from computed tomography, magnetic resonance imaging, computed tomography or magnetic resonance angiography, and digital subtraction angiography and combined these data using image-analyzing software. The simulations were used to assess the 3D relationships among the microsurgical anatomical components, the appropriate surgical approach, and the resectable parts of the tumor. Finally, we compared the results of the simulation with the operative results. RESULTS: In all patients, the 3D MFVI techniques enabled adequate visualization of the microsurgical anatomy and facilitated presurgical simulation, thereby allowing the surgeons to determine an appropriate and feasible surgical approach. All procedures to open the bone window were performed in accordance with the simulations, except for the surgical exposure of the acoustic canal for 2 acoustic neurinomas. In 3 of the 21 cases, tumor removal could not be performed according to the simulations because of unexpected bleeding or other restrictions. CONCLUSION: The 3D MFVI technique was of a sufficiently high quality to enable visualization of the 3D microsurgical anatomy. This promising method can facilitate determination of the most appropriate approach and safe and precise surgical procedures for SBTs. PMID- 21304333 TI - Virtual interactive presence and augmented reality (VIPAR) for remote surgical assistance. AB - BACKGROUND: Surgery is a highly technical field that combines continuous decision making with the coordination of spatiovisual tasks. OBJECTIVE: We designed a virtual interactive presence and augmented reality (VIPAR) platform that allows a remote surgeon to deliver real-time virtual assistance to a local surgeon, over a standard Internet connection. METHODS: The VIPAR system consisted of a "local" and a "remote" station, each situated over a surgical field and a blue screen, respectively. Each station was equipped with a digital viewpiece, composed of 2 cameras for stereoscopic capture, and a high-definition viewer displaying a virtual field. The virtual field was created by digitally compositing selected elements within the remote field into the local field. The viewpieces were controlled by workstations mutually connected by the Internet, allowing virtual remote interaction in real time. Digital renderings derived from volumetric MRI were added to the virtual field to augment the surgeon's reality. For demonstration, a fixed-formalin cadaver head and neck were obtained, and a carotid endarterectomy (CEA) and pterional craniotomy were performed under the VIPAR system. RESULTS: The VIPAR system allowed for real-time, virtual interaction between a local (resident) and remote (attending) surgeon. In both carotid and pterional dissections, major anatomic structures were visualized and identified. Virtual interaction permitted remote instruction for the local surgeon, and MRI augmentation provided spatial guidance to both surgeons. Camera resolution, color contrast, time lag, and depth perception were identified as technical issues requiring further optimization. CONCLUSION: Virtual interactive presence and augmented reality provide a novel platform for remote surgical assistance, with multiple applications in surgical training and remote expert assistance. PMID- 21304334 TI - Anatomical study of the arachnoid envelope over the pineal region. AB - BACKGROUND: The distribution of the arachnoid membrane and its relationship with the neurovascular structures in the pineal region are still not fully understood. OBJECTIVE: Because the arachnoid membrane has an intimate relationship with the neurovascular structures in the pineal region and it will always be encountered surgically, we attempted to clarify the formation and distribution of the arachnoid envelope over the pineal region (AEPG). METHODS: The formation and distribution of the AEPG and its relationship with the neurovascular structures in the pineal region were examined by anatomic dissection in 20 adult cadaveric formalin-fixed heads. RESULTS: The supratentorial and infratentorial outer arachnoid membranes converged at the tentorial apex and then embraced and ran forward along the vein of Galen to form the AEPG. The AEPG could be divided into 2 parts. Typically, the posterior part of the AEPG enveloped the vein of Galen and the terminal segments of its tributaries, and the anterior part of the AEPG enveloped the suprapineal recess, the pineal gland, and the distal segment of the internal cerebral veins. The compartment demarcated by the AEPG did not communicate with the adjacent subarachnoid cisterns or space. CONCLUSION: Previous knowledge about the AEPG, as well as the superior boundary and the contents of the quadrigeminal cistern, needs to be revised. The arrangement and individual variation of AEPG are important for a better understanding of the various growth patterns of the pineal tumors and the relationship between the tumor and the neurovascular structures in the pineal region. PMID- 21304335 TI - Transorbital endovascular embolization of dural carotid-cavernous fistula: access to cavernous sinus through direct puncture: case examples and technical report. AB - OBJECTIVE: We present 2 cases of carotid-cavernous fistulas that failed multiple attempts at transarterial and transvenous embolization. Direct transorbital puncture for embolization was successful in curing the fistulas. The relevant anatomy and technique are reviewed. CLINICAL PRESENTATION: The first case is a 39 year-old man who presented with a 2-month history of worsening right-sided chemosis, proptosis, double vision, and progressive right eye vision loss. The second case is a 79-year-old woman with a 5-month history of right-sided chemosis and a 1-month history of complete left ophthalmoplegia. Cerebral angiography revealed an indirect carotid-cavernous fistula (CCF) in both patients, supplied by meningeal branches of the internal and/or external carotid arteries. INTERVENTION: After multiple unsuccessful attempts at transarterial and transvenous embolization, the CCFs were accessed via direct percutaneous transorbital puncture of the inferior and superior ophthalmic veins, respectively. The fistulas were then successfully occluded with a combination of Onyx and detachable coils. CONCLUSION: In rare cases in which more conventional transvenous and transarterial routes to a CCF have been exhausted, direct percutaneous transorbital puncture represents a viable means of achieving catheterization of the fistulous connection. In most cases, where a prominent arterialized superior ophthalmic vein is present, direct puncture represents a reasonable alternative to ophthalmologic cut-down procedures. Transorbital puncture of the inferior ophthalmic vein provides a direct route to the cavernous sinus in cases where the superior ophthalmic vein is atretic and inaccessible by direct surgical cut-down procedures. PMID- 21304337 TI - Taking the lead. PMID- 21304338 TI - The Utrecht approach to exercise in chronic childhood conditions: the decade in review. AB - PURPOSE: To summarize and discuss current evidence and understanding of clinical pediatric exercise physiology focusing on the work the research group at Utrecht and others have performed in the last decade in a variety of chronic childhood conditions as a continuation of the legacy of Dr Bar-Or. KEY POINTS: The report discusses current research findings on the cardiopulmonary exercise performance of children (and adolescents) with juvenile idiopathic arthritis, osteogenesis imperfecta, achondroplasia, hemophilia, cerebral palsy, spina bifida, cystic fibrosis, and childhood cancer. Exercise recommendations and contraindications are provided for each condition. Implications for clinical practice and future research in this area are discussed for each of the chronic conditions presented. CLINICAL IMPLICATIONS: The authors provide a basic framework for developing an individual and/or disease-specific training program, introduce the physical activity pyramid, and recommend a core set of clinical measures to be used in clinical research. PMID- 21304339 TI - Supramaximal verification of peak oxygen uptake in adolescents with cystic fibrosis. AB - PURPOSE: To study whether peak oxygen uptake ((Equation is included in full-text article VO2 peak), attained in traditional cardiopulmonary exercise testing (CPET) in adolescents with cystic fibrosis (CF), could be verified by a supramaximal exercise test. METHODS: Sixteen adolescents with CF (forced expiratory volume in 1 second as % of predicted [range, 45%-117%]) volunteered and successively performed CPET and a supramaximal test (Steep Ramp Test [SRT] protocol). RESULTS: Cardiopulmonary exercise testing and the SRT resulted in comparable cardiorespiratory peak values. We found no significant difference in oxygen uptake ((Equation is included in full-text article VO2 peak/kg) between CPET and the SRT (38.9 +/- 7.4 and 38.8 +/- 8.5 mL min kg, respectively; P = .81). We found no systemic bias for CPET and SRT measurements of (Equation is included in full-text article VO2 peak/kg and no differences between CPET and SRT (Equation is included in full-text article VO2 peak values within and between the maximal and non-maximal effort groups (P > .4). CONCLUSION: The (Equation is included in full-text article VO2 peak measured in CPET seems to reflect the true (Equation is included in full-text article.)O2 peak in adolescents with CF. PMID- 21304340 TI - Normal values of functional reach and lateral reach tests in Indian school children. AB - PURPOSE: To establish normal values for functional reach (FR) and lateral reach (LR) in school children and to study the correlation of anthropometric measures with FR and LR values and the association between FR and LR scores. METHODS: A total of 350 children aged 6 to 12 years were randomly selected. Three successive trials of FR and LR with the child standing with feet shoulder width apart were performed and the mean of 3 trials was calculated. RESULTS: Normal values of FR and LR were obtained. Pearson product moment correlation was used to examine the association of FR and LR to age, gender, and anthropometric measures. Stepwise regression analysis was done to obtain normal values of FR and LR with respect to height. Functional reach values significantly predicted LR values and vice versa. CONCLUSION: Normal mean values of FR and LR range from 22.7 cm to 37 cm and 16.3 cm to 22.5 cm, respectively. Height significantly correlates with both FR and LR. PMID- 21304341 TI - Reference values on the 6-minute walk test for children living in the United States. AB - PURPOSE: : The purpose of this study was to investigate reference values for the 6-minute walk test (6MWT) and the relationship between 6-minute walk distance (6MWD) and age, sex, and anthropometric variables in children who are healthy, aged 7 to 11 years and living in the United States. METHODS: : The sample included 100 children, 57 female, 43 male, mean age 9.66 +/- 1.08 years. Measures included height, weight, body mass index, leg length, and 6MWD. RESULTS: : Mean 6MWD was 518.50 +/- 73.56 m. Values were lower than those reported for children living in other countries with the exception of England. There were no significant associations between the 6MWD and other variables with the exception of body mass index in males. CONCLUSION: : Our findings suggest 6MWT values for children living in other countries may not be directly applicable to children living in the United States. PMID- 21304342 TI - Treadmill training and overground gait: decision making for a toddler with spina bifida. AB - BACKGROUND AND PURPOSE: This case report describes a decision-making process that was used to progress a home-based intervention that coupled treadmill and walker stepping for a preambulatory toddler with spina bifida. CASE DESCRIPTION: The toddler in this report had an L4-L5 level lesion, and began this home-based intervention at 18 months of age when she was pulling to stand. INTERVENTION: The intervention included parameters for treadmill stepping that prepared this toddler for gait with orthotics and was progressed to overground walking with a walker using a decision-making algorithm based on data obtained from a parent log and coded video. OUTCOMES: This toddler progressed from not stepping at the start of the study to ambulating 150 m with a walker at age 23 months, after 18 weeks of this intervention. DISCUSSION AND CONCLUSION: The intervention and decision making process used in this study were family centered and may be applicable to gait intervention with other populations. PMID- 21304343 TI - Task analyses identify coat-donning delays in preschoolers in special education. AB - PURPOSE: To describe use of task analyses for school-based documentation of skill levels of a sample of preschool children in special education classes. METHOD: Coat-donning task analyses and scoring codes were developed for the traditional and coat- flip methods. Preschool children's abilities were scored 3 times per year as part of weekly classroom consultations. Of 601 charts from 2003 to 2007, 171 met inclusion criteria. RESULTS: Initially, 22 (13%) children independently donned coats; 149 (87%) required assistance. Final scores identified that 75 (44%) children achieved or regained independence, 14 (8%) still required assistance prior to kindergarten entrance, 50 (29%) were eligible for more services, and 32 (19%) had services interrupted. CONCLUSION: Task analyses and scoring codes improved efficiency and standardization of school-based documentation, demonstrated incremental changes over time, and focused task training. The majority of preschool children in this sample were initially delayed in coat-donning independence when compared with preschool children developing typically. PMID- 21304344 TI - Does orthotic use affect upper extremity support during upright play in infants with down syndrome? AB - PURPOSE: To determine whether supramalleolar orthoses use during upright play contributes to decreased upper extremity support in infants with Down syndrome. METHOD: Seventeen children with Down syndrome were assigned to 2 groups. Infants in the control group received treadmill training. Infants in the experimental group wore supramalleolar orthoses in addition to treadmill training. The participants were followed every other month from pull to stand until independent walking. Each child was videotaped playing at a table for 20 minutes. Researchers coded the tapes to determine whether the child's trunk was leaning or not and whether he or she was using 0, 1, or 2 hands for support. RESULTS: No group differences were found in hand support during time in the upright position. All children decreased the amount of 2-hand support over time (P = .05). CONCLUSION: The use of supramalleolar orthoses may improve upright stability but it does not decrease upper extremity support in infants with Down syndrome. PMID- 21304345 TI - The role of physical therapists in pediatric health promotion and obesity prevention: comparison of attitudes. AB - PURPOSE: To identify attitudes of teachers, parents, and physical therapists (PTs) toward PTs' roles in health promotion (HP), obesity prevention (OP), and physical activity (PA) for preschoolers. METHODS: Surveys (n = 618) were distributed to preschools and pediatric PTs. RESULTS: Overall response rate was 42%. Dietitians or physicians were selected as most knowledgeable about HP/OP/PA. Teachers were selected as most appropriate to educate preschoolers, whereas PTs were identified as appropriate to educate parents and teachers about HP/OP/PA. Most respondents were unaware of PTs' involvement in HP/OP/PA. CONCLUSIONS: Physical therapist expertise is underrecognized and underused for pediatric HP/OP/PA. Parents and teachers are open to PT's involvement. Physical therapists need to improve awareness and become involved. PMID- 21304346 TI - Kinesthetic sensitivity and related measures of hand sensitivity in children with nonproficient handwriting. AB - PURPOSE: This study compared measures of hand sensitivity and handwriting quality in children aged 10 to 12 years identified by their teachers as having nonproficient or proficient handwriting. We hypothesized that children with nonproficient handwriting have decreased kinesthetic sensitivity of the hands and digits. METHODS: Sixteen subjects without documented motor or cognitive concerns were tested for kinesthetic sensitivity, discriminate tactile awareness, diadochokinesia, stereognosis, and graphesthesia. Eight children were considered to have nonproficient handwriting; 8 had proficient handwriting. Nonparametric Mann-Whitney U tests were used to identify differences between groups on sensory tests. RESULTS: The 2 groups showed a statistically significant difference in handwriting legibility (P = .018). No significant difference was found on tests of kinesthetic sensitivity or other measures of sensation. CONCLUSIONS: Children presenting with handwriting difficulty as the only complaint have similar sensitivity in hands and digits as those with proficient handwriting. Failure to detect differences may result from a small sample size. PMID- 21304347 TI - A rose by any other name. PMID- 21304349 TI - Finding common ground in case management: new titles and terminology along the health care continuum. PMID- 21304350 TI - Dealing with anxiety disorders in the workplace: importance of early intervention when anxiety leads to absence from work. AB - PURPOSE: A report from the Partnership on Workplace Mental Health, a program of the American Psychiatric Foundation, supports the widely held view that intervening early in a psychiatric disability absence will result in earlier return to work and reduce the likelihood of permanent disability. Studies unfortunately reveal that patients with psychiatric illness do not receive a level of care consistent with evidence-based best practice. This article highlights the importance of early interventions that utilize best practices for anxiety disorders that impair an employee's occupational functioning. PRIMARY PRACTICE SETTING: Behavioral Health Consulting Firm. FINDINGS/CONCLUSIONS: Studies on occupational disability conclude that collaborative communication between clinicians, disability case managers, and the employer is important to facilitate a successful and timely return to work for employees with temporary psychiatric disability. Avoidance of preexisting workplace conflicts can undermine return to work. Undertreatment and ineffective treatment are common causes of delayed recovery from acute anxiety conditions. In addition, lack of urgency among clinicians regarding the crisis nature of absence from work due to psychiatric illness can contribute to lengthy and unnecessary absence from work. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: A basic understanding of the acute aspects of anxiety disorders can assist disability case managers working in collaboration with treating clinicians and employees in a successful and timely return to work when an anxiety condition leads to absence from work. PMID- 21304352 TI - A collaborative approach for the care management of geropsychiatric services. AB - PURPOSE/OBJECTIVES: To share a successful collaborative approach between the medical and behavioral health departments of a managed care organization that improved both utilization rates and management for health plan members with dementia. PRIMARY PRACTICE SETTING: Acute care hospitals FINDINGS/CONCLUSIONS: There was a significant reduction in subsequent hospital admits, beddays, and emergency department visits for this population resulting in a substantial financial savings. Patient outcomes, as well as patient and caregiver satisfaction, was improved. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: Prior to the implementation of this pilot, there was a gap in services for health plan members experiencing dangerous behavioral issues associated with their dementia diagnosis. Case management of this population was difficult because of the limited options available in our market area. This innovative program afforded a nontraditional approach to inpatient care that maximized case management possibilities for this population. PMID- 21304353 TI - Occupational therapy consultation for case managers in community mental health: exploring strategies to improve job satisfaction and self-efficacy. AB - The purpose of this study was 2-fold: (1) to examine to what extent case managers' job satisfaction and self-efficacy were impacted by the addition of an occupational therapy consultation model and (2) to identify factors that both positively and negatively impacted the occupational therapy consultation services. PRIMARY PRACTICE SETTING: The study was conducted at a mental health community support program in a local homeless center. METHODOLOGY AND SAMPLE: In a 2-year study, a mixed-methods design was used to study changes over time in job satisfaction and perceived self-efficacy among 14 case managers who received ongoing occupational therapy consultation. Job satisfaction and self-efficacy data were obtained using standardized questionnaires. Qualitative data related to factors impacting the consultation program were obtained using open-ended written questions, focus groups, and individual interviews. RESULTS: Statistically significant differences in job satisfaction and perceptions of self-efficacy were found 18 months into the study, when case managers were more actively seeking occupational therapy consultation services and were reporting improved client outcomes from occupational therapy intervention. In addition, themes related to both positive and negative factors impacting the occupational therapy consultation program were identified and provided useful data for development of future consultation services. IMPLICATION FOR CASE MANAGEMENT PRACTICE: Results suggest that ongoing training and professional support for case managers who are paraprofessionals and/or new to mental health practice may improve job satisfaction and efficacy. Occupational therapy consultation may be helpful in developing services for health promotion, including self-care management, cognitive assessments, activity-based programming, and home safety evaluation and modification. In addition, new graduates and paraprofessional case managers working with clients who are high utilizers of services may benefit from smaller caseloads and support from clinical professionals. PMID- 21304354 TI - Global case management: Model for an international case management training program. PMID- 21304355 TI - Patient-centered case management. PMID- 21304356 TI - Today's case manager and the state of the licensing dilemma. PMID- 21304358 TI - New www.medicaresuppliersnetwork.com Medicare program for medical equipment will change everything. PMID- 21304359 TI - Workers' comp case management: being an advocate amid complexity. PMID- 21304360 TI - Transitional return to work: it works, but how? PMID- 21304361 TI - Does vibration influence the initiation of intervertebral disc herniation? An examination of herniation occurrence using a porcine cervical disc model. AB - STUDY DESIGN: In vitro biomechanics, randomized control trial. OBJECTIVE: The objectives of this study were 2-fold: first, to determine the effect of exposure to axial vibration on the initiation and progression of disc herniation; second, to determine the effect of vibration exposure and the presence of disc damage on the mechanical properties of individual lamella from the annulus. SUMMARY OF BACKGROUND DATA: Vibration exposure has been linked to a higher reporting of low back pain and disc herniation via epidemiological studies. However, these studies are unable to determine causal relationships. In vitro tissue experimentation assists in determining if certain exposures, for example vibration, actually lead to herniation. METHODS: A total of 20 porcine (aged, 6-8 months; similar skeletal development as an adolescent human) functional spine units (FSU) were subjected to repetitive flexion-extension (6000 cycles), which has been shown to produce intervertebral disc herniation. While being exposed to the repeated flexion/extension, 10 FSUs were statically compressed under 1400 N (control group) and the other 10 were cyclically compressed (1260-1540 N) at a frequency of 5 Hz (vibration group). Post collection, intervertebral discs were dissected and individual lamella of the annulus was tested under uniaxial tension to failure (tension applied perpendicular to the orientation of the collagen fibers) to isolate the mechanical properties of the intralamellar matrix. RESULTS: Of the 10 control FSUs, 4 had evidence of herniation initiation while 8 of the 10 vibrated FSUs showed herniation initiation (P ? 0.01). No significant differences in disc height loss or FSU stiffness were observed between the control and vibrated groups. Further, no signficant differences were observed between the 2 groups for any of the single lamella mechanical properties. CONCLUSION: This study confirmed that vibration is a causal mechanical risk factor that significantly increases the occurrence of herniation. PMID- 21304362 TI - Trends in the use of bone morphogenetic protein as a substitute to autologous iliac crest bone grafting for spinal fusion procedures in the United States. AB - STUDY DESIGN: Analysis of Nationwide Inpatient Sample (NIS) database for data related to spinal fusion procedures. OBJECTIVE: To identify trends in the use of bone morphogenetic protein (BMP) versus iliac crest bone grafts in various spinal fusion procedures performed in the United States, explore stratification by patient demographics, and analyze the impact on treatment cost. SUMMARY OF BACKGROUND DATA: BMP has been shown to achieve better clinical outcomes in anterior lumbar interbody fusions procedures, which led to its Food and Drug Administration approval for this indication in 2002. Since then, significant off label use has occurred, without a full description of the results. METHODS: We searched the NIS for data relating to BMP administration or iliac crest bone grafting in a variety of spinal fusion procedures performed from 1993 to 2006, based on International Classification of Diseases, Ninth Revision classification. The NIS is the largest all-payer inpatient care database, with demographic, outcome, and cost data from approximately eight million annual patient discharges throughout the United States. Demographics among patients treated with BMP versus iliac crest bone graft were compared to reduce the likelihood of bias in the analysis. RESULTS: BMP became applied more frequently in each type of spinal fusion procedure examined over our study period, with the exception of anterior lumbar interbody fusions. Patients receiving iliac crest bone grafts versus BMP exhibited very similar demographic characteristics, including age, socioeconomic status, and type of health care setting. Although BMP typically increased the cost of the procedure itself, it improved outcomes and shorter hospital stays often provided a net benefit. CONCLUSION: BMP is increasingly being used in spinal fusion procedures, including ones for which it is not officially approved, because of the surgical and postsurgical benefits it provides. Given the morbidity that this may entail, monitoring outcomes trends will help to inform guidelines for BMP use and ensure that its benefits continue to outweigh its costs. PMID- 21304363 TI - Completely intracorporeal retraction of the gallbladder for laparoendoscopic single site (LESS) surgery. AB - Laparoendoscopic single site surgery (LESS) cholecystectomy requires a creative solution to retract the gallbladder. Transabdominal suture retraction is a commonly used technique to achieve adequate exposure of the critical structures within Calot's triangle. To avoid the multiple punctures of the gallbladder and abdominal wall required by such suture retraction, we developed a novel internal retractor specifically for use during LESS cholecystectomy. This retractor consists of a laparoscopic bulldog clamp fitted with a small metal hook, and was successfully used in a recent case of LESS cholecystectomy. PMID- 21304364 TI - Reconstruction of the gastrointestinal tract by hemi-double stapling method for the esophagus and jejunum using EEA OrVil in laparoscopic total gastrectomy and proximal gastrectomy. AB - We report the method of anastomosis based on a hemi-double stapling technique (hereinafter, HDST) using a trans-oral anvil delivery system (EEA OrVil) for reconstructing the esophagus and lifted jejunum following laparoscopic total gastrectomy or proximal gastric resection. As a basic technique, end-to-side anastomosis was used for the cut-off stump of the esophagus and lifted jejunum. After the gastric lymph node dissection, the esophagus was cut off obliquely to the long axis using an automated stapler. EEA OrVil was orally, and a small hole was created at the tip of the obliquely cut-off stump with scissors to let the valve tip pass through. When it was confirmed that the automated stapler and center rod were made completely linear, the anvil and the main unit were connected with each other and firing was carried out. Then, HDST-based anastomosis was completed. The method may safe laparoscopic anastomosis between the esophagus and reconstructed intestine. PMID- 21304365 TI - Thoracoscopic resection of a combined esophageal leiomyoma and diverticulum: a case report. AB - We report the case of a 66-year-old male patient with a combined esophageal leiomyoma and diverticulum. On account of the low incidence, there is little literature available with regard to the management of those conditions. Our patient underwent a simultaneous thoracoscopic enucleation of the leiomyoma and resection of the diverticulum. Though endoscopic enucleations of myoma and resections of diverticula have been described earlier, to our knowledge, we are the first, who performed those procedures in a single operation, which seems to be feasible and safe. PMID- 21304366 TI - Delayed mechanical small bowel obstruction caused by retained, free, intraperitoneal staple after laparoscopic appendectomy. AB - New techniques and instrumentation within the field of laparoscopic surgery have resulted in an increase in both the number and types of procedures performed. Many advances, such as the linear cutting stapler and automatic clip applier, are now commonplace and used in almost every laparoscopic case. However, these new devices and procedures have also led to previously unseen complications. PMID- 21304367 TI - Controlling difficult pelvic bleeding with argon beam coagulator during laparoscopic ultra low anterior resection. AB - In recent years, the standard of care for lower rectal tumors has developed to include a total mesorectal excision, which provides optimal long-term results. There has been debate with regard to the best approach for lower rectal tumors, conventional open versus less invasive procedures. As the trend toward less invasive surgical procedures progresses, similar complications, which are seen in open cases, are being encountered, such as the notorious presacral fascia bleed. These are small vessels, which are difficult to locate and control. Surgical literature suggests different methods during laparoscopic procedures. These include: placing lap pads and holding pressure, placing saline bag, placing tacks, using bone wax, and electrocautry at different settings. We present a case of a 57-year-old male, positive for lymph node disease, who underwent laparoscopic ultra low anterior resection with total mesorectal excision and protective loop ileostomy. PMID- 21304368 TI - Robotic thoracoscopic mediastinal parathyroidectomy for persistent hyperparathyroidism: case report and review of the literature. AB - Recurrent and persistent primary hyperparathyroidism remains a significant surgical challenge. Abnormal, hypersecreting parathyroid glands are found in ectopic locations in up to 15% to 20% of patients. A small portion of these ectopic glands will be found in the mediastinum at a location that precludes removal through the traditional cervical incision. Minimally invasive approaches to these glands are desirable because of the significant morbidity, pain, and hospital stay associated with sternotomy or thoracotomy. Recently, robotic approaches have been described for mediastinal parathyroids. We report a case of young woman with persistent primary hyperparathyroidism who was cured after undergoing robotic thoracoscopic mediastinal parathyroidectomy using radiooperative and intraoperative parathyroid hormone guidance. PMID- 21304369 TI - A calcified foreign body in the bladder due to : an unusual complication after laparoscopic incisional hernia repair. AB - We report a rare complication caused by a displaced tack after laparoscopic incisional hernia repair. A 41-year-old woman treated 11 months earlier for a suprapubic incisional hernia (Pfannenstiel laparotomy) received a laparoscopic repair with a bilaminar mesh fixed with tacks. Seven months later, she presented miccional irritative symptoms and chronic lower abdominal pain. Leucocyturia and microhematuria were present, and computerized tomography showed 2 calcified nodules in the bladder wall. Cystoscopy confirmed 2 calcified foreign bodies in the bladder due the tack fixation. She underwent an intra-abdominal laparoscopic exploration, which showed the protrusion of a mesh in the urinary bladder. The tacks were removed and a partial laparoscopic cystectomy including mesh protrusion was performed. The patient was discharged from hospital 4 days later without postoperative complications. At follow-up 24 months after surgery, she remains well with no pain, urinary symptoms, or hernia recurrence. PMID- 21304370 TI - Laparoscopic resection of periadrenal paraganglioma in a patient with multiple endocrine neoplasia type 2A. AB - We report here a case of recurrent pheochromocytoma successfully managed by laparoscopic surgery in a patient with multiple endocrine neoplasia type 2A. A 25 year-old man presented with the contralateral adrenal mass after earlier right adrenalectomy. For the preoperative diagnosis of left adrenal pheochromocytoma, adrenal sparing surgery was considered. From the intraoperative laparoscopic view, we found that the tumor originated in periadrenal sympathetic ganglia, and laparoscopic excision of paraganglioma was successfully performed that preserved the integrity of normal adrenal gland. Extra-adrenal pheochromocytoma is rather rare in MEN 2A and it is important to identify precise intraoperative localization of pheochromocytoma with laparoscopic surgery. PMID- 21304371 TI - Two procedures at the same robotic session: robot-assisted laparoscopic radical prostatectomy and cholecystectomy. AB - A 66-year old male patient with right upper abdominal pain was diagnosed with cholelithiasis on abdominal ultrasound and elective laparoscopic cholecystectomy was recommended. His serum prostate-specific antigen was 21.3 ng/mL and underwent a 12-core transrectal ultrasound-guided prostate biopsy, which showed prostatic adenocarcinoma (Gleason score 4+4). Owing to the presence of concomitant cholelithiasis, we performed robot-assisted laparoscopic radical prostatectomy and robot-assisted laparoscopic cholecystectomy at the same session. Console time was 257 minutes. Intraoperative blood loss was 50 mL. Patient was fit to be discharged on postoperative day 2. Surgical specimen pathology showed a bilateral prostatic adenocarcinoma of Gleason score 4+3, with unilateral extracapsular extension and negative surgical margins. Currently, he is full continent with a serum prostate-specific antigen of 0.04 ng/mL on his first-month follow-up evaluation. Combined robotic approach seems to have many benefits including shorter hospital stay, decreased cost, decreased anesthesia risk, and better cosmetic results. PMID- 21304372 TI - Laparoscopic lateral pancreaticojejunostomy for chronic pancreatitis: a case report and review of the literature. AB - BACKGROUND: Lateral pancreaticojejunostomy (LPJ) is a suitable procedure to treat unremitting abdominal pain of chronic pancreatitis (CP) in the presence of a markedly dilated pancreatic duct containing stones and when an inflammatory mass in the head of the gland is absent; this procedure is rarely performed laparoscopically. CASE REPORT: A 41-year-old woman with alcohol-related calcific CP and pancreatic endocrine and exocrine insufficiency suffered with opiate dependent abdominal pain that was associated with a dilated pancreatic duct of 8.5 mm containing several calculi, but no mass in the head of the pancreas. A laparoscopic LPJ was performed successfully with no intraoperative or postoperative complications. The patient was discharged on day 5, and reported complete relief from abdominal pain at follow up 7 months later. CONCLUSIONS: In selected patients, laparoscopic LPJ is feasible, safe, and effective in treating abdominal pain of CP. PMID- 21304373 TI - Laparoscopic sleeve gastrectomy as revisional surgery in a vertical gastroplasty with gastrogastric fistula: a simplified technique. AB - Gastrogastric fistula is one of the complications that can occur after vertical gastroplasty surgery for weight loss. We describe a novel sleeve gastrectomy technique to treat a proximal gastrogastric fistula after vertical gastroplasty. PMID- 21304374 TI - Subcutaneous metastases after laparoscopic-assisted partial hepatectomy for hepatocellular carcinoma. AB - We reported an unusual case with subcutaneous seeding of hepatocellular carcinoma 12 months after laparoscopic-assisted partial hepatectomy. A 69-year-old woman with hepatitis-C-related liver cirrhosis was found to have hepatocellular carcinoma on routine sonographic examination. The tumor located superficially in the left lateral segment. She received laparoscopic-assisted partial hepatectomy for the tumor in February 2002. She was uneventful after the surgery and serum alpha-fetoprotein level dropped from 1217 to 275 ng/mL in 3 months. Serum alpha fetoprotein level was found to rise 9 months after surgery and a subcutaneous tumor appeared over the surgical wound 12 months after surgery. Resection of lesion showed hepatocellular carcinoma. To our knowledge, seeding of hepatocellular carcinoma on surgical wound has rarely, if ever, been reported after laparoscopic-assisted surgery. The patient died of disseminated recurrence 20 months after the surgery. This case reminded us the risk of tumor seeding after laparoscopic-assisted partial hepatectomy. PMID- 21304375 TI - Endoscopic management of delayed perforation of the rectum caused by a peritoneal dialysis catheter. AB - Bowel perforation caused by a peritoneal dialysis (PD) catheter is an uncommon complication. It occurs mostly at the time of insertion of a catheter. Delayed perforation of the bowel by a PD catheter can also occur, but is even more uncommon. The ideal management of perforation of the colon by a PD catheter remains to be established because of its very low incidence. Definite surgery is the usual treatment. Here, we report on a 50-year-old male patient who presented with severe watery diarrhea owing to delayed rectal perforation caused by a PD catheter. A computed tomography scan revealed that the catheter tip was inside the lumen of the rectum. This was further confirmed by colonoscopy after bowel preparation. The PD catheter was removed via the original abdominal incision and the rectal perforation was closed using 3 endoscopic clips. The patient made an uneventful recovery. PMID- 21304376 TI - Laparoscopic resection of abdominal paragangliomas. AB - Paragangliomas are rare catecholamine-secreting tumors arising from chromaffin tissue of the autonomic nervous system. Although they can arise anywhere along the paravertebral axis, the majority is intra-abdominal in location. Frequently, these tumors are closely associated with major vascular structures, necessitating open techniques for resection. As laparoscopic techniques have advanced, minimally invasive approaches to these complex tumors have been attempted. This study presents 3 patients with abdominal paragangliomas, highlighting the use of high-quality preoperative imaging and intraoperative surgeon-performed ultrasound in allowing safe minimally invasive resection of these tumors. PMID- 21304377 TI - Laparoscopy-assisted right hepatectomy in a case of Fasciola hepatica. AB - Laparoscopic hepatectomy provides the usual advantages of a minimally invasive surgery. This study presents a case of Fasciola hepatica infection that was successfully treated with laparoscopic hepatectomy. The patient was referred because of persistent fever and right hypochondralgia with a huge mass occupying the right lobe of the liver, which was detected by imaging analysis. Serologic tests indicated an F. hepatica infection. The patient underwent a laparoscopic resection because the anthelmintic agent, triclabendazole was not effective. During the surgical technique, 5 trocars were inserted. After liver mobilization, the Glissonian pedicles and right hepatic veins were safely taped. A Penrose drain was placed behind the liver for a liver-hanging maneuver. A liver parenchymal transection was performed through an 8 cm handport site using a dissecting sealer (TissueLink Medical) after precoagulating its superficial layer by microtaze. Glissonian pedicles and the right hepatic vein were divided using an endolinear stapler (endcutter 45, Ethicon). Finally, the resected specimen was extracted from the handport. The surgical time was 450 minutes and the surgical blood loss was 370 mL. The patient was discharged 10 days after the surgery with an uneventful postoperative course. The laparoscopy-assisted hepatectomy in this case was beneficial for the patient's quality of life as a minimally invasive operation with a high degree of safety. PMID- 21304378 TI - Laparoscopic cholecystectomy on the bikini line for invisible scar. AB - BACKGROUND: A traditional laparoscopic cholecystectomy uses 4 trocar incisions on the upper abdomen, which may be the source of undesirable cosmetic outcomes. We describe here a modification of the traditional laparoscopic cholecystectomy by which scars remain underwear. Supplemental Digital Content 1, http://links.lww.com/SLE/A27. METHODS: A 32-year-old woman and 43-year-old man with symptomatic cholelithiasis were chosen for laparoscopic cholecystectomy on the bikini line. Four trocar were used, all of them were positioned at the lower abdomen in the same parallel on the bikini line. All procedure was performed with standart laparoscopic instrumentation. Gallbladder was removed through the median suprapubical trocar site. RESULTS: Both procedures were technically successful with no skin incisions outside the bikini line. The total operation times were: 65 and 45 minutes, and the hospital stay were 2 days. There were no complications during or after surgery. We left no scar on the upper abdomen. CONCLUSIONS: Laparoscopic cholecystectomy on the bikini line is technically feasible, safe, and effective. There is no need for learning curve and extralaparoscopic instrumentation. The major advantage of this method is improved cosmetic outcome with no visible abdominal scars. This new technique carries the potential to be an option for the traditional laparoscopic cholecystectomy. PMID- 21304379 TI - Hiatal hernia repair with the use of biologic meshes: a literature review. AB - During the past few years, biologic meshes, primarily evolved for routine and complex cases of abdominal wall reconstruction, have been evaluated in clinical cases and experimental models. Although there is published experience on the use of small intestine submucosa and human cadaveric dermis in hiatal hernia repair with encouraging results, porcine dermal collagen (PDC) matrix has not been subject of study to date in this patient population. A systematic review of the literature was conducted, aiming at evaluating the biomechanical characteristics of cross-linked PDC in comparison to synthetic and biologic meshes. Evidence shows that cross-linked PDC is superior to synthetic meshes in terms of incorporation, adhesion formation, and mesh fibrosis; their biodynamic and biotechnical characteristics do not seem to be superior to other bioprosthetic materials according to current data. The clinical and experimental results of cross-linked PDC implants justify their pilot clinical evaluation in hiatal hernia patients. PMID- 21304380 TI - Laparoscopic approach to retrorectal tumors: review of the literature and report of 4 cases. AB - BACKGROUND: Retrorectal or presacral tumors are extremely rare and their histologic origin varies greatly. Surgical excision is indicated to prevent complications or to rule out malignancy. A laparoscopic approach has been infrequently reported to date. The aim of this article is to report our experience in 4 cases, and to review the current world experience on laparoscopic approach to retrorectal tumors. METHODS: Between 1998 and 2009, we operated 4 cases in which a presacral tumor was diagnosed. A pure laparoscopic procedure was performed in 3 cases and a combined laparoscopic/transacral approach in a fourth. In addition, a systematic literature review and relevant reports on laparoscopic approach of these tumors were analyzed. RESULTS: All patients underwent laparoscopic dissection of the tumor with extraction through a Phannestiel incision except in 1 case that was performed transsacrally. Simultaneously, the literature review showed 11 articles with a total number of 18 patients approached by laparoscopy. CONCLUSIONS: The laparoscopic approach of retrorectal tumors is feasible. The advantages are an enhanced access and visualization of the pelvic structures and a more controlled preservation of nerve and vascular integrity. It seems to be a safe procedure and can be combined with a posterior approach if needed. PMID- 21304381 TI - Equivalency of lymph node harvest in laparoscopic versus open colorectal cancer procedures: an early surgeon's perspective. AB - PURPOSE: To compare the number of lymph nodes harvested in laparoscopic versus open colorectal cancer surgery early in a surgeon's career. METHODS: We reviewed the data of 80 patients operated upon with a primary diagnosis of colorectal cancer between September 2006 and June 2008. All data were from a single fellowship trained colorectal surgeon. The effects of laparoscopic versus open surgery, and neoadjuvant radiation were examined to assess lymph node harvest. RESULTS: There was no statistically significant difference between the lymph nodes harvested during laparoscopic versus open surgery (17.4 vs 18.5; P=0.5920). The amount of lymph nodes harvested decreased with increasing American Society of Anesthesiology grade (22.4, 17.1, 19.2, 7.0 for American Society of Anesthesiology grade I, II, III, IV, respectively; P=0.0412) and with neoadjuvant radiotherapy (18.7 vs 13.2; P=0.0151). CONCLUSIONS: Laparoscopic colorectal cancer surgery results in the same number of lymph nodes being harvested as in open surgery. PMID- 21304382 TI - Laparoscopic antireflux surgery after failed endoscopic treatments for gastroesophageal reflux disease. AB - OBJECTIVE: The aim of this study is to assess the efficacy and safety of laparoscopic antireflux surgery (LARS) after failed endoscopic treatments for gastroesophageal reflux disease. MATERIALS AND METHODS: The perioperative results of 9 patients, who had received endoscopic antireflux intervention before being subjected to LARS between March 2004 and November 2009, were analyzed retrospectively on a prospective database. RESULTS: Endoscopically, while 6 patients had received radiofrequency ablation (Stretta; Curon Medical, Fremont, CA), 2 patients had been subjected to biopolymer injection (Enteryx; Boston Scientific, Natick, MA) and 1 patient to endoluminal plication (NDO plicator; NDO Surgical, Mansfield, MA). The mean age of the patients was 40 years while the mean values for their body mass index, symptom duration, and follow-up length were 25.6, 38 months, and 35 months, respectively. Mean operation length and mean discharge time were 56 minutes and 1 day, respectively. None of the patients who were subjected to NDO plicator and Stretta showed difficulty in dissection or perioperative complication. In contrast, the patients who had been subjected to Enteryx presented serious problems during LARS, and because of severe difficulty in dissection total fundoplication could not be performed. In both of those cases, LARS did not succeed. CONCLUSIONS: In patients who received Stretta and NDO plicator procedures and failed to respond, LARS does not present any difficulty or problem. However, performing LARS among patients who received Enteryx shows problems and fails to produce a successful result. PMID- 21304383 TI - Influence of CT-measured appendiceal diameter on operation time of laparoscopic appendectomy. AB - Laparoscopic appendectomy (LA) is considered as an uncomplicated procedure, so residents are frequently chosen as LA operators. The aim of this study was to identify preoperative factors influencing operation time in LA. We proposed patient selection criteria to help choose an adequately skilled resident for performing LA. The medical records of 117 patients who underwent LA between April 2008 and August 2009 were retrospectively reviewed. Univariate and multivariate analyses were performed to identify factors influencing operation time. Accordingly multivariate analysis indicated that operation time was significantly influenced by C-reactive protein and computed tomography-measured appendiceal diameter. Appendiceal diameter was a better predicting factor for differentiating the longer and shorter operation time groups. The cut-off value for appendiceal diameter was 12 mm. We concluded that preoperative computed tomography findings of appendiceal diameter of more than 12 mm in patients suggested that LA would be technically challenging for the less experienced resident. PMID- 21304384 TI - Laparoscopic appendectomy is a safe and beneficial procedure in pregnant women. AB - BACKGROUND: Appendectomy is the most common nongynecologic surgery performed during pregnancy. Pregnancy is no longer considered an absolute contraindication for laparoscopic procedures. Laparoscopic appendectomy (LA) is a safe, effective, and beneficial procedure for the treatment of acute appendicitis. However, limited data are available regarding the safety and feasibility of LA during pregnancy. METHODS: Between May 2005 and May 2009, 20 patients with clinically suspected appendicitis in pregnancy underwent LA at Chungbuk National University Hospital. Clinical data collected retrospectively included demographic information. We compared maternal age, gestational age, operation time, anesthetic time, surgical complications, length of hospitalization, and final outcome of pregnancy. RESULTS: All the 20 patients who underwent LA did not need a conversion. Mean maternal age was 28.1 years (range, approximately 20 to 35 y), gestational age was 15.4 weeks (range, approximately 6 to 30 wk), mean operation time was 45.5 minutes (range, approximately 25 to 90 min), mean length of hospital stay was 4.7 days (range, approximately 2 to 11 d). Fifteen of 20 pregnant women delivered healthy term infants and 5 women have kept a healthy pregnancy. CONCLUSIONS: Our data support the accumulating evidence that LA is a safe and feasible procedure for the treatment of acute appendicitis in all trimesters of pregnancy. Close maternal and fetal monitoring is essential during and after the operation. PMID- 21304385 TI - Indication of endoscopic retrograde cholangiography by noninvasive predictive factors of common bile duct stones before laparoscopic cholecystectomy: a prospective clinical study. AB - PURPOSE: To evaluate the reliability of a screening method in patients with common bile duct (CBD) stones before laparoscopic cholecystectomy (LC) based on predictive factors, and to determine the cases for which preoperative therapeutic endoscopic retrograde cholangiography (ERC) is indicated. MATERIALS AND METHODS: Alkaline phosphatase, total bilirubin, amylase, and dilation of CBD results were defined as predictive factors for CBD stones. In cases in which all these 4 factors were negative, preoperative ERC was omitted, and in cases in which 1 of the 4 factors was positive, ERC was performed before LC. RESULTS: A total of 323 patients (83.7%) in whom all 4 factors were negative, ERC was omitted. In all the 63 patients (16.3%) in whom 1 of the 4 factors was positive, ERC was performed. In 52 (82.5%) of them, CBD stones were present and in 43 of them, LC was performed after endoscopic choledocholithotomy. CONCLUSIONS: For cases in which any 1 of the 4 factors was positive before LC, it was strongly recommended to perform preoperative ERC. PMID- 21304386 TI - Laparoscopy-assisted distal gastrectomy for gastric cancer patients with comorbid diseases: is it contraindicated for patients with systemic comorbidity? AB - BACKGROUND: This study was carried out to evaluate the safety and feasibility of laparoscopy-assisted distal gastrectomy (LADG) for gastric cancer patients with systemic comorbidity. MATERIALS AND METHODS: Two hundred and seventy-six patients who had undergone LADG by a single surgeon were given a physical status classification as defined by the American Society of Anesthesiologists (ASA class) and then divided into 2 criteria groups: criteria I group (ASA 1 vs ASA 2,3,4) and criteria II group (ASA 1,2 vs ASA 3,4). The clinicopathologic data of each patient were reviewed retrospectively and grouped by criteria. RESULTS: The percentage of patients with a comorbid disease was 8.1% (11 cases) in ASA class 1, 71.7% (86 cases) in class 2, 95.0% (19 cases) in class 3, and 100% (1 case) in class 4. No statistical difference was found between criteria I and II in terms of operative and postoperative results, operative time, estimated blood loss, transfusion rate, tumor size, total and positive number of dissected lymph nodes, proximal resection margin from lesion, the rate of open conversion, the duration of hospital stay, the time required before resuming a liquid diet, and the rate of complications, except the distal resection margin in criteria II (all P >0.05). There were no cases of mortality in any criteria group. CONCLUSIONS: LADG would be a safe and feasible operation for patients with gastric cancer with systemic comorbidity, without reducing radicality, losing the advantages of minimally invasive surgery, or increasing operative risk. PMID- 21304387 TI - Surgical outcomes from laparoscopic distal gastrectomy and Roux-en-Y reconstruction: evolution in a totally intracorporeal technique. AB - INTRODUCTION: Laparoscopic gastrectomy is gaining popularity. Increasingly, Roux en-Y reconstruction after distal gastrectomy is preferred because of reduced reflux and associated symptoms. Therefore, efficient and reliable techniques for intracorporeal Roux-en-Y reconstruction are in demand. AIMS: To determine the surgical outcomes from laparoscopic distal gastrectomy and Roux-en-Y reconstruction in the treatment of gastric cancer. PATIENTS AND METHODS: Laparoscopic gastrectomy is indicated for gastric cancer up to stage T1N1. Our technique for laparoscopic Roux-en-Y reconstruction incorporates intracorporeal stapled gastrojejunostomy with extracorporeal hand-sewn jejunojejunostomy, or more recently, totally intracorporeal reconstruction. RESULTS: From 2003 to 2009, 82 patients underwent laparoscopic distal gastrectomy with Roux-en-Y reconstruction. The mean age of the patients was 64.6 years (range, 39 to 83 y) and the male:female ratio was 2.4:1. Most patients (85%) had stage I disease. The mean operation time was 354 minutes (SD 82.7). The conversion rate was 0%. The mean lymph node yield was 27.2 nodes (SD 12.4). Eleven patients had totally intracorporeal reconstruction. Overall, anastomotic leakage of the gastrojejunostomy occurred in 2 patients (2.4%) both requiring reoperation. There were 2 cases (2.4%) of duodenal stump leakage, which were treated conservatively. Postoperative stasis was encountered in 2 patients (2.4%). The mean follow-up was 21 months (range, 5 to 50 mo). None of the patients developed reflux symptoms or endoscopic evidence of reflux during follow-up. Recurrence occurred in 1 patient who was the only patient with metastasis to the third tier of lymph nodes. CONCLUSIONS: Surgical outcomes from laparoscopic distal gastrectomy and Roux-en-Y reconstruction were acceptable in the context of early gastric cancer. Totally intracorporeal reconstruction was technically feasible, safe, and associated with no obvious drawbacks. PMID- 21304388 TI - Laparoendoscopic single-site surgery: adult hernia mesh repair with homemade single port. AB - BACKGROUND: Laparoendoscopic single-site surgery (LESS) is a novel technique developed to reduce the port-related morbidities and improve the cosmetic outcomes of laparoscopic surgery. To date, no series of LESS inguinal hernia repair has been published or documented. This study aimed to determine the safety and feasibility of LESS technique for inguinal hernia repairs. METHODS: Between December 2008 and March 2009, LESS procedures for inguinal hernia repair through a transumbilical incision were performed for 16 patients with symptomatic inguinal hernias. The initial 9 cases were performed by a transabdominal preperitoneal method and the remaining 7 were completed with a totally extraperitoneal approach. All procedures were accessed with our homemade single port for simultaneous passage of laparoscope and instruments. RESULTS: All procedures were completed successfully without conversion to standard laparoscopic or open surgery. These patients ranged in age from 21 to 80 years (median, 46.5 y) with a male to female ratio of 15:1. A total of 24 inguinal hernias, including 3 complicated types, were repaired. The median operative time was 83.5 minutes (range, 52 to 150 min). Two of the 16 patients suffered postoperative complications (12.5%). Most patients were discharged home on the second postoperative day. No port-related complications occurred. The cosmetic results were excellent. CONCLUSIONS: In our experience, LESS procedures for inguinal hernia repair shows this technique to be both safe and feasible, even for complicated cases. More studies are needed to compare LESS inguinal hernia repair with standard laparoscopic techniques. PMID- 21304389 TI - Laparoscopic-assisted versus open repair of Morgagni hernia in infants and children. AB - BACKGROUND: Morgagni hernia is rare and represents less than 5% of all congenital diaphragmatic hernias. The defect is repaired either by conventional open surgery or laparoscopically. The aim of this study was to compare the conventional open technique with the laparoscopic-assisted repair of Morgagni hernia. PATIENTS AND METHODS: The medical records of all infants and children with the diagnosis of Morgagni hernia were retrospectively reviewed and divided into 2 groups according to the method of repair, the laparoscopic-assisted group and the open surgery group. The 2 groups were compared according to the operative time, hospital stay, time to commencement of full feeds, requirement for postoperative analgesia, complications, and outcome. RESULTS: Twenty-three (16 male and 7 female) patients had open surgery repair. Their age ranged from 1 to 60 months (median 9 mo). Nine patients had right-sided, 5 had left-sided hernia, and 9 (39%) had bilateral hernias. Associated anomalies were seen in 18 patients (78.3%). Eight patients (34.8%) had congenital heart disease, 5 (21.7%) had malrotation of bowel, and 6 (26%) had Down syndrome. All were operated transabdominally (14 upper midline and 8 upper transverse) except for 1 patient who had a right thoracotomy. In all patients, there was a hernia sac that was excised and the defect was repaired using nonabsorbable sutures. On follow-up, 2 patients (8.7%) developed recurrence. Sixteen patients (10 boys and 6 girls) had laparoscopic-assisted repair of Morgagni hernia. Their age ranged from 8 to 42 months (median 18.5 mo). Only 1 patient had Down syndrome and congenital heart disease. Seven patients had right-sided hernia, 7 had left-sided hernia, and 2 had bilateral hernia. On follow-up, 1 patient had a small residual sac 6 months postoperatively, without clinical significance. When the 2 groups were compared, the laparoscopic-assisted group was better in terms of shorter operative time, shorter time to commencement of full feeds, less postoperative analgesia, shorter hospital stay, and better cosmetic results. CONCLUSIONS: Laparoscopic-assisted repair of Morgagni hernia is an excellent and simple alternative to open surgery. It is, however, superior over conventional open surgery and the benefits are shorter operative time, early commencement of full feeds, less postoperative analgesia, rapid recovery, shorter hospital stay, and better cosmetic results. Laparoscopic-assisted repair of Morgagni hernia should be considered as the procedure of choice for the treatment of Morgagni hernia in infants and children. Leaving the hernia sac plicated in place has no adverse effects. PMID- 21304390 TI - Percutaneous mechanical thrombectomy for acute massive lower extremity deep venous thrombosis. AB - PURPOSE: To evaluate the clinical safety and effectiveness of percutaneous mechanical thrombectomy in patients with acute massive lower extremity deep venous thrombosis. MATERIALS AND METHODS: Twenty-five consecutive patients with acute massive lower extremity deep venous thrombosis were included in this retrospective study. An inferior vena cava filter was placed prophylactically to protect against pulmonary embolism in each patient. Percutaneous mechanical thrombectomy was performed using a 7F Amplatz thrombectomy device in an angiography suite through ipsilateral popliteal vein access. Anticoagulant therapy lasted for at least 6 months. Follow-up data included 1 year's color duplex sonography and clinical interviews. RESULTS: Successful placement of an inferior vena cava filter was achieved in all 25 (100%) patients. Twenty-two patients (88%) were clinically asymptomatic within 24 hours, whereas the remaining 3 patients (12%) showed moderate improvement within 48 hours. Venogram at discharge showed grade III lysis in 23 patients (92%) and grade II lysis in 2 patients (8%). No serious complications were reported during hospitalization in this study. At 1-year follow-up, no recurrent deep venous thrombosis was reported; 1 patient developed a mild postthrombotic syndrome. CONCLUSION: Percutaneous mechanical thrombectomy is a safe and effective treatment for acute massive lower extremity deep venous thrombosis and shows promising clinical mid term results. PMID- 21304391 TI - Laparoscopic deroofing of nonparasitic liver cysts with or without greater omentum flap. AB - BACKGROUND: Laparoscopic deroofing is the standard therapy for simple nonparasitic liver cysts. The operation is performed with or without a greater omentum flap sutured into the former cyst cavity. The aim of this study was to determine whether a greater omentum flap has influence on the recurrence rate of nonparasitic liver cysts during the long-term follow-up. METHODS: From September 1999 to November 2009, 23 patients underwent laparoscopic deroofing for single or multiple nonparasitic symptomatic liver cysts. A greater omentum flap to fill the former cyst cavity was used in 8 patients, whereas in 15 patients operation was carried out without such an omentum flap. The patients were identified retrospectively and subject to a follow-up examination. The 2 groups of patients were compared according to the recurrence of the liver cysts. RESULTS: The median follow-up time was 59+/-40 months. There was an overall recurrence rate of 4.3% (1 of 23), with 1 cyst recurrence in the greater omentum flap group (1 of 8). The Fisher exact test showed no difference in the recurrence rate between the 2 groups (P=0.35). CONCLUSION: The overall recurrence rate is low. A greater omentum flap to prevent a local cyst recurrence after laparoscopic deroofing is dispensable and is a potential source of additional complications. PMID- 21304392 TI - "It is a matter of compliance". PMID- 21304393 TI - Potential and actual liver donors: is the difference predictable? PMID- 21304394 TI - Posttransplant Kaposi sarcoma and risk for deep venous thrombosis: a case-control study. PMID- 21304395 TI - Are HIV-infected donors suitable for renal transplantation? PMID- 21304397 TI - IGFBP2 as an immunohistochemical marker for prostatic adenocarcinoma. AB - AIM: The aim of the study was to evaluate the immunohistochemical expression of insulin-like growth factor binding protein 2 (IGFBP2) in normal epithelium, high grade prostatic intraepithelial neoplasia (HG-PIN), and prostatic adenocarcinoma (PAc), in patients hormonally untreated and in those having undergone complete androgen ablation. MATERIALS AND METHODS: IGFBP2 expression was evaluated in PAc, HG-PIN, and normal-appearing epithelium in 40 radical prostatectomies from hormonally untreated patients and 10 radical prostatectomies from patients under complete androgen ablation before surgery. The study also included the initial biopsies of such patients, and an additional 10 simple prostatectomies from patients with bladder outlet obstruction. Statistics included receiver-operator characteristic curves, the Wilcoxon test, and the Spearman test. Results were compared with alpha-methylacyl-CoA racemase. RESULTS: The principal findings were: (1) IGFBP2 was not expressed in normal ducts and acini of the transition and peripheral zones; (2) IGFBP2 was expressed in the cytoplasm of untreated PAc and, to a lesser extent, in HG-PIN; (3) it was also expressed in PAc and HG-PIN after complete androgen ablation, but to a lesser extent than in the untreated neoplasms; (4) alpha-methylacyl-CoA racemase was expressed both in PAc and HG PIN, the level being similar in both lesions and lower in the specimens from the patients having undergone androgen ablation. CONCLUSIONS: Results obtained show that IGFBP2 is expressed in invasive PAc, whereas its expression in HG-PIN is low. These findings can be helpful in the correct diagnosis of PAc both in biopsies and in surgical specimens, mainly in untreated patients. PMID- 21304398 TI - Establishment and large-scale expansion of minimally cultured "young" tumor infiltrating lymphocytes for adoptive transfer therapy. AB - Treatment of metastatic melanoma patients with adoptively transferred tumor infiltrating lymphocytes (TIL) has developed into an effective therapy. Various studies reported objective responses of 50% and more. The use of unselected, minimally cultured, bulk TIL (Young-TIL) has simplified the TIL production process and may therefore, allow the accessibility of this approach to cancer centers worldwide. This article describes the precise process leading to the large-scale production of Young-TIL for therapy. We have enrolled 55 melanoma patients and optimized their Young-TIL generation process. Young-TIL cultures were successfully established for 51 of 55 (93%) patients in 16.7 +/- 5.5 days. In a large-scale expansion procedure Young-TIL of 32 patients were further expanded to treatment levels, resulting in a final number of 4.5 x 1010 +/- 2.0 x 1010 TIL. Fifteen of 31 (48%) patients, who were evaluated, achieved a clinical response, including 4 complete and 11 partial responses. We confirmed the significant correlation between short culture duration, high number of infused cells, and tumor regression. A high percentage of CD8 T cells in the infusion product was beneficial to achieve an objective response. All responding patients were treated with Young-TIL cultures established in < 20 days. In summary, we describe here an efficient and reliable method to generate Young-TIL for adoptive transfer therapy, which may easily be adopted by other cancer centers and can lead to objective responses in 50% of refractory melanoma patients. In the future this approach may be used also in other types of malignancies. PMID- 21304399 TI - Adoptive immunotherapy for advanced non-small cell lung cancer using zoledronate expanded gammadeltaTcells: a phase I clinical study. AB - Human gammadelta T cells can recognize and kill non-small cell lung cancer (NSCLC) cells using the Vgamma9Vdelta2 T-cell receptor and/or NKG2D. We have established clinical grade large-scale ex vivo expansion of gammadelta T cells from peripheral blood mononuclear cells by culturing with zoledronate and interleukin-2 (IL-2). A phase I study was conducted to evaluate safety and potential antitumor effects of re-infusing ex vivo expanded gammadelta T cells in patients with recurrent or advanced NSCLC. Patient's peripheral blood mononuclear cells were stimulated with zoledronate (5 MUM) and IL-2 (1000 IU/mL) for 14 days. Harvested cells, mostly gammadelta T cells, were given intravenously every 2 weeks without additional IL-2, a total of 6 times. The cumulative number of transferred gammadelta T cells ranged from 2.6 to 45.1 x 109 (median, 15.7*109). Fifteen patients underwent adoptive immunotherapy with these gammadelta T cells. There were no severe adverse events related to the therapy. Immunomonitoring data showed that with increasing numbers of infusions, the number of peripheral gammadelta T cells gradually increased. All patients remained alive during the study period with a median survival of 589 days and median progression-free survival of 126 days. According to the Response Evaluation Criteria In Solid Tumors, there were no objective responses. Six patients had stable disease, whereas the remaining 6 evaluable patients experienced progressive disease 4 weeks after the sixth transfer. We conclude that adoptive transfer of zoledronate expanded gammadelta T cells is safe and feasible in patients with NSCLC, refractory to other treatments. PMID- 21304400 TI - Combined immunochemotherapy in selected patients with metastatic renal cell carcinoma: HLA class II genotype can help to predict response to therapy. AB - A number of new agents have been approved for systemic therapy of metastatic renal cell carcinoma (mRCC) recently. Thereby, prognostic factors may aid in predicting the effectiveness of various treatment modalities in individual cases. Aim of this study was to determine the value of human leukocyte antigen (HLA) class II characteristics in predicting response of mRCC to combined immunochemotherapy (ICT). A retrospective study of 29 patients with mRCC treated with ICT was performed: 17 patients (group A) with long-term remission and 12 (group B) with progressive disease after ICT. DNA was used for high resolution typing of HLA-DRB1, -DRB3, -DRB4, -DRB5, -DQA1, and -DQB1. Statistical evaluation started with Classification and Regression Trees analysis. The assignment of single alleles to the groups was then aggregated to create a classification on a patients' basis. Finally, the accuracy of this test algorithm was evaluated. HLA DRB1 (DRB1*0301*0401*0402*0407*1101*1501=progression) was the strongest discriminator between the 2 groups. The test algorithm defined all patients with at least one of these DRB1 alleles to be progressive after ICT. Thus, 12 of 12 patients of group B could have been identified as progressive (sensitivity=100%). However, only 10 of 17 patients of group A would have been identified as responding (specificity=58%). Thus, the test had a positive and negative predictive value of 63% and 100%, respectively. Approximately 5% to 10% of all patients with mRCC are able to benefit from ICT with long-term remission. HLA class II characteristics may aid in identifying this small subgroup of patients with mRCC. PMID- 21304401 TI - Activating signals dominate inhibitory signals in CD137L/IL-15 activated natural killer cells. AB - Natural killer (NK) cells can mediate potent antitumor effects, but factors regulating the efficiency of tumor lysis remain unclear. Studies in allogeneic stem cell transplantation highlight an important role for killer cell immunoglobulin-like receptor (KIR) mismatch in overcoming human leukocyte antigen mediated inhibitory signals. However, other activating and inhibitory signals also modulate tumor lysis by NK cells. We used rhIL15 and artificial antigen presenting cells expressing CD137L and IL15Ralpha to activate and expand peripheral blood NK cells (CD137L/IL15 NK) up to 1000-fold in 3 weeks. Compared with resting NK cells, CD137L/IL15 NK cells show modest increases in KIR expression and substantial increases in NKG2D, tumor necrosis factor-related apoptosis-inducing ligand, and natural cytotoxicity receptors (NCRs: NKp30, NKp44, NKp46). Compared with resting NK cells, CD137L/IL15 NK cells mediate enhanced cytotoxicity against allogeneic and autologous tumors and KIR signaling did not substantially inhibit cytotoxicity. Rather, tumor lysis by CD137L/IL15 activated NK cells was predominantly driven by NCR signaling as blockade of NCRs dramatically diminished the lysis of a wide array of tumor targets. Furthermore, tumor lysis by CD137L/IL15 NK cells was tightly linked to NCR expression levels that peaked on day 8 to 10 after NK activation, and cytotoxicity diminished on subsequent days as NCR expression declined. We conclude that KIR mismatch is not a prerequisite for tumor killing by CD137L/IL15 NK cells and that NCR expression provides a biomarker for predicting potency of CD137L/IL15 NK cells in studies of NK cell-based immunotherapy. PMID- 21304402 TI - Identification of T-cell epitopes by a novel mRNA PCR-based epitope chase technique. AB - The identification of specific viral and tumor antigen T-cell epitopes remains a challenge. Indeed, epitope mapping methods are generally costly and time consuming. Thus, few techniques allow for efficient CD4+ T-lymphocyte epitope identification. Here, we introduce a novel polymerase chain reaction-based mRNA epitope identification method, called mPEC, to rapidly and precisely identify relevant T-cell epitopes recognized by CD8+ or CD4+ T lymphocytes. This method is based on the use of mRNA fragments synthesized from polymerase chain reaction amplified cDNA with a choice of 3'end deletions. mRNA fragments are electroporated into autologous antigen-presenting cells to deduce an epitope's localization in a given protein antigen. Considering mRNA's sensitivity to degradation, we also inserted a defined epitope at the mRNA's 3'end to control for electroporated mRNA's integrity and its capacity to be translated. Using this method, we rapidly and successfully identified the specific epitope of 2 CD8+ and 1 CD4+ T-lymphocyte clones derived from influenza model antigens. Hence, mPEC could be used to identify new, in vivo-relevant T-cell epitopes for cancer immunotherapy and vaccination in general. PMID- 21304403 TI - A functional recombinant human 4-1BB ligand for immune costimulatory therapy of cancer. AB - Costimulatory factors hold great promise for development into novel anticancer biotherapeutics. An agonist to 4-1BB is ranked number 8 by National Cancer Institute on the list of 20 agents with high potential for use in treating cancer. We earlier reported on a recombinant murine 4-1BB ligand fusion protein that binds 4-1BB receptor on murine T cells and stimulates their proliferation in tumor-bearing mice. To facilitate clinical translation,we constructed a corresponding recombinant human 4-1BB ligand fusion protein (hIg-h4-1BBLs) and showed its ability to activate human T cells in vitro. Using Chinese hamster ovary cells transformed with a plasmid coexpressing hIg-h4-1BBLs and rat glutamine synthetase, we generated a high-producing clone by sequential selection with methionine sulfoximine. The hIg-h4-1BBLs was partially purified by protein A column chromatography and characterized biochemically and functionally, using human 4-1BB binding and human T-cell proliferation assays, in vitro.Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western Blot confirmed that the hIg-h4-1BBLs is expressed predominantly as a functionally active multimeric protein with the ability to specifically bind to cells expressing human 4-1BB receptor and induce significant T-cell proliferation in vitro using both human and monkey peripheral blood mononuclear cells. The hIg-h4-1BBLs can be produced in large quantities from the high producer clone and developed as a novel immune costimulatory biotherapeutic to treat, alone and in combination with other modalities, various malignant diseases in patients through T-cell activation. Process development of this clinical agent has been discussed with the Food and Drug Administration in a pre-Investigational New Drug meeting and presented to the Office of Biotechnology Activities in a public hearing. PMID- 21304404 TI - Rapid re-expression of retrovirally introduced versus endogenous TCRs in engineered T cells after antigen-specific stimulation. AB - To broaden the applicability of cellular immunotherapy, adoptive transfer of T cell receptor (TCR) transferred T cells may be an attractive strategy. Using this approach, high numbers of defined antigen-specific T cells can be engineered. As the introduced TCR has to compete for cell surface expression with the endogenous TCR, the introduced TCR chains are under control of a strong viral promotor, which, in contrast to the endogenous promotor, is constitutively active. We examined whether this difference in regulation would result in differences in TCR internalization and re-expression of the introduced and endogenous TCR on dual TCR engineered T cells and the antigen-responsiveness of both the TCRs. We showed comparable TCR downregulation of TCRs expressed under regulation of a retroviral promotor or the endogenous promotor. However, the introduced TCRs were rapidly re expressed on the cell surface after TCR stimulation. Despite rapid re-expression of the introduced TCR, T cells exerted similar antigen-sensitivity compared with control T cells, showing that cell mechanisms other than TCR cell surface expression are involved in antigen-sensitivity directly after antigen-specific stimulation. These results showed that TCR transduced T cells are functionally not different from nontransduced T cells and can potentially be used as an effective treatment strategy. PMID- 21304405 TI - Use of curcumin to decrease nitric oxide production during the induction of antitumor responses by IL-2. AB - Nitric oxide (NO) synthesis is strongly induced during interleukin (IL)-2 treatment of mice and humans. Although this free radical can act as a cytotoxic effector molecule against cancer cells, immunosuppressive effects have also been suggested. We evaluated the effects of curcumin on IL-2-induced NO synthesis and IL-2-induced antitumor responses in a mouse ascites tumor model. Curcumin inhibited inducible nitric oxide synthase (iNOS) expression and NO production, and thereby enhanced the proliferation and cytotoxic activity of cocultured lymphocytes and macrophages during IL-2 stimulation which we earlier established as an in vitro model of IL-2-induced NO synthesis. Curcumin also decreased apoptosis of cocultured lymphocytes and macrophages during IL-2 stimulation. In contrast, the curcumin-induced changes in proliferation and apoptosis were not observed in cultures of lymphocytes alone, macrophages alone, and cocultured lymphocytes/iNOS-knock out macrophages, all of which produced little nitrite during IL-2 stimulation. In conjunction with IL-2 treatment, oral curcumin administration significantly inhibited IL-2 therapy-induced urinary nitrite/nitrate excretion and iNOS expression of tumor tissues, and further increased the IL-2 therapy-induced prolongation of survival in a murine Meth-A ascites tumor model. Curcumin may be useful as an adjunct to increase the antitumor activity of IL-2 therapy. PMID- 21304406 TI - Interleukin-28B acts synergistically with cisplatin to suppress the growth of head and neck squamous cell carcinoma. AB - Interleukin-28B (IL-28B), also referred to as interferon-lambda3, belongs to the type III interferon family. Earlier studies showed that IL-28B suppresses proliferation of some tumor cells in vitro. IL-28B gene transfection ex vivo also resulted in growth retardation of tumor cells in mice, through either direct antiproliferative action or induction of antitumor immunity. However, it has not been reported whether in vivo therapeutic administration of recombinant IL-28B can inhibit the growth of a pre-established tumor. Here, we found that repetitive subcutaneous administration of recombinant mouse IL-28B significantly induced tumor-specific cytotoxic T lymphocytes and augmented natural killer cytolytic activity, leading to moderate suppression of the growth of a murine head and neck squamous cell carcinoma (HNSCC) cell line that was completely resistant to the direct antiproliferative effect of IL-28B. Moreover, co-administration of recombinant mouse IL-28B and cisplatin (CDDP) more significantly inhibited in vivo growth of the tumor that had been established in syngenic mice and induced tumor-specific cytotoxic T lymphocytes. The CDDP treatment induced the expression of major histocompatibility complex class I and Fas molecules on the surface of HNSCC cells both in vitro and in vivo; this may be the mechanism underlying the synergistic tumor suppression activity of IL-28B and CDDP. Unlike type I interferon, IL-28B did not suppress growth of bone marrow cells in culture. Therefore, IL-28B may be useful as a tool for a novel multidisciplinary therapy against cancer, significantly potentiating innate and adaptive antitumor immune responses, especially when co-administrated with CDDP, which is currently the first choice chemotherapeutic agent against various tumors including HNSCCs. PMID- 21304407 TI - Possibility of adoptive immunotherapy with peripheral blood-derived CD3-CD56+ and CD3+CD56+ cells for inducing antihepatocellular carcinoma and antihepatitis C virus activity. AB - We recently showed that interleukin (IL)-2-stimulated CD56+ cells derived from the liver exert vigorous cytotoxicity against hepatocellular carcinoma (HCC) by their binding to the tumor necrosis factor-related apoptosis-inducing ligand expressed on natural killer cells and the corresponding death receptors, and exhibit inhibitory effects on hepatitis C virus (HCV) replication by production of a high level of interferon-gamma. These findings prompted us to develop a technique to increase the number of such innate components of cellular immunity from peripheral blood mononuclear cells (PBMCs) so that, they can be easily applied for immunotherapy clinically. We expanded CD3-CD56+ and CD3+CD56+ cells ex vivo from PBMCs of human volunteers by using media containing IL-2 and anti CD3 monoclonal antibody. Among the various culture media used, autoserum supplemented X-VIVO 15 most efficiently supported PBMCs expansion and maintained the viability of the expanded cells (approximately 60-fold expansion after 28-d culture). Cultivation of PBMCs in this medium resulted in the highest proportion of CD3-CD56 cells among the propagated lymphocytes (approximately 40% after 28-d culture). An experiment using genomic HCV replicon-containing hepatic cells showed that the CD3-CD56+ cell-enriched expansion strongly inhibited HCV replication when compared with freshly isolated PBMCs. The additional anti-CD3 monoclonal antibody pulse stimulation induced anti-HCV activity even in the CD3+CD56+ cells among the propagated PBMCs. Further, cytotoxic assay showed that the expansion of CD3+CD56+ and CD3-CD56+ cells resulted in vigorous cytotoxicity against HCC. In conclusion, CD56+ cells obtained from the PBMCs show anti-HCV activity in addition to anti-HCC activity. PMID- 21304408 TI - Cotransfection of Poly(I: C) and siRNA of IL-10 into fusions of dendritic and glioma cells enhances antitumor T helper type 1 induction in patients with glioma. AB - Apart from generating T-helper (Th) effector responses, dendritic cells (DCs) are capable of initiating tolerance against the inciting antigens. Therefore, successful DC-based immunotherapy against malignant tumors requires an additional strategy to activate antigen-processing DCs. We studied the antitumor immune responses conferred by fusions of DCs and glioma cells in vitro. Fusion cells (FCs) were stimulated with polyriboinosinic polyribocytidylic acid [Poly(I:C)] and/or small interference RNA (siRNA) of IL-10 (IL-10-siRNA). Increased IFN-beta expression induced by Poly(I:C) transfection was accompanied by enhanced production of IL-10 and IL-12p70 in the FCs. We also found that the ability of Poly(I:C)-transfected FCs to produce IL-12p70, but not IFN-beta, was preserved when endogenous IL-10 was suppressed by IL-10-siRNA. To analyze the antigen presenting function further, DCs, glioma cells, and peripheral lymphocytes were established from patients newly diagnosed with glioma. In this experiment, peripheral lymphocytes were stimulated with autologous FCs and restimulated with autologous glioma cells. CD4T cells isolated from the stimulated lymphocytes were subjected to the ELISPOT and WST-1 assays, which revealed that the IL-10 siRNA/Poly(I:C)-cotransfected FCs elicit an efficient tumor-specific Th1 response. These findings support the relevance of using Poly(I:C) and IL-10-siRNA in clinical immunotherapy protocols with an FC-based vaccine for patients with malignant glioma as a means of promoting Th1-induced tumor antigen presentation. PMID- 21304409 TI - Serum prolidase activity and oxidative-antioxidative status in Legg-Calve-Perthes disease. AB - We aimed to find out that whether collagen turnover is altered in the context of Legg-Calve-Perthes disease (LCPD) by evaluating serum prolidase activity. We also investigated the correlation between collagen turnover and oxidative antioxidative status in LCPD. Plasma prolidase activity, total oxidant status (TOS), total antioxidant capacity, and oxidative stress index (OSI) were determined for 39 patients with LCPD and 40 healthy controls. Serum prolidase activity, TOS, and OSI were higher, but TAC was lower in patients with LCPD compared with controls. Prolidase activity was positively correlated with TOS and OSI levels. Serum prolidase activity is significantly associated with LCPD. PMID- 21304410 TI - Intracortical osteosarcoma of the tibia in a 14-year-old girl. AB - Intracortical osteosarcoma is the rarest form of osteosarcoma. The lesion is histologically characterized as a sclerosing variant of osteosarcoma. In this study, a new case of pathologically proven tibia intracortical osteosarcoma in a 14-year-old girl is presented. Imaging findings on computed tomography and magnetic resonance imaging are discussed. The role of computed tomography-guided biopsy is emphasized. PMID- 21304411 TI - Malignant lesions are rare in medial third of the clavicle in children: the European Juvenile Medial End of Clavicle Tumour study. AB - Condensing osteitis is a condition presenting to all paediatric orthopaedic services, but the prevalence of the condition and optimal management is difficult to determine from the literature. Many case reports in the orthopaedic literature describe biopsy to exclude malignancy as mandatory, whereas expert radiological opinion has suggested that lesions can be classified as typical of sclerosing osteitis on imaging alone. The aim of this study was to calculate an accurate incidence of malignancy at the medial end of the clavicle in children based on data held by national and regional cancer registries in Europe. In addition, this study determined the published success of biopsy in identifying a causative organism. The investigators wrote to 173 European national or regional cancer registries requesting the number of malignant lesions at the medial end of the clavicle in those less than 19 years of age, how long the registry had been in existence and the size of the population served. A literature review was conducted of Medline and Pubmed using the terms, 'condensing osteitis,' 'chronic recurrent multiostotic osteomyelitis,' 'acute osteomyelitis,' 'chronic osteomyelitis clavicle,' 'sclerosing osteitis' and 'sclerosing osteomyelitis' and refined to those regarding the clavicle. The incidence of malignancy at the medial end of the clavicle was found to be extremely low (one case every 275 child-years at risk). In addition, biopsy rarely identified a causative organism with only two of 89 biopsies being positive. We suggest that for a chronic nonmalignant process in which clinical features are typical, serial imaging with follow-up is sufficient although timely biopsy would be recommended when doubt exists. PMID- 21304413 TI - Novel PET biomarkers for breast cancer imaging. PMID- 21304412 TI - Lung cancer serum biomarker discovery using label-free liquid chromatography tandem mass spectrometry. AB - INTRODUCTION: Lung cancer remains the leading cause of cancer-related death with poor survival due to the late stage at which lung cancer is typically diagnosed. Given the clinical burden from lung cancer and the relatively favorable survival associated with early-stage lung cancer, biomarkers for early detection of lung cancer are of important potential clinical benefit. METHODS: We performed a global lung cancer serum biomarker discovery study using liquid chromatography tandem mass spectrometry in a set of pooled non-small cell lung cancer case sera and matched controls. Immunoaffinity subtraction was used to deplete the top most abundant serum proteins; the remaining serum proteins were subjected to trypsin digestion and analyzed in triplicate by liquid chromatography-tandem mass spectrometry. The tandem mass spectrum data were searched against the human proteome database, and the resultant spectral counting data were used to estimate the relative abundance of proteins across the case/control serum pools. The spectral counting-derived abundances of some candidate biomarker proteins were confirmed with multiple reaction monitoring mass spectrometry assays. RESULTS: A list of 49 differentially abundant candidate proteins was compiled by applying a negative binomial regression model to the spectral counting data (p < 0.01). Functional analysis with Ingenuity Pathway Analysis tools showed significant enrichment of inflammatory response proteins, key molecules in cell-cell signaling and interaction network, and differential physiological responses for the two common non-small cell lung cancer subtypes. CONCLUSIONS: We identified a set of candidate serum biomarkers with statistically significant differential abundance across the lung cancer case/control pools, which, when validated, could improve lung cancer early detection. PMID- 21304414 TI - Prone imaging allows efficient radiopharmaceutical usage by obviating the necessity of a rest study in Tc-99m-methoxyisobutylisonitrile myocardial perfusion scintigraphy. AB - OBJECTIVE: In myocardial perfusion single-photon emission computed tomography studies, diaphragmatic attenuation of the inferior wall is a common artifact, which can be minimized by prone imaging. The aim of this retrospective study was to validate the impact of stress-prone imaging on the necessity of a rest perfusion study with a final goal of effective radiopharmaceutical usage. METHODS: The findings of 98 patients who had been examined by a combined supine and prone imaging were retrospectively evaluated. Prone acquisition was performed only when reduced perfusion was observed in the inferior wall on the stress supine images. The reconstructed images were evaluated both visually and quantitatively. Rest myocardial single-photon emission computed tomography study was omitted in patients with complete normalization of uptake in the prone images. Results obtained were also compared with the clinical data and follow-up. RESULTS: Prone imaging obviated the necessity of a rest perfusion study in 76 of 98 patients (77.5%). Among normally reported patients (n=89), 76 (85.4%) were saved from a rest study due to the prone study results. Prone study provided improved results in quantitative analysis as well. The difference between the mean summed stress scores of supine and prone studies was statistically significant in normally reported patients (P=0.013). However, no significant difference was observed in scores of ischemic patients (P=0.341). CONCLUSION: Adding prone imaging to a post-stress Tc-99m-methoxyisobutylisonitrile myocardial perfusion study not only minimizes the inferior wall attenuation, but also reduces the need for a rest test, particularly in low-risk or intermediate-risk patients. Thus, prone imaging seems to be both safe and effective. PMID- 21304415 TI - 99mTc-N2S2-Tat (49-57)-bombesin internalized in nuclei of prostate and breast cancer cells: kinetics, dosimetry and effect on cellular proliferation. AB - BACKGROUND: The gastrin-releasing peptide receptor (GRP-r) is overexpressed in prostate and breast cancers. technetium-99m-bombesin (Tc-BN) has been reported as a radiopharmaceutical with specific cell GRP-r binding. The HIV Tat (49-57) derived peptide has been used to deliver a large variety of molecules to cell nuclei. A new hybrid radiopharmaceutical of type Tc-N2S2-Tat(49-57)-Lys-BN (Tc Tat-BN) internalized in cancer cell nuclei could act as an effective system of targeted radiotherapy using Auger and internal conversion electron emissions near DNA. AIM: The aim of this study was to assess the in-vitro nucleus internalization kinetics of Tc-Tat-BN in GRP r-positive cancer cells and to evaluate the subcellular-level radiation-absorbed dose associated with the observed effect on cancer cell DNA proliferation. METHODS: Tc-Tat-BN in-vitro internalization kinetics were evaluated in human prostate cancer PC-3 cells and breast carcinoma cell lines MCF7 and MDA-MB231. Nuclei from cells were isolated using a nuclear extraction kit. Total disintegration in each subcellular compartment was calculated by the integration of experimental time-activity kinetic curves. Nucleus internalization was corroborated by confocal microscopy images using immunofluorescently labelled Tat-BN. The PENELOPE code was used to simulate and calculate the absorbed dose by the contribution of Auger and internal conversion electrons in the cytoplasm and nucleus using geometric models built from immunofluorescent cell images. A cell proliferation kit was used to evaluate DNA concentration after cancer cell incubation with Tc-Tat-BN. RESULTS: The results showed that 59.7, 61.2 and 41.5% of total disintegration per unit of Tc-Tat-BN activity (1 Bq) bound to the cell occurred in the nucleus of PC-3, MCF7 and MDA-MB231, respectively. The Tc-Tat-BN absorbed doses delivered to nuclei were 0.142 mGy/decay (PC-3), 0.434 mGy/decay (MCF7) and 0.276 mGy/decay (MDA MB231). Tc-Tat-BN produced a significant decrease in PC-3 (52.98%), MCF7 (45.71%) and MDA-MB231 (35.80%) cellular proliferation with respect to untreated cells. CONCLUSION: The hybrid radiopharmaceutical could be potentially useful as a therapeutic agent for prostate and breast cancers. PMID- 21304416 TI - Coronary artery calcification detected by PET/CT scan as a marker of myocardial ischemia/coronary artery disease. AB - BACKGROUND: There have been no data with regard to the relationship between coronary artery calcification (CAC) detected with positron emission tomography (PET)/computed tomography (CT), as incidental findings, and myocardial perfusion single photon computed tomography (MPS) results in patients with cancer. OBJECTIVES: The main objective of this study was to investigate the relationship between CAC detected on the CT component of PET/CT and abnormal MPS in patients with cancer before oncologic surgery. METHOD: A total of 157 patients without known coronary disease and clinically proven indication for PET/CT underwent PET/CT and MPS as a routine preoperative workup. PET/CT and MPS were performed within 3 months. The frequency of abnormal MPS was compared with the presence or absence of CAC. CAC was evaluated visually. RESULTS: Among 81 patients with no CAC, MPS results were normal in 71 patients (88%). Only 10 patients (20%) with no CAC had abnormal MPS (P<0.005) results. However, in the total patient population with visually detectable CAC (76 patients), MPS results were normal in 36 patients (47%) and abnormal in 40 patients (53%) with no statistically significant value. CAC and diabetes mellitus were the most potent predictors of abnormal MPS by multivariable analysis. CONCLUSIONS: Visual detection of CAC in the CT component of PET/CT is a strong predictor of MPS results. The presence of CAC is associated with a high likelihood of abnormal MPS, but the absence of CAC is rarely associated with abnormal MPS. These findings imply a potential role for applying routine visual CAC detection in the CT component of PET/CT and might obviate unnecessary MPS indications in the preoperative evaluation in patients with cancer. PMID- 21304417 TI - Tip the SCALE toward quality end-of-life skin care. PMID- 21304418 TI - Docs: partners or customers? PMID- 21304419 TI - Herpes simplex virus infection in young infants during 2 decades of empiric acyclovir therapy. AB - OBJECTIVE: To describe the clinical presentation of HSV-infected young infants and to seek distinctive features that could permit a targeted approach to empiric use of acyclovir. METHODS: Case study of neonatal HSV during a 22-year period of an institutional strategy of consistent use of acyclovir empirically in all infants with onset of an illness at <= 21 days of age for which antibiotics were given empirically. Multiple sources were used to optimize HSV case data, and to estimate the rate of HSV infection in empirically treated infants. RESULTS: A total of 32 infants with perinatally acquired HSV infection were identified. All received acyclovir empirically at admission. At presentation, 50% of infants had only nonspecific complaints, which was fever in 75%. After testing, 75% of infants with HSV had central nervous system (CNS) infection, including 40% who presented with mucocutaneous lesions, 83% with seizures, and 94% with nonspecific complaints. Cerebrospinal fluid (CSF) polymerase chain reaction confirmed CNS infection in 16 of 22 (73%) patients tested. Cultures of mucocutaneous lesion yielded HSV in 8 of 10 cases, but culture of CSF was negative in all 26 cases tested, and screening cultures of unaffected mucosal sites were the only HSV confirmatory test in a single patient. Laboratory and CSF findings were not distinctive in patients with HSV. Age of <= 21 days at onset of symptoms captured 90% of all infants with HSV and 94% of those with nonspecific complaints. An estimated 1.3% of empirically treated patients had HSV infection. CONCLUSIONS: Early manifestations of perinatally acquired HSV are frequently nonspecific, yet CNS infection is common. Empiric acyclovir strategy narrowly restricted to infants with onset of illness at <= 21 days of age, who would receive antibiotics empirically, captured 90% of HSV cases and anticipated a rate of HSV CNS infection similar to that of bacterial meningitis. PMID- 21304420 TI - Induction of autophagy and autophagic cell death in damaged neural tissue after acute spinal cord injury in mice. AB - STUDY DESIGN: Expression of light chain 3 (LC3), a characteristic marker of autophagy, was examined by immunohistochemistry and Western blot using a spinal cord injury (SCI) model in mice. Electron microscopic analysis was also performed to examine the anatomic formation of autophagy and autophagic cell death in the injured spinal cord. OBJECTIVE: To examine both biochemically and anatomically the activity of autophagy in the damaged neural tissue after SCI. SUMMARY OF BACKGROUND DATA: Autophagy is the bulk degradation of intracellular proteins and organelles, and it is involved in a number of diseases. Autophagy can lead to nonapoptotic programmed cell death, which is called autophagic cell death. Recent researches have revealed the increased expression of LC3 and the anatomic formation of autophagy and autophagic cell death in damaged tissues of various disease models. However, previous studies have focused on apoptotic process but not autophagic activity as mechanism of neural tissue damage after SCI. To date, there has been no study to examine the expression of LC3 and the anatomic formation of autophagy after SCI. METHODS: The spinal cord was hemitransected at T10 in adult female C57BL/6J mice. The LC3 expression was examined by immunohistochemistry and Western blot. The anatomic formation of autophagic activity was investigated using electron microscopy. RESULTS: Immunohistochemistry showed that the number of the LC3-positive cells significantly increased at the lesion site after hemisection. The increase of LC3 positive cells was observed from 4 hours and peaked at 3 days, and it lasted for at least 21 days after hemisection. The LC3-positive cells were observed in neurons, astrocytes, and oligodendrocytes. Western blot analysis demonstrated that the level of LC3-II protein expression significantly increased in the injured spinal cord. Electron microscopy showed the formation of autophagic vacuoles to increase in the damaged cells. Furthermore, the nuclei in the transferase-mediated dUTP nick end labeling-positive cells expressed LC3 were round, which is consistent with autophagic cell death, and they were neither shrunken nor fragmented as is observed in apoptotic nuclei. CONCLUSION: This study suggested both biochemically and anatomically that autophagy was clearly activated and autophagic cell death was induced in the damaged neural tissue after SCI. PMID- 21304421 TI - Influence of low back pain status on pelvis-trunk coordination during walking and running. AB - STUDY DESIGN: Two-way repeated-measures analysis of variance. OBJECTIVE: To assess pelvis and trunk three-dimensional segmental excursions and coordination differences during walking and running between runners with low back pain (LBP), runners with resolved LBP, and a control group with no history of LBP. SUMMARY OF BACKGROUND DATA: Studies have documented differences in pelvis and trunk coordination between those with moderate to severe LBP during walking. Few studies document pelvis and trunk mechanics in those with low to moderate LBP and individuals who recover from LBP even though these individuals comprise 80% of LBP cases and are at increased risk for re-injury. METHODS: Recreational runners walked and ran on a treadmill at speeds including 0.8 to 3.8 m/s at 0.5 m/s increments. Pelvis and trunk kinematic data were collected during the last 20 s of each stage. Coordination analysis quantified the portion of gait cycle each group spent in trunk only motion, pelvis-only motion, in-phase, and antiphase relationships. RESULTS: During walking, the LBP group spent more of the gait cycle in-phase in the frontal plane (P = 0.030). During running, the LBP group showed greater pelvis axial rotation than the control group (P = 0.014) and spent more of the gait cycle in-phase in the transverse plane (P = 0.019). Also during running, the LBP (P = 0.035) and the resolved LBP (P = 0.037) groups demonstrated reduced antiphase coordination compared to controls. CONCLUSION: Coordination analysis demonstrates a reduction in relative motion between the pelvis and trunk despite low disability levels in our LBP group and no pain in our group with a history of LBP. PMID- 21304422 TI - The utility of repeated postoperative radiographs after lumbar instrumented fusion for degenerative lumbar spine. AB - STUDY DESIGN: Retrospective chart review. OBJECTIVE: To assess the impact that routine postoperative radiographs have in clinical outcome and clinical decision making. SUMMARY OF BACKGROUND DATA: No standard exists that outlines how often and when radiographs should be taken after lumbar fusion. Routine postoperative radiographs can be a source of inconvenience and cost to patients, radiation exposure, and possibly, confounding information. METHODS: The patients who underwent a single or multilevel lumbar instrumented fusion were investigated. At each time-point after surgery, it was noted if they demonstrated new symptoms or clinical deterioration. The Fisher exact test was used to analyze the categorical data. RESULTS: Sixty-three patients (25 males and 38 females) were identified with a mean age of 52 years (range, 20-87). Plain radiographs were taken at 269 visits including all time-points. In 17 (6.3%) visits, abnormal findings were found in 13 patients, including suspected pseudoarthrosis on radiographs (n = 10) and adjacent segment disease on radiographs (n = 3). They were found during 11 of 50 visits (22%) in the patients with new symptoms or clinical deterioration and during 6 of 219 visits (2.7%) in the asymptomatic patients. The probability of an abnormal finding was significantly lower in the asymptomatic patients (P < 0.001). Before the 6-month follow-up, abnormal findings were found in 1 of 111 visits (0.9%) and in 16 of 158 visits (10%) at the 6-month follow-up or later. The probability of an abnormal finding was significantly lower before the 6-month follow-up (P < 0.001). In six of the seven symptomatic patients (86%) with suspected pseudoarthrosis on radiographs, pseudoarthrosis was initially suspected between 6 and 12 months after surgery. CONCLUSION: This study suggests that plain radiographs should be performed as indicated clinically rather than routinely after instrumented lumbar fusion. The vast majority of asymptomatic patients do not require routine postoperative radiographs. PMID- 21304423 TI - Vectored cranial-cervical traction limits facial contact pressure from prone positioning during posterior spinal deformity surgery. AB - STUDY DESIGN: Prospective, two-way complete block design analyzing facial contact pressures during prone positioning with the use of cervical traction for spinal surgery. Level 2 evidence. OBJECTIVE: To assess the effect of varying traction angle and traction weight to limit facial contact pressure. SUMMARY OF BACKGROUND DATA: Posterior spine surgery has known hazards related to the prone positioning. Cervical traction is used to limit downward pressure exerted to the face to stabilize the head and neck and to aide in deformity correction. The effects of the traction angle and force on facial contact pressure have not been studied. METHODS: Facial contact pressure was measured for 10 patients undergoing posterior spine surgery in the prone position with Gardner-Wells tongs applied for cervical traction. The facial contact pressure was measured with a force transducer at each of three angles from horizontal (0 degrees , 30 degrees , 45 degrees ) and each of four traction weights (0, 5, 10,15 lb), a total of 12 measurement parameters for each patient. An in-line tensiometer provided consistent application of force throughout the traction system. RESULTS: Ten patients, average age 15 +/- 0.6 years, six female, BMI 21.3 +/- 1.7, underwent facial pressure monitoring. Post hoc analysis showed that both higher traction weights and angles significantly limited facial pressure (P = 0.0001). The lowest overall average facial pressure of 0.51 lb (95% CI = 0.28-0.73) occurred with 15 lb of traction applied at 45 degrees above the horizontal. This was significantly less facial pressure than found when traction was applied at all weights tested using the commonly employed 0 degrees in-line traction angle (P < 0.0001). CONCLUSION: A combination of upward vectored 45 degrees traction angle and 15 lb of weight significantly decreased facial contact pressure. The use of an "in-line tensiometer" assured an accurate force application. PMID- 21304424 TI - Survival analysis of 254 patients after manifestation of spinal metastases: evaluation of seven preoperative scoring systems. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: This study analyzed the predictive value of the scoring systems of Bauer, Bauer modified, Tokuhashi, Tokuhashi revised, Tomita, van der Linden, and Sioutos as well as the parameters included in these systems. SUMMARY OF BACKGROUND DATA: Metastases of the spinal column are a common manifestation of advanced cancer. Severe pain, pathologic fracture, and neurologic deficit due to spinal metastases need adequate treatment. Besides oncologic aspects and quality of life, treatment decisions should also include the survival prognosis. METHODS: Two hundred fifty-four patients with confirmed spinal metastases were investigated retrospectively (treatment 1998-2006; 62 underwent surgery and 192 had conservative treatment only). Factors related to survival, such as primary tumor, general condition (Karnofsky Performance Status Scale), neurologic deficit, number of spinal and extraspinal bone metastases, visceral metastases, and pathologic fracture, were analyzed. The survival period was calculated from date of diagnosis of the spinal metastases to date of death or last follow-up (minimum follow-up: 12 months). For statistical analysis, univariate and stepwise multivariate Cox regression analyses were performed. RESULTS: Median overall survival for all patients was 10.6 months. The following factors showed significant influence on survival in multivariate analysis: primary tumor (P < 0.0001), status of visceral metastases (P < 0.0001), and systemic therapy (P < 0.0001). Using the recommended group assignment for each system, only Bauer and Bauer modified showed significant results for the distinction between good, moderate, and poor prognosis. The other systems failed to distinguish significantly between good and moderate prognosis. The hazard ratio of the absolute score of all analyzed systems was, however, statistically significant, with a better score leading to lower risk of death. CONCLUSION: According to this analysis, the Bauer and the Bauer modified scores are the most reliable systems for predicting survival. Since the Bauer modified score furthermore consists of only four positive prognostic factors, we emphasize its impact and simplicity. PMID- 21304425 TI - Spinal navigation: standard preoperative versus intraoperative computed tomography data set acquisition for computer-guidance system: radiological and clinical study in 100 consecutive patients. AB - STUDY DESIGN: A retrospective clinical and radiological study. OBJECTIVE: To compare the safety and accuracy of pedicle screw insertion using two different computed tomography (CT) data set acquisitions (preoperative and intraoperative) for computer-guidance systems in a series of 100 consecutive patients. SUMMARY OF BACKGROUND DATA: Misplacement and pedicle cortical violation occurs in over 20% of screw placements and can result in potential neurovascular complications. Many technological innovations have been described to help reduce this range of error, such as image-guided surgery using fluoroscopy or CT-based image guidance. However, these techniques are not without their drawbacks. The next technological evolution is the use of an intraoperative CT scan, which would allow us to solve some of the critical phases of spinal navigation, such as position-dependent changes, thus granting a higher accuracy of the navigation system. The authors have compared and discussed the results of a preoperative and intraoperative CT data set acquisition mode for spinal navigation. METHODS: One hundred consecutive patients with a diagnosis of lumbar degenerative spondylolisthesis who underwent a surgical approach of lumbar pedicle screw fixation using a CT-based computer guidance system were evaluated. The population was divided into two groups: in group I, a preoperative CT scan was used for the navigation system; whereas in group II, an intraoperative CT scan acquired during surgery was used. Epidemiological and surgical data of the patients in the two groups were then analyzed and compared. The Pearson chi test was used for comparisons between groups (significance level 0.05). The evaluation and classification of the screw positioning was performed on the basis of a control CT scan according to the classification proposed by Laine. RESULTS: Out of 504 screws, 471 were correctly inserted into the pedicles (93.5%): the accuracy of group I was of 91.8%, whereas in group II it was 95.2% (no statistical significance). The overall rate of perforation was 6.5% (33 screws): 21 in group I and 12 in group II. Twenty-eight screws had a perforation of the pedicle less than 2 mm (Grade I), three comprised from 2 to 4 (Grade II), and only two more than 4 mm and less than 6 mm (Grade III). Out of 33 misplaced screws only one was replaced (graded as III in group II). Surgical time was shorter for group II, with a statistically significant difference. This result is mainly because of the automatic recognition and merging of the intraoperative images with the surgical anatomy that avoided the phase of registration with a paired-point technique. CONCLUSION: The results of this study suggest that the CT-based computer-assisted surgical navigation systems are precise, granting an elevated accuracy in pedicle screw positioning. PMID- 21304426 TI - Characterization of osteopenia/osteoporosis in adult scoliosis: does bone density affect surgical outcome? AB - STUDY DESIGN: Retrospective study. OBJECTIVE: The aim of this study is to validate the prevalence of low bone mineral density (BMD) in woman patients with adult scoliosis and to relate that to surgical treatment outcome. Despite reports of the high prevalence of low BMD among female with adolescent idiopathic, these findings have not been substantiated in any comprehensive review of adult scoliosis patients undergoing surgical treatment. SUMMARY OF BACKGROUND DATA: It has been suggested that scoliosis may predispose to osteoporosis and that degenerative scoliosis could falsely elevate spinal BMD measurements with dual energy radiograph absorptiometry (DXA). The discordance between hip and spine BMD measurement using DXA has also been shown in previous cross-sectional study for adult population. METHODS: A retrospective review of 176 women treated surgically for scoliosis. BMD of the lumbar spine and femoral neck were determined by DXA. Patients were categorized as follows: concordance (osteoporosis, osteopenia, or normal BMD on both sites), minor discordance (osteoporosis in one site and osteopenia in the other site), and major discordance (osteoporosis in one site and normal the other site). Body mass index (BMI), preoperative Cobb angle, fusion ratio, and complication were recorded. Statistical analysis included the Student t test, chi(2) test, regression coefficient test, and simple linear regression. P value was set at P < 0.05. RESULTS: The mean age was 51 +/- 12 years (26-82 years). The mean T score of the hip was -1.23 +/- 0.89 and of the spine was -0.52 +/- 1.57. Major discordance in BMD 7 (4%) points, minor discordance 68 (39%) points, and concordance was 101 (57%) points. There was moderate correlation between T score of hip and spine (R = 0.55P < 0.01). T score of the hip and of the spine showed 10.8% and 10.2% of the patients were osteoporotic. The mean Z score of the hip and of the spine showed comparable age and sex matched values. No correlation was observed between BMD and Cobb angle (R = 0.05, P = 0.464). The fusion rate was 93% and surgical complication rate was 14.9%. No significant correlation was observed between BMD and fusion (P = 0.80) complication (P = 0.13). CONCLUSION: Comparable bone density exists among adult scoliosis patients with no correlation between BMD and curve magnitude, fusion and complication rates. The difference in BMD of the hip and of spine cannot be fully explained in the review. These results will guide in surgical planning, patient selection on the treatment options. PMID- 21304427 TI - Doppler ultrasonography and computed tomography angiography demonstrate positional occlusion of vertebral artery associated with one-sided destruction of the atlantoaxial lateral mass caused by rheumatoid arthritis: a case report. AB - STUDY DESIGN: Case report of a patient with rheumatoid arthritis (RA) and a positional occlusion of the left vertebral artery (VA). OBJECTIVE: To describe the utility of Doppler ultrasonography and computed tomography (CT) angiography for the diagnosis of positional VA occlusion. SUMMARY OF BACKGROUND DATA: In previous reports of positional VA occlusion in RA, angiography has been used for the diagnosis. However, it is difficult to demonstrate the three-dimensional relationship between the arteries and the bone structure with angiography. METHODS: An 83-year-old man with a 20-year history of RA complained of severe vertigo when he leaned his head in the left-anterior direction. CT angiography in the neutral position revealed that the left VA was pinched between the posterior rim of the transverse foramen of C1 and the transverse process of C2. Doppler ultrasonography demonstrated positional VA occlusion and a severe reduction in blood flow at the position that most readily induces vertigo. Because the space between the transverse foramens of left C1 and C2 was reduced with the destruction of the left C1/C2 lateral masses, slight rotation, and anterior shift of C1 led to the occlusion of the VA. RESULTS: After posterior O-C2 fusion at the reduced position, the VA occlusion and vertigo disappeared. CONCLUSION: Doppler ultrasonography and CT angiography allow valuable measurements in the diagnosis of positional VA occlusion. The one-sided destruction of the C1/C2 lateral masses might be a causal factor for VA occlusion in RA. This is the first report of a new pathomechanism underlying positional VA occlusion demonstrated with three dimensional CT angiography. PMID- 21304428 TI - Minimally invasive approach for the resection of spinal neoplasm. AB - STUDY DESIGN: Retrospective Case Series. OBJECTIVE: To determine if extradural, intradural extramedullary, and intramedullary spinal neoplasms can be safely resected through a minimally invasive corridor. SUMMARY OF BACKGROUND DATA: The use of minimally invasive approaches for resection of spinal neoplasms has been described for intradural schwannomas and ependymomas. We demonstrate that this approach can be extended to the resection of a variety of extradural, intradural and intramedullary spinal tumors. METHODS: We undertook a retrospective review of all patients presenting with clinical and radiographic evidence of spinal neoplasm that subsequently underwent a minimally invasive approach for resection of the tumor using the METRx MAST QUADRANT Retractor System (Medtronics, Memphis, TN). Primary endpoints analyzed include completeness of resection, postoperative neurologic status, operative time, blood loss, postoperative pain, length of hospital stay, and operative complications. RESULTS: Two cervical, seven thoracic and 13 lumbar neoplasms were identified in 20 patients operated on between September 2005 and May 2009. Mean intraoperative time was 210 minutes, blood loss 428 mL and average length of hospital stay was 3 days. Four patients required postoperative patient-controlled analgesia for pain control and an average of 5.8 doses of narcotic were given per patient. Two patients developed postoperative complications. Fifteen of 22 tumors (68%) were completely resected, with only one patient requiring repeat operation for residual tumor. All but one patient were improved from preoperative status at 6 months. CONCLUSION: Intramedullary, intradural and extradural spinal neoplasms can be resected through a minimally invasive approach without increased risk for adverse neurologic outcome. This technique may be an appropriate alternative to the open approach for well circumscribed extramedullary lesions spanning one or two spinal levels. With increasing experience, reduced operative time, blood loss, complications, length of hospital stay, postoperative pain, and spinal instability may be seen. PMID- 21304429 TI - A novel method of screw placement for extremely small thoracic pedicles in scoliosis. AB - STUDY DESIGN: A retrospective clinical study. OBJECTIVE: To introduce a novel method of pedicle screw placement for extremely small thoracic pedicles in scoliosis and evaluate the safety and accuracy of the method. SUMMARY OF BACKGROUND DATA: Few studies have provided technical guidelines for screw placement in patients with extremely small thoracic pedicles in scoliosis. METHODS: In a severely rotated scoliotic spine, thoracic pedicle screw placement is challenging, and particularly more so for extremely small pedicles with a diameter less than 2 mm. The authors introduced a novel method of screw placement for these small pedicles: "medial margin targeting method."The C-arm fluoroscope is rotated until a true PA image of the rotated vertebral body is acquired and both pedicle shadows are symmetrically visualized en face. In extremely small pedicles, pedicle shadows appear as long, slender ellipses or lines. An imaginary pedicle outline is presumed with the elliptical or linear shadows being the medial margin of the pedicle. The entry point of a screw can be made at the 10 o'clock or 2-o'clock position on the presumed pedicle outline, and the screw can be safely inserted targeting the presumed medial margin with caution not to penetrate the medial cortex using the guidance of a true PA image. This is a kind of extrapedicular screw placement method.The safety and accuracy of this method were evaluated in 97 patients with scoliosis who had undergone posterior correction and instrumentation using postoperative computed tomography scans. A total of 1634 pedicle screws were inserted into thoracic pedicles, 128 of them (7.8%) being extremely small pedicles with a diameter less than 2 mm. RESULTS: Among 128 extremely small thoracic pedicles with a diameter less than 2 mm, one screw (0.8%) violated the medial cortex and 22 screws (17.6%) violated the anterior cortex of the vertebral body. No screws violated the lateral cortex of the pedicle-rib unit. There were no complications associated with screw misplacement. CONCLUSION: In scoliosis patients with extremely small thoracic pedicles, our pedicle screw placement method targeting the presumed medial margin in a true PA C-arm image allows easy application with accuracy and safety, which would not possible by any other method described so far. PMID- 21304430 TI - Osteoid osteoma of the mobile spine: surgical outcomes in 81 patients. AB - STUDY DESIGN: A restrospective review of 81 cases of osteoid osteoma of the mobile spine submitted to surgical treatment. OBJECTIVE: Analyze pro and contras of different techniques (conventional and minimally invasive) for the treatment of osteoid osteoma. SUMMARY OF BACKGROUND DATA: Intralesional excision has been considered the standard treatment for spinal osteoid osteoma. The high success rate of minimally invasive surgery in the treatment of a variety of spinal disorders lead us to believe this technique can also be applicable for the treatment of osteoid osteoma of the spine. METHODS: Eighty-one patients affected by osteoid osteoma were consecutively treated by the same team with intralesional excision using conventional or minimally invasive approach by video-assisted endoscopy, microscope, or percutaneous radiofrequency coagulation. The clinical features, the radiologic findings, and the outcome were reviewed. Pain and neurologic symptoms, were scored before surgery, after surgery and at the follow up. Complications and local recurrences were also recorded. RESULTS: Immediate relief of pain was observed after surgery in all patients. One patient showed mild neurologic impairment before treatment but became free of neurologic symptoms postoperative. Five local recurrences were found in four patients, always associated with pain. Three of these patients underwent surgery for a second time and one patient for a third time. There were two complications because surgery in two patients. One patient developed a pneumothorax, the other a hematoma. No related cases of kyphosis or scoliosis surgery were observed. CONCLUSION: Conventional excision therapy is a effective and reliable treatment for osteoid osteoma associated to low morbidity and low local recurrence rate. Minimally invasive surgery is emerging as an alternative method, reducing soft tissue trauma and the collateral damage caused by traditional surgical approach, allow patients a more rapid and complete return to normal function. PMID- 21304431 TI - Cervical epidural lymphangioma presenting as a hemorrhagic cyst: a case report. AB - STUDY DESIGN: A case report. OBJECTIVE: We report a case of epidural lymphangioma in the cervical spine, and it manifested as a hemorrhagic cyst. SUMMARY OF BACKGROUND DATA: Intraspinal lymphangioma is an uncommon tumor with only a few cases reported in the literature. Epidural lymphangioma presenting as a hemorrhagic cyst is extremely rare. METHODS: The patient chosen was a 43-year-old woman with the chief complaint of neck pain and right upper extremity numbness of 2-month duration. RESULTS: Cervical spine magnetic resonance (MR) imaging revealed an epidural cystic mass extending to the right C6-C7 neural foramen. The mass showed fluid-fluid levels on T2-weighted image and high-signal intensity on diffusion-weighted image. Surgical resection and histologic analysis confirmed the diagnosis of epidural lymphangioma with internal hemorrhage. CONCLUSION: Epidural lymphangioma is a rare benign tumor. However, it should be included in the differential diagnosis of hemorrhagic cystic mass in the epidural space, which presented with fluid-fluid levels on MR imaging and high-signal intensity on diffusion weighted imaging. PMID- 21304432 TI - Managing missing scores on the Roland Morris Disability Questionnaire. AB - STUDY DESIGN: Analysis of Roland Morris Disability Questionnaire (RMDQ) and Oswestry Disability Index (Oswestry) responses. OBJECTIVE: To determine the prevalence of unanswered questions on the RMDQ23 (23-item RMDQ version) and Oswestry questionnaires. To determine whether managing RMDQ23 missing data using proportional recalculation is more accurate than simply ignoring missing data. SUMMARY OF BACKGROUND DATA: It is likely that the most common method for calculating an RMDQ sum score is to simply ignore any unanswered questions. In contrast, the raw sum score on the Oswestry is converted to a 0 to 100 scale, with the advantage of allowing missing data to be accommodated by proportional recalculation. METHODS: The prevalence of unanswered RMDQ23 questions was measured in a research project and a routine care setting. The accuracy of the RMDQ23 proportional recalculation method was measured using 311 fully completed RMDQ23 and matching Oswestry questionnaire sets. Raw sum scores were calculated, and questions systematically dropped. At each stage, sum scores were converted to a score on a 0 to 100 scale and the error calculated. Wilcoxon Tests were used to compare the magnitude of the error scores. RESULTS: The prevalence of people who did not answer one or more questions was 29.5% (RMDQ23) in routine care, and 13.9% (Oswestry) and 20.3% (RMDQ23) in a research project. Proportional recalculation was a more accurate method to calculate RMDQ sum scores than simply ignoring missing data, when two or more questions were unanswered. CONCLUSION: Because of less error when missing data are present, the most accurate method for expressing RMDQ sum scores collected using Yes/No answers is conversion to a 0 to 100 scale. This conversion method is (a) if all questions are answered or only one question is unanswered, multiply the raw sum score by 100 divided by the total number of questions, and (b) if two or more questions are unanswered, multiply the raw sum score by 100 divided by the number of answered questions. PMID- 21304433 TI - Prolonged upright posture induces calcified hypertrophy in the cartilage end plate in rat lumbar spine. AB - STUDY DESIGN: Both forelimbs of rats were amputated and these rats were kept in the custom-made cages to keep prolonged and repeated upright posture. Changes of bone were observed in the lumbar vertebrae at three different time points after the surgery. OBJECTIVE: To investigate the effect of prolonged and repeated upright posture on the cartilage end plate of rat lumbar vertebrae. SUMMARY OF BACKGROUND DATA: Previous studies show calcified hypertrophy is related to mechanical stress, but there are no clear evidences to indicate whether or not long-term and repeated assumption of the upright posture could result in calcified hypertrophy in cartilage end plate of rat lumbar spine. METHODS: The forelimbs of 30 rats were amputated when they were 1 month old. These rats were kept in the custom-made cages and were forced to stand upright on their hind limbs and tails to obtain water and food. Normal rats of the same ages kept in regular cages were used as control. The rats were killed at 5, 7, and 9 months after the surgery and lumbar vertebrae samples were harvested for micro-CT, histologic, and immunohistochemical studies. Total RNA isolated from these samples were used for real-time RT-PCR of type X collagen (Col10alpha1), vascular endothelial growth factor (VEGF), and transforming growth factor beta1 (TGF beta1). RESULTS: Micro-CT showed increased inner part of cartilage end plate. Histologic revealed peripheral hypertrophy of disc after the surgery. Immunostaining and real-time RT-PCR showed increased protein and mRNA expression of type X collagen, VEGF, and TGF-beta1. CONCLUSION: Prolonged upright posture induces cartilage end plate calcification and hypertrophy in rat lumbar spine. PMID- 21304434 TI - Effects of minocycline on hind-limb motor function and gray and white matter injury after spinal cord ischemia in rats. AB - STUDY DESIGN: A prospective, randomized laboratory investigation. OBJECTIVE: To investigate whether administration of minocycline attenuates hind-limb motor dysfunction and gray and white matter injury after spinal cord ischemia. SUMMARY OF BACKGROUND DATA: Minocycline, a semisynthetic tetracycline antibiotic, has been shown to have neuroprotective effects in models of focal and global cerebral ischemia. However, there have been no data available regarding the effects of minocycline in a model of spinal cord ischemia. METHODS: Thirty-six rats were randomly allocated to one of three groups; control (C) group (n = 11), minocycline (M) group (n = 13), or sham group (n = 12). Minocycline or saline was intraperitoneally administered for 3 days beginning at 12 hours before 10 minutes of spinal cord ischemia or sham operation. Spinal cord ischemia was induced with intraaortic balloon catheter and blood withdrawal. Seventy-two hours after reperfusion, hind-limb motor functions were assessed using Basso, Beattie, Bresnahan (BBB) Scale (0 = paraplegia, 21 = normal). For histologic assessments, the gray and white matter injury was evaluated using the number of normal neurons and the extents of vacuolations in the white matter, respectively. Activated microglia was also evaluated using Iba-1 immunohistochemistry. RESULTS: BBB scores and the numbers of normal neurons in the M group were significantly higher than those in the C group. The percentage areas of vacuolations in the white matter and the number of Iba-1 positive cells were significantly lower in the M group compared with those in the C group. CONCLUSION: The results indicated that minocycline administration improved hind-limb motor function and attenuated gray and white matter injury and microglial activation after spinal cord ischemia in rats. PMID- 21304435 TI - Validity of surgeon perception of navigated pedicle screw position: a cadaveric study. AB - STUDY DESIGN: Human Cadaveric Experimental Study. OBJECTIVE: To determine the validity of surgeon perception of pedicle screw position inserted using intraoperative three-dimensional (O-arm) image-guided screw insertion. SUMMARY OF BACKGROUND DATA: A surgeon's ability to detect pedicle wall violations intraoperatively is crucial for optimal pedicle screw placement. Accuracy of use of a probe or sound to assess pedicle breach is not optimal and may require experience. Intraoperative navigation has been shown to improve screw placement accuracy. It has not been shown, however, whether navigation in combination with screw tract palpation can further increase the surgeon's ability to detect a pedicle breach in pedicle screw placement in the cervical, thoracic, and lumbosacral spine. METHODS: Four hundred eighteen screws were inserted using three-dimensional image guidance transpedicularly from C2 to S1 in 10 fresh frozen cadavers. Screw tracts were created using navigation and then probed. After probing, the surgeon stated whether he perceived that the screw would be in, out laterally, or out medially. After screw insertion for all the levels, open dissection was then performed to determine the actual pedicle screw position. The surgeon's perception of screw position was compared to the dissection results. RESULTS: The overall specificity, sensitivity, positive predictive value, and negative predictive value of the surgeon perception of pedicle screw position were 87%, 80%, 78% and 88%, respectively. Accuracy of surgeon perception of pedicle screw position was significantly less than in the cervical spine when compared with thoracic and lumbosacral spine. CONCLUSION: Surgeon perception of a navigated pedicle screw position is accurate in the thoracic and lumbar spine. Detection of pedicle screw violations by surgeon perception in the cervical spine is less accurate and does not reliably lead to accurate screw placement. PMID- 21304436 TI - Postural instability in early-stage idiopathic scoliosis in adolescent girls. AB - STUDY DESIGN: Cross-sectional study. OBJECTIVE: To evaluate whether the amplitude of spine deformation in adolescent idiopathic scoliosis (AIS) is an important factor for postural control at disease onset. SUMMARY OF BACKGROUND DATA: AIS is related to disorders of postural control with potential involvement of vestibular, proprioceptive, and visual input. So far no assessment of postural control has been done in an AIS population at the onset of spine deformation. METHODS: Sixty-five female patients with AIS (mean age: 11.4 +/- 2.3 years) were clinically and radiologically assessed at the time of diagnosis and evaluated in posturography, including static tests-with and without sensory conflict-and dynamic tests. Two groups were formed according to the mean Cobb angle of the primary curve. RESULTS: The mean Cobb angle was 14.8 degrees +/- 5.1 degrees ; 35 patients were included in group I with a Cobb angle of 5 degrees to 14 degrees , and 30 patients into group II with a Cobb angle of 15 degrees to 25 degrees . The latter group displayed higher body sways in static tests, characterized by a larger area covered by center of foot pressure in both eyes open and eyes closed conditions, and by higher lateral oscillations in only the eyes closed condition. Group II patients displayed poorer balance control, mainly in visual and somatosensory conflict conditions. Group II patients used fewer anticipatory strategies to stabilize body oscillations than Group I patients, especially in the more challenging sensory conflict and dynamic situations. CONCLUSION: Poorer postural performance, especially in sensory conflict situations, observed in patients with a Cobb angle greater or equal to 15 degrees , reflect less effective central information processing. PMID- 21304437 TI - Safety and effectiveness of bone allografts in anterior cervical discectomy and fusion surgery. AB - STUDY DESIGN: Systematic review. OBJECTIVE: The primary aim of this review was to evaluate clinical and radiographic outcomes in studies of anterior cervical discectomy and fusion (ACDF) using allograft versus ACDF with autograft, ACDF with cage devices, and cervical disc arthroplasty for the treatment of symptomatic cervical disc disease. SUMMARY OF BACKGROUND DATA: ACDF remains the standard of care for patients with cervical radiculopathy who are unresponsive to conservative medical care. However, no known study has compared patient outcomes after ACDF with allograft, ACDF with autograft, ACDF with cage, and disc arthroplasty. METHODS: After applying strict inclusion criteria, 21 comparisons from 20 studies formed the basis for this review. Patient outcomes included neck and arm pain, neck disability index (NDI), physical component summary (PCS), and mental component summary (MCS) scores from the SF-36, radiographic fusion rate, and select adverse events (e.g., wound infection, dysphagia, and adjacent segment degeneration). RESULTS: The four treatment groups included ACDF with allograft (allograft, n = 1341), ACDF with autograft (autograft, n = 568), ACDF with cage (cage, n = 87), and cervical disc arthroplasty (arthroplasty, n = 603). Neck pain was reduced similarly by 63% to 69% in all groups. Comparable improvements were realized in arm pain after ACDF with allograft (75%) or arthroplasty (73%) that were greater than other treatment groups (62-68%). There was notable improvement in neck disability (61-65%) with allograft and arthroplasty after treatment. PCS scores improved with allograft (42%) and arthroplasty (44%). MCS scores improved modestly (16-21%) with allograft and arthroplasty. Fusion rates were 91% for allograft and autograft and 97% for cage. Adverse events were uncommon in all groups. CONCLUSION: ACDF with allograft, ACDF with autograft, ACDF with cage, and cervical disc arthroplasty show similar improvements in pain, function, and quality of life with correspondingly low adverse event rates. All ACDF procedures result in high fusion rates. PMID- 21304438 TI - Intrawound application of vancomycin for prophylaxis in instrumented thoracolumbar fusions: efficacy, drug levels, and patient outcomes. AB - STUDY DESIGN: A retrospective cohort study from a single institution of a consecutive series of spine surgery patients. OBJECTIVE: To evaluate the safety and efficacy of adjunctive local application of vancomycin for infection prophylaxis in posterior instrumented thoracic and lumbar spine wounds compared to IV cephalexin alone. SUMMARY OF BACKGROUND DATA: Cephalosporin resistant strains of staphylococcus (MRSA and coagulase negative staph) have diminished the efficacy of intravenous antibiotic prophylaxis for instrumented spine fusion. Intravenous vancomycin prophylaxis has not been shown to decrease wound infection rates compared to IV cephalosporins. Adjunctive application of vancomycin powder in wounds for instrumented spinal fusion surgery may decrease infection rates. METHODS: Since 2000, 1732 consecutive thoracic and lumbar posterior instrumented spinal fusions have been performed with routine 24 hours of perioperative intravenous antibiotic prophylaxis with cephalexin. Since 2006, 911 of these instrumented thoracic and lumbar cases had 2 g of vancomycin powder applied to the wound before closure in addition to intravenous antibiotics. A retrospective review for infection rates and complications was performed. Oswestry and SF-36 outcomes instruments were completed before surgery, immediately after surgery, and at latest follow-up. The average follow-up is 2.5 years, range 1 to 7 years. RESULTS: Eight hundred twenty-one posterior instrumented thoracic and lumbar fusions were preformed using intravenous cephalexin prophylaxis with a total of 21 deep wound infections (2.6%). Coag negative staph was the most commonly isolated organism. Nine hundred eleven posterior instrumented thoracic and lumbar fusions have been performed with IV cephalexin plus adjunctive local vancomycin powder with two deep wound infections (0.2%). The reduction in wound infections was statistically significant (P < 0.0001). There were no adverse clinical outcomes or wound complications related to the local application of vancomycin. CONCLUSION: Adjunctive local application of vancomycin powder decreases the postsurgical wound infection rate with statistical significance in posterior instrumented thoracolumbar spine fusions. PMID- 21304439 TI - Evidence that FoxP3+ regulatory T cells may play a role in promoting long-term acceptance of composite tissue allotransplants. AB - BACKGROUND: FoxP3/CD4/CD25 regulatory T cells (Treg) play an important role in maintaining peripheral tolerance and are potent suppressors of T-cell activation. In this study, we evaluated the role of Treg in peripheral tolerance to composite tissue allografts (CTA). METHODS: Mixed allogeneic chimeric rats were prepared by preconditioning recipients with anti-alphabeta-T-cell receptor monoclonal antibody followed by total body irradiation. Animals received T-cell-depleted August Copenhagen Irish bone marrow cells followed by antilymphocyte serum and FK 506. A modified osteomyocutaneous hindlimb flap composed of bone and all limb tissue components was placed in animals with chimerism greater than or equal to 1% on day 28. Recipients with CTA surviving more than or equal to 6 months were evaluated for Treg. Skin samples from tolerant long-term allogeneic transplanted, syngeneic transplanted, rejected, and naive animals were immunostained with fluorochrome-conjugated anti-FoxP3 and anti-CD4 monoclonal antibody and visualized under a laser confocal microscope. RESULTS: Significant CD4/FoxP3 Treg infiltrates were observed in tolerant donor-allograft skin samples. No graft infiltrating FoxP3 cells were observed in rejector, naive, or skin from syngeneic CTA. In parallel experiments, mixed leukocyte reaction assays were performed to investigate the suppressor function of Treg cells. Splenocytes from tolerant, rejected, and naive rats were sorted by flow cytometry for CD4/CD25 T cells. Treg demonstrated similar suppressive levels between the three groups. CONCLUSIONS: These data suggest that Treg may play an important role in maintenance of tolerance and promoting graft acceptance in long-term CTA acceptors and may explain the favorable outcomes observed in clinical CTA recipients. PMID- 21304440 TI - MELD score less than 15 predicts prolonged survival after transjugular intrahepatic portosystemic shunt for refractory ascites after liver transplantation. AB - BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) is used in the management of refractory ascites (RA) and variceal bleeds. Little data exist on TIPS safety, efficacy, and survival after liver transplantation (LT). METHODS: We conducted a retrospective analysis of patients who underwent TIPS placement after LT for RA. Clinical success was defined as a reduction of portosystemic gradient (PSG) and resolution of RA. RESULTS: Twenty-six patients underwent TIPS. The most common indication for LT was hepatitis C virus (88%). Median time from LT to TIPS was 17 months (1-89 months). Median pre-TIPS model for end-stage liver disease (MELD) score was 15 (7-33). The median pre-TIPS PSG was 18 mm Hg (7-38 mm Hg). Median change in the PSG after TIPS was 11 mm Hg (1-27 mm Hg). Fifty-eight percent (15/26) of TIPS were considered clinically successful. Median post-TIPS patient survival was 15 months (1-109 months). Cumulative 1-year post-TIPS patient survival was 50%. On multivariate analysis, pre-TIPS MELD was a significant and independent predictor of patient survival (P<0.01). The 3- and 6 month patient mortality and graft loss for patients with a pre-TIPS MELD of more than or equal to 15 were significantly higher than those with a pre-TIPS MELD score of less than 15 (P<0.01). The overall median survival for patients with a pre-TIPS MELD score of more than or equal to 15 was 3 months (1-59 months) compared with 45 months (2-109 months) for patients with pre-TIPS MELD score of less than 15. CONCLUSIONS: TIPS after LT can be clinically effective in patients with RA with a MELD score less than 15. This suggests that TIPS could be used as a means to extend posttransplant survival but should be carefully individualized in patients with a MELD score more than or equal to 15. PMID- 21304441 TI - Sex differences in error-related performance monitoring. AB - We tested competing hypotheses for sex differences in performance monitoring using the error-related negativity and the posterror positivity components of the event-related potential (ERP). High-density ERPs were acquired while 100 female and 98 male partcipants completed a flanker task. Sexes did not differ in accuracy or posterror slowing, although females showed longer overall response times. Males showed increased amplitude error-related negativity and posterror positivity components relative to females; sexes did not differ on correct-trial ERPs. Sex differences remained in subgroups matched for depression and anxiety levels. Results indicate that participant sex should be considered in understanding the cognitive and emotional correlates of performance monitoring. PMID- 21304442 TI - Pegloticase (krystexxa) for treatment of refractory gout. PMID- 21304443 TI - In brief: benzonatate warning. PMID- 21304444 TI - Another extended-release alpha2-agonist for ADHD. PMID- 21304445 TI - In brief: pancreatic enzyme products. PMID- 21304446 TI - Drugs for Parkinson's disease. PMID- 21304447 TI - Drugs for migraine. PMID- 21304448 TI - Patient-centered rehabilitation, three years of gait recovery in a child affected by hemiplegia:. case report. AB - The aim of this report was to illustrate and to discuss a method capable of improving the person-oriented decision-making process during three years of gait rehabilitation based on the integration of: 1) the fundamental principles of motor learning and 2) the outcomes made available by both clinical standardized assessment tools (SAT) and measures made available by a gait analysis system (GA). The subject studied was a six-year-old child affected by hemiplegia after arterial ischemic stroke (AIS) who had limited upper and lower right-limb function but unaffected sensory and cognitive skills. Four different rehabilitative treatments were chosen when the child was inpatient or outpatient. Measurements of gait performance before and after selected treatments were evaluated using PEDI and GMFM (i.e., SAT) and kinematic and kinetic parameters (i.e., GA). Gait pattern and inter- and intralimb-joint coordination changed over time during the three examined years. However, after the first eight months of recovery, gait pattern modifications were detected by GA measures but not by SAT. The integration of SAT and GA findings, during the examined recovery evolution, resulted effective in the decision-making process for a person-oriented rehabilitative treatment. PMID- 21304449 TI - Effect of a cognitive task on postural control in patients with a clinically isolated syndrome suggestive of multiple sclerosis. AB - BACKGROUND: Patients with multiple sclerosis (MS) frequently experience poor postural control affecting mobility and/or cognitive impairment, even in the early stages of the disease. As postural control consumes attentional resources, it is essential to test stability during a cognitive task. AIM: To assess postural control and determine the effect of a cognitive task on balance in patients with a clinically isolated syndrome (CIS) suggestive of MS, within 3 months from onset. DESIGN: Observational case control study SETTING: Multiple Sclerosis Center and Institute of Motor Functions, Sheba Medical Center, Tel Hashomer, Israel POPULATION: Fifty-two CIS patients, aged 35.2+/-1.3 years, disease duration of 54+/-6.2 days and Expanded Disability Status Scale (EDSS) of 1.7+/-0.2, participated in the study. The control group consisted of 28 age and gender matched healthy subjects. METHODS: Stability was evaluated by the quantifying movement of the center of pressure (CoP) during standing under three conditions: eyes open, eyes closed, and while performing the modified Stroop test. Sway rate and CoP data was collected by a computerized force platform device. RESULTS: After combining major postural control parameters, only 50% of the patients performed normally. Differences in postural variables were found between patients and healthy subjects (P<0.01). Both sway rate and standard deviation of the CoP in all test conditions were significantly higher in patients compared to controls. The cognitive task resulted in an elevated sway rate both in CIS patients and the control group when compared with the eyes open task. Within 3 months of the onset of neurological symptomatology, postural instability was detected in 50% of CIS patients using a dedicated balance measurement device. CONCLUSION: As these findings are associated with the very early phase of MS, it appears that the ongoing pathological disease process is already taking place with regard to the balance control system. CLINICAL REHABILITATION IMPACT: Identification of postural abnormalities in the early stages is important in order to establish proper intervention programs. PMID- 21304451 TI - Analysis of Schwann-astrocyte interactions using in vitro assays. AB - Schwann cells are one of the commonly used cells in repair strategies following spinal cord injuries. Schwann cells are capable of supporting axonal regeneration and sprouting by secreting growth factors (1,2) and providing growth promoting adhesion molecules (3) and extracellular matrix molecules (4). In addition they myelinate the demyelinated axons at the site of injury (5). However following transplantation, Schwann cells do not migrate from the site of implant and do not intermingle with the host astrocytes (6,7). This results in formation of a sharp boundary between the Schwann cells and astrocytes, creating an obstacle for growing axons trying to exit the graft back into the host tissue proximally and distally. Astrocytes in contact with Schwann cells also undergo hypertrophy and up-regulate the inhibitory molecules (8-13). In vitro assays have been used to model Schwann cell-astrocyte interactions and have been important in understanding the mechanism underlying the cellular behaviour. These in vitro assays include boundary assay, where a co-culture is made using two different cells with each cell type occupying different territories with only a small gap separating the two cell fronts. As the cells divide and migrate, the two cellular fronts get closer to each other and finally collide. This allows the behaviour of the two cellular populations to be analyzed at the boundary. Another variation of the same technique is to mix the two cellular populations in culture and over time the two cell types segregate with Schwann cells clumped together as islands in between astrocytes together creating multiple Schwann-astrocyte boundaries. The second assay used in studying the interaction of two cell types is the migration assay where cellular movement can be tracked on the surface of the other cell type monolayer (14,15). This assay is commonly known as inverted coverslip assay. Schwann cells are cultured on small glass fragments and they are inverted face down onto the surface of astrocyte monolayers and migration is assessed from the edge of coverslip. Both assays have been instrumental in studying the underlying mechanisms involved in the cellular exclusion and boundary formation. Some of the molecules identified using these techniques include N-Cadherins 15, Chondroitin Sulphate proteoglycans(CSPGs) (16,17), FGF/Heparin (18), Eph/Ephrins(19). This article intends to describe boundary assay and migration assay in stepwise fashion and elucidate the possible technical problems that might occur. PMID- 21304452 TI - Electrophysiological recordings from the giant fiber pathway of D. melanogaster. AB - When startled adult D. melanogaster react by jumping into the air and flying away. In many invertebrate species, including D. melanogaster, the "escape" (or "startle") response during the adult stage is mediated by the multi-component neuronal circuit called the Giant Fiber System (GFS). The comparative large size of the neurons, their distinctive morphology and simple connectivity make the GFS an attractive model system for studying neuronal circuitry. The GFS pathway is composed of two bilaterally symmetrical Giant Fiber (GF) interneurons whose axons descend from the brain along the midline into the thoracic ganglion via the cervical connective. In the mesothoracic neuromere (T2) of the ventral ganglia the GFs form electro-chemical synapses with 1) the large medial dendrite of the ipsilateral motorneuron (TTMn) which drives the tergotrochanteral muscle (TTM), the main extensor for the mesothoracic femur/leg, and 2) the contralateral peripherally synapsing interneuron (PSI) which in turn forms chemical (cholinergic) synapses with the motorneurons (DLMns) of the dorsal longitudinal muscles (DLMs), the wing depressors. The neuronal pathway(s) to the dorsovental muscles (DVMs), the wing elevators, has not yet been worked out (the DLMs and DVMs are known jointly as indirect flight muscles - they are not attached directly to the wings, but rather move the wings indirectly by distorting the nearby thoracic cuticle) (King and Wyman, 1980; Allen et al., 2006). The di synaptic activation of the DLMs (via PSI) causes a small but important delay in the timing of the contraction of these muscles relative to the monosynaptic activation of TTM (~0.5 ms) allowing the TTMs to first extend the femur and propel the fly off the ground. The TTMs simultaneously stretch-activate the DLMs which in turn mutually stretch-activate the DVMs for the duration of the flight. The GF pathway can be activated either indirectly by applying a sensory (e.g."air puff" or "lights-off") stimulus, or directly by a supra-threshold electrical stimulus to the brain (described here). In both cases, an action potential reaches the TTMs and DLMs solely via the GFs, PSIs, and TTM/DLM motoneurons, although the TTMns and DLMns do have other, as yet unidentified, sensory inputs. Measuring "latency response" (the time between the stimulation and muscle depolarization) and the "following to high frequency stimulation" (the number of successful responses to a certain number of high frequency stimuli) provides a way to reproducibly and quantitatively assess the functional status of the GFS components, including both central synapses (GF-TTMn, GF-PSI, PSI-DLMn) and the chemical (glutamatergic) neuromuscular junctions (TTMn-TTM and DLMn-DLM). It has been used to identify genes involved in central synapse formation and to assess CNS function. PMID- 21304453 TI - Ex vivo expansion of tumor-reactive T cells by means of bryostatin 1/ionomycin and the common gamma chain cytokines formulation. AB - It was reported that breast cancer patients have pre-existing immune responses against their tumors(1,2). However, such immune responses fail to provide complete protection against the development or recurrence of breast cancer. To overcome this problem by increasing the frequency of tumor-reactive T cells, adoptive immunotherapy has been employed. A variety of protocols have been used for the expansion of tumor-specific T cells. These protocols, however, are restricted to the use of tumor antigens ex vivo for the activation of antigen specific T cells. Very recently, common gamma chain cytokines such as IL-2, IL-7, IL-15, and IL-21 have been used alone or in combination for the enhancement of anti-tumor immune responses(3). However, it is not clear what formulation would work best for the expansion of tumor-reactive T cells. Here we present a protocol for the selective activation and expansion of tumor-reactive T cells from the FVBN202 transgenic mouse model of HER-2/neu positive breast carcinoma for use in adoptive T cell therapy of breast cancer. The protocol includes activation of T cells with bryostatin-1/ionomycin (B/I) and IL-2 in the absence of tumor antigens for 16 hours. B/I activation mimics intracellular signals that result in T cell activation by increasing protein kinase C activity and intracellular calcium, respectively(4). This protocol specifically activates tumor-specific T cells while killing irrelevant T cells. The B/I-activated T cells are cultured with IL 7 and IL-15 for 24 hours and then pulsed with IL-2. After 24 hours, T cells are washed, split, and cultured with IL-7+IL-15 for additional 4 days. Tumor specificity and anti-tumor efficacy of the ex vivo expanded T cells is determined. PMID- 21304454 TI - Pseudomonas aeruginosa and Saccharomyces cerevisiae biofilm in flow cells. AB - Many microbial cells have the ability to form sessile microbial communities defined as biofilms that have altered physiological and pathological properties compared to free living microorganisms. Biofilms in nature are often difficult to investigate and reside under poorly defined conditions(1). Using a transparent substratum it is possible to device a system where simple biofilms can be examined in a non-destructive way in real-time: here we demonstrate the assembly and operation of a flow cell model system, for in vitro 3D studies of microbial biofilms generating high reproducibility under well-defined conditions(2,3). The system consists of a flow cell that serves as growth chamber for the biofilm. The flow cell is supplied with nutrients and oxygen from a medium flask via a peristaltic pump and spent medium is collected in a waste container. This construction of the flow system allows a continuous supply of nutrients and administration of e.g. antibiotics with minimal disturbance of the cells grown in the flow chamber. Moreover, the flow conditions within the flow cell allow studies of biofilm exposed to shear stress. A bubble trapping device confines air bubbles from the tubing which otherwise could disrupt the biofilm structure in the flow cell. The flow cell system is compatible with Confocal Laser Scanning Microscopy (CLSM) and can thereby provide highly detailed 3D information about developing microbial biofilms. Cells in the biofilm can be labeled with fluorescent probes or proteins compatible with CLSM analysis. This enables online visualization and allows investigation of niches in the developing biofilm. Microbial interrelationship, investigation of antimicrobial agents or the expression of specific genes, are of the many experimental setups that can be investigated in the flow cell system. PMID- 21304455 TI - Protein crystallization for X-ray crystallography. AB - Using the three-dimensional structure of biological macromolecules to infer how they function is one of the most important fields of modern biology. The availability of atomic resolution structures provides a deep and unique understanding of protein function, and helps to unravel the inner workings of the living cell. To date, 86% of the Protein Data Bank (rcsb-PDB) entries are macromolecular structures that were determined using X-ray crystallography. To obtain crystals suitable for crystallographic studies, the macromolecule (e.g. protein, nucleic acid, protein-protein complex or protein-nucleic acid complex) must be purified to homogeneity, or as close as possible to homogeneity. The homogeneity of the preparation is a key factor in obtaining crystals that diffract to high resolution (Bergfors, 1999; McPherson, 1999). Crystallization requires bringing the macromolecule to supersaturation. The sample should therefore be concentrated to the highest possible concentration without causing aggregation or precipitation of the macromolecule (usually 2-50 mg/mL). Introducing the sample to precipitating agent can promote the nucleation of protein crystals in the solution, which can result in large three-dimensional crystals growing from the solution. There are two main techniques to obtain crystals: vapor diffusion and batch crystallization. In vapor diffusion, a drop containing a mixture of precipitant and protein solutions is sealed in a chamber with pure precipitant. Water vapor then diffuses out of the drop until the osmolarity of the drop and the precipitant are equal (Figure 1A). The dehydration of the drop causes a slow concentration of both protein and precipitant until equilibrium is achieved, ideally in the crystal nucleation zone of the phase diagram. The batch method relies on bringing the protein directly into the nucleation zone by mixing protein with the appropriate amount of precipitant (Figure 1B). This method is usually performed under a paraffin/mineral oil mixture to prevent the diffusion of water out of the drop. Here we will demonstrate two kinds of experimental setup for vapor diffusion, hanging drop and sitting drop, in addition to batch crystallization under oil. PMID- 21304456 TI - A novel technique of rescuing capsulorhexis radial tear-out using a cystotome. AB - PART 1: PURPOSE: To demonstrate a capsulorhexis radial tear out rescue technique using a cystotome on a virtual reality cataract surgery simulator and in a human eye. PART 2: METHOD: Steps: When a capsulorhexis begins to veer radially towards the periphery beyond the pupillary margin the following steps should be applied without delay. 2.1) Stop further capsulorhexis manoeuvre and reassess the situation. 2.2) Fill the anterior chamber with ophthalmic viscosurgical device (OVD). We recommend mounting the cystotome to a syringe containing OVD so that the anterior chamber can be reinflated rapidly. 2.3) The capsulorhexis flap is then left unfolded on the lens surface. 2.4) The cystotome tip is tilted horizontally to avoid cutting or puncturing the flap and is engaged on the flap near the leading edge of the tear but not too close to the point of tear. 2.5) Gently push or pull the leading edge of tear opposite to the direction of tear. 2.6) The leading tearing edge will start to do a 'U-Turn'. Maintain the tension on the flap until the tearing edge returns to the desired trajectory. PART 3: RESULTS: Using our technique, a surgeon can respond instantly to radial tear out without having to change surgical instruments. Changing surgical instruments at this critical stage runs a risk of further radial tear due to sudden shallowing of anterior chamber as a result of forward pressure from the vitreous. Our technique also has the advantage of reducing corneal wound distortion and subsequent anterior chamber collapse. PART 4: DISCUSSION: The EYESI Surgical Simulator is a realistic training platform for surgeons to practice complex capsulorhexis tear-out techniques. Capsulorhexis is the most important and complex part of phacoemulsification and endocapsular intraocular lens implantation procedure. A successful cataract surgery depends on achieving a good capsulorhexis. During capsulorhexis, surgeons may face a challenging situation like a capsulorhexis radial tear-out. A surgeon must learn to tackle the problem promptly without making the situation worse. Some other methods of rescuing the situation have been described using a capsulorhexis forceps. However, we believe our method is quicker, more effective and easier to manipulate as demonstrated on the EYESi surgical simulator and on a human eye. PMID- 21304457 TI - A novel rescue technique for difficult intubation and difficult ventilation. AB - We describe a novel non surgical technique to maintain oxygenation and ventilation in a case of difficult intubation and difficult ventilation, which works especially well with poor mask fit. Can not intubate, can not ventilate" (CICV) is a potentially life threatening situation. In this video we present a simulation of the technique we used in a case of CICV where oxygenation and ventilation were maintained by inserting an endotracheal tube (ETT) nasally down to the level of the naso-pharynx while sealing the mouth and nares for successful positive pressure ventilation. A 13 year old patient was taken to the operating room for incision and drainage of a neck abscess and direct laryngobronchoscopy. After preoxygenation, anesthesia was induced intravenously. Mask ventilation was found to be extremely difficult because of the swelling of the soft tissue. The face mask could not fit properly on the face due to significant facial swelling as well. A direct laryngoscopy was attempted with no visualization of the larynx. Oxygen saturation was difficult to maintain, with saturations falling to 80%. In order to oxygenate and ventilate the patient, an endotracheal tube was then inserted nasally after nasal spray with nasal decongestant and lubricant. The tube was pushed gently and blindly into the hypopharynx. The mouth and nose of the patient were sealed by hand and positive pressure ventilation was possible with 100% O2 with good oxygen saturation during that period of time. Once the patient was stable and well sedated, a rigid bronchoscope was introduced by the otolaryngologist showing extensive subglottic and epiglottic edema, and a mass effect from the abscess, contributing to the airway compromise. The airway was secured with an ETT tube by the otolaryngologist.This video will show a simulation of the technique on a patient undergoing general anesthesia for dental restorations. PMID- 21304458 TI - Guidelines for elective pediatric fiberoptic intubation. AB - Fiberoptic intubation in pediatric patients is often required especially in difficult airways of syndromic patients i.e. Pierre Robin Syndrome. Small babies will desaturate very quickly if ventilation is interrupted mainly to high metabolic rate. We describe guidelines to perform a safe fiberoptic intubation while maintaining spontaneous breathing throughout the procedure. Steps requiring the use of propofol pump, fentanyl, glycopyrrolate, red rubber catheter, metal insuflation hook, afrin, lubricant and lidocaine spray are shown. PMID- 21304460 TI - Physiological experimentation with the crayfish hindgut: a student laboratory exercise. AB - The purpose of the report is to describe dissection techniques for preparing the crayfish hindgut and to demonstrate how to make physiological recordings with a force transducer to monitor the strength of contraction. In addition, we demonstrate how to visually monitor peristaltic activity, which can be used as a bioassay for various peptides, biogenic amines and neurotransmitters. This preparation is amenable to student laboratories in physiology and for demonstrating pharmacological concepts to students. This preparation has been in use for over 100 years, and it still offers much as a model for investigating the generation and regulation of peristaltic rhythms and for describing the mechanisms underlying their modulation. The pharmacological assays and receptor sub-typing that were started over 50 years ago on the hindgut still contribute to research today. This robust preparation is well suited to training students in physiology and pharmacology. PMID- 21304459 TI - Membrane potentials, synaptic responses, neuronal circuitry, neuromodulation and muscle histology using the crayfish: student laboratory exercises. AB - The purpose of this report is to help develop an understanding of the effects caused by ion gradients across a biological membrane. Two aspects that influence a cell's membrane potential and which we address in these experiments are: (1) Ion concentration of K+ on the outside of the membrane, and (2) the permeability of the membrane to specific ions. The crayfish abdominal extensor muscles are in groupings with some being tonic (slow) and others phasic (fast) in their biochemical and physiological phenotypes, as well as in their structure; the motor neurons that innervate these muscles are correspondingly different in functional characteristics. We use these muscles as well as the superficial, tonic abdominal flexor muscle to demonstrate properties in synaptic transmission. In addition, we introduce a sensory-CNS-motor neuron-muscle circuit to demonstrate the effect of cuticular sensory stimulation as well as the influence of neuromodulators on certain aspects of the circuit. With the techniques obtained in this exercise, one can begin to answer many questions remaining in other experimental preparations as well as in physiological applications related to medicine and health. We have demonstrated the usefulness of model invertebrate preparations to address fundamental questions pertinent to all animals. PMID- 21304461 TI - Modeling biological membranes with circuit boards and measuring electrical signals in axons: student laboratory exercises. AB - This is a demonstration of how electrical models can be used to characterize biological membranes. This exercise also introduces biophysical terminology used in electrophysiology. The same equipment is used in the membrane model as on live preparations. Some properties of an isolated nerve cord are investigated: nerve action potentials, recruitment of neurons, and responsiveness of the nerve cord to environmental factors. PMID- 21304462 TI - In vivo quantification of G protein coupled receptor interactions using spectrally resolved two-photon microscopy. AB - The study of protein interactions in living cells is an important area of research because the information accumulated both benefits industrial applications as well as increases basic fundamental biological knowledge. Forster (Fluorescence) Resonance Energy Transfer (FRET) between a donor molecule in an electronically excited state and a nearby acceptor molecule has been frequently utilized for studies of protein-protein interactions in living cells. The proteins of interest are tagged with two different types of fluorescent probes and expressed in biological cells. The fluorescent probes are then excited, typically using laser light, and the spectral properties of the fluorescence emission emanating from the fluorescent probes is collected and analyzed. Information regarding the degree of the protein interactions is embedded in the spectral emission data. Typically, the cell must be scanned a number of times in order to accumulate enough spectral information to accurately quantify the extent of the protein interactions for each region of interest within the cell. However, the molecular composition of these regions may change during the course of the acquisition process, limiting the spatial determination of the quantitative values of the apparent FRET efficiencies to an average over entire cells. By means of a spectrally resolved two-photon microscope, we are able to obtain a full set of spectrally resolved images after only one complete excitation scan of the sample of interest. From this pixel-level spectral data, a map of FRET efficiencies throughout the cell is calculated. By applying a simple theory of FRET in oligomeric complexes to the experimentally obtained distribution of FRET efficiencies throughout the cell, a single spectrally resolved scan reveals stoichiometric and structural information about the oligomer complex under study. Here we describe the procedure of preparing biological cells (the yeast Saccharomyces cerevisiae) expressing membrane receptors (sterile 2 alpha-factor receptors) tagged with two different types of fluorescent probes. Furthermore, we illustrate critical factors involved in collecting fluorescence data using the spectrally resolved two-photon microscopy imaging system. The use of this protocol may be extended to study any type of protein which can be expressed in a living cell with a fluorescent marker attached to it. PMID- 21304463 TI - Optimized transfection strategy for expression and electrophysiological recording of recombinant voltage-gated ion channels in HEK-293T cells. AB - The in vitro expression and electrophysiological recording of recombinant voltage gated ion channels in cultured human embryonic kidney cells (HEK-293T) is a ubiquitous research strategy. HEK-293T cells must be plated onto glass coverslips at low enough density so that they are not in contact with each other in order to allow for electrophysiological recording without confounding effects due to contact with adjacent cells. Transfected channels must also express with high efficiency at the plasma membrane for whole-cell patch clamp recording of detectable currents above noise levels. Heterologous ion channels often require long incubation periods at 28 degrees C after transfection in order to achieve adequate membrane expression, but there are increasing losses of cell-coverslip adhesion and membrane stability at this temperature. To circumvent this problem, we developed an optimized strategy to transfect and plate HEK-293T cells. This method requires that cells be transfected at a relatively high confluency, and incubated at 28 degrees C for varying incubation periods post-transfection to allow for adequate ion channel protein expression. Transfected cells are then plated onto glass coverslips and incubated at 37 degrees C for several hours, which allows for rigid cell attachment to the coverslips and membrane restabilization. Cells can be recorded shortly after plating, or can be transferred to 28 degrees C for further incubation. We find that the initial incubation at 28 degrees C, after transfection but before plating, is key for the efficient expression of heterologous ion channels that normally do not express well at the plasma membrane. Positively transfected, cultured cells are identified by co-expressed eGFP or eGFP expressed from a bicistronic vector (e.g. pIRES2-EGFP) containing the recombinant ion channel cDNA just upstream of an internal ribosome entry site and an eGFP coding sequence. Whole-cell patch clamp recording requires specialized equipment, plus the crafting of polished recording electrodes and L-shaped ground electrodes from borosilicate glass. Drug delivery to study the pharmacology of ion channels can be achieved by directly micropipetting drugs into the recording dish, or by using microperfusion or gravity flow systems that produce uninterrupted streams of drug solution over recorded cells. PMID- 21304464 TI - In vitro biofilm formation in an 8-well chamber slide. AB - The chronic nature of many diseases is attributed to the formation of bacterial biofilms which are recalcitrant to traditional antibiotic therapy. Biofilms are community-associated bacteria attached to a surface and encased in a matrix. The role of the extracellular matrix is multifaceted, including facilitating nutrient acquisition, and offers significant protection against environmental stresses (e.g. host immune responses). In an effort to acquire a better understanding as to how the bacteria within a biofilm respond to environmental stresses we have used a protocol wherein we visualize bacterial biofilms which have formed in an 8 well chamber slide. The biofilms were stained with the BacLight Live/Dead stain and examined using a confocal microscope to characterize the relative biofilm size, and structure under varying incubation conditions. Z-stack images were collected via confocal microscopy and analyzed by COMSTAT. This protocol can be used to help elucidate the mechanism and kinetics by which biofilms form, as well as identify components that are important to biofilm structure and stability. PMID- 21304465 TI - RNA interference in ticks. AB - Ticks are obligate hematophagous ectoparasites of wild and domestic animals and humans, and are considered to be second worldwide to mosquitoes as vectors of human diseases(1) and the most important vectors affecting cattle industry worldwide(2). Ticks are classified in the subclass Acari, order Parasitiformes, suborder Ixodida and are distributed worldwide from Arctic to tropical regions(3). Despite efforts to control tick infestations, these ectoparasites remain a serious problem for human and animal health(4,5). RNA interference (RNAi)(6) is a nucleic acid-based reverse genetic approach that involves disruption of gene expression in order to determine gene function or its effect on a metabolic pathway. Small interfering RNAs (siRNAs) are the effector molecules of the RNAi pathway that is initiated by double-stranded RNA (dsRNA) and results in a potent sequence-specific degradation of cytoplasmic mRNAs containing the same sequence as the dsRNA trigger(7-9). Post-transcriptional gene silencing mechanisms initiated by dsRNA have been discovered in all eukaryotes studied thus far, and RNAi has been rapidly developed in a variety of organisms as a tool for functional genomics studies and other applications(10). RNAi has become the most widely used gene-silencing technique in ticks and other organisms where alternative approaches for genetic manipulation are not available or are unreliable(5,11). The genetic characterization of ticks has been limited until the recent application of RNAi(12,13). In the short time that RNAi has been available, it has proved to be a valuable tool for studying tick gene function, the characterization of the tick-pathogen interface and the screening and characterization of tick protective antigens(14). Herein, a method for RNAi through injection of dsRNA into unfed ticks is described. It is likely that the knowledge gained from this experimental approach will contribute markedly to the understanding of basic biological systems and the development of vaccines to control tick infestations and prevent transmission of tick-borne pathogens(15 19). PMID- 21304466 TI - Electrospinning fundamentals: optimizing solution and apparatus parameters. AB - Electrospun nanofiber scaffolds have been shown to accelerate the maturation, improve the growth, and direct the migration of cells in vitro. Electrospinning is a process in which a charged polymer jet is collected on a grounded collector; a rapidly rotating collector results in aligned nanofibers while stationary collectors result in randomly oriented fiber mats. The polymer jet is formed when an applied electrostatic charge overcomes the surface tension of the solution. There is a minimum concentration for a given polymer, termed the critical entanglement concentration, below which a stable jet cannot be achieved and no nanofibers will form - although nanoparticles may be achieved (electrospray). A stable jet has two domains, a streaming segment and a whipping segment. While the whipping jet is usually invisible to the naked eye, the streaming segment is often visible under appropriate lighting conditions. Observing the length, thickness, consistency and movement of the stream is useful to predict the alignment and morphology of the nanofibers being formed. A short, non-uniform, inconsistent, and/or oscillating stream is indicative of a variety of problems, including poor fiber alignment, beading, splattering, and curlicue or wavy patterns. The stream can be optimized by adjusting the composition of the solution and the configuration of the electrospinning apparatus, thus optimizing the alignment and morphology of the fibers being produced. In this protocol, we present a procedure for setting up a basic electrospinning apparatus, empirically approximating the critical entanglement concentration of a polymer solution and optimizing the electrospinning process. In addition, we discuss some common problems and troubleshooting techniques. PMID- 21304467 TI - A microfluidic-based hydrodynamic trap for single particles. AB - The ability to confine and manipulate single particles in free solution is a key enabling technology for fundamental and applied science. Methods for particle trapping based on optical, magnetic, electrokinetic, and acoustic techniques have led to major advancements in physics and biology ranging from the molecular to cellular level. In this article, we introduce a new microfluidic-based technique for particle trapping and manipulation based solely on hydrodynamic fluid flow. Using this method, we demonstrate trapping of micro- and nano-scale particles in aqueous solutions for long time scales. The hydrodynamic trap consists of an integrated microfluidic device with a cross-slot channel geometry where two opposing laminar streams converge, thereby generating a planar extensional flow with a fluid stagnation point (zero-velocity point). In this device, particles are confined at the trap center by active control of the flow field to maintain particle position at the fluid stagnation point. In this manner, particles are effectively trapped in free solution using a feedback control algorithm implemented with a custom-built LabVIEW code. The control algorithm consists of image acquisition for a particle in the microfluidic device, followed by particle tracking, determination of particle centroid position, and active adjustment of fluid flow by regulating the pressure applied to an on-chip pneumatic valve using a pressure regulator. In this way, the on-chip dynamic metering valve functions to regulate the relative flow rates in the outlet channels, thereby enabling fine scale control of stagnation point position and particle trapping. The microfluidic-based hydrodynamic trap exhibits several advantages as a method for particle trapping. Hydrodynamic trapping is possible for any arbitrary particle without specific requirements on the physical or chemical properties of the trapped object. In addition, hydrodynamic trapping enables confinement of a "single" target object in concentrated or crowded particle suspensions, which is difficult using alternative force field-based trapping methods. The hydrodynamic trap is user-friendly, straightforward to implement and may be added to existing microfluidic devices to facilitate trapping and long-time analysis of particles. Overall, the hydrodynamic trap is a new platform for confinement, micromanipulation, and observation of particles without surface immobilization and eliminates the need for potentially perturbative optical, magnetic, and electric fields in the free-solution trapping of small particles. PMID- 21304468 TI - Generation of comprehensive thoracic oncology database--tool for translational research. AB - The Thoracic Oncology Program Database Project was created to serve as a comprehensive, verified, and accessible repository for well-annotated cancer specimens and clinical data to be available to researchers within the Thoracic Oncology Research Program. This database also captures a large volume of genomic and proteomic data obtained from various tumor tissue studies. A team of clinical and basic science researchers, a biostatistician, and a bioinformatics expert was convened to design the database. Variables of interest were clearly defined and their descriptions were written within a standard operating manual to ensure consistency of data annotation. Using a protocol for prospective tissue banking and another protocol for retrospective banking, tumor and normal tissue samples from patients consented to these protocols were collected. Clinical information such as demographics, cancer characterization, and treatment plans for these patients were abstracted and entered into an Access database. Proteomic and genomic data have been included in the database and have been linked to clinical information for patients described within the database. The data from each table were linked using the relationships function in Microsoft Access to allow the database manager to connect clinical and laboratory information during a query. The queried data can then be exported for statistical analysis and hypothesis generation. PMID- 21304469 TI - Dissection of human vitreous body elements for proteomic analysis. AB - The vitreous is an optically clear, collagenous extracellular matrix that fills the inside of the eye and overlies the retina. (1,2) Abnormal interactions between vitreous substructures and the retina underlie several vitreoretinal diseases, including retinal tear and detachment, macular pucker, macular hole, age-related macular degeneration, vitreomacular traction, proliferative vitreoretinopathy, proliferative diabetic retinopathy, and inherited vitreoretinopathies. (1,2) The molecular composition of the vitreous substructures is not known. Since the vitreous body is transparent with limited surgical access, it has been difficult to study its substructures at the molecular level. We developed a method to separate and preserve these tissues for proteomic and biochemical analysis. The dissection technique in this experimental video shows how to isolate vitreous base, anterior hyaloid, vitreous core, and vitreous cortex from postmortem human eyes. One-dimensional SDS-PAGE analyses of each vitreous component showed that our dissection technique resulted in four unique protein profiles corresponding to each substructure of the human vitreous body. Identification of differentially compartmentalized proteins will reveal candidate molecules underlying various vitreoretinal diseases. PMID- 21304470 TI - Behavioural pharmacology in classical conditioning of the proboscis extension response in honeybees (Apis mellifera). AB - Honeybees (Apis mellifera) are well known for their communication and orientation skills and for their impressive learning capability(1,2). Because the survival of a honeybee colony depends on the exploitation of food sources, forager bees learn and memorize variable flower sites as well as their profitability. Forager bees can be easily trained in natural settings where they forage at a feeding site and learn the related signals such as odor or color. Appetitive associative learning can also be studied under controlled conditions in the laboratory by conditioning the proboscis extension response (PER) of individually harnessed honeybees(3,4). This learning paradigm enables the study of the neuronal and molecular mechanisms that underlie learning and memory formation in a simple and highly reliable way(5 12). A behavioral pharmacology approach is used to study molecular mechanisms. Drugs are injected systemically to interfere with the function of specific molecules during or after learning and memory formation(13-16). Here we demonstrate how to train harnessed honeybees in PER conditioning and how to apply drugs systemically by injection into the bee flight muscle. PMID- 21304471 TI - Nucleofection and primary culture of embryonic mouse hippocampal and cortical neurons. AB - Hippocampal and cortical neurons have been used extensively to study central nervous system (CNS) neuronal polarization, axon/dendrite outgrowth, and synapse formation and function. An advantage of culturing these neurons is that they readily polarize, forming distinctive axons and dendrites, on a two dimensional substrate at very low densities. This property has made them extremely useful for determining many aspects of neuronal development. Furthermore, by providing glial conditioning for these neurons they will continue to develop, forming functional synaptic connections and surviving for several months in culture. In this protocol we outline a technique to dissect, culture and transfect embryonic mouse hippocampal and cortical neurons. Transfection is accomplished by electroporating DNA into the neurons before plating via nucleofection. This protocol has the advantage of expressing fluorescently-tagged fusion proteins early in development (~4-8 hrs after plating) to study the dynamics and function of proteins during polarization, axon outgrowth and branching. We have also discovered that this single transfection before plating maintains fluorescently-tagged fusion protein expression at levels appropriate for imaging throughout the lifetime of the neuron (>2 months in culture). Thus, this methodology is useful for studying protein localization and function throughout CNS development with little or no disruption of neuronal function. PMID- 21304472 TI - An analytical tool-box for comprehensive biochemical, structural and transcriptome evaluation of oral biofilms mediated by mutans streptococci. AB - Biofilms are highly dynamic, organized and structured communities of microbial cells enmeshed in an extracellular matrix of variable density and composition (1, 2). In general, biofilms develop from initial microbial attachment on a surface followed by formation of cell clusters (or microcolonies) and further development and stabilization of the microcolonies, which occur in a complex extracellular matrix. The majority of biofilm matrices harbor exopolysaccharides (EPS), and dental biofilms are no exception; especially those associated with caries disease, which are mostly mediated by mutans streptococci (3). The EPS are synthesized by microorganisms (S. mutans, a key contributor) by means of extracellular enzymes, such as glucosyltransferases using sucrose primarily as substrate (3). Studies of biofilms formed on tooth surfaces are particularly challenging owing to their constant exposure to environmental challenges associated with complex diet-host-microbial interactions occurring in the oral cavity. Better understanding of the dynamic changes of the structural organization and composition of the matrix, physiology and transcriptome/proteome profile of biofilm-cells in response to these complex interactions would further advance the current knowledge of how oral biofilms modulate pathogenicity. Therefore, we have developed an analytical tool-box to facilitate biofilm analysis at structural, biochemical and molecular levels by combining commonly available and novel techniques with custom-made software for data analysis. Standard analytical (colorimetric assays, RT-qPCR and microarrays) and novel fluorescence techniques (for simultaneous labeling of bacteria and EPS) were integrated with specific software for data analysis to address the complex nature of oral biofilm research. The tool-box is comprised of 4 distinct but interconnected steps (Figure 1): 1) Bioassays, 2) Raw Data Input, 3) Data Processing, and 4) Data Analysis. We used our in vitro biofilm model and specific experimental conditions to demonstrate the usefulness and flexibility of the tool box. The biofilm model is simple, reproducible and multiple replicates of a single experiment can be done simultaneously (4, 5). Moreover, it allows temporal evaluation, inclusion of various microbial species (5) and assessment of the effects of distinct experimental conditions (e.g. treatments (6); comparison of knockout mutants vs. parental strain (5); carbohydrates availability (7)). Here, we describe two specific components of the tool-box, including (i) new software for microarray data mining/organization (MDV) and fluorescence imaging analysis (DUOSTAT), and (ii) in situ EPS-labeling. We also provide an experimental case showing how the tool-box can assist with biofilms analysis, data organization, integration and interpretation. PMID- 21304473 TI - Diagnostic and therapeutic strategies for small abdominal aortic aneurysms. AB - Abdominal aortic aneurysms (AAA) affect 5% of the population in developed countries and are characterized by progressive aortic dilatation with an unpredictable time course. This condition is more common in men than in women, and in smokers than in nonsmokers. If left untreated, AAA can result in aortic rupture and death. Pathologically, aortic extracellular matrix degradation, inflammation, and neovascularization are hallmarks of AAA. Diagnosis of AAA and subsequent surveillance utilize established aortic imaging methods, such as ultrasound, CT, and MRI. More-speculative diagnostic approaches include molecular and cellular imaging methods that interrogate the underlying pathological processes at work within the aneurysm. In this Review, we explore the current diagnostic and therapeutic strategies for the management of AAA. We also describe the diagnostic potential of new imaging techniques and therapeutic potential of new treatments for the management of small AAA. PMID- 21304474 TI - HDL and cardiovascular disease: atherogenic and atheroprotective mechanisms. AB - The lipoprotein HDL has two important roles: first, it promotes reverse cholesterol transport, and second, it modulates inflammation. Epidemiological studies show that HDL-cholesterol levels are inversely correlated with the risk of cardiovascular events. However, many patients who experience a clinical event have normal, or even high, levels of HDL cholesterol. Measuring HDL-cholesterol levels provides information about the size of the HDL pool, but does not predict HDL composition or function. The main component of HDL, apolipoprotein A-I (apo A I), is largely responsible for reverse cholesterol transport through the macrophage ATP-binding cassette transporter ABCA1. Apo A-I can be damaged by oxidative mechanisms, which render the protein less able to promote cholesterol efflux. HDL also contains a number of other proteins that are affected by the oxidative environment of the acute-phase response. Modification of the protein components of HDL can convert it from an anti-inflammatory to a proinflammatory particle. Small peptides that mimic some of the properties of apo A-I have been shown in preclinical models to improve HDL function and reduce atherosclerosis without altering HDL-cholesterol levels. Robust assays to evaluate the function of HDL are needed to supplement the measurement of HDL-cholesterol levels in the clinic. PMID- 21304475 TI - The clinical significance of pancreatic steatosis. AB - More research is now focused on pancreatic steatosis. Multiple definitions, clinical associations and synonyms for pancreatic steatosis are described in the literature and can be confusing. The integration and comparison of several studies concerning this topic is therefore challenging. In the past, pancreatic steatosis was considered an innocuous condition, a bystander of many underlying diseases (such as congenital syndromes, hemochromatosis and viral infection). However, evidence that pancreatic steatosis (strongly associated with obesity and the metabolic syndrome) has a role in type 2 diabetes mellitus, pancreatic exocrine dysfunction, acute pancreatitis, pancreatic cancer and the formation of pancreatic fistula after pancreatic surgery is emerging. This Review focuses on the different etiological factors and the clinical consequences of pancreatic steatosis. PMID- 21304477 TI - IBD: measuring what counts-safety of IBD medications in pregnancy. AB - Uncertainty about the risks of medications for IBD during pregnancy is a challenge for clinicians and patients. a recent prospective cohort study suggests that women under medical care for their disease have few adverse events. PMID- 21304476 TI - The role of bacteria and pattern-recognition receptors in Crohn's disease. AB - Crohn's disease is widely regarded as a multifactorial disease, and evidence from human and animal studies suggests that bacteria have an instrumental role in its pathogenesis. Comparison of the intestinal microbiota of patients with Crohn's disease to that of healthy controls has revealed compositional changes. In most studies these changes are characterized by an increase in the abundance of Bacteroidetes and Proteobacteria and a decrease in that of Firmicutes. In addition, a number of specific mucosa-associated bacteria have been postulated to have a role in Crohn's disease, including Mycobacterium avium subspecies paratuberculosis, adherent and invasive Escherichia coli, Campylobacter and Helicobacter species. The association between mutations in pattern-recognition receptors (Toll-like receptors and Nod-like receptors) and autophagy proteins and Crohn's disease provides further evidence to suggest that defective sensing and killing of bacteria may drive the onset of disease. In this Review, we present recent advances in understanding the role of bacteria and the contribution of pattern-recognition receptors and autophagy in the pathogenesis of Crohn's disease. PMID- 21304478 TI - Vaccinating against Helicobacter pylori infection. AB - Helicobacter pylori infection of the gastric mucosa remains a cause of significant morbidity and mortality almost 30 years after its discovery. H. pylori infection can lead to several gastric maladies, including gastric cancer, and although antimicrobial therapies for the infection exist, the cost of treatment for gastric cancer and the prognosis of individuals who present with this disease make vaccine development a cost effective alternative to bacterial eradication. Experimental mucosal and systemic H. pylori vaccines in mice significantly reduce bacterial load and sometimes provide sterilizing immunity. Clinical trials of oral vaccines consisting of H. pylori proteins with bacterial exotoxin adjuvants or live attenuated bacterial vectors expressing H. pylori proteins induce adaptive immune mechanisms but fail to consistently reduce bacterial load. Clinical trials and murine studies demonstrate that where H. pylori is killed, either spontaneously or following vaccination, the host demonstrated cellular immunity. Improved efficacy of vaccines may be achieved in new trials of vaccine formulations that include multiple antigens and use methods to optimize cellular immunity. Unfortunately, the industrial sponsors that served as the primary engine for much of the previous animal and human research have withdrawn their support. A renewed or expanded commitment from the biotechnology or pharmaceutical industry that could exploit recent advances in our understanding of the host immune response to H. pylori is necessary for the advancement of an H. pylori vaccine. PMID- 21304479 TI - IBD: of mice and men-shedding new light on IL-13 activity in IBD. AB - a recent study in a mouse model of colitis has demonstrated that interleukin (Il) 13, through inhibition of the mixed type 1 and type 17 T-helper cell inflammatory response, has a protective effect. the decoyreceptor Il-13ralpha2 inhibits this protective effect, suggesting blockade of Il-13ralpha2 as a potential therapy for patients with IBD. PMID- 21304482 TI - Brain hemorrhage: restarting anticoagulation after intracranial hemorrhage. PMID- 21304480 TI - Epidemiology of Alzheimer disease. AB - The global prevalence of dementia is estimated to be as high as 24 million, and is predicted to double every 20 years through to 2040, leading to a costly burden of disease. Alzheimer disease (AD) is the leading cause of dementia and is characterized by a progressive decline in cognitive function, which typically begins with deterioration in memory. Before death, individuals with this disorder have usually become dependent on caregivers. The neuropathological hallmarks of the AD brain are diffuse and neuritic extracellular amyloid plaques-which are frequently surrounded by dystrophic neurites-and intracellular neurofibrillary tangles. These hallmark pathologies are often accompanied by the presence of reactive microgliosis and the loss of neurons, white matter and synapses. The etiological mechanisms underlying the neuropathological changes in AD remain unclear, but are probably affected by both environmental and genetic factors. Here, we provide an overview of the criteria used in the diagnosis of AD, highlighting how this disease is related to, but distinct from, normal aging. We also summarize current information relating to AD prevalence, incidence and risk factors, and review the biomarkers that may be used for risk assessment and in diagnosis. PMID- 21304481 TI - Can neuroimaging studies identify pain endophenotypes in humans? AB - Pain is a complex, multidimensional experience that has defied our understanding for centuries. Through the advent of noninvasive neuroimaging techniques, we have been able to examine the human brain and its response to nociceptive inputs. As a result, our knowledge of which brain regions are critical for generating an acute pain experience has grown, as has our understanding of how cognitive, emotional, contextual and various physiological factors influence the pain experience. Furthermore, we have been able to identify key processes within the brain that underpin the transition to and maintenance of chronic pain states, as well as highlight the dramatic consequences of chronic pain on the brain's structure and neurochemistry. Building upon this knowledge, we are now in a position to consider whether any of these brain imaging 'phenotypes' of acute or chronic pain should be considered as useful endophenotypes; thereby enabling us to relate the complex genetics that underpin everyday pain sensitivity or chronic pain states to intermediate biomarkers. This endophenotypic approach-the focus of this Review simplifies the connection between genes and behavior and is needed for complex disorders like chronic pain. PMID- 21304483 TI - Brain hemorrhage: clinical high-risk factors for subarachnoid hemorrhage. PMID- 21304485 TI - Genetic variants near the MGAT1 gene are associated with body weight, BMI and fatty acid metabolism among adults and children. AB - OBJECTIVE: Recently a genome-wide association analysis from five European populations identified a polymorphism located downstream of the mannosyl-(alpha 1,3)-glycoprotein-beta-1,2-N-acetylglucosaminyltransferase (MGAT1) gene that was associated with body-weight. In the present study, associations between MGAT1 variants combined with obesity and insulin measurements were investigated in three cohorts. Levels of fatty acids and estimated measures of Delta desaturases were also investigated among adult men. DESIGN: Six polymorphisms downstream of MGAT1 were genotyped in a cross-sectional cohort of 1152 Swedish men. Three polymorphisms were further analyzed in a case-control study of 1076 Swedish children and in a cross-sectional study of 2249 Greek children. RESULTS: Three polymorphisms, rs12186500 (odds ratio (OR): 1.892, 95% confidence interval (CI): 1.237-2.895, P=0.003), rs1021001 (OR: 2.102, 95% CI: 1.280-3.455, P=0.003) and rs4285184 (OR: 1.587, 95% CI: 1.024-2.459, P=0.038) were associated with a higher prevalence of obesity among the adult men and a trend for obesity was observed for rs4285184 among the Swedish (OR: 1.205, 95% CI: 0.987-1.471, P=0.067) and Greek children (OR: 1.192, 95%CI: 0.978-1.454, P=0.081). Association with body weight was observed for rs12186500 (P=0.017) and rs4285184 (P=0.024) among the men. The rs1021001 and rs4285184 were also associated with body mass index (BMI) in the two Swedish cohorts and similar trends were observed among the Greek children. The combined effect size for rs1021001 and rs4285184 on BMI z-score from a meta-analysis was 0.233 (95% CI:0.093-0.373, P=0.001) and 0.147 (95% CI:0.057-0.236, P=0.001), respectively. We further observed associations between the genetic variants and fatty acids (P<0.039) and estimated measures of Delta desaturases (P<0.040), as well as interactions for rs12186500 (P<0.019) with an effect on BMI. No association was found with homeostatic model assessment-insulin resistance in any cohort but increased insulin levels, insulin response and decreased insulin sensitivity were observed among the children (P<0.038). CONCLUSION: Genetic variants downstream MGAT1 seem to influence susceptibility to obesity. Moreover, these genetic variants affect the levels of serum unsaturated fatty acids and Delta desaturase indices, variables previously shown to correlate with obesity. PMID- 21304484 TI - The neurobiology of cognitive disorders in temporal lobe epilepsy. AB - Cognitive impairment, particularly memory disruption, is a major complicating feature of epilepsy. This Review will begin with a focus on the problem of memory impairment in temporal lobe epilepsy (TLE). We present a brief overview of anatomical substrates of memory disorders in TLE, followed by a discussion of how our understanding of these disorders has been improved by studying the outcomes of anterior temporal lobectomy. The clinical efforts made to predict which patients are at greatest risk of experiencing adverse cognitive outcomes following epilepsy surgery are also considered. Finally, we examine the vastly changing view of TLE, including findings demonstrating that anatomical abnormalities extend far outside the temporal lobe, and that cognitive impairments extend beyond memory function. Linkage between these distributed cognitive and anatomical abnormalities point to a new understanding of the anatomical architecture of cognitive impairment in epilepsy. Clarifying the origin of these cognitive and anatomical abnormalities, their progression over time and, most importantly, methods for protecting cognitive and brain health in epilepsy, present a challenge to neurologists. PMID- 21304486 TI - BMI was right all along: taller children really are fatter (implications of making childhood BMI independent of height) EarlyBird 48. AB - OBJECTIVE: Several studies suggest that taller children may be wrongly labelled as 'overweight' because body mass index (BMI) is not independent of height (Ht) in childhood, and recommend adjustment to render the index Ht independent. We used objective measures of %body fat and hormonal/metabolic markers of fatness to investigate whether BMI and the corresponding fat mass index (FMI) mislead in childhood, or whether taller children really are fatter. DESIGN: Longitudinal observational study measuring children annually from age 7 to 12 years. SUBJECTS: Two hundred and eighty healthy children (56% boys) from the EarlyBird study. MEASUREMENTS: BMI (body mass (BM)/Ht(2)), FMI (fat mass (FM)/Ht(2)), %body fat ((FM/BM) * 100, where FM was measured by dual-energy X-ray absorptiometry), fasting leptin (a hormonal measure of body fatness) and insulin resistance (a metabolic marker derived from the validated homeostasis model assessment program for insulin resistance--HOMA2-IR) were all analysed in relation to Ht. Alternative Ht-independent indices of BM and FM were compared with BMI and FMI as indicators of true fatness and related health risk. RESULTS: BMI and FMI correlated with Ht at each annual time point (r~0.47 and 0.46, respectively), yet these correlations were similar in strength to those between Ht and %fat (r~0.47), leptin (r~0.41) and insulin resistance (r~0.40). Also, children who grew the most between 7 and 12 years showed greater increases in BMI, FMI, leptin and insulin resistance (tertile 1 vs 3, all p<0.05). BMI and FMI explained ~20% more of the variation in %fat, ~15% more in leptin and ~10% more in insulin resistance than the respective Ht-independent reformulations (BM/Ht(3.5) and FM/Ht(7), both p<0.001). CONCLUSION: Taller children really are fatter than their shorter peers, have higher leptin levels and are more insulin resistant. Attempts to render indices of BM or FM independent of Ht in children seem inappropriate if the object of the index is to convey health risk. PMID- 21304487 TI - Metabolic sequelae of beta-blocker therapy: weighing in on the obesity epidemic? AB - BACKGROUND: Sympathetic activation is an important metabolic adaptation limiting weight gain. Propensity of weight gain associated with beta-blocker therapy in the obese modern population is unknown. OBJECTIVE: To determine whether chronic beta-blocker therapy reduces energy expenditure (EE) and increases body weight. METHODS: We undertook (i) a mechanistic study comparing EE, diet-induced thermogenesis and habitual activity between healthy volunteers (n=11) with uncomplicated hypertension treated with a beta-blocker and anthropometrically matched controls (n=19) and (ii) three cross-sectional studies comparing body weight, body mass index (BMI) and waist circumference between beta-blocker treated and untreated patients from ambulatory patients attending (a) diabetes outpatient clinic (n=214), (b) hypertension outpatient (n=84) and (c) participants in a multi-centre type 2 diabetes trial (ADVANCE) (n=11140). RESULTS: Among weight-matched beta-blocker users, diet-induced thermogenesis, fat oxidation rate and weekly habitual activity were lower by 50% (P<0.01), 32% (P=0.04) and 30% (P<0.01), respectively, compared with controls. In beta-blocker treated patients, the adjusted mean body weight was 9.2 +/- 1.2 kg (P=0.0002) higher among those attending the diabetes clinic, 17.2 +/- 3.2 kg (P=0.004) higher among those attending the hypertension clinic and 5.2 +/- 0.7 kg (P=0.0003) higher at baseline among participants in the ADVANCE trial compared with patients not treated with beta-blockers. BMI displayed a similar difference. CONCLUSIONS: EE is reduced and body weight increased in chronic beta-blocker users. We hypothesise that chronic beta-blockade causes obesity by blunting EE. PMID- 21304488 TI - Prenatal and postnatal programming of body composition in obese children and adolescents: evidence from anthropometry, DXA and the 4-component model. AB - BACKGROUND: Low-birth weight has been proposed to programme central adiposity in childhood. However, there is little information on associations between fetal weight gain and fat distribution within obese individuals. OBJECTIVES: To investigate associations between birth weight and postnatal weight gain with body composition in a sample of obese children and adolescents. SUBJECTS AND METHODS: Body composition was measured using anthropometry, dual-emission X-ray absorptiometry and the 4-component model in 45 male and 76 female obese individuals aged 5-22 years. General linear models were used to investigate associations between birth weight standard deviation score (SDS), or change in weight SDS between birth and follow-up, and body composition, adjusting for age, pubertal status, height and gender. RESULTS: Birth weight SDS ranged from -1.86 to 3.46, and was inversely associated with current weight SDS after adjustment for height SDS. Birth weight SDS was weakly associated with waist and hip girths, but not waist-hip ratio or trunk fat, after adjusting for age, height, pubertal status and gender. Change in weight SDS was strongly associated with total and central adiposity. CONCLUSIONS: Despite incorporating substantial variability, birth weight SDS was only a weak predictor of tissue masses and their distribution in obese children. Variability in central adiposity was more strongly associated with the magnitude of postnatal growth, which in turn was weakly inversely associated with birth weight SDS. In a population uniformly characterised by excess body weight, postnatal weight gain exerted the dominant impact on adiposity and fat distribution. PMID- 21304489 TI - The conserved factor DE-ETIOLATED 1 cooperates with CUL4-DDB1DDB2 to maintain genome integrity upon UV stress. AB - Plants and many other eukaryotes can make use of two major pathways to cope with mutagenic effects of light, photoreactivation and nucleotide excision repair (NER). While photoreactivation allows direct repair by photolyase enzymes using light energy, NER requires a stepwise mechanism with several protein complexes acting at the levels of lesion detection, DNA incision and resynthesis. Here we investigated the involvement in NER of DE-ETIOLATED 1 (DET1), an evolutionarily conserved factor that associates with components of the ubiquitylation machinery in plants and mammals and acts as a negative repressor of light-driven photomorphogenic development in Arabidopsis. Evidence is provided that plant DET1 acts with CULLIN4-based ubiquitin E3 ligase, and that appropriate dosage of DET1 protein is necessary for efficient removal of UV photoproducts through the NER pathway. Moreover, DET1 is required for CULLIN4-dependent targeted degradation of the UV-lesion recognition factor DDB2. Finally, DET1 protein is degraded concomitantly with DDB2 upon UV irradiation in a CUL4-dependent mechanism. Altogether, these data suggest that DET1 and DDB2 cooperate during the excision repair process. PMID- 21304490 TI - Bidirectional regulation of thermotaxis by glutamate transmissions in Caenorhabditis elegans. AB - In complex neural circuits of the brain, massive information is processed with neuronal communication through synaptic transmissions. It is thus fundamental to delineate information flows encoded by various kinds of transmissions. Here, we show that glutamate signals from two distinct sensory neurons bidirectionally affect the same postsynaptic interneuron, thereby producing the opposite behaviours. EAT-4/VGLUT (vesicular glutamate transporter)-dependent glutamate signals from AFD thermosensory neurons inhibit the postsynaptic AIY interneurons through activation of GLC-3/GluCl inhibitory glutamate receptor and behaviourally drive migration towards colder temperature. By contrast, EAT-4-dependent glutamate signals from AWC thermosensory neurons stimulate the AIY neurons to induce migration towards warmer temperature. Alteration of the strength of AFD and AWC signals led to significant changes of AIY activity, resulting in drastic modulation of behaviour. We thus provide an important insight on information processing, in which two glutamate transmissions encoding opposite information flows regulate neural activities to produce a large spectrum of behavioural outputs. PMID- 21304491 TI - Food sensitizes C. elegans avoidance behaviours through acute dopamine signalling. AB - Many behavioural states are modulated by food availability and nutritional status. Here, we report that in Caenorhabditis elegans, the presence of an external food source enhances avoidance responses to soluble repellents sensed by the polymodal ASH neurons. This enhancement requires dopamine signalling and is mimicked by exogenous dopamine. Food modulation is dependent on the mechanosensory cilia of the dopaminergic neurons, indicating that dopamine is released in response to sensation of bacteria. Activation of the dopamine neurons leads within seconds to a transient state of increased sensory acuity. In vivo imaging experiments indicate that this dopamine-dependent sensitization results in part from modality-specific increases in the magnitude and duration of gustatory responses in the ASH neurons. The D1-like dopamine receptor DOP-4 acts cell autonomously in ASH to mediate effects on response magnitude. Thus, dopamine functions as a direct signal of the presence of food to control context-dependent behavioural states. PMID- 21304492 TI - Amer1/WTX couples Wnt-induced formation of PtdIns(4,5)P2 to LRP6 phosphorylation. AB - Phosphorylation of the Wnt receptor low-density lipoprotein receptor-related protein 6 (LRP6) by glycogen synthase kinase 3beta (GSK3beta) and casein kinase 1gamma (CK1gamma) is a key step in Wnt/beta-catenin signalling, which requires Wnt-induced formation of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)). Here, we show that adenomatous polyposis coli membrane recruitment 1 (Amer1) (also called WTX), a membrane associated PtdIns(4,5)P(2)-binding protein, is essential for the activation of Wnt signalling at the LRP6 receptor level. Knockdown of Amer1 reduces Wnt-induced LRP6 phosphorylation, Axin translocation to the plasma membrane and formation of LRP6 signalosomes. Overexpression of Amer1 promotes LRP6 phosphorylation, which requires interaction of Amer1 with PtdIns(4,5)P(2). Amer1 translocates to the plasma membrane in a PtdIns(4,5)P(2) dependent manner after Wnt treatment and is required for LRP6 phosphorylation stimulated by application of PtdIns(4,5)P(2). Amer1 binds CK1gamma, recruits Axin and GSK3beta to the plasma membrane and promotes complex formation between Axin and LRP6. Fusion of Amer1 to the cytoplasmic domain of LRP6 induces LRP6 phosphorylation and stimulates robust Wnt/beta-catenin signalling. We propose a mechanism for Wnt receptor activation by which generation of PtdIns(4,5)P(2) leads to recruitment of Amer1 to the plasma membrane, which acts as a scaffold protein to stimulate phosphorylation of LRP6. PMID- 21304493 TI - Imaging stem cell-derived persistent foci after in vivo selection of lentiviral MGMT-P140K transduced murine bone marrow cells. AB - The engraftment of hematopoietic stem cells (HSCs) after drug resistance gene transfer and drug selection may recapitulate stress response hematopoiesis, but the processes remain elusive. Homing, trafficking, and localization of transduced cells and the impact of insertion site on focal expansion have not been well characterized. With the goal of optimizing and understanding these processes under conditions of low multiplicity of infection (MOI) lentiviral gene transfer, we used drug resistance gene O(6)-methylguanine-DNA methyltransferase (MGMT) P140K and in vivo selection to enrich for transduced and transgene-expressing HSCs. To systemically monitor homing, trafficking, and expansion after transplantation and drug selection over time, we linked MGMT-P140K to the firefly luciferase gene in lentiviral self-inactivating vectors. Periodic bioluminescence imaging (BLI) of transplanted recipients was followed for up to 9 months after both primary and secondary transplantation. Initial dispersion and widespread early homing and engraftment were transient, followed by detection of persistent and discrete foci at stable tissue sites after in vivo drug selection. From these studies, we concluded that drug resistance gene transfer followed by early or late drug selection can result in stable gene expression and cell expansion in persistent foci of transduced bone marrow cells that often remain in fixed sites for extended periods of time. PMID- 21304494 TI - Lentivirus-mediated Wnt11 gene transfer enhances Cardiomyogenic differentiation of skeletal muscle-derived stem cells. AB - Wnt signaling plays a crucial role in regulating cell proliferation, differentiation and inducing cardiomyogenesis. Skeletal muscle-derived stem cells (MDSCs) have been shown to be multipotent; however, their potential to aid in the healing of the heart after myocardial infarction appears to be due to the paracrine effects they impart on the host environment. The goal of this study was to investigate whether Wnt11 could promote the differentiation of MDSCs into cardiomyocytes and enhance the repair of infarcted myocardium. MDSCs transduced with a lentivirus encoding for Wnt11 increased mRNA and protein expression of the early cardiac markers NK2 transcription factor related 5 (NKx2.5) and Connexin43 (Cx43) and also led to an increased expression of late-stage cardiac markers including: alpha, beta-myosin heavy chain (MHC) and brain natriuretic protein (BNP) at the mRNA level, and MHC and Troponin I (TnI) at the protein level. We also observed that Wnt11 expression significantly enhanced c-jun N-terminal kinase activity in transduced MDSCs, and that some of the cells beat spontaneously but are not fully differentiated cardiomyocytes. Finally, lentivirus-Wnt11-transduced MDSCs showed greater survival and cardiac differentiation after being transplanted into acutely infarct-injured myocardium. These findings could one day lead to strategies that could be utilized in cardiomyoplasty treatments of myocardial infarction. PMID- 21304495 TI - Enhancers of adeno-associated virus AAV2 transduction via high throughput siRNA screening. AB - Intracellular barriers to adeno-associated virus (AAV) transduction may limit gene delivery. We screened a short interfering RNA (siRNA) library targeting 5,520 genes to help identify pathways that modulate AAV transduction of human endothelium. In replicate screening, 50 pools (three siRNAs per gene) resulted in greater than eightfold reporter gene expression enhancement. Single siRNA confirmation tests demonstrated that at least one siRNA from each of the top 10 pools provided greater than twofold enhancement. Several siRNAs when used together resulted in additive effects and two of the most potent siRNA sequences were enhancers in cultured airway epithelium. However, enhanced transduction was not correlated with mRNA knockdown by quantitative real time PCR, indicating an off-target mechanism. In fact, four of the five most potent siRNAs contained a consensus hexamer region 5'-UGUUUC-3' at positions 2-7 of the antisense strand. The point mutation U4A within this region (but not mutations at positions 1 or 14) disrupted transduction enhancement, indicating a microRNA (miRNA)-like mechanism. Transcription profiling indicated that the hexamer also resulted in perturbation of the interferon pathway via reduced interferon-induced protein 44 like (IFI44L), interferon-inducible myxovirus resistance 1 (MX1), and interferon induced protein with tetratricopeptide repeats (IFIT5) mRNAs. Direct interferon (alpha, beta, and omega) receptor 2 (IFNAR2) knockdown resulted in greater than twofold transduction enhancement. In addition to providing insight into AAV biology and enhanced transduction, the results demonstrate certain beneficial siRNA off-target effects. PMID- 21304496 TI - Apolipoprotein B knockdown by AAV-delivered shRNA lowers plasma cholesterol in mice. AB - Serum low-density lipoprotein cholesterol (LDL-C) levels are proportionate to the risk of atherosclerotic cardiovascular disease. In order to reduce serum total cholesterol and LDL-C levels in mice, RNA interference (RNAi) was used to inhibit expression of the structural protein of LDL-C, apolipoprotein B100 (ApoB). We developed and screened 19 short hairpin RNAs (shRNAs) targeting conserved sequences in human, mouse, and macaque ApoB mRNAs (shApoB) and subsequently narrowed our focus to one candidate for in vivo testing. Self-complementary adeno associated virus serotype 8 (scAAV8) was used for long-term transduction of murine liver with shApoB. A strong dose-dependent knockdown of ApoB mRNA and protein was observed, which correlated with a reduction in total cholesterol levels, without obvious signs of toxicity. Furthermore, shApoB was found to specifically reduce LDL-C in diet-induced dyslipidemic mice, whereas high-density lipoprotein cholesterol (HDL-C) remained unaffected. Finally, elevated lipid accumulation was shown in murine liver transduced with shApoB, a known phenotypic side effect of lowering ApoB levels. These results demonstrate a robust dose dependent knockdown of ApoB by AAV-delivered shRNA in murine liver, thus providing an excellent candidate for development of RNAi-based gene therapy for the treatment of hypercholesterolemia. PMID- 21304497 TI - GI training: where are we headed? AB - Gastroenterology (GI) fellowship training slots are not expected to increase over the next 10 years despite a 9% estimated US population growth. There is also no expected increase in the number of hours worked per gastroenterologist; instead, this number will probably decrease slightly, as GI will have continued growth in the percentage of women and of men in dual career families. The current trend of "sub-specialization" within GI is likely to continue, although this will not be formally recognized by further extension of the length of training or by additional board requirements. Current sub-specialties include hepatology, inflammatory bowel disease, motility, small bowel imaging, and interventional endoscopy. Most "sub-specialty" GI training will be incorporated within the 3 year fellowship, with the probable exception of interventional endoscopy, which will likely take an additional training year. End points for training and criteria for credentialing in the future will focus more on quality measures in both procedural and cognitive aspects of GI. Hopefully, this move to "competency evaluation with quality measures" will eliminate undertrained endoscopists such as the non-gastroenterologist performing occasional colonoscopy or the gastroenterologist performing occasional ERCP. Post-graduate GI training is also undergoing transformation, partly due to a decrease in industry support of graduate medical education, which has previously been heavily relied upon. The expected wider use of web-based training by the technology-comfortable younger generation of physicians may partly fill this gap. Despite the challenges facing GI training at both the fellowship and post-graduate level, GI is expected to remain a popular specialty choice. It is likely that sub-specialization within GI will continue to grow in both academic and private practices due in part to an increasing focus on quality patient outcomes. PMID- 21304498 TI - Prevalence of esophageal eosinophils in patients with Barrett's esophagus. AB - OBJECTIVES: Recent studies have demonstrated high esophageal eosinophil counts in patients with GERD similar to eosinophilic esophagitis (EoE) yet the frequency of esophageal eosinophilia in GERD is unknown. Our aim was to determine the prevalence of dense esophageal eosinophilia in patients with Barrett's esophagus as a manifestation of GERD. METHODS: The Mayo Clinic pathology database was reviewed for patients diagnosed with Barrett's esophagus from January to December 2008 with squamous mucosa obtained during endoscopic surveillance. Clinical, endoscopic, and histologic findings were reviewed. Patients with >=15 eosinophils per high powered field were identified and compared to those without esophageal eosinophilia. RESULTS: Two hundred patients with Barrett's esophagus and squamous tissue obtained at the time of biopsy were identified. Fourteen of the 200 patients (7%) had >=15 eosinophils per high powered field. Demographics, symptoms, and proton pump inhibitor therapies were similar between those with and without esophageal eosinophilia. Endoscopic features suggestive of EoE were found in the squamous mucosa of 2 patients with and 7 patients without esophageal eosinophilia. Use of photodynamic, radiofrequency ablation, or monopolar electrocoagulation therapy for ablation of Barrett's mucosa was not associated with a higher rate of esophageal eosinophilia. Basal cell hyperplasia, papillary elongation, and spongiosis occurred frequently in association with esophageal eosinophilic infiltration. CONCLUSIONS: High esophageal eosinophil counts were found in 7% of this cohort of 200 patients with Barrett's esophagus and likely underestimates prevalence. The finding of esophageal eosinophilia in this cohort was independent of proton pump inhibitor use, features of EoE, or endoscopic therapy for Barrett's esophagus. Further studies are needed to assess if these findings are applicable to all patients with GERD. PMID- 21304499 TI - Has H. pylori prevalence in bleeding peptic ulcer been underestimated? A meta regression. AB - OBJECTIVES: It has been suggested that prevalence of Helicobacter pylori (Hp) in peptic ulcer bleeding (PUB) is lower than that in non-complicated ulcers. As Hp infection is elusive in PUB, we hypothesized that this low prevalence could be related to an insufficiently intensive search for the bacteria. The aim of the study was to evaluate whether the prevalence of Hp in PUB depends on the diagnostic methods used in a given study. METHODS: A systematic review was performed of studies assessing the prevalence of Hp infection in patients with PUB. Data were extracted in duplicate. Univariate and multivariate random-effects meta-regression analyses were performed to determine the factors that explained the differences in Hp prevalence between studies. RESULTS: The review retrieved 71 articles, including 8,496 patients. The mean prevalence of Hp infection in PUB was 72%. The meta-regression analysis showed that the most significant variables associated with a high prevalence of Hp infection were the use of a diagnostic test delayed until at least 4 weeks after the PUB episode-odds ratio: 2.08, 95% confidence interval: 1.10-3.93, P=0.024-and a lower mean age of patients-odds ratio: 0.95 per additional year, 95% confidence interval: 0.92-0.99, P=0.008. CONCLUSIONS: Studies that performed a delayed test and those including younger patients found a higher prevalence of Hp, approaching that recorded in cases of non-bleeding ulcers. These results suggest that the low prevalence of Hp infection described in PUB may be related to the methodology of the studies and to patients' characteristics, and that the true prevalence of Hp in PUB is still to be determined. Our data also support the recent recommendations of the International Consensus on Non-Variceal Upper Gastrointestinal Bleeding regarding the performance of a delayed diagnostic test when Hp tests carried out during the acute PUB episode are negative. PMID- 21304500 TI - Toward uniformity in the diagnosis of eosinophilic esophagitis (EoE): the effect of guidelines on variability of diagnostic criteria for EoE. AB - OBJECTIVES: Recent consensus guidelines for diagnosis of eosinophilic esophagitis (EoE) have been published. Whether these guidelines have standardized diagnostic criteria for EoE is unknown. We aimed to determine if the EoE guidelines had an impact on the diagnostic criteria reported in the EoE literature, and whether the previously observed variability in diagnostic criteria has become more uniform. METHODS: Two investigators independently conducted a MEDLINE search from 1 January 2007 through 30 June 2010 for all publications reporting EoE in human subjects, and also searched the proceedings of the 2007-2010 American College of Gastroenterology and American Gastroenterological Association meetings, using a predefined search strategy. Data were extracted from all relevant publications. RESULTS: Of the 799 publications identified, 149 original reports, 99 reviews, and 165 abstracts were included. In all, 32 original reports (21%) used diagnostic criteria consistent with each of the three components of the consensus guidelines. There was a significant increase when comparing original articles published after the release of the guidelines with those published earlier (31 vs. 6%, P<0.001). The proportion of original articles using 15 eosinophils per high-power field (eos/hpf) as a histological cut-point increased significantly (P=0.001). There was still substantial variability in biopsy protocols and eosinophil count methodology. The majority of original articles did not report microscope high-power field (HPF) area. CONCLUSIONS: The proportion of original reports with diagnostic criteria consistent with the consensus guidelines has increased significantly. However, the majority of articles still did not conform to all three of the criteria in the guidelines, and biopsy and eosinophil count protocols continue to demonstrate significant variability. Standardization of biopsy and eosinophil count protocols is needed. PMID- 21304501 TI - Longitudinal adherence to fecal occult blood testing impacts colorectal cancer screening quality. AB - OBJECTIVES: Existing cross-sectional quality measures for colorectal cancer (CRC) screening do not assess longitudinal adherence and thus may overestimate the quality of care. Our goal was to evaluate the adherence to repeated yearly fecal occult blood tests (FOBTs) in order to better understand the extent to which longitudinal adherence may impact screening quality. METHODS: This was a retrospective cohort analysis of 1,122,645 patients aged 50-75 years seen at any of the 136 Department of Veterans Affairs medical centers across the United States in 2000 and followed through 2005. The primary outcome was receipt of adequate CRC screening as defined by receipt of FOBTs in at least 4 out of 5 years or receipt of any number of FOBTs in addition to at least one colonoscopy, flexible sigmoidoscopy, or double-contrast barium enema. In a predefined subset of patients receiving exclusively FOBT, adherence with repeated testing was determined over the 5-year study period. RESULTS: Only 41.1% of men and 43.6% of women received adequate screening. Of the 384,527 men who received exclusively FOBT, 42.1% received a single FOBT, 26.0% received 2 tests, 17.8% received 3 tests, and only 14.1% were documented to have received at least 4 tests during the study period. Among the 10,469 female veterans receiving FOBT alone, rates were similar with only 13.7% completing at least 4 FOBTs in the 5-year study period. CONCLUSIONS: Adherence to repeated FOBT is low, suggesting that cross sectional measurements of quality may overestimate the programmatic success of CRC screening. PMID- 21304502 TI - Genetics: an 18-gene signature (ColoPrint(r)) for colon cancer prognosis. PMID- 21304504 TI - Radiotherapy: has the role of WBRT in primary CNS lymphoma been settled? PMID- 21304503 TI - Integrating pharmacogenetics into gemcitabine dosing--time for a change? AB - Increasing the efficacy of anticancer agents and avoiding toxic effects is a critical issue in clinical oncology. Identifying biomarkers that predict clinical outcome would ensure improved patient care. Gemcitabine is widely used to treat various solid tumors as a single agent or in combination with other drugs. The therapeutic index of gemcitabine is narrow, and abnormal pharmacokinetics leading to changes in plasma exposure is a major cause of adverse effects. A number of biomarkers have been proposed to predict efficacy of gemcitabine, focusing on molecular determinants of response identified at the tumor level. Genetic and functional deregulations that affect the disposition of a drug could be the reason for life-threatening adverse effects or treatment failure. In particular, deregulation of cytidine deaminase, the enzyme responsible for detoxification of most nucleotide analogs, should be examined. Identifying and validating biomarkers for pharmacogenetic testing before administration of gemcitabine is a step towards personalized medicine. PMID- 21304505 TI - Therapy: Spleen tyrosine kinase inhibitors--novel therapies for RA? AB - In patients with active rheumatoid arthritis despite therapy with DMARDS, treatment with a spleen tyrosine kinase inhibitor has achieved similar response rates to those achieved in clinical trials of other drugs, including biologic agents. Where might these agents fit in the current armamentarium against this disease? PMID- 21304506 TI - Pharmacogenetics: Anti-TNF therapy in RA--towards personalized medicine? AB - A substantial proportion of patients with rheumatoid arthritis do not respond to tumor necrosis factor blocking therapy. Results of a large genome-wide association study demonstrate evidence of novel genetic factors that determine response to treatment, which could provide a basis for individualizing therapy. PMID- 21304507 TI - Immunology: Prevention of infections in patients with autoimmune diseases. AB - Several new recommendations for the vaccination of adults with autoimmune inflammatory diseases could represent an important step forward in the prevention of infections in these high-risk patients. PMID- 21304508 TI - Prostate cancer: reducing overtreatment: active surveillance in low-risk disease. PMID- 21304509 TI - Exploring a glycolytic inhibitor for the treatment of an FH-deficient type-2 papillary RCC. AB - BACKGROUND: A 24-year-old woman presented with a 45 cm complex cystic renal mass, which was resected. The tumor was a type-2 papillary renal cell carcinoma (pRCC 2), and several nodules remained. The patient was treated with mammalian target of rapamycin complex 1 (mTORC1) inhibitors, but after 5 months the tumor had progressed. Genetic testing of the patient revealed a novel heterozygous germline mutation in the gene encoding fumarate hydratase (FH), an enzyme of the tricarboxylic acid (TCA) cycle. As the tumor exhibited loss of heterozygosity for FH and markedly reduced FH activity, and in the absence of other established therapies, treatment with the glycolytic inhibitor 2DG (2-deoxy-D-glucose) was explored. INVESTIGATIONS: CT, histology, immunohistochemistry, genetic studies, 2 deoxy-2-(18F)fluoro-D-glucose (18FDG)-PET/CT, FH enzymatic assays, reconstitution experiments and in vitro studies of the effects of 2DG on FH-deficient tumor cells. DIAGNOSIS: pRCC-2 arising in a patient with a novel germline FH mutation and de novo hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome progressing after mTORC1 inhibitor therapy. MANAGEMENT: Surgical resection of the renal mass, treatment with mTORC1 inhibitors followed by 2DG. Unfortunately, 2DG was not effective, and the patient died several weeks later. PMID- 21304510 TI - The Ufm1-activating enzyme Uba5 is indispensable for erythroid differentiation in mice. AB - Post-translational protein modifications are systems designed to expand restricted genomic information through functional conversion of target molecules. Ubiquitin-like post-translational modifiers regulate numerous cellular events through their covalent linkages to target protein(s) by an enzymatic cascade analogous to ubiquitylation consisting of E1 (activating), E2 (conjugating) and E3 (ligating) enzymes. In this study, we report the essential role of Uba5, a specific activating enzyme for the ubiquitin-like modifier, Ufm1, in erythroid development. Mice lacking Uba5 exhibited severe anaemia, followed by death in utero. Although Uba5 was dispensable for the production of erythropoietin, its genetic loss led to impaired development of megakaryocyte and erythroid progenitors from common myeloid progenitors. Intriguingly, transgenic expression of Uba5 in the erythroid lineage rescued the Uba5-deficient embryos from anaemia and prolonged their survival, demonstrating the importance of Uba5 in cell autonomous erythroid differentiation. Our results suggest that one of the ubiquitin-like protein modification systems, the Ufm1 system, is involved in the regulation of haematopoiesis. PMID- 21304513 TI - Quantum networks reveal quantum nonlocality. AB - The results of local measurements on some composite quantum systems cannot be reproduced classically. This impossibility, known as quantum nonlocality, represents a milestone in the foundations of quantum theory. Quantum nonlocality is also a valuable resource for information-processing tasks, for example, quantum communication, quantum key distribution, quantum state estimation or randomness extraction. Still, deciding whether a quantum state is nonlocal remains a challenging problem. Here, we introduce a novel approach to this question: we study the nonlocal properties of quantum states when distributed and measured in networks. We show, using our framework, how any one-way entanglement distillable state leads to nonlocal correlations and prove that quantum nonlocality is a non-additive resource, which can be activated. There exist states, local at the single-copy level, that become nonlocal when taking several copies of them. Our results imply that the nonlocality of quantum states strongly depends on the measurement context. PMID- 21304511 TI - CSN-mediated deneddylation differentially modulates Ci(155) proteolysis to promote Hedgehog signalling responses. AB - The Hedgehog (Hh) morphogen directs distinct cell responses according to its distinct signalling levels. Hh signalling stabilizes transcription factor cubitus interruptus (Ci) by prohibiting SCF(Slimb)-dependent ubiquitylation and proteolysis of Ci. How graded Hh signalling confers differential SCF(Slimb) mediated Ci proteolysis in responding cells remains unclear. Here, we show that in COP9 signalosome (CSN) mutants, in which deneddylation of SCF(Slimb) is inactivated, Ci is destabilized in low-to-intermediate Hh signalling cells. As a consequence, expression of the low-threshold Hh target gene dpp is disrupted, highlighting the critical role of CSN deneddylation on low-to-intermediate Hh signalling response. The status of Ci phosphorylation and the level of E1 ubiquitin-activating enzyme are tightly coupled to this CSN regulation. We propose that the affinity of substrate-E3 interaction, ligase activity and E1 activity are three major determinants for substrate ubiquitylation and thereby substrate degradation in vivo. PMID- 21304512 TI - A bacterial proteorhodopsin proton pump in marine eukaryotes. AB - Proteorhodopsins are light-driven proton pumps involved in widespread phototrophy. Discovered in marine proteobacteria just 10 years ago, proteorhodopsins are now known to have been spread by lateral gene transfer across diverse prokaryotes, but are curiously absent from eukaryotes. In this study, we show that proteorhodopsins have been acquired by horizontal gene transfer from bacteria at least twice independently in dinoflagellate protists. We find that in the marine predator Oxyrrhis marina, proteorhodopsin is indeed the most abundantly expressed nuclear gene and its product localizes to discrete cytoplasmic structures suggestive of the endomembrane system. To date, photosystems I and II have been the only known mechanism for transducing solar energy in eukaryotes; however, it now appears that some abundant zooplankton use this alternative pathway to harness light to power biological functions. PMID- 21304514 TI - Mixtures of planetary ices at extreme conditions. AB - The interiors of Neptune and Uranus are believed to be primarily composed of a fluid mixture of methane and water. The mixture is subjected to pressures up to several hundred gigapascal, causing the ionization of water. Laboratory and simulation studies so far have focused on the properties of the individual components. Here we show, using first-principle molecular dynamic simulations, that the properties of the mixed fluid are qualitatively different with respect to those of its components at the same conditions. We observe a pressure-induced softening of the methane-water intermolecular repulsion that points to an enhancement of mixing under extreme conditions. Ionized water causes the progressive ionization of methane and the mixture becomes electronically conductive at milder conditions than pure water, indicating that the planetary magnetic field of Uranus and Neptune may originate at shallower depths than currently assumed. PMID- 21304515 TI - Predicting climate change impacts on polar bear litter size. AB - Predicting the ecological impacts of climate warming is critical for species conservation. Incorporating future warming into population models, however, is challenging because reproduction and survival cannot be measured for yet unobserved environmental conditions. In this study, we use mechanistic energy budget models and data obtainable under current conditions to predict polar bear litter size under future conditions. In western Hudson Bay, we predict climate warming-induced litter size declines that jeopardize population viability: ~28% of pregnant females failed to reproduce for energetic reasons during the early 1990s, but 40-73% could fail if spring sea ice break-up occurs 1 month earlier than during the 1990s, and 55-100% if break-up occurs 2 months earlier. Simultaneously, mean litter size would decrease by 22-67% and 44-100%, respectively. The expected timeline for these declines varies with climate-model specific sea ice predictions. Similar litter size declines may occur in over one third of the global polar bear population. PMID- 21304517 TI - Electronic phase separation at the LaAlO3/SrTiO3 interface. AB - There are many electronic and magnetic properties exhibited by complex oxides. Electronic phase separation (EPS) is one of those, the presence of which can be linked to exotic behaviours, such as colossal magnetoresistance, metal-insulator transition and high-temperature superconductivity. A variety of new and unusual electronic phases at the interfaces between complex oxides, in particular between two non-magnetic insulators LaAlO(3) and SrTiO(3), have stimulated the oxide community. However, no EPS has been observed in this system despite a theoretical prediction. Here, we report an EPS state at the LaAlO(3)/SrTiO(3) interface, where the interface charges are separated into regions of a quasi-two-dimensional electron gas, a ferromagnetic phase, which persists above room temperature, and a (superconductor like) diamagnetic/paramagnetic phase below 60 K. The EPS is due to the selective occupancy (in the form of 2D-nanoscopic metallic droplets) of interface sub-bands of the nearly degenerate Ti orbital in the SrTiO(3). The observation of this EPS demonstrates the electronic and magnetic phenomena that can emerge at the interface between complex oxides mediated by the Ti orbital. PMID- 21304516 TI - Chromatin remodelling complex dosage modulates transcription factor function in heart development. AB - Dominant mutations in cardiac transcription factor genes cause human inherited congenital heart defects (CHDs); however, their molecular basis is not understood. Interactions between transcription factors and the Brg1/Brm associated factor (BAF) chromatin remodelling complex suggest potential mechanisms; however, the role of BAF complexes in cardiogenesis is not known. In this study, we show that dosage of Brg1 is critical for mouse and zebrafish cardiogenesis. Disrupting the balance between Brg1 and disease-causing cardiac transcription factors, including Tbx5, Tbx20 and Nkx2-5, causes severe cardiac anomalies, revealing an essential allelic balance between Brg1 and these cardiac transcription factor genes. This suggests that the relative levels of transcription factors and BAF complexes are important for heart development, which is supported by reduced occupancy of Brg1 at cardiac gene promoters in Tbx5 haploinsufficient hearts. Our results reveal complex dosage-sensitive interdependence between transcription factors and BAF complexes, providing a potential mechanism underlying transcription factor haploinsufficiency, with implications for multigenic inheritance of CHDs. PMID- 21304518 TI - Glia- and neuron-specific functions of TrkB signalling during retinal degeneration and regeneration. AB - Glia, the support cells of the central nervous system, have recently attracted considerable attention both as mediators of neural cell survival and as sources of neural regeneration. To further elucidate the role of glial and neural cells in neurodegeneration, we generated TrkB(GFAP) and TrkB(c-kit) knockout mice in which TrkB, a receptor for brain-derived neurotrophic factor (BDNF), is deleted in retinal glia or inner retinal neurons, respectively. Here, we show that the extent of glutamate-induced retinal degeneration was similar in these two mutant mice. Furthermore in TrkB(GFAP) knockout mice, BDNF did not prevent photoreceptor degeneration and failed to stimulate Muller glial cell proliferation and expression of neural markers in the degenerating retina. These results demonstrate that BDNF signalling in glia has important roles in neural protection and regeneration, particularly in conversion of Muller glia to photoreceptors. In addition, our genetic models provide a system in which glia- and neuron-specific gene functions can be tested in central nervous system tissues in vivo. PMID- 21304519 TI - Prostaglandin E2 and SOCS1 have a role in intestinal immune tolerance. AB - Interleukin 10 (IL-10) and regulatory T cells (Tregs) maintain tolerance to intestinal microorganisms. However, Il10(-/-)Rag2(-/-) mice, which lack IL-10 and Tregs, remain healthy, suggesting the existence of other mechanisms of tolerance. Here, we identify suppressor of cytokine signalling 1 (SOCS1) as an essential mediator of immune tolerance in the intestine. Socs1(-/-)Rag2(-/-) mice develop severe colitis, which can be prevented by the reduction of microbiota and the transfer of IL-10-sufficient Tregs. Additionally, we find an essential role for prostaglandin E2 (PGE2) in the maintenance of tolerance within the intestine in the absence of Tregs. Socs1(-/-) dendritic cells are resistant to PGE2-mediated immunosuppression because of dysregulated cytokine signalling. Thus, we propose that SOCS1 and PGE2, potentially interacting together, act as an alternative intestinal tolerance mechanism distinct from IL-10 and Tregs. PMID- 21304520 TI - C-terminal UBA domains protect ubiquitin receptors by preventing initiation of protein degradation. AB - The ubiquitin receptors Rad23 and Dsk2 deliver polyubiquitylated substrates to the proteasome for destruction. The C-terminal ubiquitin-associated (UBA) domain of Rad23 functions as a cis-acting stabilization signal that protects this protein from proteasomal degradation. Here, we provide evidence that the C terminal UBA domains guard ubiquitin receptors from destruction by preventing initiation of degradation at the proteasome. We show that introduction of unstructured polypeptides that are sufficiently long to function as initiation sites for degradation abrogates the protective effect of UBA domains. Vice versa, degradation of substrates that contain an unstructured extension can be attenuated by the introduction of C-terminal UBA domains. Our study gains insight into the molecular mechanism responsible for the protective effect of UBA domains and explains how ubiquitin receptors can shuttle substrates to the proteasome without themselves becoming subject to proteasomal degradation. PMID- 21304521 TI - Rad23 escapes degradation because it lacks a proteasome initiation region. AB - Rad23 is an adaptor protein that binds to both ubiquitinated substrates and to the proteasome. Despite its association with the proteasome, Rad23 escapes degradation. Here we show that Rad23 remains stable because it lacks an effective initiation region at which the proteasome can engage the protein and unfold it. Rad23 contains several internal, unstructured loops, but these are too short to act as initiation regions. Experiments with model proteins show that internal loops must be surprisingly long to engage the proteasome and support degradation. These length requirements are not specific to Rad23 and reflect a general property of the proteasome. PMID- 21304522 TI - Epidermal growth factor receptor gene copy number aberration at the primary tumour is significantly associated with extracapsular spread in oral cancer. AB - BACKGROUND: Extracapsular spread (ECS) of lymph node metastasis in head and neck cancers, including oral squamous cell carcinomas (OSCCs), is known to reflect tumour aggressiveness, and is significantly associated with high rates of loco regional recurrence, distant metastasis, and poor outcome. The purpose of this study was to confirm ECS as an important prognostic indicator and to determine the significant factors associated with ECS in OSCCs. METHODS: We investigated the incidence of ECS and impact of ECS on survival in 127 OSCC patients. To determine the factors significantly correlated with ECS, we examined many factors, including the clinicopathological features of primary tumours, lymph node metastasis, and copy number aberrations of the cyclin D1 gene (CCND1) and epidermal growth factor receptor gene (EGFR) at primary tumours, and evaluated the value of predicting the risk of ECS of the metastatic lymph node. RESULTS: Kaplan-Meier and multivariate disease-free and overall survival analysis clearly demonstrated that ECS is an independent prognostic factor in OSCCs. Moreover, logistic regression analysis showed that the number of pathologically positive nodes and copy number aberrations of EGFR at the primary tumour are independent predictors of ECS. CONCLUSIONS: The findings suggest that ECS is an independent prognostic factor in OSCCs. Moreover, the number of pathologically positive lymph nodes and EGFR numerical aberrations of the primary tumour were also shown to be excellent predictors of ECS in OSCCs. Preoperative evaluation of EGFR numerical aberrations might therefore be a useful tool for selecting patients at high risk of ECS, who would benefit from targeted aggressive multimodality therapy. PMID- 21304523 TI - Silencing of ferrochelatase enhances 5-aminolevulinic acid-based fluorescence and photodynamic therapy efficacy. AB - BACKGROUND: Recurrence of glioma frequently occurs within the marginal area of the surgical cavity due to invading residual cells. 5-Aminolevulinic acid (5-ALA) fluorescence-guided resection has been used as effective therapeutic modalities to improve discrimination of brain tumour margins and patient prognosis. However, the marginal areas of glioma usually show vague fluorescence, which makes tumour identification difficult, and the applicability of 5-ALA-based photodynamic therapy (PDT) is hampered by insufficient therapeutic efficacy in glioma tissues. METHODS: To overcome these issues, we assessed the expression of ferrochelatase (FECH) gene, which encodes a key enzyme that catalyses the conversion of protoporphyrin IX (PpIX) to heme, in glioma surgical specimens and manipulated FECH in human glioma cell lines. RESULTS: Prominent downregulation of FECH mRNA expression was found in glioblastoma tissues compared with normal brain tissues, suggesting that FECH is responsible for PpIX accumulation in glioblastoma cells. Depletion of FECH by small interference RNA enhanced PpIX fluorescence after exposure to 5-ALA concomitant with increased intracellular PpIX accumulation in glioma cells. Silencing of FECH caused marked growth inhibition and apoptosis induction by PDT in glioma cells. CONCLUSION: These results suggest that knockdown of FECH is a potential approach to enhance PpIX fluorescent quality for optimising the subjective discrimination of vague fluorescence and improving the effect of 5-ALA-PDT. PMID- 21304524 TI - HE4 and CA125 as a diagnostic test in ovarian cancer: prospective validation of the Risk of Ovarian Malignancy Algorithm. AB - BACKGROUND: Recently, a Risk of Ovarian Malignancy Algorithm (ROMA) utilising human epididymis secretory protein 4 (HE4) and CA125 successfully classified patients as presenting a high or low risk for epithelial ovarian cancer (EOC). We validated this algorithm in an independent prospective study. METHODS: Women with a pelvic mass, who were scheduled to have surgery, were enrolled in a prospective study. Preoperative serum levels of HE4 and CA125 were measured in 389 patients. The performance of each of the markers, as well as that of ROMA, was analysed. RESULTS: When all malignant tumours were included, ROMA (receiver operator characteristic (ROC)-area under curve (AUC)=0.898) and HE4 (ROC-AUC)=0.857) did not perform significantly better than CA125 alone (ROC-AUC=0.877). Using a cutoff for ROMA of 12.5% for pre-menopausal patients, the test had a sensitivity of 67.5% and a specificity of 87.9%. With a cutoff of 14.4% for post-menopausal patients, the test had a sensitivity of 90.8% and a specificity of 66.3%. For EOC vs benign disease, the ROC-AUC of ROMA increased to 0.913 and for invasive EOC vs benign disease to 0.957. CONCLUSION: This independent validation study demonstrated similar performance indices to those recently published. However, in this study, HE4 and ROMA did not increase the detection of malignant disease compared with CA125 alone. Although the initial reports were promising, measurement of HE4 serum levels does not contribute to the diagnosis of ovarian cancer. PMID- 21304525 TI - Physical activity and risk of colon adenoma: a meta-analysis. AB - BACKGROUND: Little evidence is available on the relation of physical activity with colon adenomas, a colon cancer precursor. METHODS: We conducted a systematic literature review and meta-analysis of published studies (in English) through April 2010, examining physical activity or exercise and risk or prevalence of colon adenoma or polyp. Random effects models were used to estimate relative risks (RRs) and corresponding confidence intervals (CIs). A total of 20 studies were identified that examined the association and provided RRs and corresponding 95% CIs. RESULTS: A significant inverse association between physical activity and colon adenomas was found with an overall RR of 0.84 (CI: 0.77-0.92). The association was similar in men (RR=0.81, CI: 0.67-0.98) and women (RR=0.87, CI: 0.74-1.02). The association appeared slightly stronger in large/advanced polyps (RR=0.70, CI: 0.56-0.88). CONCLUSION: This study confirms previous reports of a significant inverse association of physical activity and colon adenoma, and suggests that physical activity can have an important role in colon cancer prevention. PMID- 21304526 TI - Hypertension and overall survival in metastatic colorectal cancer patients treated with bevacizumab-containing chemotherapy. AB - BACKGROUND: Hypertension (HTN) is a common toxicity of anti-VEGF (vascular endothelial growth factor) antibody treatment. It may be a marker of VEGF signalling pathway inhibition and therefore represent a cancer biomarker in metastatic colorectal cancer (mCRC) patients treated with chemotherapy and bevacizumab. METHODS: A total of 101 consecutive patients with mCRC were treated with standard chemotherapy combined with bevacizumab at dose of 2.5 mg kg(-1) per week in a single centre. The median follow-up time of the patients alive was 64 months. Blood pressure was measured before each bevacizumab infusion, and HTN was graded according to common toxicity criteria for adverse events version 3.0. RESULTS: Overall, 57 patients (56%) developed >=grade 1 HTN (median blood pressure 168/97 mm Hg), whereas 44 (44%) remained normotensive when treated with bevacizumab-containing chemotherapy regimen. Overall response rate was higher among patients with HTN (30 vs 20%; P=0.025). Hypertension was associated with improved progression-free survival (10.5 vs 5.3 months; P=0.008) and overall survival (25.8 vs 11.7 months; P<0.001), and development of HTN within 3 months had an independent, prognostic influence in a multivariate landmark survival analysis together with other known mCRC prognostic factors (P=0.007). There was no association between HTN and development of thromboembolic complications. CONCLUSION: Hypertension may predict outcome of bevacizumab-containing chemotherapy in mCRC. These data require confirmation in prospective studies including pharmacodynamic and pharmacokinetic analyses. PMID- 21304527 TI - Pre-diagnostic NSAID use but not hormone therapy is associated with improved colorectal cancer survival in women. AB - BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) and hormone therapy (HT) independently decrease the risk of colorectal cancer. However, their role in altering survival after a colorectal cancer diagnosis is not well established. METHODS: We examined the association between the use of these common medications before diagnosis and colorectal cancer survival among women in western Washington State diagnosed with incident colorectal cancer from 1997 to 2002. Cases were ascertained using the Surveillance, Epidemiology and End Results cancer registry; mortality follow-up was completed through linkages to the National Death Index. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We observed no overall association between colorectal cancer survival and pre-diagnostic NSAID use. However, when stratified by tumour sub-site, NSAID use was associated with a reduced risk of colorectal cancer mortality for women diagnosed with proximal (HR=0.55; 95% CI: 0.32-0.92), but not distal or rectal (HR=1.32; 95% CI: 0.83-2.10) tumours. The usage of HT was not associated with colorectal cancer survival overall or by tumour sub-site. CONCLUSION: Usage of NSAIDs before diagnosis may be associated with improved colorectal cancer survival among women diagnosed with proximal tumours. The usage of HT does not appear to have a function in altering colorectal cancer mortality. PMID- 21304528 TI - Cucurbitacin IIa: a novel class of anti-cancer drug inducing non-reversible actin aggregation and inhibiting survivin independent of JAK2/STAT3 phosphorylation. AB - BACKGROUND: Cucurbitacin (Cuc) and triterpene-derived natural products exhibit anti-cancer potential in addition to their conspicuous anti-bacterial and anti inflammatory activity. Recently, inhibition of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling was shown to underlie the effects of Cuc family on inducing cell death in cancer. METHOD: We purified Cuc IIa, the active component from the medicinal plant Hemsleya amalils Diels, which shows different structural modifications from other Cuc derivatives. We investigated the mechanisms of its inhibitory effects on cancer cells in vitro and tumour growth in vivo. RESULTS: Cuc IIa induced the irreversible clustering of filamentous actin and arrested cell cycle by the increases in G2/M populations. Cuc IIa resulted in the reduced phospho-Histone H3 and markedly increased cleavage of poly-(ADP-ribose) polymerase or PARP, immediate upstream of DNA breakdown as the result of caspase activation, consistent with mitotic blockage-induced cell death. However, unlike other Cuc members, Cuc IIa did not suppress JAK2/STAT3 phosphorylation or alter phosphorylation of mitogen-activated protein kinases. Instead, the expression of the cell cycle-regulated Inhibitor of Apoptosis Protein (IAP) survivin was reduced. Introducing oncoprotein delta catenin, which increased survivin expression and suppressed small GTPase RhoA, reduced efficacy of Cuc IIa to induce cell death. Supporting the effects of Cuc IIa on actin cytoskeletal signaling, RhoA phosphorylation was reduced suggesting its increased activity. CONCLUSION: Cuc IIa is a novel class of anti-cancer drug in suppression of cancer cell expansion by disrupting the actin cytoskeleton and directing the cell to undergo PARP-mediated apoptosis through the inhibition of survivin downstream of JAK2/STAT3. PMID- 21304529 TI - Aurora B kinase inhibitor AZD1152: determinants of action and ability to enhance chemotherapeutics effectiveness in pancreatic and colon cancer. AB - BACKGROUND: AZD1152, the prodrug for AZD1152-hydroxyquinazoline pyrazol anilide (HQPA), is a selective inhibitor of Aurora B kinase activity. Preclinical evaluation of AZD1152 has been reported in several human cancer models. The potentiality of this compound in combination therapy warrants further investigation in solid tumours. EXPERIMENTAL DESIGN: This study explored the effects of AZD1152-HQPA in colon and pancreatic tumour cells. The antitumour properties of AZD1152, either as single agent or in combination with chemotherapeutics, were evaluated in each study model. The efficacy and the toxicity of AZD1152 alone and in combination with gemcitabine were validated in pancreatic tumour xenograft model. RESULTS: AZD1152-HQPA treatment resulted in a dramatic increase of chromosome number, modification of cell cycle and induction of apoptosis. The most effective combination was that with chemotherapeutics given soon after AZD1152 in both tumour cell types. The effectiveness of the sequential schedule of AZD1152 with gemcitabine was confirmed in nude mice bearing MiaPaCa-2 tumours, showing inhibition of tumour volumes and delaying of tumour growth after the interruption of the treatments. Here we show that AZD1152 HQPA enhances oxaliplatin and gemcitabine effectiveness in colon and pancreatic cancer, respectively. First, we provide advances into administration schedules and dosing regimens for the combination treatment in in vivo pancreatic tumour. PMID- 21304531 TI - Streptomyces vietnamensis GIMV4.0001: a granaticin-producing strain that can be readily genetically manipulated. PMID- 21304530 TI - The tumour-suppressive function of miR-1 and miR-133a targeting TAGLN2 in bladder cancer. AB - BACKGROUND: On the base of the microRNA (miRNA) expression signature of bladder cancer (BC), we found that miR-1 and miR-133a were significantly downregulated in BC. In this study, we focussed on the functional significance of miR-1 and miR 133a in BC cell lines and identified a molecular network of these miRNAs. METHODS AND RESULTS: We investigated the miRNA expression signature of BC clinical specimens and identified several downregulated miRNAs (miR-133a, miR-204, miR-1, miR-139-5p, and miR-370). MiR-1 and miR-133a showed potential role of tumour suppressors by functional analyses of BC cells such as cell proliferation, apoptosis, migration, and invasion assays. Molecular target searches of these miRNAs showed that transgelin 2 (TAGLN2) was directly regulated by both miR-1 and miR-133a. Silencing of TAGLN2 study demonstrated significant inhibitions of cell proliferation and increase of apoptosis in BC cell lines. The immunohistochemistry showed a positive correlation between TAGLN2 expression and tumour grade in clinical BC specimens. CONCLUSIONS: The downregulation of miR-1 and miR-133a was a frequent event in BC, and these miRNAs were recognised as tumour suppressive. TAGLN2 may be a target of both miRNAs and had a potential oncogenic function. Therefore, novel molecular networks provided by miRNAs may provide new insights into the underlying molecular mechanisms of BC. PMID- 21304532 TI - Styrylpyrone-class compounds from medicinal fungi Phellinus and Inonotus spp., and their medicinal importance. AB - Members of the genera Phellinus and Inonotus, including P. linteus, P. igniarius, P. ribis, I. obliquus and I. xeranticus are well-known medicinal fungi (mushrooms) and have been used in treatment of cancer, diabetes, bacterial and viral infections and ulcer. Adverse effects of these medicinal mushrooms have not yet been reported, indicating the safe nature of these mushrooms. Polysaccharides, particularly beta-glucan, are considered the compounds responsible for the biological activity of medicinal mushrooms. However, there is only a limited amount of evidence to indicate that polysaccharides are in fact responsible for the biological effects of these medicinal mushrooms. Recently, many research groups have begun identification of active low-MW compounds in medicinal mushrooms, with a focus on the yellow polyphenol pigments, which are composed of a styrylpyrone class of compounds. Interestingly, a representative group of medicinal fungi, including P. linteus, P. igniarius, P. ribis, I. obliquus and I. xeranticus were shown to produce a large and diverse range of styrylpyrone-type polyphenol pigments that exhibited various biological activities, including anti-oxidative, anti-inflammatory, cytotoxic, anti-platelet aggregation, anti-diabetic, anti-dementia and anti-viral effects. Styrylpyrone pigments in mushrooms are thought to have a role similar to that of flavonoids in plants. The unique and unprecedented carbon skeleton of fused styrylpyrone might be an attractive molecular scaffold for pharmacological applications. In this review, the structural diversity, biological effects and biogenesis of styrylpyrone-class polyphenols from medicinal fungi are described. PMID- 21304533 TI - Isolation and structure elucidation of izuminosides A-C: a rare phenazine glycosides from Streptomyces sp. IFM 11260. AB - Three new glycosylated phenazine derivatives, named izuminosides A-C (1-3) have been isolated from the ethyl acetate extract of Streptomyces sp. IFM 11260. The structures of the new compounds were determined on the basis of their spectral data. Compounds 1-3 were evaluated for their activity in overcoming tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance in human gastric adenocarcinoma cells. Compounds 2 (10 MUM) and 3 (60 MUM) in combination with TRAIL showed synergistic activity in sensitizing TRAIL resistance AGS cells. PMID- 21304534 TI - ACT-6, a novel plasmid-encoded class C beta-lactamase in a Klebsiella pneumoniae isolate from China. AB - The purpose of this study was to investigate the phenotypic and molecular characterization of a novel plasmid-mediated AmpC-type beta-lactamase in Klebsiella pneumoniae E701 isolated from Anhui province in China. In comparison with the ACT-1, sequence analysis revealed that there were 43 point mutations in the coding gene, and 10 of which led to amino-acid substitution. Resistance could be transferred by conjugation or transformation with plasmid DNA into E. coli JM109, which was due to the production of a beta-lactamase with an isoelectric point of 8.4 named ACT-6. Cloning, expression, purification and kinetics were carried out to study the characterization of the novel AmpC-type beta-lactamase. The results of MIC determinations and substrate profiles showed there was no significant difference in the activities of the novel enzyme and ACT-1. Moreover, the class 1 integron and the whole open reading frame of the novel AmpC-type beta lactamase from K.pneumoniae E701 were detectable in the same size plasmid. This is the first report on the emergence of the novel ACT-6 type beta-lactamases in K. pneumoniae. PMID- 21304535 TI - PDGFRA rearrangement leading to hyper-eosinophilia, T-lymphoblastic lymphoma, myeloproliferative neoplasm and precursor B-cell acute lymphoblastic leukemia. PMID- 21304536 TI - Expression of TGF-beta receptor ALK-5 has a negative impact on outcome of patients with acute myeloid leukemia. PMID- 21304540 TI - Prostate cancer in 2010: GSU: misclassification or biological progression? PMID- 21304541 TI - Kidney cancer in 2010: drugs, surgery and survival in RCC. PMID- 21304542 TI - Urinary incontinence in 2010: the evolution of SUI management. PMID- 21304543 TI - Stones in 2010: urinary tract stone disease--has therapy advanced? PMID- 21304544 TI - Current status of the surgical management of Peyronie's disease. AB - Surgery is the standard treatment for patients in the chronic phase of Peyronie's disease. Reconstructive surgeries function by either shortening the convex side of the tunica albuginea (Nesbit procedure, Yachia technique and penile plication) or lengthening the concave side by incision of the plaque with subsequent grafting. Tunical shortening procedures are ideal for men with good erectile capacity, penile curvatures less than 60 degrees and predicted postprocedural length loss of less than 20% of erect penis length. Tunical lengthening procedures with grafting are indicated in patients with severe penile length loss, curvatures greater than 60 degrees and prominent hourglass deformities. Saphenous vein and tunica albuginea are the most commonly used autologous graft materials. Cadaveric or bovine pericardium and 4-layer small intestinal submucosa are promising nonautologous tissues. Penile implantation of a prosthesis is the standard procedure in men with erectile dysfunction who do not respond to conservative treatment. If residual penile curvature is less than 30 degrees after implantation, no further treatment is required. However, residual curve of greater than 30 degrees can be straightened with manual modeling. Additional procedures such as penile plication, the Nesbit procedure, or grafting can be performed if modeling fails to correct the residual deformity. PMID- 21304545 TI - Targeted resequencing of a genomic region influencing tameness and aggression reveals multiple signals of positive selection. AB - The identification of the causative genetic variants in quantitative trait loci (QTL) influencing phenotypic traits is challenging, especially in crosses between outbred strains. We have previously identified several QTL influencing tameness and aggression in a cross between two lines of wild-derived, outbred rats (Rattus norvegicus) selected for their behavior towards humans. Here, we use targeted sequence capture and massively parallel sequencing of all genes in the strongest QTL in the founder animals of the cross. We identify many novel sequence variants, several of which are potentially functionally relevant. The QTL contains several regions where either the tame or the aggressive founders contain no sequence variation, and two regions where alternative haplotypes are fixed between the founders. A re-analysis of the QTL signal showed that the causative site is likely to be fixed among the tame founder animals, but that several causative alleles may segregate among the aggressive founder animals. Using a formal test for the detection of positive selection, we find 10 putative positively selected regions, some of which are close to genes known to influence behavior. Together, these results show that the QTL is probably not caused by a single selected site, but may instead represent the joint effects of several sites that were targets of polygenic selection. PMID- 21304546 TI - Comparative population genetics of a mimicry locus among hybridizing Heliconius butterfly species. AB - The comimetic Heliconius butterfly species pair, H. erato and H. melpomene, appear to use a conserved Mendelian switch locus to generate their matching red wing patterns. Here we investigate whether H. cydno and H. pachinus, species closely related to H. melpomene, use this same switch locus to generate their highly divergent red and brown color pattern elements. Using an F2 intercross between H. cydno and H. pachinus, we first map the genomic positions of two novel red/brown wing pattern elements; the G locus, which controls the presence of red vs brown at the base of the ventral wings, and the Br locus, which controls the presence vs absence of a brown oval pattern on the ventral hind wing. The results reveal that the G locus is tightly linked to markers in the genomic interval that controls red wing pattern elements of H. erato and H. melpomene. Br is on the same linkage group but approximately 26 cM away. Next, we analyze fine-scale patterns of genetic differentiation and linkage disequilibrium throughout the G locus candidate interval in H. cydno, H. pachinus and H. melpomene, and find evidence for elevated differentiation between H. cydno and H. pachinus, but no localized signature of association. Overall, these results indicate that the G locus maps to the same interval as the locus controlling red patterning in H. melpomene and H. erato. This, in turn, suggests that the genes controlling red pattern elements may be homologous across Heliconius, supporting the hypothesis that Heliconius butterflies use a limited suite of conserved genetic switch loci to generate both convergent and divergent wing patterns. PMID- 21304547 TI - The genetic basis of divergent pigment patterns in juvenile threespine sticklebacks. AB - Animal pigment patterns are important for a range of functions, including camouflage and communication. Repeating pigment patterns, such as stripes, bars and spots have been of particular interest to developmental and theoretical biologists, but the genetic basis of natural variation in such patterns is largely unexplored. In this study, we identify a difference in a periodic pigment pattern among juvenile threespine sticklebacks (Gasterosteus aculeatus) from different environments. Freshwater sticklebacks exhibit prominent vertical bars that visually break up the body shape, but sticklebacks from marine populations do not. We hypothesize that these distinct pigment patterns are tuned to provide crypsis in different habitats. This phenotypic difference is widespread and appears in most of the freshwater populations that we sampled. We used quantitative trait locus (QTL) mapping in freshwater-marine F2 hybrids to elucidate the genetic architecture underlying divergence in this pigmentation pattern. We identified two QTL that were significantly associated with variation in barring. Interestingly, these QTL were associated with two distinct aspects of the pigment pattern: melanophore number and overall pigment level. We compared the QTL locations with positions of known pigment candidate genes in the stickleback genome. We also identified two major QTL for juvenile body size, providing new insights into the genetic basis of juvenile growth rates in natural populations. In summary, although there is a growing literature describing simple genetic bases for adaptive coloration differences, this study emphasizes that pigment patterns can also possess a more complex genetic architecture. PMID- 21304550 TI - Endocytosis: One ubiquitin does the trick. PMID- 21304548 TI - Molecular mechanisms of mechanotransduction in mammalian sensory neurons. AB - The somatosensory system mediates fundamental physiological functions, including the senses of touch, pain and proprioception. This variety of functions is matched by a diverse array of mechanosensory neurons that respond to force in a specific fashion. Mechanotransduction begins at the sensory nerve endings, which rapidly transform mechanical forces into electrical signals. Progress has been made in establishing the functional properties of mechanoreceptors, but it has been remarkably difficult to characterize mechanotranducer channels at the molecular level. However, in the past few years, new functional assays have provided insights into the basic properties and molecular identity of mechanotransducer channels in mammalian sensory neurons. The recent identification of novel families of proteins as mechanosensing molecules will undoubtedly accelerate our understanding of mechanotransduction mechanisms in mammalian somatosensation. PMID- 21304551 TI - Gene expression: Teasing out transcription. PMID- 21304549 TI - Protein scaffolds in the coupling of synaptic exocytosis and endocytosis. AB - Mechanisms that ensure robust long-term performance of synaptic transmission over a wide range of activity are crucial for the integrity of neuronal networks, for processing sensory information and for the ability to learn and store memories. Recent experiments have revealed that such robust performance requires a tight coupling between exocytic vesicle fusion at defined release sites and endocytic retrieval of synaptic vesicle membranes. Distinct presynaptic scaffolding proteins are essential for fulfilling this requirement, providing either ultrastructural coordination or acting as signalling hubs. PMID- 21304552 TI - DNA replication: Partnering to unwind. PMID- 21304553 TI - DNA damage response in adult stem cells: pathways and consequences. AB - In contrast to postmitotic or short-lived somatic cells, tissue-specific stem cells must persist and function throughout life to ensure tissue homeostasis and repair. The enormous functional demands and longevity of stem cells raises the possibility that stem cells might be uniquely equipped to maintain genomic integrity in ways different than somatic cells. Indeed, evidence suggests that stem cell compartments possess unique properties that combine to either limit or, in some instances, accelerate DNA damage accrual. PMID- 21304554 TI - Metabolic control of resting hemispheric cerebral blood flow is oxidative, not glycolytic. AB - Although the close regional coupling of resting cerebral blood flow (CBF) with both cerebral metabolic rate of oxygen (CMRO(2)) and cerebral metabolic rate of glucose (CMRglc) within individuals is well documented, there are few data regarding the coupling between whole brain flow and metabolism among different subjects. To investigate the metabolic control of resting whole brain CBF, we performed multivariate analysis of hemispheric CMRO(2), CMRglc, and other covariates as predictors of resting CBF among 23 normal humans. The univariate analysis showed that only CMRO(2) was a significant predictor of CBF. The final multivariate model contained two additional terms in addition to CMRO(2): arterial oxygen content and oxygen extraction fraction. Notably, arterial plasma glucose concentration and CMRglc were not included in the final model. Our data demonstrate that the metabolic factor controlling hemispheric CBF in the normal resting brain is CMRO(2) and that CMRglc does not make a contribution. Our findings provide evidence for compartmentalization of brain metabolism into a basal component in which CBF is coupled to oxygen metabolism and an activation component in which CBF is controlled by another mechanism. PMID- 21304555 TI - Intra- and multicenter reproducibility of pulsed, continuous and pseudo continuous arterial spin labeling methods for measuring cerebral perfusion. AB - Intra- and multicenter reproducibility of currently used arterial spin labeling (ASL) methods were assessed at three imaging centers in the Netherlands, equipped with Philips 3TMR scanners. Six healthy participants were scanned twice at each site. The imaging protocol consisted of continuous ASL (CASL), pseudo-continuous ASL (p-CASL) with and without background suppression, pulsed ASL (PASL) with single and multiple inversion times (TIs), and selective ASL for segmentation. Reproducibility was expressed in terms of the coefficient of repeatability and the repeatability index. Voxelwise analysis of variance was performed, yielding brain maps that reflected regional variability. Intra- and multicenter reproducibility were comparable for all methods, except for single TI PASL, with better intracenter reproducibility (F-test of equality of two variances, P<0.05). Pseudo-continuous ASL and multi TI PASL varied least between sites. Variability maps of all methods showed most variability near brain-feeding arteries within sessions and in gray matter between sessions. On the basis of the results of this study, one could consider the use of reference values in clinical routine, with whole-brain p-CASL perfusion varying <20% over repeated measurements within the same individuals considered to be normal. Knowledge on regional variability allows for the use of perfusion-weighted images in the assessment of local cerebral pathology. PMID- 21304556 TI - Inhibition of VEGF signaling pathway attenuates hemorrhage after tPA treatment. AB - An angiogenic factor, vascular endothelial growth factor (VEGF), might be associated with the blood-brain barrier (BBB) disruption after focal cerebral ischemia; however, it remains unknown whether hemorrhagic transformation (HT) after tissue plasminogen activator (tPA) treatment is related to the activation of VEGF signaling pathway in BBB. Here, we hypothesized that inhibition of VEGF signaling pathway can attenuate HT after tPA treatment. Rats subjected to thromboembolic focal cerebral ischemia were assigned to a permanent ischemia group and groups treated with tPA at 1 or 4 hours after ischemia. Anti-VEGF neutralizing antibody or control antibody was administered simultaneously with tPA. At 24 hours after ischemia, we evaluated the effects of the antibody on the VEGF expression, matrix metalloproteinase-9 (MMP-9) activation, degradation of BBB components, and HT. Delayed tPA treatment at 4 hours after ischemia promoted expression of VEGF in BBB, MMP-9 activation, degradation of BBB components, and HT. Compared with tPA and control antibody, combination treatment with tPA and the anti-VEGF neutralizing antibody significantly attenuated VEGF expression in BBB, MMP-9 activation, degradation of BBB components, and HT. It also improved motor outcome and mortality. Inhibition of VEGF signaling pathway may be a promising therapeutic strategy for attenuating HT after tPA treatment. PMID- 21304557 TI - Cerebral formation of free radicals during hypoxia does not cause structural damage and is associated with a reduction in mitochondrial PO2; evidence of O2 sensing in humans? AB - Cellular hypoxia triggers a homeostatic increase in mitochondrial free radical signaling. In this study, blood was obtained from the radial artery and jugular venous bulb in 10 men during normoxia and 9 hours hypoxia (12.9% O(2)). Mitochondrial oxygen tension (p(O(2))(mit)) was derived from cerebral blood flow and blood gases. The ascorbate radical (A(*-)) was detected by electron paramagnetic resonance spectroscopy and neuron-specific enolase (NSE), a biomarker of neuronal injury, by enzyme-linked immunosorbent assay. Hypoxia increased the cerebral output of A(*-) in proportion to the reduction in p(O(2))(mit), but did not affect NSE exchange. These findings suggest that neuro oxidative stress may constitute an adaptive response. PMID- 21304558 TI - Identification of regions of positive selection using Shared Genomic Segment analysis. AB - We applied a shared genomic segment (SGS) analysis, incorporating an error model, to identify complete, or near complete, selective sweeps in the HapMap phase II data sets. This method is based on detecting heterozygous sharing across all individuals within a population, to identify regions of sharing with at least one allele in common. We identified multiple interesting regions, many of which are concordant with positive selection regions detected by previous population genetic tests. Others are suggested to be novel regions. Our finding illustrates the utility of SGS as a method for identifying regions of selection, and some of these regions have been proposed to be candidate regions for harboring disease genes. PMID- 21304559 TI - Common variants near TERC are associated with leukocyte telomere length in the Chinese Han population. AB - A recent genome-wide association study has identified an association between leukocyte telomere length (LTL) and a locus at 3q26 that includes TERC. In order to evaluate the effects of the SNPs rs12696304 and rs16847897 near TERC in the population of mainland China, we conducted an association study of LTL focusing on these two candidate SNPs in a sample of 4016 Chinese Han individuals. Multiple linear regression analyses were performed to evaluate the association of LTL with each SNP adjusted for age, gender and diabetes status. In the study, we confirmed the association of SNP rs12696304 and rs16847897 near TERC with LTL in the Chinese Han population (P ~ 4.5 * 10(-3) and 9.5 * 10(-5), respectively). Each copy of the major allele of rs12696304 and rs16847897 was associated with a shorter mean telomere length of 0.024 and 0.031 T/S respectively, which is equivalent to about 3 and 4 years of average age-related telomere attrition. Our short report confirmed the effects of SNPs near TERC on LTL in the Chinese Han population for the first time. PMID- 21304560 TI - Clinical utility gene card for: Gorlin syndrome. PMID- 21304562 TI - [Does physical exercise help against fatigue?]. PMID- 21304564 TI - [Why not driving simulators?]. PMID- 21304565 TI - [The prescription registry and abuse of pregabalin]. PMID- 21304566 TI - [To know or to understand]. PMID- 21304568 TI - [Introduction of PET in Norway--not too slowly or late?]. PMID- 21304569 TI - [Learning via epicrises]. PMID- 21304570 TI - [Insufficient language tests for foreign physicians]. PMID- 21304571 TI - [Exercise therapy for patients with chronic fatigue syndrome]. AB - BACKGROUND: Post-exertional fatigue is the main symptom of chronic fatigue syndrome. Evidence-based guidelines recommend cognitive behavioral therapy and graded exercise therapy. In this article, we present a systematic review of outcome studies and discuss procedures for individualized exercise therapy for patients with chronic fatigue syndrome. MATERIAL AND METHODS: The effect of exercise treatment for these patients was assessed through a meta-analysis of randomized controlled trials which were identified through a systematic literature review. Effect size was calculated for fatigue, pain and health related quality of life and the GRADE system was used to estimate the documentation level (quality of the evidence and strength of the recommendations). RESULTS: Seven outcome studies were included in the meta analysis. They demonstrated that exercise therapy seems to reduce fatigue, but the results were inconclusive for pain and health-related quality of life. The documentation level is moderate to low and further research can modify the results in positive or negative directions. We found no indications of adverse effects of individualized exercise programs which were adapted to the patients' functional level and included adequate follow-up. INTERPRETATION: In light of general knowledge about positive health effects of exercise therapy and empirically based hypotheses about disease mechanisms in chronic fatigue syndrome, we conclude that further research has a high probability of confirming recommendations on individualized exercise therapy to these patients. PMID- 21304572 TI - [High-grade gliomas in adults]. AB - BACKGROUND: High-grade glioma is a primary malignant brain tumour which affects about 200 Norwegian patients each year. Diagnosis and treatment of high-grade gliomas in adults has been reviewed. MATERIAL AND METHODS: The article is based on recent literature retrieved through a non-systematic search in PubMed and the authors' experience with the patient group. RESULTS: The most common symptoms are focal neurological deficits, epileptic seizures and pressure symptoms. The patients should be examined by magnetic resonance (MR) imaging and the diagnosis confirmed with biopsy. No curative treatment is currently available for high grade gliomas. The standard treatment is surgical resection followed by radiation therapy alone or in combination with chemotherapy (temozolomid). Five-year survival is only 6.1 %. INTERPRETATION: The diagnosis is composite with both neurological symptoms and cognitive problems. This requires good communication with the patient and close cooperation between various departments and the primary health services. Symptomatic treatment and multidisciplinary follow-up is necessary. PMID- 21304573 TI - [Bisphosphonate treatment of osteoporosis and other skeletal diseases]. AB - BACKGROUND: Bisphosphonates are antiresorptive drugs widely used to treat osteoporosis. They are also used to treat hereditary skeletal diseases with systemic or local defects, and as a supplement in treatment of cancer. This paper provides an overview of pharmacokinetics, mode of action, and clinical effects. MATERIAL AND METHODS: Literature was retrieved through a non-systematic search in Pubmed/Medline. RESULTS: Bisphosphonates are derivates of pyrophosphate which bind to hydroxyapatite with high affinity. Aminobisphosphonates inhibit an enzyme in the mevalonate pathway, thereby inducing apoptosis and inhibiting osteoclast activity. A reduced incidence of vertebral and hip fractures has been shown for alendronate, risedronate and zoledronate, while ibandronate has been shown to only reduce vertebral fracture. Reduced mortality was observed in a study where patients with recent hip fracture were treated with zoledronic acid. Intravenous bisphosphonates improve compliance and are relatively simple to use. Bisphosphonates reduce the risk for skeletal complications and bone pain in breast cancer, myelomatosis and prostate cancer. They are also effective in the treatment of Paget's disease and bone marrow edema. Gastrointestinal adverse effects are relatively frequent with peroral bisphosphonates, while acute phase reactions with influenza-like symptoms are common with intravenous bisphosphonates. INTERPRETATION: Aminobisphoshonates are effective in the treatment of osteoporosis and in other bone diseases, and as an adjuvance in the treatment of cancer. PMID- 21304574 TI - [The Norwegian Cruciate Ligament Registry has a high degree of completeness]. AB - BACKGROUND: In 2010 the Norwegian Cruciate Ligament Registry (NCLR) achieved status as a national medical quality registry. The study aimed at evaluating completeness of reporting on anterior cruciate ligament surgery to NCLF as compared to the Surgical Logbooks-Electronic Patient Journal (SL-EPJ) and the Norwegian Patient Registry (NPR). MATERIAL AND METHODS: Data were obtained electronically, by telephone or by manual counting from NCLR, SL-EPJ and NPR for 14 randomly selected hospitals in Norway for the period 01.10.05-28.02.06. SL-EPJ in hospitals were used as the gold standard. RESULTS: According SL-EPJ, 202 operations were recorded in the study period. Among these operations seven were missing in NCLR and 21 in NPR. One private hospital only reported to NCLR and not to NPR in the study period, and according to SL-EPJ this hospital performed 19 of the 21 operations missing in NPR. Exclusion of this hospital leads to a high degree of completeness in both NCLR (97 %) and NPR (99 %) as compared to the gold standard. INTERPRETATION: The result confirms that NCLR has a high degree of registration completeness two years after establishment, and that data from the registry can be used in future research. PMID- 21304575 TI - [Warfarin combined with blood platelet inhibition]. AB - Dual antiplatelet therapy (acetylsalicylic acid and a thienopyridine) is essential after coronary stent implantation, and in the treatment of acute coronary syndrome. Many patients also need oral anticoagulation. Unfortunately, there are no prospective randomised trials to guide therapy. Triple antithrombotic therapy with acetylsalicylic acid, clopidogrel and warfarin is most commonly used. This regimen can reduce the risk of thrombosis and thromboembolism, but is associated with an increased risk of bleeding. Measures that reduce the risk of complications are reduction of INR with careful monitoring, a short duration of triple therapy (when possible) and use of radial access and a bare metal stent. PMID- 21304576 TI - [Explaining mental illness.]. PMID- 21304579 TI - Using transcription modules to identify expression clusters perturbed in Williams Beuren syndrome. AB - The genetic dissection of the phenotypes associated with Williams-Beuren Syndrome (WBS) is advancing thanks to the study of individuals carrying typical or atypical structural rearrangements, as well as in vitro and animal studies. However, little is known about the global dysregulations caused by the WBS deletion. We profiled the transcriptomes of skin fibroblasts from WBS patients and compared them to matched controls. We identified 868 differentially expressed genes that were significantly enriched in extracellular matrix genes, major histocompatibility complex (MHC) genes, as well as genes in which the products localize to the postsynaptic membrane. We then used public expression datasets from human fibroblasts to establish transcription modules, sets of genes coexpressed in this cell type. We identified those sets in which the average gene expression was altered in WBS samples. Dysregulated modules are often interconnected and share multiple common genes, suggesting that intricate regulatory networks connected by a few central genes are disturbed in WBS. This modular approach increases the power to identify pathways dysregulated in WBS patients, thus providing a testable set of additional candidates for genes and their interactions that modulate the WBS phenotypes. PMID- 21304581 TI - Distribution of introns in fungal histone genes. AB - Saccharomycotina and Taphrinomycotina lack intron in their histone genes, except for an intron in one of histone H4 genes of Yarrowia lipolytica. On the other hand, Basidiomycota and Perizomycotina have introns in their histone genes. We compared the distributions of 81, 47, 79, and 98 introns in the fungal histone H2A, H2B, H3, and H4 genes, respectively. Based on the multiple alignments of the amino acid sequences of histones, we identified 19, 13, 31, and 22 intron insertion sites in the histone H2A, H2B, H3, and H4 genes, respectively. Surprisingly only one hot spot of introns in the histone H2A gene is shared between Basidiomycota and Perizomycotina, suggesting that most of introns of Basidiomycota and Perizomycotina were acquired independently. Our findings suggest that the common ancestor of Ascomycota and Basidiomycota maybe had a few introns in the histone genes. In the course of fungal evolution, Saccharomycotina and Taphrinomycotina lost the histone introns; Basidiomycota and Perizomycotina acquired other introns independently. In addition, most of the introns have sequence similarity among introns of phylogenetically close species, strongly suggesting that horizontal intron transfer events between phylogenetically distant species have not occurred recently in the fungal histone genes. PMID- 21304580 TI - Transcription reprogramming during root nodule development in Medicago truncatula. AB - Many genes which are associated with root nodule development and activity in the model legume Medicago truncatula have been described. However information on precise stages of activation of these genes and their corresponding transcriptional regulators is often lacking. Whether these regulators are shared with other plant developmental programs also remains an open question. Here detailed microarray analyses have been used to study the transcriptome of root nodules induced by either wild type or mutant strains of Sinorhizobium meliloti. In this way we have defined eight major activation patterns in nodules and identified associated potential regulatory genes. We have shown that transcription reprogramming during consecutive stages of nodule differentiation occurs in four major phases, respectively associated with (i) early signalling events and/or bacterial infection; plant cell differentiation that is either (ii) independent or (iii) dependent on bacteroid differentiation; (iv) nitrogen fixation. Differential expression of several genes involved in cytokinin biosynthesis was observed in early symbiotic nodule zones, suggesting that cytokinin levels are actively controlled in this region. Taking advantage of databases recently developed for M. truncatula, we identified a small subset of gene expression regulators that were exclusively or predominantly expressed in nodules, whereas most other regulators were also activated under other conditions, and notably in response to abiotic or biotic stresses. We found evidence suggesting the activation of the jasmonate pathway in both wild type and mutant nodules, thus raising questions about the role of jasmonate during nodule development. Finally, quantitative RT-PCR was used to analyse the expression of a series of nodule regulator and marker genes at early symbiotic stages in roots and allowed us to distinguish several early stages of gene expression activation or repression. PMID- 21304582 TI - Microbial diversity of a Brazilian coastal region influenced by an upwelling system and anthropogenic activity. AB - BACKGROUND: Upwelling systems are characterised by an intense primary biomass production in the surface (warmest) water after the outcrop of the bottom (coldest) water, which is rich in nutrients. Although it is known that the microbial assemblage plays an important role in the food chain of marine systems and that the upwelling systems that occur in southwest Brazil drive the complex dynamics of the food chain, little is known about the microbial composition present in this region. METHODOLOGY/PRINCIPAL FINDINGS: We carried out a molecular survey based on SSU rRNA gene from the three domains of the phylogenetic tree of life present in a tropical upwelling region (Arraial do Cabo, Rio de Janeiro, Brazil). The aim was to analyse the horizontal and vertical variations of the microbial composition in two geographically close areas influenced by anthropogenic activity (sewage disposal/port activity) and upwelling phenomena, respectively. A lower estimated diversity of microorganisms of the three domains of the phylogenetic tree of life was found in the water of the area influenced by anthropogenic activity compared to the area influenced by upwelling phenomena. We observed a heterogenic distribution of the relative abundance of taxonomic groups, especially in the Archaea and Eukarya domains. The bacterial community was dominated by Proteobacteria, Cyanobacteria and Bacteroidetes phyla, whereas the microeukaryotic community was dominated by Metazoa, Fungi, Alveolata and Stramenopile. The estimated archaeal diversity was the lowest of the three domains and was dominated by uncharacterised marine Crenarchaeota that were most closely related to Marine Group I. CONCLUSIONS/SIGNIFICANCE: The variety of conditions and the presence of different microbial assemblages indicated that the area of Arraial do Cabo can be used as a model for detailed studies that contemplate the correlation between pollution indicating parameters and the depletion of microbial diversity in areas close to anthropogenic activity; functional roles and geochemical processes; phylogeny of the uncharacterised diversity; and seasonal variations of the microbial assemblages. PMID- 21304583 TI - Bacterial delivery of nuclear proteins into pluripotent and differentiated cells. AB - Numerous Gram negative pathogens possess a type III secretion system (T3SS) which allows them to inject virulent proteins directly into the eukaryotic cell cytoplasm. Injection of these proteins is dependent on a variable secretion signal sequence. In this study, we utilized the N-terminal secretion signal sequence of Pseudomonas aeruginosa exotoxin ExoS to translocate Cre recombinase containing a nuclear localization sequence (Cre-NLS). Transient exposure of human sarcoma cell line, containing Cre-dependent lacZ reporter, resulted in efficient recombination in the host chromosome, indicating that the bacterially delivered protein was not only efficiently localized to the nucleus but also retained its biological function. Using this system, we also illustrate the ability of P. aeruginosa to infect mouse embryonic stem cells (mESC) and the susceptibility of these cells to bacterially delivered Cre-NLS. A single two-hour infection caused as high as 30% of the mESC reporter cells to undergo loxP mediated chromosomal DNA recombination. A simple antibiotic treatment completely eliminated the bacterial cells following the delivery, while the use of an engineered mutant strain greatly reduced cytotoxicity. Utility of the system was demonstrated by delivery of the Cre-NLS to induced pluripotent stem cells to excise the floxed oncogenic nuclear reprogramming cassette. These results validate the use of T3SS for the delivery of transcription factors for the purpose of cellular reprogramming. PMID- 21304584 TI - Decapitation in rats: latency to unconsciousness and the 'wave of death'. AB - The question whether decapitation is a humane method of euthanasia in awake animals is being debated. To gather arguments in this debate, obsolete rats were decapitated while recording the EEG, both of awake rats and of anesthetized rats. Following decapitation a fast and global loss of power of the EEG was observed; the power in the 13-100 Hz frequency band, expressing cognitive activity, decreased according to an exponential decay function to half the initial value within 4 seconds. Whereas the pre-decapitation EEG of the anesthetized animals showed a burst suppression pattern quite different from the awake animals, the power in the postdecapitation EEG did not differ between the two groups. This might indicate that either the power of the EEG does not correlate well with consciousness or that consciousness is briefly regained in the anesthetized group after decapitation. Remarkably, after 50 seconds (awake group) or 80 seconds (anesthetized group) following decapitation, a high amplitude slow wave was observed. The EEG before this wave had more power than the signal after the wave. This wave might be due to a simultaneous massive loss of membrane potentials of the neurons. Still functioning ion channels, which keep the membrane potential intact before the wave, might explain the observed power difference. Two conclusions were drawn from this experiment. It is likely that consciousness vanishes within seconds after decapitation, implying that decapitation is a quick and not an inhumane method of euthanasia. It seems that the massive wave which can be recorded approximately one minute after decapitation reflects the ultimate border between life and death. This observation might have implications in the discussions on the appropriate time for organ donation. PMID- 21304585 TI - Identification of natural bispecific antibodies against cyclic citrullinated peptide and immunoglobulin G in rheumatoid arthritis. AB - BACKGROUND: Previous studies indicate that natural bispecific antibodies can be readily produced in vivo when the body is simultaneously stimulated with 2 distinct antigens. Patients with rheumatoid arthritis (RA) usually exhibit persistent immune responses to various autoantigens, raising the possibility that natural bispecific antibodies against 2 distinct autoantigens might exist. METHODOLOGY/PRINCIPAL FINDINGS: We identified the presence of natural bispecific antibodies against cyclic citrullinated peptide (CCP) and immunoglobulin G (IgG) in RA patients' sera by means of a double-antigen sandwich enzyme-linked immunosorbent assay (ELISA). The spontaneous emergence of bispecific antibodies was confirmed by mixing different proportions of 1 anti-CCP-positive serum and 1 rheumatoid factor (RF)-positive serum in vitro. Among the tested samples, positive correlations were found between the presence of bispecific antibodies and both IgG4 anti-CCP antibodies and IgG4 RF (r = 0.507, p<0.001 and r = 0.249, p = 0.044, respectively), suggesting that the IgG4 subclass is associated with this phenomenon. Furthermore, bispecific antibodies were selectively generated when several anti-CCP- and RF-positive sera were mixed pairwise, indicating that factors other than the monospecific antibody titers may also contribute to the production of the natural bispecific antibodies. CONCLUSIONS/SIGNIFICANCE: We successfully identified the presence of natural bispecific antibodies. Our results suggest that these antibodies originate from anti-CCP and RF in the sera of RA patients. The natural occurrence of bispecific antibodies in human diseases may provide new insights for a better understanding of the diseases. Further investigations are needed to elucidate their precise generation mechanisms and explore their clinical significance in disease development and progression in a larger study population. PMID- 21304586 TI - Evidence for epithelial-mesenchymal transition in cancer stem cells of head and neck squamous cell carcinoma. AB - Initiation, growth, recurrence, and metastasis of head and neck squamous cell carcinomas (HNSCC) have been related to the behavior of cancer stem cells (CSC) that can be identified by their aldehyde-dehydrogenase-isoform-1 (ALDH1) activity. We quantified and enriched ALDH1(+) cells within HNSCC cell lines and subsequently characterized their phenotypical and functional properties like invasion capacity and epithelial-mesenchymal transition (EMT). Spheroid culture enriched CSC from five HNSCC cell lines by up to 5-fold. In spheroid-derived cells (SDC) and the parental monolayer-derived cell line ALDH1, CD44, CD24, E Cadherin, alpha-SMA, and Vimentin expression was compared by flow-cytometry and immunofluorescence together with proliferation and cell cycle analysis. Invasion activity was evaluated by Matrigel assay and expression of stemness-related transcription factors (TF) Nanog, Oct3/4, Sox2 and EMT-related genes Snail1 and 2, and Twist by real-time PCR. All cell lines formed spheroids that could self renew and be serially re-passaged. ALDH1 expression was significantly higher in SDC. ALDH1(+) cells showed increased colony-formation. The proportion of cells with a putative CSC marker constellation of CD44(+)/CD24(-) was highly variable (0.5% to 96%) in monolayer and spheroid cultures and overlapped in 0%-33% with the CD44(+)/CD24(-)/ALDH1(+) cell subset. SDC had significantly higher invading activity. mRNA of the stemness-related genes Sox2, Nanog, and Oct3/4 was significantly increased in SDC of all cell lines. Twist was significantly increased in two while Snail2 showed a significant increase in one and a significant decrease in SDC of two cell lines. SDC had a higher G0 phase proportion, showed high-level expression of alpha-SMA and Vimentin, but significantly decreased E-Cadherin expression. HNSCC-lines harbor potential CSC, characterized by ALDH1 and stemness marker TF expression as well as properties like invasiveness, quiescence, and EMT. CSC can be enriched by anchorage independent culture techniques, which may be important for the investigation of their contribution to therapy resistance, tumor recurrence and metastasis. PMID- 21304587 TI - Double-positive CD21+CD27+ B cells are highly proliferating memory cells and their distribution differs in mucosal and peripheral tissues. AB - BACKGROUND: Several B-cell defects arise in HIV infected patients, particularly in patients with chronic infection and high viral load. Loss of memory B cells (CD27(+) B cells) in peripheral blood and lymphoid tissues is one of the major B cell dysfunctions in HIV and simian immunodeficiency virus (SIV) infection. Despite several studies, definitive identification of memory B cells based on CD27 surface expression has not been described. Similarly, the rates of cell turnover in different B cell subpopulation from lymphoid and mucosal tissues have not been well documented. In this study, we demonstrate the presence of memory B cell populations and define their distribution, frequency and immunophenotype with regards to activation, proliferation, maturation, and antibody production in normal rhesus macaques from different lymphoid tissues. METHODOLOGY/PRINCIPAL FINDINGS: Thirteen healthy, uninfected rhesus macaques were selected for this study. CD20(+) B cells were isolated from peripheral blood and sorted based on CD27 and CD21 surface markers to define memory B cell population. All the B cell subpopulation was further characterized phenotypically and their cell turnover rates were evaluated in vivo following bromodeoxyuridine (BrdU) inoculation. Double positive (DP) CD21(+)CD27(+) B cells in both peripheral and lymphoid tissues are memory B cells, able to produce antibody by polyclonal activation, and without T cell help. Peripheral and lymphoid DP CD21(+)CD27(+) B cells were also able to become activated and proliferate at higher rates than other B cell subpopulations. Increased turnover of tonsillar memory B cells were identified compared to other tissues examined. CONCLUSIONS/SIGNIFICANCE: We suggest that this DP memory B cells play a major role in the immune system and their function and proliferation might have an important role in HIV/SIV mediated B cell dysregulation and pathogenesis. PMID- 21304588 TI - Loss of Pten causes tumor initiation following differentiation of murine pluripotent stem cells due to failed repression of Nanog. AB - Pluripotent stem cells (PSCs) hold significant promise in regenerative medicine due to their unlimited capacity for self-renewal and potential to differentiate into every cell type in the body. One major barrier to the use of PSCs is their potential risk for tumor initiation following differentiation and transplantation in vivo. In the current study we sought to evaluate the role of the tumor suppressor Pten in murine PSC neoplastic progression. Using eight functional assays that have previously been used to indicate PSC adaptation or transformation, Pten null embryonic stem cells (ESCs) failed to rate as significant in five of them. Instead, our data demonstrate that the loss of Pten causes the emergence of a small number of aggressive, teratoma-initiating embryonic carcinoma cells (ECCs) during differentiation in vitro, while the remaining 90-95% of differentiated cells are non-tumorigenic. Furthermore, our data show that the mechanism by which Pten null ECCs emerge in vitro and cause tumors in vivo is through increased survival and self-renewal, due to failed repression of the transcription factor Nanog. PMID- 21304589 TI - Induction of the Wnt antagonist Dickkopf-1 is involved in stress-induced hippocampal damage. AB - The identification of mechanisms that mediate stress-induced hippocampal damage may shed new light into the pathophysiology of depressive disorders and provide new targets for therapeutic intervention. We focused on the secreted glycoprotein Dickkopf-1 (Dkk-1), an inhibitor of the canonical Wnt pathway, involved in neurodegeneration. Mice exposed to mild restraint stress showed increased hippocampal levels of Dkk-1 and reduced expression of beta-catenin, an intracellular protein positively regulated by the canonical Wnt signalling pathway. In adrenalectomized mice, Dkk-1 was induced by corticosterone injection, but not by exposure to stress. Corticosterone also induced Dkk-1 in mouse organotypic hippocampal cultures and primary cultures of hippocampal neurons and, at least in the latter model, the action of corticosterone was reversed by the type-2 glucocorticoid receptor antagonist mifepristone. To examine whether induction of Dkk-1 was causally related to stress-induced hippocampal damage, we used doubleridge mice, which are characterized by a defective induction of Dkk-1. As compared to control mice, doubleridge mice showed a paradoxical increase in basal hippocampal Dkk-1 levels, but no Dkk-1 induction in response to stress. In contrast, stress reduced Dkk-1 levels in doubleridge mice. In control mice, chronic stress induced a reduction in hippocampal volume associated with neuronal loss and dendritic atrophy in the CA1 region, and a reduced neurogenesis in the dentate gyrus. Doubleridge mice were resistant to the detrimental effect of chronic stress and, instead, responded to stress with increases in dendritic arborisation and neurogenesis. Thus, the outcome of chronic stress was tightly related to changes in Dkk-1 expression in the hippocampus. These data indicate that induction of Dkk-1 is causally related to stress-induced hippocampal damage and provide the first evidence that Dkk-1 expression is regulated by corticosteroids in the central nervous system. Drugs that rescue the canonical Wnt pathway may attenuate hippocampal damage in major depression and other stress related disorders. PMID- 21304590 TI - Conjunctive processing of locomotor signals by the ventral tegmental area neuronal population. AB - The ventral tegmental area (VTA) plays an essential role in reward and motivation. How the dopamine (DA) and non-DA neurons in the VTA engage in motivation-based locomotor behaviors is not well understood. We recorded activity of putative DA and non-DA neurons simultaneously in the VTA of awake mice engaged in motivated voluntary movements such as wheel running. Our results revealed that VTA non-DA neurons exhibited significant rhythmic activity that was correlated with the animal's running rhythms. Activity of putative DA neurons also correlated with the movement behavior, but to a lesser degree. More importantly, putative DA neurons exhibited significant burst activation at both onset and offset of voluntary movements. These findings suggest that VTA DA and non-DA neurons conjunctively process locomotor-related motivational signals that are associated with movement initiation, maintenance and termination. PMID- 21304591 TI - A recombinant vaccine of H5N1 HA1 fused with foldon and human IgG Fc induced complete cross-clade protection against divergent H5N1 viruses. AB - Development of effective vaccines to prevent influenza, particularly highly pathogenic avian influenza (HPAI) caused by influenza A virus (IAV) subtype H5N1, is a challenging goal. In this study, we designed and constructed two recombinant influenza vaccine candidates by fusing hemagglutinin 1 (HA1) fragment of A/Anhui/1/2005(H5N1) to either Fc of human IgG (HA1-Fc) or foldon plus Fc (HA1 Fdc), and evaluated their immune responses and cross-protection against divergent strains of H5N1 virus. Results showed that these two recombinant vaccines induced strong immune responses in the vaccinated mice, which specifically reacted with HA1 proteins and an inactivated heterologous H5N1 virus. Both proteins were able to cross-neutralize infections by one homologous strain (clade 2.3) and four heterologous strains belonging to clades 0, 1, and 2.2 of H5N1 pseudoviruses as well as three heterologous strains (clades 0, 1, and 2.3.4) of H5N1 live virus. Importantly, immunization with these two vaccine candidates, especially HA1-Fdc, provided complete cross-clade protection against high-dose lethal challenge of different strains of H5N1 virus covering clade 0, 1, and 2.3.4 in the tested mouse model. This study suggests that the recombinant fusion proteins, particularly HA1-Fdc, could be developed into an efficacious universal H5N1 influenza vaccine, providing cross-protection against infections by divergent strains of highly pathogenic H5N1 virus. PMID- 21304592 TI - False-positive human immunodeficiency virus enzyme immunoassay results in pregnant women. AB - OBJECTIVE: Examine whether false-positive HIV enzyme immunoassay (EIA) test results occur more frequently among pregnant women than among women who are not pregnant and men (others). DESIGN: To obtain a large number of pregnant women and others tested for HIV, we identified specimens tested at a national laboratory using Genetic Systems HIV-1/HIV-2 Plus O EIA from July 2007 to June 2008. METHODS: Specimens with EIA repeatedly reactive and Western blot-negative or indeterminate results were considered EIA false-positive. We compared the false positive rate among uninfected pregnant women and others, adjusting for HIV prevalence. Among all reactive EIAs, we evaluated the proportion of false positives, positive predictive value (PPV), and Western blot bands among indeterminates, by pregnancy status. RESULTS: HIV prevalence was 0.06% among 921,438 pregnant women and 1.34% among 1,103,961 others. The false-positive rate was lower for pregnant women than others (0.14% vs. 0.21%, odds ratio 0.65 [95% confidence interval 0.61, 0.70]). Pregnant women with reactive EIAs were more likely than others (p<0.01) to have Western blot-negative (52.9% vs. 9.8%) and indeterminate results (17.0% vs. 3.7%) and lower PPV (30% vs. 87%). The p24 band was detected more often among pregnant women (p<0.01). CONCLUSIONS: False positive HIV EIA results were rare and occurred less frequently among pregnant women than others. Pregnant women with reactive EIAs were more likely to have negative and indeterminate Western blot results due to lower HIV prevalence and higher p24 reactivity, respectively. Indeterminate results may complicate clinical management during pregnancy. Alternative methods are needed to rule out infection in persons with reactive EIAs from low prevalence populations. PMID- 21304593 TI - Early target cells of measles virus after aerosol infection of non-human primates. AB - Measles virus (MV) is highly infectious, and has long been thought to enter the host by infecting epithelial cells of the respiratory tract. However, epithelial cells do not express signaling lymphocyte activation molecule (CD150), which is the high-affinity cellular receptor for wild-type MV strains. We have generated a new recombinant MV strain expressing enhanced green fluorescent protein (EGFP), based on a wild-type genotype B3 virus isolate from Khartoum, Sudan (KS). Cynomolgus macaques were infected with a high dose of rMV(KS)EGFP by aerosol inhalation to ensure that the virus could reach the full range of potential target cells throughout the entire respiratory tract. Animals were euthanized 2, 3, 4 or 5 days post-infection (d.p.i., n = 3 per time point) and infected (EGFP(+)) cells were identified at all four time points, albeit at low levels 2 and 3 d.p.i. At these earliest time points, MV-infected cells were exclusively detected in the lungs by fluorescence microscopy, histopathology and/or virus isolation from broncho-alveolar lavage cells. On 2 d.p.i., EGFP(+) cells were phenotypically typed as large mononuclear cells present in the alveolar lumen or lining the alveolar epithelium. One to two days later, larger clusters of MV infected cells were detected in bronchus-associated lymphoid tissue (BALT) and in the tracheo-bronchial lymph nodes. From 4 d.p.i. onward, MV-infected cells were detected in peripheral blood and various lymphoid tissues. In spite of the possibility for the aerosolized virus to infect cells and lymphoid tissues of the upper respiratory tract, MV-infected cells were not detected in either the tonsils or the adenoids until after onset of viremia. These data strongly suggest that in our model MV entered the host at the alveolar level by infecting macrophages or dendritic cells, which traffic the virus to BALT or regional lymph nodes, resulting in local amplification and subsequent systemic dissemination by viremia. PMID- 21304594 TI - Genome sequence analyses of Pseudomonas savastanoi pv. glycinea and subtractive hybridization-based comparative genomics with nine pseudomonads. AB - Bacterial blight, caused by Pseudomonas savastanoi pv. glycinea (Psg), is a common disease of soybean. In an effort to compare a current field isolate with one isolated in the early 1960s, the genomes of two Psg strains, race 4 and B076, were sequenced using 454 pyrosequencing. The genomes of both Psg strains share more than 4,900 highly conserved genes, indicating very low genetic diversity between Psg genomes. Though conserved, genome rearrangements and recombination events occur commonly within the two Psg genomes. When compared to each other, 437 and 163 specific genes were identified in B076 and race 4, respectively. Most specific genes are plasmid-borne, indicating that acquisition and maintenance of plasmids may represent a major mechanism to change the genetic composition of the genome and even acquire new virulence factors. Type three secretion gene clusters of Psg strains are near identical with that of P. savastanoi pv. phaseolicola (Pph) strain 1448A and they shared 20 common effector genes. Furthermore, the coronatine biosynthetic cluster is present on a large plasmid in strain B076, but not in race 4. In silico subtractive hybridization-based comparative genomic analyses with nine sequenced phytopathogenic pseudomonads identified dozens of specific islands (SIs), and revealed that the genomes of Psg strains are more similar to those belonging to the same genomospecies such as Pph 1448A than to other phytopathogenic pseudomonads. The number of highly conserved genes (core genome) among them decreased dramatically when more genomes were included in the subtraction, suggesting the diversification of pseudomonads, and further indicating the genome heterogeneity among pseudomonads. However, the number of specific genes did not change significantly, suggesting these genes are indeed specific in Psg genomes. These results reinforce the idea of a species complex of P. syringae and support the reclassification of P. syringae into different species. PMID- 21304595 TI - A quantitative comparison of cell-type-specific microarray gene expression profiling methods in the mouse brain. AB - Expression profiling of restricted neural populations using microarrays can facilitate neuronal classification and provide insight into the molecular bases of cellular phenotypes. Due to the formidable heterogeneity of intermixed cell types that make up the brain, isolating cell types prior to microarray processing poses steep technical challenges that have been met in various ways. These methodological differences have the potential to distort cell-type-specific gene expression profiles insofar as they may insufficiently filter out contaminating mRNAs or induce aberrant cellular responses not normally present in vivo. Thus we have compared the repeatability, susceptibility to contamination from off-target cell-types, and evidence for stress-responsive gene expression of five different purification methods--Laser Capture Microdissection (LCM), Translating Ribosome Affinity Purification (TRAP), Immunopanning (PAN), Fluorescence Activated Cell Sorting (FACS), and manual sorting of fluorescently labeled cells (Manual). We found that all methods obtained comparably high levels of repeatability, however, data from LCM and TRAP showed significantly higher levels of contamination than the other methods. While PAN samples showed higher activation of apoptosis related, stress-related and immediate early genes, samples from FACS and Manual studies, which also require dissociated cells, did not. Given that TRAP targets actively translated mRNAs, whereas other methods target all transcribed mRNAs, observed differences may also reflect translational regulation. PMID- 21304596 TI - New detection systems of bacteria using highly selective media designed by SMART: selective medium-design algorithm restricted by two constraints. AB - Culturing is an indispensable technique in microbiological research, and culturing with selective media has played a crucial role in the detection of pathogenic microorganisms and the isolation of commercially useful microorganisms from environmental samples. Although numerous selective media have been developed in empirical studies, unintended microorganisms often grow on such media probably due to the enormous numbers of microorganisms in the environment. Here, we present a novel strategy for designing highly selective media based on two selective agents, a carbon source and antimicrobials. We named our strategy SMART for highly Selective Medium-design Algorithm Restricted by Two constraints. To test whether the SMART method is applicable to a wide range of microorganisms, we developed selective media for Burkholderia glumae, Acidovorax avenae, Pectobacterium carotovorum, Ralstonia solanacearum, and Xanthomonas campestris. The series of media developed by SMART specifically allowed growth of the targeted bacteria. Because these selective media exhibited high specificity for growth of the target bacteria compared to established selective media, we applied three notable detection technologies: paper-based, flow cytometry-based, and color change-based detection systems for target bacteria species. SMART facilitates not only the development of novel techniques for detecting specific bacteria, but also our understanding of the ecology and epidemiology of the targeted bacteria. PMID- 21304597 TI - Dimeric SecA couples the preprotein translocation in an asymmetric manner. AB - The Sec translocase mediates the post-translational translocation of a number of preproteins through the inner membrane in bacteria. In the initiatory translocation step, SecB targets the preprotein to the translocase by specific interaction with its receptor SecA. The latter is the ATPase of Sec translocase which mediates the post-translational translocation of preprotein through the protein-conducting channel SecYEG in the bacterial inner membrane. We examined the structures of Escherichia coli Sec intermediates in solution as visualized by negatively stained electron microscopy in order to probe the oligomeric states of SecA during this process. The symmetric interaction pattern between the SecA dimer and SecB becomes asymmetric in the presence of proOmpA, and one of the SecA protomers predominantly binds to SecB/proOmpA. Our results suggest that during preprotein translocation, the two SecA protomers are different in structure and may play different roles. PMID- 21304599 TI - Determinants outside the DevR C-terminal domain are essential for cooperativity and robust activation of dormancy genes in Mycobacterium tuberculosis. AB - BACKGROUND: DevR (also called as DosR) is a two-domain response regulator of the NarL subfamily that controls dormancy adaptation of Mycobacterium tuberculosis (M. tb). In response to inducing signals such as hypoxia and ascorbic acid, the N terminal receiver domain of DevR (DevR(N)) is phosphorylated at Asp54. This results in DevR binding to DNA via its C-terminal domain (DevR(C)) and subsequent induction of the DevR regulon. The mechanism of phosphorylation-mediated activation is not known. The present study was designed to understand the role of the N- and C-terminal domains of DevR in DevR regulon genes activation. METHODOLOGY/PRINCIPAL FINDINGS: Towards deciphering the activation mechanism of DevR, we compared the DNA binding properties of DevR(C) and DevR and correlated the findings with their ability to activate gene expression. We show that isolated DevR(C) can interact with DNA, but only with the high affinity site of a representative target promoter. Therefore, one role of DevR(N) is to mask the intrinsic DNA binding function of DevR(C). However, unlike phosphorylated DevR, isolated DevR(C) does not interact with the adjacent low affinity binding site suggesting that a second role of DevR(N) is in cooperative binding to the secondary site. Transcriptional analysis shows that consistent with unmasking of its DNA binding property, DevR(C) supports the aerobic induction, albeit feebly, of DevR regulon genes but is unable to sustain gene activation during hypoxia. CONCLUSIONS/SIGNIFICANCE: DevR is a unique response regulator that employs a dual activation mechanism including relief of inhibition and cooperative interaction with binding sites. Importantly, both these functions reside outside the C terminal domain. DevR(N) is also essential for stabilizing DevR and sustaining autoregulation under hypoxia. Hence, both domains of DevR are required for robust transcription activation. PMID- 21304598 TI - The thioredoxin TRX-1 modulates the function of the insulin-like neuropeptide DAF 28 during dauer formation in Caenorhabditis elegans. AB - Thioredoxins comprise a conserved family of redox regulators involved in many biological processes, including stress resistance and aging. We report that the C. elegans thioredoxin TRX-1 acts in ASJ head sensory neurons as a novel modulator of the insulin-like neuropeptide DAF-28 during dauer formation. We show that increased formation of stress-resistant, long-lived dauer larvae in mutants for the gene encoding the insulin-like neuropeptide DAF-28 requires TRX-1 acting in ASJ neurons, upstream of the insulin-like receptor DAF-2. Genetic rescue experiments demonstrate that redox-independent functions of TRX-1 specifically in ASJ neurons are needed for the dauer formation constitutive (Daf-c) phenotype of daf-28 mutants. GFP reporters of trx-1 and daf-28 show opposing expression patterns in dauers (i.e. trx-1 is up-regulated and daf-28 is down-regulated), an effect that is not observed in growing L2/L3 larvae. In addition, functional TRX 1 is required for the down-regulation of a GFP reporter of daf-28 during dauer formation, a process that is likely subject to DAF-28-mediated feedback regulation. Our findings demonstrate that TRX-1 modulates DAF-28 signaling by contributing to the down-regulation of daf-28 expression during dauer formation. We propose that TRX-1 acts as a fluctuating neuronal signaling modulator within ASJ neurons to monitor the adjustment of neuropeptide expression, including insulin-like proteins, during dauer formation in response to adverse environmental conditions. PMID- 21304601 TI - DNA topoisomerase II modulates insulator function in Drosophila. AB - Insulators are DNA sequences thought to be important for the establishment and maintenance of cell-type specific nuclear architecture. In Drosophila there are several classes of insulators that appear to have unique roles in gene expression. The mechanisms involved in determining and regulating the specific roles of these insulator classes are not understood. Here we report that DNA Topoisomerase II modulates the activity of the Su(Hw) insulator. Downregulation of Topo II by RNAi or mutations in the Top2 gene result in disruption of Su(Hw) insulator function. This effect is mediated by the Mod(mdg4)2.2 protein, which is a unique component of the Su(Hw) insulator complex. Co-immunoprecipitation and yeast two-hybrid experiments show that Topo II and Mod(mdg4)2.2 proteins directly interact. In addition, mutations in Top2 cause a slight decrease of Mod(mdg4)2.2 transcript but have a dramatic effect on Mod(mdg4)2.2 protein levels. In the presence of proteasome inhibitors, normal levels of Mod(mdg4)2.2 protein and its binding to polytene chromosomes are restored. Thus, Topo II is required to prevent Mod(mdg4)2.2 degradation and, consequently, to stabilize Su(Hw) insulator mediated chromatin organization. PMID- 21304600 TI - Mucosal targeting of a BoNT/A subunit vaccine adjuvanted with a mast cell activator enhances induction of BoNT/A neutralizing antibodies in rabbits. AB - BACKGROUND: We previously reported that the immunogenicity of Hcbetatre, a botulinum neurotoxin A (BoNT/A) immunogen, was enhanced by fusion to an epithelial cell binding domain, Ad2F, when nasally delivered to mice with cholera toxin (CT). This study was performed to determine if Ad2F would enhance the nasal immunogenicity of Hcbetatre in rabbits, an animal model with a nasal cavity anatomy similar to humans. Since CT is not safe for human use, we also tested the adjuvant activity of compound 48/80 (C48/80), a mast cell activating compound previously determined to safely exhibit nasal adjuvant activity in mice. METHODS: New Zealand White or Dutch Belted rabbits were nasally immunized with Hcbetatre or Hcbetatre-Ad2F alone or combined with CT or C48/80, and serum samples were tested for the presence of Hcbetatre-specific binding (ELISA) or BoNT/A neutralizing antibodies. RESULTS: Hcbetatre-Ad2F nasally administered with CT induced serum anti-Hcbetatre IgG ELISA and BoNT/A neutralizing antibody titers greater than those induced by Hcbetatre + CT. C48/80 provided significant nasal adjuvant activity and induced BoNT/A-neutralizing antibodies similar to those induced by CT. CONCLUSIONS: Ad2F enhanced the nasal immunogenicity of Hcbetatre, and the mast cell activator C48/80 was an effective adjuvant for nasal immunization in rabbits, an animal model with a nasal cavity anatomy similar to that in humans. PMID- 21304602 TI - The receptor-like kinase SERK3/BAK1 is required for basal resistance against the late blight pathogen phytophthora infestans in Nicotiana benthamiana. AB - BACKGROUND: The filamentous oomycete plant pathogen Phytophthora infestans causes late blight, an economically important disease, on members of the nightshade family (Solanaceae), such as the crop plants potato and tomato. The related plant Nicotiana benthamiana is a model system to study plant-pathogen interactions, and the susceptibility of N. benthamiana to Phytophthora species varies from susceptible to resistant. Little is known about the extent to which plant basal immunity, mediated by membrane receptors that recognise conserved pathogen associated molecular patterns (PAMPs), contributes to P. infestans resistance. PRINCIPAL FINDINGS: We found that different species of Phytophthora have varying degrees of virulence on N. benthamiana ranging from avirulence (incompatible interaction) to moderate virulence through to full aggressiveness. The leucine rich repeat receptor-like kinase (LRR-RLK) BAK1/SERK3 is a major modulator of PAMP-triggered immunity (PTI) in Arabidopsis thaliana and N. benthamiana. We cloned two NbSerk3 homologs, NbSerk3A and NbSerk3B, from N. benthamiana based on sequence similarity to the A. thaliana gene. N. benthamiana plants silenced for NbSerk3 showed markedly enhanced susceptibility to P. infestans infection but were not altered in resistance to Phytophthora mirabilis, a sister species of P. infestans that specializes on a different host plant. Furthermore, silencing of NbSerk3 reduced the cell death response triggered by the INF1, a secreted P. infestans protein with features of PAMPs. CONCLUSIONS/SIGNIFICANCE: We demonstrated that N. benthamiana NbSERK3 significantly contributes to resistance to P. infestans and regulates the immune responses triggered by the P. infestans PAMP protein INF1. In the future, the identification of novel surface receptors that associate with NbSERK3A and/or NbSERK3B should lead to the identification of new receptors that mediate recognition of oomycete PAMPs, such as INF1. PMID- 21304603 TI - The antidiabetic effect of MSCs is not impaired by insulin prophylaxis and is not improved by a second dose of cells. AB - Type 1 diabetes mellitus (T1D) is due to autoimmune destruction of pancreatic beta-cells. Previously, we have shown that intravenously administered bone marrow derived multipotent mesenchymal stromal cells (MSCs) allows pancreatic islet recovery, improves insulin secretion and reverts hyperglycemia in low doses streptozotocin (STZ)-induced diabetic mice. Here we evaluate whether insulin prophylaxis and the administration of a second dose of cells affect the antidiabetic therapeutic effect of MSC transplantation. Insulitis and subsequent elimination of pancreatic beta-cells was promoted in C57BL/6 mice by the injection of 40 mg/kg/day STZ for five days. Twenty-four days later, diabetic mice were distributed into experimental groups according to if they received or not insulin and/or one or two doses of healthy donor-derived MSCs. Three and half months later: glycemia, pancreatic islets number, insulinemia, glycated hemoglobin level and glucose tolerance were determined in animals that did not received exogenous insulin for the last 1.5 months. Also, we characterized MSCs isolated from mice healthy or diabetic. The therapeutic effect of MSC transplantation was observed in diabetic mice that received or not insulin prophylaxis. Improvements were similar irrespective if they received one or two doses of cells. Compared to MSCs from healthy mice, MSCs from diabetic mice had the same proliferation and adipogenic potentials, but were less abundant, with altered immunophenotype and no osteogenic potential.Our preclinical results should be taken into account when designing phase II clinical trials aimed to evaluate MSC transplantation in patients with T1D. Cells should be isolated form healthy donor, insulin prophylaxis could be maintained and a second dose, after an elapse of two months, appears unnecessary in the medium-term. PMID- 21304604 TI - MicroRNA-126 inhibits SOX2 expression and contributes to gastric carcinogenesis. AB - BACKGROUND: SRY (sex-determining region Y)-box 2 (SOX2) is a crucial transcription factor for the maintenance of embryonic stem cell pluripotency and the determination of cell fate. Previously, we demonstrated that SOX2 plays important roles in growth inhibition through cell cycle arrest and apoptosis, and that SOX2 expression is frequently down-regulated in gastric cancers. However, the mechanisms underlying loss of SOX2 expression and its target genes involved in gastric carcinogenesis remain largely unknown. Here, we assessed whether microRNAs (miRNAs) regulate SOX2 expression in gastric cancers. Furthermore, we attempted to find downstream target genes of SOX2 contributing to gastric carcinogenesis. METHODOLOGY/PRINCIPAL FINDINGS: We performed in silico analysis and focused on miRNA-126 (miR-126) as a potential SOX2 regulator. Gain- and loss of function experiments and luciferase assays revealed that miR-126 inhibited SOX2 expression by targeting two binding sites in the 3'-untranslated region (3' UTR) of SOX2 mRNA in multiple cell lines. In addition, miR-126 was highly expressed in some cultured and primary gastric cancer cells with low SOX2 protein levels. Furthermore, exogenous miR-126 over-expression as well as siRNA-mediated knockdown of SOX2 significantly enhanced the anchorage-dependent and -independent growth of gastric cancer cell lines. We next performed microarray analysis after SOX2 over-expression in a gastric cancer cell line, and found that expression of the placenta-specific 1 (PLAC1) gene was significantly down-regulated by SOX2 over-expression. siRNA- and miR-126-mediated SOX2 knockdown experiments revealed that miR-126 positively regulated PLAC1 expression through suppression of SOX2 expression in gastric cancer cells. CONCLUSIONS: Taken together, our results indicate that miR-126 is a novel miRNA that targets SOX2, and PLAC1 may be a novel downstream target gene of SOX2 in gastric cancer cells. These findings suggest that aberrant over-expression of miR-126 and consequent SOX2 down regulation may contribute to gastric carcinogenesis. PMID- 21304605 TI - High temperature triggers latent variation among individuals: oviposition rate and probability for outbreaks. AB - BACKGROUND: It is anticipated that extreme population events, such as extinctions and outbreaks, will become more frequent as a consequence of climate change. To evaluate the increased probability of such events, it is crucial to understand the mechanisms involved. Variation between individuals in their response to climatic factors is an important consideration, especially if microevolution is expected to change the composition of populations. METHODOLOGY/PRINCIPAL FINDINGS: Here we present data of a willow leaf beetle species, showing high variation among individuals in oviposition rate at a high temperature (20 degrees C). It is particularly noteworthy that not all individuals responded to changes in temperature; individuals laying few eggs at 20 degrees C continued to do so when transferred to 12 degrees C, whereas individuals that laid many eggs at 20 degrees C reduced their oviposition and laid the same number of eggs as the others when transferred to 12 degrees C. When transferred back to 20 degrees C most individuals reverted to their original oviposition rate. Thus, high variation among individuals was only observed at the higher temperature. Using a simple population model and based on regional climate change scenarios we show that the probability of outbreaks increases if there is a realistic increase in the number of warm summers. The probability of outbreaks also increased with increasing heritability of the ability to respond to increased temperature. CONCLUSIONS/SIGNIFICANCE: If climate becomes warmer and there is latent variation among individuals in their temperature response, the probability for outbreaks may increase. However, the likelihood for microevolution to play a role may be low. This conclusion is based on the fact that it has been difficult to show that microevolution affect the probability for extinctions. Our results highlight the urge for cautiousness when predicting the future concerning probabilities for extreme population events. PMID- 21304606 TI - Ethnobotanical study of medicinal plants used by Sabaots of Mt. Elgon Kenya. AB - Though the majority of people in Kenya and at Kopsiro Division in particular, rely on ethnomedicinal plant species to manage human ailments, the indigenous knowledge largely remains undocumented. Therefore, an ethnobotanical study was conducted on medicinal plant species used to manage human ailments at Kopsiro Division Mt. Elgon District Kenya. The objectives were to identify and document plants traditionally used for medicinal therapy by the Sabaots, to find out the method used for preparing and administering the drugs and to find out the conservation practices for the medicinal plants. Observations and semi-structured interviews were used to gather ethnobotanical data. 107 plants belonging to 56 families were identified and reported to be of medicinal value to the locals. Roots (47.3%) were the most frequently used parts of the plant followed by the bark (23.35%) then leaves (22.75%). The whole plant (1.8%), seed (1.2%), fruit (1.2%), sap (1.2%), flower (0.6%) and wood (0.6%) are least used in that order. The study revealed other hitherto undocumented medicinal plant species that may be new records for treating various ailments. Traditional medicine in Kopsiro division offers cheap, accessible and convenient remedy that suits the traditional lifestyle of the local community in comparison to the conventional medicine. Most medicinal plant species reported in this study were found to be under threat and this calls for urgent conservation measures so as to maximize the sustainable use of these vital resources in the study area. PMID- 21304607 TI - Traditional medicine as an alternative form of health care system: a preliminary case study of Nangabo sub-county, central Uganda. AB - This study was conducted in Nangabo sub-county of Wakiso district. The purpose was to document the common Traditional Medicine (TM) practices; assess the local people's preferences for TM versus western medicine (WM) and lastly to determine the awareness about the importance of TM by local people. Data were collected using semi-structured administered face-to-face with respondents. A total of 120 interviewed. Six focused group discussions (FGDs) were held to validate the questionnaire responses. Data were analyzed descriptively using Statistical Package for Social Sciences (SPSS). The findings indicated that most (43%) respondents derive their livelihoods from traditional medicine practices. Three forms of TM were reported-herbalism (67%), spiritual counseling (23%) and bone setting (10%). Although the majority (81%) of respondents were quite aware of the importance of TM in the sustenance of health care system, majority (55%) of them shunned TM in preference to WM, largely because of the belief that TM is evil founded and devilish in nature. Only 45% of the respondents preferred TM to WM. The main reasons given for visiting TM practioners rather than western medical practitioners were that TM is sometimes more effective than WM and that in many instances it has very minimal side effects on the human body. There is, however, a need for Ugandan government to legitimize the practice of TM since it contributes a lot to health care needs in areas where western medicine is insufficiently provided. In addition, there is a need for further research into the efficacy and safety of traditional medicines if it is to be adequately integrated into western medicine. PMID- 21304608 TI - Glabridin from Chinese herb licorice inhibits fatigue in mice. AB - The inhibiting effect of glabridin from Chinese herb Licorice on fatigue was investigated in male BALB/c mice. Mice were divided into the following 4 experimental groups: control group (CG), low dose group (LG), middle dose group (MG) and high dose group (HG,). The control group was given 0.5% Tween 80 solution and the treatment groups (LG, MG, HG) were given various doses of glabridin (5, 10, 20 mg/kg) for 28 consecutive days. Body mass, blood lactic acid (BLA), serum blood urea nitrogen (BUN), liver glycogen and muscle glycogen concentrations in mice were determined. Results showed that glabridin significantly inhibited fatigue, which extended the exhaustive exercise time of mice, effectively delayed the elevation of blood lactic acid and increase in the storage of liver and muscle glycogen. PMID- 21304609 TI - Teratogenic effect of the water extract of bitter gourd (Momordica charantia) on the Sprague Dawley rats. AB - It has been reported that the water extract of the whole unripe fruit of Momordica charantia can significantly reduce blood glucose levels. However the safety of its use during pregnancy has not been fully investigated. The aim of this investigation is to determine the safety of this extract during pregnancy. The water extract of the unripe fruit was given to pregnant Sprague Dawley rats on days 7, 8, 9, 10, 11, 12, 13 and 14 of gestation. The litter size was determined for each group and the litters were examined for gross malformations. The gross and histological examinations of various organs of the litters were also carried out. Results show that 8.65% of the litters from experimental animals were malformed as against 1.62% of control. It also showed that 31.2% of all the malformed litters had multiple congenital malformations. It also showed that the experimental rats had nine resorption sites while control had none. This demonstrates that the water extract of Momordica charantia is teratogenic in Sprague Dawley rats and should be used with caution in man. PMID- 21304610 TI - Antimycobacterial evaluation of fifteen medicinal plants in South Africa. AB - Fifteen plant species were collected from the Nelspruit Botanical Garden based on a list of plants provided by Phytomedicine Programme at the University of Pretoria and their ethnopharmacological information. Hexane, dichloromethane (DCM), acetone and methanolic extracts were screened for antimycobacterial activity against Mycobacterium smegmatis. The acetone extract of Milletia stulhimannii was the most active, showing activity against Mycobacterium smegmatis with minimum inhibitory concentration (MIC) value of 0.13 mg/ml. Acetone extracts for all plants had lower MIC values ranging between 0.11-1.25 mg/ml against M. smegmatis. Milletia stulhimannii, Albizia gummifera, Xanthocercis zambesiaca and Barringtonia racemosa have shown great potential as anti-tuberculosis agents. They were active against M. smegmatis with average MIC values of acetone extracts of 0.13 mg/ml. PMID- 21304611 TI - Effect of administration of aqueous extract of hippobromus pauciflorus leaves in male Wistar rats. AB - The effect of administration of aqueous extract of Hippobromus pauciflorus (L.f.) Radlk (Sapindaceae) leaves at 50, 100 and 200 mg/kg body weight for 14 days on some biochemical parameters in male Wistar rats was investigated. The extract at all the doses tested did not significantly (P>0.05) alter the levels of white blood cells, red blood cells, mean corpuscular volume, platelets, neutrophils, monocytes, lymphocytes and large unstained cells. While the levels of haemoglobin, packed cell volume and basophils increased significantly (P<0.05) at specific doses, the mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration and eosinophils decreased significantly (P<0.05). Again, the extract did not significantly (P<0.05) alter the computed liver- and kidney-body weight ratios, sodium, chloride and total protein, though, the levels of potassium, inorganic phosphorus, globulin, urea, total and conjugated bilirubin increased significantly (P<0.05) at certain doses. In contrast, the levels of albumin and creatinine also decreased significantly (P<0.05) at specific doses. While the activities of alkaline phosphatase, gamma glutamyl transferase and alanine aminotransferase remained significantly (P<0.05) unaltered in the serum, aspartate aminotransferase activity increased only at 200 mg/kg body weight. The atherogenic index as well as the concentrations of cholesterol, high- and low density lipoprotein cholesterol in the serum of the animals were not significantly (P>0.05) altered. However, the extract significantly (P<0.05) increased the concentration of triacylglycerol. The results suggest that the extract has mild and dose specific haemato-, hepato- and nephrotoxic effects and may not be completely safe as oral remedy at the doses investigated. PMID- 21304612 TI - Microanatomical effects of ethanolic extract of Cola nitida on the stomach mucosa of adult Wistar rats. AB - The study investigated the microanatomical effects of the extracts of Cola nitida on the stomach mucosa of adult male Wistar rats. Twenty adult male wistar rats were randomly divided into four equal groups of A, B, C and D (n = 5). Animals in experimental groups B, C and D were given 600 mg/kg body weight of crude extract of Cola nitida each by oral intubation for five, seven and nine consecutive days respectively, while group A (control) received equivalent volume of distilled water. Twenty four hrs after the last administration, the animals were sacrificed; tissues were harvested and fixed in 10% formol saline for histological analysis. The study revealed necrotized surface epithelium, degenerated gastric mucosa, and loss of glandular elements in the stomachs of experimental groups' vis-a-vis the control group. These observations were days dependent; as those groups which received the extract for higher number of days were seen to be adversely affected. In conclusion, Cola nitida at 600 mg/kg body weight can cause gastric lesion in animals. This lesion may be pronounced if the administration continued for days. Cola nitida should, therefore, be taken with caution to avoid gastric complications. PMID- 21304613 TI - Antifungal activity of crude extracts of gladiolus dalenii van geel (iridaceae). AB - Bulb extracts of Gladiolus dalenii reportedly used in the treatment of fungal infections in HIV/AIDS patients in the Lake Victoria region were tested for antifungal activity using the disc diffusion assay technique. Commercially used antifungal drugs, Ketaconazole and Griseofulvin (Cosmos Pharmaceuticals) were used as standards. Dichloromethane (CH2CL2)/Methanol (MeOH) in the ratio 1:1. Soluble extracts showed antifungal activity against Aspergillus niger. Direct bioautography on silica gel Thin Layer Chromatography (TLC) and appropriate spraying agents were used to identify the active component in the extract. The activities of both the extracts were higher than that of Griseofulvin. CH2CL2 soluble extract in addition showed ability to delay sporulation in A.niger. The active group of compounds in the extracts was identified as alkaloids, which offer immense potential for development of new and valuable pharmaceutical products. PMID- 21304614 TI - Studies on the antioxidant properties of Tualang honey of Malaysia. AB - Honey has been used since ancient times for its nutritional as well as curative properties. Tualang honey is collected from wild honey bees' hives on Tualang trees found in the Malaysian rain forest. It has been used traditionally for the treatment of various diseases, where its therapeutic value has partly been related to its antioxidant properties. This study therefore assessed the colour intensity, total phenolic content, antioxidant activity and antiradical activity of gamma irradiated Tualang Honey. The colour intensity at ABS450 was 489.5 +/- 1.7 mAU, total phenolic content was 251.7 +/- 7.9 mg (gallic acid) /Kg honey, total antioxidant activity by FRAP assay was 322.1 +/- 9.7 (uM Fe(II)) and the antiradical activity by DPPH assay was 41.30 +/- 0.78 (% inhibition). The data confirms that the antioxidant properties of gamma irradiated Tualang honey are similar to other types of honeys reported in the literature. PMID- 21304615 TI - Detection of antimicrobial compounds by bioautography of different extracts of leaves of selected South African tree species. AB - The hexane, acetone, dichloromethane and methanol extracts of Combretum vendae A.E. van Wyk (Combretaceae), Commiphora harveyi (Engl.) Engl. (Burseraceae), Khaya anthotheca (Welm.) C.DC (Meliaceae), Kirkia wilmsii Engl. (Kirkiaceae), Loxostylis alata A. Spreng. ex Rchb. (Anacardiaceae), Ochna natalitia (Meisn.) Walp. (Ochnaceae) and Protorhus longifolia (Bernh. Ex C. Krauss) Engl. (Anacardiaceae) were screened for their antimicrobial activity. The test organisms included bacteria (Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus), and fungi (Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans, Microsporum canis and Sporothrix schenckii). A simple bioautographic procedure, involving spraying suspensions of the bacteria or fungi on thin layer chromatography (TLC) plates developed in solvents of varying polarities was used to detect the number of antibacterial and antifungal compounds present in the extracts. All the extracts had antimicrobial activity against at least one of the test microorganisms. This activity was denoted by white spots against a red-purple background on the TLC plates after spraying with tetrazolium violet. Twenty seven TLC plates; 9 for each solvent system and 3 different solvent systems per organism were tested in the bioautographic procedure. Of the bacteria tested, S. aureus was inhibited by the most compounds separated on the TLC plates from all the tested plants. Similarly, growth of the fungus C. neoformans was also inhibited by many compounds present in the extracts. Loxostylis alata appeared to be the plant extract with the highest number of inhibition bands when compared with other plants tested against both bacteria and fungi. This species was selected for in depth further study. PMID- 21304616 TI - Traditional management of tuberculosis in Ogun State of Nigeria: the practice and ethnobotanical survey. AB - An ethnobotanical survey was conducted on plants used traditionally for the management of tuberculosis in five local government areas of Ogun State, Nigeria, in a bid to document herbs used in the management of tuberculosis with the aim of identifying possible drug lead from the phytomedicine of these communities. A semi-structured questionnaire was used to obtain the required information on the use of herbal remedies for the management. A total of 50 respondents made up of herbalists (40.0%), herb sellers (52.0%) and traditional medicine practitioners (8.0%) were interviewed in the study. The dominant age of respondents was in the range of 21-40 years (72.0%). Duration of treatment of tuberculosis with herbs was between 2-12 weeks. A total of 36 plants belonging to 20 families were proffered for the management of tuberculosis. Eighty four percent (42%) of the 50 respondents interviewed said that their clients observed no side effects and that the herbs were either available in the forest or purchased from the markets. Cola acumminata (fruit), Garcinia kola (leaf), Vitallaria parodoxa (oil), Costus afer (stem), Pycnanthus angolensis (stem bark) and Aframomum melegueta (fruit) were the most frequently mentioned herbs. The ethnomedicines of the studied areas of Ogun State, Nigeria seem to have a high potential as a source of drug discovery of anti-tuberculosis. This is of utmost importance because people living with human immunodeficiency virus (HIV) are susceptible to tuberculosis. PMID- 21304617 TI - Assesssing herbal medical practitioners in professional qualifying examination in Ghana, a model. AB - About 70% of Ghanaians depend on Alternative health practice for their primary health care needs. Hence, there is the need to streamline and regulate these practices. Graduates from the Faculty of Pharmacy and Pharmaceutical Sciences, Kwame Nkrumah University of Science and Technology (K.N.U.S.T), Kumasi-Ghana were assessed by the Professional Qualifying Examination Board of the Traditional Medicine Practice Council (TMPC), Ghana, after two years of internship training. A model of assessment took into consideration, the scope of the university training, internship and the primary health care needs of the society. PMID- 21304618 TI - A survey of medicinal plants used by Kavirajes of Chalna area, Khulna district, Bangladesh. AB - Kavirajes or traditional medicinal practitioners form the primary healthcare providers of the predominantly rural population of Bangladesh. Kavirajes use a variety of medicinal plants for treatment of different ailments. The formulations prepared from medicinal plants vary considerably between Kavirajes of different regions of the country. The objective of this study was to conduct an ethnomedicinal survey amongst the Kavirajes of Chalna area, Khulna district, Bangladesh. That area is known to contain a diversity of medicinal plants. Information on 50 plant species was obtained. These medicinal plants belonged to 49 genera and 33 families. Twenty five plants were used to treat skin diseases and twenty three plants for treatment of intestinal tract disorders, which included constipation, indigestion, stomachache, diarrhea, and dysentery. Fourteen plants were also used by the Kavirajes to treat cancer or tumor. Nine plants were used as insecticide, eight for rheumatoid arthritis, and seven for wounds. Five plants were used to treat jaundice. Five plants were also utilized to treat animal and snake bites, which included tiger bites. Six plants were used to treat diabetes, and two each for the treatment of leprosy, and sexually transmitted diseases like gonorrhea. Five plants were used to treat impotency, while one plant was used as an abortifacient. Three plants were used to treat helminthiasis, which we found to be quite common amongst the population, while four plants were used to treat heart disorders. Taken together, these plant species offer considerable potential for discovery of novel compounds of pharmacological interest. PMID- 21304619 TI - Antibacterial activity of extracts of three Croton species collected in Mpumalanga region in South Africa. AB - The antibacterial activities of three Croton species were compared using bioautography and the serial microdilution methods. The methanolic extracts of all the species had low activity against Escherichia coli. The highest activity was observed with Croton megalobotrys against Enterococcus faecalis with a minimal inhibitory concentration (MIC) value of 0.02 mg/ml. Croton steenkapianus extracts were the least active of the species investigated, only managing an MIC value of 0.625 mg/ml against Pseudomonas aeruginosa. Croton megalobotrys leaf powder was serially extracted using solvents of various polarities. The lowest MIC value (0.06 mg/ml) of the serially extracted fractions was observed with acetone against Pseudomonas aeruginosa. The liquid-liquid fractions of the methanol extract of Croton megalobotrys were also tested. The lowest MIC value of 0.02 mg/ml was observed with n-hexane fraction against Enterococcus faecalis. The carbon tetrachloride fraction was further fractionated using column chromatography with silica as the immobile phase. The resulting seven fractions were tested for activity following the bioassay-guided practice, and it emerged that the first three fractions had active compounds against Staphylococcus aureus when the bioautography method was used. PMID- 21304620 TI - Chinese medicinal herbs in treating model rats with hepatic fibrosis. AB - The objective of this study was to examine the effects of Chinese medicine formula-Yu Zhang Dan (YZD, composed of Herba Lysimachiae, Rhizoma Polygoni Cuspidati, Radix Curcumae) on the model rats with hepatic fibrosis. Forty male Sprague-Dawley (SD) rats were used in the present study, and they were separated randomly into 4 groups: a normal control group (Group A, n=5), a model control (Group B, n=15), a high dose of YZD (Group C, n=10), and a low dose of YZD (Group D, n=10). Hepatic fibrosis in rats was induced by carbon tetrachloride (CCl(4)). The variation of the serum alanine transaminase (ALT), aspartate aminotransferase (AST), hyaluronate acid (HA), laminin (LN), type * * procollagen peptide (P* *NP), L-Glutathione (GSH) was respectively measured with radioimmunoassay (RIA) and detection of transforming growth factor-beta 1 (TGF-beta1) and smooth muscle alpha actin (alpha-SMA) was conducted with immunohistochemistry. The ALT, AST HA, LN and PIII NP levels in the serum of the model control group were significantly higher than those of the normal control group (P<0.05), and both of the high dose of YZD and low dose of YZD significantly decreased the ALT, AST HA, LN and PIII NP levels of the model rats (P<0.05). The TGF-beta1 and alpha-SMA levels of the model control group were significantly higher than those of the normal control group (P<0.05), and both of the high dose of YZD and low dose of YZD significantly decreased the TGF-beta1 levels of the model rats (P<0.05) , and only the high dose of YZD significantly decreased the alpha-SMA levels of the model rats (P<0.05). The expression of TGF-beta1 and alpha-SMA in the liver tissues of the rats were in the cytoplasm of the cells. It may be through decreasing the ALT, AST, HA, LN and PIII NP levels in the serum of the model rats and decreasing the expression of TGF-beta1 and alpha-SMA in the liver tissues of the model rats that YZD significantly relieved the hepatic fibrosis. PMID- 21304621 TI - Effect of Cuscuta reflexa stem and Calotropis procera leaf extracts on glucose tolerance in glucose-induced hyperglycemic rats and mice. AB - Cuscuta reflexa (whole plant) and Calotropis procera (leaves) are used in folk medicine of Bangladesh to control blood sugar in patients suffering from diabetes mellitus. The hypoglycemic effects of methanol and chloroform extracts of whole plants of Cuscuta reflexa, and methanol extract of leaves of Calotropis procera were investigated in oral glucose tolerance tests in Long Evans rats and Swiss albino mice, respectively. Both methanol and chloroform extracts of Cuscuta reflexa whole plant demonstrated significant oral hypoglycemic activity in glucose-loaded rats at doses of 50, 100 and 200 mg/kg body weight. The methanol extract of leaves of Calotropis procera, when tested at doses of 100 and 250 mg/kg body weight did not demonstrate any oral hypoglycemic effect when tested in glucose-loaded mice. PMID- 21304622 TI - Preliminary in vitro antisickilng properties of crude juice extracts of Persia Americana, Citrus sinensis, Carica papaya and Ciklavit(r). AB - The antisickling properties of crude juice extracts of the edible portions of three commonly consumed tropical fruits namely Persia americana, Citrus sinensis, and Carica papaya were investigated in vitro alongside a new drug preparation called Ciklavit(r) that has antisickling activity. Four different solvent extracts of the crude juice of each fruit including aqueous, acidic, alkaline and alcoholic extracts were prepared and their antisickling effects on sickle cell trait (HbAS) and sickle cell disease (HbSS) blood samples checked alongside Ciklavit(r). Blood samples were stabilized using normal saline and the antisickling effects were checked by counting the number of sickle cells remaining after incubation of the blood samples with the crude fruit extracts and Ciklavit(r) for twenty-four hours. The results showed that Ciklavit(r) produced a sustained reduction in the number of sickle cells in both HbAS and HbSS blood samples. Also the alkaline and alcoholic extracts of P. americana and C. papaya produced significant reduction in the number of sickle cells. PMID- 21304623 TI - Mechanisms underlying the endothelium-dependent vasodilatory effect of an aqueous extract of Elaeis Guineensis Jacq. (Arecaceae) in porcine coronary artery rings. AB - This study was undertaken to investigate the vasodilatory effect of an aqueous extract of Elaeis guineensis Jacq (EGE) in the porcine coronary artery and elicit its possible mechanism(s) of action. Vascular effects of crude extract of dried and powdered leaves of Elaeis guineensis were evaluated on isolated coronary arteries on organ chambers. Determination of eNOS expression and the phosphorylation level of eNOS were determined by Western blot analysis. In the presence of indomethacin, EGE caused pronounced relaxations in endothelium-intact but not in endothelium-denuded coronary artery rings. Relaxations to EGE were significantly reduced by N(omega)-nitro-L-arginine (L-NA, a competitive inhibitor of NO synthase), slightly but not significantly by charybdotoxin plus apamin (two potent inhibitors of EDHF-mediated responses) and abolished by the combination of L-NA and charybdotoxin plus apamin. Relaxations to EGE were abolished by the membrane permeant, SOD mimetic, MnTMPyP, and significantly reduced by wortmannin, an inhibitor of PI3-kinase. Exposure of endothelial cells to EGE increased the phosphorylation level of eNOS at Ser1177 in a time and concentration-dependent manner. MnTMPyP abolished the EGE-induced phosphorylation of eNOS.In conclusion, the obtained data indicate that EGE induces pronounced endothelium-dependent relaxations of the porcine coronary artery, which involve predominantly NO. The stimulatory effect of EGE on eNOS involves the redox-sensitive phosphorylation of eNOS at Ser1177 most likely via the PI3-kinase pathway. PMID- 21304624 TI - Traditional complementary and alternative medicine and antiretroviral treatment adherence among HIV patients in Kwazulu-Natal, South Africa. AB - Adherence to antiretroviral medication in the treatment of HIV is critical, both to maximize efficacy and to minimize the emergence of drug resistance. The aim of this prospective study in three public hospitals in KwaZulu-Natal, South Africa, is to assess the use of Traditional Complementary and Alternative Medicine (TCAM) by HIV patients and its effect on antiretroviral (ARV) adherence 6 months after initiating ARVs. 735 (29.8% male and 70.2% female) patients who consecutively attended three HIV clinics completed assessments prior to ARV initiation and 519 after six months on antiretroviral therapy (ART) Results indicate that the use of herbal therapies for HIV declined significantly from 36.6% prior to antiretroviral treatment (ART) initiation to 7.9% after being on ARVs for 6 months. Faith healing methods, including spiritual practices and prayer for HIV declined from 35.8% to 22.1% and physical/body-mind therapy (exercise and massage) declined from 5.0% to 1.9%. In contrast, the use of micronutrients (vitamins, etc.) significantly increased from 42.6% to 87.4%. In multivariate regression analyses, ARV non-adherence (dose, schedule and food) was associated with the use of herbal treatment, not taking micronutrients and the use of over the-counter drugs. The use of TCAM declined after initiating ARVs. As herbal treatment for HIV was associated with reduced ARV adherence, patients' use of TCAM should be considered in ARV adherence management. PMID- 21304625 TI - Evaluation of the antioxidant, antibacterial, and antiproliferative activities of the acetone extract of the roots of Senna italica (Fabaceae). AB - Senna italica, a member of the Fabaceae family (subfamily Caesalpinaceae), is widely used traditionally to treat a number of disease conditions, such as sexually transmitted diseases and some forms of intestinal complications. The roots of Senna italica were collected from Zebediela subregion, Limpopo province (S.A), powdered and extracted with acetone by cold/shaking extraction method. The phytochemical composition of the extract was determined by thin layer chromatography (TLC). The chromatograms were visualised with vanillin-sulphuric acid and p-anisaldehyde reagents. The total phenolic content of the extract was determined by Folin-Ciocalteu method and expressed as TAE/g dry weight. The extract was assayed for the in vitro anticancer activity using Jurkat T cells, antioxidant activity using DPPH assay and antibacterial activity by bioautographic method and the microtitre plate method. The acetone extract of the roots of Senna italica inhibited the growth of Jurkat T cells in a dose- and time dependent manner. The extract also had free radical scavenging activity as well as reasonable antibacterial activity against Pseudomonas aeruginosa, Enterococcus faecalis, Escherichia coli and Staphylococcus aureus with MICs ranging from 0,08 to 0.16 mg/ml in the same order as ampicillin the positive control. The biological activities observed in the acetone extract validated the ethnomedicinal use of Senna italica. PMID- 21304626 TI - Microbial burden of some herbal antimalarials marketed at Elele, Rivers State. AB - Herbal antimalarials still remain an alternative to our traditional communities who can not afford orthodox antimalarials. This study was aimed at investigating the microbial quality of six herbal antimalarials using standard microbiological methods. Of the six preparations analyzed, "schnapps", palm wine and water were the media of preparation; the water base preparations recorded higher microbial load. The mean microbial load was 159.5 * 10(5) cfu/ml and 217.4 * 10(2)cfu/ml in water and alcohol base preparations respectively. The microbial profile of the preparations showed that the schnapps base preparations were predominantly contaminated with Bacillus sp (Aerobic spore bearers) and Mucor spp. The palm wine preparation harboured Bacillus sp, yeasts and Mucor spp while the water base preparations had several isolates such as Staphylococcus epidermidis, Pseudomonas aeruginosa, Escherichia coli 0157H7, Proteus mirabilis, Enterococcus feacalis, Serratia marcensces, Staph. aureus, Bacillus spp and Mucor spp. Conclusively, this study underlines the public health importance of these preparations given the high burden of such human pathogen as Ecoli O157H7, Ps aeruginosa, Stahp aureus, etc. in the preparations. PMID- 21304627 TI - Evaluation of a safer male circumcision training programme for Ndebele traditional surgeons and nurses in Gauteng, South Africa: using direct observation of circumcision procedures. AB - The aim of this study was to assess the safety of traditional male circumcision practices among Ndebele traditional surgeons following a five days training by direct observation of circumcision procedures. The sample included eight Ndebele traditional surgeons and traditional nurses and 86 initiates (abakhwetwa) from two districts in Gauteng province in South Africa. A structured observations tool was administered by a trained research doctor during circumcisions and (wound) care of the initiates of the trained traditional surgeons. Results indicate that from the observations of 86 traditional male circumcisions a high number (37%) of adverse events were recorded (excessive bleeding, excessive skin removed and damage to the penis) and in six cases the use of one instrument for the circumcision was observed. Before scaling up and/or considering integration traditional male circumcision services into medical male circumcision services in South Africa, a careful strategy to minimize unnecessary morbidity, and fundamental improvements on current traditional male circumcision techniques, are required. In addition, legislation and control of traditional male circumcision in Gauteng province, where the study took place, are recommended to make traditional male circumcision safer and to prevent adverse events to happen. PMID- 21304628 TI - Why you should not submit your work to more than one journal at a time. PMID- 21304630 TI - Standards in genomic sciences. PMID- 21304629 TI - Attitudes towards African traditional medicine and Christian spiritual healing regarding treatment of epilepsy in a rural community of northern Tanzania. AB - Most people with epilepsy (PWE) live in developing countries with limited access to health care facilities. In sub-Saharan Africa with approximately 12 million PWE, 90% do not receive adequate medical treatment. In this context, traditional medicine, being easily accessible, plays an important role. However, in sub- Saharan Africa, studies on the attitude of people (both affected and not affected by epilepsy) towards traditional medicine for treatment of epilepsy are scarce. In this study, 167 people (59 PWE, 62 relatives, 46 villagers) were interviewed at the hospital and in the community with a semi-structured validated questionnaire regarding the prevailing attitude towards traditional medicine for treatment of epilepsy in a rural area of northern Tanzania. Various traditional healing methods (THM) could be ascertained, i.e. traditional herbal medicine, spiritual healing, scarifications and spitting. 44.3% (n=74/167) of the interviewed people were convinced that epilepsy could be treated successfully with THM. Interestingly, 34.1% (n=57/167) thought that Christian prayers could cure the cause and/or treat symptoms of epilepsy. Significantly more PWE and their relatives were in favour of THM compared to villagers not knowing about epilepsy or not being immediately affected by epilepsy (chi(2)-test, p=0.004). Further factors influencing people's attitudes towards THM were gender, tribe, religion and urbanity of people's dwellings. Our study demonstrates that not only THM but also prayers in the Christian sense seem to play an important role in people's beliefs regarding successful treatment of epilepsy. Factors influencing this belief system have been identified and are discussed. PMID- 21304631 TI - Complete genome sequence of Brachybacterium faecium type strain (Schefferle 6 10). AB - Brachybacterium faecium Collins et al. 1988 is the type species of the genus, and is of phylogenetic interest because of its location in the Dermabacteraceae, a rather isolated family within the actinobacterial suborder Micrococcineae. B. faecium is known for its rod-coccus growth cycle and the ability to degrade uric acid. It grows aerobically or weakly anaerobically. The strain described in this report is a free-living, nonmotile, Gram-positive bacterium, originally isolated from poultry deep litter. Here we describe the features of this organism, together with the complete genome sequence, and annotation. This is the first complete genome sequence of a member of the actinobacterial family Dermabacteraceae, and the 3,614,992 bp long single replicon genome with its 3129 protein-coding and 69 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304632 TI - Complete genome sequence of Kytococcus sedentarius type strain (541). AB - Kytococcus sedentarius (ZoBell and Upham 1944) Stackebrandt et al. 1995 is the type strain of the species, and is of phylogenetic interest because of its location in the Dermacoccaceae, a poorly studied family within the actinobacterial suborder Micrococcineae. Kytococcus sedentarius is known for the production of oligoketide antibiotics as well as for its role as an opportunistic pathogen causing valve endocarditis, hemorrhagic pneumonia, and pitted keratolysis. It is strictly aerobic and can only grow when several amino acids are provided in the medium. The strain described in this report is a free-living, nonmotile, Gram-positive bacterium, originally isolated from a marine environment. Here we describe the features of this organism, together with the complete genome sequence, and annotation. This is the first complete genome sequence of a member of the family Dermacoccaceae and the 2,785,024 bp long single replicon genome with its 2639 protein-coding and 64 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304633 TI - Complete genome sequence of Beutenbergia cavernae type strain (HKI 0122). AB - Beutenbergia cavernae (Groth et al. 1999) is the type species of the genus and is of phylogenetic interest because of its isolated location in the actinobacterial suborder Micrococcineae. B. cavernae HKI 0122(T) is a Gram-positive, non-motile, non-spore-forming bacterium isolated from a cave in Guangxi (China). B. cavernae grows best under aerobic conditions and shows a rod-coccus growth cycle. Its cell wall peptidoglycan contains the diagnostic L-lysine <- L-glutamate interpeptide bridge. Here we describe the features of this organism, together with the complete genome sequence, and annotation. This is the first completed genome sequence from the poorly populated micrococcineal family Beutenbergiaceae, and this 4,669,183 bp long single replicon genome with its 4225 protein-coding and 53 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304634 TI - Complete genome sequence of Desulfomicrobium baculatum type strain (X). AB - Desulfomicrobium baculatum is the type species of the genus Desulfomicrobium, which is the type genus of the family Desulfomicrobiaceae. It is of phylogenetic interest because of the isolated location of the family Desulfomicrobiaceae within the order Desulfovibrionales. D. baculatum strain X(T) is a Gram-negative, motile, sulfate-reducing bacterium isolated from water-saturated manganese carbonate ore. It is strictly anaerobic and does not require NaCl for growth, although NaCl concentrations up to 6% (w/v) are tolerated. The metabolism is respiratory or fermentative. In the presence of sulfate, pyruvate and lactate are incompletely oxidized to acetate and CO(2). Here we describe the features of this organism, together with the complete genome sequence and annotation. This is the first completed genome sequence of a member of the deltaproteobacterial family Desulfomicrobiaceae, and this 3,942,657 bp long single replicon genome with its 3494 protein-coding and 72 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304635 TI - Complete genome sequence of Acidimicrobium ferrooxidans type strain (ICP). AB - Acidimicrobium ferrooxidans (Clark and Norris 1996) is the sole and type species of the genus, which until recently was the only genus within the actinobacterial family Acidimicrobiaceae and in the order Acidomicrobiales. Rapid oxidation of iron pyrite during autotrophic growth in the absence of an enhanced CO(2) concentration is characteristic for A. ferrooxidans. Here we describe the features of this organism, together with the complete genome sequence, and annotation. This is the first complete genome sequence of the order Acidomicrobiales, and the 2,158,157 bp long single replicon genome with its 2038 protein coding and 54 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304636 TI - Complete genome sequence of Actinosynnema mirum type strain (101). AB - Actinosynnema mirum Hasegawa et al. 1978 is the type species of the genus, and is of phylogenetic interest because of its central phylogenetic location in the Actino-synnemataceae, a rapidly growing family within the actinobacterial suborder Pseudo-nocardineae. A. mirum is characterized by its motile spores borne on synnemata and as a producer of nocardicin antibiotics. It is capable of growing aerobically and under a moderate CO(2) atmosphere. The strain is a Gram positive, aerial and substrate mycelium producing bacterium, originally isolated from a grass blade collected from the Raritan River, New Jersey. Here we describe the features of this organism, together with the complete genome sequence and annotation. This is the first complete genome sequence of a member of the family Actinosynnemataceae, and only the second sequence from the actinobacterial suborder Pseudonocardineae. The 8,248,144 bp long single replicon genome with its 7100 protein-coding and 77 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304637 TI - Complete genome sequence of Pedobacter heparinus type strain (HIM 762-3). AB - Pedobacter heparinus (Payza and Korn 1956) Steyn et al. 1998 comb. nov. is the type species of the rapidly growing genus Pedobacter within the family Sphingobacteriaceae of the phylum 'Bacteroidetes'. P. heparinus is of interest, because it was the first isolated strain shown to grow with heparin as sole carbon and nitrogen source and because it produces several enzymes involved in the degradation of mucopolysaccharides. All available data about this species are based on a sole strain that was isolated from dry soil. Here we describe the features of this organism, together with the complete genome sequence, and annotation. This is the first report on a complete genome sequence of a member of the genus Pedobacter, and the 5,167,383 bp long single replicon genome with its 4287 protein-coding and 54 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304638 TI - The DOE-JGI Standard Operating Procedure for the Annotations of Microbial Genomes. AB - The DOE-JGI Microbial Annotation Pipeline (DOE-JGI MAP) supports gene prediction and/or functional annotation of microbial genomes towards comparative analysis with the Integrated Microbial Genome (IMG) system. DOE-JGI MAP annotation is applied on nucleotide sequence datasets included in the IMG-ER (Expert Review) version of IMG via the IMG ER submission site. Users can submit the sequence datasets consisting of one or more contigs in a multi-fasta file. DOE-JGI MAP annotation includes prediction of protein coding and RNA genes, as well as repeats and assignment of product names to these genes. PMID- 21304639 TI - Meeting Report from the Genomic Standards Consortium (GSC) Workshops 6 and 7. AB - This report summarizes the proceedings of the 6th and 7th workshops of the Genomic Standards Consortium (GSC), held back-to-back in 2008. GSC 6 focused on furthering the activities of GSC working groups, GSC 7 focused on outreach to the wider community. GSC 6 was held October 10-14, 2008 at the European Bioinformatics Institute, Cambridge, United Kingdom and included a two-day workshop focused on the refinement of the Genomic Contextual Data Markup Language (GCDML). GSC 7 was held as the opening day of the International Congress on Metagenomics 2008 in San Diego California. Major achievements of these combined meetings included an agreement from the International Nucleotide Sequence Database Consortium (INSDC) to create a "MIGS" keyword for capturing "Minimum Information about a Genome Sequence" compliant information within INSDC (DDBJ/EMBL /Genbank) records, launch of GCDML 1.0, MIGS compliance of the first set of "Genomic Encyclopedia of Bacteria and Archaea" project genomes, approval of a proposal to extend MIGS to 16S rRNA sequences within a "Minimum Information about an Environmental Sequence", finalization of plans for the GSC eJournal, "Standards in Genomic Sciences" (SIGS), and the formation of a GSC Board. Subsequently, the GSC has been awarded a Research Co-ordination Network (RCN4GSC) grant from the National Science Foundation, held the first SIGS workshop and launched the journal. The GSC will also be hosting outreach workshops at both ISMB 2009 and PSB 2010 focused on "Metagenomics, Metadata and MetaAnalysis" (M(3)). Further information about the GSC and its range of activities can be found at http://gensc.org, including videos of all the presentations at GSC 7. PMID- 21304640 TI - Meeting report for SIGS1: First Conference of the Standards in Genomic Sciences eJournal. PMID- 21304641 TI - Studies on monitoring and tracking genetic resources: an executive summary. AB - The principles underlying fair and equitable sharing of benefits derived from the utilization of genetic resources are set out in Article 15 of the UN Convention on Biological Diversity, which stipulate that access to genetic resources is subject to the prior informed consent of the country where such resources are located and to mutually agreed terms regarding the sharing of benefits that could be derived from such access. One issue of particular concern for provider countries is how to monitor and track genetic resources once they have left the provider country and enter into use in a variety of forms. This report was commissioned to provide a detailed review of advances in DNA sequencing technologies, as those methods apply to identification of genetic resources, and the use of globally unique persistent identifiers for persistently linking to data and other forms of digital documentation that is linked to individual genetic resources. While the report was written for an audience with a mixture of technical, legal, and policy backgrounds it is relevant to the genomics community as it is an example of downstream application of genomics information. PMID- 21304642 TI - Extending Standards for Genomics and Metagenomics Data: A Research Coordination Network for the Genomic Standards Consortium (RCN4GSC). AB - Through a newly established Research Coordination Network for the Genomic Standards Consortium (RCN4GSC), the GSC will continue its leadership in establishing and integrating genomic standards through community-based efforts. These efforts, undertaken in the context of genomic and metagenomic research aim to ensure the electronic capture of all genomic data and to facilitate the achievement of a community consensus around collecting and managing relevant contextual information connected to the sequence data. The GSC operates as an open, inclusive organization, welcoming inspired biologists with a commitment to community service. Within the collaborative framework of the ongoing, international activities of the GSC, the RCN will expand the range of research domains engaged in these standardization efforts and sustain scientific networking to encourage active participation by the broader community. The RCN4GSC, funded for five years by the US National Science Foundation, will primarily support outcome-focused working meetings and the exchange of early career scientists between GSC research groups in order to advance key standards contributions such as GCDML. Focusing on the timely delivery of the extant GSC core projects, the RCN will also extend the pioneering efforts of the GSC to engage researchers active in developing ecological, environmental and biodiversity data standards. As the initial goals of the GSC are increasingly achieved, promoting the comprehensive use of effective standards will be essential to ensure the effective use of sequence and associated data, to provide access for all biologists to all of the information, and to create interdisciplinary opportunities for discovery. The RCN will facilitate these implementation activities through participation in major scientific conferences and presentations on scientific advances enabled by community usage of genomic standards. PMID- 21304643 TI - Ground truth. PMID- 21304644 TI - Complete genome sequence of Cryptobacterium curtum type strain (12-3). AB - Cryptobacterium curtum Nakazawa etal. 1999 is the type species of the genus, and is of phylogenetic interest because of its very distant and isolated position within the family Coriobacteriaceae. C. curtum is an asaccharolytic, opportunistic pathogen with a typical occurrence in the oral cavity, involved in dental and oral infections like periodontitis, inflammations and abscesses. Here we describe the features of this organism, together with the complete genome sequence, and annotation. This is the first complete genome sequence of the actinobacterial family Coriobacteriaceae, and this 1,617,804 bp long single replicon genome with its 1364 protein-coding and 58 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304645 TI - Complete genome sequence of Capnocytophaga ochracea type strain (VPI 2845). AB - Capnocytophaga ochracea (Prevot et al. 1956) Leadbetter et al. 1982 is the type species of the genus Capnocytophaga. It is of interest because of its location in the Flavobacteriaceae, a genomically not yet charted family within the order Flavobacteriales. The species grows as fusiform to rod shaped cells which tend to form clumps and are able to move by gliding. C. ochracea is known as a capnophilic (CO(2)-requiring) organism with the ability to grow under anaerobic as well as aerobic conditions (oxygen concentration larger than 15%), here only in the presence of 5% CO(2). Strain VPI 2845(T), the type strain of the species, is portrayed in this report as a gliding, Gram-negative bacterium, originally isolated from a human oral cavity. Here we describe the features of this organism, together with the complete genome sequence, and annotation. This is the first completed genome sequence from the flavobacterial genus Capnocytophaga, and the 2,612,925 bp long single replicon genome with its 2193 protein-coding and 59 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304646 TI - Complete genome sequence of Sanguibacter keddieii type strain (ST-74). AB - Sanguibacter keddieii is the type species of the genus Sanguibacter, the only genus within the family of Sanguibacteraceae. Phylogenetically, this family is located in the neighborhood of the genus Oerskovia and the family Cellulomonadaceae within the actinobacterial suborder Micrococcineae. The strain described in this report was isolated from blood of apparently healthy cows. Here we describe the features of this organism, together with the complete genome sequence, and annotation. This is the first complete genome sequence of a member of the family Sanguibacteraceae, and the 4,253,413 bp long single replicon genome with its 3735 protein-coding and 70 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304647 TI - Complete genome sequence of Catenulispora acidiphila type strain (ID 139908). AB - Catenulispora acidiphila Busti et al. 2006 is the type species of the genus Catenulispora, and is of interest because of the rather isolated phylogenetic location it occupies within the scarcely explored suborder Catenulisporineae of the order Actinomycetales. C. acidiphilia is known for its acidophilic, aerobic lifestyle, but can also grow scantly under anaerobic conditions. Under regular conditions, C. acidiphilia grows in long filaments of relatively short aerial hyphae with marked septation. It is a free living, non motile, Gram-positive bacterium isolated from a forest soil sample taken from a wooded area in Gerenzano, Italy. Here we describe the features of this organism, together with the complete genome sequence and annotation. This is the first complete genome sequence of the actinobacterial family Catenulisporaceae, and the 10,467,782 bp long single replicon genome with its 9056 protein-coding and 69 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304648 TI - Complete genome sequence of Leptotrichia buccalis type strain (C-1013-b). AB - Leptotrichia buccalis (Robin 1853) Trevisan 1879 is the type species of the genus, and is of phylogenetic interest because of its isolated location in the sparsely populated and neither taxonomically nor genomically adequately accessed family 'Leptotrichiaceae' within the phylum 'Fusobacteria'. Species of Leptotrichia are large, fusiform, non-motile, non-sporulating rods, which often populate the human oral flora. L. buccalis is anaerobic to aerotolerant, and saccharolytic. Here we describe the features of this organism, together with the complete genome sequence and annotation. This is the first complete genome sequence of the order 'Fusobacteriales' and no more than the second sequence from the phylum 'Fusobacteria'. The 2,465,610 bp long single replicon genome with its 2306 protein-coding and 61 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304649 TI - Complete genome sequence of Dyadobacter fermentans type strain (NS114). AB - Dyadobacter fermentans (Chelius and Triplett, 2000) is the type species of the genus Dyadobacter. It is of phylogenetic interest because of its location in the Cytophagaceae, a very diverse family within the order 'Sphingobacteriales'. D. fermentans has a mainly respiratory metabolism, stains Gram-negative, is non motile and oxidase and catalase positive. It is characterized by the production of cell filaments in aging cultures, a flexirubin-like pigment and its ability to ferment glucose, which is almost unique in the aerobically living members of this taxonomically difficult family. Here we describe the features of this organism, together with the complete genome sequence, and its annotation. This is the first complete genome sequence of the sphingobacterial genus Dyadobacter, and this 6,967,790 bp long single replicon genome with its 5804 protein-coding and 50 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304650 TI - Complete genome sequence of Saccharomonospora viridis type strain (P101). AB - Saccharomonospora viridis (Schuurmans et al. 1956) Nonomurea and Ohara 1971 is the type species of the genus Saccharomonospora which belongs to the family Pseudonocardiaceae. S. viridis is of interest because it is a Gram-negative organism classified among the usually Gram-positive actinomycetes. Members of the species are frequently found in hot compost and hay, and its spores can cause farmer's lung disease, bagassosis, and humidifier fever. Strains of the species S. viridis have been found to metabolize the xenobiotic pentachlorophenol (PCP). The strain described in this study has been isolated from peat-bog in Ireland. Here we describe the features of this organism, together with the complete genome sequence, and annotation. This is the first complete genome sequence of the family Pseudonocardiaceae, and the 4,308,349 bp long single replicon genome with its 3906 protein-coding and 64 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304651 TI - Complete genome sequence of Halogeometricum borinquense type strain (PR3). AB - Halogeometricum borinquense Montalvo-Rodriguez et al. 1998 is the type species of the genus, and is of phylogenetic interest because of its distinct location between the halobacterial genera Haloquadratum and Halosarcina. H. borinquense requires extremely high salt (NaCl) concentrations for growth. It can not only grow aerobically but also anaerobically using nitrate as electron acceptor. The strain described in this report is a free-living, motile, pleomorphic, euryarchaeon, which was originally isolated from the solar salterns of Cabo Rojo, Puerto Rico. Here we describe the features of this organism, together with the complete genome sequence, and annotation. This is the first complete genome sequence of the halobacterial genus Halogeometricum, and this 3,944,467 bp long six replicon genome with its 3937 protein-coding and 57 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304652 TI - Complete genome sequence of Anaerococcus prevotii type strain (PC1). AB - Anaerococcus prevotii (Foubert and Douglas 1948) Ezaki et al. 2001 is the type species of the genus, and is of phylogenetic interest because of its arguable assignment to the provisionally arranged family 'Peptostreptococcaceae'. A. prevotii is an obligate anaerobic coccus, usually arranged in clumps or tetrads. The strain, whose genome is described here, was originally isolated from human plasma; other strains of the species were also isolated from clinical specimen. Here we describe the features of this organism, together with the complete genome sequence and annotation. This is the first completed genome sequence of a member of the genus. Next to Finegoldia magna, A. prevotii is only the second species from the family 'Peptostreptococcaceae' for which a complete genome sequence is described. The 1,998,633 bp long genome (chromosome and one plasmid) with its 1852 protein-coding and 61 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304653 TI - Complete genome sequence of Atopobium parvulum type strain (IPP 1246). AB - Atopobium parvulum (Weinberg et al. 1937) Collins and Wallbanks 1993 comb. nov. is the type strain of the species and belongs to the genomically yet unstudied Atopobium/Olsenella branch of the family Coriobacteriaceae. The species A. parvulum is of interest because its members are frequently isolated from the human oral cavity and are found to be associated with halitosis (oral malodor) but not with periodontitis. Here we describe the features of this organism, together with the complete genome sequence, and annotation. This is the first complete genome sequence of the genus Atopobium, and the 1,543,805 bp long single replicon genome with its 1369 protein-coding and 49 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304654 TI - Complete genome sequence of Eggerthella lenta type strain (IPP VPI 0255). AB - Eggerthella lenta (Eggerth 1935) Wade et al. 1999, emended Wurdemann et al. 2009 is the type species of the genus Eggerthella, which belongs to the actinobacterial family Coriobacteriaceae. E. lenta is a Gram-positive, non motile, non-sporulating pathogenic bacterium that can cause severe bacteremia. The strain described in this study has been isolated from a rectal tumor in 1935. Here we describe the features of this organism, together with the complete genome sequence, and annotation. This is the first complete genome sequence of the genus Eggerthella, and the 3,632,260 bp long single replicon genome with its 3123 protein-coding and 58 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304655 TI - Complete genome sequence of Staphylothermus marinus Stetter and Fiala 1986 type strain F1. AB - Staphylothermus marinus Fiala and Stetter 1986 belongs to the order Desulfurococcales within the archaeal phylum Crenarchaeota. S. marinus is a hyperthermophilic, sulfur-dependent, anaerobic heterotroph. Strain F1 was isolated from geothermally heated sediments at Vulcano, Italy, but S. marinus has also been isolated from a hydrothermal vent on the East Pacific Rise. We report the complete genome of S. marinus strain F1, the type strain of the species. This is the fifth reported complete genome sequence from the order Desulfurococcales. PMID- 21304656 TI - Complete genome sequence of Methanoculleus marisnigri Romesser et al. 1981 type strain JR1. AB - Methanoculleus marisnigri Romesser et al. 1981 is a methanogen belonging to the order Methanomicrobiales within the archaeal phylum Euryarchaeota. The type strain, JR1, was isolated from anoxic sediments of the Black Sea. M. marisnigri is of phylogenetic interest because at the time the sequencing project began only one genome had previously been sequenced from the order Methanomicrobiales. We report here the complete genome sequence of M. marisnigri type strain JR1 and its annotation. This is part of a Joint Genome Institute 2006 Community Sequencing Program to sequence genomes of diverse Archaea. PMID- 21304657 TI - Complete genome sequence of Methanocorpusculum labreanum type strain Z. AB - Methanocorpusculum labreanum is a methanogen belonging to the order Methanomicrobiales within the archaeal kingdom Euryarchaeota. The type strain Z was isolated from surface sediments of Tar Pit Lake in the La Brea Tar Pits in Los Angeles, California. M. labreanum is of phylogenetic interest because at the time the sequencing project began only one genome had previously been sequenced from the order Methanomicrobiales. We report here the complete genome sequence of M. labreanum type strain Z and its annotation. This is part of a 2006 Joint Genome Institute Community Sequencing Program project to sequence genomes of diverse Archaea. PMID- 21304658 TI - GeneWiz browser: An Interactive Tool for Visualizing Sequenced Chromosomes. AB - We present an interactive web application for visualizing genomic data of prokaryotic chromosomes. The tool (GeneWiz browser) allows users to carry out various analyses such as mapping alignments of homologous genes to other genomes, mapping of short sequencing reads to a reference chromosome, and calculating DNA properties such as curvature or stacking energy along the chromosome. The GeneWiz browser produces an interactive graphic that enables zooming from a global scale down to single nucleotides, without changing the size of the plot. Its ability to disproportionally zoom provides optimal readability and increased functionality compared to other browsers. The tool allows the user to select the display of various genomic features, color setting and data ranges. Custom numerical data can be added to the plot allowing, for example, visualization of gene expression and regulation data. Further, standard atlases are pre-generated for all prokaryotic genomes available in GenBank, providing a fast overview of all available genomes, including recently deposited genome sequences. The tool is available online from http://www.cbs.dtu.dk/services/gwBrowser. Supplemental material including interactive atlases is available online at http://www.cbs.dtu.dk/services/gwBrowser/suppl/. PMID- 21304659 TI - Standards and standard-compliance. PMID- 21304660 TI - Complete genome sequence of Halorhabdus utahensis type strain (AX-2). AB - Halorhabdus utahensis Waino et al. 2000 is the type species of the genus, which is of phylogenetic interest because of its location on one of the deepest branches within the very extensive euryarchaeal family Halobacteriaceae. H. utahensis is a free-living, motile, rod shaped to pleomorphic, Gram-negative archaeon, which was originally isolated from a sediment sample collected from the southern arm of Great Salt Lake, Utah, USA. When grown on appropriate media, H. utahensis can form polyhydroxybutyrate (PHB). Here we describe the features of this organism, together with the complete genome sequence, and annotation. This is the first complete genome sequence of the a member of halobacterial genus Halorhabdus, and the 3,116,795 bp long single replicon genome with its 3027 protein-coding and 48 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304661 TI - Complete genome sequence of Kangiella koreensis type strain (SW-125). AB - Kangiella koreensis (Yoon et al. 2004) is the type species of the genus and is of phylogenetic interest because of the very isolated location of the genus Kangiella in the gammaproteobacterial order Oceanospirillales. K. koreensis SW 125(T) is a Gram-negative, non-motile, non-spore-forming bacterium isolated from tidal flat sediments at Daepo Beach, Yellow Sea, Korea. Here we describe the features of this organism, together with the complete genome sequence, and annotation. This is the first completed genome sequence from the genus Kangiella and only the fourth genome from the order Oceanospirillales. This 2,852,073 bp long single replicon genome with its 2647 protein-coding and 48 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304662 TI - Complete genome sequence of Stackebrandtia nassauensis type strain (LLR-40K-21). AB - Stackebrandtia nassauensis Labeda and Kroppenstedt (2005) is the type species of the genus Stackebrandtia, and a member of the actinobacterial family Glycomycetaceae. Stackebrandtia currently contains two species, which are differentiated from Glycomyces spp. by cellular fatty acid and menaquinone composition. Strain LLR-40K-21(T) is Gram-positive, aerobic, and nonmotile, with a branched substrate mycelium and on some media an aerial mycelium. The strain was originally isolated from a soil sample collected from a road side in Nassau, Bahamas. Here we describe the features of this organism, together with the complete genome sequence and annotation. This is the first complete genome sequence of the actinobacterial suborder Glycomycineae. The 6,841,557 bp long single replicon genome with its 6487 protein-coding and 53 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304664 TI - Complete genome sequence of Desulfotomaculum acetoxidans type strain (5575). AB - Desulfotomaculum acetoxidans Widdel and Pfennig 1977 was one of the first sulfate reducing bacteria known to grow with acetate as sole energy and carbon source. It is able to oxidize substrates completely to carbon dioxide with sulfate as the electron acceptor, which is reduced to hydrogen sulfide. All available data about this species are based on strain 5575(T), isolated from piggery waste in Germany. Here we describe the features of this organism, together with the complete genome sequence and annotation. This is the first completed genome sequence of a Desulfotomaculum species with validly published name. The 4,545,624 bp long single replicon genome with its 4370 protein-coding and 100 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304663 TI - Complete genome sequence of Slackia heliotrinireducens type strain (RHS 1). AB - Slackia heliotrinireducens (Lanigan 1983) Wade et al. 1999 is of phylogenetic interest because of its location in a genomically yet uncharted section of the family Coriobacteriaceae, within the deep branching Actinobacteria. Strain RHS 1(T) was originally isolated from the ruminal flora of a sheep. It is a proteolytic anaerobic coccus, able to reductively cleave pyrrolizidine alkaloids. Here we describe the features of this organism, together with the complete genome sequence, and annotation. This is the first complete genome sequence of the genus Slackia, and the 3,165,038 bp long single replicon genome with its 2798 protein coding and 60 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304665 TI - Complete genome sequence of Thermanaerovibrio acidaminovorans type strain (Su883). AB - Thermanaerovibrio acidaminovorans (Guangsheng et al. 1997) Baena et al. 1999 is the type species of the genus Thermanaerovibrio and is of phylogenetic interest because of the very isolated location of the novel phylum Synergistetes. T. acidaminovorans Su883(T) is a Gram-negative, motile, non-spore-forming bacterium isolated from an anaerobic reactor of a sugar refinery in The Netherlands. Here we describe the features of this organism, together with the complete genome sequence, and annotation. This is the first completed genome sequence from a member of the phylum Synergistetes. The 1,848,474 bp long single replicon genome with its 1765 protein-coding and 60 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304666 TI - Complete genome sequence of Jonesia denitrificans type strain (Prevot 55134). AB - Jonesia denitrificans (Prevot 1961) Rocourt et al. 1987 is the type species of the genus Jonesia, and is of phylogenetic interest because of its isolated location in the actinobacterial suborder Micrococcineae. J. denitrificans is characterized by a typical coryneform morphology and is able to form irregular nonsporulating rods showing branched and club-like forms. Coccoid cells occur in older cultures. J. denitrificans is classified as a pathogenic organism for animals (vertebrates). The type strain whose genome is described here was originally isolated from cooked ox blood. Here we describe the features of this organism, together with the complete genome sequence and annotation. This is the first completed genome sequence of a member of the genus for which a complete genome sequence is described. The 2,749,646 bp long genome with its 2558 protein coding and 71 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304667 TI - Complete genome sequence of Halomicrobium mukohataei type strain (arg-2). AB - Halomicrobium mukohataei (Ihara et al. 1997) Oren et al. 2002 is the type species of the genus Halomicrobium. It is of phylogenetic interest because of its isolated location within the large euryarchaeal family Halobacteriaceae. H. mukohataei is an extreme halophile that grows essentially aerobically, but can also grow anaerobically under a change of morphology and with nitrate as electron acceptor. The strain, whose genome is described in this report, is a free-living, motile, Gram-negative euryarchaeon, originally isolated from Salinas Grandes in Jujuy, Andes highlands, Argentina. Its genome contains three genes for the 16S rRNA that differ from each other by up to 9%. Here we describe the features of this organism, together with the complete genome sequence and annotation. This is the first completed genome sequence from the poorly populated genus Halomicrobium, and the 3,332,349 bp long genome (chromosome and one plasmid) with its 3416 protein-coding and 56 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304668 TI - Meeting Report: "Metagenomics, Metadata and Meta-analysis" (M3) Special Interest Group at ISMB 2009. AB - This report summarizes the proceedings of the "Metagenomics, Metadata and Meta analysis" (M3) Special Interest Group (SIG) meeting held at the Intelligent Systems for Molecular Biology 2009 conference. The Genomic Standards Consortium (GSC) hosted this meeting to explore the bottlenecks and emerging solutions for obtaining biological insights through large-scale comparative analysis of metagenomic datasets. The M3 SIG included 16 talks, half of which were selected from submitted abstracts, a poster session and a panel discussion involving members of the GSC Board. This report summarizes this one-day SIG, attempts to identify shared themes and recapitulates community recommendations for the future of this field. The GSC will also host an M3 workshop at the Pacific Symposium on Biocomputing (PSB) in January 2010. Further information about the GSC and its range of activities can be found at http://gensc.org/. PMID- 21304669 TI - Complete genome sequence of Rhodothermus marinus type strain (R-10). AB - Rhodothermus marinus Alfredsson et al. 1995 is the type species of the genus and is of phylogenetic interest because the Rhodothermaceae represent the deepest lineage in the phylum Bacteroidetes. R. marinus R-10(T) is a Gram-negative, non motile, non-spore-forming bacterium isolated from marine hot springs off the coast of Iceland. Strain R-10(T) is strictly aerobic and requires slightly halophilic conditions for growth. Here we describe the features of this organism, together with the complete genome sequence, and annotation. This is the first complete genome sequence of the genus Rhodothermus, and only the second sequence from members of the family Rhodothermaceae. The 3,386,737 bp genome (including a 125 kb plasmid) with its 2914 protein-coding and 48 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304670 TI - Complete genome sequence of Streptobacillus moniliformis type strain (9901). AB - Streptobacillus moniliformis Levaditi et al. 1925 is the type and sole species of the genus Streptobacillus, and is of phylogenetic interest because of its isolated location in the sparsely populated and neither taxonomically nor genomically much accessed family 'Leptotrichiaceae' within the phylum Fusobacteria. The 'Leptotrichiaceae' have not been well characterized, genomically or taxonomically. S. moniliformis,is a Gram-negative, non-motile, pleomorphic bacterium and is the etiologic agent of rat bite fever and Haverhill fever. Strain 9901(T), the type strain of the species, was isolated from a patient with rat bite fever. Here we describe the features of this organism, together with the complete genome sequence and annotation. This is only the second completed genome sequence of the order Fusobacteriales and no more than the third sequence from the phylum Fusobacteria. The 1,662,578 bp long chromosome and the 10,702 bp plasmid with a total of 1511 protein-coding and 55 RNA genes are part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304671 TI - Complete genome sequence of Pirellula staleyi type strain (ATCC 27377). AB - Pirellula staleyi Schlesner and Hirsch 1987 is the type species of the genus Pirellula of the family Planctomycetaceae. Members of this pear- or teardrop shaped bacterium show a clearly visible pointed attachment pole and can be distinguished from other Planctomycetes by a lack of true stalks. Strains closely related to the species have been isolated from fresh and brackish water, as well as from hypersaline lakes. Here we describe the features of this organism, together with the complete genome sequence and annotation. This is the first completed genome sequence of the order Planctomyces and only the second sequence from the phylum Planctobacteria/Planctomycetes. The 6,196,199 bp long genome with its 4773 protein-coding and 49 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304672 TI - Complete genome sequence of Xylanimonas cellulosilytica type strain (XIL07). AB - Xylanimonas cellulosilytica Rivas et al. 2003 is the type species of the genus Xylanimonas of the actinobacterial family Promicromonosporaceae. The species X. cellulosilytica is of interest because of its ability to hydrolyze cellulose and xylan. Here we describe the features of this organism, together with the complete genome sequence, and annotation. This is the first complete genome sequence of a member of the large family Promicromonosporaceae, and the 3,831,380 bp long genome (one chromosome plus an 88,604 bp long plasmid) with its 3485 protein coding and 61 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304673 TI - Complete genome sequence of Alicyclobacillus acidocaldarius type strain (104-IA). AB - Alicyclobacillus acidocaldarius (Darland and Brock 1971) is the type species of the larger of the two genera in the bacillal family 'Alicyclobacillaceae'. A. acidocaldarius is a free-living and non-pathogenic organism, but may also be associated with food and fruit spoilage. Due to its acidophilic nature, several enzymes from this species have since long been subjected to detailed molecular and biochemical studies. Here we describe the features of this organism, together with the complete genome sequence and annotation. This is the first completed genome sequence of the family 'Alicyclobacillaceae'. The 3,205,686 bp long genome (chromosome and three plasmids) with its 3,153 protein-coding and 82 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304675 TI - Complete genome sequence of Streptosporangium roseum type strain (NI 9100). AB - Streptosporangium roseum Crauch 1955 is the type strain of the species which is the type species of the genus Streptosporangium. The 'pinkish coiled Streptomyces like organism with a spore case' was isolated from vegetable garden soil in 1955. Here we describe the features of this organism, together with the complete genome sequence and annotation. This is the first completed genome sequence of a member of the family Streptosporangiaceae, and the second largest microbial genome sequence ever deciphered. The 10,369,518 bp long genome with its 9421 protein coding and 80 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304674 TI - Complete genome sequence of Gordonia bronchialis type strain (3410). AB - Gordonia bronchialis Tsukamura 1971 is the type species of the genus. G. bronchialis is a human-pathogenic organism that has been isolated from a large variety of human tissues. Here we describe the features of this organism, together with the complete genome sequence and annotation. This is the first completed genome sequence of the family Gordoniaceae. The 5,290,012 bp long genome with its 4,944 protein-coding and 55 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304676 TI - Complete genome sequence of Desulfohalobium retbaense type strain (HR(100)). AB - Desulfohalobium retbaense (Ollivier et al. 1991) is the type species of the polyphyletic genus Desulfohalobium, which comprises, at the time of writing, two species and represents the family Desulfohalobiaceae within the Deltaproteobacteria. D. retbaense is a moderately halophilic sulfate-reducing bacterium, which can utilize H(2) and a limited range of organic substrates, which are incompletely oxidized to acetate and CO(2), for growth. The type strain HR(100) (T) was isolated from sediments of the hypersaline Retba Lake in Senegal. Here we describe the features of this organism, together with the complete genome sequence and annotation. This is the first completed genome sequence of a member of the family Desulfohalobiaceae. The 2,909,567 bp genome (one chromosome and a 45,263 bp plasmid) with its 2,552 protein-coding and 57 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304677 TI - Complete genome sequence of Sphaerobacter thermophilus type strain (S 6022). AB - Sphaerobacter thermophilus Demharter et al. 1989 is the sole and type species of the genus Sphaerobacter, which is the type genus of the family Sphaerobacteraceae, the order Sphaerobacterales and the subclass Sphaerobacteridae. Phylogenetically, it belongs to the genomically little studied class of the Thermomicrobia in the bacterial phylum Chloroflexi. Here, the genome of strain S 6022(T) is described which is an obligate aerobe that was originally isolated from an aerated laboratory-scale fermentor that was pulse fed with municipal sewage sludge. We describe the features of this organism, together with the complete genome and annotation. This is the first complete genome sequence of the thermomicrobial subclass Sphaerobacteridae, and the second sequence from the chloroflexal class Thermomicrobia. The 3,993,764 bp genome with its 3,525 protein coding and 57 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304678 TI - Complete genome sequence of Veillonella parvula type strain (Te3). AB - Veillonella parvula (Veillon and Zuber 1898) Prevot 1933 is the type species of the genus Veillonella in the family Veillonellaceae within the order Clostridiales. The species V. parvula is of interest because it is frequently isolated from dental plaque in the human oral cavity and can cause opportunistic infections. The species is strictly anaerobic and grows as small cocci which usually occur in pairs. Veillonellae are characterized by their unusual metabolism which is centered on the activity of the enzyme methylmalonyl-CoA decarboxylase. Strain Te3(T), the type strain of the species, was isolated from the human intestinal tract. Here we describe the features of this organism, together with the complete genome sequence, and annotation. This is the first complete genome sequence of a member of the large clostridial family Veillonellaceae, and the 2,132,142 bp long single replicon genome with its 1,859 protein-coding and 61 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304679 TI - Complete genome sequence of Rhizobium leguminosarum bv trifolii strain WSM2304, an effective microsymbiont of the South American clover Trifolium polymorphum. AB - Rhizobium leguminosarum bv trifolii is the effective nitrogen fixing microsymbiont of a diverse range of annual and perennial Trifolium (clover) species. Strain WSM2304 is an aerobic, motile, non-spore forming, Gram-negative rod, isolated from Trifolium polymorphum in Uruguay in 1998. This microsymbiont predominated in the perennial grasslands of Glencoe Research Station, in Uruguay, to competitively nodulate its host, and fix atmospheric nitrogen. Here we describe the basic features of WSM2304, together with the complete genome sequence, and annotation. This is the first completed genome sequence for a nitrogen fixing microsymbiont of a clover species from the American center of origin. We reveal that its genome size is 6,872,702 bp encoding 6,643 protein coding genes and 62 RNA only encoding genes. This multipartite genome was found to contain 5 distinct replicons; a chromosome of size 4,537,948 bp and four circular plasmids of size 1,266,105 bp, 501,946 bp, 308,747 bp and 257,956 bp. PMID- 21304680 TI - Complete genome sequence of the Medicago microsymbiont Ensifer (Sinorhizobium) medicae strain WSM419. AB - Ensifer (Sinorhizobium) medicae is an effective nitrogen fixing microsymbiont of a diverse range of annual Medicago (medic) species. Strain WSM419 is an aerobic, motile, non-spore forming, Gram-negative rod isolated from a M. murex root nodule collected in Sardinia, Italy in 1981. WSM419 was manufactured commercially in Australia as an inoculant for annual medics during 1985 to 1993 due to its nitrogen fixation, saprophytic competence and acid tolerance properties. Here we describe the basic features of this organism, together with the complete genome sequence, and annotation. This is the first report of a complete genome sequence for a microsymbiont of the group of annual medic species adapted to acid soils. We reveal that its genome size is 6,817,576 bp encoding 6,518 protein-coding genes and 81 RNA only encoding genes. The genome contains a chromosome of size 3,781,904 bp and 3 plasmids of size 1,570,951 bp, 1,245,408 bp and 219,313 bp. The smallest plasmid is a feature unique to this medic microsymbiont. PMID- 21304681 TI - Complete genome sequence of Chitinophaga pinensis type strain (UQM 2034). AB - Chitinophaga pinensis Sangkhobol and Skerman 1981 is the type strain of the species which is the type species of the rapidly growing genus Chitinophaga in the sphingobacterial family 'Chitinophagaceae'. Members of the genus Chitinophaga vary in shape between filaments and spherical bodies without the production of a fruiting body, produce myxospores, and are of special interest for their ability to degrade chitin. Here we describe the features of this organism, together with the complete genome sequence, and annotation. This is the first complete genome sequence of a member of the family 'Chitinophagaceae', and the 9,127,347 bp long single replicon genome with its 7,397 protein-coding and 95 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304682 TI - Complete genome sequence of Haliangium ochraceum type strain (SMP-2). AB - Haliangium ochraceum Fudou et al. 2002 is the type species of the genus Haliangium in the myxococcal family 'Haliangiaceae'. Members of the genus Haliangium are the first halophilic myxobacterial taxa described. The cells of the species follow a multicellular lifestyle in highly organized biofilms, called swarms, they decompose bacterial and yeast cells as most myxobacteria do. The fruiting bodies contain particularly small coccoid myxospores. H. ochraceum encodes the first actin homologue identified in a bacterial genome. Here we describe the features of this organism, together with the complete genome sequence, and annotation. This is the first complete genome sequence of a member of the myxococcal suborder Nannocystineae, and the 9,446,314 bp long single replicon genome with its 6,898 protein-coding and 53 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304683 TI - Complete genome sequence of Haloterrigena turkmenica type strain (4k). AB - Haloterrigena turkmenica (Zvyagintseva and Tarasov 1987) Ventosa et al. 1999, comb. nov. is the type species of the genus Haloterrigena in the euryarchaeal family Halobacteriaceae. It is of phylogenetic interest because of the yet unclear position of the genera Haloterrigena and Natrinema within the Halobacteriaceae, which created some taxonomic problems historically. H. turkmenica, was isolated from sulfate saline soil in Turkmenistan, is a relatively fast growing, chemoorganotrophic, carotenoid-containing, extreme halophile, requiring at least 2 M NaCl for growth. Here we describe the features of this organism, together with the complete genome sequence, and annotation. This is the first complete genome sequence of the genus Haloterrigena, but the eighth genome sequence from a member of the family Halobacteriaceae. The 5,440,782 bp genome (including six plasmids) with its 5,287 protein-coding and 63 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304684 TI - Digital DNA-DNA hybridization for microbial species delineation by means of genome-to-genome sequence comparison. AB - The pragmatic species concept for Bacteria and Archaea is ultimately based on DNA DNA hybridization (DDH). While enabling the taxonomist, in principle, to obtain an estimate of the overall similarity between the genomes of two strains, this technique is tedious and error-prone and cannot be used to incrementally build up a comparative database. Recent technological progress in the area of genome sequencing calls for bioinformatics methods to replace the wet-lab DDH by in silico genome-to-genome comparison. Here we investigate state-of-the-art methods for inferring whole-genome distances in their ability to mimic DDH. Algorithms to efficiently determine high-scoring segment pairs or maximally unique matches perform well as a basis of inferring intergenomic distances. The examined distance functions, which are able to cope with heavily reduced genomes and repetitive sequence regions, outperform previously described ones regarding the correlation with and error ratios in emulating DDH. Simulation of incompletely sequenced genomes indicates that some distance formulas are very robust against missing fractions of genomic information. Digitally derived genome-to-genome distances show a better correlation with 16S rRNA gene sequence distances than DDH values. The future perspectives of genome-informed taxonomy are discussed, and the investigated methods are made available as a web service for genome-based species delineation. PMID- 21304685 TI - Standard operating procedure for computing pangenome trees. AB - We present the pan-genome tree as a tool for visualizing similarities and differences between closely related microbial genomes within a species or genus. Distance between genomes is computed as a weighted relative Manhattan distance based on gene family presence/absence. The weights can be chosen with emphasis on groups of gene families conserved to various degrees inside the pan-genome. The software is available for free as an R-package. PMID- 21304686 TI - Standard operating procedure for calculating genome-to-genome distances based on high-scoring segment pairs. AB - DNA-DNA hybridization (DDH) is a widely applied wet-lab technique to obtain an estimate of the overall similarity between the genomes of two organisms. To base the species concept for prokaryotes ultimately on DDH was chosen by microbiologists as a pragmatic approach for deciding about the recognition of novel species, but also allowed a relatively high degree of standardization compared to other areas of taxonomy. However, DDH is tedious and error-prone and first and foremost cannot be used to incrementally establish a comparative database. Recent studies have shown that in-silico methods for the comparison of genome sequences can be used to replace DDH. Considering the ongoing rapid technological progress of sequencing methods, genome-based prokaryote taxonomy is coming into reach. However, calculating distances between genomes is dependent on multiple choices for software and program settings. We here provide an overview over the modifications that can be applied to distance methods based in high scoring segment pairs (HSPs) or maximally unique matches (MUMs) and that need to be documented. General recommendations on determining HSPs using BLAST or other algorithms are also provided. As a reference implementation, we introduce the GGDC web server (http://ggdc.gbdp.org). PMID- 21304687 TI - Complete genome sequence of Acidaminococcus fermentans type strain (VR4). AB - Acidaminococcus fermentans (Rogosa 1969) is the type species of the genus Acidaminococcus, and is of phylogenetic interest because of its isolated placement in a genomically little characterized region of the Firmicutes. A. fermentans is known for its habitation of the gastrointestinal tract and its ability to oxidize trans-aconitate. Its anaerobic fermentation of glutamate has been intensively studied and will now be complemented by the genomic basis. The strain described in this report is a nonsporulating, nonmotile, Gram-negative coccus, originally isolated from a pig alimentary tract. Here we describe the features of this organism, together with the complete genome sequence, and annotation. This is the first complete genome sequence of a member of the family Acidaminococcaceae, and the 2,329,769 bp long genome with its 2,101 protein coding and 81 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304688 TI - Complete genome sequence of Cellulomonas flavigena type strain (134). AB - Cellulomonas flavigena (Kellerman and McBeth 1912) Bergey et al. 1923 is the type species of the genus Cellulomonas of the actinobacterial family Cellulomonadaceae. Members of the genus Cellulomonas are of special interest for their ability to degrade cellulose and hemicellulose, particularly with regard to the use of biomass as an alternative energy source. Here we describe the features of this organism, together with the complete genome sequence, and annotation. This is the first complete genome sequence of a member of the genus Cellulomonas, and next to the human pathogen Tropheryma whipplei the second complete genome sequence within the actinobacterial family Cellulomonadaceae. The 4,123,179 bp long single replicon genome with its 3,735 protein-coding and 53 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304689 TI - Complete genome sequence of Meiothermus ruber type strain (21). AB - Meiothermus ruber (Loginova et al. 1984) Nobre et al. 1996 is the type species of the genus Meiothermus. This thermophilic genus is of special interest, as its members share relatively low degrees of 16S rRNA gene sequence similarity and constitute a separate evolutionary lineage from members of the genus Thermus, from which they can generally be distinguished by their slightly lower temperature optima. The temperature related split is in accordance with the chemotaxonomic feature of the polar lipids. M. ruber is a representative of the low-temperature group. This is the first completed genome sequence of the genus Meiothermus and only the third genome sequence to be published from a member of the family Thermaceae. The 3,097,457 bp long genome with its 3,052 protein-coding and 53 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304690 TI - Complete genome sequence of Meiothermus silvanus type strain (VI-R2). AB - Meiothermus silvanus (Tenreiro et al. 1995) Nobre et al. 1996 belongs to a thermophilic genus whose members share relatively low degrees of 16S rRNA gene sequence similarity. Meiothermus constitutes an evolutionary lineage separate from members of the genus Thermus, from which they can generally be distinguished by their slightly lower temperature optima. M. silvanus is of special interest as it causes colored biofilms in the paper making industry and may thus be of economic importance as a biofouler. This is the second completed genome sequence of a member of the genus Meiothermus and only the third genome sequence to be published from a member of the family Thermaceae. The 3,721,669 bp long genome with its 3,667 protein-coding and 55 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304691 TI - Complete genome sequence of Planctomyces limnophilus type strain (Mu 290). AB - Planctomyces limnophilus Hirsch and Muller 1986 belongs to the order Planctomycetales, which differs from other bacterial taxa by several distinctive features such as internal cell compartmentalization, multiplication by forming buds directly from the spherical, ovoid or pear-shaped mother cell and a cell wall which is stabilized by a proteinaceous layer rather than a peptidoglycan layer. Besides Pirellula staleyi, this is the second completed genome sequence of the family Planctomycetaceae. P. limnophilus is of interest because it differs from Pirellula by the presence of a stalk and its structure of fibril bundles, its cell shape and size, the formation of multicellular rosettes, low salt tolerance and red pigmented colonies. The 5,460,085 bp long genome with its 4,304 protein-coding and 66 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304692 TI - Complete genome sequence of Acetohalobium arabaticum type strain (Z-7288). AB - Acetohalobium arabaticum Zhilina and Zavarzin 1990 is of special interest because of its physiology and its participation in the anaerobic C(1)-trophic chain in hypersaline environments. This is the first completed genome sequence of the family Halobacteroidaceae and only the second genome sequence in the order Halanaerobiales. The 2,469,596 bp long genome with its 2,353 protein-coding and 90 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304694 TI - Complete genome sequence of Olsenella uli type strain (VPI D76D-27C). AB - Olsenella uli (Olsen et al. 1991) Dewhirst et al. 2001 is the type species of the genus Olsenella, which belongs to the actinobacterial family Coriobacteriaceae. The species is of interest because it is frequently isolated from dental plaque in periodontitis patients and can cause primary endodontic infection. The species is a Gram-positive, non-motile and non-sporulating bacterium. The strain described in this study was isolated from human gingival crevices. This is the first completed sequence of the genus Olsenella and the fifth sequence from a member of the family Coriobacteriaceae. The 2,051,896 bp long genome with its 1,795 protein-coding and 55 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304695 TI - Permanent draft genome sequence of Dethiosulfovibrio peptidovorans type strain (SEBR 4207). AB - Dethiosulfovibrio peptidovorans Magot et al. 1997 is the type species of the genus Dethiosulfovibrio of the family Synergistaceae in the recently created phylum Synergistetes. The strictly anaerobic, vibriod, thiosulfate-reducing bacterium utilizes peptides and amino acids, but neither sugars nor fatty acids. It was isolated from an offshore oil well where it was been reported to be involved in pitting corrosion of mild steel. Initially, this bacterium was described as a distant relative of the genus Thermoanaerobacter, but was not assigned to a genus, it was subsequently placed into the novel phylum Synergistetes. A large number of repeats in the genome sequence prevented an economically justifiable closure of the last gaps. This is only the third published genome from a member of the phylum Synergistetes. The 2,576,359 bp long genome consists of three contigs with 2,458 protein-coding and 59 RNA genes and is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304693 TI - Complete genome sequence of Ignisphaera aggregans type strain (AQ1.S1). AB - Ignisphaera aggregans Niederberger et al. 2006 is the type and sole species of genus Ignisphaera. This archaeal species is characterized by a coccoid-shape and is strictly anaerobic, moderately acidophilic, heterotrophic hyperthermophilic and fermentative. The type strain AQ1.S1(T) was isolated from a near neutral, boiling spring in Kuirau Park, Rotorua, New Zealand. This is the first completed genome sequence of the genus Ignisphaera and the fifth genome (fourth type strain) sequence in the family Desulfurococcaceae. The 1,875,953 bp long genome with its 2,009 protein-coding and 52 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304696 TI - Meeting Report from the Genomic Standards Consortium (GSC) Workshop 8. AB - This report summarizes the proceedings of the 8th meeting of the Genomic Standards Consortium held at the Department of Energy Joint Genome Institute in Walnut Creek, CA, USA on September 9-11, 2009. This three-day workshop marked the maturing of Genomic Standards Consortium from an informal gathering of researchers interested in developing standards in the field of genomic and metagenomics to an established community with a defined governance mechanism, its own open access journal, and a family of established standards for describing genomes, metagenomes and marker studies (i.e. ribosomal RNA gene surveys). There will be increased efforts within the GSC to reach out to the wider scientific community via a range of new projects. Further information about the GSC and its activities can be found at http://gensc.org/. PMID- 21304697 TI - Complete genome sequence of Sulfurospirillum deleyianum type strain (5175). AB - Sulfurospirillum deleyianum Schumacher et al. 1993 is the type species of the genus Sulfurospirillum. S. deleyianum is a model organism for studying sulfur reduction and dissimilatory nitrate reduction as an energy source for growth. Also, it is a prominent model organism for studying the structural and functional characteristics of cytochrome c nitrite reductase. Here, we describe the features of this organism, together with the complete genome sequence and annotation. This is the first completed genome sequence of the genus Sulfurospirillum. The 2,306,351 bp long genome with its 2,291 protein-coding and 52 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304698 TI - Complete genome sequence of Geodermatophilus obscurus type strain (G-20). AB - Geodermatophilus obscurus Luedemann 1968 is the type species of the genus, which is the type genus of the family Geodermatophilaceae. G. obscurus is of interest as it has frequently been isolated from stressful environments such as rock varnish in deserts, and as it exhibits interesting phenotypes such as lytic capability of yeast cell walls, UV-C resistance, strong production of extracellular functional amyloid (FuBA) and manganese oxidation. This is the first completed genome sequence of the family Geodermatophilaceae. The 5,322,497 bp long genome with its 5,161 protein-coding and 58 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304699 TI - Complete genome sequence of Nakamurella multipartita type strain (Y-104). AB - Nakamurella multipartita (Yoshimi et al. 1996) Tao et al. 2004 is the type species of the monospecific genus Nakamurella in the actinobacterial suborder Frankineae. The nonmotile, coccus-shaped strain was isolated from activated sludge acclimated with sugar-containing synthetic wastewater, and is capable of accumulating large amounts of polysaccharides in its cells. Here we describe the features of the organism, together with the complete genome sequence and annotation. This is the first complete genome sequence of a member of the family Nakamurellaceae. The 6,060,298 bp long single replicon genome with its 5415 protein-coding and 56 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304700 TI - Complete genome sequence of Spirosoma linguale type strain (1). AB - Spirosoma linguale Migula 1894 is the type species of the genus. S. linguale is a free-living and non-pathogenic organism, known for its peculiar ringlike and horseshoe-shaped cell morphology. Here we describe the features of this organism, together with the complete genome sequence and annotation. This is only the third completed genome sequence of a member of the family Cytophagaceae. The 8,491,258 bp long genome with its eight plasmids, 7,069 protein-coding and 60 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304701 TI - Complete genome sequence of Kribbella flavida type strain (IFO 14399). AB - The genus Kribbella consists of 15 species, with Kribbella flavida (Park et al. 1999) as the type species. The name Kribbella was formed from the acronym of the Korea Research Institute of Bioscience and Biotechnology, KRIBB. Strains of the various Kribbella species were originally isolated from soil, potato, alum slate mine, patinas of catacombs or from horse racecourses. Here we describe the features of K. flavida together with the complete genome sequence and annotation. In addition to the 5.3 Mbp genome of Nocardioides sp. JS614, this is only the second completed genome sequence of the family Nocardioidaceae. The 7,579,488 bp long genome with its 7,086 protein-coding and 60 RNA genes and is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304702 TI - Complete genome sequence of Thermocrinis albus type strain (HI 11/12). AB - Thermocrinis albus Eder and Huber 2002 is one of three species in the genus Thermocrinis in the family Aquificaceae. Members of this family have become of significant interest because of their involvement in global biogeochemical cycles in high-temperature ecosystems. This interest had already spurred several genome sequencing projects for members of the family. We here report the first completed genome sequence a member of the genus Thermocrinis and the first type strain genome from a member of the family Aquificaceae. The 1,500,577 bp long genome with its 1,603 protein-coding and 47 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304703 TI - Complete genome sequence of Segniliparus rotundus type strain (CDC 1076). AB - Segniliparus rotundus Butler 2005 is the type species of the genus Segniliparus, which is currently the only genus in the corynebacterial family Segniliparaceae. This family is of large interest because of a novel late-emerging genus-specific mycolate pattern. The type strain has been isolated from human sputum and is probably an opportunistic pathogen. Here we describe the features of this organism, together with the complete genome sequence and annotation. This is the first completed genome sequence of the family Segniliparaceae. The 3,157,527 bp long genome with its 3,081 protein-coding and 52 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304704 TI - Complete genome sequence of Conexibacter woesei type strain (ID131577). AB - The genus Conexibacter (Monciardini et al. 2003) represents the type genus of the family Conexibacteraceae (Stackebrandt 2005, emend. Zhi et al. 2009) with Conexibacter woesei as the type species of the genus. C. woesei is a representative of a deep evolutionary line of descent within the class Actinobacteria. Strain ID131577(T) was originally isolated from temperate forest soil in Gerenzano (Italy). Cells are small, short rods that are motile by peritrichous flagella. They may form aggregates after a longer period of growth and, then as a typical characteristic, an undulate structure is formed by self aggregation of flagella with entangled bacterial cells. Here we describe the features of the organism, together with the complete sequence and annotation. The 6,359,369 bp long genome of C. woesei contains 5,950 protein-coding and 48 RNA genes and is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304705 TI - Complete genome sequence of Sebaldella termitidis type strain (NCTC 11300). AB - Sebaldella termitidis (Sebald 1962) Collins and Shah 1986, is the only species in the genus Sebaldella within the fusobacterial family 'Leptotrichiaceae'. The sole and type strain of the species was first isolated about 50 years ago from intestinal content of Mediterranean termites. The species is of interest for its very isolated phylogenetic position within the phylum Fusobacteria in the tree of life, with no other species sharing more than 90% 16S rRNA sequence similarity. The 4,486,650 bp long genome with its 4,210 protein-coding and 54 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304706 TI - Erratum to: Complete genome sequence of Pirellula staleyi type strain (ATCC 27377). PMID- 21304707 TI - The JCVI standard operating procedure for annotating prokaryotic metagenomic shotgun sequencing data. AB - The JCVI metagenomics analysis pipeline provides for the efficient and consistent annotation of shotgun metagenomics sequencing data for sampling communities of prokaryotic organisms. The process can be equally applied to individual sequence reads from traditional Sanger capillary electrophoresis sequences, newer technologies such as 454 pyrosequencing, or sequence assemblies derived from one or more of these data types. It includes the analysis of both coding and non coding genes, whether full-length or, as is often the case for shotgun metagenomics, fragmentary. The system is designed to provide the best-supported conservative functional annotation based on a combination of trusted homology based scientific evidence and computational assertions and an annotation value hierarchy established through extensive manual curation. The functional annotation attributes assigned by this system include gene name, gene symbol, GO terms, EC numbers, and JCVI functional role categories. PMID- 21304708 TI - Quantifying protein function specificity in the gene ontology. AB - Quantitative or numerical metrics of protein function specificity made possible by the Gene Ontology are useful in that they enable development of distance or similarity measures between protein functions. Here we describe how to calculate four measures of function specificity for GO terms: 1) number of ancestor terms; 2) number of offspring terms; 3) proportion of terms; and 4) Information Content (IC). We discuss the relationship between the metrics and the strengths and weaknesses of each. PMID- 21304709 TI - Complete genome sequence of Thermosphaera aggregans type strain (M11TL). AB - Thermosphaera aggregans Huber et al. 1998 is the type species of the genus Thermosphaera, which comprises at the time of writing only one species. This species represents archaea with a hyperthermophilic, heterotrophic, strictly anaerobic and fermentative phenotype. The type strain M11TL(T) was isolated from a water-sediment sample of a hot terrestrial spring (Obsidian Pool, Yellowstone National Park, Wyoming). Here we describe the features of this organism, together with the complete genome sequence and annotation. The 1,316,595 bp long single replicon genome with its 1,410 protein-coding and 47 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304710 TI - Complete genome sequence of Brachyspira murdochii type strain (56-150). AB - Brachyspira murdochii Stanton et al. 1992 is a non-pathogenic, host-associated spirochete of the family Brachyspiraceae. Initially isolated from the intestinal content of a healthy swine, the 'group B spirochaetes' were first described as Serpulina murdochii. Members of the family Brachyspiraceae are of great phylogenetic interest because of the extremely isolated location of this family within the phylum 'Spirochaetes'. Here we describe the features of this organism, together with the complete genome sequence and annotation. This is the first completed genome sequence of a type strain of a member of the family Brachyspiraceae and only the second genome sequence from a member of the genus Brachyspira. The 3,241,804 bp long genome with its 2,893 protein-coding and 40 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304711 TI - Complete genome sequence of Denitrovibrio acetiphilus type strain (N2460). AB - Denitrovibrio acetiphilus Myhr and Torsvik 2000 is the type species of the genus Denitrovibrio in the bacterial family Deferribacteraceae. It is of phylogenetic interest because there are only six genera described in the family Deferribacteraceae. D. acetiphilus was isolated as a representative of a population reducing nitrate to ammonia in a laboratory column simulating the conditions in off-shore oil recovery fields. When nitrate was added to this column undesirable hydrogen sulfide production was stopped because the sulfate reducing populations were superseded by these nitrate reducing bacteria. Here we describe the features of this marine, mesophilic, obligately anaerobic organism respiring by nitrate reduction, together with the complete genome sequence, and annotation. This is the second complete genome sequence of the order Deferribacterales and the class Deferribacteres, which is the sole class in the phylum Deferribacteres. The 3,222,077 bp genome with its 3,034 protein-coding and 51 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304713 TI - Complete genome sequence of Coraliomargarita akajimensis type strain (04OKA010 24). AB - Coraliomargarita akajimensis Yoon et al. 2007 is the type species of the genus Coraliomargarita. C. akajimensis is an obligately aerobic, Gram-negative, non spore-forming, non-motile, spherical bacterium that was isolated from seawater surrounding the hard coral Galaxea fascicularis. C. akajimensis is of special interest because of its phylogenetic position in a genomically under-studied area of the bacterial diversity. Here we describe the features of this organism, together with the complete genome sequence, and annotation. This is the first complete genome sequence of a member of the family Puniceicoccaceae. The 3,750,771 bp long genome with its 3,137 protein-coding and 55 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304712 TI - Complete genome sequence of Aminobacterium colombiense type strain (ALA-1). AB - Aminobacterium colombiense Baena et al. 1999 is the type species of the genus Aminobacterium. This genus is of large interest because of its isolated phylogenetic location in the family Synergistaceae, its strictly anaerobic lifestyle, and its ability to grow by fermentation of a limited range of amino acids but not carbohydrates. Here we describe the features of this organism, together with the complete genome sequence and annotation. This is the second completed genome sequence of a member of the family Synergistaceae and the first genome sequence of a member of the genus Aminobacterium. The 1,980,592 bp long genome with its 1,914 protein-coding and 56 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304714 TI - Complete genome sequence of Arcobacter nitrofigilis type strain (CI). AB - Arcobacter nitrofigilis (McClung et al. 1983) Vandamme et al. 1991 is the type species of the genus Arcobacter in the family Campylobacteraceae within the Epsilonproteobacteria. The species was first described in 1983 as Campylobacter nitrofigilis [1] after its detection as a free-living, nitrogen-fixing Campylobacter species associated with Spartina alterniflora Loisel roots [2]. It is of phylogenetic interest because of its lifestyle as a symbiotic organism in a marine environment in contrast to many other Arcobacter species which are associated with warm-blooded animals and tend to be pathogenic. Here we describe the features of this organism, together with the complete genome sequence, and annotation. This is the first complete genome sequence of a type stain of the genus Arcobacter. The 3,192,235 bp genome with its 3,154 protein-coding and 70 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304715 TI - Two genome sequences of the same bacterial strain, Gluconacetobacter diazotrophicus PAl 5, suggest a new standard in genome sequence submission. AB - Gluconacetobacter diazotrophicus PAl 5 is of agricultural significance due to its ability to provide fixed nitrogen to plants. Consequently, its genome sequence has been eagerly anticipated to enhance understanding of endophytic nitrogen fixation. Two groups have sequenced the PAl 5 genome from the same source (ATCC 49037), though the resulting sequences contain a surprisingly high number of differences. Therefore, an optical map of PAl 5 was constructed in order to determine which genome assembly more closely resembles the chromosomal DNA by aligning each sequence against a physical map of the genome. While one sequence aligned very well, over 98% of the second sequence contained numerous rearrangements. The many differences observed between these two genome sequences could be owing to either assembly errors or rapid evolutionary divergence. The extent of the differences derived from sequence assembly errors could be assessed if the raw sequencing reads were provided by both genome centers at the time of genome sequence submission. Hence, a new genome sequence standard is proposed whereby the investigator supplies the raw reads along with the closed sequence so that the community can make more accurate judgments on whether differences observed in a single stain may be of biological origin or are simply caused by differences in genome assembly procedures. PMID- 21304716 TI - Complete genome sequence of Thermobispora bispora type strain (R51). AB - Thermobispora bispora (Henssen 1957) Wang et al. 1996 is the type species of the genus Thermobispora. This genus is of great interest because it is strictly thermophilic and because it has been shown for several of its members that the genome contains substantially distinct (6.4% sequence difference) and transcriptionally active 16S rRNA genes. Here we describe the features of this organism, together with the complete genome sequence and annotation. This is the second completed genome sequence of a member from the suborder Streptosporangineae and the first genome sequence of a member of the genus Thermobispora. The 4,189,976 bp long genome with its 3,596 protein-coding and 63 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304719 TI - Meeting Report: "Metagenomics, Metadata and Meta-analysis" (M3) Workshop at the Pacific Symposium on Biocomputing 2010. AB - This report summarizes the M3 Workshop held at the January 2010 Pacific Symposium on Biocomputing. The workshop, organized by Genomic Standards Consortium members, included five contributed talks, a series of short presentations from stakeholders in the genomics standards community, a poster session, and, in the evening, an open discussion session to review current projects and examine future directions for the GSC and its stakeholders. PMID- 21304718 TI - Complete genome sequence of Rhizobium leguminosarum bv. trifolii strain WSM1325, an effective microsymbiont of annual Mediterranean clovers. AB - Rhizobium leguminosarum bv trifolii is a soil-inhabiting bacterium that has the capacity to be an effective nitrogen fixing microsymbiont of a diverse range of annual Trifolium (clover) species. Strain WSM1325 is an aerobic, motile, non spore forming, Gram-negative rod isolated from root nodules collected in 1993 from the Greek Island of Serifos. WSM1325 is produced commercially in Australia as an inoculant for a broad range of annual clovers of Mediterranean origin due to its superior attributes of saprophytic competence, nitrogen fixation and acid tolerance. Here we describe the basic features of this organism, together with the complete genome sequence, and annotation. This is the first completed genome sequence for a microsymbiont of annual clovers. We reveal that its genome size is 7,418,122 bp encoding 7,232 protein-coding genes and 61 RNA-only encoding genes. This multipartite genome contains 6 distinct replicons; a chromosome of size 4,767,043 bp and 5 plasmids of size 828,924 bp, 660,973 bp, 516,088 bp, 350,312 bp and 294,782 bp. PMID- 21304717 TI - Complete genome sequence of Archaeoglobus profundus type strain (AV18). AB - Archaeoglobus profundus (Burggraf et al. 1990) is a hyperthermophilic archaeon in the euryarchaeal class Archaeoglobi, which is currently represented by the single family Archaeoglobaceae, containing six validly named species and two strains ascribed to the genus 'Geoglobus' which is taxonomically challenged as the corresponding type species has no validly published name. All members were isolated from marine hydrothermal habitats and are obligate anaerobes. Here we describe the features of the organism, together with the complete genome sequence and annotation. This is the second completed genome sequence of a member of the class Archaeoglobi. The 1,563,423 bp genome with its 1,858 protein-coding and 52 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304720 TI - Erratum to: Complete genome sequence of Atopobium parvulum type strain (IPP 1246). PMID- 21304721 TI - The first special issue of Standards in Genomic Sciences from the Genomic Standards Consortium. PMID- 21304722 TI - Meeting Report from the Genomic Standards Consortium (GSC) Workshop 9. AB - This report summarizes the proceedings of the 9th workshop of the Genomic Standards Consortium (GSC), held at the J. Craig Venter Institute, Rockville, MD, USA. It was the first GSC workshop to have open registration and attracted over 90 participants. This workshop featured sessions that provided overviews of the full range of ongoing GSC projects. It included sessions on Standards in Genomic Sciences, the open access journal of the GSC, building standards for genome annotation, the M5 platform for next-generation collaborative computational infrastructures, building ties with the biodiversity research community and two discussion panels with government and industry participants. Progress was made on all fronts, and major outcomes included the completion of the MIENS specification for publication and the formation of the Biodiversity working group. PMID- 21304723 TI - Meeting Report from the Genomic Standards Consortium (GSC) Workshop 10. AB - This report summarizes the proceedings of the 10th workshop of the Genomic Standards Consortium (GSC), held at Argonne National Laboratory, IL, USA. It was the second GSC workshop to have open registration and attracted over 60 participants who worked together to progress the full range of projects ongoing within the GSC. Overall, the primary focus of the workshop was on advancing the M5 platform for next-generation collaborative computational infrastructures. Other key outcomes included the formation of a GSC working group focused on MIGS/MIMS/MIENS compliance using the ISA software suite and the formal launch of the GSC Developer Working Group. Further information about the GSC and its range of activities can be found at http://gensc.org/. PMID- 21304724 TI - Meeting Report: Metagenomics, Metadata and MetaAnalysis (M3) at ISMB 2010. AB - This report summarizes the proceedings of the first day of the Metagenomics, Metadata and MetaAnalysis (M3) workshop held at the Intelligent Systems for Molecular Biology 2010 conference. The second day, which was dedicated to the inaugural meeting of the BioSharing initiative is presented in a separate report. The Genomic Standards Consortium (GSC) hosted the first day of this Special Interest Group (SIG) at ISMB to continue exploring the bottlenecks and emerging solutions for obtaining biological insights through large-scale comparative analysis of metagenomic datasets. The M3 SIG included invited and selected talks and a panel discussion at the end of the day involving the plenary speakers. Further information about the GSC and its range of activities can be found at http://gensc.org. Information about the newly established BioSharing effort can be found at http://biosharing.org/. PMID- 21304725 TI - Meeting report: GSC M5 roundtable at the 13th International Society for Microbial Ecology meeting in Seattle, WA, USA August 22-27, 2010. AB - This report summarizes the proceedings of the Metagenomics, Metadata, Metaanalysis, Models and Metainfrastructure (M5) Roundtable at the 13th International Society for Microbial Ecology Meeting in Seattle, WA, USA August 22 27, 2010. The Genomic Standards Consortium (GSC) hosted this meeting as a community engagement exercise to describe the GSC to the microbial ecology community during this important international meeting. The roundtable included five talks given by members of the GSC, and was followed by audience participation in the form of a roundtable discussion. This report summarizes this event. Further information on the GSC and its range of activities can be found at http://www.gensc.org. PMID- 21304726 TI - Meeting Report: Towards a Critical Assessment of Functional Annotation Experiment (CAFAE) for bacterial genome annotation. AB - It is widely recognized that, with the advent of very high throughput, short read, and highly parallelized sequencing technologies, the generation of new DNA sequences from microbes, plants, metagenomes is outpacing the ability to assign functions to ("annotate") all this data. To begin to try to address this, on May 18 and 19, 2010, a team of roughly fifty people met to define and scope the possibility of a first Critical Assessment of Functional Annotation Experiment (CAFAE) for bacterial genome annotation in Crystal City, Virginia. Due to the fundamental importance of genomic data to its mission, the Department of Energy (DOE) BER program hosted this workshop, funding the attendance of all invitees. The workshop was co-organized by Dan Drell and Susan Gregurick (DOE), Owen White and Nikos Kyripides. PMID- 21304727 TI - Meeting report: the terabase metagenomics workshop and the vision of an Earth microbiome project. AB - Between July 18(th) and 24(th) 2010, 26 leading microbial ecology, computation, bioinformatics and statistics researchers came together in Snowbird, Utah (USA) to discuss the challenge of how to best characterize the microbial world using next-generation sequencing technologies. The meeting was entitled "Terabase Metagenomics" and was sponsored by the Institute for Computing in Science (ICiS) summer 2010 workshop program. The aim of the workshop was to explore the fundamental questions relating to microbial ecology that could be addressed using advances in sequencing potential. Technological advances in next-generation sequencing platforms such as the Illumina HiSeq 2000 can generate in excess of 250 billion base pairs of genetic information in 8 days. Thus, the generation of a trillion base pairs of genetic information is becoming a routine matter. The main outcome from this meeting was the birth of a concept and practical approach to exploring microbial life on earth, the Earth Microbiome Project (EMP). Here we briefly describe the highlights of this meeting and provide an overview of the EMP concept and how it can be applied to exploration of the microbiome of each ecosystem on this planet. PMID- 21304728 TI - The Earth Microbiome Project: Meeting report of the "1 EMP meeting on sample selection and acquisition" at Argonne National Laboratory October 6 2010. AB - This report details the outcome the first meeting of the Earth Microbiome Project to discuss sample selection and acquisition. The meeting, held at the Argonne National Laboratory on Wednesday October 6(th) 2010, focused on discussion of how to prioritize environmental samples for sequencing and metagenomic analysis as part of the global effort of the EMP to systematically determine the functional and phylogenetic diversity of microbial communities across the world. PMID- 21304729 TI - Meeting Report: BioSharing at ISMB 2010. AB - This report summarizes the proceedings of the one day BioSharing meeting held at the Intelligent Systems for Molecular Biology (ISMB) 2010 conference in Boston, MA, USA This inaugural BioSharing event was hosted by the Genomic Standards Consortium as part of its M3 & BioSharing special interest group (SIG) workshop. The BioSharing event included invited talks from a range of community leaders and a panel discussion at the end of the day. The panel session led to the formal agreement among community leaders to join together to promote cross-community knowledge exchange and collaborations. A key focus of the newly formed Biosharing community will be linking up resources to promote real-world data sharing (virtuous cycle of data) and supporting compliance with data policies through the creation of a one-stop-portal of information. Further information about the newly established BioSharing effort can be found at http://biosharing.org. PMID- 21304730 TI - Meeting Report from the Second "Minimum Information for Biological and Biomedical Investigations" (MIBBI) workshop. AB - This report summarizes the proceedings of the second workshop of the 'Minimum Information for Biological and Biomedical Investigations' (MIBBI) consortium held on Dec 1-2, 2010 in Rudesheim, Germany through the sponsorship of the Beilstein Institute. MIBBI is an umbrella organization uniting communities developing Minimum Information (MI) checklists to standardize the description of data sets, the workflows by which they were generated and the scientific context for the work. This workshop brought together representatives of more than twenty communities to present the status of their MI checklists and plans for future development. Shared challenges and solutions were identified and the role of MIBBI in MI checklist development was discussed. The meeting featured some thirty presentations, wide-ranging discussions and breakout groups. The top outcomes of the two-day workshop as defined by the participants were: 1) the chance to share best practices and to identify areas of synergy; 2) defining a series of tasks for updating the MIBBI Portal; 3) reemphasizing the need to maintain independent MI checklists for various communities while leveraging common terms and workflow elements contained in multiple checklists; and 4) revision of the concept of the MIBBI Foundry to focus on the creation of a core set of MIBBI modules intended for reuse by individual MI checklist projects while maintaining the integrity of each MI project. Further information about MIBBI and its range of activities can be found at http://mibbi.org/. PMID- 21304731 TI - Complete genome sequence of Syntrophothermus lipocalidus type strain (TGB-C1). AB - Syntrophothermus lipocalidus Sekiguchi et al. 2000 is the type species of the genus Syntrophothermus. The species is of interest because of its strictly anaerobic lifestyle, its participation in the primary step of the degradation of organic maters, and for releasing products which serve as substrates for other microorganisms. It also contributes significantly to maintain a regular pH in its environment by removing the fatty acids through beta-oxidation. The strain is able to metabolize isobutyrate and butyrate, which are the substrate and the product of degradation of the substrate, respectively. This is the first complete genome sequence of a member of the genus Syntrophothermus and the second in the family Syntrophomonadaceae. Here we describe the features of this organism, together with the complete genome sequence and annotation. The 2,405,559 bp long genome with its 2,385 protein-coding and 55 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304732 TI - Complete genome sequence of Desulfarculus baarsii type strain (2st14). AB - Desulfarculus baarsii (Widdel 1981) Kuever et al. 2006 is the type and only species of the genus Desulfarculus, which represents the family Desulfarculaceae and the order Desulfarculales. This species is a mesophilic sulfate-reducing bacterium with the capability to oxidize acetate and fatty acids of up to 18 carbon atoms completely to CO(2). The acetyl-CoA/CODH (Wood-Ljungdahl) pathway is used by this species for the complete oxidation of carbon sources and autotrophic growth on formate. The type strain 2st14(T) was isolated from a ditch sediment collected near the University of Konstanz, Germany. This is the first completed genome sequence of a member of the order Desulfarculales. The 3,655,731 bp long single replicon genome with its 3,303 protein-coding and 52 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304733 TI - Non-contiguous finished genome sequence of Aminomonas paucivorans type strain (GLU-3). AB - Aminomonas paucivorans Baena et al. 1999 is the type species of the genus Aminomonas, which belongs to the family Synergistaceae. The species is of interest because it is an asaccharolytic chemoorganotrophic bacterium which ferments quite a number of amino acids. This is the first finished genome sequence (with one gap in a rDNA region) of a member of the genus Aminomonas and the third sequence from the family Synergistaceae. The 2,630,120 bp long genome with its 2,433 protein-coding and 61 RNA genes is a part of the GenomicEncyclopedia ofBacteria andArchaea project. PMID- 21304734 TI - Complete genome sequence of Intrasporangium calvum type strain (7 KIP). AB - Intrasporangium calvum Kalakoutskii et al. 1967 is the type species of the genus Intrasporangium, which belongs to the actinobacterial family Intrasporangiaceae. The species is a Gram-positive bacterium that forms a branching mycelium, which tends to break into irregular fragments. The mycelium of this strain may bear intercalary vesicles but does not contain spores. The strain described in this study is an airborne organism that was isolated from a school dining room in 1967. One particularly interesting feature of I. calvum is that the type of its menaquinone is different from all other representatives of the family Intrasporangiaceae. This is the first completed genome sequence from a member of the genus Intrasporangium and also the first sequence from the family Intrasporangiaceae. The 4,024,382 bp long genome with its 3,653 protein-coding and 57 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304735 TI - Complete genome sequence of Ilyobacter polytropus type strain (CuHbu1). AB - Ilyobacter polytropus Stieb and Schink 1984 is the type species of the genus Ilyobacter, which belongs to the fusobacterial family Fusobacteriaceae. The species is of interest because its members are able to ferment quite a number of sugars and organic acids. I. polytropus has a broad versatility in using various fermentation pathways. Also, its members do not degrade poly-beta-hydroxybutyrate but only the monomeric 3-hydroxybutyrate. This is the first completed genome sequence of a member of the genus Ilyobacter and the second sequence from the family Fusobacteriaceae. The 3,132,314 bp long genome with its 2,934 protein coding and 108 RNA genes consists of two chromosomes (2 and 1 Mbp long) and one plasmid, and is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304736 TI - Complete genome sequence of Methanothermus fervidus type strain (V24S). AB - Methanothermus fervidus Stetter 1982 is the type strain of the genus Methanothermus. This hyperthermophilic genus is of a thought to be endemic in Icelandic hot springs. M. fervidus was not only the first characterized organism with a maximal growth temperature (97 degrees C) close to the boiling point of water, but also the first archaeon in which a detailed functional analysis of its histone protein was reported and the first one in which the function of 2,3 cyclodiphosphoglycerate in thermoadaptation was characterized. Strain V24S(T) is of interest because of its very low substrate ranges, it grows only on H(2) + CO(2). This is the first completed genome sequence of the family Methanothermaceae. Here we describe the features of this organism, together with the complete genome sequence and annotation. The 1,243,342 bp long genome with its 1,311 protein-coding and 50 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304737 TI - Complete genome sequence of Nocardiopsis dassonvillei type strain (IMRU 509). AB - Nocardiopsis dassonvillei (Brocq-Rousseau 1904) Meyer 1976 is the type species of the genus Nocardiopsis, which in turn is the type genus of the family Nocardiopsaceae. This species is of interest because of its ecological versatility. Members of N. dassonvillei have been isolated from a large variety of natural habitats such as soil and marine sediments, from different plant and animal materials as well as from human patients. Moreover, representatives of the genus Nocardiopsis participate actively in biopolymer degradation. This is the first complete genome sequence in the family Nocardiopsaceae. Here we describe the features of this organism, together with the complete genome sequence and annotation. The 6,543,312 bp long genome consist of a 5.77 Mbp chromosome and a 0.78 Mbp plasmid and with its 5,570 protein-coding and 77 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304739 TI - Complete genome sequence of Marinobacter adhaerens type strain (HP15), a diatom interacting marine microorganism. AB - Marinobacter adhaerens HP15 is the type strain of a newly identified marine species, which is phylogenetically related to M. flavimaris, M. algicola, and M. aquaeolei. It is of special interest for research on marine aggregate formation because it showed specific attachment to diatom cells. In vitro it led to exopolymer formation and aggregation of these algal cells to form marine snow particles. M. adhaerens HP15 is a free-living, motile, rod-shaped, Gram-negative gammaproteobacterium, which was originally isolated from marine particles sampled in the German Wadden Sea. M. adhaerens HP15 grows heterotrophically on various media, is easy to access genetically, and serves as a model organism to investigate the cellular and molecular interactions with the diatom Thalassiosira weissflogii. Here we describe the complete and annotated genome sequence of M. adhaerens HP15 as well as some details on flagella-associated genes. M. adhaerens HP15 possesses three replicons; the chromosome comprises 4,422,725 bp and codes for 4,180 protein-coding genes, 51 tRNAs and three rRNA operons, while the two circular plasmids are ~187 kb and ~42 kb in size and contain 178 and 52 protein coding genes, respectively. PMID- 21304738 TI - Complete genome sequence of Thermaerobacter marianensis type strain (7p75a). AB - Thermaerobacter marianensis Takai et al. 1999 is the type species of the genus Thermaerobacter, which belongs to the Clostridiales family Incertae Sedis XVII. The species is of special interest because T. marianensis is an aerobic, thermophilic marine bacterium, originally isolated from the deepest part in the western Pacific Ocean (Mariana Trench) at the depth of 10.897m. Interestingly, the taxonomic status of the genus has not been clarified until now. The genus Thermaerobacter may represent a very deep group within the Firmicutes or potentially a novel phylum. The 2,844,696 bp long genome with its 2,375 protein coding and 60 RNA genes consists of one circular chromosome and is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304740 TI - Complete genome sequence of Thermosediminibacter oceani type strain (JW/IW 1228P). AB - Thermosediminibacter oceani (Lee et al. 2006) is the type species of the genus Thermosediminibacter in the family Thermoanaerobacteraceae. The anaerobic, barophilic, chemoorganotrophic thermophile is characterized by straight to curved Gram-negative rods. The strain described in this study was isolated from a core sample of deep sea sediments of the Peruvian high productivity upwelling system. This is the first completed genome sequence of a member of the genus Thermosediminibacter and the seventh genome sequence in the family Thermoanaerobacteraceae. The 2,280,035 bp long genome with its 2,285 protein coding and 63 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304741 TI - Complete genome sequence of Vulcanisaeta distributa type strain (IC-017). AB - Vulcanisaeta distributa Itoh et al. 2002 belongs to the family Thermoproteaceae in the phylum Crenarchaeota. The genus Vulcanisaeta is characterized by a global distribution in hot and acidic springs. This is the first genome sequence from a member of the genus Vulcanisaeta and seventh genome sequence in the family Thermoproteaceae. The 2,374,137 bp long genome with its 2,544 protein-coding and 49 RNA genes is a part of the Genomic Encyclopedia of Bacteriaand Archaea project. PMID- 21304742 TI - Complete genome sequence of Arcanobacterium haemolyticum type strain (11018). AB - Arcanobacterium haemolyticum (ex MacLean et al. 1946) Collins et al. 1983 is the type species of the genus Arcanobacterium, which belongs to the family Actinomycetaceae. The strain is of interest because it is an obligate parasite of the pharynx of humans and farm animal; occasionally, it causes pharyngeal or skin lesions. It is a Gram-positive, nonmotile and non-sporulating bacterium. The strain described in this study was isolated from infections amongst American soldiers of certain islands of the North and West Pacific. This is the first completed sequence of a member of the genus Arcanobacterium and the ninth type strain genome from the family Actinomycetaceae. The 1,986,154 bp long genome with its 1,821 protein-coding and 64 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304744 TI - Standard operating procedure for optimal identification of mycobacteria using 16S rRNA gene sequences. PMID- 21304743 TI - Complete genome sequence of Spirochaeta smaragdinae type strain (SEBR 4228). AB - Spirochaeta smaragdinae Magot et al. 1998 belongs to the family Spirochaetaceae. The species is Gram-negative, motile, obligately halophilic and strictly anaerobic and is of interest because it is able to ferment numerous polysaccharides. S. smaragdinae is the only species of the family Spirochaetaceae known to reduce thiosulfate or element sulfur to sulfide. This is the first complete genome sequence in the family Spirochaetaceae. The 4,653,970 bp long genome with its 4,363 protein-coding and 57 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304745 TI - Complete genome sequence of 'Thermobaculum terrenum' type strain (YNP1). AB - 'Thermobaculum terrenum' Botero et al. 2004 is the sole species within the proposed genus 'Thermobaculum'. Strain YNP1(T) is the only cultivated member of an acid tolerant, extremely thermophilic species belonging to a phylogenetically isolated environmental clone group within the phylum Chloroflexi. At present, the name 'Thermobaculum terrenum' is not yet validly published as it contravenes Rule 30 (3a) of the Bacteriological Code. The bacterium was isolated from a slightly acidic extreme thermal soil in Yellowstone National Park, Wyoming (USA). Depending on its final taxonomic allocation, this is likely to be the third completed genome sequence of a member of the class Thermomicrobia and the seventh type strain genome from the phylum Chloroflexi. The 3,101,581 bp long genome with its 2,872 protein-coding and 58 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304746 TI - Complete genome sequence of Candidatus Ruthia magnifica. AB - The hydrothermal vent clam Calyptogena magnifica (Bivalvia: Mollusca) is a member of the Vesicomyidae. Species within this family form symbioses with chemosynthetic Gammaproteobacteria. They exist in environments such as hydrothermal vents and cold seeps and have a rudimentary gut and feeding groove, indicating a large dependence on their endosymbionts for nutrition. The C. magnifica symbiont, Candidatus Ruthia magnifica, was the first intracellular sulfur-oxidizing endosymbiont to have its genome sequenced (Newton et al. 2007). Here we expand upon the original report and provide additional details complying with the emerging MIGS/MIMS standards. The complete genome exposed the genetic blueprint of the metabolic capabilities of the symbiont. Genes which were predicted to encode the proteins required for all the metabolic pathways typical of free-living chemoautotrophs were detected in the symbiont genome. These include major pathways including carbon fixation, sulfur oxidation, nitrogen assimilation, as well as amino acid and cofactor/vitamin biosynthesis. This genome sequence is invaluable in the study of these enigmatic associations and provides insights into the origin and evolution of autotrophic endosymbiosis. PMID- 21304748 TI - Metagenomes and metatranscriptomes from the L4 long-term coastal monitoring station in the Western English Channel. AB - Both metagenomic data and metatranscriptomic data were collected from surface water (0-2m) of the L4 sampling station (50.2518 N, 4.2089 W), which is part of the Western Channel Observatory long-term coastal-marine monitoring station. We previously generated from this area a six-year time series of 16S rRNA V6 data, which demonstrated robust seasonal structure for the bacterial community, with diversity correlated with day length. Here we describe the features of these metagenomes and metatranscriptomes. We generated 8 metagenomes (4.5 million sequences, 1.9 Gbp, average read-length 350 bp) and 7 metatranscriptomes (392,632 putative mRNA-derived sequences, 159 Mbp, average read-length 272 bp) for eight time-points sampled in 2008. These time points represent three seasons (winter, spring, and summer) and include both day and night samples. These data demonstrate the major differences between genetic potential and actuality, whereby genomes follow general seasonal trends yet with surprisingly little change in the functional potential over time; transcripts tended to be far more structured by changes occurring between day and night. PMID- 21304747 TI - Complete genome sequence of Ferrimonas balearica type strain (PAT). AB - Ferrimonas balearica Rossello-Mora et al. 1996 is the type species of the genus Ferrimonas, which belongs to the family Ferrimonadaceae within the Gammaproteobacteria. The species is a Gram-negative, motile, facultatively anaerobic, non spore-forming bacterium, which is of special interest because it is a chemoorganotroph and has a strictly respiratory metabolism with oxygen, nitrate, Fe(III)-oxyhydroxide, Fe(III)-citrate, MnO(2), selenate, selenite and thiosulfate as electron acceptors. This is the first completed genome sequence of a member of the genus Ferrimonas and also the first sequence from a member of the family Ferrimonadaceae. The 4,279,159 bp long genome with its 3,803 protein coding and 144 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304749 TI - Complete genome sequence of Sulfurimonas autotrophica type strain (OK10). AB - Sulfurimonas autotrophica Inagaki et al. 2003 is the type species of the genus Sulfurimonas. This genus is of interest because of its significant contribution to the global sulfur cycle as it oxidizes sulfur compounds to sulfate and by its apparent habitation of deep-sea hydrothermal and marine sulfidic environments as potential ecological niche. Here we describe the features of this organism, together with the complete genome sequence and annotation. This is the second complete genome sequence of the genus Sulfurimonas and the 15(th) genome in the family Helicobacteraceae. The 2,153,198 bp long genome with its 2,165 protein coding and 55 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304751 TI - Metagenomics: A foundling finds its feet. PMID- 21304750 TI - Complete genome sequence of Methanoplanus petrolearius type strain (SEBR 4847). AB - Methanoplanus petrolearius Ollivier et al. 1998 is the type strain of the genus Methanoplanus. The strain was originally isolated from an offshore oil field from the Gulf of Guinea. Members of the genus Methanoplanus are of interest because they play an important role in the carbon cycle and also because of their significant contribution to the global warming by methane emission in the atmosphere. Like other archaea of the family Methanomicrobiales, the members of the genus Methanoplanus are able to use CO(2) and H(2) as a source of carbon and energy; acetate is required for growth and probably also serves as carbon source. Here we describe the features of this organism, together with the complete genome sequence and annotation. This is the first complete genome sequence of a member of the family Methanomicrobiaceae and the sixth complete genome sequence from the order Methanomicrobiales. The 2,843,290 bp long genome with its 2,824 protein coding and 57 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21304752 TI - THE MAGNIFICENT SEVENTH. PMID- 21304753 TI - Utilisation of Healthcare and Associated Services in Huntington's disease: a data mining study. AB - BACKGROUND: People with Huntington's disease (HD) often require tailored healthcare and support packages that develop as the disease progresses. The Client Service Receipt Inventory (CSRI) gathers retrospective information on service utilization. This study investigated the use of formal services and informal care as measured by the CSRI and explored associations between informal care, disease severity and functional ability as measured by the Unified Huntington's Disease Rating Scale Total Motor Score (UHDRS-TMS) and functional scales. METHODS: All monitored longitudinal data from annual clinical assessments of UHDRS-TMS and functional assessments and CSRI collected under the auspices of the European Huntington's Disease Network (EHDN) REGISTRY study between the years 2004 and 2009 were utilised in the analyses. Disease severity was reflected by UHDRS-TMS. Functional ability was measured using the UHDRS functional scales. CSRI data were analysed according to percentage use of individual formal services and total estimated hours per week of informal care. Regression analyses were conducted to identify any associations between disease severity, functional ability and hours of informal care. RESULTS: 451 HD patients (212 female; 239 male) completed one visit; 105 patients (54 females; 51 males) completed two visits and 47 patients (20 females; 27 males) completed three visits in total over the 5 year period. The mean time between visits was 1.2 years. At visit one, 74% of the participants reported being in receipt of at least one formal hospital based service in the previous six months, and 89% reported receipt of formal primary and community care services. In contrast, at the third visit, 62% of people had used hospital based services and 94% formal community based services in the previous six months. Fifty % of individuals required some form of informal care in the home at visit 1; this increased to 68% at visits 2 and 3. The mean (SD) estimated weekly total informal care hours at visits 1, 2 and 3 were 32.8 (49.4); 21.6 (53.6) and 21.3 (62.4) respectively. Only the scores on the Functional Assessment Scale (FAS) accounted for the variance in the weekly total informal care hours at each visit. CONCLUSIONS: Although it must be acknowledged that service use is supply driven, most HD patients across Europe surveyed as part of this study were in receipt of formal primary and community care services and to a lesser extent formal hospital based services. There was however a large reliance on informal care in the home. The FAS appear to have predictive value on informal care requirements and may have utility in facilitating pro-active service provision and in particular when managing carer burden in this population. PMID- 21304754 TI - The family as a social unit. AB - Family medicine, in common with most other medical specialties, is passing through a period of lively debate concerning its course and development. This paper discusses that portion of the debate attempting to define the function of the family physician in overseeing the comprehensive and continuing health care of patients and their families. One consequence of such a definition is the need to understand thoroughly the family in its functional role as a social unit. This knowledge of the family unit will affect some aspects of the practice of family medicine. Some of our approaches to training practitioners in this challenging field are outlined. PMID- 21304755 TI - Practical genetics. AB - Despite the many advances in genetics in the past two decades, and the resulting great difficulty in achieving a broad knowledge of the field, there are several ways in which a family physician can employ a few basic concepts to achieve better understanding of his patients' problems. These include not only disorders inherited in a simple Mendelian fashion, many of which are rather rare, but also other more common diseases to which the genetic contribution may be less obvious. A little time spent in taking a family history may greatly facilitate diagnosis and treatment. PMID- 21304756 TI - Office management of anxiety States. AB - Anxiety states are common problems in family medicine. Family physicians are the best people to treat this painful psychological and physical state, although they may at times feel drugs are the answer or the patients should solve the problems themselves. Drugs are only symptom relievers and may be abused. The best therapy is a cautious use of drugs, good psychological diagnostics and a short term problem solving type of crisis therapy. Some pitfalls of treatment are added as a word of caution, but the final emphasis is primary treatment of anxiety by the personal touch of the primary physician. PMID- 21304757 TI - Understanding the dying process. AB - The study of death and dying has recently experienced an increase in both popularity and importance, as evidenced by the growing number of relevant books and articles. Advances in medical technology have given physicians the ability to postpone death temporarily, thereby prolonging the dying process. This medical achievement has resulted in obvious benefits, but it has also created a need for better understanding of and response to the dying process. Medical success in the form of 'heroic' treatment is no longer being valued above the patient's psychological needs. PMID- 21304758 TI - Postpartum backache: a preventable condition. AB - Postpartum backache, an apparently 'normal' condition, responds dramatically to simple manipulation during and after pregnancy. A theory is presented to explain the cause. Associated symptoms such as 'migraine' headaches, 'tension' headaches and pseudo-angina can also be relieved by the treatment for sacroiliac torsion. PMID- 21304759 TI - Homeostasis and biofeedback. AB - Homeostasis of human organisms is the maintenance of a hierarchy of steady state conditions with little variation from, and prompt return to, a stabilized level during function. Any one of the information channels which informs the organism of the state of homeostasis can be used as 'biofeedback', i.e. to increase awareness of inadequate control and to teach new control mechanisms. If homeostasis is the basis of good health, disease may be considered a deviation from homeostasis. Through the use of biofeedback the subject may be made aware of poor health and learn to make adjustments to achieve homeostasis. Clinical application and results in several chronic disorders illustrate some successes and limitations of this approach. PMID- 21304760 TI - Biofeedback, humanistic psychology and psychosomatics in family practice. AB - An innovative educational approach to psychosomatic illness in family practice has been developed. It is a synthesis of experiential methods of non-verbal communication and creativity training developed from psychotronic applications of biofeedback, humanistic psychology and eidetics. The methodology, called eidetic biofeedback, operates on non-traditional models of human potential and involves a holistic approach to the mind-body/environment relationship. The methods work by transferring the responsibility for health back to the awareness of the individual.Of 200 office practice patients, 60 percent achieved major changes in personality integration and vitality. This was reflected in cessation of the presenting complaint, without symptom substitution and diminished demand for clinical services. PMID- 21304761 TI - What is Biofeedback? AB - Biofeedback as a process involves the 'reading' of certain signals from the autonomic nervous system. This paper gives some definition of the process, together with indications for clinical application. PMID- 21304762 TI - A resident learns about family dynamics. AB - A family medicine resident just finishing a two-year program is faced with giving a lecture on family dynamics. At first he feels that he has learned nothing about family dynamics; but later after a fruitless library search for relevant material, he realizes he has learned several important things about the relationship between medicine and how families operate. What the resident learned, how he learned it and how it has made him a better physician are described by means of case histories. PMID- 21304763 TI - [Not Available]. PMID- 21304764 TI - Visual problems in children. AB - The importance of early diagnosis of visual problems in children cannot be overemphasized. The prevention of deprivation amblyopia, a condition where the development of normal vision may be permanently arrested by the unrecognized presence of a cataract, can be achieved only by the earliest diagnosis and urgent referral. Strabismic amblyopia caused by acquired convergent strabismus occurring, almost always, in the 18 months to four year age group is a totally preventable condition and referral is a daytime emergency. The simple pinhole test is described to differentiate clearly simple refractive errors from the serious, more urgent, organic causes of poor vision. Practical comments concerning congenital nystagmus and primary reading problems (dyslexia) are included. PMID- 21304765 TI - The bonuses of breastfeeding. AB - Breastfeeding is emotionally and physically desirable for infant health. The physician can encourage a woman to nurse her baby by discussing the subject early in the prenatal visits. Some practical suggestions are briefly outlined to help the doctor help a new mother. PMID- 21304766 TI - A better approach to well baby care. AB - We believe that well baby care is being done more efficiently by nurse practitioners than by some physicians. We have attempted to lend support to this argument by exploring various reasons for this, by outlining our objectives in doing well baby care and by commenting on how we see our role as perhaps different from that of the physician in this particular area of health care provision. PMID- 21304767 TI - [Not Available]. PMID- 21304768 TI - The challenge of hearing impairments in children. AB - Preschool children with suspected impairment of hearing present the challenge of early recognition and prompt referral for diagnosis. Unfortunately, referral is seldom prompt. Most of this delay stems from most primary care physicians' unwillingness to listen to parents' opinions, their lack of knowledge about deafness in children, failure to perform routine screening tests for hearing, and reluctance to refer to a proper diagnostic facility.This paper outlines manifestations of deafness in early childhood, simple office hearing tests, and selection of patients for referral. PMID- 21304769 TI - Exotic diseases are common. AB - The Canadian family physician should be aware of the steady increase in the incidence of parasitic diseases. Some are already endemic in Canada, especially in the underdeveloped areas of this country, others are being seen as travellers return, and visitors come from the tropics. This article emphasizes the need for an increasing vigilance by the family physician. An outline of lifecycle, diagnostic aids and therapy is given, together with a list of resource personnel who can help where problems arise with diagnosis or treatment. Prevention, including immunization, is discussed. PMID- 21304770 TI - Goodpasture's Syndrome: A Nasty Dose of the 'Flu. AB - A case of Goodpasture's syndrome encountered and diagnosed in family practice is described in this article. Goodpasture's original article is reviewed with particular reference to the possible etiological relationship of influenza virus infection and the subsequent development of this strange, poorly understood disorder. PMID- 21304771 TI - Evaluation techniques in family practice residency training. AB - Evaluation is recognized as an essential component of an educational program, yet implementation of evaluation is difficult and few models exist. This article outlines an evaluation program implemented by one family practice residency. PMID- 21304772 TI - Management of stable angina pectoris. AB - A state of stable angina pectoris may persist for many years and can usually be managed medically by the family physician. Once contributing or alternate diagnoses have been dealt with, most patients will be rendered either pain-free or greatly improved by use of nitrate and/or beta-adrenoreceptor blockade. A few patients will not be sufficiently improved by medical therapy. These should be considered for aortocoronary saphenous vein bypass surgery.Risk factor modification and psychological support are also managed by the family physician in most instances. PMID- 21304773 TI - Stress testing in perspective. AB - Despite many advances in methodology, exercise electrocardiography does not reliably predict the presence or absence of coronary artery disease. However, with a physician-monitored graded stress test, significant non electrocardiographic information of both diagnostic and prognostic importance may be obtained. Thus, if properly performed (with the results interpreted in the light of the total clinical picture), stress testing is a safe and extremely useful adjunct in the investigation and management of patients with known or suspected coronary artery disease. PMID- 21304774 TI - Is there life after myocardial infarction? AB - Rehabilitation - education and activity - should begin at the moment of infarct (or even before, in high risk subjects) to minimize both physical and psychological deconditioning.Immobilization and mobilization, with decreasing proportions of the former and increasing proportions of the latter supervised and directed by the primary physician aided by the health care team, will result in individualized optimum return to healthy activity. The skeleton routine used in one hospital is cited as an example of a framework on which to build. PMID- 21304775 TI - Long Term Follow up of 'Coronary Mimic Syndrome'. AB - Twenty-two female patients (mean age 42.3 years) with chest pain and normal coronary artery angiogram have been followed from April 1966 to March 1975 (mean follow-up period 56 months). Long term follow up data are presented. Treatment consisted of reassurance. PMID- 21304777 TI - Self evaluation program. PMID- 21304776 TI - Aortic stenosis - or 'just a murmur'? AB - Systolic murmurs are commonly encountered in family practice, often necessitating distinction between ejection and regurgitant murmurs. This distinction can be made by the family physician providing he is familiar with the characteristics of both, which are described in this article. Practice on normal hearts will help to distinguish the abnormal. PMID- 21304778 TI - How Can Attempts At Preventing Coronary Artery Disease be Improved? PMID- 21304779 TI - The diagnosis of organic brain syndrome. AB - Because it stems from a variety of causes and interacting factors, organic brain syndrome is a difficult condition to diagnose. Several factors make it distinguishable from functional disorders, schizophrenia or hysteria. The syndrome cannot be considered in isolation from the patient's personality, however, since this will affect his coping with the disorder. PMID- 21304780 TI - When our patients retire. AB - With increases in the efforts of preventive medicine and lowering of mandatory retirement ages, many of our patients are experiencing the stresses involved in handling the loss of their lifetime's employment.Patients may be helped to relieve these stresses by appropriate advice about physical and mental activity, diet, use of medications, and use of health care facilities before and after retirement. PMID- 21304781 TI - Pregnancy in a blind couple. PMID- 21304782 TI - The avoidance and management of orofacial injuries. AB - Recent studies reveal an increasing incidence of orofacial injuries in sports, especially hockey, and physicians must be prepared to accept a role in the campaign to prevent these injuries which are most common at ages 11 to 18. Some aspects of head and orofacial protection are therefore discussed. For those injuries which do occur, proper immediate care may aid in early diagnosis and treatment, and also shorten the recovery period. But perhaps more important, there must also be a change in our attitudes towards sports. PMID- 21304783 TI - What did we learn from the torontolympiad? AB - The Olympiad for the Physically Disabled is held every four years in the country of the regular Olympics. The 1976 Olympiad was held in Toronto and was the second largest international amateur sporting event in the world that year. Sport for the disabled offers much in the way of benefits, not only for the athlete participants, but also for other disabled people. Through the common medium of sport, a better appreciation of the abilities of the disabled is created in the minds of the able-bodied public. The Torontolympiad was a memorable and worthwhile experience for thousands of participants and spectators. It can truly be said that these games rebuild lives. PMID- 21304784 TI - [Not Available]. PMID- 21304785 TI - Sports as a prescription. AB - Movement in all its forms has become important in the treatment of clinical problems. The physical, physiological, psychological, and social benefits of therapeutic exercise are well recorded. The prescription of a sport, a dynamic exercise with additional skills and an element of competition, can achieve a clinical objective during different phases of patient care, just as drugs are prescribed and regulated as to dosage. The prescription should fulfill the patient's individual needs and interests, and the ingredients should be adjusted and regulated according to the response. PMID- 21304787 TI - Self evaluation program. PMID- 21304786 TI - Exercise and health in the young patient. AB - Recently an increasing awareness of the benefits of regular exercise has arisen. Success in developing nation-wide programs may depend on the methods used. Adequate input into the curriculum of a well-organized kindergarten system should be considered. Various forms of handicap provide a challenge to the physician and require knowledge of both the physical activity to be undertaken and the effect on the patient. PMID- 21304788 TI - What Do You Think Of Medical Care For Canada's Athletes - Amateur and Pro? PMID- 21304789 TI - The development of sports medicine in nova scotia. AB - Doctors in Nova Scotia, as in most provinces in Canada, are facing the unique problems related to the injured athlete. With the development of Sport Nova Scotia, combined with the efforts of the Canadian Academy of Sports Medicine, sports medicine is rapidly moving to a more scientific platform. The Nova Scotia Sports Medicine Clinic, we hope, will provide the area for a multidisciplined approach to problems of the athlete and will function as an educational resource for doctors and paramedical personnel throughout the province. PMID- 21304790 TI - Helping patients to stop smoking: the current situation. AB - Patients who continue to smoke in spite of obvious damage to their health are a source of frustration to most family physicians. Current approaches in helping such patients are outlined. There are optimum times and ways to help patients stop smoking. PMID- 21304791 TI - Is it Croup - Or Epiglottitis? AB - This article presents an overview of the generally accepted diagnostic and clinical management features of common acute laryngeal obstruction, croup - laryngotracheobronchiolitis (LTB) and epiglottitis - an occasionally poorly diagnosed and frequently inappropriately managed disease. A review of recent literature suggests a more dogmatic and scientific management of the disease. PMID- 21304792 TI - Where next for canadian family medicine? AB - In 1966, two formal training programs in family medicine were launched in Canada, with a total of three residents. Now there are 16 programs with almost 700 residents. There are three current educational trends in family medicine: increased flexibility of the curriculum; increased emphasis on self-directed learning, and increased amounts of office and community based training.The issues to be faced are:1. the necessity of assisting each undergraduate to make an appropriate career choice;2. the improvement of working relationships with other clinical departments;3. the need for improved methods of educating the educators;4. the development of research and scholarship within academic departments;5. the need for agreement on a core curriculum;6. the need to find a solution to questions surrounding licensure. PMID- 21304793 TI - Infective endocarditis: prevention, diagnosis and treatment. AB - Infective endocarditis may develop after microbial invasion of the bloodstream in patients with various cardiovascular lesions. Efforts to prevent endocarditis should be concentrated on the use of prophylactic antibiotics to reduce the frequency and magnitude of streptococcal and staphylococcal bacteremias in patients with susceptible cardiac lesions. The diagnosis of endocarditis should always be considered in any patient with fever, a cardiac murmur or a positive blood culture. Successful management of these patients requires early diagnosis and the appropriate use of antibiotics. PMID- 21304794 TI - Infections in the elderly. AB - The immune response is altered in the elderly and others who may be debilitated or malnourished. This will alter response to infection, as will the presence of diseases like diabetes, or chemotherapy for cancer. Hospital acquired infections are particularly prevalent in the elderly, who are more likely to spend time in such institutions. Routs of infection and methods of prevention are discussed. PMID- 21304795 TI - Pelvic inflammatory disease. AB - Acute salpingitis is an extremely common disease with much morbidity and is undoubtedly increasing in incidence, as a result of the increasing incidence of gonorrhea and the increasing use of contraceptive measures. It must be treated early and aggressively, and follow-up is mandatory. The use of laparoscopy in the differential diagnosis of salpingitis remains almost entirely dependent upon clinical judgement. PMID- 21304796 TI - Otitis externa: a rationale for treatment. AB - Acute diffuse otitis externa due to Pseudomonas (swimmer's ear) is a common summer problem which may be empirically (and inadequately) treated. Rational treatment is based upon accurate diagnosis of the etiology of the inflammation, and meticulous treatment of the ear canal. The type of ear drop seems less important than the technique of its application and physical management of the inflamed canal itself. A rational regime of therapy is outlined and side effects of drops discussed with complications of the disease itself. PMID- 21304798 TI - Self evaluation program. PMID- 21304797 TI - Current concepts of treating vaginitis. AB - Vaginitis can be a frustrating entity to treat, since the incidence of recurrence is high. This paper examines evidence from the literature concerning diagnosis and treatment of Candida albicans, Trichomonas vaginalis, Corynebacterium vaginale, herpes simplex type 2 and gonorrhea. A protocol based on these readings is outlined. PMID- 21304799 TI - Treatment of recurrent upper respiratory infection in children. AB - The care of a child with recurrent upper respiratory infections can be a frustrating experience for the physician, parent and patient.In this presentation, the history, age incidence, etiology and therapy of recurrent respiratory infection are discussed. As in other conditions the importance of the history cannot be over-emphasized. This alone may indicate the appropriate form of therapy. The age incidence in 32 pediatric patients is presented. Regular daily administration of sulfonamide can be an effective prophylaxis. The indications for tonsillectomy and adenoidectomy are discussed, and a respiratory vaccine has also been found effective.When these measures were unsuccessful, a trial of sodium cromoglycate was undertaken in 32 children, approximately 60 percent of whom improved within ten days. Repeated respiratory infection in children may sensitize the mucosa of the respiratory tract with consequent liberation of histamine. PMID- 21304800 TI - Amebic colitis complicated by multiple amebomas. AB - When treating native patients, it is important to differentiate between ameboma and rectal or colonic carcinoma. Prompt recognition of ameboma will avoid unnecessary surgery for presumed malignancy. Medical treatment with metronidazole and diloxamide furate will produce rapid regression of the lesions and will prevent the possibility of remote complications and perforations which, untreated, could be fatal. PMID- 21304801 TI - The natural history of outpatient abdominal pain. AB - The charts of 115 patients presenting to the Ottawa Civic Hospital Emergency Department with abdominal pain were examined for objective signs, laboratory investigations, cost of investigations, and disposition of the patients. After the initial visit, 85 patients were contacted for followup. Of these, 67 percent had no abdominal pain within one week of the initial visit; 33 percent still had abdominal pain after 25 days. Few objective signs were found in either group. Laboratory results, though frequently abnormal, were often ignored. Regardless of the presence of abdominal pain after 25 days, 98 percent of the patients were satisfied with their emergency room treatment. PMID- 21304802 TI - Benign paroxysmal peritonitis: the principal manifestation of familial mediterranean Fever. AB - Two cases of familial mediterranean fever are presented. Several other members of the family were probably affected by the same disease. The etiopathogenesis, ethnic origin and clinical symptomatology are discussed in detail. The importance of history and clinical investigation in differential diagnosis is emphasized, in comparison with the non-specific results of laboratory tests. Finally, therapeutic measures are reviewed, of which only colchicine appears promising at present. PMID- 21304804 TI - Arthritides of the hand. PMID- 21304803 TI - How adequate are Canada's immunization programs? PMID- 21304805 TI - Treating the rheumatoid hand. AB - Deformities in the rheumatoid hand will vary according to whether the joints or the tendons are involved. Frequently both will be involved and several different deformities will be present in the same hand. However, a logical approach to examination and treatment, as outlined in this article, will simplify decision making and ensure prompt, appropriate treatment. PMID- 21304806 TI - Reimplantation of amputated limbs. AB - The implantation of an upper limb is probably better than the best prostheses available today, provided the patient gains some sensitivity. This is quite separate from the psychological advantage. PMID- 21304808 TI - Self evaluation program. PMID- 21304807 TI - Hand infections. AB - The family physician, who is often preoccupied by a demanding practice and a great variety of conditions, may sometimes underestimate a hand infection. Now that antibiotherapy has given us a powerful weapon, the sequelae that led to maiming in the last decades should be eliminated. All that is required is some knowledge, speedy drainage and strict observation. PMID- 21304809 TI - Blood pressure in a sample of canadian school children. AB - Before attempting any preventive action to control essential hypertension, we must know who is at risk. Normative data are needed for blood pressure, especially that measured in a non-clinical setting. This study measured blood pressure in a group of 2004 students aged six to 18. Their pressures were taken at school, and compared with those found in other studies where the pressures were taken in a clinical setting. A significant difference was found, suggesting that further investigation is needed into normative data. PMID- 21304810 TI - Geriatrics in the residency program. AB - Geriatric health care delivery in Canada is in danger of being sequestered into a traditional specialty category. This paper suggests that geriatrics is predominantly a primary care discipline and is therefore within the expertise of the family physician. Education objectives for a geriatric rotation within a family medicine residency program are outlined. PMID- 21304811 TI - Stabilization of Nrf2 protein by D3T provides protection against ethanol-induced apoptosis in PC12 cells. AB - Previous studies have demonstrated that maternal ethanol exposure induces a moderate increase in Nrf2 protein expression in mouse embryos. Pretreatment with the Nrf2 inducer, 3H-1, 2-dithiole-3-thione (D3T), significantly increases the Nrf2 protein levels and prevents apoptosis in ethanol-exposed embryos. The present study, using PC12 cells, was designed to determine whether increased Nrf2 stability is a mechanism by which D3T enhances Nrf2 activation and subsequent antioxidant protection. Ethanol and D3T treatment resulted in a significant accumulation of Nrf2 protein in PC 12 cells. CHX chase analysis has shown that ethanol treatment delayed the degradation of Nrf2 protein in PC12 cells. A significantly greater decrease in Nrf2 protein degradation was observed in the cells treated with D3T alone or with both ethanol and D3T. In addition, D3T treatment significantly reduced ethanol-induced apoptosis. These results demonstrate that the stabilization of Nrf2 protein by D3T confers protection against ethanol-induced apoptosis. PMID- 21304812 TI - Nestin-GFP transgene reveals neural precursor cells in adult skeletal muscle. AB - BACKGROUND: Therapy for neural lesions or degenerative diseases relies mainly on finding transplantable active precursor cells. Identifying them in peripheral tissues accessible for biopsy, outside the central nervous system, would circumvent the serious immunological and ethical concerns impeding cell therapy. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we isolated neural progenitor cells in cultured adult skeletal muscle from transgenic mice in which nestin regulatory elements control GFP expression. These cells also expressed the early neural marker Tuj1 and light and heavy neurofilament but not S100beta, indicating that they express typical neural but not Schwann cell markers. GFP+/Tuj1+ cells were also negative for the endothelial and pericyte markers CD31 and alpha-smooth muscle actin, respectively. We established their a) functional response to glutamate in patch-clamp recordings; b) interstitial mesenchymal origin; c) replicative capacity; and d) the environment necessary for their survival after fluorescence-activated cell sorting. CONCLUSIONS/SIGNIFICANCE: We propose that the decline in nestin-GFP expression in muscle progenitor cells and its persistence in neural precursor cells in muscle cultures provide an invaluable tool for isolating a population of predifferentiated neural cells with therapeutic potential. PMID- 21304813 TI - Interferon gamma-dependent intestinal pathology contributes to the lethality in bacterial superantigen-induced toxic shock syndrome. AB - Toxic shock syndrome (TSS) caused by the superantigen exotoxins of Staphylococcus aureus and Streptococcus pyogenes is characterized by robust T cell activation, profound elevation in systemic levels of multiple cytokines, including interferon gamma (IFN-gamma), followed by multiple organ dysfunction and often death. As IFN gamma possesses pro- as well as anti-inflammatory properties, we delineated its role in the pathogenesis of TSS. Antibody-mediated in vivo neutralization of IFN gamma or targeted disruption of IFN-gamma gene conferred significant protection from lethal TSS in HLA-DR3 transgenic mice. Following systemic high dose SEB challenge, whereas the HLA-DR3.IFN-gamma(+/+) mice became sick and succumbed to TSS, HLA-DR3.IFN-gamma(-/-) mice appeared healthy and were significantly protected from SEB-induced lethality. SEB-induced systemic cytokine storm was significantly blunted in HLA-DR3.IFN-gamma(-/-) transgenic mice. Serum concentrations of several cytokines (IL-4, IL-10, IL-12p40 and IL-17) and chemokines (KC, rantes, eotaxin and MCP-1) were significantly lower in HLA DR3.IFN-gamma(-/-) transgenic mice. However, SEB-induced T cell expansion in the spleens was unaffected and expansion of SEB-reactive TCR Vbeta8(+) CD4(+) and CD8(+) T cells was even more pronounced in HLA-DR3.IFN-gamma(-/-) transgenic mice when compared to HLA-DR3.IFN-gamma(+/+) mice. A systematic histopathological examination of several vital organs revealed that both HLA-DR3.IFN-gamma(+/+) and HLA-DR3.IFN-gamma(-/-) transgenic mice displayed comparable severe inflammatory changes in lungs, and liver during TSS. Remarkably, whereas the small intestines from HLA-DR3.IFN-gamma(+/+) transgenic mice displayed significant pathological changes during TSS, the architecture of small intestines in HLA-DR3.IFN-gamma(-/ ) transgenic mice was preserved. In concordance with these histopathological changes, the gut permeability to macromolecules was dramatically increased in HLA DR3.IFN-gamma(+/+) but not HLA-DR3.IFN-gamma(-/-) mice during TSS. Overall, IFN gamma seemed to play a lethal role in the immunopathogenesis of TSS by inflicting fatal small bowel pathology. Our study thus identifies the important role for IFN gamma in TSS. PMID- 21304814 TI - Functional polymorphism -31C/G in the promoter of BIRC5 gene and risk of nasopharyngeal carcinoma among chinese. AB - BACKGROUND: Baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5, also called as survivin) is a member of the inhibitor of apoptosis protein (IAP) family, which plays an important role in the occurrence and progression of cancer. Recently, a polymorphism in the promoter of BIRC5, -31C/G (rs9904341), was shown to influence BIRC5 expression. METHODS: We examined whether the -31C/G was related to the risk of developing nasopharyngeal carcinoma (NPC) in a case control population from Guangxi province in southern China, which consists of 855 patients with NPC and 1036 controls. This polymorphism was genotyped by TaqMan assay. The genetic associations with the occurrence and progression of NPC were estimated by logistic regression. RESULTS: We observed a statistically significant increased occurrence of NPC associated with the CC genotype (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.13-1.73; P=0.0020) compared with the genotypes containing G allele (CG + GG genotype). However, no significant association was observed for the -31C/G with the severity of NPC (as measured by tumor-node-metastasis staging system). CONCLUSION: Our findings suggest that the functional polymorphism -31C/G in the promoter of BIRC5 gene may play a role in mediating the susceptibility to NPC among Chinese. PMID- 21304815 TI - Influence of consumption of a high-protein vs. high-carbohydrate meal on the physiological cortisol and psychological mood response in men and women. AB - Consumption of meals with different macronutrient contents, especially high in carbohydrates, may influence the stress-induced physiological and psychological response. The objective of this study was to investigate effects of consumption of a high-protein vs. high-carbohydrate meal on the physiological cortisol response and psychological mood response. Subjects (n = 38, 19 m/19f, age =25 +/- 9 yrs, BMI = 25.0 +/- 3.3 kg/m2) came to the university four times, fasted, for either condition: rest-protein, stress-protein, rest-carbohydrate, stress carbohydrate (randomized cross-over design). Stress was induced by means of a psychological computer-test. The test-meal was either a high-protein meal (En% P/C/F 65/5/30) or a high-carbohydrate meal (En% P/C/F 6/64/30), both meals were matched for energy density (4 kJ/g) and daily energy requirements (30%). Per test session salivary cortisol levels, appetite profile, mood state and level of anxiety were measured. High hunger, low satiety (81 +/- 16, 12 +/- 15 mm VAS) confirmed the fasted state. The stress condition was confirmed by increased feelings of depression, tension, anger, anxiety (AUC stress vs. rest p < 0.02). Consumption of the high-protein vs. high-carbohydrate meal did not affect feelings of depression, tension, anger, anxiety. Cortisol levels did not differ between the four test-sessions in men and women (AUC nmol.min/L p > 0.1). Consumption of the test-meals increased cortisol levels in men in all conditions (p < 0.01), and in women in the rest-protein and stress-protein condition (p < 0.03). Men showed higher cortisol levels than women (AUC nmol.min/L p < 0.0001). Consumption of meals with different macronutrient contents, i.e. high-protein vs. high-carbohydrate, does not influence the physiological and psychological response differentially. Men show a higher meal-induced salivary cortisol response compared with women. PMID- 21304816 TI - The role of vascular actors in two dimensional dialogue of human bone marrow stromal cell and endothelial cell for inducing self-assembled network. AB - Angiogenesis is very important for vascularized tissue engineering. In this study, we found that a two-dimensional co-culture of human bone marrow stromal cell (HBMSC) and human umbical vein endothelial cell (HUVEC) is able to stimulate the migration of co-cultured HUVEC and induce self-assembled network formation. During this process, expression of vascular endothelial growth factor (VEGF165) was upregulated in co-cultured HBMSC. Meanwhile, VEGF165-receptor2 (KDR) and urokinase-type plasminogen activator (uPA) were upregulated in co-cultured HUVEC. Functional studies show that neutralization of VEGF165 blocked the migration and the rearrangement of the cells and downregulated the expression of uPA and its receptor. Blocking of vascular endothelial-cadherin (VE-cad) did not affect the migration of co-cultured HUVEC but suppressed the self-assembled network formation. In conclusion, co-cultures upregulated the expression of VEGF165 in co cultured HBMSC; VEGF165 then activated uPA in co-cultured HUVEC, which might be responsible for initiating the migration and the self-assembled network formation with the participation of VE-cad. All of these results indicated that only the direct contact of HBMSC and HUVEC and their respective dialogue are sufficient to stimulate secretion of soluble factors and to activate molecules that are critical for self-assembled network formation which show a great application potential for vascularization in tissue engineering. PMID- 21304817 TI - Inhibition of hedgehog signaling decreases proliferation and clonogenicity of human mesenchymal stem cells. AB - Human mesenchymal stem cells (hMSC) have the ability to differentiate into osteoblasts, adipocytes and chondrocytes. We have previously shown that hMSC were endowed with a basal level of Hedgehog signaling that decreased after differentiation of these cells. Since hMSC differentiation is associated with growth-arrest we investigated the function of Hh signaling on cell proliferation. Here, we show that inhibition of Hh signaling, using the classical inhibitor cyclopamine, or a siRNA directed against Gli-2, leads to a decrease in hMSC proliferation. This phenomenon is not linked to apoptosis but to a block of the cells in the G0/G1 phases of the cell cycle. At the molecular level, it is associated with an increase in the active form of pRB, and a decrease in cyclin A expression and MAP kinase phosphorylation. Inhibition of Hh signaling is also associated with a decrease in the ability of the cells to form clones. By contrast, inhibition of Hh signaling during hMSC proliferation does not affect their ability to differentiate. This study demonstrates that hMSC are endowed with a basal Hedgehog signaling activity that is necessary for efficient proliferation and clonogenicity of hMSC. This observation unravels an unexpected new function for Hedgehog signaling in the regulation of human mesenchymal stem cells and highlights the critical function of this morphogen in hMSC biology. PMID- 21304818 TI - Module M1 of zebrafish neuroglobin acts as a structural and functional protein building block for a cell-membrane-penetrating activity. AB - Neuroglobin (Ngb) is a recently discovered vertebrate globin that is expressed in the brain and can reversibly bind oxygen. Mammalian Ngb is involved in neuroprotection during oxidative stress that occurs, for example, during ischemia and reperfusion. Recently, we found that zebrafish, but not human, Ngb can translocate into cells. Moreover, we demonstrated that a chimeric ZHHH Ngb protein, in which the module M1 of human Ngb is replaced by the corresponding region of zebrafish Ngb, can penetrate cell membranes and protect cells against oxidative stress-induced cell death, suggesting that module M1 of zebrafish Ngb is important for protein transduction. Furthermore, we recently showed that Lys7, Lys9, Lys21, and Lys23 in module M1 of zebrafish Ngb are crucial for protein transduction activity. In the present study, we have investigated whether module M1 of zebrafish Ngb can be used as a building block to create novel cell-membrane penetrating folded proteins. First, we engineered a chimeric myoglobin (Mb), in which module M1 of zebrafish Ngb was fused to the N-terminus of full-length human Mb, and investigated its functional and structural properties. Our results showed that this chimeric Mb protein is stable and forms almost the same heme environment and alpha-helical structure as human wild-type Mb. In addition, we demonstrated that chimeric Mb has a cell-membrane-penetrating activity similar to zebrafish Ngb. Moreover, we found that glycosaminoglycan is crucial for the cell membrane-penetrating activity of chimeric Mb as well as that of zebrafish Ngb. These results enable us to conclude that such module substitutions will facilitate the design and production of novel functional proteins. PMID- 21304819 TI - A novel fry1 allele reveals the existence of a mutant phenotype unrelated to 5' >3' exoribonuclease (XRN) activities in Arabidopsis thaliana roots. AB - BACKGROUND: Mutations in the FRY1/SAL1 Arabidopsis locus are highly pleiotropic, affecting drought tolerance, leaf shape and root growth. FRY1 encodes a nucleotide phosphatase that in vitro has inositol polyphosphate 1-phosphatase and 3',(2'),5'-bisphosphate nucleotide phosphatase activities. It is not clear which activity mediates each of the diverse biological functions of FRY1 in planta. PRINCIPAL FINDINGS: A fry1 mutant was identified in a genetic screen for Arabidopsis mutants deregulated in the expression of Pi High affinity Transporter 1;4 (PHT1;4). Histological analysis revealed that, in roots, FRY1 expression was restricted to the stele and meristems. The fry1 mutant displayed an altered root architecture phenotype and an increased drought tolerance. All of the phenotypes analyzed were complemented with the AHL gene encoding a protein that converts 3' polyadenosine 5'-phosphate (PAP) into AMP and Pi. PAP is known to inhibit exoribonucleases (XRN) in vitro. Accordingly, an xrn triple mutant with mutations in all three XRNs shared the fry1 drought tolerance and root architecture phenotypes. Interestingly these two traits were also complemented by grafting, revealing that drought tolerance was primarily conferred by the rosette and that the root architecture can be complemented by long-distance regulation derived from leaves. By contrast, PHT1 expression was not altered in xrn mutants or in grafting experiments. Thus, PHT1 up-regulation probably resulted from a local depletion of Pi in the fry1 stele. This hypothesis is supported by the identification of other genes modulated by Pi deficiency in the stele, which are found induced in a fry1 background. CONCLUSIONS/SIGNIFICANCE: Our results indicate that the 3',(2'),5'-bisphosphate nucleotide phosphatase activity of FRY1 is involved in long-distance as well as local regulatory activities in roots. The local up-regulation of PHT1 genes transcription in roots likely results from local depletion of Pi and is independent of the XRNs. PMID- 21304820 TI - Environmental and genetic preconditioning for long-term anoxia responses requires AMPK in Caenorhabditis elegans. AB - BACKGROUND: Preconditioning environments or therapeutics, to suppress the cellular damage associated with severe oxygen deprivation, is of interest to our understanding of diseases associated with oxygen deprivation. Wildtype C. elegans exposed to anoxia enter into a state of suspended animation in which energy requiring processes reversibly arrest. C. elegans at all developmental stages survive 24-hours of anoxia exposure however, the ability of adult hermaphrodites to survive three days of anoxia significantly decreases. Mutations in the insulin like signaling receptor (daf-2) and LIN-12/Notch (glp-1) lead to an enhanced long term anoxia survival phenotype. METHODOLOGY/PRINCIPAL FINDINGS: In this study we show that the combined growth environment of 25 degrees C and a diet of HT115 E. coli will precondition adult hermaphrodites to survive long-term anoxia; many of these survivors have normal movement after anoxia treatment. Animals fed the drug metformin, which induces a dietary-restriction like state in animals and activates AMPK in mammalian cell culture, have a higher survival rate when exposed to long-term anoxia. Mutations in genes encoding components of AMPK (aak 2, aakb-1, aakb-2, aakg-2) suppress the environmentally and genetically induced long-term anoxia survival phenotype. We further determine that there is a correlation between the animals that survive long-term anoxia and increased levels of carminic acid staining, which is a fluorescent dye that incorporates in with carbohydrates such as glycogen. CONCLUSIONS/SIGNIFICANCE: We conclude that small changes in growth conditions such as increased temperature and food source can influence the physiology of the animal thus affecting the responses to stress such as anoxia. Furthermore, this supports the idea that metformin should be further investigated as a therapeutic tool for treatment of oxygen-deprived tissues. Finally, the capacity for an animal to survive long bouts of severe oxygen deprivation is likely dependent on specific subunits of the heterotrimeric protein AMPK and energy stores such as carbohydrates. PMID- 21304821 TI - Multilocus association testing of quantitative traits based on partial least squares analysis. AB - Because of combining the genetic information of multiple loci, multilocus association studies (MLAS) are expected to be more powerful than single locus association studies (SLAS) in disease genes mapping. However, some researchers found that MLAS had similar or reduced power relative to SLAS, which was partly attributed to the increased degrees of freedom (dfs) in MLAS. Based on partial least-squares (PLS) analysis, we develop a MLAS approach, while avoiding large dfs in MLAS. In this approach, genotypes are first decomposed into the PLS components that not only capture majority of the genetic information of multiple loci, but also are relevant for target traits. The extracted PLS components are then regressed on target traits to detect association under multilinear regression. Simulation study based on real data from the HapMap project were used to assess the performance of our PLS-based MLAS as well as other popular multilinear regression-based MLAS approaches under various scenarios, considering genetic effects and linkage disequilibrium structure of candidate genetic regions. Using PLS-based MLAS approach, we conducted a genome-wide MLAS of lean body mass, and compared it with our previous genome-wide SLAS of lean body mass. Simulations and real data analyses results support the improved power of our PLS based MLAS in disease genes mapping relative to other three MLAS approaches investigated in this study. We aim to provide an effective and powerful MLAS approach, which may help to overcome the limitations of SLAS in disease genes mapping. PMID- 21304822 TI - High genetic diversity and different distributions of glycosyl hydrolase family 10 and 11 xylanases in the goat rumen. AB - BACKGROUND: The rumen harbors a complex microbial ecosystem for efficient hydrolysis of plant polysaccharides which are the main constituent of the diet. Xylanase is crucial for hemicellulose hydrolysis and plays an important role in the plant cell wall degradation. Xylanases of ruminal strains were widely studied, but few studies have focused on their diversity in rumen microenvironment. METHODOLOGY/PRINCIPAL FINDINGS: We explored the genetic diversity of xylanases belonging to two major glycosyl hydrolase families (GH 10 and 11) in goat rumen contents by analyzing the amplicons generated with two degenerate primer sets. Fifty-two distinct GH 10 and 35 GH 11 xylanase gene fragments (similarity <95%) were retrieved, and most had low identities with known sequences. Based on phylogenetic analysis, all GH 10 xylanase sequences fell into seven clusters, and 88.5% of them were related to xylanases from Bacteroidetes. Five clusters of GH 11 xylanase sequences were identified. Of these, 85.7% were related to xylanases from Firmicutes, and 14.3% were related to those of rumen fungi. Two full-length xylanase genes (one for each family) were directly cloned and expressed in Escherichia coli. Both the recombinant enzymes showed substantial xylanase activity, and were purified and characterized. Combined with the results of sheep rumen, Bacteroidetes and Firmicutes are the two major phyla of xylan-degrading microorganisms in rumen, which is distinct from the representatives of other environments such as soil and termite hindgut, suggesting that xylan-degrading microorganisms are environment specific. CONCLUSION/SIGNIFICANCE: The numerous new xylanase genes suggested the functional diversity of xylanase in the rumen microenvironment which may have great potential applications in industry and agriculture. The phylogenetic diversity and different distributions of xylanase genes will help us understand their roles in plant cell wall degradation in the rumen microenvironment. PMID- 21304823 TI - HCV subtype characterization among injection drug users: implication for a crucial role of Zhenjiang in HCV transmission in China. AB - BACKGROUND: HCV transmission is closely associated with drug-trafficking routes in China. However, the transmission route of HCV in Eastern China remains unclear. Here, we investigate the role of Zhenjiang city of Jiangsu province, an important transportation hub linking Shanghai with other regions of China, in HCV transmission. METHODOLOGY/PRINCIPAL FINDINGS: A total of 141 whole blood samples were collected from injection drug users (IDUs) in Zhenjiang and then tested for HCV infection. Of them, 115 HCV positive plasmas were subjected to RNA extraction, RT-PCR amplification, and sequencing. The subtype characterization and the evolutionary origin of HCV strains circulating in Zhenjiang were determined using polygenetic or phylogeographic analyses. Seven HCV subtypes 1b, 2a, 3a, 3b, 6a, 6e and 6n were detected among Zhenjiang IDUs, showing a complex HCV epidemic. The most predominant subtypes were 3a (38%) and 1b (26.8%). Among these subtypes, subtypes 3b, 6n and 6e originated from Southwestern China (i.e., Yunnan and/or Guangxi), subtypes 2a and 6a from Southern China (i.e., Guangdong), subtype 1b from Central (i.e., Henan) and Northwestern (i.e., Xinjiang) China, and subtype 3a from Southwestern (i.e., Yunnan) and Northwestern (i.e., Xinjiang) China. From Zhenjiang, subtypes 1b and 2a were further spread to Eastern (i.e., Shanghai) and Northern (i.e., Beijing) China, respectively. CONCLUSIONS/SIGNIFICANCE: The mixing of seven HCV subtypes in Zhenjiang from all quarters of China indicates that as an important middle station, Zhenjiang plays a crucial role in HCV transmission, just as it is important in population migration between other regions of China and Eastern China. PMID- 21304824 TI - miR-155, a Modulator of FOXO3a Protein Expression, Is Underexpressed and Cannot Be Upregulated by Stimulation of HOZOT, a Line of Multifunctional Treg. AB - MicroRNAs (miRNAs) play important roles in regulating post-transcriptional gene repression in a variety of immunological processes. In particular, much attention has been focused on their roles in regulatory T (Treg) cells which are crucial for maintaining peripheral tolerance and controlling T cell responses. Recently, we established a novel type of human Treg cell line, termed HOZOT, multifunctional cells exhibiting a CD4(+)CD8(+) phenotype. In this study, we performed miRNA profiling to identify signature miRNAs of HOZOT, and therein identified miR-155. Although miR-155 has also been characterized as a signature miRNA for FOXP3(+) natural Treg (nTreg) cells, it was expressed quite differently in HOZOT cells. Under both stimulatory and non-stimulatory conditions, miR-155 expression remained at low levels in HOZOT, while its expression in nTreg and conventional T cells remarkably increased after stimulation. We next searched candidate target genes of miR-155 through bioinformatics, and identified FOXO3a, a negative regulator of Akt signaling, as a miR-155 target gene. Further studies by gain- and loss-of-function experiments supported a role for miR-155 in the regulation of FOXO3a protein expression in conventional T and HOZOT cells. PMID- 21304825 TI - Stage-specific expression of TNFalpha regulates bad/bid-mediated apoptosis and RIP1/ROS-mediated secondary necrosis in Birnavirus-infected fish cells. AB - Infectious pancreatic necrosis virus (IPNV) can induce Bad-mediated apoptosis followed by secondary necrosis in fish cells, but it is not known how these two types of cell death are regulated by IPNV. We found that IPNV infection can regulate Bad/Bid-mediated apoptotic and Rip1/ROS-mediated necrotic death pathways via the up-regulation of TNFalpha in zebrafish ZF4 cells. Using a DNA microarray and quantitative RT-PCR analyses, two major subsets of differentially expressed genes were characterized, including the innate immune response gene TNFalpha and the pro-apoptotic genes Bad and Bid. In the early replication stage (0-6 h post infection, or p.i.), we observed that the pro-inflammatory cytokine TNFalpha underwent a rapid six-fold induction. Then, during the early-middle replication stages (6-12 h p.i.), TNFalpha level was eight-fold induction and the pro apoptotic Bcl-2 family members Bad and Bid were up-regulated. Furthermore, specific inhibitors of TNFalpha expression (AG-126 or TNFalpha-specific siRNA) were used to block apoptotic and necrotic death signaling during the early or early-middle stages of IPNV infection. Inhibition of TNFalpha expression dramatically reduced the Bad/Bid-mediated apoptotic and Rip1/ROS-mediated necrotic cell death pathways and rescued host cell viability. Moreover, we used Rip1-specific inhibitors (Nec-1 and Rip1-specific siRNA) to block Rip1 expression. The Rip1/ROS-mediated secondary necrotic pathway appeared to be reduced in IPNV-infected fish cells during the middle-late stage of infection (12 18 h p.i.). Taken together, our results indicate that IPNV triggers two death pathways via up-stream induction of the pro-inflammatory cytokine TNFalpha, and these results may provide new insights into the pathogenesis of RNA viruses. PMID- 21304826 TI - Dependence of the cyanobacterium Prochlorococcus on hydrogen peroxide scavenging microbes for growth at the ocean's surface. AB - The phytoplankton community in the oligotrophic open ocean is numerically dominated by the cyanobacterium Prochlorococcus, accounting for approximately half of all photosynthesis. In the illuminated euphotic zone where Prochlorococcus grows, reactive oxygen species are continuously generated via photochemical reactions with dissolved organic matter. However, Prochlorococcus genomes lack catalase and additional protective mechanisms common in other aerobes, and this genus is highly susceptible to oxidative damage from hydrogen peroxide (HOOH). In this study we showed that the extant microbial community plays a vital, previously unrecognized role in cross-protecting Prochlorococcus from oxidative damage in the surface mixed layer of the oligotrophic ocean. Microbes are the primary HOOH sink in marine systems, and in the absence of the microbial community, surface waters in the Atlantic and Pacific Ocean accumulated HOOH to concentrations that were lethal for Prochlorococcus cultures. In laboratory experiments with the marine heterotroph Alteromonas sp., serving as a proxy for the natural community of HOOH-degrading microbes, bacterial depletion of HOOH from the extracellular milieu prevented oxidative damage to the cell envelope and photosystems of co-cultured Prochlorococcus, and facilitated the growth of Prochlorococcus at ecologically-relevant cell concentrations. Curiously, the more recently evolved lineages of Prochlorococcus that exploit the surface mixed layer niche were also the most sensitive to HOOH. The genomic streamlining of these evolved lineages during adaptation to the high-light exposed upper euphotic zone thus appears to be coincident with an acquired dependency on the extant HOOH-consuming community. These results underscore the importance of (indirect) biotic interactions in establishing niche boundaries, and highlight the impacts that community-level responses to stress may have in the ecological and evolutionary outcomes for co-existing species. PMID- 21304827 TI - Role of the Small GTPase Rho3 in Golgi/Endosome trafficking through functional interaction with adaptin in Fission Yeast. AB - BACKGROUND: We had previously identified the mutant allele of apm1(+) that encodes a homolog of the mammalian u1A subunit of the clathrin-associated adaptor protein-1 (AP-1) complex, and we demonstrated the role of Apm1 in Golgi/endosome trafficking, secretion, and vacuole fusion in fission yeast. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we isolated rho3(+), which encodes a Rho-family small GTPase, an important regulator of exocystosis, as a multicopy-suppressor of the temperature-sensitive growth of the apm1-1 mutant cells. Overexpression of Rho3 suppressed the Cl(-) sensitivity and immunosuppressant sensitivity of the apm1-1 mutant cells. Overexpression of Rho3 also suppressed the fragmentation of vacuoles, and the accumulation of v-SNARE Syb1 in Golgi/endosomes and partially suppressed the defective secretion associated with apm1-deletion cells. Notably, electron microscopic observation of the rho3-deletion cells revealed the accumulation of abnormal Golgi-like structures, vacuole fragmentation, and accumulation of secretory vesicles; these phenotypes were very similar to those of the apm1-deletion cells. Furthermore, the rho3-deletion cells and apm1-deletion cells showed very similar phenotypic characteristics, including the sensitivity to the immunosuppressant FK506, the cell wall-damaging agent micafungin, Cl(-), and valproic acid. Green fluorescent protein (GFP)-Rho3 was localized at Golgi/endosomes as well as the plasma membrane and division site. Finally, Rho3 was shown to form a complex with Apm1 as well as with other subunits of the clathrin-associated AP-1 complex in a GTP- and effector domain-dependent manner. CONCLUSIONS/SIGNIFICANCE: Taken together, our findings reveal a novel role of Rho3 in the regulation of Golgi/endosome trafficking and suggest that clathrin-associated adaptor protein-1 and Rho3 co ordinate in intracellular transport in fission yeast. To the best of our knowledge, this study provides the first evidence of a direct link between the small GTPase Rho and the clathrin-associated adaptor protein-1 in membrane trafficking. PMID- 21304829 TI - Genetic Stalking and Voyeurism: A New Challenge to Privacy. PMID- 21304831 TI - A preliminary study of orbitofrontal activation and hypersociability in Williams Syndrome. AB - Individuals with Williams syndrome (WS) demonstrate an abnormally positive social bias. However, the neural substrates of this hypersociability, i.e., positive attribution bias and increased drive toward social interaction, have not fully been elucidated. METHODS: We performed an event-related functional magnetic resonance imaging study while individuals with WS and typically developing controls (TD) matched positive and negative emotional faces. WS compared to TD showed reduced right amygdala activation during presentation of negative faces, as in the previous literature. In addition, WS showed a unique pattern of right orbitofrontal cortex activation. While TD showed medial orbitofrontal cortex activation in response to positive, and lateral orbitofrontal cortex activation to negative, WS showed the opposite pattern. In light of the general notion of a medial/lateral gradient of reward/punishment processing in the orbitofrontal cortex, these findings provide an additional biological explanation for, or correlate of positive attribution bias and hypersociability in WS. PMID- 21304832 TI - A Sexual Barrier Intervention for HIV+/- Zambian Women: Acceptability and Use of Vaginal Chemical Barriers. AB - OBJECTIVES: The purposes of this study were to (a) assess the efficacy of a culturally tailored behavioral intervention to increase use and acceptability of sexual barrier products among HIV+ and HIV- Zambian women, (b) compare group versus individual interventions to increase barrier use and acceptability, and (c) validate the role of cultural factors as facilitators or impediments to sexual risk reduction. METHODS: A sample of 150 HIV+ and HIV- Zambian women was recruited from the University Teaching Hospital HIV Voluntary Counseling and Testing Centre, randomized into one of three conditions, and assessed at baseline and 6 months. Group and individual intervention participants attended a 3-session intervention plus pre- and post-HIV test counseling; control participants received pre- and post-test counseling only. RESULTS: Group intervention participants increased use of sexual barriers and had higher levels of acceptability than did individual intervention participants. HIV- group participants increased use of chemical barriers and female condoms. CONCLUSIONS: Results support the use of group interventions to increase sexual barrier use and acceptability and decrease sexual risk behavior in both HIV+ and HIV- women. PMID- 21304830 TI - Botulinum toxin therapy for osteoarticular pain: an evidence-based review. AB - Botulinum (BoNT) toxin has been used for its muscle-paralyzing action in conditions such as treatment of wrinkles, cervical dystonia and blephrospasm. There is preclinical and emerging clinical evidence of another mechanism of action of BoNT, namely, an antinociceptive action. In this review, we provide an evidence-based review of clinical studies of BoNT in osteoarticular conditions, such as osteoarthritis, tennis elbow, low back pain, and hand pain. Many randomized controlled trials (RCTs) found evidence of short-term efficacy of an injection of BoNT in relief of pain, and in some cases, improvement of function and quality of life. However, more clinical trials are needed to better define the clinical use of BoNT for treatment of refractory osteoarticular pain. PMID- 21304835 TI - What's New In ENT? AB - In recent years there have been marked changes and improvements in the field of otolaryngology. Some of those which are of particular concern to the family physician are covered in this article. The promising results achieved with 'permanent' tubes for chronic eustachian tube dysfunction are described, together with impedance audiometry as a screening tool and the indications for T & A. Also included are vertigo, vasomotor rhinitis, microsurgery of the larynx and conservation surgery of the larynx. PMID- 21304834 TI - Imputation methods for doubly censored HIV data. AB - In medical research, it is common to have doubly censored survival data: origin time and event time are both subject to censoring. In this paper, we review simple and probability-based methods that are used to impute interval censored origin time and compare the performance of these methods through extensive simulations in the one-sample problem, two-sample problem and Cox regression model problem. The use of a bootstrap procedure for inference is demonstrated. PMID- 21304833 TI - Role of the pJM1 plasmid-encoded transport proteins FatB, C and D in ferric anguibactin uptake in the fish pathogen Vibrio anguillarum. AB - Vibrio anguillarum serotype O1 is part of the natural flora in the aquatic habitat, but under certain circumstances it can cause terminal haemorrhagic septicemia in marine and fresh water fish due to the action of the anguibactin iron uptake system encoded by the virulence plasmid pJM1. This plasmid harbours the genes for the biosynthesis of the siderophore anguibactin and the ferric anguibactin transport proteins FatD, C, B and A encoded in the iron transport operon. The FatA protein is the outer membrane receptor for the ferric siderophore complex and the FatB lipoprotein provides the periplasmic domain for its internalization, whereas the FatC and D proteins are located in the cytoplasmic membrane and might play a role as part of the ABC transporter for internalization of the ferric siderophore. In this work we demonstrate the essential role of these two inner membrane proteins in ferric anguibactin transport and that the lipo-protein nature of FatB is not necessary for ferric anguibactin transport. PMID- 21304836 TI - [Not Available]. PMID- 21304837 TI - Hearing loss in the elderly: the hidden handicap. AB - Hearing loss in the elderly is an extremely common handicap which must be assessed together with multiple sensory handicaps. The handicap produced is more than a peripheral loss of hearing acuity; it is a complex amalgam of end organ and neurological deficits, including the inability to inhibit unwanted sound as well as the loss of ability to detect faint sound. Methods of managing it are described. PMID- 21304838 TI - Otitis media: separating facts from fancy. AB - Based on an extensive review of the literature, this paper concludes that several popular treatment regimens for otitis media are not based on proven data. Some of the myths dispelled concern incidence, drugs of choice, length of drug therapy and the use of ventilating tubes. PMID- 21304840 TI - Self evaluation program. PMID- 21304839 TI - Presbycusis. AB - Presbycusis is a progressive sensorineural hearing loss varying with age and affecting first the higher frequencies. The physical and social handicap is not fully appreciated by most people with normal hearing. Difficulties in diagnosis exist because of co-existing sensorineural hearing loss in older people. Audiometry provides an excellent means of analyzing the auditory system and is generally accurate in localizing a site of dysfunction. Many people with presbycusis are helped by hearing aids but all of them are helped by good enunciation. There are many factors considered in the etiology but so far there is no convincing means of preventing presbycusis. PMID- 21304841 TI - Adverse reactions to contrast media. AB - Two case histories are presented of patients having adverse reactions to urographic contrast media, one severe and the other fatal. The role of the family physician is stressed in communicating with consultants and the radiological department of the hospital to which patients are referred for contrast media studies.The patient's previous history of allergies, particularly sea food allergy, and any previous reaction to urographic contrast media are of great importance. This information should be given to the radiologist at the time of referral. PMID- 21304842 TI - Tonsillectomy and adenoidectomy: a review of the literature. AB - In considering whether to refer a child for tonsillectomy and adenoidectomy, five questions must be answered. Is the patient's tonsillar enlargement due to infection? Do the tonsils and adenoids have a useful function at this period of the child's growth? What is the frequency of T & A? What are the cause and course of tonsillitis? What is the risk/benefit ratio of T & A? From an extensive review of the literature, this paper attempts to answer these questions. PMID- 21304843 TI - A special case of phantom limb pain. AB - A farmer underwent disarticulation at the right shoulder followed by numerous skin grafts. After one of these grafts a phantom hand cramp developed, which disappeared on treatment of trigger points under a split thickness grafted, scarred area on the chest wall. Each phantom finger relaxed on injection of a definite area: i.e. the 'fingers' could be mapped out on the chest wall which was devoid of normal epicritic sensibility. The discussion points out the error of central versus peripheral theories of etiology and an approach toward understanding the patient as a psychophysic entity is stressed. The special characteristics of phantom limb pain are outlined, with emphasis on its remarkable response to psychic and physical factors. PMID- 21304844 TI - What Is the Physician's Responsibility In Treating Industrial Deafness? PMID- 21304845 TI - Facing the fifties... The male point of view. AB - How a man may adapt to the multiplicity of changes that sometimes occur in himself and in his world during the fifth decade of his existence is largely predetermined by lifelong experience and conditioning. Some men have difficulty adjusting to these changes. A physician has the potential to help these men by positively applying his practical knowledge of the normal physical and behavioral changes that occur with aging and his understanding of the pertinent factors in the social background. PMID- 21304846 TI - [Not Available]. PMID- 21304847 TI - The physician in the middle years. AB - The middle years are stressful for many specific reasons. Our vigor is beginning to decline. Our patients are aging and developing ominous problems. We have the commonly identified difficulties of coping with the frustrations of our younger patients and relatives. The burden of caring for aged members of the community is increasing. Fortunately we can also enjoy the benefits of the comfortable standard of life of healthy middle-aged Canadians. PMID- 21304848 TI - Estrogens in the postmenopausal woman. AB - Newspapers, magazines, television and the medical press have all carried articles warning against a relationship between estrogens and cancer. The main causes of this outbreak seem to have been articles appearing in the New England Journal of Medicine in December 1975 and the spring of 1976.The evidence for and against a causal relationship is reviewed and no basis found for this accusation. The article goes on to review what is known about the effect of estrogens on osteoporosis, thromboembolism and arteriosclerosis. PMID- 21304849 TI - Helping the middle aged couple with sexual problems. AB - A behavioral approach developed by Jack Annon for brief sexual counselling and described here, is recommended for use by family physicians. The effects of aging on male and female sexuality sometimes result in sexual problems if patients are unaware that these effects are normal. Permission to use pleasuring (masturbation) as a therapeutic tool often must be given to those who feel guilty about it. Counselling is often necessary to avoid sexual problems resulting from surgery and illness in middle age. Given average good health and the right partner, sex in middle and old age can still be fun. PMID- 21304850 TI - As it happened: a problem case presentation. AB - A problem case is presented as it happened in family practice. The diagnosis is not revealed, because the reader is expected to participate in the solution. The management of the case is open to criticism; it is not presented as an example of faultless medicine, but as a method of stimulating the reader to do his own problem solving. PMID- 21304851 TI - The appropriate use of serum digoxin assay. AB - The serum digoxin assay has become a popular laboratory test. However, its use is only appropriate if new information is gleaned which ultimately influences the physician's decision making. There are pitfalls inherent in the test if the technique is not standardized, or if the sample is taken randomly rather than at least 12 hours after the last dose of the drug. Moreover, therapeutic levels derived from adult patients in sinus rhythm cannot be applied to infants, nor to patients with atrial fibrillation.The development and use of the serum digoxin test has broadened awareness of digitalis pharmacokinetics. Its clinical implementation has occurred concurrently with other advancements in digitalis pharmacology such as bioavailability studies and the concept of low loading dosage. Together, all these factors have had an educational effect on physicians and lowered the frequency of digitalis toxicity.The physician must consider the complete patient in his total clinical milieu, and not treat only a laboratory result, i.e. the serum digoxin level. PMID- 21304852 TI - Ghosts: their appearance during bereavement. AB - Newly bereaved patients often experience hallucinations - auditory, visual, olfactory - about the deceased person. These experiences can be frightening to the patient, who will usually not mention them to anyone. However, the hallucinations can be used as a positive part of helping the bereaved adjust to their new life. PMID- 21304853 TI - The Doctor's Records and The Law. PMID- 21304854 TI - Self evaluation program. PMID- 21304855 TI - What price admitting privileges?: a study of hospital admissions by two family physicians. AB - A study of admissions to an acute care hospital by two family physicians for the years 1967 and 1971 made special reference to the relationship of the hospital work to the total practice workload and morbidity, and to the fact that during the study period the principle hospital used became an active teaching facility with junior hospital staff.We found an increased rate of admission in 1971, following national and local trends. The average length of stay per patient was higher than the hospital average, excluding pregnancy-related admissions. The length of stay and the number of consultations per admission increased when junior hospital staff were involved. PMID- 21304856 TI - Canadian Drug Products Containing ASA. AB - A list of nearly 200 Canadian ASA-containing drug products is presented. Information was supplied by the major pharmaceutical companies and data were also obtained from various Canadian reference sources. This information should aid the physician and other health-related personnel in identifying ASA-containing products and counselling the salicylate-endangered patient. PMID- 21304857 TI - Should physicians use professional management consultants? PMID- 21304858 TI - Tools for the Job: The POMR in Preventive Medicine. AB - There is increasing interest in practical preventive care in the family doctor's office. The concepts underlying the problem oriented medical record (POMR) include the principles of preventive medicine, and it is thus an excellent vehicle for implementation. However, the classical POMR model must be modified to the context of family practice, and priorities defined by each practice.This article describes how elements of the POMR can be used in planning preventive care. An appraisal of one's own practice is a valuable part of the planning; follow up can assess patient compliance and the effectiveness of the program. PMID- 21304859 TI - Care of the healthy elderly. AB - Observers of the geriatric scene sometimes wonder whether the 'accent on youth' claimed for the general postwar population has not subtly influenced the attitudes of our doctors. 'Old age' is a normal part of life and living but if one chooses to think of it as a disease, one will tend to treat the morbid process with medication and be uniformly disappointed in the results. This can lead to low expectations of one's abilities to help older people with any problems and an unnecessarily depressive attitude may develop which is unjustified in view of the facts. Older persons recover from most accidents and illness remarkably well. PMID- 21304860 TI - Blood pressure surveys: are they worth it? AB - A review of hypertension surveys indicates that geographic (door-to-door) surveys provide the best description of the problem in a community. Participation rates in shopping centre surveys have been low (four percent in Edmonton and eight percent in Hamilton) but amongst those found hypertensive, 65-78 percent are aware of their hypertension; of these 62-65 percent are already on therapy. Among those participating in such shopping centre surveys, the proportion of subjects taking antihypertensive medications increased from approximately six percent to approximately eight percent from three to six months after the survey. Possible indirect benefits and disadvantages of such surveys are discussed. PMID- 21304861 TI - 'The checkup': why, what, when, how. AB - 'Checkups' are supposed to be good preventive medicine, but it appears that society cannot bear the costs of an expanded annual physical for everyone. Family physicians have an obligation to make rational efforts at prevention; this article reviews present epidemiologic and scientific knowledge about the value of the possible components of periodic examinations for asymptomatic patients. An instrument for recording relevant information and facilitating follow-up compatible with the problem oriented record is described. PMID- 21304862 TI - The effective treatment of obesity in the community. AB - To treat obesity effectively, a multifaceted approach is needed. This article describes a program for women involving exercise, diet counselling and group interaction. PMID- 21304863 TI - Prison medicine. AB - Recently the delivery of health care in prisons has been attacked by prisoners and public alike. Committees are appointed to study conditions inside the prison wall, and recommendations have been made. As long as the prison system itself is not changed, hope to achieve even a minimum level and quality of care is slim. PMID- 21304864 TI - Taking a family history. AB - All too frequently, a patient's family history is not taken, or only one or two perfunctory questions are asked. Many data may thereby be omitted which might have been very useful in solving the patient's problems. The lack of a genetic history may delay the formulation of a complete problem list in the medical record. Some conditions may escape notice altogether for a considerable time. On the other hand, a brief but deliberate inquiry employing proven techniques may bring out information which permits early recognition of problems as well as more precise diagnosis. This may result in better service to the patient while achieving savings in both the physician's time and the cost of providing care. PMID- 21304866 TI - [Not Available]. PMID- 21304865 TI - Uncovering sexual problems. AB - While patients frequently make it difficult for us to uncover their sexual concerns, a much greater difficulty is due to physicians' unwillingness to deal with this subject.Physicians need to acquire basic knowledge about human sexuality as well as skills in making patients feel comfortable and open. A non judgmental attitude is essential. The physician will also be able to anticipate and prevent sexual distress by education. Expertise must be developed in differentiating those problems requiring referral for specialized sexual counselling from those which the family physician can handle. PMID- 21304867 TI - The Doctor's and the Patient's Problems in Treating Obesity. AB - The major difficulties for physicians and patients alike in the management of obesity are lack of goals, poor understanding of their roles in diet therapy and often a negative, helpless attitude toward therapy itself. Physicians clearly have a key role as coordinators of a weight reduction program, through their skills in assessing overweight problems. In addition, the physician plays an important role in education, communication, motivation and organization of the weight reduction therapy. PMID- 21304868 TI - A clinical approach to alcoholism. AB - THERE ARE THREE FUNDAMENTAL OBJECTIVES IN THERAPY FOR ALCOHOLISM: to obtain and maintain control over patients' behavior; to eliminate payoffs resulting from the alcoholic behavior, and to establish payoffs for non-alcoholic behavior. These objectives apply equally to patients and the important people in their lives. PMID- 21304869 TI - Multiple sclerosis and the family physician. AB - Multiple sclerosis is difficult to diagnose since it develops over a period of time and the symptoms and signs are scattered throughout the central nervous system. Because there is no specific treatment, the problems of management are especially challenging.Case histories are presented to support the concept that multiple sclerosis is a family and community concern. Family physicians are urged to maintain a supportive role and an interested attitude towards patients with multiple sclerosis. These patients and their families have urgent and continuing needs for their doctors' skills. PMID- 21304870 TI - Portuguese patients as part of the canadian mosaic. AB - Portuguese immigration is a relatively new addition to the Canadian ethnic mosaic. To help the Canadian family doctor become familiar with this new group, the experience of a predominantly Portuguese family practice is described. The main areas of concern centre around the working wife, the problems created by the uprooting of old people and the adaptation of the children to this new environment. Some conflicts created in the family by the new situation are described and solutions suggested. PMID- 21304871 TI - The treatment of vaginismus. AB - The treatment of vaginismus was the subject of grand rounds in the Department of Obstetrics and Gynecology at Vancouver General Hospital. Staff members of the UBC Sex Therapy Unit participated in the presentation of a case of unconsummated marriage. PMID- 21304872 TI - Residents and research: a three year experience. AB - The Department of Family Medicine, University of Western Ontario, has encouraged its residents to undertake original studies since 1973. An eight step approach has been formulated; details are discussed. Abstracts of 14 completed projects are presented as examples of topics and methods that are appropriate for residents. PMID- 21304873 TI - Solving problems: how does the family physician do it? AB - Objective evidence exists for a model of clinical problem solving by family physicians. Previous studies have examined the activities of family physicians, but there have been no data indicating the mental process behind these activities. This study, exploring the thought processes of family physicians engaged in clinical problem solving, has lead to the model described in this paper. Its educational and clinical implications are considered. PMID- 21304874 TI - Why Won't Hypertensive Patients Take Their Medicine? AB - Although hypertensives must take 80 percent or more of their medications each month in order to achieve substantial falls in blood pressure toward normal levels, only about half of them do so. Most features of the antihypertensive drug regimen actively discourage compliance. Commonly recommended strategies for improving low compliance, such as teaching hypertensives about their illness and its treatment or providing convenient follow-up care at the worksite, have been found ineffective. However, more behaviorally-oriented strategies, such as increased supervision and keeping home records of blood pressure and medication taking, can 'salvage' many hypertensives who would otherwise remain uncontrolled. PMID- 21304875 TI - Investigation of fatigue. AB - Fatigue is a very common symptom and the cause can often be determined by careful history and physical examination. Since there is no organic cause for at least half of the cases of fatigue, extensive laboratory and radiological investigation may not be necessary. The minimal laboratory investigation should include a urinalysis, complete blood count, smear, sedimentation rate and chest X-ray. Further investigation will be determined by the presence of localizing symptoms and signs. If these are present, then only limited investigation may be necessary. If it is felt that the cause of the fatigue is organic and there are no localizing features, very extensive laboratory and radiological investigation will be required. PMID- 21304876 TI - La traitement dietetique de certaines pathologies gastro-intestinales. PMID- 21304877 TI - Diagnosis and management of ankylosing spondylitis. AB - The idea that ankylosing spondylitis is a separate entity from rheumatoid arthritis has recently been strengthened by the discovery that the majority of individuals suffering from ankylosing spondylitis exhibit the histocompatibility antigen HLA B27. Inflammation of the sacroiliacs must be present for a diagnosis of ankylosing spondylitis to be made. Radiological interpretation of sacroiliac films may be difficult. In patients with normal or equivocal X-rays of the sacroiliacs, radioisotope scanning of the sacroiliac joint may confirm diagnosis. Although the articular features of ankylosing spondylitis are well known, a variety of systemic complications may be attributed to some other cause. The principles of management require a precise diagnosis, control of pain and maintenance of a good functional state by means of physiotherapy. The majority of patients with ankylosing spondylitis respond well to therapy. PMID- 21304878 TI - Tracking down muscle weakness. AB - Family physicians have the unique opportunity to follow patients over long periods of time, which allows them to observe all manifestations of a disease process when one is present. The patient in this case presented initially with neurological symptoms resulting in muscle weakness. Surgery several years later produced clinical and laboratory data which showed evidence of a previously unsuspected underlying disease process. PMID- 21304879 TI - Early diagnosis of breast cancer: the breast self-examination problem. AB - Only ten percent of 1000 consecutive patients attending the St. Michael's Hospital Breast Clinic were practicing breast self-examination regularly. Seventy percent had tried and quit because of confusion, frustration and terror over what they had felt in their breasts. They were encouraged to start again and learn what 'normal' felt like on the night of the clinical examination, after each woman had been reassured that her breasts were 'normal for her'.Of 533 women who have attended subsequently for annual re-examination, 75 percent are practicing breast self-examination regularly, confident that they know what 'normal' feels like and reasonably confident that they can detect any change from normal in the future.Women should be advised not to start breast self-examination until they have had a clinical examination by their doctor. Thereupon they should start immediately to learn 'what normal feels like' and thus provide a reasonable baseline for monthly re-examination.The number of doctors' clinical examinations so stimulated will yield extra dividends in the discovery of unsuspected lumps in the breast. PMID- 21304880 TI - Drug therapy in allergic disorders. AB - There are many drugs available to the physician treating allergic disorders, so it is very easy to become confused; therefore one must be selective, get to know a few drugs well, and know how and why to use a particular drug for a particular allergic disorder. PMID- 21304881 TI - The making of a geriatrician. AB - Interest in the provision of medical care to the elderly in Canada has been minimal but is growing. Contrary to the negative attitudes that used to prevail, the medical problems of the aged are intellectually challenging and rewarding, and also will respond to appropriate action. Perceptive diagnosis and evaluation of the person and family, skillful treatment and management, a multidisciplinary team approach and careful follow-up planning and support are required. These principles and skills can be taught, and health science faculties are beginning to accept their responsibility to do so. PMID- 21304882 TI - Inhibition of Nox2 oxidase activity ameliorates influenza A virus-induced lung inflammation. AB - Influenza A virus pandemics and emerging anti-viral resistance highlight the urgent need for novel generic pharmacological strategies that reduce both viral replication and lung inflammation. We investigated whether the primary enzymatic source of inflammatory cell ROS (reactive oxygen species), Nox2-containing NADPH oxidase, is a novel pharmacological target against the lung inflammation caused by influenza A viruses. Male WT (C57BL/6) and Nox2(-/y) mice were infected intranasally with low pathogenicity (X-31, H3N2) or higher pathogenicity (PR8, H1N1) influenza A virus. Viral titer, airways inflammation, superoxide and peroxynitrite production, lung histopathology, pro-inflammatory (MCP-1) and antiviral (IL-1beta) cytokines/chemokines, CD8(+) T cell effector function and alveolar epithelial cell apoptosis were assessed. Infection of Nox2(-/y) mice with X-31 virus resulted in a significant reduction in viral titers, BALF macrophages, peri-bronchial inflammation, BALF inflammatory cell superoxide and lung tissue peroxynitrite production, MCP-1 levels and alveolar epithelial cell apoptosis when compared to WT control mice. Lung levels of IL-1beta were ~3-fold higher in Nox2(-/y) mice. The numbers of influenza-specific CD8+D(b)NP(366)+ and D(b)PA(224)+ T cells in the BALF and spleen were comparable in WT and Nox2(-/y) mice. In vivo administration of the Nox2 inhibitor apocynin significantly suppressed viral titer, airways inflammation and inflammatory cell superoxide production following infection with X-31 or PR8. In conclusion, these findings indicate that Nox2 inhibitors have therapeutic potential for control of lung inflammation and damage in an influenza strain-independent manner. PMID- 21304883 TI - Nucleosomes containing methylated DNA stabilize DNA methyltransferases 3A/3B and ensure faithful epigenetic inheritance. AB - How epigenetic information is propagated during somatic cell divisions is still unclear but is absolutely critical for preserving gene expression patterns and cellular identity. Here we show an unanticipated mechanism for inheritance of DNA methylation patterns where the epigenetic mark not only recruits the catalyzing enzyme but also regulates the protein level, i.e. the enzymatic product (5 methylcytosine) determines the level of the methylase, thus forming a novel homeostatic inheritance system. Nucleosomes containing methylated DNA stabilize de novo DNA methyltransferases, DNMT3A/3B, allowing little free DNMT3A/3B enzymes to exist in the nucleus. Stabilization of DNMT3A/3B on nucleosomes in methylated regions further promotes propagation of DNA methylation. However, reduction of cellular DNA methylation levels creating more potential CpG substrates counter intuitively results in a dramatic decrease of DNMT3A/3B proteins due to diminished nucleosome binding and subsequent degradation of the unstable free proteins. These data show an unexpected self-regulatory inheritance mechanism that not only ensures somatic propagation of methylated states by DNMT1 and DNMT3A/3B enzymes but also prevents aberrant de novo methylation by causing degradation of free DNMT3A/3B enzymes. PMID- 21304884 TI - Whole-body analysis of a viral infection: vascular endothelium is a primary target of infectious hematopoietic necrosis virus in zebrafish larvae. AB - The progression of viral infections is notoriously difficult to follow in whole organisms. The small, transparent zebrafish larva constitutes a valuable system to study how pathogens spread. We describe here the course of infection of zebrafish early larvae with a heat-adapted variant of the Infectious Hematopoietic Necrosis Virus (IHNV), a rhabdovirus that represents an important threat to the salmonid culture industry. When incubated at 24 degrees C, a permissive temperature for virus replication, larvae infected by intravenous injection died within three to four days. Macroscopic signs of infection followed a highly predictable course, with a slowdown then arrest of blood flow despite continuing heartbeat, followed by a loss of reactivity to touch and ultimately by death. Using whole-mount in situ hybridization, patterns of infection were imaged in whole larvae. The first infected cells were detectable as early as 6 hours post infection, and a steady increase in infected cell number and staining intensity occurred with time. Venous endothelium appeared as a primary target of infection, as could be confirmed in fli1:GFP transgenic larvae by live imaging and immunohistochemistry. Disruption of the first vessels took place before arrest of blood circulation, and hemorrhages could be observed in various places. Our data suggest that infection spread from the damaged vessels to underlying tissue. By shifting infected fish to a temperature of 28 degrees C that is non permissive for viral propagation, it was possible to establish when virus generated damage became irreversible. This stage was reached many hours before any detectable induction of the host response. Zebrafish larvae infected with IHNV constitute a vertebrate model of an hemorrhagic viral disease. This tractable system will allow the in vivo dissection of host-virus interactions at the whole organism scale, a feature unrivalled by other vertebrate models. PMID- 21304885 TI - In situ photodegradation of incorporated polyanion does not alter prion infectivity. AB - Single-stranded polyanions >=40 bases in length facilitate the formation of hamster scrapie prions in vitro, and polyanions co-localize with PrP(Sc) aggregates in vivo. To test the hypothesis that intact polyanionic molecules might serve as a structural backbone essential for maintaining the infectious conformation(s) of PrP(Sc), we produced synthetic prions using a photocleavable, 100-base oligonucleotide (PC-oligo). In serial Protein Misfolding Cyclic Amplification (sPMCA) reactions using purified PrP(C) substrate, PC-oligo was incorporated into physical complexes with PrP(Sc) molecules that were resistant to benzonase digestion. Exposure of these nuclease-resistant prion complexes to long wave ultraviolet light (315 nm) induced degradation of PC-oligo into 5 base fragments. Light-induced photolysis of incorporated PC-oligo did not alter the infectivity of in vitro-generated prions, as determined by bioassay in hamsters and brain homogenate sPMCA assays. Neuropathological analysis also revealed no significant differences in the neurotropism of prions containing intact versus degraded PC-oligo. These results show that polyanions >5 bases in length are not required for maintaining the infectious properties of in vitro-generated scrapie prions, and indicate that such properties are maintained either by short polyanion remnants, other co-purified cofactors, or by PrP(Sc) molecules alone. PMID- 21304886 TI - A new testing strategy to identify rare variants with either risk or protective effect on disease. AB - Rapid advances in sequencing technologies set the stage for the large-scale medical sequencing efforts to be performed in the near future, with the goal of assessing the importance of rare variants in complex diseases. The discovery of new disease susceptibility genes requires powerful statistical methods for rare variant analysis. The low frequency and the expected large number of such variants pose great difficulties for the analysis of these data. We propose here a robust and powerful testing strategy to study the role rare variants may play in affecting susceptibility to complex traits. The strategy is based on assessing whether rare variants in a genetic region collectively occur at significantly higher frequencies in cases compared with controls (or vice versa). A main feature of the proposed methodology is that, although it is an overall test assessing a possibly large number of rare variants simultaneously, the disease variants can be both protective and risk variants, with moderate decreases in statistical power when both types of variants are present. Using simulations, we show that this approach can be powerful under complex and general disease models, as well as in larger genetic regions where the proportion of disease susceptibility variants may be small. Comparisons with previously published tests on simulated data show that the proposed approach can have better power than the existing methods. An application to a recently published study on Type-1 Diabetes finds rare variants in gene IFIH1 to be protective against Type-1 Diabetes. PMID- 21304887 TI - Pathogenic VCP/TER94 alleles are dominant actives and contribute to neurodegeneration by altering cellular ATP level in a Drosophila IBMPFD model. AB - Inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) is caused by mutations in Valosin-containing protein (VCP), a hexameric AAA ATPase that participates in a variety of cellular processes such as protein degradation, organelle biogenesis, and cell-cycle regulation. To understand how VCP mutations cause IBMPFD, we have established a Drosophila model by overexpressing TER94 (the sole Drosophila VCP ortholog) carrying mutations analogous to those implicated in IBMPFD. Expression of these TER94 mutants in muscle and nervous systems causes tissue degeneration, recapitulating the pathogenic phenotypes in IBMPFD patients. TER94-induced neurodegenerative defects are enhanced by elevated expression of wild-type TER94, suggesting that the pathogenic alleles are dominant active mutations. This conclusion is further supported by the observation that TER94-induced neurodegenerative defects require the formation of hexamer complex, a prerequisite for a functional AAA ATPase. Surprisingly, while disruptions of the ubiquitin-proteasome system (UPS) and the ER-associated degradation (ERAD) have been implicated as causes for VCP-induced tissue degeneration, these processes are not significantly affected in our fly model. Instead, the neurodegenerative defect of TER94 mutants seems sensitive to the level of cellular ATP. We show that increasing cellular ATP by independent mechanisms could suppress the phenotypes of TER94 mutants. Conversely, decreasing cellular ATP would enhance the TER94 mutant phenotypes. Taken together, our analyses have defined the nature of IBMPFD-causing VCP mutations and made an unexpected link between cellular ATP level and IBMPFD pathogenesis. PMID- 21304888 TI - Whole-genome comparison reveals novel genetic elements that characterize the genome of industrial strains of Saccharomyces cerevisiae. AB - Human intervention has subjected the yeast Saccharomyces cerevisiae to multiple rounds of independent domestication and thousands of generations of artificial selection. As a result, this species comprises a genetically diverse collection of natural isolates as well as domesticated strains that are used in specific industrial applications. However the scope of genetic diversity that was captured during the domesticated evolution of the industrial representatives of this important organism remains to be determined. To begin to address this, we have produced whole-genome assemblies of six commercial strains of S. cerevisiae (four wine and two brewing strains). These represent the first genome assemblies produced from S. cerevisiae strains in their industrially-used forms and the first high-quality assemblies for S. cerevisiae strains used in brewing. By comparing these sequences to six existing high-coverage S. cerevisiae genome assemblies, clear signatures were found that defined each industrial class of yeast. This genetic variation was comprised of both single nucleotide polymorphisms and large-scale insertions and deletions, with the latter often being associated with ORF heterogeneity between strains. This included the discovery of more than twenty probable genes that had not been identified previously in the S. cerevisiae genome. Comparison of this large number of S. cerevisiae strains also enabled the characterization of a cluster of five ORFs that have integrated into the genomes of the wine and bioethanol strains on multiple occasions and at diverse genomic locations via what appears to involve the resolution of a circular DNA intermediate. This work suggests that, despite the scrutiny that has been directed at the yeast genome, there remains a significant reservoir of ORFs and novel modes of genetic transmission that may have significant phenotypic impact in this important model and industrial species. PMID- 21304889 TI - Positive signature-tagged mutagenesis in Pseudomonas aeruginosa: tracking patho adaptive mutations promoting airways chronic infection. AB - The opportunistic pathogen Pseudomonas aeruginosa can establish life-long chronic infections in the airways of cystic fibrosis (CF) patients. Persistent lifestyle is established with P. aeruginosa patho-adaptive variants, which are clonal with the initially-acquired strains. Several reports indicated that P. aeruginosa adapts by loss-of-function mutations which enhance fitness in CF airways and sustain its clonal expansion during chronic infection. To validate this model of P. aeruginosa adaptation to CF airways and to identify novel genes involved in this microevolution, we designed a novel approach of positive-selection screening by PCR-based signature-tagged mutagenesis (Pos-STM) in a murine model of chronic airways infection. A systematic positive-selection scheme using sequential rounds of in vivo screenings for bacterial maintenance, as opposed to elimination, generated a list of genes whose inactivation increased the colonization and persistence in chronic airways infection. The phenotypes associated to these Pos STM mutations reflect alterations in diverse aspects of P. aeruginosa biology which include lack of swimming and twitching motility, lack of production of the virulence factors such as pyocyanin, biofilm formation, and metabolic functions. In addition, Pos-STM mutants showed altered invasion and stimulation of immune response when tested in human respiratory epithelial cells, indicating that P. aeruginosa is prone to revise the interaction with its host during persistent lifestyle. Finally, sequence analysis of Pos-STM genes in longitudinally P. aeruginosa isolates from CF patients identified signs of patho-adaptive mutations within the genome. This novel Pos-STM approach identified bacterial functions that can have important clinical implications for the persistent lifestyle and disease progression of the airway chronic infection. PMID- 21304890 TI - The architecture of gene regulatory variation across multiple human tissues: the MuTHER study. AB - While there have been studies exploring regulatory variation in one or more tissues, the complexity of tissue-specificity in multiple primary tissues is not yet well understood. We explore in depth the role of cis-regulatory variation in three human tissues: lymphoblastoid cell lines (LCL), skin, and fat. The samples (156 LCL, 160 skin, 166 fat) were derived simultaneously from a subset of well phenotyped healthy female twins of the MuTHER resource. We discover an abundance of cis-eQTLs in each tissue similar to previous estimates (858 or 4.7% of genes). In addition, we apply factor analysis (FA) to remove effects of latent variables, thus more than doubling the number of our discoveries (1,822 eQTL genes). The unique study design (Matched Co-Twin Analysis--MCTA) permits immediate replication of eQTLs using co-twins (93%-98%) and validation of the considerable gain in eQTL discovery after FA correction. We highlight the challenges of comparing eQTLs between tissues. After verifying previous significance threshold based estimates of tissue-specificity, we show their limitations given their dependency on statistical power. We propose that continuous estimates of the proportion of tissue-shared signals and direct comparison of the magnitude of effect on the fold change in expression are essential properties that jointly provide a biologically realistic view of tissue-specificity. Under this framework we demonstrate that 30% of eQTLs are shared among the three tissues studied, while another 29% appear exclusively tissue-specific. However, even among the shared eQTLs, a substantial proportion (10%-20%) have significant differences in the magnitude of fold change between genotypic classes across tissues. Our results underline the need to account for the complexity of eQTL tissue specificity in an effort to assess consequences of such variants for complex traits. PMID- 21304891 TI - A study of CNVs as trait-associated polymorphisms and as expression quantitative trait loci. AB - We conducted a comprehensive study of copy number variants (CNVs) well-tagged by SNPs (r(2)>= 0.8) by analyzing their effect on gene expression and their association with disease susceptibility and other complex human traits. We tested whether these CNVs were more likely to be functional than frequency-matched SNPs as trait-associated loci or as expression quantitative trait loci (eQTLs) influencing phenotype by altering gene regulation. Our study found that CNV tagging SNPs are significantly enriched for cis eQTLs; furthermore, we observed that trait associations from the NHGRI catalog show an overrepresentation of SNPs tagging CNVs relative to frequency-matched SNPs. We found that these SNPs tagging CNVs are more likely to affect multiple expression traits than frequency-matched variants. Given these findings on the functional relevance of CNVs, we created an online resource of expression-associated CNVs (eCNVs) using the most comprehensive population-based map of CNVs to inform future studies of complex traits. Although previous studies of common CNVs that can be typed on existing platforms and/or interrogated by SNPs in genome-wide association studies concluded that such CNVs appear unlikely to have a major role in the genetic basis of several complex diseases examined, our findings indicate that it would be premature to dismiss the possibility that even common CNVs may contribute to complex phenotypes and at least some common diseases. PMID- 21304892 TI - Targeted sister chromatid cohesion by Sir2. AB - The protein complex known as cohesin binds pericentric regions and other sites of eukaryotic genomes to mediate cohesion of sister chromatids. In budding yeast Saccharomyces cerevisiae, cohesin also binds silent chromatin, a repressive chromatin structure that functionally resembles heterochromatin of higher eukaryotes. We developed a protein-targeting assay to investigate the mechanistic basis for cohesion of silent chromatin domains. Individual silencing factors were tethered to sites where pairing of sister chromatids could be evaluated by fluorescence microscopy. We report that the evolutionarily conserved Sir2 histone deacetylase, an essential silent chromatin component, was both necessary and sufficient for cohesion. The cohesin genes were required, but the Sir2 deacetylase activity and other silencing factors were not. Binding of cohesin to silent chromatin was achieved with a small carboxyl terminal fragment of Sir2. Taken together, these data define a unique role for Sir2 in cohesion of silent chromatin that is distinct from the enzyme's role as a histone deacetylase. PMID- 21304893 TI - CSP and takeout genes modulate the switch between attraction and repulsion during behavioral phase change in the migratory locust. AB - Behavioral plasticity is the most striking trait in locust phase transition. However, the genetic basis for behavioral plasticity in locusts is largely unknown. To unravel the molecular mechanisms underlying the behavioral phase change in the migratory locust Locusta migratoria, the gene expression patterns over the time courses of solitarization and gregarization were compared by oligonucleotide microarray analysis. Data analysis revealed that several gene categories relevant to peripheral olfactory perception are strongly regulated in a total of 1,444 differentially expressed genes during both time courses. Among these candidate genes, several CSP (chemosensory protein) genes and one takeout gene, LmigTO1, showed higher expression in gregarious and solitarious locusts, respectively, and displayed opposite expression trends during solitarization and gregarization. qRT-PCR experiments revealed that most CSP members and LmigTO1 exhibited antenna-rich expressions. RNA interference combined with olfactory behavioral experiments confirmed that the CSP gene family and one takeout gene, LmigTO1, are involved in the shift from repulsion to attraction between individuals during gregarization and in the reverse transition during solitarization. These findings suggest that the response to locust-emitted olfactory cues regulated by CSP and takeout genes is involved in the behavioral phase change in the migratory locust and provide a previously undescribed molecular mechanism linked to the formation of locust aggregations. PMID- 21304894 TI - Mapping a new spontaneous preterm birth susceptibility gene, IGF1R, using linkage, haplotype sharing, and association analysis. AB - Preterm birth is the major cause of neonatal death and serious morbidity. Most preterm births are due to spontaneous onset of labor without a known cause or effective prevention. Both maternal and fetal genomes influence the predisposition to spontaneous preterm birth (SPTB), but the susceptibility loci remain to be defined. We utilized a combination of unique population structures, family-based linkage analysis, and subsequent case-control association to identify a susceptibility haplotype for SPTB. Clinically well-characterized SPTB families from northern Finland, a subisolate founded by a relatively small founder population that has subsequently experienced a number of bottlenecks, were selected for the initial discovery sample. Genome-wide linkage analysis using a high-density single-nucleotide polymorphism (SNP) array in seven large northern Finnish non-consanginous families identified a locus on 15q26.3 (HLOD 4.68). This region contains the IGF1R gene, which encodes the type 1 insulin-like growth factor receptor IGF-1R. Haplotype segregation analysis revealed that a 55 kb 12-SNP core segment within the IGF1R gene was shared identical-by-state (IBS) in five families. A follow-up case-control study in an independent sample representing the more general Finnish population showed an association of a 6-SNP IGF1R haplotype with SPTB in the fetuses, providing further evidence for IGF1R as a SPTB predisposition gene (frequency in cases versus controls 0.11 versus 0.05, P = 0.001, odds ratio 2.3). This study demonstrates the identification of a predisposing, low-frequency haplotype in a multifactorial trait using a well characterized population and a combination of family and case-control designs. Our findings support the identification of the novel susceptibility gene IGF1R for predisposition by the fetal genome to being born preterm. PMID- 21304896 TI - Bacillus subtilis two-component system sensory kinase DegS is regulated by serine phosphorylation in its input domain. AB - Bacillus subtilis two-component system DegS/U is well known for the complexity of its regulation. The cytosolic sensory kinase DegS does not receive a single predominant input signal like most two-component kinases, instead it integrates a wide array of metabolic inputs that modulate its activity. The phosphorylation state of the response regulator DegU also does not confer a straightforward "on/off" response; it is fine-tuned and at different levels triggers different sub-regulons. Here we describe serine phosphorylation of the DegS sensing domain, which stimulates its kinase activity. We demonstrate that DegS phosphorylation can be carried out by at least two B. subtilis Hanks-type kinases in vitro, and this stimulates the phosphate transfer towards DegU. The consequences of this process were studied in vivo, using phosphomimetic (Ser76Asp) and non phosphorylatable (Ser76Ala) mutants of DegS. In a number of physiological assays focused on different processes regulated by DegU, DegS S76D phosphomimetic mutant behaved like a strain with intermediate levels of DegU phosphorylation, whereas DegS S76A behaved like a strain with lower levels of DegU phophorylation. These findings suggest a link between DegS phosphorylation at serine 76 and the level of DegU phosphorylation, establishing this post-translational modification as an additional trigger for this two-component system. PMID- 21304897 TI - Berberine improves glucose metabolism in diabetic rats by inhibition of hepatic gluconeogenesis. AB - Berberine (BBR) is a compound originally identified in a Chinese herbal medicine Huanglian (Coptis chinensis French). It improves glucose metabolism in type 2 diabetic patients. The mechanisms involve in activation of adenosine monophosphate activated protein kinase (AMPK) and improvement of insulin sensitivity. However, it is not clear if BBR reduces blood glucose through other mechanism. In this study, we addressed this issue by examining liver response to BBR in diabetic rats, in which hyperglycemia was induced in Sprague-Dawley rats by high fat diet. We observed that BBR decreased fasting glucose significantly. Gluconeogenic genes, Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6 phosphatase (G6Pase), were decreased in liver by BBR. Hepatic steatosis was also reduced by BBR and expression of fatty acid synthase (FAS) was inhibited in liver. Activities of transcription factors including Forkhead transcription factor O1 (FoxO1), sterol regulatory element-binding protein 1c (SREBP1) and carbohydrate responsive element-binding protein (ChREBP) were decreased. Insulin signaling pathway was not altered in the liver. In cultured hepatocytes, BBR inhibited oxygen consumption and reduced intracellular adenosine triphosphate (ATP) level. The data suggest that BBR improves fasting blood glucose by direct inhibition of gluconeogenesis in liver. This activity is not dependent on insulin action. The gluconeogenic inhibition is likely a result of mitochondria inhibition by BBR. The observation supports that BBR improves glucose metabolism through an insulin-independent pathway. PMID- 21304898 TI - Anti-leukemia activity of in vitro-expanded human gamma delta T cells in a xenogeneic Ph+ leukemia model. AB - Gamma delta T cells (GDTc) lyse a variety of hematological and solid tumour cells in vitro and in vivo, and are thus promising candidates for cellular immunotherapy. We have developed a protocol to expand human GDTc in vitro, yielding highly cytotoxic Vgamma9/Vdelta2 CD27/CD45RA double negative effector memory cells. These cells express CD16, CD45RO, CD56, CD95 and NKG2D. Flow cytometric, clonogenic, and chromium release assays confirmed their specific cytotoxicity against Ph(+) cell lines in vitro. We have generated a fluorescent and bioluminescent Ph(+) cell line, EM-2eGFPluc, and established a novel xenogeneic leukemia model. Intravenous injection of EM-2eGFPluc into NOD.Cg Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice resulted in significant dose-dependent bone marrow engraftment; lower levels engrafted in blood, lung, liver and spleen. In vitro-expanded human GDTc injected intraperitoneally were found at higher levels in blood and organs compared to those injected intravenously; GDTc survived at least 33 days post-injection. In therapy experiments, we documented decreased bone marrow leukemia burden in mice treated with GDTc. Live GDTc were found in spleen and bone marrow at endpoint, suggesting the potential usefulness of this therapy. PMID- 21304899 TI - Gene therapy regenerates protein expression in cone photoreceptors in Rpe65(R91W/R91W) mice. AB - Cone photoreceptors mediate visual acuity under daylight conditions, so loss of cone-mediated central vision of course dramatically affects the quality of life of patients suffering from retinal degeneration. Therefore, promoting cone survival has become the goal of many ocular therapies and defining the stage of degeneration that still allows cell rescue is of prime importance. Using the Rpe65(R91W/R91W) mouse, which carries a mutation in the Rpe65 gene leading to progressive photoreceptor degeneration in both patients and mice, we defined stages of retinal degeneration that still allow cone rescue. We evaluated the therapeutic window within which cones can be rescued, using a subretinal injection of a lentiviral vector driving expression of RPE65 in the Rpe65(R91W/R91W) mice. Surprisingly, when applied to adult mice (1 month) this treatment not only stalls or slows cone degeneration but, actually, induces cone specific protein expression that was previously absent. Before the intervention only part of the cones (40% of the number found in wild-type animals) in the Rpe65(R91W/R91W) mice expressed cone transducin (GNAT2); this fraction increased to 64% after treatment. Correct S-opsin localization is also recovered in the transduced region. In consequence these results represent an extended therapeutic window compared to the Rpe65(-/-) mice, implying that patients suffering from missense mutations might also benefit from a prolonged therapeutic window. Moreover, cones are not only rescued during the course of the degeneration, but can actually recover their initial status, meaning that a proportion of altered cones in chromophore deficiency-related disease can be rehabilitated even though they are severely affected. PMID- 21304900 TI - Individual and cumulative effects of GWAS susceptibility loci in lung cancer: associations after sub-phenotyping for COPD. AB - Epidemiological studies show that approximately 20-30% of chronic smokers develop chronic obstructive pulmonary disease (COPD) while 10-15% develop lung cancer. COPD pre-exists lung cancer in 50-90% of cases and has a heritability of 40-77%, much greater than for lung cancer with heritability of 15-25%. These data suggest that smokers susceptible to COPD may also be susceptible to lung cancer. This study examines the association of several overlapping chromosomal loci, recently implicated by GWA studies in COPD, lung function and lung cancer, in (n = 1400) subjects sub-phenotyped for the presence of COPD and matched for smoking exposure. Using this approach we show; the 15q25 locus confers susceptibility to lung cancer and COPD, the 4q31 and 4q22 loci both confer a reduced risk to both COPD and lung cancer, the 6p21 locus confers susceptibility to lung cancer in smokers with pre-existing COPD, the 5p15 and 1q23 loci both confer susceptibility to lung cancer in those with no pre-existing COPD. We also show the 5q33 locus, previously associated with reduced FEV(1), appears to confer susceptibility to both COPD and lung cancer. The 6p21 locus previously linked to reduced FEV(1) is associated with COPD only. Larger studies will be needed to distinguish whether these COPD-related effects may reflect, in part, associations specific to different lung cancer histology. We demonstrate that when the "risk genotypes" derived from the univariate analysis are incorporated into an algorithm with clinical variables, independently associated with lung cancer in multivariate analysis, modest discrimination is possible on receiver operator curve analysis (AUC = 0.70). We suggest that genetic susceptibility to lung cancer includes genes conferring susceptibility to COPD and that sub-phenotyping with spirometry is critical to identifying genes underlying the development of lung cancer. PMID- 21304901 TI - Study of muscle cell dedifferentiation after skeletal muscle injury of mice with a Cre-Lox system. AB - BACKGROUND: Dedifferentiation of muscle cells in the tissue of mammals has yet to be observed. One of the challenges facing the study of skeletal muscle cell dedifferentiation is the availability of a reliable model that can confidentially distinguish differentiated cell populations of myotubes and non-fused mononuclear cells, including stem cells that can coexist within the population of cells being studied. METHODOLOGY/PRINCIPAL FINDINGS: In the current study, we created a Cre/Lox-beta-galactosidase system, which can specifically tag differentiated multinuclear myotubes and myotube-generated mononuclear cells based on the activation of the marker gene, beta-galactosidase. By using this system in an adult mouse model, we found that beta-galactosidase positive mononuclear cells were generated from beta-galactosidase positive multinuclear myofibers upon muscle injury. We also demonstrated that these mononuclear cells can develop into a variety of different muscle cell lineages, i.e., myoblasts, satellite cells, and muscle derived stem cells. CONCLUSIONS/SIGNIFICANCE: These novel findings demonstrated, for the first time, that cellular dedifferentiation of skeletal muscle cells actually occurs in mammalian skeletal muscle following traumatic injury in vivo. PMID- 21304902 TI - The molecular mechanism of leptin secretion and expression induced by aristolochic acid in kidney fibroblast. AB - BACKGROUND: Leptin is a peptide hormone playing pivotal role in regulating food intake and energy expenditure. Growing evidence has suggested the pro inflammatory and fibrogenic properties of leptin. In addition, patients with renal fibrosis have higher level of plasma leptin, which was due to the increased leptin production. Aristolochic acid (AA) is a botanical toxin characterized to associate with the development of renal fibrosis including tubulointerstitial fibrosis. However, whether leptin is upregulated to participate in AA-induced kidney fibrosis remain completely unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study, leptin expression was increased by sublethal dose of AA in kidney fibroblast NRK49f determined by enzyme-linked immunosorbent assay and Western blot. Data from real-time reverse transcriptase-polymerase chain reaction revealed that leptin was upregulated by AA at transcriptional level. DNA binding activity of CCAAT enhancer binding protein alpha (C/EBP alpha), one of the transcription factors for leptin gene, was enhanced in DNA affinity precipitation assay and chromatin immunoprecipitation experiments. Knockdown of C/EBP alpha expression by small interfering RNA markedly reduced AA-induced leptin expression. Moreover, AA promoted Akt interaction with p-PDK1, and increased phosphorylated activation of Akt. Akt knockdown, and inhibition of Akt signaling by LY294002 and mTOR inhibitor rapamycin reduced leptin expression. Furthermore, treatment of LY294002 or rapamycin significantly suppressed AA-induced C/EBP alpha DNA-binding activity. These results suggest that Akt and C/EBP alpha activation were involved in AA-regulated leptin expression. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate the first that AA could induce secretion and expression of fibrogenic leptin in kidney fibroblasts, which reveal potential involvement of leptin in the progression of kidney fibrosis in aristolochic acid nephropathy. PMID- 21304903 TI - Conservation and diversification of an ancestral chordate gene regulatory network for dorsoventral patterning. AB - Formation of a dorsoventral axis is a key event in the early development of most animal embryos. It is well established that bone morphogenetic proteins (Bmps) and Wnts are key mediators of dorsoventral patterning in vertebrates. In the cephalochordate amphioxus, genes encoding Bmps and transcription factors downstream of Bmp signaling such as Vent are expressed in patterns reminiscent of those of their vertebrate orthologues. However, the key question is whether the conservation of expression patterns of network constituents implies conservation of functional network interactions, and if so, how an increased functional complexity can evolve. Using heterologous systems, namely by reporter gene assays in mammalian cell lines and by transgenesis in medaka fish, we have compared the gene regulatory network implicated in dorsoventral patterning of the basal chordate amphioxus and vertebrates. We found that Bmp but not canonical Wnt signaling regulates promoters of genes encoding homeodomain proteins AmphiVent1 and AmphiVent2. Furthermore, AmphiVent1 and AmphiVent2 promoters appear to be correctly regulated in the context of a vertebrate embryo. Finally, we show that AmphiVent1 is able to directly repress promoters of AmphiGoosecoid and AmphiChordin genes. Repression of genes encoding dorsal-specific signaling molecule Chordin and transcription factor Goosecoid by Xenopus and zebrafish Vent genes represents a key regulatory interaction during vertebrate axis formation. Our data indicate high evolutionary conservation of a core Bmp-triggered gene regulatory network for dorsoventral patterning in chordates and suggest that co option of the canonical Wnt signaling pathway for dorsoventral patterning in vertebrates represents one of the innovations through which an increased morphological complexity of vertebrate embryo is achieved. PMID- 21304904 TI - Genetic predisposition of donors affects the allograft outcome in kidney transplantation; polymorphisms of stromal-derived factor-1 and CXC receptor 4. AB - Genetic interaction between donor and recipient may dictate the impending responses after transplantation. In this study, we evaluated the role of the genetic predispositions of stromal-derived factor-1 (SDF1) [rs1801157 (G>A)] and CXC receptor 4 (CXCR4) [rs2228014 (C>T)] on renal allograft outcomes. A total of 335 pairs of recipients and donors were enrolled. Biopsy-proven acute rejection (BPAR) and long-term graft survival were traced. Despite similar allele frequencies between donors and recipients, minor allele of SDF1 rs1801157 (GA+AA) from donor, not from recipients, has a protective effect on the development of BPAR compared to wild type donor (GG) (P = 0.005). Adjustment for multiple covariates did not affect this result (odds ratio 0.39, 95% C.I 0.20-0.76, P = 0.006). CXCR4 rs2228014 polymorphisms from donor or recipient did not affect the incidence of acute rejection. SDF1 was differentially expressed in renal tubular epithelium with acute rejection according to genetic variations of donor rs1801157 showing higher expressions in the grafts from GG donors. Contrary to the development of BPAR, the presence of minor allele rs1801157 A, especially homozygocity, predisposed poor graft survival (P = 0.001). This association was significant after adjusting for several risk factors (hazard ratio 3.01; 95% C.I = 1.19-7.60; P = 0.020). The allelic variation of recipients, however, was not associated with graft loss. A donor-derived genetic polymorphism of SDF1 has influenced the graft outcome. Thus, the genetic predisposition of donor should be carefully considered in transplantation. PMID- 21304905 TI - Transparent meta-analysis: does aging spare prospective memory with focal vs. non focal cues? AB - BACKGROUND: Prospective memory (ProM) is the ability to become aware of a previously-formed plan at the right time and place. For over twenty years, researchers have been debating whether prospective memory declines with aging or whether it is spared by aging and, most recently, whether aging spares prospective memory with focal vs. non-focal cues. Two recent meta-analyses examining these claims did not include all relevant studies and ignored prevalent ceiling effects, age confounds, and did not distinguish between prospective memory subdomains (e.g., ProM proper, vigilance, habitual ProM) (see Uttl, 2008, PLoS ONE). The present meta-analysis focuses on the following questions: Does prospective memory decline with aging? Does prospective memory with focal vs. non focal cues decline with aging? Does the size of age-related declines with focal vs. non-focal cues vary across ProM subdomains? And are age-related declines in ProM smaller than age-related declines in retrospective memory? METHODS AND FINDINGS: A meta-analysis of event-cued ProM using data visualization and modeling, robust count methods, and conventional meta-analysis techniques revealed that first, the size of age-related declines in ProM with both focal and non-focal cues are large. Second, age-related declines in ProM with focal cues are larger in ProM proper and smaller in vigilance. Third, age-related declines in ProM proper with focal cues are as large as age-related declines in recall measures of retrospective memory. CONCLUSIONS: The results are consistent with Craik's (1983) proposal that age-related declines on ProM tasks are generally large, support the distinction between ProM proper vs. vigilance, and directly contradict widespread claims that ProM, with or without focal cues, is spared by aging. PMID- 21304906 TI - Characteristics of the mesophotic megabenthic assemblages of the vercelli seamount (north tyrrhenian sea). AB - The biodiversity of the megabenthic assemblages of the mesophotic zone of a Tyrrhenian seamount (Vercelli Seamount) is described using Remotely Operated Vehicle (ROV) video imaging from 100 m depth to the top of the mount around 61 m depth. This pinnacle hosts a rich coralligenous community characterized by three different assemblages: (i) the top shows a dense covering of the kelp Laminaria rodriguezii; (ii) the southern side biocoenosis is mainly dominated by the octocorals Paramuricea clavata and Eunicella cavolinii; while (iii) the northern side of the seamount assemblage is colonized by active filter-feeding organisms such as sponges (sometimes covering 100% of the surface) with numerous colonies of the ascidian Diazona violacea, and the polychaete Sabella pavonina. This study highlights, also for a Mediterranean seamount, the potential role of an isolated rocky peak penetrating the euphotic zone, to work as an aggregating structure, hosting abundant benthic communities dominated by suspension feeders, whose distribution may vary in accordance to the geomorphology of the area and the different local hydrodynamic conditions. PMID- 21304907 TI - Switching multiple sclerosis patients with breakthrough disease to second-line therapy. AB - BACKGROUND: Multiple sclerosis (MS) patients with breakthrough disease on immunomodulatory drugs are frequently offered to switch to natalizumab or immunosuppressants. The effect of natalizumab monotherapy in patients with breakthrough disease is unknown. METHODS: This is an open-label retrospective cohort study of 993 patients seen at least four times at the University of California San Francisco MS Center, 95 had breakthrough disease on first-line therapy (60 patients switched to natalizumab, 22 to immunosuppressants and 13 declined the switch [non-switchers]). We used Poisson regression adjusted for potential confounders to compare the relapse rate within and across groups before and after the switch. RESULTS: In the within-group analyses, the relapse rate decreased by 70% (95% CI 50,82%; p<0.001) in switchers to natalizumab and by 77% (95% CI 59,87%; p<0.001) in switchers to immunosuppressants; relapse rate in non switchers did not decrease (6%, p = 0.87). Relative to the reduction among non switchers, the relapse rate was reduced by 68% among natalizumab switchers (95% CI 19,87%; p = 0.017) and by 76% among the immunosuppressant switchers (95% CI 36,91%; p = 0.004). CONCLUSIONS: Switching to natalizumab or immunosuppressants in patients with breakthrough disease is effective in reducing clinical activity of relapsing MS. The magnitude of the effect and the risk-benefit ratio should be evaluated in randomized clinical trials and prospective cohort studies. PMID- 21304908 TI - Simple structural differences between coding and noncoding DNA. AB - BACKGROUND: The study of large-scale genome structure has revealed patterns suggesting the influence of evolutionary constraints on genome evolution. However, the results of these studies can be difficult to interpret due to the conceptual complexity of the analyses. This makes it difficult to understand how observed statistical patterns relate to the physical distribution of genomic elements. We use a simpler and more intuitive approach to evaluate patterns of genome structure. METHODOLOGY/PRINCIPAL FINDINGS: We used randomization tests based on Morisita's Index of aggregation to examine average differences in the distribution of purines and pyrimidines among coding and noncoding regions of 261 chromosomes from 223 microbial genomes representing 21 phylum level groups. Purines and pyrimidines were aggregated in the noncoding DNA of 86% of genomes, but were only aggregated in the coding regions of 52% of genomes. Coding and noncoding DNA differed in aggregation in 94% of genomes. Noncoding regions were more aggregated than coding regions in 91% of these genomes. Genome length appears to limit aggregation, but chromosome length does not. Chromosomes from the same species are similarly aggregated despite substantial differences in length. Aggregation differed among taxonomic groups, revealing support for a previously reported pattern relating genome structure to environmental conditions. CONCLUSIONS/SIGNIFICANCE: Our approach revealed several patterns of genome structure among different types of DNA, different chromosomes of the same genome, and among different taxonomic groups. Similarity in aggregation among chromosomes of varying length from the same genome suggests that individual chromosome structure has not evolved independently of the general constraints on genome structure as a whole. These patterns were detected using simple and readily interpretable methods commonly used in other areas of biology. PMID- 21304909 TI - Impact of interspecific hybridization between crops and weedy relatives on the evolution of flowering time in weedy phenotypes. AB - BACKGROUND: Like conventional crops, some GM cultivars may readily hybridize with their wild or weedy relatives. The progressive introgression of transgenes into wild or weedy populations thus appears inevitable, and we are now faced with the challenge of determining the possible evolutionary effects of these transgenes. The aim of this study was to gain insight into the impact of interspecific hybridization between transgenic plants and weedy relatives on the evolution of the weedy phenotype. METHODOLOGY/PRINCIPAL FINDINGS: Experimental populations of weedy birdseed rape (Brassica rapa) and transgenic rapeseed (B. napus) were grown under glasshouse conditions. Hybridization opportunities with transgenic plants and phenotypic traits (including phenological, morphological and reproductive traits) were measured for each weedy individual. We show that weedy individuals that flowered later and for longer periods were more likely to receive transgenic pollen from crops and weed * crop hybrids. Because stem diameter is correlated with flowering time, plants with wider stems were also more likely to be pollinated by transgenic plants. We also show that the weedy plants with the highest probability of hybridization had the lowest fecundity. CONCLUSION/SIGNIFICANCE: Our results suggest that weeds flowering late and for long periods are less fit because they have a higher probability of hybridizing with crops or weed * crop hybrids. This may result in counter-selection against this subset of weed phenotypes, and a shorter earlier flowering period. It is noteworthy that this potential evolution in flowering time does not depend on the presence of the transgene in the crop. Evolution in flowering time may even be counter-balanced by positive selection acting on the transgene if the latter was positively associated with maternal genes promoting late flowering and long flowering periods. Unfortunately, we could not verify this association in the present experiment. PMID- 21304910 TI - A dominant role for the immunoproteasome in CD8+ T cell responses to murine cytomegalovirus. AB - Murine cytomegalovirus (MCMV) is an important animal model of human cytomegalovirus (HCMV), a beta-Herpesvirus that infects the majority of the world's population and causes disease in neonates and immunocompromised adults. CD8(+) T cells are a major part of the immune response to MCMV and HCMV. Processing of peptides for presentation to CD8(+) T cells may be critically dependent on the immunoproteasome, expression of which is affected by MCMV. However, the overall importance of the immunoproteasome in the generation of immunodominant peptides from MCMV is not known. We therefore examined the role of the immunoproteasome in stimulation of CD8(+) T cell responses to MCMV - both conventional memory responses and those undergoing long-term expansion or "inflation". We infected LMP7(-/-) and C57BL/6 mice with MCMV or with newly generated recombinant vaccinia viruses (rVVs) encoding the immunodominant MCMV protein M45 in either full-length or epitope-only minigene form. We analysed CD8(+) T cell responses using intracellular cytokine stain (ICS) and MHC Class I tetramer staining for a panel of MCMV-derived epitopes. We showed a critical role for immunoproteasome in MCMV affecting all epitopes studied. Interestingly we found that memory "inflating" epitopes demonstrate reduced immunoproteasome dependence compared to non-inflating epitopes. M45-specific responses induced by rVVs remain immunoproteasome-dependent. These results help to define a critical restriction point for CD8(+) T cell epitopes in natural cytomegalovirus (CMV) infection and potentially in vaccine strategies against this and other viruses. PMID- 21304911 TI - From Levy to Brownian: a computational model based on biological fluctuation. AB - BACKGROUND: Theoretical studies predict that Levy walks maximizes the chance of encountering randomly distributed targets with a low density, but Brownian walks is favorable inside a patch of targets with high density. Recently, experimental data reports that some animals indeed show a Levy and Brownian walk movement patterns when forage for foods in areas with low and high density. This paper presents a simple, Gaussian-noise utilizing computational model that can realize such behavior. METHODOLOGY/PRINCIPAL FINDINGS: We extend Levy walks model of one of the simplest creature, Escherichia coli, based on biological fluctuation framework. We build a simulation of a simple, generic animal to observe whether Levy or Brownian walks will be performed properly depends on the target density, and investigate the emergent behavior in a commonly faced patchy environment where the density alternates. CONCLUSIONS/SIGNIFICANCE: Based on the model, animal behavior of choosing Levy or Brownian walk movement patterns based on the target density is able to be generated, without changing the essence of the stochastic property in Escherichia coli physiological mechanism as explained by related researches. The emergent behavior and its benefits in a patchy environment are also discussed. The model provides a framework for further investigation on the role of internal noise in realizing adaptive and efficient foraging behavior. PMID- 21304912 TI - Detection and removal of biases in the analysis of next-generation sequencing reads. AB - Since the emergence of next-generation sequencing (NGS) technologies, great effort has been put into the development of tools for analysis of the short reads. In parallel, knowledge is increasing regarding biases inherent in these technologies. Here we discuss four different biases we encountered while analyzing various Illumina datasets. These biases are due to both biological and statistical effects that in particular affect comparisons between different genomic regions. Specifically, we encountered biases pertaining to the distributions of nucleotides across sequencing cycles, to mappability, to contamination of pre-mRNA with mRNA, and to non-uniform hydrolysis of RNA. Most of these biases are not specific to one analyzed dataset, but are present across a variety of datasets and within a variety of genomic contexts. Importantly, some of these biases correlated in a highly significant manner with biological features, including transcript length, gene expression levels, conservation levels, and exon-intron architecture, misleadingly increasing the credibility of results due to them. We also demonstrate the relevance of these biases in the context of analyzing an NGS dataset mapping transcriptionally engaged RNA polymerase II (RNAPII) in the context of exon-intron architecture, and show that elimination of these biases is crucial for avoiding erroneous interpretation of the data. Collectively, our results highlight several important pitfalls, challenges and approaches in the analysis of NGS reads. PMID- 21304913 TI - Lysine residue 185 of Rad1 is a topological but not a functional counterpart of lysine residue 164 of PCNA. AB - Monoubiquitylation of the homotrimeric DNA sliding clamp PCNA at lysine residue 164 (PCNA(K164)) is a highly conserved, DNA damage-inducible process that is mediated by the E2/E3 complex Rad6/Rad18. This ubiquitylation event recruits translesion synthesis (TLS) polymerases capable of replicating across damaged DNA templates. Besides PCNA, the Rad6/Rad18 complex was recently shown in yeast to ubiquitylate also 9-1-1, a heterotrimeric DNA sliding clamp composed of Rad9, Rad1, and Hus1 in a DNA damage-inducible manner. Based on the highly similar crystal structures of PCNA and 9-1-1, K185 of Rad1 (Rad1(K185)) was identified as the only topological equivalent of PCNA(K164). To investigate a potential role of posttranslational modifications of Rad1(K185) in DNA damage management, we here generated a mouse model with a conditional deletable Rad1(K185R) allele. The Rad1(K185) residue was found to be dispensable for Chk1 activation, DNA damage survival, and class switch recombination of immunoglobulin genes as well as recruitment of TLS polymerases during somatic hypermutation of immunoglobulin genes. Our data indicate that Rad1(K185) is not a functional counterpart of PCNA(K164). PMID- 21304914 TI - Functional interaction between type III-secreted protein IncA of Chlamydophila psittaci and human G3BP1. AB - Chlamydophila (Cp.) psittaci, the causative agent of psittacosis in birds and humans, is the most important zoonotic pathogen of the family Chlamydiaceae. These obligate intracellular bacteria are distinguished by a unique biphasic developmental cycle, which includes proliferation in a membrane-bound compartment termed inclusion. All Chlamydiaceae spp. possess a coding capacity for core components of a Type III secretion apparatus, which mediates specific delivery of anti-host effector proteins either into the chlamydial inclusion membrane or into the cytoplasm of target eukaryotic cells. Here we describe the interaction between Type III-secreted protein IncA of Cp. psittaci and host protein G3BP1 in a yeast two-hybrid system. In GST-pull down and co-immunoprecipitation experiments both in vitro and in vivo interaction between full-length IncA and G3BP1 were shown. Using fluorescence microscopy, the localization of G3BP1 near the inclusion membrane of Cp. psittaci-infected Hep-2 cells was demonstrated. Notably, infection of Hep-2 cells with Cp. psittaci and overexpression of IncA in HEK293 cells led to a decrease in c-Myc protein concentration. This effect could be ascribed to the interaction between IncA and G3BP1 since overexpression of an IncA mutant construct disabled to interact with G3BP1 failed to reduce c-Myc concentration. We hypothesize that lowering the host cell c-Myc protein concentration may be part of a strategy employed by Cp. psittaci to avoid apoptosis and scale down host cell proliferation. PMID- 21304918 TI - Using BLAST to teach "E-value-tionary" concepts. PMID- 21304919 TI - Intermittent preventive treatment to reduce the burden of malaria in children: new evidence on integration and delivery. PMID- 21304920 TI - A c-di-GMP effector system controls cell adhesion by inside-out signaling and surface protein cleavage. AB - In Pseudomonas fluorescens Pf0-1 the availability of inorganic phosphate (Pi) is an environmental signal that controls biofilm formation through a cyclic dimeric GMP (c-di-GMP) signaling pathway. In low Pi conditions, a c-di-GMP phosphodiesterase (PDE) RapA is expressed, depleting cellular c-di-GMP and causing the loss of a critical outer-membrane adhesin LapA from the cell surface. This response involves an inner membrane protein LapD, which binds c-di-GMP in the cytoplasm and exerts a periplasmic output promoting LapA maintenance on the cell surface. Here we report how LapD differentially controls maintenance and release of LapA: c-di-GMP binding to LapD promotes interaction with and inhibition of the periplasmic protease LapG, which targets the N-terminus of LapA. We identify conserved amino acids in LapA required for cleavage by LapG. Mutating these residues in chromosomal lapA inhibits LapG activity in vivo, leading to retention of the adhesin on the cell surface. Mutations with defined effects on LapD's ability to control LapA localization in vivo show concomitant effects on c-di-GMP-dependent LapG inhibition in vitro. To establish the physiological importance of the LapD-LapG effector system, we track cell attachment and LapA protein localization during Pi starvation. Under this condition, the LapA adhesin is released from the surface of cells and biofilms detach from the substratum. This response requires c-di-GMP depletion by RapA, signaling through LapD, and proteolytic cleavage of LapA by LapG. These data, in combination with the companion study by Navarro et al. presenting a structural analysis of LapD's signaling mechanism, give a detailed description of a complete c-di-GMP control circuit--from environmental signal to molecular output. They describe a novel paradigm in bacterial signal transduction: regulation of a periplasmic enzyme by an inner membrane signaling protein that binds a cytoplasmic second messenger. PMID- 21304922 TI - Climate change could change rates of evolution. PMID- 21304921 TI - Two strategies for the delivery of IPTc in an area of seasonal malaria transmission in the Gambia: a randomised controlled trial. AB - BACKGROUND: The Expanded Programme on Immunisation (EPI) provides an effective way of delivering intermittent preventive treatment for malaria (IPT) to infants. However, it is uncertain how IPT can be delivered most effectively to older children. Therefore, we have compared two approaches to the delivery of IPT to Gambian children: distribution by village health workers (VHWs) or through reproductive and child health (RCH) trekking teams. In rural areas, RCH trekking teams provide most of the health care to children under the age of 5 years in the Infant Welfare Clinic, and provide antenatal care for pregnant women. METHODS AND FINDINGS: During the 2006 malaria transmission season, the catchment populations of 26 RCH trekking clinics in The Gambia, each with 400-500 children 6 years of age and under, were randomly allocated to receive IPT from an RCH trekking team or from a VHW. Treatment with a single dose of sulfadoxine pyrimethamine (SP) plus three doses of amodiaquine (AQ) were given at monthly intervals during the malaria transmission season. Morbidity from malaria was monitored passively throughout the malaria transmission season in all children, and a random sample of study children from each cluster was examined at the end of the malaria transmission season. The primary study endpoint was the incidence of malaria. Secondary endpoints included coverage of IPTc, mean haemoglobin (Hb) concentration, and the prevalence of asexual malaria parasitaemia at the end of malaria transmission period. Financial and economic costs associated with the two delivery strategies were collected and incremental cost and effects were compared. A nested case-control study was used to estimate efficacy of IPT treatment courses. Treatment with SP plus AQ was safe and well tolerated. There were 49 cases of malaria with parasitaemia above 5,000/ul in the areas where IPT was delivered through RCH clinics and 21 cases in the areas where IPT was delivered by VHWs, (incidence rates 2.8 and 1.2 per 1,000 child months, respectively, rate difference 1.6 [95% confidence interval (CI) -0.24 to 3.5]). Delivery through VHWs achieved a substantially higher coverage level of three courses of IPT than delivery by RCH trekking teams (74% versus 48%, a difference of 27% [95% CI 16%-38%]). For both methods of delivery, coverage was unrelated to indices of wealth, with similar coverage being achieved in the poorest and wealthiest groups. The prevalence of anaemia was low in both arms of the trial at the end of the transmission season. Efficacy of IPTc against malaria during the month after each treatment course was 87% (95% CI 54%-96%). Delivery of IPTc by VHWs was less costly in both economic and financial terms than delivery through RCH trekking teams, resulting in incremental savings of US$872 and US$1,244 respectively. The annual economic cost of delivering at least the first dose of each course of IPTc was US$3.47 and US$1.63 per child using trekking team and VHWs respectively. CONCLUSIONS: In this setting in The Gambia, delivery of IPTc to children 6 years of age and under by VHWs is more effective and less costly than delivery through RCH trekking clinics. TRIAL REGISTRATION: ClinicalTrials.gov NCT00376155. Please see later in the article for the Editors' Summary. PMID- 21304923 TI - Intermittent preventive treatment of malaria provides substantial protection against malaria in children already protected by an insecticide-treated bednet in Mali: a randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Previous studies have shown that in areas of seasonal malaria transmission, intermittent preventive treatment of malaria in children (IPTc), targeting the transmission season, reduces the incidence of clinical malaria. However, these studies were conducted in communities with low coverage with insecticide-treated nets (ITNs). Whether IPTc provides additional protection to children sleeping under an ITN has not been established. METHODS AND FINDINGS: To assess whether IPTc provides additional protection to children sleeping under an ITN, we conducted a randomised, double-blind, placebo-controlled trial of IPTc with sulphadoxine pyrimethamine (SP) plus amodiaquine (AQ) in three localities in Kati, Mali. After screening, eligible children aged 3-59 mo were given a long lasting insecticide-treated net (LLIN) and randomised to receive three rounds of active drugs or placebos. Treatments were administered under observation at monthly intervals during the high malaria transmission season in August, September, and October 2008. Adverse events were monitored immediately after the administration of each course of IPTc and throughout the follow-up period. The primary endpoint was clinical episodes of malaria recorded through passive surveillance by study clinicians available at all times during the follow-up. Cross-sectional surveys were conducted in 150 randomly selected children weekly and in all children at the end of the malaria transmission season to assess usage of ITNs and the impact of IPTc on the prevalence of malaria, anaemia, and malnutrition. Cox regression was used to compare incidence rates between intervention and control arms. The effects of IPTc on the prevalence of malaria infection and anaemia were estimated using logistic regression. 3,065 children were screened and 3,017 (1,508 in the control and 1,509 in the intervention arm) were enrolled in the study. 1,485 children (98.5%) in the control arm and 1,481 (98.1%) in the intervention arm completed follow-up. During the intervention period, the proportion of children reported to have slept under an ITN was 99.7% in the control and 99.3% in intervention arm (p = 0.45). A total of 672 episodes of clinical malaria defined as fever or a history of fever and the presence of at least 5,000 asexual forms of Plasmodium falciparum per microlitre (incidence rate of 1.90; 95% confidence interval [CI] 1.76-2.05 episodes per person year) were observed in the control arm versus 126 (incidence rate of 0.34; 95% CI 0.29-0.41 episodes per person year) in the intervention arm, indicating a protective effect (PE) of 82% (95% CI 78%-85%) (p<0.001) on the primary endpoint. There were 15 episodes of severe malaria in children in the control arm compared to two in children in the intervention group giving a PE of 87% (95% CI 42%-99%) (p = 0.001). IPTc reduced the prevalence of malaria infection by 85% (95% CI 73%-92%) (p<0.001) during the intervention period and by 46% (95% CI 31%-68%) (p<0.001) at the end of the intervention period. The prevalence of moderate anaemia (haemoglobin [Hb] <8 g/dl) was reduced by 47% (95% CI 15%-67%) (p<0.007) at the end of intervention period. The frequencies of adverse events were similar between the two arms. There was no drug-related serious adverse event. CONCLUSIONS: IPTc given during the malaria transmission season provided substantial protection against clinical episodes of malaria, malaria infection, and anaemia in children using an LLIN. SP+AQ was safe and well tolerated. These findings indicate that IPTc could make a valuable contribution to malaria control in areas of seasonal malaria transmission alongside other interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT00738946. Please see later in the article for the Editors' Summary. PMID- 21304924 TI - Biofilm adherence and detachment pathway elucidated. PMID- 21304925 TI - Intermittent preventive treatment of malaria provides substantial protection against malaria in children already protected by an insecticide-treated bednet in Burkina Faso: a randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Intermittent preventive treatment of malaria in children (IPTc) is a promising new approach to the control of malaria in areas of seasonal malaria transmission but it is not known if IPTc adds to the protection provided by an insecticide-treated net (ITN). METHODS AND FINDINGS: An individually randomised, double-blind, placebo-controlled trial of seasonal IPTc was conducted in Burkina Faso in children aged 3 to 59 months who were provided with a long-lasting insecticide-treated bednet (LLIN). Three rounds of treatment with sulphadoxine pyrimethamine plus amodiaquine or placebos were given at monthly intervals during the malaria transmission season. Passive surveillance for malaria episodes was established, a cross-sectional survey was conducted at the end of the malaria transmission season, and use of ITNs was monitored during the intervention period. Incidence rates of malaria were compared using a Cox regression model and generalized linear models were fitted to examine the effect of IPTc on the prevalence of malaria infection, anaemia, and on anthropometric indicators. 3,052 children were screened and 3,014 were enrolled in the trial; 1,505 in the control arm and 1,509 in the intervention arm. Similar proportions of children in the two treatment arms were reported to sleep under an LLIN during the intervention period (93%). The incidence of malaria, defined as fever or history of fever with parasitaemia >= 5,000/ul, was 2.88 (95% confidence interval [CI] 2.70-3.06) per child during the intervention period in the control arm versus 0.87 (95% CI 0.78 0.97) in the intervention arm, a protective efficacy (PE) of 70% (95% CI 66%-74%) (p<0.001). There was a 69% (95% CI 6%-90%) reduction in incidence of severe malaria (p = 0.04) and a 46% (95% CI 7%-69%) (p = 0.03) reduction in the incidence of all-cause hospital admissions. IPTc reduced the prevalence of malaria infection at the end of the malaria transmission season by 73% (95% CI 68%-77%) (p<0.001) and that of moderately severe anaemia by 56% (95% CI 36%-70%) (p<0.001). IPTc reduced the risks of wasting (risk ratio [RR] = 0.79; 95% CI 0.65 1.00) (p = 0.05) and of being underweight (RR = 0.84; 95% CI 0.72-0.99) (p = 0.03). Children who received IPTc were 2.8 (95% CI 2.3-3.5) (p<0.001) times more likely to vomit than children who received placebo but no drug-related serious adverse event was recorded. CONCLUSIONS: IPT of malaria provides substantial protection against malaria in children who sleep under an ITN. There is now strong evidence to support the integration of IPTc into malaria control strategies in areas of seasonal malaria transmission. TRIAL REGISTRATION: ClinicalTrials.govNCT00738946. Please see later in the article for the Editors' Summary. PMID- 21304926 TI - Structural basis for c-di-GMP-mediated inside-out signaling controlling periplasmic proteolysis. AB - The bacterial second messenger bis-(3'-5') cyclic dimeric guanosine monophosphate (c-di-GMP) has emerged as a central regulator for biofilm formation. Increased cellular c-di-GMP levels lead to stable cell attachment, which in Pseudomonas fluorescens requires the transmembrane receptor LapD. LapD exhibits a conserved and widely used modular architecture containing a HAMP domain and degenerate diguanylate cyclase and phosphodiesterase domains. c-di-GMP binding to the LapD degenerate phosphodiesterase domain is communicated via the HAMP relay to the periplasmic domain, triggering sequestration of the protease LapG, thus preventing cleavage of the surface adhesin LapA. Here, we elucidate the molecular mechanism of autoinhibition and activation of LapD based on structure-function analyses and crystal structures of the entire periplasmic domain and the intracellular signaling unit in two different states. In the absence of c-di-GMP, the intracellular module assumes an inactive conformation. Binding of c-di-GMP to the phosphodiesterase domain disrupts the inactive state, permitting the formation of a trans-subunit dimer interface between adjacent phosphodiesterase domains via interactions conserved in c-di-GMP-degrading enzymes. Efficient mechanical coupling of the conformational changes across the membrane is realized through an extensively domain-swapped, unique periplasmic fold. Our structural and functional analyses identified a conserved system for the regulation of periplasmic proteases in a wide variety of bacteria, including many free-living and pathogenic species. PMID- 21304929 TI - A mathematical framework for protein structure comparison. AB - Comparison of protein structures is important for revealing the evolutionary relationship among proteins, predicting protein functions and predicting protein structures. Many methods have been developed in the past to align two or multiple protein structures. Despite the importance of this problem, rigorous mathematical or statistical frameworks have seldom been pursued for general protein structure comparison. One notable issue in this field is that with many different distances used to measure the similarity between protein structures, none of them are proper distances when protein structures of different sequences are compared. Statistical approaches based on those non-proper distances or similarity scores as random variables are thus not mathematically rigorous. In this work, we develop a mathematical framework for protein structure comparison by treating protein structures as three-dimensional curves. Using an elastic Riemannian metric on spaces of curves, geodesic distance, a proper distance on spaces of curves, can be computed for any two protein structures. In this framework, protein structures can be treated as random variables on the shape manifold, and means and covariance can be computed for populations of protein structures. Furthermore, these moments can be used to build Gaussian-type probability distributions of protein structures for use in hypothesis testing. The covariance of a population of protein structures can reveal the population-specific variations and be helpful in improving structure classification. With curves representing protein structures, the matching is performed using elastic shape analysis of curves, which can effectively model conformational changes and insertions/deletions. We show that our method performs comparably with commonly used methods in protein structure classification on a large manually annotated data set. PMID- 21304930 TI - Structural properties of the Caenorhabditis elegans neuronal network. AB - Despite recent interest in reconstructing neuronal networks, complete wiring diagrams on the level of individual synapses remain scarce and the insights into function they can provide remain unclear. Even for Caenorhabditis elegans, whose neuronal network is relatively small and stereotypical from animal to animal, published wiring diagrams are neither accurate nor complete and self-consistent. Using materials from White et al. and new electron micrographs we assemble whole, self-consistent gap junction and chemical synapse networks of hermaphrodite C. elegans. We propose a method to visualize the wiring diagram, which reflects network signal flow. We calculate statistical and topological properties of the network, such as degree distributions, synaptic multiplicities, and small-world properties, that help in understanding network signal propagation. We identify neurons that may play central roles in information processing, and network motifs that could serve as functional modules of the network. We explore propagation of neuronal activity in response to sensory or artificial stimulation using linear systems theory and find several activity patterns that could serve as substrates of previously described behaviors. Finally, we analyze the interaction between the gap junction and the chemical synapse networks. Since several statistical properties of the C. elegans network, such as multiplicity and motif distributions are similar to those found in mammalian neocortex, they likely point to general principles of neuronal networks. The wiring diagram reported here can help in understanding the mechanistic basis of behavior by generating predictions about future experiments involving genetic perturbations, laser ablations, or monitoring propagation of neuronal activity in response to stimulation. PMID- 21304931 TI - Transcription and translation products of the cytolysin gene psm-mec on the mobile genetic element SCCmec regulate Staphylococcus aureus virulence. AB - The F region downstream of the mecI gene in the SCCmec element in hospital associated methicillin-resistant Staphylococcus aureus (HA-MRSA) contains two bidirectionally overlapping open reading frames (ORFs), the fudoh ORF and the psm mec ORF. The psm-mec ORF encodes a cytolysin, phenol-soluble modulin (PSM)-mec. Transformation of the F region into the Newman strain, which is a methicillin sensitive S. aureus (MSSA) strain, or into the MW2 (USA400) and FRP3757 (USA300) strains, which are community-acquired MRSA (CA-MRSA) strains that lack the F region, attenuated their virulence in a mouse systemic infection model. Introducing the F region to these strains suppressed colony-spreading activity and PSMalpha production, and promoted biofilm formation. By producing mutations into the psm-mec ORF, we revealed that (i) both the transcription and translation products of the psm-mec ORF suppressed colony-spreading activity and promoted biofilm formation; and (ii) the transcription product of the psm-mec ORF, but not its translation product, decreased PSMalpha production. These findings suggest that both the psm-mec transcript, acting as a regulatory RNA, and the PSM-mec protein encoded by the gene on the mobile genetic element SCCmec regulate the virulence of Staphylococcus aureus. PMID- 21304932 TI - Gene expression noise in spatial patterning: hunchback promoter structure affects noise amplitude and distribution in Drosophila segmentation. AB - Positional information in developing embryos is specified by spatial gradients of transcriptional regulators. One of the classic systems for studying this is the activation of the hunchback (hb) gene in early fruit fly (Drosophila) segmentation by the maternally-derived gradient of the Bicoid (Bcd) protein. Gene regulation is subject to intrinsic noise which can produce variable expression. This variability must be constrained in the highly reproducible and coordinated events of development. We identify means by which noise is controlled during gene expression by characterizing the dependence of hb mRNA and protein output noise on hb promoter structure and transcriptional dynamics. We use a stochastic model of the hb promoter in which the number and strength of Bcd and Hb (self regulatory) binding sites can be varied. Model parameters are fit to data from WT embryos, the self-regulation mutant hb(14F), and lacZ reporter constructs using different portions of the hb promoter. We have corroborated model noise predictions experimentally. The results indicate that WT (self-regulatory) Hb output noise is predominantly dependent on the transcription and translation dynamics of its own expression, rather than on Bcd fluctuations. The constructs and mutant, which lack self-regulation, indicate that the multiple Bcd binding sites in the hb promoter (and their strengths) also play a role in buffering noise. The model is robust to the variation in Bcd binding site number across a number of fly species. This study identifies particular ways in which promoter structure and regulatory dynamics reduce hb output noise. Insofar as many of these are common features of genes (e.g. multiple regulatory sites, cooperativity, self-feedback), the current results contribute to the general understanding of the reproducibility and determinacy of spatial patterning in early development. PMID- 21304933 TI - The ESCRT-0 component HRS is required for HIV-1 Vpu-mediated BST-2/tetherin down regulation. AB - The Endosomal Sorting Complexes Required for Transport (ESCRT) machinery, a highly conserved set of four hetero-oligomeric protein complexes, is required for multivesicular body formation, sorting ubiquitinylated membrane proteins for lysosomal degradation, cytokinesis and the final stages of assembly of a number of enveloped viruses, including the human immunodeficiency viruses. Here, we show an additional role for the ESCRT machinery in HIV-1 release. BST-2/tetherin is a restriction factor that impedes HIV release by tethering mature virus particles to the plasma membrane. We found that HRS, a key component of the ESCRT-0 complex, promotes efficient release of HIV-1 and that siRNA-mediated HRS depletion induces a BST-2/tetherin phenotype. This activity is related to the ability of the HIV-1 Vpu protein to down-regulate BST-2/tetherin. We found that BST-2/tetherin undergoes constitutive ESCRT-dependent sorting for lysosomal degradation and that this degradation is enhanced by Vpu expression. We demonstrate that Vpu-mediated BST-2/tetherin down-modulation and degradation require HRS (ESCRT-0) function and that knock down of HRS increases cellular levels of BST-2/tetherin and restricts virus release. Furthermore, HRS co precipitates with Vpu and BST-2. Our results provide further insight into the mechanism by which Vpu counteracts BST-2/tetherin and promotes HIV-1 dissemination, and they highlight an additional role for the ESCRT machinery in virus release. PMID- 21304934 TI - Stochastic theory of early viral infection: continuous versus burst production of virions. AB - Viral production from infected cells can occur continuously or in a burst that generally kills the cell. For HIV infection, both modes of production have been suggested. Standard viral dynamic models formulated as sets of ordinary differential equations can not distinguish between these two modes of viral production, as the predicted dynamics is identical as long as infected cells produce the same total number of virions over their lifespan. Here we show that in stochastic models of viral infection the two modes of viral production yield different early term dynamics. Further, we analytically determine the probability that infections initiated with any number of virions and infected cells reach extinction, the state when both the population of virions and infected cells vanish, and show this too has different solutions for continuous and burst production. We also compute the distributions of times to establish infection as well as the distribution of times to extinction starting from both a single virion as well as from a single infected cell for both modes of virion production. PMID- 21304935 TI - Pharmacodynamic modeling of anti-cancer activity of tetraiodothyroacetic acid in a perfused cell culture system. AB - Unmodified or as a poly[lactide-co-glycolide] nanoparticle, tetraiodothyroacetic acid (tetrac) acts at the integrin alphavbeta3 receptor on human cancer cells to inhibit tumor cell proliferation and xenograft growth. To study in vitro the pharmacodynamics of tetrac formulations in the absence of and in conjunction with other chemotherapeutic agents, we developed a perfusion bellows cell culture system. Cells were grown on polymer flakes and exposed to various concentrations of tetrac, nano-tetrac, resveratrol, cetuximab, or a combination for up to 18 days. Cells were harvested and counted every one or two days. Both NONMEM VI and the exact Monte Carlo parametric expectation maximization algorithm in S-ADAPT were utilized for mathematical modeling. Unmodified tetrac inhibited the proliferation of cancer cells and did so with differing potency in different cell lines. The developed mechanism-based model included two effects of tetrac on different parts of the cell cycle which could be distinguished. For human breast cancer cells, modeling suggested a higher sensitivity (lower IC50) to the effect on success rate of replication than the effect on rate of growth, whereas the capacity (Imax) was larger for the effect on growth rate. Nanoparticulate tetrac (nano-tetrac), which does not enter into cells, had a higher potency and a larger anti-proliferative effect than unmodified tetrac. Fluorescence-activated cell sorting analysis of harvested cells revealed tetrac and nano-tetrac induced concentration-dependent apoptosis that was correlated with expression of pro apoptotic proteins, such as p53, p21, PIG3 and BAD for nano-tetrac, while unmodified tetrac showed a different profile. Approximately additive anti proliferative effects were found for the combinations of tetrac and resveratrol, tetrac and cetuximab (Erbitux), and nano-tetrac and cetuximab. Our in vitro perfusion cancer cell system together with mathematical modeling successfully described the anti-proliferative effects over time of tetrac and nano-tetrac and may be useful for dose-finding and studying the pharmacodynamics of other chemotherapeutic agents or their combinations. PMID- 21304936 TI - Accurate quantification of functional analogy among close homologs. AB - Correctly evaluating functional similarities among homologous proteins is necessary for accurate transfer of experimental knowledge from one organism to another, and is of particular importance for the development of animal models of human disease. While the fact that sequence similarity implies functional similarity is a fundamental paradigm of molecular biology, sequence comparison does not directly assess the extent to which two proteins participate in the same biological processes, and has limited utility for analyzing families with several parologous members. Nevertheless, we show that it is possible to provide a cross organism functional similarity measure in an unbiased way through the exclusive use of high-throughput gene-expression data. Our methodology is based on probabilistic cross-species mapping of functionally analogous proteins based on Bayesian integrative analysis of gene expression compendia. We demonstrate that even among closely related genes, our method is able to predict functionally analogous homolog pairs better than relying on sequence comparison alone. We also demonstrate that the landscape of functional similarity is often complex and that definitive "functional orthologs" do not always exist. Even in these cases, our method and the online interface we provide are designed to allow detailed exploration of sources of inferred functional similarity that can be evaluated by the user. PMID- 21304937 TI - Ribavirin-induced anemia in hepatitis C virus patients undergoing combination therapy. AB - The current standard of care for hepatitis C virus (HCV) infection - combination therapy with pegylated interferon and ribavirin - elicits sustained responses in only ~50% of the patients treated. No alternatives exist for patients who do not respond to combination therapy. Addition of ribavirin substantially improves response rates to interferon and lowers relapse rates following the cessation of therapy, suggesting that increasing ribavirin exposure may further improve treatment response. A key limitation, however, is the toxic side-effect of ribavirin, hemolytic anemia, which often necessitates a reduction of ribavirin dosage and compromises treatment response. Maximizing treatment response thus requires striking a balance between the antiviral and hemolytic activities of ribavirin. Current models of viral kinetics describe the enhancement of treatment response due to ribavirin. Ribavirin-induced anemia, however, remains poorly understood and precludes rational optimization of combination therapy. Here, we develop a new mathematical model of the population dynamics of erythrocytes that quantitatively describes ribavirin-induced anemia in HCV patients. Based on the assumption that ribavirin accumulation decreases erythrocyte lifespan in a dose dependent manner, model predictions capture several independent experimental observations of the accumulation of ribavirin in erythrocytes and the resulting decline of hemoglobin in HCV patients undergoing combination therapy, estimate the reduced erythrocyte lifespan during therapy, and describe inter-patient variations in the severity of ribavirin-induced anemia. Further, model predictions estimate the threshold ribavirin exposure beyond which anemia becomes intolerable and suggest guidelines for the usage of growth hormones, such as erythropoietin, that stimulate erythrocyte production and avert the reduction of ribavirin dosage, thereby improving treatment response. Our model thus facilitates, in conjunction with models of viral kinetics, the rational identification of treatment protocols that maximize treatment response while curtailing side effects. PMID- 21304938 TI - Digital atlasing and standardization in the mouse brain. PMID- 21304939 TI - Charge-surrounded pockets and electrostatic interactions with small ions modulate the activity of retroviral fusion proteins. AB - Refolding of viral class-1 membrane fusion proteins from a native state to a trimer-of-hairpins structure promotes entry of viruses into cells. Here we present the structure of the bovine leukaemia virus transmembrane glycoprotein (TM) and identify a group of asparagine residues at the membrane-distal end of the trimer-of-hairpins that is strikingly conserved among divergent viruses. These asparagines are not essential for surface display of pre-fusogenic envelope. Instead, substitution of these residues dramatically disrupts membrane fusion. Our data indicate that, through electrostatic interactions with a chloride ion, the asparagine residues promote assembly and profoundly stabilize the fusion-active structures that are required for viral envelope-mediated membrane fusion. Moreover, the BLV TM structure also reveals a charge-surrounded hydrophobic pocket on the central coiled coil and interactions with basic residues that cluster around this pocket are critical to membrane fusion and form a target for peptide inhibitors of envelope function. Charge-surrounded pockets and electrostatic interactions with small ions are common among class-1 fusion proteins, suggesting that small molecules that specifically target such motifs should prevent assembly of the trimer-of-hairpins and be of value as therapeutic inhibitors of viral entry. PMID- 21304940 TI - Entrapment of viral capsids in nuclear PML cages is an intrinsic antiviral host defense against varicella-zoster virus. AB - The herpesviruses, like most other DNA viruses, replicate in the host cell nucleus. Subnuclear domains known as promyelocytic leukemia protein nuclear bodies (PML-NBs), or ND10 bodies, have been implicated in restricting early herpesviral gene expression. These viruses have evolved countermeasures to disperse PML-NBs, as shown in cells infected in vitro, but information about the fate of PML-NBs and their functions in herpesvirus infected cells in vivo is limited. Varicella-zoster virus (VZV) is an alphaherpesvirus with tropism for skin, lymphocytes and sensory ganglia, where it establishes latency. Here, we identify large PML-NBs that sequester newly assembled nucleocapsids (NC) in neurons and satellite cells of human dorsal root ganglia (DRG) and skin cells infected with VZV in vivo. Quantitative immuno-electron microscopy revealed that these distinctive nuclear bodies consisted of PML fibers forming spherical cages that enclosed mature and immature VZV NCs. Of six PML isoforms, only PML IV promoted the sequestration of NCs. PML IV significantly inhibited viral infection and interacted with the ORF23 capsid surface protein, which was identified as a target for PML-mediated NC sequestration. The unique PML IV C-terminal domain was required for both capsid entrapment and antiviral activity. Similar large PML NBs, termed clastosomes, sequester aberrant polyglutamine (polyQ) proteins, such as Huntingtin (Htt), in several neurodegenerative disorders. We found that PML IV cages co-sequester HttQ72 and ORF23 protein in VZV infected cells. Our data show that PML cages contribute to the intrinsic antiviral defense by sensing and entrapping VZV nucleocapsids, thereby preventing their nuclear egress and inhibiting formation of infectious virus particles. The efficient sequestration of virion capsids in PML cages appears to be the outcome of a basic cytoprotective function of this distinctive category of PML-NBs in sensing and safely containing nuclear aggregates of aberrant proteins. PMID- 21304942 TI - Cognitive performances are selectively enhanced during chronic caloric restriction or resveratrol supplementation in a primate. AB - Effects of an 18-month treatment with a moderate, chronic caloric restriction (CR) or an oral supplementation with resveratrol (RSV), a potential CR mimetic, on cognitive and motor performances were studied in non-human primates, grey mouse lemurs (Microcebus murinus).Thirty-three adult male mouse lemurs were assigned to three different groups: a control (CTL) group fed ad libitum, a CR group fed 70% of the CTL caloric intake, and an RSV group (RSV supplementation of 200 mg.kg(-1).day(-1)) fed ad libitum. Three different cognitive tests, two motor tests, one emotional test and an analysis of cortisol level were performed in each group.Compared to CTL animals, CR or RSV animals did not show any change in motor performances evaluated by rotarod and jump tests, but an increase in spontaneous locomotor activity was observed in both groups. Working memory was improved by both treatments in the spontaneous alternation task. Despite a trend for CR group, only RSV supplementation increased spatial memory performances in the circular platform task. Finally, none of these treatments induced additional stress to the animals as reflected by similar results in the open field test and cortisol analyses compared to CTL animals.The present data provided the earliest evidence for a beneficial effect of CR or RSV supplementation on specific cognitive functions in a primate. Taken together, these results suggest that RSV could be a good candidate to mimic long-term CR effects and support the growing evidences that nutritional interventions can have beneficial effects on brain functions even in adults. PMID- 21304941 TI - Quantitative models of the mechanisms that control genome-wide patterns of transcription factor binding during early Drosophila development. AB - Transcription factors that drive complex patterns of gene expression during animal development bind to thousands of genomic regions, with quantitative differences in binding across bound regions mediating their activity. While we now have tools to characterize the DNA affinities of these proteins and to precisely measure their genome-wide distribution in vivo, our understanding of the forces that determine where, when, and to what extent they bind remains primitive. Here we use a thermodynamic model of transcription factor binding to evaluate the contribution of different biophysical forces to the binding of five regulators of early embryonic anterior-posterior patterning in Drosophila melanogaster. Predictions based on DNA sequence and in vitro protein-DNA affinities alone achieve a correlation of ~0.4 with experimental measurements of in vivo binding. Incorporating cooperativity and competition among the five factors, and accounting for spatial patterning by modeling binding in every nucleus independently, had little effect on prediction accuracy. A major source of error was the prediction of binding events that do not occur in vivo, which we hypothesized reflected reduced accessibility of chromatin. To test this, we incorporated experimental measurements of genome-wide DNA accessibility into our model, effectively restricting predicted binding to regions of open chromatin. This dramatically improved our predictions to a correlation of 0.6-0.9 for various factors across known target genes. Finally, we used our model to quantify the roles of DNA sequence, accessibility, and binding competition and cooperativity. Our results show that, in regions of open chromatin, binding can be predicted almost exclusively by the sequence specificity of individual factors, with a minimal role for protein interactions. We suggest that a combination of experimentally determined chromatin accessibility data and simple computational models of transcription factor binding may be used to predict the binding landscape of any animal transcription factor with significant precision. PMID- 21304943 TI - Human mobility networks, travel restrictions, and the global spread of 2009 H1N1 pandemic. AB - After the emergence of the H1N1 influenza in 2009, some countries responded with travel-related controls during the early stage of the outbreak in an attempt to contain or slow down its international spread. These controls along with self imposed travel limitations contributed to a decline of about 40% in international air traffic to/from Mexico following the international alert. However, no containment was achieved by such restrictions and the virus was able to reach pandemic proportions in a short time. When gauging the value and efficacy of mobility and travel restrictions it is crucial to rely on epidemic models that integrate the wide range of features characterizing human mobility and the many options available to public health organizations for responding to a pandemic. Here we present a comprehensive computational and theoretical study of the role of travel restrictions in halting and delaying pandemics by using a model that explicitly integrates air travel and short-range mobility data with high resolution demographic data across the world and that is validated by the accumulation of data from the 2009 H1N1 pandemic. We explore alternative scenarios for the 2009 H1N1 pandemic by assessing the potential impact of mobility restrictions that vary with respect to their magnitude and their position in the pandemic timeline. We provide a quantitative discussion of the delay obtained by different mobility restrictions and the likelihood of containing outbreaks of infectious diseases at their source, confirming the limited value and feasibility of international travel restrictions. These results are rationalized in the theoretical framework characterizing the invasion dynamics of the epidemics at the metapopulation level. PMID- 21304944 TI - Genomic stability over 9 years of an isoniazid resistant Mycobacterium tuberculosis outbreak strain in Sweden. AB - In molecular epidemiological studies of drug resistant Mycobacterium tuberculosis (TB) in Sweden a large outbreak of an isoniazid resistant strain was identified, involving 115 patients, mainly from the Horn of Africa. During the outbreak period, the genomic pattern of the outbreak strain has stayed virtually unchanged with regard to drug resistance, IS6110 restriction fragment length polymorphism and spoligotyping patterns. Here we present the complete genome sequence analyses of the index isolate and two isolates sampled nine years after the index case as well as experimental data on the virulence of this outbreak strain. Even though the strain has been present in the community for nine years and passaged between patients at least five times in-between the isolates, we only found four single nucleotide polymorphisms in one of the later isolates and a small (4 amino acids) deletion in the other compared to the index isolate. In contrast to many other evolutionarily successful outbreak lineages (e.g. the Beijing lineage) this outbreak strain appears to be genetically very stable yet evolutionarily successful in a low endemic country such as Sweden. These findings further illustrate that the rate of genomic variation in TB can be highly strain dependent, something that can have important implications for epidemiological studies as well as development of resistance. PMID- 21304945 TI - BCG vaccine-induced neuroprotection in a mouse model of Parkinson's disease. AB - There is a growing interest in using vaccination with CNS antigens to induce autoreactive T cell responses that home to damaged areas in the CNS and ameliorate neurodegenerative disease. Neuroprotective vaccine studies have focused on administering oligodendrocyte antigens or Copaxone(r) in complete Freund's adjuvant (CFA). Theoretical considerations, however, suggest that vaccination with a neuronal antigen may induce more robust neuroprotective immune responses. We assessed the neuroprotective potential of vaccines containing tyrosine hydroxylase (a neuronal protein involved in dopamine synthesis) or Copaxone(r) in CFA in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Surprisingly, we observed that the main beneficial factor in these vaccines was the CFA. Since the major immunogenic component in CFA is Mycobacterium tuberculosis, which closely related to the bacille Calmette-Guerin (BCG) that is used in human vaccines, we tested BCG vaccination in the MPTP mouse model. We observed that BCG vaccination partially preserved markers of striatal dopamine system integrity and prevented an increase in activated microglia in the substantia nigra of MPTP-treated mice. These results support a new neuroprotective vaccine paradigm in which general (nonself reactive) immune stimulation in the periphery can limit potentially deleterious microglial responses to a neuronal insult and exert a neurorestorative effect in the CNS. Accordingly, BCG vaccination may provide a new strategy to augment current treatments for a wide range of neuropathological conditions. PMID- 21304946 TI - Immunogenicity and cross-reactivity of 2009-2010 inactivated seasonal influenza vaccine in US adults and elderly. AB - The campaign of 2009-2010 Northern Hemisphere seasonal vaccination was concurrent with the 2009 H1N1 pandemic. Using a hemagglutination inhibition (HAI) assay, we evaluated the immunogenicity and cross-reactivity of 2009-2010 inactivated trivalent influenza vaccine (TIV) in US adult and elderly populations. Vaccination of TIV resulted in a robust boost on the antibody response of all subjects to seasonal A/Brisbane/59/2007 (H1N1) and A/Uruguay/716/2007 (H3N2) with over 70% of recipients reaching a seroprotective titer of 40. B/Brisbane/60/2008 was the least immunogenic among the three seasonal vaccine strains with <30% of TIV recipients reaching a seroprotective titer of 40. TIV vaccination also induced a moderate boost on the pandemic specific antibody responses. Twenty-four percent of adults and 36% of elderly reached a seroprotective HAI titer of 40 or more against pandemic A/South Carolina/18/2009 (H1N1) after receiving TIV compared to 4% and 7% at the beginning of vaccination, respectively. In addition, 22% of adults and 34% of elderly showed an increase of 4-fold or more in A/South Carolina/18/2009 specific HAI titers after TIV vaccination. The pandemic specific cross-reactive antibodies strongly correlated with the post-vaccination HAI titers against the seasonal H3N2 vaccine strain in all subjects. PMID- 21304947 TI - Control of flowering and cell fate by LIF2, an RNA binding partner of the polycomb complex component LHP1. AB - Polycomb Repressive Complexes (PRC) modulate the epigenetic status of key cell fate and developmental regulators in eukaryotes. The chromo domain protein like heterochromatin protein1 (LHP1) is a subunit of a plant PRC1-like complex in Arabidopsis thaliana and recognizes histone H3 lysine 27 trimethylation, a silencing epigenetic mark deposited by the PRC2 complex. We have identified and studied an LHP1-Interacting Factor2 (LIF2). LIF2 protein has RNA recognition motifs and belongs to the large hnRNP protein family, which is involved in RNA processing. LIF2 interacts in vivo, in the cell nucleus, with the LHP1 chromo shadow domain. Expression of LIF2 was detected predominantly in vascular and meristematic tissues. Loss-of-function of LIF2 modifies flowering time, floral developmental homeostasis and gynoecium growth determination. lif2 ovaries have indeterminate growth and produce ectopic inflorescences with severely affected flowers showing proliferation of ectopic stigmatic papillae and ovules in short day conditions. To look at how LIF2 acts relative to LHP1, we conducted transcriptome analyses in lif2 and lhp1 and identified a common set of deregulated genes, which showed significant enrichment in stress-response genes. By comparing expression of LHP1 targets in lif2, lhp1 and lif2 lhp1 mutants we showed that LIF2 can either antagonize or act with LHP1. Interestingly, repression of the FLC floral transcriptional regulator in lif2 mutant is accompanied by an increase in H3K27 trimethylation at the locus, without any change in LHP1 binding, suggesting that LHP1 is targeted independently from LIF2 and that LHP1 binding does not strictly correlate with gene expression. LIF2, involved in cell identity and cell fate decision, may modulate the activity of LHP1 at specific loci, during specific developmental windows or in response to environmental cues that control cell fate determination. These results highlight a novel link between plant RNA processing and Polycomb regulation. PMID- 21304948 TI - Fluoxetine exerts age-dependent effects on behavior and amygdala neuroplasticity in the rat. AB - The selective serotonin reuptake inhibitor (SSRI) Prozac(r) (fluoxetine) is the only registered antidepressant to treat depression in children and adolescents. Yet, while the safety of SSRIs has been well established in adults, serotonin exerts neurotrophic actions in the developing brain and thereby may have harmful effects in adolescents. Here we treated adolescent and adult rats chronically with fluoxetine (12 mg/kg) at postnatal day (PND) 25 to 46 and from PND 67 to 88, respectively, and tested the animals 7-14 days after the last injection when (nor)fluoxetine in blood plasma had been washed out, as determined by HPLC. Plasma (nor)fluoxetine levels were also measured 5 hrs after the last fluoxetine injection, and matched clinical levels. Adolescent rats displayed increased behavioral despair in the forced swim test, which was not seen in adult fluoxetine treated rats. In addition, beneficial effects of fluoxetine on wakefulness as measured by electroencephalography in adults was not seen in adolescent rats, and age-dependent effects on the acoustic startle response and prepulse inhibition were observed. On the other hand, adolescent rats showed resilience to the anorexic effects of fluoxetine. Exploratory behavior in the open field test was not affected by fluoxetine treatment, but anxiety levels in the elevated plus maze test were increased in both adolescent and adult fluoxetine treated rats. Finally, in the amygdala, but not the dorsal raphe nucleus and medial prefrontal cortex, the number of PSA-NCAM (marker for synaptic remodeling) immunoreactive neurons was increased in adolescent rats, and decreased in adult rats, as a consequence of chronic fluoxetine treatment. No fluoxetine-induced changes in 5-HT(1A) receptor immunoreactivity were observed. In conclusion, we show that fluoxetine exerts both harmful and beneficial age dependent effects on depressive behavior, body weight and wakefulness, which may relate, in part, to differential fluoxetine-induced neuroplasticity in the amygdala. PMID- 21304949 TI - The cholesterol metabolite 25-hydroxycholesterol activates estrogen receptor alpha-mediated signaling in cancer cells and in cardiomyocytes. AB - BACKGROUND: The hydroxylated derivatives of cholesterol, such as the oxysterols, play important roles in lipid metabolism. In particular, 25-hydroxycholesterol (25 HC) has been implicated in a variety of metabolic events including cholesterol homeostasis and atherosclerosis. 25 HC is detectable in human plasma after ingestion of a meal rich in oxysterols and following a dietary cholesterol challenge. In addition, the levels of oxysterols, including 25 HC, have been found to be elevated in hypercholesterolemic serum. METHODOLOGY/PRINCIPAL FINDINGS: Here, we demonstrate that the estrogen receptor (ER) alpha mediates gene expression changes and growth responses induced by 25 HC in breast and ovarian cancer cells. Moreover, 25 HC exhibits the ERalpha-dependent ability like 17 beta-estradiol (E2) to inhibit the up-regulation of HIF-1alpha and connective tissue growth factor by hypoxic conditions in cardiomyocytes and rat heart preparations and to prevent the hypoxia-induced apoptosis. CONCLUSIONS/SIGNIFICANCE: The estrogen action exerted by 25 HC may be considered as an additional factor involved in the progression of breast and ovarian tumors. Moreover, the estrogen-like activity of 25 HC elicited in the cardiovascular system may play a role against hypoxic environments. PMID- 21304950 TI - Inaccurate DNA synthesis in cell extracts of yeast producing active human DNA polymerase iota. AB - Mammalian Pol iota has an unusual combination of properties: it is stimulated by Mn(2+) ions, can bypass some DNA lesions and misincorporates "G" opposite template "T" more frequently than incorporates the correct "A." We recently proposed a method of detection of Pol iota activity in animal cell extracts, based on primer extension opposite the template T with a high concentration of only two nucleotides, dGTP and dATP (incorporation of "G" versus "A" method of Gening, abbreviated as "misGvA"). We provide unambiguous proof of the "misGvA" approach concept and extend the applicability of the method for the studies of variants of Pol iota in the yeast model system with different cation cofactors. We produced human Pol iota in baker's yeast, which do not have a POLI ortholog. The "misGvA" activity is absent in cell extracts containing an empty vector, or producing catalytically dead Pol iota, or Pol iota lacking exon 2, but is robust in the strain producing wild-type Pol iota or its catalytic core, or protein with the active center L62I mutant. The signature pattern of primer extension products resulting from inaccurate DNA synthesis by extracts of cells producing either Pol iota or human Pol eta is different. The DNA sequence of the template is critical for the detection of the infidelity of DNA synthesis attributed to DNA Pol iota. The primer/template and composition of the exogenous DNA precursor pool can be adapted to monitor replication fidelity in cell extracts expressing various error prone Pols or mutator variants of accurate Pols. Finally, we demonstrate that the mutation rates in yeast strains producing human DNA Pols iota and eta are not elevated over the control strain, despite highly inaccurate DNA synthesis by their extracts. PMID- 21304951 TI - Structural characterization of outer membrane components of the type IV pili system in pathogenic Neisseria. AB - Structures of the type IV pili secretin complexes from Neisseria gonorrhoeae and Neisseria meningitidis, embedded in outer membranes were investigated by transmission electron microscopy. Single particle averaging revealed additional domains not observed previously. Secretin complexes of N. gonorrhoeae showed a double ring structure with a 14-15-fold symmetry in the central ring, and a 14 fold symmetry of the peripheral ring with 7 spikes protruding. In secretin complexes of N. meningitidis, the spikes were absent and the peripheral ring was partly or completely lacking. When present, it had a 19-fold symmetry. The structures of the complexes in several pil mutants were determined. Structures obtained from the pilC1/C2 adhesin and the pilW minor pilin deletion strains were similar to wild-type, whereas deletion of the homologue of N. meningitidis PilW resulted in the absence of secretin structures. Remarkably, the pilE pilin subunit and pilP lipoprotein deletion mutants showed a change in the symmetry of the peripheral ring from 14 to 19 and loss of spikes. The pilF ATPase mutant also lost the spikes, but maintained 14-fold symmetry. These results show that secretin complexes contain previously unidentified large and flexible extra domains with a probable role in stabilization or assembly of type IV pili. PMID- 21304952 TI - The association of left ventricular hypertrophy with metabolic syndrome is dependent on body mass index in hypertensive overweight or obese patients. AB - BACKGROUND: Overweight (Ow) and obesity (Ob) influence blood pressure (BP) and left ventricular hypertrophy (LVH). It is unclear whether the presence of metabolic syndrome (MetS) independently affects echocardiographic parameters in hypertension. METHODS: 380 Ow/Ob essential hypertensive patients (age <= 65 years) presenting for referred BP control-related problems. MetS was defined according to NCEP III/ATP with AHA modifications and LVH as LVM/h(2.7) >= 49.2 g/m(2.7) in males and >= 46.7 g/m(2.7) in females. Treatment intensity score (TIS) was used to control for BP treatment as previously reported. RESULTS: Hypertensive patients with MetS had significantly higher BMI, systolic and mean BP, interventricular septum and relative wall thickness and lower ejection fraction than those without MetS. LVM/h(2.7) was significantly higher in MetS patients (59.14 +/- 14.97 vs. 55.33 +/- 14.69 g/m(2.7); p = 0.022). Hypertensive patients with MetS had a 2.3-fold higher risk to have LVH/h(2.7) after adjustment for age, SBP and TIS (OR 2.34; 95%CI 1.40-3.92; p = 0.001), but MetS lost its independent relationship with LVH when BMI was included in the model. CONCLUSIONS: In Ow/Ob hypertensive patients MetS maintains its role of risk factor for LVH independently of age, SBP, and TIS, resulting in a useful predictor of target organ damage in clinical practice. However, MetS loses its independent relationship when BMI is taken into account, suggesting that the effects on MetS on LV parameters are mainly driven by the degree of adiposity. PMID- 21304953 TI - Facilitating stable representations: serial dependence in vision. AB - We tested whether the intervening time between multiple glances influences the independence of the resulting visual percepts. Observers estimated how many dots were present in brief displays that repeated one, two, three, four, or a random number of trials later. Estimates made farther apart in time were more independent, and thus carried more information about the stimulus when combined. In addition, estimates from different visual field locations were more independent than estimates from the same location. Our results reveal a retinotopic serial dependence in visual numerosity estimates, which may be a mechanism for maintaining the continuity of visual perception in a noisy environment. PMID- 21304954 TI - siRNA-mediated gene targeting in Aedes aegypti embryos reveals that frazzled regulates vector mosquito CNS development. AB - Although mosquito genome projects uncovered orthologues of many known developmental regulatory genes, extremely little is known about the development of vector mosquitoes. Here, we investigate the role of the Netrin receptor frazzled (fra) during embryonic nerve cord development of two vector mosquito species. Fra expression is detected in neurons just prior to and during axonogenesis in the embryonic ventral nerve cord of Aedes aegypti (dengue vector) and Anopheles gambiae (malaria vector). Analysis of fra function was investigated through siRNA-mediated knockdown in Ae. aegypti embryos. Confirmation of fra knockdown, which was maintained throughout embryogenesis, indicated that microinjection of siRNA is an effective method for studying gene function in Ae. aegypti embryos. Loss of fra during Ae. aegypti development results in thin and missing commissural axons. These defects are qualitatively similar to those observed in Dr. melanogaster fra null mutants. However, the Aa. aegypti knockdown phenotype is stronger and bears resemblance to the Drosophila commissureless mutant phenotype. The results of this investigation, the first targeted knockdown of a gene during vector mosquito embryogenesis, suggest that although Fra plays a critical role during development of the Ae. aegypti ventral nerve cord, mechanisms regulating embryonic commissural axon guidance have evolved in distantly related insects. PMID- 21304955 TI - Profiling the dead: generating microsatellite data from fossil bones of extinct megafauna--protocols, problems, and prospects. AB - We present the first set of microsatellite markers developed exclusively for an extinct taxon. Microsatellite data have been analysed in thousands of genetic studies on extant species but the technology can be problematic when applied to low copy number (LCN) DNA. It is therefore rarely used on substrates more than a few decades old. Now, with the primers and protocols presented here, microsatellite markers are available to study the extinct New Zealand moa (Aves: Dinornithiformes) and, as with single nucleotide polymorphism (SNP) technology, the markers represent a means by which the field of ancient DNA can (preservation allowing) move on from its reliance on mitochondrial DNA. Candidate markers were identified using high throughput sequencing technology (GS-FLX) on DNA extracted from fossil moa bone and eggshell. From the 'shotgun' reads, >60 primer pairs were designed and tested on DNA from bones of the South Island giant moa (Dinornis robustus). Six polymorphic loci were characterised and used to assess measures of genetic diversity. Because of low template numbers, typical of ancient DNA, allelic dropout was observed in 36-70% of the PCR reactions at each microsatellite marker. However, a comprehensive survey of allelic dropout, combined with supporting quantitative PCR data, allowed us to establish a set of criteria that maximised data fidelity. Finally, we demonstrated the viability of the primers and the protocols, by compiling a full Dinornis microsatellite dataset representing fossils of c. 600-5000 years of age. A multi-locus genotype was obtained from 74 individuals (84% success rate), and the data showed no signs of being compromised by allelic dropout. The methodology presented here provides a framework by which to generate and evaluate microsatellite data from samples of much greater antiquity than attempted before, and opens new opportunities for ancient DNA research. PMID- 21304956 TI - Experience-dependent plasticity and modulation of growth regulatory molecules at central synapses. AB - Structural remodeling or repair of neural circuits depends on the balance between intrinsic neuronal properties and regulatory cues present in the surrounding microenvironment. These processes are also influenced by experience, but it is still unclear how external stimuli modulate growth-regulatory mechanisms in the central nervous system. We asked whether environmental stimulation promotes neuronal plasticity by modifying the expression of growth-inhibitory molecules, specifically those of the extracellular matrix. We examined the effects of an enriched environment on neuritic remodeling and modulation of perineuronal nets in the deep cerebellar nuclei of adult mice. Perineuronal nets are meshworks of extracellular matrix that enwrap the neuronal perikaryon and restrict plasticity in the adult CNS. We found that exposure to an enriched environment induces significant morphological changes of Purkinje and precerebellar axon terminals in the cerebellar nuclei, accompanied by a conspicuous reduction of perineuronal nets. In the animals reared in an enriched environment, cerebellar nuclear neurons show decreased expression of mRNAs coding for key matrix components (as shown by real time PCR experiments), and enhanced activity of matrix degrading enzymes (matrix metalloproteinases 2 and 9), which was assessed by in situ zymography. Accordingly, we found that in mutant mice lacking a crucial perineuronal net component, cartilage link protein 1, perineuronal nets around cerebellar neurons are disrupted and plasticity of Purkinje cell terminal is enhanced. Moreover, all the effects of environmental stimulation are amplified if the afferent Purkinje axons are endowed with enhanced intrinsic growth capabilities, induced by overexpression of GAP-43. Our observations show that the maintenance and growth-inhibitory function of perineuronal nets are regulated by a dynamic interplay between pre- and postsynaptic neurons. External stimuli act on this interaction and shift the balance between synthesis and removal of matrix components in order to facilitate neuritic growth by locally dampening the activity of inhibitory cues. PMID- 21304957 TI - Resistance to MPTP-neurotoxicity in alpha-synuclein knockout mice is complemented by human alpha-synuclein and associated with increased beta-synuclein and Akt activation. AB - Genetic and biochemical abnormalities of alpha-synuclein are associated with the pathogenesis of Parkinson's disease. In the present study we investigated the in vivo interaction of mouse and human alpha-synuclein with the potent parkinsonian neurotoxin, MPTP. We find that while lack of mouse alpha-synuclein in mice is associated with reduced vulnerability to MPTP, increased levels of human alpha synuclein expression is not associated with obvious changes in the vulnerability of dopaminergic neurons to MPTP. However, expressing human alpha-synuclein variants (human wild type or A53T) in the alpha-synuclein null mice completely restores the vulnerability of nigral dopaminergic neurons to MPTP. These results indicate that human alpha-synuclein can functionally replace mouse alpha synuclein in regard to vulnerability of dopaminergic neurons to MPTP-toxicity. Significantly, alpha-synuclein null mice and wild type mice were equally sensitive to neurodegeneration induced by 2'NH(2)-MPTP, a MPTP analog that is selective for serotoninergic and noradrenergic neurons. These results suggest that effects of alpha-synuclein on MPTP like compounds are selective for nigral dopaminergic neurons. Immunoblot analysis of beta-synuclein and Akt levels in the mice reveals selective increases in beta-synuclein and phosphorylated Akt levels in ventral midbrain, but not in other brain regions, of alpha-synuclein null mice, implicating the alpha-synuclein-level dependent regulation of beta synuclein expression in modulation of MPTP-toxicity by alpha-synuclein. Together these findings provide new mechanistic insights on the role alpha-synuclein in modulating neurodegenerative phenotypes by regulation of Akt-mediated cell survival signaling in vivo. PMID- 21304958 TI - Defining smallness for gestational age in the early years of the Danish Medical Birth Registry. AB - BACKGROUND: Being born small for gestational age (SGA) is associated with decreased insulin sensitivity and increased blood pressure in childhood, but the association with clinical disease in early adulthood is less certain. The Danish Medical Birth Registry has registered all births in Denmark since 1973, but due to variable data quality, data is most often used only from 1981 onwards, and birth registers in other countries may have similar problems for the early years. We wanted to examine whether the data can be used for identification of children born SGA and used in future research. METHODOLOGY/PRINCIPAL FINDINGS: All persons born between 1974 and 1996 were identified in the Danish Medical Birth Registry (n = 1.704.890). Immigrants and children without data on gestational age and birth weight were excluded, and a total of 1.348.106 children were included in the analysis. The difference between the different variables used in the history of the registry were examined, and the quality of data in the birth registry from 1974-1981 was examined and compared to subsequent years. Data on birth weight and gestational age in the early years of the registry is inconsistent, and the identification of children born SGA is inaccurate, with 49% false-positives. The biggest source of error is due to the rough and inaccurate intervals used for gestational age. By using -3 standard deviations as a cut-off for the identification of children born SGA, the number of false-positives was reduced to 9%, while the amount of false-negatives were increased. CONCLUSION: Choosing -3 standard deviations for identifying children born SGA is a viable, though not optimal solution for identifying children born SGA. Overall the data in the registry is of sufficient quality to be used in further medical research. PMID- 21304959 TI - Epistasis between COMT and MTHFR in maternal-fetal dyads increases risk for preeclampsia. AB - Preeclampsia is a leading cause of perinatal morbidity and mortality. This disorder is thought to be multifactorial in origin, with multiple genes, environmental and social factors, contributing to disease. One proposed mechanism is placental hypoxia-driven imbalances in angiogenic and anti-angiogenic factors, causing endothelial cell dysfunction. Catechol-O-methyltransferase (Comt) deficient pregnant mice have a preeclampsia phenotype that is reversed by exogenous 2-methoxyestradiol (2-ME), an estrogen metabolite generated by COMT. 2 ME inhibits Hypoxia Inducible Factor 1alpha, a transcription factor mediating hypoxic responses. COMT has been shown to interact with methylenetetrahydrofolate reductase (MTHFR), which modulates the availability of S-adenosylmethionine (SAM), a COMT cofactor. Variations in MTHFR have been associated with preeclampsia. By accounting for allelic variation in both genes, the role of COMT has been clarified. COMT allelic variation is linked to enzyme activity and four single nucleotide polymorphisms (SNPs) (rs6269, rs4633, rs4680, and rs4818) form haplotypes that characterize COMT activity. We tested for association between COMT haplotypes and the MTHFR 677 C -> T polymorphism and preeclampsia risk in 1103 Chilean maternal-fetal dyads. The maternal ACCG COMT haplotype was associated with reduced risk for preeclampsia (P = 0.004), and that risk increased linearly from low to high activity haplotypes (P = 0.003). In fetal samples, we found that the fetal ATCA COMT haplotype and the fetal MTHFR minor "T" allele interact to increase preeclampsia risk (p = 0.022). We found a higher than expected number of patients with preeclampsia with both the fetal risk alleles alone (P = 0.052) and the fetal risk alleles in combination with a maternal balancing allele (P<0.001). This non-random distribution was not observed in controls (P = 0.341 and P = 0.219, respectively). Our findings demonstrate a role for both maternal and fetal COMT in preeclampsia and highlight the importance of including allelic variation in MTHFR. PMID- 21304960 TI - Marine biodiversity in the Atlantic and Pacific coasts of South America: knowledge and gaps. AB - The marine areas of South America (SA) include almost 30,000 km of coastline and encompass three different oceanic domains--the Caribbean, the Pacific, and the Atlantic--ranging in latitude from 12?N to 55?S. The 10 countries that border these coasts have different research capabilities and taxonomic traditions that affect taxonomic knowledge. This paper analyzes the status of knowledge of marine biodiversity in five subregions along the Atlantic and Pacific coasts of South America (SA): the Tropical East Pacific, the Humboldt Current,the Patagonian Shelf, the Brazilian Shelves, and the Tropical West Atlantic, and it provides a review of ecosystem threats and regional marine conservation strategies. South American marine biodiversity is least well known in the tropical subregions (with the exception of Costa Rica and Panama). Differences in total biodiversity were observed between the Atlantic and Pacific oceans at the same latitude. In the north of the continent, the Tropical East Pacific is richer in species than the Tropical West Atlantic, however, when standardized by coastal length, there is very little difference among them. In the south, the Humboldt Current system is much richer than the Patagonian Shelf. An analysis of endemism shows that 75% of the species are reported within only one of the SA regions, while about 22% of the species of SA are not reported elsewhere in the world. National and regional initiatives focusing on new exploration, especially to unknown areas and ecosystems, as well as collaboration among countries are fundamental to achieving the goal of completing inventories of species diversity and distribution.These inventories will allow accurate interpretation of the biogeography of its two oceanic coasts and latitudinal trends,and will also provide relevant information for science based policies. PMID- 21304961 TI - Anti-angiogenic and anti-inflammatory effects of SERPINA3K on corneal injury. AB - SERPINA3K is a member of the serine proteinase inhibitor (SERPIN) family. Here we evaluated the therapeutic effects of SERPINA3K on neovascularization and inflammation in a rat cornea alkali burn model that is commonly employed to study corneal wounding. Topical treatment of the injured rat cornea with SERPINA3K (20 ug/eye/day) for 7 days significantly decreased the neovascular area, compared with the groups treated with BSA or PBS. The SERPINA3K treatment also ameliorated the corneal inflammation as evaluated by the inflammatory index. Furthermore, SERPINA3K enhanced the recovery of corneal epithelium after the alkali injury. Toward the mechanism of action, SERPINA3K down-regulated the expression of the pro-angiogenic and pro-inflammatory factors, vascular endothelial growth factor and tumor necrosis factor-alpha and up-regulated the expression of the anti angiogenic factor, pigment epithelium-derived factor. SERPINA3K specifically inhibited growth of vascular endothelial cells. Meanwhile, SERPINA3K significantly up-regulated the expression of EGFR in the corneal epithelium. These findings suggest that SERPINA3K has therapeutic potential for corneal inflammation and NV. PMID- 21304962 TI - Basolateral amygdala inactivation impairs learning-induced long-term potentiation in the cerebellar cortex. AB - Learning to fear dangerous situations requires the participation of basolateral amygdala (BLA). In the present study, we provide evidence that BLA is necessary for the synaptic strengthening occurring during memory formation in the cerebellum in rats. In the cerebellar vermis the parallel fibers (PF) to Purkinje cell (PC) synapse is potentiated one day following fear learning. Pretraining BLA inactivation impaired such a learning-induced long-term potentiation (LTP). Similarly, cerebellar LTP is affected when BLA is blocked shortly, but not 6 h, after training. The latter result shows that the effects of BLA inactivation on cerebellar plasticity, when present, are specifically related to memory processes and not due to an interference with sensory or motor functions. These data indicate that fear memory induces cerebellar LTP provided that a heterosynaptic input coming from BLA sets the proper local conditions. Therefore, in the cerebellum, learning-induced plasticity is a heterosynaptic phenomenon that requires inputs from other regions. Studies employing the electrically-induced LTP in order to clarify the cellular mechanisms of memory should therefore take into account the inputs arriving from other brain sites, considering them as integrative units. Based on previous and the present findings, we proposed that BLA enables learning-related plasticity to be formed in the cerebellum in order to respond appropriately to new stimuli or situations. PMID- 21304963 TI - The cognitive impact of the ANK3 risk variant for bipolar disorder: initial evidence of selectivity to signal detection during sustained attention. AB - BACKGROUND: Abnormalities in cognition have been reported in patients with Bipolar Disorder (BD) and their first degree relatives, suggesting that susceptibility genes for BD may impact on cognitive processes. Recent genome-wide genetic studies have reported a strong association with BD in a single nucleotide polymorphism (SNP) (rs10994336) within ANK3, which codes for Ankyrin 3. This protein is involved in facilitating the propagation of action potentials by regulating the assembly of sodium gated ion channels. Since ANK3 influences the efficiency of transmission of neuronal impulses, allelic variation in this gene may have widespread cognitive effects. Preclinical data suggest that this may principally apply to sequential signal detection, a core process of sustained attention. METHODOLOGY/PRINCIPAL FINDINGS: One hundred and eighty-nine individuals of white British descent were genotyped for the ANK3 rs10994336 polymorphism and received diagnostic interviews and comprehensive neurocognitive assessment of their general intellectual ability, memory, decision making, response inhibition and sustained attention. Participants comprised euthymic BD patients (n = 47), their unaffected first-degree relatives (n = 75) and healthy controls (n = 67). The risk allele T was associated with reduced sensitivity in target detection (p = 0.0004) and increased errors of commission (p = 0.0018) during sustained attention regardless of diagnosis. We found no effect of the ANK3 genotype on general intellectual ability, memory, decision making and response inhibition. CONCLUSIONS/SIGNIFICANCE: Our results suggest that allelic variation in ANK3 impacts cognitive processes associated with signal detection and this mechanism may relate to risk for BD. However, our results require independent replication and confirmation that ANK3 (rs10994336) is a direct functional variant. PMID- 21304964 TI - Skeletal muscle 11beta-HSD1 controls glucocorticoid-induced proteolysis and expression of E3 ubiquitin ligases atrogin-1 and MuRF-1. AB - Recent studies demonstrated expression and activity of the intracellular cortisone-cortisol shuttle 11beta-hydroxysteroid dehydrogenase type 1 (11beta HSD1) in skeletal muscle and inhibition of 11beta-HSD1 in muscle cells improved insulin sensitivity. Glucocorticoids induce muscle atrophy via increased expression of the E3 ubiquitin ligases Atrogin-1 (Muscle Atrophy F-box (MAFbx)) and MuRF-1 (Muscle RING-Finger-1). We hypothesized that 11beta-HSD1 controls glucocorticoid-induced expression of atrophy E3 ubiquitin ligases in skeletal muscle. Primary human myoblasts were generated from healthy volunteers. 11beta HSD1-dependent protein degradation was analyzed by [(3)H]-tyrosine release assay. RT-PCR was used to determine mRNA expression of E3 ubiquitin ligases and 11beta HSD1 activity was measured by conversion of radioactively labeled [(3)H] cortisone to [(3)H]-cortisol separated by thin-layer chromatography. We here demonstrate that 11beta-HSD1 is expressed and biologically active in interconverting cortisone to active cortisol in murine skeletal muscle cells (C2C12) as well as in primary human myotubes. 11Beta-HSD1 expression increased during differentiation from myoblasts to mature myotubes (p < 0.01), suggesting a role of 11beta-HSD1 in skeletal muscle growth and differentiation. Treatment with cortisone increased protein degradation by about 20% (p < 0.001), which was paralleled by an elevation of Atrogin-1 and MuRF-1 mRNA expression (p < 0.01, respectively). Notably, pre-treatment with the 11beta-HSD1 inhibitor carbenoxolone (Cbx) completely abolished the effect of cortisone on protein degradation as well as on Atrogin-1 and MuRF-1 expression. In summary, our data suggest that 11beta-HSD1 controls glucocorticoid-induced protein degradation in human and murine skeletal muscle via regulation of the E3 ubiquitin ligases Atrogin-1 and MuRF-1. PMID- 21304965 TI - Group II intron-anchored gene deletion in Clostridium. AB - Clostridium plays an important role in commercial and medical use, for which targeted gene deletion is difficult. We proposed an intron-anchored gene deletion approach for Clostridium, which combines the advantage of the group II intron "ClosTron" system and homologous recombination. In this approach, an intron carrying a fragment homologous to upstream or downstream of the target site was first inserted into the genome by retrotransposition, followed by homologous recombination, resulting in gene deletion. A functional unknown operon CAC1493 1494 located in the chromosome, and an operon ctfAB located in the megaplasmid of C. acetobutylicum DSM1731 were successfully deleted by using this approach, without leaving antibiotic marker in the genome. We therefore propose this approach can be used for targeted gene deletion in Clostridium. This approach might also be applicable for gene deletion in other bacterial species if group II intron retrotransposition system is established. PMID- 21304966 TI - Perturbation with intrabodies reveals that calpain cleavage is required for degradation of huntingtin exon 1. AB - BACKGROUND: Proteolytic processing of mutant huntingtin (mHtt), the protein that causes Huntington's disease (HD), is critical for mHtt toxicity and disease progression. mHtt contains several caspase and calpain cleavage sites that generate N-terminal fragments that are more toxic than full-length mHtt. Further processing is then required for the degradation of these fragments, which in turn, reduces toxicity. This unknown, secondary degradative process represents a promising therapeutic target for HD. METHODOLOGY/PRINCIPAL FINDINGS: We have used intrabodies, intracellularly expressed antibody fragments, to gain insight into the mechanism of mutant huntingtin exon 1 (mHDx-1) clearance. Happ1, an intrabody recognizing the proline-rich region of mHDx-1, reduces the level of soluble mHDx 1 by increasing clearance. While proteasome and macroautophagy inhibitors reduce turnover of mHDx-1, Happ1 is still able to reduce mHDx-1 under these conditions, indicating Happ1-accelerated mHDx-1 clearance does not rely on these processes. In contrast, a calpain inhibitor or an inhibitor of lysosomal pH block Happ1 mediated acceleration of mHDx-1 clearance. These results suggest that mHDx-1 is cleaved by calpain, likely followed by lysosomal degradation and this process regulates the turnover rate of mHDx-1. Sequence analysis identifies amino acid (AA) 15 as a potential calpain cleavage site. Calpain cleavage of recombinant mHDx-1 in vitro yields fragments of sizes corresponding to this prediction. Moreover, when the site is blocked by binding of another intrabody, V(L)12.3, turnover of soluble mHDx-1 in living cells is blocked. CONCLUSIONS/SIGNIFICANCE: These results indicate that calpain-mediated removal of the 15 N-terminal AAs is required for the degradation of mHDx-1, a finding that may have therapeutic implications. PMID- 21304967 TI - BCG vaccination: a role for vitamin D? AB - BACKGROUND: BCG vaccination is administered in infancy in most countries with the aim of providing protection against tuberculosis. There is increasing interest in the role of vitamin D in immunity to tuberculosis. This study objective was to determine if there was an association between circulating 25(OH)D concentrations and BCG vaccination status and cytokine responses following BCG vaccination in infants. METHODS: Blood samples were collected from UK infants who were vaccinated with BCG at 3 (n = 47) and 12 (n = 37) months post BCG vaccination. These two time-points are denoted as time-point 1 and time-point 2. Two blood samples were also collected from age-matched unvaccinated infants (n = 32 and 28 respectively), as a control group. Plasma vitamin D concentrations (25(OH)D) were measured by radio-immunoassay. The cytokine IFNgamma was measured in supernatants from diluted whole blood stimulated with M.tuberculosis (M.tb) PPD for 6 days. RESULTS: 58% of infants had some level of hypovitaminosis (25(OH)D <30 ng/ml) at time-point 1, and this increased to 97% 9 months later. BCG vaccinated infants were almost 6 times (CI: 1.8-18.6) more likely to have sufficient vitamin D concentrations than unvaccinated infants at time-point 1, and the association remained strong after controlling for season of blood collection, ethnic group and sex. Among vaccinees, there was also a strong inverse association between IFNgamma response to M.tb PPD and vitamin D concentration, with infants with higher vitamin D concentrations having lower IFNgamma responses. CONCLUSIONS: Vitamin D may play an immuno-regulatory role following BCG vaccination. The increased vitamin D concentrations in BCG vaccinated infants could have important implications: vitamin D may play a role in immunity induced by BCG vaccination and may contribute to non-specific effects observed following BCG vaccination. PMID- 21304968 TI - Cytosolic guanine nucledotide binding deficient form of transglutaminase 2 (R580a) potentiates cell death in oxygen glucose deprivation. AB - Transglutaminase 2 (TG2) is a hypoxia-responsive protein that is a calcium activated transamidating enzyme, a GTPase and a scaffolding/linker protein. Upon activation TG2 undergoes a large conformational change, which likely affects not only its enzymatic activities but its non-catalytic functions as well. The focus of this study was on the role of transamidating activity, conformation and localization of TG2 in ischemic cell death. Cells expressing a GTP binding deficient form of TG2 (TG2-R580A) with high basal transamidation activity and a more extended conformation showed significantly increased cell death in response to oxygen-glucose deprivation; however, targeting TG2-R580A to the nucleus abrogated its detrimental role in oxygen-glucose deprivation. Treatment of cells expressing wild type TG2, TG2-C277S (a transamidating inactive mutant) and TG2 R580A with Cp4d, a reversible TG2 inhibitor, did not affect cell death in response to oxygen-glucose deprivation. These findings indicate that the pro-cell death effects of TG2 are dependent on its localization to the cytosol and independent of its transamidation activity. Further, the conformational state of TG2 is likely an important determinant in cell survival and the prominent function of TG2 in ischemic cell death is as a scaffold to modulate cellular processes. PMID- 21304969 TI - CYP1A1 induction in the colon by serum: involvement of the PPARalpha pathway and evidence for a new specific human PPREalpha site. AB - BACKGROUND: We previously showed that blood serum induced cytochrome P450 1A1 (CYP1A1) monooxygenase expression in vitro. OBJECTIVE: Our purpose was (i) to identify the molecular mechanism involved and (ii) to characterize the inducer compound(s) in serum involved at least in part. METHODS: Serum was fractionated on hydrophobic columns. PPARalpha involvement was demonstrated by gene reporter assays, DNA mutagenesis and EMSA. Gene expression was evaluated by qRT-PCR. Serum samples were analyzed using HS-SPME-GC-MS. RESULTS: The inductive effect of serum did not depend on the AhR pathway and was enhanced by cotransfection of PPARalpha cDNA. Mutations in the PPAR response elements of the CYP1A1 gene promoter suppressed this effect. One of the PPRE sites appeared highly specific for human PPARalpha, an unreported PPRE property. A link was found between CYP1A1 inducibility and serum hydrophobic compounds. Characterization of sera showed that hexanal, a metabolite produced by peroxidation of linoleic acid, was involved in CYP1A1 induction by serum, possibly along with other serum entities. CONCLUSION: We demonstrate that serum induces CYP1A1 via the PPARalpha pathway and that hexanal is one of the serum inducers. The two PPRE sites within the CYP1A1 promoter are functional and one of them is specific for PPARalpha. PMID- 21304970 TI - Using time-resolved fluorescence to measure serum venom-specific IgE and IgG. AB - We adapted DELFIATM (dissociation-enhanced lanthanide fluoroimmunoassay), a time resolved fluorescence method, to quantitate whole venom specific and allergenic peptide-specific IgE (sIgE), sIgG(1) and sIgG(4) in serum from people clinically allergic to Australian native ant venoms, of which the predominant cause of allergy is jack jumper ant venom (JJAV). Intra-assay CV was 6.3% and inter-assay CV was 13.7% for JJAV sIgE. DELFIA and Phadia CAP JJAV sIgE results correlated well and had similar sensitivity and specificity for the detection of JJAV sIgE against intradermal skin testing as the gold standard. DELFIA was easily adapted for detecting sIgE to a panel of other native ant venoms. PMID- 21304971 TI - Functional promoter polymorphisms govern differential expression of HMG-CoA reductase gene in mouse models of essential hypertension. AB - 3-Hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase gene (Hmgcr) is a susceptibility gene for essential hypertension. Sequencing of the Hmgcr locus in genetically hypertensive BPH (blood pressure high), genetically hypotensive BPL (blood pressure low) and genetically normotensive BPN (blood pressure normal) mice yielded a number of single nucleotide polymorphisms (SNPs). BPH/BPL/BPN Hmgcr promoter-luciferase reporter constructs were generated and transfected into liver HepG2, ovarian CHO, kidney HEK-293 and neuronal N2A cells for functional characterization of the promoter SNPs. The BPH-Hmgcr promoter showed significantly less activity than the BPL-Hmgcr promoter under basal as well as nicotine/cholesterol-treated conditions. This finding was consistent with lower endogenous Hmgcr expression in liver and lower plasma cholesterol in BPH mice. Transfection experiments using 5'-promoter deletion constructs (strategically made to assess the functional significance of each promoter SNP) and computational analysis predicted lower binding affinities of transcription factors c-Fos, n-Myc and Max with the BPH-promoter as compared to the BPL promoter. Corroboratively, the BPH promoter-luciferase reporter construct co transfected with expression plasmids of these transcription factors displayed less pronounced augmentation of luciferase activity than the BPL construct, particularly at lower amounts of transcription factor plasmids. Electrophoretic mobility shift assays also showed diminished interactions of the BPH promoter with HepG2 nuclear proteins. Taken together, this study provides mechanistic basis for the differential Hmgcr expression in these mouse models of human essential hypertension and have implications for better understanding the role of this gene in regulation of blood pressure. PMID- 21304972 TI - Na+/K+-ATPase alpha1 identified as an abundant protein in the blood-labyrinth barrier that plays an essential role in the barrier integrity. AB - BACKGROUND: The endothelial-blood/tissue barrier is critical for maintaining tissue homeostasis. The ear harbors a unique endothelial-blood/tissue barrier which we term "blood-labyrinth-barrier". This barrier is critical for maintaining inner ear homeostasis. Disruption of the blood-labyrinth-barrier is closely associated with a number of hearing disorders. Many proteins of the blood-brain barrier and blood-retinal-barrier have been identified, leading to significant advances in understanding their tissue specific functions. In contrast, capillaries in the ear are small in volume and anatomically complex. This presents a challenge for protein analysis studies, which has resulted in limited knowledge of the molecular and functional components of the blood-labyrinth barrier. In this study, we developed a novel method for isolation of the stria vascularis capillary from CBA/CaJ mouse cochlea and provided the first database of protein components in the blood-labyrinth barrier as well as evidence that the interaction of Na(+)/K(+)-ATPase alpha1 (ATP1A1) with protein kinase C eta (PKCeta) and occludin is one of the mechanisms of loud sound-induced vascular permeability increase. METHODOLOGY/PRINCIPAL FINDINGS: Using a mass-spectrometry, shotgun-proteomics approach combined with a novel "sandwich-dissociation" method, more than 600 proteins from isolated stria vascularis capillaries were identified from adult CBA/CaJ mouse cochlea. The ion transporter ATP1A1 was the most abundant protein in the blood-labyrinth barrier. Pharmacological inhibition of ATP1A1 activity resulted in hyperphosphorylation of tight junction proteins such as occludin which increased the blood-labyrinth-barrier permeability. PKCeta directly interacted with ATP1A1 and was an essential mediator of ATP1A1-initiated occludin phosphorylation. Moreover, this identified signaling pathway was involved in the breakdown of the blood-labyrinth-barrier resulting from loud sound trauma. CONCLUSIONS/SIGNIFICANCE: The results presented here provide a novel method for capillary isolation from the inner ear and the first database on protein components in the blood-labyrinth-barrier. Additionally, we found that ATP1A1 interaction with PKCeta and occludin was involved in the integrity of the blood-labyrinth-barrier. PMID- 21304973 TI - Who tests, who doesn't, and why? Uptake of mobile HIV counseling and testing in the Kilimanjaro Region of Tanzania. AB - BACKGROUND: Optimally, expanded HIV testing programs should reduce barriers to testing while attracting new and high-risk testers. We assessed barriers to testing and HIV risk among clients participating in mobile voluntary counseling and testing (MVCT) campaigns in four rural villages in the Kilimanjaro Region of Tanzania. METHODS: Between December 2007 and April 2008, 878 MVCT participants and 506 randomly selected community residents who did not access MVCT were surveyed. Gender-specific logistic regression models were used to describe differences in socioeconomic characteristics, HIV exposure risk, testing histories, HIV related stigma, and attitudes toward testing between MVCT participants and community residents who did not access MVCT. Gender-specific logistic regression models were used to describe differences in socioeconomic characteristics, HIV exposure risk, testing histories, HIV related stigma, and attitudes toward testing, between the two groups. RESULTS: MVCT clients reported greater HIV exposure risk (OR 1.20 [1.04 to 1.38] for males; OR 1.11 [1.03 to 1.19] for females). Female MVCT clients were more likely to report low household expenditures (OR 1.47 [1.04 to 2.05]), male clients reported higher rates of unstable income sources (OR 1.99 [1.22 to 3.24]). First-time testers were more likely than non-testers to cite distance to testing sites as a reason for not having previously tested (OR 2.17 [1.05 to 4.48] for males; OR 5.95 [2.85 to 12.45] for females). HIV-related stigma, fears of testing or test disclosure, and not being able to leave work were strongly associated with non-participation in MVCT (ORs from 0.11 to 0.84). CONCLUSIONS: MVCT attracted clients with increased exposure risk and fewer economic resources; HIV related stigma and testing related fears remained barriers to testing. MVCT did not disproportionately attract either first-time or frequent repeat testers. Educational campaigns to reduce stigma and fears of testing could improve the effectiveness of MVCT in attracting new and high-risk populations. PMID- 21304974 TI - Comparing the epidermal growth factor interaction with four different cell lines: intriguing effects imply strong dependency of cellular context. AB - The interaction of the epidermal growth factor (EGF) with its receptor (EGFR) is known to be complex, and the common over-expression of EGF receptor family members in a multitude of tumors makes it important to decipher this interaction and the following signaling pathways. We have investigated the affinity and kinetics of (125)I-EGF binding to EGFR in four human tumor cell lines, each using four culturing conditions, in real time by use of LigandTracer(r).Highly repeatable and precise measurements show that the overall apparent affinity of the (125)I-EGF - EGFR interaction is greatly dependent on cell line at normal culturing conditions, ranging from K(D) ~ 200 pM on SKBR3 cells to K(D)~8 nM on A431 cells. The (125)I-EGF - EGFR binding curves (irrespective of cell line) have strong signs of multiple simultaneous interactions. Furthermore, for the cell lines A431 and SKOV3, gefitinib treatment increases the (125)I-EGF - EGFR affinity, in particular when the cells are starved. The (125)I-EGF - EGFR interaction on cell line U343 is sensitive to starvation while as on SKBR3 it is insensitive to gefitinib and starvation.The intriguing pattern of the binding characteristics proves that the cellular context is important when deciphering how EGF interacts with EGFR. From a general perspective, care is advisable when generalizing ligand-receptor interaction results across multiple cell-lines. PMID- 21304976 TI - Modelers' perception of mathematical modeling in epidemiology: a web-based survey. AB - BACKGROUND: Mathematical modeling in epidemiology (MME) is being used increasingly. However, there are many uncertainties in terms of definitions, uses and quality features of MME. METHODOLOGY/PRINCIPAL FINDINGS: To delineate the current status of these models, a 10-item questionnaire on MME was devised. Proposed via an anonymous internet-based survey, the questionnaire was completed by 189 scientists who had published in the domain of MME. A small minority (18%) of respondents claimed to have in mind a concise definition of MME. Some techniques were identified by the researchers as characterizing MME (e.g. Markov models), while others-at the same level of sophistication in terms of mathematics were not (e.g. Cox regression). The researchers' opinions were also contrasted about the potential applications of MME, perceived as highly relevant for providing insight into complex mechanisms and less relevant for identifying causal factors. The quality criteria were those of good science and were not related to the size and the nature of the public health problems addressed. CONCLUSIONS/SIGNIFICANCE: This study shows that perceptions on the nature, uses and quality criteria of MME are contrasted, even among the very community of published authors in this domain. Nevertheless, MME is an emerging discipline in epidemiology and this study underlines that it is associated with specific areas of application and methods. The development of this discipline is likely to deserve a framework providing recommendations and guidance at various steps of the studies, from design to report. PMID- 21304975 TI - Considering transposable element diversification in de novo annotation approaches. AB - Transposable elements (TEs) are mobile, repetitive DNA sequences that are almost ubiquitous in prokaryotic and eukaryotic genomes. They have a large impact on genome structure, function and evolution. With the recent development of high throughput sequencing methods, many genome sequences have become available, making possible comparative studies of TE dynamics at an unprecedented scale. Several methods have been proposed for the de novo identification of TEs in sequenced genomes. Most begin with the detection of genomic repeats, but the subsequent steps for defining TE families differ. High-quality TE annotations are available for the Drosophila melanogaster and Arabidopsis thaliana genome sequences, providing a solid basis for the benchmarking of such methods. We compared the performance of specific algorithms for the clustering of interspersed repeats and found that only a particular combination of algorithms detected TE families with good recovery of the reference sequences. We then applied a new procedure for reconciling the different clustering results and classifying TE sequences. The whole approach was implemented in a pipeline using the REPET package. Finally, we show that our combined approach highlights the dynamics of well defined TE families by making it possible to identify structural variations among their copies. This approach makes it possible to annotate TE families and to study their diversification in a single analysis, improving our understanding of TE dynamics at the whole-genome scale and for diverse species. PMID- 21304977 TI - An investigation of genome-wide studies reported susceptibility loci for ulcerative colitis shows limited replication in north Indians. AB - Genome-Wide Association studies (GWAS) of both Crohn's Disease (CD) and Ulcerative Colitis (UC) have unearthed over 40 risk conferring variants. Recently, a meta-analysis on UC revealed several loci, most of which were either previously associated with UC or CD susceptibility in populations of European origin. In this study, we attempted to replicate these findings in an ethnically distinct north Indian UC cohort. 648 UC cases and 850 controls were genotyped using Infinium Human 660W-quad. Out of 59 meta-analysis index SNPs, six were not in the SNP array used in the study. Of the remaining 53 SNPs, four were found monomorphic. Association (p<0.05) at 25 SNPs was observed, of which 15 were CD specific. Only five SNPs namely rs2395185 (HLA-DRA), rs3024505 (IL10), rs6426833 (RNF186), rs3763313 (BTNL2) and rs2066843 (NOD2) retained significance after Bonferroni correction. These results (i) reveal limited replication of Caucasian based meta-analysis results; (ii) reiterate overlapping molecular mechanism(s) in UC and CD; (iii) indicate differences in genetic architecture between populations; and (iv) suggest that resources such as HapMap need to be extended to cover diverse ethnic populations. They also suggest a systematic GWAS in this terrain may be insightful for identifying population specific IBD risk conferring loci and thus enable cross-ethnicity fine mapping of disease loci. PMID- 21304978 TI - Resveratrol inhibits pancreatic cancer stem cell characteristics in human and KrasG12D transgenic mice by inhibiting pluripotency maintaining factors and epithelial-mesenchymal transition. AB - BACKGROUND: Cancer stem cells (CSCs) can proliferate and self-renew extensively due to their ability to express anti-apoptotic and drug resistant proteins, thus sustaining tumor growth. Therefore, the strategy to eradicate CSCs might have significant clinical implications. The objectives of this study were to examine the molecular mechanisms by which resveratrol inhibits stem cell characteristics of pancreatic CSCs derived from human primary tumors and Kras(G12D) transgenic mice. METHODOLOGY/PRINCIPAL FINDINGS: Human pancreatic CSCs (CD133(+)CD44(+)CD24(+)ESA(+)) are highly tumorigenic and form subcutaneous tumors in NOD/SCID mice. Human pancreatic CSCs expressing high levels of CD133, CD24, CD44, ESA, and aldehyde dehydrogenase also express significantly more Nanog, Oct-4, Notch1, MDR1 and ABCG2 than normal pancreatic tissues and primary pancreatic cancer cells. Similarly, CSCs from Kras(G12D) mice express significantly higher levels of Nanog and Oct-4 than pancreatic tissues from Pdx Cre mice. Resveratrol inhibits the growth (size and weight) and development (PanIN lesions) of pancreatic cancer in Kras(G12D) mice. Resveratrol inhibits the self-renewal capacity of pancreatic CSCs derived from human primary tumors and Kras(G12D) mice. Resveratrol induces apoptosis by activating capase-3/7 and inhibiting the expression of Bcl-2 and XIAP in human CSCs. Resveratrol inhibits pluripotency maintaining factors (Nanog, Sox-2, c-Myc and Oct-4) and drug resistance gene ABCG2 in CSCs. Inhibition of Nanog by shRNA enhances the inhibitory effects of resveratrol on self-renewal capacity of CSCs. Finally, resveratrol inhibits CSC's migration and invasion and markers of epithelial mesenchymal transition (Zeb-1, Slug and Snail). CONCLUSIONS/SIGNIFICANCE: These data suggest that resveratrol inhibits pancreatic cancer stem cell characteristics in human and Kras(G12D) transgenic mice by inhibiting pluripotency maintaining factors and epithelial-mesenchymal transition. In conclusion, resveratrol can be used for the management of pancreatic cancer. PMID- 21304979 TI - Mevalonate cascade regulation of airway mesenchymal cell autophagy and apoptosis: a dual role for p53. AB - Statins inhibit the proximal steps of cholesterol biosynthesis, and are linked to health benefits in various conditions, including cancer and lung disease. We have previously investigated apoptotic pathways triggered by statins in airway mesenchymal cells, and identified reduced prenylation of small GTPases as a primary effector mechanism leading to p53-mediated cell death. Here, we extend our studies of statin-induced cell death by assessing endpoints of both apoptosis and autophagy, and investigating their interplay and coincident regulation. Using primary cultured human airway smooth muscle (HASM) and human airway fibroblasts (HAF), autophagy, and autophagosome formation and flux were assessed by transmission electron microscopy, cytochemistry (lysosome number and co localization with LC3) and immunoblotting (LC3 lipidation and Atg12-5 complex formation). Chemical inhibition of autophagy increased simvastatin-induced caspase activation and cell death. Similarly, Atg5 silencing with shRNA, thus preventing Atg5-12 complex formation, increased pro-apoptotic effects of simvastatin. Simvastatin concomitantly increased p53-dependent expression of p53 up-regulated modulator of apoptosis (PUMA), NOXA, and damage-regulated autophagy modulator (DRAM). Notably both mevalonate cascade inhibition-induced autophagy and apoptosis were p53 dependent: simvastatin increased nuclear p53 accumulation, and both cyclic pifithrin-alpha and p53 shRNAi partially inhibited NOXA, PUMA expression and caspase-3/7 cleavage (apoptosis) and DRAM expression, Atg5-12 complex formation, LC3 lipidation, and autophagosome formation (autophagy). Furthermore, the autophagy response is induced rapidly, significantly delaying apoptosis, suggesting the existence of a temporally coordinated p53 regulation network. These findings are relevant for the development of statin-based therapeutic approaches in obstructive airway disease. PMID- 21304980 TI - Interactions between predation and resources shape zooplankton population dynamics. AB - Identifying the relative importance of predation and resources in population dynamics has a long tradition in ecology, while interactions between them have been studied less intensively. In order to disentangle the effects of predation by juvenile fish, algal resource availability and their interactive effects on zooplankton population dynamics, we conducted an enclosure experiment where zooplankton were exposed to a gradient of predation of roach (Rutilus rutilus) at different algal concentrations. We show that zooplankton populations collapse under high predation pressure irrespective of resource availability, confirming that juvenile fish are able to severely reduce zooplankton prey when occurring in high densities. At lower predation pressure, however, the effect of predation depended on algal resource availability since high algal resource supply buffered against predation. Hence, we suggest that interactions between mass-hatching of fish, and the strong fluctuations in algal resources in spring have the potential to regulate zooplankton population dynamics. In a broader perspective, increasing spring temperatures due to global warming will most likely affect the timing of these processes and have consequences for the spring and summer zooplankton dynamics. PMID- 21304981 TI - History shaped the geographic distribution of genomic admixture on the island of Puerto Rico. AB - Contemporary genetic variation among Latin Americans human groups reflects population migrations shaped by complex historical, social and economic factors. Consequently, admixture patterns may vary by geographic regions ranging from countries to neighborhoods. We examined the geographic variation of admixture across the island of Puerto Rico and the degree to which it could be explained by historic and social events. We analyzed a census-based sample of 642 Puerto Rican individuals that were genotyped for 93 ancestry informative markers (AIMs) to estimate African, European and Native American ancestry. Socioeconomic status (SES) data and geographic location were obtained for each individual. There was significant geographic variation of ancestry across the island. In particular, African ancestry demonstrated a decreasing East to West gradient that was partially explained by historical factors linked to the colonial sugar plantation system. SES also demonstrated a parallel decreasing cline from East to West. However, at a local level, SES and African ancestry were negatively correlated. European ancestry was strongly negatively correlated with African ancestry and therefore showed patterns complementary to African ancestry. By contrast, Native American ancestry showed little variation across the island and across individuals and appears to have played little social role historically. The observed geographic distributions of SES and genetic variation relate to historical social events and mating patterns, and have substantial implications for the design of studies in the recently admixed Puerto Rican population. More generally, our results demonstrate the importance of incorporating social and geographic data with genetics when studying contemporary admixed populations. PMID- 21304983 TI - Successive cambia: a developmental oddity or an adaptive structure? AB - BACKGROUND: Secondary growth by successive cambia is a rare phenomenon in woody plant species. Only few plant species, within different phylogenetic clades, have secondary growth by more than one vascular cambium. Often, these successive cambia are organised concentrically. In the mangrove genus Avicennia however, the successive cambia seem to have a more complex organisation. This study aimed (i) at understanding the development of successive cambia by giving a three dimensional description of the hydraulic architecture of Avicennia and (ii) at unveiling the possible adaptive nature of growth by successive cambia through a study of the ecological distribution of plant species with concentric internal phloem. RESULTS: Avicennia had a complex network of non-cylindrical wood patches, the complexity of which increased with more stressful ecological conditions. As internal phloem has been suggested to play a role in water storage and embolism repair, the spatial organisation of Avicennia wood could provide advantages in the ecologically stressful conditions species of this mangrove genus are growing in. Furthermore, we could observe that 84.9% of the woody shrub and tree species with concentric internal phloem occurred in either dry or saline environments strengthening the hypothesis that successive cambia provide the necessary advantages for survival in harsh environmental conditions. CONCLUSIONS: Successive cambia are an ecologically important characteristic, which seems strongly related with water-limited environments. PMID- 21304982 TI - Response to 2009 pandemic influenza A (H1N1) vaccine in HIV-infected patients and the influence of prior seasonal influenza vaccination. AB - BACKGROUND: The immunogenicity of 2009 pandemic influenza A(H1N1) (pH1N1) vaccines and the effect of previous influenza vaccination is a matter of current interest and debate. We measured the immune response to pH1N1 vaccine in HIV infected patients and in healthy controls. In addition we tested whether recent vaccination with seasonal trivalent inactivated vaccine (TIV) induced cross reactive antibodies to pH1N1. (clinicaltrials.gov Identifier:NCT01066169). METHODS AND FINDINGS: In this single-center prospective cohort study MF59 adjuvanted pH1N1 vaccine (Focetria(r), Novartis) was administered twice to 58 adult HIV-infected patients and 44 healthy controls in November 2009 (day 0 and day 21). Antibody responses were measured at baseline, day 21 and day 56 with hemagglutination-inhibition (HI) assay. The seroprotection rate (defined as HI titers >= 1 : 40) for HIV-infected patients was 88% after the first and 91% after the second vaccination. These rates were comparable to those in healthy controls. Post-vaccination GMT, a sensitive marker of the immune competence of a group, was lower in HIV-infected patients. We found a high seroprotection rate at baseline (31%). Seroprotective titers at baseline were much more common in those who had received 2009-2010 seasonal TIV three weeks prior to the first dose of pH1N1 vaccine. Using stored serum samples of 51 HIV-infected participants we measured the pH1N1 specific response to 2009-2010 seasonal TIV. The seroprotection rate to pH1N1 increased from 22% to 49% after vaccination with 2009-2010 seasonal TIV. Seasonal TIV induced higher levels of antibodies to pH1N1 in older than in younger subjects. CONCLUSION: In HIV-infected patients on combination antiretroviral therapy, with a median CD4+ T-lymphocyte count above 500 cells/mm(3), one dose of MF59-adjuvanted pH1N1 vaccine induced a high seroprotection rate comparable to that in healthy controls. A second dose had a modest additional effect. Furthermore, seasonal TIV induced cross-reactive antibodies to pH1N1 and this effect was more pronounced in older subjects. PMID- 21304984 TI - Profiling dizziness in older primary care patients: an empirical study. AB - BACKGROUND: The diagnostic approach to dizzy, older patients is not straightforward as many organ systems can be involved and evidence for diagnostic strategies is lacking. A first differentiation in diagnostic subtypes or profiles may guide the diagnostic process of dizziness and can serve as a classification system in future research. In the literature this has been done, but based on pathophysiological reasoning only. OBJECTIVE: To establish a classification of diagnostic profiles of dizziness based on empirical data. DESIGN: Cross-sectional study. PARTICIPANTS AND SETTING: 417 consecutive patients of 65 years and older presenting with dizziness to 45 primary care physicians in the Netherlands from July 2006 to January 2008. METHODS: We performed tests, including patient history, and physical and additional examination, previously selected by an international expert panel and based on an earlier systematic review. We used the results of these tests in a principal component analysis for exploration, data reduction and finally differentiation into diagnostic dizziness profiles. RESULTS: Demographic data and the results of the tests yielded 221 variables, of which 49 contributed to the classification of dizziness into six diagnostic profiles, that may be named as follows: "frailty", "psychological", "cardiovascular", "presyncope", "non-specific dizziness" and "ENT". These explained 32% of the variance. CONCLUSIONS: Empirically identified components classify dizziness into six profiles. This classification takes into account the heterogeneity and multicausality of dizziness and may serve as starting point for research on diagnostic strategies and can be a first step in an evidence based diagnostic approach of dizzy older patients. PMID- 21304985 TI - Within-host dynamics of the hepatitis C virus quasispecies population in HIV 1/HCV coinfected patients. AB - HIV/HCV coinfected individuals under highly active antiretroviral therapy (HAART) represent an interesting model for the investigation of the role played by the immune system in driving the evolution of the HCV quasispecies. We prospectively studied the intra-host evolution of the HCV heterogeneity in 8 coinfected subjects, selected from a cohort of 32 patients initiating HAART: 5 immunological responders (group A) and 3 immunological non-responders (group B), and in two HCV singly infected controls not assuming drugs (group C). For all these subjects at least two serial samples obtained at the first observation (before HAART) and more than 1 year later, underwent clonal sequence analysis of partial E1/E2 sequences, encompassing the whole HVR1. Evolutionary rates, dated phylogenies and population dynamics were co-estimated by using a Bayesian Markov Chain Monte Carlo approach, and site specific selection pressures were estimated by maximum likelihood-based methods. The intra-host evolutionary rates of HCV quasispecies was 10 times higher in subjects treated with HAART than in controls without immunodeficiency (1.9 and 2.3 * 10(-3) sub/site/month in group A and B and 0.29 * 10(-3) sub/site/month in group C individuals). The within-host Bayesian Skyline plot analysis showed an exponential growth of the quasispecies populations in immunological responders, coinciding with a peak in CD4 cell counts. On the contrary, quasispecies population remained constant in group B and in group C controls. A significant positive selection pressure was detected in a half of the patients under HAART and in none of the group C controls. Several sites under significant positive selection were described, mainly included in the HVR1. Our data indicate that different forces, in addition to the selection pressure, drive an exceptionally fast evolution of HCV during HAART immune restoration. We hypothesize that an important role is played by the enlargement of the viral replicative space. PMID- 21304986 TI - Elevated incidence of dental caries in a mouse model of cystic fibrosis. AB - BACKGROUND: Dental caries is the single most prevalent and costly infectious disease worldwide, affecting more than 90% of the population in the U.S. The development of dental cavities requires the colonization of the tooth surface by acid-producing bacteria, such as Streptococcus mutans. Saliva bicarbonate constitutes the main buffering system which neutralizes the pH fall generated by the plaque bacteria during sugar metabolism. We found that the saliva pH is severely decreased in a mouse model of cystic fibrosis disease (CF). Given the close relationship between pH and caries development, we hypothesized that caries incidence might be elevated in the mouse CF model. METHODOLOGY/PRINCIPAL FINDINGS: We induced carious lesions in CF and wildtype mice by infecting their oral cavity with S. mutans, a well-studied cariogenic bacterium. After infection, the mice were fed a high-sucrose diet for 5 weeks (diet 2000). The mice were then euthanized and their jaws removed for caries scoring and bacterial counting. A dramatic increase in caries and severity of lesions scores were apparent in CF mice compared to their wildtype littermates. The elevated incidence of carious lesions correlated with a striking increase in the S. mutans viable population in dental plaque (20-fold increase in CF vs. wildtype mice; p value < 0.003; t test). We also found that the pilocarpine-stimulated saliva bicarbonate concentration was significantly reduced in CF mice (16 +/- 2 mM vs. 31 +/- 2 mM, CF and wildtype mice, respectively; p value < 0.01; t test). CONCLUSIONS/SIGNIFICANCE: Considering that bicarbonate is the most important pH buffering system in saliva, and the adherence and survival of aciduric bacteria such as S. mutans are enhanced at low pH values, we speculate that the decrease in the bicarbonate content and pH buffering of the saliva is at least partially responsible for the increased severity of lesions observed in the CF mouse. PMID- 21304987 TI - Intracellular S1P generation is essential for S1P-induced motility of human lung endothelial cells: role of sphingosine kinase 1 and S1P lyase. AB - BACKGROUND: Earlier we have shown that extracellular sphingosine-1-phosphate (S1P) induces migration of human pulmonary artery endothelial cells (HPAECs) through the activation of S1P(1) receptor, PKCepsilon, and PLD2-PKCzeta-Rac1 signaling cascade. As endothelial cells generate intracellular S1P, here we have investigated the role of sphingosine kinases (SphKs) and S1P lyase (S1PL), that regulate intracellular S1P accumulation, in HPAEC motility. METHODOLOGY/PRINCIPAL FINDINGS: Inhibition of SphK activity with a SphK inhibitor 2-(p-Hydroxyanilino) 4-(p-Chlorophenyl) Thiazole or down-regulation of Sphk1, but not SphK2, with siRNA decreased S1P(int), and attenuated S1P(ext) or serum-induced motility of HPAECs. On the contrary, inhibition of S1PL with 4-deoxypyridoxine or knockdown of S1PL with siRNA increased S1P(int) and potentiated motility of HPAECs to S1P(ext) or serum. S1P(ext) mediates cell motility through activation of Rac1 and IQGAP1 signal transduction in HPAECs. Silencing of SphK1 by siRNA attenuated Rac1 and IQGAP1 translocation to the cell periphery; however, knockdown of S1PL with siRNA or 4-deoxypyridoxine augmented activated Rac1 and stimulated Rac1 and IQGAP1 translocation to cell periphery. The increased cell motility mediated by down-regulation was S1PL was pertussis toxin sensitive suggesting "inside-out" signaling of intracellularly generated S1P. Although S1P did not accumulate significantly in media under basal or S1PL knockdown conditions, addition of sodium vanadate increased S1P levels in the medium and inside the cells most likely by blocking phosphatases including lipid phosphate phosphatases (LPPs). Furthermore, addition of anti-S1P mAb to the incubation medium blocked S1P(ext) or 4-deoxypyridoxine-dependent endothelial cell motility. CONCLUSIONS/SIGNIFICANCE: These results suggest S1P(ext) mediated endothelial cell motility is dependent on intracellular S1P production, which is regulated, in part, by SphK1 and S1PL. PMID- 21304988 TI - Activation of the canonical Wnt/beta-catenin pathway in ATF3-induced mammary tumors. AB - Female transgenic mice that constitutively overexpress the transcription factor ATF3 in the basal epithelium of the mammary gland develop mammary carcinomas with high frequency, but only if allowed to mate and raise pups early in life. This transgenic mouse model system reproduces some features of human breast cancer in that about 20% of human breast tumor specimens exhibit overexpression of ATF3 in the tumor cells. The ATF3-induced mouse tumors are phenotypically similar to mammary tumors induced by overexpression of activating Wnt/beta-catenin pathway genes. We now show that the Wnt/beta-catenin pathway is indeed activated in ATF3 induced tumors. beta-catenin is transcriptionally up-regulated in the tumors, and high levels of nuclear beta-catenin are seen in tumor cells. A reporter gene for Wnt/beta-catenin pathway activity, TOPGAL, is up-regulated in the tumors and several downstream targets of Wnt signaling, including Ccnd1, Jun, Axin2 and Dkk4, are also expressed at higher levels in ATF3-induced tumors compared to mammary glands of transgenic females. Several positive-acting ligands for this pathway, including Wnt3, Wnt3a, Wnt7b, and Wnt5a, are significantly overexpressed in tumor tissue, and mRNA for Wnt3 is about 5-fold more abundant in transgenic mammary tissue than in non-transgenic mammary tissue. Two known transcriptional targets of ATF3, Snai1 and Snai2, are also overexpressed in the tumors, and Snail and Slug proteins are found to be located primarily in the nuclei of tumor cells. In vitro knockdown of Atf3 expression results in significant decreases in expression of Wnt7b, Tcf7, Snai2 and Jun, suggesting that these genes may be direct transcriptional targets of ATF3 protein. By chromatin immunoprecipitation analysis, both ATF3 and JUN proteins appear to bind to a particular subclass of AP-1 sites upstream of the transcriptional start sites of each of these genes. PMID- 21304989 TI - Peripheral delivery of a CNS targeted, metalo-protease reduces abeta toxicity in a mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD), an incurable, progressive neurodegenerative disorder, is the most common form of dementia. Therapeutic options have been elusive due to the inability to deliver proteins across the blood-brain barrier (BBB). In order to improve the therapeutic potential for AD, we utilized a promising new approach for delivery of proteins across the BBB. We generated a lentivirus vector expressing the amyloid beta-degrading enzyme, neprilysin, fused to the ApoB transport domain and delivered this by intra-peritoneal injection to amyloid protein precursor (APP) transgenic model of AD. Treated mice had reduced levels of Abeta, reduced plaques and increased synaptic density in the CNS. Furthermore, mice treated with the neprilysin targeting the CNS had a reversal of memory deficits. Thus, the addition of the ApoB transport domain to the secreted neprilysin generated a non-invasive therapeutic approach that may be a potential treatment in patients with AD. PMID- 21304990 TI - Biodiversity and ecosystem function in the Gulf of Maine: pattern and role of zooplankton and pelagic nekton. AB - This paper forms part of a broader overview of biodiversity of marine life in the Gulf of Maine area (GoMA), facilitated by the GoMA Census of Marine Life program. It synthesizes current data on species diversity of zooplankton and pelagic nekton, including compilation of observed species and descriptions of seasonal, regional and cross-shelf diversity patterns. Zooplankton diversity in the GoMA is characterized by spatial differences in community composition among the neritic environment, the coastal shelf, and deep offshore waters. Copepod diversity increased with depth on the Scotian Shelf. On the coastal shelf of the western Gulf of Maine, the number of higher-level taxonomic groups declined with distance from shore, reflecting more nearshore meroplankton. Copepod diversity increased in late summer, and interdecadal diversity shifts were observed, including a period of higher diversity in the 1990s. Changes in species diversity were greatest on interannual scales, intermediate on seasonal scales, and smallest across regions, in contrast to abundance patterns, suggesting that zooplankton diversity may be a more sensitive indicator of ecosystem response to inter annual climate variation than zoo plankton abundance. Local factors such as bathymetry, proximity of the coast, and advection probably drive zooplankton and pelagic nekton diversity patterns in the GoMA, while ocean-basin scale diversity patterns probably contribute to the increase in diversity at the Scotian Shelf break, a zone of mixing between the cold-temperate community of the shelf and the warm water community offshore. Pressing research needs include establishment of a comprehensive system for observing change in zooplankton and pelagic nekton diversity, enhanced observations of "underknown" but important functional components of the ecosystem, population and metapopulation studies, and development of analytical modeling tools to enhance understanding of diversity patterns and drivers. Ultimately, sustained observations and modeling analysis of biodiversity must be effectively communicated to managers and incorporated into ecosystem approaches for management of GoMA living marine resources. PMID- 21304991 TI - Large-scale cortical functional organization and speech perception across the lifespan. AB - Aging is accompanied by substantial changes in brain function, including functional reorganization of large-scale brain networks. Such differences in network architecture have been reported both at rest and during cognitive task performance, but an open question is whether these age-related differences show task-dependent effects or represent only task-independent changes attributable to a common factor (i.e., underlying physiological decline). To address this question, we used graph theoretic analysis to construct weighted cortical functional networks from hemodynamic (functional MRI) responses in 12 younger and 12 older adults during a speech perception task performed in both quiet and noisy listening conditions. Functional networks were constructed for each subject and listening condition based on inter-regional correlations of the fMRI signal among 66 cortical regions, and network measures of global and local efficiency were computed. Across listening conditions, older adult networks showed significantly decreased global (but not local) efficiency relative to younger adults after normalizing measures to surrogate random networks. Although listening condition produced no main effects on whole-cortex network organization, a significant age group x listening condition interaction was observed. Additionally, an exploratory analysis of regional effects uncovered age-related declines in both global and local efficiency concentrated exclusively in auditory areas (bilateral superior and middle temporal cortex), further suggestive of specificity to the speech perception tasks. Global efficiency also correlated positively with mean cortical thickness across all subjects, establishing gross cortical atrophy as a task-independent contributor to age-related differences in functional organization. Together, our findings provide evidence of age-related disruptions in cortical functional network organization during speech perception tasks, and suggest that although task-independent effects such as cortical atrophy clearly underlie age-related changes in cortical functional organization, age-related differences also demonstrate sensitivity to task domains. PMID- 21304992 TI - Quantitative and qualitative urinary cellular patterns correlate with progression of murine glomerulonephritis. AB - The kidney is a nonregenerative organ composed of numerous functional nephrons and collecting ducts (CDs). Glomerular and tubulointerstitial damages decrease the number of functional nephrons and cause anatomical and physiological alterations resulting in renal dysfunction. It has recently been reported that nephron constituent cells are dropped into the urine in several pathological conditions associated with renal functional deterioration. We investigated the quantitative and qualitative urinary cellular patterns in a murine glomerulonephritis model and elucidated the correlation between cellular patterns and renal pathology.Urinary cytology and renal histopathology were analyzed in BXSB/MpJ (BXSB; glomerulonephritis model) and C57BL/6 (B6; control) mice. Urinary cytology revealed that the number of urinary cells in BXSB mice changed according to the histometric score of glomerulonephritis and urinary albumin; however, no correlation was detected for the levels of blood urea nitrogen and creatinine. The expression of specific markers for podocytes, distal tubules (DTs), and CDs was detected in BXSB urine. Cells immunopositive for Wilms tumor 1 (podocyte marker) and interleukin-1 family, member 6 (damaged DT and CD marker) in the kidney significantly decreased and increased in BXSB versus B6, respectively. In the PCR array analysis of inflammatory cytokines and chemokines, Il10, Cxcl2, C3, and Il1rn showed relatively higher expression in BXSB kidneys than in B6 kidneys. In particular, the highest expression of C3 mRNA was detected in the urine from BXSB mice. Furthermore, C3 protein and mRNA were localized in the epithelia of damaged nephrons.These findings suggest that epithelial cells of the glomerulus, DT, and CD are dropped into the urine, and that these patterns are associated with renal pathology progression. We conclude that evaluation of urinary cellular patterns plays a key role in the early, noninvasive diagnosis of renal disease. PMID- 21304993 TI - Troublesome heterotopic ossification after central nervous system damage: a survey of 570 surgeries. AB - BACKGROUND: Heterotopic ossification (HO) is a frequent complication after central nervous system (CNS) damage but has seldom been studied. We aimed to investigate features of HO for the first time in a large sample and the rate of early recurrence of HO in terms of the time of surgery. METHODOLOGY/PRINCIPAL FINDINGS: We retrospectively analyzed data from an anonymous prospective survey of patients undergoing surgery between May 1993 and November 2009 in our institution for troublesome HO related to acquired neurological disease. Demographic and HO characteristics and neurological etiologies were recorded. For 357 consecutive patients, we collected data on 539 first surgeries for HO (129 surgeries for multiple sites). During the follow-up, recurrences requiring another surgery appeared in 31 cases (5.8% [31/539]; 95% confidence interval [CI]: 3.8%-7.8%; 27 patients). Most HO requiring surgery occurred after traumatic brain injury (199 patients [55.7%]), then spinal cord injury (86 [24.0%]), stroke (42 [11.8%]) and cerebral anoxia (30 [8.6%]). The hip was the primary site of HO (328 [60.9%]), then the elbow (115 [21.3%]), knee (77 [14.3%]) and shoulder (19 [3.5%]). For all patients, 181 of the surgeries were performed within the first year after the CNS damage, without recurrence of HO. Recurrence was not associated with etiology (p = 0.46), sex (p = 1.00), age at CNS damage (p = 0.2), multisite localization (p = 0.34), or delay to surgery (p = 0.7). CONCLUSIONS/SIGNIFICANCE: In patients with CNS damage, troublesome HO and recurrence occurs most frequently after traumatic brain injury and appears frequently in the hip and elbow. Early surgery for HO is not a factor of recurrence. PMID- 21304994 TI - Cycle flux algebra for ion and water flux through the KcsA channel single-file pore links microscopic trajectories and macroscopic observables. AB - In narrow pore ion channels, ions and water molecules diffuse in a single-file manner and cannot pass each other. Under such constraints, ion and water fluxes are coupled, leading to experimentally observable phenomena such as the streaming potential. Analysis of this coupled flux would provide unprecedented insights into the mechanism of permeation. In this study, ion and water permeation through the KcsA potassium channel was the focus, for which an eight-state discrete-state Markov model has been proposed based on the crystal structure, exhibiting four ion-binding sites. Random transitions on the model lead to the generation of the net flux. Here we introduced the concept of cycle flux to derive exact solutions of experimental observables from the permeation model. There are multiple cyclic paths on the model, and random transitions complete the cycles. The rate of cycle completion is called the cycle flux. The net flux is generated by a combination of cyclic paths with their own cycle flux. T.L. Hill developed a graphical method of exact solutions for the cycle flux. This method was extended to calculate one way cycle fluxes of the KcsA channel. By assigning the stoichiometric numbers for ion and water transfer to each cycle, we established a method to calculate the water-ion coupling ratio (CR(w-i)) through cycle flux algebra. These calculations predicted that CR(w-i) would increase at low potassium concentrations. One envisions an intuitive picture of permeation as random transitions among cyclic paths, and the relative contributions of the cycle fluxes afford experimental observables. PMID- 21304995 TI - Structural and functional characterization of Pseudomonas aeruginosa CupB chaperones. AB - Pseudomonas aeruginosa, an important human pathogen, is estimated to be responsible for ~10% of nosocomial infections worldwide. The pathogenesis of P. aeruginosa starts from its colonization in the damaged tissue or medical devices (e.g. catheters, prothesis and implanted heart valve etc.) facilitated by several extracellular adhesive factors including fimbrial pili. Several clusters containing fimbrial genes have been previously identified on the P. aeruginosa chromosome and named cup[1]. The assembly of the CupB pili is thought to be coordinated by two chaperones, CupB2 and CupB4. However, due to the lack of structural and biochemical data, their chaperone activities remain speculative. In this study, we report the 2.5 A crystal structure of P. aeruginosa CupB2. Based on the structure, we further tested the binding specificity of CupB2 and CupB4 towards CupB1 (the presumed major pilus subunit) and CupB6 (the putative adhesin) using limited trypsin digestion and strep-tactin pull-down assay. The structural and biochemical data suggest that CupB2 and CupB4 might play different, but not redundant, roles in CupB secretion. CupB2 is likely to be the chaperone of CupB1, and CupB4 could be the chaperone of CupB4:CupB5:CupB6, in which the interaction of CupB4 and CupB6 might be mediated via CupB5. PMID- 21304996 TI - Quantitative trait loci involved in sex determination and body growth in the gilthead sea bream (Sparus aurata L.) through targeted genome scan. AB - Among vertebrates, teleost fish exhibit a considerably wide range of sex determination patterns that may be influenced by extrinsic parameters. However even for model fish species like the zebrafish Danio rerio the precise mechanisms involved in primary sex determination have not been studied extensively. The zebrafish, a gonochoristic species, is lacking discernible sex chromosomes and the sex of juvenile fish is difficult to determine. Sequential protandrous hermaphrodite species provide distinct determination of the gender and allow studying the sex determination process by looking at the mechanism of sex reversal. This is the first attempt to understand the genetic basis of phenotypic variation for sex determination and body weight in a sequential protandrous hermaphrodite species, the gilthead sea bream (Sparus aurata). This work demonstrates a fast and efficient strategy for Quantitative Trait Loci (QTL) detection in the gilthead sea bream, a non-model but target hermaphrodite fish species. Therefore a comparative mapping approach was performed to query syntenies against two other Perciformes, the European sea bass (Dicentrarchus labrax), a gonochoristic species and the Asian sea bass (Lates calcarifer) a protandrous hermaphrodite. In this manner two significant QTLs, one QTL affecting both body weight and sex and one QTL affecting sex, were detected on the same linkage group. The co-segregation of the two QTLs provides a genomic base to the observed genetic correlation between these two traits in sea bream as well as in other teleosts. The identification of QTLs linked to sex reversal and growth, will contribute significantly to a better understanding of the complex nature of sex determination in S. aurata where most individuals reverse to the female sex at the age of two years through development and maturation of the ovarian portion of the gonad and regression of the testicular area. [Genomic sequences reported in this manuscript have been submitted to GenBank under accession numbers HQ021443-HQ021749.]. PMID- 21304997 TI - Agreement of blood spot card measurements of vitamin D levels with serum, whole blood specimen types and a dietary recall instrument. AB - BACKGROUND: The ability to measure 25-hydroxyvitamin D (25OHD) levels from blood spot cards can simplify sample collection versus samples obtained by venipuncture, particularly in populations in whom it is difficult to draw blood. We sought to validate the use of blood spot samples for the measurement of 25OHD compared to serum or whole blood samples and correlate the measured levels with intake estimated from dietary recall. METHODS: Utilizing 109 biological mothers of infants enrolled in the Tennessee Children's Respiratory Initiative cohort, we measured 25OHD levels through highly selective liquid chromatography-tandem mass spectrometry on samples from blood spot cards, serum, and whole blood collected at enrollment. Dietary questionnaires (n = 65) were used to assess 25OHD intake by dietary recall. Sample collection measures were assessed for agreement and 25OHD levels for association with dietary 25OHD intake. RESULTS: The mean absolute differences (95%CI) in 25OHD levels measured between whole blood and blood spot (n = 50 pairs) or serum and blood spot (n = 20) were 3.2 (95%CI:1.6, 4.8) ng/ml and 1.5 (95%CI:-0.5,3.4) ng/mL. Intake by dietary recall was marginally associated with 25OHD levels after adjustment for current smoking and race in linear regression. DISCUSSION: 25OHD levels determined by mass spectrometry from blood spot cards, serum and whole blood show relatively good agreement, although 25OHD levels are slightly lower when measured by blood spot cards. Blood spot samples are a less invasive means of obtaining 25OHD measurements, particularly in large population-based samples, or among children when venipuncture may decrease study participation. PMID- 21304998 TI - Propofol directly increases tau phosphorylation. AB - In Alzheimer's disease (AD) and other tauopathies, the microtubule-associated protein tau can undergo aberrant hyperphosphorylation potentially leading to the development of neurofibrillary pathology. Anesthetics have been previously shown to induce tau hyperphosphorylation through a mechanism involving hypothermia induced inhibition of protein phosphatase 2A (PP2A) activity. However, the effects of propofol, a common clinically used intravenous anesthetic, on tau phosphorylation under normothermic conditions are unknown. We investigated the effects of a general anesthetic dose of propofol on levels of phosphorylated tau in the mouse hippocampus and cortex under normothermic conditions. Thirty min following the administration of propofol 250 mg/kg i.p., significant increases in tau phosphorylation were observed at the AT8, CP13, and PHF-1 phosphoepitopes in the hippocampus, as well as at AT8, PHF-1, MC6, pS262, and pS422 epitopes in the cortex. However, we did not detect somatodendritic relocalization of tau. In both brain regions, tau hyperphosphorylation persisted at the AT8 epitope 2 h following propofol, although the sedative effects of the drug were no longer evident at this time point. By 6 h following propofol, levels of phosphorylated tau at AT8 returned to control levels. An initial decrease in the activity and expression of PP2A were observed, suggesting that PP2A inhibition is at least partly responsible for the hyperphosphorylation of tau at multiple sites following 30 min of propofol exposure. We also examined tau phosphorylation in SH SY5Y cells transfected to overexpress human tau. A 1 h exposure to a clinically relevant concentration of propofol in vitro was also associated with tau hyperphosphorylation. These findings suggest that propofol increases tau phosphorylation both in vivo and in vitro under normothermic conditions, and further studies are warranted to determine the impact of this anesthetic on the acceleration of neurofibrillary pathology. PMID- 21304999 TI - Epistatic interactions in genetic regulation of t-PA and PAI-1 levels in a Ghanaian population. AB - The proteins, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1), act in concert to balance thrombus formation and degradation, thereby modulating the development of arterial thrombosis and excessive bleeding. PAI-1 is upregulated by the renin-angiotensin system (RAS), specifically by angiotensin II, the product of angiotensin converting enzyme (ACE) cleavage of angiotensin I, which is produced by the cleavage of angiotensinogen (AGT) by renin (REN). ACE indirectly stimulates the release of t PA which, in turn, activates the corresponding fibrinolytic system. Single polymorphisms in these pathways have been shown to significantly impact plasma levels of t-PA and PAI-1 differently in Ghanaian males and females. Here we explore the involvement of epistatic interactions between the same polymorphisms in central genes of the RAS and fibrinolytic systems on plasma t-PA and PAI-1 levels within the same population (n = 992). Statistical modeling of pairwise interactions was done using two-way ANOVA between polymorphisms in the ETNK2, RENIN, ACE, PAI-1, t-PA, and AGT genes. The most significant interactions that associated with t-PA levels were between the ETNK2 A6135G and the REN T9435C polymorphisms in females (p = 0.006) and the REN T9435C and the TPA I/D polymorphisms (p = 0.005) in males. The most significant interactions for PAI-1 levels were with REN T9435C and the TPA I/D polymorphisms (p = 0.001) in females, and the association of REN G6567T with the TPA I/D polymorphisms (p = 0.032) in males. Our results provide evidence for multiple genetic effects that may not be detected using single SNP analysis. Because t-PA and PAI-1 have been implicated in cardiovascular disease these results support the idea that the genetic architecture of cardiovascular disease is complex. Therefore, it is necessary to consider the relationship between interacting polymorphisms of pathway specific genes that predict t-PA and PAI-1 levels. PMID- 21305000 TI - The herpesvirus associated ubiquitin specific protease, USP7, is a negative regulator of PML proteins and PML nuclear bodies. AB - The PML tumor suppressor is the founding component of the multiprotein nuclear structures known as PML nuclear bodies (PML-NBs), which control several cellular functions including apoptosis and antiviral effects. The ubiquitin specific protease USP7 (also called HAUSP) is known to associate with PML-NBs and to be a tight binding partner of two herpesvirus proteins that disrupt PML NBs. Here we investigated whether USP7 itself regulates PML-NBs. Silencing of USP7 was found to increase the number of PML-NBs, to increase the levels of PML protein and to inhibit PML polyubiquitylation in nasopharyngeal carcinoma cells. This effect of USP7 was independent of p53 as PML loss was observed in p53-null cells. PML-NBs disruption was induced by USP7 overexpression independently of its catalytic activity and was induced by either of the protein interaction domains of USP7, each of which localized to PML-NBs. USP7 also disrupted NBs formed from some single PML isoforms, most notably isoforms I and IV. CK2alpha and RNF4, which are known regulators of PML, were dispensable for USP7-associated PML-NB disruption. The results are consistent with a novel model of PML regulation where a deubiquitylase disrupts PML-NBs through recruitment of another cellular protein(s) to PML NBs, independently of its catalytic activity. PMID- 21305001 TI - Multimodality imaging of abnormal vascular perfusion and morphology in preclinical 9L gliosarcoma model. AB - BACKGROUND: This study demonstrates that a dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) perfusion parameter may indicate vascular abnormality in a brain tumor model and reflects an effect of dexamethasone treatment. In addition, X-ray computed tomography (CT) measurements of vascular tortuosity and tissue markers of vascular morphology were performed to investigate the underpinnings of tumor response to dexamethasone. METHODOLOGY/PRINCIPAL FINDINGS: One cohort of Fisher 344 rats (N = 13), inoculated intracerebrally with 9L gliosarcoma cells, was treated with dexamethasone (i.p. 3 mg/kg/day) for five consecutive days, and another cohort (N = 11) was treated with equal volume of saline. Longitudinal DSC-MRI studies were performed at the first (baseline), third and fifth day of treatments. Relative cerebral blood volume (rCBV) was significantly reduced on the third day of dexamethasone treatment (0.65 +/- .13) as compared to the fifth day during treatment (1.26 +/-.19, p < 0.05). In saline treated rats, relative CBV gradually increased during treatment (0.89 +/-.13, 1.00 +/- .21, 1.13 +/- .23) with no significant difference on the third day of treatment (p>0.05). In separate serial studies, microfocal X-ray CT of ex vivo brain specimens (N = 9) and immunohistochemistry for endothelial cell marker anti-CD31 (N = 8) were performed. Vascular morphology of ex vivo rat brains from micro-CT analysis showed hypervascular characteristics in tumors, and both vessel density (41.32 +/ 2.34 branches/mm(3), p<0.001) and vessel tortuosity (p<0.05) were significantly reduced in tumors of rats treated with dexamethasone compared to saline (74.29 +/ 3.51 branches/mm(3)). The vascular architecture of rat brain tissue was examined with anti-CD31 antibody, and dexamethasone treated tumor regions showed reduced vessel area (16.45 +/- 1.36 um(2)) as compared to saline treated tumor regions (30.83 +/- 4.31 um(2), p<0.001) and non-tumor regions (22.80 +/- 1.11 um(2), p<0.01). CONCLUSIONS/SIGNIFICANCE: Increased vascular density and tortuosity are culprit to abnormal perfusion, which is transiently reduced during dexamethasone treatment. PMID- 21305003 TI - Virulence and pathogen multiplication: a serial passage experiment in the hypervirulent bacterial insect-pathogen Xenorhabdus nematophila. AB - The trade-off hypothesis proposes that the evolution of pathogens' virulence is shaped by a link between virulence and contagiousness. This link is often assumed to come from the fact that pathogens are contagious only if they can reach high parasitic load in the infected host. In this paper we present an experimental test of the hypothesis that selection on fast replication can affect virulence. In a serial passage experiment, we selected 80 lines of the bacterial insect pathogen Xenorhabdus nematophila to multiply fast in an artificial culture medium. This selection resulted in shortened lag phase in our selected bacteria. We then injected these bacteria into insects and observed an increase in virulence. This could be taken as a sign that virulence in Xenorhabdus is linked to fast multiplication. But we found, among the selected lineages, either no link or a positive correlation between lag duration and virulence: the most virulent bacteria were the last to start multiplying. We then surveyed phenotypes that are under the control of the flhDC super regulon, which has been shown to be involved in Xenorhabdus virulence. We found that, in one treatment, the flhDC regulon has evolved rapidly, but that the changes we observed were not connected to virulence. All together, these results indicate that virulence is, in Xenorhabdus as in many other pathogens, a multifactorial trait. Being able to grow fast is one way to be virulent. But other ways exist which renders the evolution of virulence hard to predict. PMID- 21305002 TI - A novel soluble immune-type receptor (SITR) in teleost fish: carp SITR is involved in the nitric oxide-mediated response to a protozoan parasite. AB - BACKGROUND: The innate immune system relies upon a wide range of germ-line encoded receptors including a large number of immunoglobulin superfamily (IgSF) receptors. Different Ig-like immune receptor families have been reported in mammals, birds, amphibians and fish. Most innate immune receptors of the IgSF are type I transmembrane proteins containing one or more extracellular Ig-like domains and their regulation of effector functions is mediated intracellularly by distinct stimulatory or inhibitory pathways. METHODOLOGY/PRINCIPAL FINDINGS: Carp SITR was found in a substracted cDNA repertoire from carp macrophages, enriched for genes up-regulated in response to the protozoan parasite Trypanoplasma borreli. Carp SITR is a type I protein with two extracellular Ig domains in a unique organisation of a N-proximal V/C2 (or I-) type and a C-proximal V-type Ig domain, devoid of a transmembrane domain or any intracytoplasmic signalling motif. The carp SITR C-proximal V-type Ig domain, in particular, has a close sequence similarity and conserved structural characteristics to the mammalian CD300 molecules. By generating an anti-SITR antibody we could show that SITR protein expression was restricted to cells of the myeloid lineage. Carp SITR is abundantly expressed in macrophages and is secreted upon in vitro stimulation with the protozoan parasite T. borreli. Secretion of SITR protein during in vivo T. borreli infection suggests a role for this IgSF receptor in the host response to this protozoan parasite. Overexpression of carp SITR in mouse macrophages and knock-down of SITR protein expression in carp macrophages, using morpholino antisense technology, provided evidence for the involvement of carp SITR in the parasite-induced NO production. CONCLUSION/SIGNIFICANCE: We report the structural and functional characterization of a novel soluble immune-type receptor (SITR) in a teleost fish and propose a role for carp SITR in the NO-mediated response to a protozoan parasite. PMID- 21305004 TI - Non-compliance with growth hormone treatment in children is common and impairs linear growth. AB - BACKGROUND: GH therapy requires daily injections over many years and compliance can be difficult to sustain. As growth hormone (GH) is expensive, non-compliance is likely to lead to suboptimal growth, at considerable cost. Thus, we aimed to assess the compliance rate of children and adolescents with GH treatment in New Zealand. METHODS: This was a national survey of GH compliance, in which all children receiving government-funded GH for a four-month interval were included. Compliance was defined as >= 85% adherence (no more than one missed dose a week on average) to prescribed treatment. Compliance was determined based on two parameters: either the number of GH vials requested (GHreq) by the family or the number of empty GH vials returned (GHret). Data are presented as mean +/- SEM. FINDINGS: 177 patients were receiving GH in the study period, aged 12.1 +/- 0.6 years. The rate of returned vials, but not number of vials requested, was positively associated with HVSDS (p < 0.05), such that patients with good compliance had significantly greater linear growth over the study period (p<0.05). GHret was therefore used for subsequent analyses. 66% of patients were non-compliant, and this outcome was not affected by sex, age or clinical diagnosis. However, Maori ethnicity was associated with a lower rate of compliance. INTERPRETATION: An objective assessment of compliance such as returned vials is much more reliable than compliance based on parental or patient based information. Non-compliance with GH treatment is common, and associated with reduced linear growth. Non-compliance should be considered in all patients with apparently suboptimal response to GH treatment. PMID- 21305006 TI - Predictions of native American population structure using linguistic covariates in a hidden regression framework. AB - BACKGROUND: The mainland of the Americas is home to a remarkable diversity of languages, and the relationships between genes and languages have attracted considerable attention in the past. Here we investigate to which extent geography and languages can predict the genetic structure of Native American populations. METHODOLOGY/PRINCIPAL FINDINGS: Our approach is based on a Bayesian latent cluster regression model in which cluster membership is explained by geographic and linguistic covariates. After correcting for geographic effects, we find that the inclusion of linguistic information improves the prediction of individual membership to genetic clusters. We further compare the predictive power of Greenberg's and The Ethnologue classifications of Amerindian languages. We report that The Ethnologue classification provides a better genetic proxy than Greenberg's classification at the stock and at the group levels. Although high predictive values can be achieved from The Ethnologue classification, we nevertheless emphasize that Choco, Chibchan and Tupi linguistic families do not exhibit a univocal correspondence with genetic clusters. CONCLUSIONS/SIGNIFICANCE: The Bayesian latent class regression model described here is efficient at predicting population genetic structure using geographic and linguistic information in Native American populations. PMID- 21305005 TI - A low T regulatory cell response may contribute to both viral control and generalized immune activation in HIV controllers. AB - HIV-infected individuals maintaining undetectable viremia in the absence of therapy (HIV controllers) often maintain high HIV-specific T cell responses, which has spurred the development of vaccines eliciting HIV-specific T cell responses. However, controllers also often have abnormally high T cell activation levels, potentially contributing to T cell dysfunction, CD4+ T cell depletion, and non-AIDS morbidity. We hypothesized that a weak T regulatory cell (Treg) response might contribute to the control of viral replication in HIV controllers, but might also contribute to generalized immune activation, contributing to CD4+ T cell loss. To address these hypotheses, we measured frequencies of activated (CD38+ HLA-DR+), regulatory (CD4+CD25+CD127(dim)), HIV-specific, and CMV-specific T cells among HIV controllers and 3 control populations: HIV-infected individuals with treatment-mediated viral suppression (ART-suppressed), untreated HIV infected "non-controllers" with high levels of viremia, and HIV-uninfected individuals. Despite abnormally high T cell activation levels, controllers had lower Treg frequencies than HIV-uninfected controls (P = 0.014). Supporting the propensity for an unusually low Treg response to viral infection in HIV controllers, we observed unusually high CMV-specific CD4+ T cell frequencies and a strong correlation between HIV-specific CD4+ T cell responses and generalized CD8+ T cell activation levels in HIV controllers (P <= 0.001). These data support a model in which low frequencies of Tregs in HIV controllers may contribute to an effective adaptive immune response, but may also contribute to generalized immune activation, potentially contributing to CD4 depletion. PMID- 21305007 TI - Regulation of brown fat adipogenesis by protein tyrosine phosphatase 1B. AB - BACKGROUND: Protein-tyrosine phosphatase 1B (PTP1B) is a physiological regulator of insulin signaling and energy balance, but its role in brown fat adipogenesis requires additional investigation. METHODOLOGY/PRINCIPAL FINDINGS: To precisely determine the role of PTP1B in adipogenesis, we established preadipocyte cell lines from wild type and PTP1B knockout (KO) mice. In addition, we reconstituted KO cells with wild type, substrate-trapping (D/A) and sumoylation-resistant (K/R) PTP1B mutants, then characterized differentiation and signaling in these cells. KO, D/A- and WT-reconstituted cells fully differentiated into mature adipocytes with KO and D/A cells exhibiting a trend for enhanced differentiation. In contrast, K/R cells exhibited marked attenuation in differentiation and lipid accumulation compared with WT cells. Expression of adipogenic markers PPARgamma, C/EBPalpha, C/EBPdelta, and PGC1alpha mirrored the differentiation pattern. In addition, the differentiation deficit in K/R cells could be reversed completely by the PPARgamma activator troglitazone. PTP1B deficiency enhanced insulin receptor (IR) and insulin receptor substrate 1 (IRS1) tyrosyl phosphorylation, while K/R cells exhibited attenuated insulin-induced IR and IRS1 phosphorylation and glucose uptake compared with WT cells. In addition, substrate-trapping studies revealed that IRS1 is a substrate for PTP1B in brown adipocytes. Moreover, KO, D/A and K/R cells exhibited elevated AMPK and ACC phosphorylation compared with WT cells. CONCLUSIONS: These data indicate that PTP1B is a modulator of brown fat adipogenesis and suggest that adipocyte differentiation requires regulated expression of PTP1B. PMID- 21305008 TI - Light converts endosymbiotic fungus to pathogen, influencing seedling survival and niche-space filling of a common tropical tree, Iriartea deltoidea. AB - Pathogens are hypothesized to play an important role in the maintenance of tropical forest plant species richness. Notably, species richness may be promoted by incomplete filling of niche space due interactions of host populations with their pathogens. A potentially important group of pathogens are endophytic fungi, which asymptomatically colonize plants and are diverse and abundant in tropical ecosystems. Endophytes may alter competitive abilities of host individuals and improve host fitness under stress, but may also become pathogenic. Little is known of the impacts of endophytes on niche-space filling of their hosts.Here we evaluate how a widespread fungal endophyte infecting a common tropical palm influences its recruitment and survival in natural ecosystems, and whether this impact is modulated by the abiotic environment, potentially constraining host niche-space filling. Iriartea deltoidea dominates many wet lowland Neotropical forests. Diplodia mutila is a common asymptomatic endophyte in mature plants; however, it causes disease in some seedlings. We investigated the effects of light availability on D. mutila disease expression.We found I. deltoidea seedlings to preferentially occur under shady conditions. Correspondingly, we also found that high light triggers endophyte pathogenicity, while low light favors endosymbiotic development, constraining recruitment of endophyte-infested seedlings to shaded understory by reducing seedling survival in direct light. Pathogenicity of D. mutila under high light is proposed to result from light induced production of H(2)O(2) by the fungus, triggering hypersensitivity, cell death, and tissue necrosis in the palm. This is the first study to demonstrate that endophytes respond to abiotic factors to influence plant distributions in natural ecosystems; and the first to identify light as a factor influencing where an endophyte is placed on the endosymbiont-pathogen continuum. Our findings show that pathogens can indeed constrain niche-space filling of otherwise successful tropical plant species, providing unoccupied niche space for other species. PMID- 21305009 TI - Odorant binding proteins of the red imported fire ant, Solenopsis invicta: an example of the problems facing the analysis of widely divergent proteins. AB - We describe the odorant binding proteins (OBPs) of the red imported fire ant, Solenopsis invicta, obtained from analyses of an EST library and separate 454 sequencing runs of two normalized cDNA libraries. We identified a total of 18 putative functional OBPs in this ant. A third of the fire ant OBPs are orthologs to honey bee OBPs. Another third of the OBPs belong to a lineage-specific expansion, which is a common feature of insect OBP evolution. Like other OBPs, the different fire ant OBPs share little sequence similarity (~ 20%), rendering evolutionary analyses difficult. We discuss the resulting problems with sequence alignment, phylogenetic analysis, and tests of selection. As previously suggested, our results underscore the importance for careful exploration of the sensitivity to the effects of alignment methods for data comprising widely divergent sequences. PMID- 21305010 TI - Quantification of ploidy in proteobacteria revealed the existence of monoploid, (mero-)oligoploid and polyploid species. AB - Bacteria are generally assumed to be monoploid (haploid). This assumption is mainly based on generalization of the results obtained with the most intensely studied model bacterium, Escherichia coli (a gamma-proteobacterium), which is monoploid during very slow growth. However, several species of proteobacteria are oligo- or polyploid, respectively. To get a better overview of the distribution of ploidy levels, genome copy numbers were quantified in four species of three different groups of proteobacteria. A recently developed Real Time PCR approach, which had been used to determine the ploidy levels of halophilic archaea, was optimized for the quantification of genome copy numbers of bacteria. Slow-growing (doubling time 103 minutes) and fast-growing (doubling time 25 minutes) E. coli cultures were used as a positive control. The copy numbers of the origin and terminus region of the chromosome were determined and the results were in excellent agreement with published data. The approach was also used to determine the ploidy levels of Caulobacter crescentus (an alpha-proteobacterium) and Wolinella succinogenes (an epsilon-proteobacterium), both of which are monoploid. In contrast, Pseudomonas putida (a gamma-proteobacterium) contains 20 genome copies and is thus polyploid. A survey of the proteobacteria with experimentally determined genome copy numbers revealed that only three to four of 11 species are monoploid and thus monoploidy is not typical for proteobacteria. The ploidy level is not conserved within the groups of proteobacteria, and there are no obvious correlations between the ploidy levels with other parameters like genome size, optimal growth temperature or mode of life. PMID- 21305011 TI - Molecular malaria epidemiology: mapping and burden estimates for the Democratic Republic of the Congo, 2007. AB - BACKGROUND: Epidemiologic data on malaria are scant in many high-burden countries including the Democratic Republic of the Congo (DRC), which suffers the second highest global burden of malaria. Malaria control efforts in regions with challenging infrastructure require reproducible and efficient surveillance. We employed new high-throughput molecular testing to characterize the state of malaria control in the DRC and estimate childhood mortality attributable to excess malaria transmission. METHODS AND FINDINGS: The Demographic and Health Survey was a cross-sectional, population-based cluster household survey of adults aged 15-59 years in 2007 employing structured questionnaires and dried blood spot collection. Parasitemia was detected by real-time PCR, and survey responses measured adoption of malaria control measures and under-5 health indices. The response rate was 99% at the household level, and 8,886 households were surveyed in 300 clusters; from 8,838 respondents molecular results were available. The overall prevalence of parasitemia was 33.5% (95% confidence interval [C.I.] 32 34.9); P. falciparum was the most prevalent species, either as monoinfection (90.4%; 95% C.I. 88.8-92.1) or combined with P. malariae (4.9%; 95% C.I. 3.7-5.9) or P. ovale (0.6%; 95% C.I. 0.1-0.9). Only 7.7% (95% CI 6.8-8.6) of households with children under 5 owned an insecticide-treated bednet (ITN), and only 6.8% (95% CI 6.1-7.5) of under-fives slept under an ITN the preceding night. The overall under-5 mortality rate was 147 deaths per 1,000 live births (95% C.I. 141 153) and between clusters was associated with increased P. falciparum prevalence; based on the population attributable fraction, 26,488 yearly under-5 deaths were attributable to excess malaria transmission. CONCLUSIONS: Adult P. falciparum prevalence is substantial in the DRC and is associated with under-5 mortality. Molecular testing offers a new, generalizable, and efficient approach to characterizing malaria endemicity in underserved countries. PMID- 21305012 TI - Humanization and characterization of an anti-human TNF-alpha murine monoclonal antibody. AB - A murine monoclonal antibody, m357, showing the highly neutralizing activities for human tumor necrosis factor (TNF-alpha) was chosen to be humanized by a variable domain resurfacing approach. The non-conserved surface residues in the framework regions of both the heavy and light chain variable regions were identified via a molecular modeling of m357 built by computer-assisted homology modeling. By replacing these critical surface residues with the human counterparts, a humanized version, h357, was generated. The humanized h357 IgG(1) was then stably expressed in a mammalian cell line and the purified antibody maintained the high antigen binding affinity as compared with the parental m357 based on a soluble TNF-alpha neutralization bioassay. Furthermore, h357 IgG(1) possesses the ability to mediate antibody-dependent cell-mediated cytotoxicity and complement dependent cytotoxicity upon binding to cells bearing the transmembrane form of TNF-alpha. In a mouse model of collagen antibody-induced arthritis, h357 IgG significantly inhibited disease progression by intra peritoneal injection of 50 ug/mouse once-daily for 9 consecutive days. These results provided a basis for the development of h357 IgG as therapeutic use. PMID- 21305013 TI - Ancestry of the Iban is predominantly Southeast Asian: genetic evidence from autosomal, mitochondrial, and Y chromosomes. AB - Humans reached present-day Island Southeast Asia (ISEA) in one of the first major human migrations out of Africa. Population movements in the millennia following this initial settlement are thought to have greatly influenced the genetic makeup of current inhabitants, yet the extent attributed to different events is not clear. Recent studies suggest that south-to-north gene flow largely influenced present-day patterns of genetic variation in Southeast Asian populations and that late Pleistocene and early Holocene migrations from Southeast Asia are responsible for a substantial proportion of ISEA ancestry. Archaeological and linguistic evidence suggests that the ancestors of present-day inhabitants came mainly from north-to-south migrations from Taiwan and throughout ISEA approximately 4,000 years ago. We report a large-scale genetic analysis of human variation in the Iban population from the Malaysian state of Sarawak in northwestern Borneo, located in the center of ISEA. Genome-wide single-nucleotide polymorphism (SNP) markers analyzed here suggest that the Iban exhibit greatest genetic similarity to Indonesian and mainland Southeast Asian populations. The most common non-recombining Y (NRY) and mitochondrial (mt) DNA haplogroups present in the Iban are associated with populations of Southeast Asia. We conclude that migrations from Southeast Asia made a large contribution to Iban ancestry, although evidence of potential gene flow from Taiwan is also seen in uniparentally inherited marker data. PMID- 21305014 TI - The Pseudomonas aeruginosa autoinducer 3O-C12 homoserine lactone provokes hyperinflammatory responses from cystic fibrosis airway epithelial cells. AB - The discovery of novel antiinflammatory targets to treat inflammation in the cystic fibrosis (CF) lung stands to benefit patient populations suffering with this disease. The Pseudomonas aeruginosa quorum sensing autoinducer N-3 oxododecanoyl homoserine lactone (3O-C12) is an important bacterial virulence factor that has been reported to induce proinflammatory cytokine production from a variety of cell types. The goal of this study was to examine the ability of 3O C12 to induce proinflammatory cytokine production in normal and CF bronchial epithelial cells, and better understand the cellular mechanisms by which this cytokine induction occurs. 3O-C12 was found to induce higher levels of IL-6 production in the CF cell lines IB3-1 and CuFi, compared to their corresponding control cell lines C38 and NuLi. Systems biology and network analysis revealed a high predominance of over-represented innate immune pathways bridged together by calcium-dependant transcription factors governing the transcriptional responses of A549 airway cells to stimulation with 3O-C12. Using calcium-flux assays, 3O C12 was found to induce larger and more sustained increases in intracellular calcium in IB3-1 cells compared to C38, and blocking this calcium flux with BAPTA AM reduced the production of IL-6 by IB3-1 to the levels produced by C38. These data suggest that 3O-C12 induces proinflammatory cytokine production in airway epithelial cells in a calcium-dependent manner, and that dysregulated calcium storage or signalling in CF cells results in an increased production of proinflammatory cytokines. PMID- 21305015 TI - Mayday SeaSight: combined analysis of deep sequencing and microarray data. AB - Recently emerged deep sequencing technologies offer new high-throughput methods to quantify gene expression, epigenetic modifications and DNA-protein binding. From a computational point of view, the data is very different from that produced by the already established microarray technology, providing a new perspective on the samples under study and complementing microarray gene expression data. Software offering the integrated analysis of data from different technologies is of growing importance as new data emerge in systems biology studies. Mayday is an extensible platform for visual data exploration and interactive analysis and provides many methods for dissecting complex transcriptome datasets. We present Mayday SeaSight, an extension that allows to integrate data from different platforms such as deep sequencing and microarrays. It offers methods for computing expression values from mapped reads and raw microarray data, background correction and normalization and linking microarray probes to genomic coordinates. It is now possible to use Mayday's wealth of methods to analyze sequencing data and to combine data from different technologies in one analysis. PMID- 21305016 TI - beta-arrestin functionally regulates the non-bleaching pigment parapinopsin in lamprey pineal. AB - The light response of vertebrate visual cells is achieved by light-sensing proteins such as opsin-based pigments as well as signal transduction proteins, including visual arrestin. Previous studies have indicated that the pineal pigment parapinopsin has evolutionally and physiologically important characteristics. Parapinopsin is phylogenetically related to vertebrate visual pigments. However, unlike the photoproduct of the visual pigment rhodopsin, which is unstable, dissociating from its chromophore and bleaching, the parapinopsin photoproduct is stable and does not release its chromophore. Here, we investigated arrestin, which regulates parapinopsin signaling, in the lamprey pineal organ, where parapinopsin and rhodopsin are localized to distinct photoreceptor cells. We found that beta-arrestin, which binds to stimulated G protein-coupled receptors (GPCRs) other than opsin-based pigments, was localized to parapinopsin-containing cells. This result stands in contrast to the localization of visual arrestin in rhodopsin-containing cells. Beta-arrestin bound to cultured cell membranes containing parapinopsin light-dependently and translocated to the outer segments of pineal parapinopsin-containing cells, suggesting that beta-arrestin binds to parapinopsin to arrest parapinopsin signaling. Interestingly, beta-arrestin colocalized with parapinopsin in the granules of the parapinopsin-expressing cell bodies under light illumination. Because beta-arrestin, which is a mediator of clathrin-mediated GPCR internalization, also served as a mediator of parapinopsin internalization in cultured cells, these results suggest that the granules were generated light dependently by beta-arrestin-mediated internalization of parapinopsins from the outer segments. Therefore, our findings imply that beta-arrestin-mediated internalization is responsible for eliminating the stable photoproduct and restoring cell conditions to the original dark state. Taken together with a previous finding that the bleaching pigment evolved from a non-bleaching pigment, vertebrate visual arrestin may have evolved from a "beta-like" arrestin by losing its clathrin-binding domain and its function as an internalization mediator. Such changes would have followed the evolution of vertebrate visual pigments, which generate unstable photoproducts that independently decay by chromophore dissociation. PMID- 21305017 TI - The proteomic profile of hereditary inclusion body myopathy. AB - Hereditary inclusion body myopathy (HIBM) is an adult onset, slowly progressive distal and proximal myopathy. Although the causing gene, GNE, encodes for a key enzyme in the biosynthesis of sialic acid, its primary function in HIBM remains unknown. The goal of this study was to unravel new clues on the biological pathways leading to HIBM by proteomic comparison. Muscle cultures and biopsies were analyzed by two dimensional gel electrophoresis (2-DE) and the same biopsy extracts by isobaric tag for relative and absolute quantitation (iTRAQ). Proteins that were differentially expressed in all HIBM specimens versus all controls in each analysis were identified by mass spectrometry. The muscle cultures 2-DE analysis yielded 41 such proteins, while the biopsies 2-DE analysis showed 26 differentially expressed proteins. Out of the 400 proteins identified in biopsies by iTRAQ, 41 showed altered expression. In spite of the different nature of specimens (muscle primary cultures versus muscle biopsies) and of the different methods applied (2D gels versus iTRAQ) the differentially expressed proteins identified in each of the three analyses where related mainly to the same pathways, ubiquitination, stress response and mitochondrial processes, but the most robust cluster (30%) was assigned to cytoskeleton and sarcomere organization. Taken together, these findings indicate a possible novel function of GNE in the muscle filamentous apparatus that could be involved in the pathogenesis of HIBM. PMID- 21305018 TI - MicroRNAs differentially expressed in postnatal aortic development downregulate elastin via 3' UTR and coding-sequence binding sites. AB - Elastin production is characteristically turned off during the maturation of elastin-rich organs such as the aorta. MicroRNAs (miRNAs) are small regulatory RNAs that down-regulate target mRNAs by binding to miRNA regulatory elements (MREs) typically located in the 3' UTR. Here we show a striking up-regulation of miR-29 and miR-15 family miRNAs during murine aortic development with commensurate down-regulation of targets including elastin and other extracellular matrix (ECM) genes. There were a total of 14 MREs for miR-29 in the coding sequences (CDS) and 3' UTR of elastin, which was highly significant, and up to 22 miR-29 MREs were found in the CDS of multiple ECM genes including several collagens. This overrepresentation was conserved throughout mammalian evolution. Luciferase reporter assays showed synergistic effects of miR-29 and miR-15 family miRNAs on 3' UTR and coding-sequence elastin constructs. Our results demonstrate that multiple miR-29 and miR-15 family MREs are characteristic for some ECM genes and suggest that miR-29 and miR-15 family miRNAs are involved in the down regulation of elastin in the adult aorta. PMID- 21305020 TI - High-dimensional coexistence of temperate tree species: functional traits, demographic rates, life-history stages, and their physical context. AB - Theoretical models indicate that trade-offs between growth and survival strategies of tree species can lead to coexistence across life history stages (ontogeny) and physical conditions experienced by individuals. There exist predicted physiological mechanisms regulating these trade-offs, such as an investment in leaf characters that may increase survival in stressful environments at the expense of investment in bole or root growth. Confirming these mechanisms, however, requires that potential environmental, ontogenetic, and trait influences are analyzed together. Here, we infer growth and mortality of tree species given size, site, and light characteristics from forest inventory data from Wisconsin to test hypotheses about growth-survival trade-offs given species functional trait values under different ontogenetic and environmental states. A series of regression analyses including traits and rates their interactions with environmental and ontogenetic stages supported the relationships between traits and vital rates expected from the expectations from tree physiology. A combined model including interactions between all variables indicated that relationships between demographic rates and functional traits supports growth-survival trade-offs and their differences across species in high dimensional niche space. The combined model explained 65% of the variation in tree growth and supports a concept of community coexistence similar to Hutchinson's n-dimensional hypervolume and not a low-dimensional niche model or neutral model. PMID- 21305019 TI - Neural action fields for optic flow based navigation: a simulation study of the fly lobula plate network. AB - Optic flow based navigation is a fundamental way of visual course control described in many different species including man. In the fly, an essential part of optic flow analysis is performed in the lobula plate, a retinotopic map of motion in the environment. There, the so-called lobula plate tangential cells possess large receptive fields with different preferred directions in different parts of the visual field. Previous studies demonstrated an extensive connectivity between different tangential cells, providing, in principle, the structural basis for their large and complex receptive fields. We present a network simulation of the tangential cells, comprising most of the neurons studied so far (22 on each hemisphere) with all the known connectivity between them. On their dendrite, model neurons receive input from a retinotopic array of Reichardt-type motion detectors. Model neurons exhibit receptive fields much like their natural counterparts, demonstrating that the connectivity between the lobula plate tangential cells indeed can account for their complex receptive field structure. We describe the tuning of a model neuron to particular types of ego-motion (rotation as well as translation around/along a given body axis) by its 'action field'. As we show for model neurons of the vertical system (VS cells), each of them displays a different type of action field, i.e., responds maximally when the fly is rotating around a particular body axis. However, the tuning width of the rotational action fields is relatively broad, comparable to the one with dendritic input only. The additional intra-lobula-plate connectivity mainly reduces their translational action field amplitude, i.e., their sensitivity to translational movements along any body axis of the fly. PMID- 21305021 TI - Successful protein extraction from over-fixed and long-term stored formalin-fixed tissues. AB - One of the major breakthroughs in molecular pathology during the last decade was the successful extraction of full-length proteins from formalin-fixed and paraffin-embedded (FFPE) clinical tissues. However, only limited data are available for the protein extraction efficiency of over-fixed tissues and FFPE blocks that had been stored for more than 15 years in pathology archives. In this study we evaluated the protein extraction efficiency of FFPE tissues which had been formalin-fixed for up to 144 hours and tissue blocks that were stored for 20 years, comparing an established and a new commercial buffer system. Although there is a decrease in protein yield with increasing fixation time, the new buffer system allows a protein recovery of 66% from 144 hours fixed tissues compared to tissues that were fixed for 6 hours. Using the established extraction procedure, less than 50% protein recovery was seen. Similarly, the protein extraction efficiency decreases with longer storage times of the paraffin blocks. Comparing the two buffer systems, we found that 50% more proteins can be extracted from FFPE blocks that were stored for 20 years when the new buffer system is used. Taken together, our data show that the new buffer system is superior compared to the established one. Because tissue fixation times vary in the routine clinical setting and pathology archives contain billions of FFPE tissues blocks, our data are highly relevant for research, diagnosis, and treatment of disease. PMID- 21305022 TI - Identification of novel molecular targets for endometrial cancer using a drill down LC-MS/MS approach with iTRAQ. AB - BACKGROUND: The number of patients with endometrial carcinoma (EmCa) with advanced stage or high histological grade is increasing and prognosis has not improved for over the last decade. There is an urgent need for the discovery of novel molecular targets for diagnosis, prognosis and treatment of EmCa, which will have the potential to improve the clinical strategy and outcome of this disease. METHODOLOGY AND RESULTS: We used a "drill-down" proteomics approach to facilitate the identification of novel molecular targets for diagnosis, prognosis and/or therapeutic intervention for EmCa. Based on peptide ions identified and their retention times in the first LC-MS/MS analysis, an exclusion list was generated for subsequent iterations. A total of 1529 proteins have been identified below the Proteinpilot(r) 5% error threshold from the seven sets of iTRAQ experiments performed. On average, the second iteration added 78% new peptides to those identified after the first run, while the third iteration added 36% additional peptides. Of the 1529 proteins identified, only 40 satisfied our criteria for significant differential expression in EmCa in comparison to normal proliferative tissues. These proteins included metabolic enzymes (pyruvate kinase M2 and lactate dehydrogenase A); calcium binding proteins (S100A6, calcyphosine and calumenin), and proteins involved in regulating inflammation, proliferation and invasion (annexin A1, interleukin enhancer-binding factor 3, alpha-1 antitrypsin, macrophage capping protein and cathepsin B). Network analyses revealed regulation of these molecular targets by c-myc, Her2/neu and TNF alpha, suggesting intervention with these pathways may be a promising strategy for the development of novel molecular targeted therapies for EmCa. CONCLUSIONS: Our analyses revealed the significance of drill-down proteomics approach in combination with iTRAQ to overcome some of the limitations of current proteomics strategies. This study led to the identification of a number of novel molecular targets having therapeutic potential for targeted molecular therapies for endometrial carcinoma. PMID- 21305023 TI - Non-sexual transmission of Trichomonas vaginalis in adolescent girls attending school in Ndola, Zambia. AB - OBJECTIVES: To identify risk factors for trichomoniasis among young women in Ndola, Zambia. METHOD: The study was a cross-sectional study among adolescent girls aged 13-16 years in Ndola, Zambia. Study participants were recruited from schools in selected administrative areas that represented the different socio economic strata in town. Consenting participants were interviewed about their socio-demographic characteristics; sexual behaviour; and hygiene practices. Self administered vaginal swabs were tested for Trichomonas vaginalis. HSV-2 antibodies were determined on serum to validate the self-reported sexual activity. RESULTS: A total of 460 girls participated in the study. The overall prevalence of trichomoniasis was 27.1%, 33.9% among girls who reported that they had ever had sex and 24.7% among virgins. In multivariate analysis the only statistically significant risk factor for trichomoniasis was inconsistent use of soap. For the virgins, none of the risk factors was significantly associated with trichomoniasis, but the association with use of soap (not always versus always) and type of toilet used (pit latrine/bush versus flush toilet) was of borderline significance. CONCLUSION: We found a high prevalence of trichomoniasis in girls in Ndola who reported that they had never had sex. We postulate that the high prevalence of trichomoniasis in virgins in Ndola is due to non-sexual transmission of trichomoniasis via shared bathing water and inconsistent use of soap. PMID- 21305024 TI - Immunisation with recombinant PfEMP1 domains elicits functional rosette inhibiting and phagocytosis-inducing antibodies to Plasmodium falciparum. AB - BACKGROUND: Rosetting is a Plasmodium falciparum virulence factor implicated in the pathogenesis of life-threatening malaria. Rosetting occurs when parasite derived P. falciparum Erythrocyte Membrane Protein One (PfEMP1) on the surface of infected erythrocytes binds to human receptors on uninfected erythrocytes. PfEMP1 is a possible target for a vaccine to induce antibodies to inhibit rosetting and prevent severe malaria. METHODOLOGY/FINDINGS: We examined the vaccine potential of the six extracellular domains of a rosette-mediating PfEMP1 variant (ITvar9/R29var1 from the R29 parasite strain) by immunizing rabbits with recombinant proteins expressed in E. coli. Antibodies raised to each domain were tested for surface fluorescence with live infected erythrocytes, rosette inhibition and phagocytosis-induction. Antibodies to all PfEMP1 domains recognized the surface of live infected erythrocytes down to low concentrations (0.02-1.56 ug/ml of total IgG). Antibodies to all PfEMP1 domains except for the second Duffy-Binding-Like region inhibited rosetting (50% inhibitory concentration 0.04-4 ug/ml) and were able to opsonize and induce phagocytosis of infected erythrocytes at low concentrations (1.56-6.25 ug/ml). Antibodies to the N-terminal region (NTS-DBL1alpha) were the most effective in all assays. All antibodies were specific for the R29 parasite strain, and showed no functional activity against five other rosetting strains. CONCLUSIONS/SIGNIFICANCE: These results are encouraging for vaccine development as they show that potent antibodies can be generated to recombinant PfEMP1 domains that will inhibit rosetting and induce phagocytosis of infected erythrocytes. However, further work is needed on rosetting mechanisms and cross-reactivity in field isolates to define a set of PfEMP1 variants that could induce functional antibodies against a broad range of P. falciparum rosetting parasites. PMID- 21305025 TI - Landscape mapping of functional proteins in insulin signal transduction and insulin resistance: a network-based protein-protein interaction analysis. AB - The type 2 diabetes has increased rapidly in recent years throughout the world. The insulin signal transduction mechanism gets disrupted sometimes and it's known as insulin-resistance. It is one of the primary causes associated with type-2 diabetes. The signaling mechanisms involved several proteins that include 7 major functional proteins such as INS, INSR, IRS1, IRS2, PIK3CA, Akt2, and GLUT4. Using these 7 principal proteins, multiple sequences alignment has been created. The scores between sequences also have been developed. We have constructed a phylogenetic tree and modified it with node and distance. Besides, we have generated sequence logos and ultimately developed the protein-protein interaction network. The small insulin signal transduction protein arrangement shows complex network between the functional proteins. PMID- 21305026 TI - Tartronate semialdehyde reductase defines a novel rate-limiting step in assimilation and bioconversion of glycerol in Ustilago maydis. AB - BACKGROUND: Glycerol is a by-product of biodiesel production. Currently, it has limited applications with low bioconversion efficiency to most metabolites reported. This is partly attributed to the poor knowledge on the glycerol metabolic pathway in bacteria and fungi. METHODOLOGY/PRINCIPAL FINDINGS: We have established a fast screening method for identification of genes that improve glycerol utilization in Ustilago maydis. This was done by comparing the growth rates of T-DNA tagged mutant colonies on solid medium using glycerol as the sole carbon source. We present a detailed characterization of one of the mutants, GUM1, which contains a T-DNA element inserted into the promoter region of UM02592 locus (MIPS Ustilago maydis database, MUMDB), leading to enhanced and constitutive expression of its mRNA. We have demonstrated that um02592 encodes a functional tartronate semialdehyde reductase (Tsr1), which showed dual specificity to cofactors NAD(+) and NADP(+) and strong substrate specificity and enantioselectivity for D-glycerate. Improved glycerol assimilation in GUM1 was associated with elevated expression of tsr1 mRNA and this could be phenocopied by over-expression of the gene. Glycolipid accumulation was reduced by 45.2% in the knockout mutant whereas introduction of an extra copy of tsr1 driven by the glyceraldehyde phosphate dehydrogenase promoter increased it by 40.4%. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that tartronate semialdehyde reductase (TSR) plays an important role in glycerol assimilation in U. maydis and defines a novel target in genetic engineering for improved conversion of glycerol to higher value products. Our results add significant depth to the understanding of the glycerol metabolic pathway in fungi. We have demonstrated, for the first time, a biological role of a eukaryotic TSR. PMID- 21305027 TI - Effect of population heterogenization on the reproducibility of mouse behavior: a multi-laboratory study. AB - In animal experiments, animals, husbandry and test procedures are traditionally standardized to maximize test sensitivity and minimize animal use, assuming that this will also guarantee reproducibility. However, by reducing within-experiment variation, standardization may limit inference to the specific experimental conditions. Indeed, we have recently shown in mice that standardization may generate spurious results in behavioral tests, accounting for poor reproducibility, and that this can be avoided by population heterogenization through systematic variation of experimental conditions. Here, we examined whether a simple form of heterogenization effectively improves reproducibility of test results in a multi-laboratory situation. Each of six laboratories independently ordered 64 female mice of two inbred strains (C57BL/6NCrl, DBA/2NCrl) and examined them for strain differences in five commonly used behavioral tests under two different experimental designs. In the standardized design, experimental conditions were standardized as much as possible in each laboratory, while they were systematically varied with respect to the animals' test age and cage enrichment in the heterogenized design. Although heterogenization tended to improve reproducibility by increasing within experiment variation relative to between-experiment variation, the effect was too weak to account for the large variation between laboratories. However, our findings confirm the potential of systematic heterogenization for improving reproducibility of animal experiments and highlight the need for effective and practicable heterogenization strategies. PMID- 21305028 TI - ReadDepth: a parallel R package for detecting copy number alterations from short sequencing reads. AB - Copy number alterations are important contributors to many genetic diseases, including cancer. We present the readDepth package for R, which can detect these aberrations by measuring the depth of coverage obtained by massively parallel sequencing of the genome. In addition to achieving higher accuracy than existing packages, our tool runs much faster by utilizing multi-core architectures to parallelize the processing of these large data sets. In contrast to other published methods, readDepth does not require the sequencing of a reference sample, and uses a robust statistical model that accounts for overdispersed data. It includes a method for effectively increasing the resolution obtained from low coverage experiments by utilizing breakpoint information from paired end sequencing to do positional refinement. We also demonstrate a method for inferring copy number using reads generated by whole-genome bisulfite sequencing, thus enabling integrative study of epigenomic and copy number alterations. Finally, we apply this tool to two genomes, showing that it performs well on genomes sequenced to both low and high coverage. The readDepth package runs on Linux and MacOSX, is released under the Apache 2.0 license, and is available at http://code.google.com/p/readdepth/. PMID- 21305029 TI - Identification of candidate small-molecule therapeutics to cancer by gene signature perturbation in connectivity mapping. AB - Connectivity mapping is a recently developed technique for discovering the underlying connections between different biological states based on gene expression similarities. The sscMap method has been shown to provide enhanced sensitivity in mapping meaningful connections leading to testable biological hypotheses and in identifying drug candidates with particular pharmacological and/or toxicological properties. Challenges remain, however, as to how to prioritise the large number of discovered connections in an unbiased manner such that the success rate of any following-up investigation can be maximised. We introduce a new concept, gene-signature perturbation, which aims to test whether an identified connection is stable enough against systematic minor changes (perturbation) to the gene-signature. We applied the perturbation method to three independent datasets obtained from the GEO database: acute myeloid leukemia (AML), cervical cancer, and breast cancer treated with letrozole. We demonstrate that the perturbation approach helps to identify meaningful biological connections which suggest the most relevant candidate drugs. In the case of AML, we found that the prevalent compounds were retinoic acids and PPAR activators. For cervical cancer, our results suggested that potential drugs are likely to involve the EGFR pathway; and with the breast cancer dataset, we identified candidates that are involved in prostaglandin inhibition. Thus the gene-signature perturbation approach added real values to the whole connectivity mapping process, allowing for increased specificity in the identification of possible therapeutic candidates. PMID- 21305030 TI - Novel mouse model reveals distinct activity-dependent and -independent contributions to synapse development. AB - The balanced action of both pre- and postsynaptic organizers regulates the formation of neuromuscular junctions (NMJ). The precise mechanisms that control the regional specialization of acetylcholine receptor (AChR) aggregation, guide ingrowing axons and contribute to correct synaptic patterning are unknown. Synaptic activity is of central importance and to understand synaptogenesis, it is necessary to distinguish between activity-dependent and activity-independent processes. By engineering a mutated fetal AChR subunit, we used homologous recombination to develop a mouse line that expresses AChR with massively reduced open probability during embryonic development. Through histological and immunochemical methods as well as electrophysiological techniques, we observed that endplate anatomy and distribution are severely aberrant and innervation patterns are completely disrupted. Nonetheless, in the absence of activity AChRs form postsynaptic specializations attracting motor axons and permitting generation of multiple nerve/muscle contacts on individual fibers. This process is not restricted to a specialized central zone of the diaphragm and proceeds throughout embryonic development. Phenotypes can be attributed to separate activity-dependent and -independent pathways. The correct patterning of synaptic connections, prevention of multiple contacts and control of nerve growth require AChR-mediated activity. In contrast, myotube survival and acetylcholine-mediated dispersal of AChRs are maintained even in the absence of AChR-mediated activity. Because mouse models in which acetylcholine is entirely absent do not display similar effects, we conclude that acetylcholine binding to the AChR initiates activity-dependent and activity-independent pathways whereby the AChR modulates formation of the NMJ. PMID- 21305031 TI - IS-linked movement of a restriction-modification system. AB - Potential mobility of restriction-modification systems has been suggested by evolutionary/bioinformatic analysis of prokaryotic genomes. Here we demonstrate in vivo movement of a restriction-modification system within a genome under a laboratory condition. After blocking replication of a temperature-sensitive plasmid carrying a PaeR7I restriction-modification system in Escherichia coli cells, the plasmid was found integrated into the chromosome of the surviving cells. Sequence analysis revealed that, in the majority of products, the restriction-modification system was linked to chromosomal insertion sequences (ISs). Three types of products were: (I) apparent co-integration of the plasmid and the chromosome at a chromosomal IS1 or IS5 copy (24/28 analyzed); (II) de novo insertion of IS1 with the entire plasmid except for a 1-3 bp terminal deletion (2/28); and (III) reciprocal crossing-over between the plasmid and the chromosome involving 1-3 bp of sequence identity (2/28). An R-negative mutation apparently decreased the efficiency of successful integration by two orders of magnitude. Reconstruction experiments demonstrated that the restriction dependence was mainly due to selection against cells without proper integration: their growth was inhibited by the restriction enzyme action. These results demonstrate collaboration of a mobile element and a restriction-modification system for successful joint migration. This collaboration may have promoted the spread and, therefore, the long-term persistence of these complexes and restriction-modification systems in a wide range of prokaryotes. PMID- 21305032 TI - Bifunctional avidin with covalently modifiable ligand binding site. AB - The extensive use of avidin and streptavidin in life sciences originates from the extraordinary tight biotin-binding affinity of these tetrameric proteins. Numerous studies have been performed to modify the biotin-binding affinity of (strept)avidin to improve the existing applications. Even so, (strept)avidin greatly favours its natural ligand, biotin. Here we engineered the biotin-binding pocket of avidin with a single point mutation S16C and thus introduced a chemically active thiol group, which could be covalently coupled with thiol reactive molecules. This approach was applied to the previously reported bivalent dual chain avidin by modifying one binding site while preserving the other one intact. Maleimide was then coupled to the modified binding site resulting in a decrease in biotin affinity. Furthermore, we showed that this thiol could be covalently coupled to other maleimide derivatives, for instance fluorescent labels, allowing intratetrameric FRET. The bifunctional avidins described here provide improved and novel tools for applications such as the biofunctionalization of surfaces. PMID- 21305034 TI - Clutch frequency affects the offspring size-number trade-off in lizards. AB - BACKGROUND: Studies of lizards have shown that offspring size cannot be altered by manipulating clutch size in species with a high clutch frequency. This raises a question of whether clutch frequency has a key role in influencing the offspring size-number trade-off in lizards. METHODOLOGY/PRINCIPAL FINDINGS: To test the hypothesis that females reproducing more frequently are less likely to tradeoff offspring size against offspring number, we applied the follicle ablation technique to female Eremias argus (Lacertidae) from Handan (HD) and Gonghe (GH), the two populations that differ in clutch frequency. Follicle ablation resulted in enlargement of egg size in GH females, but not in HD females. GH females switched from producing a larger number of smaller eggs in the first clutch to a smaller number of larger eggs in the second clutch; HD females showed a similar pattern of seasonal shifts in egg size, but kept clutch size constant between the first two clutches. Thus, the egg size-number trade-off was evident in GH females, but not in HD females. CONCLUSIONS/SIGNIFICANCE: As HD females (mean = 3.1 clutches per year) reproduce more frequently than do GH females (mean = 1.6 clutches per year), our data therefore validate the hypothesis tested. Our data also provide an inference that maximization of maternal fitness could be achieved in females by diverting a large enough, rather than a higher-than-usual, fraction of the available energy to individual offspring in a given reproductive episode. PMID- 21305033 TI - The influence of chronic cerebral hypoperfusion on cognitive function and amyloid beta metabolism in APP overexpressing mice. AB - BACKGROUND AND PURPOSE: Cognitive impairment resulting from cerebrovascular insufficiency has been termed vascular cognitive impairment, and is generally accepted to be distinct from Alzheimer's disease resulting from a neurodegenerative process. However, it is clear that this simple dichotomy may need revision in light of the apparent occurrence of several shared features between Alzheimer's disease and vascular cognitive impairment. Nevertheless, it still remains largely unknown whether the burden of vascular- and Alzheimer-type neuropathology are independent or interdependent. Therefore, we investigated whether chronic cerebral hypoperfusion influences cognitive ability or amyloid beta deposition in amyloid precursor protein (APP) overexpressing transgenic mice. METHODS: Two months old mice overexpressing a mutant form of the human APP bearing both the Swedish and Indiana mutations (APP(Sw/Ind)-Tg mice), or their wild-type littermates, were subjected to chronic cerebral hypoperfusion with bilateral common carotid artery stenosis (BCAS) using microcoils or sham operation. Barnes maze test performance and histopathological findings were analyzed at eight months old by 2 * 2 factorial experimental designs with four groups. RESULTS: BCAS-operated APP(Sw/Ind)-Tg mice showed significantly impaired learning ability compared to the other three groups of mice. Two-way repeated measures analysis of variance showed a synergistic interaction between the APP genotype and BCAS operation in inducing learning impairment. The cognitive performances were significantly correlated with the neuronal densities. BCAS significantly reduced the density of Nissl-stained neurons and silver-stained cored plaques in the hippocampus of APP(Sw/Ind)-Tg mice but increased the amount of filter-trap amyloid beta in the extracellular-enriched soluble brain fraction, compared to those from sham operated mice. CONCLUSIONS: The results suggest interaction between chronic cerebral hypoperfusion and APP(Sw/Ind) overexpression in cognitive decline in mice through enhanced neuronal loss and altered amyloid beta metabolism. PMID- 21305035 TI - Parallel expansions of Sox transcription factor group B predating the diversifications of the arthropods and jawed vertebrates. AB - Group B of the Sox transcription factor family is crucial in embryo development in the insects and vertebrates. Sox group B, unlike the other Sox groups, has an unusually enlarged functional repertoire in insects, but the timing and mechanism of the expansion of this group were unclear. We collected and analyzed data for Sox group B from 36 species of 12 phyla representing the major metazoan clades, with an emphasis on arthropods, to reconstruct the evolutionary history of SoxB in bilaterians and to date the expansion of Sox group B in insects. We found that the genome of the bilaterian last common ancestor probably contained one SoxB1 and one SoxB2 gene only and that tandem duplications of SoxB2 occurred before the arthropod diversification but after the arthropod-nematode divergence, resulting in the basal repertoire of Sox group B in diverse arthropod lineages. The arthropod Sox group B repertoire expanded differently from the vertebrate repertoire, which resulted from genome duplications. The parallel increases in the Sox group B repertoires of the arthropods and vertebrates are consistent with the parallel increases in the complexity and diversification of these two important organismal groups. PMID- 21305036 TI - Alternative oxidase dependent respiration leads to an increased mitochondrial content in two long-lived mutants of the aging model Podospora anserina. AB - The retrograde response constitutes an important signalling pathway from mitochondria to the nucleus which induces several genes to allow compensation of mitochondrial impairments. In the filamentous ascomycete Podospora anserina, an example for such a response is the induction of a nuclear-encoded and iron dependent alternative oxidase (AOX) occurring when cytochrome-c oxidase (COX) dependent respiration is affected. Several long-lived mutants are known which predominantly or exclusively respire via AOX. Here we show that two AOX-utilising mutants, grisea and PaCox17::ble, are able to compensate partially for lowered OXPHOS efficiency resulting from AOX-dependent respiration by increasing mitochondrial content. At the physiological level this is demonstrated by an elevated oxygen consumption and increased heat production. However, in the two mutants, ATP levels do not reach WT levels. Interestingly, mutant PaCox17::ble is characterized by a highly increased release of the reactive oxygen species (ROS) hydrogen peroxide. Both grisea and PaCox17::ble contain elevated levels of mitochondrial proteins involved in quality control, i. e. LON protease and the molecular chaperone HSP60. Taken together, our work demonstrates that AOX dependent respiration in two mutants of the ageing model P. anserina is linked to a novel mechanism involved in the retrograde response pathway, mitochondrial biogenesis, which might also play an important role for cellular maintenance in other organisms. PMID- 21305038 TI - Setting research priorities to reduce almost one million deaths from birth asphyxia by 2015. PMID- 21305039 TI - Hippocampal representation of touch-guided behavior in rats: persistent and independent traces of stimulus and reward location. AB - Understanding the mechanisms by which sensory experiences are stored remains a compelling challenge for neuroscience. Previous work has described how the activity of neurons in the sensory cortex allows rats to discriminate the physical features of an object contacted with their whiskers. But to date there is no evidence about how neurons represent the behavioural significance of tactile stimuli, or how they are encoded in memory. To investigate these issues, we recorded single-unit firing and local field potentials from the CA1 region of hippocampus while rats performed a task in which tactile stimuli specified reward location. On each trial the rat touched a textured plate with its whiskers, and then turned towards the Left or Right water spout. Two textures were associated with each reward location. To determine the influence of the rat's position on sensory coding, we placed it on a second platform in the same room where it performed the identical texture discrimination task. Over 25 percent of the sampled neurons encoded texture identity--their firing differed for two stimuli associated with the same reward location--and over 50 percent of neurons encoded the reward location with which the stimuli were associated. The neuronal population carried texture and reward location signals continuously, from the moment of stimulus contact until the end of reward collection. The set of neurons discriminating between one texture pair was found to be independent of, and partially overlapping, the set of neurons encoding the discrimination between a different texture pair. In a given neuron, the presence of a tactile signal was uncorrelated with the presence, magnitude, or timing of reward location signals. These experiments indicate that neurons in CA1 form a texture representation independently of the action the stimulus is associated with and retain the stimulus representation through reward collection. PMID- 21305040 TI - Expression profiling of major histocompatibility and natural killer complex genes reveals candidates for controlling risk of graft versus host disease. AB - BACKGROUND: The major histocompatibility complex (MHC) is the most important genomic region that contributes to the risk of graft versus host disease (GVHD) after haematopoietic stem cell transplantation. Matching of MHC class I and II genes is essential for the success of transplantation. However, the MHC contains additional genes that also contribute to the risk of developing acute GVHD. It is difficult to identify these genes by genetic association studies alone due to linkage disequilibrium in this region. Therefore, we aimed to identify MHC genes and other genes involved in the pathophysiology of GVHD by mRNA expression profiling. METHODOLOGY/PRINCIPAL FINDINGS: To reduce the complexity of the task, we used genetically well-defined rat inbred strains and a rat skin explant assay, an in-vitro-model of the graft versus host reaction (GVHR), to analyze the expression of MHC, natural killer complex (NKC), and other genes in cutaneous GVHR. We observed a statistically significant and strong up or down regulation of 11 MHC, 6 NKC, and 168 genes encoded in other genomic regions, i.e. 4.9%, 14.0%, and 2.6% of the tested genes respectively. The regulation of 7 selected MHC and 3 NKC genes was confirmed by quantitative real-time PCR and in independent skin explant assays. In addition, similar regulations of most of the selected genes were observed in GVHD-affected skin lesions of transplanted rats and in human skin explant assays. CONCLUSIONS/SIGNIFICANCE: We identified rat and human MHC and NKC genes that are regulated during GVHR in skin explant assays and could therefore serve as biomarkers for GVHD. Several of the respective human genes, including HLA-DMB, C2, AIF1, SPR1, UBD, and OLR1, are polymorphic. These candidates may therefore contribute to the genetic risk of GVHD in patients. PMID- 21305042 TI - Large scale loss of data in low-diversity illumina sequencing libraries can be recovered by deferred cluster calling. AB - Massively parallel DNA sequencing is capable of sequencing tens of millions of DNA fragments at the same time. However, sequence bias in the initial cycles, which are used to determine the coordinates of individual clusters, causes a loss of fidelity in cluster identification on Illumina Genome Analysers. This can result in a significant reduction in the numbers of clusters that can be analysed. Such low sample diversity is an intrinsic problem of sequencing libraries that are generated by restriction enzyme digestion, such as e4C-seq or reduced-representation libraries. Similarly, this problem can also arise through the combined sequencing of barcoded, multiplexed libraries. We describe a procedure to defer the mapping of cluster coordinates until low-diversity sequences have been passed. This simple procedure can recover substantial amounts of next generation sequencing data that would otherwise be lost. PMID- 21305041 TI - A comparative transcriptomic analysis of uveal melanoma and normal uveal melanocyte. AB - BACKGROUND: Uveal melanoma is the most common primary intraocular tumor in adults in western countries. It is associated with very severe visual morbidity and may lead to distant metastases even after successful treatment of the primary tumor. In order to gain better insight into molecular mechanisms related to tumorigenesis and metastasis of uveal melanoma, we used next-generation sequencing technology (SOLiD, Life Technologies) to acquire global transcriptome alteration between posterior uveal melanoma cells and normal uveal melanocyte. RESULTS: From mRNAs of the cultured uveal melanoma cells and normal uveal melanocytes, we annotated more than 3.7 * 10(7) and 2.7 * 10(7) sequencing tags based on human Ensembl databases, respectively. For detailed analysis, we chose 5155 well-annotated genes mainly involved in the MAPK signaling pathway, cell cycle, cell adhesion junction, apoptosis, and P53 signaling pathways as well as melanogenesis. In an effort to confirm the authenticity of our sequencing results, we validated twenty-one identically differentially expressed genes by using quantitative real time PCR from cultured cell lines of other posterior uveal melanoma cells and normal uveal melanocytes. CONCLUSION: We have identified a large number of potentially interesting genes for biological investigation of uveal melanoma. The expression profiling also provides useful resources for other functional genomic and transcriptome studies. These 21 potential genes could discriminate between uveal melanoma cells and normal uveal melanocyte, which may be indicative of tumorigenesis process. Our results further suggest that high throughput sequencing technology provides a powerful tool to study mechanisms of tumogenesis in the molecular level. PMID- 21305043 TI - Dynein/Dynactin-mediated transport of kinetochore components off kinetochores and onto spindle poles induced by nordihydroguaiaretic acid. AB - The mitotic checkpoint functions to ensure accurate chromosome segregation by regulating the progression from metaphase to anaphase. Once the checkpoint has been satisfied, it is inactivated in order to allow the cell to proceed into anaphase and complete the cell cycle. The minus end-directed microtubule motor dynein/dynactin has been implicated in the silencing of the mitotic checkpoint by "stripping" checkpoint proteins off kinetochores. A recent study suggested that Nordihydroguaiaretic acid (NDGA) stimulates dynein/dynactin-mediated transport of its cargo including ZW10 (Zeste White 10). We analyzed the effects of NDGA on dynein/dynactin dependent transport of the RZZ (Zeste White 10, Roughdeal, Zwilch) complex as well as other kinetochore components from kinetochores to spindle poles. Through this approach we have catalogued several kinetochore and centromere components as dynein/dynactin cargo. These include hZW10, hZwilch, hROD, hSpindly, hMad1, hMad2, hCENP-E, hCdc27, cyclin-B and hMps1. Furthermore, we found that treatment with NDGA induced a robust accumulation and complete stabilization of hZW10 at spindle poles. This finding suggests that NDGA may not induce dynein/dynactin transport but rather interfere with cargo release. Lastly, we determined that NDGA induced accumulation of checkpoint proteins at the poles requires dynein/dynactin-mediated transport, hZW10 kinetochore localization and kinetochore-microtubule attachments but not tension or Aurora B kinase activity. PMID- 21305044 TI - Novel analysis of oceanic surface water metagenomes suggests importance of polyphosphate metabolism in oligotrophic environments. AB - Polyphosphate is a ubiquitous linear homopolymer of phosphate residues linked by high-energy bonds similar to those found in ATP. It has been associated with many processes including pathogenicity, DNA uptake and multiple stress responses across all domains. Bacteria have also been shown to use polyphosphate as a way to store phosphate when transferred from phosphate-limited to phosphate-rich media--a process exploited in wastewater treatment and other environmental contaminant remediation. Despite this, there has, to date, been little research into the role of polyphosphate in the survival of marine bacterioplankton in oligotrophic environments. The three main proteins involved in polyphosphate metabolism, Ppk1, Ppk2 and Ppx are multi-domain and have differential inter domain and inter-gene conservation, making unbiased analysis of relative abundance in metagenomic datasets difficult. This paper describes the development of a novel Isofunctional Homolog Annotation Tool (IHAT) to detect homologs of genes with a broad range of conservation without bias of traditional expect-value cutoffs. IHAT analysis of the Global Ocean Sampling (GOS) dataset revealed that genes associated with polyphosphate metabolism are more abundant in environments where available phosphate is limited, suggesting an important role for polyphosphate metabolism in marine oligotrophs. PMID- 21305045 TI - Superior neutralizing antibody response and protection in mice vaccinated with heterologous DNA prime and virus like particle boost against HPAI H5N1 virus. AB - BACKGROUND: Although DNA plasmid and virus-like particle (VLP) vaccines have been individually tested against highly pathogenic avian influenza (HPAI) H5N1 viruses, the combination of both vaccines into a heterologous prime-boost strategy against HPAI H5N1 viruses has not been reported before. METHODOLOGY/PRINCIPAL FINDINGS: We constructed DNA plasmid encoding H5HA (A/Shenzhen/406H/06, subclade 2.3.4) and generated VLP expressing the same H5HA and N1NA. We then compared neutralizing antibody responses and immune protection elicited with heterologous DNA-VLP, homologous DNA-DNA and VLP-VLP prime-boost strategies against HPAI H5N1 viruses in mice. We demonstrate that DNA-VLP elicits the highest neutralizing antibody titers among the three prime-boost strategies, whereas DNA-DNA elicits higher neutralizing antibody titers than VLP-VLP. We show that although all three prime-boost strategies protect mice from death caused by 10 MLD(50) of homologous and heterologous H5N1 challenge, only DNA-VLP and DNA DNA protect mice from infection as manifested by no weight loss and no lung pathology. In addition, we show that although DNA-VLP and DNA-DNA protect mice from death caused by 1,000 MLD(50) of homologous H5N1 challenge, only DNA-VLP protects mice from infection. Moreover, we show that after 1,000 MLD(50) of heterologous H5N1 challenge, while all mice in PBS, VLP-VLP and DNA-DNA died, 3 of 6 mice in DNA-VLP actually survived. Finally, we show that DNA-VLP completely protects mice from infection after 1,000 MLD(50) of homologous H5N1 challenge even when the challenge was administrated at 60 days post the boost. CONCLUSIONS/SIGNIFICANCE: These results provide strong support for clinical evaluation of heterologous DNA-VLP prime-boost strategy as a public health intervention against a possible H5N1 pandemic. PMID- 21305046 TI - Orally administrated cinnamon extract reduces beta-amyloid oligomerization and corrects cognitive impairment in Alzheimer's disease animal models. AB - An increasing body of evidence indicates that accumulation of soluble oligomeric assemblies of beta-amyloid polypeptide (Abeta) play a key role in Alzheimer's disease (AD) pathology. Specifically, 56 kDa oligomeric species were shown to be correlated with impaired cognitive function in AD model mice. Several reports have documented the inhibition of Abeta plaque formation by compounds from natural sources. Yet, evidence for the ability of common edible elements to modulate Abeta oligomerization remains an unmet challenge. Here we identify a natural substance, based on cinnamon extract (CEppt), which markedly inhibits the formation of toxic Abeta oligomers and prevents the toxicity of Abeta on neuronal PC12 cells. When administered to an AD fly model, CEppt rectified their reduced longevity, fully recovered their locomotion defects and totally abolished tetrameric species of Abeta in their brain. Furthermore, oral administration of CEppt to an aggressive AD transgenic mice model led to marked decrease in 56 kDa Abeta oligomers, reduction of plaques and improvement in cognitive behavior. Our results present a novel prophylactic approach for inhibition of toxic oligomeric Abeta species formation in AD through the utilization of a compound that is currently in use in human diet. PMID- 21305047 TI - Variation in LPA is associated with Lp(a) levels in three populations from the Third National Health and Nutrition Examination Survey. AB - The distribution of lipoprotein(a) [Lp(a)] levels can differ dramatically across diverse racial/ethnic populations. The extent to which genetic variation in LPA can explain these differences is not fully understood. To explore this, 19 LPA tagSNPs were genotyped in 7,159 participants from the Third National Health and Nutrition Examination Survey (NHANES III). NHANES III is a diverse population based survey with DNA samples linked to hundreds of quantitative traits, including serum Lp(a). Tests of association between LPA variants and transformed Lp(a) levels were performed across the three different NHANES subpopulations (non Hispanic whites, non-Hispanic blacks, and Mexican Americans). At a significance threshold of p<0.0001, 15 of the 19 SNPs tested were strongly associated with Lp(a) levels in at least one subpopulation, six in at least two subpopulations, and none in all three subpopulations. In non-Hispanic whites, three variants were associated with Lp(a) levels, including previously known rs6919246 (p = 1.18 * 10(-30)). Additionally, 12 and 6 variants had significant associations in non Hispanic blacks and Mexican Americans, respectively. The additive effects of these associated alleles explained up to 11% of the variance observed for Lp(a) levels in the different racial/ethnic populations. The findings reported here replicate previous candidate gene and genome-wide association studies for Lp(a) levels in European-descent populations and extend these findings to other populations. While we demonstrate that LPA is an important contributor to Lp(a) levels regardless of race/ethnicity, the lack of generalization of associations across all subpopulations suggests that specific LPA variants may be contributing to the observed Lp(a) between-population variance. PMID- 21305048 TI - Cell cycle control and DNA damage response of conditionally immortalized urothelial cells. AB - BACKGROUND: Children with complex urogenital anomalies often require bladder reconstruction. Gastrointestinal tissues used in bladder augmentations exhibit a greatly increased risk of malignancy, and the bladder microenvironment may play a role in this carcinogenesis. Investigating the influences of the bladder microenvironment on gastrointestinal and urothelial cell cycle checkpoint activation and DNA damage response has been limited by the lack of an appropriate well-differentiated urothelial cell line system. METHODOLOGY/PRINCIPAL FINDINGS: To meet this need, we have developed a well-differentiated conditionally immortalized urothelial cell line by isolating it from the H-2K(b)-tsA58 transgenic mouse. These cells express a thermosensitive SV40 large T antigen that can be deactivated by adjustment of cell culture conditions, allowing the cell line to regain normal control of the cell cycle. The isolated urothelial cell line demonstrates a polygonal, dome-shaped morphology, expresses cytokeratin 18, and exhibits well-developed tight junctions. Adaptation of the urothelial cell line to hyperosmolal culture conditions induces expression of both cytokeratin 20 and uroplakin II, markers of a superficial urothelial cell or "umbrella cell." This cell line can be maintained indefinitely in culture under permissive conditions but when cultured under non-permissive conditions, large T antigen expression is reduced substantially, leading to increased p53 activity and reduced cellular proliferation. CONCLUSIONS/SIGNIFICANCE: This new model of urothelial cells, along with gastrointestinal cell lines previously derived from the H-2K(b)-tsA58 transgenic mouse, will be useful for studying the potential mechanisms of carcinogenesis of the augmented bladder. PMID- 21305049 TI - HPRT deficiency coordinately dysregulates canonical Wnt and presenilin-1 signaling: a neuro-developmental regulatory role for a housekeeping gene? AB - We have used microarray-based methods of global gene expression together with quantitative PCR and Western blot analysis to identify dysregulation of genes and aberrant cellular processes in human fibroblasts and in SH-SY5Y neuroblastoma cells made HPRT-deficient by transduction with a retrovirus stably expressing an shRNA targeted against HPRT. Analysis of the microarray expression data by Gene ontology (GO) and Gene Set Enrichment Analysis (GSEA) as well as significant pathway analysis by GeneSpring GX10 and Panther Classification System reveal that HPRT deficiency is accompanied by aberrations in a variety of pathways known to regulate neurogenesis or to be implicated in neurodegenerative disease, including the canonical Wnt/beta-catenin and the Alzheimer's disease/presenilin signaling pathways. Dysregulation of the Wnt/beta-catenin pathway is confirmed by Western blot demonstration of cytosolic sequestration of beta-catenin during in vitro differentiation of the SH-SY5Y cells toward the neuronal phenotype. We also demonstrate that two key transcription factor genes known to be regulated by Wnt signaling and to be vital for the generation and function of dopaminergic neurons; i.e., Lmx1a and Engrailed 1, are down-regulated in the HPRT knockdown SH SY5Y cells. In addition to the Wnt signaling aberration, we found that expression of presenilin-1 shows severely aberrant expression in HPRT-deficient SH-SY5Y cells, reflected by marked deficiency of the 23 kDa C-terminal fragment of presenilin-1 in knockdown cells. Western blot analysis of primary fibroblast cultures from two LND patients also shows dysregulated presenilin-1 expression, including aberrant proteolytic processing of presenilin-1. These demonstrations of dysregulated Wnt signaling and presenilin-1 expression together with impaired expression of dopaminergic transcription factors reveal broad pleitropic neuro regulatory defects played by HPRT expression and suggest new directions for investigating mechanisms of aberrant neurogenesis and neuropathology in LND and potential new targets for restoration of effective signaling in this neuro developmental defect. PMID- 21305050 TI - Characterizing ligand-gated ion channel receptors with genetically encoded Ca2++ sensors. AB - We present a cell based system and experimental approach to characterize agonist and antagonist selectivity for ligand-gated ion channels (LGIC) by developing sensor cells stably expressing a Ca(2+) permeable LGIC and a genetically encoded Forster (or fluorescence) resonance energy transfer (FRET)-based calcium sensor. In particular, we describe separate lines with human alpha7 and human alpha4beta2 nicotinic acetylcholine receptors, mouse 5-HT(3A) serotonin receptors and a chimera of human alpha7/mouse 5-HT(3A) receptors. Complete concentration-response curves for agonists and Schild plots of antagonists were generated from these sensors and the results validate known pharmacology of the receptors tested. Concentration-response relations can be generated from either the initial rate or maximal amplitudes of FRET-signal. Although assaying at a medium throughput level, this pharmacological fluorescence detection technique employs a clonal line for stability and has versatility for screening laboratory generated congeners as agonists or antagonists on multiple subtypes of ligand-gated ion channels. The clonal sensor lines are also compatible with in vivo usage to measure indirectly receptor activation by endogenous neurotransmitters. PMID- 21305051 TI - MicroRNAs profiling in murine models of acute and chronic asthma: a relationship with mRNAs targets. AB - BACKGROUND: miRNAs are now recognized as key regulator elements in gene expression. Although they have been associated with a number of human diseases, their implication in acute and chronic asthma and their association with lung remodelling have never been thoroughly investigated. METHODOLOGY/PRINCIPAL FINDINGS: In order to establish a miRNAs expression profile in lung tissue, mice were sensitized and challenged with ovalbumin mimicking acute, intermediate and chronic human asthma. Levels of lung miRNAs were profiled by microarray and in silico analyses were performed to identify potential mRNA targets and to point out signalling pathways and biological processes regulated by miRNA-dependent mechanisms. Fifty-eight, 66 and 75 miRNAs were found to be significantly modulated at short-, intermediate- and long-term challenge, respectively. Inverse correlation with the expression of potential mRNA targets identified mmu-miR 146b, -223, -29b, -29c, -483, -574-5p, -672 and -690 as the best candidates for an active implication in asthma pathogenesis. A functional validation assay was performed by cotransfecting in human lung fibroblasts (WI26) synthetic miRNAs and engineered expression constructs containing the coding sequence of luciferase upstream of the 3'UTR of various potential mRNA targets. The bioinformatics analysis identified miRNA-linked regulation of several signalling pathways, as matrix metalloproteinases, inflammatory response and TGF-beta signalling, and biological processes, including apoptosis and inflammation. CONCLUSIONS/SIGNIFICANCE: This study highlights that specific miRNAs are likely to be involved in asthma disease and could represent a valuable resource both for biological makers identification and for unveiling mechanisms underlying the pathogenesis of asthma. PMID- 21305052 TI - Nr4a1-eGFP is a marker of striosome-matrix architecture, development and activity in the extended striatum. AB - Transgenic mice expressing eGFP under population specific promoters are widely used in neuroscience to identify specific subsets of neurons in situ and as sensors of neuronal activity in vivo. Mice expressing eGFP from a bacterial artificial chromosome under the Nr4a1 promoter have high expression within the basal ganglia, particularly within the striosome compartments and striatal-like regions of the extended amygdala (bed nucleus of the stria terminalis, striatal fundus, central amygdaloid nucleus and intercalated cells). Grossly, eGFP expression is inverse to the matrix marker calbindin 28K and overlaps with mu opioid receptor immunoreactivity in the striatum. This pattern of expression is similar to Drd1, but not Drd2, dopamine receptor driven eGFP expression in structures targeted by medium spiny neuron afferents. Striosomal expression is strong developmentally where Nr4a1-eGFP expression overlaps with Drd1, TrkB, tyrosine hydroxylase and phospho-ERK, but not phospho-CREB, immunoreactivity in "dopamine islands". Exposure of adolescent mice to methylphenidate resulted in an increase in eGFP in both compartments in the dorsolateral striatum but eGFP expression remained brighter in the striosomes. To address the role of activity in Nr4a1-eGFP expression, primary striatal cultures were prepared from neonatal mice and treated with forskolin, BDNF, SKF-83822 or high extracellular potassium and eGFP was measured fluorometrically in lysates. eGFP was induced in both neurons and contaminating glia in response to forskolin but SKF-83822, brain derived neurotrophic factor and depolarization increased eGFP in neuronal-like cells selectively. High levels of eGFP were primarily associated with Drd1+ neurons in vitro detected by immunofluorescence; however ~15% of the brightly expressing cells contained punctate met-enkephalin immunoreactivity. The Nr4a1 GFP mouse strain will be a useful model for examining the connectivity, physiology, activity and development of the striosome system. PMID- 21305053 TI - p38 MAPK-Mediated Bmi-1 down-regulation and defective proliferation in ATM deficient neural stem cells can be restored by Akt activation. AB - A-T (ataxia telangiectasia) is a genetic disease caused by a mutation in the Atm (A-T mutated) gene that leads to neurodegeneration. Despite an increase in the numbers of studies in this area in recent years, the mechanisms underlying neurodegeneration in human A-T are still poorly understood. Previous studies demonstrated that neural stem cells (NSCs) isolated from the subventricular zone (SVZ) of Atm(-/-) mouse brains show defective self-renewal and proliferation, which is accompanied by activation of chronic p38 mitogen-activated protein kinase (MAPK) and a lower level of the polycomb protein Bmi-1. However, the mechanism underlying Bmi-1 down-regulation and its relevance to defective proliferation in Atm(-/-) NSCs remained unclear. Here, we show that over expression of Bmi-1 increases self-renewal and proliferation of Atm(-/-) NSCs to normal, indicating that defective proliferation in Atm(-/-) NSCs is a consequence of down-regulation of Bmi-1. We also demonstrate that epidermal growth factor (EGF)-induced Akt phosphorylation renders Bmi-1 resistant to the proteasomal degradation, leading to its stabilization and accumulation in the nucleus. However, inhibition of the Akt-dependent Bmi-1 stabilizing process by p38 MAPK signaling reduces the levels of Bmi-1. Treatment of the Atm(-/-) NSCs with a specific p38 MAPK inhibitor SB203580 extended Bmi-1 posttranscriptional turnover and H2A ubiquitination in Atm(-/-) NSCs. Our observations demonstrate the molecular basis underlying the impairment of self-renewal and proliferation in Atm(-/-) NSCs through the p38 MAPK-Akt-Bmi-1-p21 signaling pathway. PMID- 21305054 TI - Endocannabinoids generated by Ca2+ or by metabotropic glutamate receptors appear to arise from different pools of diacylglycerol lipase. AB - The identity and subcellular sources of endocannabinoids (eCBs) will shape their ability to affect synaptic transmission and, ultimately, behavior. Recent discoveries support the conclusion that 2-arachidonoyl glycerol, 2-AG, is the major signaling eCB, however, some important issues remain open. 2-AG can be synthesized by a mechanism that is strictly Ca(2+)-dependent, and another that is initiated by G-protein coupled receptors (GPCRs) and facilitated by Ca(2+). An important question is whether or not the 2-AG in these cases is synthesized by the same pool of diacylglycerol lipase alpha (DAGLalpha). Using whole-cell voltage-clamp techniques in CA1 pyramidal cells in acute in vitro rat hippocampal slices, we investigated two mechanistically distinct eCB-mediated responses to address this issue. We now report that pharmacological inhibitors of DGLalpha have quantitatively different effects on eCB-mediated responses triggered by different stimuli, suggesting that functional, and perhaps physical, distinctions among pools of DAGLalpha exist. PMID- 21305055 TI - Detection of dynamic spatiotemporal response to periodic chemical stimulation in a Xenopus embryonic tissue. AB - Embryonic development is guided by a complex and integrated set of stimuli that results in collective system-wide organization that is both time and space regulated. These regulatory interactions result in the emergence of highly functional units, which are correlated to frequency-modulated stimulation profiles. We have determined the dynamic response of vertebrate embryonic tissues to highly controlled, time-varying localized chemical stimulation using a microfluidic system with feedback control. Our approach has enabled localized spatiotemporal manipulation of the steroid hormone dexamethasone (DEX) in Animal Cap (AC) tissues isolated from gastrulating Xenopus embryos. Using this approach we investigated cell-scale responses to precisely controlled stimulation by tracking the redistribution of a GFP-tagged DEX-reporter constructed from the human glucocorticoid receptor (GR). We exposed defined regions of a single AC explant to different stimulation conditions--continuous stimulation, periodic stimulation, and no stimulation. We observed collective behavior of the GR transport into the nucleus was first-order. Furthermore, the dynamic response was well-modeled by a first-order differential equation with a single time derivative. The model predicted that responses to periodic stimulations closely matched the results of the frequency-based experiments. We find that stimulation with localized bursts versus continuous stimulation can result in highly distinct responses. This finding is critical as controlled space and time exposure to growth factors is a hallmark of complex processes in embryonic development. These complex responses to cellular signaling and transport machinery were similar to emergent behaviors in other complex systems, suggesting that even within a complex embryonic tissue, the overall system can converge toward a predictive first-order response. PMID- 21305056 TI - Loss of guanylyl cyclase C (GCC) signaling leads to dysfunctional intestinal barrier. AB - BACKGROUND: Guanylyl Cyclase C (GCC) signaling via uroguanylin (UGN) and guanylin activation is a critical mediator of intestinal fluid homeostasis, intestinal cell proliferation/apoptosis, and tumorigenesis. As a mechanism for some of these effects, we hypothesized that GCC signaling mediates regulation of intestinal barrier function. METHODOLOGY/PRINCIPAL FINDINGS: Paracellular permeability of intestinal segments was assessed in wild type (WT) and GCC deficient (GCC-/-) mice with and without lipopolysaccharide (LPS) challenge, as well as in UGN deficient (UGN-/-) mice. IFNgamma and myosin light chain kinase (MLCK) levels were determined by real time PCR. Expression of tight junction proteins (TJPs), phosphorylation of myosin II regulatory light chain (MLC), and STAT1 activation were examined in intestinal epithelial cells (IECs) and intestinal mucosa. The permeability of Caco-2 and HT-29 IEC monolayers, grown on Transwell filters was determined in the absence and presence of GCC RNA interference (RNAi). We found that intestinal permeability was increased in GCC-/- and UGN-/- mice compared to WT, accompanied by increased IFNgamma levels, MLCK and STAT1 activation in IECs. LPS challenge promotes greater IFNgamma and STAT1 activation in IECs of GCC-/- mice compared to WT mice. Claudin-2 and JAM-A expression were reduced in GCC deficient intestine; the level of phosphorylated MLC in IECs was significantly increased in GCC-/- and UGN-/- mice compared to WT. GCC knockdown induced MLC phosphorylation, increased permeability in IEC monolayers under basal conditions, and enhanced TNFalpha and IFNgamma-induced monolayer hyperpermeability. CONCLUSIONS/SIGNIFICANCE: GCC signaling plays a protective role in the integrity of the intestinal mucosal barrier by regulating MLCK activation and TJ disassembly. GCC signaling activation may therefore represent a novel mechanism in maintaining the small bowel barrier in response to injury. PMID- 21305057 TI - An antiviral defense role of AGO2 in plants. AB - BACKGROUND: Argonaute (AGO) proteins bind to small-interfering (si)RNAs and micro (mi)RNAs to target RNA silencing against viruses, transgenes and in regulation of mRNAs. Plants encode multiple AGO proteins but, in Arabidopsis, only AGO1 is known to have an antiviral role. METHODOLOGY/PRINCIPAL FINDINGS: To uncover the roles of specific AGOs in limiting virus accumulation we inoculated turnip crinkle virus (TCV) to Arabidopsis plants that were mutant for each of the ten AGO genes. The viral symptoms on most of the plants were the same as on wild type plants although the ago2 mutants were markedly hyper-susceptible to this virus. ago2 plants were also hyper-susceptible to cucumber mosaic virus (CMV), confirming that the antiviral role of AGO2 is not specific to a single virus. For both viruses, this phenotype was associated with transient increase in virus accumulation. In wild type plants the AGO2 protein was induced by TCV and CMV infection. CONCLUSIONS/SIGNIFICANCE: Based on these results we propose that there are multiple layers to RNA-mediated defense and counter-defense in the interactions between plants and their viruses. AGO1 represents a first layer. With some viruses, including TCV and CMV, this layer is overcome by viral suppressors of silencing that can target AGO1 and a second layer involving AGO2 limits virus accumulation. The second layer is activated when the first layer is suppressed because AGO2 is repressed by AGO1 via miR403. The activation of the second layer is therefore a direct consequence of the loss of the first layer of defense. PMID- 21305058 TI - The development and characterization of a human mesothelioma in vitro 3D model to investigate immunotoxin therapy. AB - BACKGROUND: Tumor microenvironments present significant barriers to penetration by antibodies and immunoconjugates. Tumor microenvironments, however, are difficult to study in vitro. Cells cultured as monolayers exhibit less resistance to therapy than those grown in vivo and an alternative research model more representative of the in vivo tumor is more desirable. SS1P is an immunotoxin composed of the Fv portion of a mesothelin-specific antibody fused to a bacterial toxin that is presently undergoing clinical trials in mesothelioma. METHODOLOGY/PRINCIPAL FINDINGS: Here, we examined how the tumor microenvironment affects the penetration and killing activity of SS1P in a new three-dimensional (3D) spheroid model cultured in vitro using the human mesothelioma cell line (NCI H226) and two primary cell lines isolated from the ascites of malignant mesothelioma patients. Mesothelioma cells grown as monolayers or as spheroids expressed comparable levels of mesothelin; however, spheroids were at least 100 times less affected by SS1P. To understand this disparity in cytotoxicity, we made fluorescence-labeled SS1P molecules and used confocal microscopy to examine the time course of SS1P penetration within spheroids. The penetration was limited after 4 hours. Interestingly, we found a significant increase in the number of tight junctions in the core area of spheroids by electron microscopy. Expression of E-Cadherin, a protein involved in the assembly and sealing of tight junctions and highly expressed in malignant mesothelioma, was found significantly increased in spheroids as compared to monolayers. Moreover, we found that siRNA silencing and antibody inhibition targeting E-Cadherin could enhance SS1P immunotoxin therapy in vitro. CONCLUSION/SIGNIFICANCE: This work is one of the first to investigate immunotoxins in 3D tumor spheroids in vitro. This initial description of an in vitro tumor model may offer a simple and more representative model of in vivo tumors and will allow for further investigations of the microenvironmental effects on drug penetration and tumor cell killing. We believe that the methods developed here may apply to the studies of other tumor-targeting antibodies and immunoconjugates in vitro. PMID- 21305059 TI - Proteotyping to establish gene origin within reassortant influenza viruses. AB - The application of a rapid and direct proteotyping approach with which to identify the gene origin of viral antigens in a reassortant influenza strain is demonstrated. The reassortant strain, constructed for a vaccine against type A 2009 H1N1 pandemic influenza, contains genes derived from a wild-type pandemic strain (A/California/7/2009) and an egg adapted high-growth strain (denoted NYMC X-157) derived from an earlier A/Puerto Rico/8/34 strain. The proteotyping approach employs modern proteomics methods and high resolution mass spectrometry to correctly establish that the genes of the surface antigens, hemagglutinin and neuraminidase, are derived from the A/California/7/2009 strain while those for nucleoprotein and matrix protein M1 antigens are derived from the NYMC X-157 strain. This is achieved for both gel-separated antigens and those from a whole vaccine digest. Furthermore, signature peptides detected in the mass spectra of the digested antigens enable the engineered reassortant strain to be identified as a type A virus of the H1N1 subtype in accord with earlier studies. The results demonstrate that proteotyping approach provides a more direct and rapid approach over RT-PCR with which to characterize reassortant strains of the influenza virus at the molecular protein level. Given that these strains pose the greatest risk to human and animal health and have been responsible for all human pandemics of the 20th and 21st centuries, there is a vital need for the origins and evolutionary history of these strains to be rapidly established. PMID- 21305060 TI - Cord blood Valpha24-Vbeta11 natural killer T cells display a Th2-chemokine receptor profile and cytokine responses. AB - BACKGROUND: The fetal immune system is characterized by a Th2 bias but it is unclear how the Th2 predominance is established. Natural killer T (NKT) cells are a rare subset of T cells with immune regulatory functions and are already activated in utero. To test the hypothesis that NKT cells are part of the regulatory network that sets the fetal Th2 predominance, percentages of Valpha24(+)Vbeta11(+) NKT cells expressing Th1/Th2-related chemokine receptors (CKR) were assessed in cord blood. Furthermore, IL-4 and IFN-gamma secreting NKT cells were quantified within the single CKR(+) subsets. RESULTS: Cord blood NKT cells expressed the Th2-related CCR4 and CCR8 at significantly higher frequencies compared to peripheral blood NKT cells from adults, while CXCR3(+) and CCR5(+) cord blood NKT cells (Th1-related) were present at lower percentages. Within CD4(neg)CD8(neg) (DN) NKT cells, the frequency of IL-4 producing NKT cells was significantly higher in cord blood, while frequencies of IFN-gamma secreting DN NKT cells tended to be lower. A further subanalysis showed that the higher percentage of IL-4 secreting DN NKT cells was restricted to CCR3(+), CCR4(+), CCR5(+), CCR6(+), CCR7(+), CCR8(+) and CXCR4(+) DN subsets in cord blood. This resulted in significantly decreased IFN-gamma /IL-4 ratios of CCR3(+), CCR6(+) and CCR8(+) cord blood DN NKT cells. Sequencing of VA24AJ18 T cell receptor (TCR) transcripts in sorted cord blood Valpha24Vbeta11 cells confirmed the invariant TCR alpha-chain ruling out the possibility that these cells represent an unusual subset of conventional T cells. CONCLUSIONS: Despite the heterogeneity of cord blood NKT cells, we observed a clear Th2-bias at the phenotypic and functional level which was mainly found in the DN subset. Therefore, we speculate that NKT cells are important for the initiation and control of the fetal Th2 environment which is needed to maintain tolerance towards self-antigens as well as non inherited maternal antigens. PMID- 21305061 TI - Executive decision-making in the domestic sheep. AB - Two new large animal models of Huntington's disease (HD) have been developed recently, an old world monkey (macaque) and a sheep. Macaques, with their large brains and complex repertoire of behaviors are the 'gold-standard' laboratory animals for testing cognitive function, but there are many practical and ethical issues that must be resolved before HD macaques can be used for pre-clinical research. By contrast, despite their comparable brain size, sheep do not enjoy a reputation for intelligence, and are not used for pre-clinical cognitive testing. Given that cognitive decline is a major therapeutic target in HD, the feasibility of testing cognitive function in sheep must be explored if they are to be considered seriously as models of HD. Here we tested the ability of sheep to perform tests of executive function (discrimination learning, reversal learning and attentional set-shifting). Significantly, we found that not only could sheep perform discrimination learning and reversals, but they could also perform the intradimensional (ID) and extradimensional (ED) set-shifting tasks that are sensitive tests of cognitive dysfunction in humans. Their performance on the ID/ED shifts mirrored that seen in humans and macaques, with significantly more errors to reach criterion in the ED than the ID shift. Thus, sheep can perform 'executive' cognitive tasks that are an important part of the primate behavioral repertoire, but which have never been shown previously to exist in any other large animal. Sheep have great potential, not only for use as a large animal model of HD, but also for studying cognitive function and the evolution of complex behaviours in normal animals. PMID- 21305062 TI - Detection of cancerous cervical cells using physical adhesion of fluorescent silica particles and centripetal force. AB - Here we describe a non-traditional method to identify cancerous human cervical epithelial cells in a culture dish based on physical adhesion between silica beads and cells. It is a simple optical fluorescence-based technique which detects the relative difference in the amount of fluorescent silica beads physically adherent to surfaces of cancerous and normal cervical cells. The method utilizes the centripetal force gradient that occurs in a rotating culture dish. Due to the variation in the balance between adhesion and centripetal forces, cancerous and normal cells demonstrate clearly distinctive distributions of the fluorescent particles adherent to the cell surface over the culture dish. The method demonstrates higher adhesion of silica particles to normal cells compared to cancerous cells. The difference in adhesion was initially observed by atomic force microscopy (AFM). The AFM data were used to design the parameters of the rotational dish experiment. The optical method that we describe is much faster and technically simpler than AFM. This work provides proof of the concept that physical interactions can be used to accurately discriminate normal and cancer cells. PMID- 21305063 TI - N-containing compounds of macromycetes. AB - This review surveys the chemical, biological, and mycological literature dealing with the isolation, structural elucidation, biological activities, and synthesis of nitrogen-containing compounds from the fruiting bodies or the culture broths of macromycetes. PMID- 21305064 TI - Accelerating fluorescent sensor discovery: unbiased screening of a diversity oriented BODIPY library. AB - Herein, we report the first systematic and unbiased evaluation of the BODIPY fluorophore library against a wide panel of biologically relevant molecules, and discoveries of 2 novel fluorescent probes for BSA and dopamine. PMID- 21305066 TI - Interaction of peptides with graphene oxide and its application for real-time monitoring of protease activity. AB - We have developed a novel graphene-based biosensing platform using peptides as probe biomolecules, and demonstrated its feasibility in the application of real time monitoring of protease activity based on FRET between GO and dye-labeled peptides. This assay allows the rapid and accurate determination of enzyme kinetic parameters as well as inhibition constants. PMID- 21305065 TI - Discovery of novel anti-HIV active G-quadruplex-forming oligonucleotides. AB - A series of d((5')TGGGAG(3')) sequences, 5'-conjugated with a variety of aromatic groups through phosphodiester linkages, were synthesized, showing CD spectra diagnostic of parallel-stranded, tetramolecular G-quadruplex structures. When tested for anti-HIV-1 and HIV-2 activity, potent inhibition of HIV-1 infection in CEM cell cultures was found, associated with high selectivity index values. Surface Plasmon Resonance assays revealed specific binding to HIV-1 gp120 and gp41. PMID- 21305067 TI - Molecular organization and effective energy transfer in iridium metallosurfactant porphyrin assemblies embedded in Langmuir-Schaefer films. AB - Mixed Langmuir monolayers and Langmuir-Schaefer (LS) films containing the cationic metallosurfactant bis(2-phenylpyridine)(4,4'-diheptadecyl-2,2' bipyridine)-iridium(III) chloride (Ir-complex) and the anionic tetrakis(4 sulfonatophenyl)porphyrin (TSPP) in 4:1 molar ratio have been successfully prepared by the co-spreading method at the air-water interface. The presence of both luminescent species at the interface, as well as the organization of the TSPP underneath the Ir-complex matrix in Langmuir and LS films, is inferred by surface techniques such as pi-A isotherms, reflection spectroscopy, Brewster angle microscopy (BAM) and UV-visible absorption spectroscopy. A red-shift in the absorption band of the porphyrin under the compression of the mixed monolayer suggests the J-aggregation of the TSPP under the Ir-complex matrix. To date, this is the first report of Langmuir and/or LS films containing these two types of species together. Furthermore, the intermolecular energy transfer between Ir complex and TSPP molecules in solution and in transferred mixed films is investigated through steady-state fluorescence and lifetime measurements. These results indicate that effective intermolecular energy transfer occurs from the Ir complex to the TSPP molecules in LS films. The influence of the spatial proximity of donor and acceptor molecules has been studied by the insertion of lipid interlayers among them. PMID- 21305068 TI - Charge carrier mobility in poly[methyl(phenyl)silylene] studied by time-resolved terahertz spectroscopy and molecular modelling. AB - Time-resolved terahertz spectroscopy and combination of quantum chemistry modeling and molecular dynamics simulations were used for the determination of charge carrier mobility in poly[methyl(phenyl)silylene]. Using time-resolved THz spectroscopy we established the on-chain charge carrier drift mobility in PMPSi as 0.02 cm(2) V(-1) s(-1). This value is low due to the formation of polarons: the hole is self-trapped in a potential formed by local chain distortion and the transient THz conductivity spectra show signatures of its oscillations within this potential well. This view is supported by the agreement between experimental and calculated values of the on-chain charge carrier mobility. PMID- 21305069 TI - Design of optimally switchable molecules by genetic algorithms. AB - We demonstrate the possibility to design molecules for specific tasks, using a fully automatic global optimization setup employing genetic algorithms. As an example, we tune the two excitation wavelengths of a molecular switch backbone to arbitrarily pre-set values, by an automatic optimization of the substituent pattern. PMID- 21305070 TI - Electrostatic effects on (di)terpene synthase product outcome. AB - Terpene synthases catalyze complex reactions, often forming multiple chiral centers in cyclized olefin products from acyclic allylic diphosphate precursors, yet have been suggested to largely control their reactions via steric effects, serving as templates. However, recent results highlight electrostatic effects also exerted by these enzymes. Perhaps not surprisingly, the pyrophosphate co product released in the initiating and rate-limiting chemical step provides an obvious counter-ion that may steer carbocation migration towards itself. This is emphasized by the striking effects of a recently uncovered single residue switch for diterpene synthase product outcome, whereby substitution of hydroxyl residues for particular aliphatic residues has been shown to be sufficient to "short circuit" complex cyclization and/or rearrangement reactions, with the converse change further found to be sufficient to increase reaction complexity. The mechanistic hypothesis for the observed effects is hydroxyl dipole stabilization of the specific carbocation formed by initial cyclization, enabling deprotonation of this early intermediate, whereas the lack of such stabilization (i.e. in the presence of an aliphatic side chain) leads to carbocation migration towards the pyrophosphate co-product, resulting in a more complex reaction. This is further consistent with the greater synergy exhibited between pyrophosphate and aza analogs of late, relative to early, stage carbocation intermediates, and crystallographic analysis of the monoterpene cyclase bornyl diphosphate synthase wherein mechanistically non-relevant counter-ion pairing between aza-analogs of early stage carbocation intermediates and pyrophosphate is observed. Thus, (di)terpene synthases seem to mediate specific reaction outcomes, at least in part, by providing electrostatic effects to counteract those exerted by the pyrophosphate co-product. PMID- 21305071 TI - Synthesis of cationic quantum dots via a two-step ligand exchange process. AB - A new class of quaternary ammonium derivatives has been used to synthesize cationic CdSe/ZnS quantum dots with exceptional stability in water as well as in biological media. PMID- 21305075 TI - A comparison of methionine, histidine and cysteine in copper(I)-binding peptides reveals differences relevant to copper uptake by organisms in diverse environments. AB - The N-terminal, extracellular regions of eukaryotic high affinity copper transport (Ctr) proteins vary in composition of the Cu(i) binding amino acids: methionine, histidine, and cysteine. To examine why certain amino acids are exploited over others in Ctrs from different organisms, the relative Cu(i) binding affinity and the dependence of binding on pH were examined for 3 peptides of the sequence MG(2)XG(2)MK, where X is either Met, His, or Cys. Cu(i) affinity was examined using an ascorbic acid oxidation assay, an electrospray ionization mass spectrometry technique, and spectrophotometric titration with a competitive Cu(i) chelator. The relative affinities of the peptides with Cu(i) reveal a trend whereby Cys > His > Met at pH 7.4 and Cys > Met > His at pH 4.5. Ligand geometry and metric parameters were determined with X-ray absorption spectroscopy. Susceptibility of the peptides to oxidation by hydrogen peroxide and copper catalyzed oxidative conditions was evaluated by mass spectrometry. These results support hypotheses as to why certain Cu(i) binding amino acids are preferred over others in proteins expressed at different pH and exposed to oxidative environments. The results also have implications for interpreting site-directed mutagenesis studies aimed at identifying copper binding amino acids in copper trafficking proteins. PMID- 21305081 TI - Fabrication of a visible-light response mesoporous TiO2 membrane with superior water permeability via a weak alkaline sol-gel process. AB - A visible-light response TiO(2) ultrafiltration membrane was fabricated via a weakly alkaline sol-gel method for the first time, and exhibited a cut-off molecular weight of 7500 Da and high pure water flux of 170 L m(-1) h(-1) bar( 1). PMID- 21305082 TI - New talent: Asia. PMID- 21305083 TI - Ultrasensitive fluorescence polarization DNA detection by target assisted exonuclease III-catalyzed signal amplification. AB - Single stranded DNA sequences can be detected by target assisted exonuclease III catalyzed signal amplification fluorescence polarization (TAECA-FP). The method offers an impressive detection limit of 83 aM within one hour for DNA detection and exhibits high discrimination ability even against a single base mismatch. PMID- 21305084 TI - Dual-signal fenamithion probe by combining fluorescence with colorimetry based on Rhodamine B modified silver nanoparticles. AB - A versatile yet simple strategy for the fabrication of a highly selective and sensitive fenamithion probe based on Rhodamine B (RB) modified silver nanoparticles (RB-Ag NPs) was developed. The advantage of our system over classical assays is that it combined fluorescence with colorimetry which can realize the prompt on-site and real-time detection of fenamithion with high sensitivity (0.1 nM) in aqueous solution. Moreover, the detection system presents excellent anti-disturbance ability when exposed to a series of interfering ionic/pesticides mixtures and can be applied to the determination of fenamithion in real vegetables and different water samples with the limit of detection (LOD) as low as 10 nM (0.0026 mg L(-1)), which is in accord with the maximum contamination level of 0.001~0.25 mg L(-1) for organophosphorus pesticides as defined by the U.S. Environmental Protection Agency (EPA). Advantage is taken of the fact that RB would be displaced from the surface of the Ag NPs because of the stronger coordination ability of Ag NPs with fenamithion, an amino-containing organophosphorus pesticide, accompanying the clustered Ag NPs (9 nm) dissipating into smaller individual particles (7 nm). Based on this phenomenon, a novel analyte-induced etching mechanism was proposed. PMID- 21305085 TI - Ionic liquid-modified dyes and their sensing performance toward acids in aqueous and non-aqueous solutions. AB - Six ionic liquid (IL)-modified dyes were synthesized and characterized. Compared to the methyl red and methyl orange, these IL-modified [MR](-)- or [MO](-)-based dyes exhibit lower melting points and enhanced solubility, and can be used as sensitive indicators towards free proton in both aqueous and non-aqueous solutions. This work also supplies a new concept of developing novel modified materials with the ILs. PMID- 21305086 TI - Efficient functionalization of aqueous CdSe/ZnS nanocrystals using small-molecule chemical activators. AB - Small molecular reagents that can efficiently functionalize water soluble CdSe/ZnS nanocrystals (NCs) are reported. These reagents do not cause quenching or precipitation of NCs as seen with commercially available activators. The results demonstrate that controlling the electrostatic character of the materials is critical in the design of functionalization schemes. PMID- 21305087 TI - Theoretical study on charge carrier mobilities of tetrathiafulvalene derivatives. AB - We calculated the hole and electron mobilities of tetrathiafulvalene (TTF) derivative crystals using first-principles calculations and the Marcus theory of electron transfer. The hole and electron reorganization energies were found to decrease with the extension of pi-conjugated orbitals. The calculated hole mobilities of TTF, dibenzo-tetrathiafulvalene (DB-TTF), and dinaphtho tetrathiafulvalene (DN-TTF) agree well with the experimental results. In addition, with the increase of the number of benzene rings attached to the TTF skeleton, the hole mobilities decrease and the electron mobilities increase. The calculated electron mobility of dianthro-tetrathiafulvalene (DA-TTF) based on a virtual crystal structure is much larger than the hole one due to the small electron reorganization energy and large electron coupling. This suggests that the charge transfer properties of the TTF derivatives can be modified when the number of aromatic rings on TTF skeleton increases. PMID- 21305088 TI - A slice imaging and multisurface wave packet study of the photodissociation of CH3I at 304 nm. AB - The role of the conical intersection between the (1)Q(1) and (3)Q(0) excited states in the photodissociation of CH(3)I at 304 nm is investigated drawing a comparison between the adiabatic--through direct absorption to the (3)Q(1) state- and non-adiabatic--via the (1)Q(1)->(3)Q(0) conical intersection--production of I atoms in the ground (2)P(3/2) state. The versatility of the slice imaging technique in combination with resonance enhanced multiphoton ionization (REMPI) detection of I((2)P(3/2)) atoms allow distinct measurements of the competing processes. The I((2)P(3/2)) atom kinetic energy distributions (KEDs) obtained in both cases reflect inverted vibrational progressions of the nu(2) umbrella mode of the CH(3) co-product. The experimental results show a satisfactory agreement with multisurface wave packet calculations using a reduced dimensionality (pseudotriatomic) model carried out on the available ab initio potential energy surfaces. PMID- 21305089 TI - Unfolding dynamics of cytochrome c revealed by single-molecule and ensemble averaged spectroscopy. AB - Denaturant-induced conformational change of yeast iso-1-cytochrome c (Cytc) has been comprehensively investigated in the single-molecule and bulk phases. By fluorescence-quenching experiments with dye-labelled heme-protein (Alexa 488 labelled Cytc, Cytc-A488), we clearly show that the fluorescence quenching observed from folded Cytc-A488 is due mainly to photoinduced electron transfer (PET) between electron-donating amino acids such as tryptophan and the dye attached to the protein. In addition, the unfolding process of Cytc-A488 observed in the single-molecule and bulk phases can be explained well in terms of a three state model: Cytc unfolds through an intermediate with a native-like compactness. By quantitative analysis of fluorescence correlation spectroscopy (FCS) data, we were able to observe a relaxation time of ~1.5 MUs corresponding to segmental motion and fast folding dynamics of 55 MUs in the unfolded state of Cytc. The results presented here also suggest that a combination of single-molecule and ensemble-averaged spectroscopy is necessary to provide convincing and comprehensive assignments of protein kinetics. PMID- 21305090 TI - Oxidative cyclization of thiosemicarbazone: an optical and turn-on fluorescent chemodosimeter for Cu(II). AB - A weakly fluorescent thiosemicabazone (L(1)H) was found to be a selective optical and "turn-on" fluorescent chemodosimeter for Cu(2+) ion in aqueous medium. A significant fluorescence enhancement along with change in color was only observed for Cu(2+) ion; among the other tested metal ions (viz. Na(+), K(+), Mg(2+), Ca(2+), Cr(3+), Zn(2+), Cd(2+), Hg(2+), Pb(2+), Ag(+), Ni(2+), Co(2+), Fe(3+) and Mn(2+)). The Cu(2+) selectivity resulted from an oxidative cyclization of the weak fluorescent L(1)H into highly fluorescent rigid 4,5-dihydro-5,5-dimethyl-4 (naphthalen-5-yl)-1,2,4-triazole-3-thione (L(2)). The signaling mechanism has been confirmed by independent synthesis with detail characterization of L(2). PMID- 21305091 TI - Synthesis and optical property of large-scale centimetres-long silicon carbide nanowires by catalyst-free CVD route under superatmospheric pressure conditions. AB - Large-scale centimetres-long single-crystal beta-SiC nanowires have been prepared using CH(4) as the carbon source and SiO or the mixture of Si and SiO(2) as the silicon source by a simple catalyst-free CVD route under superatmospheric pressure conditions. The nanowries grown on ceramic boat or corundum substrates, with lengths of several centimetres and the average diameters of around 40 nm, were composed of single-crystal beta-SiC core along the [111] direction and amorphous SiO(2) shell of about 1-30 nm thick depending on the growth position along the flowing direction of the carrier gas. The total gas pressure is an important factor for the synthesis of the large-scale centimetres-long beta-SiC nanowires, which can easily adjust the pressure of the vapors to supersaturation condition. The growth of the nanowires was governed by the Vapor-Solid mechanism. The beta-SiC nanowires showed an intense blue light emission at room temperature. PMID- 21305092 TI - Facile preparation of size-controlled gold nanoparticles using versatile and end functionalized thioether polymer ligands. AB - At present, thiol ligands are generally used whenever the classical Brust Schiffrin two-phase method is employed to prepare metal nanoparticles. In general, the previous research was mainly focused on utilizing small molecular thiol compounds or thiol polymers as the stabilizers in organic phase to obtain small sized and uniform gold nanoparticles (Au NPs). Such preparations are usually associated with the problems of ligand exchange on the nanoparticle's surface due to strong Au-thiol interaction. Herein, we report an approach to produce fairly uniform Au NPs with diameters about 2-6 nm using thioether end functional polymer ligands (DDT-PVAc and PTMP-PVAc) as the capping agents. These nanoparticles are thoroughly characterized using DLS, TEM, UV-Vis spectroscopy and other complementary techniques. The results indicate that multidentate thioether polymeric ligands (PTMP-PVAc) lead to formation of smaller but special 'multimer' morphology in organic phase; whereas fairly uniform nanoparticles are produced using monodentate thioether functionalized ligands (DDT-PVAc). Further modification of such polymer ligands to introduce the hydrophilic functionalities realizes the phase transfer of Au NPs from organic to aqueous media. PMID- 21305093 TI - A cationic surfactant assisted selective etching strategy to hollow mesoporous silica spheres. AB - Hollow mesoporous silica spheres have recently attracted increasing attention. However, effective synthesis of uniform hollow mesoporous spheres with controllable well-defined pore structures for fundamental research and practical applications has remained a significant challenge. In this work, a straightforward and effective "cationic surfactant assisted selective etching" synthetic strategy was developed for the preparation of high-quality hollow mesoporous silica spheres with either wormhole-like or oriented mesoporous shell. The as-prepared hollow mesoporous silica spheres have large surface area, high pore volume, and controllable structure parameters. Our experiments demonstrated that cationic surfactant plays critical roles in forming the hollow mesoporous structure. A formation mechanism involving the etching of solid SiO(2) accelerated by cationic surfactant followed by the redeposition of dissolved silica species directed by cationic surfactant is proposed. Furthermore, the strategy can be extended as a general strategy to transform silica-coated composite materials into yolk-shell structures with either wormhole-like or oriented mesoporous shell. PMID- 21305094 TI - C1-symmetric carbohydrate diphosphite ligands for asymmetric Pd-allylic alkylation reactions. Study of the key Pd-allyl intermediates. AB - A series of C(1)-symmetrical 1,3-diphosphite ligands with a furanoside backbone have been applied in the Pd-catalysed asymmetric allylic alkylation of mono- and disubstituted linear substrates. These diphosphite ligands were designed by selective modification of the successful diphosphite ligand L1a with the 6-deoxy 1,2-O-isopropylidene-glucofuranose backbone in order to study the effect of the ligand structure on the catalytic performance. The effect of the solvent, the substrate/metal ratio and ligand/metal ratio were also investigated. The results in the Pd-allylic alkylation of rac-1,3-diphenyl-3-acetoxyprop-1-ene showed that the ligand structure and the reaction conditions had a considerable effect on enantioselectivity and on the kinetics of the reaction producing the kinetic resolution of the substrate. The alkylated product 2 was therefore obtained in 95% ee at 53% conversion and the enantiopure substrate 1 was recovered in 99.9% ee. Furthermore, the effect of the ligand structure and solvent were also observed in the Pd-allylic alkylation of monosubstituted 1-phenyl-3-acetoxyprop-1 ene. The use of a pro-chiral nucleophile was also explored in this reaction leading to excellent regioselectivities but moderate enantioselectivities. Finally, in order to determine how the ligand structure affected the chiral pocket of the Pd-pi-allyl intermediates, the complexes [Pd(eta(3) C(15)H(13))(L)]PF(6), where L = L1a, L5-L8a, were synthesised and characterised by NMR spectroscopy. PMID- 21305095 TI - S(N)2' addition/1,2-elimination of dimethylsulfonium methylide with epoxy vinyl sulfones: synthesis of exocyclic cross-conjugated dienyl sulfones. AB - Dimethylsulfonium methylide undergoes S(N)2' addition/1,2-elimination with epoxy vinyl sulfones to generate enantiopure six and seven membered cross-conjugated hydroxy vinyl sulfones. Moderate to excellent yields were obtained for both six and seven membered substrates. PMID- 21305096 TI - A water-soluble carbon nanotube network conjugated by nanoparticles with defined nanometre gaps. AB - Cage-shaped proteins with an affinity for carbonaceous materials were constructed and used to assemble a nanostructure in which single-walled carbon nanotubes are surrounded by cobalt oxide nanoparticles with nanometre gaps. By changing the size of proteins and materials incorporated inside the cavity, similar structures with distinctively different properties can be fabricated. PMID- 21305097 TI - A Li-O2/CO2 battery. AB - A new gas-utilizing battery using mixed gas of O(2) and CO(2) was developed and proved its very high discharge capacity. The capacity reached three times as much as that of a non-aqueous Li-air (O(2)) battery. The unique point of the battery is expected to be the rapid consumption of superoxide anion radical by CO(2) as well as the slow filling property of the Li(2)CO(3) in the cathode. PMID- 21305098 TI - First prebiotic generation of a ribonucleotide from adenine, D-ribose and trimetaphosphate. AB - Adenosine monophosphate isomers are obtained by self-assembling of adenine, D ribose and trimetaphosphate in aqueous solution in good yields. This generation of a ribonucleotide from its three molecular components occurs in a one-pot reaction at room temperature for about 30-40 days and with high chemio-, regio-, and stereo-selectivity. Similar results are obtained with guanine. A mechanism is also proposed. PMID- 21305099 TI - Characterization of bioparticles using a miniature cylindrical ion trap mass spectrometer operated at rough vacuum. AB - A miniature cylindrical ion trap mass spectrometer (CIT-MS) equipped with an inexpensive mechanical pump was constructed, and used to measure the masses of cells and microparticles generated by laser induced acoustic desorption ionization. Compared with a previous lab scale quadrupole ion trap mass spectrometer (QIT-MS), the novel miniature CIT-MS had smaller volume (the radius r(0)=5 mm), simpler ion trap fabrication and overall instrument construction, required a lower trapping voltage, and reduced the weight, power and cost of the instrument. The CIT-MS was calibrated using standard polystyrene beads of 2.982 um diameter. The CIT-MS was used to measure the total dry weight of human red blood cells (RBCs) from a healthy female adult (2.12*10(13) Da) and a patient with anemia (1.35*10(13) Da). The coefficient of variance (CV) for the healthy individual was 21% and that for the patient was 30.4%. The CIT-MS was also applied to guinea pig RBCs and the total dry weight was determined as 1.34*10(13) Da with a CV of 37.9%. These measurements are consistent with previous QIT-MS measurements. The new miniaturized instrument has potential for applications in field-portable, biological and aerosol analysis. PMID- 21305106 TI - Synchrotron radiation for direct analysis of metalloproteins on electrophoresis gels. AB - Metalloproteomics requires analytical techniques able to assess and quantify the inorganic species in metalloproteins. The most widely used methods are hyphenated techniques, based on the coupling of a high resolution chromatographic method with a high sensitivity method for metal analysis in solution. An alternative approach is the use of methods for solid sample analysis, combining metalloprotein separation by gel electrophoresis and direct analysis of the gels. Direct methods are based on beam analysis, such as lasers, ion beams or synchrotron radiation beams. The aim of this review article is to present the main features of synchrotron radiation based methods and their applications for metalloprotein analysis directly on electrophoresis gels. Synchrotron radiation X ray fluorescence has been successfully employed for sensitive metal identification, and X-ray absorption spectroscopy for metal local structure speciation in proteins. Synchrotron based methods will be compared to ion beam and mass spectrometry for direct analysis of metalloproteins in electrophoresis gels. PMID- 21305107 TI - Elemental bio-imaging of calcium phosphate crystal deposits in knee samples from arthritic patients. AB - Laser ablation inductively coupled plasma mass spectrometry (LA ICP-MS) was employed to image deposits of calcium phosphate based crystals in knee cartilage and synovial fluid from arthritic patients. A reaction/collision cell containing hydrogen minimised plasma interferences on calcium and also improved the image quality without significant sensitivity reduction. Areas of high calcium and phosphorus intensities consistent with crystal deposits were observed for both the cartilage and synovial fluid samples. These areas were also characterised by high magnesium and strontium intensities. Distribution patterns of other elements such as copper and sulfur did not correlate with the crystal deposits. Filtered and non-filtered solutions of calcium phosphate crystals grown in synthetic synovial fluid were also imaged as further evidence of crystal deposits. The crystal deposits were detected in the unfiltered solution, and were absent from the filtered solutions. PMID- 21305108 TI - Intramolecular hydrogen bonding as a determinant of the inhibitory potency of N unsubstituted imidazole derivatives towards mammalian hemoproteins. AB - Enzymes involved in the mammalian microsomal metabolism of drugs are, in numerous cases, inhibited by compounds bearing an imidazolyl scaffold. However, the inhibition potency is highly dependent upon the accessibility of the imidazolyl nitrogen lone pair. In order to highlight some structural parameters of inhibitors that control this phenomenon, a series of compounds containing a nitrogen unsubstituted imidazolyl moiety with varying degrees of nitrogen lone pair accessibility was tested on human and rat hepatic cytochromes P450 and microperoxidase 8, an enzymatically active peptide derived from cytochrome c. In each case, we have shown that the accessibility of the imidazole lone pair determined the extent of inhibition. Nitrogen accessibility was tuned not only by varying the steric hindrance in the vicinity of the imidazolyl ring but also by modifying its surrounding hydrogen bonding network. Compounds in which there exists intramolecular hydrogen bonding between the imidazole moiety and an H-bond acceptor, such as an appropriately positioned amide carbonyl group, demonstrated enhanced inhibitory effects. Conversely, imidazole moieties which are in proximity to H-bond donors, such as an amide NH group, displayed reduced potency. This trend was observed in cyclo-peptide derivatives in which the intramolecular H-bond network was adjusted through the modification of the stereochemistry of a dehydrohistidine residue. It was observed that (Z)-isomers weakly bind heme, whereas (E)-isomers demonstrated higher degrees of metal binding. Therefore, enzymatic inhibition of heme-containing proteins by compounds bearing a dehydrohistidine motif seems to be closely related to its stereochemistry and hydrogen binding propensity. At neutral pH, these differences in binding affinities can be confidently attributed to the ambident H-bond properties of imidazole nitrogen atoms. This structure-activity relationship may be of use for the design of novel imidazolyl compounds as new P450 inhibitors or drug candidates. PMID- 21305109 TI - The role of copper in cysteine oxidation: study of intra- and inter-molecular reactions in mass spectrometry. AB - Cysteine-containing peptide oxidation was studied both by using an inert platinum electrode and a sacrificial electrode (copper or zinc) generating metallic ions in electrospray ionization mass spectrometry (ESI-MS). Using peptides containing one, two and three cysteines, we have compared the different chemical and electrochemical oxidation pathways of cysteine (RS(-II)H) to cystine (RS(-I)S( I)R) and to sulfenic, sulfinic and sulfonic acid (RS(0)OH, RS(II)O(2)H and RS(IV)O(3)H, respectively). In the absence of copper ions, intra-molecular reactions were the most abundant, whereas inter-molecular reactions were found to be enhanced by the presence of copper ions. These cations favor the formation of 2 : 1 (peptide : copper) complexes compared to 1 : 1 complexes, thus enhancing the formation of inter-molecular bridges. This study highlights the importance of the position of cysteine inside a peptide during disulfide bridge formation. PMID- 21305110 TI - Effects of titanium(iv) ions on human monocyte-derived dendritic cells. AB - Orthopaedic metal implants composed of titanium are routinely used in bone fracture repair and for joint replacement therapies. A considerable fraction of implant recipients are unable to benefit due to implant failure resulting from aseptic loosening, while others may experience cutaneous sensitivity to titanium after implantation. An adaptive immune reactivity towards titanium ions, originating from the biocorrosion of the implants, could play a role. As an initiator of the adaptive immune response, dendritic cells (DC) were studied for uptake and characteristics after titanium exposure. Energy filtered transmission electron microscopy showed uptake of titanium(iv) (Ti(iv)) ions by DCs in vitro and co-localisation with phosphorus-rich cell structures of the DC membranes (phospholipids), cytoplasm (ribosomes and phosphorylated proteins) and the nucleus (DNA). DC maturation and function were investigated by measuring cell surface marker expression by flow cytometry. After exposure, DCs showed a decrease in MHC class II (HLA-DR), co-stimulatory molecules (CD40, CD80 & CD86) and chemokine receptors (CCR) 6 and CCR7 but an increase in CCR4 after Ti(iv) treatment. However, Ti(iv) treated DCs had an increased stimulatory capacity towards allogenic lymphocytes. A Ti(iv) concentration dependant increase of IL 12p70 was observed amidst decrease of the other measured cytokines (TGF-beta1 and TGF-beta2). Hence, Ti(iv) alters DC properties, resulting in an enhanced T lymphocyte reactivity and deviation towards a Th1 type immune response. This effect may be responsible for the inflammatory side effects of titanium implants seen in patients. PMID- 21305116 TI - Changing the face of scientific publishing. PMID- 21305117 TI - Advances in developing tris(8-quinolinolato)gallium(iii) as an anticancer drug: critical appraisal and prospects. AB - Gallium-based anticancer chemotherapeutics are appreciably progressing in clinical studies. A steady interest of drug developers and clinicians in gallium compounds is due to a proven ability of gallium cations to inhibit tumour growth, on the one hand, and enhanced bioavailability and moderate toxicity provided by the conversion of gallium into chelate complexes, on the other. One of the complexes suitable for a more convenient oral administration is tris(8 quinolinolato)gallium(iii) (KP46). Nominated from a range of gallium complexes for the clinical stage of development, KP46 has finished phase I trials with the outcome of promising tolerability and evidence of clinical activity in renal cell carcinoma. Therefore, there is obviously a need to codify and critically evaluate the continuing advances in the emergence of KP46 as a lead-drug candidate. Additionally, many questions remain unanswered regarding the relevant biological reactivity, modes of delivery and action and potential cell target(s) of KP46. The timely publication of the present review is also an attempt to shed light on these pertinent drug assets and to accelerate research activities towards further clinical development of KP46. PMID- 21305118 TI - Zinc and tetrathiomolybdate for the treatment of Wilson's disease and the potential efficacy of anticopper therapy in a wide variety of diseases. AB - Wilson's disease, an autosomal recessive disease of copper accumulation and copper toxicity primarily in the liver and brain, has been the engine that has driven the development of anticopper drugs. Here we first briefly review Wilson's disease, then review the four anticopper drugs used to treat Wilson's disease. We then discuss the results of therapy with anticopper drugs in Wilson's disease, with special emphasis on the newer and better drugs, zinc and tetrathiomolybdate. We then discuss new areas of anticopper therapy, lowering copper availability with tetrathiomolybdate as a therapy in fibrotic, inflammatory, and autoimmune disorders. Many of the cytokines which promote these disorders are copper dependent, and lowering copper availability lessens the activity of these cytokines, favorably influencing a variety of disease processes. Copper in the blood can be thought of as in two pools. One pool is covalently bound in ceruloplasmin, a protein containing six coppers, synthesized by the liver and secreted into the blood. Ceruloplasmin copper accounts for almost 85 to 90% of the blood copper in normal people. This copper is tightly bound and not readily available for cellular uptake and copper toxicity. The other 10-15% of copper is more loosely bound to albumin and other small molecules in the blood, and is readily and freely available to cells and available to cause copper toxicity, if this pool of copper is increased. We call this latter pool of copper "free" copper because of its more ready availability. However, it should be understood that it is not completely free, always being bound to albumin and other molecules. It is this pool of free copper that is greatly expanded in untreated Wilson's patients undergoing copper toxicity. PMID- 21305119 TI - Independent metal-binding features of recombinant metallothioneins convergently draw a step gradation between Zn- and Cu-thioneins. AB - Data on the metal-binding behaviour of circa 20 recombinant metallothioneins (MTs) from evolutionary divergent organisms, gathered after years of systematic research, are here comprehensively analyzed. The consideration of four independent in vivo and in vitro metal-binding features reveals a gradation of the metal-binding character of the MTs considered that significantly coincides in a robust new classification: a stepwise gradation between Zn- and Cu-thioneins. The intermediate positions in this list are occupied by a group of polyvalent MTs, exhibiting a merging Zn-/Cu-thionein character that would suit general metal handling purposes. In contrast, the extreme positions are respectively occupied by those MTs that would have evolved to fulfil specialized Zn- or Cu-related physiological roles. Overall, the analyzed trends allow the proposal of a chemically- and biologically-sound new reflection on MT classification criteria. PMID- 21305120 TI - Characterization of metal-peptide complexes in feed supplements of essential trace elements. AB - Metal chelates with biomolecules are increasingly used in animal supplementation to increase the bioavailability of essential trace elements. However, the transfer of the chelates is not well understood and speciation studies may bring a comprehensive insight to further investigate the biological uptake mechanism(s) implicated. An analytical method was developed for the characterization of the water-soluble metal complexes in animal feed supplements obtained by reaction of a metal salt with a non-GMO soybean enzymatic digest. The method was based on fractionation of the extract by size-exclusion chromatography followed by the analysis of the metal-containing fraction by reversed-phase nanoHPLC with parallel ICP MS and electrospray MS/MS detection. The metal complexes were identified in the mass spectra owing to the Cu characteristic isotopic pattern; the complexation was corroborated by the presence of a peak corresponding to the non-metallated peptide. The study demonstrated the feasibility of SEC-ICP MS to produce characteristic metal (Cu, Zn, Mn, Fe) distribution patterns, which can be of interest to test batch-to-batch reproducibility and to determine the origin of the supplement. The use of the method could be extended to animal feeds prepared using the metal-chelated complexes. Electrospray MS/MS allowed the identification of a number of Cu complexes with peptides. Four different structure conformations were modeled by means of molecular mechanics investigations to assess the chelation stability. PMID- 21305121 TI - Unusual flexibility of distal and proximal histidine residues in the haem pocket of Drosophila melanogaster haemoglobin. AB - Several pH-dependent low-spin ferric haem forms are identified in a frozen solution of the ferric 121Cys->Ser mutant of Drosophila melanogaster haemoglobin (DmHb1*) using electron paramagnetic resonance (EPR) techniques. Different forms with EPR parameters typical of bis-histidine coordinated haem iron centers were observed. Strong pH-dependent changes in the EPR signatures were observed related to changes in the haem pocket. The pulsed EPR data indicate that both the distal and proximal histidine exhibit a large libration around the Fe-N(His) axis. The resonance Raman spectra of the CO-ligated ferrous form of Drosophila melanogaster haemoglobin are typical of an open conformation, with little stabilization of the CO ligand by the surrounding amino-acid residues. The EPR data of the cyanide ligated ferric DmHb1* indicates a close similarity with cyanide-ligated ferric myoglobin. The structural characteristics of DmHb1* are found to clearly differ from those of other bis-histidine-coordinated globins. PMID- 21305127 TI - Metal trafficking: from maintaining the metal homeostasis to future drug design. AB - The diverse proteins and enzymes involved in metal trafficking between and inside human cells form numerous transport networks which are highly specific for each essential metal ion and apoprotein. Individual players include voltage-gated ion channels, import and export proteins, intracellular metal-ion sensors, storage proteins and chaperones. In the case of calcium, iron and copper, some of the most apparent trafficking avenues are now well established in eukaryotes, while others are just emerging (e.g. for zinc, manganese and molybdenum). Chemistry provides an important contribution to many issues surrounding these transport pathways, from metal binding-constants and ion specificity to metal-ion exchange kinetics. Ultimately, a better understanding of these processes opens up opportunities for metal-ion-related therapy, which goes beyond traditional chelate-based metal ion detoxification. PMID- 21305128 TI - Metal imaging in non-denaturating 2D electrophoresis gels by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) for the detection of metalloproteins. AB - Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) was developed as a powerful analytical technique for metal imaging of 2D gels for the detection of metalloproteins in rat kidney after electrophoretic separation. Protein complexes, extracted with water, were separated in their native state in the first and second dimension by blue native gel electrophoresis (BN-PAGE). Essential and toxic metals, such as zinc, copper, iron, manganese and lead, were monitored by LA-ICP-MS after gel ablation by a focused laser beam in a way that the total surface of a selected fragment of the gel was totally ablated. The metal distribution of this part of the gel was then constructed by plotting the metal (isotope) signal intensity as a function of the x,y (isoelectric point, molecular mass) coordinates of the gel. The proteins at locations rich in metals were cut out, digested with trypsin and analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). PMID- 21305129 TI - Identification of anionic selenium species in Se-rich yeast by electrospray QTOF MS/MS and hybrid linear ion trap/orbitrap MSn. AB - An analytical approach allowing the identification of unknown selenium metabolites in selenium-rich yeast was described. Anion-exchange HPLC of the Se metabolome fraction co-eluting with salts in size-exclusion chromatography allowed the separation of nine selenium species (excluding isomers and selenate) as monitored by inductively coupled plasma mass spectrometry (ICP MS). The individual fractions were analyzed by electrospray QTOF MS/MS and hybrid linear ion trap/Orbitrap MSn after sample introduction by reversed-phase nanoHPLC and by hydrophilic interaction LC (HILIC), respectively. Out of the nine detected species, eight were identified on the basis of accurate mass measurements and collision induced dissociation/fragmentation information. Seven Se-species (selenohomolanthionine, gamma-Glu-selenocystathionine, 2,3-DHP selenocystathionine, N-acetyl-selenocystathionine, 2,3-DHP-selenohomolanthionine, Se-methyl-selenoglutathione, and 2,3-DHP-Se-methylselenocysteine) were reported for the first time in Se-rich yeast, five of them have never been reported in any biological sample before. PMID- 21305130 TI - Use of synchrotron- and plasma-based spectroscopic techniques to determine the uptake and biotransformation of chromium(III) and chromium(VI) by Parkinsonia aculeata. AB - In this study, a combination of inductively coupled plasma optical emission spectroscopy and X-ray absorption spectroscopy (XAS) was used to study the uptake and speciation of chromium in Parkinsonia aculeata, commonly known as Mexican Palo Verde. Plants were treated for 14 days in a modified Hoagland solution containing chromium(III) or chromium(VI) at several concentrations. The results showed that plants treated with 70 mg Cr(III) L(-1) and 30 mg Cr(VI) L(-1) had similar Cr concentrations in leaves (~200 mg kg(-1) dry weight, DW). The results also showed that neither Cr(III) nor Cr(VI) affected the uptake of phosphorus and sulfur. However, the concentration of calcium in the stems of plants treated with Cr(VI) at 40 mg L(-1) (about 6000 mg Ca kg(-1) DW) was significantly higher compared to the Ca concentration (about 3000 mg kg(-1) DW) found in the stems of plants treated with 150 mg Cr(III) L(-1). However, no differences were observed in potassium and magnesium concentrations. The iron concentration (about 1000 mg kg(-1) DW) in roots treated with 40 mg Cr(VI) L(-1) was similar to the iron concentration found in the roots of plants treated with 110 mg Cr(III) L(-1). The XAS data showed that Cr(VI) was reduced to Cr(III) in/on the plant roots and transported as Cr(III) to the stems and leaves. The XAS studies also showed that Cr(III) within plants was present as an octahedral complex. PMID- 21305131 TI - Metallic elements in exhaled breath condensate and serum of patients with exacerbation of chronic obstructive pulmonary disease. AB - Biomarkers in exacerbated chronic obstructive pulmonary disease may be useful in aiding diagnosis, defining specific phenotypes of disease, monitoring the disease and evaluating the effects of drugs. The aim of this study was the characterization of metallic elements in exhaled breath condensate and serum as novel biomarkers of exposure and susceptibility in exacerbated chronic obstructive pulmonary disease using reference analytical techniques. C-Reactive protein and procalcitonin were assessed as previously validated diagnostic and prognostic biomarkers which have been associated with disease exacerbation, thus useful as a basis of comparison with metal levels. Exhaled breath condensate and serum were obtained in 28 patients at the beginning of an episode of disease exacerbation and when they recovered. Trace elements and toxic metals were measured by inductively coupled plasma-mass spectrometry. Serum biomarkers were measured by immunoassay. Exhaled manganese and magnesium levels were influenced by exacerbation of chronic obstructive pulmonary disease, an increase in their concentrations--respectively by 20 and 50%--being observed at exacerbation in comparison with values obtained at recovery; serum elemental composition was not modified by exacerbation; serum levels of C-reactive protein and procalcitonin at exacerbation were higher than values at recovery. In outpatients who experienced a mild-moderate chronic obstructive pulmonary disease exacerbation, manganese and magnesium levels in exhaled breath condensate are elevated at admission in comparison with values at recovery, whereas no other changes were observed in metallic elements at both the pulmonary and systemic level. PMID- 21305132 TI - Selenosugar determination in porcine liver using multidimensional HPLC with atomic and molecular mass spectrometry. AB - A methodology based on liquid chromatography coupled online with atomic and molecular mass spectrometry was developed for identifying trace amounts of the selenosugar methyl 2-acetamido-2-deoxy-1-seleno-beta-D-galactopyranoside (SeGalNAc) in porcine liver, obtained from an animal that had not received selenium supplementation. Sample preparation was especially critical for the identification of SeGalNAc by molecular mass spectrometry. This involved liver extraction using a Tris buffer, followed by sequential centrifugations. The resulting cytosolic fraction was pre-concentrated and the low molecular weight selenium (LMWSe) fraction obtained from a size exclusion column was collected, concentrated, and subsequently analyzed using a tandem dual-column HPLC-ICP-MS system which consisted of strong cation exchange (SCX) and reversed phase (RP) columns coupled in tandem. Hepatocytosolic SeGalNAc was tentatively identified by retention time matching and spiking. Its identity was further confirmed by using the same type of chromatography on-line with atmospheric pressure chemical ionization tandem mass spectrometry operated in the selected reaction monitoring (SRM) mode. Four SRM transitions, characteristic of SeGalNAc, were monitored and their intensity ratios determined in order to confirm SeGalNAc identification. Instrument limits of detection for SeGalNAc by SCX-RP HPLC-ICP-MS and SCX-RP HPLC APCI-MS/MS were 3.4 and 2.9 MUg Se L(-1), respectively. Selenium mass balance analysis revealed that trace amounts of SeGalNAc, 2.16+/-0.94 MUg Se kg(-1) liver (wet weight) were present in the liver cytosol, corresponding to 0.4% of the total Se content in the porcine liver. PMID- 21305133 TI - Characterization of phytochelatin synthase produced by the primitive red alga Cyanidioschyzon merolae. AB - Phytochelatins (PCs), non-protein peptides with the general structure [(gamma-Glu Cys)n-Gly (n>= 2)], are involved in the detoxification of toxic heavy metals mainly in higher plants. The synthesis of the peptides is mediated by phytochelatin synthase (PCS), which is activated by a range of heavy metals. CmPCS, a PCS-like gene found in the genomic DNA of the primitive red alga Cyanidioschyzon merolae, was isolated and a recombinant protein (rCmPCS) fused with a hexahistidine tag at the N-terminus of CmPCS was produced. The finding that this protein mediated PC synthesis from glutathione in a metal-dependent way clearly establishes that rCmPCS is functional. The maximum activity was attained at a reaction temperature of 50 degrees C, considerably higher than the temperature required for the maximal activity of PCS isolated from the higher plant Silene cucubalus, probably due to the alga being a thermophile. CmPCS showed optimal pH in a slightly higher region than higher plant PCSs, probably due to the less effective charge relay network in the catalytic triad. In addition, the pattern of enzyme activation by metal ions was specific to rCmPCS, with Ag+, Cu2+, and Hg2+ showing only limited activation. In contrast to other eukaryotic PCSs, CmPCS has an extra domain in the N-terminal region from residues 1 to 109, and contains fewer cysteine residues in the C-terminal domain. These differences may be responsible for the metal specificity of the activation of CmPCS. Although the enzyme preparation lost PCS activity progressively when stored at 4 degrees C, the inclusion of Cd2+ in the preparation effectively prevented the reduction of activity. Furthermore, Cd2+ effectively restored the activity of the inactivated enzyme. These results indicate that Cd2+ ions bind the enzyme to maintain the structural integrity of the peptides. PMID- 21305139 TI - Gastrins, iron and colorectal cancer. AB - This minireview explores the connections between circulating gastrins, iron status and colorectal cancer. The peptide hormone gastrin is a major regulator of acid secretion and a potent mitogen for normal and malignant gastrointestinal cells. Gastrins bind two ferric ions with MUM affinity and, in the case of non amidated forms of the hormone, iron binding is essential for biological activity. The ferric ion ligands have been identified as glutamates 7, 8 and 9 in the 18 amino acid peptide glycine-extended gastrin. An interaction between gastrin and transferrin was first demonstrated by covalent crosslinking techniques, and has been recently confirmed by surface plasmon resonance. We have therefore proposed that gastrins act as catalysts in the loading of transferrin with iron. Several recent lines of evidence, including the facts that the concentrations of circulating gastrins are increased in mice and humans with the iron overload disease haemochromatosis, and that transferrin saturation positively correlates with circulating gastrin concentrations, suggest that gastrins may be involved in iron homeostasis. In addition the recognition that ferric ions may play an unexpected role in the biological activity of non-amidated gastrins may assist in the development of new therapies for colorectal carcinoma. PMID- 21305140 TI - Chromium interactions in plants: current status and future strategies. AB - Chromium has received relatively little attention from plant scientists compared to other heavy metals in recent times in spite of it being a very a hazardous environmental pollutant. One of the reasons for this is the complexity of the metal's interactions with biological systems and the difficulty in studying them. Although the possible mode of entry into the plants, resultant toxicity mechanisms and tolerance potential has been worked out in plants there is still a need to get a complete picture of the Cr-plant interactome. With the advent of hyphenated technologies and global gene/protein and metabolite expression/quantification techniques, studies to elucidate the complete metallome are possible albeit resource intensive. This minireview focuses on the recent developments in the field of Cr-plant interactions and proposes a model using a systems biology and integrated -omics approach to decipher the intricacies of Cr plant interaction. PMID- 21305141 TI - Metallomic EPR spectroscopy. AB - Based on explicit definitions of biomolecular EPR spectroscopy and of the metallome, this tutorial review positions EPR in the field of metallomics as a unique method to study native, integrated systems of metallobiomolecular coordination complexes subject to external stimuli. The specific techniques of whole-system bioEPR spectroscopy are described and their historic, recent, and anticipated applications are discussed. PMID- 21305142 TI - Metal ion binding of the first external loop of DCT1 in aqueous solution. AB - The binding of the external loop1 of DCT1 with divalent metal cations was first verified by the NMR measurements of isolated peptides and the binding sites were determined. PMID- 21305143 TI - The tungsten metallome of Pyrococcus furiosus. AB - The tungsten metallome of the hyperthermophilic archaeon Pyrococcus furiosus has been investigated using electroanalytical metal analysis and native-native 2D PAGE with the radioactive tungsten isotope (187)W (t(1/2) = 23.9 h). P. furiosus cells have an intracellular tungsten concentration of 29 MUM, of which ca. 30% appears to be free tungsten, probably in the form of tungstate or polytungstates. The remaining 70% is bound by five different tungsten enzymes: formaldehyde ferredoxin oxidoreductase, aldehyde ferredoxin oxidoreductase, glyceraldehyde-3 phosphate ferredoxin oxidoreductase and the tungsten-containing oxidoreductases WOR4 and WOR5. The membrane proteome of P. furiosus is devoid of tungsten. The differential expression, as measured by the tungsten level, of the five soluble tungsten enzymes when the cells are subjected to a cold-shock shows a strong correlation with previously published DNA microarray analyses. PMID- 21305144 TI - Probing the interaction of arsenobetaine with blood plasma constituents in vitro: an SEC-ICP-AES study. AB - Arsenobetaine, which is frequently ingested by humans via the consumption of seafood, is rapidly excreted unchanged in urine, but not much is known about its transport in the mammalian bloodstream. To assess whether this transport involves binding to plasma proteins, rabbit and human plasma were spiked with arsenobetaine and the mixture was analyzed (after 5 min and again after 6 h) by size-exclusion chromatography (SEC) coupled on-line to an inductively coupled plasma atomic emission spectrometer (ICP-AES). Simultaneous monitoring of the emission lines of As, Cu, Fe and Zn in the column effluent allowed us to determine the elution of arsenobetaine relative to that of the major Cu, Fe and Zn-containing metalloproteins. Over the investigated time period, a single As peak eluted near the inclusion volume on two different SEC columns with fractionation ranges of 600-10 KDa and 7000-100 Da. These results indicate that arsenobetaine did not bind to plasma proteins and that SEC-ICP-AES is a useful tool to rapidly probe toxicologically and pharmacologically-relevant interactions between organometalloid compounds and mammalian blood plasma constituents in vitro. PMID- 21305145 TI - Synthesis and evaluation of Ciprofloxacin derivatives as diagnostic tools for bacterial infection by Staphylococcus aureus. AB - Development of target-specific diagnostic radiopharmaceuticals has always been a challenging task. For this purpose, design and development of the imaging friendly variant of a potent antibiotic could aid in treatment planning and follow-up of patients with hard-to-diagnose bacterial infections. Fluoroquinolone analogues were synthesized taking the lead from Ciprofloxacin (the broad spectrum antibiotic) molecule. The idea of modifying fluoroquinolones, and subsequently labeling them, was to preserve their capacity to bind bacteria and thereby enable the compound to specifically target those microorganisms. Three compounds were thus synthesized as derivatives of Ciprofloxacin. The fluoroquinolone analogues were labeled with (99m)Tc by using (99m)Tc pertechnetate with high labeling efficiency for all the formulations. The complexes formed by chelation of (99m)Tc with our synthesized fluoroquinolone analogues showed good in vitro serum stability. The blood clearance study performed in New Zealand White rabbits exhibited a curve indicating the initial fast phase in which radiocomplexed drugs cleared from blood very quickly followed by a slow phase. The in vivo evaluation showed that fluoroquinolone-based radiopharmaceuticals bind to the bacteria present at the site of infection, which results in the retention of the agent at sites of active bacterial infection. The biodistribution data and the scintigrams demonstrated that Staphylococcus aureus bacteria in animal infection models took up the radiopharmaceutical formulations, confirming our hypothesis that (99m)Tc fluoroquinolone derivatives might be useful as diagnostic agents for targeted delivery in bacterial infections. PMID- 21305146 TI - Simultaneous iron, zinc, sulfur and phosphorus speciation analysis of barley grain tissues using SEC-ICP-MS and IP-ICP-MS. AB - The increasing prevalence of iron (Fe) and zinc (Zn) deficiencies in human populations worldwide has stressed the need for more information about the distribution and chemical speciation of these elements in cereal products. In order to investigate these aspects, barley grains were fractionated into awns, embryo, bran and endosperm and analysed for Fe and Zn. Simultaneously, phosphorus (P) and sulfur (S) were determined since these elements are major constituents of phytic acid and proteins, respectively, compounds which are potentially involved in Fe and Zn binding. A novel analytical method was developed in which oxygen was added to the octopole reaction cell of the ICP-MS. This approach greatly improved the sensitivity of sulfur, measured as (48)SO(+). Simultaneously, Fe was measured as (72)FeO(+), P as (47)PO(+), and Zn as (66)Zn(+), enabling sensitive and simultaneous analysis of these four elements. The highest concentrations of Zn, Fe, S and P were found in the bran and embryo fractions. Further analysis of the embryo using SEC-ICP-MS revealed that the speciation of Fe and Zn differed. The majority of Fe co-eluted with P as a species with the apparent mass of 12.3 kDa, whereas the majority of Zn co-eluted with S as a 3 kDa species, devoid of any co eluting P. Subsequent ion pairing chromatography of the Fe/P peak showed that phytic acid (myo-inositol-1,2,3,4,5,6-hexakisphosphate: IP(6)) was the main Fe binding ligand, with the stoichiometry Fe(4)(IP(6))(18). When incubating the embryo tissue with phytase, the enzyme responsible for degradation of phytic acid, the extraction efficiency of both Fe and P was doubled, whereas that of Zn and S was unaffected. Protein degradation on the other hand, using protease XIV, boosted the extraction of Zn and S, but not that of Fe and P. It is concluded that Fe and Zn have a different speciation in cereal grain tissues; Zn appears to be mainly bound to peptides, while Fe is mainly associated with phytic acid. PMID- 21305147 TI - Novel gold(I) phosphine compounds inhibit HIV-1 enzymes. AB - The increasing incidence of human immunodeficiency virus (HIV) infection and the associated acquired immune deficiency syndrome (AIDS) mortality rates as well as the sometimes severe side effects of highly active anti retroviral therapy (HAART) warrants the continuous search for new, less toxic drug candidates. The anti-HIV activity (inhibition of reverse transcriptase-RT and protease-PR in direct enzyme assays) of eleven gold(i) phosphine compounds are reported here. Uptake of the compounds by peripheral blood mononuclear cells (PBMCs) was demonstrated by inductively coupled plasma atomic emission spectroscopy (ICP-AES) while the effect of the compounds on cell viability was assessed using flow cytometry with annexin V and propidium iodide (PI). Of the 11 gold compounds tested, 7 significantly (p < 0.05) inhibited RT activity at concentrations of 25 and 250 MUM while 3 compounds significantly inhibited its activity at 6.25 MUM. In the anti-protease assay, 4 of the compounds significantly inhibited the enzyme (p < 0.05) at 100 MUM. All of the compounds were taken up by PBMCs (demonstrated by ICP-AES) and were non toxic to these cells at clinically tolerable concentrations. The potential of these novel gold(i) phosphine compounds as anti HIV agents is therefore promising and worthy of further investigation. PMID- 21305148 TI - Reactivity of an antimetastatic organometallic ruthenium compound with metallothionein-2: relevance to the mechanism of action. AB - The reaction of metallothionein-2 (MT-2) with the organometallic antitumour compound [Ru(eta(6)-p-cymene)Cl(2)(pta)], RAPTA-C, was investigated using ESI MS and ICP AES. The studies were performed in comparison to cisplatin and significant differences in the binding of the two complexes were observed. RAPTA C forms monoadducts with MT-2, at variance with cisplatin, that has been observed to form up to four adducts. These data, combined with ICP AES analysis, show that binding of both RAPTA-C and cisplatin to MT-2 requires the displacement of an equivalent amount of zinc, suggesting that Cys residues are the target binding sites for the two metallodrugs. The competitive binding of RAPTA-C and cisplatin towards a mixture of ubiquitin (Ub) and MT-2 was also studied, showing that MT-2 can abstract RAPTA-C from Ub more efficiently than it can abstract cisplatin. The mechanistic implications of these results are discussed. PMID- 21305154 TI - Recent developments in ruthenium anticancer drugs. AB - Interest in Ru anticancer drugs has been growing rapidly since NAMI-A ((ImH(+))[Ru(III)Cl(4)(Im)(S-dmso)], where Im = imidazole and S-dmso = S-bound dimethylsulfoxide) or KP1019 ((IndH(+))[Ru(III)Cl(4)(Ind)(2)], where Ind = indazole) have successfully completed phase I clinical trials and an array of other Ru complexes have shown promise for future development. Herein, the recent literature is reviewed critically to ascertain likely mechanisms of action of Ru based anticancer drugs, with the emphasis on their reactions with biological media. The most likely interactions of Ru complexes are with: (i) albumin and transferrin in blood plasma, the former serving as a Ru depot, and the latter possibly providing active transport of Ru into cells; (ii) collagens of the extracellular matrix and actins on the cell surface, which are likely to be involved in the specific anti-metastatic action of Ru complexes; (iii) regulatory enzymes within the cell membrane and/or in the cytoplasm; and (iv) DNA in the cell nucleus. Some types of Ru complexes can also promote the intracellular formation of free radical species, either through irradiation (photodynamic therapy), or through reactions with cellular reductants. The metabolic pathways involve competition among reduction, aquation, and hydrolysis in the extracellular medium; binding to transport proteins, the extracellular matrix, and cell-surface biomolecules; and diffusion into cells; with the extent to which individual drugs participate in various steps along these pathways being crucial factors in determining whether they are mainly anti-metastatic or cytotoxic. This diversity of modes of action of Ru anticancer drugs is also likely to enhance their anticancer activities and to reduce the potential for them to develop tumour resistance. New approaches to metabolic studies, such as X-ray absorption spectroscopy and X-ray fluorescence microscopy, are required to provide further mechanistic insights, which could lead to the rational design of improved Ru anticancer drugs. PMID- 21305155 TI - Beryllium uptake and related biological effects studied in THP-1 differentiated macrophages. AB - Investigation of cellular uptake of metal compounds is important in understanding metal-related toxicity and diseases. Inhalation of beryllium aerosols can cause chronic beryllium disease, a progressive, granulomatous fibrosis of the lung. Studies in laboratory animals and cultured animal cells indicate that alveolar macrophages take up beryllium compounds and participate in a hypersensitivity immune response to a beryllium-containing antigen. In the present work, human monocyte cell line THP-1 was induced with phorbol myristate acetate to differentiate into a macrophage. This cell with characteristics of human alveolar macrophages was employed to study cellular beryllium uptake and related biological effects. Morphological changes, phagocytosis of fluorescent latex beads, and cell surface CD14 expression were used to verify the successful differentiation of THP-1 monocytes into macrophages. An improved mass spectrometry method for quantitative analysis of intracellular beryllium as opposed to the traditional radioisotopic approach was developed using ICP-MS. The influence of the solubility of beryllium compounds, exposure duration, and beryllium concentration on the incorporation of beryllium was studied. Our data indicated that the uptake of particulate BeO was much more significant than that of soluble BeSO(4), suggesting the major cellular uptake pathway is phagocytosis. Nevertheless, subsequent DAPI nuclear staining and PARP cleavage study indicated that beryllium uptake had a negligible effect on the apoptosis of THP-1 macrophages compared to the unstimulated macrophage control. Meanwhile, no substantial variation of tumour necrosis factor-alpha production was observed for THP-1 macrophages upon beryllium exposure. These data imply alveolar macrophages could have some level of tolerance to beryllium and this may explain why most Be exposed individuals remain healthy throughout life. PMID- 21305156 TI - Incorporation of excess gadolinium into human bone from medical contrast agents. AB - We find anomalously high gadolinium (Gd) concentrations in the femoral head bones of patients exposed to chelated Gd, commonly used as a contrast agent for medical imaging. Gd is introduced in chelated form to protect patients from exposure to toxic free Gd(3+), a calcium antagonist which disrupts cellular processes. Recent studies suggest Gd chelates break down in vivo, and Gd accumulation in tissue is linked to medical conditions such as nephrogenic systemic fibrosis (NSF), acute kidney failure, and in some cases death. We measure Gd and other rare earth element (REE) concentrations in 35 femoral heads by solution based ICP-MS. Gd concentrations in patients with documented exposure to Gd-based contrast agents (n = 13: Gd DTPA-BMA (Omniscan) n = 6; Gd HP-DO3A (Prohance) n = 5; unknown type n = 4) are significantly higher (p < 0.001) than the control group (n = 17). We use our control group to establish the 'natural' background level of Gd in human bone (cortical 95% CI: 0.023, 0.041 nmol/g; trabecular 95% CI: 0.054, 0.107 nmol/g). A control group outlier reveals the occurrence of individuals with high concentrations of all REEs, including Gd. Because of this, we calculate Gd anomalies from the concentrations of adjacent REEs and normalize to the control group mean to isolate Gd input from contrast agents. Normalized Gd anomalies, (Gd/Gd*)(N), for exposed patients range up to >800 times the 'natural' level (95% CI: 124, 460). Our data confirm that Gd, introduced in chelated form, incorporates into bone and is retained for more than 8 years. No difference was observed in bone Gd concentrations and anomalies between patients dosed with Gd DTPA-BMA (Omniscan; n = 6) and Gd HP-DO3A (Prohance; n = 5). Osteoporotic fracture patients exposed to Gd have significantly lower Gd concentrations than osteoarthritis patients (p < 0.001). This indicates different mechanisms of metal incorporation and/or retention in osteoporotic bone tissues, and may signal an increased risk of endogenous Gd release for patients with increased rates of bone resorption (e.g. osteoporosis patients and menopausal, pregnant, and lactating women) who are exposed to Gd-based contrast agents. PMID- 21305157 TI - The plant metallothionein 2 from Cicer arietinum forms a single metal-thiolate cluster. AB - The plant metallothionein 2 from Cicer arietinum (chickpea; cicMT2) is a typical member of this subfamily and features two cysteine-rich regions containing eight and six cysteine residues, respectively, separated by a linker region 41 amino acids in length. This metallothionein thus differs significantly from the well studied vertebrate forms. A synthetic gene encoding cicMT2 was designed, cloned into a suitable vector, and the protein was over-expressed in Escherichia coli. For the first time, an in-depth spectroscopic characterization of cicMT2 in the presence of divalent metal ions is performed showing a binding capacity for five Zn(II), Cd(II), or Co(II) ions and the typical features of metal-thiolate clusters. Based on proteolytic digestion experiments, the cluster arrangement formed by the divalent metal ions and the cysteine thiolate groups connects the amino-terminal with the carboxy-terminal cysteine-rich region. The cluster formation process, put into effect with the addition of the fourth metal ion to the apo protein, was investigated using the characteristic shift of absorption bands observed in the UV/Vis spectra upon titration with Co(II). The pH-dependent Zn(II)- and Cd(II)-thiolate cluster stability is one of the highest observed for plant MTs so far, but lower than that usually found in vertebrate metallothioneins. The dependence of the pH stability on the ionic strength of the solution is more pronounced for the Cd(II)- than for the Zn(II)-form of the protein. PMID- 21305158 TI - Denaturing and non-denaturing microsolution isoelectric focussing to mine the metalloproteome. AB - Metals bound to proteins play essential roles in living systems. Elements such as phosphorus, selenium and iodine are commonly covalently linked to proteins while others are non-covalently complexed. Thus, the identification and characterization of the metal-protein complexes require a careful hyphenation of techniques able to separate and detect the intact binding complexes with both high resolution and high sensitivity. This study has investigated for the first time the potential of microsolution isoelectric focussing to separate a mixture of metal-binding protein standards under well-established denaturing conditions and a novel non-denaturing separation protocol has also been developed. SEC-ICP MS analysis was used to evaluate the ability of the two separation procedures to separate and maintain the integrity of standard metal-protein complexes. Microsolution isoelectric focussing under denaturing conditions separates the metalloprotein mixtures with high resolution, although the stability of the complexes is affected. Microsolution isoelectric focussing under our newly developed non-denaturing conditions shows a lower degree of resolution, although the stability of the metal-protein complexes is preserved. The applicability of the two procedures to a biological metalloproteome has also been evaluated. PMID- 21305159 TI - Pseudo-halide derivatives of titanocene: synthesis and cytotoxicity studies. AB - The well-known anticancer drug candidate bis-[(p-methoxybenzyl)cyclopentadienyl] titanium(IV) dichloride (Titanocene ) was reacted with sodium azide or potassium cyanate, thiocyanate or selenocyanate in order to give pseudo-halide analogues of Titanocene . and were characterised by single crystal X-ray diffraction, which confirmed the expected nitrogen binding of the cyanate and thiocyanate to the titanium centre. All four titanocenes had their cytotoxicity investigated through preliminary in vitro testing on the LLC-PK (pig kidney epithelial) cell line in an MTT based assay in order to determine their IC50 values. Titanocenes were found to have IC50 values of 24 (+/- 8) MUM, 101 (+/- 14) MUM, 54 (+/- 21) MUM and 27 (+/- 4) MUM respectively. All four titanocene derivatives show significant cytotoxicity improvement when compared to unsubstituted titanocene dichloride and and showed similiar cytotoxic behaviour to Titanocene in vitro. PMID- 21305160 TI - The metallomics approach: use of Fe(II) and Cu(II) footprinting to examine metal binding sites on serum albumins. AB - Metal binding to serum albumins is examined by oxidative protein-cleavage chemistry, and relative affinities of multiple metal ions to particular sites on these proteins were identified using a fast and reliable chemical footprinting approach. Fe(ii) and Cu(ii), for example, mediate protein cleavage at their respective binding sites on serum albumins, in the presence of hydrogen peroxide and ascorbate. This metal-mediated protein-cleavge reaction is used to evaluate the binding of metal ions, Na(+), Mg(2+), Ca(2+), Al(3+), Cr(3+), Mn(2+), Co(2+), Ni(2+), Zn(2+), Cd(2+), Hg(2+), Pb(2+), and Ce(3+) to albumins, and the relative affinities (selectivities) of the metal ions are rapidly evaluated by examining the extent of inhibition of protein cleavage. Four distinct systems Fe(II)/BSA, Cu(II)/BSA, Fe(II)/HSA and Cu(II)/HSA are examined using the above strategy. This metallomics approach is novel, even though the cleavage of serum albumins by Fe(II)/Cu(II) has been reported previously by this laboratory and many others. The protein cleavage products were analyzed by SDS PAGE, and the intensities of the product bands quantified to evaluate the extent of inhibition of the cleavage and thereby evaluate the relative binding affinities of specific metal ions to particular sites on albumins. The data show that Co(II) and Cr(III) showed the highest degree of inhibition, across the table, followed by Mn(II) and Ce(III). Alakali metal ions and alkaline earth metal ions showed very poor affinity for these metal sites on albumins. Thus, metal binding profiles for particular sites on proteins can be obtained quickly and accurately, using the metallomics approach. PMID- 21305227 TI - Effects of botulinum toxin A in ambulant adults with spastic cerebral palsy: a randomized double-blind placebo controlled-trial. AB - OBJECTIVE: This study aimed to assess short-term effects of botulinum toxin A in ambulant adults with spastic cerebral palsy. DESIGN: A single-centre double blind, placebo-controlled, randomized clinical trial. SUBJECTS: Patients were recruited through advertisements. Inclusion criteria were: spastic cerebral palsy, age 18-65 years, decreased walking, walking without aids for minimum 20 m, and no cognitive impairments. METHODS: A total of 66 participants, mean age 37 (standard deviation 11.4) years, were enrolled and received injections of either botulinum toxin A (n=33) or placebo (n=33). Primary outcomes were: sagittal kinematics of ankle, knee and hip, and health-related quality of life (Short Form 36). Secondary outcomes were: visual analogue scale for muscle stiffness/spasticity, Timed Up and Go, 6-minute walk test, and Global Scale of perceived effect. RESULTS: No significant differences were found between the groups in the primary outcomes. In the secondary outcomes the botulinum toxin A group rated improvement in visual analogue scale muscle-stiffness/spasticity and the Global Scale of perceived effect. No serious adverse events occurred. CONCLUSION: Botulinum toxin A injections alone gave no benefit over placebo in lower limb sagittal kinematics and Short Form 36 in ambulatory adults with cerebral palsy. However, self-reported rating of muscle-stiffness/spasticity and global effects indicated positive effects of botulinum toxin A. Further studies with specific post-injection rehabilitation and longer study period are warranted. PMID- 21305228 TI - Feasibility of using an in-home video conferencing system in geriatric rehabilitation. AB - OBJECTIVE: This pilot study trialled an in-home videoconferencing system to determine the feasibility of delivering rehabilitation services remotely to aged clients. METHODS: Patients approved for community-based transition care were prospectively recruited to trial the eHABTM video-conferencing system. Staff completed patient logs to record reasons for patient exclusion/inclusion. A staff satisfaction survey recorded qualitative feedback on the operation of eHABTM. RESULTS: Of 44 patients admitted to transition care, 34 (77%) were considered unsuitable for telerehabilitation, due mainly to hearing and/or vision impairment, client/carer anxiety, lack of space in the home, and cognitive impairment. Three proceeded with set-up and use of eHABTM. Staff reported that telerehabilitation was particularly challenging because of the complexity of cases, with many requiring "hands-on" therapy. CONCLUSION: To implement telerehabilitation more widely in older people there are barriers to be overcome relating to patient limitations, staff issues and the logistics of the system. PMID- 21305229 TI - Early rehabilitation management after stroke: what do stroke patients prefer? AB - BACKGROUND: Stroke rehabilitation is moving towards more intense therapy models that incorporate technologies such as robotics and computer games. It is unclear how acceptable these changes will be to stroke survivors, as little is known about which aspects of rehabilitation programmes are currently valued. Discrete choice experiments are a potential approach to assessing patient preferences, as they reveal the characteristics of programmes that are most important to consumers. METHODS: A discrete choice experiment was presented as a face-to-face interview to assess the priorities and preferences of stroke survivors (n=50, mean age 72 years) for alternative rehabilitation service configurations. The discrete choice experiment was presented to the participants while they were on the stroke rehabilitation ward (approximately 3-4 weeks following stroke). RESULTS: Participants were highly focused on recovery and expressed strong preferences for therapy delivered one-to-one, but they did not favour very high intensity programmes (6 hours per day). While the attitudinal statements indicated high levels of agreement for programmes to incorporate the latest technology, the results from the discrete choice experiment indicated that participants were averse to computer-delivered therapy. CONCLUSION: Whilst rehabilitation therapy is highly valued, stroke survivors exhibited stronger preferences for low-intensity programmes and rest periods. High-intensity therapy protocols or approaches dependent on new technologies will require careful introduction to achieve uptake and acceptability. PMID- 21305230 TI - Religiousness affects mental health, pain and quality of life in older people in an outpatient rehabilitation setting. AB - OBJECTIVES: To evaluate the relationship between religiousness and mental health, hospitalization, pain, disability and quality of life in older adults from an outpatient rehabilitation setting in Sao Paulo, Brazil. DESIGN: Cross-sectional study. SUBJECTS/PATIENTS: A total of 110 patients aged 60 years or older were interviewed during attendance at an outpatient rehabilitation service. METHODS: Researchers administered a standardized questionnaire that assessed socio demographic data, religiousness, self-reported quality of life, anxiety, physical activity limitation, depression, pain and cognition. Predictors were included in each model analysis, and a backward conditional method was used for variable selection using logistic regression (categorical outcomes) or linear regression (continuous outcomes). RESULTS: Thirty-one patients (28.2%) fulfilled criteria for significant depressive symptoms, 27 (24.5%) for anxiety, and 10 (9.6%) for cognitive impairment. Pain was present in 89 (80.7%) patients. Limited depressive symptoms (as assessed by the Geriatric Depression Scale), and greater self reported quality of life were related to greater self-reported religiousness, as were scores on the Mini-Mental State Examination (less cognitive impairment), and lower ratings of pain. CONCLUSION: Religiousness is related to significantly less depressive symptoms, better quality of life, less cognitive impairment, and less perceived pain. Clinicians should consider taking a spiritual history and ensuring that spiritual needs are addressed among older patients in rehabilitation settings. PMID- 21305231 TI - Effects of selective tibial nerve neurotomy as a treatment for adults presenting with spastic equinovarus foot: a systematic review. AB - OBJECTIVE: Spastic equinovarus foot is a major cause of disability for neurorehabilitation patients, impairing their daily activities, social participation and general quality of life. Selective tibial nerve neurotomy is a neurosurgical treatment for focal spasticity, whose acceptance as treatment for spastic equinovarus foot remains controversial. We performed a systematic review of the literature to assess the efficacy of tibial nerve neurotomy as a treatment for adult patients presenting with spastic equinovarus foot. METHODS: We queried PubMed, Science Direct, Trip Database and PEDro databases with the following keywords: "equinus deformity" OR "muscle spasticity" AND "neurotomy." RESULTS: We selected a total of 11 non-randomized and uncontrolled studies, suggesting that neurotomy could be an efficient treatment to reduce impairments in spastic equinovarus foot patients. DISCUSSION: Our conclusions are based primarily on case series studies. The effects of tibial nerve neurotomy had not been compared with a reference treatment through a randomized controlled trial, which would be necessary to increase the level of scientific evidence. Moreover, further studies using quantitative, validated and objective assessment tools are required to evaluate the efficacy of tibial nerve neurotomy accurately based on the International Classification of Functioning, Disability and Health from the World Health Organization. PMID- 21305232 TI - Systematic review of outcome measures used in the evaluation of robot-assisted upper limb exercise in stroke. AB - OBJECTIVE: To classify and evaluate outcome measures currently used in robot assisted exercise trials (RAET) in stroke, and to determine selection criteria for outcome measures in future trials. METHODS: Outcome measures used in RAET were identified from MEDLINE, EMBASE, CINAHL, PubMed and PsychINFO databases. The scale items were categorized into International Classification of Functioning Disability and Health (ICF) domains. The psychometric properties of scale were rated using a standardized pro forma. RESULTS: Thirty outcome measures were identified from 28 published RAET. Commonly used ICF body function scales were: Fugl-Meyer (FM) (24 studies), Modified Ashworth Scale (13 studies), Medical Research Council (11 studies), Kinematic measures (8 studies) and Motor Status Score (6 studies); ICF activity scale was Functional Independence Measure (FIMTM) (9 studies); ICF participation, personal and environmental factors scales were rarely used. Standard-ized rating identified that FM, kinematic measures, Action Research Arm Test, Wolf Motor Function Test, FIMTM, and ABILHAND have adequate measurement properties for use in RAET. CONCLUSION: Some of the currently used outcome measures seem appropriate for RAET. The use of the ICF framework enables selection of an appropriate combination of outcome measures depending on patient characteristics, such as severity of weakness and chronicity of stroke impairments. PMID- 21305233 TI - Coping styles within the family system in the chronic phase following acquired brain injury: its relation to families' and patients' functioning. AB - OBJECTIVE: To investigate how the functioning of family members and the coping styles they use are related to the psychosocial functioning both of the family members and of the person who has sustained a brain injury. DESIGN: Cross sectional study. SUBJECTS: Primary caregivers (n = 61) and other family members (n = 15) of 61 patients with brain injury. METHODS: Primary caregivers completed the Utrecht Coping List, the Life Satisfaction Questionnaire 9, and the Caregiver Strain Index. All family members completed the Family Assessment Device. Data for the patients were collected retrospectively. RESULTS: Primary caregivers who had a preference for passive coping styles reported that they experienced a lower level of family functioning, a lower quality of life, and a higher strain. Neither the coping styles nor the psychosocial outcomes of the primary caregivers were significantly associated with patients' self-reported quality of life. Furthermore, there was no correlation between the level of family functioning and a patient's quality of life. CONCLUSION: Coping styles of caregivers are important determinants for their own psychosocial functioning, but not for patients' psychosocial functioning, although causality cannot be inferred. To enhance caregivers' psychosocial functioning, rehabilitation should focus on changing their coping styles into ones that are less passive. Furthermore, distinct or additional interventions may be needed to change the patient's coping style. PMID- 21305234 TI - Prevalence and impact of joint symptoms in people with stroke aged 55 years and over. AB - OBJECTIVE: To establish the prevalence and patterns of self-reported musculoskeletal symptoms in community-dwelling stroke survivors and their impact on common activities of daily living. METHODS: Analysis of data from two consecutive postal surveys in northern England. Data on overall joint pain, swelling or stiffness and difficulties with daily living tasks were obtained from 16,222 individuals aged >= 55 years (a response rate of 86%). Information on stroke-specific impairments was obtained from the 415 individuals who reported a stroke. RESULTS: Forty-seven percent of stroke survivors reported musculoskeletal symptoms. There was a greater prevalence of reported symptoms in the smaller peripheral joints: 23.4% of stroke survivors reported symptoms in the ankle joint compared with 12.3% in the general population aged >= 55 years. Although both stroke-specific impairments and musculoskeletal pain contributed to difficulty in functional tasks, the effect of both was more than additive (for example, left hip symptoms increased the risk of having difficulty with standing and walking by 10.3 times (95% confidence interval 1.0, 106.3); stroke affecting the right leg increased the odds by 4.8 times (95% confidence interval 2.5, 9.2). Having both impairments increased the odds by 49.1 times (95% confidence interval 10.7, 225.4)). CONCLUSION: Musculoskeletal symptoms are common in people with stroke and can have a significant additional effect on disability. PMID- 21305235 TI - Support/services and family carers of persons with stroke impairment: perceived importance and services received. AB - OBJECTIVE: To examine what family carers of persons with stroke impairment perceive as important support and service quality characteristics in relation to their experienced strain/burden, and to explore to what extent family carers receive support/services perceived as important. DESIGN: Data from a cross sectional study. SUBJECTS: A sample of 183 family carers in Sweden, 64 experiencing lower and 119 experiencing higher strain/burden, a subsample of the EUROFAMCARE project. METHODS: Carers were interviewed using a structured questionnaire. RESULTS: There are few differences between carers experiencing high and low strain/burden in what they perceive and receive in terms of important support and service quality characteristics. Information, relief, and counselling support/services are highly valued. It is also important that services improve quality of life, and have good process qualities regarding interaction with staff and individualization. Most services regarded as important are received by less than 60% of carers. CONCLUSION: The variation is rather high on an individual level in terms of what carers regard as important, indicating that factors other than negative impact may influence their perceptions of support/service and service quality. Thus, it is important to know carers' perceptions in order to individualize support/service, and thus make it more available and efficient. PMID- 21305236 TI - Correlation of shoulder range of motion limitations at discharge with limitations in activities and participation one year later in persons with spinal cord injury. AB - OBJECTIVE: To study the correlation between limited shoulder range of motion in persons with spinal cord injury at discharge and the performance of activities, wheeling performance, transfers and participation one year later. DESIGN: Multicentre prospective cohort study. SUBJECTS: A total of 146 newly injured subjects with spinal cord injury. METHODS: Shoulder range of motion was measured at discharge. One year later, Functional Independence Measure (FIM), transfer ability, wheelchair circuit and Physical Activity Scale for Individuals with Physical Disabilities (PASIPD) were assessed. Corrections were made for possible confounding factors (age, gender, level and completeness of injury, time since injury and shoulder pain). RESULTS: All subjects with limited shoulder range of motion at discharge had a lower FIM motor score and were less likely (total group 5 times, and subjects with tetraplegia 10 times less likely) to be able to perform an independent transfer one year later. Subjects with limited shoulder range of motion in the total group needed more time to complete the wheelchair circuit. No significant associations with the PASIPD were found in either group. CONCLUSION: Persons with spinal cord injury and limited shoulder range of motion at discharge are more limited in their activities one year later than those without limited shoulder range of motion. PMID- 21305237 TI - A randomized controlled trial of prospective memory rehabilitation in adults with traumatic brain injury. AB - OBJECTIVE: To examine the efficacy of compensatory prospective memory training, preceded by self-awareness training for adults with traumatic brain injury. DESIGN: Randomized controlled trial with 4 intervention groups: (i) self awareness plus compensatory prospective memory training; (ii) self-awareness training plus active control; (iii) active control plus compensatory prospective memory training; and (iv) active control only. SUBJECTS: Forty-five rehabilitation patients with moderate-severe traumatic brain injury living in the community. METHODS: Four groups of participants completed an 8-session individual intervention programme with pre- and post-assessment by a blind assessor on a standardized test of prospective memory, actual strategy use, relatives' ratings of prospective memory failure, and level of psychosocial reintegration. RESULTS: Larger changes in prospective memory test score and strategy use were found in groups with compensatory prospective memory training compared with those groups without. CONCLUSION: The results provide evidence that prospective memory can be improved in patients with traumatic brain injury using a compensatory approach in a relatively short duration and low intensity intervention. PMID- 21305238 TI - Effectiveness of back school for treatment of pain and functional disability in patients with chronic low back pain: a randomized controlled trial. AB - OBJECTIVE: To evaluate the effectiveness of the addition of back school to exercise and physical treatment modalities in relieving pain and improving the functional status of patients with chronic low back pain. DESIGN: A randomized controlled trial. PATIENTS: A total of 146 patients with chronic low back pain were enrolled in the study. METHODS: Subjects were divided into 2 groups: the back school group received exercise, physical treatment modalities and a back school programme; and the control group received exercise and physical treatment modalities. Treatment efficacy was evaluated at the end of treatment and 3 months post-treatment, in terms of pain, measured with the Visual Analogue Scale, and functional status, measured with the Oswestry Low Back Pain Disability Questionnaire. RESULTS: In both groups, Visual Analogue Scale and Oswestry Low Back Pain Disability Questionnaire were significantly reduced after therapy (p < 0.01), but the difference between the scores at the end of treatment and 3 months post-treatment was not significant. There was a significant improvement in Visual Analogue Scale and Oswestry Low Back Pain Disability Questionnaire in the back school group compared with the control group at the end of therapy and 3 months post-treatment (p < 0.05). CONCLUSION: The addition of back school was more effective than exercise and physical treatment modalities alone in the treatment of patients with chronic low back pain. PMID- 21305239 TI - A long-term intensive behavioral treatment study in patients with persistent vegetative state or minimally conscious state. AB - OBJECTIVE: Persistent vegetative state is regarded as "permanent", if it persists for more than 1 year for traumatic aetiology, or for more than 3 months for other aetiologies. This is also the case for patients in a minimally conscious state. In order to investigate possible improvements after this period we treated and observed 7 such patients over a period of 6 months. DESIGN AND METHODS: An ABA BAB study design was used, with sensory stimulation and social-tactile intervention as treatment regimes. Changes were documented by clinical evaluation and blind behavioural assessment through video monitoring. RESULTS: Clinical scores improved significantly after treatment. Video assessment also indicated significant changes in the patients' behaviour. During the initial period of therapy, social tactile interaction improved patients' activity, while sensory stimulation impaired activity. During the main part of therapy, both types of treatment yielded similar positive results. CONCLUSION: This study indicates the possibility of achieving behavioural improvements with regard to the responsiveness of patients with long-lasting persistent vegetative state and minimally conscious state by use of long-term treatment. PMID- 21305240 TI - Cardiovascular disease risk and the need for prevention after paraplegia determined by conventional multifactorial risk models: the Stockholm spinal cord injury study. AB - OBJECTIVE: To assess the need for intervention on cardio-vascular disease risks in persons with paraplegia according to: (i) two multifactorial risk models; and (ii) these models in combination with the additional risk of overweight/obesity. DESIGN: Cross-sectional. SUBJECTS: A total of 134 out of 153 persons, comprising more than 80% of a regional prevalence population with traumatic paraplegia (American Spinal Injury Association Impairment Scale A-C) of minimum one year duration. METHODS: Participants were screened for cardiovascular disease risk using two multifactorial risk models: the Systematic Coronary Risk Evaluation and the Framingham Risk Equation. Risk factors included were: age, gender, systolic blood pressure, antihypertensive medication, smoking, total cholesterol, high density lipoprotein cholesterol, and total cholesterol/total cholesterol ratio. In addition, overweight/obesity was assessed by body mass index. RESULTS: Twenty seven percent to 36% of the cohort was eligible for cardiovascular disease risk intervention, depending on the risk model used. When overweight/obesity (spinal cord injury adjusted cut-score body mass index >= 22) was also considered, over 80% of the participants qualified for intervention. CONCLUSION: Almost one-third of persons with paraplegia were eligible for cardiovascular disease risk intervention according to authoritative assessment tools. The number in need of intervention was dramatically increased when overweight/obesity as a cardiovascular disease risk was considered. PMID- 21305241 TI - Development and validation of the Chinese version of the Reintegration to Normal Living Index for use with stroke patients. AB - OBJECTIVE: To develop and validate a Chinese version of the Reintegration to Normal Living Index. DESIGN: Descriptive case-series. SUBJECTS: Seventy-five individuals with chronic stroke and 55 age-matched healthy subjects. METHODS: The English version of the Reintegration to Normal Living Index was translated into Chinese using standardized procedures, and then administered to both the stroke and control groups. The same instrument was administered again to the stroke subjects 1-2 weeks later. RESULTS: The Chinese version of the Reintegration to Normal Living Index had good internal consistency (Cronbach's alpha = 0.92) and test-retest reliability (intraclass coefficient = 0.87). The minimal detectable difference of the Index score was 14.8 (out of 100). Convergent validity of the Index was demonstrated by its significant association with Frenchay Activities Index (r = 0.439, p < 0.001) and Personal Wellbeing Index (r = 0.250, p = 0.033) scores among stroke subjects. The Reintegration to Normal Living Index score was significantly lower in the stroke group than in controls (p < 0.001), thus demonstrating discriminant validity. Factor analysis confirmed the two-factor structure of the Index, namely, daily functioning and perception of self. CONCLUSION: The Reintegration to Normal Living Index is a reliable and valid tool for assessing satisfaction with community reintegration among Chinese people with chronic stroke. PMID- 21305242 TI - Tactile spatial resolution in unilateral brain lesions and its correlation with digital dexterity. AB - OBJECTIVE: To test the tactile spatial resolution in chronic unilateral brain lesions. Additionally, since sensory deficits are thought to have an impact on motor deficits, this study investigated the correlation between tactile spatial resolution and finger dexterity. DESIGN: Descriptive cross-sectional study. PATIENTS: Twenty-two patients with unilateral brain lesions (12 children with congenital hemiplegia and 10 patients after stroke). METHODS: Tactile spatial resolution was measured with a grating orientation task, and finger dexterity with the Purdue Pegboard Test. RESULTS: Major tactile spatial resolution deficits were measured on the paretic hand and preserved abilities on the non-paretic hand, both in children with congenital hemiplegia and in patients after stroke. No correlation was found between the deficits of tactile spatial resolution and digital dexterity in the paretic hand (r = 0.126; p = 0.572). CONCLUSION: The specific location of tactile spatial resolution deficits on the hand contralateral to the lesion was surprising when one considers the left hemispheric dominance of tactile spatial resolution in healthy subjects. The absence of correlation between tactile spatial resolution and dexterity deficits suggest that these abilities are not related, suggesting that they should be considered separately and equally integrated into the rehabilitation of unilateral brain lesions. PMID- 21305243 TI - Frequency of discriminative sensory loss in the hand after stroke in a rehabilitation setting. AB - OBJECTIVE: Somatosensory loss following stroke is common, with negative consequences for functional outcome. However, existing studies typically do not include quantitative measures of discriminative sensibility. The aim of this study was to quantify the proportion of stroke patients presenting with discriminative sensory loss of the hand in the post-acute rehabilitation phase. DESIGN: Prospective cohort study of stroke survivors presenting for rehabilitation. PATIENTS: Fifty-one consecutive patients admitted to a metropolitan rehabilitation centre over a continuous 12-month period who met selection criteria. METHODS: Quantitative measures of touch discrimination and limb position sense, with high re-test reliability, good discriminative test properties and objective criteria of abnormality, were employed. Both upper limbs were tested, in counterbalanced order. RESULTS: Impaired touch discrimination was identified in the hand contralateral to the lesion in 47% of patients, and in the ipsilesional hand in 16%. Forty-nine percent showed impaired limb position sense in the contralesional limb and 20% in the ipsilesional limb. Sixty-seven percent demonstrated impairment of at least one modality in the contralesional limb. Ipsilesional impairment was less severe. CONCLUSION: Discriminative sensory impairment was quantified in the contralesional hand in approximately half of stroke patients presenting for rehabilitation. A clinically significant number also experienced impairment in the ipsilesional "unaffected" hand. PMID- 21305244 TI - Contra-lesional somatosensory cortex activity and somatosensory recovery in two stroke patients. AB - OBJECTIVE: We describe here 2 stroke patients who showed activation of the contra lesional somatosensory cortex without activation of the ipsi-lesional somatosensory cortex during proprioceptive input on the affected hand. CASE DESCRIPTION: One patient with intracerebral haemorrhage (a 52-year-old man), 1 patient with middle cerebral artery infarct (a 54-year-old man), and 8 control subjects were recruited. The subscale for kinaesthetic sensation (full mark: 24) of the Nottingham Sensory Assessment improved from 2 points (patient 1 and 2; onset) to 8 points (patient 1) and 12 points (patient 2) at 6 months after onset. Functional magnetic resonance imaging was conducted at 6 months after onset using a 1.5-T Philips MR scanner. Passive movements were performed at the metacarpophalangeal joint. RESULTS: On functional magnetic resonance imaging the contra--lesional (left) primary somatosensory cortex and posterior parietal cortex were activated during passive movements of either hand, which was not observed in control subjects. CONCLUSION: The activation of only the contra lesional somatosensory cortex during passive hand movements in these patients suggests the involvement of this area in somatosensory processing for passive movements after stroke. This area appeared to contribute to recovery of proprioceptive function of the affected hands after stroke. PMID- 21305245 TI - ICF, theories, paradigms and scientific revolution. Re: Towards a unifying theory of rehabilitation. PMID- 21305246 TI - Forty years history of physical medicine and rehabilitation in Iran. PMID- 21305247 TI - Association between change in physical activity and short-term disability progression in multiple sclerosis. AB - OBJECTIVE: This study examined change in physical activity as a behavioral correlate of short-term disability progression in persons with multiple sclerosis over a 6-month period. DESIGN: Panel design. SUBJECTS: The sample included 292 persons with multiple sclerosis. METHODS: Participants wore an accelerometer for 7 days as a measure of physical activity and then provided demographics and clinical information and completed the Patient Determined Disease Steps scale as a measure of disability. After a 6-month period, participants provided information about the occurrence of a relapse in the previous 6 months and again wore an accelerometer for 7 days and completed the Patient Determined Disease Steps scale. RESULTS: Panel analysis indicated associations between baseline physical activity and disability (path coefficient= -0.41, p<0.001) and 6-month change in physical activity and disability progression (path coefficient= -0.09, p=0.025). CONCLUSION: Such findings provide preliminary support for a reduction in physical activity as a behavioral correlate, but not necessarily cause, of short-term disability progression in persons with multiple sclerosis. PMID- 21305248 TI - Suicide gene therapy in head and neck carcinoma cells: an in vitro study. AB - The aim of gene therapy includes the tight spatial and temporal control of transgenic expression. There are several approaches concerning the externally inducible gene promoters used for the control of suicide genes. We have tested the mifepristone-dependent system GeneSwitch to regulate the expression of a deletion mutant of Pseudomonas exotoxin A in the hypopharyngeal carcinoma cell line, FADU. The GeneSwitch system consists of two plasmids, the regulatory plasmid, pSwitch, and the pGene/V5-His plasmid, in which we cloned the toxin mutant (pGene/V5-His-ETA). We stably transfected FADU cells with pSwitch and subsequently transiently separated pSwitch clones with pGene/V5-His-ETA. We tested the inductive capacities of single pSwitch clones, the influence of experimental variations in transfection, the inductive capacities without antibiotic selection pressure, the inductive capacity after re-induction, as well as the background expression levels. In FADU cells the GeneSwitch-ETA combination worked precisely and effectively. Our in vitro study revealed that the use of toxin genes in combination with the GeneSwitch system is a promising approach for gene therapy in head and neck cancer. PMID- 21305249 TI - Effects and relationship of ERK1 and ERK2 in interleukin-1beta-induced alterations in MMP3, MMP13, type II collagen and aggrecan expression in human chondrocytes. AB - Interleukin (IL)-1beta plays an important role in the pathogenesis of osteoarthritis and catabolic processes in articular cartilage. Growing evidence suggests that ERK1/2 activation is involved in IL-1beta-mediated matrix metalloproteinase (MMP) 3, MMP13, type II collagen and aggrecan expression in chondrocytes. To investigate the respective effects and the relationship of ERK1 and ERK2, knockdown of ERK1 and/or ERK2 was performed in human chondrocytes using specific small interfering RNAs (siRNAs), and the cells were treated with IL 1beta (10 ng/ml) for 24 h. Uninfected chondrocytes treated with IL-1beta (10 ng/ml) were used as a positive control. Other cells cultured without IL-1beta or siRNA treatment were used as a negative control. The mRNA levels of MMP3, MMP13, type II collagen and aggrecan were evaluated by quantitative real-time PCR. The protein levels of MMP3 and MMP13 in the culture medium were examined by ELISA. The protein levels of type II collagen, aggrecan, ERK1/2 and phospho-ERK1/2 were evaluated by western blotting. The results indicate that IL-1beta enhances MMP3 and MMP13 expression and inhibits type II collagen and aggrecan expression. Activation of the MAPK/ERK pathway was observed. Knockdown of ERK1 or ERK2 significantly reversed these effects to similar degree. Combined knockdown of ERK1 and ERK2 displayed synergistic effects. ERK1 and phospho-ERK1 or ERK2 and phospho-ERK2 were inhibited by knockdown of ERK1 or ERK2, respectively. No compensatory effect by up-regulation of the opposite isoform was observed. The combined knockdown suppressed ERK1/2 and phospho-ERK1/2. The data suggest that although inhibition of both ERK1 and ERK2 is more effective, inhibition of either ERK isoform may be sufficient and could be used for novel therapies or as drug targets for pharmacological intervention in cartilage breakdown in osteoarthritis. PMID- 21305250 TI - Involvement of endoplasmic reticulum stress-associated apoptosis in a heart failure model induced by chronic myocardial ischemia. AB - Apoptosis plays a critical role in the pathogenesis of chronic myocardial ischemia (CMI) and heart failure (HF). Endoplasmic reticulum stress (ERS) is one of the newly defined signaling pathways which initiate apoptosis. Previous studies have shown that ERS-associated apoptosis is involved in the pathogenesis of HF induced by pressure-overload and acute myocardial infarction. Also, in vitro experiments have proved that ischemia is a strong stimulus of ERS. This study aimed to demonstrate whether ERS-associated apoptosis is involved in the pathogenesis of CMI-induced HF. We established a HF model induced by CMI in mini pigs via placement of an ameroid constrictor around the proximal anterior descending branch of the left coronary artery (LAD). Furthermore, we used myocardial perfusion imaging, echocardiographic and hemodynamic measurements, hematoxylin-eosin staining, and terminal deoxynucleotidyl transferase-mediated DNA nick-end labeling staining to identify the existence of myocardial ischemia and cardiac dysfunction and of enhanced apoptosis in the ischemic heart. We performed immunohistochemistry, Western blot, and real-time PCR to analyze the hallmark of ERS glucose-regulated protein 78 (GRP78). The ERS-associated apoptotic pathways, CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12, and c-Jun NH2-terminal kinase 1 (JNK1) were also examined. We found that all three of these pathways were activated and that GRP78 protein and mRNA levels were significantly enhanced in the myocardium of HF mini pigs induced by CMI. These results suggest that ERS is present in the CMI-induced HF pig model, and that ERS-associated apoptosis is involved in the pathophysiology of HF induced by CMI. PMID- 21305251 TI - Increased expression of neutrophil gelatinase-associated lipocalin receptor by interleukin-1beta in human mesangial cells via MAPK/ERK activation. AB - Neutrophil gelatinase-associated lipocalin (NGAL), one of the most promising next generation biomarkers in clinical nephrology, has received extensive attention. However, the basic role of its receptor (NGALR) remains unclear. Here, we have assessed the expression pattern of NGALR in injured glomeruli and explored the possible mechanism of the NGALR involvement in inflammation in human mesangial cells (HMC). The expression pattern of NGALR was detected by immunohistochemistry in biopsy samples of 93 glomerulonephritis patients and healthy controls, and the regulation of NGALR by the proinflammatory cytokines, TGF-beta1, TNF-alpha and IL 1beta in HMC was analyzed by real-time PCR and Western blotting. NGALR was found to be expressed in glomeruli. Its expression was significantly higher in acute proliferative glomerulonephritis and lupus nephritis than that in other types of glomerulonephritis or healthy kidney tissues. In in vitro experiments, both mRNA and protein levels of NGALR were dramatically induced by treatment of IL-1beta, whereas TGF-beta1 or TNF-alpha did not have the same effect. Furthermore, it was shown that the IL-1beta-induced NGALR expression is mediated via the MAPK/ERK signaling pathway by using pharmacological inhibitors. Interestingly, the basal mRNA levels of NGAL detected in HMC, could be induced by IL-1beta. However, NGAL protein could not be detected, even with IL-1beta treatment. The ability of HMC to express NGAL protein was ascertained by exogenous administration of NGAL. In conclusion, the data show that NGALR is differentially expressed in human glomerular disease and is significantly up-regulated by Il-1beta in HMC via MAPK/ERK activation. Furthermore, exogenous NGAL can be uptaken into HMC. PMID- 21305252 TI - Resistance to telomerase inhibition by human squamous cell carcinoma cell lines. AB - Telomeres are nucleoprotein structures at the ends of chromosomes that are composed of a repetitive G rich sequence and telomeric binding proteins. Telomeres prevent the degradation of chromosomal ends and protect against inappropriate recombination. Telomere attrition involves a tumor suppressor pathway that limits the replication of premalignant cells. The loss of telomeric DNA with each round of replication leads to growth arrest accompanied by senescence or apoptosis. Many tumor cells activate the telomerase gene to bypass senescence. Telomerase is a multisubunit ribonucleoprotein that uses an RNA template to catalyze the addition of telomeric DNA to chromosomal ends. Overexpression of the TERT subunit leads to telomere lengthening and extension of the replicative lifespan. Dominant-negative telomerase has been shown to inhibit telomerase activity in many tumor cell lines, and this is associated with telomere shortening and apoptosis. Additionally, pharmacological telomerase inhibitors have been developed which lead to progressive telomere shortening and programmed cell death. In this study, we report a series of human squamous cell carcinoma cell lines that have high telomerase activity and short telomeres. Dominant-negative telomerase expression and pharmacological telomerase inhibition failed to completely inhibit enzymatic activity which was accompanied by the lack of telomere shortening. These cells continued to proliferate and demonstrated fewer responsive genes when treated with a pharmacological telomerase inhibitor. We concluded that some human squamous cell carcinoma cell lines are resistant to telomerase inhibition. PMID- 21305253 TI - Gene expression analysis using long-term preserved formalin-fixed and paraffin embedded tissue of non-small cell lung cancer. AB - This study was performed to evaluate RNA extraction and gene expression analysis of non-small cell lung cancer (NSCLC) using formalin-fixed and paraffin-embedded (FFPE) specimens stored for more than 20 years by quantitative PCR (qPCR) and DNA microarrays. Long-term preserved FFPE materials enable large retrospective studies correlating molecular features with therapeutic response and clinical outcome. qPCR was used to evaluate RNA extraction methods and to compare DNA microarray gene expression profiles of FFPE and fresh frozen (FF) tissue. The Ambion RecoverAll kit appeared to be suited for RNA extraction of long-term preserved FFPE tissues. Microarray analysis using the Affymetrix platform displayed a high degree of correlation for endogenous control genes comparing FF and FFPE tissues and identified known NSCLC signature genes in both specimens. We conclude that high quality gene expression signatures can be recognized using the Affymetrix gene expression platform on FFPE tissue stored for more than 20 years. However, a general interpretation must be done with caution as different FFPE procedures have varying effects on RNA quality. PMID- 21305254 TI - Proteomics-based signature for human benign prostate hyperplasia and prostate adenocarcinoma. AB - Prostate adenocarcinoma often presents at a late stage, due to a lack of early clinical symptoms and lack of accurate objective markers. This study aimed to identify and validate proteomics-based biomarkers useful for prostate cancer diagnosis and to establish a marker-panel for prostate cancer and benign prostate hyperplasia (BPH). Global protein expression patterns in fresh tissue specimens from 8 patients with prostate carcinoma and 16 with BPH were analyzed by two dimensional gel electrophoresis. Differentially expressed proteins were identified by MALDI-TOF mass spectrometry. We compared our results with those of published studies and defined a set of common biomarkers. We identified 22 differentially expressed proteins between BPH and prostate carcinomas. The up regulated proteins in cancer compared to BPH included protein disulfide isomerase, 14-3-3-protein, Enoyl CoA-hydrase, prohibitin and B-tubulin beta-2. Keratin-II, desmin, HSP71, ATP-synthase-beta-chain and creatine kinase-beta-chain were down-regulated. Survey of the literature showed that 15 of our 22 identified proteins have been previously reported to differ in their expression levels between BPH and prostate cancer by other laboratories. The expression patterns of these biomarkers could successfully cluster BPH and adenocarcinomas as well as prostate cancer of low and high Gleason scores. This study validates protein biomarkers that can be useful for accurate diagnosis and prognostic monitoring of prostate adenocarcinoma. Despite varied prevalence of the disease between different ethnic populations (i.e., high in Sweden, low in Saudi Arabia); the biomarkers indicate that BPH and prostate cancers are biologically 'homogeneous' in their protein expression patterns across wide geographical regions. PMID- 21305255 TI - Enhanced effect of gemcitabine by emodin against pancreatic cancer in vivo via cytochrome C-regulated apoptosis. AB - Gemcitabine is currently the best treatment available for pancreatic cancer, but causes high toxicity. Agents that can enhance the effects of gemcitabine with no or low toxicity are needed for the treatment of pancreatic cancer. Emodin, a natural anthraquinone derivative, is one such agent that has been shown to induce apoptosis in other tumor cells via down-regulation of Bcl-2/Bax and promoting the release of Cytochrome C (CytC), but with very low toxicity. The aim of this study was to evaluate whether emodin can enhance the effect of gemcitabine on pancreatic cancer in vitro and in vivo and to investigate the possible mechanisms of the enhancement. In vitro, emodin inhibited the proliferation of the SW1990 cell line and potentiated the apoptosis induced by gemcitabine, which was demonstrated by activation of caspase-3 in the combination group. In vivo, tumors from nude mice subcutaneously injected with SW1990 cells and treated with a combination of emodin (40 mg/kg) and gemcitabine (80 mg/kg) showed significant reductions in volume, Ki-67 proliferation index and expression of the Bcl-2/Bax ratio (compared with tumors from mice treated with sodium chloride, emodin alone (40 mg/kg) or gemcitabine alone (125 mg/kg), which induced increasing release of CytC from the mitochondria to the cytoplasm and triggered caspase-3 activation leading to apoptosis. Taken together, our results suggest that emodin improved the anti-tumor effect of gemcitabine, even at a lower dose of gemcitabine which could decrease the toxicity of chemotherapy, on transplanted tumors of the SW1990 cell line through the enhancement of apoptosis induced by gemcitabine, the mechanism of which may be through down-regulation of the Bcl-2/Bax ratio and promoting release of CytC from the mitochondria into the cytoplasm. PMID- 21305256 TI - NLS-dependent and insufficient nuclear localization of XAGE-1 splice variants. AB - XAGE-1 is a member of the cancer/testis antigen family and it was first identified by searching for the PAGE/ GAGE-related genes. Four transcript variants XAGE-1a, -1b, -1c and XAGE-1d have been discovered and have a broad expression in cancer. As a prominent transcript, XAGE-1b is encoded by 81 amino acids with a molecular weight of 9 kDa. We determined the cellular localization of all four splice variants by confocal microscopy analysis. Among these, XAGE 1a, -1b and -1c showed distinct speckled nuclear localization, while XAGE-1d was distributed evenly both in the cytoplasm and nucleus. By deletion mutagenesis and site directed mutagenesis, we identified the bipartite nuclear localization signal and found that it contributes to the nuclear localization of XAGE-1 variants; but the nuclear localization signal (NLS) only cannot form the characterized distribution of XAGE-1b; amino acids 25-42 also play a role in the formation of nuclear speckles. XAGE-1b, the main transcript of XAGE-1, may act as a partner protein or a member of a protein complex, which plays a role in tumor development and progression. PMID- 21305257 TI - [Anesthesia for laparoscopic interventions]. AB - Laparoscopic techniques are used in many surgical disciplines and have partially become a standard procedure. Cholecystectomy is performed laparoscopically in 90% of cases. During a pneumoperitoneum changes occur which have a large influence on physiological homeostasis. Furthermore there are specific complications of laparoscopy which can have severe consequences. For adequate management the anesthetist has to be aware of both in order to react in the correct way. PMID- 21305258 TI - [Female patient with Sjoegren's syndrome and cardiolipin antibodies]. AB - Cross-reactions with cardiolipin antibodies and serological lues tests are common. We examined a 37 year old patient with neurological symptoms and signs of Sjoegren's syndrome and secondary antiphospholipid syndrome. But the lues screening test was also positive and the serological tests following approved the lues infection. When an autoimmune disease is diagnosed with the presence of cardiolipin antibodies we recommend also testing for treponema pallidum as a possible disease. PMID- 21305259 TI - [Forced sterilisation based on the Law for the Prevention of Hereditarily Diseased Offspring. The role of the Heil- und Pflegeanstalt (State Hospital) Gunzburg]. AB - OBJECTIVE: From 1934 to 1945, 350,000-400,000 human beings were sterilised by force in the German Reich. Forced sterilisation was based on the Gesetz zur Verhutung erbkranken Nachwuchses (Law for the Prevention of Hereditarily Diseased Offspring). The Heil- und Pflegeanstalt (State Hospital) Gunzburg was one of the institutions where compulsory sterilisation was practised. METHODS: Data evaluation was based on patient documents and annual reports of the archives of today's district hospital at Gunzburg. Patient records were analysed with respect to predefined criteria. The municipal archives of Gunzburg provided further historical sources and data. RESULTS: Between 1934 and 1943, 366 patients were sterilised in the Heil- und Pflegeanstalt (State Hospital) Gunzburg. Age, sex and diagnosis were found to be criteria relevant for selection of patients for sterilisation. CONCLUSIONS: The study was able to show the active involvement of the Heil- und Pflegeanstalt (State Hospital) Gunzburg in the compulsory sterilisation programme. PMID- 21305260 TI - [Training in iterative hypothesis testing as part of psychiatric education. A randomized study]. AB - BACKGROUND: The improvement of medical education is at the center of efforts to reform the studies of medicine. Furthermore, an excellent teaching program for students is a quality feature of medical universities. Besides teaching of disease-specific contents, the acquisition of interpersonal and decision-making skills is important. However, the cognitive style of senior physicians leading to a diagnosis cannot easily be taught. Therefore, the following study aimed at examining whether specific training in iterative hypothesis testing (IHT) may improve the correctness of the diagnostic process. MATERIALS AND METHODS: Seventy one medical students in their 9th-11th terms were randomized to medical teaching as usual or to IHT training for 4 weeks. The intervention group received specific training according to the method of IHT. All students were examined by a multiple choice (MC) exam and additionally by simulated patients (SP). The SPs were instructed to represent either a patient with depression and comorbid anxiety and substance use disorder (SP1) or to represent a patient with depression, obsessive compulsive disorder and acute suicidal tendencies (SP2). RESULTS: All students identified the diagnosis of major depression in the SPs, but IHT-trained students recognized more diagnostic criteria. Furthermore, IHT-trained students recognized acute suicide tendencies in SP2 more often and identified more comorbid psychiatric disorders. The results of the MC exam were comparable in both groups. An analysis of the satisfaction with the different training programs revealed that the IHT training received a better appraisal. CONCLUSIONS: Our results point to the role of IHT in teaching diagnostic skills. However, the results of the MC exam were not influenced by IHT training. Furthermore, our results show that students are in need of training in practical clinical skills. PMID- 21305261 TI - [Epidemiology and psychopathology of persons running amok. Initial results of an analysis of criminal acts perpetrated by 27 persons running amok]. AB - In order to clarify psychosocial and psychopathological components that may contribute to causes of running amok, judgements and forensic-psychiatric certificates of 27 amok runners were examined. While in the last 20 years there was no increase of amok events in general, a remarkable increase in so-called school shootings occurred; 74% of the culprits had a history of psychiatric disorder, most importantly schizophrenic psychoses, affective disorder or alcoholism. According to the forensic psychiatric certificates, 70% were not or not fully responsible for the crime. Three prototypes of amok runners were found: (1) adolescents with long-term difficulties at school or apprenticeship and suicidal ideas; (2) persons suffering from paranoid psychoses; and (3) adults with personality disorders after breakdowns of close social relationships. Despite these predisposing factors it remains unknown which pathological conditions of brain function finally cause this most deleterious form of violence. PMID- 21305262 TI - [Survey of attention deficit hyperactivity disorder in adults]. AB - Attention deficit hyperactivity disorder (ADHD) represents a serious illness which involves impairments in childhood and adolescence that are of considerable importance for the process of social adaptation and thus the development of social competence. If left untreated this leads in a high percentage of cases to disturbances which seriously affect all areas of life reaching into adulthood. Hence, it makes sense and is necessary that adequate treatment is carried out preferably during childhood and adolescence and also at an adult age. Due to the persistence of the disorder in adults with ADHS, various problems arise in formulating expert opinions in conjunction with criminal, social and civil law, in road traffic law and within the scope of conscription. They result from the essential symptoms of ADHS like inattentiveness, overactivity and impulsiveness, but also particularly from the diverse comorbidities. PMID- 21305263 TI - [Diffusion-weighted imaging of the pancreas]. AB - Diffusion-weighted imaging (DWI) has increasingly gained in importance over the last 10 years especially in cancer imaging for differentiation of malignant and benign lesions. Through development of fast magnetic resonance imaging (MRI) sequences DWI is not only applicable in neuroradiology but also in abdominal imaging. As a diagnostic tool of the pancreas DWI enables a differentiation between normal tissue, cancer and chronic pancreatitis. The ADC values (apparent diffusion coefficient, the so-called effective diffusion coefficient) reported in the literature for healthy pancreatic tissue are in the range from 1.49 to 1.9*10(-3) mm(2)/s, for pancreatic cancer in the range from 1.24 to 1.46*10(-3) mm(2)/s and for autoimmune pancreatitis an average ADC value of 1.012*10(-3) mm(2)/s. There are controversial data in the literature concerning the differentiation between chronic pancreatitis and pancreatic cancer. Using DWI derived IVIM (intravoxel incoherent motion) the parameter f (perfusion fraction) seems to be advantageous but it is important to use several b values. In the literature the mean f value in chronic pancreatitis is around 16%, in pancreatic cancer 8% and in healthy pancreatic tissue around 25%. So far, DWI has not been helpful for differentiating cystic lesions of the pancreas. There are many references with other tumor entities and in animal models which indicate that there is a possible benefit of DWI in monitoring therapy of pancreatic cancer but so far no original work has been published. PMID- 21305264 TI - Suicidal behavior among Muslim Arabs in Israel. AB - PURPOSE: Countries with Muslim populations report relatively lower rates of suicide. However, authors have noted methodological flaws in the data. This study examined reliable rates of completed suicide, suicide ideation, planning and attempts among Muslims as compared to Jews in Israel. METHODS: For completed suicide, information was extracted from death certificates (2003-2007); the National Emergency Room Admissions Database (NERAD) provided data on suicide attempts (2003-2007); and the Israel National Health Survey (INHS) (2003-2004) was used for self reports on lifetime suicide ideation, planning and attempts. RESULTS: Completed suicide rates among Muslim-Israelis (3.0 per 100,000) were lower compared to Jewish-Israelis (8.2 per 100,000). Based on NERAD, attempted suicide rates among men were lower for Muslims compared to Jews, while among women aged 15-44 no differences were found. In the INHS, the rate of self reported lifetime suicide attempts was significantly higher among Muslims (2.8%) compared to Jews (1.2%), while lifetime prevalence rates of suicide ideation (6.6%) and planning (2.1%) in Muslims did not differ from Jews (5.2 and 1.9%, respectively). CONCLUSIONS: Conceivably, the lower rate of completed suicide among Muslim-Israelis might be explained by the strenuous proscription of suicide by the Koran. However, its extension to suicide attempts is equivocal: attempts were higher among Muslims than among Jews according to self-reports but lower in the NERAD records. Social pressures exerted on the reporting agents may bias the diagnosis of self-harm in both the latter data source and in the death certificates. PMID- 21305265 TI - Intensive Care Medicine: the journal's status and readers' opinions. PMID- 21305266 TI - Serum sclerostin levels positively correlate with lumbar spinal bone mineral density in postmenopausal women--the six-month effect of risedronate and teriparatide. AB - Sclerostin is expressed by osteocytes and inhibits bone formation by osteoblasts. In this study, serum sclerostin was positively correlated with either lumbar spinal bone mineral density or T-score. Furthermore, serum sclerostin was increased after 6 months treatment with risedronate, whereas remained unchanged after 6 months teriparatide treatment. INTRODUCTION: The primary aim of this study was the evaluation of serum sclerostin levels in postmenopausal women and their association with bone mineral density (BMD) and bone turnover markers. The secondary aim was the evaluation of treatment with either teriparatide (TPTD) or risedronate (RIS) on serum sclerostin levels in women with postmenopausal osteoporosis. METHODS: Women with postmenopausal osteoporosis, assigned to receive either TPTD (TPTD group, n = 13) or RIS (RIS group, n = 36) for 6 months, and non-osteoporotic early postmenopausal women (NOEP group, n = 13) were recruited. Main outcome measure was serum sclerostin levels. RESULTS: Serum sclerostin was higher in the NOEP group at baseline compared with either TPTD group (p = 0.007) or RIS group (p = 0.049). Sclerostin was positively correlated with both lumbar spinal (LS) BMD (r = 0.353; p = 0.005) and T-score (r = 0.501; p < 0.001) and negatively correlated with intact parathyroid hormone (r = -0.343; p = 0.024) at baseline. Multiple regression analysis showed that either LS BMD (Beta = 0.653; p = 0.018) or T-score (Beta = 0.711; p = 0.005) were independent predictors of serum sclerostin levels. No significant correlation was observed between serum sclerostin and bone turnover markers or estradiol at baseline. Sclerostin was significantly increased 6 months post-treatment in RIS group (p = 0.002), whereas remained statistically unaffected in the TPTD group. CONCLUSIONS: Serum sclerostin is decreased in women with postmenopausal osteoporosis compared with non-osteoporotic early postmenopausal women and is positively correlated to either LS BMD or LS T-score. Furthermore, serum sclerostin was increased after 6 months treatment with RIS, whereas remained essentially unchanged after 6 months TPTD treatment. PMID- 21305267 TI - A review of patient-centred post-fracture interventions in the context of theories of health behaviour change. AB - The purpose of this literature review is to determine whether and to what extent current post-fracture osteoporosis interventions utilize theories of health behaviour change and whether those that are theory-based are more successful in producing desired behaviour changes. Studies were identified by applying additional criteria to the final selection stage of a systematic review of non surgical osteoporosis interventions in the orthopaedic environment. We identified 42 primary studies targeted at patients and improving post-fracture osteoporosis care. As well as describing the studies (in terms of design, population, interventions, outcomes), we focused on theoretical framework and elements of behaviour change models. The 42 studies included in this review utilized a variety of post-fracture interventions; however, none of them reported using an underlying theoretical base. Only three studies drew on what we felt to be elements of a theoretical framework. The lack of theoretically based studies points to a currently under-utilized area of behaviour change research that could be applied to post-fracture interventions in order to make them more effective. Despite an abundance of literature supporting theories of behaviour change, post fracture osteoporosis interventions do not report utilizing these theories. Theories of behaviour change could be applied to post-fracture osteoporosis interventions to explain why patients initiate osteoporosis management. Future research should explore the application of theories of health behaviour change to post-fracture interventions. PMID- 21305268 TI - Performance of comorbidity measures for predicting outcomes in population-based osteoporosis cohorts. AB - The performance of five comorbidity measures, including the Charlson and Elixhauser indices, was investigated for predicting mortality, hospitalization, and fracture outcomes in two osteoporosis cohorts defined from administrative databases. The optimal comorbidity measure depended on the outcome of interest, although overall the Elixhauser index performed well. INTRODUCTION: Studies that use administrative data to investigate population-based health outcomes often adopt risk-adjustment models that include comorbidities, conditions that coexist with the index disease. There has been limited research about the measurement of comorbidity in osteoporotic populations. The study purpose was to compare the performance of comorbidity measures for predicting mortality, fracture, and health service utilization outcomes in two cohorts with diagnosed or treated osteoporosis. METHODS: Administrative data were from the province of Saskatchewan, Canada. Osteoporosis cohorts were identified from diagnoses in hospital and physician data and prescriptions for osteo-protective medications using case definitions with high sensitivity or high specificity. Five diagnosis- and medication-based comorbidity measures and five 1-year outcomes, including mortality, hospitalization (two measures), osteoporotic-related fracture, and hip fracture, were defined. Performance of the comorbidity measures was assessed using the c-statistic (discrimination) and Brier score (prediction error) for multiple logistic regression models. RESULTS: In the specific cohort (n = 9,849) for the mortality outcome, the Elixhauser index resulted in the largest improvement (8.96%) in the c-statistic and lowest Brier score compared to a model that contained demographic and socioeconomic variables, followed by the Charlson index (6.06%). For hospitalization, the number of different diagnoses resulted in the largest improvement (14.01%) in the c-statistic. The Elixhauser index resulted in significant improvements in the c-statistic for osteoporosis-related and hip fractures. Similar results were observed for the sensitive cohort (n = 28,068). CONCLUSIONS: Recommendations about the optimal comorbidity measure will vary with the outcome under investigation. Overall, the Elixhauser index performed well. PMID- 21305269 TI - Changes in first hip fracture rates in British Columbia Canada, 1990-2004. AB - We determined age-standardized first hip fracture rates in British Columbia between 1990 and 2004. We found sex and fracture type rates in keeping with previous reports and that fracture rates have decreased approximately 18% overall in both men and women. INTRODUCTION: To determine whether there have been changes in the age-, sex-, and subtype-specific first hip fracture rates in Canadian province of British Columbia (BC) between 1990 and 2004. METHODS: Records of all persons aged 60 years and older hospitalized with hip fractures in BC between 1985 and 2004 were obtained from the Canadian Institute for Health Information Discharge Abstract Database. Only the first hip fracture records were included, and fractures likely due to causes other than trauma were excluded. Age- and sex specific rates were calculated using population denominators from Statistics Canada and direct standardization was used. Age-standardized rates allowed for comparison across years with adjustment for age distribution. RESULTS: There were 41,990 records of first hip fracture included, and 73% were in women. Trends in age-specific rates by fracture type were similar to previous reports. Between 1990 and 2004, there has been an age-adjusted 18% decrease in first hip fracture rates in women, and 19% decrease in first hip fracture rates in men. The decrease was statistically significant in femoral neck fractures in women, but not in men. CONCLUSIONS: There has been a decrease in age-adjusted hip fracture rates in BC between 1990 and 2004, which is in contrast to previous projections for hip fracture rates in Canada. PMID- 21305270 TI - No effect of rosuvastatin in the zoledronate-induced acute-phase response. AB - The acute-phase response (APR) is frequently observed in patients treated with intravenous (iv) zoledronate (ZOL). We investigated whether a short course of rosuvastatin (ROSU) could attenuate the ZOL--induced APR through blocking the mevalonate pathway at a proximal level. Twenty-eight osteoporotic postmenopausal women with no prior bisphosphonate use (mean age 65.3 +/- 1.9 years) were subjected to ZOL iv infusion. Patients were randomly assigned into either a ROSU+ group (n = 12), which received ROSU 10 mg/day starting 5 days before the infusion of ZOL for a total period of 11 days, or a ROSU- group (n = 16), which did not receive ROSU. The visual analog pain scale (VAS) for musculoskeletal symptoms and body temperature was used to define clinically APR. In addition, white blood cell (WBC) count, leukocytic subpopulations, and C-reactive protein (CRP) were obtained before and 48 h following the infusion. Seven (58.3%) patients in the ROSU+ group and 13 (81.3%) in the ROSU- group experienced APR (P = not significant). No difference was found in fever and VAS measurements. CRP and granulocytes increased significantly in both groups; WBC count increased, while lymphocytes and eosinophils decreased significantly only in the ROSU- group. In a post hoc analysis of only patients with an APR, all laboratory parameters exhibited a similar significant change solely within the ROSU- group. In conclusion, our data suggest that a short course of ROS at this dose cannot prevent the ZOL-induced APR among osteoporotic women. Milder changes in acute phase laboratory parameters in ROSU+ patients suggest that studies with higher doses may be warranted. PMID- 21305271 TI - Antihypertensive effects exerted by enalapril in mild to moderate hypertension are not associated with changes in the circulating levels of nitric oxide-related markers. AB - PURPOSE: The antihypertensive effects of angiotensin-converting enzyme inhibitors (ACEi) are explained, at least in part, by enhanced bradykinin-dependent nitric oxide (NO) formation and decreased angiotensin II-induced oxidative stress and vasoconstriction. We examined for the first time whether treatment with enalapril increases the plasma levels of markers of NO formation and decreases oxidative stress in mild to moderate hypertensive patients. METHODS: Eighteen untreated hypertensive patients were treated with enalapril 10 mg/day (n=10) or 20 mg/day (n=8) for 60 days. Eighteen normotensive healthy controls were followed for the same period. Venous blood samples were collected at baseline and after 30/60 days of treatment with enalapril. Plasma NOx (nitrites + nitrates) concentrations were determined by using the Griess reaction. Plasma nitrite and whole blood nitrite concentrations were determined by using an ozone-based chemiluminescence assay. Plasma thiobarbituric acid-reactive species (TBARS) and 8-isoprostane concentrations were determined by a fluorimetric method and by ELISA, respectively. RESULTS: Treatment with enalapril decreased blood pressure in hypertensive patients. However, we found no significant changes in plasma NOx, nitrite, whole blood nitrite, and in the levels of markers of oxidative stress in both normotensive controls and hypertensive patients treated with enalapril. CONCLUSIONS: Our data show that enalapril 10-20 mg/day does not affect the concentrations of relevant markers of NO formation or markers of oxidative stress in mild to moderately hypertensive subjects, despite satisfactory blood pressure control. Our findings do not rule out the possibility that ACEi may produce such effects in more severely hypertensive patients treated with higher doses of ACEi. PMID- 21305272 TI - In vitro-in vivo extrapolation of CYP2C8-catalyzed paclitaxel 6alpha hydroxylation: effects of albumin on in vitro kinetic parameters and assessment of interindividual variability in predicted clearance. AB - OBJECTIVES: This study aimed to characterize the effects of bovine serum albumin (BSA) on the kinetics of CYP2C8-catalyzed paclitaxel 6alpha-hydroxylation in vitro; determine whether the addition of BSA to incubations improves the prediction of paclitaxel hepatic clearance via this pathway in vivo; and assess interindividual variability in predicted clearance. METHODS: The kinetics of paclitaxel 6alpha-hydroxlation by human liver microsomes (HLM) and recombinant CYP2C8 were characterized in incubations performed with and without BSA (2% w/v) supplementation, and the in vitro kinetic data were extrapolated to provide estimates of in vivo clearances. The Simcyp population-based ADME simulator was used to determine interindividual variability in the predicted clearances. RESULTS: Supplementation of incubations of HLM with BSA resulted in a 3.6-fold increase in the microsomal intrinsic clearance for paclitaxel 6alpha hydroxylation, due mainly to a reduction in K(m) (7.08 +/- 2.50 to 2.26 +/- 0.39 MUM), while addition of BSA to incubations of recombinant CYP2C8 resulted in an approximate doubling of intrinsic clearance. Mean values of predicted in vivo hepatic clearance were in good agreement with clinical data when in vitro data obtained in the presence of BSA were used for IV-IVE. Simcyp predicted 20- to 30 fold interindividual variability in in vivo paclitaxel hepatic clearance via the 6alpha-hydroxylation pathway. CONCLUSIONS: Human liver microsomal K(m) and intrinsic clearance values are over- and underpredicted, respectively, when incubations of the CYP2C8 substrate paclitaxel are performed without BSA supplementation. IV-IVE based on kinetic parameters generated in the presence of BSA improves the accuracy of predicted paclitaxel hepatic clearance. PMID- 21305273 TI - Effect of the ADRB1 1165C>G and 145A>G polymorphisms on hemodynamic response during dobutamine stress echocardiography. AB - PURPOSE: The aim of this study was to determine an association between the ADRB1 1165C>G and 145A>G polymorphisms and hemodynamic response [heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressure] to dobutamine during dobutamine stress echocardiography (DSE). METHODS: The study involved 144 patients with clinical indications for DSE. The PCR-restriction fragment length polymorphism method was used to identify the ADRB1 1165C>G and 145A>G polymorphisms. RESULTS: Heart rate during DSE increased in all analyzed study groups. Patients with the ADRB1 1165CC and 1165CG+GG polymorphisms demonstrated similar HR, including magnitude of response [change in heart rate (DeltaHR 0-30): 42.1 +/- 17.5 vs. 46.1 +/- 15.5 bpm, respectively]. HR and DeltaHR 0-30 were comparable in ADRB1145AA and 145AG subjects in the course of DSE. SBP and DBP at all stages of DSE were similar in subjects with either polymorphism and did not differentiate patients with the ADRB1 145AA polymorphism from those with the ADRB1 145AG polymorphism, nor those with the ADRB1 1165CC polymorphism from those with the ADRB1 1165CG+GG polymorphism. No differences were noted in the magnitude of response, with the increase in SBP and DBP comparable in all genotypes. Similar observations were made in patients (25/144 studied) with atropine requirements during DSE. CONCLUSION: The ADRB1 1165C>G and 145A>G polymorphisms are not associated with the HR, SBP and DBP responses in Polish Caucasian patients requiring diagnostic dobutamine stress echocardiography. PMID- 21305274 TI - Effect of Yerbimat herbicide on lipid peroxidation, catalase activity, and histological damage in gills and liver of the freshwater fish Goodea atripinnis. AB - The use of herbicides for agricultural and aquatic weed control has increased worldwide. These substances are potentially toxic pollutants because they induce the production of reactive oxygen species for biological systems and exert oxidative stress in nontarget organisms living in the treated aquatic systems. Recent evidence suggests differences in the toxicity of glyphosate in the form of an active ingredient compared to the toxicity of glyphosate in combination with surfactants, such as those found in commercial formulations. In Mexico, one of the most widely used glyphosate-based herbicides is Yerbimat, which has agricultural as well as aquatic weed control applications. However, there are no aquatic toxicity data, particularly regarding native fish. Therefore, we determined the acute toxicity of commercial-formulation Yerbimat in a static bioassay at 96 h (LC(50)). We also determined its toxicity at 96 h in sublethal concentrations to assess the lipid peroxidation levels (LPX), catalase activity, hepatic glycogen content, and histological damage in the liver and gills of the fish Goodea atripinnis associated with chronic exposure (75 days). The LC(50) was 38.95 +/- 0.33 mg/L. The results of the short-term exposure study indicate that Yerbimat can potentially induce oxidative stress in G. atripinnis, because LPX was increased in the gills and liver. Catalase activity was reduced in the gills but increased in the liver, whereas hepatic glycogen was depleted. Chronic exposure was associated with histopathological damage in the gills and liver, some of which was irreversible. Yerbimat represents a potential risk for aquatic biota; therefore, we recommend that its application be carefully considered. PMID- 21305275 TI - An assessment of three harpacticoid copepod species for use in ecotoxicological testing. AB - The relatively short life cycles of harpacticoid copepods makes them appropriate animals for use in tests that rapidly assess the acute, sublethal, or chronic effects of sediment contaminants. In this study, four harpacticoid copepod species (Nitocra spinipes, Tisbe tenuimana, Robertgurneya hopkinsi, and Halectinosoma sp.) were isolated from clean marine sediments, and procedures for laboratory culturing were developed. Halectinosoma sp. was abandoned due to handling difficulties. For the remaining species, the influence of food type and quantity on life-cycle progression was assessed. A mixed diet, comprising two species of algae (Tetraselmis sp. and Isochrysis sp.) and fish food (Sera Micron) was found to maintain healthy cultures and was fed during laboratory tests. Water only exposure to dissolved copper (Cu) showed that the times (range) required to cause 50% lethality (LT(50)) were 24 (22-27) h at 50 MUg Cu/l for T. tenuimana; 114 (100-131) and 36 (32-40) h for 200 and 400 MUg Cu/l, respectively, for N. spinipes; and 119 (71-201) and 25 (18-33) h for 200 and 400 MUg Cu/l, respectively, for R. hopkinsi. 96-h LC(50) (concentration causing 50% lethality) were also determined for adult N. spinipes exposed to cadmium, copper, zinc, ammonia, and phenol. A ranking system was generated based on the ease handling and culturing, rate of maturity, food selectivity and sensitivity to Cu. From this ranking, N. spinipes was determined to be the most suitable species for use in developing sediment-toxicity tests. The measurement of total reproductive output of N. spinipes during 10-day exposure to whole sediment was found to provide a useful end point for assessing the effects of sediment contamination. PMID- 21305276 TI - Functional classification of class II human leukocyte antigen (HLA) molecules reveals seven different supertypes and a surprising degree of repertoire sharing across supertypes. AB - Previous studies have attempted to define human leukocyte antigen (HLA) class II supertypes, analogous to the case for class I, on the basis of shared peptide binding motifs or structure. In the present study, we determined the binding capacity of a large panel of non-redundant peptides for a set of 27 common HLA DR, DQ, and DP molecules. The measured binding data were then used to define class II supertypes on the basis of shared binding repertoires. Seven different supertypes (main DR, DR4, DRB3, main DQ, DQ7, main DP, and DP2) were defined. The molecules associated with the respective supertypes fell largely along lines defined by MHC locus and reflect, in broad terms, commonalities in reported peptide-binding motifs. Repertoire overlaps between molecules within the same class II supertype were found to be similar in magnitude to what has been observed for HLA class I supertypes. Surprisingly, however, the degree to which repertoires between molecules in the different class II supertypes also overlapped was found to be five to tenfold higher than repertoire overlaps noted between molecules in different class I supertypes. These results highlight a high degree of repertoire overlap amongst all HLA class II molecules, perhaps reflecting binding in multiple registers, and more pronounced dependence on backbone interactions rather than peptide anchor residues. This fundamental difference between HLA class I and class II would not have been predicted on the basis of analysis of either binding motifs or the sequence/predicted structures of the HLA molecules. PMID- 21305277 TI - Performance of a pilot-scale continuous flow microbial electrolysis cell fed winery wastewater. AB - A pilot-scale (1,000 L) continuous flow microbial electrolysis cell was constructed and tested for current generation and COD removal with winery wastewater. The reactor contained 144 electrode pairs in 24 modules. Enrichment of an exoelectrogenic biofilm required ~60 days, which is longer than typically needed for laboratory reactors. Current generation was enhanced by ensuring adequate organic volatile fatty acid content (VFA/SCOD >= 0.5) and by raising the wastewater temperature (31 +/- 1 degrees C). Once enriched, SCOD removal (62 +/- 20%) was consistent at a hydraulic retention time of 1 day (applied voltage of 0.9 V). Current generation reached a maximum of 7.4 A/m(3) by the planned end of the test (after 100 days). Gas production reached a maximum of 0.19 +/- 0.04 L/L/day, although most of the product gas was converted to methane (86 +/- 6%). In order to increase hydrogen recovery in future tests, better methods will be needed to isolate hydrogen gas produced at the cathode. These results show that inoculation and enrichment procedures are critical to the initial success of larger-scale systems. Acetate amendments, warmer temperatures, and pH control during startup were found to be critical for proper enrichment of exoelectrogenic biofilms and improved reactor performance. PMID- 21305278 TI - Removal of L-alanine from the production of L-2-aminobutyric acid by introduction of alanine racemase and D-amino acid oxidase. AB - L-2-Aminobutyric acid can be synthesized in a transamination reaction from L threonine and L-aspartic acid as substrates by the action of threonine deaminase and aromatic aminotransferase, but the by-product L-alanine was produced simultaneously. A small amount of L-alanine increased the complexity of the L-2 aminobutyric acid recovery process because of their extreme similarity in physical and chemical properties. Acetolactate synthase has been introduced to remove the pyruvate intermediate for reducing the L-alanine concentration partially. To eliminate the remnant L-alanine, alanine racemase of Bacillus subtilis in combination with D-amino acid oxidase of Rhodotorula gracilis or Trigonopsis variabilis respectively was introduced into the reaction system for the L-2-aminobutyric acid synthesis. L-Alanine could be completely removed by the action of alanine racemase of B. subtilis and D-amino acid oxidase of R. gracilis; thereby, high-purity L-2-aminobutyric acid was achieved. The results revealed that alanine racemase could discriminate effectively between L-alanine and L-2-aminobutyric acid, and selectively catalyzed L-alanine to D-alanine reversibly. D-Amino acid oxidase then catalyzed D-alanine to pyruvate stereoselectively. Furthermore, this method was also successfully used to remove the by-product L-alanine in the production of other neutral amino acids such as L tertiary leucine and L-valine, suggesting that multienzymatic whole-cell catalysis can be employed to provide high purity products. PMID- 21305279 TI - An altered camelid-like single domain anti-idiotypic antibody fragment of HM-1 killer toxin: acts as an effective antifungal agent. AB - Phage-display and competitive panning elution leads to the identification of minimum-sized antigen binders together with conventional antibodies from a mouse cDNA library constructed from HM-1 killer toxin neutralizing monoclonal antibody (nmAb-KT). Antigen-specific altered camelid-like single-domain heavy chain antibody (scFv K2) and a conventional antibody (scFv K1) have been isolated against the idiotypic antigen nmAb-KT. The objectives of the study were to examine (1) their properties as compared to conventional antibodies and also (2) their antifungal activity against different pathogenic and non-pathogenic fungal species. The alternative small antigen-binder, i.e., the single-domain heavy chain antibody, was originated from a conventional mouse scFv phage library through somatic hyper-mutation while selection against antigen. This single domain antibody fragment was well expressed in bacteria and specifically bound with the idiotypic antigen nmAb-KT and had a high stability and solubility. Experimental data showed that the binding affinity for this single-domain antibody was 272-fold higher (K(d)=1.07*10(-10) M) and antifungal activity was three- to fivefold more efficient (IC(50)=0.46*10(-6) to 1.17*10(-6) M) than that for the conventional antibody (K(d)=2.91*10(-8) M and IC(50)=2.14*10(-6) to 3.78*10(-6) M). The derived single-domain antibody might be an ideal scaffold for anti-idiotypic antibody therapy and the development of smaller peptides or peptide mimetic drugs due to their less complex antigen-binding site. We expect that such single-domain synthetic antibodies will find their way into a number of biotechnological or medical applications. PMID- 21305280 TI - A proteomic analysis of the Pichia pastoris secretome in methanol-induced cultures. AB - The secreted proteome of Pichia pastoris X-33 was investigated in methanol induced cultures with a goal to enhance the secretion and purification of recombinant proteins. In a fed-batch fermentation at 30 degrees C, more host proteins were found in greater concentrations compared to cultures grown at 25 degrees C. Protein samples collected directly from the culture media at 25 degrees C, as well as separated by two-dimensional (2D) gel, were subjected to ESI-MS/MS analysis. A total of 75 proteins were identified in the media from different conditions including pre- and post-methanol induction and in a strain overexpressing a recombinant schistosomiasis vaccine, Sm14-C62V. The identified proteins include native secreted proteins and some intracellular proteins, most of which have low isoelectric points (pI < 6). 2D gel analyses further revealed important characteristics, such as abundance, degradation, and glycosylation of these identified proteins in this proteome. Cell wall-associated proteins involved in cell wall biogenesis, structure, and modification comprised the majority of the secreted proteins which have been identified. Intracellular proteins such as alcohol oxidase and superoxide dismutase were also found in the proteome, suggesting some degree of cell lysis. However, both protocols show that their concentrations are significantly lower than the native secreted proteins. This study identifies proteins secreted or released into the culture media in the methanol-induced fermentation cultures of P. pastoris X-33 and suggests potential biotechnology applications based on the discovery of this proteome. PMID- 21305281 TI - Glutamate production from beta-glucan using endoglucanase-secreting Corynebacterium glutamicum. AB - We demonstrate glutamate production from beta-glucan using endoglucanase (EG) expressing Corynebacterium glutamicum. The signal sequence torA derived from Escherichia coli K12, which belongs to the Tat pathway, was suitable for secreting EG of Clostridium thermocellum using C. glutamicum as a host. Using the torA signal sequence, endoglucanase from Clostridium cellulovorans 743B was successfully expressed, and the secreted EG produced 123 mg of reducing sugar from 5 g of beta-glucan at 30 degrees C for 72 h, which is the optimal condition for C. glutamicum growth. Subsequently, glutamate fermentation from beta-glucan was carried out with the addition of Aspergillus aculeatus beta-glucosidase produced by recombinant Aspergillus oryzae. Using EG-secreting C. glutamicum, 178 mg/l of glutamate was produced from 15 g of beta-glucan. This is the first report of glutamate fermentation from beta-glucan using endoglucanase-secreting C. glutamicum. PMID- 21305282 TI - Percutaneous vertebroplasty in multiple myeloma: prospective long-term follow-up in 106 consecutive patients. AB - PURPOSE: Percutaneous vertebroplasty (PV) is a minimally invasive procedure involving the injection of bone cement within a collapsed vertebral body. Although this procedure was demonstrated to be effective in osteoporosis and metastases, few studies have been reported in cases of multiple myeloma (MM). We prospectively evaluated the safety and efficacy of PV in the treatment of vertebral compression fractures (VCFs) resulting from MM. MATERIALS AND METHODS: PV was performed in 106 consecutive MM patients who had back pain due to VCFs, the treatment of which had failed conservative therapies. Follow-up (28.2 +/- 12.1 months) was evaluated at 7 and 15 days as well as at 1, 3, 6, 12, 18, and every 6 months after PV. Visual analog scale (VAS) pain score, opioid use, external brace support, and Oswestry Disability Index (ODI) score were recorded. RESULTS: The median pretreatment VAS score of 9 (range 4-10) significantly (P < 0.001) decreased to 1 (range 0-9) after PV. Median pre-ODI values of 82% (range 36-89%) significantly improved to 7% (range 0-82%) (P < 0.001). Differences in pretreatment and posttreatment use of analgesic drug were statistically significant (P < 0.001). The majority of patients (70 of 81; 86%) did not use an external brace after PV (P < 0.001). CONCLUSION: PV is a safe, effective, and long-lasting procedure for the treatment of vertebral compression pain resulting from MM. PMID- 21305283 TI - A novel fenestration technique for abdominal aortic dissection membranes using a combination of a needle re-entry catheter and the "cheese-wire" technique. AB - PURPOSE: This study was designed to demonstrate the applicability of a combined needle-based re-entry catheter and "cheese-wire" technique for fenestration of abdominal aortic dissection membranes. METHODS: Four male patients (mean age: 65 years) with acute complicated aortic type B dissections were treated at our institution by fenestrating the abdominal aortic dissection membrane using a hybrid technique. This technique combined an initial membrane puncture with a needle-based re-entry catheter using a transfemoral approach. A guidewire was passed through the re-entry catheter and across the membrane. Using a contralateral transfemoral access, this guidewire was then snared, creating a through-and-through wire access. The membrane was then fenestrated using the cheese-wire maneuver. RESULTS: We successfully performed: (a) membrane puncture; (b) guidewire passage; (c) guidewire snaring; and (d) cheese-wire maneuver in all four cases. After this maneuver, decompression of the false lumen and acceptable arterial inflow into the true lumen was observed in all cases. The dependent visceral arteries were reperfused. In one case, portions of the fenestrated membrane occluded the common iliac artery, which was immediately and successfully stented. In another case, long-standing intestinal hypoperfusion before the fenestration resulted in reperfusion-related shock and intraoperative death of the patient. CONCLUSIONS: The described hybrid approach for fenestration of dissection membranes is technically feasible and may be established as a therapeutic method in cases with a complicated type B dissection. PMID- 21305284 TI - Chemoembolization via branches from the splenic artery in patients with hepatocellular carcinoma. AB - PURPOSE: This study was designed to evaluate the radiologic findings and imaging response of chemoembolization via branches of the splenic artery in patients with hepatocellular carcinoma (HCC). METHODS: From January 2001 to July 2010, we observed tumor staining supplied by branches of the splenic artery in 34 (0.6%) of 5,413 patients with HCC. Computed tomography (CT) scans and digital subtraction angiograms of these patients were retrospectively reviewed in consensus by two investigators. RESULTS: A total of 39 tumor feeding-vessels in 34 patients were identified: omental branches from the left gastroepiploic artery (n = 5), branches from the short gastric artery (n = 9), and omental branches directly from the splenic artery (n = 25). Branches of the splenic artery that supplied tumors were revealed on the celiac angiogram in 29 (85%) of 34 patients and were detected on pre-procedure CT images in 27 (79%) of 34 patients. Selective chemoembolization was achieved in 38 of 39 tumor-feeding vessels. Complete or partial response of the tumor fed by branches of the splenic artery, as depicted on follow-up CT scans, was achieved in 21 (62%) patients. No patient developed severe complications directly related to chemoembolization via branches of the splenic artery. CONCLUSIONS: Omental branches directly from the splenic artery are common tumor-feeding vessels of the splenic artery in cases of advanced HCC with multiple previous chemoembolizations. Tumor-feeding vessels of the splenic artery are usually visualized on the celiac angiogram or CT scan, and chemoembolization through them can be safely performed in most patients. PMID- 21305285 TI - Endovascular aneurysm repair using a reverse chimney technique in a patient with Marfan syndrome and contained ruptured chronic type B dissection. AB - We report endovascular thoracic and abdominal aneurysm repair (EVAR) with reverse chimney technique in a patient with contained ruptured type B dissection. EVAR seems feasible as a bailout option in Marfan patients with acute life-threatening disease. PMID- 21305286 TI - RMI study and clinical correlations of ankle retinacula damage and outcomes of ankle sprain. AB - Recent studies reveal the role of the ankle retinacula in proprioception and functional stability of the ankle, but there is no clear evidence of their role in the outcomes of ankle sprain. 25 patients with outcomes of ankle sprain were evaluated by MRI to analyze possible damage to the ankle retinacula. Patients with damage were subdivided into two groups: group A comprised cases with ankle retinacula damage only, and group B those also with anterior talofibular ligament rupture or bone marrow edema. Both groups were examined by VAS, CRTA and static posturography and underwent three treatments of deep connective tissue massage (Fascial Manipulation technique). All evaluations were repeated after the end of treatment and at 1, 3 and 6 months. At MRI, alteration of at least one of the ankle retinacula was evident in 21 subjects, and a further lesion was also identified in 7 subjects. After treatment, VAS and CRTA evaluations showed a statistically significant decrease in values with respect to those before treatment (p < 0.0001). There were also significant improvements (p < 0.05) in stabilometric platform results. No significant difference was found between groups A and B. The initial benefit was generally maintained at follow-up. The alteration of retinacula at MRI clearly corresponds to the proprioceptive damage revealed by static posturography and clinical examination. Treatment focused on the retinacula may improve clinical outcomes and stabilometric data. PMID- 21305288 TI - Epilepsy in the cancer patient. AB - PURPOSE: Epileptic seizures in patients with malignancies usually occur as a consequence of brain metastases from systemic cancer or the presence of a primary brain tumor. Other less-frequent causes include metabolic disorders such as electrolyte abnormalities, hypoglycemia, hypoxia and liver failure, paraneoplastic encephalitis, leptomeningeal carcinomatosis, side effects of certain chemotherapeutic agents, central nervous system infections, and pre existing epilepsy. METHODS: We reviewed all published literature in the English language regarding the use of antiepileptic drugs in patients with cancer. RESULTS: In patients with brain metastases or primary brain tumors that had never experienced seizures, prophylactic anticonvulsant treatment is justified only for a period up to 6 months postoperatively after surgical excision of a cerebral tumor, since approximately half of the patients will never develop seizures and the anti-epileptic drugs may cause toxicity and interactions with antineoplastic therapies. For brief prophylaxis, newer antiepileptic drugs such as levetiracetam and oxcarbazepine are superior to older agents like phenytoin. In patients with a malignancy and seizures, certain antiepileptic drugs that express tumor inhibitory properties should be used such as valproic acid and levetiracetam, followed by oxcarbazepine and topiramate that exhibit good tolerance, efficient seizure control and absence of significant interactions with the chemotherapy. CONCLUSIONS: Future clinical trials in patients with cancer and epilepsy should focus on combinations of chemotherapeutic interventions with antiepileptic drugs that demonstrate antineoplastic activities. PMID- 21305287 TI - Phase I clinical and pharmacokinetic study of UTD1, a genetically engineered epothilone analog in patients with advanced solid tumors. AB - PURPOSE: The epothilones are a novel class of microtubule-stabilizing agents. UTD1 is an epothilone analog generated by genetic manipulation of the polyketide biosynthetic gene cluster. This phase I study was designed to evaluate the safety and pharmacokinetic(PK) profiles of UTD1 in patients with advanced solid tumors. PATIENTS AND METHODS: This was an open-label, single-arm, one site, phase I, dose escalation study. Patients were treated with escalating doses of UTD1 as a 3-h intravenous infusion every 3 weeks. RESULTS: Twenty-one patients were enrolled and received UTD1 at six dose levels ranging from 25 to 225 mg/m(2). Dose limiting toxicity (DLT) was ataxia, and other frequent non-haematological toxicities were peripheral neuropathy, gastrointestinal disorders, fatigue, and myalgia/arthralgia. Myelosuppression was rare, with no grade 3 and 4 neutropenia, in contrast to paclitaxel and ixabepilone. The maximum-tolerated dose was established as 170 mg/m(2). Preliminary results showed linear pharmacokinetics along the range of doses tested. Prolonged disease stabilization was observed in patients with breast cancer, non-small lung cancer, and other cancers. CONCLUSIONS: The recommended phase II dose of UTD1 is 170 mg/m(2) as a 3-h infusion every 3 weeks. Ataxia was the DLT. UTD1 showed advantages over paclitaxel and Ixapebilone in relation to safety profile, especially myelosuppression. The acceptable tolerability warrants further phase II study. PMID- 21305289 TI - Evaluation of combined bevacizumab and intraperitoneal carboplatin or paclitaxel therapy in a mouse model of ovarian cancer. AB - PURPOSE: To evaluate the pharmacokinetics of bevacizumab following IP and IV administration, and to investigate combined bevacizumab therapy (IP or IV) with IP paclitaxel or carboplatin in a mouse model of ovarian cancer. METHODS: Bevacizumab pharmacokinetics were investigated following IV or IP dosing, and mice bearing peritoneal A2780 xenografts were treated with vehicle, IV or IP bevacizumab, IP paclitaxel, IP paclitaxel with co-administration of IV or IP bevacizumab, IP carboplatin, and IP carboplatin with co-administration of IV or IP bevacizumab. Survival time was defined as the time to death or the time to reach 120% of baseline body weight. RESULTS: Following IP administration, bevacizumab was rapidly absorbed and bioavailability was 92.8%. Median survival time, which was 33 days for control mice, was increased by 24% with IP paclitaxel. IP carboplatin failed to increase survival time when administered alone. IV and IP bevacizumab increased survival time by 42 and 33%. Combined bevacizumab and IP paclitaxel was superior to paclitaxel alone (P = 0.01 for IV and P = 0.04 for IP bevacizumab), and combined bevacizumab and IP carboplatin was superior to carboplatin alone (P = 0.002 for IV and P = 0.02 for IP bevacizumab). There were no significant differences in survival between groups receiving bevacizumab IV or IP, either alone (P = 0.586), in combination with paclitaxel (P = 0.467), or in combination with carboplatin (P = 0.149). CONCLUSIONS: Following IP administration to mice, bevacizumab demonstrates rapid and near complete absorption. Bevacizumab therapy, initiated prior to IP carboplatin or paclitaxel administration, increased survival time significantly in mice, and results were not dependent on the route of bevacizumab administration (IV vs. IP). PMID- 21305290 TI - A phase I study of MN-029 (denibulin), a novel vascular-disrupting agent, in patients with advanced solid tumors. AB - PURPOSE: MN-029 (denibulin HCl) is a novel vascular-disrupting agent that reversibly inhibits microtubule assembly, resulting in disruption of the cytoskeleton of tumor vascular endothelial cells. This study determined the safety, pharmacokinetics, and acute anti-vascular effects of MN-029. METHODS: Patients were treated with escalating doses of MN-029 (4.0-225 mg/m(2)) administered IV at 3-week intervals. This first-in-human study followed an accelerated titration design, with intra-patient dose escalation. Plasma samples were assayed to determine PK parameters. DCE-MRI scans were acquired at baseline and at 6-8 h post-dose. RESULTS: Thirty-four patients received 151 infusions of MN-029. The most common toxicities of MN-029 included nausea and vomiting (which appeared to be dose related), diarrhea, fatigue, headache, and anorexia. No clinically significant myelotoxicity, stomatitis or alopecia was observed. There was no evidence of cumulative toxicity in patients receiving multiple courses of therapy. The cohort at 180 mg/m(2) was expanded to six patients due to a reversible episode of acute coronary ischemia, without sequelae and with preservation of myocardial function. Two dose-limiting toxicities occurred at 225 mg/m(2), a transient ischemic attack and grade 3 transaminitis, thus ending dose escalation. Pharmacokinetic data indicated dose-related increases in C (max) and AUC values, although substantial inter-subject variability was observed. No objective responses were noted; however, five patients had stable disease >=6 months. A significant linear correlation was found between reduction in K (trans) and exposure to MN-029. CONCLUSIONS: MN-029 was generally well tolerated and showed decrease in tumor vascular parameters. The maximum tolerated dose was 180 mg/m(2). PMID- 21305291 TI - Presence of 46 kDa gelatinase on the outer membrane of Leptospira. AB - Leptospira infection involves the adhesion of the bacteria followed by invasion of the host crossing the extracellular matrix barrier. In an effort to understand the molecular mechanism of this process, the possibility of occurrence of matrix degrading enzymes from Leptospira was investigated. Zymographic analysis showed that the outer membrane of Leptospires contains a gelatinase of average molecular size of 46 kDa. The gelatinase exhibited maximum activity at neutral pH and was inhibited by metal chelators such as EGTA, EDTA, and Orthophenanthroline and was activated by calcium, magnesium, zinc, and copper, suggesting that it is a membrane-associated neutral matrix metalloproteinase. Analysis of the production of the enzyme by various serovars showed that the pathogenic serovars expressed significant amount of this enzyme while nonpathogenic forms either did not express or showed only very low activity, suggesting that this enzyme may be associated with pathogenesis of leptospirosis. PMID- 21305292 TI - Improvement of bioinsecticides production by sporeless Bacillus thuringiensis strains in response to various stresses in low cost medium. AB - The use of bioinsecticides, particularly those produced by sporeless Bacillus thuringiensis strains, has been shown to be a good alternative in pest management. Two types of sporeless mutants were distinguished. The asporogenic mutants which completely lack spores produce a regular bipyramidal crystal inclusion. The oligosporogenic mutants kept the ability to produce insecticidal crystal proteins. However, sporulation in such mutants was not totally blocked and very few of them could still produce spores. In order to improve bioinsecticides production, adaptation of sporeless strains to heat shock and osmotic stress was investigated. Delta-endotoxin production by 78% of sporeless mutants was significantly improved by osmotic stress with an overproduction of about 17%, compared to the wild strain BNS3. However, toxin production was improved by only 21% of mutants after heat shock, in low cost medium. The statistical analysis proved that delta-endotoxin production, cell growth, and spore formation of asporogenic and oligosporogenic mutants depended on the type of applied stress. Each strain has an important potential when applying the adequate stress. Moreover, adaptation of sporeless mutants to NaCl may allow the substitution of all minerals of the medium by diluted sea water which appeared to be a good alternative for the economic production of bioinsecticides at industrial scale which is of great importance from the practical point of view. PMID- 21305293 TI - Effects of copper exposure on expression of glutathione-related genes in Acidithiobacillus ferrooxidans. AB - The response of Acidithiobacillus ferrooxidans to variations in extracellular Cu exposure was investigated in terms of glutathione-related genes expression profiling based on reverse-transcription quantitative PCR analysis. The results show that the higher concentration of Cu would induce the expression of glutathione-related enzymes and cells elicited specific transcriptional responses when challenged with environmental Cu (0.08 mol l(-1)) conditions over a 60-min period. In comparison to the control, glutathione S-transferases (GST) and glutathione reductase (GR) were highly expressed when the cells were grown in the medium with copper, and the increase of glutathione and glutathione-related enzymes makes the cells acclimate to oxidative stress induced by Cu and protects the cells from toxicity caused by Cu exposure. It suggests that in order for Acidithiobacillus ferrooxidans to counteract the conditions of external Cu exposure, it modulated its expression level of GST, GR, glutathione hydrolase, and glutathione synthetase, which may protect organisms from oxidative damage. These parameters may be used to assess the biological impact of Cu in mining activities. PMID- 21305294 TI - Refining the relationship between homozygosity and the frequency of the most frequent allele. AB - Recent work has established that for an arbitrary genetic locus with its number of alleles unspecified, the homozygosity of the locus confines the frequency of the most frequent allele within a narrow range, and vice versa. Here we extend beyond this limiting case by investigating the relationship between homozygosity and the frequency of the most frequent allele when the number of alleles at the locus is treated as known. Given the homozygosity of a locus with at most K alleles, we find that by taking into account the value of K, the width of the allowed range for the frequency of the most frequent allele decreases from 2/3 - pi(2)/18 ~ 0.1184 to 1/3 - 1/(3K) - {K/[3(K - 1)]} Sigma(K)(k = 2) 1/k(2). We further show that properties of the relationship between homozygosity and the frequency of the most frequent allele in the unspecified-K case can be obtained from the specified-K case by taking limits as K -> infinity. The results contribute to a greater understanding of the mathematical properties of fundamental statistics employed in population-genetic analysis. PMID- 21305295 TI - Calcium metabolism disorders simulating rheumatologic diseases. AB - Hypoparathyroidism and hyperparathyroidism may lead to spondylarthropathy or spondylarthropathy-like problems and crystal arthropathy, respectively. In this report, we present 2 cases with hypoparathyroidism and 1 case with hyperparathyroidism who developed spondylarthropathy-like disease, rheumatoid arthritis-like disease, and chondrocalcinosis, respectively. We briefly discussed relationship between calcium metabolism disorders and rheumatologic manifestations. As rheumatologists, we should be always open to other diagnosis if the treatment does not work in patients with rheumatologic diseases. PMID- 21305296 TI - Evaluation of disease activity indices in Korean patients with rheumatoid arthritis. AB - The aim of this study is to examine the validity of the rheumatoid arthritis (RA), disease activity score (DAS), 28-C-reactive protein (CRP), the simplified disease activity index (SDAI), and the clinical disease activity index (CDAI) against the DAS28-erythrocyte sedimentation rate (ESR) and determine cut-off values for each tool in Korean patients with RA. A total of 223 RA patients were consecutively recruited from the Hanyang University Hospital for Rheumatic Diseases in Seoul, Korea. DAS28-CRP, SDAI, and CDAI were measured and compared with DAS28-ESR. The correlation coefficients of DAS28-ESR with DAS28-CRP, SDAI, and CDAI were 0.93, 0.85, and 0.84, demonstrating strong linear relationships. The cut-off values of DAS28-CRP classifying RA patients into four categories of disease activity were defined as 2.19, 2.60, and 4.07. SDAI cut-off values were defined as 3.75, 7.50, and 16.88. CDAI cut-off values were defined as 3.62, 7.38, and 16.50. DAS28-CRP, SDAI, and CDAI are valid and sensitive assessment indices of disease activity that are comparable to DAS28-ESR. The cut-off values of each tool derived in this study might be useful for routine monitoring and therapeutic decision-making in Korean RA patients. PMID- 21305297 TI - Ehlers-Danlos syndrome: case report and an electron microscopy study. AB - Ehlers-Danlos syndrome (EDS) type III is a inherited connective tissue disorders characterized by extensibility of the skin, hypermobility of the joints, chronic pain, tissue fragility, easy bruising, and delayed wound healing with result of atrophic scars. The patients report commonly a history of recurrent dislocations of the shoulders and knees after low-impact trauma, chronic joint pain, and early osteoarthritis, which lead to diagnosis. The pathogenesis of this condition is unknown, and the diagnosis is generally made in adult age, based only on clinical criteria. In this report, we describe a case of a 50-year-old woman with a 30 year history of recurrent dislocations and atrophic scars. We performed diagnosis of EDS type III after a complete clinical and instrumental evaluation, comprising of histological and electron microscopic studies, that highlighted collagen abnormalities. PMID- 21305298 TI - Anti-Saccharomyces cerevisiae (ASCA) and anti-endomysial antibodies in spondyloarthritis. AB - Spondyloarthritis (SpA) are diseases with increased gut inflammation. To search for (anti-Saccharomyces cerevisiae) ASCA IgA, ASCA IgG, and anti-endomysial antibodies (EmA-IgA) in a cohort of 70 patients with SpA, we found 18.6% (13/70) positive for IgA-ASCA in the SpA group and 3/57 (5.2%) in the control group (P = 0.031). ASCA IgG and EmA-IgA were found at the same frequency in SpA and controls. No relationship of ASCA IgA positivity could be established with disease activity (measured by ESR, C-reactive protein, and BASDAI), presence of uveitis, or peripheral arthritis neither with functional status measured by BASFI. SpA patients present an increase in the IgA-ASCA positivity without any relationship to disease activity, functional index, clinical profile or the presence of HLA-B27. There is no evidence of higher prevalence of EmA-IgA in SpA patients in the studied sample. PMID- 21305299 TI - Molecular characterization of major allergens Ara h 1, 2, 3 in peanut seed. AB - Peanut is among the most commonly used dietary seeds, but peanut allergens, especially Ara h 1 (Arachis hypogaea allergy 1), 2 and 3, can cause severe IgE mediated reactions. In this study, the molecular characterization and expression pattern of three allergens in peanut LUHUA 8, the representative of the cultivated lines in China, are reported. In situ hybridization and real time PCR analysis revealed high expression levels and different tissue expression patterns of the three allergens, which might be connected with many aspects, such as the strong conservation of intron phase of the allergen genes, the low energy of the mRNA's regions, and the complicated post-translational modifications. Furthermore, the different sequences between the cloned allergens and the reported sequences previously involved the charged amino acids especially in IgE epitopes, which might alter specific physicochemical and physiological properties, and thus influence the immunity of the allergens. The identification of the specific features of the allergen genes would be of considerable importance to the basic understanding of the specific characteristics of peanut seed allergens. PMID- 21305300 TI - Low night temperature acclimation of Phalaenopsis. AB - The capability of Phalaenopsis to acclimate its photosynthetic capacity and metabolic activity to cool night temperature conditions is crucial for improving orchid production in terms of efficient greenhouse heating. The extent to which Phalaenopsis possesses acclimation potential and the mechanistic background of the metabolic processes involved, have, however, not been studied before. Plants were subjected to a direct and gradual shift from a day to night temperature regime of 28/28-28/16 degrees C, the cold stress and cold acclimation treatment, respectively. In comparison with the cold stress treatment, the cold acclimation treatment led to a higher malate accumulation and a reduction in leaf net CO(2) uptake. Consistently, the contribution of respiratory CO(2) recycling to nocturnal malate synthesis was calculated to be 23.5 and 47.0% for the cold stress and cold acclimation treatment, respectively. Moreover, the lower levels of starch measured in the cold acclimated leaves confirmed the suggested enhanced respiratory CO(2) recycling, implying that Phalaenopsis CAM operation evolved towards CAM idling. It is, however, plausible that this adjustment was not an effect of the low night temperature per se but a consequence of cool-root induced drought stress. Apart from that, at the start of the photoperiod, membrane stability showed a depression which was directly counteracted by an increased generation of glucose, fructose and sucrose. From these observations, it can be concluded that the observed plasticity in CAM operation and metabolic flexibility may be recognized as important steps in the low night temperature acclimation of Phalaenopsis. PMID- 21305301 TI - Efficient sweet pepper transformation mediated by the BABY BOOM transcription factor. AB - Pepper (Capsicum L.) is a nutritionally and economically important crop that is cultivated throughout the world as a vegetable, condiment, and food additive. Genetic transformation using Agrobacterium tumefaciens (agrobacterium) is a powerful biotechnology tool that could be used in pepper to develop community based functional genomics resources and to introduce important agronomic traits. However, pepper is considered to be highly recalcitrant for agrobacterium mediated transformation, and current transformation protocols are either inefficient, cumbersome or highly genotype dependent. The main bottleneck in pepper transformation is the inability to generate cells that are competent for both regeneration and transformation. Here, we report that ectopic expression of the Brassica napus BABY BOOM AP2/ERF transcription factor overcomes this bottleneck and can be used to efficiently regenerate transgenic plants from otherwise recalcitrant sweet pepper (C. annuum) varieties. Transient activation of BABY BOOM in the progeny plants induced prolific cell regeneration and was used to produce a large number of somatic embryos that could be converted readily to seedlings. The data highlight the utility of combining biotechnology and classical plant tissue culture approaches to develop an efficient transformation and regeneration system for a highly recalcitrant vegetable crop. PMID- 21305302 TI - Gynogenesis in gentians (Gentiana triflora, G. scabra): production of haploids and doubled haploids. AB - Gynogenesis was investigated on gentian (Gentiana triflora, G. scabra and their hybrids), which is an important ornamental flower. When unfertilized ovules were cultured in 1/2 NLN medium containing a high concentration of sucrose (100 g/l), embryo-like structures (ELS) were induced. Although genotypic variation was observed in ELS induction, all four genotypes produced ELSs ranging from 0.93 to 0.04 ELSs per flower bud. The ovules collected from flower buds of later stages (just before anthesis or flower anthesis) tended to exhibit higher response. The dark culture condition produced more than four times as many ELSs than in 16-h light condition. A significant number of plantlets were directly regenerated from ELSs on MS regeneration medium. The ploidy levels of 179 regenerated plants were determined by flow cytometry, revealing that the majority of them were diploid (55.9%) and haploid (31.3%). When a total of 54 diploid plants were examined by molecular genetic markers, 52 (96.3%) were considered as doubled haploids (DHs). This is the first report showing successful gynogenesis in gentian. The production of haploids and DHs by unfertilized ovule culture opens a novel prospect in gentian F1 hybrid breeding. PMID- 21305303 TI - Waterjet hydrodissection: first experiences and short-term outcomes of a novel approach to bladder tumor resection. AB - INTRODUCTION: TURB is the standard approach to bladder tumors but suffers from several disadvantages. Waterjet hydrodissection is a new technology for removing superficial tumors in the GI tract promising to preserve the histological structures of biopsy specimens with favorable long-term results as recent studies have shown. The aim of this study was to show the feasibility and applicability of waterjet hydrodissection for removing papillary superficial bladder tumors. MATERIALS AND METHODS: In five patients diagnosed with superficial papillary bladder tumor, transurethral submucosal dissection was conducted using the T-type I-Jet HybridKnife (Erbe, Tuebingen). The resection edges were labeled by means of electrical coagulation with the HybridKnife. Subsequently, a submucosal fluid cushion specific to the tissue layer was formed by the waterjet implementation function of the HybridKnife, thereby elevating the tumorous tissue. The tumor was endoscopically extracted with a retrieval bag. Biopsy specimens of the tumor edges and base were subsequently collected. RESULTS: All tumors could be resected en bloc, and the lamina propria was intact in all specimens, allowing the pathologist to distinguish between superficial and invasive tumors. Pathological analysis confirmed R0 resection in all samples. CONCLUSION: These initial results prove the feasibility of waterjet hydrodissection for removing bladder tumors. In contrast to conventional TURB, this new technique allows the pathologist to assess the entire lamina propria and the resection edges due to the en-bloc resection and to determine invasiveness as well as R0 versus R1 resection. These first results are promising, long-term oncological follow-up, and prospective randomized surveys investigating the recurrence rate have to be evaluated. PMID- 21305304 TI - Duration tuning in the auditory midbrain of echolocating and non-echolocating vertebrates. AB - Neurons tuned for stimulus duration were first discovered in the auditory midbrain of frogs. Duration-tuned neurons (DTNs) have since been reported from the central auditory system of both echolocating and non-echolocating mammals, and from the central visual system of cats. We hypothesize that the functional significance of auditory duration tuning likely varies between species with different evolutionary histories, sensory ecologies, and bioacoustic constraints. For example, in non-echolocating animals such as frogs and mice the temporal filtering properties of auditory DTNs may function to discriminate species specific communication sounds. In echolocating bats duration tuning may also be used to create cells with highly selective responses for specific rates of frequency modulation and/or pulse-echo delays. The ability to echolocate appears to have selected for high temporal acuity in the duration tuning curves of inferior colliculus neurons in bats. Our understanding of the neural mechanisms underlying sound duration selectivity has improved substantially since DTNs were first discovered almost 50 years ago, but additional research is required for a comprehensive understanding of the functional role and the behavioral significance that duration tuning plays in sensory systems. PMID- 21305305 TI - The management of subependymal giant cell tumors in tuberous sclerosis: a clinician's perspective. AB - BACKGROUND: Tuberous sclerosis (TSC) is a genetic multisystem disorder associated with hamartomas in several organs including subependymal giant cell tumors (SGCT). SGCT have the potential to grow and therefore to become symptomatic and are one of the main causes of death in TSC individuals. Surgical resection is the procedure of choice for SGCT. However, the discovery of mTOR pathway upregulation in TSC-associated tumors and recent evidence that mTOR inhibitors may induce regression of SGCT open up new treatment strategies. Based on a review of the currently available literature and on personal experience, current options for the management of TSC patients and appropriate indications, taking into account benefits and risks of surgery and pharmacotherapy, are discussed. DISCUSSION: An earlier diagnosis of SGCT in neurologically asymptomatic children may allow a precocious surgical removal of the tumor, thus minimizing surgery-related morbidity and mortality. Biologically targeted pharmacotherapy with mTOR inhibitors such as sirolimus and everolimus provides a safe and efficacious treatment option for patients with SGCT and has the potential to change the clinical management of these tumors. However, whether pharmacotherapy is sufficient to control growth or if it only delays the need for surgical removal of symptomatic SGCT remains unclear. Further studies are needed to determine the optimal levels of mTOR inhibitors that preserve maximal anti-tumor efficacy while minimizing side effects. PMID- 21305306 TI - Mycophenolate mofetil-induced pseudotumor cerebri in a boy with autoimmune lymphoproliferative disease. AB - INTRODUCTION: Pseudotumor cerebri (PTC) is a syndrome characterized with increased intracranial pressure, normal cerebrospinal fluid content (CSF), and a normal brain on imaging studies. In this case report, PTC has been linked to mycophenolate mofetil (MMF) that has been used for autoimmune lymphoproliferative syndrome (ALPS). CASE REPORT: A 5-year-old boy, who was using MMF for 4 months because of the ALPS, suffered from occipital headache and vomiting with no other symptom. The initial physical examination was normal expect bilateral papilledema. The patient underwent a lumbar puncture which showed elevated opening pressure (590 mmH2O) but no laboratory abnormalities of the CSF. A diagnosis of PTC was established. MMF was stopped, and the child was started on an acetazolamide treatment for 2 weeks. His symptoms and complaints recovered after this treatment. DISCUSSION: According to our knowledge, we report the first case of MMF-induced PTC in a boy with ALPS. This case illustrates that despite the rarity of MMF-induced PTC, the physicians should be aware of this possibility. Furthermore, in the setting of new-onset headaches or visual changes, early ophthalmologic examination for papilledema is recommended for early diagnosis. PMID- 21305307 TI - Assessment of endoscopic treatment for middle cranial fossa arachnoid cysts. AB - BACKGROUND: Endoscopic cystocisternotomy is one of three surgical methods used to treat middle cranial fossa arachnoid cysts. There is debate about which method is the best. OBJECTIVE: The aim of this study is to evaluate the effectiveness and safety of endoscopic cystocisternotomy for treatment of arachnoid cysts of the middle cranial fossa. METHODS: Thirty-two patients with arachnoid cysts of the middle cranial fossa who had undergone endoscopic cystocisternal fenestration between 2004 and 2009 were studied retrospectively. Data were obtained on clinical and neuroradiological presentation, indications to treat, surgical technique, complications, and the results of clinical and neuroradiological follow-up. RESULTS: Among the 27 patients with symptoms before surgery, 8 had disappearance of symptoms and 17 had improvement of symptoms. The cyst was reduced in size or it completely disappeared in 24 (75%) patients. The incidence rate of complications was 18.8%. CONCLUSIONS: Endoscopic cystocisternal fenestration is an effective treatment for symptomatic arachnoid cysts of the middle cranial fossa and should be the initial surgical procedure. PMID- 21305308 TI - [Protein-losing enteropathy: a cause of hypoalbuminaemia in patients with systemic lupus erythematosus]. AB - Lupus nephritis is the most common cause of extended edema and hypoalbuminemia in patients with systemic lupus erythematosus (SLE). However, the same immune complex mechanisms which lead to renal protein loss can also be active in the gastrointestinal tract, resulting in severe hypoproteinemia through enteral protein loss. The case of a young female patient with otherwise mild SLE and severe hypoproteinemia through bowel manifestation of the disease is presented here. No gastrointestinal symptoms such as diarrhoea were present, but immunohistology of the smaller and larger bowel showed severe immunocomplex disease with focus on the submucosa and the basal membrane. Other causes of hypoproteinemia were excluded. Treatment with prednisolone and azathioprine led to fast and durable resolution of symptoms. PMID- 21305309 TI - Calcium phosphate bone cement: a possible alternative to autologous bone graft. A radiological and biomechanical comparison in rat tibial bone. AB - BACKGROUND: Donor site morbidity is a problem after autologous bone transplantation. An injectable CaP bone cement indicates properties similar to bone. MATERIALS AND METHODS: Double osteotomies on rat tibias were performed. The intercalated segments were avascular (10), vascular (10), or avascular with Norian SRS((r)) CaP bone cement replacing cancellous bone (10). Controls were non operated contralateral tibias (15). All osteotomies were stabilised with an intra medullary nail. After 8 weeks, all rats were killed. The harvested tibias were compared using X-ray, DEXA scanning, microCT scans and a biomechanical torsional test. RESULTS: No difference in healing processes or biomechanical results has been found between the avascular bone graft, vascular bone graft and CaP bone cement groups. CONCLUSION: The injectable CaP bone cement confirms its similarities to bone, implying that it can be used as an adjunct to secure bone fragments and as a possible alternative to autologous bone transplantation in clinical practice. PMID- 21305310 TI - Outcome after supracricoid laryngectomies in the material of ENT Department, Poznan University of Medical Sciences. AB - All patients with T1 and T2 laryngeal cancer should be treated with the intent to preserve the larynx. In T3 glottic low-volume tumors, larynx preservation is an appropriate standard treatment option. Supracricoid partial laryngectomy remains a reasonable alternative to radiotherapy for patients with T2-T3 glottic cancer. Prospective clinical study aims to evaluate the oncological results of supracricoid partial laryngectomy as a treatment for selected glottic and supraglottic carcinoma, and to determine the different prognostic factors that may influence local control and survival. In the period of 2000-2007, 145 patients were treated at the academic tertiary referral medical center: ENT Department, University of Medical Sciences, Poznan, Poland. The ages of the analyzed group of patients ranged from 23 to 79, with mean 56.5 age for men and 25 for women. All of the patients had biopsy proven squamous cell carcinoma. Of the 145 patients 82 had glottic cancer and 63 had supraglottic cancer. The patients were staged according to the 2003 edition of the TNM classification established by the AJCC. The pathological TNM classification was additionally taken into consideration. All patients were treated by means of supracricoid and transglottic partial laryngectomy. The type of supracricoid partial laryngectomy was based on tumor localization and extension. Four patients underwent cricohyoidopexy, 57 cricohyoidoepiglottopexy, 65 reconstruction modo Calearo, and 19 modo Sedlacek-Tucker. We performed 21 unilateral selective neck dissections and none bilateral. A nasogastric feeding tube was inserted in all patients, and removed in patients that regained proper swallowing. As a result, we took into consideration the oncological and functional results. Histopathological examination of the operating specimen revealed the presence of dysplasia or invasive carcinoma at the margins, or a close margin of less than 5 mm from the edge of the resection (16 cases). The metastases were found on the neck in three cases, predominantly in the level II (2 cases) and III (1 case). Metastasis was found in one patient that had undergone CHP, Sedlacek-Tucker, and Calearo, respectively. Five patients received postoperative radiotherapy. The decision to use adjuvant radiotherapy was based on the presence of invasive carcinoma at the resection margin and on the presence of multiple positive neck nodes or extracapsular spread of the disease. The Kaplan-Meier estimated 3- and 5-year overall survival rates in the group of 122 because 23 patients did not report for medical check-ups. PMID- 21305311 TI - Histopathological incidence of facial canal dehiscence in otosclerosis. AB - The objective of this study was to evaluate the histopathological incidence of facial canal dehiscence in otosclerosis cases compared with non-otosclerotic controls. 133 temporal bones from 84 otosclerosis (35 unilateral otosclerosis, 49 bilateral otosclerosis) cases were compared to 102 age-matched normal temporal bones from 70 subjects (38 unilateral normal cases, 32 bilateral normal cases). Temporal bones were serially sectioned in the horizontal plane at a thickness of 20 MUm, and were stained with hematoxylin and eosin. We evaluated the location and the invasion of otosclerosis to the facial canal and incidence of facial canal dehiscence under light microscopy. Facial canal was subdivided into four portions: (1) the geniculate ganglion, (2) the tensor tympani muscle, (3) the oval window, and (4) mastoid. The incidence of facial canal dehiscence in otosclerosis [66 temporal bones (49.6%)] was significantly lower than normal controls [67 control temporal bones (65.7%)] in the oval window area (P = 0.019). Temporal bones with otosclerotic invasion to the thin bone of the canal were significantly less likely to have dehiscence [10 temporal bones (31.3%)] compared to the otosclerotic bones without invasion [56 temporal bones (55.5%)] (P = 0.025). There was no significant difference in the incidence of facial canal dehiscence between temporal bones with and without otosclerosis in the entire segment of facial nerve. Our findings in this study suggest that otosclerotic lesions have the potential to close dehiscence of the facial canal in the oval window area. PMID- 21305312 TI - Suitability of auditory speech sound evaluation (ASE(r)) in German cochlear implant patients. AB - ASE(r) is an audiological evaluation tool based on speech sounds as stimuli and was developed by The Eargroup, Antwerp. It consists of three levels: detection, discrimination and identification of phonemes and is a sufficient tool to measure supraliminal auditory capacities in Flemish language of children 10 months and older as well as adults. The aim of this study was to test the suitability of patients for cochlear implant in Germany, using 245 consecutive measurements (141 adults, 79 children, 25 controls) in a standard test protocol for phoneme detection and discrimination, Mainzer and Gottinger in children and Freiburger in adults pre-, 3 and 6 months and 1 year after implantation. Results in detection and discrimination regarding frequency spectrum and fitting parameters were evaluated using the following statistical methods: t test and correlation analysis. Detection improves first, followed by numbers, phoneme discrimination and monosyllables. Test results compared pre- to 3, 6 months and later, postoperatively, differ significantly (p < 0.05). A "ceiling-effect" is obtained between 6 months and 1 year (reproduction in ASE(r) >90%). Development of detection and discrimination correlates directly with results in numbers and monosyllables (r = 0.92). Non-German speaking patients cope better with ASE(r) than with numbers and monosyllables. Evaluation of phoneme discrimination enables better frequency specific fitting. Results indicated that ASE(r) is a valuable diagnostic supplement in fitting and therapy of cochlear implant patients regardless of cognitive level, age and language. Important information on frequency-resolving power of cochlear nerve after implantation is gained. Use of ASE(r) enables comparability and evaluation of study results in different countries. PMID- 21305313 TI - Increased seroprevalence of Toxoplasma gondii in a population of patients with Bell's palsy: a sceptical interpretation of the results regarding the pathogenesis of facial nerve palsy. AB - Facial nerve oedema and anatomical predisposition to compression within the fallopian tube seem to be the only generally accepted facts in the pathophysiology of Bell's palsy. Several infectious causes have been suggested as possible triggers of this oedema. Most of the suggested pathogens have been associated with facial nerve lesions during latent infections, reinfections or endogenous reactivations. The aim of this study was to investigate the seroprevalence of three such pathogens Toxoplasma gondii, Epstein-Barr virus (EBV) and cytomegalovirus (CMV) in a population of patients with facial nerve palsy. Fifty-six patients with Bell's palsy were included in the study. A group of 25 individuals with similar age and gender distribution was used as control. Seropositivity for T. gondii, EBV viral capsid antigen (VCA) and CMV-specific IgM and IgG antibodies was investigated 2-5 days after the onset of the palsy. Comparisons for both IgM and IgG antibodies against T. gondii attributed significantly higher seroprevalence in the patients' group than in the control group (p = 0.024 and 0.013, respectively). The respective examinations for EBV and CMV attributed no significant results. The roles of EBV and CMV in the pathogenesis of Bell's palsy were not confirmed by this study. However, a significantly higher seroprevalence of IgM- and IgG-specific T. gondii antibodies was detected in patients with Bell's palsy when compared to healthy controls. The possibility that facial nerve palsy might be a late complication of acquired toxoplasmosis may need to be addressed in further studies. PMID- 21305314 TI - Choroidal metastasis from hepatocellular carcinoma, diagnosed by fine needle aspiration biopsy and treated by iodine-125 brachytherapy. AB - PURPOSE: To report a rare case of choroidal metastasis from hepatocellular carcinoma. METHODS: A 63-year-old man with known hepatocellular carcinoma (HCC) and treated clavicular metastasis noted reduced visual acuity in the right eye. He was found to have an amelanotic choroidal tumor measuring 18 * 14 * 9.3 mm and with retinal detachment. Fine needle aspiration biopsy confirmed metastatic HCC. RESULTS: The choroidal metastasis was treated with 5 days of iodine-125 plaque brachytherapy (3500 cGy to apex). Tumor regression to 2.6 mm thickness with resolution of retinal detachment and preservation of visual acuity at 20/40 at the 4-month follow-up was documented. CONCLUSIONS: HCC metastasis to the choroid can be treated with focal plaque brachytherapy, with preservation of vision and quality of life. PMID- 21305315 TI - Scleral buckling versus primary vitrectomy in rhegmatogenous retinal detachment study (SPR Study): predictive factors for functional outcome. Study report no. 6. AB - PURPOSE: To identify risk factors associated with best-corrected visual acuity (BCVA) 1 year after initial surgery following primary vitrectomy (PV) and scleral buckling surgery (SB) for rhegmatogenous retinal detachment (RRD). METHODS: Relating the final BCVA at the 1-year follow-up visit to pre- and intraoperative findings in the "randomized, prospective, multicenter clinical trial comparing scleral buckling versus primary vitrectomy for repair of rhegmatogenous retinal detachment" (SPR Study) using multivariate statistical methods. RESULTS: In the phakic subtrial, final BCVA is associated with the number of breaks (p = 0.0259), duration of symptoms (p = 0.0476), baseline BCVA (p = 0.0002), retinal detachment central to major vessels arcades (p = 0.0088), total detachment (p = 0.0027), and chain formation of breaks (p = 0.0129). In the pseudophakic/aphakic subtrial, final BCVA is related to the number of retinal breaks (p = 0.0010), secondary cataract or central capsular fibrosis (p = 0.0141), intraoperative laser photocoagulation (p = 0.0373), and inferior detachment with breaks below the 4 and 8 o'clock positions (p = 0.0173). CONCLUSION: Final BCVA is the most important outcome for patients undergoing RRD surgery. Our results demonstrate that the final BCVA is related to a higher preoperative number of breaks in both subtrials. Additional risk factors varied between phakic and pseudophakic subgroups. PMID- 21305316 TI - Association of ACE ID and ACE G2350A polymorphism with increased blood pressure in persons exposed to different sound levels in Pakistan. AB - PURPOSE: To investigate the role of ACE ID and ACE G2350A polymorphism in increasing the blood pressure of persons exposed to different sound levels. METHOD: Persons exposed to normal sound level (<=80 dBA) and noise (>80 dBA) were divided in two categories on the basis of blood pressure. Category A was comprised of the individuals with blood pressure ranges equal or less than that for normotensive persons. Category B was composed of the workers with blood pressure above than that for category A. ACE ID and ACE G2350A polymorphism was detected for analysis of its association with the increased blood pressure considering noise as modifier. RESULTS: Least homozygous allele model for ACE ID polymorphism indicates no association of DD allele with the increased blood pressure in persons exposed to normal sound (Odds ratio: 0.831; 95% Confidence interval: 0.340-2.030). Similar findings were noted in persons exposed to noise (Odds ratio: 0.992; 95% Confidence interval: 0.536-1.835). Combining all the samples did not change the results (Odds ratio: 0.948; 95% Confidence interval: 0.580-1.549). For ACE G2350A polymorphism, least common homozygote model revealed that AA allele did not affect the chances of increased blood pressure in normal sound exposed group (Odds ratio: 0.827; 95% Confidence interval: 0.169-4.042) and noise exposed group (Odds ratio: 1.416; 95% Confidence interval: 0.682-2.941). There was no prominent variation in the results on combining all the samples (Odds ratio: 1.529; 95% Confidence interval: 0.807-2.872). CONCLUSIONS: No association was observed between ACE ID/ACE G2350A polymorphism and the increased blood pressure in persons exposed to normal sound and noise in Pakistani population. PMID- 21305317 TI - Differentially expressed genes in giant cell tumor of bone. AB - Giant cells tumors of bone (GCTB) are benign in nature but cause osteolytic destruction with a number of particular characteristics. These tumors can have uncertain biological behavior often contain a significant proportion of highly multinucleated cells, and may show aggressive behavior. We have studied differential gene expression in GCTB that may give a better understanding of their physiopathology, and might be helpful in prognosis and treatment. Rapid subtractive hybridization (RaSH) was used to identify and measure novel genes that appear to be differentially expressed, including KTN1, NEB, ROCK1, and ZAK using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry in the samples of GCTBs compared to normal bone tissue. Normal bone was used in the methodology RaSH for comparison with the GCTB in identification of differentially expressed genes. Functional annotation indicated that these genes are involved in cellular processes related to their tumor phenotype. The differential expression of KTN1, ROCK1, and ZAK was independently confirmed by qRT-PCR and immunohistochemistry. The expression of the KTN1 and ROCK1 genes were increased in samples by qRT-PCR and immunohistochemistry, and ZAK had reduced expression. Since ZAK have CpG islands in their promoter region and low expression in tumor tissue, their methylation pattern was analyzed by MSP PCR. The genes identified KTN1, ROCK1, and ZAK may be responsible for loss of cellular homeostasis in GCTB since they are responsible for various functions related to tumorigenesis such as cell migration, cytoskeletal organization, apoptosis, and cell cycle control and thus may contribute at some stage in the process of formation and development of GCTB. PMID- 21305318 TI - Transcriptional analysis of the titin cap gene. AB - Mutations in titin cap (Tcap), also known as telethonin, cause limb-girdle muscular dystrophy type 2G (LGMD2G). Tcap is one of the titin interacting Z-disc proteins involved in the regulation and development of normal sarcomeric structure. Given the essential role of Tcap in establishing and maintaining normal skeletal muscle architecture, we were interested in determining the regulatory elements required for expression of this gene in myoblasts. We have defined a highly conserved 421 bp promoter proximal promoter fragment that contains two E boxes and multiple putative Mef2 binding sequences. This promoter can be activated by MyoD and myogenin in NIH3T3 fibroblast cells, and maintains the differentiated cell-specific expression pattern of the endogenous Tcap in C2C12 cells. We find that while both E boxes are required for full activation by MyoD or myogenin in NIH3T3 cells, the promoter proximal E box has a greater contribution to activation of this promoter in C2C12 cells and to activation by MyoD in NIH3T3 cells. Together, the data suggest an important role for MyoD in activating Tcap expression through the promoter proximal E box. We also show that myogenin is required for normal expression in vivo and physically binds to the Tcap promoter during embryogenesis. PMID- 21305319 TI - Joint effects of germ-line TP53 mutation, MDM2 SNP309, and gender on cancer risk in family studies of Li-Fraumeni syndrome. AB - Li-Fraumeni syndrome (LFS) is a rare familial cancer syndrome characterized by early cancer onset, diverse tumor types, and multiple primary tumors. Germ-line TP53 mutations have been identified in most LFS families. A high-frequency single nucleotide polymorphism, SNP309 (rs2279744), in MDM2 was recently confirmed to be a modifier of cancer risk in several case-series studies: substantially earlier cancer onset was observed in SNP309 G-allele carriers than in wild-type individuals by 7-16 years. However, cancer risk analyses that jointly account for measured hereditary TP53 mutations and MDM2 SNP309 have not been systematically investigated in familial cases. Here, we determined the combined effects of measured TP53 mutations, MDM2 SNP309, and gender and their interactions simultaneously in LFS families. We used the method that is designed for extended pedigrees and structured for age-specific risk models based on Cox proportional hazards regression. We analyzed the cancer incidence in 19 extended pedigrees with germ-line TP53 mutations ascertained through the clinical LFS phenotype. The dataset consisted of 463 individuals with 129 TP53 mutation carriers. Our analyses showed that the TP53 germ-line mutation and its interaction with gender were strongly associated with familial cancer incidence and that the association between MDM2 SNP309 and increased cancer risk was modest. In contrast with several case-series studies, the interaction between MDM2 SNP309 and TP53 mutation was not statistically significant in our LFS family cohort. Our results showed that SNP309 G-alleles were associated with accelerated tumor formation in both carriers and non-carriers of germ-line TP53 mutations. PMID- 21305320 TI - Deleterious effects of intestinal ischemia/reperfusion injury in the mouse enteric nervous system are associated with protein nitrosylation. AB - Changes in intestinal function, notably impaired transit, following ischemia/reperfusion (I/R) injury are likely to derive, at least in part, from damage to the enteric nervous system. Currently, there is a lack of quantitative data and methods on which to base quantitation of changes that occur in enteric neurons. In the present work, we have investigated quantifiable changes in response to ischemia of the mouse small intestine followed by reperfusion from 1 h to 7 days. I/R caused distortion of nitric oxide synthase (NOS)-containing neurons, the appearance of a TUNEL reaction in neurons, protein nitrosylation and translocation of Hu protein. Protein nitrosylation was detected after 1 h and was detectable in 10% of neurons by 6 h in the ischemic region, indicating that reactive peroxynitrites are rapidly produced and can interact with proteins soon after reperfusion. Apoptosis, revealed by TUNEL staining, was apparent at 6 h. The profile sizes of NOS neurons were increased by 60% at 2 days and neurons were still swollen at 7 days, both in the ischemic region and proximal to the ischemia. The distribution of the enteric neuron marker and oligonucleotide binding protein, Hu, was significantly changed in both regions. Hu protein translocation to the nucleus was apparent by 3 h and persisted for up to 7 days. Particulate Hu immunoreactivity was observed in the ganglia 3 h after I/R but was never observed in control. Our observations indicate that effects of I/R injury can be detected after 1 h and that neuronal changes persist to at least 7 days. Involvement of NO and reactive oxygen species in the changes is indicated by the accumulation of nitrosylated protein aggregates and the swelling and distortion of nitrergic neurons. It is concluded that damage to the enteric nervous system, which is likely to contribute to functional deficits following ischemia and re oxygenation in the intestine, can be quantified by Hu protein translocation, protein nitrosylation, swelling of nitrergic neurons and apoptosis. PMID- 21305321 TI - A multi-scale comparison of trait linkages to environmental and spatial variables in fish communities across a large freshwater lake. AB - Species present in communities are affected by the prevailing environmental conditions, and the traits that these species display may be sensitive indicators of community responses to environmental change. However, interpretation of community responses may be confounded by environmental variation at different spatial scales. Using a hierarchical approach, we assessed the spatial and temporal variation of traits in coastal fish communities in Lake Huron over a 5 year time period (2001-2005) in response to biotic and abiotic environmental factors. The association of environmental and spatial variables with trophic, life-history, and thermal traits at two spatial scales (regional basin-scale, local site-scale) was quantified using multivariate statistics and variation partitioning. We defined these two scales (regional, local) on which to measure variation and then applied this measurement framework identically in all 5 study years. With this framework, we found that there was no change in the spatial scales of fish community traits over the course of the study, although there were small inter-annual shifts in the importance of regional basin- and local site scale variables in determining community trait composition (e.g., life-history, trophic, and thermal). The overriding effects of regional-scale variables may be related to inter-annual variation in average summer temperature. Additionally, drivers of fish community traits were highly variable among study years, with some years dominated by environmental variation and others dominated by spatially structured variation. The influence of spatial factors on trait composition was dynamic, which suggests that spatial patterns in fish communities over large landscapes are transient. Air temperature and vegetation were significant variables in most years, underscoring the importance of future climate change and shoreline development as drivers of fish community structure. Overall, a trait based hierarchical framework may be a useful conservation tool, as it highlights the multi-scaled interactive effect of variables over a large landscape. PMID- 21305322 TI - Epidemic size determines population-level effects of fungal parasites on Daphnia hosts. AB - Parasites frequently reduce the fecundity, growth, and survival of individual hosts. How often do these virulent effects reduce the density of host populations? Spectacular examples show that recently invaded parasites can severely impact host populations--but what about parasites persisting long-term in host populations? We have addressed this issue using a zooplankton host (Daphnia dentifera) that becomes infected with a fungal microparasite (Metschnikowia bicuspidata). We combined observations of epidemics in nine lakes over 6 years, fine-scale sampling of three epidemics, and a mesocosm experiment. Most epidemics remained small (<10% maximum prevalence) and exerted little influence on host densities. However, larger epidemics more severely depressed the populations of their hosts. These large/severe epidemics started and peaked earlier than smaller/benign ones. The larger epidemics also exerted particularly negative effects on host densities at certain lags, reflecting the delayed consequences of infection on fecundity reduction and host mortality. Notably, negative effects on the juvenile stage class manifested later than those on the adult stage class. The results of the experiment further emphasized depression of host density by the fungus, especially on the density of the juvenile stage class. Consequently, this common parasite reduces the density of host populations when conditions foster larger outbreaks characterized by an earlier start and earlier peak. Given these considerable effects on host density seen in a number of large epidemics, parasitism may sometimes rank highly among other factors (predation, resource availability) driving the population dynamics of these hosts. PMID- 21305324 TI - Nitric oxide induces HIF-1alpha stabilization and expression of intestinal trefoil factor in the damaged rat jejunum and modulates ulcer healing. AB - BACKGROUND: The induction of intestinal trefoil factor (ITF) has been reported to depend on hypoxia-inducible factor-1 (HIF-1). Nitric oxide modulates HIF-1 activity. The present study aims to analyze the role of nitric oxide in jejunum damage induced by indomethacin and its ability to modulate epithelial function through the expression of ITF. METHODS: Rats received indomethacin (7.5 mg/kg, s.c., twice), and a time course analysis of damage was performed (24-96 h after the first administration). In these animals, the role of nitric oxide was analyzed by using 1400W, a selective iNOS activity inhibitor (5 mg/kg, i.p./day), on: (1) intestinal damage, (2) ulcer healing, (3) the presence of nitrated proteins in the jejunum and (4) the protein expression of inducible nitric oxide synthase (iNOS), HIF-1alpha and ITF. RESULTS: Indomethacin induced damage in the jejunum that was apparent at 24 h and peaked at 48-72 h. An increase in iNOS, HIF 1alpha, ITF and nitrated proteins was observed in the injured jejunum. Immunoprecipitation of HIF-1alpha allowed determination of the nitration/nitrosylation of this protein by using nitrotyrosine and nitrocysteine antibodies. Blockade of iNOS activity did not significantly modify damage or iNOS expression, but did significantly impede ITF induction, HIF-1alpha stabilization and HIF-1alpha detection with antibodies against nitrated proteins. In parallel to these results, pre-treatment with 1400W delayed the healing of the ulcer provoked by indomethacin. CONCLUSIONS: These results suggest that iNOS-derived NO is involved in HIF-1alpha stabilization, probably through S-nitrosylation, and ITF expression in goblet cells of the damaged jejunum of indomethacin-treated rats and mediates ulcer healing. PMID- 21305325 TI - Transaminase levels in the upper normal range are associated with oral hypoglycemic drug therapy failure in patients with type 2 diabetes. AB - Incident diabetes and the worsening of diabetes have recently been linked to hepatic steatosis. Aim of our study was to determine whether oral hypoglycemic agent failure is associated with higher transaminase levels (valid measure of liver steatosis). We selected 200 patients, attenders (3 consecutive annual evaluations) in our clinic, with type 2 diabetes among which 100 with oral hypoglycemic agents failure and 100 who were still responsive to oral therapy. Failure to therapy was defined as glycated hemoglobin >7.5% despite maximal-dose oral therapy. We analyzed patient histories and laboratory data. Compared with oral-therapy-responsive patients, those with failure had a significantly higher level mostly of alanine aminotransferase at the time of therapy failure and 2 years before. They were more likely to have had symptoms of hyperglycemia at the time of diabetes diagnosis. Regression analysis indicated that each 5-unit increase in transaminase levels independently increased the risk for oral hypoglycemic agents failure by 1.70. Higher liver transaminase levels, especially in patients who had symptomatic hyperglycemia at diabetes diagnosis, associate with oral hypoglycemic agent failure. The possible pathogenetic link between transaminase and declining islet function might consist of insulin resistance and increased circulating fatty acid levels, in turn causing liver steatosis and beta cell dysfunction. PMID- 21305326 TI - Complete nucleotide sequence of a new variant of grapevine rupestris stem pitting associated virus from southern Italy. PMID- 21305327 TI - A large outbreak of hand, foot, and mouth disease caused by EV71 and CAV16 in Guangdong, China, 2009. AB - A large outbreak of hand, foot and mouth disease (HFMD) occurred in Guangdong, China, in 2009. A total of 92,749 cases were officially reported to the Center for Disease Control and Prevention of Guangdong (GDCDC). To clarify the pathogen causing the outbreak, 600 specimens, including stool, rectal swabs, vesicular swabs, cerebrospinal fluid, and throat swabs, were collected from 541 patients and subjected to one-step RT-PCR. Four hundred eighty-nine of 541 patient samples were positive for enterovirus. All positive samples were cultured on RD and Hep2 cells; 307 specimens displayed CPE. Sequence analysis of PCR fragment and typing real-time PCR indicated that these isolates included EV71 (56%), CAV16 (35.5%), CAV6 (2.0%), CAV10 (1.0%), CAV2 (0.7%), CAV4 (1.3%), Echo30 (0.7%), Echo25 (1.0%), Echo4 (0.3%), CBV5 (1.0%) and human rhinovirus (0.7%). 100% (12/12) of fatal cases and 97.2% (140/144) of severe cases carried EV71 and CAV16. The results implied that EV71 and CAV16 were mainly responsible for the outbreak. Comparison with the three global types of EV71 and the five clusters of genotype C showed that the sequences from mainland China (not including the Hong Kong region) are located in subgenogroup C-4 and originate from isolates from the Shenzhen area of Guangdong Province. Results from this study show that the C-4 genotype has been a prevalent pathogen in mainland China since 1998. PMID- 21305328 TI - The nuclear localization signal sequence of porcine circovirus type 2 ORF2 enhances intracellular delivery of plasmid DNA. AB - The phospholipid bilayer of the cell membrane is a natural barrier that prevents large molecules from entering the cell. Cationic liposomes are commonly used for transfection of plasmid DNA but they have high cost and toxicity. Many reports have shown that cell-penetrating peptides (CPP) are able to translocate across the cell membrane efficiently. The VP22 peptide of herpes simplex virus (HSV) was synthesized as a CPP. Two fusion protein candidates, containing binding/condensing protein (VP22-TmHU) and porcine circovirus type 2 nuclear localization signal (VP22-TmHU-PCV2.NLS), were constructed and expressed in E. coli in an attempt to improve delivery of plasmid DNA (pDNA). Firstly, as shown by the electrophoretic mobility shift assay (EMSA), VP22-TmHU (VT) and VP22-TmHU PCV2.NLS (VTN) were able to bind to pDNA (pEGFP-N1) effectively. Secondly, intracellular transport of pEGFP-N1 was observed by fluorescence microscopy and quantified by flow cytometry after transfection. VTN was successful in delivering pEGFP-N1 intracellularly but VT was not. Thirdly, two protein candidates were combined with Lipofectamine, and both VT and VTN enhanced the transfection rate to 65%, compared to 25% with Lipofectamine alone. Lastly, mice were injected intramuscularly with PBS, pcDNA3-ORF2, pcDNA3-ORF2 plus Lipofectamine, pcDNA3 ORF2 plus VT, pcDNA3-ORF2 plus VT plus Lipofectamine, pcDNA3-ORF2 plus VTN, and pcDNA3-ORF2 plus VTN plus Lipofectamine. The highest level of antibodies raised against PCV2 ORF2 Cap protein was detected with pcDNA3-ORF2 plus VTN. Contrary to the in vitro results, VTN delivered pDNA effectively in vivo without Lipofectamine. In summary, the nuclear localization signal sequence of porcine circovirus type 2 ORF2 can enhance intracellular delivery of pDNA. PMID- 21305329 TI - Perceptual mechanism underlying gaze guidance in chimpanzees and humans. AB - Previous studies comparing eye movements between humans and their closest relatives, chimpanzees, have revealed similarities and differences between the species in terms of where individuals fixate their gaze during free viewing of a naturalistic scene, including social stimuli (e.g. body and face). However, those results were somewhat confounded by the fact that gaze behavior is influenced by low-level stimulus properties (e.g., color and form) and by high-level processes such as social sensitivity and knowledge about the scene. Given the known perceptual and cognitive similarities between chimpanzees and humans, it is expected that such low-level effects do not play a critical role in explaining the high-level similarities and differences between the species. However, there is no quantitative evidence to support this assumption. To estimate the effect of local stimulus saliency on such eye-movement patterns, this study used a well established bottom-up saliency model. In addition, to elucidate the cues that the viewers use to guide their gaze, we presented scenes in which we had manipulated various stimulus properties. As expected, the saliency model did not fully predict the fixation patterns actually observed in chimpanzees and humans. In addition, both species used multiple cues to fixate socially significant areas such as the face. There was no evidence suggesting any differences between chimpanzees and humans in their responses to low-level saliency. Therefore, this study found a substantial amount of similarity in the perceptual mechanisms underlying gaze guidance in chimpanzees and humans and thereby offers a foundation for direct comparisons between them. PMID- 21305330 TI - Bioactivity, chemical profiling, and 16S rRNA-based phylogeny of Pseudoalteromonas strains collected on a global research cruise. AB - One hundred one antibacterial Pseudoalteromonas strains that inhibited growth of a Vibrio anguillarum test strain were collected on a global research cruise (Galathea 3), and 51 of the strains repeatedly demonstrated antibacterial activity. Here, we profile secondary metabolites of these strains to determine if particular compounds serve as strain or species markers and to determine if the secondary metabolite profile of one strain represents the bioactivity of the entire species. 16S rRNA gene similarity divided the strains into two primary groups: One group (51 strains) consisted of bacteria which retained antibacterial activity, 48 of which were pigmented, and another group (50 strains) of bacteria which lost antibacterial activity upon sub-culturing, two of which were pigmented. The group that retained antibacterial activity consisted of six clusters in which strains were identified as Pseudoalteromonas luteoviolacea, Pseudoalteromonas aurantia, Pseudoalteromonas phenolica, Pseudoalteromonas ruthenica, Pseudoalteromonas rubra, and Pseudoalteromonas piscicida. HPLC-UV/VIS analyses identified key peaks, such as violacein in P. luteoviolacea. Some compounds, such as a novel bromoalterochromide, were detected in several species. HPLC-UV/VIS detected systematic intra-species differences for some groups, and testing several strains of a species was required to determine these differences. The majority of non-antibacterial, non-pigmented strains were identified as Pseudoalteromonas agarivorans, and HPLC-UV/VIS did not further differentiate this group. Pseudoalteromonas retaining antibacterial were more likely to originate from biotic or abiotic surfaces in contrast to planktonic strains. Hence, the pigmented, antibacterial Pseudoalteromonas have a niche specificity, and sampling from marine biofilm environments is a strategy for isolating novel marine bacteria that produce antibacterial compounds. PMID- 21305331 TI - Fabella fracture with CT imaging: a case report. AB - Fracture of the fabella is rare, may be easily overlooked, and can be a clinically important cause of posterolateral knee pain following traumatic injury or total knee arthroplasty. To date, nine case reports of fabella fracture with radiographic documentation have been reported in the literature. This report documents a 55-year-old male pedestrian who was struck by an automobile and presented with radiographs demonstrating depressed lateral tibial plateau and proximal fibula fractures. Computed tomography (CT) was performed for surgical planning and demonstrated the additional finding of a radiographically occult nondisplaced fabella fracture. To the best of our knowledge, this is the first case in which CT documentation of a fabella fracture is reported. Fracture of the fabella is a rare but important clinical entity which may be overlooked clinically and radiographically. Clinical information can provide a high index of suspicion, and when coupled with radiographic and CT findings, may lead to the correct diagnosis. CT imaging of the knee may confirm a suspected fabella fracture or may help detect a radiographically occult fracture. PMID- 21305332 TI - Exophytic hypothalamic cavernous malformation mimicking an extra-axial suprasellar mass. AB - We report the case of a 31-year-old male who presented to the ER with a 1-week history of progressively worsening, throbbing, left retro-orbital headache, ptosis, and subjective worsening of short-term memory function. Initial review of systems and laboratory data were noncontributory. Non-contrasted CT demonstrated a large hyperdense mass centered in the suprasellar cistern without evidence of dissecting extra-axial hemorrhage. Though the initial appearance mimicked a basilar tip aneurysm or another primary extra-axial suprasellar pathology such as a hemorrhagic or proteinaceous craniopharyngioma, germinoma, or optic glioma, a second smaller, clearly intra-axial, hyperdense lesion was observed in the left periventricular forceps major white matter. Consideration for multiple cavernomas versus hypervascular metastatic disease such as renal malignancy, thyroid malignancy, or melanoma was raised. CTA confirmed normal intracranial vasculature. Subsequent MRI images showed an acutely hemorrhagic mass centered at the left paramedian hypothalamus and tuber cinereum with numerous secondary foci, demonstrating mature hemorrhagic elements and confirming the diagnosis of multiple cavernomas. PMID- 21305334 TI - I feel good! Gender differences and reporting heterogeneity in self-assessed health. AB - For empirical analysis and policy-oriented recommendations, the precise measurement of individual health or well-being is essential. The difficulty is that the answer may depend on individual reporting behaviour. Moreover, if an individual's health perception varies with certain attitudes of the respondent, reporting heterogeneity may lead to index or cut-point shifts of the health distribution, causing estimation problems. An index shift is a parallel shift in the thresholds of the underlying distribution of health categories. In contrast, a cut-point shift means that the relative position of the thresholds changes, implying different response behaviour. Our paper aims to detect how socioeconomic determinants and health experiences influence the individual valuation of health. We analyse the reporting behaviour of individuals on their self-assessed health status, a five-point categorical variable. Using German panel data, we control for observed heterogeneity in the categorical health variable as well as unobserved individual heterogeneity in the panel estimation. In the empirical analysis, we find strong evidence for cut-point shifts. Our estimation results show different impacts of socioeconomic and health-related variables on the five categories of self-assessed health. Moreover, the answering behaviour varies between female and male respondents, pointing to gender-specific perception and assessment of health. Hence, in case of reporting heterogeneity, using self assessed measures in empirical studies may be misleading and the information needs to be handled with care. PMID- 21305333 TI - A review of treatment modalities for vestibular schwannoma. AB - Vestibular schwannomas are benign intracranial tumors arising from the vestibular nerve. Treatment options include observation, stereotactic radiosurgery, fractionated radiotherapy, and microsurgery. We review the evidence describing efficacy and side-effect profiles of each of these modalities. This was accomplished by outlining the results of published meta-analyses and performing a systematic search of the literature for individual studies published between 2004 and June 2009. Without intervention, 29-54% of tumors will grow and 16-26% of patients require additional treatment, with 54-63% preserving functional hearing. With radiosurgery, only 2-4% require additional treatment and hearing preservation is accomplished in 44-66% of cases. Reviewing contemporary studies, it appears that reduced marginal doses may have decreased morbidity risks associated with radiosurgery without sacrificing efficacy. With fractionated radiotherapy, 3-7% will require additional treatment and hearing preservation is reported at 59-94% of patients, although long-term outcomes are not known. Microsurgery is an alternative for eligible patients, with fewer than 2% requiring additional treatment; however, the risk of hearing loss, facial neuropathy, and other morbidities is relatively high. There are significant limitations with comparing the efficacy and morbidity rates across interventions because of selection bias and confounding factors. Additional prospective comparative trials and randomized studies are needed to improve our understanding of the relative benefits of each modality. PMID- 21305335 TI - Incremental net benefit and acceptability of alternative health policies: a case study of mass screening for colorectal cancer. AB - The incremental net benefit (INB) and the related acceptability curves for public health programs provide valuable tools for decision making. We proposed to apply them to the assessment of mass screening of colorectal cancer. The now standard guaiac fecal occult blood test (FOBT) is already implemented in several countries. We considered the innovative immunological FOBT and computed tomography colonography (CTC) as competing screening technologies. Using biennial guaiac FOBT as the reference strategy, we estimated the cost-effectiveness of the following alternatives: biennial immunological FOBT, CTC every 5 years (strategy CTC5), and CTC every 10 years (strategy CTC10). Over a 30-year horizon and from the perspective of a third-party payer, we developed a Markov model on a hypothetical cohort of 100,000 subjects at average risk of colorectal cancer. Close expected net benefits between immunological FOBT and CTC5 induced uncertainty in the choice of the optimal strategy. Probabilistic sensibility analysis then suggested that below a willingness to pay (WTP) per life-years gained (LYG) of 8,587 ?/LYG, CTC10 was optimal, while CTC5 would be preferred beyond a WTP of 8,587 ?/LYG. PMID- 21305336 TI - Enhancement of subchondral bone quality by alendronate administration for the reduction of cartilage degeneration in the early phase of experimental osteoarthritis. AB - To evaluate the effects of alendronate (ALN) on the subchondral bone quality and cartilage degeneration in the early phase of experimental model of osteoarthritis after anterior cruciate ligament transaction (ACLT). Thirty male adult healthy Japanese white rabbits after right ACLT or sham operation were divided into three groups (n = 10 per group): Sham; ACLT + ALN [after ACLT, the rabbits were treated with ALN daily starting from 4 days after surgery (10 MUg/kg/d subcutaneously)]; and ACLT + NS group (after ACLT, the rabbits were injected saline as a placebo). At 60 days postsurgery, specimens from the affected knees were harvested. Histological analysis (HE and Safranin-O staining) as well as Mankin score were carried out to assess the cartilage degradation. BMP-2 and MMP-13 immunohistochemistry were also performed to demonstrate the alterations of cartilage molecular metabolism. Subchondral bone quality was evaluated by bone mineral density (BMD) and microstructure histomorphometry assay. For bone mineral density evaluation, 1/4 distal femurs, medial and lateral regions of femoral condylus were scanned with dual X-ray absorptiometry to assess the subchondral bone mass. Giemsa, von Kossa stain, and fluorescence technique for undecalcified bone section were carried out to examine the morphometry of the subchondral trabecular bone and subchondral plate. Histological and Mankin score analyses displayed that ALN treatment markedly reduced cartilage lesions and delayed the cartilage degeneration in OA joints. Immunohistochemistry assay further indicated that this cartilage-protective role of ALN was associated with elevating BMP-2 while inhibiting MMP-13 expression. BMD assessment demonstrated that ALN treatment significantly suppressed subchondral bone resorption. The results from histomorphometry assay of subchondral bone revealed that ALN treatment markedly increased the percent trabecular area (BV/TV), trabecular thickness (Tb.Th), and trabecular number (Tb.N). Moreover, both thickness and the porosity of the subchondral plate in ACLT + ALN group presented significantly higher than that in ACLT + NS group, while no significant difference was found between ACLT + ALN and Sham group. ALN plays an important role in cartilage protection in OA joints that is associated with the improvement of subchondral bone quality through reduction of subchondral bone resorption. ALN could be potentially used as a disease modifying strategy to limit the progression of OA. PMID- 21305337 TI - Density functional calculations of backbone 15N shielding tensors in beta-sheet and turn residues of protein G. AB - We performed density functional calculations of backbone (15)N shielding tensors in the regions of beta-sheet and turns of protein G. The calculations were carried out for all twenty-four beta-sheet residues and eight beta-turn residues in the protein GB3 and the results were compared with the available experimental data from solid-state and solution NMR measurements. Together with the alpha helix data, our calculations cover 39 out of the 55 residues (or 71%) in GB3. The applicability of several computational models developed previously (Cai et al. in J Biomol NMR 45:245-253, 2009) to compute (15)N shielding tensors of alpha helical residues is assessed. We show that the proposed quantum chemical computational model is capable of predicting isotropic (15)N chemical shifts for an entire protein that are in good correlation with experimental data. However, the individual components of the predicted (15)N shielding tensor agree with experiment less well: the computed values show much larger spread than the experimental data, and there is a profound difference in the behavior of the tensor components for alpha-helix/turns and beta-sheet residues. We discuss possible reasons for this. PMID- 21305338 TI - Competing conceptions of animal welfare and their ethical implications for the treatment of non-human animals. AB - Animal welfare has been conceptualized in such a way that the use of animals in science and for food seems justified. I argue that those who have done this have appropriated the concept of animal welfare, claiming to give a scientific account that is more objective than the "sentimental" account given by animal liberationists. This strategy seems to play a major role in supporting merely limited reform in the use of animals and seems to support the assumption that there are conditions under which animals may be raised and slaughtered for food that are ethically acceptable. Reformists do not need to make this assumption, but they tend to conceptualize animal welfare is such a way that death does not count as harmful to the interests of animals, nor prolonged life a benefit. In addition to this prudential value assumption, some members of this community have developed strategies for defending suitably reformed farming practices as ethical even granting that death and some other forms of constraints are harms. One such strategy is the fiction of a domestic contract. However, if one accepts the conceptualization of human welfare give by L. W. Sumner, and applies it to animals in the way that I think is justified, an accurate conceptualization of animal welfare has different implications for which uses of animals should be regarded as ethically acceptable. In this paper I give an historical and philosophical account of animal welfare conceptulization and use this account to argue that animal breeders, as custodians of the animals they breed, have the ethical responsibility to help their animal wards achieve as much autonomy as possible in choosing the form of life made available to them and to provide that life. Attempts to avoid these implications by alluding to a contract model of the relationship between custodians and their wards fail to relieve custodians of their ethical responsibilities of care. PMID- 21305339 TI - Real-world practices to prevent venous thromboembolism with pharmacological prophylaxis in US orthopedic surgery patients: an analysis of an integrated healthcare database. AB - Major orthopedic surgery patients are at high risk of venous thromboembolism (VTE) in-hospital and post-discharge. This study assessed real-world inpatient and outpatient thromboprophylaxis practices following knee or hip arthroplasty. Patients from the Henry Ford Health System aged >=18 years undergoing knee and hip arthroplasty (January 1997-June 2007) were identified using Current Procedural Terminology codes from administrative databases. Patients with <18 months of continuous enrollment in the system's health maintenance organization or with a current diagnosis of atrial fibrillation were excluded. Both inpatient and outpatient pharmacological prophylaxis was assessed. The analysis included 1393 (58.5%) patients following knee arthroplasty and 989 (41.5%) following hip arthroplasty. Average length of hospitalization was 4.9 days over the study period, although the median stay decreased from 5 days in 1997 to 3 days in 2007. Of patients included, 72.7% received pharmacological prophylaxis only in the inpatient setting following knee arthroplasty and 73.9% following hip arthroplasty. Both inpatient and outpatient pharmacological prophylaxis was received by 12.5% of knee and 12.3% of hip arthroplasty patients. Total length of pharmacological prophylaxis fluctuated between 2 to 4 days between 1997 and 2005, but increased to 11.5 +/- 9.0 days in 2007. Although the duration of prophylaxis has recently increased, considerable numbers of hip and knee arthroplasty patients only receive prophylaxis for part of the time period recommended by guidelines. Further efforts are required to ensure the recommended duration of thromboprophylaxis is prescribed to all patients and continued outpatient VTE prophylaxis is provided. PMID- 21305340 TI - Free form fabricated features on CoCr implants with and without hydroxyapatite coating in vivo: a comparative study of bone contact and bone growth induction. AB - The current study evaluates the in vivo response to free form fabricated cobalt chromium (CoCr) implants with and without hydroxyapatite (HA) plasma sprayed coatings. The free form fabrication method allowed for integration of complicated pyramidal surface structures on the cylindrical implant. Implants were press fit into the tibial metaphysis of nine New Zealand white rabbits. Animals were sacrificed and implants were removed and embedded. Histological analysis, histomorphometry and electron microscopy studies were performed. Focused ion beam was used to prepare thin sections for high-resolution transmission electron microscopy examination. The fabricated features allowed for effective bone in growth and firm fixation after 6 weeks. Transmission electron microscopy investigations revealed intimate bone-implant integration at the nanometre scale for the HA coated samples. In addition, histomorphometry revealed a significantly higher bone contact on HA coated implants compared to native CoCr implants. It is concluded that free form fabrication in combination with HA coating improves the early fixation in bone under experimental conditions. PMID- 21305341 TI - Improved protocol for processing stented porcine coronary arteries for immunostaining. AB - Percutaneous coronary intervention has resulted in a paradigm shift in the treatment of coronary artery disease and myocardial infarction. However, neither bare-metal stents nor polymer-coated drug-eluting stents represent ideal therapies at this time due to the undesired in-stent stenosis or delayed thrombosis. Hence there is pressing clinical need for greater understanding of the cellular mechanisms involved. It is hoped that this in turn will provide insight into designing and developing the next generation of stents. Although immunohistochemistry and immunofluorescence are appropriate tools in understanding the molecular histology, performing these techniques on stented blood vessels is technically challenging because of poor permeability of antibodies into the stented blood vessels which are embedded in methacrylate based resins and inadequate image resolution due to autofluorescence. Hence there is a need to develop techniques which can facilitate immunohistochemistry/immunofluorescence procedures on stented blood vessel cross sections. In this study we describe an improved protocol for processing stented porcine coronary arteries for immunostaining with smooth muscle cell, endothelial cell, monocyte and macrophage markers. We first identified the optimal conditions for resin embedding of stented artery and cross sectioned the vessels using high speed precision wafering diamond blade. The sections were then ground using two levels of water sandpaper on a Metaserve 2000 grinder to achieve the desired thickness. For immunostaining, we developed a novel deplasticization protocol which favors optimal antibody permeabilization. Our protocol not only provides feasibility of improved immunostaining of stented artery sections but also results in high quality images. PMID- 21305342 TI - Differential expression pattern of ZAC in developing mouse and human pancreas. AB - ZAC is a transcription factor and cofactor, a strong candidate for transient neonatal diabetes mellitus (TNDM). TNDM involves impaired beta-cell development and is probably due to a double dose of ZAC, which is normally expressed only from the paternal copy. ZAC and Zac1 (its mouse orthologue) are strongly expressed in the proliferating progenitor/stem cells in many systems and also in some differentiated sites in human and mouse, suggesting a dual role in cell proliferation and differentiation control. Little is known about its expression in developing pancreas, the organ affected in TNDM. In this study, we examined ZAC/Zac1 expression in developing mouse and human pancreas by real-time PCR and dual in situ hybridization and immunofluorescence. Overall pancreatic expression drastically declined during gestation and early post-natal life in the mouse, and between the second trimester and adult in the human. Zac1 was predominantly expressed in mesenchyme in the mouse embryo, while ZAC was specifically expressed in islets of the human fetus. Thus, ZAC/Zac1 may play different roles in mouse and human pancreas development. The specific expression of ZAC in the human fetal beta-cells supports it as the gene involved in TNDM and the different expression pattern of Zac1 in mice from human may explain the much milder phenotype in the mouse model of ZAC double dose. PMID- 21305343 TI - Effect of preischemic treatment with fenofibrate, a peroxisome proliferator activated receptor-alpha ligand, on hepatic ischemia-reperfusion injury in rats. AB - Liver ischemia/reperfusion (I/R) injury is a serious clinical problem. The reactive oxygen species (ROS) and tumor necrosis factor alpha (TNF-alpha) are important mediators in liver I/R injury. This study was designed to investigate the effect of preischemic treatment with fenofibrate (Peroxisome proliferator activated receptor- alpha agonist) on the oxidative stress and inflammatory response to hepatic I/R injury in rats. Hepatic I/R was induced by clamping the blood supply of the left lateral and median lobes of the liver for 60 min, followed by reperfusion for 4 h. Each animal group was pretreated with a single dose of fenofibrate (50 mg/kg body weight) intraperitoneally 1 h before ischemia. At the end of reperfusion, blood samples and liver tissues were obtained to assess serum alanine aminotransferase (ALT), TNF-alpha, hepatic malondialdehyde (MDA) and superoxide dismutase activity (SOD). Liver specimens were obtained and processed for light and electron microscopic study. Hepatic I/R induced a significant elevation of serum ALT and TNF-alpha with significant elevation of hepatic MDA and reduction of SOD activity. Histopathological examination revealed hepatic inflammation, necrosis and apoptosis. Preischemic treatment with fenofibrate at a dose of 50 mg/kg significantly attenuated the biochemical and structural alterations of I/R-induced liver injury. PMID- 21305344 TI - Expression of non-coding RNA AB063319 derived from Rian gene during mouse development. AB - The regulatory functions of many non-coding RNAs (ncRNAs) were widely recognized. However, there are very few publications on long intronic ncRNAs. The transcriptional hierarchy driving a large amount of long and short ncRNAs originated from the maternal chromosome is not clarified in the Dlk1-Dio3 imprinted clusters of mouse distal chromosome 12. Here, we only focused on the previously identified long ncRNA AB063319 which derives from the large imprinted gene Rian and contains three retained introns of Rian, and tried to unsderstand this ncRNAs part of biological functions. We used in situ hybridization and quantitative real-time RT-PCR (QRT-PCR) to characterize the spatiotemporal expression pattern of AB063319 during mouse development. The in situ hybridization results showed that AB063319 was prominently expressed in the brain at embryonic day 10.5 (E10.5) and E11.5, and abundantly expressed in brain, muscle, liver, lung and neuroendocrine tissues at E15.5. Furthermore, quantitative analyses results showed that AB063319 was gradually up-regulated from E9.5 to E18.5 and down-regulated at E19.5 during the mouse embryonic development, and AB063319 was highly expressed in tongue and brain at E12.5, E15.5 and E18.5. Alternatively, AB063319 expression was also predominantly detected in tongue and brain at mouse postnatal day 6 (P6) by semi-quantitative RT-PCR. These results indicated that AB063319, as a stable transcriptional ncRNA, might play the important roles in the morphogenesis of diverse organs and tissues, especially associated with brain and muscle development at mouse embryonic and postnatal stages. PMID- 21305346 TI - Peripheral immune challenge with dsRNA enhances kainic acid-induced status epilepticus. AB - Clinical evidence implicates peripheral inflammatory diseases as comorbid factors in epilepsy. The present study was designed to determine the effect of the acute phase of antiviral response on seizure susceptibility. Young adult mice were intraperitoneally injected with 12 mg/kg of a viral mimic, polyinosinic:polycytidylic acid (PIC). After 48 h, seizures were induced by subcutaneous injection of kainic acid (KA). PIC-pretreatment profoundly enhances vulnerability to excitotoxic insult as evidenced by increased seizure intensity and extended duration of status epilepticus. These results support the notion that peripheral viral infections may alter brain function resulting in enhanced predilection to seizures. PMID- 21305347 TI - Effects of flavonoids on glycosaminoglycan synthesis: implications for substrate reduction therapy in Sanfilippo disease and other mucopolysaccharidoses. AB - Sanfilippo disease (mucopolysaccharidosis type III, MPS III) is a severe metabolic disorder caused by accumulation of heparan sulfate (HS), one of glycosaminoglycans (GAGs), due to a genetic defect resulting in a deficiency of GAG hydrolysis. This disorder is characterized as the most severe neurological form of MPS, revealing rapid deterioration of brain functions. Among therapeutic approaches for MPS III, one of the most promising appears to be the substrate reduction therapy (SRT). Genistein (5, 7-dihydroxy-3- (4-hydroxyphenyl)-4H-1 benzopyran-4-one) is an isoflavone that has been used in SRT for MPS III. In this report, we tested effects of other flavonoids (apigenin, daidzein, kaempferol and naringenin) on GAG synthesis. Their cytotoxicity and anti-proliferation features were also tested. We found that daidzein and kaempferol inhibited GAG synthesis significantly. Moreover, these compounds were able to reduce lysosomal storage in MPS IIIA fibroblasts. Interestingly, although genistein is believed to inhibit GAG synthesis by blocking the tyrosine kinase activity of the epidermal growth factor receptor, we found that effects of other flavonoids were not due to this mechanism. In fact, combinations of various flavonoids resulted in significantly more effective inhibition of GAG synthesis than the use of any of these compounds alone. These results, together with results published recently by others, suggest that combination of flavonoids can be considered as a method for improvement of efficiency of SRT for MPS III. PMID- 21305349 TI - Causal attributions among patients undergoing coronary artery bypass surgery: gender aspects and relation to depressive symptomatology. AB - Causal attributions made by patients for their coronary heart disease may contribute to gender differences in emotional adjustment. The purpose of this study was to determine gender differences in causal attributions and to analyze the associations between causal attributions and depressive symptomatology in patients undergoing coronary artery bypass graft (CABG) surgery. Nine hundred and seventy-nine patients (mean age 66.8 years, 19.9% women) completed a modified version of the Illness Perception Questionnaire (IPQ) and the depression module of the Patient Health Questionnaire (PHQ-9) 1-3 days before CABG-surgery and 1 year after surgery. Men were more likely to name their health behavior (men: 40.2%, women: 26.9%, P < .001) as a cause of disease, whereas women were more likely to cite destiny (women: 34.7%, men: 25.7%, P = .012). Regression analyses showed cross-sectional and longitudinal associations of attributions with depressive symptomatology which were independent of gender, sociodemographic and clinical variables. Attribution to personality and stress were associated with an increase in depressive symptomatology. Causal attributions may present a valuable approach for identifying patients at risk for depression and the implementation of targeted interventions. PMID- 21305350 TI - Adaptive style and physiological reactivity during a laboratory stress paradigm in children with cancer and healthy controls. AB - Repressive adaptation has been conceptualized as one pathway to psychological resilience in children with cancer, but the physiological costs of maintaining a repressive adaptive style are currently unknown. The goal of this study was to examine physiological functioning as a function of adaptive style in children with cancer (N = 120) and healthy controls (N = 120). Children completed self report measures of state anxiety and defensiveness prior to participating in three verbal stress tasks while monitoring blood pressure, electrocardiogram, and electrodermal response, and rated their anxiety following each task. Findings indicated no consistent differences in baseline indices and physiological reactivity as a function of adaptive style or health status (cancer vs. control). In addition, children identified as having a repressive adaptive style did not exhibit greater verbal-autonomic discrepancy than low-anxious children. In contrast to findings with adults, children with a repressive adaptive style do not appear to experience adverse effects of this coping style in terms of physiological reactivity. PMID- 21305351 TI - Robust association tests under different genetic models, allowing for binary or quantitative traits and covariates. AB - The association of genetic variants with outcomes is usually assessed under an additive model, for example by the trend test. However, misspecification of the genetic model will lead to a reduction in power. More robust tests for association might therefore be preferred. A useful approach is to consider the maximum of the three test statistics under additive, dominant and recessive models (MAX3). The p-value however has to be adjusted to maintain the type I error rate. Previous studies and software on robust association tests have focused on binary traits without covariates. In this study we developed an analytic approach to robust association tests using MAX3, allowing for quantitative or binary traits as well as covariates. The p-values from our theoretical calculations match very well with those from a bootstrap resampling procedure. The methodology is implemented in the R package RobustSNP which is able to handle both small-scale studies and GWAS. The package and documentation are available at http://sites.google.com/site/honcheongso/software/robustsnp . PMID- 21305352 TI - Transition of young adults with phenylketonuria from pediatric to adult care. AB - BACKGROUND: Transition from pediatric to adult health care is a particularly vulnerable period for patients with inborn metabolic diseases. Aim of the present study was to evaluate the current transition situation of patients with phenylketonuria (PKU) in Leipzig, Germany, by analysis of the medical care, metabolic control, patients' satisfaction, socio-economic and psychosocial status, in order to identify areas of weakness and potential improvement. METHODS: Patients who had been transferred from pediatric to adult medical care between 2005 and 2008 were identified. An interview was performed using a questionnaire. Pediatric case notes and the present physician's case notes were analyzed retrospectively. Socio-demographic data were compared to data derived from the annual statistics of the city of Leipzig, Germany in 2008. RESULTS: seventy two transferred patients were identified and included in the study, 48 patients responded to the questionnaire, the data of 24 non-responders were analysed retrospectively. About 90% of the responding patients with PKU were satisfied with the current transition situation. However, they agreed to several suggestions of improvement. Most specifically an interdisciplinary appointment before the definite transfer to the adult clinics was asked for. At the time of transition, most of the patients were in good metabolic control according to current treatment guidelines (median dried blood phenylalanine concentration 853 MUmol/l before versus 690 MUmol/l after transition). Of the interviewed patients 92% were still on a low phenylalanine diet in combination with the intake of a phenylalanine free amino acid mixture. Of the interviewees 77% carried a secondary school certificate or a secondary modern school qualification, but only 19% had achieved senior high school diploma (controls 38.2%). Marital status was comparable with the population of Leipzig. However, fewer patients with PKU had children (15% versus 37%). CONCLUSION: Transition of patients with PKU from pediatric to adult care seems to be successful in Leipzig. Patients were mostly satisfied with the transition situation. Still, some suggestions for improvements appeared to be desirable. During transition medical care and metabolic control were stable. However, with regard to psychosocial and socioeconomic data differences to the control population were detected. PMID- 21305353 TI - Non-invasive measurements of atherosclerosis in adult cystinosis patients. AB - BACKGROUND: Cystinosis is characterized by intralysosomal cystine accumulation, causing end stage renal disease around 10 years of age if not treated with cysteamine. Cystine accumulation in blood vessels might increase atheroma formation or arterial stiffness and therefore increase the risk for cardiovascular disease (CVD). This study aimed to investigate the risk for CVD by non-invasive measures of atherosclerosis (NIMA) and to evaluate the effect of cysteamine treatment. PATIENTS AND METHODS: Thirteen Dutch adult cystinosis patients were included. White blood cell (WBC) cystine levels, glomerular filtration rate (GFR) and concommitant medications were obtained from medical records. NIMA included carotid intima-media thickness (cIMT, n = 13), pulse wave velocity (PWV, n = 8) and pulse wave analysis (PWA, n = 6). RESULTS: GFR ranged between 4-95 mL/min/1.73 m2. All but one patient were treated with cysteamine, mean WBC cystine values ranged between 0.34-1.64 nmol cystine/mg protein, 8 patients had mean WBC cystine levels <1 nmol cystine/mg protein. When compared to healthy subjects, cIMT and PWV levels were above normal values in 1 patient for each measure. PWA measurements showed high augmentation index in three patients who did not receive lipid-lowering medication. When corrected for renal function, cIMT and PWV levels were within the normal range. CONCLUSION: Young adult cystinosis patients treated with cysteamine have no additional risk for CVD when compared to patients with chronic kidney disease of other causes. PMID- 21305354 TI - Pyridoxal 5'-phosphate in cerebrospinal fluid; factors affecting concentration. AB - Analysis of pyridoxal 5'-phosphate (PLP) concentration in 256 cerebrospinal fluid (CSF) samples from patients with neurological symptoms showed that the variance is greater than indicated by previous studies. The age-related lower reference limit has been revised to detect inborn errors of metabolism that lead to PLP depletion without a high false positive rate: < 30 days, 26 nmol/L; 30 days to 12 months, 14 nmol/L; 1-2 years, 11 nmol/L; > 3 years, 10 nmol/L. Inborn errors leading to PLP concentrations below these values include pyridoxine-dependent epilepsy due to antiquitin deficiency, and molybdenum cofactor deficiency that leads to the accumulation of sulfite, a nucleophile capable of reacting with PLP. Low PLP levels were also seen in a group of children with transiently elevated urinary excretion of sulfite and/or sulfocysteine, suggesting that there may be other situations in which sulfite accumulates and inactivates PLP. There was no evidence that seizures or the anticonvulsant drugs prescribed for patients in this study led to significant lowering of CSF PLP. A small proportion of patients receiving L-dopa therapy were found to have a CSF PLP concentration below the appropriate reference range. This may have implications for monitoring and treatment. A positive correlation was seen between the CSF PLP and 5-methyl tetrahydrofolate (5-MTHF) and tetrahydrobiopterin (BH(4)) concentrations. All are susceptible to attack by nucleophiles and oxygen-derived free-radicals, and CSF has relatively low concentrations of other molecules that can react with these compounds. Further studies of CSF PLP levels in a wide range of neurological diseases might lead to improved understanding of pathogenesis and possibilities for treatment. PMID- 21305355 TI - Gender variability in presentation with Alpers' syndrome: a report of eight patients from the UAE. AB - INTRODUCTION: Alpers' syndrome is a progressive and often fatal cerebral and hepatic degeneration caused by a mutation in the polymerase gamma (POLG) gene involved in mitochondrial DNA replication. OBJECTIVE: We report on eight successive cases from five families. METHODS: Our analysis consisted of case series reports and literature search. RESULTS: The eight patients were from five extended families, all with clinical manifestations of the syndrome. Seven were confirmed by POLG sequence analysis and one died before testing was possible. We observed that whereas the five females presented with advanced hepatic disease at the onset of neurological symptoms, the three males had normal hepatic function well after presentation, with progressive neurological disease. Two of the three males are distant relatives; two of the five females were sisters of two male patients. DISCUSSION: Most authors report the coexistence of both hepatic and cerebral disease at the onset of Alpers' syndrome. It is unusual that all three males in our series had no signs of liver disease but had advanced neurological signs. CONCLUSION: Initial manifestations in Alpers' syndrome may be gender specific. In males, the condition should be considered in patients with seizures and encephalopathy, even in the absence of hepatic disease. PMID- 21305356 TI - A cross-sectional study of docosahexaenoic acid status and cognitive outcomes in females of reproductive age with phenylketonuria. AB - Diet therapy for phenylketonuria (PKU) requires restricted phenylalanine (Phe) intake, with the majority of protein and other nutrients coming from synthetic medical food. The fatty acid docosahexaenoic acid (DHA) is important in brain development and function; however, there are reports of low blood DHA concentrations in people treated for PKU. Although the implications of this low blood DHA are unclear, subtle cognitive deficits have been reported in those treated early and continuously for PKU. For this study, we investigated the relationship between DHA status and cognitive performance in 41 females 12 years and older with PKU. Participants were attending the baseline visit of a research based camp or a supplementation trial. We assessed the domains of verbal ability, processing speed, and executive function using standardized tests, and the proportions of DHA in plasma and red blood cell (RBC) total lipids using gas chromatography/mass spectrometry. Percent plasma and RBC total lipid DHA were significantly lower in the participants compared with laboratory controls (P < .001), and participants consumed no appreciable DHA according to diet records. Plasma and RBC DHA both negatively correlated with plasma Phe (P < .02), and performance on the verbal ability task positively correlated with RBC DHA controlling for plasma Phe (R = .32, P = .03). The relationship between DHA and domains related to verbal ability, such as learning and memory, should be confirmed in a controlled trial. Domains of processing speed and executive function may require a larger sample size to clarify any association with DHA. PMID- 21305357 TI - Left ventricular torsion and longitudinal shortening: two fundamental components of myocardial mechanics assessed by tagged cine-MRI in normal subjects. AB - Cardiac magnetic resonance imaging (Cardiac MRI) has become a gold standard diagnostic technique for the assessment of cardiac mechanics, allowing the non invasive calculation of left ventricular long axis longitudinal shortening (LVLS) and absolute myocardial torsion (AMT) between basal and apical left ventricular slices, a movement directly related to the helicoidal anatomic disposition of the myocardial fibers. The aim of this study is to determine AMT and LVLS behaviour and normal values from a group of healthy subjects. A group of 21 healthy volunteers (15 males) (age: 23-55 y.o., mean: 30.7 +/- 7.5) were prospectively included in an observational study by cardiac MRI. Left ventricular rotation (degrees) was calculated by custom-made software (Harmonic Phase Flow) in consecutive LV short axis planes tagged cine-MRI sequences. AMT was determined from the difference between basal and apical planes LV rotations. LVLS (%) was determined from the LV longitudinal and horizontal axis cine-MRI images. All the 21 cases studied were interpretable, although in three cases the value of the LV apical rotation could not be determined. The mean rotation of the basal and apical planes at end-systole were -3.71 degrees +/- 0.84 degrees and 6.73 degrees +/- 1.69 degrees (n:18) respectively, resulting in a LV mean AMT of 10.48 degrees +/- 1.63 degrees (n:18). End-systolic mean LVLS was 19.07 +/- 2.71%. Cardiac MRI allows for the calculation of AMT and LVLS, fundamental functional components of the ventricular twist mechanics conditioned, in turn, by the anatomical helical layout of the myocardial fibers. These values provide complementary information about systolic ventricular function in relation to the traditional parameters used in daily practice. PMID- 21305358 TI - Primary aldosteronism: A Japanese perspective. AB - Primary aldosteronism (PA) is the most common cause of secondary hypertension, accounting for 10% of all hypertension. Far from being benign, hypertension due to PA is associated with high cardiovascular morbidity and mortality. However, PA is still underdiagnosed in general practice. Recent reports strongly recommend that identifying patients with PA is cost-beneficial based on improved cardiovascular outcomes afforded by specific surgical and medical treatment. This review provides an update of PA including controversial aspects of diagnosis and treatment. PMID- 21305359 TI - Treatment of primary aldosteronism: Where are we now? AB - Primary aldosteronism (PA) is an important cause of secondary hypertension, is being increasingly diagnosed and may account for more than 10% of hypertensive patients, both in primary care and in referral centers. Aldosterone excess is associated with adverse cardiovascular, renal and metabolic effects that are in part hypertension-independent. Laparoscopic adrenalectomy remains the mainstay of treatment for unilateral forms of PA, whereas medical treatment is recommended for bilateral forms of PA. However, a favourable surgical outcome depends on several factors and many patients are not suitable for this treatment. On the other hand, surgery in patients considered to have bilateral PA may contribute to better blood pressure control. In this review, established and novel strategies for the management of different types of PA are discussed. PMID- 21305360 TI - Viability of cryopreserved human skin allografts: effects of transport media and cryoprotectant. AB - Human skin allografts can be preserved by different methods. In our clinical practice, human skin allografts are harvested on multi-organ and tissue donors, transferred at +4 degrees C in Ringer Lactate, cryopreserved with 15% Glycerol and held in the vapor phase of a liquid nitrogen freezer until delivery to the burn center. The aim of this experimental study was to evaluate the impact of transport medium and cryoprotectant on the viability of human skin allografts. For this purpose, we compared skin samples harvested from 19 multi-organ and tissue donors with two different transport media and two different cryoprotectants. Viability was assessed by the MTT assay after harvesting at laboratory reception, during storage (at +4 degrees C) at day 2 and day 7, and after cryopreservation and thawing. Histopathological analysis was performed for each MTT assay. Results indicate that, when stored at +4 degrees C, skin retains more viability with RPMI, whereas Glycerol and DMSO are equivalent cryoprotectants regardless of the transport medium. In conclusion, our protocol could be improved by the utilization of RPMI as transport medium. PMID- 21305361 TI - Face activated neurodynamic cortical networks. AB - Previous neuroimaging studies have shown that complex visual stimuli, such as faces, activate multiple brain regions, yet little is known on the dynamics and complexity of the activated cortical networks during the entire measurable evoked response. In this study, we used simulated and face-evoked empirical MEG data from an oddball study to investigate the feasibility of accurate, efficient, and reliable spatio-temporal tracking of cortical pathways over prolonged time intervals. We applied a data-driven, semiautomated approach to spatio-temporal source localization with no prior assumptions on active cortical regions to explore non-invasively face-processing dynamics and their modulation by task. Simulations demonstrated that the use of multi-start downhill simplex and data driven selections of time intervals submitted to the Calibrated Start Spatio Temporal (CSST) algorithm resulted in improved accuracy of the source localization and the estimation of the onset of their activity. Locations and dynamics of the identified sources indicated a distributed cortical network involved in face processing whose complexity was task dependent. This MEG study provided the first non-invasive demonstration, agreeing with intracranial recordings, of an early onset of the activity in the fusiform face gyrus (FFG), and that frontal activation preceded parietal for responses elicited by target faces. PMID- 21305362 TI - Abstracts of the Neuroscience Ireland Annual Conference UCD. September 2-3, 2010. Dublin, Ireland. PMID- 21305364 TI - Models and simulation of 3D neuronal dendritic trees using Bayesian networks. AB - Neuron morphology is crucial for neuronal connectivity and brain information processing. Computational models are important tools for studying dendritic morphology and its role in brain function. We applied a class of probabilistic graphical models called Bayesian networks to generate virtual dendrites from layer III pyramidal neurons from three different regions of the neocortex of the mouse. A set of 41 morphological variables were measured from the 3D reconstructions of real dendrites and their probability distributions used in a machine learning algorithm to induce the model from the data. A simulation algorithm is also proposed to obtain new dendrites by sampling values from Bayesian networks. The main advantage of this approach is that it takes into account and automatically locates the relationships between variables in the data instead of using predefined dependencies. Therefore, the methodology can be applied to any neuronal class while at the same time exploiting class-specific properties. Also, a Bayesian network was defined for each part of the dendrite, allowing the relationships to change in the different sections and to model heterogeneous developmental factors or spatial influences. Several univariate statistical tests and a novel multivariate test based on Kullback-Leibler divergence estimation confirmed that virtual dendrites were similar to real ones. The analyses of the models showed relationships that conform to current neuroanatomical knowledge and support model correctness. At the same time, studying the relationships in the models can help to identify new interactions between variables related to dendritic morphology. PMID- 21305365 TI - Liver involvement in hereditary hemorrhagic telangiectasia: can breath test unmask impaired hepatic first-pass effect? AB - Hepatic arteriovenous malformations (HAVMs) in hereditary hemorrhagic telangiectasia (HHT) have long been considered to have scarce clinical significance in most cases. Nevertheless, data are lacking regarding the influence of HAVMs on the liver first-pass effect on drugs in HHT patients. To gain insight into the effect of HAVMs on hepatic drug clearance by means of two specific (13)C-labeled probes, namely the (13)C-methacetin and (13)C-aminopyrine, 46 HHT patients and 44-matched healthy controls were enrolled. The liver first pass effect was studied by the (13)C-based breath test using methacetin and aminopyrine. The methacetin breath test showed statistically significant reduced metabolism rates (p < 0.0001) in HHT when compared with controls, both in patients with and without CT-detectable HAVMs, and when expressed both as cumulative (13)C-percentage dose per hour and as (13)C-percentage peak after 15 min. In contrast, no significant difference was found between HHT and controls regarding aminopyrin metabolism rates. In HHT, (13)C%-methacetin breath test values are significantly lower than those found in normal subjects, probably due to the effect of hepatic shunts. A reduced perfusion and an impaired hepatic metabolism might affect hepatic drug clearance in HHT. Therefore, an appropriate dosage adjustments should be considered when high-hepatic-metabolism drugs are administered to HHT patients. PMID- 21305366 TI - Surface marker epithelial cell adhesion molecule and E-cadherin facilitate the identification and selection of induced pluripotent stem cells. AB - The derivation of induced pluripotent stem cells (iPSCs) requires not only efficient reprogramming methods, but also reliable markers for identification and purification of iPSCs. Here, we demonstrate that surface markers, epithelial cells adhesion molecule (EpCAM) and epithelial cadherin (E-cadherin) can be used for efficient identification and/or isolation of reprogrammed mouse iPSCs. By viral transduction of Oct4, Sox2, Klf4 and n- or c-Myc into mouse embryonic fibroblasts, we observed that the conventional mouse embryonic stem cell (mESC) markers, alkaline phosphatase (AP) and stage-specific embryonic antigen 1 (SSEA1), were expressed in incompletely reprogrammed cells that did not express all the exogenous reprogramming factors or failed to acquire pluripotent status even though exogenous reprogramming factors were expressed. EpCAM and E-cadherin, however, remained inactivated in these cells. Expression of EpCAM and E-cadherin correlated with the activation of Nanog and endogenous Oct4, and was only seen in the successfully reprogrammed iPSCs. Furthermore, purification of EpCAM expressing cells at late reprogramming stage by FACS enriched the Nanog expressing cell population suggesting the feasibility of selecting successful reprogrammed mouse iPSCs by EpCAM expression. We have thus identified new surface markers that can efficiently identify successfully reprogrammed iPSCs and provide an effective means for iPSC isolation. PMID- 21305367 TI - Oral verruciform xanthoma associated with chronic graft-versus-host disease: a report of five cases and a review of the literature. AB - Verruciform xanthoma (VX) is an uncommon benign inflammatory mucocutaneous condition that chiefly occurs in the oral cavity. It is often associated with pre existing epithelial and/or inflammatory disorder and is characterized histopathologically by papillary epithelial hyperplasia and the presence of foamy macrophages in connective tissue papillae. We report of a series of five cases with VX who concurrently had chronic oral graft-versus-host disease following hematopoietic stem cell transplantation. PMID- 21305368 TI - Adenosquamous carcinoma of the head and neck: relationship to human papillomavirus and review of the literature. AB - Adenosquamous carcinoma (ADSC) of the head and neck is an aggressive variant of squamous cell carcinoma (SCC). Certain variants of head and neck SCC are human papillomavirus (HPV)-related and have better prognosis. The relationship of HPV to head and neck ADSC has not been investigated. We searched our files for the term "adenosquamous" and head and neck subsites and found cases from 1998 to 2009. The requisite histologic criteria were the presence of SCC combined with distinct gland formation and/or intracellular mucin. DNA in situ hybridization for high-risk HPV, RNA in situ hybridization for high risk HPV E6 and E7 transcripts, and immunohistochemistry for p16 and p53 were performed. The existing literature on ADSC was also reviewed. Of the 18 cases, eight were from the larynx and hypopharynx, four from the oral cavity, three from the oropharynx, and three from the nasal cavity. Three cases (16%) showed both high risk HPV E6 and E7 and p16 expression, one from the nasal cavity and two from the oropharynx. Both oropharyngeal carcinoma patients were alive and disease free at 34 and 103 months, respectively. ADSCs of the head and neck are a heterogeneous group of tumors. A small minority of cases harbor HPV and most of these, particularly those occurring at sites with known high prevalence of HPV, show active viral transcription with detectable E6 and E7 and overexpression of p16. The HPV related oropharyngeal cases, though rare, appear to do very well clinically, while the remaining cohort of ADSC patients do quite poorly. Head and neck ADSC appears to be a mixed variant that can be further classified according to its HPV status. PMID- 21305369 TI - Oxidative stress induced by gibberellic acid on kidney tissue of female rats and their progeny: biochemical and histopathological studies. AB - Gibberellic acid (GA(3)) is an endogenous plant growth regulator used worldwide in agriculture. The objective of this study was to investigate the effects of GA(3) on the kidney function of adult rats and their pups. Female Wistar rats were given daily 200 ppm GA(3) in drinking water from the 14th day of pregnancy until day 14 after delivery. GA(3) induced nephrotoxicity, as evidenced by a reduction in the 24-h urine volume and an increase in plasma creatinine, urea and uric acid levels. Nephrotoxicity was objectified by a significant increase of malondialdehyde level and a decrease of antioxidant enzyme activities like catalase, superoxide dismutase, glutathione peroxidase and glutathione content in kidneys of suckling pups and their mothers. Kidney histological studies confirmed biochemical parameters. We concluded that the exposure of rats to GA(3) induced oxidative stress and histopathological changes in kidneys of suckling rats and their mothers during late pregnancy and early postnatal periods. PMID- 21305371 TI - Monosaccharide compositional analysis of marine polysaccharides by hydrophilic interaction liquid chromatography-tandem mass spectrometry. AB - A simple and sensitive method was developed using hydrophilic interaction liquid chromatography coupled to tandem mass spectrometry for determination of monosaccharides liberated from marine polysaccharides by acidic hydrolysis. Optimal separation of diastereomeric monosaccharides including hexoses, pentoses, and deoxyhexoses was achieved using an aminopropyl bonded column with mobile phase containing ternary solvents (acetonitrile/methanol/water) in conjunction with MS/MS in SRM mode. Mechanisms for fragmentation of deprotonated monosaccharides with regard to cross-ring cleavage were proposed. Matrix effects from coeluting interferences were observed and isotopic-labeled internal standard was used to compensate for the signal suppression. The method demonstrated excellent instrumental limits of detection (LOD), ranging from 0.7 to 4.2 pg. Method LODs range from 0.9 to 5.1 nM. The proposed method was applied to the analysis of polysaccharides in seawater collected from the open leads of the central Arctic Ocean in the summer of 2008. PMID- 21305370 TI - Reexamining the possible benefits of visual crowding: dissociating crowding from ensemble percepts. AB - Peripheral objects and their features become indistinct when closely surrounding but nonoverlapping objects are present. Most models suggest that this phenomenon, called crowding, reflects limitations of visual processing, but an intriguing idea is that it may be, in part, adaptive. Specifically, the mechanism generating crowding may simultaneously facilitate ensemble representations of features, leaving meaningful information about clusters of objects. In two experiments, we tested whether visual crowding and the perception of ensemble features share a common mechanism. Observers judged the orientation of a crowded bar, or the ensemble orientation of all bars in the upper and lower visual fields. While crowding was predictably stronger in the upper relative to the lower visual field, the ensemble percept did not vary between the visual fields. Featural averaging within the crowded region does not always scale with the resolution limit defined by crowding, suggesting that dissociable processes contribute to visual crowding and ensemble percepts. PMID- 21305372 TI - A headspace SPME-GC-ECD method suitable for determination of chlorophenols in water samples. AB - A headspace solid phase microextraction coupled to gas chromatography with electron capture detector (HS-SPME-GC-ECD) method was optimized for the determination of seven chlorophenols (CPs) with different levels of chlorination. This is the first time that HS-SPME-GC-ECD with acetylation of the analytes is used for the simultaneous determination of CPs in water samples. The influence of fibre type, derivatization conditions, salt addition, temperature and time of extraction and temperature of desorption was checked. Possible sources of contamination and analyte losses were considered. The best results were obtained with the polydimethylsiloxane/divinylbenzene fibre, derivatization by acetylation using 100 MUL of acetic anhydride and 0.1 g of anhydrous sodium carbonate per 10 mL of sample, salt addition of 100 g L(-1) sodium chloride, extraction at 70 degrees C for 60 min and desorption in the GC injector at 260 degrees C for 6 min. The limits of detection (LOD) for monochlorophenols were 12 and 122 ng L(-1) for 2-chlorophenol and 4-chlorophenol, respectively. For polychlorinated CPs, the LODs were lower than 6 ng L(-1), values similar to the existing methods that use SPME with derivatization for CPs determination in water samples. The method is suitable for the determination of CPs in most environmental aqueous samples. Repeatability and reproducibility were less than 16.8% and 11.7%, respectively. The optimized method was successfully applied for the analysis of waters with complex matrices such as river and estuarine water samples. PMID- 21305376 TI - Cerebellar brain inhibition is decreased in active and surround muscles at the onset of voluntary movement. AB - Highly selective activation of the desired muscles for each movement and inhibition of adjacent muscles is attributed to surround inhibition (SI) which differentially modulates corticospinal excitability in active and surrounding muscles. Cerebellar brain inhibition (CBI) is another inhibitory neuronal network which is known to be active at rest and during tonic muscle contraction. The way in which CBI may be modulated at movement onset and its relationship with SI has not previously been investigated. We assessed motor evoked potential (MEP) size and CBI in first dorsal interosseus (FDI) and abductor digiti minimi (ADM) muscles at rest and during a simple motor task where FDI was an active muscle and ADM was not involved in the movement (surround muscle). At onset of movement, MEP size in ADM was significantly suppressed, confirming the existence of SI. In contrast, CBI in both muscles was found to be significantly decreased at the onset of the movement. This was confirmed even after adjustments for changes in MEP size occurring due to onset of muscle activity in FDI and the effects of SI in ADM. Our findings fail to functionally link SI with CBI, but they do indicate a non-topographically specific modulation of CBI in association with initiation of voluntary movement. PMID- 21305377 TI - Adaptation to constant-magnitude assistive forces: kinematic and neural correlates. AB - In many robot-assisted rehabilitation and motor skill learning applications, robots generate forces that facilitate movement performance. While there is some evidence that assistance is beneficial, the underlying mechanisms of action are largely unknown, and it is unclear what force patterns are more effective. Here, we investigate how reaching movements (and their neural correlates) are altered by 'assistive' forces. Subjects performed center-out reaching movements, under the influence of a robot-generated force, constant in magnitude and always directed toward the target. The experimental protocol included three phases: (1) baseline (no forces), (2) force field (with two different force levels, 3 N and 6 N, applied in random order), and (3) after-effect (no forces). EEG activity was recorded from motor and frontal cortical areas. In both movement kinematics and EEG activity, we looked at the effects of forces, of adaptation to such forces and at the aftereffects of such adaptation. Assistive forces initially induced a degraded performance and in general alterations in movement kinematics. However, subjects quickly adapted to the perturbation by improving their performance. With regard to EEG activity, we found (1) an increased beta band synchronization just before movements and an alpha band synchronization in the ipsilateral hemisphere, both proportional to force magnitude; (2) a gradual decrease in alpha band synchronization with practice in the contralateral hemisphere; (3) an increase in theta band synchronization in the later stage of the force epochs; and (4) an ipsilateral to contralateral shift (from baseline to aftereffect) of theta band synchronization. These results point to the need for a careful design of assistive forces to effectively facilitate motor performance and motor learning. Moreover, EEG signals exhibit distinct features related to force and adaptation. Therefore, at least in principle, the latter might be used to monitor the learning process and/or to regulate the amount of assistance. PMID- 21305378 TI - Antihysteresis of perceived longitudinal body axis during continuous quasi-static whole-body rotation in the earth-vertical roll plane. AB - Estimation of subjective whole-body tilt in stationary roll positions after rapid rotations shows hysteresis. We asked whether this phenomenon is also present during continuous quasi-static whole-body rotation and whether gravitational cues are a major contributing factor. Using a motorized turntable, 8 healthy subjects were rotated continuously about the earth-horizontal naso-occipital axis (earth vertical roll plane) and the earth-vertical naso-occipital axis (earth-horizontal roll plane). In both planes, three full constant velocity rotations (2 degrees /s) were completed in clockwise and counterclockwise directions (acceleration = 0.05 degrees /s(2), velocity plateau reached after 40 s). Subjects adjusted a visual line along the perceived longitudinal body axis (pLBA) every 2 s. pLBA deviation from the longitudinal body axis was plotted as a function of whole-body roll position, and a sine function was fitted. At identical whole-body earth vertical roll plane positions, pLBA differed depending on whether the position was reached by a rotation from upright or by passing through upside down. After the first 360 degrees rotation, pLBA at upright whole-body position deviated significantly in the direction of rotation relative to pLBA prior to rotation initiation. This deviation remained unchanged after subsequent full rotations. In contrast, earth-horizontal roll plane rotations resulted in similar pLBA before and after each rotation cycle. We conclude that the deviation of pLBA in the direction of rotation during quasi-static earth-vertical roll plane rotations reflects static antihysteresis and might be a consequence of the known static hysteresis of ocular counterroll: a visual line that is perceived that earth vertical is expected to be antihysteretic, if ocular torsion is hysteretic. PMID- 21305380 TI - [Heart transplantation. Pathology, clinical work-up and therapy]. AB - Since the first heart transplantation in 1967, the procedure has become an established therapy in the treatment of terminal heart failure. Constant advances in the development of potent immunosuppressive drugs, as well as greater clinical experience and pathological diagnostics have improved patient survival dramatically. The first grading system for rejection was published in 1990 by the International Society for Heart and Lung Transplantation (ISHLT) and revised in 2004. The 2004 grading system comprises three grades of severity (1R, 2R, 3R), whereby the former grade 2 in the 1990 system has been incorporated in the new grade 1R. Recommendations are made for the histological diagnosis of acute antibody-mediated rejection using immunohistochemical staining against C4d and macrophages. To the present day, the pathological examination of endomyocardial biopsies remains the gold standard for post-transplant diagnostic procedures. Whether or not non-invasive diagnostic approaches (e.g. gene array profile analysis on leukocytes) can replace morphological investigations needs to be clarified in randomised, prospective clinical studies. PMID- 21305379 TI - In vitro generated anti-tumor T lymphocytes exhibit distinct subsets mimicking in vivo antigen-experienced cells. AB - The T-lymphocyte pool can be subdivided into naive (Tn), effector memory (Tem), and central memory (Tcm) T cells. In this study, we characterized in vitro short term cultured anti-tumor human T lymphocytes generated by lentiviral transduction with an anti-tumor antigen TCR vector. Within 2 weeks of in vitro culture, the cultured T cells showed a Tcm-like phenotype illustrated by a high percentage of CD62L and CD45RO cells. When the cells were sorted into populations that were CD45RO+/CD62L-(Tem), CD45RO+/CD62L+(Tcm), or CD45RO(low)/CD62L+(Tn) and co cultured with antigen-matched tumor lines, the magnitude of cytokine release from these populations for IFNgamma (Tn < Tcm < Tem) and IL-2 (Tn > Tcm > Tem) mimicked the types of immune cell responses observed in vivo. In comparing cell mediated effector function, Tn were found to be deficient (relative to Tcm and Tem) in the ability to form conjugates with tumor cells and subsequent lytic activity. Moreover, analysis of the gene expression profiles of the in vitro cultured and sorted T-cell populations also demonstrated patterns consistent with their in vivo counterparts. When Tcm and Tem were tested for the ability to survive in vivo, Tcm displayed significantly increased engraftment and persistence in NOD/SCID/gammac(-/-) mice. In general, a large percentage of in vitro generated anti-tumor T lymphocytes mimic a Tcm-like phenotype (based on phenotype, effector function, and increased persistence in vivo), which suggests that these Tcm-like cultured T cells may be optimal for adoptive immunotherapy. PMID- 21305381 TI - Febrile urinary tract infection, vesicoureteral reflux, and renal scarring: current controversies in approach to evaluation. AB - The ideal approach to the radiological evaluation of children with urinary tract infection (UTI) is in a state of confusion. The conventional bottom-up approach, with its focus on the detection of upper and lower urinary tract abnormalities, including vesicoureteral reflux, has been challenged by the top-down approach, which focuses on confirming the diagnosis of acute pyelonephritis before more invasive imaging is considered. Controversies abound regarding which approach may best assess the ultimate risk for reflux-related renal scarring. Evolving practices motivated by the emerging evidence, the desire to minimize unnecessary interventions, as well as improve compliance with recommended testing, have added to the current controversies. Recent guideline updates and ongoing clinical trials hopefully will help in addressing some of these concerns. PMID- 21305382 TI - Relevance of individual characteristics for thermoregulation during exercise in a hot-dry environment. AB - The aim of this study was to investigate the relevance of individual characteristics for thermoregulation during prolonged cycling in the heat. For this purpose, 28 subjects cycled for 60 min at 60% VO(2peak) in a hot-dry environment (36 +/- 1 degrees C; 25 +/- 2% relative humidity, airflow 2.5 m/s). Subjects had a wide range of body mass (99-43 kg), body surface area (2.2-1.4 m(2)), body fatness (28-5%) and aerobic fitness level (VO(2peak) = 5.0-2.1 L/min). At rest and during exercise, rectal and mean skin temperatures were measured to calculate the increase in body temperature (DeltaT (body)) during the trial. Net metabolic heat production (M (NET)) and potential heat loss (by means of evaporation, radiation and convection) were calculated. Although subjects exercised at the same relative intensity, DeltaT (body) presented high between subjects variability (range from 0.44 to 1.65 degrees C). DeltaT (body) correlated negatively with body mass (r = -0.49; P < 0.01), body surface area (r = -0.47; P < 0.01) and T(body) at rest (r = -0.37; P < 0.05), but it did not significantly correlate with body fatness (r = 0.12; P > 0.05). DeltaT (body) positively correlated with the body surface area/mass ratio (r = 0.46; P < 0.01) and the difference between M (NET) and potential heat loss (r = 0.56; P < 0.01). In conclusion, a large body size (mass and body surface area) is beneficial to reduce DeltaT (body) during cycling exercise in the heat. However, subjects with higher absolute heat production (more aerobically fit) accumulate more heat because heat production may exceed potential heat loss (uncompensability). PMID- 21305383 TI - [Pain therapy in teaching--Quo vadis?]. PMID- 21305384 TI - [Differences between myofascial trigger points and tender points]. AB - The article describes and compares the characteristics of myofascial trigger points (MTrPs) of the myofascial pain syndrome and the tender points (TePs) of the fibromyalgia syndrome. Many statements are hypothetical, because not all aspects of the disorders have been clarified in solid studies. Signs and symptoms of MTrPs: (1) palpable nodule, often located close to the muscle belly, (2) often single, (3) allodynia and hyperalgesia at the MTrP, (4) referral of the MTrP pain, (5) normal pain sensitivity outside the MTrPs, (6) local twitch response, (7) local contracture in biopsy material, (8) peripheral mechanism probable. Signs and symptoms of TePs: (1) no palpable nodule, (2) location often close to the muscle attachments, (3) multiple by definition, (4) allodynia and hyperalgesia also outside the TePs, (5) enhanced pain under psychic stress, (6) unspecific histological changes in biopsy material, (7) central nervous mechanism probable. The multitude of differences speak against a common aetiology and pathophysiology. PMID- 21305385 TI - Effects of tetracycline hydrochloride on measurements with the laser fluorescence device DIAGNOdent: in vitro and in vivo studies. AB - Dental materials that fluoresce affect the reading of the laser fluorescence device DIAGNOdent. Tetracycline hydrochloride (TCH) shows fluorescence and is retained in teeth. The aim of this study was to evaluate the effects of TCH on the DIAGNOdent reading. Filter-paper discs that contained various amounts of TCH were prepared (0.16-10 mg per disc). One-day-old newborn rats were subcutaneously injected with TCH for 29 days, and their mandibles were then removed. The DIAGNOdent values (D-V) of the discs and first molars of the rats were measured before and after they were subjected to ultraviolet irradiation (UV). The D-V of discs containing TCH increased depending on the amount of TCH. The D-Vs of discs with lower amounts of TCH (0.16-1.25 mg) were approximately 10-15, and these values increased to 30-40 under UV. In addition, the D-Vs of molars after UV were twofold greater than those before UV. These results suggest that TCH might affect the readings obtained by DIAGNOdent. PMID- 21305386 TI - Identifying the processes underpinning anticipation and decision-making in a dynamic time-constrained task. AB - A novel, representative task was used to examine skill-based differences in the perceptual and cognitive processes underlying performance on a dynamic, externally paced task. Skilled and less skilled soccer players were required to move and interact with life-size, action sequences involving 11 versus 11 soccer situations filmed from the perspective of a central defender in soccer. The ability of participants to anticipate the intentions of their opponents and to make decisions about how they should respond was measured across two separate experiments. In Experiment 1, visual search behaviors were examined using an eye movement registration system. In Experiment 2, retrospective verbal reports of thinking were gathered from a new sample of skilled and less skilled participants. Skilled participants were more accurate than less skilled participants at anticipating the intentions of opponents and in deciding on an appropriate course of action. The skilled players employed a search strategy involving more fixations of shorter duration in a different sequential order and toward more disparate and informative locations in the display when compared with the less skilled counterparts. The skilled players generated a greater number of verbal report statements with a higher proportion of evaluation, prediction, and planning statements than the less skilled players, suggesting they employed more complex domain-specific memory representations to solve the task. Theoretical, methodological, and practical implications are discussed. PMID- 21305387 TI - Circulating Tregs correlate with viral load reduction in chronic HBV-treated patients with tenofovir disoproxil fumarate. AB - Limited response to current hepatitis B virus (HBV) drugs is possibly due to inadequate host cytotoxic cellular responses. Circulating Tregs have been shown to be associated with chronicity of HBV infection, but their profile during antiviral therapy has not been studied. We analyzed the frequency and effect of Tregs on cellular immune responses against HBV in 35 chronic hepatitis B eAg-ve and eAg+ve patients treated with tenofovir 300 mg/day. Frequency of Tregs and their modulatory role in cytokine-secreting cells were determined after stimulation with HBsAg or HBcAg in the absence or presence of Tregs and after blockage of PD-1/PDL-1 in peripheral blood mononuclear cells (PBMCs). Prior to therapy, eAg-ve patients had lower HBV DNA levels, reduced CD8 T cells, increased Tregs, and T cells expressing PD1. After 12 weeks of therapy, >2 log HBV viral reduction was observed in both groups, along with an increase frequencies of CD8 T cells in eAg-ve patients and increased expression of chemokine receptors/Toll like receptors in both groups. PD-1 expression on CD8 cells in PBMCs was decreased in both groups during therapy but not on Tregs. In eAg-ve group, sustained increase of Tregs was observed till week 12, which declined at week 24. In both groups, after 24 weeks, depletion of CD4(+)CD25(+) Tregs from PBMCs enhanced HBV-specific T cell responses, and blockage of PD-1/PDL1 pathway did enhance pro-inflammatory cytokine production in eAg+ve patients but not in eAg ve. We conclude that Tregs induced by HBV replication in vivo are expanded in eAg ve patients more. Reduction in HBV DNA by tenofovir partially restored adaptive immune responses and also reduced the Tregs. Blockage of PD-1/PDL1, enhanced cytokine production in eAg+ve patients but not in eAg-ve, suggests that distinctly different immunologic mechanisms are involved in eAg+ve and eAg-ve patients. PMID- 21305388 TI - Trichostatin differentially regulates Th1 and Th2 responses and alleviates rheumatoid arthritis in mice. AB - OBJECTIVE: Histone deacetylase inhibitors have shown suppressive effects on tumor growth and in some autoimmune diseases. However, the molecular mechanisms of their effects are not very clear. The purpose of this study was to investigate the effects of trichostatin A (TSA) on collagen-induced rheumatoid arthritis (CIA) in a mouse model and its underlying mechanisms. METHODS: CIA was induced in DBA/1 mice with type II collagen. Paws were scored to assess disease severity. Inflammation of joints was evaluated by histological examination. Real-time PCR was used to determine cytokine mRNA levels. Cytokine production in serum and in supernatants from dendritic to T cell co-cultures was measured by ELISA. T cell proliferation was determined using [(3)H] incorporation. Intracellular cytokine staining was used to measure interferon gamma (IFN-gamma)- and interleukin (IL)-4 producing T cells in splenocytes. Chromatin immunoprecipitation was used to examine histone H3 and H4 acetylation. RESULTS: TSA potently suppressed the severity of arthritis and type II collagen-specific T cell responses in CIA. IFN gamma expression was high in CIA mice, but was inhibited by TSA treatment either at the same time as immunization or at the onset of arthritis manifestation. T cells from TSA-treated mice produced higher levels of IL-4 than cells from the control group. TSA predominantly suppressed Th1 cell proliferation in vitro by induction of apoptosis. In addition, TSA enhanced IL-4 gene expression of in vitro differentiated Th2 cells, and the mechanism is associated with an increased level of histone acetylation in the IL-4 gene promoter. CONCLUSIONS: While TSA selectively suppresses a Th1 response by inducing apoptosis, it upregulates IL-4 expression probably by increasing histone H3 and H4 acetylation of the IL-4 gene promoter. We conclude that TSA can induce a Th1/Th2 balance in vivo and exert protective effects on CIA. PMID- 21305390 TI - Aspiration pneumonia and esophagotracheal fistula secondary to button battery ingestion. AB - We report a case of acute bronchopneumonia and esophagotracheal fistula caused by a swallowed button battery in a 3-year-old girl. It was unclear exactly how long the battery had been trapped in the esophagus. The patient had undergone a tonsillectomy and adenoidectomy 3 weeks before the battery was finally exposed on an X-ray film. She refused to eat solid food after the surgery and stopped eating completely 10 days later. Three weeks after surgery, she presented to the Emergency Department with vomiting and acute respiratory distress, experienced cardiopulmonary arrest in the intensive care unit and could not be resuscitated. Postmortem examination revealed severe acute bronchopneumonia and massive blood aspiration due to an esophagotracheal fistula secondary to a button battery lodged in the esophagus. This case highlights the importance of including a swallowed button battery in the differential diagnosis of a toddler with dysphagia and anorexia. PMID- 21305389 TI - Pharmacogenetic regulation of acetylcholinesterase activity in Drosophila reveals the regulatory mechanisms of AChE inhibitors in synaptic plasticity. AB - We conducted experiments in Drosophila to investigate the consequences of altered acetylcholinesterase (AChE) activity in the nervous system. In ace hypomorphic mutant larvae, the amount of ace mRNA and the activity of AChE both in vivo and in vitro were significantly reduced compared with those of controls. Reduced Ace in Drosophila larvae resulted in significant down-regulation of branch length and the number of boutons in Type 1 glutamatergic neuromuscular junctions (NMJs). These defects in ace hypomorphic mutant larvae were suppressed when Musca domestica AChE was transgenically expressed. Because AChE inhibitors are utilized for medications for Alzheimer's disease, we investigated whether pharmacological inhibition of AChE activity induced any synaptic defects. We found that controls exposed to a sublethal dose of DDVP phenocopied the synaptic structural defects of the ace hypomorphic mutant. These results suggest that down-regulation of AChE activity, regardless of whether it is due to genetic or pharmacological manipulations, results in altered synaptic architecture. Our study suggests that exposure to AChE inhibitors for 6-12 months may induce altered synaptic architectures in human brains with Alzheimer's diseases, similar to those reported here. These changes may underlie or contribute to the loss of efficacy of AChE inhibitors after prolonged treatment. PMID- 21305391 TI - Job loss and health in the U.S. labor market. AB - While U.S. unemployment rates remain low, rates of job loss are high and rising. Job loss is also becoming increasingly common in more advantaged, white-collar occupations. This article is concerned with how these patterns impact the health of U.S. workers. Drawing on recent data from the U.S. Panel Study of Income Dynamics, I find that job loss harms health, beyond sicker people being more likely to lose their jobs. Respondents who lost jobs but were reemployed at the survey faced an increased risk of developing new health conditions; they were not, however, more likely to describe their health in negative terms. This suggests that recent job "churning" within the United States (i.e., high rates of job loss but low unemployment) may impact certain health outcomes but not others. I find no evidence that the health consequences of job loss differ across white- and blue-collar occupations, although health-related selection out of jobs appears stronger within the blue-collar category. PMID- 21305392 TI - Unwed fathers' ability to pay child support: new estimates accounting for multiple-partner fertility. AB - We present new estimates of unwed fathers' ability to pay child support. Prior research relied on surveys that drastically undercounted nonresident unwed fathers and provided no link to their children who lived in separate households. To overcome these limitations, previous research assumed assortative mating and that each mother partnered with one father who was actually eligible to pay support and had no other child support obligations. Because the Fragile Families and Child Wellbeing Study contains data on couples, multiple-partner fertility, and a rich array of other previously unmeasured characteristics of fathers, it is uniquely suited to address the limitations of previous research. We also use an improved method of dealing with missing data. Our findings suggest that previous research overestimated the aggregate ability of unwed nonresident fathers to pay child support by 33% to 60%. PMID- 21305393 TI - Parental imprisonment, the prison boom, and the concentration of childhood disadvantage. AB - Although much research has focused on how imprisonment transforms the life course of disadvantaged black men, researchers have paid little attention to how parental imprisonment alters the social experience of childhood. This article estimates the risk of parental imprisonment by age 14 for black and white children born in 1978 and 1990. This article also estimates the risk of parental imprisonment for children whose parents did not finish high school, finished high school only, or attended college. Results show the following: (1) 1 in 40 white children born in 1978 and 1 in 25 white children born in 1990 had a parent imprisoned; (2) 1 in 7 black children born in 1978 and 1 in 4 black children born in 1990 had a parent imprisoned; (3) inequality in the risk of parental imprisonment between white children of college-educated parents and all other children is growing; and (4) by age 14, 50.5% of black children born in 1990 to high school dropouts had a father imprisoned. These estimates, robustness checks, and extensions to longitudinal data indicate that parental imprisonment has emerged as a novel-and distinctively American-childhood risk that is concentrated among black children and children of low-education parents. PMID- 21305394 TI - Nature's experiment? Handedness and early childhood development. AB - In recent years, a large body of research has investigated the various factors affecting child development and the consequent impact of child development on future educational and labor market outcomes. In this article, we contribute to this literature by investigating the effect of handedness on child development. This is an important issue given that around 10% of the world's population is left-handed and given recent research demonstrating that child development strongly affects adult outcomes. Using a large, nationally representative sample of young children, we find that the probability of a child being left-handed is not significantly related to child health at birth, family composition, parental employment, or household income. We also find robust evidence that left-handed (and mixed-handed) children perform significantly worse in nearly all measures of development than right-handed children, with the relative disadvantage being larger for boys than girls. Importantly, these differentials cannot be explained by different socioeconomic characteristics of the household, parental attitudes, or investments in learning resources. PMID- 21305395 TI - Is the relationship between socioeconomic status and health stronger for older children in developing countries? AB - Recent research on the relationship between child health and income in developed countries reveals a positive gradient that is more pronounced for older children, suggesting that the impact of income upon health accumulates. This article examines whether the same is true in a developing country. Using data from the Indonesian Family Life Survey on children aged 0 to 14 years, we find that although low income adversely affects health, its impact does not differ by age. This finding is robust to the use of both subjective and objective health measures, controlling for selective mortality, the use of alternative measures of households' resources, and the inclusion of indicators of health at birth and parental health. One explanation for the constancy of the health-income relationship that we explore is the dominant role played by acute illness in determining the general health status of children in a developing-country context compared with the more central role played by chronic conditions in developed countries. PMID- 21305396 TI - Proximate sources of population sex imbalance in India. AB - There is a population sex imbalance in India. Despite a consensus that this imbalance is due to excess female mortality, the specific source of this excess mortality remains poorly understood. I use microdata on child survival in India to analyze the proximate sources of the sex imbalance. I address two questions: when in life does the sex imbalance arise, and what health or nutritional investments are specifically responsible for its appearance? I present a new methodology that uses microdata on child survival. This methodology explicitly takes into account both the possibility of naturally occurring sex differences in survival and possible differences between investments in their importance for survival. Consistent with existing literature, I find significant excess female mortality in childhood, particularly between the ages of 1 and 5, and argue that the sex imbalance that exists by age 5 is large enough to explain virtually the entire imbalance in the population. Within this age group, sex differences in vaccinations explain between 20% and 30% of excess female mortality, malnutrition explains an additional 20%, and differences in treatment for illness play a smaller role. Together, these investments account for approximately 50% of the sex imbalance in mortality in India. PMID- 21305397 TI - Motherhood, labor force behavior, and women's careers: an empirical assessment of the wage penalty for motherhood in Britain, Germany, and the United States. AB - Using harmonized longitudinal data from the British Household Panel Survey (BHPS), the German Socio-Economic Panel (GSOEP), and the National Longitudinal Survey of Youth (NLSY), we trace career prospects after motherhood for five cohorts of American, British, and West German women around the 1960s. We establish wage penalties for motherhood between 9% and 18% per child, with wage losses among American and British mothers being lower than those experienced by mothers in Germany. Labor market mechanisms generating the observed wage penalty for motherhood differ markedly across countries, however. For British and American women, work interruptions and subsequent mobility into mother-friendly jobs fully account for mothers' wage losses. In contrast, respective penalties are considerably smaller in Germany, yet we observe a substantial residual wage penalty that is unaccounted for by mothers' observable labor market behavior. We interpret this finding as indicating a comparatively more pronounced role for statistical discrimination against mothers in the German labor market. PMID- 21305398 TI - Modeling transition rates using panel current-status data: how serious is the bias? AB - Studies of disability dynamics and active life expectancy often rely on transition rates or probabilities that are estimated using panel survey data in which respondents report on current health or functional status. If respondents are contacted at intervals of one or two years, then relatively short periods of disability or recovery between surveys may be missed. Much published research that uses such data assumes that there are no unrecorded transitions, applying event-history techniques to estimate transition rates. In recent years, a different approach based on embedded Markov chains has received growing use. We assessed the performance of both approaches, using as a criterion their ability to reproduce the parameters of a "true" model based on panel data collected at one-month intervals. Neither of the widely used approaches performs particularly well, and neither is uniformly superior to the other. PMID- 21305399 TI - Reconstructing childhood health histories. AB - This article provides evidence about the quality of retrospective childhood health histories given to respondents in the Health and Retirement Survey (HRS) and the Panel Study of Income Dynamics (PSID). Even though information on early life health events is critical, there is legitimate skepticism about the ability of older respondents to remember specific health problems that they had during childhood. The evidence presented in this article suggests that this view is too negative. Respondents appear to remember salient childhood events about themselves, such as the illnesses they had during childhood, quite well. Moreover, these physical and psychological childhood health events are important correlates of adult health during middle age. PMID- 21305400 TI - Can knowledge improve population forecasts at subcounty levels? AB - Recent developments in urban and regional planning require more accurate population forecasts at subcounty levels, as well as a consideration of interactions among population growth, traffic flow, land use, and environmental impacts. However, the extrapolation methods, currently the most often used demographic forecasting techniques for subcounty areas, cannot meet the demand. This study tests a knowledge-based regression approach, which has been successfully used for forecasts at the national level, for subcounty population forecasting. In particular, this study applies four regression models that incorporate demographic characteristics, socioeconomic conditions, transportation accessibility, natural amenities, and land development to examine the population change since 1970 and to prepare the 1990-based forecast of year 2000 population at the minor civil division level in Wisconsin. The findings indicate that this approach does not outperform the extrapolation projections. Although the regression methods produce more precise projections, the least biased projections are often generated by one of the extrapolation techniques. The performance of the knowledge-based regression methods is discounted at subcounty levels by temporal instability and the scale effect. The regression coefficients exhibit a statistically significant level of temporal instability across the estimation and projection periods and tend to change more rapidly at finer geographic scales. PMID- 21305409 TI - Age at marriage as a factor in state divorce rate differentials. AB - The prominent East-to-West gradient in state divorce rates has frequently been partially attributed to an ecological factor called "frontier atmosphere," which incorporates the effects of mobility on social integration. This paper employs linear statistical procedures to show that, after adjustment of state divorce rates for age distribution, the percent ever married among teenage females is the best statistical predictor of 1960 and 1970 divorce rates, whereas "frontierness," conventionally measured by population mobility, is shown to have negligible effect, controlling for other selected legal and nonlegal factors. This finding suggests that previous ecological studies of divorce have overemphasized the effect of mobility and social stability on geographic divorce rate differentials, perhaps due to the neglect of demographic variables such as age distribution and especially age at marriage. PMID- 21305410 TI - Legal abortion and fertility in Maryland, 1960-1971. AB - In the brief period between 1967 and 1971 about one-third of the state legislatures passed abortion reform bills, and in states such as Maryland the number of legal abortions soared. Maryland with its good reporting system for legal abortions, as well as its demographic representativeness, appears to offer an ideal "test situation" for assessing the impact on fertility of the new liberalization. Data on live births and reported induced abortions to residents of the state have been compiled and analyzed in an effort to interpret the recent changes in birth rates. Variables examined include maternal age, birth order, race, and legitimacy.Since 1968, Maryland, along with higher than national average abortion ratios, has experienced a rate of decline in fertility greater than that for the nation. In addition, most of the age and parity groups with high abortion ratios show fertility declines greater than those for groups not using abortion as extensively, Nevertheless, because a number of different factors simultaneously influence fertility, it is hazardous to make accurate cause-and-effect statements on the relationship of any single one of these to the observed change. PMID- 21305411 TI - Nuptiality and fertility of birth cohorts. AB - The impact of changes in age patterns of nuptiality on the net reproduction rate is examined using life table techniques and assuming that age-specific fertility within marriage and fertility outside of marriage are fixed. In the second section, a standardization technique is used to investigate the impact of changes in nuptiality on age-cumulative measures of marital fertility. Examples using data for selected generations of Australian women demonstrate the extent to which recent changes in average completed family size in Australia were affected by changing nuptiality patterns. PMID- 21305412 TI - Economic development and fertility change in Mexico, 1950-1970. AB - This paper is an attempt to isolate the determinants of fertility in Mexico. Of the variables included, two are significant in accounting for differences in the level of completed fertility in the 32 "states" in 1970. They are the share of the labor force in agriculture, which is directly related to fertility, and the percentage of the population speaking an indigenous language, which shows an inverse relationship.The most important factors acting to reduce total fertility rates over time are increases in life expectancy and declines in the share of the labor force in agriculture. However, based on the estimated linear relationship, these two variables by themselves are not adequate to achieve a rapid decline in fertility in the future. PMID- 21305413 TI - Interregional differences in fertility in Brazil, 1950-1970. AB - Trends and interregional differences in the birth rate in Brazil between 1950 and 1970 are examined. Estimates are based on data from the 1950 and 1970 censuses. Regional differences in birth measures (crude and general rates) were found to widen between 1950 and 1970 despite a decline in fertility at the national level and a narrowing of regional differences in important socioeconomicvariables like income and urbanization, The substantial interregional migration flows which occurred in Brazil between 1950 and 1970 are examined for their possible impact on differentials. The effects are mixed, but the conclusion is that migration contributed to widening differences. PMID- 21305414 TI - A note on differential fertility in Sri Lanka. AB - In this paper an attempt has been made to study differential fertility by urban rural and regional classifications, using data obtained from complete tabulations of the 1963 Census of Population, the four rounds of the Socio-Economic Survey conducted from November 1969 to October 1970, and the Registrar General's Department. The analysis of current fertility indicates that the traditional pattern of lower urban fertility relative to rural held true in both 1963 and 1970 and also shows a narrowing of the differentials. The country was divided into four zones on an agro-climatic basis for regional analysis. A consistent ranking of the zones in relation to current fertility emerges in both 1963 and 1970. Changing patterns of age-specific fertility and age-specific marital fertility are discussed. Data on average size of family by urban-rural and regional classifications are also analyzed. An attempt has also been made to identify some of the possible causes for the differentials observed. PMID- 21305415 TI - The relationship of the crude birth rate and its components to social and economic development. AB - Using well-known techniques of regression analysis, we decompose the crude birth rate into six analytical components, indicating illegitimacy, the marriage rate, legitimate fertility, and sex and age composition. All the components except sex structure are important in determining differences in crude birth rates across countries of the world. The model is elaborated by showing how economic development affects the crude birth rate through its basic demographic components. PMID- 21305416 TI - The multiregional net maternity function and multiregional stable growth. AB - This paper extends recent efforts to generalize Lotka's integral equation to the case of a multiregional population that experiences internal migration. It develops the concept of a multiregional net maternity function and considers the relationships between a multiregional population's schedule of fertility, mortality, and migration and its stable growth properties. PMID- 21305417 TI - Modeling and forecasting populations by time series: The Swedish case. AB - Time series analysis techniques are used to model and to forecast populations. An autoregressive (AR) and a moving average (MA) model, which seem to fit the population of Sweden very well, are found. Forecasts are calculated using both models and are compared with the forecasts obtained by other methods. This comparison is very favorable for the time series models. Although our study is confined to the mid-year population of Sweden, there are good reasons to expect that the technique can be successfully applied to other population parameters. PMID- 21305418 TI - Metropolitan retail nucleation. AB - We argue that U.S. metropolitan retail nucleation, as represented by sales in the Central Business District and in retail centers, is a consequence of population growth in at least three transportation epochs, the walking and horse era, the electric streetcar era, and the automobile period. Population growth in each epoch has had a different effect on retail nucleation, with the most recent growth having had a pronounced positive effect on development of retail centers and a slight negative effect on the sales of the Central Business District. PMID- 21305419 TI - Differential life-styles between migrants and nonmigrants: A case study of the city of Shiraz, Iran. AB - The migration pattern to Shiraz, a southern city of Iran, is not consistent with the general pattern observed in cities of the other developing nations. Migrants to Shiraz are largely from other cities, and they are more advanced educationally and socioeconomically and less traditional than native Shirazi. This study is based on 1,061 interview cases collected at random. The sample consists of 612 nonmigrants, 125 rural migrants and 324 urban migrants. These groups were compared on thirtyfour indices measuring various facets of the respondents' life styles. The three groups differed statistically on most of the indices. Fatalism and possession of modern appliances were the most important factors differentiating the three groups. PMID- 21305420 TI - The Social ecology of Madrid: Stratification in comparative perspective. AB - This paper examines the characteristics of residential zones in Madrid, Spain. The primary difference between zones is found to lie in a new bourgeoisie life style dimension. Working women are found to be the best indicator of this dimension, which also involves servants, natives of Madrid and high degrees of literacy. Fertility-related considerations, however, are unrelated to working women, and this is explained as due to the availability of domestic help and "women-oriented" working arrangements. Fertility and socioeconomic status are found to be interrelated and constitute a second dimension of residential segregation. In conclusion, Madrid is examined in relation to both more and less industrialized cities, leading to a further modification of social area theory contentions concerning the ecology of stratification in developing cities. PMID- 21305421 TI - Comment on G. Hendershot's "Population size, military power, and antinatal policy". PMID- 21305422 TI - In praise of conventional research methods for medical education research. PMID- 21305423 TI - The seventh element of quality: the doctor-patient relationship. AB - BACKGROUND AND OBJECTIVES: National experts have defined the elements of quality health care, but community-based physicians have not been systematically asked their opinions about quality. This study explored primary care clinicians' beliefs about the elements of quality care. METHODS: Responses from structured interviews with 12 primary care clinicians and open-ended comments in a subsequent survey of 85 clinicians, all employed by a large urban federally qualified community health center, were coded independently by two researchers and analyzed for major themes. After discovering that these themes resembled the six elements advanced by the Institute of Medicine, the data were recoded to identify additional perceptions about quality. RESULTS: Clinicians believe that the relationship with patients is a core element of quality health care. They also reconfirm the elements of quality advanced by the Institute of Medicine- safety, timeliness, effectiveness, efficiency, equity, and patient centeredness, with safety mentioned infrequently. The clinicians also emphasized preventive care. CONCLUSIONS: While primary care clinicians' beliefs about quality are generally consistent with experts' definitions, they emphasize relationships and rarely mention safety. Successful efforts to promote quality in primary care should be consistent with clinicians' beliefs about what constitutes high quality. PMID- 21305424 TI - Role modeling the doctor-patient relationship in the clinical curriculum. AB - BACKGROUND AND OBJECTIVES: Training in relationship skills relies heavily on role modeling: students observing clinicians at work. This study explored student and faculty perceptions of student learning about relationship skills in hospital and ambulatory settings. METHODS: Qualitative data from focus groups and long interviews were coded by the authors through an iterative dialogic process. Participants were 15 faculty and 35 medical students in clinical training in a New Zealand medical school. RESULTS: Teaching of doctor-patient relationship skills was highly variable, rarely explicit, and heavily dependent on role modeling. Students noted variable focus on relational skills between rotations, incongruity between preclinical training and the behaviors observed in clinical environments, and a need to discern which relational skills were facilitative. Role models who transparently shared their personal experiences of doctoring were more effective in helping students learn relationship skills. CONCLUSIONS: Role modeling alone is insufficient for helping students acquire exemplary doctor patient relationship skills. Role models must explicitly reflect upon the complex intricacies of interacting with patients to help students understand and incorporate specific skills. Lack of transparency is a barrier to quality role modeling that may be mitigated in ambulatory, primary care settings. PMID- 21305425 TI - A reduction in emergency department use by children from a parent educational intervention. AB - BACKGROUND AND OBJECTIVES: A substantial proportion of emergency department (ED) visits by children are for non-urgent care. The objective of this research is to determine whether a parent-focused educational intervention can reduce non-urgent ED visits. METHODS: A regional hospital system (which includes a central hospital, four satellite hospitals, and two primary care clinics) provided monthly data retrospectively from January 2006 to October 2007 on ED visits by children. The same information was provided prospectively from November 2007 to April 2009. Starting in November 2007, a family medicine residency program affiliated with the same hospital network distributed a 6.7 grade reading level booklet on non-urgent care of children to the parents who brought their children to the outpatient clinic. The number of ED visits as a proportion of outpatient clinic visits at the residency program was calculated for each month and compared to historical and geographic trends. RESULTS: Long-term changes were observed only among the intervention group. There was a substantial and statistically significant reduction in ED use for non-urgent care of children. There was also a proportional reduction in ED charges for this group. CONCLUSION: An educational intervention among parents can substantially reduce non-urgent ED visits for their children. PMID- 21305426 TI - What makes a realistic evaluation? PMID- 21305427 TI - Learner-directed intentional diversification: the experience of three P4 programs. AB - BACKGROUND: This paper presents early outcomes of three residency programs participating in Preparing the Personal Physician for Practice (P4), family medicine's innovative residency redesign initiative. The three programs allow learner-directed diversification and either allow or require extra time, up to 4 years of residency, to complete these experiences. Residents endorse the changes by two measures: they choose a wide variety of areas of concentration, and a significant minority (40%) of residents chose to extend their residency training to 4 years, a proportion that grew significantly from 2006 to 2008. PMID- 21305428 TI - Internet availability and interest in patients at a family medicine residency clinic. AB - BACKGROUND AND OBJECTIVES: The Internet has affected the day-to-day lives of physicians, hospitals, and patients. The medical information for each is available at a moment's notice. We surveyed patients to see how many have access to the Internet and whether they are interested in using the Internet to communicate about their medical care. METHODS: An anonymous one-page survey was given to patients over the age of 18 who had an office visit at the Family Medicine Center. RESULTS: A total of 258 of 300 surveys were returned. A majority of these patients have access to the Internet (80.6%). Patients were most interested in being able to receive appointment reminders by e-mail (44.6%), get answers to medical questions (41.9%), and schedule appointments online (41.5%). CONCLUSIONS: Patients would like to be active participants in their medical care electronically. We encourage other physicians to investigate what patients in their practice would consider a service to provide electronically. PMID- 21305429 TI - Cosmetic services in the family health center: a roadmap. PMID- 21305431 TI - Which "placebo effect"? (and why it matters). PMID- 21305432 TI - The family practice pledge. PMID- 21305433 TI - Clinical strategies for maximizing the placebo effect. PMID- 21305434 TI - Sharing experiences and practical learning in practice transformation. PMID- 21305435 TI - [Elastography - true or false?]. PMID- 21305436 TI - [Interventional endosonography]. PMID- 21305437 TI - Individualized correction for maternal weight in calculating the risk of chromosomal abnormalities with first-trimester screening data. AB - AIM: In the algorithm developed by the Fetal Medicine Foundation (FMF) Germany designed to evaluate the findings of routine first-trimester screening, the false positive rate (FPR) was determined for the entire study group without stratification by maternal weight. Based on the data received from the continuous audit we were able to identify an increase in the FPR for the weight-related subgroups of patients, particularly for patients with extremely high body weights. The aim of this study was to demonstrate that the variability of the FPR can be reduced through adjusting the concentrations of free beta-HCG and PAPP-A measured in the maternal serum by means of a nonlinear regression function modeling the dependence of these values on maternal weight. MATERIAL AND METHODS: The database used to establish a version of the algorithm enabling control of the FPR over the whole range of maternal weight consisted of n = 123 546 pregnancies resulting in the birth of a child without chromosomal anomalies. The group with positive outcomes covered n = 500 cases of trisomy 21 and n = 159 trisomies 13 or 18. The dependency of the serum parameters free beta-HCG and PAPP-A on maternal weight was analyzed in the sample of negative outcomes by means of nonlinear regression. The fitted regression curve was of exponential form with negative slope. Using this model, all individual measurements were corrected through multiplication with a factor obtained as the ratio of the concentration level predicted by the model to belong to the average maternal body weight of 68.2 kg, over the ordinate of that point on the regression curve which belongs to the weight actually measured. Subsequently, the totality of all values of free beta HCG and PAPP-A corrected for deviation from average weight were used as input data for carrying out the construction of diagnostic discrimination rules described in our recent paper for a database to which no corrections for over- or under-weight had been applied. This entailed in particular the construction of new reference bands for the corrected biochemical values as the basis for calculating the degree of extremeness (DOE) measures to replace the more traditional MOMs. In the final and most crucial step, stratified FPRs were computed and compared over a set of intervals partitioning the whole range of maternal weight into 18 classes. RESULTS: For the posterior risks of both trisomy 21 and 13 / 18 computed from the weight-corrected database, the use of a cutoff value of 1:150 turned out to be an appropriate choice. For T 21, the overall FPR obtained through comparing the individual risks with this cutoff was found to be 3.51 %. The corresponding proportion of ascertained cases of trisomy 21 detected by means of the new algorithm was 86.2 %. For the trisomy 13 / 18 group, the analogous results were a FPR of 2.07 % and a detection rate (DTR) of 83.0 %, respectively. A comparison between the FPRs obtained for the 18 intervals into which the range of maternal weight had been partitioned, showed the deviation of the strata-specific from the overall FPR to be fairly small: for T 21, the FPR ranged from 2.72 to 4.86 %, and the maximum was found in the group of 87.5 - 95.0 kg. For women with a weight of more than 120 kg, the FPR was only slightly above the FPR for the total sample (3.69 as compared to 3.51 %). Similar results were obtained for the discrimination rule constructed for diagnosing T 13 / 18: here, the minimum FPR (1.17 %) was found for patients weighing more than 120 kg, whereas the maximum (2.66 %) occurred in the interval 75.0 - 77.5 kg. CONCLUSION: In this study we demonstrated that the new algorithm developed by the FMF Germany to estimate risks for fetal trisomies 21 and 13 / 18 combines very good misclassification rates with a far-reaching stability of the false-positive rate against even extreme deviations from the average maternal weight. PMID- 21305438 TI - Intraoperative sonography: a technique for localizing focal forms of congenital hyperinsulinism in the pancreas. AB - Congenital hyperinsulinism (CHI), syn. nesidioblastosis, is the most frequent cause of persistent, recurrent hypoglycemia in infancy. One third of patients show a single circumscribed focus. Enucleation of the focus and the removal of all affected beta-cells with preservation of healthy tissue is the treatment of choice. The intrapancreatic choledochus as well as the ductus pancreaticus major must remain intact. The diagnostic gold standard is 18F-DOPA-PET/CT. Intraoperative sonography is carried out to correctly visualize the focus preoperatively localized by PET/CT in situ during the operation. The enucleation of the focus was carried out 3 - 20 days after PET/CT in 5 patients at an age of 3.5 - 14 months. Intraoperative ultrasound was carried out with high-capacity devices of different manufacturers under use of broadband probes (9 - 14 MHz). The localization by intraoperative ultrasound was accurate in all 5 patients with focal CHI, with regard to the intraoperative localization as previously described by PET/CT and histology. D. choledochus and D. pancreaticus major were separated intraoperatively by ultrasound. 3 of 5 patients were cured by complete enucleation of the focus. Nevertheless, the entire intraoperative identification of the segmented focus is still problematic. Characteristic sonographic features of a CHI focus are: hypoechogenicity, variable homogeneous and inhomogenous texture, blurred, irregular limitation without capsule, filiform, lobular processes, and insular dispersal into the surrounding tissue. Intraoperative high resolution sonography helps the pediatric surgeon to determine size, configuration and topography of a CHI focus. PMID- 21305439 TI - Primum non nocere? Why can't we use second generation ultrasound contrast agents for the examination of children? PMID- 21305443 TI - "Acutely" enlarging breast: intracystic papillary carcinoma. PMID- 21305442 TI - [Periinterventional cone-beam-CT: application at transarterial chemoembolization of liver tumors]. AB - Periinterventional Cone-Beam CT (CBCT) today is a valuable tool in complex radiological interventions. Only little experience exists about CBCT in transarterial chemoembolisations (TACE) of liver tumors. 25 patients underwent periinterventional CBCT. We used a C-arc DSA with 30 * 40 cm flat panel detector. Image data with axial, coronal and 3D-reconstruction were acquired by 217 degrees rotation in 8 seconds. In all 25 cases CBCT had an influence on the TACE regarding the decision which vessels to catheterize, the amount of retention of the embolisation agent or an abort because of insufficient vascularisation. In comparison with DSA alone, CBCT allows a better visualisation of tumour vessels, simplifies selective catheterisation, the decision whether an embolisation is possible and enables a good visualisation of Lipiodol retention. Hence, CBCT is a helpful periinterventional tool but cannot substitute CT and MRI in follow up. PMID- 21305444 TI - Warm-up affects diurnal variation in power output. AB - The purpose of this study was to examine whether time of day variations in power output can be accounted for by the diurnal fluctuations existent in body temperature. 8 recreationally trained males (29.8+/-5.2 yrs; 178.3+/-5.2 cm; 80.3+/-6.5 kg) were assessed on 4 occasions following a: (a) control warm-up at 8.00 am; (b) control warm-up at 4.00 pm; (c) extended warm-up at 8.00 am; and, (d) extended warm-up at 4.00 pm. The control warm-up consisted of dynamic exercises and practice jumps. The extended warm-up incorporated a 20 min general warm-up on a stationary bike prior to completion of the control warm-up, resulting in a whole body temperature increase of 0.3+/-0.2 degrees C. Kinetic and kinematic variables were measured using a linear optical encoder attached to a barbell during 6 loaded counter-movement jumps. Results were 2-6% higher in the afternoon control condition than morning control condition. No substantial performance differences were observed between the extended morning condition and afternoon control condition where body temperatures were similar. Results indicate that diurnal variation in whole body temperature may explain diurnal performance differences in explosive power output and associated variables. It is suggested that warm-up protocols designed to increase body temperature are beneficial in reducing diurnal differences in jump performance. PMID- 21305445 TI - [A short-term diagnostic and economic impact model of neonatal screening for cystic fibrosis]. AB - BACKGROUND: Screening for cystic fibrosis (CF) is currently not a part of the neonatal screening program in Germany, but its implementation is being debated. The aim of this study was to model the short-term diagnostic and economic consequences of the implementation of such a screening. PATIENTS: Cohort of all newborns in Germany per year. METHODS: In total, 3 screening strategies were evaluated by decision modelling. The 3 screening protocols compared were alternative combinations of IRT- and DNA-testing with a final sweat test. RESULTS: All modelled screening strategies show a comparable diagnostic yield (171-175 CF-cases per year). There is a tendency of slightly higher sensitivity and shorter time to diagnosis for the "IRT-DNA with failsafe" protocol. In comparison to other strategies, the total number of screening-related visits for this protocol is lower, whereas the amount of sweat tests is the highest. All screening strategies are comparable in terms of avoided cases of extremely low height- or weight-for-age (37-38 and 13-14 cases, respectively). The incremental annual diagnostic costs (with deducted diagnostic costs without screening) are 1.13 to 1.16 million EUR. After 3 years of model runtime there is a nearly neutral total budget impact of screening (diagnostic and treatment costs) per cohort. CONCLUSION: All screening strategies lead to a considerable reduction of time to diagnosis at acceptable financial expenditures. The findings of this study broaden the current basis for discussion regarding the implementation of cystic fibrosis screening in Germany. PMID- 21305446 TI - Inhibition of stromelysin-1 by caffeic acid derivatives from a propolis sample from Algeria. AB - Stromelysin-1 (matrix metalloproteinase-3: MMP-3) occupies a central position in collagenolytic and elastolytic cascades, leading to cutaneous intrinsic and extrinsic aging. We screened extracts of a propolis sample from Algeria with the aim to isolate compounds able to selectively inhibit this enzyme. A butanolic extract (B (3)) of the investigated propolis sample was found to potently inhibit MMP-3 activity (IC (50) = 0.15 +/- 0.03 ug/mL), with no or only weak activity on other MMPs. This fraction also inhibited plasmin amidolytic activity (IC (50) = 0.05 ug/mL) and impeded plasmin-mediated proMMP-3 activation. B (3) was fractionated by HPLC, and one compound, characterized by NMR and mass spectroscopy and not previously identified in propolis, i.e., (+)-chicoric acid, displayed potent IN VITRO MMP-3 inhibitory activity (IC (50) = 6.3 * 10 (-7) M). In addition, both caffeic acid and (+)-chicoric acid methyl ester present in fraction B (3) significantly inhibited UVA-mediated MMP-3 upregulation by fibroblasts. PMID- 21305447 TI - Effects of ginger constituents on the gastrointestinal tract: role of cholinergic M3 and serotonergic 5-HT3 and 5-HT4 receptors. AB - The herbal drug ginger (Zingiber officinale Roscoe) may be effective for treating nausea, vomiting, and gastric hypomotility. In these conditions, cholinergic M (3) receptors and serotonergic 5-HT (3) and 5-HT (4) receptors are involved. The major chemical constituents of ginger are [6]-gingerol, [8]-gingerol, [10] gingerol, and [6]-shogaol. We studied the interaction of [6]-gingerol, [8] gingerol, [10]-gingerol (racemates), and [6]-shogaol with guinea pig M (3) receptors, guinea pig 5-HT (3) receptors, and rat 5-HT (4) receptors. In whole segments of guinea pig ileum (bioassay for contractile M (3) receptors), [6] gingerol, [8]-gingerol, [10]-gingerol, and [6]-shogaol slightly but significantly depressed the maximal carbachol response at an antagonist concentration of 10 uM. In the guinea pig myenteric plexus preparation (bioassay for contractile 5-HT (3) receptors), 5-HT maximal responses were depressed by [10]-gingerol from 93 +/- 3 % to 65 +/- 6 % at an antagonist concentration of 3 uM and to 48 +/- 3 % at an antagonist concentration of 5 uM following desensitization of 5-HT (4) receptors and blockade of 5-HT (1) and 5-HT (2) receptors. [6]-Shogaol (3 uM) induced depression to 61 +/- 3 %. In rat esophageal tunica muscularis mucosae (bioassay for relaxant 5-HT (4) receptors), [6]-gingerol, [8]-gingerol, [10]-gingerol, and [6]-shogaol (2-6.3 uM) showed no agonist effects. The maximal 5-HT response remained unaffected in the presence of the compounds. It is concluded that the efficiency of ginger in reducing nausea and vomiting may be based on a weak inhibitory effect of gingerols and shogaols at M (3) and 5-HT (3) receptors. 5-HT (4) receptors, which play a role in gastroduodenal motility, appear not to be involved in the action of these compounds. PMID- 21305448 TI - Cytotoxic and antimicrobial activities of aporphine alkaloids isolated from Stephania venosa (Blume) Spreng. AB - The cytotoxic activity of five alkaloids, namely 4,5-dioxo-dehydrocrebanine (1), dehydrocrebanine (2), crebanine (3), oxostephanine (4), and thailandine (5) isolated from the tuber and leaves of Stephania venosa (Blume) Spreng was investigated. Thailandine showed the strongest activity against lung carcinoma cells (A549) (IC50 of 0.30 ug/mL) with very low cytotoxicity against normal embryonic lung cells (MRC-5). Thailandine also demonstrated strong activity against Plasmodium falciparum, K1 strain (IC50 of 20 ng/mL), and Mycobacterium tuberculosis H(37)Ra (MIC of 6.25 ug/mL) as well as gram-positive bacteria such as Streptococcus pneumoniae and Staphylococcus aureus. Oxostephanine exhibited strong activity against breast cancer (BC) and acute lymphoblastic leukemia cells (MOLT-3) with an IC50 of 0.24 and 0.71 ug/mL, respectively, and exhibited very low cytotoxicity against MRC-5 cells. Dehydrocrebanine demonstrated strong activity against promyelocytic leukemia cells (HL-60) with an IC50 of 2.14 ug/mL whereas crebanine showed weak activity against cancer cell lines. However, both of them showed cytotoxicity against MRC-5 cells. PMID- 21305449 TI - Catechol, a bioactive degradation product of salicortin, reduces TNF-alpha induced ICAM-1 expression in human endothelial cells. AB - The phenolic glucoside salicortin was isolated from a Willow bark extract, and its ability to reduce the TNF- alpha induced ICAM-1 expression (10 ng/mL, 30 min pretreatment with salicortin) was tested IN VITRO on human microvascular endothelial cells (HMEC-1). After 24 h, 25 uM salicortin decreased the TNF- alpha induced ICAM-1 expression to 65.9 % compared to cells which were treated only with TNF- alpha. In parallel, the stability of 25 uM salicortin under assay conditions was determined by HPLC. Within 24 h, the salicortin concentration decreased to 3.1 uM whereas catechol, a known NF- kappaB inhibitor, rose as a metabolite. After 8 h the catechol concentration was relatively constant and varied between 8.2 and 10.9 uM. Considering this degradation in the IN VITRO test system, 10 uM catechol was added 8 h after TNF- alpha stimulation, and 16 h later the ICAM-1 expression was determined. In this setting, the ICAM-1 expression was reduced to 74.8 %. This is comparable to the effect obtained from 25 uM salicortin and indicates that its activity is related to the generation of catechol, as salicin, saligenin, and salicylic acid are only marginally active or inactive in this test system in a concentration up to 50 uM. These results indicate catechol as an important bioactive metabolite from salicortin. PMID- 21305450 TI - [Malignant melanoma of the skin: does screening for cancer influence the incidence and mortality?]. AB - BACKGROUND: The increase in incidence of malignant melanoma, early diagnosis activities increasingly reaching ever larger population groups and mortality remaining at a constant level in trend comprise the background of the study. We aimed at answering the question whether the early diagnosis can have an influence on the increase in incidence and how one can one judge the effect on the reduction of the mortality. METHODOLOGY: The study is based on data from official tumour registries of the regions Saarland, Schleswig-Holstein, the administrative district Munster, the former GDR and the New Dfederal states (Berlin, Brandenburg, Mecklenburg-Vorpommern, Sachsen, Sachsen-Anhalt, Thuringen), as well as that of Queensland (Australia). RESULTS: Parallel to the increasing incidence, there is also an increase in the number of melanomas detected at early stages. Hence, it is obvious to assume that this increase in incidence is due to a large extent to screening programmes. In a non-determinable number of cases, overdiagnostics could have contributed to the increase in incidence. In the period of observation mortality remained constant in the regions described in this study. It can be assumed the mortality risk is influenced by tumours with a high degree of malignancy whose share in the number of melanomas remains roughly constant. CONCLUSION: The early diagnosis of cancer, the inclusion of increasingly larger groups of the populations in the regions described, and constant mortality rates for men and women during the period of observation all relate the use of early diagnosis. If the efficiency of population screening is measured against the outcome reduction of the mortality rate, it appears to be sufficient to continue cancer early detection according to SGB V S 25. A preventive check-up is indicated for risk groups, e. g., those with a positive familiar history or if potentially malignant skin alterations have been diagnosed. PMID- 21305451 TI - [Public health measures at the airport of Hamburg during the early phase of pandemic influenza (H1N1) 2009]. AB - BACKGROUND AND METHODS: After the World Health Organization issued a global alert for the occurrence of a novel pandemic influenza (H1N1) in 2009, most international airports in Germany implemented intensified public health measures to delay local transmission. At Hamburg airport it was decided not to implement a general entry and exit screening of all travelers during the pandemic influenza (H1N1) 2009. Travelers were advised on symptoms and protective measures by public information displayed in the airport. A mobile Airport Medical Assessment Center (AMAC) for up to 260 persons was used which barred 6 gates from traffic for this reason. Travelers were medically examined by the public health authority after notification from the flight captain according to Article 28 (4) of the International Health Regulations or were referred to the medical assessment by other service providers such as the information desk in the airport. From May to August 2009 n=108 affected travelers were medically examined and advised by the public health authority at the airport. 9 out of 108 affected travelers (8.3%) who presented to the public health service at the airport were diagnosed with pandemic influenza (H1N1) 2009. Overall, only 0.002% of all travelers through the airport in the given time-frame were seen by the service. Most of the affected travelers presented themselves to the public health service before embarkation or after disembarkation. On 6 occasions the pilots declared a person with illness on board to the public health authority. Out of the 6 persons 4 were diagnosed with pandemic influenza (H1N1) 2009. In the case of notification, the delay in traveling for contact persons ranged from 30 min to 2 h. None of the sick travelers was referred to a hospital, all returned home. In addition to the medical assessment of affected travelers the public health authority issued "free pratique" according to Article 28 (3) of the International Health Regulations, after talking to the cabin crew or flight captain. Out of 167 (0.3% of all flights to Hamburg) inspected airplanes only in one case was a notification not issued by the pilot despite a known case of sickness on the plane. CONCLUSIONS: To avoid unnecessary interference with travel, the public health service at airports must be able to react in a timely manner to notifications of disease. During the influenza pandemic (H1N1) 2009, 4 out 9 (36%) of the cases that were diagnosed with pandemic influenza (H1N1) 2009 were notified to the public health authority via the aircraft. It is the authors' experience during the pandemic influenza (H1N1) 2009 that the notification requirement of the pilot is of importance because it enables the public health service to react before disembarkation. However, more often affected persons sought advice from the public health service before or after the flight. A prerequisite for this is that the public health service is known to the relevant bodies at the airport and accessible to the public. Routine health inspections of airplanes with visual inspection of travelers result in high manpower requirements. In the authors' view these routine inspections of airplanes are only justified if there is a suspicion of disease on board, or to train the staff of public health authorities. It can be concluded from the experiences during the pandemic influenza (H1N1) 2009 that the core capacities required for designated airports according to Annex 1 B of the International Health Regulations must include trained medical professionals, communication and transportation infrastructure amongst appropriate facilities. One must distinguish between medical facilities for some affected travelers in the public areas of the airport, and a medical assessment area in the security area of the airport that is appropriate for the number of persons that may be carried by the largest vessel to that destination. PMID- 21305452 TI - [Perinatal mortality by mother's country of origin in Tyrol 2000-2008]. AB - INTRODUCTION: This study analyses for the first time the Tyrolean perinatal mortality stratified by the country of origin of the mother. Data of the Tyrolean birth registry were evaluated from 2000-2008. The aim of our study was to analyse differences in perinatal mortality according to the country of origin of the mother. METHODS: 58 787 single births were assessed between the years 2000-2008. Mothers with similar experiences of how to access the health-care system were aggregated into 5 groups: (1) "Tyrol/Austria", (2) "western Europe/West", (3) "former Yugoslavia/eastern Europe", (4) "Turkey" and (5) "other countries". The odds ratio for perinatal mortality according to the country of origin of the mother was calculated in a multivariate model. The following independent variables were included: age of mother at birth, parity, housewife during pregnancy, week of gestation at the first check-up visit, smoking, preterm delivery and weight of the newborn. RESULTS: The number of mothers of Tyrolean/Austrian origin decreased over the years by 2% whereas the number of mothers from Western Europe/West increased by 3%. The other migration groups remained constant or were slightly decreased. In the multivariate model; the perinatal mortality [odds ratio (CI)] was for the subgroups "Turkey" 1.06 (0.61 1.83) and for "western Europe/West" 1.09 (0.64-1.86), and therefore almost identical with the reference subgroup "Tyrol/Austria" (OR=1); the perinatal mortality was significantly increased with 2.14 (1.37-3.34) for the subgroup "former Yugoslavia/eastern Europe and for the subgroup "other countries" 2.54 (1.21-5.36). The variables "age under 18 years" OR 1.99 (0.80-4.93) and "mulitpara" OR 1.30 (0.96-1.74) were not significantly increased. Significantly increased was "preterm delivery" OR 4.53 (2.80-7.33) and "low birthweight" (<1 500 g) OR 53.60 (32.02-89.73) and 1 500 to 2 499 g OR 4.85 (2.96-7.96). There are considerable differences comparing the odds ratios between the 5 subgroups for perinatal mortality. The subgroups "Turkey" and "western Europe/West" have a similar odds ratio compared to the reference group "Tyrol/Austria". The subgroups "former Yugoslavia" and "other countries" have a significantly increased perinatal mortality (OR 2-2.5). CONCLUSION: The good outcome of the mothers from "Turkey" can be seen as similar to the "Latina paradoxon", which means a better outcome of pregnancy and birth of mothers from "Turkey", even though they are more comparable with other migrant groups in some risk factors, such as a lower socioeconomic standard, late check-ups, language difficulties and cultural factors. A single case analysis would be necessary to examine the exact causes. PMID- 21305453 TI - [Cement-augmented anterior odontoid screw fixation of a Anderson-D'Alonzo type II fracture with massive osteoporosis. Case report]. AB - Anterior screw fixation is a standard treatment procedure in the case of an uncomplicated Anderson-D'Alonzo type II odontoid fracture in younger patients. Insufficient bony screw hold can cause severe procedure-related complications and result in screw breakouts with secondary fracture dislocation. Hence, the procedure is limited to patients with an adequate bone mineral density. This case report summarises a technical modification of anterior screw fixation in elderly patients suffering from severe osteoporosis to avoid a posterior spondylodesis of C1/2. Two patients with odontoid fractures of Anderson-D'Alonzo type II were operated using anterior screw fixation and additional vertebroplasty of C2 to increase the screw hold. During follow-up a regular bony healing without screw complication was observed. In conclusion, cement-augmented anterior screw fixation of odontoid fractures type II according to Anderson-D'Alonzo and persistent severe osteoporosis can be an alternative to posterior C1/2 spondylodesis in individual cases. PMID- 21305454 TI - [Vacuum-assisted closure therapy for the treatment of skin and soft-tissue infections. Are wound specimens of use in planning secondary wound closure?]. AB - AIM: Vacuum-assisted closure is used frequently for the treatment of skin and soft-tissue infections (SSTI) of the extremities. After debridement and repeated VAC dressing changes, the wounds are closed by secondary suture, split-thickness skin grafts or local flaps. However, no objective parameters describe the time point for secondary wound closure. Our thesis was that negative microbiological results from wound specimens can indicate the time for secondary wound closure. PATIENTS AND METHODS: 24 patients with SSTI of the extremities were treated by serial debridements and VAC therapy and analysed prospectively. Debridements were repeated until the wounds were macroscopically free from signs of infection (good granulation/no necrosis). During each revision specimens were taken for microbiological analysis. Moreover, number of revisions, bacterial cultures, type of wound closure and wound status after 3 years and 5 months on average after the last surgery were analysed. RESULTS: 6.3 revisions on average were performed until secondary wound closure was possible. In spite of the absence of macroscopic infection, bacteria were still found in tissue samples from 14 of 24 wounds. 6 wounds were free of bacteria for the first time right before wound closure, 3 wounds had become negative during the treatment. After 3.4 years on average, the wounds of all 18 patients available for examination had healed well and were free from signs of infection. CONCLUSION: Vacuum-assisted closure resulted in clean, good granulating wounds without necrosis. However, in more than half of the wounds bacteria persisted. This bacterial load had no correlation to wound healing and outcome after over 3 years. In conclusion, microbiological tissue samples are not suitable as indicator for the time point of secondary wound closure in SSTI. PMID- 21305455 TI - [Bucket handle tears]. PMID- 21305466 TI - [Reimbursed fee recourse in illegal creation of partnership practice contracts. Comments on the decision of the Federal Social Court of 23 June 2010 Az.: B6 KA 7/09 R-]. PMID- 21305467 TI - Interventional radiological retrieval of embolized vascular access device fragments. AB - PURPOSE: Vascular access device fragment embolization is a relatively rare but potentially serious complication. The purpose of this study was to report our experience with endovascular retrieval of embolized vascular access device fragments by interventional radiological means. MATERIALS AND METHODS: Ten patients with a vascular access device fragment embolism were treated between 2004 and 2010. Attempted retrieval from the vascular bed was performed for five port catheter fragments, two temporary catheter fragments and three guide wires. The demographic data, underlying disease of the patients, type of inserted catheters, interval between implantation and discovery of embolism, interval between discovery of embolization and retrieval and localization and length of the embolized fragments were identified from the patient charts. RESULTS: In nine of the ten patients (90%), radiologic intervention retrieval of the embolized vascular access device fragments was successful. The reasons for intravascular fragment embolism consisted of rupture at the connection site of the chamber or the external hub and the intravascular catheter (n=4), pinchoff syndrome (n=3), operator inexperience (n=3). Embolized catheter fragments or guide wires were retrieved under fluoroscopy by a gooseneck snare. The postprocedural course was uneventful. CONCLUSION: The radiological retrieval of embolized vascular access device fragments is the preferred method, and it has a high success rate. Considering the potential for devastating complications, patients should be referred to interventional radiology, and the embolized catheters should be retrieved using interventional endovascular techniques. PMID- 21305468 TI - Accuracy of parathyroid imaging: a comparison of planar scintigraphy, SPECT, SPECT-CT, and C-11 methionine PET for the detection of parathyroid adenomas and glandular hyperplasia. AB - PURPOSE: To compare the accuracy of planar scintigraphy, single photon emission computed tomography (SPECT), SPECT-CT, and positron emission tomography (PET) with C-11 methionine for the pre-operative detection of parathyroid adenomas. MATERIALS AND METHODS: We retrospectively evaluated the pre-operative studies of 60 patients with primary (n=56) and secondary (n=4) hyperparathyroidism. In 25/60 patients (Group 1), only planar scans were obtained, and additional SPECT and SPECT-CT were carried out in 35/60 patients (Group 2). PET or PET-CT with C-11 methionine was conducted in 8/60 patients (Group 3). RESULTS: The results of the planar scans (Group 1) were true positive in 19/25 patients and false negative in 6/25 patients (sensitivity per patient, 76%). Histopathology confirmed 27 adenomas and two hyperplasia. Planar imaging identified 20/29 of these pathologies, whereas 9/29 were missed (sensitivity per adenoma, 69%). SPECT (Group 2) results were true positive in 34/35 patients and false negative in only one case (sensitivity per patient, 97%). On a lesion-based analysis, 38 adenomas were identified, and two were missed (sensitivity per adenoma, 95%). The sensitivities of SPECT and SPECT-CT were equal; however, SPECT-CT provided superior topographic information. C-11 methionine PET (Group 3) results were true positive in all eight patients. In one case, surgery confirmed two ipsilateral adenomas, only one of which was identified by PET (sensitivity per patient, 100%; per adenoma, 88.9%). CONCLUSION: SPECT is superior to planar imaging. SPECT-CT has identical sensitivity compared to SPECT alone, but it provides additional topographic information. The sensitivity of PET appears to be even higher compared to SPECT. In the case of negative scintigraphic findings and proven hyperparathyroidism, additional C-11 methionine PET or PET-CT is recommended. PMID- 21305469 TI - Regulation of programmed cell death during neural induction in the chick embryo. AB - To study early responses to neural inducing signals from the organizer (Hensen's node), a differential screen was performed in primitive streak stage chick embryos, comparing cells that had or had not been exposed to a node graft for 5 hours. Three of the genes isolated have been implicated in Programmed Cell Death (PCD): Defender Against Cell Death (Dad1), Polyubiquitin II (UbII) and Ferritin Heavy chain (fth1). We therefore explored the potential involvement of PCD in neural induction. Dad1, UbII and fth1 are expressed in partly overlapping domains during early neural plate development, along with the pro-apoptotic gene Cas9 and the death effector Cas3. Dad1 and UbII are induced by a node graft within 3 hours. TUNEL staining revealed that PCD is initially random, but both during normal development and following neural induction by a grafted node, it becomes concentrated at the border of the forming neural plate and anterior non-neural ectoderm and downregulated from the neural plate itself. PCD was observed in regions of Caspase expression that are free from Dad1, consistent with the known anti-apoptotic role of Dad1. However, gain- and loss-of-function of any of these genes had no detectable effect on cell identity or on neural plate development. This study reveals that early development of the neural plate is accompanied by induction of putative pro- and anti-apoptotic genes in distinct domains. We suggest that the neural plate is protected against apoptosis, confining cell death to its border and adjacent non-neural ectoderm. PMID- 21305470 TI - Modulation of mitochondrial biogenesis and bioenergetic metabolism upon in vitro and in vivo differentiation of human ES and iPS cells. AB - Reprogramming somatic cells to induced pluripotent stem (iPS) cells transforms differentiated cells to an embryonic stem (ES) cell-like state characterized by the acquisition of pluripotency and self-renewal capabilities. We recently demonstrated that human ES and iPS cells share similar mitochondrial properties and bioenergetic metabolism, which are distinct from those of fibroblasts. In the present study, we have applied a global transcriptome profiling approach to compare the mitochondrial-related transcriptional signature upon the loss of self renewal and pluripotency in human ES and iPS cells. This was achieved by inducing in vitro and in vivo spontaneous differentiation. ES and iPS cells showed a similar degree of correlation both in the undifferentiated state and in all the stages of differentiation analyzed, suggesting that their transcriptional similarities are retained upon differentiation. Moreover, comparable induction of transcripts involved in epithelial to mesenchymal transition was observed in both cell types. Analysis of mitochondrial-related nuclear transcripts revealed consensual regulation of genes involved in mitochondrial biogenesis and bioenergetic metabolism upon in vitro differentiation of human ES and iPS cells, while specific differences were identified within in vivo differentiated cells. Significant changes were not detected for antioxidant-related genes. Finally, we formulate a "metabolic state hypothesis" linking mitochondrial state and cellular metabolism to the stage of differentiation. Overall, our data unveil differences and similarities between human ES and iPS cells during spontaneous differentiation and suggest that the study of mitochondrial and metabolic remodeling may reveal key mechanisms underlying the acquisition, maintenance and exit of a self-renewing pluripotent state. PMID- 21305471 TI - Growth factor-defined culture medium for human mesenchymal stem cells. AB - Human bone marrow-derived mesenchymal stem cells (hMSCs) are potential cellular sources of therapeutic stem cells as they have the ability to proliferate and differentiate into a wide array of mesenchymal cell types such as osteoblasts, chondroblasts and adipocytes. hMSCs have been used clinically to treat patients with graft vs. host disease, osteogenesis imperfect, or alveolar cleft, suggesting that transplantation of hMSCs is comparatively safe as a stem cell based therapy. However, conventional culture medium for hMSCs contains fetal bovine serum (FBS). In the present study, we developed a growth factor-defined, serum-free medium for culturing hMSCs. Under these conditions, TGF-beta1 promoted proliferation of hMSCs. The expanded hMSC population expressed the human pluripotency markers SSEA-3, -4, NANOG, OCT3/4 and SOX2. Furthermore, double positive cells for SSEA-3 and a mesenchymal cell marker, CD105, were detected in the population. The potential to differentiate into osteoblasts and adipocytes was confirmed. This work provides a useful tool to understand the basic biological properties of hMSCs in culture. PMID- 21305472 TI - Porcine induced pluripotent stem cells analogous to naive and primed embryonic stem cells of the mouse. AB - Authentic or naive embryonic stem cells (ESC) have probably never been derived from the inner cell mass (ICM) of pig blastocysts, despite over 25 years of effort. Recently, several groups, including ours, have reported induced pluripotent stem cells (iPSC) from swine by reprogramming somatic cells with a combination of four factors, OCT4 (POU5F1)/SOX2/KLF4/c-MYC delivered by retroviral transduction. The porcine (p) iPSC resembled human (h) ESC and the mouse "Epiblast stem cells" (EpiSC) in their colony morphology and expression of pluripotent genes, and are likely dependent on FGF2/ACTIVIN/NODAL signaling, therefore representing a primed ESC state. These cells are likely to advance swine as a model in biomedical research, since grafts could potentially be matched to the animal that donated the cells for re-programming. The objective of the present work has been to develop naive piPSC. Employing a combination of seven reprogramming factors assembled on episomal vectors, we successfully reprogrammed porcine embryonic fibroblasts on a modified LIF-medium supplemented with two kinase inhibitors; CHIR99021, which inhibits GSK-3beta, and PD0325901, a MEK inhibitor. The derived piPSC bear a striking resemblance to naive mESC in colony morphology, are dependent on LIF to maintain an undifferentiated phenotype, and express markers consistent with pluripotency. They exhibit high telomerase activity, a short cell cycle interval, and a normal karyotype, and are able to generate teratomas. Currently, the competence of these lines for contributing to germ-line chimeras is being tested. PMID- 21305473 TI - Reprogramming cell fate to pluripotency: the decision-making signalling pathways. AB - Pluripotency can be defined as the ability of individual cells to initiate all of the lineages of the mature organism in response to signals from the environment. It has long been assumed that during development, pluripotency is progressively and irreversibly lost through a mechanism that requires strict coordination of the signalling pathways involved in cell proliferation, differentiation and migration. However, recent breakthroughs have highlighted evidence that terminally differentiated cells can be reprogrammed into pluripotent stem cells, prompting a re-evaluation of the reversibility of cell differentiation. Generations of pluripotent cells can arise from somatic cells following ectopic expression of specific transcription factors; however, these factors might well not be the unique essential reprogramming factors. Furthermore, they can be the end-point targets of signalling pathways. Indeed, recent evidence shows that modulation of the Wnt/beta-catenin, MAPK/ERK, TGF-beta or PI3K/Akt signalling pathways strikingly enhances somatic-cell reprogramming. Nevertheless, we still know relatively little about the underlying mechanisms by which somatic cells de differentiate to pluripotency. In this review, we provide an overview of the signalling pathways promoting the re-acquisition and maintenance of pluripotency and we discuss the possible mechanisms underlying nuclear reprogramming. PMID- 21305474 TI - Sox17-dependent gene expression and early heart and gut development in Sox17 deficient mouse embryos. AB - Sox17 is a transcription factor that is required for maintenance of the definitive endoderm in mouse embryos. By expression profiling of wild-type and mutant embryos and Sox17-overexpressing hepatoma cells, we identified genes with Sox17-dependent expression. Among the genes that were up-regulated in Sox17-null embryos and down-regulated by Sox17 expressing HepG2 cells is a set of genes that are expressed in the developing liver, suggesting that one function of Sox17 is the repression of liver gene expression, which is compatible with a role for Sox17 in maintaining the definitive endoderm in a progenitor state. Consistent with these findings, Sox17(-/-) cells display a diminished capacity to contribute to the definitive endoderm when transplanted into wild-type hosts. Analysis of gene ontology further revealed that many genes related to heart development were downregulated in Sox17-null embryos. This is associated with the defective development of the heart in the mutant embryos, which is accompanied by localised loss of Myocd-expressing cardiogenic progenitors and the malformation of the anterior intestinal portal. PMID- 21305475 TI - A review of diversity in the evolution and development of cartilage: the search for the origin of the chondrocyte. AB - Mammalian cartilage is a complex and developmentally important tissue type. Outside the mammalian lineage, cartilage may persist as an adult tissue, which shows a much wider diversity of histological structure. Tissues similar to vertebrate cartilage are also found within multiple invertebrate lineages, including mollusks, arthropods, and polychaetes, however the relationship of these tissues to vertebrate cartilage is unknown. Detailed molecular analysis of these invertebrate tissues is necessary to assess the degree of homology, if any, of cartilage throughout the metazoans. The purpose of the following review is to introduce readers to this diversity of cartilage and to synthesize the known genetic interactions that give rise to vertebrate cartilage into the format of a gene regulatory network (GRN). This chondrogenesis GRN highlights a large number of transcription factors known to be expressed during chondrogenesis, whose role in this process has yet to be elucidated. Verification and expansion of this initial GRN will assist in the identification of the core set of the genetic interactions necessary for the specification of the vertebrate chondrocyte. This is the necessary first step in allowing detailed comparison of the molecular signature of vertebrate chondrocytes with that of invertebrates with the ultimate goal of understanding the evolutionary origin of this important skeletal cell type. PMID- 21305476 TI - Effects of strontium-doped bioactive glass on the differentiation of cultured osteogenic cells. AB - There is accumulating evidence that strontium-containing biomaterials have positive effects on bone tissue repair. We investigated the in vitro effect of a new Sr-doped bioactive glass manufactured by the sol-gel method on osteoblast viability and differentiation. Osteoblasts isolated from foetal mouse calvaria were cultured in the presence of bioactive glass particles; particles were undoped (B75) or Sr-doped with 1 wt.% (B75-Sr1) and 5 wt.% (B75-Sr5). Morphological analysis was carried out by contrast-phase microscopy and scanning electron microscopy (SEM). Cell viability was evaluated by the MTS assay at 24 h, 48 h and 72 h. At 24 h, day 6 and day 12, osteoblast differentiation was evaluated by assaying alkaline phosphatase (ALP) activity, osteocalcin (OC) secretion and gene expression of various bone markers, using Real-Time-PCR. Alizarin Red staining and ALP histoenzymatic localisation were performed on day 12. Microscopic observations and MTS showed an absence of cytotoxicity in the three investigated bioactive glasses. B75-Sr5 particles in cell cultures, in comparison with those of B75 and B75-Sr1, resulted in a significant up-regulation of Runx2, Osterix, Dlx5, collagen I, ALP, bone sialoprotein (BSP) and OC mRNA levels on day 12, which was associated with an increase of ALP activity on day 6 and OC secretion on day 12. In conclusion, osteoblast differentiation of foetal mouse calvarial cells was enhanced in the presence of bioactive glass particles containing 5 wt.% strontium. Thus, B75-Sr5 may represent a promising bone grafting material for bone regeneration procedures. PMID- 21305477 TI - Comparative study assessing effects of sonic hedgehog and VEGF in a human co culture model for bone vascularisation strategies. AB - The morphogen sonic hedgehog (Shh) seems to mediate adult repair processes in bone regeneration and vascularisation. In this study we investigated the effects of Shh on co-cultures consisting of human primary osteoblasts and outgrowth endothelial cells in terms of angiogenic activation and vessel maturation in comparison to the treatment with the commonly used proangiogenic factor, VEGF. Both, stimulation with VEGF or Shh, leads to an increase in the formation of microvessel-like structures compared to untreated controls. In contrast to VEGF, proangiogenic effects by Shh could already be observed after 24 h of treatment. Nevertheless, after 14 days the angiogenic activity of OEC was comparable in VEGF or Shh-treated co-cultures. Furthermore, Shh and VEGF resulted in different growth factor expression or release profiles. Compared to VEGF, Shh stimulates also the expression and secretion of angiopoietins which was detected as early as 24 h of treatment. Moreover, smooth muscle cell-related markers, such as alpha smooth muscle actin, desmin and myocardin, as well as basement membrane components were clearly upregulated in response to Shh treatment compared to VEGF or untreated controls. In terms of growth factors relevant for vessel stabilisation and maturation increased levels of PDGF-BB, angiopoietin-1 and TGF beta were observed in cell culture supernatants when treated with Shh. This was in accordance with higher levels of smooth muscle actin in Shh-treated samples indicating the potential of Shh to improve the angiogenic activity and vessel stabilisation of human tissue engineered constructs. Experiments using cyclopamine, a Shh pathway inhibitor, blocked the effects of Shh. PMID- 21305478 TI - Cardiology Journal - five years later. PMID- 21305479 TI - Practical and updated guidelines on performing meta-analyses of non-randomized studies in interventional cardiology. AB - The use of meta-analysis in medicine is widespread nowadays, particularly in the field of interventional cardiology. Meta-analysis is a statistical approach aiming to combine date from a large number of patients from randomized clinical studies and/or non-randomized registries so as to obtain a pooled estimate of the results and to answer specific research questions. It is important to take the correct methodological approach in order to reach unbiased conclusions. In this article, we provide an updated review of the methodological approaches needed to perform meta-analyses of non-randomized data, and we suggest a simplified check list of items to be considered when attempting to deploy this kind of meta analysis. PMID- 21305480 TI - Prognostic significance of QRS duration and morphology. AB - QRS duration and morphology, evaluated via a standard 12-lead electrocardiogram (ECG), represent an opportunity to derive useful prognostic information regarding the risk of subsequent cardiac events or therapeutic outcomes. Prolonged QRS duration, and the presence of intraventricular conduction abnormalities, usually indicate the presence of changes in the myocardium due to underlying heart disease. Prolonged QRS duration is often associated with depressed ejection fraction or enlarged left ventricular volumes, but several studies have demonstrated that this simple ECG measure provides independent prognostic value, after adjusting for relevant clinical covariates. Post-infarction patients with prolonged QRS duration have a significantly increased risk of mortality, although data associating QRS prolongation specifically with sudden death is less supportive. In non-ischemic cardiomyopathy, there is no evidence that QRS duration has prognostic significance in predicting mortality or sudden death. Prolonged QRS duration, and especially presence of left bundle branch block, seems to predict a benefit from cardiac resynchronization therapy in both ischemic and non-ischemic cardiomyopathy patients. Therefore, QRS duration and morphology should not only be considered a predictor of death or sudden death in patients after myocardial infarction, and in those suspected of coronary artery disease, but also as a predictor of benefit from cardiac resynchronization therapy in patients with heart failure, whether of an ischemic or non-ischemic origin. PMID- 21305482 TI - Fractal dimensions of skin microcirculation flow in subjects with familial predisposition or newly diagnosed hypertension. AB - BACKGROUND: Fractal analysis has been shown to be capable of characterizing irregular time series generated in non-linear systems. Fluctuations in skin flow signals have a fractal nature, but to date there has been no analysis of subjects with hypertension. The aim of this study is to assess the fractal dimensions of skin microcirculation flows in subjects with a familial predisposition or newly diagnosed hypertension. METHODS: A four-minutes rest flow (RF), minimal flow (BZ) during three-minutes ischemia and eight-minutes heat flow (HF) were recorded (using laser Doppler flowmetry) in patients with untreated hypertension, and in normotensives with no [NT(-)] or with a familial predisposition to hypertension [NT(+)]. Average one-minute surface areas under the curve of flow records and box dimensions (D) were calculated. Anova Kruskall-Wallis, c2 statistic and multivariate reverse regression analysis were used for calculation. RESULTS: We studied 70 people (average age 36.1 +/- 10.3 years, 39 men). Hypertensives (n = 31) had significantly higher values of both clinical blood pressure and 24-hour ambulatory blood pressure, body mass index, glucose, triglycerides and insulin than the NT(-), (n = 17) and NT(+), (n = 22) groups. Mean values of flows and surface area under the curve of RF, BZ, HF records, D RF and D HF were comparable in studied groups, but D BZ differed (1.13 +/- +/- 0.05 vs 1.15 +/- 0.05 vs 1.11 +/- 0.05, respectively; p = 0.04). A family history of hypertension, insulin level and variability of 24-hour diastolic blood pressure were significant predictors of D BZ lower values in the multiple regression model. CONCLUSIONS: Subjects with a familial predisposition to hypertension reveal altered homeodynamics of microvascular flow, with diminished chaotic ischemic flow. PMID- 21305481 TI - Prevalence and variables predictive of depressive symptoms in patients hospitalized for heart failure. AB - BACKGROUND: Our study set out to determine the prevalence of depressive symptoms and variables that influence its presence in patients hospitalized for heart failure. Depression is associated with a substantially increased risk of developing heart failure in individuals at risk, and has been related to adverse outcomes in patients with established heart failure. It is important to determine its prevalence in different populations and assess related causes. METHODS: We conducted a cross-sectional study of 103 patients with heart failure, admitted to public hospital, via a questionnaire that evaluates clinical variables, socio demographics and we applied the Beck Depression Inventory to determine the prevalence of depressive symptoms and predictors of their presence. We used the chi2, Student test and considered significant when < 0.05 and subjected to logistic regression analysis when between 0.05 and 0.1. RESULTS: The mean age of the patients in our study was 65.4 +/- 13.6. Depressive symptoms were present in 69 (67%) patients: 35 (34%) had mild depressive symptoms, 22 (21.3%) had moderate symptoms and 12 (11.6%) patients presented severe symptoms. Marital status was significant when analyzed, and the predictors of depressive symptoms were marital status, sex, living arrangements and heart failure etiology. CONCLUSIONS: Because depressive symptoms in patients hospitalized for heart failure are very common, it is important to detect these disorders. The prevalence of these varies according to socio-demographic and clinical data, and these factors should be taken into consideration when planning future studies, as well as screening and intervention programs for co-morbid depressive disorders in hospitalized patients with heart failure. PMID- 21305483 TI - Efficacy of low energy rectilinear biphasic cardioversion for regular atrial tachyarrhythmias. AB - BACKGROUND: External, rectilinear biphasic cardioversion (RBC), as against monophasic cardioversion, requires lower energy and has been documented to be more effective in restoring sinus rhythm in atrial fibrillation (AF). There is, however, limited data on the optimal protocol of low energy RBC in atrial flutter (AFl) and regular atrial tachyarrhythmias (AT). METHODS AND RESULTS: A prospective, single-center study was conducted, wherein 50 consecutive patients (mean age: 70.8 +/- 8.7; 24 males) undergoing cardioversion of persistent or paroxysmal AFl or AT were randomized into two protocols of subsequent RBC shocks: 1) 10 J, 20 J, 50 J, 100 J, 200 J or 2) 20 J, 50 J, 100 J, 200 J. Initial energy was effective in 9/28 (32%) patients using Protocol 1 and in 12/22 (52%) patients using Protocol 2 (NS). In 9/12 patients with pacemakers, energy of 10 J or 20 J restored sinus or atrial-paced rhythm. Mean cumulative energy and number of shocks was 67 +/- 70 J vs 64 +/- 62 J (NS) and 2.0 +/- 0.8 vs 1.6 +/- 0.7 (p = 0.05) for both protocols, respectively. Mean successful energy was higher for AFl patients than for AT patients 66 +/- 49 J vs 30 +/- 19 J, p < 0.04. In approximately 25% of patients, conversion of AFl/AT into AF was observed after initial energy. CONCLUSIONS: Low energy RBC is effective in 32-52% of patients with AFl/AT. Energy of 50 J is effective in 73% of patients and should be recommended as an initial energy in regular AT. Low energy RBC may be especially indicated in patients with pacemakers. PMID- 21305484 TI - Hemodynamic response in one session of strength exercise with and without electrostimulation in heart failure patients: A randomized controlled trial. AB - BACKGROUND: Studies have investigated the influence of neuromuscular electrostimulation on the exercise/muscle capacity of patients with heart failure (HF), but the hemodynamic overload has never been investigated. The aim of our study was to evaluate the heart rate (HR), systolic and diastolic blood pressures in one session of strength exercises with and without neuromuscular electrostimulation (quadriceps) in HF patients and in healthy subjects. METHODS: Ten (50% male) HF patients and healthy subjects performed three sets of eight repetitions with and without neuromuscular electrostimulation randomly, with one week between sessions. Throughout, electromyography was performed to guarantee the electrostimulation was effective. The hemodynamic variables were measured at rest, again immediately after the end of each set of exercises, and during the recovery period. RESULTS: Systolic and diastolic blood pressures did not change during each set of exercises among either the HF patients or the controls. Without electrostimulation: among the controls, the HR corresponding to the first (85 +/- 13 bpm, p = 0.002), second (84 +/- 10 bpm, p < 0.001), third (89 +/- 17, p < 0.001) sets and recuperation (83 +/- 16 bpm, p = 0.012) were different compared to the resting HR (77 bpm). Moreover, the recuperation was different to the third set (0.018). Among HF patients, the HR corresponding to the first (84 +/- 9 bpm, p = 0.041) and third (84 +/- 10 bpm, p = 0.036) sets were different compared to the resting HR (80 +/- 7 bpm), but this increase of 4 bpm is clinically irrelevant to HF. With electrostimulation: among the controls, the HR corresponding to the third set (84 +/- 9 bpm) was different compared to the resting HR (80 +/- 7 bmp, p = 0.016). Among HF patients, there were no statistical differences between the sets. The procedure was well tolerated and no subjects reported muscle pain after 24 hours. CONCLUSIONS: One session of strength exercises with and without neuromuscular electrostimulation does not promote a hemodynamic overload in HF patients. PMID- 21305485 TI - Abnormal heart rate recovery after exercise predicts coronary artery disease severity. AB - BACKGROUND: Slow heart rate recovery (HRR) after exercise is considered to represent impaired parasympathetic tone and to be a predictor of all-cause and cardiovascular mortality, but the independent value of abnormal HRR in predicting the presence and severity of coronary artery disease (CAD) is unknown. The aim of this study was to evaluate these relationships in our patients. METHODS: This prospective cross-sectional study included 208 patients (67.3% men), aged 34 to 74 (mean 53) years. Patients who had an ischemic response during symptom-limited exercise testing underwent selective coronary angiography. The value for HRR was defined as the decrease in heart rate from peak exercise to one minute after the exercise ceased. Eighteen beats per minute was defined as the lowest normal value for HRR. RESULTS: Significant CAD was detected in 140 (67.3%) patients. There were 66 (31.7%) patients with an abnormal HRR. In multivariable logistic regression analysis adjusted for established CAD risk factors, abnormal HRR was independently correlated with the extent of major epicardial coronary involvement (p = 0.04). The sensitivity, specificity, positive and negative predictive values, and accuracy of abnormal HRR for predicting extensive CAD were 48%, 83.3%, 72.7%, and 63.4%, respectively. There was also a significant correlation between HRR one minute after exercise and smoking (p = 0.004), chronotropic variables (p = 0.001), and the calculated risk score for the exercise test (p = 0.03). There was no significant correlation between HRR and other risk factors including age and gender, left ventricular systolic function, and history of myocardial infarction. CONCLUSIONS: There is a significant correlation between abnormal post-exercise HRR at one minute and the extent of major epicardial coronary involvement. PMID- 21305486 TI - Plasma homocysteine and the severity of heart failure in patients with previous myocardial infarction. AB - BACKGROUND: Homocysteine is considered to be a risk factor, or an indicator of risk, for the development of cardiovascular disease. Little data is available on its significance in patients with previous myocardial infarction. The aim of our study was to assess the plasma level of homocysteine and its relationship with the severity of heart failure in patients with chronic myocardial infarction. METHODS: We studied 144 patients with previous myocardial infarction. Patients were divided into two groups according to the presence or absence of heart failure, as certified by clinical evidence of heart failure and by echocardiographic criteria for left ventricular systolic dysfunction. RESULTS: Of the patients with prior myocardial infarction (144; 63.6 +/- 9.6 years) included in the study, 65 had heart failure. The mean level of homocysteine was significantly higher in the heart failure group (18.9 mmol/L) than in the non heart failure group (14.1 mmol/L; p <= 0.001). Our study demonstrated that there is a statistically significant correlation between homocysteine plasma levels and the severity of heart failure in patients with prior myocardial infarction. Homocysteine levels have proved to become higher with NYHA class progression. A significant cross-sectional correlation has been assessed between homocysteine and tissue Doppler echocardiography parameters. CONCLUSIONS: Increased plasma homocysteine levels independently correlate with the severity of heart failure in patients with chronic myocardial infarction. We suggest that homocysteine can be used in clinical practice as a valuable heart failure risk marker in patients with chronic myocardial infarction. PMID- 21305487 TI - Postural orthostatic tachycardia syndrome following Lyme disease. AB - BACKGROUND: A subgroup of patients suffering from Lyme disease (LD) may initially respond to antibiotics only to later develop a syndrome of fatigue, joint pain and cognitive dysfunction referred to as 'post treatment LD syndrome'. We report on a series of patients who developed autonomic dysfunction in the form of postural orthostatic tachycardia syndrome (POTS). METHODS: All of the patients in this report had suffered from LD in the past and were successfully treated with antibiotics. All patients were apparently well, until years later when they presented with fatigue, cognitive dysfunction and orthostatic intolerance. These patients were diagnosed with POTS on the basis of clinical features and results of the tilt table (HUTT) testing. RESULTS: Five patients (all women), aged 22-44 years, were identified for inclusion in this study. These patients developed symptoms of fatigue, cognitive dysfunction, orthostatic palpitations and either near syncope or frank syncope. The debilitating nature of these symptoms had resulted in lost of the employment or inability to attend school. Three patients were also suffering from migraine, two from anxiety and depression and one from hypertension. All patients demonstrated a good response to the employed treatment. Four of the five were able to engage in their activities of daily living and either resumed employment or returned to school. CONCLUSIONS: In an appropriate clinical setting, evaluation for POTS in patients suffering from post LD syndrome may lead to early recognition and treatment, with subsequent improvement in symptoms of orthostatic intolerance. PMID- 21305488 TI - Cardiovascular causes of death in an east African country: an autopsy study. AB - BACKGROUND: The spectrum of cardiovascular diseases varies between countries. Data from east Africa is scarce, but important in formulating disease management strategies. The aim of this study was to describe the spectrum of cardiovascular causes of death in Kenya. METHODS: One hundred and thirty four autopsy cases of cardiovascular related deaths examined at the Department of Human Anatomy, University of Nairobi, from December 2005 to November 2009 were analyzed for disease type, age and gender distribution. Only cases in which cardiovascular disease was the most likely cause of death were included. Data was analyzed using SPSS version 15.0 for Windows and presented using tables and bar graphs. RESULTS: Cardiovascular causes comprised 13.2% of all autopsy cases. Common conditions included myocardial infarction (18.7%), cardiomyopathy (17.2%), subarachnoid hemorrhage (15.7%), pulmonary thromboembolism (14.2%), ruptured aortic aneurysm (11.2%) and hypertensive heart disease (9.0%). Infective pericarditis and rheumatic heart disease comprised 7.5% and 6.7%, respectively. Mean age was 50.4 years, peaking at 40-60 years, with 56.7% aged 50 years and younger. Male: female ratio was 2.7:1. CONCLUSIONS: Cardiovascular disease contributes more than 13% of overall mortality in Kenya. Myocardial infarction is the commonest, while rheumatic heart disease is the rarest. It is predominantly male and mainly affects those aged under 50 years. This suggests that non-communicable diseases, while predominant, overlap with infectious conditions as causes of cardiovascular mortality. A search for, and the prevention of, risk factors, combined with prudent management of infection, are recommended. PMID- 21305489 TI - An isolated fistula between the right pulmonary artery and the right pulmonary vein: an unusual cause of stroke in a young female. AB - We describe the case of a 29 year-old female who presented with right sided hemiparesis with global aphasia. She had a history of transient ischemic attack with migraine headaches. Diagnostic workup revealed a right to left cardiac shunt. An isolated right pulmonary artery to left pulmonary vein fistula was diagnosed on pulmonary angiogram. The fistula was occluded successfully by cardiac catheterization. Early recognition and intervention is indicated to prevent further complications. PMID- 21305490 TI - The treatment of acute myocardial infarction due to the occlusion of the left main coronary disease. AB - Acute myocardial infarction (AMI) due to the occlusion of the left main coronary artery (LMCA) is a rare but serious condition in the era of percutaneus coronary intervention (PCI). Even more rare is AMI involved with both LMCA and its branches like trifurcartion or bifurcation: this is challenging for interventional cardiologists, because it involves the extension of the myocardium complicated by cardiogenic shock and its technical difficulties. Trifurcating coronary artery disease is a complex atherosclerotic process involving the origin of one or more of three side branches arising from a left main coronary vessel or trunk, with or without the involvement of LMCA itself. There is no classification or standardized methodology to treat LMCA disease in elective percutaneous intervention procedures. Furthermore, acute myocardial infarction presenting with left main coronary artery trifurcation lesion seems to be more troublesome, especially in young patients. Few series of PCI on significant lesions of the left main trifurcations have been described. Herein, we describe a patient who successfully underwent PCI and was supported by post intravascular ultrasound sonography and multislice computed angiography (MSCA), and after an uneventful follow-up with MSCA is now on the ninth month. PMID- 21305491 TI - Stress-induced cardiomyopathy complicating severe babesiosis. AB - A post-menopausal lady with severe babesiosis developed a basal-type stress induced cardiomyopathy. Left ventricular function normalized at three months. We believe this is the first reported case of stress cardiomyopathy complicating severe babesiosis. Cardiac biomarker elevation disproportionate to the area of myocardial dysfunction, electrocardiographic changes, the patient's clinical condition, and close follow-up of left ventricular function parameters are all vital in diagnosing stress cardiomyopathy and may exclude the need for coronary angiography. There may be a possible association between severe babesiosis and stress cardiomyopathy. PMID- 21305492 TI - Late emergency arterial duct stenting in a patient with tetralogy of Fallot and occluded Blalock-Taussig shunt. AB - Over the last decade or so, stent implantation to the arterial duct has achieved acceptance as an alternative to aortopulmonary shunt procedure. We present the case of a patient with tetralogy of Fallot with diminished pulmonary flow and complete proximal occlusion of a right-sided Blalock-Taussig shunt. Surgical repair was not possible because of relative contraindications, and the interventional shunt recanalisation attempt was unsuccessful. The coronary stent was implanted into arterial duct. This resulted in oxygen saturation increase with normal contrast flow to the left pulmonary artery and right pulmonary artery (prior to the procedure we suspected non-confluent pulmonary artery). This brief report evaluates the feasibility of this new therapeutical option in such special patients with duct-dependent pulmonary blood flow. PMID- 21305493 TI - Role of multi-slice computed tomography in the recognition of pericardial cyst. AB - A pericardial cyst is, according to the definition, a collection of fluid or blood in the pericardial space (inside the pericardial sac) around the heart. New visualization methods can help in the non-invasive diagnosis of pericardial cysts. Based on a presented case, we conclude that multi-slice computed tomography can have a great impact on the detection of pericardium diseases such as a pericardial cyst. PMID- 21305494 TI - A failed case of percutaneous septal closure of fenestrated atrial septal defect. AB - A patient presenting with a history of palpitation and exertional dyspnea was initially diagnosed with two separate secundum-type atrial septal defects by transesophageal echocardiography. Subsequent transesophageal echocardiography, after failure of closure with two separate closure devices, showed another defect and an ongoing left to right shunt. During surgery, more defects were observed. The defects were successfully repaired using pericardial patch without incident. PMID- 21305495 TI - Complicated Holter tracing with an incidence of inappropriate mode switch due to sensing abnormalities in a patient with dual-chamber pacemaker. AB - 24-hour Holter monitoring of a 59 year-old man with DDDR pacemaker (programmed mode: DDD) implanted for sick sinus syndrome with paroxysmal atrial fibrillation was performed one month after implantation, due to palpitations. Several episodes of rapid pacing of decreasing rate were detected. Intracardiac recording stored in the pacemaker memory had shown episodes of atrial lead oversensing, which led to the mode switch, resulting in DDIR mode. Signals which caused oversensing were not seen in Holter tracing. PMID- 21305496 TI - Catheter-based renal sympathetic denervation: a targeted approach to resistant hypertension. PMID- 21305497 TI - Optimal strategies for the management of antiplatelet and anticoagulation medications prior to cardiac device implantation. AB - Choosing the optimal management strategy for antiplatelet and anticoagulation medications at the time of cardiac device implantation can be challenging. Simply withholding or reversing these medications puts patients at risk of subsequent thromboembolic events. Equally, continuing these medications may unnecessarily increase the risk of bleeding complications. This article summarizes recent findings and provides compelling evidence challenging current recommendations outlined by various professional organizations. PMID- 21305498 TI - Polish cardiology started in Lodz 60 years ago - 1950-2010. PMID- 21305499 TI - Electrocardiographic evaluation of successful reperfusion: Time to revisit. PMID- 21305500 TI - Mechanisms and clinical relevance of TRAIL-triggered responses in the synovial fibroblasts of patients with rheumatoid arthritis. AB - OBJECTIVE: Results of studies in mice suggest a protective role for TRAIL in arthritis. The aim of this study was to investigate the role of TRAIL in patients with rheumatoid arthritis (RA). METHODS: In the present study, we compared RA fibroblast-like synoviocytes (FLS) that were resistant or sensitive to TRAIL induced apoptosis and the expression of TRAIL receptors in these cells, and also investigated the clinical features of the patients from whom the FLS were derived. Furthermore, we evaluated the levels of TRAIL and its soluble decoy receptor osteoprotegerin (OPG) in patients with RA, patients with osteoarthritis (OA), and patients with spondylarthritis (SpA). RESULTS: Sensitivity to TRAIL induced apoptosis varied in FLS from different patients, and the severity of disease in patients with RA was inversely correlated with the susceptibility of their FLS to TRAIL-induced apoptosis. TRAIL-sensitive cells expressed significantly lower levels of TRAILR-1, and silencing of TRAILR-1 increased TRAIL induced apoptosis in RA FLS. TRAIL levels were elevated in the arthritic joints of patients with established RA, and TRAIL levels in the synovial fluid of these patients were elevated compared with levels in the synovial fluid of patients with OA or SpA. At baseline, a low OPG-to-TRAIL ratio in the sera of patients with early RA was associated with a better evolution of disease activity, but high serum levels of TRAIL at followup were associated with joint damage. CONCLUSION: These findings suggest that TRAIL has a dual role in RA, and that the resistance of RA FLS to TRAIL-induced apoptosis is associated with a disease promoting activity of TRAIL in RA. PMID- 21305501 TI - Interferon regulatory factor 5 is critical for the development of lupus in MRL/lpr mice. AB - OBJECTIVE: Interferon regulatory factor 5 (IRF-5) is a transcription factor that mediates intracellular signals activated by engagement of Toll-like receptors (TLRs). IRF5 polymorphisms are associated with an increased or decreased risk of systemic lupus erythematosus (SLE) in various human populations, but the precise role of IRF5 in SLE development is not fully understood. This study was undertaken to examine the role of IRF5 in the development of murine lupus. METHODS: We crossed gene-targeted IRF5-deficient (IRF5(-/-) ) mice with MRL/MpJ lpr/lpr (MRL/lpr) mice and examined the progeny for survival, glomerulonephritis, autoantibody levels, immune system cell populations, and dendritic cell function. RESULTS: IRF5(-/-) MRL/lpr mice survived longer than control IRF5(+/+) MRL/lpr mice and displayed only very mild glomerulonephritis. Autoantibodies to SLE related nuclear antigens were lower in IRF5(-/-) MRL/lpr mouse serum, and numbers of activated CD4+ T cells were reduced in the spleen. Splenic DCs from IRF5(-/-) MRL/lpr mice produced lower levels of inflammatory cytokines when treated in vitro with TLR-7 or TLR-9 ligands or immune complexes. Interferon-alpha production in response to CpG was also decreased. CONCLUSION: Our results show that IRF5 is a crucial driver of lupus development in mice, and indicate that IRF5 may be an attractive new target for therapeutic intervention to control disease in SLE patients. PMID- 21305502 TI - Temporal relationship between serum adipokines, biomarkers of bone and cartilage turnover, and cartilage volume loss in a population with clinical knee osteoarthritis. AB - OBJECTIVE: The association of obesity with both hand and knee osteoarthritis (OA) is suggestive of a link between dysfunctional metabolism and joint integrity. Given the role of adipokines in mediating bone and cartilage homeostasis, we undertook this study to examine the relationship between adipokines and bone and cartilage biomarkers in a population of subjects with OA, and to determine whether adipokine levels predicted 2-year cartilage integrity. METHODS: One hundred seventeen subjects underwent magnetic resonance imaging at baseline and at 2-year followup. Cartilage volume was assessed from these images. Serum adipokine levels were measured at baseline. Bone and cartilage biomarker levels were measured at baseline and at 2-year followup. Linear regression was used to examine the relationship between baseline levels of adipokines and adipokine receptors (leptin, soluble leptin receptor [sOB-Rb], resistin, and adiponectin) and changes in levels of bone biomarkers (osteocalcin, N-terminal type I procollagen propeptide [PINP], C-terminal crosslinking telopeptide of type I collagen, N-terminal crosslinking telopeptide of type I collagen, or C-terminal crosslinking telopeptide of type I collagen generated by matrix metalloproteinases), levels of cartilage biomarkers (cartilage oligomeric matrix protein, N-terminal type IIA procollagen propeptide [PIIANP], or C2C), cartilage defects score, and cartilage volume over 2 years. RESULTS: Baseline leptin was associated with increased levels of bone formation biomarkers (osteocalcin and PINP) over 2 years, while sOB-Rb was associated with reduced levels of osteocalcin. Baseline sOB-Rb was associated with reduced levels of the cartilage formation biomarker PIIANP, an increased cartilage defects score, and increased cartilage volume loss over 2 years. All results were independent of age, sex, and body mass index. CONCLUSION: The findings of this study support the concept that serum adipokines may provide a nonmechanical link between obesity and joint integrity (which may be mediated by bone and cartilage turnover) that subsequently results in changes to the cartilage defects score and cartilage volume loss. This may facilitate our understanding of the mechanisms by which obesity is involved in the pathogenesis of OA. PMID- 21305503 TI - Association of HTR2A polymorphisms with chronic widespread pain and the extent of musculoskeletal pain: results from two population-based cohorts. AB - OBJECTIVE: The aim of the current study was to investigate whether genetic variation in genes across the serotoninergic system is associated with chronic widespread pain (CWP) and the number of pain sites reported. METHODS: A discovery cohort, with pain data at 3 time points, was used to investigate genetic associations with 2 phenotypes: 1) CWP (at >= 2 time points; n = 164) compared with pain-free controls (at 3 time points; n = 172), and 2) the maximum number of pain sites reported at any 1 of the 3 time points (range of sites 0-29; n = 989). A cohort of 2,285 men for whom a DNA sample and pain data were available (including 203 CWP cases and 929 controls) was used for validation. Pairwise tagging (r(2) > 0.8) single-nucleotide polymorphisms (SNPs) were genotyped. Logistic and zero-inflated negative binomial regression analyses were used to test for SNP associations with CWP and the number of pain sites, respectively. RESULTS: SNPs in HTR2A were associated with both pain phenotypes in the discovery cohort, and a number of these SNP associations were replicated in the validation cohort, some of which were attenuated after adjustment for depression. There was an increased likelihood of having CWP in subjects with 1 or 2 copies of the T allele of rs12584920 (odds ratio [OR] 1.64, 95% confidence interval [95% CI] 1.01 2.60 [P = 0.03] in the discovery cohort, and OR 1.46, 95% CI 1.07-2.00 [P = 0.018] in the validation cohort). A similar association was observed between rs17289394 and the maximum number of pain sites reported in both cohorts. Results from a meta-analysis of the data from the 2 cohorts further strengthened these findings. CONCLUSION: The findings of this study support the role of HTR2A in the genetic predisposition to musculoskeletal pain. PMID- 21305504 TI - Alterations in type I hemidesmosome components suggestive of epigenetic control in the salivary glands of patients with Sjogren's syndrome. PMID- 21305505 TI - Erroneous augmentation of multiplex assay measurements in patients with rheumatoid arthritis due to heterophilic binding by serum rheumatoid factor. AB - OBJECTIVE: Serum rheumatoid factor (RF) and other heterophilic antibodies potentially interfere with antibody-based immunoassays by nonspecifically binding detection reagents. The purpose of this study was to assess whether these factors confound multiplex-based immunoassays, which are used with increasing frequency to measure cytokine and chemokine analytes in patients with rheumatoid arthritis (RA). METHODS: We performed multiplex immunoassays using different platforms to measure analyte concentrations in RA patient samples. Samples were depleted of RF by column-based affinity absorption or were exposed to agents that block heterophilic binding activity. RESULTS: In RA patients with high-titer RF, 69% of analytes demonstrated at least a 2-fold stronger multiplex signal in non-RF depleted samples as compared to RF-depleted samples. This degree of erroneous signal amplification was less frequent in low-titer RF samples (17% of analytes; P < 0.0000001). Signal amplification by heterophilic antibodies was blocked effectively by HeteroBlock (>= 150 MUg/ml). In 35 RA patients, multiplex signals for 14 of 22 analytes were amplified erroneously in unblocked samples as compared to blocked samples (some >100-fold), but only in patients with high-titer RF (P < 0.002). Two other blocking agents, heterophilic blocking reagent and immunoglobulin-inhibiting reagent, also blocked heterophilic activity. CONCLUSION: All multiplex protein detection platforms we tested exhibited significant confounding by RF or other heterophilic antibodies. These findings have broad-reaching implications in the acquisition and interpretation of data derived from multiplex immunoassay testing of RA patient serum and possibly also in other conditions in which RF or other heterophilic antibodies may be present. Several available blocking agents effectively suppressed this erroneous signal amplification in the multiplex platforms tested. PMID- 21305506 TI - Nicotine-induced differential modulation of autoimmune arthritis in the Lewis rat involves changes in interleukin-17 and anti-cyclic citrullinated peptide antibodies. AB - OBJECTIVE: Rheumatoid arthritis (RA) is a debilitating autoimmune disease, and smoking is an important environmental factor in a subset of RA patients. A role of the cholinergic antiinflammatory pathway in autoimmune inflammation is increasingly being realized. Nicotine is a major component of cigarette smoke, and it stimulates the alpha7 nicotinic acetylcholine receptors. Therefore, defining the mechanisms underlying the immunomodulatory effects of nicotine on arthritis is of high relevance. The purpose of this study was to address this issue using the rat adjuvant-induced arthritis (AIA) model of human RA. METHODS: Lewis rats were immunized subcutaneously with heat-killed Mycobacterium tuberculosis H37Ra for disease induction. Rats were treated with nicotine intraperitoneally either before (pretreatment) or after (posttreatment) the onset of AIA. Control rats received the vehicle (buffer) in place of nicotine. The severity of arthritis was assessed and graded. The draining lymph node cells were tested for T cell proliferative and cytokine responses against the disease related antigen mycobacterial heat-shock protein 65. The sera were tested for anti-cyclic citrullinated peptide (anti-CCP) antibodies and anti-mycobacterial Hsp65 antibodies. RESULTS: Nicotine pretreatment aggravated the arthritis, whereas nicotine posttreatment suppressed the disease. This altered severity of AIA directly correlated with the levels of the anti-CCP antibodies, of the Th1/Th17 cytokines, and of the corresponding dendritic cell-derived cytokines. The majority of these effects on cellular responses could be replicated in vitro. CONCLUSION: Nicotine-induced modulation of AIA involves specific alterations in the disease-related cellular and humoral immune responses in AIA. These results are of significance in advancing our understanding of the pathogenesis of RA. PMID- 21305508 TI - In vivo effects of the anti-interleukin-6 receptor inhibitor tocilizumab on the B cell compartment. AB - OBJECTIVE: Interleukin-6 (IL-6) receptor inhibition by tocilizumab was recently licensed for the treatment of rheumatoid arthritis (RA). IL-6 induces in vitro differentiation of B cells into antibody-forming cells; however, the in vivo effects of IL-6 inhibition on the B cell compartment are currently not known. The purpose of this study was to examine this feature. METHODS: Sixteen patients with active RA were treated in an open-label study with tocilizumab (8 mg/kg every 4 weeks). Immunophenotyping was performed at baseline, week 12, and week 24. RESULTS: Memory B cell subsets declined significantly during tocilizumab therapy. Preswitch memory B cells decreased from a median of 19.6% to 12.3% at week 24 and postswitch memory B cells declined from a median of 18.6% to 15.0% at week 24 (P = 0.04). In parallel, CD19+IgA+ and CD19+IgG+ B cells decreased significantly. The proportion of IgA-expressing B cells fell from a median of 9.2% at baseline to 4.3% at week 12 and to 3.6% at week 24 (P = 0.01). IgG+ B cells declined from a median of 6.7% at baseline to 4.9% at week 12 (P = 0.007) and 2.8% at week 24 (P = 0.01). In parallel, serum levels of IgA and IgG were significantly diminished at week 24 (P < 0.05). There was a good correlation between relative and absolute numbers of IgA+ B cells with serum IgA at week 24. CONCLUSION: Tocilizumab induced a significant reduction in the frequency of peripheral preswitch and postswitch memory B cells. In addition, the number of IgG+ and IgA+ B cells declined and correlated well with reduced serum immunoglobulin levels. The data indicate that IL-6 blockade affects the B cell hyperreactivity in RA patients. PMID- 21305507 TI - Low frequency of primary lipid screening among medicare patients with rheumatoid arthritis. AB - OBJECTIVE: Although studies have demonstrated suboptimal preventive care in RA patients, performance of primary lipid screening (i.e., testing before cardiovascular disease [CVD], CVD risk equivalents, or hyperlipidemia is evident) has not been systematically examined. The purpose of this study was to examine associations between primary lipid screening and visits to primary care providers (PCPs) and rheumatologists among a national sample of older RA patients. METHODS: This retrospective cohort study examined a 5% Medicare sample that included 3,298 RA patients without baseline CVD, diabetes mellitus, or hyperlipidemia, who were considered eligible for primary lipid screening during the years 2004-2006. The outcome was probability of lipid screening by the relative frequency of primary care and rheumatology visits, or seeing a PCP at least once each year. RESULTS: Primary lipid screening was performed in only 45% of RA patients. Overall, 65% of patients received both primary and rheumatology care, and 50% saw a rheumatologist as often as a PCP. Any primary care predicted more lipid screening than lone rheumatology care (26% [95% confidence interval (95% CI) 21-32]). As long as a PCP was involved, performance of lipid screening was similar regardless of the balance between primary and rheumatology visits (44-48% [95% CI 41-51]). Not seeing a PCP at least annually decreased screening by 22% (adjusted risk ratio 0.78 [95% CI 0.71-0.84]). CONCLUSION: Primary lipid screening was performed in fewer than half of eligible RA patients, highlighting a key target for CVD risk reduction efforts. Annual visits to a PCP improved lipid screening, although performance remained poor (51%). Half of RA patients saw their rheumatologist as often or more often than they saw a PCP, illustrating the need to study optimal partnerships between PCPs and rheumatologists for screening patients for CVD risks. PMID- 21305509 TI - Looking beyond incidence in the relationship between anti-tumor necrosis factor therapy and malignancy. PMID- 21305510 TI - Clinical Images: Hippokrates confirmed by positron emission tomography. PMID- 21305512 TI - Hypoxia activates the notch signaling pathway in cells of the intervertebral disc: implications in degenerative disc disease. AB - OBJECTIVE: To investigate whether hypoxia regulates Notch signaling, and whether Notch plays a role in intervertebral disc cell proliferation. METHODS: Reverse transcription-polymerase chain reaction and Western blotting were used to measure expression of Notch signaling components in intervertebral disc tissue from mature rats and from human discs. Transfections were performed to determine the effects of hypoxia and Notch on target gene activity. RESULTS: Cells of the nucleus pulposus and annulus fibrosus of rat disc tissue expressed components of the Notch signaling pathway. Expression of Notch-2 was higher than that of the other Notch receptors in both the nucleus pulposus and annulus fibrosus. In both tissues, hypoxia increased Notch1 and Notch4 messenger RNA (mRNA) expression. In the annulus fibrosus, mRNA expression of the Notch ligand Jagged1 was induced by hypoxia, while Jagged2 mRNA expression was highly sensitive to hypoxia in both tissues. A Notch signaling inhibitor, L685458, blocked hypoxic induction of the activity of the Notch-responsive luciferase reporters 12xCSL and CBF1. Expression of the Notch target gene Hes1 was induced by hypoxia, while coexpression with the Notch-intracellular domain increased Hes1 promoter activity. Moreover, inhibition of Notch signaling blocked disc cell proliferation. Analysis of human disc tissue showed that there was increased expression of Notch signaling proteins in degenerated discs. CONCLUSION: In intervertebral disc cells, hypoxia promotes expression of Notch signaling proteins. Notch signaling is an important process in the maintenance of disc cell proliferation, and thus offers a therapeutic target for the restoration of cell numbers during degenerative disc disease. PMID- 21305514 TI - The importance of the nondominant hand in clinical examination-oriented joint injections: comment on the article by Cunnington et al. PMID- 21305513 TI - Does cancer that occurs during or after anti-tumor necrosis factor therapy have a worse prognosis? A national assessment of overall and site-specific cancer survival in rheumatoid arthritis patients treated with biologic agents. AB - OBJECTIVE: Tumor necrosis factor (TNF) may affect tumor development and spreading. While data on the incidence of cancer following anti-TNF therapy have been published, the purpose of this study was to examine the clinical presentation and outcome of cancers that develop during or after anti-TNF therapy. METHODS: By linking data from Swedish clinical registries of rheumatoid arthritis (RA) patients, including Anti-Rheumatic Therapy in Sweden (ARTIS), the Swedish Biologics Register, with nationwide data on hospitalizations and outpatient visits for RA, we assembled a cohort of 78,483 RA patients who were alive in 1999 or who entered the cohort thereafter. Of these, 8,562 patients started therapy with a biologic agent (98% started an anti-TNF) during the period from January 1, 1999 to December 31, 2007. Linkage to the Swedish Cancer Register and other registers identified first primary cancers occurring during 1999-2007 as well as post-cancer survival through March 31, 2009. Through this linkage, we identified 314 cancers in patients who were undergoing, or had a history of, treatment with biologic agents and 4,650 cancers in patients who were biologics naive at the time of cancer diagnosis. The distributions of tumor stage among the biologics-exposed and the biologics-naive patients were compared. The relative risk of death among the biologics-exposed versus the 586 matched biologics-naive cancer cases were assessed by Cox regression analyses. Through chart review in a defined subset, we gathered additional clinical information and validated the diagnoses. RESULTS: For all cancers combined, the distribution of cancer stages at the time of cancer diagnosis was largely similar between those in the biologics-exposed and the matched biologics-naive groups. Based on the total of 113 deaths among those with cancer in the biologics-exposed group versus the 256 deaths among those with cancer in the biologics-naive group, the relative risk of death following cancer associated with exposure to anti-TNF was 1.1 (95% confidence interval 0.8-1.6). CONCLUSION: During routine care, cancers that occur following anti-TNF therapy are not characterized by any markedly altered stage at presentation or by altered post-cancer survival rates. PMID- 21305515 TI - Caspase 3 as a therapeutic target for regulation of intervertebral disc degeneration in rabbits. AB - OBJECTIVE: Although the etiology of intervertebral disc degeneration is poorly understood, one possible approach for its regulation is apoptosis inhibition. This study was undertaken to investigate the antiapoptotic effects of caspase 3 in intervertebral disc degeneration in rabbits. METHODS: We investigated the effects of caspase 3 small interfering RNA (siRNA) on rabbit nucleus pulposus cells in a serum-starved medium. The effects of direct injection of Alexa Fluor 555-labeled caspase 3 siRNA into the intervertebral disc were also determined in vivo using the rabbit anular needle puncture model. RESULTS: Rabbit nucleus pulposus cells transfected with caspase 3 siRNA showed a significant decrease in serum-starved apoptotic cells. After local injection of caspase 3 siRNA into intervertebral discs, red fluorescence was observed in the nucleus pulposus upon treatment with Alexa Fluor 555-labeled caspase 3 siRNA. Caspase 3 messenger RNA and protein were down-regulated in the caspase 3 siRNA group. Magnetic resonance imaging and histologic evaluation showed that degenerative changes were significantly suppressed in the caspase 3 siRNA group 4 and 8 weeks after injection. Quantification of TUNEL staining showed that the caspase 3 siRNA group had significantly fewer apoptotic nucleus pulposus cells than the control siRNA group. CONCLUSION: Our findings indicate that caspase 3 knockdown in rabbit intervertebral disc cells is effective in preventing apoptotic cell death, thus regulating intervertebral disc degeneration. PMID- 21305516 TI - Inhibition of cell death in the intervertebral disc by caspase 3 small interfering RNA. PMID- 21305518 TI - Activation-induced cytidine deaminase catalytic domain as a target to eliminate pathogenic autoantibodies. PMID- 21305520 TI - Clinical Image: digital necrosis due to severe carpal tunnel syndrome. PMID- 21305519 TI - Inhibition of the catalytic function of activation-induced cytidine deaminase promotes apoptosis of germinal center B cells in BXD2 mice. AB - OBJECTIVE: To determine whether functional suppression of the catalytic domain of activation-induced cytidine deaminase (AID) can suppress the hyperreactive germinal center (GC) responses in BXD2 mice. METHODS: We generated transgenic BXD2 mice expressing a dominant-negative (DN) form of Aicda at the somatic hypermutation site (BXD2-Aicda-DN-transgenic mice). Real-time quantitative reverse transcriptase-polymerase chain reaction was used to determine the expression of Aicda and DNA damage/repair genes. Enzyme-linked immunosorbent assay was used to measure serum levels of autoantibodies and immune complexes (ICs). Development of GCs and antibody-containing ICs as well as numbers of proliferative and apoptotic cells were determined using flow cytometry and/or immunohistochemical analyses. Development of arthritis and kidney disease was evaluated histologically in 6-8-month-old mice. RESULTS: Suppression of the somatic hypermutation function of AID resulted in a significant decrease in autoantibody production without affecting the expression of DNA damage-related genes in GC B cells of BXD2-Aicda-DN-transgenic mice. There was decreased proliferation, increased apoptosis, increased expression of caspase 9 messenger RNA in GC B cells, and lower numbers of GCs in the spleens of BXD2-Aicda-DN transgenic mice. Decreased GC response was associated with lower levels of IgG containing ICs. Anti-IgM- and anti-CD40 plus anti-Ig-induced B cell proliferative responses were decreased in BXD2-Aicda-DN-transgenic mice. CONCLUSION: Inhibition of the AID somatic hypermutation function in BXD2 mice suppressed development of spontaneous GCs, generation of autoantibody-producing B cells, and autoimmunity in BXD2 mice. Suppression of AID catalytic function to limit selection-based survival of GC B cells could become a novel therapy for the treatment of autoimmune disease. PMID- 21305521 TI - Trans heterodimer between two non-arthritis-associated HLA alleles can predispose to arthritis in humanized mice. AB - OBJECTIVE: Certain HLA class II alleles are associated with susceptibility to the development of arthritis. However, the development of arthritis in some persons carrying non-rheumatoid arthritis (RA)-associated alleles remains unexplained. An individual who is heterozygous for the DQA1 and DQB1 genes can express the DQ molecule in cis or trans heterodimers. In a cis heterodimer, the alpha-chain interacts with the beta-chain coded by the same chromosome, while in a trans heterodimer it interacts with the beta-chain on the other chromosome. In this study, we used a humanized mouse model of arthritis in an attempt to determine whether a trans heterodimer of 2 nonassociated alleles, DQB1*0601 and DQB1*0604, can predispose to arthritis. METHODS: DQB1*0601 and *0604 occur in linkage with DQA1*0103 and *0102, respectively. To understand the role of trans heterodimers, we generated DQB1*0604/DQA1*0103-transgenic mice lacking endogenous HLA class II molecules. RESULTS: Severe arthritis developed in the DQB1*0604/A1*0103-trangenic mice, and an antigen-specific response was generated in vitro. DQB1*0604/DQA1*0103 presented type II collagen-derived peptides that were not presented by the arthritis-resistant DQB1*0601 allele, suggesting that trans heterodimer molecules between 2 DQB1 and DQA1 molecules may result in the presentation of unique antigens and susceptibility to the development of arthritis. Molecular modeling of type II collagen peptides showed that DQB1*0604/DQA1*0103 shares a p4 pocket with the arthritis-susceptible DQB1*0302 allele, suggesting a critical role of the p4 and p9 pockets in susceptibility to arthritis. CONCLUSION: These results provide a possible explanation for the parental inheritance of nonsusceptibility alleles in some patients with RA and a mechanism by which they can predispose to the development of arthritis. PMID- 21305522 TI - Proteoglycan-induced arthritis and recombinant human proteoglycan aggrecan G1 domain-induced arthritis in BALB/c mice resembling two subtypes of rheumatoid arthritis. AB - OBJECTIVE: To develop a simplified and relatively inexpensive version of cartilage proteoglycan-induced arthritis (PGIA), an autoimmunity model of rheumatoid arthritis (RA), and to evaluate the extent to which this new model replicates the disease parameters of PGIA and RA. METHODS: Recombinant human G1 domain of human cartilage PG containing "arthritogenic" T cell epitopes was generated in a mammalian expression system and used for immunization of BALB/c mice. The development and progression of arthritis in recombinant human PG G1 immunized mice (designated recombinant human PG G1-induced arthritis [GIA]) was monitored, and disease parameters were compared with those in the parent PGIA model. RESULTS: GIA strongly resembled PGIA, although the clinical symptoms and immune responses in mice with GIA were more uniform than in those with PGIA. Mice with GIA showed evidence of stronger Th1 and Th17 polarization than those with PGIA, and anti-mouse PG autoantibodies were produced in different isotype ratios in the 2 models. Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies were detected in both models; however, serum levels of IgG RF and anti-CCP antibodies were different in GIA and PGIA, and both parameters correlated better with disease severity in GIA than in PGIA. CONCLUSION: GIA is a novel model of seropositive RA that exhibits all of the characteristics of PGIA. Although the clinical phenotypes are similar, GIA and PGIA are characterized by different autoantibody profiles, and the 2 models may represent 2 subtypes of seropositive RA, in which more than 1 type of autoantibody can be used to monitor disease severity and response to treatment. PMID- 21305524 TI - The effects of golimumab on radiographic progression in rheumatoid arthritis: results of randomized controlled studies of golimumab before methotrexate therapy and golimumab after methotrexate therapy. AB - OBJECTIVE: To evaluate the effects of golimumab on radiographic progression in patients with rheumatoid arthritis (RA). METHODS: Methotrexate (MTX)-naive patients (in the Golimumab Before Employing Methotrexate as theFirst-Line Option in the Treatment of Rheumatoid Arthritis of Early Onset [GO-BEFORE] study; n = 637)and patients with active RA despite MTX therapy (in the Golimumab in Active Rheumatoid Arthritis Despite Methotrexate Therapy [GO-FORWARD] study; n =444) were randomly assigned to receive placebo plus MTX (group 1), golimumab 100 mg plus placebo (group 2), golimumab 50 mg plus MTX (group 3), or golimumab 100 mg plus MTX (group 4). Golimumab orplacebo was administered subcutaneously every 4 weeks. Radiographs of the hands and feet were taken at baseline, week 28, and week 52 in the GO-BEFORE study and at baseline, week 24 (week 16 for patients who entered early escape), and week 52 in the GO-FORWARD study. Radiographs were scored by 2 independent readers in each study using the van der Heijde modification of the Sharp score. RESULTS: In the GO-BEFORE study, the mean +/- SD changes in the modified Sharp score from base line to week 52 (control period) were 1.4 +/- 4.6 in group 1, 1.3 +/- 6.2 in group 2 (P = 0.266), 0.7 +/- 5.2 in group 3 (P = 0.015), and 0.1 +/- 1.8 in group 4 (P = 0.025). In the GO-FORWARD study, changes from baseline to week 24 (control period) were 0.6 +/- 2.4 in group 1, 0.3 +/- 1.6 in group 2 (P = 0.361), 0.6 +/- 2.7 in group 3 (P = 0.953), and 0.2 +/- 1.3 in group 4 (P = 0.293). CONCLUSION: Golimumab in combination with MTX inhibited radiographic progression significantly better than did MTX alone in the GO-BEFORE study. Radiographic progression in the GO-FORWARD study was minimal in all treatment arms, precluding an adequate assessment of the effect of golimumab on radiographic progression in this study. PMID- 21305523 TI - Amelioration of dermal fibrosis by genetic deletion or pharmacologic antagonism of lysophosphatidic acid receptor 1 in a mouse model of scleroderma. AB - OBJECTIVE: Scleroderma (systemic sclerosis [SSc]), is characterized by progressive multiorgan fibrosis. We recently implicated lysophosphatidic acid (LPA) in the pathogenesis of pulmonary fibrosis. The purpose of the present study was to investigate the roles of LPA and two of its receptors, LPA1 and LPA2, in dermal fibrosis in a mouse model of SSc. METHODS: Wild type (WT), and LPA1 knockout (KO) and LPA2-KO mice were injected subcutaneously with bleomycin or phosphate buffered saline (PBS) once daily for 28 days. Dermal thickness, collagen content, and numbers of cells positive for alpha-smooth muscle actin (alpha-SMA) or phospho-Smad2 were determined in bleomycin-injected and PBS injected skin. In separate experiments, a novel selective LPA1 antagonist AM095 or vehicle alone was administered by oral gavage to C57BL/6 mice that were challenged with 28 daily injections of bleomycin or PBS. AM095 or vehicle treatments were initiated concurrently with, or 7 or 14 days after, the initiation of bleomycin and PBS injections and continued to the end of the experiments. Dermal thickness and collagen content were determined in injected skin. RESULTS: The LPA1 -KO mice were markedly resistant to bleomycin-induced increases in dermal thickness and collagen content, whereas the LPA2-KO mice were as susceptible as the WT mice. Bleomycin-induced increases in dermal alpha-SMA+ and phospho-Smad2+ cells were abrogated in LPA1-KO mice. Pharmacologic antagonism of LPA1 with AM095 significantly attenuated bleomycin-induced dermal fibrosis when administered according to either a preventive regimen or two therapeutic regimens. CONCLUSION: These results suggest that LPA/LPA1 pathway inhibition has the potential to be an effective new therapeutic strategy for SSc, and that LPA1 is an attractive pharmacologic target in dermal fibrosis. PMID- 21305525 TI - Methotrexate treatment in juvenile localized scleroderma: a randomized, double blind, placebo-controlled trial. AB - OBJECTIVE: Juvenile localized scleroderma is a chronic progressive fibrotic disorder of the skin that causes permanent disability and aesthetic damage. This study was undertaken to assess the safety and efficacy of methotrexate (MTX) in the treatment of juvenile localized scleroderma. METHODS: In this double-blind study, patients with active juvenile localized scleroderma were randomized (2:1) to receive oral MTX (15 mg/m2, maximum 20 mg) or placebo once weekly, for 12 months or until treatment failure. Both groups received oral prednisone (1 mg/kg/day, maximum 50 mg) for the first 3 months. A target lesion was evaluated clinically, with infrared thermography and using a computerized scoring system with skin score rate (SSR) evaluation. Response to treatment was defined as the absence of new lesions, SSR <= 1, and a decrease in lesion temperature of at least 10% compared to baseline. Treatment failure was defined as the occurrence of new lesions, SSR > 1, or increased lesion temperature. All analyses were done on the intent-to-treat population. RESULTS: Of the 85 patients screened, 70 (ages 6-17 years) were randomized (46 to the MTX group, 24 to the placebo group). The mean disease duration was 2.3 years. After an initial response in all patients, disease relapsed in 15 MTX-treated patients (32.6%) and 17 placebo-treated patients (70.8%) (P < 0.005). New lesions appeared in 3 MTX-treated patients (6.5%) versus 4 placebo-treated patients (16.7%). The mean SSR decreased from 1 to 0.79 in the MTX group and increased from 1 to 1.1 in the placebo group, and the mean target lesion temperature decreased by 44.4% in the MTX group versus 12.1% in the placebo group. Twenty-six patients in the MTX group (56.5%) and 11 patients in the placebo group (45.8%) developed mild side effects related to treatment. None of the side effects were severe enough to necessitate treatment discontinuation. CONCLUSION: Our findings indicate that MTX is efficacious in the treatment of juvenile localized scleroderma and is well tolerated. PMID- 21305527 TI - Methotrexate in juvenile localized scleroderma: adding to the evidence. PMID- 21305528 TI - Clinical images: Subcutaneous elbow and forearm sarcoidosis presenting as olecranon bursitis. PMID- 21305526 TI - Carotid atherosclerosis predicts incident acute coronary syndromes in rheumatoid arthritis. AB - OBJECTIVE: The role of atherosclerosis in the acute coronary syndromes (ACS) that occur in patients with rheumatoid arthritis (RA) has not been quantified in detail. We undertook this study to determine the extent to which ACS are associated with carotid atherosclerosis in RA. METHODS: We prospectively ascertained ACS, defined as myocardial infarction, unstable angina, cardiac arrest, or death due to ischemic heart disease, in an RA cohort. We measured carotid atherosclerosis using high-resolution ultrasound. We used Cox proportional hazards models to estimate the association between ACS and atherosclerosis, adjusting for demographic features, cardiovascular (CV) risk factors, and RA manifestations. RESULTS: We performed carotid ultrasound on 636 patients whom we followed up for 3,402 person-years. During this time, 84 patients experienced 121 new or recurrent ACS events, a rate of 3.5 ACS events per 100 patient-years (95% confidence interval [95% CI] 3.0-4.3). Among the 599 patients without a history of ACS, 66 incident ACS events occurred over 3,085 person-years, an incidence of 2.1 ACS events per 100 person-years (95% CI 1.7 2.7). The incidence of new ACS events per 100 patient-years was 1.1 (95% CI 0.6 1.7) among patients without plaque, 2.5 (95% CI 1.7-3.8) among patients with unilateral plaque, and 4.3 (95% CI 2.9-6.3) among patients with bilateral plaque. Covariates associated with incident ACS events independent of atherosclerosis included male sex, diabetes mellitus, and a cumulative glucocorticoid dose of >= 20 gm. CONCLUSION: Atherosclerosis is strongly associated with ACS in RA. RA patients with carotid plaque, multiple CV risk factors (particularly diabetes mellitus or hypertension), many swollen joints, and a high cumulative dose of glucocorticoids, as well as RA patients who are men, are at high risk of ACS. PMID- 21305530 TI - Identification of CXCL13 as a marker for rheumatoid arthritis outcome using an in silico model of the rheumatic joint. AB - OBJECTIVE: Rheumatoid arthritis (RA) is characterized by inflammation and joint destruction, with the degree of damage varying greatly among patients. Prediction of disease severity using known clinical and serologic risk factors is inaccurate. This study was undertaken to identify new serologic markers for RA severity using an in silico model of the rheumatic joint. METHODS: An in silico model of a prototypical rheumatic joint was used to predict candidate markers associated with erosiveness. The following 4 markers were chosen for validation: tartrate-resistant acid phosphatase 5b (TRAP-5b), N-telopeptide of type I collagen (NTX), angiopoietin 2 (Ang-2), and CXCL13. Serum from 74 RA patients was used to study whether radiologic joint destruction (total erosion score and total Sharp/van der Heijde score [SHS]) after 4 years of disease was associated with serum levels at the time of diagnosis. Serum marker levels were determined using enzyme-linked immunosorbent assays. For confirmation, baseline serum levels were analyzed for an association with progression of joint damage over 7 years of followup in a cohort of 155 patients with early RA. RESULTS: Comparison of high and low quartiles of erosion score and SHS at 4 years showed a difference in baseline serum CXCL13 level (P = 0.011 and P = 0.018, respectively). In the confirmation cohort, elevated baseline CXCL13 levels were associated with increased rates of joint destruction during 7 years of followup (P < 0.001 unadjusted and P <= 0.004 with adjustment for C-reactive protein level). Analyzing anti-CCP-2-positive and anti-CCP-2-negative RA separately yielded a significant result only in the anti-CCP-2-negative group (P <= 0.001). CONCLUSION: Our findings indicate that CXCL13 is a novel serologic marker predictive of RA severity.This marker was identified with the help of an in silicomodel of the RA joint. PMID- 21305531 TI - Switching gears to an arthritis gene expression network by SirT1 cleavage. PMID- 21305529 TI - JNK-1 deficiency limits macrophage-mediated antigen-induced arthritis. AB - OBJECTIVE: To elucidate the nonredundant roles of JNK-1 and JNK-2 in antigen induced arthritis (AIA). METHODS: Mice that were genetically disrupted in Jnk1 or Jnk2 were primed by injection of methylated bovine serum albumin (mBSA) in Freund's complete adjuvant and then challenged on day 21 by intraarticular injection of mBSA into the right knee. Bone marrow chimeras were generated and similarly treated. Joints were harvested and prepared for histologic assessment. T cell responses were verified by cytokine and proliferation responses, and relative immunoglobulin responses were measured by enzyme-linked immunosorbent assay. Cytokine messenger RNA expression levels were measured by quantitative polymerase chain reaction analysis. Thioglycollate-elicited and zymosan A elicited macrophage recruitment was tested in vivo, and cell migration was tested in vitro. The peptide inhibitor D-JNKi was injected daily starting 4 days after intraarticular injection of mBSA into wild-type (WT) mice, and inflammation was scored histologically. RESULTS: JNK-1-deficient, but not JNK-2-deficient, mice had a reduction in inflammatory cell infiltration and joint damage. This effect was primarily restricted to hematopoietic cells, but B and T cell responses were preserved in mBSA-injected mice. JNK-1-deficient macrophages produced cytokines and chemokines at a level comparable to that in their WT counterparts. However, macrophage migration was impaired in vivo and in vitro. Targeting JNK with the peptide inhibitor D-JNKi dramatically reduced inflammation and joint destruction in WT mice. CONCLUSION: AIA is dependent on JNK-1, but not JNK-2. JNK-1 is a promising molecular target for reducing autoimmune inflammation, since its inhibition impairs macrophage migration. PMID- 21305532 TI - Interleukin-17-induced proliferation of fibroblast-like synovial cells is mTOR dependent. PMID- 21305533 TI - Tumor necrosis factor alpha-mediated cleavage and inactivation of SirT1 in human osteoarthritic chondrocytes. AB - OBJECTIVE: The protein deacetylase SirT1 positively regulates cartilage-specific gene expression, while the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) negatively regulates these same genes. This study was undertaken to test the hypothesis that SirT1 is adversely affected by TNFalpha, resulting in altered gene expression. METHODS: Cartilage-specific gene expression, SirT1 activity, and results of chromatin immunoprecipitation analysis at the alpha2(I) collagen enhancer site were determined in RNA, protein extracts, and nuclei of human osteoarthritic chondrocytes left untreated or treated with TNFalpha. Protein extracts from human chondrocytes transfected with epitope-tagged SirT1 that had been left untreated or had been treated with TNFalpha were analyzed by immunoblotting with SirT1 and epitope-specific antibodies. The 75-kd SirT1 reactive protein present in TNFalpha-treated extracts was identified by mass spectroscopy, and its amino-terminal cleavage site was identified via Edman sequencing. SirT1 activity was assayed following an in vitro cathepsin B cleavage reaction. Cathepsin B small interfering RNA (siRNA) was transfected into chondrocytes left untreated or treated with TNFalpha. RESULTS: TNFalpha-treated chondrocytes had impaired SirT1 enzymatic activity and displayed 2 forms of the enzyme: a full-length 110-kd protein and a smaller 75-kd fragment. The 75-kd SirT1 fragment was found to lack the carboxy-terminus. Cathepsin B was identified as the TNFalpha-responsive protease that cleaves SirT1 at residue 533. Reducing cathepsin B levels via siRNA following TNFalpha exposure blocked the generation of the 75-kd SirT1 fragment. CONCLUSION: These data indicate that TNFalpha, a cytokine that mediates joint inflammation in arthritis, induces cathepsin B mediated cleavage of SirT1, resulting in reduced SirT1 activity. This reduced SirT1 activity correlates with the reduced cartilage-specific gene expression evident in these TNFalpha-treated cells. PMID- 21305534 TI - A novel N-ethyl-N-nitrosourea-induced mutation in phospholipase Cgamma2 causes inflammatory arthritis, metabolic defects, and male infertility in vitro in a murine model. AB - OBJECTIVE: It is difficult to identify a single causative factor for inflammatory arthritis because of the multifactorial nature of the disease. This study was undertaken to dissect the molecular complexity of systemic inflammatory disease, utilizing a combined approach of mutagenesis and systematic phenotype screening in a murine model. METHODS: In a large-scale N-ethyl-N-nitrosourea mutagenesis project, the Ali14 mutant mouse strain was established because of dominant inheritance of spontaneous swelling and inflammation of the hind paws. Genetic mapping and subsequent candidate gene sequencing were conducted to find the causative gene, and systematic phenotyping of Ali14/+ mice was performed in the German Mouse Clinic. RESULTS: A novel missense mutation in the phospholipase Cgamma2 gene (Plcg2) was identified in Ali14/+ mice. Because of the hyperreactive external entry of calcium observed in cultured B cells and other in vitro experiments, the Ali14 mutation is thought to be a novel gain-of-function allele of Plcg2. Findings from systematic screening of Ali14/+ mice demonstrated various phenotypic changes: an abnormally high T cell:B cell ratio, up-regulation of Ig, alterations in body composition, and a reduction in cholesterol and triglyceride levels in peripheral blood. In addition, spermatozoa from Ali14/+ mice failed to fertilize eggs in vitro, despite the normal fertility of the Ali14/+ male mice in vivo. CONCLUSION: These results suggest that the Plcg2-mediated pathways play a crucial role in various metabolic and sperm functions, in addition to initiating and maintaining the immune system. These findings may indicate the importance of the Ali14/+ mouse strain as a model for systemic inflammatory diseases and inflammation-related metabolic changes in humans. PMID- 21305535 TI - Natural orifice specimen extraction versus conventional laparoscopically assisted right hemicolectomy. AB - BACKGROUND: This case-control study compared the clinical outcomes of totally laparoscopic hemicolectomy with natural orifice specimen extraction (NOSE) and the conventional laparoscopically assisted approach for right-sided colonic cancer. METHODS: Consecutive patients who underwent totally laparoscopic mobilization of the right colon with transvaginal resection, anastomosis and specimen extraction between April 2007 and December 2009 were matched by various clinicopathological characteristics with patients who had conventional laparoscopically assisted procedures. RESULTS: Thirty-four patients in each group were studied. The number of lymph nodes harvested and the resection margin status were similar in the two groups. After NOSE, patients experienced less pain (mean(s.e.m.) pain score on day 1: 4.2(0.3) versus 5.7(0.3), P = 0.001; on day 3: 2.6(0.2) versus 3.5(0.2), P = 0.010) and had a shorter hospital stay (mean(s.d.) 7.9(0.8) versus 8.8(1.5) days; P = 0.003). The NOSE group had less surgical morbidity than the laparoscopically assisted group, but the difference was not significant (4 of 34 versus 9 of 34; P = 0.119). After a median follow-up of 23 (range 5-40) months, there was no transvaginal access-site recurrence or posterior colpotomy-related complications. NOSE was associated with significantly better cosmetic results (mean(s.d.) score 7.5(1.7) versus 6.6(1.8); P = 0.037). CONCLUSION: The NOSE approach is feasible with favourable short-term surgical outcomes. PMID- 21305536 TI - Randomized controlled trial of standard versus high-dose intravenous omeprazole after endoscopic therapy in high-risk patients with acute peptic ulcer bleeding. AB - BACKGROUND: Rebleeding from peptic ulcers is a major contributor to death. This study compared standard (40-mg intravenous infusion of omeprazole once daily for 3 days) and high-dose (80-mg bolus of omeprazole followed by 8-mg/h infusion for 72 h) in reducing the rebleeding rate (primary endpoint), need for surgery, duration of hospital stay and mortality in patients with peptic ulcer bleeding after successful endoscopic therapy. METHODS: This was a single-institution prospective randomized controlled study based on a postulated therapeutic equivalence of the two treatments. All patients who had successful endoscopic haemostasis of a bleeding peptic ulcer (Forrest classification Ia, Ib, IIa or IIb) were recruited. Informed consent was obtained and patients were randomized to receive standard- or high-dose infusions of intravenous omeprazole. RESULTS: Two (3 per cent) of 61 patients in the high-dose group and ten (16 per cent) of 61 in the standard-dose group exhibited rebleeding, a difference of - 13 (95 per cent confidence interval - 25 to - 2) per cent. The upper limit of the one-sided confidence interval exceeded a predefined equivalence absolute difference of 16 per cent. Equivalence of standard- and high-dose omeprazole in preventing rebleeding was not demonstrated. CONCLUSION: Intravenous standard-dose omeprazole was inferior to high-dose omeprazole in preventing rebleeding after endoscopic haemostasis for peptic ulcer bleeding. REGISTRATION NUMBER: NCT00519519 (http://www.clinicaltrials.gov). PMID- 21305537 TI - Interventions to improve teamwork and communications among healthcare staff. AB - BACKGROUND: Concern over the frequency of unintended harm to patients has focused attention on the importance of teamwork and communication in avoiding errors. This has led to experiments with teamwork training programmes for clinical staff, mostly based on aviation models. These are widely assumed to be effective in improving patient safety, but the extent to which this assumption is justified by evidence remains unclear. METHODS: A systematic literature review on the effects of teamwork training for clinical staff was performed. Information was sought on outcomes including staff attitudes, teamwork skills, technical performance, efficiency and clinical outcomes. RESULTS: Of 1036 relevant abstracts identified, 14 articles were analysed in detail: four randomized trials and ten non randomized studies. Overall study quality was poor, with particular problems over blinding, subjective measures and Hawthorne effects. Few studies reported on every outcome category. Most reported improved staff attitudes, and six of eight reported significantly better teamwork after training. Five of eight studies reported improved technical performance, improved efficiency or reduced errors. Three studies reported evidence of clinical benefit, but this was modest or of borderline significance in each case. Studies with a stronger intervention were more likely to report benefits than those providing less training. None of the randomized trials found evidence of technical or clinical benefit. CONCLUSION: The evidence for technical or clinical benefit from teamwork training in medicine is weak. There is some evidence of benefit from studies with more intensive training programmes, but better quality research and cost-benefit analysis are needed. PMID- 21305538 TI - Dysfunctional transforming growth factor-beta signaling with constitutively active Notch signaling in Barrett's esophageal adenocarcinoma. AB - BACKGROUND: Esophageal adenocarcinoma is often considered to arise from a clonal stem-like population of cells, which is potentially responsible for its poor prognosis. Transforming growth factor beta (TGF-beta) and Notch signaling pathways play important roles in regulating self-renewal of stem cells and cell fate determination. Both pathways are frequently implicated in gastrointestinal carcinogenesis. However, their contributions to esophageal adenocarcinoma remain unclear. METHODS: We evaluated TGF-beta and Notch signaling components in normal esophagus, Barrett's esophagus, and adenocarcinoma tissues and cell lines via immunohistochemical analysis and immunoblotting; Hes-1 transcription was assayed using a Hes-1 luciferase reporter. RESULTS: We observed loss of Smad4 (P<.05) and beta2 spectrin (beta2SP) (P<.01) in 5/10 Barrett's esophagus and 17/22 adenocarcinoma tissue sections. Concomitantly, dramatically raised levels of Notch signaling components Hes1 and Jagged1 occurred in adenocarcinoma tissues and cell lines compared with normal tissues. In normal esophagus, Oct3/4-positive cells are located in the basal layer (2-3 per cluster), representing a pool of progenitor cells. We observed an expansion of this pool of Oct3/4 positive cells in esophageal adenocarcinoma (15 per cluster). Furthermore, a panel of SOXs proteins documented for stem cell markers exhibit increased expression in tumor cells, indicating expansion of putative cancer stem cells. Finally, we observed growth inhibition in BE3 cells with a gamma-secretase inhibitor, but not in SKGT 4 cells. Unlike SKGT-4 cells, BE3 cells have activated Notch signaling with disruption of TGF-beta signaling. CONCLUSIONS: Our findings demonstrated a potential therapeutic value for targeted therapy in esophageal adenocarcinoma in the setting of loss of beta2SP/TGF-beta with concomitant constitutively active Notch signaling. PMID- 21305539 TI - Prediction of pathologic complete response to sequential paclitaxel and 5 fluorouracil/epirubicin/cyclophosphamide therapy using a 70-gene classifier for breast cancers. AB - BACKGROUND: Sequential administration of paclitaxel plus combined fluorouracil, epirubicin, and cyclophosphamide (P-FEC) is 1 of the most common neoadjuvant chemotherapies for patients with primary breast cancer and produces pathologic complete response (pCR) rates of 20% to 30%. However, a predictor of pCR to this chemotherapy has yet to be developed. The authors developed such a predictor by using a proprietary DNA microarray for gene expression analysis of breast tumor tissues. METHODS: Tumor samples were obtained from 84 patients with breast cancer by core-needle biopsy before the patients received P-FEC, and the gene expression profile was analyzed in those samples to construct a classifier for predicting pCR to P-FEC. In addition, the authors analyzed the gene expression profile of tumor tissues that were obtained at surgery from 105 patients with lymph node negative and estrogen receptor-positive breast cancer who received adjuvant hormone therapy alone to determine the prognostic significance of the classifier. RESULTS: The 70-gene classifier for predicting pCR to P-FEC was constructed by using the training set (n = 50) and subsequently was validated successfully in the validation set (n = 34), revealing high sensitivity (88%; 95% confidence interval [CI], 47%-100%) and high negative predictive value (93%; 95% CI, 68% 100%). Specificity and positive predictive value were 54% (95% CI, 33%-73%) and 37% (95% CI, 16%-62%), respectively. Among the various parameters (estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and Ki 67 status, etc), the 70-gene classifier had the strongest association with pCR (P = .015). In an additional study, genetically assumed complete responders were associated significantly (P = .047) with a poor prognosis. CONCLUSIONS: The 70 gene classifier that was constructed for predicting pCR to P-FEC for breast tumors was successful, with high sensitivity and high negative predictive value. The classifier also appeared to be useful for predicting the prognosis of patients with lymph node-negative and estrogen receptor-positive breast cancer who receive adjuvant hormone therapy alone. PMID- 21305540 TI - Obesity is associated with breast cancer in African-American women but not Hispanic women in South Los Angeles. AB - BACKGROUND: Obesity is considered a risk factor for breast cancer. Modifying life styles that reduce obesity offers the potential for prevention and improved outcomes from cancer. The effects of obesity and breast cancer among African American women and Hispanic women have been explored in a limited number of studies. The objective of the current study was to investigate the association of obesity with breast cancer in a minority cohort. METHODS: This was a cross sectional study of 471 African-American and Hispanic women with and without breast cancer in South Los Angeles. Data regarding body mass index (BMI) and clinical factors were obtained by medical record abstraction. Data were assessed using logistic regression with multivariate analysis. Kaplan-Meier survival analysis was used to assess disease-free survival. RESULTS: Women with breast cancer were more likely to be obese (BMI >30 kg/m(2)) than women without breast cancer (odds ratio [OR], 2.0; P = .01). There was a significant association of being overweight or obese and breast cancer among postmenopausal women (OR, 2.3 [P = .03] and 2.9 [P < .01], respectively). The association between obesity and breast cancer was significant only among African-American women (OR, 2.70; P < .01) and was especially significant among postmenopausal African-American women (OR, 4.8; P < .01). There was a borderline significant association between obesity and later disease stage at diagnosis (P = .06). An association also was observed between higher BMI (for cutoff points of both 30 kg/m(2) and 28 kg/m(2)) and poorer disease-free survival (P = .045 and P = .019, respectively). CONCLUSIONS: The current data suggested an association between obesity and breast cancer, especially among postmenopausal women and most significantly in the African-American cohort. PMID- 21305541 TI - The "enduring mission" of Zing-Yang Kuo to eliminate the nature-nurture dichotomy in psychology. AB - This paper reviews the arguments against the instinct concept and the nature nurture dichotomy put forward by Zing-Yang Kuo (1898-1970) during the 1920s. Kuo insisted that nativism represented a kind of finished psychology, and that the labels of nature and nurture reflected and promoted one's ignorance of the development of a trait. Also discussed are his lesser known lines of research on the origins of the so-called rat-killing instinct in cats and his analysis on the determinants of animal fighting. His research illustrated the shortcomings of a nature-nurture framework and highlighted the necessity of his developmentally grounded alternative to studying behavior. Reasons for why Kuo's work has been marginalized in modern histories of psychology are also discussed. PMID- 21305542 TI - Effects of physical exercise on ADHD-like behavior in male and female adolescent spontaneously hypertensive rats. AB - The present study examined the effects of exercising (voluntary wheel running) during adolescence on attentional function in male and female spontaneously hypertensive rats (SHRs), a commonly used animal model of attention deficit/hyperactivity disorder (ADHD). Once rats reached adulthood, they received one session in which a light was presented 12 times but not reinforced, followed by training sessions in which the light was paired with a food reward. Male and female SHRs that had access to running wheels exhibited levels of unconditioned orienting behavior that were similar to Wistar-Kyoto rats (normo-active control) while SHRs that did not have access to running wheels exhibited higher levels of unconditioned orienting behavior. When the light was later paired with food there were no differences between the groups of male rats, but exercising female SHRs exhibited a decrease in conditioned food cup behavior. Consistent with their established phenotype, SHR rats exhibited more locomotor activity during an open field exploration session than WKY rats, but there was no relationship between orienting behavior and locomotor activity. Together these data suggest that physical exercise during adolescence can benefit attentional capabilities. PMID- 21305543 TI - Change in self-protect ion and symptoms after dynamic psychotherapy: the influence of pretreatment motivation. AB - The First Experimental Study of Transference-interpretations (FEST) is a dismantling, randomized clinical trial of the long-term effects of transference interpretation. This article looks at the influence of motivation on the ability to self-protect and symptoms. Patients were randomized to receive a moderate level of transference interpretations or no transference interpretation. Assessments were made at pretreatment, midtreatment, posttreatment, and at two follow-ups. The outcome measure, change in ability to self-protect, was cluster 4 of the Structural Analysis of Social Behavior (SASB) Long Form Intrex Introject Questionnaire, a measure close to the SASB-coded treatment process. Symptom change (SCL-90) was also analyzed. Pretreatment motivation was a significant moderator of change in the ability to self-protect and in symptom distress. Those with low motivation had a significant, positive, and long-term treatment effect of transference interpretation. Patients with low motivation showed a significant, negative effect of transference interpretation. PMID- 21305544 TI - Role of sensitivity to anxiety symptoms in responsiveness to mindfulness versus suppression strategies for coping with smoking cravings. AB - Mindfulness strategies for managing cravings involve present-moment, nonjudgmental awareness of cravings without acting on them, while suppression involves pushing cravings out of awareness. Few studies have investigated individual differences in responding to these strategies. The current study examined whether individual differences in anxiety sensitivity moderate responsiveness to mindfulness versus suppression for coping with smoking cravings. Participants (N=61) utilized a mindfulness or suppression strategy to manage cravings during cue exposure to cigarettes and were evaluated for self efficacy 7 days later. Greater anxiety sensitivity after cue exposure was associated with increased self-efficacy in the suppression condition. This suggests that anxiety-sensitive individuals who utilize suppression may cope better with cravings, at least in the early days after learning these strategies. PMID- 21305545 TI - Development of pegylated liposomal vincristine using novel sulfobutyl ether cyclodextrin gradient: is improved drug retention sufficient to surpass DSPE-PEG induced drug leakage? AB - The purpose of this study is to develop novel stable PEGylated liposome vincristine formulations with optimal antitumor efficacy. Vincristine could interact with negatively charged distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG), leading to rapid drug release from vesicles. To improve drug retention, vincristine was loaded into vesicles using sulfobutyl ether cyclodextrin (sbe-CD) as trapping agent. Despite that, vincristine could not form a precipitate with sbe-CD; the aggregation status of vincristine/sbe-CD inside vesicles must be complicated because drug retention was considerably improved in vivo. Theoretical consideration revealed that the release constant K equals to pA(m)k(1)k(2)/([H(+)](i)[sbe(-)](i)V(i) ), which can be used to expound why increasing drug/lipid ratio induced decreased vincristine circulation half-life. The stabilization effect afforded by sbe-CD was sufficient to surpass DSPE-PEG induced drug leakage, so PEGylated liposomal vincristine formulations with prolonged circulation half-life (t(1/2): from 43.6 to 70.0 h) could be achieved, of which the formulation pLV-c-2.9-3 exhibited optimal antitumor effects and reduced toxicity. The strategy might be used to load other vinca alkaloids into PEGylated liposomes and improve their retention inside vesicles. PMID- 21305546 TI - Evaluation of the fixed nitrogen-to-protein (N:P) conversion factor (6.25) versus ingredient specific N:P conversion factors in feedstuffs. AB - BACKGROUND: The crude protein (CP) of feedstuffs is important as an indicator of essential and non-essential amino acids for livestock. The protein (P) level needs to be known accurately, to minimize the feeding of excess nitrogen (N) and to reduce N pollution. Laboratory methods for determining N content report N from amino acids, but also N from ammonia and from non-amino acid sources. The determined CP based on 6.25 * N level typically overestimates the true protein of feedstuffs. RESULTS: Determined ingredient-specific N:P conversion factors k(A) , k(P) and k were not equal to the standard 6.25 factor. The k(A) had the highest value in all ingredients, which leads to the estimation of specific crude protein (SCP), which is closer to true protein (the summation of the total amino acid residues from amino acid analyses). The SCP(k(A) ) was lower than CP and true protein in all ingredients, demonstrating that CP might overestimate the actual protein in feedstuffs. CONCLUSION: Based on data from 677 feedstuff samples from 2009, it is concluded that the mean k(A) should be 5.68 for corn, 5.64 for soybean meal, 5.74 for corn DDGS, 5.45 for poultry by-product meal and 5.37 for meat and bone meal. PMID- 21305547 TI - Gossypiboma: an unusual intracranial complication of endoscopic sinus surgery. AB - We report a case of a 52-year-old man who presented with iatrogenic bilateral nasoethmoidal meningoencephaloceles following endoscopic nasal surgery performed in a neighboring country 8 years ago. Imaging studies, including computed tomography and magnetic resonance imaging of the paranasal sinuses and anterior skull base, demonstrated bilateral meningoencephaloceles and a suspicious intracranial lesion. In view of the intracranial lesion and size of the skull base defect, an external approach via a bicoronal flap was used for exploration and repair. Intraoperative findings revealed the suspicious intracranial lesion to be a retained piece of gauze. The patient underwent a successful removal of the foreign body and repair of the skull base defect. Postoperative recovery was uneventful. To our knowledge, an iatrogenic intracranial foreign body following an endonasal endoscopic procedure has never been reported before. PMID- 21305548 TI - Hearing assessment in Meniere's disease. AB - OBJECTIVES: To investigate the level of hearing loss and the configuration of the mean audiometric curve over the course of Meniere's disease, correcting the data according to patient age. STUDY DESIGN: A retrospective study of 3,963 hearing tests. METHODS: Descriptive, longitudinal study of pure-tone audiometries of 237 patients at a tertiary hospital who had been diagnosed with definitive Meniere's disease according to the American Academy of Otorhinolaryngology criteria. All audiometric results were age-corrected, and patients were followed for 1 to 31 years. In patients who had undergone surgery, only the data collected before the operation were assessed. RESULTS: In patients with unilateral disease, the mean hearing loss was characteristically low frequency, even in very advanced stages of the disease. Hearing loss was accentuated at 5 and 15 years from onset. In bilateral cases, hearing loss was slightly more severe and the average loss produced a flatter audiometric curve than in unilateral cases. CONCLUSIONS: In Meniere's disease, audiometry results corrected for patient age show an inherent upward-sloping configuration of the mean audiometric curve at all time points during the disease. The hearing pattern differs between unilateral and bilateral disease. The audiometric curve configuration may be an indicator of future bilateral disease. PMID- 21305549 TI - Overcoming obstacles to setting up office-based ultrasound for evaluation of thyroid and parathyroid diseases. AB - Ultrasound is an integral part of the preoperative workup for patients who are being evaluated for thyroid and parathyroid surgery. It helps improve the accuracy of a fine-needle aspiration biopsy and complements other imaging modalities used for planning the extent of surgery. It also allows imaging of vital structures in relation to the thyroid and parathyroid. The compact nature and portability of ultrasound machines in recent years has made it easier for motivated surgeons (head and neck, general, and endocrine surgeons) to incorporate them into their practice. However, successfully setting up such a service needs adequate planning and an understanding of the obstacles that are involved. We aim to discuss these obstacles in detail, with practical suggestions on how to overcome them. This review may serve as a resource when dealing with issues such as purchasing equipment, training, credentialing, billing, documentation, and collaboration. Although these are discussed with respect to surgeons with an interest in endocrine disease, with some modifications they may also apply to any surgeon who uses ultrasound frequently. PMID- 21305550 TI - Correlations between symptoms, nasal endoscopy, and in-office computed tomography in post-surgical chronic rhinosinusitis patients. AB - OBJECTIVES: To determine correlations between symptoms, nasal endoscopy findings, and computed tomography (CT) scan findings in post-surgical chronic rhinosinusitis (CRS) patients. STUDY DESIGN: Cross-sectional. MATERIAL AND METHODS: A total of 51 CRS patients who had undergone endoscopic sinus surgery (ESS) completed symptom questionnaires, underwent endoscopy, and received an in office sinus CT scan during one clinic visit. For metrics, we used the Sinonasal Outcomes Test-20 (SNOT-20) questionnaire, visual analog symptom scale (VAS), Lund Kennedy endoscopy scoring scale, and Lund-MacKay (LM) CT scoring scale. We determined Pearson correlation coefficients, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) between scores for symptoms, endoscopy, and CT. RESULTS: The SNOT-20 score and most VAS symptoms had poor correlation coefficients with both endoscopy and CT scores (0.03-0.24). Nasal drainage of pus, nasal congestion, and impaired sense of smell had moderate correlation coefficients with endoscopy and CT (0.24-0.42). Endoscopy had a strong correlation coefficient with CT (0.76). Drainage, edema, and polyps had strong correlation coefficients with CT (0.80, 0.69, and 0.49, respectively). Endoscopy had a PPV of 92.5% and NPV of 45.5% for detecting an abnormal sinus CT (LM score >=1). CONCLUSIONS: In post-ESS CRS patients, most symptoms do not correlate well with either endoscopy or CT findings. Endoscopy and CT scores correlate well. Abnormal endoscopy findings have the ability to confidently rule in the presence of CT opacification, thus validating the importance of endoscopy in clinical decision making. However, a normal endoscopy cannot assure a normal CT. Thus, symptoms, endoscopy, and CT are complementary in the evaluation of the post-ESS CRS patient. PMID- 21305551 TI - Correlative study of indirect computed tomography lymphography using iopamidol and histopathology in a cervical lymph node metastasis model. AB - OBJECTIVES/HYPOTHESIS: To investigate the potential usefulness of indirect computed tomography lymphography (CT-LG) with iopamidol in the detection of cervical lymph node metastases in a VX2 rabbit tongue cancer model. STUDY DESIGN: Randomized controlled trial. METHODS: Thirty-seven rabbits were randomly divided into control (n = 7) and tongue tumor-bearing (n = 30) groups. In the control group, indirect CT-LG was performed with 0.5- and 0.25-mL injections of iopamidol in the right and left tongue submucosa, respectively. In the tumor-bearing group, indirect CT-LG with 0.5 mL of iopamidol was performed on day 11 (n = 8), 14 (n = 8), 21 (n = 8), or 28 (n = 6) after carcinoma transplant. The correlation between indirect CT-LG and histopathology was investigated. RESULTS: In normal rabbits, oval or round enhanced cervical lymph nodes in each side of the neck were visualized by indirect CT-LG. In tumor-bearing rabbits, one enhanced lymph node on each side of the neck was visualized with or without filling defects in all rabbits except two on day 28 in which lymph nodes were not enhanced. The sensitivity, specificity, accuracy, and positive and negative predictive values for using filling defects on CT-LG as a diagnostic criterion were 77.4%, 77.8%, 77.6%, 80%, and 75%, respectively. Indirect CT-LG detected 84.6% of 2- to 6-mm intranodal tumor deposits. CONCLUSIONS: Indirect CT-LG may be useful for differentiating metastatic from nonmetastatic lymph nodes. PMID- 21305552 TI - Influence of glycemic control on tympanic membrane healing in diabetic rats. AB - OBJECTIVES/HYPOTHESIS: It is generally assumed that glycemic control in diabetic patients is important in optimizing wound healing. The goal of this study was to examine tympanic membrane (TM) wound healing in spontaneously diabetic rats depending on the diabetic metabolic state compared to nondiabetic control animals. STUDY DESIGN: Prospective controlled study in experimental animals. METHODS: Right-sided myringotomy was performed in 20 normoglycemic rats, 17 well compensated, and 23 poorly compensated diabetic rats. TMs were observed for a total of 3 weeks. Effect of diabetic metabolic state on the healing of the TMs was evaluated by closure rates and histology. RESULTS: Diabetic rats showed a significant delay in TM wound healing compared to the control group, but there were no significant differences between both diabetes groups. CONCLUSIONS: Glycemic control does not influence TM wound repair in an animal model of type 1 diabetes. PMID- 21305553 TI - Risk factors for auditory neuropathy spectrum disorder in NICU infants compared to normal-hearing NICU controls. AB - OBJECTIVES: To evaluate independent etiologic factors associated with auditory neuropathy spectrum disorder (ANSD) in infants who have been admitted to the neonatal intensive care unit (NICU) compared to normal-hearing controls. STUDY DESIGN: Case-control study. METHODS: We included all infants (n = 9) with the ANSD profile admitted to the NICU of Sophia Children's Hospital between 2004 and 2009. Each patient was matched with four normal-hearing controls of the same gender and postconceptional age. The following possible risk factors were studied: birth weight, dysmorphic features, APGAR scores (at 1, 5, and 10 minutes), respiratory distress (IRDS), cytomegalovirus (CMV) infection, sepsis, meningitis, cerebral bleeding, hyperbilirubinemia requiring phototherapy, peak total bilirubin level, furosemide, dexamethason, vancomycin, gentamycin, and tobramycin administration. RESULTS: Nine infants met the ANSD criteria in one or both ears. IRDS (P = .02), meningitis (P = .04), and vancomycin administration (P = .009) were significantly increased in infants with ANSD compared to controls. CONCLUSIONS: In high-risk NICU infants IRDS, meningitis and vancomycin administration are associated with auditory neuropathy spectrum disorder. PMID- 21305554 TI - Preliminary investigation of adjustable balloon implant for type I thyroplasty. AB - OBJECTIVE: We present the adjustable balloon implant (ABI), a novel implant to be used in type I thyroplasty for the treatment of vocal fold paralysis. The ABI offers the same medialization provided by other implants, but can easily be catered to individual patient anatomy as well as modified postoperatively without the need for a revision thyroplasty. STUDY DESIGN: Repeated measures with each larynx serving as its own control. METHODS: Medialization thyroplasty (MT) with the ABI was performed on five excised canine larynges. Mucosal wave, aerodynamic, and acoustic parameters were measured for three conditions: normal; right vocal fold paralysis; and paralysis with the ABI. RESULTS: Insertion of the ABI resulted in significant decreases in both phonation threshold pressure and phonation threshold flow. Perturbation parameters of percent jitter and percent shimmer were also significantly decreased and restored to normal levels. Signal to-noise ratio was significantly increased to the normal level as well. The mucosal wave was preserved after implant insertion. CONCLUSIONS: This preliminary experiment showing significant improvements in aerodynamic and acoustic parameters demonstrates the potential of the ABI as a thyroplasty implant. Effective medialization and preservation of the mucosal wave combined with postoperative adjustability makes it a potentially valuable clinical device. PMID- 21305555 TI - Traumatic perilymphatic fistula with pneumolabyrinth: diagnosis and management. AB - A perilymphatic fistula (PLF) is an abnormal communication between the inner and middle ear resulting in vestibular or cochlear symptoms. We review three pediatric traumatic temporal bone fractures with pneumolabyrinth, confirmed radiologically by the presence of air within the cochlea (pneumocochlea) or vestibule (pneumovestibule). Patients were treated conservatively with complete resolution of vestibulopathy. Hearing outcome was variable and worse in two patients with pneumocochlea. A pneumolabyrinth on radiologic imaging confirms a PLF and obviates the need for exploration to reach a diagnosis. We suggest exploration be reserved for patients with persisting cerebrospinal fluid leakage, progressive sensorineural hearing loss, or vestibular symptomatology. PMID- 21305556 TI - In reference to The canalith repositioning procedure for benign positional vertigo: a meta-analysis. PMID- 21305557 TI - Cytomegalovirus DNA retrieval in the inner ear fluids of a congenitally deaf child one month after primary infection: a case report. AB - In the present article we report cytomegalovirus (CMV) DNA localization in the inner ear of a 15-month-old deaf boy 1 month after a virologically documented primary infection. CMV DNA retrieval was possible thanks to polymerase chain reaction analysis of the perilymph collected at cochlear implant surgery. To the authors' knowledge this is the first demonstration of CMV persistence in the cochlea of an immunocompetent subject after an acquired infection. PMID- 21305559 TI - Evolution of Eustachian tube surgery. AB - Eustachian tube dysfunction (ETD) is a common condition that lacks a widely accepted treatment. Attempts to address ETD surgically have spanned several centuries and have often fallen short of success. It is probable that occult anatomic position, unclear function, and misunderstood physiology have contributed to the delayed development of effective interventions for ETD. This article traces the evolution of therapeutic interventions of the Eustachian tube through the present day. Reasons for success and failure are highlighted, with implications for the future of Eustachian tube surgery. PMID- 21305558 TI - The role of cephalometry in assessing velopharyngeal dysfunction in velocardiofacial syndrome. AB - OBJECTIVE: To report our experience with cephalometry in evaluating velopharyngeal dysfunction (VPD) in velocardiofacial syndrome (VCFS) and its utility in assessing the role of cervical spine abnormalities in VPD, prior to surgical correction of VPD. DESIGN: Clinical charts and cephalometric radiographs done prior to surgery for VPD were retrospectively analyzed to ascertain velopharyngeal measurements and cervical spine abnormalities. PATIENTS: Twenty six patients (age: 6-23 years) with molecularly confirmed VCFS. SETTING: Wake Forest University Health Sciences (1997-2005). MEASUREMENTS: Cranial base angle, nasopharyngeal depth, velum length, and Need ratio at rest, velar dimple location, and velopharyngeal length during phonation; information on presence/absence of submucous cleft palate and cervical spine abnormalities were also obtained. The relationship between C1 anterior arch abnormalities and Need ratio was examined. RESULTS: Seventy-three percent of the VCFS patients had excessive nasopharyngeal depth, 80% had an abnormal Need ratio, 50% had a short velum, 81% had a submucous or occult submucous cleft palate, 90.5% had a cervical spine abnormality (C1 anterior arch abnormalities in 38%) and 11.5% had platybasia. There was a significant difference in the Need ratio between patients with and without C1 anterior arch abnormalities. CONCLUSION: Cephalometry can be used to delineate factors such as C1 vertebral abnormalities, excessive pharyngeal depth, and short velum that contribute to VPD in VCFS. This would help otolaryngologists better understand the anatomy prior to surgical treatment of VPD. This is the first study to highlight the frequent occurrence of C1 anterior arch abnormalities in VCFS. PMID- 21305560 TI - The effect of corticosteroid on metalloproteinase levels of nasal polyposis. AB - OBJECTIVES: The aim of this study was to investigate the effect of corticosteroid treatment on topical and systemic metalloproteinase levels of patients with nasal polyposis (NP). STUDY DESIGN: Prospective clinical trial. METHODS: The study included patients undergoing a paranasal sinus operation due to NP. Oral corticosteroid therapy was performed on all patients before endoscopic sinus surgery. Endoscopic and radiological evaluation were performed and nasal tissue specimens and venous blood samples were collected before (preop phase) and after corticosteroid treatment (periop phase) and also one month after surgery (postop phase). Endoscopic and computed tomography scan findings were scored adequately and all tissue and blood samples were examined cumulatively. RESULTS: The study included 27 patients with inflammatory NP. Preop tissue matrix metalloproteinase 2 (MMP-2) levels were found to be significantly lower than preop and postop concentrations. In contrast, periop serum MMP-2 levels were found to be significantly higher than preop and postop concentrations. Periop tissue inhibitor of metalloproteinase-1 (TIMP-1) levels were also found to be significantly lower than preop and postop concentrations, similar to MMP-2 tissue concentrations. However, there was no statistical difference among tissue MMP-9 concentrations of the three phases. In addition, there was also no statistical difference among serum MMP-9 levels of the three phases. CONCLUSIONS: Oral corticosteroid treatment especially reduces tissue MMP-2, then TIMP-1. Severity of nasal polyposis primarily correlates with increasing tissue MMP-2/TIMP-1 ratio, then MMP-9/TIMP-1. These results suggest that selective inhibition for MMP 2 and activation for TIMP-1 might be a novel therapeutic strategy for patients with nasal polyposis. PMID- 21305562 TI - The Oculobulbar Facial Respiratory score is a tool to assess bulbar function in myasthenia gravis patients. AB - The Oculobulbar Facial Respiratory (OBFR) score is a tool that objectively measures bulbar function in myasthenia gravis (MG). In this study, we analyzed the relation between the OBFR and the MG Activities of Daily Living (MG-ADL) score, and also with the more recently described MG Composite and 15-item MG Quality-of-Life (MG-QOL15) scales. We recruited 42 patients from two centers and assessed them on two occasions, approximately 6 months apart, using the OBFR, MG Composite, MG-ADL, and MG-QOL15 scales. The 'modified' OBFR score was derived from the original OBFR score. The OBFR score correlated significantly with the MG Composite, MG-ADL, and MG-QOL15 scores for both assessments, and with the sum of the bulbar items for all three scores. It also correlated strongly with the individual bulbar-related items of all three scores. The 'modified' OBFR score also correlated significantly with all the aforementioned scores. This study confirmed construct validity of the OBFR and 'modified' OBFR scores. PMID- 21305563 TI - Calpain activity is increased in skeletal muscle from gastric cancer patients with no or minimal weight loss. AB - The influence of cancer on skeletal muscle calpain expression and activity in humans is poorly understood. We tested the hypothesis that calpain activity is increased in skeletal muscle from gastric cancer patients with no or <5% weight loss. Muscle biopsies were obtained from rectus abdominis muscle in 15 patients who underwent surgery for gastric cancer and had <5% weight loss and also in 15 control patients. Calpain activity was determined using a calpain-specific substrate in the absence or presence of calcium. The expression of MU- and m calpain, calpastatin, atrogin-1, and MuRF1 was determined by real-time polymerase chain reaction. Calpain activity was increased by 70% in cancer patients compared with controls. There were no differences in mRNA levels for MU- and m-calpain, calpastatin, atrogin-1, or MuRF1 between control and cancer patients. Calpain activity may be increased in muscle from gastric cancer patients even before changes in molecular markers of muscle wasting and significant weight loss occur. PMID- 21305564 TI - High resting level and weak response of baroreflex-governed sympathetic outflow in amyotrophic lateral sclerosis. AB - Both altered sympathetic function and insulin resistance have been observed in amyotrophic lateral sclerosis (ALS). Insulin is a sympathetic stimulator. We recorded muscle sympathetic nerve activity (MSNA) by microneurography in 9 patients with ALS and 9 healthy controls during rest. We also initiated a number of sympathoexcitatory maneuvers, including intake of 100 g of glucose. Patients showed reduced glucose tolerance and a higher heart rate and higher level of MSNA at rest than controls (61.0 +/- 15.2 vs. 41.2 +/- 5.8 bursts/min, P = 0.006); baroreflex inhibitory influence was present. In contrast, MSNA in ALS patients responded more weakly to maneuvers. This inverse relationship is interpreted as a "ceiling effect," as ALS patients use nearly maximal MSNA capacity already at rest and do not have sympathetic failure. The increased level of MSNA may be a primary feature of ALS, but insulin stimulation may also contribute. Our findings are assessed in relation to previous, sometimes seemingly contradictory observations. PMID- 21305566 TI - Prenatal diagnosis of Duchenne/Becker muscular dystrophy by short tandem repeat segregation analysis in Argentine families. AB - INTRODUCTION: Duchenne/Becker muscular dystrophies (DMD/BMD) are X-linked recessive diseases caused by mutations in the dystrophin gene. METHODS: We used multiplex polymerase chain reaction (PCR) and short tandem repeat (STR) segregation analysis for DMD/BMD-carrier detection and prenatal diagnosis. RESULTS: Twenty-four at-risk pregnancies were evaluated: 17 were excluded from carrying dystrophin gene mutations with 95-100% certainty. Of the remaining cases, 2 were determined to carry a dystrophin gene mutation with 95-100% certainty. Three cases had a 67% probability of carrying the mutation, and 2 others were not informative. The certainty of the test increased to ~100% in some cases due to the identification of several genetic events: 4 recombinations; 4 de novo mutations; and 8 deletions encompassing some of the STRs evaluated. DISCUSSION: Overall, 19 of 24 (79%) molecular prenatal diagnoses were informative, indicating that multiplex PCR/STR segregation analysis is a reliable method for carrier detection and prenatal diagnosis when other more sophisticated techniques are unavailable. PMID- 21305565 TI - Selectively reshaping a muscle phenotype: functional overload of cat plantaris. AB - INTRODUCTION: Functional overload (FO) of the fast plantaris muscle was studied in treadmill-exercised (FO-Ex) or sedentary (FO-Sed) adult cats. METHODS: Mechanical, phenotype, and kinematics analyses were performed. RESULTS: Plantigrade vs. normal digitigrade posture was observed early post-FO. Relative plantaris mass was greater in FO-Sed (10%) and FO-Ex (60%) cats than in controls 12 weeks post-FO. Specific tension was similar across groups, indicating functional hypertrophy. Fiber size was greater, percent slow fibers higher, percent IIa myosin heavy chain (MHC) higher, and IIx MHC lower in FO-Ex than controls. Twitch and half-relaxation times were longer, and the frequency-tension curve shifted toward that observed in slow muscles. Electromyography (EMG) and tendon force amplitudes during stepping were larger, and the yield (lengthening) phase occurred at a longer muscle length before compared with after FO. DISCUSSION: Reshaping the plantaris phenotype was highly dependent on the overload stimulus, indicating that electrical stimulation paradigms used during rehabilitation should be performed with the muscles under "loaded" conditions. PMID- 21305567 TI - Transplantation of olfactory ensheathing cells promotes axonal regeneration and functional recovery of peripheral nerve lesion in rats. AB - INTRODUCTION: Olfactory ensheathing cells (OECs) hold promise for cell therapy because they may promote regeneration of the central nervous system. However, OECs have been less studied after peripheral nerve injury (PNI). The purpose of this investigation was to determine the effect of OEC transplantation on a severe sciatic nerve (SN) lesion. METHODS: OECs were injected in rats after section and 2-cm resection of the SN. RESULTS: Three months after therapy, muscle strength and morphometric studies showed complete restoration of the contractile properties of the gastrocnemius and complete repair of the SN. Immunohistochemistry and RT-PCR studies indicated an increase in the presence of neurotrophic factors. Interestingly, tracking of green fluorescent protein (GFP) positive OECs showed that no OECs were present in the SN. DISCUSSION: Our results demonstrate that, after severe PNI, OECs have remarkable potential for nerve regeneration by creating a favorable microenvironment. PMID- 21305568 TI - Passive and active exercise improve regeneration and muscle reinnervation after peripheral nerve injury in the rat. AB - INTRODUCTION: Lesions of peripheral nerves cause loss of motor and sensory function and also lead to hyperreflexia and hyperalgesia. Activity-dependent therapies promote axonal regeneration and functional recovery and may improve sensory-motor coordination and restoration of adequate circuitry at the spinal level. METHODS: We compared the effects of passive (bicycle) and active (treadmill) exercise on nerve regeneration and modulation of the spinal H reflex after transection and repair of the rat sciatic nerve. Animals were evaluated during 2 months using electrophysiological, functional, and histological methods. RESULTS: Moderate exercise for 1 hour/day, either active treadmill walking or passive cycling, improved muscle reinnervation, increased the number of regenerated axons in the distal nerve, and reduced the increased excitability of spinal reflexes after nerve lesion. DISCUSSION: Maintenance of denervated muscle activity and afferent input, by active or passive exercise, may increase trophic factor release to act on regenerating axons and to modulate central neuronal plasticity. PMID- 21305569 TI - Muscle endurance, cancer-related fatigue, and radiotherapy in prostate cancer survivors. AB - INTRODUCTION: In this study we investigated muscle and cancer-related fatigue (CRF) in prostate cancer survivors (CS) undergoing radiotherapy (RT). METHODS: In 13 CS and 12 controls, CRF was assessed by the Piper Fatigue Scale (PFS), Epworth Sleepiness Scale--Depression subscale (CES-D), physical activity (accelerometer), and hemoglobin levels (Hb). Muscle measures included strength, activation, contractile properties, and endurance during intermittent dorsiflexion. Testing occurred before and after 6 weeks of RT in CS. RESULTS: After RT, the PFS score increased from initial levels in CS only without changes in sleepiness, depression, or physical activity. Hb decreased in CS only [mean (SD): pre, 15 (1.1); post, 14.5 (1.1) g/dl; P = 0.04]. Endurance decreased in CS [mean (SD): pre, 519 (340) s; post, 388 (203) s; P = 0.04] and increased in controls [mean (SD: pre, 616 (387) s; post, 753 (553) s; P = 0.03]. Only endurance was associated with PFS in CS (r = -0.55, P = 0.05). DISCUSSION: Muscle endurance is impaired after RT and may contribute to CRF in CS. PMID- 21305570 TI - Do A-waves help predict intravenous immunoglobulin response in multifocal motor neuropathy without block? AB - INTRODUCTION: Are there electrophysiological findings that predict response to intravenous immunoglobulin (IVIg) in patients with lower motor neuron (LMN) syndromes without multifocal conduction block (MCB)? METHODS: We enrolled 9 patients with LMN syndromes without MCB to receive 18 weeks of IVIg therapy. Response was measured at weeks 2 and 18 using the Appel Amyotrophic Lateral Sclerosis (AALS) score (includes grip and pincer strength measures), ALS Functional Rating Scale (ALSFRS), and electrophysiological measures, including motor unit estimates (MUNEs). RESULTS: No change occurred in AALS or ALSFRS scores posttreatment. Grip/pincer strength increased in 7 patients (P = 0.028) after initial treatment (responders); 2 showed no improvement (non-responders). No electrophysiological measure changed after treatment in either group but MUNEs trended higher (P = 0.055). "Abnormal A-waves" (complex, repetitive biphasic, or present in multiple nerves) occurred in pretreatment studies more often in responders (P = 0.028). DISCUSSION: "Abnormal A-waves" may signal IVIg-responsive LMN syndromes even if conduction block is absent. PMID- 21305571 TI - Neuromuscular toxicology of the venom of Collett's snake (Pseudechis colletti): a histopathological study. AB - INTRODUCTION: A bite by Collett's snake, (Pseudechis colletti) can cause rhabdomyolysis in human victims but no signs of neurotoxicity. The pathology of muscle and peripheral nerve has not been described previously. In this study we investigated neuromuscular toxicity in rats. METHODS: The venom was inoculated subcutaneously into the anterolateral aspect of one hindlimb of adult rats at a dose replicating that inoculated into an adult human male during an envenoming bite. RESULTS: The venom caused edema, an increase in muscle wet weight, and the degeneration of 20-35% of the underlying soleus muscle. Muscle fiber regeneration began at 4 days and was complete by 8 weeks. There was little evidence of either post- or presynaptic toxicity. CONCLUSIONS: The dominant effect of this venom in mammals is myotoxicity. PMID- 21305572 TI - An ultrasound study of anatomic variants of the sural nerve. AB - INTRODUCTION: There are anatomic variations of the sural nerve (SN). Knowledge of these morphological types and the length of the SN are important for planning surgical reconstruction of peripheral nerves. Our purpose was to classify the morphological types of the SN by using ultrasound. METHODS: Two-hundred SNs in 100 normal subjects were examined by ultrasound with 13-MHz linear-array transducers. Classification of the SN was evaluated by its formation. The distance between the union and the distal point of the lateral malleolus was measured. RESULTS: SN variants could be classified into three types: type I (81%); type II (18%); and type III (1%). In type I, the average length of the SN was 15.8 +/- 5.7 cm. CONCLUSIONS: The morphological types of the SN can be determined using ultrasound. Ultrasound classification of the SN is useful with regard to donor nerve surgical reconstruction of peripheral nerves. PMID- 21305573 TI - Investigation for RAPSN and DOK-7 mutations in a cohort of seronegative myasthenia gravis patients. AB - INTRODUCTION: Myasthenia gravis (MG) is an autoimmune disease. Patients without detectable antibodies against the nicotinic acetylcholine receptor or the muscle specific tyrosine kinase are referred to as seronegative MG (SNMG). Because late onset congenital myasthenic syndromes (CMSs) due to RAPSN or DOK7 mutations may be mistaken for SNMG, we investigated their frequency in a nationwide SNMG cohort. METHODS: We performed sequencing of RAPSN and DOK7 in all Norwegian SNMG patients (n = 74) and 37 healthy controls, examining for the N88K and c.1124_1127dupTGCC mutations, respectively. RESULTS: We found 1 patient homozygous for N88K and 2 carriers of the N88K mutation. Sequencing of DOK7 revealed no mutations. CONCLUSIONS: This study confirms that rapsn CMS can be mistaken for SNMG. In addition, the frequency of rapsn CMS in our nationwide SNMG cohort was found to be low. SNMG patients with an atypical clinical presentation and pediatric cases should be tested for the N88K mutation before initiation of immunosuppressive drug treatment or thymectomy. PMID- 21305574 TI - Central mechanisms during fatiguing muscle exercise in muscular dystrophy and fibromyalgia syndrome: a study with transcranial magnetic stimulation. AB - INTRODUCTION: The aim of this study was to apply paired-pulse transcranial magnetic stimulation (TMS) to assess intracortical inhibition (ICI) during fatiguing muscle exercise in healthy humans and patients with muscular dystrophy (MD) and fibromyalgia syndrome (FMS) to obtain insight into differential central mechanisms. METHODS: We studied 23 patients with MD, 16 patients with FMS, and 23 healthy controls. All participants performed a fatiguing motor task. TMS recordings were taken pre-exercise, immediately post-exercise, and 40 minutes post-exercise. RESULTS: ICI was already reduced pre-exercise in MD and FMS, whereas ICI decreased significantly during fatiguing muscle exercise only in healthy subjects. DISCUSSION: Reduced baseline ICI in patients might prevent further utilization of this presumably compensatory mechanism during fatiguing muscle exercise. Although reduced baseline to be ICI in MD can be explained as compensatory due to peripheral weakness, in FMS reduced ICI must be considered an indicator of primary central disinhibition. PMID- 21305575 TI - Demographic, psychosocial, and contextual correlates of tobacco use in sexual minority women. AB - Demographic, psychosocial, and contextual correlates of tobacco use among sexual minority women (SMW) were assessed using data from a larger lesbian, gay, bisexual, and transgender (LGBT) study. Of the 171 participants, 42% (n = 71) were smokers. However, 61% of smokers reported a recent quit attempt, and 39% were taking action toward or planning to quit. In multivariable logistic regression, lack of insurance, frequent attendance at LGBT bars, greater awareness of anti-smoking messages, and fewer perceived deterrents to smoking were associated with greater odds of smoking. Our findings provide additional support for elevated smoking rates among SMW and help to identify factors associated with smoking in this population. Awareness of prevention campaigns, recent quit attempts, and intention to quit were high, suggesting opportunities for smoking cessation. PMID- 21305576 TI - Influence of historical industrial epochs on pore water and partitioning profiles of polycyclic aromatic hydrocarbons and polychlorinated biphenyls in Oslo Harbor, Norway, sediment cores. AB - Contaminant levels in urban harbor sediments vary with contaminant emission levels, sedimentation rates, and sediment resuspension processes such as propeller wash. Levels of polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) are decreasing in many urban harbors, as heavily contaminated sediments that accumulated during past decades are being buried by less-contaminated sediments. However, PAHs and PCBs remain a concern in areas where burial is slow or resuspension processes re-expose heavily contaminated older layers. Chronostratigraphic sediment core studies typically characterize contaminant level histories by using total sediment concentrations, C(sed) , and do not determine the freely dissolved porewater concentrations, C(pw) , which provide a better measure of bioavailability. Here both C(sed) and C(pw) profiles were established for PAHs and PCBs in dated sediment cores from diverse areas of Oslo Harbor, Norway. Sediment-porewater partitioning profiles were established alongside profiles of various sorbing carbonaceous phases, including total organic carbon (TOC), black carbon, and diverse carbonaceous geosorbents identified by petrographic analysis. Stratigraphic trends in carbonaceous phases and C(sed) could be associated with different industrial epochs: hydropower (post 1960, approximately), manufactured gas (~1925-1960), coal (~1910-1925), and early industry (~1860-1910). Partitioning was highly variable and correlated best with the TOC. Hydropower-epoch sediments exhibit decreasing C(sed) with time and a relatively strong sorption capacity compared with the manufactured-gas epoch. Sediments from the manufactured-gas epoch exhibit substantial PAH and metal contamination, large amounts of coke and char, and a low sorption capacity. Reexposure of sediments of this epoch increases risks to local benthic species. Implications on natural recovery as a sediment management strategy are discussed. PMID- 21305577 TI - Toxicity of silicon carbide nanowires to sediment-dwelling invertebrates in water or sediment exposures. AB - Silicon carbide nanowires (SiCNW) are insoluble in water. When released into an aquatic environment, SiCNW would likely accumulate in sediment. The objective of this study was to assess the toxicity of SiCNW to four freshwater sediment dwelling organisms: amphipods (Hyalella azteca), midges (Chironomus dilutus), oligochaetes (Lumbriculus variegatus), and mussels (Lampsilis siliquoidea). Amphipods were exposed to either sonicated or nonsonicated SiCNW in water (1.0 g/L) for 48 h. Midges, mussels, and oligochaetes were exposed only to sonicated SiCNW in water for 96 h. In addition, amphipods were exposed to sonicated SiCNW in whole sediment for 10 d (44% SiCNW on dry wt basis). Mean 48-h survival of amphipods exposed to nonsonicated SiCNW in water was not significantly different from the control, whereas mean survival of amphipods exposed to sonicated SiCNW in two 48-h exposures (0 or 15% survival) was significantly different from the control (90 or 98% survival). In contrast, no effect of sonicated SiCNW was observed on survival of midges, mussels, or oligochaetes. Survival of amphipods was not significantly reduced in 10-d exposures to sonicated SiCNW either mixed in the sediment or layered on the sediment surface. However, significant reduction in amphipod biomass was observed with the SiCNW either mixed in sediment or layered on the sediment surface, and the reduction was more pronounced for SiCNW layered on the sediment. These results indicated that, under the experimental conditions, nonsonicated SiCNW in water were not acutely toxic to amphipods, sonicated SiCNW in water were acutely toxic to the amphipods, but not to other organisms tested, and sonicated SiCNW in sediment affected the growth but not the survival of amphipods. PMID- 21305578 TI - Mercury speciation and biomagnification in the food web of Caddo Lake, Texas and Louisiana, USA, a subtropical freshwater ecosystem. AB - We studied the biomagnification of total mercury and methylmercury in a subtropical freshwater lake, Caddo Lake, Texas and Louisiana, USA. The present study is unique in that it not only included invertebrates (seven species) and fish (six species) but also an amphibian (one species), reptiles (three species), and mammals (three species). Nonfish vertebrates such as those included in the present study are often not included in assessments of trophic transfer of Hg. Mean trophic position (determined using stable isotopes of nitrogen) ranged from 2.0 (indicative of a primary consumer) to 3.8 (indicative of a tertiary consumer). Mean total Hg concentrations ranged from 36 to 3,292 ng/g dry weight in muscle and whole body and from 150 to 30,171 ng/g dry weight in liver. Most of the Hg in muscle and whole-body tissue was found as methylmercury, and at least 50% of the Hg found in liver was in the inorganic form (with the exception of largemouth bass, Micropterus salmoides). Mercury concentrations were positively correlated with trophic position, indicating that biomagnification occurs in the food web of Caddo Lake. The food web magnification factors (FWMFs; slope of the relationship between mean Hg concentration and trophic position) for both total Hg and methylmercury were similar to those observed in other studies. Because most of the total Hg in consumers was methylmercury, the FWMF for methylmercury was not significantly different from the FWMF for total Hg. Some vertebrates examined in the present study had low Hg concentrations in their tissues similar to those observed in invertebrates, whereas others had concentrations of Hg in their tissues that in previous studies have been associated with negative health consequences in fish. PMID- 21305579 TI - Acute oral toxicity of the organophosphorus pesticide fenitrothion to fat-tailed and stripe-faced dunnarts and its relevance for pesticide risk assessments in Australia. AB - The scarcity of information on the effects of pesticides on native Australian vertebrates constrains the development of biologically relevant risk assessments in Australia for the registration of pesticides. The concern that endemically old and unique Australian vertebrate fauna might display high sensitivity to pesticides used for locust control provoked examination of the acute oral toxicity of the organophosphorus pesticide fenitrothion for the fat-tailed dunnart, Sminthopsis crassicaudata (Gould 1844), and the stripe-faced dunnart, S. macroura (Gould 1845). By using the up-and-down method for determining acute oral toxicity, S. crassicaudata and S. macroura were found to have estimated median lethal doses (LD50s) of 129 mg/kg (95% confidence interval [CI] = 74.2-159.0) and 97 mg/kg (95% CI = 88.3-120.0), respectively. These values are 10 to 14 times lower than the reported LD50 values for a similar-sized eutherian mammal, Mus musculus (L. 1758; LD50 = 1,100-1,400 mg/kg) and lower than all other reported mammalian LD50 values. Such wide interspecific variation in sensitivity to fenitrothion may be a consequence of underlying differences in the metabolic pathway for fenitrothion detoxification in mammals and a possible explanation for the increased toxicity of fenitrothion to dunnarts, compared with other mammals, is proposed. The unexpectedly high sensitivity of these Australian marsupials to fenitrothion emphasises the importance of adequately evaluating the risks of pesticides to endemic Australian fauna. PMID- 21305580 TI - Estrogenic activity of tropical fish food can alter baseline vitellogenin concentrations in male fathead minnow (Pimephales promelas). AB - Vitellogenin (VTG) is a precursor of egg-yolk protein and is therefore present at high concentrations in the plasma of female fish. In male fish, VTG concentrations are usually undetectable or low but can be induced upon exposure to estrogenic substances either via the water or the diet. This work was performed to determine the reason for the apparently elevated VTG concentrations in unexposed stock male fathead minnow maintained in our laboratory. The results showed clearly that some of the food given to the fish was estrogenic and that replacement of this with nonestrogenic food led to a significant reduction in the basal VTG levels measured in male fish after a six-month period. This reduction in male VTG concentrations drastically increased the sensitivity of the VTG test in further studies carried out with these fish. Moreover, a review of published concentrations of VTG in unexposed male fathead minnow suggests that this problem may exist in other laboratories. The fathead minnow is a standard ecotoxicological fish test species, so these findings will be of interest to any laboratory carrying out fish tests on endocrine-disrupting chemicals. PMID- 21305581 TI - Improving ecological risk assessment in the Mediterranean area: selection of reference soils and evaluating the influence of soil properties on avoidance and reproduction of two oligochaete species. AB - A current challenge in soil ecotoxicology is the use of natural soils as test substrates to increase ecological relevance of data. Despite the existence of six natural reference soils (the Euro-soils), some parallel projects showed that these soils do not accurately represent the diversity of European soils. Particularly, Mediterranean soils are not properly represented. To fill this gap, 12 natural soils from the Mediterranean regions of Alentejo, Portugal; Cataluna, Spain; and Liguria, Italy, were selected and used in reproduction and avoidance tests to evaluate the soil habitat function for earthworms (Eisenia andrei) and enchytraeids (Enchytraeus crypticus). Predictive models on the influence of soil properties on the responses of these organisms were developed using generalized linear models. Results indicate that the selected soils can impact reproduction and avoidance behavior of both Oligochaete species. Reproduction of enchytraeids was affected by different soil properties, but the test validity criteria were fulfilled. The avoidance response of enchytraeids was highly variable, but significant effects of texture and pH were found. Earthworms were more sensitive to soil properties. They did not reproduce successfully in three of the 10 soils, and a positive influence of moisture, fine sand, pH, and organic matter and a negative influence of clay were found. Moreover, they strongly avoided soils with extreme textures. Despite these limitations, most of the selected soils are suitable substrates for ecotoxicological evaluations. PMID- 21305582 TI - Binding of pyrene to fulvic acid fractions isolated by polarity-based sequential elution. AB - Binding between pyrene and four fulvic acid factions sequentially eluted by 0.01 M HCl (F1), 0.01 M HCl + 20% methanol (F2), 0.01 M HCl + 40% methanol (F3), and 0.01 M HCl + 100% methanol (F4) was measured by fluorescence quenching. The influences of the functional groups of the fractions under different pH conditions on the binding behavior are discussed. The results showed that the binding coefficient (log K(DOC) ) of pyrene for F1 to F4 increased from 4.19 to 5.3. Log K(DOC) was positively correlated with the aromaticity of fulvic acid fractions but negatively correlated with the ratio of (O + N)/C and the ratio of UV absorption at 250 nm and 365 nm (E2/E3). As an indicator of polarity around the pyrene molecule, the ratio of intensity of pyrene at 374 nm and 384 nm (I1/I3) decreased with the increase of fulvic acid fraction concentrations. All fractions decreased in ability to quench as the pH increased. For a given pH value, the quenching ability followed the order of F1 < F2 < F3 < F4. The differences in the effects of pH on the quenching ability of fulvic acid fractions could be attributed mainly to the conformation of the fulvic acid fractions. Hydrophobic effect and the interactions of pi-electrons from the aromatic regions of the fulvic acid and pyrene played dominant roles in the binding process. PMID- 21305583 TI - Persistency assessment and aerobic biodegradation of selected cyclic sesquiterpenes present in essential oils. AB - Sesquiterpenes are ubiquitous in essential oils but an assessment of their environmental behavior is still required for their use as components of natural fragrance ingredients and oral care flavors. Persistency plays a key role in hazard and risk assessment, but the current knowledge on the biodegradation of sesquiterpenes in the aquatic environment is limited. This could have important consequences for the persistent, bioaccumulative and toxic (PBT) assessment of essential oils because most of the sesquiterpene components have a log K(OW) of >4.5 and are identified as potentially bioaccumulating according to REACH screening criteria. In the present study, a persistency screening assessment was conducted on 11 cyclic sesquiterpenes selected from 10 different families of sesquiterpenes characterized by their carbon skeleton. Current biodegradation prediction models (BioWinTM, BioHCwin, and Catalogic) were found to be of limited use because most of the sesquiterpenes studied were outside the structural domain of the models. Aerobic biodegradation was measured in a standard or prolonged Organisation for Economic Co-operation and Development (OECD) 301F Manometric Respirometry test for ready biodegradability. alpha-Bisabolol, alpha-humulene, beta-caryophyllene, alpha-cedrene, cedrol, longifolene, and delta-cadinene exceeded the pass level of 60% degradation and can be regarded as not persistent. Alpha-gurjunene, himachalenes (alpha, beta, gamma), and (-)-thujopsene almost achieved the pass level reaching between 51% and 56% ultimate biodegradation. Although germacrene D only achieved 24% ultimate biodegradation, specific analysis at the end of the test did indicate complete primary degradation. Given that the shape of the biodegradation curves indicates poor bioavailability and ready biodegradability tests are very stringent, it is expected that all the sesquiterpenes tested in the present study would be degraded under environmental conditions. PMID- 21305584 TI - Test of significant toxicity: a statistical application for assessing whether an effluent or site water is truly toxic. AB - The U.S. Environmental Protection Agency (U.S. EPA) and state agencies implement the Clean Water Act, in part, by evaluating the toxicity of effluent and surface water samples. A common goal for both regulatory authorities and permittees is confidence in an individual test result (e.g., no-observed-effect concentration [NOEC], pass/fail, 25% effective concentration [EC25]), which is used to make regulatory decisions, such as reasonable potential determinations, permit compliance, and watershed assessments. This paper discusses an additional statistical approach (test of significant toxicity [TST]), based on bioequivalence hypothesis testing, or, more appropriately, test of noninferiority, which examines whether there is a nontoxic effect at a single concentration of concern compared with a control. Unlike the traditional hypothesis testing approach in whole effluent toxicity (WET) testing, TST is designed to incorporate explicitly both alpha and beta error rates at levels of toxicity that are unacceptable and acceptable, given routine laboratory test performance for a given test method. Regulatory management decisions are used to identify unacceptable toxicity levels for acute and chronic tests, and the null hypothesis is constructed such that test power is associated with the ability to declare correctly a truly nontoxic sample as acceptable. This approach provides a positive incentive to generate high-quality WET data to make informed decisions regarding regulatory decisions. This paper illustrates how alpha and beta error rates were established for specific test method designs and tests the TST approach using both simulation analyses and actual WET data. In general, those WET test endpoints having higher routine (e.g., 50th percentile) within-test control variation, on average, have higher method-specific alpha values (type I error rate), to maintain a desired type II error rate. This paper delineates the technical underpinnings of this approach and demonstrates the benefits to both regulatory authorities and permitted entities. PMID- 21305585 TI - Unilateral ureteral obstruction evokes renal tubular apoptosis via the enhanced oxidative stress and endoplasmic reticulum stress in the rat. AB - PURPOSE: Oxidative stress and endoplasmic reticulum (ER) stress may induce renal apoptosis and contribute to the pathogenesis of the kidney with unilateral ureteral obstruction (UUO). MATERIALS AND METHODS: We induced UUO the female Wistar rats by ligation of the left ureter at the ureteropelvic junction. The UUO kidney was performed from 4 hr to 7 days course. At the indicated time, we measured the arterial blood pressure and renal blood flow in each rat, renal ROS measurement in vivo by a chemiluminescence analyzer. We performed immunohistochemistry of monocyte/macrophage (ED-1) stain for leukocyte infiltration, 4-hydroxynoneal (4-HNE) stain for ROS products, and apoptosis by terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) and Western blot to analyze ER stress-associated and apoptosis-related proteins expression in the UUO kidney. RESULTS: We found that UUO decreased renal blood flow and increased renal vascular resistance and renal ROS. UUO decreased renal manganese superoxide dismutase (MnSOD) and catalase protein expression in a time dependent manner. Increased 4-HNE stain in the renal tubules and ED-1 stain in the renal tubulointerstitial compartment occurred after 4 hr of UUO in the kidney. UUO significantly enhanced ER stress markers like ER stress-response protein 25 and glucose-regulated protein 78 and ER-associated apoptosis proteins, c-JUN NH(2) -terminal kinase, and caspase 12, in the kidney. Subsequently, UUO enhanced renal pro-apoptotic Bax and caspase 3 expression and decreased anti apoptotic Bcl-2 expression, leading to renal tubular apoptosis. CONCLUSIONS: Our data suggest that renal tubular apoptosis induced by oxidative stress and ER stress occurred in the UUO kidney. PMID- 21305586 TI - Loperamide-induced rat prostate relaxation through activation of peripheral u opioid receptors. AB - AIMS: The effect of u-opioid receptor (MOR) agonist, loperamide on prostate relaxation and the role of potassium channel in this action were studied in isolated Wistar rat prostate. METHODS: Tissue strips from rat prostate ventral lobe were hung in organ bath containing: group 1: standard Tyrode's solution (TS); group 2: TS with 1 uM naloxone; group 3: TS with 0.1 uM naloxonazine; and group 4: TS with 0.01-1 uM glybenclamide. The strips were pre-contracted with either 50 mM KCl or 1 uM phenylephrine. Dose-response study on the prostate strip was performed by cumulative administration of loperamide 0.1-10 uM into the organ bath. Western blot study was performed to detect the presence of MOR protein and adenosine triphosphate (ATP)-sensitive potassium channel (K(ATP) ) subunit Kir6.2 protein expressions in the prostate tissue. RESULTS: Loperamide induced relaxation of the pre-contracted prostate strips in a dose-dependent fashion. Pre treatment with 1 uM naloxone significantly inhibited the relaxation, thus suggesting activation of MOR in the loperamide effect. Pre-treatment with 0.1 uM naloxonazine inhibited relaxation only in the phenylephrine-contracted strips. The K(ATP) channel blocker glybenclamide significantly inhibited the loperamide induced relaxation, indicating involvement of K(ATP) channels in mediating the prostate relaxation. Western blots showed the expression of MOR and Kir6.2 protein in the rat prostate. CONCLUSIONS: MOR and Kir6.2 are expressed in the rat prostate and loperamide induces rat prostate relaxation through activation of peripheral MOR. K(ATP) channels are involved in mediating the effect of loperamide on the relaxation of prostate. PMID- 21305587 TI - Pathogenesis of reduced or increased bladder sensation. AB - OBJECTIVE: Pathogenesis of reduced or increased bladder sensation is not well known. Hence, we systematically investigated the frequency of reduced or increased bladder sensation in neurologic/mental diseases. METHODS: We analyzed 911 patients who were referred from within our hospital. Data registries included a diagnosis, a lower urinary tract symptom questionnaire, a urodynamic study, and neurological examinations. Reduced bladder sensation is defined as bladder volume at the first sensation >300 ml. Increased bladder sensation is defined as bladder volume at the first sensation <100 ml. These patients were stratified into those with and without DO. RESULTS: Neuropathies are the most common cause of reduced bladder sensation (33.3-43.8% in diabetic neuropathy, etc.). Myelopathies are the second most common cause (17.4-25.0% in multiple sclerosis, etc.). Less common is brain diseases (9.6% in multiple system atrophy, etc.). In contrast, myelopathies are the most common cause of increased bladder sensation without DO (25.0-40.0% in spinal forms of systemic lupus erythematosus, Sjogren's syndrome, etc.). Neuropathies are the second most common (17.3-22.2% in post-pelvic organ surgery, diabetic neuropathy, etc.). Less common is brain/mental diseases (20.0% in psychogenic bladder dysfunction, 8.1% in Parkinson's disease, etc.). CONCLUSION: The present study revealed that neuropathies are the most common cause of reduced bladder sensation in neurologic/mental diseases. Increased bladder sensation without DO occurs mainly in peripheral and central sensory pathway lesions, as well as in basal ganglia lesions and psychogenic bladder dysfunction. Reduced and increased bladder sensation should be a major treatment target for maximizing patients' quality of life. PMID- 21305588 TI - Transcutaneous posterior tibial nerve stimulation for treatment of the overactive bladder syndrome in multiple sclerosis: results of a multicenter prospective study. AB - AIMS: Electrostimulation is an established therapeutic option for neurogenic urinary disorders. The aim of this study was to investigate the efficacy of the noninvasive technique of transcutaneous posterior tibial nerve stimulation (TPTNS) in patients with multiple sclerosis (MS) and troublesome symptoms of an overactive bladder (OAB). METHODS: A multicentric study enrolled 70 MS patients, suffering from OAB for a 3-month study period. INTERVENTION: Daily sessions of 20 min of TPTNS were provided. No change of associated treatments during the study period. The primary outcome measurement was Urgency and Frequency reported by bladder diary and symptom score performed before the treatment (Day 0, D0) and at D30 and D90. The secondary outcomes measurements were continence, symptom score, quality of life, psychosocial burden at DO, D30, and D90 and cystometry at baseline, with and without TPTNS and at D90. RESULTS: Clinical improvement of OAB was shown in 82.6% and 83.3% of the patients on D30 and D90, respectively, with significant improvement of primary and secondary outcomes compared to baseline. The initial acute cystometric response to TPTNS was positive in 51.2% of the patients (increase of >30% of cystometric capacity and/or reflex volume), without correlation with TPTNS clinical efficiency. The procedure was well tolerated. CONCLUSIONS: Chronic TPTNS appears to be effective in the management of severe OAB in MS, without compromising bladder emptying or inducing side effect. Treatment may be effective even in the absence of an acute cystometric effect. Additional works are required to demonstrate long-term efficacy of TPTNS. PMID- 21305589 TI - Italian version of Qualiveen-30: cultural adaptation of a neurogenic urinary disorder-specific instrument. AB - PURPOSE: Qualiveen-30 is a neurological urinary disorder (UD)-specific health related quality of life (HRQL) instrument, recommended in the European Association of Urology guideline 2008. The objective is to complete the cultural adaptation of Qualiveen-30 into Italian. MATERIALS AND METHODS: One hundred and twenty eight Italian-speaking spinal cord injury (SCI) patients completed Qualiveen-30 and the SF-12 physical and mental component (PC and MC) at enrollment and 4 weeks later. At follow-up, patients also made global ratings of change (GRC) in urinary HRQL (GRC). RESULTS: Qualiveen-30 proved reliable (intraclass correlation coefficients of four domains: 0.77-0.90). Correlations with SF-12 and GRC were generally consistent with our a priori predictions. Qualiveen-30 domains showed weak-to-moderate cross-sectional correlations with SF 12 scores (0.31-0.45 PC and 0.28-0.45 MC). Correlations between changes in Qualiveen-30 scores and in SF-12-PC scores were weak or absent. Correlations between changes in Qualiveen-30 scores and in SF-12-MC scores were weak to moderate (0.25-0.38). Relationships between change in Qualiveen-30 and GRC were moderate to strong (0.48-0.56). The responsiveness was excellent, similar to the original form (SMR: 1.76-2.31). Minimally important difference values in the four domains varied from 0.34 to 0.47. CONCLUSIONS: Italian Qualiveen-30 is a reliable, valid, and responsive measure of UD-related HRQL in SPI patients. Investigators can be confident of the Qualiveen-30 questionnaire's ability in distinguishing between patients in a cross-sectional survey, as well as in measuring within-subject changes over time in clinical trials in French, English, and Italian. PMID- 21305590 TI - Reducing nocturia in the elderly: a randomized placebo-controlled trial of staggered furosemide and desmopressin. AB - AIMS: The purpose of this study was to investigate efficacy, safety, and impact on quality of sleep of staggered furosemide and desmopressin in the treatment of nocturia in the elderly. METHODS: Patients aged >60 years with nocturia at least two voids per night were screened for enrollment into the study. A 3-week dose titration phase established the optimum desmopressin dose (0.1, 0.2, or 0.4 mg). After a 1-week "washout" period, patients who showed sufficient response during the dose-titration period were randomized to receive staggered furosemide and the optimal dose of desmopressin or placebo in a double-blind design for 3 weeks. Voiding diaries were assessed before and after the treatment. RESULTS: In all, 82 patients were randomized to either staggered furosemide and desmopressin (n=41) or placebo (n=41). In the study group, most patients reported a good response with both reduced nocturnal voids (3.5 vs. 2.0, P<0.01) and urine volume (919.6 ml vs. 584.2 ml, P<0.01). The mean duration of the first sleep period was improved by 70 min (133.6 vs. 203.2, P<0.01). Compared to placebo, staggered furosemide and desmopressin resulted in a significant reduction in the mean number of nocturnal voids (43% vs. 9%; P<0.01), nocturnal urine volume (37% vs. 5%; P<0.01), and increase in the mean duration of the first sleep period (52% vs. 19%, P<0.01). Adverse events were mild. CONCLUSIONS: Staggered furosemide and desmopressin provide an effective and well-tolerated treatment for nocturia in the elderly. PMID- 21305591 TI - Comparison of air-charged and water-filled urodynamic pressure measurement catheters. AB - AIMS: Catheter systems are utilized to measure pressure for diagnosis of voiding dysfunction. In a clinical setting, patient movement and urodynamic pumps introduce hydrostatic and motion artifacts into measurements. Therefore, complete characterization of a catheter system includes its response to artifacts as well its frequency response. The objective of this study was to compare the response of two disposable clinical catheter systems: water-filled and air-charged, to controlled pressure signals to assess their similarities and differences in pressure transduction. METHODS: We characterized frequency response using a transient step test, which exposed the catheters to a sudden change in pressure; and a sinusoidal frequency sweep test, which exposed the catheters to a sinusoidal pressure wave from 1 to 30 Hz. The response of the catheters to motion artifacts was tested using a vortex and the response to hydrostatic pressure changes was tested by moving the catheter tips to calibrated heights. RESULTS: Water-filled catheters acted as an underdamped system, resonating at 10.13 +/- 1.03 Hz and attenuating signals at frequencies higher than 19 Hz. They demonstrated significant motion and hydrostatic artifacts. Air-charged catheters acted as an overdamped system and attenuated signals at frequencies higher than 3.02 +/- 0.13 Hz. They demonstrated significantly less motion and hydrostatic artifacts than water-filled catheters. The transient step and frequency sweep tests gave comparable results. CONCLUSIONS: Air-charged and water-filled catheters respond to pressure changes in dramatically different ways. Knowledge of the characteristics of the pressure-measuring system is essential to finding the best match for a specific application. PMID- 21305592 TI - Urinary incontinence among group fitness instructors including yoga and pilates teachers. AB - AIMS: Controversies exist on the role of physical activity on urinary incontinence (UI), and search on PubMed revealed no studies on UI in fitness instructors. The aim of this study was to investigate the prevalence of UI among female group fitness instructors, including Pilates and yoga teachers. METHODS: This was a cross-sectional study of 1,473 instructors representing three of the largest fitness companies recruited from 59 fitness centers in Norway. They filled in an online survey (Questback) about general health, educational background, and number of hours teaching per week. Prevalence of UI was evaluated by the International Consensus on Incontinence Questionnaire, short form (ICIQ-UI SF). RESULTS: Three out of 152 men (2%) reported UI. Six hundred eighty-five women, mean age 32.7 years (range 18-68) answered the questionnaire. 26.3% of all the female instructors reported to have UI, with 21.4% reporting leakage >= once a week, 3.2% 2-3 times/week and 1.7% >= once per day. 24.4% reported the leakage to be small to moderate and the bother score was 4.6 (SD 2.4) out of 21. 15.3% reported leakage during physical activity and 10.9% when coughing/sneezing. 25.9% of yoga and Pilates instructors reported UI. CONCLUSIONS: This is the first report on UI among fitness instructors and the results indicate that UI is prevalent among female fitness instructors, including yoga and Pilates teachers. More information about this topic seems to be important in the basic education of fitness instructors. PMID- 21305593 TI - 19F MRI detection of acute allograft rejection with in vivo perfluorocarbon labeling of immune cells. AB - Current diagnosis of organ rejection following transplantation relies on tissue biopsy, which is not ideal due to sampling limitations and risks associated with the invasive procedure.We have previously shown that cellular magnetic resonance imaging (MRI) of iron-oxide labeled immune-cell infiltration can provide a noninvasive measure of rejection status by detecting areas of hypointensity on T 2*-weighted images. In this study, we tested the feasibility of using a fluorine based cellular tracer agent to detect macrophage accumulation in rodent models of acute allograft rejection by fluorine-19 ((19) F) MRI and magnetic resonance spectroscopy. This study used two rat models of acute rejection, including abdominal heterotopic cardiac transplant and orthotopic kidney transplant models. Following in vivo labeling of monocytes and macrophages with a commercially available agent containing perfluoro-15-crown-5-ether, we observed (19) F-signal intensity in the organs experiencing rejection by (19) F MRI, and conventional (1) H MRI was used for anatomical context. Immunofluorescence and histology confirmed macrophage labeling. These results are consistent with our previous studies and show the complementary nature of the two cellular imaging techniques. With no background signal, (19) F MRI/magnetic resonance spectroscopy can provide unambiguous detection of fluorine labeled cells, and may be a useful technique for detecting and quantifying rejection grade in patients. PMID- 21305594 TI - Regularized iterative reconstruction for undersampled BLADE and its applications in three-point Dixon water-fat separation. AB - In MRI, the suppression of fat signal is very important for many applications. Multipoint Dixon based water-fat separation methods are commonly used due to its robustness to B(0) homogeneity compared with other fat suppression methods, such as spectral fat saturation. The traditional Cartesian k-space trajectory based multipoint Dixon technique is sensitive to motion, such as pulsatile blood flow, resulting in artifacts that compromise image quality. This work presents a three point Dixon water-fat separation method using undersampled BLADE (aka PROPELLER) for motion robustness and speed. A regularized iterative reconstruction method is then proposed for reducing the streaking artifacts coming from undersampling. In this study, the performance of the regularized iterative reconstruction method is first tested by simulations and on MR phantoms. The performance of the proposed technique is then evaluated in vivo by comparing it with conventional fat suppression methods on the human brain and knee. Experiments show that the presented method delivers reliable water-fat separation results. The reconstruction method suppresses streaking artifacts typical for undersampled BLADE acquisition schemes without missing fine structures in the image. PMID- 21305595 TI - Microscopic and compartment shape anisotropies in gray and white matter revealed by angular bipolar double-PFG MR. AB - Diffusion MR has become one of the most important tools for studying neuronal tissues. Conventional single-pulsed-field-gradient methodologies are capable of faithfully depicting diffusion anisotropy in coherently ordered structures, providing important microstructural information; however, it is extremely difficult to characterize randomly oriented compartments using conventional single-pulsed-field-gradient MR. The angular double-pulsed-field-gradient methodology can potentially overcome the limitations of conventional single pulsed-field-gradient MR, and offer microstructural information on microscopic anisotropy and compartment shape anisotropy even when anisotropic compartments are completely randomly oriented. Here, we used angular double-pulsed-field gradient MR at different mixing times to study isolated gray matter and white matter, respectively, and the results are compared with phantoms in which compartments are randomly oriented and coherently organized, respectively. We find that angular bipolar double-pulsed-field-gradient MR offers novel microstructural information, especially in the gray matter, depicting the local microscopic and compartment shape anisotropies present. Furthermore, direct comparison between the angular dependencies arising from white and gray matter at different mixing times reveals signatures for these tissues that are based on compartment shape anisotropy. These findings demonstrate that microstructural information can indeed be obtained from gray matter, and therefore, angular double-pulsed-field-gradient MR is promising for future application in MRI of the central-nervous-system. PMID- 21305596 TI - Optimization of iron oxide nanoparticle detection using ultrashort echo time pulse sequences: comparison of T1, T2*, and synergistic T1- T2* contrast mechanisms. AB - Iron oxide nanoparticles (IONPs) are used in various MRI applications as negative contrast agents. A major challenge is to distinguish regions of signal void due to IONPs from those due to low signal tissues or susceptibility artifacts. To overcome this limitation, several positive contrast strategies have been proposed. Relying on IONP T(1) shortening effects to generate positive contrast is a particularly appealing strategy because it should provide additional specificity when associated with the usual negative contrast from effective transverse relaxation time (T(2)*) effects. In this article, ultrashort echo time imaging is shown to be a powerful technique which can take full advantage of both contrast mechanisms. Methods of comparing T(1) and T(2)* contrast efficiency are described and general rules that allow optimizing IONP detection sensitivity are derived. Contrary to conventional wisdom, optimizing T(1) contrast is often a good strategy for imaging IONPs. Under certain conditions, subtraction of a later echo signal from the ultrashort echo time signal not only improves IONP specificity by providing long T(2)* background suppression but also increases detection sensitivity, as it enables a synergistic combination of usually antagonist T(1) and T(2)* contrasts. In vitro experiments support our theory, and a molecular imaging application is demonstrated using tumor-targeted IONPs in vivo. PMID- 21305597 TI - Neural precursors exhibit distinctly different patterns of cell migration upon transplantation during either the acute or chronic phase of EAE: a serial MR imaging study. AB - As the complex pathogenesis of multiple sclerosis contributes to spatiotemporal variations in the trophic micromilieu of the central nervous system, the optimal intervention period for cell-replacement therapy must be systematically defined. We applied serial, 3D high-resolution magnetic resonance imaging to transplanted neural precursor cells (NPCs) labeled with superparamagnetic iron oxide nanoparticles and 5-bromo-2-deoxyuridine, and compared the migration pattern of NPCs in acute inflamed (n = 10) versus chronic demyelinated (n = 9) brains of mice induced with experimental allergic encephalomyelitis (EAE). Serial in vivo and ex-vivo 3D magnetic resonance imaging revealed that NPCs migrated 2.5 +/- 1.3 mm along the corpus callosum in acute EAE. In chronic EAE, cell migration was slightly reduced (2.3 +/- 1.3 mm) and only occurred in the lateral side of transplantation. Surprisingly, in 6/10 acute EAE brains, NPCs were found to migrate in a radial pattern along RECA-1(+) cortical blood vessels, in a pattern hitherto only reported for migrating glioblastoma cells. This striking radial biodistribution pattern was not detected in either chronic EAE or disease-free control brains. In both acute and chronic EAE brain, Iba1(+) microglia/macrophage number was significantly higher in central nervous system regions containing migrating NPCs. The existence of differential NPC migration patterns is an important consideration for implementing future translational studies in multiple sclerosis patients with variable disease. PMID- 21305598 TI - MRI artifacts in human brain tissue after prolonged formalin storage. AB - For the interpretation of magnetic resonance imaging (MRI) abnormalities in brain pathology, often ex vivo tissue is used. The purpose of this study was to determine the pathological substrate of several distinct forms of MR hypointensities that were found in formalin-fixed brain tissue with amyloid-beta deposits. Samples of brain cortex were scanned using effective transverse relaxation time-weighted protocols at several resolutions on a 9.4 T MRI scanner. High resolution MRI showed large coarse hypointensities throughout the cortical gray and white matter, corresponding to macroscopic discolorations and microscopic circumscribed areas of granular basophilic neuropil changes, without any further specific tissue reactions or amyloid-beta related pathology. These coarse MRI hypointensities were identified as localized areas of absent neuropil replaced by membrane/myelin sheath remnants using electron microscopy. Interestingly, the presence/absence of these tissue alterations was not related to amyloid deposits, but strongly correlated to the fixation time of the samples in unrefreshed formalin. These findings show that prolonged storaged of formalin fixed brain tissue results in subtle histology artifacts, which show on MRI as hypointensities that on first appearance are indistinguishable from genuine brain pathology. This indicates that postmortem MRI should be interpreted with caution, especially if the history of tissue preservation is not fully known. PMID- 21305599 TI - Effects of inflow and radiofrequency spoiling on the arterial input function in dynamic contrast-enhanced MRI: a combined phantom and simulation study. AB - The arterial input function is crucial in pharmacokinetic analysis of dynamic contrast-enhanced MRI data. Among other artifacts in arterial input function quantification, the blood inflow effect and nonideal radiofrequency spoiling can induce large measurement errors with subsequent reduction of accuracy in the pharmacokinetic parameters. These errors were investigated for a 3D spoiled gradient-echo sequence using a pulsatile flow phantom and a total of 144 typical imaging settings. In the presence of large inflow effects, results showed poor average accuracy and large spread between imaging settings, when the standard spoiled gradient-echo signal equation was used in the analysis. For example, one of the investigated inflow conditions resulted in a mean error of about 40% and a spread, given by the coefficient of variation, of 20% for K(trans). Minimizing inflow effects by appropriate slice placement, combined with compensation for nonideal radiofrequency spoiling, significantly improved the results, but they remained poorer than without flow (e.g., 3-4 times larger coefficient of variation for K(trans)). It was concluded that the 3D spoiled gradient-echo sequence is not optimal for accurate arterial input function quantification and that correction for nonideal radiofrequency spoiling in combination with inflow minimizing slice placement should be used to reduce the errors. PMID- 21305600 TI - Investigating temporal fluctuations in tumor vasculature with combined carbogen and ultrasmall superparamagnetic iron oxide particle (CUSPIO) imaging. AB - A combined carbogen ultrasmall superparamagnetic iron oxide (USPIO) imaging protocol was developed and applied in vivo in two murine colorectal tumor xenograft models, HCT116 and SW1222, with established disparate vascular morphology, to investigate whether additional information could be extracted from the combination of two susceptibility MRI biomarkers. Tumors were imaged before and during carbogen breathing and subsequently following intravenous administration of USPIO particles. A novel segmentation method was applied to the image data, from which six categories of R(2)* response were identified, and compared with histological analysis of the vasculature. In particular, a strong association between a negative DeltaR(2)*(carbogen) followed by positive DeltaR(2)*(USPIO) with the uptake of the perfusion marker Hoechst 33342 was determined. Regions of tumor tissue where there was a significant DeltaR(2)*(carbogen) but no significant DeltaR(2)*(USPIO) were also identified, suggesting these regions became temporally isolated from the vascular supply during the experimental timecourse. These areas correlated with regions of tumor tissue where there was CD31 staining but no Hoechst 33342 uptake. Significantly, different combined carbogen USPIO responses were determined between the two tumor models. Combining DeltaR(2)*(carbogen) and DeltaR(2)*(USPIO) with a novel segmentation scheme can facilitate the interpretation of susceptibility contrast MRI data and enable a deeper interrogation of tumor vascular function and architecture. PMID- 21305601 TI - Contrast-enhanced whole-heart coronary magnetic resonance angiography at 3 T with radial EPI. AB - Whole-heart coronary magnetic resonance angiography is a promising method for detecting coronary artery disease. However, the imaging time is relatively long (typically 10-15 min). The goal of this study was to implement a radial echo planar imaging sequence for contrast-enhanced whole-heart coronary magnetic resonance angiography, with the aim of combining the scan efficiency of echo planar imaging with the motion insensitivity of radial k-space sampling. A self calibrating phase correction technique was used to correct for off-resonance effects, trajectory measurement was used to correct for k-space trajectory errors, and variable density sampling was used in the partition direction to reduce streaking artifacts. Seven healthy volunteers and two patients were scanned with the proposed radial echo planar imaging sequence, and the images were compared with a traditional gradient echo and X-ray angiography techniques, respectively. Whole-heart images with the radial EPI technique were acquired with a resolution of 1.0 * 1.0 * 2.0 mm(3) in a scan time of 5 min. In healthy volunteers, the average image quality scores and visualized vessel lengths of the RCA and LAD were similar for the radial EPI and gradient echo techniques (P value > 0.05 for all). Anecdotal patient studies showed excellent agreement of the radial EPI technique with X-ray angiography. PMID- 21305602 TI - Spectrally selective pencil-beam navigator for motion compensation of MR-guided high-intensity focused ultrasound therapy of abdominal organs. AB - MR-guided high-intensity focused ultrasound (MR-HIFU) is a noninvasive technique for depositing thermal energy in a controlled manner deep within the body. However, the MR-HIFU treatment of mobile abdominal organs is problematic as motion-related thermometry artifacts need to be corrected and the focal point position must be updated in order to follow the moving organ to avoid damaging healthy tissue. In this article, a fat-selective pencil-beam navigator is proposed for real-time monitoring and compensation of through-plane motion. As opposed to the conventional spectrally nonselective navigator, the fat-selective navigator does not perturb the water-proton magnetization used for proton resonance frequency shift thermometry. This allows the proposed navigator to be placed directly on the target organ for improved motion estimation accuracy. The spectral and spatial selectivity of the proposed navigator pulse is evaluated through simulations and experiments, and the improved slice tracking performance is demonstrated in vivo by tracking experiments on a human kidney and on a human liver. The direct motion estimation provided by the fat-selective navigator is also shown to enable accurate motion compensated MR-HIFU therapy of in vivo porcine kidney, including motion compensation of thermometry and beam steering based on the observed three-dimensional kidney motion. PMID- 21305603 TI - Preterm neonatal diffusion processing using detection and replacement of outliers prior to resampling. AB - In diffusion weighted MRI, subject motion and brain pulsation lead both to signal drop-outs and image misalignment. Unsedated neonates, with their higher heart rate and propensity for motion are particularly prone to degraded scan quality that impairs diffusion tensor estimation. Retrospective registration and robust estimators are two methods that have previously been demonstrated to address motion and intensity outliers, respectively, in diffusion data. However, when taken together, the resampling of images to correct for misalignment can have the effect of averaging outlier voxels with uncorrupted voxels, thereby making outliers more difficult to detect. This article presents a method to remove outliers prior to resampling while taking misalignment into account so that this averaging of outliers with good data can be avoided. The proposed method is compared to other processing pipelines using simulations and data from unsedated preterm neonates. These results demonstrate advantages to the proposed method, particularly in subjects with high motion. PMID- 21305604 TI - Concurrent MR blood volume and vessel size estimation in tumors by robust and simultaneous DeltaR2 and DeltaR2* quantification. AB - This work presents a novel method for concurrent estimation of the fractional blood volume and the mean vessel size of tumors based on a multi-gradient-echo multi-spin-echo sequence and the injection of a super-paramagnetic blood-pool agent. The approach further comprises a post-processing technique for simultaneous estimation of changes in the transverse relaxation rates R(2) and R(2)*, which is robust against global B(0) and B(1) field inhomogeneities and slice imperfections. The accuracy of the simultaneous DeltaR(2) and DeltaR(2)* quantification approach is evaluated in a phantom. The simultaneous blood volume and vessel size estimates, obtained with MR, compare well to the immunohistological findings in a preclinical experiment (HT1080 cells, implanted in nude mice). Clinical translation is achieved in a patient with a pleomorphic sarcoma in the left pubic bone. The latter demonstrates the robustness of the technique against changes in the contrast agent concentration in blood during washout. PMID- 21305605 TI - Association of hip strength estimates by finite-element analysis with fractures in women and men. AB - Finite-element analysis (FEA) of quantitative computed tomography (QCT) scans can estimate site-specific whole-bone strength. However, it is uncertain whether the site-specific detail included in FEA-estimated proximal femur (hip) strength can determine fracture risk at sites with different biomechanical characteristics. To address this question, we used FEA of proximal femur QCT scans to estimate hip strength and load-to-strength ratio during a simulated sideways fall and measured total hip areal and volumetric bone mineral density (aBMD and vBMD) from QCT images in an age-stratified random sample of community-dwelling adults age 35 years or older. Among 314 women (mean age +/- SD: 61 +/- 15 years; 235 postmenopausal) and 266 men (62 +/- 16 years), 139 women and 104 men had any prevalent fracture, whereas 55 Women and 28 men had a prevalent osteoporotic fracture that had occurred at age 35 years or older. Odds ratios by age-adjusted logistic regression analysis for prevalent overall and osteoporotic fractures each were similar for FEA hip strength and load-to-strength ratio, as well as for total hip aBMD and vBMD. C-statistics (estimated areas under ROC curves) also were similar [eg, 0.84 to 0.85 (women) and 0.75 to 0.78 (men) for osteoporotic fractures]. In women and men, the association with prevalent osteoporotic fractures increased below an estimated hip strength of approximately 3000 N. Despite its site-specific nature, FEA-estimated hip strength worked equally well at predicting prevalent overall and osteoporotic fractures. Furthermore, an estimated hip strength below 3000 N may represent a critical level of systemic skeletal fragility in both sexes that warrants further investigation. PMID- 21305606 TI - Differences in bone microarchitecture between postmenopausal Chinese-American and white women. AB - Chinese-American women have lower rates of hip and forearm fracture than white women despite lower areal bone density (aBMD) by dual X-ray absorptiometry (DXA). We recently reported higher trabecular (D(trab) ) and cortical (D(comp) ) bone density as well as greater trabecular (Tb.Th) and cortical thickness (C.Th) but smaller bone area (CSA), as measured by high-resolution peripheral quantitative computed tomography (HR-pQCT), in premenopausal Chinese-American compared with white women. These findings may help to account for the lower fracture rate among Chinese-American women but were limited to measurements in premenopausal women. This study was designed to extend these investigations to postmenopausal Chinese American (n = 29) and white (n = 68) women. Radius CSA was 10% smaller in the Chinese-American versus the white group (p = .008), whereas their C.Th and D(comp) values were 18% and 6% greater (p < .001 for both). Tibial HR-pQCT results for cortical bone were similar to the radius, but Tb.Th was 11% greater in Chinese-American versus white women (p = .007). Tibial trabecular number and spacing were 17% lower and 20% greater, respectively, in Chinese-American women (p < .0001 for both). There were no differences in trabecular or whole-bone stiffness estimated by microstructural finite-element analysis, but Chinese American women had a greater percentage of load carried by the cortical bone compartment at the distal radius and tibia. There was no difference in load distribution at the proximal radius or tibia. Whole-bone finite-element analysis may indicate that the thicker, more dense cortical bone and thicker trabeculae in postmenopausal Chinese-American women compensate for fewer trabeculae and smaller bone size. PMID- 21305607 TI - Osteal macrophages promote in vivo intramembranous bone healing in a mouse tibial injury model. AB - Bone-lining tissues contain a population of resident macrophages termed osteomacs that interact with osteoblasts in vivo and control mineralization in vitro. The role of osteomacs in bone repair was investigated using a mouse tibial bone injury model that heals primarily through intramembranous ossification and progresses through all major phases of stabilized fracture repair. Immunohistochemical studies revealed that at least two macrophage populations, F4/80(+) Mac-2(-/low) TRACP(-) osteomacs and F4/80(+) Mac-2(hi) TRACP(-) inflammatory macrophages, were present within the bone injury site and persisted throughout the healing time course. In vivo depletion of osteomacs/macrophages (either using the Mafia transgenic mouse model or clodronate liposome delivery) or osteoclasts (recombinant osteoprotegerin treatment) established that osteomacs were required for deposition of collagen type 1(+) (CT1(+)) matrix and bone mineralization in the tibial injury model, as assessed by quantitative immunohistology and micro-computed tomography. Conversely, administration of the macrophage growth factor colony-stimulating factor 1 (CSF-1) increased the number of osteomacs/macrophages at the injury site significantly with a concurrent increase in new CT1(+) matrix deposition and enhanced mineralization. This study establishes osteomacs as participants in intramembranous bone healing and as targets for primary anabolic bone therapies. PMID- 21305608 TI - The V-ATPase a3 subunit mutation R740S is dominant negative and results in osteopetrosis in mice. AB - A mouse founder with high bone mineral density and an osteopetrotic phenotype was identified in an N-ethyl-N-nitrosourea (ENU) screen. It was found to carry a dominant missense mutation in the Tcirg1 gene that encodes the a3 subunit of the vacuolar type H(+)-ATPase (V-ATPase), resulting in replacement of a highly conserved amino acid (R740S). The +/R740S mice have normal appearance, size, and weight but exhibit high bone density. Osteoblast parameters are unaffected in bones of +/R740S mice, whereas osteoclast number and marker expression are increased, concomitant with a decrease in the number of apoptotic osteoclasts. Consistent with reduced osteoclast apoptosis, expression of Rankl and Bcl2 is elevated, whereas Casp3 is reduced. Transmission electron microscopy revealed that unlike other known mutations in the a3 subunit of V-ATPase, polarization and ruffled border formation appear normal in +/R740S osteoclasts. However, V-ATPases from +/R740S osteoclast membranes have severely reduced proton transport, whereas ATP hydrolysis is not significantly affected. We show for the first time that a point mutation within the a3 subunit, R740S, which is dominant negative for proton pumping and bone resorption, also uncouples proton pumping from ATP hydrolysis but has no effect on ruffled border formation or polarization of osteoclasts. These results suggest that the V(0) complex has proton-pumping independent functions in mammalian cells. PMID- 21305609 TI - Regulation of RANKL-induced osteoclastogenesis by TGF-beta through molecular interaction between Smad3 and Traf6. AB - Previous studies have shown that transforming growth factor beta (TGF-beta) promotes receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclastogenesis. However, the underlying molecular mechanisms have not been elucidated. When TGF-beta signals were blocked either by a specific inhibitor of TGF-beta type 1 receptor kinase activity, SB431542, or by introducing a dominant negative mutant of TGF-beta type 2 receptor, RANKL-induced osteoclastogenesis was almost completely suppressed. Blockade of Smad signaling by overexpression of Smad7 or c-Ski markedly suppressed RANKL-induced osteoclastogenesis, and retroviral induction of an activated mutant of Smad2 or Smad3 reversed the inhibitory effect of SB431542. Immunoprecipitation analysis revealed that Smad2/3 directly associates with the TRAF6-TAB1-TAK1 molecular complex, which is generated in response to RANKL stimulation and plays an essential role in osteoclast differentiation. TRAF6-TAB1-TAK1 complex formation was not observed when TGF-beta signaling was blocked. Analysis using deletion mutants revealed that the MH2 domain of Smad3 is necessary for TRAF6-TAB1-TAK1 complex formation, downstream signal transduction, and osteoclast formation. In addition, gene silencing of Smad3 in osteoclast precursors markedly suppressed RANKL-induced osteoclast differentiation. In summary, TGF-beta is indispensable in RANKL induced osteoclastogenesis, and the binding of Smad3 to the TRAF6-TAB1-TAK1 complex is crucial for RANKL-induced osteoclastogenic signaling. PMID- 21305610 TI - Prolactin as a biomarker for treatment response and tardive dyskinesia in schizophrenia subjects: old thoughts revisited from a genetic perspective. AB - Previous studies investigated whether prolactin (PRL) serum level was a biomarker of antipsychotic response, schizophrenia symptomatology, and tardive dyskinesia. Most of the findings support that antipsychotic drugs modulate PRL levels but PRL is not a steady indicator. Recent results suggest a genetic effect of PRL and PRL receptor (PRLR) polymorphisms in PRL levels indicating that independently of antipsychotic therapy subjects could have altered PRL levels due to their genetic background.We evaluated whether PRL and PRLR variants were associated with treatment outcome and tardive dyskinesia. We observed no association of PRL/PRLR polymorphism with treatment response (best genotypic results include PRL rs849885 and PRLR rs4703509 permuted p=0.326). Regarding tardive dyskinesia, the major allele of PRL rs37364 was nominally associated with risk for tardive dyskinesia in the European ancestry sub-sample (permuted p=0.183). Although we reported no significant associations, it is definitely worthy of investigation to see if together (genetic variants in the PRL system and PRL serum measures) could be a reliable biomarker for antipsychotic response and TD prevalence. Our results suggest that more studies in this context are required to shed light in the molecular mechanisms underlying antipsychotic response and tardive dyskinesia occurrence. PMID- 21305611 TI - The acute effect of Swedish-style snus on cigarette craving and self administration in male and female smokers. AB - INTRODUCTION: Swedish-style snus (SS) has recently garnered controversy for its proposed use as a smoking cessation aid and/or harm reduction tool. However, to date, little work has been done to evaluate the extent to which SS affects cigarette cravings and smoking behavior under double-blind controlled conditions. METHODS: During four double-blind placebo-controlled randomized sessions, 15 smokers (8 male) administered SS, placebo (nicotine/tobacco-free) snus (PS), a nicotine-containing lozenge (NL), or a placebo lozenge (PL) for 30 min and assessed their effects using Visual Analogue Scales and the Brief Questionnaire of Smoking Urges. They could then self-administer their usual brand of cigarettes using a progressive ratio task over the next 60 min. Following the completion of their final session, 11 participants (6 male) ranked each of the products used in the study in terms of their preferences. RESULTS: Relative to the other products, SS was associated with a decreased intention to smoke as well as a delayed onset of cigarette smoking in men but not women. However, SS administration was also associated with increased feelings of frustration and irritability relative to NL and SS was ranked as being the least preferred product used in the study. DISCUSSION: Findings suggest that SS is effective in acutely suppressing craving and smoking in at least some smokers, but that its acceptability may be limited. PMID- 21305612 TI - An open, non-randomised comparison of escitalopram and duloxetine for the treatment of subjects with Generalized Anxiety Disorder. AB - OBJECTIVES: This study compares the effectiveness of a 6-months treatment with escitalopram (ESC), a selective serotonin reuptake inhibitor, or duloxetine (DUL), a balanced serotonin and nor-adrenaline reuptake inhibitor, in 43 subjects with Generalized Anxiety Disorder (GAD). METHODS: Assessment was made with the Hamilton Anxiety and Depression scales (HAM-A; HAM-D), with the CGI, and with the GAF at T0 (intake), T1, T3, T6 (1, 3, and 6 months later). The comparison among the two treatment groups (ESC=20; DUL=23) at the four endpoints was made through a GLM-ANOVA for repeated measures. Rates of remission (HAM-A<7), response (HAM-A reduction of 50% or above) and dropout were evaluated. RESULTS: At 1, 3, and 6 months after treatment inception both treatment groups showed a significant improvement in the scores of CGI, HAMA, HAM-D, and GAF, and an equivalent rate of dropout. The DUL group registered a greater amount of remission and response rates at T1 against the ESC group in all the scales except in the HAM-D scale. Duloxetine was more effective than escitalopram after the first month of treatment only in the somatic subscale of HAM-A. The presence of a cluster C personality disorder was associated in both groups to greater difficulties in attaining remission and to dropout. CONCLUSIONS: Implications for clinical practice are discussed. PMID- 21305613 TI - Maintenance and regulation of extracellular volume and the ion environment in Drosophila larval nerves. AB - In mammals and insects, paracellular blood barriers isolate the nervous system from the rest of the animal. Glia and accessory cells of the nervous system use pumps, channels, cotransporters, and exchangers collectively to maintain the extracellular ion environment and osmotic balance in the nervous system. At present, the molecular mechanisms that regulate this process remain unclear. In humans, loss of extracellular ion and volume regulation in the nervous system poses serious health threats. Drosophila is a model genetic organism with a proven track record for uncovering molecular mechanisms relevant to human health and disease. Here, we review what is known about extracellular ion and volume regulation in larval abdominal nerves, present some new data about the impact of neural activity on the extracellular environment, and relate the findings to mammalian systems. Homologies have been found at the level of morphology, physiology, molecular mechanisms, and mutant phenotypes. The Fray-Ncc69 module regulates extracellular volume in larval nerves. Genetic rescue experiments with the mammalian orthologs prove this module has a direct correlate in humans. This and other molecular homologies, together with the similar physiological needs, suggest that uncovering the molecular mechanisms of ion and volume regulation in larval nerves will likely provide significant insights into this process in mammalian systems. PMID- 21305615 TI - Differential expression of inwardly rectifying K+ channels and aquaporins 4 and 5 in autoimmune uveitis indicates misbalance in Muller glial cell-dependent ion and water homeostasis. AB - Reactive gliosis is a well-established response to virtually every retinal disease. Autoimmune uveitis, a sight threatening disease, is characterized by recurrent relapses through autoaggressive T-cells. The purpose of this study was to assess retinal Muller glial cell function in equine recurrent uveitis (ERU), a spontaneous disease model resembling the human disease, by investigating membrane proteins implicated in ion and water homeostasis. We found that Kir2.1 was highly expressed in diseased retinas, whereas Kir4.1 was downregulated in comparison to controls. Distribution of Kir2.1 appeared Muller cell associated in controls, whereas staining of cell somata in the inner nuclear layer was observed in uveitis. In contrast to other subunits, Kir4.1 was evenly expressed along equine Muller cells, whereas in ERU, Kir4.1 almost disappeared from Muller cells. Hence, we suggest a different mechanism for potassium buffering in the avascular equine retina and, moreover, an impairment in uveitis. Uveitic retinas showed significantly increased expression of AQP4 as well as a displaced expression from Muller cells in healthy specimens to an intense circular expression pattern in the outer nuclear layer in ERU cases. Most interestingly, we detected the aquaporin family member protein AQP5 to be expressed in Muller cells with strong enrichments in Muller cell secondary processes. This finding indicates that fluid regulation within the equine retina may be achieved by an additional aquaporin. Furthermore, AQP5 was significantly decreased in uveitis. We conclude that the Muller cell response in autoimmune uveitis implies considerable changes in its potassium and water physiology. PMID- 21305614 TI - New tools for the analysis of glial cell biology in Drosophila. AB - Because of its genetic, molecular, and behavioral tractability, Drosophila has emerged as a powerful model system for studying molecular and cellular mechanisms underlying the development and function of nervous systems. The Drosophila nervous system has fewer neurons and exhibits a lower glia:neuron ratio than is seen in vertebrate nervous systems. Despite the simplicity of the Drosophila nervous system, glial organization in flies is as sophisticated as it is in vertebrates. Furthermore, fly glial cells play vital roles in neural development and behavior. In addition, powerful genetic tools are continuously being created to explore cell function in vivo. In taking advantage of these features, the fly nervous system serves as an excellent model system to study general aspects of glial cell development and function in vivo. In this article, we review and discuss advanced genetic tools that are potentially useful for understanding glial cell biology in Drosophila. PMID- 21305616 TI - Pattern of invasion of the embryonic mouse spinal cord by microglial cells at the time of the onset of functional neuronal networks. AB - Microglial cells invade the central nervous system during embryonic development, but their developmental functional roles in vivo remain largely unknown. Accordingly, their invasion pattern during early embryonic development is still poorly understood. To address this issue, we analyzed the initial developmental pattern of microglial cell invasion in the spinal cord of CX3CR1-eGFP mouse embryos using immunohistochemistry. Microglial cells began to invade the mouse embryonic spinal cord at a developmental period corresponding to the onset of spontaneous electrical activity and of synaptogenesis. Microglial cells reached the spinal cord through the peripheral vasculature and began to invade the parenchyma at 11.5 days of embryonic age (E11.5). Remarkably, at E12.5, activated microglial cells aggregated in the dorsolateral region close to terminals of dying dorsal root ganglia neurons. At E13.5, microglial cells in the ventral marginal zone interacted with radial glial cells, whereas ramified microglial cells within the parenchyma interacted with growing capillaries. At this age, activated microglial cells (Mac-2 staining) also accumulated within the lateral motor columns at the onset of the developmental cell death of motoneurons. This cell aggregation was still observed at E14.5, but microglial cells no longer expressed Mac-2. At E15.5, microglial cells were randomly distributed within the parenchyma. Our results provide the essential basis for further studies on the role of microglial cells in the early development of spinal cord neuronal networks in vivo. PMID- 21305618 TI - Prediction of sexual trauma via disruption of sex-aggression associations. AB - A variant of the Implicit Association Test focusing on the association of sexual and aggressive themes was administered to 90 college students (61 women) and correlated with a series of variables based on participant history of sexually traumatic events. A history of sexual abuse was correlated with increased difficulties in processing sexual and aggressive concepts simultaneously. Furthermore, this relationship remained significant after controlling for general level of emotional distress, and even after controlling for self-reported aggressiveness and positive feelings towards sex. The findings provide grounds for further exploration of deficits in associations between sexual and aggressive concepts as a possible indicator of the cognitive effects of sexual abuse. PMID- 21305619 TI - Resource loss and posttraumatic responses in Bedouin members of the Israeli Defense Forces. AB - This study examined the impact of exposure to traumatizing events in an ethnic minority group of Bedouin members of the Israel Defense Forces (N = 317). Guided by the conservation of resources (COR) theory (Hobfoll, 1988), the authors hypothesized that loss of resources would mediate the relationship between trauma and posttraumatic responses. We found that loss of personal resources (e.g., self esteem, self-mastery) was the best predictor of psychological distress among traumatized Bedouin servicemen. Our findings suggest the significance of personal resources within collectivist communities in coping with trauma and maintaining resilience. This study contributes to the understanding of the ethnocultural aspects of trauma and the potential interventions that may be tailored for minority groups. PMID- 21305617 TI - Genetic modeling of gliomas in mice: new tools to tackle old problems. AB - The recently published comprehensive profiles of genomic alterations in glioma have led to a refinement in our understanding of the molecular events that underlie this cancer. Using state-of-the-art genomic tools, several laboratories have created and characterized accurate genetically engineered mouse models of glioma based on specific genetic alterations observed in human tumors. These in vivo brain tumor models faithfully recapitulate the histopathology, etiology, and biology of gliomas and provide an exceptional experimental system to discover novel therapeutic targets and test therapeutic agents. This review focuses on mouse models of glioma with a special emphasis on genetically engineered models developed around key genetic glioma signature mutations in the PDGFR, EGFR, and NF1 genes and pathways. The resulting animal models have provided insight into many fundamental and mechanistic facets of tumor initiation, maintenance and resistance to therapeutic intervention and will continue to do so in the future. PMID- 21305621 TI - Ring-rearrangement metathesis of nitroso Diels-Alder cycloadducts. AB - Strained nitroso Diels-Alder bicyclo[2.2.1] or [2.2.2] adducts functionalized with alkene side chains of diverse length undergo a ring-rearrangement metathesis process with external alkenes and Grubbs II or Hoveyda-Grubbs II ruthenium catalysts, under microwave irradiation or classical heating, to deliver cis-fused bicycles of various ring sizes, which contain a N-O bond. These scaffolds are of synthetic relevance for the generation of molecular diversity and to the total synthesis of alkaloids. The observation of unexpected reactions, such as epimerization or one-carbon homologation of the alkene side chain, is also reported. PMID- 21305620 TI - A click fluorophore sensor that can distinguish Cu(II) and Hg(II) via selective anion-induced demetallation. AB - A cyclam-based fluorescent sensor featuring a novel triazole pendant arm has been synthesised using click chemistry. The sensor is highly responsive to both Cu(II) and Hg(II) in neutral aqueous solution and displays excellent selectivity in the presence of various competing metal ions in 50-fold excess. The addition of specific anions such as I(-) and S(2)O(3)(2-) causes a complete revival of fluorescence only in the case of Hg(II), providing a simple and effective method for distinguishing solutions containing Cu(II), Hg(II) or a mixture of both ions, even in doped seawater samples. X-ray crystal structures of both the Hg(II) sensor complex and a model Cu(II) complex show that pendant triazole coordination occurs through the central nitrogen atom (N2), providing to the best of our knowledge the first reported examples of this unusual coordination mode in macrocycles. Fluorescence, mass spectrometry and (1)H NMR experiments reveal that the mechanism of anion-induced fluorescence revival involves either displacement of pendant coordination or complete removal of the Hg(II) from the macrocycle, depending on the anion. PMID- 21305622 TI - Coke formation during the methanol-to-olefin conversion: in situ microspectroscopy on individual H-ZSM-5 crystals with different Bronsted acidity. AB - Coke formation during the methanol-to-olefin (MTO) conversion has been studied at the single-particle level with in situ UV/Vis and confocal fluorescence microscopy. For this purpose, large H-ZSM-5 crystals differing in their Si/Al molar ratio have been investigated. During MTO, performed at 623 and 773 K, three major UV/Vis bands assigned to different carbonaceous deposits and their precursors are observed. The absorption at 420 nm, assigned to methyl-substituted aromatic compounds, initiates the buildup of the optically active coke species. With time-on-stream, these carbonaceous compounds expand in size, resulting in the gradual development of a second absorption band at around 500 nm. An additional broad absorption band in the 600 nm region indicates the enhanced formation of extended carbonaceous compounds that form as the reaction temperature is raised. Overall, the rate of coke formation decreases with decreasing aluminum content. Analysis of the reaction kinetics indicates that an increased Bronsted acid site density facilitates the formation of larger coke species and enhances their formation rate. The use of multiple excitation wavelengths in confocal fluorescence microscopy enables the localization of coke compounds with different molecular dimensions in an individual H-ZSM-5 crystal. It demonstrates that small coke species evenly spread throughout the entire H-ZSM 5 crystal, whereas extended coke deposits primarily form near the crystal edges and surfaces. Polarization-dependent UV/Vis spectroscopy measurements illustrate that extended coke species are predominantly formed in the straight channels of H ZSM-5. In addition, at higher temperatures, fast deactivation leads to the formation of large aromatic compounds within channel intersections and at the external zeolite surface, where the lack of spatial restrictions allows the formation of graphite-like coke. PMID- 21305623 TI - Enlightened enzymes: strategies to create novel photoresponsive proteins. AB - The photocontrol of protein functions, enzymatic reactions, and concomitantly biological activities in living cells and organisms represents a rapidly developing and interdisciplinary field of research at the interface of chemistry and biology. The nature of light allows for a non-invasive gearing with unprecedented spatiotemporal resolution to exert control at the molecular and cellular level. This concept article aims to illustrate some of the classic as well as recently developed strategies employing protein-engineering and chemical biological hybrid methods to achieve photocontrol of biological processes. Recent cell biological examples will be highlighted and possible biotechnological applications will be presented. PMID- 21305625 TI - A cationic dye triplet as a unique "glue" that can connect fully matched termini of DNA duplexes. AB - In this study, we propose that three consecutive cationic p-methylstilbazoles tethered on D-threoninols (Z residues) at 5' termini act as a unique "glue" connecting DNA duplexes by their interstrand cluster formation. Interstrand clustering of p-methylstilbazoles (ZZZ triplets) induces narrowing and hypsochromic shift of bands at 350 nm, which can be assigned to the absorption of p-methylstilbazole. However, single-stranded DNA conjugates involving a ZZZ triplet at the 5' terminus of 8-mer native nucleotides is found not to induce such large spectral changes, which implies that the intrinsic self-assembling property of ZZZ triplets is weak. Interestingly, when this conjugate is hybridized with a complementary 8-mer native oligonucleotide, a remarkable spectral change is observed, indicating the dimerization of a duplex through the interstrand clustering of ZZZ triplets. Dimerization of the duplex is also evidenced by cold-spray ionization mass spectrometry. This interstrand clustering is observed only when a ZZZ triplet is tethered to a 5' rather than 3' terminus. Furthermore, the stability of the interstrand cluster increases by increasing the number of nucleobases of the DNA portion, and when mismatched base pairs are incorporated or when a base next to the Z residue is deleted, the stability substantially drops. When we apply the ZZZ triplet to the formation of a nanowire using two complementary DNA conjugates, each of which has a ZZZ triplet at the 5' termini as overhang, we demonstrate the successful formation of a nanowire by native PAGE analysis. Since native sticky ends that have three nucleotides do not serve as "glue", ZZZ triplets with their unique glue-like properties are prime candidates for constructing DNA-based nanoarchitectures. PMID- 21305624 TI - Genotyping by alkaline dehybridization using graphically encoded particles. AB - This work describes a nonenzymatic, isothermal genotyping method based on the kinetic differences exhibited in the dehybridization of perfectly matched (PM) and single-base mismatched (MM) DNA duplexes in an alkaline solution. Multifunctional encoded hydrogel particles incorporating allele-specific oligonucleotide (ASO) probes in two distinct regions were fabricated by using microfluidic-based stop-flow lithography. Each particle contained two distinct ASO probe sequences differing at a single base position, and thus each particle was capable of simultaneously probing two distinct target alleles. Fluorescently labeled target alleles were annealed to both probe regions of a particle, and the rate of duplex dehybridization was monitored by using fluorescence microscopy. Duplex dehybridization was achieved through an alkaline stimulus using either a pH step function or a temporal pH gradient. When a single target probe sequence was used, the rate of mismatch duplex dehybridization could be discriminated from the rate of perfect match duplex dehybridization. In a more demanding application in which two distinct probe sequences were used, we found that the rate profiles provided a means to discriminate probe dehybridizations from both of the two mismatched duplexes as well as to distinguish at high certainty the dehybridization of the two perfectly matched duplexes. These results demonstrate an ability of alkaline dehybridization to correctly discriminate the rank hierarchy of thermodynamic stability among four sets of perfect match and single base mismatch duplexes. We further demonstrate that these rate profiles are strongly temperature dependent and illustrate how the sensitivity can be compensated beneficially by the use of an actuating gradient pH field. PMID- 21305626 TI - Engineering O-glycosylation points in non-extended peptides: implications for the molecular recognition of short tumor-associated glycopeptides. AB - The ties that bind: The incorporation of non-natural residues in the peptide backbone allows the design of O-glycosylation points in helical segments. This strategy could help to modulate the binding properties between glycopeptides and their protein receptors, such as lectins and antibodies. PMID- 21305627 TI - Chloropupukeanolides C-E: cytotoxic pupukeanane chlorides with a spiroketal skeleton from Pestalotiopsis fici. AB - Chloropupukeanolides C-E (8-10), three highly functionalized secondary metabolites featuring a novel spiroketal skeleton derived from the chlorinated tricyclo-[4.3.1.0(3, 7)]-decane (pupukeanane) and the 2,6-dihydroxy-4 methylbenzoic acid moieties, were isolated from the scale-up fermentation extract of the plant endophytic fungus Pestalotiopsis fici. The constitutions of compounds 8-10 were elucidated primarily by NMR experiments. Their relative configurations were deduced by analogy to metabolites 4-6, which were previously isolated from the same fungus. The absolute configuration of 8 was assigned by X ray crystallography and those of 9 and 10 by quantum-chemical CD calculations. Biogenetically, chloropupukeanolides C-E (8-10) are presumably derived from the same oxidation-induced Diels-Alder reaction pathway as compounds 1 and 4-7, via the putative biosynthetic precursors 2 and 3. The opposite configurations of the complete "Southern parts" of 8 and 9 suggests that this Diels-Alder reaction is stereochemically not very selective. Compounds 8-10 showed significant cytotoxicity against a small panel of human tumor cell lines and weak activities against the pathogens of tropical diseases. PMID- 21305628 TI - Pd-NHC catalyzed conjugate addition versus the Mizoroki-Heck reaction. AB - Ace of base: A catalytic system is presented that, solely by choice of the base, selectively switches between conjugate addition and the Mizoroki-Heck reaction of aryl halides with Michael acceptors (see scheme; R, R' = alkyl, aryl). For conjugate addition reactions, this avoids the preparation and use of organometallics. PMID- 21305629 TI - Endophytic fungi from Dragon's blood specimens: isolation, identification, phylogenetic diversity and bioactivity. AB - Endophytic fungi from Dragon's blood specimens of different locations of China were characterized taxonomically and investigated concerning their antimicrobial and antitumor activity against six pathogenic microbes and five tumor cells. A total of 49 endophytic fungi were obtained from Dragon's blood materials of Dracaena spp., 18 taxa were represented by 43 (87.8%) isolates and only six (12.2%) isolates were unknown. Twenty (40.8%) of the isolates displayed antimicrobial activity against at least one pathogenic microorganism. Three isolates YNDC07, BJDC06 and BJDC09 displayed significant antimicrobial activities against Staphylococcus aureus, Cryptococcus neoformans and Aspergillus fumigates, respectively. The results of antitumor activity by the MTT assay revealed that 26.5%, 69.4%, 48.9%, 6.1% and 42.9% of isolate fermentation broths displayed growth inhibition on HepG2 cells, SKVO3 cells, MCF7 cells, HL-60 cells and 293-T cells, respectively. HNDC09 and HNDC10 showed very strong antitumor activity against MCF7 and 293-T, respectively. The results showed that endophytic fungi in Dragon's blood samples were valuable in screening antitumor and antimicrobial bioactivity agents. PMID- 21305630 TI - Inhibition of secretion, production and gene expression of mucin from cultured airway epithelial cells by prunetin. AB - This study investigated whether prunetin significantly affects the secretion, production and gene expression of mucin from cultured airway epithelial cells. Confluent primary rat tracheal surface epithelial (RTSE) cells were pretreated with adenosine triphosphate (ATP) for 5 min and then chased for 30 min in the presence of prunetin to assess the effect on mucin secretion using enzyme-linked immunosorbent assay (ELISA). At the same time, confluent NCI-H292 cells were pretreated with prunetin for 30 min and then stimulated with epidermal growth factor (EGF) or phorbol 12-myristate 13-acetate (PMA) for 24 h, respectively. The MUC5AC mucin gene expression and mucin protein production were measured by reverse transcription-polymerase chain reaction (RT-PCR) and ELISA. The results were as follows: (1) prunetin significantly suppressed ATP-induced mucin secretion from cultured RTSE cells; (2) prunetin inhibited the production of MUC5AC mucin protein induced by EGF or PMA from NCI-H292 cells; (3) prunetin also inhibited the expression of MUC5AC mucin gene induced by EGF or PMA from NCI-H292 cells. This result suggests that prunetin can regulate the secretion, production and gene expression of mucin, by directly acting on airway epithelial cells. PMID- 21305631 TI - Wound-healing properties of the oils of Vitis vinifera and Vaccinium macrocarpon. AB - Vitis vinifera (grape) and Vaccinium macrocarpon (cranberry) are well known medicinal plants; most of the pharmacologically active phytochemicals have been isolated from the skin, fruit juice, fermented extract and alcohol fractions of the plants above. Here, the pharmacological properties of the phytochemical constituents present in oils of cranberry and grape were investigated. The oil of grape and cranberry has been evaluated for their wound healing activity by using an excision wound model in rats. The animals were divided into four groups of six each (n = 6). The experimental group 1 and 2 animals were treated topically with the grape and cranberry oil (100 mg/kg body weight), respectively. The controls were treated with petroleum jelly. The standard group of animals were treated with mupirocin ointment (100 mg/kg body weight). The healing was assessed by the rate of wound contraction and hydroxyproline content. On day 13, animals treated with cranberry oil exhibited a (88.1%) reduction in the wound area compared with grape-oil treated (84.6%), controls (74.1%) and standard group animals (78.4%) (p < 0.001). The hydroxyproline content of the granulation tissue was significantly higher in the animals treated with cranberry and the grape-oil (p < 0.000). Comparative investigation of the curative properties of the oils of V. vinifera and V. macrocarpon revealed a significant result which suggests their wound healing potential. PMID- 21305632 TI - Are herbal compounds the next frontier for alleviating learning and memory impairments? An integrative look at memory, dementia and the promising therapeutics of traditional chinese medicines. AB - Recent advances in neuroscience have revealed a greater, in-depth understanding of the complexities associated with memory. Contemporary theories hold that an integral relationship between memory formation, stabilization and consolidation revolve around plasticity of neuronal networks. The associated requisite receptors alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N methyl-d-aspartate (NMDA) and cellular mechanisms surrounding plasticity (posed to incite molecular functionality), also display strong correlations in the pathogenesis of dementias. When the brain is in a diseased state as a result of malignant neurotransmission (i.e. in Alzheimer's disease; AD), the homeostatic balance required for normal neuronal processes is disrupted, which leads to degeneration of neural circuitry. Present efforts to find new treatments aimed at reversing or halting neurodegeneration are immense, with increasing attention being placed on investigating various herbal medicines. A wide variety of herbal plants (i.e. Panax ginseng, Polygala tenuifolia, Acorus gramineus and Huperzia serrata, examined here within), extracts and compounds have, to date, already presented advantageous results when tested against known pathogenic markers related to AD-associated dementia. The efficaciousness of herbal medicines appears to be a modulatory effect on neurotrophins, kinases and their substrates that, in turn, initiate or take part in intracellular cascades related to memory processes. PMID- 21305633 TI - Protective effects of methoxyflavone derivatives from black galingale against glutamate induced neurotoxicity in primary cultured rat cortical cells. AB - To examine the neuroprotective effects of black galingale, its protection was tested against glutamate-induced neurotoxicity in primary cortical cultured neurons. It was found that an aqueous extract of this medicinal plant exhibited significant protection against glutamate-induced toxicity in primary cultured rat cortical cells. In order to clarify the neuroprotective mechanism(s) of this observed effect, isolation was performed to seek and identify active fractions and components. By such fractionation, bioactive methoxyflavone derivatives were isolated from the methanol extracts from the air-dried rhizomes of black galingale. 5-Hydroxy-3,7,3',4'-tetramethoxyflavone exhibited significant neuroprotective activities against glutamate-induced toxicity, exhibiting cell viability of about 60-70%, at concentrations ranging from 0.1 MUm to 10 MUm. Therefore, the neuroprotective effect of black galingale might be due to the inhibition of glutamate-induced toxicity by the methoxyflavone derivatives it contains. PMID- 21305634 TI - Cardamonin stimulates glucose uptake through translocation of glucose transporter 4 in L6 myotubes. AB - Glucose transporter-4 (GLUT4) is a transmembrane protein that plays a major role in insulin-mediated glucose transport in muscle and adipocytes. For glucose transport to occur, the GLUT4 protein needs to be translocated from the intracellular pool to the plasma membrane, and certain compounds may enhance this process. The present study investigated the promotion of glucose uptake in differentiated L6 myotubes by cardamonin, isolated from Alpinia katsumadai. Cardamonin increased translocation of GLUT4 to the plasma membrane in L6 cells, but did not activate protein kinase C zeta/lambda, Akt, or AMP-activated protein kinase, all of which are known to regulate GLUT4 translocation. The glucose uptake-promoting activity of cardamonin was not lowered by treatment with a phosphatidylinositol 3'-kinase inhibitor. These results suggest that cardamonin is a promising active compound for maintaining glucose homeostasis, and that it acts via an unknown mechanism that does not involve activation of the downstream insulin signal and AMP-activated protein kinase. PMID- 21305635 TI - Imaging of gynecological disease (6): clinical and ultrasound characteristics of ovarian dysgerminoma. AB - OBJECTIVES: To describe the clinical history and ultrasound findings in patients with ovarian dysgerminoma. METHODS: This was a retrospective study of patients with a histological diagnosis of ovarian dysgerminoma who had undergone preoperative ultrasound examination. The patients were identified from the databases of 11 ultrasound centers. The tumors were described by the principal investigator at each contributing center on the basis of ultrasound images, ultrasound reports and research protocols (when applicable) using the terms and definitions of the International Ovarian Tumor Analysis (IOTA) group. In addition, three authors reviewed all available electronic ultrasound images (gray scale images and color/power Doppler images were available for 18 patients and 14 patients, respectively) and described them using subjective evaluation of gray scale and color Doppler ultrasound findings (here called pattern recognition). RESULTS: Twenty-one patients with ovarian dysgerminoma were identified (including one woman with bilateral masses). Twenty patients had a primary ovarian dysgerminoma (including the one with bilateral masses) and one patient had a recurrence of dysgerminoma in her retained ovary. One of the 21 patients was pregnant. All tumors except one were pure dysgerminomas, one being a mixed germinal cell tumor with 30% dysgerminoma component. Median age was 20 (range, 16 31) years. Information on clinical symptoms was available for 18 patients. In four patients, the tumor was detected incidentally, whereas 14 patients presented with one or more of the following symptoms: acute pain (n = 4), chronic pain (n = 8), bloating (n = 8), menstrual disorders (n = 5) and infertility problems (n = 1). One (5%) patient had ascites. Using the IOTA terms and definitions, all but one dysgerminoma were moderately (43%) or very well (50%) vascularized solid tumors. One tumor was multilocular-solid. According to pattern recognition, most dysgerminomas were highly vascularized, purely solid tumors with heterogeneous internal echogenicity divided into several lobules, had a smooth and sometimes lobulated contour and were well-defined relative to the surrounding organs. CONCLUSION: The ultrasound finding of a highly vascularized, large, solid, lobulated adnexal mass with irregular internal echogenicity in a woman 20-30 years old should raise the suspicion of ovarian dysgerminoma. PMID- 21305636 TI - An algorithm based on OmniView technology to reconstruct sagittal and coronal planes of the fetal brain from volume datasets acquired by three-dimensional ultrasound. AB - OBJECTIVE: To describe a novel algorithm, based on the new display technology 'OmniView', developed to visualize diagnostic sagittal and coronal planes of the fetal brain from volumes obtained by three-dimensional (3D) ultrasonography. METHODS: We developed an algorithm to image standard neurosonographic planes by drawing dissecting lines through the axial transventricular view of 3D volume datasets acquired transabdominally. The algorithm was tested on 106 normal fetuses at 18-24 weeks of gestation and the visualization rates of brain diagnostic planes were evaluated by two independent reviewers. The algorithm was also applied to nine cases with proven brain defects. RESULTS: The two reviewers, using the algorithm on normal fetuses, found satisfactory images with visualization rates ranging between 71.7% and 96.2% for sagittal planes and between 76.4% and 90.6% for coronal planes. The agreement rate between the two reviewers, as expressed by Cohen's kappa coefficient, was > 0.93 for sagittal planes and > 0.89 for coronal planes. All nine abnormal volumes were identified by a single observer from among a series including normal brains, and eight of these nine cases were diagnosed correctly. CONCLUSIONS: This novel algorithm can be used to visualize standard sagittal and coronal planes in the fetal brain. This approach may simplify the examination of the fetal brain and reduce dependency of success on operator skill. PMID- 21305637 TI - Fetal cardiac dimensions at 14-40 weeks' gestation obtained using cardio-STIC-M. AB - OBJECTIVES: To establish normative reference ranges of fetal cardiac dimensions derived from volume datasets acquired using spatiotemporal image correlation with M-mode display (cardio-STIC-M). METHODS: A cross-sectional study was undertaken on singleton pregnancies with normal fetuses and accurate gestational ages. Cardio-STIC volume datasets were acquired by experienced operators using a high resolution ultrasound machine; these were maneuvered to obtain a four chamber view with exactly horizontal interventricular septum (IVS). Cardiac dimensions were measured in STIC-M-mode using 4D View software. RESULTS: A total of 657 measurements, at a rate of between 15 and 37 per week, were obtained. Normal reference ranges for biventricular outer diameter, left and right ventricular inner diameter, left and right ventricular wall thickness, IVS thickness, left to right ventricular diameter ratio and left and right ventricular shortening fractions were constructed based on best-fit equations as a function of gestational age, fetal head circumference and biparietal diameter. Thirty-four volume datasets of abnormal fetal hearts were also separately assessed, many of which showed abnormal cardiac dimensions. CONCLUSIONS: This is the first report on normal ranges of fetal cardiac dimensions constructed using the new cardio STIC-M technology. Preliminary evaluation suggests that these reference ranges may be a useful tool in the assessment of fetal cardiac abnormalities. PMID- 21305638 TI - Sonographic cervical length measurement in pregnant women with a cervical pessary. AB - OBJECTIVES: The aims of this study were to describe and assess the feasibility of measuring cervical length by standard transvaginal sonography (TVS) and transperineal sonography (TPS) in women with a cervical pessary and compare these measurements with those obtained with a new transvaginal technique. METHODS: Measurement of cervical length by TPS was attempted immediately before measurement using TVS in 48 women with a cervical pessary at between 22 and 23 weeks' gestation. The TVS procedure consisted of two types of measurement: in the first, the probe was placed on the anterior fornix (standard technique) and in the second, the probe was inserted into the pessary to touch the anterior cervical lip (new technique). Two physicians consecutively performed these procedures and compared the measurements obtained. Intraclass correlation coefficients (ICCs) with 95% CI were used to evaluate interobserver reliability, and Bland-Altman analysis was used to assess interobserver agreement. RESULTS: In total, 258 measurements (obtained from 43 women) were analyzed. Interobserver ICCs of the measurements obtained were 0.58 (95% CI, 0.34-0.75) for TPS, 0.65 (95% CI, 0.44-0.79) for the standard TVS technique and 0.97 (95% CI, 0.95-0.98) for the new TVS technique. Bland-Altman analysis showed small mean differences between measurements obtained by two physicians for the three methods, but with narrower limits of agreements (LOA) for the new TVS technique: TPS mean difference - 0.99 mm (95% LOA, - 13.23 to 11.25 mm), standard TVS technique mean difference - 0.23 mm (95% LOA, - 10.90 to 10.44 mm) and new TVS technique mean difference - 0.01 mm (95% LOA, - 2.57 to 2.55 mm). It was apparent from the images obtained that the external os was not visible in 89% of cases when either the TPS or standard TVS technique was used. However, the external os was visible in all cases when the new TVS method was used. CONCLUSIONS: We propose a new technique for measuring and monitoring cervical length in women with a cervical pessary that provides improved visualization of the cervix and increased reliability in comparison to established techniques. PMID- 21305639 TI - Handedness in the helsinki ultrasound trial. AB - OBJECTIVES: To determine whether exposure to prenatal ultrasound increases non right-handedness in boys. METHODS: The association between exposure to prenatal ultrasound and handedness was tested, using logistic regression analysis, in the Helsinki Ultrasound Trial data. We applied an intention-to-treat approach in this analysis of a subset of 4150 subjects whose parents answered a follow-up questionnaire on handedness when the children were aged 13-15 years. RESULTS: The odds ratio for non-right-handedness of children who had been exposed to prenatal ultrasound was 1.16 (0.98-1.37) for all subjects, 1.12 (0.89-1.41) for boys and 1.24 (0.97-1.58) for girls. CONCLUSIONS: We could not confirm the hypothesis that prenatal ultrasound exposure and handedness are associated. Our findings were independent of the particular definition of handedness used, whether it was considered according to the writing hand alone or defined using a laterality quotient. PMID- 21305640 TI - Frequency of KRAS, BRAF, and NRAS mutations in colorectal cancer. AB - Mutational analysis of KRAS codons 12 and 13 is standard for patients with metastatic colorectal cancer since mutations in these codons predict lack of response to anti-EGFR therapies. However, even among patients whose tumors are wildtype for KRAS codons 12 and 13, only a subset respond to therapy. Since additional activating mutations downstream of EGFR may also play a role in treatment resistance, we sought to establish the frequency of these mutations. We evaluated 2121 colorectal tumors for mutations in codons 12 and 13 of the KRAS gene. A subset of these samples, comprised of 513 samples wildtype for KRAS codons 12 and 13, were tested for mutations in codons 61 and 146 of KRAS, codon 600 of BRAF, and codons 12, 13, and 61 of NRAS. Mutation status was determined by targeted pyrosequencing. Mutations in KRAS codon 12 or 13 were identified in 900/2121 (42.4%) samples. Of the 513 wildtype samples tested for additional mutations, 78 samples were mutant for BRAF, 19 for KRAS codon 61, 17 for KRAS codon 146, and 26 for NRAS. In total, 140/513 (27.3%) tumors wildtype for KRAS codons 12 and 13 harbored a mutation in another of the RAS pathway genes. While further study is needed to determine the full therapeutic implications of mutations in these codons, mutational testing of these codons may be useful for identifying a significant proportion of patients who may also be resistant to anti-EGFR therapies. PMID- 21305641 TI - Integrative genomic profiling reveals conserved genetic mechanisms for tumorigenesis in common entities of non-Hodgkin's lymphoma. AB - Recent developments in genomic technologies have resulted in increased understanding of pathogenic mechanisms and emphasized the importance of central survival pathways. Here, we use a novel bioinformatic based integrative genomic profiling approach to elucidate conserved mechanisms of lymphomagenesis in the three commonest non-Hodgkin's lymphoma (NHL) entities: diffuse large B-cell lymphoma, follicular lymphoma, and B-cell chronic lymphocytic leukemia. By integrating genome-wide DNA copy number analysis and transcriptome profiling of tumor cohorts, we identified genetic lesions present in each entity and highlighted their likely target genes. This revealed a significant enrichment of components of both the apoptosis pathway and the mitogen activated protein kinase pathway, including amplification of the MAP3K12 locus in all three entities, within the set of genes targeted by genetic alterations in these diseases. Furthermore, amplification of 12p13.33 was identified in all three entities and found to target the FOXM1 oncogene. Amplification of FOXM1 was subsequently found to be associated with an increased MYC oncogenic signaling signature, and siRNA mediated knock-down of FOXM1 resulted in decreased MYC expression and induced G2 arrest. Together, these findings underscore genetic alteration of the MAPK and apoptosis pathways, and genetic amplification of FOXM1 as conserved mechanisms of lymphomagenesis in common NHL entities. Integrative genomic profiling identifies common central survival mechanisms and highlights them as attractive targets for directed therapy. PMID- 21305642 TI - Prognostic value of SOX2 expression in neuroblastoma. PMID- 21305643 TI - Loss at chromosome arm 16q in retinoblastoma: confirmation of the association with diffuse vitreous seeding and refinement of the recurrently deleted region. AB - In addition to mutations in both alleles of the retinoblastoma gene (RB1) alleles, retinoblastomas frequently show additional alterations including loss of chromosome arm 16q. In a previous study, the presence of 16q alterations was found to be associated with diffuse vitreous seeding of this tumor. This growth pattern is clinically important as it determines therapeutic decisions. The present study was designed to test this association and to narrow down the list of candidate genes in the minimal region of genomic loss on chromosome arm 16q. Our data confirm the association of 16q loss and diffuse vitreous seeding and define a minimal region of genomic loss of 6.6 Mb on 16q containing 86 known genes. As retinoblastoma is an embryonic tumor, we assumed that any gene relevant for its progression is likely to show regulated expression during retinogenesis. Microarray expression analysis of RNA from a continuous developmental series of murine retinas identified murine orthologs with regulated expression and these data helped to narrow the number of candidate genes in minimal region to 35. Analysis of gene expression in retinoblastomas with and without the loss of heterozygosity (LOH) on chromosome 16q further reduced this number to 26 candidate genes. One of these genes is cadherin 13 (CDH13) and notably, downregulation of CHD13 has previously been associated with poorer prognosis in various other cancers. PMID- 21305644 TI - Fusion gene microarray reveals cancer type-specificity among fusion genes. AB - Detection of fusion genes for diagnostic purposes and as a guide to treatment is well-established in hematological malignancies, and the prevalence of fusion genes in epithelial cancers is also increasingly appreciated. To study whether established fusion genes are present within additional cancer types, we have used an updated version of our fusion gene microarray in a systematic survey of reported fusion genes in multiple cancer types. We assembled a comprehensive database of published fusion genes, including those reported only in individual studies and samples, and fusion genes resulting from deep sequencing of cancer genomes and transcriptomes. From the total set of 548 fusion genes, we designed 599,839 oligonucleotides, targeting both chimeric transcript junctions as well as sequences internal to each of the fusion gene partners. We investigated the presence of fusion genes in a series of 67 cell lines representing 15 different cancer types. Data from ten leukemia cell lines with known fusion gene status were used to develop an automated scoring algorithm, and in five cell lines the correct fusion gene was the top scoring hit, and one came second. Two additional fusion genes, BCAS4-BCAS3 in the MCF-7 breast cancer cell line and CCDC6-RET in the TPC-1 thyroid cancer cell line were validated as true positive fusion transcripts. However, these fusion genes were not new to these cancer types, and none of 548 fusion genes were identified from a novel cancer type. We therefore find it unlikely that the assayed fusion genes are commonly present across multiple cancer types. PMID- 21305645 TI - The impact of long-term participation in the supplemental nutrition assistance program on child obesity. AB - Participation in the Supplemental Nutrition Assistance Program (SNAP) reached an all-time high of 40.2 million persons in March 2010, which means the program affects a substantial fraction of Americans. A significant body of research has emerged suggesting that participation in SNAP increases the probability of being obese for adult women and has little effect on the probability for adult men. However, studies addressing the effects of participation on children have produced mixed results. This paper examines the effect of long-term SNAP participation on the Body Mass Index (BMI) percentile and probability of being overweight or obese for children ages 5-18 using data from the National Longitudinal Survey of Youth 1979 Children and Young Adults data set. An instrumental variables identification strategy that exploits exogenous variation in state-level program parameters, as well as state and federal expansions of the Earned Income Tax Credit (EITC), is used to address the endogeneity between SNAP participation and obesity. SNAP participation is found to significantly reduce BMI percentile and the probability of being overweight or obese for boys and girls ages 5-11 and boys ages 12-18. For girls ages 12-18, SNAP participation appears to have no significant effect on these outcomes. PMID- 21305646 TI - What do 1281 distress screeners tell us about cancer patients in a community cancer center? AB - OBJECTIVE: The 2008 Institute of Medicine's Report, Cancer Care for the Whole Patient (IOM, 2008), recommends screening cancer patients for distress. Cancer programs throughout the United States are struggling to achieve this standard. The IOM report indicates that only 14% of 1000 randomly selected American Society of Clinical Oncology (ASCO) members and eight of 15 National Comprehensive Cancer Network (NCCN) centers reported screening for distress in at least some of their patients [J Natl Compr Cancer Netw 2007;5:99-103]. Without adequate screening, distress often goes unnoticed by cancer professionals and there is little information about the prevalence of distress. The main objective of this article is to present data from 1281 distress screenings completed by patients treated within a community cancer center. Specifically, this article reports the intensity of distress, frequency of problem endorsement, and requests for specific psychosocial providers by cancer patients. METHOD: Medical and radiation oncology patients completed a distress screener before their first physician appointment. The screening instrument included the Distress Thermometer, a symptom checklist, and a list of psychosocial providers that the patient could request to meet. RESULTS: Thirty-two percent of this sample rated distress above the threshold level. Worry was the most common problem endorsed followed by financial issues. Emotional concerns were endorsed by 59% of the sample. The cancer dietitian was the psychosocial professional most frequently requested by patients. CONCLUSION: Distress screening can be accomplished within a community cancer center but the provision of psychosocial services is difficult given the high volume of need. PMID- 21305647 TI - Examining the links between perceived impact of breast cancer and psychosocial adjustment: the buffering role of posttraumatic growth. AB - OBJECTIVES: Finding positive changes in the aftermath of breast cancer (BC) may protect women against impaired adjustment. This study examines posttraumatic growth (PTG) in a sample of women receiving treatment for BC and explores the buffering role of PTG on the links between perceived impact of BC and emotional distress and quality of life (QoL). METHODS: Seventy-eight women receiving chemotherapy (n = 57) or radiotherapy (n = 21) completed the Portuguese versions of the Posttraumatic Growth Inventory, the Hospital Anxiety and Depression Scale, the World Health Organization for QoL-Bref and Consequences sub-scale of the Brief Illness Perception Questionnaire (assessing perceived impact of BC). RESULTS: PTG was frequently reported and co-existed with distress and dysfunction. A more negative perception of the impact of BC was significantly associated with higher emotional distress and impaired Physical and Psychological QoL, but was unrelated to PTG. Hierarchical regression analyses showed that PTG moderated these relationships, acting as a stress-buffering mechanism. Among women who perceived BC as having a more negative impact on their lives, higher levels of PTG buffered this negative perceived impact on Psychological and Social QoL (p<0.01) and also on Depression (p<0.06). This effect was not found for Physical QoL and Anxiety. CONCLUSIONS: Results provide support for the stress buffering role of PTG. Finding positive changes in cancer experience seems to protect women from the effects of a negative perception of the impact of BC on adjustment. Psychosocial intervention programs should facilitate PTG in order to promote women's adjustment. PMID- 21305648 TI - Dedifferentiation and the role of sall4 in reprogramming and patterning during amphibian limb regeneration. AB - A central feature of epimorphic regeneration during amphibian limb regeneration is cellular dedifferentiation. Two questions are discussed. First, what is the origin and nature of the soluble factors involved in triggering local cellular and tissue dedifferentiation? Secondly, what role does the key stem cell transcription factor Sall4 play in reprogramming gene expression during dedifferentiation? The pattern of Sall4 expression during Xenopus hindlimb regeneration is consistent with the hypothesis that Sall4 plays a role in dedifferentiation (reprogramming) and in maintaining limb blastema cells in an undifferentiated state. Sall4 is involved in maintenance of ESC pluripotency, is a major repressor of differentiation, plays a major role in reprogramming differentiated cells into iPSCs, and is a component of the stemness regulatory circuit of pluripotent ESCs and iPSCs. These functions suggest Sall4 as an excellent candidate to regulate reprogramming events that produce and maintain dedifferentiated blastema cells required for epimorphic regeneration. PMID- 21305650 TI - The planar cell polarity pathway in vertebrate development. AB - Directing the orientation of cells in three dimensions is a fundamental aspect of many of the processes underlying the generation of the appropriate shape and function of tissues and organs during embryonic development. In an epithelium, this requires not only the establishment of apicobasal polarity, but also cell arrangement in a specific direction in the plane of the cell sheet. The molecular pathway central to regulating this planar cell polarity (PCP) was originally discovered in the fruit fly Drosophila melanogaster and has more recently been shown to act in a highly analogous way in vertebrates, involving a strongly overlapping set of genes. Mutant studies and molecular analyses have led to insights into the role of ordered planar cell polarity in the development of a wide variety of organs and tissues. In this review, we give an overview of recent developments in the study of planar polarity signaling in vertebrates. PMID- 21305649 TI - Sulfated is a negative feedback regulator of wingless in Drosophila. AB - Drosophila Wingless (Wg) acts as a morphogen to control pattern formation in a concentration dependent manner. Previous studies demonstrated important roles of heparan sulfate proteoglycans (HSPGs) in controlling Wg signaling and distribution. Here, we examined the role of Sulfated (Sulf1), a Drosophila homolog of vertebrate heparan sulfate 6-O endosulfatase, in Wg signaling and distribution. We show that sulf1 is specifically up-regulated by Wg signaling in the wing disc. We found that expression of Wg target gene senseless (sens) was elevated in the sulf1 mutant wing discs. Sulf1 also negatively regulate extracellular levels of Wg. Genetic interaction experiments indicate that Wg antagonist Notum may work synergistically with Sulf1 to restrict Wg signaling, and Dally, a member of Drosophila HSPGs, is a potential target of Sulf1. Our results demonstrate that sulf1 is a novel Wg target gene and by a feedback mechanism, it negatively regulated Wg signaling and distribution in vivo. PMID- 21305651 TI - Developmental arrest of scNT-derived fetuses by disruption of the developing endometrial gland as a result of impaired trophoblast migration and invasiveness. AB - Somatic cell nuclear transfer (scNT)-derived pig placenta tissues of gestational day 30 displayed avascularization and hypovascularization. Most of the cytotrophoblast-like cells of the developing scNT-derived placenta villi were improperly localized or exhibited impaired migration to their targeting loci. Id 2, Met, MMP-9, and MCM-7 were barely detectable in the cytotrophoblast cells of the scNT-derived placenta villi. Active MMP-2 and MMP-9 expression was significantly down-regulated in the scNT-embryo transferred recipient uteri. scNT clones exhibited a hypermethylated pattern within the pig MMP-9 promoter region and the significance of GC box in the regulation of MMP-9 promoter activity. Marked apoptosis was observed in the developing endometrial gland of scNT-embryo transferred recipient uteri. Collectively, our data strongly indicated that early gestational death of scNT clones is caused, at least in part, by disruption of the developing endometrial gland as a result of impaired trophoblast migration and invasiveness due to the down-regulation of active MMP-9 expression. PMID- 21305652 TI - Different requirements for GATA factors in cardiogenesis are mediated by non canonical Wnt signaling. AB - GATA factors and Wnt signals are key regulators of vertebrate cardiogenesis, but specific roles for individual GATA factors and how they interact with Wnt signaling remain unknown. We use loss of function and overexpression approaches to elucidate how these molecules regulate early cardiogenesis in Xenopus. In order to minimize indirect effects due to abnormal early embryogenesis, we use pluripotent embryonic tissues as cardiogenic assays. We confirm central roles for GATA4, 5, and 6 in cardiogenesis, but also discover individual and different requirements. We show that GATA4 or 6 regulate both cardiogenic potential and subsequent cardiomyocyte differentiation but that GATA5 is involved in regulating cardiomyocyte differentiation. We also show that Wnt11b signaling can rescue reduced cardiac differentiation resulting from loss of function of GATA4 and 6 but not GATA5. We conclude that Wnt11b mediates the differential requirements for GATA factors during vertebrate cardiogenesis. PMID- 21305653 TI - Massive parallel amplicon sequencing of the breast cancer genes BRCA1 and BRCA2: opportunities, challenges, and limitations. AB - This study describes how the new massive parallel sequencing technology can be implemented in a diagnostic setting for the breast cancer susceptibility genes (BRCA1 and BRCA2). The throughput was maximized by increasing uniformity in coverage, obtained by a multiplex approach, which outperformed pooling of singleplex PCRs. We evaluated the sensitivity by analysis of 133 distinct sequence variants; three (2%) deletions or duplications in homopolymers of greater than or equal to seven nucleotides remained undetected, illustrating a limitation of pyrosequencing. Furthermore, other limitations like nonrandom sequencing errors, pseudogene amplification, and failure to detect multiexon deletions are thoroughly described. Our workflow illustrates the potential of massive parallel sequencing of large genes in a diagnostic setting, which is of great importance to meet the increasing expectations of genetic testing. Implementation of this approach will hopefully lead to a strong reduction in turnaround times. As a consequence a wider spectrum of at risk women will be able to benefit from therapeutic interventions and prophylactic interventions. PMID- 21305654 TI - Initiating a Human Variome Project Country Node. AB - Genetic diseases are a pressing global health problem that requires comprehensive access to basic clinical and genetic data to counter. The creation of regional and international databases that can be easily accessed by clinicians and diagnostic labs will greatly improve our ability to accurately diagnose and treat patients with genetic disorders. The Human Variome Project is currently working in conjunction with human genetics societies to achieve this by establishing systems to collect every mutation reported by a diagnostic laboratory, clinic, or research laboratory in a country and store these within a national repository, or HVP Country Node. Nodes have already been initiated in Australia, Belgium, China, Egypt, Malaysia, and Kuwait. Each is examining how to systematically collect and share genetic, clinical, and biochemical information in a country-specific manner that is sensitive to local ethical and cultural issues. This article gathers cases of genetic data collection within countries and takes recommendations from the global community to develop a procedure for countries wishing to establish their own collection system as part of the Human Variome Project. We hope this may lead to standard practices to facilitate global collection of data and allow efficient use in clinical practice, research and therapy. PMID- 21305655 TI - Systematic biochemical analysis of somatic missense mutations in DNA polymerase beta found in prostate cancer reveal alteration of enzymatic function. AB - DNA polymerase beta is essential for short-patch base excision repair. We have previously identified 20 somatic pol beta mutations in prostate tumors, many of them missense. In the current article we describe the effect of all of these somatic missense pol beta mutations (p.K27N, p.E123K, p.E232K, p.P242R, p.E216K, p.M236L, and the triple mutant p.P261L/T292A/I298T) on the biochemical properties of the polymerase in vitro, following bacterial expression and purification of the respective enzymatic variants. We report that all missense somatic pol beta mutations significantly affect enzyme function. Two of the pol beta variants reduce catalytic efficiency, while the remaining five missense mutations alter the fidelity of DNA synthesis. Thus, we conclude that a significant proportion (9 out of 26; 35%) of prostate cancer patients have functionally important somatic mutations of pol beta. Many of these missense mutations are clonal in the tumors, and/or are associated with loss of heterozygosity and microsatellite instability. These results suggest that interfering with normal polymerase beta function may be a frequent mechanism of prostate tumor progression. Furthermore, the availability of detailed structural information for pol beta allows understanding of the potential mechanistic effects of these mutants on polymerase function. PMID- 21305656 TI - Heterogeneity in the processing of CLCN5 mutants related to Dent disease. AB - Mutations in the electrogenic Cl(-)/H(+) exchanger ClC-5 gene CLCN5 are frequently associated with Dent disease, an X-linked recessive disorder affecting the proximal tubules. Here, we investigate the consequences in Xenopus laevis oocytes and in HEK293 cells of nine previously reported, pathogenic, missense mutations of ClC-5, most of them which are located in regions forming the subunit interface. Two mutants trafficked normally to the cell surface and to early endosomes, and displayed complex glycosylation at the cell surface like wild-type ClC-5, but exhibited reduced currents. Three mutants displayed improper N glycosylation, and were nonfunctional due to being retained and degraded at the endoplasmic reticulum. Functional characterization of four mutants allowed us to identify a novel mechanism leading to ClC-5 dysfunction in Dent disease. We report that these mutant proteins were delayed in their processing, and that the stability of their complex glycosylated form was reduced, causing lower cell surface expression. The early endosome distribution of these mutants was normal. Half of these mutants displayed reduced currents, whereas the other half showed abolished currents. Our study revealed distinct cellular mechanisms accounting for ClC-5 loss of function in Dent disease. PMID- 21305657 TI - Pure intronic rearrangements leading to aberrant pseudoexon inclusion in dystrophinopathy: a new class of mutations? AB - We report on two unprecedented cases of pseudoexon (PE) activation in the DMD gene resulting from pure intronic double-deletion events that possibly involve microhomology-mediated mechanisms. Array comparative genomic hybridization analysis and direct genomic sequencing allowed us to elucidate the causes of the pathological PE inclusion detected in the RNA of the patients. In the first case (Duchenne phenotype), we showed that the inserted 387-bp PE was originated from an inverted ~57 kb genomic region of intron 44 flanked by two deleted ~52 kb and ~1 kb segments. In the second case (Becker phenotype), we identified in intron 56 two small deletions of 592 bp (del 1) and 29 bp (del 2) directly flanking a 166 bp PE located in very close proximity (134 bp) to exon 57. The key role of del 1 in PE activation was established by using splicing reporter minigenes. However, the analysis of mutant constructs failed to identify cis elements that regulate the inclusion of the PE and suggested that other splicing regulatory factors may be involved such as RNA structure. Our study introduces a new class of mutations in the DMD gene and emphasizes the potential role of underdetected intronic rearrangements in human diseases. PMID- 21305658 TI - Human dermal fibroblasts derived from oculodentodigital dysplasia patients suggest that patients may have wound-healing defects. AB - Oculodentodigital dysplasia (ODDD) is primarily an autosomal dominant human disease caused by any one of over 60 mutations in the GJA1 gene encoding the gap junction protein Cx43. In the present study, wound healing was investigated in a G60S ODDD mutant mouse model and by using dermal fibroblasts isolated from two ODDD patients harboring the p.D3N and p.V216L mutants along with dermal fibroblasts isolated from their respective unaffected relatives. Punch biopsies revealed a delay in wound closure in the G60S mutant mice in comparison to wild type littermates, and this delay appeared to be due to defects in the dermal fibroblasts. Although both the p.D3N and p.V216L mutants reduced gap junctional intercellular communication in human dermal fibroblasts, immunolocalization studies revealed that Cx43 gap junctions were prevalent at the cell surface of p.D3N expressing fibroblasts but greatly reduced in p.V216L expressing fibroblasts. Mutant expressing fibroblasts were further found to have reduced proliferation and migration capabilities. Finally, in response to TGFbeta1, mutant expressing fibroblasts expressed significantly less alpha smooth muscle actin suggesting they were inefficient in their ability to differentiate into myofibroblasts. Collectively, our results suggest that ODDD patients may have subclinical defects in wound healing due to impaired function of dermal fibroblasts. PMID- 21305659 TI - Seeing touch in the somatosensory cortex: a TMS study of the visual perception of touch. AB - Recent studies suggest the existence of a visuo-tactile mirror system, comprising the primary (SI) and secondary (SII) somatosensory cortices, which matches observed touch with felt touch. Here, repetitive transcranial magnetic stimulation (rTMS) was used to determine whether SI or SII play a functional role in the visual processing of tactile events. Healthy participants performed a visual discrimination task with tactile stimuli (a finger touching a hand) and a control task (a finger moving without touching). During both tasks, rTMS was applied over either SI or SII, and to the occipital cortex. rTMS over SI selectively reduced subject performance for interpreting whether a contralateral visual tactile stimulus contains a tactile event, whereas SII stimulation impaired visual processing regardless of the tactile component. These findings provide evidence for a multimodal sensory-motor system with mirror properties, where somatic and visual properties of action converge. SI, a cortical area traditionally viewed as modality-specific, is selectively implicated in the visual processing of touch. These results are in line with the existence of a sensory mirror system mediating the embodied simulation concept. PMID- 21305660 TI - Detection of large gene rearrangements in X-linked genes by dosage analysis: identification of novel alpha-galactosidase A (GLA) deletions causing Fabry disease. AB - For most Mendelian disorders, targeted genome sequencing is an effective method to detect causative mutations. However, sequencing PCR-amplified exonic regions and their intronic boundaries can miss large deletions or duplications and mutations that lead to PCR failures in autosomal dominant disorders and in heterozygote detection for X-linked diseases. Here, a method is described for detecting large (>50 bp) deletions/duplications in the X-linked alpha galactosidase A (GLA) gene, which cause Fabry disease. Briefly, multiplex PCR mixtures were designed to amplify each GLA exon and an unrelated internal control exon to normalize GLA exonic amplicon peak heights. For each normalized GLA amplicon, the normal control female to male peak-height ratios were 1.8 to 2.2 (expected 2.0), whereas the expected ratios for deletions or duplications would be ~1.0 or 3.0, respectively. Using this method, three novel deletions, c.369+3_547+954del4096insT, c.194+2049_369+773del2619insCG, and c.207_369+651del814ins231, were detected in unrelated women with signs and/or symptoms suggestive of Fabry disease, but no "sequencing-detectable" mutations. The deletions were confirmed by sequencing their respective GLA RT-PCR products. This method can identify gene rearrangements that may be cryptic to genomic DNA sequencing and can be readily adapted to other X-linked or autosomal dominant genes. PMID- 21305661 TI - Thickness profile generation for the corpus callosum using Laplace's equation. AB - The corpus callosum facilitates communication between the cerebral hemispheres. Morphological abnormalities of the corpus callosum have been identified in numerous psychiatric and neurological disorders. To quantitatively analyze the thickness profile of the corpus callosum, we adapted an automatic thickness measurement method, which was originally used on magnetic resonance (MR) images of the cerebral cortex (Hutton et al. [2008]: NeuroImage 40:1701-10; Jones et al. [2002]: Hum Brain Mapp 11:12-32; Schmitt and Bohme [2002]: NeuroImage 16:1103-9; Yezzi and Prince [2003]: IEEE Trans Med Imaging 22:1332-9), to MR images of the corpus callosum. The thickness model was derived by computing a solution to Laplace's equation evaluated on callosal voxels. The streamlines from this solution form non-overlapping, cross-sectional contours the lengths of which are modeled as the callosal thickness. Apart from the semi-automated segmentation and endpoint selection procedures, the method is fully automated, robust, and reproducible. We compared the Laplace method with the orthogonal projection technique previously published (Walterfang et al. [2009a]: Psych Res Neuroimaging 173:77-82; Walterfang et al. [2008a]: Br J Psychiatry 192:429-34; Walterfang et al. [2008b]: Schizophr Res 103:1-10) on a cohort of 296 subjects, composed of 86 patients with chronic schizophrenia (CSZ), 110 individuals with first-episode psychosis, 100 individuals at ultra-high risk for psychosis (UHR; 27 of whom later developed psychosis, UHR-P, and 73 who did not, UHR-NP), and 55 control subjects (CTL). We report similar patterns of statistically significant differences in regional callosal thickness with respect to the comparisons CSZ vs. CTL, UHR vs. CTL, UHR-P vs. UHR-NP, and UHR vs. CTL. PMID- 21305662 TI - Involvement of glutamate in rest-stimulus interaction between perigenual and supragenual anterior cingulate cortex: a combined fMRI-MRS study. AB - The brain shows a high degree of activity at rest. The significance of this activity has come increasingly into focus. At present, however, the interaction between this activity and stimulus-induced activity is not well defined. The interaction between a task-negative (perigenual anterior cingulate cortex, pgACC) and task-positive (supragenual anterior cingulate cortex, sgACC) region during a simple task was thus investigated using a combination of fMRI and MRS. Negative BOLD responses in the pgACC were found to show a unidirectional effective connectivity with task-induced positive BOLD responses in the sgACC. This connectivity was shown to be related specifically with glutamate levels in the pgACC. These results demonstrate an interaction between deactivation from resting state and resting-state glutamate levels in a task-negative region (pgACC), and task-induced activity in a task-positive region (sgACC). This provides insight into the neuronal and biochemical mechanisms by means of which the resting state activity of the brain potentially impacts upon subsequent stimulus-induced activity. PMID- 21305663 TI - Feature-based attention modulates direction-selective hemodynamic activity within human MT. AB - Attending to the spatial location or to nonspatial features of a stimulus modulates neural activity in cortical areas that process its perceptual attributes. The feature-based attentional selection of the direction of a moving stimulus is associated with increased firing of individual neurons tuned to the direction of the movement in area V5/MT, while responses of neurons tuned to opposite directions are suppressed. However, it is not known how these multiplicatively scaled responses of individual neurons tuned to different motion directions are integrated at the population level, in order to facilitate the processing of stimuli that match the perceptual goals. Using functional magnetic resonance imaging (fMRI) the present study revealed that attending to the movement direction of a dot field enhances the response in a number of areas including the human MT region (hMT) as a function of the coherence of the stimulus. Attending the opposite direction, however, lead to a suppressed response in hMT that was inversely correlated with stimulus-coherence. These findings demonstrate that the multiplicative scaling of single-neuron responses by feature-based attention results in an enhanced direction-selective population response within those cortical modules that processes the physical attributes of the attended stimuli. Our results provide strong support for the validity of the "feature similarity gain model" on the integrated population response as quantified by parametric fMRI in humans. PMID- 21305664 TI - Event-related potential activity in the basal ganglia differentiates rewards from nonrewards: temporospatial principal components analysis and source localization of the feedback negativity. AB - Event-related potential studies of reward processing have consistently identified the feedback negativity (FN), an early neural response that differentiates feedback indicating unfavorable versus favorable outcomes. Several important questions remain, however, about the nature of this response. In this study, the FN was recorded in response to monetary gains and losses during a laboratory gambling task, and temporospatial principal components analysis was used to separate the FN from overlapping responses. The FN was identified as a positive deflection at frontocentral recording sites that was enhanced for rewards compared with nonrewards. Furthermore, source localization techniques identified the striatum as a likely neural generator. These data indicate that this apparent FN reflects increased striatal activation in response to favorable outcomes that is reduced or absent for unfavorable outcomes, thereby providing unique information about the timing and nature of basal ganglia activity related to reward processing. PMID- 21305665 TI - Temporal dynamics of reward processing revealed by magnetoencephalography. AB - Monetary gains and losses in gambling situations are associated with a distinct electroencephalographic signature: in the event-related potentials (ERPs), a mediofrontal feedback-related negativity (FRN) is seen for losses, whereas oscillatory activity shows a burst of in the theta-range for losses and in the beta-range for gains. We used whole-head magnetoencephalography to pinpoint the magnetic counterparts of these effects in young healthy adults and explore their evolution over time. On each trial, participants bet on one of two visually presented numbers (25 or 5) by button-press. Both numbers changed color: if the chosen number turned green (red), it indicated a gain (loss) of the corresponding sum in Euro cent. For losses, we found the magnetic correlate of the FRN extending between 230 and 465 ms. Source localization with low-resolution electromagnetic tomography indicated a first generator in posterior cingulate cortex with subsequent activity in the anterior cingulate cortex. Importantly, this effect was sensitive to the magnitude of the monetary loss (25 cent > 5 cent). Later activation was also found in the right insula. Time-frequency analysis revealed a number of oscillatory components in the theta, alpha, and high-beta/low-gamma bands associated to gains, and in the high-beta band, associated to the magnitude of the loss. All together, these effects provide a more fine-grained picture of the temporal dynamics of the processing of monetary rewards and losses in the brain. PMID- 21305666 TI - Cortical network differences in the sighted versus early blind for recognition of human-produced action sounds. AB - Both sighted and blind individuals can readily interpret meaning behind everyday real-world sounds. In sighted listeners, we previously reported that regions along the bilateral posterior superior temporal sulci (pSTS) and middle temporal gyri (pMTG) are preferentially activated when presented with recognizable action sounds. These regions have generally been hypothesized to represent primary loci for complex motion processing, including visual biological motion processing and audio-visual integration. However, it remained unclear whether, or to what degree, life-long visual experience might impact functions related to hearing perception or memory of sound-source actions. Using functional magnetic resonance imaging (fMRI), we compared brain regions activated in congenitally blind versus sighted listeners in response to hearing a wide range of recognizable human produced action sounds (excluding vocalizations) versus unrecognized, backward played versions of those sounds. Here, we show that recognized human action sounds commonly evoked activity in both groups along most of the left pSTS/pMTG complex, though with relatively greater activity in the right pSTS/pMTG by the blind group. These results indicate that portions of the postero-lateral temporal cortices contain domain-specific hubs for biological and/or complex motion processing independent of sensory-modality experience. Contrasting the two groups, the sighted listeners preferentially activated bilateral parietal plus medial and lateral frontal networks, whereas the blind listeners preferentially activated left anterior insula plus bilateral anterior calcarine and medial occipital regions, including what would otherwise have been visual-related cortex. These global-level network differences suggest that blind and sighted listeners may preferentially use different memory retrieval strategies when hearing and attempting to recognize action sounds. PMID- 21305667 TI - Minimizing within-experiment and within-group effects in Activation Likelihood Estimation meta-analyses. AB - Activation Likelihood Estimation (ALE) is an objective, quantitative technique for coordinate-based meta-analysis (CBMA) of neuroimaging results that has been validated for a variety of uses. Stepwise modifications have improved ALE's theoretical and statistical rigor since its introduction. Here, we evaluate two avenues to further optimize ALE. First, we demonstrate that the maximum contribution of an experiment makes to an ALE map is related to the number of foci it reports and their proximity. We present a modified ALE algorithm that eliminates these within-experiment effects. However, we show that these effects only account for 2-3% of cumulative ALE values, and removing them has little impact on thresholded ALE maps. Next, we present an alternate organizational approach to datasets that prevents subject groups with multiple experiments in a dataset from influencing ALE values more than others. This modification decreases cumulative ALE values by 7-9%, changes the relative magnitude of some clusters, and reduces cluster extents. Overall, differences between results of the standard approach and these new methods were small. This finding validates previous ALE reports against concerns that they were driven by within-experiment or within group effects. We suggest that the modified ALE algorithm is theoretically advantageous compared with the current algorithm, and that the alternate organization of datasets is the most conservative approach for typical ALE analyses and other CBMA methods. Combining the two modifications minimizes both within-experiment and within-group effects, optimizing the degree to which ALE values represent concordance of findings across independent reports. PMID- 21305668 TI - Identification of human gustatory cortex by activation likelihood estimation. AB - Over the last two decades, neuroimaging methods have identified a variety of taste-responsive brain regions. Their precise location, however, remains in dispute. For example, taste stimulation activates areas throughout the insula and overlying operculum, but identification of subregions has been inconsistent. Furthermore, literature reviews and summaries of gustatory brain activations tend to reiterate rather than resolve this ambiguity. Here, we used a new meta analytic method [activation likelihood estimation (ALE)] to obtain a probability map of the location of gustatory brain activation across 15 studies. The map of activation likelihood values can also serve as a source of independent coordinates for future region-of-interest analyses. We observed significant cortical activation probabilities in: bilateral anterior insula and overlying frontal operculum, bilateral mid dorsal insula and overlying Rolandic operculum, and bilateral posterior insula/parietal operculum/postcentral gyrus, left lateral orbitofrontal cortex (OFC), right medial OFC, pregenual anterior cingulate cortex (prACC) and right mediodorsal thalamus. This analysis confirms the involvement of multiple cortical areas within insula and overlying operculum in gustatory processing and provides a functional "taste map" which can be used as an inclusive mask in the data analyses of future studies. In light of this new analysis, we discuss human central processing of gustatory stimuli and identify topics where increased research effort is warranted. PMID- 21305669 TI - Enhancing the utility of complex-valued functional magnetic resonance imaging detection of neurobiological processes through postacquisition estimation and correction of dynamic B(0) errors and motion. AB - Functional magnetic resonance imaging (fMRI) time series analysis is typically performed using only the magnitude portion of the data. The phase information remains unused largely due to its sensitivity to temporal variations in the magnetic field unrelated to the functional response of interest. These phase changes are commonly the result of physiologic processes such as breathing or motion either inside or outside the imaging field of view. As a result, although the functional phase response carries pertinent physiological information concerning the vasculature, one aspect of which is the location of large draining veins, the full hemodynamic phase response is understudied and is poorly understood, especially in comparison with the magnitude response. It is likely that the magnitude and phase contain disjoint information, which could be used in tandem to better characterize functional hemodynamics. In this work, simulated and human fMRI experimental data are used to demonstrate how statistical analysis of complex-valued fMRI time series can be problematic, and how robust analysis using these powerful and flexible complex-valued statistics is possible through postprocessing with correction for dynamic magnetic field fluctuations in conjunction with estimated motion parameters. These techniques require no special pulse sequence modifications and can be applied to any complex-valued echo planar imaging data set. This analysis shows that the phase component appears to contain information complementary to that in the magnitude and that processing and analysis techniques are available to investigate it in a robust and flexible manner. PMID- 21305670 TI - Concise review: culture mediated changes in fate and/or potency of stem cells. AB - Although Gurdon demonstrated already in 1958 that the nucleus of intestinal epithelial cells could be reprogrammed to give rise to adult frogs, the field of cellular reprogramming has only recently come of age with the description by Takahashi and Yamanaka in 2006, which defined transcription factors can reprogram fibroblasts to an embryonic stem cell-like fate. With the mounting interest in the use of human pluripotent stem cells and culture-expanded somatic stem/progenitor cells, such as mesenchymal stem cells, increasing attention has been given to the effect of changes in the in vitro microenvironment on the fate of stem cells. These studies have demonstrated that changes in culture conditions may change the potency of pluripotent stem cells or reprogram adult stem/progenitor cells to endow them with a broader differentiation potential. The mechanisms underlying these fate and potency changes by ex vivo culture should be further investigated and considered when designing clinical therapies with stem/progenitor cells. PMID- 21305672 TI - Conditional activation of Bmi1 expression regulates self-renewal, apoptosis, and differentiation of neural stem/progenitor cells in vitro and in vivo. AB - The Polycomb group protein Bmi1 is a key regulator of self-renewal of embryonic and adult central nervous system stem cells, and its overexpression has been shown to occur in several types of brain tumors. In a Cre/LoxP-based conditional transgenic mouse model, we show that fine-tuning of Bmi1 expression in embryonic neural stem cell (NSC) is sufficient to increase their proliferation and self renewal potential both in vitro and in vivo. This is linked to downregulation of both the ink4a/ARF and the p21/Foxg1 axes. However, increased and ectopic proliferation induced by overexpression of Bmi1 in progenitors committed toward a neuronal lineage during embryonic cortical development, triggers apoptosis through a survivin-mediated mechanism and leads to reduced brain size. Postnatally, however, increased self-renewal capacity of neural stem/progenitor cells (NSPC) is independent of Foxg1 and resistance to apoptosis is observed in neural progenitors derived from NSC-overexpressing Bmi1. Neoplastic transformation is absent in mice-overexpressing Bmi1 aged up to 20 months. These studies provide strong evidence that fine tuning of Bmi1 expression is a viable tool to increase self-renewal capacity of NSCs both in vitro and in vivo without eliciting neoplastic transformation of these cells. PMID- 21305671 TI - Concise review: adipose-derived stromal cells for skeletal regenerative medicine. AB - As the average age of the population grows, the incidence of osteoporosis and skeletal diseases continues to rise. Current treatment options for skeletal repair include immobilization, rigid fixation, alloplastic materials, and bone grafts, all which have significant limitations, especially in the elderly. Adipose-derived stromal cells (ASCs) represent a readily available abundant supply of mesenchymal stem cells, which demonstrate the ability to undergo osteogenesis in vitro and in vivo, making ASCs a promising source of skeletal progenitor cells. Current protocols allow for the harvest of over one million cells from only 15 ml of lipoaspirate. Despite the clinical use of ASCs to treat systemic inflammatory diseases, no large human clinical trials exist using ASCs for skeletal tissue engineering. The aim of this review is to define ASCs, to describe the isolation procedure of ASCs, to review the basic biology of their osteogenic differentiation, discuss cell types and scaffolds available for bone tissue engineering, and finally, to explore imaging of ASCs and their potential future role in human skeletal tissue engineering efforts. PMID- 21305673 TI - LacdiNAc (GalNAcbeta1-4GlcNAc) contributes to self-renewal of mouse embryonic stem cells by regulating leukemia inhibitory factor/STAT3 signaling. AB - Self-renewal of mouse embryonic stem cells (mESCs) is maintained by leukemia inhibitory factor (LIF)/signal transducer and activator of transcription (STAT3) signaling. However, this signaling control does not function in neither mouse epiblast stem cells (mEpiSCs) nor human ESCs (hESCs) or human induced pluripotent stem cells (hiPSCs). To date, the underlying molecular mechanisms that determine this differential LIF-responsiveness have not been clarified. Here, we show that the cell surface glycan LacdiNAc (GalNAcbeta1-4GlcNAc) is required for LIF/STAT3 signaling. Undifferentiated state mESCs expressed LacdiNAc at a higher level than differentiated state cells. Knockdown of beta4GalNAc-T3 reduced LacdiNAc expression and caused a decrease in LIF/STAT3 signaling that lessened the rate of self-renewal of mESCs. A biochemical analysis showed that LacdiNAc expression on LIF receptor (LIFR) and gp130 was required for the stable localization of the receptors with lipid raft/caveolar components, such as caveolin-1. This localization is required for transduction of a sufficiently strong LIF/STAT3 signal. In primed state pluripotent stem cells, such as hiPSCs and mEpiSC-like cells produced from mESCs, LacdiNAc expression on LIFR and gp130 was extremely weak and the level of localization of these receptors on rafts/caveolae was also low. Furthermore, knockdown of beta4GalNAc-T3 decreased LacdiNAc expression and reduced the efficiency of reversion of primed state mEpiSC-like cells into naive state mESCs. These findings show that the different LIF-responsiveness of naive state (mESCs) and primed state (mEpiSCs, hESCs, and hiPSCs) cells is dependent on the expression of LacdiNAc on LIFR and gp130 and that this expression is required for the induction and maintenance of the naive state. PMID- 21305674 TI - Reprogramming of trophoblast stem cells into pluripotent stem cells by Oct4. AB - ESCs and trophoblast stem (TS) cells are both derived from early embryos, yet these cells have distinct differentiation properties. ESCs can differentiate into all three germ layer cell types, whereas TS cells can only differentiate into placental cells. It has not been determined whether TS cells can be converted into ES-like pluripotent stem (PS) cells. Here, we report that overexpression of a single transcription factor, Oct4, in TS cells is sufficient to reprogram TS cells into a pluripotent state. These Oct4-induced PS (OiPS) cells have the epigenetic characteristics of ESCs, including X chromosome reactivation, elevated H3K27 me3 modifications, and hypomethylation of promoter regions in Oct4 and Nanog genes. Meanwhile, methylation of promoter region in the Elf5 gene occurred during reprogramming of TS cells. The gene expression profile of OiPS cells was very similar to ESCs. Moreover, OiPS cells can differentiate into the three germ layer cell types in vitro and in vivo. More importantly, chimeric mice with germline transmission could be efficiently produced from OiPS cells. Our results demonstrate that one single transcription factor, Oct4, could reprogram the nonembryonic TS cells into PS cells. PMID- 21305675 TI - Disordered eating and group membership among members of a pro-anorexic online community. AB - OBJECTIVE: The objective of this study was to explore motivations to become a member of a French-language 'pro-ana' online community, perceptions of support provided by other members and the nature of the information provided. METHOD: A sample of 29 members of an online community were assessed for disordered eating and responded to open-ended questions exploring perceptions of the online community. RESULTS: All participants reported high levels of disordered eating (Eating Attitudes Test > 30). The main motive for joining the online community was to be provided with both advice regarding weight loss and support. The majority of them equated thinness with happiness and were satisfied with their membership. Participants also described the types of advice that they had received concerning weight loss. CONCLUSIONS: Members of pro-ana online communities are likely to display high levels of disordered eating. Furthermore, membership to the online community was motivated not only by weight concerns but also by the support provided. Our findings confirmed the role of these online communities in encouraging harmful weight-loss and weight-control practices. PMID- 21305676 TI - Reluctance to recover in anorexia nervosa. AB - OBJECTIVE: Reluctance to recover may explain poor treatment outcome and high dropout and relapse rates in the treatment of anorexia nervosa (AN). This study systematically explored what AN patients describe as interfering with their wish to recover. METHOD: Two independent samples of women with AN (total N = 36) were interviewed in-depth using a phenomenological study design. Interviews were tape recorded, transcribed and analysed using QSR-NVivo7 (QSR International, Melbourne, Australia) software. RESULTS: Seven core obstacles were found to interfere with informants' wish to recover as follows: (i) 'perceiving judgements'; (ii) 'feeling stuck'; (iii) 'feeling distressed'; (iv) 'denying AN'; (v) 'eating'; (vi) 'gaining weight'; and (vii) 'appreciating the benefits'. CONCLUSION: The wish to recover is an autonomously based, fundamental motivational requirement for becoming ready to change. Understanding factors that contribute to this wish adds to the clinician's toolbox in motivational work with AN patients. PMID- 21305677 TI - IRF4 regulates IL-17A promoter activity and controls RORgammat-dependent Th17 colitis in vivo. AB - BACKGROUND: The transcription factor IRF4 is involved in several T-cell-dependent chronic inflammatory diseases. To elucidate the mechanisms for pathological cytokine production in colitis, we addressed the role of the IRF transcription factors in human inflammatory bowel disease (IBD) and experimental colitis. METHODS: IRF levels and cytokine production in IBD patients were studied as well as the effects of IRF4 deficiency in experimental colitis. RESULTS: In contrast to IRF1, IRF5, and IRF8, IRF4 expression in IBD was augmented in the presence of active inflammation. Furthermore, IRF4 levels significantly correlated with IL-6 and IL-17 mRNA expression and to a lesser extent with IL-22 mRNA expression in IBD. To further explore the role of IRF4 under in vivo conditions, we studied IRF4-deficient and wildtype mice in experimental colitis. In contrast to DSS colitis, IRF4 deficiency was protective in T-cell-dependent transfer colitis associated with reduced RORalpha/gammat levels and impaired IL-6, IL-17a, and IL 22 production, suggesting that IRF4 acts as a master regulator of mucosal Th17 cell differentiation. Subsequent mechanistic studies using database analysis, chromatin immunoprecipitation, and electrophoretic mobility shift assays identified a novel IRF4 binding site in the IL-17 gene promoter. Overexpression of IRF4 using retroviral infection induced IL-17 production and IL-17 together with IL-6 induced RORgammat expression. CONCLUSIONS: IRF4 can directly bind to the IL-17 promotor and induces mucosal RORgammat levels and IL-17 gene expression thereby controlling Th17-dependent colitis. Targeting of this molecular mechanism may lead to novel therapeutic approaches in human IBD. PMID- 21305679 TI - H2 generation in the early universe governs the formation of the first stars. PMID- 21305678 TI - Allelic variation of the matrix metalloproteinase-9 gene is associated with collagenous colitis. AB - BACKGROUND: Collagenous colitis is a chronic inflammatory bowel disease of unknown origin characterized by a thickened subepithelial collagen layer. Differential expression of matrix-metalloproteinases (MMPs) have been implicated in the pathogenesis of collagenous colitis. The aim was to assess genetic polymorphisms of MMP-1, -7, and -9 in a case-control setting for susceptibility to collagenous colitis. METHODS: Seventy-five patients with symptomatic collagenous colitis and 334 healthy blood donors were genotyped for single nucleotide polymorphisms (SNPs) in MMP-1-1607, MMP-7-153, MMP-7-181, and MMP-9 exon 6 using TaqMan technology. Susceptibility to collagenous colitis was tested by comparison of the carrier status of the rare allele. RESULTS: The carrier frequency of the allele GG of the coding SNP MMP-9 in exon 6 was 24% in patients with collagenous colitis and 14.3% in healthy blood donors (P = 0.039). The carriage of the allele GG significantly increased the risk for collagenous colitis with an odds ratio of 1.9 (95% confidence interval: 1.0-3.5). None of the other SNPs of MMP-1, MMP-7-153, and MMP-7-181 were associated with collagenous colitis. CONCLUSIONS: Allelic variation in the MMP-9 gene may be part of a complex genetic risk profile for collagenous colitis. Further studies are needed to confirm this observation and to explore the functional role of this gene polymorphism in collagenous colitis. PMID- 21305680 TI - New trends towards well-defined low-valent iron catalysts. PMID- 21305681 TI - The chemoselective one-step alkylation and isolation of thiophosphorylated cdk2 substrates in the presence of native cysteine. AB - The elucidation of signalling pathways relies heavily upon the identification of protein kinase substrates. Recent investigations have demonstrated the efficacy of chemical genetics using ATP analogues and modified protein kinases for specific substrate labelling. Here we combine N(6) -(cyclohexyl)ATPgammaS with an analogue-sensitive cdk2 variant to thiophosphorylate its substrates and demonstrate a pH-dependent, chemoselective, one-step alkylation to facilitate the detection or isolation of thiophosphorylated peptides. PMID- 21305682 TI - Oxorhenium-mediated assembly of noncyclic selective integrin antagonists: a combinatorial approach. AB - The parallel oxorhenium-mediated assembly of 288 noncyclic RGD analogues is reported. All complexes contain a NS(2) +S chelating motif that enables the unambiguous coordination of the oxorhenium and oxotechnetium cores. In this study, "modules S" contain a variety of pending guanidinium groups whereas the "NS(2) modules" are made of a series of N-acylated amino acids. Combination of sets of "NS(2) " and "S modules" together with tetrabutylammonium tetrachlorooxorhenate gave the corresponding oxorhenium complexes in good yields and satisfactory purities. Evaluation of these metalloconstructs towards integrins alpha(V) beta(3) , alpha(IIb) beta(3) , and alpha(V) beta(5) led to the identification of micromolar and submicromolar antagonists of theses integrins. These compounds exhibit interesting selectivities and promise attractive applications for the molecular imaging of integrin-dependent pathologies. PMID- 21305683 TI - Improving FRET-based monitoring of single chemomechanical rotary motors at work. AB - Protein dynamics are observable in real time using internal distance measurements of reference positions. Based on Forster resonance energy transfer (FRET) as the distance ruler between two fluorescent markers, investigations of single molecules one at a time have modified our views of protein conformational changes. X-ray crystallography provides trapped conformations at atomic resolution and NMR can add information about flexible parts of proteins, but the pathways between these structures including unknown conformations are often not directly accessible. Especially for membrane enzymes comprising multiple subunits, limited structural information requires alternative experimental methods to follow conformational pathways. Herein we summarize the knowledge gathered from single-molecule FRET studies of the membrane-embedded rotary nanomotor F(o)F(1)-ATP synthase. In addition, new ideas and concepts to shift and extend the current limitations of the confocal FRET detection approach using freely diffusing, liposome-reconstituted, individual enzymes are discussed: nanodiamonds as new fluorophores, optimized laser excitation schemes, Hidden Markov Models for software-based FRET trajectory analysis, and application of the anti-Brownian electrokinetic trap (ABELtrap) to keep the single enzyme in focus. PMID- 21305684 TI - A mixed quantum-classical description of excitation energy transfer in supramolecular complexes: Forster theory and beyond. AB - Electronic excitation energy transfer (EET) is described theoretically for the chromophore complex P(4) formed by a butanediamine dendrimer to which four pheophorbide-a molecules are covalently linked. To achieve a description with atomic resolution, and to account for the effect of an ethanol solvent, a mixed quantum-classical methodology is utilized. Room-temperature molecular dynamics simulations are used to describe the nuclear dynamics, and EET is accounted for in utilizing a mixed quantum-classical formulation of the transition rates. Therefore, the full quantum expression of the EET rates is given and the change to a mixed quantum-classical version is briefly explained. The description results in the calculation of transition rates which coincide rather satisfactory with available experimental data on P(4). It is also shown that different assumptions of classical Forster theory are not valid for P(4). The temporal behavior of EET deduced from the rate equations is confronted with that following from the solution of the time-dependent Schrodinger equation entering the mixed quantum-classical description of EET. From this we can conclude that EET in flexible chromophore complexes such as P(4) can be rather satisfactory estimated by single transition rates. A correct description, however, is only achievable by using a sufficiently large set of rates that correspond to the various possible equilibrium configurations of the complex. PMID- 21305685 TI - Chiral reconstruction of a metal surface by adsorption of racemic malic acid. AB - The adsorption of racemic malic acid on Cu(110) has been studied in ultrahigh vacuum (UHV) by means of scanning tunneling microscopy (STM), low-energy electron diffraction (LEED), X-ray photoelectron spectroscopy (XPS) and reflection absorption infrared spectroscopy (RAIRS). In contrast to enantiopure malic acid, which forms eleven different ordered phases on Cu(110), only four structures are observed for the racemate. Three of them are superpositions of enantiomorphous phases that have not been observed for the pure enantiomers. Only the non enantiomorphous c(2*4) saturation structure was found for pure enantiomers and for the racemate, but also shows differences at short-range order. This suggests that heterochiral two-dimensional (2D) phases are present in all cases. A restructuring of the copper surface is clearly identified in STM for some phases after careful annealing, causing chirality transfer via the metal substrate. PMID- 21305686 TI - Design, synthesis and structure-activity relationship of novel coumarin derivatives. AB - BACKGROUND: The lead coumarin derivative (E)-methyl 3-methoxy-2-[2-(4 methylcoumarin-7-yloxymethyl)phenyl]acrylate was discovered by using an intermediate derivatisation method. To discover new coumarin derivatives with improved activity, a series of substituted coumarins were synthesised and bioassayed. RESULTS: The compounds were identified by 1H NMR, IR, MS and elemental analysis. Bioassays demonstrated that some of the title compounds exhibited excellent fungicidal activity against cucumber downy mildew at 25 mg L 1. The relationship between structure and fungicidal activity is reported. CONCLUSION: The present work demonstrates that coumarin derivatives containing methoxyacrylate moieties can be used as possible lead compounds for developing novel fungicides. PMID- 21305687 TI - C. elegans meg-1 and meg-2 differentially interact with nanos family members to either promote or inhibit germ cell proliferation and survival. AB - The closely related C. elegans MEG-1 and MEG-2 proteins localize to P granules during a brief period of embryogenesis when the germ lineage is being separated from the soma. Embryonic primordial germ cells still develop in the absence of MEG activity, but major defects emerge during larval stages when germ cells fail to proliferate or differentiate normally, resulting in sterility. To investigate meg-1 function, we conducted a targeted RNAi screen for enhancers and suppressors of meg-1 sterility. Here, we show that meg-1 interacts with multiple pathways that promote germ cell proliferation and survival. Surprisingly, we found that two nanos family members had opposing effects on the meg-1 phenotype. Loss of nos 3 suppressed the meg-1 phenotype, restoring fertility, while loss of nos-2 enhanced the meg-1 phenotype, abolishing proliferation and causing early and pronounced germ cell degeneration. Together, our analyses suggest that, under circumstances that favor proliferation, MEG function is not essential for germ cells to proliferate, although it is important for optimal proliferation. Additionally, MEG activity is likely more directly involved in germ cell survival than previously thought. genesis 49:380-391, 2011. PMID- 21305688 TI - A phenotype-driven ENU mutagenesis screen identifies novel alleles with functional roles in early mouse craniofacial development. AB - Proper craniofacial development begins during gastrulation and requires the coordinated integration of each germ layer tissue (ectoderm, mesoderm, and endoderm) and its derivatives in concert with the precise regulation of cell proliferation, migration, and differentiation. Neural crest cells, which are derived from ectoderm, are a migratory progenitor cell population that generates most of the cartilage, bone, and connective tissue of the head and face. Neural crest cell development is regulated by a combination of intrinsic cell autonomous signals acquired during their formation, balanced with extrinsic signals from tissues with which the neural crest cells interact during their migration and differentiation. Although craniofacial anomalies are typically attributed to defects in neural crest cell development, the cause may be intrinsic or extrinsic. Therefore, we performed a phenotype-driven ENU mutagenesis screen in mice with the aim of identifying novel alleles in an unbiased manner, that are critically required for early craniofacial development. Here we describe 10 new mutant lines, which exhibit phenotypes affecting frontonasal and pharyngeal arch patterning, neural and vascular development as well as sensory organ morphogenesis. Interestingly, our data imply that neural crest cells and endothelial cells may employ similar developmental programs and be interdependent during early embryogenesis, which collectively is critical for normal craniofacial morphogenesis. Furthermore our novel mutants that model human conditions such as exencephaly, craniorachischisis, DiGeorge, and Velocardiofacial sydnromes could be very useful in furthering our understanding of the complexities of specific human diseases. PMID- 21305689 TI - The emerging face of primary cilia. AB - Primary cilia are microtubule-based organelles that serve as hubs for the transduction of various developmental signaling pathways including Hedgehog, Wnt, FGF, and PDGF. Ciliary dysfunction contributes to a range of disorders, collectively known as the ciliopathies. Recently, interest has grown in these syndromes, particularly among craniofacial biologists, as many known and putative ciliopathies have severe craniofacial defects. Herein we discuss the current understanding of ciliary biology and craniofacial development in an attempt to gain insight into the molecular etiology for craniofacial ciliopathies, and uncover a characteristic ciliopathic craniofacial gestalt. PMID- 21305690 TI - Time-lapse imaging of neural development: zebrafish lead the way into the fourth dimension. AB - Time-lapse imaging is often the only way to appreciate fully the many dynamic cell movements critical to neural development. Zebrafish possess many advantages that make them the best vertebrate model organism for live imaging of dynamic development events. This review will discuss technical considerations of time lapse imaging experiments in zebrafish, describe selected examples of imaging studies in zebrafish that revealed new features or principles of neural development, and consider the promise and challenges of future time-lapse studies of neural development in zebrafish embryos and adults. PMID- 21305691 TI - Dysbindin-1 gene contributes differentially to early- and adult-onset forms of functional psychosis. AB - Dysbindin-1 is a relatively ubiquitous protein in the brain which is involved in the modulation of synaptic homeostasis. The dysbindin-1 gene (DTNBP1) has been associated with schizophrenia and bipolar disorder diagnoses. However, its contribution to the severity of the clinical and neurocognitive expression of these disorders remains controversial. We aimed to explore the association between DTNBP1 and the phenotypes which are more directly linked with the underlying biology, such as age at onset and neurocognitive impairment. The present family sample comprised 894 Caucasian individuals: 268 patients affected by functional psychosis [58% with illness onset before 18 years, mean age at onset (SD): 14.71 (2.10)], 483 parents and 143 siblings. Ten DTNBP1 single nucleotide polymorphisms were genotyped in all individuals and their transmission disequilibrium was tested in relation to: (i) the risk for psychosis; (ii) patients' age at onset; and (iii) familial neurocognitive performance (including IQ estimation and executive functioning). In early-onset families a 5-marker haplotype encompassing exons 2-4 and the surrounding introns was significantly over-transmitted to cases, while in adult-onset families two haplotypes corresponding to the region between introns 4 and 7 were over-transmitted to cases. Estimated IQ was associated with the rs760666 marker in the whole sample, whereas a significant association between executive functioning and the rs2619522 marker appeared in early-onset families. Our findings confirm the role of the dysbindin-1 gene in the risk for functional psychosis and show a differential haplotypic risk pattern in families with early as opposed to adult onset in the affected offspring. PMID- 21305693 TI - Age at onset of psychotic disorder: cannabis, BDNF Val66Met, and sex-specific models of gene-environment interaction. AB - Discovering modifiable predictors for age at onset may help to identify predictors of transition to psychotic disorder in the "at-risk mental state." Inconsistent effects of sex, BDNF Val66Met (rs6265), and cannabis use on age of onset were previously reported. BDNF Val66Met and cannabis use before illness onset were retrospectively assessed in a sample of 585 patients with schizophrenia and their association with age at onset was evaluated. Cannabis use was significantly associated with earlier age at onset of psychotic disorder (AOP; average difference 2.7 years, P < 0.001), showing dose-response effects with higher frequency and earlier age at first use. There was a weak association between BDNF Val66Met genotype and AOP (difference 1.2 years; P = 0.050). No evidence was found for BDNF * cannabis interaction (interaction chi(2) (1) = 0.65, P = 0.420). However, a significant BDNF * cannabis * sex interaction was found (interaction chi(2) (1) = 4.99, P = 0.026). In female patients, cannabis use was associated with earlier AOP in BDNF Met-carriers (difference 7 years), but not in Val/Val-genotypes. In male patients, cannabis use was associated with earlier AOP irrespective of BDNF Val66Met genotype (difference 1.3 years). BDNF Val66Met genotype in the absence of cannabis use did not influence AOP, neither in female or male patients with psychotic disorder. Complex interactions between cannabis and BDNF may shape age at onset in female individuals at risk of psychotic disorder. No compelling evidence was found that BDNF genotype is associated with age at onset of psychotic disorder in the absence of cannabis use. PMID- 21305694 TI - Fabrication of DNA polymer brush arrays by destructive micropatterning and rolling-circle amplification. AB - A method for fabricating DNA polymer brush arrays using photolithography and plasma etching followed by solid-phase enzymatic DNA amplification is reported. After attaching oligonucleotide primers to the surface of a glass coverslip, a thin layer of photoresist is spin-coated on the glass and patterned via photolithography to generate an array of posts in the resist. An oxygen-based plasma is then used to destroy the exposed oligonucleotide primers. The glass coverslip with the primer array is assembled into a microfluidic chip and DNA polymer brushes are synthesized on the oligonucleotide array by rolling-circle DNA amplification. We have demonstrated that the linear polymers can be rapidly synthesized in situ with a high degree of control over their density and length. PMID- 21305695 TI - Synthesis of poly(propylene glycol)-block-polyethylenimine triblock copolymers for the delivery of nucleic acids. AB - LPEIs, which are efficient DNA transfection agents, were found to be far less effective for the delivery of siRNAs. Here, two amphiphilic triblock copolymers LPEI(50) -b-PPG(36) -b-LPEI(50) (2) and LPEI(14) -b-PPG(68) -b-LPEI(14) (4) have been synthesized. The transfection assays showed that compound 2 was efficient for DNA transfection whilst it was almost inactive for siRNA delivery. In contrast, polymer 4 was inefficient for DNA transfection while it showed capabilities for siRNA delivery. Taken together, our results indicate that the properties required for DNA and siRNA delivery are different. Moreover, we show that introduction of a hydrophobic segment that allows self-assembly confers siRNA delivery capacities. PMID- 21305696 TI - Dead cell counts during serum cultivation are underestimated by the fluorescent live/dead assay. AB - The live/dead fluorescent assay provides a quick method for assessing the proportion of live and dead cells in cell culture systems or tissues and is widely used. Dead cells are detected by the fluorescence produced when propidium iodide (PI) binds to DNA; PI and similar molecules are excluded from live cells but can penetrate dead cells because of their loss of membrane integrity. Here we investigated the effect of serum in the culture medium on the reliability of the method. We assessed viability of chondrocytes with/without serum using both a live/dead assay kit and also trypan blue staining. We found that after 2 days of culture, the DNA-binding dye PI could no longer detect dead cells if serum was present but they were readily detected in serum-free medium or if an inhibitor to DNase I was added to the serum-containing medium. Dead cells could be detected by trypan blue staining in all cultures. Hence dead cells are no longer detected as the DNase I present in serum degrades their DNA. DNA-binding dyes may thus not give a reliable estimate of the number of dead cells in systems that have been cultured in the presence of serum for several days. PMID- 21305697 TI - Stress-related challenges in pentose fermentation to ethanol by the yeast Saccharomyces cerevisiae. AB - Conversion of agricultural residues, energy crops and forest residues into bioethanol requires hydrolysis of the biomass and fermentation of the released sugars. During the hydrolysis of the hemicellulose fraction, substantial amounts of pentose sugars, in particular xylose, are released. Fermentation of these pentose sugars to ethanol by engineered Saccharomyces cerevisiae under industrial process conditions is the subject of this review. First, fermentation challenges originating from the main steps of ethanol production from lignocellulosic feedstocks are discussed, followed by genetic modifications that have been implemented in S. cerevisiae to obtain xylose and arabinose fermenting capacity per se. Finally, the fermentation of a real lignocellulosic medium is discussed in terms of inhibitory effects of furaldehydes, phenolics and weak acids and the presence of contaminating microbiota. PMID- 21305692 TI - Genome-wide association analysis of age at onset and psychotic symptoms in bipolar disorder. AB - Genome-wide association studies (GWAS) have identified several susceptibility loci for bipolar disorder (BP), most notably ANK3. However, most of the inherited risk for BP remains unexplained. One reason for the limited success may be the genetic heterogeneity of BP. Clinical sub-phenotypes of BP may identify more etiologically homogeneous subsets of patients, which can be studied with increased power to detect genetic variation. Here, we report on a mega-analysis of two widely studied sub-phenotypes of BP, age at onset and psychotic symptoms, which are familial and clinically significant. We combined data from three GWAS: NIMH Bipolar Disorder Genetic Association Information Network (GAIN-BP), NIMH Bipolar Disorder Genome Study (BiGS), and a German sample. The combined sample consisted of 2,836 BP cases with information on sub-phenotypes and 2,744 controls. Imputation was performed, resulting in 2.3 million SNPs available for analysis. No SNP reached genome-wide significance for either sub-phenotype. In addition, no SNP reached genome-wide significance in a meta-analysis with an independent replication sample. We had 80% power to detect associations with a common SNP at an OR of 1.6 for psychotic symptoms and a mean difference of 1.8 years in age at onset. Age at onset and psychotic symptoms in BP may be influenced by many genes of smaller effect sizes or other variants not measured well by SNP arrays, such as rare alleles. PMID- 21305698 TI - A strategy for neuraminidase inhibitors using mechanism-based labeling information. AB - A potent inhibitor for Vibrio cholerae neuraminidase (VCNA) was developed by using a novel two-step strategy, a target amino acid validation using mechanism based labeling information, and a potent inhibitor search using a focused library. The labeling information suggested the hidden dynamics of a loop structure of VCNA, which can be a potential target of the novel inhibitor. A focused library composed of 187 compounds was prepared from a 9-azide derivative of 2,3-dehydro-N-acetylneuraminic acid (DANA) to interrupt the function of the loop of the labeled residues. Inhibitor 3 c showed potent inhibition properties and was the strongest inhibitor with FANA, a N-trifluoroacetyl derivative of DANA. Validation studies of the inhibitor with a detergent and a Lineweaver-Burk plot suggested that the 9-substitution group would interact hydrophobically with the target loop moiety, adding a noncompetitive inhibition property to the DANA skeleton. This information enabled us to design compound 4 having the combined structure of 3 c and FANA. Compound 4 showed the most potent inhibition (K(i) =73 nM, mixed inhibition) of VCNA with high selectivity among the tested viral, bacterial, and mammal neuraminidases. PMID- 21305699 TI - Effects of transforming growth factor-beta subtypes on in vitro cartilage production and mineralization of human bone marrow stromal-derived mesenchymal stem cells. AB - Human bone marrow stromal-derived mesenchymal stem cells (hBMSCs) will differentiate into chondrocytes in response to defined chondrogenic medium containing transforming growth factor-beta (TGFbeta). Results in the literature suggest that the three mammalian subtypes of TGFbeta (TGFbeta1, TGFbeta2 and TGFbeta3) provoke certain subtype-specific activities. Therefore, the aim of our study was to investigate whether the TGFbeta subtypes affect chondrogenic differentiation of in vitro cultured hBMSCs differently. HBMSC pellets were cultured for 5 weeks in chondrogenic media containing either 2.5, 10 or 25 ng/ml of TGFbeta1, TGFbeta2 or TGFbeta3. All TGFbeta subtypes showed a comparable dose response curve, with significantly less cartilage when 2.5 ng/ml was used and no differences between 10 and 25 ng/ml. Four donors with variable chondrogenic capacity were used to evaluate the effect of 10 ng/ml of either TGFbeta subtype on cartilage formation. No significant TGFbeta subtype-dependent differences were observed in the total amount of collagen or glycosaminoglycans. Cells from a donor with low chondrogenic capacity performed equally badly with all TGFbeta subtypes, while a good donor overall performed well. After addition of beta glycerophosphate during the last 2 weeks of culture, the expression of hypertrophy markers was analysed and mineralization was demonstrated by alkaline phosphatase activity and alizarin red staining. No significant TGFbeta subtype dependent differences were observed in expression collagen type X or VEGF secretion. Nevertheless, pellets cultured with TGFbeta1 had significantly less mineralization than pellets cultured with TGFbeta3. In conclusion, this study suggests that TGFbeta subtypes do affect terminal differentiation of in vitro cultured hBMSCs differently. PMID- 21305700 TI - Clinically applicable transplantation procedure of dermal papilla cells for hair follicle regeneration. AB - Dermal papilla cells (DPCs) interact with epithelial stem cells and induce hair folliculogenesis. Cell-based therapies using expanded DPCs for hair regeneration have been unsuccessful in humans. Two major challenges remain: first, expanded DPCs obtained from adult hair follicles have functional limitations; second, a clinically applicable method is needed for transplanting DPCs. This study aimed to identify an efficient, minimally invasive and economical DPC transplantation procedure for use in clinical settings. Five clinically applicable transplantation procedures were tested, termed the Pinhole, Laser, Slit, Non vascularized sandwich (NVS) and Hemi-vascularized sandwich (HVS) methods. Labelled rat dermal papilla tissue was transplanted into rat sole skin, and hair follicle regeneration was evaluated histologically. Regenerated follicles and labelled DPCs were detected for all methods, although some follicles showed abnormal growth, i.e. a cystic or inverted appearance. The HVS method, pioneered here, resulted in significantly larger number of regenerated follicles that were more mature and regular than those observed using the other methods. Moreover, hair growth was detected after expanded adult-derived DPC transplantation using the HVS method. These results suggest that direct contact of epithelial and dermal components and better vascularization/oxygenation of the recipient site are critical for hair regeneration in cell-based therapies. PMID- 21305701 TI - Systems physiology--the heart of the matter or a bone of contention? PMID- 21305703 TI - MicroRNAs in cardiomyocyte development. AB - MicroRNAs (miRNAs) negatively regulate gene expression at the post transcriptional level, primarily by base-pairing with the 3'-untranslated region (3'-UTR) of their target mRNAs. Many miRNAs are expressed in a tissue/organ specific manner and are associated with an increasing number of cell proliferation, differentiation, and tissue development events. Cardiac muscle expresses distinct genes encoding structural proteins and a subset of signal molecules that control tissue specification and differentiation. The transcriptional regulation of cardiomyocyte development has been well established, yet only until recently has it been uncovered that miRNAs participate in the regulatory networks. A subset of miRNAs are either specifically or highly expressed in cardiac muscle, providing an opportunity to understand how gene expression is controlled by miRNAs at the post transcriptional level in this muscle type. miR-1, miR-133, miR-206, and miR-208 have been found to be muscle-specific, and thus have been called myomiRs. The discovery of myomiRs as a previously unrecognized component in the regulation of gene expression adds an entirely new layer of complexity to our understanding of cardiac muscle development. Investigating myomiRs will not only reveal novel molecular mechanisms of the miRNA-mediated regulatory network in cardiomyocyte development, but also raise new opportunities for therapeutic intervention for cardiovascular disease. PMID- 21305704 TI - Estrogen receptor-positive breast cancer: a multidisciplinary challenge. AB - Estrogen receptor (ER)-positive breast cancer research is an ideal example of how systems biology can be applied to better understand a specific clinical issue. By integrating vast data sets from tumor-derived expression arrays, genome-wide transcription factor/chromatin interactions, proteomics and computational analyses, we may better understand the concept of breast cancer development, heterogeneity, and its treatment. Resistance to endocrine treatment, such as anti estrogens, often occurs and systems biology may prove to be a valuable asset in tailoring treatment for each patient. In such a multidisciplinary setup, it is essential to try and connect these massive data streams with the known pathological background and cell biology. In this review, we describe the current status of such studies and the challenges that are to be met in order to fully understand the concept of anti-estrogen resistance from a holistic perspective. PMID- 21305706 TI - Taking care with confidentiality. PMID- 21305705 TI - Signaling pathways that control cell migration: models and analysis. AB - Dissecting the intracellular signaling mechanisms that govern the movement of eukaryotic cells presents a major challenge, not only because of the large number of molecular players involved, but even more so because of the dynamic nature of their regulation by both biochemical and mechanical interactions. Computational modeling and analysis have emerged as useful tools for understanding how the physical properties of cells and their microenvironment are coupled with certain biochemical pathways to actuate and control cell motility. In this focused review, we highlight some of the more recent applications of quantitative modeling and analysis in the field of cell migration. Both in modeling and experiment, it has been prudent to follow a reductionist approach in order to characterize what are arguably the principal modules: spatial polarization of signaling pathways, regulation of the actin cytoskeleton, and dynamics of focal adhesions. While it is important that we 'cut our teeth' on these subsystems, focusing on the details of certain aspects while ignoring or coarse-graining others, it is clear that the challenge ahead will be to characterize the couplings between them in an integrated framework. PMID- 21305707 TI - Surgical registries: Effective, but how to pay for them?: Comment on "More recurrences after hernia mesh fixation with short-term absorbable sutures". PMID- 21305702 TI - Role of the nuclear envelope in genome organization and gene expression. AB - Although often depicted as a static structure upon which proteinaceous factors bind to control gene expression, the genome is actually highly mobile and capable of exploring the complex domain architecture of the nucleus, which in turn controls genome maintenance and gene expression. Numerous genes relocate from the nuclear periphery to the nuclear interior upon activation and are hypothesized to interact with pre-assembled sites of transcription. In contrast to the nuclear interior, the nuclear periphery is widely regarded as transcriptionally silent. This is reflected by the preferential association of heterochromatin with the nuclear envelope (NE). However, some activated genes are recruited to the nuclear periphery through interactions with nuclear pore complexes (NPCs), and NPC components are capable of preventing the spread of silent chromatin into adjacent regions of active chromatin, leading to the speculation that NPCs may facilitate the transition of chromatin between transcriptional states. Thus, the NE might better be considered as a discontinuous platform that promotes both gene activation and repression. As such, it is perhaps not surprising that many disease states are frequently associated with alterations in the NE. Here, we review the effects of the NE and its constituents on chromatin organization and gene expression. PMID- 21305708 TI - AFP in OLT for HCC?: Another shadow on the cave wall: Comment on "Evaluation of absolute serum alpha-fetoprotein levels in liver transplant for hepatocellular cancer". PMID- 21305709 TI - Beware of the sleeping panther: Comment on "Implementing Liberia's poverty reduction strategy: An assessment of emergency and essential surgical care". PMID- 21305710 TI - Disparities in access to care: Does it translate into worse outcomes?: Comment on "Possible geographical barriers to trauma center access for vulnerable patients in the United States". PMID- 21305711 TI - Failure is not a fate worse than death: Comment on "Special report: Suicidal ideation among American surgeons". PMID- 21305712 TI - The more things change, the more they stay the same: Comment on "Single-incision multiport laparoscopic cholecystectomy". PMID- 21305713 TI - Teaching residents to pass and catch the baton: Comment on "Integration of a formalized handoff system into the surgical curriculum". PMID- 21305714 TI - Primum non nocere, or leave that ostomy alone: Comment on "Incisional hernias in temporary stoma wounds". PMID- 21305715 TI - Abstracts of the 33rd Annual Meeting of the United Kingdom Environmental Mutagen Society, July 12-14, 2010, Derby, United Kingdom. PMID- 21305716 TI - Proceedings of the 18th International Conference on Chelation (ICOC). December 13 16, 2008, Athens, Greece. PMID- 21305718 TI - Proceedings of the LXIII Annual Meeting of the Italian Society for Veterinary Sciences (SISVET). 2009, Udine, Italy. PMID- 21305717 TI - Prevalence and correlates of sexual behavior and risk management among HIV positive adults over 50. AB - BACKGROUND: This study examined the prevalence and correlates of sexual behavior, sexual risk, and behavioral risk reduction strategies among a diverse sample of HIV-positive adults over age 50. METHODS: Individual surveys were conducted with 914 HIV-positive adults age 50 and over (640 male, 264 female, 10 transgender) living in New York City. RESULTS: Over half the sample reported sexual activity in the past 3 months, and one-third of sexually active participants reported unprotected anal or vaginal sex in that time period. Sexually active participants were more likely to be younger and male, but did not differ on physical health status. Participants reported a range of risk-management strategies, including 100% condom use (49% of sexually active participants), serosorting (17%), and strategic positioning (4%). The prevalence of strategies differed by gender/sexual identity subgroups. In multivariate modeling, unprotected sex was significantly associated with recent substance use and loneliness. CONCLUSIONS: Older HIV-positive adults are sexually active, and engage in both high-risk and risk-management behaviors. Loneliness emerged as the dominant risk factor in this sample. Findings provide meaningful implications for HIV prevention interventions targeting this population. PMID- 21305719 TI - The future for military anaesthesia after operations in Afghanistan. PMID- 21305720 TI - Medical perspective: macular degeneration (AMD) and human sight in the future. AB - The author concisely presents the results of his 30-year investigations about the harmful influence of the higher sun radiation on the eyes. The investigations were carried out among the population of the Island of Rab, situated in the northern part of the Adriatic sea. This geographical region has been characterized by higher doses of the global sun radiation compared with the remaining part of the Republic of Croatia, and partly with the rest of the Mediterranean. The author proved it by his own measurements of UV-B, UV-A and the global sun radiation. The number of the diseased from the macular degeneration (AMD), cataract and precancerous pterygium has been significantly increased in those inhabitants being more exposed to the sun radiation. Investigating the retinal threshold, of the macula and peripherally--meridian thresholds, even the children more exposed to the sun radiation without protection, are established to have the increased excitation threshold of the retina, making later the basis and risk factor for the earlier AMD development. The author also points out that the periphery of retina and the macula are damaged in AMD. Later stages of macular degeneration transfer to the clinical form of the optic nerve atrophy. The author pathohistologically proved that the whole retina has been degeneratively involved in AMD, not only the photoreceptors and the retinal pigment. Therefore, the author pleads for the idea of children protection from the higher sun radiation to become a national problem of each country, and the coordination must be with the World Health Organization (WHO). PMID- 21305721 TI - Amniotic membrane transplantation in the treatment of persistent epithelial defect on the corneal graft. AB - It has been shown that amniotic membrane transplantation (AMT) improves healing of the epithelium defects as it serves as a basement membrane for endothelial cells growth, prevents inflammatory cell infiltration and reduces apoptosis in keratocytes. Having in mind the healing properties of AM we investigated the efficacy of AMT in persistent epithelial defect (PED) on the corneal graft. 80 corneal grafts were prospectively followed up for presence of PED 10 months after surgery. PED was detected in 12 cases (15%) having surgery for: rejected graft (n = 4), keratoconus (n = 3), keratoconus following PK on a second eye (n = 3), corneal perforation (n = 1) and Stevens-Johnson keratopathy (n = 1). Epithelial defect (ED) developed 14 +/- 7 days after surgery in 10 cases and 1.5 month in other two. All patients were primarily conservatively treated with subconjuctival steroids and artificial tears for 10 days and systemic steroid therapy if needed after, until the period of 2 weeks. 4 patients were healed. Since ED was unresponsive to all previous treatments for more than 2 weeks, one layer of AM was placed on the corneal lesion in 5 patients, and in 3 cases of deep PED several layers of AM were placed. Healing of the defect was obtained in 7/8 (87.5%) eyes. In 1 patient second AM transplantation was necessary. Mean epithelization time was 2 weeks (range 1-3 weeks) in monolayer and 3 weeks (range 2-4 weeks) for multilayer cases. 5 out of 8 patients retained the same best corrected visual acuity (BCVA) while 3/8 patients improved their vision more than 2 lines. Preoperative corneal thickness of 255 +/- 40 mm increased to 455 +/- 90 mm. AM transplantation facilitates healing of corneal epithelium. PED on the corneal graft unresponsive to conventional treatment can be effectively cured when covered with one or more amniotic membrane layers. PMID- 21305722 TI - Forensic aspects in domestic homicide. AB - The aim of the study was investigation of specific forensic aspects in offenders involved in domestic homicide cases in regard to sociodemographic and psychosocial variables and modalities of the offense. The research was conducted at the Department of Forensic Psychiatry in Neuropsychiatric Hospital "Dr. Ivan Barbot" in Popovaca, Croatia. The sample in this study consisted of domestic homicide group (N = 162). The results showed certain characteristics within the group of domestic homicide offenders. Generally speaking the offenders in domestic homicide cases were often married and were living in their families. Moreover, they were brought up in families with both parents and they had history of regular military service. Furthermore, offenders in domestic homicide cases were less involved in intervention from social services with rare history of home runaway and substance abuse during adolescence. Finally, the same group of offenders was less often had mothers or close friends with antisocial personality disorder but had frequent language and speech problems during adolescent period. In regard to the victims of domestic homicide they were often aged females. The offenders usually commit crime in their living space, either in the house or in the apartment. Based on these findings we conclude there are certain specific characteristics in the domestic homicide cases compared to homicide in general. PMID- 21305723 TI - Epidemiologic data of malignant melanoma in Osijek-Baranya County (Eastern Croatia) during the period of 2000-2008. AB - During the past several decades there has been a substantial increase in the incidence of malignant melanoma worldwide. The highest incidences were reported in New Zealand and Australia. In Europe the northern countries generally have a higher incidence. The aim of this retrospective study was to provide the incidence and mortality for all patients with malignant melanoma diagnosed in Osijek-Baranya County, Eastern Croatia, during 2000-2008. In the past 30 years in the Republic of Croatia the incidence of melanoma increased by 337%. During the period of 2000-2006 in Osijek-Baranja County, the incidence of melanoma increased by 13%. The incidence of melanoma increases with age, but in past decades melanoma is more often diagnosed in people aged 25-40. The mortality between 2000 and 2008 increased by 18%. The incidence of melanoma generally increases equally in men and women. The most common localization of skin melanoma in males was trunk and in females the lower extremities. Presently, in Osijek-Baranya County melanoma is 15th on the list of malignant tumors and represent 2% of all malignant tumors. In New Zealand, Australia and European northern countries mortality is reduced, as result of earlier diagnosis and education of risk groups. Unfortunately, in Osijek-Baranya County, in a comparison with these countries, the mortality is higher although incidence is the same or lower. PMID- 21305724 TI - What associates Charles Bonnet syndrome with age-related macular degeneration? AB - Charles Bonnet syndrome (CBS) is a condition related to patients with visual loss due to age related macular degeneration or glaucoma that are having complex visual hallucinations. The CBS was first described by Swiss physician Charles Bonnet in 1760. Affected patients, who are otherwise mentally healthy people with significant visual loss, have vivid, complex recurrent visual hallucinations (VHs). One characteristic of these hallucinations is that they usually are "Lilliputian hallucinations" as patients experience micropsia (hallucinations in which the characters or objects are distorted and much smaller than normal). The prevalence of Charles Bonnet Syndrome has been reported to be between 10% and 40%; a recent Australian study has found the prevalence to be 17.5%. The high incidence of non-reported CBS is thought to be as a result of patient's fear to report the symptoms as they could be labeled as mentally insane since those type of visual hallucinations could be found in variety of psychiatric and neurological disorders such as drug or alcohol abuse (delirium tremens), Alice in Wonderland syndrome (AIWS), psychosis, schizophrenia, dementia, narcolepsy, epilepsy, Parkinson disease, brain tumors, migraine, as well as, in long term sleep deprivation. VHs can also be presented as the initial sign of the Epstein Barr virus infection in infectious mononucleosis. Patients who suffer from CBS usually possess insight into the unreality of their visual experiences, which are commonly pleasant but may sometimes cause distress. The hallucinations consist of well-defined, organized, and clear images over which the subject has little control. It is believed that they represent release phenomena due to deafferentiation of the visual association areas of the cerebral cortex, leading to a form of phantom vision. Cognitive defects, social isolation, and sensory deprivation have also been implicated in the etiology of this condition. This study was conducted on 350 patients diagnosed with Age-Related Macular Degeneration (AMD) and shows incidence of CBS in 13% of patients with AMD. Furthermore, we have found higher incidence of CBS in patients with massive loss of vision in peripheral visual field which is not age related. PMID- 21305725 TI - Focused high risk--population screening for carotid stenosis and retinal microangiopathia after radiotherapy for laryngeal carcinoma. AB - Carotid artery stenosis (CAS) is one of the major complications of external irradiation (radiotherapy, RT) for laryngeal carcinoma. Considering amaurosis fugax is often one of the first signs of significant CAS our focus was to determine weather patients with post-irradiation CAS also develop ocular microangiopathy as a result of insufficient ophthalmic circulation. In our study Carotid Duplex ultrasound scans revealed that 33.33% of patients had significant radiation-induced CAS. The majority (over 85.71%) of radiation-induced CAS had more than one atherosclerotic plaque including any degree of stenosis in the RT group, and had significantly more than that of the control group. Microangiopathic changes were documented only with the patients that have had an increased cerebrovascular risk (diabetes mellitus and arterial hypertension). PMID- 21305726 TI - Bone morphogenetic protein-7 expression in human pyelonephritis. AB - Bone morphogenetic protein 7 (BMP- 7) is a member of the transforming growth factor (TGF) beta superfamily and is involved in regeneration, repair, and development of specific tissues, for example kidney and skeleton. The experimental studies have shown its protective role against fibrotic processes. Tubulointerstitial changes are present in the pyelonephritic kidney which progresses to fibrosis. Renal fibrosis may lead to the loss of renal function. The aim of this study was to investigate BMP-7 expression in acute and chronic pyelonephritis in humans. Seven patients with acute pyelonephritis and 7 with chronic pyelonephritis were treated in Department of Nephrology Clinical Hospital, Rijeka. Tissue biopsy was taken and renal tissue was studied histopathologically by use of hematoxylin and eosin and scored for diagnosis of pyelonephritis. BMP-7 expression was studied by immunohistochemical staining. BMP 7 expression was observed in the tubular area of the pyelonephritic kidneys. The expression of BMP- 7 was stronger in the acute pyelonephritic group and less in the chronic pyelonephritic group of patients. The results imply that BMP-7 has a role in chronic pyelonephritis. Tubular BMP-7 expression had a negative correlation with fibrosis and tubular, atrophy. Our results are suggesting that BMP- 7 plays an important protective role in renal inflammatory diseases preventing greater damage and fibrosis. PMID- 21305727 TI - Anti-VEGF in treatment of central retinal vein occlusion. AB - Macular edema along with macular ischemia is responsible for decreased visual acuity in central retinal vein occlusion. Bevacizumab (Avastin, Genentech) blocks vascular endothelial growth factor (VEGF) induced hyperpermeability of blood vessels. In this prospective case series we investigated the efficacy of anti VEGF treatment in reduction of central retinal thickness (CRT) and improvement in visual acuity (VA). 25 patients were followed up for 12 months and treated monthly with intravitreal bevacizumab. VA and CRT were measured at each visit. Treatment was discontinued as the peak improvement of either parameter was reached and reinstituted in case of deterioration/recurrence of edema. Study endpoints included: VA using ETDRS charts, CRT and number of injections at 12 months. Mean VA from all 25 patients increased by 3.1 logMAR lines (p < 0.05 compared to baseline). The improvement of VA after bevacizumab injection was in correlation with a decrease in CRT In subgroup analyses, patients receiving bevacizumab injection within the first 3 months after CRVO showed an average VA gain of 4.2 logMAR lines. Mean of 4.5 injections was needed to control the disease during the follow-up period. Bevacizumab treatment was effective in VA and reducing CRT. It appears from subgroup analysis that initiation of treatment early in the course of disease produced better functional outcome. Several injections were needed to control the disease. Regular OCT examinations and retreatment are advised in order to maintain initially reached VA. PMID- 21305728 TI - Chromotherapy of macular degeneration with transitions lenses and green-yellow medical filters and special programme for psychoorganic disturbances. AB - Optical spectrum of the sunlight consists of visible or chromatic spectrum, with the range of wavelengths of electromagnetic vibrations from 7700 to 3900 AU, and the invisible spectrum: infrared and ultraviolet. Chromatic spectrum gives rise to the sensation of colour, capable for simulating specialized retinal photoreceptors and is perceptible as light. This rule of perception of the particular range of the optical spectrum goes mainly for man, while particular deviations, more or less, are applicable to the rest of animal and plant life. The optical part of the spectrum belongs to nonionizing radiation. It created the life on the Earth, maintaining it nowadays and even threatening the human organ of vision, because the retina had not been yet adequately accommodated through evolution with its photoreactive metabolism. Human retina is very sensitive about possible harmful influence of ultraviolet and blue light even today in evolution, but also phototoxic on complete strong visible light. In their clinical and experimental work on animals, the authors prove with their own patent (P 20020077A)-Vojnikovic B&D, and in collaboration with Essilor Optic Austria GmbH, that particular medical filters in the range of green-yellow colour especially (565 to 570 nm), and in combination with "Transitions" successfully threat macular degeneration-AMD, slowing down its progression and having positive psychoorganic effect on the depressive mood of such patients with threatened sight. Full attention has been paid to the design of medical filter, so the periphery of the lens plays a positive role in blood concentration of melatonin, while the central part stimulates the sight and the concentration of serotonine. Thus the physiological balance of melatonin and serotonin and the stability of psychophysical disturbances have been achieved. PMID- 21305729 TI - Intravitreal bevacizumab with or without triamcinolone for refractory diabetic macular oedema. AB - We evaluate the effect of intravitreal injections of Bevacizumab (IVB) alone or combined with triamcinolone (IVT) in the first injection for treatment of refractory diabetic macular oedema (DME). Sixty eyes of sixty patients with refractory DME were included. Half of the receive injections of IVB (1.25 mg/0.05 mL) or combined IVB and IVT (1.25 mg/0.05 mL and 2 mg/0.05 mL respectively). The primary outcome measure was change in central macular thickness (CMT). Secondary outcome measures were change in best-corrected logMAR visual acuity (BCVA) and incidence of potential adverse events. Central macular thickness was reduced significantly in both the IVB and IVB/IVT groups. At week 24, CMT change compared to the baseline was -95.7 microm (95% CI, -172.2 to -19.26) in the IVB group and 92.1 pm (95% CI, -154.4 to -29.7) in the IVB/IVT group. There was not a significant difference between the IVB and the IVB/IVT groups (p = 0.022). Improvement of BCVA was initiated at weeks 6 and 12 in the IVB/IVT and IVB groups respectively. In terms of BCVA change compared to the baseline at 24 weeks, the differences between the IVB and the IVB/IVT groups (p = 0.006) were significant. Anterior Chamber reaction was noticed in six (20%) and six (20%) eyes respectively in the IVB and IVB/IVT groups the day after injection, and it resolved with no sequel. Elevation of IOP occurred in two eyes (6%) in the IVB/ IVT group. Intravitreal injections of Bevacizumab had a beneficial effect on refractory DME in terms of CMT reduction and BCVA improvement. Addition of triamcinolone in the injection seemed to induce earlier visual improvement; however, it did not show any significant additive effect later during follow-up. PMID- 21305730 TI - Muscle loss in elderly. AB - Aging is associated with loss of skeletal muscle mass, strength and endurance. The aim of this study was to determinate age related changes in human muscles with different function and location in the body (vastus lateralis muscle and intercostal internus muscle). Our results suggest that age related muscle atrophy affect both human skeletal muscles. Also, the results showed the increase in percentage of muscle fibers with high oxidative activity during aging. PMID- 21305731 TI - The role of air quality in perception of health of the local population. AB - The research aim was to investigate and establish the perception of health among population groups with different number of industrial polluters in their living environment. Namely, the Kostrena living area (3250 inhabitants) is situated near big industrial pollutant producers: INA oil refinery Urinj, thermo power plant Rijeka, shipyard "Viktor Lenac", while in Crikvenica living area such pollutant producers do not exist. In this research 146 subjects from Kostrena participated (74 men and 72 women with age average 40.8, SD 9.2 years), and 157 subjects from Crikvenica area (79 men and 78 women with age average 39.4, SD 10.1 years). The perception of health was measured by the means of SF-36 questionnaire variables. Lung function (FEV1, FVC, FEV25/75, PEF), cardiovascular function (systolic and diastolic arterial blood pressure, heart rate were also measured, including body proportion measures by the means of waste and hip circumference and silhouette test, in order to establish the eventual objective physical health parameter difference among examined population groups. Subjects from Kostrena perceived their general health, mental health, and vitality worse than subjects from Crikvenica. Group from Kostrena felt themself more limited in their roles due to emotional problems, perceiving more pain than group from Crikvenica. On the opposite site, social functioning of subjects from Kostrena was better in comparison to Crikvenica group. No signifficant differences between groups were found in physical functioning and in role limitation due to physical problems. In addition, there were no significant differences between groups in objective physical health parameters, such as pulmonary function, arterial blood pressure, pulse, and waist to hip ratio. Subjects using sensoric systems and the mental cognition about harmful environmental factors, perceive their health worse if there are present industrial resources in their environment, even when concentration of the pollutants are within legal ranges. PMID- 21305732 TI - The town of Cabar, Croatia, a high risk area for multiple sclerosis--analytic epidemiology of dietary factors. AB - Multiple sclerosis (MS) is demyelization disease of central nervous system of unidentified causes. Analytic epidemiological research of 19 patients, clinically approved cases of MS and 25 controls, autochthonic inhabitants of town of Cabar, Croatia, the high-risk zone for the disease, was made. The research plan included case-control investigation--the "door to door" questionnaire--about nutrition habits. An odds ratio (OR) was calculated for all the factors which were more frequently found in the patients than in the controls, and vice versa. The variables that were connected with significant risk for MS in the town of Cabar included: alcohol consumption (p = 0.05), animal fats/dried meat products consumption (p = 0.007), nitrate salting (p = 0.03), strong spices (p = 0.007), mixed bread (p = 0.002), oat and oat products consumption (p = 0.0075). No connection was found with regular consumption of vegetables and fruit (p = 0.009), blue fresh fish (p = 0.028), other fresh fish (p = 0.03), freshwater fish (p = 0.002), canned fish (p = 0.004), dormouse meat (p = 0.007), air-dried meat products (p = 0.004) and using the water from water supply (p = 0.011). In the town of Cabar nutritional customs, primarily food rich in animal fats, alcohol abuse, and oat consumption could have an influence on MS pathogenesis in genetically inclined individuals. PMID- 21305733 TI - The town of Cabar, Croatia, familiar pseudocluster for multiple sclerosis- descriptive epidemiological study. AB - Previous descriptive surveys in the town of Cabar, Croatia carried out by our own epidemiological research group, have established that this area is at high risk for MS. To confirm the above assumption and to update MS frequency in this area we conducted a community-based intensive prevalence and incidence study. On December 31st 2001, the average prevalence was 205.7 per 100,000 with prevailing age-specific prevalence in the group of patients between 30 and 49 years of age. The average incidence (1948-2004) was 5.52/100.000 population per year (95% CI = 3.27-8.72), average mortality in the year was 2.76/100 000 inhabitants (95% CI = 1.26-5.24). Sexual index stood at 1:11, starting time was 10:04 +/- 28.53 in the year, and the average duration of the disease to the prevalence 11:11 +/- 27.26 years. PMID- 21305734 TI - Effect of preoperative feeding on gallbladder size and peristaltic of the small bowel following spinal anesthesia for the hip surgery. AB - The main aim of our study was to determine the influence of preoperative feeding with clear carbohydrate rich drink (PreOp 200 mL) on peristaltic of the small intestine and gallbladder size early after the orthopedic surgery in spinal anesthesia. Clinical study includes 120 patients with fracture of femoral neck or pertrochanteric fracture. All patients were randomized in two groups, sixty patients, PreOp group, consumed carbohydrate drink two hours before surgery. Other 60 patients, Control group, represent patients who fasted overnight. After surgery, patients were submitted to ultrasound examination for measurement of the small bowel motions and gallbladder size. Four quadrants (up-right, up-left, down right and down-left) of the abdomen were examined, each one in duration of 30 seconds. The results show that the length of the gallbladder is considerably different across the two groups; 5.866 cm in the PreOp group and 7.178 cm in the Control group (p = 0.00). The width, however, differed somewhat less (PreOp group 2.437 cm, Control group 2.735 cm) and the statistically significant difference can be observed at 7% level (p = 0.073). We found no statistically significant relationship between PreOp and Control group variables of each abdominal quadrant (lowest p > 0.087). Accordingly, the means of the variables were found statistically significantly different between groups (p > 0.05). In conclusion our study showed that the preoperative feeding of the patients undergoing orthopedic surgery in spinal anesthesia shortens the length but not the width of the gallbladder when compared with overnight fasting patients and also clearly enhance motility of the small bowel in all four quadrant of the abdomen. PMID- 21305735 TI - Hip fractures in elderly--ten years analysis. AB - Geriatric hip fractures (GHP) are the major problem in the geriatric traumatology and it is estimated that treatment of GHF will spend a large amount of health care resources. The aim of this retrospective study was to compare differences in incidence of operatively treated patients with GHF, type of treatment depending of the type of fracture, early postoperative mortality, length of stay and costs of used implants within a 10 years period. Surgically treated 2478 patients, older than 65 years with hip fractures were included in the study. Patients were grouped according to the type of fracture (femoral neck fracture or intertrochanteric femoral fracture) and used implant. Results showed increasing trend in GHF in our County in the last 10 years. There was a shifting trend in used implants, and new surgical techniques were used more commonly in the last few years. In observed period there were no significant changes in revision surgery and length of hospital stay. The mortality decreased, especially in males, but generally it was not in correlation with used implant. At the 10-years period increase in patients with GHF of 179% was followed with 4 time higher increase in implant prices. Present reimbursement in health care system does not calculate the difference of implant costs in hospital expenses, therefore proper usage of modern implants and careful planning in the treatment of GHF is necessary. PMID- 21305736 TI - Perioperative and early postoperative neurological deficit in older patients during carotid artery thrombendarterectomy. AB - Cerebrovascular accidents, strokes in particular, are among the most frequent causes of death today in developed countries. In the last two decades, stroke was the second most frequent cause of death in Primorsko-Goranska Region in Croatia. In older patients, individuals older than 65 years of age have an increased risk of stroke, mainly because the degree of carotid artery stenosis increases with age. The most frequent complication of the high percent stenosis of the carotid arteries is thrombosis in the area of atherosclerotic changes of blood vessels. With the increase in the age of the population, there is also an increase in the number of risk factors of cerebrovascular accident. Doppler ultrasound sonography and Multi Slice CT scans have the most prominent role in the early detection of atherosclerotic changes and in the assessment of the degree of carotid artery narrowing. Today, in Croatia as well as worldwide, thrombendarterectomy holds the most important place in stroke prevention. Between 2006 and 2009, 209 patients underwent surgical intervention at the Clinical Hospital Center in Rijeka for high degree of carotid artery narrowing. In the group younger than 65 years of age, which consisted of 53 patients, a neurological deficit was noted in 4 patients (7.54%) in the perioperative and early postoperative course. In the group of individuals older than 65 years of age, which consisted of 156 patients, a neurological deficit was noted in 9 patients (5.76%). There was no significant statistical difference in the incidence of neurological deficit, nor in the mortality in individuals older than 65 years of age during carotid arteries thrombendarterectomy. PMID- 21305737 TI - Postinfectious glomerulonephritis and Epstein-barr virus co-infection. AB - Contrary to group A beta-hemolytic streptococcus as the most common cause of postinfectious glomerulonephritis (PIGN), Epstein-Barr virus (EBV) is only occasionally associated with acute renal involvement. We describe an 11-year-old boy who presented with clinical signs of infective mononucleosis and acute glomerulonephritis characterized by edema, hypertension and dark colored urine with diminished renal function. Serology tests confirmed streptococcal infection and acute EBV infection. Persistently depressed C3 complement and gross hematuria indicated renal biopsy which shows PIGN-type picture and, in addition, acute interstitial nephritis, both conclusive of streptococcal infection. We performed tissue DNA extraction by polymerase chain reaction (PCR) and demonstrated EBV-DNA from the kidney specimen supporting EBV involvement in renal tissue. This is the first reported case of PIGN with serologically-proven streptococcal and simultaneously, acute EBV co-infection. EBV-DNA extraction supported the EBV involvement in renal tissue suggesting that both etiologic agents might have contributed to renal inflammation. Adding serology evaluation for EBV in cases with typical clinical signs of infective mononucleosis and renal symptoms, EBV might be more commonly associated with PIGN than is currently appreciated. PMID- 21305738 TI - Transrectal sonography in prostate cancer detection--our 25 years experience of implementation. AB - Prostate cancer is a leading public health problem of male population in developed countries. Gold standard for prostate cancer diagnosis is true cut biopsy guided by transrectal ultrasound. Aim of this study was to determine sensitivity, specificity, accuracy, positive and negative predictive value of transrectal sonography (TRUS) in prostate cancer detection. The analysis was made for two time periods, before and after routine implementation of prostate specific antigen (PSA) in prostate cancer diagnostics. From 1984 to 1993 TRUS guided prostate biopsy was performed in 564, and from 1994 to 2008 in 5678 patients. In the second period PSA was routinely used in prostate cancer diagnostics. In the first period by TRUS we have made an exact diagnosis of prostate cancer in 18.97% of patients what was confirmed by biopsy. 4.61% ware false positive and 11.34% ware false negative. In the second period prostate cancer was recognized in 30.34% of patients, confirmed by biopsy. False positive cases ware 6.11% and false negative 29.31%. Sensitivity of transrectal sonography in the first period was 62.57%, specificity 94.2%, accuracy 86.2%, positive predictive value 80.45% and negative predictive value 87.72%. In the second period sensitivity was 50.87%, specificity 91.93%, accuracy 73.84%, positive predictive value 83.24% and negative predictive value 70.39%. Based on our experience we can conclude that prostate cancer is mostly found in the peripheral zone. Smaller tumors are hypoechoic and bigger tumors are hyperechoic. Prostate cancer lesions are impossible to differentiate from chronic prostatitis only by TRUS. Implementation of PSA has significantly decrease sensitivity, accuracy and negative predictive value of TRUS in prostate cancer detection. TRUS guided true cut biopsy is a gold standard in prostate cancer diagnostics. PMID- 21305739 TI - Application of wound closure Molndal technique after laparoscopic cholecystectomy -initial comparative study. AB - Because of a possible delayed wound healing, critical colonization and infection of wounds present a problem for surgeons. Colonized and infected wounds are a potential source for cross-infection. Molndal technique of wound dressing has proven to be effective in prevention of infection. Also the wound heal better and faster. In our study we wanted to describe the benefits of the Molndal technique wound dressing after laparoscopic cholecistectomy compared to traditional wound dressing technique. Molndal technique consisted of wound dressing with Aquacel Ag -Hydrofiber (ConvaTec, Dublin, Ireland). Traditional technique was performed using gauze compresses and hypoallergic adhesives. We analyzed the results of 100 patients after laparoscopic cholecystectomy. 50 patients were treated by Molndal technique and 50 patients by the traditional technique of wound dressing. In the group treated by Molndal technique only 1 (2%) patient has revealed a wound infection, proven by positive microbiological examination and suppuration, mostly in the subumbilical incision. In the traditional technique group 7 (14%) patients developed wound infection also predominantly in the subumbilical incision. The difference was statistically significant (p < 0.01). Our results are clearly showing that Molndal technique is effective in preventing the infection of subumbilical incision wound and is to by recommend for regular use at designated site after laparoscopic cholecistectomy. PMID- 21305740 TI - Skin disease in a geriatric patients group in outpatient dermatologic clinic Karlovac, Croatia. AB - To determine the characteristic pattern and frequency of dermatoses in dermatologic patients over 65 years we used electronic data base of General hospital Karlovac and conducted a retrospective cross sectional study evaluating age, sex and proportion of dermatoses. Total number of patients was 3200. There were 822 (25.69%) patients older than 65 years, and 2378 (74.31%) patients aged from 18-64 years. Ratio male/female in population over 65 years in our study was 0.76:1. Males had higher frequncy of verrucae vulgares 26 (7.3%) and dermatitis nummularis 47 (13.2%) then female and that difference was statistically significant. Female had higher frequency of keratosis acitinca 124 (26.61%) and fibroma 23 (4.94%), and that difference was statistically significant. The ten most common diagnosis in population over 65 years old were: keratosis actinica in 184 patients (22.38%) verrucae seborrhoicae in 156 (18.98%), dermatitits nummularis in 77 patients (9.37%), dermatitis allergica e contactu in 60 (7.30%) patients, mycosis in 56 (6.81%) patients, psoriasis in 51 (6.20%), verrucae vulgares in 39 (4.74%), fibromas in 27 (3.28%), naevi in 9 (1.09%) and acne in 1 (0.12%) patient. The number of patients with diagnosis of keratosis actinica, verrucae seborrhoicae and mycoses in population over 65 years old are greater then in younger subpopulation and that difference was statistically significant. There are specific pattern of frequency of dermatoses in elderly. Verrucae seborrhoica, keratosis actinica and mycoses are more common then in general population. In elderly risk for development of skin cancer is increased. Early detection of skin cancers and treatment of precanceroses is of utmost interest of health providers. PMID- 21305741 TI - Splenic hematoma as a first manifestation of cytomegalovirus infection. AB - Splenic rupture is rare but life threatening complication of mononucleosis syndrome. It has been suggested that subcapsular splenic hematoma formation precedes rupture. The case of 44-year-old, previously healthy, male with splenic hematoma occurring after rising of heavy cargo is reported. Mononucleosis syndrome was suggested based on routine laboratory tests (elevated white blood cell count with predominance of lymphocytes and raised serum transaminases) and CMV infection was confirmed by serological test. Nonoperative management was used since the patient was hemodynamically stable with no further signs of splenic rupture. The same approach has been used in growing number of cases of patients with spontaneous splenic rupture in mononucleosis syndrome. Importance of considering splenic hematoma and/or rupture if abdominal pain occurs in the course of mononucleosis syndrome is outlined as well as importance of routine laboratory tests in suspecting mononucleosis syndrome in otherwise clinically silent patient. PMID- 21305742 TI - Pyostomatitis vegetans associated with inflammatory bowel disease--report of two cases. AB - Pyostomatitis vegetans (PV) is a rare, chronic mucocutaneous disorder associated with inflammatory bowel disease (IBD). Oral lesions of PV are distinct and present as multiple white or yellow pustules with an erythematous base that coalesce and undergo necrosis to form a typical "snail tracks" appearance. Two cases of PV associated with IBD--one with Crohn's disease (CD) and the other with ulcerative colitis (UC) are reported. In the first case, adalimumab therapy brought the oral and gastrointestinal manifestations to complete remission. In the second case, the remission was achieved with systemic steroid therapy, but the disease relapsed after therapy discontinuation. Azathioprine was added leading to sustained remission of PV. Because of persistent active intestinal manifestation of UC, in spite of immunosuppressive therapy, infliximab was introduced. With the therapy remission of intestinal manifestation of UC was achieved as well. Our cases confirm previously reported good experience with immunomodulators and biologics in the treatment of PV. But, before using them we have to exclude an infectious etiology of oral lesions. PMID- 21305743 TI - Prognostic values of morphological and clinical parameters in pT2-pT3 prostate cancer in elderly people. AB - Prostate cancer is a disease of elderly men, the incidence of which increases in an age dependent manner. This study presents the correlation of clinical and morphological parameters in locally confined (pT2) and locally advanced (pT3) prostate cancer. We analyzed a group of elderly men treated with radical prostatectomy in the period 1999-2008 in the University Hospital Rijeka. We found no statistical association between pT stage and age categories, preoperative prostate-specific antigen, digitorectal examination and biopsy Gleason score. There was a significant correlation of higher Gleason score in prostate specimens after radical prostatectomy and a higher frequency of a positive surgical margin in tumors with pT3 than in pT2 stage (p = 0.003; p = 0.011 respectively). Recurrence-free survival was shorter in patients with tumors with positive surgical margins as well as in patients with pT3 stage (p = 0.030; p = 0.001 respectively). We conclude that higher tumor grade and positive surgical margins are indicators of a worse prognosis in our patients. PMID- 21305744 TI - Neuroimaging techniques in modern forensic psychiatry. AB - Applied neuroscientific knowledge such as brain neuroimaging has widespread application in the medical diagnostic and treatment areas. Neuroscientific progress such as cognitive neuroscience has strong implications in specific medical fields such as forensic psychiatry. Significant progress in forensic psychiatry has affected the practice of law, in which an understanding of the complex relationship among mind, brain, and behavior is becoming necessary. Forensic psychiatry is concerned with the relationship between psychiatric abnormalities and legal violations and crimes. Due to the lack of available biological criteria, assessment, evaluation and therapy in forensic psychiatry have so far been restricted to psychosocial and mental criteria of offender personality. Recent advances in nuclear radiology such as brain imaging techniques (fMRI, DT-MRI, PET SPECT) allow a closer approach to the neural correlates of personality, moral judgments and decision-making. Introduction of neurobiological criteria (based on advanced neuroimaging techniques) in the field of forensic psychiatry and establishing the rules to what extent such biological criteria will be more reliable choice in evaluating mentally ill offenders would be of fundamental value in the modern forensic psychiatry. Psychosocial and subjective criteria in forensic evaluation will be more accomplished by biopsychosocial and objective criteria. Advances in the neuroimaging techniques bring specificity to the problems underlying the application of neuroscience to criminal law. PMID- 21305745 TI - Merkel cell carcinoma: case report. AB - Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine carcinoma of the skin. Although it is 40 times less common than malignant melanoma, its mortality is much higher compared to melanoma. From 1986 to 2001 there was rapidly increasing incidence in reported cases of MCC, with a tripling in the rate over this 15-year period. The vast majority of MCC presents on sun-exposed skin. The head and neck area is the most common site of tumor occurrence. We present 70 year old female patient with painless red-colored nodule, size 2 x 2 x 2 cm on the dorsal side of mid left forearm. The surgical excision with negative margins was performed, and pathohistological analysis confirmed Merkel cell carcinoma. Sentinel lymph node biopsy was negative. In conclusion, as MCC is a very aggressive rare skin carcinoma with lethal outcome, it should be mandatory to perform biopsies of any suspected skin lesion. PMID- 21305746 TI - "Halo nevi" and UV radiation. AB - Halo nevi, also termed Sutton nevi, are defined as benign melanocytic nevi that are surrounded by an area of depigmentation resembling a halo. Halo nevi are common in children and young adults, with a mean age at onset of 15 years. The incidence in the population is estimated to be approximately 1%. Affected individuals frequently have multiple lesions which are usually localized on the back. A familial tendency for halo nevi has been reported. The etiology of halo nevi is unknown. It is an autoimmune response and T lymphocytes are considered to play a key role in the progressive destruction of nevus cells. Halo nevi may be associated with autoimmune disorders such as vitiligo, Hashimoto thyroiditis, alopecia areata, celiac disease, atopic dermatitis and others. It has been proved that halo nevi are detected after an intense sun exposure especially after sunburns. The etiology of halo nevi, association with malignant melanoma and the role of sun exposure in the development of halo nevi are discussed. PMID- 21305747 TI - Lentigo maligna melanoma--the review. AB - Lentigo maligna melanoma (LMM) is a slowly growing tumor of elderly white population. It typically develops on chronically sun-exposed skin of the head and neck area which indicates that the cumulative exposure to the UV radiation has crucial role in the development of LMM. Precursor lesion is lentigo maligna (LM) which commonly presents as an irregular brownish pigmented macular lesion persisting for years. Women are affected more often as men by LMM, with the average age of over 60 years. The age of onset has dropped over the past years and this tumour is nowadays also diagnosed in 40-year-old individuals. However, the incidence rate increases with age and peaks in the seventh and eighth decades of life. The prognosis for invasive lentigo maligna melanoma does not differ from that for other histogenetic types of melanoma after controlling for tumour thickness. The diagnosis and treatment of LMM remain challenging. In this presentation, we review the epidemiology, clinical presentation, histopathology, and treatment of LMM. PMID- 21305748 TI - A case report of an unrecognized nevoid melanoma in a young woman- clinicopathological diagnostic challenge. AB - Nevoid melanoma is a rare form of melanoma histologically resembling benign melanocytic nevi and may be overlooked in routine histological sections. Authors are presenting a case of a 31-year-old woman who presented with bizarre pigmented skin lesions in the area of the postoperative scar on the back where, 6 years earlier, a "nevus pigmentosus epidermo-dermalis" was excised and hystologically confirmed in outer institution. The lesions were surgically removed and histopathological findings were characteristic for nevoid melanoma. Additionally, specimen of primary removed lesion was reexamined and primary nevoid melanoma was then recognized, therefore indicating that the lesions our patient presented with are nevoid melanoma recidivisms. Extensive diagnostic procedures showed no signs of melanoma dissemination. Three months later, the patient returned for consultation and presented with two new brownish-pigmented papules in the area of the new postoperative scar. The lesions were excised and new nevoid melanoma recidivism was confirmed. The patient remained under the regular follow up and, almost 9 years after the removal of primary nevoid melanoma, followed by two cutaneous recidivisms, remains disease-free. This case aims to highlight the problematic area in the analysis of pigmented skin lesions where nevoid melanoma represents one of the clinical and pathological diagnostic challenges. PMID- 21305749 TI - 11 for 2011: eleven important ways to assess your health. Include some of these proven health checks among your New Year's resolutions. PMID- 21305750 TI - Abnormal uterine bleeding in peri- and postmenopausal women. When should you see a clinician about excessive or unexpected bleeding? PMID- 21305751 TI - Pelvic floor muscle training can help reverse pelvic organ prolapse. PMID- 21305752 TI - Easing bedbug anxiety. What you need to know about the recent bedbug resurgence. PMID- 21305753 TI - Ask the doctor. I have osteoporosis and a recent spine fracture. I hear there's a minor surgical procedure that can fix the fracture. Can you tell me anything about it? PMID- 21305754 TI - Spondyloarthritis: from inflammation to osteoproliferation. PMID- 21305755 TI - [The challenge of the geriatric orthopedics]. PMID- 21305756 TI - [Evaluation of the results of the treatment of Vancouver B1 periprosthetic fractures and proposed indications for the use of cortical allograft as part of the fixation]. AB - Currently there is limited information on the indications for the use of cortical allograft for the treatment of periprosthetic fractures on a stable stem. The purpose of this study was to retrospectively evaluate the treatment and the results obtained in this type of fractures and propose a series of criteria for the use of cortical allograft. Between 2003 and 2008 a total of 31 periprosthetic femur fractures were treated at our institution. Twelve of them were classified as B1: 6 were treated with a Dall-Miles (Stryker) system plate and 6 with the same plate supplemented with a structural cortical allograft over the medial cortex of the femur (DM and DM-Allo groups, respectively). An evaluation of the clinical and radiologic results was performed in the latest follow-up available. A patient in the DM-Allo group had rupture of a screw and 10 degrees varization; the fracture healed despite this and the patient had a satisfactory clinical course. The Oxford Hip Score was 9 points lower in the DM group compared with the DM-Allo group, and the EQ-5D health scale was 0.10 better for the DM group. The DM-Allo group had a longer hospital stay and more transfusion-related requirements. We think that the patients with clinical or radiologic criteria of osteoporotic bone may benefit from the use of a cortical allograft to favor healing and increase the bone stock. However, those advantages should be weighed considering the higher risk of surgical-related morbidity associated with the surgical insult. PMID- 21305757 TI - [Functional result in distal radius fractures. Comparison between the severity of the fracture, the treatment of choice and the baseline X-ray parameters]. AB - BACKGROUND: The AO classification has a prognostic value and assists physicians in the planning of fracture management. The X-ray data and the DASH questionnaire are used to assess the outcome of radial fractures. A trend towards open treatment, opposite to closed or percutaneous approaches, has been observed in the past ten years. METHODS: Descriptive study evaluating the functional outcome, with a follow-up from 6-months to one year, using the DASH questionnaire and correlating the outcomes with the treatment used, the type of fracture, the AO and Frykman classifications, and the baseline X-ray parameters. The fracture stability and the treatment of choice were recorded. Patients were grouped according to the treatment used. RESULTS: A DASH score < or = 20 was considered as good, and > 20 as poor. The questionnaires were applied at the 6- and 12-month follow-up visits, the mean score was 14.46. No statistical difference was found between the good or bad outcomes and the type of treatment. A correlation was found between both the type of fracture and the X-ray parameters and the functional outcome. CONCLUSIONS: Regardless of the treatment of choice of distal radius fractures, the major goal is to restore the normal X-ray parameters to improve the functional outcome and decrease the complications. No difference was found in the functional outcome among the treatment options used to treat the distal radius fractures. The AO classification is valid as a prognostic indicator and useful to make therapeutic decisions. PMID- 21305758 TI - [Functional outcomes in patients subjected to acetabular revision with reinforcement rings]. AB - BACKGROUND: Total hip arthroplasty is the most successful orthopedic procedure and the frequency of use of revision components has grown exponentially. The increased number of revisions results from the longer life expectancy of the population and the greater frequency of the hip arthroplasty indication among young patients. The purpose of this study is to evaluate the functional results of patients subjected to revision of the acetabular component using reinforcement rings. MATERIAL AND METHODS: The study included patients with a diagnosis of septic or aseptic prosthetic loosening and sequelae of acetabular fractures between January 2007 and November 2009 in whom a reinforcement ring was used. The WOMAC scale was used for the functional evaluation. RESULTS: According to the WOMAC scale, the patient functionality results showed a mean preoperative score of 41.89 and a mean postoperative score of 74.26, which represented an improvement of 33.11 points in the median of patients subjected to the surgical intervention, with a statistically significant difference (p = 0.036). DISCUSSION: This study shows an improvement in the functionality of the patients subjected to surgery with a reinforcement ring, as, first and foremost, a statistically significant difference was seen between the preoperative and postoperative values and, secondly, there are papers published in the literature showing that a difference of more than 12 points between the preoperative and postoperative scores in the WOMAC scale indicates a significant clinical improvement of patients. CONCLUSION: Patients subjected to acetabular revision with a reinforcement ring together with cemented polyethylene have an improved quality of life after the surgical intervention. PMID- 21305759 TI - [Clinical course of the quintus varus supraductus osteotomy in postoperative patients subjected to the LP-INR surgical approach]. AB - OBJECTIVE: To evaluate the clinical course of patients subjected to the osteotomy designed at the National Rehabilitation Institute (LP-INR) with a memory staple to treat the congenital quintus varus supraductus deformity, from December 2002 to August 2009. Moreover, to show that the LP-INR osteotomy decreases weight bearing under the 5th metatarsal head, descends the phalanx, spares the metatarsophalangeal joint, and prevents relapses and pain. MATERIAL AND METHODS: The study was conducted from December 2002 to August 2009 and included 51 patients with quintus varus supra-ductus deformity and 78 feet; 33 patients were males (64.7%) and 18 were females (35.2%), the Maryland clinical scale was applied at postoperative month six. The AOFAS scale was applied in the preoperative and postoperative periods to assess pain, gait and alignment. RESULTS: The Maryland scale showed excellent results in 42 patients (84.3%), good results in 3 patients (5.8%), fair in 3 patients (5.8%) with a score of 75 to 50, and poor in 3 patients (5.8%). The AOFAS scale score for the forefoot was 55 + 8 preoperatively and 90 + 5 postoperatively. The Student t test was statistically significant in the preoperative and postoperative periods < 0.05. DISCUSSION: The LP-INR osteotomy for the treatment of the congenital quintus varus supraductus deformity provides appropriate alignment of the 5th toe with decreased load on the 5th metatarsal head and avoids broad resections that result in both cosmetic and functional alterations. PMID- 21305760 TI - [Surgical treatment of hip fractures]. AB - OBJECTIVE: Evaluate the experience acquired in the surgical management of hip fractures. MATERIAL AND METHODS: Retrospective study of 206 patients undergoing surgical treatment of hip fracture from June 2005 to June 2007. Besides the demographic variables, the following variables were recorded: Fracture classification, interval between the occurrence of the fracture and its surgical treatment, physical status according to the American Society of Anesthesiology classification, preoperative comorbid conditions, type of implant used, approach used if a prosthesis was used, operative time, prophylaxis with antibiotics and for thromboembolic events, complications during the postoperative period and during a 24-month follow-up period. A descriptive statistical analysis was carried out. RESULTS: Fifty patients were males and 156 females, mean age was 80 years (50-99 years). The most frequent types of fractures were the intertrochanteric fracture (130 patients) and the displaced intracapsular fracture (38 patients). The most frequent surgical procedures were the placement of a compression ring and plate (133 patients) and hemiarthroplasty (49 patients). Ten patients had various postoperative complications. Two patients died during the follow-up period (24 months). CONCLUSIONS: Fixation was performed in young patients with undisplaced fractures and in all patients with an impacted and stable subcapital fracture. Arthroplasty was preferred in patients with a displaced fracture. PMID- 21305761 TI - [Sensitivity and specificity of the Tc-99m ciprofloxacin scan in pediatric osteomyelitis]. AB - INTRODUCTION: The Tc-99m-ciprofloxacin complex, introduced in 1993, has been extensively evaluated all over the world with good results for the diagnosis of active bacterial osteoarticular infections. There are only a few publications on the use of this procedure in pediatric ages. In our study we evaluated the efficacy of the Tc-99m ciprofloxacin scan for the diagnosis of osteoarticular infections in the pediatric population assessing its sensitivity, specificity, and positive and negative predictive value. MATERIAL AND METHODS: A retrospective, descriptive, observational study was done in 94 patients with clinical suspicion of osteoarticular infection in whom a Tc-99m ciprofloxacin bone scan was performed; the diagnosis was confirmed with intraoperative cultures and blood cultures. The results obtained with the Tc-99m ciprofloxacin scan and the culture reports were analyzed, as well as the sensitivity, specificity and the positive and negative predictive values of the Tc-99m ciprofloxacin scan. RESULTS: Among the patients with intraoperative and blood cultures, 80 cases (85.1%) were positive and 14 cases (14.9%) were negative for bone infection. In the Tc-99m ciprofloxacin scan 78 cases (83%) were found to be positive for infection and 16 cases (17%) were negative. There were two false negatives. We found a 97.6% sensitivity and 100% specificity, with a 100% positive predictive value and an 87.5% negative predictive value. CONCLUSION: The Tc-99m ciprofloxacin complex is useful to make the differential diagnosis between inflammation and infection in pediatric patients in whom an osteoarticular infectious process is suspected. PMID- 21305762 TI - [Fracture dislocation of the proximal interphalangeal joint]. AB - INTRODUCTION: The proximal interphalangeal (PIP) joint is the most commonly dislocated joint in the body and the hand. We did a review of the literature and report herein our experience treating this condition at the ABC Medical Center from 1991 to 2007. MATERIAL AND METHODS: Systematic review of the literature. Retrospective and descriptive study. RESULTS: A total of 13 patients were included between 1991 and 2007. Three of them were managed with ORIF with Kirschner nails, 3 with OR and Kirschner nails blocking extension, 2 with plasty with volar plate interposition, and one with CRIF with a Kirschner nail. Mean follow-up was 4.8 months in 8 patients, the ranges of motion were recorded. The following factors were negatively correlated with the range of motion: age, time elapsed between the injury and the treatment, the combined approaches, and the pins blocking extension. Those treated with interposition arthroplasty had a better range of motion. CONCLUSION: The fracture dislocation of the PIP joint is a rare pathology with multiple treatments and variable outcomes that usually result in the limitation of flexion and extension. PMID- 21305763 TI - [Traumatic hip dislocation in pediatric patients. Report of 5 cases]. AB - We present five cases of patients with traumatic hip dislocation diagnosed clinically, with X-rays and CT scan. Closed reduction was performed under IV sedation and fluoroscopic control. Patients wore a Dennis Brown brace at 45 degrees of abduction and neutral rotation. Weight bearing was totally forbidden for three weeks. Later, with the brace in place, rehabilitation consisting of muscle strengthening was started; patients recovered the ranges of motion without any relapses of dislocation. No X-ray alterations occurred, nor alterations in the functional ranges of motion within the 12 months following. No neurovascular lesions occurred during this study. PMID- 21305765 TI - [Aggressive pediatric hip fibromatosis with severe joint destruction. A case report]. AB - Fibrous or desmoid tumors are grouped under the term fibromatosis; there are several groups; the pediatric aggressive form is rare, especially the pelvis and/or hip presentation. This causes a variable degree of destruction of the surrounding tissues. It is a diagnosis by exclusion and histopathologic testing; treatment is always surgical and conservative treatment is indicated only for special locations and/or patient conditions. This article reports a case of aggressive pediatric hip fibromatosis with severe joint destruction, as well as the work-up and management protocol followed at the National Pediatrics Institute Pediatric Orthopedics Service to approach bone tumors. No cases similar to this one have been reported. PMID- 21305764 TI - [Fabella syndrome in a high performance runner. Case presentation and literature review]. AB - OBJECTIVE: To present a case of fabella syndrome in a 27-year-old high performance runner who responded favorably to the surgical resection of this sesamoid bone, after multiple failed conservative treatments. To discuss the difficulty to diagnose this syndrome due to its anatomical location, and mention the frequent performance of unnecessary arthroscopic studies and procedures in this type of patients. We present the case of a high performance runner who underwent multiple tests and treatments for left posterolateral knee pain, which was resolved surgically; the specimen was sent to pathology for the confirmation of the diagnosis. The presence of a symptomatic fabella was reported in a high performance athlete whose pain was relieved only after surgery. The athlete resumed training and high international level competitions 3 months after surgery. At the 2-year and 10-month follow-up she was completely asymptomatic and competing in high performance athletic races. CONCLUSIONS: posterolateral knee pain located in the anatomical area of the fabella, in cases in which the latter is present and after ruling out concomitant lesions like that of the lateral meniscus, should initially be managed conservatively. But if symptoms persist, the resection of the fabella, with the appropriate reconstruction of the posterolateral corner of the knee, is a definitive treatment effective for allowing the athlete to resume training and competitions. PMID- 21305766 TI - [Type V floating elbow with type III A3 exposure and nerve injury. Initial and definitive treatment with a minimally invasive technique. A case report]. AB - BACKGROUND: The increased number of high energy accidents has led to the occurrence of several injuries in a single extremity, particularly among youths. Stanitski and Micheli defined the floating elbow as a forearm fracture plus an ipsilateral supracondylar fracture. Its incidence ranges from 3% to 13%, predominant ages are 7 to 11 years, with a 2:2 male:female ratio. The mechanism of injury is as follows: fall from a height with elbow hyperextension and wrist dorsiflexion and pronation of the forearm. OBJECTIVE: To present the case of a child with a type V left open floating elbow injury, severe soft tissue injury and median and radial nerve injury. CLINICAL CASE: A 12-year-old male weighing 70 kg and a height of 170 cm fell from a height of around 50 cm while riding on a skateboard and sustained a type V floating elbow injury. He was managed with a double antibiotic regimen, decontaminating wound care and fracture stabilization with a minimally invasive approach, using crossed Kirschner nails in the elbow, and centromedullary and retrograde nails in the radius and ulna. He underwent early rehabilitation. The patient resumed his usual activities at month 3 and was assessed using the DASH scale. The nerve injury was classified as neurapraxia. RESULTS: The skin healed at ten days. Passive motion of the elbow and wrist was started at week 2. Bone healing of the radio-ulna occurred at 35 days and of the humerus at 30 days. The nerve injury evolved properly without leaving any sensory or motor sequelae. According to the DASH Scale, the functional course was appropriate; the patient resumed his usual activities at month 3. No infection or compartmental syndrome occurred. CONCLUSIONS: The early and thorough washing of these injuries is an important factor to decrease the risk of infection. The minimally invasive approach is perfect to treat these injuries in children; it is less aggressive and preserves the integrity of soft tissues. Early rehabilitation and the prompt management of the nerve injury are fundamental to the functional result. The DASH Scale identifies the functional course, is easy to use and convenient for the patient. PMID- 21305768 TI - [An overview of biomedical publications in Venezuela]. PMID- 21305767 TI - [Georg Clemens Perthes (1869-1927)]. PMID- 21305769 TI - [Effect of noise on blood pressure in workers of a Venezuelan oil company]. AB - Occupational noise has been related to cardiovascular events, although epidemiologically, there is not a clear explanation. To determine the development of arterial hypertension in workers exposed to a noise level higher than 85 dB (A) and to relate it with the working place, labor antiquity and the use of auditive protection, a case-control study was done in a Venezuelan oil company. Fifty working men, that fulfilled the inclusion and exclusion criteria, were included in each group. The information was obtained from the occupational clinical history, based on international guidelines, to evaluate the parameters of the study, The intensity of environmental noise was obtained according to recommended Venezuelan "Norma COVENIN 1565-95". The mean age of cases and controls were 39 +/- 0.06 and 44 +/- 0.44 years old respectively; the labor seniority was similar in both groups; 22 an 48% of cases and controls respectively had a family history of arterial hypertension (p<0.05), without a high significant prevalence in both groups. In both groups we observed overweight. In 92% of cases and 80% of controls there were normal levels of glucose (p<0.01); 68 and 84% of cases and controls, respectively, presented alterations of the lipid levels (p<0.05). The measurements of environmental noise registered levels that exceeded 85 dB (A), being the mean 87.78 +/- 1.10 dB (A); 94% of the cases used hearing protective equipment and 60% of them presented arterial hypertension and 80% of those that did not used it, showed arterial hypertension. There was not a significant relationship among the auditive loss induced by occupational noise, its intensity and labor seniority with the prevalence of arterial hypertension. We cannot conclude that occupational noise is a decisive factor in the development of arterial hypertension in noise exposed workers. PMID- 21305770 TI - [Serological and cellular reactivity to mycobacterial proteins in Hansen's disease]. AB - The study was designed for evaluating immunological reactivity to various mycobacterial protein preparations using serological and cell-mediated immunological tests in patients with clinical leprosy signs, predominantly, with the multibacillary forms. All patients were adults with ages between 20 and 30 years. Fifty eight (n = 81) percent corresponded to Lepromatous Leprosy (LL), 29% (n = 41) to Borderline Lepromatous Leprosy (BL) and 10% (n = 41) to Borderline Borderline Leprosy (BB); only 3% were Borderline Tuberculoid (BT) patients: 74% males and 26% females. The most frequent reactional phenomenon was of the Erythema Nodosum (ENL) type. The mycobacterial proteins tested were: total crude Mycobacterium leprae antigens (MISA); Mycobacterium bovis (MbSA and excretion MbSA); partially purified excretion protein antigen, with a 30 kDa relative movility (Ml30); and recombinant M. leprae proteins (Mt70, Mb 65, Ml 36, 28, 18 and 10 kDa). Two of the recombinant proteins (Ml10 and Ml 36 kDa) presented a statiscally significant higher serological reactivity, directly related with a larger bacillary load (p = 0.0051 and 0.050 respectively). The 30 kDa protein was predominantly recognized by antibodies from multibacillary patients. Results show that mean antibody values were higher in non reactional patients when tested against complete proteins (MbSA and ex MbSA) when compared with the group of patients who presented reactional phenomena (p = 0.000567 and 0.000061, respectively). Comparing reactional with non reactional patients, it was seen that mean antibody values against complete proteins (MbSA and ex MbSA) were higher in non reactional individuals (p = 0.000567 and 0.000061, respectively). This same behavior occurred towards individual mycobacterial proteins (30, 10 and 36 kDa). The T lymphocyte prolypherative response in reactional and non reactional patients towards mycobacterial proteins (MlSA, Ml 10 kDa, MbSA, ex MbSA) was negative. PMID- 21305771 TI - [Assessment of nucleic acid testing (NAT) for screening hepatitis B in blood donors. Systematic review]. AB - The new techniques of molecular biology called "nucleic acid testing" (NAT), enable the detection of particles of viral DNA in hepatitis B, regardless of the disease stage. These NAT techniques increase the sensitivity of screening, so the risk of infection through transfusion could be reduced. The aim of the study was to assess NAT techniques for screening hepatitis B in blood donors. We carried out a systematic review in Medline and Embase databases (2000-2008), as well as INAHTA, Cochrane Library and EuroScan. MeSH terms used were "Hepatitis B", "Blood Transfusion", "Blood Donors", and "Nucleic Acid Amplification Techniques", and free terms as "hepatitis B", "hbv", "nat", "nat-hbv" and "nucleic acid amplification testing". Twelve studies were included, four of them used self-made PCRs, obtaining mixed results, three used Procleix (two samples identified by NAT were HBsAg (-), 0.05% and 0.013%; and the third study with 135 patients who received anti-HBV therapy and had HBsAg (-), showed 80% of positive samples by NAT techniques). Four papers about MPX reported percentages ranging between 0.083 and 0.0015. In the study of diagnostic tests including the two techniques, they showed the same sensitivity. Both NAT techniques, have a good capacity for screening hepatitis B and showed similar results in sensitivity. They may be a significant advance in automation of blood banks and increase the safety of transfused patients. PMID- 21305772 TI - [Beta-galactosidase activity as a marker of senescence in primary cultures of the ovarian surface epithelium]. AB - Beta-galactosidase activity reflects the rate of cellular aging in vitro. Such activity was quantified at pH 6 in ovarian epithelial cells from 28 donors without a history of cancer, by the chemoluminiscent method. The cells were serially cultured until they achieved the state of permanent growth arrest. During the exponential growth phase, all cultures showed a similar pattern of growth and low beta-galactosidase activity. However, both in the onset of decrease replicative activity, as well as in the onset of the stationary phase, there was a significant rise in the enzyme activity. Our results showed that beta galactosidase activity can be considered as a replicative senescence marker of the ovarian surface epithelium at pH 6. PMID- 21305773 TI - [Role of the expression of c-Met receptor in the progression of gastric cancer]. AB - The product of the proto-oncogene C-MET (the c-Met receptor) and its ligand, hepatocyte growth factor (HGF), have been implicated in the progression of gastric cancer. The aim of this study was to analyze the expression of c-Met receptor, HGF and proliferating cell nuclear antigen (PCNA) by the immunohistochemistry method of labeled streptavidin-biotin, as well as survival, and they were correlated with anatomopathological factors in stomach specimens of 40 patients, who underwent gastrectomy for gastric cancer in the Department of General Surgery, Hospital Central Universitario "Antonio Maria Pineda" in Barquisimeto, Venezuela, in 2001-2004. High expression of c-Met receptor and PCNA was observed in patients with advanced stages of gastric cancer (III and IV) compared with early stages (I and II) (p<0.01). There was also overexpression of the c-Met receptor in histologic variables with low degree of differentiation, deeper tumor invasion into the submucosa, liver metastases and it is reported a lower survival rate in patients with increased receptor expression (+++ and ++++) when compared with patients with the lowest expression (+ and ++) (p<0.01). The expression of HGF was constant in both, advanced and early groups. The c-Met receptor is associated with proliferation and cell migration in Venezuelan patients with gastric cancer and could be used as a prognostic factor in this pathology. PMID- 21305774 TI - [Using the polymerase chain reaction to Borrelia burgdorferi infection in localized scleroderma injure (morphea), in Venezuelan patients]. AB - Borrelia burgdorferi is the causative agent of Lyme Borreliosis, an infectious multisystemic disease transmitted to humans by the Ixodes ticks bite. A possible association of Borrelia burgdorferi with localized scleroderma has been postulated. However, published data do not provide unequivocal results. Previous serologic analysis of patients with localized scleroderma in South American countries (including Venezuela), have been reported as yielding some reactivity. The present study looked for evidence of Borrelia burgdorferi infection in venezuelan patients with localized scleroderma, using the polymerase chain reaction to analyze 21 skin samples of patients with this skin condition. The results were negative in all the samples studied. Our data do not support an association of Borrelia burgdorferi infection and the sclerotic lesions of localized scleroderma; but do not rule out the possibility of a relationship between localized scleroderma and an unknown geno-specie of Borrelia burgdorferi sensu lato complex, a different Borrelia specie or a different spirochetal organism, as the etiological agents of the skin lesions in this area. PMID- 21305775 TI - [Intragenic polymorphisms of factor VIII and IX genes and their utility in the indirect diagnosis of carriers of Haemophilias A and B]. AB - Haemophilia A and B are considered sex-linked inherited diseases caused by mutations in genes that encode factors VIII and IX, respectively. This results in the deficiency of these proteins plasma levels which are actively involved in the mechanism of blood coagulation. It has been reported that several mutations are responsible for the alteration of these genes, which is why the application of a molecular diagnostic method for the direct identification of female carriers is impractical. An appropriate diagnostic strategy is the indirect analysis of polymorphisms linked to the gene. The aim of this study was to identify female carriers in different families with history of HA and HB that live in Zulia State, Venezuela, characterizing intragenic gene polymorphisms of the clotting factors VIII and IX, which helped to identify and assign haplotypes, to diagnose or to exclude the carrying condition, to 95% of women who were needing the study for HA and to 100% for HB. PMID- 21305776 TI - [Aicardi syndrome: a report of four Venezuelan patients]. AB - Aicardi syndrome is characterized by agenesis of the corpus callosum, infantile spasms and chorioretinal lacunae. The evolution of this disorder is variable, with a severe outcome over the first five years of age. The purpose of this report was to demonstrate the spectrum of the clinical phenotype and the course of this disorder in four Venezuelan patients. All patients met the major criteria, had severe psychomotor impairment and early onset seizures. There were microphtalmia in two of the patients. Three patients (75%) showed coloboma, interhemispheric cyst and periventricular heterotopias. The first patient, with longer follow-up, is currently aged 22. They all exhibited a typical asymmetric pattern on the electroencephalogram. These cases illustrate the variable clinical expression and severity of the Aicardi syndrome. A diagnosis of this disorder should be considered in girls with developmental delay, particularly, when there are accompanying recurrent seizures occurring in early childhood. PMID- 21305777 TI - [Discussion of dementia nursing]. PMID- 21305778 TI - ["The world of Mr. Lind is based on false conclusions"]. PMID- 21305779 TI - ["One need not drive away every cow encountering the dementia patient]. PMID- 21305780 TI - [Emergency nursing center is available around the clock. By telephone call: help]. PMID- 21305781 TI - [Multiple use of pen needles in diabetes therapy. Disposable instead of multiple use!]. PMID- 21305782 TI - [Reuse of injection needles of insulin pens and disposable insulin needles and skin disinfection before subcutaneous insulin injection. Consensus report of the German Society of Hospital Hygiene]. PMID- 21305783 TI - [Disinfection requirements of different urinary catheterization procedures. Preventing infection]. PMID- 21305784 TI - [Locked in syndrome: a frequently misdiagnosed disease picture. Imprisoned within the body]. PMID- 21305785 TI - [Sexuality in the elderly. Between rooms for love and taboos]. PMID- 21305786 TI - [Robots appear on the nursing horizon. Between transport robot and animateur]. PMID- 21305787 TI - [Nurse practitioner in America. Competent and independent]. PMID- 21305788 TI - [Leadership in modern geriatric nursing. Organization of a management cockpit]. PMID- 21305789 TI - [Properly integrating students and new employee. Assessment made easy]. PMID- 21305790 TI - [From case to case. When pathogens enter...]. PMID- 21305791 TI - [Recognizing and understanding illnesses. Hypotension as the leading symptom]. PMID- 21305792 TI - [Economics under scrutiny - experts discuss long acting insulin analogs]. PMID- 21305793 TI - [ZtoService: production and distribution of individualized cytostatic drugs]. PMID- 21305794 TI - [Naturalism, novel and society in 19th-20th century transition in Spain.]. AB - The second half of the nineteenth century in Spain was a period characterized by a strong presence of social science, which even came to permeate the masses. Evolutionary theories and some figures such as Charles Darwin himself were present in areas far from the scientific activity proper. The use of concepts and laws of biological origin for the diagnosis and political practice against certain problematic social realities, such as crime or poverty, gave rise to theories and intellectual schools that asserted the value of evolutionary principles for the analysis of complex realities of socio-cultural inequality. The attraction for difference and the scientific method, with the possibility of observation of poverty and social inequality that industrial development and modernity put forward to the writers, added to the naturalist and biological interest a literary curiosity for the degeneration, both physical and cultural, of that unfortunate part of humanity. PMID- 21305795 TI - [The politics of the self: psychological science and bourgeois subjectivity in 19th century Spain.]. AB - This paper offers an analysis of the process of institutionalization of psychological knowledge in Spain following the educative reforms implemented during the second third of the 19th century, which prescribed its inclusion in the curricular program of the new secondary education. After a detailed examination of the theoretical orientation, the ideological assumptions and the socio-political connections of the contents transmitted to the students throughout the century, its militant spiritualism is interpreted as a highly significant attempt on the part of the liberal elites to articulate a pedagogy of subjectivity intended to counteract the trends toward reduction, naturalization and fragmentation of psychic life inherent to the development of modern science. PMID- 21305796 TI - Displayed dexterity and distorted knowledge: amateurism and precision in late 18th century Spain. AB - This paper explores the links between scientific practice and precision both in expert networks and popular literature in the second half 18th century Spain. It will be argued that scientific instruments were used and understood in different ways in these two networks, which required opposing strategies for visualizing the degree and goodness of users' dexterities, thereby fostering the emergence of different collective and individual (epistemic) subjects. I will also argue that these subjects' differences and affinities were constructed around three themes: firstly, the degree of precision needed to establish a correlation between data and the world, or, in other words, the degree of fluidity admitted in connecting material and cultural worlds; secondly, the relevance attributed to body and bod(il)y knowledge in producing reliable data and stabilizing expertise; and thirdly, the weight attributed to opinion in leaning towards ephemeral or lasting data. The first part of the paper looks at the epistemological and political confluences which in late 18th century Spain nurtured the emergence of both a culture of precision and a sphere of public opinion, and to the strained relationship that existed between them. The other three sections explore how Spanish people used different sets of practices to construct different images of themselves as supporters of a moral of precision. PMID- 21305797 TI - The Ayala Mazar-Xiaohe culture: new archaeological discoveries in the Taklamakan desert, China. AB - This article, accompanied by colour photos, records the author's recent archaeological expedition in the Taklamakan Desert. His advance northwards along the now mostly sand-covered beds of the Keriya River proved to be a march backward through time, from the Iron Age city of Jumbulakum to the early Bronze Age necropolis of Ayala Mazar. The artifacts he found are contemporary with, and similar to Chinese discoveries at Xiaohe. This proves that Xiaohe was not an isolated case and provides evidence for a whole culture based on some sort of fertility cult. The remains also suggest that some, at least, of the peoples concerned had Indo-European affiliations. PMID- 21305798 TI - Incredible India: the inconvenient truth. AB - The author's objective is to correct many of the misconceptions about India and to combat mistaken analysis. He highlights the hundreds of millions who live in poverty, the rampant corruption and the incompetence of the administration. He asserts that comparisons with China are always to the disadvantage of India, except in the field of democracy, and suggests that the Indian Space Programme is symptomatic of a wide-spread misallocation of resources. And to suggest that the traffic problems in Delhi and Mumbai are being caused by more motor vehicles is a misdiagnosis. The real cause is an increase in the number of bullock carts. PMID- 21305799 TI - Thyroid disorders and hypocoagulability. AB - This review focuses attention on some practical aspects of the relationship between thyroid disorders and hypocoagulability, as related to an impairment of hemostasis and fibrinolysis. An understanding of this topic in daily clinical practice is important given that the interaction between hemostatic abnormalities and thyroid disorders is still poorly recognized by the medical community. Even if the bleeding tendency is in general mild and may be reversed by restoration of an euthyroid state, severe hemorrhagic events may complicate the course of both hyper- and hypothyroidism, as precipitated by such conditions as thrombocytopenia, acquired von Willebrand syndrome, and acquired hemophilia. The pathogenesis of the hemostatic abnormalities resides in either the direct effect of thyroid hormones or some conditions in an autoimmune mechanism. Physicians and endocrinologists should pay close attention to both clinical hemorrhagic events in their patients as well as to any laboratory abnormalities identified by blood coagulation testing. PMID- 21305800 TI - Acquired von Willebrand syndrome associated with hypothyroidism: a mild bleeding disorder to be further investigated. AB - Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder with laboratory findings similar to those for congenital von Willebrand disease (VWD). Unlike VWD, AVWS usually occurs in individuals with no personal or family history of bleeding. The prevalence of AVWS in the general population is unknown because data from large prospective studies of this syndrome are not available. Although AVWS is more frequently associated with lympho-myeloproliferative and cardiovascular disorders, it can also occur in solid tumors and in immunological and other miscellaneous conditions. Among these miscellaneous conditions, hypothyroidism has been associated with AVWS type 1 with a frequency of ~2 to 5%. In the 47 cases reported in the literature, the low VWF is apparently due to a reduction in its synthesis and/or secretion. Diagnosis of AVWS is based on assays measuring the level and activity of von Willebrand factor (VWF). These tend to be low, whereas factor VIII (FVIII) coagulant activity can be normal. In patients with AVWS associated with hypothyroidism, mucocutaneous bleeding episodes are the most frequent and can be managed with local therapy and/or systemic administrations of antifibrinolytic agents and desmopressin. VWF/FVIII concentrates have been used in only a few patients. The use of thyroid hormones can reverse this abnormality. PMID- 21305801 TI - Antiphospholipid syndrome: endocrinologic manifestations and organ involvement. AB - Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombotic tendency that affects most organ systems in the human body. In this report, we present a review of the endocrinologic manifestations associated with APS by evaluating the medical literature from 1968 to 2009 using MEDLINE and these keywords: APS, antiphospholipid syndrome, antiphospholipid antibodies, anticardiolipin antibodies, lupus anticoagulant, anti beta-2 glycoprotein I, pituitary, adrenal, thyroid, parathyroid, ovary, testes, diabetes mellitus, and diabetes insipidus. Adrenal insufficiency was found to be the most common endocrine manifestation associated with APS. Autoimmune thyroid disease was associated with increased titers of antiphospholipid antibodies (aPL) without any APS clinical manifestations. In addition, hypopituitarism and Sheehan syndrome are increasingly being reported in association with aPL. Data regarding the prevalence and significance of aPL in diabetic patients remains uncertain. Finally, only a few cases of ovarian and testicular derangements have been reported. APS should be considered in any patient with adrenal insufficiency even in the absence of other thrombotic manifestations. It is also advisable to assess aPL in the sera of patients presenting with pituitary insufficiency. Further studies are needed to clarify the relationship between aPL and thyroid disorders and diabetes mellitus. PMID- 21305802 TI - Venous thromboembolism in chronic liver disease. AB - The liver plays a central role in the maintenance of a normal hemostatic balance by synthesizing several factors belonging to the pathways of coagulation, anticoagulation, and fibrinolysis. It is thereby unsurprising that patients with chronic liver disease (CLD) or cirrhosis may experience a kaleidoscope of hemostatic disorders. A bleeding tendency represents the most frequent and clinically severe hemostatic complication of CLD or cirrhosis. Perhaps less anticipated, growing evidence now suggests that a procoagulant state may be also associated with CLD, so that patients with CLD or cirrhosis, irrespective of its etiology, rather than be "naturally anticoagulated" might also experience a large spectrum of spontaneous or unprovoked venous thrombotic complications. The clinical significance of an increased risk of venous thromboembolism in CLD is an important topic for future research, and the initiation of new randomized studies of potential treatments for this complication is needed. PMID- 21305803 TI - Global strategy for women's and children's health. PMID- 21305804 TI - [Autopsy case with autonomic failure, parkinsonism and progressive fronto temporal atrophy]. PMID- 21305805 TI - [Classification of dementia with Lewy body and frontotemporal lobar degeneration]. PMID- 21305806 TI - [One hundred books which built up neurology (48)--Roberto Remak "Observationes anatomicae et microscopicae de systematis nervosi structura"]. PMID- 21305807 TI - Comparison of various spherical aberration compensation methods in pseudophakic eyes. AB - PURPOSE: To provide a numerical comparison of the efficiency of spherical aberration (SA) compensation methods commonly used in commercial aspheric intraocular lenses (IOLs). METHODS: Numerical simulations were performed using the wavefront data of 139 right eyes implanted with a spherical Morcher 89A ("Bag in-the-Lens") IOL. Simulations were done for spherical, constant aspherical and SA-free IOLs, as well as for the customized selection method. RESULTS: Constant aspherical IOLs bought 49.6% of the eyes to a targeted postoperative SA value +/- 0.05 microm, while zero-SA IOLs brought 61.2% of the eyes to this range. However with customized selection 95% of the eyes could be brought to this target, resulting in more control over the postoperative spherical aberration. If no aspherical correction was used, only 8.6% of the eyes could reach the set target. CONCLUSION: These numerical results suggest that IOLs with an asphericity as a function of IOL power, supplemented by a customized selection from a number of fixed SA values according to preoperative corneal SA, may provide sufficient control over the postoperative SA. Given the surgeon centration possibility of the Bag-in-the-Lens IOL used in this study, as well as its centration stability, this is an ideal lens to implement the customized selection method. PMID- 21305808 TI - Goldenhar syndrome: ocular features. AB - Goldenhar syndrome is a rare congenital anomaly which consists of a triad of an ocular dermoid cyst, preauricular skin tags and vertebral dysplasia. We report two cases of Goldenhar syndrome, diagnosed in a 4-year-old girl and in a 20-year old young adult. The dermoid cyst is a benign tumour with serious ophthalmologic complications. PMID- 21305809 TI - A 5-year-old boy with acute intermittent acquired Brown's syndrome. AB - We report a case of unilateral acute acquired intermittent Brown's syndrome in a 5-year-old boy, that resolved spontaneously but recurred at regular intervals afterwards. A specific cause could not be found. We discuss the possible pathophysiological mechanisms of acquired Brown's syndrome in children. PMID- 21305810 TI - Appraisal of optic disc stereo photos pre- and post-training session. AB - PURPOSE: To determine whether the diagnostic accuracy of judging serial optic disc color stereo photographs for glaucomatous change by non-expert ophthalmologists changed after a training session. METHODS: 24 ophthalmologists in training at the University Hospitals Leuven classified 50 eyes with varying severity of glaucoma as stable or progressing based on the appraisal of serial optic disc stereo photographs. A comparison between the diagnostic accuracy of residents (n=18) and trainees (n=6) was made before and after a training session. RESULTS: The mean agreement (kappa) with the reference standard before training was lower for the trainees than for the residents. The mean kappa before training was 0.37 for the residents and 0.29 for the trainees (p = 0.18). The mean agreement with the reference standard improved significantly after a training (from 0.29 to 0.56 [p = 0.031 for the trainees, and from 0.37 to 0.48 for the residents [p = 0.005]). The overall mean kappa was 0.35 pre-training and 0.50 post-training (p < 0.001). CONCLUSIONS: The agreement and diagnostic accuracy of residents in training in appraising serial optic disc photos improved significantly after a training session. PMID- 21305811 TI - Intermittent palpebral oedema following surgery for nasofrontal encephalocele. AB - PURPOSE: To report a case of intermittent palpebral oedema secondary to a cerebrospinal fluid (CSF) leakage, following encephalocele surgery. CLINICAL CASE: A 9-year-old girl consulted with a history of intermittent swelling of the left upper and lower eyelid. The symptoms started at the age of one. As a relevant fact in her medical history, a neurosurgical repair of a nasofrontal encephalocele at the age of 9 months was withheld. Elaborate imaging studies demonstrated a leakage of cerebrospinal fluid (CSF) into the preseptal periorbital soft tissues, originating from a bony defect in the medial orbital wall. The patient was treated conservatively. CONCLUSION: A CSF leakage in the orbital or periorbital region is a rare finding. In the literature, similar defects have been reported after trauma or associated with neoplasia. To our knowledge, this is the first case of periorbital CSF leakage after encephalocele surgery reported in the literature. PMID- 21305812 TI - Reversal of optic disc cupping with improvement of visual field and stereometric parameters after trabeculectomy in young adult patients (two case reports). AB - The authors report two cases of mid- to long-term reversal of optic disc cupping after trabeculectomy with mitomycine-C in young adult patients suffering from secondary glaucoma. The cup to disc ratio reversed from 0.80 and 0.60 to 0.65 and 0.40 respectively and remained unchanged until the last follow-up visit at 6 and 36 months respectively. Concomitantly, there was an improvement of the visual field and of the optic disc stereometric parameters on the Heidelberg Retina Tomograph. PMID- 21305813 TI - Bilateral acute angle-closure glaucoma after blepharoplasty. AB - A 54-year-old man had bilateral acute angle-closure glaucoma that resulted in severe loss of vision in both eyes the day after undergoing uneventful upper eyelid blepharoplasty. Acute angle-closure glaucoma is a rare, but potentially blinding complication after uneventful eyelid surgery. In the literature only four previous cases have been reported to our knowledge. Moreover blepharoplasty is frequently performed by plastic surgeons and dermatologists who are unaware of this serious complication. Considering that immediate appropriate therapy may reverse the angle closure and thus prevent visual loss, a better awareness and prompt recognition of this condition is imperative. PMID- 21305814 TI - Descemet membrane detachment after alkali ocular surface burn. PMID- 21305815 TI - Haab's striae. PMID- 21305816 TI - Role of patient race/ethnicity, insurance and age on Pap smear compliance across ten community health centers in Florida. AB - Community Health Centers (CHCs) are the nation's primary care safety net for vulnerable populations, including racial/ethnic minorities, immigrants, migrant workers, and those who are uninsured. Women from such population sub-groups contribute disproportionately to cervical cancer incidence, morbidity, and mortality due, in large part, to the underutilization of Papanicolau (Pap) smear screening. Routine Pap smear screening can detect the onset and prevent progression of cervical malignancies. This article reports findings of a cross sectional study to investigate the association between Pap smear compliance and patient race/ethnicity, insurance, and age for more than 60,000 women seen in a network of CHCs in Florida. Results of this study indicated a strong association between race/ ethnicity and Pap smear screening in CHCs. Among women aged 21-45 years, Hispanics were twice as likely to receive Pap smear screening, while Blacks were 1.45 times more likely to receive Pap smear screening, when compared to White women. These results were unexpected because most studies have shown that Hispanic women are less likely to receive screening than their Black and White counterparts. These findings highlight the need to further explore the contribution of race/ethnicity, insurance, age, and other risks on health disparities associated with cervical cancer screening in CHCs. Moreover, results from this study have subsequently led to the development of clinical data reporting software to support Pap smear compliance monitoring within CHCs, as well as best practices regarding standardized documentation of Pap smear within electronic health records. PMID- 21305817 TI - Awareness and knowledge about human papillomavirus among Latina immigrants. AB - OBJECTIVE: Few studies have examined associations with the public's awareness and knowledge of the human papillomavirus (HPV) among Latina immigrants. The primary purpose of this study was to assess HPV awareness and knowledge, while examining demographic and healthcare utilization associations. METHODS: From 2007-2009 as part of a larger randomized control trial, 543 Latina immigrants living in Birmingham, Alabama completed an interviewer-administered questionnaire. RESULTS: Only 47% of the participants were aware of HPV. Women aged 40-50 years were more likely to be aware of HPV than women 19 to 29 (odds ratio [OR] 2.54; 95% confidence interval [CI] 1.34, 4.78). Having a Pap smear in the past year was associated with awareness (OR 1.82; 95% CI 1.14, 2.90). Among those aware of HPV, the mean knowledge score was 7.5 out of 11. Deficiencies in knowledge were noted for vaccinations, genital warts, and the clearing of HPV without treatment. Multivariable analysis found a Pap smear in the past year (OR 4.10; 95% CI 1.93, 8.69), and number of HPV information sources (OR 1.38; 95% CI 1.09, 1.75) significantly associated with higher knowledge. Also, women aged 30 to 39 years and 40 to 50 were more likely to have higher HPV knowledge than those 19 to 29 (OR 2.64; 95% CI 1.35, 5.17 and OR 4.46; 95% CI 1.53, 12.98, respectively). CONCLUSIONS: Less than half of the participants were aware of HPV. However, among those aware, knowledge scores were high. Age and having a Pap smear within the last year were associated with HPV awareness and knowledge. PMID- 21305818 TI - All Nations Breath of Life: using community-based participatory research to address health disparities in cigarette smoking among American Indians. AB - Using a community-based participatory research (CBPR) approach, we developed the All Nations Breath of Life smoking cessation program and pilot-tested it in urban and reservation communities. The program combines weekly in-person group support sessions with individual telephone calls using motivational interviewing. All sessions include discussion of sacred tobacco and information about quitting and health. We have assessed the scientific validity, cultural-appropriateness, and readability of our program materials and found them to be adequate; participant satisfaction is high. The program shows promise for improving quit rates among American Indians, who have the highest smoking rates and lowest quit rates of any ethnic group. Our preliminary self-report data show quit rates of 65% at program completion and 25% at six months post-baseline. PMID- 21305819 TI - Medication assistance programs: do all in need benefit equally? AB - OBJECTIVE: To determine if medication assistance programs (MAPs) provided by pharmaceutical companies were used differently by African Americans and Whites. RESEARCH DESIGN: A cross-sectional survey was conducted among patients of primary care practices from 2005 to 2007 within the Alabama Nonsteroidal Anti Inflammatory Drug (NSAID) Patient Safety Study. SETTING: Telephone survey. PARTICIPANTS: Respondents were 568 African American and White patients reporting annual household incomes < $50,000. MAIN OUTCOME MEASURE: Use of MAPs. RESULTS: Of all patients, 12.8% used MAPs, 39.5% were African American, 75.2% were female, 69.1% were aged > 65 years, 79.8% had annual household incomes < $25,000, and 35.5% indicated that their income was inadequate to meet their basic needs. MAPs were used by 11.2% African-Americans and 14.0% Whites. After multivariable adjustment, MAP use was higher among respondents with incomes not adequate to meet basic needs (odds ratio [OR]: 2.19, 95% confidence interval [CI]: 1.17-4.08) but lower among African Americans than Whites (OR: 0.49, 95% CI: 0.25-0.95). Physician characteristics did not independently predict MAP use. CONCLUSIONS: Overall MAP use was low even among the most vulnerable, and especially among African Americans. As currently used, MAPs may contribute to disparities in medication access. PMID- 21305820 TI - Racial difference in lean mass distribution among reproductive-aged women. AB - OBJECTIVE: Lean mass is an important determinant of bone mineral density (BMD) accrual, yet data regarding its correlates based on multiethnic premenopausal women are lacking. We examined the influence of age, race/ethnicity, and lifestyle variables on total and regional lean mass distribution in this population. DESIGN: A cross-sectional study was conducted on 708 healthy Black, White, and Hispanic women aged 16-33 years who were seen in an outpatient clinic. In addition, 218 of these women were followed for up to 36 months to observe changes in the relevant variables. We measured body weight, height, and lean mass distribution using a digital scale, wall-mounted stadiometer, and dual-energy absorptiometry (DXA), respectively. Multiple linear regression and mixed-model regression analyses were used to model the relationship of age, race/ethnicity and lifestyle variables to total and regional lean mass. RESULTS: For a given body mass index (BMI), Black women had higher total body lean mass (LM(total)) and leg lean mass (LM(leg)) than White and Hispanic women. Hispanic women had significantly lower LM(total), trunk lean mass (LM(trunk)), and LM(leg) than Black and White women. The difference between Blacks and Whites with regard to LM(total) significantly magnified with increasing BMI. Weight-bearing exercise and age at menarche were positively associated with lean mass variables, while parity was negatively associated with LM(leg). LM(total) and LM(trunk) increased over 36 months. Calcium intake was positively associated with increase in LM(totaI) over time. CONCLUSIONS: Our study shows that racial differences exist in the distribution of lean mass for a given BMI among reproductive-aged women. PMID- 21305821 TI - Cutaneous malignant melanoma among white Hispanics and non-Hispanics in the United States. AB - AIM: To explore whether disparities exist in melanoma incidence and prognosis between White Hispanics and White non-Hispanics. METHODS: Analyses were based on 42,770 patients with malignant melanoma in the United States, 2004 through 2006. RESULTS: Hispanics were significantly less likely to be diagnosed with superficial spreading melanoma or Hutchinson's melanotic freckle, but significantly more likely to be diagnosed with nodular melanoma or acral lentiginous melanoma. Hispanics were also significantly less likely to have multiple primary cancers and less likely to receive surgical treatment. Among those diagnosed during the study period, 12.4% (n = 142) of Hispanic patients and 8.5% (n = 3,235) of non-Hispanic patients died sometime during these years. Approximately 7.3% of Hispanic patients and 4.8% of non-Hispanic patients died specifically from melanoma. Later stage at diagnosis was the primary explanation for the difference in death from melanoma between Hispanic and non-Hispanic Whites. CONCLUSIONS: Hispanic melanoma patients experience significantly poorer prognostic findings at diagnosis. The disparity in melanoma stage, tumor depth, and ulcerated tumors at diagnosis emphasizes the need for greater secondary prevention efforts among this group. PMID- 21305822 TI - Understanding racial and ethnic disparities in colorectal cancer screening: Behavioral Risk Factor Surveillance System, 2002 and 2004. AB - INTRODUCTION: Racial/ethnic disparities in colorectal cancer (CRC) screening exist. The literature suggests that differential treatment by race may influence health behaviors and health outcomes. OBJECTIVE: We examined the impact of Reactions to Race-based treatment on being up-to-date with colorectal cancer screening with endoscopy or fecal occult blood testing (FOBT) among non-Hispanic White, non-Hispanic Black, and Hispanic men and women aged > or = 50 years. DESIGN: Secondary data analysis of the Reactions to Race Module on the 2002 and 2004 Behavioral Risk Factor Surveillance System (BRFSS) was performed. Using logistic regression, we examined the strength of association between Reactions to Race-based treatment variables with up-to-date CRC screening tests after adjusting for demographic and access variables. MAIN OUTCOME MEASURES: CRC screening tests were analyzed independently as FOBT within 2 years (n = 30,134) and endoscopy (colonoscopy or sigmoidoscopy) within 5 years (n = 30,210). RESULTS: Among Whites, 34% reported FOBT, compared with 30.6% of Blacks and 15.3% of Hispanics (P < .05). Forty-five percent of Whites reported endoscopy, compared with 40.7% of Blacks and 32.1% of Hispanics (P < .05). After adjusting for sociodemographic characteristics, Hispanics who always thought about their race were 73% (OR = .27; 95% CI: .13-.57) less likely to receive FOBT. CONCLUSIONS: While screening disparities were largest among persons without insurance and a usual source of care, more research is needed to understand the influence of Reactions to Race-based treatment as an additional barrier to CRC screening. PMID- 21305823 TI - Household density and obesity in young black and white adults. AB - Racial and ethnic disparities in obesity persist despite a narrowing in obesity risk associated with socioeconomic status. The household environment has been shown to be important in understanding obesity-promoting behaviors in diverse populations. Our current study was designed to examine the relationship between household density and obesity in young Black and White adults aged 18-30 years from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. All sociodemographic and leisure-time physical activity (LTPA) information for this study was collected by questionnaire between 1990-1991. Height was collected using a mounted centimeter ruler. Weight was measured on a balance beam scale. Obesity was defined as a body mass index > or = 30 kg/m2. Household density (HD) was defined as the ratio of people to bedrooms in the home. High HD was defined as a ratio > 1. Bivariate analysis showed that more women tend to live in high density households compared to men (45.4% vs 38.9%; P < .01) and more Blacks tend to live in high density households compared to Whites (53.7% vs 31.8%). Leisure time physical activity index was lower in Blacks than in Whites (2.5% vs 2.6%; P < .01). Blacks had a higher prevalence of obesity than Whites (27.1% vs 11.8%; P < .01). Logistic regression analysis showed that Black women within high HD were at highest risk for obesity compared to White women living within low HD (OR = 4.88%; 95% CI: 3.56-6.67). HD may provide an important context in understanding racial disparities in obesity-promoting behaviors. PMID- 21305824 TI - Sex differences in blood pressure levels and its association with obesity indices: who is at greater risk. AB - OBJECTIVE: The aim of our study was to investigate blood pressure (BP) levels and their association with different indices of body fat in adult Baniyas. DESIGN AND SETTING: A cross-sectional survey was carried out on an endogamous group of 577 adults (307 females and 270 males) aged 25-60 years in Delhi, India. METHODS: Data were collected for weight, height, waist circumference and blood pressure using standardized procedure. Body mass index (BMI), waist to hip ratio (WHR), waist to height ratio (WHtR) and grand mean thickness (GMT) were calculated to assess obesity. Also, the sex-specific prevalence estimates for various BP categories was calculated. Correlation was calculated between systolic and diastolic BP and various indices of obesity. Odds ratios for association of hypertension with obesity indices were obtained using multiple logistic regression. RESULTS: Prevalence of prehypertension and hypertension was higher among males and prevalence of obesity was higher in females. Correlations of BP with all indices of obesity were significant. Odds ratio of hypertension was higher in males than in females for all the indices of obesity at 95% CI. CONCLUSION: Although obesity was found to be higher among females, males were found to be at higher risk of hypertension. High odds ratios of obesity indicate that the optimum cut-off should be calculated for screening those who are at-risk of becoming hypertensive and thus are at the greater risk of developing cardiovascular diseases. PMID- 21305825 TI - Socioeconomic position, stress, and cortisol in relation to waist circumference in African American and white women. AB - OBJECTIVE: Abdominal fat deposition has been shown to be related to hypertension, dyslipidemia and diabetes. Studies have shown a correlation between cortisol (a stress hormone) and abdominal fat deposition. Low socioeconomic position (SEP) has also been shown to be related to abdominal fat deposition. It is hypothesized that chronic stress associated with low SEP leads to high cortisol levels which in turn lead to abdominal fat deposition. Previous research in this area has included mainly European subjects. The purpose of this study was to examine the evidence for the SEP-chronic stress-cortisol-abdominal fat hypothesis in a sample of African American and White American women. DESIGN: Data from the Regional Assessment Health Surveillance Study (RAHSS), a survey and physical examination of a representative sample of African American and White adults residing in six counties in Georgia, were utilized. The study population included 111 African American and 119 White women. Abdominal fat deposition was measured by waist circumference (inches). Education and income were the measures of SEP. Other exposures examined included serum cortisol, self-reported daily stress level, cigarette smoking, marital status, and number of children. Associations were examined using multiple linear regression models adjusted for age and body mass index (BMI). RESULTS: Among White women, less-educated women had a waist circumference 2.22 inches larger (P < .05) than more highly educated women. Among African American women, separated or divorced women (+2.29 in, P < .05) and widowed women (+3.13 in, P < .01) had larger waist circumferences than married women. No other factors were significantly associated with waist circumference. CONCLUSIONS: The SEP-chronic stress abdominal fat accumulation hypothesis was only partially supported by the data. Different stressors and pathways may be important in producing abdominal fat accumulation in African American and White women. PMID- 21305826 TI - Physical activity and obesity in African Americans: the Jackson Heart Study. AB - OBJECTIVES: To better understand how obesity and low levels of physical activity (PA) contribute to racial health disparities, we examined the association of PA domains (work, home life, and leisure) with indicators of socioeconomic status and markers of obesity in African Americans. METHODS: These cross sectional analyses of interview and clinical measures from the baseline visit of the Jackson Heart Study of cardiovascular disease (CVD) in African Americans of the Jackson, Mississippi metropolitan statistical area included 3,174 women and 1,830 men aged 21-95 years. The main measures were active living, sport, work, home life, and total PA scores; participation in regular moderate or vigorous intensity leisure physical activity (MVLPA); demographics, body mass index (BMI), waist circumference (WC) and CVD risk factors. RESULTS: The sample was 63% female, 81% high school or college graduates, with 51% aged 45-64 years, and mostly overweight (32%) or obese (53%). Women were less active than men in all domains except home life. Total PA was inversely associated with WC in women and men. The overweight (BMI 25-29.9) group was most active in all domains except work; active living and sport PA and prevalence of MVLPA then declined in a dose response association with increasing BMI. Work PA was associated with the lowest BMI but otherwise with indicators of less favorable socioeconomic status and health. CONCLUSIONS: Observed differences in PA in African Americans by domain and association with obesity biomarkers suggest areas for future study and intervention to reduce health disparities. PMID- 21305827 TI - A comparison of physical activity environments between South Asians and white Caucasians with coronary heart disease. AB - South Asians (SA) are predisposed to developing premature coronary heart disease (CHD), partly due to the early onset of classic risk factors, including physical inactivity. The nature of physical activity (PA) environments in South Asians in Canada remains unknown. Our objective was to examine differences in PA environments for South Asian vs White Caucasian (WC) CHD patients. In a cross sectional study, 2657 hospitalized CHD patients in Ontario completed The Perceived Environments Related to Physical Activity Questionnaire to assess their home and neighborhood environment, perceived neighborhood safety and availability of recreational facilities. Patients self-reporting their ethnocultural background as WC (N = 1301, 48.6%) or SA (N = 171, 6.4%) were included in this study. South Asians were significantly younger, had lower body mass index, higher levels of education, lower income, were less likely to smoke and reside rurally, and were more likely to be married, have diabetes mellitus and have experienced prior myocardial infarction (MI) than WC patients. South Asians also had lower availability of home exercise equipment and perceived convenience of local PA facilities, but better and safer neighborhood environments than WC patients. Multivariate analyses revealed that SA ethnocultural background remained significantly related to reduced availability of home exercise equipment and fewer convenient local PA facilities. Since physical inactivity is an important CHD risk factor, and SA ethnocultural background is associated with high CHD risk, this may represent a novel target for risk reduction. Thus, further research is required to optimize SA awareness of the need for PA, and access to equipment and facilities. PMID- 21305829 TI - Clinical risk factors demonstrate an age-dependent relationship with oxidative stress biomarkers in African Americans. AB - OBJECTIVE: To examine the interaction of oxidative stress biomarkers with age, and also factors that influence oxidative stress such as body mass index (BMI) and fitness in a population of individuals with established higher risk of cardiovascular disease, African Americans. METHODS: Blood samples were obtained from healthy college-age and middle-age to older African Americans. Participants underwent a graded exercise test. Superoxide dismutase (SOD) activity, total antioxidant capacity and thiobarbituric acid reactive substances (TBARS) levels were measured. RESULTS: TBARS levels were significantly (P = .001) lower in young participants relative to middle-age to older participants. SOD activity was significantly (P = .001) lower in middle-age to older participants with low fitness relative to participants with normal fitness, and lower (P = .04) in middle-age to older participants that were overweight relative to normal weight participants. DISCUSSION: In a healthy middle-age to older population of African Americans, BMI and fitness are crucial for maintaining a healthy endothelium. PMID- 21305830 TI - Effect of African American race on hypertension management: a real-world observational study among 28 US physician practices. AB - OBJECTIVE: To assess the impact of African American race on hypertension management among a real-world hypertensive population. DESIGN: Cross-sectional study. SETTING: 28 US physician practices. PATIENTS: Adult patients with a hypertension diagnosis between November 2006 and September 2008. MAIN OUTCOME MEASURES: Blood pressure (BP) control (< 140/90 mm Hg for non-diabetic, and < 130/80 mm Hg for diabetic, patients). RESULTS: African American patients (n = 1,079) were younger than Caucasian patients (n = 3,884) (60.2 vs 66.0 years, P < .01), were more likely to be female (60.1% vs 52.5%, P < .01), were more likely to be obese (55.9% vs 48.5%, P < .01) and had a higher diabetes prevalence (29.4% vs 23.8%, P < .01). African American hypertensive patients had significantly higher BP as compared to Caucasian hypertensive patients (135.2/82.9 mm Hg vs 130.5/76.4 mm Hg, P < .01). Both diabetic and non-diabetic African Americans were prescribed more antihypertensive medications than Caucasians and were more likely to be prescribed combination regimens. African Americans were less likely to be prescribed beta blockers, and more likely to be prescribed calcium channel blockers or diuretics. Among non-diabetic and diabetic patients, African Americans had 54% and 53% lower adjusted odds, respectively, of controlled BP. The use of specific antihypertensive medication classes was not associated with BP control. CONCLUSIONS: Although African Americans were prescribed more aggressive medication regimens, they had lower probability of BP control. While African American race influenced the choice of prescribed antihypertensive medications, those regimens did not affect the probability of BP control. African American race should not deter providers from prescribing specific antihypertensive medication classes, particularly in the presence of compelling indications. PMID- 21305828 TI - Cardiovascular risk factor variation within a Hispanic cohort: SWAN, the Study of Women's Health Across the Nation. AB - OBJECTIVES: Hispanics have less favorable cardiovascular risk profiles relative to other groups, although little is known regarding variability in risk profiles according to country of origin. Our goal was to examine the association of cardiovascular risk factors with country of origin and acculturation in a cohort of middle-aged Hispanic women. SETTING: Baseline data for participants at the New Jersey Site of the Study of Women's Health Across the Nation (SWAN). PARTICIPANTS: 419 women, aged 42-52 years, comprising 142 non-Hispanic Whites and 277 Hispanic: Central American (n = 29), South American (n = 106), Puerto Rican (n = 56), Dominican (n = 42) and Cuban (n = 44). MAIN OUTCOME MEASURES: BMI, smoking, blood pressure, lipid profiles, and presence of hypertension, hyperlipidemia, diabetes and metabolic syndrome were compared using univariate and multivariable models. RESULTS: LDL and HDL varied significantly across Hispanic subgroups (overall P < or = .05). Prevalence of metabolic syndrome was greatest in Puerto Rican women (48.2% vs 40.0%, 35.0%, 13.9% and 29.3% in Central American, South American, Dominican and Cuban women, respectively, P = .016). Central American women were least likely to smoke (P < .05 vs Puerto Rican, Cuban and South American). Prevalence of hypertension and diabetes were similar across groups. Differences in lipids and metabolic syndrome were not explained by acculturation, financial strain, education, physical activity, smoking or dietary fat intake. CONCLUSIONS: There is significant heterogeneity in cardiovascular risk status among middle-aged Puerto Rican, Cuban, Dominican, Central American and South American women, not explained by acculturation or socioeconomic indicators. These differences may be important for targeting screening and preventive interventions. PMID- 21305831 TI - Obesity and other cardiovascular disease risk factors and their association with osteoarthritis in Southern California American Indians, 2002-2006. AB - OBJECTIVE: Assess age and sex differences in the association of obesity and other CVD risk factors with osteoarthritis (OA) in Southern California American Indian/Alaska Native (AIAN) adults. DESIGN: Cross-sectional study. SETTING: Southern California. PARTICIPANTS: 6,299 AIAN adults aged 35+ years from health clinic system. MAIN OUTCOME MEASURES: Osteoarthritis prevalence. RESULTS: Age adjusted OA prevalence was 16.5% in women and 11.5% in men. OA prevalence increased with age and was higher in women. Very and morbid levels of obesity were associated with higher OA prevalence in some age groups. Hypertension was strongly associated with increased OA and current smoking tended to be associated with increased OA. For men, we found no association between diabetes and OA; however, diabetes was associated with more OA for women aged 35-54 years. CONCLUSIONS: Southern California AIANs may have lower OA prevalence than the US population as a whole. Comparisons of OA prevalence with other AIAN communities were not possible due to lack of other similar published results. Further studies are needed to determine the impact of OA within this understudied minority population. PMID- 21305832 TI - Prevalence of cardiometabolic risk factors in Hispanics living with HIV. AB - OBJECTIVE: Human immunodeficiency virus (HIV) infection and antiretroviral treatment are associated with metabolic and cardiovascular complications that resemble metabolic syndrome (MetS) and potentially increase the risk of diabetes and cardiovascular disease in this population. The purpose of this study was to determine the prevalence of MetS and its individual components among Hispanics living with HIV in Puerto Rico. METHODS: Data from 909 clinical records were extracted and the prevalence of MetS determined using the NCEP-ATPIII criteria. Fisher's exact test was used to detect sex differences, and logistic regression to examine the effect of age, sex, smoking, years of HIV infection, antiretroviral therapy, and Hepatitis C coinfection. RESULTS: The prevalence of MetS in our study group (35.4%) was higher than previously reported in the United States, but not higher than in the general population in Puerto Rico. Females had a higher prevalence of MetS (44.2%) than males (30.5%); mostly explained by high body mass index and waist circumference. Age and sex were associated with the presence of MetS. CONCLUSION: Understanding ethnic and sex differences in the prevalence of metabolic risk factors is essential for the implementation of specific targeted interventions to prevent subsequent vascular morbidity and mortality in this population. PMID- 21305833 TI - Validation of a dietary history questionnaire for American Indian and Alaska Native people. AB - OBJECTIVE: We assessed reliability and relative validity of a self-administered computer-assisted dietary history questionnaire (DHQ) for use in a prospective study of diet, lifestyle, and chronic disease in American Indians in the Dakotas and Southwestern US and Alaska Native people. DESIGN: Reliability was assessed by one-month test-retest of the dietary history questionnaire. Validity was assessed by comparison of the weighted average of up to 12 monthly 24-hour recalls collected prospectively and a dietary history questionnaire completed in the 13th month. PARTICIPANTS: Participants were recruited at the baseline visit of the Education and Research Toward Health Study in Alaska, the Northern Plains and the Dakotas. RESULTS: Reliability (Pearson correlation) of the DHQ ranged from r = 0.43 for vitamin A density to r = 0.90 for energy intake. The association of nutrient and food estimates assessed by 24-hour recalls and the DHQ completed at the end of the year reflected no bias towards recent intake. Macronutrients expressed as density (nutrients per 1000 calories) did appear to be valid (r = 0.50-0.71) as did several micronutrients (range r = .22 to 0.59), fiber (r = 0.51), and servings of red meat (r = 0.67). However, the DHQ overestimated intake and gross amounts of nutrients were not strongly associated with the weighted average of the 24-hour recalls. CONCLUSIONS: The DHQ developed for estimation of dietary intake in American Indians and Native people in Alaska is reliable. Estimates of nutrient density appeared to have acceptable relative validity for use in epidemiologic studies. PMID- 21305834 TI - Recruiting black Americans in a large cohort study: the Adventist Health Study-2 (AHS-2) design, methods and participant characteristics. AB - OBJECTIVE: The goal of the prospective Adventist Health Study-2 (AHS-2) was to examine the relationship between diet and risk of breast, prostate and colon cancers in Black and White participants. This paper describes the study design, recruitment methods, response rates, and characteristics of Blacks in the AHS-2, thus providing insights about effective strategies to recruit Blacks to participate in research studies. DESIGN: We designed a church-based recruitment model and trained local recruiters who used various strategies to recruit participants in their churches. Participants completed a 50-page self administered dietary and lifestyle questionnaire. PARTICIPANTS: Participants are Black Seventh-day Adventists, aged 30-109 years, and members of 1,209 Black churches throughout the United States and Canada. RESULTS: Approximately 48,328 Blacks from an estimated target group of over 90,000 signed up for the study and 25,087 completed the questionnaire, comprising about 26% of the larger 97,000 AHS 2-member cohort. Participants were diverse in age, geographic location, education, and income. Seventy percent were female with a median age of 59 years. CONCLUSION: In spite of many recruitment challenges and barriers, we successfully recruited a large cohort whose data should provide some answers as to why Blacks have poorer health outcomes than several other ethnic groups, and help explain existing health disparities. PMID- 21305835 TI - Dental caries in American Indian toddlers after a community-based beverage intervention. AB - OBJECTIVE/SETTING: The Toddler Overweight and Tooth Decay Prevention Study (TOTS) was an overweight and early childhood caries (ECC) project in the Pacific Northwest. It targeted American Indian (AI) toddlers from birth, to effect changes in breastfeeding and sweetened beverage consumption. DESIGN/INTERVENTION/PARTICIPANTS: The intervention cohort was children born in three communities during 12 months; expectant mothers were identified through prenatal visits, and recruited by tribal coordinators. The local comparison cohorts were children in those communities who were aged 18-30 months at study start. A control longitudinal cohort consisted of annual samples of children aged 18-30 months in a fourth community, supplying secular trends. OUTCOME MEASURES: d1-2mfs was used to identify incident caries in intervention, comparison, and control cohorts after 18-to-30 months of follow-up in 2006. RESULTS: No missing or filled teeth were found. For d1t, all three intervention cohorts showed statistically significant downward intervention effects, decreases of between 0.300 and 0.631 in terms of the fraction of affected mouths. The results for d2t were similar but of smaller magnitudes, decreases of between 0.342 and 0.449; these results met the .05 level for significance in two of three cases. In light of an estimated secular increase in dental caries in the control site, all three intervention cohorts showed improvements in both d1t and d1t. CONCLUSION: Simple interventions targeting sweetened beverage availability (in combination with related measures) reduced high tooth decay trends, and were both feasible and acceptable to the AI communities we studied. PMID- 21305836 TI - Comparisons of Latinos, African Americans, and Caucasians with multiple sclerosis. AB - OBJECTIVE: Identify racial/ethnic differences among people with multiple sclerosis (MS) in demographics, MS disease characteristics, and health services received. PARTICIPANTS: We analyzed enrollment data from the Registry of the North American Research Committee on Multiple Sclerosis (NARCOMS) Project to compare 26,967 Caucasians, 715 Latinos, and 1,313 African Americans with MS. DESIGN: Racial/ethnic analyses of NARCOMS data focused on descriptive characteristics, using ANOVA and chi-square tests to identify significant differences in means and frequencies among Caucasians, Latinos, and African Americans. RESULTS: We identified significant racial/ethnic differences in demographics, MS disease characteristics, and treatments. Caucasians were older when first MS symptoms were experienced (30.1 years) and at MS diagnosis (37.4 years) than Latinos (28.6 years and 34.5 years) or African Americans (29.8 years and 35.8 years). Larger proportions of Latinos reported normal function for mobility and bladder/bowel function compared to Caucasians. Larger proportions of Latinos (44.2 percent) and African Americans (45.8 percent) reported at least mild depression compared to only 38.7 percent of Caucasians. Larger proportions of Latinos never received mental health care or care from rehabilitation specialists than Caucasians or African Americans. A larger proportion of African Americans had never been treated by a neurologist specializing in MS and a smaller proportion of African Americans received care at a MS clinic than Caucasians or Latinos. CONCLUSIONS: Our findings highlight the need for future analyses to determine if age, disease duration, MS symptoms, and disability levels provide additional insights into racial/ethic differences in the use of MS related providers. PMID- 21305837 TI - Perceived cancer risk among American Indians: implications for intervention research. AB - OBJECTIVE: Perceived risk of disease plays a key role in health behaviors, making it an important issue for cancer-prevention research. We investigate associations between perceived cancer risk and selected cancer risk factors in a population based sample of American Indians. STUDY DESIGN AND POPULATION: Data for this cross-sectional study come from a random sample of 182 American Indian adults, aged > or = 40 years, residing on the Hopi Reservation in northeastern Arizona. OUTCOME MEASURES: Perception of cancer risk was ascertained with the 5-point Likert scale question, "How likely do you think it is that you will develop cancer in the future?" dichotomized into low perceived risk and high perceived risk. RESULTS: Participants reporting a family member with cancer were more likely, by greater than five times, to report the perception that they would get cancer (OR = 5.3; 95% CI: 2.3, 12.3). After controlling for age and family history of cancer, knowledge of cancer risk factors and attitude about cancer prevention were not significantly associated with risk perception. CONCLUSIONS: Perceived cancer risk was significantly associated with self-reported family history of cancer, supporting the importance of personal knowledge of cancer among American Indians. Further research is needed to obtain a more complete picture of the factors associated with perceptions of cancer risk among American Indians in order to develop effective interventions. PMID- 21305838 TI - Promoting a breast cancer screening clinic for underserved women: a community collaboration. AB - OBJECTIVE: To increase breast cancer (BC) awareness, screening services, and education for local underserved women. DESIGN: Mayo Clinic launched a twice monthly, half-day outreach breast clinic composed of 3 women physicians, a nurse and medical interpreters. SETTING: Community Adult Literacy Learning Center in Rochester, Minnesota. PATIENTS: Underserved women from immigrant and minority backgrounds in Rochester. INTERVENTIONS: The clinic offered clinical breast examinations, breast imaging, follow-up appointments, assistance in accessing government paid health coverage programs, educational classes, transportation vouchers, and follow-up surveys. MAIN OUTCOME MEASURES: We assessed the number of patients seen, number of mammograms, breast sonograms, number of patients diagnosed with BC, number of interpreters, quantity of transportation vouchers and results of follow-up surveys. RESULTS: Between December 1, 2005 and July 31, 2009 there were 177 patient visits (including 46 follow-up visits) provided to 131 women on 58 days spent in the clinic. One hundred thirteen women (86.3%) had mammograms, sonograms, or both. Screening identified one woman with a diagnosis of breast cancer, 5 with symptomatic breast cysts and 3 women who underwent breast biopsy after a suspicious lesion was identified with breast imaging. One hundred and twenty women required an interpreter for the initial examination and mammogram visit. Transportation vouchers were used by 51 women. All follow-up surveys indicated overall satisfaction with the breast clinic, services and screening procedures. CONCLUSIONS: For effective breast screening of underserved in a community setting, it is important to address racial/ethnic background, socioeconomic status, English language proficiency, and access to health care in general. PMID- 21305839 TI - Evaluating the relationships among psychological distress, executive cognitive function and economic factors on mammography use in unaffected African American women at risk for breast cancer. AB - OBJECTIVE: Psychological distress impairs the cognitive function involved in planning and decision-making (executive cognitive function), and hinders engagement in health promoting behaviors. This study examined the relationship among distress, executive cognitive function (ECF) and mammography use in African American women at risk for breast cancer. DESIGN: A cross-sectional sample of mammography screening adherers (n = 44) and non-adherers (n = 16) completed measures of psychological distress (Brief Symptom Inventory) and executive cognitive function, (Wisconsin Card Sort Task and Stroop Color Word Test). RESULTS: More than one-quarter of the high-risk sample had high levels of distress. Distress scores explained 12% of the variance in two ECF components (abstract concept formation and cognitive flexibility), suggesting a significant relationship between psychological distress and cognitive function. Distress scores and ECF measures did not predict mammography use; employment status emerged as the strongest predictor of mammography screening (OR = 4.36, 95% CI: 1.18-16.07). CONCLUSION: Elevated psychological distress is evident in high-risk African American women and appears to have an effect on the cognitive function involved in behavioral regulation and planning. Results also support the role of socioeconomic status as a significant predictor of mammography use. PMID- 21305840 TI - South Asians and risk of cardiovascular disease: current insights and trends. AB - Patients from the Indian subcontinent have a distinct cardiovascular risk profile with profound health consequences. South Asians tend to develop more severe coronary artery disease at a younger age, and may also suffer from earlier myocardial infarction and heart failure. The genesis of this risk is multi factorial. One important culprit is increased insulin resistance, possibly due to recently identified genetic polymorphisms. Another possible explanation is subclinical inflammation and a prothrombotic environment, as evidenced by increased levels of homocysteine, plasminogen activator inhibitor-1, and fibrinogen. The lipid profile of South Asians may play a role, as this population is known to have elevated levels of lipoprotein (a), as well as lower levels of HDL. In addition, this HDL may be dysfunctional, as this population may have a higher prevalence of low levels of HDL2b, as well as an increased preponderance of smaller HDL. Current guidelines for primary and secondary prevention have not reflected our growing insight into the unique characteristics of the South Asian population, and may need to evolve to reflect our knowledge. PMID- 21305841 TI - A proposition against using the terms "Hispanic" and "Latino" in research on HIV associated neurocognitive disorders. AB - In the United States, the term "Hispanic" has been used to refer to a person or groups of persons who originate from Spanish-speaking countries. However, this term fails to account for variables such as nationality, ethnicity, race, and cultural origin as well as the extent of assimilation to a new culture. In addition, factors such as the individual's generation, specific migratory status, years of education in each country, fluency, and day-to-day language usage contribute to variance in neuropsychological testing outcomes, which are sensitive to these factors. We have noted that the usage of the terms "Hispanic" and "Latino" is problematic in HIV-associated neurocognitive disorder (HAND) research; therefore, we propose grouping individuals by nationality or by the Spanish-speaking culture to which they belong. The rationale for not using these terms is based upon the sociodemographic findings among Spanish speakers infected with HIV and how these terms inadequately describe the rich heterogeneity of this population. PMID- 21305842 TI - A proposed new food guide: why pyramids should stop at traffic lights. AB - Many food guides are used around the world, with most based on a graphical design to indicate how much of each food group should be eaten. However, the most recent versions of the food guides used in the United States (MyPyramid) and Canada (Eating Well with Canada's Food Guide) have moved away from using a graphical design. In this article, we evaluate the design of these various food guides and describe an alternative design for a food guide based on a traffic lights approach. Foods are classed as green (eat freely based on recommended amounts), amber (eat in limited amounts), and red (eat little or none). The food guide is accompanied by a set of simple rules for selecting an appropriate diet. This design has several advantages over conventional designs. In particular, the proposed design more closely reflects the actual composition of foods, namely that foods within each food group tend to fall into three distinct groups based on nutritional composition, a point which is much less clear with conventional food guide designs. The simplicity of the design may make it especially valuable in developing countries and among communities where educational standards are poor. Only a limited amount of research has been conducted on traffic lights food guides, mainly for its use in the treatment of childhood obesity. Further research is therefore required. PMID- 21305843 TI - For the patient. Heart disease and physical activity for South Asians in Canada. PMID- 21305844 TI - For the patient. Awareness and knowledge about human papillomavirus among Latina immigrants. PMID- 21305845 TI - For the patient. Physical activity and obesity in the Jackson Heart Study population. PMID- 21305846 TI - Hepatoprotective effect of morin on ethanol-induced hepatotoxicity in rats. AB - Morin is a flavonoid that exists in nature and is the major component of traditional medicinal herbs. Here we evaluated morin for its hepatoprotective effect against chronic ethanol-induced biochemical changes in male Wistar rats. Ethanol administration (7.9 g/kg bwt) for 60 days induced hepatic and renal damage by increasing oxidative stress and decreasing antioxidant levels. The status of lipid peroxidation (thiobarbituric reactive substances (TBARS) and hydroperoxides (HP)), antioxidant (vitamin C, vitamin E, GSH), serum hepatic markers (AST, ALT, ALP, GGT, bilirubin), and renal markers (urea, creatinine) were assessed as biochemical endpoints to determine the hepatic protective effect of morin. Oral administration of morin (100 mg/kg b.w) to alcohol-intoxicated rats for 30 days showed significant decreases in lipid peroxidation and restoration of antioxidant, hepatic, and renal markers to normal. Histopathologic observations of liver were also in correlation with biochemical parameters. The results indicate that morin might be beneficial in ameliorating alcohol-induced oxidative damage in rat liver. PMID- 21305847 TI - Extract of Xylopia aethiopica (Annonaceae) protects against gamma-radiation induced testicular damage in Wistar rats. AB - Ionizing radiation is an important environmental risk factor and, a major therapeutic agent for cancer treatment. This study was designed to evaluate the protective effect of extract of Xylopia aethiopica (XA) on gamma-radiation induced testicular damage in rats. Vitamin C (VC) served as the reference antioxidant during the study. The study consists of 4 groups of 11 rats each. Group I received corn oil (vehicle), groups II and IV were pretreated with XA (250 mg/kg) and VC (250mg/kg) for 6 weeks before and 8 weeks after exposure to gamma-radiation; group III was exposed to a single dose of gamma-radiation (5 Gy). Biochemical analysis revealed that gamma-irradiation caused a significant increase (p < .05) in serum and testicular lipid peroxidation (LPO) levels by 217% and 221%, respectively. Irradiated rats had markedly decreased testicular catalase (CAT), superoxide dismutase (SOD), glutathione-S-transferase (GST), and reduced glutathione (GSH) levels. Irradiation resulted in 59% and 40% decreases in spermatozoa motility and live/dead sperm count, respectively, and a 161% increase in total sperm abnormalities. Histologically, testes of the irradiated rats showed extensive degenerative changes in the seminiferous tubules and defoliation of spermatocytes. Supplementation of XA and VC reversed the adverse effects of gamma-radiation on biochemical and histological indices of the rats. These findings demonstrated that Xylopia aethiopica has a protective effect by inhibiting oxidative damage in testes of irradiated rats. PMID- 21305848 TI - Acclimation to heat interpreted from the analysis of heart-rate variability by the Multipole Method. AB - The Multipole Method is a recently developed method to describe time series with highly complex time evolution, such as cardiac rhythm. We hypothesized that applying this method in the analysis of heart rate variability (HRV) could provide valuable physiological information that usually cannot be extracted from the commonly used time and frequency domains analyses. The hypothesis was tested during a 12-day heat acclimation process on four young healthy, male subjects. On the first and the last day of acclimation, HRV was investigated by two different measures: the conventional Standard Deviation of Normal to Normal R-R intervals (SDNN), and the Multipole Method. The analyses revealed that stress on the cardiovascular system was still evident after the 12th day of acclimation, but both methods showed that stress was diminished. Using the Multipole analysis, following acclimation to heat, the autonomic nervous system shows a more effective response. We conclude that the Multipole Method is a very valuable tool for investigating the series of R-R intervals, which are a non-stationary and non linear complex time series, reflecting a complex regulatory physiological mechanism. Specifically, we showed that stress on the cardiovascular system diminishes following the course of acclimation, but not to its complete relief, which indicates that acclimation to heat is a much longer process than can be judged from the early phenotypic picture. PMID- 21305849 TI - L-ascorbic acid and alpha tocopherol supplementation and antioxidant status in nickel- or lead-exposed rat brain tissue. AB - We evaluated the effect of L-ascorbic acid and alpha-tocopherol supplementation on plasma and whole brain nitric oxide level and antioxidant status in nickel sulfate- or lead acetate- treated male albino rats. Nitric oxide and lipid peroxide levels in whole brain tissue and plasma increased following nickel and lead treatment but significantly returned to near-normal values upon L-ascorbic acid or alpha-tocopherol supplementation. In brain tissue, antioxidant enzymes- superoxide dismutase, glutathione peroxidase, glutathione peroxidase, and catalase--along with the glutathione level decreased significantly after both treatments but significantly improved upon simultaneous supplementation with L ascorbic acid or alpha-tocopherol. Lead-treated animals showed a greater improvement with alpha-tocopherol, whereas nickel-treated rats showed a greater improvement with L-ascorbic acid. In both groups, combined supplementation with L ascorbic acid and alpha-tocopherol did not change the percentage improvement in comparison with supplementation with a single vitamin alone. PMID- 21305850 TI - Antinociceptive activity of Premna corymbosa (Burm.f.)Rottl. & Willd. AB - The aim of this work was to evaluate the acute toxicity and antinociceptive activity of an ethanolic extract of Premna corymbosa in animal models. In the acute toxicity study, the ethanolic extract showed no clinical signs and mortality of the animals and was found to be safe. In the acetic acid-induced writhing model, the ethanolic extract at a dose of 200 or 400 mg kg(-1) body weight significantly (p < .01) inhibited the writhing response by 42.57% and 54.67%, respectively. In the hot plate test, the extract produced a significant (p < .01) increase in latency with 34.50% and 51.08% of protection in a dose related manner. This study has established the analgesic properties of P. corymbosa (Burm.f.) Rottl. and Willd. The beta-sitosterol or luteolin present in the ethanolic extract may contribute the antinociceptive activity of P. corymbosa. PMID- 21305851 TI - Relative role of neural substrates in the aggressive behavior of rats. AB - Early animal studies have shown an association between aggression and brain dysfunction. The goal of the present study was to compare the effects of lesions of different parts of brain on aggression in rats. Adult rats (n = 40, weighing 200-260 g) were randomly divided into four groups of ten animals each and subjected to lesions of the septum (Group I), medial preoptic area (Group II), medial accumbens (Group III), and bed nucleus of stria terminalis (Group IV), using stereotaxy apparatus. Aggression toward an unfamiliar male intruder was observed before and after the lesion. The aggression score of each animal was recorded three times before lesion and averaged for use in analysis. Analysis of variance (ANOVA) was applied for finding homogeneity of the groups. Postoperative scores were also similarly recorded and summarized as mean +/- standard deviation. Pre- and post-lesion scores were compared using the t test. The scores were significantly reduced in Group I, II, and III, but increased in Group IV. We can conclude that the septum, medial preoptic area, medial accumbens, and bed nucleus of stria terminalis, by virtue of their interconnections, influence aggressive behavior. PMID- 21305852 TI - Protective effects of syringic acid against acetaminophen-induced hepatic damage in albino rats. AB - The protective effect of the phenolic compound syringic acid, one of the major benzoic acid derivatives from edible plants and fruits, was evaluated against acetaminophen (APAP)-induced hepatotoxicity in rats. Toxicity was induced in adult male albino Wistar rats by the administration of APAP (750 mg/kg body weight) intraperitoneally. Rats were treated with syringic acid (25, 50, and 100 mg/kg body weight) by the oral route. We assessed the activity of hepatic markers aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma glutamyl transferase, and bilirubin. Lipid peroxidative markers thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides, and a decrease in enzymatic antioxidants superoxide dismutase, catalase, glutathione peroxidase, and non-enzymatic antioxidants vitamin C, vitamin E and reduced glutathione levels. Liver histology also showed convincing evidence regarding their protective nature against fatty changes induced during APAP intoxication. Syringic acid administered at a dose of 50 mg/kg body weight significantly decreased the activities of hepatic and renal function markers to near normal values when compared with the other two doses. The results suggest that syringic acid could afford a significant protective effect against APAP induced hepatic damage in rats. PMID- 21305853 TI - Anti-hyperlipidemic and cardioprotective effects of Ocimum sanctum L. fixed oil in rats fed a high fat diet. AB - Ocimum sanctum (OS) has a lipid-lowering action in both normal and diabetic animals. Because OS leaves are rich in oil, the present study was conducted to explain the anti-hyperlipidemic and organ-protective effect of OS fixed oil in rats fed with a high fat (HF) diet. OS fixed oil was extracted by hexane and the fatty acids composition identified by GC-MS. Four groups of male Wistar rats included a normal control group, a high fat fed-diet (HF) group, a HF group treated with OS fixed oil, and a HF group treated with a reference drug simvastatin. The results show that OS fixed oil contains five kinds of fatty acids, of which alpha-linolenic acid was the major fatty acid. OS fixed oil depressed high serum levels of total cholesterol, triglyceride, LDL-C, and AI, whereas no significant effect on HDL-C was observed. OS fixed oil also suppressed high levels of liver cholesterol and triglyceride with no significant effect on both lipids in feces. In addition, OS fixed oil normalized the high serum levels of LDH and CK-MB but no significant effect on high serum levels of ALT, AST, and ALP was obtained. We conclude that treatment with OS fixed oil during the last three weeks of HF diet feeding decreased the high serum lipid profile and expressed antiartherogenic and cardioprotective actions against hyperlipidemia. The anti-hyperlipidemic action of OS fixed oil was mainly resulted from the suppression of liver lipid synthesis. Linolenic acid and linoleic acid contained in OS fixed oil were possibly responsible for both lipid-lowering and cardiac protective action against hyperlipidemia. PMID- 21305855 TI - Neurology. PMID- 21305854 TI - Protective potential [correction of potencial] of Euphorbia hirta against cytotoxicity induced in hepatocytes and a HepG2 cell line. AB - Medicinal plants play a key role in human health care. Frustration over the side effects of allopathic drugs has driven the medical world to take asylum in the plant kingdom for the treatment of various ailments. Euphorbia hirta belonging to the family of Euphorbiacae has been reported to possess antibacterial, antiviral, and anticancer activity. The aim of the present study was to investigate the protective effect of E. hirta against antitubercular drug-induced cytotoxicity in freshly isolated hepatocytes. The extent of cytotoxicity of the plant extracts was also analyzed using human liver derived HepG2 cell line by estimating the viability of cells (MTT assay). The alcoholic plant extract normalized the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), triacylglycerol (TAG), cholesterol, total protein, albumin, total and direct bilirubin, which were altered due to antitubercular drug intoxication. A dose-dependent increase in percent viability was observed when antitubercular drug exposed HepG2 cells were treated with different concentrations of plant extracts (125, 250, 500 and 1000 microg/mL) which were compared with a standard hepatoprotective drug silymarin. The highest percentage viability of HepG2 was observed at a concentration of 1000 microg/mL. The results suggest that E. hirta exerts protection against antitubercular drug-induced cytotoxicity in this vitro model system. PMID- 21305856 TI - Proton magnetic resonance spectroscopy in Alzheimer's disease, a review. AB - Alzheimer disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia in the elderly. Current consensus statements have emphasized the need for early recognition of AD. In vivo magnetic resonance spectroscopy (MRS) has recently opened new possibilities for noninvasively assessing metabolic and functional correlates of dementia in research and clinical settings. The purpose of this article is to provide a conceptual review, covering the principles of MRS and main pathological findings related to AD. H1 MRS has the possibility of being a neuroimaging marker because the potential clinical applications in patients with AD include a role in early diagnosis and differential diagnosis of AD, a role in prognosis of disease severity, a role in predicting future progression to AD in patients with mild cognitive impairment and tracking disease progression. MRS can also help in the evaluation of treatment effects and in the development of new therapies. In conclusion, H1 MRS has great potential in becoming an adjunct to clinical evaluation and management of dementia in the future. Nevertheless, there is still need for further research for the implementation of this neuroimaging technique in the management of dementia. PMID- 21305857 TI - Risk factors and treatment of stroke at the time of recurrence. AB - The profile of recurrent ischemic strokes has not been much investigated. The aim of this study was to evaluate how the therapeutic strategies recommended for secondary prevention after an ischemic stroke are implemented in the real world of clinical practice. All patients admitted for a recurrent ischemic stroke or TIA were prospectively registered. The etiology was determined according to the TOAST classification. The risk factors and cardiovascular treatment at the time of the recurrence were recorded. A total of 168 patients were evaluated. Most of the patients (61%) recurred after 1 year. The recurrent stroke was not associated with a particular etiological subtype. The most frequent risk factor was hypertension (79%), followed by hypercholesterolemia (43%), smoking (25%), and diabetes (22%). Most of the patients had more than 1 risk factor (84%). Hypertension was not satisfactorily controlled in 38% of patients, hypercholesterolemia in 42%, and diabetes in 59%. A significant minority of patients (15%) were not taking any antithrombotic agent despite a history of stroke or TIA. Only 34% of the cases with a known atrial fibrillation were on anticoagulant therapy and the International Normalized Ratio was < 2.0 in 71% of them. In conclusion, stroke prevention needs to be improved by better implementation of therapeutic strategies in clinical practice. The patients should also be better informed about target values as well as the importance of physical activity and smoking cessation. PMID- 21305858 TI - Vascular risk factors in patients with peripheral vestibular disorders. AB - OBJECTIVES: The present observational retrospective study investigates whether there are differences in vascular risk factors between patients with spontaneous benign paroxysmal positional vertigo (BPPV) and those with Meniere's disease (MD). PATIENTS AND METHODS: Out of a series of 1617 consecutive admitted patients, 36 presented isolated recurrent vertiginous events. Twenty patients with BPPV and 16 with MD were compared. In addition to extensive audiovestibular investigations, all patients had a complete cardio-vascular work-up. A computed tomography (CT) and a magnetic resonance imaging (MRI) of the brain were performed in all patients. The vascular risk factors and the CT/MRI findings were compared between the patients with BPPV and MD. RESULTS: Small old cerebral infarcts were observed in 25% of the BPPV and 31.2% of the MD patients, although none of them had a prior history of stroke. All other vascular risk factors tended to be more frequent in the former group although only a statistically significant difference was found for coronary artery disease (P = 0.03). CONCLUSIONS: In this pilot study BPPV does not appear to be such a benign condition but can indicate progression of general atherosclerotic disease. PMID- 21305859 TI - Gait analysis in children treated by surgery followed by adjuvant therapy for posterior fossa tumors. AB - Children affected by posterior fossa tumors show signs and symptoms of neurological dysfunction, associated both to cancer itself and to cancer therapies. Abnormal gait and coordination difficulties are frequent presenting features. Radiation therapy represents the main adjuvant treatment for these patients. However it can produce significant neurologic injury, also manifested as gait disturbance months after treatment. We have analyzed temporo-spatial parameters of gait in sixteen children treated for posterior fossa tumors, mainly medulloblastomas. In all children we found a typical gait pattern of cerebellar ataxia. There were no significant differences between data obtained in children affected by severe neurological impairment and those having slight or even hardly recognizable physical signs. Although the number of patients studied is not large enough to allow definitive conclusions and gait analyses were performed after treatment, our results suggest that most children treated for posterior fossa tumors have gait disturbances and in some of them these are subclinical. Standard gait analysis laboratory methods can thus be a valuable tool for the careful assessment and follow-up of these patients. PMID- 21305860 TI - Weight changes in Parkinson's disease patients after subthalamic nucleus deep brain stimulation surgery. AB - BACKGROUND: After Sub-Thalamic Nucleus Deep Brain Stimulation (STN-DBS), an effective treatment for Parkinson disease patients, weight gain has been observed. As this method of treatment is only in use since two years in Iran, no information regarding its side effects (including weight gain) existed thus far. OBJECTIVE: We conducted this study to evaluate the weight gain 1 and 3 months after the DBS surgery. METHODS: We enrolled all patients who underwent bilateral STN-DBS in Rasool Akram Hospital affiliated to Iran University of Medical Sciences in 2008- 2009. Unified Parkinson Disease Rating Scale (UPDRS), neuropsychological assessment, pulmonary and cardiac evaluation before the surgery were carried out for all patients. They were weighted before, 1 and 3 months after the STN-DBS. RESULTS: The average weight of patients was 70.7 +/- 14.4, 74.1 +/- 16.2 and 76.6 +/- 14.4 Kg before, 1 and 3 months after the STN DBS, respectively (P < 0.037). CONCLUSION: Our results confirm that rapid weight gain (as soon as 1 month after surgery) occurred in STN-DBS treated parkinsonian patients. PMID- 21305861 TI - Carcinoembryonic antigen in the CSF of cancer patients--the value of intrathecal synthesis and correlation with IgA-diffusion dynamics. AB - OBJECTIVE: The diagnostic impact of carcinoembryonic antigen (CEA) was evaluated in serum and CSF of cancer and control patients. METHODS: 97 analyses of CEA in CSF and serum from 83 cancer patients were compared with 41 cases without malignancy. CEA diffusion dynamics were evaluated with IgA CSF/serum quotients (Q IgA). Intrathecal synthesis of CEA was analysed both by calculating an index Q CEA/Q IgA and within the IgA-diagram. RESULTS: In 73 samples without synthesis of IgA or CEA, both quotients correlated well with a mean Q CEA/Q IgA of 1.1 (95% CI 0.97-1.2). The Q CEA/Q IgA was significantly higher in metastasizing adenocarcinomas than in controls or other malignancies. In leptomeningeal disease from adenocarcinoma, Q CEA/Q IgA was significantly higher than in controls, while patients with CNS and/or bone metastases had intermediate values. The sensitivity to detect leptomeningeal disease was 91% and 69% for brain metastases. Q CEA/Q IgA and CEA synthesis assessed with the IgA diagram were equally sensitive. CONCLUSIONS: Evaluation of CEA in the IgA diagram is feasible and of clinical value. The consideration of intrathecal CEA synthesis correlates better with the clinical status than absolute CSF-CEA or the correlation with albumin. PMID- 21305862 TI - Ocular vestibular evoked myogenic potentials in patients with migraine. AB - BACKGROUND: Subclinical cerebello-vestibular impairment has been described in migraine patients. OBJECTIVES: Our aim was to investigate the presence of subclinical vestibulopathy in migraine patients using ocular vestibular evoked myogenic potentials (oVEMP). PATIENTS AND METHODS: Forty-three patients suffering from migraine without aura who had no vestibular complaints and 29 healthy controls were included in the study. The responses were recorded from contralateral lower eyelid just above of the inferior oblique muscle during 120 dB click stimulation. RESULTS: Eight migraine patients (18.6%) disclosed no response. Bilateral or unilateral response rates in the migraine group were 46.5% (n = 20) and 34.9% (n = 15) respectively. In controls, bilateral or unilateral responses could be obtained from 25 (86.7%), and 4 (13.2%) cases, respectively. In migraineurs group mean latencies of N1 and P1 were significantly longer, while N1-P1 amplitudes were found meaningfully lower. CONCLUSION: These data demonstrate that using oVEMP subclinical vestibular dysfunction can be elicited in migraine patients without vestibular complaints. PMID- 21305863 TI - Primary diffuse leptomeningeal gliomatosis: an autopsy case and review of the literature. AB - We report a case of primary diffuse leptomeningeal gliomatosis (PDLG) in a 76 year-old male presenting with confusion, dysarthria, diplopia, lumbal pain and headaches of recent onset. Neurological examination revealed nuchal rigidity and bilateral sixth cranial nerve palsy. The cerebrospinal fluid showed a marked hyperproteinorachia (4711 mg/L) and mild cytorachia (5-10 leucocytes/mm3) with a few atypical lymphoid cells. On admission, brain CT scan and MRI demonstrated diffuse and nodular leptomeningeal contrast enhancement predominant at the skull base and several osteolytic lesions in the right parietal bone. Extensive serological studies for infectious, autoimmune or neoplastic diseases were negative. The work-up diagnosis was neurosarcoidosis or multiple meningeal and osseous metastases of an unknown primary cancer. Surgical biopsy of the right parietal bone lesion showed only fibrous tissue with no evidence of tumour or inflammation. The patient was treated with high dose corticosteroids but its neurological status progressively worsened and he died of aspiration pneumonia 35 days after admission. Post-mortem examination revealed a PDLG, a rare fatal tumour with about 60 cases reported. PDGL is characterized by the diffusion of neoplastic glial cells throughout the leptomeninges without evidence of a primary intra-parenchymal lesion. Recognition of this rare brain tumour is important as recent reports suggest that radiotherapy and chemotherapy can improve patient survival. PMID- 21305864 TI - Asperger syndrome, violent thoughts and clinically isolated syndrome. AB - A young man, 23 years old, with a clinically isolated syndrome (CIS), presented violent thoughts during a neurological consultation. He was diagnosed with Asperger Syndrome based on a psychiatric and (neuro)psychological examination. Possible risk factors for acting-out and the implications for treatment, if CIS would evolve to MS, are discussed based on a review of the literature. PMID- 21305865 TI - A case with a rare type of trigemino-oculomotor synkinesis: clinical and blink reflex study. AB - Several abnormal synkinetic eye movements during jaw movements may often be seen after trauma or congenitally in the Marcus Gunn jaw winking phenomenon. The most frequent type consists of unilateral ptosis and retraction of the ptotic lid upon moving the jaw. The authors describe a case with isolated simultaneous adduction of the left eye upon jaw movement. This paper presents a rare case of Marcus Gunn jaw winking with trigemino-oculomotor synkinesis. PMID- 21305866 TI - Acute disseminated encephalomyelitis following herpes simplex encephalitis. AB - Acute disseminated encephalomyelitis is an acute immunomediated demyelinating disorder of the central nervous system, usually encountered in children or adolescents and characterized by multifocal neurologic deficits of rapid onset. It is often preceded by various infectious diseases or vaccination, but acute disseminated encephalomyelitis developing after herpes simplex encephalitis is rare. We report such a case in a 2-year-old girl which illustrates the importance of MRI features to consider acute disseminated encephalomyelitis in a patient who develops neurologic signs after the onset of HVS encephalitis. PMID- 21305867 TI - Overlooked early CT signs of cerebral venous thrombosis with lethal outcome. AB - The aim of this report is to emphasize the consequences of overlooked initial CT signs of cerebral venous thrombosis. Brain CT was ordered in an afebrile patient with neck pain and occipital headache. Since no abnormalities were noted on non contrast CT study, the patient was discharged with recommendation for routine laboratory tests and plain X-ray of the cervical spine. Right hemiparesis developed the next day with persistent headache and the patient was sent back to the Neurology Clinic where he developed myoclonic seizures compatible with focal motor status epilepticus. Neuroimaging, performed two days later, revealed a huge hemorrhagic venous infarcts in the left posterior cerebral hemisphere associated with typical signs of dural sinus thrombosis. Subtle curvilinear hyperdensities were detected within the left parietal cortico-subcortical border zone on reevaluation of the initial brain CT. A posteriori these were thought to be compatible with a developing venous infarct, associated with subtle signs most consistent with combined cortical vein and sinus thrombosis. No improvement was noted after administration of anticoagulant treatment and the patient died 11 days after the initial CT scan. Detection of early CT signs of cerebral venous thrombosis is extremely important, since delaying adequate treatment may have catastrophic consequences. PMID- 21305868 TI - Cerebrovascular symptomatic involvement in sarcoidosis. AB - Clinical reports of cerebrovascular system involvement in sarcoidosis are extremely rare though pathological studies frequently describe granulomatous cerebral arterial and venous lesions. We report the case of a 47-year-old man with a history of pulmonary sarcoidosis at age 32 and abducens palsy at age 40, who presented cerebral pseudotumoral histologically proven sarcoidosis. He was admitted for acute left hemiplegia. Brain CT scan and MRI demonstrated a right posterior parietal haematoma associated with a superior sagittal sinus occlusion. He received intravenous corticosteroids and anticoagulant therapy. Six months later, he presented a right motor status epilepticus. MRI revealed new parenchymal haematomas. Cerebral angiography demonstrated cerebral vasculitis. PMID- 21305869 TI - Massive cerebral arterial air embolism and hemorrhagic stroke. PMID- 21305870 TI - Bilateral basal ganglia hemorrhagic necrosis due to methanol toxicity. PMID- 21305871 TI - A retroclival cystic craniopharyngioma. PMID- 21305872 TI - CT coronary angiography for the follow-up of coronary stent. AB - The treatment of coronary artery stenosis has progressively shifted over the past decades, from surgical (CABG) to percutaneous (PCI and stenting). The recent introduction of drug-eluting stents further reduced the occurrence of in-stent re stenosis (ISR). However, a non-negligible number of patients need imaging/functional tests when symptoms recur. Multi-Slice CT Coronary Angiography (CT-CA) is a clinical reality for the evaluation of coronary artery stenosis, but still under evaluation in the follow-up of coronary stents. Several factors may impair proper depiction of in-stent lumen even with the most recent CT equipments. In highly selected populations CT-CA may play a clinical role even though the performance requirements both from the technical standpoint (i.e., CT scanner) and from the training (i.e., operators' experience) are still very demanding. In the meantime CT technology should improve towards higher contrast, spatial and temporal resolution in order to achieve the results that may be proper for clinical implementation. PMID- 21305873 TI - Osteoarthritis and degenerative joint disease: local treatment options update. AB - This review describes intra-articular drugs therapy of arthritis and degenerative joint disease) with a range of old and recent molecules with specific focus on hyaluronic acid. HA is a cartilage matrix basic component secreted by chondrocytes: it prevents cartilage degradation by a complex interpherence between metalloproteinases, pain mediators and cells. Local injections of HA improve functional activity and pain management, particularly when it is combined with other selected drugs. PMID- 21305874 TI - Biotechnological advancement in isolation of anti-neoplastic compounds from natural origin: a novel source of L-asparaginase. AB - L-asparaginase catalyzes the hydrolysis of L-asparagine into aspartate and ammonia, which is used as an anti-neoplastic agent. Isolation of asparaginase from microorganisms may be cardinal for producing this anticancer agent at industrial level. A total of three hundred fungal isolates were screened for L asparaginase production. These fungal isolates were growing on various fruits and vegetables. Among these, the Fusariumn sp. isolate that was growing on green chilly showed highest enzyme production. This study may give an outstanding contribution for finding organisms with high yielding L-asparaginase. Fungal L asparaginase is superior in terms of its eukaryotic origin that may be responsible for its lesser toxicity. PMID- 21305875 TI - Respiratory function in subjects with chronic obstructive pulmonary disease (COPD) and atmospheric pollution in the city of Parma. Preliminary analysis. AB - A hospital case record study was carried out enlisting urgently hospitalized subjects for chronic obstructive pulmonary disease (COPD) in order to study the percentage values variations of Vital Capacity (VC), Forced Vital Capacity (FVC) and maximum expiratory volume in 1 second (FEV1) based on atmospheric pollution trend in Parma city evaluated by PM10, NO2 and O3 concentrations. The results showed an association only between PM10 and hospitalizations for COPD with statistically significant differences between PM10 concentrations assessed 3-4 days before hospitalizations of the study subjects and the ones established in the days without any hospitalization. The regression analysis between PM10 and respiratory function concerning PM10 concentration at 24, 48, 72, 96 hours before the hospitalization showed significant association between FVC% and FEV1% and PM10 concentrations at 96 hours. The calculated odd ratio resulted equal to 1016 (L.C. 1001-1032) which corresponds to an increase of hospitalization probability for COPD equal to 1.6% for PM10 increment unit. PMID- 21305876 TI - The IMPROVE study--a multinational, multicentre, observational study in type 2 diabetes: results from the Italian cohort. AB - AIMS: The IMPROVE study evaluated the safety and effectiveness of biphasic insulin aspart 30/70 (BIAsp 30) in type 2 diabetes patients in the routine practice. Here we present the results for patients from Italy. METHODS: Adverse events, hypoglycaemia, glycaemic control, patient treatment satisfaction and physician resource utilisation were assessed at baseline and 26 weeks. RESULTS: Out of the 1371 patients enrolled, 84.1% (n=1153) were receiving BIAsp 30 at baseline (in accordance with local regulations), and were included in the study. Mean HlbA, reduction was--0.63% after 26 weeks (p < 0.001); 26.5% and 13.5% of patients reached the HbA(1c) targets of < 7% and < 6.5%, respectively. Fasting and postprandial blood glucose significantly decreased; 65% of patients were using BIAsp 30 once daily and 32% twice daily at final visit. Rates of major and minor hypoglycaemic events also significantly decreased. Small weight increase was observed, and total insulin daily dose increased from 0.29 IU/kg pre-study to 0.32 IU/kg at final visit. CONCLUSIONS: In Italy, BIAsp 30 in the routine care improved glycaemic control and reduced hypoglycaemia; however, there was little intensification and titration. This may partly explain the relatively small improvement in glycaemic control in Italy compared with other countries in the IMPROVE study. PMID- 21305877 TI - Bleeding in orthopaedic surgery: the role of blood transfusion and erythropoietin alpha. AB - High energy trauma is often responsible for acute bleeding. Long bone and pelvis fractures are correlated with increased blood loss. Hypovolaemia could become a life threatening complication especially in elderly patients because of the reduced physiological response. Furthermore it could compromise the course of associated morbidities. Haemorrage is also associated in both comminuted fractures and osteoporosis. An increased intraoperative bleeding often occurs when a prolonged surgical time is required to obtain an appropriate ostheosynthesis. The final consequence of a mayor bleeding is hypovolaemic shock. The reduced oxygen tension of the tissue may be responsible for heart attack, arrhythmia, stroke, multi organ deficiency. For these reasons, it is important to immediately recognize and correct all potential bleeding in order to avoid complications. PMID- 21305878 TI - What's happened to paraphrenia? A case-report and review of the literature. AB - Paraphrenia is a chronic psychotic disorder similar to paranoid schizophrenia, but with a better-preserved affect and relation and a much less personality deterioration. It was firstly systematically described by Kraepelin in 1913 in order to define a group of psychotic patients who exhibited characteristic symptoms of dementia praecox, but with minimal disturbances of emotion and volition, and marked delusions. After the publication of the Mayer-Gross's report in 1921, the view to differentiate paraphrenia from schizophrenia was considered to be unfounded and the term "paraphrenia" was not included in the current DSM-IV TR diagnostic criteria. Consequently, now this disorder is infrequently diagnosed. However, several authors suggest that the concept of paraphrenia has not lost its usefulness. It seems to be that some psychiatrists recognize the illness, but labelled it as "atypical psychosis", "schizoaffective disorder", "delusional disorder" or "psychotic disorder not otherwise specified" for the lack of a better diagnostic category. Very few systematic studies on paraphrenia have been carried out in the past 70 years. Aim of this article is to describe a case of chronic delusional psychosis who meets the Ravindran's modern diagnostic criteria for "paraphrenia redefined", suggesting that it is possible to define and recognize the illness if the practitioners are induced to use a viable diagnostic entity. Further research would benefit paraphrenic and schizophrenic patients. PMID- 21305879 TI - Caesarean delivery through deliberate posterior hysterotomy in irreducible uterine torsion: case report. AB - Gravid uterus rotation is a normal finding in the third trimester of pregnancy. However, a rotation greater than 45 degrees around the longitudinal axis of the uterus--uterine torsion--is a rare pathological condition in the obstetrical practice. We reporte the case of 180 degrees torsion of a myomatous uterus at preterm in which the foetus, in breech presentation, was delivered through a deliberate posterior hysterotomy. An emergency caesarean section was arranged after prolonged foetal bradycardia. Uterine torsion treatment depends on when the torsion occurs during the pregnancy. However, laparotomy is imperative in all cases. When derotation of the uterus is not possible, a transverse incision in the lower posterior uterine segment, if feasible, is a safe choice. PMID- 21305880 TI - Apparent life threatening event and gastric antral ulcer in a full-term infant: any possible relationship? AB - We describe the case of an apparently healthy newborn infant who in 7th day of life showed an episode of haematemesis and in 13th day of life presented an episode of apparent life threatening event (ALTE). A fibroscopy of the upper digestive tract showed a great ulcer of the gastric antrum and esophagitis limited to the mucosa. Gastrinemia in the blood showed high values (121 pg/ml). The relationship between ALTE and gastric ulcer may be casual, however in literature a gastroenteric cause is present in about 50% of ALTE in which an etiologic cause is found. We speculate that in the present case the increase of gastrin secretion reduced gastric pH which facilitated the onset of gastric ulcer and esophagitis with ALTE due to pain or reflex. PMID- 21305881 TI - Hourglass cystic schwannoma of the trochlear nerve. AB - Cranial nerves' schwannomas most commonly arise from the vestibular nerve. Involvement of other cranial nerves, in absence of neurofibromatosis, is extremely rare. A case of a pathology proven trochlear nerve schwannoma, with internal cystic components, in a patient with isolated right superior oblique muscle palsy, is described. Only 67 cases of such entity have been previously reported in the literature. PMID- 21305882 TI - Performance analysis of a solar-powered organic rankine cycle engine. AB - This paper presents the performance analysis of a power plant with the Organic Rankine Cycle (ORC). The power plant is supplied by thermal energy utilized from a solar energy collector. R245fa was the working fluid in the thermodynamic cycle. The organic cycle with heat regeneration was built and tested experimentally. The ORC with a heat regenerator obtained the maximum thermodynamic efficiency of approximately 9%. PMID- 21305883 TI - Determination of buffering capacity of total suspended particle and its source apportionment using the chemical mass balance approach. AB - The samples of total suspended particle (TSP) from sources and TSP in the ambient atmosphere were collected in 2006 at Tianjin, People's Republic of China and analyzed for 16 chemical elements, two water-soluble ions, total carbon, and organic carbon. On the basis of the chemical mass balance (CMB) model, the contributions of different TSP sources to the ambient TSP were identified. The results showed that resuspended dust has the biggest contributions to the concentration of ambient TSP. The buffering capacity of each TSP source was also determined by an analytical chemistry method, and the result showed that the constructive dust (the dust emitted from construction work) had the strongest buffering capacity among the measured sources, whereas the coal combustion dust had the weakest buffering capacity. A calculation formula of the source of buffering capacity of ambient TSP was developed based on the result of TSP source apportionment and the identification of the buffering capacity of each TSP source in this study. The results of the source apportionment of the buffering capacity of ambient TSP indicated that open sources (including soil dust, resuspended dust, and constructive dust) were the dominant sources of the buffering capacity of the ambient TSP. Acid rain pollution in cities in Northern China might become serious with a decrease of open source pollution without reducing acidic sources. More efforts must be made to evaluate this potential risk, and countermeasures should be proposed as early as possible. PMID- 21305884 TI - Effectiveness of emission control technologies for auxiliary engines on ocean going vessels. AB - Large auxiliary engines operated on ocean-going vessels in transit and at berth impact the air quality of populated areas near ports. This paper presents new information on the comparison of emission ranges from three similar engines and the effectiveness of three control technologies: switching to cleaner burning fuels, operating in the low oxides of nitrogen (NOx) mode, and selective catalytic reduction (SCR). In-use measurements of gaseous (NOx, carbon monoxide [CO], carbon dioxide [CO2]) and fine particulate matter (PM2.5; total and speciated) emissions were made on three auxiliary engines on post-PanaMax class container vessels following the International Organization for Standardization 8178-1 protocol. The in-use NOx emissions for the MAN B&W 7L32/40 engine family vary from 15 to 21.1 g/kW-hr for heavy fuel oil and 8.9 to 19.6 g/kW-hr for marine distillate oil. Use of cleaner burning fuels resulted in NOx reductions ranging from 7 to 41% across different engines and a PM2.5 reduction of up to 83%. The NOx reductions are a consequence of fuel nitrogen content and engine operation; the PM2.5 reduction is attributed to the large reductions in the hydrated sulfate and organic carbon (OC) fractions. As expected, operating in the low-NOx mode reduced NOx emissions by approximately 32% and nearly doubled elemental carbon (EC) emissions. However, PM2.5 emission factors were nearly unchanged because the EC emission factor is only approximately 5% of the total PM2.5 mass. SCR reduced the NOx emission factor to less than 2.4 g/kW-hr, but it increased the PM2.5 emissions by a factor of 1.5-3.8. This increase was a direct consequence of the conversion of sulfur dioxide to sulfate emissions on the SCR catalyst. The EC and OC fractions of PM2.5 reduced across the SCR unit. PMID- 21305885 TI - Remote sensing-based estimates of annual and seasonal emissions from crop residue burning in the contiguous United States. AB - Crop residue burning is an extensive agricultural practice in the contiguous United States (CONUS). This analysis presents the results of a remote sensing based study of crop residue burning emissions in the CONUS for the time period 2003-2007 for the atmospheric species of carbon dioxide (CO2), methane (CH4), carbon monoxide (CO), nitrogen dioxide (NO2, sulfur dioxide (SO2), PM2.5 (particulate matter [PM] < or = 2.5 microm in aerodynamic diameter), and PM10 (PM < or = 10 microm in aerodynamic diameter). Cropland burned area and associated crop types were derived from Moderate Resolution Imaging Spectroradiometer (MODIS) products. Emission factors, fuel load, and combustion completeness estimates were derived from the scientific literature, governmental reports, and expert knowledge. Emissions were calculated using the bottom-up approach in which emissions are the product of burned area, fuel load, and combustion completeness for each specific crop type. On average, annual crop residue burning in the CONUS emitted 6.1 Tg of CO2, 8.9 Gg of CH4, 232.4 Gg of CO, 10.6 Gg of NO2, 4.4 Gg of SO2, 20.9 Gg of PM2.5, and 28.5 Gg of PM10. These emissions remained fairly consistent, with an average interannual variability of crop residue burning emissions of +/- 10%. The states with the highest emissions were Arkansas, California, Florida, Idaho, Texas, and Washington. Most emissions were clustered in the southeastern United States, the Great Plains, and the Pacific Northwest. Air quality and carbon emissions were concentrated in the spring, summer, and fall, with an exception because of winter harvesting of sugarcane in Florida, Louisiana, and Texas. Sugarcane, wheat, and rice residues accounted for approximately 70% of all crop residue burning and associated emissions. Estimates of CO and CH4 from agricultural waste burning by the U.S. Environmental Protection Agency were 73 and 78% higher than the CO and CH4 emission estimates from this analysis, respectively. This analysis also showed that crop residue burning emissions are a minor source of CH4 emissions (< 1%) compared with the CH4 emissions from other agricultural sources, specifically enteric fermentation, manure management, and rice cultivation. PMID- 21305886 TI - A study on dynamic volatile organic compound emission characterization of water based paints. AB - Volatile organic compounds (VOCs) emitted from surface coatings have caused growing public concern for air quality. Even the low-emitted VOC impact from water-based paints on indoor air quality in urban areas has caused concern. This paper presents experimental data using a mathematical model to simulate dynamic VOC emissions from water-based paints that is based on mass transfer and molecular diffusion theories. A series of field-analogous experiments were carried out to continuously measure the VOCs emitted from two typical water-based paints using a gas chromatography-flame-ionization detector monitor in an artificial wind tunnel system. In the study cases, the mass flux of VOCs emitted from the water-based paints was up to 50 microg/m2sec. It was found that the time needed to completely emit VOCs from water-based paints is just hundreds of seconds. However, the order of magnitude of the VOC emission rate from water based paints is not lower than that from some dry building materials and solvent based paints. The experimental data were used to produce a useful semiempirical correlation to estimate the VOC emission rates for water-based paints. This correlation is valid under appropriate conditions as suggested by this work with a statistical deviation of +/- 7.6%. With this correlation, it seems feasible to predict the dynamic emission rates for VOCs during a painting process. This correlation is applicable for assessing the hazardous air pollutant impact on indoor air quality or for environmental risk assessment. Associated with the dynamic VOC emission characterization, the air-exchange rate effect on the VOC emission rates is also discussed. PMID- 21305887 TI - Estimation of the respiratory ventilation rate of preschool children in daily life using accelerometers. AB - Inhalation rate is an essential factor for determining the inhaled dose of air pollutants. Here, accelerometers were used to develop regression equations for predicting the minute ventilation rate (V(E)) to estimate the daily inhalation rate in young children. Body acceleration and heart rate were measured in 29 Japanese preschool children (6 yr of age) during nine different levels of activities (lying down, sitting, standing, playing with plastic bricks, walking, building with blocks, climbing stairs, ball tossing, and running) using the Actical omnidirectional accelerometer, the ActivTracer triaxial accelerometer, and a heart rate monitor. Measurements were calibrated against the V(E) measured by the Douglas bag method. ActivTracer accelerometer measurements gave a strong correlation with V(E) (Pearson's r = 0.913), which was marginally stronger than that for the Actical counts (r = 0.886) and comparable to the correlation between heart rate and logarithmic V(E) (r = 0.909). According to the linear regression equation, the V(E) for lying down, sitting, standing, playing with plastic bricks, walking, and running was overestimated by 14-60% by the Actical and by 14 37% by the ActivTracer. By comparison, for building with blocks, climbing stairs, and ball tossing, the V(E) was underestimated by 19-23% by the Actical and by 13 18% by the ActivTracer. When these three activities were excluded, a stronger correlation was found between the V(E) and ActivTracer measurements (r = 0.949); this correlation was 0.761 for the three excluded activities. Discriminant analysis showed that the ratio between vertical and horizontal acceleration obtained by the ActivTracer could discriminate walking from building with blocks, climbing stairs, and ball tossing with a sensitivity of 75%. The error in estimating V(E) was considerably improved for the ActivTracer measurements by the use of two regression equations developed for each type of activity. PMID- 21305888 TI - A model for the implementation of a two-shift municipal solid waste and recyclable material collection plan that offers greater convenience to residents. AB - Separating recyclables from municipal solid waste (MSW) before collection reduces not only the quantity of MSW that needs to be treated but also the depletion of resources. However, the participation of residents is essential for a successful recycling program, and the level of participation usually depends on the degree of convenience associated with accessing recycling collection points. The residential accessing convenience (RAC) of a collection plan is determined by the proximity of its collection points to all residents and its temporal flexibility in response to resident requirements. The degree of proximity to all residents is determined by using a coverage radius that represents the maximum distance residents need to travel to access a recycling point. The temporal flexibility is assessed by the availability of proximal recycling points at times suitable to the lifestyles of all residents concerned. In Taiwan, the MSW collection is implemented at fixed locations and at fixed times. Residents must deposit their garbage directly into the collection vehicle. To facilitate the assignment of collection vehicles and to encourage residents to thoroughly separate their recyclables, in Taiwan MSW and recyclable materials are usually collected at the same time by different vehicles. A heuristic procedure including an integer programming (IP) model and ant colony optimization (ACO) is explored in this study to determine an efficient two-shift collection plan that takes into account RAC factors. The IP model has been developed to determine convenient collection points in each shift on the basis of proximity, and then the ACO algorithm is applied to determine the most effective routing plan of each shift. With the use of a case study involving a city in Taiwan, this study has demonstrated that collection plans generated using the above procedure are superior to current collection plans on the basis of proximity and total collection distance. PMID- 21305889 TI - Emission reductions from woody biomass waste for energy as an alternative to open burning. AB - Woody biomass waste is generated throughout California from forest management, hazardous fuel reduction, and agricultural operations. Open pile burning in the vicinity of generation is frequently the only economic disposal option. A framework is developed to quantify air emissions reductions for projects that alternatively utilize biomass waste as fuel for energy production. A demonstration project was conducted involving the grinding and 97-km one-way transport of 6096 bone-dry metric tons (BDT) of mixed conifer forest slash in the Sierra Nevada foothills for use as fuel in a biomass power cogeneration facility. Compared with the traditional open pile burning method of disposal for the forest harvest slash, utilization of the slash for fuel reduced particulate matter (PM) emissions by 98% (6 kg PM/BDT biomass), nitrogen oxides (NOx) by 54% (1.6 kg NOx/BDT), nonmethane volatile organics (NMOCs) by 99% (4.7 kg NMOCs/BDT), carbon monoxide (CO) by 97% (58 kg CO/BDT), and carbon dioxide equivalents (CO2e) by 17% (0.38 t CO2e/BDT). Emission contributions from biomass processing and transport operations are negligible. CO2e benefits are dependent on the emission characteristics of the displaced marginal electricity supply. Monetization of emissions reductions will assist with fuel sourcing activities and the conduct of biomass energy projects. PMID- 21305890 TI - Spatial heterogeneity of PM10 and O3 in Sao Paulo, Brazil, and implications for human health studies. AB - Developing exposure estimates is a challenging aspect of investigating the health effects of air pollution. Pollutant levels recorded at centrally located ambient air quality monitors in a community are commonly used as proxies for population exposures. However, if ample intraurban spatial variation in pollutants exists, city-wide averages of concentrations may introduce exposure misclassification. We assessed spatial heterogeneity of particulate matter with an aerodynamic diameter < or = 10 microm (PM10) and ozone (O3) and evaluated implications for epidemiological studies in Sao Paulo, Brazil, using daily (24-hr) and daytime (12 hr) averages and 1-hr daily maximums of pollutant levels recorded at the regulatory monitoring network. Monitor locations were also analyzed with respect to a socioeconomic status index developed by the municipal government. Hourly PM10 and O3 data for the Sao Paulo Municipality and Metropolitan Region (1999 2006) were used to evaluate heterogeneity by comparing distance between monitors with pollutants' correlations and coefficients of divergence (CODs). Both pollutants showed high correlations across monitoring sites (median = 0.8 for daily averages). CODs across sites averaged 0.20. Distance was a good predictor of CODs for PM10 (p < 0.01) but not O3, whereas distance was a good predictor of correlations for O3 (p < 0.01) but not PM10. High COD values and low temporal correlation indicate a spatially heterogeneous distribution of PM10. Ozone levels were highly correlated (r > or = 0.75), but high CODs suggest that averaging over O3 levels may obscure important spatial variations. Of municipal districts in the highest of five socioeconomic groups, 40% have > or = 1 monitor, whereas districts in the lowest two groups, representing half the population, have no monitors. Results suggest that there is a potential for exposure misclassification based on the available monitoring network and that spatial heterogeneity depends on pollutant metric (e.g., daily average vs. daily 1-hr maximum). A denser monitoring network or alternative exposure methods may be needed for epidemiological research. Findings demonstrate the importance of considering spatial heterogeneity and differential exposure misclassification by subpopulation. PMID- 21305891 TI - Stabilization of residues obtained from the treatment of laboratory waste: Part 2 -transformation of plasma vitrified slag into composites. AB - The Sustainable Environment Research Center of National Cheng Kung University in Taiwan has set up a treatment plant to dispose of laboratory waste. In the treatment process, the residue from the incineration system and the physical and chemical system is vitrified by a plasma melting system. Part 1 of this study described the treatment path of metals during vitrification. In Part 2, plasma vitrified slag is reused by using a molding technology. Unsaturated polyester resin and glass fiber were used as the molding material and additive, respectively, in the molding process. With an appropriate mixing ratio of unsaturated polyester resin, glass fiber, and slag, the physical properties of composites improved, and the ultimate tensile strength reached 17.6 MPa. However, an excess amount of slag reduced the strength and even retarded the production of composites. Differential thermal analysis and the water bathing test results show that the composite decomposed at 80 degrees C and that it vaporized at 187 degrees C. Although the unsaturated polyester resin decomposed, the metal encapsulated in the slag did not leach out. The results show that the reuse of slag using molding technology should be taken into consideration. PMID- 21305892 TI - Application of reutilization technology to calcium fluoride sludge from semiconductor manufacturers. AB - Glass ceramics were prepared from mixtures of wastes generated from refining of waste glass and semiconductor industrial wastewater sludge. The aim is then indeed to study the possible use and effects of integrating calcium fluoride (CaF2) as present in semiconductor wastewater sludge in the silica (glass) melts. CaF2 sludge was blended with a conditioner according to characteristics of the target. Calcium oxide-silicon dioxide-aluminum oxide system glass ceramics have relatively high melting points. Addition of CaF2 sludge to fluxes can significantly reduce the melting point and hence improve the kinetics of the reactions. CaF2 sludge and waste glass were co-melted in various ratios to elucidate their interactions at various heating temperatures. The results indicate that the lowest melting temperature was 1163 degrees C, obtained for the CaF2 sludge-waste glass mixture at a ratio 6:4 (wt:wt), which is significantly lower than that of CaF2 sludge (1378 degrees C). The benefits of using melting to dispose of sludge are the reduction of waste and the fixation of heavy metals. Heat treatment was used to convert the obtained glass into glass ceramics. Heavy metal leaching tests revealed that melting conditions lowered the heavy metal concentrations in the leachate to an order of magnitude lower than that in the sludge. Consequently, industrial sludge can be safely used as a fine aggregate material for a potentially wide range of construction applications. PMID- 21305894 TI - Surgical video systems. Scoping out models from four manufacturers. PMID- 21305893 TI - Impact of biogenic emission uncertainties on the simulated response of ozone and fine particulate matter to anthropogenic emission reductions. AB - The role of emissions of volatile organic compounds and nitric oxide from biogenic sources is becoming increasingly important in regulatory air quality modeling as levels of anthropogenic emissions continue to decrease and stricter health-based air quality standards are being adopted. However, considerable uncertainties still exist in the current estimation methodologies for biogenic emissions. The impact of these uncertainties on ozone and fine particulate matter (PM2.5) levels for the eastern United States was studied, focusing on biogenic emissions estimates from two commonly used biogenic emission models, the Model of Emissions of Gases and Aerosols from Nature (MEGAN) and the Biogenic Emissions Inventory System (BEIS). Photochemical grid modeling simulations were performed for two scenarios: one reflecting present day conditions and the other reflecting a hypothetical future year with reductions in emissions of anthropogenic oxides of nitrogen (NOx). For ozone, the use of MEGAN emissions resulted in a higher ozone response to hypothetical anthropogenic NOx emission reductions compared with BEIS. Applying the current U.S. Environmental Protection Agency guidance on regulatory air quality modeling in conjunction with typical maximum ozone concentrations, the differences in estimated future year ozone design values (DVF) stemming from differences in biogenic emissions estimates were on the order of 4 parts per billion (ppb), corresponding to approximately 5% of the daily maximum 8-hr ozone National Ambient Air Quality Standard (NAAQS) of 75 ppb. For PM2.5, the differences were 0.1-0.25 microg/m3 in the summer total organic mass component of DVFs, corresponding to approximately 1-2% of the value of the annual PM2.5 NAAQS of 15 microg/m3. Spatial variations in the ozone and PM2.5 differences also reveal that the impacts of different biogenic emission estimates on ozone and PM2.5 levels are dependent on ambient levels of anthropogenic emissions. PMID- 21305895 TI - Hospitals should begin removing certain interpower power cords from service. AB - Some power cords manufactured by Interpower Corporation may be susceptible to failure in the healthcare setting, posing a risk of shocks, burns, fires, or device failures. We believe hospitals should remove these cords-which are supplied with equipment from a variety of medical device manufacturers-from service. The removal process should not take place all at once, but should be carried out over time, making sure that the process does not impede patient care. We published a similar report on power cords from Electri-Cord Manufacturing in our December 2009 issue. The problem related to the Interpower cords is the same, and our recommendations are basically identical. PMID- 21305896 TI - CooperSurgical Colpotomizer Koh Cups are being left in patients after uterine surgery. AB - The Koh cup--a component of the CooperSurgical Koh Colpotomizer system, which is used in some surgeries of the uterus-may detach during removal of the system from the patient, presenting the risk that it will be retained in the patient following surgery. Users should confirm that the system is intact when it is removed from the patient. PMID- 21305897 TI - Staff can be injured by sudden drop of GCX VHM wall mounts. AB - Under certain circumstances, variable height mounts (VHMs) manufactured by GCX Corporation-which are used to support physiologic monitors and displays-may unexpectedly drop to the wall mount support arm's lowest position, presenting the risk of staff injury or equipment damage. Hospitals can reduce the likelihood of this hazard by carrying out the company's recommended twice-annual inspection and by leaving the mount's height-locking lever disengaged during routine use. PMID- 21305898 TI - Magnetic resonance systems. A look at the whole field. AB - THE magnetic resonance marketplace can be overwhelming. With the constant stream of new systems and features (and the myriad of vendor-specific names), the task of finding the right system may leave you scratching your head. We'll tell you which capabilities really make a difference, which ones don't, and which products surpass the competition. PMID- 21305899 TI - ECRI Institute offers recommendations on Cardiac Science AED recall. AB - In late 2009, Cardiac Science voluntarily recalled certain automated external defibrillator (AED) models because of rare component failures that could cause the units to fail to deliver therapy. These failures were not being detected by the units' automated self-tests. More recently, the U.S. Food and Drug Administration (FDA) issued recommendations about the recall that differ from those of Cardiac Science. ECRI Institute is presenting its own recommendations to help clarify the situation. PMID- 21305900 TI - Choosing a replacement for your Baxter Colleague pumps. PMID- 21305901 TI - Critical care beds. Providing needed support for ICU patients. AB - Beds for critical care patients are available with a variety of features and functions that aid patient therapy and help caregivers. The three main characteristics on which we rated the beds are the ability to be used with a variety of suppliers' support surfaces, their positioning capabilities, and features that make them easy to use. Find out which beds were rated highest. PMID- 21305902 TI - Getting your signals straight. Comparing radio-frequency ablation and cryoablation for treating cardiac arrhythmias. AB - Radio-frequency ablation has proven to be an effective method for treating cardiac arrhythmias. However, a newer treatment method called cryoablation is becoming increasingly popular. In this article, we discuss the advantages and disadvantages of each. PMID- 21305903 TI - CareFusion Alaris PC and Medley PC Model 8000 may display incorrect total dose in rare cases. AB - The Model 8000 versions of the CareFusion Alaris Point-of-Care (PC) and Medley PC may, in rare cases, display an incorrect total dose value when programmed to deliver a bolus. The manufacturer states that its investigation of the problem is ongoing but recommends that users of affected pumps carefully verify that the bolus dose has been programmed correctly before initiating a delivery. PMID- 21305904 TI - Recent incident reaffirms importance of action plan for gas-related emergencies. AB - Contaminated gas supplies present a risk to clinical staff and patients, with serious and possibly even fatal consequences. Hospitals should have policies in place so that staff can react quickly in the event of gas contamination or other gas-related emergencies. PMID- 21305905 TI - FDA and Baxter announce details of colleague infusion pump recall. PMID- 21305906 TI - Sex, drugs, and cognition: effects of marijuana. AB - Despite the knowledge that many drugs affect men and women differently, few studies exploring the effects of marijuana use on cognition have included women. Findings from both animal and human studies suggest marijuana may have more marked effects in women. This study examined sex differences in the acute effects of marijuana on cognition in 70 (n=35 male, 35 female) occasional users of marijuana. Tasks were chosen to tap a wide variety of cognitive domains affected by sex and/or marijuana including attention, cognitive flexibility, time estimation, and visuospatial processing. As expected, acute marijuana use impaired performance on selective and divided attention, time estimation, and cognitive flexibility. While there did not appear to be sex differences in marijuana's effects on cognition, women requested to discontinue the smoking session more often than men, likely leading to an underestimation of differences. Further study of psychological differences in marijuana's effects on men and women following both acute and residual effects of marijuana is warranted. PMID- 21305907 TI - What did we learn from our study on sober living houses and where do we go from here? AB - Lack of a stable, alcohol- and drug-free living environment can be a serious obstacle to sustained abstinence. Destructive living environments can derail recovery for even highly motivated individuals. Sober living houses (SLHs) are alcohol- and drug-free living environments for individuals attempting to abstain from alcohol and other drugs. They are not licensed or funded by state or local governments and the residents themselves pay for costs. The philosophy of recovery emphasizes 12-Step group attendance and peer support. We studied 300 individuals entering two different types of SLHs over an 18-month period. This article summarizes our published findings documenting resident improvement on measures of alcohol and drug use, employment, arrests, and psychiatric symptoms. Involvement in 12-Step groups and characteristics of the social network were strong predictors of outcome, reaffirming the importance of social and environmental factors in recovery. This article adds to our previous reports by providing a discussion of implications for treatment and criminal justice systems. We also describe the next steps in our research on SLHs, which will include: (1) an attempt to improve outcomes for residents referred from the criminal justice system and (2) a depiction of how attitudes of stakeholder groups create a community context that can facilitate and hinder the legitimacy of SLHs as a recovery modality. PMID- 21305909 TI - Self-esteem and HIV risk practices among young adult ecstasy users. AB - This study examines the role that self-esteem plays in HIV-related risk taking among users of the drug, Ecstasy. The first part of the analysis focuses on the relationship of self-esteem to HIV risk-taking. The second part examines predictors of self-esteem in this population. Conducted between 2002 and 2004, the research is based on a sample of 283 young adult Ecstasy users who completed approximately two-hour-long, face-to-face interviews via computer-assisted structured interviews. Study participants were recruited in the Atlanta, Georgia metropolitan area using targeted sampling and ethnographic mapping. Results indicated that self-esteem is associated with a variety of risky practices, including: the number of sex partners that people had, individuals' likelihood of having multiple sex partners, the number of different illegal drugs people used, and their condom use self-efficacy. The multivariate analysis conducted to ascertain the factors that impact participants' levels of self-esteem yielded six factors: educational attainment (positive), coming from a family-of-origin whose members got along well (positive), the extent of alcohol problems (negative), the number of positive effects experienced as a result of Ecstasy use (positive), the number of negative effects experienced as a result of Ecstasy use (negative), and the extent of experiencing symptoms of post-traumatic stress disorder (negative). PMID- 21305908 TI - Predictors of depressive symptomatology among rural stimulant users. AB - This study examined sociodemographic and drug-related predictors of depressive symptoms among a rural, multistate sample of not-in-treatment stimulant drug users (n=710). Participants were recruited using respondent-driven sampling in Ohio, Arkansas, and Kentucky. The Patient Health Questionnaire (PHQ-9) was used to measure symptoms of depression. Moderate to severe depressive symptomatology was reported by 43.0% of the sample. Cumulative logistic regression analysis showed that daily and nondaily crack use as well as the daily use of cocaine HCl increased the odds of depressive symptoms. Methamphetamine use had no significant association with depression. The daily use of marijuana, the illicit use of tranquilizers, light/moderate cigarette smoking, and injection drug use also increased the risk of depressive symptoms. Living in Kentucky or Ohio (compared to Arkansas), having unstable living arrangements, and being White, female, and older were related to higher odds of depressive symptoms. These results suggest that a host of drug and nondrug factors need to be considered when addressing depressive symptoms in stimulant users. PMID- 21305910 TI - Correlates of heavy drinking behaviors of Latino mothers and their adult daughters. AB - This study explored associations between adult Latina heavy drinking behaviors and potential psychosocial and demographic correlates. It used mother-daughter dyads and a cross-sectional design. Data were drawn from a community-based sample of 158 dyads of adult Latinas (n=316), age 18 years or older, recruited between 2004 and 2006. Bivariate and multivariate statistical methods, including logistic regression and pathway models, were used to analyze data. The study found that protective factors for heavy drinking behaviors for the mother included daughter's social support and mother's age, while for the daughter, they were mother's attachment and daughter's country of birth. Risk factors for daughter's heavy drinking behaviors were mother's social support and daughter's education. For both mother and daughter, chronic stress and drinking behavior associations were mediated by attachment and social support. Preventive interventions should target increasing levels of mother-daughter attachment and daughter's social support while decreasing stress levels for mothers and daughters. PMID- 21305911 TI - Association between psychopathology and substance use among school-going adolescents in Cape Town, South Africa. AB - Limited information exists regarding the association between psychopathology and specific substance use in young people both globally and locally. We examined the association between psychopathology and substance use in high school students to determine the nature of the associations and the role of demographic factors in these associations. Grade 8 (N=480) and Grade 11 (N=459) students from 39 high schools in Cape Town, South Africa, completed a self-administered questionnaire. Psychopathology information was obtained from total scores on the Harvard Trauma Questionnaire, Beck Depression Inventory and the Zung Self-Rating Anxiety Scale. Lifetime prevalence rates were calculated for tobacco, alcohol, cannabis and inhalant use. Associations between psychopathology and substance use were determined using regression analyses and structural equation modeling. On adjusting for demographic characteristics, significant associations were found between PTSD and all substance use, between depression, alcohol, cannabis and inhalant use, and between anxiety and cannabis use. The associations of PTSD and depression with alcohol and cannabis use, and between anxiety and cannabis use, were moderated by grade. Although psychopathology and substance use were associated with each other, these associations occurred in accordance with substance and grade. Roles for gender, age and ethnicity emerged in the associations, but further investigation is recommended to examine these. PMID- 21305912 TI - Evolutionary and anthropological approaches towards understanding human need for psychotropic and mood altering substances. AB - Human addiction to psychotropic and mood altering substances is an ongoing international problem. While the phenomenon of psychoactive drug use has received considerable theoretical attention there need to be more comparative approaches into this area. Evolutionary and anthropological approaches for understanding human need for psychotropic and mood altering substances offer the reader various insightful angles for analyzing this phenomenon. While evolutionary approaches investigate the evolutionary behaviors and mechanisms of human ancestral psychotropic use, anthropological approaches emphasize the social and religious meanings of individual drug use. While each approach proffers different ideas, a comparative approach, which is utilized in this study, may provide a novel and invaluable insight for understanding human need for psychotropic and mood altering substances. PMID- 21305913 TI - Strange fires, weird smokes and psychoactive combustibles: entheogens and incense in ancient traditions. AB - This paper seeks to emphasize what may be the most primary mode of altering consciousness in the ancient world: namely, the burning of substances for inhalation in enclosed areas. While there is abundant literature on archaic uses of entheogenic plants, the literature on psychoactive incenses is quite deficient. From the tents of nomadic tribes to the small meditation rooms of Taoist adepts, the smoldering fumes of plants and resins have been used to invoke and banish and for shamanic travels since humanity mastered fire. The text provides details of primary "incense cults" while highlighting some commonalities and shared influences when possible. Further speculation suggests that selective burning of certain substances, such as mercury and sulphur, may have contributed to their lasting use and veneration in alchemy from India and China to the Arabian and European protochemists. This article would have a companion online database for images and further examples of ingredients in various incenses from China to ancient Greece. PMID- 21305914 TI - Revisiting Wasson's Soma: exploring the effects of preparation on the chemistry of Amanita muscaria. AB - In 1968 R. Gordon Wasson first proposed his groundbreaking theory identifying Soma, the hallucinogenic sacrament of the Vedas, as the Amanita muscaria mushroom. While Wasson's theory has garnered acclaim, it is not without its faults. One omission in Wasson's theory is his failure to explain how pressing and filtering Soma, as described in the Rig Veda, supports his theory of Soma's identity. Several critics have reasoned that such preparation should be unnecessary if equivalent results can be obtained by consuming the raw plant, as is done with other psychoactive mushrooms. In order to address these specific criticisms over 600 anecdotal accounts of Amanita muscaria inebriation were collected and analyzed to determine the impact of preparation on Amanita muscaria's effects. The findings of this study demonstrated that the effects of Amanita muscaria were related to the type of preparation employed, and that its toxic effects were considerably reduced by preparations that paralleled those described for Soma in the Rig Veda. While unlikely to end debate over the identity of Soma, this study's findings help to solidify the foundation of Wasson's theory, and also to demonstrate the importance of preparation in understanding and uncovering the true identity of Soma. PMID- 21305915 TI - Datura stramonium intake: a report on three cases. AB - This article describes three cases of Datura stramonium intake on two nonconsecutive days. In the first case, the patient took a small amount of D. stramonium seeds without showing any symptoms of intoxication. The other two patients had taken a considerable amount of seeds and reported a sudden surge in strength and energy, with some aggressive compulsion towards their peers. They showed delirium as well as confusion and disorientation. The absence of any specific legislation makes D. stramonium a tempting alternative to other psychoactive substances. Thus, it is extremely important to be able to recognize its symptoms so as to be able to diagnose any signs of intoxication properly. PMID- 21305916 TI - Correction and clarification of an error in an article that I wrote (with Michael Winkelman) called "Maria Sabina, wise lady of the mushrooms". PMID- 21305917 TI - The rhinoplasties: foreword. PMID- 21305918 TI - Rhinomanometry and acoustic rhinometry in rhinoplasty. AB - Acoustic rhinometry (AR) and rhinomanometry (RMM) study two different parameters of nasal ventilation: respiratory function and the anatomy of nasal cavities. This article looks at their usefulness, in particular in the surgical field. We list the normal values for these tests. Nasal obstruction is a symptom of multifactorial origin. Nasal patency is only one factor influencing the sensation of nasal ventilation. Despite the range of divergent opinions in both the literature and among rhinological clinicians, the objective assessment of nasal patency in functional rhinoplasty or septorhinoplasty seems to be advisable. The roles of AR and RMM still have to be established. PMID- 21305919 TI - Morphing in rhinoplasty: predictive accuracy and reasons for use. AB - A critical step in successful surgery is the precise definition of the surgical goals by both the patient and the surgeon. Much of the discussion between the surgeon and the patient is about managing expectations. Today's technology provides an easy way of forecasting the result of a rhinoplasty procedure, as long as surgeons themselves do the morphing. In a retrospective study of 133 rhinoplasty patients, we analysed the correlation between pre-operative morphing and surgical results. The match was good (identical or similar) in 85.7% of patients (n = 114), approximate in 11.3% of patients (n = 15), and poor in 3% (n = 4). There was a significant correlation with an increased need for adjunctive procedures or revision surgery when the match was approximate or poor. The approach also proved useful for careful pre-operative planning by the surgeon, requiring detailed facial analysis and the establishment of precise goals before surgery. Overly optimistic morphing is not recommended given the risk of raising false expectations. PMID- 21305920 TI - Rhinoplasty: why do I not use morphing? AB - Recent years have seen the emergence of software for pre-operative morphing in rhinoplasty. However, a number of issues persist, such as price, time investment, limited number of modifiable variables, reduction of complexity, false expectations, informed consent, medico-legal implications and classical ENT practice. The use of preoperative morphing cannot be recommended yet. PMID- 21305921 TI - Why do I favour the endonasal approach? AB - The endonasal approach to rhinoplasty can deal adequately with the vast majority of nasal problems that present to the facial plastic surgeon. Adequate training of surgeons can overcome the rigid dichotomy of "endonasal" versus "external" approaches and pave the way for a combination of the best of both worlds towards the concept of hybrid rhinoplasty. PMID- 21305922 TI - Why do we prefer the external approach? AB - Open structure rhinoplasty (OSR) is an old technique that has gained in popularity amongst plastic surgeons and otolaryngologists over the past twenty years. Opponents of the external approach cite potential problems such as unnecessary scaring, reduction of tip support, extended operative time and excessive post-operative tip swelling. However, even relatively inexperienced rhinoplastic surgeons embrace this approach, especially in cases with more complex tip deformities and skeletal abnormalities. Concerns about scarring and post-operative tissue reaction due to the more "aggressive" external approach make it necessary to consider the indications for the open approach carefully. Various incisions have been described for open rhinoplasty to reduce scarring, such as the Z, V, reverse V, and W incisions. There should be a strong emphasis on post-operative care in open approach rhinoplasty since open structure rhinoplasty is generally considered to be a more traumatic technique than the endonasal approach. Careful incision and dissection of the skin flap in the right surgical plane and proper suturing are essential to avoid short- and long-term complications. In conclusion, the external approach is preferable in selected cases where extended exposure (asymmetry cases, for example), per-operative assessment (revision cases), grafting and suturing are required. It allows the surgeon to work bimanually during reconstruction and the better per-operative evaluation reduces the revision rate. PMID- 21305923 TI - A review of nasal dorsal hump reduction techniques, with a particular emphasis on a comparison of component and composite removal. AB - Nasal dorsal hump reduction is a frequently performed and basic step in non functional rhinoplasty. The literature has described multiple techniques for nasal hump removal. However, most of the descriptions consider new or modified techniques. No papers have been published comparing any of these different surgical interventions. The aim of this paper is to review several techniques in common use, looking at their inherent advantages and disadvantages in the light of the authors' personal experiences. Particular attention is devoted to a comparison of component and composite hump reduction. The latest trends in hump removal techniques aim for predictable and realistic results with pleasing aesthetic outcomes based on precise resection techniques and the optimal preservation of nasal anatomy and function. PMID- 21305924 TI - External or internal lateral osteotomy: why I choose the external percutaneous approach. AB - The authors present their surgical experience with the management of patients with dorsum deformities using a precise technique: the external percutaneous approach. The indications for this technique have still not been set out very clearly in the rhinological textbooks or manuals, and so novices (and not only novices) have difficulty in understanding and applying it. We therefore try to systematise and clarify these indications in brief, together with the technical details, providing a comparison with another technique that is in very widespread use at present: the internal lateral osteotomy. Although the external percutaneous approach is not used very often--in our experience in 30% of cases only--we find the results very satisfactory and we recommend it when it is required by the anatomic conditions. PMID- 21305925 TI - Why do I continue to perform vestibular osteotomies? AB - The rhinoplasty surgeon can choose from different osteotomy techniques. Historically, when changing the bony contour of the nasal pyramid, more attention has been devoted to refining approach to osteotomy techniques and adapting the instruments used. The importance of less damage to the soft tissues led rhinology surgeons to develop more refined osteotomy instruments. The author gives an overview of historical developments leading to our current array of techniques for addressing specific demands about aesthetic and functional outcome. A brief outline is given of the advantages, drawbacks and pitfalls of different osteotomy techniques. PMID- 21305926 TI - Which techniques are relevant in the surgical management of the nasal tip? AB - In this article, we give an overview of safe and consistent techniques for nasal tip surgery. A change in the morphology of the tip has an impact on the profile of the face. A knowledge of facial proportions is therefore important when performing rhinoplastic surgery. We prefer an external approach because it provides the best overview and because the possibility of bimanual working makes manipulation of the lower lateral cartilages easier. The techniques described here can be used to alter the nasal tip in a controllable way. PMID- 21305927 TI - My surgery of the nasal valve. AB - We discuss the physiopathology and relevant anatomy of the nasal valves--internal and external--paying particular attention to the dynamics of the airflows in this area. We describe and comment on methods for medical examination, anterior rhinoscopy, endoscopy and fibrescopy of the valve, as well as the causes and sites of nasal valve dysfunction. We propose a review of the various treatments, medical and surgical, with a special emphasis on nasal valve surgery. Surgical techniques commonly used by the authors in daily practice for nasal valvuloplasty (such as spreader grafts and Z-plasty of the nostrils) are discussed and illustrated in depth. Some one-year postoperative results are presented and discussed. PMID- 21305928 TI - The judicious use of grafts in endonasal septorhinoplasty. AB - The use of grafts in rhinoplasty has increased exponentially over the past three decades, specially after the advent of the external approach to the nasal dorsum. The same results can be achieved with the endonasal approach, with judicious use of a small number of grafts, and still maintain the structural integrity of the nose. PMID- 21305929 TI - The use of grafting material in rhinoseptoplasty. AB - Grafting is one of the current range of instruments that rhinoplasticians deploy to achieve durable and desired aesthetic and functional outcomes. Grafts can be classified according to anatomical site and, in the vast majority of cases, they involve augmentation rhinoseptoplasty. Visible grafting material is used for aesthetic purposes and functional grafting may involve invisible grafts. This article reviews the more widely described and more common indications for grafts in rhinoseptoplasty. The authors' rhinoseptoplasty philosophy involves a preference for autogenous grafts rather than alloplastic implants to achieve both aesthetically and functionally favourable results, particularly in long-term follow-up. They also prefer grafts in an open approach, reserving graft insertion with an endonasal approach for selected cases. The rate of complications associated with grafting is very low. The aim of this paper is to discuss the relevant anatomy, functional purpose and terminology, and to describe the authors' philosophy for grafting in rhinoseptoplasty. PMID- 21305930 TI - Unique approach to secondary cleft-lip rhinoplasty in facial plastic surgery. AB - Rhinoplasty occupies a unique position in facial plastic surgery due to the central position of the nose in the face and the vital functions of the nose. Among facial plastic surgeons, secondary rhinoplasty in adult cleft-lip patients is considered to be one of the most challenging surgical interventions due to the congenital distortion of the cartilaginous and bony nasal pyramid, with consequences for both nasal aesthetics and breathing. In spite of the challenging nature of the procedure, post-operative satisfaction is high, matching that of non-cleft-lip patients, as long as appropriate surgical techniques are applied. Specific rhinoplasty methods are used in unilateral or bilateral cleft-lip patients with extensive grafting, combined efforts for aligning the nasal dorsum and the creation of symmetry in the nasal tip, medialisation of the anterior nasal spine with augmentation of the premaxilla, correction of nasal vestibulum stenosis and specific post-operative care with a nasal vestibulum device. This review aims to address some specific surgical issues relating to cleft-lip rhinoplasty, resulting in the high subjective satisfaction rate reported by cleft patients operated upon in the University Hospitals Leuven. PMID- 21305931 TI - Rhinoplasty outcome measurement. AB - The literature includes few publications dealing with the measurement of rhinoplasty outcomes. We also lack reliable instruments for such measurements. In a population of 228 patients who underwent rhinoplasty performed by the same surgeon, we evaluated patient satisfaction using Alsarraf's questionnaire and an evaluation of cosmetic improvement using standardised pre- and post-operative photographs (Photograph Score from 1- great to 7- monstrous). We correlated these data with the severity of the pre-operative nasal deformities, (Predictable Difficulty Score) with the complexity of the surgical procedure, (Surgical Complexity Score) and with four specific surgical procedures (Spreader Grafting, Domal Interruption, Grafting of the Dorsum, Tip Grafting). Both Alsarraf's questionnaire and the photograph score identified a significant difference between the pre-operative and post-operative data and appear to be reliable instruments for measuring patient satisfaction. The questionnaire takes into account the functional outcome that the PS did not. In our hands, the mean improvement evaluated by the questionnaire was 50.2%, and 2.8 according to the PS, regardless of primary or revision surgery, traumatic or non-traumatic nose, mixed cosmetic/functional or purely cosmetic goals. The relative size of the difference between the pre- and post-operative scores was linked more to the satisfaction of the patient than to the absolute post-operative level. These two instruments (the questionnaire and the photograph score), although they are in agreement, did not allow for the establishment of any correlation between the satisfaction of the patient and the predicted difficulty score (PDS), the surgical complexity score (SCS), or three of the four specific procedures that were considered (SG, DI, GD and TG). Domal interruption was the only procedure in which we found that patient satisfaction was higher than with the other procedures (65.6% for the questionnaire and 3.8 for the photograph score). PMID- 21305932 TI - Consensus in rhinoplasty. AB - Reading textbooks or manuals about rhinoplasty techniques, the novice may be disconcerted by the multitude of different surgical manoeuvres, all intended to achieve the same result: a cosmetically appealing and functional nose. This article describes a survey of 30 rhinoplasticians that investigated, using a questionnaire with 51 items, current opinion and practice in rhinoplasty with the aim of identifying areas of consensus or disagreement. Only 16 questions in 51 (31%) identified a strong consensus, mainly in the areas of informed consent, lateral osteotomies, and the accuracy and predictability of some graft procedures (columellar strut, spreader graft). There was also a consensus about the rejection of some unusual procedures (electric-powered rasping of the dorsum, allopathic implants). However, no consensus was found in many domains, such as tip or columella management, resection of the dome, dome sutures, alar batten grafts, dorsal graft, nasal packing, pre-operative functional investigations, morphing, alar base reduction or the management of septal perforation. Our survey found a dramatic lack of agreement about rhinoplastic procedures, which remain highly dependent on the skill and experience of surgeons who favour the techniques with which they have achieved good results in the past. It also identifies a case for adopting, as in other fields of medicine, guidelines based upon consensual expert opinion and the evaluation of outcomes with appropriate and validated instruments. PMID- 21305933 TI - The rhinoplasties: conclusions. PMID- 21305934 TI - CT radiation dose. Understanding and controlling the risks. PMID- 21305935 TI - Clearing the air. Ensuring proper oxygen concentration delivery from medical gas systems. PMID- 21305936 TI - Arthrex AR-6400 and AR-6475 arthroscopy pumps can deliver excessive pressure without alerting user. AB - Under certain conditions, Arthrex AR-6400 and AR-6475 arthroscopic irrigation/distention pumps can create pressures within the patient's joint that are more than twice the desired pressure without alerting the clinician, increasing the potential for serious patient injury due to extracapsular solution infiltration. Facilities need to thoroughly understand the behavior of these pumps and determine whether the clinical benefits of using them outweigh the solution-infiltration concerns. If your facility is not comfortable with the behavior of these pumps, use an alternative pump. PMID- 21305937 TI - Smiths Medical Medfusion 3010a syringe pump may overinfuse if software is outdated. AB - Smiths Medical Medfusion 3010a syringe pumps that aren't equipped with the latest software version (2.0.6) could overinfuse if the "recall last settings" function is used following an infusion in volume/time mode. If your facility has pumps equipped with software versions older than 2.0.6, contact Smiths Medical to obtain an upgrade. PMID- 21305938 TI - Alarm-notification problem spotlighted in Boston globe is all too common. PMID- 21305939 TI - Real-time locating systems. A focus on tags and platform components. PMID- 21305940 TI - Parks Medical Flo-Lab 2100-SX may interpret IR emissions from CenTrak RTLS as user commands. AB - The Parks Medical Flo-Lab 2100-SX vascular laboratory system may react to infrared (IR) emissions from the CenTrak real-time locating system (RTLS) as if they were remote-control commands, causing the Flo-Lab to operate without user action. Parks Medical plans to offer a redesigned remote control to eliminate susceptibility of its product to IR interference. In addition, CenTrak has designed an assessment tool that will help identify devices that may be vulnerable to IR interference from its RTLS. PMID- 21305941 TI - User experience network. Medical gas quick-connects may spontaneously detach. AB - "Quick-connect" medical gas connectors may occasionally fail and spontaneously detach from medical gas outlets. Minor injuries are possible, though unlikely. ECRI Institute believes this problem may occur with devices from any supplier and that the best solution is to ensure that they are assessed frequently and removed at the first sign of problems. PMID- 21305942 TI - Certificate of medical necessity, required for continued use of Baxter Colleague infusion pumps, is now available. PMID- 21305943 TI - The mentee as mentor. PMID- 21305944 TI - Hospital lobbyists are working overtime to secure a flow of nurses that do not require the expensive training that domestically trained nurses need. PMID- 21305945 TI - Clover McClennon: using heart, hands and skill to make a difference. Interview by Amy Funk. PMID- 21305946 TI - Mentorship: indirect and direct mentors. PMID- 21305947 TI - Breakthrough to nursing. Interview by Reneka Turner. PMID- 21305948 TI - Mentoring values: lighting the way. PMID- 21305949 TI - Embracing mentors and facing tormentors. PMID- 21305950 TI - Florence Nightingale: the legend continues. PMID- 21305951 TI - Towards a better approach to medical humanitarian assistance in Iraq and future counterinsurgency operations. PMID- 21305952 TI - Tactical evacuation: extending critical care on rotary wing platforms to forward surgical facilities. PMID- 21305953 TI - Role of hardiness in the psychological well-being of Canadian Forces officer candidates. AB - Previous research has found that hardiness is associated with greater psychological well-being and lower levels of stress. This study examined the role of hardiness in the psychological well-being of military officer candidates undergoing basic training. Although most researchers have conceptualized hardiness as a global psychological construct, it is possible that military specific hardiness, which pertains specifically to work experiences in the military environment, may be a more relevant measure. The role of both general and military-specific hardiness in life satisfaction, health symptoms, training satisfaction, and training stress was examined. The results of this study were consistent with those of previous research, suggesting that military-specific hardiness is an important predictor of psychological well-being of military personnel. Furthermore, military-specific hardiness served as a better predictor of the psychological well-being of military personnel than general hardiness. The implications of the findings and future research suggestions are discussed. PMID- 21305954 TI - Exploring pre-enlistment and military factors associated with the morale of members of the UK Armed Forces. AB - There is a paucity of evidence to show the importance of morale within military units. The aim of this study was to explore how pre-enlistment and postenlistment factors influence morale and to ascertain which has the greater contribution. A cross-sectional study of the UK military involved in operations to Iraq was conducted between 2004 and 2006. The sample was randomly selected and was representative of the UK Armed Forces. Data were collected via questionnaires and included measures on unit cohesion and leadership, childhood adversity, and current service factors (e.g., whether individuals deployed as individuals or within formed units). Although childhood adversity was found to affect self reported morale, current service factors were found to have a greater influence. PMID- 21305955 TI - Families overcoming under stress: implementing family-centered prevention for military families facing wartime deployments and combat operational stress. AB - The toll of multiple and prolonged deployments on families has become clearer in recent years as military families have seen an increase in childhood anxiety, parental psychological distress, and marital discord. Families overcoming under stress (FOCUS), a family-centered evidence-informed resiliency training program developed at University of California, Los Angeles and Harvard Medical School, is being implemented at military installations through an initiative from Navy Bureau of Medicine and Surgery. The research foundation for FOCUS includes evidence-based preventive interventions that were adapted to meet the specific needs of military families facing combat operational stress associated with wartime deployments. Using a family narrative approach, FOCUS includes a customized approach utilizing core intervention components, including psychoeducation, emotional regulation skills, goal setting and problem solving skills, traumatic stress reminder management techniques, and family communication skills. The purpose of this study is to describe the development and implementation of FOCUS for military families. A case example is also presented. PMID- 21305956 TI - Determinants of health-promoting behaviors in military spouses during deployment separation. AB - The purpose of this research was to describe predictors of participation in health-promoting behaviors among military spouses. A total of 105 female spouses of currently deployed active duty military members were surveyed to determine their perceived stress and participation in the health-promoting behaviors of exercise, diet, checkups, substance use/avoidance, social behaviors, stress management/rest, and safety/environmental behaviors. Demographic and deployment information was also collected. Regression analyses showed perceived stress was predictive of several health behaviors including exercise, social behaviors, stress management/rest, and safety/environmental behaviors. Increased perceived stress was associated with decreased participation in these behaviors. Deployment factors predicted only dietary behaviors and stress management/rest. As the minimum anticipated length of the deployment increased, healthy dietary behavior decreased. Likewise, as the number of deployments experienced increased, stress management and rest decreased. Stress brought on by military deployment may have detrimental effects upon participation in a health-promoting lifestyle. PMID- 21305957 TI - Less body fat improves physical and physiological performance in army soldiers. AB - The purpose of this study was to compare physical and physiological fitness test performance between Soldiers meeting the Department of Defense (DoD) body fat standard (< or = 18%) and those exceeding the standard (> 18%). Ninety-nine male 101st Airborne (Air Assault) Soldiers were assigned to group 1: < or = 18% body fat (BF) or group 2: > 18% BE. Groups 1 and 2 had similar amounts of fat-free mass (FFM) (66.8 +/- 8.2 vs. 64.6 +/- 8.0, p = 177). Each subject performed a Wingate cycle protocol to test anaerobic power and capacity, an incremental treadmill maximal oxygen uptake test for aerobic capacity, isokinetic tests for knee flexion/extension and shoulder internal/external rotation strength, and the Army Physical Fitness Test. Results showed group 1: < 18% BF performed significantly better on 7 of the 10 fitness tests. In Soldiers with similar amounts of FFM, Soldiers with less body fat had improved aerobic and anaerobic capacity and increased muscular strength. PMID- 21305958 TI - Obesity in the United Kingdom Armed Forces: prevalence based on measured and self reported data. AB - OBJECTIVES: To assess the prevalence of obesity in the United Kingdom military and general population and the extent to which self-reported data underestimates obesity. METHODS: Height and weight data from military personnel (measured data: 2,073 men, 308 women; self-reported data: 6,374 men, 609 women) and from the general population (measured data: 1,121 men, 1,396 women; self-reported data: 1,234 men, 1,543 women). RESULTS: Obesity (defined as having a body mass index of 30+) was 6.2% in those under 25 years old and 24.5% in those over 35 years old in military males, and the prevalence of obesity was 12% in those under 25 years old and 25% in those over 35 years old in military women. Self-reported body mass index underestimated obesity. CONCLUSIONS: Obesity is uncommon in those under 25 years old in the United Kingdom military. The prevalence of obesity based on self reported data underestimates true prevalence. PMID- 21305959 TI - Medical waivers for atopic conditions did not affect attrition among U.S. military academy cadets. AB - BACKGROUND: Atopic conditions account for approximately 35% of medical disqualifications among West Point applicants each year. There are limited outcome data concerning the utility of the atopic disqualification standards in predicting military success. METHODS: Cadets entering the United States Military Academy (USMA) from 2001-2004 were selected as the cohort for this study. They were classified as exposed (medical waiver for an atopic condition) and unexposed (no medical waiver) and followed throughout their enrollment at the USMA. The outcome measures were attrition from school and frequency of clinic visits. RESULTS: After adjusting for gender and age, waiver status was not associated with attrition (OR = 1.02) but was associated with an increased odds of being a high clinic user (OR = 1.37). Time-to-event analysis found an equal risk of attrition between the groups over time (HR = 1.03). CONCLUSION: Relaxing atopic disqualification standards will not increase the drop-out rate from the USMA, but may increase clinic utilization. PMID- 21305960 TI - "March fractures" on a female military recruit. AB - Stress fractures are caused by repetitive low-impact activities. It is important to have a high index of suspicion in diagnosing and treating stress fractures early for remodeling to occur. This is a case report of a 19-year-old female military recruit with stress fractures of the right foot. The patient had an extended non-weight-bearing treatment that eventually had a successful outcome after allowing the fracture to heal by starting the patient on weight-bearing activities and a "walk-to-run" program. Treatment points in managing stress fractures including female-specific issues are also discussed. PMID- 21305961 TI - Trends of stress fracture prevalence among Israel Defense Forces basic trainees. AB - Stress fractures (SFs) are a common type of overuse injury encountered in training soldiers. High rates of SF may cause a tremendous negative effect on the military unit capability to perform its missions. In this study, we reviewed the medical registry of Israel Defense Forces (IDF) soldiers assigned to combat basic training programs between the years 1998 and 2007. SF rates among IDF combat basic trainees were as high as 20% in several companies during the first years of the study. Amendments in training programs were targeted to fit the different capability and the qualifications required from combat soldiers. As a result, a steady decline of SF rates was observed, with a yearly average of 5% in the later years of the study. Increasing awareness of both medical and commanding personnel to SF and their prevention led to the gradual decline in their frequency observed in IDF basic training programs during recent years. PMID- 21305962 TI - Discrepancies in clinical definitions of stress fractures: implications for the United States Army. AB - ABSTRACT In the United States Army initial entry training (IET) environment, stress fractures are common musculoskeletal injuries. Due to the repetitive physical demands placed on soldiers, stress fractures are particularly common in individuals matriculating through basic combat training (BCT) and advanced individual training (AIT). Within the Army medical department, the clinical definitions of stress fractures vary widely among providers who are directly responsible for diagnosing these injuries. The use of diversified definitions of stress fractures in patient evaluations, treatment, communication measures, and injury data collection negatively affect patient dispositions and soldier training outcomes. This report identifies discrepancies in clinical definitions of stress fractures and the implications for the Army regarding the lack of a standardized definition for stress fractures. PMID- 21305963 TI - Operation Enduring Freedom: trends in combat casualty care by forward surgical teams deployed to Afghanistan. AB - This study examined the clinical experience of a U.S. Army Forward Surgical Team (FST) deployed to Afghanistan in 2005 and compared the findings with those of 3 previously deployed FSTs. Medical records of all patients evaluated by the FST were abstracted for analysis. Demographically, the cohort (n = 614) was predominantly male (94%), with a median age of 24, and distributed according to the following: disease (8.6%), nonbattle injury (42%), and battle injury (49%). Combat casualties were mostly Afghan National Army or Police (56%) and U.S. military (21%). Predominant wounding instruments were small arms (34%), improvised explosive devices (33%), and rocket-propelled grenades (15%). Anatomical sites of battle injury were extremities (38%), external soft tissue (35%), and head/neck/torso (28%). Operative procedures for combat injury (n = 227) were primarily orthopedic (45%) or thoracic/abdominal (36%). Combat casualty statistics provide insight to trauma epidemiology, patterns, and trends vital for surgical management. Workload statistics guides the structuring, training, and employment of FSTs. PMID- 21305964 TI - Effects of altitude-related hypoxia on aircrews in aircraft with unpressurized cabins. AB - INTRODUCTION: Generally, hypoxia at less than 10,000 ft (3,048 m) has no apparent effect on aircrews. Nevertheless, several hypoxic incidents have been reported in flights below 10,000 ft. A recently introduced pulse oximeter using finger probes allows accurate monitoring of oxygen saturation (SPO2) in the aeromedical environment. Using such a pulse oximeter, in-flight SPO2 levels were evaluated in aircrew in unpressurized aircraft. In addition, career in-flight hypoxic experiences were surveyed. METHODS: In-flight SPO2 was measured in aircrews operating UH-60J helicopters at up to 13,000 ft, and 338 aircrew members operating unpressurized cabin aircraft were surveyed concerning possible in flight hypoxic experiences. RESULTS: In aircrews operating UH-60J helicopters, SPO2 decreased significantly at altitudes over 5,000 ft, most markedly at 13,000 ft (vs. ground level). The survey identified three aircrew members with experiences suggesting hypoxemia at below 5,000 ft. CONCLUSIONS: Careful attention should be paid to the possibility of hypoxia in aircrews operating unpressurized cabin aircraft. PMID- 21305965 TI - Laboratory evaluation of the SAVe simplified automated resuscitator. AB - OBJECTIVE: To evaluate the SAVe simplified automated ventilator in a laboratory setting to determine performance characteristics, accuracy of tidal volume delivery at various lung compliance, and battery life at sea level and at altitude. METHODS: Three SAVe ventilators were used for the evaluation. Each ventilator was attached to a test lung with volume, pressure, and flow measured with a fixed orifice pneumotachometer and FIO2 measured with a fast-response oxygen analyzer. All measurements were made at sea level, 4,000, 8,000, 12,000, and 18,000 feet. RESULTS: Delivered tidal volume and inspiratory time varied when changing lung model conditions as well as between devices within the same lung model condition. The largest reduction in tidal volume was at the lowest compliance. CONCLUSIONS: The SAVe could potentially be used for ventilatory support of carefully selected military casualties but caregivers must be aware of the limitations. PMID- 21305966 TI - Prevalence of methicillin-resistant staphylococcus aureus in a combat support hospital in Iraq. AB - Methicillin-resistant Staphylococcus aureus (MRSA) in health-care settings results in life-threatening infections. We examined the incidence of MRSA at the combat support hospital located at the Ibn Sina Hospital in Baghdad, Iraq. We compiled isolate data from 2005 to 2009 characterizing antibiotic susceptibilities, annual trends, patient populations, infection sites, and hospital locations. Approximately 46.1% of S. aureus were MRSA, with increase in numbers of yearly isolates. MRSA was isolated in higher numbers from U.S. military personnel. Non-U.S. patient isolates displayed higher antibiotic susceptibility compared to U.S. military personnel isolates. Outpatient clinic, forward operating bases, and intermediate care ward 1 isolated the most MRSA. Common isolation sites were wound and skin cultures. Community-acquired MRSA was likely present in 291 out of 303 isolates based on antibiotic susceptibility. Our data suggests that most MRSA were community-acquired with limited nosocomial spread. We recommend increases in combat support hospital molecular lab capability to rapidly identify both MRSA categories. PMID- 21305967 TI - Lessons learned from casualty statistics in health care system development: Afghanistan 2008-2009. AB - A retrospective study of Afghanistan National Army casualty rates for a 1-year period was completed to assist in health care system assessment and further development during a period of rapid force expansion. Battle and disease nonbattle injuries by Corps area were determined from data on soldier visits from all military health care facilities. The number of fielded forces in each Corps was used to calculate the populations at risk. Total manpower losses from all casualties were tabulated. The 15,336 casualties (175 per thousand fielded soldiers) resulted in the loss of 146,986 duty days (average 9.5 days per casualty). Battle casualties were 739 (8.4 per 1,000) and nonbattle casualties were 14,597(166 per 1,000) with 72% secondary to infectious diseases. Casualty rates from both battle and disease nonbattle injuries were high, but casualty rates were particularly high from infectious diseases. Rapid force expansion in developing countries requires early consideration for resourcing and implementation of preventive medicine programs. PMID- 21305968 TI - Understanding common statistical methods, Part I: descriptive methods, probability, and continuous data. AB - Statistical methods are pervasive in medical research and general medical literature. Understanding general statistical concepts will enhance our ability to critically appraise the current literature and ultimately improve the delivery of patient care. This article intends to provide an overview of the common statistical methods relevant to medicine. PMID- 21305969 TI - PCR for rapid diagnosis of acute Q fever at a combat support hospital in Iraq. AB - Acute Q fever is occasionally seen in U.S. military service members deployed to Iraq. Diagnosis relies on serology, which is not available in the combat zone. Improved diagnostic modalities are needed. We performed a pilot study investigating whether Joint Biological Agent Identification and Diagnostic System (JBAIDS), a ruggedized, deployable polymerase chain reaction (PCR) platform, might be useful in the diagnosis of acute Q fever. Patients presenting to a Combat Support Hospital in Iraq with undifferentiated fever had blood drawn for Q fever PCR and these results were compared with serology. PCR was positive in 6 of 9 patients with acute Q fever by serology and negative in all 9 patients with negative serology. These results suggest that PCR using the JBAIDS platform could be of use in the diagnosis of Q fever in deployed settings. Further research into this modality is warranted. PMID- 21305970 TI - Management of neck pain in Royal Australian Air Force fast jet aircrew. AB - To examine the type and effectiveness of various strategies used by Royal Australian Air Force (RAAF) fast jet (FJ) aircrew in self-referral and management of flight-related neck pain, a 6-section, 18-question survey tool was distributed to 86 eligible RAAF aircrew. Selective results from the sections evaluating aircrew demographics, incidence of flight-related neck pain, and the self referral strategies of aircrew to manage these injuries are presented here. Eighty-two RAAF FJ aircrew responded to the survey. Ninety-five percent of the respondents experienced flight-related neck pain. The most commonly sought treatment modalities were on-base medical and physiotherapy services. Many respondents reported that currently provided on-base treatment and ancillary services such as chiropractic therapy are the most effective in alleviating symptoms. Further investigation into the effectiveness and safety of these ancillary therapies needs to be performed to allow appropriate consideration of their place in the management of neck pain in FJ aircrew. PMID- 21305971 TI - Primary blast injury: an intact tympanic membrane does not indicate the lack of a pulmonary blast injury. AB - The tympanic membrane (TM) has long been viewed as an indicator of primary blast injury. A primary blast injury occurs due overpressure occurring as a result of the detonation of high explosives. Cadaver studies indicated pressure required for perforation of the tympanic membrane to be 137 kPa for adults. The accepted range in which other organs (lung, colon, and intestines) are damaged by the pressure wave emanating from an explosion is in the 400-kPa range. The use of the perforation of the tympanic membrane as an indicator of a primary blast injury missed a range of up to 50% of those suffering a primary blast injury to the lung. The status of the tympanic membrane following exposure to a blast does not preclude the need for further investigations for a primary blast injury and the clinician needs to evaluate the patient dependent on their particular exposure to an explosion. PMID- 21305972 TI - Interdisciplinary approach to the management of an 18-month-old burn victim in Afghanistan. AB - An 18-month-old boy with partial and full thickness burns to his upper face and scalp was treated by an interdisciplinary team at the Role 3 Multinational Medical Unit in Kandahar. A novel approach to his burn management is presented, highlighting some of the issues and constraints that military surgeons are faced with while on operational deployment in a theater of conflict. PMID- 21305973 TI - Possible vicarious contrast excretion causing symptomatic cholelithiasis. AB - A case report of a unique malleable, rubbery, white mass found at cholecystectomy after a diagnosis of symptomatic cholelithiasis. This likely represents either a unique form of a calcium-containing or contrast-containing stone. There are no reported incidents of vicarious contrast stones and calcium-containing stones are reported to be crystalline and hard. PMID- 21305975 TI - Integration --> inclusion --> oblivion. PMID- 21305974 TI - A cluster of septic olecranon bursitis in association with infantry training. AB - Septic olecranon bursitis (OB) is caused primarily by Staphylococcus aureus (SA) usually in association with occupations involving trauma to the elbows. An outbreak of septic OB was identified in an infantry platoon. The severity of the injury to the skin overlying the elbows was scored and compared to a parallel platoon of the same unit. All soldiers were tested for SA carriage and pulse field gel electrophoresis (PFGE) was performed on available isolates. Nine cases of septic OB were identified only in platoon A. The significant risk factor for septic OB was a moderately or severely injured elbow (RR = 3.86). SA was isolated from the anterior nares and elbows of 29/36 (80.6%) of the soldiers in the unit (platoons A + B); however, this did not account for the difference in morbidity between the two platoons. This is the first report of a cluster of septic OB in association with intense infantry training. PMID- 21305976 TI - Teachers' use and perceptions of progress monitoring. AB - Progress monitoring is a set of techniques used to assess students' academic performance on a regular and frequent basis. Different forms of progress monitoring have been used effectively in the field of general special education for more than 20 years. However, to date, limited information about how progress monitoring is being used in the field of deaf education is available. The present study was undertaken to examine how progress monitoring is being used with students who are deaf or hard of hearing and to find out teachers' perceptions about the utilization and value of using progress monitoring. Overall, participants were very positive. They reported that the use of progress monitoring improved students' motivation and helped them better evaluate the effectiveness of their instruction. Participants' primary concern was with the amount of time progress monitoring takes away from teaching. Additional results and recommendations are provided. PMID- 21305977 TI - Codeswitching techniques: evidence-based instructional practices for the ASL/English bilingual classroom. AB - The authors present a perspective on emerging bilingual deaf students who are exposed to, learning, and developing two languages--American Sign Language (ASL) and English (spoken English, manually coded English, and English reading and writing). The authors suggest that though deaf children may lack proficiency or fluency in either language during early language-learning development, they still engage in codeswitching activities, in which they go back and forth between signing and English to communicate. The authors then provide a second meaning of codeswitching--as a purpose-driven instructional technique in which the teacher strategically changes from ASL to English print for purposes of vocabulary and reading comprehension. The results of four studies are examined that suggest that certain codeswitching strategies support English vocabulary learning and reading comprehension. These instructional strategies are couched in a five-pronged approach to furthering the development of bilingual education for deaf students. PMID- 21305978 TI - Conceptually based vocabulary intervention: second graders' development of vocabulary words. AB - An instructional strategy was investigated that addressed the needs of deaf and hard of hearing students through a conceptually based sign language vocabulary intervention. A single-subject multiple-baseline design was used to determine the effects of the vocabulary intervention on word recognition, production, and comprehension. Six students took part in the 30-minute intervention over 6-8 weeks, learning 12 new vocabulary words each week by means of the three intervention components: (a) word introduction, (b) word activity (semantic mapping), and (c) practice. Results indicated that the vocabulary intervention successfully improved all students' recognition, production, and comprehension of the vocabulary words and phrases. PMID- 21305979 TI - Black deaf individuals' reading skills: influence of ASL, culture, family characteristics, reading experience, and education. AB - Previous research on the reading abilities of Deaf individuals from various cultural groups suggests that Black Deaf and Hispanic Deaf individuals lag behind their White Deaf peers. The present study compared the reading skills of Black Deaf and White Deaf individuals, investigating the influence of American Sign Language (ASL), culture, family characteristics, reading experience, and education. (The descriptor Black is used throughout the present article, as Black Deaf individuals prefer this term to African American. For purposes of parallel construction, the term White is used instead of European American.) It was found that Black Deaf study participants scored lower on measures of both reading and ASL. These findings provide implications for possible interventions at the primary, secondary, and college levels of education. PMID- 21305980 TI - Deaf and hard of hearing children and adolescents in China: their fears and anxieties. AB - The study examined the fears and anxieties of Chinese deaf and hard of hearing children and adolescents, and the ability of parents and teachers to report the presence of these fears and anxieties. Chinese deaf youth are at risk due to a lack of trained teachers, an overemphasis on oral education in schools, negative stereotypes, and parental overprotectiveness. The deaf children and adolescents in the study reported significantly higher levels of total fears, total anxieties, fear of the unknown, fear of injury and small animals, fear of medical procedures, and concentration anxiety than their hearing counterparts. Girls reported more total fears, fear of the unknown, fear of minor injury and small animals, and fear of failure and criticism than boys. Parents showed a better ability than teachers to confirm these reports of fears and anxieties. Implications and directions for future studies are presented. PMID- 21305981 TI - Contributions of the emergent literacy environment to literacy outcomes for young children who are deaf. AB - Specific characteristics of early literacy environments support hearing children's emergent literacy. The researchers investigated these characteristics' role in emergent literacy in young deaf and hard of hearing (DHH) children, using the Early Language and Literacy Classroom Observation (ELLCO; M. W. Smith, Dickinson, Sangeorge, & Anastasopoulos, 2002). Eighteen self-contained classrooms of preschool, kindergarten, and first-grade DHH children (N = 40) were studied. Hierarchical linear analysis was used to examine study participants' classroom environment and growth in emergent literacy skills. Correlations suggested that classroom environment was more closely related to vocabulary and phonological awareness in DHH children than in typically hearing children. Major differences among classrooms were also indicated. However, growth in children's skills did not correlate strongly with attributes captured by the ELLCO. This suggests that classrooms promoting emergent literacy skills acquisition in DHH children may differ from classrooms of typically developing hearing children. PMID- 21305982 TI - Approaches to teaching in mainstream and separate postsecondary classrooms. AB - The study examined attitudes toward teaching reported by university instructors who normally teach hearing students (with the occasional deaf or hard of hearing student) and by instructors who normally teach deaf and hard of hearing students at the same institution. Overall, a view of instruction as information transmission was associated with a teacher-focused approach to instruction, whereas viewing instruction as a means of promoting conceptual change was associated with a student-focused approach. Instructors in mainstream classrooms were more oriented toward information transmission than conceptual change, whereas instructors experienced in separate classrooms for deaf and hard of hearing students reported seeking to promote conceptual change in students and adopting more student-focused approaches to teaching. These results are consistent with previous findings concerning instructors' approaches to teaching and deaf and hard of hearing students' approaches to learning, and may help explain recent findings regarding student outcomes in separate versus mainstream secondary classrooms. PMID- 21305983 TI - South African Deaf education and the Deaf community. AB - In a special section of the american Annals of the Deaf, Deaf education and the Deaf community in South Africa are discussed. The special section is organized into 7 segments: a historical overview to establish context, the educational context, educators and learners, postgraduate education and employment, perspectives of Deaf children and their parents, sport and the arts, and spiritual lives and mental health. Throughout the entire section, however, the central focus is on the overall foundation (or lack thereof) of education for Deaf learners in South Africa. PMID- 21305984 TI - The power of collaboration. PMID- 21305985 TI - Shedding light on hidden costs: more savings in labor, supply chain than you know. PMID- 21305986 TI - On the road to ACO: plotting a course for quality and cost-effective care. PMID- 21305987 TI - The digital medicine revolution in healthcare. PMID- 21305988 TI - ACHE in 2010: preparing for a new era. PMID- 21305989 TI - The dilemma of the difficult employee. PMID- 21305991 TI - The Ben Franklin effect. PMID- 21305990 TI - Using engagement to drive performance cost effectively. PMID- 21305992 TI - Culture clashes and moral judgments. Culturally diverse society requires reconciling competing values. PMID- 21305993 TI - Putting it all together. Education and the right tools establish a culture of service. PMID- 21305994 TI - Driving through access barriers. Mobile van delivers care to kids in need. PMID- 21305995 TI - Use of observation days is on the rise. Health reform provision may quicken pace. PMID- 21305996 TI - Health reform and your career. No better time than now to assess skills and determine a career strategy. PMID- 21305997 TI - Four practices focused on accountability. Board education and certification, peer review, director credentialing and quality. PMID- 21305998 TI - End-of-life care: 6 leadership actions. Executives play a key role in initiatives to honor preferences of patients with advanced illness. PMID- 21305999 TI - Disruptive physician behavior. Strategies for addressing the cause and effect. PMID- 21306000 TI - Thinking out of the box. Chapters develop innovative programs to serve their affiliates. PMID- 21306001 TI - Creating an ethical culture within the healthcare organization. PMID- 21306002 TI - 7 for 11. Health information management and technology stories to watch in 2011. AB - Seven stories unfolding in 2011 illustrate the sweeping changes under way in what will be an active and sometimes tumultuous year in health information management. PMID- 21306003 TI - Sorting out advance directives. AB - Important differences exist in advance directives. Only some grant access to another person's medical records, and that can change with time. PMID- 21306004 TI - Independent contractor or employee? PMID- 21306005 TI - Cybersecurity insurance. PMID- 21306006 TI - Print restrictions in the EHR. PMID- 21306007 TI - ICD-10's impact on noncovered entities. PMID- 21306008 TI - Diagnosing documentation ailments. PMID- 21306009 TI - EHR adoption in LTC and the HIM value. PMID- 21306010 TI - Coding injuries in ICD-10-CM. PMID- 21306011 TI - RAC forensics 101. Part 1: Medical record requests and the discussion period. PMID- 21306012 TI - Power of attorney? The unexpected is always one record request away. PMID- 21306013 TI - Don't let the noise fool you--reform is the law. PMID- 21306014 TI - Vision 2020--a commitment to anawim. PMID- 21306015 TI - Palliative care: a hallmark of Catholic mission. PMID- 21306016 TI - Palliative care: what and why. PMID- 21306017 TI - Study: early palliative care helps quality of life. PMID- 21306018 TI - From a faith perspective: aging and dying, a time of grace. PMID- 21306019 TI - Approaching death: improving care at the end of life. PMID- 21306020 TI - How four Catholic systems approach palliative care. PMID- 21306021 TI - No patient left behind: Universal screening for palliative needs. PMID- 21306023 TI - Policy changes may help palliative care. PMID- 21306022 TI - Addressing spiritual pain. PMID- 21306024 TI - Community Mercy Health Partners honors heritages. PMID- 21306025 TI - Training doctors, combating myths. PMID- 21306026 TI - Inside Francis House: 'I can't believe I could be loved this much'. PMID- 21306027 TI - A moral compass: blessed are the poor. PMID- 21306028 TI - Report cites need for better integrated spiritual care. PMID- 21306029 TI - Palliative care needs a culture to sustain it. PMID- 21306030 TI - New assessment tool. PMID- 21306032 TI - A tipple a day keeps the cardiologist away. AB - Regular and moderate drinking throughout the week confers a low risk of IHD whereas binge drinking is associated with a higher risk, a study comparing drinking habits in France and the UK has found. Binge drinkers had almost twice the risk of MI or coronary death compared with regular drinkers. The Prospective Epidemiological Study of Myocardial Infarction (PRIME) study, in the BMJ, investigated the effects of alcohol intake patterns on the incidence of IHD in two countries with contrasting lifestyles. Overall, 683 of the 9,778 (7.0%) participants experienced IHD events during the 10 year follow-up of which 322 (3.3%) were hard coronary events and 361(3.7%) angina events. The annual incidence of hard coronary events per 1,000 person years was 5.63 in Belfast and 2.78 in France. After adjustment for classic cardiovascular risk factors and centre, although interestingly not for diet, the hazard ratio for hard coronary events for binge drinkers compared with regular drinkers was 1.97 The hazard ratio for never drinkers compared with regular drinkers was 2.03 and 1.57 for former drinkers compared with regular drinkers. PMID- 21306033 TI - Constipation. 1910. PMID- 21306034 TI - Disease remission the goal of therapy in rheumatoid arthritis. AB - In order to achieve remission, rapid diagnosis of rheumatoid arthritis (RA) is a key priority. The new RA classification system allows a diagnosis to be made much earlier than previously. The criteria focus on clinical, biochemical and immunological features associated with persistent and/or erosive disease. Following presentation to primary care, patients with symptoms and signs of an inflammatory arthritis should be referred to a rheumatologist. Any patient with suspected persistent synovitis of undetermined cause should be referred for specialist opinion and urgent referral if any of the following apply: the small joints of the hands or feet are affected; > 1 joint is affected; there has been a delay of > 3 months between onset of symptoms and seeking medical advice. Early treatment results in a greater chance of inducing remission. Ideally, this should be within 6 weeks of symptom onset. Patients who develop severe persistent inflammatory arthritis who have normal investigations at disease onset should be referred regardless. Similarly, referral should not be delayed pending investigations. A fundamental shift in the approach to treating RA has occurred with the archaic 'start low, go slow' management pyramid having been rejected. EULAR recommends initiating traditional DMARDs as soon as the diagnosis of RA is made, aiming to achieve the target of remission or low disease activity as rapidly as possible. Once prolonged and satisfactory levels of disease control have been achieved, drug doses may be cautiously reduced to levels that still maintain disease control. EULAR guidelines state that if the treatment target is not achieved following the first traditional DMARD strategy, in the presence of poor prognostic factors, or in patients responding insufficiently to DMARDs, then biologic therapy should be considered. PMID- 21306035 TI - Optimising pain control in osteoarthritis. AB - A recent large survey showed that 81% of people with osteoarthritis (OA) are in constant pain or are limited in their ability to perform everyday tasks. Patients present with joint pain and stiffness and are often unable to carry out their usual activities which impacts significantly on their quality of life. Anxiety and depression are common in patients with OA and will affect their mood and response to pain so identifying and treating associated anxiety and depression is very important. The PHQ9 and GAD7 can be used to screen for depression and anxiety. The OA process affects all structures within a joint, including the synovial lining and the subchondral bone. When sensitive MRI techniques are used synovitis is found to be almost ubiquitous in painful knee OA. When ultrasound is used, synovitis is seen in up to 45% of patients with painful hand OA. Many current treatments for OA are thought to target the synovium e.g. NSAIDs and this may be why they are effective. Changes in the subchondral bone are also common on MRI and associated with pain. Paracetamol and topical NSAIDs should be tried before oral NSAIDs. Topical NSAIDs are effective in the short-term and are not associated with systemic toxicity. Oral NSAIDs should be used at the lowest effective dose for the shortest possible time. All oral NSAIDs and COX-2 drugs should be prescribed with a PPI. There is less trial data on opioids than on NSAIDs but there is evidence for their efficacy. Patients who have moderate to severe pain that is not responding to oral analgesics or anti-inflammatories may benefit from intra-articular corticosteroids. Timing of analgesia is important. Advise patients to use analgesia before they exercise, so adherence to exercise routines is maintained. Consider long-acting preparations so pain relief is at a maximum throughout the most symptomatic period of the day or night. PMID- 21306039 TI - Physic in Shakespeare's time. 1910. PMID- 21306041 TI - Surgical lights. An illuminating look at the LED marketplace. AB - LED-based surgical lights are quickly replacing halogen models in operating rooms, due to advantages such as superior lighting characteristics and cooler operating temperatures. Choosing the right led light depends on both performance and user preference. PMID- 21306042 TI - Top 10 technology hazards for 2011. A guide for prioritizing your patient safety initiatives. AB - Most adverse incidents involving health technology are preventable. But they need to be clearly understood and thoughtfully acted upon. Here are 10 sources of potential danger that warrant particular attention in 2011, along with recommendations for protecting patients and staff. PMID- 21306043 TI - Gambro Prismaflex continuous renal replacement therapy system's touchscreen may not respond to user commands. AB - The touchscreen interface used in the Gambro Prismaflex continuous renal replacement therapy (CRRT) system may occasionally become unresponsive. Gambro has developed software that addresses the problem; the software has not yet been released in the United States. Until that software is available, facilities should develop an action plan for users to follow if the problem occurs. PMID- 21306044 TI - Using Medtronic's MAST Quadrant, Radiance, and Radiance X Illumination Systems with high-power light sources increases burn risk. AB - Connecting the Medtronic MAST Quadrant Illumination System, Radiance Illumination System, or Radiance X Illumination System--all of which are specialized fiberoptic light cables used with the company's minimally invasive spinal products--to a high-power surgical light source significantly increases the risk of patient burns. Hospitals should ensure that the products are used only with 100 W light sources and 5 mm light cables, as prescribed in the product labeling. PMID- 21306045 TI - Power cords on some InterMetro mobile workstations may experience insulation breakdown. AB - The outer insulation layer of some power cords supplied with certain InterMetro mobile workstations (the Flo 1750, the Flo 1800 computing workstation, and the Flo 2400 medication workstation) may experience degradation along the inner surface of the coiled portion of the cord, which may expose the internal wires and increase the risk of electric shock. The damage is often not evident unless the cord is stretched out. InterMetro will provide free replacements for cords exhibiting this damage. PMID- 21306046 TI - Clear channels. AB - Ineffective reprocessing of flexible endoscopes can have devastating consequences for your patients-and for your facility's bottom line. Protecting your patients and your institution requires developing an effective reprocessing protocol, following that protocol without exception, and selecting and using compatible devices and methods. We illustrate the kinds of problems that can occur and describe the steps to follow to avoid them. PMID- 21306047 TI - Anti-malware software and medical devices. AB - Just as much as healthcare information systems, medical devices need protection against cybersecurity threats. Anti-malware software can help safeguard the devices in your facility-but it has limitations and even risks. Find out what steps you can take to manage anti-malware applications in your devices. PMID- 21306048 TI - Elastomeric pain pumps. AB - Elastomeric pain pumps work on purely mechanical principles to deliver analgesic medications to ambulatory patients. They are simpler and more cost effective than electronic pumps, but also less sophisticated. Learn the pros and cons of these pumps, and find out how they fared in our testing. PMID- 21306049 TI - Kaiser permanente wins health devices achievement award. National implant registries provide comprehensive implant data, help improve care. PMID- 21306050 TI - Breathing circuit support arm on Maquet Servo-i ventilator may restrict gas flow to patient. AB - When mounted on the same side as the inspiratory port, the breathing circuit support arm used with the Maquet Servo-i ventilator can be positioned in such a way that it compresses the circuit's inspiratory limb, restricting gas flow to the patient. (This problem is possible only on the mobile cart configuration.) Users can avoid this problem by securing the arm above the port or by mounting it on another side of the ventilator. PMID- 21306051 TI - User experience network. Erroneous downstream occlusion alarms may disable Smiths Medical CADD-Solis infusion pumps. AB - Due to an issue in manufacturing, downstream occlusion (DSO) sensors in some Smiths Medical CADD-Solis infusion pumps may drift out of calibration, potentially resulting in erroneous alarms that disable the units. Hospitals experiencing the problem should return affected units to Smiths Medical for recalibration (free of charge) and should consider testing all their CADD-Solis pumps during routine maintenance to ensure that they alarm appropriately for downstream occlusions. PMID- 21306052 TI - Baxter colleague certificate of medical necessity: get it right--right now. PMID- 21306053 TI - A pilot study on the improvement of the lying area of finishing pigs by a soft lying mat. AB - In this pilot study, we tested whether a soft mat (foam covered with a heat sealed thermoplastic) reduces alterations and injuries at the skin and the leg joints.The soft mat in the lying area of partly slatted pens was compared to a lying area consisting of either bare or slightly littered (100 g straw per pig and day) concrete flooring. In this study we focused on skin lesions on the legs of finishing pigs as indicators of impaired welfare. Pigs were kept in 19 groups of 8-10 individuals and were examined for skin lesions around the carpal and tarsal joints either at a weight of <35 kg, or at close to 100 kg. The likelihood of hairless patches and wounds at the tarsal joints was significantly lower in pens with the soft lying mat than in pens with a bare concrete floor. Pens with a littered concrete floor did not differ compared to pens with a bare concrete floor. The soft lying mat thus improved floor quality in the lying area in terms of preventing skin lesions compared to bare and slightly littered concrete flooring. Such soft lying mats have thus the potential to improve lying comfort and welfare of finishing pigs. PMID- 21306054 TI - Comparative growth performance of pigs immunised with a gonadotrophin releasing factor vaccine with surgically castrated pigs and entire boars raised under conventionally managed conditions. AB - The objective of this study was to determine the effect of using a gonadotrophin releasing factor (GnRF) vaccine on growth performance of male pigs. Vaccinated pigs were compared with surgically castrated pigs and entire males under conventionally managed farm conditions. Male pigs were randomly assigned to three treatment groups: pigs surgically castrated during the first week of life (group "C", n=274), pigs immunised twice during the fattening period with a GnRF vaccine, the first when 13-14 weeks of age and the second when 20-21 weeks of age (group "V" n=280) and entire males (group "E", n=56). Average daily weight gain (ADG) was measured during the study. Additionally, feed conversion ratio (FCR) as defined by feed intake/weight gain and feed consumption was assessed during the fattening period. No difference in the ADG during the fattening period could be determined between "C" and "V". From the start of the study until slaughter at study day 160/173 the ADG in group "E" was lower (625 g/day; P) than in group "C" (681 g/day; P < 0.001) and group "V" (675 g/day; P < 0.01). The FCR during the fattening period until study day 160, three days before the first batch of pigs were slaughtered at 24-25 weeks of age, was higher in group"C" (2.72 kg feed intake/kg weight gain) compared with group "V" (2.44 kg feed intake/kg weight gain; P < 0.001) and group "E" (2.44 kg feed intake/kg weight gain; P <0.01). Pigs in group "V" performed similarly to those in group "E" until the second vaccination (day 135) after which time they showed a substantial increase in feed intake and ADG, while retaining an FCR advantage over group C. PMID- 21306055 TI - Vaccination with canine parvovirus type 2 (CPV-2) protects against challenge with virulent CPV-2b and CPV-2c. AB - Mutations in canine parvovirus (CPV) field isolates have created concerns regarding the ability of vaccines containing CPV-2 to protect against infection with the newly identified antigenic types CPV-2b and CPV-2c. To address this concern, the efficacy of CPV-2 strain NL-35-D currently in use as a commercial vaccine was demonstrated against an oral challenge with CPV-2b and CPV-2c, respectively. Clinically healthy specific pathogen free Beagle dogs were either vaccinated or treated with water for injection first at 8-9 weeks of age and again at 11-12 weeks of age. All dogs were challenged either with CPV-2b or CPV 2c three weeks after the second vaccination. During the two week period following challenge, clinical signs, white blood cell counts, serology by haemagglutination inhibition (HI) and serum neutralisation tests, and virus shedding by haemagglutination test were assessed. All control dogs developed clinical signs of parvovirosis (including pyrexia and leucopenia) and shed virus. Vaccinated dogs seroconverted (HI titres > or =80), remained healthy throughout the study and shed more than 100 times less virus than controls. In conclusion, vaccination with the low passage, high titre CPV-2 strain NL-35-D cross-protects dogs against virulent challenges with CPV-2b or CPV-2c by preventing disease and substantially reducing viral shedding. PMID- 21306056 TI - Porcine proliferative enteropathy in Estonian pig herds: histopathology and detection of Lawsonia intracellularis by PCR. AB - Lawsonia intracellularis is the causative agent of proliferative enteritis in pigs (PPE). This bacterium is difficult to culture from clinical samples and antemortem demonstration is therefore usually performed by PCR on faecal samples. The aim of this study was to elucidate the frequency of L. intracellularis infection in pig herds in Estonia using PCR, histopathological methods and electronmicroscopical studies. The frequency of demonstration of L. intracellularis was highest in 9-12 weeks old pigs (68.1%). It was more frequent in growing pigs with enteritis on small farms where the system of "all-in all out" was not practiced and where standards of hygiene were poor. Gross and histopathological studies demonstrated that characteristic macroscopic changes associated with PPE were localised to the distal jejunum and ileum.Thickened longitudinal and circumferential folds occurred in the mucosa of the affected regions of the bowel. Samples from pigs aged 4 to 20 weeks exhibited the most intensive inflammatory changes. The distal part of the jejunum, ileum and the upper third of proximal colon and cecum wall were visibly thickened with reduced luminal diameter. Hyperplasia of lymphoid tissue and, in many cases, pseudomembranous or fibrinous inflammation was found. L. intracellularis was detected in 56 young pigs using histopathological methods. Additionally, in 8 of these pigs intracellular bacteria were demonstrated in ilial epithelial cells by transmission electronmicroscopical (TEM) investigation. On the basis of these TEM investigations it was concluded that L. intracellularis causes disturbances of normal growth, differentiation and apoptosis of the epithelial cells of ileum. PMID- 21306057 TI - Frequency of Salmonella detection in a broiler flock depending on different litter materials--a field study. AB - During the fattening period of a broiler flock four different litter materials (peat, chopped straw, shavings, silage) were tested simultaneously.The separated sections were tested for the presence of Salmonella bacteria using the sock sampling method as described in the regulation EC No. 646/2007 with slight modifications in the sampling technique and the laboratory protocol. In addition, some chemical and physical parameters regarding litter quality and house climate were analysed. Samples were taken at day 0 (housing of animals), day 14, and day 30. At the end of the fattening period Salmonella Paratyphi B (d-tartrate +), representing a common strain in German broiler flocks, were isolated from culture. According to the various types of bedding materials some differences in the frequency of Salmonella detection were found. With three samples out of six samples being positive, wood shavings showed the highest Salmonella prevalence, followed by peat with two positive results. Corn silage was found to be a suitable alternative for common litter materials and revealed only one positive sample. Chopped straw was found to be free of Salmonella in our study. However, the latter had a higher risk for negative side effects concerning animal health and house climate. The study showed that the choice of an appropriate litter material might be of considerable importance in order to decrease the Salmonella burden within poultry flocks. PMID- 21306058 TI - Finite element modelling of the canine and feline outer ear canal: benefits for local drug delivery? AB - Current therapeutic regimes of outer ear infections in dogs and cats aim at the application of efficient local therapeutics after cleaning of the acoustic meatus. One so far insufficiently answered question is if the local application of these substances results in an individually suitable drug concentration in the external ear canal. Thus, the purpose of the present study was to develop a finite element model to calculate the values of the different areas of the external acoustic meatus in dogs and cats in order to provide a tool for the benefit of an appropriate local drug dosage determination. A 3D finite element model (FEM), based on computer tomographic (CT) data sets of four dogs and two cats, was generated to determine areas and volumes of the outer ear canal. Furthermore, various ear therapeutics and cleansers were tested concerning their optimal distribution on 5 cm2 dog and cat skin. The data shows major variations of the area values of the external auditory canal in case of the different dogs but not in the examined cats. These results suggest that manufacturer's recommendations of the pharmaceuticals might be insufficient in terms of achieving an optimal drug concentration in the outer ear canal especially in larger dogs. In conclusion, the developed finite element model has shown to be suitable to calculate areas of the outer ear canal in cats and dogs and could be of help in context with the definition of optimal drug concentrations for a local drug delivery. PMID- 21306059 TI - Plasma and urine concentrations of marbofloxacin following single subcutaneous administration to cats. AB - The pharmacokinetic properties of marbofoxacin, a third generation fluoroquinolone, were investigated in 12 healthy adult cats after single subcutaneous (SC) administration of 2 mg/kg BW (Part I, n=8 cats) and 4 mg/kg BW (Part II, n=4 cats). In each part of the study blood and urine samples were collected before treatment and thereafter for 5 days. The plasma and urine concentrations of marbofloxacin were determined by HPLC with UV detection. Pharmacokinetic calculations were performed for each treated animal using an open one-compartment-model with first-order elimination after SC dosing. Marbofloxacin in plasma (means): Maximum concentrations (Cmax) of about 1.2 and 3.0 microg/ml were measured 2.3 and 4 hours (tmax) after dosing of 2 and 4 mg/kg BW, respectively. Elimination from the body was low with a total clearance (Cl/F) of approximately 0.1 l/h/kg for both dosages. The half-life (t 1/2) for this process was calculated with 8-10 hours. AUC increased almost proportional when doubling the dose, i.e., 19.77 +/- 6.25 microg * h/ml (2 mg/kg BW) and 51.26 +/- 11.83 microg * h/ml (4 mg/kg BW). Plasma kinetics measured were in accordance with data from literature. Marbofloxacin in urine (means): Maximum drug concentrations were detected 4 and 8 hours after dosing with 70 microg/ml (2 mg/kg BW) and 160 microg/ml (4 mg/kg BW), respectively. Inhibitory effects of the urinary matrix on the antimicrobial activity of the drug were taken into account when performing PK/PD calculations. However, a concentration-dependent bactericidal activity (Cmax/MIC > 8-10) which is claimed for fluoroquinolones was sufficiently met with focus on Escherichia (E.) coli (MIC90 0.5 microg/ml). In the same matrix a threshold value of 1.0 microg/ml was undercut 82 and 116 hours after SC dosing, respectively. Hence, a time-dependent bacteria killing kinetic (T > MIC) which may be of relevance for some Gram-positive germs like Staphylococcus spp. (MIC90 1.0 microg/ml) should be covered, too. PMID- 21306060 TI - A multifaceted approach to education, observation, and feedback in a successful hand hygiene campaign. AB - BACKGROUND: Prevention of health care-associated infections starts with scrupulous hand hygiene (HH). Improving HH compliance is a major target for the World Health Organization Patient Safety Challenge and is one of The Joint Commission's National Patient Safety Goals. Yet, adherence to HH protocols is generally poor for health care professionals, despite interventions designed to improve compliance. At Tufts Medical Center (Boston), HH compliance rates were consistently low despite the presence of a traditional HH campaign that used communication and education. METHODS: A comprehensive program incorporated strong commitment by hospital leadership-who were actively involved in responsibilities previously only performed by infection preventionists and quality and patient safety staff-dedication of financial resources, including securing a grant; collaborating with a private advertising firm in a marketing campaign; and employing a multifaceted approach to education, observation, and feedback. RESULTS: This campaign resulted in a rapid and sustained improvement in HH compliance: Compared with the mean HH compliance rate for the six months before the campaign (72%), postcampaign HH compliance (mean = 94%) was significantly greater (p < .0001). Factors contributing to the success of the campaign included the development of the marketing campaign to fit this academic medical center's particular culture, strong support from the medical center leadership, a multifaceted educational approach, and monthly feedback on HH compliance. CONCLUSIONS: A comprehensive campaign resulted in rapid and sustained improvement in HH compliance at an academic medical center after traditional communication and education strategies failed to improve HH performance. PMID- 21306061 TI - Developing a policy for do not resuscitate orders within a framework of goals of care. AB - BACKGROUND: Discussions about DNR (do not resuscitate) orders or code status are common but can be difficult and may not lead to accurate understanding between clinicians and patients. These discussion are often isolated from the larger context of a patient's plan of care. Addressing patients goals of care, which provide a basic orientation for clinical and ethical decision making, may improve clinicians' understanding about patients' code-status preferences. A POLICY FOR DNR ORDERS WITHIN A FRAMEWORK OF GOALS OF CARE: On the basis of experience at the University of Iowa Hospitals and Clinics, which entailed incorporating goals of care in ethics education, identifying six goals of care through a structured literature review, surveying hospitalized adults, and integrating goals of care into palliative care education, the University of Iowa Hospitals and Clinics ethics committee revised the hospital policy regarding DNR orders. The intention was to avoid treating DNR orders as an isolated clinical phenomenon and to instead place the discussion of DNR orders in the more general context of end-of life discussions and to place both of these discussions within an even more general framework of goals of care. CONCLUSIONS: The DNR order policy represents an effort to translate conceptual analysis, empirical research, and clinical experience into hospital policy so that clinicians are encouraged to place code status discussions within a larger, goal-oriented context. Using goals of care to guide decision making about DNR orders and other treatments should enhance the quality of patient care by improving the fit between the biomedical information we provide patients and the values our patients rely on to make their medical decisions. PMID- 21306062 TI - Designing an abstraction instrument: lessons from efforts to validate the AHRQ patient safety indicators. AB - BACKGROUND: The U.S. Agency for Healthcare Research and Quality (AHRQ) and other organizations have developed quality indicators based on hospital administrative data. Characteristics of effective abstraction instruments were identified for determining both the positive predictive value (PPV) of Patient Safety Indicators (PSIs) and the extent to which hospitals and clinicians could have prevented adverse events. METHODS: Through an iterative process involving nurse abstractors, physicians, and nurses with quality improvement experience, and health services researchers, 25 abstraction instruments were designed for 12 AHRQ provider-level morbidity PSIs. Data were analyzed from 13 of these instruments, and data are being collected using several more. FINDINGS: Common problems in designing the instruments included avoiding uninformative questions and premature termination of the abstraction process, anticipating misinterpretation of questions, allowing an appropriate range of response options; using clear terminology, optimizing the flow of the abstraction process, balancing the utility of data against abstractor burden, and recognizing the needs of end users, such as hospitals and quality improvement professionals and researchers, for the abstracted information. CONCLUSIONS: Designing medical record abstraction instruments for quality improvement research involves several potential pitfalls. Understanding how we addressed these challenges might help both investigators and users of outcome indicators to appreciate the strengths and limitations of outcome-based quality indicators and tools designed to validate or investigate such indicators within provider organizations. PMID- 21306063 TI - Standardizing hospital discharge planning at the Mayo Clinic. AB - BACKGROUND: Improving the quality of patient coordination in the transition from hospital to home is a high-priority health care concern. The Centers for Medicare & Medicaid Services (CMS) Hospital Conditions of Participation in the Medicare Program require that hospitals have a discharge planning (DP) process in effect that applies to all patients. The impact of a practice change in DP practice on the quality of care coordination at discharge was evaluated from patients' perspectives. METHODS: A multifactor, evidence-based DP practice change, which included merging of DP specialist roles and use of an early screen for DP decision support tool, was initiated in a large, Midwestern academic medical center and evaluated in a nonequivalent comparison group design with separate pre and postpractice change samples. The three-item Care Transitions Measure (CTM-3) was mailed to adults recently discharged from one medical and one surgical nursing unit before and after the practice change. RESULTS: Response rates were 52.4% before (218/416) and 39.5% (153/387) after the practice change. There were no significant differences between characteristics of the pre- and postpractice change participants. The mean CTM-3 score of patients who received assistance from the nurse/ social worker DP team improved by 14 points (67.2 to 81.2), although the data were skewed with a ceiling effect, rendering the results inconclusive. CONCLUSIONS: Although the CTM-3 results were inconclusive, the practice change resulted in a clinically meaningful decrease in length of stay for a group of older patients at greater risk for complex discharge plans. The proactive approach to DP proved to be a valuable shift. The successes of the standardization of DP processes and improved multidisciplinary teamwork were important considerations for implementation throughout the organization. PMID- 21306064 TI - Experiences of participants in a collaborative to develop performance measures for hospice care. AB - BACKGROUND: There has been increasing attention paid to quality assessment in hospice as the industry has grown and diversified. In response, policymakers have called for standardized approaches to monitoring hospice quality. The experiences of a set of hospices involved with the National Association for Home Care & Hospice (NAHC) Quality Assessment and Performance Improvement Collaborative, which was designed to test the use of a standardized patient symptom assessment tool as an exemplar of efforts to standardize symptom assessment in hospice, were examined. METHODS: Transcripts of semistructured telephone interviews with 24 individuals from eight of the nine participating hospices, which were conducted in July-August 2007, were analyzed using the constant comparative method. Interview questions centered on the collaborative's impact on the process of quality assessment at the hospices. FINDINGS: The collaborative activities influenced several hospices' quality assessment processes, most beneficially by prompting greater attention to quality assessment processes, by promoting the adoption of quality assessment tools, and by creating a supportive community. Challenges included the limits of distance communication technology, participants' misconceptions about data to be received, and potential lack of support and resources for quality assessment. CONCLUSIONS: The experiences of the participating hospices in the NAHC collaborative are intended to inform the design of future interorganizational learning efforts to promote quality assessment initiatives within hospice settings. Future hospice collaboratives should use multiple methods of communication to build a close participant network and be clear about collaborative goals and participant expectations and about the reciprocal relationship of the collaborative and the participants. PMID- 21306065 TI - Multiple perspectives on the accessibility of e-learning in Canadian colleges and universities. AB - An exploratory study identified and compared the views of 77 campus disability service providers, 38 professors, and 45 e-learning professionals from Canadian colleges and universities regarding their experiences with e-learning and its accessibility to students with disabilities. Findings indicate that all groups saw benefit in having someone who makes e-learning accessible to students with disabilities on campus and that problems related to e-learning accessibility were most likely to go to campus disability service providers and least likely to e learning professionals. Only half of the participants indicated that professors are taught about e-learning accessibility, that there is someone on campus who makes e-learning accessible, that accessibility is a criterion for selecting new types of e-learning, and that their school has e-learning accessibility guidelines or policies. These findings suggest that important e-learning accessibility problems remain. Recommendations for colleges and universities on how to increase e-learning accessibility are provided. PMID- 21306066 TI - A review of preservice training in augmentative and alternative communication for speech-language pathologists, special education teachers, and occupational therapists. AB - Speech-language pathologists, special education teachers, and occupational therapists are all likely to encounter individuals with complex communication needs who require augmentative and alternative communication (AAC) in clinical and educational practice. The research on preservice AAC training for these professionals was thus reviewed to investigate the adequacy and effectiveness of current practices. Results indicate that many preservice programs offer minimal AAC training, faculty members have minimal expertise in AAC, and the effectiveness of preservice programs in equipping professionals for entry-level AAC practice is unclear. Speech-language pathologists, special education teachers, and occupational therapists may thus be at risk of graduating with minimal to no exposure to AAC, with little knowledge or skill in AAC service provision, and may be unprepared for entry-level practice. Strengths and limitations of the reviewed research and future research directions are discussed, along with implications for improving preservice training in AAC. PMID- 21306067 TI - Patient satisfaction with telerehabilitation assessments for wheeled mobility and seating. AB - Wheeled mobility and seating assessments for individuals with mobility impairments living in rural or distant locations are problematic due to the lack of expertise and available resources. The objective of this study was to measure satisfaction based on one's evaluation and prescription as well as comfort level when being evaluated by telerehabilitation (TR). Patient satisfaction data from real-time interactive TR clinical consultations between an expert practitioner located at least 125 miles away and four remote wheelchair clinics set up by the research team were collected and evaluated. The results revealed that there was a statistically significant difference between participants' pre- and postevaluation scores, t(39) = -13.92, p < .05, as well as pre- and postprescription scores, t(39) = -13.15, p < .05. In addition, all mean scores were significantly higher than the scale midpoint of3.5 on a TR survey. The study's findings are consistent with those of previous telemedicine satisfaction studies. Overall, the results indicate a high level of patient satisfaction using TR. PMID- 21306068 TI - Text entry via character stroke disambiguation for an adolescent with severe motor impairment and cortical visual impairment. AB - This study proposed a single-switch text entry system by hierarchical scanning of character strokes for an 11-year-old girl with severe physical disabilities and low vision. She could only perceive magnified straight line segments and chords presented against high-contrast, colored backgrounds. In a descriptive case study, the participant used the proposed system in the community for 8 months. Assessment included theoretical evaluation of text entry performance and empirical evaluation of the participant's proficiency. The proposed system had a lower error-free text entry rate but comparable proneness to user error as a real world implementation of row-column virtual scanning keyboard with character frequency layout. The participant's proficiency, in terms of mean number of single-switch activations and time to type one character, showed statistically significant improvements as the case study progressed. The proposed system feasibly addressed the participant's typing needs, in a context where traditional row-column scanning and codeword-based text entry systems were not successful. PMID- 21306069 TI - Assessment of the ISO impact damping test for wheelchair cushions. AB - The International Organization for Standardization (ISO) has published a test method that characterizes the ability of a wheelchair cushion to reduce impact loading. The objectives of this project were to improve the methodology described in the ISO standard, determine the repeatability of the accelerations resulting from the ISO test method and assess the test method's ability to distinguish the impact damping performance of different cushion designs. A small cohort of cushion was identified to reflect different material constructions and included flat elastic foam, flat viscoelastic foam, Roho High Profile, and Cloud. The ISO test method was deployed after changes to the equipment were made to better insure repeatable placement of the indenter onto the cushion. Three operators tested different cushions over two days. Acceleration of the indenter was collected and used to calculate acceleration magnitudes during indenter impact and rebound. The results of a Gage Repeatability & Reproducibility analysis indicated high reliability over operators and test days. Analysis of initial impact acceleration indicated that the test could distinguish between the different cushion designs. Ratios of successive impacts and rebounds were calculated and analyzed. Both showed high repeatability and could distinguish all cushion pairs except one. Assessment of this and previously collected data led to the suggestion that the ratio of impact accelerations should be reported rather than the rebound accelerations. In summary, with some slight but significant changes to the test rig, the ISO Impact Damping test method is a reliable means to characterize acceleration responses of wheelchair cushions. PMID- 21306070 TI - 2011: Another year with unlimited opportunities! PMID- 21306071 TI - Building trust with patient education. PMID- 21306072 TI - Stem cells in dentistry and medicine: the dentist's role. AB - Research has shown that teeth are a source of high quality stem cells that may be used for the treatment of medical and dental disease. The discovery that odontogenic tissues are a source of adult stem cells has opened up a new role for dentists in the field of medicine. Dentists are positioned to become one of the key providers of stem cells, and as a result, their linkage with the medical field will become very intimate. Dental stem cells have the potential to be used in the treatment of a full range of oral pathoses. Dentists can be involved in the extraction, collection, and storage of the stem cells from their patients' teeth. Ongoing research suggests that these stem cells will soon be used for dental purposes such as to replace lost bone around teeth, periodontal ligament or dental pulp; treat periodontal disease; and someday even produce new teeth, as well as for medical applications. In order for dentists to fully participate in this new role, they should become aware of the applications, clinical use, and banking of dental stem cells. PMID- 21306073 TI - Manual versus mechanical endodontic glidepath. AB - This article, the second in a series of 3 articles on the endodontic Glidepath beginning with the September 2010 issue of Dentistry Today (archived articles can be found at dentistrytoday.com), represents an inquiry into the critical distinctions of the endodontic Glidepath. First, we reviewed the need for a confirmed and reproducible Glidepath as prerequisite to rotary or reciprocal shaping. In order to be safe, before rotary shaping, the dentist must always discover that a Glidepath already exists or that one needs to be created. Second, an emphasis was placed on a "finishing checklist" for Glidepath preparation for safe and successful rotary. The checklist is 2 parts: (1) minimum super loose No. 10 file sized k tunnel is verified; (2) the super loose No. 10 file sized tunnel must run from canal orifice through the canal PT to the RT. In this way, patency is preserved and yet the delicate and often fragile cemental anatomy remains undamaged and unchanged, therefore meeting Schilder's fourth mechanical objective of "keeping the foramen as small as practical." Third, we discussed that the question should not be "manual versus mechanical" but rather "manual, then mechanical." Always measure the existence of a Glidepath with manual before mechanical. The key elements for improving your performance of Glidepath mastery include a clear intention of what needs to be accomplished and yet at the same time, restraint; gentleness; copious irrigation with sodium hypochlorite; curved files; randomness; discovery; expecting the unexpected and surrendering to, honoring, and respecting the delicate anatomical structure called the root canal system. After all, nature has been demonstrating how to make a Glidepath for a long time, but we have not been paying attention. We have been too heavy-handed, we have pushed, we have forced, and we have not always been good stewards of nature's fragile framework. She has been giving us and teaching us the Glidepath answer all along. Listen to Mother Nature as she sends her legacy to us: "You have never seen a canal like me before. I am full of curves and booby traps. Treat me gracefully--I know that may sound corny--and respect my delicate tissues and structures. I am waiting for you. All you have to do is follow me to my end. Make me smooth and big enough for safe rotary and you can have your way with me. Once cleaned, shaped, and packed, I will reward you with the gift of healing." In an upcoming issue of Dentistry Today, I will present useful guidelines for implementation of the endodontic Glifepath. Remember, knowing what to do is only half the answer to mastering elegant, artistic, and successful Glidepaths. The other half is to be able to bring these skills into the everyday clinical practice; implementation is often the missing link In order to do this, you will need a plan to design a culture, environment, and ergonomics in your office that will allow the time and energy to do it right. PMID- 21306074 TI - Simplifying fixed implant dental prosthetics. AB - Through following the FPPD protocol for multiple adjacent implants, and delivering final abutments, picking up the metal framework, and delivering provisionals, many benefits are gained. The benefits of following the FPPD protocol are as follows: The restorative dentist is trying-in and delivering the final abutments in one visit as opposed to removing them and placing them multiple times. This requires less chair time and time for the patient. It also reduces the mechanical stress on the abutment screw and implant body due to the elimination of multiple try-in appointments. When the metal framework is tried-in and verified for fit, the restorative dentist has the opportunity check the retention, check the margins, and make any corrections that might be needed. The abutments will be staying in the mouth when the framework is picked up. This metal try-in allows for a verification of the bite to be given to the dental lab. The delivery of provisionals manufactured by the dental laboratory offers many advantages in the FPPD technique. The patient has a form of tooth much earlier in the traditional appointment sequence. The patient can now offer feedback to the doctor and laboratory for fabrication of the permanent prosthesis with regards to shape and color. The laboratory-fabricated provisionals offer progressive loading to the implants through having a reduced occlusion yet allowing food to stimulate the implants. Overall, the FPPD technique offers shorter appointment times, more rapid delivery of fixed supported teeth, improved doctor-technician communication, and less mechanical wear on the implant parts. PMID- 21306075 TI - Optimizing occlusal results for crown and bridge prostheses. PMID- 21306076 TI - Crown lengthening in the aesthetic zone. PMID- 21306077 TI - Technology enhances caries diagnosis and treatment. PMID- 21306078 TI - Improving precision with CBCT imaging. PMID- 21306079 TI - Ethical considerations for adjunctive screening technologies. PMID- 21306080 TI - An endoimplantologist's perspective: interdisciplinary acceptance. PMID- 21306081 TI - Effectively treating dental hypersensitivity. PMID- 21306082 TI - 401(k) plan asset allocation, account balances, and loan activity in 2009. AB - CONSISTENT SAMPLE: Because 401(k) balances can fluctuate with market returns from year to year, meaningful analysis of 401(k) plans must examine how participants' accounts have performed over the long term. Looking at consistent participants in the EBRI/ICI 401(k) database over the six-year period from 2003 to 2009 (which included one of the worst bear markets for stocks since the Great Depression), the study found: After rising in 2003 and for the next four consecutive years, the average 401(k) retirement account fell 27.8 percent in 2008, before rising 31.9 percent in 2009. The average 401(k) account balance moved up and down with stock market performance, but over the entire six-year time period increased at an average annual growth rate of 10.5 percent, attaining $109,723 at year-end 2009. The median (or midpoint, half above and half below) 401(k) account balance increased at an average annual growth rate of 14.7 percent over the 2003-2009 period to $59,381 at year-end 2009. THE BULK OF 401(K) ASSETS CONTINUED TO BE INVESTED IN STOCKS: On average, at year-end 2009, 60 percent of 401(k) participants' assets were invested in equity securities through equity funds, the equity portion of balanced funds, and company stock. Thirty-six percent was in fixed-income securities such as stable-value investments and bond and money funds. MORE THAN THREE-QUARTERS OF 401(K) PLANS INCLUDED TARGET-DATE FUNDS IN THEIR INVESTMENT LINEUP AT YEAR-END 2009: At year-end 2009, nearly 10 percent of the assets in the EBRI/ICI 401(k) database was invested in target-date funds and 33 percent of 401(k) participants held target-date funds. Also known as lifecycle funds, they are designed to simplify investing and to automate account rebalancing. NEW EMPLOYEES CONTINUED TO USE BALANCED FUNDS, INCLUDING TARGET-DATE FUNDS: Across all but the oldest age group, more new or recent hires invested their 401(k) assets in balanced funds, including target-date funds. At year-end 2009, about 42 percent of the account balances of recently hired participants in their 20s were invested in balanced funds, compared with 36 percent in 2008, and about 7 percent in 1998. At year-end 2009, 31 percent of the account balances of recently hired participants in their 20s was invested in lifecycle funds, compared with almost 23 percent at year-end 2008. 401(K) PARTICIPANTS CONTINUED TO SEEK DIVERSIFICATION OF THEIR INVESTMENTS: The share of 401(k) accounts invested in company stock continued to shrink, falling by half of a percentage point (to 9.2 percent) in 2009. That continued a steady decline that started in 1999. Recently hired 401(k) participants contributed to this trend: They tended to be less likely to hold employer stock. PARTICIPANTS' 401(K) LOAN ACTIVITY ROSE IN 2009: In 2009, 21 percent of all 401(k) participants eligible for loans had a loan outstanding against their 401(k) account, compared with 18 percent at year end 2008 and year-end 2007. Loans outstanding amounted to 15 percent of the remaining account balance, on average, at year-end 2009, compared with 16 percent at year-end 2008. Loan amounts remained in line with the past few years in terms of typical dollar amounts. PMID- 21306083 TI - Aesthetic evaluation in subjects treated due to congenitally missing maxillary laterals. A comparison of perception in patients, parents and dentists. AB - The treatment of the congenitally missing maxillary lateral incisor is a challenge to the dental profession. The demand for optimal orthodontic and prosthetic treatment is high because the condition has an impact on facial aesthetic. The aims of the present study were to determine how different outcome of treatment were perceived by professionals and laypeople and to identify situations that caused dissatisfaction or satisfaction after space closure or tooth replacement. A panel of four groups (patients with missing laterals, parents to these subjects, patients with other malocclusion and general dental practitioners) were included. Sixteen cases with uni- or bilateral missing maxillary lateral incisors, treated with space closure or with prosthetic replacements were presented photographically to the panel. The prosthetic replacements included resin-bonded bridges, porcelain bonded to gold bridges and implants. The panel was asked to rate the overall appearance of the mouth, to rank up to three disturbing features and to rank the most important treatment goals in case of treatment need. An obvious difference between the panel groups was found. The general practitioners were less critical than laypeople in rating the overall appearance. Amongst dentists the tooth colour, the tooth shape and asymmetry were the most disturbing factors whilst laypeople were disturbed by colour, spacing and tooth shape. Half of the dentists did not find any treatment need whilst the corresponding figure amongst laypeople was 19 per cent.When a treatment need was confirmed the most common treatment goals amongst dentists were to change the colour or the shape of the teeth. The laypeople wanted to change the colour, the space condition or the shape of the teeth. The study has shown that professionals and laypeople are of different opinion when rating treatment outcome in cases with missing maxillary laterals. Careful planning to achieve optimal aesthetics should be performed. PMID- 21306084 TI - Dental erosion and soft drink consumption in Swedish children and adolescents and the development of a simplified erosion partial recording system. AB - The aims of this study were to investigate the prevalence of dental erosion among Swedish children and adolescents and to examine its relation to soft drink consumption. It was hypothesized that the prevalence of dental erosion would be higher in boys than girls,that it would show a correlation with soft drink consumption and that a further simplification ofa previously-used partial recording screening system for dental erosion would have an acceptable sensitivity and specificity. 801 individuals were invited to participate, of whom 609 (75%) accepted. 135 were 5-6 years, 227 were 13-14 years, and 247 were18-19 years old. A questionnaire survey of each individual's soft drink consumption habits, in addition to a clinical examination, were performed. Severe erosion extending into dentine on one or more maxillary anterior teeth/ molars was found to be 13.3% in the 5-6 group, 11.9% in 13-14 group and 22.3% in 18-19 group. The total prevalence for all age groups was 16.4%. The severity of erosion was highest among 18-19 year-old boys, 34.4 % of whom exhibited one or more teeth with severe erosive damage while none of the girls did so. Soft drink consumption was significantly correlated with severity of dental erosion in the 18-19 and 13 14 groups but not in the 5-6 years old group. A simplified erosion partial recording system (SEPRS) using 4 (permanent) or 6 (primary) surfaces as markers showed excellent sensitivity (100%/100%, respectively) and specificity (98%/100%, respectively) in relation to scoring of all maxillary canines/incisors and first permanent/all primary molars. In view of the high prevalence of dental erosion and soft drink consumption among Swedish children and adolescents reported here,there is clearly a need for a national epidemiological registration system as well as for community-based preventive programs to be implemented. The hypothesis that dental erosion would be higher in boys than girls and that it would show a correlation with soft drink intake was confirmed. PMID- 21306085 TI - Influence of dietary supplementation with Lactobacillus reuteri on the oral flora of healthy subjects. AB - Investigate the presence of Lactobacillus reuteri in saliva after supplementation with L. reuteri and the probiotic effect of L. reuteri on plaque index and supra- and subgingival microbiota. MATERIAL AND METHODS: The study included 23 healthy individuals, randomised into test or control subjects. At baseline and after 12 weeks saliva samples, plaque index and supra- and subgingival plaque samples were obtained. The test subjects were given the study product (containing L. reuteri, ATCC 55730 and ATCC PTA 5289) and the control subjects placebo for 12 weeks. Microbiological analyses were done by checkerboard DNA-DNA hybridization technique and selective culturing for lactobacilli determination. RESULTS: A significant increase in total Lactobacillus counts in saliva occurred in both groups (p < 0.05) with a significant increase of L. reuteri (p = 0.008) in the test group.Termination of intervention resulted in a wash out of L. reuteri. The control group demonstrated a statistically significant increase in PII after 12 weeks (p = 0.023) whilst there was no significant change in the test group. A significant increase was found for most bacterial species in both groups in supra and subgingival plaque with no significant difference for any of the species between the groups. The ratio between "bad/good" supragingival bacteria decreased for the test group but this decrease did not reach significance. The corresponding ratio for subgingival bacteria decreased significantly in both groups. Supplementation of L. reuteri resulted in presence of L. reuteri in saliva but L. reuteri was washed out after termination of intervention. No significant effect on supra- or subgingival microbiota was observed. The significant increase in PII in the control group with no significant change in the test group may, however, indicate a probiotic effect of L. reuteri in this study population. PMID- 21306086 TI - Self-perceived oral health and obesity among 65 years old in two Swedish counties. AB - The aim of this study was to explore the association between oral health and obesity. The study was conducted in the spring of 2007 as a postal survey of all inhabitants born in 1942 and living in the two Swedish counties of Orebro and Ostergotland.This questionnaire survey has been conducted everyfiveyears since 1992 but has been updated continually with additional questions and for the sweep used here, height and weight data were collected. A total of 8,313 individuals received the questionnaire and 6,078 of those responded (73.1%). The outcome variable oral health was measured using one global question and four detailed questions representing different aspects of oral health. The independent variable Body Mass Index (BMI) was calculated using self-reported height and weight. A difference in oral health between various BMI groups was found. The difference was both statistically significant and of clinical importance, particularly among the group with severe obesity who reported poorer self-perceived chewing capacity, lower satisfaction with dental appearance, increased mouth dryness and fewer teeth and lower overall satisfaction with oral health. In view of the increased risk of poor oral health demonstrated in this study for those with severe obesity, it may be of value to increase cooperation between dental care and primary health care for these patients. PMID- 21306087 TI - Dental care utilization in a Swedish county in 1993 and 2003. AB - The aim of the present study is to analyse factors influencing the patterns of utilization of dental care in an adult urban Swedish population aged between 30 and 80 in the years 1993 and 2003. This study is part of two large epidemiological dental studies of randomly selected individuals, performed in 1993 and 2003. It comprises clinical and questionnaire data from 555 and 505 individuals in the two studyyears. In 1993, more patients visited the private dental care system more often than the public system. This difference still existed in 2003, but to a 50% lower extent. All age groups had less utilization of dental care in 2003 than in 1993. The largest change was seen in the 30-year age group in utilization patterns of dental care between the two study years. A hierarchical block regression method was performed in four steps, analysing utilization for the two study years separately. The dental service system influenced the utilization patterns significantly for both years. The health factors strengthened this main result. Irrespective of dental health, patients were predicted to visit the private dental care service system more often in both 1993 and 2003. The socio-economic differences between people in Sweden were of no consequence for dental care utilization. As to age and attitude towards treatment costs, a substantial change was observed and might reflect a change in social patterns with greater inequalities, but the overall picture of equal access in dental care in Sweden remains. PMID- 21306088 TI - What is professionalism? PMID- 21306089 TI - Residential proximity to toxic release sites and the implications for low birth weight and premature delivery. AB - The objective of the study discussed in this article was to evaluate the impact of residential proximity to toxic release sites (TRS) and potential implications for low birth weight (LBW) and premature delivery in Shelby County, Tennessee women. The sample (N = 369) included pregnant women who participated in the Blues Project (2007-2009). ArcGIS was used to map the mother's residence at delivery and distance from each of the 10 TRS. Multivariate logistic regression was used to predict LBW and prematurity based on proximity to TRS, while adjusting for probable confounders and effect modifiers. Proximity to Site 8 (odds ratio [OR] = 4.018, confidence interval [CI] = 1.103-14.643) and Site 10 (OR = 2.667, CI = 1.036-6.862) put mothers at increased risk for preterm births. The authors' findings suggest that residential proximity to Site 8 or Site 10 may be a risk factor for premature delivery in Shelby County women. PMID- 21306090 TI - Public officials' perspectives on tracking and investigating symptoms reported near sewage sludge land application sites. AB - A majority of treated sewage sludge (biosolids) from U.S. wastewater treatment plants is applied to farmland as a soil amendment. Residents living close to treated farmland have reported becoming ill following land application of sludge. No systematic tracking or investigation of these reports or of land application practices that could affect off-site migration of chemical and biological constituents of the sludge has occurred, however. In the study described in this article, the authors conducted a web-based survey and phone interviews with officials at federal, state, and local regulatory and health agencies and municipal wastewater treatment plants for input on how to design and implement an investigation protocol for tracking and responding to reports of human illness near land application sites. Officials expressed a need for and interest in implementing a systematic, standardized investigation protocol and offered insights on aids and barriers to its use and collaboration among diverse agencies. Additional opinions and innovative solutions expressed in this article will assist interested users in the implementation of the investigation protocol. PMID- 21306092 TI - Residential carbon monoxide alarm use: opportunities for poisoning prevention. AB - Prevalence of carbon monoxide (CO) alarm usage in localities where they are not required is poorly defined and the reasons for failing to have a home CO alarm have never been described. In this study, the authors conducted a computer-based survey among employees of similar major medical centers in Seattle, Washington, and Salt Lake City, Utah. Questions were asked about the prevalence of use of residential smoke and CO alarms with regard to home style and structure, ownership status, and energy use. Respondents not using home CO detectors were asked the reasons. Among 1,351 individuals participating in the survey, 98% reported residential use of smoke alarms, while only 51% used CO alarms. CO alarm use was more common among residents of Utah than Washington, among home owners than renters, and among those with single family homes rather than other styles. Reasons for failure to use CO alarms related largely to lack of knowledge about the devices and motivation. PMID- 21306091 TI - A study on bicycle-related injuries and their costs in Shanghai, China. AB - China is known as the Bicycle Kingdom, but the nature, extent, and costs of bicycle-related injuries remain largely unknown. The authors' findings showed that the bicycle-related mortality rate increased 99% from 1992 to 2004, and it increased with age, from 0.64 per 100,000 population in the 0-14 age group to 5.93 per 100,000 population in the 65 and older age group. Labor force groups represented the majority of fatalities (70.8%) and nonfatal injuries (81.5%). The male mortality rate was 2.4 times higher than the female mortality rate. Head injuries accounted for 71.9% of fatalities and 33.1% of the hospitalizations. People with lower levels of education had higher injury rates. The poorer districts located in the countryside had the highest mortality rates compared to those located in the central, wealthier regions. The total annual cost of bicycle related injuries was 1.1 billion CHY (Chinese Yuan) (over $137 million U.S.). To reduce bicycle-related injuries, mandatory helmet legislations, environmental modifications, and representative monitoring systems in China are required. PMID- 21306093 TI - Dioxin furan blood lipid and attic dust concentrations in populations living near four wood treatment facilities in the United States. AB - To evaluate historical exposure from wood treatment facilities, attic dust samples were collected from residential structures and blood samples were collected from current and past residents of four communities surrounding wood treatment facilities throughout the United States. The pattern of dioxin/furan congeners detected in both attic dust and blood samples was found to be consistent with exposure to contaminants generated during the wood treatment process. Levels in the U.S. population of 2,3,7,8-tetrachloro-p-dibenzodioxin toxic equivalents (2,3,7,8-TCDD TEQs) for all 17 carcinogenic dioxin/furan congeners as well as octa-chlorinated dibenzo-p-dioxin (OCDD) adjusted to its TEQ value and 1,2,3,4,6,7,8-hepta-chlorinated dibenzo-p-dioxin (1,2,3,4,6,7,8-HpCDD) adjusted to its TEQ value were compared to the TEQ levels in the combined data set for all four communities and in the data sets for each individual community. TEQ concentrations in these communities were found to be significantly greater than in the general U.S. population. The levels of dioxins in attic dust were compared to the U.S. Environmental Protection Agency's regional screening levels and found to far exceed the levels that are regarded as safe for the general population. These findings reveal that a very significant potential for contaminant-related health risks exists in communities surrounding wood treatment facilities. PMID- 21306094 TI - Sulfide tails management within the framework of sustainable development in mineral sand mines--the case study of Sierra Rutile Ltd. AB - The study discussed here assessed Sierra Rutile Ltd.'s (SRLs) water-cover sulfide tails management method. Monthly and quarterly water samples from SRLs Sulfide Tails Pond (STP), Total Tails Pond (TTP), and the Titan Domestic Pond (TDP) were analyzed for 15 months. Results indicated acceptable quality for the STP. From Student's t-test analysis, it was found that the mean pH of the TTP was significantly lower than that of the TDP (p < .05). Results did not indicate pollution of the TDP by SRLs tailings management. The water-cover method significantly suppressed sulfide oxidation in the STP. Concerns to be addressed, however, include potential overtopping of the pond, water level fluctuations, and the need for periodic reinforcement of the tailings embankments. A dedicated environmental monitoring campaign that includes other proximate water bodies is suggested; this should inform timely mitigation of any environmental contamination and promote sound environmental and public health outcomes. PMID- 21306095 TI - Air pollution and vulnerability: solving the puzzle of prioritization. AB - While ambient air pollution levels in excess of prescribed health standards are generally unacceptable, the exceedance is even more serious in areas where people reside. Vulnerability caused by poverty, disease, lack of education, and poor living conditions exacerbates the problem. Air quality management plans identify prioritized strategies for improved air quality independent of consideration of vulnerability. A population exposure and vulnerability risk prioritization framework comprising five themes (air pollution sources; air pollution levels; air pollution potential; community awareness, observations, perceptions, and actions; and vulnerability factors) was proposed and applied to the eThekwini Municipality (Durban, South Africa). Data were scored according to predetermined risk threshold values to ascertain at-risk communities. While those urban wards located in a known air pollution hotspot had the highest air pollution levels, a periurban ward with moderate exposure levels was most vulnerable. This framework will prove invaluable for the development of focused interventions to reduce vulnerability and air pollution-associated adverse health impacts. PMID- 21306096 TI - Evaluation of a local health department's food handler training program. AB - The impact of a food handler training (FHT) program was measured by comparing rates of total and critical violations from routine inspections of food service establishments before (2001-2004) and after (2005-2007) the implementation of an FHT program. A quasiexperimental design compared rates of inspection violations related and unrelated to the responsibilities of food handlers. A subset analysis focused on establishments in business for the entire time period. Violation rates decreased for total and critical food handler-related violations and in practically all individual categories of food handler-related violations. The rate of control violations, however, decreased even more (e.g., critical violations decreased by 4.9% in the food handler group and 24.7% in the control group). Results were similar in the subset analyses. Compared to the control group, no measurable benefit was seen from the FHT program. Improved training through the use of multiple teaching methods and process and qualitative evaluations are recommended. PMID- 21306097 TI - Food safety education: child-to-parent instruction in an immigrant population. AB - A quasi-experimental pretest-posttest design was used to examine increases in food handling knowledge among eastern European refugee restaurant candidates as a result of educational material taught either by the employee's child or the Salt Lake Valley Health Department. Participants were nonrandomly assigned to a study (n = 15) or control group (n = 17). The study group was taught by their children in their native language. The control group was taught by an SLVHD instructor in English. All participants completed pre- and posttests that measured four areas of food handling knowledge: personal hygiene and hand washing (PHHW), cooking and holding time/temperature (COOKTT), cooling and holding time/temperature (COOLTT), and cross-contamination (CC). Both groups demonstrated a significant increase in knowledge of PHHW, but only the study group demonstrated significant improvements in COOKTT and CC knowledge. These study results suggest that food handling education programs are effective in increasing knowledge and mode of delivery may be an important factor. PMID- 21306098 TI - Developing new hazard category language for the Agency for Toxic Substances and Disease Registry's public health assessment products. PMID- 21306099 TI - Guided-inquiry learning in environmental health. AB - The field of environmental health requires the knowledge of many facts and terms, and it also requires mastery of an array of concepts that can be difficult for many students to thoroughly comprehend. Guided-inquiry learning is a process by which students "discover" basic concepts through active investigation. In this article, the authors describe several guided-inquiry learning modules used in their undergraduate environmental health program and their experience in using them. Some modules are used in professional courses while others are used in a general education course. Overall, the authors experienced increased student engagement and interest with guided-inquiry learning. Students are able to comprehend some abstract concepts more quickly and seem to retain the concepts longer. PMID- 21306100 TI - A survey of environmental safety issues at 20 medical clinics. AB - In the study described in this article, the authors performed safety walk throughs or inspections for 20 clinics located both inside a major medical center clinic (onsite) and away from the main clinic site (offsite). A checklist was used to evaluate compliance with institutional, local, state, and federal guidelines and regulations. The results obtained at onsite clinics were compared with the results from offsite clinics. Findings suggested no overall difference in the number of yes (desirable) answers. A marginally significant difference, however, was observed between the onsite and offsite clinics with regard to knowledge of infection control and waste/infection control questions. The walk throughs helped create an improved working relationship between clinic personnel and environmental safety personnel, allowed for correction of safety issues, enabled an informal training opportunity, and increased institutional compliance with guidelines and regulations. PMID- 21306101 TI - Putting theory into practice--CDC's summer program in environmental health (SUPEH). PMID- 21306102 TI - Comment on "Photocatalytic oxidation mechanism of As(III) on TiO2: unique role of As(III) as a charge recombinant species". PMID- 21306104 TI - Pu and 137Cs in the Yangtze River estuary sediments: distribution and source identification. AB - Pu isotopes and (137)Cs were analyzed using sector field ICP-MS and gamma spectrometry, respectively, in surface sediment and core sediment samples from the Yangtze River estuary. (239+240)Pu activity and (240)Pu/(239)Pu atom ratios (>0.18) shows a generally increasing trend from land to sea and from north to south in the estuary. This spatial distribution pattern indicates that the Pacific Proving Grounds (PPG) source Pu transported by ocean currents was intensively scavenged into the suspended sediment under favorable conditions, and mixed with riverine sediment as the water circulated in the estuary. This process is the main control for the distribution of Pu in the estuary. Moreover, Pu is also an important indicator for monitoring the changes of environmental radioactivity in the estuary as the river basin is currently the site of extensive human activities and the sea level is rising because of global climate changes. For core sediment samples the maximum peak of (239+240)Pu activity was observed at a depth of 172 cm. The sedimentation rate was estimated on the basis of the Pu maximum deposition peak in 1963-1964 to be 4.1 cm/a. The contributions of the PPG close-in fallout Pu (44%) and the riverine Pu (45%) in Yangtze River estuary sediments are equally important for the total Pu deposition in the estuary, which challenges the current hypothesis that the riverine Pu input was the major source of Pu budget in this area. PMID- 21306105 TI - Textural properties and their correlation to cell structure in porous food materials. AB - This paper focuses on understanding the role of structural parameters and starch crystallization on the toughness of cake samples. Accurate mechanical measurements were performed to obtain toughness values, and these were related to structural parameters obtained from image analyses. Three-dimensional skeletons of food samples were generated by using X-ray tomography technique. The structural parameters (cell diameter, cell wall thickness, thickness to radius ratio (t/R), fragmentation index) were obtained after processing of the images with CTan software. The basic hypothesis of the paper is to show that the structural parameter t/R is a determinant for predicting toughness, which is a critical indicator of freshness. Freshness in cakes and other baked products is a leading factor in consumer perception. For this purpose three different cake formulations were stored at 37 and 50 degrees C. Cycling from these temperatures to lower storage temperatures of 25 and 4 degrees C was done to accelerate the starch retrogradation rate. Experimental results indicated that there was a strong interrelationship between morphological structure and the mechanical properties with regression coefficients of 0.68 and 0.95. Starch retrogradation, which was followed by X-ray diffractometry, was found to be directly proportional to toughness values, where the percent relative crystallinity increased with storage temperature. PMID- 21306106 TI - Rice bran fermented with saccharomyces boulardii generates novel metabolite profiles with bioactivity. AB - Emerging evidence supporting chronic disease fighting properties of rice bran has advanced the development of stabilized rice bran for human use as a functional food and dietary supplement. A global and targeted metabolomic investigation of stabilized rice bran fermented with Saccharomyces boulardii was performed in three rice varieties. Metabolites from S. boulardii-fermented rice bran were detected by gas chromatography-mass spectrometry (GC-MS) and assessed for bioactivity compared to nonfermented rice bran in normal and malignant lymphocytes. Global metabolite profiling revealed significant differences in the metabolome that led to discovery of candidate compounds modulated by S. boulardii fermentation. Fermented rice bran extracts from three rice varieties reduced growth of human B lymphomas compared to each variety's nonfermented control and revealed that fermentation differentially altered bioactive compounds. These data support that integration of global and targeted metabolite analysis can be utilized for assessing health properties of rice bran phytochemicals that are enhanced by yeast fermentation and that differ across rice varieties. PMID- 21306107 TI - Effect of nanogrinding on the pigment and bioactivity of Djulis ( Chenopodium formosanum Koidz.). AB - Betanin is an antioxidant pigment found in djulis, a grain native to Taiwan, and is a natural source food coloring, but the bright red color degrades rapidly if submitted to light, heat, or oxygen. The effects of nanogrinding on the stability of pigments and bioactive components are unknown. In this study, the color characteristics and bioactivity (antioxidant capacity and enzyme activity) of nanoparticle (NP) djulis was compared with those of intact granules (IG) and microparticles (MP). Results showed that the NP samples exhibited the highest betanin content (2.04 mg/g), which was almost twice that of IG. It was observed that nanogrinding resulted in higher pigment extraction efficiency. However, during storage (5-35 degrees C for 56 days), NP samples showed the most serious pigment degradation, and this color degradation, as expected, had the lowest activation energy. This was more evident when the storage temperature was high. Antioxidant capacities showed the same trends. MP and NP exhibited significantly higher activity of superoxide dismutaste-like activity, lactoperoxidase (LPO), and lysozyme than IG. Gel permeation chromatography confirmed the degradation of larger particles during nanogrinding, which might favor enzyme extraction and their activities. Statistical analysis revealed a close relationship between betanin and antioxidant capacity. PMID- 21306108 TI - Isolation and identification of the DNA aptamer target to acetamiprid. AB - As an alternative to antibodies, aptamers have a great potential as analytical tools for pesticide detection. In this work, aptamers targeting acetamiprid were selected by a specific systematic evolution of ligands by exponential enrichment (SELEX) strategy, where a single-stranded DNA (ssDNA) library was immobilized and target modification was eliminated. After 18 rounds of repeated selection, the ssDNA pool was enriched and then 14 sequences were selected and carefully identified. At last, an acetamiprid-specific aptamer with the apparent dissociation constant (K(d)) estimated to be 4.98 MUM was successfully obtained. Further work is ongoing to develop an aptamer-based detection method for field determination of this pesticides in agricultural products and environmental samples. PMID- 21306111 TI - Split Bull's eye shaped aluminum antenna for plasmon-enhanced nanometer scale germanium photodetector. AB - Bull's eye antennas are capable of efficiently collecting and concentrating optical signals into an ultrasmall area, offering an excellent solution to break the bottleneck between speed and photoresponse in subwavelength photodetectors. Here, we exploit the idea of split bull's eye antenna for a nanometer germanium photodetector operating at a standard communication wavelength of 1310 nm. The nontraditional plasmonic metal aluminum has been implemented in the resonant antenna structure fabricated by standard complementary metal-oxide-semiconductor (CMOS) processing. A significant enhancement in photoresponse could be achieved over the conventional bull's eye scheme due to an increased optical near-field in the active region. Moreover, with this novel antenna design the effective grating area could be significantly reduced without sacrificing device performance. This work paves the way for the future development of low-cost, high-density, and high speed CMOS-compatible germanium-based optoelectronic devices. PMID- 21306110 TI - HIV-1 integrase and neuraminidase inhibitors from Alpinia zerumbet. AB - AIDS and influenza are viral pandemics and remain one of the leading causes of human deaths worldwide. The increasing resistance of these diseases to synthetic drugs demands the search for novel compounds from plant-based sources. In this regard, the leaves and rhizomes of Alpinia zerumbet, a traditionally important economic plant in Okinawa, were investigated for activity against HIV-1 integrase (IN) and neuraminidase (NA). The aqueous extracts of leaves and rhizomes had IN inhibitory activity with IC(50) values of 30 and 188 MUg/mL, whereas against NA they showed 50% inhibition at concentrations of 43 and 57 MUg/mL, respectively. 5,6-Dehydrokawain (DK), dihydro-5,6-dehydrokawain (DDK), and 8(17),12-labdadiene 15,16-dial (labdadiene) were isolated from the rhizomes and were tested for enzyme inhibitions. DK and DDK strongly inhibited IN with IC(50) of 4.4 and 3.6 MUg/mL, respectively. Against NA, DK, DDK, and labdadiene exhibited mixed type of inhibition with respective IC(50) values of 25.5, 24.6, and 36.6 MUM and K(i) values ranging from 0.3 to 2.8 MUM. It was found that DDK is a slow and time dependent reversible inhibitor of NA, probably with a methoxy group as its functionally active site. These results suggest that alpinia could be used as a source of bioactive compounds against IN and NA and that DK and DDK may have possibilities in the design of drugs against these viral diseases. PMID- 21306112 TI - Gate-induced fermi level tuning in InP nanowires at efficiency close to the thermal limit. AB - As downscaling of semiconductor devices continues, one or a few randomly placed dopants may dominate the characteristics. Furthermore, due to the large surface to-volume ratio of one-dimensional devices, the position of the Fermi level is often determined primarily by surface pinning, regardless of doping level. In this work, we investigate the possibility of tuning the Fermi level dynamically with wrap-around gates, instead of statically setting it using the impurity concentration. This is done using Omega-gated metal-oxide-semiconductor field effect transistors with HfO(2)-capped InP nanowires as channel material. It is found that induced n-type devices exhibit an optimal inverse subthreshold slope of 68 mV/decade. By adjusting the growth and process parameters, it is possible to produce ambipolar devices, in which the Fermi level can be tuned across the entire band gap, making it possible to induce both n-type and p-type conduction. PMID- 21306113 TI - Flexible Zn2SnO4/MnO2 core/shell nanocable-carbon microfiber hybrid composites for high-performance supercapacitor electrodes. AB - We demonstrate the design and fabrication of a novel flexible nanoarchitecture by facile coating ultrathin (several nanometers thick) films of MnO2 to highly electrical conductive Zn2SnO4 (ZTO) nanowires grown radially on carbon microfibers (CMFs) to achieve high specific capacitance, high-energy density, high-power density, and long-term life for supercapacitor electrode applications. The crystalline ZTO nanowires grown on CMFs were uniquely served as highly conductive cores to support a highly electrolytic accessible surface area of redox active MnO2 shells and also provide reliable electrical connections to the MnO2 shells. The maximum specific capacitances of 621.6 F/g (based on pristine MnO2) by cyclic voltammetry (CV) at a scan rate of 2 mV/s and 642.4 F/g by chronopotentiometry at a current density of 1 A/g were achieved in 1 M Na2SO4 aqueous solution. The hybrid MnO2/ZTO/CMF hybrid composite also exhibited excellent rate capability with specific energy of 36.8 Wh/kg and specific power of 32 kW/kg at current density of 40 A/g, respectively, and good long-term cycling stability (only 1.2% loss of its initial specific capacitance after 1000 cycles). These results suggest that such MnO2/ZTO/CF hybrid composite architecture is very promising for next generation high-performance supercapacitors. PMID- 21306114 TI - Local temperature determination of optically excited nanoparticles and nanodots. AB - A thin film of Al(0.94)Ga(0.06)N embedded with Er(3+) ions is used as an optical temperature sensor to image the temperature profile around optically excited gold nanostructures of 40 nm gold nanoparticles and lithographically prepared gold nanodots. The sensor is calibrated to give the local temperature of a hot nanostructure by comparing the measured temperature change of a spherical 40 nm gold NP to the theoretical temperature change calculated from the absorption cross section. The calibration allows us to measure the temperature where a lithographically prepared gold nanodot melts, in agreement with the bulk melting point of gold, and the size of the nanodot, in agreement with SEM and AFM results. Also, we measure an enhancement in the Er(3+) photoluminescence due to an interaction of the NP and Er(3+). We use this enhancement to determine the laser intensity that melts the NP and find that there is a positive discontinuous temperature of 833 K. We use this discontinuous temperature to obtain an interface conductance of ~10 MW/m(2)-K for the gold NP on our thermal sensor surface. PMID- 21306115 TI - Rapid halogen substitution and dibenzodioxin formation during tyrosinase catalyzed oxidation of 4-halocatechols. AB - 4-Fluoro-1,2-benzoquinone, generated by tyrosinase oxidation of 4-fluorocatechol in aqueous buffer, rapidly undergoes substitution by O-nucleophiles (water or catechols) with release of fluoride. 4-Chloro- and 4-bromocatechol behave similarly. The reactions, which have toxicological implications, have been monitored by spectrophotometry and HPLC/MS, and intermediate and final products, including dibenzodioxins, identified. PMID- 21306116 TI - DNA alkylation with N-methylquinolinium quinone methide to N2-dG adducts resulting in extensive stops in primer extension with DNA polymerases and subsequent suppression of GFP expression in A549 cells. AB - Quinone methides (QMs) are involved in the metabolism of many drugs and carcinogens as reactive intermediates to form covalent nucleobase adducts in DNA that associate with high mutagenicity. Recently, a plethora of synthetic QM DNA alkylating agents have been developed to form various nucleobase adducts as potential antitumor agents. However, the mutagenic potential of these synthetic QM alkylating agents has not been fully investigated. In this report, N methylquinolinium QM was developed as a synthetic model to study biological consequences of the formation of nucleobase adducts in a DNA target. N Methylquinolinium QM was generated in situ via an elimination process from a bis quaternary ammonium precursor that was synthesized from a quinoline derivative. Alkylation with N-methylquinolinium QM on a DNA target produced mostly a stable N(2)-dG adduct as revealed by gel electrophoresis and DNA digestion assays and confirmed by mass and NMR analyses. The formation of N(2)-dG adducts of a DNA target was found to cause extensive stops in the primer extension with high fidelity DNA polymerase T7 and even low fidelity error prone Dpo4. The direct biological impact of a prealkylated green fluorescence protein plasmid with N methylquinolinium QM was demonstrated as significant suppression of protein expression in A549 cells. Overall, our results suggested that nucleobase-QM adducts could potentially block nucleobase mismatch/translesion in the error prone process to reduce the mutagenic potential if designed carefully. PMID- 21306117 TI - Synthesis and photochemical behavior of the tetrazolo tautomer of 2-azido-4 pyrimidinone-2'-deoxyriboside. AB - The 2-azido analogue of 2'-deoxyuridine was prepared in three steps from 2'-deoxy 2-thiouridine. The sulfur atom of the 2-thio nucleoside was methylated and then displaced by hydrazine to furnish the corresponding 2-hydrazino derivative. After diazotization, the 2-azido compound that exists as its tetrazolo tautomer was obtained. Upon UV irradiation in aqueous solution, the title compound led to isocytosine. PMID- 21306119 TI - Corticosteroid hormone receptors and prereceptors as new biomarkers of the illegal use of glucocorticoids in meat production. AB - Despite the European ban on the use of growth promoters in cattle, veterinary surveillance reports indicate that the illicit use of corticosteroids persists both alone and in combination with anabolic hormones and beta-agonists. Current control strategies should be informed by research into the effects of corticosteroids on bovine metabolism and improved through the development of specific, sensitive diagnostic methods that utilize potential molecular biomarkers of corticosteroid treatment. The actions of corticosteroids on target tissues are principally regulated by two receptors: the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). The effects of these steroids are modulated by prereceptor enzyme-mediated metabolism: the two isoforms of the 11beta-hydroxysteroid dehydrogenase (11beta-HSDs) enzyme catalyze the interconversion between active glucocorticoids, such as cortisol, into inactive compounds, such as cortisone. This study aimed to determine whether the expression of the prereceptor system and of the corticosteroid receptors could be regulated in different target tissues by the administration of dexamethasone and prednisolone in cattle. It was observed that greater up-regulation of the GR and MR genes followed dexamethasone treatment in the muscle tissues than in the kidney, liver, and salivary glands; up-regulation of GR and MR expression following prednisolone treatment was higher in adipose tissue than in the other tissues. The thymus seemed to respond to dexamethasone treatment but not to prednisolone treatment. Both treatments significantly down-regulated 11beta-HSD2 gene expression in the adrenal tissues, but only dexamethasone treatment down regulated 11beta-HSD2 expression in the bulbourethral and prostate glands. Together, these data indicate that the combination of GR, MR, and 11beta-HSD2 could provide a useful biomarker system to detect the use of illicit glucocorticoid treatment in cattle. PMID- 21306120 TI - Expeditious construction of a carbobicyclic skeleton via sp3-C-H functionalization: hydride shift from an aliphatic tertiary position in an internal redox process. AB - Described herein is the first example of an aliphatic, nonbenzylic hydride shift/cyclization sequence that contains two types of novel sp(3)-C-H functionalization: (1) construction of a tetraline skeleton via [1,5]-hydride shift/cyclization and (2) [1,6]-hydride shift/cyclization to form a five-membered ring (indane derivatives). PMID- 21306121 TI - Reductive cyclization cascades of lactones using SmI2-H2O. AB - Lactones bearing two alkenes or an alkene and an alkyne undergo reductive cyclization cascades upon treatment with SmI(2)-H(2)O, giving decorated azulene motifs in excellent yields with good diastereocontrol. PMID- 21306122 TI - A stereodynamic probe providing a chiroptical response to substrate-controlled induction of an axially chiral arylacetylene framework. AB - A stereodynamic probe containing a central 1,4-di(phenylethynyl)benzene rod and two 2-formylphenylethynyl branches has been prepared through a series of Sonogashira cross-coupling reactions with 62% overall yield. This CD silent diarylacetylene-based framework carries two terminal aldehyde groups and provides a strong chiroptical response to substrate-controlled induction of three chiral axes upon diimine formation. The chiral amplification results in intense Cotton effects that can be used for in situ ICD analysis of the absolute configuration and ee of a wide range of amines. PMID- 21306123 TI - Detection of a foreign protein in milk using surface-enhanced Raman spectroscopy coupled with antibody-modified silver dendrites. AB - Herein we developed a rapid and simple method which used surface-enhanced Raman spectroscopy (SERS) coupled with antibody-modified silver dendrites to detect ovalbumin (OVA), the egg white protein, introduced into whole milk. OVA was first captured out of milk by use of antibody-modified silver dendrites and then directly measured on the silver dendrites by Raman spectroscopy. Results show that this method is capable of detecting OVA at 0.1 MUg/mL in phosphate buffered saline (PBS) and 5 MUg/mL in milk within 30 min based on the principal component analysis. This method has the potential for wide use in areas such as allergenic protein detection and bioterrorism agent detection in complex matrixes. PMID- 21306124 TI - Ultratrace enrichment of tyrosine phosphorylated peptides on an imprinted polymer. AB - Novel molecularly imprinted polymers (MIPs) designed to bind the side chain of phosphotyrosine can be used as artificial receptors for affinity-based enrichment of proteolytic peptides. In comparison with general enrichment methods for phosphorylated peptides such as TiO(2)-based methods, the pTyr-imprinted polymers offered high selectivity for pTyr-containing peptides down to the low fmol level. This suggests MIPs as a new tool for affinity-based proteomics. PMID- 21306125 TI - Fabrication of PbS nanoparticle-sensitized TiO2 nanotube arrays and their photoelectrochemical properties. AB - TiO(2) nanotube arrays (NTAs) are modified with PbS nanoparticles by successive ionic layer adsorption and reaction (SILAR) or electrodeposition, with an aim towards tuning the photoelectrochemical cell to the visible region. The PbS modification of the TiO(2) NTAs results in an increase in the visible light adsorption, however the increase in photocurrent is dependent on the modification method. PbS/TiO(2) NTAs prepared by SILAR and electrodeposition show, respectively, photocurrents of 11.02 and 5.72 mA/cm(2). The increase in photocurrent is attributed to enhanced charge separation efficiency and improved electron transport. PMID- 21306126 TI - All-optical full-color displays using polymer nanofibers. AB - We report a number of crossed nanofiber structures for full-color micro/nanodisplays, which were formed by assembling flexible poly(trimethylene terephthalate) (PTT) nanofibers under an optical microscope with the assistance of micromanipulators. The color pixels of the displays consist of micro/nanometer sized color spots in a radius of 300-1500 nm, which were realized through crossed junctions of the PTT nanofibers. The colors of the spots were tuned by changing the power ratios of the launched red, green, and blue lights. We further present a new way to develop white light illumination by combination of red, green, and blue lights with assembly techniques and low production costs. PMID- 21306127 TI - Gold nanoparticle-based simple colorimetric and ultrasensitive dynamic light scattering assay for the selective detection of Pb(II) from paints, plastics, and water samples. AB - Pb (II) is a common water pollutant with high toxicity. According to the CDC, about 310,000 U.S. children of ages 1-5 have high levels of lead in their blood that it is due to the exposure to lead from plastic toys and other products. As a result, the development of ultrasensitive assays for the real-time detection of Pb(II) from plastic toys and paints is very important for water controlling, clinical toxicology and industrial processes. Driven by the need to detect trace amounts of Pb(II) from water samples, we report a label-free, highly selective and ultra sensitive glutathione modified gold nanoparticle based dynamic light scattering (DLS) probe for Pb(II) recognition in 100 ppt level from aqueous solution with excellent discrimination against other heavy metals. The sensitivity of our assay to detect Pb(II) level in water is almost 2 orders of magnitude higher than the EPA standard limit. We have also demonstrated that our DLS assay is capable of measuring the amount of Pb(II) in paint, plastic toys, and water from MS river. A possible mechanism and operating principles of our DLS assay have been discussed. Ultimately, this nanotechnology driven assay could have enormous potential applications in rapid, on-site monitoring of Pb(II) from day-to-day sample. PMID- 21306128 TI - Gradient solvent vapor annealing of block copolymer thin films using a microfluidic mixing device. AB - Solvent vapor annealing (SVA) with solvent mixtures is a promising approach for controlling block copolymer thin film self-assembly. In this work, we present the design and fabrication of a solvent-resistant microfluidic mixing device to produce discrete SVA gradients in solvent composition and/or total solvent concentration. Using this device, we identified solvent composition dependent morphology transformations in poly(styrene-b-isoprene-b-styrene) films. This device enables faster and more robust exploration of SVA parameter space, providing insight into self-assembly phenomena. PMID- 21306129 TI - Inhibitors of the oncogenic transcription factor AP-1 from Podocarpus latifolius. AB - An activator protein-1 (AP-1) based bioassay-guided phytochemical investigation on Podocarpus latifolius led to the isolation of three new sempervirol-type diterpenes, cycloinumakiol (1), inumakal (2), and inumakoic acid (3), along with three known norditerpenes (4-6). Compounds 4 and 6 were responsible for the observed bioactivity. PMID- 21306130 TI - Total synthesis of citridone A. AB - The first total synthesis of citridone A has been achieved through regioselective intramolecular iodocyclization and regio- and stereoselective Pd(0)-catalyzed coupling as key reactions. PMID- 21306132 TI - Atmospheric pressure laser-induced acoustic desorption chemical ionization Fourier transform ion cyclotron resonance mass spectrometry for the analysis of complex mixtures. AB - We present a novel nonresonant laser-based matrix-free atmospheric pressure ionization technique, atmospheric pressure laser-induced acoustic desorption chemical ionization (AP/LIAD-CI). The technique decouples analyte desorption from subsequent ionization by reagent ions generated from a corona discharge initiated in ambient air or in the presence of vaporized toluene as a CI dopant at room temperature. Analyte desorption is initiated by a shock wave induced in a titanium foil coated with electrosprayed sample, irradiated from the rear side by high-energy laser pulses. The technique enables facile and independent optimization of the analyte desorption, ionization, and sampling events, for coupling to any mass analyzer with an AP interface. Moreover, the generated analyte ions are efficiently thermalized by collisions with atmospheric gases, thereby reducing fragmentation. We have coupled AP/LIAD-CI to ultrahigh resolution FT-ICR MS to generate predominantly [M + H](+) or M(+*) ions to resolve and identify thousands of elemental compositions from organic mixtures as complex as petroleum crude oil distillates. Finally, we have optimized the AP/LIAD CI process and investigated ionization mechanisms by systematic variation of placement of the sample, placement of the corona discharge needle, discharge current, gas flow rate, and inclusion of toluene as a dopant. PMID- 21306131 TI - Photocatalytically patterned TiO2 arrays for on-plate selective enrichment of phosphopeptides and direct MALDI MS analysis. AB - We report the development of photocatalytically patterned TiO(2) arrays for selective on-plate enrichment and direct matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) analysis of phosphopeptides. A thin TiO(2) nanofilm with controlled porosity is prepared on gold-covered glass slides by a layer-by-layer (LbL) deposition/calcination process. The highly porous and rough nanostructure offers high surface area for selective binding of phosphorylated species. The patterned arrays are generated using an octadecyltrichlorosilane (OTS) coating in combination of UV irradiation with a photomask, followed by NaOH etching. The resulting hydrophilic TiO(2) spots are thus surrounded by a hydrophobic OTS layer, which can facilitate the enrichment of low-abundance components by confining a large volume sample into a small area. The TiO(2) arrays exhibit high specificity toward phosphopeptides in complex samples including phosphoprotein digests and human serum, and the detection can be made in the fmole range. Additional advantages of the arrays include excellent stability, reusability/reproducibility, and low cost. This method has been successfully applied to the analysis of phosphopeptides in nonfat milk. The patterned TiO(2) arrays provide an attractive interface for performing on-plate reactions, including selective capture of target species for MALDI-MS analysis, and can serve as a versatile lab-on-a-chip platform for high throughput analysis in phosphoproteome research. PMID- 21306133 TI - A squaraine-based colorimetric and "turn on" fluorescent sensor for selective detection of Hg2+ in an aqueous medium. AB - A novel squaraine-based chemosensor SQ-1 has been synthesized, and its sensing behavior toward various metal ions was investigated by UV-vis and fluorescence spectroscopies. In AcOH-H(2)O (40:60, v/v) solution, Hg(2+) ions coordinate with SQ-1 causing a deaggregation which induces a visual color and absorption spectral changes as well as strong fluorescence. In contrast, the addition of other metals (e.g., Pb(2+), Cd(2+), Cu(2+), Zn(2+), Al(3+), Ni(2+), Co(2+), Fe(3+), Ca(2+), K(+), Mg(2+), Na(+), and Ag(+)) does not induce these changes at all. Thus SQ-1 is a specific Hg(2+) sensing agent due to the inducing deaggregation of the dye molecule by Hg(2+). PMID- 21306134 TI - Synthesis of (+/-)-acetylnorloline via stereoselective tethered aminohydroxylation. AB - Loline alkaloids exhibit a strained ether-bridged pyrrolizidine skeleton and possess insecticidal and insect antifeedant properties. The synthesis of acetylnorloline, a prototypical member of the alkaloid family, is described. Central to the route is a stereoselective tethered aminohydroxylation (TA) of a homoallylic carbamate. Allylic (A1,3) strain is exploited to enforce diastereofacial selectivity during the aminohydroxylation. PMID- 21306135 TI - Palladium-catalyzed selective heck-type diarylation of allylic esters with aryl halides involving a beta-OAc elimination process. AB - Palladium-catalyzed selective Heck-type diarylation of allylic esters with aryl halides has been developed. Allylic esters are reacted with aryl iodides to provide the corresponding 1,3-diaryl propenes through a beta-OAc elimination process. It is noteworthy that the methodology can be applied in constructing the indole and benzofuran skeletons. PMID- 21306136 TI - Solid-state photoluminescence sensitization of Tb3+ by novel Au2Pt2 and Au2Pt4 cyanide clusters. AB - The syntheses are reported for two novel Tb(3+) heterotrimetallic cyanometallates, K(2)[Tb(H(2)O)(4)(Pt(CN)(4))(2)]Au(CN)(2).2H(2)O (1) and [Tb(C(10)N(2)H(8))(H(2)O)(4)(Pt(CN)(4))(Au(CN)(2))].1.5C(10)N(2)H(8).2H(2)O (2) (C(10)N(2)H(8) = 2,2'-bipyridine). Both compounds have been isolated as colorless crystals, and single-crystal X-ray diffraction has been used to investigate their structural features. Crystallographic data (MoKalpha, lambda = 0.71073 A, T = 290 K): 1, tetragonal, space group P4(2)/nnm, a = 11.9706(2) A, c = 17.8224(3) A, V = 2553.85(7) A(3), Z = 4; 2, triclinic, space group P1, a = 10.0646(2) A, b = 10.7649(2) A, c = 17.6655(3) A, alpha = 101.410(2) degrees , beta = 92.067(2) degrees , gamma = 91.196(2) degrees , V = 1874.14(6) A(3), Z = 2. For the case of 1, the structure contains Au(2)Pt(4) hexameric noble metal clusters, while 2 includes Au(2)Pt(2) tetrameric clusters. The clusters are alike in that they contain Au-Au and Au-Pt, but not Pt-Pt, metallophilic interactions. Also, the discrete clusters are directly coordinated to Tb(3+) and sensitize its emission in both solid-state compounds, 1 and 2. The Photoluminescence (PL) spectra of 1 show broad excitation bands corresponding to donor groups when monitored at the Tb(3+) ion f-f transitions, which is typical of donor/acceptor energy transfer (ET) behavior in the system. The compound also displays a broad emission band at ~445 nm, assignable to a donor metal centered (MC) emission of the Au(2)Pt(4) clusters. The PL properties of 2 show a similar Tb(3+) emission in the visible region and a lack of donor-based emission at room temperature; however, at 77 K a weak, broad emission occurs at 400 nm, indicative of uncoordinated 2,2' bipyridine, along with strong Tb(3+) transitions. The absolute quantum yield (QY) for the Tb(3+) emission ((5)D(4) -> (7)F(J (J = 6-3))) in 1 is 16.3% with a lifetime of 616 MUs when excited at 325 nm. In contrast the weak MC emission at 445 nm has a quantum yield of 0.9% with a significantly shorter lifetime of 0.61 MUs. For 2 the QY value decreases to 9.3% with a slightly shorter lifetime of 562 MUs. The reduced QY in 2 is considered to be a consequence of (1) the slightly increased donor-acceptor excited energy gap relative to the optimal gap suggested for Tb(3+) and (2) Tb(3+) emission quenching via a bpy ligand-to-metal charge transfer (LMCT) excited state. PMID- 21306137 TI - Europium(III) DOTA-derivatives having ketone donor pendant arms display dramatically slower water exchange. AB - A series of new 1,4,7,10-tetraazacyclododecane-derivatives having a combination of amide and ketone donor groups as side-arms were prepared, and their complexes with europium(III) studied in detail by high resolution NMR spectroscopy. The chemical shift of the Eu(3+)-bound water resonance, the chemical exchange saturation transfer (CEST) characteristics of the complexes, and the bound water residence lifetimes (tau(m)) were found to vary dramatically with the chemical structure of the side-arms. Substitution of ketone oxygen donor atoms for amide oxygen donor atoms resulted in an increase in residence water lifetimes (tau(m)) and a decrease in chemical shift of the Eu(3+)-bound water molecule (Deltaomega). These experimental results along with density functional theory (DFT) calculations demonstrate that introduction of weakly donating oxygen atoms in these complexes results in a much weaker ligand field, more positive charge on the Eu(3+) ion, and an increased water residence lifetime as expected for a dissociative mechanism. These results provide new insights into the design of paramagnetic CEST agents with even slower water exchange kinetics that will make them more efficient for in vivo imaging applications. PMID- 21306138 TI - Fluorescent phosphane selenide as efficient mercury chemodosimeter. AB - The synthesis and photophysical properties of a novel fluorescent sensor are described. The phosphorus-selenium moiety allowed a selective mercury salt complexation, followed by the formation of phosphane oxide, which leads to a turn on of the fluorescence. The sensibility and selectivity toward mercury cations were evaluated (0.18 ppb) and found to be in complete adequation with the targeted level of the World Health Organization, which makes the dye an efficient dosimeter for mercury cations. PMID- 21306139 TI - Interpretation of intermolecular geometric isotope effect in hydrogen bonds: nuclear orbital plus molecular orbital study. AB - The intermolecular geometric isotope effect (GIE) in hydrogen bond A-X...B (X = H and D) is investigated theoretically using the nuclear orbital plus molecular orbital (NOMO) theory. To interpret the GIE in terms of physically meaningful energy components such as electrostatic and exchange-repulsion interactions, the reduced variational space self-consistent-field method is extended to the NOMO scheme. The intermolecular GIE is analyzed as a two-stage process: the intramolecular bond shrinkage and the intermolecular bond elongation. According to the isotopic shifts of energy components described by the NOMO/MP2 method, the intermolecular GIE is approximately interpreted as a process reducing the exchange-repulsion interaction after the decrease of electrostatic interaction. PMID- 21306140 TI - Effect of structure on the rate constants for reaction of NO3 radicals with a series of linear and branched C5-C7 1-alkenes at 296 +/- 2 K. AB - Rate constants for the gas-phase reactions of NO3 radicals with 13 linear and branched C5-C7 1-alkenes, CH2?CHR, where R = alkyl, have been measured at 296 +/- 2 K and atmospheric pressure of air by a relative rate method. 1-Butene was used as the reference compound, and the rate constants obtained (in units of 10(-14) cm(3) molecule(-1) s(-1)) were as follows: 1-pentene, 1.50 +/- 0.07; 1-hexene, 1.80 +/- 0.08; 1-heptene, 2.06 +/- 0.14; 3-methyl-1-butene, 1.39 +/- 0.04; 3 methyl-1-pentene, 1.39 +/- 0.03; 4-methyl-1-pentene, 1.52 +/- 0.04; 3,3-dimethyl 1-butene, 1.54 +/- 0.03; 3-methyl-1-hexene, 1.65 +/- 0.08; 4-methyl-1-hexene, 1.86 +/- 0.08; 5-methyl-1-hexene, 2.14 +/- 0.08; 3,3-dimethyl-1-pentene, 1.44 +/- 0.07; 3,4-dimethyl-1-pentene, 1.49 +/- 0.10; and 4,4-dimethyl-1-pentene, 1.37 +/- 0.06; where the indicated errors are two least-squares standard deviations and do not include uncertainties in the rate constant for the reference compound 1 butene. These rate constants increase along the series 1-butene < 1-pentene < 1 hexene < 1-heptene, and this is attributed to inductive effects. For a given carbon number, the rate constants depend on the position and degree of branching, and the observed trend of measured rate constants with position and degree of branching in the alkyl substituent group R correlates well with steric hindrance as calculated by McGillen et al. ( Phys. Chem. Chem. Phys. 2008 , 10 , 1757 ). PMID- 21306141 TI - Preparation of a versatile bifunctional zeolite for targeted imaging applications. AB - Bifunctional zeolite Y was prepared for use in targeted in vivo molecular imaging applications. The strategy involved functionalization of the external surface of zeolite Y with chloropropyltriethoxysilane followed by reaction with sodium azide to form azide-functionalized NaY, which is amenable to copper(1)-catalyzed click chemistry. In this study, a model alkyne (4-pentyn-1-ol) was attached to the azide-terminated surface via click chemistry to demonstrate feasibility for attachment of molecular targeting vectors (e.g., peptides, aptamers) to the zeolite surface. The modified particle efficiently incorporates the imaging radioisotope gallium-68 ((68)Ga) into the pores of the azide-functionalized NaY zeolite to form a stable bifunctional molecular targeting vector. The result is a versatile "clickable" zeolite platform that can be tailored for future in vivo molecular targeting and imaging modalities. PMID- 21306142 TI - Swapping FAD binding motifs between plastidic and bacterial ferredoxin-NADP(H) reductases. AB - Plant-type ferredoxin-NADP(H) reductases (FNRs) are grouped in two classes, plastidic with an extended FAD conformation and high catalytic rates and bacterial with a folded flavin nucleotide and low turnover rates. The 112-123 beta-hairpin from a plastidic FNR and the carboxy-terminal tryptophan of a bacterial FNR, suggested to be responsible for the FAD differential conformation, were mutually exchanged. The plastidic FNR lacking the beta-hairpin was unable to fold properly. An extra tryptophan at the carboxy terminus, emulating the bacterial FNR, resulted in an enzyme with decreased affinity for FAD and reduced diaphorase and ferredoxin-dependent cytochrome c reductase activities. The insertion of the beta-hairpin into the corresponding position of the bacterial FNR increased FAD affinity but did not affect its catalytic properties. The same insertion with simultaneous deletion of the carboxy-terminal tryptophan produced a bacterial chimera emulating the plastidic architecture with an increased k(cat) and an increased catalytic efficiency for the diaphorase activity and a decrease in the enzyme's ability to react with its substrates ferredoxin and flavodoxin. Crystallographic structures of the chimeras showed no significant changes in their overall structure, although alterations in the FAD conformations were observed. Plastidic and bacterial FNRs thus reveal differential effects of key structural elements. While the 112-123 beta-hairpin modulates the catalytic efficiency of plastidic FNR, it seems not to affect the bacterial FNR behavior, which instead can be improved by the loss of the C-terminal tryptophan. This report highlights the role of the FAD moiety conformation and the structural determinants involved in stabilizing it, ultimately modulating the functional output of FNRs. PMID- 21306143 TI - VX680 binding in Aurora A: pi-pi interactions involving the conserved aromatic amino acid of the flexible glycine-rich loop. AB - The regulation of protein kinases requires flexibility, especially near the ATP binding site. The cancer drug target Aurora A is inhibited by the ATP site inhibitor VX680, and published crystal structures show two distinct conformations. In one, a refolded glycine-rich loop creates a stacked pi-pi interaction between the conserved aromatic residue of the glycine-rich loop hairpin turn (F144) and the inhibitor. This refolding, associated with binding to a peptide derived from the cofactor TPX2, is absent in the other structure. We use surface plasmon resonance to measure VX680 binding to native and mutant F144A Aurora A kinase domains, with and without the TPX2 peptide. Results show that the F144 aromatic side chain contributes 2 kcal/mol to the VX680 binding energy, independent of the TPX2 peptide. This indicates that distinct VX680 bound conformations of Aurora A cannot be simply correlated with TPX2 binding and that Aurora A retains flexibility when inhibitor-bound. Molecular dynamics simulations show that alternate geometries for the pi-pi interactions are feasible in the absence of the rigidifying packing interactions seen in the crystal lattice. PMID- 21306144 TI - Ab initio coupled cluster determination of the heats of formation of C2H2F2, C2F2, and C2F4. AB - Heats of formation at 298.15 K were computed for cis- and trans-1,2 difluoroethylene, 1,1-difluoroethylene, difluoroethyne, and tetrafluoroethylene using conventional coupled cluster theory through perturbative triples and basis sets up through augmented 6zeta or 7zeta quality. As an independent check, calculations were also performed with the explicitly correlated F12b method and basis sets up through 4zeta quality. F12b calculations converge to the basis set limit much more rapidly than the conventional method. Both approaches were subsequently extrapolated to the complete basis set limit using a variety of simple formulas. After the 1-particle basis set limits were established, corrections were applied for core/valence, scalar relativistic, non-Born Oppenheimer, and higher order correlation effects through explicit quadruple excitations. A final correction for the remaining error relative to full configuration interaction theory, the exact result for a given basis set, was included. Although this general approach produced excellent agreement with recently reported semiexperimental structures for the difluoroethylene compounds, the level of agreement with the available tabulated experimental heats of formation for 1,1-difluoroethylene is considerably poorer. The best theoretical DeltaHf(0)(298K) estimates (with experimental values from tabulations given in parentheses) are 1,1-difluoroethylene = -84.1 +/- 0.6 kcal/mol (-80.5 +/- 0.2); cis-1,2-difluoroethylene = -74.4 +/- 0.6 kcal/mol (-73.3 +/- 1.2); trans-1,2 difluoroethylene = -73.5 +/- 0.6 kcal/mol (-72.6 +/- 1.2). In the other two cases, where Active Thermochemical Table values were available, the agreement was much better: C2F2 = 1.0 +/- 0.3 (0.7 +/- 0.4) and C2F4 = -161.3 +/- 0.8 kcal/mol (-161.8 +/- 0.2). Considering the demonstrated accuracy of the approach in previous studies for the three difluoroethylene equilibrium structures and its performance in predicting the enthalpies of formation of over 100 small-to-medium size chemical systems, we believe the magnitude of disagreement between theory and experiment for 1,1-difluoroethylene merits a re-examination of the experimental value. PMID- 21306145 TI - Consistency in the sum frequency generation intensity and phase vibrational spectra of the air/neat water interface. AB - Substantial progress has been made in the quantitative understanding and interpretation of the hydrogen bonding and ordering structure of the air/water interface since the first sum-frequency generation vibrational spectroscopy (SFG VS) measurement by Q. Du et al. in 1993 (Phys. Rev. Lett. 1993, 70, 2312-2316). However, there are still disagreements and controversies on the consistency between the different experimental measurements, as well as in the theoretical and computational results. One critical problem lies in the lack of consistency between the SFG-VS intensity measurements and the recently developed SFG-VS phase spectra measurements of the neat air/water interface, which has inspired various theoretical efforts. In this report, the reliability of the SFG-VS intensity spectra of the air/neat water interface is to be quantitatively examined, and possible sources of inaccuracies in the SFG-VS phase spectral measurement are to be discussed based on the nonresonant SHG phase measurements. Solid evidence is shown indicating that the SFG-VS intensity spectra from different laboratories are now quantitatively converging and in agreement with each other. However, the possible inaccuracies and inconsistencies in the SFG-VS phase spectra measurements need to be carefully examined against a properly corrected phase standard to take full advantage of this powerful experimental tool. PMID- 21306146 TI - CH2Cl2 + OH- reaction in aqueous solution: a combined quantum mechanical and molecular mechanics study. AB - The CH2Cl2 + OH(-) reaction in aqueous solution was investigated using combined quantum mechanical and molecular mechanics approach. We present analysis of the reactant, transition, and product state structures and calculate the free energy reaction profile through the CCSD(T) level of the theory for the reactive region. Our results show that the aqueous environment has a significant impact on the reaction process, raising the reaction barrier by ~ 17 kcal/mol and the reaction energy by ~ 20 kcal/mol. While solvation effects play a predominant role, we also find sizable contributions from solvent-induced polarization effects. PMID- 21306147 TI - Effect of osmolytes on protein dynamics in the lactate dehydrogenase-catalyzed reaction. AB - Laser-induced temperature jump relaxation spectroscopy was used to probe the effect of osmolytes on the microscopic rate constants of the lactate dehydrogenase-catalyzed reaction. NADH fluorescence and absorption relaxation kinetics were measured for the lactate dehydrogenase (LDH) reaction system in the presence of varying amounts of trimethylamine N-oxide (TMAO), a protein stabilizing osmolyte, or urea, a protein-destabilizing osmolyte. Trimethylamine N oxide (TMAO) at a concentration of 1 M strongly increases the rate of hydride transfer, nearly nullifies its activation energy, and also slightly increases the enthalpy of hydride transfer. In 1 M urea, the hydride transfer enthalpy is almost nullified, but the activation energy of the step is not affected significantly. TMAO increases the preference of the closed conformation of the active site loop in the LDH.NAD(+).lactate complex; urea decreases it. The loop opening rate in the LDH.NADH.pyruvate complex changes its temperature dependence to inverse Arrhenius with TMAO. In this complex, urea accelerates the loop motion, without changing the loop opening enthalpy. A strong, non-Arrhenius decrease in the pyruvate binding rate in the presence of TMAO offers a decrease in the fraction of the open loop, pyruvate binding competent form at higher temperatures. The pyruvate off rate is not affected by urea but decreases with TMAO. Thus, the osmolytes strongly affect the rates and thermodynamics of specific events along the LDH-catalyzed reaction: binding of substrates, loop closure, and the chemical event. Qualitatively, these results can be understood as an osmolyte-induced change in the energy landscape of the protein complexes, shifting the conformational nature of functional substates within the protein ensemble. PMID- 21306148 TI - Comparative die-off of Escherichia coli O157:H7 and fecal indicator bacteria in pond water. AB - In situ and in vitro experiments were performed to assess the effects of solar radiation and predation by indigenous microflora on the relative die-off rates of a toxigenic strain of Escherichia coli O157:H7, commensal E. coli, and fecal enterococci in surface waters from ponds in agricultural watersheds. The objective of these experiments was to discern a mechanism of persistence of E. coli O157:H7 in surface waters compared to fecal indicator bacteria. Results of these experiments indicated that E. coli and fecal enterococci were affected by both insolation and apparent predation; whereas E. coli O157:H7 appeared to be resistant to both of these environmental stressors. The number of days to reach 99% die-off (T(99)-values) for E. coli O157:H7 was significantly greater than that for the indicator bacteria. The capacity to prolong die-off may be connected to the apparent persistence of E. coli O157:H7 in surface waters. PMID- 21306149 TI - Trapping a labile adduct formed between an ortho-quinone methide and 2' deoxycytidine. AB - Selective oxidation by bis[(trifluoroacetoxy)iodo]benzene (BTI) provides an effective trap for quenching adducts formed reversibly between dC and an ortho quinone methide (QM) under physiological conditions. A model adduct generated by 4-methyl-o-QM and 2'-deoxycytidine is rapidly converted by intramolecular cyclization and loss of aromaticity to a characteristic product for quantifying QM alkylation. However, BTI induces a surprising rearrangement driven by overoxidation of a derivative lacking an alkyl substituent at the 4-position of the QM. PMID- 21306150 TI - O2-(N-hydroxy(methoxy)-2-ethanesulfonamido) protected diazen-1-ium-1,2-diolates: nitric oxide release via a base-induced beta-elimination cleavage. AB - O(2)-(Ethanesulfohydroxamic acid) and O(2)-(N-methoxy-2-ethanesulfonylamido) diazen-1-ium-1,2-diolates (4-7), a novel type of O(2)-(protected) diazeniumdiolate, were synthesized using a key thioacetate oxidation reaction. Nitric oxide release studies showed that O(2)-(N-methoxy-2-ethanesulfonylamido) diazeniumdiolates 5 and 7 released NO in a nonphysiological alkaline buffer, in the presence of bases such as the basic natural amino acids Arg and His, or the non-nucleophilic organic base DBU in PBS at pH 7.4, via a beta-elimination cleavage reaction. PMID- 21306151 TI - Asymmetric synthesis of amines by the Knochel-type MgCl2-enhanced addition of benzyl zinc reagents to N-tert-butanesulfinyl aldimines. AB - The MgCl(2)-enhanced addition of benzyl zinc reagents to N-tert-butanesulfinyl imines proceeds readily at room temperature to afford the N-tert-butanesulfinyl protected amine products in good yields and diastereomeric ratios. This method is functional group tolerant in both the imine substrate and benzyl zinc coupling partner. Moreover, benzyl zinc reagent addition to the N-tert-butanesulfinyl imine 3o prepared from isopropylidene-protected glyceraldehyde proceeds in high yield and with exceptional selectivity to provide rapid entry to hydroxyethylamine-based aspartyl protease inhibitors. PMID- 21306152 TI - Catalytic thia-Sommelet-Hauser rearrangement: application to the synthesis of oxindoles. AB - A series of 3-arylthio-1,3-disubstituted-oxindoles were prepared in good yields by the reaction of alpha-diazocarbonyl compounds and sulfenamides. The reaction involves a Rh-catalyzed thia-Sommelet-Hauser-type rearrangement. PMID- 21306153 TI - Nanonet-based hematite heteronanostructures for efficient solar water splitting. AB - We report the highest external quantum efficiency measured on hematite (alpha Fe(2)O(3)) without intentional doping in a water-splitting environment: 46% at lambda = 400 nm. This result was enabled by the introduction of TiSi(2) nanonets, which are highly conductive and have suitably high surface areas. The nanonets serve a dual role as a structural support and an efficient charge collector, allowing for maximum photon-to-charge conversion. Without the addition of any oxygen-evolving catalysts, we obtained photocurrents of 1.6 and 2.7 mA/cm(2) at 1.23 and 1.53 V vs RHE, respectively. These results highlight the importance of charge transport in semiconductor-based water splitting, particularly for materials whose performance is limited by poor charge diffusion. Our design introduces material components to provide a dedicated charge-transport pathway, alleviating the reliance on the materials' intrinsic properties, and therefore has the potential to greatly broaden where and how various existing materials can be used in energy-related applications. PMID- 21306154 TI - Detecting nanoscale size dependence in VO2 phase transition using a split-ring resonator metamaterial. AB - We have measured the size dependence of a solid-solid phase transformation in discrete nanoscale volumes of vanadium dioxide (VO(2)) defined by split-ring resonators. By monitoring the in-coupling plasmonic mode while thermally cycling through the insulator-metal transition, we show that hysteresis width broadens with reduced interrogation volume (i.e., number of intrinsic nucleation sites). The results further imply a volume range over which both electronic and structural components of the switching exhibit similar size dependence. PMID- 21306155 TI - Efficient synthesis of 5H-cyclopenta[c]quinoline derivatives via palladium catalyzed domino reactions of o-alkynylhalobenzene with amine. AB - A novel and efficient route for the synthesis of 5H-cyclopenta[c]quinoline derivatives via a palladium-catalyzed domino reaction of o-alkynylhalobenzene with amine is described. The starting materials are easily available, and the reaction proceeds smoothly with high efficiency, which shows broad scope with good functional group tolerance. PMID- 21306156 TI - Three-coordinate NiII: tracing the origin of an unusual, facile Si-C(sp3) bond cleavage in [(tBu2PCH2SiMe2)2N]Ni+. AB - All attempts to synthesize (PNP)Ni(OTf) form instead ((t)Bu(2)PCH(2)SiMe(2)NSiMe(2)OTf)Ni(CH(2)P(t)Bu(2)). Abstraction of F(-) from (PNP)NiF by even a catalytic amount of BF(3) causes rearrangement of the (transient) (PNP)Ni(+) to analogous ring-opened [((t)Bu(2)PCH(2)SiMe(2)NSiMe(2)F)]Ni(CH(2)P(t)Bu(2)). Abstraction of Cl(-) from (PNP)NiCl with NaB(C(6)H(3)(CF(3))(2))(4) in CH(2)Cl(2) or C(6)H(5)F gives (PNP)NiB(C(6)H(3)(CF(3))(2))(4), the key intermediate in these reactions is (PNP)Ni(+), [(PNP)Ni](+), in which one Si-C bond (together with N and two P) donates to Ni. This makes this Si-C bond subject to nucleophilic attack by F(-), triflate, and alkoxide/ether (from THF). This sigma(Si-C) complex binds CO in the time of mixing and also binds chloride, both at nickel. Evidence is offered of a "self-healing" process, where the broken Si-C bond can be reformed in an equilibrium process. (PNP)Ni(+) reacts rapidly with H(2) to give (PN(H)P)NiH(+), which can be deprotonated to form (PNP)NiH. A variety of nucleophilic attacks (and THF polymerization) on the coordinated Si-C bond are envisioned to occur perpendicular to the Si-C bond, based on the character of the LUMO of (PNP)Ni(+). PMID- 21306157 TI - Concentration and temperature dependency of regio- and stereoselectivity in a photochemical [2 + 2] cycloaddition reaction (the Paterno-Buchi reaction): origin of the hydroxy-group directivity. AB - A set of photochemical oxetane formation reactions, i.e., the Paterno-Buchi (PB) reactions, of tetrahydrobenzofuranol derivatives 1a-d with benzophenone (BP) was investigated to examine poorly understood hydroxy-group directivity on regio- and stereoselectivity. The selectivities of the PB reactions for allylic alcohols 1a,d were found to be largely dependent upon the concentration of the allylic alcohols and the reaction temperature. The temperature-dependent change of the regioselectivity at high concentrations of allylic alcohols was similar to that of the hydroxy-protected methyl ether 1b and tetrahydrobenzofuran (1c). The effect of concentration on regioselectivity can be explained by the hydrogen bonded aggregates, which mimic the selectivities observed during the PB reaction of 1b,c. The hydroxy-directed cis-selectivity of the higher-substituted oxetane 3a,d formed at low concentration of 1a,d was found to be larger than that at the higher concentration of 1a,d. The cis-selectivity of 3a,d was found to be higher than that of the lower-substituted oxetane 2a,d. The regioselectivity of the cis configured oxetanes was higher than that of the trans-configured oxetanes. These experimental results strongly suggest that hydroxy-group directivity, induced by hydrogen-bonding stabilization, plays a role in controlling the regio- and stereoselectivity of the PB reactions. The steric effect was also responsible for the diastereoselectivity, as shown by the fact that the cis selectivity in 3d was higher than that in 3a. Computational studies at the (U)MP2 and (U)DFT level of theory revealed that hydrogen-bonding stabilization becomes important only in the excited complex (exciplex) between the triplet excited state of carbonyls and alkenes, in which the charge transfer occurs from the alkene to the excited carbonyl to make the carbonyl oxygen nucleophilic. No significant stabilization energy was found in the intermediary triplet state of biradicals. The combined experimental and computational studies have clarified the origin of the poorly understood hydroxy-group effect on a high degree of regio- and stereoselectivity, i.e., the cooperative effect of hydrogen-bonding stabilization in exciplexes and the steric bulk of the substituents. PMID- 21306158 TI - Chain packing in glassy polymers by natural-abundance 13C-13C spin diffusion using 2D centerband-only detection of exchange. AB - The proximities of specific subgroups of nearest-neighbor chains in glassy polymers are revealed by distance-dependent (13)C-(13)C dipolar couplings and spin diffusion. The measurement of such proximities is practical even with natural-abundance levels of (13)C using a 2D version of centerband-only detection of exchange (CODEX). Two-dimensional CODEX is a relaxation-compensated experiment that avoids the problems associated with variations in T(1)(C)'s due to dynamic site heterogeneity in the glass. Isotropic chemical shifts are encoded in the t(1) preparation times before and after mixing, and variations in T(2)'s are compensated by an S(0) reference (no mixing). Data acquisition involves acquisition of an S(0) reference signal on alternate scans, and the active control of power amplifiers, to achieve stability and accuracy over long accumulation times. The model system to calibrate spin diffusion is the polymer itself. For a mixing time of 200 ms, only (13)C-(13)C pairs separated by one or two bonds (2.5 A) show cross peaks, which therefore identify reference intrachain proximities. For a mixing time of 1200 ms, 5 A interchain proximities appear. The resulting cross peaks are used in a simple and direct way to compare nonrandom chain packing for two commercial polycarbonates with decidedly different mechanical properties. PMID- 21306160 TI - Low-bandgap donor-acceptor conjugated polymer sensitizers for dye-sensitized solar cells. AB - A set of two donor-acceptor type conjugated polymers with carboxylic acid side groups have been synthesized and utilized as active materials for dye-sensitized solar cells (DSSCs). The polymers feature a pi-conjugated backbone consisting of an electron-poor 2,1,3-benzothiadiazole (BTD, acceptor) unit, alternating with either a thiophene-fluorene-thiophene triad (2a) or a terthiophene (3a) segment as the donor. The donor-acceptor polymers absorb broadly throughout the visible region, with terthiophene-BTD polymer 3a exhibiting an absorption onset at approximately 625 nm corresponding to a ~1.9 eV bandgap. The polymers adsorb onto the surface of nanostructured TiO(2) due to interaction of the polar carboxylic acid units with the metal oxide surface. The resulting films absorb visible light strongly, and their spectra approximately mirror the polymers' solution absorption. Interestingly, a series of samples of 3a with different molecular weight (M(n)) adsorb to TiO(2) to an extent that varies inversely with M(n). DSSCs that utilize the donor-acceptor polymers as sensitizers were tested using an I(-)/I(3)(-) electrolyte. Importantly, for the set of polymer sensitizers 3a with varying M(n), the DSSC efficiency varies inversely with M(n), a result that reflects the difference in adsorption efficiency observed in the film absorption experiments. The best DSSC cell tested is based on a sample of 3a with M(n) ~ 4000, and it exhibits a ~65% peak IPCE with J(sc) ~12.6 mA cm(-2) under AM1.5 illumination and an overall power conversion efficiency of ~3%. PMID- 21306159 TI - Relative helix-helix conformations in branched aromatic oligoamide foldamers. AB - The de novo design and synthesis of large and well-organized, tertiary-like, alpha-peptidic folded architectures is difficult because it relies on multiple cooperative interactions within and between secondary folded motifs of relatively weak intrinsic stability. The very stable helical structures of oligoamides of 8 amino-2-quinoline carboxylic acid offer a way to circumvent this difficulty thanks to their ability to fold into predictable and stable secondary motifs. Branched architectures comprised of two pairs of tetrameric (1), pentameric (2), or octameric (3) oligomers connected via an ethylene glycol spacer were designed and synthesized. The short spacer holds two helices in close proximity, thus enabling interactions between them. Degrees of freedom allowed in the system are well-defined: the relative P or M handedness of the two helices; the relative orientation of the helix axes; and the gauche or anti conformation of the ethylene spacer. Investigating the structures of 1-3 in the solid state and in solution allowed a detailed picture to be drawn of their conformational preferences and dynamics. The high variability of the solid state structures provides many snapshots of possible solution conformations. Helix-helix handedness communication was evidenced and shown to depend both on solvent and on a defined set of side chains at the helix-helix interface. Interdigitation of the side chains was found to restrict free rotation about the ethylene spacer. One solid state structure shows a high level of symmetry and provides a firm basis to further design specific side chain/side chain directional interactions. PMID- 21306161 TI - Controlling nanocrystal superlattice symmetry and shape-anisotropic interactions through variable ligand surface coverage. AB - The assembly of colloidal nanocrystals (NCs) into superstructures with long-range translational and orientational order is sensitive to the molecular interactions between ligands bound to the NC surface. We illustrate how ligand coverage on colloidal PbS NCs can be exploited as a tunable parameter to direct the self assembly of superlattices with predefined symmetry. We show that PbS NCs with dense ligand coverage assemble into face-centered cubic (fcc) superlattices whereas NCs with sparse ligand coverage assemble into body-centered cubic (bcc) superlattices which also exhibit orientational ordering of NCs in their lattice sites. Surface chemistry characterization combined with density functional theory calculations suggest that the loss of ligands occurs preferentially on {100} than on reconstructed {111} NC facets. The resulting anisotropic ligand distribution amplifies the role of NC shape in the assembly and leads to the formation of superlattices with translational and orientational order. PMID- 21306162 TI - Charge transfer via the dative N-B bond and dihydrogen contacts. Experimental and theoretical electron density studies of four deltahedral boranes. AB - In an approach combining high resolution X-ray diffraction at low temperatures with density functional calculations, two closo-borates, B12H12(2-) (1) and B10H10(2-) (2), and two arachno-boranes, B10H12L2 (L = amine (3) or acetonitrile (4)), are studied by means of Atoms In Molecules (AIM) theory and Electron Localizability Indicator (ELI-D). The charge transfer via the dative N-B bonds in the arachno-boranes and via dihydrogen contacts in the closo-borates is quantified. The dative N-B bond in 4 is significantly shorter and stronger than that in 3 and in small N-B Lewis acid base adducts from the literature. It is even shorter in the gas phase than in the crystal environment in contrast to the bond shortening in the crystal generally found for N-B Lewis acid-base adducts. Furthermore, the calculated charge transfer in terms of AIM charges is opposite to the expected N -> B direction but still weak as found for all other N-B bonds. The intramolecular charge redistributions due to intermolecular interactions are quantified by the AIM and ELI-D analysis of contact ion pairs. The latter method gives a deeper understanding of delocalization effects in the borane cages as well as in the counterions. Since dihydrogen bonds are rarely found in crystal structures, one focus was directed to the topologies of the large number of 58 experimentally found contacts of this type. The analysis reveals that the electron density at the bond critical point, the corresponding Laplace function, and the curvature along the bond path (lambda3) show a behavior that clearly discriminates these interactions from classical hydrogen bonds, confirming earlier theoretical findings. PMID- 21306163 TI - Asymmetric synthesis of alpha-methyl-alpha-amino acids via diastereoselective alkylation of (1S)-(+)-3-carene derived tricyclic iminolactone. AB - A novel carene-based alanine-equivalent tricyclic iminolactone 16 has been synthesized via stereoselective dihydroxylation of the double bond, IBX oxidation of the secondary alcohol, esterification of the tertiary alcohol, deprotection of the resulting ester, and subsequent cyclization from commercially available (1S) (+)-3-carene in 79% overall yield. The iminolactone 16 demonstrated high reactivity toward alkylation with a wide range of electrophiles at room temperature under phase-transfer catalysis conditions. The alkylated products were produced with excellent diastereoselectivities (>98% de) in good isolated yields (86-94%). High yields (83-91%) of optically pure (S)-alpha-methyl-alpha substituted-alpha-amino acids were obtained by basic hydrolysis of the dialkylated iminolactones with the recovery of the chiral auxiliary 15 (78-87%). PMID- 21306164 TI - Stoichiometric and oxygen-rich M2O(n)- and M2O(n) (M = Nb, Ta; n = 5-7) clusters: molecular models for oxygen radicals, diradicals, and superoxides. AB - We investigated the structures and bonding of two series of early transition metal oxide clusters, M(2)O(n)(-) and M(2)O(n) (M = Nb, Ta; n = 5-7) using photoelectron spectroscopy (PES) and density-functional theory (DFT). The stoichiometric M(2)O(5) clusters are found to be closed shell with large HOMO LUMO gaps, and their electron affinities (EAs) are measured to be 3.33 and 3.71 eV for M = Nb and Ta, respectively; whereas EAs for the oxygen-rich clusters are found to be much higher: 5.35, 5.25, 5.28, and 5.15 eV for Nb(2)O(6), Nb(2)O(7), Ta(2)O(6), and Ta(2)O(7), respectively. Structural searches at the B3LYP level yield triplet and doublet ground states for the oxygen-rich neutral and anionic clusters, respectively. Spin density analyses reveal oxygen radical, diradical, and superoxide characters in the oxygen-rich clusters. The M(2)O(7)(-) and M(2)O(7) clusters, which can be viewed to be formed by M(2)O(5)(-/0) + O(2), are utilized as molecular models to understand dioxygen activation on M(2)O(5)(-) and M(2)O(5) clusters. The O(2) adsorption energies on the stoichiometric M(2)O(5) neutrals are shown to be surprisingly high (1.3-1.9 eV), suggesting strong capabilities to activate O(2) by structural defects in Nb and Ta oxides. The PES data also provides valuable benchmarks for various density functionals (B3LYP, BP86, and PW91) for the Nb and Ta oxides. PMID- 21306166 TI - Targeted biocompatible nanoparticles for the delivery of (-)-epigallocatechin 3 gallate to prostate cancer cells. AB - Molecular targeted cancer therapy mediated by nanoparticles (NPs) is a promising strategy to overcome the lack of specificity of conventional chemotherapeutic agents. In this context, the prostate-specific membrane antigen (PSMA) has demonstrated a powerful potential for the management of prostate cancer (PCa). Cancer chemoprevention by phytochemicals is emerging as a suitable approach for the treatment of early carcinogenic processes. Since (-)-epigallocatechin 3 gallate (EGCG) has shown potent chemopreventive efficacy for PCa, we designed and developed novel targeted NPs in order to selectively deliver EGCG to cancer cells. Herein, to explore the recent concept of "nanochemoprevention", we present a study on EGCG-loaded NPs consisting of biocompatible polymers, functionalized with small molecules targeting PSMA, that exhibited a selective in vitro efficacy against PSMA-expressing PCa cells. This approach could be beneficial for high risk patients and would fulfill a significant therapeutic need, thus opening new perspectives for novel and effective treatment for PCa. PMID- 21306165 TI - Rapid grafting of azido-labeled oligo(ethylene glycol)s onto an alkynyl terminated monolayer on nonoxidized silicon via microwave-assisted "click" reaction. AB - Microwave (MW) irradiation was used for the grafting of azido-labeled oligo(ethylene oxide) (OEG) on alkynyl-terminated nonoxidized silicon substrates via copper-catalyzed "click" reaction. The "clickable" monolayers were prepared by photografting of an alpha,omega-alkynene, where the alkynyl terminus was protected by a trimethylgermanyl (TMG) group, onto hydrogen-terminated Si(111) surfaces. X-ray photoelectron spectroscopy (XPS) was primarily employed to characterize the monolayers, and the data obtained were utilized to calculate the surface density of the TMG-alkynyl-functionalized substrate. MW-assisted one-pot deprotection/click reaction was optimized on the surfaces using azido-tagged OEG derivatives. Using MW instead of conventional heating led to a substantial improvement in the rate of the reaction while suppressing the oxidation of the silicon interface and OEG degradation. The antifouling property of the resulting substrates was evaluated using fibrinogen as a model protein. Results show that the OEG-modification reduced the protein adsorption by >90%. PMID- 21306167 TI - Discovery of novel and potent orally active calcium-sensing receptor antagonists that stimulate pulselike parathyroid hormone secretion: synthesis and structure activity relationships of tetrahydropyrazolopyrimidine derivatives. AB - As part of our research for novel calcium-sensing receptor (CaSR) antagonists that can function as oral bone anabolic agents, we recently reported the discovery of a tetrahydropyrazolopyrimidine derivative featuring adamantyl group 1b with potent CaSR antagonistic activity. To explore the potential of this calcilytic congener, we introduced the gem-dialkyl benzyl group at the 3-position of the tetrahydropyrazolopyrimidine ring, forming a bioisostere of the adamantyl group by mimicking the adamantyl group's lipophilicity and bulkiness. Optimization directed toward the improvement of solubility and metabolic stability led to the discovery of compound 9e, which stimulated transient PTH secretion when orally administered to normal rats. Further, compound 9e proved to be fully effective in an osteopenic ovariectomized rat model. PMID- 21306169 TI - Synthesis of X(Y)-(EO)(n)-OCH3 type heterobifunctional and X(Y)-(EO)(n)-Z type heterotrifunctional poly(ethylene glycol)s. AB - A synthetic route to prepare acetal-protected heterobifunctional poly(ethylene glycol), allyl(1-ethoxyethoxy)-PEG-OH (allyl(EE)-PEG-OH), was successfully established using a newly synthesized initiator, trimethylolpropane allyl (1 ethoxyethoxy) ether (TMPAEEE). Heterobifunctional allyl(OH)-mPEG and heterotrifunctional allyl(OH)-PEG-alkyne were obtained, respectively, after modification from this precursor polymer. The polymers were characterized by SEC, 1H NMR, and MALDI-TOF mass spectroscopy. This approach is applicable for synthesizing a wide variety of X(Y)-(EO)(n)-OCH3 type heterobifunctional and X(Y) (EO)(n)-Z type heterotrifunctional PEGs. PMID- 21306170 TI - Investigation of layer-by-layer assembly of polyelectrolytes on fully functional human red blood cells in suspension for attenuated immune response. AB - The encapsulation of live cells with polymeric coat-ings is a versatile approach to modulate or control the response cells to their environment. The layer-by layer (LbL) self-assembly of nonimmunogenic polyelectrolytes is employed here to attenuate or suppress the binding of antibodies to live red blood cells (RBCs) and, consequently, decrease their inherent immunogenicity toward foreign RBCs. The optimized shell was composed of four bilayers of alginate (AL) and chitosan graft-phosphorylcholine (CH-PC) surrounded by two bilayers of AL and poly-l lysine-graft-polyethylene glycol (PLL-PEG). Experimental parameters, including the polyelectrolytes and RBCs concentrations and the cell handling and purification protocols, were optimized to achieve effective encapsulation of live and functional RBCs in suspension. The viability and functionality of coated RBCs were confirmed by a hemolysis assay and by their ability to take up oxygen. The successful immunocamouflage of RBCs was confirmed by observing that the recognition of the ABO/D (Rh) blood group antigens present on the surface of RBCs by their respective antibodies was muted in the case of coated RBCs. The results of this studies mark an important step toward the production of universal RBCs. PMID- 21306168 TI - Incorporation of a bioactive reverse-turn heterocycle into a peptide template using solid-phase synthesis to probe melanocortin receptor selectivity and ligand conformations by 2D 1H NMR. AB - By use of a solid-phase synthetic approach, a bioactive reverse turn heterocycle was incorporated into a cyclic peptide template to probe melanocortin receptor potency and ligand structural conformations. The five melanocortin receptor isoforms (MC1R-MC5R) are G-protein-coupled receptors (GPCRs) that are regulated by endogenous agonists and antagonists. This pathway is involved in pigmentation, weight, and energy homeostasis. Herein, we report novel analogues of the chimeric AGRP-melanocortin peptide template integrated with a small molecule moiety to probe the structural and functional consequences of the core His-Phe-Arg-Trp peptide domain using a reverse-turn heterocycle. A series of six compounds are reported that result in inactive to full agonists with nanomolar potency. Biophysical structural analysis [2D (1)H NMR and computer-assisted molecular modeling (CAMM)] were performed on selected analogues, resulting in the identification that these peptide-small molecule hybrids possessed increased flexibility and fewer discrete conformational families compared to the reference peptide and result in a novel template for further structure-function studies. PMID- 21306171 TI - Numerically efficient real space theory of scattering from colloidal crystals. AB - The production of high-quality colloidal crystals demands precise quantitative characterization of their nanostructures. While small-angle radiation scattering is the technique of choice, a procedure for a comprehensive quantitative modeling of the data is still pending. A novel theory based on the pertinent radial pair distribution which takes into account orientational, positional, stacking disorder and grain effects is developed here. We also show how the scattering length density of the particles can be estimated from the positions of minima in the form factor. The obtained results can be cast as sums of analytical functions over the distribution function and, as such, are suitable for easy (automatic) parallelization. On the experimental side, we report on a strong extinction effect coming from grazing incidence specular reflection that we have been able to model analytically. PMID- 21306172 TI - Switchable bactericidal effects from novel silica-coated silver nanoparticles mediated by light irradiation. AB - Here we report on the triggering of antibacterial activity by a new type of silver nanoparticle coated with porous silica, Ag@silica, irradiated at their surface plasmon resonant frequency. The nanoparticles are able to bind readily to the surface of bacterial cells, although this does not affect bacterial growth since the silica shell largely attenuates the intrinsic toxicity of silver. However, upon simultaneous exposure to light corresponding to the absorption band of the nanoparticles, bacterial death is enhanced selectively on the irradiated zone. Because of the low power density used for the treatments, we discard thermal effects as the cause of cell killing. Instead, we propose that the increase in toxicity is due to the enhanced electromagnetic field in the proximity of the nanoparticles, which indirectly, most likely through induced photochemical reactions, is able to cause cell death. PMID- 21306173 TI - Theoretical investigations on the mechanism of benzoin condensation catalyzed by pyrido[1,2-a]-2-ethyl[1,2,4]triazol-3-ylidene. AB - A new annulated N-heterocyclic carbene (NHC), pyrido[1,2-a]-2-ethyl[1,2,4]triazol 3-ylidene, has been synthesized and its good catalytic activity for benzoin condensation has been experimentally determined by You and co-workers recently [ Ma , Y. J. , Wei , S. P. , Lan , J. B. , Wang , J. Z. , Xie , R. G. , and You , J. S. J. Org. Chem. 2008 , 73 , 8256 ]. In this work, the mechanism of the title reaction has been intensively studied computationally by employing the density functional theory (B3LYP) method in conjunction with 6-31+G(d) and 6-311+G(2d,p) basis sets. Our results indicate that path A (in which a sequence of intermolecular proton transfers between two carbene/benzaldehyde coupling intermediates affords enamine) and path B (in which a t-BuOH assisted hydrogen transfer generates enamine) proposed on the basis of the Breslow mechanism are competitive for their similar barriers. In path A, the first intermolecular proton transfer between two N-heterocyclic carbene/benzaldehyde coupled intermediates to form tertiary alcohol and enolate anion is theoretically the rate-determining step with corresponding barrier (30.93 kcal/mol), while the t BuOH assisted hydrogen transfer generating Breslow enamine is the rate determining step with corresponding barrier (28.84 kcal/mol) in path B. The coupling of carbene and benzaldehyde, and the coupling of enamine and another benzaldehyde to form a C-C bond are partially rate-determining for their relatively significant barriers (24.06 and 26.95 kcal/mol, respectively), being the same in both paths A and B. Our results are in nice agreement with the experimental result in a kinetic investigation of thiazolium ion-catalyzed benzoin condensation performed by White and Leeper in 2001. PMID- 21306174 TI - Single molecule diffusion and the solution of the spherically symmetric residence time equation. AB - The residence time of a single dye molecule diffusing within a laser spot is propotional to the total number of photons emitted by it. With this application in mind, we solve the spherically symmetric "residence time equation" (RTE) to obtain the solution for the Laplace transform of the mean residence time (MRT) within a d-dimensional ball, as a function of the initial location of the particle and the observation time. The solutions for initial conditions of potential experimental interest, starting in the center, on the surface or uniformly within the ball, are explicitly presented. Special cases for dimensions 1, 2, and 3 are obtained, which can be Laplace inverted analytically for d = 1 and 3. In addition, the analytic short- and long-time asymptotic behaviors of the MRT are derived and compared with the exact solutions for d = 1, 2, and 3. As a demonstration of the simplification afforded by the RTE, the Appendix obtains the residence time distribution by solving the Feynman-Kac equation, from which the MRT is obtained by differentiation. Single-molecule diffusion experiments could be devised to test the results for the MRT presented in this work. PMID- 21306175 TI - Prediction of solubility parameters and miscibility of pharmaceutical compounds by molecular dynamics simulations. AB - The objectives of this study were (i) to develop a computational model based on molecular dynamics technique to predict the miscibility of indomethacin in carriers (polyethylene oxide, glucose, and sucrose) and (ii) to experimentally verify the in silico predictions by characterizing the drug-carrier mixtures using thermoanalytical techniques. Molecular dynamics (MD) simulations were performed using the COMPASS force field, and the cohesive energy density and the solubility parameters were determined for the model compounds. The magnitude of difference in the solubility parameters of drug and carrier is indicative of their miscibility. The MD simulations predicted indomethacin to be miscible with polyethylene oxide and to be borderline miscible with sucrose and immiscible with glucose. The solubility parameter values obtained using the MD simulations values were in reasonable agreement with those calculated using group contribution methods. Differential scanning calorimetry showed melting point depression of polyethylene oxide with increasing levels of indomethacin accompanied by peak broadening, confirming miscibility. In contrast, thermal analysis of blends of indomethacin with sucrose and glucose verified general immiscibility. The findings demonstrate that molecular modeling is a powerful technique for determining the solubility parameters and predicting miscibility of pharmaceutical compounds. PMID- 21306177 TI - Donor-acceptor assisted alkyne hydration: a luminescent boron-stabilized enol. AB - An alkyne molecule 2-(2'-BMes(2)-phenylethynyl)pyridine (1) that contains a Lewis acidic BMes(2) group and a Lewis basic pyridyl group has been found to undergo facile hydration under ambient conditions in the presence of CuI, forming a highly emissive and stable enol ester (2). The lack of any hydration reactivity by a control compound 2-(2'-BMes(2)-phenylethynyl)benzene (3) under the same conditions supports that the cooperativity between the Lewis donor and acceptor groups plays a key role in the formation of 2. PMID- 21306179 TI - Update 1 of: alpha,beta-Diamino acids: biological significance and synthetic approaches. PMID- 21306178 TI - Binding between a distal C-terminus fragment of cannabinoid receptor 1 and arrestin-2. AB - Internalization of G-protein-coupled receptors is mediated by phosphorylation of the C-terminus, followed by binding with the cytosolic protein arrestin. To explore structural factors that may play a role in internalization of cannabinoid receptor 1 (CB1), we utilize a phosphorylated peptide derived from the distal C terminus of CB1 (CB1(5P)(454-473)). Complexes formed between the peptide and human arrestin-2 (wt-arr2(1-418)) were compared to those formed with a truncated arrestin-2 mutant (tr-arr2(1-382)) using isothermal titration calorimetry and nuclear magnetic resonance spectroscopy. The pentaphosphopeptide CB1(5P)(454-473) adopts a helix-loop conformation, whether binding to full-length arrestin-2 or its truncated mutant. This structure is similar to that of a heptaphosphopeptide, mimicking the distal segment of the rhodopsin C-tail (Rh(7P)(330-348)), binding to visual arrestin, suggesting that this adopted structure bears functional significance. Isothermal titration calorimetry (ITC) experiments show that the CB1(5P)(454-473) peptide binds to tr-arr2(1-382) with higher affinity than to the full-length wt-arr2(1-418). As the observed structure of the bound peptides is similar in either case, we attribute the increased affinity to a more exposed binding site on the N-domain of the truncated arrestin construct. The transferred NOE data from the bound phosphopeptides are used to predict a model describing the interaction with arrestin, using the data driven HADDOCK docking program. The truncation of arrestin-2 provides scope for positively charged residues in the polar core of the protein to interact with phosphates present in the loop of the CB1(5P)(454-473) peptide. PMID- 21306180 TI - Update 2 of: electrophilicity index. PMID- 21306181 TI - Proteomics of wound exudate in snake venom-induced pathology: search for biomarkers to assess tissue damage and therapeutic success. AB - Tissue damage analysis by traditional laboratory techniques is problematic. Proteomic analysis of exudates collected from affected tissue constitutes a powerful approach to assess tissue alterations, since biomarkers associated with pathologies can be identified in very low concentrations. In this study we proteomically explore the pathological effects induced by the venom of the viperid snake Bothrops asper in the gastrocnemius muscle of mice. Predominant proteins identified in the exudates included intracellular proteins, plasma proteins, extracellular matrix proteins and cell membrane-associated proteins. The presence of such proteins indicates cytotoxicity, plasma exudation, extracellular matrix degradation and shedding of membrane proteins. Some of these proteins may represent useful biomarkers for myonecrosis and microvascular damage. The effect of fucoidan, an inhibitor of myotoxic phospholipases A(2), and batimastat, an inhibitor of metalloproteinases, on the pathological effects induced by B. asper venom were also investigated. Fucoidan reduced the presence of intracellular proteins in exudates, whereas batimastat reduced the amount of relevant extracellular matrix proteins. The combination of these inhibitors resulted in the abrogation of the most relevant pathological effects of this venom. Thus, proteomic analysis of exudates represents a valuable approach to assess the characteristics of tissue damage in pathological models and the success of therapeutic interventions. PMID- 21306182 TI - Internet-based therapy: too good to be true? PMID- 21306183 TI - The ironies of clozapine. PMID- 21306184 TI - Is it possible to predict suicide? PMID- 21306185 TI - The heavy drinking culture is primarily an adult issue: not what you read in the newspapers. PMID- 21306187 TI - Early human pregnancy serum cytokine levels predict autoimmunity in offspring. AB - It is generally believed that pregnancy is mediated by a Th2 response, which includes cytokines that promote placental growth and are involved in inducing tolerance to the foetus. If the balance between Th1/and Th2-mediated cytokines is disrupted, systemic and local changes could predispose the foetus to future disease. Therefore, a shift in the Th1/Th2 balance during pregnancy, possibly caused by underlying environmental factors, could be associated with post-partum autoimmune disease in the offspring. Based on this presumption, we used celiac disease as a model to investigate whether autoimmunity is triggered in the foetus during early pregnancy, observed as changes in the mother's cytokine profile. Ten cytokines were measured by electro-chemi-luminescent multiplex ELISA in serum samples obtained from mothers during early pregnancy. Cases included women with children who had developed verified celiac disease before the age of 5, who were compared with other women as matched controls. We observed that 7 out of 10 cytokine levels were significantly increased in our case mothers when compared to controls. Five of these belonged to what is generally known as a Th1-mediated response (TNFalpha, IFNgamma, IL-2, IL-1beta and IL-12) and two were Th2 cytokines (IL-13 and IL-10). However, the IL-10 cytokine is known to have features from both arms of the immune system. These results were confirmed in a logistic regression model where five out of the initial seven cytokines remained. This study suggests that increase in Th1 serum cytokines may be associated with celiac disease in offspring. PMID- 21306188 TI - The effect of regulatory T-cell depletion on the spectrum of organ-specific autoimmune diseases in nonobese diabetic mice at different ages. AB - The nonobese diabetic (NOD) mouse spontaneously develops several autoimmune diseases, including type 1 diabetes and to a lesser extent thyroiditis and sialitis. Imbalance between effector T cells (Teffs) and regulatory T cells (Tregs) has recently been proposed as a mechanism for the disease pathogenesis in NOD mice, but previous studies have shown the various outcomes by different timing and methods of Treg-depletion. This study was, therefore, designed to compare the consequences of Treg-depletion by the same method (anti-CD25 antibody) on the spectrum of organ-specific autoimmune diseases in NOD mice of different ages. Treg-depletion by anti-CD25 antibody at 10 days of age accelerated development of all three diseases we examined (insulitis/diabetes, thyroiditis, and sialitis); Treg-depletion at 4 weeks of age accelerated only diabetes but not thyroiditis or sialitis; and Treg-depletion at 12 weeks of age hastened only development of thyroiditis and exhibited little influence on diabetes or sialitis. Increased levels of insulin autoantibodies (IAA) were, however, observed in mice depleted of Tregs at 10 days of age, not in those at 4 weeks. Thus, the consequences of Treg-depletion on the spectrum of organ-specific autoimmune diseases depend on the timing of anti-CD25 antibody injection in NOD mice. Aging gradually tips balance between Teffs and Tregs toward Teff-dominance for diabetes, but this balance for thyroiditis and sialitis likely alters more intricately. Our data also suggest that the levels of IAA are not necessarily correlated with diabetes development. PMID- 21306189 TI - Effect of cooking on physical and sensory properties of fresh yellow alkaline noodles prepared by partial substitution of wheat flour with soy protein isolate and treated with cross-linking agents. AB - Yellow alkaline noodles (YAN) prepared by partial substitution of wheat flour with soy protein isolate and treated with microbial transglutaminase (MTG) and ribose were investigated during cooking. Cooking caused an increase in lightness but a decrease in redness and yellowness, pH, tensile strength and elasticity values of noodles. The extents of these changes were influenced by formulation and cross-linking treatments. The pH and lightness for YAN-ribose were lowest but the yellowness and redness were the highest whilst the tensile strength and elasticity values remained moderate. For YAN-MTG, the color and pH values were moderate, but tensile strength and elasticity values were the highest. YAN prepared with both cross-linking agents had physical values between YAN-ribose and YAN-MTG. Although certain sensory parameters showed differences in score, the overall acceptability of all 10-min-cooked YAN was similar. It is possible to employ cross-linking agents to improve physical properties of cooked YAN. PMID- 21306191 TI - Use of sodium stearoyl lactylate and azodicarbonamide in wheat flour breads with added pea flour. AB - Different amounts of sodium stearoyl lactylate (SSL) (X(1)) and azodicarbonamide (ADA) (X(2)) were analyzed to measure their effect on breadmaking using wheat flour with incorporation of pea flour (Pisum sativum) to the dough. The objective of the present work was to optimize the physical properties of dough (Y(1)Y(2)Y(3)Y(4)), the dough consistency during mixing (Y(5)Y(6)) and the baking performance (Y(7)Y(8)Y(9)). A central composite design and second-order models for Y(i) were employed. For dough physical properties and dough consistency during mixing, the best response was found when SSL varied between 0.5 and 1.5% and ADA between 110 and 170 ppm. For responses concerning the baking performance, better values for specific volume, crumb texture scores and bread score were obtained using SSL between 0.9 and 1.4% and ADA between 50 and 80 ppm. It is concluded that for baking with wheat flour replaced at about 10% with inactivated pea flour it should be advised to use SSL at levels close to 1% with ADA between 50 and 80 ppm. PMID- 21306190 TI - Lyophilization decreases the formation of dialyzable iron by extraction and digestion of chicken breast muscle. AB - We studied the effect of lyophilization of chicken breast muscle on the formation of dialyzable iron from ferric iron. Chicken breast muscle was used chilled, frozen or lyophilized and was analyzed for sulfhydryl and histidine content. It was then homogenized and mixed with ferric iron. The mixture was extracted with acid or digested with pepsin and pancreatin. The extracts and digests were analyzed for dialyzable ferrous and dialyzable total iron and also for protein. In the chilled muscle, similar amounts of dialyzable iron were formed after acid extraction and after proteolytic digestion; however, digestion led to more dialyzable ferrous iron. Freezing had no effect but lyophilization of the homogenized muscle caused large decreases in dialyzable iron and dialyzable ferrous iron for both extraction and digestion processes. Lyophilization also resulted in decreased extraction of peptides, decreased digestion of muscle proteins and reduced levels of sulfhydryl and histidine residues. Our results demonstrate that dialyzable iron is produced both by acid-soluble low molecular weight muscle component(s) and also by peptides resulting from digestion of muscle proteins: both of which reduce and chelate iron. Reduced formation of dialyzable iron by both mechanisms following lyophilization could be explained by sulfhydryl oxidation and impaired digestion due to protein crosslinking. PMID- 21306193 TI - Peripheral precocious puberty in a 4-month-old girl: role of pesticides? AB - A 4-month-old girl presented with sexual development, including breast enlargement, menstruation, uterine length of 69 mm at ultrasonography, and dramatically high estrogen bioactivity, but no growth acceleration, pubic hair, pelvis masses or adrenal tumors. Gas chromatography with an electron capture detector and mass spectrometry detected pesticides (p,p'-DDD, p,p'-DDT, lindane and endosulfan sulfate) in plasma from the infant, the mother, and the 38-year old father, who reported a dramatic decrease in libido, and in soil samples from their farm. The precocious sexual development was probably caused by the estrogen activity of the environmental contamination by tons of pesticides stored in the family farm. PMID- 21306192 TI - Solid lipid nanoparticles reduce systemic toxicity of docetaxel: performance and mechanism in animal. AB - Nanotechnology presents great potential for increasing efficacy of docetaxel while reducing side-effects and toxicity. However, in vivo toxicity of nano formulation of docetaxel has not been systemically investigated yet. Herein, the new docetaxel-loaded solid lipid nanoparticles (DSNs) were prepared, and systemic toxicity of DSNs in different animals was comprehensively investigated. The experimental results showed that no allergenicity and vascular irritation were induced by DSNs at the highest drug concentration of clinical infusion. The maximum tolerated dose (MTD) of DSNs was as high as 400 mg/kg in mice while the medial lethal dose (LD50) of Taxotere(r) was 149.31 mg/kg. The long-term toxicity of DSNs compared with Taxotere(r) in beagle dogs by intravenous infusion weekly for four weeks showed that the administration of Taxotere(r) at 1 mg/kg brought about severe signs of toxicity such as skin flushing, vocalization and salivation. However, no abnormal reactions appeared on animals treated with DSNs at dose of 4 mg/kg. At the same dose level, DSNs induced more minor decreases in body weight gains, slighter hemotoxicity (changes in some clinical hematology and biochemistry parameters), cardiac toxicity, hepatotoxicity and myelosuppression than Taxotere(r). These results could provide an important reference for developing the novel delivery system of docetaxel. PMID- 21306194 TI - Cognitive function and improvement of balance after stroke in elderly people: the Gothenburg cognitive stroke study in the elderly. AB - PURPOSE: The ability to balance is no longer automatic after stroke in patients with motor impairment and needs to be relearned. Learning requires cognitive and executive abilities. It is well known that cognitive and executive impairments are common after stroke, but how these are related to balance has not yet been fully studied. We, therefore, wanted to explore the impact of pre-stroke cognitive impairment, global and selective cognitive and executive impairment in the early phase after stroke and at the 1-year follow-up on balance and on the improvement of balance during the first year after stroke. METHOD: Seventy-four patients were included consecutively on admission following stroke to a geriatric stroke unit and followed prospectively for 1 year. Balance was assessed using the Berg Balance Scale on admission, on discharge and 1 year after stroke. RESULTS: Cognitive impairment before stroke, measured using the Cognitive Impairment Questionnaire, was found to lead to poor balance on discharge and 1 year after stroke. Patients with impaired logical deductive ability and executive function, measured using a neuropsychological test battery both in the early phase and 1 year after stroke, also had significantly poorer balance 1 year after stroke than patients with intact functions. Most importantly, only patients with intact cognitive function, before stroke, on admission and at the 1-year follow-up, significantly improved their balance after discharge. CONCLUSIONS: Our results show that cognitive status, both before and after stroke, is important for balance and improvement of balance after stroke. PMID- 21306195 TI - Measurement properties of a modified Reintegration to Normal Living Index in a community-dwelling adult rehabilitation population. AB - PURPOSE: To examine the validity and reliability of a modified Reintegration to Normal Living Index (mRNL Index) with a sample of community-dwelling adults with mixed diagnoses. METHOD: Forty-six adults (mean 55.2 +/- 20.3 years) were recruited through convenience sampling from outpatient rehabilitation services. They completed the mRNL Index, Community Integration Measure (CIM) and Life Space Assessment (LSA) and were invited to complete them again 2 weeks later. RESULTS: Construct validity of the mRNL Index was confirmed by good fit to the Rasch measurement model. The mRNL Index demonstrated acceptable internal consistency (Cronbach's alpha = 0.80), as did the Daily Functioning subscale (Cronbach's alpha = 0.80) and Personal Integration subscale (Cronbach's alpha = 0.82). Test retest reliability was also acceptable (intraclass correlation coefficient (3,1) = 0.83, p = .0001). As hypothesised, the LSA did not correlate with the Personal Integration subscale (Spearman rho = 0.08) and moderately correlated to the Daily Functioning subscale (Spearman rho = 0.59). The CIM was moderately correlated with the Personal Integration subscales (Spearman rho = 0.54) and the Daily Functioning subscale (Spearman rho = 0.53), though higher correlation was expected with the latter. CONCLUSION: Modifications to the phrasing, rating scale and subscales improved the validity of the original RNL Index for a mixed rehabilitation, community-dwelling population. PMID- 21306196 TI - Factors associated with the development of cytomegalovirus infection following solid organ transplantation. AB - BACKGROUND: Infection with cytomegalovirus (CMV) remains a potentially serious complication in transplant patients. In this study we explored the risk factors for CMV infection in the 12 months following a solid organ transplantation (n = 242) in patients monitored for CMV infection from 2004 to 2007. METHODS: CMV infection was defined as 2 consecutive quantifiable CMV-polymerase chain reaction (PCR) values or 1 measurement of >3000 copies/ml. Data describing pre- and post transplantation variables were extracted from electronic health records. Time to CMV infection was investigated using Cox proportional hazards analysis. RESULTS: Overall, 31% (75/242) of solid organ transplant patients developed CMV infection: 4/8 (50.0%) heart, 15/43 (34.9%) liver, 30/89 (33.7%) lung and 26/102 (25.5%) kidney transplant patients. The risk of CMV infection according to donor (D)/recipient (R) CMV serostatus (positive + or negative-) was highest for D+/R (adjusted hazard ratio 2.6, 95% confidence interval 1.6-4.2) vs D+/R+, and was reduced for D-/R+(adjusted hazard ratio 0.2, 95% confidence interval 0.2-0.8) vs D+/R+. CONCLUSION: Positive donor CMV-serostatus is a major risk factor for CMV infection in CMV-na ve recipients, but also in recipients with positive CMV serostatus. Conversely, if donor is CMV serostatus is negative, the risk of CMV infection is low, irrespective of recipients CMV-serostatus. These findings suggest poorer immune function towards donor-induced strains of CMV versus recipient own latent strains. PMID- 21306197 TI - Co-aggregation and growth inhibition of probiotic lactobacilli and clinical isolates of mutans streptococci: an in vitro study. AB - OBJECTIVE: Co-aggregation and growth inhibition abilities of probiotic bacteria may play a key role in their interference with the oral biofilm. The aim was to investigate the in vitro ability of selected commercial probiotic lactobacilli to co-aggregate and inhibit growth of oral mutans steptococci isolated from adults with contrasting levels of caries. MATERIALS AND METHODS: Mutans streptococci (MS) strains were isolated from caries-free (n = 3) and caries-susceptible (n = 5) young adults and processed with eight commercial probiotic lactobacilli strains. One laboratory reference strain (S. mutans Ingbritt) was selected as control. Co-aggregation was determined spectrophotometrically and growth inhibition was assessed with the agar overlay technique. RESULTS: All probiotic lactobacilli showed an ability to co-aggregate with the isolated MS strains. Statistically significant differences (p < 0.05) were found between strains from different individuals when compared with the reference strain. The selected lactobacilli inhibited MS growth, but the ability varied between the strains and was clearly related to pH. No differences were observed between the different MS strains from caries-free and caries-susceptible individuals. CONCLUSIONS: The selected lactobacilli displayed co-aggregation activity and inhibited growth of clinical mutans streptococci. The growth inhibition was strain-specific and dependent on pH and cell concentration. The findings indicate that the outcome of lactobacilli-derived probiotic therapy might vary between individuals and depend on the specific strain used. PMID- 21306198 TI - Misfit of pure titanium frameworks: effect of veneer coverage and spark erosion process. AB - OBJECTIVE. The purpose of this study was to evaluate the influence of veneer application on the misfit level of implant-supported frameworks. MATERIALS AND METHODS. Thirty commercially pure titanium (Tritan, Dentaurum, Pforzheim, Germany) frameworks were fabricated from a metallic index containing five Branemark-type multi-unit abutments. Analogs of the abutments were positioned into the framework to manufacture an index for each framework, which permitted the evaluation of the marginal gap caused only by the veneer coverage. The frameworks were grouped (n = 10) in the following manner: (G1) heat-cured acrylic resin (Classico, Classico, Sao Paulo, Brazil); (G2) light-cured resin (Versyo.com, Heraeus Kulzer, Brazil); and (G3) porcelain (Triceram, Dentaurum, Pforzheim, Germany). Marginal refinement with spark erosion was then conducted. The marginal gap was verified before and after the veneer coverage and the spark erosion procedure, following the single screw test protocol (tightening force of 10 Ncm). Data were submitted to an analysis of variance (ANOVA) in a split-plot design for repeated measurements followed by a Tukey test (p = 0.05). RESULTS. The veneer application was associated with a significant increase in the mean misfit values of all groups. The lowest values were presented by G2. After the spark erosion process, the mean misfit value decreased only on G3. CONCLUSIONS. Heat-cured acrylic resin and porcelain produced the highest values of marginal gaps, whereas light-cured acrylic resin produced the lowest. In addition, the spark erosion process was effective only in the marginal gap of the porcelain application group. PMID- 21306199 TI - Outpatient treatment of children and adolescents with antipsychotic drugs in Croatia. AB - BACKGROUND: A large increase in the use of atypical antipsychotics (AAPs) in the Western developed countries has been reported. Patterns of antipsychotic therapy and the extent of use of AAPs for youth outside of the developed world are lacking. AIMS: To evaluate patterns of antipsychotic treatment of pediatric outpatients in Croatia, including the rate of AAP use. MATERIAL AND METHODS: Retrospective analysis of outpatient visits to child psychiatrists by persons aged 18 and younger that included prescription of antipsychotics. Antipsychotic treatment data were identified by frequency, medication class, subclass and drug entity and were analyzed in relation to age group, gender and psychiatric diagnosis. RESULTS: Overall, 1.3% (106/7953) of pediatric outpatients received antipsychotic therapy during the study period. Antipsychotic treatment was significantly more common in boys and in adolescents. AAPs (80.1%) were significantly more often prescribed than typical antipsychotics (19.9%) (t = 7.76; P < 0.01). In all diagnostic categories (behavior disorders, pervasive developmental disorders and mental retardation, psychotic disorders, mood and tic disorders), the treatment with AAPs was more frequent than typical antipsychotics (chi(2) = 9.92, df = 4, P < 0.05). AAPs were used as monotherapy in 62.2% of outpatients. Off-label prescribing was found in 52.9% of young patients who had received AAPs. CONCLUSIONS: AAPs comprise most of the antipsychotic medications prescribed to pediatric outpatients in Croatia in all diagnostic categories, reflecting trends in other countries. Unfortunately, such practice occurs in the absence of supporting data about long-term safety and in spite of the lack of evidence regarding their efficacy in some indications. PMID- 21306200 TI - Biological dosimetry intercomparison exercise: an evaluation of triage and routine mode results by robust methods. AB - Well-defined protocols and quality management standards are indispensable for biological dosimetry laboratories. Participation in periodic proficiency testing by interlaboratory comparisons is also required. This harmonization is essential if a cooperative network is used to respond to a mass casualty event. Here we present an international intercomparison based on dicentric chromosome analysis for dose assessment performed in the framework of the IAEA Regional Latin American RLA/9/054 Project. The exercise involved 14 laboratories, 8 from Latin America and 6 from Europe. The performance of each laboratory and the reproducibility of the exercise were evaluated using robust methods described in ISO standards. The study was based on the analysis of slides from samples irradiated with 0.75 (DI) and 2.5 Gy (DII). Laboratories were required to score the frequency of dicentrics and convert them to estimated doses, using their own dose-effect curves, after the analysis of 50 or 100 cells (triage mode) and after conventional scoring of 500 cells or 100 dicentrics. In the conntional scoring, at both doses, all reported frequencies were considered as satisfactory, and two reported doses were considered as questionable. The analysis of the data dispersion among the dicentric frequencies and among doses indicated a better reproducibility for estimated doses (15.6% for DI and 8.8% for DII) than for frequencies (24.4% for DI and 11.4% for DII), expressed by the coefficient of variation. In the two triage modes, although robust analysis classified some reported frequencies or doses as unsatisfactory or questionable, all estimated doses were in agreement with the accepted error of +/-0.5 Gy. However, at the DI dose and for 50 scored cells, 5 out of the 14 reported confidence intervals that included zero dose and could be interpreted as false negatives. This improved with 100 cells, where only one confidence interval included zero dose. At the DII dose, all estimations fell within +/-0.5 Gy of the reference dose interval. The results obtained in this triage exercise indicated that it is better to report doses than frequencies. Overall, in both triage and conventional scoring modes, the laboratory performances were satisfactory for mutual cooperation purposes. These data reinforce the view that collaborative networking in the case of a mass casualty event can be successful. PMID- 21306202 TI - Can virtual reality offer enriched environments for rehabilitation? PMID- 21306201 TI - Epigenetic gene silencing is a novel mechanism involved in delayed manifestation of radiation-induced genomic instability in mammalian cells. AB - We examined mechanisms involved in delayed mutagenesis in CHO-LacZeo cells harboring the fusion gene between the bacterial LacZ and the Zeocin-resistance genes. After X irradiation, Zeocin-resistant primary colonies were isolated, and the primary clones were subjected to the secondary colony formation in the absence of Zeocin. We found that the surviving primary clones showed a significantly higher delayed mutation frequency compared with those derived from nonirradiated CHO-LacZeo cells. The mutation spectrum of the LacZ gene was analyzed by the LacZ gene-specific PCR. We found that more than 90% of the spontaneous and direct mutants were PCR-product negative, indicating that deletion of the LacZ gene was a predominant change in these mutants. While deletion of the LacZ gene was also observed in delayed mutants, we found that more than 20% of delayed mutants had a PCR product similar to that of the parental CHO-LacZeo cells. These PCR product-positive mutants spontaneously reverted to LacZ-positive (LacZ(+)) cells, and all of these mutants became LacZ positive after 5-azacytidine treatment. These results indicate that epigenetic gene silencing, in addition to elevated recombination, is involved in delayed mutagenesis, which is a novel mechanism underlying delayed manifestations of radiation-induced genomic instability. PMID- 21306203 TI - Is oxytocin a promising treatment for schizophrenia? PMID- 21306205 TI - Sugammadex: a novel approach to reversal of neuromuscular blockade. AB - Sugammadex is the first in a new class of medications termed selective relaxant binding agents. This medication acts to encapsulate free circulating steroidal nondepolarizing neuromuscular blocking agents. The encapsulation of neuromuscular agents effectively decreases the amount of neuromuscular blocker interacting at the neuromuscular receptor. This binding has a very high association rate, rendering the incidence of residual block extremely low, while avoiding the side effects associated with traditional reversal agents. Currently approved for clinical use in over 50 countries, sugammadex was not approved by the US FDA in 2008 due to concerns over potential hypersensitivity reactions. It is hoped that further study and clinical experience will help to better define the risk associated with sugammadex and eventually lead to the approval of this novel medication in the USA. PMID- 21306206 TI - Recent advances in basic and translational stroke research. AB - Since 1998, the biannual International Symposium on Neuroprotection and Neurorepair, also known as the Magdeburg Meeting series, has provided a platform for the discussion of recent advances in basic and translational stroke research. The 2010 meeting reviewed highly relevant topics, including astrogliosis and microgliosis, neuroimmunological processes, cell-based therapies, novel imaging approaches, mechanisms of poststroke regeneration and metabolic phenomena in neuroprotection. It further focused on common pitfalls and opportunities in the translational process, from preclinical research to clinical application. PMID- 21306207 TI - World Parkinson Congress: bringing together the Parkinson's community. AB - The World Parkinson Congress, which was recently held in Glasgow, aimed to establish a worldwide dialogue to help expedite the discovery of a cure and best treatment practices for Parkinson's disease. The congress brought together experts from a range of disciplines, from basic sciences to translational research and clinical sciences to models of care. International governmental organisations and professional societies were also present in force. The Parkinson's community was represented by the many people with the condition who attended and their carers, as well as national and international voluntary associations. This complete spectrum of individuals and entities involved in the search for a cure and deciding on the best care for Parkinson's disease provided the perfect conditions for a globally reaching discourse on the condition. PMID- 21306208 TI - Could virtual reality be effective in treating children with phobias? AB - The use of virtual reality to treat anxiety disorders in adults is gaining popularity and its efficacy is supported by numerous outcome studies. Similar research for children is lagging behind. The outcome studies on the use of virtual reality to treat anxiety disorders in children currently address only specific phobias, and all of the available trials are reviewed in this article. Despite the limited number of studies, results are very encouraging for the treatment of school and spider phobias. A study with adolescents suggests that, at least for social anxiety, exposure stimuli would be more effective if they were developed specifically for younger populations. Virtual reality may not increase children's motivation towards therapy unless their fearful apprehension is addressed before initiating the treatment. PMID- 21306209 TI - Efficacy and safety of ramelteon in Japanese adults with chronic insomnia: a randomized, double-blind, placebo-controlled study. AB - This randomized, double-blind, placebo-controlled study assessed the efficacy and safety of ramelteon 4 and 8 mg in Japanese adults with chronic insomnia. A secondary objective was to evaluate efficacy and safety when doses were uptitrated from placebo, ramelteon 4 and 8 mg to 4, 8 and 16 mg, respectively. Patient-reported sleep data were collected using sleep diaries. There was no statistically significant difference between ramelteon and placebo in the change in subjective sleep latency (sSL) in the full analysis set (n = 1130). Significant improvement was observed in the change in subjective total sleep time with ramelteon 8 mg at week 1. In post hoc analyses, ramelteon 8 mg reduced sSL in individuals with smaller fluctuations (within +/-30 min) of sSL at baseline, in those with a shorter (<1 year) history of insomnia and in individuals who had not used benzodiazepines. Ramelteon up to 16 mg nightly was safe and well tolerated. PMID- 21306210 TI - Inflammatory and neuroendocrine biomarkers of prognosis after ischemic stroke. AB - Stroke is the third leading cause of mortality in the USA and one of the leading causes of severe morbidity. It is important to provide stroke patients and physicians with the most accurate prognostic information to optimize care and allocation of healthcare resources. Reliable prognostic markers available during the initial phase after acute stroke may aid clinical decision-making. Several interesting candidate biomarkers have been studied to address prognostic questions; this article will focus on selected inflammatory and neuroendocrine markers. The utility of a biomarker is defined by its ability to improve clinical decision-making and add timely information beyond that readily available from clinical examination and routine imaging. This aim has not been completely achieved yet for any biomarkers, but promising data are available and further studies are ongoing. PMID- 21306211 TI - Reno-cerebrovascular disease: linking the nephron and neuron. AB - Chronic kidney disease (CKD), a growing public health concern, carries a substantial burden and is a well-known independent predictor of coronary artery disease outcomes. In the last few years, attention has been focused on various CKD indices and their prognostic impact among individuals with, or at risk for, cerebrovascular disease. Mounting evidence suggests that the presence of CKD in various forms (filtration rate and barrier impairments), and even at mild stages, is associated with surrogate cerebrovascular disease markers, confers higher future risk of ischemic and hemorrhagic cerebrovascular events, and predicts poor clinical outcomes after an index stroke. However, a better understanding of these links is required. For instance, the direction and strength of the association of CKD with a heterogeneous vascular disease entity, such as cerebrovascular disease (vs coronary artery disease), appears to be greatly influenced by stroke type and ischemic stroke subtype, as well as CKD index and CKD stage. Furthermore, the potential mechanisms underlying the independent relation of baseline CKD and stroke risk need to be better delineated, since a causal association cannot be assumed. Additional investigation is also warranted to clarify whether CKD indices can usefully enhance cerebrovascular disease stratification beyond traditional risk factors. In the meantime, with several recent systematic reviews of published evidence supporting a robust and independent association of CKD with subsequent cerebrovascular disease risk, optimal implementation of established stroke risk reduction strategies in individuals with CKD might improve stroke outcomes. This article summarizes the compelling epidemiological and clinical evidence relating CKD to stroke, and presents the rationale for conducting future studies to assess the role of CKD as a risk marker or potential therapeutic target in individuals with, or at risk for, stroke. PMID- 21306213 TI - Sonothrombolysis for the treatment of acute stroke: current concepts and future directions. AB - Achieving rapid reperfusion transcranial color-coded duplex is the critical issue in acute stroke treatment. Ultrasound (US) generates negative pressure waves that are associated with an increase in either intrinsic or intravenous tissue plasminogen activator (tPA)-induced fibrinolytic activity. Higher rates of tPA induced arterial recanalization, associated with a trend towards better functional outcome, have been safely achieved by using high-frequency US. By contrast, the use of low-frequency US and transcranial color-coded duplex has been linked to significant hemorrhagic complications. US-accelerated thrombolysis has been safely enhanced by lowering the amount of energy needed for acoustic cavitation with the administration of microbubbles. Other applications of US are being studied, including its intra-arterial use. Operator-independent devices, which will spread the use of these US techniques further, are also being developed. This article reviews the present status of sonothrombolysis in acute stroke treatment, highlighting both experimental and clinical studies addressing this issue, and discusses its future regarding both efficacy and safety. PMID- 21306212 TI - Antiplatelet resistance in stroke. AB - Although the exact prevalence of antiplatelet resistance in ischemic stroke is not known, estimates about the two most widely used antiplatelet agents - aspirin and clopidogrel - suggest that the resistance rate is high, irrespective of the definition used and parameters measured. Inadequate antiplatelet responsiveness correlates with an increased risk of recurrent ischemic vascular events in patients with stroke and acute coronary syndrome. It is not currently known whether tailoring antiplatelet therapy based on platelet function test results translates into a more effective strategy to prevent secondary vascular events after stroke. Large-scale clinical trials using a universally accepted definition and standardized measurement techniques for antiplatelet resistance are needed to demonstrate whether a 'platelet-function test-guided antiplatelet treatment' strategy translates into improved stroke care. This article gives an overview of the clinical importance of laboratory antiplatelet resistance, describes the challenges for platelet-function test-guided antiplatelet treatment and discusses practical issues about the management of patients with aspirin and/or clopidogrel resistance. PMID- 21306215 TI - Assessment of obsessive-compulsive disorder: review and future directions. AB - Careful evaluation of obsessive-compulsive disorder (OCD) is critical owing to its under-recognition, difficulty ascertaining accurate diagnoses and the need for detailed treatment planning. We review current methods for the assessment of OCD in adults, including unstandardized clinical interviews, standardized diagnostic and other clinical interviews, patient- and family-report measures, and brief or web-based screening measures. Depending upon the question of interest, clinicians and researchers may select from these measures to best assess obsessive-compulsive symptoms in multiple settings. Current research regarding the assessment of OCD has focused on the underlying symptom dimensions, suggesting that each symptom dimension may be associated with different etiology and require tailored treatment. In the future, research may show that effective assessment of OCD involves identification of relevant symptom dimensions to facilitate the choice of appropriate treatment. PMID- 21306214 TI - Functional neuroimaging studies of post-traumatic stress disorder. AB - Post-traumatic stress disorder (PTSD) is a significant problem that can affect individuals who have been exposed to a traumatic event or events, such as combat, violent crime or childhood abuse. Over the past several years, neuroimaging studies of PTSD have focused on elucidating the brain circuits that mediate this disorder. In this article, we will briefly introduce some of the methods used in functional neuroimaging studies of PTSD. We will then review functional neuroimaging studies that have reported significant findings in the amygdala, medial prefrontal cortex, hippocampus and insula. Finally, we will suggest future directions for research. PMID- 21306217 TI - Cross-cultural variations in the prevalence and presentation of anxiety disorders. AB - Considerable cross-cultural variation exists in the prevalence and presentation of the anxiety disorders as defined by the fourth edition of the Diagnostic and Statistical Manual. Researchers debate whether this variation represents cultural differences in the phenomenology of universal disorders or the existence of unique culturally constructed disorders. This article reviews recent literature on the prevalence and presentation of five anxiety disorders: generalized anxiety disorder, social anxiety disorder, panic disorder, specific phobia and post traumatic stress disorder, both across countries and within the USA. This article indicates that certain anxiety disorders (e.g., generalized anxiety disorder and panic disorder) may vary greatly in rate across cultural groups. It indicates that the clinical presentation of anxiety disorders, with respect to symptom presentation and the interpretation of symptoms, varies across cultures. A difference in catastrophic cognitions about anxiety symptoms across cultures is hypothesized to be a key aspect of cross-cultural variation in the anxiety disorders. Future research directions are suggested. PMID- 21306216 TI - Cognitive bias modification for anxiety: current evidence and future directions. AB - Cognitive bias modification (CBM) is an innovative approach to modifying cognitive biases that confer vulnerability to anxiety. CBM interventions are designed to directly modify attention and interpretation biases via repeated practice on cognitive tasks. Analogue studies have demonstrated that CBM affects cognitive biases and anxiety in a number of anxiety conditions. Multisession CBM treatments have shown preliminary efficacy for generalized social phobia and generalized anxiety disorder, with effect sizes comparable to existing treatments. However, with any newly developing field, there are a number of important limitations of the existing data that need to be addressed before making firm conclusions regarding CBM's efficacy for anxiety disorders. This article focuses on the theoretical rationale for CBM and the current evidence from analogue and clinical samples. PMID- 21306220 TI - Molecular characterization of newborn glaucoma including a distinct aniridic phenotype. AB - PURPOSE: To characterize the underlying genetic defect in otherwise healthy Saudi newborns with buphthalmos, including those with iris abnormalities. METHODS: Prospective case series of affected Saudi Arabian probands who were referred for genetic counseling over a 4 year period. All had CYP1B1 sequencing. Selected patients with visible iris abnormalities had PAX6, FOXC1, and PITX2 sequencing. CYP1B1-negative patients had LTBP2 sequencing. RESULTS: All 67 probands had corneal enlargement with variable haze/scarring evident to caregivers at birth; 46 had a family history of infantile or early childhood glaucoma. All families were consanguineous except for 6, 2 of which were endogamous. Eight probands had mild ectropion uveae with partial aniridia; 2 probands had thick scarred corneas that precluded careful iris examination. Homozygous or compound heterozygous CYP1B1 mutations were identified in 91% (61/67), including all 8 probands with ectopion uveae and partial aniridia. The common Saudi mutation p.G61E occurred in most cases (38 homozygous, 8 compound heterozygous). Four novel mutations were identified (p.N252K, p.V460E, p.S485F, p.N519D). No mutations were identified in the other screened genes. CONCLUSIONS: Newborn glaucoma on the Arabian Peninsula is typically CYP1B1-related even in the setting of developmental iris abnormality. Mild iris ectropion with partial aniridia in a newborn with glaucoma suggests mutations in CYP1B1 rather than in other genes associated with anterior segment dysgenesis. On the Arabian Peninsula p.G61E mutations are the major cause of newborn glaucoma but novel CYP1B1 mutations continue to be documented. The fact that the 9% of cases that were CYP1B1-negative did not have mutations in LTBP2 suggests that there exists at least 1 additional locus for this condition. PMID- 21306221 TI - Arch dimension changes from successful slow maxillary expansion of unilateral posterior crossbite. AB - OBJECTIVE: To evaluate the long-term effects of successful slow maxillary expansion without fixed appliances or retainers in the mixed dentition on patients with unilateral crossbites, using Haas-type, hyrax, or quad helix appliances. MATERIALS AND METHODS: Serial dental casts of 110 patients were evaluated at three time points: preexpansion (T1) (mean age 7 years/7 months), postexpansion (T2) (mean age 8 years/8 months), and approximately 4 years later in the permanent dentition (T3) (mean age 12 years/9 months). Maxillary and mandibular intercanine and intermolar widths, arch length, and perimeter and molar angulation were measured at all three time intervals with the Michigan published growth norms serving as a control. RESULTS: Successful treatment by slow maxillary expansion (SME) produced similarly favorable expansion by all three expanders in all measurements for both arches. Maxillary arch widths were narrower than controls pretreatment (T1) and wider than controls immediately post treatment (T2). Long-term (T3) maxillary intermolar width was the same as controls, with intercanine width significantly wider than controls. Maxillary intercanine and intermolar width increased from T1 to T3, by 4.5 mm and 3.5 mm, respectively, with 98% of intercanine and 80% of intermolar expansion remaining at T3. Maxillary arch circumference increased by 1 mm from T1 to T3. Mandibular width did not change significantly. CONCLUSION: Maxillary arch dimensions in early mixed dentition in patients with unilateral posterior crossbite showed good stability 4 years post treatment in the permanent dentition. PMID- 21306222 TI - Predictors of adolescent compliance with oral hygiene instructions during two arch multibracket fixed orthodontic treatment. AB - OBJECTIVE: To determine compliance with oral hygiene instructions (OHI) of adolescents receiving two-arch multibracket fixed appliances and identify its predictive factors. MATERIALS AND METHODS: Forty-one patients in a longitudinal study were provided standardized OHI and assessed at baseline: before bonding (T0mo), approximately 30 days after bonding (T1mo), and approximately 150 days (T5mo) after bonding straight-wire appliances simultaneously in the maxillary and mandibular arches. Oral hygiene (OH) performance was measured using plaque and gingival indices. Compliance predictors were identified from questionnaires administered to patients and their parents and from patients' charts. RESULTS: OH performance worsened from T0mo to T1mo but then improved from T1mo to T5mo. At T5mo, 73% of the sample had good OH. Univariate analyses found perceived severity of malocclusion, school performance, and parental marital status to be significant predictors of good OH performance at T5mo. Multiple logistic regressions identified having married parents and good academic performance in school as significant predictors. CONCLUSIONS: In the sample studied, after initially worsening, compliance with OHI improved at 5 months after bonding. Adolescents with married parents and those reporting good academic performance in school were found more likely to have complied with OHI provided at baseline and to perform better OH. PMID- 21306223 TI - Friction properties according to vertical and horizontal tooth displacement and bracket type during initial leveling and alignment. AB - OBJECTIVE: To compare frictional properties according to the amounts of vertical displacement (VD) and horizontal displacement (HD) of teeth and bracket types during the initial leveling/alignment stage. METHODS: Combinations of self ligating brackets (SLBs; two active type: In-Ovation-R and In-Ovation-C; four passive type: Damon-3Mx, Damon-Q, SmartClip-SL3, and Clarity-SL) and 0.014-inch nickel-titanium archwires (austenitic type, A-NiTi, and copper type, Cu-NiTi) were tested in a stereolithographically made typodont system that could simulate malocclusion status and periodontal ligament space. The upper canines (UCs) were displaced in the gingival direction and the upper lateral incisors (ULIs) in the lingual direction from their ideal positions by up to 3 mm, with 1-mm intervals, respectively. Two conventional brackets were used as controls. Static and kinetic frictional forces were measured. One-way analysis of variance test with post hoc test was performed for statistical analysis. RESULTS: In the gingival displacement of UCs, Clarity-SL produced significantly lower frictional force (P < .001), while Damon-3Mx, In-Ovation-R, and SmartClip-SL3 produced higher frictional force among SLBs. In the lingual displacement of ULIs, Damon-Q and Damon-3Mx produced significantly lower frictional force (P < .01), while Clarity SL produced the highest frictional force among SLBs (P < .001). Clarity-SL combined with A-NiTi and C-NiTi, Damon-3Mx combined with A-NiTi, and In-Ovation-C combined with Cu-NiTi showed differences in frictional properties between VD and HD. CONCLUSIONS: Since the frictional properties of SLBs would be different between VD and HD of teeth, it is necessary to develop SLBs with low friction in both VD and HD of teeth. PMID- 21306224 TI - Periodontal health and relative quantity of subgingival Porphyromonas gingivalis during orthodontic treatment. AB - OBJECTIVE: To examine periodontal changes and the relative quantity of subgingival Porphyromonas gingivalis during orthodontic treatment. MATERIALS AND METHODS: The study subjects were recruited consecutively among malocclusion patients seeking orthodontic treatment. Group A comprised 28 subjects (17.6 +/- 5.68 years of age) at the beginning of orthodontic treatment, and group B comprised 20 subjects (17.8 +/- 4.49 years of age) at the end of orthodontic treatment. Plaque index (Pl.I), gingival index (GI), and probing pocket depth (PPD) were measured before and after appliance placement in group A and before and after appliance removal in group B. Real-time quantitative polymerase chain reaction was used to quantify P. gingivalis in subgingival plaque at each time point. RESULTS: There was a significant increase in Pl.I and GI during the first 3 months of appliance placement but a significant decrease in Pl.I, GI, and PPD during the first 6 months after appliance removal. The carriage and relative quantity of subgingival P. gingivalis were high at the end of orthodontic treatment, and they decreased significantly after appliance removal. The amount of subgingival P. gingivalis after appliance removal (for a period of 6 months) was higher than the amount measured before appliance placement. CONCLUSIONS: Fixed orthodontic treatment is conducive to dental plaque accumulation and gingival inflammation. In our study, after removal of orthodontic appliances, periodontal health improved, and the carriage and amount of subgingival P. gingivalis decreased. Nevertheless, the amount of subgingival P. gingivalis remained high for 6 months after appliance removal, and this finding might imply a potential risk to periodontal health in certain patients. PMID- 21306225 TI - Changes in hyoid bone position following rapid maxillary expansion in adolescents. AB - OBJECTIVE: To examine changes in hyoid to mandibular plane distance (H-MP) and tongue length (TL) between children who had orthodontic treatment with and without rapid maxillary expansion (RME). MATERIALS AND METHODS: Lateral and frontal cephalograms of 138 patients treated with RME and 148 controls treated without RME were used to measure pretreatment (T(1)) and posttreatment (T(2)) intermolar (IM) distance, lateronasal width (LNW), H-MP, and TL. Medical histories were used to collect demographic information, history of mouth breathing, difficulty breathing through the nose, and previous adenotonsillectomy. Groups were group-matched for age and gender. Descriptive statistics were calculated. Group means were compared using t-tests and chi square statistics. Reliability was estimated using intraclass correlations and kappa statistics. Statistical significance was set at P < .05. RESULTS: At T(1), the RME group showed smaller LNW (24.83 +/- 1.99 vs 26.18 +/- 2.05) and IM (50.17 +/- 2.3 vs 51.58 +/- 2.83). The distance from H-MP was longer in the RME group (15.69 +/- 3.95 vs 13.86 +/- 3.4). Mean changes (T(2) - T(1)) in the RME group were increased LNW (+2.48 +/- 1.38 vs +0.94 +/- 1.11 for the non-RME group) and IM (+3.21 +/- 1.72 vs +0.98 +/- 1.67). The mean change (T(2) - T(1)) in H-MP for the RME group was -0.68 +/- 3.67 compared with +1.1 +/- 2.96 for the non-RME group. Mean changes for TL were not statistically significant. No significant differences were noted at T(2) between groups for LNW, H-MP, or TL. CONCLUSIONS: In this sample, RME produced significant changes in H-MP, and TL was unaffected. PMID- 21306226 TI - Stability comparison between commercially available mini-implants and a novel design: part 1. AB - OBJECTIVE: To compare mechanical stability among five mini-implant designs--a newly invented design and four commercially available designs that vary by shape and threading; to calculate external surface area of each design using high resolution micro-computed tomography; and to evaluate the relationship between surface area and stability results. MATERIALS AND METHODS: The four commercially available mini-implants--single-threaded and cylindrical (SC), single-threaded and tapered (ST), double-threaded and cylindrical (DC), double-threaded and tapered (DT)--and a new implant that is designed to engage mostly in cortical bone with shorter and wider dimensions (N1) were inserted in simulated bone with cortical and trabecular bone layers. The mechanical study consisted of torque measurements and lateral displacement tests. External surface area was computed using a 25-um micro-CT. RESULTS: Maximum insertion torque, maximum removal torque, and force levels for displacements were the highest in N1, followed by DT, ST, DC, and SC (alpha = .05). The surface area was largest in DT, followed by N1, ST, DC, and SC. Surface area engaged in cortical bone, however, was the greatest in N1. The surface area of mini-implants had positive correlation with stability. CONCLUSION: Among commercial designs, both added tapering and double threading improved stability. N1 was the most stable design within this research design. The new design has the potential to be clinically superior; it has enhanced stability and there is diminished risk of endangering nearby anatomic structures during placement and orthodontic treatment, but the design requires refinements to reduce insertion torque to avoid clinical difficulty and patient discomfort. PMID- 21306227 TI - Effect of adhesive application prior to bracket bonding with flowable composites. AB - OBJECTIVE: To evaluate the effect of applying an adhesive, prior to different flowable composite resins, on the shear bond strength (SBS) of orthodontic brackets to acid-etched human enamel. MATERIALS AND METHODS: One hundred metal brackets were bonded to 35% phosphoric acid-etched human premolars using four flowable composites (Admira Flow, Tetric Flow, Filtek Supreme, Transbond Supreme) and a conventional orthodontic composite resin (Transbond XT). For each experimental group, half of the specimens were bonded in combination with Transbond XT adhesive. After 24 hours of storage, an SBS test was performed. Adhesive remnant index scores were determined after the failure of brackets. Two way analysis of variance and Student-Newman-Keuls multiple comparison tests were performed at P < .05. RESULTS: When using an adhesive system, the five composites performed equally. The application of adhesive had a significant effect on SBS. Without adhesive, SBS decreased in all groups, except for Transbond Supreme LV. All the test groups exhibited similar bracket failure modes. CONCLUSIONS: When using an adhesive system, flowable composite resins exhibited similar SBS. Transbond Supreme was the only resin performing similarly with or without adhesive system application. PMID- 21306228 TI - Spatial changes in the relationship of the mandible and maxilla with different extraction patterns and techniques. AB - OBJECTIVE: To assess the spatial changes in the relationship of the mandible to the maxilla with different extraction patterns and techniques when treated Class II patients are compared with untreated subjects. MATERIALS AND METHODS: Pretreatment and posttreatment cephalometric radiographs of 125 Class II adolescent patients and 30 untreated Class II patients were traced. The treated patients were divided by technique and extraction pattern into four groups: preangulated appliance with four first premolar (4/4) extractions, preangulated appliance with maxillary first and mandibular second premolar (4/5) extractions, standard edgewise (Tweed-Merrifield technique) with four first premolar (4/4) extractions, and standard edgewise (Tweed-Merrifield technique) with maxillary first and mandibular second premolar (4/5) extractions. The mandibular displacement vector angle was determined by using two different superimposition methods: the superimposition on the cranial base and the superimposition on the maxillary base. RESULTS: The differences in the mean vector angles of mandibular displacement in the two superimposition methods were statistically compared. There was a significant difference between the vector angle of mandibular displacement in each treated group when the superimposition techniques (ie, cranial base and maxillary base) were compared. Significant differences between the standard edgewise treated group and the preangulated treated group were found using both superimposition methods. CONCLUSIONS: The standard edgewise appliance groups showed a more forward horizontal displacement of the mandible than the preangulated appliance groups. Within the standard edgewise sample, the patients with four first premolars extracted had a greater horizontal mandibular displacement than did the maxillary first, mandibular second premolar extraction sample. PMID- 21306229 TI - Molar height and dentoalveolar compensation in adult subjects with skeletal open bite. AB - OBJECTIVE: To evaluate the skeletal and dentoalveolar components in adult subjects with skeletal open bite in the presence or absence of dental compensation. MATERIALS AND METHODS: The study sample included 69 adult female subjects who belonged to three groups according to skeletal vertical relationships and overbite. A total of 15 variables (5 angular, 10 linear) were evaluated. Values in the dentally compensated open bite group (COBG), the dentally noncompensated open bite group (NCOBG), and the control group with normal vertical skeletal relationships and overbite (CG) were compared by means of parametric statistics. RESULTS: The COBG and the NCOBG showed significantly greater incisor and molar heights in both jaws than the CG. No significant difference in upper or lower molar height was found between COBG and NCOBG. Incisor height was significantly greater in COBG than in NCOBG. Elongation in the incisor region was accompanied by significant narrowing of the lower anterior alveolar process in both skeletal open bite groups. Proclination of the upper incisors was significantly smaller in the COBG than in the other groups. CONCLUSIONS: Dentoalveolar components consisting of incisor elongation and inclination play a significant role in compensating for skeletal open bite configuration in adult subjects. Increased molar height is a common finding in adults with skeletal open bite. PMID- 21306230 TI - Effects of Er:YAG laser and air abrasion on the microleakage of a resin-based fissure sealant material. AB - OBJECTIVES: The aim of the present study was to evaluate the effects of different surface pre-treatment techniques on the microleakage of a resin-based fissure sealant material. METHODS: Thirty-five molars were divided into the following seven groups based on the surface pre-treatment technique used: (a) Erbium: Yttrium Aluminium Garnet (Er:YAG) laser (7 W); (b) Er:YAG laser (7 W)+acid etching (with 37% phosphoric acid); (c) Er:YAG laser (5.5 W); (d) Er:YAG laser (5.5 W)+acid etching; (e) air abrasion+acid etching; (f) air abrasion; and (g) conventional acid etching. The sealant was placed according to the manufacturers' instructions and light-cured for 20 sec. The sealed teeth were thermocycled for 10,000 cycles (5 degrees -55 degrees C), then immersed in 5% methylene blue for 24 h and sectioned mesiodistally. Each section was analyzed and photographed using a light microscope. Microleakage was assessed quantitatively by the degree of dye penetration and also qualitatively, scored on a three-point rating scale. Data were analyzed by one-way analysis of variance (ANOVA) and the Kruskal-Wallis test. The level of significance was set at p < 0.05. RESULTS: Regardless of the fissure morphology and penetration depth, enamel surfaces conditioned with Er:YAG laser irradiation exhibited significantly higher microleakage than those conditioned with air abrasion followed by acid etching, and those conditioned with conventional acid etching (p < 0.05). Air abrasion followed by acid etching, as well as conventional acid etching, provided a sufficient seal, whereas laser irradiation alone or in combination with acid etching exhibited higher microleakage than did the other groups. CONCLUSIONS: Conventional acid etching remains the most effective and the simplest technique. PMID- 21306231 TI - Low-level laser therapy induces differential expression of osteogenic genes during bone repair in rats. AB - OBJECTIVES: The aim of this study was to measure the temporal pattern of the expression of osteogenic genes after low-level laser therapy during the process of bone healing. We used quantitative real-time polymerase chain reaction (qPCR) along with histology to assess gene expression following laser irradiation on created bone defects in tibias of rats. MATERIAL AND METHODS: The animals were randomly distributed into two groups: control or laser-irradiated group. Noncritical size bone defects were surgically created at the upper third of the tibia. Laser irradiation started 24 h post-surgery and was performed for 3, 6, and 12 sessions, with an interval of 48 h. A 830 nm laser, 50 J/cm(2), 30 mW, was used. On days 7, 13, and 25 post-injury, rats were sacrificed individually by carbon dioxide asphyxia. The tibias were removed for analysis. RESULTS: The histological results revealed intense new bone formation surrounded by highly vascularized connective tissue presenting slight osteogenic activity, with primary bone deposition in the group exposed to laser in the intermediary (13 days) and late stages of repair (25 days). The quantitative real-time PCR showed that laser irradiation produced an upregulation of BMP-4 at day 13 post-surgery and an upregulation of BMP4, ALP, and Runx 2 at day 25 after surgery. CONCLUSION: Our results indicate that laser therapy improves bone repair in rats as depicted by differential histopathological and osteogenic genes expression, mainly at the late stages of recovery. PMID- 21306232 TI - Constructing understandings of end-of-life care in Europe: a qualitative study involving cognitive interviewing with implications for cross-national surveys. AB - BACKGROUND: Although national findings regarding people's end-of-life care (EoLC) preferences and priorities are available within Europe, a lack of research coordination between countries has meant that cross-national understandings of EoLC remain unknown. PURPOSE: To (1) identify English and German understandings of EoLC within the context of an EoLC survey, and (2) to synthesise these understandings to aid interpretation of results from a cross-national survey. METHODS: An inductive and interpretive two-phased sequential design involving (1) qualitative analysis of cognitive interview data from 15 English and 15 German respondents to develop country-related categories, and (2) qualitative synthesis to identify a conceptually coherent understanding of EoLC. RESULTS: Open and axial coding resulted in six English and six German categories. Commonalities included (a) the importance of social and relational dimensions, (b) dynamic decision making comprising uncertainty, (c) a valuing of life's quality and quantity, and (d) expectations for holistic care involving autonomy, choice, and timely information from trusted professionals. Differences involved attention to practical matters, and thoughts about prolongation of life, preferred place of death, and the role of media and context. Synthesis resulted in four concepts with underlying coherence: expectations of a high standard of EoLC involving autonomy, choice, and context; evolving decision making amid anticipated change; thoughts about living and existing; and worldviews shaping EoLC preferences in real and hypothetical scenarios. CONCLUSION: Individual and country-related diversity must be remembered when quantifying EoLC understandings. Inductive interpretive analysis of cognitive interview data aids interpretation of survey findings. Cross-national research coordination and qualitative synthesis assists EoLC in Europe. PMID- 21306233 TI - Fetal surgery for myelomeningocele? PMID- 21306234 TI - Interactive medical case. Lying low. PMID- 21306235 TI - Images in clinical medicine. Limbal dermoid. PMID- 21306236 TI - A recipe for medical schools to produce primary care physicians. PMID- 21306237 TI - Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. AB - BACKGROUND: The multitargeted tyrosine kinase inhibitor sunitinib has shown activity against pancreatic neuroendocrine tumors in preclinical models and phase 1 and 2 trials. METHODS: We conducted a multinational, randomized, double-blind, placebo-controlled phase 3 trial of sunitinib in patients with advanced, well differentiated pancreatic neuroendocrine tumors. All patients had Response Evaluation Criteria in Solid Tumors-defined disease progression documented within 12 months before baseline. A total of 171 patients were randomly assigned (in a 1:1 ratio) to receive best supportive care with either sunitinib at a dose of 37.5 mg per day or placebo. The primary end point was progression-free survival; secondary end points included the objective response rate, overall survival, and safety. RESULTS: The study was discontinued early, after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group as well as a difference in progression-free survival favoring sunitinib. Median progression-free survival was 11.4 months in the sunitinib group as compared with 5.5 months in the placebo group (hazard ratio for progression or death, 0.42; 95% confidence interval [CI], 0.26 to 0.66; P<0.001). A Cox proportional-hazards analysis of progression-free survival according to baseline characteristics favored sunitinib in all subgroups studied. The objective response rate was 9.3% in the sunitinib group versus 0% in the placebo group. At the data cutoff point, 9 deaths were reported in the sunitinib group (10%) versus 21 deaths in the placebo group (25%) (hazard ratio for death, 0.41; 95% CI, 0.19 to 0.89; P=0.02). The most frequent adverse events in the sunitinib group were diarrhea, nausea, vomiting, asthenia, and fatigue. CONCLUSIONS: Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors. (Funded by Pfizer; ClinicalTrials.gov number, NCT00428597.). PMID- 21306239 TI - The role of public-sector research in the discovery of drugs and vaccines. AB - BACKGROUND: Historically, public-sector researchers have performed the upstream, basic research that elucidated the underlying mechanisms of disease and identified promising points of intervention, whereas corporate researchers have performed the downstream, applied research resulting in the discovery of drugs for the treatment of diseases and have carried out development activities to bring them to market. However, the boundaries between the roles of the public and private sectors have shifted substantially since the dawn of the biotechnology era, and the public sector now has a much more direct role in the applied research phase of drug discovery. METHODS: We identified new drugs and vaccines approved by the Food and Drug Administration (FDA) that were discovered by public sector research institutions (PSRIs) and classified them according to their therapeutic category and potential therapeutic effect. RESULTS: We found that during the past 40 years, 153 new FDA-approved drugs, vaccines, or new indications for existing drugs were discovered through research carried out in PSRIs. These drugs included 93 small-molecule drugs, 36 biologic agents, 15 vaccines, 8 in vivo diagnostic materials, and 1 over-the-counter drug. More than half of these drugs have been used in the treatment or prevention of cancer or infectious diseases. PSRI-discovered drugs are expected to have a disproportionately large therapeutic effect. CONCLUSIONS: Public-sector research has had a more immediate effect on improving public health than was previously realized. PMID- 21306238 TI - Everolimus for advanced pancreatic neuroendocrine tumors. AB - BACKGROUND: Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study. METHODS: We randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus. RESULTS: The median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks). CONCLUSIONS: Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. (Funded by Novartis Oncology; RADIANT-3 ClinicalTrials.gov number, NCT00510068.). PMID- 21306240 TI - Radioiodine therapy for hyperthyroidism. PMID- 21306241 TI - Images in clinical medicine. Sialolith of the submandibular salivary gland. PMID- 21306242 TI - Case records of the Massachusetts General Hospital. Case 4-2011. A 4-year-old boy with back pain and hypercalcemia. PMID- 21306245 TI - Biomedical research and health advances. PMID- 21306243 TI - Promising advances in the treatment of malignant pancreatic endocrine tumors. PMID- 21306246 TI - Leukodystrophy and gene therapy with a dimmer switch. PMID- 21306247 TI - Safety of recombinant activated factor VII in randomized clinical trials. PMID- 21306248 TI - Safety of recombinant activated factor VII in randomized clinical trials. PMID- 21306249 TI - Safety of recombinant activated factor VII in randomized clinical trials. PMID- 21306250 TI - Safety of recombinant activated factor VII in randomized clinical trials. PMID- 21306252 TI - Everolimus and giant-cell astrocytomas in tuberous sclerosis. PMID- 21306253 TI - Everolimus and giant-cell astrocytomas in tuberous sclerosis. PMID- 21306255 TI - Tiotropium step-up therapy in asthma. PMID- 21306256 TI - Tiotropium step-up therapy in asthma. PMID- 21306258 TI - Reimbursement policy and androgen-deprivation therapy for prostate cancer. PMID- 21306259 TI - Reimbursement policy and androgen-deprivation therapy for prostate cancer. PMID- 21306261 TI - Guidelines for immune thrombocytopenia. PMID- 21306263 TI - Ranibizumab for age-related macular degeneration. PMID- 21306264 TI - Ranibizumab for age-related macular degeneration. PMID- 21306266 TI - Bisphosphonates for osteoporosis. PMID- 21306267 TI - Bisphosphonates for osteoporosis. PMID- 21306269 TI - Hemodialysis. PMID- 21306270 TI - Hemodialysis. PMID- 21306272 TI - Writing new rules for insurers. PMID- 21306273 TI - NK-cell and B-cell deficiency with a thymic mass. PMID- 21306278 TI - Transforming graduate medical education to improve health care value. PMID- 21306279 TI - Arachnoid cells on culture plates and collagen scaffolds: phenotype and transport properties. AB - INTRODUCTION: The arachnoid tissue is a critical component of cerebrospinal fluid removal. Failure of that function results in hydrocephalus, a serious medical condition. The purpose of this study was to characterize arachnoid cell transport in culture and on three-dimensional collagen scaffold. METHODS: Arachnoid cells were harvested from rat brainstems and cultured onto bilayered bovine collagen scaffolds. Cell growth and phenotype (protein expression and morphometry) were determined. Permeability and hydraulic conductivity were quantified. RESULTS: Cells harvested from the anterior brainstem surface exhibited arachnoid cell phenotype (positive for vimentin, desmoplakin, and cytokeratin), readily penetrated the collagen scaffold, and doubled approximately every 2-3 days. The transepithelial electrical resistance value for a monolayer of cells was 160 Omega cm(2) and the permeability of indigo carmine was 6.7*10(-6)+/-1.1*10(-6) cm/s. Hydraulic conductivity of the collagen construct was 6.39 mL/min/mmHg/cm(2). CONCLUSION: Cells isolated from the anterior brain stem exhibited the same phenotype as those found in the native tissue and exhibited aspects of barrier function found in vivo. These studies suggest that an ex vivo model for the arachnoid granulation can be developed. PMID- 21306277 TI - A randomized trial of prenatal versus postnatal repair of myelomeningocele. AB - BACKGROUND: Prenatal repair of myelomeningocele, the most common form of spina bifida, may result in better neurologic function than repair deferred until after delivery. We compared outcomes of in utero repair with standard postnatal repair. METHODS: We randomly assigned eligible women to undergo either prenatal surgery before 26 weeks of gestation or standard postnatal repair. One primary outcome was a composite of fetal or neonatal death or the need for placement of a cerebrospinal fluid shunt by the age of 12 months. Another primary outcome at 30 months was a composite of mental development and motor function. RESULTS: The trial was stopped for efficacy of prenatal surgery after the recruitment of 183 of a planned 200 patients. This report is based on results in 158 patients whose children were evaluated at 12 months. The first primary outcome occurred in 68% of the infants in the prenatal-surgery group and in 98% of those in the postnatal surgery group (relative risk, 0.70; 97.7% confidence interval [CI], 0.58 to 0.84; P<0.001). Actual rates of shunt placement were 40% in the prenatal-surgery group and 82% in the postnatal-surgery group (relative risk, 0.48; 97.7% CI, 0.36 to 0.64; P<0.001). Prenatal surgery also resulted in improvement in the composite score for mental development and motor function at 30 months (P=0.007) and in improvement in several secondary outcomes, including hindbrain herniation by 12 months and ambulation by 30 months. However, prenatal surgery was associated with an increased risk of preterm delivery and uterine dehiscence at delivery. CONCLUSIONS: Prenatal surgery for myelomeningocele reduced the need for shunting and improved motor outcomes at 30 months but was associated with maternal and fetal risks. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00060606.). PMID- 21306280 TI - Osteoblasts on rod shaped hydroxyapatite nanoparticles incorporated PCL film provide an optimal osteogenic niche for stem cell differentiation. AB - After the clinical insertion of a bone biomaterial, the surrounding osteoblasts would migrate and attach to the implant surface and foster a microenvironment that largely determines the differentiation fate of the comigrated mesenchymal stem cells. Whether the fostered microenvironment is suitable for osteogenic differentiation of mesenchymal stem cells is critical for the subsequent osseointegration. In this study, we determined (1) how the spherical or rod shaped hydroxyapatite nanoparticles (nHA) incorporated poly(E-caprolactone) (PCL) films (PCL-spherical nHA, PCL-rod nHA) interact with primary human osteoblasts (HOBs); (2) how the microenvironment rendered by their interaction affects osteogenic differentiation of adipose tissue-derived mesenchymal stem cells (ASCs). HOBs were seeded on PCL, PCL-spherical nHA, and PCL-rod nHA films, respectively. When cultured alone, the HOBs on PCL-rod nHA films showed most efficient osteoblastic differentiation compared with those on PCL or PCL spherical nHA films. When cocultured with ASCs in an indirect coculture system, only the HOBs on PCL-rod nHA films up-regulated the gene expression of Runx2, bone sialoprotein, and osteocalcin of ASCs. Additionally, the HOBs on PCL-rod nHA films showed significant up-regulation of bone morphogenic protein 2 gene and protein expression and induced highest phosphorylated Smad1/5 protein level in ASCs. Treatment of the coculture medium with bone morphogenic protein 2 inhibitor (Noggin) largely abolished the osteogenic differentiation of the ASCs induced by the HOBs on PCL-rod nHA films. In conclusion, HOBs can not only best display their osteoblastic phenotype by culturing on PCL-rod nHA films but also render an optimal osteogenic niche for the differentiation of stem cells. PMID- 21306281 TI - Laquinimod: a promising oral medication for the treatment of relapsing-remitting multiple sclerosis. AB - INTRODUCTION: MS is a chronic immunological disease of the CNS. Due to a lack of curative treatment approaches, current principles aim at the reduction of inflammatory disease activity. Today, many different substances are under investigation in Phase III clinical trials and hold promise in the treatment of relapsing-remitting MS (RRMS). Laquinimod is a promising new orally administered substance which has demonstrated beneficial effects in placebo-controlled trials in patients with RRMS and is currently under investigation in two global Phase III trials. AREAS COVERED: The authors review the pharmaceutical properties of laquinimod, its suggested mechanisms of action, clinical efficacy and adverse profile. This review contains data that have been presented by experts in the field at international meetings and congresses and that have been published in peer-reviewed journals. EXPERT OPINION: While laquinimod has been shown to have a promising safety profile, its mechanisms of action are not completely understood and further research is necessary to clarify this. Studies conducted in EAE, the mouse model of MS, have demonstrated immunomodulatory and neuroprotective mechanisms of action. Hopefully, the two current pivotal Phase III trials currently underway will shed some light on laquinimod confirming its clinical potential and add to the current armamentarium for the treatment of RRMS. PMID- 21306282 TI - Accumulated safety data of micafungin in therapy and prophylaxis in fungal diseases. AB - OBJECTIVE: To define better the safety profile of micafungin, an analysis of micafungin clinical trial safety data was undertaken. RESEARCH DESIGN AND METHODS: Adverse event data were pooled worldwide from 17 clinical efficacy and safety studies. Adverse events were coded using the Medical Dictionary for Regulatory Activities version 5.0. RESULTS: In the pooled clinical trial data set, 3028 patients received at least one dose of micafungin. The mean age of patients was 41.4 years; with 296 (9.8%) children (< 16 years) and 387 (12.8%) elderly patients (>= 65 years). Common underlying conditions were hematopoietic stem cell and other transplantations (26.1%), malignancies (20.8%) and HIV (32.9%). Mean exposure was 18 days for adults and 29 days for children. The most frequently reported treatment-related adverse events were nausea (2.8%), vomiting (2.5%), phlebitis (2.5%), hypokalemia (2.1%), fever/pyrexia (2.1%) and diarrhea (2%), as well as increases in alkaline phosphatase (2.7%), aspartate aminotransferase (2.3%) and alanine aminotransferase (2%). Although elderly adults had a higher incidence of renal impairment (1%) compared with non-elderly adult (0.1%) and pediatric patients (0.3%), there were no clear trends showing an association between higher doses of micafungin or longer treatment durations and increased incidence rates of treatment-related adverse events. CONCLUSIONS: Analysis of a large database demonstrated a favorable clinical safety profile for micafungin similar to other echinocandins. PMID- 21306283 TI - Medical management of ascites. AB - INTRODUCTION: Ascites is a common complication of advanced cirrhosis that has a significant negative impact on survival. This review updates the reader on the medical management of ascites. AREAS COVERED: This review explores the pathophysiology of ascites formation in cirrhosis; the current mainstays of medical management (treating the underlying cause of cirrhosis, avoiding nephrotoxic agents, sodium restriction, and combination diuretic therapy); potential novel agents, such as vasoconstrictors and vaptans; and albumin infusions. The literature research covers all aspects of medical management of ascites from the English literature, concentrating on publications from the past 10 years. It provides a thorough understanding of how the correction of pathophysiology of ascites formation helps to improve ascites; knowledge on the monitoring of patients with cirrhosis and ascites receiving medical management, and on prophylaxis against potentially life-threatening complication such as spontaneous bacterial peritonitis; and potential new treatments for ascites. EXPERT OPINION: Management of patients with cirrhosis and ascites requires careful attention to fluid and electrolyte balance and avoidance of complications. Recognition of refractory ascites allows for the use of second line treatments. All patients with cirrhosis and ascites should be considered for liver transplantation. PMID- 21306284 TI - A comparison of peptide and folate receptor targeting of cancer cells: from single agent to nanoparticle. AB - INTRODUCTION: There is broad interest in a targeted strategy that delivers a concentrated therapeutic payload to tumor cells, because of the significant potential for improvements in therapeutic outcomes and reduction of side effects if therapeutics can be delivered only to diseased tissue. AREAS COVERED: This review describes how the coupling chemistry and surface charge effects of peptide labeling in nanoparticle drug delivery strategies have proved difficult to control, resulting in many studies that use folate instead. However, the successful peptide targeting of structural, hormonal, cytokine and endocrine receptors in the delivery of therapeutic and diagnostic radionuclides provides a strong indication that it is worth finding methods to synthesize peptide-targeted nanoparticles. EXPERT OPINION: Chemical conjugation to peptides reduces colloidal stability, which is a limiting factor in the development of targeting nanoparticles. Mechanistic studies are needed in order to develop peptide targeting for nanoparticles to rival the selectivity that has been achieved with the small molecule folate. Although most of the work so far has been done using gold nanoparticles, biological and polymer nanoparticles are more colloidally stable and present enormous opportunities for coupling to peptides. PMID- 21306286 TI - Risk of new-onset diabetes mellitus associated with beta-blocker treatment for hypertension. AB - BACKGROUND: This study investigated the risk of new-onset diabetes (NOD) among hypertensive patients initiating carvedilol therapy vs other beta-blocker (BB) therapy in a clinical practice setting. METHODS: Patients aged >=18 years with >=1 pharmacy claim for a BB of interest (carvedilol immediate-release [IR]/controlled-release [CR], atenolol, metoprolol succinate, or metoprolol tartrate) were identified in the IMS LifeLink Health Plan Claims Database. Index date was the first chronologically occurring prescription for any BB during the enrollment period (July 1, 2000-December 31, 2007). Patients had to be continuously eligible to receive healthcare services 6 months prior to and a minimum of 3 months after index date and have >=1 diagnostic code for hypertension (ICD-9-CM: 401.xx-405.xx) during this time frame. Patients were excluded for having a diagnosis of diabetes mellitus (ICD-9-CM: 250.xx) and/or prescription for antidiabetic therapy in the 6 months prior to and/or 3 months after index date. Eligible patients were propensity-score matched in a 1:3 ratio (carvedilol : other BBs). Mean duration of follow-up was 12.8 and 14.8 months for the carvedilol group and other BB group, respectively. Primary outcome of interest was presence and timing of NOD. RESULTS: Among 3084 patients in the carvedilol group and 9252 in the other BB group, mean age was 56 years, with 54% male. NOD rate was 3.16 per 100 person-years for carvedilol patients vs 3.36 for patients in the other BB group (NS). Risk of NOD was similar between groups (HR 0.971, 95% CI: 0.78, 1.21; P = 0.792). CONCLUSIONS: Findings suggest the risk of NOD among hypertensive patients is similar between carvedilol and other BB agents (i.e., atenolol, metoprolol succinate, or metoprolol tartrate). LIMITATIONS: The use of administrative claims data and relatively short follow-up period may limit the generalizability of results. PMID- 21306287 TI - Progression to type 2 diabetes, healthcare utilization, and cost among pre diabetic patients with or without comorbid hypertension. AB - OBJECTIVE: This study examined progression to type 2 diabetes and compared healthcare utilization and costs among patients with pre-diabetes, with or without comorbid hypertension. RESEARCH DESIGN AND METHODS: This study drew from a large national claims database (2003-2008). Patients were >=18 years of age with a medical claim or lab value indicating the presence of pre-diabetes. The index date was the first pre-diabetes diagnosis (ICD-9 codes 790.21, 790.22, 790.29) or qualifying lab value of fasting plasma glucose or impaired glucose intolerance. All patients had >=12-month data pre- and post- index date. Multivariate analysis was conducted to identify risk factors affecting progression to type 2 diabetes, and to estimate the impact of hypertension status and diabetes progression on healthcare utilization and cost. RESULTS: 144,410 patients met study criteria, with an average follow-up of 802 (SD 344) days. Among participants, 30.7% progressed to diabetes, with a mean 288 (SD 340) days from pre-diabetes identification to diabetes diagnosis. Compared with patients who did not progress, the total adjusted medical costs for patients who developed diabetes increased by $1429 in 1 year, $2451 in 2 years, and $3621 in 3 years (p < 0.001). Patients with concomitant hypertension were significantly more likely to progress to type 2 diabetes, and had higher total medical costs compared to patients without hypertension ($476 higher in 1 year, $949 in 2 years, $1378 in 3 years). CONCLUSIONS: Patients with pre-diabetes who progressed to type 2 diabetes had higher healthcare utilization and costs compared with patients who did not. The presence of hypertension substantially increased costs and was associated with higher likelihood of diabetes progression. Blood pressure, lifestyle intervention, body mass index, and other factors cannot be examined due to the limitations of the data. Results may not be generalizable to patients with insurance other than commercial or Medicare. PMID- 21306288 TI - Pharmacotherapy for pediatric soft-tissue sarcomas. AB - INTRODUCTION: Soft-tissue sarcomas are rare, but they represent about 8% of all malignancies in pediatric age. Developing a multidisciplinary approach to treatment based on risk stratification has led to a dramatic improvement in survival, but a plateau has been reached with current treatment options in the last 20 years. Chemotherapy is usually effective for rhabdomyosarcoma and should be seen as the keystone of its treatment, while non-rhabdomyosarcoma soft-tissue sarcomas are still generally considered scarcely chemosensitive. AREAS COVERED: An overview of current, emerging and possible future medical therapies for pediatric soft-tissue sarcomas is provided. Insight into different chemotherapeutic strategies based on risk stratification for rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcomas in pediatric age is given. EXPERT OPINION: Integrating systemic therapy with local treatments (surgery and/or radiotherapy) is complex and requires adequate experience, which can only be assured by referral institutions. Future challenges include identifying novel targeted therapies and optimizing treatment protocols for customized patient care. PMID- 21306289 TI - Present and future therapeutic options for locally advanced and metastatic renal cell carcinoma. AB - INTRODUCTION: Locally advanced or metastatic renal cell carcinoma (RCC) is notoriously chemo- and radioresistant, leaving immunotherapy as the only treatment option. In recent years, targeted therapies have offered significant increases in progression-free survival (PFS). Despite this, the majority of patients soon develops resistant disease and finally succumbs. The need to implement treatment strategies that improve overall survival while having an acceptable safety profile is imperative. AREAS COVERED: This review provides information on the efficacy of recently studied treatment strategies for advanced RCC. These include sequential and combination therapy of established drugs as well as data on agents in early clinical development. The Medline and ASCO database were searched for clinical trials on medical therapy of advanced RCC from 2004 until May 2010. Data on targeted therapies, including tyrosine kinase inhibitors, vascular endothelial growth factor inhibitors, mammalian target of rapamycin inhibitors, and antiepidermal growth factor receptor agents are summarized. EXPERT OPINION: Improvements in response rates and PFS in patients with advanced RCC have been observed with new treatment strategies. The benefit in overall survival is less clear and needs further evaluation. Toxicity represents a concern especially in combination regiments. PMID- 21306291 TI - Reactivation of hepatitis B virus following bendamustine-containing chemotherapy in a patient with multiple myeloma. PMID- 21306292 TI - Esophageal preservation in five male patients after endoscopic inner-layer circumferential resection in the setting of superficial cancer: a regenerative medicine approach with a biologic scaffold. AB - As a result of injury caused by chronic gastroesophageal reflux, Barrett's esophagus with high-grade dysplasia and esophageal adenocarcinoma are rapidly increasing problems in the United States. The current standard of care involves esophagectomy, a procedure associated with a high morbidity, a negative impact on long term quality of life, and a mortality rate of 1-6 percent. An entirely endoscopic technique for circumferential, long segment en bloc removal of the mucosa and submucosa with subsequent placement of a biologic scaffold material that promotes a constructive remodeling response and minimizes stricture is described herein. The results of this approach are reported for five patients with 4-24-month follow-up. Restoration of normal mature, K4+/K14+, squamous epithelium, and return to a normal diet without significant dysphagia is reported for all patients. Two of five patients show a small focus of recurrent Barrett's esophagus at the gastroesophageal junction, but the entire length and circumference of the reconstituted esophageal mucosa remains free of disease. This experience provides evidence that a regenerative medicine approach may, for the first time, enable aggressive endoscopic resection of early stage neoplasia without the need for esophagectomy and its associated complications. PMID- 21306285 TI - Proactive multiple cardiovascular risk factor management compared with usual care in patients with hypertension and additional risk factors: the CRUCIAL trial. AB - OBJECTIVE: To investigate whether a proactive multifactorial risk factor intervention strategy using single-pill amlodipine/atorvastatin (5/10, 10/10 mg) in addition to other antihypertensive and lipid-lowering therapy, as required, resulted in greater reduction in calculated Framingham 10-year coronary heart disease (CHD) risk compared with usual care (UC) after 52-weeks treatment. RESEARCH DESIGN AND METHODS: Prospective, multinational, open-label, cluster randomized trial, with the investigator as the unit of randomization. Eligible hypertensive patients were 35-79 years of age, with >=3 additional cardiovascular risk factors, but no history of CHD and baseline total cholesterol (TC) <=6.5 mmol/l. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov ; trial identifier NCT00407537. MAIN OUTCOME MEASURE: The primary endpoint was calculated Framingham 10-year CHD risk at 52 weeks. RESULTS: Of the 140 randomized sites, 136 sites contributed 1461 patients. Mean baseline age and low-density lipoprotein cholesterol (LDL-C) were comparable between treatment arms. Mean baseline BP (150.3/89.7 vs. 144.3/86.5 mmHg) and Framingham CHD risk (20.0 vs. 18.1%) were higher in the proactive intervention versus the UC arm (p < 0.002 for both). At week 52, mean CHD risk was 12.5% in the proactive intervention arm and 16.3% in the UC arm (p < 0.001). The difference, observed at weeks 16 and 52, was primarily driven by significant differences in systolic BP and in TC between the two arms. Overall, adverse events (AEs) were reported in 48.8% and 44.0% of patients in the proactive intervention and the UC arm, respectively. Although there were differences in the incidence of AEs between the treatment arms, the AE profile in the proactive intervention arm was consistent with previous safety experience for this medication. CONCLUSIONS: A proactive multifactorial risk factor intervention strategy that simultaneously treated both BP and cholesterol regardless of individual risk factors per se, is more effective in reducing calculated Framingham 10-year CHD risk than UC in patients with hypertension and additional risk factors. PMID- 21306294 TI - Development of a multisegmental test body to calibrate and validate studies with spinal testing devices with follower load. AB - INTRODUCTION: Spinal testing devices need a tool for calibration and comparison of accomplished studies. The objective of this study was the development of a polysegmental test body, which simulates several functional spinal motion units and provides a standard calibration. MATERIALS AND METHODS: The test body consists of aluminum moldings simulating the vertebral bodies, rubber discs simulating the intervertebral discs and cylindrical guide elements with ball joints simulating the vertebral joints. The test body was tested multidirectional with a moment of 7.5 Nm and follower loads up to 800 N. RESULTS: The results showed sigmoid load-deformation curves of the test body similar to a human lumbar cadaver spine, but with a higher range of motion (ROM). The follower load had no influence during extension-flexion, but an increasing follower load during lateral bending and rotation caused increased friction and restoring forces with a decrea-sed ROM. DISCUSSION: The polysegmental test body does not show the same mechanical behavior like a polysegmental human cadaver spine in all directions of motion, but it provides reproducible values without requiring preconditioning as proposed for human specimen. CONCLUSION: This test body could improve the comparability of cadaver studies performed with different spinal testing devices by standardization of the test set-ups. PMID- 21306293 TI - Synthesis and characterization of tunable poly(ethylene glycol): gelatin methacrylate composite hydrogels. AB - Poly(ethylene glycol) (PEG) hydrogels are popular for cell culture and tissue engineering applications because they are nontoxic and exhibit favorable hydration and nutrient transport properties. However, cells cannot adhere to, remodel, proliferate within, or degrade PEG hydrogels. Methacrylated gelatin (GelMA), derived from denatured collagen, yields an enzymatically degradable, photocrosslinkable hydrogel that cells can degrade, adhere to and spread within. To combine the desirable features of each of these materials we synthesized PEG GelMA composite hydrogels, hypothesizing that copolymerization would enable adjustable cell binding, mechanical, and degradation properties. The addition of GelMA to PEG resulted in a composite hydrogel that exhibited tunable mechanical and biological profiles. Adding GelMA (5%-15% w/v) to PEG (5% and 10% w/v) proportionally increased fibroblast surface binding and spreading as compared to PEG hydrogels (p<0.05). Encapsulated fibroblasts were also able to form 3D cellular networks 7 days after photoencapsulation only within composite hydrogels as compared to PEG alone. Additionally, PEG-GelMA hydrogels displayed tunable enzymatic degradation and stiffness profiles. PEG-GelMA composite hydrogels show great promise as tunable, cell-responsive hydrogels for 3D cell culture and regenerative medicine applications. PMID- 21306295 TI - Formulation study of topically applied O/W lotion containing vitamin D3 derivative, focusing on skin permeability of the drug. AB - Permeation of 22-oxacalcitriol-1alpha, 25-dihydroxyvitamin D(3) (OCT) through excited hairless mouse skin was determined after application of OCT as solutions and O/W lotions consisted of different polarities of solvents: medium-chain fatty acid triglyceride (MCT), myristate isopropyl (IPM), 1,3-butylene glycol (1,3-BG), and propylene glycol (PG). OCT concentration in skin was also followed after applying these formulations. A two-layer diffusion model was composed to analyze dermatopharmacokinetic profiles of OCT for each vehicle. In the OCT solutions, skin permeation profile of OCT differed depending on solvent polarity. The O/W lotion with a high MCT content led to a low amount of OCT in skin. On the other hand, the O/W lotion with a high 1,3-BG content led to a high amount of OCT in skin. This dermatopharmacokinetic analysis indicated that addition of MCT to the formulation decreases the skin/vehicle partition coefficient of OCT and increases the diffusion coefficient of OCT in skin. However, the opposite effects on these two parameters were found in the case of 1,3-BG. Thus, skin permeability of OCT differed depending on the solvents used in the formulation. These results indicate that skin permeability of OCT is influenced by the physicochemical properties (i.e. polarity) of OCT, solvent, and skin. Our findings on the solvent effects of the skin permeability of OCT are thus useful for designing topical drug formulation, especially in aiming for bioequivalent dosage formulas. PMID- 21306297 TI - Alcohol and drug misuse in the elderly. PMID- 21306296 TI - Effect of "motivational interviewing" on quality of care measures in screen detected type 2 diabetes patients: a one-year follow-up of an RCT, ADDITION Denmark. AB - OBJECTIVE. "Motivational interviewing" (MI) has shown to be broadly applicable in the management of behavioural problems and diseases. Only a few studies have evaluated the effect of MI on type 2 diabetes treatment and none has explored the effect of MI on target-driven intensive treatment. METHODS. Patients were cluster randomized by GPs, who were randomized to training in MI or not. Both groups received training in target-driven intensive treatment of type 2 diabetes. The intervention consisted of a 11/2-day residential course in MI with half-day follow-up twice during the first year. Blood samples, case record forms, national registry files, and validated questionnaires from patients were obtained. RESULTS. After one year significantly improved metabolic status measured by HbA1c (p < 0.01) was achieved in both groups. There was no difference between groups. Medication adherence was close to 100% within both treatment groups. GPs in the intervention group did not use more than an average of 1.7 out of three possible MI consultations. CONCLUSION. The study found no effect of MI on metabolic status or on adherence of medication in people with screen detected type 2 diabetes. However, there was a significantly improved metabolic status and excellent medication adherence after one year within both study groups. An explanation may be that GPs in the control group may have taken up core elements of MI, and that GPs trained in MI used less than two out of three planned MI consultations. The five-year follow-up of this study will reveal whether MI has an effect over a longer period. PMID- 21306298 TI - Different proposed applications of bacteriorhodopsin. AB - Bacteriorhodopsin (BR) is an integral membrane protein found in "purple membrane" (the Archaea cell membrane) mainly in Halobacteria. This protein absorbs green light (wavelength 500-650 nm, with the absorption maximum at 568 nm) and converts it into an electrochemical gradient. This gradient in turn is used for ATP production. The ability of BR to convert light energy into chemical energy or sunlight into electricity has been used in different applications mainly optical appliances but also for therapeutic/medical applications and research. This review surveys some of these applications that have been patented in the last five years. PMID- 21306299 TI - Trans-interaction of nephrin and Neph1/Neph3 induces cell adhesion that associates with decreased tyrosine phosphorylation of nephrin. AB - Slit diaphragms are specialized junctions between glomerular epithelial cells (podocytes) that are crucial for glomerular ultrafiltration. The Ig superfamily members nephrin and Neph1 are essential components of the slit diaphragm, whereas the role of Neph1 homologue Neph3 in the slit diaphragm is unknown. In the present paper we show that Neph3 homodimerizes and heterodimerizes with nephrin and Neph1. We further investigated whether these interactions play a role in cell adhesion by using mouse L fibroblasts that lack endogenous cell-adhesion activity and found that Neph1 and Neph3 are able to induce cell adhesion alone, whereas nephrin needs to trans-interact with Neph1 or Neph3 in order to promote formation of cell-cell contacts. Tyrosine phosphorylation of nephrin was down-regulated after nephrin trans-interacted with either Neph1 or Neph3 leading to formation of cell-cell contacts. We further found that the expression of Neph3 was increased in nephrin-deficient mouse podocytes. The findings of the present paper show that nephrin and Neph1 or Neph3 trans-interactions promote cell-contact formation, suggesting that they may also function together in slit diaphragm assembly. PMID- 21306300 TI - A2A adenosine receptor ligand binding and signalling is allosterically modulated by adenosine deaminase. AB - A2ARs (adenosine A2A receptors) are highly enriched in the striatum, which is the main motor control CNS (central nervous system) area. BRET (bioluminescence resonance energy transfer) assays showed that A2AR homomers may act as cell surface ADA (adenosine deaminase; EC 3.5.4.4)-binding proteins. ADA binding affected the quaternary structure of A2ARs present on the cell surface. ADA binding to adenosine A2ARs increased both agonist and antagonist affinity on ligand binding to striatal membranes where these proteins are co-expressed. ADA also increased receptor-mediated ERK1/2 (extracellular-signal-regulated kinase 1/2) phosphorylation. Collectively, the results of the present study show that ADA, apart from regulating the concentration of extracellular adenosine, may behave as an allosteric modulator that markedly enhances ligand affinity and receptor function. This powerful regulation may have implications for the physiology and pharmacology of neuronal A2ARs. PMID- 21306301 TI - Neuropilin-1 mediates PDGF stimulation of vascular smooth muscle cell migration and signalling via p130Cas. AB - NRP1 (neuropilin-1) is a co-receptor for members of the VEGF (vascular endothelial growth factor) family in endothelial cells, but is increasingly implicated in signalling induced by other growth factors. NRP1 is expressed in VSMCs (vascular smooth muscle cells), but its function and the mechanisms involved are poorly understood. The present study aimed to determine the role of NRP1 in the migratory response of HCASMCs (human coronary artery smooth muscle cells) to PDGF (platelet-derived growth factor), and to identify the signalling mechanisms involved. NRP1 is highly expressed in HAoSMCs (human aortic smooth muscle cells) and HCASMCs, and modified in VSMCs by CS (chondroitin sulfate)-rich O-linked glycosylation at Ser612. HCASMC migration induced by PDGF-BB and PDGF-AA was inhibited by NRP1 siRNA (small interfering RNA), and by adenoviral overexpression of an NRP1 mutant lacking the intracellular domain (Ad.NRP1DeltaC). NRP1 co-immunoprecipitated with PDGFRalpha (PDGF receptor alpha), and immunofluorescent staining indicated that NRP1 and PDGFRalpha co localized in VSMCs. NRP1 siRNA also inhibited PDGF-induced PDGFRalpha activation. NRP1-specific siRNA, Ad.NRP1DeltaC and removal of CS glycans using chondroitinase all inhibited PDGF-BB and -AA stimulation of tyrosine phosphorylation of the adapter protein, p130Cas (Cas is Crk-associated substrate), with little effect on other major signalling pathways, and p130Cas knockdown inhibited HCASMC migration. Chemotaxis and p130Cas phosphorylation induced by PDGF were inhibited by chondroitinase, and, additionally, adenoviral expression of a non glycosylatable NRP1S612A mutant inhibited chemotaxis, but not p130Cas phosphorylation. These results indicate a role for NRP1 and NRP1 glycosylation in mediating PDGF-induced VSMC migration, possibly by acting as a co-receptor for PDGFRalpha and via selective mobilization of a novel p130Cas tyrosine phosphorylation pathway. PMID- 21306302 TI - Autotransporter passenger domain secretion requires a hydrophobic cavity at the extracellular entrance of the beta-domain pore. AB - Whooping cough (pertussis) is a highly contagious acute respiratory illness of humans caused by the Gram-negative bacterial pathogen Bordetella pertussis. The AT (autotransporter) BrkA (Bordetella serum-resistance killing protein A) is an important B. pertussis virulence factor that confers serum resistance and mediates adherence. In the present study, we have solved the crystal structure of the BrkA beta-domain at 3 A (1 A=0.1 nm) resolution. Special features are a hairpin-like structure formed by the external loop L4, which is observed fortuitously sitting inside the pore of the crystallographic adjacent beta domain, and a previously undiscovered hydrophobic cavity formed by patches on loop L4 and beta-strands S5 and S6. This adopts a ubiquitous structure characteristic of all AT beta-domains. Mutagenesis studies have demonstrated that the hairpin-like structure and hydrophobic cavity are crucial for BrkA passenger domain (virulence effector) translocation. This structure helps in understanding the molecular mechanism of AT assembly and secretion and provides a potential target for anti-pertussis drug design. PMID- 21306303 TI - Regulation of VEGF, MMP-9 and metastasis by CXCR4 in a prostate cancer cell line. AB - To investigate the mechanisms involved in PCa (prostate cancer) metastasis and CXCR4 (CXC chemokine receptor-4)-mediated VEGF (vascular endothelial growth factor) and MMP-9 (matrix metalloproteinase-9) expression, we used lentivirus mediated RNAi (RNA interference) to reduce the expression of CXCR4 in a PCa cell line. We found that the silencing of CXCR4 led to a significant down-regulation of VEGF and MMP-9 at both the mRNA and protein levels compared with the control in vitro. Using an animal model, we confirmed that CXCR4 silencing via subcutaneous injection could reduce tumour growth as well as inhibit metastasis, particularly bone metastasis, of PCa. Using in vivo immunohistochemistry, we also found that the expression of VEGF and MMP-9 were reduced by the knockdown of CXCR4 in the primary tumours of mice. Collectively, our results indicate that CXCR4 plays an important role in PCa metastasis through the up-regulation of VEGF and MMP-9. These findings may aid future intervention strategies. PMID- 21306304 TI - Systemic inflammation is linked to low arginine and high ADMA plasma levels resulting in an unfavourable NOS substrate-to-inhibitor ratio: the Hoorn Study. AB - Inflammation is associated with a reduced availability of NO in the vasculature. We investigated the possible involvement of altered levels of the substrate (arginine) and the inhibitor [ADMA (asymmetric omega-NG,NG-dimethylarginine)] of NOS (NO synthase). Plasma concentrations of arginine and ADMA, the inflammatory markers CRP (C-reactive protein) and MPO (myeloperoxidase), and oxLDL [oxidized LDL (low-density lipoprotein)] were measured in 369 male and 377 female participants (aged 50-87 years) of a population-based cohort study. The arginine/ADMA ratio decreased significantly across increasing tertiles of CRP and MPO. These negative associations remained significant in a linear regression model with both MPO (P = 0.002) and CRP (P < 0.001) as independent variables and adjusted for age, sex and cardiovascular risk factors. In a fully adjusted regression model, MPO was positively associated with ADMA {5.4 [95% CI (confidence interval), 1.3-9.4] nmol/l change of ADMA per S.D. increase in MPO; P = 0.010}, whereas CRP was not (P = 0.36). Conversely, in a fully adjusted model, CRP was negatively associated with arginine [-2.8 (95% CI, -4.0 to -1.6) MUmol/l arginine per S.D. of CRP; P < 0.001], without a significant contribution of MPO (P = 0.23). The relationship between MPO and ADMA became stronger with increasing levels of oxLDL (1.8, 5.2 and 8.7 nmol/l ADMA per S.D. of MPO for increasing tertiles of oxLDL), consistent with the ability of MPO to amplify oxidative stress. In contrast, the relationship between CRP and arginine was not modified by levels of oxLDL. In conclusion, an unfavourable NOS substrate/inhibitor ratio may contribute to the reduced NO bioavailability associated with inflammation. PMID- 21306305 TI - Complete rupture of anal sphincter in primiparas: long-term effects and subsequent delivery. AB - OBJECTIVE: To study long-term effects with respect to anal incontinence, pain, attitude to and mode of second delivery following complete rupture of the anal sphincter. DESIGN: Case-control study. Settings. Sodersjukhuset, a university hospital in Stockholm. POPULATION: A case group of 136 primiparas who had experienced a complete rupture of the anal sphincter. Two matched control groups of primiparas, one of whom had cesarean section and the other a normal vaginal delivery. METHODS: The case women were examined and asked for symptoms of anal incontinence 3-6 months after delivery; 3-8 years later they and two matched control groups answered a postal questionnaire. Response rate was 89%. MAIN OUTCOME MEASURES: Symptoms of pelvic floor dysfunction and, as secondary end point, the attitude to and mode of second delivery. RESULTS: Anal incontinence after delivery was reported by 31% in the case group, and at long-term follow-up by 54% in the case group, 21% in the cesarean section and 23% in the normal delivery group (p < 0.0001). A wish to postpone or abandon further childbirth was significantly more common in the case women (33 and 18%) than in the other groups, but about 60% delivered again in all groups. In the case group, the next delivery was by cesarean section in 49%. CONCLUSION: At long-term follow-up after a complete rupture of the anal sphincter, anal incontinence was common and many women wished to postpone or avoid further delivery. PMID- 21306306 TI - Prenatal alcohol exposure - a systematic review of the effects on child motor function. AB - OBJECTIVE: To systematically review the available evidence on the effects of prenatal alcohol exposure on motor function in humans. DESIGN: Systematic review. POPULATION: Pregnant women and their offspring. METHODS: The search strategy included Medline, Embase, The Cochrane Library and Scopus. The authors read titles and abstracts, and the articles that met the predefined criteria for inclusion were obtained and the full text read. The articles were assessed for quality using the Newcastle-Ottawa Quality Assessment Scale. MAIN OUTCOME MEASURES: Motor function measured on standardized or validated tests. RESULTS: The search resulted in 311 titles and abstracts, of which 39 were found relevant for inclusion. The findings of this review suggest a negative effect when the maternal consumption exceeded a certain level. Of all studies reporting a maternal intake of more than four drinks/day, only one study showed no effect on motor function, and of all studies reporting intake levels of less than 10 drinks/week, only one study showed deficit on the children's motor function. CONCLUSIONS: While it appears consistent that high daily alcohol intake is associated with deficits in gross and fine motor function, and low weekly intake is not associated with such deficits, the issue of binge drinking is unsettled. PMID- 21306307 TI - Neonatal complications and risk factors among women with gestational diabetes mellitus. AB - OBJECTIVE: This study aimed to identify risk factors for gestational diabetes mellitus (GDM) and assess the effects of GDM on the risk of adverse pregnancy outcomes. MATERIAL AND METHODS: This was a cross-sectional study using data from the German Perinatal Quality Registry, which is a complete national registry containing information on all hospital births across Germany. The Registry for 2006 contains data on a complete birth cohort of 668,085 newborn infants and 647,392 mothers from all 896 German hospitals. All data were taken from maternity log records and analyzed by multivariate logistic regression. Each recorded case of GDM was identified by a gynecologist or in hospital. RESULTS: The prevalence of GDM was 2.3% (14,990 of 647,385). High-risk groups were migrants, women of lower socioeconomic status (adjusted odds ratio 1.16, 95% confidence interval 1.05-1.28) and obese women (adjusted odds ratio 4.96, 95% confidence interval 4.70-5.24). A higher risk of fetal malformations was found for those diagnosed with GDM (adjusted odds ratio 1.32, 95% confidence interval 1.15-1.53). CONCLUSION: The higher risk of fetal malformations with GDM suggests that many of these women may have high glucose levels even during the first trimester. Policies and interventions regarding prenatal care should therefore focus not only on how better diagnostic and treatment procedures can be implemented, but also on how they can reach older and migrant women as well as women of lower socioeconomic status. PMID- 21306308 TI - Secondary abdominal pregnancy with live birth. PMID- 21306309 TI - Relations between fetal brain-sparing circulation, oxytocin challenge test, mode of delivery and fetal outcome in growth-restricted term fetuses. AB - OBJECTIVE: The study was designed as a prospective non-interventional, observational study to elucidate the potential value of fetal middle cerebral artery Doppler velocimetry to identify brain-sparing flow in a surveillance program for suspected intrauterine growth restriction (IUGR). MATERIAL AND METHODS: The study was carried out at Skane University Hospital, Malmo, Sweden. One hundred and twenty-six single pregnancies suspected of IUGR at >=36 gestational weeks were assessed. The main outcome measures were positive/negative oxytocin challenge test (OCT) and cesarean/vaginal delivery. The pregnancies were managed with ultrasound fetometry, uterine and umbilical artery Doppler flow velocimetry, nonstress test, and an OCT to decide the optimal time and mode of delivery. Cases with a positive OCT were promptly delivered by cesarean section, whereas negative cases were allowed a trial of labor. Middle cerebral artery Doppler flow velocimetry results were blinded to the managing obstetricians. Brain-sparing flow was defined as a middle cerebral artery-to-umbilical artery pulsatility index ratio of <1.08. Nonparametric statistics with significance set at p < 0.05 were used, and Cohen's kappa coefficient was calculated for congruence of brain-sparing flow with OCT and mode of delivery, respectively. RESULTS: The positive predictive value and sensitivity figures of brain-sparing flow to indicate a positive OCT and cesarean delivery were 33-63%. The inter rater reliability of brain-sparing flow vs. positive OCT showed a kappa coefficient of 0.19, and brain-sparing flow vs. cesarean section among OCT negative cases a kappa coefficient of 0.23. CONCLUSION: Fetal brain-sparing flow is a poor predictor of a positive OCT, and of cesarean section in OCT-negative cases. PMID- 21306310 TI - Centralized treatment of advanced stages of ovarian cancer improves survival: a nationwide Danish survey. AB - OBJECTIVE: This retrospective, nationwide, observational study was designed to compare treatment in tertiary referral centers vs. regional hospitals on overall survival for patients with stage IIIC and IV ovarian cancer. MATERIAL AND METHODS: The study took place in all gynecological departments in Denmark, involving a total of 1,160 patients with stage IIIC or IV ovarian cancer. Data were extracted for 2,024 patients with all stages of ovarian cancer recorded in the Danish Gynecological Cancer Database between 1 January 2005 and 31 December 2008. The main outcome measure was overall survival. RESULTS: No difference was found between tertiary centers and regional hospitals with regard to age, body mass index, American Society of Anesthesiologists score or comorbidity. Patients in regional hospitals had poorer Eastern Cooperative Oncology Group performance status, i.e.1.0 vs. 2.0 (p= 0.005). Patients in referral centers presented more often with stage IIIC and IV disease, i.e. 59.7 vs. 51.7% (p < 0.001). Patients with stage IIIC and IV disease in regional vs. tertiary hospitals had a higher rate of primary cytoreductive surgery, i.e. 89.5 vs. 82.5% (p= 0.004), a poorer rate of complete cytoreductive surgery following primary cytoreductive surgery, i.e. 13.9 vs. 25.2% (p < 0.001), a lower rate of neoadjuvant chemotherapy, i.e. 5.5 vs. 13.4% (p < 0.001), and more often underwent acute surgery, i.e. 17.0 vs. 9.2% (p < 0.001). Patients treated in referral centers had better overall survival (p= 0.021). Treatment in a referral center was an independent prognostic factor for overall survival hazard ratio, 0.83 (confidence interval 0.70-0.98). CONCLUSION: Patients with stage IIIC and IV ovarian cancer benefit from treatment in a tertiary referral center. PMID- 21306311 TI - Fetomaternal hemorrhage in women undergoing elective cesarean section. AB - OBJECTIVE: To investigate the degree of fetomaternal hemorrhage (FMH) caused by elective cesarean section. DESIGN: Descriptive study. SETTINGS: University Hospitals in Copenhagen, Denmark. POPULATION: Women scheduled for elective cesarean section, in the period September 2007 to January 2009, at the Department of Gynecology and Obstetrics, Hvidovre Hospital, University of Copenhagen, Denmark. METHODS: Two maternal blood samples were taken, the first before cesarean section and the second immediately after. Both samples were analyzed at the Blood Bank, Rigshospitalet, Copenhagen, for the presence of fetal red blood cells (fRBCs) using flow cytometry. FMH associated with cesarean section was defined as the difference between the volumes of fRBCs in the two samples. MAIN OUTCOME MEASURES: The frequency and volume of FMH caused by elective cesarean section. RESULTS: 207 women were included in the study. FMH was detected in 38 cases (18.4%). Of these, 22 women (10.6%) had FMH of less than 1 ml fRBCs, 13 women (6.3%) had FMH between 1 and 4 ml fRBCs, and three women (1.4%) had FMH above 4 ml fRBCs. CONCLUSIONS: We found no evidence for recommending general screening for FMH in connection with elective cesarean section, provided guidelines such as the current Danish guidelines for Rhesus prophylaxis are followed. PMID- 21306312 TI - Morbidity with total laparoscopic and laparoscopically assisted vaginal hysterectomy. AB - We evaluated the operative and postoperative morbidity among 103 women who underwent total laparoscopic hysterectomy and 107 others who underwent laparoscopically assisted vaginal hysterectomy. Blood loss was significantly greater in the assisted vaginal hysterectomy group (178.0 +/- 12.1 ml) than in the total hysterectomy group (130.2 +/- 10.7 ml) (p < 0.001). Despite higher uterine weight in the total hysterectomy group, the operative time of both techniques was similar. The complications of both hysterectomies were also comparable. The results from our study suggest that the complication rates of laparoscopically assisted vaginal hysterectomy and total hysterectomy are similar. However, laparoscopically assisted vaginal hysterectomy is associated with increased blood loss. PMID- 21306313 TI - Modified anchored B-Lynch uterine compression suture for post partum bleeding with uterine atony. AB - A prospective observational study was performed to evaluate the performance of a modified uterine compression suturing technique for the management of refractory post partum hemorrhage (PPH) at two leading tertiary referral centers in Colombo, Sri Lanka. An modified anchored B-Lynch suture was done in 17 women with PPH due to uterine atony. In 13 of the women (76%), bleeding was arrested and the uterus conserved. Four women (24%) did not respond to the anchored compression sutures, necessitating emergency post partum hysterectomy. Mean age was 31.2 years. Nine of the women (53%) were primiparous and eight (47%) parous. Mean estimated blood loss was 1994 ml (range 1200-3300 ml). This newly modified anchor B-Lynch compression suture appeared effective in controlling about 75% of PPH due to uterine atony, which allowed uterine conservation. This simple modification can provide a first line surgical step to control PPH. PMID- 21306314 TI - Compliance with leisure-time physical activity recommendations in pregnant women. AB - OBJECTIVE: The aim of this study was to identify the prevalence and factors associated with the performance of minimal beneficial leisure-time physical activity in the first half of pregnancy according to the criteria of the American College of Sport and Medicine (ACSM) and the American College of Obstetricians and Gynecologists (ACOG). MATERIAL AND METHODS: This was a cross-sectional study carried out at the Maternal and Neonatal University Hospital in Granada, which services the whole population of the hospital reference area. We studied 1,175 healthy pregnant women aged over 18 years. Information about sociodemographics, lifestyles, obstetric antecedents and anthropometric variables were collected. The amount of leisure-time physical activity was quantified by assigning metabolic equivalents to each activity. The ACSM and ACOG criteria were used to define optimal physical activity in the first half of pregnancy. The frequency of compliance for both criteria was estimated. Multiple logistic regression models were fitted to study the factors associated with the recommendations. RESULTS: Only 20.3% (95% confidence interval 15.50-26.10) of the women complied with ACOG criteria. More women complied with ACSM recommendations (70.8%, 95% confidence interval 67.5-73.8), which are less restrictive criteria. Women aged 30 years old or older and those with a university degree tended to devote more time to exercising according to both recommendations. CONCLUSION: The prevalence of pregnant women who performed minimal beneficial leisure-time physical activity was lower with the dominant and more accepted criteria. It is necessary to encourage physical activity, mainly among those who are younger, and those with lower levels of educational attainment. PMID- 21306315 TI - Ectopic pregnancy: using the hCG ratio to select women for expectant or medical management. AB - OBJECTIVE: To identify variables that can be used to select women with an ectopic pregnancy for expectant or medical management with systemic methotrexate. DESIGN: Cohort study. SETTING: Early Pregnancy Unit of a London teaching hospital. POPULATION: Women with a tubal ectopic pregnancy managed non-surgically. METHODS: The diagnosis of tubal ectopic pregnancy was made using transvaginal sonography. Human chorionic gonadotrophin (hCG) levels had to be taken at 0 hour and 48 hours pre-treatment. Other recorded variables include presenting complaints, gestational age, progesterone levels, size of the ectopic mass and appearance of the ectopic on transvaginal sonography. Women were followed up until the outcome (success or failure) of management was known. MAIN OUTCOME MEASURES: Univariable analysis was performed to identify the variables associated with successful management using area under curves and relative risks. RESULTS: Thirty-nine women underwent expectant management (overall success rate 71.8%) and 42 had medical management (overall success rate 76.2%). The pre-treatment hCG ratio (hCG 48 hours/hCG 0 hour) was related to the failure of both expectant (area under curve 0.86, 95% CI 0.67-0.94) and medical (area under curve 0.79, 95% CI 0.58-0.90) management. History of ectopic pregnancy was related to failure of expectant management only (relative risk 0.46, 95% CI 0.16-0.92). CONCLUSIONS: The most important variable for predicting the likelihood of successful non-surgical management was the pre-treatment hCG ratio. New studies are required to validate the use of this variable and of history of ectopic pregnancy to predict the likelihood of successful non-surgical management in clinical practice. PMID- 21306316 TI - Pregnancy planning in Sweden--a pilot study among 270 women attending antenatal clinics. AB - OBJECTIVE: Health status and lifestyle before and at the time of conception could affect the health of both mother and child, but there is a lack of knowledge about the degree to which pregnancies are planned. The aim of this pilot study was to investigate whether and how women plan their pregnancies. MATERIAL AND METHODS: The main outcome measures were use of timetables, ovulation tests and lifestyle changes. Women (n= 322) visiting four antenatal clinics were asked to fill out a questionnaire (participation rate = 83.9%, n= 270). RESULTS: Three of four pregnancies (n= 202) were very or rather well planned, whereas 4.4% (n= 12) were totally unplanned. During the planning period, 37.1% (n= 100) made up a timetable for getting pregnant, 23% (n= 62) used ovulation tests, 20.7% (n= 56) took folic acid and 10.4% (n= 28) changed alcohol consumption. CONCLUSION: Although a majority of these women had planned pregnancies, only one in five had taken folic acid during the planning period. PMID- 21306317 TI - Emergency cesarean sections can be predicted by markers for stress, worry and sleep disturbances in first-time mothers. AB - OBJECTIVE: To identify predictors as free-text markers for mental ill-health from an electronic perinatal record (EMR) system and the association with emergency cesarean section (CS) in nulliparous women. MATERIAL AND METHODS: This was a population-based study using an EMR system, set in the catchment area of Malmo University Hospital in Sweden. Of 10,662 nulliparous women presenting with a singleton cephalic baby for vaginal delivery between 2001 and 2006, 6,467 women with complete EMRs were selected. A free-text search of markers for mental ill health was carried out, and results were analysed by multivariate logistic regression. Eleven markers for mental ill-health were tested with Cohen's kappa for agreement and used as exposure variables. Odds ratios (OR) with 95% confidence intervals (CI) were calculated for emergency CS, and adjusted for maternal age, diabetes, epidural anesthesia and gestational weeks <37 and >41 by a multivariate logistic regression model with vaginal delivery as the reference. RESULTS: Three markers identified from the EMR system reached statistically significant associations with an increased risk for emergency CS in nulliparous women: stress, adjusted OR 1.66 (95% CI 1.34-2.06); sleep, adjusted OR 1.57 (95% CI 1.14-2.16); and worry, adjusted OR 1.41 (95% CI 1.10-1.79). CONCLUSION: Free text words in medical records that indicated stress, sleep disturbances or worry predicted increased adjusted OR for emergency CS in first-time mothers. Recognizing pregnant women's reporting of their mental health status could have a predictive bearing on delivery outcomes. PMID- 21306318 TI - PCOS--what matters in early pregnancy?--data from a cross-sectional, multicenter study. AB - OBJECTIVE: To describe patient characteristics according to different diagnostic criteria in early pregnancy, in women with polycystic ovary syndrome (PCOS). DESIGN: Descriptive, cross-sectional study of 257 women with PCOS in the first trimester of pregnancy. SETTING: Data from a multicenter trial at the time of inclusion. POPULATION: 257 PCOS women with singleton pregnancies. METHODS: Investigator-administrated questionnaires were filled out. Clinical examination was performed by the investigators. Fasting blood samples were collected. MAIN OUTCOME MEASURES: Biometric data, androgens, glucose and insulin levels. RESULTS: Women who met the National Institutes of Health (NIH) criteria for PCOS had higher body mass index (BMI), testosterone, dehydroepiandrostenedione, free testosterone index (FTI) and insulin levels compared with those who only met the Rotterdam consensus criteria. Adjusted for age and BMI, only testosterone and FTI were higher in those who met the NIH criteria. BMI was a strong, independent predictor of both systolic and diastolic blood pressure in early PCOS pregnancy, while both FTI and fasting insulin were independent predictors of systolic blood pressure. Twenty-two (9%) of the participants had gestational diabetes mellitus in the first trimester of pregnancy. CONCLUSIONS: In the first trimester, PCOS women diagnosed according to NIH criteria were more metabolically and endocrinologically abnormal compared with those who only met the Rotterdam consensus criteria. BMI and FTI were independent predictive factors for blood pressure. There was a high prevalence of gestational diabetes mellitus in early PCOS pregnancies. PMID- 21306319 TI - Women's sexual behavior. Population-based study among 65,000 women from four Nordic countries before introduction of human papillomavirus vaccination. AB - OBJECTIVE: Sexual behavior is of public health interest because of the association with reproductive health and sexually transmitted infections such as human papillomavirus, which is the causal factor of cervical cancer. The aim of the study was to describe patterns in women's sexual behavior in four Nordic countries. DESIGN: Population-based cross-sectional study. SETTING: Denmark, Iceland, Norway, and Sweden (November 2004-June 2005). POPULATION: A random sample of 18-45-year-old women from the female population in the four participating Nordic countries. The participation rate ranged from 81.3% in Denmark to 54.5% in Iceland. In total, 65 623 women were included. METHODS: Each participant completed a structured questionnaire containing questions about sociodemographic factors, lifestyle factors and sexual behavior. MAIN OUTCOME MEASURES: Age-specific and country-specific descriptive measures of sexual behavior, notably age at first intercourse and lifetime number of partners. In addition, risk factors for having had multiple (>10) sexual partners were examined. RESULTS: Overall, median age at first intercourse was 16, and 30.2% (95% CI: 29.9-30.6) of the participating women reported having had >=10 partners. There was great variation with birth cohort but limited variation between countries. The main correlates of multiple sexual partners were increasing age at enrollment, a higher alcohol intake and young age at first intercourse. CONCLUSIONS: These measurements of sexual behavior before the introduction of national human papillomavirus vaccination programs will form the basis for a comparison with a similar survey performed after vaccination has been introduced. PMID- 21306320 TI - Serum magnesium concentrations and metabolic variables in polycystic ovary syndrome. AB - OBJECTIVE: Hypomagnesemia is associated with diabetes mellitus type 2 and other components of the metabolic syndrome in older patients. Whether serum magnesium concentrations correlate with insulin resistance, obesity, hypertension, dyslipidemia, or other components of metabolic syndrome in younger women with polycystic ovary syndrome (PCOS) is currently unknown. DESIGN: Cross-sectional analysis. SETTING: Academic medical center. POPULATION: 100 consecutive women with PCOS by the Rotterdam criteria and 20 age- and BMI-matched normal women. METHODS: Statistical analysis of the relationship between magnesium levels and a variety of physical, endocrine, and metabolic variables. The STROBE guidelines for a cross-sectional analysis were followed. MAIN OUTCOME MEASUREMENTS: Serum magnesium levels, insulin sensitivity indices, and glucose assessments. BMI, waist circumference, blood pressure, and lipids served as secondary endpoint measurements. RESULTS: No patient demonstrated hypomagnesemia. Magnesium levels did not differ between women with and those without insulin resistance, glucose intolerance, or hypertension. Magnesium levels were similar across PCOS phenotypes and WHO-defined BMI categories. Multiple regression analysis did not suggest that serum magnesium concentrations correlated with any physical, metabolic, or endocrine variable. CONCLUSIONS: Magnesium levels do not correspond with age, BMI, waist circumference, insulin sensitivity, glycemic levels, blood pressure, or lipid levels in reproductive-age women with PCOS. Magnesium concentrations are similar across PCOS phenotypes and indistinguishable from women without PCOS. PMID- 21306321 TI - Prevalence and risk factors for anal incontinence after obstetric anal sphincter rupture. AB - OBJECTIVE: To study prevalence and risk factors for anal incontinence (AI) after obstetric anal sphincter rupture. MATERIAL AND METHODS: This was a retrospective clinical observational study. Among 14 959 vaginal deliveries, 591 women were diagnosed with obstetric anal sphincter ruptures (3.9%) at one Norwegian University Hospital in 2003-2005. Patients were examined and interviewed approximately 10 months after delivery. Anal continence was classified with St. Mark's incontinence score (0, complete anal continence; >=3, anal incontinence), and defects in anal sphincter muscles were diagnosed by endoanal ultrasound. Prevalence of anal incontinence was assessed in relation to obstetrical and maternal characteristics as well as the correlation between anal incontinence and ultrasound-detectable defects of sphincter muscle. RESULTS: Anal incontinence with a St. Mark's score of >=3 was reported by 21% of women with obstetric anal sphincter rupture, with inability to control gas as the most prevalent symptom. Women with AI were more likely to report urinary incontinence compared with women having no AI. In a multiple regression analysis of maternal and obstetrical risk factors, fourth degree sphincter tear was the only significant risk factor for AI. Anal incontinence was more frequent in patients diagnosed with than without ultrasound-identified anal sphincter muscle defects at 10 months postpartum follow-up. CONCLUSION: Anal as well as urinary incontinence after delivery with obstetric anal sphincter rupture is common, and prenatal obstetric and maternal variables could not predict anal incontinence. Fourth degree perineal tear and a persistent ultrasound-detected defect in the anal sphincter muscles are associated with AI. PMID- 21306322 TI - Health-related quality of life and postoperative recovery in fast-track hysterectomy. AB - OBJECTIVE: To determine whether health-related quality of life (HRQoL) and postoperative recovery of women who undergo abdominal hysterectomy in a fast track program under general anesthesia (GA) differ from women who receive spinal anesthesia with intrathecal morphine (SA). DESIGN: Secondary analysis from an open randomized controlled multicenter study. SETTING: Five hospitals in south east Sweden. POPULATION: One hundred and eighty women admitted for abdominal hysterectomy for benign disease were randomized; 162 completed the study, 80 with GA and 82 with SA. METHODS: The HRQoL was measured preoperatively using the EuroQoL EQ-5D and the Short-Form-36 health survey (SF-36) questionnaires. The EQ 5D was used daily for 1 week; thereafter, once weekly for 4 weeks and again 6 months after operation. The SF-36 was completed at 5 weeks and 6 months. Dates of commencing and ending sick leave were registered. MAIN OUTCOME MEASURES: Changes in HRQoL; duration of sick leave. RESULTS: The HRQoL improved significantly faster in women after SA than after GA. Sick leave was significantly shorter after SA than after GA (median 22.5 vs. 28 days). Recovery of HRQoL and duration of sick leave were negatively influenced by postoperative complications. In particular, the mental component of HRQoL was negatively affected by minor complications, even 6 months after the operation. CONCLUSIONS: Spinal anesthesia with intrathecal morphine provided substantial advantages in fast-track abdominal hysterectomy for benign gynecological disorders by providing faster recovery and shorter sick leave compared with general anesthesia. PMID- 21306323 TI - Trends in incidence of borderline ovarian tumors in Denmark 1978-2006. AB - OBJECTIVE: To examine period-, age- and histology-specific trends in the incidence rate of borderline ovarian tumors in Denmark in 1978-2006. DESIGN: Register-based cohort study. SETTING: Denmark 1978-2006. POPULATION: 5079 women diagnosed with a borderline ovarian tumor in at least one of two nationwide registries (4312 epithelial tumors and 767 non-epithelial/unspecified tumors). METHODS: Estimation of overall incidence rates and period-, age- and histology specific incidence rates. Age-adjustment was done using the World Standard POPULATION. To evaluate incidence trends over time, we estimated average annual percentage change and 95% confidence intervals (CI) using log-linear Poisson models. MAIN OUTCOME MEASURES: Age-standardized and age-specific incidence rates and average annual percentage change. RESULTS: The incidence of epithelial borderline ovarian tumors increased from 2.6 to 5.5 per 100,000 women-years between 1978 and 2006, with an average annual percentage change of 2.6% (95% CI: 2.2-3.0). The median age at diagnosis was 52 years. Women 40 years or older had a higher average annual percentage change than women younger than 40 years. Most tumors were mucinous (49.9%) and serous tumors (44.4%). Women with mucinous tumors were younger at diagnosis (50 years) compared with women with serous tumors (53 years). Women with serous tumors had a higher average annual percentage incidence change than women with mucinous tumors. CONCLUSIONS: The incidence rate of borderline ovarian tumors increased significantly in Denmark in 1978-2006. In line with results for ovarian cancer, Denmark had a higher incidence rate of borderline ovarian tumors compared with the other Nordic countries in 1978-2006. PMID- 21306324 TI - The impact of insulin resistance on the outcome of laparoscopic ovarian diathermy in women with polycystic ovarian syndrome. AB - OBJECTIVE: Insulin resistance (IR), which is common in women with polycystic ovarian syndrome (PCOS), may adversely affect the outcome of ovulation induction due to its detrimental effect on ovarian function. The aim of this study was to evaluate the impact of IR on the outcome of laparoscopic ovarian diathermy (LOD). DESIGN: Prospective observational study. SETTING: Tertiary fertility centre. POPULATION: Forty-four anovulatory women with PCOS undergoing LOD. METHODS: Fasting serum concentrations of insulin and glucose were measured before and after LOD. Insulin sensitivity was determined using the homeostasis model assessment (HOMA) index. Values of HOMA index >=2.1 were considered abnormal, indicating IR. MAIN OUTCOME MEASURES: Ovulation and pregnancy rates were compared between women with and without IR using chi(2) test and odds ratio (OR) with 95% confidence interval (CI). RESULTS: Eighteen women (41%) had elevated HOMA index (>=2.1). There was no change of HOMA index after LOD (median 1.89, range 0.53 8.48 vs. 1.92, range 0.53-8.46). The ovulation rate in women with IR (12 of 18, 67%) was significantly (p=0.013, OR 0.08; 95% CI 0.01-0.74) lower than that (25 of 26, 96%) of women without IR. Likewise, the pregnancy rate (six of 18, 33%) was significantly (p=0.037, OR 0.26; 95% CI 0.07-0.94) lower in women with IR than that of women without IR (17 of 26, 65%). Using a receiver operating characteristics curve, the HOMA index was useful in predicting no ovulation after LOD (area under the curve 0.826). CONCLUSIONS: Insulin resistance appears to have an adverse effect on the outcome of LOD and seems to be a useful prognostic factor. PMID- 21306325 TI - To treat or not to treat; the clinical dilemma of atypical squamous cells of undetermined significance (ASC-US). AB - OBJECTIVE: Management of patients diagnosed on cervical smears with twice consecutively atypical squamous cells of undetermined significance (ASC-US) remains a clinical dilemma. We describe a follow-up of aggressive vs. less aggressive colposcopic treatment in order to determine which treatment is preferable. DESIGN: Retrospective cohort study with a follow-up of 10 years. SETTING: Two hospitals in The Netherlands. POPULATION: Women referred for primary colposcopy with two consecutive ASC-US smears (n=230) to either one of the two hospitals. METHODS: In one hospital, patients underwent direct loop excision of all colposcopically detected abnormalities, even if not suspected for cervical intraepithelial neoplasia (CIN; aggressive strategy; n=118). In the other hospital, a less aggressive policy was followed when low-grade CIN lesions were suspected at colposcopy (less aggressive strategy; n=112). MAIN OUTCOME MEASURES: The number of loop excisions, detection of CIN lesions and cytological follow-up of both groups. RESULTS: Less aggressive management resulted in less loop excisions (p<0.001). At initial colposcopy, the aggressive group showed a 10-fold incidence of histologically detected CIN lesions compared with the less aggressive group (1.8 vs. 19.5%). During 10 years of follow-up, both groups showed the same percentages of CIN lesions (8.1 vs. 8.4%). Aggressive management resulted in faster normalization of cervical smears (p<0.001). However, at final follow-up, there was no statistical difference in the percentage of normalization of cervical smears between both groups. CONCLUSIONS: Aggressive and less aggressive colposcopic strategies are equally safe and show good clinical outcomes. Treatment decisions, however, must be adjusted to women's individual demands. PMID- 21306326 TI - Intrauterine insemination versus timed intercourse with clomiphene citrate in polycystic ovary syndrome: a randomized controlled trial. AB - OBJECTIVE: To compare the efficacy of intrauterine insemination vs. timed intercourse with clomiphene citrate as a first-line treatment for anovulatory infertility associated with polycystic ovary syndrome. DESIGN: A randomized controlled trial following the CONSORT criteria. SETTING: A university hospital and a private practice setting. PATIENTS: 188 women (525 cycles) with polycystic ovary syndrome. MAIN OUTCOME MEASURES: Women received three consecutive cycles of ovulation induction with clomiphene citrate and intrauterine insemination (n=93, 259 cycles) or three consecutive cycles of clomiphene citrate with timed intercourse (n=95, 266 cycles). OUTCOME MEASURES: Clinical pregnancy rate per cycle, number of growing and mature follicles, serum estradiol, endometrial thickness at the hCG day, serum progesterone, ovulation, miscarriage and live birth rates. RESULTS: There were no differences between the two groups regarding the clinical pregnancy rate per cycle or per woman (8.49 vs. 7.89% and 23.6 vs. 22.1%; p=0.26 and p=0.33, respectively). Two twin pregnancies occurred in each group. Miscarriage and live birth rates were comparable (18.1 vs. 19% and 19.35 vs. 17.89%; p=0.31 and p=0.33, respectively). No ectopic, higher-order pregnancies or cases of ovarian hyperstimulation syndrome occurred. No differences were found regarding the number of follicles, serum progesterone, ovulation rates, estradiol levels or endometrial thickness at the hCG day (7.7+/ 0.4 vs. 7.5+/-0.6mm; p=0.54). CONCLUSIONS: Ovulation induction with clomiphene citrate and timed intercourse is as effective as that with intrauterine insemination for achieving pregnancy in polycystic ovary syndrome and could represent the initial treatment option, being less invasive and less expensive than intrauterine insemination. PMID- 21306327 TI - Trends in live births in the past 20 years in Zhengzhou, China. AB - OBJECTIVE: To evaluate changing trends in neonatal births and deaths in a provincial women's and children's hospital over the past 20 years. DESIGN: Retrospective longitudinal study. SETTING: Henan Provincial Women's and Children's Hospital, China. POPULATION: Live births in Henan Provincial Women's and Children's Hospital from January 1987 to December 2006. METHODS: Data was stratified by sex, birth weight, delivery type, maternal age, gestational age, and single or multiple births. The incidence of low Apgar scores and neonatal death was calculated for each fiscal year. MAIN OUTCOME MEASURES: Trends in the fundamental status of hospital-born live births and risk factors for neonatal death. RESULTS: 26 760 hospital live births were included. The ratio of males to females was 1.16:1. The mean gestational age decreased from 39.5+/-1.4 weeks to 38.4+/-2.5 weeks (p <0.001) and multiple births increased from 1.5 to 7.3% (p<0.001). The proportion of preterm births increased from 4.7 to 18.9% (p<0.001), maternal age increased from 25.9+/-3.7 years to 29.0+/-4.4 years (p<0.001), and cesarean deliveries increased from 23.7 to 65.5% (p<0.001). The incidence of low Apgar scores decreased from 12.9 to 1.1% (p<0.001). The incidence of neonatal death was 8.5/1 000 live births, with preterm births and low Apgar scores accounting for 72.8 and 16.2% of all neonatal deaths, respectively. CONCLUSION: Preterm births, multiple births, and cesarean deliveries increased dramatically. Preterm birth is the leading cause of neonatal death. PMID- 21306328 TI - Association between 5 min Apgar scores and planned mode of delivery in diabetic pregnancies. AB - OBJECTIVE: Due to the high incidence of neonatal complications in diabetic pregnancies, the aim of our study was to investigate whether elective cesarean section could prevent adverse neonatal outcome. DESIGN: Population-based study. SETTING: Data were extracted from the Swedish Medical Birth Registry. POPULATION: All women (n=13 491) with diabetic pregnancies during the period 1990-2007. METHODS: Neonatal outcome in diabetic pregnancies was compared after elective cesarean section at 38 completed gestational weeks with planned vaginal delivery at 39 completed weeks of gestation or later. Odds ratios with 95% confidence intervals for Apgar scores <7 at 5 min after birth were calculated using multiple logistic regression. MAIN OUTCOME MEASURES: Apgar score <7 at 5 min after birth. RESULTS: A significantly decreased risk of Apgar score <7 at 5 min after birth in the group who underwent an elective cesarean section at 38 completed gestational weeks was found compared with those who continued pregnancy to 39 completed weeks of gestation or more, irrespective of final mode of delivery. CONCLUSIONS: Our results indicate a protective effect of planned cesarean section on the risk of low Apgar scores in diabetic pregnancies. PMID- 21306329 TI - Change in the frequency of HRT use from 2000 to 2005 and reasons to discontinue: follow-up of a normal cohort in Finland. AB - OBJECTIVE: To examine frequencies of the use of hormone replacement therapy (HRT) in a follow-up cohort of women aged 57-61 years in 2005 and to discover reasons why the women who used HRT in 2000 discontinued it. DESIGN: Questionnaire survey. SETTING: Five-year cross-sectional follow-up study. SAMPLE: Cohort of 52- to 56 year-old Finnish women. METHODS: Single- and multi-predictor model analyses. MAIN OUTCOME MEASURES: Frequency of HRT users and quitters and reasons behind the discontinuation. RESULTS: Altogether, 35.9% of the women aged 57-61 years used HRT in 2005. Main reasons for the initial use of HRT among users and among those who discontinued included the perceived experience of severe climacteric symptoms as well as maintenance of health and prevention of mostly cardiovascular diseases. Main reasons to discontinue HRT included desire to stay without medication, side-effects, reaction to recent controversial findings in 'HRT publications' and fear of cancer. Those women who used but discontinued HRT had used it for less time than those who continued. Women who discontinued were older and initially started using HRT to maintain health. Neither the severity of climacteric symptoms nor reporting on positive or negative effects prior to starting use had influence on the women's discontinuance of HRT. CONCLUSIONS: The use of HRT was still frequent in Finland in 2005 despite the impact of controversial research results from the early 2000s. For those who discontinued HRT, these reports played an important role. PMID- 21306330 TI - Risk of torsion and malignancy by adnexal mass size in pregnant women. AB - OBJECTIVE: To investigate risks of torsion and malignancy by adnexal mass size during pregnancy. DESIGN: Retrospective review of medical records. SETTING: General university hospital and healthcare center. POPULATION: Four hundred and seventy women who underwent surgery for adnexal masses during pregnancy between 2002 and 2009. MAIN OUTCOME MEASURES: Rate of torsion and malignancy according to mass size classified into four groups: <6, 6-10, 10-15 and >=15 cm. RESULTS: Torsion was encountered in 55 patients (11.7%) and malignancy was confirmed in 20 (4.3%). A mass size of 6-10 cm had a significantly higher risk of torsion than a mass <6 cm (odds ratio 2.68, 95% confidence interval 1.33-5.40, p=0.006). Masses >=15 cm had an approximately 12-fold higher risk of malignancy compared with masses <6 cm (odds ratio 12.36, 95% confidence interval 2.90-52.67, p=0.001). However, for masses of 10-15 cm, the risks of both torsion and malignancy were not higher than those of masses <6 cm. CONCLUSIONS: Risks of torsion and malignancy are not directly proportional to increasing mass size in pregnant women. Physicians should be aware of a high risk of malignancy in women with an adnexal mass of over 15 cm. However, if a mass is smaller, the size should not be considered as a single independent factor in a decision for surgery. PMID- 21306331 TI - Second trimester fetal magnetic resonance imaging improves diagnosis of non central nervous system anomalies. AB - OBJECTIVE: To evaluate the additional information of second trimester magnetic resonance imaging (MRI) compared with ultrasound in fetuses with identified or suspected non-CNS anomalies and to study the clinical impact of the MRI information on pregnancy management. DESIGN: Prospective study during 2003-2007. The fetal MRI examination was planned to be performed within 3 days after the ultrasound. SETTING: Uppsala University hospital. SAMPLE: Sixty-three women in whom the second trimester ultrasound identified or raised suspicion of fetal anomalies were included. METHODS: Ultrasound was compared to MRI in relation to the final diagnosis, which was based on the assessment of all available data, including postpartum clinical follow-up and autopsy results. MAIN OUTCOME MEASURES: Evaluation of the additional information gained from MRI and the consequences it had on pregnancy management. RESULTS: The mean interval between ultrasound and MRI was 2.6 days (range 0-15 days). In 42 (67%) women MRI was performed within 3 days. All MRI examinations were assessable. In 43 (68%) fetuses MRI provided no additional information, in 17 (27%) MRI added information without changing the management and in three (5%) MRI provided additional information which changed the management. All these three cases had oligohydramnios. In all six cases of diaphragmatic hernia MRI provided additional information. CONCLUSIONS: Fetal MRI of non-CNS anomalies in the second trimester seems to be a valuable adjunct to ultrasound diagnosis of non-CNS anomalies, especially in cases of oligohydramnios and diaphragmatic hernia. PMID- 21306332 TI - Acute pancreatitis in pregnancy. AB - OBJECTIVE: The highest maternal-fetal risk from pancreatitis in pregnancy is likely to be posed by the most severe cases, which we have compared with mild cases. DESIGN: Retrospective observational study. SETTING: A general surgery department of a university referral hospital in Nanjing, China. POPULATION: Eighteen pregnancies complicated with severe acute pancreatitis and 51 pregnancies complicated with mild acute pancreatitis. METHODS: Medical records were reviewed for every pregnant woman with mild or severe acute pancreatitis during January 1999 to December 2009. MAIN OUTCOME MEASURES: Information on demographics, clinical and laboratory data, maternal and fetal outcomes. RESULTS: Gestational age of onset was significantly higher in the severe acute pancreatitis group than in the mild acute pancreatitis group. Severe hypertriglyceridemia was considered the main cause of severe acute pancreatitis (OR 20.7; 95% CI 4.6-92.4, p<0.001), while biliary disease contributed to the etiology of mild acute pancreatitis (OR 7.3; 95% CI 1.8-30.1, p<0.01). Abortions and preterm infants contributed to fetal loss in the mild group, while fetal death and stillbirth contributed in the severe group. CONCLUSIONS: Hyperlipidemic pancreatitis and biliary pancreatitis are the main causes of severe and mild disease, respectively. Severe acute pancreatitis in pregnancy usually occurs in the third trimester, and the affected severe patients are more liable to develop a critical condition that results in higher risk of intrauterine fetal death. PMID- 21306333 TI - Placenta accreta: a cause of failed medical abortion. PMID- 21306334 TI - Spontaneous pregnancy and birth with corrected cloacal exstrophy. PMID- 21306335 TI - Clamping compared to cauterization for subcutaneous hemostasis in Pfannenstiel incision. AB - We compared subcutaneous clamping and cauterization for hemostasis at laparotomy with Pfannenstiel incision with reference to surgical site infection, postoperative fever and time taken for incision. A total of 214 patients with consecutive hysterectomies were alternately assigned to incisional hemostasis by clamping (n= 107) or cauterization (n= 107). The groups were similar in terms of age, gravidity, parity, body mass index, uterine size and mean hemoglobin drop. Rates of surgical site infection, postoperative fever and time from skin incision to peritoneal cavity entry were significantly higher in the group with cauterization (p < 0.05). PMID- 21306336 TI - Measuring and improving quality in obstetrics--the implementation of national indicators in Denmark. AB - From September 2010, all births in Denmark will be monitored from a quality perspective with the Danish National Indicator Project in order to document and develop the quality of the care provided during delivery. We describe the process of selecting the indicators based on relevance, scientific evidence, usefulness and applicability, acceptability and patient safety. Eight indicators were selected covering different aspects of delivery: anesthesia/pain relief; continuous support for women in the delivery room; lacerations, 3rd or 4th degree; acute cesarean section; post-partum hemorrhage; establishment of skin-to skin contact between mother and newborn infant; severe fetal hypoxia; delivery of a healthy child after uncomplicated delivery. Registration will be mandatory for all delivery units in Denmark. Subsequently, the clinical units will receive feedback in the form of real-time monthly and quarterly standard reports including unadjusted results that may be used for the unit's own internal monitoring and development of quality. PMID- 21306337 TI - Incidence and risk factors of fetal death in Norway: a case-control study. AB - OBJECTIVE: To estimate incidence and risk factors for intrauterine fetal death (IUFD) in a Norwegian study-population applying two different control groups. DESIGN: Case-control study. SETTING: Two university hospitals in Oslo, Norway, January 1990 through December 2003. SAMPLE: The cases: 377 women with IUFD. CONTROLS: 1) all women delivering at the study-hospitals in the period (facility based), and 2) 1 215 women with live births at one study-hospital in the period (selected). METHODS: Information from cases and selected controls was collected from medical records. Data on facility-based controls were provided by the Medical Birth Registry of Norway. Data were analyzed using chi-squared test and logistic regression. MAIN OUTCOME MEASURES: Incidence of IUFD and adjusted odds ratios of risk factors. RESULTS: The incidence was 4.1/1 000 deliveries. Small for-gestational age (SGA) and placental abruption were the strongest risk factors for IUFD. Hypertensive disorders were of low risk if not associated with SGA. Low to moderate risk factors were pre-pregnancy diabetes mellitus, thyroid disease, placenta previa, gestational diabetes, smoking and twin pregnancy. Advanced maternal age was significant when compared with facility-based controls. Risk estimates pointed in the same direction independent of control-group. Hypertension appeared overestimated when using facility-based controls, whereas advanced age was underestimated in the analysis among selected controls. CONCLUSION: SGA has a strong association with IUFD, and the risk of hypertensive disorders is mediated through SGA. The other risk factors, except placental abruption, are of low prevalence and of limited importance in the prevention of a relatively low incidence, although dramatic, event like IUFD. PMID- 21306338 TI - A reliable way to predict intraabdominal adhesions at repeat cesarean delivery: scar characteristics. AB - OBJECTIVE: To evaluate association between scar characteristics and intraabdominal adhesions at repeat cesarean delivery. DESIGN: A prospective, cross-sectional study. SETTING: Tertiary Government Maternity Training Hospital in Ankara, Turkey. POPULATION: 295 pregnant women with at least one prior cesarean delivery. METHODS: All women were at least 36 weeks pregnant. Appearance of previous cesarean delivery scars was categorized into three groups - flat, depressed and elevated. Pigmentation status was also noted (non-pigmented or pigmented). MAIN OUTCOME MEASURES: Intraoperatively detected adhesions, evaluated and classified into three groups (no adhesion, filmy adhesion and dense adhesion groups) by a modified Nair's classification. RESULTS: Elevated scars had significantly more dense adhesion formation than depressed ones (31.4 vs. 12.7%, p=0.02). No difference was found for dense adhesions when depressed and flat scars were compared (12.7 vs. 6.8%, p=0.124). Of flat scars, 93.2% were free of dense adhesions. Pigmented scars had more dense adhesions than non-pigmented (26.6 vs. 9.3%, p<0.01). Using logistic regression analysis scar length, scar width and appearance of scar (flat or non-flat) were directly related to adhesion formation. CONCLUSION: There is an association between scar type and adhesions, particularly for hypertrophic scars and dense adhesions. PMID- 21306339 TI - Racial disparities in preterm birth rates and short inter-pregnancy interval: an overview. AB - OBJECTIVE: We seek to expand on a biopsychosocial framework underlying the etiology of excess preterm birth experienced by African-American women by exploring short inter-pregnancy intervals as a partial explanatory factor. DESIGN: We conducted a qualitative analyses of published studies that met specified criteria for assessing the association of inter-pregnancy interval and preterm birth. METHODS: We determine whether inter-pregnancy interval is associated with preterm birth, what the underlying causal mechanism may be, whether African-American women are more likely than Caucasian women to have short intervals, and whether achieving an optimal interval will result in reduced African-American-Caucasian gap in preterm births. MAIN OUTCOME MEASURES: Crude and adjusted odds ratios for preterm birth, with the referent group being the interval closest to the 'ideal' of 18-23 months and the exposed group having intervals <12 months or some subset of that inter-pregnancy interval. Results. Inter-pregnancy interval less than six months increases preterm birth by about 40%. The mechanism may be through failure to replenish maternal nutritional stores. While there may not be an interaction between race and short inter pregnancy interval, short intervals can explain about 4% of the African-American Caucasian gap in preterm birth because African-American women are approximately 1.8 times as likely to have inter-pregnancy intervals of less than six months. Limited studies indicate that optimal intervals can be achieved through appropriate counseling and health care. CONCLUSIONS: Excess risk for preterm birth may be reduced by up to 8% among African-Americans and up to 4% among Caucasians through increasing inter-pregnancy intervals to the optimal length of 18-23 months. PMID- 21306340 TI - Subtle perturbations of genital microflora alter mucosal immunity among low-risk pregnant women. AB - OBJECTIVE: Alteration in the vaginal flora has been associated with adverse pregnancy outcomes. The objective of this study was to examine the impact of changes in individual microflora on genital immunity among low-risk pregnant women in early pregnancy. DESIGN: Cross-sectional study. SETTING: Large, tertiary care, academic hospital clinic. POPULATION: Low-risk women were enrolled prior to 14 weeks' gestation. METHODS: Women were included if they had no medical or previous obstetrical complications, were non-smokers, had no sexually transmitted infections and no intercourse in the last 48 hours. Consenting women underwent speculum examination for collection of vaginal culture and Dacron swabs for cytokine analysis. Semi-quantitative vaginal cultures were performed in a reference laboratory. MAIN OUTCOME MEASURES: Concentrations of immune mediators were compared in the presence of various organisms. Concentrations were converted to multiples of the median to standardize the values of each mediator. Regression analyses were performed to control for race. RESULTS: We enrolled 47 women. The frequencies of genital microorganisms were: H(2)O(2) -producing lactobacilli (70%), Ureaplasma urealyticum (66%), Gardnerella vaginalis (45%), anaerobic non pigmented Gram-negative rods (ANPGNR, 40%), anaerobic pigmented Gram-negative rods (APGNR, 17%). After adjusting for race and body mass index, interleukin 1beta, interferon-gamma, tumor necrosis factor-alpha and granulocyte macrophage colony stimulating factor were increased in the presence of G. vaginalis, ANPGNR, and APGNR. There was no consistent impact on the other markers of immune activation. CONCLUSION: The presence of individual species impacts genital immunity among low-risk pregnant women. Perturbations in genital immunity could partially explain heterogeneity in adverse pregnancy outcomes. PMID- 21306341 TI - Prevalence and correlates of intimate partner violence against HIV-seropositive pregnant women in a Nigerian population. AB - OBJECTIVE: To evaluate the prevalence and correlates of intimate partner violence among HIV-positive pregnant Nigerian women. DESIGN: Cross-sectional study using an anonymous semi-structured interviewer-administered questionnaire. SETTING: The antenatal clinic at the University of Benin Teaching Hospital, Nigeria, from June 2008 to December 2009. POPULATION: 305 HIV-positive women receiving antenatal care. METHODS: An anonymous semi-structured World Health Organization modified questionnaire that elicited information on the experiences of intimate partner violence, was administered to the women by trained female interviewers. MAIN OUTCOME MEASURES: Prevalence, pattern and risk factors associated with experiencing intimate partner violence. RESULTS: The prevalence of intimate partner violence among the women was 32.5%, with psychological violence being the most common form of violence reported (27.5%) and physical violence the least reported (5.9%). Identified risk factors for experiencing violence were multiparity (Odds ratio 9.4; CI 1.23-71.33), respondents with an HIV-positive child (Odds ratio 9.2; CI 4.53-18.84), experience of violence before they were diagnosed HIV-positive (Odds ratio 44.4; 10.33-190.42) and women with partners without post-secondary education (Odds ratio 2.3; CI 1.40-3.91). CONCLUSION: Intimate partner violence is a prevalent public health problem among HIV-infected pregnant women in our community and it may hinder efforts to scale up prevention of mother-child transmission programs, especially in developing countries. Screening for intimate partner violence to identify abused women should be incorporated into these programs to offer these women optimal care. PMID- 21306342 TI - Sacrospinous vaginal fixation--current status. AB - There has been a trend towards increased use of synthetic meshes and abdominal procedures with decreased use of sacrospinous fixation (SSF). A Medline search was performed for the MeSH terms 'sacrospinous ligament', 'sacrospinous fixation', 'sacrospinous ligament suspension' and 'sacrospinous colpopexy'. Published papers from 1996-2010 were selected for analysis. Outcome measures were assessed in terms of efficacy, complications and quality of life after sacrospinous vaginal fixation. Studies on bilateral SSF and fixing uterus to the sacrospinous ligament, use of concomitant anti-incontinence procedures along with SSF were not included in this review. Sacrospinous vaginal fixation provides good long-term objective and subjective outcomes and improves quality of life of women with pelvic organ prolapse. Further, complication rates of SSF are comparable to abdominal sacrocolpopexy and are much less than transvaginal mesh procedures and SSF is a cost-effective procedure. SSF is a time-tested surgical procedure with a reduction in surgical extent and has a definite place in modern pelvic reconstructive surgery. PMID- 21306343 TI - Validation of the Swedish short forms of the Pelvic Floor Impact Questionnaire (PFIQ-7), Pelvic Floor Distress Inventory (PFDI-20) and Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12). AB - OBJECTIVE: To psychometrically evaluate the Swedish translations of the short forms of the Pelvic Floor Impact Questionnaire (PFIQ-7), Pelvic Floor Distress Inventory (PFDI-20) and Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12). DESIGN AND SETTING: Cross-sectional design, University hospital. SAMPLE: Forty-four patients awaiting prolapse surgery. METHODS: The dual-panel translation method followed by an evaluation of validity and reliability in prolapse patients. MAIN OUTCOME MEASURES: Construct, convergent and discriminant validity, reliability via test-retest and internal consistency. RESULTS: Item response rates were high (range 95.5-100%) for PFIQ-7 and PFDI-20. The corrected item-total correlations showed acceptable construct validity for PFIQ-7 (r=0.338-0.826) but low for PFDI-20 (r=0.116-0.581) and PISQ-12 (r=0.024 0.735). Acceptable convergent validity was found in all three instruments, with a negative correlation with the SF-12. There were no floor or ceiling effects in the three instruments. In the test-retest analysis, intraclass correlation coefficients were significant (r=0.888-0.943). Cronbach's alpha varied between 0.57 and 0.94. CONCLUSION: This is the first validated translation of the PFIQ-7, PFDI-20 and PISQ-12 in Swedish. All three instruments indicated acceptable psychometric properties. PMID- 21306344 TI - Plasminogen activator inhibitor-1 4G/5G polymorphism in infertile women with and without endometriosis. AB - OBJECTIVE: To evaluate PAI-1 genotypes in a group of infertile women with or without endometriosis and control subjects. DESIGN: Case-control study. SETTING: Human Reproduction Center of Medicina do ABC Faculty. POPULATION: One hundred and forty infertile women with endometriosis, 64 women with idiopathic infertility and 148 fertile women as control subjects. METHODS: The PAI-1 4G/5G polymorphism was identified by restriction fragment length polymorphism-polymerase chain reaction. MAIN OUTCOME MEASURES: Genotype distribution and allele frequency of the 4G/5G polymorphism of the PAI-1 gene. RESULTS: The frequencies of genotypes 4G/4G, 4G/5G and 5G/5G of the PAI-1 gene in the infertile women with endometriosis were 38.6, 37.1 and 24.3%, respectively, and in the control group 24.3, 33.8 and 41.9%, respectively (p=0.003). When the infertile women with endometriosis were divided according to their endometriosis stage, genotypes 4G/4G, 4G/5G and 5G/5G were identified, respectively, in 36.7, 32.9 and 30.4% of the patients with minimal/mild endometriosis (p=0.102) and in 41.0, 42.6 and 16.4% of the patients with moderate/severe endometriosis (p=0.001); in the women with idiopathic infertility, these genotypes were found at a frequency of 29.7, 34.3 and 36%, respectively (p=0.637). CONCLUSION: The data suggest that, in Brazilian women, the PAI-1 4G/5G polymorphism may be associated with a risk of endometriosis-associated infertility. PMID- 21306345 TI - Can de novo stress incontinence after anterior wall repair be predicted? AB - OBJECTIVE: To locate preoperatively continent women with pelvic organ prolapse at risk of developing incontinence after surgery by means of reducing the prolapse preoperatively with a speculum and a pessary. DESIGN: Prospective observational cohort study. SETTING: Departments of Obstetrics and Gynecology at Northern Alvborgs County Hospital, Varbergs Hospital, and Sahlgrenska University Hospital, Sweden, between 2000 and 2004. POPULATION: Patients scheduled for anterior wall repair with no history of incontinence. METHODS: Data were collected using a questionnaire, a voiding diary, a gynecological examination including staging of prolapse with the Pelvic Organ Quantification System and clinical testing preoperatively and one year after vaginal repair. The first test included a cough test while the prolapse was reduced with a speculum. The second test was performed with the patient undergoing a standardized quantification test and a 48 hour pad test after reducing the prolapse with a pessary. Postoperatively, clinical testing was repeated one year after surgery without any device in place. MAIN OUTCOME MEASURES: Reported symptoms of leakage during movement or coughing. RESULTS: Seventy-four patients were included. Before surgery, six (8.1%) women tested positive during the speculum test and seven (9.5%) during the pessary test. Eight women (10.8%) were found to have subjective urinary stress incontinence after 1 year. This was only confirmed in four women during stress testing. The positive predictive values for subjective stress incontinence of the speculum and the pessary tests were 42.9% (95%CI 12.0-76.9) and 33.3% (95%CI -4.4 to +71.5), respectively. The negative predictive values of the tests were 92.5% (95%CI 90.3-1.00) and 91.1% (95%CI 88.5-99.7). CONCLUSIONS: The tested preoperative methods predicting de novo subjective stress incontinence after anterior wall repair did not show sufficient positive predictive values to be clinically useful. PMID- 21306346 TI - Maternal and child outcome after in vitro fertilization--a review of 25 years of population-based data from Sweden. AB - OBJECTIVE: To summarize data on deliveries after in vitro fertilization (IVF) performed in Sweden up to 2006. DESIGN: Cohort study of women and children, conceived after IVF, with comparisons of deliveries after IVF before and after 1 April 2001. SETTING: Study based on Swedish health registers. POPULATION: Births registered in the Swedish Medical Birth Register with information on IVF from all IVF clinics in Sweden. METHODS: Results from the second study period are summarized, and outcomes between the two periods are compared. Long-term follow up is based on data from both periods. MAIN OUTCOME MEASURES: Maternal and perinatal outcomes, long-term sequels. RESULTS: Some maternal pregnancy complications decreased in rate, notably pre-eclampsia and premature rupture of membranes. The rate of multiple births and preterm births decreased dramatically, with a better neonatal outcome, including reduced neonatal mortality. No difference in outcome existed between IVF and intracytoplasmic sperm injection or between the use of fresh and cryopreserved embryos, but children born after blastocyst transfer had a slightly higher risk for preterm birth and congenital malformations than children born after cleavage stage transfer. An increased risk for cerebral palsy, possibly for attention deficit and hyperactivity disorder, for impaired visual acuity and for childhood cancer was noted, but these outcomes were rare also after IVF. An increased risk for asthma was demonstrated. No effect on maternal cancer risk was seen. CONCLUSION: A marked decrease in multiple births was the main reason for better pregnancy and neonatal outcome and may also have a beneficial effect on long-term results, notably cerebral palsy. PMID- 21306347 TI - Obesity, diabetes, and the risk of infections diagnosed in hospital and post discharge infections after cesarean section: a prospective cohort study. AB - OBJECTIVE: To assess the impact of obesity and diabetes on the risk of post cesarean infections. DESIGN: Prospective cohort study. SETTING: Obstetric departments at three hospitals in Denmark. POPULATION: 2,492 consecutive women having cesarean section (CS) from February 2007 to August 2008. METHODS: We collected complete data from medical records and databases on CS, body mass index, diabetes (type 1, type 2, and gestational), and post-cesarean infections. Post-discharge infections diagnosed by general practitioners were ascertained through positive microbiological cultures and antibiotic prescriptions. MAIN OUTCOME MEASURES: Cumulative incidences of infections within 30 days after CS. RESULTS: Of 2,492 women having CS, 373 (15.2%) were obese and 123 (4.9%) had diabetes. Overall, 458 women (18.4%) had a post-cesarean infection within 30 days and 174 (7.0%) were diagnosed in-hospital. The risk of post-cesarean infections was higher among obese than non-obese women: adjusted (for diabetes and emergency/elective CS) odds ratio (OR)=1.43; 95% confidence interval (CI): 1.09 1.88, particularly for in-hospital infections (OR=1.86; 95%CI: 1.28-2.72). After controlling for obesity and mode of CS, type 2 or gestational diabetes were weak predictors of infection risk (OR=1.18; 95%CI: 0.72-1.93), whereas the adjusted OR in women with type 1 diabetes was 1.65 (95%CI: 0.64-4.25). Among diabetic women, obesity increased the risk of post-cesarean infections more than twofold; the adjusted ORs were 2.06 (95%CI: 1.13-3.75) for infections overall and 2.74 (95%CI: 1.25-6.01) for in-hospital infections. CONCLUSION: Obesity increases the risk of post-cesarean infections and diabetes further strengthens this association. PMID- 21306348 TI - A systematic review of gynecological cancer surveillance in women belonging to hereditary nonpolyposis colorectal cancer (Lynch syndrome) families. AB - OBJECTIVE/DESIGN: We performed a systematic review of studies that evaluate the role of gynecological cancer surveillance in women who carry a hereditary nonpolyposis colorectal cancer (HNPCC) mutation or belong to a family that fulfills the criteria for HNPCC. METHODS: The PubMed database and a clinical trials database were used to identify relevant studies. We included studies that reported results of gynecological cancer surveillance in women who carry a HNPCC mutation, belong to a family in which a HNPCC mutation was detected or belong to a family fulfilling the Amsterdam II criteria. MAIN OUTCOME MEASURES: Number and stage of cancers, interval cancers and cancer precursor states detected at screening. RESULTS: Five studies fulfilled our review criteria. Surveillance modalities for endometrial cancer included transvaginal ultrasound combined with endometrial sampling when indicated, or transvaginal ultrasound with a routine endometrial biopsy, and, in certain studies, the tumor marker CA-125. The highest yield of pathological findings in surveillance visits, from 5 to 6.5%, occurred in studies that included routine endometrial biopsies. Without a routine sampling, 7/14 cancers and 11/18 hyperplasias would have been missed. One case of advanced ovarian cancer was detected at surveillance. CONCLUSIONS: Currently available published studies on gynecological cancer surveillance in women with HNPCC do not adequately allow for evidence-based clinical decisions. Detection of endometrial cancer or hyperplasia in nonsymptomatic women belonging to an HNPCC family is improved by adding routine endometrial sampling along with transvaginal ultrasound for surveillance visits. No benefit was shown for ovarian cancer surveillance. PMID- 21306349 TI - Psychological burden of testing positive for high-risk human papillomavirus on women with atypical cervical cytology: a prospective study. AB - OBJECTIVE: To assess the psychological burden of testing positive for high-risk human papillomavirus (HPV) on Chinese women with atypical squamous cells of undetermined significance (ASCUS). DESIGN: Prospective observational study. SETTING: Five community women's health clinics in Hong Kong. POPULATION: Ethnic Chinese women (n=299) with ASCUS who underwent reflex HPV testing (of whom 142 tested HPV negative and 157 tested HPV positive). METHODS: Women's psychological condition was assessed by self-administered questionnaires at smear result notification and by structured telephone interviews six months after notification. All women who tested positive for HPV were referred for colposcopy. MAIN OUTCOME MEASURES: State anxiety, cervical cancer worry and psychosocial burden. RESULTS: At result notification, the HPV-positive group had significantly higher state anxiety, cervical cancer worry and psychosocial burden than the HPV negative group (all p<0.001). Irrespective of the HPV results, all outcome scores decreased over time. About 80% of the women who were HPV positive attended colposcopy as recommended. At six months, the two groups did not differ in state anxiety, cervical cancer worry, perceived risk of cervical cancer and satisfaction with intimate relationship, but psychosocial burden remained higher in the HPV-positive group (p=0.001). CONCLUSIONS: A concurrent positive HPV result intensified the distress of women with ASCUS at result notification. With time and after colposcopy, their initial heightened anxiety and cervical cancer worry were significantly lowered. However, HPV positivity may pose a prolonged psychosocial burden on women even after having had the necessary follow-up for their cervical abnormalities. PMID- 21306350 TI - Circulating interleukin-6 concentrations during and after gestational diabetes mellitus. AB - OBJECTIVE: Recent studies have shown that high interleukin-6 (IL-6) secretion may aggravate insulin resistance in pregnancy and participate in the pathogenesis of gestational diabetes mellitus (GDM). The aim of this study was to determine whether the presence of GDM is associated with elevated IL-6 concentrations and whether this association remains after delivery, independent of body mass index. DESIGN: Longitudinal study. SETTING: Hospital-based. SAMPLE: Forty-seven women were screened for GDM with a 75g oral glucose tolerance test at 26.1+/-3.7 weeks of pregnancy following the Canadian Diabetes Association guidelines (20 GDM, 27 control subjects). MAIN OUTCOME MEASURES: Interleukin-6 levels were measured by ELISA at the time of GDM screening and two months post-partum. RESULTS: Interleukin-6 concentrations were significantly higher in women with GDM compared with control women at the time of GDM screening (1.47+/-0.72 vs. 0.90+/ 0.32pg/mL, p<=0.01). Similar results were obtained two months post-partum, where IL-6 levels remained significantly higher in women with GDM compared with control women (1.88+/-0.85 vs. 1.41+/-0.87pg/mL, p<=0.05). Interleukin-6 concentrations were significantly correlated with the Matsuda insulin sensitivity index, measured at the two time points (r=-0.60, p<=0.01 and r=-0.34, p<=0.05). The Matsuda insulin sensitivity index was an independent and significant predictor of IL-6 concentrations at the time of GDM screening, explaining 35.6% of the variance (p<=0.0001) in this variable. IL-6 concentration measured at GDM screening was identified as an independent and significant predictor of post partum IL-6 concentrations, explaining 28.6% of the variance (p<=0.001). CONCLUSIONS: These results show that GDM is associated with elevated IL-6 levels independent of obesity levels, both during pregnancy and after delivery. PMID- 21306351 TI - Full-term delivery in a pregnant breast cancer patient. PMID- 21306352 TI - Dynamic predictions and prospective accuracy in joint models for longitudinal and time-to-event data. AB - In longitudinal studies it is often of interest to investigate how a marker that is repeatedly measured in time is associated with a time to an event of interest. This type of research question has given rise to a rapidly developing field of biostatistics research that deals with the joint modeling of longitudinal and time-to-event data. In this article, we consider this modeling framework and focus particularly on the assessment of the predictive ability of the longitudinal marker for the time-to-event outcome. In particular, we start by presenting how survival probabilities can be estimated for future subjects based on their available longitudinal measurements and a fitted joint model. Following we derive accuracy measures under the joint modeling framework and assess how well the marker is capable of discriminating between subjects who experience the event within a medically meaningful time frame from subjects who do not. We illustrate our proposals on a real data set on human immunodeficiency virus infected patients for which we are interested in predicting the time-to-death using their longitudinal CD4 cell count measurements. PMID- 21306353 TI - Generalized causal mediation analysis. AB - The goal of mediation analysis is to assess direct and indirect effects of a treatment or exposure on an outcome. More generally, we may be interested in the context of a causal model as characterized by a directed acyclic graph (DAG), where mediation via a specific path from exposure to outcome may involve an arbitrary number of links (or "stages"). Methods for estimating mediation (or pathway) effects are available for a continuous outcome and a continuous mediator related via a linear model, while for a categorical outcome or categorical mediator, methods are usually limited to two-stage mediation. We present a method applicable to multiple stages of mediation and mixed variable types using generalized linear models. We define pathway effects using a potential outcomes framework and present a general formula that provides the effect of exposure through any specified pathway. Some pathway effects are nonidentifiable and their estimation requires an assumption regarding the correlation between counterfactuals. We provide a sensitivity analysis to assess the impact of this assumption. Confidence intervals for pathway effect estimates are obtained via a bootstrap method. The method is applied to a cohort study of dental caries in very low birth weight adolescents. A simulation study demonstrates low bias of pathway effect estimators and close-to-nominal coverage rates of confidence intervals. We also find low sensitivity to the counterfactual correlation in most scenarios. PMID- 21306354 TI - Statistical inference in mixed models and analysis of twin and family data. AB - Analysis of data from twin and family studies provides the foundation for studies of disease inheritance. The development of advanced theory and computational software for general linear models has generated considerable interest for using mixed-effect models to analyze twin and family data, as a computationally more convenient and theoretically more sound alternative to the classical structure equation modeling. Despite the long history of twin and family data analysis, some fundamental questions remain unanswered. We addressed two important issues. One is to determine the necessary and sufficient conditions for the identifiability in the mixed-effects models for twin and family data. The other is to derive the asymptotic distribution of the likelihood ratio test, which is novel due to the fact that the standard regularity conditions are not satisfied. We considered a series of specific yet important examples in which we demonstrated how to formulate mixed-effect models to appropriately reflect the data, and our key idea is the use of the Cholesky decomposition. Finally, we applied our method and theory to provide a more precise estimate of the heritability of two data sets than the previously reported estimate. PMID- 21306355 TI - Matrix-based concordance correlation coefficient for repeated measures. AB - In many clinical studies, Lin's concordance correlation coefficient (CCC) is a common tool to assess the agreement of a continuous response measured by two raters or methods. However, the need for measures of agreement may arise for more complex situations, such as when the responses are measured on more than one occasion by each rater or method. In this work, we propose a new CCC in the presence of repeated measurements, called the matrix-based concordance correlation coefficient (MCCC) based on a matrix norm that possesses the properties needed to characterize the level of agreement between two p* 1 vectors of random variables. It can be shown that the MCCC reduces to Lin's CCC when p= 1. For inference, we propose an estimator for the MCCC based on U-statistics. Furthermore, we derive the asymptotic distribution of the estimator of the MCCC, which is proven to be normal. The simulation studies confirm that overall in terms of accuracy, precision, and coverage probability, the estimator of the MCCC works very well in general cases especially when n is greater than 40. Finally, we use real data from an Asthma Clinical Research Network (ACRN) study and the Penn State Young Women's Health Study for demonstration. PMID- 21306356 TI - Flexible nonhomogeneous markov models for panel observed data. AB - Methods for fitting nonhomogeneous Markov models to panel-observed data using direct numerical solution to the Kolmogorov Forward equations are developed. Nonhomogeneous Markov models occur most commonly when baseline transition intensities depend on calendar time, but may also occur with deterministic time dependent covariates such as age. We propose transition intensities based on B splines as a smooth alternative to piecewise constant intensities and also as a generalization of time transformation models. An expansion of the system of differential equations allows first derivatives of the likelihood to be obtained, which can be used in a Fisher scoring algorithm for maximum likelihood estimation. The method is evaluated through a small simulation study and demonstrated on data relating to the development of cardiac allograft vasculopathy in posttransplantation patients. PMID- 21306357 TI - Bioattenuation in groundwater impacted by landfill leachate traced with delta13C. AB - The impact on groundwater imparted by the infiltration of high dissolved organic carbon (DOC) leachate from capped, unlined landfills can be attenuated by biogeochemical reactions beyond the waste source, although such reactive loss in the aquifer is difficult to distinguish from conservative advective dispersion. Compound-specific measurement of delta(13)C in carbon species, including CH(4), dissolved inorganic carbon (DIC), and the major DOC compounds (acetate, humic acid, and fulvic acid) provides a constraint in this assessment that can assist in exercises of modeling and prediction of leachate transport. The Trail Road municipal landfill near Ottawa, Ontario, Canada, hosts an unlined sector which produces a highly enriched leachate (DOC >4500 mg/L) that provides a good site to examine reactive attenuation within the receptor aquifer. Acetate, a sentinel component of leachate DOC (~1000 mg C/L), is absent in impacted groundwater. Mass balance calculations together with reaction modeling suggest continued acetate fermentation with calcite control on DIC and delta(13)C(DIC) evolution. In groundwater within 50 m of the landfill, methane concentrations are elevated (~10 mg/L), consistent with acetate fermentation, whereas delta(13)C(CH4) measurements in deeper groundwater range down to -510/00 compared with -600/00 in the landfill demonstrating oxidative loss. DOC in the deep aquifer is remarkably depleted to values less than -400/00 suggesting methanotrophic bacteria selectively consume isotopically light CH(4) to fix carbon. Continued reaction of leachate DOC in groundwater is demonstrated by evolution away from conservative mixing lines on diagrams of delta(13)C vs. concentrations of DIC and DOC. PMID- 21306358 TI - A review of thermal response test analysis using pumping test concepts. AB - The design of ground-coupled heat pump systems requires knowledge of the thermal properties of the subsurface and boreholes. These properties can be measured with in situ thermal response tests (TRT), where a heat transfer fluid flowing in a ground heat exchanger is heated with an electric element and the resulting temperature perturbation is monitored. These tests are analogous to standard pumping tests conducted in hydrogeology, because a system that is initially assumed at equilibrium is perturbed and the response is monitored in time, to assess the system's properties with inverse modeling. Although pumping test analysis is a mature topic in hydrogeology, the current analysis of temperature measurements in the context of TRTs is comparatively a new topic and it could benefit from the application of concepts related to pumping tests. The purpose of this work is to review the methodology of TRTs and improve their analysis using pumping test concepts, such as the well function, the superposition principle, and the radius of influence. The improvements are demonstrated with three TRTs. The first test was conducted in unsaturated waste rock at an active mine and the other two tests aimed at evaluating the performance of thermally enhanced pipe installed in a fully saturated sedimentary rock formation. The concepts borrowed from pumping tests allowed the planning of the duration of the TRTs and the analysis of variable heat injection rate tests accounting for external heat transfer and temperature recovery, which reduces the uncertainty in the estimation of thermal properties. PMID- 21306359 TI - Contaminant plume classification system based on mass discharge. AB - Estimation of mass discharge has become an increasingly valuable analysis technique at sites with contaminated groundwater plumes. We propose a simple plume magnitude classification system based on mass discharge comprised of 10 separate magnitude categories, such as a "Mag 7 plume." This system can be a useful tool for scientists, engineers, regulators, and stakeholders to better communicate site conceptual models, prioritize sites, evaluate plumes both spatially and temporally, and determine potential impacts. PMID- 21306360 TI - Design and application of a direct-push vadose zone gravel permeameter. AB - A borehole permeameter is well suited for testing saturated hydraulic conductivity (K(sat)) at specific depths in the vadose zone. Most applications of the method involve fine-grained soils that allow hand auguring of test holes and require a small water reservoir to maintain a constant head. In non-cohesive gravels, hand-dug test holes are difficult to excavate, holes are prone to collapse, and large volumes of water are necessary to maintain a constant head for the duration of the test. For coarse alluvial gravels, a direct-push steel permeameter was designed to place a slotted pipe at a specific sampling depth. Measurements can be made at successive depths at the same location. A 3790 L (1000 gallons) trailer-mounted water tank maintained a constant head in the permeameter. Head in the portable tank was measured with a pressure transducer and flow was calculated based on a volumetric rating curve. A U.S. Bureau of Reclamation analytical method was utilized to calculate K(sat). Measurements with the permeameter at a field site were similar to those reported from falling-head tests. PMID- 21306361 TI - Capture--rates and directions of groundwater flow don't matter! PMID- 21306362 TI - A computer program for flow-log analysis of single holes (FLASH). AB - A new computer program, FLASH (Flow-Log Analysis of Single Holes), is presented for the analysis of borehole vertical flow logs. The code is based on an analytical solution for steady-state multilayer radial flow to a borehole. The code includes options for (1) discrete fractures and (2) multilayer aquifers. Given vertical flow profiles collected under both ambient and stressed (pumping or injection) conditions, the user can estimate fracture (or layer) transmissivities and far-field hydraulic heads. FLASH is coded in Microsoft Excel(5) with Visual Basic for Applications routines. The code supports manual and automated model calibration. PMID- 21306363 TI - Increasing time costs and copayments for prescription drugs: an analysis of policy changes in a complex environment. AB - OBJECTIVE: To estimate the effect of two separate policy changes in the North Carolina Medicaid program: (1) reduced prescription lengths from 100 to 34 days' supply, and (2) increased copayments for brand name medications. DATA SOURCES/STUDY SETTING: Medicaid claims data were obtained from the Centers for Medicare and Medicaid Services for January 1, 2000-December 31, 2002. STUDY DESIGN: We used a pre-post controlled partial difference-in-difference-in differences design to examine the effect of the policy change on adults in North Carolina; adult Medicaid recipients from Georgia served as controls. Outcomes examined include medication adherence and Medicaid expenditures. DATA COLLECTION/EXTRACTION METHODS: Data were aggregated to the person-quarter level. Individuals in HMOs, nursing homes, pregnant, or deceased in the quarter were excluded. PRINCIPAL FINDINGS: Both policies decreased medication adherence. The days' supply policy had a much larger effect on adherence than did the copayment increase. Total Medicaid spending declined from the days' supply policy, but the copayment policy resulted in a net increase in Medicaid expenditures. CONCLUSIONS: Although Medicaid costs decreased with the change in days supply policy, these savings were due to reduced adherence to these chronic medications. Additional research should examine the effect of these policy changes from the perspective of Medicaid enrollees. PMID- 21306364 TI - Transitions from private to public health coverage among children: estimating effects on out-of-pocket medical costs and health insurance premium costs. AB - OBJECTIVE: To assess the effects of transitions from private to public health insurance by children on out-of-pocket medical expenditures and health insurance premium costs. DATA SOURCES: Data are drawn from the 1996 and 2001 panels of the Survey of Income and Program Participation. We construct a nationally representative, longitudinal sample of children, ages 0-18, and their families for the period 1998-2003, a period in which states raised public health insurance eligibility rates for children. STUDY DESIGN: We exploit the Survey of Income and Program Participation's longitudinal design to identify children in our sample who transition from private to public health insurance. We then use a bootstrapped instrumental variable approach to estimate the effects of these transitions on out-of-pocket expenditures and health insurance premium costs. PRINCIPAL FINDINGS: Children who transition from private to public coverage are relatively low-income, are disproportionately likely to live in single-mother households, and are more likely to be Black or of Hispanic origin. Child health status is highly predictive of transitions. We estimate that these transitions provide a cash-equivalent transfer of nearly U.S.$1,500 annually for families in the form of reduced out-of-pocket and health insurance premium costs. CONCLUSIONS: Transitions from private to public health coverage by children can bring important social benefits to vulnerable families. This suggests that instead of being a net societal cost, such transitions may provide an important social benefit. PMID- 21306365 TI - Cost implications of improving blood pressure management among U.S. adults. AB - OBJECTIVE: To examine the cost-effectiveness of improving blood pressure management from the payer perspective. DATA SOURCE/STUDY SETTING: Medical record data for 4,500 U.S. adults with hypertension from the Community Quality Index (CQI) study (1996-2002), pharmaceutical claims from four Massachusetts health plans (2004-2006), Medicare fee schedule (2009), and published literature. STUDY DESIGN: A probability tree depicted blood pressure management over 2 years. DATA COLLECTION/EXTRACTION METHODS: We determined how frequently CQI study subjects received recommended care processes and attained accepted treatment goals, estimated utilization of visits and medications associated with recommended care, assigned costs based on utilization, and then modeled how hospitalization rates, costs, and goal attainment would change if all recommended care was provided. PRINCIPAL FINDINGS: Relative to current care, improved care would cost payers U.S.$170 more per hypertensive person annually (2009 dollars). The incremental cost per person newly attaining treatment goals over 2 years would be U.S.$1,696 overall, U.S.$801 for moderate hypertension, and U.S.$850 for severe hypertension. Among people with severe hypertension, blood pressure would decline substantially but seldom reach goal; the incremental cost per person attaining a relaxed goal (<= stage 1) would be U.S.$185. CONCLUSIONS: Under the Health Care Effectiveness Data and Information Set program, which monitors the attainment of blood pressure treatment goals, payers will find it slightly more cost-effective to improve care for moderate than severe hypertension. Having a secondary, relaxed goal would substantially increase payers' incentive to improve care for severe hypertension. PMID- 21306366 TI - Effect of usual source of care on depression among Medicare beneficiaries: an application of a simultaneous-equations model. AB - OBJECTIVE: To investigate whether having a usual source of care (USOC) resulted in lower depression prevalence among the elderly. DATA SOURCES: The 2001-2003 Medicare Current Beneficiaries Survey and 2002 Area Resource File. STUDY DESIGN: Twenty thousand four hundred and fifty-five community-dwelling person-years were identified for respondents aged 65+, covered by both Medicare Parts A and B in Medicare fee-for-service for a full year. USOC was defined by the question "Is there a particular medical person or a clinic you usually go to when you are sick or for advice about your health?" Ambulatory care use (ACU) was defined by having at least one physician office visit and/or hospital outpatient visit using Medicare claims. Depression was identified by a two-item screen (sadness and/or anhedonia). All measures were for the past 12 months. A simultaneous-equations (trivariate probit) model was estimated, adjusted for sampling weights and study design effects. PRINCIPAL FINDINGS: Based on the simultaneous-equations model, USOC is associated with 3.8 percent lower probability of having depression symptoms (p=.03). Also, it had a positive effect on having any ACU (p<.001). Having any ACU had no statistically significant effect on depression (p=.96). CONCLUSIONS: USOC was associated with lower depression prevalence and higher realized access (ACU) among community-dwelling Medicare beneficiaries. PMID- 21306367 TI - Variation in emergency medical technician partner familiarity. AB - OBJECTIVE: To characterize patterns of Emergency Medical Technician (EMT) partner familiarity in three Emergency Medical Services (EMS) agencies. STUDY DESIGN/DATA SOURCES: We utilized a case study design and retrospective review of administrative data from three EMS agencies and 182 EMTs over 12 months. We used the Kruskal-Wallis test and Bonferroni corrected p-values to compare measures of partner familiarity. Measures included the annual mean number of partners, rate of partners per 10 shifts, mean shifts per EMT, and proportion of shifts worked with same partner. We standardized select measures by size of agency to account for a greater number of possible partnerships in larger agencies. PRINCIPAL FINDINGS: Across all agencies, the mean number of shifts worked annually by EMTs was (mean [SD]) 77.3 (59.8). The unstandardized mean number of EMT partnerships was 19.3 (12.4) and did not vary across EMS agencies after standardizing by agency size (p=.328). The unstandardized mean rate of EMT partnerships for every 10 shifts worked was 4.0 (2.7) and varied across agencies after standardizing (p<.001). The mean proportion of shifts worked with the same partner was 34.8 percent and varied across agencies (p<.001). CONCLUSIONS: There was wide variation in select measures of EMT partner familiarity. PMID- 21306368 TI - Following the money: factors associated with the cost of treating high-cost Medicare beneficiaries. AB - OBJECTIVE: To identify factors associated with the cost of treating high-cost Medicare beneficiaries. DATA SOURCES: A national sample of 1.6 million elderly, Medicare beneficiaries linked to 2004-2005 Community Tracking Study Physician Survey respondents and local market data from secondary sources. STUDY DESIGN: Using 12 months of claims data from 2005 to 2006, the sample was divided into predicted high-cost (top quartile) and lower cost beneficiaries using a risk adjustment model. For each group, total annual standardized costs of care were regressed on beneficiary, usual source of care physician, practice, and market characteristics. PRINCIPAL FINDINGS: Among high-cost beneficiaries, health was the predominant predictor of costs, with most physician and practice and many market factors (including provider supply) insignificant or weakly related to cost. Beneficiaries whose usual physician was a medical specialist or reported inadequate office visit time, medical specialist supply, provider for-profit status, care fragmentation, and Medicare fees were associated with higher costs. CONCLUSIONS: Health reform policies currently envisioned to improve care and lower costs may have small effects on high-cost patients who consume most resources. Instead, developing interventions tailored to improve care and lowering cost for specific types of complex and costly patients may hold greater potential for "bending the cost curve." PMID- 21306369 TI - The impact of Medicare Part D on hospitalization rates. AB - OBJECTIVE: To determine whether the change in prescription drug insurance coverage associated with Medicare Part D reduced hospitalization rates for conditions sensitive to drug adherence. DATA SOURCES/STUDY SETTING: Hospital discharge data from 2005 to 2007 for 23 states, linked with state-level data on drug coverage. STUDY DESIGN: We use a difference-in-difference-in-differences approach, comparing changes in the probability of hospitalization before and after the introduction of the Part D benefit in 2006, for individuals aged 65 and older (versus individuals aged 60-64) in states with low drug coverage in 2005 (versus those in states with high pre-Part D drug coverage). DATA COLLECTION/EXTRACTION METHODS: Hospitalization rates for selected ambulatory care sensitive conditions in 23 states were computed using data from the Census and Health Care Utilization Project. Drug coverage rates were computed using data from several sources. PRINCIPAL FINDINGS: For the conditions studied, our point estimates suggest that Part D reduced the overall rate of hospitalization by 20.5 per 10,000 (4.1 percent), representing approximately 42,000 admissions, about half of the reduction in admissions over our study period. Conclusions. The increase in drug coverage associated with Medicare Part D had positive effects on the health of elderly Americans, which reduced use of nondrug health care resources. PMID- 21306371 TI - Health-related unmet needs of supplemental security income youth after the age-18 redetermination. AB - OBJECTIVE: Young adults who exit Supplemental Security Income (SSI) after their age-18 eligibility redetermination may have greater health-related unmet needs than those who remain on SSI. The objective of this paper is to determine the magnitude and causes of this gap. DATA SOURCES: Uses the 2001-2002 National Survey of SSI Children and Families, a nationally representative survey of SSI youth. STUDY DESIGN: Self-reported unmet medical, dental, and prescription drug needs of 869 individuals ages 19-23 who have had their SSI eligibility redetermined are compared. In addition to raw differences in unmet needs, logistic regressions are used to determine the sources of these differences. PRINCIPAL FINDINGS: Young adults who exit SSI are almost twice as likely to have health-related unmet needs subsequent to their exit as those who remain on SSI after the age-18 redetermination. Access to care, particularly insurance coverage (either Medicaid or non-Medicaid), accounts for much of the difference between these two groups; measures of health status do not explain much of the difference. CONCLUSION: Policies addressing access to health care are likely to be more successful in addressing unmet needs than policies focused on disability specific issues in health for youth who lose access to SSI after their age-18 redetermination. PMID- 21306372 TI - The effect of ionizing gamma radiation on natural and synthetic fibers and its implications for the forensic examination of fiber evidence. AB - Circumstances of criminal activities involving radioactive materials may mean fiber evidence recovered from a crime scene could have been exposed to materials emitting ionizing radiation. The consequences of radiation exposed fibers on the result of the forensic analysis and interpretation is explored. The effect of exposure to 1-1000 kGy radiation doses in natural and synthetic fibers was noticeable using comparative forensic examination methods, such as optical microscopy, microspectrophotometry, and thin-layer chromatography. Fourier transform infrared spectroscopy analysis showed no signs of radiation-induced chemical changes in any of the fiber structures. The outcome of the comparative methods highlights the risk of "false negatives" associated in comparing colors of recovered fibers that may have been exposed to unknown radiation doses. Consideration of such results supports the requirement to know the context, including the environmental conditions, as much as possible before undertaking a forensic fiber examination. PMID- 21306370 TI - How do the experiences of Medicare beneficiary subgroups differ between managed care and original Medicare? AB - OBJECTIVE: To examine whether disparities in health care experiences of Medicare beneficiaries differ between managed care (Medicare Advantage [MA]) and traditional fee-for-service (FFS) Medicare. DATA SOURCES: 132,937 MA and 201,444 FFS respondents to the 2007 Medicare Consumer Assessment of Health Care Providers and Systems (CAHPS) survey. STUDY DESIGN: We defined seven subgroup characteristics: low-income subsidy eligible, no high school degree, poor or fair self-rated health, age 85 and older, female, Hispanic, and black. We estimated disparities in CAHPS experience of care scores between each of these groups and beneficiaries without those characteristics within MA and FFS for 11 CAHPS measures and assessed differences between MA and FFS disparities in linear models. PRINCIPAL FINDINGS: The seven subgroup characteristics had significant (p<.05) negative interactions with MA (larger disparities in MA) in 27 of 77 instances, with only four significant positive interactions. CONCLUSION: Managed care may provide less uniform care than FFS for patients; specifically there may be larger disparities in MA than FFS between beneficiaries who have low incomes, are less healthy, older, female, and who did not complete high school, compared with their counterparts. There may be potential for MA quality improvement targeted at the care provided to particular subgroups. PMID- 21306373 TI - Skeletal identification by radiographic comparison: blind tests of a morphoscopic method using antemortem chest radiographs. AB - This study investigated the value of antemortem (AM) and postmortem (PM) radiographs of the claviculae and C3-T4 vertebrae to identify skeletons of missing U.S. soldiers from past military operations. In total, 12 field-recovered skeletons and AM chest radiographs of 1460 individuals were used. For each skeleton, examiners analyzed an array of AM chest radiographs (up to 1000 individuals) and attempted to identify the correct PM/AM radiographic match. When examiners were able to compare all images within a single test, only true positive identifications were made. When AM radiographs were presented one-at-a time, in sequential order, and without examiners having knowledge of array size, erroneous identifications resulted but they were almost exclusively made by untrained examiners (accuracy = 35% vs. 90% for trained examiners). This study demonstrates the value of chest radiographs for the identification of disarticulated and even eroded skeletons, but only when methods are wielded by trained examiners. PMID- 21306374 TI - Rat bite fever, a fatal case of Streptobacillus moniliformis infection in a 14 month-old boy. AB - Streptobacillus moniliformis is the primary cause of rat bite fever in North America. Children under 12 years of age are primarily infected, presenting with an acute syndrome of fever, rash, and polyarthritis. Common vectors include rats and mice. Transmission is predominantly from a bite or scratch, but contact with or ingestion of food contaminated with feces or saliva has also been reported. We report a fatal case of S. moniliformis infection in a 14-month-old-boy. At home, the child was exposed to filthy living conditions and the family had pet ferrets. Autopsy revealed a red-pink, mostly confluent rash and a circumscribed area suspicious for a possible bite mark. Cerebrospinal fluid cultures were positive for S. moniliformis. This case highlighted key features, such as the morbiliform rash, but lacked lymphadenopathy or joint manifestations. It is important to consider rat or rodent exposure as a source of infection. PMID- 21306375 TI - Traumatic testicular displacement in motorcycle drivers. AB - Testicular displacement is a rare clinical presentation of blunt scrotal injury that may take place in road traffic accidents involving motorcycle occupants. We are presenting two cases of motorcycle occupant fatalities, 21 and 24 years of age, where testicular displacement and other signs of groin trauma have been determined. In both cases, discrete external signs of scrotal trauma were noted on examination, while unilateral and bilateral traumatic testicular displacement, respectively, have been documented at autopsy. For motorcycle occupants involved in collision, it is necessary to perform a thorough analysis of injuries, in particular to look for specific trauma arising from fuel-tank impact to genitalia and/or groin. These injuries are of great medico-legal importance both at postmortem and in clinical cases involving motorcycle occupants involved in collision. PMID- 21306376 TI - Lethal manifestations of systemic lupus erythematosus in a forensic context. AB - Systemic lupus erythematosus is an autoimmune connective tissue disorder that affects multiple organs. While the clinical manifestations may vary in intensity over time and be associated with chronic disease, occasional cases occur where sudden and unexpected death has occurred. Cardiovascular disease is common, with accelerated atherosclerosis, intravascular thrombosis associated with antiphospholipid syndrome, and hypertensive cardiomegaly. Vasculitis with superimposed thrombosis may result in critical reduction in blood to vital organs, such as the heart and brain with infarction. Mesenteric ischemia may be caused by vasculitis, thrombosis, and accelerated atherosclerosis and may result in lethal intestinal infarction. Other diverse causes of sudden death include myocarditis, epilepsy, pulmonary hypertension, pulmonary thromboembolism, and sepsis. The autopsy evaluation of such cases requires careful examination of all organs with extensive histological sampling to include blood vessels, and microbiological sampling for bacteria, viruses, and fungi. PMID- 21306377 TI - Solid-state acquisition of fingermark topology using dense columnar thin films. AB - Various vacuum techniques are employed to develop fingermarks on evidentiary items. In this work, a vacuum was used to deposit columnar thin films (CTFs) on untreated, cyanoacrylate-fumed or dusted fingermarks on a limited selection of nonporous surfaces (microscope glass slides and evidence tape). CTF deposition was not attempted on fingermarks deposited on porous surfaces. The fingermarks were placed in a vacuum chamber with the fingermark side facing an evaporating source boat containing either chalcogenide glass or MgF(2). Thermal evaporation of chalcogenide glass or MgF(2) under a 1 MUTorr vacuum for 30 min formed dense CTFs on fingermark ridges, capturing the topographical features. The results show that it is possible to capture fingermark topology using CTFs on selected untreated, vacuumed cyanoacrylate-fumed or black powder-dusted nonporous surfaces. Additionally, the results suggested this might be a mechanism to help elucidate the sequence of deposition. PMID- 21306378 TI - Inter-species variation in bone mineral behavior upon heating. AB - The characterization of inter-species variation in bone mineral (b-HAP) is of relevance to forensic science and archaeology, but has not previously been widely explored. Results of an investigation into unheated bone mineral and behavior of bone upon heating for 12 animal species (including human) demonstrate that b-HAP characteristics, quantitatively measured using X-ray diffraction (XRD) analysis, exhibit significant inter-species variation. Human bone was found to be significantly different to all other species in terms of b-HAP lattice parameter values from unheated and heated bone and in terms of recrystallization behavior of b-HAP upon heating bone to 600 degrees C. The amounts of b-HAP thermal decomposition products were also significantly different for human bone heated to 1400 degrees C compared to those obtained for most other species. Therefore, there is potential for the development of an XRD-based method of species identification, particularly one that distinguishes human from non-human bone. PMID- 21306379 TI - The prevalence of mental disorders in prisoners in the city of Salvador, Bahia, Brazil. AB - The number of individuals affected by serious psychiatric disorders in Brazilian prisons is unknown. This cross-sectional study was conducted in prison complexes within the city of Salvador, Bahia, Brazil. The sample consisted of 497 prisoners, and the outcome measure was the Brazilian Portuguese version of the Mini International Neuropsychiatric Interview. The prevalence rates found in the closed and semi-open prison systems, respectively, were as follows: depression 17.6% and 18.8%; bipolar mood disorder 5.2% and 10.1%; anxiety disorders 6.9% and 14.4%; borderline personality disorder 19.7% and 34.8%; antisocial personality disorder 26.9% and 24.2%; alcohol addiction 26.6% and 35.3%; drug addiction 27.9% and 32.4%; psychosis 1.4% and 12.6%; attention deficit/hyperactivity disorder (ADHD) in childhood 10.3% and 22.2%; and ADHD in adulthood 4.1% and 5.3%. This study revealed higher rates of substance-related disorders and lower rates of psychotic and mood disorders compared to other prevalence studies carried out in prison populations. PMID- 21306380 TI - Evaluation of age estimation technique: testing traits of the acetabulum to estimate age at death in adult males. AB - This study evaluates the accuracy and precision of a skeletal age estimation method, using the acetabulum of 100 male ossa coxae from the Grant Collection (GRO) at the University of Toronto, Canada. Age at death was obtained using Bayesian inference and a computational application (IDADE2) that requires a reference population, close in geographic and temporal distribution to the target case, to calibrate age ranges from scores generated by the technique. The inaccuracy of this method is 8 years. The direction of bias indicates the acetabulum technique tends to underestimate age. The categories 46-65 and 76-90 years exhibit the smallest inaccuracy (0.2), suggesting that this method may be appropriate for individuals over 40 years. Eighty-three percent of age estimates were +/-12 years of known age; 79% were +/-10 years of known age; and 62% were +/ 5 years of known age. Identifying a suitable reference population is the most significant limitation of this technique for forensic applications. PMID- 21306381 TI - Identification of group affinity from cross-sectional contours of the human midfacial skeleton using digital morphometrics and 3D laser scanning technology. AB - Identifying group affinity from human crania is a long-standing problem in forensic and physical anthropology. Many craniofacial differences used in forensic skeletal identification are difficult to quantify, although certain measurements of the midfacial skeleton have shown high predictive value for group classifications. This study presents a new method for analyzing midfacial shape variation between different geographic groups. Three-dimensional laser scan models of 90 crania from three populations were used to obtain cross-sectional midfacial contours defined by three standard craniometric landmarks. Elliptic Fourier transforms of the contours were used to extract Fourier coefficients for statistical analysis. After cross-validation, discriminant functions based on the Fourier coefficients provided an average of 86% correct classifications for crania from the three groups. The high rate of accuracy of this method indicates its usefulness for identifying group affinities among human skeletal remains and demonstrates the advantages of digital 3D model-based analysis in forensic research. PMID- 21306382 TI - The Fourth ISN Special Neurochemistry Conference--"Membrane domains in CNS physiology and pathology", Erice, Trapani, Sicily, 22-26 May 2010. PMID- 21306383 TI - Phosphatidylglucoside: a novel marker for adult neural stem cells. AB - We investigated the expression of a novel glycophospholipid, phosphatidylglucoside (PtdGlc), in adult mouse brains. Immunohistochemical analysis with DIM21 antibody, a monoclonal anti-PtdGlc antibody, revealed robust PtdGlc staining in the two primary neurogenic regions of the adult rodent brain, the subventricular zone (SVZ) lining the lateral ventricle and the subgranular zone of the dentate gyrus. Intriguingly, the staining pattern of PtdGlc appeared to overlap that of glial fibrillary acidic protein, an adult neural stem cell marker in these regions. Further immunohistochemical analysis revealed that PtdGlc expression on the cell membranes of adult SVZ neural stem cells significantly overlapped with other proposed adult neural stem cell markers. Moreover, PtdGlc(+) cells isolated from adult mouse SVZs by fluorescence activated cell sorting with anti-PtdGlc antibody efficiently generated neurospheres in cell culture. These cells differentiated into neurons, astrocytes, and oligodendrocytes in vitro, directly demonstrating that PtdGlc expressing cells possessed multipotency. Our data suggest that PtdGlc could be a useful adult stem cell marker. PMID- 21306384 TI - Na-K-Cl cotransporter-1 in the mechanism of cell swelling in cultured astrocytes after fluid percussion injury. AB - Brain edema and associated increased intracranial pressure are major consequences of traumatic brain injury (TBI). An important early component of the edema associated with TBI is astrocyte swelling (cytotoxic edema). Mechanisms for such swelling, however, are poorly understood. Ion channels/transporters/exchangers play a major role in cell volume regulation, and a disturbance in one or more of these systems may result in cell swelling. To examine potential mechanisms in TBI mediated brain edema, we employed a fluid percussion model of in vitro barotrauma and examined the role of the ion transporter Na(+)-K(+)-2Cl(-)-cotransporter 1 (NKCC1) in trauma-induced astrocyte swelling as this transporter has been strongly implicated in the mechanism of cell swelling in various neurological conditions. Cultures exposed to trauma (3, 4, 5 atm pressure) caused a significant increase in NKCC1 activity (21%, 42%, 110%, respectively) at 3 h. At 5 atm pressure, trauma significantly increased NKCC1 activity at 1 h and it remained increased for up to 3 h. Trauma also increased the phosphorylation (activation) of NKCC1 at 1 and 3 h. Inhibition of MAPKs and oxidative/nitrosative stress diminished the trauma-induced NKCC1 phosphorylation as well as its activity. Bumetanide, an inhibitor of NKCC1, significantly reduced the trauma induced astrocyte swelling (61%). Silencing NKCC1 with siRNA led to a reduction in trauma-induced NKCC1 activity as well as in cell swelling. These findings demonstrate the critical involvement of NKCC1 in the astrocyte swelling following in vitro trauma, and suggest that blocking NKCC1 activity may represent a useful therapeutic strategy for the cytotoxic brain edema associated with the early phase of TBI. PMID- 21306387 TI - The trifecta of nursing. PMID- 21306385 TI - Potent anti-inflammatory effects of systemically administered curcumin modulate periodontal disease in vivo. AB - BACKGROUND AND OBJECTIVE: Curcumin is a plant-derived dietary spice with various biological activities, including anticarcinogenic and anti-inflammatory effects. Its therapeutic applications have been studied in a variety of conditions, including rheumatoid arthritis, colon cancer and depression, but no studies have evaluated the effects of curcumin on periodontal disease in vivo. MATERIAL AND METHODS: Experimental periodontal disease was induced in rats by placing cotton ligatures around both lower first molars. Curcumin was given to the rats by the intragastric route daily at two dosages (30 and 100 mg/kg) for 15 d. Control animals received ligatures but only the corn oil vehicle by gavage, and no treatment-negative control animals were included. Bone resorption was assessed by micro-computed tomography, and the inflammatory status was evaluated by stereometric analysis. Both RT-qPCR and ELISA were used to determine the expression of interleukin-6, tumor necrosis factor-alpha and prostaglandin E(2) synthase in the gingival tissues. Modulation of p38 MAPK and nuclear factor kappaB activation were assessed by western blotting. RESULTS: Bone resorption was effectively induced in the experimental period, but it was not affected by either dose of curcumin. Curcumin effectively inhibited cytokine gene expression at both the mRNA and the protein level and produced a dose-dependent inhibition of the activation of nuclear factor-kappaB in the gingival tissues. Activation of p38 MAPK was not inhibited by curcumin. Curcumin-treated animals also presented a marked reduction of the inflammatory cell infiltrate and increased collagen content and fibroblastic cell numbers. CONCLUSION: Curcumin did not prevent alveolar bone resorption, but its potent anti-inflammatory effect suggests that it may have a therapeutic potential in periodontal diseases. PMID- 21306391 TI - Family nursing: walking the talk. AB - This article discusses a study exploring the lived experience of family nursing for novice registered nurses. There has been an increased emphasis on including family content in Canadian nursing education curricula. Literature on family nursing is ambiguous about differentiating family nursing at the generalist and specialist level, and acknowledges that there is a blurring of lines between the two. The study utilized a phenomenological approach to examine how nurses with 2 years or less in practice experience family nursing in a variety of settings. Following ethical approval, invitations were sent to all nurses employed in two health authorities, who met the study criteria. Five nurses were interviewed using a semistructured interview. Participants shared how they practice family nursing in the current nursing situation of shortages and constraints. This study adds to our understanding of what happens at a beginning level of family nursing, how nurses understand and experience caring for families in the everyday enactment of their professional role, and barriers and facilitators to including family in nursing care. The findings provide important information for nurse educators in grounding the teaching of family nursing in the real world of nurses. PMID- 21306390 TI - Nurse reports from the frontlines: analysis of a statewide nurse survey. AB - BACKGROUND: Registered nurses on the frontlines of care are increasingly burdened by changes in staffing, increased turnover, demands on their time and the continual need for advanced knowledge and training. We identify employment and environmental characteristics that may ultimately affect the quality of care METHODS: Surveys were mailed to a random sample of all registered nurses licensed and residing in large southeastern US State. Responses from 10, 951 nurses providing direct patient care were compared to national findings. Descriptive statistics were used to examine demographics, the practice environment, nurse outcomes and the quality of care. RESULTS: Nurses in this state are more racially diverse and less educated when compared to nurses nationally. Theses nurses report high levels of burnout and job dissatisfaction, and almost one-quarter intend to leave their jobs within the next year. The majority of nurses report good working relationships with physicians, but perceive problems with workplace management. CONCLUSION: Nurses report inadequate resources and the administrative support necessary to provide quality care. The proportion of nurses with baccalaureate and graduate education qualifications is less than is needed now and certainly insufficient for the future. Policy efforts must address these issues to retain our nurse workforce and improve the quality of patient care. PMID- 21306392 TI - The image of male nurses and nursing leadership mobility. AB - Research consistently reveals that white men maintain an advantage over other status groups such as women in positions of authority pertaining to human capital. This paper examines male underrepresentation in the nursing profession, including difficulties such as discrimination and advantages for them determined by their gender. The literature suggests that men are given fair, if not preferential, treatment in hiring and promotion decisions, are accepted by supervisors and colleagues, and are well integrated into the workplace subculture. PMID- 21306393 TI - Defining and assessing organizational culture. AB - PROBLEM: Using theories from several disciplines, the concept of organizational culture remains controversial. Conflicting definitions, lack of semantic clarity, and debate over the most appropriate methods for assessing organizational culture have led to disagreement over the value and validity of such inquiry. METHODS: This paper reviews development of the concept of organizational culture and methods for assessing organizational culture, focusing on the healthcare environment. FINDINGS: Most work on organizational culture concerns the traditional corporation. Therefore, some adaptation to the central goals and focus of a human services organization are necessary before application to healthcare settings. PMID- 21306394 TI - Evidence-based practice: issues, paradigms, and future pathways. AB - Evidence-based practice (EBP) has become a real buzz word, not only in the discipline of nursing, but in all healthcare professions. EBP has been identified as the foundation of accountable, professional nursing practice and it would seem that few could argue with the apparent benefits; however, debate does exist in the literature about whether EBP can realistically be attained. As such, a critical discourse regarding the future of EBP for nursing needs to occur. One of the key questions to be addressed through this discourse is, "what counts as evidence?" A review of the nursing literature on the concept of EBP will be presented in this paper along with a discussion of several of the issues associated with EBP within the discipline of nursing. I will also present some ideas about the implications of the EBP movement in nursing and examine the future pathways for nursing. PMID- 21306395 TI - Physical assessment: a continuing need for clarification. AB - PROBLEM: Physical assessment skills are a mainstay of the nursing process and are taught to pre-licensure learners. Little research has been conducted on the skills that are actually used in practice compared to those that are taught in pre-licensure education. METHOD: This article provides an integrated literature review regarding physical assessment skills and their practical application. FINDINGS: Physical assessment skills are consistently referred to as part of the first step of the nursing process, but further clarification about which skills are included in the definition is needed. CONCLUSIONS: Further research is needed to clarify if what is taught is actually used and to what extent in clinical practice. PMID- 21306396 TI - Comparable in vivo anti-inflammatory potency at trough using inhaled fluticasone furoate and propionate. PMID- 21306398 TI - Age-dependent antibody response to Plasmodium falciparum merozoite surface protein 2 (MSP-2). AB - Merozoite surface protein 2 (MSP-2), a very immunogenic malaria antigen, is a highly polymorphic 45-53 kDa merozoite surface protein, which is regarded as a promising vaccine candidate. The highly polymorphic nature of MSP-2 suggests that the molecule can be involved in protective immunity against malaria. The antibody responses to MSP-2 antigen are mostly directed against polymorphic and dimorphic regions of the protein. The current study aimed at testing the reactivity of human sera from a malaria-endemic area of Gambia against MSP-2 regions 2, 3 and 4 compared to crude schizont extract in a period of 20 years. The age-dependent immunity was analysed in a manner of cross-sectional study (the data of the first visit) and also a longitudinal study design (analysing the data at four different time points from 1960 to 1980) testing the sera of 178 individuals randomly selected from the Keneba Serum Collection by using MSP-2 recombinant protein. The total IgG responses were measured by ELISA. Kolmogorov-Smirnov was used to check the normal distribution of OD, Hb and parasitaemia, and then Spearman correlation was applied to analyse the data. Most sera recognized, predominantly, the variable regions of the MSP-2, particularly the domain 3. The IgG response against all the antigens increased with age. The IgG responses against domain 3 of MSP-2 were associated with an increase in haemoglobin levels but a decrease in parasitaemia, suggesting that this immune response may be one of the most useful means for further studies on protective immunity against malaria. PMID- 21306399 TI - Heligmosomoides bakeri antigen rescues CD4-positive T cells from glucocorticoid induced apoptosis by Bcl-2 protein expression. AB - Heligmosomoides bakeri infection in mice is associated with a dominant CD4(+) T cell response and with the activity of natural Treg cells with CD4(+) CD25(+) phenotype. The polarization of Th2 T-cell phenotype and the increase in the CD4(+) CD25(+) T cell population are regulated by glucocorticoids that induce apoptosis in CD4(+) CD25(-) T cells and inhibit apoptosis in CD4(+) CD25(+) T cells. However, exposure of mice to H. bakeri antigen induces a high glucocorticoid concentration in serum and a reduction in the number of CD4 positive; CD4(+) CD25(-) and CD4(+) CD25(+) apoptotic T cells in mesenteric lymph node cells. In this study to evaluate the in vitro effect of the anti-apoptotic property of H. bakeri antigen on T cells, apoptosis of these cells was induced by glucocorticoids-dexamethasone (Dex). Excretory-secretory (ES) antigen of the nematode prevented Dex-induced apoptosis in CD4-positive T cells with CD4(+) CD25(-) and CD4(+) CD25(High) phenotype by Bcl-2 protein expression. Contrary to the effect on CD4-positive T cells, survival of CD8(+) T cells was not connected with expression of Bcl-2 protein. This suggest that H. bakeri antigen modulates CD4-positive T cell sensitivity to glucocorticoid-induced apoptosis by induction of Bcl-2 protein. PMID- 21306400 TI - The magnitude of CD4(+) T-cell activation rather than TCR diversity determines the outcome of Leishmania infection in mice. AB - CD4(+) T cells play a critical role in determining the disease outcome in murine cutaneous leishmaniasis, and selective usage of T-cell receptor (TCR) is implied in promoting Leishmania major infection. However, little information is available on TCR usage in Leishmania-specific, IFN-gamma-producing CD4(+) T cells. In this study, we investigated the TCR diversity and activation of CD4(+) T cells in a nonhealing model associated with L. amazonensis (La) infection and a self-healing model associated with L. braziliensis (Lb) infection. While marked expansion in the absolute number of several subsets was observed in Lb-infected mice, the percentages of TCR Vbeta(+) CD4(+) -cell subsets were comparable in draining LN- and lesion-derived T cells in two infection models. We found that multiple TCR Vbeta CD4(+) T cells contributed collectively and comparably to IFN-gamma production and that the overall levels of IFN-gamma production positively correlated with the control of Lb infection. Moreover, pre-infection with Lb parasites provided cross-protection against secondary La infection, owing to an enhanced magnitude of T-cell activation and IFN-gamma production. Collectively, this study suggests that the magnitude of CD4(+) T-cell activation, rather than the TCR diversity, is the major determining factor for the outcome of Leishmania infection. PMID- 21306401 TI - Favourable prognostic value of antibodies anti-HSP20 in patients with cystic echinococcosis: a differential immunoproteomic approach. AB - Seeking biomarkers reflecting disease development in cystic echinococcosis (CE), we used a proteomic approach linked to immunological characterisation for the identification of respective antigens. Two-dimensional gel electrophoresis (2-DE) of sheep hydatid fluid, followed by immunoblot analysis (IB) with sera from patients with distinct phases of disease, enabled us to identify by mass spectrometry heat shock protein 20 (HSP20) as a potential marker of active CE. Using IB, antibodies specific to the 34 kDa band of HSP20 were detected in sera from 61/95 (64%) patients with CE, but not in sera from healthy subjects. IB revealed anti-HSP20 antibodies in a higher percentage of sera from patients with active disease than in sera from patients with inactive disease (81 vs. 24%; P = 10(-4)). These primary results were confirmed in a long-term follow-up study after pharmacological and surgical treatment. Herewith anti-HSP20 antibody levels significantly decreased over the course of treatment in sera from patients with cured disease, relative to sera from patients with progressive disease (P = 0.017). Thus, during CE, a comprehensive strategy of proteomic identification combined with immunological validation represents a promising approach for the identification of biomarkers useful for the prognostic assessment of treatment of CE patients. PMID- 21306402 TI - Comparison of working length determination with radiographs and four electronic apex locators. AB - AIM: To evaluate the accuracy of the Root ZX, Elements-Diagnostic, Precision AL and Raypex 5 electronic apex locators when compared to radiographs for locating the apical constriction. METHODOLOGY: The apical constriction of 693 canals in 245 maxillary and mandibular teeth was located in vivo with four electronic apex locators (EALs) and radiographically. After extraction the actual location of the apical constriction was determined visually and with magnification. A paired samples t-test, X2 test and a repeated measure anova at the 0.05 level of significance were used to determine differences between the groups. RESULTS: For anterior teeth, the Root ZX, Elements, Precision AL, Raypex 5 and radiographs located the apical constriction 89.09%, 83.63%, 85.45%, 81.81% and 32.72% of the time, respectively. For premolar teeth, the Root ZX, Elements, Precision AL, Raypex 5 and radiographs located the apical constriction 75%, 61.60%, 64.28%, 61.60% and 32.14% of the time, respectively. For molar teeth, the Root ZX, Elements, Precision AL, Raypex 5 and radiographs located the apical constriction 69.01%, 50.49%, 65.40%, 43.93% and 14.59% of the time, respectively. There was no statistically significant difference between the four EALs (P = 0.05). CONCLUSION: Measuring the location of the apical constriction using the four apex locators was more accurate than radiographs and would reduce the risk of instrumenting and filling beyond the apical foramen. PMID- 21306403 TI - An ex vivo investigation of the relationship between apical root impedance and canal anatomy. AB - AIM: To investigate a possible relationship between apical root impedance and canal anatomy. METHODOLOGY: Twenty-three roots from human extracted teeth with different apical anatomy (classified by number of apical canal exits) were selected. After impedance measurements, the root canals were stained and the teeth cleared to confirm their division into simple (S - Vertucci type 1; n=12) and complex (C - various Vertucci canal types with multiple exits; n=11) root types. Impedance measurements were taken using a frequency response analyser at seven apico-coronal levels in each root (0.0, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0 mm short of the apical terminus) at 14 frequencies ranging from 1120 to 100,000 Hz. Potential confounding factors were controlled. The impedance characteristics of individual roots were compared with 37 equivalent circuits to select best fit. The association between impedance characteristic (described by the selected equivalent circuit) and canal anatomy (S/C) was investigated using logistic regression with robust standard error to account for multiple data-sets from the same root. RESULTS: Canal anatomy had a significant (P= 0.046) effect on the equivalent circuit model. One circuit (model 10) occurred significantly more commonly in the simple canals. The odds of selecting circuit-model-10 were 2.2 times (odds ratio 2.17, 95% confidence interval 1.01-4.63) higher in canals with simple anatomy compared to those with complex anatomy. CONCLUSION: Canal anatomy had a significant effect on the equivalent circuit describing its impedance characteristics. It is theoretically possible to use impedance spectroscopy to clinically predict and image apical canal complexities. PMID- 21306404 TI - Cytotoxicity of 5 endodontic sealers on L929 cell line and human dental pulp cells. AB - AIM: To investigate the cytotoxicity of five root canal sealers on L929 mouse fibroblasts and primary human dental pulp cells. METHODOLOGY: Cylindrical specimens of AH Plus (Dentsply De Trey GmbH, Konstanz, Germany), RoekoSeal (Coltene Whaledent, Langenau, Germany), EndoREZ (Ultradent Products Inc., South Jordan, UT, USA), Epiphany (Pentron Clinical Technologies, LLCC, Wallingford, CT, USA) and Activ GP (Brasseller Inc., USA, Savannah, GA, USA) were kept at 37 degrees C in a humidified atmosphere of 5% CO(2) for thrice the length of the setting time given by the manufacturer. Extraction of specimens was performed after setting in cell growth medium for 1, 4 and 7 days. Undiluted, 50% and 25% diluted eluates were incubated with cultured cells for 24 and 72 h. Cytotoxicity was assessed using MTS colorimetric bioassay. Kruskal-Wallis test and post hoc Dunn's multiple comparison test were used to compare the sealers and diluted/undiluted eluates in terms of cell viability (% of control). Friedman test and post hoc Dunn's multiple comparison test were performed to compare extraction periods. Wilcoxon test was utilized in comparing 24- and 72-h readings. RESULTS: Undiluted 1-day eluate of Activ GP was significantly more cytotoxic than all other sealers (P < 0.0001). Undiluted 4- and 7-day eluates of Epiphany and Activ GP were significantly more cytotoxic than the other three sealers (P < 0.0001). Diluted eluates of Activ GP and Epiphany were generally less toxic than the undiluted ones. The cytotoxicity of Epiphany significantly increased as the extraction period increased (P < 0.0001). Epiphany became more toxic with time of exposure to cells. No or minimal cytotoxicity was observed with RoekoSeal, AH Plus and EndoREZ. CONCLUSIONS: The sealers exhibited varying degrees of cytotoxicity dependent on their chemical composition. PMID- 21306405 TI - Functional cis-expression of phaCAB genes for poly(3-hydroxybutyrate) production by Escherichia coli. AB - AIMS: To develop a microbial strain producing poly(3-hydroxybutyrate) [P(3HB)], in the absence of antibiotic supplementation (normally required to stabilize a recombinant plasmid), by constructing a recombinant Escherichia coli strain with phaCAB and vgb integrated into the chromosome. METHODS AND RESULTS: The polyhydroxyalkanoate (PHA) synthesis operon (phaCAB) and the bacterial haemoglobin gene (vgb) were integrated downstream of nlpB (novel lipoprotein B) in E. coli K12, via homologous recombination, to form a recombinant strain, termed YH100. VHb encoded by the vgb gene was successfully expressed in YH100, as confirmed by Western blotting. P(3HB) synthesis by the YH100 strain grown in the absence of antibiotic was analysed by transmission electron microscopy. The yield of P(3HB) is 208 mg g(-1) . The thermal stability of P(3HB) produced from YH100 was similar to that of commercial P(3HB). Further, the polydispersity index (PDI) of the P(3HB) polymer derived from YH100 was 1.37, indicating that polymer uniformity was greater than that of commercial P(3HB), which had a PDI of 1.47. CONCLUSIONS: We successfully constructed a recombinant E. coli strain expressing exogenous genes, specifically phaCAB from Cupriavidus necator and vgb from Vitreoscilla stercoraria, integrated into the downstream of chromosomal dapA-nlpB locus. P(3HB) was stably produced by this strain, without any need for antibiotic supplementation to stabilize a recombinant plasmid at least for 48h. SIGNIFICANCE AND IMPACT OF THE STUDY: We report a genetic locus, the downstream of the nlpB locus in E. coli, in which the transcription of the exogenous genes is driven by the dapA-nlpB promoter without the need for the addition of inducer and antibiotic. PMID- 21306406 TI - Review article: the pathogenesis of diverticular disease--current perspectives on motility and neurotransmitters. AB - BACKGROUND: Low-fibre diet, structural abnormalities and ageing are traditional aetiological factors implicated in the development of diverticular disease. More recently, motility disorders are implicated in its causation leading to speculation that neurotransmitters play a role in mediating these disturbances. AIMS: To draw together studies on the role of neurotransmitters in the development of diverticular disease and its symptoms. METHODS: Medline, GoogleScholar and Pubmed were searched for evidence on this subject using the terms neurotransmitters, motility, diverticular disease and pathogenesis. Articles relevant to the subject were cited and linked references were also reviewed. RESULTS: Serotonin, which has been found to be an excitatory colonic neurotransmitter, has been found in early studies to be increased in colonic enterochromaffin cells. Acetylcholine, which is thought to be an excitatory neurotransmitter and cholinergic activity, has also seen to be increased in diverticular disease. These findings may suggest that an increase in excitatory neurotransmitters may result in the hypersegmentation thought to cause pulsion diverticula. Similarly, a decrease in nitric oxide which is inhibitory is found. CONCLUSIONS: There is some evidence that neurotransmitters may play a role in the motility disturbances seen in diverticular disease; however, a clear role is yet to be ascertained. PMID- 21306407 TI - Review article: the design of clinical trials in hepatic encephalopathy--an International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus statement. AB - BACKGROUND: The clinical classification of hepatic encephalopathy is largely subjective, which has led to difficulties in designing trials in this field. AIMS: To review the current classification of hepatic encephalopathy and to develop consensus guidelines on the design and conduct of future clinical trials. METHODS: A round table was convened at the 14th International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) meeting. Key discussion points were the nomenclature of hepatic encephalopathy and the selection of patients, standards of care and end-points for assessing the treatment and secondary prevention of hepatic encephalopathy. RESULTS: It was generally agreed that severity assessment of hepatic encephalopathy in patients with cirrhosis, whether made clinically or more objectively, should be continuous rather than categorical, and a system for assessing the SONIC (Spectrum of Neuro-cognitive Impairment in Cirrhosis) was proposed. Within this system, patients currently classified as having minimal hepatic encephalopathy and Grade I hepatic encephalopathy would be classified as having Covert hepatic encephalopathy, whereas those with apparent clinical abnormalities would continue to be classified as overt hepatic encephalopathy. Some aspects of the terminology require further debate. Consensus was also reached on the patient populations, standards of care and endpoints to assess clinical trial outcomes. However, some compromises had to be made as there is considerable inter- and intravariability in the availability of some of the more objective surrogate performance markers. CONCLUSIONS: The objectives of the round table were met. Robust, defendable guidelines for the conduct of future studies into hepatic encephalopathy have been provided. Outstanding issues are few and will continue to be discussed. PMID- 21306408 TI - Apples to apples: the origin and magnitude of differences in asbestos cancer risk estimates derived using varying protocols. AB - Given that new protocols for assessing asbestos-related cancer risk have recently been published, questions arise concerning how they compare to the "IRIS" protocol currently used by regulators. The newest protocols incorporate findings from 20 additional years of literature. Thus, differences between the IRIS and newer Berman and Crump protocols are examined to evaluate whether these protocols can be reconciled. Risks estimated by applying these protocols to real exposure data from both laboratory and field studies are also compared to assess the relative health protectiveness of each protocol. The reliability of risks estimated using the two protocols are compared by evaluating the degree with which each potentially reproduces the known epidemiology study risks. Results indicate that the IRIS and Berman and Crump protocols can be reconciled; while environment-specific variation within fiber type is apparently due primarily to size effects (not addressed by IRIS), the 10-fold (average) difference between amphibole asbestos risks estimated using each protocol is attributable to an arbitrary selection of the lowest of available mesothelioma potency factors in the IRIS protocol. Thus, the IRIS protocol may substantially underestimate risk when exposure is primarily to amphibole asbestos. Moreover, while the Berman and Crump protocol is more reliable than the IRIS protocol overall (especially for predicting amphibole risk), evidence is presented suggesting a new fiber-size related adjustment to the Berman and Crump protocol may ultimately succeed in reconciling the entire epidemiology database. However, additional data need to be developed before the performance of the adjusted protocol can be fully validated. PMID- 21306409 TI - Elastin staining of 'Clark/dysplastic' nevi with florid fibroplasia associated with pseudomelanomatous features. PMID- 21306410 TI - Cutaneous metastasis of prostatic adenocarcinoma: a cautionary tale. AB - With the exception of skin cancer, prostatic adenocarcinoma represents the most common cancer among men in the United States and the second most common cause of cancer mortality. Mortality is often associated with metastatic disease, which in the case of prostatic adenocarcinoma typically involves bones and only rarely affects the skin. Although clinical history and examination, laboratory tests and routine pathology can suggest the prostate as a source of metastatic disease, immunohistochemistry - specifically, for prostate-specific antigen (PSA) - is often used to help establish the diagnosis. We report a case of cutaneous metastatic prostatic adenocarcinoma presenting in the inguinal region of a 78 year-old man 5 years after his initial diagnosis. The case is unusual in that the clinical appearance mimicked a vascular proliferation and in that the metastatic prostatic adenocarcinoma failed to express PSA. Rather, expression of prostatic acid phosphatase was observed. PMID- 21306411 TI - Apoptosis of neutrophils resulting after emperipolesis in cutaneous Rosai-Dorfman disease: a new ultrastructural finding. PMID- 21306412 TI - Stability of tissue PO2 in the face of altered perfusion: a phenomenon specific to the renal cortex and independent of resting renal oxygen consumption. AB - 1. Oxygen tension (PO(2)) in renal cortical tissue can remain relatively constant when renal blood flow changes in the physiological range, even when changes in renal oxygen delivery (DO(2)) and oxygen consumption (VO(2)) are mismatched. In the current study, we examined whether this also occurs in the renal medulla and skeletal muscle, or if it is an unusual property of the renal cortex. We also examined the potential for dysfunction of the mechanisms underlying this phenomenon to contribute to kidney hypoxia in disease states associated with increased renal VO(2) . 2. In both the kidney and hindlimb of pentobarbitone anaesthetized rabbits, whole organ blood flow was reduced by intra-arterial infusion of angiotensin-II and increased by acetylcholine infusion. In the kidney, this was carried out before and during renal arterial infusion of the mitochondrial uncoupler, 2,4-dinitrophenol (DNP), or its vehicle. 3. Angiotensin II reduced renal (-34%) and hindlimb (-25%) DO(2) , whereas acetylcholine increased renal (+38%) and hindlimb (+66%) DO(2) . However, neither renal nor hindlimb VO(2) were altered. Tissue PO(2) varied with local perfusion in the renal medulla and biceps femoris, but not the renal cortex. DNP increased renal VO(2) (+38%) and reduced cortical tissue PO(2) (-44%), but both still remained stable during subsequent infusion of angiotensin-II and acetylcholine. 4. We conclude that maintenance of tissue PO(2) in the face of mismatched changes in local perfusion and VO(2) is an unusual property of the renal cortex. The underlying mechanisms remain unknown, but our current findings suggest they are not compromised when resting renal VO(2) is increased. PMID- 21306413 TI - Amlodipine ameliorates endothelial dysfunction in mesenteric arteries from spontaneously hypertensive rats. AB - 1. Endothelial dysfunction plays a critical role in the development and progression or pathogenesis of hypertension. Amlodipine, a calcium channel blocker, is an effective antihypertensive agent. We investigated the effects of amlodipine on endothelial dysfunction in mesenteric arteries from spontaneously hypertensive rats (SHR). 2. Eight-week-old SHR were treated with amlodipine (10 mg/kg per day) for 8 weeks. Control SHR and Wistar-Kyoto (WKY) rats were treated with saline. Systolic blood pressure (SBP) was measured by the tail-cuff method. Isometric tension changes of isolated mesenteric arterial rings were recorded continuously by a myograph system. Serum contents of malondialdehyde (MDA) and total nitrate/nitrite (NO(x) ) were determined. Vascular superoxide anion production was analysed with dihydroethidium (DHE) fluorescence. 3. The contractile responses to KCl and phenylephrine were greater in untreated SHR than in WKY. Acetylcholine (ACh)-induced relaxation was significantly impaired in untreated SHR. Amlodipine treatment reduced the contractions and improved relaxation to ACh. In WKY, relaxation to ACh was inhibited by N(G) -nitro-l arginine methyl ester (l-NAME) and not changed by ascorbic acid. In untreated SHR, the response to ACh was unaffected by l-NAME, whereas it was improved by ascorbic acid. Amlodipine restored the inhibitory effect of l-NAME on ACh-induced relaxation, but ascorbic acid no longer exerted its facilitating effect. Amlodipine prevented the rise in SBP and ameliorated abnormalities in serum MDA and NO in untreated SHR. DHE assay showed an increased intravascular superoxide generation in untreated SHR, which was abrogated by amlodipine. 4. Treatment of SHR with amlodipine resulted in amelioration of endothelial dysfunction by anti oxidant activity and improvement in NO availability. PMID- 21306414 TI - The DPP-4 inhibitor linagliptin does not prolong the QT interval at therapeutic and supratherapeutic doses. AB - AIM: To evaluate the potential effects of therapeutic and supratherapeutic doses of linagliptin (BI 1356) on the QT/QT(c) interval in healthy subjects. METHODS: The study was a randomized, double-blind, placebo-controlled, four-period crossover study using single oral doses of linagliptin (5 mg and 100 mg), moxifloxacin (400 mg) and placebo. Electrocardiogram (ECG) profiles using triplicates of 12-lead 10-s ECGs were digitally recorded pre-dose and after drug administration. The mean change from baseline (MCfB) of the individually heart rate corrected QT interval (QT(c) I) between 1 and 4 h postdrug administration was the primary end point. Blood samples to measure plasma concentrations of linagliptin and its main metabolite were also obtained. RESULTS: Forty-four Caucasian subjects (26 male) entered the study and 43 subjects completed the study as planned in the protocol. Linagliptin was not associated with an increase in the baseline-adjusted mean QT(c) I, at any time point. The placebo-corrected MCfB of QT(c) I was -1.1 (90% CI -2.7, 0.5) ms and -2.5 (-4.1, -0.9) ms for linagliptin 5 mg and 100 mg, respectively, thus within the non-inferiority margin of 10 ms according to ICH E14. Linagliptin was well tolerated; the assessment of ECGs and other safety parameters gave no clinically relevant findings at either dose tested. Maximum plasma concentrations after administration of 100-mg linagliptin were ~24-fold higher than those observed previously for chronic treatment with the therapeutic 5-mg dose. Assay sensitivity was confirmed by a placebo-corrected MCfB of QT(c) I with moxifloxacin of 6.9 (90% CI 5.4, 8.5) ms. CONCLUSIONS: Therapeutic and significantly supratherapeutic exposure to linagliptin is not associated with QT interval prolongation. PMID- 21306416 TI - General principles of investigating and managing drug allergy. AB - Adverse reactions to medication are common. Some are predictable side-effects of the drug, others involve individual sensitivity to the drug. Allergic reactions are an important subset of these, but other specific sensitivities are caused by variations in the metabolism or mode of action of the drug. Patients who have experienced adverse reactions to medication will often refer to themselves as being allergic to the drug, regardless of the actual mechanism that caused the reaction. Consequently, anyone taking a history of 'drug allergy' needs to keep an open mind about the mechanism that may have been involved. Fortunately, most idiosyncratic reactions are minor, but some are severe, or even life-threatening. In most situations, there are satisfactory alternatives for the drug in question, but sometimes it is necessary to investigate and get an accurate diagnosis. The over-riding priority is to distinguish anaphylactic, potentially life-threatening reactions from other types of drug reaction, which are generally more protracted, less dangerous and usually managed by simple avoidance. While all doctors need to understand the underlying principles, drug challenges should only be undertaken by clinicians experienced in this area. PMID- 21306415 TI - Population pharmacokinetics of pregabalin in healthy subjects and patients with post-herpetic neuralgia or diabetic peripheral neuropathy. AB - AIM: Pregabalin, a chemical analogue of the mammalian neurotransmitter gamma aminobutyric acid, has been approved in many countries for partial-onset seizures, generalized anxiety disorder and various other pain disorders, including neuropathic pain associated with post-herpetic neuralgia and diabetic peripheral neuropathy and fibromyalgia. The aim of this study was to develop a population pharmacokinetic model and quantify the influence of covariates on the parameters. METHODS: This pregabalin population pharmacokinetic analysis was conducted on data from 14 clinical trials involving healthy subjects, subjects with impaired renal function and patients with post-herpetic neuralgia or diabetic peripheral neuropathy (n= 616). The data analysis was performed using nonlinear mixed effects modelling methodology as implemented by NONMEM. RESULTS: A one-compartment model with first-order absorption and elimination adequately described pregabalin pharmacokinetics. The model indicated that pregabalin apparent clearance (CL/F) was proportional to estimated creatinine clearance (CL(cr) ). The pregabalin systemic exposure in patients with lower renal function who received pregabalin 150 mg twice daily was almost equal to that of patients with normal renal function administered pregabalin 300 mg twice daily. The systemic exposure stratified by lower or normal renal function was similar between patients with post-herpetic neuralgia and diabetic peripheral neuropathy. CONCLUSION: The developed model identified CL(cr) and ideal body weight as clinically influential covariates on CL/F and volume of distribution, respectively. This study indicates that renal function accounts for variability in the apparent clearance of pregabalin which is consistent with what is known about the elimination of this drug. PMID- 21306417 TI - The effect of decontamination procedures on the pharmacodynamics of venlafaxine in overdose. AB - AIMS: To investigate the relationship between decontamination procedures and seizure events caused by venlafaxine overdose and to estimate the time at which 90% of patients would have had their first seizure in the presence and absence of decontamination. METHODS: Data were collected from 319 patients who took an overdose of venlafaxine on 436 occasions. Seizures occurred on 24 of 436 occasions (5%). Patients received one of single dose activated charcoal (SDAC), whole bowel irrigation (WBI), a combination of either (SDAC/WBI) or no decontamination. Logistic regression and time to event analysis were used to investigate the influence of dose and decontamination on the probability of seizures and time to 90% (t(90) ) of seizure, respectively. RESULTS: A linear logistic regression model described the data. Simulation from the model showed that the probability of seizure was 0.05 (0.03-0.08), 0.19 (0.09-0.35) and 0.75 (0.30-0.96) at 1000, 5000 and 10 000 mg, respectively (median and 95% credible interval). At the mean dose of 2100 mg the odds ratios (OR) in the presence of SDAC, WBI and SDAC/WBI were 0.48 (0.25-0.89), 0.71 (0.35-1.22) and 0.25 (0.08 0.62), respectively. A modified Gompertz model described the time to seizure events. Simulations from the Gompertz model showed that the t(90) values for first seizure was 26 h and was not affected by dose or decontamination procedure. CONCLUSION: SDAC/WBI provided greater benefits than the sum of the independent effects of SDAC and WBI. Patients should be observed for at least 24 h for seizures based on the dose and risk of seizure occurring. PMID- 21306418 TI - Adherence to national guidelines for initiation of antiretroviral regimens in HIV patients: a Danish nationwide study. AB - AIM: To determine the adherence to the national guidelines for start of highly active antiretroviral treatment (HAART) in HIV infected patients. METHODS: We used a Danish nationwide cohort of HIV infected patients to calculate the fraction of patients who in the period 1997-2006 started HAART according to the guidelines from The Danish Society of Infectious Diseases. We used Kaplan-Meier tables to estimate time from fulfilling the criteria for start of HAART to initiation of the treatment. Cox regression and logistic regression was used to identify risk factors for delayed initiation of treatment and chance of being included in clinical trials. RESULTS: The study included 3223 patients, 74% of whom initiated HAART in the study period. Ninety-four% fulfilled the criteria for start of HAART, with minor differences over calendar periods. Ninety-four% initiated a recommended regimen or were included in a clinical trial. Intravenous drug use predicted initiation of a non-recommended regimen and delay in start of HAART, while non-Caucasians were less likely to be included in clinical trials. CONCLUSIONS: In a Western world setting, the adherence to national guidelines for start of HAART can be high. We suggest that simplicity of the guidelines, centralization of treatment and involvement of local clinicians in the development of guidelines are of major importance for high adherence to treatment guidelines. PMID- 21306419 TI - Pharmacokinetic-pharmacodynamic relationships of central nervous system effects of scopolamine in healthy subjects. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * The cholinergic system is important for different central nervous system functions, including memory, learning and attention. Scopolamine, a centrally active muscarinic antagonist, has been used to model dementia and to demonstrate the pharmacological effects of cholinergic drugs, but for most effects the concentration-effect relationships are unknown. WHAT THIS STUDY ADDS: * We determined the pharmacokinetic-pharmacodynamic relationships of scopolamine using a multidimensional central nervous system test battery in a large group of healthy volunteers. The results suggested there are various functional cholinergic systems with different pharmacological characteristics, which can be used to study the effects of drugs that directly or indirectly modify cholinergic systems. The design of such studies should take the different concentration-effect relationships into account. AIM(S) Although scopolamine is a frequently used memory impairment model, the relationships between exposure and corresponding central nervous system (CNS) effects are mostly unknown. The aim of our study was to characterize these using pharmacokinetic-pharmacodynamic (PK-PD) modelling. METHODS: In two double-blind, placebo-controlled, four-way crossover studies, 0.5-mg scopolamine was administered i.v. to 90 healthy male subjects. PK and PD/safety measures were monitored pre-dose and up to 8.5 h after administration. PK-PD relationships were modelled using non-linear mixed-effect modelling. RESULTS: Most PD responses following scopolamine administration in 85 subjects differed significantly from placebo. As PD measures lagged behind the plasma PK profile, PK-PD relationships were modelled using an effect compartment and arbitrarily categorized according to their equilibration half-lives (t(1/2) k(eo) ; hysteresis measure). t(1/2) k(eo) for heart rate was 17 min, saccadic eye movements and adaptive tracking 1 1.5 h, body sway, smooth pursuit, visual analogue scales alertness and psychedelic 2.5-3.5 h, pupil size, finger tapping and visual analogue scales feeling high more than 8 h. CONCLUSIONS: Scopolamine affected different CNS functions in a concentration-dependent manner, which based on their distinct PK PD characteristics seemed to reflect multiple distinct functional pathways of the cholinergic system. All PD effects showed considerable albeit variable delays compared with plasma concentrations. The t(1/2) k(eo) of the central effects was longer than of the peripheral effects on heart rate, which at least partly reflects the long CNS retention of scopolamine, but possibly also the triggering of independent secondary mechanisms. PK-PD analysis can optimize scopolamine administration regimens for future research and give insight into the physiology and pharmacology of human cholinergic systems. PMID- 21306420 TI - A theoretical framework of caring in the Chinese context: a grounded theory study. AB - AIM: This paper is a report of a study describing the components of nurse caring in the Chinese cultural context. BACKGROUND: The expressions, dimensions and patterns of caring vary in different cultures. Caring is deeply embedded in the Chinese culture and nurses are told to care for patients as if they were related by blood. However, to put caring in a professional and practical context, it must extend meaning with a deeper philosophical inspiration that is transcendent and described to guide nursing practices. METHODS: A grounded theory research design and the Delphi method were adopted. First, a total of 16 individual non structured interviews were conducted with noted scholars on nursing education, clinical nursing, nursing administration, medical education and the humanities between January 2006 and June 2007. All interviews were audio recorded, transcribed and analysed using constant comparative data analysis. Secondly, 20 experts with the same inclusion criteria were recruited to conduct a two-round Delphi study to enrich and validate the theoretical framework of caring. Experts were asked to score 0 = disagree or 1 = agree for each listed item and its description in a scale. Consensus was considered when 90% or more agreement was reached. Data were collected from May 2007 to February 2009 and calculated for the agreement rates using SPSS version 11.0. RESULTS: Four attributes of caring including attitude of caring, knowledge of caring, ability of caring and perceptions of caring were determined, along with 8 associated subcategories and 22 statements. Among them, caring attitude is central for presenting care in daily practice. Professional knowledge of nursing, the humanities and social science give the basic theoretical guidance for nurses to exhibit caring behaviour. In the education process, perceptions of giving and receiving care are the key factors for cultivating care. CONCLUSIONS: The framework could be interpreted as a list of teaching objectives and could contribute to the further development of an integrated approach for teaching care in nursing curricula. It would also be beneficial for applying and evaluating care in the practice of clinical nursing and nursing education in the Chinese culture. PMID- 21306421 TI - Improving family-staff relationships in assisted living facilities: the views of family. AB - AIMS: This article is a report of a study of the key influences on family-staff collaboration in low level residential aged care (assisted living) facilities in Australia as seen by the family carers of residents. BACKGROUND: Collaboration with the willing family is widely acknowledged to be important in the care of the older person. Previous work in nursing homes has shown that staff-family relationships are often ambiguous. Relatively little is known about the issue of staff-family relationships in assisted living facilities. METHODS: Using qualitative methodology twelve family carers from five assisted living facilities were interviewed and transcripts analysed thematically. Data were collected in 2006/2007. RESULTS: Four factors important to the establishment and maintenance of collaborative staff-family relationships were identified: comfort, communication, consultation and confidence. CONCLUSION: Low level care facilities need to create environments that are conducive to the establishment and maintenance of constructive staff-family relationships. A number of practice considerations for care staff to foster relationship-centred care with the family in these types of facilities are presented. PMID- 21306422 TI - Empathic accuracy of nurses' immediate responses to fibromyalgia patients' expressions of negative emotions: an evaluation using interaction analysis. AB - AIM: This paper is a report of an observation study designed to describe and evaluate nurses' immediate responses to fibromyalgia patients' expressions of negative emotions in first consultations at a pain clinic. BACKGROUND: Providing comfort to patients in emotional distress is an important task for nurses. Empathic accurate perception of patients' emotions is a precondition for empathic accurate responses. METHODS: We analysed 58 videotaped assessment consultations with patients with fibromyalgia performed from April 2005 to June 2007. Implicit and explicit negative emotional expressions were identified with the Verona Coding Definitions of Emotional Sequences. Nurses' responses were coded with the Hierarchical Coding System for Sensitivity of Comforting Strategies, with three levels of response to the person's perspective: (i) denial, (ii) implicit recognition or approval and (iii) explicit recognition of the expressed emotion. RESULTS: We identified 801 expressions of negative emotions, 591 implicit and 210 explicit, on average 14 per consultation. Nurses responded with implicit recognition, mostly using minimal encouragement, to 75% of emotional expressions, with explicit recognition to 13% of expressions while 12% of responses were not within the perspective of the patient. Nurses responded with a higher degree of explicit recognition (Level 3 responses) to patients' explicit negative emotional expressions. CONCLUSION: The effects of empathic accurate response to implicit and explicit expressions of negative emotions should be explored further. The combination of coding systems used appears to be valid and reliable for assessing verbal empathic accuracy by observers in nursing settings. PMID- 21306423 TI - Nurses' and patients' perceptions of caring behaviours: quantitative systematic review of comparative studies. AB - AIM: This paper is a report of a systematic review conducted to test the hypothesis that nurses and patients perceive the concept of caring in nursing differently. BACKGROUND: Caring is viewed as the central focus of nursing. However, despite its fundamental place in clinical practice, researchers and scholars have failed in reaching a common definition. This failure has led to eliciting for nebulous interpretations of the concept often leading to perplexity and opposing views between patients and nurses. DATA SOURCES: Extensive search was conducted using MEDLINE, CINAHL and EMBASE between March and May 2009 with no publishing time limit and the keywords 'care', 'caring', 'nurse', 'nursing', 'behavio(u)rs', 'patient', 'perception', 'quantitative' and 'comparative'. REVIEW METHODS: This quantitative systematic review of comparative studies followed the guidance of the Centre for Reviews and Dissemination. A seven-item 'yes' or 'no' checklist was developed and used for appraising the quality status of the selected literature. Narrative summary technique was used to report outcomes. RESULTS: Evidence of incongruence of perceptions between patients and nurses is mainly supported by the literature. Few studies, however, report aspects of congruence. CONCLUSION: There is considerable evidence of the assertion that there is no congruence of perceptions between patients and nurses as regards to which behaviours are considered caring and intended caring is not always perceived as such by the patient. Further research is needed, however, to generate more knowledge on the relationship between caring behaviours, patient outcomes and health or nursing costs. PMID- 21306424 TI - Online communities of practice as a communication resource for community health nurses working with homeless persons. AB - AIMS: This study explored community health nurses' viewpoints about a Canadian online community of practice to support their practice with homeless or under housed populations. BACKGROUND: Community health nurses who specifically work with homeless and marginally housed populations often report feelings of isolation and stress in managing complex problems in resource constraints. To strengthen intra-professional ties and enhance information access, an online community of practice was designed, implemented and evaluated by and for them. METHODS: Q-methodology was used. Sixty-six statements about the community of practice were collected from an online survey and focus groups, refined and reduced to 44 statements. In 2009, sixteen participants completed the Q-sort activity, rating each statement relative to the others. Scores for each participant were subjected to by-person factor analysis. RESULTS: Respondents fell into two groups -tacit knowledge warriors and tacit knowledge communicators. Warriors strongly believed that the community of practice could combat stigma associated with homelessness and promote awareness of homelessness issues, and valued its potential to validate and improve practice. Communicators would have used the community of practice more with increased discussion, facilitation and prompt responses. Generally, nurses viewed the community of practice as a place to share stories, validate practice and adapt best practices to their work context. CONCLUSIONS: Online communities of practice can be valuable to nurses in specialized fields with limited peer support and access to information resources. Tacit knowledge development is important to nurses working with homeless populations: this needs to be valued in conjunction with scientifically based knowledge. PMID- 21306425 TI - Immunohistochemical analyses of NPAS3 expression in the developing human fetal brain. AB - The NPAS3 gene encodes a transcription factor with disease roles in neurodevelopment, neoplasia and neurobehaviour. We report the first immunohistochemical findings on NPAS3 protein expression in the developing human fetal brain during the three trimesters (10-41 weeks) of gestational development. In the first trimester, NPAS3 expression is largely confined in the nucleus of cells of the ventricular zone. Similarly, strong nuclear expression in the hippocampus is noted as early as the first trimester, but with progressive increases in expression becoming more apparent in the molecular layer and layer III of the maturing neocortex during the second and third trimesters. In the cerebellum, nuclear expression is seen in basket cells and in Bergmann glia, but some cytoplasmic staining present in the internal granule layer of neurons. Findings from this study will assist in understanding the role of NPAS3 in human gestational brain development and consequently the pathological involvement in human diseases. PMID- 21306426 TI - Evidence that Polymyxa species may infect Arabidopsis thaliana. AB - Polymyxa spp. are obligate biotrophs belonging to the plasmodiophorid group, responsible for transmitting a large number of plant viruses to many crop species. Their obligate nature makes them difficult to study. Controlled environment experiments were used to investigate the potential of infection of Arabidopsis thaliana by Polymyxa spp. to provide a more tractable system. Two ecotypes of Arabidopsis, Columbia and Landsberg erecta, were grown in soils known to be infested with Polymyxa. At the end of a 2-month growth period, both ecotypes were found to harbour Polymyxa-like structures or spores. These findings were confirmed by Polymyxa-specific PCR tests and rDNA sequencing, which positively identified the presence of Polymyxa in the roots of both ecotypes of Arabidopsis. Both Polymyxa graminis and Polymyxa betae were identified. This is the first report of infection of Arabidopsis by Polymyxa spp. and shows the possibility of using this system for studies of infection biology and host parasite interactions. PMID- 21306427 TI - Functional genomics of the initial phase of cold adaptation of Pseudomonas putida KT2440. AB - The cold stress response of Pseudomonas putida KT2440 was investigated by genomewide deep cDNA sequencing and gel-free MS-based protein profiling. Transcriptome and proteome profiles were assessed at 30 degrees C and 2 h after a downshift from 30 to 10 degrees C. Pseudomonas putida adapted to lower ambient temperature by the activation of ribosome-associated functional modules that facilitate translational efficiency. The outer membrane profile was reorganized, anabolic pathways and core as well as energy metabolism were repressed and the alginate regulon and sugar catabolism were activated. At the investigated early time point of cold adaptation, the transcriptome was reprogrammed in almost all functional categories, but the protein profile had still not adapted to the change of living conditions in the cold. PMID- 21306428 TI - Characterization of MbrC involved in bacitracin resistance in Streptococcus mutans. AB - Streptococcus mutans, a major etiological agent of dental caries, is resistant to bacitracin. Microarray analysis revealed that mbrA and mbrB, encoding a putative ATP-binding cassette transporter, are prominently induced in the presence of bacitracin. On the basis of the latest report that MbrC, a putative response regulator in a two-component signaling system, binds the promoter region of mbrA and thus regulates its transcription, we cut into the mechanism by generating a mutant MbrC (D(54) N-MbrC) that substituted asparagine for aspartate at position 54, the predicted phosphorylation site. MbrC, but not the mutant D(54) N-MbrC, showed affinity for a DNA probe that contained the hypothetical mbrA promoter sequence. Furthermore, we introduced a point mutation (D(54) N-MbrC) into UA159; this mutant strain exhibited neither mbrA induction nor resistance in the presence of bacitracin. These data suggest that the aspartate residue at position 54 of MbrC is a promising candidate for phosphorylation in a bacitracin-sensing system and indispensable for S. mutans bacitracin resistance. PMID- 21306429 TI - Steroid hormones as bactericidal agents to Helicobacter pylori. AB - Helicobacter pylori is a unique bacterial species that assimilates various steroids as membrane lipid components. Our group has recently found, however, that certain steroids may impair the viability of H. pylori. In this study, we go on to reveal that estradiol, androstenedione, and progesterone (PS) all have the potential to inhibit the growth of H. pylori. Of these three steroid hormones, progesterone demonstrated the most effective anti-H. pylori action. 17alpha hydroxyprogesterone caproate (17alphaPSCE), a synthetic progesterone derivative, had a much stronger anti-H. pylori action than progesterone, whereas 17alpha hydroxyprogesterone, a natural progesterone derivative, completely failed to inhibit the growth of the organism. Progesterone and 17alphaPSCE were both found to kill H. pylori through their bacteriolytic action. Among five bacterial species investigated, H. pylori was the only species susceptible to the bactericidal action of progesterone and 17alphaPSCE. The other four species, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epiderimidis, all resisted this action. Progesterone and free cholesterol (FC) obstructed each other's effects against the H. pylori cell. Taken in sum, these results suggest that progesterone and FC may bind to the identical region on the H. pylori cell surface. We expect these findings to contribute to the development of a novel anti-H. pylori steroidal agent. PMID- 21306430 TI - Identification of Pantoea ananatis gene encoding membrane pyrroloquinoline quinone (PQQ)-dependent glucose dehydrogenase and pqqABCDEF operon essential for PQQ biosynthesis. AB - Pantoea ananatis accumulates gluconate during aerobic growth in the presence of glucose. Computer analysis of the P. ananatis SC17(0) sequenced genome revealed an ORF encoding a homologue (named gcd) of the mGDH (EC 1.1.99.17) apoenzyme from Escherichia coli and a putative pyrroloquinoline quinone (PQQ) biosynthetic operon homologous to pqqABCDEF from Klebsiella pneumoniae. Construction of Deltagcd and Deltapqq mutants of P. ananatis confirmed the proposed functions of these genetic elements. The P. ananatis pqqABCDEF was cloned in vivo and integrated into the chromosomes of P. ananatis and E. coli according to the Dual In/Out strategy. Introduction of a second copy of pqqABCDEF to P. ananatis SC17(0) doubled the accumulation of PQQ. Integration of the operon into E. coli MG1655DeltaptsGDeltamanXY restored the growth of bacteria on glucose. The obtained data show the essential role of pqqABCDEF in PQQ biosynthesis in P. ananatis and E. coli. We propose that the cloned operon could be useful for an efficient phosphoenolpyruvate-independent glucose consumption pathway due to glucose oxidation and construction of E. coli strains with the advantage of phosphoenolpyruvate-derived metabolite production. PMID- 21306431 TI - Relationship between subjective assessment of oral health and medical expenses in community-dwelling elderly persons. AB - OBJECTIVES: The increasing medical expenses of elderly persons in Japan's rapidly ageing society have become a major concern. It is therefore important to elucidate the factors associated with such escalation. Here, we focused on the relationship between subjective self-assessment of oral health, as an index of general health, and medical expenses (excluding dental repair) under the hypothesis that oral health contributes to general medical expenses. Several studies have shown that oral health status is correlated with general health status among elderly persons. We speculated that oral health status might show a relation with medical costs among elderly persons. However, few studies have investigated this relationship to date. MATERIALS AND METHODS: Participants were 259 elderly subjects (range: 65-84 years; 120 men, 139 women) residing independently. Subjective assessment of oral health was evaluated by their responses ('Good', 'Not good' and 'Not at all good') on a survey questionnaire. The correlation between subjective assessment of oral health and medical expenditure was analysed using Spearman's rank method, the Mann-Whitney U-test and the Kruskal-Wallis test. Medical expenses were used as the dependent variable in multinomial logistic regression analysis with background and intraoral factors as independent variables. RESULTS: A slight yet statistically significant correlation was observed between subjective assessment of oral health and outpatient treatment fees. CONCLUSION: The findings revealed that subjective assessment of oral health is significantly and independently related to the medical expenses of community-dwelling elderly persons after adjusting for social background, living environment and physical factors. PMID- 21306432 TI - Potentiation of acute morphine-induced analgesia measured by a thermal test in bone cancer-bearing mice. AB - Agonists of MU-opioid receptors are currently used in the management of cancer pain. However, several data suggest that the analgesic effect of morphine can diminish during the development of experimental tumors. By using a thermal test, we have studied whether the analgesic effect evoked by morphine is altered in mice bearing two painful bone tumors. The analgesic effect evoked by systemic morphine remained unaltered after the intratibial inoculation of B16-F10 melanoma cells and was potentiated after the inoculation of NCTC 2472 osteosarcoma cells. Although the number of spinal MU-opioid receptors measured by western blot studies was not augmented in osteosarcoma-bearing mice, the analgesia evoked by intrathecal (i.t.) morphine was also enhanced. The analgesic response produced by the spinal administration of the Gi/o protein activator mastoparan was amplified, whereas the analgesic response evoked by the i.t. administration of the N-type calcium channel blocker omega-conotoxin remained unaltered. The efficacy of the GIRK channel blocker tertiapin-Q to antagonize the analgesic effect produced by a maximal dose of morphine was also increased in osteosarcoma-bearing mice. Our results seem to indicate that the analgesic effect of morphine on thermal nociception can be enhanced in response to the development of particular bone tumors in mice, being this potentiation probably related to a greater efficacy of the transduction system driven by Gi/o proteins and GIRK channels. PMID- 21306433 TI - Sphincter of Oddi manometry by choledochoscope in patients with duodenobiliary reflux. AB - BACKGROUND AND AIM: Previous research has confirmed that duodenobiliary reflux exists in patients with choledocholithiasis. The objective of this study was to investigate whether the motor activity of the sphincter of Oddi (SO) has an effect on duodenobiliary reflux. METHODS: A total of 51 patients orally ingested 1mL water containing technetium-99m diethylenetriaminepentaacetatic acid, and a 2-h bile collection was obtained from the T tube. Technetium counts in the collected bile were performed using an RM905 radioactivity meter. The patients were divided into two groups: reflux group (duodenobiliary reflux positive) and control group (duodenobiliary reflux negative). Next, 33 cases were randomly selected and double blinded to receive SO manometry by choledochoscope. RESULTS: Of the 51 total cases, 16 bile samples exhibited radioactivity. The average SO basal pressure and contraction pressure values were 7.2+/-3.9mmHg and 53.5+/-24.5mmHg, respectively, in the reflux group, and 14.7+/-11.0mmHg and 117.2+/-65.6mmHg, respectively, in the control group. The choledochus pressure values were 5.1+/-1.6mmHg and 11.5+/-7.4mmHg in the reflux group and the control group, respectively. The differences between the groups were statistically significant; however, the SO contraction frequency, SO contraction duration, and duodenum pressure values were not significantly different between the groups. CONCLUSION: The decreases in the SO basal pressure and SO contraction pressure, and the decrease in choledochus pressure, might play a role in duodenobiliary reflux. PMID- 21306434 TI - Radiosynovectomy in patients with chronic haemophilic synovitis: when is more than one injection necessary? AB - One hundred and fifty-six radiosynovectomies (RSs) were performed in 104 joints of 78 haemophilic patients diagnosed with chronic haemophilic synovitis. Mean patient age was 18 yr. Previous studies on the same group of patients indicated that RS is an effective procedure for treating chronic haemophilic synovitis, which may require the performance of 1-3 injections (RS-1, RS-2, RS-3), with a 6 month interval between them. Those studies also revealed that the parameters showing the greatest improvement after RS were pain and haemarthrosis, followed by the World Federation of Haemophilia (WFH) clinical score and muscle strength and range of motion. Such studies also demonstrated that the improvement achieved further to RS is independent of the patient's age, the type and severity of haemophilia, the previous haematologic treatment regime administered (on demand or prophylactic), the presence or absence of a circulating inhibitor, the patients' previous level or activity (or inactivity), the presence or absence of previous arthropathy (joint degeneration), of the isotope used (yttrium-90 or rhenium-186) and of the appearance or otherwise of RS-derived complications. In this study, we looked into the potential relationship between the type of joint treated and the degree of synovitis present with the need of one or more further RSs, and we found that the knee requires more injections than the elbow or the ankle and that the more severe synovites require a higher number of RS procedures. PMID- 21306435 TI - Cytoplasmic inclusions in leukocytes associated to cryoglobulinemia and IgG-kappa monoclonal gammapathy of undetermined significance. PMID- 21306436 TI - Maintenance of ribosomal protein S19 in plasma by complex formation with prothrombin. AB - We have demonstrated that the cross-linking of ribosomal protein S19 (RP S19) on platelets by activated factor XIII provides chemotactic potency to monocytes/macrophages for a resolution of coagulum. Factor XIII is activated by an active form of prothrombin, thrombin. We here report that RP S19 is present as a complex with prothrombin in the blood stream. Formation of this complex was blocked by a mutation of the glycosaminoglycan-binding basic cluster (Lys(23) Lys(29) ) in RP S19. Prothrombin-RP S19 interaction was enhanced by an absence of Ca(2+) and the plasma RP S19 concentration was significantly low in the patient treated with warfarin, indicating participation of the gamma-carboxyl glutamic acid domain of prothrombin making a salt bridge with the basic cluster. The complex formation likely explains why a protein as small as RP S19 can prevent from a filtering system of renal glomeruli at a steady state. The translocation of RP S19 from prothrombin to platelets during blood coagulation seems to be also advantageous for RP S19 from the perspective of oligomerisation by activated factor XIII, which should have been activated by thrombin. PMID- 21306437 TI - Effects of thermal discomfort in an office on perceived air quality, SBS symptoms, physiological responses, and human performance. AB - The effects of thermal discomfort on health and human performance were investigated in an office, in an attempt to elucidate the physiological mechanisms involved. Twelve subjects (six men and six women) performed neurobehavioral tests and tasks typical of office work while thermally neutral (at 22 degrees C) and while warm (at 30 degrees C). Multiple physiological measurements and subjective assessment were made. The results show that when the subjects felt warm, they assessed the air quality to be worse, reported increased intensity of many sick building syndrome symptoms, expressed more negative mood, and were less willing to exert effort. Task performance decreased when the subjects felt warm. Their heart rate, respiratory ventilation, and end-tidal partial pressure of carbon dioxide increased significantly, and their arterial oxygen saturation decreased. Tear film quality was found to be significantly reduced at the higher temperature when they felt warm. No effects were observed on salivary biomarkers (alpha-amylase and cortisol). The present results imply that the negative effects on health and performance that occur when people feel thermally warm at raised temperatures are caused by physiological mechanisms. PRACTICAL IMPLICATIONS: This study indicates to what extent elevated temperatures and thermal discomfort because of warmth result in negative effects on health and performance and shows that these could be caused by physiological responses to warmth, not by the distraction of subjective discomfort. This implies that they will occur independently of discomfort, i.e. even if subjects have become adaptively habituated to subjective discomfort. The findings make it possible to estimate the negative economic consequences of reducing energy use in buildings in cases where this results in elevated indoor temperatures. They show clearly that thermal discomfort because of raised temperatures should be avoided in workplaces. PMID- 21306438 TI - Predictors of symptomatic lymphocele after radical prostatectomy and bilateral pelvic lymph node dissection. AB - OBJECTIVES: Lymphocele is the most common complication of pelvic lymphadenectomy (PLND). We sought to determine predictors of symptomatic lymphocele after radical prostatectomy (RP) and PLND, and in particular, to determine if the number of drains placed represents an independent predictor. METHODS: Between January 1999 and June 2007, 4173 consecutive patients underwent bilateral PLND at the time of either open or laparoscopic RP. Lymphoceles were identified in patients undergoing imaging as a result of symptoms suspicious for lymphocele, such as fever, abdominal pain or lower extremity swelling. Routine postoperative imaging was not carried out. Cox proportional hazards analysis was carried out using forced variable entry to obtain maximum likelihood estimates of the hazard ratios and 95% confidence intervals using the number of drains placed, number of nodes removed, RP approach and use of prophylactic low-molecular-weight heparin (LMWH) as predictors of symptomatic lymphocele. RESULTS: There were 164 patients (4%) with a symptomatic lymphocele on follow up, with a median time to presentation of 19 days. The primary presenting complaints were fever in 47%, abdominal pain in 40%, lower extremity swelling in 37%, genital swelling in 25%, groin pain in 22%, abdominal swelling in 9%, and back and flank pain in 6% and 5%, respectively. Median lymphocele diameter was 5 cm. Significant predictors of symptomatic lymphocele on multivariate analysis included number of nodes removed and use of LMWH, but not number of drains placed. CONCLUSIONS: Use of prophylactic LMWH and a higher node count are predictive of a higher incidence of symptomatic lymphocele after RP and PLND. PMID- 21306439 TI - Requirement for acetyl-CoA carboxylase in Trypanosoma brucei is dependent upon the growth environment. AB - Trypanosoma brucei, the causative agent of human African trypanosomiasis, possesses two fatty acid synthesis pathways: a major de novo synthesis pathway in the ER and a mitochondrial pathway. The 2-carbon donor for both pathways is malonyl-CoA, which is synthesized from acetyl-CoA by Acetyl-CoA carboxylase (ACC). Here, we show that T. brucei ACC shares the same enzyme architecture and moderate ~ 30% identity with yeast and human ACCs. ACC is cytoplasmic and appears to be distributed throughout the cell in numerous puncta distinct from glycosomes and other organelles. ACC is active in both bloodstream and procyclic forms. Reduction of ACC activity by RNA interference (RNAi) resulted in a stage-specific phenotype. In procyclic forms, ACC RNAi resulted in 50-75% reduction in fatty acid elongation and a 64% reduction in growth in low-lipid media. In bloodstream forms, ACC RNAi resulted in a minor 15% decrease in fatty acid elongation and no growth defect in culture, even in low-lipid media. However, ACC RNAi did attenuate virulence in a mouse model of infection. Thus the requirement for ACC in T. brucei is dependent upon the growth environment in two different life cycle stages. PMID- 21306440 TI - In Salmonella enterica, the sirtuin-dependent protein acylation/deacylation system (SDPADS) maintains energy homeostasis during growth on low concentrations of acetate. AB - Acetyl-coenzyme A synthetase (Acs) activates acetate into acetyl-coenzyme A (Ac CoA) in most cells. In Salmonella enterica, acs expression and Acs activity are controlled. It is unclear why the sirtuin-dependent protein acylation/deacylation system (SDPADS) controls the activity of Acs. Here we show that, during growth on 10 mM acetate, acs(+) induction in a S. enterica strain that cannot acetylate (i.e. inactivate) Acs leads to growth arrest, a condition that correlates with a drop in energy charge (0.17) in the acetylation-deficient strain, relative to the energy charge in the acetylation-proficient strain (0.71). Growth arrest was caused by elevated Acs activity, a conclusion supported by the isolation of a single-amino-acid variant (Acs(G266S)), whose overproduction did not arrest growth. Acs-dependent depletion of ATP, coupled with the rise in AMP levels, prevented the synthesis of ADP needed to replenish the pool of ATP. Consistent with this idea, overproduction of ADP-forming Ac-CoA-synthesizing systems did not affect the growth behaviour of acetylation-deficient or acetylation-proficient strains. The Acs(G266S) variant was >2 orders of magnitude less efficient than the Acs(WT) enzyme, but still supported growth on 10 mM acetate. This work provides the first evidence that SDPADS function helps cells maintain energy homeostasis during growth on acetate. PMID- 21306441 TI - A type III effector protease NleC from enteropathogenic Escherichia coli targets NF-kappaB for degradation. AB - Many bacterial pathogens utilize a type III secretion system (T3SS) to inject virulence effector proteins into host cells during infection. Previously, we found that enteropathogenic Escherichia coli (EPEC) uses the type III effector, NleE, to block the inflammatory response by inhibiting IkappaB degradation and nuclear translocation of the p65 subunit of NF-kappaB. Here we screened further effectors with unknown function for their capacity to prevent p65 nuclear translocation. We observed that ectopic expression of GFP-NleC in HeLa cells led to the degradation of p65. Delivery of NleC by the T3SS of EPEC also induced degradation of p65 in infected cells as well as other NF-kappaB components, c-Rel and p50. Recombinant His(6) -NleC induced p65 and p50 cleavage in HeLa cell lysates and mutation of a consensus zinc metalloprotease motif, HEIIH, abrogated NleC proteolytic activity. NleC inhibited IL-8 production during prolonged EPEC infection of HeLa cells in a protease activity-dependent manner. A double nleE/nleC mutant was further impaired for its ability to inhibit IL-8 secretion than either a single nleE or a single nleC mutant. We conclude that NleC is a type III effector protease that degrades NF-kappaB thereby contributing the arsenal of bacterial effectors that inhibit innate immune activation. PMID- 21306442 TI - FMP30 is required for the maintenance of a normal cardiolipin level and mitochondrial morphology in the absence of mitochondrial phosphatidylethanolamine synthesis. AB - Mitochondria of the yeast Saccharomyces cerevisiae contain enzymes Crd1p and Psd1p, which synthesize cardiolipin (CL) and phosphatidylethanolamine respectively. A previous study indicated that crd1Delta is synthetically lethal with psd1Delta. In this study, to identify novel genes involved in CL metabolism, we searched for genes that genetically interact with Psd1p, and found that deletion of FMP30 encoding a mitochondrial inner membrane protein results in a synthetic growth defect with psd1Delta. Although fmp30Delta cells grew normally and exhibited a slightly decreased CL level, fmp30Deltapsd1Delta cells exhibited a severe growth defect and an about 20-fold reduction in the CL level, as compared with the wild-type control. We found also that deletion of FMP30 caused a defect in mitochondrial morphology. Furthermore, FMP30 genetically interacted with seven mitochondrial morphology genes. These results indicated that Fmp30p is involved in the maintenance of mitochondrial morphology and required for the accumulation of a normal level of CL in the absence of mitochondrial phosphatidylethanolamine synthesis. PMID- 21306443 TI - Secretion, but not overall synthesis, of catecholate siderophores contributes to virulence of extraintestinal pathogenic Escherichia coli. AB - Extraintestinal pathogenic Escherichia coli (ExPEC) use siderophores to sequester iron during infection. Enterobactin and salmochelins are catecholate siderophores produced by some ExPEC strains and other pathogenic enterobacteria. Siderophore export and synthesis mutants of avian ExPEC strain chi7122 were tested in a chicken infection model. In single-strain infections, siderophore-negative (DeltaentDDeltaiuc), DeltaentS and DeltaentSDeltairoC export mutants were attenuated in tissues and blood, whereas the DeltairoC export mutant was only attenuated in blood. Interestingly, the DeltaentD mutant, producing only aerobactin, retained full virulence, and loss of entD in the DeltaentSDeltairoC mutant restored virulence. LC-MS/MS quantification of siderophores in export mutants demonstrated that loss of entS impaired enterobactin and mono glucosylated enterobactin secretion, whereas loss of iroC impaired di- and tri glucosylated enterobactin secretion. Loss of entS and/or iroC resulted in intracellular accumulation and increased secretion of siderophore monomers. Catecholate siderophore export mutants also demonstrated decreased fitness in a co-challenge infection model. By contrast, catecholate siderophore synthesis mutants (DeltaentD and DeltairoB) competed as well as the wild-type strain. Results establish that EntS and IroC mediate specific export of catecholate siderophores and the role of these exporters for ExPEC virulence is contingent on enterobactin synthesis, which is not required when other siderophores like aerobactin are functional. PMID- 21306444 TI - AlgW regulates multiple Pseudomonas syringae virulence strategies. AB - Gram-negative bacterial pathogens have evolved a number of virulence-promoting strategies including the production of extracellular polysaccharides such as alginate and the injection of effector proteins into host cells. The induction of these virulence mechanisms can be associated with concomitant downregulation of the abundance of proteins that trigger the host immune system, such as bacterial flagellin. In Pseudomonas syringae, we observed that bacterial motility and the abundance of flagellin were significantly reduced under conditions that induce the type III secretion system. To identify genes involved in this negative regulation, we conducted a forward genetic screen with P. syringae pv. maculicola ES4326 using motility as a screening phenotype. We identified the periplasmic protease AlgW as a key negative regulator of flagellin abundance that also positively regulates alginate biosynthesis and the type III secretion system. We also demonstrate that AlgW constitutes a major virulence determinant of P. syringae required to dampen plant immune responses. Our findings support the conclusion that P. syringae co-ordinately regulates virulence strategies through AlgW in order to effectively suppress host immunity. PMID- 21306445 TI - Oligonucleotides stimulate genomic alterations of Legionella pneumophila. AB - Genetic variation generates diversity in all kingdoms of life. The corresponding mechanisms can also be harnessed for laboratory studies of fundamental cellular processes. Here we report that oligonucleotides (oligos) generate mutations on the Legionella pneumophila chromosome by a mechanism that requires homologous DNA, but not RecA, RadA or any known phage recombinase. Instead we propose that DNA replication contributes, as oligo-induced mutagenesis required >= 21 nucleotides of homology, was strand-dependent, and was most efficient in exponential phase. Mutagenesis did not require canonical 5' phosphate or 3' hydroxyl groups, but the primosomal protein PriA and DNA Pol I contributed. After electroporation, oligos stimulated excision of 2.1 kb of chromosomal DNA or insertion of 18 bp, and non-homologous flanking sequences were also processed. We exploited this endogenous activity to generate chromosomal deletions and to insert an epitope into a chromosomal coding sequence. Compared with Escherichia coli, L. pneumophila encodes fewer canonical single-stranded exonucleases, and the frequency of mutagenesis increased substantially when either its RecJ and ExoVII nucleases were inactivated or the oligos modified by nuclease-resistant bases. In addition to genetic engineering, oligo-induced mutagenesis may have evolutionary implications as a mechanism to incorporate divergent DNA sequences with only short regions of homology. PMID- 21306446 TI - Heterochromatin formation in bistable chromatin domains controls the epigenetic repression of clonally variant Plasmodium falciparum genes linked to erythrocyte invasion. AB - Clonally variant gene expression is a common survival strategy used by many pathogens, including the malaria parasite Plasmodium falciparum. Among the genes that show variant expression in this parasite are several members of small gene families linked to erythrocyte invasion, including the clag and eba families. The active or repressed state of these genes is clonally transmitted by epigenetic mechanisms. Here we characterized the promoters of clag3.1, clag3.2 and eba-140, and compared nuclease accessibility and post-translational histone modifications between their active and repressed states. Activity of these promoters in an episomal context is similar between parasite subclones characterized by different patterns of expression of the endogenous genes. Variant expression is controlled by the euchromatic or heterochromatic state of bistable chromatin domains. Repression is mediated by H3K9me3-based heterochromatin, whereas the active state is characterized by H3K9ac. These marks are maintained throughout the asexual blood cycle to transmit the epigenetic memory. Furthermore, eba-140 is organized in two distinct chromatin domains, probably separated by a barrier insulator located within its ORF. The 5' chromatin domain controls expression of the gene, whereas the 3' domain shares the chromatin conformation with the upstream region of the neighbouring phista family gene, which also shows variant expression. PMID- 21306447 TI - The Ime2 protein kinase family in fungi: more duties than just meiosis. AB - Ime2 of the budding yeast Saccharomyces cerevisiae belongs to a family of conserved protein kinases displaying sequence similarities to both cyclin dependent kinases and mitogen-activated protein kinases. Ime2 has a pivotal role for meiosis and sporulation. The involvement of this protein kinase in the regulation of various key events in meiosis, such as the initiation of DNA replication, the expression of meiosis-specific genes and the passage through the two consecutive rounds of nuclear divisions has been characterized in detail. More than 20 years after the identification of the IME2 gene, a recent report has provided the first evidence for a function of this gene outside of meiosis, which is the regulation of pseudohyphal growth. In the last few years, Ime2-related protein kinases from various fungal species were studied. Remarkably, these homologues are not generally required for meiosis, but instead have other specific tasks. In filamentous ascomycete species, Ime2 homologues are involved in the inhibition of fruiting body formation in response to environmental signals. In the pathogenic basidiomycetes Ustilago maydis and Cryptococcus neoformans, members of this kinase family apparently have primary roles in regulating mating. Thus, Ime2-related kinases exhibit an amazing variety in controlling sexual developmental programs in fungi. PMID- 21306448 TI - Broad-spectrum antimicrobial peptide resistance by MprF-mediated aminoacylation and flipping of phospholipids. AB - Bacteria are frequently exposed to cationic antimicrobial peptides (CAMPs) from eukaryotic hosts (host defence peptides) or from prokaryotic competitors (bacteriocins). However, many bacteria, among them most of the major human pathogens, achieve CAMP resistance by MprF, a unique enzyme that modifies anionic phospholipids with l-lysine or l-alanine thereby introducing positive charges into the membrane surface and reducing the affinity for CAMPs. The lysyl or alanyl groups are derived from aminoacyl tRNAs and are usually transferred to phosphatidylglycerol (PG). Recent studies with MprF from Staphylococcus aureus demonstrated that production of Lys-PG only leads to CAMP resistance when an additional flippase domain of MprF is present that translocates Lys-PG and exposes it at the outer leaflet of the membrane. Thus, MprF exerts two specific functions that have hardly been found in other bacterial proteins. MprF proteins are crucial virulence factors of many human pathogens, which recommends them as targets for new anti-virulence drugs. Intriguingly, specific point mutations in mprF cause resistance to the CAMP-like antibiotic daptomycin in a yet unclear way that may involve altered Lys-PG synthesis and/or Lys-PG flipping capacities. Thus, a thorough characterization of MprF domains and functions will help to unravel how bacteria maintain and protect their cytoplasmic membranes. PMID- 21306450 TI - Differential effect of prenatal stress on the expression of corticotrophin releasing hormone and its receptors in the hypothalamus and amygdala in male and female rats. AB - The present study examined the effect of prenatal stress in rats from days 13-20 of gestation on anxiogenic behaviour in the elevated plus maze (EPM) together with changes in the gene expression of corticotrophin-releasing hormone (CRH), its receptors, CRHR1 and CRHR2, as well as CRH binding protein (CRH-BP) in the paraventricular nucleus (PVN) and amygdala of their male and female offspring. Both prenatally-stressed (PS) males and females showed heightened anxiety in the EPM. Prenatal stress did not alter the gene expression of CRH or its receptors in the male PVN, although it decreased CRH-BP mRNA, which could augment the activity of free CRH. In the PVN of PS females, there was an increase in the expression of CRH, coupled with a decrease in that of CRHR2 and CRH-BP. These changes are compatible with the greater activation of the hypothalamic pituitary adrenal axis to stress in females. Anxiogenic behaviour of PS rats was associated with a reduction of CRHR2 mRNA and of CRH-BP mRNA in the amygdala of males and an increase in CRH mRNA and decrease in CRHR2 mRNA in females. Two hours after acute stress of exposure to the elevated plus maze in which heightened anxiety was manifested, increases were seen only in the amygdala of females in CRH and CRHR1 signalling, whereas CRHR2 mRNA was reduced in both sexes. The data show that both prenatal stress and acute stress in adulthood have a differential sex-dependent effect on the expression of CRH its receptors and binding protein in the PVN and amygdala of rats. PMID- 21306449 TI - Biphasic control logic of HAMP domain signalling in the Escherichia coli serine chemoreceptor. AB - HAMP domains mediate input-output communication in many bacterial signalling proteins. To explore the dynamic bundle model of HAMP signalling (Zhou et al., Mol. Microbiol. 73: 801, 2009), we characterized the signal outputs of 118 HAMP missense mutants of the serine chemoreceptor, Tsr, by flagellar rotation patterns. Receptors with proline or charged amino acid replacements at critical hydrophobic packing residues in the AS1 and AS2 HAMP helices had locked kinase off outputs, indicating that drastic destabilization of the Tsr-HAMP bundle prevents kinase activation, both in the absence and presence of the sensory adaptation enzymes, CheB and CheR. Attractant-mimic lesions that enhance the structural stability of the HAMP bundle also suppressed kinase activity, demonstrating that Tsr-HAMP has two kinase-off output states at opposite extremes of its stability range. HAMP mutants with locked-on kinase outputs appeared to have intermediate bundle stabilities, implying a biphasic relationship between HAMP stability and kinase activity. Some Tsr-HAMP mutant receptors exhibited reversed output responses to CheB and CheR action that are readily explained by a biphasic control logic. The findings of this study provide strong support for a three-state dynamic bundle model of HAMP signalling in Tsr, and possibly in other bacterial transducers as well. PMID- 21306451 TI - Hollow spheroids in ascites of ovarian clear cell carcinoma: how are they formed and how do they behave? AB - OBJECTIVE: Although the multicellular aggregates (spheroids) in malignant ascites are usually solid throughout, they sometimes have acellular hollow spaces, especially in ascites of ovarian clear cell carcinoma. The purpose of this study is to analyse the origin and behaviour of hollow spheroids. METHODS: Archival cytological and histological specimens of 32 ovarian carcinomas, including 12 clear cell carcinomas, were reviewed. HAC-2, a clear cell carcinoma cell line, was injected into the abdominal cavity of nude mice for direct comparison of ascitic cytology and tumour histology. Spheroids that were collected from nude mice ascites were cultured in vitro to observe their behaviour. RESULTS: Five of six clear cell carcinomas with hollow spheroids showed spherule-like hyaluronan rich stroma in their tumour tissue, whereas those without hollow spheroids did not. After heterotransplantation, both ascites and tumour imprints showed small or large hollow spheroids. Hyaluronan was detected in the former but not in the latter. The abdominal tumours showed compact spherule-like hyaluronan-rich stroma, enlarged oedematous stroma or intermediate stroma. In both size and hyaluronan status, small and large hollow spheroids were approximately comparable to spherule-like hyaluronan-rich stroma and oedematous stroma, respectively. During culture in vitro, hollow spheroids were maintained as hollow spheroids in suspension, and produced daughter hollow spheroids. CONCLUSIONS: The hollow space in the spheroids originates from spherule-like hyaluronan-rich stroma, where water trapping by hyaluronan causes enlargement of the space. The matrix within the hollow space serves as a scaffold that regulates cell polarity and matrix production. PMID- 21306452 TI - The alveolar bone height of the primary and first permanent molars in healthy 6- to 9-year-old Jordanian children. AB - AIM: To establish a threshold cemantoenamel junction (CEJ)-alveolar bone crest (ABC) distance in healthy 6- to 9-year-old Jordanian children and determine the effect of pathological changes, physiological changes, gender, and age on the CEJ ABC distance. DESIGN: Bitewing radiographs were made for 539 6- to 9-year-old children. Plaque index (PI), gingival index (GI), calculus index (CI), DMFS score, and pocket depth were all assessed through clinical examination. CEJ-ABC distance was measured from radiographs at the mesial surface of permanent first molars (PFM), and the mesial and distal surfaces of primary molars. RESULTS: The CEJ-ABC distance ranged from 0.00 to 4.49 mm, the mean for all surfaces was 0.84 +/- 0.44 mm, no gender or age group differences were found. The mesial surface of the PFMs had the smallest mean CEJ-ABC distance. The CEJ-ABC distances were greater in the maxilla than in the mandible. No significant effect of PI, GI or CI on CEJ-ABC distance was found. Caries, faulty restorations, exfoliation, and partial eruption adjacent to measured surfaces had significant effect on the CEJ ABC distance. CONCLUSION: The mean CEJ-ABC distance was <1 mm. Threshold CEJ-ABC distances of 1.0 and 1.5 mm for PFMs and primary molars, respectively, are suggested to be used in 6- to 9-year-old children. PMID- 21306453 TI - Complementary and alternative therapy (CAT) use and highly active antiretroviral therapy (HAART): current evidence in the literature, 2000-2009. AB - AIM AND OBJECTIVE: To determine current evidence about the use of complementary and alternative medicine in the context of highly active antiretroviral therapy. The following objectives included identifying the risks and benefits of using complementary and alternative medicine when living with the human immunodeficiency virus (HIV) and taking such medications. BACKGROUND: In Canada and the USA, HIV/AIDS service organisations recognise that people affected or infected by HIV are increasingly choosing to use complementary and alternative medicine to cope with this disease. These same organisations advocate for increased access to complementary and alternative medicine and more information about the safe use of complementary and alternative medicine to make informed decisions. Based on the increased integral use of complementary and alternative medicine and conventional medicine in Canada and the USA, the literature review was limited to these two countries. DESIGN: Systematic review. METHOD: Available full-text abstracts published in English from 2000-2009 were retrieved by electronic searches of selected databases, including the websites of Health Canada and American National Center for Complementary and Alternate Medicine (NCCAM). Forty studies were examined and were categorised by referring to the NCCAM (2007) four types of complementary and alternative medicine. RESULTS: Insufficient evidence exists to support the use of a particular complementary and alternate therapy to enhance the management of HIV disease. CONCLUSION: Decisions about using complementary and alternative medicine in conjunction with highly active antiretroviral therapy are often poorly informed. Safety risks and potential drug interactions are frequently ignored as people who use highly active antiretroviral therapy prefer to focus on the physical and mental benefits of using selected complementary and alternate therapies to promote their quality of life. RELEVANCE TO CLINICAL PRACTICE: As life expectancy increases, from the use of highly active antiretroviral therapy, it is important for health professionals like nurses to be knowledgeable about the prevention, assessment and treatment of HIV symptoms and treatment side effects. Given the increased trend of using complementary and alternative medicine by the general population, it is also important to understand the appropriate use of complementary and alternative medicine for symptom management in HIV/AIDS care. PMID- 21306454 TI - Community vs. institutional elders' evaluations of and preferences for yoga exercises. AB - AIMS: To evaluate and compare the appropriateness of the Silver Yoga exercise programme for community and institutional elders and to determine their preferences towards yoga exercises. BACKGROUND: Yoga has been used to promote the health of elders. The Silver Yoga was developed to accommodate the physical tolerance and body flexibility of elders and applied to community and institutional elders with positive health promotion benefits. DESIGN: Descriptive design with quantitative programme evaluation and semi-structured interviews. METHOD: A convenience sample of 97 participants (64 community elders; 33 institutional elders) was interviewed individually after six months of Silver Yoga exercises. Participants rated the level of difficulty, acceptability, feasibility and helpfulness of the Silver Yoga programme (four phases: warm-up, hatha yoga, relaxation and guided-imagery meditation) and the abdominal breathing technique, based on a 10-point Cantril ladder scale. Further, participants expressed their preferences of yoga exercises based on four open-ended questions. RESULTS: The programme was fairly acceptable, feasible and helpful for community and institutional elders (means ranged from 8.33-9.70). The warm-up, relaxation, guided-imagery meditation and abdominal breathing are fairly easy to follow and perform (means ranged from 0.20-0.94). However, the postures in hatha yoga phase were relatively challenging but still manageable for the institutional elders (mean = 1.97, SD 2.33). Further, community elders preferred to practise yoga 61 90 minutes everyday in a group of 11-20, while the institutional elders preferred to practise yoga 31-60 minutes three times per week, in a group of <10. CONCLUSIONS: The Silver Yoga exercise programme is acceptable, feasible, helpful and manageable for community and institutional elders. However, different exercise protocols, such as practice intensity and group size, could be applied to different older populations. RELEVANCE TO CLINICAL PRACTICE: The Silver Yoga exercise programme could be applied to both community and institutional elders to promote their health. PMID- 21306455 TI - Selection and efficacy of self-management strategies for dysmenorrhea in young Taiwanese women. AB - AIMS: This study investigates the selection and efficacy of various strategies employed by young Taiwanese women in the self-management of dysmenorrhea. BACKGROUND: Dysmenorrhea is the common gynaecological problem in reproductive aged women. In the past, non-specific treatments such as heat and exercise were found to be less effective. Current therapies for dysmenorrhea include prostaglandin synthetase inhibitors and herbal remedies. DESIGN: Descriptive survey. METHOD: The researcher-designed questionnaire listed common strategies used in Taiwan to self-manage dysmenorrhea. Content validity was applied for the determination of content items in measures. The total reliability of menstrual distress questionnaire was 0.95, menstrual symptoms questionnaire was 0.92 and coping strategies questionnaire was 0.94. The participants were asked to indicate if they used any of the methods over the past 12 months and, if so, if they were effective. Chi-square test comparisons were used to analyse the data collected. RESULTS: Of the 616 individuals who completed the questionnaire, 570 reported experiencing dysmenorrhea at least once in the past year. Of these, 180 reported dysmenorrhea at every period and were categorised as Group I. The remaining 390 women were classified as Group II. Women in Group I used all of the listed strategies more frequently; however, they benefited less from all therapies except paracetamol. The most effective strategies in both groups were found to be paracetamol and Dang-Qui-Shao-Ya-San. CONCLUSIONS: Paracetamol and Dang-Qui-Shao Ya-San are the most effective strategies in relieving dysmenorrhea in young Taiwanese women, while other less effective strategies are used more frequently. RELEVANCE TO CLINICAL PRACTICE: Identification of the most effective therapies for dysmenorrhea among commonly used strategies will help women choose the right therapy for them. As some young, inexperienced women might take two or more medications simultaneously because of ineffectiveness, thus increasing the risk of adverse effects, this study is of critical importance in promoting the safe use of medication for self-management of dysmenorrhea. PMID- 21306456 TI - Birthgiving women's feelings and perceptions of quality of intrapartal care: a nationwide Swedish cross-sectional study. AB - AIM: The aim was to explore the relationships between the feelings of women who give birth and several birth-related care conditions, the womens' socio demographic background, personality and perceptions of the quality of intrapartum care. BACKGROUND: Childbirth is a highly significant emotional event for women and it is an explicit goal that each woman should have a positive childbirth experience. DESIGN: The nationwide study is cross-sectional and was conducted at Swedish maternity units over two months in 2007. METHODS: The study group consisted of 739 women (63% response rate). A dimensionality analysis of six emotion items was performed using structural equation modelling (SEM). Non parametric tests and generalised linear mixed effects model analyses were used to study relationships and to make subgroup comparisons. RESULTS: In the SEM analysis, a positive and a negative feeling factor were identified. Strong associations between the feeling factors and the womens' perceptions of the quality of care were found, particularly in regard to the so-called identity oriented approach of the midwives and other health professionals. In addition, a higher intensity of negative feelings was associated with a personality pattern characterised by extraversion, emotional instability and lower degree of conscientiousness, a lower level of education and having had delivery through Caesarean section. CONCLUSIONS: The positive and negative feelings of women who give birth strongly covary with the women's perception of the quality of their intrapartum care. This pertains in particular to information issues, the midwives showing commitment, empathy and respect, being present during labour and allowing the women to actively participate as much as they want to. RELEVANCE TO CLINICAL PRACTICE: Subgroup differences indicate that midwives should pay increased attention to childbearing women who have primary school education only, a lower emotional stability and/or deliver through Caesarean section. PMID- 21306457 TI - An evaluation of the effectiveness of relaxation therapy for patients receiving joint replacement surgery. AB - AIM AND OBJECTIVE: To examine the effect of relaxation therapy on reducing patient anxiety and pain before and after total joint replacement. BACKGROUND: Despite the use of analgesics, patients may feel anxiety and pain before and after surgery, delaying their recovery. DESIGN: An experimental control group pretest-post-test quasi-experimental design was employed. METHOD: Subjects (n = 93) recruited from a medical centre in Taipei, Taiwan, from November 2006-March 2007 were randomly assigned to experimental (n = 45) and control (n = 48) groups. Subjects in the experimental group received relaxation therapy from the day before surgery to the third postoperative day. Researchers helped participants listen to a breath relaxation and guided imagery tape for 20 minutes daily. A pain and anxiety scale questionnaire, the State-Trait Anxiety Inventory questionnaire, blood pressure and heart rate were monitored before and after intervention. RESULTS: The average age of the 93 patients was 71.0 (SD 11.1) years. The least pain severity scores in the experimental were lower than those in the control group (p < 0.05) but both experienced the same level of worst or average pain (p > 0.05). The mean difference in the pain score before and after intervention in the experimental group on the pre-op day (t = 2.675, p = 0.009) and post-op day one (t = 3.059, p = 0.003) was greater than that in the control group (0.48 SD 0.94 vs. 0.10 SD 0.30 and 0.93 SD 1.46 vs. 0.20 SD 0.71, respectively). The two groups differed significantly in systolic blood pressure (F = 6.750, p < 0.05) but not in mean blood pressure, heart rate, or State-Trait Anxiety Inventory scores (p > 0.05). Patients reported that relaxation therapy helped them relax and promoted sleep. CONCLUSION: Relaxation therapy could complement analgesics to help postoperative patients better manage pain and anxiety. RELEVANCE TO CLINICAL PRACTICE: Clinical practice should include complementary relaxation therapy to alleviate pain and anxiety in patients with joint replacement. PMID- 21306458 TI - Iranian version of Form B of the Multidimensional Health Locus of Control Scales among the youth. AB - AIMS: The purpose of this study was to translate the Form B of Multidimensional Health Locus of Control Scales into Persian and then to measure its psychometric characteristics among the Iranian youth. BACKGROUND: The Health Locus of Control is regarded as an effective variable in developing health behaviours, clinical capacities and in determining health problems. Many studies have been conducted on Form B in the world, which have led to valuable results in health behaviours, health outcomes and health cares. DESIGN: Questionnaire survey. METHODS: Undergraduate students (n=448) participated in this study. The reliability of the scale was calculated through three methods of estimating reliability, namely, test-retest, parallel forms and Cronbach's alpha. To calculate the validity of the scale, we used content, concurrent, construct and predictive methods. RESULTS: We determined the content validity of the scale by forward and backward translating each item from English into Persian. The concurrent validity of the questionnaire was estimated as acceptable. To determine the predictive validity, the relationship between Form B and health status was used, an action that showed that health status correlated positively with Internal but negatively with Chance and did not correlate with Powerful others Health Locus of Control. The exploratory factor analysis indicated that the factor structure of the translated scale was quite similar to that of the original one. The internal consistency ranged from 0.69-0.72 and parallel forms reliability indices ranged from 0.70 0.72 for its subscales. CONCLUSION: The results indicated that psychometric characteristics of the Iranian version of Form B were estimated acceptable among the youth. RELEVANCE TO CLINICAL PRACTICE: The findings will assist professional health educators and nurses to develop educational interventions that should be designed to support and strengthen students' abilities so that they could recognise, understand and predict health behaviours. PMID- 21306459 TI - Adaptive divergence for a fitness-related trait among invasive Ambrosia artemisiifolia populations in France. AB - The impact of natural selection on the adaptive divergence of invasive populations can be assessed by testing the null hypothesis that the extent of quantitative genetic differentiation (Q(ST) ) would be similar to that of neutral molecular differentiation (F(ST) ). Using eight microsatellite loci and a common garden approach, we compared Q(ST) and F(ST) among ten populations of an invasive species Ambrosia artemisiifolia (common ragweed) in France. In a common garden study with varying water and nutrient levels, we measured Q(ST) for five traits (height, total biomass, reproductive allocation, above- to belowground biomass ratio, and days to flowering). Although low F(ST) indicated weak genetic structure and strong gene flow among populations, we found significant diversifying selection (Q(ST) > F(ST) ) for reproductive allocation that may be closely related to fitness. It suggests that abiotic conditions may have exerted selection pressure on A. artemisiifolia populations to differentiate adaptively, such that populations at higher altitude or latitude evolved greater reproductive allocation. As previous studies indicate multiple introductions from various source populations of A. artemisiifolia in North America, our results suggest that the admixture of introduced populations may have increased genetic diversity and additive genetic variance, and in turn, promoted the rapid evolution and adaptation of this invasive species. PMID- 21306460 TI - Sleep for all ages: at home or in the laboratory? PMID- 21306461 TI - Sperm competition does not influence sperm hook morphology in selection lines of house mice. AB - Sperm show a remarkable degree of variation in size, shape and complexity. Murine rodents exhibit a sperm head morphology that differs greatly from the ovoid shape that is characteristic of most mammals. These rodents have sperm that bear one or more apical hooks, the function of which is currently surrounded by much controversy. It has been suggested that the hook serves to facilitate the formation of sperm groups, which in some species exhibit relatively faster velocities than single cells and thus, may provide an advantage when ejaculates are competing for fertilisations. In support of this hypothesis, a comparative study reported a positive association between the strength of sperm competition (estimated from testes size) and the curvature of the sperm hook amongst 37 murine species. Here, we assessed whether sperm competition influences sperm hookedness at the intra-specific level. Following 16 generations of selection, we used geometric morphometry (GM) to describe sperm head morphology in selection lines of house mice evolving with (polygamous) and without (monogamous) sperm competition. Although the GM analysis returned two relative warps that described variation in the curvature of the sperm hook, we found no evidence of divergence between the selection lines. Thus, we can conclude that sperm competition does not influence the degree of sperm hookedness in house mice. PMID- 21306462 TI - Quantitative genetic variation for thermal performance curves within and among natural populations of Drosophila serrata. AB - Thermal performance curves (TPCs) provide a powerful framework for studying the evolution of continuous reaction norms and for testing hypotheses of thermal adaptation. Although featured heavily in comparative studies, the framework has been comparatively underutilized for quantitative genetic tests of thermal adaptation. We assayed the distribution of genetic (co)variance for TPC (locomotor activity) within and among three natural populations of Drosophila serrata and performed replicated tests of two hypotheses of thermal adaptation- that 'hotter is better' and that a generalist-specialist trade-off underpins the evolution of thermal sensitivity. We detected significant genetic variance within, and divergence among, populations. The 'hotter is better' hypothesis was not supported as the genetic correlations between optimal temperature (T(opt)) and maximum performance (z(max)) were consistently negative. A pattern of variation consistent with a generalist-specialist trade-off was detected within populations and divergence among populations indicated that performance curves were narrower and had higher optimal temperatures in the warmer, but less variable tropical population. PMID- 21306463 TI - Brood sex ratio variation in a cooperatively breeding bird. AB - In cooperatively breeding species, the fitness consequences of producing sons or daughters depend upon the fitness impacts of positive (repayment hypothesis) and negative (local competition hypothesis) social interactions among relatives. In this study, we examine brood sex allocation in relation to the predictions of both the repayment and the local competition hypotheses in the cooperatively breeding long-tailed tit Aegithalos caudatus. At the population level, we found that annual brood sex ratio was negatively related to the number of male survivors across years, as predicted by the local competition hypothesis. At an individual level, in contrast to predictions of the repayment hypothesis, there was no evidence for facultative control of brood sex ratio. However, immigrant females produced a greater proportion of sons than resident females, a result consistent with both hypotheses. We conclude that female long-tailed tits make adaptive decisions about brood sex allocation. PMID- 21306464 TI - No evidence for general condition-dependence of structural plumage colour in blue tits: an experiment. AB - Condition-dependence is a central but contentious tenet of evolutionary theories on the maintenance of ornamental traits, and this is particularly true for structural plumage colour. By providing diets of different nutritional quality to moulting male and female blue tits, we experimentally manipulated general condition within the natural range, avoiding deprivation or stressful treatments. We measured reflectance of the structural-coloured UV/blue crown, a sexually selected trait in males, and the white cheek, a nonpigmented structural colour, directly after moult and again during the following spring mating season. We employed a variety of colour indices, based on spectral shape and avian visual models but, despite significant variation in condition and coloration, found no evidence for condition-dependence of UV/blue or white plumage colour during either season. These and previously published results suggest that structural colour might be sensitive to stress, rather than reduced body condition, during moult. PMID- 21306465 TI - The expression and impact of antifungal grooming in ants. AB - Parasites can cause extensive damage to animal societies in which many related individuals frequently interact. In response, social animals have evolved diverse individual and collective defences. Here, we measured the expression and efficiency of self-grooming and allo-grooming when workers of the ant Formica selysi were contaminated with spores of the fungal entomopathogen Metarhizium anisopliae. The amount of self-grooming increased in the presence of fungal spores, which shows that the ants are able to detect the risk of infection. In contrast, the amount of allo-grooming did not depend on fungal contamination. Workers groomed all nestmate workers that were re-introduced into their groups. The amount of allo-grooming towards noncontaminated individuals was higher when the group had been previously exposed to the pathogen. Allo-grooming decreased the number of fungal spores on the surface of contaminated workers, but did not prevent infection in the conditions tested (high dose of spores and late allo grooming). The rate of disease transmission to groomers and other nestmates was extremely low. The systematic allo-grooming of all individuals returning to the colony, be they contaminated or not, is probably a simple but robust prophylactic defence preventing the spread of fungal diseases in insect societies. PMID- 21306466 TI - Testicular melanization has evolved in birds with high mtDNA mutation rates. AB - Melanin is mainly found in the integument of animals, but it also appears in several extracutaneous tissues. The presence of melanin in testes has been anecdotally reported in all vertebrate groups, but the causes and functions of this melanin remain unknown. Similar to other extracutaneous melanins, testicular melanin may protect male germ cells from oxidative stress. Given the high respiratory activity of spermatozoa, oxidative stress generated by mitochondrial dysfunction as a consequence of mtDNA mutations directly affects sperm viability. Thus, natural selection may favour testicular melanization in males of species with high historical mutation rates in the mitochondrial genome. Here, we tested this hypothesis using information on occurrence of testicular melanization and mutation accumulation as reflected by cytochrome b mtDNA base pair substitution rates in a large set of 134 species of birds, controlling for the confounding effects of body mass, reproductive activity and phylogeny. We found that testicular melanization has evolved in species with high rates of accumulated mitochondrial mutations and propose that this is an adaptive response related to the protective capacity of melanin against oxidative stress. In support of this hypothesis, testicular melanization was more frequently observed during the breeding season of birds (i.e. when spermatogenesis is likely to occur) than during reproductive inactivity. In contrast to other extracutaneous melanins whose abundance seems to reflect skin and coat colour, we did not find a correlation between the proportion of plumage coloured by melanins and occurrence of testicular melanization. Whereas future experimental studies should test these hypotheses, our study highlights for the first time that melanization patterns in animals may evolve as a response to historical mutation rates. PMID- 21306467 TI - Increased prevalence of IL-17-producing peripheral blood lymphocytes in pre eclampsia. AB - PROBLEM: Systemic inflammation is a dominant component in the pathogenesis of pre eclampsia. Besides the imbalance of Th1 and Th2 cells, alterations of the prevalence of Th17 and regulatory T cells have also been suggested to contribute to inflammation. We aimed to describe the prevalence of these four CD4 lymphocyte subtypes in pre-eclampsia and normal pregnancy, along with that of IL-17 producing CD8 and NK cells. METHOD OF STUDY: Twenty pre-eclamptic and 22 normal pregnant women were enrolled in this study. Using flow cytometry, we determined the prevalence of IL-17-producing cells among the CD4, CD8 and NK cell subsets. Furthermore, we measured the prevalence of CD4+ Tregs, and Th1/Th2 cells were characterized using cell surface chemokine receptor markers. RESULTS: We demonstrated that there is a shift not only in the Th1/Th2 but also in the Th17/Treg balance favouring skewness towards a pro-inflammatory status in pre eclampsia. The proportion of CD8 and NK cells that express IL-17 was also higher in pre-eclampsia. CONCLUSION: The prevalence of IL-17-producing CD4, CD8 and NK cells is elevated in pre-eclampsia, indicating that both the innate and adaptive arms of the immune system are involved in the development of the exaggerated maternal systemic inflammation observed in this pregnancy-specific disorder. PMID- 21306468 TI - Immunomarker studies of fine-needle cytopuncture cell blocks for tumor response prediction after preoperative chemotherapy and prognosis in operable nonmetastatic primary breast carcinoma. AB - Neo-adjuvant chemotherapy of breast cancer provides an opportunity to evaluate predictive factors at initial tumor biopsy. We evaluated these factors on cell blocks obtained by diagnostic fine-needle cytopuncture (FNC), with respect to tumor regression and outcome. A prospective study (1996-2003, median follow-up 82 months) involved 163 patients with breast carcinoma (T2 >= 3 cm, T3, T4 noninflammatory) diagnosed by means of FNC. Malignancy, cytologic grade, and the presence of lymphocytes were determined on cytologic smears. Ki67, estrogen receptor (ER), progesterone receptor (PgR), HER2, and p53 expression was assessed on cell blocks by means of immunohistochemistry. All the patients received anthracycline-based chemotherapy. A combined clinical and pathologic tumor regression score was calculated. Twelve cases (7.5%) showed a complete regression, 72 cases (44%) a partial regression and 79 cases (48.5%) no regression. Factors predictive of regression were high grade, presence of lymphocytes, pN0, high Ki67 expression, hormone receptor negativity, and the "triple negative" phenotype. In univariate analysis 5-year metastasis-free survival rate (MFS) correlated with cytologic grade, pN, ER, and p53 status, while overall survival (OS) correlated with cytologic grade, type of surgery, pN, and ER status. In multivariate analysis, MFS was significantly influenced by the regression score, Ki67, age, ER status, pN, HER2, and initial tumor size. Except for age, the same parameters correlated with OS. FNC with the cell block technique is a rapid, minimally invasive, reliable, and inexpensive method for analyzing predictive biomarkers, and may thus be useful in the management of breast cancer patients requiring neo-adjuvant chemotherapy. PMID- 21306469 TI - Breast conserving therapy with accelerated partial breast versus external beam whole breast irradiation: comparison of imaging sequela and complications in a matched population. AB - Our purpose was to evaluate and compare the imaging sequela and complications of accelerated partial breast irradiation (APBI) with those occurring in patients treated with standard external beam therapy. Patient selection included those who met the criteria for possible ABPI: age 45 or older; cancer stage T1N0M0 or ductal carcinoma in situ 3 cm or less, and negative surgical margins. One hundred and ninety seven had complete records and films available for review. Ninety seven (49%) were treated with APBI (MammoSite) and 100(51%) were treated with external beam. Image findings for APBI versus external beam were: distortion 90(93%) versus 83(83%), seroma 67(69%) versus 7(7%), skin edema 52(54%) versus 47(47%), increased stroma 75(77%) versus 66(66%), calcifications 10(10%) versus 6(6%), and fat necrosis 12(12%) versus 6(6%). For APBI, skin and stromal edema was more commonly focal. At imaging, the seroma rate was statistically and significantly different between the two treatment modes (p < 0.0001). For patients treated with APBI, seroma formation was not related to balloon size and only weakly related to lumpectomy cavity size. The complication rate was significantly higher for those treated with APBI (36 versus 20%) and the types and treatment of complications differed. There were three recurrences among the APBI group and none among those treated with external beam radiation. PMID- 21306470 TI - Sonobreast: predicting individualized probabilities of malignancy in solid breast masses with echographic expression. AB - To create an individualized predictive tool for the risk of malignancy in solid breast masses, based on echographic and clinical characteristics. Research Ethics Committee approval and informed consent were obtained. This multi-center study included 1,403 solid breast masses prospectively. Each ultrasound feature was analyzed and compared with the definitive diagnosis. The ultrasound results, women's ages and family histories of breast cancer were included in a multivariate logistic regression model. Among the 1,403 lesions included in the study, 1,390 (99.1%) had a conclusive diagnosis: 343 malignant tumors (24.7%), and 1,047 benign masses (75.3%). The odds ratio (and confidence interval) for breast malignancy for each variable included in the model, as calculated by multivariate analysis, were as follows: irregular shape/noncircumscribed margins, 16.02 (7.75-33.09); heterogeneous echo texture, 4.50 (2.42-8.23); vertical orientation (not parallel to the skin), 2.23 (1.04-4.75); anterior echogenic rim, 2.62 (1.09-6.31); posterior shadowing, 2.38 (1.23-4.62); age more than 40 years, 2.19 (1.26-3.81); positive first-degree family history (mother, sister or daughter), 7.50 (2.65-21.18). There was no advantage in including the presence of internal vascularity, presence of thickened Cooper's ligaments or size of the mass, in the model. The predictive tool was named SONOBREAST and it is freely available for medical purposes on the internet site: http://www.sonobreast.com. The probability of malignancy in breast masses can be specified based on their ultrasound features, the woman's age and the family history of breast cancer. PMID- 21306471 TI - Breast hormonal receptors test should be repeated on excisional biopsy after negative core needle biopsy. AB - Therapeutic decision-making for women diagnosed with breast cancer requires accurate determination of the estrogen receptor (ER) and progesterone receptor (PR). Decisions about adjuvant therapy are often based on the immunohistochemical (IHC) profile of the core needle biopsy sample (CNB) because the staining is not repeated on the final excisional biopsy (EB). The purpose of this study was to assess the concordance of breast cancer IHC receptor assays on CNB and EB. We identified 176 patients with matching breast CNB and EB that had available ER and PR. While the CNBs were processed and stained in different laboratories, the EB were processed and stained in our institution. The following antibodies were used 1D5, 6F11 and SP1 for ER, and PgR636, 16 and 1E2 for PR, from Dako, Leica and Ventana respectively. Correlation of scores of CNBs with matching EB was analyzed using Spearman correlation coefficients. Sensitivity, specificity, overall agreement and the kappa statistic were used to measure the concordance between CNB and EB. For CNB, there were 141 (80.1%) cases positive for ER and 118 (67%) cases positive for PR. For EB, there were 143 (81.3%) cases positive for ER and 130 (73.9%) cases positive for PR. Overall agreement for ER and PR was seen in 93% (95% CI = 0.88, 0.96) and 90% (95% CI = 0.84, 0.94) respectively. Overall, ER CNB/ER+ EB was seen in seven (4%) cases and PR- CNB/PR+ EB in 15 (8.5%) cases. ER+ CNB/ER- EB was seen in five (2.8%) cases and PR+ CNB/PR- EB in three (1.7%) cases. To avoid erroneous omission of life-saving endocrine therapy ER and PR should be repeated on the EB for patients whose CNB has negative hormonal receptors. PMID- 21306472 TI - Critical incidents and mortality reporting in pediatric anesthesia: the Australian experience. AB - Since 1960, the collection and analysis of mortality data for anesthesia in Australia has been of significant benefit to practising anesthetists. These figures include pediatric deaths which fortunately have been rare and often inevitable because of severe underlying disease and patient risk factors. The reporting of critical incidents and serious morbidity, on the other hand, has been far less impressive. Only one state in Australia, Victoria, currently has a committee that collects morbidity data and, as this reporting is voluntary, is likely to under-represent the true numbers of critical events. There is no specific pediatric morbidity database in Australia so much of this discussion will be regarding overall anesthesia critical event reporting which includes pediatrics as a subset. PMID- 21306473 TI - The effect of caudal vs intravenous morphine on early extubation and postoperative analgesic requirements for stage 2 and 3 single-ventricle palliation: a double blind randomized trial. AB - BACKGROUND: High-dose single-shot caudal morphine has been postulated to facilitate early extubation and to lower initial analgesic requirements after staged single-ventricle (SV) palliation. METHODS: With Institutional Review Board approval and written informed parental consent, 64 SV children aged 75-1667 days were randomized to pre-incisional caudal morphine-bupivacaine (100 MUg.kg(-1) morphine (concentration 0.1%), mixed with 0.25% bupivacaine with 1 : 200,000 epinephrine, total 1 ml.kg(-1)) and postcardiopulmonary bypass (CPB) intravenous (IV) droperidol (75 MUg.kg(-1)) ('active caudal group') or pre-incisional caudal saline (1 ml.kg(-1)) and post-CPB IV morphine (150 MUg.kg(-1)) with droperidol (75 MUg.kg(-1)) ('active IV group'). Assignment remained concealed from families and the care teams throughout the trial. Early extubation failure rates (primary or reintubation within 24 h), time to first postoperative rescue morphine analgesia, and 12-h postoperative morphine requirements were assessed for extubated patients. RESULTS: Thirty-one (12 stage 2) SV patients received caudal morphine and 32 (15 stage 2) received IV morphine. Extubation failure rates were 6/31 (19%) for caudal and 5/32 (16%) for IV morphine. For successfully extubated patients (n = 54), active caudal treatment significantly delayed the need for postoperative rescue morphine in stage 3 patients (P = 0.02) but not in stage 2 patients (P = 0.189) (Kaplan-Meier survival analysis with LogRank test). The reduction in 12-h postoperative morphine requirements with active caudal treatment did not reach significance (P = 0.085) but morphine requirements were significantly higher for stage 2 compared with stage 3 patients (P < 0.001) (two way anova in n = 50 extubated patients). CONCLUSIONS: High-dose caudal morphine with bupivacaine delayed the need for rescue morphine analgesia in stage 3 patients. All stage 2 patients required early rescue morphine and had significantly higher postoperative 12-h morphine requirements than stage 3 patients. Early extubation is feasible for the majority of stage 2 and 3 SV patients regardless of analgesic regimen. The study was underpowered to assess differences in extubation failure rates. PMID- 21306474 TI - Perioperative management of low birth weight infants for open-heart surgery. AB - Infants of birth weight <=2500 g are termed low birth weight (LBW). These children often have considerable morbidity from prematurity and intra-uterine growth restriction. Additionally, LBW infants have increased risk for cardiac and noncardiac congenital anomalies and may require surgery. Primary rather than palliative surgical repair of cardiac lesions has been preferred in recent years. However, LBW remains a risk factor for increased mortality and morbidity after open-heart surgery (OHS). There is a paucity of information about the anesthetic challenges presented by LBW infants undergoing OHS. This review summarizes the perioperative issues of relevance to anesthesiologists who manage these high-risk patients. Emphasis is placed on management concerns that are unique to LBW infants. Retrospective data from the authors' institution are provided for those aspects of anesthetic care that lack published studies. Successful outcome often requires substantial hospital resources and collaborative multi-disciplinary effort. PMID- 21306475 TI - Factors associated with acute kidney injury or failure in children undergoing cardiopulmonary bypass: a case-controlled study. AB - Acute kidney injury (AKI) is a serious complication that occurs commonly following cardiopulmonary bypass (CPB) in infants and children. Underlying risk factors for AKI remain unclear, given changes in CPB practices during recent years. This retrospective, case-control study examined the relationships between patient, perioperative factors, AKI, and kidney failure in children who underwent CPB. METHODS: Cohorts of children with and without AKI were identified from the cardiac perfusion and nephrology consult databases. Demographic, perioperative, and postoperative outcome data were extracted from the databases and from medical records. Children were stratified into groups based on the Acute Dialysis Quality Initiative's RIFLE definitions for acute kidney risk or injury (AKI-RI) and kidney failure. RESULTS: The study groups included 308 controls (no AKI-RI or failure), 161 with AKI-RI, and 89 with failure. Young age, preoperative need for mechanical ventilation, milrinone, or gentamicin; intraoperative use of milrinone and furosemide; durations of CPB and anesthesia; multiple cross-clamp and transfusion of blood products were significantly associated with AKI or failure. Young age, perioperative use of milrinone, multiple cross-clamps, extracorporeal membrane oxygenation, cardiac failure, neurological complications, sepsis, and failure significantly increased the odds of mortality. CONCLUSION: This study identified multiple perioperative risk factors for AKI-RI, failure, and mortality in children undergoing CPB. In addition to commonly known risk factors, perioperative use of milrinone, particularly in young infants, and furosemide were independently predictive of poor renal outcomes in this sample. Findings suggest a need for the development of protocols aimed at renal protection in specific at risk patients. PMID- 21306476 TI - Prognostic value of dynamic soluble triggering receptor expressed on myeloid cells in bronchoalveolar lavage fluid of patients with ventilator-associated pneumonia. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to investigate the time course, and correlation with prognosis, of BAL fluid concentrations of soluble triggering receptor expressed on myeloid cells (sTREM-1) in patients with ventilator-associated pneumonia (VAP). METHODS: The study included 35 patients with clinically diagnosed VAP, eight of whom were BAL fluid culture-negative and 27 BAL fluid culture-positive (16 survivors, 11 non-survivors). sTREM-1 levels were measured in BAL fluid of these mechanically ventilated patients, at the time of diagnosis, on days 4-5 and on days 7-9. The time course of this biomarker and its prognostic value for outcome in patients with culture-positive VAP were assessed. RESULTS: sTREM-1 concentrations were significantly greater in culture positive VAP patients than in culture-negative VAP patients. sTREM-1 levels decreased significantly with time in surviving patients with culture-positive VAP, but increased significantly with time in non-survivors. In contrast, PaO(2)/fraction of inspired oxygen (FiO(2)) increased significantly with time in survivors and decreased significantly with time in non-survivors. At a cut-off value of -10 pg/mL 7-9 days after initial diagnosis, sTREM levels had a sensitivity of 90% and a specificity of 87.5% for predicting mortality. CONCLUSIONS: sTREM-1 concentrations in BAL fluid are of potential prognostic value in patients with VAP. PMID- 21306477 TI - Vitamin D: stronger lungs as well as stronger bones? PMID- 21306478 TI - ABO blood group alleles and the risk of pancreatic cancer in a Japanese population. AB - Several studies have investigated a possible association between the ABO blood group and the risk of pancreatic cancer (PC), but this association has not been fully evaluated in Asian populations. The present study aimed to assess the impact of genotype-derived ABO blood types, particularly ABO alleles, on the risk of PC in a Japanese population. We conducted a case-control study using 185 PC and 1465 control patients who visited Aichi Cancer Center in Nagoya, Japan. Using rs8176719 as a marker for the O allele, and rs8176746 and rs8176747 for the B allele, all participants' two ABO alleles were inferred. The impact of ABO blood type on PC risk was examined by multivariate analysis, with adjustment for potential confounders to estimate odds ratios (OR) and 95% confidence intervals (CI). An increased risk of PC was observed with the addition of any non-O allele (trend P = 0.012). Compared with subjects with the OO genotype, those with AO and BB genotypes had significantly increased OR of 1.67 (CI, 1.08-2.57) and 3.28 (CI, 1.38-7.80), respectively. Consistent with earlier reports showing a higher risk of PC for individuals with the non-O blood type, the previously reported protective allele (T) for rs505922 was found to be strongly correlated (r(2) = 0.96) with the O allele. In conclusion, this case-control study showed a statistically significant association between ABO blood group and PC risk in a Japanese population. Further studies are necessary to define the mechanisms by which the ABO gene or closely linked genetic variants influence PC risk. PMID- 21306479 TI - Monocarboxylate transporters 1 and 4 are involved in the invasion activity of human lung cancer cells. AB - Cancer cells show constitutive upregulation of glycolysis, and the concentration of lactate thus produced correlates with prognosis. Here, we examined whether lactate concentration and lactate transporter expression are related to migration and invasion activity. We found that the expression of the monocarboxylate transporters MCT1 and MCT4, but not MCT5, in human lung cancer cell lines was significantly correlated with invasiveness. To clarify the effects of MCT1 and MCT4 expression on invasion, we performed migration and invasion assays after transfection with siRNA specific for MCT1 or MCT4. Knockdown of MCT1 or MCT4 did not influence cell migration but reduced invasion; this was also observed for knockdown of the lactate transporter-associated protein basigin. We also demonstrated that both expression and activity of MMP9 and MMP2 were not correlated with invasion activity and not regulated by MCT1, MCT4 and basigin. Furthermore, the addition of lactate did not increase migration and invasion activity, but low concentration of 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS), a general anion channel blocker, as well as other MCT inhibitors quercetin and simvastatin, inhibited cell invasion without influencing migration activity and the cellular expression of MCT1 and MCT4. This is the first report suggesting that lactate transporters are involved in human cancer cell invasiveness. As such, these proteins may be promising targets for the prevention of cancer invasion and metastasis. PMID- 21306480 TI - TGF-beta1 gene polymorphism in renal transplant patients with and without gingival overgrowth. AB - BACKGROUND: The incidence of gingival overgrowth among renal transplant patients treated with cyclosporine A ranges from 13% to 84.6%, and the overgrowth is not only esthetic but also a medical problem. We studied the determination of association between TGF-beta1 (TGFB1) gene polymorphism and gingival overgrowth in kidney transplant patients medicated with cyclosporin A. METHODS: Eighty-four kidney transplant patients with gingival overgrowth and 140 control transplant patients without overgrowth were enrolled into the case control study. TGFB1 polymorphism was determined using the PCR-RFLP assay for +869T > C in codon 10 and +915G > C in codon 25 as well as TaqMan real-time PCR assays for promoter 800G>A and -509C > T SNPs. RESULTS: In kidney transplant patients suffering from gingival overgrowth, mean score of gingival overgrowth was 1.38 +/- 0.60, whereas in control subjects it was 0.0. The patients with gingival overgrowth were characterized by similar distribution of TGFB1 genotypes and allele in comparison to subjects without gingival overgrowth. Among 16 potentially possible haplotypes of TGFB1 gene, only four were observed in the studied sample of kidney transplant patients: G_C_T_G, G_T_C_G, G_C_C_C, and A_C_T_G, with similar frequency in patients with and without gingival overgrowth. CONCLUSION: No association between the TGFB1 gene polymorphism and gingival overgrowth was revealed in kidney transplant patients administered cyclosporine A. PMID- 21306481 TI - Oral complications in the treatment of cancer patients. AB - While treatment for cancer in terms of chemotherapy and radiation therapy have evolved significantly since their inception, both of these cancer treatment modalities, especially if used in combination (e.g., as with head and neck cancers), have a very real potential to result in painful and debilitating adverse effects that clearly decrease quality of life and, potentially, increase mortality due to cancer. Herein, we discuss the prevalence and etiology of three broad categories of oral complications found during the treatment of cancer patients: mucositis, dysgeusia, and infectious disease. Lastly, we present therapeutic options that may be helpful in ameliorating these uncomfortable and, sometimes, life-threatening oral complications. PMID- 21306482 TI - Neural crest-derived multipotent cells in the adult mouse iris stroma. AB - The purpose of this study was to characterize neural crest-derived cells within the adult murine iris. The iris was isolated from P0-Cre/Floxed-EGFP transgenic (TG) mice. The isolated iris cells formed EGFP-positive spheres on non-adhesive culture plates. Immunostaining showed that these EGFP-positive spheres expressed neural crest markers including Sox10 and p75NTR, and these cells showing in vitro sphere-forming ability were originally resided in the iris stroma (IS), in vivo. Real-time RT-PCR showed that the EGFP-positive spheres expressed significantly higher levels of the neural crest markers than EGFP-negative spheres and bone marrow-derived mesenchymal stem cells. Furthermore, the iris stromal sphere had capability to differentiate into various cell lineages including smooth muscle and cartilage. These data indicate that neural crest-derived multipotent cells can be isolated from the murine IS and expanded in sphere culture. PMID- 21306483 TI - Equine major histocompatibility complex class I molecules act as entry receptors that bind to equine herpesvirus-1 glycoprotein D. AB - The endotheliotropism of equine herpesvirus-1 (EHV-1) leads to encephalomyelitis secondary to vasculitis and thrombosis in the infected horse central nervous system (CNS). To identify the host factors involved in EHV-1 infection of CNS endothelial cells, we performed functional cloning using an equine brain microvascular endothelial cell cDNA library. Exogenous expression of equine major histocompatibility complex (MHC) class I heavy chain genes conferred susceptibility to EHV-1 infection in mouse NIH3T3 cells, which are not naturally susceptible to EHV-1 infection. Equine MHC class I molecules bound to EHV-1 glycoprotein D (gD), and both anti-gD antibodies and a soluble form of gD blocked viral entry into NIH3T3 cells stably expressing the equine MHC class I heavy chain gene (3T3-A68 cells). Treatment with an anti-equine MHC class I monoclonal antibody blocked EHV-1 entry into 3T3-A68 cells, equine dermis (E. Derm) cells and equine brain microvascular endothelial cells. In addition, inhibition of cell surface expression of MHC class I molecules in E. Derm cells drastically reduced their susceptibility to EHV-1 infection. These results suggest that equine MHC class I is a functional gD receptor that plays a pivotal role in EHV-1 entry into equine cells. PMID- 21306484 TI - Cross-national analysis of the risk factors of child malnutrition among children made vulnerable by HIV/AIDS in sub-Saharan Africa: evidence from the DHS. AB - OBJECTIVE: To examine the risk factors of malnutrition among children whose mothers are infected with HIV in sub-Saharan Africa (SSA). METHODS: Multilevel logistic regression models applied to Demographic and Health Survey (DHS) data collected during 2003-2008 from 18 countries in SSA, where the DHS included HIV test data for adults of reproductive age. RESULTS: Across countries in SSA, the risk of malnutrition among children whose mothers are infected with HIV is particularly high among children aged one, boys, multiple/twin births, those who were smaller than average at birth, or whose mothers had no education, or in poorest or single parent households. Although these risk factors generally apply to all children from the same communities, the higher risk of child malnutrition among those in the poorest households is amplified among children whose mothers are infected with HIV. Also, while in general children who are breastfed for up to 6 months are significantly less likely to be malnourished than those who were never breastfed; the benefit of breastfeeding is not evident among children whose mothers are infected with HIV. CONCLUSION: Contextual community/country HIV prevalences show interesting patterns: the risk of malnutrition among children whose mothers are infected with HIV is lower in countries with higher HIV prevalence. These findings have important implications for interventions to address malnutrition among children made vulnerable by HIV/AIDS in the SSA region. PMID- 21306485 TI - Demographic characteristics and opportunistic diseases associated with attrition during preparation for antiretroviral therapy in primary health centres in Kibera, Kenya. AB - Using routine data from HIV-positive adult patients eligible for antiretroviral therapy (ART), we report on routinely collected demographic characteristics and opportunistic diseases associated with pre-ART attrition (deaths and loss to follow-up). Among 2471 ART eligible patients, enrolled between January 2005 and November 2008, 446 (18%) were lost to attrition pre-ART. Adjusted risk factors significantly associated with pre-ART attrition included age <35 years (Odds Ratio, OR 1.4, 95% Confidence Interval, CI 1.1-1.8), severe malnutrition (OR 1.5, 95% CI 1.1-2.0), active pulmonary tuberculosis (OR 1.6, 95% CI 1.1-2.4), severe bacterial infections including severe bacterial pneumonia (OR 1.9, 95% CI 1.2 2.8) and prolonged unexplained fever (>1 month), (OR 2.6, 95% CI 1.3-5.2). This study highlights a number of clinical markers associated with pre-ART attrition that could serve as 'pointers' or screening tools to identify patients who merit fast-tracking onto ART and/or closer clinical attention and follow-up. PMID- 21306486 TI - The sugar is sIRVed: sorting Glut4 and its fellow travelers. AB - Translocation of Glut4 to the plasma membrane of fat and skeletal muscle cells is mediated by specialized insulin-responsive vesicles (IRVs), whose protein composition consists primarily of glucose transporter isoform 4 (Glut4), insulin responsive amino peptidase (IRAP), sortilin, lipoprotein receptor-related protein 1 (LRP1) and v-SNAREs. How can these proteins find each other in the cell and form functional vesicles after endocytosis from the plasma membrane? We are proposing a model according to which the IRV component proteins are internalized into sorting endosomes and are delivered to the IRV donor compartment(s), recycling endosomes and/or the trans-Golgi network (TGN), by cellugyrin-positive transport vesicles. The cytoplasmic tails of Glut4, IRAP, LRP1 and sortilin play an important targeting role in this process. Once these proteins arrive in the donor compartment, they interact with each other via their lumenal domains. This facilitates clustering of the IRV proteins into an oligomeric complex, which can then be distributed from the donor membranes to the IRV as a single entity with the help of adaptors, such as Golgi-localized, gamma-adaptin ear-containing, ARF binding (GGA). PMID- 21306487 TI - Translokin (Cep57) interacts with cyclin D1 and prevents its nuclear accumulation in quiescent fibroblasts. AB - Nuclear accumulation of cyclin D1 because of altered trafficking or degradation is thought to contribute directly to neoplastic transformation and growth. Mechanisms of cyclin D1 localization in S phase have been studied in detail, but its control during exit from the cell cycle and quiescence is poorly understood. Here we report that translokin (Tlk), a microtubule-associated protein also termed Cep57, interacts with cyclin D1 and controls its nucleocytoplasmic distribution in quiescent cells. Tlk binds to regions of cyclin D1 also involved in binding to cyclin-dependent kinase 4 (Cdk4), and a fraction of cyclin D1 associates to the juxtanuclear Tlk network in the cell. Downregulation of Tlk levels results in undue nuclear accumulation of cyclin D1 and increased Cdk4 dependent phosphorylation of pRB under quiescence conditions. In turn, overexpression of Tlk prevents proper cyclin D1 accumulation in the nucleus of proliferating cells in an interaction-dependent manner, inhibits Cdk4-dependent phosphorylation of pRB and hinders cell cycle progression to S phase. We propose that the Tlk acts as a key negative regulator in the pathway that drives nuclear import of cyclin D1, thus contributing to prevent pRB inactivation and to maintain cellular quiescence. PMID- 21306488 TI - Prey change behaviour with predation threat, but demographic effects vary with prey density: experiments with grasshoppers and birds. AB - Increasingly, ecologists emphasize that prey frequently change behaviour in the presence of predators and these behavioural changes can reduce prey survival and reproduction as much or more than predation itself. However, the effects of behavioural changes on survival and reproduction may vary with prey density due to intraspecific competition. In field experiments, we varied grasshopper density and threat of avian predation and measured grasshopper behaviour, survival and reproduction. Grasshopper behaviour changed with the threat of predation and these behavioural changes were invariant with grasshopper density. Behavioural changes with the threat of predation decreased per capita reproduction over all grasshopper densities; whereas the behavioural changes increased survival at low grasshopper densities and then decreased survival at high densities. At low grasshopper densities, the total reproductive output of the grasshopper population remained unchanged with predation threat, but declined at higher densities. The effects of behavioural changes with predation threat varied with grasshopper density because of a trade-off between survival and reproduction as intraspecific competition increased with density. Therefore, resource availability may need to be considered when assessing how prey behavioural changes with predation threat affect population and food web dynamics. PMID- 21306556 TI - SIR2 and other genes are abundantly expressed in long-lived natural segregants for replicative aging of the budding yeast Saccharomyces cerevisiae. AB - We investigated the mechanism underlying the natural variation in longevity within natural populations using the model budding yeast, Saccharomyces cerevisiae. We analyzed whole-genome gene expression in four progeny of a natural S. cerevisiae strain that display differential replicative aging. Genes with different expression levels in short- and long-lived strains were classified disproportionately into metabolism, transport, development, transcription or cell cycle, and organelle organization (mitochondrial, chromosomal, and cytoskeletal). With several independent validating experiments, we detected 15 genes with consistent differential expression levels between the long- and the short-lived progeny. Among those 15, SIR2, HSP30, and TIM17 were upregulated in long-lived strains, which is consistent with the known effects of gene silencing, stress response, and mitochondrial function on aging. The link between SIR2 and yeast natural life span variation offers some intriguing ties to the allelic association of the human homolog SIRT1 to visceral obesity and metabolic response to lifestyle intervention. PMID- 21306557 TI - Low oxygen tension positively influences cardiomyocyte progenitor cell function. AB - Previously we observed that cardiomyocyte progenitor cells (hCMPCs) isolated from the human heart differentiate spontaneously into cardiomyocytes and vascular cells when transplanted after myocardial infarction (MI) in the ischemic heart. After MI, deprivation of oxygen is the first major change in the cardiac environment. How cells handle hypoxia is highly cell type dependent. The effect of hypoxia on cardiac stem or progenitor cells remains to be elucidated. Here, we show for the first time that short- and long-term hypoxia have different effects on hCMPCs. Short-term hypoxia increased the migratory and invasive capacities of hCMPCs likely via mesenchymal transformation. Although long-term exposure to low oxygen levels did not induce differentiation of hCMPCs into mature cardiomyocytes or endothelial cells, it did increase their proliferation, stimulated the secretome of the cells which was shifted to a more anti-inflammatory profile and dampened the migration by altering matrix metalloproteinase (MMP) modulators. Interestingly, hypoxia greatly induced the expression of the extracellular matrix modulator thrombospondin-2 (TSP-2). Knockdown of TSP-2 resulted in increased proliferation, migration and MMP activity. In conclusion, short exposure to hypoxia increases migratory and invasive capacities of hCMPCs and prolonged exposure induces proliferation, an angiogenic secretion profile and dampens migration, likely controlled by TSP-2. PMID- 21306558 TI - Insights into the fate of the N-terminal amyloidogenic polypeptide of ApoA-I in cultured target cells. AB - Apolipoprotein A-I (ApoA-I) is an extracellular lipid acceptor, whose role in cholesterol efflux and high-density lipoprotein formation is mediated by ATP binding cassette transporter A1 (ABCA1). Nevertheless, some ApoA-I variants are associated to systemic forms of amyloidosis, characterized by extracellular fibril deposition in peripheral organs. Heart amyloid fibrils were found to be mainly constituted by the 93-residue N-terminal fragment of ApoA-I, named [1 93]ApoA-I. In this paper, rat cardiomyoblasts were used as target cells to analyse binding, internalization and intracellular fate of the fibrillogenic polypeptide in comparison to full-length ApoA-I. We provide evidence that the polypeptide: (i) binds to specific sites on cell membrane (K(d) = 5.90 +/- 0.70 * 10(-7) M), where it partially co-localizes with ABCA1, as also described for ApoA I; (ii) is internalized mostly by chlatrin-mediated endocytosis and lipid rafts, whereas ApoA-I is internalized preferentially by chlatrin-coated pits and macropinocytosis and (iii) is rapidly degraded by proteasome and lysosomes, whereas ApoA-I partially co-localizes with recycling endosomes. Vice versa, amyloid fibrils, obtained by in vitro aggregation of [1-93]ApoA-I, were found to be unable to enter the cells. We propose that internalization and intracellular degradation of [1-93]ApoA-I may divert the polypeptide from amyloid fibril formation and contribute to the slow progression and late onset that characterize this pathology. PMID- 21306559 TI - The use of fluorescence correlation spectroscopy (FCS) as an alternative biomarker detection technique: a preliminary study. AB - Biomarkers are essential part of daily medical practice. Currently, biomarkers are being used both for diagnostic and prognostic purposes. There are many approaches e.g. ELISA by which biomarker levels are detected from patient samples. However, all these approaches are laborious, time consuming and expensive. There is therefore a general need for exploring new technique which can overcome these drawbacks. Here, we present a preliminary study for detection of serum biomarkers by fluorescence correlation spectroscopy (FCS) based diagnostic technique. FCS is a technique basically used for spatial and temporal analysis of molecular interactions of extremely low-concentration biomolecules in solution. FCS is able to measure diffusion time of the fluorescent molecules passing through the open detection volume and it can also measure the average number of fluorescent molecules passing through the detection volume. Because diffusion speed is correlated with shape and molecular mass of the fluorescent molecule, this property makes it possible to study the complex formation between a small fluorescently labelled and a large unlabelled molecule. In this preliminary study, we utilize this FCS property for detection of serum biomarker. Further studies on various pathological serum samples are warranted to explore further aspects of this technique. PMID- 21306561 TI - Re-evaluation of the function of the F420 dehydrogenase in electron transport of Methanosarcina mazei. AB - Methanosarcina mazei is a methanogenic archaeon that is able to thrive on various substrates and therefore contains a variety of redox-active proteins involved in both cytoplasmic and membrane-bound electron transport. The organism possesses a complex branched respiratory chain that has the ability to utilize different electron donors. In this study, two knockout mutants of the membrane-bound F(420) dehydrogenase (DeltafpoF and DeltafpoA-O) were constructed and analyzed. They exhibited severe growth deficiencies with trimethylamine, but not with acetate, as substrates. In cell lysates of the fpo mutants, the F(420):heterodisulfide oxidoreductase activity was strongly reduced, although soluble F(420) hydrogenase was still present. This led to the conclusion that the predominant part of cellular oxidation of the reduced form of F(420) (F(420)H(2)) in Ms. mazei is performed by F(420) dehydrogenase. Enzyme assays of cytoplasmic fractions revealed that ferredoxin (Fd):F(420) oxidoreductase activity was essentially absent in the DeltafpoF mutant. Subsequently, FpoF was produced in Escherichia coli and purified for further characterization. The purified FpoF protein catalyzed the Fd:F(420) oxidoreductase reaction with high specificity (the K(M) for reduced Fd was 0.5 MUM) but with low velocity (V(max) = 225 mU.mg(-1)) and was present in the Ms. mazei cytoplasm in considerable amounts. Consequently, soluble FpoF might participate in electron carrier equilibrium and facilitate survival of the Ms. mazei Deltaech mutant that lacks the membrane-bound Fd oxidizing Ech hydrogenase. PMID- 21306560 TI - Antidepressant-like responses to lithium in genetically diverse mouse strains. AB - A mood stabilizing and antidepressant response to lithium is only found in a subgroup of patients with bipolar disorder and depression. Identifying strains of mice that manifest differential behavioral responses to lithium may assist in the identification of genomic and other biologic factors that play a role in lithium responsiveness. Mouse strains were tested in the forced swim test (FST), tail suspension test (TST) and open-field test after acute and chronic systemic and intracerebroventricular (ICV) lithium treatments. Serum and brain lithium levels were measured. Three (129S6/SvEvTac, C3H/HeNHsd and C57BL/6J) of the eight inbred strains tested, and one (CD-1) of the three outbred strains, showed an antidepressant-like response in the FST following acute systemic administration of lithium. The three responsive inbred strains, as well as the DBA/2J strain, displayed antidepressant-like responses to lithium in the FST after chronic administration of lithium. However, in the TST, acute lithium resulted in an antidepressant-like effect only in C3H/HeNHsd mice. Only C57BL/6J and DBA/2J showed an antidepressant-like response to lithium in the TST after chronic administration. ICV lithium administration resulted in a similar response profile in BALB/cJ (non-responsive) and C57BL/6J (responsive) strains. Serum and brain lithium concentrations showed that behavioral results were not because of differential pharmacokinetics of lithium in individual strains, suggesting that genetic factors likely regulate these behavioral responses to lithium. Our results indicate that antidepressant-like responses to lithium in tests of antidepressant efficacy varies among genetically diverse mouse strains. These results will assist in identifying genomic factors associated with lithium responsiveness and the mechanisms of lithium action. PMID- 21306562 TI - Catalytic mechanism of the primary human prostaglandin F2alpha synthase, aldo keto reductase 1B1--prostaglandin D2 synthase activity in the absence of NADP(H). AB - Aldo-keto reductase 1B1 and 1B3 (AKR1B1 and AKR1B3) are the primary human and mouse prostaglandin F(2alpha) (PGF(2alpha)) synthases, respectively, which catalyze the NADPH-dependent reduction of PGH(2), a common intermediate of various prostanoids, to form PGF(2alpha). In this study, we found that AKR1B1 and AKR1B3, but not AKR1B7 and AKR1C3, also catalyzed the isomerization of PGH(2) to PGD(2) in the absence of NADPH or NADP(+). Both PGD(2) and PGF(2alpha) synthase activities of AKR1B1 and AKR1B3 completely disappeared in the presence of NADP(+) or after heat treatment of these enzymes at 100 degrees C for 5 min. The K(m), V(max), pK and optimum pH values of the PGD(2) synthase activities of AKR1B1 and AKR1B3 were 23 and 18 MUM, 151 and 57 nmol.min(-1).(mg protein)(-1), 7.9 and 7.6, and pH 8.5 for both AKRs, respectively, and those of PGF(2alpha) synthase activity were 29 and 33 MUM, 169 and 240 nmol.min(-1).(mg protein)(-1), 6.2 and 5.4, and pH 5.5 and pH 5.0, respectively, in the presence of 0.5 mm NADPH. Site directed mutagenesis of the catalytic tetrad of AKR1B1, composed of Tyr, Lys, His and Asp, revealed that the triad of Asp43, Lys77 and His110, but not Tyr48, acts as a proton donor in most AKR activities, and is crucial for PGD(2) and PGF(2alpha) synthase activities. These results, together with molecular docking simulation of PGH(2) to the crystallographic structure of AKR1B1, indicate that His110 acts as a base in concert with Asp43 and Lys77 and as an acid to generate PGD(2) and PGF(2alpha) in the absence of NADPH or NADP(+) and in the presence of NADPH, respectively. PMID- 21306563 TI - Specific biomarkers for stochastic division patterns and starvation-induced quiescence under limited glucose levels in fission yeast. AB - Glucose as a source of energy is centrally important to our understanding of life. We investigated the cell division-quiescence behavior of the fission yeast Schizosaccharomyces pombe under a wide range of glucose concentrations (0-111 mM). The mode of S. pombe cell division under a microfluidic perfusion system was surprisingly normal under highly diluted glucose concentrations (5.6 mM, 1/20 of the standard medium, within human blood sugar levels). Division became stochastic, accompanied by a curious division-timing inheritance, in 2.2-4.4 mM glucose. A critical transition from division to quiescence occurred within a narrow range of concentrations (2.2-1.7 mM). Under starvation (1.1 mM) conditions, cells were mostly quiescent and only a small population of cells divided. Under fasting (0 mM) conditions, division was immediately arrested with a short chronological lifespan (16 h). When cells were first glucose starved prior to fasting, they possessed a substantially extended lifespan (~14 days). We employed a quantitative metabolomic approach for S. pombe cell extracts, and identified specific metabolites (e.g. biotin, trehalose, ergothioneine, S adenosyl methionine and CDP-choline), which increased or decreased at different glucose concentrations, whereas nucleotide triphosphates, such as ATP, maintained high concentrations even under starvation. Under starvation, the level of S adenosyl methionine increased sharply, accompanied by an increase in methylated amino acids and nucleotides. Under fasting, cells rapidly lost antioxidant and energy compounds, such as glutathione and ATP, but, in fasting cells after starvation, these and other metabolites ensuring longevity remained abundant. Glucose-starved cells became resistant to 40 mM H(2)O(2) as a result of the accumulation of antioxidant compounds. PMID- 21306564 TI - Intravital monitoring of microcirculatory and angiogenic response to lactocapromer terpolymer matrix in a wound model. AB - The aim of this study was to assess the impact of an epidermal substitute, a lactocapromer terpolymer matrix, on microcirculation in wounds. Lactocapromer terpolymer matrices were placed into the dorsal skinfold chamber of mice (n = 10). Untreated chamber preparations served as controls (n = 10). The microcirculation in tissue adjacent to the implant was observed by intravital fluorescence microscopy. Alongside the stable microhaemodynamics, a strong induction of angiogenesis adjacent to the implants was observed. A progressive increase in the functional vessel density was detected throughout the observation time of 10 days. Additionally, a stable and increasing perfusion within the newly developed vascular network in the outer circumference of the matrix was noted. The lactocapromer terpolymer matrix showed no adverse effect on the microcirculation in the host tissue. In contrast, as detected by intravital microscopy, the biomaterial protected the microcirculation and induced angiogenesis. PMID- 21306565 TI - Hla-B alleles and lamotrigine-induced cutaneous adverse drug reactions in the Han Chinese population. AB - Lamotrigine (LTG) is a commonly used antiepileptic drug. However, the use of LTG is limited because of its cutaneous adverse drug reactions (cADRs) ranging from mild maculopapular eruption (MPE) to severe Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). A strong association between HLA-B*1502 and carbamazepine-induced SJS/TEN has been identified in Chinese and Thai. Although three of seven cases with HLA-B*1502 have been reported in LTG-induced SJS/TEN so far, the relationship between HLA-B*1502 and LTG-induced SJS/TEN needs further investigation. It is also unclear whether there is a specific genetic marker associated with LTG-induced MPE in Chinese. In this study, we genotyped 43 Han Chinese patients treated with LTG (14 cases with LTG-induced cADRs and 29 LTG tolerant controls), using PCR-SSP for HLA-B*1502 testing and low-resolution genotyping, as well as sequencing for four-digit genotyping. The two cases with SJS were negative for HLA-B*1502, with B1301/1301 and 4601/5610, respectively. Combining the data with previous studies, there was no significant difference in the frequency of subjects with HLA-B*1502 between the LTG-induced SJS/TEN group and the LTG-tolerant group (p = 0.08, OR 4.23, 95% CI 0.94-18.97). In the MPE group, only one was positive for HLA-B*1502. There was no significant difference in the frequency of a specific HLA-B allele between the MPE group and the LTG tolerant group either. In this study, no significant association between HLA B*1502 and LTG-induced SJS or MPE was found. Given the small sample size and only HLA-B locus genotyping, further large-scale studies are required to explore genetic associations with LTG-induced cADRs. PMID- 21306567 TI - Synthesis and antiviral evaluation of new N-acylhydrazones containing glycine residue. AB - N-acylhydrazones containing glycine residue 3a-j and 8a-h were synthesized as HIV 1 capsid protein assembly inhibitors. The structures of the novel N-acylhydrazone derivatives were characterized using different spectroscopic methods. Antiviral activity demonstrated that compound 8c bearing 4-methylphenyl moiety was the most active with low cytotoxicity. PMID- 21306568 TI - Baicalein and wogonin are activators of rat TREK-2 two-pore domain K+ channel. AB - AIM: Earlier studies have shown that TREK-1 and TREK-2 (TREKs), members of the two-pore domain K(+) (K(2P)) channel family that are highly expressed under pathological conditions, are activated by neuroprotective agents. Baicalein and wogonin, oriental flavonoids originating from the root of the medicinal herb Scutellaria baicalensis, are known to have beneficial effects for neuroprotection. However, little is known about the effects of baicalein and wogonin on ion channels including TREKs. We investigated whether baicalein and wogonin modulate the TREK-2 channel, which has been less studied than TREK-1. METHODS: Single-channel recordings were performed in COS-7 cells transfected with rat TREK-2 and analyzed baicalein- or wogonin-induced channel activity. RESULTS: We found that baicalein and wogonin activated the TREK-2 current by increasing the opening frequency (channel activity: from 0.05 +/- 0.01 to 0.17 +/- 0.06 in baicalein treatment and from 0.03 +/- 0.01 to 0.29 +/- 0.09 in wogonin treatment, P < 0.05), while leaving the single-channel conductance and mean open time unchanged. Baicalein continuously activated TREK-2, whereas wogonin transiently activated TREK-2. Application of baicalein and wogonin activated TREK-2 in both cell attached and excised patches, suggesting that baicalein and wogonin may modulate TREK-2 either directly or indirectly with different mechanisms. CONCLUSION: These results suggest that baicalein- and wogonin-induced TREK-2 activation help set the resting membrane potential of cells exposed to pathological conditions and thus may give beneficial effects in neuroprotection. PMID- 21306569 TI - The relative efficacy of trivalent live attenuated and inactivated influenza vaccines in children and adults. AB - In the United States, two types of vaccines are recommended for the prevention of influenza: an intranasal live attenuated influenza vaccine (LAIV) for eligible individuals aged 2-49 years and unadjuvanted injectable trivalent inactivated vaccines (TIV) for eligible individuals aged >= 6 months. Several recent studies have compared the efficacy of the 2 vaccines in children and adults. In children 6 months to 18 years of age, each of the four comparative studies of LAIV and TIV demonstrated that LAIV was more protective. In individuals 17-49 years of age, most comparative studies have demonstrated that LAIV and TIV were similarly efficacious or that TIV was more efficacious. However, LAIV was shown to be more protective than TIV in new military recruits of all ages, and placebo-controlled studies in adults in 1997-1998 suggested that LAIV was more protective against the mismatched A/H3N2 strain. The relative efficacy of LAIV and TIV among young adults may vary depending on the specific population and the antigenic match between the vaccines and circulating strains. In adults 60 years of age and older, limited data suggest that the two vaccines are similarly effective. In children and adults, studies also suggest that the relative efficacy of LAIV versus TIV may increase when measured against more severe illness. Additional research comparing LAIV and TIV is needed in adults and would also be valuable in older children and adolescents. Studies should examine the role of pre-existing immunity as well as vaccine impact on influenza illness of varying severity. PMID- 21306570 TI - Mortality attributable to pandemic influenza A (H1N1) 2009 in San Luis Potosi, Mexico. AB - BACKGROUND: Acute respiratory infections are a leading cause of morbidity and mortality worldwide. Starting in 2009, pandemic influenza A(H1N1) 2009 virus has become one of the leading respiratory pathogens worldwide. However, the overall impact of this virus as a cause of mortality has not been clearly defined. OBJECTIVES: To determine the impact of pandemic influenza A(H1N1) 2009 on mortality in a Mexican population. METHODS: We assessed the impact of pandemic influenza virus on mortality during the first and second outbreaks in San Luis Potosi, Mexico, and compared it to mortality associated with seasonal influenza and respiratory syncytial virus (RSV) during the previous winter seasons. RESULTS: We estimated that, on average, 8.1% of all deaths that occurred during the 2003-2009 seasons were attributable to influenza and RSV. During the first pandemic influenza A(H1N1) 2009 outbreak, there was an increase in mortality in persons 5-59 years of age, but not during the second outbreak (Fall of 2009). Overall, pandemic influenza A (H1N1) 2009 outbreaks had similar effects on mortality to those associated with seasonal influenza virus epidemics. CONCLUSIONS: The impact of influenza A(H1N1) 2009 virus on mortality during the first year of the pandemic was similar to that observed for seasonal influenza. The establishment of real-time surveillance systems capable of integrating virological, morbidity, and mortality data may result in the timely identification of outbreaks so as to allow for the institution of appropriate control measures to reduce the impact of emerging pathogens on the population. PMID- 21306571 TI - Canada in the face of the 2009 H1N1 pandemic. AB - BACKGROUND: Initial public health responses to the 2009 influenza H1N1 pandemic were based on difficult decisions in the face of substantial uncertainty. Policy effectiveness depends critically on such decisions, and future planning for maximum protection of community health requires understanding of the impact of public health responses in observed scenarios. OBJECTIVES: In alignment with the objectives of the Pandemic Influenza Outbreak Research Modelling Team (Pan InfORM) and the Centre for Disease Modelling (CDM), a focused workshop was organized to: (i) evaluate Canada's response to the spring and autumn waves of the novel H1N1 pandemic; (ii) learn lessons from public health responses, and identify challenges that await public health planners and decision-makers; and (iii) understand how best to integrate resources to overcome these challenges. MAIN OUTCOME MEASURES: We report on key presentations and discussions that took place to achieve the objectives of the workshop. CONCLUSIONS: Future emerging infectious diseases are likely to bring far greater challenges than those imposed by the 2009 H1N1 pandemic. Canada must address these challenges and enhance its capacity for emergency responses by integrating modelling, surveillance, planning, and decision-making. PMID- 21306572 TI - Understanding mortality in the 1918-1919 influenza pandemic in England and Wales. AB - BACKGROUND: The causes of recurrent waves in the 1918-1919 influenza pandemic are not fully understood. OBJECTIVES: To identify the risk factors for influenza onset, spread and mortality in waves 1, 2 and 3 (summer, autumn and winter) in England and Wales in 1918-1919. METHODS: Influenza mortality rates for 333 population units and putative risk factors were analysed by correlation and by regressions weighted by population size and adjusted for spatial trends. RESULTS: For waves 1 and 3, influenza mortality was higher in younger, northerly and socially disadvantaged populations experiencing higher all-cause mortality in 1911-1914. Influenza mortality was greatest in wave 2, but less dependent on underlying population characteristics. Wave duration was shorter in areas with higher influenza mortality, typically associated with increasing population density. Regression analyses confirmed the importance of geographical factors and pre-pandemic mortality for all three waves. Age effects were complex, with the suggestion that younger populations with greater mortality in wave 1 had lesser mortality in wave 2. CONCLUSIONS: Our findings suggest that socially disadvantaged populations were more vulnerable, that older populations were partially protected by prior immunity in wave 1 and that exposure of (younger) populations in one wave could protect against mortality in the subsequent wave. An increase in viral virulence could explain the greater mortality in wave 2. Further modelling of causal processes will help to explain, in considerable detail, how social and geographical factors, season, pre-existing and acquired immunity and virulence affected viral transmission and pandemic mortality in 1918 1919. PMID- 21306573 TI - Sensitivity and specificity of rapid influenza testing of children in a community setting. AB - INTRODUCTION: Rapid influenza testing (RFT) allows for a rapid point-of-care diagnosis of influenza. The Quidel QuickVue Influenza A+B test (QuickVue) has a reported manufacturer's sensitivity and specificity of 73% and 96%, respectively, with nasal swabs. However, investigators have shown sensitivities ranging from 22% to 77% in community settings. METHODS: The QuickVue rapid influenza test was evaluated in a population of elementary (K-5) school children, using testing in the home, as part of the Pittsburgh Influenza Prevention Project during the 2007 2008 influenza season. The QuickVue test was performed with nasal swab in full accordance with package instructions and compared with the results of nasal swab semi-quantitative RT-PCR. RESULTS: Sensitivity of the QuickVue was found to be 27% in this sample. There was no statistically valid correlation between the semi quantitative PCR result and the QuickVue result. CONCLUSIONS: This study is consistent with the low sensitivity of the QuickVue test also reported by others. Viral load, technique, and the use of nasal swabs were examined as contributing factors but were not found to be explanations for this result. Community testing includes patients who are on the lower spectrum of illness which would not be the case in hospital or clinic samples. This suggests that RFT is less sensitive for patients at the lower spectrum of illness, with less severe disease. PMID- 21306574 TI - Using the full spectral capacity (six channels) of a real-time PCR instrument can simplify diagnostic laboratory screening and typing protocols for pandemic H1N1 influenza. AB - BACKGROUND: Timely reporting of influenza A virus subtype affects patient management. Real-time PCR is a rapid and sensitive method routinely used to characterise viral nucleic acid, but the full spectral capability of the instruments is not employed. OBJECTIVES: To evaluate a hexaplex real-time PCR assay (Flu-6plx assay) capable of detecting influenza A and B, hMPV, respiratory syncytial virus (RSV) and distinguishing 2008 'human' influenza A/H1 from 2009 pandemic A/H1 subtypes. METHODS: Respiratory specimens (n = 213) were tested using the Flu-6plx assay and a further four monoplex PCRs targeting hMPV, RSV, influenza A and B. The FDA-approved ProFlu ST test was used to validate the Flu 6plx PCR influenza A/H1 subtyping components. Discrepant 2009 pandemic A/H1 results were further tested using the CDC swine H1 assay. Results The Flu-6plx assay had excellent sensitivity identifying 106/106 influenza A RNA-positive samples. The ProFlu ST test was a less sensitive subtyping test, and discrepant analysis could not confirm A/H1 status for four samples resulting in Flu-6plx PCR specificities of 98% and 95% for human A/H1 and 2009 pandemic A/H1, respectively. Co-infection affected the sensitivity of the Flu-6plx PCR hMPV component whereby low-level hMPV RNA could be masked by much higher concentrations of influenza A virus RNA. CONCLUSIONS: The Flu-6plx assay is a sensitive and specific test for the universal detection of influenza A infection and determination of A/H1 subtype. Concomitant detection of influenza B, hMPV and RSV demonstrates the utility of hexaplex real-time PCRs in viral diagnostics. PMID- 21306575 TI - Cross-protection between antigenically distinct H1N1 swine influenza viruses from Europe and North America. AB - BACKGROUND: An avian-like H1N1 swine influenza virus (SIV) is enzootic in swine populations of Western Europe. The virus is antigenically distinct from H1N1 SIVs in North America that have a classical swine virus-lineage H1 hemagglutinin, as does the pandemic (H1N1) 2009 virus. However, the significance of this antigenic difference for cross-protection among pigs remains unknown. OBJECTIVES: We examined protection against infection with a North American triple reassortant H1N1 SIV [A/swine/Iowa/H04YS2/04 (sw/IA/04)] in pigs infected with a European avian-like SIV [A/swine/Belgium/1/98 (sw/B/98)] 4 weeks earlier. We also examined the genetic relationships and serologic cross-reactivity between both SIVs and with a pandemic (H1N1) 2009 virus [A/California/04/09 (Calif/09)]. RESULTS: After intranasal inoculation with sw/IA/04, all previously uninfected control pigs showed nasal virus excretion, high virus titers in the entire respiratory tract at 4 days post-challenge (DPCh) and macroscopic lung lesions. Most pigs previously infected with sw/B/98 tested negative for sw/IA/04 in nasal swabs and respiratory tissues, and none had lung lesions. At challenge, these pigs had low levels of cross-reactive virus neutralizing and neuraminidase inhibiting (NI) antibodies to sw/IA/04, but no hemagglutination-inhibiting antibodies. They showed similar antibody profiles when tested against Calif/09, but NI antibody titers were higher against Calif/09 than sw/IA/04, reflecting the higher genetic homology of the sw/B/98 neuraminidase with Calif/09. CONCLUSIONS: Our data indicate that immunity induced by infection with European avian-like H1N1 SIV affords protection for pigs against North American H1N1 SIVs with a classical H1, and they suggest cross-protection against the pandemic (H1N1) 2009 virus. PMID- 21306576 TI - Influenza and other respiratory viruses in three Central American countries. AB - BACKGROUND: Despite the disease burden imposed by respiratory diseases on children in Central America, there is a paucity of data describing the etiologic agents of the disease. AIMS: To analyze viral etiologic agents associated with influenza-like illness (ILI) in participants reporting to one outpatient health center, one pediatric hospital, and three general hospitals in El Salvador, Honduras, and Nicaragua Material & METHODS: Between August 2006 and April 2009, pharyngeal swabs were collected from outpatients and inpatients. Patient specimens were inoculated onto cultured cell monolayers, and viral antigens were detected by indirect and direct immunofluorescence staining. RESULTS: A total of 1,756 patients were enrolled, of whom 1,195 (68.3%) were under the age of 5; and 183 (10.4%) required hospitalization. One or more viral agents were identified in 434 (24.7%) cases, of which 17 (3.9%) were dual infections. The most common viruses isolated were influenza A virus (130; 7.4% of cases), respiratory syncytial virus (122; 6.9%), adenoviruses (63; 3.6%), parainfluenza viruses (57; 3.2%), influenza B virus (47; 2.7% of cases), and herpes simplex virus 1 (22; 1.3%). In addition, human metapneumovirus and enteroviruses (coxsackie and echovirus) were isolated from patient specimens. DISCUSSION: When compared to the rest of the population, viruses were isolated from a significantly higher percentage of patients age 5 or younger. The prevalence of influenza A virus or influenza B virus infections was similar between the younger and older age groups. RSV was the most commonly detected pathogen in infants age 5 and younger and was significantly associated with pneumonia (p < 0.0001) and hospitalization (p < 0.0001). CONCLUSION: Genetic analysis of influenza isolates identified A (H3N2), A (H1N1), and B viruses. It also showed that the mutation H274Y conferring resistance to oseltamivir was first detected in Honduran influenza A/H1N1 strains at the beginning of 2008. These data demonstrate that a diverse range of respiratory pathogens are associated with ILI in Honduras, El Salvador, and Nicaragua. RSV infection in particular appears to be associated with severe disease in infants in the region. PMID- 21306577 TI - Annual influenza vaccination: coverage and attitudes of primary care staff in Australia. AB - BACKGROUND: Annual influenza vaccination is recommended for all Australian health care workers (HCWs) including those working in primary health care. There is limited published data on coverage, workplace provision, attitudes and personal barriers to influenza vaccination amongst primary health care staff. The aim of this study was to contribute to the limited literature base in this important area by investigating these issues in the primary health care setting in New South Wales (NSW), Australia. METHODS: A postal survey was sent to general practitioners (GPs) and practice nurses (PNs) from inner city, semi-urban and rural areas of NSW, Australia. There were 139 responses in total (response rate 36%) from 79 GPs (response rate 30%) and 60 PNs (response rate 46%). RESULTS: Reported influenza vaccination coverage in both 2007 and 2008 was greater than 70%, with GPs reporting higher coverage than PNs in both years. The main barriers identified were lack of awareness of vaccination recommendations for general practice staff and concern about adverse effects from the vaccine. CONCLUSIONS: Rates of influenza vaccination coverage reported in this study were higher than in previous studies of hospital and institutional HCWs, though it is possible that the study design may have contributed to these higher results. Nevertheless, these findings highlight that more needs to be done to understand barriers to vaccination in this group, to inform the development of appropriate strategies to increase vaccination coverage in primary health care staff, with a special focus on PNs. PMID- 21306578 TI - Brucella canis in a HIV-infected patient. AB - The true incidence of Brucella canis in humans is unknown, but immunocompromised patients in direct contact with dogs are thought to be at a higher risk for infection. In this case report, we present a human case of B. canis in a patient infected with human immunodeficiency virus. PMID- 21306579 TI - Cigarette smoke and alpha,beta-unsaturated aldehydes elicit VEGF release through the p38 MAPK pathway in human airway smooth muscle cells and lung fibroblasts. AB - BACKGROUND AND PURPOSE: Vascular endothelial growth factor (VEGF) is an angiogenic factor known to be elevated in the sputum of asymptomatic smokers as well as smokers with bronchitis type of chronic obstructive pulmonary disease. The aim of this study was to investigate whether acute exposure to cigarette smoke extract altered VEGF production in lung parenchymal cells. EXPERIMENTAL APPROACH: We exposed human airway smooth muscle cells (ASMC), normal human lung fibroblasts (NHLF) and small airways epithelial cells (SAEC) to aqueous cigarette smoke extract (CSE) in order to investigate the effect of cigarette smoke on VEGF expression and release. KEY RESULTS: Vascular endothelial growth factor release was elevated by sub-toxic concentrations of CSE in both ASMC and NHLF, but not in SAEC. CSE-evoked VEGF release was mimicked by its component acrolein at concentrations (10-100 uM) found in CSE, and prevented by the antioxidant and alpha,beta-unsaturated aldehyde scavenger, N-acetylcysteine (NAC). Both CSE and acrolein (30 uM) induced VEGF mRNA expression in ASMC cultures, suggesting an effect at transcriptional level. Crotonaldehyde and 4-hydroxy-2-nonenal, an endogenous alpha,beta-unsaturated aldehyde, stimulated VEGF release, as did H(2)O(2). CSE-evoked VEGF release was accompanied by rapid and lasting phosphorylation of p38 MAPK (mitogen-activated protein kinase), which was abolished by NAC and mimicked by acrolein. Both CSE- and acrolein-evoked VEGF release were blocked by selective inhibition of p38 MAPK signalling. CONCLUSIONS AND IMPLICATIONS: alpha,beta-Unsaturated aldehydes and possibly reactive oxygen species contained in cigarette smoke stimulate VEGF expression and release from pulmonary cells through p38 MAPK signalling. PMID- 21306580 TI - Colchicine inhibits cationic dye uptake induced by ATP in P2X2 and P2X7 receptor expressing cells: implications for its therapeutic action. AB - BACKGROUND AND PURPOSE: The two longest C-termini of the purinergic P2X receptors occur in the P2X2 and P2X7 receptors and are thought to interact with multiple cytoplasmic proteins, among which are members of the cytoskeleton, including microtubules. In this work we asked whether disrupting the microtubule cytoskeleton might affect the functions of these receptors. EXPERIMENTAL APPROACH: Functions of heterologously expressed P2X2 and P2X7 receptors were evaluated with electrophysiology and dye uptake following ATP application. Permeabilization and secretion of pro-inflammatory agents were quantified from fresh or cultured peritoneal mouse macrophages, treated in vitro or in vivo with colchicine. KEY RESULTS: Disrupting the microtubule network with colchicine did not affect currents generated by ATP in P2X2 and P2X7 receptor-expressing cells but inhibited uptake of the dye Yo-Pro-1 in Xenopus oocytes and HEK293 cells expressing these channels. Peritoneal mouse macrophages showed less ATP-induced permeabilization to ethidium bromide in the presence of colchicine, and less reactive oxygen species (ROS) formation, nitric oxide (NO) and interleukin (IL) 1beta release. Colchicine treatment did not affect ATP-evoked currents in macrophages. Finally, in vivo assays with mice inoculated with lipopolysaccharide and ATP showed diminished ROS, IL-1beta, interferon-gamma and NO production after colchicine treatment. CONCLUSIONS AND IMPLICATIONS: Colchicine has known anti inflammatory actions and is used to treat several conditions involving innate immunity, including gout and familial Mediterranean fever. Here we propose a new mechanism of action - inhibition of pore formation induced by activation of P2X receptors - which could explain some of the anti-inflammatory effects of colchicine. PMID- 21306581 TI - How can we improve our understanding of cardiovascular safety liabilities to develop safer medicines? AB - Given that cardiovascular safety liabilities remain a major cause of drug attrition during preclinical and clinical development, adverse drug reactions, and post-approval withdrawal of medicines, the Medical Research Council Centre for Drug Safety Science hosted a workshop to discuss current challenges in determining, understanding and addressing 'Cardiovascular Toxicity of Medicines'. This article summarizes the key discussions from the workshop that aimed to address three major questions: (i) what are the key cardiovascular safety liabilities in drug discovery, drug development and clinical practice? (ii) how good are preclinical and clinical strategies for detecting cardiovascular liabilities? and (iii) do we have a mechanistic understanding of these liabilities? It was concluded that in order to understand, address and ultimately reduce cardiovascular safety liabilities of new therapeutic agents there is an urgent need to: * Fully characterize the incidence, prevalence and impact of drug induced cardiovascular issues at all stages of the drug development process. * Ascertain the predictive value of existing non-clinical models and assays towards the clinical outcome. * Understand the mechanistic basis of cardiovascular liabilities; by addressing areas where it is currently not possible to predict clinical outcome based on preclinical safety data. * Provide scientists in all disciplines with additional skills to enable them to better integrate preclinical and clinical data and to better understand the biological and clinical significance of observed changes. * Develop more appropriate, highly relevant and predictive tools and assays to identify and wherever feasible to eliminate cardiovascular safety liabilities from molecules and wherever appropriate to develop clinically relevant and reliable safety biomarkers. PMID- 21306583 TI - Formoterol and salmeterol induce a similar degree of beta2-adrenoceptor tolerance in human small airways but via different mechanisms. AB - BACKGROUND AND PURPOSE: Steroids prevent and reverse salbutamol-induced beta(2) adrenoceptor tolerance in human small airways. This study examines the effects of the long-acting beta(2) agonists (LABAs) formoterol and salmeterol, and the ability of budesonide to prevent desensitization. EXPERIMENTAL APPROACH: Long acting beta(2) agonists in the presence and absence of budesonide were incubated with human precision-cut lung slices containing small airways. Tolerance was deduced from measurements of reduced bronchodilator responses to isoprenaline and correlated with beta(2)-adrenoceptor trafficking using a virally transduced, fluorescent-tagged receptor. The ability of the LABAs to protect airways against muscarinic-induced contraction was also assessed. KEY RESULTS: Following a 12 h incubation, both formoterol and salmeterol attenuated isoprenaline-induced bronchodilatation to a similar degree and these effects were not reversible by washing. Pre-incubation with budesonide prevented the desensitization induced by formoterol, but not that induced by salmeterol. Formoterol also protected the airways from carbachol-induced bronchoconstriction to a greater extent than salmeterol. In the epithelial cells of small airways, incubation with formoterol promoted receptor internalization but this did not appear to occur following incubation with salmeterol. Budesonide inhibited the formoterol-induced reduction in plasma membrane beta(2)-adrenoceptor fluorescence. CONCLUSIONS AND IMPLICATIONS: Although both formoterol and salmeterol attenuate isoprenaline induced bronchodilatation, they appear to induce beta(2)-adrenoceptor tolerance via different mechanisms; formoterol, but not salmeterol, enhances receptor internalization. Budesonide protection against beta(2)-adrenoceptor tolerance was correlated with the retention of receptor fluorescence on the plasma membrane, thereby suggesting a mechanism by which steroids alter beta(2)-adrenoceptor function. PMID- 21306585 TI - Francisella infections in fish and shellfish. AB - A series of recent reports have implicated bacteria from the family Francisellaceae as the cause of disease in farmed and wild fish and shellfish species such as Atlantic cod, Gadus morhua L., tilapia, Oreochromis spp., Atlantic salmon, Salmo salar L., three-line grunt, Parapristipoma trilineatum (Thunberg), ornamental cichlid species, hybrid striped bass Morone chrysops x M. saxatilis and, recently, a shellfish species, the giant abalone, Haliotisgigantea Gmelin. The range of taxa affected will very probably rise as it is likely that there has been considerable under-reporting to date of these disease agents. In common with other Francisella species, their isolation and culture require specialized solid and liquid media containing cysteine and a source of iron. This likely restricted earlier efforts to identify them correctly as the cause of disease in aquatic animals. The most information to date relates to disease in cod, caused by F. noatunensis and tilapia, caused by F. noatunensis subsp. orientalis (also termed F. asiatica), both causing granulomatous inflammatory reactions. Mortalities in both species can be high and, as the disease can likely be transferred via live fish movements, they pose a significant threat to tilapia and cod aquaculture operations. Although the fish-pathogenic Francisella species are classified in the same genus as the human pathogens F. tularensis, causative agent of tularemia, and F. philomiragia, the risk to humans from the fish and shellfish pathogenic Francisella species is considered very low. PMID- 21306582 TI - T-type voltage-gated calcium channels as targets for the development of novel pain therapies. AB - It is well recognized that voltage-gated calcium (Ca(2+)) channels modulate the function of peripheral and central pain pathways by influencing fast synaptic transmission and neuronal excitability. In the past, attention focused on the modulation of different subtypes of high-voltage-activated-type Ca(2+) channels; more recently, the function of low-voltage-activated or transient (T)-type Ca(2+) channels (T-channels) in nociception has been well documented. Currently, available pain therapies remain insufficient for certain forms of pain associated with chronic disorders (e.g. neuropathic pain) and often have serious side effects. Hence, the identification of selective and potent inhibitors and modulators of neuronal T-channels may help greatly in the development of safer, more effective pain therapies. Here, we summarize the available information implicating peripheral and central T-channels in nociception. We also discuss possible future developments aimed at selective modulation of function of these channels, which are highly expressed in nociceptors. PMID- 21306584 TI - Effect of verapamil on the action of methanethiosulfonate reagents on human voltage-gated K(v)1.3 channels: implications for the C-type inactivated state. AB - BACKGROUND AND PURPOSE: Voltage-gated K(v)1.3 channels appear on T-lymphocytes and are characterized by their typical C-type inactivation. In order to develop drugs stabilizing the C-type inactivated state and thus potentially useful in treatment of autoimmune diseases, it is important to know more about the three dimensional structure of this inactivated state of the channel. EXPERIMENTAL APPROACH: The patch-clamp technique was used to study effects of methanethiosulphonate (MTS) compounds on currents through wild-type human K(v)1.3 (hK(v)1.3) and two mutant channels, hK(v)1.3 V417C and hK(v) 1.3 H399T-V417C, in the closed, open and inactivated states. KEY RESULTS: Extracellular application of 2-aminoethyl methanethiosulphonate (MTSEA) irreversibly reduced currents through hK(v) 1.3 V417C channels in the open and inactivated, but not in the closed state, indicating that a modification was possible. Co-application of verapamil prevented this reduction. Intracellular application of MTSEA and [2 (trimethylammonium)ethyl] methanethiosulphonate (MTSET) also modified the mutant channels, whereas extra- and intracellular application of sodium (2 sulfonatoethyl)methanethiosulphonate (MTSES) and intracellular application of MTSET did not. CONCLUSIONS AND IMPLICATIONS: Our experiments showed that the binding site for MTS compounds was intracellular in the mutant channels and that the V417C mutant channels were modified in the open and the inactivated states, and this modification was prevented by verapamil. Therefore, the activation gate on the intracellular side of the selectivity filter must be open during inactivation. Furthermore, although the S6 segment is moving further apart during inactivation, this change does not include a movement of the side chain of the amino acid at position 417, away from lining the channel pore. PMID- 21306586 TI - Real-time RT-PCR detection of betanodavirus in naturally and experimentally infected fish from Spain. AB - Infections with betanodavirus affect a wide range of wild and farmed fish species throughout the world, mostly from the marine environment. The aim of this work was to develop and validate real-time RT-PCR assays for sensitive and specific detection of nodavirus in diseased or carrier fish. The new detection assay was used to study the transmission and development of nodavirus infection in juvenile sea bass, Dicentrarchus labrax (L.), challenged by different routes, and also to screen for nodavirus in various farmed fish species. On average, the sensitivity was 10-100 times higher than a standard RT-PCR, and the assay was able to detect asymptomatic carrier fish that otherwise could have been classified as free of infection. Clinical signs of nodavirus infection were reproduced in fish infected following bath exposure or intramuscular injection, demonstrating horizontal transmission of the disease. Nodavirus was always detected in the brain of diseased fish but also in many recovered fish. The new assay enables us to confirm the presence of the virus at an early phase in the production cycle and may represent a useful tool to prevent or slow down the spread of nodavirus to new locations. PMID- 21306587 TI - Surface properties of Streptococcus phocae strains isolated from diseased Atlantic salmon, Salmo salar L. AB - Streptococcus phocae is an emerging pathogen for Chilean Atlantic salmon, Salmo salar, but the factors determining its virulence are not yet elucidated. In this work, cell surface-related properties such as hydrophobicity and haemagglutination, adhesion to mucus and cell lines, capsule detection, survival and biofilm formation in skin mucus and serum resistance of the isolates responsible for outbreaks in Atlantic salmon and seals were examined. Adhesion to hydrocarbons and the results of salt aggregation tests indicated most of the S. phocae were strongly hydrophobic. All isolates exhibited a similar ability to attach to the Chinook salmon embryo (CHSE) cells line, but were not able to enter CHSE cells. Haemagglutination was not detected. Our data clearly indicate that S. phocae can resist the killing activity of mucus and serum and proliferate in them, which could be associated with the presence of a capsular layer around the cells. Pathogenicity studies using seal and fish isolates demonstrated mortality or pathological signs in fish injected only with the Atlantic salmon isolate. No mortalities or histopathological alterations were observed in fish injected with extracellular products. PMID- 21306588 TI - Spinal deformity in triploid grass carp Ctenopharyngodon idella (Valenciennes). AB - From mid-2004 to mid-2005, several grass carp, Ctenophayngodon idella (Valenciennes), showing evidence of spinal deformity were presented to the Aquatic Animal Health Program, Cornell University. The carp were from three separate locations in New York State. The first case involved several fish from a natural body of water in the Catskill Mountain region of south-eastern New York State. The second was a single affected individual from a private pond in the Fingerlakes region of Central New York State. The third was a single individual from the Cold Springs Harbor Fish Hatchery, Cold Springs Harbor, Long Island. All fish were at least 7 years of age. Radiographs and computed tomography (CT) scans revealed the deformities to be of bony origin. The spinal deformities were characterized by variable amounts of kyphosis, scoliosis and rotation. While it is not possible to determine the specific cause(s) of the lesions, we consider a genetic component as a likely contributor to the observed pathology. PMID- 21306589 TI - A selective and differential medium for Vibrio alginolyticus. AB - In this paper, we present a selective and differential medium, termed Vibrio alginolyticus (VAL) agar, developed for the isolation and identification of V. alginolyticus. The presence of bile salts, high salinity and high incubation temperature allows the selective growth of moderately halophilic Vibrio species. Differentiation of bacteria is achieved by identifying species capable of sucrose fermentation, made visible by the pH indicator bromocresol purple. In this study, all of the 26 strains of V. alginolyticus and only three of the 99 strains representing 30 species (including 19 Vibrio species) other than V. alginolyticus were able to grow in the VAL medium. The remaining three strains could be further differentiated from V. alginolyticus according to colour or the diameter of colonies produced on VAL agar plates. Colonies isolated from shellfish rearing water and infected shrimp through the use of VAL agar plates were all positively identified as V. alginolyticus by conventional tests and 16S rDNA sequencing. The testing of specificity and differentiation capability of VAL shows the potential of the agar as a medium for the primary isolation of V. alginolyticus from pathological and environmental samples. PMID- 21306590 TI - Immunohistochemical and Taqman real-time PCR detection of mycobacterial infections in fish. AB - Real-time PCR and immunohistochemistry (IHC) assays were developed to detect fish mycobacterial infections at the genus level, based on the RNA polymerase beta subunit (rpoB) gene and polyclonal anti-Mycobacterium rabbit serum, respectively. The PCR assay positively identified a number of pathogenic mycobacteria including Mycobacterium abscessus, M. avium ssp. avium, M. bohemicum, M. chelonae ssp. chelonae, M. farcinogenes, M. flavescens, M. fortuitum ssp. fortuitum, M. gastri, M. gordonae, M. immunogenicum, M. malmoense, M. marinum, M. montefiorense, M. phlei, M. phocaicum, M. pseudoshottsii, M. salmoniphilum, M. senegalense, M. shottsii, M. smegmatis, M. szulgi and M. wolinskyi. A detection limit equivalent to 10(2) cfu g(-1) was registered for M. salmoniphilum-infected fish tissue. The IHC precisely localized both free and intracellular mycobacteria in tissues and detected mycobacterial infections down to 10(2) cfu g(-1) tissue. Both assays were found to be more sensitive than Ziehl-Neelsen (ZN) staining, where the detection limit was below 8 * 10(3) cfu g(-1) tissue. Although specificity testing of the real-time PCR against a panel of non-Mycobacterium spp. revealed a degree of cross-reaction against pure DNA extracted from Nocardia seriolae and Rhodococcus erythropolis, no cross-reactions were identified (by either real-time PCR or IHC) on testing of formalin-fixed paraffin-embedded (FFPE) tissues confirmed to be infected with these bacteria. The broad applicability of both assays was confirmed by analysis of FFPE tissues from a range of fish species infected with diverse Mycobacterium spp. The results indicate that both assays, alone or in combination, constitute sensitive tools for initial, rapid diagnosis of mycobacteriosis in fish. This should in turn allow rapid application of more specific studies, i.e. culture based, to identify the specific Mycobacterium sp. involved. PMID- 21306591 TI - Immunization of rainbow trout, Oncorhynchus mykiss (Walbaum), with Flavobacterium psychrophilum proteins elongation factor-Tu, SufB Fe-S assembly protein and ATP synthasebeta. PMID- 21306592 TI - Streptococcus dysgalactiae as an agent of septicaemia in Nile tilapia, Oreochromis niloticus (L.). PMID- 21306593 TI - Genetics of the association between intelligence and nicotine dependence: a study of male Swedish twins. AB - AIMS: Previous studies have found inverse associations between intelligence quotient (IQ) and cigarette smoking, but the causal pathways linking IQ with smoking status and nicotine dependence (ND) are not well understood. The aim of this study was to explore the associations between IQ and ND using a genetically informative twin design to detect whether any association is because of shared genetic or environmental factors. DESIGN: A population-based twin cohort with IQ measured in adolescence and ND later in life, analysed by classical twin modeling based on linear structural equations. SETTING: Swedish national registry data. PARTICIPANTS: A total of 5040 male twins born 1951-84. MEASUREMENTS: IQ was measured at military conscription at a mean age of 18 years. ND was self-reported at the ages of 22-57 years using the Fagerstrom Test for ND scale (FTND). Both cigarette smoking and Swedish snus use were analysed. FINDINGS: Both IQ and ND showed moderate heritability (0.58 and 0.39, respectively). The heritability of ND was similar for cigarette smoking and snus use. The phenotypic correlation between IQ and ND was weak: -0.11 (-0.16, -0.06) for total ND. Bivariate analysis revealed that this correlation was mainly because of genetic factors, but still the genetic correlation between IQ and ND from cigarette smoking was only -0.24. CONCLUSIONS: Nicotine dependence, as measured by the Fagerstrom Test for Nicotine Dependence, shows moderate heritability in both smokers and snus users but is only weakly associated with intelligence quotient; common genetic factors underlying nicotine dependence and intelligence quotient probably account for little of the observed association between smoking and intelligence quotient. PMID- 21306594 TI - Drug violations and aviation accidents: findings from the US mandatory drug testing programs. AB - AIMS: To assess the role of drug violations in aviation accidents. DESIGN: Case control analysis. SETTING: Commercial aviation in the United States. PARTICIPANTS: Aviation employees who were tested for drugs during 1995-2005 under the post-accident testing program (cases, n = 4977) or under the random testing program (controls, n = 1 129 922). MEASUREMENTS: Point prevalence of drug violations, odds ratio of accident involvement and attributable risk in the population. A drug violation was defined as a confirmed positive test for marijuana (>=50 ng/ml), cocaine (>=300 ng/ml), amphetamines (>=1000 ng/ml), opiates (>=2000 ng/ml) or phencyclidine (>=25 ng/ml). FINDINGS: The prevalence of drug violations was 0.64% [95% confidence interval (CI): 0.62-0.65%] in random drug tests and 1.82% (95% CI: 1.47-2.24%) in post-accident tests. The odds of accident involvement for employees who tested positive for drugs was almost three times the odds for those who tested negative (odds ratio 2.90, 95% CI: 2.35 3.57), with an estimated attributable risk of 1.2%. Marijuana accounted for 67.3% of the illicit drugs detected. The proportion of illicit drugs represented by amphetamines increased progressively during the study period, from 3.4% in 1995 to 10.3% in 2005 (P < 0.0001). CONCLUSIONS: Use of illicit drugs by aviation employees is associated with a significantly increased risk of accident involvement. Due to the very low prevalence, drug violations contribute to only a small fraction of aviation accidents. PMID- 21306595 TI - Effects of major depression on crack use and arrests among women in drug court. AB - AIMS: We examined whether a current major depressive episode (MDE) at baseline predicted crack use and arrests at follow-up among women enrolled in drug court. DESIGN: Primary analyses used zero-inflated Poisson (ZIP) and zero-inflated negative binomial (ZINB) regression analyses to predict both yes/no and number of (i) days of crack use and (ii) arrests at 4-month follow-up from current (30-day) MDE at baseline. Secondary analyses addressed risk conferred by current versus past MDE at baseline. SETTING/PARTICIPANTS: Participants were 261 women in drug court. MEASUREMENTS: MDE was assessed using the Diagnostic Interview Schedule. Days using crack and number of arrests were assessed using the Washington University Risk Behavior Assessment for Women. FINDINGS: Having a current MDE at baseline predicted likelihood of crack use at follow-up, but not days of crack use among those who used. Current MDE at baseline did not predict presence or number of arrests at the 4-month follow-up. Women with current MDE at baseline were more likely to be using crack at follow-up than were those with recent (31+ days to 12 months) but not current MDE (odds ratio = 5.71); past MDE at baseline did not increase risk of crack use. CONCLUSIONS: Predictors of any versus no crack use or arrests appear to differ from predictors of frequency of these behaviors. Current major depression, but not past major depression, appears to be associated with increased risk of crack use among women attending drug court. PMID- 21306596 TI - Empirically derived subtypes of opioid use and related behaviors. AB - AIMS: To identify and validate homogeneous subtypes of opioid use and related behaviors. DESIGN: Family-based and case-control genetic studies of opioid and/or cocaine dependence. SETTINGS: Clinical and general community samples from Connecticut, Massachusetts, Pennsylvania and South Carolina. PARTICIPANTS: A total of 4061 individuals (2003 individuals from 835 families and 2058 unrelated individuals) recruited to participate in genetic studies. MEASUREMENTS: The computer-assisted Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA) was used to assess participants' demographics, medical history, substance use behaviors and disorders and other psychiatric disorders. FINDINGS: Five homogeneous subtypes were identified, which differed on opioid-related measures, demographics and prevalence rates of substance use and psychiatric disorders. Heritability estimates for the two most severely affected subtypes exceeded 0.60. CONCLUSIONS: An empirical approach based on opioid use and related behaviors can yield homogeneous subtypes that could be of value in gene finding for opioid dependence. PMID- 21306597 TI - Influence of traditional tobacco use on smoking cessation among American Indians. AB - AIMS: To examine the influence of traditional tobacco use on smoking cessation among American Indian adult smokers. DESIGN, SETTING AND PARTICIPANTS: A cross sectional survey of self-identified American Indians was conducted from 2008 to 2009. A total of 998 American Indian adults (18 years and older) from the Midwest participated in the study. MEASUREMENTS: Traditional tobacco use and method of traditional use were both assessed. Commercial tobacco use (current smoking) was obtained through self-reported information as well as the length of their most recent quit attempt. We also assessed knowledge and awareness of pharmacotherapy for current smokers. FINDINGS: Among participants in our study, 33.3% were current smokers and they reported smoking an average of 10 cigarettes per day. American Indian current smokers who used traditional tobacco reported a greater number of days abstinent during their last quit attempt compared to those who do not use traditional tobacco (P = 0.01). However, it appears that this protective effect of traditional tobacco use is diminished if the person smokes traditional tobacco. Finally, very few (fewer than 20% of current smokers) were aware of more recent forms of pharmacotherapy such as Chantix or bupropion. CONCLUSIONS: American Indians appear to show low levels of awareness of effective pharmacotherapies to aid smoking cessation, but those who use 'traditional tobacco' report somewhat longer periods of abstinence from past quit attempts. PMID- 21306598 TI - Overestimation of peer drinking: error of judgement or methodological artefact? AB - AIMS: To examine whether inclusion of both self- and peer-referent items in the context of a single social norms drinking questionnaire plays an active role in producing the much-reported tendency for young people to overestimate the extent of peers' alcohol-related behaviour and the permissiveness of their attitudes towards alcohol. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: In a between subjects design pupils attending two Scottish secondary schools (n=1074; 12-18 years; 52.5% male) completed one of three questionnaires designed to measure a range of alcohol-related behaviours, attitudes and perceptions: a paradigmatic multiple-target questionnaire included self- and peer-referent items while two single-target questionnaires included self-referent or peer-referent items only. FINDINGS: Pupils' self-reported drinking behaviours and attitudes were similar, regardless of whether multiple or single-target versions of the questionnaire were used, as were perceptions of peers' frequencies of alcohol use and drunkenness. In contrast, by comparison with pupils who responded to a single target version that omitted self-referent items, use of a multiple-target questionnaire was significantly more likely to result in reports that peers would consume alcoholic drinks when with friends and hold more permissive or liberal attitudes towards alcohol. CONCLUSIONS: Social norms research and related health promotion programmes that seek to reduce the extent of overestimation of peer drinking norms are heavily reliant upon multiple-target drinking questionnaires. The use of such a questionnaire may lead to more distorted or extreme perceptions being reported by pupils compared to single-target versions, which omit self referent drinking items. By implication, use of multiple-target questionnaires may encourage young people to 'over-overestimate' peer drinking norms. PMID- 21306599 TI - Non-suicidal self-injury by intravenous application of nicotine in a patient with borderline personality disorder resulting in substance dependence. AB - BACKGROUND: Non-suicidal self-injury in many different forms is a classic struggle for those diagnosed with borderline personality disorder (BPD). Some common ways of NSSI are cutting, scratching and head-banging. CASE DESCRIPTION: A 23-year old woman with BPD presented in our clinic with a 4-month history of intravenous application of a liquid dosage form of nicotine that is generally used for nasal application. Accordingly, the patient developed nicotine dependency (ICD-10 F17.25). Before her admission to our ward the daily intravenous nicotine application was around 33 mg. The in-patient detoxification proceeded without a remarkable withdrawal syndrome. CONCLUSION: A case of regular intravenous administration of nicotine has been observed, apparently resulting in nicotine dependence in a person with borderline personality disorder. The original intent appears to have been self-harm. PMID- 21306603 TI - Clinical presentations and outcomes of Filipino juvenile systemic lupus erythematosus. AB - OBJECTIVE: Juvenile Systemic Lupus Erythematosus (SLE) varies by location and ethnicity. This study describes the clinical, laboratory profile and outcome of juvenile SLE seen at Philippine General Hospital (PGH) from 2004-2008. METHOD: Medical charts of all Filipino Juvenile SLE cases admitted at PGH during the 5 year period were reviewed collecting demographic profile, clinical and laboratory manifestations and treatment during disease course. RESULTS: Seventy-eight cases of juvenile SLE were reviewed. There were 7 boys and 71 girls. The mean age at diagnosis was 14 years (SD 2.7) with a range of 8-18 years. Fever (52.5%) and malar rash (41.0%) were the most common features at disease onset. At the time of diagnosis, the most common features were malar rash (65.3%), renal involvement (62.8%) and photosensitivity (55.1%). Mucocutaneous (92.3%), renal (71.7%) and hematologic (69.2%) involvement were the most common features during the entire course of illness. Infection (34.5%) and neurologic (19.0%) complications were observed most frequently. Corticocosteroid treatment was given in most of the patients in the form of prednisone (97.4%) and concomitant methylprednisolone intravenous pulses (29.4%). Nine patients died during the study period. The overall 5-year mortality rate was 11.5%. Infection (77.0%) was the most frequent cause of death. CONCLUSION: Malar rash was a common feature at disease onset and at diagnosis among Filipinos with juvenile SLE. Throughout the disease course, renal involvement occurs in 71.7% of patients. Infection was the leading cause of complication and death. The clinical presentations of Filipinos with juvenile SLE were similar to juvenile SLE in other countries. PMID- 21306604 TI - Rationale and development of a survey tool for describing and auditing the composition of, and flows between, specialist and community clinical services for sexually transmitted infections. AB - BACKGROUND: National health strategies have called for an expansion of the role of primary care in England to increase access to sexual health services. However, there is little guidance for service planners and commissioners as to the public health impact of different combinations of specialist genitourinary medicine (GUM) clinics and primary care based services for local populations. Service planning for infectious diseases like sexually transmitted infections (STI) is further complicated because the goal of early detection and treatment is not only to improve the health of the individual, but to benefit the wider population and reduce future treatment costs by preventing onward transmission. Therefore, we are developing a survey tool that will enable service planners to better understand the needs of their local STI care-seeking population and which will help inform evidence-based decision-making about current and future service configurations. Here we describe the rationale and development of this survey tool. METHODS/DESIGN: A pen-and-paper questionnaire asking about sociodemographics, reasons for attendance, care pathways, and recent sexual risk behaviours, is being developed for patients to complete in waiting rooms of diverse clinical services, including GUM clinics and primary-care based services in sociodemographically- and geographically-contrasting populations in England. The questionnaire was cognitively tested before being piloted. In the pilot, 67% of patients participated, of whom 84% consented to our linking their questionnaire to data on STI testing and diagnosis and partner notification outcomes from their clinical records. DISCUSSION: The pilot study suggests that both the questionnaire and its linkage to routinely-collected clinical data are likely to be acceptable to patients. By supplementing existing surveillance, data gathered by the survey tool will inform service planners' and providers' understanding of the needs and care-pathways of their patients, facilitating improved services and greater public health benefit. PMID- 21306605 TI - Identification of a natural human serotype 3 parainfluenza virus. AB - Parainfluenza virus is an important pathogen threatening the health of animals and human, which brings human many kinds of disease, especially lower respiratory tract infection involving infants and young children. In order to control the virus, it is necessary to fully understand the molecular basis resulting in the genetic diversity of the virus. Homologous recombination is one of mechanisms for the rapid change of genetic diversity. However, as a negative-strand virus, it is unknown whether the recombination can naturally take place in human PIV. In this study, we isolated and identified a mosaic serotype 3 human PIV (HPIV3) from in China, and also provided several putative PIV mosaics from previous reports to reveal that the recombination can naturally occur in the virus. In addition, two swine PIV3 isolates transferred from cattle to pigs were found to have mosaic genomes. These results suggest that homologous recombination can promote the genetic diversity and potentially bring some novel biologic characteristics of HPIV. PMID- 21306606 TI - Overexpression of LCMR1 is significantly associated with clinical stage in human NSCLC. AB - BACKGROUND: Lung cancer is one of the most common human cancers and the leading cause of cancer death worldwide. The identification of lung cancer associated genes is essential for lung cancer diagnosis and treatment. METHODS: Differential Display-PCR technique was used to achieve the novel cDNA, which were then verified by real-time PCR. Northern blot was utilized to observe the expression of LCMR1 in different human tissues. 84 cases human NSCLC tissues and normal counterparts were analyzed for the expression of LCMR1 by immunohistochemistry. RESULTS: A novel 778-bp cDNA fragment from human large cell lung carcinoma cell lines 95C and 95D was obtained, and named LCMR1 (Lung Cancer Metastasis Related protein 1). LCMR1 was differentially expressed in different human tissues. LCMR1 was strongly overexpressed in NSCLC and its expression was significantly associated with clinical stage. CONCLUSION: Our data indicated that LCMR1, strongly overexpressed in NSCLC, might have applications in the clinical diagnosis and treatment of lung cancer. PMID- 21306607 TI - Inadvertent malposition of a permanent pacemaker ventricular lead into the left ventricle which was initially missed and diagnosed two years later: a case report. AB - INTRODUCTION: Inadvertent malposition of a pacemaker ventricular lead into the left ventricle is an uncommon event, and its actual incidence is probably unknown. It may be underestimated and underreported because of a possible asymptomatic course. A 12-lead electrocardiogram is important to confirm proper placement. CASE PRESENTATION: We report a case of a 60-year-old Caucasian man with a malpositioned transvenous permanent pacing lead into the left ventricle via a patent foramen ovale that was not suspected during implantation and went undiagnosed for two years without complications. The patient remained asymptomatic as he was being treated with oral anticoagulation therapy for atrial fibrillation. The decision was made to leave the pacing lead in place and continue lifelong warfarin therapy. CONCLUSIONS: Inadvertent insertion of pacing wires into the left ventricle is a potentially dangerous complication that may happen under fluoroscopic guidance and may be overlooked by routine pacemaker interrogation. It is advisable to obtain a 12-lead electrocardiogram during or immediately after transvenous pacemaker implantation rather than use a routine pacemaker interrogation or a limited electrocardiogram. PMID- 21306608 TI - A biregional survey and review of first-line treatment failure and second-line paediatric antiretroviral access and use in Asia and southern Africa. AB - BACKGROUND: To better understand the need for paediatric second-line antiretroviral therapy (ART), an ART management survey and a cross-sectional analysis of second-line ART use were conducted in the TREAT Asia Paediatric HIV Observational Database and the IeDEA Southern Africa (International Epidemiologic Databases to Evaluate AIDS) regional cohorts. METHODS: Surveys were conducted in April 2009. Analysis data from the Asia cohort were collected in March 2009 from 12 centres in Cambodia, India, Indonesia, Malaysia, and Thailand. Data from the IeDEA Southern Africa cohort were finalized in February 2008 from 10 centres in Malawi, Mozambique, South Africa and Zimbabwe. RESULTS: Survey responses reflected inter-regional variations in drug access and national guidelines. A total of 1301 children in the TREAT Asia and 4561 children in the IeDEA Southern Africa cohorts met inclusion criteria for the cross-sectional analysis. Ten percent of Asian and 3.3% of African children were on second-line ART at the time of data transfer. Median age (interquartile range) in months at second-line initiation was 120 (78-145) months in the Asian cohort and 66 (29-112) months in the southern African cohort. Regimens varied, and the then current World Health Organization-recommended nucleoside reverse transcriptase combination of abacavir and didanosine was used in less than 5% of children in each region. CONCLUSIONS: In order to provide life-long ART for children, better use of current first-line regimens and broader access to heat-stable, paediatric second-line and salvage formulations are needed. There will be limited benefit to earlier diagnosis of treatment failure unless providers and patients have access to appropriate drugs for children to switch to. PMID- 21306609 TI - Coordinated gene expression during gilthead sea bream skeletogenesis and its disruption by nutritional hypervitaminosis A. AB - BACKGROUND: Vitamin A (VA) has a key role in vertebrate morphogenesis, determining body patterning and growth through the control of cell proliferation and differentiation processes. VA regulates primary molecular pathways of those processes by the binding of its active metabolite (retinoic acid) to two types of specific nuclear receptors: retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which promote transcription of downstream target genes. This process is well known in most of higher vertebrates; however, scarce information is available regarding fishes. Therefore, in order to gain further knowledge of fish larval development and its disruption by nutritional VA imbalance, the relative expression of some RARs and RXRs, as well as several genes involved in morpho- and skeletogenesis such as peroxisome proliferator-activated receptors (PPARA, PPARB and PPARG); retinol-binding protein (RBP); insulin-like growth factors I and II (IGF1 and IGF2, respectively); bone morphogenetic protein 2 (Bmp2); transforming growth factor beta-1 (TGFB1); and genes encoding different extracellular matrix (ECM) proteins such as matrix Gla protein (mgp), osteocalcin (bglap), osteopontin (SPP1), secreted protein acidic and rich in cysteine (SPARC) and type I collagen alpha1 chain (COL1A1) have been studied in gilthead sea bream. RESULTS: During gilthead sea bream larval development, specific expression profiles for each gene were tightly regulated during fish morphogenesis and correlated with specific morphogenetic events and tissue development. Dietary hypervitaminosis A during early larval development disrupted the normal gene expression profile for genes involved in RA signalling (RARA), VA homeostasis (RBP) and several genes encoding ECM proteins that are linked to skeletogenesis, such as bglap and mgp. CONCLUSIONS: Present data reflects the specific gene expression patterns of several genes involved in larval fish RA signalling and skeletogenesis; and how specific gene disruption induced by a nutritional VA imbalance underlie the skeletal deformities. Our results are of basic interest for fish VA signalling and point out some of the potential molecular players involved in fish skeletogenesis. Increased incidences of skeletal deformities in gilthead sea bream fed with hypervitaminosis A were the likely ultimate consequence of specific gene expression disruption at critical development stages. PMID- 21306610 TI - Clinical prediction rules combining signs, symptoms and epidemiological context to distinguish influenza from influenza-like illnesses in primary care: a cross sectional study. AB - BACKGROUND: During an influenza epidemic prompt diagnosis of influenza is important. This diagnosis however is still essentially based on the interpretation of symptoms and signs by general practitioners. No single symptom is specific enough to be useful in differentiating influenza from other respiratory infections. Our objective is to formulate prediction rules for the diagnosis of influenza with the best diagnostic performance, combining symptoms, signs and context among patients with influenza-like illness. METHODS: During five consecutive winter periods (2002-2007) 138 sentinel general practitioners sampled (naso- and oropharyngeal swabs) 4597 patients with an influenza-like illness (ILI) and registered their symptoms and signs, general characteristics and contextual information. The samples were analysed by a DirectigenFlu-A&B and RT-PCR tests. 4584 records were useful for further analysis.Starting from the most relevant variables in a Generalized Estimating Equations (GEE) model, we calculated the area under the Receiver Operating Characteristic curve (ROC AUC), sensitivity, specificity and likelihood ratios for positive (LR+) and negative test results (LR-) of single and combined signs, symptoms and context taking into account pre-test and post-test odds. RESULTS: In total 52.6% (2409/4584) of the samples were positive for influenza virus: 64% (2066/3212) during and 25% (343/1372) pre/post an influenza epidemic. During and pre/post an influenza epidemic the LR+ of 'previous flu-like contacts', 'coughing', 'expectoration on the first day of illness' and 'body temperature above 37.8 degrees C' is 3.35 (95%CI 2.67-4.03) and 1.34 (95%CI 0.97-1.72), respectively. During and pre/post an influenza epidemic the LR- of 'coughing' and 'a body temperature above 37.8 degrees C' is 0.34 (95%CI 0.27-0.41) and 0.07 (95%CI 0.05-0.08), respectively. CONCLUSIONS: Ruling out influenza using clinical and contextual information is easier than ruling it in. Outside an influenza epidemic the absence of cough and fever (> 37,8 degrees C) makes influenza 14 times less likely in ILI patients. During an epidemic the presence of 'previous flu-like contacts', cough, 'expectoration on the first day of illness' and fever (>37,8 degrees C) increases the likelihood for influenza threefold. The additional diagnostic value of rapid point of care tests especially for confirming influenza still has to be established. PMID- 21306611 TI - The expression of the ubiquitin ligase SIAH2 (seven in absentia homolog 2) is mediated through gene copy number in breast cancer and is associated with a basal like phenotype and p53 expression. AB - INTRODUCTION: The seven in absentia homolog 2 (SIAH2) protein plays a significant role in the hypoxic response by regulating the abundance of hypoxia-inducible factor-alpha; however, its role in breast carcinoma is unclear. We investigated the frequency and expression pattern of SIAH2 in two independent cohorts of sporadic breast cancers. METHODS: Immunohistochemical evaluation of SIAH2protein expression was conducted in normal breast tissues and in tissue microarrays comprising ductal carcinoma in situ (DCIS) and a cohort of invasive breast carcinomas. Correlation analysis was performed between SIAH2 and clinicopathological variables and intrinsic breast cancer subgroups and validated in a cohort of 293 invasive ductal carcinomas. Promoter methylation, gene copy number and mRNA expression of SIAH2 were determined in a panel of basal-like tumors and cell lines. RESULTS: There was a significant increase in nuclear SIAH2 expression from normal breast tissues through to DCIS and progression to invasive cancers. A significant inverse correlation was apparent between SIAH2 and estrogen receptor and progesterone receptor and a positive association with tumor grade, HER2, p53 and an intrinsic basal-like subtype. Logistic regression analysis confirmed the significant positive association between SIAH2 expression and the basal-like phenotype. No SIAH2 promoter methylation was identified, yet there was a significant correlation between SIAH2 mRNA and gene copy number. SIAH2-positive tumors were associated with a shorter relapse-free survival in univariate but not multivariate analysis. CONCLUSIONS: SIAH2 expression is upregulated in basal-like breast cancers via copy number changes and/or transcriptional activation by p53 and is likely to be partly responsible for the enhanced hypoxic drive through abrogation of the prolyl hydroxylases. PMID- 21306612 TI - Cognitive training plus a comprehensive psychosocial programme (OPUS) versus the comprehensive psychosocial programme alone for patients with first-episode schizophrenia (the NEUROCOM trial): a study protocol for a centrally randomised, observer-blinded multi-centre clinical trial. AB - BACKGROUND: Up to 85% of patients with schizophrenia demonstrate cognitive dysfunction in at least one domain. Cognitive dysfunction plays a major role in functional outcome. It is hypothesized that addition of cognitive training to a comprehensive psychosocial programme (OPUS) enhances both cognitive and everyday functional capacity of patients more than the comprehensive psychosocial programme alone. METHODS: The NEUROCOM trial examines the effect on cognitive functioning and everyday functional capacity of patients with schizophrenia of a 16-week manualised programme of individual cognitive training integrated in a comprehensive psychosocial programme versus the comprehensive psychosocial programme alone. The cognitive training consists of four modules focusing on attention, executive functioning, learning, and memory. Cognitive training involves computer-assisted training tasks as well as practical everyday tasks and calendar training. It takes place twice a week, and every other week the patient and trainer engage in a dialogue on the patient's cognitive difficulties, motivational goals, and progress in competence level. Cognitive training relies on errorless learning principles, scaffolding, and verbalisation in its effort to improve cognitive abilities and teach patients how to apply compensation strategies as well as structured problem solving techniques. At 16-week post training and at ten-months follow-up, assessments are conducted to investigate immediate outcome and possible long-term effects of cognitive training. We conduct blinded assessments of cognition, everyday functional capacity and associations with the labour market, symptom severity, and self-esteem. DISCUSSION: Results from four-month and ten-month follow-ups have the potential of reliably providing documentation of the long-term effect of CT for patients with schizophrenia. TRIAL REGISTRATION: Clinicaltrials.gov NCT00472862. PMID- 21306613 TI - Integration of linkage maps for the Amphidiploid Brassica napus and comparative mapping with Arabidopsis and Brassica rapa. AB - BACKGROUND: The large number of genetic linkage maps representing Brassica chromosomes constitute a potential platform for studying crop traits and genome evolution within Brassicaceae. However, the alignment of existing maps remains a major challenge. The integration of these genetic maps will enhance genetic resolution, and provide a means to navigate between sequence-tagged loci, and with contiguous genome sequences as these become available. RESULTS: We report the first genome-wide integration of Brassica maps based on an automated pipeline which involved collation of genome-wide genotype data for sequence-tagged markers scored on three extensively used amphidiploid Brassica napus (2n = 38) populations. Representative markers were selected from consolidated maps for each population, and skeleton bin maps were generated. The skeleton maps for the three populations were then combined to generate an integrated map for each LG, comparing two different approaches, one encapsulated in JoinMap and the other in MergeMap. The BnaWAIT_01_2010a integrated genetic map was generated using JoinMap, and includes 5,162 genetic markers mapped onto 2,196 loci, with a total genetic length of 1,792 cM. The map density of one locus every 0.82 cM, corresponding to 515 Kbp, increases by at least three-fold the locus and marker density within the original maps. Within the B. napus integrated map we identified 103 conserved collinearity blocks relative to Arabidopsis, including five previously unreported blocks. The BnaWAIT_01_2010a map was used to investigate the integrity and conservation of order proposed for genome sequence scaffolds generated from the constituent A genome of Brassica rapa. CONCLUSIONS: Our results provide a comprehensive genetic integration of the B. napus genome from a range of sources, which we anticipate will provide valuable information for rapeseed and Canola research. PMID- 21306614 TI - Introduction of organised mammography screening in Tyrol: results of a one-year pilot phase. AB - BACKGROUND: Efficiency and efficacy of organised mammography screening programs have been proven in large randomised trials. But every local implementation of mammography screening has to check whether the well established quality standards are met. Therefore it was the aim of this study to analyse the most common quality indices after introducing organised mammography screening in Tyrol, Austria, in a smooth transition from the existing system of opportunistic screening. METHODS: In June 2007, the system of opportunistic mammography screening in Tyrol was changed to an organised system by introducing a personal invitation system, a training program, a quality assurance program and by setting up a screening database. All procedures are noted in a written protocol. Most EU recommendations for organised mammography screening were followed, except double reading. All women living in Tyrol and covered by social insurance are now invited for a mammography, in age group 40-59 annually and in age group 60-69 biannually. Screening mammography is offered mainly by radiologists in private practice. We report on the results of the first year of piloting organised mammography screening in two counties in Tyrol. RESULTS: 56,432 women were invited. Estimated participation rate was 34.5% at one year of follow-up (and 55.5% at the second year of follow-up); 3.4% of screened women were recalled for further assessment or intermediate screening within six months. Per 1000 mammograms nine biopsies were performed and four breast cancer cases detected (N = 68). Of invasive breast cancer cases 34.4% were <= 10 mm in size and 65.6% were node-negative. In total, six interval cancer cases were detected during one year of follow-up; this is 19% of the background incidence rate. CONCLUSIONS: In the Tyrolean breast cancer screening program, a smooth transition from a spontaneous to an organised mammography screening system was achieved in a short time and with minimal additional resources. One year after introduction of the screening program, most of the quality indicators recommended by the European guidelines had been reached.However, it will be necessary to introduce double reading, to change the rule for BI-RADS 3, and to concentrate on actions toward improving the participation rate. PMID- 21306615 TI - Trends in primary total hip arthroplasty in Spain from 2001 to 2008: evaluating changes in demographics, comorbidity, incidence rates, length of stay, costs and mortality. AB - BACKGROUND: Hip arthroplasties is one of the most frequent surgical procedures in Spain and are conducted mainly in elderly subjects. We aim to analyze changes in incidence, co-morbidity profile, length of hospital stay (LOHS), costs and in hospital mortality (IHM) of patients undergoing primary total hip arthroplasty (THA) over an 8-year study period in Spain. METHODS: We selected all surgical admissions in individuals aged >= 40 years who had received a primary THA (ICD-9 CM procedure code 81.51) between 2001 and 2008 from the National Hospital Discharge Database. Age- and sex-specific incidence rates, LOHS, costs and IHM were estimated for each year. Co-morbidity was assessed using the Charlson comorbidity index.Multivariate analysis of time trends was conducted using Poisson regression. Logistic regression models were conducted to analyze IHM. RESULTS: We identified a total of 161,791 discharges of patients having undergone THA from 2001 to 2008. Overall crude incidence had increased from 99 to 105 THA per 100.000 inhabitants from 2001 to 2008 (p < 0.001). In 2001, 81% of patients had a Charlson Index of 0, 18.4% of 1-2, and 0.6% > 2 and in 2008, the prevalence of 1-2 or >2 had increased to 20.4% and 1.1% respectively (p < 0.001). The mean LOHS was 13 days in 2001 and decreased to 10.45 days in 2008 (p < 0.001). During the period studied, the mean cost per patient increased from 6,634 to 9,474 Euros. Multivariate analysis shows that from 2001 to 2008 the incidence of THA hospitalizations has significantly increased for both sexes and only men showed a significant reduction in IHM after THA. CONCLUSIONS: The current study provides clear and valid data indicating increased incidence of primary THA in Spain from 2001 to 2008 with concomitant reductions in LOHS, slight reduction IHM, but a significant increase in cost per patient. The health profile of the patient undergoing a THA seems to be worsening in Spain. PMID- 21306616 TI - Impacts of selected stimulation patterns on the perception threshold in electrocutaneous stimulation. AB - BACKGROUND: Consistency is one of the most important concerns to convey stable artificially induced sensory feedback. However, the constancy of perceived sensations cannot be guaranteed, as the artificially evoked sensation is a function of the interaction of stimulation parameters. The hypothesis of this study is that the selected stimulation parameters in multi-electrode cutaneous stimulation have significant impacts on the perception threshold. METHODS: The investigated parameters included the stimulated location, the number of active electrodes, the number of pulses, and the interleaved time between a pair of electrodes. Biphasic, rectangular pulses were applied via five surface electrodes placed on the forearm of 12 healthy subjects. RESULTS: Our main findings were: 1) the perception thresholds at the five stimulated locations were significantly different (p < 0.0001), 2) dual-channel simultaneous stimulation lowered the perception thresholds and led to smaller variance in perception thresholds compared to single-channel stimulation, 3) the perception threshold was inversely related to the number of pulses, and 4) the perception threshold increased with increasing interleaved time when the interleaved time between two electrodes was below 500 MUs. CONCLUSIONS: To maintain a consistent perception threshold, our findings indicate that dual-channel simultaneous stimulation with at least five pulses should be used, and that the interleaved time between two electrodes should be longer than 500 MUs. We believe that these findings have implications for design of reliable sensory feedback codes. PMID- 21306617 TI - Optimized diffusion of buck semen for saving genetic variability in selected dairy goat populations. AB - BACKGROUND: Current research on quantitative genetics has provided efficient guidelines for the sustainable management of selected populations: genetic gain is maximized while the loss of genetic diversity is maintained at a reasonable rate. However, actual selection schemes are complex, especially for large domestic species, and they have to take into account many operational constraints. This paper deals with the actual selection of dairy goats where the challenge is to optimize diffusion of buck semen on the field. Three objectives are considered simultaneously: i) natural service buck replacement (NSR); ii) goat replacement (GR); iii) semen distribution of young bucks to be progeny tested. An appropriate optimization method is developed, which involves five analytical steps. Solutions are obtained by simulated annealing and the corresponding algorithms are presented in detail. RESULTS: The whole procedure was tested on two French goat populations (Alpine and Saanen breeds) and the results presented in the abstract were based on the average of the two breeds. The procedure induced an immediate acceleration of genetic gain in comparison with the current annual genetic gain (0.15 genetic standard deviation unit), as shown by two facts. First, the genetic level of replacement natural service (NS) bucks was predicted, 1.5 years ahead at the moment of reproduction, to be equivalent to that of the progeny-tested bucks in service, born from the current breeding scheme. Second, the genetic level of replacement goats was much higher than that of their dams (0.86 unit), which represented 6 years of selection, although dams were only 3 years older than their replacement daughters. This improved genetic gain could be achieved while decreasing inbreeding coefficients substantially. Inbreeding coefficients (%) of NS bucks was lower than that of the progeny-tested bucks (-0.17). Goats were also less inbred than their dams ( 0.67). CONCLUSIONS: It was possible to account for complex operational constraints while developing goat selection schemes, both efficient and sustainable. Therefore, the recommended selection and mating decisions might receive attention from goat breeders using both AI and NS. PMID- 21306618 TI - Central administration of insulin-like growth factor-I decreases depressive-like behavior and brain cytokine expression in mice. AB - Exogenous administration of insulin-like growth factor (IGF)-I has anti depressant properties in rodent models of depression. However, nothing is known about the anti-depressant properties of IGF-I during inflammation, nor have mechanisms by which IGF-I alters behavior following activation of the innate immune system been clarified. We hypothesized that central IGF-I would diminish depressive-like behavior on a background of an inflammatory response and that it would do so by inducing expression of the brain-derived neurotrophic factor (BDNF) while decreasing pro-inflammatory cytokine expression in the brain. IGF-I (1,000 ng) was administered intracerebroventricularly (i.c.v.) to CD-1 mice. Mice were subsequently given lipopolysaccharide i.c.v. (LPS, 10 ng). Sickness and depressive-like behaviors were assessed followed by analysis of brain steady state mRNA expression. Central LPS elicited typical transient signs of sickness of mice, including body weight loss, reduced feed intake and decreased social exploration toward a novel juvenile. Similarly, LPS increased time of immobility in the tail suspension test (TST). Pretreatment with IGF-I or antidepressants significantly decreased duration of immobility in the TST in both the absence and presence of LPS. To elucidate the mechanisms underlying the anti-depressant action of IGF-I, we quantified steady-state mRNA expression of inflammatory mediators in whole brain using real-time RT-PCR. LPS increased, whereas IGF-I decreased, expression of inflammatory markers interleukin-1beta (IL-1beta), tumor necrosis factor-(TNF)alpha, inducible nitric oxide synthase (iNOS) and glial fibrillary acidic protein (GFAP). Moreover, IGF-I increased expression of BDNF. These results indicate that IGF-I down regulates glial activation and induces expression of an endogenous growth factor that shares anti-depressant activity. These actions of IGF-I parallel its ability to diminish depressive-like behavior. PMID- 21306620 TI - Translating evidence into policy for cardiovascular disease control in India. AB - Cardiovascular diseases (CVD) are leading causes of premature mortality in India. Evidence from developed countries shows that mortality from these can be substantially prevented using population-wide and individual-based strategies. Policy initiatives for control of CVD in India have been suggested but evidence of efficacy has emerged only recently. These initiatives can have immediate impact in reducing morbidity and mortality. Of the prevention strategies, primordial involve improvement in socioeconomic status and literacy, adequate healthcare financing and public health insurance, effective national CVD control programme, smoking control policies, legislative control of saturated fats, trans fats, salt and alcohol, and development of facilities for increasing physical activity through better urban planning and school-based and worksite interventions. Primary prevention entails change in medical educational curriculum and improved healthcare delivery for control of CVD risk factors smoking, hypertension, dyslipidemia and diabetes. Secondary prevention involves creation of facilities and human resources for optimum acute CVD care and secondary prevention. There is need to integrate various policy makers, develop effective policies and modify healthcare systems for effective delivery of CVD preventive care. PMID- 21306619 TI - Responsiveness of genes to manipulation of transcription factors in ES cells is associated with histone modifications and tissue specificity. AB - BACKGROUND: In addition to determining static states of gene expression (high vs. low), it is important to characterize their dynamic status. For example, genes with H3K27me3 chromatin marks are not only suppressed but also poised for activation. However, the responsiveness of genes to perturbations has never been studied systematically. To distinguish gene responses to specific factors from responsiveness in general, it is necessary to analyze gene expression profiles of cells responding to a large variety of disturbances, and such databases did not exist before. RESULTS: We estimated the responsiveness of all genes in mouse ES cells using our recently published database on expression change after controlled induction of 53 transcription factors (TFs) and other genes. Responsive genes (N=4746), which were readily upregulated or downregulated depending on the kind of perturbation, mostly have regulatory functions and a propensity to become tissue-specific upon differentiation. Tissue-specific expression was evaluated on the basis of published (GNF) and our new data for 15 organs and tissues. Non responsive genes (N=9562), which did not change their expression much following any perturbation, were enriched in housekeeping functions. We found that TF responsiveness in ES cells is the best predictor known for tissue-specificity in gene expression. Among genes with CpG islands, high responsiveness is associated with H3K27me3 chromatin marks, and low responsiveness is associated with H3K36me3 chromatin, stronger tri-methylation of H3K4, binding of E2F1, and GABP binding motifs in promoters. CONCLUSIONS: We thus propose the responsiveness of expression to perturbations as a new way to define the dynamic status of genes, which brings new insights into mechanisms of regulation of gene expression and tissue specificity. PMID- 21306621 TI - Analysis of protein composition of rabbit aqueous humor following two different cataract surgery incision procedures using 2-DE and LC-MS/MS. AB - BACKGROUND: The aqueous humor (AH), a liquid of the anterior and posterior chamber of the eye, comprises many proteins with various roles and important biological functions. Many of these proteins have not been identified yet and their functions in AH are still unknown. Recently, our laboratory published the protein database of AH obtained from healthy rabbits which expanded known protein identifications by 65%. Our present study extends our previous work and analyses AH following two types of cataract surgery incision procedures (clear corneal and limbal incisions) by using two dimensional gel electrophoresis (2-DE) and liquid chromatography tandem mass spectrometry (LC-MS/MS). Although both incision protocols are commonly used during cataract surgeries, the difference in protein composition and their release into AH following each surgery has never been systematically compared and remains unclear. The first step, which is the focus of this work, is to assess the scale of the protein change, at which time does maximum release occurs and when possible, to identify protein changes. RESULTS: Samples of AH obtained prior to surgery and at different time points (0.5, 2, 12, 24 and 48 hours) following surgery (n = 3/protocol) underwent protein concentration determination, 2-DE and LC-MS/MS. There was a large (9.7 to 31.2 mg/mL) and rapid (~0.5 hour) influx of proteins into AH following either incision with a return to baseline quantities after 12 hours and 24 hours for clear corneal and limbal incision, respectively. We identified 80 non-redundant proteins, and compared to our previous study on healthy AH, 67.5% of proteins were found to be surgery-specific. In addition, 51% of those proteins have been found either in clear corneal (20%) or limbal incision (31%) samples. CONCLUSIONS: Our results imply that a mechanism of protein release into AH after surgery is a global response to the surgery rather than increase in amount of protective proteins found in healthy AH and a mechanism of protein release for each type of incision procedure could be different. Although the total protein concentration was increased (at 0.5 and 2 hour time points and between types of surgery) many of 2-DE protein spots were similar based on 2-DE and MS analyses, and only a small number of protein spots changed with either the time points or surgical conditions (0.4 -1.9%). This suggests that the high protein content is due to an increase in the concentration of the same proteins with only a few unique proteins being altered per time point and with the different surgery type. This is the first report on the comparison of AH protein composition following two different cataract surgery procedures and it establishes the basis for better understanding of protein release into AH during events such as cataract surgery or other possible intervention to the eyes. PMID- 21306622 TI - Transthoracic echocardiography for the diagnosis of left ventricular thrombosis in the postoperative care unit. AB - INTRODUCTION: Transthoracic echocardiography (TTE) is a reliable, noninvasive imaging method that is useful in the evaluation of cardiovascular thrombosis. We conducted a retrospective study of all the echocardiograms from patients in the postoperative care unit to assess the role of TTE in thrombus identification in the left ventricle. METHODS: This retrospective database evaluation included all echocardiograms during a 14-month period. The echocardiographic examination protocol included the subcostal four-chamber view, the apical four-chamber view, the apical two-chamber view and the parasternal view, along the long and short axes in both spontaneously and mechanically ventilated patients. All echocardiograms were obtained within the 48 hours immediately following surgery. RESULTS: In total, 160 postoperative echocardiograms were obtained from 160 patients and resulted in the detection of five cases of left ventricular thrombosis. Subgroup analysis showed that 21 and 35 of the 160 patients examined had either dilated or ischemic cardiomyopathy, respectively. In these patients, preoperative echocardiograms had been obtained recently prior to surgery and were negative for left ventricular thrombus. In three of 35 patients with ischemic cardiomyopathy and two of 21 patients with dilated cardiomyopathy, thrombus was identified in the left ventricle. The thrombi were mobile, uncalcified and pedunculated and were located in the apex of the left ventricle. In addition, no clinical consequences of the left ventricular thrombi were recorded. CONCLUSIONS: Low-flow conditions in heart chambers due to ischemic or dilated cardiomyopathy in conjunction with the hypercoagulability caused by perioperative prothrombotic factors may lead to thrombotic events in the left ventricle. PMID- 21306623 TI - Pseudomonas aeruginosa acquisition on an intensive care unit: relationship between antibiotic selective pressure and patients' environment. AB - INTRODUCTION: The purpose of this study was to investigate the relationship among Pseudomonas aeruginosa acquisition on the intensive care unit (ICU), environmental contamination and antibiotic selective pressure against P. aeruginosa. METHODS: An open, prospective cohort study was carried out in a 16 bed medical ICU where P. aeruginosa was endemic. Over a six-month period, all patients without P. aeruginosa on admission and with a length of stay >72 h were included. Throat, nasal, rectal, sputum and urine samples were taken on admission and at weekly intervals and screened for P. aeruginosa. All antibiotic treatments were recorded daily. Environmental analysis included weekly tap water specimen culture and the presence of other patients colonized with P. aeruginosa. RESULTS: A total of 126 patients were included, comprising 1,345 patient-days. Antibiotics were given to 106 patients (antibiotic selective pressure for P. aeruginosa in 39). P. aeruginosa was acquired by 20 patients (16%) and was isolated from 164/536 environmental samples (31%). Two conditions were independently associated with P. aeruginosa acquisition by multivariate analysis: (i) patients receiving >=3 days of antibiotic selective pressure together with at least one colonized patient on the same ward on the previous day (odds ratio (OR) = 10.3 ((% confidence interval (CI): 1.8 to 57.4); P = 0.01); and (ii) presence of an invasive device (OR = 7.7 (95% CI: 2.3 to 25.7); P = 0.001). CONCLUSIONS: Specific interaction between both patient colonization pressure and selective antibiotic pressure is the most relevant factor for P. aeruginosa acquisition on an ICU. This suggests that combined efforts are needed against both factors to decrease colonization with P. aeruginosa. PMID- 21306624 TI - Anger management for people with mild to moderate learning disabilities: study protocol for a multi-centre cluster randomized controlled trial of a manualized intervention delivered by day-service staff. AB - BACKGROUND: Cognitive behaviour therapy (CBT) is the treatment of choice for common mental health problems, but this approach has only recently been adapted for people with learning disabilities, and there is a limited evidence base for the use of CBT with this client group. Anger treatment is the one area where there exists a reasonable number of small controlled trials. This study will evaluate the effectiveness of a manualized 12-week CBT intervention for anger. The intervention will be delivered by staff working in the day services that the participants attend, following training to act as 'lay therapists' by a Clinical Psychologist, who will also provide supervision. METHODS/DESIGN: This is a multi centre cluster randomized controlled trial of a group intervention versus a 'support as usual' waiting-list control group, with randomization at the level of the group. Outcomes will be assessed at the end of the intervention and again 6 months later. After completion of the 6-month follow-up assessments, the intervention will also be delivered to the waiting-list groups. The study will include a range of anger/aggression and mental health measures, some of which will be completed by service users and also by their day service key-workers and by home carers. Qualitative data will be collected to assess the impact of the intervention on participants, lay therapists, and services, and the study will also include a service-utilization cost and consequences analysis. DISCUSSION: This will be the first trial to investigate formally how effectively staff working in services providing day activities for people with learning disabilities are able to use a therapy manual to deliver a CBT based anger management intervention, following brief training by a Clinical Psychologist. The demonstration that service staff can successfully deliver anger management to people with learning disabilities, by widening the pool of potential therapists, would have very significant benefits in relation to the current policy of improving access to psychological therapies, in addition to addressing more effectively an important and often unmet need of this vulnerable client group. The economic analysis will identify the direct and indirect costs (and/or savings) of the intervention and consider these in relation to the range of observed effects. The qualitative analyses will enhance the interpretation of the quantitative data, and if the study shows positive results, will inform the roll out of the intervention to the wider community. TRIAL REGISTRATION: ISRCTN: ISRCTN37509773. PMID- 21306625 TI - The cost-effectiveness of preventing mother-to-child transmission of HIV in low- and middle-income countries: systematic review. AB - BACKGROUND: Although highly effective prevention interventions exist, the epidemic of paediatric HIV continues to challenge control efforts in resource limited settings. We reviewed the cost-effectiveness of interventions to prevent mother-to-child transmission (MTCT) of HIV in low- and middle-income countries (LMICs). This article presents syntheses of evidence on the costs, effects and cost-effectiveness of HIV MTCT strategies for LMICs from the published literature and evaluates their implications for policy and future research. METHODS: Candidate studies were identified through a comprehensive database search including PubMed, Embase, Cochrane Library, and EconLit restricted by language (English or French), date (January 1st, 1994 to January 17th, 2011) and article type (original research). Articles reporting full economic evaluations of interventions to prevent or reduce HIV MTCT were eligible for inclusion. We searched article bibliographies to identify additional studies. Two authors independently assessed eligibility and extracted data from studies retained for review. Study quality was appraised using a modified BMJ checklist for economic evaluations. Data were synthesised in narrative form. RESULTS: We identified 19 articles published in 9 journals from 1996 to 2010, 16 concerning sub-Saharan Africa. Collectively, the articles suggest that interventions to prevent paediatric infections are cost-effective in a variety of LMIC settings as measured against accepted international benchmarks. In concentrated epidemics where HIV prevalence in the general population is very low, MTCT strategies based on universal testing of pregnant women may not compare well against cost effectiveness benchmarks, or may satisfy formal criteria for cost-effectiveness but offer a low relative value as compared to competing interventions to improve population health. CONCLUSIONS AND RECOMMENDATIONS: Interventions to prevent HIV MTCT are compelling on economic grounds in many resource-limited settings and should remain at the forefront of global HIV prevention efforts. Future cost effectiveness analyses can help to ensure that pMTCT interventions for LMICs reach their full potential by focussing on unanswered questions in four areas: local assessment of rapidly evolving HIV MTCT options; strategies to improve coverage and reach underserved populations; evaluation of a more comprehensive set of MTCT approaches including primary HIV prevention and reproductive counselling; integration of HIV MTCT and other sexual and reproductive health services. PMID- 21306626 TI - Identification of early changes in specific symptoms that predict longer-term response to atypical antipsychotics in the treatment of patients with schizophrenia. AB - BACKGROUND: To identify a simple decision tree using early symptom change to predict response to atypical antipsychotic therapy in patients with (Diagnostic and Statistical Manual, Fourth Edition, Text Revised) chronic schizophrenia. METHODS: Data were pooled from moderately to severely ill patients (n = 1494) from 6 randomized, double-blind trials (N = 2543). Response was defined as a >= 30% reduction in Positive and Negative Syndrome Scale (PANSS) Total score by Week 8 of treatment. Analyzed predictors were change in individual PANSS items at Weeks 1 and 2. A decision tree was constructed using classification and regression tree (CART) analysis to identify predictors that most effectively differentiated responders from non-responders. RESULTS: A 2-branch, 6-item decision tree was created, producing 3 distinct groups. First branch criterion was a 2-point score decrease in at least 2 of 5 PANSS positive items (Week 2). Second branch criterion was a 2-point score decrease in the PANSS excitement item (Week 2). "Likely responders" met the first branch criteria; "likely non responders" did not meet first or second criterion; "not predictable" patients did not meet the first but did meet the second criterion. Using this approach, response to treatment could be predicted in most patients (92%) with high positive predictive value (79%) and high negative predictive value (75%). Predictive findings were confirmed through analysis of data from 2 independent trials. CONCLUSIONS: Using a data-driven approach, we identified decision rules using early change in the scores of selected PANSS items to accurately predict longer-term treatment response or non-response to atypical antipsychotic therapy. This could lead to development of a simple quantitative evaluation tool to help guide early treatment decisions. TRIAL REGISTRATION: This is a retrospective, non intervention study in which pooled results from 6 previously published reports were analyzed; thus, clinical trial registration is not required. PMID- 21306627 TI - At the frontiers of surgery: review. AB - The complete surgical removal of disease is a desirable outcome particularly in oncology. Unfortunately much disease is microscopic and difficult to detect causing a liability to recurrence and worsened overall prognosis with attendant costs in terms of morbidity and mortality. It is hoped that by advances in optical diagnostic technology we could better define our surgical margin and so increase the rate of truly negative margins on the one hand and on the other hand to take out only the necessary amount of tissue and leave more unaffected non diseased areas so preserving function of vital structures. The task has not been easy but progress is being made as exemplified by the presentations at the 2nd Scientific Meeting of the Head and Neck Optical Diagnostics Society (HNODS) in San Francisco in January 2010. We review the salient advances in the field and propose further directions of investigation. PMID- 21306628 TI - A telemedicine instrument for remote evaluation of tremor: design and initial applications in fatigue and patients with Parkinson's disease. AB - INTRODUCTION: A novel system that combines a compact mobile instrument and Internet communications is presented in this paper for remote evaluation of tremors. The system presents a high potential application in Parkinson's disease and connects to the Internet through a TCP/IP protocol. Tremor transduction is carried out by accelerometers, and the data processing, presentation and storage were obtained by a virtual instrument. The system supplies the peak frequency (fp), the amplitude (Afp) and power in this frequency (Pfp), the total power (Ptot), and the power in low (1-4 Hz) and high (4-7 Hz) frequencies (Plf and Phf, respectively). METHODS: The ability of the proposed system to detect abnormal tremors was initially demonstrated by a fatigue study in normal subjects. In close agreement with physiological fundamentals, the presence of fatigue increased fp, Afp, Pfp and Pt (p < 0.05), while the removal of fatigue reduced all the mentioned parameters (p < 0.05). The system was also evaluated in a preliminary in vivo test in parkinsonian patients. Afp, Pfp, Ptot, Plf and Phf were the most accurate parameters in the detection of the adverse effects of this disease (Se = 100%, Sp = 100%), followed by fp (Se = 100%, Sp = 80%). Tests for Internet transmission that realistically simulated clinical conditions revealed adequate acquisition and analysis of tremor signals and also revealed that the user could adequately receive medical recommendations. CONCLUSIONS: The proposed system can be used in a wide spectrum of telemedicine scenarios, enabling the home evaluation of tremor occurrence under specific medical treatments and contributing to reduce the costs of the assistance offered to these patients. PMID- 21306629 TI - Dosimetric accuracy of tomotherapy dose calculation in thorax lesions. AB - BACKGROUND: To analyse limits and capabilities in dose calculation of collapsed cone-convolution (CCC) algorithm implemented in helical tomotherapy (HT) treatment planning system for thorax lesions. METHODS: The agreement between measured and calculated dose was verified both in homogeneous (Cheese Phantom) and in a custom-made inhomogeneous phantom. The inhomogeneous phantom was employed to mimic a patient's thorax region with lung density encountered in extreme cases and acrylic inserts of various dimensions and positions inside the lung cavity. For both phantoms, different lung treatment plans (single or multiple metastases and targets in the mediastinum) using HT technique were simulated and verified. Point and planar dose measurements, both with radiographic extended-dose-range (EDR2) and radiochromic external-beam-therapy (EBT2) films, were performed. Absolute point dose measurements, dose profile comparisons and quantitative analysis of gamma function distributions were analyzed. RESULTS: An excellent agreement between measured and calculated dose distributions was found in homogeneous media, both for point and planar dose measurements. Absolute dose deviations <3% were found for all considered measurement points, both inside the PTV and in critical structures. Very good results were also found for planar dose distribution comparisons, where at least 96% of all points satisfied the gamma acceptance criteria (3%-3 mm), both for EDR2 and for EBT2 films. Acceptable results were also reported for the inhomogeneous phantom. Similar point dose deviations were found with slightly worse agreement for the planar dose distribution comparison: 96% of all points passed the gamma analysis test with acceptable levels of 4%-4 mm and 5%-4 mm, for EDR2 and EBT2 films respectively. Lower accuracy was observed in high dose/low density regions, where CCC seems to overestimate the measured dose around 4-5%. CONCLUSIONS: Very acceptable accuracy was found for complex lung treatment plans calculated with CCC algorithm implemented in the tomotherapy TPS even in the heterogeneous phantom with very low lung-density. PMID- 21306630 TI - Tremendous bleeding complication after vacuum-assisted sternal closure. AB - Vacuum-assisted closure (VAC) of complex infected wounds has recently gained popularity among various surgical specialties. The system is based on the application of negative pressure by controlled suction to the wound surface. The effectiveness of the VAC System on microcirculation and the promotion of granulation tissue proliferation are proved. No contraindications for the use in deep sternal wounds in cardiac surgery are described. In our case report we illustrate a scenario were a patient developed severe bleeding from the ascending aorta by penetration of wire fragments in the vessel. We conclude that all free particles in the sternum have to be removed completely before negative pressure is used. PMID- 21306631 TI - Vectorial status and insecticide resistance of Anopheles funestus from a sugar estate in southern Mozambique. AB - BACKGROUND: The dual problems of rising insecticide resistance in the malaria vectors and increasing human malaria cases since 2001 in southern Mozambique are cause for serious concern. The selection of insecticides for use in indoor residual spraying (IRS) programmes is highly dependent on the extent to which local mosquitoes are susceptible to the approved classes of insecticides. The insecticide resistance status and role in malaria transmission of Anopheles funestus was evaluated at the Maragra Sugar Estate in southern Mozambique where an IRS vector control programme has been in operation for seven years using the carbamate insecticide bendiocarb. RESULTS: No Anopheles species were captured inside the sugar estate control area. Anopheles funestus group captured outside of the estate represented 90% (n = 475) of the total collections. Of the specimens identified to species by PCR (n = 167), 95% were An. funestus s.s. One An. rivulorum was identified and seven specimens did not amplify. The Anopheles gambiae complex was less abundant (n = 53) and of those identified (n = 33) 76% were An. arabiensis and 24% An. merus. Insecticide susceptibility tests showed that wild-caught and F-1 family An. funestus were resistant to deltamethrin (32.5% mortality) and lambda-cyhalothrin (14.6% mortality), less so to bendiocarb (71.5% mortality) and fully susceptible to both malathion and DDT (100%). Bendiocarb and pyrethroid resistance was nullified using 4% piperonyl butoxide (Pbo), strongly suggesting that both are mediated by P450 monooxygenase detoxification. ELISA tests of An. funestus for Plasmodium falciparum, gave a sporozoite rate of 6.02% (n = 166). One unidentified member of the An. gambiae complex tested positive for P. falciparum sporozoites. CONCLUSION: Anopheles funestus was found to be the most abundant and principle vector of malaria in this area, with members of the An. gambiae complex being secondary vectors. Despite the continual use of bendiocarb within the estate for seven years and the level of An. funestus resistance to this insecticide, the IVC programme is still effective against this and other Anopheles in that no vectors were found inside the control area. However, the Mozambique National Malaria Control Programme ceased the use of DDT and bendiocarb in this area of its operations in 2009, and replaced these insecticides with a pyrethroid which will increase insecticide resistance selection pressure and impact on control programmes such as the Maragra IVC. PMID- 21306633 TI - Evolutionary patterns of phosphorylated serines. AB - Posttranslationally modified amino acids are chemically distinct types of amino acids and in terms of evolution they might behave differently from their non modified counterparts. In order to check this possibility, we reconstructed the evolutionary history of phosphorylated serines in several groups of organisms. Comparisons of substitution vectors have revealed some significant differences in the evolution of modified and corresponding non-modified amino acids. In particular, phosphoserines are more frequently substituted to aspartate and glutamate, compared to non-phosphorylated serines. PMID- 21306632 TI - Problems and challenges in the development and validation of human cell-based assays to determine nanoparticle-induced immunomodulatory effects. AB - BACKGROUND: With the increasing use of nanomaterials, the need for methods and assays to examine their immunosafety is becoming urgent, in particular for nanomaterials that are deliberately administered to human subjects (as in the case of nanomedicines). To obtain reliable results, standardised in vitro immunotoxicological tests should be used to determine the effects of engineered nanoparticles on human immune responses. However, before assays can be standardised, it is important that suitable methods are established and validated. RESULTS: In a collaborative work between European laboratories, existing immunological and toxicological in vitro assays were tested and compared for their suitability to test effects of nanoparticles on immune responses. The prototypical nanoparticles used were metal (oxide) particles, either custom generated by wet synthesis or commercially available as powders. Several problems and challenges were encountered during assay validation, ranging from particle agglomeration in biological media and optical interference with assay systems, to chemical immunotoxicity of solvents and contamination with endotoxin. CONCLUSION: The problems that were encountered in the immunological assay systems used in this study, such as chemical or endotoxin contamination and optical interference caused by the dense material, significantly affected the data obtained. These problems have to be solved to enable the development of reliable assays for the assessment of nano-immunosafety. PMID- 21306634 TI - Tree Pruner: An efficient tool for selecting data from a biased genetic database. AB - BACKGROUND: Large databases of genetic data are often biased in their representation. Thus, selection of genetic data with desired properties, such as evolutionary representation or shared genotypes, is problematic. Selection on the basis of epidemiological variables may not achieve the desired properties. Available automated approaches to the selection of influenza genetic data make a tradeoff between speed and simplicity on the one hand and control over quality and contents of the dataset on the other hand. A poorly chosen dataset may be detrimental to subsequent analyses. RESULTS: We developed a tool, Tree Pruner, for obtaining a dataset with desired evolutionary properties from a large, biased genetic database. Tree Pruner provides the user with an interactive phylogenetic tree as a means of editing the initial dataset from which the tree was inferred. The tree visualization changes dynamically, using colors and shading, reflecting Tree Pruner actions. At the end of a Tree Pruner session, the editing actions are implemented in the dataset. Currently, Tree Pruner is implemented on the Influenza Research Database (IRD). The data management capabilities of the IRD allow the user to store a pruned dataset for additional pruning or for subsequent analysis. Tree Pruner can be easily adapted for use with other organisms. CONCLUSIONS: Tree Pruner is an efficient, manual tool for selecting a high quality dataset with desired evolutionary properties from a biased database of genetic sequences. It offers an important alternative to automated approaches to the same goal, by providing the user with a dynamic, visual guide to the ongoing selection process and ultimate control over the contents (and therefore quality) of the dataset. PMID- 21306636 TI - Prevalence of Plasmodium falciparum infection in asymptomatic rural Gabonese populations. AB - BACKGROUND: Malaria may be perennial or epidemic in sub-Saharan Africa, and its transmission may be stable or unstable, depending on the region. The prevalence of asymptomatic Plasmodium falciparum carriage is poorly documented in Gabon. A large survey of P. falciparum infection was conducted in asymptomatic individuals living in rural Gabon. METHODS: Two hundred and twenty-two villages were randomly selected in the nine administrative regions. With the participants' informed consent, blood samples were collected for thick and thin blood film examination after 20% Giemsa staining. Prevalence rates were calculated per village, per region and per ecosystem, and nationwide. Demographic risk factors were identified with STATA software version 9.0. Significance was assumed at p < 0.05. RESULTS AND DISCUSSION: The prevalence of P. falciparum in adults was 6.2% (269/4342) nationwide, with a maximum of 37.2% in one village; a linear decrease was observed with increasing age (p = 0.045). Only 5% of the 399 children from forest areas tested positive. The prevalence was significantly higher in forest areas (7%) than in savannah (4%) and lakeland (2.5%). Within the forest region, the prevalence was significantly higher in forest grassland (10.9%) than in the mountain forest (3.5%), interior forest (6.8%) and north-eastern forest (4.5%). CONCLUSION: Plasmodium falciparum carriage remains high among adults in rural Gabon. Control measures must be adapted to the region and ecosystem. Routine treatment of asymptomatic individuals should be considered. PMID- 21306635 TI - Variable expressivity of FGF3 mutations associated with deafness and LAMM syndrome. AB - BACKGROUND: Recessive mutations of fibroblast growth factor 3 (FGF3) can cause LAMM syndrome (OMIM 610706), characterized by fully penetrant complete labyrinthine aplasia, microtia and microdontia. METHODS: We performed a prospective molecular genetic and clinical study of families segregating hearing loss linked to FGF3 mutations. Ten affected individuals from three large Pakistani families segregating FGF3 mutations were imaged with CT, MRI, or both to detect inner ear abnormalities. We also modeled the three dimensional structure of FGF3 to better understand the structural consequences of the three missense mutations. RESULTS: Two families segregated reported mutations (p.R104X and p.R95W) and one family segregated a novel mutation (p.R132GfsX26) of FGF3. All individuals homozygous for p.R104X or p.R132GfsX26 had fully penetrant features of LAMM syndrome. However, recessive p.R95W mutations were associated with nearly normal looking auricles and variable inner ear structural phenotypes, similar to that reported for a Somali family also segregating p.R95W. This suggests that the mild phenotype is not entirely due to genetic background. Molecular modeling result suggests a less drastic effect of p.R95W on FGF3 function compared with known missense mutations detected in fully penetrant LAMM syndrome. Since we detected significant intrafamilial variability of the inner ear structural phenotype in the family segregating p.R95W, we also sequenced FGF10 as a likely candidate for a modifier. However, we did not find any sequence variation, pointing out that a larger sample size will be needed to map and identify a modifier. We also observed a mild to moderate bilateral conductive hearing loss in three carriers of p.R95W, suggesting either a semi-dominant effect of this mutant allele of FGF3, otitis media, or a consequence of genetic background in these three family members. CONCLUSIONS: We noted a less prominent dental and external ear phenotype in association with the homozygous p.R95W. Therefore, we conclude that the manifestations of recessive FGF3 mutations range from fully penetrant LAMM syndrome to deafness with residual inner ear structures and, by extension, with minimal syndromic features, an observation with implications for cochlear implantation candidacy. PMID- 21306637 TI - Two-step cleavage of hairpin RNA with 5' overhangs by human DICER. AB - BACKGROUND: DICER is an RNase III family endoribonuclease that processes precursor microRNAs (pre-miRNAs) and long double-stranded RNAs, generating microRNA (miRNA) duplexes and short interfering RNA duplexes with 20~23 nucleotides (nts) in length. The typical form of pre-miRNA processed by the Drosha protein is a hairpin RNA with 2-nt 3' overhangs. On the other hand, production of mature miRNA from an endogenous hairpin RNA with 5' overhangs has also been reported, although the mechanism for this process is unknown. RESULTS: In this study, we show that human recombinant DICER protein (rDICER) processes a hairpin RNA with 5' overhangs in vitro and generates an intermediate duplex with a 29 nt-5' strand and a 23 nt-3' strand, which was eventually cleaved into a canonical miRNA duplex via a two-step cleavage. The previously identified endogenous pre-miRNA with 5' overhangs, pre-mmu-mir-1982 RNA, is also determined to be a substrate of rDICER through the same two-step cleavage. CONCLUSIONS: The two-step cleavage of a hairpin RNA with 5' overhangs shows that DICER releases double-stranded RNAs after the first cleavage and binds them again in the inverse direction for a second cleavage. These findings have implications for how DICER may be able to interact with or process differing precursor structures. PMID- 21306638 TI - A novel HPV 16 L1-based chimeric virus-like particle containing E6 and E7 seroreactive epitopes permits highly specific detection of antibodies in patients with CIN 1 and HPV-16 infection. AB - BACKGROUND: The presence of IgG antibodies to HPV-16 L1-virus like particles (VLPs) in serum has been reported as a result of persistent exposure to the virus and as a marker of disease progression. However, detection of VLP-specific antibodies in sera does not always indicate a malignant lesion as positive results may also be due to a nonmalignant viral infection. Furthermore, malignant lesions are associated with an increased antibody titer for E6 and E7 proteins. The aim of this study was to develop an ELISA using a novel chimeric virus-like particle (cVLP) encoding an L1 protein fused with a string of HPV-16 E6 and E7 seroreactive epitopes to its C-terminus to be used for detection of HPV-16 specific antibodies in patients with cervical intraepithelial lesion grade 1 (CIN 1). RESULTS: The sera of 30 patients with CIN 1 who also tested positive for HPV 16 DNA and of 30 age-matched normal donors negative for HPV infection were tested for the presence of IgG antibodies specific for either VLP-L1 (HPV-16 L1), gVLP (derived from Gardasil), or cVLP by ELISA. The cVLP-reactive sera yielded two distinct groups of results: (H) reactivity levels that presented very strong cVLP specific titers, and (L) reactivity levels with significantly lower titers similar to those obtained with VLP-L1 and gVLP antigens. Additionally, the sera that presented the higher cVLP titers closely matched those that had significantly stronger reactivity to E6 and E7 epitopes. Interestingly, the samples with the highest titers corresponded to patients with the higher numbers of sexual partners and pregnancies. On the other hand only 4 out of the 12 sera that harbored antibodies with VLP neutralizing ability corresponded to the group with high cVLP antibody titers. CONCLUSION: We report for the first time that chimeric particles containing HPV-16 L1 protein fused with E6 and E7 seroreactive epitopes enable much better detection of IgG antibodies in the sera of CIN 1 patients positive for HPV-16 infection than those obtained with VLPs containing only the HPV-16 L1 protein. We also found that the sera with higher cVLP antibody titers corresponded to patients with more sexual partners and pregnancies, and not always with to those with a high neutralizing activity. This novel assay could help in the development of a tool to evaluate cervical cancer risk. PMID- 21306640 TI - Comparison of the incidence, nature and cause of injuries sustained on dirt field and artificial turf field by amateur football players. AB - BACKGROUND: Data on the incidence, nature, severity and cause of match football injuries sustained on dirt field are scarce. The objectives of this study was to compare the incidence, nature, severity and cause of match injuries sustained on dirt field and artificial turf field by amateur male football players. METHODS: A prospective two-cohort design was employed. Participants were 252 male football players (mean age 27 years, range 18-43) in 14 teams who participated in a local championship carried on a dirt field and 216 male football players (mean age 28 years, range 17-40) in 12 teams who participated in a local championship carried on a artificial turf field in the same zone of the city. Injury definitions and recording procedures were compliant with the international consensus statement for epidemiological studies of injuries in football. RESULTS: The overall incidence of match injuries for men was 36.9 injuries/1000 player hours on dirt field and 19.5 on artificial turf (incidence rate ratio 1.88; 95% CI 1.19 3.05).Most common injured part on dirt field was ankle (26.7%) and on artificial turf was knee (24.3%). The most common injury type in the dirt field was skin injuries (abrasion and laceration) and in the artificial turf was sprain and ligament injury followed by haematoma/contusion/bruise.Most injuries were acute (artificial turf 89%, dirt field 91%) and resulted from player-to-player contact (artificial turf 59.2%, dirt field 51.4%).Most injuries were slight and minimal in dirt field cohort but in artificial turf cohort the most injuries were mild. CONCLUSIONS: There were differences in the incidence and type of football match injuries sustained on dirt field and artificial turf. PMID- 21306639 TI - Comparative phylogenies and host specialization in the alder ectomycorrhizal fungi Alnicola, Alpova and Lactarius (Basidiomycota) in Europe. AB - BACKGROUND: Mycorrhizal fungi form intimate associations with their host plants that constitute their carbon resource and habitat. Alnus spp. (Betulaceae) are known to host an exceptional species-poor and specialized ectomycorrhizal (ECM) fungal community compared to other tree species, but the host-specificity pattern and its significance in terms of fungal diversification and speciation remain poorly documented. The degree of parallel speciation, host switching, and patterns of biogeography were explored in the historical associations between alders and three ECM taxa of Basidiomycetes: Alnicola (Agaricales), Alpova (Boletales), and Lactarius (Russulales). The aim was to develop an evolutionary framework on host specificity and diversification of Basidiomycetes in this highly specialized plant-fungus symbiosis. RESULTS: Sporocarps of Alnicola (220), Lactarius (61) and Alpova (29) were collected from stands of the four European alder species (A. alnobetula including the endemic subsp. suaveolens in Corsica, A. cordata, A. glutinosa, A. incana) in Western Europe (mainly in France and Austria), from 1995 to 2009. Specimens were morphologically identified to the species level. From these, 402 sequences of four DNA regions (ITS, rpb2, gpd, and the V9 domain of the mit-SSU rDNA) were successfully obtained and analyzed in addition with 89 sequences available in GenBank and UNITE databases. Phylogenetic analyses were conducted on all sequence data sets (individual and combined) using maximum likelihood reconstruction and Bayesian inference. Fungal phylogenies are compared and discussed in relation to the host, with a focus on species boundaries by associating taxonomic, systematic and molecular information. CONCLUSIONS: Patterns of host specificity and phylogenies of Alnicola and Lactarius suggest coevolution as a basal factor of speciation in relation with the subgeneric diversification of Alnus, possibly due to the very selective pressure of the host. A second element of the historical associations between Alnus and its fungal symbionts is a host-dependent speciation (radiation without host change), here observed in Alnicola and Alpova in relation with Alnus subgen. Alnus. Finally host shifts from Alnus subgen. Alnus to A. alnobetula are found in most lineages of Alnicola (at least four times), Alpova (twice) and Lactarius (once), but they do not represent such a common event as could be expected by geographic proximity of trees from the two subgenera. However, active or very recent host extensions clearly occurred in Corsica, where some fungi usually associated with Alnus glutinosa on mainland Europe locally extend there to A. alnobetula subsp. suaveolens without significant genetic or morphological deviation. PMID- 21306641 TI - The role of FGF-2 and BMP-2 in regulation of gene induction, cell proliferation and mineralization. AB - INTRODUCTION: The difficulty in re-growing and mineralizing new bone after severe fracture can result in loss of ambulation or limb. Here we describe the sequential roles of FGF-2 in inducing gene expression, cell growth and BMP-2 in gene expression and mineralization of bone. MATERIALS AND METHODS: The regulation of gene expression was determined using real-time RTPCR (qRTPCR) and cell proliferation was measured by thymidine incorporation or fluorescent analysis of DNA content in MC3T3E1 osteoblast-like cells. Photomicroscopy was used to identify newly mineralized tissue and fluorescence was used to quantify mineralization. RESULTS: Fibroblast growth factor-2 (FGF-2) had the greatest ability to induce proliferation after 24 hours of treatment when compared to transforming growth factor beta (TGFbeta, insulin-like growth factor-1 (IGF-1), bone morphogenic protein (BMP-2), platelet derived growth factor (PDGF) or prostaglandin E2 (PGE2). We found that FGF-2 caused the most significant induction of expression of early growth response-1 (egr-1), fgf-2, cyclo oxygenase-2 (cox-2), tgfbeta and matrix metalloproteinase-3 (mmp-3) associated with proliferation and expression of angiogenic genes like vascular endothelial growth factor A (vegfA) and its receptor vegfr1. We found that FGF-2 significantly reduced gene expression associated with mineralization, e.g. collagen type-1 (col1a1), fibronectin (fn), osteocalcin (oc), IGF-1, noggin, bone morphogenic protein (bmp-2) and alkaline phosphatase (alp). In contrast, BMP-2 significantly stimulated expression of the mineralization associated genes but had little or no effect on gene expression associated with growth. CONCLUSIONS: The ability of FGF-2 to re-program a mineralizing gene expression profile to one of proliferation suggests that FGF-2 plays a critical role of osteoblast growth in early fracture repair while BMP-2 is instrumental in stimulating mineralization. PMID- 21306642 TI - Whole-genome amplified DNA from stored dried blood spots is reliable in high resolution melting curve and sequencing analysis. AB - BACKGROUND: The use of dried blood spots (DBS) samples in genomic workup has been limited by the relative low amounts of genomic DNA (gDNA) they contain. It remains to be proven that whole genome amplified DNA (wgaDNA) from stored DBS samples, constitutes a reliable alternative to gDNA.We wanted to compare melting curves and sequencing results from wgaDNA derived from DBS samples with gDNA derived from whole blood. METHODS: gDNA was extracted from whole blood obtained from 10 patients with lone atrial fibrillation (mean age 22.3 years). From their newborn DBS samples, stored at -24 degrees C, genomic DNA was extracted and whole genome amplified in triplicates. Using high resolution melting curve analysis and direct sequencing in both wgaDNA and gDNA samples, all coding regions and adjacent intron regions of the genes SCN5A and KCNA5 were investigated. RESULTS: Altered melting curves was present in 85 of wgaDNA samples and 81 of gDNA samples. Sequence analysis identified a total of 31 variants in the 10 wgaDNA samples. The same 31 variants were found in the exact same pattern of samples in the gDNA group. There was no false positive or negative sequence variation in the wgaDNA group. CONCLUSIONS: The use of DNA amplified in triplicates from DBS samples is reliable and can be used both for high resolution curve melting analysis as well as direct sequence analysis. DBS samples therefore can serve as an alternative to whole blood in sequence analysis. PMID- 21306643 TI - Measuring adherence to antiretroviral therapy in northern Tanzania: feasibility and acceptability of the Medication Event Monitoring System. AB - BACKGROUND: An often-used tool to measure adherence to antiretroviral therapy (ART) is the Medication Event Monitoring System (MEMS), an electronic pill-cap that registers date and time of pill-bottle openings. Despite its strengths, MEMS data can be compromised by inaccurate use and acceptability problems due to its design. These barriers remain, however, to be investigated in resource-limited settings. We evaluated the feasibility and acceptability of using MEMS-caps to monitor adherence among HIV-infected patients attending a rural clinic in Tanzania's Kilimanjaro Region. METHODS: Eligible patients were approached and asked to use the MEMS-caps for three consecutive months. Thereafter, qualitative, in-depth interviews about the use of MEMS were conducted with the patients. MEMS data were used to corroborate the interview results. RESULTS: Twenty-three of the 24 patients approached agreed to participate. Apart from MEMS-use on travel occasions, patients reported no barriers regarding MEMS-use. Unexpectedly, the MEMS-bottle design reduced the patients' fear for HIV-status disclosure. Patients indicated that having their behavior monitored motivated them to adhere better. MEMS-data showed that most patients had high levels of adherence and there were no bottle-openings that could not be accounted for by medication intake. Non adherence in the days prior to clinic visits was common and due to the clinic dispensing too few pills. CONCLUSION: MEMS-bottle use was readily accepted by patients. Although the MEMS-bottle was used accurately by most patients, patients need to be more explicitly instructed to continue MEMS-use when travelling. Even HIV-clinics with sufficient staff and free medication may impose structural adherence barriers by supplying an insufficient amount of pills. PMID- 21306644 TI - Foot kinematics in patients with two patterns of pathological plantar hyperkeratosis. AB - BACKGROUND: The Root paradigm of foot function continues to underpin the majority of clinical foot biomechanics practice and foot orthotic therapy. There are great number of assumptions in this popular paradigm, most of which have not been thoroughly tested. One component supposes that patterns of plantar pressure and associated hyperkeratosis lesions should be associated with distinct rearfoot, mid foot, first metatarsal and hallux kinematic patterns. Our aim was to investigate the extent to which this was true. METHODS: Twenty-seven subjects with planter pathological hyperkeratosis were recruited into one of two groups. Group 1 displayed pathological plantar hyperkeratosis only under metatarsal heads 2, 3 and 4 (n = 14). Group 2 displayed pathological plantar hyperkeratosis only under the 1st and 5th metatarsal heads (n = 13). Foot kinematics were measured using reflective markers on the leg, heel, midfoot, first metatarsal and hallux. RESULTS: The kinematic data failed to identify distinct differences between these two groups of subjects, however there were several subtle (generally <3 degrees ) differences in kinematic data between these groups. Group 1 displayed a less everted heel, a less abducted heel and a more plantarflexed heel compared to group 2, which is contrary to the Root paradigm. CONCLUSIONS: There was some evidence of small differences between planter pathological hyperkeratosis groups. Nevertheless, there was too much similarity between the kinematic data displayed in each group to classify them as distinct foot types as the current clinical paradigm proposes. PMID- 21306645 TI - Implications of ICU triage decisions on patient mortality: a cost-effectiveness analysis. AB - INTRODUCTION: Intensive care is generally regarded as expensive, and as a result beds are limited. This has raised serious questions about rationing when there are insufficient beds for all those referred. However, the evidence for the cost effectiveness of intensive care is weak and the work that does exist usually assumes that those who are not admitted do not survive, which is not always the case. Randomised studies of the effectiveness of intensive care are difficult to justify on ethical grounds; therefore, this observational study examined the cost effectiveness of ICU admission by comparing patients who were accepted into ICU after ICU triage to those who were not accepted, while attempting to adjust such comparison for confounding factors. METHODS: This multi-centre observational cohort study involved 11 hospitals in 7 EU countries and was designed to assess the cost effectiveness of admission to intensive care after ICU triage. A total of 7,659 consecutive patients referred to the intensive care unit (ICU) were divided into those accepted for admission and those not accepted. The two groups were compared in terms of cost and mortality using multilevel regression models to account for differences across centres, and after adjusting for age, Karnofsky score and indication for ICU admission. The analyses were also stratified by categories of Simplified Acute Physiology Score (SAPS) II predicted mortality (< 5%, 5% to 40% and >40%). Cost effectiveness was evaluated as cost per life saved and cost per life-year saved. RESULTS: Admission to ICU produced a relative reduction in mortality risk, expressed as odds ratio, of 0.70 (0.52 to 0.94) at 28 days. When stratified by predicted mortality, the odds ratio was 1.49 (0.79 to 2.81), 0.7 (0.51 to 0.97) and 0.55 (0.37 to 0.83) for <5%, 5% to 40% and >40% predicted mortality, respectively. Average cost per life saved for all patients was $103,771 (?82,358) and cost per life-year saved was $7,065 (?5,607). These figures decreased substantially for patients with predicted mortality higher than 40%, $60,046 (?47,656) and $4,088 (?3,244), respectively. Results were very similar when considering three-month mortality. Sensitivity analyses performed to assess the robustness of the results provided findings similar to the main analyses. CONCLUSIONS: Not only does ICU appear to produce an improvement in survival, but the cost per life saved falls for patients with greater severity of illness. This suggests that intensive care is similarly cost effective to other therapies that are generally regarded as essential. PMID- 21306647 TI - Hypertrophic cardiomyopathy in young Maine Coon cats caused by the p.A31P cMyBP-C mutation--the clinical significance of having the mutation. AB - BACKGROUND: In Maine Coon (MC) cats the c.91G > C mutation in the gene MYBPC3, coding for cardiac myosin binding protein C (cMyBP-C), is associated with feline hypertrophic cardiomyopathy (fHCM). The mutation causes a substitution of an alanine for a proline at residue 31 (p.A31P) of cMyBP-C. The pattern of inheritance has been considered autosomal dominant based on a single pedigree. However, larger studies are needed to establish the significance of cats being heterozygous or homozygous for the mutation with respect to echocardiographic indices and the probability of developing fHCM. The objective of the present study was to establish the clinical significance of being homozygous or heterozygous for the p.A31P cMyBP-C mutation in young to middle-aged cats. METHODS: The cohort consisted of 332 MC cats, 282 cats < 4 years (85%). All cats were examined by 2-D and M-mode echocardiography. DNA was extracted from blood samples or buccal swabs and screened for the p.A31P cMyBP-C mutation in exon 3 of the gene, using polymerase chain reaction followed by DNA sequencing. RESULTS: The fHCM prevalence was 6.3% in the cohort. Eighteen cats were homozygous and 89 cats were heterozygous for the mutation. The odds ratio for having fHCM for homozygous cats was 21.6 (95% confidence interval 7.01-66.2) - when the group of equivocal cats was categorized as non-affected. Overall, 50% of the cats that were homozygous for the mutation had fHCM. p.A31P heterozygosity was not associated with a significant odds ratio for fHCM. In cats in the 4 to 6 years of age range a similar, non significant, odds ratio was seen in heterozygous cats. Only two cats over four years were homozygous and both were diagnosed with fHCM. CONCLUSION: As there is no significant odds ratio associated with being heterozygous for the pA31P cMyBP-C mutation at this age, the mutation must have a very low penetrance in this group. From our data it would appear that most MC cats that develop fHCM due to the p.A31P mutation prior to the age of approximately 6 years do so because they are homozygous for this mutation. PMID- 21306646 TI - Enhanced immunogenicity of pneumococcal surface adhesin A (PsaA) in mice via fusion to recombinant human B lymphocyte stimulator (BLyS). AB - BACKGROUND: B lymphocyte stimulator (BLyS) is a member of the tumor necrosis factor superfamily of ligands that mediates its action through three known receptors. BLyS has been shown to enhance the production of antibodies against heterologous antigens when present at elevated concentrations, supporting an immunostimulatory role for BLyS in vivo. METHODS: We constructed a fusion protein consisting of human BLyS and Pneumococcal Surface Adhesin A (PsaA) and used this molecule to immunize mice. The immunostimulatory attributes mediated by BLyS in vivo were evaluated by characterizing immune responses directed against PsaA. RESULTS: The PsaA-BLyS fusion protein was able to act as a co-stimulant for murine spleen cell proliferation induced with F(ab')2 fragments of anti-IgM in vitro in a fashion similar to recombinant BLyS, and immunization of mice with the PsaA-BLyS fusion protein resulted in dramatically elevated serum antibodies specific for PsaA. Mice immunized with PsaA admixed with recombinant BLyS exhibited only modest elevations in PsaA-specific responses following two immunizations, while mice immunized twice with PsaA alone exhibited undetectable PsaA-specific serum antibody responses. Sera obtained from PsaA-BLyS immunized mice exhibited high titers of IgG1, IgG2a, IgG2b, and IgG3, but no IgA, while mice immunized with PsaA admixed with BLyS exhibited only elevated titers of IgG1 following two immunizations. Splenocytes from PsaA-BLyS immunized mice exhibited elevated levels of secretion of IL-2, IL-4 and IL-5, and a very modest but consistent elevation of IFN-gamma following in vitro stimulation with PsaA. In contrast, mice immunized with either PsaA admixed with BLyS or PsaA alone exhibited modestly elevated to absent PsaA-specific recall responses for the same cytokines. Mice deficient for one of the three receptors for BLyS designated Transmembrane activator, calcium modulator, and cyclophilin ligand [CAML] interactor (TACI) exhibited attenuated PsaA-specific serum antibody responses following immunization with PsaA-BLyS relative to wild-type littermates. TACI deficient mice also exhibited decreased responsiveness to a standard pneumococcal conjugate vaccine. CONCLUSION: This study identifies covalent attachment of BLyS as a highly effective adjuvant strategy that may yield improved vaccines. In addition, this is the first report demonstrating an unexpected role for TACI in the elicitation of antibodies by the PsaA-BLyS fusion protein. REVIEWERS: This article was reviewed by Jonathan Yewdell, Rachel Gerstein, and Michael Cancro (nominated by Andy Caton). PMID- 21306648 TI - In vivo identification and specificity assessment of mRNA markers of hypoxia in human and mouse tumors. AB - BACKGROUND: Tumor hypoxia is linked to poor prognosis, but identification and quantification of tissue hypoxia remains a challenge. The hypoxia-specificity of HIF-1alpha target genes in vivo has been questioned due to the confounding influence of other microenvironmental abnormalities known to affect gene expression (e.g., low pH). Here we describe a new technique that by exploiting intratumoral oxygenation heterogeneity allows us to identify and objectively rank the most robust mRNA hypoxia biomarkers. METHODS: Mice carrying human (FaDudd) or murine (SCCVII) tumors were injected with the PET hypoxia tracer FAZA. Four hours post-injection tumors were removed, frozen, and crushed into milligram-sized fragments, which were transferred individually to pre-weighed tubes containing RNAlater and then weighed. For each fragment radioactivity per tissue mass and expression patterns of selected mRNA biomarkers were analyzed and compared. RESULTS: In both tumour models, fragmentation into pieces weighing 10 to 60 mg resulted in tissue fragments with highly variable relative content of hypoxic cells as evidenced by an up to 13-fold variation in FAZA radioactivity per mass of tissue. Linear regression analysis comparing FAZA retention with patterns of gene expression in individual tissue fragments revealed that CA9, GLUT1 and LOX mRNA levels were equally and strongly correlated to hypoxic extent in FaDudd. The same link between hypoxia and gene expression profile was observed for CA9 and GLUT1, but not LOX, in SCCVII tumors. Apparent in vivo hypoxia-specificity for other putative molecular markers of tissue hypoxia was considerably weaker. CONCLUSIONS: The portrayed technique allows multiple pairwise measurements of mRNA transcript levels and extent of hypoxia in individual tumors at a smallest possible volumetric scale which (by limiting averaging effects inherent to whole tumor analysis) strengthen the conclusiveness on true hypoxia-specificity of candidate genes while limiting the required number of tumors. Among tested genes, our study identified CA9, GLUT1 and possibly LOX as highly specific biomarkers of tumor hypoxia in vivo. PMID- 21306649 TI - Parathyroid hormone is a plausible mediator for the metabolic syndrome in the morbidly obese: a cross-sectional study. AB - BACKGROUND: The biological mechanisms in the association between the metabolic syndrome (MS) and various biomarkers, such as 25-hydroxyvitamin D (vit D) and magnesium, are not fully understood. Several of the proposed predictors of MS are also possible predictors of parathyroid hormone (PTH). We aimed to explore whether PTH is a possible mediator between MS and various possible explanatory variables in morbidly obese patients. METHODS: Fasting serum levels of PTH, vit D and magnesium were assessed in a cross-sectional study of 1,017 consecutive morbidly obese patients (68% women). Dependencies between MS and a total of seven possible explanatory variables as suggested in the literature, including PTH, vit D and magnesium, were specified in a path diagram, including both direct and indirect effects. Possible gender differences were also included. Effects were estimated using Bayesian path analysis, a multivariable regression technique, and expressed using standardized regression coefficients. RESULTS: Sixty-eight percent of the patients had MS. In addition to type 2 diabetes and age, both PTH and serum phosphate had significant direct effects on MS; 0.36 (95% Credibility Interval (CrI) [0.15, 0.57]) and 0.28 (95% CrI [0.10,0.47]), respectively. However, due to significant gender differences, an increase in either PTH or phosphate corresponded to an increased OR for MS in women only. All proposed predictors of MS had significant direct effects on PTH, with vit D and phosphate the strongest; -0.27 (95% CrI [-0.33,-0.21]) and -0.26 (95% CrI [-0.32,-0.20]), respectively. Though neither vit D nor magnesium had significant direct effects on MS, for women they both affected MS indirectly, due to the strong direct effect of PTH on MS. For phosphate, the indirect effect on MS, mediated through serum calcium and PTH, had opposite sign than the direct effect, resulting in the total effect on MS being somewhat attenuated compared to the direct effect only. CONCLUSION: Our results indicate that for women PTH is a plausible mediator in the association between MS and a range of explanatory variables, including vit D, magnesium and phosphate. PMID- 21306650 TI - Circulating lymphocyte is an important determinant of the effectiveness of preoperative radiotherapy in advanced rectal cancer. AB - BACKGROUND: Although preoperative radiotherapy (RT) is widely used as the initial treatment for locally advanced rectal cancer (RC) in the neoadjuvant setting, factors determining clinical response have not been adequately defined. In order to find other factors possibly related with radiosensitivity, we evaluated the relationships between circulating blood cell counts and RT effects. METHODS: In 179 cases with advanced RC, we retrospectively examined hemoglobin (Hb) levels and counts of white blood cells (WBC), platelets and WBC subsets before and after RT and investigated their associations with the complete response (CR) rate together with other clinicopathological factors. RESULTS: The ratio of lymphocytes in WBC taken before RT was significantly greater in 15 CR cases as compared with those in non-CR cases. Patients with high lymphocyte percentages (25.7%) showed better outcome than the counterparts. Conversely, the ratio of neutrophiles was reduced in CR cases. The lymphocyte ratio showed an independent association with CR with multivariate analysis, and tended to be maintained at relatively high levels in CR cases. CONCLUSIONS: In RC patients, peripheral blood lymphocytes have a significant impact on the CR rate in response to RT. Lymphocyte-mediated immune reactions are supposed to have positive roles on clinical response in radiotherapy for RC. PMID- 21306651 TI - Transmission of new CRF07_BC strains with 7 amino acid deletion in Gag p6. AB - A 7 amino acid deletion in Gag p6 (P6delta7) emerged in Chinese prevalent HIV-1 strain CRF07_BC from different epidemic regions. It is important to determine whether this mutation could be transmitted and spread. In this study, HIV-1 Gag sequences from 5 different epidemic regions in China were collected to trace the transmission linkage and to analyze genetic evolution of P6delta7 strains. The sequence analysis demonstrated that P6delta7 is a CRF07_BC specific deletion, different P6delta7 strains could be originated from different parental CRF07_BC recombinants in different epidemic regions, and the transmission of P6delta7 strain has occurred in IDU populations. This is for the first time to identify the transmission linkage for P6delta7 strains and serves as a wake-up call for further monitoring in the future; In addition, P6delta7 deletion may represent an evolutionary feature which might exert influence on the fitness of CRF07_BC strain. PMID- 21306652 TI - Enterovirus 71 induces degradation of TRIM38, a potential E3 ubiquitin ligase. AB - BACKGROUND: The tripartite motif (TRIM) proteins are a family of more than 70 members in human. However, only a few of them have been well studied. The TRIM proteins contain the conserved RING, B-box, coiled-coil, and SPRY domains, most of which are involved in protein ubiquitination. TRIM38 is a member of the TRIM protein family, which we studied in more detail here as its functions are largely unknown. RESULTS: Our study shows that, similar to other TRIM family members, TRIM38 is localized in the cytoplasm. TRIM38 increases ubiquitination of other cellular proteins and catalyzes self-ubiquitination. TRIM38 also promotes K63- and K48-linked ubiquitination of cellular proteins. An intact RING domain is important for the functions of TRIM38. In addition, enterovirus 71 infection induces TRIM38 degradation. CONCLUSIONS: Our observations demonstrate that TRIM38 has E3 ubiquitin ligase activity and can be degraded during virus infection. These findings may provide insight into innate immune signaling pathways. PMID- 21306653 TI - Assessment of phytochemical content, polyphenolic composition, antioxidant and antibacterial activities of Leguminosae medicinal plants in Peninsular Malaysia. AB - BACKGROUND: Many medicinal plants from Leguminosae family can be found easily in Malaysia. These plants have been used as traditional medicines by local ethnic groups, where they are prepared as decoction, pastes for wound infections, and some have been eaten as salad. This paper focused on the assessment of antioxidant potential, antibacterial activity and classes of phytochemicals of nine plants from the Leguminosae family. METHODS: Acacia auriculiformis, Bauhinia kockiana, Bauhinia purpurea, Caesalpinia pulcherrima, Calliandra tergemina, Cassia surattensis, Leucaena leucocephala, Peltophorum pterocarpum, and Samanea saman were extracted with aqueous methanol and dichloromethane:methanol mixture to test for antioxidant and antibacterial activities. The Folin-Ciocalteu assay was conducted to quantify the total phenolic content and 2, 2-diphenyl-1 picrylhydrazyl (DPPH) assay was used to determine the free radical quenching capacity. Antibacterial activity was assessed using disc diffusion (Kirby-Bauer) assay. Screening for major classes of phytochemical was done using standard chemical tests. RESULTS: B. kockiana flowers and C. pulcherrima leaves contained high total phenolic content (TPC) and strong DPPH radical scavenging ability with TPC of 8280 +/- 498 mg GAE/100 g, IC(50) of 27.0 +/- 5.0 MUg/mL and TPC of 5030 +/- 602 mg GAE/100 g, IC(50) of 50.0 +/- 5.0 MUg/mL respectively. Positive correlation was observed between TPC and free radical scavenging ability. Most extracts showed antibacterial activity against Gram positive bacteria at 1 mg, while none showed activity against Gram negative bacteria at the same dose. All extracts (except Samanea saman flower) showed antibacterial activity against two strains of methicillin resistant Staphylococcus aureus (MRSA) with MID values ranging between 100 MUg/disc and 500 MUg/disc. CONCLUSION: The potential source of antioxidant and antibacterial agents, especially for MRSA infection treatments were found in B. kockiana, C. pulcherrima, C. tergemina and P. pterocarpum. These preliminary results would be a guide in the selection of potential candidates for further pharmacological study and in search of new drug candidate in treating MRSA infections. PMID- 21306654 TI - Equalisation of alcohol participation among socioeconomic groups over time: an analysis based on the total differential approach and longitudinal data from Sweden. AB - BACKGROUND: Health inequality and its social determinants are well-studied, but the determinants of inequality of alcohol consumption are less well-investigated. METHODS: The total differential approach of decomposition of changes in the concentration index of the probability of participation in alcohol consumption was applied to 8-year longitudinal data for Swedish women aged 28-76 in 1988/89. RESULTS: Alcohol consumption showed a pro-rich inequality, with income being a strong contributor. Overall participation remained fairly constant, but the inequality decreased over time as abstinence became less common among the poor and more common among the rich. This was mainly due to changes in the relative weights of certain population groups, such as a decrease in the proportional size of the oldest cohorts. CONCLUSIONS: Inequality in participation in alcohol consumption is pro-rich in Sweden. This inequality has tended to decrease over time, due to changes in population composition rather than to policy intervention. PMID- 21306655 TI - Effect of carboxymethyl cellulose concentration on physical properties of biodegradable cassava starch-based films. AB - BACKGROUND: Cassava starch, the economically important agricultural commodity in Thailand, can readily be cast into films. However, the cassava starch film is brittle and weak, leading to inadequate mechanical properties. The properties of starch film can be improved by adding plasticizers and blending with the other biopolymers. RESULTS: Cassava starch (5%w/v) based films plasticized with glycerol (30 g/100 g starch) were characterized with respect to the effect of carboxymethyl cellulose (CMC) concentrations (0, 10, 20, 30 and 40%w/w total solid) and relative humidity (34 and 54%RH) on the mechanical properties of the films. Additionally, intermolecular interactions were determined by Fourier transform infrared spectroscopy (FT-IR), melting temperature by differential scanning calorimetry (DSC), and morphology by scanning electron microscopy (SEM). Water solubility of the films was also determined. Increasing concentration of CMC increased tensile strength, reduced elongation at break, and decreased water solubility of the blended films. FT-IR spectra indicated intermolecular interactions between cassava starch and CMC in blended films by shifting of carboxyl (C = O) and OH groups. DSC thermograms and SEM micrographs confirmed homogeneity of cassava starch-CMC films. CONCLUSION: The addition of CMC to the cassava starch films increased tensile strength and reduced elongation at break of the blended films. This was ascribed to the good interaction between cassava starch and CMC. Cassava starch-CMC composite films have the potential to replace conventional packaging, and the films developed in this work are suggested to be suitable for low moisture food and pharmaceutical products. PMID- 21306657 TI - A case-marking cue for filler-gap dependencies in children's relative clauses in Japanese. AB - Object relative clauses have traditionally been thought to be more difficult than subject relative clauses in child English. However, recent studies as well as Japanese data show contradictory results. This study disclosed preschool children's superior performance on object relative clauses in Japanese; however, this dominance disappeared for the children who could use both the nominative and accusative case markers as cues for the comprehension of single-argument sentences. Assuming a filler-gap dependency for the relative clause formation, we suggest that there is no difference in the difficulty between subject and object relative clauses in the grammar of Japanese-speaking children. PMID- 21306656 TI - Evolution of the axial system in craniates: morphology and function of the perivertebral musculature. AB - The axial musculoskeletal system represents the plesiomorphic locomotor engine of the vertebrate body, playing a central role in locomotion. In craniates, the evolution of the postcranial skeleton is characterized by two major transformations. First, the axial skeleton became increasingly functionally and morphologically regionalized. Second, the axial-based locomotion plesiomorphic for craniates became progressively appendage-based with the evolution of extremities in tetrapods. These changes, together with the transition to land, caused increased complexity in the planes in which axial movements occur and moments act on the body and were accompanied by profound changes in axial muscle function. To increase our understanding of the evolutionary transformations of the structure and function of the perivertebral musculature, this review integrates recent anatomical and physiological data (e.g., muscle fiber types, activation patterns) with gross-anatomical and kinematic findings for pivotal craniate taxa. This information is mapped onto a phylogenetic hypothesis to infer the putative character set of the last common ancestor of the respective taxa and to conjecture patterns of locomotor and muscular evolution. The increasing anatomical and functional complexity in the muscular arrangement during craniate evolution is associated with changes in fiber angulation and fiber-type distribution, i.e., increasing obliqueness in fiber orientation and segregation of fatigue-resistant fibers in deeper muscle regions. The loss of superficial fatigue-resistant fibers may be related to the profound gross anatomical reorganization of the axial musculature during the tetrapod evolution. The plesiomorphic function of the axial musculature -mobilization- is retained in all craniates. Along with the evolution of limbs and the subsequent transition to land, axial muscles additionally function to globally stabilize the trunk against inertial and extrinsic limb muscle forces as well as gravitational forces. Associated with the evolution of sagittal mobility and a parasagittal limb posture, axial muscles in mammals also stabilize the trunk against sagittal components of extrinsic limb muscle action as well as the inertia of the body's center of mass. Thus, the axial system is central to the static and dynamic control of the body posture in all craniates and, in gnathostomes, additionally provides the foundation for the mechanical work of the appendicular system. PMID- 21306658 TI - Infants' gestures influence mothers' provision of object, action and internal state labels. AB - Twenty-four infants at 1 ; 1 and their mothers were videotaped for 18 minutes while playing. Infants' pointing, reaching and object-extending gestures were coded in three communicative intent contexts: proto-declarative, or commenting; proto-imperative, or requesting; and ambiguous. Mothers' responses to infants' gestures were coded as object labels, action labels, internal state labels and non-labeling utterances. Infants most often pointed in the proto-declarative and used object extensions in the proto-imperative context. Infants produced pointing and reaching equivalently in the ambiguous context. Mothers' responses included object labels more often in response to points than object extensions. In contrast, mothers provided action labels most often in response to object extensions. Mothers produced large proportions of internal state labels, although the type varied by gesture. Results suggest mothers' labels following infants' gestures may serve as a mechanism for vocabulary acquisition and internal state understanding. PMID- 21306659 TI - Variation in the sex ratio of Rhabdochona fortunatowi (Spirurida: Rhabdochonidae) in Capoeta capoeta gracilis (Cypriniformes: Cyprinidae), relative to levels of infection, host size and temperature. AB - In the present study, 81 specimens of Capoeta capoeta gracilis (Keyserling, 1861) were collected from the Shiroud River, the Caspian drainage basin, Iran in June and October 2007. The fish were examined for infection with the nematode Rhabdochona fortunatowi (Dinnik, 1933). Nematodes were counted and sexed, then the sex ratio and intestinal site preference of the R. fortunatowi individuals and the intersexual interactions of the parasites were investigated. Significant differences were observed in the prevalence and intensity of infection in relation to host size and sampling season, but not host sex. Parasite burden (mean intensity) was higher in October than in June and the results revealed a decrease in female-to-male sex ratio (FMR) in the fish in October compared to the ones in June. In other words, as the mean intensity of infection of R. fortunatowi increases, the proportion of male worms increases, too. The female biased sex ratio in June was replaced by a male-biased one in October. Nematode distribution rose to a significant peak in the mid-region of the fish intestine relative to the anterior and posterior parts. Some changes in the distribution of male and female worms in different parts of the host intestine were also observed during June and October. Density-dependent selection and intersexual competition seem to be the main factors driving such a shift in the sex ratio and its variation in different parts of the host intestine. PMID- 21306660 TI - Interaction between a history of depression and rumination on neural response to emotional faces. AB - BACKGROUND: Both past depressive episodes and the personality trait of depressive rumination are strong risk factors for future depression. Depression is associated with abnormal emotional processing, which may be a neurobiological marker for vulnerability to depression. A consistent picture has yet to emerge as to how a history of depression and the tendency to ruminate influence emotional processing. The aim of this study was to investigate the relationship between rumination, past depression and neural responses when processing face emotions. METHOD: The Ruminative Responses Scale (RRS) was completed by 30 remitted depressives and 37 controls who underwent functional magnetic resonance imaging (fMRI) scanning while viewing happy, sad, fearful and neutral faces. RESULTS: The remitted depressives showed overall reductions in neural responses to negative emotions relative to the controls. However, in the remitted depressives, but not the controls, RRS scores were correlated with increased neural responses to negative emotions and decreased responses to happiness in limbic regions. CONCLUSIONS: Automatic emotion processing biases and rumination seem to be correlated to aspects of vulnerability to depression. However, remission from depression may be maintained by a general suppression of limbic responsiveness to negative emotion. PMID- 21306661 TI - Facial emotional expression in reaction to social exclusion in borderline personality disorder. AB - BACKGROUND: Disturbances in social interaction are a defining feature of patients with borderline personality disorder (BPD). In this study, facial emotional expressions, which are crucial for adaptive interactions in social contexts, were assessed in patients with BPD in response to social exclusion. METHOD: We examined facial emotional reactions of 35 patients with BPD and 33 healthy controls when playing Cyberball, a virtual ball-tossing game that reliably induces social exclusion. Besides self-reported emotional responses, facial emotional expressions were analyzed by applying the Emotional Facial Action Coding System (EMFACS). RESULTS: Patients with BPD showed a biased perception of participation. They more readily reported feeling excluded compared to controls even when they were included. In BPD, social exclusion led to an increase in self reported other-focused negative emotions. Overall, EMFACS analyses revealed that BPD patients reacted with fewer positive expressions and with significantly more mixed emotional expressions (two emotional facial expressions at the same time) compared to the healthy control group when excluded. CONCLUSIONS: Besides a negative bias for perceived social participation, ambiguous facial emotional expressions may play an important role in the disturbed relatedness in patients with BPD. PMID- 21306662 TI - Major depression during and after the menopausal transition: Study of Women's Health Across the Nation (SWAN). AB - BACKGROUND: It is unclear whether risk for major depression during the menopausal transition or immediately thereafter is increased relative to pre-menopause. We aimed to examine whether the odds of experiencing major depression were greater when women were peri- or post-menopausal compared to when they were pre menopausal, independent of a history of major depression at study entry and annual measures of vasomotor symptoms (VMS), serum levels of, or changes in, estradiol (E2), follicular stimulating hormone (FSH) or testosterone (T) and relevant confounders. METHOD: Participants included the 221 African American and Caucasian women, aged 42-52 years, who were pre-menopausal at entry into the Pittsburgh site of a community-based study of menopause, the Study of Women's Health Across the Nation (SWAN). We conducted the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) to assess diagnoses of lifetime, annual and current major depression at baseline and at annual follow-ups. Psychosocial and health factors, and blood samples for assay of reproductive hormones, were obtained annually. RESULTS: Women were two to four times more likely to experience a major depressive episode (MDE) when they were peri-menopausal or early post-menopausal. Repeated-measures logistic regression analyses showed that the effect of menopausal status was independent of history of major depression and annually measured upsetting life events, psychotropic medication use, VMS and serum levels of or changes in reproductive hormones. History of major depression was a strong predictor of major depression throughout the study. CONCLUSIONS: The risk of major depression is greater for women during and immediately after the menopausal transition than when they are pre-menopausal. PMID- 21306663 TI - Caregivers' attitudes and practices: influence on childhood body weight. AB - Childhood excess weight is probably associated with, or reflected in, parental attitudes. The objective of this study was to study the relationships between childhood excess weight and parental attitudes. The study subjects were 53 boys and 56 girls, aged 6-10, regularly attending schools in Porto Alegre, south Brazil, and one of their parents or caregivers. Attitudes of the parents or caregivers were assessed by the Child Feeding Questionnaire (CFD). Weight and height of the children were measured, parents self-reported their weight and height and body mass indexes were calculated for both. The WHO criteria for overweight and obesity were used for the adults. The CDC criteria for overweight and risk for overweight were used for the corresponding children. Boys presented excess weight more often than girls. The parents of children with excess weight showed higher scores for perceived child weight, concern about child weight, restriction and monitoring. In logistic regression, excess weight in children was associated with perceived child weight, restriction and male sex; pressure to eat was negatively associated with excess BMI. In Porto Alegre, south Brazil, excess body weight in children aged 6-10 is associated with parental perceived child weight and concern about it, monitoring and restriction; being a boy increases the odds of being overweight. PMID- 21306664 TI - Association between healthy life expectancy at birth and consanguineous marriages in 63 countries. AB - In order to investigate the association between mean inbreeding coefficient (alpha) and healthy life expectancy at birth (HALE; years) the present ecological study on 63 countries was done. Statistical analysis showed that HALE negatively and positively correlated with log(10)alpha and log(10)GNI per capita, respectively (p<0.001). It should be noted that log(10)alpha and log(10)GNI per capita were significantly correlated with each other (p<0.001). After controlling for log(10)GNI per capita, significant negative correlations between log(10)alpha and HALE were observed. The countries were stratified according to their GNI per capita into low- and high-income countries. In countries with high income, after controlling for log(10)GNI per capita, the correlation between HALE at birth and log(10)alpha was significant (for males r=-0.399, df=32, p=0.001; for females r= 0.683, df=32, p<0.001). In high-income Asian and African countries, where consanguineous marriage is common, after controlling for log(10)GNI per capita, the correlation between HALE at birth and log(10)alpha was significant (for males r=-0.819, df=8, p=0.004; for females r=-0.936, df=8, p<0.001). It seems that consanguinity influences HALE independent of country income. PMID- 21306665 TI - A study using demographic data of genetic drift and natural selection in an isolated Mediterranean community: Bayarcal (La Alpujarra, south-east Spain). AB - Natural selection and genetic drift are two evolutionary mechanisms that can be analysed in human populations using their fertility and mortality patterns, and their reproductive size and isolation, respectively. This paper analyses the models of natural selection and genetic drift in Bayarcal, south-east Spain, and compares them with the observed models in the rest of the Alpujarran region. Demographic data were obtained from a sample of 77 families (48.45% of the population, with 547 inhabitants). The genetic drift and natural selection action was evaluated with the Coefficient of Breeding Isolation (CBI of Lasker and Kaplan) and Crow's index, respectively. The CBI (23.23/12.61) suggests that genetic drift is near to acting, and Crow's index (I=0.58) is slightly higher than that observed in the rest of La Alpujarra. Although the reproductive isolation of Bayarcal is not effective enough for genetic drift to act, it is near when marital migrants inside the Bayarcal valley are considered as a native population. The natural selection pattern is not different from that of the rest of La Alpujarra, but it tends towards the model of developing communities, where the demographic transition has not yet begun. PMID- 21306666 TI - Parent's responses to nutrient claims and sports celebrity endorsements on energy dense and nutrient-poor foods: an experimental study. AB - OBJECTIVE: To assess parents' responses to common, potentially misleading strategies for marketing energy-dense and nutrient-poor (EDNP) child-oriented foods. DESIGN: Between-subjects online experiment to test whether nutrient claims and sports celebrity endorsements on the front of packs of EDNP products lead parents to prefer and rate these foods more favourably. SETTING: Australia. SUBJECTS: A total of 1551 parents of children aged 5-12 years, who were the main household grocery buyers. RESULTS: Inclusion of nutrient claims or sports celebrity endorsements on EDNP products led parents to perceive these products to be more nutritious than if they did not include such promotions. When asked to choose between a pair of different products (EDNP v. healthier), 56 % of parents did not read a nutrition information panel (NIP) before making their choice and this did not differ by promotion condition. These parents were more likely to choose an EDNP product if it included a nutrient claim (OR = 1.83, 95 % CI 1.31, 2.56; P < 0.001) or sports celebrity endorsement (OR = 2.37, 95 % CI 1.70, 3.32; P < 0.001). Sports celebrity endorsements also enhanced parent's perceptions of typical consumers of the product, perceptions of product healthiness and quality, as well as purchase intentions. CONCLUSIONS: Nutrient claims and sports celebrity endorsements tip consumer preferences towards EDNP products bearing such promotions, especially among the majority who do not read the NIP. As parents largely determine what foods are available to children at home, it is critical that initiatives aimed at reducing the persuasive impact of food marketing include this target group. PMID- 21306667 TI - Lack of dietary diversity and dyslipidaemia among stunted overweight children: the 2002 China National Nutrition and Health Survey. AB - OBJECTIVE: Both stunting and overweight are present in children across China. Seemingly paradoxical, these two conditions can also coexist in the same child. The aim was to examine the associations between dietary food/nutrient intake and plasma lipid profiles related to stunting and overweight status. DESIGN: The 2002 China National Nutrition and Health Survey was a family-based nationally representative cross-sectional study. SETTING: Thirty-one provinces, autonomous regions and municipalities. SUBJECTS: The study included 13,770 children aged 2 17 years. The sample size for the four exposure groups was 10,814 for children of normal height and weight, 2128 for stunted, 729 for overweight and 99 for stunted overweight. RESULTS: Compared with children of normal height and weight, stunted and stunted overweight children consumed more high-energy-dense foods with a lower dietary diversity score, less protein, polyunsaturated fat and Fe, and a higher molar ratio of phytate to Ca. On the contrary, overweight children tended to consume significantly less carbohydrates and more protein and fat. Overall, stunted overweight children consumed lower amounts of vegetables, fruit, white meat (poultry and fish) and more milk. The OR for prevalent dyslipidaemia were 1.32 (95% CI 1.13, 1.53), 1.76 (95% CI 1.48, 2.09) and 2.59 (95% CI 1.65, 4.07) among stunted, overweight and stunted overweight children, respectively, compared with children of normal height and weight. In addition, being overweight was significantly associated with high glucose concentrations, whereas stunting was significantly associated with having anaemia. CONCLUSIONS: Limited dietary diversity and intake of high-energy-dense foods were notably observed among stunted overweight children. Furthermore, being stunted and/or overweight was associated with an increased likelihood of unhealthy lipid profiles. PMID- 21306668 TI - Demographic and socio-economic factors related to food intake and adherence to nutritional recommendations in a cohort of pre-school children. AB - OBJECTIVE: To examine: (i) children's food intake and adherence to both Canada's Food Guide for Healthy Eating and Dietary Reference Intakes; and (ii) the social and demographic factors related to children's food intake. DESIGN: A cross sectional study. SETTING: Data were obtained through the Quebec Longitudinal Study of Child Development 1998-2010, a representative sample (n 2103) of children born in 1998 in the province of Quebec, Canada. Information on energy, macronutrient and food consumption was derived from responses to a 24 h dietary recall interview addressed to children's mothers and day-care staff when the children were 4 years old. SUBJECTS: A total of 1549 children aged 4 years who participated in a nutritional sub-study. RESULTS: The mean daily total energy intake was 6360 kJ (1520 kcal) for girls and 6916 kJ (1653 kcal) for boys. For boys and girls alike, energy intake was comprised of approximately 54 % carbohydrates, 31 % fats and 15 % proteins. The mean number of servings consumed from each of the four essential food groups closely approached the dietary recommendations made by Canada's Food Guide for Healthy Eating; however, <2 % of the children in the present study actually met the full dietary guidelines. The dietary intake of pre-school children was associated with socio-economic and demographic factors, most notably mother's level of education, mother's immigrant status and sex of the child. CONCLUSIONS: Diet-related disparities associated with socio-economic and demographic factors exist from as early as 4 years of age. PMID- 21306669 TI - Anaemia, lead poisoning and vitamin D deficiency in low-income children: do current screening recommendations match the burden of illness? AB - OBJECTIVE: Low-income children are routinely screened for anaemia and elevated blood lead levels (EBLL) but not for vitamin D deficiency. We sought to determine the relative prevalence of and the relationship among vitamin D deficiency, anaemia and EBLL among healthy low-income paediatric clinic patients. DESIGN: Retrospective chart review. SETTING: Paediatric outpatient clinic in an urban safety net hospital in a northern US state. SUBJECTS: Healthy toddlers and children under 6 years of age (n 127) who were seen for a routine well child check-up (WCC). RESULTS: The prevalence of vitamin D insufficiency (25 hydroxyvitamin D (25(OH)D) < 30 ng/ml) was 62 %; the prevalence of vitamin D deficiency (25(OH)D < 20 ng/ml) was 29 %. These rates were far higher than those for anaemia (Hb < 11.0 g/dl) at 10 %, EBLL (Pb > 9 MUg/dl) at 1 % or even mildly EBLL (Pb 5-9 MUg/dl) at 4 % (range: 1-11). There was no relationship among any of the following: vitamin D status, anaemia or EBLL. The vast majority of children with vitamin D deficiency had both normal Hb (86 %) and Pb level (100 %). After controlling for child's age, gender and race/ethnicity, there was no association between Hb (continuous, g/dl) and vitamin D deficiency (adjusted OR (aOR) = 0.97, 95 % CI 0.64, 1.47; P = 0.88). The only significant predictor of vitamin D deficiency was increasing age in years (aOR = 1.39, 95 % CI 1.03, 1.86; P = 0.03). None of these associations changed materially when deficiency was defined as <15 ng/ml. CONCLUSIONS: Vitamin D deficiency was far more common than anaemia or EBLL, and Hb and Pb status were not predictors of vitamin D status. PMID- 21306670 TI - Okadaic acid-sensitive phosphatase is related to MII/G1 transition in mouse oocytes. AB - It is reported that okadaic acid (OA)-sensitive phosphatase is related to mitogen activated protein kinase (MAPK)/p90rsk activation in mammalian oocytes. OA is also involved in the positive feedback loop between M phase-promoting factor (MPF) and cdc25c in Xenopus oocytes during meiotic maturation. However, the effect of phosphatase inhibition by OA on MPF and MAPK activities at the MII/G1 in oocytes remains unknown. The aim of this study is to clarify the relationship between OA-sensitive phosphatase and mitosis MII/G1 transition in mouse oocytes. MII-arrested oocytes were, isolated from mice, inseminated and cultured in TYH medium (control group) or TYH medium supplemented with 2.5 MUM of OA (OA group). Histone H1 kinase and myelin basic protein (MBP) kinase activities were measured as indicators of MPF and p42 MAPK activities after insemination. Phosphorylation of cdc25c after insemination was analized in OA and control group by western blotting. Seven hours after insemination a pronucleus (PN) was formed in 84.1% (69/85) of oocytes in the control group. However, no PN was formed in oocytes of the OA group (p < 0.001). Although MPF and MAPK activities in the control group significantly decreased at 3, 4, 5, and 7 h after insemination, these decreases were significantly inhibited by OA addition (p < 0.05). Furthermore, OA addition prevented cdc25c dephosphorylation 7 h after insemination. In conclusion, OA sensitive phosphatase correlates with inactivation of MPF and MAPK, and with the dephosphorylation of cdc25c at the MII/G1 transition in mouse oocytes. PMID- 21306671 TI - [Evidence-based medicine in lung cancer]. PMID- 21306672 TI - [Practice guidelines in diagnosis and staging of lung cancer]. PMID- 21306673 TI - [The preliminary results of a phase II randomized clinical trial of high-dose toremifene chemosensitization in stage IIIB/IV non-small cell lung cancer]. AB - BACKGROUND: To investigate whether high-dose toremifene can enhance the efficacy of chemotherapy in non small cell lung cancer. METHODS: Untreated stage IIIB/IV non-small cell lung cancer patients were randomly devided into group A (high-dose toremifene combined with the platinum-based chemotherapy) or group B (the same platinum-based chemotherapy alone). RESULTS: A total of 30 eligible patients had been recruited. Hemotologic and nonhemotologic toxicities were similar with no statistic difference. The median survival for group A was 8 months, 95% CI (6.63 9.37) versus 7.5 months, 95% CI (4.75-10.25) for group B ( P =0.9). One year survival rate was 31% for group A versus 28% for group B ( P =0.87). The response rate was 25% for group A versus 21% for group B ( P =0.99). CONCLUSIONS: The results suggest that high-dose toremifene does not enhance the efficacy of platinum-based chemotherapy for IIIB/IV non-small cell lung cancer but toxicities are well tolerated. PMID- 21306674 TI - [A randomized clinical trial on adjuvant interferon-alpha for completely resected stage I-II non-small cell lung cancer]. AB - BACKGROUND: To investigate the role of interferon-alpha (IFN-alpha) in completely resected stage I and II non-small cell lung cancer (NSCLC) patients. METHODS: Forty-four stageIand II NSCLC patients were randomized to two groups. Study group (surgery+IFN-alpha) received IFN-alpha injection, 3 million unit, every two days, with a period of treatment of 90 days. Control group (surgery only) received no adjuvant therapy until relapse or metastasis were detected. pTNM stage, histological types, relapse or metastasis, survival time were observed and evaluated. RESULTS: Median follow-up was 49.9 months. The 1-, 2-, 3-, 4-year survival rates were 90.5%, 80.9%, 52.4%, 52.4% in the study group and 95.2%, 80.9%, 66.0%, 50.8% in the control group respectively. No significant statistic difference was found between the two groups ( P = 0.663 9 ). Kaplan-Meier and Cox Model analysis showed pTNM stage ( P =0.010 2), N status ( P =0.015) and weight loss ( P =0.030) were prognostic factors in completely resected stage I and II NSCLC. CONCLUSIONS: Postoperative low-dose IFN-alpha short-term therapy cannot significantly improve 3- and 4-year survival rates of patients with stage I and II completely resected NSCLC. PMID- 21306675 TI - [Common recognition and highlights in the treatment of non-small cell lung cancer]. PMID- 21306676 TI - [Study on high-rate and low-rate metastatic large-cell lung cancer cell lines via differential display reverse transcript PCR]. AB - BACKGROUND: To investigate the differentially expressed gene profile between high rate and low-rate metastatic large-cell lung cancer cell lines via differential display reverse transcript PCR (DDRT-PCR). METHODS: DDRT-PCR was performed in two large-cell lung cancer cell lines with different metastatic ability. The differentially displayed cDNA were cloned and sequenced and compared with the sequences in the GenBank. RESULTS: Fifty differentially displayed cDNAs were acquired, including 18 function-known genes, 16 function-unknown genes, 16 genomic DNA fragments and 4 ESTs. CONCLUSIONS: The cell lines have different gene expression profiles, and metastasis is affected by multi-gene expression and regulation. Some genes which contribute to the metastasis of lung cancer could be found by DDRT-PCR, and this study gives some new clues to cancer diagnosis and therapy. PMID- 21306677 TI - [Study on p16 methylation status of BEP2D cells during its malignant transformation]. AB - BACKGROUND: To study p16 methylation status and p16 mRNA transcription of BEP2D cells during its malignant transformation. METHODS: Normal BEP2D cell and BEP2D cells irradiated by alpha particle for 20 weeks (R-20), 21 weeks (R-21), 35 weeks (T-35) and 54 weeks (T-54) respectively were chosen to study the p16 methylation status by methylation-specific PCR (MSP). Meanwhile, RT-PCR was used to study p16 mRNA transcription of the above cells. RESULTS: (1) p16 methylation was found in R-20, R-21, T-35 and T-54 cells, but not in normal BEP2D cell. (2) The p16 mRNA transcription levels of R-20, R-21, T-35 and T-54 cells were much lower than that of normal BEP2D cell. CONCLUSIONS: The p16 methylation occurs in the early stage of lung cancer. The methylation of p16 gene may cause the inactivation of p16 gene. PMID- 21306678 TI - [The expression of DNA-PKcs in non-small cell lung cancer and its relationship with apoptosis associated proteins]. AB - BACKGROUND: To study the expression of catalylic subunit of DNA-dependent protein kinase (DNA-PKcs) in non-small cell lung cancer (NSCLC) and its relationship with apoptosis. METHODS: NSCLC tissues from 113 untreated patients were analyzed immnohistochemically with antibodies to DNA-PKcs, p53 and bcl-2. RESULTS: There were expressions of DNA-PKcs, p53 and bcl-2 in NSCLC at different levels. The positive rate of DNA-PKcs, p53 and bcl-2 was 89.38%(101/113), 61.95%(70/113) and 59.29%(67/113) respectively. The expression of DNA-PKcs was significantly related with the histological types. Its expression in squamous carcinoma was significantly lower than that in adenocarcinoma and bronchioloalveolar carcinoma. The expression of DNA-PKcs increased with the increasing differentiated degree of NSCLC ( P < 0.05), but had no relationship with lymph node metastasis. There was no significant relation between the expression of p53 and the pathological type of NSCLC. A significant difference of bcl-2 expression existed in the histological types of lung cancer ( P < 0.01). Its expression in squamous carcinoma was significantly higher than that in adenocarcinoma, bronchioloalveolar carcinoma and adenosquamous carcinoma, but had no relationship with the differentiated degree of lung cancer and lymph node metastasis. The expressions were significantly related between DNA-PKcs and p53 ( P < 0.01), p53 and bcl-2 ( P < 0.05). CONCLUSIONS: The expression of DNA-PKcs is fairly high in NSCLC. The high expression of DNA-PKcs and overexpressions of mutated p53 and bcl 2 may be important causes of radioresistance in NSCLC. PMID- 21306679 TI - [The diagnostic value of FCM DNA content and S-phase fraction in bronchial biopsy specimen for lung cancer]. AB - BACKGROUND: To assess the sensitivity and specificity of flow cytometry (FCM) DNA content analysis in diagnosing malignancy as well as premalignancy and to evaluate the diagnostic role of FCM DNA content analysis in fiberoptic bronchoscopic specimens of lung cancer. METHODS: Fresh specimens taken by fiberoptic bronchoscope from 41 patients with lung cancer (28 squamous cell carcinoma, 2 bronchioloalveolar carcinoma, 11 small cell lung cancer) and 21 patients with non-malignant pulmonary lesions were measured for DNA index (DI), S phase fraction (SPF) by using FACSCalibur 4200 flow cytometry. The diagnostic value of this method was compared with fiberoptic bronchoscopic biopsy, brushing and sputum examination. RESULTS: 1. DI was 1.18+/-0.33 and 0.99+/-0.07 in lung cancer and non-malignant groups respectively. The percentage of heteroploid was 78.04% in lung cancer and 4.8% in non malignant. DI and the positive rate of heteroploid in lung cancer group were significantly higher than that in non malignant group ( P < 0.01). If the presence of heteroploid was used as a diagnostic criterion, the sensitivity of DNA analysis was 78.04% and the specificity was 95.24%. There was no diagnostic sensitivity difference between FCM DNA content analysis and biopsy (90.26%) ( P > 0.05), as well as brushing (65.85%) ( P > 0.05). 2.Athough DI and the rate of heteroploid increased as the pathological grade and TNM stage advanced, there were no significant differences ( P > 0.05). 3. SPF in lung cancer group was significant higher than that in non malignant group. The SPF of heteroploid tumors was higher than that of diploid tumors ( P < 0.05); SPF correlated with TNM stage ( P < 0.05). CONCLUSIONS: FCM DNA content analysis has an adjunctive value in diagnosis of lung cancer. The analysis of DNA content and SPF by FCM provides a beneficial method for the evaluation of tumor behavior. PMID- 21306680 TI - [Clinical significance of telomerase activity in lung cancer]. AB - BACKGROUND: To evaluate the clinical significance of telomerase activity in lung cancer and to investigate the possibility of telomerase as cancer marker for lung cancer. METHODS: The activity of telomerase was investigated by TRAP-PCR-ELISA in lung cancer tissues and corresponding adjacent noncancerous tissues obtained from resected specimens of 48 patients with lung cancer and 42 specimens of benign pulmonary lesions were examined simultaneously. RESULTS: Telomerase activity was detected in 42 (87.5%) of the 48 tumors and only 4 (8.3%) of the 48 adjacent noncancerous lung tissue samples (Chi-Square=13.029, P < 0.01), but in none of 42 specimens of benign pulmonary lesions (Chi-Square=14.016, P < 0.01). Correlation with pathological parameters showed that the expression of telomerase activity was associated with lymph node metastasis (93.5% vs 76.4% , Chi-Square=63.511, P < 0.01), but not with histological type, location and differenciated grade of tumor. CONCLUSIONS: Telomerase activation correlates with the carcinogenesis and aggressiveness of lung cancer. Telomerase might be one of the important diagnostic and prognostic factors in patients with lung cancer. PMID- 21306681 TI - [Evaluation of cardiopulmonary exercise test on predicting post-operative respiratory failure in patients with lung cancer]. AB - BACKGROUND: To evaluate the clinical significance of predicting post-operative respiratory failure in patients with lung cancer using cardiopulmonary exercise test (CPET). METHODS: Before operation, 260 patients with lung cancer underwent CPET with incremental protocol. W%, VO2%P, VO2/kg, AT, MET, O2 pulse, VTe, BF and VE were measured in the end of load exercise. RESULTS: (1) In patients after pneumonectomy, the values of the above indexes of CPET in the respiratory failure group were significantly lower than those in the non-respiratory failure group ( P < 0.05 or P < 0.01) except VTe. In patients after lobectomy, the values of 9 indexes of CPET in the respiratory failure group were similar to those in the non respiratory failure group ( P > 0.05). However, when the patients after lobectomy were further divided into groups of upper and lower lobectomy, W% in the respiratory failure group was remarkably lower than that in the non-respiratory failure group after lower lobectomy ( P < 0.05). (2) Chi-Square test showed that abnormality of CPET indexes in different degrees was related to the morbidity of respiratory failure after pneumonectomy. Logistic regression showed that O2 pulse < 80% and BF < 30/min correlated with the morbidity of post-operative respiratory failure. (3) For predicting post-operative respiratory failure, the sensitivity and specificity of VO2%P < 60%, BF < 30/min, VE < 35 L/min were all more than 60% and their negative predictive values were all more than 90%. CONCLUSIONS: CPET is suitable to predict post-pneumonectomy respiratory failure. As a comprehensive index indicating cardiopulmonary function during exercise, VO2%P < 60% should be selected to predict respiratory failure and evaluate indication of lung resection for patients with lung cancer. PMID- 21306682 TI - [Concomitant whole brain radiotherapy and FUDR+VM-26+DDP chemotherapy in brain metastasis of non-small cell lung cancer: a report of short term efficacy]. AB - BACKGROUND: To evaluate the efficacy and toxicity of concomitant chemoradiotherapy in patients with brain metastases from non-small cell lung cancer (NSCLC). METHODS: Thirty patients suffering from NSCLC with brain metastasis were prospectively included in this study. Twenty-four patients had neurological symptoms and an ECOG performance index between 0 and 3. Treatment consisted of concomitant whole brain radiotherapy (WBRT) with a dose of 30 Gy in 15 fractions, followed by a local boosted dose of 20 Gy in 10 fractions for those that the number of the remained lesions were less than 3, or by WBRT with a total dose of 50 Gy for those that the number of the remained lesions were more than 3. Concomitant chemotherapy of FVP regimen with floxuridine 600 mg/(m2*d), teniposide 60 mg/(m2*d), cisplatin 20 mg/(m2*d) on d1 to d5,repeating every 3 or 4 weeks. The response was evaluated by brain CT or MRI after WBRT and 2 cycles of chemotherapy being completed. RESULTS: All the patients completed WBRT and concomitant chemotherapy including 68 cycles (2 to 4 cycles for each patient). The follow-up rate was 93.3% with a median survival duration of 11.3 months. Total response rate was 46.7%, with CR for 2 and PR for 12. Specific evaluation of brain response demonstrated CR for 8 patients, and PR for 10 patients (the objective brain response rate, 60.0% ). The objective primary disease response rate was 18% for 22 cases of previously untreated primary NSCLC. Other specific evaluation of metastases included 1 PR patient in 6 patients with lung metastases, 3 CR patients and 4 PR patients in 17 patients with lymph node metastases, 1 PR patient with liver metastases, and 1 PR patient with eye metastasis. Twenty four patients with neurological symptoms benefited improvements to different extent. The main adverse effects were myelotoxicity, nausea/vomiting, constipation and alopecia. Grade III and IV toxicities were observed as following: leucopenia (19.1%), anemia (10.3%), thrombocytopenia (7.4%), nausea/vomiting (4.4%), diarrhea (2.9%), alopecia (5.9%), glutamio oxaloacetic transaminase (GOT) and glutamio pyruvic transaminase (GPT) elevation (1.5%). Dehydration therapy was needed at 2 weeks after WBRT in all patients. CONCLUSIONS: Concomitant WBRT plus FUDR+VM-26+DDP chemotherapy is tolerable in NSCLC patients with brain metastases and the short term response is comparable to the results of others. PMID- 21306683 TI - [Weekly administration of gemcitabine and docetaxel combinations in the treatment of advanced non-small cell lung cancer]. AB - BACKGROUND: To evaluate the efficacy and side effects of weekly administration of gemcitabine combined with docetaxel in the treatment of advanced non-small cell lung cancer. METHODS: Twenty-six patients with advanced non-small cell lung cancer, with or without prior chemotherapy, were entered into this study. Gemcitabine and docetaxel were administrated weekly for 3 consecutive weeks, followed by 1 week rest. Gemcitabine was given as 800-1 200 mg/m2 by intravenous infusion on days 1, 8, 15; while docetaxel was 35 mg/m2 intravenously on the same days as gemcitabine. The efficacy including response rate and median survival duration and toxicity were observed. RESULTS: Of the 26 patients, one achieved complete response (CR), and 6 achieved partial response (PR), with an overall response rate of 27%. The median survival duration was 9.5 months and 1-year survival rate was 38% (10/26). The main toxicities were neutropenia and thrombocytopenia. One patient died from allergic shock. CONCLUSIONS: The combination of docetaxel and gemcitabine is effective and well-tolerated in the treatment of advanced NSCLC. PMID- 21306684 TI - [Clinical research of selective bronchial artery infusion and chemotherapy of lung cancer]. AB - BACKGROUND: To study the effect of selective bronchial artery infusion (BAI) and chemotherapy in the treatment of patients with intermediate and advanced lung cancer. METHODS: Forty-five cases of advanced lung cancer were treated by BAI, which were compared with 40 cases of advanced lung cancer treated by systemic chemotherapy. RESULTS: The response rate of BAI (33/44, 75.0%) was better than that of systemic chemotherapy (20/40, 50.0%)( P < 0.05). The side-effect of BAI was lower than that of systemic chemotherapy ( P < 0.05), but one case occured paraplegia after BAI. The response rate of small cell undifferentiated lung cancer, squamous cell carcinoma and adenocarcinoma was 94.5% (17/18), 66.6% (14/21) and 40.0% (2/5) respectively in the BAI group. Significant difference of the response rate was found in squamous cell carcinoma and adenocarcinoma between the two groups ( P < 0.05). CONCLUSIONS: BAI has better response rate and less toxicity than systemic chemotherapy in intermediate and advanced lung cancer, especially in patients with squamous cell carcinoma. Small cell undifferentiated lung carcinoma should be treated by systemic chemotherapy firstly and then BAI. Adenocarcinoma should be treated by BAI firstly and then other therapy. PMID- 21306685 TI - [Clinical research on combined chemotherapy of vinorelbine and cisplatin in the treatment of non-small cell lung cancer]. AB - BACKGROUND: To evaluate the efficacy, side-effects, median survival duration and survival rate of vinorelbine (NVB) combined with cisplatin (DDP) in the treatment of non-small cell lung cancer (NSCLC). METHODS: A total of 220 patients with inoperable NSCLC received NVB and DDP combined chemotherapy: NVB 25-30 mg/(m2*d) on days 1 and 5 (or 8), DDP 60-80 mg/(m2*d) on day 2. The schedule was repeated every 28 days. The efficacy and side-effects were analysed and followed-up after at least two cycles of chemotherapy. RESULTS: The overall response rate (CR+PR) was 30.9% (68/220). The response rate was 31.3% (51/163) in initial treatment group, and 29.8% (17/57) in retreatment group. The median survival duration was 8.3 months. The 1-, 2- and 3-year survival rates were 39.23%, 19.31% and 6.32%, respectively. The main side-effects were myelosuppression and digestive tract reactions. CONCLUSIONS: Vinorelbine plus cisplatin is an effective and well tolerated regimen for non small cell lung cancer and myelosuppression is its dose limiting toxicity. PMID- 21306686 TI - [A clinical study on paclitaxel plus cisplatin combined therapy in the treatment of non-small cell lung cancer]. AB - BACKGROUND: To evaluate the results of combined chemotherapy with paclitaxel (PTX, taxol) plus cisplatin (DDP) in the treatment of advanced non small cell lung cancer (NSCLC). METHODS: From January 1997 to December 2002, forty-seven patients with advanced non-small cell lung cancer received PTX 135-180 mg/m2 by intravenous infusion, on day 1, and DDP 40 mg/time by intravenous infusion,on days 1-3. The treatment was repeated every 3 weeks, up to 2 or 3 cycles. RESULTS: Forty-six patients were evaluable for efficacy. One patient got complete response (2.2%), and 16 got partial response (34.8%), with an overall response rate of 37.0%. The main toxicities were myelosuppression, nausea and vomiting, and other side effects were mild. CONCLUSIONS: A high response rate can be obtained in advanced NSCLC by PTX plus DDP. PTX is a promising antitumor agent with tolerable toxicity. PMID- 21306687 TI - [NVB and DDP combination chemotherapy in the treatment of advanced non-small cell lung cancer]. AB - BACKGROUND: To evaluate the clinical effect and toxicity of NVB and DDP combination chemotherapy in the treatment of advanced non-small cell lung cancer. METHODS: All 52 patients were treated with NP regimen: NVB 25 mg/m2 iv, D1, D8; DDP 80 mg/m2 iv, D1. The regimen was repeated every 3 weeks, tumor assessment was done after 2 cycles. RESULTS: There were 2 complete responses (CR) and 26 partial responses (PR). The overall responses rate (CR+PR) was 53.8%, and the main toxicity was leucopenia, nause, vomiting and phlebitis. CONCLUSIONS: The NP regimen is effective in the treatment of advanced non-small cell lung cancer, the toxicity is well tolerated. Hence the regimen can be regarded as first-line regimen of advanced non-small cell lung cancer. PMID- 21306688 TI - [Curettage for the treatment of molluscum contagiosum: a descriptive study]. PMID- 21306689 TI - [Prevalence and clinical features of congenital melanocytic nevi in 1,000 Spanish newborns]. AB - BACKGROUND: Congenital melanocytic nevus is a benign proliferation of melanocytes that is present at birth or develops in the first months of life. Although such lesions are common, few studies have analyzed their prevalence in Spain. OBJECTIVES: The aim of this study was to define the prevalence and most frequent anatomical areas affected by congenital melanocytic nevi in our health service area. We also analyzed the influence of maternal and neonatal factors in the development of these lesions. PATIENTS AND METHODS: We performed a prospective study of 1000 consecutive neonates seen in the first 72hours of life in the perinatology clinic of the Pediatrics Department of Hospital Arquitecto Marcide in Ferrol, Spain, recording specific maternal and neonatal variables and the size and site of congenital melanocytic nevi if present. RESULTS: Fourteen infants (10 girls and 4 boys; 12 white European, 2 North African; 1.4% of the study population) presented at least 1 melanocytic nevus. None had more than 1 lesion. Eight of the nevi were located on the trunk, 2 on the face, 2 on the upper limbs, and 2 on the lower limbs. The diameter of the lesions was less than 1.5 cm in half of cases and between 1.5 and 3.5 cm in the remainder. CONCLUSIONS: There was a higher prevalence of congenital melanocytic nevi in preterm infants, females, and nonwhite infants. Maternal age, number of previous pregnancies, and birth weight do not appear to influence the prevalence of these lesions. PMID- 21306690 TI - [Long-standing macular lesions on the face]. PMID- 21306692 TI - [The Olavide Museum. Past, present, and future]. PMID- 21306691 TI - [Portfolios: a tool for the training and assessment of residents in dermatology, part 1]. AB - The medical resident's portfolio is a collection of materials that show reflective learning in the context of clinical practice. A portfolio contains documents (such as case histories and questionnaires the resident has used), images, and video recordings that reveal that an individual has acquired the competencies needed for professional practice. A portfolio is an assessment tool that simultaneously supports learning and gives evidence for certifying competence. It encourages independent continuing professional development that is incremental and centered on answering questions about what one has learned, how it might be applied, what still needs to be learned, and what must be done to reach one's goal. Answering such questions provides evidence of competencies that have been acquired and what is still lacking, allowing the trainee to develop a plan for personal improvement and evaluate subsequent achievements. The first step in creating a portfolio is to list required skills and abilities, along with the actions that will allow the resident to acquire them during each year of residency training. The ultimate goal is to define the resident's professional competence. We describe a model on which to base a training and assessment portfolio for residents in dermatology. PMID- 21306693 TI - Comparison of radiation dose and image quality of triple-rule-out computed tomography angiography between conventional helical scanning and a strategy incorporating sequential scanning. AB - Triple-rule-out computed tomographic angiography (TRO CTA), performed to evaluate the coronary arteries, pulmonary arteries, and thoracic aorta, has been associated with high radiation exposure. The use of sequential scanning for coronary computed tomographic angiography reduces the radiation dose. The application of sequential scanning to TRO CTA is much less well defined. We analyzed the radiation dose and image quality from TRO CTA performed at a single outpatient center, comparing the scans from a period during which helical scanning with electrocardiographically controlled tube current modulation was used for all patients (n = 35) and after adoption of a strategy incorporating sequential scanning whenever appropriate (n = 35). Sequential scanning was able to be used for 86% of the cases. The sequential-if-appropriate strategy, compared to the helical-only strategy, was associated with a 61.6% dose decrease (mean dose-length product of 439 mGy * cm vs 1,144 mGy * cm and mean effective dose of 7.5 mSv vs 19.4 mSv, respectively, p <0.0001). Similarly, a 71.5% dose reduction occurred among the 30 patients scanned with the sequential protocol compared to the 40 patients scanned with the helical protocol using either strategy (326 mGy * cm vs 1,141 mGy * cm and 5.5 mSv vs 19.4 mSv, respectively, p <0.0001). Although the image quality did not differ between the strategies, a nonstatistically significant trend was seen toward better quality in the sequential protocol than in the helical protocol. In conclusion, approaching TRO CTA with a diagnostic strategy of sequential scanning, as appropriate, can offer a marked reduction in the radiation dose while maintaining the image quality. PMID- 21306694 TI - Electrocardiographic detection of emphysema. AB - Emphysema of any pathogenesis (nearly always chronic obstructive pulmonary disease) verticalizes the frontal P-wave axis >60 degrees in adults, which, as a single criterion, has screened for obstructive pulmonary disease. In patients with emphysema, the QRS was of a significantly shorter duration than that in matched control patients. We investigated whether combining these 2 criteria would better detect or screen for emphysema. From consecutive unselected daily electrocardiograms with sinus rhythm, 50 were selected with a P-wave axis of >60 degrees . An equal control group from the same electrocardiogram continuum with a P-wave axis of <=60 degrees was matched for age and gender. The QRS durations were those measured by the electrocardiographic computer and manually verified individually. The charts were then reviewed for the diagnosis of chronic obstructive pulmonary disease and/or pulmonary emphysema according to the pulmonary function test and chest radiographic findings, respectively. The patients and controls were well matched demographically. Those with a vertical P axis had a strikingly greater incidence of emphysema than did the controls (86% vs 4%, respectively). The sensitivity of a P axis >60 degrees was 96% and the specificity was 87%. The mean QRS duration with emphysema was significantly shorter (78 +/- 8 vs 89 +/- 6 ms, p <0.01). The combination of QRS duration <75 ms in conjunction with a P axis of >60 degrees achieved a specificity of 100%, although the sensitivity decreased to 33%. We have reported multiple other cutpoints for each and for the combination. In conclusion, a P axis >60 degrees can be used alone with very high sensitivity and specificity to detect emphysema. The verticality of the P axis is usually immediately visible in the limb leads; therefore, this could be a rapid screening test for emphysema. The specificity was increased when combined with a shortened QRS duration, at the cost of the sensitivity. PMID- 21306695 TI - Patterns and predictors of fast food consumption after acute myocardial infarction. AB - Although fast food is affordable and convenient, it is also high in calories, saturated fat, and sodium. The frequency of fast food intake at the time of and after acute myocardial infarction (AMI) is modifiable. However, patterns of fast food intake and characteristics associated with its consumption in patients with AMI are unknown. The aim of this study was to study fast food consumption at the time of AMI and 6 months later in 2,481 patients from the prospective, 24-center Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status (TRIUMPH) study of patients with AMI. Fast food intake was categorized as frequent (weekly or more often) or infrequent (less than weekly). Multivariate log-binomial regression was used to identify patient characteristics associated with frequent fast food intake 6 months after AMI. At baseline, 884 patients (36%) reported frequent fast food intake, which decreased to 503 (20%) 6 months after discharge (p <0.001). Male gender, white race, lack of college education, current employment, and dyslipidemia were independently associated with frequent fast food intake 6 months after AMI. In contrast, older patients and those who underwent coronary bypass surgery were less likely to eat fast food frequently. Documentation of discharge dietary counseling was not associated with 6-month fast food intake. In conclusion, fast food consumption by patients with AMI decreased 6 months after the index hospitalization, but certain populations, including younger patients, men, those currently working, and less educated patients were more likely to consume fast food, at least weekly, during follow-up. Novel interventions that go beyond traditional dietary counseling may be needed to address continued fast food consumption after AMI in these patients. PMID- 21306696 TI - Relation of whole blood n-3 fatty acid levels to exercise parameters in patients with stable coronary artery disease (from the heart and soul study). AB - Dietary intake of n-3 polyunsaturated fatty acids is associated with a lower incidence of cardiovascular events. Mechanisms underlying this association are poorly understood but may include beneficial effects on physical conditioning and vagal tone. We investigated the association of n-3 fatty acid levels to exercise parameters in 992 subjects with stable coronary artery disease. Cross-sectional associations of heart rate recovery time, treadmill exercise capacity, and exercise time with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) levels were evaluated in multivariable linear and logistic regression models adjusted for demographics, cardiovascular risk factors, co-morbidities, self reported physical activity, medication use, and left ventricular function. After multivariable adjustment, n-3 fatty acid levels (DHA + EPA) were strongly associated with heart rate recovery (beta 2.1, p = 0.003), exercise capacity (beta 0.8, p <0.0001), and exercise time (beta 0.9, p <0.0001). Increasing levels of (DHA + EPA) were also associated with decreased risk of impaired heart rate recovery (odds ratio 0.8, p = 0.004) and exercise time (odds ratio 0.7, p = 0.01) and trended toward significance for exercise capacity (odds ratio 0.8, p = 0.07). These associations were not modified by demographics, body mass index, smoking, co-morbid conditions, statin use, or beta-blocker use (p for interaction >0.1 for all comparisons). In conclusion, an independent association exists between n-3 fatty acid levels and important exercise parameters in patients with stable coronary artery disease. These findings support the hypothesis that n-3 fatty acids may increase vagal tone and physical conditioning. PMID- 21306698 TI - Laparoscopic sacral colpopexy versus total vaginal mesh for vaginal vault prolapse: a randomized trial. AB - OBJECTIVE: To compare the laparoscopic sacral colpopexy and total vaginal mesh for vaginal vault prolapse. STUDY DESIGN: Women with symptomatic stage >=2 vault prolapse were randomly allocated the laparoscopic sacral colpopexy (53) or total vaginal mesh (55). Primary outcome measures were objective success rates at pelvic organ prolapse quantification sites individually and collectively. Secondary outcome measures included perioperative outcomes, patient satisfaction, quality of life outcomes, complications, and reoperations. RESULTS: The laparoscopic sacral colpopexy group had a longer operating time, reduced inpatient days, and quicker return to activities of daily living as compared with the total vaginal mesh group. At the 2-year review, the total objective success rate at all vaginal sites was 41 of 53 (77%) for laparoscopic sacral colpopexy as compared with 23 of 55 (43%) in total vaginal mesh (P < .001). Reoperation rate was significantly higher after the vaginal mesh surgery 12 of 55 (22%) as compared with laparoscopic sacral colpopexy 3 of 53 (5%) (P = .006). CONCLUSION: At 2 years, the laparoscopic sacral colpopexy had a higher satisfaction rate and objective success rate than the total vaginal mesh with lower perioperative morbidity and reoperation rate. PMID- 21306697 TI - Mifepristone and misoprostol for early pregnancy failure: a cohort analysis. AB - OBJECTIVE: We sought to examine outcomes of mifepristone and misoprostol for early pregnancy failure (EPF) treatment in a nonresearch setting. STUDY DESIGN: A protocol was developed for physicians to use mifepristone 200 mg orally and misoprostol 800 MUg vaginally for EPF. Success rates were analyzed and an adjusted multivariable regression was used to identify factors predictive of success. RESULTS: Treatment success occurred in 99 (80%; 95% confidence interval, 72-87%) of 123 patients after mifepristone and a single dose of misoprostol and 102 (83%; 95% confidence interval, 75-89%) patients overall. The odds of successful medical treatment were increased in women with a diagnosis of intrauterine embryonic/fetal demise (odds ratio, 3.80) and decreased in women who made additional emergency department visits (odds ratio, 0.12). CONCLUSION: Patients and clinicians may be more likely to intervene surgically with an EPF when a strict study protocol is not being followed. PMID- 21306699 TI - Nicorandil-induced rectovaginal fistula. AB - An 82-year-old woman was admitted with feculent vaginal discharge and bleeding per vagina. Investigations revealed the presence of a rectovaginal fistula with no obvious etiology. Due to the surgical team's previous experience with nicorandil-induced ulceration, the drug was stopped. The rectovaginal fistula healed completely within 6 months. PMID- 21306700 TI - Obstetric and neonatal risks among extremely macrosomic babies and their mothers. AB - OBJECTIVE: We estimated the risk of complications at birth of extremely large babies (>=5000 g). STUDY DESIGN: This was a cohort study including all births of extremely large babies in 1996 through 2005 and comparison cohort with normal birthweight (1:2) identified in the national birth registration. RESULTS: There were 343 extremely large babies or 0.9% of all singletons. Compared to the normal birthweight cohort (n = 679), there were increased odds of shoulder dystocia (odds ratio [OR], 26.9; 95% confidence interval [CI], 11.1-65.1), emergency cesarean section (OR, 5.2; 95% CI, 3.4-8.0), and failed labor induction (OR, 4.3; 95% CI, 1.7-11.0). The risk of elective section was not increased (OR, 1.1; 95% CI, 0.6-2.0). Minor congenital malformations were more frequent (OR, 2.1; 95% CI, 1.2-3.7), as were birth injuries (OR, 3.7; 95% CI, 2.1-6.8) and minor metabolic disturbance (OR, 2.5; 95% CI, 1.1-6.2), but not asphyxial births. CONCLUSION: The risk of shoulder dystocia for very large babies is markedly raised, as are minor complications, while for mothers the main risk is emergency section. PMID- 21306701 TI - Patient safety in obstetrics--the Hospital Corporation of America experience. AB - We report an update on obstetric patient safety efforts and results in the nation's largest obstetric health care delivery system. The application of principles advocated by the Institute of Medicine a decade ago has resulted in reduced adverse outcomes, as reflected by claims experience. Particular progress has been made in standardization and documentation of critical processes, establishment of national quality benchmarks, reduction in elective deliveries <39 weeks' gestation, and reduction in fatal postcesarean pulmonary embolism. Our experience provides a useful blueprint for similar progress in other health care systems. PMID- 21306702 TI - [Cannabis and myocardial infarction without angiographic stenosis in young patient: guilty or not guilty? A case report]. AB - Cannabis is the most consumed drug in France, particularly in young adults. Few reports have suggested a causal role of cannabis in the development of cardiovascular events. We describe one case of 26-year-old man, cannabis and tobacco smoker, admitted with recurrent ischemic stroke cause by post-myocardial infarction left ventricular thrombus. Coronary arteries were angiographicaly normal and etiological tests were negative. We suggest the possible relationship between marijuana use with coronary heart disease. PMID- 21306703 TI - Expression of IL-6, IL-10, IL-17 and IL-8 in the peri-implant crevicular fluid of patients with peri-implantitis. AB - OBJECTIVES: The aim of this study was to compare the levels of cytokines IL-6, IL 10 and IL-17 and the chemokine IL-8 in the peri-implant crevicular fluid (PCF) between the group of patients with peri-implantitis (PP) and peri-implantar healthy patients (HP). DESIGN: The PCF was collected from 40 implants regarding 25 patients, being 14 patients with PP and 11 HP totalizing 20 implants from each group. The PCF samples collected from each patient were quantified for IL-6, IL 17, IL-8 and IL-10 using the enzymatic immunosorbent assay (ELISA). RESULTS: The expression of IL-17 was significantly higher in the PP group when compared to HP (p < 0.05). There was no significant difference when comparing the levels of IL 6, IL-8 and IL-10 between both groups HP and PP. Also, there was a significant positive correlation between levels of IL-6 and IL-8 in the PP group. CONCLUSIONS: This study demonstrates that in patients with peri-implantitis there is an increase of IL-17 which may induce the production of other inflammatory cytokines, contributing to the pathogenesis of bone loss in peri-implantitis. PMID- 21306704 TI - Pharmacologic rescue of impaired cognitive flexibility, social deficits, increased aggression, and seizure susceptibility in oxytocin receptor null mice: a neurobehavioral model of autism. AB - BACKGROUND: Oxytocin (OT) has been suggested as a treatment to improve social behavior in autistic patients. Accordingly, the OT (Oxt(-/-)) and the OT receptor null mice (Oxtr(-/-)) display autistic-like deficits in social behavior, increased aggression, and reduced ultrasonic vocalization. METHODS: Oxtr(-/-) mice were characterized for general health, sociability, social novelty, cognitive flexibility, aggression, and seizure susceptibility. Because vasopressin (AVP) and OT cooperate in controlling social behavior, learning, and aggression, they were tested for possible rescue of the impaired behaviors. Primary hyppocampal cultures from Oxtr(+/+) and Oxtr(-/-) mouse embryos were established to investigate the balance between gamma-aminobutyric acid (GABA) and glutamate synapses and the expression levels of OT and AVP (V1a) receptors were determined by autoradiography. RESULTS: Oxtr(-/-) mice display two additional, highly relevant, phenotypic characteristics: 1) a resistance to change in a learned pattern of behavior, comparable to restricted interests and repetitive behavior in autism, and 2) an increased susceptibility to seizures, a frequent and clinically relevant symptom of autism. We also show that intracerebral administration of both OT and AVP lowers aggression and fully reverts social and learning defects by acting on V1a receptors and that seizure susceptibility is antagonized by peripherally administered OT. Finally, we detect a decreased ratio of GABA-ergic versus total presynapses in hippocampal neurons of Oxtr(-/-) mice. CONCLUSIONS: Autistic-like symptoms are rescued on administration of AVP and OT to young Oxtr(-/-) adult animals. The Oxtr(-/-) mouse is thus instrumental to investigate the neurochemical and synaptic abnormalities underlying autistic-like disturbances and to test new strategies of pharmacologic intervention. PMID- 21306705 TI - Reliability and validity of the Time-Sensitive ADHD Symptom Scale in adults. AB - OBJECTIVES: The objective of this study was to examine the psychometric properties of the Time-Sensitive ADHD Symptom Scale (TASS) to evaluate change of attention-deficit/hyperactivity disorder (ADHD) symptoms over the course of a day in adults. METHODS: Eighty adults with ADHD participated in 1 or 2 visits, 1 to 9 weeks apart. At each visit, participants completed the TASS followed by raters administering the ADHD Rating Scale (ADHD-RS). Additional TASS and ADHD-RS ratings were completed 2 to 6 hours after each visit via telephone. Internal consistency of TASS items was assessed by Cronbach's alpha. Convergent validity of TASS and ADHD-RS total mean item scores was assessed using Pearson's correlation coefficients. kappa correlations were calculated to assess item-by item reliability between TASS and ADHD-RS items. RESULTS: Internal consistency of TASS items was high, with an overall Cronbach's alpha coefficient of .93. The Pearson's correlation coefficient between the TASS and ADHD-RS was significant for all visits (r = 0.70, P < .0001). There was moderate agreement between individual items on the TASS and ADHD-RS, with significant kappa coefficients for almost all items (P < .05). DISCUSSION: The TASS showed high internal consistency and concurrent validity with the clinician-administered ADHD-RS and is a valid and reliable scale for measuring change in ADHD symptoms over the course of a day in adults. PMID- 21306706 TI - Shyness and social phobia in Israeli Jewish vs Arab students. AB - BACKGROUND: Social anxiety disorder (SAD) has been repeatedly shown to be very prevalent in the Western society with prevalence rates of 10% or above. However, very few studies have been performed in the Middle East and in Arab countries. METHODS: A total of 300 Israeli students participated in our study and were administered the Liebowitz Social Anxiety Scale (LSAS), the Cheek and Buss Shyness Questionnaire (CBSQ), and a sociodemographic questionnaire. RESULTS: A total of 153 Jewish and 147 Arab students participated in the survey. Social anxiety disorder was found in 12.33% of the sample, according to the LSAS cutoff score of more than 60. The 2 subsamples had similar LSAS and CBSQ scores and similar SAD-positive rates (LSAS >60). Females had higher scores on the LSAS, as were those without a spouse and those who had been in psychological treatment. Based on a regression analysis, the significant predictors of the LSAS score were the CBSQ score and female sex. A very high correlation was found between the LSAS and the CBSQ scores. CONCLUSIONS: Although our sample is not representative of the whole Israeli population, we conclude that SAD and shyness were similarly prevalent in Jewish and Arab students in Israel. Social anxiety disorder scores were higher among females, those without a spouse, and those who received psychological treatment. Further studies on the clinical and cultural characteristics of SAD in Israeli subcultures would add to the growing body of knowledge on SAD in various cultures. PMID- 21306707 TI - Phantom limbs - or phantoms of phantom limbs? PMID- 21306708 TI - Trafficking mechanisms and HIV status among sex-trafficking survivors in Calcutta, India. PMID- 21306709 TI - Influence of epidural dexamethasone on maternal temperature and serum cytokine concentration after labor epidural analgesia. AB - OBJECTIVE: To evaluate the effects of epidural dexamethasone on maternal temperature and serum cytokine levels after labor epidural analgesia. METHODS: Sixty healthy term nulliparas in spontaneous labor were randomized to receive epidural analgesia alone using bupivacaine 0.125% and fentanyl 1 MUg/mL (group I) or epidural analgesia combined with dexamethasone 0.2mg/mL (group II) (n=30 per group). Maternal tympanic temperature was measured before epidural analgesia and hourly thereafter until delivery. Maternal and cord venous blood were sampled for analysis of interleukin-6 (IL-6), tumor necrosis factor-alpha, and interleukin-10 levels. RESULTS: There was no difference in the incidence of intrapartum fever (38 degrees C or more) between the 2 groups (3/30 versus 1/30, P=0.612). The mean maternal temperature increased with time in group I, with the elevation reaching statistical significance at 4 hours post analgesia and at delivery compared with baseline (P=0.012 and P=0.043, respectively). A similar trend was observed with maternal serum IL-6 levels in group I. In group II, maternal temperature and IL-6 levels did not differ from baseline at any time point during labor. CONCLUSION: Epidural dexamethasone alleviates maternal temperature elevation after epidural analgesia. This effect can be attributed to the decrease in IL-6 levels. PMID- 21306710 TI - Obstetric and neonatal outcomes for women with reversed and non-reversed type III female genital mutilation. AB - OBJECTIVE: To record and compare obstetric and neonatal complication rates in women with reversed and non-reversed type III female genital mutilation (FGM). METHODS: A retrospective observational study comparing cesarean delivery rates and neonatal outcomes of primiparous and multiparous women who had or had not undergone reversal of FGM III. RESULTS: Of the 250 women, 230 (92%) had an FGM reversal. Of these, 50 (21.7%) were primiparous (cesarean delivery rate 17/50; 34%) and 180 (78.3%) were multiparous (cesarean delivery rate 28/180; 15.6%). Of the 20 women who had not had an FGM reversal, 7 (35%) were primiparous (cesarean delivery rate 5/7; 71.4%) and 13 (65%) were multiparous (cesarean delivery rate 7/13; 53.8%). The cesarean delivery rates for primiparae and multiparae were 32.9% and 25%, respectively. Multiparous women with FGM III reversal had a lower possibility of cesarean delivery compared with the hospital multiparous population (P=0.003) and multiparae who had not undergone FGM III reversal (P=0.007). There was no significant association between Apgar scores or blood loss at vaginal delivery and FGM reversal. CONCLUSION: Reversal of FGM III significantly reduced the increased risk of cesarean delivery seen with multiparae who have FGM III. PMID- 21306711 TI - The relationship between metabolic syndrome, its components, and the whole-body atherosclerotic disease burden as measured by computed tomography angiography. AB - OBJECTIVE: Quantify the whole-body atherosclerotic disease in asymptomatic subjects with and without metabolic syndrome (MetS) and to assess the contribution of the syndrome and its components to the atherosclerotic burden. METHODS: Sixty-five subjects with and 51 without ATPIII-defined MetS underwent a 64-slice computed tomography angiography (CTA). Plaques causing >0% stenosis in coronary or extra-coronary arteries were classified as positive. RESULTS: The prevalence of plaques in coronary, carotid and peripheral arteries as well as their severity did not differ between groups. Conversely, it was seen an almost 3 fold increased likelihood (OR=2.70; 95% CI 1.30-5.57; P<0.001) of atherosclerosis in any district across categories of MetS components (0-1 vs. 2-3 vs. 4-5). Hypertriglyceridemia (P<0.05) and high blood glucose (P<0.05) were independent predictors of the atherosclerotic burden. CONCLUSIONS: Atherosclerotic burden as revealed by 64-TCA appears to be more strongly associated with the number of MetS related factors than to the clinical diagnosis of MetS itself. PMID- 21306712 TI - Augmented angiogenesis in adventitia promotes growth of atherosclerotic plaque in apolipoprotein E-deficient mice. AB - OBJECTIVE: Accumulating evidence suggests that exaggerated formation of vasa vasorum (VV) plays an important role in the pathogenesis of atherosclerosis. However, it remains unclear whether augmented angiogenesis in the adventitia could promote hyperlipidemia-induced atherosclerotic lesion formation. METHODS AND RESULTS: First, we analyzed the time course of VV development in apolipoprotein E-deficient (ApoE-/-) mice. VV proliferation was observed only after atherosclerotic lesion formation. Next, we investigated whether forced perivascular angiogenesis could promote plaque progression. Basic fibroblast growth factor (bFGF) (100 MUg/body) incorporated in acid gelatin hydrogel microspheres (AGHM) (bFGF+AGHM group, n=10), AGHM alone (AGHM group, n=7), or PBS (control group, n=8) was administered into the periaortic area of the retroperitoneal space in 10- to 11-week-old male ApoE-/- mice. At 13 weeks after the operation, lesions were significantly larger in the bFGF+AGHM group than in others (bFGF+AGHM: 3.4 +/- 0.7 * 10(4)MUm(2); AGHM: 0.1 +/- 0.1 * 10(4)MUm(2); control: 0 MUm(2); p<0.0001), which was associated with increased neovascularization in the adventitia. The number of adventitial capillaries correlated with plaque size (r=0.69, p<0.0001). In the bFGF+AGHM group, an increase in the number of VV and accumulation of Mac3-positive macrophages were observed prior to atherosclerotic lesion formation. CONCLUSIONS: Our findings demonstrated that local administration of bFGF in the adventitia induced development of VV and accelerated plaque progression in ApoE-/- mice, supporting the notion that VV formation plays a crucial role in the pathogenesis of atherosclerosis. PMID- 21306713 TI - Effects of attachment position and shoulder orientation during calibration on the accuracy of the acromial tracker. AB - The acromial tracker is used to measure scapular rotations during dynamic movements. The method has low accuracy in high elevations and is sensitive to its attachment location on the acromion. The aim of this study was to investigate the effect of the attachment position and shoulder orientation during calibration on the tracker accuracy. The tracker was attached to one of three positions: near the anterior edge of the acromion process, just above the acromial angle and the meeting point between the acromion and the scapular spine. The scapula locator was used to track the scapula during bilateral abduction simultaneously. The locator was used to calibrate the tracker at: no abduction, 30 degrees , 60 degrees , 90 degrees and 120 degrees humerothoracic abduction. ANOVA tests compared RMS errors for different attachment positions and calibration angles. The results showed that attaching the device at the meeting point between the acromion and the scapular spine gave the smallest errors and it was best to calibrate the device at 60 degrees for elevations <=90 degrees , at 120 degrees for elevations >90 degrees and at 90 degrees or 120 degrees for the full range of abduction. The accuracy of the tracker is significantly improved if attached appropriately and calibrated for the range of movement being measured. PMID- 21306714 TI - Identifying gait asymmetry using gyroscopes--a cross-correlation and Normalized Symmetry Index approach. AB - Injury to a lower limb may disrupt natural walking and cause asymmetrical gait, therefore assessing the gait asymmetry has become one of the important procedures in gait analysis. This paper proposes the use of wireless gyroscopes as a new instrument to determine gait asymmetry. It also introduces two novel approaches: normalized cross-correlations (Cc(norm)) and Normalized Symmetry Index (SI(norm)). Cc(norm) evaluates the waveform patterns generated by the lower limb in each gait cycle. SI(norm) provides indications on the timing and magnitude of the bilateral differences between the limbs while addressing the drawbacks of the conventional methods. One-way ANOVA test reveals that Cc(norm) can be considered as single value indicator that determines the gait asymmetry (p<0.01). The experiment results showed that SI(norm) in asymmetrical gait were different from normal gait. SI(norm) in asymmetrical gait were found to be approximately 20% greater than SI(norm) in normal gait during pre-swing and initial swing. PMID- 21306715 TI - The effect of lunate position on range of motion after a four-corner arthrodesis: a biomechanical simulation study. AB - A four-corner arthrodesis of the wrist is a salvage procedure for the treatment of specific wrist disorders, to achieve a movable, stable and pain free joint. However, a partial arthrodesis limits the postoperative range of motion (ROM). The goal of this study is to understand the mechanism of the reduction of the ROM and to evaluate the effect of the orientation of the lunate in the four-corner arthrodesis on the range of motion by using a biomechanical model, containing articular contacts and ligaments. Multi-body models of a normal wrist and a four corner arthrodesis wrist with different orientation of the lunate were used for simulations of flexion-extension motion (FEM) and radial-ulnar deviation motion (RUD). The ROM of the postoperative wrist was reduced from 145 degrees to 82 degrees of the total arc of FEM and from 73 degrees to 41.5 degrees of the total arc of RUD. The model simulations show that the range of motion reduction is caused by overtension of the extrinsic wrist ligaments. Different positioning of the lunate changes the balance between the contact forces and ligament forces in the wrist. This explains the effect on the postoperative range of motion. The 20 degrees flexed lunate did not give any gain in the extension motion of the wrist, caused joint luxation in flexion and limitation in RUD. The 30 degrees extended lunate caused overtension of the extrinsic ligaments attached to the lunate. The ROM in this case is dramatically reduced. The model simulations suggest that the neutral position of the lunate seems to be most favorable for mobility of the wrist after a four-corner arthrodesis procedure. PMID- 21306717 TI - Monolithic columns based on a poly(styrene-divinylbenzene-methacrylic acid) copolymer for capillary liquid chromatography of small organic molecules. AB - A very simple and readily performed method is described for the preparation of poly(styrene-divinylbenzene-methacrylic acid) monolithic columns for capillary liquid chromatography. The effect of the methacrylic acid content on the morphological and chromatographic properties has been investigated. Methacrylic acid is shown to be essential for isocratic separations of small organic analytes by capillary liquid chromatography. Column efficiencies of about 28,000 theoretical plates/m have been obtained for all the test compounds. The batch-to batch and run-to-run repeatability of the retention times is better than 1.5%. PMID- 21306716 TI - In vivo dynamic strains of the ovine anterior mitral valve leaflet. AB - Understanding the mechanics of the mitral valve is crucial in terms of designing and evaluating medical devices and techniques for mitral valve repair. In the current study we characterize the in vivo strains of the anterior mitral valve leaflet. On cardiopulmonary bypass, we sew miniature markers onto the leaflets of 57 sheep. During the cardiac cycle, the coordinates of these markers are recorded via biplane fluoroscopy. From the resulting four-dimensional data sets, we calculate areal, maximum principal, circumferential, and radial leaflet strains and display their profiles on the averaged leaflet geometry. Average peak areal strains are 13.8+/-6.3%, maximum principal strains are 13.0+/-4.7%, circumferential strains are 5.0+/-2.7%, and radial strains are 7.8+/-4.3%. Maximum principal strains are largest in the belly region, where they are aligned with the circumferential direction during diastole switching into the radial direction during systole. Circumferential strains are concentrated at the distal portion of the belly region close to the free edge of the leaflet, while radial strains are highest in the center of the leaflet, stretching from the posterior to the anterior commissure. In summary, leaflet strains display significant temporal, regional, and directional variations with largest values inside the belly region and toward the free edge. Characterizing strain distribution profiles might be of particular clinical significance when optimizing mitral valve repair techniques in terms of forces on suture lines and on medical devices. PMID- 21306718 TI - Rapeseed oil methyl ester pyrolysis: on-line product analysis using comprehensive two-dimensional gas chromatography. AB - Thermochemical conversion processes play a crucial role in all routes from fossil and renewable resources to base chemicals, fuels and energy. Hence, a fundamental understanding of these chemical processes can help to resolve the upcoming challenges of our society. A bench scale pyrolysis set-up has been used to study the thermochemical conversion of rapeseed oil methyl ester (RME), i.e. a mixture of fatty acid methyl esters. A GC*GC, equipped with both a flame ionization detector (FID) and a time-of-flight mass spectrometer (TOF-MS), allows quantitative and qualitative characterization of the reactor feed and product. Analysis of the latter is accomplished using a dedicated high temperature on-line sampling system. Temperature programmed analysis, starting at -40 degrees C, permits effluent characterization from methane up to lignoceric acid methyl ester (C(25)H(50)O(2)), in a single run of the GC*GC. The latter combines a 100% dimethylpolysiloxane primary column with a 50% phenyl polysilphenylene-siloxane secondary column. Modulation is started when the oven temperature reaches 40 degrees C, thus dividing the chromatogram in a conventional 1D and a comprehensive 2D part. The proposed quantification approach allows to combine the quantitative GC*GC analysis with 2 other on-line 1D GC analyses, resulting in a complete and detailed product composition including the measurement of CO, CO(2), formaldehyde and water. The GC*GC reveals that the product stream contains a huge variety of valuable products, such as linear alpha olefins, unsaturated esters and aromatics, that could not have been identified and quantified accurately with conventional 1D GC because of peak overlap. PMID- 21306719 TI - Development and validation of a multiclass method for the analysis of antibiotic residues in eggs by liquid chromatography-tandem mass spectrometry. AB - A multiclass method for the analysis of residues, in egg matrices, of 41 antimicrobial agents belonging to seven families (sulfonamides, diaminopyridine derivates, quinolones, tetracyclines, macrolides, penicillins and lincosamides) was developed and validated according to the requirements of European Commission Decision 2002/657. Compounds were extracted with a pressurized liquid extraction (PLE) technique using a 1:1 mixture of acetonitrile and a succinic acid buffer (pH 6.0) at 70 degrees C. As this resulted in clear extracts, no further clean up was necessary. Analytes were determined by ultra-high-pressure liquid chromatography-tandem mass spectrometry (UHPL-MS/MS) in a chromatographic run of 13 min. Calibration was carried out with spiked blank samples subjected to the entire analytical procedure. Five compounds, two of them isotopically labelled, were used as internal standards. Most analytes were quantified with errors below 10%. Precision in terms of reproducibility standard deviation was between 10% and 20% in most cases. CCalpha values were in the range 0.5-3.8 MUg kg-1 for the non authorized compounds. The proposed method would enable an experienced analyst to process about 25 samples per day. PMID- 21306720 TI - A capillary electrophoresis-tandem mass spectrometry methodology for the determination of non-protein amino acids in vegetable oils as novel markers for the detection of adulterations in olive oils. AB - A new analytical methodology based on capillary electrophoresis-mass spectrometry (CE-MS(2)) is presented in this work, enabling the identification and determination of six non-protein amino acids (ornithine, beta-alanine, GABA, alloisoleucine, citrulline and pyroglutamic acid) in vegetable oils. This methodology is based on a previous derivatization with butanol and subsequent separation using acidic conditions followed by on-line coupling to an ion trap analyzer for MS(2) detection established through an electrospray-coaxial sheath flow interface. The electrophoretic and interface parameters were optimized obtaining the separation of all compounds in less than 15 min and with resolutions higher than 5. The proposed method was validated by assessing its accuracy, precision (RSD<7% for corrected peak areas), LODs and LOQs (between 0.04-0.19 ng/g and 0.06-0.31 ng/g, respectively) and linearity range (R(2)>0.99), and it was used in order to identify the selected non-protein amino acids in soybean oils, sunflower oils, corn oils and extra virgin olive oils. MS(2) experiments performed the fingerprint fragmentation of these compounds allowing to corroborate ornithine and alloisoleucine in seed oils but not in olive oils. The method was applied to identify and quantify olive oil adulterations with soybean oil detecting in a single run the amino acids in mixtures up to 2% (w/w). The results showed a high potential in using these compounds as novel markers for the detection of adulterations of extra virgin olive oils with seed oils. Thus, the developed method could be considered a simple, rapid and reliable method for the quality evaluation of extra virgin olive oil permitting its authentication. PMID- 21306721 TI - Adsorption of deamidated antibody variants on macroporous and dextran-grafted cation exchangers: I. Adsorption equilibrium. AB - Single and multicomponent adsorption isotherms were obtained for deamidated variants of a monoclonal antibody on two cation exchangers with different pore structures, one with a macroporous architecture--UNOsphere S, and the other with charged dextran grafts--Capto S. No selectivity between the different deamidated forms was seen at pH 5 for either stationary phase. However, although the binding strength was lower, both media exhibited substantial selectivity at pH 7.5. The effective binding charge, determined from linear gradient elution experiments and from the steric mass action model, was different for the two different media, but remained nearly the same for the different variants suggesting that the selectivity is determined by the strength of binding, rather than by the binding charge. This result agrees with the higher binding constants determined for the less deamidated forms. At low ionic strength, the binding capacity of the dextran grafted media was much higher than that of the macroporous matrix at either pH. However, similar capacities were obtained for the two stationary phases at ~140 mM Na+ for pH 5 and at 50 mM Na+ for pH 7.5. For both materials, predictions of multicomponent adsorption based on the steric mass action model were in good agreement with experimental results indicating that the different variants bind in competition with each other. In general, this work demonstrates the utility of modeling adsorption equilibrium allowing an accurate description of competitive binding, which is a necessary step for a complete description of a chromatographic separation process. PMID- 21306722 TI - Highly efficient adsorbents of poly(o-phenylenediamine) solid and hollow sub microspheres towards lead ions: a comparative study. AB - Two kinds of different-shaped poly(o-phenylenediamine) (PoPD) polymers: solid and hollow sub-microspheres with both size of about 700 nm synthesized by a solution route without any additional directing agents, were employed as efficient adsorbents for removal of Pb(II) ions from water. Firstly, chemical structures of PoPD sub-microspheres were performed by Fourier-transform infrared (FT-IR), UV vis, (1)H NMR spectra, X-ray diffraction (XRD) and GPC analysis. When used as adsorbents, both PoPD hollow and solid sub-microspheres showed high adsorptivity and adsorption capacity towards Pb(II) ions in water, and mechanisms of adsorption behaviors were revealed by XRD and X-ray photoelectron spectra (XPS). It was found that the pH and concentration of Pb(II) ion solution, as well as contact time and adsorbent dosage affect the degree of adsorption. Adsorption isotherms and kinetics of Pb(II) ions onto PoPD sub-microspheres were also investigated according to experimental data. Comparative investigations of adsorption behaviors revealed that hollow sub-microspheres showed enhanced adsorptivity adsorption capacity towards Pb(II) ions as compared with solid sub microspheres typical at low adsorbent dosage. PoPD hollow sub-microspheres also showed good adsorptivity for other heavy-metal ions, such as Hg(II), Cd(II) and Cu(II), which implied their potential applications as effective adsorbents for heavy-metal ions in water. PMID- 21306723 TI - Multifunctional NO-delivery vessel derived from aminopropyl-modified mesoporous zeolites. AB - A new strategy, releasing nitric oxide (NO) and adsorbing nitrosamines simultaneously by zeolitic materials in the digestive system, is validated in this paper. Three types of moisture-saturated molecular sieves, HZSM-5 zeolite, mesoporous zeolite, and mesoporous silica MCM-41, are used as NO-delivery vessels in mimic gastric juice after modification of gamma-aminopropyltriethoxysilane (APTES). APTES modification dramatically increased the capability of zeolite and mesoporous silica in NO release in acidic solution, because more NO can be adsorbed in the composite and stored in the form of nitrite. Some composites released the NO 10 times more than their parent materials, and synchronously captured the carcinogen nitrosamines in mimic gastric juice. The influences of APTES modification on the porous structure and surface state of zeolite and mesoporous silica were investigated by XRD, N(2) adsorption, and FTIR tests, through which the mesoporous zeolite is proven to be the optimal support. With this hierarchical material a controllable APTES modification is realized in which a lot of aminopropyl groups are grafted in mesopores while the zeolitic structure is maintained, so the resulting sample exhibits a high capability in releasing NO and adsorbing nitrosamines. This investigation provides a clue for elevating the efficiency of zeolites in the application of life science. PMID- 21306724 TI - Synthesis and surface photochemistry of graphitized carbon quantum dots. AB - Graphitized carbon quantum dots (CQDs) were synthesized by a simple hydrothermal process with cetyltrimethylammonium bromide (CTAB) as the starting material and nitric acid as surface oxidant. The photoluminescent quantum yield (QY) of CQDs could be greatly enhanced through surface esterification with glycol. Based on the structure characterization, we proposed that the CQDs consisted of the stack of graphene sheets sized several nanometers and their excitation-dependent photoluminescence (PL) should be attributed to the n->pi* transition of CO bond of surface carboxylic groups. And the PL of CQDs was obviously enhanced by the esterification of carboxylic groups, possibly due to the increase of the molecular coplanarity or the rigidity. PMID- 21306725 TI - Adsorption and wetting characterization of hydrophobic SBA-15 silicas. AB - This work describes adsorption and wetting characterization of hydrophobic ordered mesoporous silicas (OMSs) with the SBA-15 motif. Three synthetic approaches to prepare hydrophobic SBA-15 silicas were explored: grafting with (1) covalently-attached monolayers (CAMs) of C(n)H(2)(n+1)Si(CH(3))(2)N(CH(3))(2), (2) self-assembled monolayers (SAMs) of C(n)H(2)(n+1)Si(OEt)(3), and (3) direct ("one-pot") co-condensation of TEOS with C(n)H(2)(n+1)Si(OEt)(3) in presence of P123 (n=1-18). The materials prepared were characterized by nitrogen adsorption, TEM, and chemical analysis. The surface properties of the materials were assessed by water contact angles (CAs) and by BET C constants. The results showed that, while loadings of the alkyl groups (%C) were comparable, the surface properties and pore ordering of the materials prepared through different methods were quite different. The best quality hydrophobic surfaces were prepared for SBA-15 grafted with CAMs of alkylsilanes. For these materials, the water CAs were above ~120 degrees /100 degrees (adv/rec) and BET C constants were in the range of ~15-25, indicating uniform low-energy surfaces of closely packed alkyl groups on external and internal surfaces of the pores respectively. Moreover, surfaces grafted with the long-chained (C(12)-C(18)) silanes showed super-hydrophobic behavior (CAs~150 180 degrees ) and extremely low adhesion for water. The pore uniformity of parental SBA-15 was largely preserved and the pore volume and pore diameter were consistent with the formation of a single layer of alkylsilyl groups inside the pores. Post-synthesis grafting of SBA-15 with SAMs worked not as well as CAMs: the surfaces prepared demonstrated lower water CAs and higher BET C constants, thereby indicating a small amount of accessible polar groups (Si-OH) related to packing constrains for SAMs supported on highly curved surfaces of mesopores. The co-condensation method produced substantially more disordered materials and less hydrophobic surfaces than any of the grafting methods. The surfaces of these materials showed low water CAs and high BET C constants (~100-200) thereby demonstrating a non-uniform surface coverage and presence of unmodified silica. It is concluded that CAMs chemistry is the most efficient approach in preparation of the functionalized OMS materials with uniform surfaces and pores. PMID- 21306726 TI - Stable polydiacetylene/ZnO nanocomposites with two-steps reversible and irreversible thermochromism: the influence of strong surface anchoring. AB - This contribution introduces a versatile method to prepare a new class of polydiacetylene(PDA)-based material. ZnO nanoparticle is used as a nano-substrate for spontaneous assembling of diacetylene monomer, 10,12-pentacosadiynoic acid, on its surface. An irradiation of the organized assemblies by UV light results in PDA/ZnO nanocomposites with deep blue color. Strong ionic interaction and hydrogen bonding at the ZnO surface restrict the dynamics of alkyl side chains and promote the PDA ordering, which in turn drastically affects its thermochromic behaviors. We have found that the PDA/ZnO nanocomposite exhibits two-steps color transition upon increasing temperature. The first transition of the nanocomposite in aqueous suspension, causing the color change from blue to purple, occurs reversibly at ~90 degrees C. The transition temperature shifts to ~100 degrees C when the nanocomposite is embedded in polyvinyl alcohol matrix. Further increasing temperature to 145 degrees C induces the second transition, which causes irreversible color change from purple to red. PMID- 21306727 TI - Multifocal granulomatous jejunitis associated with an argyrophilic gram-positive segmented filamentous bacterium in a Holstein cow. AB - Multifocal, raised, ulcerated firm nodules accompanied by an intussuscepted area were detected in the jejunum of an 8-year-old Holstein cow. The cut surfaces of the nodules were yellow-white. Microscopically, the lamina propria was expanded by an intense infiltration of epithelioid cells, multinucleate giant cells, macrophages, lymphocytes and neutrophils. Numerous bacteria were found within the granulomatous lesions. These were argyrophilic, gram-positive, periodic acid Schiff-positive, segmented, rarely branched, elongate filamentous bacteria (2-28 MUm in length, 0.2-0.35 MUm in diameter). Ultrastructurally, a cell wall with an electron-transparent zone was detected. The present pathogen was clearly different from the argyrophilic, gram-negative, non-segmented, filamentous bacterium previously reported in a Holstein cow with jejunal granuloma. Comparative 16S rDNA gene sequencing analysis revealed that the organism was an unpublished species (GenBank accession number AB539875). This is the first report of bovine jejunal granuloma associated with an argyrophilic gram-positive segmented filamentous bacterium. PMID- 21306728 TI - Malignant mesenchymoma in the nasal cavity of a bull. AB - A 4-year-old bull was presented with facial distortion and abnormal respiratory noise. Endoscopically, a proliferative mass was found obliterating the left nasal cavity and a tumour was suspected. The head was examined after slaughter and there was a well-circumscribed solid structure (15*12*6 cm) extending into the paranasal sinus, the choanal region and the bones of the orbit, with focal penetration of the nasal septum. Microscopically, the mass consisted of well differentiated trabeculae of woven and lamellar bone, areas of chondromyxomatous, immature and mature cartilaginous tissue, and regions with irregular whorled spindle cells. Tissue differentiation of the mass was variable. Centrally, there was osseous differentiation with an outermost fibromatous area resembling a zone of endochondral ossification. There was suppurative and ulcerative inflammation where the tumour extended through the hard palate and into the pharynx. A nasal malignant mesenchymoma was diagnosed on the basis of these features. PMID- 21306729 TI - Dystrophic epidermolysis bullosa in Assaf lambs. AB - Dystrophic epidermolysis bullosa (DEB) was diagnosed in five newborn Assaf lambs from a flock in which around 1-2% of the lambs were lame. Affected animals had marked erythema of the coronary band and subsequent detachment of the hooves. Blisters were present on the lips and in the oral and oesophageal mucosae. Erosions and crusts were noted in the axillary and inguinal areas. Microscopically, there was detachment of the epidermis from the dermis. The roof of these bullous spaces was formed by the intact epidermis with its basement membrane. The bullae were generally filled with pale eosinophilic proteinaceous fluid and erythrocytes. Immunohistochemical analysis revealed absence of collagen VII in the basement membrane zone. The disease in these lambs appears similar to the severe recessive form of human DEB. PMID- 21306730 TI - Pericardial myxoid liposarcoma in a common eland (Taurotragus oryx). AB - A pericardial myxoid liposarcoma was diagnosed in a common eland (Taurotragus oryx) based on gross, microscopical and immunohistochemical findings. The pericardial and epicardial tissues were soft and uniformly thickened. Microscopically, the neoplastic mass consisted of stellate cells embedded in a myxoid matrix. These cells contained cytoplasmic vacuoles stained by oil red O. Immunohistochemical analysis showed the neoplastic cells to express vimentin and S-100. PMID- 21306731 TI - Pulmonary arteriovenous malformations: clinical and radiological presentation. PMID- 21306732 TI - Inefficiently increased anterior cingulate modulation of cortical systems during working memory in young offspring of schizophrenia patients. AB - BACKGROUND: Children and adolescent offspring of schizophrenia patients are at increased risk for schizophrenia and are also characterized by impairments in brain structure and function. To date, few studies have investigated whether functional interactions between brain regions are intact or altered. Using an established verbal working memory paradigm with variable levels of memory load, we investigated the modulatory effect of activity in cognitive control regions of the brain (specifically the dorsal anterior cingulate cortex) on activity in core working memory regions, in particular the dorsal prefrontal cortex and the parietal lobe. METHODS: Forty four subjects participated. An n-back task with two levels of working memory load (1- and 2-back) was employed during fMRI (4 T Bruker MedSpec system). Data were processed with SPM5 and the modulatory effects of the anterior cingulate were investigated using psycho-physiological interaction (PPI). RESULTS: In spite of only subtle activation differences, and no significant differences in performance accuracy, a significant group x memory load interaction in the parietal lobe, indicated aberrantly increased modulatory inputs to this region under conditions of high working memory load in schizophrenia offspring. DISCUSSION: Increased modulatory inputs from a central control region like the anterior cingulate presumably reflect relative inefficiency in intra-cortical interactions in the vulnerable brain. This inefficiency may reflect a developmentally mediated impairment in functional brain interactions in this important vulnerable population. It is highly plausible that the resultant effect of these altered interactions is an increased vulnerability to impaired brain development, and therefore to psychiatric disorders including schizophrenia. PMID- 21306733 TI - Severe insomnia is associated with more severe presentation and greater functional deficits in depression. AB - Depression is among the most common reasons for seeking psychiatric treatment, and insomnia symptoms are common in the clinical picture of depression. The present study examines the clinical presentation and psychosocial functioning among depressed outpatients with severe symptoms of insomnia in comparison to depressed outpatients without severe insomnia symptoms. The present sample included 2900 treatment-seeking individuals, with 1057 patients having a principal diagnosis of major depressive disorder (MDD). All patients were evaluated using the Structured Clinical Interview for DSM-IV Disorders (SCID), Schedule for Affective Disorders (SADS), and self-report measures of mood and psychosocial functioning. SADS Insomnia ratings were used to determine the presence of severe insomnia symptoms. Clinical, demographic, and psychosocial variables were obtained from the SCID and self-report measures. Among the patients with MDD, 24.7% endorsed severe insomnia symptoms. These individuals were older at time of presentation, were less likely to be married, had a lower education level, had a longer duration of the current depressive episode, were rated as more severe on the CGI, had poorer current functioning via GAF, and had higher HAM-D 21 scores. After controlling for severity, MDD patients with severe insomnia symptoms had poorer social functioning over the past 5 years, though this did not reach the significance level of p < .01, and significantly lower scores on 3 of the 8 SF-36 subscales (p < 0.01). These findings indicate that severe insomnia symptoms are associated with poorer psychosocial functioning and a more severe clinical presentation in patients with MDD. This argues for addressing severe insomnia symptoms among depressed patients, either via behavioral treatment or pharmacologic treatment options. PMID- 21306734 TI - Mean diffusivity and fractional anisotropy as indicators of disease and genetic liability to schizophrenia. AB - The goals of this study were to first determine whether the fractional anisotropy (FA) and mean diffusivity (MD) of major white matter pathways associate with schizophrenia, and secondly to characterize the extent to which differences in these metrics might reflect a genetic predisposition to schizophrenia. Differences in FA and MD were identified using a comprehensive atlas-based tract mapping approach using diffusion tensor imaging and high-resolution structural data from 35 patients, 28 unaffected first-degree relatives of patients, 29 community controls, and 14 first-degree relatives of controls. Schizophrenia patients had significantly higher MD in the following tracts compared to controls: the right anterior thalamic radiations, the forceps minor, the bilateral inferior fronto-occipital fasciculus (IFO), the temporal component of the left superior longitudinal fasciculus (tSLF), and the bilateral uncinate. FA showed schizophrenia effects and a linear relationship to genetic liability (represented by schizophrenia patients, first-degree relatives, and controls) for the bilateral IFO, the left inferior longitudinal fasciculus (ILF), and the left tSLF. Diffusion tensor imaging studies have previously identified white matter abnormalities in all three of these tracts in schizophrenia; however, this study is the first to identify a significant genetic liability. Thus, FA of these three tracts may serve as biomarkers for studies seeking to identify how genes influence brain structure predisposing to schizophrenia. However, differences in FA and MD in frontal and temporal white matter pathways may be additionally driven by state variables that involve processes associated with the disease. PMID- 21306735 TI - The characteristics of a discrete mood episode, neuro-cognitive impairment and re hospitalization in bipolar disorder. AB - This longitudinal study examined characteristics of a discrete mood episode that predict re-hospitalization for bipolar disorder, highlighting associated cognitive dysfunction as a potential mechanism linking episode severity and relapse. Eighty-two inpatients meeting DSM-IV-TR diagnostic criteria for bipolar I disorder completed the study. Twenty-two of the patients were readmitted to the hospital within 3 months of discharge. The study compared these patients to the remaining 60 patients who were not readmitted to the hospital during this period. Patients were compared on several factors related to the severity of the mood episode and the course of illness more generally. Analysis also compared the groups on measures of mood and neuro-cognitive functioning, assessed 24-48 h before initial hospitalization discharge. Re-hospitalized patients had longer initial hospital stays (t = -3.10, p < 0.01), higher rates of psychosis while in the hospital (Chi square = 5.1, p < 0.02), and lower GAF scores on discharge (t = 2.37, p < 0.05). The groups did not differ in age of illness onset or number of previous psychiatric hospitalizations. With respect to neuro-cognitive functioning, analysis indicated poorer performance for re-hospitalized patients on measures of executive functioning (Wilks' Lambda, F (7, 71) = 9.0, p < 0.001), IQ (Wilks' Lambda, F (2, 76) = 5.06, p < 0.01), and memory (Wilks' Lambda, F (6,72) = 4.19, p < 0.001). Trends in the expected direction emerged for attention/working memory tests (Wilks' Lambda, F (7, 71) = 1.79, p < 0.10). Results highlight features of a discrete mood episode associated with increased rates of re-hospitalization. This study observed connections among episode severity, cognitive dysfunction at hospital discharge and re-hospitalization. PMID- 21306737 TI - Overexpression of myosin-IIB in the brain of a rat model of streptozotocin induced diabetes. AB - The Ca(2+)/calmodulin complex interacts with and regulates various enzymes and target proteins known as calmodulin-binding proteins (CaMBPs). This group of proteins includes molecular motors such as myosins. In this study, we show that non-muscle myosin-IIB is overexpressed in the brains of diabetic rats. We isolated CaMBPs from the brains of non-diabetic rats and rats with streptozotocin induced diabetes and purified them by immobilized-calmodulin affinity chromatography. The proteins were eluted with EGTA and urea, separated by SDS PAGE, digested and submitted to peptide mass fingerprinting analysis. Thirteen intense bands were found in both types of brains, two were found exclusively in non-diabetic brains and four were found exclusively in diabetic brains. A large fraction of the eluted proteins contained putative IQ motifs or calmodulin binding sites. The results of the myosin-IIB affinity chromatography elution, western blot and RT-PCR analyses suggest that myosin-IIB protein and mRNA are expressed at high levels in diabetic brains. This is the first study that has demonstrated differential expression of CaMBPs in diabetic and non-diabetic brain tissue through a comparative proteomic analysis, and it opens up a new approach to studying the relationship between the expression of myosins in the brain, hyperglycemia and intracellular calcium regulation. PMID- 21306736 TI - Epigenetic modification of hippocampal Bdnf DNA in adult rats in an animal model of post-traumatic stress disorder. AB - Epigenetic alterations of the brain-derived neurotrophic factor (Bdnf) gene have been linked with memory, stress, and neuropsychiatric disorders. Here we examined whether there was a link between an established rat model of post-traumatic stress disorder (PTSD) and Bdnf DNA methylation. Adult male Sprague-Dawley rats were given psychosocial stress composed of two acute cat exposures in conjunction with 31 days of daily social instability. These manipulations have been shown previously to produce physiological and behavioral sequelae in rats that are comparable to symptoms observed in traumatized people with PTSD. We then assessed Bdnf DNA methylation patterns (at exon IV) and gene expression. We have found here that the psychosocial stress regimen significantly increased Bdnf DNA methylation in the dorsal hippocampus, with the most robust hypermethylation detected in the dorsal CA1 subregion. Conversely, the psychosocial stress regimen significantly decreased methylation in the ventral hippocampus (CA3). No changes in Bdnf DNA methylation were detected in the medial prefrontal cortex or basolateral amygdala. In addition, there were decreased levels of Bdnf mRNA in both the dorsal and ventral CA1. These results provide evidence that traumatic stress occurring in adulthood can induce CNS gene methylation, and specifically, support the hypothesis that epigenetic marking of the Bdnf gene may underlie hippocampal dysfunction in response to traumatic stress. Furthermore, this work provides support for the speculative notion that altered hippocampal Bdnf DNA methylation is a cellular mechanism underlying the persistent cognitive deficits which are prominent features of the pathophysiology of PTSD. PMID- 21306739 TI - Olfactory ensheathing cells can reduce the tissue loss but not the cavity formation in contused spinal cord of rats. AB - In recent years, olfactory ensheathing cells (OECs) have been used as a therapeutic strategy to repair the anatomical structure and promote the function recovery of injured spinal cord in both animal and human. In this study, OECs were transplanted into contused spinal cords of adult rats. After dorsal laminectomy at T10 vertebra, spinal cord was injured by a force of 10 g with NYU II impactor from 25 mm above the exposed cord. The contused spinal cord received injections of OECs in DMEM or DMEM alone at one week after injury. The migration and distribution of OECs in the contused spinal cord were observed by the light microscope. The intact tissue area, injured tissue area, cavity size, number of myelinated nerve fibers and neurons labeled by CB-HRP in T8 segment were measured and counted by the semi-quantitative techniques at 6 weeks after transplantation. Locomotor ability and conductive function of the spinal cord were evaluated by the BBB score and cortical somatosensory evoked potentials (CSEP) recording. OECs were found in both lesion site and tissue near the lesion. The intact tissue area was significantly larger in the OECs-transplanted rats than that in the DMEM injected animals, whereas the injured tissue area was significantly smaller in the OECs-rats than that in the DMEM-rats. The number of myelinated nerve fibers in the lesion site and preserved neurons in T8 was significantly greater in the OECs-group than in the DMEM-group, but the cavity size detected was not significantly different between the two groups. The BBB score and CSEP recording showed a better performance of locomotor ability and conductive function in the OECs-transplanted rats than in the DMEM-injected animals. These results indicate that OECs can counteract secondary tissue degeneration after spinal cord injury. Although they cannot reduce the cavity formation, they can promote morphological preservation and functional improvement of the contused spinal cord. PMID- 21306738 TI - Reduced resting potentials in dystrophic (mdx) muscle fibers are secondary to NF kappaB-dependent negative modulation of ouabain sensitive Na+-K+ pump activity. AB - To examine potential mechanisms for the reduced resting membrane potentials (RPs) of mature dystrophic (mdx) muscle fibers, the Na(+)-K(+) pump inhibitor ouabain was added to freshly isolated nondystrophic and mdx fibers. Ouabain produced a 71% smaller depolarization in mdx fibers than in nondystrophic fibers, increased the [Na(+)](i) in nondystrophic fibers by 40%, but had no significant effect on the [Na(+)](i) of mdx fibers, which was approximately double that observed in untreated nondystrophic fibers. Western blots indicated no difference in total and phosphorylated Na(+)-K(+) ATPase catalytic alpha1 subunit between nondystrophic and mdx muscle. Examination of the effects of the NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC) indicated that direct application of the drug slowly hyperpolarized mdx fibers (7 mV in 90 min) but had no effect on nondystrophic fibers. Pretreatment with ouabain abolished this hyperpolarization, and pretreatment with PDTC restored ouabain-induced depolarization and reduced [Na(+)](i). Administration of an NF-kappaB inhibitor that utilizes a different mechanism for reducing nuclear NF-kappaB activation, ursodeoxycholic acid (UDCA), also hyperpolarized mdx fibers. These results suggest that in situ Na(+)-K(+) pump activity is depressed in mature dystrophic fibers by NF-kappaB dependent modulators, and that this reduced pump activity contributes to the weakness characteristic of dystrophic muscle. PMID- 21306741 TI - Fate of the esophagogastric anastomosis. AB - OBJECTIVE: The study objective was to evaluate histopathology of the esophagogastric anastomosis after esophagectomy, determine time trends of histologic changes, and identify factors influencing those findings. METHODS: A total of 231 patients underwent 468 upper gastrointestinal endoscopies with anastomotic biopsy a median of 3.5 years after esophagectomy. Mean age was 59 +/- 12 years, 74% (171) were male, and 96% (222) were white. Seventy-eight percent (179) had esophagectomy for cancer, 13% (30) had chemoradiotherapy, and 13% (30) had prior esophageal surgery. The anastomosis was 20 +/- 2.0 cm from the incisors. Anti-reflux medications were used in 59% of patients (276/468) at esophagoscopy. Histopathology was graded as normal (0), consistent with reflux (1), cardia mucosa (2), intestinal metaplasia (3), and dysplasia (4). Repeated measures nonlinear time-trend analysis and multivariable analyses were used. RESULTS: Grades 0 and 1 were constant, 5% and 92% at 10 years, respectively. Anti reflux medication, induction therapy, and higher anastomosis were predictive of less grade 1 histopathology. Grades 2 and 3 increased with time: 12% and 33% at 5 years and 4% and 16% at 10 years, respectively. No variable was predictive of grade 2 or 3 (P > .15) except passage of time. No patient's condition progressed to dysplasia or cancer. CONCLUSIONS: The esophagogastric anastomosis is subject to gastroesophageal reflux. To minimize histopathologic changes of reflux, the anastomosis should be constructed as high as possible (closer to incisors) and anti-reflux medications prescribed. Surveillance endoscopy, if performed, will document a time-related progression of reflux-related histopathologic changes. However, during surveillance, intestinal metaplasia is uncommon and progression to cancer rare. PMID- 21306742 TI - [Care of patients with terminal illnesses: citizens' opinion]. PMID- 21306743 TI - [Risk factors for cerebrospinal fluid shunt infection]. AB - BACKGROUND AND OBJECTIVE: Shunt-related infection is a major complication. The effort to face up to this problem has focused on therapy, analysis of risk factors and primary prevention. The aim of this study is to identify risk factors for cerebrospinal fluid shunt infection. MATERIAL AND METHOD: We retrospectively reviewed all patients who underwent shunt placement at our hospital during the period of study. Procedures followed for less than 90 days were excluded. One hundred and nineteen procedures were included in the final analysis. RESULTS: Infection rate per procedure was 8.4%. Previous cerebrospinal fluid infection, previous shunt and complete substitution of the shunt were identified as risk factors for infection in the univariate analysis. However, a multivariate analysis confirmed that previous cerebrospinal fluid infection was the only independent risk factor for shunt-related infection (p=0.011). CONCLUSION: Previous cerebrospinal fluid infection is an independent risk factor for shunt related infection. Other factors such as age, gender, etiology of hydrocephalus, previous shunt or complete substitution of the shunt were not associated with increased risk of infection. PMID- 21306744 TI - [Endocrinological abnormalities in 1,105 children and adolescents with Down syndrome]. AB - BACKGROUND AND OBJECTIVE: Children and adolescents with Down syndrome (DS) show a greater prevalence of endocrinological abnormalities when compared with the general population. Our aim is to analyze endocrinological abnormalities in 1,105 patients with DS. PATIENTS AND METHODS: A review of 1,105 cases of children and adolescents with DS under care in our Department (ages between 0 and 18 years) analyzed retrospectively the presence of thyroid pathology and diabetes mellitus throughout development. RESULTS: Our data indicate the presence of endocrinological abnormalities in 222 patients [216 with thyroid pathology (19.5%) and 6 cases with diabetes mellitus type 1 (0.45%)]. Subclinical primary hypothyroidism was present in 168 cases, congenital primary hypothyroidism in 15 cases, clinical primary hypothyroidism in 24 cases and 5 cases had hyperthyroidism. In addition, 16.9% of these patients exhibit criteria of obesity and 28.2% had overweight. The prevalence of endocrinological comorbidities in children and adolescents with DS is higher than in the general population. CONCLUSION: Subclinical primary hypothyroidism, due to autoimmune causes in most of the patients, without a higher incidence in females, is the most common endocrinological pathology associated with DS. The high frequency of thyroid pathology and diabetes mellitus type 1 in these patients should induce us to have a closer clinical control of children and adolescents with DS. PMID- 21306745 TI - Polymorphisms in Toll-like receptor 4 are associated with factors of the metabolic syndrome and modify the association between dietary saturated fat and fasting high-density lipoprotein cholesterol. AB - Toll-like receptor 4 (TLR4) is a protein of the innate immune system hypothesized to mediate some of the effects of a high-fat diet on inflammation and insulin resistance. As both these factors are associated with the metabolic syndrome (MetS), genetic variation in TLR4 may affect the relationship between dietary lipids and MetS. The objective of the study was to determine whether 2 polymorphisms in TLR4 (rs4986790 Asp299Gly and rs5030728 G>A) modify the relationship between dietary fat and markers of the MetS. Participants were healthy young men and women of various ethnocultural backgrounds. Dietary intake was estimated using a 1-month semiquantitative food frequency questionnaire, and fasting blood samples were taken for genotyping and biomarker measurement. The Asp299Gly polymorphism in TLR4 was associated with increased insulin, homeostasis model assessment of insulin resistance (P < .05), and homeostasis model assessment of beta-cell function (P < .05) and family history of diabetes (P = .0002). The intronic polymorphism rs5030728 modified the relationship between dietary saturated fatty acids (SFAs) and high-density lipoprotein (HDL) cholesterol (P = .003 for interaction). The SFA intake was inversely associated with HDL cholesterol among individuals homozygous for the G allele (beta = -0.015 +/- 0.007 mmol/L, P = .04), whereas a positive relationship was observed for heterozygotes (beta = 0.025 +/- 0.01 mmol/L, P = .02). There was no association between dietary SFAs and HDL cholesterol among individuals homozygous for the A allele. These observations suggest that both diet and innate immunity may interact to influence components of the MetS. PMID- 21306746 TI - Fenofibrate administration does not affect muscle triglyceride concentration or insulin sensitivity in humans. AB - Animal data suggest that males, in particular, rely on peroxisome proliferator activated receptor-alpha activity to maintain normal muscle triglyceride metabolism. We sought to examine whether this was also true in men vs women and its relationship to insulin sensitivity (Si). Normolipidemic obese men (n = 9) and women (n = 9) underwent an assessment of Si (intravenous glucose tolerance test) and intramuscular triglyceride (IMTG) metabolism (gas chromatography/mass spectrometry and gas chromatography-combustion isotope ratio mass spectrometry from plasma and muscle biopsies taken after infusion of [U-(13)C]palmitate) before and after 12 weeks of fenofibrate treatment. Women were more insulin sensitive (Si: 5.2 +/- 0.7 vs 2.4 +/- 0.4 *10(-4)/ MUU/mL, W vs M, P < .01) at baseline despite similar IMTG concentration (41.9 +/- 15.5 vs 30.8 +/- 5.1 MUg/mg dry weight, W vs M, P = .43) and IMTG fractional synthesis rate (FSR) (0.27%/h +/ 0.07%/h vs 0.35%/h +/- 0.06%/h, W vs M, P = .41) as men. Fenofibrate enhanced FSR in men (0.35 +/- 0.06 to 0.54 +/- 0.06, P = .05), with no such change seen in women (0.27 +/- 0.07 to 0.32 +/- 0.13, P = .73) and no change in IMTG concentration in either group (23.0 +/- 3.9 in M, P = .26 vs baseline; 36.3 +/- 12.0 in W, P = .79 vs baseline). Insulin sensitivity was unaffected by fenofibrate (P >= .68). Lower percentage saturation of IMTG in women vs men before (29.1% +/- 2.3% vs 35.2% +/- 1.7%, P = .06) and after (27.3% +/- 2.8% vs 35.1% +/- 1.9%, P = .04) fenofibrate most closely related to their greater Si (R(2) = 0.34, P = .10) and was largely unchanged by the drug. Peroxisome proliferator activated receptor-alpha agonist therapy had little effect on IMTG metabolism in men or women. Intramuscular triglyceride saturation, rather than IMTG concentration or FSR, most closely (but not significantly) related to Si and was unchanged by fenofibrate administration. PMID- 21306747 TI - Abnormal left ventricular torsion and cardiac autonomic dysfunction in subjects with type 1 diabetes mellitus. AB - Left ventricular torsion is increased and cardiac energetics are reduced in uncomplicated type 1 diabetes mellitus (T1DM). Our aim was to determine the relationships of these abnormalities to cardiovascular autonomic neuropathy (CAN) in subjects with T1DM. A cross-sectional study was conducted in 20 subjects with T1DM free of known coronary heart disease attending an outpatient clinic. Cardiovascular autonomic neuropathy was assessed using heart rate variability studies and the continuous wavelet transform method. Left ventricular function was determined by speckle tracking echocardiography. Magnetic resonance spectroscopy and stress magnetic resonance imaging were used to measure cardiac energetics and myocardial perfusion reserve index, respectively. Twenty subjects (age, 35 +/- 8 years; diabetes duration, 16 +/- 9 years; hemoglobin A(1c), 8.0% +/- 1.1%) were recruited. Forty percent of the subjects exhibited definite or borderline CAN. Log peak radial strain was significantly increased in subjects with CAN compared with those without (1.56 +/- 0.06 vs 1.43 +/- 0.14, respectively; P = .011). Data were adjusted for log duration of diabetes, and log left ventricular torsion correlated (r = 0.593, P = .01) with log low-frequency to high-frequency ratio during the Valsalva maneuver. Log isovolumic relaxation time correlated significantly with log Valsalva ratio and log proportion of differences in consecutive RR intervals of normal beats greater than 50 milliseconds during deep breathing. However, CAN did not correlate with cardiac energetics or myocardial perfusion reserve index. Spectral analysis of low frequency to high-frequency ratio power during the Valsalva maneuver is associated with altered left ventricular torsion in subjects with T1DM. Parasympathetic dysfunction is closely associated with diastolic deficits. Cardiovascular autonomic neuropathy is not however the principal cause of impaired cardiac energetics. The role of CAN in the development of cardiomyopathy warrants further evaluation. PMID- 21306749 TI - Low-density lipoprotein cholesterol to apolipoprotein B ratio is independently associated with metabolic syndrome in Korean men. AB - The low-density lipoprotein cholesterol to apolipoprotein B (LDL-C/apo B) ratio is associated with cardiovascular risk factors and the prevalence of metabolic syndrome. The aim of this study was to assess the relationship between LDL-C/apo B ratio and metabolic syndrome in Korean men. This study included 499 men (mean age, 49.1 years) without metabolic syndrome at baseline who were followed for an average of 2.9 years. Subjects were divided into 4 groups according to baseline LDL-C/apo B ratio quartiles: greater than 1.243 in group I, 1.164 to 1.243 in group II, 1.070 to 1.163 in group III, and less than 1.070 in group IV. The incidence of metabolic syndrome at follow-up was compared according to LDL-C/apo B ratio group. Metabolic syndrome was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria. The overall incidence of metabolic syndrome was 9.6%: 1.6% in the highest quartile (group I), 9.7% in group II, 11.2% in group III, and 16.0% in the lowest quartile (group IV) (P = .001). In multivariable regression analysis model adjusting for age, lifestyle status, homeostasis model assessment of insulin resistance, LDL-C, and high sensitivity C-reactive protein, groups II, III, and IV had significantly increased odds ratio for the incidence of metabolic syndrome compared with the highest LDL-C/apo B quartile (group I). The LDL-C/apo B ratio is independently associated with metabolic syndrome in Korean men, indicating that this ratio may provide additional information when assessing cardiometabolic risks and predicting future development of metabolic syndrome. PMID- 21306748 TI - The association of the angiotensinogen gene with insulin sensitivity in humans: a tagging single nucleotide polymorphism and haplotype approach. AB - The purpose of this study was to clarify the association of the angiotensinogen gene (AGT) with insulin sensitivity using single nucleotide polymorphism (SNP) and haplotype analyses in a white cohort. A candidate gene association study was conducted in white persons with and without hypertension (N = 449). Seventeen SNPs of the AGT gene and their haplotypes were analyzed for an association with homeostasis model assessment of insulin resistance (HOMA-IR). Multivariate regression model accounting for age, sex, body mass index, hypertension status, study site, and sibling relatedness was used to test the hypothesis. Nine of the 17 SNPs were significantly associated with lower HOMA-IR levels. Homozygous minor allele carriers of the most significant SNP, rs2493134 (GG), a surrogate for the gain-of-function mutation rs699 (AGT p.M268T), had significantly lower HOMA-IR levels (P = .0001) than heterozygous or homozygous major allele carriers (AG, AA). Direct genotyping of rs699 in a subset of the population showed similar results, with minor allele carriers exhibiting significantly decreased HOMA-IR levels (P = .003). Haplotype analysis demonstrated that haplotypes rs2493137A|rs5050A|rs3789678G|rs2493134A and rs2004776G|rs11122576A|rs699T|rs6687360G were also significantly associated with HOMA-IR (P = .0009, P = .02), and these results were driven by rs2493134 and rs699. This study confirms an association between the AGT gene and insulin sensitivity in white humans. Haplotype analysis extends this finding and implicates SNPs rs2493134 and rs699 as the most influential. Thus, AGT gene variants, previously shown to be associated with AGT levels, are also associated with insulin sensitivity; suggesting a relationship between the AGT gene, AGT levels, and insulin sensitivity in humans. PMID- 21306750 TI - Lower expression of PKAalpha impairs insulin secretion in islets isolated from low-density lipoprotein receptor (LDLR(-/-)) knockout mice. AB - Hypercholesterolemic low-density lipoprotein receptor knockout mice (LDLR(-/-)) show normal whole-body insulin sensitivity, but impaired glucose tolerance due to a reduced insulin secretion in response to glucose. Here, we investigate the possible mechanisms involved in such a defect in isolated LDLR(-/-) mice islets. Low-fat chow-fed female and male mice aged 20 weeks, LDLR(-/-) mice, and wild type (WT) mice were used in this study. Static insulin secretion, cytoplasmatic Ca(2+) analysis, and protein expression were measured in islets isolated from LDLR(-/-) and WT mice. At basal (2.8 mmol/L) and stimulatory (11.1 mmol/L) glucose concentrations, the insulin secretion rates induced by depolarizing agents such as KCl, L-arginine, and tolbutamide were significantly reduced in LDLR(-/-) when compared with control (WT) islets. In addition, KCl-induced Ca(2+) influx at 2.8 mmol/L glucose was lower in LDLR(-/-) islets, suggesting a defect downstream of the substrate metabolism step of the insulin secretion pathway. Insulin secretion induced by the protein kinase A (PKA) activators forskolin and 3-isobutyl-1-methyl-xanthine, in the presence of 11.1 mmol/L glucose, was lower in LDLR(-/-) islets and was normalized in the presence of the protein kinase C pathway activators carbachol and phorbol 12-myristate 13-acetate. Western blotting analysis showed that phospholipase Cbeta(2) expression was increased and PKAalpha was decreased in LDLR(-/-) compared with WT islets. Results indicate that the lower insulin secretion observed in islets from LDLR(-/-) mice at postprandial levels of glucose can be explained, at least in part, by the reduced expression of PKAalpha in these islets. PMID- 21306751 TI - Differential effects of various fish proteins in altering body weight, adiposity, inflammatory status, and insulin sensitivity in high-fat-fed rats. AB - Mounting evidence suggests that the benefits of fish consumption are not limited to the well-appreciated effects of omega-3 fatty acids. We previously demonstrated that cod protein protects against the development of diet-induced insulin resistance. The goal of this study was to determine whether other fish protein sources present similar beneficial effects. Rats were fed a high-fat, high-sucrose diet containing protein from casein or fish proteins from bonito, herring, mackerel, or salmon. After 28 days, oral glucose tolerance tests or hyperinsulinemic-euglycemic clamps were performed; and tissues and plasma were harvested for biochemical analyses. Despite equal energy intake among all groups, the salmon-protein-fed group presented significantly lower weight gain that was associated with reduced fat accrual in epididymal white adipose tissue. Although this reduction in visceral adiposity was not associated with improved glucose tolerance, we found that whole-body insulin sensitivity for glucose metabolism was improved using the very sensitive hyperinsulinemic-euglycemic clamp technique. Importantly, expression of both tumor necrosis factor-alpha and interleukin-6 was reduced in visceral adipose tissue of all fish-protein-fed groups when compared with the casein-fed control group, suggesting that fish proteins carry anti-inflammatory properties that may protect against obesity linked metabolic complications. Interestingly, consumption of the salmon protein diet was also found to raise circulating salmon calcitonin levels, which may underlie the reduction of weight gain in these rats. These data suggest that not all fish protein sources exert the same beneficial properties on the metabolic syndrome, although anti-inflammatory actions appear to be common. PMID- 21306752 TI - Oak leaf (Quercus pyrenaica) poisoning in cattle. AB - Three experiments were conducted to study the clinical and pathological findings associated with poisoning in cattle due to ingestion of young oak leaves (OL) and the main factors responsible for toxicosis. In Experiment 1, six 1.4 year-old bulls were fed up to 5 kg of young OL per animal per day and showed no signs of toxicity, apart from a slight proteinuria. In Experiment 2, another six 1.4 year old bulls were first subjected to severe feed restriction for eight days and then fed a higher amount of OL (approx. 10 kg) daily. A marked increase of serum creatinine and blood urea (BUN) was detected in urine as well as clinical signs consistent with renal failure. At necropsy, animals showed gastrointestinal ulcers and kidney tubular necrosis. Since these results suggested a crucial role of the feed restricting period, a third experiment was conducted administering the same amount of young OL as in Experiment 1, but adding the severe feed restricting period as in Experiment 2. There was a wide variation in clinical signs, with one bull showing clinical signs and lesions, another recovering after showing mild clinical signs and high levels of creatinine and BUN, and the third appearing clinically normal. The relevance of restriction access to food in the development of OL toxicosis appears to be critical because the intoxication was only elicited when the OL administration was preceded by a severe feed restricting period. PMID- 21306753 TI - Biodegradation potential of bulking agents used in sludge bio-drying and their contribution to bio-generated heat. AB - Straw and sawdust are commonly used bulking agents in sludge composting or bio drying. It is important to determine if they contribute to the biodegradable volatile solids pool. A sludge bio-drying process was performed in this study using straw, sawdust and their combination as the bulking agents. The results revealed that straw has substantial biodegradation potential in the aerobic process and sawdust has poor capacity to be degraded. The temperature profile and bio-drying efficiency were highest in the trial that straw was added, as indicated by a moisture removal ratio and VS loss ratio of 62.3 and 31.0%, respectively. In separate aerobic incubation tests, straw obtained the highest oxygen uptake rate (OUR) of 2.14 and 4.75 mg O(2) g(-1)VS h(-1) at 35 degrees C and 50 degrees C, respectively, while the highest OUR values of sludge were 12.1 and 5.68 mg O(2) g(-1)VS h(-1) at 35 degrees C and 50 degrees C and those of sawdust were 0.286 and 0.332 mg O(2) g(-1)VS h(-1), respectively. The distribution of biochemical fractions revealed that soluble fractions in hot water and hot neutral detergent were the main substrates directly attacked by microorganisms, which accounted for the initial OUR peak. The cellulose-like fraction in straw was transformed to soluble fractions, resulting in an increased duration of aerobic respiration. Based on the potential VS degradation rate, no bio-generated heat was contributed by sawdust, while that contribution by straw was about 41.7% and the ratio of sludge/straw was 5:1 (w/w, wet basis). PMID- 21306754 TI - Distribution of total mercury and methylmercury in lake sediments in Arctic Ny Alesund. AB - The toxicities and bioavailabilities of total mercury (THg) and methylmercury (MeHg) in aquatic systems have made them the subjects of recent research. In this study, we collected a lake sediment core from Ny-Alesund in Svalbard and analyzed the distributions of THg and MeHg in the sediments. The increased trend of THg was caused by anthropogenic contamination since the 14th century through long range transportation, especially after the industrial era. However, the peak values of Hg in surface sediment samples could be explained by the increased algal scavenging process in recent decades. All the biogeochemical proxies (e.g., pigments and diatom biomass) revealed recent sharp increases in aquatic primary production due to the current climate warming. Rock-Eval analyses indicated that algal-derived organic matter took up a large portion, and quantitative calculation showed that 89.6-95.8% of the Hg in post-1950 could be explained by scavenging. The distribution of MeHg has a close relationship with total Hg and organic matter. The oxidation-reduction condition is one of the possible factors affecting the methylation rates in H2 lake sediments. Higher algal productivity and organic matter actually led to the increased trend of methylation in the uppermost sediment. This study supports some new key hypotheses on climate-driven factors affecting Hg and MeHg cycling in High Arctic lake sediments. PMID- 21306755 TI - Differential global profiling as a new analytical strategy for revealing micropollutant treatment by-products: application to ethinylestradiol and chlorination water treatment. AB - The detection and structural elucidation of micropollutants treatment by-products are major issues to estimate efficiencies of the processes employed for drinking water production versus endocrine disruptive compounds contamination. This issue was mainly investigated at the laboratory scale and in high concentration conditions. However, potential by-products generated after chlorination can be influenced by the dilution factor employed in real conditions. The present study proposes a new methodology borrowed to the metabolomic science, using liquid chromatography coupled to high-resolution mass spectrometry, in order to reveal potential chlorination by-products of ethinylestradiol in spiked real water samples at the part-per-billion level (5 MUg L(-1)). Conventional targeted measurements first demonstrated that chlorination with sodium hypochlorite (0.8 mg L(-1)) led to removals of ethinylestradiol over 97%. Then, the developed differential global profiling approach permitted to reveal eight chlorination by products of EE2, six of them being described for the first time. Among these eight halogenated compounds, five have been structurally identified, demonstrating the potential capabilities of this new methodology applied to environmental samples. PMID- 21306756 TI - The impact of EDTA on the rate of accumulation and root/shoot partitioning of cadmium in mature dwarf sunflowers. AB - In addition to increasing the mobility of metal ions in the soil solution, chelating agents such as EDTA have been reported to alter both the total metal accumulated by plants and its distribution within the plant structures. Here, mature Mini-Sun Hybrid dwarf sunflowers exposed to 300 MUM Cd(2+) in hydroponic solution had initial translocation rates of at least 0.12 mmol kg(-1)h(-1) and reached leaf saturation levels within a day when a 3-fold molar excess of EDTA was used. EDTA also promoted cadmium transfer from roots to the shoots. A threefold excess of EDTA increased the translocation factor (TF) 100-fold, resulting in cadmium levels in the leaves of 580 MUg g(-1) and extracting 1400 MUg plant(-1). When plants were exposed to dissolved cadmium without EDTA, the vast majority of the metal remained bound to the exterior of the root. The initial accumulation could be successfully modeled with a standard biosorption pseudo second-order kinetic equation. Initial accumulation rates ranged from 0.0359 to 0.262 mg g(-1)min(-1). The cadmium binding could be cycled, and did not show evidence of saturation under the experimental conditions employed, suggesting it might be a viable biosorbant for aqueous cadmium. PMID- 21306757 TI - Stratigraphy and chronology of the WLH 50 human remains, Willandra Lakes World Heritage Area, Australia. AB - We present a detailed description of the geological setting of the burial site of the WLH 50 human remains along with attempts to constrain the age of this important human fossil. Freshwater shells collected at the surface of Unit 3, which is most closely associated with the human remains, and a carbonate sample that encrusted the human bone were analysed. Gamma spectrometry was carried out on the WLH 50 calvaria and TIMS U-series analysis on a small post-cranial bone fragment. OSL dating was applied to a sample from Unit 3 at a level from which the WLH 50 remains may have eroded, as well as from the underlying sediments. Considering the geochemistry of the samples analysed, as well as the possibility of reworking or burial from younger layers, the age of the WLH 50 remains lies between 12.2 +/- 1.8 and 32.8 +/- 4.6 ka (2-sigma errors). PMID- 21306759 TI - Methylation of HPV16 genome CpG sites is associated with cervix precancer and cancer. AB - OBJECTIVE: Invasive cervix cancer (ICC) is the second most common malignant tumor in women. Human papillomavirus 16 (HPV16) causes more than 50% of all ICC and is a major cause of cervix intraepithelial neoplasia (CIN). DNA methylation is a covalent modification predominantly occurring at CpG dinucleotides. Such epigenetic modifications are associated with changes in DNA-protein interactions and gene activation. This study examined the association of viral and host genomic methylation patterns and cervix neoplasia. METHODS: Exfoliated cervical lavage samples positive for HPV16 from women with and without cytomorphic changes of infection (n=46), CIN2 (n=12), and CIN3+ (n=27) were used to interrogate the methylation patterns of the HPV16 L1 gene and upstream regulatory region (URR), five host nuclear genes (TERT, RARB, DAPK1, MAL, and CADM1), and mitochondrial DNA (mtDNA). DNA isolated from exfoliated cervicovaginal cells was treated with bisulfite, specific regions of the viral and host genome were PCR amplified and CpG methylation was quantified using EpiTYPER and pyrosequencing. RESULTS: Methylation at 14 of the tested CpG sites within the HPV16 L1 region were significantly higher in CIN3+ compared to HPV16 genomes from women without CIN3+. In contrast, 2/16 CpG sites in HPV16 URR, 5/5 in TERT, 1/4 in DAPK1 and 1/3 mtDNA, and 2/5 in RARB were associated with increased methylation in CIN3+. CONCLUSIONS: These results indicate that increased methylation of CpG sites in the HPV16 L1 ORF is associated with CIN3+ and, thus, may constitute a potential biomarker for precancerous and cancerous cervix disease. PMID- 21306760 TI - When should we put evidence into clinical practice? PMID- 21306761 TI - Age- and serotype-dependent antibody response to pneumococcal polysaccharides. PMID- 21306764 TI - Dose-dependence of sublingual immunotherapy shown by meta-analysis. PMID- 21306765 TI - Necessity of product-specific assessments or restrictions of meta-analyses to well-designed and well-powered studies. PMID- 21306766 TI - Toward a global classification of mast cell activation diseases. PMID- 21306768 TI - Single chain anti-c-Met antibody conjugated nanoparticles for in vivo tumor targeted imaging and drug delivery. AB - Aberrantly expressed c-Met, the receptor for hepatocyte growth factor (HGF), has been implicated in human lung cancer as well as malignancy, metastasis and drug resistance in other human cancers. Thus, this molecule could be a potential target for antibody-based cancer therapy. Targeting delivery of compound to tumor represented benefit for cancer detection and therapy. In this study, we utilized phage display to identify human single chain variable fragment (scFv) antibodies that specifically bound to c-Met protein. The anti-c-Met scFvs selectively bound to and internalized in several lung cancer cell lines expressing c-Met. Conjugation of anti-c-Met scFv with PEGylated liposomes enabled the efficient delivery of doxorubicin into cancer cells where it exerted cytotoxic activity by inducing apoptosis pathway. In addition, in vivo fluorescent imaging by scFv conjugated quantum dots showed higher tumor uptake and increased tumor-normal tissue ratios. In a tumor xenograft model, anti-c-Met immunoliposome was found to selectively increase tumor accumulation of a chemotherapeutic drug and enhance its antitumor activity. Taken together, our results suggest that anti-c-Met scFv mediated drug delivery systems show great promise in tumor-targeted therapy and imaging. PMID- 21306769 TI - The structural orientation of antibody layers bound to engineered biosensor surfaces. AB - This paper describes a membrane protein array that binds immunoglobulin G at its constant regions whilst leaving the variable regions free to bind antigen. The scaffold of the array is the transmembrane domain of outer membrane protein A (tOmpA) from Escherichia coli engineered to assemble as an oriented monolayer on gold surfaces via a single cysteine residue. Other protein domains can be fused to the N and C termini of the scaffold. In this study we use circularly permuted ctOmpA fused to two Z domains of Staphylococcus aureus protein A (ZZctOmpA) to create the immunoglobulin G-binding array. The solution structure of the engineered proteins was assessed by circular dichroism spectroscopy. Assembly of the array, attachment of antibodies and antigen binding were measured using surface plasmon resonance and neutron reflection. Compared to mouse IgG2, polyclonal IgG from rabbit bound very strongly to ZZctOmpA and the dissociation of the immunoglobulin was slow enough to allow neutron reflection studies of the assembled layer with antigen. Using both magnetic and isotopic contrasts a complete layer by layer model was defined which revealed that the 223 A high layer contains antibodies in an upright orientation. PMID- 21306770 TI - Improved biological half-life and anti-tumor activity of TNF-related apoptosis inducing ligand (TRAIL) using PEG-exposed nanoparticles. AB - TRAIL has received considerable attention as a potential anti-cancer agent due to its specific ability to target tumors. However, recombinant TRAIL has several limitations, such as, its short biological half-life, its inherent instability, and its potential hepatotoxicity. In this study, we developed a sustained release nanoparticle formulation of TRAIL and investigated its therapeutic effects in tumor-bearing mice. TRAIL-loaded nanoparticles (NPs) were prepared by mixing PEGylated heparin (PEG-HE), poly-L-lysine (PLL), and TRAIL. NPs prepared by the ionic interaction between polymer and TRAIL showed uniform spherical structures of diameter 213.3 +/- 9.7 nm and a surface charge of 5.33 +/- 1.2 mV. An in vitro study of the bioactivity of TRAIL in NPs showed that TRAIL-loaded PEG-HE/PLL NPs (TRAIL-PEG-NPs) were slightly less cytotoxic than TRAIL in vitro. To investigate pharmacokinetic parameters, TRAIL and TRAIL-PEG-NPs were intravenously injected into SD rats. The PEG-NP-based formulation demonstrated a 28.3 fold greater half life than TRAIL alone. To evaluate the anti-tumor effect, TRAIL, TRAIL-loaded HE/PLL NPs (TRAIL-NPs), and TRAIL-PEG-NPs were intravenously injected into HCT 116 tumor-bearing BALB/c athymic mice. The TRAIL-PEG-NP formulation efficiently suppressed tumor growth (>70%), and histological findings confirmed that NPs induced significant tumor cell apoptosis without inducing liver toxicity. The PEG exposed NP fabrication method applied in this study could be widely applied to protein and peptide delivery systems. PMID- 21306771 TI - The promotion of neurological recovery in an intracerebral hemorrhage model using fibrin-binding brain derived neurotrophic factor. AB - Brain derived neurotrophic factor (BDNF) has been shown to ameliorate recovery after intracerebral hemorrhage (ICH). The injured brain tissue after ICH is surrounded by hematoma formed from hemorrhage. Fibrin is abundant in hematoma, which could be a binding target for BDNF. In this work, we have fused a fibrin binding domain (FBD) to BDNF (FBD-BDNF), and results demonstrate that FBD-BDNF has specific binding ability to fibrin and is retained in hematoma. Using the rat ICH model induced by bacterial collagenase, injected FBD-BDNF has been concentrated and retained at the hematoma. FBD has facilitated BDNF to exert targeting neuroprotective effect to the injured brain tissue around the hematoma after ICH. FBD-BDNF has significantly reduced the hemotoma volume, reduced tissue loss, promoted neural regeneration, and improved the rat behavioral performance. PMID- 21306772 TI - Double-shell gold nanoparticle-based DNA-carriers with poly-L-lysine binding surface. AB - In view of the prospective applications of polyamine coatings in functional gold nanoparticles for use as carriers in gene delivery systems, in tissue repair and as bactericidal and virucidal non-toxic vehicle, we have investigated the interactions of poly-l-lysine (PLL) with gold nanoparticles (AuNP). Since direct binding of PLL to AuNP is not strong at neutral pH, we have focused on PLL interactions with carboxylated self-assembled monolayers (SAM) on AuNP, such as the citrate-capped AuNP. The double-shell nanoparticles AuNP@Cit/PLL thus produced do not contain any toxic thiols. We have observed strong electrostatic interactions between polycationic chains of PLL and AuNP@Cit in weakly acidic to weakly alkaline solutions (pH 5-9), as evidenced by the bathochromic shift of the local surface plasmon (SP) band and strong increase in resonance elastic light scattering (RELS) intensity. The stoichiometry of interactions evaluated on the basis of RELS data indicates on a hyper-Langmuirian type of interactions with stoichiometric coefficient n = 1.35 (PLL : AuNP@Cit). From the RELS titration data, a shift of the deprotonation constant for the bound PLL has been determined (pK(a) = 11.6 for the bound PLL vs. 10.48 for the free PLL). The deprotonation of PLL leads to AuNP aggregate disassembly, evidenced by sharp RELS decline and hypsochromic shift of SP band. We have found that under these conditions, a residual aggregation due to the interparticle interactions between beta-sheets of PLL overcoat become predominant. The molecular dynamics simulations indicate that multiple hydrogen bonds can also be formed between the PLL linker and the shell molecules of AuNP@Cit. The double-shell nanoparticles, AuNP@Cit/PLL, have been shown to attract DNA molecules using highly sensitive RELS measurements presenting the proof-of-concept for the suitability of this non-toxic nanostructured material for gene delivery applications. The advantage of the proposed material is no toxicity related to the ligand release in gene delivery processes in contrast to the thiol-functionalized AuNP. PMID- 21306773 TI - Tunable physiologic interactions of adhesion molecules for inflamed cell selective drug delivery. AB - Dysregulated inflammation contributes to the pathogenesis of various diseases. Therapeutic efficacy of anti-inflammatory agents, however, falls short against resilient inflammatory responses, whereas long-term and high-dose systemic administration can cause adverse side effects. Site-directed drug delivery systems would thus render more effective and safer treatments by increasing local dosage and minimizing toxicity. Nonetheless, achieving clinically effective targeted delivery to inflammatory sites has been difficult due to diverse cellular players involved in immunity and endogenous targets being expressed at basal levels. Here we exploit a physiological molecular interaction between intercellular adhesion molecule (ICAM)-1 and lymphocyte function associated antigen (LFA)-1 to deliver a potent anti-inflammatory drug, celastrol, specifically and comprehensively to inflamed cells. We found that affinity and avidity adjusted inserted (I) domain, the major binding site of LFA-1, on liposome surface enhanced the specificity toward lipopolysaccharides (LPS) treated or inflamed endothelial cells (HMEC-1) and monocytes (THP-1) via ICAM-1 overexpression, reflecting inherent affinity and avidity modulation of these molecules in physiology. Targeted delivery of celastrol protected cells from recurring LPS challenges, suppressing pro-inflammatory responses and inflammation induced cell proliferation. Targeted delivery also blocked THP-1 adhesion to inflamed HMEC-1, forming barriers to immune cell accumulation and to aggravating inflammatory signals. Our results demonstrate affinity and avidity of targeting moieties on nanoparticles as important design parameters to ensure specificity and avoid toxicities. We anticipate that such tunable physiologic interactions could be used for designing effective drug carriers for in vivo applications and contribute to treating a range of immune and inflammatory diseases. PMID- 21306774 TI - The antitumor efficacy of functional paclitaxel nanomicelles in treating resistant breast cancers by oral delivery. AB - Paclitaxel has shown potent efficacy against a wide spectrum of cancers in clinical treatment. However, chemotherapy with paclitaxel has been limited due to serious allergic reactions in patients caused by cremophor EL, and multidrug resistance in many types of tumors, and the restricted permeability across the intestinal barrier. Functional paclitaxel nanomicelles were developed to overcome these obstacles. Evaluations were performed on the breast cancer MCF-7 and resistant MCF-7/Adr cells, MCF-7 and MCF-7/Adr tumor spheroids, Caco-2 cell manolayers, everted gut sacs and the xenografted resistant MCF-7/Adr cancers in nude mice. The functional paclitaxel nanomicelles were approximately of 15 nm in diameter, significantly increased the intracellular uptake of paclitaxel, and selectively accumulated into mitochondria and endoplasmic reticulum after treatment, showing strong inhibitory effect on MCF-7 and MCF-7/Adr cells. They were able to penetrate deeply into the central region of the MCF-7 and MCF-7/Adr spheroids, resulting in a significant reduction in the size of the spheroids. TEM observations showed that the intact functional paclitaxel nanomicelles were transported across the Caco-2 cell manolayer or the everted gut sac. A significant antitumor efficacy in the xenografted resistant MCF-7/Adr cancers in mice was evidenced by oral administration, which was comparable to intravenous administration. The functional paclitaxel nanomicelles would provide a strategy for oral administration of paclitaxel, increasing solubility of paclitaxel, and overcoming the multidrug resistant cancers. PMID- 21306775 TI - A perfluoropolyether corneal inlay for the correction of refractive error. AB - This study assessed the long-term biological response of a perfluoropolyether based polymer developed as a corneal inlay to correct refractive error. The polymer formulation met chemical and physical specifications and was non cytotoxic when tested using standard in vitro techniques. It was cast into small microporous membranes that were implanted as inlays into corneas of rabbits (n = 5) and unsighted humans (n = 5 + 1 surgical control) which were monitored for up to 23 and 48 months respectively. Overall, the inlays were well tolerated during study period with the corneas remaining clear and holding a normal tear film and with no increased vascularisation or redness recorded. Inlays in three human corneas continued past 48 months without sequelae. Inlays in two human corneas were removed early due to small, focal erosions developing 5 and 24 months post implantation. Polymer inlays maintained their integrity and corneal position for the study duration although the optical clarity of the inlays reduced slowly with time. Inlays induced corneal curvature changes in human subjects that showed stability with time and the refractive effect was reversed when the inlay was removed. Outcomes showed the potential of a perfluoropolyether inlay as a biologically acceptable corneal implant with which to provide stable correction of refractive error. PMID- 21306776 TI - Review: Toward an integrated evolutionary understanding of the mammalian placenta. AB - The placenta is fundamentally important for the success of pregnancy. Disruptions outside the normal range for placental function can result in pregnancy failure and other complications. The anatomy of the placenta varies greatly across mammals, as do key parameters in pregnancy such as neonatal body mass, length of gestation and number of offspring per pregnancy. An accurate understanding of the evolution of the mammalian placenta will require at minimum the integration of anatomical, developmental, physiological, genetic, and epigenetic data. Currently available data suggest that the placenta is a dynamic organ that has evolved rapidly in a lineage specific manner. Examination of the placenta from the perspective of human evolution shows that many anatomical features of the human placenta are relatively conserved. Despite the anatomical conservation of the human placenta there are many recently evolved placenta-specific genes (e.g. CGB, LGALS13, GH2) that are important in the development and function of the human placenta. Other mammalian genomes have also evolved specific suites of placenta expressed genes. For example, rodents have undergone expansions of the cathepsin and prolactin families, and artiodactyls have expanded their suite of pregnancy associated glycoproteins. In addition to lineage specific birth and death of gene family members, the pattern of imprinted loci varies greatly among species. Taken together, these studies suggest that a strategy reliant upon the sampling of placentally expressed and imprinted genes from a phylogenetically diverse range of species is appropriate for unraveling the conserved and derived aspects of placental biology. PMID- 21306777 TI - Switching on cytotoxicity by a single mutation at the heavy chain variable region of an anti-ganglioside antibody. AB - Gangliosides are sialic acid-containing glycosphingolipids present in the plasma membrane of most mammalian cells. In humans, the expression of the N-glycolylated (Neu5Gc) variant of the sialic acid has been associated with malignant transformation, constituting therefore an attractive target for cancer immunotherapy. P3 monoclonal antibody (mAb) recognizes Neu5Gc-containing gangliosides, as well as sulfatides. Heavy chain CDR3 (H-CDR3) arginine residues have been shown to be crucial for ganglioside recognition, but less important for anti-idiotypic antibody binding. Here, we describe the effect on antibody reactivity of different mutations involving a single H-CDR3 acid residue. Substitution of glutamate 99 (Kabat numbering) by arginine, aspartate or serine residues resulted in no differences in anti-idiotype binding. However, the first mutation caused increased reactivity with the antigen, including a cytotoxic effect of the antibody on ganglioside-expressing cells previously unseen for the wild type antibody. Another antibody that recognizes N-glycolyl-GM3 ganglioside (GM3(Neu5Gc)), but not other glycolipids, named 14F7, exhibits also an arginine enriched H-CDR3 and a complement-independent cell death activity. Unlike 14F7 mAb, the cytotoxicity of the P3 E(99)->R mutant antibody did not exclusively depend on ganglioside expression on tumor cells. PMID- 21306778 TI - Appropriate hearing screening in the pediatric patient with head trauma. AB - PURPOSE: To develop an algorithm for the appropriate audiologic screening of in children with head trauma. METHODS: Participants were the first consecutive 50 children admitted to a children's hospital trauma service after October 1, 2005, whose injuries resulted in a Glasgow Coma Scale (GCS) score <=13 and/or loss of consciousness (LOC) but no history of hearing loss. Screening tympanometry, otoacoustic emissions testing, and/or routine audiometric evaluation were performed as soon as possible after admission. Age, GCS score, Pediatric Trauma Score, Injury Severity Score, presence of head and neck soft tissue injury, temporal bone fracture, skull fracture not involving the temporal bone, midface/mandible fractures, intracranial abnormality on computed tomography, and cervical fracture were analyzed as risk factors for hearing loss. RESULTS: Seventeen (34%) of the 50 children had abnormal hearing test results. Fischer's exact test showed abnormal test results were most strongly related to temporal bone fracture (p=0.0041), non-temporal bone skull fracture (p=0.0211) and younger age (p=0.0638). CONCLUSIONS: Any child with head trauma and clinical or radiologic evidence of temporal bone fracture should have early hearing evaluation. Using the proposed algorithm to test children with head trauma and GCS <=13 and/or LOC and age <3 years or any type of skull fracture may help identify children with hearing loss in a more cost effective manner. PMID- 21306779 TI - Reviewing model application to support animal health decision making. AB - Animal health is of societal importance as it affects human welfare, and anthropogenic interests shape decision making to assure animal health. Scientific advice to support decision making is manifold. Modelling, as one piece of the scientific toolbox, is appreciated for its ability to describe and structure data, to give insight in complex processes and to predict future outcome. In this paper we study the application of scientific modelling to support practical animal health decisions. We reviewed the 35 animal health related scientific opinions adopted by the Animal Health and Animal Welfare Panel of the European Food Safety Authority (EFSA). Thirteen of these documents were based on the application of models. The review took two viewpoints, the decision maker's need and the modeller's approach. In the reviewed material three types of modelling questions were addressed by four specific model types. The correspondence between tasks and models underpinned the importance of the modelling question in triggering the modelling approach. End point quantifications were the dominating request from decision makers, implying that prediction of risk is a major need. However, due to knowledge gaps corresponding modelling studies often shed away from providing exact numbers. Instead, comparative scenario analyses were performed, furthering the understanding of the decision problem and effects of alternative management options. In conclusion, the most adequate scientific support for decision making - including available modelling capacity - might be expected if the required advice is clearly stated. PMID- 21306780 TI - Changes in compulsory schooling and the causal effect of education on health: evidence from Germany. AB - In this paper we investigate the causal effect of years of schooling on health and health-related behavior in West Germany. We apply an instrumental variables approach using as natural experiments several changes in compulsory schooling laws between 1949 and 1969. These law changes generate exogenous variation in years of schooling both across states and over time. We find evidence for a strong and significant causal effect of years of schooling on long-term illness for men but not for women. Moreover, we provide somewhat weaker evidence of a causal effect of education on the likelihood of having weight problems for both sexes. On the other hand, we find little evidence for a causal effect of education on smoking behavior. Overall, our estimates suggest significant non monetary returns to education with respect to health outcomes but not necessarily with respect to health-related behavior. PMID- 21306781 TI - Athletic experience influences shoulder rotations when running through apertures. AB - In order to pass through apertures safely and efficiently, individuals must perceive the width of the aperture relative to (1) the width of the person-plus object system and to (2) their (anticipated) movement speed. The present study investigated whether athletes who have extensive experience playing sports that require running through narrow spaces while wearing shoulder pads control their shoulder rotations differently while performing this behavior than athletes who lack such experience. Groups of athletes with experience competing in different sports (American football, rugby, and control athletes) performed a behavioral task in which they ran or walked between two tucking dummies with or without wearing shoulder pads. They also performed a psychophysical task in which they reported perceived width of the body and shoulder pads. When running through the apertures, the athletes who played American football exhibited smaller magnitudes and later onset of shoulder rotations than control athletes. No such difference was found when walking through the apertures. There was no difference in perception of the width of the shoulder pads among three groups. These findings suggest that performance of this behavior is action-scaled and task-specific. PMID- 21306782 TI - A fully automated scheme for mammographic segmentation and classification based on breast density and asymmetry. AB - This paper presents a fully automated segmentation and classification scheme for mammograms, based on breast density estimation and detection of asymmetry. First, image preprocessing and segmentation techniques are applied, including a breast boundary extraction algorithm and an improved version of a pectoral muscle segmentation scheme. Features for breast density categorization are extracted, including a new fractal dimension-related feature, and support vector machines (SVMs) are employed for classification, achieving accuracy of up to 85.7%. Most of these properties are used to extract a new set of statistical features for each breast; the differences among these feature values from the two images of each pair of mammograms are used to detect breast asymmetry, using an one-class SVM classifier, which resulted in a success rate of 84.47%. This composite methodology has been applied to the miniMIAS database, consisting of 322 (MLO) mammograms -including 15 asymmetric pairs of images-, obtained via a (noisy) digitization procedure. The results were evaluated by expert radiologists and are very promising, showing equal or higher success rates compared to other related works, despite the fact that some of them used only selected portions of this specific mammographic database. In contrast, our methodology is applied to the complete miniMIAS database and it exhibits the reliability that is normally required for clinical use in CAD systems. PMID- 21306783 TI - Physiological responses and differential gene expression in Prunus rootstocks under iron deficiency conditions. AB - Two Prunus rootstocks, the Myrobalan plum P 2175 and the interspecific peach almond hybrid, Felinem, were studied to characterize their biochemical and molecular responses induced under iron-Deficient conditions. Plants of both genotypes were submitted to different treatments using a hydroponic system that permitted removal of Fe from the nutrient solution. Control plants were grown in 90 MUM Fe (III)-EDTA, Deficient plants were grown in an iron free solution, and plants submitted to an Inductor treatment were resupplied with 180 MUM Fe (III) EDTA over 1 and 2 days after a period of 4 or 15 days of growth on an iron-free solution. Felinem increased the activity of the iron chelate reductase (FC-R) in the Inductor treatment after 4 days of iron deprivation. In contrast, P 2175 did not show any response after at least 15 days without iron. The induction of the FC-R activity in this genotype was coincident in time with the medium acidification. These results suggest two different mechanisms of iron chlorosis tolerance in both Strategy I genotypes. Felinem would use the iron reduction as the main mechanism to capture the iron from the soil, and in P 2175, the mechanism of response would be slower and start with the acidification of the medium synchronized with the gradual loss of chlorophyll in leaves. To better understand the control of these responses at the molecular level, the differential expression of PFRO2, PIRT1 and PAHA2 genes involved in the reductase activity, the iron transport in roots, and the proton release, respectively, were analyzed. The expression of these genes, estimated by quantitative real-time PCR, was different between genotypes and among treatments. The results were in agreement with the physiological responses observed. PMID- 21306784 TI - Low prevalence of psoriasis among children and adolescents in a large multiethnic cohort in southern California. AB - BACKGROUND: Little information is available on the prevalence of psoriasis in children and adolescents. OBJECTIVE: We sought to estimate the prevalence of pediatric psoriasis in southern California and to investigate the validity of psoriasis diagnosis by a dermatologist compared with a nondermatologist. METHODS: In a southern California population of 710,949 children who were enrolled in an integrated prepaid health plan in 2007 through 2008, cases of psoriasis were identified from electronic medical records and validated by medical chart review. Positive predictive values for valid diagnosis were reported for dermatologists and nondermatologists. RESULTS: The prevalence of pediatric psoriasis confirmed by medical chart review was 19/10,000 patients. The prevalence of psoriasis diagnosis (confirmed and unconfirmed) was 30/10,000 patients. The age at onset of psoriasis was slightly earlier in boys than in girls. The positive predictive value for a valid diagnosis of psoriasis was 63.7% when the diagnosis was made by any health care provider, 90.0% by a dermatologist, and 26.6% by a nondermatologist. The prevalence of psoriasis was higher in girls than in boys. Psoriasis affected 29 (95% confidence interval [CI] 27-32) non-Hispanic whites, 20 (95% CI 16-24) Asian/Pacific Islanders, 16 (95% CI 15-18) Hispanic whites, and 6 (95% CI 4-9) blacks per 10,000 patients. LIMITATIONS: Information on the age at onset was estimated based on the first documented diagnosis of psoriasis. CONCLUSION: The overall prevalence of pediatric psoriasis was lower compared with other published studies. This could be in part a result of underdiagnosis because of greater sunlight exposure in southern California and a lower proportion of non Hispanic whites in the population. PMID- 21306785 TI - Guidelines of care for the management of psoriasis and psoriatic arthritis: section 6. Guidelines of care for the treatment of psoriasis and psoriatic arthritis: case-based presentations and evidence-based conclusions. AB - Psoriasis is a common, chronic, inflammatory, multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In the first 5 parts of the American Academy of Dermatology Psoriasis Guidelines of Care, we have presented evidence supporting the use of topical treatments, phototherapy, traditional systemic agents, and biological therapies for patients with psoriasis and psoriatic arthritis. In this sixth and final section of the Psoriasis Guidelines of Care, we will present cases to illustrate how to practically use these guidelines in specific clinical scenarios. We will describe the approach to treating patients with psoriasis across the entire spectrum of this fascinating disease from mild to moderate to severe, with and without psoriatic arthritis, based on the 5 prior published guidelines. Although specific therapeutic recommendations are given for each of the cases presented, it is important that treatment be tailored to meet individual patients' needs. In addition, we will update the prior 5 guidelines and address gaps in research and care that currently exist, while making suggestions for further studies that could be performed to help address these limitations in our knowledge base. PMID- 21306786 TI - Advanced management of acute iliofemoral deep venous thrombosis: emergency department and beyond. AB - Recent attention to the increasing incidence of venous thromboembolism has included a call to action from the surgeon general and new guidelines from various specialty organizations. The standard of care for treatment of deep venous thrombosis in the emergency department (ED), supported by the 2008 American College of Chest Physicians (ACCP) guidelines, involves initiation of anticoagulation with low-molecular-weight heparin, pentasaccharide, or unfractionated heparin. For selected appropriate patients with extensive acute proximal deep venous thrombosis, the ACCP guidelines now recommend thrombolysis in addition to anticoagulation to reduce not only the risk of pulmonary embolism but also the risk of subsequent postthrombotic syndrome and recurrent deep venous thrombosis. Postthrombotic syndrome is a potentially debilitating chronic cluster of lower-extremity symptoms occurring in 20% to 50% of deep venous thrombosis patients subsequent to the acute insult, sometimes not until years later. A strategy of early thrombus burden reduction or frank removal might reduce the incidence of postthrombotic syndrome, as per natural history studies, venous thrombectomy data, observations after systemic and catheter-directed thrombolysis, and the still-limited number of randomized trials of catheter directed thrombolysis (with anticoagulation) versus anticoagulation alone. Contemporary invasive (endovascular) treatments mitigate the drawbacks historically associated with thrombolytic approaches by means of intrathrombus delivery of drugs with greater fibrin specificity and lower allergenicity, followed by mechanical dispersion to accelerate lysis and then aspiration of remaining drug and clot debris. With a 2016 target completion date, the National Heart, Lung, and Blood Institute--sponsored Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-Directed Thrombolysis trial is comparing the safety and efficacy, in terms of both deep venous thrombosis and postthrombotic syndrome parameters, of the most evolved pharmacomechanical catheter-directed thrombolysis devices versus standard anticoagulation therapy alone. This article reviews the grounds for use of adjunctive thrombolysis in patients with acute proximal deep venous thrombosis and begins to identify types of deep venous thrombosis patients encountered in the ED who might benefit most from multidisciplinary consideration of early referral for possible endovascular therapy. PMID- 21306787 TI - Horizontal glottectomy: is it an out-of-date procedure? AB - PURPOSE: The aim of the study is to illustrate our experience with horizontal glottectomy (HG), reviewing the indications and results of this uncommon partial laryngectomy. MATERIALS AND METHODS: It is a retrospective study. We completed a chart review of patients who underwent partial laryngectomy between May 2003 and June 2010. Patients who underwent HG were included in the study. Data obtained were collected and analyzed. RESULTS: Seven male patients were included in the study (mean age was 78 years; range, 69-88 years). In all cases, the TNM classification was pT1bN0M0 apart from one patient who had pT1N1M0. Three patients had a moderately differentiated neoplasm (G2), whereas 4 patients had a well-differentiated tumor (G1). Tracheotomy tube removal, oral feeding, and voice analysis have been evaluated and reported in the study. Mean follow-up was 16 months. CONCLUSIONS: Horizontal glottectomy might be a worthwhile treatment option in selected patients nowadays. In older patients with anterior commissure involvement, this procedure guarantees adequate functional and good oncological results. This study may possibly help surgeons dealing with glottic cancer involving the anterior commissure because we believe that some patients could benefit from HG, even in this radiotherapy and transoral laser surgery "era." PMID- 21306788 TI - The effect of histamine on ciliary beat frequency in the acute phase of allergic rhinitis. AB - BACKGROUND: There have been few studies about the effect of histamine on ciliary beat frequency (CBF) in the acute phase of allergic rhinitis. OBJECTIVE: The present study was designed to investigate CBF in the acute phase of allergic rhinitis and the effect of histamine on CBF. MATERIALS AND METHODS: Nasal septal mucosae were obtained from 13 mice that had been systemically immunized and locally challenged with ovalbumin (OVA) (group A), 11 OVA immunized and phosphate buffered saline-challenged mice (group B), and 12 nontreated negative control mice (group C). The CBFs were observed within 20 minutes of local challenge with OVA. Ciliary beat frequencies were measured before and after treatment with 10( 5), 10(-3), and 10(-1) mol/L histamine and after administering antihistamine or Dulbecco's modified Eagle's medium to histamine-exposed mucosa. RESULTS: The baseline CBF in group A was higher than in groups B and C. After treatment with 10(-1) mol/L histamine, CBF in all groups decreased to 0 within 5 to 7 minutes, whereas treatment with 10(-5) or 10(-3) mol/L histamine had no effect. The application of 100 MUmol/L fexofenadine or Dulbecco's modified Eagle's medium solution restored histamine-induced ciliostasis to near baseline CBF after 10 minutes. CONCLUSIONS: Ciliary beat frequency increased in the acute phase of a mouse model of allergic rhinitis. Physiologic concentrations of histamine had no effect on CBF, and thus, it appears that other mechanisms control CBF in the acute phase of allergic rhinitis. PMID- 21306789 TI - Response to research letter titled "Severe transient hypertension after greater palatine foramen block in a patient taking midodrine". PMID- 21306790 TI - Head-shaking nystagmus predicts greater disability in unilateral peripheral vestibulopathy. AB - OBJECTIVES: The objective of this study was to determine the association of the bedside test of head-shaking nystagmus (HSN) with patients' self-perceived dizziness handicap as well as this test's sensitivity and specificity in unilateral peripheral vestibular hypofunction. STUDY DESIGN: A retrospective case control study was performed. SETTING: The study was held at an academic, tertiary referral center. METHODS: Fifty-three adult patients with unilateral peripheral hypofunction defined by the caloric test of the videonystagmography with documented bedside HSN and who had completed questionnaires of self-perceived dizziness handicap were included. The sensitivity and specificity of the bedside HSN in patients and 10 healthy controls in diagnosing unilateral vestibular hypofunction defined by videonystagmographic caloric testing and by abnormal gain and symmetry of the vestibular-ocular reflex by rotary chair testing were determined. Scores of the screening test of the Dizziness Handicap Index and Functional Level Scale questionnaires were taken. RESULTS: When using the caloric irrigation test as the reference standard for unilateral vestibular hypofunction, the sensitivity, specificity, and positive predictive value of the bedside HSN were 31%, 96%, and 97%, respectively. When comparing with results of rotational chair testing (vestibular-ocular reflex gain and symmetry), the sensitivity of the HSN test increases to 71%. Patients with positive bedside HSN had higher scores (greater self-perceived dizziness handicap) of the Dizziness Handicap Index (P = .049) and higher (worse) scores of the Functional Level Scale (P = .0377) than those with negative bedside HSN (Wilcoxon rank test). CONCLUSIONS: Greater perceived handicap was correlated with a positive bedside HSN in patients with unilateral peripheral vestibulopathy. The HSN has sufficient sensitivity to be used as screening test of uncompensated vestibulopathy in this series. However, a negative HSN alone does not rule out the diagnosis of peripheral vestibular dysfunction. PMID- 21306792 TI - Does extensive dissection of recurrent laryngeal nerve during thyroid operation increase the risk of nerve injury? Evidence from the application of intraoperative neuromonitoring. AB - PURPOSE: Extensive dissection of recurrent laryngeal nerve (RLN) is inevitable in some complicated thyroid operations. The study aimed to determine whether extensive dissection of RLN increases the risk of nerve injury. METHOD: Three hundred thirty-one patients (506 nerves at risk) who underwent thyroid operations with intraoperative neuromonitoring were included. The study chiefly focused on the 101 RLNs on which extensive nerve dissection from the thoracic inlet to the entry of larynx was performed and for which the nerve exposure was longer than 5 cm. Electromyographic (EMG) signals were obtained from the RLN and vagus nerve before and after complete RLN dissection, and these were defined as R(1), V(1) and R(2), V(2) signals, respectively. The RLN palsy rates and the change of EMG signals were evaluated and analyzed. RESULTS: Among 101 nerves with extensive dissection, 13 nerves were due to the operation for recurrent goiter; 41 nerves, for large goiter with substernal extension; and 47 nerves, for thyroid cancer with paratracheal nodal metastasis. No permanent palsy occurred, but 2 nerves experienced loss of EMG signal after complete RLN dissection from a large recurrent goiter and developed temporary palsy. The palsy rates were 2% (2/101) in the extensive dissection group and 2.5% (10/405) in the nonextensive dissection group (P = .77). Among 99 nerves with normal vocal function after operation, none experienced weakened signal after complete RLN dissection, and the mean amplitudes of R(2) and V(2) signals were not significantly different from those of R(1) and V(1) signals (R(2) vs R(1); 1038 vs 1030 MUV; P = .74; V(2) vs V(1); 824 vs 816 MUV; P = .75). CONCLUSIONS: The results of this study suggest that careful surgical dissection is well tolerated by the RLN. PMID- 21306793 TI - Detecting and identifying nonrecurrent laryngeal nerve with the application of intraoperative neuromonitoring during thyroid and parathyroid operation. AB - PURPOSE: The nonrecurrent laryngeal nerve (NRLN) is a rare anatomical variant but associated with high risk of nerve injury during thyroid and parathyroid operations. Therefore, intraoperative detection and verification of NRLN are necessary. METHOD: A total of 390 consecutive patients who underwent thyroid and parathyroid operations (310 RLNs dissected on the right side and 293 nerves on the left side) were enrolled. Electrically evoked electromyography was recorded from the vocalis muscles via an endotracheal tube with glottis surface recording electrodes. At an early stage of operation, vagal nerve was routinely stimulated at the level of inferior thyroid pole to ensure normal path of RLN. If there is a negative response from lower position but positive response from upper vagal stimulation, it indicates the occurrence of a NRLN, and we localize its separation point and path. RESULTS: Four right NRLNs (1.3%) without preoperative recognition were successfully detected at an early stage of operation. Three patients were operated on for thyroid disease, one for parathyroid adenoma and all were associated with right aberrant subclavian artery. All NRLNs were localized and identified precisely with intraoperative neuromonitoring. Functional integrity of all nerves was confirmed by the intraoperative neuromonitoring and postoperative laryngeal examination. CONCLUSIONS: Vagal stimulation at the early stage of operation is a simple, useful, and reliable procedure to detect and identify the NRLN. PMID- 21306794 TI - Endoscopic repair of Zenker's diverticulum by harmonic scalpel. AB - PURPOSE: Although endoscopic staple-assisted esophagodiverticulostomy (ESED) has become the initial treatment of choice for most patients with Zenker's diverticulum (ZD), anatomical restraints prevent its use in all cases. We describe an endoscopic approach for treating ZD using the harmonic scalpel, which can be used in certain cases where diverticulum anatomy precludes ESED. MATERIALS AND METHODS: Medical records of 7 consecutive patients who underwent endoscopic repair of ZD using the harmonic scalpel (Harmonic Ace, Ethicon Endo-Surgery, Inc, Cincinnati, OH) were reviewed. Data collected included demographics, symptoms, surgical details, complications, and postoperative outcomes. Main outcome measures were time to resumption of oral diet, symptom resolution, and complications. RESULTS: All patients (N = 7) who underwent endoscopic repair of ZD using the harmonic scalpel resumed an oral diet at initial follow-up visit after surgery (mean, 7 days; range, 4-9 days) and rated their symptoms as being completely resolved at subsequent follow-up (mean, 4 months; range, 1.5-8 months). There were no complications. CONCLUSIONS: Endoscopic repair of ZD using the ultrasonic cutting shears is a safe and efficacious procedure that allows for endoscopic treatment in certain cases that cannot be treated by ESED. Further study is warranted in larger series to determine efficacy and safety compared with established endoscopic techniques. PMID- 21306795 TI - A simple closure technique for reversal of tracheoesophageal puncture. AB - Speech restoration after total laryngectomy has been revolutionized by the technique of tracheoesophageal puncture (TEP) and speech valve prosthesis placement. Unfortunately, complications may arise from this procedure, sometimes necessitating reversal and surgical closure of the TEP. We present a simple yet effective method of closing a TEP and review previously described techniques. PMID- 21306796 TI - Bipolar scissor turbinectomy: a new technique for day-case turbinectomy. AB - HYPOTHESIS: The study aimed to assess the efficacy of bipolar scissor in the treatment for patients with inferior turbinate hypertrophy. MATERIALS AND METHODS: A prospective cohort clinical study was conducted on 10 adult patients who were chosen with a diagnosis of turbinate hypertrophy. RESULTS: Ninety percent of our cases were satisfied with the procedure, there were significant drops in the sensation of nasal obstruction, the average duration of the procedure was 20 minutes for both sides, and only a single case was complicated with a small burn on the vestibule. DISCUSSION: Bipolar scissor could be applied safely in turbinate surgery to perform a rapid effective turbinectomy without packing or overnight hospital stay. PMID- 21306797 TI - Three swipes and you're out: how many swipes are needed to decontaminate plastic with disposable wipes? AB - At our hospital, health care workers use commercially available wipes to reduce bacterial counts on plastic surfaces. The workers use the wipes in a cursory fashion--swiping objects once for one to two seconds. We sought to measure the ability of wipes to reduce bacterial counts when swiped across plastic surfaces using various routines. PMID- 21306798 TI - Findings from a pilot investigation of the effectiveness of a snoezelen room in residential care: should we be engaging with our residents more? AB - There is increasing literature on multisensory therapy or Snoezelen, with some evidence suggesting it promotes positive mood and reduces maladaptive behavior in people with dementia. We undertook a pilot evaluation of a Snoezelen room in residential care and compared effects with a condition in which staff took residents out to a garden. This study was therefore a comparison between a Snoezelen room containing prescriptive, expensive equipment and a more everyday existing location that, inevitably, also contained several sensory stimuli. The study was difficult to implement, with low numbers because some staff failed to attend sessions, and the frequent although rarely reported difficulty of introducing psychosocial interventions and doing research in residential care is one of the main stories of this study. No staff member used the room outside of the study, and we found no significant difference between Snoezelen and garden conditions. Results, although highly equivocal because of low numbers, raised the issue of the implementation of standard therapies in dementia care outpacing the evidence, possibly at the expense of less elaborate practices. PMID- 21306799 TI - [Satisfactory ageing]. PMID- 21306800 TI - Design, synthesis and potential 6 Hz psychomotor seizure test activity of some novel 2-(substituted)-3-{[substituted]amino}quinazolin-4(3H)-one. AB - Thirty new 2-(substituted)-3-{[substituted]amino}quinazolin-4(3H)-one were designed and synthesized keeping in view the structural requirement of pharmacophore and evaluated for anticonvulsant activity and neurotoxicity. The anticonvulsant activity of the titled compounds was assessed using the 6 Hz psychomotor seizure test. The most active compound of the series was 3-({(E)-[3 (4-chloro-3-methylphenoxy)phenyl]methylidene}amino)-2-phenylquinazolin-4(3H)-one PhQZ 7, which showed 100% protection (4/4, 0.5 h) and 75% protection (3/4, 0.25 h) at a dose of 100 mg/kg in mice. A computational study was carried out for calculation of pharmacophore pattern and prediction of pharmacokinetic properties. Titled compounds have also exhibited good binding properties with epilepsy molecular targets such as glutamate, GABA (A) delta and GABA (A) alpha-1 receptors, in Lamarckian genetic algorithm based flexible docking studies. PMID- 21306801 TI - Exerpts from the history of alpha recoils. AB - Any confined air volume holding radon ((222)Rn) gas bears a memory of past radon concentrations due to (210)Pb (T(1/2) = 22 y) and its progenies entrapped in all solid objects in the volume. The efforts of quantifying past radon exposures by means of the left-behind long-lived radon progenies started in 1987 with this author's unsuccessful trials of removing (214)Po from radon exposed glass objects. In this contribution the history and different techniques of assessing radon exposure to man in retrospect will be overviewed. The main focus will be on the implantation of alpha recoils into glass surfaces, but also potential traps in radon dwellings will be discussed. It is concluded that for a successful retrospective application, three crucial imperatives must be met, i.e. firstly, the object must persistently store a certain fraction of the created (210)Pb atoms, secondly, be resistant over decades towards disturbances from the outside and thirdly, all (210)Pb atoms analysed must originate from airborne radon only. For large-scale radon epidemiological studies, non-destructive and inexpensive measurement techniques are essential. Large-scale studies cannot be based on objects rarely found in dwellings or not available for measurements. PMID- 21306802 TI - Pre-concentration of naturally occurring radionuclides and the determination of (212)Pb from fresh waters. AB - A novel technique has been developed for determining the (212)Pb activity of fresh waters. This is of interest to environmental monitoring programmes that utilise gross alpha-activity methods to screen for anthropogenic radionuclides. The contribution from (212)Pb varies, and is difficult to experimentally measure due to its relatively short half-life (t(1/2) = 10.6 h) and low environmental activity (<0.1 Bq l(-1)). The use of a three-stage technique that encompasses a unique form of pre-concentration, separation and analysis by liquid scintillation counting allows a lower detection limit of 0.006 Bq l(-1) with a chemical yield of 92.5 +/- 5.6%. The measurement can be obtained within 7 h of sample collection, and is calculated using the radioactive decay of (212)Bi. Other naturally occurring radionuclides may also be extracted using the pre concentration stage of the technique, with efficiencies above 90% at a range of pH values. PMID- 21306803 TI - Hairy intraoral flap--an unusual indication for laser epilation: a series of 5 cases and review of the literature. AB - A variety of the flaps used to reconstruct defects of the head and neck region following surgery for malignant disease contain hair follicles that may result in unwanted hair growth. This can cause significant distress to the patients in a variety of ways. We report 5 cases of significant intraoral hair growth of which 4 cases were successfully managed with long-pulsed alexandrite laser. One patient was not treated due to technical difficulties. We review the literature on the management of hair growth on intraoral flaps. PMID- 21306804 TI - Use of an acrylic occlusal splint during operations on cleft palate to prevent iatrogenic injury to the teeth. PMID- 21306805 TI - Patterns of hip flexion motion predict frontal and transverse plane knee torques during a single-leg land-and-cut maneuver. AB - BACKGROUND: Impulsive frontal plane knee joint torques directly strain the anterior cruciate ligament and therefore may contribute to injury risk. Because deleterious torques may in part be related to aberrant kinematic movement patterns the primary purpose of this study was to establish a prediction model for frontal plane knee joint torques based on motion characteristics derived from Principal Component Analysis. METHODS: Eighteen healthy NCAA Division I female athletes performed a single-leg land-and-cut maneuver (n=5 trials) with their dominant limb. Ensemble average lower extremity joint angles for the hip, knee, and ankle along with normalized external knee abduction torques were calculated for the entire stance phase. The ensemble kinematic data were individually submitted to a Principal Component Analysis. Principal component scores were used in a forward step-wise regression model to establish a prediction equation for peak ensemble-averaged knee abduction torque. FINDINGS: Approximately 31% of the variance in knee abduction torque was explained by a principal component that captured relative magnitudes of hip flexion motion during early stance. Likewise, approximately 32% of the variance in knee internal rotation torque was explained by a principal component that captured overall hip flexion during stance. INTERPRETATION: Rapid hip flexion motion during the first half of the stance phase of a single-leg land-and-cut maneuver is associated with greater knee abduction joint torques, whereas greater overall flexion during the entire stance phase is associated with smaller internal rotation torques. PMID- 21306806 TI - Analyzing trophic transfer of heavy metals for food webs in the newly-formed wetlands of the Yellow River Delta, China. AB - Nine heavy metals sampled from water, sediments, and aquatic organisms in the newly-formed wetlands of the Yellow River Delta (YRD) of China were analyzed to evaluate their concentrations and trophic transfer in food webs. The stable carbon (delta13C) and nitrogen (delta15N) isotopes were used to investigate trophic interactions. Results show that most of heavy metals detected in water and sediments are lower than that in Yangtze River Delta and Pearl River Delta. The longest food web is approximately 4 with the highest trophic level of birds. The difference of heavy metal concentrations between endangered Saunders's Gull and other three kinds of protected birds is not obvious. Cd, Zn, and Hg were identified to have an increase with the trophic level (TL), while As, Cr, Cu, Mn, Ni and Pb show an opposite trend, however, the biomagnification of the selected nine heavy metals in the food webs is not significant. PMID- 21306807 TI - Physician social capital and the reported adoption of evidence-based medicine: exploring the role of structural holes. AB - The present study explores the role that professional networks play in the propensity of hospital physicians to adopt and implement evidence-based medicine (EBM) into clinical practice. Using attributional and relational data collected from a sample of 207 physicians in six Italian National Health Service hospitals, social network techniques were used to analyze the structure of the networks representing professional interactions among the surveyed hospital physicians. Ordinal logistic regression was applied to analyze the association between the structural features of physicians' networks and their self-reported propensity to implement EBM into daily practice. Physicians who were highly constrained in their interpersonal networks were less likely to report adopting EBM, suggesting that the cohesion induced by social interactions may hamper, rather than foster, the diffusion of scientific information within professional groups. We discuss the implications of the observed interaction patterns for hospital administrators and policy makers. PMID- 21306809 TI - Silenced voices: Israeli mothers' experience of feticide. AB - The study is a qualitative analysis of 13 interviews with Israeli women who experienced feticide by injection at a late stage of their pregnancy due to fetus abnormality. Neither the public nor health care professionals are fully aware of the implications and significance of feticide to the mother. The goal of this study which was conducted from May 2008 until October 2009 was to understand and give voice to the women's experience. Three themes were discovered: (a) difficult decision making process and outcomes; (b) the unbearable experience of feticide; and (c) feticide as an unspoken experience. Feticide was revealed to incorporate both social and psychological layers; thus, the findings highlight the interface between a personal experience and a social phenomenon. The women's experience is discussed within the Israeli social context, where feticide is a relatively common yet unspoken procedure. PMID- 21306808 TI - Health inputs and cumulative health deficits among the older Chinese. AB - Using a health economics framework, we examined how both individual level investments at different life stages and current community-level environmental factors affect individual health stock and flows at old ages. We used a nationwide dataset from the 2002 and 2005 waves of the Chinese Longitudinal Healthy Longevity Survey, which included more than 15,000 adults aged 65 and older from 22 provinces in mainland China. We measured health stock with a cumulative health deficit index, a measure developed in geriatrics and gerontology that reflects deficits, illnesses, and functional impairment in numerous domains of health. The cumulative health deficit index has not been used in health economics before, but is a significant contribution because it captures the health stock concept very well and overcomes the problems of inconsistency resulting from the use of different measures of health stock in research. Our results show that several proxy measures for individual health investments in both childhood (nutritional status and parental survival status) and adulthood (family financial condition and access to healthcare) yielded positive returns to health stock measured by the cumulative health deficit index. Investments in social connections and healthy behaviors (religious involvement, alcohol use, and exercise) also produced positive returns in health stock. Current community-level factors such as air quality and labor force participation rate were significantly associated with levels of health deficits in old age as well. Yet, most of these individual investment and community environment variables did not significantly affect short-term health flows (improvement or deterioration in health status over three years). Our findings have important implications for developing preventive health programs in the context of population aging by focusing on policy-relevant predictors and a comprehensive indicator of health status in later life. PMID- 21306810 TI - The effects of local medicinal knowledge and hygiene on helminth infections in an Amazonian society. AB - Social science has long recognized the importance of understanding how interactions between culture and behavior shape disease patterns, especially in resource-poor areas where individuals draw on multiple medical treatments to maintain health. While global health programs aimed at controlling high infection rates of soil-transmitted helminthes among indigenous groups often acknowledge the value of local culture, little research has been able to examine this value. This study investigates the association between parental ethnomedical knowledge, parental biomedical knowledge, and household sanitation behavior and childhood soil-transmitted helminth infections among a group of foragers-farmers in the Bolivian Amazon (Tsimane'). During 2007, a parasitological survey was completed for 329 children (<= 16 years of age) from 109 households in combination with a comprehensive survey of both of the child's parents to assess biomedical and ethnomedical knowledge and household sanitary environment. Soil-transmitted helminthes were found to be common with 67% of sample positive for hookworm species. Indices that capture a household's relative state of risky and preventive hygienic behavior were significantly associated with risk of hookworm infection. Mother's but not father's ethnomedical knowledge was also negatively associated with a child's probability of being positive for hookworm infection. The effect was stronger for young children and boys. Like many rural populations, Tsimane' actively draw upon multiple medical systems to respond to health challenges. Integration into markets and national societies is likely to affect local medical systems by increasing the use of biomedicine as formal education prioritizes biomedical over ethnomedical systems. This study underscores the value of considering both ethnomedical knowledge systems and household hygiene in public health campaigns to treat and control soil-transmitted helminths. There is no question that providing medication is critical, but this study demonstrates that poverty is not synonymous with either poor hygiene or the lack of valuable ethnomedicinal knowledge. PMID- 21306811 TI - The role of housing in determining HIV risk among female sex workers in Andhra Pradesh, India: considering women's life contexts. AB - Recent research on HIV prevention, regardless of the population, has increasingly recognized the relevance of contextual factors in determining HIV risk. Investigating such factors among female sex workers (FSW) is especially relevant in the South Indian state of Andhra Pradesh, where HIV rates are among the highest across Indian states and where HIV has largely affected FSW. Stable housing is a particular contextual challenge experienced by female sex workers in this region (as well as elsewhere); however, local studies have not examined the impact of this issue on HIV risk. In this paper, we examine residential instability, defined as a high frequency of reported evictions, among FSW and relation to experiences of violence (as a factor increasing risk for HIV) and sexual risk factors for HIV. Women were recruited through respondent-driven sampling for a survey on HIV risk. Using logistic regression models, we assessed: (1) residential instability and association with HIV sexual risk variables (including unprotected sex, reported STIs, and recent physical and sexual victimization) and (2) whether the association between residential instability and reported STI (as an indicator of HIV risk) was attenuated by individual risk behaviors and violence. In adjusted logistic regression models, FSW who reported residential instability were more likely to report: sexual violence, physical violence, accepting more money for unprotected sex, and a recent STI symptom. Violence associated with residential instability contributed to reported STIs; however, residential instability remained significantly associated with STIs beyond the influence of both violence and unprotected sex with clients. Findings highlight the interrelation among residential instability, violence, and HIV risk. Residential instability appears to be associated with women's HIV risk, above and beyond its association with individual risky sexual behaviors. PMID- 21306812 TI - Managing hope, denial or temporal anomie? Informal cancer carers' accounts of spouses' cancer diagnoses. AB - Carers of cancer patients' emotional responses to cancer diagnoses have been a central focus within psycho-oncology. Some of this literature asserts that the maladaptive coping strategy denial is prevalent amongst carers. Using semi structured, longitudinal interviews with 32 Australian Capital Territory carers of a spouse with cancer and an interactionist sociology of emotions framework to understanding their emotions, this study aimed to both contribute to the literature on cancer carers' coping strategies and provide a richer sociological depiction of carers' emotional reactions to a cancer diagnosis. The results raise questions about the value of singularly examining denial in cancer carers. Instead, these data suggest that carers use a range of coping strategies in the short-term and do emotion work to adapt to a challenged temporal orientation. The term temporal anomie is offered to describe carers' disrupted orientations in time and facilitate further discussion on the link between time and emotion work. Findings also show the importance of medical professionals' casting of the prognosis, from imminent death to certain future, to this temporal re-orientation and emotion work process. Instead of 'managing hope,' as much of the cancer communication literature describes it, findings suggest that physicians address cancer carers' and patients' temporal anomie. Future research might benefit from moving beyond individualistic conceptualisations of carers' emotions to include the cultural, temporal and interactionist influences. PMID- 21306813 TI - Decision Preceding Negativity in the Iowa Gambling Task: an ERP study. AB - The present study aimed to investigate the slow negative potential (termed Decision Preceding Negativity, DPN, from the family of the Readiness Potential) which precedes a willed risky decision. To this end, evoked potentials preceding and following an economic choice were measured in a sample of 16 male students during the Iowa Gambling Task modified for ERPs recording. Statistics revealed reduced positivity/relative greater negativity (marking relative activation) in right prefrontal sites and reduced negativity (indicating relative inhibition of DPN) in central clusters over left premotor cortex, 500 ms before picking from economically disadvantageous risky decks. Analyses of the potentials elicited by the economic outcome (wins vs. losses) showed the classical frontal negativity (N260) to the economic losses. Results are consistent with the view that an economically risky decision is preceded by a relative inhibition of the planned motor response together with the activation of emotion-related right frontal sites. PMID- 21306814 TI - Sinus node disfunction due to lithium intoxication. PMID- 21306815 TI - Protective effect of intra-peritoneal epinephrine on postoperative renal function after cisplatin-based intra-peritoneal intra-operative chemotherapy. AB - OBJECTIVES: Intra-operative cisplatin-based intra-peritoneal chemotherapy (IPC) may alter renal function in patients with advanced ovarian cancer. The aim of this study was to describe postoperative alteration of renal function after cisplatin-based IPC and to identify risk factors for moderate to severe acute renal failure. STUDY DESIGN: This prospective observational study was carried out on 77 consecutive patients who underwent cisplatin-based IPC procedures, with (n=23) or without (n=54) intra-peritoneal epinephrine, for advanced ovarian cancer. Postoperative renal function was assessed using serial serum creatinine measurements and was based on serum creatinine changes from pre-operative values, according to the risk, injury, failure, loss, end-stage kidney disease (RIFLE) classification. Patients were divided into two groups according to postoperative renal function: patients with renal injury or failure (IF group) or patients with no renal alteration or renal risk (NR group). Clinical variables were compared between the IF and NR groups using univariate and multivariate analysis. RESULTS: Postoperative acute change in renal function was observed in 34 (44.2%) patients (unimodal distribution), among whom 23 patients (29.8%) constituted the IF group. In univariate analysis, the absence of epinephrine in the IPC bath, a higher duration of severe hypotension, a lower postoperative blood protein level, and a lower volume of intra-operative diuresis were significantly associated with the occurrence of renal injury or failure. In multivariate analysis, the absence of epinephrine was the only factor associated with the occurrence of moderate to severe acute renal failure (odds ratio [95% confidence interval]=4.49 [1.36 14.80]). CONCLUSIONS: Transient acute renal dysfunction after cisplatin-based IPC associated with cytoreductive surgery is frequent and intra-peritoneal epinephrine plays a protective role. PMID- 21306816 TI - Oncologic and reproductive outcomes in patients with advanced-stage borderline ovarian tumors. AB - OBJECTIVE: To evaluate the oncologic safety and reproductive outcomes in patients with advanced-stage borderline ovarian tumors (BOTs). STUDY DESIGN: The medical records of patients with advanced-stage BOTs who were treated between 1997 and 2009 were reviewed retrospectively. Reproductive outcomes were assessed by telephone interviews. RESULTS: Six (24%) and 19 patients (76%) had stages II and III disease, respectively. Twenty patients (80%) were treated by radical surgery and five patients (20%) underwent fertility-sparing surgery. Five patients (20%) had invasive implants and 20 patients (80%) had non-invasive implants. The median follow-up time was 71.4 months (range, 10-135 months). Four patients relapsed after a median interval of 40 months (range, 16-77 months) following primary treatment. Of these four patients, two who initially had invasive implants relapsed in the form of invasive ovarian carcinoma. Patients with invasive implants (2 of 5 [40%]) tend to relapse more frequently than patients with non invasive implants (2 of 20 [10%]). Among five women who underwent fertility sparing surgery, four attempted to conceive and five singleton pregnancies occurred. CONCLUSION: Patients with advanced-stage BOTs with non-invasive implants have an excellent prognosis. Fertility-sparing surgery should be considered if there are no invasive implants. Indeed, reproductive outcomes after fertility-sparing surgery with non-invasive implants are promising. PMID- 21306817 TI - Human parthenogenetic stem cells produce enriched populations of definitive endoderm cells after trichostatin A pretreatment. AB - Human parthenogenetic stem cells (hpSC) hold great promise as a source of pluripotent stem cells for cell-based transplantation therapy due to their ethical method of derivation as well as the enhanced capacity for immunomatching with significant segments of the human population. We report here the directed differentiation of hpSC to produce enriched populations of definitive endoderm. Moreover, we find that treatment of undifferentiated hpSC by trichostatin A (TSA) before applying the directed differentiation protocol significantly increases the proportion of definitive endoderm cells in the final population. TSA-pretreated as well as non-TSA-treated hpSC undergoing differentiation toward definitive endoderm demonstrate a similar temporal sequence of gene expression to that which occurs in the course of definitive endoderm differentiation during vertebrate gastrulation and for differentiation of hESCs to definitive endoderm. Creation of the definitive endoderm lineages from hpSC represents the critical first step toward the development of hpSC-based cellular therapies for diseases of the liver or pancreas. PMID- 21306818 TI - Urban reconciliation ecology: the potential of living roofs and walls. AB - Reconciling human and non-human use of urban regions to support biological conservation represents a major challenge for the 21st century. The concept of reconciliation ecology, by which the anthropogenic environment may be modified to encourage non-human use and biodiversity preservation without compromising societal utilization, potentially represents an appropriate paradigm for urban conservation given the generally poor opportunities that exist for reserve establishment and ecological restoration in urban areas. Two habitat improvement techniques with great potential for reconciliation ecology in urban areas are the installation of living roofs and walls, which have been shown to support a range of taxa at local scales. This paper evaluates the reconciliation potential of living roofs and walls, in particular highlighting both ecological and societal limitations that need to be overcome for application at the landscape scale. We further consider that successful utilization of living roofs and walls for urban reconciliation ecology will rely heavily on the participation of urban citizens, and that a 'citizen science' model is needed to facilitate public participation and support and to create an evidence base to determine their effectiveness. Living roofs and walls are just one aspect of urban reconciliation ecology, but are particularly important 'bottom-up' techniques for improving urban biodiversity that can be performed directly by the citizenry. PMID- 21306819 TI - Comparison of four early posttherapy imaging changes (EPTIC; RECIST 1.0, tumor shrinkage, computed tomography tumor density, Choi criteria) in assessing outcome to vascular endothelial growth factor-targeted therapy in patients with advanced renal cell carcinoma. AB - BACKGROUND: Vascular endothelial growth factor (VEGF)-targeted therapy has become standard treatment for patients with metastatic renal cell cancer (mRCC). Since these therapies can induce tumor necrosis and minimal tumor shrinkage, Response Evaluation Criteria in Solid Tumors (RECIST) may not be optimal for predicting clinical outcome. OBJECTIVE: To systematically determine the optimal early posttherapy imaging changes (EPTIC) to separate responders and nonresponders at the first posttreatment follow-up computed tomography (CT). DESIGN, SETTING, AND PARTICIPANTS: Seventy mRCC patients with 155 target lesions treated with first line sunitinib, sorafenib, or bevacizumab at academic medical centers underwent contrast-enhanced thoracic and abdominal CT at baseline and first follow-up after therapy initiation (median: 78 d after therapy initiation; range: 31-223 d). MEASUREMENTS: Evaluations were performed according to (1) RECIST 1.0; (2) Choi criteria; (3) tumor shrinkage (TS) of >=10% decrease in sum of the longest unidimensional diameter (SLD); and (4) 15% or 20% decrease in mean CT tumor density. Correlation with time to treatment failure (TTF) and overall survival (OS) were compared and stratified by response to each of the radiologic criteria. RESULTS AND LIMITATIONS: Eleven patients were considered responders by RECIST 1.0; 49 based on Choi criteria; 31 patients had >=10% decrease in the SLD; and 36 and 32 patients had >=15% and >=20% decrease, respectively, in mean tumor density on CT. Only the threshold of 10% decrease in the SLD was statistically significant in predicting TTF (10.4 vs 5.1 mo; p=0.02) and OS (32.5 vs 15.8 mo; p=0.002). Receiver operating characteristic analysis yielded a 10% decrease in SLD as the optimal size change threshold for responders. The retrospective nature of the study and measurements by a single oncoradiologist are inherent limitations. CONCLUSIONS: In the retrospectively analyzed study population of mRCC patients receiving VEGF-targeted agents, a 10% reduction in the SLD on the first follow-up CT was an optimal early predictor of outcome. PMID- 21306820 TI - The prevalence of clinically meaningful overactive bladder: bother and quality of life results from the population-based FINNO study. AB - BACKGROUND: Wide variation exists in prevalence estimates of overactive bladder (OAB) syndrome. OBJECTIVE: To determine how the frequency of urinary urgency or urgency urinary incontinence (UUI)--the cornerstone symptoms of OAB--affects symptom-related bother, health-related quality of life (HRQL), and ultimately clinically meaningful prevalence. DESIGN, SETTING, AND PARTICIPANTS: Questionnaires were mailed to 6000 subjects (18-79 yr of age) randomly identified from the Finnish Population Register in 2003-2004. MEASUREMENTS: The frequency (scale: never, rarely, often, always) and bother (scale: none, small, moderate, major) of urgency and UUI were assessed using the Danish Prostatic Symptom Score (DAN-PSS). HRQL was measured with the generic 15D instrument. For HRQL analyses, respondents were classified according to six symptom categories by frequency of urgency and UUI. RESULTS AND LIMITATIONS: Of those subjects queried, 62.4% responded to the survey (53.7% female). Any urgency was reported by more than half of all respondents (54.2% [95% confidence interval (CI), 51.6-56.7] of men; 56.9% [95% CI, 52.9-61.0] of women), whereas any UUI was reported by one in nine men (10.7% [95% CI, 8.9-12.4]) and one in four women (25.7% [95% CI, 22.8-28.7]). However, only one in seven of all respondents with urgency and less than one in three with UUI reported at least moderate bother. With increasing OAB severity, statistically significant decreases were found in the total 15D score and on all 15D dimensions (p<0.001 for all). Reporting often urgency without UUI or rare urgency with rare UUI is associated with a clinically important decrease in HRQL. Although the response proportion was high, approximately one-third of those contacted did not participate. CONCLUSIONS: Increased severity of urgency and UUI is associated with a statistically significant and clinically important decrease in HRQL. Assessing bother associated with OAB drastically modifies the measured OAB prevalence and accounts for variation among studies. PMID- 21306821 TI - Antitumor activity of HM781-36B, an irreversible Pan-HER inhibitor, alone or in combination with cytotoxic chemotherapeutic agents in gastric cancer. AB - Trastuzumab, a HER2 directed treatment has shown clinical benefit in HER2 amplified gastric cancer. This study demonstrated the potent antitumor activity of HM781-36B, a quinazoline-based irreversible pan-HER inhibitor, in HER2 amplified gastric cancer cells (SNU216 and N87) in vitro and in vivo. HM781-36B inhibited phosphorylation of HER family and downstream signaling molecules, and induced apoptosis and G1 arrest. Furthermore, HM781-36B exerted synergistic effects with chemotherapeutic agents in both HER2 amplified and HER2 non amplified gastric cancer cells. Therefore, HM781-36B may be useful for the treatment of HER2 amplified gastric cancer alone or in combination with chemotherapeutic agents. PMID- 21306822 TI - Adeno-associated virus-mediated anti-DR5 chimeric antibody expression suppresses human tumor growth in nude mice. AB - In the present study we demonstrate that adeno-associated virus (AAV)-mediated anti-DR5 (death receptor 5) mouse-human chimeric antibody (shorten as Adximab) expression significantly suppressed tumor cell growth by inducing apoptosis both in vitro and in vivo. The viral-expressed and cell-secreted Adximab efficiently bound DR5 with an affinity of 0.7nM and induced apoptosis of various tumor cells, but not normal cells. A single intramuscular injection of recombinant AAV particles resulted in a stable expression of Adximab in mouse serum for at least 70days. AAV-mediated Adximab expression led to a significant suppression of tumor growth in nude mice receiving xenografts of human liver and colon cancer. These data suggest that chimeric antibody gene transfer may provide an alternative strategy for the therapy of varieties of cancers. PMID- 21306823 TI - Oncogenic virus-mediated cell fusion: new insights into initiation and progression of oncogenic viruses--related cancers. AB - Cell fusion is fundamental to the development and physiology of multicellular organisms, such as fertilization, placentation, development of skeletal muscle and bone. Oncogenic virus-mediated cell fusion, however, may lead to chromosomal instability (CIN) by various mechanisms when tumor suppressor p53 is deregulated and produce oncogenic aneuploid cells. It is worth noting that all human oncogenic viruses, including human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), human herpesviruses-8/Kaposi sarcoma herpesvirus (HHV-8/KSHV) and human T-cell lymphotropic virus type 1 (HTLV 1), are capable of both inducing cell fusion and inhibiting the functions of p53 as well as pRb. Although it is now not clear whether a link between virus mediated cell fusion and cancer established in experimental systems also exists in humans, the fact that the observation of tetraploid cells is more frequent in virus-positive than virus-negative premalignant lesions supports this link. Additionally, there are now no available vaccines against most oncogenic viruses except for HBV and HPV. Given these, developing fusion inhibitors is beneficial to cancer prevention and therapy of virus-associated cancers via inhibiting virus entry, spread and oncogenic role. PMID- 21306824 TI - Activated carbon modifications to enhance its water treatment applications. An overview. AB - The main objective of this study was to list and compare the advantages and disadvantages of different methodologies to modify the surface of activated carbons (ACs) for their application as adsorbents to remove organic and inorganic pollutants from aqueous phase. These methodologies have been categorized into four broad groups: oxidation, sulfuration, ammonification, and coordinated ligand anchorage. Numerous investigations into the removal of metals from water have modified carbon surfaces to increase their content of acidic surface functional groups by using H(2)O(2), O(3) and HNO(3). Because these treatments can reduce the AC surface area, researchers are seeking alternative methods to modify and/or create surface functional groups without the undesirable effect of pore blockage. The nitrogenation or sulfuration of the AC surface can increase its basicity favoring the adsorption of organic compounds. The introduction of nitrogen or sulfur complexes on the carbon surface increases the surface polarity and, therefore, the specific interaction with polar pollutants. Different coordinated ligands have also been used to modify ACs, showing that coordinated ligand anchorage on the AC surface modifies its textural and chemical properties, but research to date has largely focused on the use of these modified materials to remove heavy metals from water by complexes formation. PMID- 21306826 TI - Symptoms of depression and stress mediate the effect of pain on disability. AB - The mechanism or mechanisms involved in the development of pain-related disability in people with low back pain is unclear. Psychological distress has been identified as one potential pathway by which an episode of pain influences the development of persistent disabling symptoms; however, the relationship has not been formally investigated. This study investigated the causal relationship between pain and disability via psychological distress (and its components depression, stress, and anxiety) by using mediation path analysis. The study sample included 231 participants with subacute low back pain (6 to 12 weeks' pain duration) who had been recruited for an exercise-based randomised, controlled trial. All participants completed self-report assessments of pain (0-10 numerical rating scale), disability (Roland Morris Disability Questionnaire), and psychological distress (Depression Anxiety and Stress Scale) at baseline and again at 2 follow-up time points (6 and 12 weeks after baseline). The results of the mediation analysis suggest that approximately 30% of the relationship between subacute pain and later disability is dependent on the level of patients' psychological distress. The finding that psychological distress only partially (30%) mediated the pain-disability relationship indicates that other factors should also be explored. Further analysis into the components of psychological distress revealed that the symptoms of depression and stress, but not anxiety, are responsible for mediation of the pain-disability relationship. These findings provide an opportunity to decrease the risk of long-term disability through early identification and management of depressive and stress symptoms. PMID- 21306827 TI - Resistance to cypermethrin, deltamethrin and chlorpyriphos in populations of Rhipicephalus (Boophilus) microplus (Acari: Ixodidae) from small farms of the State of Sao Paulo, Brazil. AB - A field survey of resistance was conducted based on the larval packet test technique with synthetic pyrethroids (cypermethrin and deltamethrin) and organophosphates (chlorpyriphos) in Rhipicephalus (Boophilus) microplus field populations from six different regions of the State of Sao Paulo (Brazil). 82.6% of the populations showed resistance to cypermethrin, 86.36% to deltamethrin and 65.25% to chlorpyriphos, with 50% presenting resistance to both SP and OP acaricide. According to the questionnaires completed by the producers, OP+SP mixtures followed by SP-only formulations were the products most commonly used for controlling the cattle tick in the surveyed areas. The present study showed high occurrence of resistance to SP and OP in the State of Sao Paulo, Brazil and revealed the type of strategy adopted by small dairy farms in this state. This information is fundamental in order to establish the monitoring of resistance on each farm individually, contributing to the rational use of acaricides for the control of R. (B.) microplus. PMID- 21306828 TI - A novel technology approach to pain management in children with burns: A prospective randomized controlled trial. AB - BACKGROUND: Non-pharmacological approaches to supporting young children through painful medical procedures are an essential component of burn pain management protocols. New technology developed from collaborations between healthcare professionals and IT teams can enhance the preparation and distraction approaches used with children. This study follows on from previous studies using such technology, and aim to determine whether levels of pain and distress using a combined preparation and distraction content can be further reduced, and offer more efficient clinical outcomes. METHODS: Forty children (3-10 years) undergoing acute burn care procedures were randomized to two groups: (1) Standard Distraction (SD) Group and (2) Multi Modal Distraction (MMD) Group (combined protocol of procedural preparation and distraction). Pain intensity and child distress were measured prior to and during the procedure. Clinical utility end points were also included; length of treatment, days to healing and adverse pain events. RESULTS: A combined MMD protocol significantly reduced pain intensity (p<0.001) and distress scores (p<0.001) when compared to SD. Length of treatment (p<0.05), days to healing and the number of pain adverse events were also reduced (p<0.05) with the use of the MMD protocol. CONCLUSIONS: A combined MMD protocol reduces the pain experiences for young children during burn care procedures. When compared with a previous MMD trial, outcomes reiterated the use of procedural preparation as an essential component of non-pharmacological approaches. In addition to minimizing pain and distress, this innovative technology reduced treatment length and pain adverse events, and may have an impact on reducing days to healing, providing evidence of clinical efficacy and utility. PMID- 21306830 TI - Predicting adolescent substance use: the effects of depressed mood and positive expectancies. AB - This study examined whether sixth-graders' depressed mood and positive substance use expectancies predicted increases over the next two years in students' lifetime and 30-day cigarette, alcohol, and marijuana use, and whether sixth graders' positive substance use expectancies moderated the relationship between baseline depressed mood and changes over the next two years in the use of these substances. Study data came from a randomized controlled trial of Project ALERT, a school-based substance use prevention program, in which students from 34 schools completed self-report surveys as sixth (n=5782), seventh (n=5065), and eighth graders (n=4940). Primary analyses were performed using Hierarchical Nonlinear Modeling. Over time, there were significant effects of baseline positive expectancies on each of the six measures of substance use. Baseline depressed mood predicted increases over time only for lifetime use of cigarettes and alcohol, and for 30-day alcohol use. Positive expectancies significantly moderated the effects of adolescent depressed mood only on lifetime marijuana use. Although depressed mood predicted substance use for half of our variables, our results suggest that positive expectancies are a more consistent predictor of adolescent substance use, and that they may moderate the effects of depressed mood on marijuana, but not cigarette or alcohol, use. Substance use prevention programs may benefit from addressing adolescents' perceptions about the positive consequences of drug use. PMID- 21306829 TI - Citalopram improves metabolic risk factors among high hostile adults: results of a placebo-controlled intervention. AB - Hostility is associated with a number of metabolic risk factors for cardiovascular disease, including waist-hip ratio, glucose, and triglycerides. Along with hostility, many of these measures have also been shown to be associated with reduced central serotonergic function. We have previously reported that a citalopram intervention was successful in reducing hostility by self-report assessment (Kamarck et al., 2009). Here we examine the effects of this serotonergic intervention on metabolic risk factors in the same sample. 159 healthy adults with elevated hostility scores were randomized to citalopram or placebo for a 2-month period. Citalopram favorably changed metabolic risk factors, including waist circumference (p=.003), glucose (p=.02), HDL cholesterol (p=.04), triglycerides (p=.03), insulin sensitivity (p=.045) and diastolic blood pressure by automated assessment (p=.0021). All of these metabolic changes were significantly mediated by treatment-related changes in body mass index (in most cases, p<.01). In addition, the changes in blood glucose were significantly mediated by treatment-related changes in hostility (p<.05). Mechanisms accounting for these associations remain to be explored. PMID- 21306831 TI - Neuro-chemical activation of brain reward meso-limbic circuitry is associated with relapse prevention and drug hunger: a hypothesis. AB - BACKGROUND: It is no surprise that it has taken over four decades to confirm and extend the crucial role of dopamine and related genes and gene deficits in the etiology of risk for drug dependence. Hundreds of studies, enabled by neuroscience neuroimaging and genetic advances, have been reported. While dopamine theories have been reported, confirmed, replicated and replicated again, changes have been slow to move from the bench to the bedside. Unlike penicillin used to target certain infections, addiction requires the consent, motivation and enthusiastic participation of the patient. Clearly, current treatment has not caught up with advances in the science. In-patient and out-patient treatment still relies on detoxification, abstinence and 12 step programs. Addiction is a chronic and relapsing disease. Addiction treatment can be reported as cures at 3 or 6 weeks, only to be clearly failures at 1 or 5 years. The logical standard of care should focus on detoxifying, stabilizing and returning the patient to the pre-loss of control or pre-addiction neurochemical state. METHOD: Pre-clinical and clinical data on neurochemistry and neurogenetics of Substance Use Disorder (SUD) as it relates to both relapse and drug hunger has been reviewed. RESULTS: We are proposing herein that efforts to physiologically integrate known neural mechanisms with other psychotherapeutic treatment options to combat relapse should be encouraged. It is well known that after prolonged abstinence, recovered addicts are particularly vulnerable to relapse. Individuals who use their drug of choice after abstinence experience a powerful euphoria that can quickly precipitate a full-blown relapse. While a biological explanation for this conundrum has remained elusive, we hypothesize that this clinically observed "supersensitivity" might be the result of pre-morbid or state genetic hypodopaminergic polymorphisms. HYPOTHESIS: We are proposing that recent studies have indicated that genetic, personality and environmental factors are predictors of drug use in adolescents. Exploration of various treatment approaches for the most part reveal poor outcomes in terms of relapse prevention and continued drug hunger. The authors are proposing a new paradigm shift in residential, non residential and aftercare involving the incorporation of genetic testing to identify risk alleles coupled with D2 receptor stimulation using neuroadatogen amino acid precursor enkephlinase--catecholamine-methyltransferase (COMT) inhibition therapy. A natural but therapeutic nutraceutical formulation potentially induces DA release could cause the induction of D2-directed mRNA and proliferation of D2 receptors in the human. We further hypothesize that this proliferation of D2 receptors in turn will induce the attenuation of drug-like craving behavior. Finally, pharmacological therapies have had limited success because these powerful agents have focused on maintenance or interference with drug euphoria rather than correcting or compensating for pre-morbid dopamine system deficits These concepts await further confirmation via required neuro imaging studies. PMID- 21306832 TI - Hemodynamic changes in the posterior cerebral circulation triggered by insufficient sympathetic innervation--cause of primary intracerebral hemorrhage? AB - Primary intracerebral hemorrhage (ICH) is caused by hypertensive disease of small penetrating blood vessels in the basal ganglia, brain stem and cerebellum. Those regions are supplied by arteries of the so-called posterior brain circulation with insufficient sympathetic innervation. We propose the following hypothesis: due to insufficient sympathetic innervation hemodynamic changes occur in the vascular bed of the posterior brain circulation serving as a key factor for arterial rupture. If autoregulation is insufficient to maintain normal cerebral blood flow, in abrupt rise in the blood pressure, the amount of blood is rising causing higher static pressure, and according to Laplace's law higher pressure and larger radius leads to higher wall tension and subsequent rupture of arterial wall previously weakened by prolonged hypertension. PMID- 21306833 TI - Intracranial hemangiopericytoma: Case study with cytogenetics and genome wide SNP A analysis. AB - The tumor entity of hemangiopericytoma is not universally recognized as a nosological entity by pathologists, and there is a trend toward reassigning it to other categories gradually. However, hemangiopericytomas occurring in the nervous system are included in the new WHO classification of brain tumors, and are distinguished from both meningioma and fibrous tumors. Since there are few genetic studies, we performed a comprehensive cytogenetic analysis of an infratentorial hemangiopericytoma in a 55-year-old female. It was originally classified as a grade II tumor but recurred as a grade III tumor with a proliferation index of 20%. Using trypsin-Giemsa staining (GTG-banding) and multicolor fluorescence in situ hybridization (M-FISH), we could confirm the loss of chromosomal material 10q, which has been previously described in hemangiopericytoma, and we identified de novo chromosomal aberrations on chromosome 8. Applying genome-wide high-density single nucleotide polymorphism array (SNP-A) analysis, we detected segments with loss or gain, as well as clonal deletions or regions suggestive of segmental uniparental disomy. These findings, together with the results of conventional histological and immunohistochemical characterization, provide additional evidence for the nosological separation of hemangiopericytoma in the central nervous system as a biologically different entity. PMID- 21306834 TI - Solitary osteochondroma of the trapezium: case report. AB - Osteochondroma of the carpal is rare. We found only 1 case of osteochondroma of the trapezium in the literature. We present a case of a 52-year-old woman with an osteochondroma of the left trapezium and trapeziometacarpal arthritis. PMID- 21306835 TI - Quantification of partial or complete A4 pulley release with FDP repair in cadaveric tendons. AB - PURPOSE: Repair of a lacerated flexor digitorum profundus (FDP) tendon underneath or just distal to the A4 pulley can be technically challenging, and success can be confounded by tendon triggering and scarring to the pulley. The purpose of this study was to quantify the effect of partial and complete A4 pulley release in the context of a lacerated and repaired FDP tendon just distal to the A4 pulley. METHODS: Tendon biomechanics were tested in 6 cadaveric hands secured to a rigid frame, permitting measurement of tendon excursion, tendon force, and finger range of motion. After control testing, each finger had laceration and repair of the FDP tendon at the distal margin of the A4 pulley using a 6-strand core suture technique and epitendinous repair. Testing was then repeated after the following interventions: (1) intact A4 pulley, (2) release of the distal half of the A4 pulley, (3) complete release of the A4 pulley, and (4) continued proximal release of the sheath to the distal edge of A2 (release of C2, A3, and C1 pulleys). Release of the pulleys was performed by incision; no tissue was removed from the specimens. RESULTS: From full extension to full flexion, average FDP tendon excursion for all intact digits was 37.9 +/- 1.5 mm, and tendon repair resulted in average tendon shortening of 1.6 +/- 0.4 mm. Flexion lag increased from <1 mm to >4 mm with venting of the A4 pulley, complete A4 release, and proximal sheath release, respectively. Compared to the intact state, repair of the tendon with an intact A4 pulley, release of half the A4 pulley, complete A4 release, and proximal sheath release resulted in percentage increases in work of flexion of 11.5 +/- 3.1%, 0.83 +/- 2.8%, 2.6 +/- 2.4%, and 3.25 +/- 2.2%, respectively. CONCLUSIONS: After FDP laceration and repair in the region of the A4 pulley, work of flexion did not increase by more than 3% from control conditions after partial or complete A4 pulley release, and work of flexion was significantly less than that achieved by performing a repair and leaving the A4 pulley intact. PMID- 21306836 TI - Deconstructing the architecture of alcohol abuse and dependence symptoms in a community sample of late adolescent and emerging adult women: an item response approach. AB - The objective of this study was to examine the underlying factorial architecture of lifetime DSM-IV alcohol use disorder (AUD) criteria in a population-based sample of adolescent and emerging adult female twins who had ever used alcohol (n=2832; aged 18-25 years), and to determine whether thresholds and factor loadings differed by age. Item response modeling was applied to DSM-IV AUD criteria. Compound criteria (e.g., persistent desire or unsuccessful attempts to quit or cut down) were included as separate items. Of the remaining 16 items, tolerance and use despite physical problems were the most and least commonly endorsed items, respectively. Underlying the items was a single factor representing liability to AUDs. Factor loadings ranged from 0.67 for blackouts to 0.90 for time spent using/recovering from effects. Some items assessing different DSM-IV criteria had very similar measurement characteristics, while others assessing the same criterion showed markedly different thresholds and factor loadings. Compared to that of women aged 21-25 years, the threshold for hazardous use was higher in women aged 18-20 years, but lower for used longer than intended and persistent desire to cut down. After accounting for threshold differences, no variations in discrimination across age groups were observed. In agreement with the extant literature, our findings indicate that the factorial structure of AUD is unidimensional, with no support for the abuse/dependence distinction. Individual components of compound criteria may differ in measurement properties; therefore pooling information from such divergent items will reduce information about the AUD construct. PMID- 21306837 TI - A pilot randomized clinical trial of two medication adherence and drug use interventions for HIV+ crack cocaine users. AB - BACKGROUND: Crack cocaine use undermines adherence to highly active antiretroviral therapy (HAART). This pilot randomized clinical trial tested the feasibility and efficacy of 2 interventions based on the Information-Motivation Behavioral Skill model to improve HAART adherence and reduce crack cocaine problems. METHODS: Participants were 54 adults with crack cocaine use and HIV with <90% HAART adherence. Most participants were African-American (82%) heterosexual (59%), and crack cocaine dependent (92%). Average adherence was 58% in the past 2 weeks. Average viral loads (VL) were detectable (logVL 2.97). The interventions included 6 sessions of Motivational Interviewing plus feedback and skills building (MI+), or Video information plus debriefing (Video+) over 8 weeks. Primary outcomes were adherence by 14-day timeline follow-back and Addiction Severity Index (ASI) Drug Composite Scores at 3 and 6 months. Repeated measure ANOVA assessed main effects of the interventions and interactions by condition. RESULTS: Significant increases in adherence and reductions in ASI Drug Composite Scores occurred in both conditions by 3 months and were maintained at 6 months, representing medium effect sizes. No between group differences were observed. No VL changes were observed in either group. Treatment credibility, retention, and satisfaction were high and not different by condition. CONCLUSIONS: A counseling and a video intervention both improved adherence and drug problems durably among people with crack cocaine use and poor adherence in this pilot study. The interventions should be tested further among drug users with poor adherence. Video interventions may be feasible and scalable for people with HIV and drug use. PMID- 21306839 TI - Care procedures for healthy term newborn in maternity ward: the "open" nursery. PMID- 21306838 TI - Psychoticism and neuroticism predict cocaine dependence and future cocaine use via different mechanisms. AB - BACKGROUND: Personality characteristics have been associated with cocaine use. However, little is known about the mechanisms through which personality could impact drug use. The present study investigated the cross-sectional and prospective relationships between personality dimensions (i.e., impulsivity, neuroticism) and problematic cocaine use. Reactivity to a pharmacological stressor as a potential mediator of the relationship between neuroticism and future cocaine use was also examined. METHODS: Participants were 53 cocaine dependent individuals and 47 non-dependent controls. Subjects completed the Eysenck Personality Questionnaire (EPQ) at baseline and were administered i.v. corticotrophin releasing hormone (CRH; 1 MUg/kg). Cocaine use in the 30 days following CRH administration was measured. RESULTS: Cocaine-dependent individuals had higher scores on the psychoticism (i.e., impulsivity, aggression; p=0.02) and neuroticism (p<0.01) scales of the EPQ than non-dependent controls. Cocaine dependent individuals also had a greater subjective stress response to CRH than controls (p<0.01). Cocaine-dependent individuals with elevated psychoticism used significantly more cocaine over the follow-up period (p<0.05), whereas individuals with elevated neuroticism trended towards using cocaine more frequently over the follow-up (p=0.07). Finally, there was a trend for an indirect effect of neuroticism on frequency of cocaine use through subjective reactivity to CRH. CONCLUSIONS: The findings extend past research on the association between personality and cocaine use, and suggest that motives for cocaine use may systematically vary across personality characteristics. Moreover, tailoring therapeutic interventions to individuals' personalities may be an area that warrants further investigation. PMID- 21306840 TI - Outcome of critically ill baby: nursing aspects about the stabilization at birth. PMID- 21306841 TI - Nurses' ethical problems in the care of extremely low birth weight infants. PMID- 21306842 TI - Long term effect of Ovum Pick-up in buffalo species. AB - The aim of this study was to evaluate the effect of an Ovum Pick-up (OPU) treatment carried out for 9 months in buffalo (Bubalus bubalis) species. Eight pluriparous non-lactating buffalo cows underwent OPU for 9 months. Recovered cumulus enclosed oocytes (COCs) were classified and COCs suitable for in vitro embryo production (IVEP) were in vitro matured (IVM), fertilized (IVF) and cultured (IVC) to the blastocyst (Bl) stage. Animals were monitored for a total period of 270 days, but at the summer solstice, follicular turnover decreased and at the 68-day of the trial, we decided to increase the OPU sampling interval from 3-4 to 7 days. It was therefore possible to distinguish two phases: a first phase (18 sessions), during which OPU was carried out twice weekly and a second phase (16 sessions) during which OPU sessions were performed weekly. This reduction did not modify the percentage of good quality COCs, while the incidence of grade D COCs decreased (P<0.01). Furthermore, embryo production was higher in the second phase, either if embryos were calculated on the total recovered COCs (8.3% vs. 21.4%; P<0.01) and on grade A+B COCs (13.0% vs. 32.1%; P<0.01), that supposedly should have given similar blastocyst yield. During the total period of the trial it was possible to distinguish a first period of 6 months (34 sessions) characterized by blastocyst production (0.36 blastocyst/buffalo/session), followed by an unproductive period of 3 months (12 sessions), during which embryos were not produced. During the first 6 months a higher (P<0.01) number of follicles (5.06 vs. 3.71), small follicles (3.38 vs. 2.07), total COCs (2.58 vs. 1.56) and good quality (A+B) COCs (1.51 vs. 0.94) per subject/session were recorded compared to the last 3 months. No Blastocyst were produced during the second period, even if the percentage of grade A+B COCs was similar to that recorded during the first period. In conclusion, buffalo cows submitted to repeated OPU sampling for a 9-month period, showed a decline of follicle recruitment and oocyte collection after the first two months of samplings. After 6-month of samplings, in spite of the quality grade of the collected oocytes, we found a drop in their developmental competence. PMID- 21306843 TI - Twice daily collection yields greater semen output and does not affect male libido in the ostrich. AB - The success of an artificial insemination program in ostriches is highly dependent on the yield of viable semen. We, therefore, tested how semen output is affected by three different collection frequencies: once every 2d (48h interval), daily (24h interval), and twice a day (6h interval). Ejaculates were collected from seven male ostriches (aged 2-4 years) for 10 consecutive days using the dummy female method. We assessed semen characteristics (sperm motility, volume, concentration, number of sperm per ejaculate and sperm viability) and male libido (the delay between the presentation of the dummy and ejaculation, and the willingness to mount the dummy). The total daily output of semen and the number of sperm were greater at the 6h collection interval than at the 24h or 48h interval while sperm motility and viability were not affected. At the 6h interval, the number of live normal sperm increased over the treatment period while the number of live abnormal sperm was reduced. Furthermore, the time that males took to mount the dummy and their willingness to copulate with the dummy were unaffected by collection frequency. Across males we observed great individual variation in both semen characteristics and libido suggesting there is the potential to increase the efficiency of semen collection by selecting superior males. These results indicate not only that two collections per day yield maximum semen output and may improve semen viability, but also that quantifying variation between males may help further increase semen collection efficiency. PMID- 21306844 TI - Improved gas chromatography-negative ion chemical ionization tandem mass spectrometric method for determination of 11-nor-Delta9-tetrahydrocannabinol-9 carboxylic acid in hair using mechanical pulverization and bead-assisted liquid liquid extraction. AB - A gas chromatography-negative ion chemical ionization tandem mass spectrometric (GC-NCI-MS/MS) method was developed and validated for the determination of 11-nor Delta(9)-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) in human hair. After decontamination, hair samples were weighed (25mg), mechanically pulverized with a bead mill, and incubated in 0.7 mL of 1.0M sodium hydroxide at 95 degrees C for 30 min. Bead-assisted liquid-liquid extraction was performed with n-hexane:ethyl acetate (9:1, v/v), a method developed in our laboratory. The extract was evaporated to dryness, derivatized with pentafluoropropanol and pentafluoropropionic anhydride, and analyzed by GC-MS/MS in the negative ion chemical ionization mode using methane as the reagent gas. The linear ranges were 0.05-10.0 pg/mg for THC-COOH with the coefficient of determination (r(2) = 0.9976). The intra-day and inter-day precisions were within 1.7 and 13.8%, respectively. The intra-day and inter-day accuracies were -4.8 to 10.0% and -3.9 to 3.8%, respectively. The limit of detection and quantification were 0.015 and 0.05 pg/mg, respectively. The recoveries were in the range of 79.4-87.1%. The results indicate that the proposed method is simple, rapid, accurate, and precise for determination of THC-COOH in hair. The method identified THC-COOH in hair specimens from suspected marijuana abusers. PMID- 21306845 TI - LC-MS-MS analysis of buprenorphine and norbuprenorphine in whole blood from suspected drug users. AB - A liquid chromatography tandem mass spectrometry method is described for the analysis of buprenorphine and norbuprenorphine in whole blood. Linearity was achieved between 0.2-5 ng/g for buprenorphine and 0.5-5 ng/g for norbuprenorphine. Stability studies on spiked whole blood and an authentic sample showed no degradation of buprenorphine- and norbuprenorphine-glucuronide to their respective aglycones. Buprenorphine and norbuprenorphine showed some degradation when stored at 4 degrees C for three weeks, but was stable when stored at -20 degrees C for 4 weeks. The method was applied to forensic cases of driving under the influence of drugs (DUID) and petty drug offences (PDO) during 2007-2009. Out of 2459 cases analyzed, 322 were positive for both buprenorphine and norbuprenorphine (13%), 219 for buprenorphine only (9%), and 12 for norbuprenorphine only (0.5%). The mean and median concentrations (N=322) were 1.7 and 1.0 ng/g, respectively, for buprenorphine and norbuprenorphine. The mean and median norbuprenorphine/buprenorphine ratios were 1.5 and 1.1, respectively. There was no significant difference in concentration ratios for DUID and PDO cases (p>0.05). We conclude that the described method for analysis of buprenorphine and norbuprenorphine in whole blood could be used to investigate use or misuse of buprenorphine but that many of the cases presented with very low concentrations of buprenorphine. We also conclude that analysis should be performed within two weeks unless samples are stored frozen prior to analysis. PMID- 21306846 TI - Simple clearing technique as species determination tool in blowfly larvae. AB - A simple clearing technique is presented by which species specific structures and organs of blowfly larvae can easily be visualized and displayed without any danger of mechanical damages or dislocations of delicate formations and without fixation of the object. PMID- 21306847 TI - Usefulness of US-CT 3D dual imaging for the planning and monitoring of hepatocellular carcinoma treatment using HIFU. AB - PURPOSE: We evaluated the safety and usefulness of high-intensity focused ultrasound (HIFU) assisted by ultrasound-computed tomography three-dimensional (US-CT 3D) dual imaging for the treatment of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: HIFU ablation was performed in 13 patients with small HCC (<=3 lesions, <=3 cm in diameter). The HIFU system (Chongqing Haifu Tech) was used under ultrasound guidance. By transferring the sagittal or axial plane of the 3D US and the CT volume data into the ZioM900, multiplanar reconstruction images were displayed in a manner resembling conventional monitor US to assist the HIFU treatment. RESULTS: Overall, 69% (9/13) of the patients in whom good visualization using B-mode sonography could not be obtained because of the influence of multi-reflections, rib shadows, and unclear tumor margins were successfully treated under the guidance of US-CT 3D dual imaging. In 5 of the 13 patients, multi-reflections were responsible for the poor visualization. In 2 cases, the tumor was poorly visualized because of a rib shadow. In one case, the margin of the tumor was too unclear to be detected using ultrasography. The 3D US images obtained as part of the US-CT 3D dual imaging had a high resolution and were useful for examining the area of HCC invasion and for determining the extent of the ablation area. The CT images, which are not influenced by bone shadows or multi-reflections, were useful for detecting the tumors and for visualizing the presence of the intestines in the sonication zone. HIFU treatments were successfully performed in all the patients with the assistance of US-CT 3D dual imaging. CONCLUSION: US-CT 3D dual imaging is useful for HIFU treatment for HCC, compensating for the occasionally poor visualization provided by US monitor. PMID- 21306848 TI - Application of sonoelastography: comparison of performance between mass and non mass lesion. AB - OBJECTIVES: The purpose of this study was to determine the performance of the conventional ultrasonography (US) and sonoelastography (SE) in three conditions of all lesions, confined to mass, and confined to non-mass lesion and to compare the performance of each modality between mass and non-mass lesion. MATERIALS AND METHODS: A total 364 patients with 375 lesions were evaluated with US and subsequently SE before performing US-guided biopsy. Two radiologists retrospectively analyzed conventional US and elasticity images by consensus. The US findings were classified as mass or non-mass lesion. With final pathology as reference, in each case of all lesions, masses, and non-mass lesions, areas under the ROC curves (Az) were calculated and compared for the two techniques. The comparison of Az values between the curves for US and SE, and between the curves for mass and non-mass lesion was performed. RESULTS: Among 375 lesions, 104 (28%) lesions were malignant and 271 (72%) lesions were benign. 36 (9.6%) of 375 lesions were classified as non-mass lesion at US. There were statistically significant difference of performance between US and SE in cases of all lesion (p=0.003) and mass (p=0.023). However, there was no statistically significant difference of performance in case of non-mass lesion (p=0.5). Comparisons of the Az values of US and SE between mass and non-mass lesions were not statistically significant (p=0.745, p=0.415, respectively). CONCLUSION: There was no statistically significant difference of performance of US and SE between mass and non-mass lesion. PMID- 21306849 TI - Imaging findings of liver resection using a bipolar radiofrequency electrosurgical device--initial observations. AB - OBJECTIVE: To assess contrast-enhanced US (CEUS), computed tomography (CT) and magnetic resonance (MR) imaging findings and serial changes of the treated area at follow-up in patients who underwent liver resection using a bipolar radiofrequency electrosurgical device. METHODS: Imaging findings of 27 patients with resected hepatocellular carcinomas (HCCs) (n=24) and metastases (n=3) (mean size: 2.6cm), were retrospectively evaluated. Two readers assessed: the (a) presence, (b) thickness, (c) shape and (d) echogenicity (CEUS)/attenuation (CT)/signal intensity (MR imaging) at coagulated site and the (e) presence of residual tumor of the bipolar radiofrequency electrosurgical device resection margin. RESULTS: Follow-up was performed with either CT (n=20) or MR imaging (n=7) and repeated in 16 patients with CT (n=7), MR imaging (n=4), or both techniques (n=5). Four patients also had a single CEUS examination. At first imaging follow-up a peripheral halo was depicted at resection site (100%). A fluid collection within the surgical area was found in 67% of patients. During the following imaging examinations a progressive involution of both findings was observed, respectively, in 81% and 62% of patients. Viable tissue was detected in three patients (11%). CONCLUSIONS: After liver resection with bipolar radiofrequency electrosurgical device successfully ablated tumor is demonstrated at imaging by an unenhancing partial linear peripheral halo, in most cases, surrounding a fluid collection reducing in size during follow-up. PMID- 21306850 TI - Application of CT perfusion imaging to the histological differentiation of adrenal gland tumors. AB - BACKGROUND: CT perfusion imaging has been used in diagnosis and classification of tumors widely and in assess tumor angiogenesis in some organs. However, there are few reports describing CT perfusion imaging of adrenal gland tumors. OBJECTIVE: This study aimed to evaluate the application of CT perfusion imaging in analysis of angiogenesis in adrenal tumors and in diagnosis of adrenal tumors. PATIENTS AND METHODS: Forty four patients with adrenal gland tumors (26 with adenomas and 18 with nonadenomas) were enrolled in this study. CT scan of adrenal glands was performed with the perfusion of non-ionic contrast medium Ultravist. The obtained images were processed with deconvolution algorithms-based perfusion software and then perfusion parameter maps and values (blood flow, blood volume, mean transit time, and permeability surface-area production) were generated and analyzed respectively. RESULTS: Univariate multivariate logistic regression indicated that blood volume (OR: 1.261, 95% CI: 1.056, 1.505, P=0.010) was associated with the likelihood of adrenal adenoma. Receiver operating characteristic analysis showed that the blood volume value of >=9.325 ml min(-1) 100 g(-1) predicted adrenal adenoma with sensitivity of 76.9% and specificity of 73.2%. In addition, permeability surface-area production in adenoma was higher than in non-adenoma (27.11+/-15.45 vs. 16.76+/-14.44 ml min(-1) 100 g(-1), P<0.05). The other parameters had no clear prognostic significance. CONCLUSIONS: CT perfusion imaging can quantitatively distinguish adrenal gland tumors with different histological characteristics. Especially, blood volume can be used in differentiating adrenal adenomas from nonadenomas. PMID- 21306851 TI - Computed tomography findings from patients with ARDS due to Influenza A (H1N1) virus-associated pneumonia. AB - PURPOSE: The purpose of this study was to retrospectively evaluate whether computed tomography (CT) findings have prognostic value for the prediction of mortality and severity of the clinical course in patients presenting with early stage of acute respiratory distress syndrome (ARDS) due to swine-origin influenza A (S-OIV). MATERIALS AND METHODS: Chest CT (16-/64-row multidetector CT) of 23 patients (of whom 9 patients died) were retrospectively reviewed by three independent blinded observers. The CT findings were graded on a 3-point scale (1: normal attenuation, 2: ground-glass attenuation, 3: consolidation). The extent of each abnormality was determined by visually estimating the percentage (to the nearest 10%) of the affected lung parenchyma in each zone and multiplied by the CT-score described above. RESULTS: All patients presented with a mixture of bilateral patchy consolidations and ground glass opacities. Spearman rank correlation in evaluation of the presence and extent of lung abnormalities by the three different observers was good (correlation coefficient, 0.876-0.922; p < 0.001). The overall CT-score in survivors (mean, 96.0 (+/- 26.2); range, 53-158) was significantly lower than that in non-survivors (mean, 116.2 (+/- 14.0); range, 101-139). ROC analysis revealed an area under curve of 0.79 (p = 0.021) for the CT score with an optimal cutoff value of a CT-score of 100 for prediction of survival, with a sensitivity of 100% and a specificity of 64% (accuracy, 78%). For this optimal cutoff, Kaplan-Meier estimator showed a significant difference for the survival ratio (p = 0.011). CONCLUSION: In patients with severe ARDS due to S-OIV-infection, the CT-score has a prognostic value in the prediction of mortality. PMID- 21306852 TI - MRI of the female pelvis: a possible pitfall in the differentiation of haemorrhagic vs. fatty lesions using fat saturated sequences with inversion recovery. AB - The use of fat-saturated techniques should be an integral part of the work-up of any T1-hyperintense structure in the female pelvis for tissue characterization and for differentiation of a fat-containing ovarian mature teratoma from a haemorrhagic lesion. Two cases with haematocolpos and haematometra are presented, respectively. The haemorrhagic content showed high signal both on T1- and T2 weighted images, whereas an unexpected signal decrease in the fat-saturated T2 weighted inversion-recovery sequence was encountered. This unspecific suppression of signal in tissues with similar T1 relaxation times as fat can lead to a diagnostic pitfall both in T1- and T2-weighted STIR pulse sequences. Furthermore, a loss of signal on T2-weighting may also be due to the phenomenon of "T2 shading" in T1-bright ovarian endometrioma. Therefore, the fat-specific spectral fat-saturation of T1-weighted images is strongly recommended for tissue characterization in gynaecological disease. PMID- 21306853 TI - Pediatric rhabdomyosarcoma at presentation: can cross-sectional imaging findings predict pathologic tumor subtype? AB - OBJECTIVE: The purpose of the study is to determine whether there are cross sectional imaging features of pediatric rhabdomyosarcoma that are specific to the different pathologic subtypes of the tumor. MATERIALS AND METHODS: Medical records of 14 pediatric patients who were diagnosed with rhabdomyosarcoma were reviewed retrospectively. Patient demographics, including age and sex, as well as final pathologic report were obtained. The initial CT, MRI, or both obtained at presentation, prior to the diagnosis being established, were reviewed by two radiologists. We recorded tumor features including site, size, margins, local extension, and presence of metastases. Presence of calcification, hemorrhage, or necrosis as well as attenuation and heterogeneity of the tumor were also recorded. RESULTS: Ten of our fourteen patients were formally diagnosed with the embryonal subtype of rhabdomyosarcoma, while three were found to have the alveolar subtype, and one subtype was poorly differentiated. There was no significant difference in the attenuation and in the heterogeneity of the tumor between the embryonal and the alveolar subtype on CT. CONCLUSION: Imaging features at presentation, such as attenuation and heterogeneity, could not correlate to the pathologic subtype of pediatric rhabdomyosarcoma. PMID- 21306854 TI - Symbiovars in rhizobia reflect bacterial adaptation to legumes. AB - Legume specificity is encoded in rhizobial genetic elements that may be transferred among species and genera. Dissemination (by lateral transfer) of gene assemblies dictating host range accounts for the existence of the same biological variant (biovar) in distinct microbiological species. Different alternative biovars may exist in a single species expanding their adaptation to different niches (legume nodules). A review of all reported biovars is presented. Instead of the term biovar, symbiotic variant (symbiovar) is proposed as a parallel term to pathovar in pathogenic bacteria. Symbiovars should be determined based on the symbiotic capabilities in plant hosts, distinguished by the differences in host range and supported by symbiotic gene sequence information. PMID- 21306855 TI - Research in communication skills training translated into practice in a large organization: a proactive use of the RE-AIM framework. AB - OBJECTIVE: To describe how a specific communication course for health professionals has been evaluated and implemented in clinical practice and how it will be transferred and evaluated at the entire hospital. METHODS: The different phases of the research process from generating the hypothesis to implementing the results are described and exemplified by means of published studies and a study under planning. RE-AIM, an acronym for Reach, Efficacy/Effectiveness, Adoption, Implementation, and Maintenance, is used to describe the process. RESULTS: In descriptive studies we identified a need for improving the communication with patients. By evaluating the efficacy and effectiveness of communication skills training we showed that the courses could improve clinicians' self-efficacy in specific communication tasks. After all clinicians had participated in the communication course the proportion of satisfied parents increased significantly. Based on these experiences a program for implementing the communication course at the entire hospital is being planned. CONCLUSION: To succeed in translating the research results into practice, long-term commitment is needed in order to create a conducive climate for the implementation. PRACTICE IMPLICATIONS: This focused and goal-oriented approach may inspire other researchers when planning, conducting, and evaluating their research. PMID- 21306856 TI - An illustrated leaflet containing antiretroviral information targeted for low literate readers: development and evaluation. AB - OBJECTIVE: To apply a dual visual/textual modal approach in developing and evaluating a medicine information leaflet with pictograms suitable for low literate HIV/AIDS patients. To identify and recommend best practices in this type of information design. METHODS: A simple leaflet incorporating pictograms was designed for an antiretroviral regimen. Cognitive testing for understanding was conducted in 39 low-literate, South African, antiretroviral-naive adults. Participants were required to locate and explain the information, and were questioned on their opinion of leaflet layout and contents. RESULTS: Average understanding of the leaflet was 60%. Basic medication information was the best understood. An overall lack of knowledge of HIV/AIDS and its core concepts was found. Only half the participants considered this simple leaflet "easy" to read. All endorsed the inclusion of pictograms. CONCLUSION: This testing method used in ARV-naive individuals was invaluable in identifying areas needing modification before its use in patients. Text associated with pictograms was more noticeable and better understood, but only if they were closely juxtaposed. PRACTICE IMPLICATIONS: Leaflet design should consider culture and literacy skills, be informed by learning theory and design principles, include visuals to enhance appeal and improve understanding, and involve end-users. Verbal counseling should accompany written information. PMID- 21306857 TI - An examination into audience targeting and the use of storytelling or statistical evidence on breast cancer websites. AB - OBJECTIVE: This research sought to address the presence of information targeting low literacy, racially diverse, non-English speaking, and age diverse audiences on breast cancer websites. In addition, this study documented the utilization of evidence strategies, either statistics or storytelling, for these audiences. METHODS: This research examined these relationships on 157 breast cancer websites through content analysis. RESULTS: Nearly half of websites did not contain any of the elements targeting diverse literacy, racial/ethnic, language, and age audiences. Websites with multiple languages were more likely than monolingual websites to use statistics, and websites with low literacy sections were less likely than others to do so. Websites with ethnic or racial diversity and age diversity were more likely than other websites to use first person storytelling about breast cancer. CONCLUSION: Current breast cancer websites demonstrate promising use of targeting specific audiences and employing evidence strategies prescribed as effective by past research, however there is room for improvement. PRACTICE IMPLICATIONS: Tip sheets for incorporating audience targeting, readability, and storytelling should be created for health organizations to use in the process of developing their websites, as these constructs were found only sparingly on the assessed sites. PMID- 21306858 TI - The "cash or care" conflict in general practice--a cautionary tale with methodological reflections. PMID- 21306859 TI - Navigating patient-centered goal setting in inpatient stroke rehabilitation: how clinicians control the process to meet perceived professional responsibilities. AB - OBJECTIVE: Patient-centered goal setting, while central to contemporary rehabilitation, has been associated with growing uncertainty regarding its application in clinical practice. We aimed to examine the application of goal setting in inpatient stroke rehabilitation. METHODS: Data collected from 44 participants (nine patients, seven family members, 28 health professionals), using multiple data sources (interviews, recorded clinical sessions, team meetings, participant-observation, and clinical documentation), were analyzed using constant comparative methods. RESULTS: Certain goals (characterized by short timeframes, conservative estimation of outcomes, and physical function) were privileged over others. Involvement of patients and family in goal setting resulted in interactional dilemmas when their objectives, skills and perceived capacity did not align with privileged goals. When alignment did occur, greater patient involvement still did not appear to influence clinical reasoning. CONCLUSION: This study raises questions about how 'patient-centered' current goal setting practices are and whether a 'patient-centered' approach is even possible in inpatient stroke rehabilitation when considering predominant funding and health system models. PRACTICE IMPLICATIONS: For 'patient-centered' goal setting to be more than rhetorical, clinicians need to examine the values they attribute to certain types of goals, the influence of organizational drivers on goal selection, and how goals are actually used to influence clinical practice. PMID- 21306860 TI - Management of lobular carcinoma in-situ and atypical lobular hyperplasia of the breast--a review. AB - OBJECTIVES: To determine the incidence of malignancy (invasive carcinoma or DCIS) in patients diagnosed with lobular neoplasia (B3) on core needle biopsy (CNB) of breast lesions by reviewing the published literature. METHODS: Medline, Embase, OVID-database and reference lists were searched to identify and review all English-language articles addressing the management of LN diagnosed on CNB. Studies on mixed breast pathologies were excluded. RESULTS: Of 1229 LN diagnosed on CNB, 789 (64%) underwent surgical excision. 211 (27%) of excisions contained either DCIS or invasive disease. 280 of the excision specimens were classified as ALH, 241 as LCIS, 22 as pleomorphic LCIS and 246 unspecified LN on the original CNB. After surgical excision, 19% of the ALH cases, 32% of the LCIS cases and 41% of the PLCIS cases, contained malignancy. 29% of the unspecified LNs were upgraded to malignancy. The higher incidence of malignancy within excision specimens for LCIS and PLCIS compared to ALH was significant (P < 0.04, <0.003 respectively). CONCLUSION: There is a significant underestimation of malignancy in patients diagnosed with breast LN on CNB. 27% cases of CNB-diagnosed LN were found to contain malignancy following surgical excision. All patients diagnosed with LN on CNB should be considered for surgical excision biopsy. PMID- 21306861 TI - NTPDase activity in human lymphocytes is not affected by therapeutic doses of anti-HIV drugs. AB - NTPDase (EC 3.6.1.5) is an enzyme that hydrolyzes extracellular nucleoside tri- and/or diphoshates forming AMP that can serve as a substrate for an ecto-5' nucleotidase (EC 3.1.3.5) with liberation of adenosine, a modulator of vascular tone and inhibitor of platelet aggregation. These enzymes also occur in lymphocytes playing an important role in immune function. In this study, it was investigated if anti-HIV therapy could affect NTPDase activity in human lymphocytes. Samples of lymphocytes were incubated with different concentrations of anti-HIV drugs and NTPDase activity was determined by colorimetric assay with quantification of inorganic phosphate released. There is not significant difference of NTPDase activity among samples with therapeutic doses of anti-HIV drugs tested when compared with controls. NTPDase activity in peripheral human lymphocytes is not altered by anti-HIV therapy. PMID- 21306862 TI - Cutaneous nerve transection for the management of intractable upper extremity pain caused by invasive squamous cell carcinoma. AB - A recurrent clinical dilemma in the management of patients with painful metastatic lesions is achieving a balance between effective analgesic therapies versus intolerable side effects, in particular altered mental status. We present the case of an immunosuppressed patient post-lung transplant who was suffering from intractable pain caused by widely metastatic squamous cell carcinoma. The patient's progressive, excruciating neuropathic pain was localized to the area of the left wrist and forearm. Additionally, the patient complained of moderate pain at sites of tumor involvement on her right arm and scalp. Attempts to adequately manage her left upper extremity pain included a combination of pharmacologic treatments intended to treat neuropathic pain (gabapentin, SNRI, ketamine, opioids) and focused regional analgesia (infraclavicular infusion of local anesthetic). However, the patient developed intolerable side effects including altered mental status and delirium associated with the systemic agents and suboptimal control with the infraclavicular infusion. Given that the most severe pain was well localized, we undertook a diagnostic block of the cutaneous nerves of the left forearm. As this intervention significantly reduced her pain, we subsequently performed neurectomies to the left superficial radial nerve, lateral cutaneous nerve of the forearm and the posterior cutaneous nerve of the forearm. This resulted in immediate and continued relief of her left upper extremity pain without an altered mental status. Residual focal pain from lesions over her right arm and scalp was successfully managed with daily topical applications of lidocaine and capsaicin cream. Successful pain control continued until the patient's death five months later. PMID- 21306863 TI - The analgesic effect of magnetic acupressure in cancer patients undergoing bone marrow aspiration and biopsy: a randomized, blinded, controlled trial. AB - CONTEXT: Bone marrow aspiration and biopsy (BMAB) is a frequently performed and painful procedure. OBJECTIVES: To evaluate the efficacy of magnetic acupressure in reducing pain in cancer patients undergoing BMAB. METHODS: Cancer patients without previous acupuncture or acupressure experience were stratified by the number of prior BMAB and randomized to having magnetic acupressure delivered to either the large intestine 4 (LI4) acupoint or a sham site. The primary study endpoint was the patient's pain intensity rating during the procedure using a visual analogue scale (VAS). RESULTS: Seventy-seven eligible patients received magnetic acupressure: 37 were randomized to treatment at the LI4 site arm and 40 at the designated sham site arm. There was no significant difference between the median pain scores of patients treated at the LI4 site and the sham site (P=0.87). However, severe pain (VAS >= 7) was reported in only one patient (2.7%) treated at the LI4 site compared with eight patients (20%) at the sham site (P=0.03). No patients experienced significant magnetic acupressure-related toxicities. CONCLUSION: Magnetic acupressure at the LI4 acupoint requires minimal training and expense and is well tolerated. Although its use did not significantly reduce median pain scores in patients undergoing BMAB, it does appear to reduce the proportion of patients with severe pain associated with this invasive procedure. PMID- 21306864 TI - Association between self-reported sleep disturbance and other symptoms in patients with advanced cancer. AB - CONTEXT: Sleep disturbance (SD) is a significant source of distress for patients with cancer. Studies of patients with advanced cancer receiving palliative care to identify symptoms associated with the severity of SD are limited. OBJECTIVES: In this study, we sought to identify the symptoms measured by the Edmonton Symptom Assessment Scale (ESAS) that are associated with SD, as measured by the Pittsburgh Sleep Quality Index (PSQI). Secondary aims of the study were to determine the association between occurrences of SD with occurrences of other symptoms and screening performance of the ESAS-Sleep item against the PSQI. METHODS: We reviewed the completed ESAS and PSQI assessments of 101 patients with advanced cancer who were receiving palliative care and had been admitted to prospective clinical trials previously initiated by us. Patients with a PSQI score of >= 5 were considered to have an SD. The frequency and severity of the ESAS symptoms items, their correlation with each other, the PSQI score, and the screening performance of the ESAS-Sleep item were calculated. RESULTS: The median age of patients was 60 years. Most were white non-Hispanic (73%), had lung or breast cancer (41%), and were diagnosed with SD (85%). The PSQI score was correlated with the ESAS items of pain (r=0.27, P=0.006), dyspnea (r=0.25, P<0.001), well-being (r=0.35, P<0.0001), and sleep (r=0.44, P<0.0001). Compared with patients without SD, those with SD were more likely to report pain (P=0.0132), depression (P=0.019), anxiety (P=0.01), and a poorer sense of well being (P=0.035). An ESAS-Sleep item cutoff score of >= 3 (of 10) resulted in a sensitivity of 74% and a specificity of 73%. CONCLUSION: SD is associated with increased frequency of pain, depression, anxiety, and a worse sense of well being. These four symptoms should be assessed in all patients with advanced cancer with a complaint of SD. The ideal cutoff point of the ESAS-Sleep item for screening for SD is a score of >= 3. More research is needed to better characterize this frequent and distressing syndrome. PMID- 21306865 TI - Development and initial validation of the Three-Levels-of-Needs Questionnaire for self-assessment of palliative needs in patients with cancer. AB - CONTEXT: To improve palliative care, it is important that questionnaires accurately assess the needs of the patients. No questionnaire existed that combined three different and important approaches to needs assessment. We developed such a questionnaire, called the Three-Levels-of-Needs Questionnaire (3LNQ), based on literature searches. The 3LNQ measures 12 important needs with three different approaches when used as a supplement to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ C30): problem intensity, problem burden, and felt need. OBJECTIVES: To investigate the initial validity of the 3LNQ. METHODS: We used a relatively new method that investigates whether the questionnaire has the same meaning for the patients as for the researchers. To do this, 74 patients with advanced cancer filled out the questionnaire and participated in an open-ended interview. The patients' responses to the questionnaire before the interview were compared against the researchers' responses based on the interviews. Items showing substantial agreement were accepted as valid without further analysis. For the remaining items, reasons for disagreements were analyzed qualitatively. RESULTS: All items on problem intensity, eight of 12 items on problem burden, and three of 12 items on felt need were accepted as valid because of high agreement. Analysis of the qualitative data concerning the remaining items showed that most disagreements did not indicate problems with the patients' self-assessment. Instead, different causes for disagreements were elucidated, but these did not interfere with validity. CONCLUSION: The 3LNQ appears to measure palliative needs comprehensively, and this initial validation showed satisfactory results. The analysis gave important insights into the patients' perceptions of their own situations, into their expectations of the health care system, and into the complexity of needs assessment. PMID- 21306866 TI - The measurement of spirituality in palliative care and the content of tools validated cross-culturally: a systematic review. AB - CONTEXT: Despite the need to assess spiritual outcomes in palliative care, little is known about the properties of the tools currently used to do so. In addition, measures of spirituality have been criticized in the literature for cultural bias, and it is unclear which tools have been validated cross-culturally. OBJECTIVES: This systematic review aimed to identify and categorize spiritual outcome measures validated in advanced cancer, human immunodeficiency virus (HIV), or palliative care populations; to assess the tools' cross-cultural applicability; and for those measures validated cross-culturally, to determine and categorize the concepts used to measure spirituality. METHODS: Eight databases were searched to identify relevant validation and research studies. An extensive search strategy included search terms in three categories: palliative care, spirituality, and outcome measurement. Tools were evaluated according to two criteria: 1) validation in advanced cancer, HIV, or palliative care and 2) validation in an ethnically diverse context. Tools that met Criterion 1 were categorized by type; tools that also met Criterion 2 were subjected to content analysis to identify and categorize the spiritual concepts they use. RESULTS: One hundred ninety-one articles were identified, yielding 85 tools. Fifty different tools had been reported in research studies; however, 30 of these had not been validated in palliative care populations. Thirty-eight tools met Criterion 1: general multidimensional measures (n=21), functional measures (n=11), and substantive measures (n=6). Nine measures met Criterion 2; these used spiritual concepts relating to six themes: Beliefs, practices, and experiences; Relationships; Spiritual resources; Outlook on life/self; Outlook on death/dying; and Indicators of spiritual well-being. A conceptual model of spirituality is presented on the basis of the content analysis. Recommendations include consideration of both the clinical and cultural population in which spiritual instruments have been validated when selecting an appropriate measure for research purposes. Areas in need of further research are identified. CONCLUSION: The nine tools identified in this review are those that have currently been validated in cross-cultural palliative care populations and, subject to appraisal of their psychometric properties, may be suitable for cross-cultural research. PMID- 21306867 TI - Catheter-directed thrombolysis for acute iliofemoral deep venous thrombosis. AB - Patients with acute iliofemoral deep venous thrombosis often experience severe postthrombotic complications that result from venous obstruction and valve incompetence. Conventional anticoagulation prevents thrombus extension, fatal pulmonary embolism, and recurrence of the deep venous thrombosis, but it can hardly minimize the postthrombotic complications. Whether early thrombus removal significantly reduces the postthrombotic morbidity is an important question related to the treatment of these patients. This article will chiefly introduce rationale for and evidence supporting early thrombus removal for acute iliofemoral deep venous thrombosis, and the development and current status of catheter-directed thrombolysis and adjunctive percutaneous mechanical thrombectomy or pharmacomechanical thrombolysis, which are usually the first line of therapy for early removal of an acute thrombus in the proximal veins of the leg. In addition, we will briefly introduce the development of new pharmacologic agents. PMID- 21306868 TI - Visual feedback of the non-moving limb improves active joint-position sense of the impaired limb in Spastic Hemiparetic Cerebral Palsy. AB - This study examined the active joint-position sense in children with Spastic Hemiparetic Cerebral Palsy (SHCP) and the effect of static visual feedback and static mirror visual feedback, of the non-moving limb, on the joint-position sense. Participants were asked to match the position of one upper limb with that of the contralateral limb. The task was performed in three visual conditions: without visual feedback (no vision); with visual feedback of the non-moving limb (screen); and with visual feedback of the non-moving limb and its mirror reflection (mirror). In addition to the proprioceptive measure, a functional test [Quality of Upper Extremity Skills Test (QUEST)] was performed and the amount of spasticity was determined in order to examine their relation with proprioceptive ability. The accuracy of matching was significantly influenced by the distance that had to be covered by the matching limb; a larger distance resulted in a lower matching accuracy. Moreover it was demonstrated that static (mirror) visual feedback improved the matching accuracy. A clear relation between functionality, as measured by the QUEST, and active joint-position sense was not found. This might be explained by the availability of visual information during the performance of the QUEST. It is concluded that static visual feedback improves matching accuracy in children with SHCP and that the initial distance between the limbs is an influential factor which has to be taken into account when measuring joint-position sense. PMID- 21306869 TI - The effects of muscle hypotonia and weakness on balance: a study on Prader-Willi and Ehlers-Danlos syndrome patients. AB - Prader-Willi syndrome (PWS) and Ehlers-Danlos syndrome (EDS) are two different genetical disorders both characterized, among other features, by muscular hypotonia. Postural control seems to be impaired in both conditions. The aim of the present study was to quantitatively compare postural control in adult PWS and EDS using stabilometric platform to unveil possible common determinants of impaired balance. We enrolled 11 PWS and 21 EDS adult patients and 20 age-matched controls. They were instructed to maintain an upright standing position for 30s with open eyes (OEs) focusing on a 6 cm black circle positioned at a distance of 1.5m. Both PWS and EDS patients were characterized by higher RANGEML, RANGEAP and trajectory length of CoP values as compared to CG. No statistically differences were found between PWS and EDS in terms of any of these parameters. The results demonstrated that both PWS and EDS are characterized by a severe postural instability. Muscle hypotonia and weakness may account for reduced balance capacity. Quantitative characterization of instability is important to identify, develop and enhance rehabilitation interventions. PMID- 21306870 TI - Graded motor imagery. AB - New information regarding cortical changes in patients with chronic pain has prompted a reevaluation of the typical "bottom up" treatment for pain, which focuses on peripheral nociceptive stimuli. More recently, increasing considerations for chronic pain are focused from the "top down" cortical central processing perspective. Graded motor imagery (GMI) is one treatment technique from the "top down" paradigm designed to treat chronic pain. This technique attempts to sequentially normalize central processing to remediate chronic pain. This article briefly summarizes the basic components of GMI, targeting complex regional pain in the upper limb, and describes a case where this method was successfully integrated. The initial research and clinical experience is promising and indicates that patients with chronic pain may benefit from using GMI to "retrain the brain." PMID- 21306871 TI - Muscle activation during hand dexterity tasks in women with hand osteoarthritis and control subjects. AB - STUDY DESIGN: Descriptive cross-sectional study. INTRODUCTION: Hand osteoarthritis (OA) is a condition that results in hand pain and disability. It is important to understand how muscle function impairments contribute to impaired dexterity. PURPOSE OF THE STUDY: To compare muscle activation in women with and without hand OA and determine if the activation relates to measures of impairment and disability. METHODS: Electromyography (EMG) was recorded from four muscles of the hand/forearm while subjects threaded (assembly) and unthreaded (disassembly) a small bolt. The groups were compared on the integrated EMG (IEMG) of four muscles using two-way repeated-measures analyses of covariance for the assembly and disassembly tasks. RESULTS: No differences were found in muscle activation between groups when IEMG values were normalized by time (p>0.05). CONCLUSIONS: Patients with OA have some indicators of altered muscle function. It is unclear whether these are adaptive or predisposing changes. When controlling for the time to perform a task, there were no significant IEMG differences between women with hand OA and control subjects. LEVEL OF EVIDENCE: 2b. PMID- 21306872 TI - The role of science and psychology in optimizing care of hand illness. PMID- 21306873 TI - Static-progressive splinting in under 25 minutes and 25 dollars. AB - Wrist stiffness can occur after injury to the wrist and surrounding structures. Frequently hand therapists treat this stiffness with static-progressive splinting techniques in an attempt to lengthen shortened tissues through tissue growth and collagen reorganization. The hand therapist's goal is to fabricate a splint that effectively increases range of motion in a timely and cost-effective manner. Through creative images, these authors illustrate their fabrication of a static progressive wrist extension and/or flexion splint that is cost effective and can be fabricated in 22 minutes. PMID- 21306874 TI - Cost-effectiveness of pediatric epilepsy surgery compared to medical treatment in children with intractable epilepsy. AB - PURPOSE: Due to differences in epilepsy types and surgery, economic evaluations of epilepsy treatment in adults cannot be extrapolated to children. We evaluated the cost-effectiveness of epilepsy surgery compared to medical treatment in children with intractable epilepsy. METHOD: Decision tree analysis was used to evaluate the cost-effectiveness of surgery relative to medical management. Fifteen patients had surgery and 15 had medical treatment. Cost data included inpatient and outpatient costs for the period April 2007 to September 2009, physician fee, and medication costs. Outcome measure was percentage seizure reduction at one-year follow-up. Incremental cost-effectiveness ratio (ICER) was assessed. Sensitivity analysis was performed for different probabilities of surgical and medical treatment outcomes and costs, and surgical mortality or morbidity. RESULTS: More patients managed surgically experienced Engel class I and II outcomes compared to medical treatment at one-year follow-up. Base-case analysis yielded an ICER of $369 per patient for each percentage reduction in seizures for the surgery group relative to medical group. Sensitivity analysis showed robustness for the different probabilities tested. CONCLUSION: Surgical treatment resulted in greater reduction in seizure frequency compared to medical therapy and was a cost-effective treatment option in children with intractable epilepsy who were evaluated for epilepsy surgery and subsequently underwent surgery compared to continuing medical therapy. However, larger sample size and long-term follow-up are needed to validate these findings. PMID- 21306875 TI - Model membrane approaches to determine the role of calcium for the antimicrobial activity of friulimicin. AB - Friulimicin is a cyclic lipopeptide antibiotic, currently in clinical development, that possesses excellent activity against Gram-positive bacteria, including multiresistant strains. A recent study on the mode of action of friulimicin reported on the interference with bacterial cell wall biosynthesis via a calcium-dependent complexing of the bactoprenol phosphate carrier C55-P. The calcium dependency of this non-common targeted activity remains to be elucidated. In the present model membrane approach, the role of calcium for friulimicin targeting to C55-P was investigated by biosensor-based detection of binding affinities. The findings were supplemented by atomic force microscopy (AFM) and circular dichroism (CD) spectroscopy. Comparing the calcium salt of friulimicin with the calcium-free peptide, calcium appeared to be essential for friulimicin interaction with DOPC model membranes. The binding affinity was even higher in the presence of 0.1 mol% C55-P (0.21 MUM vs. 1.22 MUM), confirming the targeted mode of action. Binding experiments with supplemented calcium salts suggest (i) the phosphate group as the essential moiety of C55-P, referring to a bridging function of calcium between the negatively charged friulimicin and C55 P, and (ii) a structural effect of calcium shifting the peptide into a suitable binding conformation (CD spectra). AFM images confirmed that calcium has no, or only a minor, effect on the aggregate formation of friulimicin. These data shed new light on the mechanisms of antibacterial activity of friulimicin. PMID- 21306876 TI - The burden of mental disorders in primary care. AB - OBJECTIVES: To describe and compare the prevalence of mental disorders across primary care populations, and estimate their impact on quality of life. METHODS: Cross-sectional multilevel analysis of a systematic sample of 2539 attendees to eight primary care centres in different regions of Spain, assessed with the WHO Composite International Diagnostic Interview (CIDI 1.1), the Short Form Health Survey (SF-36) quality of life questionnaire and the SF-6D utility index. RESULTS: The 12-month prevalence of any mental disorder was 23% (95% confidence interval: 21-24%), 10% had mood, 9% anxiety, 5% organic, 4% somatoform, and 1% alcohol use disorders, with a significant between-centre variability (P<0.001). People with mental disorders had one standard deviation lower mental quality of life than the general population. We estimated that 1831 quality-adjusted life years (QALYs) are lost annually per 100,000 patients due to mental disorders, without considering mortality. Mood disorders have the worst impact with an annual loss of 1124 QALYs per 100,000 patients, excluding mortality (95% confidence interval: 912-1351). CONCLUSIONS: Prevalence rates were similar to those obtained in international studies using the same diagnostic instrument and, given the significant between-centre variability found, it is recommended that mental health statistics be considered at small area level. Mental disorders, and especially mood disorders, are associated with very poor quality of life and higher scores on disability indexes than other common chronic conditions. PMID- 21306877 TI - Chronic vagus nerve stimulation for treatment-resistant depression increases regional cerebral blood flow in the dorsolateral prefrontal cortex. AB - The purpose of the present study was to assess the effects of vagus nerve stimulation (VNS) therapy on regional cerebral blood flow (rCBF) in depressed patients. Regional cerebral blood flow (rCBF) was assessed by [(99m)Tc]-HMPAO single photon emission computed tomography (SPECT) before and after 10weeks of VNS in patients participating in an open, uncontrolled European multi-center study investigating efficacy and safety of VNS. Patients suffered from major depression, with a baseline score of>=20 on the 24-item Hamilton Depression Rating Scale (HDRS) and had been unsuccessfully treated with at least two adequately prescribed antidepressant drugs. Data of 15 patients could be analyzed using SPM 2. After 10weeks of VNS (20Hz, 500MUs pulse width, stimulation during 30s every 5min at the maximal comfortable level) rCBF was increased in the left dorsolateral/ventrolateral prefrontal cortex (Brodmann areas 46 and 47) and decreased in the right posterior cingulate area, the lingual gyrus and the left insula. Our findings are in line with earlier results which showed that VNS increases rCBF in the left dorsolateral prefrontal cortex. The modulation of the activity in this region could be associated with the antidepressant efficacy of VNS. PMID- 21306878 TI - Temperature-responsive ionic-crosslinked polymeric nanocapsules via 'self templating' approach. AB - The temperature-responsive ionic-crosslinked polymeric nanocapsules (TRICNs) were fabricated via the 'self-templating' approach from the poly(tert-butyl acrylate co-N-isopropylacrylamide-co-acrylic acid) (poly(tBA-co-NIPAm-co-AA)) terpolymer nanoparticles prepared via the emulsifier-free emulsion polymerization. After the surface carboxyl groups of the terpolymer nanoparticles were crosslinked with calcium ions, the TRICNs were achieved after the cores of the shell-crosslinked nanoparticles had been etched by being dissolved with acetone. Transmission electron microscope (TEM) showed the particle size of the individual nanocapsules was about 200 nm with the inner diameter of about 140 nm. The lower critical solution temperature (LCST) of the TRICNs was found to be about 31 degrees C from the dynamic light scattering (DLS) analysis. Furthermore, the nanocapsules could disintegrate in acidic media while they were stable in the neutral or alkaline media. PMID- 21306879 TI - Exploring the binding mechanism of dihydropyrimidinones to human serum albumin: spectroscopic and molecular modeling techniques. AB - The binding mechanism of molecular interaction between 5-(ethoxycarbonyl)-6 methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one (a dihydropyrimidinones derivative, EMPD) and human serum albumin (HSA) was studied using spectroscopic methods and modeling technique. The quenching mechanism was investigated in terms of the binding constants and the basic thermodynamic parameters. The results of spectroscopic measurements suggested that EMPD have a strong ability to quench the intrinsic fluorescence of HSA through static quenching procedure. The drug protein complex was stabilized by hydrophobic forces and hydrogen bonding as indicated from the thermodynamic parameters and synchronous fluorescence spectra, which was consistent with the results of molecular docking and accessible surface area calculation. Competitive experiments indicated that a displacement of warfarin by EMPD, which revealed that the binding site of EMPD to HSA was located at the subdomains IIA. The distance between the donor and the acceptor was 4.85nm as estimated according to Forster's theory of non-radiation energy transfer. The effect of metal ions on the binding constants was also investigated. The results indicated that the binding constants between EMPD and HSA increased in the presence of common metal ions. PMID- 21306880 TI - [Neonatal molding for minor deformities of auricular cartilage: a simple method]. AB - Non-surgical correction of minor ear deformities by external splinting during neonatal age is a well-known, effective technique, but not frequently used in France. We would like to popularize an established, simple method that uses cheap, available means (a wire, adhesive strips and a silicone probe). It can be performed by parents, paediatricians and nurses. Spreading this method would allow early onset of treatment and better clinical results. On the long run, it would have a certain economic aftermath on national health insurance by reducing the number of surgical procedures for deformed ears. PMID- 21306881 TI - Stereotactic body radiotherapy. Guidelines for commissioners, providers and clinicians: a national report. PMID- 21306882 TI - WITHDRAWN: Recent Advances in Angiopoietin Biology in Cancer - A Review. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 21306883 TI - Reversal of multidrug resistance in human breast cancer cells by Curcuma wenyujin and Chrysanthemum indicum. AB - The emergence of multidrug resistance (MDR) is a big challenge to cancer chemotherapy. Plant-derived agents have great potential to prevent onset or delay progression of the carcinogenic process, and enhance the efficacy of mainstream antitumor agents. In this study, fractionated extracts of Curcuma wenyujin and Chrysanthemum indicum were tested for their potential to modulate the MDR phenotype and function of P-gp in MCF-7/ADR and A549/Taxol cells in vitro. Fractions C. wenyujin C10, E10 from Curcuma wenyujin, and C. indicum E10 from Chrysanthemum indicum, exhibited significant effects in sensitization of these resistant cancer cells at non-toxic concentration to doxorubicin and docetaxel by MTT method. They also increased the intracellular doxorubicin accumulation and retention in MCF-7/ADR cells. In mechanism study, an increase of Rh123 accumulation and a decrease of Rh123 efflux were observed in MCF-7/ADR cells treated with these fractions, indicating a blockage of the activity of P-gp. Furthermore, C. wenyujin C10 had the ability to down-regulate the expression of P gp. All these fractions could enhance the apoptosis induced by doxorubicin in MCF 7/ADR cells, and restore the effect of docetaxel on the induction of G2/M arrest in A549/Taxol cells. C. wenyujin C10 and E10 also owned the ability to induce S phase arrest. These results showed the therapeutic value of the three fractions as potential MDR-reversing agents and warranted further investigations. PMID- 21306885 TI - Protein homeostasis networks in physiology and disease. PMID- 21306884 TI - Spermicidal action of a protein isolated from ethanolic root extracts of Achyranthes aspera: an in vitro study. AB - A previous study conducted in our department, showed that 50% ethanolic extract of the roots of Achyranthes aspera possess spermatotoxic effects. Preliminary studies also revealed that the active principle may be a protein. In this study a 58 kDa Achyranthes protein (Ap) was isolated from Achyranthes aspera using standard protocols and their effects on the rat sperm was studied in vitro in comparison with nonoxynol-9 (N-9). The sperm immobilization studies showed that about 150 MUg of Ap was able to immobilize sperms completely within seconds at a lower concentration than N-9 (250 MUg). The sperm revival test revealed that the spermicidal effect was irreversible. There was also a significant reduction in sperm viability and hypo-osmotic swelling in the Ap-treated and N-9 treated groups in comparison to the control. In the Ap and N-9 treated groups the number of acrosome reacted cells were found to be high and it also caused agglutination of the sperms indicating the loss of intactness of the plasma membrane which was further supported by the significant reduction in the activity of membrane bound 5' nucleotidase and acrosin enzyme. Hence this study showed that the protein isolated from the roots of Achyranthes aspera possess spermicidal activity in vitro and can act as a spermicide similar to that of nonoxynol 9. Ap also possessed spermicidal activity against human sperms in vitro. PMID- 21306886 TI - MSWI boiler fly ashes: magnetic separation for material recovery. AB - Nowadays, ferrous materials are usually recovered from Municipal Solid Waste Incineration (MSWI) bottom ash by magnetic separation. To our knowledge, such a physical technique has not been applied so far to other MSWI residues. This study focuses thus on the applicability of magnetic separation on boiler fly ashes (BFA). Different types of magnet are used to extract the magnetic particles. We investigate the magnetic particle composition, as well as their leaching behaviour (EN 12457-1 leaching test). The magnetic particles present higher Cr, Fe, Mn and Ni concentration than the non-magnetic (NM) fraction. Magnetic separation does not improve the leachability of the NM fraction. To approximate industrial conditions, magnetic separation is also applied to BFA mixed with water by using a pilot. BFA magnetic separation is economically evaluated. This study globally shows that it is possible to extract some magnetic particles from MSWI boiler fly ashes. However, the magnetic particles only represent from 23 to 120 g/kg of the BFA and, though they are enriched in Fe, are composed of similar elements to the raw ashes. The industrial application of magnetic separation would only be profitable if large amounts of ashes were treated (more than 15 kt/y), and the process should be ideally completed by other recovery methods or advanced treatments. PMID- 21306887 TI - A quantum dot-aptamer beacon using a DNA intercalating dye as the FRET reporter: application to label-free thrombin detection. AB - A new quantum dot (QD)-aptamer (apt) beacon that acts by folding-induced dissociation of a DNA intercalating dye, BOBO-3(B), is demonstrated with label free thrombin detection. The beacon, denoted as QD-apt:B, is constructed by (1) coupling of a single-stranded thrombin aptamer to Qdot 565 via EDC/Sulfo-NHS chemistry and (2) staining the duplex regions of the aptamer on QD with excess BOBO-3 before thrombin binding. When mixing a thrombin sample with QD-apt:B, BOBO 3 is competed away from the beacon due to target-induced aptamer folding, which then causes a decrease in QD fluorescence resonance energy transfer (FRET) mediated BOBO-3 emission and achieves thrombin quantitation. In this work, the effects of Mg(2+), coupling time, and aptamer type on the beacon's performances are investigated and discussed thoroughly with various methods, including transmission electron microscopy (TEM), dynamic light scattering (DLS), and two color differential gel electrophoresis. Using the best aptamer beacon (HTQ37), we attain highly specific and wide-range detection (from nM to MUM) of thrombin in buffer, and the beacon can sense nM-range thrombin in 15% diluted serum. Compared to the reported QD aptamer assays, our method is advantageous from the aspect of using a simple sensory unit design without losing the detection sensitivity. Therefore, we consider the QD-apt:B beacon a potential alternative to immuno reagents and an effective tool to study nucleic acid folding on QD as well. PMID- 21306889 TI - The foot heath status questionnaire--correct scale score calculation. PMID- 21306888 TI - Bioconjugation of hydrogels for tissue engineering. AB - Success of tissue engineered constructs in regenerative medicine is limited by the lack of cellmatrix interactions to guide devleopment of the seeded cells into the desired tissue. This review highlights the most exciting developments in bioconjugation of synthetic hydrogels targeted to tissue engineering. Application of conjugation techniques has resulted in the synthesis of novel biomimetic cell responsive hydrogels to control the cascade of cell migration, adhesion, survival, differentiation, and maturation to the desired lineage concurrent with matrix remodeling. The future outlook includes developing conjugated patterned hydrogel matrices, developing novel hydrogel matrices to support self-renewal and pluripotency of embryonic and adult stem cells, and merging 3D printing with bioconjugation to fabricate hydrogels with anatomical arrangement of cells and biomolecules. PMID- 21306890 TI - Implications of corn prices on water footprints of bioethanol. AB - Previously reported water footprints (WFPs) of corn ethanol have been estimated based on the assumption that corn ethanol feedstock could be supplied by the same states where the corn is grown. However, ethanol conversion facilities may choose out-of-state feedstock suppliers depending on the total price of feedstock they have to pay including both the corn price and transportation costs. The purpose of this study is to evaluate the WFPs and total water use (TWU) of corn ethanol considering an optimal allocation of corn with heterogeneous corn feedstock prices across states. The results show that the WFPs of corn ethanol are less than 100 l of water per liter of ethanol (Lw/Le) for all ethanol-producing states based on both the 2008 corn price and transportation costs for rail and truck. Results also reveal that WFPs are very sensitive to the market price of corn and that additional greenhouse gas emissions due to corn trade between states are not significant. PMID- 21306891 TI - Comparison of denitrification at low temperature using encapsulated Paracoccus denitrificans, Pseudomonas fluorescens and mixed culture. AB - The aim of this work was to compare denitrification activity of three types of encapsulated biomass containing pure culture of Paracoccus denitrificans or Pseudomonas fluorescens or mixed culture of psychrophilic denitrifiers cultivated at 5 degrees C from activated sludge. The experiments were held with synthetic wastewater containing 50 mg L(-1) N-NO(3)(-) under the temperature 15, 10, 8 and 5 degrees C. Specific denitrification rates related to the weight of pellets and to the protein content were calculated and the temperature coefficients describing the dependence of denitrification rate on the temperature were determined. Although the mixed culture showed the highest denitrification rate at the temperatures below 10 degrees C, using of pellets containing pure culture is recommended as the mixed culture has slow growth rate and its activity at temperatures above 10 degrees C is very low. PMID- 21306892 TI - Improvement strategy on enhanced biological phosphorus removal for municipal wastewater treatment plants: full-scale operating parameters, sludge activities, and microbial features. AB - The poor quality of effluent discharged by municipal wastewater treatment plants (WWTPs) is threatening the safety of water ecology. This study, which integrated a field survey, batch tests, and microbial community identification, was designed to improve the effectiveness of the enhanced biological phosphorus removal (EBPR) process for WWTPs. Over two-thirds of the investigated WWTPs could not achieve total P in effluent lower than 0.5 mg/L, mainly due to the high ratio of chemical oxygen demand to P (28.6-196.2) in the influent. The rates of anaerobic P release and aerobic P uptake for the activated sludge varied from 0.22 to 7.9 mg/g VSS/h and 0.43 to 8.11 mg/g VSS/h, respectively. The fraction of Accumulibacter (PAOs: polyphosphate accumulating organisms) was 4.8 +/- 2.0% of the total biomass, while Competibacter (GAOs: glycogen-accumulating organisms) accounted for 4.8 +/- 6.4%. The anaerobic P-release rate was found to be an effective indicator of EBPR. Four classifications of the principal components were identified to improve the EBPR effluent quality and sludge activity. PMID- 21306893 TI - Effect of enzyme additions on methane production and lignin degradation of landfilled sample of municipal solid waste. AB - Operation of waste cells as landfill bioreactors with leachate recirculation is known to accelerate waste degradation and landfill gas generation. However, waste degradation rates in landfill bioreactors decrease with time, with the accumulation of difficult to degrade materials, such as lignin-rich waste. Although, potential exists to modify the leachate quality to promote further degradation of such waste, very little information is available in literature. The objective of this study was to determine the viability of augmenting leachate with enzymes to increase the rate of degradation of lignin-rich waste materials. Among the enzymes evaluated MnP enzyme showed the best performance in terms of methane yield and substrate (lignin) utilization. Methane production of 200 mL CH(4)/g VS was observed for the MnP amended reactor as compared to 5.7 mL CH(4)/g VS for the control reactor. The lignin reduction in the MnP amended reactor and control reactor was 68.4% and 6.2%, respectively. PMID- 21306894 TI - Influence of sward maturity and pre-conditioning temperature on the energy production from grass silage through the integrated generation of solid fuel and biogas from biomass (IFBB): 2. Properties of energy carriers and energy yield. AB - In order to determine influencing parameters on energy production of the IFBB process, herbage from a lowland hay meadow (Arrhenaterion) was sampled and ensiled at eight dates between 27 April and 21 June 2007. The silage from each date was processed in six IFBB treatments with and without hydrothermal conditioning at different temperatures. Methane yields and higher heating values were determined and an energy balance was calculated with whole-crop digestion (WCD) of the silage as reference system. Maximum net energy yields were 10.2 MWh ha(-1) for the IFBB treatment without hydrothermal conditioning and 9.0 MWh ha( 1) for the treatment with hydrothermal conditioning at 50 degrees C. WCD achieved a maximum net energy yield of 3.7 MWh ha(-1). Energy conversion efficiency ranged from 0.24 to 0.54 and was predicted with high accuracy by temperature of hydrothermal conditioning as well as concentration of neutral detergent fibre and dry matter in the silage (R(2)=0.90). PMID- 21306895 TI - Discovery of beta-aminoacyl containing thiazolidine derivatives as potent and selective dipeptidyl peptidase IV inhibitors. AB - A series of beta-aminoacyl containing thiazolidine derivatives was synthesized and evaluated for their ability to inhibit DPP-IV. Several thiazolidine derivatives with an acid moiety were found to be potent DPP-IV inhibitors. Among them, compound 2da is the most active in this series with an IC(50) value of 1 nM, and it showed excellent selectivity over DPP-IV related enzymes including DPP 2, DPP-8, and DPP-9. Compound 2da is chemically and metabolically stable, and showed no CYP inhibition, hERG binding or cytotoxicity. Compound 2db, an ester prodrug of 2da, showed good in vivo DPP-IV inhibition after oral administration in rat and dog models. PMID- 21306896 TI - Investigation of a novel molecular descriptor for the lead optimization of 4 aminoquinazolines as vascular endothelial growth factor receptor-2 inhibitors: application for quantitative structure-activity relationship analysis in lead optimization. AB - We investigated the use of infrared vibrational frequency of ligands as a potential novel molecular descriptor in three different molecular target and chemical series. The vibrational energy of a ligand was approximated from the sum of infrared (IR) absorptions of each functional group within a molecule and normalized by its molecular weight (MDIR). Calculations were performed on a set of 4-aminoquinazolines with similar docking scores for the VEGFR2/KDR receptor. 4 Aminoquinazolines with MDIR values ranging 192-196 provided compounds with KDR inhibitory activity. The correlation of KDR inhibitory activity was similarly observed in a separate chemical series, the pyrazolo[1,5-a]pyrimidines. Initial exploration of this molecular descriptor supports a tool for rapid lead optimization in the 4-aminoquinazoline chemical series and a potential method for scaffold hopping in pursuit of new inhibitors. PMID- 21306897 TI - Synthesis of chroman aldehydes that inhibit HIV. AB - Chroman aldehydes bearing an acetyl group plus alkoxyl or hydroxyl groups inhibit HIV infectivity in HeLa37 cells. PMID- 21306898 TI - Synthesis and anti-migrative evaluation of moverastin derivatives. AB - Cell migration of tumor cells is essential for invasion of the extracellular matrix and for cell dissemination. Inhibition of the cell migration involved in the invasion process represents a potential therapeutic approach to the treatment of tumor metastasis; therefore, a novel series of derivatives of moverastins (moverastins A and B), an inhibitor of tumor cell migration, was designed and chemically synthesized. Among these moverastin derivatives, several compounds showed stronger cell migration inhibitory activity than parental moverastins, and UTKO1 was found to have the most potent inhibitory activity against the migration of human esophageal tumor EC17 cells in a chemotaxis cell chamber assay. Interestingly, although moverastins are considered to inhibit tumor cell migration by inhibiting farnesyltransferase (FTase), UTKO1 did not inhibit FTase, indicating that UTKO1 inhibited tumor cell migration by a mechanism other than the inhibition of FTase. PMID- 21306899 TI - Reasons for risk-reducing mastectomy versus MRI-screening in a cohort of women at high hereditary risk of breast cancer. AB - OBJECTIVE: To determine the reasons that motivate women in a cohort of women under intensive surveillance for breast cancer to undergo risk-reducing mastectomy (RRM). PATIENTS AND METHODS: Women with a BRCA1 or BRCA2 mutation who were enrolled in an MRI-based breast screening study were eligible to participate in this survey. A self-administered questionnaire was given to women who did, and who did not terminate annual MRI-based surveillance in order to undergo RRM. The questionnaire included information on family history, risk perception and satisfaction with screening. In addition, women were asked to provide the principal reason for their choice of having preventive surgery or not, and were asked about their satisfaction with this choice. RESULTS: 246 women without breast cancer participated in the study. Of these, 39 women (16%) elected to have RRM at some point after initiating screening. Although women who had a mother or sister with breast cancer were more likely to opt for RRM than were women with no affected first-degree relative (21% versus 10%) this did not reach statistical significance. Women who perceived their breast cancer risk to be greater than 50% were more likely to opt for RRM than were women who estimated their risk to be less than 50% (19% versus 6%). Fear of cancer was the most common reason cited for choosing to have RRM (38% of respondents) followed by having had a previous cancer, (25%), then concern over their children (16%). CONCLUSION: Among women with a BRCA mutation who are enrolled in an MRI-based screening program, a high perception of personal breast cancer risk and a history of breast cancer in a first-degree relative are predictors of the decision to have RRM. PMID- 21306901 TI - LRRK2 signaling pathways: the key to unlocking neurodegeneration? AB - Mutations in PARK8, encoding leucine-rich repeat kinase 2 (LRRK2), are a major cause of Parkinson's disease. We contrast data suggesting that changes in LRRK2 activity cause alterations in mitogen-activated protein kinase, translational control, tumor necrosis factor alpha/Fas ligand and Wnt signaling pathways with the cell biological functions of LRRK2 such as vesicle trafficking. Despite scarce in vivo data on cell signaling, involvement in diverse cell biological functions suggests a role for LRRK2 as an upstream regulator in events leading to neurodegeneration. To stimulate discussion and give direction for future research, we further suggest that despite the importance of the catalytic activity for cytotoxicity, the main cellular function of LRRK2 is linked to assembly of signaling complexes. PMID- 21306900 TI - Merotelic kinetochore attachment: causes and effects. AB - Accurate chromosome segregation depends on the proper attachment of sister kinetochores to microtubules emanating from opposite spindle poles. Merotelic kinetochore orientation is an error in which a single kinetochore is attached to microtubules emanating from both spindle poles. Despite correction mechanisms, merotelically attached kinetochores can persist until anaphase, causing chromatids to lag on the mitotic spindle and hindering their timely segregation. Recent studies showing that merotelic kinetochore attachment represents a major mechanism of aneuploidy in mitotic cells and is the primary mechanism of chromosomal instability in cancer cells have underlined the importance of studying merotely. Here, we highlight recent progress in our understanding of how cells prevent and correct merotelic kinetochore attachments. PMID- 21306902 TI - Surgical cannulation of a cortical draining vein for endovascular treatment of a dural arteriovenous fistula of the cavernous sinus. AB - Dural arteriovenous fistulas (DAVF) of the cavernous sinus most commonly present with ocular symptoms and can be observed or treated with endovascular approaches, surgery, or radiosurgery. Combined surgical-endovascular approaches have been used for fistulas that are not amenable to standard endovascular approaches. A 40 year-old man presented with ocular symptoms from a cavernous sinus DAVF. Multiple previous transarterial and transvenous embolization attempts had failed. The patient underwent craniotomy for surgical exposure and cannulation of an arterialized sylvian vein. Subsequently he underwent coiling and onyx embolization of the DAVF. The intervention resulted in effective obliteration of the fistula. If a cavernous sinus DAVF is refractory to treatment, surgical exposure and cannulation of a cortical draining vein can facilitate transvenous endovascular treatments. PMID- 21306903 TI - Synthesis and hydrolytic evaluation of acid-labile imine-linked cytotoxic isatin model systems. AB - In this study a series of isatin-based, pH-sensitive aryl imine derivatives with differing aromatic substituents and substitution patterns were synthesised and their acid-catalysed hydrolysis evaluated. These derivatives were functionalised at the C3 carbonyl group of a potent N-substituted isatin cytotoxin and were stable at physiological pH but readily cleaved at pH 4.5. Observed rates of hydrolysis for the embedded imine-acid moiety were in the order para phenylpropionic acid>phenylacetic acid (para>meta)>benzoic acid (meta>para). The ability to fine-tune hydrolysis rates in this way has potential implications for optimising imine linked, tumour targeting cytotoxin-protein conjugates. PMID- 21306904 TI - Synthesis and biological evaluation of 1,4-benzodiazepin-2-ones with antitrypanosomal activity. AB - A library of 1,4-benzodiazepines has been synthesized and evaluated against Trypanosoma brucei, a causative parasite of Human African trypanosomiasis. Benzodiazepines possessing a P2- transporter motif were found to have MIC values as low as 0.78 MUM. PMID- 21306905 TI - Simplification of the tetracyclic SIRT1-selective inhibitor MC2141: coumarin- and pyrimidine-based SIRT1/2 inhibitors with different selectivity profile. AB - In this report we describe the synthesis and biological characterization of two series of sirtuins' inhibitors (SIRTi), designed as simplification products of the previously reported SIRT1-selective inhibitor MC2141 (4). In the first series (5a-t) we report a number of 2-substituted-1,2-dihydrobenzo[f]chromen-3-ones with a marked selectivity for the inhibition of SIRT2 over SIRT1. Some of such derivatives showed also high pro-apoptotic (5i and 5l) and/or cytodifferentiating (5d, 5i, and 5o) properties in a human leukemia cell line (U937). The second group of SIRTi (6a-q) is characterized by some analogues of cambinol (3), a well known SIRTi active against the Burkitt lymphoma. Such compounds, differently from the unselective prototype, are endowed with a selective inhibition of SIRT1 over SIRT2, and, in some cases (6j, 6k, and 6q), are more efficient than 3 to induce apoptosis in U937 cells. PMID- 21306906 TI - After the grape rush: sirtuins as epigenetic drug targets in neurodegenerative disorders. AB - Class III histone deacetylases (sirtuins) are becoming increasingly recognized as important epigenetic drug targets in cancer and metabolic disorders. As key regulators involved in numerous cellular signalling pathways, sirtuins are also emerging as potential targets in various neurodegenerative diseases such as Alzheimer, Parkinson's disease and others, thus suggesting modulation of sirtuin activity could provide an interesting and novel therapeutic option. In particular, much attention has been raised by neuroprotective effects attributed to SIRT1 activation due to genetically induced sirtuin overexpression or administration of resveratrol, a natural compound found in the skin of red grapes and also in wine. Similarly, also sirtuin inhibitors display benefits in various neuropathologic disease models. In light of the growing interest in sirtuin modulation and with regard to the lack of conclusive data on small molecule activators of sirtuins this review recapitulates the known facts about sirtuins and their relevance in neurodegenerative diseases. PMID- 21306907 TI - Structure based design of heat shock protein 90 inhibitors acting as anticancer agents. AB - Structure based drug design (SBDD) was used to discover heat shock protein 90 (HSP90) inhibitors useful in the treatment of cancer. By using the crystal structure of HSP90-ligand complex (1uyi), a docking model was prepared and was validated by external dataset containing known HSP90 inhibitors. This validated model was then used to virtually screen commercial databases, selected hits of which were bought and sent for real biological evaluation. Further as an alternative method, pharmacophores were generated using crystal structure conformations of ligands in HSP90 complexes (1uyi and 2bz5) and where used for virtual screening. Both cases yielded several hits containing novel scaffolds, particularly compound KHSP8 showed an IC(50) value of 0.902 MUM in case of colon cancer (HT29), which is comparable to doxorubicin (0.828 MUM). These compounds were being now used as leads for constructing small molecular libraries to get compounds with favourable pharmacokinetics and drug like properties. PMID- 21306908 TI - Saddle nose deformity, palatal perforation and truncus arteriosus in a patient with Crohn's disease. AB - Crohn's disease (CD) is a chronic granulomatous inflammatory bowel disease which may also involve the extraintestinal organs such as joints, liver, skin and perianal tissue. Involvement of the nasal cavity is quite rare in CD. This case report presents a 28-year-old girl with CD and saddle nose deformity, alar collapse and palatal perforation as extraintestinal manifestations of the disease in addition to persistent truncus arteriosus-type 4. PMID- 21306909 TI - Comparison of surgical result of anterolateral thigh flap in reconstruction of through-and-through cheek defect with/without CT angiography guidance. AB - OBJECTIVES: Anterolateral thigh flap (ALT) is an useful flap for head and neck reconstruction, but the variable perforators may limit its applications. Our goal was to clarify the benefits of preoperative CT angiography (CTA) in mapping of free ALT perforators for reconstruction of cheek through-and-through defects. METHOD: We retrospectively reviewed 32 patients undergoing reconstruction of through-and-through cheek defects with a free ALT flap between February 2005 and July 2009. These patients were divided into two groups. Group I (N=17): the ALT flap was designed based on the traditional handheld Doppler probe. Group II (N=15): preoperative imaging with CTA was used to map the perforator's number, size and variations. Surgical results were evaluated for both major and minor complications, as with the operation time, length of hospital stay and donor-site morbidity. RESULTS: Overall flap survival was 96.88% (31 of 32 flaps). The use of preoperative CTA was associated with a significant reduction in major surgical complications, length of surgery and the need for a secondary debulking procedure (p<0.05). There was no difference in minor complication and donor-site morbidity. CONCLUSIONS: The use of CTA for preoperative navigation of ALT flap for cheek reconstruction is associated with improved operative outcomes. Detailed data from images allow the surgeon to interpret any anatomical variations, choosing the exact suitable thigh, facilitate flap design, and greatly reduce major postoperative complications. PMID- 21306910 TI - The retromandibular transparotid approach: our clinical experience. AB - INTRODUCTION: Mandibular condylar fractures are very common. There is general agreement that an intracapsular fracture requires conservative treatment, but the treatment of extra-capsular fractures is controversial. Extraoral approaches have different advantages and disadvantages. The possibility of damage to the facial nerve is always present but, in our experience, always recovers in a short time. MATERIALS AND METHODS: From June 2008 to June 2009, we admitted 25 patients with mandibular condylar fractures to our department. Nineteen patients received a retromandibular transparotid approach to identify and stabilize the condylar fracture site. None of them developed infection. SURGICAL TECHNIQUE: A 2 cm incision extending in the retromandibular hollow is the first step. Initial dissection in a forward and upward in the direction of the SMAS layer is mandatory to gain good mobility of the soft tissue flaps. Blunt dissection through the parotid gland is performed between the marginal and buccal branches of the facial nerve. Periosteal elevation of all the lateral surface of the mandible provides good exposure of the bony surfaces and mobilization of the soft tissues. CONCLUSIONS: We believe that this approach is a safe and time sparing alternative to the intraoral endoscopic approach. PMID- 21306911 TI - Different cell death mechanisms are induced by a hydrophobic flavin in human tumor cells after visible light irradiation. AB - Riboflavin (RF) is an endogenous cell component and an efficient photosensitizer that can act by both types I and II photochemical mechanisms. Human tumor cells lines cultured in vitro, were used as model to study the effect of a photosensitizer synthesized from riboflavin, the 2',3',4',5'-riboflavin tetrabutyrate (RTB), to increase the flavin concentration in the human promyelocytic leukemia cell line HL-60 and the human epithelial cervical cancer cell line HeLa. We demonstrate that this compound, alone or with Trp, has a toxic dose-response effect evidenced by abnormal cell morphology and a decrease in the cell proliferation rate. The mechanism of cell death was investigated and the experimental evidence indicates that it proceeds primarily via apoptosis; however, autophagy cannot be discarded. Nuclear fluorescent staining with Hoechst 33258 and transmission electron microscopy of the cells showed condensed chromatin margination at the nuclear periphery and the formation of apoptotic bodies. Furthermore, Caspase-3 activity was demonstrated in both cell lines. In addition, the characteristic apoptotic DNA ladder was observed in HL-60 cells. On the other hand, a high cytoplasmic vacuolization was observed by electron transmission and confocal microscopy. LysoTraker-red localization in the vacuoles was observed by fluorescence microscopy, and a significant decrease in the number of vacuoles and in the cell proliferation rate diminution was observed when irradiation was performed in the presence of the autophagy inhibitor 3 methyladenine. Considering that both cell death mechanisms have a dual role in the killing of tumor cells in vivo, a harmful effect that does not cause inflammation leading to tumor prophylaxis, we conclude that RTB could have potential clinical applications. PMID- 21306912 TI - T cell receptor recognition of self and foreign antigens in the induction of autoimmunity. AB - The major histocompatibility complex (MHC) on human chromosome 6 represents the most important genetic locus for a number of common human autoimmune diseases. Specific alleles that differ from closely related alleles by only one or a few amino acids in the peptide binding groove are frequently strongly associated with disease susceptibility, raising the important question of which peptide presentation events are critical in disease initiation and progression. This review will cover a number of topics pertinent to this fundamental question, including MHC linked disease susceptibility to autoimmune diseases, molecular mechanisms for the role of MHC molecules in autoimmune diseases as well as the recognition of self and microbial peptides by self-reactive T cell receptors (TCRs). PMID- 21306913 TI - Toll-like receptor driven B cell activation in the induction of systemic autoimmunity. AB - Studies over the past decade have demonstrated a key role for pattern recognition receptors in the activation of autoreactive B cells. Self reactive B cells that manage to escape negative selection often express relatively low affinity receptors for self antigens (ignorant B cells), and can only be activated by integrating a relatively weak BCR signal with signals from additional receptors. Members of the toll-like receptor (TLR) gene family, and especially the nucleic acid binding receptors TLR 7, 8 and 9, appear to play a key role in this regard and promote the production of autoantibodies reactive with DNA- or RNA-associated autoantigens. These autoantibodies are able to form immune complexes with soluble or cell-bound ligands, and these immune complexes can in turn activate a second round of proinflammatory cells that further contribute to the autoimmune disease process. Recent data have emerged showing a pathogenic role for TLR7, with an opposing, protective role for TLR9. Targeting these disregulated pathways offers a therapeutic opportunity to treat autoimmune diseases without crippling the entire immune system. Further understanding of the role of specific receptors, cell subsets, and inhibitory signals that govern these TLR-associated pathways will enable future therapeutics to be tailored to specific categories of autoimmune disease. PMID- 21306914 TI - Device, protocol and measurement of regional spinal stiffness. AB - Spinal stiffness is commonly assessed by manual therapists but the methodology varies widely. The current study presents a novel device - Therapeutic Spinal Mobilizer - to measure spinal stiffness safely and reliably. The methodology developed allows exertion of a force perpendicular to the spinal skin surface over a selected spinous process at a preselected frequency for predetermined duration cyclically in a repeatable manner. The loading rate is governed by the gravity feed. The force applied and displacements produced were used to calculate the spinal stiffness at that level. The results revealed a significant difference in stiffness due to magnitude of load (loading rate) (p<0.01) but no significant difference in stiffness between different cycles of loading with same load. The phase of respiration significantly affected stiffness, with total lung capacity being stiffest and residual functional capacity the least stiff (p<0.05). There was a significant difference in stiffness of the three spinal levels tested (p<0.05). In conclusion, the standardized methodology revealed that spinal stiffness of one region may be very different from another. Different loads yield significantly different stiffness (p<0.01). PMID- 21306915 TI - Pain and motor control: From the laboratory to rehabilitation. AB - Movement is changed in pain and is the target of clinical interventions. Yet the understanding of the physiological basis for movement adaptation in pain remains limited. Contemporary theories are relatively simplistic and fall short of providing an explanation for the variety of permutations of changes in movement control identified in clinical and experimental contexts. The link between current theories and rehabilitation is weak at best. New theories are required that both account for the breadth of changes in motor control in pain and provide direction for development and refinement of clinical interventions. This paper describes an expanded theory of the motor adaptation to pain to address these two issues. The new theory, based on clinical and experimental data argues that: activity is redistributed within and between muscles rather than stereotypical inhibition or excitation of muscles; modifies the mechanical behaviour in a variable manner with the objective to "protect" the tissues from further pain or injury, or threatened pain or injury; involves changes at multiple levels of the motor system that may be complementary, additive or competitive; and has short term benefit, but with potential long-term consequences due to factors such as increased load, decreased movement, and decreased variability. This expanded theory provides guidance for rehabilitation directed at alleviating a mechanical contribution to the recurrence and persistence of pain that must be balanced with other aspects of a multifaceted intervention that includes management of psychosocial aspects of the pain experience. PMID- 21306916 TI - A comparison of training intensity between whole-body vibration and conventional squat exercise. AB - The aim of this study was to investigate surface electromyographic activity (sEMG) and rate of perceived exertion (RPE) during semi-squat exercise on vibration platform compared with semi-squat exercise performed on a Smith machine. Twenty-three recreationally active students (15 males and 8 females) were exposed to six different loads in one of both exercise modes: vibration or Smith machine. The subject performed a squat in six experimental conditions; the load differed per experimental condition. For each subject the exercise mode (n=2) and the different loads per mode (n=6) were assigned in a random order to check the influence of vibration magnitude (acceleration: ms(-2)) as well as weight (kg) on sEMG and RPE. Two-way ANOVA for RPE, lumbar and lower-body sEMG revealed a significant weight main effect (P<0.01) and a significant acceleration main effect (P<0.01). The results from this study demonstrate that the training stimulus resulting from an isometric semi-squat exercise on a vibration platform (acceleration: from 12 to 89 ms(-2)) is similar to the training stimulus of an isometric semi-squat exercise on Smith machine (weight: from 20 to 70 kg) according to lower-body sEMG and RPE. However, the impact of semi-squat on vibration platform exercise for lumbar muscle is relatively small compared with semi-squat on Smith machine. PMID- 21306917 TI - Mini-trampoline exercise related to mechanisms of dynamic stability improves the ability to regain balance in elderly. AB - Falls have been described by several studies as the major cause of hip and femur fractures among the elderly. Therefore, interventions to reduce fall risks, improve dynamic stability and the falling recovery strategies in the elderly population are highly relevant. This study aimed at investigating the effects of a 14-week mini-trampoline exercise intervention regarding the mechanisms of dynamic stability on elderly balance ability during sudden forward falls. Twenty two elderly subjects participated on mini-trampoline training and 12 subjects were taken as controls. The subjects of the experimental group were evaluated before and after the 14-week trampoline training (exercised group), whereas control subjects were evaluated twice in the forward fall task with a three-month interval. The applied exercise intervention increased the plantarflexors muscle strength (~10%) as well as the ability to regain balance during the forward falls (~35%). The 14-week mini-trampoline training intervention increased elderly abilities to recover balance during forward falls; the improvement was attributed to the higher rate of hip moment generation. PMID- 21306918 TI - Central venous catheter insertion via the vertebral vein and the sixth transverse foramen. PMID- 21306919 TI - Advanced chronic obstructive pulmonary disease is associated with high levels of high-density lipoprotein cholesterol. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an inflammatory systemic disease associated with numerous extrapulmonary manifestations. Amongst these is an increased risk for cardiovascular disease. The mechanisms for this association remain unclear. We sought to examine lipid trends in a well characterized cohort of patients with severe COPD. METHODS: We conducted a retrospective prospective analysis of 126 consecutive individuals evaluated for lung transplantation with a diagnosis of COPD in whom lipid values were available. Observed lipid values were compared with a reference population without severe COPD. RESULTS: Compared with the reference population, mean low density lipoprotein cholesterol (LDL-C) levels were slightly reduced at 108 +/- 44 vs 117 +/- 29.5 mg/dl (p = 0.02) in men but were no different in women. Mean high-density lipoprotein cholesterol (HDL-C) levels were significantly elevated at 62 +/- 24 vs 45 +/- 12 mg/dl (p < 0.0001) in men and at 83 +/- 27 vs 59 +/- 16 mg/dl in women (p < 0.0001). Prednisone use correlated with higher HDL-C levels but did not fully explain the extent of elevation. Angiographically proven coronary artery disease was found in 61% of individuals and was unrelated to HDL C levels. CONCLUSIONS: Severe COPD is associated with increased levels of HDL-C, which is partially attributable to oral steroid use. HDL-C in this population is not associated with reduced risk of angiographically proven coronary artery disease. PMID- 21306920 TI - Scene congruency biases Binocular Rivalry. AB - Contextual regularities, that is, objects' tendency to appear with certain other objects, facilitate the processing of visual scenes and confer contextually incongruent objects with a special attentional status. This study was aimed at investigating the mechanisms underlying this attentional advantage using Binocular Rivalry (BR). In two experiments, congruent and incongruent images (e.g., a man drinking from a glass vs. a man "drinking" from a hairbrush) were pitted against each other, yielding a version of BR in which two objects rival within a given scene. Incongruent objects predominated in awareness longer than congruent ones. This effect stemmed from the fact that their dominance epochs lasted longer on the average than those of congruent objects, suggesting a difficulty to disengage attention from such objects. On the other hand, no support was found for the notion that incongruent objects also attract attention. PMID- 21306921 TI - Reduced serum content and increased matrix stiffness promote the cardiac myofibroblast transition in 3D collagen matrices. AB - INTRODUCTION: The fibroblast-myofibroblast transition is an important event in the development of cardiac fibrosis and scar formation initiated after myocardial ischemia. The goals of the present study were to better understand the contribution of environmental factors to this transition and determine whether myofibroblasts provide equally important feedback to the surrounding environment. METHODS: The influence of matrix stiffness and serum concentration on the myofibroblast transition was assessed by measuring message levels of a panel of cardiac fibroblast phenotype markers using quantitative reverse transcriptase polymerase chain reaction. Cell-mediated gel compaction measured the influence of environmental factors on cardiac fibroblast contractility. Immunohistochemistry characterized alpha-smooth muscle actin expression and cell morphology, while static and dynamic compression testing evaluated the effect of the cell response on the mechanical properties of the cell-seeded collagen hydrogels. RESULTS: Both reduced serum content and increased matrix stiffness contributed to the myofibroblast transition, as indicated by contractile compaction of the gels, increased message levels of col3alpha1 and alpha-smooth muscle actin, and a less stellate morphology. However, the effects of serum and matrix stiffness were not additive. Mechanical testing indicated that reduced serum content increased the initial elastic modulus of cell-seeded gels and that gels lost their viscous character with time. CONCLUSIONS: The results suggest that reduced serum and increased matrix stiffness promote the myofibroblast phenotype in the myocardium. This transition both enhances and is promoted by matrix stiffness, indicating the presence of positive feedback that may contribute to the pathogenesis of cardiac fibrosis. PMID- 21306922 TI - Combining antiepileptic drugs--rational polytherapy? AB - The global introduction of 14 new antiepileptic drugs (AEDs) over the past 20 years as adjunctive treatment in refractory epilepsy has triggered an increased interest in optimising combination therapy. With a widening range of available mechanisms of AED action, much activity has been focused on the defining and refining "rational polytherapy" with AEDs that have differing pharmacological properties. This paper reviews the available animal and human data exploring this issue. The experimental and clinical evidence in support of "rational polytherapy" is sparse, with only the combination of sodium valproate with lamotrigine demonstrating synergism. Robust evidence to guide clinicians on how and when to combine AEDs is lacking and current practice recommendations are largely empirical. Practical guidance for the clinician is summarised and discussed in this review. In particular, care should be taken to avoid excessive drug load, which can be associated with decreased tolerability and, therefore, reduced likelihood of seizure freedom. A palliative strategy should be defined early for the more than 30% of patients with refractory epilepsy. Nevertheless, the availability of an increasing number of pharmacologically distinct AEDs has produced a modest improvement in prognosis with combination therapy, which will encourage the clinician to persevere with continued pharmacological manipulation when other therapeutic options have been tried or are not appropriate. PMID- 21306923 TI - Open or endovascular repair of secondary aortoenteric fistulae? PMID- 21306924 TI - Diagnostic criteria for unicystic ameloblastoma: ameloblastic versus ameloblastomatous epithelium. PMID- 21306925 TI - Polymorphonuclear neutrophils from JAK2(V617F) positive MPD patients do not support hypercoagulability: A study with calibrated automated thrombography (CAT). AB - Essential thrombocythemia and polycythemia vera are myeloproliferative disorders (MPD) with an elevated thrombotic risk. Leukocytosis has recently emerged as a new risk factor and there is increasing evidence that polymorphonuclear neutrophils (PMN) are involved. Procoagulant activity (PCA) of PMN in MPD has not yet been investigated. PCA of PMN from 22 patients with JAK2(V617F) positive MPD and 26 healthy subjects was studied using calibrated automated thrombography: in vitro thrombin generation induced with 1 pM tissue factor in the presence of added procoagulant phospholipids. There were no differences between patients and controls regarding the ability of PMN to increase thrombin generation. More surprisingly, basal thrombin generation in acellular MPD-plasma was found decreased for as yet unknown reasons. The presence of an active protein C pathway or platelets might provide a better insight into the coagulation phenotype in MPD. PMID- 21306926 TI - Low rather than high dose lipopolysaccharide 'priming' of muscle provides an animal model of persistent elevated mechanical sensitivity for the study of chronic pain. AB - Experimental animal pain models involving peripheral nerve lesions have expanded the understanding of the pathological changes caused by nerve damage. However models for the pathogenesis of chronic pain patients lacking obvious nerve injuries have not been developed to the same extent. Guided by clinical observations, we focused on the initiating noxious event, the context when applying nociceptive stimulation targeting long-lasting pain elicited by muscle insult. The administration of a nociceptive agent (6% hypertonic saline: HS; 5 time repeated-injection: HS5) after pretreatment with an immuno-inflammatory agent (lipopolysaccharide: LPS, 2 MUg/kg) into one gastrocnemius muscle produced markedly long-persisting biphasic sustained mechanical hypersensitivity on the plantar surface of both hindpaws. In the acute phase, the blockade of afferent inputs from the injected-site was effective in returning the contralateral enhanced-responses to baseline levels. In contrast, similar blockade during the chronic phase did not affect the contralateral enhanced-responses, indicating that the hypersensitivity in the two phases was probably induced by different mechanisms. However, increasing the dose of LPS (20 MUg/kg) before applying HS5 eliminated the development of mechanical hypersensitivity in the chronic phase, while the hypersensitivity in the acute phase was significantly more severe than with low-dose LPS-pretreatment. In this model, the development of hypersensitivity could be modulated by manipulating LPS-doses prior to noxious stimulation. This novel chronic pain model based on a preceding 'priming' myalgic stimulus provides an intriguing means for studying the pathogenesis of chronic pain. PMID- 21306927 TI - o-Semiquinonato and o-iminosemiquinonato rhodium complexes. EPR study of the reactions in coordination sphere of rhodium. AB - The number of dicarbonyl-o-semiquinonato (o-iminosemiquinonato) rhodium complexes was isolated and characterized. Some reactions of these compounds with tertiary phosphines (substitution, addition) were studied by EPR in solution using o semiquinones (o-iminosemiquinones) as spin labels. PMID- 21306928 TI - Supercycled SW(f)-TPPM sequence for heteronuclear dipolar decoupling in solid state nuclear magnetic resonance. AB - The performance of a supercycled SW(f)-TPPM sequence for heteronuclear dipolar decoupling in solid-state NMR is analyzed here. The decoupling performance of this sequence with respect to experimental parameters, such as, the phase angle, proton offset and MAS frequency is studied. A comparison is made with two other commonly used decoupling schemes in solid-state NMR namely, SPINAL-64 and SW(f) TPPM, on a sample of U-13C-labeled tyrosine. Our results show that supercycled SW(f)-TPPM performs better than the former sequences. Also, numerical spin dynamics studies are presented which support the experimentally observed efficiency in the decoupling. PMID- 21306930 TI - [Further thoughts on the impact factor]. PMID- 21306929 TI - Homozygosity for a novel missense mutation in the leptin receptor gene (P316T) in two Egyptian cousins with severe early onset obesity. AB - Congenital deficiency of the leptin receptor is a very rare cause of severe early onset obesity. To date, only 9 families have been reported in the literature to have mutations in the leptin receptor gene. The clinical features include severe early onset obesity, severe hyperphagia, hypogonadotropic hypogonadism, and T cell and neuroendocrine/metabolic dysfunction. Here we report two cousins with severe early onset obesity and recurrent respiratory tract infections. Their serum leptin levels were elevated but they were within the range predicted by the elevated fat mass in both cousins. Direct sequencing of the entire coding sequence of the leptin receptor gene revealed a novel homozygous missense mutation in exon 6, P316T. The mutation was found in the homozygous form in both cousins and in the heterozygote state in their parents. This mutation was not found in 200 chromosomes from 100 unrelated normal weight control subjects of Egyptian origin using PCR-RFLP analysis. In conclusion, finding this new mutation in the LEPR beside our previous mutation in the LEP gene implies that monogenic obesity syndromes may be common in the Egyptian population owing to the high rates of consanguineous marriages. Further screening of more families for mutations in LEP, LEPR, and MC4 might confirm this assumption. PMID- 21306931 TI - Secondary syphilis presenting as rash and annular hyperkeratotic lesions. PMID- 21306932 TI - [Mortality and morbidity conference: A tool for quality and safety of care continuous improvement]. AB - OBJECTIVE: The mortality and morbidity conference (MMC) is one of the keystones in the evaluation of quality of care. The objective of this work was to describe a MMC by presenting a case report. CASE REPORT: A 16-year old man suffering from chronic anaemia had to be transfused with two units of red blood cells in an outpatient unit. Although the transfusion went well for the first unit, the patient presented haemolysis during the transfusion of the second unit because the nurse administered the wrong unit. The incident was analysed during a mortality and morbidity conference with the attendance of the hemovigilance local correspondent. Immediate causes of the event were the failure to respect the transfusion procedure: in advance compatibility testing, failure to check the patient and blood component identification just before the transfusion. Factors contributing to the event were the deviation of transfusion practices, poor working conditions of nurses, linked to inadequate staff in relation to the activity. The discussion of the incident led to develop an action plan. DISCUSSION: This case shows the interest for staff members to discuss an adverse event. However, a well-defined methodology for conducting mortality and morbidity conferences is lacking and leads to a wide heterogeneity between teams. Major differences refer to criteria for case selection and quality of participants. This heterogeneity is likely to have an impact of the efficacy of mortality and morbidity conferences regarding the quality and safety of care. PMID- 21306933 TI - Intensifying glycaemic control with insulin reduces adiponectin and its HMW isoform moderately in type 2, but not in type 1, diabetes. AB - INTRODUCTION: As the impact of diabetes control was not tested on adiponectin (ADPN) levels, this study was designed to assess whether or not controlling hyperglycaemia can affect ADPN. PATIENTS AND METHODS: A total of 15 T1D and 48 T2D patients with HbA(1c) greater than 10% were studied at the time of hospitalization for uncontrolled diabetes. Total, and high-, medium- and low molecular-weight (HMW, MMW, LMW) ADPN were measured at the time of study inclusion, on days 1 and 8, and at 1, 3 and 6 months after insulin treatment. RESULTS: While diabetes control improved, total and HMW APDN decreased on days 1 and 8, but remained steady thereafter in T2D patients. In T1D patients, ADPN levels remained unchanged throughout the study. CONCLUSION: Glycaemic control with insulin reduces ADPN in T2D patients in the short-term, but was ineffective in T1D. PMID- 21306934 TI - Ultrasound stimuli on viscometric change of aqueous copolymers having acrylic acid and N-isopropyl acrylamide for thermo-sensitive segments. AB - Ultrasound (US) was used to change the shear viscosity of an aqueous solution of copolymers having acrylic acid (AA) and N-isopropylacrylamide (NIPAM) segments. The US effect on the shear viscosity of the copolymers containing 10, 50 and 90 mol% of the NIPAM group having thermo-responsible property was examined when the US was exposed to the aqueous solution at different temperatures. The shear viscosity of the solution had a significant change at about 30-35 degrees C when the viscosity was measured in the range of 0-60 degrees C. While, the viscosity decreased with the increase of the temperature, the US operated at 28, 45 and 100 kHz also induced significant reduction of the shear viscosity. Evidence of the US effect on the shear viscosity reduction was observed by measurement of FT-IR spectra of the copolymer solution when the US was exposed. It was noted that considerable change of the spectra at the 28 kHz US was observed relative to that of the 45 and 100 kHz US. The tendency of the change in the shear viscosity and IR spectra was almost similar. Furthermore, the shear viscosity and IR spectra changed gradually to recover its original value as the US was stopped. This was due to the breaking and reformation of the hydrogen bonding between NIPAM and AA segments when the US was exposed and stopped, respectively. PMID- 21306935 TI - Dopamine D1 and D2 receptor subtypes functional regulation in cerebral cortex of unilateral rotenone lesioned Parkinson's rat model: Effect of serotonin, dopamine and norepinephrine. AB - Parkinson's disease is a progressive neurodegenerative disorder characterized by selective degeneration of dopaminergic neurons in substantia nigra pars compacta leading to marked reduction of dopamine levels in the cerebral cortex. The present study analysed the effect of serotonin, dopamine and norepinephrine as treatment on rotenone induced Hemi-Parkinson's disease in rats and its role in the regulation of dopamine receptor subtypes in the cerebral cortex of the experimental rats. Unilateral stereotaxic single dose infusions of rotenone were administered to the substantia nigra of adult male Wistar rats. Neurotransmitters -serotonin, dopamine and norepinephrine treatments--were given to rotenone induced Hemi-Parkinson's rats. Scatchard analysis of Dopamine D1 and D2 receptor showed a significant increase (p < 0.001) in the cerebral cortex of the Parkinson's rats compared to control. These altered parameters were reversed to near control in the serotonin and norepinephrine treated Parkinson's disease rats and no change was observed in dopamine treated Parkinson's rats. Real-time PCR results confirmed the receptor data. Our results showed serotonin and norepinephrine functionally reversed the dopamine receptors significantly in rotenone induced Hemi-Parkinson's rat. This has clinical significance in the therapeutic management of Parkinson's disease. PMID- 21306936 TI - Self-incompatibility: Smi silences through a novel sRNA pathway. AB - Self-incompatibility in Brassicaceae is determined by the interaction between S Locus Protein 11 (SP11) on the pollen and S-receptor kinase (SRK) in the stigma. Pollen from heterozygotes generally displays products of both SP11 alleles, but in some heterozygotes SP11 expression is monoallelic, with one allele (SP11(R)) being silenced by promoter methylation. An exciting development in understanding the mechanism behind monoallelic silencing came recently when Y. Tarutani et al. [Nature 2010;466:983-986] identified a 24-nucleotide sRNA (termed Smi) derived from a non-coding gene within the dominant S-haplotype, and suggested that Smi directs promoter methylation. We propose that rather than having a direct effect on DNA methylation, Smi is the first step in a novel cis-acting siRNA pathway that directs widespread monoallelic SP11(R) promoter methylation. PMID- 21306937 TI - Density functional theory calculations on the molecular structures and vibration spectra of platinum(II) antitumor drugs. AB - A comparison of six density functional theory (DFT) methods and six basis sets for predicting the molecular structures and vibration spectra of cisplatin is reported. The theoretical results are discussed and compared with the experimental data. It is remarkable that LSDA/SDD level is clearly superior to all the remaining density functional methods (including mPW1PW) in predicting the structures of cisplatin. Mean deviation between the calculated harmonic and observed fundamental vibration frequencies for each method is also calculated. The results indicate that PBE1PBE/SDD is the best method to predict all frequencies on average for cisplatin molecule in DFT methods. PMID- 21306938 TI - Thermoluminescence properties of natural zoisite mineral under gamma-irradiations and high temperature annealing. AB - Natural silicate mineral of zoisite, Ca(2)Al(3)(SiO(4))(Si(2)O(7))O(OH), has been investigated concerning gamma-radiation, UV-radiation and high temperature annealing effects on thermoluminescence (TL). X-ray diffraction (XRD) measurement confirmed zoisite structure and X-ray fluorescence (XRF) analysis revealed besides Si, Al and Ca that are the main crystal components, other oxides of Fe, Mg, Cr, Na, K, Sr, Ti, Ba and Mn which are present in more than 0.05 wt%. The TL glow curve of natural sample contains (130-150), (340-370) and (435-475) degrees C peaks. Their shapes indicated a possibility that they are result of composition of two or more peaks strongly superposed, a fact confirmed by deconvolution method. Once pre-annealed at 600 degrees C for 1h, the shape of the glow curves change and the zoisite acquires high sensitivity. Several peaks between 100 and 400 degrees C appear superposed, and the high temperature peak around 435 degrees C cannot be seen. The ultraviolet radiation, on the other hand, produces one TL peak around 130 degrees C and the second one around 200 degrees C and no more. PMID- 21306939 TI - Study of the interaction between N-confused porphyrin and bovine serum albumin by fluorescence spectroscopy. AB - The fluorescence and ultraviolet spectroscopy were explored to study the interaction between N-confused porphyrins (NCP) and bovine serum albumin (BSA) under imitated physiological condition. The experimental results indicated that the fluorescence quenching mechanism between BSA and NCP was static quenching procedure at low NCP concentration at 293 and 305 K or a combined quenching (static and dynamic) procedure at higher NCP concentration at 305 K. The binding constants, binding sites and the corresponding thermodynamic parameters DeltaH, DeltaS, and DeltaG were calculated at different temperatures. The comparison of binding potency of the three NCP to BSA showed that the substituting groups in benzene ring could enhance the binding affinity. From the thermodynamic parameters, we concluded that the action force was mainly hydrophobic interaction. The binding distances between NCP and BSA were calculated using Forster non-radiation energy transfer theory. In addition, the effect of NCP on the conformation of BSA was analyzed using synchronous fluorescence spectroscopy. PMID- 21306940 TI - Leadership structures in emergency care settings: a study of two trauma centers. AB - BACKGROUND: Trauma resuscitation involves multidisciplinary teams under surgical leadership in most US trauma centers. Because many trauma centers have also incorporated emergency department (ED) physicians, shared and cross-disciplinary leadership structures often occur. Our study identifies leadership structures and examines the effects of cross-disciplinary leadership on trauma teamwork. METHODS: We conducted an ethnographic study at two US Level-1 trauma centers, one of which is a dedicated pediatric trauma center. We used observation, videotaping and interviews to contextualize and classify leadership structures in trauma resuscitation. Leadership structures were evaluated based on three dimensions of team performance: defined leadership, likelihood of conflict in decision making, and appropriate care. FINDINGS: We identified five common leadership structures, grouped under two broad leadership categories: solo decision-making and intervening models within intra-disciplinary leadership; intervening, parallel, and collaborative models within cross-disciplinary leadership. CONCLUSION: Most important weaknesses of different leadership structures are manifested in inefficient teamwork or inappropriate patient care. These inefficiencies are particularly problematic when leadership is shared between physicians from different disciplines with different levels of experience, which often leads to conflict, reduces teamwork efficiency and lowers the quality of care. We discuss practical implications for technology design. PMID- 21306941 TI - Lack of HPV 16 and 18 detection in serum of colposcopy clinic patients. AB - BACKGROUND: Persistent infection with high-risk human papillomavirus (HPV) types is necessary for the development of high-grade cervical dysplasia and cervical carcinoma. The presence of HPV DNA in the blood of cervical cancer patients has been reported; however, whether HPV DNA is detectable in the blood of patients with pre-invasive cervical disease is unclear. OBJECTIVES: The objectives of this study were to determine if HPV 16 and HPV 18 DNA could be detected in the serum of colposcopy clinic patients, and if serum HPV detection was associated with grade of cervical disease and HPV cofactors. STUDY DESIGN: Samples were selected from a biorepository collected from non-pregnant, HIV-negative women ages 18-69 attending colposcopy clinics at two urban public hospitals. Cervical disease status was based on review of colposcopy, biopsy and cytology findings. Serum HPV DNA detection was conducted using a novel PCR and mass spectroscopy-based assay. RESULTS: Of the 116 adequate serum samples, all (100%) were negative for HPV 16 and HPV 18. Over half (51.7%) of participants had cervical HPV 16 and/or HPV 18 infection. Nearly one-third (31.1%) had high grade, 10.3% had low grade, and 50.9% had no cervical disease. Nearly one-third (28.5%) had ever regularly smoked cigarettes, 70.7% had early onset of sexual intercourse, and 75% had ever used oral contraceptives. CONCLUSIONS: In this colposcopy clinic population with a range of clinical characteristics and established HPV cofactors, HPV DNA was undetectable in their serum. Our findings suggest that serum HPV DNA detection is not a cervical cancer screening tool. PMID- 21306942 TI - Echovirus 30 in EV71-associated hand, foot and mouth disease outbreak, Guangxi, China. PMID- 21306943 TI - Paired-pulse flash-visual evoked potentials: new methods revive an old test. AB - OBJECTIVE: We aimed at reviving with modern technology the paired flash-visual evoked potential (F-VEP) testing of the visual system excitability. In the 1960s, methodological problems hindered this test, which was expected to provide important physiologic information. METHODS: We studied 22 consenting healthy subjects (10 men). We recorded F-VEPs from electrodes over occipital and central brain regions. We delivered single flashes, mixed at random to flash pairs at the interstimulus interval (ISI) of 333, 125, 62.5, 50, 33, and 16.5 ms, (i.e. an internal frequency (IF) of 3, 8, 16, 20, 30, and 60 Hz). Recordings were performed with the subject's eyes closed and opened. The F-VEP was split into a "main complex" and an "afterdischarge", which we analyzed statistically in relation to the eye state (closed or open) and to the changes due to paired stimulation. RESULTS: The eye state affected the single F-VEP size, latency and shape significantly (p<0.05). On paired stimulation, the test (second) F-VEP exhibited significant (p<0.05), ISI-dependent size changes, such as a progressive decrease for ISIs from 62.5 to 16.5 ms (IFs of 16-60 Hz), whose timing/amount varied significantly (p<0.05) according to the eye state and to the F-VEP epoch considered. Suppression of the test F-VEP was never complete, even for the shortest ISI (ISI=16.5 ms, IF=60 Hz). CONCLUSIONS: The eye state (closed or open) must be considered meticulously when studying F-VEPs. F-VEP changes on paired stimulation express neural inhibition within the visual system, which can be depicted as ISI-dependent curves. SIGNIFICANCE: Modern equipment and simplified measures render this an easy test, with statistical validity, providing specific information on the excitability properties of the visual system. PMID- 21306944 TI - Interhemispheric enhancement of somatosensory cortical excitability through contralateral repetitive transcranial magnetic stimulation. AB - OBJECTIVES: Somatosensory evoked potentials (SEPs) were used to index somatosensory-somatosensory interhemispheric interactions and highlight potential mechanisms by which TMS alters contralateral somatosensory cortex excitability. METHODS: Fifteen healthy individuals participated in three sessions on separate days. On each day participants received either: (1) continuous theta burst (cTBS), (2) 1 Hz repetitive transcranial magnetic stimulation (rTMS) or (3) control TMS over left somatosensory cortex. SEPs from right somatosensory cortex were recorded before and after TMS while participants were at rest, performed sensorimotor tracking or the sustained attention to response task (SART). Left handed tracking performance was also indexed. RESULTS: N20-P27 amplitude was increased following 1 Hz rTMS while participants were at rest. This increased amplitude was not observed during right-handed tracking or the SART. N20-P27 amplitude was not influenced by cTBS or control TMS. P15-N20 and N34-P50 SEP components were not influenced by TMS. Right- and left-handed tracking performance was not transiently influenced by TMS. CONCLUSIONS: The results support TMS induced somatosensory-somatosensory interactions and offer converging evidence for an intercortical, rather that intracortical, mechanism that mediates contralateral sensory processing. These interactions appear to be dependent on concurrent attention/task demands. SIGNIFICANCE: Somatosensory-somatosensory interactions are reflected by intercortical mechanisms that are state and task dependent. PMID- 21306945 TI - Ocular and cervical VEMPs: a study of 74 patients suffering from peripheral vestibular disorders. AB - OBJECTIVE: This study compared the results of ocular and cervical vestibular evoked myogenic potentials (VEMPs) tests for healthy subjects with those for patients suffering from vestibular diseases to try to determine the clinical usefulness of combined ocular and cervical STB VEMP testing. METHODS: Thirty-two healthy volunteers and 74 patients with unilateral vestibular dysfunction underwent tests for ocular and cervical VEMPs induced by AC 100 dB nHL 500 Hz STB combined with caloric and audiometric tests. RESULTS: In healthy subjects, the mean P13-N23 peak-to-peak amplitude of cervical VEMPs was much larger than the mean n1-p1 peak-to-peak amplitude of ocular VEMPs. In patients, cervical and ocular VEMPs may be dissociated. The peak-to-peak amplitude of both cervical and ocular tests was abnormally in most of patients suffering from vestibular lesions. No correlations were found between VEMPs, the degree of hearing loss and/or of horizontal canalar paresis. CONCLUSIONS: Ocular and cervical VEMPs provide complementary information about saccular and utricular otolithic function. SIGNIFICANCE: Testing of ocular and cervical VEMPs allows the crossed vestibulo-ocular reflex and ipsilateral sacculo-collic reflex to be determined. These tests can help describe vestibular lesions and assess the effects of treatment and should therefore be used clinically. PMID- 21306946 TI - Blunted respiratory-related evoked potential in awake obstructive sleep apnoea subjects: a NEP technique study. AB - OBJECTIVE: Respiratory-related evoked potentials (RREP) elicited by transmural pressure in obstructive sleep apnoea (OSA) subjects have reported conflicting data. Different features of pressure stimuli and/or in the timing of stimuli application seem to account for these contradictory results. The negative expiratory pressure (NEP) technique, highly reproducible in terms of rise time and pressure values, allows to minimize the methodological confounding factors. We determined whether the afferent activity from the upper airway (UA) is altered in OSA subjects. METHODS: RREP potentials were examined in 10 OSA and in 12 non apnoeic awake subjects by means of the NEP technique. RESULTS: All controls showed a cortical response to all pressure stimuli. All OSA subjects showed responses to -5 and -10 cmH(2)O whereas six of them showed no responses to -1 cmH(2)O. The amplitude of the P22, N45 and P85 components of the RREP was significantly reduced in OSA with respect to the controls in response to both the -5 and -10 cmH(2)O stimuli. We found no significant differences in latencies. CONCLUSIONS: Awake OSA subjects had a raised threshold to pressure stimuli and blunted respiratory-related evoked potentials. SIGNIFICANCE: These data indicate a deficit in afferent activity in the UA. PMID- 21306947 TI - Molecular cloning and characterization of a beta-glucanase from Piromyces rhizinflatus. AB - Cellulose is the most abundant renewable polysaccharide with a high potential for degradation to useful end products. In nature, most cellulose is produced as crystalline cellulose. Therefore, cellulases with high hydrolytic activity against crystalline cellulose are of great interest. In this study, a crystalline cellulose degradation enzyme was investigated. The cDNA encoding a beta glucanase, CbhYW23-2, was cloned from the ruminal fungus Piromyces rhizinflatus. To examine the enzyme activities, CbhYW23-2 was expressed in Escherichia coli as a recombinant His(6) fusion protein and purified by immobilized metal ion affinity chromatography. Response surface modeling (RSM) combined with central composite design (CCD) and regression analysis was then employed for the planned statistical optimization of the beta-glucanase activities of CbhYW23-2. The optimal conditions for the highest beta-glucanase activity of CbhYW23-2 were observed at 46.4 degrees C and pH 6.0. The results suggested that RSM combined with CCD and regression analysis were effective in determining optimized temperature and pH conditions for the enzyme activity of CbhYW23-2. CbhYW23-2 also showed hydrolytic activities toward Avicel, carboxymethyl cellulose (CMC), lichenan, and pachyman. The results also proved that the high activity of CbhYW23 2 on crystalline cellulose makes it a promising candidate enzyme for biotechnological and industrial applications. PMID- 21306948 TI - Effects of aqueous chlorine dioxide treatment on nutritional components and shelf life of mulberry fruit (Morus alba L.). AB - Effects of aqueous chlorine dioxide (ClO(2)) treatment on nutritional components and shelf-life of mulberry fruit (Morus alba L.) were investigated. Mulberry fruit were immersed into 20, 60, and 80 mg/l ClO(2) solutions for 5, 10, and 15 min, respectively. Mulberries were then rinsed with potable tap water for 1 min and stored at -1 degrees C for 14 d. ClO(2) treatment was effective in retention of flavonoid, ascorbic acid, reducing sugar, and titratable acid. ClO(2) concentration and treatment time were significant factors affecting ClO(2) treatment. The shelf-life of the samples treated by 60 mg/l ClO(2) for 15 min was extended to 14 d compared to 8 d for the control. No ClO(2), ClO(2)(-), or ClO(3)(-) residues were detected in samples treated by 60 mg/l ClO(2) for 15 min. These results indicated that ClO(2) treatment was a promising approach to preserve mulberry fruit with no significant risks of chemical residues. PMID- 21306949 TI - Positional therapy in ischemic stroke patients with obstructive sleep apnea. AB - BACKGROUND: Obstructive sleep apnea (OSA) is common in stroke patients and is associated with poor functional outcome. The effects of positional therapy in ischemic stroke patients with OSA have not been investigated. We tested the hypothesis that ischemic stroke patients have less severe OSA during positional therapy that promotes nonsupine positioning. METHODS: We conducted a randomized, controlled, cross-over study. Sleep apnea screening studies were performed on two consecutive nights, using a portable respiratory monitoring system, on 18 subjects within the first 14days of ischemic stroke. An apnea-hypopnea index (AHI) ?5 established the diagnosis of OSA. Subjects were randomized to positional therapy that included the use of a therapeutic pillow on either the first or second night. On the control night, subjects used the hospital pillow and were positioned ad lib. Treatment effect on AHI was estimated using a repeated measures model. RESULTS: All ischemic stroke subjects studied had OSA. The predominantly male group had a median age of 58years, BMI of 29kg/m(2), NIH Stroke Scale score of 3, and a median AHI on the nontherapeutic night of 39 (interquartile range: 21-54). Positional therapy reduced the amount of supine positioning by 36% (95% CI: 18-55% (P<0.001)). The AHI was reduced by 19.5% (95% CI: 4.9-31.9% (P=0.011)), when using positional therapy compared to sleeping ad lib. CONCLUSIONS: Positional therapy to avoid supine positioning modestly reduces sleep apnea severity after ischemic stroke, and may therefore improve outcomes. PMID- 21306950 TI - Right pneumonectomy for T4 non-small cell lung cancer invading intrapericardial pulmonary vein in a patient with a right aortic arch. AB - A 59 year-old man with a right-sided aortic arch who had a T4 right lung cancer invading the proximal superior pulmonary vein underwent an intrapericardial pneumonectomy with partial left atrium resection and a radical lymphadenectomy. The presence of a right-sided aortic arch required particular attention during dissection of the lymph nodes. This is the first case of a right-pneumonectomy for T4-lung cancer in a patient with a right-sided aortic arch. PMID- 21306951 TI - Quality of life of sarcoma patients from diagnosis to treatments: predictors and longitudinal trajectories. AB - PURPOSE: Quality of life (QoL) has been increasingly examined in sarcoma patients, but longitudinal research on its variation across different phases of the disease is lacking. The present study aims to analyse change or stability in sarcoma patients' QoL, and to identify the distinct trajectories of change from diagnostic to treatment phase. Demographic and clinical predictors of QoL during treatments are also explored. METHOD: QoL of 36 Portuguese sarcoma patients was assessed at time of diagnosis (baseline) and again at 3-6 months after the beginning of treatment (T1), using the EORTC QLQ C-30 (Portuguese version). RESULTS: At diagnostic and treatment phases, patients reported a diminished QoL in the majority of QLQ C-30 domains. From baseline to T1, global health/QoL improved significantly, and physical functioning declined. Over time, 38.9% of patients maintained a poor QoL, 27.8% remained in the "High QoL" cluster, and 22.2% changed towards a worse QoL. Marital status, age, professional status, and radiotherapy predicted QoL scores during treatments. CONCLUSIONS: Results suggest that sarcoma patients may experience a diminished QoL, both at diagnosis and during treatments, and reveal a tendency for stability in QoL scores rather than for change. Initial functioning and some demographic and clinical variables have a predictive role for QoL in the treatment phase. Assessment of QoL and multidisciplinary interventions must be a part of routine cancer care, and should be implemented in an initial phase and during treatments. PMID- 21306952 TI - Informal caregiving in Hematopoietic Blood and Marrow Transplant patients. AB - PURPOSE: Hematopoietic cell transplant patients are among the most vulnerable and acutely ill cancer populations (Bevans et al., 2008). The responsibility of caring for the daily physical and psychosocial needs of these patients after transplant is placed mostly on family caregivers (Williams, 2007). The purpose of this descriptive correlational research study was to describe caregiving experiences of 56 caregivers of HCT patients 3-12 months following transplant. METHODS & SAMPLE: Patients and caregivers were recruited from two west coast regional transplant programs in the United States. Variables studied were: relationship quality, rewards of caregiving, predictability, role strain, patient function, caregiving activities, and caregiver quality of life (QOL). KEY RESULTS: Results indicated that all areas of role strain are significantly negatively correlated with caregiver's QOL. Predictability was negatively associated with problem solving and emotional strain indicating that as the level of predictability of the situation decreases, caregiver strain and problem solving increase. Predictability was positively correlated to caregiver QOL indicating that as the situation is more predictable caregiver QOL increases. Emotional strain, problem-solving strain, and usual care strain were significantly positively related, indicating that emotional strain and problem solving strain increased together. As usual care strain increased, so did problem solving strain and emotional strain. CONCLUSIONS: Suggestions for interventions include assessing and responding to caregiver issues such as emotional strain, problem-solving strain, usual care strain, unpredictability, and QOL. Examples of caregiver-focused interventions include providing timely appropriate information about these caregiver concerns including elements that make the caregiving situation predictable, and incorporating best practices for preventing and minimizing caregiver emotional strain. PMID- 21306953 TI - Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. AB - BACKGROUND: Axitinib is a potent, selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. A randomised phase 2 trial of gemcitabine with or without axitinib in advanced pancreatic cancer suggested increased overall survival in axitinib-treated patients. On the basis of these results, we aimed to assess the effect of treatment with gemcitabine plus axitinib on overall survival in a phase 3 trial. METHODS: In this double-blind, placebo-controlled, phase 3 study, eligible patients had metastatic or locally advanced pancreatic adenocarcinoma, no uncontrolled hypertension or venous thrombosis, and Eastern Cooperative Oncology Group performance status 0 or 1. Patients, stratified by disease extent (metastatic vs locally advanced), were randomly assigned (1:1) to receive gemcitabine 1000 mg/m(2) intravenously on days 1, 8, and 15 every 28 days plus either axitinib or placebo. Axitinib or placebo were administered orally with food at a starting dose of 5 mg twice a day, which could be dose-titrated up to 10 mg twice daily if well tolerated. A centralised randomisation procedure was used to assign patients to each treatment group, with randomised permuted blocks within strata. Patients, investigators, and the trial sponsor were masked to treatment assignments. The primary endpoint was overall survival. All efficacy analyses were done in all patients assigned to treatment groups for whom data were available; safety and treatment administration and compliance assessments were based on treatment received. This study is registered at ClinicalTrials.gov, number NCT00471146. FINDINGS: Between July 27, 2007, and Oct 31, 2008, 632 patients were enrolled and assigned to treatment groups (316 axitinib, 316 placebo). At an interim analysis in January, 2009, the independent data monitoring committee concluded that the futility boundary had been crossed. Median overall survival was 8.5 months (95% CI 6.9-9.5) for gemcitabine plus axitinib (n=314, data missing for two patients) and 8.3 months (6.9-10.3) for gemcitabine plus placebo (n=316; hazard ratio 1.014, 95% CI 0.786-1.309; one sided p=0.5436). The most common grade 3 or higher adverse events for gemcitabine plus axitinib and gemcitabine plus placebo were hypertension (20 [7%] and 5 [2%] events, respectively), abdominal pain (20 [7%] and 17 [6%]), fatigue (27 [9%] and 21 [7%]), and anorexia (19 [6%] and 11 [4%]). INTERPRETATION: The addition of axitinib to gemcitabine does not improve overall survival in advanced pancreatic cancer. These results add to increasing evidence that targeting of VEGF signalling is an ineffective strategy in this disease. FUNDING: Pfizer. PMID- 21306954 TI - Development of targeted therapies for pancreatic cancer. PMID- 21306955 TI - Rural hospital interdisciplinary team members' experience of undergraduate nursing preceptorship: a qualitative descriptive study. AB - Rural hospital preceptorships offer Canadian undergraduate nursing students the opportunity to work with interdisciplinary teams. In a qualitative descriptive study, rural hospital interdisciplinary team members' experience of preceptorship was explored. Five focus groups and eight individual in-depth semi-structured interviews were conducted with professionals from nursing, medicine, social work, respiratory, recreational, occupational therapy, records keeping, dietary, pharmacy, hospital administration, and laboratory services. The data suggests time and patterns of communication within the clinical learning environment influence students' ability to effectively work within an interdisciplinary healthcare team framework. As a result, students' exposure to the interdisciplinary team must be deliberately and carefully planned. As well, students need to learn to work effectively within the team approach through interdisciplinary education. PMID- 21306956 TI - Re: Tubularized incised plate proximal hypospadias repair: continued evolution and extended applications. PMID- 21306957 TI - Risk of adverse events on epilepsy monitoring units: a survey of epilepsy professionals. AB - In 2008 a workgroup of health care professionals from the American Epilepsy Society (AES) was convened to address the lack of consensus regarding patient care in epilepsy monitoring units (EMUs). The group developed a questionnaire designed to identify the extent to which selected adverse events occurred in EMUs, and it was sent via email to all members of the AES. We asked that only one representative from each center report. Seventy responses were received. The number of centers reporting the following adverse events included: falls by 69%, status epilepticus by 63%, and postictal psychosis by 54%. Infrequent events with serious consequences were also reported including pneumonia by 10%, cardiac arrest by 7%, fractures by 6%, and death by 3% (N=2). Of the 58 respondents who reported using intracranial electrodes, 37.9% (N=22) reported that patients pulled out or dislodged electrodes. This study highlights the need for EMUs to identify and address potential safety risks in their environment, patient population, and system of care. PMID- 21306958 TI - Mimetic automatisms expressing a negative affect in two patients with temporal lobe epilepsy. AB - Ictal automatisms of fear or sadness, of which the patient is unaware and which are not preceded by a corresponding emotion, have not been well characterized. Of 557 patients admitted for video/EEG monitoring, 2 (0.36%) were identified who had automatisms of fear and sadness. One patient was found to have a sudden ictal expression of sadness of which he was not aware. The second patient showed a sudden fearful expression, followed by oral automatisms, staring, and amnesia for the event. Both patients had left mesial temporal lobe epilepsy. The patient with ictal fear underwent further invasive monitoring and became seizure free after a limited mesial temporal resection. The mesial temporal structures not only mediate emotional experiences, but can also activate stereotyped expressions of fear or sadness without the patient's awareness, arguing for an efferent pathway for expressing negative affects within the mesial temporal lobe. PMID- 21306960 TI - Longterm effects of cardiac mediastinal nerve cryoablation on neural inducibility of atrial fibrillation in canines. AB - In canines, excessive activation of select mediastinal nerve inputs to the intrinsic cardiac nervous system induces atrial fibrillation (AF). Since ablation of neural elements is proposed as an adjunct to circumferential pulmonary vein ablation for AF, we investigated the short and long-term effects of mediastinal nerve ablation on AF inducibility. Under general anesthesia, in 11 dogs several mediastinal nerve sites were identified on the superior vena cava that, when stimulated electrically during the atrial refractory period, reproducibly initiated AF. Cryoablation of one nerve site was then performed and inducibility retested early (1-2 months post Cryo; n=7) or late (4 months post Cryo; n=4). Four additional dogs that underwent a sham procedure were retested 1 to 2 months post-surgery. Stimulation induced AF at 91% of nerve sites tested in control versus 21% nerve sites early and 54% late post-ablation (both P<0.05). Fewer stimuli were required to induce AF in controls versus the Early Cryo group; this capacity returned to normal values in the Late Cryo group. AF episodes were longer in control versus the Early or Late Cryo groups. Heart rate responses to vagal or stellate ganglion stimulation, as well as to local nicotine infusion into the right coronary artery, were similar in all groups. In conclusion, focal damage to intrinsic cardiac neuronal inputs causes short-term stunning of neuronal inducibility of AF without major loss of overall adrenergic or cholinergic efferent neuronal control. That recovery of AF inducibility occurs rapidly post-surgery indicates the plasticity of intrathoracic neuronal elements to focal injury. PMID- 21306959 TI - Displacement of periurethral stranded seeds and its dosimetric consequences in prostate brachytherapy. AB - PURPOSE: The use of stranded seeds for prostate brachytherapy has raised concern that displacement of strands, particularly in the periurethral region, may result in inadequate coverage of the prostate. We sought here to evaluate the displacement of periurethral stranded seeds after a prostate brachytherapy implant (Day 0) and its dosimetric consequences 1 month later (Day 30). METHODS AND MATERIALS: Subjects were 10 consecutive patients who underwent implantation with (125)I stranded seeds via a peripheral-loading technique. Computed tomography scanning was done on Days 0 and 30. Seeds were located and dose distributions calculated with a Variseed 7.2 treatment planning system (Varian Medical Systems). Images were registered by two methods, one using the penile bulb as reference and the other using the pubic bones for verification. Only seeds within the periurethral strands were analyzed. RESULTS: The mean displacement of periurethral stranded seeds relative to the prostate did not exceed 1mm in any direction. Calculated displacements were not affected by the registration method used. The mean dose covering 90% of the prostate volume (D(90)) and prostate volume receiving 100% of the prescribed dose (V(100)) were 169Gy and 97% on Day 0 and 186.5Gy and 98.7% on Day 30 (p<0.001 for D(90)). CONCLUSIONS: Displacement of periurethral stranded seeds 30 days after implantation was minimal and did not compromise dosimetric coverage of the prostate. PMID- 21306961 TI - Isolation and purification of series bioactive components from Hypericum perforatum L. by counter-current chromatography. AB - Counter-current chromatography (CCC) combined with pre-separation by ultrasonic solvent extraction was successively used for the separation of series bioactive compounds from the crude extract of Hypericum perforatum L. The petroleum ether extract was separated by the solvent system of n-heptane-methanol-acetonitrile (1.5:0.5:0.5, v/v) and n-heptane-methanol (1.5:1, v/v) in gradient elution, yielding a phloroglucinol compound, hyperforin with HPLC purity over 98%. The ethyl acetate extract was separated by using the solvent system composed of hexane-ethyl acetate-methanol-water (1:1:1:1 and 1:3:1:3, v/v) in gradient through both reverse phase and normal phase elution mode, yielding a naphthodianthrone compound, hypericin with HPLC purity about 95%. The n-butanol extract was separated with the solvent system composed of n-butanol-ethyl acetate water (1:4:5 and 1.5:3.5:5, v/v) in elution and back-extrusion mode, yielding two of flavones, rutin and hyperoside, with HPLC purity over 95%. HPLC-MS, reference sample and UV spectrum were selectively used in separation to search for target compounds from HPLC-DAD profiles of different sub-extracts. The structures of isolated compounds were further identified by ESI-MS, 1HNMR and 13CNMR. PMID- 21306962 TI - [Prediction of intestinal histological lesions in paediatric patients with coeliac disease]. AB - INTRODUCTION: Serological markers are of great interest in coeliac disease (CD), although intestinal biopsy is still the gold standard for establishing the diagnosis. Tissue transglutaminase IgA antibodies (AATGt-IgA) and antiendomysial antibodies IgA (AAE-IgA) are closely correlated to intestinal damage observed in biopsies. Villous atrophy (Marsh 3) plays a major role in CD diagnosis. Marsh 2 stage (crypt hyperplasia) as a CD marker is still under debate. OBJECTIVE: To ascertain an AATGt-IgA level that corresponds to a positive predictive value (PPV) of 100% for a histological CD diagnosis. MATERIAL AND METHODS: A series of 120 patients younger than 14 years, non- IgA deficient, who underwent an intestinal biopsy and were positive for both serological markers (AATGt-IgA and AAE-IgA). For AATGt-IgA, according to the manufacturer's recommendations, a value greater than 16 IU/mL is considered as a positive value. The PPV of AATGt was determined for different cut-off points. RESULTS: The histological findings distribution is directly correlated to the AATGt-IgA cut-off point. When the cut off point is set above 7.5-10.6 times the commercial reference value, there is a 2.1% of Marsh 2 lessions and 93.4% of Marsh 3; above 10.6 times the reference value, all biopsies where Marsh 3 (100%). The PPV that considers Marsh 3 is (93.4%). The PPV, for considering Marsh 3 is low (55%) when AATGt-IgA serology is positive with levels between 16 and 67 IU/ml (1-4.2 times the cut-off point) and a higher value (92%) for concentrations between 68 and 118 IU/ml (4.3-7.4 times) and for cases with 69-170 IU/ml (7.5-10.6 times); above 170 IU/ml (>10.6 times) PPV is 100%. CONCLUSION: The use of values higher than the recommended cut-off point must logically improve specificity and PPV. In 31.6% patients positive for AATGt-IgA and AAE-IgA (38/120) it would have been possible to diagnose the disease without intestinal biopsy as of the PPV was 100%. It is not possible to standardise results as there are different commercial kits with variable cut-off points, so we must be cautious when setting recommendations based on AATGt-IgA. PMID- 21306963 TI - [Acute infantile haemorrhagic edema]. PMID- 21306964 TI - Clinical perinatal genetics. PMID- 21306965 TI - Breast augmentation in Familial Partial Lipodystrophy: a case report. AB - Familial Partial Lipodystrophy (or Dunnigan-Kobberling syndrome) is characterised by the progressive loss of peripheral subcutaneous fat, with or without truncal involvement. The resultant physical changes in appearance may be dramatic, especially in women, and their psychological impact underestimated. There are limited reports regarding the role of reconstructive procedures to address the physical defects imposed by the various lipodystrophy syndromes, and much of the work to date has focused around facial lipoatrophy in patients with HIV-1 protease inhibitor induced disease. We, however, present a single case report pertaining to the role of breast augmentation in patients with truncal lipoatrophy, as in Familial Partial Lipodystrophy. PMID- 21306966 TI - Principlism: the simplicity of complexity, or the complexity of simplicity? PMID- 21306967 TI - Incidence of diabetes in Asian-Indian subjects: a five year follow-up study from Bangladesh. AB - AIMS: To determine the incidence of Type 2 diabetes and its risk factors. Further, to examine the effect of relative changes in obesity (BMI and waist circumference). METHODS: A sample of 2011 non-diabetic adults aged 20 and above were randomly selected and followed from 1999 to 2004. Fasting blood glucose including biophysical and anthropometric measures was measured. RESULTS: The overall 5 year cumulative incidence of diabetes was 16.4 per 1000 person-years and 65.1 per 1000 person-years in those with impaired fasting glucose adjusted for age and sex. Among obesity measures, only waist >85in. increased the risk for diabetes in males (RR=3.0). Relative changes stratified by loss in BMI and WC >=5% or gain of BMI >15% from the baseline values for men were significantly associated with the incidental cases of diabetes. Increased hip circumference for men was significantly associated with a protective effect while an opposite association was observed for women. CONCLUSION: Relative change in both loss and excessive gain of BMI were risks for increased diabetes. Targeted intervention in those with impaired fasting blood glucose will expectedly reduce the incidental cases. Further investigations are needed for non obese related diabetes in Asian Indian subjects. PMID- 21306968 TI - Cardiomyopathy in Boxer dogs: a retrospective study of the clinical presentation, diagnostic findings and survival. AB - OBJECTIVES: To retrospectively compare and contrast the clinical presentation, diagnostic findings and survival in Boxer dogs with cardiomyopathy, with or without left ventricular (LV) systolic failure. ANIMALS, MATERIALS AND METHODS: Medical records of Boxers referred between 1993 and 2008 in which a diagnosis of ventricular arrhythmias and/or cardiomyopathy was made, were reviewed. Dogs were divided into two groups according to their left ventricular (LV) systolic diameter, group A normal (20 dogs) or group B dilated (59 dogs). RESULTS: Dogs in group A had a better outcome than dogs in group B (median survival time of 124 and 17 weeks respectively, p < 0.001). In group B, dogs with a history of collapse had a worse outcome (median survival time of 10 weeks) compared with dogs not showing collapse (median survival time 24 weeks) (p = 0.031). CONCLUSIONS: The majority of dogs, in this UK study, presented with the myocardial dysfunction form of the disease, with LV dilation and congestive heart failure signs. The prognosis was worse in dogs with LV dilation compared to dogs with a normal LV and ventricular arrhythmias. In the Boxers with LV dilation, dogs with collapse had a worse prognosis than those without. PMID- 21306969 TI - The medical home as a mediator of the relation between mental health symptoms and family burden among children with special health care needs. AB - OBJECTIVE: This study explores the role of medical home as a mediator of the relationship between emotional and behavioral difficulties among CSHCN and financial- and employment-related burden experienced by their families. METHODS: Data were obtained from the 2005-2006 NS-CSHCN, a nationally representative cross sectional survey of 40 465 CSHCN. Family burden was measured using parent reported financial problems and changes in family member employment resulting from the child's needs. Emotional and behavioral symptoms were reported by parents using 3 binary items capturing difficulty with depression, anxiety, disordered eating, and emotional or behavior problems. Medical home was measured according to the framework of the American Academy of Pediatrics. Bivariate and multivariate analyses were used to explore the role of medical home in the relation between mental health symptoms and family burden. RESULTS: A smaller proportion of CSHCN with emotional or behavioral difficulties had a medical home or related components compared to CSHCN generally, and a greater proportion of their families experienced burdens. Multivariate analyses showed that the mediated effect of care coordination on the relation between emotional or behavioral symptoms and family burden explained 18% to 35% of the total effect of these symptoms on financial problems and employment changes. Overall medical home access explained 16% to 28% of the total effect of symptoms on burden. CONCLUSIONS: Medical home access, and care coordination in particular, may partially mediate the relation between emotional and behavioral symptoms and financial hardship. Future efforts to implement the medical home model may benefit from an increased focus on care coordination as a means of reducing these burdens. PMID- 21306970 TI - Hepatocellular cancer in the non-cirrhotic liver. AB - Less than 20% of hepatocellular carcinoma (HCC) develops in the non-cirrhotic liver (NCL). The diagnosis of HCC in NCL is suggested by a large hypervascular tumor in a 60-75 year old patient (usually male), particularly if the alpha fetoprotein (AFP) level is high. But AFP is normal more often than not. Surgical resection is the only curative therapy of HCC; resection is more commonly feasible in HCC in NCL due to the healthy parenchyma of the underlying liver. The prognosis of HCC in NCL is better than that for HCC on cirrhosis with a 5-year survival approaching 50%. Prognosis is best in the patient with a small HCC with no vascular invasion or satellite nodules for whom an R0 resection can be achieved without the need for intra-operative transfusion. While intra-hepatic recurrence occurs frequently, it should be aggressively sought and treated; there is a major role for repeat hepatic resection and a lesser role for hepatic transplantation where results are poorer than those obtained for HCC on cirrhosis. PMID- 21306971 TI - Volumetric change of selected organs at risk during IMRT for oropharyngeal cancer. AB - PURPOSE: To assess volumetric changes of selected organs at risk (OAR) during intensity-modulated radiotherapy (IMRT) for oropharyngeal carcinoma. MATERIALS AND METHODS: Twenty-six consecutive patients that were treated with definitive IMRT +/- chemotherapy between November 2007 and November 2008 were selected for the present study. As part of an internal quality assurances program, a repeat kilovolt (KV) computed tomography was planned weekly during the 7-week treatment course. On each available scan, a single observer contoured the parotid submandibular, and thyroid glands (PG/SMG/TG), larynx (L), and constrictor, masticatory, and sternocleidomastoid muscles (CM/MM/SCM) as appropriate. The volume at each scan was compared with the one at planning CT in a pair-wise fashion. p values <0.05 after correction for multiple testing were considered significant. RESULTS: A total of 159 scans was obtained during treatment for a total of 185 scans, including the baseline imaging. All OARs showed statistically significant changes over baseline by week 5. At week 7, the PG showed the largest absolute change with an average reduction of ~10 mL followed by both the SCM and MM (~-5 mL). The largest (~-30%) relative change was observed for the salivary glands. L and CM showed a ~15% increase in volume during treatment. CONCLUSION: All selected OAR undergo significant volumetric changes during a course of IMRT for oropharyngeal squamous cell carcinoma. PMID- 21306972 TI - The International Collaboration on Air Pollution and Pregnancy Outcomes: initial results. AB - BACKGROUND: The findings of prior studies of air pollution effects on adverse birth outcomes are difficult to synthesize because of differences in study design. OBJECTIVES: The International Collaboration on Air Pollution and Pregnancy Outcomes was formed to understand how differences in research methods contribute to variations in findings. We initiated a feasibility study to a) assess the ability of geographically diverse research groups to analyze their data sets using a common protocol and b) perform location-specific analyses of air pollution effects on birth weight using a standardized statistical approach. METHODS: Fourteen research groups from nine countries participated. We developed a protocol to estimate odds ratios (ORs) for the association between particulate matter <= 10 MUm in aerodynamic diameter (PM10) and low birth weight (LBW) among term births, adjusted first for socioeconomic status (SES) and second for additional location-specific variables. RESULTS: Among locations with data for the PM10 analysis, ORs estimating the relative risk of term LBW associated with a 10-MUg/m3 increase in average PM10 concentration during pregnancy, adjusted for SES, ranged from 0.63 [95% confidence interval (CI), 0.30-1.35] for the Netherlands to 1.15 (95% CI, 0.61-2.18) for Vancouver, with six research groups reporting statistically significant adverse associations. We found evidence of statistically significant heterogeneity in estimated effects among locations. CONCLUSIONS: Variability in PM10-LBW relationships among study locations remained despite use of a common statistical approach. A more detailed meta-analysis and use of more complex protocols for future analysis may uncover reasons for heterogeneity across locations. However, our findings confirm the potential for a diverse group of researchers to analyze their data in a standardized way to improve understanding of air pollution effects on birth outcomes. PMID- 21306974 TI - The D-batable Institute of Medicine report: a D-lightful perspective. PMID- 21306976 TI - Trends in the incidence of occupational diseases in Lithuania between 1999 and 2008. AB - OBJECTIVES: The aim of the study was to investigate the trends in the incidence of occupational diseases in Lithuania during the period of 1999-2008. The analysis concerned both the individuals with diagnosed disease(s) and the number of diagnosed cases. MATERIAL AND METHODS: Incidence rates were calculated using data from the Republic of Lithuania National Register of Occupational Diseases and data on the employed population provided by the government Department of Statistics. The rates were age-standardized using the direct standardization method. The changes in the incidence rates throughout the study period were analyzed using segmented regression calculated with the JOINPOINT (v. 3.3.1) statistical software. We determined joinpoints in the dynamic lines of the incidence rates and calculated mean annual absolute change and mean annual relative (percentage) change for each period. RESULTS AND CONCLUSIONS: During the study period, the number of occupational diseases was, on average, 1.5 times as high as the number of individuals diagnosed with such diseases. Joinpoint positions in the dynamic lines of the incidence rates coincided for individuals with occupational diseases and for the cases of occupational diseases. The incidence was found to slightly increase during the period of 1999-2003, then to rise more rapidly during that of 2003-2006, and to decrease from 2006 to 2008. PMID- 21306975 TI - Description of a large-scale study design to assess work-stress-disease associations for cardiovascular disease. AB - We claim that a new level of studies is needed to answer a series of important questions about the expanding global chronic disease burden for cardiovascular disease (CVD) and for related conditions such as diabetes, metabolic syndrome, and obesity. These require a new study design structure, related to a new level of theory that goes beyond the current single-factor, a-theoretic epidemiological studies. This new platform for the design of large-scale Work/Stress/Disease studies would assess CVD-related disease mechanisms in a more general and dynamic form, based on the use of new tools for measuring autonomic functions in an occupational stress context and a new theory of disease causation. A sample outline is presented for such a study, based on Stress-Disequilibrium Theory (SDT) hypotheses, building on analytic tools developed for the assessment of stress-related exhaustion effects and chronic disease risks from Heart Rate Variability (HRV) research studies. The goal is to assess the associations between social organizational risks, particularly at work, and hypertension, metabolic syndrome, and diabetes II. The study design is multi-stage, spanning across several levels of disease-related de-regulation, and addressing co morbidity of the conditions themselves. The study design is meant to span across a broad social population at all levels and would probably be multi-site, involving several countries, to yield the larger sample increased power for finding associations for work - physiological effects. PMID- 21306977 TI - Noise exposure during ambulance flights and repatriation operations. AB - OBJECTIVES: Although ambulance flights are routine work and thousands of employees work in repatriation organizations, there is no data on noise exposure which may be used for preventive advice. We investigated the noise exposure of crews working in ambulance flight organizations for international patient repatriation to get the data for specific guidelines concerning noise protection. MATERIAL AND METHODS: Noise levels inside Learjet 35A, the aircraft type which is most often used for repatriation operations, were collected from locations where flight crews typically spend their time. A sound level meter class 1 meeting the DIN IEC 651 requirements was used for noise measurements, but several factors during the real flight situations caused a measurement error of ~3%. Therefore, the results fulfill the specifications for class 2. The data was collected during several real repatriation operations and was combined with the flight data (hours per day) regarding the personnel to evaluate the occupationally encountered equivalent noise level according to DIN 45645-2. RESULTS AND CONCLUSIONS: The measured noise levels were safely just below the 85 dB(A) threshold and should not induce permanent threshold shifts, provided that additional high noise exposure by non-occupational or private activities was avoided. As the levels of the noise produced by the engines outside the cabin are significantly above the 85 dB(A) threshold, the doors of the aircraft must be kept closed while the engines are running, and any activity performed outside the aircraft - or with the doors opened while the engines are running - must be done with adequate noise protection. The new EU noise directive (2003/10/EG) states that protective equipment must be made available to the aircrew to protect their hearing, though its use is not mandatory. PMID- 21306978 TI - Workplace exposures and male infertility - a case-control study. AB - OBJECTIVES: This study examined the association between male infertility and certain occupational exposures. MATERIAL AND METHODS: A case-control study was carried out from January 2008 to February 2009; on 255 infertile men and 267 fertile men controls. Occupational exposure to certain chemical, physical and psychological workplace hazards was assessed by self-report questionnaire. General and andrological examination was conducted for all participants, however, semen analysis was done only for the infertile men cases, because the fertile men controls refused to give semen samples. RESULTS: After adjustment of confounders, the results revealed that the following workplace exposure factors significantly increased the risk of male infertility: solvents and painting materials (OR: 3.88, 95% CI: 1.50-10.03), lead (OR: 5.43, 95% CI: 1.28-23.13), VDTs and computers (OR: 8.01, 95% CI: 4.03-15.87), shift work (OR: 3.60, 95% CI: 1.12 11.57) and work-related stress (fairly present: OR: 3.11, 95% CI: 1.85-5.24; often present: OR: 3.76, 95% CI: 1.96-7.52). CONCLUSION: In spite of the limitations of this study, it supports other studies that raise the attention to minimize the exposure to the workplace hazards that may affect the fertility of male workers. PMID- 21306979 TI - Exposure to polycyclic aromatic hydrocarbons and newborn biometric indicators. AB - OBJECTIVES: The aim of the study was to examine the impact of polycyclic aromatic hydrocarbons (PAH) on foetal growth. MATERIALS AND METHODS: The prospective Polish Mother and Child Cohort study was performed in 8 regions of Poland. The study population consisted of 449 mother-child pairs All women were interviewed three times during pregnancy (once in each trimester). 1-hydroxypyrene (1-HP) concentration in urine was chosen as the biomarker of exposure to PAH. The urine sample collected from the participant women between 20-24 weeks of pregnancy was analysed using high performance liquid chromatography (HPLC). The active and passive smoking exposure was verified by determination of saliva cotinine level using high performance liquid chromatography coupled with tandem mass spectrometry/positive electrospray ionisation (LC-ESI+MS/MS) and isotope dilution method. RESULTS: The exposure to PAH measured by 1-HP level in urine of pregnant women was significantly associated with child birth weight (beta = -158.3; p = 0.01), chest circumference (beta = -0.7; p = 0.02) and cephalisation index (beta = 4.2; p = 0.01) after adjustment for gestational age, child gender, pregnant woman marital status, educational level, season of last menstruation period (LMP), prepregnancy body mass index (BMI), and weight gain in pregnancy. After inclusion salivary cotinine levels into the analysis, the results were not statistically significant. CONCLUSIONS: Prenatal exposures to PAH adversely influence foetal development including child weight, length, head and chest circumference. Tobacco smoking is the important source of PAH. After controlling for active and passive smoking, the observed associations were not statistically significant. PMID- 21306980 TI - Effects of occupational exposure to arsenic on the nervous system: clinical and neurophysiological studies. AB - OBJECTIVES: A number of metals, especially heavy metals, exhibit neurotoxic properties. Neurological and neurophysiological studies indicate that the functions of the central (CNS) and peripheral nervous system (PNS) may be impaired under conditions of exposure to arsenic (As). The aim of the present study was to assess the effects of inorganic arsenic on the central and peripheral nervous system. MATERIALS AND METHODS: The study covered a group of 21 male workers (mean age: 41.9 yr; SD: 7.6; range: 31-55 yr) employed in a copper smelting factory. Their employment duration ranged from 5 to 33 years (mean: 18.1 yr; SD: 7.8). Arsenic concentrations in workplace air amounted to 0.01003 mg/m3 on average (SD: 0.00866). Urine arsenic concentrations ranged from 3.48 to 23.63 MUg/l (mean: 11.91 MUg/l; SD: 9.5). The control group consisted of 16 males non occupationally exposed to As, matched for gender, age and work shift pattern. The evaluation of neurological effects was based on the findings of neurological examination, electroencephalography (EEG), visual evoked potentials (VEPs) and electroneurography (ENeG). RESULTS: Clinical symptoms, such as sleeplessness or sleepiness, irritability, headache, painful spasms in extremity muscles, extremity paresthesia and pain, and muscular fatigue prevailed among functional disorders of the nervous system in workers chronically exposed to As. Neurological examination did not reveal any organic lesions in the CNS or PNS. In EEG records classified as abnormal, generalized changes were most common. VEP examinations revealed abnormalities in evoked response latency. Stimulation of the motor fibers of the peroneal and medial nerves resulted in a decreased amplitude of the motor potential. Stimulation of the sensory fibers of medial nerves brought about a decreased amplitude of the sensory potential and a lower conduction velocity of the sural nerves. CONCLUSION: The findings of the study indicate that exposure to As concentrations within the threshold limit values (TLV) can induce subclinical effects on the nervous system, especially subclinical neuropathy. PMID- 21306981 TI - Poisonings with street drugs:a review of 1993-2008 data from the toxicology unit in Poland. AB - OBJECTIVE: Drugs of abuse have been known in many cultures and geographical zones, and also in Poland the extent of substance abuse has been increasing. MATERIAL AND METHODS: This report refers to patients treated for poisonings with street drugs at the Toxicology Unit (TU), Lodz, Poland during the period 1993 2008. The data to be analyzed was obtained from medical files of all patients treated for street drugs or hallucinogens abuse. RESULTS: The kind of the drugs used has changed significantly; between 1993 and 1998 the majority of patients were opiate users, in 1999-2002 the dominant drug was amphetamine and in 2003 2008 there was recurrent increase in the number of opiate poisonings. Male patients were represented in the studied group more often than female ones. The percentages of patients treated after suicidal attempts ranged from 9.3% in 1993 1994 to 15.9% in 2007-2008. During the analyzed period 1993-2008, cases of overdose were less frequent, while accidental intoxications became more common. CONCLUSIONS: Drug abuse is a serious problem in Poland, it has expanded in recent years and it is likely to expand further in the years to come. The treatment of drug-addicted people needs to be improved and a suitable prevention program should be developed. PMID- 21306982 TI - Changes in blood pressure with compensatory heart rate decrease and in the level of aerobic capacity in response to repeated whole-body cryostimulation in normotensive, young and physically active men. AB - OBJECTIVE: In Poland and all over the world, whole-body cryostimulation is becoming more and more popular in the treatment of different diseases and in sport. However, changes that occur in the human body subjected to cryogenic temperatures are still not completely understood. Therefore, the aim of this study was to evaluate changes in blood circulation and aerobic capacity induced by repeated exposure to whole-body cryostimulation of young and clinically healthy male subjects. MATERIAL AND METHODS: The study included 25 young men, aged 21 +/- 0.9 years, average body weight 74.65 +/- 6.98 kg and height 179.5 +/- 5.12 cm. The participants were exposed to extremely low temperatures in a cryogenic chamber once a day for 15 days. Each session lasted 3 min at -130 degrees C and was preceded by 30-second, adaptation in a vestibule at -60 degrees C. Blood pressure and heart rate were measured before entering the chamber, immediately after exiting and 10 min later. We also calculated pulse pressure and the mean arterial blood pressure. Before and after the treatment the maximal oxygen uptake was measured. RESULTS: Our results showed a significant increase in systolic blood pressure after each cryostimulation (by an average of 19 mmHg) and an increase in diastolic blood pressure only after the first cryostimulation (by 6 mm Hg). The increase in systolic blood pressure was accompanied by a significant decrease in heart rate (by about 7 bpm). No adaptation changes were observed after 15 treatments. There were no changes in aerobic capacity after 15 sessions of WBC, however we observed a significant decrease in RBC and hemoglobin concentration. CONCLUSION: Due to the increase in systolic blood pressure after WBC, this kind of physiotherapy treatment is not recommended for people with advanced or not pharmacologically controlled hypertension. PMID- 21306983 TI - Static magnetic field affects oxidative stress in mouse cochlea. AB - OBJECTIVE: It has been shown that oxidative stress plays an important role in development of noise induced hearing loss. Since static magnetic fields (SMF) exposure may alter dynamics of oxidative processes in the tissue, the aim of the study was to assess the influence of SMF on noise-induced alteration in the cochlear level of reactive oxygen species (ROS) and hearing thresholds. MATERIALS AND METHODS: Auditory brainstem response (ABR), lipid peroxidation (LPO) levels, super-oxide dismutase (SOD) activity and catalase activity were assessed in the cochlea prior to, and at five time-points over two weeks following exposure of C57BL/6 mice to 8h, 119 dB SPL, 4 kHz octave band noise. RESULTS: The ABR indicated no permanent functional damage due to noise exposure either for the 4 kHz and 8 kHz SMF-exposed group or for animals not exposed to SMF. However, significant differences in LPO level, catalase and SOD activity between animals exposed to noise and SMF and those exposed to noise only were observed. CONCLUSIONS: The results suggest that SMF causes an increase in ROS level in the cochlea after noise exposure and, at the same time, it speeds up activation of antioxidative enzymes. PMID- 21306984 TI - The toxicokinetics of 2-methylnaphtalene in rats. AB - BACKGROUND: The aim of the study was to evaluate the toxicokinetics of 2 methylnaphtalene (2-MN) during and after inhalation exposure. MATERIAL AND METHODS: Male Wistar rats were exposed to 2-MN vapours at nominal concentrations of 200 or 400 mg/m3 in the dynamic inhalation chamber for 6 hours or 5 days (6 h/day). Blood samples were collected during and after exposure. Blood concentrations of 2-MN were estimated by gas chromatography using the headspace technique. RESULTS: During a 6-hour exposure to 200 or 400 mg/m3, blood 2-MN concentration increased rapidly within the first or second hour of exposure, respectively, after reaching a plateau. The elimination of 2-MN from blood followed an open two-compartment model. CONCLUSION: 2-MN was rapidly eliminated from blood of the animals exposed by inhalation to 2-MN. During exposure, lung retention of the chemical was found to decrease. Under conditions of repeated 2 MN exposure, no significant systemic 2-MN accumulation could be observed. PMID- 21306985 TI - Prevalence of latex allergy among healthcare workers. AB - OBJECTIVES: The use of latex gloves has increased by several folds in the recent past due to concerns about blood-borne infections. Data from Asian countries with regard to latex allergy is scarce. The objective of this study was to determine the prevalence and risk factors of latex allergy among healthcare workers in a tertiary hospital in Sri Lanka. MATERIAL AND METHODS: A cross-sectional survey was carried out among different categories of employees in the hospital. A self administered questionnaire was used to collect data related to latex allergy. RESULTS: A total of 524 employees was recruited and 62% responded to the questionnaire. Among them 49.2% wore gloves for more than 1 hour a day. Symptoms suggestive of latex allergy were reported by 53 (16.3%) subjects. A considerable proportion (11.4%) of workers had been suffering from latex allergy for more than 5 years. Nurses accounted for the highest prevalence for any job category, while the unit with the highest rate was the surgical ward. Duration in the service (OR = 1.006, P = 0.048) and wearing gloves for more than one hour a day (OR = 3.292, P = 0.004) were significant risk factors for latex allergy, but not atopy or family history of atopy. Seven employees noticed that they developed food allergy after assuming duties as healthcare personnel. CONCLUSIONS: Prevalence of latex allergy is high among healthcare workers in this study population. Environmental factors rather than genetic predisposition play the major role in the development of this condition. PMID- 21306986 TI - Investigating genetic outcomes following 1984 Toxic Union Carbide disaster in India: epidemiological challenges. PMID- 21306988 TI - The jasmonate-responsive element from the ORCA3 promoter from Catharanthus roseus is active in Arabidopsis and is controlled by the transcription factor AtMYC2. AB - Jasmonates are plant signaling molecules that play key roles in protection against certain pathogens and against insects by switching on the expression of genes encoding defense proteins including enzymes involved in the biosynthesis of toxic secondary metabolites. In Catharanthus roseus, the ethylene response factor (ERF) transcription factor ORCA3 controls the jasmonate-responsive activation of terpenoid indole alkaloid biosynthetic genes. ORCA3 gene expression is itself induced by jasmonate. Its promoter contains an autonomous jasmonate-responsive element (JRE). Here we describe the jasmonate-responsive activity of the JRE from the ORCA3 promoter in Arabidopsis thaliana. We found that it interacts in vitro and in vivo with the basic helix-loop-helix transcription factor AtMYC2. Analysis of JRE-mediated reporter gene expression in an atmyc2-1 mutant background showed that the activity was strictly dependent on AtMYC2. PMID- 21306989 TI - Common conformational changes induced in type 2 picornavirus IRESs by cognate trans-acting factors. AB - Type 2 internal ribosomal entry sites (IRESs) of encephalomyocarditis virus (EMCV), foot-and-mouth disease virus (FMDV) and other picornaviruses comprise five major domains H-L. Initiation of translation on these IRESs begins with specific binding of the central domain of initiation factor, eIF4G to the J-K domains, which is stimulated by eIF4A. eIF4G/eIF4A then restructure the region of ribosomal attachment on the IRES and promote recruitment of ribosomal 43S pre initiation complexes. In addition to canonical translation factors, type 2 IRESs also require IRES trans-acting factors (ITAFs) that are hypothesized to stabilize the optimal IRES conformation that supports efficient ribosomal recruitment: the EMCV IRES is stimulated by pyrimidine tract binding protein (PTB), whereas the FMDV IRES requires PTB and ITAF(45). To test this hypothesis, we assessed the effect of ITAFs on the conformations of EMCV and FMDV IRESs by comparing their influence on hydroxyl radical cleavage of these IRESs from the central domain of eIF4G. The observed changes in cleavage patterns suggest that cognate ITAFs promote similar conformational changes that are consistent with adoption by the IRESs of comparable, more compact structures, in which domain J undergoes local conformational changes and is brought into closer proximity to the base of domain I. PMID- 21306990 TI - QDMR: a quantitative method for identification of differentially methylated regions by entropy. AB - DNA methylation plays critical roles in transcriptional regulation and chromatin remodeling. Differentially methylated regions (DMRs) have important implications for development, aging and diseases. Therefore, genome-wide mapping of DMRs across various temporal and spatial methylomes is important in revealing the impact of epigenetic modifications on heritable phenotypic variation. We present a quantitative approach, quantitative differentially methylated regions (QDMRs), to quantify methylation difference and identify DMRs from genome-wide methylation profiles by adapting Shannon entropy. QDMR was applied to synthetic methylation patterns and methylation profiles detected by methylated DNA immunoprecipitation microarray (MeDIP-chip) in human tissues/cells. This approach can give a reasonable quantitative measure of methylation difference across multiple samples. Then DMR threshold was determined from methylation probability model. Using this threshold, QDMR identified 10,651 tissue DMRs which are related to the genes enriched for cell differentiation, including 4740 DMRs not identified by the method developed by Rakyan et al. QDMR can also measure the sample specificity of each DMR. Finally, the application to methylation profiles detected by reduced representation bisulphite sequencing (RRBS) in mouse showed the platform-free and species-free nature of QDMR. This approach provides an effective tool for the high-throughput identification of potential functional regions involved in epigenetic regulation. PMID- 21306991 TI - RATT: Rapid Annotation Transfer Tool. AB - Second-generation sequencing technologies have made large-scale sequencing projects commonplace. However, making use of these datasets often requires gene function to be ascribed genome wide. Although tool development has kept pace with the changes in sequence production, for tasks such as mapping, de novo assembly or visualization, genome annotation remains a challenge. We have developed a method to rapidly provide accurate annotation for new genomes using previously annotated genomes as a reference. The method, implemented in a tool called RATT (Rapid Annotation Transfer Tool), transfers annotations from a high-quality reference to a new genome on the basis of conserved synteny. We demonstrate that a Mycobacterium tuberculosis genome or a single 2.5 Mb chromosome from a malaria parasite can be annotated in less than five minutes with only modest computational resources. RATT is available at http://ratt.sourceforge.net. PMID- 21306992 TI - Assay of both activities of the bifunctional tRNA-modifying enzyme MnmC reveals a kinetic basis for selective full modification of cmnm5s2U to mnm5s2U. AB - Transfer RNA (tRNA) contains a number of complex 'hypermodified' nucleosides that are essential for a number of genetic processes. Intermediate forms of these nucleosides are rarely found in tRNA despite the fact that modification is not generally a complete process. We propose that the modification machinery is tuned into an efficient 'assembly line' that performs the modification steps at similar, or sequentially increasing, rates to avoid build-up of possibly deleterious intermediates. To investigate this concept, we measured steady-state kinetics for the final two steps of the biosynthesis of the mnm(5)s(2)U nucleoside in Escherichia coli tRNA(Glu), which are both catalysed by the bifunctional MnmC enzyme. High-performance liquid chromatography-based assays using selectively under-modified tRNA substrates gave a K(m) value of 600 nM and k(cat) 0.34 s(-1) for the first step, and K(m) 70 nM and k(cat) 0.31 s(-1) for the second step. These values show that the second reaction occurs faster than the first reaction, or at a similar rate at very high substrate concentrations. This result indicates that the enzyme is kinetically tuned to produce fully modified mnm(5)(s(2))U while avoiding build-up of the nm(5)(s(2))U intermediate. The assay method developed here represents a general approach for the comparative analysis of tRNA-modifying enzymes. PMID- 21306993 TI - Distant positioning of proteasomal proteolysis relative to actively transcribed genes. AB - While it is widely acknowledged that the ubiquitin-proteasome system plays an important role in transcription, little is known concerning the mechanistic basis, in particular the spatial organization of proteasome-dependent proteolysis at the transcription site. Here, we show that proteasomal activity and tetraubiquitinated proteins concentrate to nucleoplasmic microenvironments in the euchromatin. Such proteolytic domains are immobile and distinctly positioned in relation to transcriptional processes. Analysis of gene arrays and early genes in Caenorhabditis elegans embryos reveals that proteasomes and proteasomal activity are distantly located relative to transcriptionally active genes. In contrast, transcriptional inhibition generally induces local overlap of proteolytic microdomains with components of the transcription machinery and degradation of RNA polymerase II. The results establish that spatial organization of proteasomal activity differs with respect to distinct phases of the transcription cycle in at least some genes, and thus might contribute to the plasticity of gene expression in response to environmental stimuli. PMID- 21306994 TI - Adenovirus vector-mediated assay system for hepatitis C virus replication. AB - The efficient delivery of the hepatitis C virus (HCV) RNA subgenomic replicon into cells is useful for basic and pharmaceutical studies. The adenovirus (Ad) vector is a convenient and efficient tool for the transduction of foreign genes into cells in vitro and in vivo. However, an Ad vector expressing the HCV replicon has never been developed. In the present study, we developed Ad vector containing an RNA polymerase (pol) I-dependent expression cassette and a tetracycline-controllable RNA pol I-dependent expression system. We prepared a hybrid promoter from the tetracycline-responsive element and the RNA pol I promoter. Ad vector particles coding the hybrid promoter-driven HCV replicon could be amplified, and interferon, an inhibitor of HCV replication, reduced HCV replication in cells transduced with the Ad vector coding HCV replicon. This is the first report of the development of an Ad vector-mediated HCV replicon system. PMID- 21306998 TI - Peripheral neuropathy is associated with increased serum levels of uric acid in type 2 diabetes mellitus. AB - We assessed serum uric acid (SUA) levels in patients with type 2 diabetes mellitus (T2DM) with or without peripheral neuropathy (diagnosed by the Neuropathy Disability score [NDS]). We enrolled 64 patients with T2DM with peripheral neuropathy (group A: 31 men, mean age 63.0 +/- 2.8 years) and 66 age-, gender-, renal function- and T2DM duration-matched patients without neuropathy (group B: 32 men, mean age 62.4 +/- 3.1 years). Serum uric acid was significantly higher in group A (P < .001). There was a significant correlation between SUA and NDS in both groups (group A: r(s) = .93, P < .001; group B: r( s) = .95, P < .001). C-reactive protein (CRP) was also significantly higher in group A (P < .001) and correlated significantly with SUA in both groups (group A: r(s) = .93, P < .001; group B: r(s) = .87, P < .001). Serum uric acid is increased in patients with T2DM with neuropathy versus those without. Whether SUA is involved in the pathogenesis of T2DM peripheral neuropathy remains to be established. PMID- 21306995 TI - A novel immunity system for bacterial nucleic acid degrading toxins and its recruitment in various eukaryotic and DNA viral systems. AB - The use of nucleases as toxins for defense, offense or addiction of selfish elements is widely encountered across all life forms. Using sensitive sequence profile analysis methods, we characterize a novel superfamily (the SUKH superfamily) that unites a diverse group of proteins including Smi1/Knr4, PGs2, FBXO3, SKIP16, Syd, herpesviral US22, IRS1 and TRS1, and their bacterial homologs. Using contextual analysis we present evidence that the bacterial members of this superfamily are potential immunity proteins for a variety of toxin systems that also include the recently characterized contact-dependent inhibition (CDI) systems of proteobacteria. By analyzing the toxin proteins encoded in the neighborhood of the SUKH superfamily we predict that they possess domains belonging to diverse nuclease and nucleic acid deaminase families. These include at least eight distinct types of DNases belonging to HNH/EndoVII- and restriction endonuclease-fold, and RNases of the EndoU-like and colicin E3-like cytotoxic RNases-folds. The N-terminal domains of these toxins indicate that they are extruded by several distinct secretory mechanisms such as the two-partner system (shared with the CDI systems) in proteobacteria, ESAT-6/WXG-like ATP dependent secretory systems in Gram-positive bacteria and the conventional Sec dependent system in several bacterial lineages. The hedgehog-intein domain might also release a subset of toxic nuclease domains through auto-proteolytic action. Unlike classical colicin-like nuclease toxins, the overwhelming majority of toxin systems with the SUKH superfamily is chromosomally encoded and appears to have diversified through a recombination process combining different C-terminal nuclease domains to N-terminal secretion-related domains. Across the bacterial superkingdom these systems might participate in discriminating 'self' or kin from 'non-self' or non-kin strains. Using structural analysis we demonstrate that the SUKH domain possesses a versatile scaffold that can be used to bind a wide range of protein partners. In eukaryotes it appears to have been recruited as an adaptor to regulate modification of proteins by ubiquitination or polyglutamylation. Similarly, another widespread immunity protein from these toxin systems, namely the suppressor of fused (SuFu) superfamily has been recruited for comparable roles in eukaryotes. In animal DNA viruses, such as herpesviruses, poxviruses, iridoviruses and adenoviruses, the ability of the SUKH domain to bind diverse targets has been deployed to counter diverse anti-viral responses by interacting with specific host proteins. PMID- 21306997 TI - Knockdown of oncogenic KRAS in non-small cell lung cancers suppresses tumor growth and sensitizes tumor cells to targeted therapy. AB - Oncogenic KRAS is found in more than 25% of lung adenocarcinomas, the major histologic subtype of non-small cell lung cancer (NSCLC), and is an important target for drug development. To this end, we generated four NSCLC lines with stable knockdown selective for oncogenic KRAS. As expected, stable knockdown of oncogenic KRAS led to inhibition of in vitro and in vivo tumor growth in the KRAS mutant NSCLC cells, but not in NSCLC cells that have wild-type KRAS (but mutant NRAS). Surprisingly, we did not see large-scale induction of cell death and the growth inhibitory effect was not complete. To further understand the ability of NSCLCs to grow despite selective removal of mutant KRAS expression, we conducted microarray expression profiling of NSCLC cell lines with or without mutant KRAS knockdown and isogenic human bronchial epithelial cell lines with and without oncogenic KRAS. We found that although the mitogen-activated protein kinase pathway is significantly downregulated after mutant KRAS knockdown, these NSCLCs showed increased levels of phospho-STAT3 and phospho-epidermal growth factor receptor, and variable changes in phospho-Akt. In addition, mutant KRAS knockdown sensitized the NSCLCs to p38 and EGFR inhibitors. Our findings suggest that targeting oncogenic KRAS by itself will not be sufficient treatment, but may offer possibilities of combining anti-KRAS strategies with other targeted drugs. PMID- 21306999 TI - Is deferasirox implicated in multiple organ failure in a patient with homozygous beta-thalassemia? AB - We herein report a case of a thalassemic-patient who was on deferasirox chelation therapy and admitted to the emergency department because of fever, diffuse abdominal pain and altered mental status. Despite the appropriate treatment he died two days later due to cardiac arrest. As we failed to recognize any etiology and the patients' relatives denied a post mortem examination due to religious reasons, we cannot provide any additional data. However, we are wondering whether this incident might be related to deferasirox. PMID- 21307000 TI - Coronary artery endothelial dysfunction associated with sleep apnea. AB - There is little information about coronary artery endothelial dysfunction in patients with sleep apnea. We evaluated relation between severity of sleep apnea and coronary artery endothelial dysfunction. In all, 26 patients without significant coronary stenoses were enrolled. Endothelial function was estimated by measuring coronary vasoreactivity in response to acetylcholine infusion (10( 7) mol/L) into coronary arteries. Vasoconstriction rate was defined as ([lumen diameter after isosorbide dinitrate injection - lumen diameter after acetylcholine injection]/lumen diameter after isosorbide dinitrate injection * 100). Vasoconstriction rate was calculated at each major coronary artery and the highest value was used for that patient. Overnight sleep study was performed and the apnea-hypopnea index (AHI) was calculated as the mean number of apneas and hypopneas per hour of sleep. There was significant correlation between AHI and vasoconstriction rate (P = .04). There is significant correlation between severity of sleep apnea and endothelial function of coronary arteries. PMID- 21307001 TI - The management of asymptomatic carotid plaque disease: our assumptions when we are less radical. AB - The management of asymptomatic carotid artery stenosis (CAS) has been the subject of extensive debate. Current evidence suggests that the annual risk of stroke in patients with CAS and without previous cerebrovascular symptoms is 1% which makes carotid endarterectomy unjustifiable. Conservative treatment with statins and antiplatelets, the identification of the high risk individuals as well as aggressive life style modifications are considered sufficient measures for the protection of these patients. However, there are reasons to believe that this approach may be less effective than we think. Best medical treatment is only effective when compliance is adequate and lipid or blood pressure target levels are achieved. However this is not always the case and the same applies regarding life style modification changes such as smoking. In addition, there is no consensus regarding the identification of the high risk individuals despite recent encouraging evidence. The introduction of a structured network of risk factor modification clinics in conjunction with the vascular clinics and the identification of ways to objectively risk-stratify patients with asymptomatic CAS could enable us to optimize the management of these patients when we decide to be less radical. PMID- 21307002 TI - Validation of the GRACE Risk score for hospital mortality in patients with acute coronary syndrome in the Arab Middle East. AB - Our objective was to validate the Global Registry of Acute Coronary Events (GRACE) risk score for in-hospital mortality in a Middle Eastern acute coronary syndrome (ACS) population enrolled in the Gulf Registry of Acute Coronary Events (Gulf RACE). Out of 8176, unselected, consecutive patients with ACS, during 6 months in 2006 and 2007 from 63 hospitals in 6 Arab countries in the Middle East Gulf region, 7709 (94.3%) with available data were included. The main outcome measures were discriminatory performance (using C-index) and calibration of the GRACE risk score (in-hospital mortality predicted by GRACE risk score versus the actual mortality). In-hospital mortality in the Gulf RACE was 3.09% (n = 238). The discriminatory performance of the GRACE risk scores in the Gulf RACE was good overall (C-index = 0.86). Observed and predicted risk corresponded well in each stratum of risk of in-hospital mortality. This suggests its suitability for clinical use in this patient population. PMID- 21307003 TI - Homocysteine and serum-lipid levels in pulmonary embolism. AB - Pulmonary embolism (PE) is a fatal disease that arises from genetic and environmental factors. There is little evidence for low high-density lipoprotein cholesterol (HDL-C) with hyperhomocysteinemia to lead to PE. Therefore, we evaluated homocysteine levels and lipid profile in PE patients and to display risk for PE. Forty six patients with proven PE and 46 healthy controls were included in the study. Homocysteine and serum lipid levels were calculated and compared in both groups. There were no significant differences between two groups in terms of total cholesterol, triglyceride, and low-density lipoprotein cholesterol. In PE group, HDL-C levels were found significantly lower in comparison to the control group (P = .004). Mean homocysteine levels were significantly higher in PE group than in the control group (P = .001). High density lipoprotein cholesterol levels were significantly low in which homocysteine levels were high in the PE group. We thought that low HDL-C level with hyperhomocysteinemia is susceptible to PE. PMID- 21307004 TI - Elevated cardiac biomarkers with normal right ventricular size indicate an unlikely diagnosis of acute pulmonary embolism in stable patients. AB - The purpose of this investigation is to assess the prevalence of elevated cardiac biomarkers, with or without estimates of right ventricular (RV) size, in stable patients with acute pulmonary embolism (PE). Our hypothesis is that the combination of high levels of cardiac troponin I (cTnI), high creatine kinase isoenzyme MB (CK-MB), and normal size RV are sufficiently uncommon in stable patients with PE to make the diagnosis of PE unlikely. Retrospective review showed a high cTnI plus high CK-MB in 20 (3.4%) of 585 stable patients with acute PE. A high cTnI plus high CK-MB with normal RV size was shown in 5 (1.9%) of 264 patients. In stable patients with such findings, therefore, PE is unlikely and other diagnoses, particularly acute coronary syndrome, should be considered before pursuing a diagnosis of PE. PMID- 21307005 TI - Nursing structures in New Zealand public hospitals: current configurations. AB - This article reports research reviewing the configuration of nursing leadership in New Zealand public hospitals. It represents an analysis of Phase 1 of a larger study. Leadership in nursing is critical if the profession is to meet the challenges of health services in the 21st century. The research focuses on how leadership in public hospitals is structured at a strategic level. The preliminary summary of findings of this phase of the research show that reporting lines between directors of nursing (DON) and the chief executive officer (CEO) are not always direct, and organizational charts and nursing structures are not readily aligned. Clear financial or budget holding reporting lines by nursing leadership are not easily identified, or are professional and operational accountability lines clearly defined. From 15 total responses received, the organizations are structured differently both organizationally and in the nursing structures. PMID- 21307007 TI - Pharmacokinetics of ropivacaine in patients with chronic renal failure. AB - BACKGROUND: As ropivacaine and its metabolites are excreted by the kidneys, we studied their disposition in subjects with renal dysfunction. METHODS: Twenty patients with moderate or severe renal insufficiency and 10 healthy volunteers received ropivacaine 1 mg kg(-1) i.v. over 30 min. The concentrations of ropivacaine and its main metabolites, pipecoloxylidide (PPX) and 3-hydroxy ropivacaine, were measured in plasma and urine for 16-48 h. The relationship between pharmacokinetic parameters and creatinine clearance (CL(CR)) was assessed. A model for estimating non-renal clearance of a metabolite of ropivacaine is described. RESULTS: Renal dysfunction had little or no influence on the pharmacokinetics of ropivacaine. The median plasma concentrations of unbound ropivacaine were similar in uraemic and non-uraemic subjects. Renal clearance of PPX correlated significantly with CL(CR) (R(2)=0.81). Lack of correlation between total PPX exposure, expressed as area under the total plasma concentration-time curve from zero to infinity, and CL(CR) suggests that the clearance of PPX also includes non-renal elimination. However, in two uraemic patients, there was increased exposure to PPX resulting from low non-renal elimination. CONCLUSIONS: The pharmacokinetics of ropivacaine is not affected by renal failure. Although the renal clearance of PPX correlates with CL(CR), non renal elimination seems to compensate for reduced renal clearance in most patients. PPX may accumulate in plasma during long-term postoperative infusions, in particular in patients with co-existing low non-renal elimination. Systemic toxicity is still unlikely because PPX is markedly less toxic than ropivacaine. PMID- 21307006 TI - Normal adult aging and the contextual influences affecting speech and meaningful sound perception. AB - It is widely accepted that hearing loss increases markedly with age, beginning in the fourth decade ISO 7029 (2000). Age-related hearing loss is typified by high frequency threshold elevation and associated reductions in speech perception because speech sounds, especially consonants, become inaudible. Nevertheless, older adults often report additional and progressive difficulties in the perception and comprehension of speech, often highlighted in adverse listening conditions that exceed those reported by younger adults with a similar degree of high-frequency hearing loss (Dubno, Dirks, & Morgan) leading to communication difficulties and social isolation (Weinstein & Ventry). Some of the age-related decline in speech perception can be accounted for by peripheral sensory problems but cognitive aging can also be a contributing factor. In this article, we review findings from the psycholinguistic literature predominantly over the last four years and present a pilot study illustrating how normal age-related changes in cognition and the linguistic context can influence speech-processing difficulties in older adults. For significant progress in understanding and improving the auditory performance of aging listeners to be made, we discuss how future research will have to be much more specific not only about which interactions between auditory and cognitive abilities are critical but also how they are modulated in the brain. PMID- 21307008 TI - Propofol inhibits lipopolysaccharide-induced lung epithelial cell injury by reducing hypoxia-inducible factor-1alpha expression. AB - BACKGROUND: Lipopolysaccharide (LPS) may activate hypoxia-inducible factor (HIF) 1alpha, which up-regulates cytokine expression and the lethality of LPS-induced shock. We investigated the effect of propofol on HIF-1alpha expression and acute lung injury in LPS-treated mice. METHODS: A series of both positive and negative control experiments were performed. We injected BALB/C mice with propofol or vehicle i.p. immediately and 12 h after an LPS challenge. After 24 h, we examined the lung wet/dry weight ratio, neutrophil infiltration, and HIF-1alpha mRNA expression and inflammatory cytokines in the lung tissue. Survival was determined for 48 h after LPS injection. In vitro, we determined the responses of A549 cells, with and without HIF-1alpha silenced, to treatment with LPS alone and LPS plus propofol. RESULTS: Propofol prolonged survival and attenuated acute lung injury and decreased the expression of HIF-1alpha, interleukin (IL)-6, keratinocyte-derived chemokine, and tumour necrosis factor-alpha (TNF-alpha) in the lungs of endotoxaemic mice. In HIF-1alpha knockdown-A549 cells, LPS-induced TNF-alpha, IL-6, and the pro-apoptotic gene, BNIP3 expression and apoptosis were reduced. Propofol, but not an inhibitor of nuclear factor kappaB, reduced HIF 1alpha expression in LPS-stimulated A549 cells. Propofol also down-regulated, in A549 cells, the expression of IL-6, IL-8, and TNF-alpha, Bcl-2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3), and apoptosis. CONCLUSIONS: Propofol reduces apoptosis in LPS-stimulated lung epithelial cells by decreasing HIF-1alpha, BNIP3, and cytokine production. Using propofol to inhibit HIF-1alpha expression may protect against the acute lung injury caused by LPS-induced sepsis. PMID- 21307009 TI - Dexmedetomidine inhibits gastric emptying and oro-caecal transit in healthy volunteers. AB - BACKGROUND: Dexmedetomidine is a potent and selective alpha2-adrenoceptor agonist used for perioperative and intensive care sedation with certain beneficial qualities. However, based on preclinical observations, it might inhibit gastric emptying and gastrointestinal transit, which could result in unwanted effects in intensive care patients. This study evaluated the effects of dexmedetomidine on gastric emptying and oro-caecal transit time in healthy volunteers. METHODS: Twelve healthy male subjects were given 1 ug kg(-1) of dexmedetomidine i.v. over 20 min followed by a continuous i.v. infusion of 0.7 ug kg(-1) h(-1) for 190 min. For comparison, subjects were also given 0.10 mg kg(-1) of morphine hydrochloride i.v. over 20 min and a placebo infusion in a randomized order. Gastric emptying was assessed with the paracetamol absorption test and oro-caecal transit time with the hydrogen breath test. RESULTS: The time to maximum paracetamol concentration in plasma was significantly longer, maximum paracetamol concentration was significantly lower, the area under the plasma paracetamol concentration-time curve was significantly smaller, and oro-caecal transit time was significantly longer during dexmedetomidine infusion compared with morphine or placebo infusion. CONCLUSIONS: Dexmedetomidine markedly inhibits gastric emptying and gastrointestinal transit in healthy volunteers. PMID- 21307010 TI - Video thoracoscopic assistance in open en bloc 2-stage esophagectomy facilitates both R0 dissection and thoracostomy tube placement. PMID- 21307011 TI - The culdotomy two U procedure for vaginal ovarian cystectomy. AB - When transvaginal removal of ovarian cysts is performed successfully, the procedure compares favorably with laparoscopy in terms of invasiveness. However, the approach into peritoneal cavity has been laborious. The objective was to evaluate feasibility of an ultrasound-guided culdotomy using a newly developed umbrella needle. New culdotomy was performed on 36 patients with ovarian cysts. Each cyst was directly punctured by the needle from vagina under ultrasound guidance. The vaginal walls on both sides of the needle were incised with an electric scalpel. Through the wound, cyst was exteriorized and enucleated. Preoperative characteristics of patients, outcome, operating time, blood loss, complications, and cyst histology were analyzed. Culdotomy was performed successfully in all cases. Operating time was less than 10 minutes and blood loss was less than 10 mL. There were no culdotomy-associated complications. Culdotomy assisted by ultrasound imaging and an umbrella needle is a simple, safe, and reliable method for vaginal ovarian cystectomy. PMID- 21307012 TI - Hand-assisted laparoscopic donor nephrectomy: are hand port devices really necessary? AB - BACKGROUND: Hand port devices (HPD) are used routinely for hand-assisted laparoscopic surgery including hand-assisted laparoscopic donor nephrectomy (HALDN). However, the cost of such devices may prove prohibitive, particularly in centers with financial constraints. The authors aimed to identify any adverse effects of performing device-free HALDN. METHODS: A retrospective analysis was performed of patients undergoing HALDN at the authors' unit over a 3-year period (2007-2010). Eighty-four patients underwent device-free HALDN, whereas in 80 patients a HPD was used. The primary endpoint was duration of operation, with secondary endpoints including postoperative wound infections and incisional hernias. RESULTS: here was no difference in duration of operation for the device free (98 minutes; range = 43-215 minutes) compared with the HPD group (94 minutes; range = 36-180 minutes; P = .37). A device was required in 3 (3.6%) patients in which a device-free approach was attempted. There was no difference in either group in terms of rates of postoperative wound infections (0% vs 2.5%, respectively; P = .24) or incisional hernia incidence (1.5% vs 1.4%, respectively; P = .50). CONCLUSION: Device-free HALDN can be performed with no discernable compromise in operating time or patient outcome. This has implications in both cost benefit and translation of this technique to developing units. PMID- 21307013 TI - A novel low-cost simulator for laparoscopic inguinal hernia repair. AB - Despite the advantages of laparoscopic inguinal hernia repair over the open approach in selected situations, laparoscopic inguinal hernia repair (LIHR) remains a challenge to teach and learn. The purpose of this study was to develop and validate a low-cost adaptable simulator for evaluation and training of LIHR. McGill Laparoscopic Inguinal Hernia Simulator (MLIHS) is a physical simulator that accurately represents inguinal anatomy. MLIHS permits to perform both transabdominal pre-peritoneal (TAPP) and totally extraperitoneal (TEP) repairs. Six experienced surgeons performed TAPP repairs using MLIHS. They were surveyed to establish face validity, and were scored using a previously validated global rating scale (maximum score = 25). Experienced surgeons considered MLIHS a useful tool for evaluating and training of LIHR. The mean (SD) global rating scores were 24.0 (+/- 0.6). The experienced surgeons considered MLIHS very useful for training and assessment. MLIHS is a valuable and affordable tool for training and evaluation of LIHR. PMID- 21307014 TI - Transoral incisionless fundoplication offers high patient satisfaction and relief of therapy-resistant typical and atypical symptoms of GERD in community practice. AB - This retrospective study evaluated clinical outcomes in 124 consecutive gastroesophageal reflux disease (GERD) patients who underwent transoral incisionless fundoplication (TIF) at 2 community hospitals. Out of 123 patients treated successfully, 110 gave consent (74% female, median age 60 [range 21-87] years, body mass index 27.5 [19.0-47.9]). At a median 7-month follow-up (range 5 17), typical and atypical symptom scores were normalized in 75% to 80% of patients, proton pump inhibitors (PPIs) were completely discontinued by 93%, and 83% were satisfied with their current health condition. Endoscopy in 53 patients revealed Hill grade I tight valves in 89% of the cases, reduced hiatal hernia in 33/34 (97%), and healed reflux esophagitis in 25/30 (83%). Based on global analysis, 72% of the patients were in remission, 20% improved symptomatically, and only 8% had ongoing GERD. These results supported the safety and efficacy of TIF as well as encouraged its application as an alternative treatment of GERD refractory to PPIs. PMID- 21307015 TI - Usefulness of harmonic focus during axillary lymph node dissection: a prospective study. AB - BACKGROUND: Axillary node dissection (ALND) is affected by various complications, (hematoma, seroma, lymphocele, infections). The aim of this study was to evaluate the effectiveness of Harmonic Focus (HF) in reducing these complications. MATERIALS AND METHODS: 92 patients requiring ALND, were divided into two group: Group A (HF) (33 women, 14 men), and Group B (control) (28 women, 17 men). RESULTS: Operating time was lower in Group A than in Group B. The amount of drain volume was lower in Group A than in Group B, the drain was removed earlier in Group A than in Group B. Seroma incidence was lower in Group A than in Group B. CONCLUSIONS: The use of HF during ALND is effective in reducing operating time, drain volume and complications. PMID- 21307016 TI - Quasi-continuous autodriven system with multiple rates for distraction osteogenesis. AB - INTRODUCTION: For a given rate of distraction a greater frequency of distraction improves bone formation. However, the current distractors used in clinic are activated manually and produces intermittent advancement. METHOD: The authors developed an automatic driver that is capable of producing quasi-continuous distraction at a set of rates of 0.5, 1.0, 1.5, 2.0, 2.5, and 3.0 mm/d. Using a customized in vitro experimental system, the function and stability of the autodriven system were tested during loading. RESULTS: The angular displacement of the automatic driver was quite regular while driving a constant torque of 4.268 * 10-(3) kg m. The driving achieved the target speed with the constant torque. CONCLUSIONS: The automatic driven system provides a useful tool to assess the tissue healing at variable distraction rates with quasi-continuous traction. It demonstrates a potential for clinical application to shorten the treatment course of distraction osteogenesis. PMID- 21307017 TI - Cerebrovascular biomodeling for aneurysm surgery: simulation-based training by means of rapid prototyping technologies. AB - OBJECTIVE: Opportunities for developing procedural skills are progressively rare. Therefore, sophisticated educational tools are highly warranted. METHODS: This study compared stereolithography and 3-dimensional printing for simulating cerebral aneurysm surgery. The latter jets multiple materials simultaneously and thus has the ability to print assemblies of multiple materials with different features. The authors created the solid skull and the cerebral vessels in different materials to simulate the real aneurysm when clipped. RESULTS: Precise plastic replicas of complex anatomical data provide intuitive tactile views that can be scrutinized from any perspective. Hollowed out vessel sections allow serial clipping efforts, evaluation of different clips, and clip positions. The models can be used for accurate prediction of vascular anatomy, for optimization of teaching surgical skills, for advanced procedural competency training, and for patient counseling. CONCLUSION: Simultaneous 3-dimensional printing is the most promising rapid prototyping technique to produce biomodels that meet the high demands of neurovascular surgery. PMID- 21307018 TI - Comparison of different surgical techniques in distal pancreatectomy: an experimental study in a porcine model. AB - AIMS: Different surgical transection methods have been used for distal pancreatectomy (DP), but none of them has yet achieved perfect results. This study compares 2 standard transection techniques with the alternative LigaSure technique. METHODS: Forty-eight pigs underwent a DP. Sixteen animals were operated on with a scalpel followed by hand suturing. Sixteen pigs received a DP using an Endo GIA, and the pancreas of 16 pigs was transected with LigaSure. The transection surface of remnant pancreas was observed for liquid collection and abscess on postoperative day 7. RESULTS: Operating time on the day of DP was significantly different, with a shorter operating time in the stapler and LigaSure groups. The morbidity on postoperative day 7 was similar in all groups. CONCLUSION: In the present experimental animal study, LigaSure seems to be fast and safe as well as comparable with the standard transection and closure techniques in DP. PMID- 21307019 TI - Stapled trans-anal rectal resection (STARR) in the surgical treatment of the obstructed defecation syndrome: results of STARR Italian Registry. AB - PURPOSE: This study was designed to evaluate the safety and efficacy of stapled trans-anal rectal resection (STARR) in the treatment of obstructed defecation syndrome ODS by the analysis of the data collected in the STARR Italian Registry (SIR) with a special emphasis on the analysis of symptoms and quality of life. METHODS: Collected data included, preoperative tests findings, and the evaluation of symptoms; the latter was obtained by using dedicated tools such as the Obstructed Defecation Syndrome Score (ODS-S), the Severity Symptom Score (SSS), and the Continence Grading Scale (CGS). Data on the quality of life were collected by Patient Assessment of Constipation Quality of Life (PAC-QoL) and the Euro Quality of Life-5 Domains Visual Analogue Scale (EQ-5D VAS). The evaluation of the symptoms and the quality of life was repeated 6 and 12 months after surgery. RESULTS: The SIR had collected data on 2171 patients (1653 females, 76.1%; mean age 56.2 years; range 20-96 years). A significant improvement (P < .0001) was seen between preoperative and 12-month follow-up in all scores: ODS-S (16.7 vs. 5.0), SSS (15.6 vs. 2.6), CGS (2.0 vs. 0.7), PAC-QoL (51.0 vs. 22.1), and EQ-5D VAS (57.5 vs. 85.7). Complications included defecatory urgency (4.5% at 12 months), bleeding (3.6%), perineal sepsis (3.4%), and one case of rectovaginal fistula (0.05%). CONCLUSION: The analysis of SIR data seems to confirm that STARR is a safe and effective procedure in the treatment of ODS. However, further studies are required to evaluate the long-term stability of results. PMID- 21307020 TI - Catheter ablation of ventricular tachycardia originating from the diverticulum of the right ventricular outflow tract. PMID- 21307021 TI - Catheter ablation of right ventricular outflow tract tachycardia: a simplified remote-controlled approach. AB - AIMS: Manual mapping and ablation of right ventricular outflow tract (RVOT) tachycardia may be associated with cardiac perforation and complicated by mechanically induced ventricular extrasystoles (VESs). The aim of this study was to assess remote-controlled magnetic (RCM) mapping and ablation of RVOT ventricular tachycardia (VT)/VES utilizing a soft magnetic catheter. METHODS AND RESULTS: Mapping and ablation of RVOT VT/VES were performed using the magnetic navigation system (MNS, Niobe II, Stereotaxis, St Louis, MO) in conjunction with a cardiodrive motor unit (Stereotaxis). A soft magnetic catheter (Celsius RMT, 4 mm solid tip, Biosense Webster, Diamond Bar, CA) was navigated to the RVOT using a sequence of pre-installed magnetic vectors. The primary endpoint was defined as successful RCM VT/VES ablation. Other parameters observed included RCM RVOT accessibility, mapping-induced mechanical VES, fluoroscopy time, complications, and arrhythmia recurrence. Thirteen consecutive patients (mean age: 50 +/- 14 years; 10 females, 6 RVOT VT) underwent RCM mapping and ablation. The RVOT was reached in all patients utilizing solely the MNS. Successful RCM RVOT ablation was achieved in {12 of 13} (92.3%) patients. Mean procedure and fluoroscopy times were 116.5 +/- 48.9 and 7.5 +/- 4.3 min, respectively. Catheter-induced VES during RVOT mapping were observed in {1 in 13} patients (7.7%, three VES). No complications occurred. During a mean follow-up of 252 +/- 211 days, clinical arrhythmia recurrence was observed in {1 in 13} (7.7%) patients. CONCLUSIONS: Automatic RCM RVOT access is feasible, while RVOT mapping and ablation appear to be safe, fast, and effective. The soft magnetic catheter rarely induces mechanical VES. PMID- 21307022 TI - Excretion of volatile 131I from rats following administration of Na131I or MIBG 131I. AB - Current practice for radiation protection associated with (131)I therapy mainly focuses on external and internal exposure caused by physical contamination of the hospital staff, other patients and family members. However, if volatile (131)I is excreted by the treated patients, these individuals could also be exposed through inhalation of (131)I. This study quantifies the amount of volatile (131)I excreted by rats after intravenous administration of metaiodobenzylguanidine (MIBG)-(131)I or Na(131)I, the two most common forms of (131)I therapy. The results indicate that in 4 d following administration, the total excretion of volatile (131)I was 0.036 and 0.17 % of the administered activities of MIBG (131)I and Na(131)I, respectively. As administered activities for (131)I therapy are typically of the order of 1-10 GBq, the overall excretion of volatile (131)I from a patient can be as high as 20 MBq. As a result, a family member can receive up to 0.07 mSv committed effective dose from inhaling the volatile (131)I excreted by the patient. PMID- 21307023 TI - Housing, heat stress and health in a changing climate: promoting the adaptive capacity of vulnerable households, a suggested way forward. AB - In many places extreme heat causes more deaths than floods, cyclones and bushfires. However, efforts to manage the health implications of heat and increase the adaptive capacity of vulnerable populations are in their infancy, requiring urgent attention from research and policy. This paper presents a case for research exploring the influence of social and contextual factors on vulnerable populations' capacity to adapt to heat in the context of climate change. We argue such research is imperative given current prioritization of short-sighted policy solutions such as installation and use of greenhouse intensive domestic air-conditioners as moderators of heat stress. Globally, vulnerability to heat stress is most often assessed by epidemiological analysis of past morbidity and mortality data; yet a range of other factors need to be accounted for in interpreting and understanding these patterns of ill-health and loss of life, and further in determining how vulnerability is created, exacerbated and alleviated by broader societal conditions. Such factors include: the cooling technologies and infrastructures available to householders, practical knowledge about how to moderate heat stress, and social and cultural understandings of comfort and vulnerability. To investigate these factors, new methodologies are required. Social practice theory, which conceptualizes the dynamic interactions between individuals and wider systems of power, infrastructure, technologies, society and culture as components of practices such as household cooling, is presented as a way forward. The development of a practice-based methodology and conceptual framework to understand adaptation to heat will provide a multidimensional, systems-oriented understanding of how vulnerability can potentially be reduced. PMID- 21307024 TI - Barriers and catalysts of nutrition literacy among elderly Japanese people. AB - Improving skills for accessing and utilizing diet/nutrition information is important for preventing non-communicable diseases and frailty among elderly people. With the rapidly increasing number of elderly people in the world, promoting nutrition literacy among them is a pivotal health policy for maintaining and promoting health. This article describes the barriers and catalysts of nutrition literacy among elderly Japanese people (aged >=75 years). A cross-sectional analysis of the responses to a questionnaire administered to 678 study participants (men = 347, women = 331) was conducted. Logistic regression analysis revealed that more men had limited nutrition literacy than did women. After stratification by gender, the limited nutrition literacy group was associated with cognitive difficulty in men and women, visual impairment in men and hearing impairment in women. Lower education level and economic status were associated with limited nutrition literacy among women. Adjusted odds ratios (ORs) controlling for age, education level and economic status, as well as cognitive, visual and hearing function, indicated that informational support [OR = 5.59, 95% confidence interval (95% CI) = 1.28-24.49] and diet/nutrition information obtained from friends of the participants (OR = 2.16, 95% CI = 1.11 4.20) were both associated with adequate nutrition literacy among men, whereas diet/nutrition information from health professionals (OR = 3.96, 95% CI = 1.97 7.95) had a significant relation with adequate nutrition literacy among women. Moreover, in the adequate nutrition literacy group, men were more likely to be overweight (OR = 2.17, 95% CI = 1.20-3.91). These findings suggested that cognitive and sensory functions should be taken into account when diet information is provided to older adults. Enhancement of social networks is also a key point in improving nutrition literacy. An effective intervention to improve nutrition literacy in elderly people, particular old men, warrants further investigation. PMID- 21307025 TI - Control of embryonic stem cell metastability by L-proline catabolism. AB - The molecular mechanisms controlling mouse embryonic stem cell (ESC) metastability, i.e. their capacity to fluctuate between different states of pluripotency, are not fully resolved. We developed and used a novel automation platform, the Cell(maker), to screen a library of metabolites on two ESC-based phenotypic assays (i.e. proliferation and colony phenotype) and identified two metabolically related amino acids, namely l-proline (l-Pro) and l-ornithine (l Orn), as key regulators of ESC metastability. Both compounds, but mainly l-Pro, force ESCs toward a novel epiblast stem cell (EpiSC)-like state, in a dose- and time-dependent manner. Unlike EpiSCs, l-Pro-induced cells (PiCs) contribute to chimeric embryos and rely on leukemia inhibitor factor (LIF) to self-renew. Furthermore, PiCs revert to ESCs or differentiate randomly upon removal of either l-Pro or LIF, respectively. Remarkably, PiC generation depends on both l-Pro metabolism (uptake and oxidation) and Fgf5 induction, and is strongly counteracted by antioxidants, mainly l-ascorbic acid (vitamin C, Vc). ESCs <-> PiCs phenotypic transition thus represents a previously undefined dynamic equilibrium between pluripotent states, which can be unbalanced either toward an EpiSC-like or an ESC phenotype by l-Pro/l-Orn or Vc treatments, respectively. All together, our data provide evidence that ESC metastability can be regulated at a metabolic level. PMID- 21307026 TI - Guest editor's introduction: Part I: Methodological advances in recruitment and assessment. PMID- 21307027 TI - Collaborating with police departments: recruitment in the Oklahoma Lethality Assessment (OK-LA) study. AB - In a study to evaluate a collaborative police and social service intervention, researchers asked police officers to recruit intimate partner violence victims at the scene of domestic violence incidents. This article reviews the process of building successful partnerships with police departments as well as the strategies developed with collaborating police departments to create successful recruitment methods and enhance officer and department engagement with recruitment procedures. Over a period of 298 days, 800 victims were referred to the research study. Of these referrals, we were unable to contact 41.3%; of those contacted (n = 471), we conducted interviews with 67.73%. PMID- 21307028 TI - Enhancing Latinas' participation in research on sexual assault: cultural considerations in the design and implementation of research in the Latino community. AB - To provide a more complete picture of the prevalence, impact, and treatment of sexual assault among Latinas, researchers must begin to develop and employ culturally competent recruitment and data-collection procedures that can facilitate participation and disclosure. In this article, we sought to synthesize recommendations from research with Latino populations, community-based and participatory action research, and research on sexual assault to provide a list of suggestions for conducting culturally competent research about sexual assault with Latino populations. Innovative examples from our own focus group study with Latinas are provided throughout. PMID- 21307029 TI - Longitudinal tracking methods in a study of adult women sexual assault survivors. AB - Standard methods of tracking participants longitudinally are discussed in the context of the experience of one research team studying the impact of sexual assault on victims over time. The researchers considered implementing standard tracking methods used in population-based studies to retain participants over time, but chose to adapt and modify such methods in an effort to build trust and rapport with sexual assault victims recruited from the community. Issues related to methodological decision making and implementation in longitudinal studies are discussed, including effects tracking methods might have on participants and the reality of studying and retaining participants from sensitive populations. PMID- 21307030 TI - Emerging issues in the measurement of rape victimization. AB - We provide an overview of emerging directions in the measurement of rape, the most extreme form of sexual victimization. The context for our overview is how operational definitions of rape have evolved, where consensus has emerged, and where it eludes the field. We discuss two approaches to the detection of rape victimization in survey methods, namely behaviorally specific questions and a new, two-stage approach, and how each can be evaluated in terms of validity. We point out promises and pitfalls of the two-stage approach and make suggestions for its implementation and evaluation. We conclude that all empirical research to date supports the use of behaviorally specific compared to broad questions, that a standard definition of rape and its components of act, tactics, and nonconsent is imperative to move the field forward, and that research to systematically validate methods of detecting rape victimization is needed. To that end, we propose an agenda. PMID- 21307031 TI - Comparing sexual assault prevalence estimates obtained with direct and indirect questioning techniques. AB - Concerns have been expressed about the validity of self-reported data on sexual assault, as victims might be reluctant to disclose what happened to them. In this study, using an anonymous, web-based survey, a sample of 5,446 undergraduate women were asked about their experiences with physically forced sexual assault using both direct and indirect questioning methods. The prevalence of physically forced sexual assault obtained via indirect questioning was slightly higher than, though not substantially or statistically different from, the estimate obtained via direct questioning. The results suggest that either direct questioning yields reasonably valid estimates of the prevalence of sexual assault or that the item count technique does not produce estimates that are any more valid. PMID- 21307032 TI - Advancing the study of violence against women using mixed methods: integrating qualitative methods into a quantitative research program. AB - A mixed methods approach, combining quantitative with qualitative data methods and analysis, offers a promising means of advancing the study of violence. Integrating semi-structured interviews and qualitative analysis into a quantitative program of research on women's sexual victimization has resulted in valuable scientific insight and generation of novel hypotheses for testing. This mixed methods approach is described and recommendations for integrating qualitative data into quantitative research are provided. PMID- 21307033 TI - Applying experience sampling methods to partner violence research: safety and feasibility in a 90-day study of community women. AB - An experience sampling method (ESM) rarely has been applied in studies of intimate partner violence (IPV) despite the benefits to be gained. Because ESM approaches and women who experience IPV present unique challenges for data collection, an empirical question exists: Is it safe and feasible to apply ESM to community women who currently are experiencing IPV? A 90-day, design-driven feasibility study examined daily telephone data collection, daily paper diaries, and monthly retrospective semistructured interview methods among a community sample of 123 women currently experiencing IPV to study within-person relationships between IPV and substance use. Findings suggest that ESM is a promising method for collecting data among this population and can elucidate daily dynamics of victimization as well as associated behaviors and experiences. Lessons learned from the application of ESM to this population are also discussed. PMID- 21307034 TI - Narrative possibilities: poor women of color and the complexities of intimate partner violence. AB - This article shows how a narrative methodological approach is particularly suited to examining the dynamics of intimate partner violence, especially among poor women of color in South Africa. We show how a narrative approach allowed women to represent their experiences of violence according to their own frames of meaning, examining the complexities of abuse as it is informed by sociocultural factors of gender, poverty, and deprivation. In particular, we show how a narrative approach departs from other qualitative work by enabling women to construct particular forms of identity, thereby giving them agency in authoring their own stories of violence. PMID- 21307036 TI - Impact of concomitant heart failure on outcomes in patients undergoing percutaneous coronary interventions: analysis of the Melbourne Interventional Group registry. AB - AIMS: The presence of heart failure (HF) is an established risk factor for adverse outcomes in patients undergoing percutaneous coronary intervention (PCI). The aim of this study was to determine the prevalence and impact of concomitant HF on major outcomes in contemporary PCI practice. METHODS AND RESULTS: We analysed 5006 consecutive PCIs (2004-2006) enrolled in the Melbourne Interventional Group registry. Baseline characteristics, in-hospital, 30-day, and 12-month outcomes of patients with a history of HF (n = 189, 3.8%) were compared with patients without HF (n = 4817, 96.2%). Patients with a history of HF were older (mean age 72.9 +/- 9.8 vs. 64.3 +/- 12 years, P < 0.01) and had higher rates of diabetes (37.0 vs. 23.5%, P < 0.01), renal dysfunction (Cr > 200 MUmol/L; 16.5 vs. 3.9%, P < 0.01), multi-vessel disease (79.8 vs. 58.7%, P < 0.01), and presentation with cardiogenic shock (4.8 vs. 2.1%, P = 0.02). At 12 months, patients with HF had higher overall mortality (13.7 vs. 3.5%, P < 0.01) and rates of HF admission (10.4 vs. 2.0%, P < 0.01). Independent predictors of recurrent HF admission included history of HF [odds ratio (OR) 2.2, 95% confidence interval (CI) 1.2-4.2, P < 0.01] and renal dysfunction (OR 2.5, 95% CI 1.4-4.4, P < 0.01). At 12 months, patients with HF had lower rates of statin (73.9 vs. 89.2%, P < 0.01) and beta-blocker use (55.6 vs. 59.0%, P < 0.01). Angiotensin-converting enzyme-inhibitor/angiotensin receptor blocker use was also relatively low in HF patients (79.6%). CONCLUSION: While the overall incidence of HF in patients undergoing PCI is low, underutilization of HF therapies may contribute to an increased likelihood of subsequent re-admission and increased mortality. PMID- 21307037 TI - Relationship between risk stratification at admission and treatment effects of early invasive management following fibrinolysis: insights from the Trial of Routine ANgioplasty and Stenting After Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI). AB - AIMS: We sought to determine the effectiveness of early routine percutaneous coronary intervention (PCI) post-fibrinolysis for ST-elevation myocardial infarction (STEMI) in relation to baseline risk status. METHODS AND RESULTS: In this post hoc subgroup analysis of Trial of Routine Angioplasty and Stenting after Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI), we stratified 1059 STEMI patients receiving tenecteplase into low intermediate [Global Registry of Acute Coronary Events (GRACE) risk score<155; n=889] vs. high-risk (GRACE risk score >=155; n=170) groups, based on the GRACE risk score for in-hospital mortality. There was a significant interaction between treatment assignment and risk status for the composite endpoint of death/re-MI at 30 days (P for interaction<0.001). Compared with the standard treatment, pharmacoinvasive therapy (early routine PCI) was associated with a lower rate of death/re-MI at 30 days in the low-intermediate risk stratum (8.1 vs. 2.9%, P<0.001), but a higher rate of death/re-MI in the high-risk group (13.8 vs. 27.8%, P=0.025). We found similar heterogeneity in the treatment effects on 30 day mortality and death/re-MI at 1 year (P for interaction=0.008 and 0.001, respectively), when the GRACE risk score was analysed as a continuous variable (P for interaction<0.001) and when patients were stratified by the Thrombolysis In Myocardial Infarction (TIMI) risk score (P for interaction=0.001). CONCLUSION: We observed a strong heterogeneity in the treatment effects of a pharmacoinvasive strategy after fibrinolysis for STEMI, which is associated with improved outcomes only among patients with a low-intermediate GRACE risk score. Conversely, the early invasive strategy is associated with worse outcomes in high-risk patients. These novel findings should be considered exploratory only and require confirmation in other trials and meta-analyses. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.clinicaltrials.gov/ct2/show/NCT00164190 ClinicalTrials.gov number, NCT00164190. PMID- 21307039 TI - Searching for gene flow from cultivated to wild strawberries in Central Europe. AB - BACKGROUND AND AIMS: Experimental crosses between the diploid woodland strawberry (Fragaria vesca L.) and the octoploid garden strawberry (F. * ananassa Duch.) can lead to the formation of viable hybrids. However, the extent of such hybrid formation under natural conditions is unknown, but is of fundamental interest and importance in the light of the potential future cultivation of transgenic strawberries. A hybrid survey was therefore conducted in the surroundings of ten farms in Switzerland and southern Germany, where strawberries have been cultivated for at least 10 years and where wild strawberries occur in the close vicinity. METHODS: In 2007 and 2008, 370 wild F. vesca plants were sampled at natural populations around farms and analysed with microsatellite markers. In 2010, natural populations were revisited and morphological traits of 3050 F. vesca plants were inspected. DNA contents of cell nuclei of morphologically deviating plants were estimated by flow cytometry to identify hybrids. As controls, 50 hybrid plants from interspecific hand-crosses were analysed using microsatellite analysis and DNA contents of cell nuclei were estimated by flow cytometry. KEY RESULTS: None of the wild samples collected in 2007 and 2008 contained F. * ananassa microsatellite markers, while all hybrids from hand crosses clearly contained markers of both parent species. Morphological inspection of wild populations carried out in 2010 and subsequent flow cytometry of ten morphologically deviating plants revealed no hybrids. CONCLUSIONS: Hybrid formation or hybrid establishment in natural populations in the survey area is at best a rare event. PMID- 21307038 TI - Pollen tube growth and guidance: roles of small, secreted proteins. AB - BACKGROUND: Pollination is a crucial step in angiosperm (flowering plant) reproduction. Highly orchestrated pollen-pistil interactions and signalling events enable plant species to avoid inbreeding and outcrossing as a species specific barrier. In compatible pollination, pollen tubes carrying two sperm cells grow through the pistil transmitting tract and are precisely guided to the ovules, discharging the sperm cells to the embryo sac for fertilization. SCOPE: In Lilium longiflorum pollination, growing pollen tubes utilize two critical mechanisms, adhesion and chemotropism, for directional growth to the ovules. Among several molecular factors discovered in the past decade, two small, secreted cysteine-rich proteins have been shown to play major roles in pollen tube adhesion and reorientation bioassays: stigma/style cysteine-rich adhesin (SCA, approx. 9.3 kDa) and chemocyanin (approx. 9.8 kDa). SCA, a lipid transfer protein (LTP) secreted from the stylar transmitting tract epidermis, functions in lily pollen tube tip growth as well as in forming the adhesive pectin matrix at the growing pollen tube wall back from the tip. Lily chemocyanin is a plantacyanin family member and acts as a directional cue for reorienting pollen tubes. Recent consecutive studies revealed that Arabidopsis thaliana homologues for SCA and chemocyanin play pivotal roles in tip polarity and directionality of pollen tube growth, respectively. This review outlines the biological roles of various secreted proteins in angiosperm pollination, focusing on plant LTPs and chemocyanin. PMID- 21307040 TI - Dysfunctional thalamus-related networks in schizophrenia. AB - Thalamus abnormalities are common in neurological and psychiatric illnesses. Therefore, it is essential to understand the properties of the thalamus-related networks. The thalamic reticular nucleus (TRN) is a thin GABAergic layer interface strategically located between the thalamus and the neocortex. It is, at the very beginning of life, an essential neurodevelopmental guide for the accurate build up of reciprocal anatomical glutamatergic connections between the thalamus and neocortex. It is more than the mediator of selective attention. It appears as a combinatorial matrix because it holds and can combine multiple functional modalities. TRN cells work like integrators, thanks to their extraordinary intrinsic electrophysiological properties, under the contextual and leading influence of corticothalamic inputs. The TRN and thalamus principally form 2-neuron open-loop circuits (no reciprocal connection). The major functioning principle of such GABAergic-glutamatergic circuits is lateral inhibition, which is a gold standard device to set up, via differential amplifications, coherent structured thalamocortical activity patterns. Thereby, it selects relevant streams of information and deletes distractors during action, resting states, and information integration, including during consciousness, cognition, emotion, and thought. Disruption of thalamic lateral inhibition may contribute to a lack of coordination in activity between brain regions, as observed in psychiatric disorders like schizophrenia. PMID- 21307042 TI - Colour-producing beta-keratin nanofibres in blue penguin (Eudyptula minor) feathers. AB - The colours of living organisms are produced by the differential absorption of light by pigments (e.g. carotenoids, melanins) and/or by the physical interactions of light with biological nanostructures, referred to as structural colours. Only two fundamental morphologies of non-iridescent nanostructures are known in feathers, and recent work has proposed that they self-assemble by intracellular phase separation processes. Here, we report a new biophotonic nanostructure in the non-iridescent blue feather barbs of blue penguins (Eudyptula minor) composed of parallel beta-keratin nanofibres organized into densely packed bundles. Synchrotron small angle X-ray scattering and two dimensional Fourier analysis of electron micrographs of the barb nanostructure revealed short-range order in the organization of fibres at the appropriate size scale needed to produce the observed colour by coherent scattering. These two dimensional quasi-ordered penguin nanostructures are convergent with similar arrays of parallel collagen fibres in avian and mammalian skin, but constitute a novel morphology for feathers. The identification of a new class of beta-keratin nanostructures adds significantly to the known mechanisms of colour production in birds and suggests additional complexity in their self-assembly. PMID- 21307041 TI - Comparative effectiveness of second-generation antipsychotic medications in early onset schizophrenia. AB - Scant information exists to guide pharmacological treatment of early-onset schizophrenia. We examine variation across commonly prescribed second-generation antipsychotic medications in medication discontinuation and psychiatric hospital admission among children and adolescents clinically diagnosed with schizophrenia. A 45-state Medicaid claims file (2001-2005) was analyzed focusing on outpatients, aged 6-17 years, diagnosed with schizophrenia or a related disorder prior to starting a new episode of antipsychotic monotherapy with risperidone (n = 805), olanzapine (n = 382), quetiapine (n = 260), aripiprazole (n = 173), or ziprasidone (n = 125). Cox proportional hazard regressions estimated adjusted hazard ratios of 180-day antipsychotic medication discontinuation and 180-day psychiatric hospitalization for patients treated with each medication. During the first 180 days following antipsychotic initiation, most youth treated with quetiapine (70.7%), ziprasidone (73.3%), olanzapine (73.7%), risperidone (74.7%), and aripirazole (76.5%) discontinued their medication (chi(2) = 1.69, df = 4, P = .79). Compared with risperidone, the adjusted hazards of antipsychotic discontinuation did not significantly differ for any of the 4-comparator medications. The percentages of youth receiving inpatient psychiatric treatment while receiving their initial antipsychotic medication ranged from 7.19% (aripiprazole) to 9.89% (quetiapine) (chi(2) = 0.79, df = 4, P = .94). As compared with risperidone, the adjusted hazard ratio of psychiatric hospital admission was 0.96 (95% CI: 0.57-1.61) for olanzapine, 1.03 (95% CI: 0.59-1.81) for quetiapine, 0.85 (95% CI: 0.43-1.70) for aripiprazole, and 1.22 (95% CI: 0.60 2.51) for ziprasidone. The results suggest that rapid antipsychotic medication discontinuation and psychiatric hospital admission are common in the community treatment of early-onset schizophrenia. No significant differences were detected in risk of either adverse outcome across 5 commonly prescribed second-generation antipsychotic medications. PMID- 21307043 TI - Bone remodelling in Neanderthal mandibles from the El Sidron site (Asturias, Spain). AB - Skull morphology results from the bone remodelling mechanism that underlies the specific bone growth dynamics. Histological study of the bone surface from Neanderthal mandible specimens of El Sidron (Spain) provides information about the distribution of the remodelling fields (bone remodelling patterns or BRP) indicative of the bone growth directions. In comparison with other primate species, BRP shows that Neanderthal mandibles from the El Sidron (Spain) sample present a specific BRP. The interpretation of this map allows inferences concerning the growth directions that explain specific morphological traits of the Neanderthal mandible, such as its quadrangular shape and the posterior location of the mental foramen. PMID- 21307044 TI - A common heritable factor influences prosocial obligations across multiple domains. AB - Although it has been shown that prosocial behaviour is heritable, it has not yet been established whether narrower aspects of prosociality are heritable, nor whether a common mechanism influences prosociality across its multiple domains. Here, we examine civic duty, work-place commitment and concern for the welfare of others with a study of prosocial obligations in 958 adult twin-pairs. Multivariate modelling indicated the existence of genetic factors underlying general prosocial obligations in females, with familial effects (genetic and shared-environment effects were indistinguishable) influencing this general mechanism in males. At the domain-specific level, modest genetic effects were observed in females for civic and work obligations, with shared-environment effects influencing welfare obligations. In males, genetic influences were observed for welfare obligation, with unique environments affecting work and civic duty. PMID- 21307045 TI - Individuality in bird migration: routes and timing. AB - The exploration of animal migration has entered a new era with individual-based tracking during multiple years. Here, we investigated repeated migratory journeys of a long-distance migrating bird, the marsh harrier Circus aeruginosus, in order to analyse the variation within and between individuals with respect to routes and timing. We found that there was a stronger individual repeatability in time than in space. Thus, the annual timing of migration varied much less between repeated journeys of the same individual than between different individuals, while there was considerable variation in the routes of the same individual on repeated journeys. The overall contrast in repeatability between time and space was unexpected and may be owing to strong endogenous control of timing, while short-term variation in environmental conditions (weather and habitat) might promote route flexibility. The individual variation in migration routes indicates that the birds navigate mainly by other means than detailed route recapitulation based on landmark recognition. PMID- 21307046 TI - Ant queens adjust egg fertilization to benefit from both sexual and asexual reproduction. AB - An enduring problem in evolutionary biology is the near ubiquity of sexual reproduction despite the inherent cost of transmitting only half the parent's genes to progeny. Queens of some ant species circumvent this cost by using selectively both sexual reproduction and parthenogenesis: workers arise from fertilized eggs, while new queens are produced by parthenogenesis. We show that queens of the ant Cataglyphis cursor maximize the transmission rate of their genes by regulating the proportion of fertilized and parthenogenetic eggs laid over time. Parthenogenetic offspring are produced in early spring, when workers raise the brood into sexuals. After the mating period, queens lay mostly fertilized eggs that will be reared as the non-reproductive caste. PMID- 21307047 TI - Nocturnal insects use optic flow for flight control. AB - To avoid collisions when navigating through cluttered environments, flying insects must control their flight so that their sensory systems have time to detect obstacles and avoid them. To do this, day-active insects rely primarily on the pattern of apparent motion generated on the retina during flight (optic flow). However, many flying insects are active at night, when obtaining reliable visual information for flight control presents much more of a challenge. To assess whether nocturnal flying insects also rely on optic flow cues to control flight in dim light, we recorded flights of the nocturnal neotropical sweat bee, Megalopta genalis, flying along an experimental tunnel when: (i) the visual texture on each wall generated strong horizontal (front-to-back) optic flow cues, (ii) the texture on only one wall generated these cues, and (iii) horizontal optic flow cues were removed from both walls. We find that Megalopta increase their groundspeed when horizontal motion cues in the tunnel are reduced (conditions (ii) and (iii)). However, differences in the amount of horizontal optic flow on each wall of the tunnel (condition (ii)) do not affect the centred position of the bee within the flight tunnel. To better understand the behavioural response of Megalopta, we repeated the experiments on day-active bumble-bees (Bombus terrestris). Overall, our findings demonstrate that despite the limitations imposed by dim light, Megalopta-like their day-active relatives rely heavily on vision to control flight, but that they use visual cues in a different manner from diurnal insects. PMID- 21307048 TI - Stress associated with group living in a long-lived bird. AB - Many long-lived avian species adopt life strategies that involve a gregarious way of life at juvenile and sub-adult stages and territoriality during adulthood. However, the potential associated costs of these life styles, such as stress, are poorly understood. We examined the effects of group living, sex and parasite load on the baseline concentration of faecal stress hormone (corticosterone) metabolites in a wild population of common ravens (Corvus corax). Corticosterone concentrations were significantly higher in non-breeding gregarious ravens than in territorial adults. Among territorial birds, males showed higher stress levels than their mates. Parasite burdens did not affect hormone levels. Our results suggest a key role of the social context in the stress profiles of the two population fractions, and that group living may be more energetically demanding than maintaining a territory. These findings have implications for understanding hormonal mechanisms under different life styles and may inspire further research on the link between hormone levels and selective pressures modulating gregarious and territorial strategies in long-lived birds. PMID- 21307049 TI - Short Form 36 (SF-36) Health Survey Questionnaire: normative data for Wales. AB - BACKGROUND: The Short Form 36 Health Survey Questionnaire (SF-36) is used to indicate the health status of particular populations, to help with service planning and to measure the impact of clinical and social interventions. Culture specific data are required to calculate SF-36 norm-based scores. Currently, in the UK normative sources are nearly two decades old, Anglocentric and lack data on the older population. We draw on raw data from the Welsh Health Survey (2007) to provide population norms for the eight SF-36 dimensions for Wales and its regions. METHODS: We test the SF-36 dimensions for reliability and rating scaling assumptions and construct validity. We compare the Wales' norms to those reported in existing UK sources and examine the data between countries and by region. RESULTS: The scale is reliable and has content validity. The relationships found between the SF-36 domains and a range of variables known to be related to health also demonstrate construct validity. There are differences in population health norms between England and Wales and between the regions of Wales. CONCLUSIONS: The results suggest that it is imperative that the accurate normative data provided in this paper is used in population studies in Wales to provide an indication of the health status of particular populations. PMID- 21307050 TI - Acoustic facilitation of object movement detection during self-motion. AB - In humans, as well as most animal species, perception of object motion is critical to successful interaction with the surrounding environment. Yet, as the observer also moves, the retinal projections of the various motion components add to each other and extracting accurate object motion becomes computationally challenging. Recent psychophysical studies have demonstrated that observers use a flow-parsing mechanism to estimate and subtract self-motion from the optic flow field. We investigated whether concurrent acoustic cues for motion can facilitate visual flow parsing, thereby enhancing the detection of moving objects during simulated self-motion. Participants identified an object (the target) that moved either forward or backward within a visual scene containing nine identical textured objects simulating forward observer translation. We found that spatially co-localized, directionally congruent, moving auditory stimuli enhanced object motion detection. Interestingly, subjects who performed poorly on the visual-only task benefited more from the addition of moving auditory stimuli. When auditory stimuli were not co-localized to the visual target, improvements in detection rates were weak. Taken together, these results suggest that parsing object motion from self-motion-induced optic flow can operate on multisensory object representations. PMID- 21307051 TI - Bats are able to maintain long-term social relationships despite the high fission fusion dynamics of their groups. AB - Elephants, dolphins, as well as some carnivores and primates maintain social links despite their frequent splitting and merging in groups of variable composition, a phenomenon known as fission-fusion. Information on the dynamics of social links and interactions among individuals is of high importance to the understanding of the evolution of animal sociality, including that of humans. However, detailed long-term data on such dynamics in wild mammals with fully known demography and kin structures are scarce. Applying a weighted network analysis on 20,500 individual roosting observations over 5 years, we show that in two wild Bechstein's bat colonies with high fission-fusion dynamics, individuals of different age, size, reproductive status and relatedness maintain long-term social relationships. In the larger colony, we detected two stable subunits, each comprising bats from several family lineages. Links between these subunits were mainly maintained by older bats and persisted over all years. Moreover, we show that the full details of the social structure become apparent only when large datasets are used. The stable multi-level social structures in Bechstein's bat colonies resemble that of elephants, dolphins and some primates. Our findings thus may shed new light on the link between social complexity and social cognition in mammals. PMID- 21307052 TI - Natural variation in Pristionchus pacificus dauer formation reveals cross preference rather than self-preference of nematode dauer pheromones. AB - Many free-living nematodes, including the laboratory model organisms Caenorhabditis elegans and Pristionchus pacificus, have a choice between direct and indirect development, representing an important case of phenotypic plasticity. Under harsh environmental conditions, these nematodes form dauer larvae, which arrest development, show high resistance to environmental stress and constitute a dispersal stage. Pristionchus pacificus occurs in a strong association with scarab beetles in the wild and remains in the dauer stage on the living beetle. Here, we explored the circumstances under which P. pacificus enters and exits the dauer stage by using a natural variation approach. The analysis of survival, recovery and fitness after dauer exit of eight P. pacificus strains revealed that dauer larvae can survive for up to 1 year under experimental conditions. In a second experiment, we isolated dauer pheromones from 16 P. pacificus strains, and tested for natural variation in pheromone production and sensitivity in cross-reactivity assays. Surprisingly, 13 of the 16 strains produce a pheromone that induces the highest dauer formation in individuals of other genotypes. These results argue against a simple adaptation model for natural variation in dauer formation and suggest that strains may have evolved to induce dauer formation precociously in other strains in order to reduce the fitness of these strains. We therefore discuss intraspecific competition among genotypes as a previously unconsidered aspect of dauer formation. PMID- 21307053 TI - Host-parasite local adaptation after experimental coevolution of Caenorhabditis elegans and its microparasite Bacillus thuringiensis. AB - Coevolving hosts and parasites can adapt to their local antagonist. In studies on natural populations, the observation of local adaptation patterns is thus often taken as indirect evidence for coevolution. Based on this approach, coevolution was previously inferred from an overall pattern of either parasite or host local adaptation. Many studies, however, failed to detect such a pattern. One explanation is that the studied system was not subject to coevolution. Alternatively, coevolution occurred, but remained undetected because it took different routes in different populations. In some populations, it is the host that is locally adapted, whereas in others it is the parasite, leading to the absence of an overall local adaptation pattern. Here, we test for overall as well as population-specific patterns of local adaptation using experimentally coevolved populations of the nematode Caenorhabditis elegans and its bacterial microparasite Bacillus thuringiensis. Furthermore, we assessed the importance of random interaction effects using control populations that evolved in the absence of the respective antagonist. Our results demonstrate that experimental coevolution produces distinct local adaptation patterns in different replicate populations, including host, parasite or absence of local adaptation. Our study thus provides experimental evidence of the predictions of the geographical mosaic theory of coevolution, i.e. that the interaction between parasite and host varies across populations. PMID- 21307054 TI - Craig Franklin joins JEB editorial team. PMID- 21307055 TI - Dynamics of gecko locomotion: a force-measuring array to measure 3D reaction forces. AB - Measuring the interaction between each foot of an animal and the substrate is one of the most effective ways to understand the dynamics of legged locomotion. Here, a new facility - the force-measuring array (FMA) - was developed and applied to measure 3D reaction forces of geckos on different slope surfaces. The FMA consists of 16 3D sensors with resolution to the mN level. At the same time the locomotion behaviour of geckos freely moving on the FMA was recorded by high speed camera. The reaction forces acting on the gecko's individual feet measured by the FMA and correlated with locomotion behaviour provided enough information to reveal the mechanical and dynamic secrets of gecko locomotion. Moreover, dynamic forces were also measured by a force platform and correlated with locomotion behaviour. The difference between the forces measured by the two methods is discussed. From the results we conclude that FMA is the best way to obtain true reaction forces acting on the gecko's individual feet. PMID- 21307056 TI - The effects of salinity and temperature on the transparency of the grass shrimp Palaemonetes pugio. AB - Transparency is an effective form of camouflage, but it must be present throughout the entire volume of an animal to succeed. Certain environmental stressors may cause physiological responses that increase internal light scattering, making tissue less transparent and more conspicuous to predators. We tested this in the transparent grass shrimp, Palaemonetes pugio, which is found in shallow estuaries where both salinity and temperature change rapidly because of tidal cycles, evaporation and runoff. Animals originally kept at a salinity of 15 p.p.t. and a temperature of 20 degrees C were placed into solutions with salinities of 0, 15, 25 or 30 p.p.t. and temperatures of 13, 20 or 27 degrees C for 12 h (N=26 for each of 12 treatments). Under the control conditions of 15 p.p.t. at 20 degrees C, the transparency of grass shrimp tails was 54+/-3% (mean +/- s.e.). At higher salinities and at both higher and lower temperatures, transparency dropped significantly (P<0.001, two-way ANOVA), reaching 0.04+/ 0.01% at 30 p.p.t. at 27 degrees C. Confocal microscopy of P. pugio's tail suggested that the observed loss of transparency was due to the pooling of low refractive index hemolymph between the high index muscle fibers, creating many index boundaries that increased light scattering. Analysis of a year-long salinity and temperature record from a North Carolina estuary showed that changes of the order of those found in this study are relatively common, suggesting that P. pugio may undergo periods of reduced crypsis, potentially leading to increased predation. PMID- 21307057 TI - Ontogeny of lift and drag production in ground birds. AB - The juvenile period is often a crucial interval for selective pressure on locomotor ability. Although flight is central to avian biology, little is known about factors that limit flight performance during development. To improve understanding of flight ontogeny, we used a propeller (revolving wing) model to test how wing shape and feather structure influence aerodynamic performance during development in the precocial chukar partridge (Alectoris chukar, 4 to >100 days post hatching). We spun wings in mid-downstroke posture and measured lift (L) and drag (D) using a force plate upon which the propeller assembly was mounted. Our findings demonstrate a clear relationship between feather morphology and aerodynamic performance. Independent of size and velocity, older wings with stiffer and more asymmetrical feathers, high numbers of barbicels and a high degree of overlap between barbules generate greater L and L:D ratios than younger wings with flexible, relatively symmetrical and less cohesive feathers. The gradual transition from immature feathers and drag-based performance to more mature feathers and lift-based performance appears to coincide with ontogenetic transitions in locomotor capacity. Younger birds engage in behaviors that require little aerodynamic force and that allow D to contribute to weight support, whereas older birds may expand their behavioral repertoire by flapping with higher tip velocities and generating greater L. Incipient wings are, therefore, uniquely but immediately functional and provide flight-incapable juveniles with access to three-dimensional environments and refugia. Such access may have conferred selective advantages to theropods with protowings during the evolution of avian flight. PMID- 21307058 TI - The role of the gut in insect chilling injury: cold-induced disruption of osmoregulation in the fall field cricket, Gryllus pennsylvanicus. AB - To predict the effects of changing climates on insect distribution and abundance, a clear understanding of the mechanisms that underlie critical thermal limits is required. In insects, the loss of muscle function and onset of cold-induced injury has previously been correlated with a loss of muscle resting potential. To determine the cause of this loss of function, we measured the effects of cold exposure on ion and water homeostasis in muscle tissue, hemolymph and the alimentary canal of the fall field cricket, Gryllus pennsylvanicus, during an exposure to 0 degrees C that caused chilling injury and death. Low temperature exposure had little effect on muscle osmotic balance but it dissipated muscle ion equilibrium potentials through interactions between the hemolymph and gut. Hemolymph volume declined by 84% during cold exposure whereas gut water content rose in a comparable manner. This rise in water content was driven by a failure to maintain osmotic equilibrium across the gut wall, which resulted in considerable migration of Na(+), Ca(2+) and Mg(2+) into the alimentary canal during cold exposure. This loss of homeostasis is likely to be a primary mechanism driving the cold-induced loss of muscle excitability and progression of chilling injury in chill-susceptible insect species. PMID- 21307059 TI - Estimation of musculoskeletal models from in situ measurements of muscle action in the rat hindlimb. AB - Musculoskeletal models are often created by making detailed anatomical measurements of muscle properties. These measurements can then be used to determine the parameters of canonical models of muscle action. We describe here a complementary approach for developing and validating muscle models, using in situ measurements of muscle actions. We characterized the actions of two rat hindlimb muscles: the gracilis posticus (GRp) and the posterior head of biceps femoris (BFp; excluding the anterior head with vertebral origin). The GRp is a relatively simple muscle, with a circumscribed origin and insertion. The BFp is more complex, with an insertion distributed along the tibia. We measured the six dimensional isometric forces and moments at the ankle evoked from stimulating each muscle at a range of limb configurations. The variation of forces and moments across the workspace provides a succinct characterization of muscle action. We then used this data to create a simple muscle model with a single point insertion and origin. The model parameters were optimized to best explain the observed force-moment data. This model explained the relatively simple muscle, GRp, very well (R(2)>0.85). Surprisingly, this simple model was also able to explain the action of the BFp, despite its greater complexity (R(2)>0.84). We then compared the actions observed here with those predicted using recently published anatomical measurements. Although the forces and moments predicted for the GRp were very similar to those observed here, the predictions for the BFp differed. These results show the potential utility of the approach described here for the development and refinement of musculoskeletal models based on in situ measurements of muscle actions. PMID- 21307060 TI - Behavioural evidence for a sleep-like quiescent state in a pulmonate mollusc, Lymnaea stagnalis (Linnaeus). AB - The objective of this study was to determine whether the great pond snail, Lymnaea stagnalis, expresses a sleep-like behavioural state. We found that snails spontaneously enter a relatively brief (22+/-1 min) quiescent state characterized by postural relaxation of the foot, mantle and tentacles, and cessation of radula rasping. Quiescence was reversed ('aroused') by appetitive (sucrose solution) and aversive (tactile) stimuli. Responsiveness to both stimuli was significantly lower in quiescent snails than in active snails. However, tactile stimuli evoked a more sustained defensive response in quiescent snails. Quiescence bouts were consolidated into 'clusters' over an infradian timescale and were only weakly affected by time of day. Clusters contained 7+/-0.5 bouts, lasted 13+/-1 h and were separated by long (37+/-4 h) intervals of almost continuous activity. Analysis of Kaplan-Meier survival curves revealed that the quiescent bout duration was described by an exponential probability distribution (time constant 15+/-1 min). Active bout duration was described by a bi-exponential probability distribution (time constants 62+/-4 and 592+/-48 min). We found no evidence for a 'sleep rebound' mechanism and quiescence expression appeared to be regulated through stochastic processes causing state transitions to resemble a Markovian random walk. We conclude that Lymnaea is a potentially valuable model system for studies of cellular function in sleep. PMID- 21307061 TI - Evidence of a central pattern generator regulating spermathecal muscle activity in Locusta migratoria and its coordination with oviposition. AB - Electrophysiological recordings were conducted to determine the control of spermathecal contractions during oviposition of interrupted egg-laying locusts, Locusta migratoria. Following transection of the central nervous system below the metathoracic ganglion, rhythmic patterned bursting was detected by extracellular recordings of the nerve N2B2 that innervates the muscles of the spermatheca. Subsequent transections at more posterior regions of the ventral nerve cord revealed more robust rhythmic bursting in N2B2. This rhythmic bursting pattern was found to be coordinated with bursting in the ventral opener nerve (N2B1) that innervates the ventral opener muscle. This muscle controls the ventral ovipositor valves. Electromyographic recordings from the spermathecal muscle and ventral opener muscle confirmed a rhythmic bursting pattern resulting in an increase in muscle activity. Taken together, the results indicate that there is probably a central pattern generator (CPG), which is regulated by descending inhibition, that controls the spermathecal muscle activity. This CPG appears to be located within the VIIth and VIIIth abdominal ganglia, and was found to integrate with the CPG that regulates oviposition digging in locusts. These results provide further insight into the intricate coordination and control of reproductive tissues underlying reproductive behaviours in locusts. PMID- 21307062 TI - Using double-stranded RNA to explore the role of heat shock protein genes in heat tolerance in Bemisia tabaci (Gennadius). AB - The whitefly, Bemisia tabaci (Gennadius) (Homoptera: Aleyrodidae) biotype B, is one of the most destructive invasive pests of field and glasshouse crops, and has a high tolerance to heat. Our previous work found that whitefly females are more heat tolerant than males. In the present study, real-time PCR and double-stranded RNA (dsRNA) methods were used to explore the role of heat shock protein (Hsp) genes in whitefly of both sexes; this provided further evidence of the mechanism underlying the differential heat tolerance abilities of females and males. The results showed that both hsp23 and hsp70 mRNA expression levels were higher in females than in males from 37.5 to 42 degrees C, while at the extreme temperature of 44 degrees C the hsp70 mRNA level was higher in males than in females. There was no significant difference in hsp90 mRNA expression between females and males under heat shock conditions. Furthermore, the survival rate of females fed hsp23 or hsp70 dsRNA significantly decreased following heat shock at 44 degrees C for 1 h, but male survival rate was not significantly affected. Additionally, the survival rate of both females and males showed no significant change after they were fed with hsp90 dsRNA. Collectively, the present study shows that the optimum mRNA expression of Hsp genes in females promotes a higher survival rate under heat shock conditions; hsp23 and hsp70 play a key role for heat tolerance in females but not in males, and hsp90 shows no significant role in heat tolerance in either females or males. Further, our study indicates that feeding with dsRNA is an effective method by which to study gene function, and the simplicity of this approach opens the way for further research on gene function in different sexes and diverse groups of species. PMID- 21307063 TI - Twilight spectral dynamics and the coral reef invertebrate spawning response. AB - There are dramatic and physiologically relevant changes in both skylight color and intensity during evening twilight as the pathlength of direct sunlight through the atmosphere increases, ozone increasingly absorbs long wavelengths and skylight becomes increasingly blue shifted. The moon is above the horizon at sunset during the waxing phase of the lunar cycle, on the horizon at sunset on the night of the full moon and below the horizon during the waning phase. Moonlight is red shifted compared with daylight, so the presence, phase and position of the moon in the sky could modulate the blue shifts during twilight. Therefore, the influence of the moon on twilight color is likely to differ somewhat each night of the lunar cycle, and to vary especially rapidly around the full moon, as the moon transitions from above to below the horizon during twilight. Many important light-mediated biological processes occur during twilight, and this lunar effect may play a role. One particularly intriguing biological event tightly correlated with these twilight processes is the occurrence of mass spawning events on coral reefs. Therefore, we measured downwelling underwater hyperspectral irradiance on a coral reef during twilight for several nights before and after the full moon. We demonstrate that shifts in twilight color and intensity on nights both within and between evenings, immediately before and after the full moon, are correlated with the observed times of synchronized mass spawning, and that these optical phenomena are a biologically plausible cue for the synchronization of these mass spawning events. PMID- 21307064 TI - Mechanical filtering for narrow-band hearing in the weta. AB - This paper constitutes a major attempt to associate tympanic deflections with the mechanoreceptor organ location in an acoustic insect. The New Zealand tree weta (Hemideina thoracica) has tympanal ears located on each of the prothoracic tibiae. The tympana exhibit a sclerotized oval plate, membranous processes bulging out from the tibial cuticle and many loosely suspended ripples. We used microscanning laser Doppler vibrometry to determine how such a tympanal membrane vibrates in response to sound and whether the sclerotized region plays a role in hearing. The tympanum displays a single resonance at the calling frequency of the male, an unusual example of an insect tympana acting as a narrow bandpass filter. Both tympana resonate in phase with the stimulus and with each other. Histological sections show that the tympanal area is divided into two distinct regions, as in other ensiferans. An oval plate lies in the middle of a thickened region and is surrounded by a transparent and uniformly thin region. It is hinged dorsally to the tympanal rim and thus resembles the model of a 'hinged flap'. The thickened region appears to act as a damping mass on the oscillation of the thin region, and vibration displacement is reduced in this area. The thinner area vibrates with higher amplitude, inducing mechanical pressure on the dorsal area adjacent to the crista acustica. We present a new model showing how the thickened region might confer a mechanical gain onto the activation of the crista acustica sensory neurons during the sound-induced oscillations. PMID- 21307065 TI - Climbing flight performance and load carrying in lesser dog-faced fruit bats (Cynopterus brachyotis). AB - The metabolic cost of flight increases with mass, so animals that fly tend to exhibit morphological traits that reduce body weight. However, all flying animals must sometimes fly while carrying loads. Load carrying is especially relevant for bats, which experience nightly and seasonal fluctuations in body mass of 40% or more. In this study, we examined how the climbing flight performance of fruit bats (Cynopterus brachyotis; N=4) was affected by added loads. The body weights of animals were experimentally increased by 0, 7, 14 or 21% by means of intra peritoneal injections of saline solution, and flights were recorded as animals flew upwards in a small enclosure. Using a model based on actuator disk theory, we estimated the mechanical power expended by the bats as they flew and separated that cost into different components, including the estimated costs of hovering, climbing and increasing kinetic energy. We found that even our most heavily loaded bats were capable of upward flight, but as the magnitude of the load increased, flight performance diminished. Although the cost of flight increased with loading, bats did not vary total induced power across loading treatment. This resulted in a diminished vertical velocity and thus shallower climbing angle with increased loads. Among trials there was considerable variation in power production, and those with greater power production tended to exhibit higher wingbeat frequencies and lower wing stroke amplitudes than trials with lower power production. Changes in stroke plane angle, downstroke wingtip velocity and wing extension did not correlate significantly with changes in power output. We thus observed the manner in which bats modulated power output through changes in kinematics and conclude that the bats in our study did not respond to increases in loading with increased power output because their typical kinematics already resulted in sufficient aerodynamic power to accommodate even a 21% increase in body weight. PMID- 21307066 TI - Environmental complexity, seasonality and brain cell proliferation in a weakly electric fish, Brachyhypopomus gauderio. AB - Environmental complexity and season both influence brain cell proliferation in adult vertebrates, but their relative importance and interaction have not been directly assessed. We examined brain cell proliferation during both the breeding and non-breeding seasons in adult male electric fish, Brachyhypopomus gauderio, exposed to three environments that differed in complexity: (1) a complex natural habitat in northern Uruguay, (2) an enriched captive environment where fish were housed socially and (3) a simple laboratory setting where fish were isolated. We injected fish with BrdU 2.5 h before sacrifice to label newborn cells. We examined the hindbrain and midbrain and quantified the density of BrdU+ cells in whole transverse sections, proliferative zones and two brain nuclei in the electrocommunication circuitry (the pacemaker nucleus and the electrosensory lateral line lobe). Season had the largest effect on cell proliferation, with fish during the breeding season having three to seven times more BrdU+ cells than those during the non-breeding season. Although the effect was smaller, fish from a natural environment had greater rates of cell proliferation than fish in social or isolated captive environments. For most brain regions, fish in social and isolated captive environments had equivalent levels of cell proliferation. However, for brain regions in the electrocommunication circuitry, group-housed fish had more cell proliferation than isolated fish, but only during the breeding season (season * environment interaction). The regionally and seasonally specific effect of social environment on cell proliferation suggests that addition of new cells to these nuclei may contribute to seasonal changes in electrocommunication behavior. PMID- 21307067 TI - Survival and energetic costs of repeated cold exposure in the Antarctic midge, Belgica antarctica: a comparison between frozen and supercooled larvae. AB - In this study, we examined the effects of repeated cold exposure (RCE) on the survival, energy content and stress protein expression of larvae of the Antarctic midge, Belgica antarctica (Diptera: Chironomidae). Additionally, we compared results between larvae that were frozen at -5 degrees C in the presence of water during RCE and those that were supercooled at -5 degrees C in a dry environment. Although >95% of larvae survived a single 12 h bout of freezing at -5 degrees C, after five cycles of RCE survival of frozen larvae dropped below 70%. Meanwhile, the survival of control and supercooled larvae was unchanged, remaining around 90% for the duration of the study. At the tissue level, frozen larvae had higher rates of cell mortality in the midgut than control and supercooled larvae. Furthermore, larvae that were frozen during RCE experienced a dramatic reduction in energy reserves; after five cycles, frozen larvae had 25% less lipid, 30% less glycogen and nearly 40% less trehalose than supercooled larvae. Finally, larvae that were frozen during RCE had higher expression of hsp70 than those that were supercooled, indicating a higher degree of protein damage in the frozen group. Results were similar between larvae that had accumulated 60 h of freezing at -5 degrees C over five cycles of RCE and those that were frozen continuously for 60 h, suggesting that the total time spent frozen determines the physiological response. Our results suggest that it is preferable, both from a survival and energetic standpoint, for larvae to seek dry microhabitats where they can avoid inoculative freezing and remain unfrozen during RCE. PMID- 21307068 TI - Multimodal signal variation in space and time: how important is matching a signal with its signaler? AB - Multimodal signals (acoustic+visual) are known to be used by many anuran amphibians during courtship displays. The relative degree to which each signal component influences female mate choice, however, remains poorly understood. In this study we used a robotic frog with an inflating vocal sac and acoustic playbacks to document responses of female tungara frogs to unimodal signal components (acoustic and visual). We then tested female responses to a synchronous multimodal signal. Finally, we tested the influence of spatial and temporal variation between signal components for female attraction. Females failed to approach the isolated visual cue of the robotic frog and they showed a significant preference for the call over the spatially separate robotic frog. When presented with a call that was temporally synchronous with the vocal sac inflation of the robotic frog, females did not show a significant preference for this over the call alone; when presented with a call that was temporally asynchronous with vocal sac inflation of the robotic frog, females discriminated strongly against the asynchronous multimodal signal in favor of the call alone. Our data suggest that although the visual cue is neither necessary nor sufficient for attraction, it can strongly modulate mate choice if females perceive a temporal disjunction relative to the primary acoustic signal. PMID- 21307069 TI - Coping with novelty and stress in free-living house sparrows. AB - Individuals respond differently to stressors and it has been suggested that stress responses are related to coping styles (consistent individual differences in behavior and physiology). We studied behavioral responses to a novel object and corticosterone response to stress during chick rearing in free-living female house sparrows (Passer domesticus). To prevent mates from influencing each others' behavior, we removed the males temporarily from nests and tested the females the following day either with a novel object placed on the nest box or as control. The two groups differed only in behaviors that were a priori defined as responses to the novel object (latency to first feeding, time spent near the nest, and inspecting the novel object by hovering in front of it) indicating that mate-removal per se had no effect on female behavior. Based on these variables, females' coping behaviors were categorized as 'bold', 'inquisitive' or 'shy' by discriminant analysis. Baseline corticosterone, measured on the day following the novel-object or control test, was not related to any measure of coping. Stress induced corticosterone, however, was negatively related to number of hoverings in front of the nest (a measure of explorativeness) and accordingly differed between the behavioral coping categories, with 'inquisitive' birds having the lowest stress response. We propose that the relationship between physiological stress response and behavioral response to novelty (a component of personality or coping style) may be more complex than previously suggested, and individuals cannot always be unambiguously categorized along a single personality axis. PMID- 21307070 TI - Understanding the energetic costs of living in saline environments: effects of salinity on basal metabolic rate, body mass and daily energy consumption of a long-distance migratory shorebird. AB - Many migratory vertebrates typically move between habitats with varying salinities during the annual cycle. These organisms clearly exhibit a remarkable phenotypic flexibility in their 'osmoregulatory machinery', but the metabolic consequences of salinity acclimatization are still not well understood. We investigated the effects of salinity on basal metabolic rate (BMR), body mass and daily energy consumption of a long-distance migratory shorebird, the dunlin (Calidris alpina), outside the breeding season. Mass-corrected BMR and daily energy consumption increased significantly by 17 and 20% between freshwater (0.30/00 NaCl) and saltwater (33.0-35.00/00 NaCl), respectively. Body mass in both captive and wild dunlins was lower (9-16%) in saline than in freshwater environments. These changes on BMR and body mass were quickly reversed by returning the birds to freshwater, suggesting that metabolic adjustment to saltwater and metabolic readjustment to freshwater are both processes that occur in a few days. Our findings support empirically that the processes of developing and maintaining an active osmoregulatory machinery are energetically expensive, and they could help to explain diet and/or habitat selection patterns along the flyway. Finally, we discuss whether body mass loss in saltwater may be a strategy to reduce maintenance cost in osmotically stressful conditions such as overwintering in marine habitats, and raise some methodological implications for studies of BMR-related outcomes using captive birds captured in saline environments. PMID- 21307071 TI - Biomechanics of jumping in the flea. AB - It has long been established that fleas jump by storing and releasing energy in a cuticular spring, but it is not known how forces from that spring are transmitted to the ground. One hypothesis is that the recoil of the spring pushes the trochanter onto the ground, thereby generating the jump. A second hypothesis is that the recoil of the spring acts through a lever system to push the tibia and tarsus onto the ground. To decide which of these two hypotheses is correct, we built a kinetic model to simulate the different possible velocities and accelerations produced by each proposed process and compared those simulations with the kinematics measured from high-speed images of natural jumping. The in vivo velocity and acceleration kinematics are consistent with the model that directs ground forces through the tibia and tarsus. Moreover, in some natural jumps there was no contact between the trochanter and the ground. There were also no observable differences between the kinematics of jumps that began with the trochanter on the ground and jumps that did not. Scanning electron microscopy showed that the tibia and tarsus have spines appropriate for applying forces to the ground, whereas no such structures were seen on the trochanter. Based on these observations, we discount the hypothesis that fleas use their trochantera to apply forces to the ground and conclude that fleas jump by applying forces to the ground through the end of the tibiae. PMID- 21307072 TI - The protective role of aquaporins in the freeze-tolerant insect Eurosta solidaginis: functional characterization and tissue abundance of EsAQP1. AB - The movement of water and small solutes is integral to the survival of freezing and desiccation in insects, yet the underlying mechanisms of these processes are not fully known. Recent evidence suggests that aquaporin (AQP) water channels play critical roles in protecting cells from osmotic damage during freezing and desiccation. Our study sequenced, functionally characterized and measured the tissue abundance of an AQP from freeze-tolerant larvae of the gall fly, Eurosta solidaginis (Diptera: Tephritidae). The newly characterized EsAQP1 contains two NPA motifs and six transmembrane regions, and is phylogenetically related to an AQP from the anhydrobiotic chironomid Polypedilum vanderplanki. Using a Xenopus laevis oocyte swelling assay, we demonstrated that EsAQP1 increases water permeability to nine times that of simple diffusion through the membrane. In contrast to its high water permeability, EsAQP1 was impermeable to both glycerol and urea. The abundance of EsAQP1 increased from October to December in all tissues tested and was most abundant in the brain of winter larvae. Because the nervous system is thought to be the primary site of freezing injury, EsAQP1 may cryoprotect the brain from damage associated with water imbalance. The sequence, phylogenetic relationship, osmotic permeability, tissue distribution and seasonal abundance of EsAQP1 further support the role of AQPs in promoting freezing tolerance. PMID- 21307073 TI - Resting and action potentials under hypotonic conditions, unlike Na+ pump activity, depend only on the alteration of intracellular [Na+] and [K+] in frog skeletal muscle. AB - It is well established that hypotonicity generates a marked and unexpected increase in active Na(+) efflux in frog muscle fibers as well as in other cells like cardiac myocytes, astrocytes, brain synaptosomes and renal cells. The effect of hypotonicity on the electrical activity of skeletal muscle related to Na(+) and K(+) voltage-gated channels, however, has not been specifically addressed. The results of the present investigation show that the changes in resting and action potentials produced by hypotonicity can be fully explained by the reduction of intracellular [Na(+)] and [K(+)] due to the increase in cellular water content. PMID- 21307074 TI - Biomechanics of hair cell kinocilia: experimental measurement of kinocilium shaft stiffness and base rotational stiffness with Euler-Bernoulli and Timoshenko beam analysis. AB - Vestibular hair cell bundles in the inner ear contain a single kinocilium composed of a 9+2 microtubule structure. Kinocilia play a crucial role in transmitting movement of the overlying mass, otoconial membrane or cupula to the mechanotransducing portion of the hair cell bundle. Little is known regarding the mechanical deformation properties of the kinocilium. Using a force-deflection technique, we measured two important mechanical properties of kinocilia in the utricle of a turtle, Trachemys (Pseudemys) scripta elegans. First, we measured the stiffness of kinocilia with different heights. These kinocilia were assumed to be homogenous cylindrical rods and were modeled as both isotropic Euler Bernoulli beams and transversely isotropic Timoshenko beams. Two mechanical properties of the kinocilia were derived from the beam analysis: flexural rigidity (EI) and shear rigidity (kGA). The Timoshenko model produced a better fit to the experimental data, predicting EI=10,400 pN MUm(2) and kGA=247 pN. Assuming a homogenous rod, the shear modulus (G=1.9 kPa) was four orders of magnitude less than Young's modulus (E=14.1 MPa), indicating that significant shear deformation occurs within deflected kinocilia. When analyzed as an Euler Bernoulli beam, which neglects translational shear, EI increased linearly with kinocilium height, giving underestimates of EI for shorter kinocilia. Second, we measured the rotational stiffness of the kinocilium insertion (kappa) into the hair cell's apical surface. Following BAPTA treatment to break the kinocilial links, the kinocilia remained upright, and kappa was measured as 177+/-47 pN MUm rad(-1). The mechanical parameters we quantified are important for understanding how forces arising from head movement are transduced and encoded by hair cells. PMID- 21307075 TI - Not-so-simple setae. PMID- 21307076 TI - Evidence that nasal insulin induces immune tolerance to insulin in adults with autoimmune diabetes. AB - OBJECTIVE: Insulin in pancreatic beta-cells is a target of autoimmunity in type 1 diabetes. In the NOD mouse model of type 1 diabetes, oral or nasal administration of insulin induces immune tolerance to insulin and protects against autoimmune diabetes. Evidence for tolerance to mucosally administered insulin or other autoantigens is poorly documented in humans. Adults with recent-onset type 1 diabetes in whom the disease process is subacute afford an opportunity to determine whether mucosal insulin induces tolerance to insulin subsequently injected for treatment. RESEARCH DESIGN AND METHODS: We randomized 52 adults with recent-onset, noninsulin-requiring type 1 diabetes to nasal insulin or placebo for 12 months. Fasting blood glucose and serum C-peptide, glucagon-stimulated serum C-peptide, and serum antibodies to islet antigens were monitored three times monthly for 24 months. An enhanced ELISpot assay was used to measure the T cell response to human proinsulin. RESULTS: beta-Cell function declined by 35% overall, and 23 of 52 participants (44%) progressed to insulin treatment. Metabolic parameters remained similar between nasal insulin and placebo groups, but the insulin antibody response to injected insulin was significantly blunted in a sustained manner in those who had received nasal insulin. In a small cohort, the interferon-gamma response of blood T-cells to proinsulin was suppressed after nasal insulin. CONCLUSIONS: Although nasal insulin did not retard loss of residual beta-cell function in adults with established type 1 diabetes, evidence that it induced immune tolerance to insulin provides a rationale for its application to prevent diabetes in at-risk individuals. PMID- 21307077 TI - Stepwise or linear decrease in penetrance of type 1 diabetes with lower-risk HLA genotypes over the past 40 years. AB - OBJECTIVE: The objective of this study was to test if the proportion of new-onset diabetic subjects with the HLA-DR3/4-DQB1*0302 genotype is decreasing over time. RESEARCH DESIGN AND METHODS: We analyzed HLA class II genotype frequencies over time in two large populations with type 1 diabetes diagnosed at <=18 years of age. There were 4,075 subjects from the Type 1 Diabetes Genetics Consortium (T1DGC) and 1,675 subjects from the Barbara Davis Center (BDC). RESULTS: Both T1DGC and BDC cohorts showed a decrease of the highest-risk HLA-DR3/4-DQB1*0302 genotype over time. This decrease was greatest over time in T1DGC subjects with age of onset <=5 years (P = 0.004) and onset between ages 6 and 10 years (P = 0.002). The overall percent of HLA-DR3/4-DQB1*0302 was greater in the T1DGC population compared with the BDC population. There was an increased percent over time of other HLA genotypes without HLA-DR3 or -DR4 in T1DGC new onsets (P = 0.003), and the trend was similar in BDC subjects (P = 0.08). Analyzing time trend, there appears to be a large stepwise decrease in percent DR3/4 in the 1980s in T1DGC subjects with onset age <5 years (P = 0.0001). CONCLUSIONS: The change in frequency of multiple different genotypes and a possible stepwise decrease in percent DR3/4 suggest a change in genetic risk factors and environmental determinants of type 1 diabetes. Larger studies are needed to confirm the changing pattern of genetic risk because a stepwise change may have direct bearing on defining critical environmental determinants of type 1 diabetes. PMID- 21307078 TI - Glucose and inflammation control islet vascular density and beta-cell function in NOD mice: control of islet vasculature and vascular endothelial growth factor by glucose. AB - OBJECTIVE: beta-Cell and islet endothelial cell destruction occurs during the progression of type 1 diabetes, but, paradoxically, beta-cell proliferation is increased during this period. Altered glucose tolerance may affect beta-cell mass and its association with endothelial cells. Our objective was to study the effects of glucose and inflammation on islet vascularity and on beta function, mass, and insulin in immunologically tolerant anti-CD3 monoclonal antibody (mAb) treated and prediabetic NOD mice. RESEARCH DESIGN AND METHODS: The effects of phloridzin or glucose injections on beta-cells and endothelial cells were tested in prediabetic and previously diabetic NOD mice treated with anti-CD3 mAbs. Glucose tolerance, immunofluorescence staining, and examination of islet cultures ex vivo were evaluated. RESULTS: Islet endothelial cell density decreased in NOD mice and failed to recover after anti-CD3 mAb treatment despite baseline euglycemia. Glucose treatment of anti-CD3 mAb-treated mice showed increased islet vascular density and increased insulin content, which was associated with improved glucose tolerance. The increase in the vascular area was dependent on islet inflammation. Increased islet endothelial cell density was associated with increased production of vascular endothelial growth factor (VEGF) by islets from NOD mice. This response was recapitulated ex vivo by the transfer of supernatants from NOD islets cultured in high-glucose levels. CONCLUSIONS: Our results demonstrate a novel role for glucose and inflammation in the control of islet vasculature and insulin content of beta-cells in prediabetic and anti-CD3-treated NOD mice. VEGF production by the islets is affected by glucose levels and is imparted by soluble factors released by inflamed islets. PMID- 21307079 TI - Unmasking genes in a type 1 diabetes-resistant mouse strain that enhances pathogenic CD8 T-cell responses. AB - OBJECTIVE: Nominally resistant mouse strains such as C57BL/6 (B6) harbor latent type 1 diabetes susceptibility genes uncovered in outcross to disease-susceptible NOD mice. However, identification of possible recessively acting B6-derived susceptibility genes is limited because very few F2 progeny derived from outcrossing this strain with NOD develop spontaneous autoimmune diabetes. Thus, we assessed whether a transgenic T-cell receptor (TCR) disease transfer model allowed the mapping of recessively acting B6 genetic loci that in the proper context contribute to diabetes. RESEARCH DESIGN AND METHODS: CD8 T-cells transgenically expressing the diabetogenic AI4 TCR were transferred into 91 (NODxB6.H2(g7))F1xB6.H2(g7) first-backcross (BC1) females. A genome-wide scan was performed for loci affecting clinical diabetes and insulitis severity. RESULTS: A major locus on chromosome 11 in tight linkage with the marker D11Mit48 (logarithm of odds score = 13.2) strongly determined whether BC1 progeny were susceptible to AI4 T-cell-mediated diabetes. Mice homozygous versus heterozygous for B6 markers of this chromosome 11 genetic locus were, respectively, highly susceptible or resistant to AI4-induced insulitis and diabetes. The genetic effect is manifest by host CD4 T-cells. Microarray analyses of mRNA transcript expression identified a limited number of candidate genes. CONCLUSIONS: The distal region of chromosome 11 in B6 mice harbors a previously unrecognized recessively acting gene(s) that can promote autoreactive diabetogenic CD8 T-cell responses. Future identification of this gene(s) may further aid the screening of heterogeneous humans at future risk for diabetes, and might also provide a target for possible disease interventions. PMID- 21307080 TI - Risk of injury for bicycling on cycle tracks versus in the street. AB - Most individuals prefer bicycling separated from motor traffic. However, cycle tracks (physically separated bicycle-exclusive paths along roads, as found in The Netherlands) are discouraged in the USA by engineering guidance that suggests that facilities such as cycle tracks are more dangerous than the street. The objective of this study conducted in Montreal (with a longstanding network of cycle tracks) was to compare bicyclist injury rates on cycle tracks versus in the street. For six cycle tracks and comparable reference streets, vehicle/bicycle crashes and health record injury counts were obtained and use counts conducted. The relative risk (RR) of injury on cycle tracks, compared with reference streets, was determined. Overall, 2.5 times as many cyclists rode on cycle tracks compared with reference streets and there were 8.5 injuries and 10.5 crashes per million bicycle-kilometres. The RR of injury on cycle tracks was 0.72 (95% CI 0.60 to 0.85) compared with bicycling in reference streets. These data suggest that the injury risk of bicycling on cycle tracks is less than bicycling in streets. The construction of cycle tracks should not be discouraged. PMID- 21307081 TI - Complications and outcomes of brown recluse spider bites in children. AB - Brown recluse spider bites may cause severe local and systemic morbidity, but data regarding morbidity in children are limited. This study reviewed inpatient medical records (n = 26; 10 years) with a discharge diagnosis of "spider bite" from a tertiary pediatric hospital. The majority (85%) of children had an inflammatory response accompanying necrosis, usually with signs of secondary cellulitis (77%). Hemolytic anemia (50%), rhabdomyolysis (27%), and acute renal failure (12%) were the most prevalent systemic effects. Hemolytic anemia was bimodal in distribution relative to the time-of-onset of the bite (early, 2.2 +/- 0.4; late, 6.9 +/- 1.5 days postbite, respectively; P = .004). Although no fatalities occurred in the population, 65% of children had major morbidity, including wound complications requiring surgical care and acute orbital compartment syndrome. The findings emphasize the importance of anticipatory patient/family education for outpatients and careful monitoring for systemic morbidity in inpatients. Timely and appropriate supportive care should yield favorable outcomes in most cases. PMID- 21307082 TI - An infant with an MRSA ventriculo-gallbladder shunt infection. PMID- 21307083 TI - Current acute otitis media (AOM) pathogen surveillance data. PMID- 21307084 TI - Illness, everyday life and narrative montage: the visual aesthetics of cancer in Sara Bro's Diary. AB - This article presents a study of Sara Bro's Diary (2004), a book montage of images and texts recording the experiences of a Danish breast cancer survivor, Sara Bro. It examines two montages of photography and text, drawing on Roland Barthes' concept of 'the third meaning' to explain and discuss the effect of the layered meanings in the montage alongside their multi-medium and self-referential expression. The discussion is centred on the aesthetic practices that are invited by Bro's book montage. The article considers how the juxtaposition of images and texts are experienced and co-created by the reader. It points to the effect of the aesthetics of disguise and carnival implicit in the visual-verbal montage and argues that these generate a third meaning. This meaning is associated with the breast cancer experience but is not directly discernible in the montage. The article concludes by discussing how Bro's montage acts as an ideological statement, subverting or 'poaching on' the health care system. PMID- 21307085 TI - Comorbidity of anxiety and depressive disorders: a comparative population study in Western and non-Western inhabitants in the Netherlands. AB - BACKGROUND: Overlap of depressive and anxiety symptoms is supposedly more common in non-Western populations. This can lead to diagnostic uncertainity and undertreatment. AIMS: The aim of this study was to assess cross-cultural differences regarding the comorbidity of anxiety and depressive disorders in a comparative population study. METHODS: In a random urban population sample, stratified for descent, in Amsterdam, the Netherlands, diagnostic interviews were held by bilingual interviewers. Diagnoses of anxiety and depressive disorders, based on the Composite International Diagnostic Interview, were obtained for 307 native Dutch subjects, 205 Turkish-Dutch subjects and 186 Moroccan-Dutch subjects. RESULTS: The prevalence rate of comorbid anxiety and depressive disorders was higher in Turkish-Dutch (9.8 %) and Moroccan-Dutch (3.8%) subjects compared to native Dutch subjects (2.3%). However, this could be explained by differences in baseline prevalence rate and level of severity of the separate disorders. The onset order of anxiety disorders and depressive disorders was comparable in each ethnic group. CONCLUSIONS: The high prevalence rate of comorbid anxiety and depressive diorders in non-Western immigrants in the Netherlands necessitates assesssment and treatment of both disorders. There was no indication of a - culturally influenced - stronger overlap between anxiety and depressive disorders in non-Western immigrants in the Netherlands. PMID- 21307086 TI - Gender differences in mental health literacy among Chinese-speaking Australians in Melbourne, Australia. AB - OBJECTIVE: This study attempted to understand gender differences in knowledge of mental illness, preference for professional help, and medications and treatment methods among Australians of Chinese-speaking background. METHODS: This study adopted a cluster convenience sampling method in which subjects were taken from the four major areas in cosmopolitan Melbourne where most Chinese people are living. A total of 200 Chinese-speaking Australians participated in the study. They were presented with two vignettes describing an individual with acute depression or acute schizophrenia and then questions were asked to assess their understanding of the conditions, preference for professional help, medications and treatment methods. RESULTS: More female than male respondents could correctly identify the conditions in the two vignettes. Female participants also perceived medications to be relatively more harmful than their male counterparts. In contrast, there were significantly more males than females who adhered to traditional views on the causation of mental illness; had significantly higher percentages of endorsement of 'deal with it alone'; believed 'traditional Chinese medical doctor' and 'Chinese herbal medicines' to be helpful to the person in the schizophrenia vignette; and significantly endorsed 'psychiatric ward', 'electro convulsive treatment', 'changing fungshui' and 'traditional Chinese worship' to be helpful for the persons in both vignettes. A combination of factors, which included age, duration of migration and traditional Chinese cultural values, were put forward to explain the above differences. CONCLUSIONS: Campaigns to improve the mental health literacy of Chinese-speaking Australians must take into account the gender differences between male and female Chinese-speaking Australians so that culturally relevant and gender-specific education programmes can be developed. PMID- 21307087 TI - Premature death and neurologic abnormalities in transgenic mice expressing a mutant huntingtin exon-2 fragment. AB - Huntington's disease (HD) is a fatal neurodegenerative disease characterized pathologically by aggregates composed of N-terminal fragments of the mutant form of the protein huntingtin (htt). The role of these N-terminal fragments in disease pathogenesis has been questioned based in part on studies in transgenic mice. In one important example, mice that express an N-terminal fragment of mutant htt terminating at the C-terminus of exon 2 (termed the Shortstop mouse) were reported to develop robust inclusion pathology without developing phenotypic abnormalities seen in the R6/2 or N171-82Q models of HD, which are also based on expression of mutant N-terminal htt fragments. To further explore the capacity of mutant exon-2 htt fragments to produce neurologic abnormalities (N-terminal 118 amino acids; N118), we generated transgenic mice expressing cDNA that encodes htt N118-82Q with the mouse prion promoter vector. In mice generated in this manner, we demonstrate robust inclusion pathology accompanied by early death and failure to gain weight. These phenotypes are the most robust abnormalities identified in the R6/2 and N171-82Q models. We conclude that the lack of an overt phenotype in the initial Shortstop mice cannot be completely explained by the properties of mutant htt N118 fragments. PMID- 21307088 TI - Genome-wide association studies in Asians confirm the involvement of ATOH7 and TGFBR3, and further identify CARD10 as a novel locus influencing optic disc area. AB - Damage to the optic nerve (e.g. from glaucoma) has an adverse and often irreversible impact on vision. Earlier studies have suggested that the size of the optic nerve head could be governed by hereditary factors. We conducted a genome-wide association study (GWAS) on 4445 Singaporean individuals (n = 2132 of Indian and n = 2313 of Malay ancestry, respectively), with replication in Rotterdam, the Netherlands (n = 9326 individuals of Caucasian ancestry) using the most widely reported parameter for optic disc traits, the optic disc area. We identified a novel locus on chromosome 22q13.1, CARD10, which strongly associates with optic disc area in both Singaporean cohorts as well as in the Rotterdam Study (RS; rs9607469, per-allele change in optic disc area = 0.051 mm(2); P(meta) = 2.73*10(-12)) and confirmed the association between CDC7/TGFBR3 (lead single nucleotide polymorphism (SNP) rs1192415, P(meta) = 7.57*10(-17)) and ATOH7 (lead SNP rs7916697, P(meta) = 2.00 * 10(-15)) and optic disc area in Asians. This is the first Asian-based GWAS on optic disc area, identifying a novel locus for the optic disc area, but also confirming the results found in Caucasian persons suggesting that there are general genetic determinants applicable to the size of the optic disc across different ethnicities. PMID- 21307089 TI - Signalling during an ischaemic preconditioning protocol: new role players? PMID- 21307090 TI - Expression and regulation of sFRP family members in human granulosa cells. AB - Follicular development and ovulation are major processes in the reproductive system. Understanding their complexity is important to female fertility treatments and the control of reproductive processes. Wnt signaling pathway components were shown to be involved in reproduction in animal models. The secreted frizzled-related protein-4 (sFRP4), a potential modulator of Wnt4 signaling pathway, was shown to be induced by LH in rodents and expressed in the corpus lutea, but the pattern of its expression in human ovaries remains unknown. We evaluated the expression pattern of sFRP4 and other sFRP family members in human mural and cumulus granulosa cells (GCs), as well as their regulation by LH/hCG. GCs were obtained from follicles aspirated during in vitro maturation and IVF procedures. GCs were also plated and grown in culture. We showed that the human sFRP4 expression decreases as follicles grows to the preovulatory stage and its expression was higher in cumulus GCs than in mural GCs. Interestingly, LH/hCG stimulation of GCs in vivo and in culture resulted in decreased expression of sFRP4. Of the other sFRP family members, sFRP5 expression was found in mural and cumulus GC in vivo and was shown to be induced by LH/hCG in vitro and in vivo. In summary, sFRP4 is expressed in human GCs and its expression declines during late antral follicular growth. sFRP4 expression is also inhibited by LH/hCG, unlike its rodent homolog. In human GC, sFRP5 may substitute the role of sFRP4 in mouse GC. PMID- 21307091 TI - A landmark-free morphometric staging system for the mouse limb bud. AB - We have created a 2D morphometric analysis of the developing mouse hindlimb bud. This analysis has provided two useful resources for the study of limb development. First, a temporally accurate numerical description of shape changes during normal mouse limb development. Second, a web-based morphometric staging system, which has the advantage of being easy to use, and with a reproducibility of about +/-2 hours. It allows users to upload a dorsal-view photo of a limb bud, draw a spline curve and thereby stage the bud within a couple of minutes. We describe how the system is constructed, its robustness to user variation and illustrate one application: the accurate tracking of spatiotemporal dynamics of gene expression patterns. PMID- 21307092 TI - Apical ectodermal ridge morphogenesis in limb development is controlled by Arid3b mediated regulation of cell movements. AB - The apical ectodermal ridge (AER) is a specialized epithelium located at the distal edge of the limb bud that directs outgrowth along the proximodistal axis. Although the molecular basis for its function is well known, the cellular mechanisms that lead to its maturation are not fully understood. Here, we show that Arid3b, a member of the ARID family of transcriptional regulators, is expressed in the AER in mouse and chick embryos, and that interference with its activity leads to aberrant AER development, in which normal structure is not achieved. This happens without alterations in cell numbers or gene expression in main signalling pathways. Cells that are defective in Arid3b show an abnormal distribution of the actin cytoskeleton and decreased motility in vitro. Moreover, movements of pre-AER cells and their contribution to the AER were defective in vivo in embryos with reduced Arid3b function. Our results show that Arid3b is involved in the regulation of cell motility and rearrangements that lead to AER maturation. PMID- 21307093 TI - Pkd1l1 establishes left-right asymmetry and physically interacts with Pkd2. AB - In mammals, left-right (L-R) asymmetry is established by posteriorly oriented cilia driving a leftwards laminar flow in the embryonic node, thereby activating asymmetric gene expression. The two-cilia hypothesis argues that immotile cilia detect and respond to this flow through a Pkd2-mediated mechanism; a putative sensory partner protein has, however, remained unidentified. We have identified the Pkd1-related locus Pkd1l1 as a crucial component of L-R patterning in mouse. Systematic comparison of Pkd1l1 and Pkd2 point mutants reveals strong phenocopying, evidenced by both morphological and molecular markers of sidedness; both mutants fail to activate asymmetric gene expression at the node or in the lateral plate and exhibit right isomerism of the lungs. Node and cilia morphology were normal in mutants and cilia demonstrated typical motility, consistent with Pkd1l1 and Pkd2 activity downstream of nodal flow. Cell biological analysis reveals that Pkd1l1 and Pkd2 localise to the cilium and biochemical experiments demonstrate that they can physically interact. Together with co-expression in the node, these data argue that Pkd1l1 is the elusive Pkd2 binding partner required for L-R patterning and support the two-cilia hypothesis. PMID- 21307094 TI - Aplexone targets the HMG-CoA reductase pathway and differentially regulates arteriovenous angiogenesis. AB - Arterial and venous endothelial cells exhibit distinct molecular characteristics at early developmental stages. These lineage-specific molecular programs are instructive to the development of distinct vascular architectures and physiological conditions of arteries and veins, but their roles in angiogenesis remain unexplored. Here, we show that the caudal vein plexus in zebrafish forms by endothelial cell sprouting, migration and anastomosis, providing a venous specific angiogenesis model. Using this model, we have identified a novel compound, aplexone, which effectively suppresses venous, but not arterial, angiogenesis. Multiple lines of evidence indicate that aplexone differentially regulates arteriovenous angiogenesis by targeting the HMG-CoA reductase (HMGCR) pathway. Treatment with aplexone affects the transcription of enzymes in the HMGCR pathway and reduces cellular cholesterol levels. Injecting mevalonate, a metabolic product of HMGCR, reverses the inhibitory effect of aplexone on venous angiogenesis. In addition, aplexone treatment inhibits protein prenylation and blocking the activity of geranylgeranyl transferase induces a venous angiogenesis phenotype resembling that observed in aplexone-treated embryos. Furthermore, endothelial cells of venous origin have higher levels of proteins requiring geranylgeranylation than arterial endothelial cells and inhibiting the activity of Rac or Rho kinase effectively reduces the migration of venous, but not arterial, endothelial cells. Taken together, our findings indicate that angiogenesis is differentially regulated by the HMGCR pathway via an arteriovenous-dependent requirement for protein prenylation in zebrafish and human endothelial cells. PMID- 21307095 TI - Regulation of mouse stomach development and Barx1 expression by specific microRNAs. AB - Although microRNAs (miRNAs) are postulated to fine-tune many developmental processes, their relationships with specific targets and tissues remain largely undefined. The mesenchymal transcription factor Barx1 controls spleen and stomach morphogenesis and is required to specify stomach-specific epithelium in adjacent endoderm. Barx1 expression is precisely regulated in space and time, with a sharp drop in stomach levels after epithelial specification. We tested the hypothesis that specific miRNAs mediate this marked decline in Barx1 levels. Depletion of the miRNA-processing enzyme Dicer in cultured stomach mesenchyme and conditional Dicer gene deletion in mice significantly increased Barx1 levels, disrupted stomach and intestine development and caused spleen agenesis. Computational and experimental studies identified miR-7a and miR-203 as candidate miRNAs that regulate Barx1 and are expressed in inverse proportion to it in the fetal mouse stomach. Through specific interactions with cognate sequences in the Barx1 3' untranslated region, miR-7a and miR-203 repress Barx1 expression in stomach mesenchymal cells and its function in inducing gastric epithelium. These results indicate that miRNAs are required for proper digestive tract organogenesis and that miR-7a and miR-203 control expression of the stomach homeotic regulator Barx1. PMID- 21307096 TI - Multiple developmental programs are altered by loss of Zic1 and Zic4 to cause Dandy-Walker malformation cerebellar pathogenesis. AB - Heterozygous deletions encompassing the ZIC1;ZIC4 locus have been identified in a subset of individuals with the common cerebellar birth defect Dandy-Walker malformation (DWM). Deletion of Zic1 and Zic4 in mice produces both cerebellar size and foliation defects similar to human DWM, confirming a requirement for these genes in cerebellar development and providing a model to delineate the developmental basis of this clinically important congenital malformation. Here, we show that reduced cerebellar size in Zic1 and Zic4 mutants results from decreased postnatal granule cell progenitor proliferation. Through genetic and molecular analyses, we show that Zic1 and Zic4 have Shh-dependent function promoting proliferation of granule cell progenitors. Expression of the Shh downstream genes Ptch1, Gli1 and Mycn was downregulated in Zic1/4 mutants, although Shh production and Purkinje cell gene expression were normal. Reduction of Shh dose on the Zic1(+/-);Zic4(+/-) background also resulted in cerebellar size reductions and gene expression changes comparable with those observed in Zic1(-/-);Zic4(-/-) mice. Zic1 and Zic4 are additionally required to pattern anterior vermis foliation. Zic mutant folial patterning abnormalities correlated with disrupted cerebellar anlage gene expression and Purkinje cell topography during late embryonic stages; however, this phenotype was Shh independent. In Zic1(+/-);Zic4(+/-);Shh(+/-), we observed normal cerebellar anlage patterning and foliation. Furthermore, cerebellar patterning was normal in both Gli2-cko and Smo cko mutant mice, where all Shh function was removed from the developing cerebellum. Thus, our data demonstrate that Zic1 and Zic4 have both Shh-dependent and -independent roles during cerebellar development and that multiple developmental disruptions underlie Zic1/4-related DWM. PMID- 21307097 TI - EGF signaling regulates the proliferation of intestinal stem cells in Drosophila. AB - Precise control of somatic stem cell proliferation is crucial to ensure maintenance of tissue homeostasis in high-turnover tissues. In Drosophila, intestinal stem cells (ISCs) are essential for homeostatic turnover of the intestinal epithelium and ensure epithelial regeneration after tissue damage. To accommodate these functions, ISC proliferation is regulated dynamically by various growth factors and stress signaling pathways. How these signals are integrated is poorly understood. Here, we show that EGF receptor signaling is required to maintain the proliferative capacity of ISCs. The EGF ligand Vein is expressed in the muscle surrounding the intestinal epithelium, providing a permissive signal for ISC proliferation. We find that the AP-1 transcription factor FOS serves as a convergence point for this signal and for the Jun N terminal kinase (JNK) pathway, which promotes ISC proliferation in response to stress. Our results support the notion that the visceral muscle serves as a functional 'niche' for ISCs, and identify FOS as a central integrator of a niche derived permissive signal with stress-induced instructive signals, adjusting ISC proliferation to environmental conditions. PMID- 21307098 TI - Pkd1l1 complexes with Pkd2 on motile cilia and functions to establish the left right axis. AB - The internal organs of vertebrates show distinctive left-right asymmetry. Leftward extracellular fluid flow at the node (nodal flow), which is generated by the rotational movement of node cilia, is essential for left-right patterning in the mouse and other vertebrates. However, the identity of the pathways by which nodal flow is interpreted remains controversial as the molecular sensors of this process are unknown. In the current study, we show that the medaka left-right mutant abecobe (abc) is defective for left-right asymmetric expression of southpaw, lefty and charon, but not for nodal flow. We identify the abc gene as pkd1l1, the expression of which is confined to Kupffer's vesicle (KV, an organ equivalent to the node). Pkd1l1 can interact and interdependently colocalize with Pkd2 at the cilia in KV. We further demonstrate that all KV cilia contain Pkd1l1 and Pkd2 and left-right dynein, and that they are motile. These results suggest that Pkd1l1 and Pkd2 form a complex that functions as the nodal flow sensor in the motile cilia of the medaka KV. We propose a new model for the role of cilia in left-right patterning in which the KV cilia have a dual function: to generate nodal flow and to interpret it through Pkd1l1-Pkd2 complexes. PMID- 21307101 TI - Neck lump in a young woman. PMID- 21307100 TI - Kinesin-1 tail autoregulation and microtubule-binding regions function in saltatory transport but not ooplasmic streaming. AB - The N-terminal head domain of kinesin heavy chain (Khc) is well known for generating force for transport along microtubules in cytoplasmic organization processes during metazoan development, but the functions of the C-terminal tail are not clear. To address this, we studied the effects of tail mutations on mitochondria transport, determinant mRNA localization and cytoplasmic streaming in Drosophila. Our results show that two biochemically defined elements of the tail - the ATP-independent microtubule-binding sequence and the IAK autoinhibitory motif - are essential for development and viability. Both elements have positive functions in the axonal transport of mitochondria and determinant mRNA localization in oocytes, processes that are accomplished by biased saltatory movement of individual cargoes. Surprisingly, there were no indications that the IAK autoinhibitory motif acts as a general downregulator of Kinesin-1 in those processes. Time-lapse imaging indicated that neither tail region is needed for fast cytoplasmic streaming in oocytes, which is a non-saltatory bulk transport process driven solely by Kinesin-1. Thus, the Khc tail is not constitutively required for Kinesin-1 activation, force transduction or linkage to cargo. It might instead be crucial for more subtle elements of motor control and coordination in the stop-and-go movements of biased saltatory transport. PMID- 21307099 TI - The C. elegans SoxC protein SEM-2 opposes differentiation factors to promote a proliferative blast cell fate in the postembryonic mesoderm. AB - The proper development of multicellular organisms requires precise regulation and coordination of cell fate specification, cell proliferation and differentiation. Abnormal regulation and coordination of these processes could lead to disease, including cancer. We have examined the function of the sole C. elegans SoxC protein, SEM-2, in the M lineage, which produces the postembryonic mesoderm. We found that SEM-2/SoxC is both necessary and sufficient to promote a proliferating blast cell fate, the sex myoblast fate, over a differentiated striated bodywall muscle fate. A number of factors control the specific expression of sem-2 in the sex myoblast precursors and their descendants. This includes direct control of sem-2 expression by a Hox-PBC complex. The crucial nature of the HOX/PBC factors in directly enhancing expression of this proliferative factor in the C. elegans M lineage suggests a possible more general link between Hox-PBC factors and SoxC proteins in regulating cell proliferation. PMID- 21307102 TI - Private finance initiatives during NHS austerity. PMID- 21307103 TI - Outcomes of kidney transplantation are better in Spain than the US, a study finds. PMID- 21307105 TI - Payment by results may undermine services for drug users, warn specialists. PMID- 21307106 TI - WHO backs further probes into possible link between H1N1 vaccine and narcolepsy in children. PMID- 21307108 TI - Improving patient safety through education. PMID- 21307109 TI - Qualitative methods: an alternative view. PMID- 21307111 TI - Withholding versus withdrawal of life support: is there an ethical difference? PMID- 21307112 TI - Old drugs, new tricks. PMID- 21307115 TI - Lactation wars. PMID- 21307116 TI - Care less. PMID- 21307117 TI - Semi-customizing patient surveys: linking results and organizational conditions. AB - OBJECTIVE: The study investigated the needs and consequences of semi-customizing patient satisfaction surveys to low organizational levels and explored whether patient satisfaction was correlated with local organizational conditions. DESIGN: From 1999 to 2006, the County of Aarhus carried out 398 surveys during four rounds in eight hospitals. To explain differences between the wards, data on the 40 wards with the best and the 40 wards with the worst evaluations (identified by patient surveys) were compared with the data from job satisfaction surveys and management information systems. SETTING: Eight public hospitals in a Danish county. PARTICIPANTS: 32,809 inpatients and 1842 nurses on 84 wards. MAIN OUTCOME MEASURE: Optimal organizational level for measuring patient satisfaction and correlations between overall patient satisfaction and organizational context. RESULTS: In all, 71.4% of the departments chose to have the survey results specified at the subunit level or for specific diagnostic groups. Substantial differences in patient satisfaction between wards are illustrated. On the wards with the highest improvement potential, we found significantly higher occupancy rates, acute rates, rates of sickness absenteeism, staff perceptions of high workload and low experience of professionalism. CONCLUSIONS: The study confirmed that departments desired individual, detailed descriptions of the results. Differences in patient satisfaction were associated with differences in organizational conditions. Establishing a link between patient satisfaction and organizational variables broadens the quality development focus to include more than simply analysis of specific questions. Semi-customizing patient surveys are recommended. PMID- 21307118 TI - Hospitalized patients' participation and its impact on quality of care and patient safety. AB - OBJECTIVE: To understand the extent to which hospitalized patients participate in their care, and the association of patient participation with quality of care and patient safety. DESIGN: Random sample telephone survey and medical record review. SETTING: US acute care hospitals in 2003. PARTICIPANTS: A total of 2025 recently hospitalized adults. MAIN OUTCOME MEASURES: Hospitalized patients reported participation in their own care, assessments of overall quality of care and the presence of adverse events (AEs) in telephone interviews. Physician reviewers rated the severity and preventability of AEs identified by interview and chart review among 788 surveyed patients who also consented to medical record review. RESULTS: Of the 2025 patients surveyed, 99.9% of patients reported positive responses to at least one of seven measures of participation. High participation (use of >4 activities) was strongly associated with patients' favorable ratings of the hospital quality of care (adjusted OR: 5.46, 95% CI: 4.15-7.19). Among the 788 patients with both patient survey and chart review data, there was an inverse relationship between participation and adverse events. In multivariable logistic regression analyses, patients with high participation were half as likely to have at least one adverse event during the admission (adjusted OR = 0.49, 0.31-0.78). CONCLUSIONS: Most hospitalized patients participated in some aspects of their care. Participation was strongly associated with favorable judgments about hospital quality and reduced the risk of experiencing an adverse event. PMID- 21307119 TI - Extracellular matrix and cell signalling: the dynamic cooperation of integrin, proteoglycan and growth factor receptor. AB - Extracellular matrices (ECM) are secreted molecules that constitute the cell microenvironment, composed of a dynamic and complex array of glycoproteins, collagens, glycosaminoglycans and proteoglycans. ECM provides the bulk, shape and strength of many tissues in vivo, such as basement membrane, bone and cartilage. In vitro, most animal cells can only grow when they are attached to surfaces through ECM. ECM is also the substrate for cell migration. However, ECM provides much more than just mechanical and structural support, with implications in developmental patterning, stem cell niches and cancer. ECM imparts spatial context for signalling events by various cell surface growth factor receptors and adhesion molecules such as integrins. The external physical properties of ECM may also have a role in the signalling process. ECM molecules can be flexible and extendable, and mechanical tension can expose cryptic sites, which could further interact with growth factors or their receptors. ECM proteins and structures can determine the cell behaviour, polarity, migration, differentiation, proliferation and survival by communicating with the intracellular cytoskeleton and transmission of growth factor signals. Integrins and proteoglycans are the major ECM adhesion receptors which cooperate in signalling events, determining the signalling outcomes, and thus the cell fate. This review focuses on the emerging concept of spatial cell biology of ECM, especially the current understanding of integrins and heparan sulphate proteoglycans as the essential cellular machineries that sense, integrate and respond to the physical and chemical environmental information either by directly connecting with the local adhesion sites or by regulating global cellular processes through growth factor receptor signalling pathways, leading to the integration of both external and internal signals in space and time. PMID- 21307120 TI - Suppression of lactation and acceleration of involution in the bovine mammary gland by a selective serotonin reuptake inhibitor. AB - Serotonin (5-HT) is a homeostatic regulator of lactation. Selective 5-HT reuptake inhibitors (SSRI) are commonly prescribed pharmaceuticals that inhibit activity of the 5-HT reuptake transporter, increasing cellular exposure to 5-HT. Use of SSRIs has been shown to alter lactation performance in humans and 5-HT has been shown to reduce milk yield in cattle. However, it has not been determined how SSRI treatments affect the bovine mammary gland. We evaluated the effects of SSRI (fluoxetine (FLX)) administration on tight junctions (TJs) and milk protein gene expression in a lactogenic culture model, using primary bovine mammary epithelial cells (pBMEC). Additionally, we evaluated the effects of intramammary infusions of FLX and 5-hydroxytryptophan on milk production and TJ status in multiparous Holstein cows at dry-off. Treatment of pBMEC cultured on permeable membranes disrupted TJs, as measured by transepithelial resistance and immunostaining for zona occludens 1. Correspondingly, treatment of '3D', collagen-embedded lactogenic cultures of pBMEC with FLX suppressed milk protein gene expression (alpha-lactalbumin and beta-casein) in a concentration-dependent manner. Finally, intramammary treatment of Holstein cows with FLX resulted in an accelerated rate of milk decline. Additionally, TJ permeability increased in FLX-treated animals, as measured by plasma lactose and milk Na(+) and K(+) levels. Results of these experiments imply that SSRI administration accelerates the rate of mammary gland involution through disassembly of TJs and inhibition of milk protein gene expression in vitro and in vivo, leading to reduction of milk yield. PMID- 21307121 TI - Thyroid hormone ameliorates diabetic nephropathy in a mouse model of type II diabetes. AB - Conventional therapies for diabetic patients, such as strict glycemic control, do not completely stop the progression of diabetic nephropathy. Serum-free tri iodothyronine (T3) levels were lower in patients with type II diabetes. The purpose of this study was to test a hypothesis that treatment with T3 would improve diabetic nephropathy in db/db mice, a model of type II diabetes. Male db/db mice (16 weeks) were treated with T3 for 4 weeks. Urinary excretions of albumin and blood glucose levels were measured. Kidneys were collected for histological examination and molecular assays of transforming growth factor-beta1 (TGF-beta1) expression and phosphatidylinositol 3-kinase (PI3K). T3 attenuated albuminuria in db/db mice, suggesting an improved kidney function. T3 significantly decreased accumulation of collagenous components in cortical interstitium (interstitial fibrosis) and expansion of mesangial matrix in glomeruli (glomerulosclerosis) and prevented the loss of glomeruli in db/db mice. Therefore, T3 improved the renal structural damage seen in diabetic mice. Notably, diabetic nephropathy was accompanied by a significant decrease in PI3K activity and an increase in TGF-beta1 expression in kidneys. T3 restored renal PI3K activity, attenuated hyperglycemia, and decreased renal TGF-beta1 expression in db/db mice. These effects of T3 were abolished by simultaneous treatment with PI3K inhibitor (LY294002). These data suggest that T3 prevented progressive kidney damage and remodeling in db/db mice by improving insulin signaling (e.g. PI3K activity). PMID- 21307122 TI - Genome-wide screening in human growth plates during puberty in one patient suggests a role for RUNX2 in epiphyseal maturation. AB - In late puberty, estrogen decelerates bone growth by stimulating growth plate maturation. In this study, we analyzed the mechanism of estrogen action using two pubertal growth plate specimens of one girl at Tanner stage B2 and Tanner stage B3. Histological analysis showed that progression of puberty coincided with characteristic morphological changes: a decrease in total growth plate height (P=0.002), height of the individual zones (P<0.001), and an increase in intercolumnar space (P<0.001). Microarray analysis of the specimens identified 394 genes (72% upregulated and 28% downregulated) that changed with the progression of puberty. Overall changes in gene expression were small (average 1.38-fold upregulated and 1.36-fold downregulated genes). The 394 genes mapped to 13 significantly changing pathways (P<0.05) associated with growth plate maturation (e.g. extracellular matrix, cell cycle, and cell death). We next scanned the upstream promoter regions of the 394 genes for the presence of evolutionarily conserved binding sites for transcription factors implicated in growth plate maturation such as estrogen receptor (ER), androgen receptor, ELK1, STAT5B, cyclic AMP response element (CREB), and RUNX2. High-quality motif sites for RUNX2 (87 genes), ELK1 (43 genes), and STAT5B (31 genes), but not ER, were evolutionarily conserved, indicating their functional relevance across primates. Moreover, we show that some of these sites are direct target genes of these transcription factors as shown by ChIP assays. PMID- 21307123 TI - Second transmembrane domain modulates epithelial sodium channel gating in response to shear stress. AB - Na(+) absorption and K(+) secretion in the distal segments of the nephron are modulated by the tubular flow rate. Epithelial Na(+) channels (ENaC), composed of alpha-, beta-, and gamma-subunits respond to laminar shear stress (LSS) with an increase in open probability. Higher vertebrates express a delta-ENaC subunit that is functionally related to the alpha-subunit, while sharing only 35% of sequence identity. We investigated the response of deltabetagamma channels to LSS. Both the time course and magnitude of activation of deltabetagamma channels by LSS were remarkably different from those of alphabetagamma channels. ENaC subunits have similar topology, with an extracellular region connected by two transmembrane domains with intracellular N and C termini. To identify the specific domains that are responsible for the differences in the response to flow of alphabetagamma and deltabetagamma channels, we generated a series of alpha delta chimeras and site-specific alpha-subunit mutants and examined parameters of activation by LSS. We found that specific sites in the region encompassing and just preceding the second transmembrane domain were responsible for the differences in the magnitude and time course of channel activation by LSS. PMID- 21307124 TI - Regulation of the water channel aquaporin-2 by posttranslational modification. AB - The cellular functions of many eukaryotic membrane proteins, including the vasopressin-regulated water channel aquaporin-2 (AQP2), are regulated by posttranslational modifications. In this article, we discuss the experimental discoveries that have advanced our understanding of how posttranslational modifications affect AQP2 function, especially as they relate to the role of AQP2 in the kidney. We review the most recent data demonstrating that glycosylation and, in particular, phosphorylation and ubiquitination are mechanisms that regulate AQP2 activity, subcellular sorting and distribution, degradation, and protein interactions. From a clinical perspective, posttranslational modification resulting in protein misrouting or degradation may explain certain forms of nephrogenic diabetes insipidus. In addition to providing major insight into the function and dynamics of renal AQP2 regulation, the analysis of AQP2 posttranslational modification may provide general clues as to the role of posttranslational modification for regulation of other membrane proteins. PMID- 21307125 TI - p53 target Siva regulates apoptosis in ischemic kidneys. AB - The role of p53 in inducing apoptosis following acute kidney injury is well established; however, the molecular mechanisms remain largely unknown. We report here that the p53 proapoptotic target Siva and its receptor CD27, a member of the tumor necrosis factor receptor family, are upregulated following renal ischemia reperfusion injury (IRI). Inhibition of Siva using antisense oligonucleotides conferred functional and morphological protection, and it prevented apoptosis postrenal IRI in mice. Renal IRI in CD27-deficient mice displayed functional protection and partial inhibition of apoptosis, suggesting an incomplete role for CD27 in Siva-mediated apoptosis. To further elucidate mechanisms by which Siva elicits apoptosis, in vitro studies were performed. In Siva-transfected LLC PK(1)cells, Siva is persistently expressed in the nucleus at 3 h onwards and its translocation to mitochondria and the plasma membrane occurred at 6 h. Moreover, Siva overexpression induced mitochondrial permeability, cytochrome c release, caspase-8 and -9 activation, translocation of apoptosis-inducing factor (AIF) to the nucleus, and apoptosis. Inhibition of Siva in ischemic kidneys prevented mitochondrial release of cytochrome c and AIF. These data indicate that Siva function is pivotal in regulating apoptosis in the pathology of renal IRI. Targeting Siva may offer a potential therapeutic strategy for renal IRI. PMID- 21307126 TI - High salt differentially regulates surface NKCC2 expression in thick ascending limbs of Dahl salt-sensitive and salt-resistant rats. AB - NaCl reabsorption by the thick ascending limb of the loop of Henle (THAL) occurs via the apical Na-K-2Cl cotransporter, NKCC2. Overall, NKCC2 activity and NaCl reabsorption are regulated by the amount of NKCC2 at the apical surface, and also by phosphorylation. Dahl salt-sensitive rats (SS) exhibit higher NaCl reabsorption by the THAL compared with Dahl salt-resistant rats (SR), and they become hypertensive during high-salt (HS) intake. However, the effect of HS on THAL transport, surface NKCC2 expression, and NKCC2 NH(2)-terminus phosphorylation has not been studied. We hypothesized that HS enhances surface NKCC2 and its phosphorylation in THALs from Dahl SS. THAL suspensions were obtained from a group of SS and SR rats on normal-salt (NS) or HS intake. In SR rats THAL NaCl transport measured as furosemide-sensitive oxygen consumption was decreased by HS (-34%, P < 0.05). In contrast, HS did not affect THAL transport in SS rats. As expected, HS increased systolic blood pressure only in SS rats (Delta 23 +/- 2 mmHg, P < 0.002) but not in SR rats (Delta 5 +/- 3 mmHg). We next tested the effect of HS intake on apical surface NKCC2 and its NH(2)-terminus threonine phosphorylation (P-NKCC2) in SS and SR rats. HS intake decreased surface NKCC2 by 15 +/- 2% (P < 0.03) in THALs from SR without affecting total NKCC2 or NH(2)-terminus P-NKCC2. In contrast, in SS rats HS intake increased surface NKCC2 by 54 +/- 6% (P < 0.01) without affecting total NKCC2 expression or P-NKCC2. We conclude that HS intake causes different effects on surface NKCC2 in SS and SR rats. Our data suggest that enhanced surface NKCC2 in SS rats might contribute to enhanced NaCl reabsorption in SS rats during HS intake. PMID- 21307127 TI - Effect of metabolic acidosis on progression of chronic kidney disease. PMID- 21307128 TI - Intrarenal transfer of an intracellular fluorescent fusion of angiotensin II selectively in proximal tubules increases blood pressure in rats and mice. AB - The present study tested the hypothesis that intrarenal adenoviral transfer of an intracellular cyan fluorescent fusion of angiotensin II (ECFP/ANG II) selectively in proximal tubules of the kidney increases blood pressure by activating AT(1) (AT(1a)) receptors. Intrarenal transfer of ECFP/ANG II was induced in the superficial cortex of rat and mouse kidneys, and the sodium and glucose cotransporter 2 (sglt2) promoter was used to drive ECFP/ANG II expression selectively in proximal tubules. Intrarenal transfer of ECFP/ANG II induced a time-dependent, proximal tubule-selective expression of ECFP/ANG II in the cortex, which peaked at 2 wk and was sustained for 4 wk. ECFP/ANG II expression was low in the glomeruli and the entire medulla and was absent in the contralateral kidney or extrarenal tissues. At its peak of expression in proximal tubules at day 14, ANG II was increased by twofold in the kidney (P < 0.01) and more than threefold in proximal tubules (P < 0.01), but remained unchanged in plasma or urine. Systolic blood pressure was increased in ECFP/ANG II-transferred rats by 28 +/- 6 mmHg (P < 0.01), whereas fractional sodium excretion was decreased by 20% (P < 0.01) and fractional lithium excretion was reduced by 24% (P < 0.01). These effects were blocked by losartan and prevented in AT(1a) knockout mice. Transfer of a scrambled ECFP/ANG IIc had no effects on blood pressure, kidney, and proximal tubule ANG II, or sodium excretion. These results provide evidence that proximal tubule-selective transfer of an intracellular ANG II fusion protein increases blood pressure by activating AT(1a) receptors and increasing sodium reabsorption in proximal tubules. PMID- 21307129 TI - Phosphate overload induces podocyte injury via type III Na-dependent phosphate transporter. AB - Uptake of P(i) at the cellular membrane is essential for the maintenance of cell viability. However, phosphate overload is also stressful for cells and can result in cellular damage. In the present study, we investigated the effects of the transgenic overexpression of type III P(i) transporter Pit-1 to explore the role of extracellular P(i) in glomerular sclerosis during chronic renal disease. Pit-1 transgenic (TG) rats showed progressive proteinuria associated with hypoalbuminemia and dyslipidemia. Ultrastructural analysis of TG rat kidney by transmission electron microscopy showed a diffuse effacement of the foot processes of podocytes and a thickening of the glomerular basement membrane, which were progressively exhibited since 8 wk after birth. TG rats died at 32 wk of age due to cachexia. At this time, more thickening of the glomerular basement membrane and segmental sclerosis were observed in glomeruli of the TG rats. Immunohistochemical examination using anti-connexin 43 and anti-desmin antibodies suggested the progressive injury of podocytes in TG rats. TG rats showed higher P(i) uptake in podocytes than wild-type rats, especially under low P(i) concentration. When 8-wk-old wild-type and TG rats were fed a 0.6% normal phosphate (NP) or 1.2% phosphate (HP) diet for 12 wk, HP diet-treated TG rats showed more progressive proteinuria and higher serum creatinine levels than NP diet-treated TG rats. In conclusion, our findings suggest that overexpression of Pit-1 in rats induces phosphate-dependent podocyte injury and damage to the glomerular barrier, which result in the progression of glomerular sclerosis in the kidney. PMID- 21307130 TI - eEF-2 kinase dictates cross-talk between autophagy and apoptosis induced by Akt Inhibition, thereby modulating cytotoxicity of novel Akt inhibitor MK-2206. AB - Inhibition of the survival kinase Akt can trigger apoptosis, and also has been found to activate autophagy, which may confound tumor attack. In this study, we investigated regulatory mechanisms through which apoptosis and autophagy were modulated in tumor cells subjected to Akt inhibition by MK-2206, the first allosteric small molecule inhibitor of Akt to enter clinical development. In human glioma cells, Akt inhibition by MK-2206 or siRNA-mediated attenuation strongly activated autophagy, whereas silencing of eukaryotic elongation factor-2 (eEF-2) kinase, a protein synthesis regulator, blunted this autophagic response. Suppression of MK-2206-induced autophagy by eEF-2 silencing was accompanied by a promotion of apoptotic cell death. Similarly, siRNA-mediated inhibition of eEF-2 kinase potentiated the efficacy of MK-2206 against glioma cells. Together, these results showed that blunting autophagy and augmenting apoptosis by inhibition of eEF-2 kinase could modulate the sensitivity of glioma cells to Akt inhibition. Our findings suggest that targeting eEF-2 kinase may reinforce the antitumor efficacy of Akt inhibitors such as MK-2206. PMID- 21307131 TI - IL-15 and type I interferon are required for activation of tumoricidal NK cells by virus-infected dendritic cells. AB - There is increasing evidence that natural killer (NK) cells play an important role in antitumor immunity following dendritic cell (DC) vaccination. Little is known, however, about the optimal stimulation of DCs that favors NK activation in tumor-bearing hosts. In this study, we demonstrate that treatment with toll-like receptor (TLR) ligands and infection with a mutant vesicular stomatitis virus (VSV-DeltaM51) both induced DC maturation. Further, inoculation of these DCs led to robust NK-mediated protection against tumor challenge. Strikingly, only VSV DeltaM51-infected DCs were capable of suppressing the growth of established tumors, suggesting that additional signals provided by viral infection may be required to activate tumoricidal NK cells in tumor-bearing hosts. VSV-DeltaM51 infection of DCs induced greater type I interferon (IFN I) production than TLR ligand treatment, and disruption of the IFN I pathway in DCs eliminated their ability to induce NK activation and tumor protection. However, further studies indicated that IFN I alone was not sufficient to activate NK cells, especially in the presence of a tumor, and DC-derived IL-15 was additionally required for tumoricidal NK activation. These results suggest that induction of IFN I by VSV DeltaM51 allows DCs to overcome tumor-associated immunosuppression and facilitate IL-15-mediated priming of tumoricidal NK cells. Thus, the mode of DC maturation should be carefully considered when designing DC-based cancer immunotherapies. PMID- 21307132 TI - Abrogating TNF-alpha expression prevents bystander destruction of normal tissues during iNOS-mediated elimination of intraocular tumors. AB - Although intraocular tumors reside in an immune privileged site, some tumors are rejected nonetheless. For example, intraocular adenovirus-induced (Ad5E1; adenovirus type 5 early region 1) tumors are rejected in syngeneic C57BL/6 mice by one of two pathways. One pathway leads to extensive necrosis of innocent bystander cells and culminates in destruction of the eye, a condition called phthisis. The second pathway is characterized by piecemeal tumor cell death that rids the eye of the tumor while preserving the architecture and function of the eye. To study the mechanisms of phthisical tumor rejection, we isolated a cell clone-designated clone 2.1 that consistently undergoes rejection in a phthisical manner. CD4(+) T cells and macrophages were required for phthisical rejection of intraocular clone 2.1 tumors and M1 macrophages were involved in mediating tumor rejection. In vitro and in vivo inhibition of iNOS (inducible nitric oxide synthase) abolished macrophage-mediated killing of tumor cells and rejection of intraocular tumors. A role for M1 macrophages was further supported by investigations showing that intraocular tumors grew progressively in IFN-gamma KO (knockout) mice. Studies in mice deficient in TNF-alpha, TNF receptor-1, or TNF receptor-2 revealed that although TNF-alpha was not needed for tumor rejection, it was required for the development of necrotizing inflammation and phthisis of tumor-bearing eyes. Together, our findings suggest new strategies to successfully eliminate ocular tumors while preserving the integrity of the eye. PMID- 21307133 TI - Gonadotropin-releasing hormone agonist treatment in postmenopausal women with hyperandrogenism of ovarian origin. AB - CONTEXT: The most frequent cause of virilization in postmenopausal women is excessive androgen production of ovarian origin. Bilateral oophorectomy is usually performed, even in cases of benign tumors or hyperthecosis. This is the first report of a case series of long-term GnRH-agonist treatment of hyperandrogenism in postmenopausal women. OBJECTIVE: We present three women with postmenopausal hyperandrogenism of ovarian origin who were treated with GnRH agonists. PATIENTS: We describe three cases of postmenopausal women with virilization and hyperandrogenism of presumed ovarian origin, all with slight enlargement of the ovaries but without visualization of a tumor, who had long term treatment with GnRH agonists. No histological diagnosis was available, and therefore all patients received careful follow-up, including periodic testing of androgen levels and ovarian imaging by computed tomography scans. The three patients responded in different ways to treatment with GnRH agonists. CONCLUSIONS: Long-term GnRH agonist treatment is an acceptable choice for treatment of postmenopausal hyperandrogenism in patients where ovarian origin of androgen excess is ascertained, and especially in those patients who have an increased risk for surgery due to comorbidities or who are unwilling to undergo bilateral oophorectomy. PMID- 21307134 TI - The metabolic status modulates the effect of metformin on the antimullerian hormone-androgens-insulin interplay in obese women with polycystic ovary syndrome. AB - CONTEXT: In the adult ovary, antimullerian hormone (AMH) is produced by the granulosa cells of preantral and small antral follicles and negatively regulates folliculogenesis. AMH is overproduced in the polycystic ovary and was recently proposed to play a role in the ovulatory dysfunction of polycystic ovary syndrome (PCOS). OBJECTIVE: The aim of the study was to investigate the effects of metformin administration on AMH levels in relation with the clinical and endocrine-metabolic parameters in obese women with PCOS. DESIGN AND SETTING: We conducted a pilot prospective study in an academic research environment. PATIENTS: We studied 28 obese PCOS women. INTERVENTIONS: We performed ultrasonographic pelvic exams, hirsutism score evaluation, hormonal profile assays, oral glucose tolerance test, euglycemic hyperinsulinemic clamp, and lipid profile at baseline and after 6 months of metformin treatment (850 mg twice a day orally). MAIN OUTCOME MEASURES: We measured AMH, hormonal assays, ultrasound aspect of the ovaries, and indexes of glucose and insulin metabolism. RESULTS: Insulin secretion and body mass index significantly decreased after treatment. Almost 70% of subjects experienced an amelioration of menstrual irregularities. Mean androstenedione, testosterone, and 17-hydroxyprogesterone levels and hirsutism score were significantly improved by metformin. However, no significant changes in AMH levels occurred. Data were further analyzed after dividing patients on the basis of pretreatment insulinemic response to the oral glucose tolerance test; metformin was effective in reducing insulin secretion, AMH levels, and, interestingly, ovarian volume exclusively in PCOS patients with hyperinsulinism; none of these changes occurred in the normoinsulinemic group. CONCLUSIONS: Metformin differentially affects the interplay between insulin and the ovarian function in obese PCOS women; the presence of hyperinsulinemia seems to be predictive of the efficacy of the treatment. PMID- 21307135 TI - Interleukin 1B variant -1473G/C (rs1143623) influences triglyceride and interleukin 6 metabolism. AB - CONTEXT: IL1b (IL1B or IL1beta), a key modulator of the immune response, exerts its functions mainly via IL6 regulation. Fatty meals cause transient hypertriglyceridemia and are considered to be proinflammatory, but the extent of these responses shows high interindividual susceptibility. OBJECTIVE: We evaluated the influence of a genetic variant located in the promoter region of IL1B (-1473G/C) on fasting and postprandial lipids and IL6. DESIGN, SETTING, AND PARTICIPANTS: A total of 477 people over age 65 yr were genotyped for IL1B 1473G/C, and we evaluated fasting lipids depending on genotype. Then, 88 healthy young men were also genotyped and were fed a saturated fatty acid-rich meal. Serial blood samples were drawn for 11 h after the meal, and lipid fractions and IL6 were assayed. MAIN OUTCOME AND INTERVENTIONS: Fasting lipids were studied in the aged persons. Fasting and postprandial measurements of lipids and IL6 were performed in the healthy young men. RESULTS: In the aged persons, CC subjects (minor allele homozygotes) showed higher triglyceride (P = 0.002) and cholesterol (P = 0.011) levels. Healthy young male carriers of the minor C allele showed higher postprandial triglycerides (P = 0.037), and those carried into large triglyceride-rich lipoproteins (P = 0.004). In addition, they showed higher postprandial IL6 concentrations (P = 0.008). CONCLUSIONS: Our work shows that inflammatory genes may regulate fasting and postprandial lipids because the carriers of the minor allele of an IL gene variant have altered lipid metabolism. To reinforce these gene-phenotype findings, IL6 (the natural effector of IL1B) was increased in these persons. PMID- 21307137 TI - DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. AB - CONTEXT: We wanted to understand the effects of once-weekly vs. twice-daily glucagon-like peptide-1 receptor agonism for treatment of patients with type 2 diabetes. OBJECTIVE: The objective of the study was to compare effects of exenatide once weekly (ExQW) and exenatide twice daily (ExBID) on glycemic control, body weight, and safety. DESIGN: This was a 24-wk, randomized, open label, comparator-controlled study. SETTING: The study was conducted at 43 sites in the United States. PATIENTS: The study population was 252 intent-to-treat patients with type 2 diabetes [baseline (mean +/- SD): glycosylated hemoglobin (HbA1c) 8.4 +/- 1.2%, fasting plasma glucose 171 +/- 47 mg/dl, weight 96 +/- 20 kg] that were drug naive (19%) or previously treated with one (47%) or multiple (35%) oral antidiabetic medications. INTERVENTIONS: Interventions included ExQW 2 mg for 24 wk or ExBID 5 MUg for 4 wk followed by ExBID 10 MUg for 20 wk. MAIN OUTCOME MEASURE: The change in HbA1c from baseline to wk 24 was measured. RESULTS: At 24 wk, ExQW produced significantly greater changes from baseline (least squares mean +/- SE) vs. ExBID in HbA1c (-1.6 +/- 0.1% vs. -0.9 +/- 0.1%; P < 0.0001) and fasting plasma glucose (-35 +/- 5 mg/dl vs. -12 +/- 5 mg/dl; P = 0.0008). Similar reductions in mean body weight from baseline to wk 24 were observed in both groups (-2.3 +/- 0.4 kg and -1.4 +/- 0.4 kg). Both treatments were generally well tolerated. Transient and predominantly mild to moderate nausea, the most frequent adverse event, was less common with ExQW (14%) than with ExBID (35%). Injection-site reactions were infrequent, but more common with ExQW. No major hypoglycemia occurred. CONCLUSIONS: Continuous glucagon-like peptide-1 receptor agonism with ExQW resulted in superior glycemic control, with less nausea, compared with ExBID in patients with type 2 diabetes. Both groups lost weight. PMID- 21307136 TI - Skeletal muscle mitochondrial capacity and insulin resistance in type 2 diabetes. AB - OBJECTIVE: The objective of this study was to determine the role of maximum mitochondrial capacity on the variation in insulin sensitivity within a population of patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: Fifty-eight participants enrolled in a cross-sectional design: eight active controls [maximum aerobic capacity (VO(2max)) > 40 ml/kg . min], 17 healthy sedentary controls without a family history (FH-) and seven with a family history (FH+) of diabetes, four obese participants, and 21 patients with T2DM. Mitochondrial capacity was measured noninvasively using (31)P magnetic resonance spectroscopy of the vastus lateralis. Maximal ATP synthetic rate (ATP(max)) was determined from the rate of phosphocreatine (PCr) recovery after short-term isometric exercise. RESULTS: ATP(max) was lower (P < 0.001) in T2DM and higher (P < 0.001) in active as compared with healthy sedentary FH- (active, 1.01 +/- 0.2; FH-, 0.7 +/- 0.2; FH+, 0.6 +/- 0.1; obese, 0.6 +/- 0.1; T2DM, 0.5 +/- 0.2 mm ATP/sec; ANOVA P < 0.0001). Insulin sensitivity, measured by euglycemic hyperinsulinemic (80 mIU/m(2) . min) clamp was also reduced in T2DM (P < 0.001) (active, 12.0 +/- 3.2; FH-, 7.8 +/- 2.2; FH+, 6.8 +/- 3.5; obese, 3.1 +/- 1.0; T2DM, 3.4 +/- 1.6; mg/kg estimated metabolic body size . min; ANOVA P < 0.0001). Unexpectedly, there was a broad range of ATP(max) within the T2DM population where 52% of subjects with T2DM had ATP(max) values that were within the range observed in healthy sedentary controls. In addition, 24% of the T2DM subjects overlapped with the active control group (range, 0.65-1.27 mm ATP/sec). In contrast to the positive correlation between ATP(max) and M-value in the whole population (r(2) = 0.35; P < 0.0001), there was no correlation between ATP(max) and M-value in the patients with T2DM (r(2) = 0.004; P = 0.79). CONCLUSIONS: Mitochondrial capacity is not associated with insulin action in T2DM. PMID- 21307138 TI - Increased rate of intracranial saccular aneurysms in acromegaly: an MR angiography study and review of the literature. AB - BACKGROUND: The concurrence of intracranial aneurysms and acromegaly has been reported and debated previously. Our study in a large number of patients aimed to verify whether acromegaly patients carry a higher risk of harboring intracranial saccular aneurysms and to evaluate the possible relationship using clinical, laboratory, and imaging techniques. MATERIALS AND METHODS: A total of 152 of 161 consecutive acromegaly patients (median age, 55.7 yr; 82 females) underwent neuroimaging evaluation of the circle of Willis. Clinical data (disease duration and disease control, hypertension, smoking history, diabetes and dyslipidemia, previous surgery or radiotherapy, previous or current pharmacological therapy), laboratory findings (GH and IGF-I at onset and shortly before examination), and pituitary adenoma imaging features (size and invasiveness of the cavernous sinus) were recorded. RESULTS: Twenty-six patients (17.3%) harbored 40 newly diagnosed intracranial aneurysms; two other patients had previously undergone aneurysm clipping due to subarachnoid hemorrhage. Ten patients had multiple aneurysms; most of the aneurysms were located in the intracranial tract of the internal carotid artery (67.5%); no aneurysms belonged to the vertebrobasilar circulation. The presence of intracranial aneurysms correlated with GH serum values at disease onset (P < 0.05) and showed a trend to a positive correlation with poor disease control (P = 0.06); no other laboratory, clinical, and radiological findings correlated with the presence of intracranial aneurysms. CONCLUSIONS: GH serum excess seems to carry an increased risk of developing intracranial aneurysms. A neuroradiological evaluation of the intracranial circulation might therefore be considered in the diagnostic work-up of patients affected with acromegaly. PMID- 21307139 TI - Assessment of Leydig and Sertoli cell functions in infants with nonmosaic Klinefelter syndrome: insulin-like peptide 3 levels are normal and positively correlated with LH levels. AB - CONTEXT: Klinefelter syndrome (KS) is the most common sex chromosome disorder and a major cause of male infertility. In adult patients, serum inhibin B and anti Mullerian-hormone (AMH) are undetectable, testosterone secretion is often impaired, and the tubules are depleted of germ cells. Before puberty, inhibin B, AMH, and testosterone levels are within the normal range. OBJECTIVE: Sertoli and Leydig cell secretions, including insulin-like peptide-3 (INSL3), were evaluated in infants with nonmosaic XXY karyotype to assess testicular function soon after birth. DESIGN: The study was conducted in four University Pediatric Departments from the United States and France. SUBJECTS: Sixty-eight prenatally diagnosed infants aged 2-750 d were enrolled. MAIN OUTCOME MEASURES: Serum FSH, LH, inhibin B, AMH, and INSL3 were measured by immunoassay, and testosterone was measured by tandem mass-spectrometry. RESULTS: In infants with KS, INSL3 levels transiently increased at 2-3 months of age and were significantly correlated with testosterone (Spearman r = 0.57) and LH (Spearman r = 0.73) levels. They did not differ from controls. Testosterone levels were within the normal range, but most of them were below the median of controls. Inhibin B and AMH levels were also within normal range. Inhibin B was correlated with FSH (Spearman r = 0.49). AMH was not correlated with FSH or testosterone. FSH levels were above normal in 25% of patients, despite normal inhibin B levels. CONCLUSIONS: In infants with KS, Leydig cells are normally sensitive to the LH proliferative effect. In contrast, the Sertoli cell sensitivity to FSH is questionable, which may be prophetic of the postpubertal Sertoli cell resistance to FSH. PMID- 21307140 TI - Variants near CCNL1/LEKR1 and in ADCY5 and fetal growth characteristics in different trimesters. AB - CONTEXT: A recent genome-wide association study identified variants near CCNL1/LEKR1 (rs900400) and in ADCY5 (rs9883204) to be associated with birth weight. We examined the associations of these variants with fetal growth characteristics in different trimesters, with a main interest in the timing of the associations and the affected body proportions. METHODS: We used data from two prospective cohort studies from fetal life onward in The Netherlands and Australia. Repeated fetal ultrasound examinations were performed to measure head circumference (HC), abdominal circumference (AC), femur length (FL), and estimated fetal weight (EFW). Analyses were based on a total group of 3909 subjects. RESULTS: The C-allele of rs900400 was associated in second trimester with smaller fetal HC and FL, and in third trimester with smaller HC, AC, FL, and EFW. For each C-allele, the combined effect estimate for EFW in third trimester was -18.6 g (95% confidence interval, -27.5, -9.7 g; P = 4.2 * 10(-5)). The C allele of rs9883204 was not associated with fetal growth characteristics in second trimester but was associated with restriction of all growth characteristics, except HC, in third trimester and at birth. For each C-allele, the combined effect estimate was -16.9 g (95% confidence interval, -26.8, -7.0 g; P = 8.4 * 10(-4)) for EFW in third trimester. Both genetic variants were associated with lower birth and placenta weight. CONCLUSIONS: Our results suggest that a genetic variant of rs900400 leads to symmetric growth restriction from early pregnancy onward, whereas a genetic variant of rs9883204 leads to asymmetric growth restriction, characterized by a relatively larger HC, from third trimester. PMID- 21307141 TI - The human placenta expresses CYP17 and generates androgens de novo. AB - INTRODUCTION: The human placenta is believed to have insignificant CYP17 expression, rendering it dependent on the maternal and fetal compartments for the necessary androgenic precursors to yield the high levels of estrogens seen in pregnancy. OBJECTIVE: The aim of the study was to analyze whether the human trophoblast is capable of expressing CYP17 and producing androgens de novo. METHODS: Human trophoblasts from fresh placentas and JEG-3 cells were used for all experiments. CYP17 mRNA analysis was performed via RT-PCR, and protein detection by Western blot and immunohistochemical staining. Steroid products were quantified using RIAs. RESULTS: CYP17 mRNA was expressed in both cell types. CYP17 protein was detected by Western blotting and localized by immunostaining mainly to the cytoplasm of syncytiotrophoblasts. Measurement of 17alpha hydroxyprogesterone, androstenedione, and their aromatized products in the media further demonstrated CYP17 expression and activity in the human trophoblast. Baseline levels of CYP17 steroid products were higher in primary cells and significantly increased in the presence of 22-hydroxycholesterol. CONCLUSIONS: We have demonstrated CYP17 mRNA and protein expression and activity in human trophoblasts. Considering the precursor concentration, blood flow, and mass of the placenta, we suggest that its contribution of androgens is an important source of estrogen production in pregnancy. PMID- 21307142 TI - Follicular phase endocrine characteristics during ovarian stimulation and GnRH antagonist cotreatment for IVF: RCT comparing recFSH initiated on cycle day 2 or 5. AB - CONTEXT: Strategies involving mild ovarian stimulation protocols for in vitro fertilization (IVF) might lessen discomfort to the patient and substantially lower complication rates. OBJECTIVE: The objective of the study was to compare the follicular-phase endocrine characteristics and follicular development in patients who started recombinant FSH (recFSH) on cycle day (CD) 2 or CD5 in IVF treatment, using GnRH antagonist as comedication. DESIGN: This was a prospective randomized controlled trial in two university centers in Belgium and The Netherlands. PATIENTS: Seventy-six IVF/intracytoplasmic sperm injection patients were included in the study. INTERVENTIONS: The control group (CD2) received a standard treatment with 150 IU recFSH from CD2, whereas in the study group (CD5), stimulation was started on d 5 of the cycle. The GnRH antagonist was administered daily from CD6 onward in both treatment arms. MAIN OUTCOME MEASURE: Endocrine follicular phase profile during ovarian stimulation was measured. RESULTS: Follicular-phase patterns of gonadotropin and steroid concentrations were found to be comparable in both treatment groups, except for serum estradiol being significantly higher in the CD2 group on d 6 of the cycle (295.6 +/- 202.5 ng/liter in the CD2 vs. 102.5 +/- 47.9 ng/liter in the CD5 group; P < 0.01) and LH being significantly higher in the CD5 group on d 6 of the cycle (1.7 +/- 0.7 IU/liter in the CD2 vs. 5.0 +/- 2.1 IU/liter in the CD5 group; P < 0.01). With regard to follicular development, there was no difference in the numbers of small follicles (<10 mm), intermediate follicles (10-12 and > 12-14 mm) and large follicles (>14 mm) in both groups. CONCLUSIONS: This study shows that the administration of recFSH starting on d 2 or d 5 of the cycle in a GnRH antagonist protocol for IVF/intracytoplasmic sperm injection patients yields a comparable endocrine profile and follicular development. Future studies should focus on the design of more patient-tailored ovarian stimulation protocols. PMID- 21307143 TI - Impact of different cut-off limits of peak GH after GHRH-arginine stimulatory test, single IGF1 measurement, or their combination in identifying adult patients with GH deficiency. AB - OBJECTIVE: To evaluate the impact of different peak GH cut-off limits after GHRH Arg test, IGF1 measurement, or their combination in identifying patients with GH deficit (GHD). DESIGN AND PATIENTS: Totally, 894 normal subjects (used for determining IGF1 normative limits) and 302 patients with suspected GHD were included. Different peak GH cut-off limits (used by European (depending on body mass index (BMI)) or North American (4.1 MUg/l) Endocrine Societies, by HypoCCs (2.5 MUg/l), or with 95% specificity (based on BMI), Method 1, 2, 3, or 4 respectively) and IGF1 were considered. METHODS: Peak GH after GHRH-Arg and IGF1. RESULTS: Different peak GH cut-off limits recognized different proportions of GHD (range, 24.8-62.9%). Methods 1 and 2 with high sensitivity recognized a higher proportion (95.5 and 92.5% respectively) of GHD among patients with three (T) pituitary hormone deficits (HD), whereas Method 4 (with high specificity) identified 96.7% normal subjects among those without pituitary HD; on the contrary, Method 4 identified only 75% GHD among patients with THD, whereas Method 1 recognized a high proportion (40%) of GHD among subjects without HD. Of the total patients, 82% with THD and 84.5% without HD were recognized as GHD or normal respectively by IGF1. Among the remaining patients with THD and normal IGF1, 75% was recognized as GHD by Method 1; among patients without HD and abnormal IGF1, 87.5% was identified as normal by Method 4. Overall, combination of IGF1 and Method 1 or Method 4 identified 95.5% GHD among patients with THD and 98.1% normal subjects among those without HD. CONCLUSIONS: Single peak GH cut offs have limits to sharply differentiate GHD from normal subjects; IGF1 may be used for selecting patients to be submitted to the GHRH-Arg test; the peak GH cut off limits to be used for identifying healthy or diseased patients depend mainly on the clinical context. PMID- 21307144 TI - HER2 protein and gene variation between primary and metastatic breast cancer: significance and impact on patient care. AB - PURPOSE: To analyze HER2 status in primary breast cancer (PBC) compared with correspondent metachronous metastases and to investigate whether BC phenotype may be predictive of change in HER2 expression. EXPERIMENTAL DESIGN: HER2 was investigated by immunohistochemistry, silver in situ hybridization (SISH), and FISH, in a series of 137 tumors, building up a tissue microarray to concurrently analyze each single PBC and metastatic (MBC) on the same slide. RESULTS: HER2 status was discordant in 14 cases (10%): 12 negative in PBC and positive in metastases and two positive in PBC and negative in metastases (P = 0.04). These findings were confirmed by a PCR based test termed Multiplex Ligation-dependent Probe Amplification (MLPA). HER2 status changed in hormone receptor-positive BC more frequently than in negative ones (P = 0.002). In addition, we evaluated HER2 gene and chromosome 17 copy number by SISH in the 123 cases with unchanged HER2 status during progression. We found consistent HER2 gene copy number stability in the 100 nonamplified cases. Conversely, of the 23 amplified PBC, 13 (57%) demonstrated a significant increase in the HER2 gene and chromosome 17 copy number in their paired metastases (P = 0.01), as defined by SISH (k = 0.54, P < 0.0001) and MLPA. Patients who changed HER2 status from negative to positive, presented significant longer time to progression when treated with trastuzumab compared to those who were untreated (P = 0.04). CONCLUSIONS: When feasible, HER2 reassessment in metastatic lesions should be carefully taken into account, especially for metastases coming from primary hormone receptor-positive BC. PMID- 21307145 TI - Lenalidomide restrains motility and overangiogenic potential of bone marrow endothelial cells in patients with active multiple myeloma. AB - PURPOSE: To determine the in vivo and in vitro antiangiogenic power of lenalidomide, a "lead compound" of IMiD immunomodulatory drugs in bone marrow (BM) endothelial cells (EC) of patients with multiple myeloma (MM) in active phase (MMEC). EXPERIMENTAL DESIGN: The antiangiogenic effect in vivo was studied using the chorioallantoic membrane (CAM) assay. Functional studies in vitro (angiogenesis, "wound" healing and chemotaxis, cell viability, adhesion, and apoptosis) were conducted in both primary MMECs and ECs of patients with monoclonal gammopathies (MGUS) of undetermined significance (MGEC) or healthy human umbilical vein endothelial cells (HUVEC). Real-time reverse transcriptase PCR, Western blotting, and differential proteomic analysis were used to correlate morphologic and biological EC features with the lenalidomide effects at the gene and protein levels. RESULTS: Lenalidomide exerted a relevant antiangiogenic effect in vivo at 1.75 MUmol/L, a dose reached in interstitial fluids of patients treated with 25 mg/d. In vitro, lenalidomide inhibited angiogenesis and migration of MMECs, but not of MGECs or control HUVECs, and had no effect on MMEC viability, apoptosis, or fibronectin- and vitronectin-mediated adhesion. Lenalidomide-treated MMECs showed changes in VEGF/VEGFR2 signaling pathway and several proteins controlling EC motility, cytoskeleton remodeling, and energy metabolism pathways. CONCLUSIONS: This study provides information on the molecular mechanisms associated with the antimigratory and antiangiogenic effects of lenalidomide in primary MMECs, thus giving new avenues for effective endothelium-targeted therapies in MM. PMID- 21307146 TI - A pathobiological role of the insulin receptor in chronic lymphocytic leukemia. AB - PURPOSE: The chromosomal deletion 11q affects biology and clinical outcome in chronic lymphocytic leukemia (CLL) but del11q-deregulated genes remain incompletely characterized. EXPERIMENTAL DESIGN: We have employed integrated genomic profiling approaches on CLL cases with and without del11q to identify 11q relevant genes. RESULTS: We have identified differential expression of the insulin receptor (INSR) in CLL, including high-level INSR expression in the majority of CLL with del11q. High INSR mRNA expression in 11q CLL (~10-fold higher mean levels than other genomic categories) was confirmed by quantitative PCR in 247 CLL cases. INSR protein measurements in 257 CLL cases through flow cytometry, compared with measurements in normal CD19(+) B cells and monocytes, confirmed that a subset of CLL aberrantly expresses high INSR levels. INSR stimulation by insulin in CLL cells ex vivo resulted in the activation of canonical INSR signaling pathways, including the AKT-mTOR and Ras/Raf/Erk pathways, and INSR activation partially abrogated spontaneous CLL cell apoptosis ex vivo. Higher INSR levels correlated with shorter time to first therapy and shorter overall survival (OS). In bivariate analysis, INSR expression predicted for rapid initial disease progression and shorter OS in ZAP-70-low/negative CLL. Finally, in multivariate analysis (ZAP-70 status, IgV(H) status, and INSR expression), we detected elevated HRs and trends for short OS for CLL cases with high INSR expression (analyzed inclusive or exclusive of cases with del11q). CONCLUSIONS: Our aggregate biochemical and clinical outcome data suggest biologically meaningful elevated INSR expression in a substantial subset of all CLL cases, including many cases with del11q. PMID- 21307147 TI - Phase I study of NGR-hTNF, a selective vascular targeting agent, in combination with cisplatin in refractory solid tumors. AB - PURPOSE: NGR-hTNF exploits the tumor-homing peptide asparagine-glycine-arginine (NGR) for selectively targeting TNF-alpha to an aminopeptidase N overexpressed on cancer endothelial cells. Preclinical synergism with cisplatin was displayed even at low doses. This study primarily aimed to explore the safety of low-dose NGR hTNF combined with cisplatin in resistant/refractory malignancies. Secondary aims included pharmacokinetics (PKs), pharmacodynamics, and activity. EXPERIMENTAL DESIGN: NGR-hTNF was escalated using a doubling-dose scheme (0.2-0.4-0.8-1.6 MUg/m(2)) in combination with fixed-dose of cisplatin (80 mg/m(2)), both given intravenously once every three weeks. PKs and circulating TNF-receptors (sTNF-Rs) were assessed over the first three cycles. RESULTS: Globally, 22 patients (12 pretreated with platinum) received a range of one to ten cycles. Consistently with the low-dose range tested, maximum-tolerated dose was not reached. No dose limiting toxicities (DLTs) were observed at 0.2 (n = 4) and 0.4 MUg/m(2) (n = 3). One DLT (grade 3 infusion-related reaction) was observed at 0.8 MUg/m(2). This dose cohort was expanded to six patients without further DLTs. No DLTs were noted also at 1.6 MUg/m(2) (n = 3). NGR-hTNF exposure increased dose-proportionally without apparent PK interactions with cisplatin. No shedding of sTNF-Rs was detected up to 0.8 MUg/m(2). At the dose level of 0.8 MUg/m(2), expanded to 12 patients for activity assessment, a platinum-pretreated lung cancer patient achieved a partial response lasting more than six months and five patients maintained stable disease for a median time of 5.9 months. CONCLUSIONS: The combination of NGR-hTNF 0.8 MUg/m(2) with cisplatin 80 mg/m(2) showed favorable toxicity profile and promising antitumor activity. PMID- 21307148 TI - Second-generation tyrosine kinase inhibitors: the future of frontline CML therapy. AB - All available data from ongoing studies of second-generation tyrosine kinase inhibitors (TKIs) for treatment of patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) were reviewed. In two nilotinib phase 2 trials, the speed and depth of molecular and cytogenetic responses were greater than responses to imatinib. Furthermore, only one patient in each study progressed to accelerated or blastic phase. In the phase 3 ENESTnd study, molecular and cytogenetic responses to nilotinib were superior to imatinib, and more patients achieved undetectable levels of disease with nilotinib. Nilotinib also demonstrated significantly lower progression than did imatinib. In the ongoing phase 2 study of dasatinib, the speed and depth of molecular and cytogenetic responses were higher compared with expected responses to imatinib; no patient to date has progressed. In the phase 3 DASISION study, molecular and cytogenetic responses to dasatinib were superior to those of imatinib and fewer patients progressed. The results suggest that second-generation TKIs have the potential to replace imatinib as the standard of care for patients with early CML CP. Future CML therapy might include earlier use of these agents to help more patients achieve complete molecular response and may be a path to a CML cure. PMID- 21307150 TI - Asymptomatic muscle metastasis from pulmonary adenocarcinoma. PMID- 21307149 TI - Occult tumor burden predicts disease recurrence in lymph node-negative colorectal cancer. AB - PURPOSE: Lymph node involvement by histopathology informs colorectal cancer prognosis, whereas recurrence in 25% of node-negative patients suggests the presence of occult metastasis. GUCY2C (guanylyl cyclase C) is a marker of colorectal cancer cells that identifies occult nodal metastases associated with recurrence risk. Here, we defined the association of occult tumor burden, quantified by GUCY2C reverse transcriptase-PCR (RT-PCR), with outcomes in colorectal cancer. EXPERIMENTAL DESIGN: Lymph nodes (range: 2-159) from 291 prospectively enrolled node-negative colorectal cancer patients were analyzed by histopathology and GUCY2C quantitative RT-PCR. Participants were followed for a median of 24 months (range: 2-63). Time to recurrence and disease-free survival served as primary and secondary outcomes, respectively. Association of outcomes with prognostic markers, including molecular tumor burden, was estimated by recursive partitioning and Cox models. RESULTS: In this cohort, 176 (60%) patients exhibited low tumor burden (Mol(Low)), and all but four remained free of disease [recurrence rate 2.3% (95% CI, 0.1-4.5%)]. Also, 90 (31%) patients exhibited intermediate tumor burden (Mol(Int)) and 30 [33.3% (23.7-44.1)] developed recurrent disease. Furthermore, 25 (9%) patients exhibited high tumor burden (Mol(High)) and 17 [68.0% (46.5-85.1)] developed recurrent disease (P < 0.001). Occult tumor burden was an independent marker of prognosis. Mol(Int) and Mol(High) patients exhibited a graded risk of earlier time to recurrence [Mol(Int), adjusted HR 25.52 (11.08-143.18); P < 0.001; Mol(High), 65.38 (39.01 676.94); P < 0.001] and reduced disease-free survival [Mol(Int), 9.77 (6.26 87.26); P < 0.001; Mol(High), 22.97 (21.59-316.16); P < 0.001]. CONCLUSION: Molecular tumor burden in lymph nodes is independently associated with time to recurrence and disease-free survival in patients with node-negative colorectal cancer. PMID- 21307151 TI - Tumour necrosis factor G-308A polymorphism modifies the effect of home dampness on childhood asthma. AB - OBJECTIVES: Environmental exposure at home, such as dampness, has been shown to have adverse effects on respiratory health. However, few studies explored the association between home dampness and genetic polymorphisms on childhood asthma. The aim of the study is to evaluate the effects of home dampness and tumour necrosis factor-alpha gene (TNF-alpha) on asthma in Taiwanese children. METHODS: The authors investigated 3810 schoolchildren in Taiwan Children Health Study from 14 communities. Children's exposure and disease status were measured from a parental questionnaire. Multiple logistic regression models were fitted to estimate the effects of home dampness exposure and TNF-alpha genotypes on the prevalence of asthma and wheeze. RESULTS: Mildewy odour at home was significantly associated with increased prevalence of lifetime wheeze (OR=1.36, 95% CI 1.05 to 1.77, p for trend=0.04). The effects of water stamp on the wall at home were associated with lifetime asthma and lifetime wheeze. Children with water stamp on the wall at home and TNF-308 A allele had increased risks on lifetime asthma, active asthma and lifetime wheeze. TNF-alpha showed significant interactive effects with mildewy odour on lifetime asthma (p for interaction=0.01), and with water stamp on the wall at home on lifetime wheeze (p for interaction=0.04). Under stratification by TNF-308 genotypes, we found that the frequency of water stamp on the wall was associated with increased risks of all asthma subcategories and lifetime wheeze among TNF-308 GA or AA genotypes (p for trend<0.05). CONCLUSIONS: Home dampness is a risk factor for asthma and wheeze among children, especially for those with the TNF-308 A allele. PMID- 21307152 TI - Performance of the Focus HerpeSelect-2 enzyme immunoassay for the detection of herpes simplex virus type 2 antibodies in seven African countries. AB - OBJECTIVE: To compare the performance of the Focus HerpeSelect-2 enzyme immunoassay (EIA) with the gold standard herpes simplex virus (HSV) type 2 western blot, among HIV-1-uninfected men and women in east and southern Africa. METHODS: 3399 HIV-1-uninfected women and men from seven countries in east and southern Africa were tested for HSV-2 antibody using the Focus HerpeSelect-2 EIA. The performance of the HerpesSelect-2 EIA was compared with the gold standard HSV 2-specific western blot. RESULTS: Two-thirds (2294/3399) of participants were male and two-thirds (2242/3399) were from east Africa. By western blot testing, HSV-2 prevalence was 68%; 59% in men and 85% in women. At the manufacturer's recommended cut-off value of greater than 1.1, the HerpeSelect-2 EIA had a sensitivity of 98.3% and specificity of 80.3%. Receiver operating characteristic plot analysis indicated that the optimum cut-off was 2.1 or greater, with sensitivity 93.9% and specificity 90.5%. Diagnostic accuracy was modestly higher for southern Africa (area under the curve (AUC) 0.979, 95% CI 0.970 to 0.988) compared with east Africa (AUC 0.954, 95% CI 0.942 to 0.965; p<0.001 for southern vs east Africa). CONCLUSIONS: The Focus HerpeSelect-2 EIA has acceptable diagnostic accuracy for the determination of HSV-2 serostatus in African HIV-1 uninfected adults. An assay cut-off value of 2.1 or greater results in approximately 90% sensitivity and specificity, against a gold standard HSV-2 western blot. Diagnostic accuracy differed slightly by geographical region. PMID- 21307153 TI - Gonorrhoea positivity among women aged 15-24 years in the USA, 2005-2007. AB - OBJECTIVE: To examine the epidemiology of young women screened for gonorrhoea in the USA. METHODS: Data on tests for gonorrhoea among women aged 15-24 years attending family planning clinics from 2005 to 2007 were obtained through the infertility prevention project. Clinics testing 90% or more of women for gonorrhoea and sending 50 or more gonorrhoea tests per year were included. Gonorrhoea positivity on a state and county level was calculated and compared by age and race/ethnicity. RESULTS: A total of 1,119,394 tests from 948 clinics was eligible for inclusion. Median state-specific gonorrhoea positivity was 1.3% (IQR 0.7-2.0%). Positivity was higher among women aged 15-19 years (1.4%, IQR 0.9 2.6%) than among those aged 20-24 years (1.1%, IQR 0.6-1.4%, p=0.03) and among non-Hispanic black women (3.8%, IQR 3.2-4.6%) than non-Hispanic white women (0.6%, IQR 0.4-0.8%, p<0.0001). Half of all gonorrhoea cases in these women originated from 57 of 753 counties. Among non-Hispanic white women, positivity was 2.0% or greater in 4% of counties, while 83% of counties had gonorrhoea positivity of less than 1.0%. Gonorrhoea positivity among non-Hispanic black women was 2.0% or greater in 58% of counties, and less than 1.0% in only one third of counties. These disparities were present diffusely across the geographical areas included in this analysis. CONCLUSIONS: Gonorrhea positivity was consistently high for young non-Hispanic black women attending family planning clinics across multiple geographical regions. A large proportion of gonorrhoea morbidity was concentrated in a relatively small number of counties in the USA among this population of young women. PMID- 21307154 TI - High prevalence of quinolone resistance in Neisseria gonorrhoeae in coastal Kenya. PMID- 21307155 TI - Osteoprotegerin, RANKL and bone turnover in postmenopausal osteoporosis. AB - BACKGROUND: Osteoprotegerin (OPG) and receptor activator of nuclear factor kappa B ligand (RANKL) play a critical role in the regulation of bone turnover, but the relative importance of these two cytokines in the pathogenesis of postmenopausal osteoporosis is controversial. AIM: To investigate the relationship between circulating levels of OPG, RANKL, bone turnover and bone mineral density (BMD) in postmenopausal women. METHODS: A cross-sectional study of 185 women with osteoporosis and 185 age- and sex-matched control subjects was undertaken. Measurements were made of plasma OPG, RANKL, interleukin-6 (IL-6), sex steroids, calciotropic hormones, biochemical markers of bone turnover, BMD and anthropometry. Health questionnaires were administered. RESULTS: Plasma RANKL was significantly higher (p<0.0001) in women with osteoporosis (0.66+/-0.67 pmol/l) than in control subjects (0.37+/-0.38 pmol/l), as was plasma OPG (18.70+/-9.70 pmol/l in women with osteoporosis, 10.44+/-5.85 pmol/l in control subjects; p<0.0001). OPG/RANKL ratio was higher in women with osteoporosis (51.3) than in control subjects (36.6). The women with osteoporosis also had significantly higher biochemical markers of bone turnover, IL-6 and parathyroid hormone and lower 25-hydroxyvitamin D and oestradiol than the control subjects. Multiple regression analysis showed that lumbar spine and femoral neck BMD in postmenopausal women were best predicted by OPG and RANKL, giving an R(2) value of 15.5% and 14.9%, respectively. CONCLUSIONS: This study indicates that the circulating levels of OPG and RANKL are inversely related to BMD and contribute to the development of osteoporosis in postmenopausal women. PMID- 21307156 TI - Adenomyoepithelioma of the breast: a review stressing its propensity for malignant transformation. AB - This review describes the classification, clinical presentation, pathological features and clinical behaviour of adenomyoepithelioma (AME) of the breast. It is based on an extensive review of the literature and study of a collection of cases built up over a 17-year period at the British Columbia Cancer Agency. The diversity of the morphology encountered in both benign and malignant AME is described. The behaviour of malignant AME seems to be related to the grade of the malignant component. PMID- 21307157 TI - Late referrals to home palliative care service affecting death at home in advanced cancer patients in Japan: a nationwide survey. AB - BACKGROUND: To identify factors influencing place of death among home palliative care patients with advanced cancer, focusing on the timing of referrals from hospital to home care settings. METHODS: A cross-sectional nationwide questionnaire survey was conducted on home palliative care patients at 1000 randomly selected home care agencies in Japan. A total of 568 responses were analyzed (effective response rate, 69%). RESULTS: Multivariate logistic regression analysis revealed that (i) predischarge health care supports in hospital (e.g. early referral 8 days or more before discharge; clear explanation by hospital staffs to patients and families regarding discharge to live and die at home) and (ii) postdischarge health care supports after transferring home care (e.g. signing a 24-h support insurance contract of network between primary physician and nurse as a home palliative care team; primary nurse consultation with primary physician >3 times during the first week after discharge) have an effect on place of death among home palliative care patients. CONCLUSION: An early and carefully coordinated referral support system for smooth discharge by hospital staffs as well as intensive and highly qualified support just after discharge by the home care team would help to increase the number of patients who could die at home. PMID- 21307158 TI - Alcohol drinking and colorectal cancer risk: an overall and dose-response meta analysis of published studies. AB - BACKGROUND: The International Agency for Research on Cancer (IARC) concluded that alcohol consumption is related to colorectal cancer (CRC). However, several issues remain unresolved, including quantification of the association for light (<=1 drink/day) and moderate (2-3 drinks/day) alcohol drinking, investigation of the dose-response relationship, and potential heterogeneity of effects by sex, colorectal site, and geographical region. METHODS: Twenty-seven cohort and 34 case-control studies presenting results for at least three categories of alcohol intake were identified from a PubMed search of articles published before May 2010. The summary relative risks (RRs) were estimated by the random effects model. Second-order fractional polynomials and random effects meta-regression models were used for modeling the dose-risk relation. RESULTS: The RRs were 1.21 [95% confidence interval (CI) 1.13-1.28] for moderate and 1.52 (95% CI 1.27-1.81) for heavy (>=4 drinks/day) alcohol drinking. The RR for moderate drinkers, compared with non-/occasional drinkers, was stronger for men (RR = 1.24, 95% CI 1.13-1.37) than for women (RR = 1.08, 95% CI 1.03-1.13; P(heterogeneity) = 0.02). For heavy drinkers, the association was stronger in Asian studies (RR = 1.81, 95% CI 1.33-2.46; P(heterogeneity) = 0.04). The dose-risk analysis estimated RRs of 1.07 (95% CI 1.04-1.10), 1.38 (95% CI 1.28-1.50), and 1.82 (95% CI 1.41-2.35) for 10, 50, and 100 g/day of alcohol, respectively. CONCLUSIONS: This meta-analysis provides strong evidence for an association between alcohol drinking of >1 drink/day and colorectal cancer risk. PMID- 21307159 TI - Relationship between impacts attributed to malocclusion and psychological stress in young Japanese adults. AB - Identifying risk factors is important to prevent a wide range of health-damaging behaviours and to improve the quality of life of young people. The aim of this study was to investigate the relationship between impacts on daily performance attributed to malocclusion and psychological stress in healthy young Japanese adults. Medical and oral health data were collected during a cross-sectional examination conducted by the Health Service Center of Okayama University. Systemically healthy non-smoking students aged 18 and 19 years (n = 641; 329 males and 312 females) were included. Malocclusion was defined using a modified version of the Index of Orthodontic Treatment Need (IOTN). The impacts on daily performance attributed to malocclusion and psychological stress were assessed using self-reported questionnaires, the condition-specific oral impacts on daily performances (CS-OIDP), and the Hopkins Symptoms Checklist. Mann-Whitney U- and chi-square tests and structural equation modelling (SEM) were used for statistical analysis. Forty per cent of subjects had a malocclusion (n = 255). Subjects with impacts on daily performance had a significantly higher prevalence of malocclusion than those without impacts (P < 0.001). SEM showed that psychological stress, especially interpersonal sensitivity and depression, was significantly correlated with CS-OIDP and malocclusion. Negative impacts on daily performance attributed to malocclusion may contribute to psychological stress in young Japanese adults. PMID- 21307160 TI - Typification of Smittium, an important genus in the taxonomy of Harpellales. AB - The Harpellales genus Smittium is based on a type species, S. arvernense, which was described by Poisson in 1937 without designation of a type specimen. Smittium arvernense has not been reported since its original publication. Because the other 79 species of Smittium cannot be compared to the type species, a lectotype is proposed as well as an epitype for that lectotype that is also the holotype of S. mucronatum. Because Smittium is believed to be polyphyletic these type designations will provide stable application of names and, as well resolved phylogenetic analyses of member species emerge based on morphological and DNA sequence characters, they will provide a foundation for a more robust and revised classification. PMID- 21307161 TI - The genus Chaetomium in Iran, a phylogenetic study including six new species. AB - Twenty-one species of Chaetomium known from Iran were compared on the basis of morphological and molecular characters. Six new species are recognized, five isolated from cereals and one from nematode cysts. A combined sequence dataset of the ITS region, partial LSU rDNA, and beta-tubulin gene sufficiently resolved five species groups of Chaetomium that are largely concordant with combined features of peridium structure, ascospore shape and germ pore position. Among the new species C. undulatulum is a close relative of C. globosum, C. rectangulare is close to C. elatum, C. interruptum and C. grande are close to C. megalocarpum, altogether forming the C. globosum species group. Chaetomium iranianum and C. truncatulum are members of the C. carinthiacum species group, characterized by spirally coiled ascomatal hairs and fusiform ascospores. A chrysosporium-like anamorph is newly described for C. acropullum. PMID- 21307162 TI - A new species of Lepiota from China. AB - In this report we describe the three species in Lepiota sect. Lepiota occurring in tropical China. Lepiota attenuata is a new species and is characterized by a pileus with brownish yellow squamules and radially sulcate striate margin, penguin-shaped spores that are distinctively narrowed toward the apex and inflated submoniliform or catenulate elements in the pileus covering. We compared the type specimens of L. metulispora and L. thrombophora with tropical Chinese specimens; both taxa occur in the study area. Phylogenetic relationships among the tropical Chinese species and other closely related species in the genus were inferred based on DNA sequences of the nuclear ribosomal genes (ITS, LSU and IGS) and the mitochondrial small ribosomal RNA gene (mtSSU). PMID- 21307163 TI - Phylogeny and diversity of Japanese truffles (Tuber spp.) inferred from sequences of four nuclear loci. AB - The genus Tuber, which includes some highly valued truffles, comprises ascomycetous ectomycorrhizal fungi associated with ecologically important tree species. Although the genus is distributed over northern temperate regions, we know little about the phylogeny and diversity of Tuber species in Japan. We have collected 186 new Tuber ascoma samples in Japan over a 10 y period. The identities and phylogenies of the samples were analyzed with sequences of four nuclear loci (i.e. internal transcribed spacer [ITS] and large subunit [LSU] regions of rDNA, elongation factor 1 alpha [EF1-alpha], and RNA polymerase II large subunit [rpb2] genes). Based on the species delimitation of 95% sequence matches in the ITS region, which is a suitable region for species-level identification of higher fungi, we identified 20 Tuber species. The number of observed species did not reach an asymptote with our maximum sampling localities in a species accumulation curve. The Chao2 species richness estimator indicated that at least 40 Tuber species should be present in Japan. Molecular phylogenetic analyses revealed that Japanese Tuber species belong to five major phylogroups, including Macrosporum, which had not been reported previously in Asia. Two Japanese species were morphologically and phylogenetically distinct from other known phylogroups, and here we propose a new Tuber phylogroup, Japonicum. In addition most of the other Japanese species formed separate clades within individual major phylogroups and deserve to be proposed as new species. Detailed molecular phylogeny within individual phylogroups revealed the existence of phylogeographic structures at both continental and within-Asia scales, indicating that migration and allopatric speciation have occurred even between the mainland and islands in Asia. Although our findings substantially advance current understanding of Tuber diversity and phylogeny, comparable richness estimation and multilocus phylogeny in other geographic regions are necessary to unequivocally address global patterns of Tuber diversity and biogeography. PMID- 21307164 TI - Colonization of roots of cultivated Solanum lycopersicum by dark septate and other ascomycetous endophytes. AB - Tomato (Solanum lycopersicum L.) roots from four different crop sites in Colombia were surface sterilized and 51 fungal isolates were obtained and conserved for further analysis. Based on microscopical observations and growth characteristics, 20 fungal isolates corresponded to genus Fusarium, six presented asexual conidia different from Fusarium, eight were sterile mycelia, seven of which had dark septate hyphae and 17 did not continue to grow on plates after being recovered from conservation. Growth on different media, detailed morphological characterization and ITS region sequencing of the six sporulating and eight sterile isolates revealed that they belonged to different orders of Ascomycota and that the sterile dark septate endophytes did not correspond to the well known Phialocephala group. Interactions of nine isolates with tomato plantlets were assessed in vitro. No effect on shoot development was revealed, but three isolates caused brown spots in roots. Colonization patterns as analyzed by confocal microscopy differed among the isolates and ranged from epidermal to cortical penetration. Altogether 11 new isolates from root endophytic fungi were obtained, seven of which showed features of dark septate endophytes. Four known morphotypes were represented by five isolates, while six isolates belonged to five morphotypes of putative new unknown species. PMID- 21307165 TI - Two new species of Cladorrhinum. AB - Two new species of Cladorrhinum, C. flexuosum and C. microsclerotigenum, are described and their sequences of the 5.8S and 28S ribosomal DNA and internal transcribed spacers 1 and 2 of the ribosomal RNA gene cluster analyzed. Cladorrhinum flexuosum, isolated from soil in Spain, forms fast-growing, dull yellow colonies, flexuous conidiophores and globose to dacryoid conidia. Cladorrhinum microsclerotigenum, isolated from Musa sp. in Turkey, strongly resembles Cladorrhinum phialophoroides in the production of abundant terminal phialides, ellipsoid conidia and microsclerotia in culture. It differs from C. phialophoroides in its ability to grow at 36 C and high number of intercalary phialides, which only infrequently occur in C. phialophoroides. PMID- 21307166 TI - Klastostachys, a new genus of Harpellales in Chironomidae larvae. AB - Klastostachys reflexa, a new genus and species combination in the Harpellales, is established herein based on Stachylina reflexa, which was described in 1988. This gut fungus was found attached to the peritrophic matrix of small bloodworms, Cryptochironomus sp. (Chironomidae), in the Rocky Mountains of Colorado, USA. Klastostachys resembles Stachylina, a genus common in Chironomidae, but the unbranched thalli of Klastostachys disarticulate and disperse with the trichospores remaining attached to their generative cells. This manner of dissemination is unusual among Harpellales, being noted also for Carouxella spp., but members of that genus have zygospores attached at one pole to the zygosporophore (Type IV), whereas Klastostachys zygospores are medially attached to the zygosporophore at right angles (Type I). PMID- 21307167 TI - Dacryodiomyces, a new genus of Harpellales in Chironomidae larvae. AB - A new genus of gut fungus in the Harpellales (Trichomycetes) with the type species Dacryodiomyces oklahomensis, found in Chironomidae larvae, is described from northeastern Oklahoma, USA. The most distinguishing characters are the elongate-ovoid zygospores attached to their zygosporophore at one end (Type IV), together with trichospores bearing a collar and a single appendage. PMID- 21307168 TI - beta-catenin tyrosine 654 phosphorylation increases Wnt signalling and intestinal tumorigenesis. AB - Objective Deregulation of the Wnt signalling pathway by mutations in the Apc or beta-catenin genes underlies colorectal carcinogenesis. As a result, beta-catenin stabilises, translocates to the nucleus, and activates gene transcription. Intestinal tumours show a heterogeneous pattern of nuclear beta-catenin, with the highest levels observed at the invasion front. Activation of receptor tyrosine kinases in these tumour areas by growth factors expressed by surrounding stromal cells phosphorylate beta-catenin at tyrosine residues, which is thought to increase beta-catenin nuclear translocation and tumour invasiveness. This study investigates the relevance of beta-catenin tyrosine phosphorylation for Wnt signalling and intestinal tumorigenesis in vivo. Design A conditional knock-in mouse model was generated into which the phospho-mimicking Y654E modification in the endogenous beta-catenin gene was introduced. Results This study provided in vivo evidence that beta-catenin(E654) is characterised by reduced affinity for cadherins, increased signalling and strongly increased phosphorylation at serine 675 by protein kinase A (PKA). In addition, homozygosity for the beta catenin(E654) targeted allele caused embryonic lethality, whereas heterozygosity predisposed to intestinal tumour development, and strongly enhanced Apc-driven intestinal tumour initiation associated with increased nuclear accumulation of betacatenin. Surprisingly, the expression of beta-catenin(E654) did not affect histological grade or induce tumour invasiveness. Conclusions A thus far unknown mechanism was uncovered in which Y654 phosphorylation of beta-catenin facilitates additional phosphorylation at serine 675 by PKA. In addition, in contrast to the current belief that beta-catenin Y654 phosphorylation increases tumour progression to a more invasive phenotype, these results show that it rather increases tumour initiation by enhancing Wnt signalling. PMID- 21307169 TI - Safety of stenting and endarterectomy by symptomatic status in the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST). AB - BACKGROUND AND PURPOSE: The safety of carotid artery stenting (CAS) and carotid endarterectomy (CEA) has varied by symptomatic status in previous trials. The Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) data were analyzed to determine safety in symptomatic and asymptomatic patients. METHODS: CREST is a randomized trial comparing safety and efficacy of CAS versus CEA in patients with high-grade carotid stenoses. Patients were defined as symptomatic if they had relevant symptoms within 180 days of randomization. The primary end point was stroke, myocardial infarction, or death within the periprocedural period or ipsilateral stroke up to 4 years. RESULTS: For 1321 symptomatic and 1181 asymptomatic patients, the periprocedural aggregate of stroke, myocardial infarction, and death did not differ between CAS and CEA (5.2% versus 4.5%; hazard ratio, 1.18; 95% CI, 0.82 to 1.68; P=0.38). The stroke and death rate was higher for CAS versus CEA (4.4% versus 2.3%; hazard ratio, 1.90; 95% CI, 1.21 to 2.98; P=0.005). For symptomatic patients, the periprocedural stroke and death rates were 6.0%+/-0.9% for CAS and 3.2%+/-0.7% for CEA (hazard ratio, 1.89; 95% CI, 1.11 to 3.21; P=0.02). For asymptomatic patients, the stroke and death rates were 2.5%+/-0.6% for CAS and 1.4%+/-0.5% for CEA (hazard ratio, 1.88; 95% CI, 0.79 to 4.42; P=0.15). Rates were lower for those aged <80 years. CONCLUSIONS: There were no significant differences between CAS versus CEA by symptomatic status for the primary CREST end point. Periprocedural stroke and death rates were significantly lower for CEA in symptomatic patients. However, for both CAS and CEA, stroke and death rates were below or comparable to those of previous randomized trials and were within the complication thresholds suggested in current guidelines for both symptomatic and asymptomatic patients. PMID- 21307170 TI - Incidence of cerebral microbleeds in the general population: the Rotterdam Scan Study. AB - BACKGROUND AND PURPOSE: Cerebral microbleeds are frequently seen in the general elderly population, but it is unknown at what rate they occur with aging and whether once present can disappear over time. METHODS: As part of the Rotterdam Scan Study, 831 persons (mean age, 68.5 years) underwent repeated brain MRI with a mean interval of 3.4 years. We assessed determinants of incident microbleeds in relation to their location with multiple logistic regressions. RESULTS: Overall prevalence of microbleeds increased from 24.4% at baseline to 28.0% at follow-up. Eighty-five persons (10.2%) developed new microbleeds. Microbleeds at baseline predicted development of new microbleeds (OR, 5.38; 95% CI, 3.34 to 8.67). In only 6 persons with microbleeds at baseline, fewer microbleeds were present at the follow-up examination. Cardiovascular risk factors, presence of lacunar infarcts, and larger white matter lesion volume at baseline were all associated with incident deep or infratentorial microbleeds, whereas people with the apolipoprotein E epsilon4/epsilon4 genotype or larger white matter lesion volume had a higher risk of incident strictly lobar microbleeds. CONCLUSIONS: Incidence of microbleeds in the general population over a 3-year interval was substantial and microbleeds rarely disappeared. Risk factors for incident microbleeds were similar to those for prevalent microbleeds and differed according to microbleed location. These results support the assessment of microbleeds on T2-weighted MRI as a possible marker of both cerebral amyloid angiopathy and hypertensive vasculopathy progression. PMID- 21307171 TI - Neurological picture. Pott's puffy tumour: harbinger of intracranial sepsis. PMID- 21307172 TI - Definition of chronic kidney disease and measurement of kidney function in original research papers: a review of the literature. AB - BACKGROUND: Over the past decade, chronic kidney disease (CKD) has become an area of intensive clinical and epidemiological research. Despite the clarity provided by the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines, there appears to be within the CKD research literature significant disagreement on how to define CKD and measure kidney function. METHODS: The objectives of this study were to investigate the variety of methods used to define CKD and to measure kidney function in original research papers as well as to investigate whether the quality of the journal had any effect on the quality of the methodology used. This was a descriptive review and not a meta-analysis. Information was extracted from each article including publication details (including the journal's impact factor), definition of CKD, method used to estimate kidney function and quantity of serum creatinine readings used to define CKD. An electronic search of MEDLINE through OVID was completed using the search term CKD. The search was limited to articles in English published in 2009. Studies were included in the review only if they were original research articles including patients with CKD. Articles were excluded if they reported data from a paediatric population, a population solely on dialysis or if there was no full-text access through OVID. Each article was assessed for quality with respect to using KDOQI CKD definition criteria. A description of the pooled data was completed and chi-square tests were used to investigate the relation between article quality and journal quality. Analysis was carried out using SPSS (15.0) and a P-value of <0.05 was considered to indicate statistical significance. RESULTS: The final review included 301 articles. There were a variety of methods used to define CKD in original research articles. Less than 20% (n = 59) of the articles adhered to the established international criteria for defining CKD. The majority of articles (52.1%) did not indicate the quantity of serum creatinine measurements used to define CKD. The impact factor or specialist nature of the scientific journal appears to have no bearing on whether or not published articles use the gold standard KDOQI guidelines for labelling a patient with a diagnosis of CKD. CONCLUSIONS: This review of literature found that a variety of definitions are being used in original research articles to define CKD and measure kidney function which calls into question the validity and reliability of such research findings and associated clinical guidelines. International consensus is urgently required to improve validity and generalizability of CKD research findings. PMID- 21307173 TI - An integrative, experience-based theory of attentional control. AB - Although diverse, theories of visual attention generally share the notion that attention is controlled by some combination of three distinct strategies: (1) exogenous cuing from locally contrasting primitive visual features, such as abrupt onsets or color singletons (e.g., L. Itti, C. Koch, & E. Neiber, 1998), (2) endogenous gain modulation of exogenous activations, used to guide attention to task-relevant features (e.g., V. Navalpakkam & L. Itti, 2007; J. Wolfe, 1994, 2007), and (3) endogenous prediction of likely locations of interest, based on task and scene gist (e.g., A. Torralba, A. Oliva, M. Castelhano, & J. Henderson, 2006). However, little work has been done to synthesize these disparate theories. In this work, we propose a unifying conceptualization in which attention is controlled along two dimensions: the degree of task focus and the contextual scale of operation. Previously proposed strategies-and their combinations-can be viewed as instances of this one mechanism. Thus, this theory serves not as a replacement for existing models but as a means of bringing them into a coherent framework. We present an implementation of this theory and demonstrate its applicability to a wide range of attentional phenomena. The model accounts for key results in visual search with synthetic images and makes reasonable predictions for human eye movements in search tasks involving real-world images. In addition, the theory offers an unusual perspective on attention that places a fundamental emphasis on the role of experience and task-related knowledge. PMID- 21307175 TI - On the origins of cultural differences in conformity: four tests of the pathogen prevalence hypothesis. AB - What are the origins of cultural differences in conformity? The authors deduce the hypothesis that these cultural differences may reflect historical variability in the prevalence of disease-causing pathogens: Where pathogens were more prevalent, there were likely to emerge cultural norms promoting greater conformity. The authors conducted four tests of this hypothesis, using countries as units of analysis. Results support the pathogen prevalence hypothesis. Pathogen prevalence positively predicts cultural differences in effect sizes that emerge from behavioral conformity experiments (r=.49, n=17) and in the percentage of the population who prioritize obedience (r=.48, n=83). Pathogen prevalence also negatively predicted two indicators of tolerance for nonconformity: within country dispositional variability (r=-.48, n=33) and the percentage of the population who are left-handed (r=-.73, n=20). Additional analyses address plausible alternative causal explanations. Discussion focuses on plausible underlying mechanisms (e.g., genetic, developmental, cognitive). PMID- 21307176 TI - Dishonest deed, clear conscience: when cheating leads to moral disengagement and motivated forgetting. AB - People routinely engage in dishonest acts without feeling guilty about their behavior. When and why does this occur? Across four studies, people justified their dishonest deeds through moral disengagement and exhibited motivated forgetting of information that might otherwise limit their dishonesty. Using hypothetical scenarios (Studies 1 and 2) and real tasks involving the opportunity to cheat (Studies 3 and 4), the authors find that one's own dishonest behavior increased moral disengagement and motivated forgetting of moral rules. Such changes did not occur in the case of honest behavior or consideration of the dishonest behavior of others. In addition, increasing moral saliency by having participants read or sign an honor code significantly reduced unethical behavior and prevented subsequent moral disengagement. Although dishonest behavior motivated moral leniency and led to forgetting of moral rules, honest behavior motivated moral stringency and diligent recollection of moral rules. PMID- 21307174 TI - Response normalization and blur adaptation: data and multi-scale model. AB - Adapting to blurred or sharpened images alters perceived blur of a focused image (M. A. Webster, M. A. Georgeson, & S. M. Webster, 2002). We asked whether blur adaptation results in (a) renormalization of perceived focus or (b) a repulsion aftereffect. Images were checkerboards or 2-D Gaussian noise, whose amplitude spectra had (log-log) slopes from -2 (strongly blurred) to 0 (strongly sharpened). Observers adjusted the spectral slope of a comparison image to match different test slopes after adaptation to blurred or sharpened images. Results did not show repulsion effects but were consistent with some renormalization. Test blur levels at and near a blurred or sharpened adaptation level were matched by more focused slopes (closer to 1/f) but with little or no change in appearance after adaptation to focused (1/f) images. A model of contrast adaptation and blur coding by multiple-scale spatial filters predicts these blur aftereffects and those of Webster et al. (2002). A key proposal is that observers are pre-adapted to natural spectra, and blurred or sharpened spectra induce changes in the state of adaptation. The model illustrates how norms might be encoded and recalibrated in the visual system even when they are represented only implicitly by the distribution of responses across multiple channels. PMID- 21307177 TI - My nation, my self: divergent framings of America influence American selves. AB - Current public discourse calls for America to act more interdependently in the world or act more like a conjoint agent. America and American selves, however, are typically associated acting independently or disjoint agency. Since nation is a significant sociocultural source of self, the authors examine what happens to American selves if America is instead associated with conjoint agency. Study 1 surveyed participants in America and nine nations (N=610) about America's role in the world and found that although people currently associate America with disjoint agency, they overwhelmingly prefer America to be a conjoint agent. Studies 2-4 demonstrated that framing America's role in the world with conjoint agency rather than disjoint agency led Americans to see themselves more positively (Studies 2 and 3) and be less individualistic in their self descriptions and actions (Study 4). The results reveal how changes in the sociocultural context can catalyze a corresponding change in the selves that inhabit that context. PMID- 21307178 TI - The effect of commitment on relative left frontal cortical activity: tests of the action-based model of dissonance. AB - The action-based model of dissonance and recent advances in neuroscience suggest that commitment to action should cause greater relative left frontal cortical activity. Two experiments were conducted in which electroencephalographic activity was recorded following commitment to action, operationalized with a perceived choice manipulation. Perceived high as compared to low choice to engage in the action, regardless of whether it was counterattitudinal or proattitudinal, caused greater relative left frontal cortical activity. Moreover, perceived high as compared to low choice caused attitudes to be more consistent with the action. These results broaden the theoretical reach of the action-based model by suggesting that similar neural and motivational processes are involved in attitudinal responses to counterattitudinal and proattitudinal commitments. PMID- 21307179 TI - The origins of extraversion: joint effects of facultative calibration and genetic polymorphism. AB - The origins of variation in extraversion are largely mysterious. Recent theories and some findings suggest that personality variation can be orchestrated by specific genetic polymorphisms. Few studies, however, have examined an alternative hypothesis that personality traits are facultatively calibrated to variations in other phenotypic features, and none have considered how these distinct processes may interact in personality determination. Since physical strength and physical attractiveness likely predicted the reproductive payoffs of extraverted behavioral strategies over most of human history, it was theorized that extraversion is calibrated to variation in these characteristics. Confirming these predicted patterns, strength and attractiveness together explained a surprisingly large fraction of variance in extraversion across two studies- effects that were independent of variance explained by an androgen receptor gene polymorphism. These novel findings initially support an integrative model wherein facultative calibration and specific genetic polymorphisms operate in concert to determine personality variation. PMID- 21307180 TI - Does fast or slow evaluation foster greater certainty? AB - This research investigates the effect of perceived evaluation duration--that is, the perceived time or speed with which one generates an evaluation--on attitude certainty. Integrating diverse findings from past research, the authors propose that perceiving either fast or slow evaluation can augment attitude certainty depending on specifiable factors. Across three studies, it is shown that when people express opinions, evaluate familiar objects, or typically trust their gut reactions, perceiving fast rather than slow evaluation generally promotes greater certainty. In contrast, when people form opinions, evaluate unfamiliar objects, or typically trust more thoughtful responses, perceiving slow rather than fast evaluation generally promotes greater certainty. Mediation analyses reveal that these effects stem from trade-offs between perceived rational thought and the perceived ease of retrieving an attitude. Implications for research on deliberative versus intuitive decision making are discussed. PMID- 21307181 TI - Adolescent political activism and long-term happiness: a 21-year longitudinal study on the development of micro- and macrosocial worries. AB - Utilizing latent growth modeling, the long-term development of worries among peace movement supporters is examined. Data originate from a seven-wave German longitudinal study started in 1985 with on average 14-year-olds. Waves were interspersed 3 and a half years each. Activists are assumed to have lower (self related) microworries (Hypothesis 1) and higher macroworries (concerned with larger entities; Hypothesis 2) than nonactivists at the onset of the study. Nonactivists who appraised the threat of nuclear war as high in 1985 are assumed to report worse mental health than their activist age-mates 21 years later (Hypothesis 3). Activists are assumed to express relatively more macroworries than nonactivists in midadulthood (Hypothesis 4). All four hypotheses were confirmed. Results are interpreted in a stress-coping (Lazarus) and resource (Elder) framework, suggesting that refraining from acting out against a perceived sociopolitical threat is a long-term risk for a positive mental health trajectory. PMID- 21307182 TI - A role for tRNA(His) guanylyltransferase (Thg1)-like proteins from Dictyostelium discoideum in mitochondrial 5'-tRNA editing. AB - Genes with sequence similarity to the yeast tRNA(His) guanylyltransferase (Thg1) gene have been identified in all three domains of life, and Thg1 family enzymes are implicated in diverse processes, ranging from tRNA(His) maturation to 5'-end repair of tRNAs. All of these activities take advantage of the ability of Thg1 family enzymes to catalyze 3'-5' nucleotide addition reactions. Although many Thg1-containing organisms have a single Thg1-related gene, certain eukaryotic microbes possess multiple genes with sequence similarity to Thg1. Here we investigate the activities of four Thg1-like proteins (TLPs) encoded by the genome of the slime mold, Dictyostelium discoideum (a member of the eukaryotic supergroup Amoebozoa). We show that one of the four TLPs is a bona fide Thg1 ortholog, a cytoplasmic G(-1) addition enzyme likely to be responsible for tRNA(His) maturation in D. discoideum. Two other D. discoideum TLPs exhibit biochemical activities consistent with a role for these enzymes in mitochondrial 5'-tRNA editing, based on their ability to efficiently repair the 5' ends of mitochondrial tRNA editing substrates. Although 5'-tRNA editing was discovered nearly two decades ago, the identity of the protein(s) that catalyze this activity has remained elusive. This article provides the first identification of any purified protein that appears to play a role in the 5'-tRNA editing reaction. Moreover, the presence of multiple Thg1 family members in D. discoideum suggests that gene duplication and divergence during evolution has resulted in paralogous proteins that use 3'-5' nucleotide addition reactions for diverse biological functions in the same organism. PMID- 21307183 TI - Improved annotation of C. elegans microRNAs by deep sequencing reveals structures associated with processing by Drosha and Dicer. AB - MicroRNAs (miRNAs) are small regulatory RNAs that are essential in all studied metazoans. Research has focused on the prediction and identification of novel miRNAs, while little has been done to validate, annotate, and characterize identified miRNAs. Using Illumina sequencing, ~20 million small RNA sequences were obtained from Caenorhabditis elegans. Of the 175 miRNAs listed on the miRBase database, 106 were validated as deriving from a stem-loop precursor with hallmark characteristics of miRNAs. This result suggests that not all sequences identified as miRNAs belong in this category of small RNAs. Our large data set of validated miRNAs facilitated the determination of general sequence and structural characteristics of miRNAs and miRNA precursors. In contrast to previous observations, we did not observe a preference for the 5' nucleotide of the miRNA to be unpaired compared to the 5' nucleotide of the miRNA*, nor a preference for the miRNA to be on either the 5' or 3' arm of the miRNA precursor stem-loop. We observed that steady-state pools of miRNAs have fairly homogeneous termini, especially at their 5' end. Nearly all mature miRNA-miRNA* duplexes had two nucleotide 3' overhangs, and there was a preference for a uracil in the first and ninth position of the mature miRNA. Finally, we observed that specific nucleotides and structural distortions were overrepresented at certain positions adjacent to Drosha and Dicer cleavage sites. Our study offers a comprehensive data set of C. elegans miRNAs and their precursors that significantly decreases the uncertainty associated with the identity of these molecules in existing databases. PMID- 21307184 TI - Human cytomegalovirus pUS27 G protein-coupled receptor homologue is required for efficient spread by the extracellular route but not for direct cell-to-cell spread. AB - Human cytomegalovirus (HCMV) encodes multiple G protein-coupled receptor (GPCR) homologues, including pUS27, pUS28, pUL33, and pUL78. To explore the function of pUS27, we constructed pUS27-deficient derivates of two clinical isolates of HCMV. BFX-GFPstopUS27 is a FIX variant with a single base pair change in the US27 open reading frame, generating a stop codon that ablates accumulation of the GPCR homologue, and TB40/E-mCherrydlUS27 lacks the entire US27 coding region. BFX GFPstopUS27 generated 10-fold less extracellular progeny in fibroblasts, and TB40/E-mCherrydlUS27 exhibited a similar defect in endothelial cells. The pUS27 deficient FIX derivative produced normal quantities of viral DNA and viral proteins tested, and a late virion protein was appropriately localized to the cytoplasmic assembly zone. After infection at a low multiplicity with wild-type FIX virus, neutralizing antibody reduced the accumulation of intracellular viral DNA and intracellular virions, as would be expected if the virus is limited to direct cell-to-cell spread by neutralization of extracellular virus. In contrast, the antibody had little effect on the spread of the BFX-GFPstopUS27 virus. Further, after infection at a low multiplicity, the pUS27-deficient TB40/E virus exhibited a growth defect in endothelial cells, where the clinical isolate normally generates extracellular virus, but the TB40/E derivative exhibited little defect in epithelial cells, where the wild-type virus does not produce extracellular virus. Thus, mutants lacking pUS27 rely primarily on direct cell-to cell spread, and we conclude that the viral GCPR homologue acts at a late stage of the HCMV replication cycle to support spread of virus by the extracellular route. PMID- 21307185 TI - Epitope-specific CD8+ T lymphocytes cross-recognize mutant simian immunodeficiency virus (SIV) sequences but fail to contain very early evolution and eventual fixation of epitope escape mutations during SIV infection. AB - Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) evade containment by CD8(+) T lymphocytes through focused epitope mutations. However, because of limitations in the numbers of viral sequences that can be sampled, traditional sequencing technologies have not provided a true representation of the plasticity of these viruses or the intensity of CD8(+) T lymphocyte-mediated selection pressure. Moreover, the strategy by which CD8(+) T lymphocytes contain evolving viral quasispecies has not been characterized fully. In the present study we have employed ultradeep 454 pyrosequencing of virus and simultaneous staining of CD8(+) T lymphocytes with multiple tetramers in the SIV/rhesus monkey model to explore the coevolution of virus and the cellular immune response during primary infection. We demonstrated that cytotoxic T lymphocyte (CTL)-mediated selection pressure on the infecting virus was manifested by epitope mutations as early as 21 days following infection. We also showed that CD8(+) T lymphocytes cross-recognized wild-type and mutant epitopes and that these cross-reactive cell populations were present at a time when mutant forms of virus were present at frequencies of as low as 1 in 22,000 sequenced clones. Surprisingly, these cross reactive cells became enriched in the epitope-specific CD8(+) T lymphocyte population as viruses with mutant epitope sequences largely replaced those with epitope sequences of the transmitted virus. These studies demonstrate that mutant epitope-specific CD8(+) T lymphocytes that are present at a time when viral mutant epitope sequences are detected at extremely low frequencies fail to contain the later accumulation and fixation of the mutant epitope sequences in the viral quasispecies. PMID- 21307186 TI - The early interferon response to rotavirus is regulated by PKR and depends on MAVS/IPS-1, RIG-I, MDA-5, and IRF3. AB - In mouse embryonic fibroblasts (MEFs), the bovine rotavirus (UK strain) but not the simian rhesus rotavirus (RRV) robustly triggers beta interferon (IFN-beta) secretion, resulting in an IFN-dependent restriction of replication. We now find that both rotavirus strains trigger antiviral transcriptional responses early during infection and that both transcriptional responses and IFN-beta secretion are completely abrogated in MAVS/IPS-1(-/-) MEFs. Replication of UK virus could be rescued in MAVS/IPS-1(-/-) MEFs, and synthesis of viral RNA significantly increased early during virus infection. UK virus induced IFN-beta secretion and transcription of IFN-stimulated genes (ISGs) in both RIG-I(-/-) and MDA-5(-/-) MEFs, and neither receptor was essential by itself for the antiviral response to UK rotavirus. However, when receptors RIG-I and MDA-5 were depleted using RNA interference, we found that both contribute to the magnitude of the IFN response. IRF3 was found to be essential for MAVS/IPS-1-directed ISG transcription and IFN beta secretion during rotavirus infection. Interestingly, absence of the double stranded RNA-dependent protein kinase PKR led to a profound defect in the capacity of host cells to secrete IFN-beta in response to virus. Both PKR and IRF3 restricted the early replication of UK as indicated by significant increases in viral RNA in fibroblasts lacking either gene. Despite the loss in IFN-beta secretion in PKR(-/-) MEFs, we did not observe decreased IRF3- or NF-kappaB dependent early ISG transcription in these cells. Levels of transcripts encoding IFN-alpha4, IFN-alpha5, and IFN-beta were high in infected PKR(-/-) MEFs, indicating that during rotavirus infection, PKR functions at a stage between IFN gene transcription and subsequent IFN-beta secretion. These findings reveal that activation of the antiviral response by rotavirus is dependent on MAVS/IPS-1 and IRF3 and involves both RIG-I and MDA-5 and that IFN-beta secretion during rotavirus infection is regulated by PKR. PMID- 21307187 TI - Bovine plasmacytoid dendritic cells are the major source of type I interferon in response to foot-and-mouth disease virus in vitro and in vivo. AB - Type I interferons (alpha/beta interferons [IFN-alpha/beta]) are the main innate cytokines that are able to induce a cellular antiviral state, thereby limiting viral replication and disease pathology. Plasmacytoid dendritic cells (pDCs) play a crucial role in the control of viral infections, especially in response to viruses that have evolved mechanisms to block the type I IFN signal transduction pathway. Using density gradient separation and cell sorting, we have highly enriched a population of bovine cells capable of producing high levels of biologically active type I IFN. These cells represented less than 0.1% of the total lymphocyte population in blood, pseudoafferent lymph, and lymph nodes. Phenotypic analysis identified these cells as bovine pDCs (CD3(-) CD14(-) CD21(-) CD11c(-) NK(-) TCRdelta(-) CD4(+) MHC II(+) CD45RB(+) CD172a(+) CD32(+)). High levels of type I IFN were generated by these cells in vitro in response to Toll like receptor 9 (TLR-9) agonist CpG and foot-and-mouth disease virus (FMDV) immune complexes. In contrast, immune complexes formed with UV-inactivated FMDV or FMDV empty capsids failed to elicit a type I IFN response. Depletion of CD4 cells in vivo resulted in levels of type I IFN in serum early during FMDV infection that were significantly lower than those for control animals. In conclusion, pDCs interacting with immune-complexed virus are the major source of type I interferon production during acute FMDV infection in cattle. PMID- 21307188 TI - A Rab11- and microtubule-dependent mechanism for cytoplasmic transport of influenza A virus viral RNA. AB - The viral RNA (vRNA) genome of influenza A virus is replicated in the nucleus, exported to the cytoplasm as ribonucleoproteins (RNPs), and trafficked to the plasma membrane through uncertain means. Using fluorescent in situ hybridization to detect vRNA as well as the live cell imaging of fluorescently labeled RNPs, we show that an early event in vRNA cytoplasmic trafficking involves accumulation near the microtubule organizing center in multiple cell types and viral strains. Here, RNPs colocalized with Rab11, a pericentriolar recycling endosome marker. Cytoplasmic RNP localization was perturbed by inhibitors of vesicular trafficking, microtubules, or the short interfering RNA-mediated depletion of Rab11. Green fluorescent protein (GFP)-tagged RNPs in living cells demonstrated rapid, bidirectional, and saltatory movement, which is characteristic of microtubule-based transport, and also cotrafficked with fluorescent Rab11. Coprecipitation experiments showed an interaction between RNPs and the GTP-bound form of Rab11, potentially mediated via the PB2 subunit of the polymerase. We propose that influenza virus RNPs are routed from the nucleus to the pericentriolar recycling endosome (RE), where they access a Rab11-dependent vesicular transport pathway to the cell periphery. PMID- 21307189 TI - Epstein-Barr virus LMP1 activates EGFR, STAT3, and ERK through effects on PKCdelta. AB - Epstein-Barr virus (EBV) is a ubiquitous herpesvirus that infects more than 90% of the world's adult population and is linked to multiple malignancies, including Burkitt lymphoma, Hodgkin disease, and nasopharyngeal carcinoma (NPC). The EBV oncoprotein LMP1 induces transcription of the epidermal growth factor receptor (EGFR), which is expressed at high levels in NPC. EGFR transcription is induced by LMP1 through a p50 NFkappaB1-Bcl-3 complex, and Bcl-3 is induced by LMP1 mediated activation of STAT3. This study reveals that LMP1, through its carboxyl terminal activation domain 1 (LMP1-CTAR1), activates both STAT3 and EGFR in a serum-independent manner with constitutive serine phosphorylation of STAT3. Upon treatment with EGF, the LMP1-CTAR1-induced EGFR was additionally phosphorylated and STAT3 became phosphorylated on tyrosine, concomitant with upregulation of a subset of STAT3 target genes. The kinase responsible for LMP1-CTAR1-mediated serine phosphorylation of STAT3 was identified to be PKCdelta using specific RNAi, a dominant negative PKCdelta, and the PKCdelta inhibitor rottlerin. Interestingly, inhibition of PKCdelta also inhibited constitutive phosphorylation of EGFR and LMP1-CTAR1-induced phosphorylation of ERK. Inhibition of PKCdelta blocked LMP1-CTAR1-mediated transformation of Rat-1 cells, likely through the inhibition of ERK activation. These findings indicate that LMP1 activates multiple distinct signaling pathways and suggest that PKCdelta functions as a master regulator of EGFR, STAT3, and ERK activation by LMP1-CTAR1. PMID- 21307190 TI - Hydrolyzable tannins (chebulagic acid and punicalagin) target viral glycoprotein glycosaminoglycan interactions to inhibit herpes simplex virus 1 entry and cell to-cell spread. AB - Herpes simplex virus 1 (HSV-1) is a common human pathogen that causes lifelong latent infection of sensory neurons. Non-nucleoside inhibitors that can limit HSV 1 recurrence are particularly useful in treating immunocompromised individuals or cases of emerging acyclovir-resistant strains of herpesvirus. We report that chebulagic acid (CHLA) and punicalagin (PUG), two hydrolyzable tannins isolated from the dried fruits of Terminalia chebula Retz. (Combretaceae), inhibit HSV-1 entry at noncytotoxic doses in A549 human lung cells. Experiments revealed that both tannins targeted and inactivated HSV-1 viral particles and could prevent binding, penetration, and cell-to-cell spread, as well as secondary infection. The antiviral effect from either of the tannins was not associated with induction of type I interferon-mediated responses, nor was pretreatment of the host cell protective against HSV-1. Their inhibitory activities targeted HSV-1 glycoproteins since both natural compounds were able to block polykaryocyte formation mediated by expression of recombinant viral glycoproteins involved in attachment and membrane fusion. Our results indicated that CHLA and PUG blocked interactions between cell surface glycosaminoglycans and HSV-1 glycoproteins. Furthermore, the antiviral activities from the two tannins were significantly diminished in mutant cell lines unable to produce heparan sulfate and chondroitin sulfate and could be rescued upon reconstitution of heparan sulfate biosynthesis. We suggest that the hydrolyzable tannins CHLA and PUG may be useful as competitors for glycosaminoglycans in the management of HSV-1 infections and that they may help reduce the risk for development of viral drug resistance during therapy with nucleoside analogues. PMID- 21307191 TI - Both nonstructural proteins NS1 and NS2 of pneumonia virus of mice are inhibitors of the interferon type I and type III responses in vivo. AB - Infection of mice with pneumonia virus of mice (PVM) provides a convenient experimental pathogenesis model in a natural host for a human respiratory syncytial virus-related virus. Extending our previous work showing that the PVM nonstructural (NS) proteins were pathogenicity factors in mice, we identify both the NS1 and NS2 proteins as antagonists of alpha/beta interferon (IFN-alpha/beta) and IFN-lambda by use of recombinant PVM (rPVM) with single and combined deletions of the NS proteins (DeltaNS1, DeltaNS2, and DeltaNS1 DeltaNS2). Wild type and NS deletion PVMs were evaluated for growth and pathogenesis by infecting knockout mice that lack functional receptors to IFN-alpha/beta, IFN-lambda, or both. The absence of the receptor to IFN-alpha/beta (IFNAR) or IFN-lambda (interleukin-28 receptor alpha chain [IL-28Ralpha]) individually did not reverse the attenuated virulence of the NS deletion viruses although loss of IFNAR partially restored replication efficiency. When both receptors were deleted, replication and virulence were largely rescued for rPVM DeltaNS1 and were significantly but not completely rescued for rPVM DeltaNS2. As for rPVM DeltaNS1 DeltaNS2, the effect was mostly limited to partial enhancement of replication. This indicates that both IFN-alpha/beta and IFN-lambda contributed to restricting the NS deletion viruses, with the former playing the greater role. Interestingly, the replication and virulence of wild-type PVM were completely unaffected by the presence or absence of functional receptors to IFN-alpha/beta and IFN-lambda, indicating that both systems are strongly suppressed during infection. However, pretreatment of mice with IFN-alpha/beta was protective against lethal rPVM challenge, whereas pretreatment with IFN-lambda delayed but did not prevent disease and, in some cases, reduced mortality. The fact that virulence of rPVM lacking NS2 was not recovered completely when both interferon receptors were deleted suggests that NS2 may have further functions outside the IFN system. PMID- 21307192 TI - The changing role of mTOR kinase in the maintenance of protein synthesis during human cytomegalovirus infection. AB - The mammalian target of rapamycin (mTOR) kinase occurs in mTOR complex 1 (mTORC1) and complex 2 (mTORC2), primarily differing by the substrate specificity factors raptor (in mTORC1) and rictor (in mTORC2). Both complexes are activated during human cytomegalovirus (HCMV) infection. mTORC1 phosphorylates eukaryotic initiation factor 4E (eIF4E)-binding protein (4E-BP1) and p70S6 kinase (S6K) in uninfected cells, and this activity is lost upon raptor depletion. In infected cells, 4E-BP1 and S6K phosphorylation is maintained when raptor or rictor is depleted, suggesting that either mTOR complex can phosphorylate 4E-BP1 and S6K. Studies using the mTOR inhibitor Torin1 show that phosphorylation of 4E-BP1 and S6K in infected cells depends on mTOR kinase. The total levels of 4E-BP1 and viral proteins representative of all temporal classes were lowered by Torin1 treatment and by raptor, but not rictor, depletion, suggesting that mTORC1 is involved in the production of all classes of HCMV proteins. We also show that Torin1 inhibition of mTOR kinase is rapid and most deleterious at early times of infection. While Torin1 treatment from the beginning of infection significantly inhibited translation of viral proteins, its addition at later time points had far less effect. Thus, with respect to mTOR's role in translational control, HCMV depends on it early in infection but can bypass it at later times of infection. Depletion of 4E-BP1 by use of short hairpin RNAs (shRNAs) did not rescue HCMV growth in Torin1-treated human fibroblasts as it has been shown to in murine cytomegalovirus (MCMV)-infected 4E-BP1(-/-) mouse embryo fibroblasts (MEFs), suggesting that during HCMV infection mTOR kinase has additional roles other than phosphorylating and inactivating 4E-BP1. Overall, our data suggest a dynamic relationship between HCMV and mTOR kinase which changes during the course of infection. PMID- 21307193 TI - Evidence for Ebola virus superantigen activity. PMID- 21307194 TI - A novel human polyomavirus closely related to the african green monkey-derived lymphotropic polyomavirus. AB - We identified a novel human polyomavirus from a kidney transplant patient under immunosuppressive treatment, by use of a generic PCR. The genome of the virus was completely amplified and sequenced. In phylogenetic analyses, it appeared as the closest relative to the African green monkey-derived lymphotropic polyomavirus (LPV). Further investigation of clinical samples from immunocompromised patients with specific nested PCR revealed additional positive samples, indicating that the virus naturally infects humans. The virus was tentatively named human polyomavirus 9 (HPyV9). The previously observed seroreactivity to LPV in human populations might find a partial explanation in the circulation of HPyV9. PMID- 21307195 TI - Immune-induced evolutionary selection focused on a single reading frame in overlapping hepatitis B virus proteins. AB - Viruses employ various means to evade immune detection. Reduction of CD8(+) T cell epitopes is one of the common strategies used for this purpose. Hepatitis B virus (HBV), a member of the Hepadnaviridae family, has four open reading frames, with about 50% overlap between the genes they encode. We computed the CD8(+) T cell epitope density within HBV proteins and the mutations within the epitopes. Our results suggest that HBV accumulates escape mutations that reduce the number of epitopes. These mutations are not equally distributed among genes and reading frames. While the highly expressed core and X proteins are selected to have low epitope density, polymerase, which is expressed at low levels, does not undergo the same selection. In overlapping regions, mutations in one protein-coding sequence also affect the other protein-coding sequence. We show that mutations lead to the removal of epitopes in X and surface proteins even at the expense of the addition of epitopes in polymerase. The total escape mutation rate for overlapping regions is lower than that for nonoverlapping regions. The lower epitope replacement rate for overlapping regions slows the evolutionary escape rate of these regions but leads to the accumulation of mutations more robust in the transfer between hosts, such as mutations preventing proteasomal cleavage into epitopes. PMID- 21307197 TI - Kaposi's sarcoma-associated herpesvirus bacterial artificial chromosome contains a duplication of a long unique-region fragment within the terminal repeat region. AB - Use of the Kaposi's sarcoma-associated herpesvirus (KSHV) bacterial artificial chromosome 36 (KSHV-BAC36) genome permits reverse genetics approaches to study KSHV biology. While sequencing the complete KSHV-BAC36 genome, we noted a duplication of a 9-kb fragment of the long unique region in the terminal repeat region. This duplication covers a part of open reading frame (ORF) 19, the complete ORFs 18, 17, 16, K7, K6, and K5, and the putative ORF in the left origin of lytic replication, and it contains the BAC cassette. This observation needs to be kept in mind if viral genes located within the duplicated region are to be mutated in KSHV-BAC36. PMID- 21307196 TI - The role of LAT in increased CD8+ T cell exhaustion in trigeminal ganglia of mice latently infected with herpes simplex virus 1. AB - Herpes simplex virus (HSV) infection is a classic example of latent viral infection in humans and experimental animal models. The HSV-1 latency-associated transcript (LAT) plays a major role in the HSV-1 latency reactivation cycle and thus in recurrent disease. Whether the presence of LAT leads to generation of dysfunctional T cell responses in the trigeminal ganglia (TG) of latently infected mice is not known. To address this issue, we used LAT-positive [LAT(+)] and LAT-deficient [LAT(-)] viruses to evaluate the effect of LAT on CD8 T cell exhaustion in TG of latently infected mice. The amount of latency as determined by quantitative reverse transcription-PCR (qRT-PCR) of viral DNA in total TG extracts was 3-fold higher with LAT(+) than with LAT(-) virus. LAT expression and increased latency correlated with increased mRNA levels of CD8, PD-1, and Tim-3. PD-1 is both a marker for exhaustion and a primary factor leading to exhaustion, and Tim-3 can also contribute to exhaustion. These results suggested that LAT(+) TG contain both more CD8(+) T cells and more CD8(+) T cells expressing the exhaustion markers PD-1 and Tim-3. This was confirmed by flow cytometry analyses of expression of CD3/CD8/PD-1/Tim-3, HSV-1, CD8(+) T cell pentamer (specific for a peptide derived from residues 498 to 505 of glycoprotein B [gB(498-505)]), interleukin-2 (IL-2), and tumor necrosis factor alpha (TNF-alpha). The functional significance of PD-1 and its ligands in HSV-1 latency was demonstrated by the significantly reduced amount of HSV-1 latency in PD-1- and PD-L1-deficient mice. Together, these results may suggest that both PD-1 and Tim-3 are mediators of CD8(+) T cell exhaustion and latency in HSV-1 infection. PMID- 21307198 TI - Oligonucleotide motifs that disappear during the evolution of influenza virus in humans increase alpha interferon secretion by plasmacytoid dendritic cells. AB - CpG motifs in an A/U context have been preferentially eliminated from classical H1N1 influenza virus genomes during virus evolution in humans. The hypothesis of the current work is that CpG motifs in a uracil context represent sequence patterns with the capacity to induce an immune response, and the avoidance of this immunostimulatory signal is the reason for the observed preferential decline. To analyze the immunogenicity of these domains, we used plasmacytoid dendritic cells (pDCs). pDCs express pattern recognition receptors, including Toll-like receptor 7 (TLR7), which recognizes guanosine- and uridine-rich viral single-stranded RNA (ssRNA), including influenza virus ssRNA. The signaling through TLR7 results in the induction of inflammatory cytokines and type I interferon (IFN-I), an essential process for the induction of specific adaptive immune responses and for mounting a robust antiviral response mediated by IFN alpha. Secretion of IFN-alpha is also linked to the activation of other immune cells, potentially amplifying the effect of an initial IFN-alpha secretion. We therefore also examined the role of IFN-alpha-driven activation of NK cells as another source of selective pressure on the viral genome. We found direct evidence that CpG RNA motifs in a U-rich context control pDC activation and IFN alpha-driven activation of NK cells, likely through TLR7. These data provide a potential explanation for the loss of CpG motifs from avian influenza viruses as they adapt to mammalian hosts. The selective decrease of CpG motifs surrounded by U/A may be a viral strategy to avoid immune recognition, a strategy likely shared by highly expressed human immune genes. PMID- 21307199 TI - The proapoptotic Bcl-2 protein Bax plays an important role in the pathogenesis of reovirus encephalitis. AB - Encephalitis induced by reovirus serotype 3 (T3) strains results from the apoptotic death of infected neurons. Extrinsic apoptotic signaling is activated in reovirus-infected neurons in vitro and in vivo, but the role of intrinsic apoptosis signaling during encephalitis is largely unknown. Bax plays a key role in intrinsic apoptotic signaling in neurons by allowing the release of mitochondrial cytochrome c. We found Bax activation and cytochrome c release in neurons following infection of neonatal mice with T3 reoviruses. Bax(-/-) mice infected with T3 Abney (T3A) have reduced central nervous system (CNS) tissue injury and decreased apoptosis, despite viral replication that is similar to that in wild-type (WT) Bax(+/+) mice. In contrast, in the heart, T3A-infected Bax(-/-) mice have viral growth, caspase activation, and injury comparable to those in WT mice, indicating that the role of Bax in pathogenesis is organ specific. Nonmyocarditic T3 Dearing (T3D)-infected Bax(-/-) mice had delayed disease and enhanced survival compared to WT mice. T3D-infected Bax(-/-) mice had significantly lower viral titers and levels of activated caspase 3 in the brain despite unaffected transneuronal spread of virus. Cytochrome c and Smac release occurred in some reovirus-infected neurons in the absence of Bax; however, this was clearly reduced compared to levels seen in Bax(+/+) wild-type mice, indicating that Bax is necessary for efficient activation of proapoptotic mitochondrial signaling in infected neurons. Our studies suggest that Bax is important for reovirus growth and pathogenesis in neurons and that the intrinsic pathway of apoptosis, mediated by Bax, is important for full expression of disease, CNS tissue injury, apoptosis, and viral growth in the CNS of reovirus infected mice. PMID- 21307200 TI - Chimeric porcine circoviruses (PCV) containing amino acid epitope tags in the C terminus of the capsid gene are infectious and elicit both anti-epitope tag antibodies and anti-PCV type 2 neutralizing antibodies in pigs. AB - A chimeric porcine circovirus (PCV1-2) with the capsid gene of pathogenic PCV2 cloned into the genomic backbone of nonpathogenic PCV1 is attenuated in pigs but elicits protective immunity against PCV2. In this study, short epitope tags were inserted into the C terminus of the capsid protein of the chimeric PCV1-2 vaccine virus, resulting in a tractable marker virus that is infectious both in vitro and in vivo. Pigs experimentally infected with the epitope-tagged PCV1-2 vaccine viruses produced tag-specific antibodies, as well as anti-PCV2 neutralizing antibodies, indicating that the epitope-tagged viruses could potentially serve as a positive-marker modified live-attenuated vaccine. PMID- 21307201 TI - The leader proteinase of foot-and-mouth disease virus negatively regulates the type I interferon pathway by acting as a viral deubiquitinase. AB - The leader proteinase (L(pro)) of foot-and-mouth disease virus (FMDV) is a papain like proteinase that plays an important role in FMDV pathogenesis. Previously, it has been shown that L(pro) is involved in the inhibition of the type I interferon (IFN) response by FMDV. However, the underlying mechanisms remain unclear. Here we demonstrate that FMDV Lb(pro), a shorter form of L(pro), has deubiquitinating activity. Sequence alignment and structural bioinformatics analyses revealed that the catalytic residues (Cys51 and His148) are highly conserved in FMDV Lb(pro) of all seven serotypes and that the topology of FMDV Lb(pro) is remarkably similar to that of ubiquitin-specific protease 14 (USP14), a cellular deubiquitylation enzyme (DUB), and to that of severe acute respiratory syndrome coronavirus (SARS CoV) papain-like protease (PLpro), a coronaviral DUB. Both purified Lb(pro) protein and in vivo ectopically expressed Lb(pro) removed ubiquitin (Ub) moieties from cellular substrates, acting on both lysine-48- and lysine-63-linked polyubiquitin chains. Furthermore, Lb(pro) significantly inhibited ubiquitination of retinoic acid-inducible gene I (RIG-I), TANK-binding kinase 1 (TBK1), TNF receptor-associated factor 6 (TRAF6), and TRAF3, key signaling molecules in activation of type I IFN response. Mutations in Lb(pro) that ablate the catalytic activity (C51A or D163N/D164N) or disrupt the SAP (for SAF-A/B, Acinus, and PIAS) domain (I83A/L86A) abrogated the DUB activity of Lb(pro) as well as its ability to block signaling to the IFN-beta promoter. Collectively, these results demonstrate that FMDV Lb(pro) possesses DUB activity in addition to serving as a viral proteinase and describe a novel mechanism evolved by FMDV to counteract host innate antiviral responses. PMID- 21307202 TI - Soluble respiratory syncytial virus fusion protein in the fully cleaved, pretriggered state is triggered by exposure to low-molarity buffer. AB - The paramyxovirus fusion (F) glycoprotein is anchored in the virion membrane in a metastable, pretriggered form. Once triggered, the F protein undergoes a dramatic conformational extension that inserts its hydrophobic fusion peptide into the target cell membrane, then folds back on itself to bring the membranes together and initiate fusion. Unlike most other paramyxoviruses, the respiratory syncytial virus (RSV) F protein alone is sufficient to mediate membrane fusion and virus infection. To study the triggering mechanism of the RSV F protein, we have generated a soluble F (sF) protein by replacing the transmembrane and cytoplasmic tail domains with a 6His tag. The sF protein is secreted efficiently from 293T cells in a fully cleaved form. It is recognized by neutralizing monoclonal antibodies, appears spherical by electron microscopic analysis, and is not aggregated, all consistent with a native, pretriggered trimer. The sF protein was purified on a Ni(+2) column and eluted with 50 mM phosphate buffer containing 500 mM NaCl and 250 mM imidazole. Dialysis against 10 mM buffer caused the sF protein to trigger, forming "hat pin"-shaped molecules that aggregated as rosettes, characteristic of the posttriggered form. Further dialysis experiments indicated that the efficiency of triggering correlated well with the reduction of buffer molarity. Reduction of buffer molarity by dilution also resulted in exposure of the fusion peptide, as detected by liposome association, confirming sF protein triggering. Mutation of the furin cleavage site adjacent to the fusion peptide prevented liposome association, further confirming that association is via the fusion peptide. PMID- 21307203 TI - Restriction of porcine endogenous retrovirus by porcine APOBEC3 cytidine deaminases. AB - Xenotransplantation of porcine cells, tissues, and organs shows promise to surmount the shortage of human donor materials. Among the barriers to pig-to human xenotransplantation are porcine endogenous retroviruses (PERV) since functional representatives of the two polytropic classes, PERV-A and PERV-B, are able to infect human embryonic kidney cells in vitro, suggesting that a xenozoonosis in vivo could occur. To assess the capacity of human and porcine cells to counteract PERV infections, we analyzed human and porcine APOBEC3 (A3) proteins. This multigene family of cytidine deaminases contributes to the cellular intrinsic immunity and act as potent inhibitors of retroviruses and retrotransposons. Our data show that the porcine A3 gene locus on chromosome 5 consists of the two single-domain genes A3Z2 and A3Z3. The evolutionary relationships of the A3Z3 genes reflect the evolutionary history of mammals. The two A3 genes encode at least four different mRNAs: A3Z2, A3Z3, A3Z2-Z3, and A3Z2 Z3 splice variant A (SVA). Porcine and human A3s have been tested toward their antiretroviral activity against PERV and murine leukemia virus (MuLV) using novel single-round reporter viruses. The porcine A3Z2, A3Z3 and A3Z2-Z3 were packaged into PERV particles and inhibited PERV replication in a dose-dependent manner. The antiretroviral effect correlated with editing by the porcine A3s with a trinucleotide preference for 5' TGC for A3Z2 and A3Z2-Z3 and 5' CAC for A3Z3. These results strongly imply that human and porcine A3s could inhibit PERV replication in vivo, thereby reducing the risk of infection of human cells by PERV in the context of pig-to-human xenotransplantation. PMID- 21307204 TI - In vivo fitness associated with high virulence in a vertebrate virus is a complex trait regulated by host entry, replication, and shedding. AB - The relationship between pathogen fitness and virulence is typically examined by quantifying only one or two pathogen fitness traits. More specifically, it is regularly assumed that within-host replication, as a precursor to transmission, is the driving force behind virulence. In reality, many traits contribute to pathogen fitness, and each trait could drive the evolution of virulence in different ways. Here, we independently quantified four viral infection cycle traits, namely, host entry, within-host replication, within-host coinfection fitness, and shedding, in vivo, in the vertebrate virus Infectious hematopoietic necrosis virus (IHNV). We examined how each of these stages of the viral infection cycle contributes to the fitness of IHNV genotypes that differ in virulence in rainbow trout. This enabled us to determine how infection cycle fitness traits are independently associated with virulence. We found that viral fitness was independently regulated by each of the traits examined, with the largest impact on fitness being provided by within-host replication. Furthermore, the more virulent of the two genotypes of IHNV we used had advantages in all of the traits quantified. Our results are thus congruent with the assumption that virulence and within-host replication are correlated but suggest that infection cycle fitness is complex and that replication is not the only trait associated with virulence. PMID- 21307205 TI - The IRF-3/Bax-mediated apoptotic pathway, activated by viral cytoplasmic RNA and DNA, inhibits virus replication. AB - Induction of apoptosis in cells infected by Sendai virus (SeV), which triggers the cytosolic RIG-I pathway, requires the presence of interferon regulatory factor 3 (IRF-3). Independent of IRF-3's transcriptional role, a novel IRF-3 activation pathway causes its interaction with the proapoptotic protein Bax and its mitochondrial translocation to induce apoptosis. Here we report that two other RNA viruses, vesicular stomatitis virus (VSV) and encephalomyocarditis virus (EMCV), may also activate the same pathway. Moreover, cytosolic DNA, produced by adenovirus or introduced by transfection, activated the pathway in an RNA polymerase III-dependent fashion. To evaluate the contribution of this newly discovered apoptotic pathway to the host's overall antiviral response, we measured the efficiencies of replication of various viruses in vitro and viral pathogenesis in vivo, using cells and mice that are selectively deficient in components required for the apoptotic pathway of IRF-3. Our results clearly demonstrate that the IRF-3/Bax-mediated apoptotic signaling branch contributes significantly to the host's protection from viral infection and consequent pathogenesis. PMID- 21307206 TI - Efficient rescue of recombinant Lassa virus reveals the influence of S segment noncoding regions on virus replication and virulence. AB - Lassa virus (LASV), is a significant cause of severe, often fatal, hemorrhagic fever in humans throughout western Africa, with an estimated 100,000 infections each year. No vaccines are commercially available. We report the development of an efficient reverse genetics system to rescue recombinant LASV and to investigate the contributions of the long 5' and 3' noncoding regions (NCRs) of the S genomic segment to in vitro growth and in vivo virulence. This work demonstrates that deletions of large portions of these NCRs confer an attenuated phenotype and are a first step toward further insights into the high virulence of LASV. PMID- 21307207 TI - Assembly of helper-dependent adenovirus DNA into chromatin promotes efficient gene expression. AB - Helper-dependent adenovirus (hdAd) vectors have shown tremendous potential in animal models of human disease in numerous preclinical studies. Expression of a therapeutic transgene can be maintained for several years after a single administration of the hdAd vector. However, despite the long-term persistence of hdAd DNA in the transduced cell, little is known of the fate and structure of hdAd DNA within the host nucleus. In this study, we have characterized the assembly of hdAd DNA into chromatin in tissue culture. Eviction of the Ad DNA packaging protein VII, histone deposition, and vector-associated gene expression all began within 2 to 6 h of host cell transduction. Inhibition of transcription elongation through the vector DNA template had no effect on the loss of VII, suggesting that transcription was not necessary for removal of the majority of protein VII. Vector DNA assembled into physiologically spaced nucleosomes within 6 h. hdAd vectors incorporated the histone H3 variant H3.3, which was dependent on the histone chaperone HIRA. Knockdown of HIRA reduced hdAd association with histones and reduced expression of the vector-carried transgene by 2- to 3-fold. Our study elucidates an essential role for hdAd DNA chromatinization for optimal vector gene expression. PMID- 21307208 TI - Standardization of hepatitis E virus (HEV) nucleic acid amplification technique based assays: an initial study to evaluate a panel of HEV strains and investigate laboratory performance. AB - The performance of hepatitis E virus (HEV) RNA nucleic acid amplification (NAT) based assays has been investigated using a panel of HEV-containing plasma samples. The panel comprised 22 HEV-positive plasma samples representing 10-fold serial dilutions of HEV genotypes 3a, 3b, 3f, and 4c obtained from blood donors. Two negative-control plasma samples were included. All samples were blinded. The plasma samples were prepared as liquid/frozen materials and distributed to participants on dry ice. Laboratories were requested to test the panel using their routine HEV assays and to score samples as either positive or negative and could optionally return data in copies/ml for HEV RNA. Twenty laboratories from 10 different countries participated in the study. Data were returned by all participating laboratories; 10 laboratories returned quantitative data. All assays except one were developed in-house using conventional or real-time reverse transcriptase PCR (RT-PCR) methodologies. There was a 100- to 1,000-fold difference in sensitivity between the majority of assays, independent of the virus strain. Although the quantitative data were limited, for the samples in the range of ~6 to 4 log(10) copies/ml, the standard deviations of the geometric means of the samples ranged between 0.38 and 1.09. Except for one equivocal result, HEV RNA was not detected in the negative samples. The variability of assay sensitivity highlights the need for the standardization of HEV RNA NAT assays. PMID- 21307209 TI - First report of performance of the Versant CT/GC DNA 1.0 assay (kPCR) for detection of Chlamydia trachomatis and Neisseria gonorrhoeae. AB - We evaluated the analytical, work flow, and clinical performance of the Versant CT/GC DNA 1.0 assay (Versant CT/GC assay, where "CT" represents Chlamydia trachomatis and "GC" represents Neisseria gonorrhoeae). The assay simultaneously detects Chlamydia trachomatis and Neisseria gonorrhoeae in swab and first-catch urine (FCU) specimens. The limit of detection (LoD) was determined to be 342 copies/ml for C. trachomatis and 137 copies/ml for GC. The Versant CT/GC assay detected 15 C. trachomatis serovars and 46 GC strains. The Versant CT/GC assay demonstrated no cross-reactivity with 136 potentially cross-reacting organisms. Clinical concordance of the Versant CT/GC assay to the Aptima Combo 2 (AC2) assay from Gen-Probe was demonstrated using 1,129 patient specimens, including 589 urine and 540 swab specimens. Discrepant specimens were subjected to DNA sequencing to identify the presence of amplified targets and to identify false positive and false-negative results. Overall percent agreement was greater than 98%. Positive and negative percent agreements for detection of C. trachomatis were 94.4% and 99.1%, respectively, in urine specimens and 95.8% and 99.8%, respectively, in swab specimens. Positive percent agreement for the detection of N. gonorrhoeae was 100% in both urine and swab specimens, and negative percent agreements were 99.6% and 99% in urine and swab specimens, respectively. In conclusion, the performance of the Versant CT/GC assay was comparable to that of the AC2 assay. The Versant CT/GC assay can be recommended for the detection of C. trachomatis and N. gonorrhoeae in swab and urine specimens of symptomatic and asymptomatic individuals. PMID- 21307210 TI - Genotypic and phenotypic characterization of methicillin-susceptible Staphylococcus aureus isolates misidentified as methicillin-resistant Staphylococcus aureus by the BD GeneOhm MRSA assay. AB - Twenty-three nasal swab samples that tested positive for methicillin-resistant Staphylococcus aureus (MRSA) on initial testing by the BD GeneOhm MRSA assay (BD MRSA PCR; BD GeneOhm, San Diego, CA) were culture positive only for methicillin susceptible S. aureus (MSSA) from an enrichment broth. The 23 recovered isolates were confirmed as MSSA by a variety of phenotypic methods, including the BD Phoenix automated microbiology system (BD Diagnostics, Sparks, MD), oxacillin screening agar (BD Diagnostics), BBL CHROMagar MRSA (BD Diagnostics), and a PBP2' assay (Denka Seiken Co., Tokyo, Japan); susceptibilities were determined by using Mueller-Hinton agar with oxacillin. All were positive by nuc PCR, specific for S. aureus, but negative for mecA with one exception. Isolates were characterized by using multiplex PCR methodology to determine structural types and variants (SCCmec typing); additional PCRs were performed for the detection of the ccr and mec complexes, the junkyard regions as well as the Panton-Valentine leukocidin. Pulsed-field gel electrophoresis was used to determine clonality. One phenotypic MSSA isolate contained an intact SCCmec. Twelve MSSA isolates tested positive for MRSA by the BD-MRSA PCR because of amplification of the mec priming site flanking the SCC insertion point, although these isolates lacked mecA. The 10 remaining isolates were not MRSA and tested as MSSA by phenotypic and genotypic assays. In our patient population, diagnostic and surveillance testing and subsequent infection control practices may be impacted by the frequency of these excision events when using the BD-MRSA PCR for MRSA detection. PMID- 21307211 TI - Adenoid reservoir for pathogenic biofilm bacteria. AB - Biofilms of pathogenic bacteria are present on the middle ear mucosa of children with chronic otitis media (COM) and may contribute to the persistence of pathogens and the recalcitrance of COM to antibiotic treatment. Controlled studies indicate that adenoidectomy is effective in the treatment of COM, suggesting that the adenoids may act as a reservoir for COM pathogens. To investigate the bacterial community in the adenoid, samples were obtained from 35 children undergoing adenoidectomy for chronic OM or obstructive sleep apnea. We used a novel, culture-independent molecular diagnostic methodology, followed by confocal microscopy, to investigate the in situ distribution and organization of pathogens in the adenoids to determine whether pathogenic bacteria exhibited criteria characteristic of biofilms. The Ibis T5000 Universal Biosensor System was used to interrogate the extent of the microbial diversity within adenoid biopsy specimens. Using a suite of 16 broad-range bacterial primers, we demonstrated that adenoids from both diagnostic groups were colonized with polymicrobial biofilms. Haemophilus influenzae was present in more adenoids from the COM group (P = 0.005), but there was no significant difference between the two patient groups for Streptococcus pneumoniae or Staphylococcus aureus. Fluorescence in situ hybridization, lectin binding, and the use of antibodies specific for host epithelial cells demonstrated that pathogens were aggregated, surrounded by a carbohydrate matrix, and localized on and within the epithelial cell surface, which is consistent with criteria for bacterial biofilms. PMID- 21307212 TI - Parvovirus among patients with cytopenia of unknown origin in Brazil: a case control study. AB - The molecular prevalence of human parvovirus B19V (B19V) in bone marrow (BM) samples from 120 cases with cytopenias of unknown etiology was compared with that in samples from 45 BM donors (control group 1) and 120 oncohematological patients (control group 2) to determine the role that B19V genotypes may play in unexplained cytopenias. Of the 285 participants, the BM samples of 39 (13.7%) contained B19V DNA (21 with genotype 1, 5 with genotype 2, and 13 with genotype 3). The prevalences of B19V were similar between case and control subjects (15.0% versus 12.7%, respectively). Genotypes 2 and 3 were associated with older age and were detected in similar proportions between case and control group 2 subjects. The results of this study do not support a role for B19V genotype variants in the etiology of unexplained cytopenias. PMID- 21307213 TI - Strain variation among Bordetella pertussis isolates circulating in Poland after 50 years of whole-cell pertussis vaccine use. AB - In the present study, clinical isolates of Bordetella pertussis collected in Poland from 1960 to 2005 were analyzed by pulsed-field gel electrophoresis (PFGE) according to protocols recommended in previous studies. Among the 110 isolates from 1995 to 2005, 59 PFGE patterns were found, most of which were different from those currently circulating in other European Union (EU) countries for which data are available. The PFGE patterns of currently disseminating B. pertussis clones were found within PFGE groups III and IV, as elsewhere in the EU, and in newly identified clusters A and C. Up to 70, 26, and 4%, respectively, of the currently isolated strains in Poland harbored ptxA1-prn1, ptxA1-prn2, and ptxA1-prn3 allele combinations, and most (82%) were found to be of the Fim2 phenotype. Differences in the extent of heterogeneity estimated by PFGE typing in B. pertussis populations circulating in Poland in comparison to other EU countries may be due to the different vaccine composition strategy, since routine pertussis vaccination was initiated in Poland in 1960. PMID- 21307214 TI - Molecular analysis of a novel simian virus 40 (SV40) type in rhesus macaques and evidence for double infections with the classical SV40 type. AB - The incidence of simian virus 40 (SV40) infections in rhesus macaques infected with simian-human immunodeficiency viruses (SHIV) and in uninfected animals was determined using PCR. Rates varied from 5% in peripheral blood mononuclear cells of uninfected monkeys to 19.6% in SHIV-infected macaques. Much higher detection rates, up to 75%, were found in lymph nodes and spleen samples of SHIV-infected animals. Sequence analysis of PCR amplicons revealed that they form two genetic clusters, one containing the majority of known SV40 strains and the other formed by variants with 7% genetic difference. Based on this difference, we propose two SV40 types: "type 1" or "classical type" for the majority of SV40 strains and "type 2" for the novel SV40 variants. The genome of one variant, SV40-Ri257, was completely sequenced and analyzed. The agnogene of SV40-Ri257 extends into the VP2 open reading frame and encodes a typical agnoprotein fused to a C-terminal hydrophobic region. The transcriptional control region (TCR) of SV40-Ri257 is the least conserved region compared to type 1 viruses. Particularly, the 3' end of the TCR, containing the early promoter and enhancer region, exhibits considerable variation. Further analysis of SHIV-infected macaques with type-specific PCRs revealed that the TCR of type 1 was completely conserved, whereas this region in type 2 varied considerably within the early enhancer region. We provide evidence here for the existence of a novel SV40 type in rhesus macaques and show that double infections with both types frequently occur. PMID- 21307215 TI - Comparison of the DiversiLab repetitive element PCR system with spa typing and pulsed-field gel electrophoresis for clonal characterization of methicillin resistant Staphylococcus aureus. AB - The emergence of methicillin-resistant Staphylococcus aureus (MRSA) has become an increasing problem worldwide in recent decades. Molecular typing methods have been developed to identify clonality of strains and monitor spread of MRSA. We compared a new commercially available DiversiLab (DL) repetitive element PCR system with spa typing, spa clonal cluster analysis, and pulsed-field gel electrophoresis (PFGE) in terms of discriminatory power and concordance. A collection of 106 well-defined MRSA strains from our hospital was analyzed, isolated between 1994 and 2006. In addition, we analyzed 6 USA300 strains collected in our institution. DL typing separated the 106 MRSA isolates in 10 distinct clusters and 8 singleton patterns. Clustering analysis into spa clonal complexes resulted in 3 clusters: spa-CC 067/548, spa-CC 008, and spa-CC 012. The discriminatory powers (Simpson's index of diversity) were 0.982, 0.950, 0.846, and 0.757 for PFGE, spa typing, DL typing, and spa clonal clustering, respectively. DL typing and spa clonal clustering showed the highest concordance, calculated by adjusted Rand's coefficients. The 6 USA300 isolates grouped homogeneously into distinct PFGE and DL clusters, and all belonged to spa type t008 and spa-CC 008. Among the three methods, DL proved to be rapid and easy to perform. DL typing qualifies for initial screening during outbreak investigation. However, compared to PFGE and spa typing, DL typing has limited discriminatory power and therefore should be complemented by more discriminative methods in isolates that share identical DL patterns. PMID- 21307216 TI - TaqMan real-time reverse transcription-PCR assay for universal detection and quantification of avian hepatitis E virus from clinical samples in the presence of a heterologous internal control RNA. AB - Avian hepatitis E virus (HEV) isolates could be separated into at least three genotypes. In this study, the development of the first duplex TaqMan real-time reverse transcription-PCR (RT-PCR) assay for detection and quantification of avian HEV is presented. Primers and probes binding within relatively conserved open reading frame 3 (ORF3) were designed. Tenfold dilution series of in vitro transcribed avian HEV RNA were used as the standard for quantification. A 712-bp region of the green fluorescent protein gene was transcribed in vitro and used as a heterologous internal control for both RNA isolation and real-time RT-PCR. The duplex real-time RT-PCR for avian HEV had an efficiency of 1.04, a regression squared value of 0.996, and a sensitivity of approximately 3.6 * 10(3) copies per reaction mixture when in vitro-transcribed RNA was used as the template. The presence of in vitro-transcribed heterologous internal control RNA did not affect amplification of avian HEV RNA compared to that achieved by the single assay. The sensitivity of the real-time RT-PCR assay was comparable to that of conventional RT-PCR, and it was shown to be highly specific, as tissues from uninfected chickens, mammalian HEVs, and other viral genomes did not produce positive signals. All tested field samples with virus belonging to different avian HEV genotypes were successfully detected with this new duplex TaqMan real-time RT-PCR assay. PMID- 21307217 TI - Detection of hemagglutinin variants of the pandemic influenza A (H1N1) 2009 virus by pyrosequencing. AB - For influenza viruses, pyrosequencing has been successfully applied to the high throughput detection of resistance markers in genes encoding the drug-targeted M2 protein and neuraminidase. In this study, we expanded the utility of this assay to the detection of multiple receptor binding variants of the hemagglutinin protein of influenza viruses directly in clinical specimens. Specifically, a customized pyrosequencing protocol that permits detection of virus variants with the D, G, N, or E amino acid at position 222 in the hemagglutinin of the 2009 pandemic influenza A (H1N1) virus was developed. This customized pyrosequencing protocol was applied to the analysis of 241 clinical specimens. The use of the optimized nucleotide dispensation order allowed detection of mixtures of variants in 10 samples (4.1%) which the standard cyclic nucleotide dispensation protocol failed to detect. The optimized pyrosequencing protocol is expected to provide a more accurate tool in the analysis of virus variant composition. PMID- 21307218 TI - Detection of Group 1 Trypanosoma brucei gambiense by loop-mediated isothermal amplification. AB - Trypanosoma brucei gambiense group 1 is the major causative agent of the Gambian human African trypanosomiasis (HAT). Accurate diagnosis of Gambian HAT is still challenged by lack of precise diagnostic methods, low and fluctuating parasitemia, and generally poor services in the areas of endemicity. In this study, we designed a rapid loop-mediated isothermal amplification (LAMP) test for T. b. gambiense based on the 3' end of the T. b. gambiense-specific glycoprotein (TgsGP) gene. The test is specific and amplifies DNA from T. b. gambiense isolates and clinical samples at 62 degrees C within 40 min using a normal water bath. The analytical sensitivity of the TgsGP LAMP was equivalent to 10 trypanosomes/ml using purified DNA and ~1 trypanosome/ml using supernatant prepared from boiled blood, while those of classical PCR tests ranged from 10 to 10(3) trypanosomes/ml. There was 100% agreement in the detection of the LAMP product by real-time gel electrophoresis and the DNA-intercalating dye SYBR green I. The LAMP amplicons were unequivocally confirmed through sequencing and analysis of melting curves. The assay was able to amplify parasite DNA from native cerebrospinal fluid (CSF) and double-centrifuged supernatant prepared from boiled buffy coat and bone marrow aspirate. The robustness, superior sensitivity, and ability to inspect results visually through color change indicate the potential of TgsGP LAMP as a future point-of-care test. PMID- 21307219 TI - Simultaneous detection of Rift Valley Fever, bluetongue, rinderpest, and Peste des petits ruminants viruses by a single-tube multiplex reverse transcriptase-PCR assay using a dual-priming oligonucleotide system. AB - The aim of this study was to develop a highly sensitive and specific one-step multiplex reverse transcriptase PCR assay for the simultaneous and differential detection of Rift Valley Fever virus (RVFV), bluetongue virus (BTV), rinderpest virus (RPV), and Peste des petits ruminants virus (PPRV). These viruses cause mucosal lesions in cattle, sheep, and goats, and they are difficult to differentiate from one another based solely on their clinical presentation in suspected disease cases. In this study, we developed a multiplex reverse transcriptase PCR to detect these viruses using a novel dual-priming oligonucleotide (DPO). The DPO contains two separate priming regions joined by a polydeoxyinosine linker, which blocks extension of nonspecifically primed templates and consistently allows high PCR specificity even under less-than optimal PCR conditions. A total of 19 DPO primers were designed to detect and discriminate between RVFV, BTV, RPV, and PPRV by the generation of 205-, 440-, 115-, and 243-bp cDNA products, respectively. The multiplex reverse transcriptase PCR described here enables the early diagnosis of these four viruses and may also be useful as part of a testing regime for cattle, sheep, or goats exhibiting similar clinical signs, including mucosal lesions. PMID- 21307220 TI - Comparison of BD Bactec Plus blood culture media to VersaTREK Redox blood culture media for detection of bacterial pathogens in simulated adult blood cultures containing therapeutic concentrations of antibiotics. AB - Antibiotic neutralization in blood culture media from two automated systems was evaluated by measuring the recovery of organisms and times to detection in simulated cultures. Overall, BD Bactec Plus media (Bactec FX system) outperformed TREK 80 ml Redox media (VersaTREK system), although results suggest a relative rather than an absolute increased rate of recovery for the Bactec media. PMID- 21307221 TI - High levels of HCV core+1 antibodies in HCV patients with hepatocellular carcinoma. AB - The core region of the hepatitis C virus (HCV) genome possesses an overlapping ORF that has been shown to encode a protein, known as the alternate reading frame protein (ARFP), F or core+1. The biological role of this protein remains elusive, as it appears to be non-essential for virus replication. However, a number of independent studies have shown that the ARFP/F/core+1 protein elicits humoral and cellular immune responses in HCV-infected individuals and interacts with important cellular proteins. To assess the significance of the core+1 humoral response in HCV-infected patients, we examined the prevalence of anti-core+1 antibodies in sera from patients with hepatocellular carcinoma (HCC) in comparison with chronically HCV-infected individuals without HCC. We produced two HCV core+1 histidine-tagged recombinant proteins for genotypes 1a (aa 11-160) and 1b (aa 11-144), as well as a non-tagged highly purified recombinant core+1/S protein (aa 85-144) of HCV-1b. Using an in-house ELISA, we tested the prevalence of core+1 antibodies in 45 patients with HCC in comparison with 47 chronically HCV-infected patients without HCC and 77 negative-control sera. More than 50 % of the serum samples from HCC patients reacted with all core+1 antigens, whereas <26 % of the sera from the non-HCC HCV-infected individuals tested positive. No core+1-specific reactivity was detected in any of the control samples. In conclusion, the high occurrence of anti-core+1 antibodies in the serum of HCC patients suggests a role for the ARFP/F/core+1 protein in the pathogenesis of HCC. PMID- 21307222 TI - Novel structural protein in porcine reproductive and respiratory syndrome virus encoded by an alternative ORF5 present in all arteriviruses. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is an arterivirus that emerged in the late 1980s in both Europe and North America as the causative agent of porcine reproductive and respiratory syndrome (PRRS), now the most important disease of swine worldwide. Despite extensive characterization of PRRSV proteins by direct analysis and comparison with other arteriviruses, determinants of virulence, pathogenesis and protective immune recognition remain poorly understood. Thus, we hypothesized that additional ORFs are present in the PRRSV genome that may contribute to its biological properties, and so we screened highly purified virions of strain VR2332, the prototype type 2 PRRSV, for evidence of novel polypeptides. A 51 aa polypeptide was discovered that is encoded by an alternative ORF of the subgenomic mRNA encoding the major envelope glycoprotein, GP5, and which is incorporated into virions. The protein, referred to as ORF5a protein, is expressed in infected cells, and pigs infected with PRRSV express anti-ORF5a protein antibodies. A similar ORF is present as an alternative reading frame in all PRRSV subgenomic RNA5 genes and in all other arteriviruses, suggesting that this ORF5a protein plays a significant role in arterivirology. Its discovery also provides a new potential target for immunological and pharmacological intervention in PRRS. PMID- 21307223 TI - Discovery of a small arterivirus gene that overlaps the GP5 coding sequence and is important for virus production. AB - The arterivirus family (order Nidovirales) of single-stranded, positive-sense RNA viruses includes porcine respiratory and reproductive syndrome virus and equine arteritis virus (EAV). Their replicative enzymes are translated from their genomic RNA, while their seven structural proteins are encoded by a set of small, partially overlapping genes in the genomic 3'-proximal region. The latter are expressed via synthesis of a set of subgenomic mRNAs that, in general, are functionally monocistronic (except for a bicistronic mRNA encoding the E and GP2 proteins). ORF5, which encodes the major glycoprotein GP5, has been used extensively for phylogenetic analyses. However, an in-depth computational analysis now reveals the arterivirus-wide conservation of an additional AUG initiated ORF, here termed ORF5a, that overlaps the 5' end of ORF5. The pattern of substitutions across sequence alignments indicated that ORF5a is subject to functional constraints at the amino acid level, while an analysis of substitutions at synonymous sites in ORF5 revealed a greatly reduced frequency of substitution in the portion of ORF5 that is overlapped by ORF5a. The 43-64 aa ORF5a protein and GP5 are probably expressed from the same subgenomic mRNA, via a translation initiation mechanism involving leaky ribosomal scanning. Inactivation of ORF5a expression by reverse genetics yielded a severely crippled EAV mutant, which displayed lower titres and a tiny plaque phenotype. These defects, which could be partially complemented in ORF5a-expressing cells, indicate that the novel protein, which may be the eighth structural protein of arteriviruses, is expressed and important for arterivirus infection. PMID- 21307224 TI - Serological evidence of vertical transmission of JC and BK polyomaviruses in humans. AB - Vertical transmission of JC virus and BK virus has been investigated by few authors, with conflicting results. We performed a combined serological and genomic study of 19 unselected pregnant women and their newborns. Blood and urine samples were collected during each gestational trimester from the pregnant women. Umbilical cord blood, peripheral blood, urine and nasopharyngeal secretion samples were taken from newborns at delivery and after 1 week and 1 month of life. Polyomavirus DNA was detected by nested PCR. Polyomavirus IgG-, IgM- and IgA-specific antibodies were measured in maternal and newborn serum samples using a virus-like-particle-based ELISA method. BKV and JCV DNA were detected in urine from 4 (21 %) and 5 (26 %) women, respectively. BKV and JCV seroprevalences in the pregnant women were 84 % and 42 %, respectively. Using a rise in the IgG level or the transient appearance of an IgA or IgM response as evidence of infection in the newborn, we detected BKV and JCV infections in four (21 %) and three (16 %) newborns, respectively. Three infants had serological evidence of infection with both BKV and JCV. In two of the four possible BKV-infected newborns, the mothers seroconverted during pregnancy, while another mother was viruric and IgA seropositive. The mother of one of the three possible JCV infected newborns was viruric and IgA seropositive; another mother was viruric. These results suggest JC virus and BK virus can be transmitted from mother to newborn during pregnancy or soon after birth. PMID- 21307225 TI - Distinct cavemoviruses interact synergistically with sweet potato chlorotic stunt virus (genus Crinivirus) in cultivated sweet potato. AB - Two serologically unrelated sweet potato viruses causing symptoms of vein clearing in the indicator plant Ipomoea setosa were isolated and their genomes have been sequenced. They are associated with symptomless infections in sweet potato but distinct vein-clearing symptoms and higher virus titres were observed when these viruses co-infected with sweet potato chlorotic stunt virus (SPCSV), a virus that is distributed worldwide and is a mediator of severe virus diseases in this crop. Molecular characterization and phylogenetic analysis revealed an overall nucleotide identity of 47.6 % and an arrangement of the movement protein and coat protein domains characteristic of members of the genus Cavemovirus, in the family Caulimoviridae. We detected both cavemoviruses in cultivated sweet potato from East Africa, Central America and the Caribbean islands, but not in samples from South America. One of the viruses characterized showed a similar genome organization as, and formed a phylogenetic sublineage with, tobacco vein clearing virus (TVCV), giving further support to the previously suggested separation of TVCV, and related viral sequences, into a new caulimovirid genus. Given their geographical distribution and previous reports of similar but yet unidentified viruses, sweet potato cavemoviruses may co-occur with SPCSV more often than previously thought and they could therefore contribute to the extensive yield losses and cultivar decline caused by mixed viral infections in sweet potato. PMID- 21307226 TI - Endogenously expressed matrix protein M1 and nucleoprotein of influenza A are efficiently presented by class I and class II major histocompatibility complexes. AB - Current influenza vaccines containing primarily hypervariable haemagglutinin and neuraminidase proteins must be prepared against frequent new antigenic variants. Therefore, there is an ongoing effort to develop influenza vaccines that also elicit strong and sustained cytotoxic responses against highly conserved determinants such as the matrix (M1) protein and nucleoprotein (NP). However, their antigenic presentation properties in humans are less defined. Accordingly, we analysed MHC class I and class II presentation of endogenously processed M1 and NP in human antigen presenting cells and observed expansion of both CD8(+)- and CD4(+)-specific effector T lymphocytes secreting gamma interferon and tumour necrosis factor. Further enhancement of basal MHC-II antigenic presentation did not improve CD4(+) or CD8(+) T-cell quality based on cytokine production upon challenge, suggesting that endogenous M1 and NP MHC-II presentation is sufficient. These new insights about T-lymphocyte expansion following endogenous M1 and NP MHC-I and -II presentation will be important to design complementary heterosubtypic vaccination strategies. PMID- 21307227 TI - Reassorted pandemic (H1N1) 2009 influenza A virus discovered from pigs in Germany. AB - A natural reassortant influenza A virus consisting of seven genome segments from pandemic (H1N1) 2009 virus and a neuraminidase segment from a Eurasian porcine H1N1 influenza A virus was detected in a pig herd in Germany. The obvious reassortment compatibility between the pandemic (H1N1) 2009 and H1N1 viruses of porcine origin raises concern as to whether swine may become a reservoir for further reassortants of pandemic (H1N1) 2009 viruses with unknown implications for human health and swine production. PMID- 21307228 TI - Recombinant glycoprotein B vaccine formulation with Toll-like receptor 9 agonist and immune-stimulating complex induces specific immunity against multiple strains of cytomegalovirus. AB - Natural human cytomegalovirus (CMV) infection is characterized by a strain specific neutralizing antibody response. This is particularly relevant in clinical settings such as transplantation and pregnancy where reinfection with heterologous strains occurs and the immune system does not mount an effective response against the infecting strain due to underlying immunosuppression. There is an emerging argument that a CMV vaccine that induces high titres of cross neutralizing antibodies will be more effective in protecting individuals from infection with antigenically different CMV strains. In addition, induction of cell-mediated immunity offers the additional advantage of targeting virus infected cells. This study presents a novel formulation of a CMV vaccine that, by combining recombinant soluble gB protein with a Toll-like receptor 9 agonist (CpG ODN1826) and immune-stimulating complexes (AbISCO 100), was able to elicit strong polyfunctional CMV-specific cellular and cross-neutralizing humoral immune responses. These data demonstrated that prime-boost immunization of human leukocyte antigen (HLA)-A2 mice with gB protein in combination with CpG ODN1826 and AbISCO 100 induced long-lasting CMV-specific CD4(+) and CD8(+) T-cell and humoral responses. Furthermore, these responses neutralized infection with multiple strains of CMV expressing different gB genotypes and afforded protection against challenge with recombinant vaccinia virus encoding the gB protein. These observations argue that this novel vaccine strategy, if applied to humans, should facilitate the generation of a robust, pluripotent immune response, which may be more effective in preventing infection with multiple strains of CMV. PMID- 21307229 TI - Influence of the 5'-proximal elements of the 5'-untranslated region of classical swine fever virus on translation and replication. AB - The 5'-terminal sequence spanning nt 1-29 of the 5'-untranslated region of classical swine fever virus (CSFV) forms a 5'-proximal stem-loop structure known as domain Ia. Deletions and replacement mutations were performed to examine the role of this domain. Deletion of the 5'-proximal nucleotides and disruption of the stem-loop structure greatly increased internal ribosome entry site-mediated translation but abolished the replication of the replicons. Internal deletions resulting in a change in the size of the loop of domain Ia, and even removal of the entire domain, did not substantially change the translation activity, but reduced the replication of CSFV replicons provided the replicons contained the extreme 5'-GUAU terminal sequence. Internal replacements leading to a change in the nucleotide sequence of the loop did not alter the translation and replication activities of the CSFV RNA replicon, and did not influence the rescue of viruses and growth characteristics of new viruses. These results may be important for our understanding of the regulation of translation, replication and encapsidation in CSFV and other positive-sense RNA viruses. PMID- 21307230 TI - Corticotropin-releasing factor in the hippocampus: eustress or distress? PMID- 21307231 TI - Trigeminal nociceptive transmission in migraineurs predicts migraine attacks. AB - Several lines of evidence suggest a major role of the trigeminovascular system in the pathogenesis of migraine. Using functional magnetic resonance imaging (fMRI), we compared brain responses during trigeminal pain processing in migraine patients with those of healthy control subjects. The main finding is that the activity of the spinal trigeminal nuclei in response to nociceptive stimulation showed a cycling behavior over the migraine interval. Although interictal (i.e., outside of attack) migraine patients revealed lower activations in the spinal trigeminal nuclei compared with controls, preictal (i.e., shortly before attack) patients showed activity similar to controls, which demonstrates that the trigeminal activation level increases over the pain-free migraine interval. Remarkably, the distance to the next headache attack was predictable by the height of the signal intensities in the spinal nuclei. Migraine patients scanned during the acute spontaneous migraine attack showed significantly lower signal intensities in the trigeminal nuclei compared with controls, demonstrating activity levels similar to interictal patients. Additionally we found-for the first time using fMRI-that migraineurs showed a significant increase in activation of dorsal parts of the pons, previously coined "migraine generator." Unlike the dorsal pons activation usually linked to migraine attacks, the gradient-like activity following nociceptive stimulation in the spinal trigeminal neurons likely reflects a raise in susceptibility of the brain to generate the next attack, as these areas increase their activity long before headache starts. This oscillating behavior may be a key player in the generation of migraine headache, whereas attack-specific pons activations are most likely a secondary event. PMID- 21307232 TI - Direct corticospinal control of force derivative. AB - During simultaneous generation of static and dynamic forces, motor cortical signals only predict the dynamic components, suggesting a key role in the coding of force changes. However, such a role is obscured by uncertainties regarding the representation of dynamic force signals in corticospinal outputs. We used transcranial magnetic stimulation (TMS) of the motor cortex in humans during a task that dissociated the direction of instantaneous net force and that of force derivative. The direction of TMS-evoked force outputs was closely associated with that of the force derivative, and had no relationship with that of the net force generated simultaneously, even though the magnitude of the instantaneous net force largely exceeded that of the force derivative. This observation supports the hypothesis that during dynamic force generation, the motor cortex and the corticospinal system assume a pivotal role in coding the direction of force changes, through selective recruitment of spinal motoneurons. PMID- 21307233 TI - A circuit model for saccadic suppression in the superior colliculus. AB - Attenuation of visual activity in the superficial layers (SLs), stratum griseum superficiale and stratum opticum, of the superior colliculus during saccades may contribute to reducing perceptual blur during saccades and also may help prevent subsequent unwanted saccades. GABAergic neurons in the intermediate, premotor, layer (SGI), stratum griseum intermedium, send an inhibitory input to SL. This pathway provided the basis for a model proposing that the SGI premotor cells that project to brainstem gaze centers and discharge before saccades also activate neighboring GABAergic neurons that suppress saccade-induced visual activity in SL. The in vitro method allowed us to test this model. We made whole-cell patch clamp recordings in collicular slices from either rats or GAD67-GFP knock-in mice, in which GABAergic neurons could be identified by their expression of green fluorescence protein (GFP). Antidromic electrical stimulation of SGI premotor cells was produced by applying pulse currents in which their axons congregate after exiting the superior colliculus. The stimulation evoked monosynaptic EPSCs in SGI GABAergic neurons that project to SL, as would be predicted if these neurons receive excitatory input from the premotor cells. Second, IPSCs were evoked in SL neurons, some of which project to the visual thalamus. These IPSCs were polysynaptically mediated by the GABAergic neurons that were excited by the antidromically activated SGI neurons. These results support the hypothesis that collaterals of premotor neuron axons excite GABAergic neurons that inhibit SL visuosensory cells. PMID- 21307234 TI - Heparan sulfate sugar modifications mediate the functions of slits and other factors needed for mouse forebrain commissure development. AB - Heparan sulfate proteoglycans are cell surface and secretory proteins that modulate intercellular signaling pathways including Slit/Robo and FGF/FGFR. The heparan sulfate sugar moieties on HSPGs are subject to extensive postsynthetic modification, generating enormous molecular complexity that has been postulated to provide increased diversity in the ability of individual cells to respond to specific signaling molecules. This diversity could help explain how a relatively small number of axon guidance molecules are able to instruct the extremely complex connectivity of the mammalian brain. Consistent with this hypothesis, we previously showed that mutant mice lacking the heparan sulfotransferases (Hsts) Hs2st or Hs6st1 display major axon guidance defects at the developing optic chiasm. Here we further explore the role of these Hsts at the optic chiasm and investigate their function in corpus callosum development. Each Hst is expressed in a distinct pattern and each mutant displays a specific spectrum of axon guidance defects. Particular Hs2st(-/-) and Hs6st1(-/-) phenotypes closely match those of Slit1(-/-) and Slit2(-/-) embryos respectively, suggesting possible functional relationships. To test functional interactions between Hs2st or Hs6st1 and Slits we examined optic chiasm and corpus callosum phenotypes in a panel of genotypes where Hs2st or Hs6st1 and Slit1 or Slit2 function were simultaneously reduced or absent. We find examples of Hs2st and Hs6st1 having epistatic, synergistic, and antagonistic genetic relationships with Slit1 and/or Slit2 depending on the context. At the corpus callosum we find that Hs6st1 has Slit independent functions and our data indicate additional roles in FGF signaling. PMID- 21307235 TI - Infragranular sources of sustained local field potential responses in macaque primary visual cortex. AB - A local field potential (LFP) response can be measured throughout the visual cortex in response to the abrupt appearance of a visual stimulus. Averaging LFP responses to many stimulus presentations isolates transient, phase-locked components of the response that are consistent from trial to trial. However, stimulus responses are also composed of sustained components, which differ in their phase from trial to trial and therefore must be evaluated using other methods, such as computing the power of the response of each trial before averaging. Here, we investigate the basis of phase-locked and non-phase-locked LFP responses in the primary visual cortex of the macaque monkey using a novel variant of current source density (CSD) analysis. We applied a linear array of electrode contacts spanning the thickness of the cortex to measure the LFP and compute band-limited CSD power to identify the laminar sites of persistent current exchange that may be the basis of sustained visual LFP responses. In agreement with previous studies, we found a short-latency phase-locked current sink, thought to correspond to thalamocortical input to layer 4C. In addition, we found a prominent non-phase-locked component of the CSD that persisted as long as the stimulus was physically present. The latter was relatively broadband, lasted throughout the stimulus presentation, and was centered ~500 MUm deeper than the initial current sink. These findings demonstrate a fundamental difference in the neural mechanisms underlying the initial and sustained processing of simple visual stimuli in the V1 microcircuit. PMID- 21307236 TI - Control of breathing by raphe obscurus serotonergic neurons in mice. AB - We used optogenetics to determine the global respiratory effects produced by selectively stimulating raphe obscurus (RO) serotonergic neurons in anesthetized mice and to test whether these neurons detect changes in the partial pressure of CO(2), and hence function as central respiratory chemoreceptors. Channelrhodopsin 2 (ChR2) was selectively (~97%) incorporated into ~50% of RO serotonergic neurons by injecting AAV2 DIO ChR2-mCherry (adeno-associated viral vector double-floxed inverse open reading frame of ChR2-mCherry) into the RO of ePet-Cre mice. The transfected neurons heavily innervated lower brainstem and spinal cord regions involved in autonomic and somatic motor control plus breathing but eschewed sensory related regions. Pulsed laser photostimulation of ChR2-transfected serotonergic neurons increased respiratory frequency (fR) and diaphragmatic EMG (dEMG) amplitude in relation to the duration and frequency of the light pulses (half saturation, 1 ms; 5-10 Hz). dEMG amplitude and fR increased slowly (half saturation after 10-15 s) and relaxed monoexponentially (tau, 13-15 s). The breathing stimulation was reduced ~55% by methysergide (broad spectrum serotonin antagonist) and potentiated (~16%) at elevated levels of inspired CO(2) (8%). RO serotonergic neurons, identified by their entrainment to short light pulses (threshold, 0.1-1 ms) were silent (nine cells) or had a low and regular level of activity (2.1 +/- 0.4 Hz; 11 cells) that was not synchronized with respiration. These and nine surrounding neurons with similar characteristics were unaffected by adding up to 10% CO(2) to the breathing mixture. In conclusion, RO serotonergic neurons activate breathing frequency and amplitude and potentiate the central respiratory chemoreflex but do not appear to have a central respiratory chemoreceptor function. PMID- 21307237 TI - Activity-dependent regulation of surface glucose transporter-3. AB - Glucose transporter 3 (GLUT3) is the main facilitative glucose transporter in neurons. Glucose provides neurons with a critical energy source for neuronal activity. However, the mechanism by which neuronal activity controls glucose influx via GLUT3 is unknown. We investigated the influence of synaptic stimulation on GLUT3 surface expression and glucose import in primary cultured cortical and hippocampal neurons. Synaptic activity increased surface expression of GLUT3 leading to an elevation of intracellular glucose. The effect was blocked by NMDA receptor (NMDAR) and neuronal nitric oxide synthase (nNOS) inhibition. The Akt inhibitor I (Akt-I) blocked NMDAR-induced GLUT3 surface expression while a nNOS-phosphomimetic mutant (S1412D) enhanced GLUT3 expression at cell surface. These results suggest that NMDAR/Akt-dependent nNOS phosphorylation is coupled to GLUT3 trafficking. We demonstrated that activation of cGMP-dependent protein kinase (cGK) increased the surface expression of GLUT3, which was repressed by Rp 8-pCPT-cGMPS, a potent cell-permeable inhibitor of cGKs. These studies characterize the molecular basis for activity-dependent increases in surface GLUT3 after stimulation of the NMDARs. NMDAR-induced increase in surface GLUT3 represents a novel pathway for control of energy supply during neuronal activity that is critical for maintaining glucose homeostasis during neuronal transmission. PMID- 21307238 TI - Active zones and the readily releasable pool of synaptic vesicles at the neuromuscular junction of the mouse. AB - Synchronous neurotransmitter release is a highly regulated process that takes place at specializations at the presynaptic membrane called active zones (AZs). The relationships between AZs, quantal release, and vesicle replenishment are not well understood in a mature synapse. We have measured the number, distribution, and other properties of AZs in mouse motor nerve terminals and combined these observations with electrophysiological estimates of the size of the readily releasable pool (RRP) of synaptic vesicles. On average, we counted 850 AZs per terminal. Assuming two primary docked vesicles per AZ, we predict a total of ~1700 vesicles optimally positioned for exocytosis. Electrophysiological estimates of the size of the RRP, using a simple kinetic model that assumes exponential depletion of the initial pool and refilling by recruitment, gave an average value of 1730 quanta during 100 Hz stimulation, in satisfying agreement with the morphology. At lower stimulus frequencies, however, the model revealed that the estimated RRP size is smaller, suggesting that not all AZs participate in release at low stimulation frequencies. PMID- 21307239 TI - Actin polymerization is essential for myelin sheath fragmentation during Wallerian degeneration. AB - The mechanisms that trigger Wallerian degeneration (WD) of peripheral nerves after injury are not well understood. During the early period of WD, fragmentation of myelin into ovoid structures occurs near the Schmidt-Lantermann incisures (SLI), a noncompact region of the myelin sheath containing autotypical adherens junction. In this study, we found that new filamentous actin polymerization occurs in the SLI of mouse sciatic nerves after injury and that its inhibition prevented not only the degradation of E-cadherin in the SLI but also myelin ovoid formation. However, the inhibition of actin polymerization could not block Schwann cell dedifferentiation. The activation of Rac GTPase was observed in the distal stump of the injured nerves, and a specific Rac inhibitor, a dominant-negative Rac, and Rac1-RNA interference blocked myelin ovoid formation. Together, these findings suggest that dynamic changes in actin in the SLI are essential for initiation of demyelination after peripheral nerve injury. PMID- 21307240 TI - Orienting attention to an upcoming tactile event involves a spatially and temporally specific modulation of sensorimotor alpha- and beta-band oscillations. AB - Our perception is facilitated if we know where and when a sensory stimulus will occur. This phenomenon is accounted for by spatial and temporal orienting of attention. Whereas spatial orienting of attention has repeatedly been shown to involve spatially specific modulations of ongoing oscillations within sensory cortex, it is not clear to what extent anticipatory modulations of ongoing oscillations are involved in temporal orienting of attention. To address this, we recorded magnetoencephalography while human participants performed a tactile discrimination task. We cued participants to the left or the right hand, after which a tactile stimulus was presented at one of several fixed temporal delays. We thus assessed whether and how ongoing sensorimotor oscillations are modulated during tactile anticipation. We provide evidence for three phenomena. First, orienting to an upcoming tactile event involves a spatially specific contralateral suppression of alpha- and beta-band oscillations within sensorimotor cortex. Second, this modulation is deployed with temporal specificity, and this is more pronounced for beta-band compared with alpha-band oscillations. Third, the contralateral suppression of beta-band oscillations is associated with faster responses to subsequently presented tactile stimuli. Control measures showed that these results cannot be explained by motor planning or execution. We conclude that the modulation of ongoing oscillations within sensory cortex reflects a unifying mechanism underlying both spatial and temporal orienting of attention. PMID- 21307241 TI - A subtraction mechanism of temporal coding in cerebellar cortex. AB - The temporally specific learning displayed by the cerebellum facilitates mechanistic analysis of neural timing and temporal coding. We report evidence for a subtraction-like mechanism of temporal coding in cerebellar cortex in which activity in a subset of granule cells specifically codes the interval between the offset of two mossy fiber inputs. In a large-scale cerebellar simulation, cessation of one of two ongoing mossy fiber inputs produces a robust temporal code in the population of granule cells. This activity supports simulation learning in response to temporal patterns of stimuli, even when those same stimuli do not support learning when presented individually. Using stimulation of mossy fiber inputs to the cerebellum as training stimuli in rabbits, we confirmed these unusual predictions in a cerebellum-dependent form of learning. Analysis of the simulations reveals a specific working hypothesis for this temporal subtraction process that involves interactions between granule cells and the inhibitory Golgi cells. The results suggest how feedforward inhibition, such as that present in the cerebellar cortex, can contribute to temporal coding. PMID- 21307243 TI - Drosophila Acyl-CoA synthetase long-chain family member 4 regulates axonal transport of synaptic vesicles and is required for synaptic development and transmission. AB - Acyl-CoA synthetase long-chain family member 4 (ACSL4) converts long-chain fatty acids to acyl-CoAs that are indispensable for lipid metabolism and cell signaling. Mutations in ACSL4 cause nonsyndromic X-linked mental retardation. We previously demonstrated that Drosophila dAcsl is functionally homologous to human ACSL4, and is required for axonal targeting in the brain. Here, we report that Drosophila dAcsl mutants exhibited distally biased axonal aggregates that were immunopositive for the synaptic-vesicle proteins synaptotagmin (Syt) and cysteine string protein, the late endosome/lysosome marker lysosome-associated membrane protein 1, the autophagosomal marker Atg8, and the multivesicular body marker Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate). In contrast, the axonal distribution of mitochondria and the cell adhesion molecule Fas II (fasciclin II) was normal. Electron microscopy revealed accumulation of prelysomes and multivesicle bodies. These aggregates appear as retrograde instead of anterograde cargos. Live imaging analysis revealed that dAcsl mutations increased the velocity of anterograde transport but reduced the flux, velocity, and processivity of retrograde transport of Syt-enhanced green fluorescent protein-labeled vesicles. Immunohistochemical and electrophysiological analyses showed significantly reduced growth and stability of neuromuscular synapses, and impaired glutamatergic neurotransmission in dAcsl mutants. The axonal aggregates and synaptic defects in dAcsl mutants were fully rescued by neuronal expression of human ACSL4, supporting a functional conservation of ACSL4 across species in the nervous system. Together, our findings demonstrate that dAcsl regulates axonal transport of synaptic vesicles and is required for synaptic development and function. Defects in axonal transport and synaptic function may account, at least in part, for the pathogenesis of ACSL4-related mental retardation. PMID- 21307242 TI - alpha-Synuclein negatively regulates protein kinase Cdelta expression to suppress apoptosis in dopaminergic neurons by reducing p300 histone acetyltransferase activity. AB - We recently demonstrated that protein kinase Cdelta (PKCdelta), an important member of the novel PKC family, is a key oxidative stress-sensitive kinase that can be activated by caspase-3-dependent proteolytic cleavage to induce dopaminergic neuronal cell death. We now report a novel association between alpha synuclein (alphasyn), a protein associated with the pathogenesis of Parkinson's disease, and PKCdelta, in which alphasyn negatively modulates the p300- and nuclear factor-kappaB (NFkappaB)-dependent transactivation to downregulate proapoptotic kinase PKCdelta expression and thereby protects against apoptosis in dopaminergic neuronal cells. Stable expression of human wild-type alphasyn at physiological levels in dopaminergic neuronal cells resulted in an isoform dependent transcriptional suppression of PKCdelta expression without changes in the stability of mRNA and protein or DNA methylation. The reduction in PKCdelta transcription was mediated, in part, through the suppression of constitutive NFkappaB activity targeted at two proximal PKCdelta promoter kappaB sites. This occurred independently of NFkappaB/IkappaBalpha (inhibitor of kappaBalpha) nuclear translocation but was associated with decreased NFkappaB-p65 acetylation. Also, alphasyn reduced p300 levels and its HAT (histone acetyltransferase) activity, thereby contributing to diminished PKCdelta transactivation. Importantly, reduced PKCdelta and p300 expression also were observed within nigral dopaminergic neurons in alphasyn-transgenic mice. These findings expand the role of alphasyn in neuroprotection by modulating the expression of the key proapoptotic kinase PKCdelta in dopaminergic neurons. PMID- 21307244 TI - Visuotopic organization of macaque posterior parietal cortex: a functional magnetic resonance imaging study. AB - Macaque anatomy and physiology studies have revealed multiple visual areas in posterior parietal cortex (PPC). While many response properties of PPC neurons have been probed, little is known about PPC's large-scale functional topography specifically related to visuotopic organization. Using high-resolution functional magnetic resonance imaging at 3 T with a phase-encoded retinotopic mapping paradigm in the awake macaque, a large-scale visuotopic organization along lateral portions of PPC anterior to area V3a and extending into the lateral intraparietal sulcus (LIP) was found. We identify two new visual field maps anterior to V3a within caudal PPC, referred to as caudal intraparietal-1 (CIP-1) and CIP-2. The polar angle representation in CIP-1 extends from regions near the upper vertical meridian (that is the shared border with V3a and dorsal prelunate) to those within the lower visual field (that is the shared border with CIP-2). The polar angle representation in CIP-2 is a mirror reversal of the CIP-1 representation. CIP-1 and CIP-2 share a representation of central space on the lateral border. Anterior to CIP-2, a third polar angle representation was found within LIP, referred to as visuotopic LIP. The polar angle representation in LIP extends from regions near the upper vertical meridian (that is the shared border with CIP-2) to those near the lower vertical meridian. Representations of central visual space were identified within dorsal portions of LIP with peripheral representations in ventral portions. We also consider the topographic large-scale organization found within macaque PPC relative to that observed in human PPC. PMID- 21307245 TI - Region-specific involvement of BDNF secretion and synthesis in conditioned taste aversion memory formation. AB - Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase receptor B (TrkB), play a critical role in activity-dependent plasticity processes such as long-term potentiation, learning, and memory. It has been shown that BDNF exerts different or even opposite effects on behavior depending on the neural circuit. However, the detailed role of BDNF in memory process on the basis of its location has not been fully understood. Here, we aim to investigate the regional specific involvement of BDNF/TrkB in hippocampal-independent conditioned taste aversion (CTA) memory processes. We found region-specific changes in BDNF expression during CTA learning. CTA conditioning induced increased BDNF levels in the central nuclei of amygdala (CeA) and insular cortex, but not in the basolateral amygdala (BLA) and ventromedial prefrontal cortex. Interestingly, we found that the enhanced TrkB phosphorylation occurred at the time point before the increased BDNF expression, suggesting rapid induction of activity-dependent BDNF secretion by CTA learning. Moreover, targeted infusion of BDNF antibodies or BDNF antisense oligonucleotides revealed that activity-dependent BDNF secretion and synthesis in the CeA, but not the BLA, was respectively involved in the short and long-term memory formation of CTA. Finally, we found that infusion of exogenous BDNF into the CeA could enhance CTA learning. These data suggest that region-specific BDNF release and synthesis temporally regulate different CTA memory phases through activation of TrkB receptors. PMID- 21307246 TI - Nonuniform high-gamma (60-500 Hz) power changes dissociate cognitive task and anatomy in human cortex. AB - High-gamma-band (>60 Hz) power changes in cortical electrophysiology are a reliable indicator of focal, event-related cortical activity. Despite discoveries of oscillatory subthreshold and synchronous suprathreshold activity at the cellular level, there is an increasingly popular view that high-gamma-band amplitude changes recorded from cellular ensembles are the result of asynchronous firing activity that yields wideband and uniform power increases. Others have demonstrated independence of power changes in the low- and high-gamma bands, but to date, no studies have shown evidence of any such independence above 60 Hz. Based on nonuniformities in time-frequency analyses of electrocorticographic (ECoG) signals, we hypothesized that induced high-gamma-band (60-500 Hz) power changes are more heterogeneous than currently understood. Using single-word repetition tasks in six human subjects, we showed that functional responsiveness of different ECoG high-gamma sub-bands can discriminate cognitive task (e.g., hearing, reading, speaking) and cortical locations. Power changes in these sub bands of the high-gamma range are consistently present within single trials and have statistically different time courses within the trial structure. Moreover, when consolidated across all subjects within three task-relevant anatomic regions (sensorimotor, Broca's area, and superior temporal gyrus), these behavior- and location-dependent power changes evidenced nonuniform trends across the population. Together, the independence and nonuniformity of power changes across a broad range of frequencies suggest that a new approach to evaluating high-gamma band cortical activity is necessary. These findings show that in addition to time and location, frequency is another fundamental dimension of high-gamma dynamics. PMID- 21307247 TI - Extracellular spermine exacerbates ischemic neuronal injury through sensitization of ASIC1a channels to extracellular acidosis. AB - Ischemic brain injury is a major problem associated with stroke. It has been increasingly recognized that acid-sensing ion channels (ASICs) contribute significantly to ischemic neuronal damage, but the underlying mechanism has remained elusive. Here, we show that extracellular spermine, one of the endogenous polyamines, exacerbates ischemic neuronal injury through sensitization of ASIC1a channels to extracellular acidosis. Pharmacological blockade of ASIC1a or deletion of the ASIC1 gene greatly reduces the enhancing effect of spermine in ischemic neuronal damage both in cultures of dissociated neurons and in a mouse model of focal ischemia. Mechanistically, spermine profoundly reduces desensitization of ASIC1a by slowing down desensitization in the open state, shifting steady-state desensitization to more acidic pH, and accelerating recovery between repeated periods of acid stimulation. Spermine-mediated potentiation of ASIC1a activity is occluded by PcTX1 (psalmotoxin 1), a specific ASIC1a inhibitor binding to its extracellular domain. Functionally, the enhanced channel activity is accompanied by increased acid-induced neuronal membrane depolarization and cytoplasmic Ca(2+) overload, which may partially explain the exacerbated neuronal damage caused by spermine. More importantly, blocking endogenous spermine synthesis significantly attenuates ischemic brain injury mediated by ASIC1a but not that by NMDA receptors. Thus, extracellular spermine contributes significantly to ischemic neuronal injury through enhancing ASIC1a activity. Our data suggest new neuroprotective strategies for stroke patients via inhibition of polyamine synthesis and subsequent spermine-ASIC interaction. PMID- 21307248 TI - Spinal phosphinositide 3-kinase-Akt-mammalian target of rapamycin signaling cascades in inflammation-induced hyperalgesia. AB - Phosphinositide 3-kinase (PI3K), Akt, and their downstream kinase, mammalian target of rapamycin (mTOR), are implicated in neural plasticity. The functional linkages of this signaling cascade in spinal dorsal horn and their role in inflammatory hyperalgesia have not been elucidated. In the present work, we identified the following characteristics of this cascade. (1) Local inflammation led to increase in rat dorsal horn phosphorylation (activation) of Akt (pAkt) and mTOR (pmTOR), as assessed by Western blotting and immunocytochemistry. (2) Increased pAkt and pmTOR were prominent in neurons in laminae I, III, and IV, whereas pmTOR and its downstream targets (pS6, p4EBP) were also observed in glial cells. (3) Intrathecal treatment with inhibitors to PI3K or Akt attenuated Formalin-induced second-phase flinching behavior, as well as carrageenan-induced thermal hyperalgesia and tactile allodynia. (4) Intrathecal rapamycin (an mTORC1 inhibitor) displayed anti-hyperalgesic effect in both inflammatory pain models. Importantly, intrathecal wortmannin at anti-hyperalgesic doses reversed the evoked increase not only in Akt but also in mTORC1 signaling (pS6/p4EBP). (5) pAkt and pmTOR are expressed in neurokinin 1 receptor-positive neurons in laminae I-III after peripheral inflammation. Intrathecal injection of Substance P activated this cascade (increased phosphorylation) and resulted in hyperalgesia, both of which effects were blocked by intrathecal wortmannin and rapamycin. Together, these findings reveal that afferent inputs trigged by peripheral inflammation initiate spinal activation of PI3K-Akt-mTOR signaling pathway, a component of which participates in neuronal circuits of facilitated pain processing. PMID- 21307249 TI - Akt suppresses retrograde degeneration of dopaminergic axons by inhibition of macroautophagy. AB - Axon degeneration is a hallmark of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Such degeneration is not a passive event but rather an active process mediated by mechanisms that are distinct from the canonical pathways of programmed cell death that mediate destruction of the cell soma. Little is known of the diverse mechanisms involved, particularly those of retrograde axon degeneration. We have previously observed in living animal models of degeneration in the nigrostriatal projection that a constitutively active form of the kinase, myristoylated Akt (Myr-Akt), demonstrates an ability to suppress programmed cell death and preserve the soma of dopamine neurons. Here, we show in both neurotoxin and physical injury (axotomy) models that Myr Akt is also able to preserve dopaminergic axons due to suppression of acute retrograde axon degeneration. This cellular phenotype is associated with increased mammalian target of rapamycin (mTor) activity and can be recapitulated by a constitutively active form of the small GTPase Rheb, an upstream activator of mTor. Axon degeneration in these models is accompanied by the occurrence of macroautophagy, which is suppressed by Myr-Akt. Conditional deletion of the essential autophagy mediator Atg7 in adult mice also achieves striking axon protection in these acute models of retrograde degeneration. The protection afforded by both Myr-Akt and Atg7 deletion is robust and lasting, because it is still observed as protection of both axons and dopaminergic striatal innervation weeks after injury. We conclude that acute retrograde axon degeneration is regulated by Akt/Rheb/mTor signaling pathways. PMID- 21307250 TI - Cations but not anions regulate the responsiveness of kainate receptors. AB - Kainate-selective ionotropic glutamate receptors are unique among ligand-gated ion channels in their obligate requirement of external anions and cations for activation. Although it is established that the degree of kainate receptor (KAR) activation is shaped by the chemical nature of the agonist molecule, the possible complementary role of external ions has yet to be examined. Here we show that external cations but not anions regulate the responsiveness to a range of full and partial agonists acting on rat GluK2 receptors. This observation is unexpected as previous work has assumed anions and cations affect KARs in an identical manner through functionally coupled binding sites. However, our data demonstrate that anion- and cation-binding pockets behave discretely. We suggest cations uniquely regulate a pregating or flipping step that impacts the closed cleft stability of the agonist-binding domain (ABD). This model departs from a previous proposal that KAR agonist efficacy is governed by the degree of closure elicited in the ABD by ligand binding. Our findings are, however, in line with recent studies on Cys-loop ligand-gated ion channels suggesting that the "flipping" mechanism has been conserved by structurally diverse ligand-gated ion channel families as a common means of regulating neurotransmitter behavior. PMID- 21307251 TI - Fine spatial information represented in a population of retinal ganglion cells. AB - Detailed measurement of ganglion cell receptive fields often reveals significant deviations from a smooth, Gaussian profile. We studied the effect of these irregularities on the representation of fine spatial information in the retina. We recorded from nearby clusters of ganglion cells, testing their ability to determine the location of small flashed spots, and we compared the results to the prediction of a Gaussian receptive field model derived from reverse correlation. Despite considerable receptive field overlap, almost all ganglion cell pairs signaled nearly independently. For groups of five cells with highly overlapping receptive fields, the measured light-evoked currents encoded ~33% more information than predicted by the Gaussian receptive field model. Including measured local irregularities in the receptive field model increased performance to the level observed experimentally. These results suggest that instead of being an unavoidable defect, irregularities may be a positive design feature of population neural codes. PMID- 21307252 TI - Two layers of synaptic processing by principal neurons in piriform cortex. AB - The primary olfactory (or piriform) cortex is a trilaminar paleocortex that is thought to construct unified "odor images" from the odor components identified by the olfactory bulb. How the piriform cortex (PC) accomplishes this sophisticated synthetic task, despite its relatively simple architecture, is unknown. Here we used in vitro patch-clamp recordings from acute slices of the anterior PC of mice to identify microcircuits involved in excitatory synaptic processing. Cluster analysis confirmed the presence of two prominent classes of glutamatergic principal cells in the main input layer (layer II) of the PC: semilunar (SL) cells and superficial pyramidal (SP) cells. SL cells received stronger afferent excitatory input from the olfactory bulb, on average, than did SP cells. This was due to the larger mean strength of single-fiber afferents onto SL cells. In contrast, SP cells received stronger associational (intracortical) excitatory inputs, most likely due to their more extensive dendritic trees within the associational layers. Tissue-cut experiments and dual recordings from SL and SP cells in disinhibited slices were consistent with the distinctive patterns of connectivity of these two cell classes. Our findings suggest that the anterior PC employs at least two layers of excitatory synaptic processing: one involving strong afferent inputs onto SL cells, and another involving strong intracortical inputs onto SP cells. This architecture may allow the PC to sequentially process olfactory information within segregated subcircuits. PMID- 21307253 TI - The UNC5C netrin receptor regulates dorsal guidance of mouse hindbrain axons. AB - The cerebellum receives its input from multiple precerebellar nuclei located in the brainstem and sends processed information to other brain structures via the deep cerebellar neurons. Guidance molecules that regulate the complex migrations of precerebellar neurons and the initial guidance of their leading processes have been identified. However, the molecules necessary for dorsal guidance of precerebellar axons to the developing cerebellum or for guidance of decussating axons of the deep nuclei are not known. To determine whether Unc5c plays a role in the dorsal guidance of precerebellar and deep cerebellar axons, we studied axonal trajectories of these neurons in Unc5c(-/-) mice. Our results show that Unc5c is expressed broadly in the precerebellar and deep cerebellar neurons. Unc5c deletion disrupted long-range dorsal guidance of inferior olivary and pontine axons after crossing the midline. In addition, dorsal guidance of the axons from the medial deep cerebellar and external cuneate neurons was affected in Unc5c(-/-) mice, as were anterior migrations of pontine neurons. Coincident with the guidance defects of their axons, degeneration of neurons in the external cuneate nucleus and subdivisions of the inferior olivary nucleus was observed in Unc5c(-/-) mice. Lastly, transgenic expression of Unc5c in deep neurons and pontine neurons by the Atoh1 promoter rescued defects of the medial deep cerebellar and pontine axons observed in Unc5c(-/-) embryos, demonstrating that Unc5c acts cell autonomously in the guidance of these axons. Our results suggest that Unc5c plays a broad role in dorsal guidance of axons in the developing hindbrain. PMID- 21307254 TI - Lyn kinase regulates mesolimbic dopamine release: implication for alcohol reward. AB - We report here that the Src family tyrosine kinase Lyn negatively regulates the release of dopamine (DA) in the mesolimbic system, as well as the rewarding properties of alcohol. Specifically, we show that RNA interference-mediated knockdown of Lyn expression results in an increase in KCl-induced DA release in DAergic-like SH-SY5Y cells, whereas overexpression of a constitutively active form of Lyn (CA-Lyn) leads to a decrease of DA release. Activation of ventral tegmental area (VTA) DAergic neurons results in DA overflow in the nucleus accumbens (NAc), and we found that the evoked release of DA was higher in the NAc of Lyn knock-out (Lyn KO) mice compared with wild-type littermate (Lyn WT) controls. Acute exposure of rodents to alcohol causes a rapid increase in DA release in the NAc, and we show that overexpression of CA-Lyn in the VTA of mice blocked alcohol-induced (2 g/kg) DA release in the NAc. Increase in DA levels in the NAc is closely associated with reward-related behaviors, and overexpression of CA-Lyn in the VTA of mice led to an attenuation of alcohol reward, measured in a conditioned place preference paradigm. Conversely, alcohol place preference was increased in Lyn KO mice compared with Lyn WT controls. Together, our results suggest a novel role for Lyn kinase in the regulation of DA release in the mesolimbic system, which leads to the control of alcohol reward. PMID- 21307256 TI - Lesions of the basolateral amygdala and orbitofrontal cortex differentially affect acquisition and performance of a rodent gambling task. AB - Risky decision making on the Iowa Gambling Task (IGT) has been observed in several psychiatric disorders, including substance abuse, schizophrenia, and pathological gambling. Such deficits are often attributed to impaired processing within the orbitofrontal cortex (OFC) because patients with damage to this area or to the amygdala, which is strongly interconnected with the OFC, can likewise show enhanced choice of high-risk options. However, whether damage to the OFC or amygdala impairs subjects' ability to learn the task, or actually affects the decision-making process itself, is currently unclear. To address these issues, rats were trained to perform a rodent gambling task (rGT) either before or after bilateral excitotoxic lesions to the basolateral amygdala (BLA) or OFC. Maximum profits in both the rGT and IGT are obtained by favoring smaller rewards associated with lower penalties, and avoiding the tempting, yet ultimately disadvantageous, large reward options. Lesions of the OFC or BLA made before task acquisition initially impaired animals' ability to determine the optimal strategy, but did not disrupt decision making in the long term. In contrast, lesions of the BLA, but not the OFC, made after the task had been acquired increased risky choice. These results suggest that, although both regions contribute to the development of appropriate choice behavior under risk, the BLA maintains a more fundamental role in guiding these decisions. The maladaptive choice pattern observed on the IGT in patients with OFC lesions could therefore partially reflect a learning deficit, whereas amygdala damage may give rise to a more robust decision-making impairment. PMID- 21307255 TI - PICK1 loss of function occludes homeostatic synaptic scaling. AB - Homeostatic synaptic scaling calibrates neuronal excitability by adjusting synaptic strengths during prolonged changes in synaptic activity. The molecular mechanisms that regulate the trafficking of AMPA receptors (AMPARs) during synaptic scaling are largely unknown. Here, we show that chronic activity blockade reduces PICK1 protein level on a time scale that coincides with the accumulation of surface AMPARs. PICK1 loss of function alters the subunit composition and the abundance of GluA2-containing AMPARs. Due to aberrant trafficking of these receptors, the increase in synaptic strength in response to synaptic inactivity is occluded in neurons generated from PICK1 knock-out mouse. In agreement with electrophysiological recordings, no defect of AMPAR trafficking is observed in PICK1 knock-out neurons in response to elevated neuronal activity. Overall, our data reveal an important role of PICK1 in inactivity-induced synaptic scaling by regulating the subunit composition, abundance, and trafficking of GluA2-containing AMPARs. PMID- 21307257 TI - Fragile X mental retardation protein regulates new neuron differentiation in the adult olfactory bulb. AB - The fragile X mental retardation protein (FMRP) is an RNA-binding protein essential for multiple aspects of neuronal mRNA metabolism. Its absence leads to the fragile X syndrome, the most prevalent genetic form of mental retardation. The anatomical landmark of the disease, also present in the Fmr1 knock-out (KO) mice, is the hyperabundance of immature-looking lengthened dendritic spines. We used the well known continuous production of adult-born granule cells (GCs) in the mouse olfactory bulb (OB) to analyze the consequences of Fmrp loss on the differentiation of GCs. Morphological analysis of GCs in the Fmr1 KO mice showed an increase in spine density without a change in spine length. We developed an RNA interference strategy to cell-autonomously mutate Fmr1 in a wild-type OB network. Mutated GCs displayed an increase in spine density and spine length. Detailed analysis of the spines through immunohistochemistry, electron microscopy, and electrophysiology surprisingly showed that, despite these abnormalities, spines receive normal glutamatergic synapses, and thus that mutated adult-born neurons are synaptically integrated into the OB circuitry. Time-course analysis of the spine defects showed that Fmrp cell-autonomously downregulates the level and rate of spine production and limits their overgrowth. Finally, we report that Fmrp does not regulate dendritogenesis in standard conditions but is necessary for activity-dependent dendritic remodeling. Overall, our study of Fmrp in the context of adult neurogenesis has enabled us to carry out a precise dissection of the role of Fmrp in neuronal differentiation and underscores its pleiotropic involvement in both spinogenesis and dendritogenesis. PMID- 21307258 TI - The Caenorhabditis elegans JIP3 protein UNC-16 functions as an adaptor to link kinesin-1 with cytoplasmic dynein. AB - Kinesin-1 is a microtubule plus-end-directed motor that transports various cargos along the axon. Previous studies have elucidated the physical and genetic interactions between kinesin-1 and cytoplasmic dynein, a microtubule minus-end directed motor, in neuronal cells. However, the physiological importance of kinesin-1 in the dynein-dependent retrograde transport of cargo molecules remains obscure. Here, we show that Caenorhabditis elegans kinesin-1 forms a complex with dynein via its interaction with UNC-16, which binds to the dynein light intermediate (DLI) chain. Both kinesin-1 and UNC-16 are required for localization of DLI-1 at the plus ends of nerve process microtubules. In addition, retrograde transport of APL-1 depends on kinesin-1, UNC-16, and dynein. These results suggest that kinesin-1 mediates the anterograde transport of dynein using UNC-16 as a scaffold and that dynein in turn mediates the retrograde transport of cargo molecules in vivo. Thus, UNC-16 functions as an adaptor for kinesin-1-mediated transport of dynein. PMID- 21307259 TI - LRRK2 controls synaptic vesicle storage and mobilization within the recycling pool. AB - Mutations in leucine-rich repeat kinase 2 (LRRK2) are the single most common cause of inherited Parkinson's disease. Little is known about its involvement in the pathogenesis of Parkinson's disease mainly because of the lack of knowledge about the physiological role of LRRK2. To determine the function of LRRK2, we studied the impact of short hairpin RNA-mediated silencing of LRRK2 expression in cortical neurons. Paired recording indicated that LRRK2 silencing affects evoked postsynaptic currents. Furthermore, LRRK2 silencing induces at the presynaptic site a redistribution of vesicles within the bouton, altered recycling dynamics, and increased vesicle kinetics. Accordingly, LRRK2 protein is present in the synaptosomal compartment of cortical neurons in which it interacts with several proteins involved in vesicular recycling. Our results suggest that LRRK2 modulates synaptic vesicle trafficking and distribution in neurons and in consequence participates in regulating the dynamics between vesicle pools inside the presynaptic bouton. PMID- 21307260 TI - Polarization-sensitive descending neurons in the locust: connecting the brain to thoracic ganglia. AB - Many animal species, in particular insects, exploit the E-vector pattern of the blue sky for sun compass navigation. Like other insects, locusts detect dorsal polarized light via photoreceptors in a specialized dorsal rim area of the compound eye. Polarized light information is transmitted through several processing stages to the central complex, a brain area involved in the control of goal-directed orientation behavior. To investigate how polarized light information is transmitted to thoracic motor circuits, we studied the responses of locust descending neurons to polarized light. Three sets of polarization sensitive descending neurons were characterized through intracellular recordings from axonal fibers in the neck connectives combined with single-cell dye injections. Two descending neurons from the brain, one with ipsilaterally and the second with contralaterally descending axon, are likely to bridge the gap between polarization-sensitive neurons in the brain and thoracic motor centers. In both neurons, E-vector tuning changed linearly with daytime, suggesting that they signal time-compensated spatial directions, an important prerequisite for navigation using celestial signals. The third type connects the suboesophageal ganglion with the prothoracic ganglion. It showed no evidence for time compensation in E-vector tuning and might play a role in flight stabilization and control of head movements. PMID- 21307261 TI - Membrane penetration by synaptotagmin is required for coupling calcium binding to vesicle fusion in vivo. AB - The vesicle protein synaptotagmin I is the Ca(2+) sensor that triggers fast, synchronous release of neurotransmitter. Specifically, Ca(2+) binding by the C(2)B domain of synaptotagmin is required at intact synapses, yet the mechanism whereby Ca(2+) binding results in vesicle fusion remains controversial. Ca(2+) dependent interactions between synaptotagmin and SNARE (soluble N-ethylmaleimide sensitive fusion protein attachment receptor) complexes and/or anionic membranes are possible effector interactions. However, no effector-interaction mutations to date impact synaptic transmission as severely as mutation of the C(2)B Ca(2+) binding motif, suggesting that these interactions are facilitatory rather than essential. Here we use Drosophila to show the functional role of a highly conserved, hydrophobic residue located at the tip of each of the two Ca(2+) binding pockets of synaptotagmin. Mutation of this residue in the C(2)A domain (F286) resulted in a ~50% decrease in evoked transmitter release at an intact synapse, again indicative of a facilitatory role. Mutation of this hydrophobic residue in the C(2)B domain (I420), on the other hand, blocked all locomotion, was embryonic lethal even in syt I heterozygotes, and resulted in less evoked transmitter release than that in syt(null) mutants, which is more severe than the phenotype of C(2)B Ca(2+)-binding mutants. Thus, mutation of a single, C(2)B hydrophobic residue required for Ca(2+)-dependent penetration of anionic membranes results in the most severe disruption of synaptotagmin function in vivo to date. Our results provide direct support for the hypothesis that plasma membrane penetration, specifically by the C(2)B domain of synaptotagmin, is the critical effector interaction for coupling Ca(2+) binding with vesicle fusion. PMID- 21307262 TI - Role of extracellular signal-regulated kinase in synaptic transmission and plasticity of a nociceptive input on capsular central amygdaloid neurons in normal and acid-induced muscle pain mice. AB - Application of phorbol 12,13-diacetate (PDA) caused marked enhancement of synaptic transmission of nociceptive parabrachio-amygdaloid (PBA) input onto neurons of the capsular central amygdaloid (CeAC) nucleus. The potentiation of PBA-CeAC EPSCs by PDA involved a presynaptic protein kinase C (PKC)-dependent component and a postsynaptic PKC-extracellular-regulated kinase (ERK)-dependent component. NMDA glutamatergic receptor (NMDAR)-dependent long-term potentiation (LTP) of PBA-CeAC EPSCs, which was also dependent on the PKC-ERK signaling pathway, was induced by tetanus stimulation at 100 Hz. In slices from mice subjected to acid-induced muscle pain (AIMP), phosphorylated ERK levels in the CeAC increased, and PBA-CeAC synaptic transmission was postsynaptically enhanced. The enhanced PBA-CeAC synaptic transmission in AIMP mice shared common mechanisms with the postsynaptic potentiation effect of PDA and induction of NMDAR-dependent LTP by high-frequency stimulation in normal slices, both of which required ERK activation. Since the CeAC plays an important role in the emotionality of pain, enhanced synaptic function of nociceptive (PBA) inputs onto CeAC neurons might partially account for the supraspinal mechanisms underlying central sensitization. PMID- 21307263 TI - Dual encoding of muscle tension and eye position by abducens motoneurons. AB - Extraocular muscle tension associated with spontaneous eye movements has a pulse slide-step profile similar to that of motoneuron firing rate. Existing models only relate motoneuron firing to eye position, velocity and acceleration. We measured and quantitatively compared lateral rectus muscle force and eye position with the firing of abducens motoneurons in the cat to determine fundamental encoding correlations. During fixations (step), muscle force increased exponentially with eccentric eye position, consistent with a model of estimate ensemble motor innervation based on neuronal sensitivities and recruitment order. Moreover, firing rate in all motoneurons tested was better related to eye position than to muscle tension during fixations. In contrast, during the postsaccadic slide phase, the time constant of firing rate decay was closely related to that of muscle force decay, suggesting that all motoneurons encode muscle tension as well. Discharge characteristics of abducens motoneurons formed overlapping clusters of phasic and tonic motoneurons, thus, tonic units recruited earlier and had a larger slide signal. We conclude that the slide signal is a discharge characteristic of the motoneuron that controls muscle tension during the postsaccadic phase and that motoneurons are specialized for both tension and position-related properties. The organization of signal content in the pool of abducens motoneurons from the very phasic to the very tonic units is possibly a result of the differential trophic background received from distinct types of muscle fibers. PMID- 21307264 TI - Network oscillations in rod-degenerated mouse retinas. AB - In the mammalian retina, excitatory and inhibitory circuitries enable retinal ganglion cells (RGCs) to signal the occurrence of visual features to higher brain areas. This functionality disappears in certain diseases of retinal degeneration because of the progressive loss of photoreceptors. Recent work in a mouse model of retinal degeneration (rd1) found that, although some intraretinal circuitry is preserved and RGCs maintain characteristic physiological properties, they exhibit increased and aberrant rhythmic activity. Here, extracellular recordings were made to assess the degree of aberrant activity in adult rd1 retinas and to investigate the mechanism underlying such behavior. A multi-transistor array with thousands of densely packed sensors allowed for simultaneous recordings of spiking activity in populations of RGCs and of local field potentials (LFPs). The majority of identified RGCs displayed rhythmic (7-10 Hz) but asynchronous activity. The spiking activity correlated with the LFPs, which reflect an average synchronized excitatory input to the RGCs. LFPs initiated from random positions and propagated across the retina. They disappeared when ionotrophic glutamate receptors or electrical synapses were blocked. They persisted in the presence of other pharmacological blockers, including TTX and inhibitory receptor antagonists. Our results suggest that excitation-transmitted laterally through a network of electrically coupled interneurons-leads to large-scale retinal network oscillations, reflected in the rhythmic spiking of most rd1 RGCs. This result may explain forms of photopsias reported by blind patients, while the mechanism involved should be considered in future treatment strategies targeting the disease of retinitis pigmentosa. PMID- 21307265 TI - p75NTR regulates Abeta deposition by increasing Abeta production but inhibiting Abeta aggregation with its extracellular domain. AB - Accumulation of toxic amyloid-beta (Abeta) in the cerebral cortex and hippocampus is a major pathological feature of Alzheimer's disease (AD). The neurotrophin receptor p75NTR has been proposed to mediate Abeta-induced neurotoxicity; however, its role in the development of AD remains to be clarified. The p75NTR/ExonIII-/- mice and APPSwe/PS1dE9 mice were crossed to generate transgenic AD mice with deletion of p75NTR gene. In APPSwe/PS1dE9 transgenic mice, p75NTR expression was localized in the basal forebrain neurons and degenerative neurites in neocortex, increased with aging, and further activated by Abeta accumulation. Deletion of the p75NTR gene in APPSwe/PS1dE9 mice reduced soluble Abeta levels in the brain and serum, but increased the accumulation of insoluble Abeta and Abeta plaque formation. There was no change in the levels of amyloid precursor protein (APP) and its proteolytic derivatives, or alpha-, beta-, and gamma-secretase activities, or in levels of BACE1, neprilysin (NEP), and insulin-degrading enzyme (IDE) proteins. Abeta production by cortical neurons of APPSwe/PS1dE9 mice was reduced by deletion of p75NTR gene in vitro. Recombinant extracellular domain of p75NTR attenuated the oligomerization and fibrillation of synthetic Abeta(42) peptide in vitro, and reduced local Abeta plaques after hippocampus injection in vivo. In addition, deletion of p75NTR attenuated microgliosis but increased the microhemorrhage profiles in the brain. The deletion of p75NTR did not significantly change the cognitive function of the mice up to the age of 9 months. Our data suggest that p75NTR plays a critical role in regulating Abeta levels by both increasing Abeta production and attenuating its aggregation, and they caution that a therapeutic intervention simply reducing p75NTR may exacerbate AD pathology. PMID- 21307266 TI - Cerebellar plasticity and the automation of first-order rules. AB - Theories of corticocerebellar function propose roles for the cerebellum in automating motor control, a process thought to depend on plasticity in cerebellar circuits that exchange information with the motor cortex. Little is known, however, about automating behaviors beyond the motor domain. The present study tested the hypothesis that cerebellar plasticity also subserves the development of automaticity in behavior based on low-order rules. Human subjects were required to learn two sets of first-order rules in which visual stimuli of different shapes each arbitrarily instructed a particular finger movement. We used event-related functional magnetic resonance imaging to scan subjects while these response rules became increasingly automatic with practice, as assessed with a dual-task procedure. We found that the amplitude of the blood oxygenation level-dependent signal gradually decreased as a function of practice, as responses became increasingly automatic, and that this effect was greater for a set of rules that became automatic rapidly compared with a second set, which became automatic more slowly. These trial-by-trial activity changes occurred in Crus I of cerebellar cortical lobule HVIIA, in which neurons exchange information with the prefrontal cortex rather than the motor cortex. Activity in Crus I was time locked specifically to the processing of these rules, rather than to subsequent actions. The results support the hypothesis that decreases in cerebellar cortical activity underlie the automation of behavior, whether related to motor control and motor cortex or to response rules and prefrontal cortex. PMID- 21307267 TI - Inhibition of amyloid-beta (Abeta) peptide-binding alcohol dehydrogenase-Abeta interaction reduces Abeta accumulation and improves mitochondrial function in a mouse model of Alzheimer's disease. AB - Amyloid-beta (Abeta) peptide-binding alcohol dehydrogenase (ABAD), an enzyme present in neuronal mitochondria, exacerbates Abeta-induced cell stress. The interaction of ABAD with Abeta exacerbates Abeta-induced mitochondrial and neuronal dysfunction. Here, we show that inhibition of the ABAD-Abeta interaction, using a decoy peptide (DP) in vitro and in vivo, protects against aberrant mitochondrial and neuronal function and improves spatial learning/memory. Intraperitoneal administration of ABAD-DP [fused to the transduction of human immunodeficiency virus 1-transactivator (Tat) protein and linked to the mitochondrial targeting sequence (Mito) (TAT-mito-DP) to transgenic APP mice (Tg mAPP)] blocked formation of ABAD-Abeta complex in mitochondria, increased oxygen consumption and enzyme activity associated with the mitochondrial respiratory chain, attenuated mitochondrial oxidative stress, and improved spatial memory. Similar protective effects were observed in Tg mAPP mice overexpressing neuronal ABAD decoy peptide (Tg mAPP/mito-ABAD). Notably, inhibition of the ABAD-Abeta interaction significantly reduced mitochondrial Abeta accumulation. In parallel, the activity of mitochondrial Abeta-degrading enzyme PreP (presequence peptidase) was enhanced in Tg mAPP mitochondria expressing the ABAD decoy peptide. These data indicate that segregating ABAD from Abeta protects mitochondria/neurons from Abeta toxicity; thus, ABAD-Abeta interaction is an important mechanism underlying Abeta-mediated mitochondrial and neuronal perturbation. Inhibitors of ABAD-Abeta interaction may hold promise as targets for the prevention and treatment of Alzheimer's disease. PMID- 21307268 TI - Spike-train communities: finding groups of similar spike trains. AB - Identifying similar spike-train patterns is a key element in understanding neural coding and computation. For single neurons, similar spike patterns evoked by stimuli are evidence of common coding. Across multiple neurons, similar spike trains indicate potential cell assemblies. As recording technology advances, so does the urgent need for grouping methods to make sense of large-scale datasets of spike trains. Existing methods require specifying the number of groups in advance, limiting their use in exploratory analyses. I derive a new method from network theory that solves this key difficulty: it self-determines the maximum number of groups in any set of spike trains, and groups them to maximize intragroup similarity. This method brings us revealing new insights into the encoding of aversive stimuli by dopaminergic neurons, and the organization of spontaneous neural activity in cortex. I show that the characteristic pause response of a rat's dopaminergic neuron depends on the state of the superior colliculus: when it is inactive, aversive stimuli invoke a single pattern of dopaminergic neuron spiking; when active, multiple patterns occur, yet the spike timing in each is reliable. In spontaneous multineuron activity from the cortex of anesthetized cat, I show the existence of neural ensembles that evolve in membership and characteristic timescale of organization during global slow oscillations. I validate these findings by showing that the method both is remarkably reliable at detecting known groups and can detect large-scale organization of dynamics in a model of the striatum. PMID- 21307269 TI - Rapamycin suppresses mossy fiber sprouting but not seizure frequency in a mouse model of temporal lobe epilepsy. AB - Temporal lobe epilepsy is prevalent and can be difficult to treat effectively. Granule cell axon (mossy fiber) sprouting is a common neuropathological finding in patients with mesial temporal lobe epilepsy, but its role in epileptogenesis is unclear and controversial. Focally infused or systemic rapamycin inhibits the mammalian target of rapamycin (mTOR) signaling pathway and suppresses mossy fiber sprouting in rats. We tested whether long-term systemic treatment with rapamycin, beginning 1 d after pilocarpine-induced status epilepticus in mice, would suppress mossy fiber sprouting and affect the development of spontaneous seizures. Mice that had experienced status epilepticus and were treated for 2 months with rapamycin displayed significantly less mossy fiber sprouting (42% of vehicle-treated animals), and the effect was dose dependent. However, behavioral and video/EEG monitoring revealed that rapamycin- and vehicle-treated mice displayed spontaneous seizures at similar frequencies. These findings suggest mossy fiber sprouting is neither pro- nor anti-convulsant; however, there are caveats. Rapamycin treatment also reduced epilepsy-related hypertrophy of the dentate gyrus but did not significantly affect granule cell proliferation, hilar neuron loss, or generation of ectopic granule cells. These findings are consistent with the hypotheses that hilar neuron loss and ectopic granule cells might contribute to temporal lobe epileptogenesis. PMID- 21307270 TI - Adjudin, a potential male contraceptive, exerts its effects locally in the seminiferous epithelium of mammalian testes. AB - Adjudin is a derivative of 1H-indazole-3-carboxylic acid that was shown to have potent anti-spermatogenic activity in rats, rabbits, and dogs. It exerts its effects most notably locally in the apical compartment of the seminiferous epithelium, behind the blood-testis barrier, by disrupting adhesion of germ cells, most notably spermatids to the Sertoli cells, thereby inducing release of immature spermatids from the epithelium that leads to infertility. After adjudin is metabolized, the remaining spermatogonial stem cells and spermatogonia repopulate the seminiferous epithelium gradually via spermatogonial self-renewal and differentiation, to be followed by meiosis and spermiogenesis, and thus fertility rebounds. Recent studies in rats have demonstrated unequivocally that the primary and initial cellular target of adjudin in the testis is the apical ectoplasmic specialization, a testis-specific anchoring junction type restricted to the interface between Sertoli cells and elongating spermatids (from step 8 to 19 spermatids). In this review, we highlight some of the recent advances and obstacles regarding the possible use of adjudin as a male contraceptive. PMID- 21307271 TI - Sperm competition leads to functional adaptations in avian testes to maximize sperm quantity and quality. AB - The outcome of sperm competition (i.e. competition for fertilization between ejaculates from different males) is primarily determined by the relative number and quality of rival sperm. Therefore, the testes are under strong selection to maximize both sperm number and quality, which are likely to result in trade-offs in the process of spermatogenesis (e.g. between the rate of spermatogenesis and sperm length or sperm energetics). Comparative studies have shown positive associations between the level of sperm competition and both relative testis size and the proportion of seminiferous (sperm-producing) tissue within the testes. However, it is unknown how the seminiferous tissue itself or the process of spermatogenesis might evolve in response to sperm competition. Therefore, we quantified the different germ cell types and Sertoli cells (SC) in testes to assess the efficiency of sperm production and its associations with sperm length and mating system across 10 species of New World Blackbirds (Icteridae) that show marked variation in sperm length and sperm competition level. We found that species under strong sperm competition generate more round spermatids (RS)/spermatogonium and have SC that support a greater number of germ cells, both of which are likely to increase the maximum sperm output. However, fewer of the RS appeared to elongate to mature spermatozoa in these species, which might be the result of selection for discarding spermatids with undesirable characteristics as they develop. Our results suggest that, in addition to overall size and gross morphology, testes have also evolved functional adaptations to maximize sperm quantity and quality. PMID- 21307272 TI - Reduced signaling through the hedgehog pathway in the uterine stroma causes deferred implantation and embryonic loss. AB - The role of the hedgehog (HH) signaling pathway in implantation was studied in mice in which the HH signal transducer, smoothened (SMO), was conditionally deleted in the stromal compartment of the uterus, using CRE recombinase expressed through the Amhr2(cre) allele. In Amhr2(cre/+)Smo(null/flox)-mutant mice, Smo mRNA in uterine stroma was reduced 49% compared to that in Amhr2(+/+)Smo(null/flox) control mice, while levels in the luminal epithelium were not different. Litter size was reduced 60% in mutants compared with controls, but ovulation rate and the number of implantation sites on day 7 of pregnancy did not differ. The number of corpora lutea was equivalent to the number of implantation sites, indicating that most ovulations resulted in implanted embryos. However, on days 13 to 15, the rate of embryo resorption was elevated in mutants. In control mice, on day 5, implantation sites were present and blastocysts were well-attached. In contrast, blastocysts were readily flushed from uteri of mutant mice on day 5 and implantation sites were rare. On days 5.5 and 6, implantation sites were present in mutant mice, and by day 6 embryos could not be flushed from the uterus. The weight of implantation sites on day 7 was decreased by 42% in mutant mice, consistent with delayed development. Signaling through SMO in the endometrial stroma is required for optimal timing of implantation, and deferred implantation leads to defective embryo development and subsequent pregnancy loss. PMID- 21307274 TI - A bad taste in the mouth: gustatory disgust influences moral judgment. AB - Can sweet-tasting substances trigger kind, favorable judgments about other people? What about substances that are disgusting and bitter? Various studies have linked physical disgust to moral disgust, but despite the rich and sometimes striking findings these studies have yielded, no research has explored morality in conjunction with taste, which can vary greatly and may differentially affect cognition. The research reported here tested the effects of taste perception on moral judgments. After consuming a sweet beverage, a bitter beverage, or water, participants rated a variety of moral transgressions. Results showed that taste perception significantly affected moral judgments, such that physical disgust (induced via a bitter taste) elicited feelings of moral disgust. Further, this effect was more pronounced in participants with politically conservative views than in participants with politically liberal views. Taken together, these differential findings suggest that embodied gustatory experiences may affect moral processing more than previously thought. PMID- 21307273 TI - When does feeling of fluency matter?: how abstract and concrete thinking influence fluency effects. AB - It has been widely documented that fluency (ease of information processing) increases positive evaluation. We proposed and demonstrated in three studies that this was not the case when people construed objects abstractly rather than concretely. Specifically, we found that priming people to think abstractly mitigated the effect of fluency on subsequent evaluative judgments (Studies 1 and 2). However, when feelings such as fluency were understood to be signals of value, fluency increased liking in people primed to think abstractly (Study 3). These results suggest that abstract thinking helps distinguish central decision inputs from less important incidental inputs, whereas concrete thinking does not make such a distinction. Thus, abstract thinking can augment or attenuate fluency effects, depending on whether fluency is considered important or incidental information, respectively. PMID- 21307275 TI - Neem leaf glycoprotein partially rectifies suppressed dendritic cell functions and associated T cell efficacy in patients with stage IIIB cervical cancer. AB - Myeloid-derived dendritic cells (DCs) generated from monocytes obtained from stage IIIB cervical cancer (CaCx IIIB) patients show dysfunctional maturation; thus, antitumor T cell functions are dysregulated. In an objective to optimize these dysregulated immune functions, the present study is focused on the ability of neem leaf glycoprotein (NLGP), a nontoxic preparation of the neem leaf, to induce optimum maturation of dendritic cells from CaCx IIIB patients. In vitro NLGP treatment of immature DCs (iDCs) obtained from CaCx IIIB patients results in upregulated expression of various cell surface markers (CD40, CD83, CD80, CD86, and HLA-ABC), which indicates DC maturation. Consequently, NLGP-matured DCs displayed balanced cytokine secretions, with type 1 bias and noteworthy functional properties. These DCs displayed substantial T cell allostimulatory capacity and promoted the generation of cytotoxic T lymphocytes (CTLs). Although NLGP-matured DCs derived from CaCx monocytes are generally subdued compared to those with a healthy monocyte origin, considerable revival of the suppressed DC based immune functions is noted in vitro at a fairly advanced stage of CaCx, and thus, further exploration of ex vivo and in vivo DC-based vaccines is proposed. Moreover, the DC maturating efficacy of NLGP might be much more effective in the earlier stages of CaCx, where the extent of immune dysregulation is less and, thus, the scope of further investigation may be explored. PMID- 21307276 TI - Needleless vaccine delivery using micro-shock waves. AB - Shock waves are one of the most efficient mechanisms of energy dissipation observed in nature. In this study, utilizing the instantaneous mechanical impulse generated behind a micro-shock wave during a controlled explosion, a novel nonintrusive needleless vaccine delivery system has been developed. It is well known that antigens in the epidermis are efficiently presented by resident Langerhans cells, eliciting the requisite immune response, making them a good target for vaccine delivery. Unfortunately, needle-free devices for epidermal delivery have inherent problems from the perspective of the safety and comfort of the patient. The penetration depth of less than 100 MUm in the skin can elicit higher immune response without any pain. Here we show the efficient utilization of our needleless device (that uses micro-shock waves) for vaccination. The production of liquid jet was confirmed by high-speed microscopy, and the penetration in acrylamide gel and mouse skin was observed by confocal microscopy. Salmonella enterica serovar Typhimurium vaccine strain pmrG-HM-D (DV-STM-07) was delivered using our device in the murine salmonellosis model, and the effectiveness of the delivery system for vaccination was compared with other routes of vaccination. Vaccination using our device elicits better protection and an IgG response even at a lower vaccine dose (10-fold less) compared to other routes of vaccination. We anticipate that our novel method can be utilized for effective, cheap, and safe vaccination in the near future. PMID- 21307277 TI - Comparison of Western immunobloting to an enzyme-linked immunosorbent assay for the determination of anti-Bordetella pertussis antibodies. AB - During Bordetella pertussis infection, it has been established that an increase of anti-pertussis toxin (PT) and anti-filamentous hemagglutinin (FHA) antibodies occurs. Immunoblots from two manufacturers using FHA and PT antigens were compared with an enzyme-linked immunosorbent assay (ELISA) that used both FHA and PT. One manufacturer used two concentrations of PT bands for the IgG immunoblot, calibrated to the World Health Organization standard for PT in international units (IU/ml), 100 IU/ml (PT-100) and 8 IU/ml (PT). The second immunoblot kit measured antibodies to a single calibrated PT band. Both kits measured IgA antibodies, and one additionally measured IgM antibodies. Two of 41 (5%) ELISA IgM positives were confirmed positive by IgM immunoblotting, suggesting poor specificity of the IgM ELISA. The agreements of the IgG and IgA immunoblots with the ELISA ranged from 72.5% to 85.3%, with only 38 to 51% of IgA positives confirmed by immunoblotting and only 61 to 68% of IgG positives confirmed by immunoblotting. The two immunoblots correlated well with each other, with 91.7% and 94.3% agreement for IgG and IgA, respectively. When the FHA band was used with the PT band as the criterion for positivity, significant differences existed in specificity compared to the ELISA (IgG, 84.1% versus 33.3%; IgA, 82.4% versus 71.0%). When the positive IgA immunoblots (evidence of natural recent infection) were compared to the positive PT-100 IgG immunoblots (evidence of recent infection or vaccination), the PT-100 blot showed a 71% sensitivity in detecting natural recent infection. B. pertussis immunoblots, alone or in combination with ELISAs, can aid in the diagnosis of B. pertussis infection. PMID- 21307278 TI - Histoplasma antigen clearance during treatment of histoplasmosis in patients with AIDS determined by a quantitative antigen enzyme immunoassay. AB - Clearance of Histoplasma antigen has been used as a marker for response to treatment of progressive disseminated histoplasmosis (PDH) in patients with AIDS. Advancements in Histoplasma antigen detection permit accurate quantification of antigen concentration. We compared the clearance of antigenemia and antigenuria during effective treatment of PDH. Urine and serum specimens were serially collected from patients with AIDS who were successfully treated for PDH as part of two prospective clinical trials. Samples were stored frozen until they were tested in the quantitative Histoplasma antigen enzyme immunoassay. The kinetics of antigen clearance during the first 12 weeks of therapy were assessed in urine and serum during treatment with liposomal or deoxycholate amphotericin B followed by itraconazole and, in a separate analysis, in patients receiving only itraconazole. Latent class growth analysis was performed to define patterns of antigen clearance over time. In patients receiving amphotericin B, antigen levels declined the most during the first 2 weeks of treatment and antigenemia decreased more rapidly than antigenuria (5.90 ng/ml per week versus 4.21 ng/ml per week, respectively; P = 0.09). Mean reductions of antigen levels from baseline at weeks 2 and 12 were greater in sera than in urine: 11.26 ng/ml versus 7.65 ng/ml (P = 0.0948) and 18.52 ng/ml versus 14.64 ng/ml (P = 0.0440), respectively. In patients who received itraconazole alone, most of the decline in antigenuria occurred later during treatment and was overall slower than that seen with amphotericin B (P < 0.0001). Results of latent class growth modeling showed two distinct trajectories for each parameter. With effective therapy, Histoplasma antigenemia decreases more rapidly than antigenuria, providing a more sensitive early laboratory marker for response to treatment. Antigenuria declines earlier with amphotericin B than with itraconazole. PMID- 21307282 TI - Manganese accumulation in the olfactory bulbs and other brain regions of "asymptomatic" welders. AB - Welding-generated metallic fumes contain a substantial amount of manganese (Mn), making welders susceptible to Mn toxicity. Although overt Mn toxicity manifests as a type of parkinsonism, the consequences of chronic, low-level Mn exposure are unknown. To explore region-specific Mn accumulation and its potential functional consequences at subclinical levels of Mn exposure, we studied seven welders without obvious neurological deficits and seven age- and gender-matched controls. Mn exposure for welders was estimated by an occupational questionnaire. High resolution brain magnetic resonance imaging (MRI), Grooved Pegboard performance of both hands, Trail making, and olfactory function tests were obtained from all subjects. Compared with controls, the welders had a significantly higher T1 relaxation rate (R1) in the olfactory bulb (OB, p = 0.02), mean T1-weighted intensity at frontal white matter (FWM; p = 0.01), bilateral globus pallidus (GP; p = 0.03), and putamen (p = 0.03). The welders scored worse than the controls on the Grooved Pegboard test for both dominant (p = 0.06) and nondominant hand (p = 0.03). The dominant hand Grooved Pegboard scores correlated best with mean MRI intensity of FWM (R2 = 0.51, p = 0.004), GP (R2 = 0.51, p = 0.004), putamen (R2 = 0.49, p= 0.006), and frontal gray matter (R2 = 0.42, p = 0.01), whereas the nondominant hand scores correlated best with intensity of FWM (R2 = 0.37, p = 0.02) and GP (R2 = 0.28, p = 0.05). No statistical differences were observed in either the Trail-making test or the olfactory test between the two groups. This study suggests that Mn accumulates in OB and multiple other brain regions in "asymptomatic" welders and that MRI abnormalities correlate with fine motor but not cognitive deficits. Further investigations of subclinical Mn exposure are warranted. PMID- 21307283 TI - RICE MORPHOLOGY DETERMINANT encodes the type II formin FH5 and regulates rice morphogenesis. AB - Multicellular organisms contain a large number of formins; however, their physiological roles in plants remain poorly understood. Here, we reveal that formin homology 5 (FH5), a type II formin mutated in rice morphology determinant (rmd), plays a crucial role in determining rice (Oryza sativa) morphology. FH5/RMD encodes a formin-like protein consisting of an N-terminal phosphatase tensin (PTEN)-like domain, an FH1 domain, and an FH2 domain. The rmd mutants display a bending growth pattern in seedlings, are stunted as adult plants, and have aberrant inflorescence (panicle) and seed shape. Cytological analysis showed that rmd mutants have severe cell elongation defects and abnormal microtubule and microfilament arrays. FH5/RMD is ubiquitously expressed in rice tissues, and its protein localization to the chloroplast surface is mediated by the PTEN domain. Biochemical assays demonstrated that recombinant FH5 protein can nucleate actin polymerization from monomeric G-actin or actin/profilin complexes, cap the barbed end of actin filaments, and bundle actin filaments in vitro. Moreover, FH5 can directly bind to and bundle microtubules through its FH2 domain in vitro. Our findings suggest that the rice formin protein FH5 plays a critical role in determining plant morphology by regulating actin dynamics and proper spatial organization of microtubules and microfilaments. PMID- 21307284 TI - Crosstalk between Hsp90 and Hsp70 chaperones and heat stress transcription factors in tomato. AB - Heat stress transcription factors (Hsfs) regulate gene expression in response to environmental stress. The Hsf network in plants is controlled at the transcriptional level by cooperation of distinct Hsf members and by interaction with chaperones. We found two general mechanisms of Hsf regulation by chaperones while analyzing the three major Hsfs, A1, A2, and B1, in tomato (Solanum lycopersicum). First, Hsp70 and Hsp90 regulate Hsf function by direct interactions. Hsp70 represses the activity of HsfA1, including its DNA binding, and the coactivator function of HsfB1 in the complex with HsfA2, while the DNA binding activity of HsfB1 is stimulated by Hsp90. Second, Hsp90 affects the abundance of HsfA2 and HsfB1 by modulating hsfA2 transcript degradation involved in regulation of the timing of HsfA2 synthesis. By contrast, HsfB1 binding to Hsp90 and to DNA are prerequisites for targeting this Hsf for proteasomal degradation, which also depends on a sequence element in its carboxyl-terminal domain. Thus, HsfB1 represents an Hsp90 client protein that, by interacting with the chaperone, is targeted for, rather than protected from, degradation. Based on these findings, we propose a versatile regulatory regime involving Hsp90, Hsp70, and the three Hsfs in the control of heat stress response. PMID- 21307285 TI - BENT UPPERMOST INTERNODE1 encodes the class II formin FH5 crucial for actin organization and rice development. AB - The actin cytoskeleton is an important regulator of cell expansion and morphogenesis in plants. However, the molecular mechanisms linking the actin cytoskeleton to these processes remain largely unknown. Here, we report the functional analysis of rice (Oryza sativa) FH5/BENT UPPERMOST INTERNODE1 (BUI1), which encodes a formin-type actin nucleation factor and affects cell expansion and plant morphogenesis in rice. The bui1 mutant displayed pleiotropic phenotypes, including bent uppermost internode, dwarfism, wavy panicle rachis, and enhanced gravitropic response. Cytological observation indicated that the growth defects of bui1 were caused mainly by inhibition of cell expansion. Map based cloning revealed that BUI1 encodes the class II formin FH5. FH5 contains a phosphatase tensin-like domain at its amino terminus and two highly conserved formin-homology domains, FH1 and FH2. In vitro biochemical analyses indicated that FH5 is capable of nucleating actin assembly from free or profilin-bound monomeric actin. FH5 also interacts with the barbed end of actin filaments and prevents the addition and loss of actin subunits from the same end. Interestingly, the FH2 domain of FH5 could bundle actin filaments directly and stabilize actin filaments in vitro. Consistent with these in vitro biochemical activities of FH5/BUI1, the amount of filamentous actin decreased, and the longitudinal actin cables almost disappeared in bui1 cells. The FH2 or FH1FH2 domains of FH5 could also bind to and bundle microtubules in vitro. Thus, our study identified a rice formin protein that regulates de novo actin nucleation and spatial organization of the actin filaments, which are important for proper cell expansion and rice morphogenesis. PMID- 21307287 TI - CD23-dependent transcytosis of IgE and immune complex across the polarized human respiratory epithelial cells. AB - IgE-mediated allergic inflammation occurs when allergens cross-link IgE on the surface of immune cells, thereby triggering the release of inflammatory mediators as well as enhancing Ag presentations. IgE is frequently present in airway secretions, and its level can be enhanced in human patients with allergic rhinitis and bronchial asthma. However, it remains completely unknown how IgE appears in the airway secretions. In this study, we show that CD23 (FcepsilonRII) is constitutively expressed in established or primary human airway epithelial cells, and its expression is significantly upregulated when airway epithelial cells were subjected to IL-4 stimulation. In a transcytosis assay, human IgE or IgE-derived immune complex (IC) was transported across a polarized Calu-3 monolayer. Exposure of the Calu-3 monolayer to IL-4 stimulation also enhanced the transcytosis of either human IgE or the IC. A CD23-specific Ab or soluble CD23 significantly reduced the efficiency of IgE or IC transcytosis, suggesting a specific receptor-mediated transport by CD23. Transcytosis of both IgE and the IC was further verified in primary human airway epithelial cell monolayers. Furthermore, the transcytosed Ag-IgE complexes were competent in inducing degranulation of the cultured human mast cells. Because airway epithelial cells are the first cell layer to come into contact with inhaled allergens, our study implies CD23-mediated IgE transcytosis in human airway epithelial cells may play a critical role in initiating and contributing to the perpetuation of airway allergic inflammation. PMID- 21307286 TI - Antisense inhibition of the iron-sulphur subunit of succinate dehydrogenase enhances photosynthesis and growth in tomato via an organic acid-mediated effect on stomatal aperture. AB - Transgenic tomato (Solanum lycopersicum) plants expressing a fragment of the Sl SDH2-2 gene encoding the iron sulfur subunit of the succinate dehydrogenase protein complex in the antisense orientation under the control of the 35S promoter exhibit an enhanced rate of photosynthesis. The rate of the tricarboxylic acid (TCA) cycle was reduced in these transformants, and there were changes in the levels of metabolites associated with the TCA cycle. Furthermore, in comparison to wild-type plants, carbon dioxide assimilation was enhanced by up to 25% in the transgenic plants under ambient conditions, and mature plants were characterized by an increased biomass. Analysis of additional photosynthetic parameters revealed that the rate of transpiration and stomatal conductance were markedly elevated in the transgenic plants. The transformants displayed a strongly enhanced assimilation rate under both ambient and suboptimal environmental conditions, as well as an elevated maximal stomatal aperture. By contrast, when the Sl SDH2-2 gene was repressed by antisense RNA in a guard cell specific manner, changes in neither stomatal aperture nor photosynthesis were observed. The data obtained are discussed in the context of the role of TCA cycle intermediates both generally with respect to photosynthetic metabolism and specifically with respect to their role in the regulation of stomatal aperture. PMID- 21307288 TI - Stat3 phosphorylation mediates resistance of primary human T cells to regulatory T cell suppression. AB - Human autoimmune diseases are characterized by systemic T cell dysfunction, resulting in chronically activated Th1 and Th17 cells that are inadequately suppressed by regulatory T cells (Tregs). IL-6, which is overexpressed in tissue and serum of patients with autoimmune diseases, inhibits human Treg function. We sought to determine the mechanism for the antitolerogenic properties of IL-6 by examining the signaling pathways downstream of IL-6R in primary human T cells. Inhibition of Stat3 signaling in MLCs containing IL-6 restores Treg-mediated suppression, demonstrating that IL-6-mediated loss of Treg suppression requires phosphorylation of Stat3. Cultures in which either effector T cells (Teffs) or Tregs were pretreated with Stat3 inhibitors indicate that phosphorylated (p)Stat3 is required in both T cell populations for IL-6-mediated reversal of Treg function. IL-21, which signals preferentially through pStat3, also reverses Treg suppression, in contrast to IL-27 and IFN-gamma, which signal preferentially through Stat1 and do not inhibit Treg function. Interestingly, both Teffs and Tregs respond to IL-6 stimulation through strong Stat3 phosphorylation with minimal MAPK/Erk activation and moderate Stat1 phosphorylation. Finally, Teffs stimulated strongly through the TCR are also resistant to suppression by Tregs and show concurrent Stat3 phosphorylation. In these cultures, inhibition of pStat3 restores functional suppression by Tregs. Taken together, our findings suggest that an early dominance of Stat3 signaling, prior to subsequent T cell activation, is required for the loss of functional Treg suppression and that kinase-specific inhibitors may hold therapeutic promise in the treatment of autoimmune and chronic inflammatory diseases. PMID- 21307289 TI - Alterations in marginal zone macrophages and marginal zone B cells in old mice. AB - Marginal zones (MZs) are architecturally organized for clearance of and rapid response against blood-borne Ags entering the spleen. MZ macrophages (MZMs) and MZ B cells are particularly important in host defense against T-independent pathogens and may be crucial for the prevention of diseases, such as streptococcal pneumonia, that are devastating in older patients. Our objective was to determine whether there are changes in the cellular components of the MZ between old and young mice. Using immunocytochemistry and a blinded scoring system, we observed gross architectural changes in the MZs of old mice, including reduction in the abundance of MZMs surrounding the MZ sinus as well as disruptions in positioning of mucosal addressin cell adhesion molecule 1 (MAdCAM 1)(+) sinus lining cells and metallophilic macrophages. Loss of frequency of MZMs was corroborated by flow cytometry. A majority of old mice also showed reduced frequency of MZ B cells, which correlated with decreased abundance of MZM in individual old mice. The spleens of old mice showed less deposition of intravenously injected dextran particles within the MZ, likely because of the decreased frequency in MZMs, because SIGN-R1 expression was not reduced on MZM from old mice. The phagocytic ability of individual MZMs was examined using Staphylococcus aureus bioparticles, and no differences in phagocytosis were found between macrophages from young or old spleens. In summary, an anatomical breakdown of the MZ occurs in advanced age, and a reduction in frequency of MZM may affect the ability of the MZM compartment to clear blood-borne Ags and mount proper T-independent immune responses. PMID- 21307290 TI - Primary human CD4+ T cells have diverse levels of membrane lipid order that correlate with their function. AB - Membrane lipid microdomains (lipid rafts) play an important role in T cell function by forming areas of high lipid order that facilitate activation. However, their role in regulating T cell differentiation and function remains controversial. In this study, by applying a new approach involving microscopy and flow cytometry, we characterize membrane lipid order in ex vivo primary human CD4(+) T cells. We reveal that differential membrane lipid order dictates the response to TCR stimulation. T cells with high membrane order formed stable immune synapses and proliferated robustly, intermediate order cells had reduced proliferative ability accompanied by unstable immune synapse formation, whereas low order T cells were profoundly unresponsive to TCR activation. We also observed that T cells from patients with autoimmune rheumatic disease had expanded intermediate order populations compared with healthy volunteers. This may be important in dictating the nature of the immune response since most IFN gamma(+)CD4(+) T cells were confined within intermediate membrane order populations, whereas IL-4(+)CD4(+) T cells were contained within the high order populations. Importantly, we were able to alter T cell function by pharmacologically manipulating membrane order. Thus, the results presented from this study identify that ex vivo CD4(+) T cells sustain a gradient of plasma membrane lipid order that influences their function in terms of proliferation and cytokine production. This could represent a new mechanism to control T cell functional plasticity, raising the possibility that therapeutic targeting of membrane lipid order could direct altered immune cell activation in pathology. PMID- 21307291 TI - Muramyl dipeptide induces Th17 polarization through activation of endothelial cells. AB - Endothelial cells (ECs) express the nucleotide-binding oligomerization domain (Nod) receptor 2, which recognizes the bacterial derivate muramyl dipeptide (MDP). MDP stimulation of these cells enhances their IL-6 production and may thus contribute to the immune and inflammatory activities in the skin. However, whether ECs are capable of influencing the development of T cell priming and its polarization remains unknown. We report that in vitro the murine bEnd.3 EC line induces, following MDP stimulation, a Th17 polarization at the expense of Th1 and Th2 polarization in the setting of Langerhans cell (LC) Ag presentation to responsive T cells as assessed by IL-17, IL-6, IFN-gamma, and IL-4 production. Interestingly, IL-22 production, which has been associated with Th17 priming, was not influenced by MDP-treated bEnd.3 cells, illustrating differential regulation of this cytokine from IL-17. Additional analysis confirmed a significantly increased percentage of IL-17(+)CD4(+) T cells by flow cytometry and an increased mRNA level of the specific Th17 transcription factor retinoic acid-related orphan receptor gammat in cocultures of LCs and responsive T cells in the presence of activated bEnd.3 cells. Experiments using the RNA interference technique to knockdown IL-6 in bEnd.3 cells confirmed that IL-6 produced by bEnd.3 cells stimulated by MDP is at least partially involved in Th17 polarization. Our data suggest that activated ECs are capable of influencing LC Ag processing and presentation to T cells and induce a Th17 polarization. These results are important for the understanding of Th17-related disorders of the skin such as psoriasis. PMID- 21307292 TI - Epigallocatechin-3-gallate reduces airway inflammation in mice through binding to proinflammatory chemokines and inhibiting inflammatory cell recruitment. AB - One major activity of chemokines is the recruitment of immune cells to sites of infection and inflammation. CD4(+) Th1 cells play critical roles in host defense against pathogens and in the pathogenesis of many immune-mediated diseases. It was reported that epigallocatechin-3-gallate (EGCG) exhibits anti-inflammatory properties, but the mechanisms have not been completely defined. In this study, we found that EGCG markedly decreased recruitment of murine OVA-specific Th1 cells and other inflammatory cells into the airways in a Th1 adoptive-transfer mouse model. In vitro analysis revealed that EGCG inhibited CXCR3 ligand-driven chemotaxis of murine and human cells. Surface plasmon resonance studies revealed that EGCG bound directly to chemokines CXCL9, CXCL10, and CXCL11. These results indicated that one anti-inflammatory mechanism of EGCG is binding of proinflammatory chemokines and limiting their biological activities. These findings support further development of EGCG as a potent therapeutic for inflammatory diseases. PMID- 21307293 TI - Dopamine induces IL-6-dependent IL-17 production via D1-like receptor on CD4 naive T cells and D1-like receptor antagonist SCH-23390 inhibits cartilage destruction in a human rheumatoid arthritis/SCID mouse chimera model. AB - A major neurotransmitter dopamine transmits signals via five different seven transmembrane G protein-coupled receptors termed D1-D5. Several studies have shown that dopamine not only mediates interactions into the nervous system, but can contribute to the modulation of immunity via receptors expressed on immune cells. We have previously shown an autocrine/paracrine release of dopamine by dendritic cells (DCs) during Ag presentation to naive CD4(+) T cells and found efficacious results of a D1-like receptor antagonist SCH-23390 in the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis and in the NOD mouse model of type I diabetes, with inhibition of Th17 response. This study aimed to assess the role of dopaminergic signaling in Th17-mediated immune responses and in the pathogenesis of rheumatoid arthritis (RA). In human naive CD4(+) T cells, dopamine increased IL-6-dependent IL-17 production via D1-like receptors, in response to anti-CD3 plus anti-CD28 mAb. Furthermore, dopamine was localized with DCs in the synovial tissue of RA patients and significantly increased in RA synovial fluid. In the RA synovial/SCID mouse chimera model, although a selective D2-like receptor antagonist haloperidol significantly induced accumulation of IL-6(+) and IL-17(+) T cells with exacerbated cartilage destruction, SCH-23390 strongly suppressed these responses. Taken together, these findings indicate that dopamine released by DCs induces IL-6-Th17 axis and causes aggravation of synovial inflammation of RA, which is the first time, to our knowledge, that actual evidence has shown the pathological relevance of dopaminergic signaling with RA. PMID- 21307294 TI - CCR5 blockade in combination with cyclosporine increased cardiac graft survival and generated alternatively activated macrophages in primates. AB - Maraviroc (MVC), a specific antagonist of CCR5 expressed on macrophages and activated T cells, may modulate inflammation and may be useful in patients with HIV infection. In this study we used nonhuman primates to examine the effect and mechanism of MVC alone or in combination with cyclosporine (CsA) to prolong cardiac allograft survivals. In an established rhesus monkey cardiac allograft model, recipients treated with MVC plus CsA showed significantly prolonged survival of heart allografts (>240 d, p < 0.001). These in vivo results in the MVC/CsA group correlated with delayed alloantibody response and markedly decreased graft infiltration by CCR5(+), CD4(+), CD8(+), and CD68(+) cells (p < 0.05), as compared with other groups. Furthermore, grafts from the MVC/CsA group had elevated numbers of alternatively activated macrophages (AAMs) and the expression of peroxisome proliferator-activated receptor gamma (PPARgamma). Blockade of PPARgamma abrogated the prolonged allograft survival (median survival time, 45 d) and the upregulated AAMs in MVC/CsA-treated recipients. In conclusion, MVC/CsA protects cardiac allograft in primates and this effect is associated with generating AAMs through activation of the PPARgamma nuclear receptor. PMID- 21307295 TI - Cutting edge: CD8+ T cell priming in the absence of NK cells leads to enhanced memory responses. AB - It is uncertain whether NK cells modulate T cell memory differentiation. By using a genetic model that allows the selective depletion of NK cells, we show in this study that NK cells shape CD8(+) T cell fate by killing recently activated CD8(+) T cells in an NKG2D- and perforin-dependent manner. In the absence of NK cells, the differentiation of CD8(+) T cells is strongly biased toward a central memory T cell phenotype. Although, on a per-cell basis, memory CD8(+) T cells generated in the presence or the absence of NK cells have similar functional features and recall capabilities, NK cell deletion resulted in a significantly higher number of memory Ag-specific CD8(+) T cells, leading to more effective control of tumors carrying model Ags. The enhanced memory responses induced by the transient deletion of NK cells may provide a rational basis for the design of new vaccination strategies. PMID- 21307296 TI - Epigenetic changes at Il12rb2 and Tbx21 in relation to plasticity behavior of Th17 cells. AB - Plasticity within Th cell populations may play a role in enabling site-specific immune responses to infections while limiting tissue destruction. Epigenetic processes are fundamental to such plasticity; however, to date, most investigations have focused on in vitro-generated T cells. In this study, we have examined the molecular mechanisms underpinning murine Th17 plasticity in vivo by assessing H3K4 and H3K27 trimethylation marks at Tbx21, Rorc, Il17a, Ifng, and Il12rb2 loci in purified ex vivo-isolated and in vitro-generated Th17 cells. Although both populations had largely comparable epigenetic signatures, including bivalent marks at Tbx21, freshly isolated ex vivo Th17 cells displayed restricted expression from Il12rb2 due to the presence of repressive chromatin modifications. This receptor, however, could be upregulated on isolated ex vivo Th17 cells after in vitro activation or by in vivo immunization and was augmented by the presence of IFN-gamma. Such activated cells could then be deviated toward a Th1-like profile. We show that IL-12 stimulation removes H3K27 trimethylation modifications at Tbx21/T-bet leading to enhanced T-bet expression with in vitro Th17 cells. Our study reveals important potential phenotypic differences between ex vivo- and in vitro-generated Th17 cells and provides mechanistic insight into Th17 cell plasticity. PMID- 21307297 TI - Transcriptomes of the B and T lineages compared by multiplatform microarray profiling. AB - T and B lymphocytes are developmentally and functionally related cells of the immune system, representing the two major branches of adaptive immunity. Although originating from a common precursor, they play very different roles: T cells contribute to and drive cell-mediated immunity, whereas B cells secrete Abs. Because of their functional importance and well-characterized differentiation pathways, T and B lymphocytes are ideal cell types with which to understand how functional differences are encoded at the transcriptional level. Although there has been a great deal of interest in defining regulatory factors that distinguish T and B cells, a truly genomewide view of the transcriptional differences between these two cells types has not yet been taken. To obtain a more global perspective of the transcriptional differences underlying T and B cells, we exploited the statistical power of combinatorial profiling on different microarray platforms, and the breadth of the Immunological Genome Project gene expression database, to generate robust differential signatures. We find that differential expression in T and B cells is pervasive, with the majority of transcripts showing statistically significant differences. These distinguishing characteristics are acquired gradually, through all stages of B and T differentiation. In contrast, very few T versus B signature genes are uniquely expressed in these lineages, but are shared throughout immune cells. PMID- 21307298 TI - Zygomycetes, microsporidia, and the evolutionary ancestry of sex determination. AB - Zygomycetes and their alleged sister taxon, the microsporidia, exclusively share the presence of a cluster of three genes encoding a sugar transporter, a high mobility group (HMG)-type transcription factor, and an RNA helicase. In zygomycetes, the HMG-type transcription factor acts as the sole sex determinant. This intimately ties the evolutionary history of this gene cluster to the evolution of sex determination. Here, we have unraveled the relationships of the two gene clusters by vicariously analyzing the sugar transporters and the RNA helicases. We show that if the two gene clusters share a common ancestry, it dates back to the early days of eukaryotic evolution. As a consequence, the zygomycete MAT locus would be old enough to represent the archetype of fungal and animal sex determination. However, the evolutionary scenario that has to be invoked is complex. An independent assembly of the two clusters deserves therefore consideration. In either case, shared ancestry or convergent evolution, the presence of the gene cluster in microsporidia and in zygomycetes represents at best a plesiomorphy. Hence, it is not phylogenetically informative. A further genome-wide reanalysis of gene order conservation reveals that gene order is not significantly more similar between microsporidia and zygomycetes than between microsporidia and any other fungal taxon or even humans. Consequently, the phylogenetic placement of microsporidia as sister to the zygomycetes needs to be reconsidered. PMID- 21307299 TI - Power to the people: participant ownership of clinical trial data. AB - Participation in clinical trials is dismally low. In this age of electronic sharing of information of all sorts, trial participants can easily share clinical trial data. The benefits of participant ownership and sharing of trial data appear to outweigh the risks. Thus, the time has come to crowd-source data for diagnostic and therapy development. PMID- 21307300 TI - Electronic consent channels: preserving patient privacy without handcuffing researchers. AB - Advances in health information technology and electronic medical records have the tremendous potential to accelerate translational and clinical research. However, privacy concerns threaten to be a rate-limiting factor. By recognizing and responding to patient privacy concerns, policy-makers, researchers, and information technology leaders have the opportunity to transform trial recruitment and make it safer to electronically locate and convey sensitive health information. PMID- 21307301 TI - Photodynamic ablation of lymphatic vessels and intralymphatic cancer cells prevents metastasis. AB - The dissemination of tumor cells to sites far from the primary tumor (metastasis) is the principal cause of death in cancer patients. Tumor-associated lymphatic vessels are a key conduit for metastatic tumor cells, which typically first colonize the lymph nodes. Although the primary tumor and affected lymph nodes can be removed during surgery, tumor cells inside lymphatic vessels are left behind. Here, we show that in-transit tumor cells inside lymphatic vessels in mice bearing mouse melanomas or human lung tumors give rise to metastases. Using photodynamic therapy with the benzoporphyrin derivative verteporfin, we selectively destroyed lymphatic vessels in mice and pigs. Destruction of tumor associated lymphatic vessels also eradicated intralymphatic tumor cells and prevented metastasis of mouse melanoma cells and subsequent relapse. Photodynamic therapy, when combined with anti-lymphangiogenic therapy, prevented further tumor invasion of lymphatic vessels. These findings highlight the potential of targeting in-transit tumor cells in patients. PMID- 21307302 TI - 5-Lipoxygenase metabolite 4-HDHA is a mediator of the antiangiogenic effect of omega-3 polyunsaturated fatty acids. AB - Lipid signaling is dysregulated in many diseases with vascular pathology, including cancer, diabetic retinopathy, retinopathy of prematurity, and age related macular degeneration. We have previously demonstrated that diets enriched in omega-3 polyunsaturated fatty acids (PUFAs) effectively reduce pathological retinal neovascularization in a mouse model of oxygen-induced retinopathy, in part through metabolic products that suppress microglial-derived tumor necrosis factor-alpha. To better understand the protective effects of omega-3 PUFAs, we examined the relative importance of major lipid metabolic pathways and their products in contributing to this effect. omega-3 PUFA diets were fed to four lines of mice deficient in each key lipid-processing enzyme (cyclooxygenase 1 or 2, or lipoxygenase 5 or 12/15), retinopathy was induced by oxygen exposure; only loss of 5-lipoxygenase (5-LOX) abrogated the protection against retinopathy of dietary omega-3 PUFAs. This protective effect was due to 5-LOX oxidation of the omega-3 PUFA lipid docosahexaenoic acid to 4-hydroxy-docosahexaenoic acid (4 HDHA). 4-HDHA directly inhibited endothelial cell proliferation and sprouting angiogenesis via peroxisome proliferator-activated receptor gamma (PPARgamma), independent of 4-HDHA's anti-inflammatory effects. Our study suggests that omega 3 PUFAs may be profitably used as an alternative or supplement to current anti vascular endothelial growth factor (VEGF) treatment for proliferative retinopathy and points to the therapeutic potential of omega-3 PUFAs and metabolites in other diseases of vasoproliferation. It also suggests that cyclooxygenase inhibitors such as aspirin and ibuprofen (but not lipoxygenase inhibitors such as zileuton) might be used without losing the beneficial effect of dietary omega-3 PUFA. PMID- 21307303 TI - Racial variation in umbilical cord blood leptin concentration in male babies. AB - BACKGROUND: We hypothesize that racial differences in utero contribute to the racial disparity in prostate cancer risk. Leptin is a candidate for evaluating this hypothesis because it influences fetal development and newborn growth. METHODS: We measured leptin concentration by ELISA in venous cord blood collected from 70 African-American and 37 white male full-term babies. We measured sex steroid hormones and insulin-like growth factor (IGF) axis concentrations previously. Separately by race, we calculated the geometric mean leptin concentration and estimated the geometric mean adjusted for birth and placental weights, mother's age and parity, time of day and season of birth, and sex steroid hormone and IGF axis concentrations by linear regression. RESULTS: Leptin was positively correlated with birth (r = 0.34) and placental (r = 0.25) weights, IGF-1 (r = 0.21), and IGF binding protein-3 (r = 0.29) adjusting for race. Unadjusted geometric mean leptin did not differ (P = 0.92) between African Americans (5,280 pg/mL; 95% CI: 4,322-6,451) and whites (5,187 pg/mL; 95% CI: 3,938-6,832). Adjusted geometric mean leptin was nonstatistically significantly higher (P = 0.15) in African Americans (5,954 pg/mL; 95% CI: 4,725-7,502) than in whites (4,133 pg/mL; 95% CI: 2,890-5,910). CONCLUSION: We observed a nonsignificantly higher adjusted cord blood leptin concentration in African American male babies than in white male babies, although unadjusted levels were similar. IMPACT: These findings do not support the hypothesis that leptin level in utero contributes to the racial disparity in prostate cancer risk in adulthood. PMID- 21307304 TI - Disclosing individual CDKN2A research results to melanoma survivors: interest, impact, and demands on researchers. AB - BACKGROUND: Whether to return individual research results from cancer genetics studies is widely debated, but little is known about how participants respond to results disclosure or about its time and cost burdens on investigators. METHODS: We recontacted participants at one site of a multicenter genetic epidemiologic study regarding their CDKN2A gene test results and implications for melanoma risk. Interested participants were disclosed their results by telephone and followed for 3 months. RESULTS: Among 39 patients approached, 27 were successfully contacted, and 19 (70% uptake) sought results, including three with mutations. Prior to disclosure, participants endorsed numerous benefits of receiving results (mean=7.7 of 9 posed), including gaining information relevant to their children's disease risk. Mean psychological well-being scores did not change from baseline, and no decreases to melanoma prevention behaviors were noted. Fifty-nine percent of participants reported that disclosure made participation in future research more likely. Preparation for disclosure required 40 minutes and $611 per recontact attempt. An additional 78 minutes and $68 was needed to disclose results. CONCLUSION: Cancer epidemiology research participants who received their individual genetic research results showed no evidence of psychological harm or false reassurance from disclosure and expressed strong trust in the accuracy of results. Burdens to our investigators were high, but protocols may differ in their demands and disclosure may increase participants' willingness to enroll in future studies. IMPACT: Providing individual study results to cancer genetics research participants poses potential challenges for investigators, but many participants desire and respond positively to this information. PMID- 21307305 TI - Serum salicylate levels and risk of recurrent colorectal adenomas. AB - BACKGROUND: Intake of aspirin is associated with reduction in risk of colorectal adenoma and carcinoma. Some plants contain salicylates, and individuals not taking aspirin may have measurable salicylate levels. However, the association between serum salicylate level and recurrence of adenoma in nonusers of aspirin has not been studied. METHODS: We measured serum salicylate levels in participants in a randomized controlled trial with calcium supplementation for the prevention of colorectal adenomas. Generalized linear models were used to assess the association between serum levels and adenoma risk during the follow-up period of the trial. RESULTS: We did not find an association with recurrence of adenomas or advanced adenomas with serum salicylate levels at year 1 among nonusers of aspirin. There was no effect modification of the chemopreventive effect of calcium supplementation in reducing risk of recurrent adenomas or advanced adenomas. CONCLUSIONS: Among nonusers of ASA, serum salicylate levels are not associated with risk of recurrence of adenomas. IMPACT: Serum salicylate levels can be detected in individuals not taking aspirin, but the levels may be too low to confer protection from risk of recurrent adenomas. PMID- 21307306 TI - Molecular basis for enhancement of the meiotic DMC1 recombinase by RAD51 associated protein 1 (RAD51AP1). AB - Homologous recombination is needed for meiotic chromosome segregation, genome maintenance, and tumor suppression. RAD51AP1 (RAD51 associated protein 1) has been shown to interact with and enhance the recombinase activity of RAD51. Accordingly, genetic ablation of RAD51AP1 leads to enhanced sensitivity to and also chromosome aberrations upon DNA damage, demonstrating a role for RAD51AP1 in mitotic homologous recombination. Here we show physical association of RAD51AP1 with the meiosis-specific recombinase DMC1 and a stimulatory effect of RAD51AP1 on the DMC1-mediated D-loop reaction. Mechanistic studies have revealed that RAD51AP1 enhances the ability of the DMC1 presynaptic filament to capture the duplex-DNA partner and to assemble the synaptic complex, in which the recombining DNA strands are homologously aligned. We also provide evidence that functional cooperation is dependent on complex formation between DMC1 and RAD51AP1 and that distinct epitopes in RAD51AP1 mediate interactions with RAD51 and DMC1. Finally, we show that RAD51AP1 is expressed in mouse testes, and that RAD51AP1 foci colocalize with a subset of DMC1 foci in spermatocytes. These results suggest that RAD51AP1 also serves an important role in meiotic homologous recombination. PMID- 21307307 TI - Frustration, specific sequence dependence, and nonlinearity in large-amplitude fluctuations of allosteric proteins. AB - Proteins have often evolved sequences so as to acquire the ability for regulation via allosteric conformational change. Here we investigate how allosteric dynamics is designed through sequences with nonlinear interaction features. First, for 71 allosteric proteins of which two, open and closed, structures are available, a statistical survey of interactions using an all-atom model with effective solvation shows that those residue contact interactions specific to one of the two states are significantly weaker than are the contact interactions shared by the two states. This interaction feature indicates there is underlying sequence design to facilitate conformational change. Second, based on the energy landscape theory, we implement these interaction features into a new atomic-interaction based coarse-grained model via a multiscale simulation protocol (AICG). The AICG model outperforms standard coarse-grained models for predictions of the native state mean fluctuations and of the conformational change direction. Third, using the new model for adenylate kinase, we show that intrinsic fluctuations in one state contain rare and large-amplitude motions nearly reaching the other state. Such large-amplitude motions are realized partly by sequence specificity and partly by the nonlinear nature of contact interactions, leading to cracking. Both features enhance conformational transition rates. PMID- 21307308 TI - Regulation of an intracellular subtilisin protease activity by a short propeptide sequence through an original combined dual mechanism. AB - A distinct class of the biologically important subtilisin family of serine proteases functions exclusively within the cell and forms a major component of the bacilli degradome. However, the mode and mechanism of posttranslational regulation of intracellular protease activity are unknown. Here we describe the role played by a short N-terminal extension prosequence novel amongst the subtilisins that regulates intracellular subtilisin protease (ISP) activity through two distinct modes: active site blocking and catalytic triad rearrangement. The full-length proenzyme (proISP) is inactive until specific proteolytic processing removes the first 18 amino acids that comprise the N terminal extension, with processing appearing to be performed by ISP itself. A synthetic peptide corresponding to the N-terminal extension behaves as a mixed noncompetitive inhibitor of active ISP with a K(i) of 1 MUM. The structure of the processed form has been determined at 2.6 A resolution and compared with that of the full-length protein, in which the N-terminal extension binds back over the active site. Unique to ISP, a conserved proline introduces a backbone kink that shifts the scissile bond beyond reach of the catalytic serine and in addition the catalytic triad is disrupted. In the processed form, access to the active site is unblocked by removal of the N-terminal extension and the catalytic triad rearranges to a functional conformation. These studies provide a new molecular insight concerning the mechanisms by which subtilisins and protease activity as a whole, especially within the confines of a cell, can be regulated. PMID- 21307309 TI - Selective pharmacogenetic inhibition of mammalian target of Rapamycin complex I (mTORC1) blocks long-term synaptic plasticity and memory storage. AB - Both the formation of long-term memory (LTM) and late-long-term potentiation (L LTP), which is thought to represent the cellular model of learning and memory, require de novo protein synthesis. The mammalian target of Rapamycin (mTOR) complex I (mTORC1) integrates information from various synaptic inputs and its best characterized function is the regulation of translation. Although initial studies have shown that rapamycin reduces L-LTP and partially blocks LTM, recent genetic and pharmacological evidence indicating that mTORC1 promotes L-LTP and LTM is controversial. Thus, the role of mTORC1 in L-LTP and LTM is unclear. To selectively inhibit mTORC1 activity in the adult brain, we used a "pharmacogenetic" approach that relies on the synergistic action of a drug (rapamycin) and a genetic manipulation (mTOR heterozygotes, mTOR(+/-) mice) on the same target (mTORC1). Although L-LTP and LTM are normal in mTOR(+/-) mice, application of a low concentration of rapamycin-one that is subthreshold for WT mice-prevented L-LTP and LTM only in mTOR(+/-) mice. Furthermore, we found that mTORC1-mediated translational control is required for memory reconsolidation. We provide here direct genetic evidence supporting the role of mTORC1 in L-LTP and behavioral memory. PMID- 21307310 TI - The pINDUCER lentiviral toolkit for inducible RNA interference in vitro and in vivo. AB - The discovery of RNAi has revolutionized loss-of-function genetic studies in mammalian systems. However, significant challenges still remain to fully exploit RNAi for mammalian genetics. For instance, genetic screens and in vivo studies could be broadly improved by methods that allow inducible and uniform gene expression control. To achieve this, we built the lentiviral pINDUCER series of expression vehicles for inducible RNAi in vivo. Using a multicistronic design, pINDUCER vehicles enable tracking of viral transduction and shRNA or cDNA induction in a broad spectrum of mammalian cell types in vivo. They achieve this uniform temporal, dose-dependent, and reversible control of gene expression across heterogenous cell populations via fluorescence-based quantification of reverse tet-transactivator expression. This feature allows isolation of cell populations that exhibit a potent, inducible target knockdown in vitro and in vivo that can be used in human xenotransplantation models to examine cancer drug targets. PMID- 21307311 TI - Compartmentalization increases food-web persistence. AB - It has recently been noted that empirical food webs are significantly compartmentalized; that is, subsets of species exist that interact more frequently among themselves than with other species in the community. Although the dynamic implications of compartmentalization have been debated for at least four decades, a general answer has remained elusive. Here, we unambiguously demonstrate that compartmentalization acts to increase the persistence of multitrophic food webs. We then identify the mechanisms behind this result. Compartments in food webs act directly to buffer the propagation of extinctions throughout the community and augment the long-term persistence of its constituent species. This contribution to persistence is greater the more complex the food web, which helps to reconcile the simultaneous complexity and stability of natural communities. PMID- 21307312 TI - End game: getting the most out of microRNAs. PMID- 21307313 TI - Should we screen children with type 1 diabetes for Addison's disease? PMID- 21307314 TI - PICU staff attitude towards organ donor identification and donation after circulatory death. PMID- 21307315 TI - Contributions of skin and muscle afferent input to movement sense in the human hand. AB - In the stationary hand, static joint-position sense originates from multimodal somatosensory input (e.g., joint, skin, and muscle). In the moving hand, however, it is uncertain how movement sense arises from these different submodalities of proprioceptors. In contrast to static-position sense, movement sense includes multiple parameters such as motion detection, direction, joint angle, and velocity. Because movement sense is both multimodal and multiparametric, it is not known how different movement parameters are represented by different afferent submodalities. In theory, each submodality could redundantly represent all movement parameters, or, alternatively, different afferent submodalities could be tuned to distinctly different movement parameters. The study described in this paper investigated how skin input and muscle input each contributes to movement sense of the hand, in particular, to the movement parameters dynamic position and velocity. Healthy adult subjects were instructed to indicate with the left hand when they sensed the unseen fingers of the right hand being passively flexed at the metacarpophalangeal (MCP) joint through a previously learned target angle. The experimental approach was to suppress input from skin and/or muscle: skin input by anesthetizing the hand, and muscle input by unexpectedly extending the wrist to prevent MCP flexion from stretching the finger extensor muscle. Input from joint afferents was assumed not to play a significant role because the task was carried out with the MCP joints near their neutral positions. We found that, during passive finger movement near the neutral position in healthy adult humans, both skin and muscle receptors contribute to movement sense but qualitatively differently. Whereas skin input contributes to both dynamic position and velocity sense, muscle input may contribute only to velocity sense. PMID- 21307316 TI - Temporal coding of taste in the parabrachial nucleus of the pons of the rat. AB - Recent studies have provided evidence that temporal coding contributes significantly to encoding taste stimuli at the first central relay for taste, the nucleus of the solitary tract (NTS). However, it is not known whether this coding mechanism is also used at the next synapse in the central taste pathway, the parabrachial nucleus of the pons (PbN). In the present study, electrophysiological responses to taste stimuli (sucrose, NaCl, HCl, and quinine) were recorded from 44 cells in the PbN of anesthetized rats. In 29 cells, the contribution of the temporal characteristics of the response to the discrimination of various taste qualities was assessed. A family of metrics that quantifies the similarity of two spike trains in terms of spike count and spike timing was used. Results showed that spike timing in 14 PbN cells (48%) conveyed a significant amount of information about taste quality, beyond what could be conveyed by spike count alone. In another 14 cells (48%), the rate envelope (time course) of the response contributed significantly more information than spike count alone. Across cells there was a significant correlation (r = 0.51; P < 0.01) between breadth of tuning and the proportion of information conveyed by temporal dynamics. Comparison with previous data from the NTS (Di Lorenzo PM and Victor JD. J Neurophysiol 90: 1418-31, 2003 and J Neurophysiol 97: 1857-1861, 2007) showed that temporal coding in the NTS occurred in a similar proportion of cells and contributed a similar fraction of the total information at the same average level of temporal precision, even though trial-to-trial variability was higher in the PbN than in the NTS. These data suggest that information about taste quality conveyed by the temporal characteristics of evoked responses is transmitted with high fidelity from the NTS to the PbN. PMID- 21307317 TI - Advance cueing produces enhanced action-boundary patterns of spike activity in the sensorimotor striatum. AB - One of the most characteristic features of habitual behaviors is that they can be evoked by a single cue. In the experiments reported here, we tested for the effects of such advance cueing on the firing patterns of striatal neurons in the sensorimotor striatum. Rats ran in a T-maze with instruction cues about the location of reward given at the start of the runs. This advance cueing about reward produced a highly augmented task-bracketing pattern of activity at the beginning and end of procedural task performance relative to the patterns found previously with midtask cueing. Remarkably, the largest increase in activity early during the T-maze runs was not associated with the instruction cues themselves, the earliest predictors of reward; instead, the highest peak of early activity was associated with the beginning of the motor period of the task. We suggest that the advance cueing, reducing midrun demands for decision making but adding a working-memory load, facilitated chunking of the maze runs as executable scripts anchored to sensorimotor aspects of the task and unencumbered by midtask decision-making demands. Our findings suggest that the acquisition of stronger task-bracketing patterns of striatal activity in the sensorimotor striatum could reflect this enhancement of behavioral chunking. Deficits in such representations of learned sequential behaviors could contribute to motor and cognitive problems in a range of neurological disorders affecting the basal ganglia, including Parkinson's disease. PMID- 21307318 TI - Mechano- and thermosensitivity of injured muscle afferents. AB - Injury of limb nerves leading to neuropathic pain mostly affects deep somatic nerves including muscle nerves. Here, we investigated the functional properties of injured afferent fibers innervating the lateral gastrocnemius-soleus muscle 4 13 h [time period (TP) I] and 4-7 days (TP II) after nerve crush in anesthetized rats using neurophysiological recordings from either the sciatic nerve (165 A-, 137 C-fibers) or the dorsal root L(5) (43 A-, 28 C-fibers). Ongoing activity and responses to mechanical or thermal stimulation of the injury site of the nerve were studied quantitatively. Of the electrically identified A- and C-fibers, 5 and 38% exhibited ectopic activity, respectively, in TP I and 51 and 61%, respectively, in TP II. Thus all afferent fibers in an injured muscle nerve developed ectopic activity since ~ 50% of the fibers in a muscle nerve are somatomotor or sympathetic postganglionic. Ongoing activity was present in 50% of the afferent A-fibers (TP II) and in 53-56% of the afferent C-fibers (TP I and II). In TP II, mechanical, cold, and heat sensitivity were present in 91, 63, and 52% of the afferent A-fibers and in 50, 40, and 66% of the afferent C-fibers. The cold and heat activation thresholds were 5-27 and 35-48 degrees C, respectively, covering the noxious and innocuous range. Most afferent fibers showed combinations of these sensitivities. Mechano- and cold sensitivity had a significantly higher representation in A- than in C-fibers, but heat sensitivity had a significantly higher representation in C- than in A-fibers. These functional differences between A- and C-fibers applied to large- as well as small diameter A-fibers. Comparing the functional properties of injured muscle A- and C afferents with those of injured cutaneous A- and C-afferents shows that both populations of injured afferent neurons behave differently in several aspects. PMID- 21307319 TI - Synchronization of presynaptic input to motor units of tongue, inspiratory intercostal, and diaphragm muscles. AB - The respiratory central pattern generator distributes rhythmic excitatory input to phrenic, intercostal, and hypoglossal premotor neurons. The degree to which this input shapes motor neuron activity can vary across respiratory muscles and motor neuron pools. We evaluated the extent to which respiratory drive synchronizes the activation of motor unit pairs in tongue (genioglossus, hyoglossus) and chest-wall (diaphragm, external intercostals) muscles using coherence analysis. This is a frequency domain technique, which characterizes the frequency and relative strength of neural inputs that are common to each of the recorded motor units. We also examined coherence across the two tongue muscles, as our previous work shows that, despite being antagonists, they are strongly coactivated during the inspiratory phase, suggesting that excitatory input from the premotor neurons is distributed broadly throughout the hypoglossal motoneuron pool. All motor unit pairs showed highly correlated activity in the low-frequency range (1-8 Hz), reflecting the fundamental respiratory frequency and its harmonics. Coherence of motor unit pairs recorded either within or across the tongue muscles was similar, consistent with broadly distributed premotor input to the hypoglossal motoneuron pool. Interestingly, motor units from diaphragm and external intercostal muscles showed significantly higher coherence across the 10 20-Hz bandwidth than tongue-muscle units. We propose that the lower coherence in tongue-muscle motor units over this range reflects a larger constellation of presynaptic inputs, which collectively lead to a reduction in the coherence between hypoglossal motoneurons in this frequency band. This, in turn, may reflect the relative simplicity of the respiratory drive to the diaphragm and intercostal muscles, compared with the greater diversity of functions fulfilled by muscles of the tongue. PMID- 21307320 TI - Improved stimulus representation by short interspike intervals in primary auditory cortex. AB - We analyzed the receptive field information conveyed by interspike intervals (ISIs) in the auditory cortex. In the visual system, different ISIs may both code for different visual features and convey differing amounts of stimulus information. To determine their potential role in auditory signal processing, we obtained extracellular recordings in the primary auditory cortex (AI) of the cat while presenting a dynamic moving ripple stimulus and then used the responses to construct spectrotemporal receptive fields (STRFs). For each neuron, we constructed three STRFs, one for short-ISI events (ISI < 15 ms); one for isolated, long-ISI events (ISI > 15 ms); and one including all events. To characterize stimulus encoding, we calculated the feature selectivity and event information for each of the STRFs. Short-ISI spikes were more feature selective and conveyed information more efficiently. The different ISI regimens of AI neurons did not represent different stimulus features, but short-ISI spike events did contribute over-proportionately to the full spike train STRF information. Thus short-ISIs constitute a robust representation of auditory features, and they are particularly effective at driving postsynaptic activity. This suggests that short-ISI events are especially suited to provide noise immunity and high fidelity information transmission in AI. PMID- 21307322 TI - Impact of visual motion adaptation on neural responses to objects and its dependence on the temporal characteristics of optic flow. AB - It is still unclear how sensory systems efficiently encode signals with statistics as experienced by animals in the real world and what role adaptation plays during normal behavior. Therefore, we studied the performance of visual motion-sensitive neurons of blowflies, the horizontal system neurons, with optic flow that was reconstructed from the head trajectories of semi-free-flying flies. To test how motion adaptation is affected by optic flow dynamics, we manipulated the seminatural optic flow by targeted modifications of the flight trajectories and assessed to what extent neuronal responses to an object located close to the flight trajectory depend on adaptation dynamics. For all types of adapting optic flow object-induced response increments were stronger in the adapted compared with the nonadapted state. Adaptation with optic flow characterized by the typical alternation between translational and rotational segments produced this effect but also adaptation with optic flow that lacked these distinguishing features and even pure rotation at a constant angular velocity. The enhancement of object-induced response increments had a direction-selective component because preferred-direction rotation and natural optic flow were more efficient adaptors than null-direction rotation. These results indicate that natural dynamics of optic flow is not a basic requirement to adapt neurons in a specific, presumably functionally beneficial way. Our findings are discussed in the light of adaptation mechanisms proposed on the basis of experiments previously done with conventional experimenter-defined stimuli. PMID- 21307321 TI - Bidirectional control of BK channel open probability by CAMKII and PKC in medial vestibular nucleus neurons. AB - Large conductance K(+) (BK) channels are a key determinant of neuronal excitability. Medial vestibular nucleus (MVN) neurons regulate eye movements to ensure image stabilization during head movement, and changes in their intrinsic excitability may play a critical role in plasticity of the vestibulo-ocular reflex. Plasticity of intrinsic excitability in MVN neurons is mediated by kinases, and BK channels influence excitability, but whether endogenous BK channels are directly modulated by kinases is unknown. Double somatic patch-clamp recordings from MVN neurons revealed large conductance potassium channel openings during spontaneous action potential firing. These channels displayed Ca(2+) and voltage dependence in excised patches, identifying them as BK channels. Recording isolated single channel currents at physiological temperature revealed a novel kinase-mediated bidirectional control in the range of voltages over which BK channels are activated. Application of activated Ca(2+)/calmodulin-dependent kinase II (CAMKII) increased BK channel open probability by shifting the voltage activation range towards more hyperpolarized potentials. An opposite shift in BK channel open probability was revealed by inhibition of phosphatases and was occluded by blockade of protein kinase C (PKC), suggesting that active PKC associated with BK channel complexes in patches was responsible for this effect. Accordingly, direct activation of endogenous PKC by PMA induced a decrease in BK open probability. BK channel activity affects excitability in MVN neurons and bidirectional control of BK channels by CAMKII, and PKC suggests that cellular signaling cascades engaged during plasticity may dynamically control excitability by regulating BK channel open probability. PMID- 21307323 TI - Impaired muscle phasing systematically adapts to varied relative angular relationships during locomotion in people poststroke. AB - After stroke, hemiparesis will result in impairments to locomotor control. Specifically, muscle coordination deficits, in the form of inappropriately phased muscle-activity patterns, occur in both the paretic and nonparetic limbs. These dysfunctional paretic muscle-coordination patterns can adapt to somatosensory inputs, and also the sensorimotor state of nonparetic limb can influence paretic limb. However, the relative contribution of interlimb pathways for improving paretic muscle-activation patterns in terms of phasing remains unknown. In this study, we investigated whether the paretic muscle-activity phasing can be influenced by the relative angular-spatial relationship of the nonparetic limb by using a split-crank ergometer, where the cranks could be decoupled. Eighteen participants with chronic stroke were asked to pedal bilaterally during each task while surface electromyogram signals were recorded bilaterally from four lower extremity muscles (vastus medialis, rectus femoris, tibialis anterior, and soleus). During each experiment, the relative angular crank positions were manipulated by increasing or decreasing their difference by randomly ordered increments of 30 degrees over the complete cycle [0 degrees (in phase pedaling), 30 degrees , 60 degrees , 90 degrees , 120 degrees , 150 degrees , 180 degrees (standard pedaling), 210 degrees , 240 degrees , 270 degrees , 300 degrees , 330 degrees (out of phase pedaling)]. We found that the paretic and nonparetic muscle phasing in the cycle systematically adapted to varied relative angular relationships, and this systematic relationship was well modeled by a sinusoidal relationship. Also, the paretic uniarticular muscle (vastus medialis) showed larger phase shifts compared with biarticular muscle (rectus femoris). More importantly, for each stroke subject, we demonstrated an exclusive crank angular relation that resulted in the generation of more appropriately phased paretic muscle activity. These findings provide new evidence to better understand the capability of impaired nervous system to produce a more normalized muscle phasing pattern poststroke. PMID- 21307325 TI - Effects of visual stimulation on LFPs, spikes, and LFP-spike relations in PRR. AB - Local field potentials (LFPs) have shown diverse relations to the spikes across different brain areas and stimulus features, suggesting that LFP-spike relationships are highly specific to the underlying connectivity of a local network. If so, the LFP-spike relationship may vary even within one brain area under the same task condition if neurons have heterogeneous connectivity with the active input sources during the task. Here, we tested this hypothesis in the parietal reach region (PRR), which includes two distinct classes of motor goal planning neurons with different connectivity to the visual input, i.e., visuomotor neurons receive stronger visual input than motor neurons. We predicted that the visual stimulation would render both the spike response and the LFP spike relationship different between the two neuronal subpopulations. Thus we examined how visual stimulations affect spikes, LFPs, and LFP-spike relationships in PRR by comparing their planning (delay) period activity between two conditions: with or without a visual stimulus at the reach target. Neurons were classified as visuomotor if the visual stimulation increased their firing rate, or as motor otherwise. We found that the visual stimulation increased LFP power in gamma bands >40 Hz for both classes. Moreover, confirming our prediction, the correlation between the LFP gamma power and the firing rate became higher for the visuomotor than motor neurons in the presence of visual stimulation. We conclude that LFPs vary with the stimulation condition and that the LFP-spike relationship depends on a given neuron's connectivity to the dominant input sources in a particular stimulation condition. PMID- 21307324 TI - Locomotor-activated neurons of the cat. II. Noradrenergic innervation and colocalization with NEalpha 1a or NEalpha 2b receptors in the thoraco-lumbar spinal cord. AB - Norepinephrine (NE) is a strong modulator and/or activator of spinal locomotor networks. Thus noradrenergic fibers likely contact neurons involved in generating locomotion. The aim of the present study was to investigate the noradrenergic innervation of functionally related, locomotor-activated neurons within the thoraco-lumbar spinal cord. This was accomplished by immunohistochemical colocalization of noradrenergic fibers using dopamine-beta-hydroxylase or NEalpha(1A) and NEalpha(2B) receptors with cells expressing the c-fos gene activity-dependent marker Fos. Experiments were performed on paralyzed, precollicular-postmamillary decerebrate cats, in which locomotion was induced by electrical stimulation of the mesencephalic locomotor region. The majority of Fos labeled neurons, especially abundant in laminae VII and VIII throughout the thoraco-lumbar (T13-L7) region of locomotor animals, showed close contacts with multiple noradrenergic boutons. A small percentage (10-40%) of Fos neurons in the T7-L7 segments showed colocalization with NEalpha(1A) receptors. In contrast, NEalpha(2B) receptor immunoreactivity was observed in 70-90% of Fos cells, with no obvious rostrocaudal gradient. In comparison with results obtained from our previous study on the same animals, a significantly smaller proportion of Fos labeled neurons were innervated by noradrenergic than serotonergic fibers, with significant differences observed for laminae VII and VIII in some segments. In lamina VII of the lumbar segments, the degree of monoaminergic receptor subtype/Fos colocalization examined statistically generally fell into the following order: NEalpha(2B) = 5-HT(2A) >= 5-HT(7) = 5-HT(1A) > NEalpha(1A). These results suggest that noradrenergic modulation of locomotion involves NEalpha(1A)/NEalpha(2B) receptors on noradrenergic-innervated locomotor-activated neurons within laminae VII and VIII of thoraco-lumbar segments. Further study of the functional role of these receptors in locomotion is warranted. PMID- 21307326 TI - Unsupervised quantification of whisking and head movement in freely moving rodents. AB - The rodent whisker system has become the leading experimental paradigm for the study of active sensing. Thanks to more sophisticated behavioral paradigms, progressively better neurophysiological methods, and improved video hardware/software, there is now the prospect of defining the precise connection between the sensory apparatus and brain activity in awake, exploring animals. Achieving this ambitious goal requires quantitative, objective characterization of head and whisker kinematics. This study presents the methodology and potential uses of a new automated motion analysis routine. The program provides full quantification of head orientation and translation, as well as the angle, frequency, amplitude, and bilateral symmetry of whisking. The system operates without any need for manual tracing by the user. Quantitative comparison to whisker detection by expert humans indicates that the program's correct detection rate is at >95% even on animals with all whiskers intact. Particular attention has been paid to obtaining reliable performance under nonoptimal lighting or video conditions and at frame rates as low as 100. Variation of the zoom across time is compensated for without user intervention. The program adapts automatically to the size and shape of different species. The outcome of our testing indicates that the program can be a valuable tool in quantifying rodent sensorimotor behavior. PMID- 21307328 TI - Systematic mapping of the monkey inferior colliculus reveals enhanced low frequency sound representation. AB - We investigated the functional architecture of the inferior colliculus (IC) in rhesus monkeys. We systematically mapped multiunit responses to tonal stimuli and noise in the IC and surrounding tissue of six rhesus macaques, collecting data at evenly placed locations and recording nonresponsive locations to define boundaries. The results show a modest tonotopically organized region (17 of 100 recording penetration locations in 4 of 6 monkeys) surrounded by a large mass of tissue that, although vigorously responsive, showed no clear topographic arrangement (68 of 100 penetration locations). Rather, most cells in these recordings responded best to frequencies at the low end of the macaque auditory range. The remaining 15 (of 100) locations exhibited auditory responses that were not sensitive to sound frequency. Potential anatomical correlates of functionally defined regions and implications for midbrain auditory prosthetic devices are discussed. PMID- 21307327 TI - Network hyperexcitability in hippocampal slices from Mecp2 mutant mice revealed by voltage-sensitive dye imaging. AB - Dysfunctions of neuronal and network excitability have emerged as common features in disorders associated with intellectual disabilities, autism, and seizure activity, all common clinical manifestations of Rett syndrome (RTT), a neurodevelopmental disorder caused by loss-of-function mutations in the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). Here, we evaluated the consequences of Mecp2 mutation on hippocampal network excitability, as well as synapse structure and function using a combination of imaging and electrophysiological approaches in acute slices. Imaging the amplitude and spatiotemporal spread of neuronal depolarizations with voltage-sensitive dyes (VSD) revealed that the CA1 and CA3 regions of hippocampal slices from symptomatic male Mecp2 mutant mice are highly hyperexcitable. However, only the density of docked synaptic vesicles and the rate of release from the readily releasable pool are impaired in Mecp2 mutant mice, while synapse density and morphology are unaffected. The differences in network excitability were not observed in surgically isolated CA1 minislices, and blockade of GABAergic inhibition enhanced VSD signals to the same extent in Mecp2 mutant and wild-type mice, suggesting that network excitability originates in area CA3. Indeed, extracellular multiunit recordings revealed a higher level of spontaneous firing of CA3 pyramidal neurons in slices from symptomatic Mecp2 mutant mice. The neuromodulator adenosine reduced the amplitude and spatiotemporal spread of VSD signals evoked in CA1 of Mecp2 mutant slices to wild-type levels, suggesting its potential use as an anticonvulsant in RTT individuals. The present results suggest that hyperactive CA3 pyramidal neurons contribute to hippocampal dysfunction and possibly to limbic seizures observed in Mecp2 mutant mice and RTT individuals. PMID- 21307329 TI - Information transmission and detection thresholds in the vestibular nuclei: single neurons vs. population encoding. AB - Understanding how sensory neurons transmit information about relevant stimuli remains a major goal in neuroscience. Of particular relevance are the roles of neural variability and spike timing in neural coding. Peripheral vestibular afferents display differential variability that is correlated with the importance of spike timing; regular afferents display little variability and use a timing code to transmit information about sensory input. Irregular afferents, conversely, display greater variability and instead use a rate code. We studied how central neurons within the vestibular nuclei integrate information from both afferent classes by recording from a group of neurons termed vestibular only (VO) that are known to make contributions to vestibulospinal reflexes and project to higher-order centers. We found that, although individual central neurons had sensitivities that were greater than or equal to those of individual afferents, they transmitted less information. In addition, their velocity detection thresholds were significantly greater than those of individual afferents. This is because VO neurons display greater variability, which is detrimental to information transmission and signal detection. Combining activities from multiple VO neurons increased information transmission. However, the information rates were still much lower than those of equivalent afferent populations. Furthermore, combining responses from multiple VO neurons led to lower velocity detection threshold values approaching those measured from behavior (~ 2.5 vs. 0.5-1 degrees /s). Our results suggest that the detailed time course of vestibular stimuli encoded by afferents is not transmitted by VO neurons. Instead, they suggest that higher vestibular pathways must integrate information from central vestibular neuron populations to give rise to behaviorally observed detection thresholds. PMID- 21307330 TI - AMPA receptor subunit GluR1 (GluA1) serine-845 site is involved in synaptic depression but not in spine shrinkage associated with chemical long-term depression. AB - The structure of dendritic spines is highly plastic and can be modified by neuronal activity. In addition, there is evidence that spine head size correlates with the synaptic alpha-amino-3-hydroxy-5-methylisoxazole propionic acid (AMPA) receptor (AMPAR) content, which suggests that they may be coregulated. Although there is evidence that there are overlapping mechanisms for structural and functional plasticity, the extent of the overlap needs further investigation. Specifically, it is unknown whether AMPAR levels determine spine size or whether both are regulated via parallel pathways. We studied the correlation between spine structural plasticity and long-term synaptic plasticity following chemical induced long-term depression (chemLTD). In particular, we examined whether the regulation of AMPARs, which is implicated in LTD, is critical for spine morphological plasticity. We used mutant mice specifically lacking the serine-845 site on the type 1 glutamate receptor (GluR1, or GluA1) subunit of AMPARs (mutants). These mice specifically lack N-methyl-D-aspartate (NMDA) receptor (NMDAR)-dependent LTD and NMDAR activation-induced AMPAR endocytosis. We found that chemLTD causes a rapid and persistent shrinkage in spine head volume of hippocampal CA1 pyramidal neurons in wild types similar to that reported in other studies using low-frequency stimulation (LFS)-induced LTD. Surprisingly, we found that although S845A mutant mice display impaired chemLTD, the shrinkage of spine head volume occurred to a similar magnitude to that observed in wild types. Our results suggest that there is dissociation in the molecular mechanisms underlying functional LTD and spine shrinkage and that GluR1-S845 regulation is not necessary for spine morphological plasticity. PMID- 21307331 TI - Peripheral nerve damage does not alter release properties of developing central trigeminal afferents. AB - The infraorbital branch of the trigeminal nerve (ION) is essential in whisker specific neural patterning ("barrelettes") in the principal nucleus of the trigeminal nerve (PrV). The barrelettes are formed by the ION terminal arbors, somata, and dendrites of the PrV cells; they are abolished after neonatal damage to the ION. Physiological studies show that disruption of the barrelettes is accompanied by conversion of functional synapses into silent synapses in the PrV. In this study, we used whole cell recordings with a paired-pulse stimulation protocol and MK-801 blocking rate to estimate the presynaptic release probability (Pr) of ION central trigeminal afferent terminals in the PrV. We investigated Pr during postnatal development, following neonatal ION damage, and determined whether conversion of functional synapses into silent synapses after peripheral denervation results from changes in Pr. The paired-pulse ratio (PPR) was quite variable ranging from 40% (paired-pulse depression) to 175% (paired-pulse facilitation). The results from paired-pulse protocol were confirmed by MK-801 blocking rate experiments. The nonuniform PPRs did not show target cell specificity and developmental regulation. The distribution of PPRs fit nicely to Gaussian function with a peak at ~ 100%. In addition, neonatal ION transections did not alter the distribution pattern of PPR in their central terminals, suggesting that the conversion from functional synapses into silent synapses in the peripherally denervated PrV is not caused by changes in the Pr. PMID- 21307332 TI - State-dependent sensorimotor processing: gaze and posture stability during simulated flight in birds. AB - Vestibular responses play an important role in maintaining gaze and posture stability during rotational motion. Previous studies suggest that these responses are state dependent, their expression varying with the environmental and locomotor conditions of the animal. In this study, we simulated an ethologically relevant state in the laboratory to study state-dependent vestibular responses in birds. We used frontal airflow to simulate gliding flight and measured pigeons' eye, head, and tail responses to rotational motion in darkness, under both head fixed and head-free conditions. We show that both eye and head response gains are significantly higher during flight, thus enhancing gaze and head-in-space stability. We also characterize state-specific tail responses to pitch and roll rotation that would help to maintain body-in-space orientation during flight. These results demonstrate that vestibular sensorimotor processing is not fixed but depends instead on the animal's behavioral state. PMID- 21307333 TI - Membrane-tethered peptides patterned after the TRP domain (TRPducins) selectively inhibit TRPV1 channel activity. AB - The transient receptor potential vanilloid 1 (TRPV1) channel is a thermosensory receptor implicated in diverse physiological and pathological processes. The TRP domain, a highly conserved region in the C terminus adjacent to the internal channel gate, is critical for subunit tetramerization and channel gating. Here, we show that cell-penetrating, membrane-anchored peptides patterned after this protein domain are moderate and selective TRPV1 antagonists both in vitro and in vivo, blocking receptor activity in intact rat primary sensory neurons and their peripheral axons with mean decline time of 30 min. The most potent lipopeptide, TRP-p5, blocked all modes of TRPV1 gating with micromolar efficacy (IC(50)<10 MUM), without significantly affecting other thermoTRP channels. In contrast, its retrosequence or the corresponding sequences of other TRPV channels did not alter TRPV1 channel activity (IC(50)>100 MUM). TRP-p5 did not affect the capsaicin sensitivity of the vanilloid receptor. Our data suggest that TRP-p5 interferes with protein-protein interactions at the level of the TRP domain that are essential for the "conformational" change that leads to gate opening. Therefore, these palmitoylated peptides, which we termed TRPducins, are noncompetitive, voltage-independent, sequence-specific TRPV1 blockers. Our findings indicate that TRPducin-like peptides may embody a novel molecular strategy that can be exploited to generate a selective pharmacological arsenal for the TRP superfamily of ion channels. PMID- 21307334 TI - Salivary glands act as mucosal inductive sites via the formation of ectopic germinal centers after site-restricted MCMV infection. AB - We investigated the hypothesis that salivary gland inoculation stimulates formation of ectopic germinal centers (GCs), transforming the gland into a mucosal inductive site. Intraglandular infection of mice with murine cytomegalovirus (MCMV; control: UV-inactivated MCMV) induces salivary gland ectopic follicles comprising cognate interactions between CD4(+) and B220(+) lymphocytes, IgM(+) and isotype-switched IgG(+) and IgA(+) B cells, antigen presenting cells, and follicular dendritic cells. B cells coexpressed the GC markers GCT (57%) and GL7 (52%), and bound the lectin peanut agglutinin. Lymphoid follicles were characterized by a 2- to 3-fold increase in mRNA for CXCL13 (lymphoid neogenesis), syndecan-1 (plasma cells), Blimp-1 (plasma cell development/differentiation), and a 2- to 6-fold increase for activation-induced cytidine deaminase, PAX5, and the nonexcised rearranged DNA of an IgA class switch event, supporting somatic hypermutation and class-switch recombination within the salivary follicles. Intraglandular inoculation also provided protection against a systemic MCMV challenge, as evidenced by decreased viral titers (10(5) plaque-forming units to undetectable), and restoration of normal salivary flow rates from a 6-fold decrease. Therefore, these features suggest that the salivary gland participates in oral mucosal immunity via generation of ectopic GCs, which function as ectopic mucosal inductive sites. PMID- 21307335 TI - Leukotriene B4/antimicrobial peptide LL-37 proinflammatory circuits are mediated by BLT1 and FPR2/ALX and are counterregulated by lipoxin A4 and resolvin E1. AB - In humans, the antimicrobial peptide LL-37 and leukotriene B(4) (LTB(4)) are important proinflammatory mediators, whereas lipoxin A(4) (LXA(4)) and resolvin E1 (RvE1) possess anti-inflammatory, proresolving properties. Previously, we reported that LTB(4) triggers LL-37 release from human neutrophils (PMNs) and, conversely, that LL-37 promotes LTB(4) production from these cells. Here we show that this effect of LL-37 is mediated via the GPCR FPR2/ALX. LL-37 (5-30 MUg/ml) induces intracellular calcium mobilization in a dose-dependent manner, and the signal transduction leading to LTB(4) release involves p38 MAP kinase and phosphorylation of cPLA(2). LXA(4), an endogenous lipid ligand of FPR2/ALX, and a stable LXA(4) analog [benzo-LXA(4)] were ineffective as stimuli at the concentrations of 0.1-10 nM for LTB(4) release from PMNs. Likewise, the BLT1 ligand RvE1, a derivative of eicosapentaenoic acid, inhibited LTB(4)-induced LL 37 production from PMNs at 1-100 nM, whereas chemerin, a peptide ligand of the RvE1 receptor ChemR23, failed to block LTB(4)-induced LL-37 release at the same concentrations. Hence, in human neutrophils, binding of LL-37 to FPR2/ALX promotes LTB(4) production, which can bind to BLT1 and elicit further LL-37 release. This proinflammatory circuit might be inhibited by LXA(4) and RvE(1) acting at FPR2/ALX and BLT1, respectively, leading to dampened mediator release. PMID- 21307336 TI - The posttranslational modification of tubulin undergoes a switch from detyrosination to acetylation as epithelial cells become polarized. AB - Tubulin posttranslational modifications (PTMs) have been suggested to provide navigational cues for molecular motors to deliver cargo to spatially segregated subcellular domains, but the molecular details of this process remain unclear. Here we show that in Madin-Darby Canine Kidney (MDCK) epithelial cells, microtubules express several tubulin PTMs. These modifications, however, are not coordinated, and cells have multiple subpopulations of microtubules that are marked by different combinations of PTMs. Furthermore these subpopulations show differential sensitivity to both drug- and cold-induced depolymerization, suggesting that they are functionally different as well. The composition and distribution of modified microtubules change as cells undergo the morphogenesis associated with polarization. Two-dimensionally polarized spreading cells have more detyrosinated microtubules that are oriented toward the leading edge, but three-dimensionally polarized cells have more acetylated microtubules that are oriented toward the apical domain. These data suggest that the transition from 2D polarity to 3D polarity involves both a reorganization of the microtubule cytoskeleton and a change in tubulin PTMs. However, in both 2D polarized and 3D polarized cells, the modified microtubules are oriented to support vectorial cargo transport to areas of high need. PMID- 21307337 TI - IFT20 is required for opsin trafficking and photoreceptor outer segment development. AB - The light-detecting outer segments of vertebrate photoreceptors are cilia. Like other cilia, all materials needed for assembly and maintenance are synthesized in the cell body and transported into the cilium. The highly elaborated nature of the outer segment and its high rate of turnover necessitate unusually high levels of transport into the cilium. In this work, we examine the role of the IFT20 subunit of the intraflagellar transport (IFT) particle in photoreceptor cells. IFT20 was deleted in developing cones by a cone-specific Cre and in mature rods and cones by a tamoxifen-activatable Cre. Loss of IFT20 during cone development leads to opsin accumulation in the inner segment even when the connecting cilium and outer segment are still intact. With time this causes cone cell degeneration. Similarly, deletion of IFT20 in mature rods causes rapid accumulation of rhodopsin in the cell body, where it is concentrated at the Golgi complex. We further show that IFT20, acting both as part of the IFT particle and independent of the particle, binds to rhodopsin and RG-opsin. Since IFT20 dynamically moves between the Golgi complex and the connecting cilium, the current work suggests that rhodopsin and opsins are cargo for IFT transport. PMID- 21307338 TI - CK1 activates minus-end-directed transport of membrane organelles along microtubules. AB - Microtubule (MT)-based organelle transport is driven by MT motor proteins that move cargoes toward MT minus-ends clustered in the cell center (dyneins) or plus ends extended to the periphery (kinesins). Cells are able to rapidly switch the direction of transport in response to external cues, but the signaling events that control switching remain poorly understood. Here, we examined the signaling mechanism responsible for the rapid activation of dynein-dependent MT minus-end directed pigment granule movement in Xenopus melanophores (pigment aggregation). We found that, along with the previously identified protein phosphatase 2A (PP2A), pigment aggregation signaling also involved casein kinase 1epsilon (CK1epsilon), that both enzymes were bound to pigment granules, and that their activities were increased during pigment aggregation. Furthermore we found that CK1epsilon functioned downstream of PP2A in the pigment aggregation signaling pathway. Finally, we discovered that stimulation of pigment aggregation increased phosphorylation of dynein intermediate chain (DIC) and that this increase was partially suppressed by CK1epsilon inhibition. We propose that signal transduction during pigment aggregation involves successive activation of PP2A and CK1epsilon and CK1epsilon-dependent phosphorylation of DIC, which stimulates dynein motor activity and increases minus-end-directed runs of pigment granules. PMID- 21307339 TI - Dynamic and structural signatures of lamellar actomyosin force generation. AB - The regulation of cellular traction forces on the extracellular matrix is critical to cell adhesion, migration, proliferation, and differentiation. Diverse lamellar actin organizations ranging from contractile lamellar networks to stress fibers are observed in adherent cells. Although lamellar organization is thought to reflect the extent of cellular force generation, understanding of the physical behaviors of the lamellar actin cytoskeleton is lacking. To elucidate these properties, we visualized the actomyosin dynamics and organization in U2OS cells over a broad range of forces. At low forces, contractile lamellar networks predominate and force generation is strongly correlated to actomyosin retrograde flow dynamics with nominal change in organization. Lamellar networks build ~60% of cellular tension over rapid time scales. At high forces, reorganization of the lamellar network into stress fibers results in moderate changes in cellular tension over slower time scales. As stress fibers build and tension increases, myosin band spacing decreases and alpha-actinin bands form. On soft matrices, force generation by lamellar networks is unaffected, whereas tension-dependent stress fiber assembly is abrogated. These data elucidate the dynamic and structural signatures of the actomyosin cytoskeleton at different levels of tension and set a foundation for quantitative models of cell and tissue mechanics. PMID- 21307340 TI - UXT-V1 protects cells against TNF-induced apoptosis through modulating complex II formation. AB - Proteins that directly regulate tumor necrosis factor (TNF) signaling have critical roles in determining cell death and survival. Previously we characterized ubiquitously expressed transcript (UXT)-V2 as a novel transcriptional cofactor to regulate nuclear factor-kappaB in the nucleus. Here we report that another splicing isoform of UXT, UXT-V1, localizes in cytoplasm and regulates TNF-induced apoptosis. UXT-V1 knockdown cells are hypersensitive to TNF-induced apoptosis. We demonstrated that UXT-V1 is a new component of TNF receptor signaling complex. We found that UXT-V1 binds to TNF receptor-associated factor 2 and prevents TNF receptor-associated death domain protein from recruiting Fas-associated protein with death domain. More importantly, UXT-V1 is a short-half-life protein, the degradation of which facilitates the formation of the apoptotic receptor complex II in response to TNF treatment. This study demonstrates that UXT-V1 is a novel regulator of TNF-induced apoptosis and sheds new light on the underlying molecular mechanism of this process. PMID- 21307341 TI - The disruption of central CO2 chemosensitivity in a mouse model of Rett syndrome. AB - People with Rett syndrome (RTT) have breathing instability in addition to other neuropathological manifestations. The breathing disturbances contribute to the high incidence of unexplained death and abnormal brain development. However, the cellular mechanisms underlying the breathing abnormalities remain unclear. To test the hypothesis that the central CO(2) chemoreception in these people is disrupted, we studied the CO(2) chemosensitivity in a mouse model of RTT. The Mecp2-null mice showed a selective loss of their respiratory response to 1-3% CO(2) (mild hypercapnia), whereas they displayed more regular breathing in response to 6-9% CO(2) (severe hypercapnia). The defect was alleviated with the NE uptake blocker desipramine (10 mg.kg(-1).day(-1) ip, for 5-7 days). Consistent with the in vivo observations, in vitro studies in brain slices indicated that CO(2) chemosensitivity of locus coeruleus (LC) neurons was impaired in Mecp2-null mice. Two major neuronal pH-sensitive Kir currents that resembled homomeric Kir4.1 and heteromeric Ki4.1/Kir5.1 channels were identified in the LC neurons. The screening of Kir channels with real-time PCR indicated the overexpression of Kir4.1 in the LC region of Mecp2-null mice. In a heterologous expression system, an overexpression of Kir4.1 resulted in a reduction in the pH sensitivity of the heteromeric Kir4.1-Kir5.1 channels. Given that Kir4.1 and Kir5.1 subunits are also expressed in brain stem respiration-related areas, the Kir4.1 overexpression may not allow CO(2) to be detected until hypercapnia becomes severe, leading to periodical hyper- and hypoventilation in Mecp2-null mice and, perhaps, in people with RTT as well. PMID- 21307342 TI - Live pancreatic acinar imaging of exocytosis using syncollin-pHluorin. AB - In this report, a novel live acinar exocytosis imaging technique is described. An adenovirus was engineered, encoding for an endogenous zymogen granule (ZG) protein (syncollin) fused to pHluorin, a pH-dependent green fluorescent protein (GFP). Short-term culture of mouse acini infected with this virus permits exogenous adenoviral protein expression while retaining acinar secretory competence and cell polarity. The syncollin-pHluorin fusion protein was shown to be correctly localized to ZGs, and the pH-dependent fluorescence of pHluorin was retained. Coupled with the use of a spinning disk confocal microscope, the syncollin-pHluorin fusion protein exploits the ZG luminal pH changes that occur during exocytosis to visualize exocytic events of live acinar cells in real-time with high spatial resolution in three dimensions. Apical and basolateral exocytic events were observed on stimulation of acinar cells with maximal and supramaximal cholecystokinin concentrations, respectively. Sequential exocytic events were also observed. Coupled with the use of transgenic mice and/or adenovirus-mediated protein expression, this syncollin-pHluorin imaging method offers a superior approach to studying pancreatic acinar exocytosis. This assay can also be applied to acinar disease models to elucidate the mechanisms implicated in pancreatitis. PMID- 21307343 TI - Expression of TASK-2 and its upregulation by B cell receptor stimulation in WEHI 231 mouse immature B cells. AB - Stimulation of B cell receptors (BCR ligation) induces apoptosis of immature B cells, which is critical to the elimination of self-reactive clones. In the mouse immature B cell line WEHI-231, the authors previously reported two types of background K+ channels with large (~300 pS, LK(bg)) and medium (~100 pS, MK(bg)) conductance in divalent cation-free conditions. While the authors have recently identified LK(bg) as TREK-2, the molecular nature of MK(bg) is unknown yet. In the present study, the authors found that BCR ligation markedly increased the background K+ conductance of WEHI-231. A single-channel study revealed that MK(bg) activity is increased by BCR ligation and that the biophysical properties (unitary conductance and pH sensitivity) of MK(bg) are consistent with those of TWIK-related acid-sensitive K+ channel 2 (TASK-2). The expression of TASK-2 and its upregulation by BCR ligation were confirmed by RT-PCR and immunoblot assays in WEHI-231. The BCR ligation-induced increase of K+ current was prevented by calcineurin inhibitors (cyclosporine A or FK506), and also by TASK-2-specific small interfering RNA (siRNA) transfection (si-TASK-2). Furthermore, si-TASK-2 attenuated the apoptosis of WEHI-231 caused by BCR ligation. TASK-2 activity and its mRNA were also confirmed in the primary splenic B cells of mouse. Summarizing, the authors report for the first time the expression of TASK-2 in B cells and surmise that the upregulation of TASK-2 by BCR ligation is associated with the apoptosis of immature B cells. PMID- 21307344 TI - Establishment of esophageal-like non-keratinized stratified epithelium using normal human bronchial epithelial cells. AB - Current experimental models of esophageal epithelium in vitro suffer from either poor differentiation or complicated culture systems. We have established a model to study stratified squamous epithelium in vitro, which is very similar to esophageal epithelium in vivo. A stratified squamous multilayer epithelium was formed by seeding primary normal human bronchial epithelial (NHBE) cells onto collagen- and fibronectin-coated trans-well inserts and then cultivating the cells under air-liquid interface (ALI) conditions in the presence of growth factors and low levels of all-trans-retinoic acid. Trans-epithelial electrical resistance (TEER) measurements revealed the presence of a tight barrier, previously only achievable with esophageal biopsies mounted in Ussing chambers. Molecular markers for desmosomes, cornified envelope, tight junctions, and mature esophageal epithelium were upregulated in the differentiating culture in parallel with functional properties, such as decreased permeability and acid resistance and restoration. Acid exposure resulted in a decrease in TEER, but following 1-h recovery the TEER values were fully restored. Treatment with all-trans-retinoic acid decreased TEER and inhibited the recovery after acid challenge. PPAR-delta agonist treatment increased TEER, and this temporary increase in TEER was consistent with an increase in involucrin mRNA. Global gene expression analysis showed that ALI-differentiated NHBE cells had expression profiles more similar to epithelial biopsies from the esophageal tissue of healthy volunteers than to any other cell line. With respect to morphology, molecular markers, barrier properties, and acid resistance, this model presents a new way to investigate barrier properties and the possible effects of different agents on human esophagus-like epithelium. PMID- 21307345 TI - Episodic ataxia type 1 mutations affect fast inactivation of K+ channels by a reduction in either subunit surface expression or affinity for inactivation domain. AB - Episodic ataxia type 1 (EA1) is an autosomal dominant disorder characterized by continuous myokymia and episodic attacks of ataxia. Mutations in the gene KCNA1 that encodes the voltage-gated potassium channel Kv1.1 are responsible for EA1. In several brain areas, Kv1.1 coassembles with Kv1.4, which confers N-type inactivating properties to heteromeric channels. It is therefore likely that the rate of inactivation will be determined by the number of Kv1.4 inactivation particles, as set by the precise subunit stoichiometry. We propose that EA1 mutations affect the rate of N-type inactivation either by reduced subunit surface expression, giving rise to a reduced number of Kv1.1 subunits in heterotetramer Kv1.1-Kv1.4 channels, or by reduced affinity for the Kv1.4 inactivation domain. To test this hypothesis, quantified amounts of mRNA for Kv1.4 or Kv1.1 containing selected EA1 mutations either in the inner vestibule of Kv1.1 on S6 or in the transmembrane regions were injected into Xenopus laevis oocytes and the relative rates of inactivation and stoichiometry were determined. The S6 mutations, V404I and V408A, which had normal surface expression, reduced the rate of inactivation by a decreased affinity for the inactivation domain while the mutations I177N in S1 and E325D in S5, which had reduced subunit surface expression, increased the rate of N-type inactivation due to a stoichiometric increase in the number of Kv1.4 subunits. PMID- 21307346 TI - Response gene to complement 32 interacts with Smad3 to promote epithelial mesenchymal transition of human renal tubular cells. AB - Previous studies demonstrate that response gene to complement 32 (RGC-32) mediates transforming growth factor-beta(1)-induced epithelial-mesenchymal transition (EMT) of human renal proximal tubular cells. However, the mechanisms underlying RGC-32 function remain largely unknown. In the present study, we found that RGC-32 function in EMT is associated with Smad3. Coexpression of RGC-32 and Smad3, but not Smad2, induces a higher mesenchymal marker alpha-smooth muscle actin (alpha-SMA) protein expression as compared with RGC-32 or Smad3 alone, while knockdown of Smad3 using short hairpin interfering RNA blocks RGC-32 induced alpha-SMA expression. These data suggest that RGC-32 interacts with Smad3, but not Smad2, in the regulation of EMT. In addition to alpha-SMA, RGC-32 and Smad3 also synergistically activate the expression of extracellular matrix protein fibronectin and downregulate the epithelial marker E-cadherin. RGC-32 colocalizes with Smad3 in the nuclei of renal proximal tubular cells. Coimmunoprecipitation assays showed that Smad3, but not Smad2, physically interacts with RGC-32 in renal proximal tubular cells. Mechanistically, RGC-32 and Smad3 coordinate the induction of EMT by regulating the EMT regulators Slug and Snail. Taken together, our data demonstrate for the first time that RGC-32 interacts with Smad3 to mediate the EMT of human renal proximal tubular cells. PMID- 21307347 TI - Collagen IV contributes to nitric oxide-induced angiogenesis of lung endothelial cells. AB - Nitric oxide (NO) mediates endothelial angiogenesis via inducing the expression of integrin alpha(v)beta(3). During angiogenesis, endothelial cells adhere to and migrate into the extracellular matrix through integrins. Collagen IV binds to integrin alpha(v)beta(3), leading to integrin activation, which affects a number of signaling processes in endothelial cells. In the present study, we evaluated the role of collagen IV in NO-induced angiogenesis. We found that NO donor 2,2' (hydroxynitrosohydrazino)bis-ethanamine (NOC-18) causes increases in collagen IV mRNA and protein in lung endothelial cells and collagen IV release into the medium. Addition of collagen IV into the coating of endothelial culture increases endothelial monolayer wound repair, proliferation, and tube formation. Inhibition of collagen IV synthesis using gene silencing attenuates NOC-18-induced increases in monolayer wound repair, cell proliferation, and tube formation as well as in the phosphorylation of focal adhesion kinase (FAK). Integrin blocking antibody LM609 prevents NOC-18-induced increase in endothelial monolayer wound repair. Inhibition of protein kinase G (PKG) using the specific PKG inhibitor KT5823 or PKG small interfering RNA prevents NOC-18-induced increases in collagen IV protein and mRNA and endothelial angiogenesis. Together, these results indicate that NO promotes collagen IV synthesis via a PKG signaling pathway and that the increase in collagen IV synthesis contributes to NO-induced angiogenesis of lung endothelial cells through integrin-FAK signaling. Manipulation of collagen IV could be a novel approach for the prevention and treatment of diseases such as alveolar capillary dysplasia, severe pulmonary arterial hypertension, and tumor invasion. PMID- 21307348 TI - Aldolase directly interacts with ARNO and modulates cell morphology and acidic vesicle distribution. AB - Previously, we demonstrated that the vacuolar-type H(+)-ATPase (V-ATPase) a2 subunit functions as an endosomal pH sensor that interacts with the ADP ribosylation factor (Arf) guanine nucleotide exchange factor, ARNO. In the present study, we showed that ARNO directly interacts not only with the a2 subunit but with all a-isoforms (a1-a4) of the V-ATPase, indicating a widespread regulatory interaction between V-ATPase and Arf GTPases. We then extended our search for other ARNO effectors that may modulate V-ATPase-dependent vesicular trafficking events and actin cytoskeleton remodeling. Pull-down experiments using cytosol of mouse proximal tubule cells (MTCs) showed that ARNO interacts with aldolase, but not with other enzymes of the glycolytic pathway. Direct interaction of aldolase with the pleckstrin homology domain of ARNO was revealed by pull-down assays using recombinant proteins, and surface plasmon resonance revealed their high avidity interaction with a dissociation constant: K(D) = 2.84 * 10(-10) M. MTC cell fractionation revealed that aldolase is also associated with membranes of early endosomes. Functionally, aldolase knockdown in HeLa cells produced striking morphological changes accompanied by long filamentous cell protrusions and acidic vesicle redistribution. However, the 50% knockdown we achieved did not modulate the acidification capacity of endosomal/lysosomal compartments. Finally, a combination of small interfering RNA knockdown and overexpression revealed that the expression of aldolase is inversely correlated with gelsolin levels in HeLa cells. In summary, we have shown that aldolase forms a complex with ARNO/Arf6 and the V-ATPase and that it may contribute to remodeling of the actin cytoskeleton and/or the trafficking and redistribution of V-ATPase-dependent acidic compartments via a combination of protein-protein interaction and gene expression mechanisms. PMID- 21307349 TI - Effect of dexamethasone on Na+/Ca2+ exchanger in dendritic cells. AB - Ca(+)-dependent signaling regulates the function of dendritic cells (DCs), antigen-presenting cells linking innate and adaptive immunity. The activity of DCs is suppressed by glucocorticoids, potent immunosuppressive hormones. The present study explored whether the glucocorticoid dexamethasone influences the cytosolic Ca(2+) concentration ([Ca(2+)](i)) in DCs. To this end, DCs were isolated from mouse bone marrow. According to fura-2 fluorescence, exposure of DCs to lipopolysaccharide (LPS, 100 ng/ml) increased [Ca(2+)](i), an effect significantly blunted by overnight incubation with 10 nM dexamethasone before LPS treatment. Dexamethasone did not affect the Ca(2+) content of intracellular stores, sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA)2 and SERCA3 expression, ryanodine receptor (RyR)1 expression, or Ca(2+) entry through store operated Ca(2+) channels. In contrast, dexamethasone increased the transcript level and the membrane protein abundance of the Na(+)/Ca(2+) exchanger NCX3. The activity of Na(+)/Ca(2+) exchangers was assessed by removal of extracellular Na(+) in the presence of external Ca(2+), a maneuver triggering the Ca(2+) influx mode. Indeed, Na(+) removal resulted in a rapid transient increase of [Ca(2+)](i) and induced an outwardly directed current as measured in whole cell patch-clamp experiments. Dexamethasone significantly augmented the increase of [Ca(2+)](i) and the outward current following removal of extracellular Na(+). The NCX blocker KB-R7943 reversed the inhibitory effect of dexamethasone on LPS-induced increase in [Ca(2+)](i). Dexamethasone blunted LPS-induced stimulation of CD86 expression and TNF-alpha production, an effect significantly less pronounced in the presence of NCX blocker KB-R7943. In conclusion, our results show that glucocorticoid treatment blunts LPS-induced increase in [Ca(2+)](i) in DCs by increasing expression and activity of Na(+)/Ca(2+) exchanger NCX3. The effect contributes to the inhibitory effect of the glucocorticoid on DC maturation. PMID- 21307350 TI - Evidence for two different broad-specificity oligopeptide transporters in intestinal cell line Caco-2 and colonic cell line CCD841. AB - Recently the existence of two different Na(+)-coupled oligopeptide transport systems has been described in mammalian cells. These transport systems are distinct from the previously known H(+)/peptide cotransporters PEPT1 and PEPT2, which transport only dipeptides and tripeptides. To date, the only peptide transport system known to exist in the intestine is PEPT1. Here we investigated the expression of the Na(+)-coupled oligopeptide transporters in intestinal cell lines, using the hydrolysis-resistant synthetic oligopeptides deltorphin II and [d-Ala(2),d-Leu(5)]enkephalin (DADLE) as model substrates. Caco-2 cells and CCD841 cells, both representing epithelial cells from human intestinal tract, were able to take up these oligopeptides. Uptake of deltorphin II was mostly Na(+) dependent, with more than 2 Na(+) involved in the uptake process. In contrast, DADLE uptake was only partially Na(+) dependent. The uptake of both peptides was also influenced by H(+) and Cl(-), although to a varying degree. The processes responsible for the uptake of deltorphin II and DADLE could be differentiated not only by their Na(+) dependence but also by their modulation by small peptides. Several dipeptides and tripeptides stimulated deltorphin II uptake but inhibited DADLE uptake. These modulating small peptides were, however, not transportable substrates for the transport systems that mediate deltorphin II or DADLE uptake. These two oligopeptide transport systems were also able to take up several nonopioid oligopeptides, consisting of 9-17 amino acids. This represents the first report on the existence of transport systems in intestinal cells that are distinct from PEPT1 and capable of transporting oligopeptides consisting of five or more amino acids. PMID- 21307351 TI - Re: "Invited commentary: personality as a causal factor in cancer risk and mortality--time to retire a hypothesis?". PMID- 21307353 TI - The metabolic landscape of Tourette syndrome: learning to view the elephant as an elephant. PMID- 21307352 TI - Nonconvulsive seizures are common in critically ill children. AB - BACKGROUND: Retrospective studies have reported the occurrence of nonconvulsive seizures in critically ill children. We aimed to prospectively determine the incidence and risk factors of nonconvulsive seizures in critically ill children using predetermined EEG monitoring indications and EEG interpretation terminology. METHODS: Critically ill children (non-neonates) with acute encephalopathy underwent continuous EEG monitoring if they met institutional clinical practice criteria. Study enrollment and data collection were prospective. Logistic regression analysis was utilized to identify risk factors for seizure occurrence. RESULTS: One hundred children were evaluated. Electrographic seizures occurred in 46 and electrographic status epilepticus occurred in 19. Seizures were exclusively nonconvulsive in 32. The only clinical risk factor for seizure occurrence was younger age (p=0.03). Of patients with seizures, only 52% had seizures detected in the first hour of monitoring, while 87% were detected within 24 hours. CONCLUSIONS: Seizures were common in critically ill children with acute encephalopathy. Most were nonconvulsive. Clinical features had little predictive value for seizure occurrence. Further study is needed to confirm these data in independent high-risk populations, to clarify which children are at highest risk for seizures so limited monitoring resources can be allocated optimally, and to determine whether seizure detection and management improves outcome. PMID- 21307355 TI - Delirium in the acute phase after stroke: incidence, risk factors, and outcome. AB - OBJECTIVES: This prospective cohort study assesses incidence of delirium after stroke. In addition, risk factors during the first week were assessed. Finally, outcome in relation to development of delirium was studied. METHODS: A total of 527 consecutive patients with stroke (median age, 72 years; range, 29-96 years) were screened for delirium during the first week after admission. We diagnosed delirium with the Confusion Assessment Method. Cognitive functioning prior to the stroke was assessed with the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Neurologic deficits were assessed with the NIH Stroke Scale. RESULTS: A total of 62 patients with stroke (11.8%) developed delirium during the first week of admission. Independent risk factors were preexisting cognitive decline (odds ratio [OR] for IQCODE above 50: 2.6, 95% confidence interval [CI] 1.2-5.7) and infection (OR 3.4, 95% CI 1.7-6.8). Furthermore, right-sided hemispheric stroke (OR 2.0, 95% CI 1.0-3.0), anterior circulation large-vessel stroke (OR 3.4, 95% CI 1.1-10.2), the highest tertile of the NIH Stroke Scale (OR for highest vs lowest tertile 15.1, 95% CI 3.3-69.0), and brain atrophy (OR for highest versus lowest tertile 2.7, 95% CI 1.1-6.8) increased the risk for delirium. Delirium was associated with a worse outcome in terms of duration of hospitalization, mortality, and functional outcome. CONCLUSIONS: Delirium occurs in almost 1 out of every 8 patients with stroke on a stroke unit and is associated with cognitive decline, infection, right-sided hemispheric stroke, anterior circulation large-vessel stroke, stroke severity, and brain atrophy. Delirium after stroke is associated with a worse outcome. PMID- 21307354 TI - Abnormal metabolic brain networks in Tourette syndrome. AB - OBJECTIVES: To identify metabolic brain networks that are associated with Tourette syndrome (TS) and comorbid obsessive-compulsive disorder (OCD). METHODS: We utilized [(18)F]-fluorodeoxyglucose and PET imaging to examine brain metabolism in 12 unmedicated patients with TS and 12 age-matched controls. We utilized a spatial covariance analysis to identify 2 disease-related metabolic brain networks, one associated with TS in general (distinguishing TS subjects from controls), and another correlating with OCD severity (within the TS group alone). RESULTS: Analysis of the combined group of patients with TS and healthy subjects revealed an abnormal spatial covariance pattern that completely separated patients from controls (p < 0.0001). This TS-related pattern (TSRP) was characterized by reduced resting metabolic activity of the striatum and orbitofrontal cortex associated with relative increases in premotor cortex and cerebellum. Analysis of the TS cohort alone revealed the presence of a second metabolic pattern that correlated with OCD in these patients. This OCD-related pattern (OCDRP) was characterized by reduced activity of the anterior cingulate and dorsolateral prefrontal cortical regions associated with relative increases in primary motor cortex and precuneus. Subject expression of OCDRP correlated with the severity of this symptom (r = 0.79, p < 0.005). CONCLUSION: These findings suggest that the different clinical manifestations of TS are associated with the expression of 2 distinct abnormal metabolic brain networks. These, and potentially other disease-related spatial covariance patterns, may prove useful as biomarkers for assessing responses to new therapies for TS and related comorbidities. PMID- 21307356 TI - Nonconvulsive seizures among critically ill children: look and you shall find. PMID- 21307357 TI - Longitudinal patterns of emerging literacy in beginning deaf and hearing readers. AB - The emerging reading and spelling abilities of 24 deaf and 23 hearing beginning readers were followed over 2 years. The deaf children varied in their language backgrounds and preferred mode of communication. All children were given a range of literacy, cognitive and language-based tasks every 12 months. Deaf and hearing children made similar progress in literacy in the beginning stages of reading development and then their trajectories began to diverge. The longitudinal correlates of beginning reading in the deaf children were earlier vocabulary, letter-sound knowledge, and speechreading. Earlier phonological awareness was not a longitudinal correlate of reading ability once earlier reading levels were controlled. Only letter name knowledge was longitudinally related to spelling ability. Speechreading was also a strong longitudinal correlate of reading and spelling in the hearing children. The findings suggested that deaf and hearing children utilize slightly different reading strategies over the first 2 years of schooling. PMID- 21307358 TI - Evidence that a higher ATP cost of muscular contraction contributes to the lower mechanical efficiency associated with COPD: preliminary findings. AB - Impaired metabolism in peripheral skeletal muscles potentially contributes to exercise intolerance in chronic obstructive pulmonary disease (COPD). We used (31)P-magnetic resonance spectroscopy ((31)P-MRS) to examine the energy cost and skeletal muscle energetics in six patients with COPD during dynamic plantar flexion exercise compared with six well-matched healthy control subjects. Patients with COPD displayed a higher energy cost of muscle contraction compared with the controls (control: 6.1 +/- 3.1% of rest.min(-1).W(-1), COPD: 13.6 +/- 8.3% of rest.min(-1).W(-1), P = 0.01). Although, the initial phosphocreatine resynthesis rate was also significantly attenuated in patients with COPD compared with controls (control: 74 +/- 17% of rest/min, COPD: 52 +/- 13% of rest/min, P = 0.04), when scaled to power output, oxidative ATP synthesis was similar between groups (6.5 +/- 2.3% of rest.min(-1).W(-1) in control and 7.8 +/- 3.9% of rest.min(-1).W(-1) in COPD, P = 0.52). Therefore, our results reveal, for the first time that in a small subset of patients with COPD a higher ATP cost of muscle contraction may substantially contribute to the lower mechanical efficiency previously reported in this population. In addition, it appears that some patients with COPD have preserved mitochondrial function and normal energy supply in lower limb skeletal muscle. PMID- 21307359 TI - Elevated seawater PCO2 differentially affects branchial acid-base transporters over the course of development in the cephalopod Sepia officinalis. AB - The specific transporters involved in maintenance of blood pH homeostasis in cephalopod molluscs have not been identified to date. Using in situ hybridization and immunohistochemical methods, we demonstrate that Na(+)/K(+)-ATPase (soNKA), a V-type H(+)-ATPase (soV-HA), and Na(+)/HCO(3)(-) cotransporter (soNBC) are colocalized in NKA-rich cells in the gills of Sepia officinalis. mRNA expression patterns of these transporters and selected metabolic genes were examined in response to moderately elevated seawater Pco(2) (0.16 and 0.35 kPa) over a time course of 6 wk in different ontogenetic stages. The applied CO(2) concentrations are relevant for ocean acidification scenarios projected for the coming decades. We determined strong expression changes in late-stage embryos and hatchlings, with one to three log2-fold reductions in soNKA, soNBCe, socCAII, and COX. In contrast, no hypercapnia-induced changes in mRNA expression were observed in juveniles during both short- and long-term exposure. However, a transiently increased ion regulatory demand was evident during the initial acclimation reaction to elevated seawater Pco(2). Gill Na(+)/K(+)-ATPase activity and protein concentration were increased by ~15% during short (2-11 days) but not long-term (42-days) exposure. Our findings support the hypothesis that the energy budget of adult cephalopods is not significantly compromised during long-term exposure to moderate environmental hypercapnia. However, the downregulation of ion regulatory and metabolic genes in late-stage embryos, taken together with a significant reduction in somatic growth, indicates that cephalopod early life stages are challenged by elevated seawater Pco(2). PMID- 21307360 TI - Voluntary exercise in pregnant rats positively influences fetal growth without initiating a maternal physiological stress response. AB - The effects of increased physical activity during pregnancy on the health of the offspring in later life are unknown. Research in this field requires an animal model of exercise during pregnancy that is sufficiently strenuous to cause an effect but does not elicit a stress response. Previously, we demonstrated that two models of voluntary exercise in the nonpregnant rat, tower climbing and rising to an erect bipedal stance (squat), cause bone modeling without elevating the stress hormone corticosterone. In this study, these same models were applied to pregnant rats. Gravid Wistar rats were randomly divided into three groups: control, tower climbing, and squat exercise. The rats exercised throughout pregnancy and were killed at day 19. Maternal stress was assessed by fecal corticosterone measurement. Maternal bone and soft tissue responses to exercise were assessed by peripheral quantitative computed tomography and dual-energy X ray absorptiometry. Maternal weight gain during the first 19 days of pregnancy was less in exercised than in nonexercised pregnant control rats. Fecal corticosterone levels did not differ between the three maternal groups. The fetuses responded to maternal exercise in a uterine position-dependent manner. Mid-uterine horn fetuses from the squat exercise group were heavier (P < 0.0001) and longer (P < 0.0001) and had a greater placental weight (P = 0.001) than those from control rats. Fetuses from tower-climbing dams were longer (P < 0.0001) and had heavier placentas (P = 0.01) than those from control rats, but fetal weight did not differ from controls. These models of voluntary exercise in the rat may be useful for future studies of the effects of exercise during pregnancy on the developmental origins of health and disease. PMID- 21307361 TI - Sucrose self-administration and CNS activation in the rat. AB - We have previously reported that administration of insulin into the arcuate nucleus of the hypothalamus decreases motivation for sucrose, assessed by a self administration task, in rats. Because the pattern of central nervous system (CNS) activation in association with sucrose self-administration has not been evaluated, in the present study, we measured expression of c-Fos as an index of neuronal activation. We trained rats to bar-press for sucrose, according to a fixed-ratio (FR) or progressive-ratio (PR) schedule and mapped expression of c Fos immunoreactivity in the CNS, compared with c-Fos expression in handled controls. We observed a unique expression of c-Fos in the medial hypothalamus (the arcuate, paraventricular, retrochiasmatic, dorsomedial, and ventromedial nuclei) in association with the onset of PR performance, and expression of c-Fos in the lateral hypothalamus and the bed nucleus of stria terminalis in association with the onset of FR performance. c-Fos expression was increased in the nucleus accumbens of both FR and PR rats. Our study emphasizes the importance of both hypothalamic energy homeostasis circuitry and limbic circuitry in the performance of a food reward task. Given the role of the medial hypothalamus in regulation of energy balance, our study suggests that this circuitry may contribute to reward regulation within the larger context of energy homeostasis. PMID- 21307362 TI - Renovascular disease, microcirculation, and the progression of renal injury: role of angiogenesis. AB - Emerging evidence supports the pivotal role of renal microvascular disease as a determinant of tubulo-interstitial and glomerular fibrosis in chronic kidney disease. An intact microcirculation is vital to restore blood flow to the injured tissues, which is a crucial step to achieve a successful repair response. The purpose of this review is to discuss the impact and mechanisms of the functional and structural changes of the renal microvascular network, as well as the role of these changes in the progression and irreversibility of renal injury. Damage of the renal microcirculation and deterioration of the angiogenic response may constitute early steps in the complex pathways involved in progressive renal injury. There is limited but provocative evidence that stimulation of vascular proliferation and repair may stabilize renal function and slow the progression of renal disease. The feasibility of novel potential therapeutic interventions for stabilizing the renal microvasculature is also discussed. Targeted interventions to enhance endogenous renoprotective mechanisms focused on the microcirculation, such as cell-based therapy or the use of angiogenic cytokines have shown promising results in some experimental and clinical settings. PMID- 21307363 TI - Effects of beta-adrenergic receptor agonists on drinking and arterial blood pressure in young and old rats. AB - These experiments examined water-drinking and arterial blood pressure responses to beta-adrenergic receptor activation in young (4 mo), "middle-aged" adult (12 mo), and old (29 mo) male rats of the Brown-Norway strain. We used isoproterenol to simultaneously activate beta(1)- and beta(2)-adrenergic receptors, salbutamol to selectively activate beta(2)-adrenergic receptors, and the combination of isoproterenol and the beta(2)-adrenergic receptor antagonist ICI 118,551 to stimulate only beta(1)-adrenergic receptors. Animals received one of the drug treatments, and water drinking was measured for 90 min. About 1 wk later, animals received the same drug treatment for measurement of arterial blood pressure responses for 90 min. In some rats, levels of renin and aldosterone secretion in response to isoproterenol or salbutamol were measured in additional tests. Old and middle-aged rats drank significantly less after isoproterenol than did young rats and also had greater reductions in arterial blood pressure. Old and middle aged rats drank significantly less after salbutamol than did young rats, although reductions in arterial blood pressure were equivalent across the ages. The beta(2)-adrenergic antagonist ICI 118,551 abolished drinking after isoproterenol and prevented most of the observed hypotension. Renin secretion after isoproterenol and salbutamol was greater in young rats than in middle-aged rats, and wholly absent in old rats. Aldosterone secretion was reduced in old rats compared with young and middle-aged rats after treatment with isoproterenol, but not after treatment with salbutamol. In conclusion, there are age-related differences in beta-adrenergic receptor-mediated drinking that can be explained only in part by age-related differences in renin secretion after beta-adrenergic receptor stimulation. PMID- 21307364 TI - Effects of increasing doses of glucagon-like peptide-1 on insulin-releasing phases during intravenous glucose administration in mice. AB - The increase in insulin secretion caused by glucagon-like peptide-1 (GLP-1) and GLP-1 mimetics observed during an intravenous glucose test (IVGTT) has been reported in both normal and disease animal models, as well as in humans. In this study, a hierarchical population modeling approach is used, together with a previously reported model relating glucose to insulin appearance, to determine quantitative in vivo dose-response relationships between GLP-1 dose level and both first- and second-phase insulin release. Parameters of the insulin kinetic model were estimated from the complete set of glucose and insulin data collected in 219 anesthetized nonfasted NMR-imaged mice after intravenous injection of glucose (1 g/kg) alone or with GLP-1 (0.03-100 nmol/kg). The resulting dose response curves indicate a difference in GLP-1 effect on the two release phases, as is also evident from the different ED(50) parameter values (0.107 vs. 6.65 nmol/kg for phase 1 vs. phase 2 insulin release parameters). The first phase of insulin release is gradually augmented with increasing GLP-1 dose, reaching saturation at a dose of ~1 nmol/kg, while the second-phase release changes more abruptly at GLP-1 doses between 3 and 10 nmol/kg and shows a more pronounced 100 fold increase between control and the high GLP-1 dose of 100 nmol/kg Moreover, separate disposition indices calculated for phase 1 and 2 insulin release, show a different pattern of increase with increasing GLP-1 dose. PMID- 21307365 TI - End-tidal carbon dioxide tension reflects arterial carbon dioxide tension in the heat-stressed human with and without simulated hemorrhage. AB - End-tidal carbon dioxide tension (Pet(CO(2))) is reduced during an orthostatic challenge, during heat stress, and during a combination of these two conditions. The importance of these changes is dependent on Pet(CO(2)) being an accurate surrogate for arterial carbon dioxide tension (Pa(CO(2))), the latter being the physiologically relevant variable. This study tested the hypothesis that Pet(CO(2)) provides an accurate assessment of Pa(CO(2)) during the aforementioned conditions. Comparisons between these measures were made: 1) after two levels of heat stress (N = 11); 2) during combined heat stress and simulated hemorrhage [via lower-body negative pressure (LBNP), N = 8]; and 3) during an end-tidal clamping protocol to attenuate heat stress-induced reductions in Pet(CO(2)) (N = 7). Pet(CO(2)) and Pa(CO(2)) decreased during heat stress (P < 0.001); however, there was no group difference between Pa(CO(2)) and Pet(CO(2)) (P = 0.36) nor was there a significant interaction between thermal condition and measurement technique (P = 0.06). To verify that this nonsignificant trend for the interaction was not due to a type II error, Pet(CO(2)) and Pa(CO(2)) at three distinct thermal conditions were also compared using paired t-tests, revealing no difference between Pa(CO(2)) and Pet(CO(2)) while normothermic (P = 0.14) and following a 1.0 +/- 0.2 degrees C (P = 0.21) and 1.4 +/- 0.2 degrees C (P = 0.28) increase in internal temperature. During LBNP while heat stressed, measures of Pet(CO(2)) and Pa(CO(2)) were similar (P = 0.61). Likewise, during the end-tidal carbon dioxide clamping protocol, the increases in Pet(CO(2)) (7.5 +/- 2.8 mmHg) and Pa(CO(2)) (6.6 +/- 3.4 mmHg) were similar (P = 0.31). These data indicate that mean Pet(CO(2)) reflects mean Pa(CO(2)) during the evaluated conditions. PMID- 21307366 TI - Effect of N-2-mercaptopropionyl glycine on exercise-induced cardiac adaptations. AB - The purpose of this study was to test the hypothesis that exercise-induced cardiac adaptations would be attenuated by the free radical scavenger N-2 mercaptopropionyl glycine (MPG). Male Sprague-Dawley rats were divided into four groups (n = 9-13 per group) for 3-4 wk: sedentary (S), S+MPG (100 mg/kg ip daily), exercised on a treadmill (E) (60 min/day, 5 days/wk, at a speed of 20 m/min up a 6 degrees grade in a 6 degrees C room), or E+MPG given 10 min prior to exercise. Additional rats (n = 55) were used to determine acute exercise effects on myocardial redox state [nonprotein nonglutathione sulfhydryls (NPNGSH)] and PI3K/Akt signaling pathway activation. Compared with S, NPNGSH levels were 48% lower in E (P < 0.05) and unchanged in E+MPG (P > 0.05). MPG also attenuated exercise-induced activation of the signaling proteins Akt and S6. Hearts from the 4-wk groups were weighed, and cardiac function was evaluated using an isolated perfused working heart preparation. Similar increases (P < 0.05) in both exercised groups were observed for heart weight and heart weight-to body weight ratio. Cardiac function improved in E vs. S, as indicated by greater (P < 0.05) external work performed (cardiac output * systolic pressure) and efficiency of external work (work/Vo(2)). MPG prevented these exercise-induced functional improvements. Skeletal muscle mitochondria content increased to similar levels in E and E+MPG. This study provides evidence that free radicals do not play an essential role in the development of exercise-induced cardiac hypertrophy; however, they appear to be involved in functional cardiac adaptations, which may be mediated through the PI3K/Akt pathway. PMID- 21307367 TI - Cellulose synthases and synthesis in Arabidopsis. AB - Plant cell walls are complex structures composed of high-molecular-weight polysaccharides, proteins, and lignins. Among the wall polysaccharides, cellulose, a hydrogen-bonded beta-1,4-linked glucan microfibril, is the main load bearing wall component and a key precursor for industrial applications. Cellulose is synthesized by large multi-meric cellulose synthase (CesA) complexes, tracking along cortical microtubules at the plasma membrane. The only known components of these complexes are the cellulose synthase proteins. Recent studies have identified tentative interaction partners for the CesAs and shown that the migratory patterns of the CesA complexes depend on phosphorylation status. These advances may become good platforms for expanding our knowledge about cellulose synthesis in the near future. In addition, our current understanding of cellulose chain polymerization in the context of the CesA complex is discussed. PMID- 21307368 TI - Sub-compartmental organization of Golgi-resident N-glycan processing enzymes in plants. AB - In all eukaryotes, the Golgi apparatus is the main site of protein glycosylation. It is widely accepted that the glycosidases and glycosyltransferases involved in N-glycan processing are found concentrated within the Golgi stack where they provide their function. This means that enzymes catalyzing early steps in the processing pathway are located mainly at the cis-side, whereas late-acting enzymes mostly locate to the trans-side of the stacks, creating a non-uniform distribution along the cis-trans axis of the Golgi. There is compelling evidence that the information for their sorting to specific Golgi cisternae depends on signals encoded in the proteins themselves as well as on the trafficking machinery that recognizes these signals and it is believed that cisternal sub compartmentalization is achieved and maintained by a combination of retention and retrieval mechanisms. Yet, the signals, mechanism(s), and molecular factors involved are still unknown. Here, we address recent findings and summarize the current understanding of this fundamental process in plant cell biology. PMID- 21307369 TI - AtFH8 is involved in root development under effect of low-dose latrunculin B in dividing cells. AB - Formins have been paid much attention for their potent nucleating activity. However, the connection between the in vivo functions of AtFHs (Arabidopsis thaliana formin homologs) and their effects on actin organization is poorly understood. In this study, we characterized the bundling activity of AtFH8 in vitro and in vivo. Biochemical analysis showed that AtFH8(FH1FH2) could form dimers and bundle preformed actin filaments or induce stellar structures during actin polymerization. Expression of truncated forms of AtFH8 and immunolocalization analysis showed that AtFH8 localized primarily to nuclear envelope in interphase and to the new cell wall after cytokinesis, depending primarily on its N-terminal transmembrane domain. GUS histochemical staining showed AtFH8 was predominantly expressed in Arabidopsis root meristem, vasculature, and outgrowth points of lateral roots. The primary root growth and lateral root initiation of atfh8 could be decreased by latrunculin B (LatB). Analysis of the number of dividing cells in Arabidopsis root tips showed that much fewer dividing cells in Lat B-treated atfh8 plants than wild-type plants, which indicates that AtFH8 was involved in cell division. Actin cytoskeleton in root meristem of atfh8-1 was more sensitive to LatB treatment than that of wild type. Altogether, our results indicate that AtFH8 is an actin filament nucleator and bundler that functions in cell division and root development. PMID- 21307370 TI - Should we move from syringe exchange to distribution? PMID- 21307372 TI - Promoting health near and far. PMID- 21307371 TI - Distinguishing between health education and health information dissemination. PMID- 21307373 TI - Safety in the Heat: a comprehensive program for prevention of heat illness among workers in Abu Dhabi, United Arab Emirates. AB - The Safety in the Heat program was developed in response to the extreme heat stress conditions experienced by workers in the United Arab Emirates and other Middle Eastern countries each summer, where ambient air temperatures often reach 45 degrees C (135 degrees F) and higher with 90% humidity. A comprehensive, multimedia, economical education and awareness program targeting companies in the region was developed; 465 companies employing 814 996 heat-exposed workers across 6254 work and labor residence sites were reached. Feedback from program participants indicated a high level of support and satisfaction. Results indicated a marked reduction in heat related illness over a period of 2 years (2008-2009) at 2 companies, one of which reported a combined 79.5% decrease in cases (15.3 vs 1.16 cases per 1000 workers) while the other experienced a 50% reduction in serious cases (0.08-0.04 cases per 100,000 work hours). PMID- 21307374 TI - Drug addictions, a public health problem. 1914. PMID- 21307375 TI - Charles E. Terry (1878-1945): early campaigner against drug addiction. PMID- 21307376 TI - Picturing the coping strategies of caregiving children in Western Kenya: from images to action. PMID- 21307377 TI - The invention of Braille. PMID- 21307378 TI - High-normal HbA1c is a strong predictor of type 2 diabetes in the general population. AB - OBJECTIVE: Glycosylated hemoglobin (HbA(1c)) recently has been recommended for the diagnosis of diabetes by the American Diabetes Association, but its value in the prediction of type 2 diabetes is poorly understood. In this study we evaluated how high-normal HbA(1c) levels predict type 2 diabetes. RESEARCH DESIGN AND METHODS: We measured HbA(1c) in 919 Caucasian subjects, aged 40-79 years, and recorded new cases of type 2 diabetes in the following 15 years. Diabetes was diagnosed with HbA(1c). RESULTS: Subjects were stratified according to baseline HbA(1c) (<5.0, 5.00-5.49 [reference], 5.50-5.99, and 6.00-6.49%). Sex- and age adjusted hazard ratios (95% CI) for type 2 diabetes were 1.11 (0.30-4.41), 1.00, 3.79 (1.79-8.06), and 12.50 (5.51-28.34), respectively. Results did not change after adjusting for several putative confounding factors and were confirmed when models with updated variables were used. CONCLUSIONS: HbA(1c) is an independent risk factor for type 2 diabetes. Subjects with high-normal levels of HbA(1c) deserve particular attention because they have a strong risk of developing diabetes. PMID- 21307379 TI - Glomerular and tubular damage markers are elevated in patients with diabetes. AB - OBJECTIVE: We investigated in a cross-sectional study the levels of serum and urinary damage markers in diabetic patients (n = 94) and nondiabetic control subjects (n = 45) to study the association of glomerular (IgG), proximal tubular (kidney injury molecule [KIM]-1, N-acetyl-beta-d-glucosaminidase [NAG], neutrophil gelatinase-associated lipocalin [NGAL], and cystatin C), and distal tubular (heart fatty acid-binding protein [H-FABP]) damage markers with kidney disease severity, as assessed by albuminuria and estimated glomerular filtration rate (eGFR). RESEARCH DESIGN AND METHODS: Damage markers were measured in triplicate in fresh morning urine samples and in plasma. RESULTS: Of the diabetic patients, 41 were normoalbuminuric, 41 were microalbuminuric, and 12 were macroalbuminuric. Urinary NAG (ninefold), NGAL (1.5-fold), and H-FABP (3.5-fold) were significantly elevated in normoalbuminuric diabetic patients compared with nondiabetic control subjects. Urinary concentrations of all markers increased per albuminuria stratum, except KIM-1. All urinary damage markers, except KIM-1, were significantly associated with albuminuria, independent of age, sex, and plasma concentrations of the corresponding biomarker (standard betas between 0.35 and 0.87; all P <= 0.001). All urinary damage markers, except KIM-1, were significantly associated with the eGFR in univariate models (standard betas between -0.38 and -0.21; all P < 0.04). After adjusting for age, sex, plasma concentration of the corresponding damage marker, and albuminuria, only the association of H-FABP with eGFR remained significant (standard beta -0.26; P = 0.037). CONCLUSIONS: Glomerular and tubular markers are associated with albuminuria, independently of eGFR, suggesting that albuminuria reflects both glomerular and tubulointerstitial damage. Only urinary H-FABP is associated with eGFR independently of albuminuria and, therefore, may be a promising urinary damage marker to assess diabetic kidney disease. PMID- 21307380 TI - Skin intrinsic fluorescence correlates with autonomic and distal symmetrical polyneuropathy in individuals with type 1 diabetes. AB - OBJECTIVE: To determine whether skin intrinsic fluorescence (SIF) was associated with autonomic neuropathy and confirmed distal symmetrical polyneuropathy (CDSP) in 111 individuals with type 1 diabetes (mean age 49 years, mean diabetes duration 40 years). RESEARCH DESIGN AND METHODS: SIF was measured using the SCOUT DM device. Autonomic neuropathy was defined as an electrocardiographic abnormal heart rate response to deep breathing (expiration-to-inspiration ratio <1.1). CDSP was defined using the Diabetes Control and Complications Trial clinical exam protocol (the presence of two or more of the following: symptoms, sensory and/or motor signs, and/or reduced/absent tendon reflexes consistent with DSP) confirmed by the presence of an abnormal age-specific vibratory threshold (using a Vibratron II tester). RESULTS: The prevalence of autonomic neuropathy and CDSP were 61 and 66%, respectively. SIF was higher in those with autonomic neuropathy (P < 0.0001). In multivariable analyses controlling for age and updated mean (18 year average) HbA(1c), and allowing for other univariately and clinically significant correlates of autonomic neuropathy, each SD change in SIF was associated with a 2.6-greater likelihood of autonomic neuropathy (P = 0.006). Receiver operating characteristic (ROC) analyses revealed that SIF and updated mean HbA(1c) accounted for 80 and 57%, respectively, of the area under the curve (AUC) for autonomic neuropathy. SIF also was higher in those with CDSP (P < 0.0001) and remained so in multivariable analyses (odds ratio 2.70; P = 0.005). ROC analyses revealed that SIF and updated mean HbA(1c) accounted for 78 and 59%, respectively, of the AUC for CDSP. CONCLUSIONS: SIF, a marker of dermal advanced glycation end products, appears to be more strongly associated with the presence of both CDSP and autonomic neuropathy than mean HbA(1c). PMID- 21307381 TI - Diagnostic accuracy of point-of-care testing for diabetic ketoacidosis at emergency-department triage: {beta}-hydroxybutyrate versus the urine dipstick. AB - OBJECTIVE: In the emergency department, hyperglycemic patients are screened for diabetic ketoacidosis (DKA) via a urine dipstick. In this prospective study, we compared the test characteristics of point-of-care beta-hydroxybutyrate (beta OHB) analysis with the urine dipstick. RESEARCH DESIGN AND METHODS: Emergency department patients with blood glucose >=250 mg/dL had urine dipstick, chemistry panel, venous blood gas, and capillary beta-OHB measurements. DKA was diagnosed according to American Diabetes Association criteria. RESULTS: Of 516 hyperglycemic subjects, 54 had DKA. The urine dipstick had a sensitivity of 98.1% (95% CI 90.1-100), a specificity of 35.1% (30.7-39.6), a positive predictive value of 15% (11.5-19.2), and a negative predictive value of 99.4% (96.6-100) for DKA. Using the manufacturer-suggested cutoff of >1.5 mmol/L, beta-OHB had a sensitivity of 98.1% (90.1-100), a specificity of 78.6% (74.5-82.2), a positive predictive value of 34.9% (27.3-43), and a negative predictive value of 99.7% (98.5-100) for DKA. CONCLUSIONS: Point-of-care beta-OHB and the urine dipstick are equally sensitive for detecting DKA (98.1%). However, beta-OHB is more specific (78.6 vs. 35.1%), offering the potential to significantly reduce unnecessary DKA work-ups among hyperglycemic patients in the emergency department. PMID- 21307382 TI - The association between dietary sodium intake, ESRD, and all-cause mortality in patients with type 1 diabetes. AB - OBJECTIVE: Many guidelines recommend reduced consumption of salt in patients with type 1 diabetes, but it is unclear whether dietary sodium intake is associated with mortality and end-stage renal disease (ESRD). RESEARCH DESIGN AND METHODS: In a nationwide multicenter study (the FinnDiane Study) between 1998 and 2002, 2,807 enrolled adults with type 1 diabetes without ESRD were prospectively followed. Baseline urinary sodium excretion was estimated on a 24-h urine collection. The predictors of all-cause mortality and ESRD were determined by Cox regression and competing risk modeling, respectively. RESULTS: The median follow up for survival analyses was 10 years, during which 217 deaths were recorded (7.7%). Urinary sodium excretion was nonlinearly associated with all-cause mortality, such that individuals with the highest daily urinary sodium excretion, as well as the lowest excretion, had reduced survival. This association was independent age, sex, duration of diabetes, the presence and severity of chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] and log albumin excretion rate), the presence of established cardiovascular disease, and systolic blood pressure. During follow-up, 126 patients developed ESRD (4.5%). Urinary sodium excretion was inversely associated with the cumulative incidence of ESRD, such that individuals with the lowest sodium excretion had the highest cumulative incidence of ESRD. CONCLUSIONS: In patients with type 1 diabetes, sodium was independently associated with all-cause mortality and ESRD. Although we have not demonstrated causality, these findings support the calls for caution before applying salt restriction universally. Clinical trials must be performed in diabetic patients to formally test the utility/risk of sodium restriction in this setting. PMID- 21307383 TI - Auxin conjugates: their role for plant development and in the evolution of land plants. AB - Auxin conjugates are thought to play important roles as storage forms for the active plant hormone indole-3-acetic acid (IAA). In its free form, IAA comprises only up to 25% of the total amount of IAA, depending on the tissue and the plant species studied. The major forms of IAA conjugate are low molecular weight ester or amide forms, but there is increasing evidence of the occurrence of peptides and proteins modified by IAA. Since the discovery of genes and enzymes involved in synthesis and hydrolysis of auxin conjugates, much knowledge has been gained on the biochemistry and function of these compounds, but there is still much to discover. For example, recent work has shown that some auxin conjugate hydrolases prefer conjugates with longer-chain auxins such as indole-3-propionic acid and indole-3-butyric acid as substrate. Also, the compartmentation of these reactions in the cell or in tissues has not been resolved in great detail. The function of auxin conjugates has been mainly elucidated by mutant analysis in genes for synthesis or hydrolysis and a possible function for conjugates inferred from these results. In the evolution of land plants auxin conjugates seem to be connected with the development of certain traits such as embryo, shoot, and vasculature. Most likely, the synthesis of auxin conjugates was developed first, since it has been already detected in moss, whereas sequences typical of auxin conjugate hydrolases were found according to database entries first in moss ferns. The implications for the regulation of auxin levels in different species will be discussed. PMID- 21307384 TI - Nodulation enhances dark CO2 fixation and recycling in the model legume Lotus japonicus. AB - During symbiotic nitrogen fixation (SNF), the nodule becomes a strong sink for photosynthetic carbon. Here, it was studied whether nodule dark CO(2) fixation could participate in a mechanism for CO(2) recycling through C(4)-type photosynthesis. Differences in the natural delta(13)C abundance between Lotus japonicus inoculated or not with the N-fixing Mesorhizobium loti were assessed. (13)C labelling and gene expression of key enzymes of CO(2) metabolism were applied in plants inoculated with wild-type or mutant fix(-) (deficient in N fixation) strains of M. loti, and in non-inoculated plants. Compared with non inoculated legumes, inoculated legumes had higher natural delta(13)C abundance and total C in their hypergeous organs and nodules. In stems, (13)C accumulation and expression of genes coding for enzymes of malate metabolism were greater in inoculated compared with non-inoculated plants. Malate-oxidizing activity was localized in stem xylem parenchyma, sieve tubes, and photosynthetic outer cortex parenchyma of inoculated plants. In stems of plants inoculated with fix(-) M. loti strains, (13)C accumulation remained high, while accumulation of transcripts coding for malic enzyme isoforms increased. A potential mechanism is proposed for reducing carbon losses during SNF by the direct reincorporation of CO(2) respired by nodules and the transport and metabolism of C-containing metabolites in hypergeous organs. PMID- 21307385 TI - Regulation of plant MSH2 and MSH6 genes in the UV-B-induced DNA damage response. AB - Deleterious effects of UV-B radiation on DNA include the formation of cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs). These lesions must be repaired to maintain the integrity of DNA and provide genetic stability. Of the several repair systems involved in the recognition and removal of UV-B-induced lesions in DNA, the focus in the present study was on the mismatch repair system (MMR). The contribution of MutSalpha (MSH2-MSH6) to UV induced DNA lesion repair and cell cycle regulation was investigated. MSH2 and MSH6 genes in Arabidopsis and maize are up-regulated by UV-B, indicating that MMR may have a role in UV-B-induced DNA damage responses. Analysis of promoter sequences identified MSH6 as a target of the E2F transcription factors. Using electrophoretic mobility shift assays, MSH6 was experimentally validated as an E2F target gene, suggesting an interaction between MMR genes and the cell cycle control. Mutations in MSH2 or MSH6 caused an increased accumulation of CPDs relative to wild-type plants. In addition, msh2 mutant plants showed a different expression pattern of cell cycle marker genes after the UV-B treatment when compared with wild-type plants. Taken together, these data provide evidence that plant MutSalpha is involved in a UV-B-induced DNA damage response pathway. PMID- 21307386 TI - Panicum milioides (C(3)-C(4)) does not have improved water or nitrogen economies relative to C(3) and C(4) congeners exposed to industrial-age climate change. AB - The physiological implications of C(3)-C(4) photosynthesis were investigated using closely related Panicum species exposed to industrial-age climate change. Panicum bisulcatum (C(3)), P. milioides (C(3)-C(4)), and P. coloratum (C(4)) were grown in a glasshouse at three CO(2) concentrations ([CO(2)]: 280, 400, and 650 MUl l(-1)) and two air temperatures [ambient (27/19 degrees C day/night) and ambient + 4 degrees C] for 12 weeks. Under current ambient [CO(2)] and temperature, the C(3)-C(4) species had higher photosynthetic rates and lower stomatal limitation and electron cost of photosynthesis relative to the C(3) species. These photosynthetic advantages did not improve leaf- or plant-level water (WUE) or nitrogen (NUE) use efficiencies of the C(3)-C(4) relative to the C(3) Panicum species. In contrast, the C(4) species had higher photosynthetic rates and WUE but similar NUE to the C(3) species. Increasing [CO(2)] mainly stimulated photosynthesis of the C(3) and C(3)-C(4) species, while high temperature had no or negative effects on photosynthesis of the Panicum species. Under ambient temperature, increasing [CO(2)] enhanced the biomass of the C(3) species only. Under high temperature, increasing [CO(2)] enhanced the biomass of the C(3) and C(3)-C(4) species to the same extent, indicating increased CO(2) limitation in the C(3)-C(4) intermediate at high temperature. Growth [CO(2)] and temperature had complex interactive effects, but did not alter the ranking of key physiological parameters amongst the Panicum species. In conclusion, the ability of C(3)-C(4) intermediate species partially to recycle photorespired CO(2) did not improve WUE or NUE relative to congeneric C(3) or C(4) species grown under varying [CO(2)] and temperature conditions. PMID- 21307387 TI - Strigolactones interact with ethylene and auxin in regulating root-hair elongation in Arabidopsis. AB - Strigolactones (SLs) or derivatives thereof have been identified as phytohormones, and shown to act as long-distance shoot-branching inhibitors. In Arabidopsis roots, SLs have been suggested to have a positive effect on root-hair (RH) elongation, mediated via the MAX2 F-box. Two other phytohormones, auxin and ethylene, have been shown to have positive effects on RH elongation. Hence, in the present work, Arabidopsis RH elongation was used as a bioassay to determine epistatic relations between SLs, auxin, and ethylene. Analysis of the effect of hormonal treatments on RH elongation in the wild type and hormone-signalling mutants suggested that SLs and ethylene regulate RH elongation via a common regulatory pathway, in which ethylene is epistatic to SLs, whereas the effect of SLs on RH elongation requires ethylene synthesis. SL signalling was not needed for the auxin response, whereas auxin signalling was not necessary, but enhanced RH response to SLs, suggesting that the SL and auxin hormonal pathways converge for regulation of RH elongation. The ethylene pathway requirement for the RH response to SLs suggests that ethylene forms a cross-talk junction between the SL and auxin pathways. PMID- 21307388 TI - Challenges in the gynecologic care of premenopausal women with breast cancer. AB - Premenopausal women with a new diagnosis of breast cancer are faced with many challenges. Providing health care for issues such as gynecologic comorbidities, reproductive health concerns, and vasomotor symptom control can be complicated because of the risks of hormone treatments and the adverse effects of adjuvant therapies. It is paramount that health care professionals understand and be knowledgeable about hormonal and nonhormonal treatments and their pharmacological parameters so they can offer appropriate care to women who have breast cancer, with the goal of improving quality of life. Articles for this review were identified by searching the PubMed database with no date limitations. The following search terms were used: abnormal uterine bleeding, physiologic sex steroids, endometrial ablation, hysteroscopic sterilization, fertility preservation in endometrial cancer, tranexamic acid and breast cancer, menorrhagia treatment and breast cancer, abnormal uterine bleeding and premenopausal breast cancer, levonorgestrel IUD and breast cancer, tamoxifen and gynecologic abnormalities, tamoxifen metabolism, hormones and breast cancer risk, contraception and breast cancer, pregnancy and breast cancer, and breast cancer and infertility treatment. PMID- 21307389 TI - Residential treatment compared with outpatient treatment for tobacco use and dependence. AB - OBJECTIVE: To compare the effectiveness of outpatient vs residential treatment for tobacco dependence in a large referral practice. PATIENTS AND METHODS: We analyzed data from 2 cohorts of cigarette smokers who received either comprehensive outpatient or intensive 8-day residential treatment for tobacco dependence between January 1, 2004, and December 31, 2007. Self-reported 7-day point prevalence abstinence from smoking at 6 months was obtained via telephone interview. Logistic regression was used to assess the likelihood of increased abstinence with residential treatment. RESULTS: Overall, 4327 cigarette smokers received comprehensive outpatient treatment for tobacco dependence, and 226 smokers received treatment in an intensive 8-day residential program. Compared with outpatients, residential patients smoked more cigarettes per day (mean +/- SD, 31.1 +/- 14.4 vs 21.2 +/- 11.2), had more severe nicotine dependence (Fagerstrom Test for Nicotine Dependence score, 6.9 +/- 2.0 vs 5.1 +/- 2.3), and were more likely to have been treated for alcoholism (58/222 [26%] vs 649/4327 [15%]) or depression (124/222 [56%] vs 1817/4327 [42%]; P<.001 for all comparisons). The 6-month smoking abstinence rate was significantly higher for residential patients compared with outpatients (115/222 [52%] vs 1168/4327 [27%]; unadjusted odds ratio, 3.0; 95% confidence interval, 2.3-3.9), with similar findings after adjusting for baseline characteristics (adjusted odds ratio, 3.58; 95% confidence interval, 2.6-4.9). CONCLUSION: Compared with smokers who received outpatient treatment, those who received residential treatment had more severe tobacco dependence. Residential treatment for tobacco dependence was associated with a significantly greater odds of 6-month smoking abstinence compared with outpatient treatment among smokers in a referral clinic setting. PMID- 21307390 TI - Effect of 16-hour duty periods on patient care and resident education. AB - OBJECTIVE: To measure the effect of duty periods no longer than 16 hours on patient care and resident education. PATIENTS AND METHODS: As part of our Educational Innovations Project, we piloted a novel resident schedule for an inpatient service that eliminated shifts longer than 16 hours without increased staffing or decreased patient admissions on 2 gastroenterology services from August 29 to November 27, 2009. Patient care variables were obtained through medical record review. Resident well-being and educational variables were collected by weekly surveys, end of rotation evaluations, and an electronic card swipe system. RESULTS: Patient care metrics, including 30-day mortality, 30-day readmission rate, and length of stay, were unchanged for the 196 patient care episodes in the 5-week intervention month compared with the 274 episodes in the 8 weeks of control months. However, residents felt less prepared to manage cross cover of patients (P = .006). There was a nonsignificant trend toward decreased perception of quality of education and balance of personal and professional life during the intervention month. Residents reported working fewer weekly hours overall during the intervention (64.3 vs 68.9 hours; P = .40), but they had significantly more episodes with fewer than 10 hours off between shifts (24 vs 2 episodes; P = .004). CONCLUSION: Inpatient hospital services can be staffed with residents working shifts less than 16 hours without additional residents. However, cross-cover of care, quality of education, and time off between shifts may be adversely affected. PMID- 21307391 TI - Duty hour recommendations and implications for meeting the ACGME core competencies: views of residency directors. AB - OBJECTIVE: To describe the views of residency program directors regarding the effect of the 2010 duty hour recommendations on the 6 core competencies of graduate medical education. METHODS: US residency program directors in internal medicine, pediatrics, and general surgery were e-mailed a survey from July 8 through July 20, 2010, after the 2010 Accreditation Council for Graduate Medical Education (ACGME) duty hour recommendations were published. Directors were asked to rate the implications of the new recommendations for the 6 ACGME core competencies as well as for continuity of inpatient care and resident fatigue. RESULTS: Of 719 eligible program directors, 464 (65%) responded. Most program directors believe that the new ACGME recommendations will decrease residents' continuity with hospitalized patients (404/464 [87%]) and will not change (303/464 [65%]) or will increase (26/464 [6%]) resident fatigue. Additionally, most program directors (249-363/464 [53%-78%]) believe that the new duty hour restrictions will decrease residents' ability to develop competency in 5 of the 6 core areas. Surgery directors were more likely than internal medicine directors to believe that the ACGME recommendations will decrease residents' competency in patient care (odds ratio [OR], 3.9; 95% confidence interval [CI], 2.5-6.3), medical knowledge (OR, 1.9; 95% CI, 1.2-3.2), practice-based learning and improvement (OR, 2.7; 95% CI, 1.7-4.4), interpersonal and communication skills (OR, 1.9; 95% CI, 1.2-3.0), and professionalism (OR, 2.5; 95% CI, 1.5-4.0). CONCLUSION: Residency program directors' reactions to ACGME duty hour recommendations demonstrate a marked degree of concern about educating a competent generation of future physicians in the face of increasing duty hour standards and regulation. PMID- 21307392 TI - Conditional HIF-1 induction produces multistage neovascularization with stage specific sensitivity to VEGFR inhibitors and myeloid cell independence. AB - Neovascularization is a crucial component of tumor growth and ischemia. Although prior work primarily used disease models, delineation of neovascularization in the absence of disease can reveal intrinsic mechanisms of microvessel regulation amenable to manipulation in illness. We created a conditional model of epithelial HIF-1 induction in adult mice (TetON-HIF-1 mice). Longitudinal photoacoustic microscopy (L-PAM) was coincidentally developed for noninvasive, label-free serial imaging of red blood cell-perfused vasculature in the same mouse for weeks to months. TetON-HIF-1 mice evidenced 3 stages of neovascularization: development, maintenance, and transgene-dependent regression. Regression occurred despite extensive and tight pericyte coverage. L-PAM mapped microvascular architecture and quantified volumetric changes in neocapillary morphogenesis, arteriovenous remodeling, and microvessel regression. Developmental stage endothelial proliferation down-regulation was associated with a DNA damage checkpoint consisting of p53, p21, and endothelial gamma-H2AX induction. The neovasculature was temporally responsive to VEGFR2 immuno-blockade, with the developmental stage sensitive, and the maintenance stage resistant, to DC101 treatment. L-PAM analysis also pinpointed microvessels ablated or resistant to VEGFR2 immuno-blockade. HIF-1-recruited myeloid cells did not mediate VEGFR2 inhibitor resistance. Thus, HIF-1 neovascularization in the absence of disease is self-regulated via cell autonomous endothelial checkpoints, and resistant to angiogenesis inhibitors independent of myeloid cells. PMID- 21307394 TI - Genetics behind barbed wire: Masuo Kodani, emigre geneticists, and wartime genetics research at Manzanar relocation center. AB - This article explores the sociopolitical backdrop of genetics research during the politically turbulent decades of the mid-20th century that saw the persecution, displacement, and relocation of unpopular minorities in both the United States and Europe. It explores how geneticists in the United States accommodated these disruptions through formal and informal emigre networks and how the subsequent war affected their research programs and their lives. It does so by focusing on the career and life of geneticist Masuo Kodani, who, as a Japanese American, found himself conducting unexpected cytogenetics research in Manzanar, a "relocation center," or internment camp, located in the California desert, after the attack on Pearl Harbor. After the war, Kodani's subsequent career continued to be shaped by his experiences as a Japanese American and by the specific skills as a cytogeneticist that he demonstrated at a critical period in the history of 20th-century genetics. His many relocations in search of employment culminated in his work with the Atomic Bomb Casualty Commission on human chromosomes, for which he is best known. PMID- 21307396 TI - Bone marrow stromal cells promote skilled motor recovery and enhance contralesional axonal connections after ischemic stroke in adult mice. AB - BACKGROUND AND PURPOSE: We tested the effect of bone marrow stromal cells (BMSCs) on neuronal remodeling of the corticospinal tract originating from the contralesional cortex in mice subjected to unilateral pyramidotomy (PT) followed by middle cerebral artery occlusion (MCAO). METHODS: Adult mice with transgenic yellow fluorescent protein labeling in the corticospinal tract were subjected to right hemispheric PT and right permanent or sham MCAO. One day later, the mice were treated intravenously with BMSCs or phosphate-buffered saline. A Foot-Fault test and a single pellet-reaching test were performed before surgery, 3 days after MCAO, and weekly thereafter. Pseudorabies virus-614-monomeric red fluorescent protein was injected into the left forelimb flexor muscles 28 days after surgery (4 days before euthanasia). The brain and cervical cord were processed for fluorescent microscopy to detect red fluorescent protein and yellow fluorescent protein labeling, respectively. RESULTS: Significant functional improvements were evident in PT-MCAO mice treated with BMSCs (n=9) compared with phosphate-buffered saline-treated mice (n=9, P<0.05), but not in mice with PT sham MCAO treated with either phosphate-buffered saline (n=9) or BMSCs (n=10). Furthermore, in PT-MCAO mice, both corticospinal tract axonal density in the denervated side of the cervical gray matter and red fluorescent protein-labeled pyramidal neurons in the left intact cortex were significantly increased compared with PT-sham MCAO mice (P<0.05). BMSCs significantly enhanced both corticospinal tract density and red fluorescent protein labeling in PT-MCAO mice (P<0.05) only. The behavioral outcome was highly correlated with corticospinal tract density and red fluorescent protein labeling. CONCLUSIONS: BMSCs amplify stroke-induced contralesional neuronal remodeling, which contributes to motor recovery after stroke. PMID- 21307397 TI - P3Kalpha: a driver of tumor metastasis? PMID- 21307398 TI - The heme oxygenase-1 and c-FLIP in acute myeloid leukemias: two non-redundant but mutually exclusive cellular safeguards protecting cells against TNF-induced cell death? PMID- 21307399 TI - Membrane lipids in invadopodia and podosomes: key structures for cancer invasion and metastasis. AB - Invadopodia are extracellular matrix (ECM)-degrading protrusions formed by invasive cancer cells. Podosomes are structures functionally similar to invadopodia that are found in oncogene-transformed fibroblasts and monocyte derived cells, including macrophages and osteoclasts. These structures are thought to play important roles in the pericellular remodeling of ECM during cancer invasion and metastasis. Much effort has been directed toward identification of the molecular components and regulators of invadopodia/podosomes, which could be therapeutic targets in the treatment of malignant cancers. However, it remains largely unknown how these components are assembled into invadopodia/podosomes and how the assembly process is spatially and temporally regulated. This review will summarize recent progress on the molecular mechanisms of invadopodia/podosome formation, with strong emphasis on the roles of lipid rafts and phosphoinositides. PMID- 21307400 TI - FLIP regulation of HO-1 and TNF signalling in human acute myeloid leukemia provides a unique secondary anti-apoptotic mechanism. AB - Acute myeloid leukemia (AML) comprises a heterogeneous group of clonal disorders of hematopoietic progenitors. We previously showed that heme oxygenase-1 (HO 1/Hsp32) underlies resistance of AML to TNF-induced apoptosis. Here we show for the first time that the modulatory protein, FLICE-inhibitory protein (FLIP) indirectly regulates induction of HO-1 in response to TNF in human AML blasts, but not non-cancerous control cells. In AML cells, TNF-induced FLIP expression was an NF-kappaB-dependent event, and silencing of FLIP isoforms (FLIPL, FLIPS and FLIPR) induced pro-apoptotic responses to TNF, with FLIPL knock-down providing the greatest apoptotic switch. However, FLIPL knock-down consequently increased expression of HO-1; a response that occurred in AML (but not non cancerous) cells to protect a proportion of them from apoptotic death. Our results show that increases in HO-1 induced an apoptotic-resistant form in AML cells in the absence of FLIPL. This is the first time that FLIPL has been shown to regulate the expression of HO-1. These data reveal unique regulatory networks in cancerous AML cells whereby FLIP regulation of HO-1 provides AML cells with secondary anti-apoptotic protection against extrinsic factors (eg TNF/chemotherapies) that try to switch on death signals in these highly death resistant cells. Future AML therapies should target these mechanisms. PMID- 21307401 TI - What are genome-wide association studies telling us about B-cell tumor development? AB - It has long been speculated that common genetic variation influences the development of B-cell malignancy, however until recently evidence for this assertion was lacking. The advent of genome-wide association studies (GWAS) has allowed the search for this class of susceptibility allele to be conducted on a genome-wide basis. Recent GWAS of chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL) have identified novel disease genes for CLL and ALL and underscore the importance of polymorphic variation in B-cell development genes as determinants of leukemia risk. PMID- 21307402 TI - Mouse models of hepatocarcinogenesis: what can we learn for the prevention of human hepatocellular carcinoma? AB - There is growing evidence that chronic inflammatory processes are involved in triggering the sequence from chronic liver injury to liver fibrosis, ultimately leading to liver cancer. In the last years this process has been recapitulated in a growing number of different mouse models. However, it has remained unclear whether and how these mouse models reflect the clinical reality of human hepatocellular carcinoma (HCC). Research with animal models but also human liver specimens has indicated that the NF-kappaB signaling pathway might withhold a crucial function in the mediation of chronic hepatic inflammation and the transition to HCC in humans. However, previous studies led to divergent and partly conflicting results with regards to the functional role of NF-kappaB in hepatocarcinogenesis. Here, we discuss a new genetic mouse model for HCC, the liver-specific TAK1 knockout mouse, which lacks the NF-kappaB activating kinase TAK1 specifically in parenchymal liver cells. Molecular findings in this mouse model and their possible significance for chemopreventive strategies against HCC are compared to other murine HCC models. PMID- 21307403 TI - SirT1 brings stemness closer to cancer and aging. AB - Sirtuin 1 acts in various cell processes, deacetylating both chromatin and non histone proteins, and its role in cancer and aging has long been studied and debated. Here we discuss another aspect of SirT1 biology, its function as a stem cell pluripotency and differentiation regulator. We evaluate the implications of these findings in sirtuin inhibition-based cancer treatment and in the application of sirtuin activation for anti-aging therapy. PMID- 21307404 TI - SIRT-ain relief from age-inducing stress. AB - Aging is one of the most fundamental biological processes. It results in a decline in physiological function and an increased risk for pernicious diseases such as cancer. Oxidative stress has been proposed as a major cause of aging, but experimental tests of this hypothesis have been discouraging. Calorie restriction (CR) prevents age-related decline, but there are still gaps in our knowledge of the exact mechanisms underlying this feat. Finally, a tenuous balance exists between aging and cancer, calling for a search for interventions that prevent both aging and cancer. Recent work on the mammalian sirtuin SIRT3 has shed light on these long-standing issues and suggested new approaches to ameliorate the ravages of aging. PMID- 21307405 TI - Soft X-Ray Emission of Laser-Produced Plasmas: Comparison for 30-ps and 20-ns Laser Pulses. AB - Soft x-ray emission spectra (250-875 eV) are presented for plasmas, produced by picosecond and nanosecond frequency-doubled Nd:YAG-glass laser pulses incident on 14 different target materials. The emitted spectra have been corrected for various apparatus functions which enables a direct comparison between plasmas produced by pico- and nanosecond laser pulses. The relative integrated emission intensity as a function of Z number, obtained from the corrected spectra, shows an oscillatory behavior, with distinct maxima for those elements exhibiting a dominant line emission in our photon energy window. We found for our two pulse lengths an approximately equal conversion efficiency from laser light into x-ray photons. General suggestions are given as to what target material should be used for different applications using the laser plasma as x-ray source in the energy range Studied. PMID- 21307406 TI - Phase measurement x-ray interferometry. AB - A phase-step procedure is used with an x-ray interferometer to allow the use of standard phase-plot methods of fringe analysis. When used to measure displacement, this method allows more precise and reliable interpolation of fringe spacings than methods previously reported and is more tolerant of experimental uncertainties. Using the silicon (111) lattice planes as diffracting elements (period 0.3135625 nm), displacement measurements with a standard deviation of 0.003 nm can be routinely achieved. The experimental and data analysis methods required to achieve this resolution are reported. PMID- 21307407 TI - Charge Coupled Device (CCD) Area Detector for On-Line (40- to 80-ms) Acquisition of Laue Diffraction Data from Protein Crystals. AB - A direct charge coupled device (CCD) detector has been used to record Laue diffraction data from a protein crystal illuminated with a synchrotron radiation beam of continuous wavelengths 0.2 A < lambda < 2.5 A. The exposure time used to record the data was 40-80 ms. The point spread factor of the detector was negligible. The sensitivity of CCD detectors at high photon energies is discussed in relation to other electronic area detector schemes. The lack of fine energy resolution of this or any other electronic area detector is not considered a limiting factor because of the high proportion of spots of single wavelength arising from single reciprocal lattice points. A time-resolved study of radiation damage to a crystal of concanavalin A was performed. PMID- 21307408 TI - Diamond vs Beryllium Films for Improving Survivability of Metal Mirrors against X Rays. AB - In this paper, we show the usefulness of diamond films for improving the survivability of thin film metal mirrors against intense x rays. Essentially, the low-Z, high thermal conductivity diamond film acts as an efficient heat sink, thus reducing the temperature in the metal film. A comparison is made between a diamond film and a beryllium film interposed between an aluminum/fused silica mirror. It is shown that at relatively low x-ray fluence, beryllium is somewhat more effective in reducing the aluminum temperature, whereas at high fluence, diamond is more effective. PMID- 21307409 TI - A Comparison of DEF X-Ray Film and a Photodiode Array (Reticon) as Detectors for an X-Ray Crystal Spectrometer. AB - A crystal spectrometer with a photodiode array (PDA) detector was tested for a range of x-ray energies between 1 and 2 keV. A laser-produced plasma has been used as an x-ray source and was generated by the high-power (Vulcan) glass laser system at the SERC Rutherford Appleton Laboratory, UK. The performance of the array was directly compared with the response of Kodak DEF x-ray film. In order to compare quantitatively the performances of the PDA and the film, detective quantum efficiency (DQE) considerations are presented for both devices. It is demonstrated that the PDA has a useful dynamic range which is approximately seven times greater than that of film, a peak DQE of approximately six times that of film, and a greatly superior low-signal performance. The operational characteristics of the PDA are discussed. PMID- 21307410 TI - The use of color in image enhancement of x-ray microtomographs. AB - This paper examines the effectiveness in displaying monochrome images as color images and presents a pseudo-color enhancement technique for enhancing features in x-ray microtomographs of biological and inorganic materials. The technique utilizes the knowledge that the gray levels (intensities) in the image represent the linear absorption coefficients of the elements in the material and assigns pixels with similar gray levels and hence similar absorption coefficients to a color. Since each color in the pseudo-color enhanced image represents a range of gray levels and this corresponds to an element or phase in the material, its microstructure can easily be determined. This paper also discusses the problems associated with the selection of colors and presents a scheme which uses the CIE 1976 L*u*v* uniform color space to select 256 colors for replacing the 256 gray shades used to represent the monochrome image. PMID- 21307411 TI - Design of a normal incidence multilayer imaging x-ray microscope. AB - Normal incidence multilayer Cassegrain x-ray telescopes were flown on the Stanford/MSFC Rocket X-Ray Spectroheliograph. These instruments produced high spatial resolution images of the Sun and conclusively demonstrated that doubly reflecting multilayer x-ray optical systems are feasible. The images indicated that aplanatic imaging soft x-ray /EUV microscopes should be achievable using multilayer optics technology. We have designed a doubly reflecting normal incidence multilayer imaging x-ray microscope based on the Schwarzschild configuration. The Schwarzschild microscope utilizes two spherical mirrors with concentric radii of curvature which are chosen such that the third-order spherical aberration and coma are minimized. We discuss the design of the microscope and the results of the optical system ray trace analysis which indicates that diffraction-limited performance with 600 A spatial resolution should be obtainable over a 1 mm field of view at a wavelength of 100 A. Fabrication of several imaging soft x-ray microscopes based upon these designs, for use in conjunction with x-ray telescopes and laser fusion research, is now in progress. High resolution aplanatic imaging x-ray microscopes using normal incidence multilayer x-ray mirrors should have many important applications in advanced x-ray astronomical instrumentation, x-ray lithography, biological, biomedical, metallurgical, and laser fusion research. PMID- 21307412 TI - Improved resolution of soft x-ray contact images using laser-produced plasmas. AB - Soft x-ray contact images have been obtained of diatom skeletons using laser generated plasmas of low energy (2 J IR). These images have a resolution of less than 60 nm, which is superior to that reported previously for biological specimens, using this technique. PMID- 21307413 TI - 3rd international symposium on x-ray microscopy preliminary announcement and call for papers. PMID- 21307414 TI - Laser-generated plasmas: source requirements for x-ray microscopy. AB - Microscopic imaging using x rays has been made feasible by recent developments in techniques for manufacturing x-ray optical components and in synchrotron radiation sources. However, it is clear that x-ray microscopes cannot become widely available instruments if they have to rely on synchrotron radiation sources. Laser-generated plasmas can give intense bursts of x rays, and in this paper the requirements for two types of imaging, contact microradiography and scanning transmission x-ray microscopy, are discussed, with particular reference to the use of small commercially available lasers. Such lasers could be of use, particularly for scanning x-ray microscopes, but it is unlikely they will be capable of completely replacing synchrotrons as sources for x-ray microscopy. PMID- 21307415 TI - Design and Characterization of X-Ray Multilayer Analyzers for the 50-1000 eV Region. AB - This report describes a synthesis of more than 10 years of this program's development and application of multilayer analyzers for absolute Bragg spectrometry in the low-energy x-ray region of 50-1000 eV. Multilayers, denned here as systems of periodic layered structures parallel to the analyzer surface, have been applied principally in the diagnostics and application of the new, intense sources of synchrotron and high-temperature plasma x radiation. Detailed absolute reflectivity characterizations are presented for selected examples of these multilayers which have been semiempirically determined for mica, potassium acid phthalate, and the fabricated Langmuir-Blodgett and sputtered multilayer analyzers with d-spacings in the 10-200 A range. Design requirements for absolute spectrometry are established. Efficient analytical multilayer reflectivity models are derived and parameterized (based upon a modification of the Darwin-Prins model for the low-energy x-ray region), including, for the sputtered multilayers, parameters for defining interface structure. The dependence of the reflectivity characteristics, high-order Bragg diffraction suppression, and overall efficiency upon the model parameters is analyzed. A special spectrograph and procedure for the absolute measurement of the relevant reflectivity characteristics are described. Detailed measurements and semiempirical characterizations are presented. Programs for small laboratory computers have been developed that allow rapid and flexible spectral analysis, transforming measured spectra to absolute Spectra. PMID- 21307416 TI - Editorial. PMID- 21307417 TI - The early days of x-ray optics-a personal memoir. PMID- 21307418 TI - Revolution in x-ray optics. AB - In the past half decade or so there has been a technological revolution in our ability to generate, control, manipulate, focus, and detect x rays. The emergence of x-ray lasers and synchrotron insertion devices has increased the brightness of laboratory x-ray sources 8 to 12 orders of magnitude over what was available in the late 1960s. In addition, the past few years have been witness to significant advances in the development of normal incidence x-ray mirrors and beam splitters, diffraction limited x-ray lenses, x-ray microscopy, x-ray holography, x-ray waveguides, and CCD x-ray detector arrays. Utilizing these new capabilities, workers in the field are taking the first steps toward the development of sophisticated soft x-ray optical systems, including soft x-ray interferometers, high-intensity x-ray lasers, and projection optics for x-ray lithography. Details of these developments are discussed, as is the question, Why is this happening now? PMID- 21307419 TI - Generation of Soft X-Ray/VUV Photons with a Hybrid/Bias Micropole Undulator on the LLNL Linac. AB - The recently introduced class of micropole undulators, i.e., undulators with submilli-meter periods, promises a wide variety of useful applications in x-ray science and technology. One of the most important of these could turn out to be the efficient generation of highly coherent soft x rays on economical low-energy storage rings or linacs. Over the last year and a half, an intensive experimental effort has been in progress at the Lawrence Livermore National Laboratory (LLNL) to characterize the radiation emitted on a linac by a novel hybrid/bias micropole undulator fabricated at the Stanford Synchrotron Radiation Laboratory. In this initial report, the properties of this new 706-MUm-period insertion device and its generation of 66-eV soft x rays on the LLNL linac are described. Although in the present experiment power levels of a fraction of a picowatt at linac currents of several tens of picoamperes were generated, this was in agreement with theoretical predictions. Operation of our prototype device on a higher energy machine at currents of several milliamperes could consequently be expected to produce milliwatt levels of soft x-ray output, making it an x-ray source potentially competitive with bending magnets on high-energy storage rings. PMID- 21307420 TI - Measured response of multilayers to damaging fluxes. AB - We have measured the response of WC/C multilayers to x-ray fluxes on the order of 200 MW/cm2 using laser-generated plasmas and found that these multilayers will maintain near peak reflectivity for at least 1 ns but are eventually destroyed. A description of the experiments and data analysis methods is given. Transmission electron micrographs of WC/C multilayers before and after irradiation show melting to be the dominant damage mechanism. The results of the experiments will be compared with simulations. PMID- 21307421 TI - Scanning interferometer for the measurement of anomalous dispersion with synchrotron x rays. AB - We describe an x-ray interferometer optimized for operation with synchrotron radiation at the storage ring DORIS at DESY, Hamburg. Function principles, design, and manufacture are discussed. Interference fringes are created by scanning the analyzer crystal of the instrument in increments below 0.1 A. Special attention is paid to minimize warping due to gravitational forces and disturbances from acoustic noise and ground vibration. The characteristics of two different monochromators with respect to harmonic rejection or harmonic selection and beam stability are considered. The instrument is best suited to the measurement of anomalous dispersion, for which an example is given. PMID- 21307422 TI - Studies of multilayers and thin-foil x-ray mirrors using a soft x-ray diffractometer. AB - A versatile x-ray diffractometer is described in detail. Two applications to the study of x-ray optical elements are presented. The first is a Bragg reflection study of state-of-the-art multilayers deposited both on conventional Si-wafer substrates and on superpolished substrates such as fused quartz and electroless nickel. These data are compared to data previously obtained at FeKalpha. The second study is a reflectivity and scattering study of various thin-foil x-ray reflectors proposed for up-coming x-ray satellite missions. All the data have been obtained at MgKalpha = 1.2536 keV. PMID- 21307423 TI - A new three-dimensional reconstruction method using algebraic reconstruction techniques. AB - Three-dimensional image reconstruction plays a very important role in noninvasive diagnosis of biological systems and nondestructive evaluation of manufactured work-pieces. A new direct three-dimensional reconstruction algorithm, called TART (Three-dimensional ART), is presented in this paper. Oblique projection data are used and an ART-based algorithm is introduced to compensate for the limiting constraints of incomplete projection and/or limited angular coverage. The fact that oblique projection gives useful information to the reconstruction algorithm is shown mathematically. The algorithm can be used to solve the reconstruction problem under the conditions of both complete data and incomplete data. The algorithm first maps geometric information and projection data from an oblique plane into a horizontal plane, then calculates the weighting factors for the voxels based on this horizontal plane, and finally performs a 3-D ART reconstruction. Two experimental results illustrate the superiority of the algorithm over the previous reconstruction methods. PMID- 21307424 TI - Focusing and collimation of x rays using microchannel plates: an experimental investigation. AB - Focusing and collimation of 8 keV x rays has been demonstrated using microchannel plate (MCP) blanks with cylindrical channels. The focusing effect arises from total external reflection of x rays at the interior surfaces of the channels of a MCP and has been described previously by the authors. Point to point focusing was observed with flat and curved MCPs, and collimation from a point source to a quasi-parallel beam was observed with a curved MCP. Intensity profiles at the image plane and at other planes behind a flat MCP were obtained for a 20 * 40 MUm2 x-ray source, and agree well with theoretical predictions. The flux in a 40 MUm-diameter collector in the image plane was compared with the flux in the same plane, but without a MCP. The relative gain in flux increases linearly with the source to MCP distance, as predicted. A maximum relative gain in flux of 18 +/- 1 was observed for a source to detector distance of 50 cm. PMID- 21307425 TI - Thermal x-ray emission from ion-beam-heated matter. AB - The conversion of ion beam energy into thermal x-ray radiation by means of stretched cylindrical plasma volumes is studied by analytic modeling and numerical simulation. The analysis is restricted to one-dimensional radiation hydrodynamics. Scaling relations for different materials are derived. Due to equation-of-state properties, high-Z material turns out superior for achieving high conversion efficiency. The paper provides practical answers for thermal x ray generation with intense heavy ion beams. Deposition powers in the order of 10l6 W/g are required for applications to ion beam inertial confinement fusion. PMID- 21307426 TI - Measurement of x-ray spectral line wavelengths by using two bragg reflections. AB - A novel method of measuring absolute x-ray wavelengths using simultaneous Bragg reflections at two parallel crystal plates of equal atomic spacing is presented. The accuracy of wavelength determination Deltalambda/lambda for this method is discussed and a value of 5 * 10-5is achieved. Absolute wavelengths of L-shell laser-produced spectra of Cu, Ge, As, and Se and M-shell spectra of Gd and Tb have been measured in the wavelength region 7.5-8.5 A using a quartz (10T0) quasimonolithic crystal blank. PMID- 21307427 TI - Normal-incidence multilayer mirrors for the 120-450 a wavelength region. AB - An electron-beam deposition method is used to fabricate spherical and flat mirrors with a peak reflectivity of 20% for wavelengths between 120 and 450 A. It is experimentally shown that the fabricated mirrors can be employed to form an image with a resolution of 1 MUm for ultrasoft x rays. The possibility of producing intense directional high-temperature plasma radiation by spherical multilayer mirrors is demonstrated. A radiation intensity of 107 W/cm2 around 182 A has been experimentally obtained in the laser plasma image plane. PMID- 21307428 TI - Application of x-ray microtomography in materials science illustrated by a study of a continuous fiber metal matrix composite. AB - The advantages of the use of x-ray microtomography in materials science are discussed, and illustrated by the nondestructive study of the mechanical damage in a continuous fiber SiC/Al composite at a resolution of about 25 MUm. A laboratory x-ray source was used, and it was shown that quantitative measurements of the linear absorption coefficient at this resolution are possible, even though the AgKalpha radiation used is accompanied by a considerable amount of white radiation, provided that the counter system is properly corrected for pulse pile up and dead-time. PMID- 21307429 TI - Characterization of pinhole transmission gratings. AB - Gold pinhole transmission gratings fabricated by Heidenhain GmbH primarily for the purpose of studying the radiation of intense soft x-ray sources have been tested with the synchrotron radiation of BESSY. Typical results for the spectral dependence of the grating efficiency into the various diffraction orders are presented in a wavelength region ranging from 4 to 20 nm. Also the influence of grating irregularities has been studied. With appropriate grating parameters quite good agreement between the experimental results and theoretical Calculations is Obtained. PMID- 21307430 TI - Coherent Radiation for X-Ray Imaging-The Soft X-Ray Undulator and the X1A Beamline at the NSLS. AB - An undulator-based beamline was built and commissioned at the National Synchrotron Light Source to provide tunable coherent radiation in the 200-800 eV range. The low emittance of the storage ring means that the undulator source has high brightness so that a large flux of coherent x rays is delivered to experimental stations. The beamline uses a horizontally dispersing bichromator that allows two experiments to run simultaneously, making use of the first and second harmonics of the undulator output. In addition, the use of horizontally deflecting optics enables the beamline alignment to be insensitive to electron beam motion since the horizontal electron beam size is quite large. The beamline and its performance are discussed with emphasis on the optics and on stability, radiation, and vacuum considerations. PMID- 21307431 TI - Synthesized bragg-fresnel multilayer optics. PMID- 21307432 TI - X-Ray Study of State-of-the-Art Small (d-Spacing W/B4C Multilayers. AB - Two small d-spacing W/B4C multilayers have been studied at three different x-ray energies CuKalpha1, AlKalpha, and FeLalpha. Measurements of total reflection, specular and mosaic Bragg reflection, and high resolution studies were made at Cu Kalpha1. Multilayer parameters are deduced from the data and the perfection of the multilayer structure is evaluated by Comparison with model Calculations. PMID- 21307433 TI - Influence of exposure time on the sensitivity of kodak 101 x-ray film. AB - The sensitivity of Kodak 101-07 film to 1-keV x-ray photons was measured at extremely different dose rates by using two sources: a laser-produced plasma with nanosecond emission and a CW x-ray source. Whereas almost equal sensitivities were obtained at lower exposures, the gamma values and the saturation densities at higher exposures differed in the two cases, showing the existence of reciprocity failure. PMID- 21307434 TI - Characterization of a Multilayer Coated Laminar Reflection Grating at lambda = 0.154 nm. AB - A laminar grating of 1200 1/mm was coated with an x-ray reflecting multilayer coating. The multilayer coating consisted of 41 alternating layers of ReW and C having a period of 2.3 nm. In this paper we report on diffraction measurements of the coated grating at the CuKalpha emission line. We describe its reflection behavior using a simple theoretical model and derive two diffraction conditions, corresponding to the grating relation and the Bragg law, for which peak intensities are to be observed. We find that grating order efficiencies are modulated by the multilayer reflection. PMID- 21307435 TI - Effective Area of the AXAF X-Ray Telescope: Dependence upon Dielectric Constants of Coating Materials. AB - This study examines the dependence of the effective area of the AXAF x-ray telescope, upon the complex dielectric constants of possible mirror coatings, over the energy range 0.1-10 keV. At energies near and above the astrophysically important iron-line complex near 6.7 keV, the effective area is very sensitive to the coating density on the three innermost of the telescope's six mirror pairs. Thus, it is desirable to achieve as high a density as feasible. The telescope's spectral response exhibits sharp features at absorption edges of the coating materials. In view of the exceptional energy resolution of the AXAF spectrometers and uncertainties in reflectivities (especially near absorption edges), the AXAF goal of 1% accuracy requires both precise x-ray calibration of the telescope and improved modeling of the telescope and calibration sources. Presented here in the form of plots, the results are also available (on floppy disks) in tabular form. PMID- 21307436 TI - A review of microfabrication technologies: application to x-ray optics. AB - We present an outline of various microfabrication techniques and processes, particularly for applications to x-ray optics. Emphasis is placed on both high resolution diffractive components such as gratings and zone plates and multidimensional reflective diffracting structures using multilayer interference mirrors. Some selected examples are also discussed. PMID- 21307437 TI - Diffraction effects in grazing incidence x-ray telescopes. AB - There is increasing interest worldwide in the use of tightly nested grazing incidence imaging mirrors for high-throughput x-ray telescopes. Diffraction effects of x-ray optical systems are often (justifiably) ignored due to the small wavelength of the x-ray radiation. However, the extremely large obscuration ratio inherent to grazing incidence optical systems produces profound degradation of the diffraction image over that produced by a moderately obscured aperture of the same diameter. Although many of the intended applications are moderate-resolution spectroscopic instruments, there is always a desire for high-resolution imaging as well. In this paper we show that diffraction effects can dominate other potential error sources at the low-energy (long-wavelength) end of the intended operating spectral range of some existing or planned x-ray telescopes. Parametric performance predictions are presented and compared with x-ray astronomy performance goals. PMID- 21307438 TI - Tissue characterization using low angle x-ray scattering. AB - Diffraction studies of polyenergetic x-ray beams at low angles can be used to investigate tissues. Recent evidence on molecular form factors indicates that unique "fingerprints" exist for materials in the form of scattering information at angles between 0 degrees and 10 degrees . We have measured low angle scattering information in the form of energy spectra using a tungsten target x ray source. It is shown that for certain scattering angles these spectra are highly structured, where this structure can be related to tissue type. We propose that these measurements will be diagnostic for various conditions such as osteoporosis or gall stone disease. PMID- 21307439 TI - A scanning soft x-ray microscope with an ellipsoidal focusing mirror. AB - We have developed and brought into operation a new type of scanning soft x-ray microscope which can operate at any photon energy from 20 to 1300 eV. This microscope demagnifies a diaphragm by means of an annular section of an ellipsoidal mirror to a smallest spot size of, at present, about 0.4 MUm (FWHM), certainly containing only a small fraction of the total intensity. The sample is scanned across this spot. Between mirror and focus a free space of 30 mm is available for detectors, and particles emitted from a surface at more than 30 degrees to the normal can be extracted into a mass or energy analyzer. Transmission, photoemission, luminescence, photostimulated desorption, reflectivity, and other signals may serve for imaging. In addition, a static analysis of very small samples or spots on a sample will become feasible. PMID- 21307440 TI - Structure of nickel layers in ni-C multilayer coatings: influence of annealing. AB - The structure of Ni-C multilayer and single nickel layer samples has been analyzed before and after annealing, using two techniques: fluorescence EXAFS (F1EXAFS) at the Ni-K. edge and CuKalpha reflection. Annealing at a temperature of 450 degrees C resulted in a change in the structure of the nickel layers from amorphous like to crystalline like. A reduction of the Bragg reflectivity by a factor of 7 was also found. Comparison between the EXAFS data of the annealed sample and of a nickel foil show a difference in the amplitude of the EXAFS. This is ascribed to a non-Gaussian atomic distribution of the backscattering atoms in the annealed sample around their average positions, whereas the atomic distribution in the (polycrystalline) Ni foil is a Gaussian one. From the annealing experiments we conclude that no irreversible changes take place in the structure of the nickel layers at temperatures below 200 degrees C. PMID- 21307441 TI - Tungsten/Magnesium silicide multilayers for soft x-ray optics. AB - W/Mg2Si multilayers for soft x-ray optics above the MgKalpha and MgLalpha lines have been deposited by RF sputtering. Their structural characteristics have been deduced from in situ kinetic ellipsometry, ex situ grazing x-ray reflection measurements, and high-resolution electron microscopy. Their soft x-ray performances have been measured by synchrotron radiation around the MgKalpha and MgLalpha lines and related to the structural characteristics. For short wavelengths, first Bragg peak reflectivities as high as 31% have been measured for multilayers with double period equal to 84 A. For samples with smaller layer thicknesses, these performances decrease due to finite interdiffusion at the interfaces. Nevertheless, well-defined Bragg peaks are observed even when the double period is as low as 44 A. Near the MgLalpha line, more than 20% reflectivity at the first Bragg peak has been measured at normal incidence. At the same wavelength the selectivity is two times higher than that of conventional systems such as Mo/Si. PMID- 21307442 TI - Performance Optimization of a High-Repetition-Rate KrF Laser Plasma X-Ray Source for Microlithography. AB - In order to develop a high-intensity laser plasma x-ray source appropriate for industrial application of x-ray lithography, experiments have been carried out using a high-repetition-rate (up to 40 Hz) excimer laser (249 nm, 300 mJ) with a power density of 2 * 1013 W/ cm2 in the laser focus. In this study emphasis is given to remedying specific problems inherent in operating the laser plasma x-ray source at high repetition rates and in its prolonged operation. Two different methods of minimizing the production of target debris are investigated. First, the use of helium as a quenching gas results in a reduction of the amount of atomic debris particles by more than two orders of magnitude with negligible x ray absorption. Second, a tape target as opposed to a solid target reduces the production of larger debris particles by a further factor of 100. Remaining debris is stopped by an aluminized plastic or beryllium filter used to avoid exposure of the resist by plasma ultraviolet radiation. The x-ray source has been used to image x-ray transmission mask structures down to 0.3 MUm onto general purpose x-ray photo-resist. Results have been analyzed with SEM. The x-ray emission spectrum of the repetitive laser plasmas created from an iron target has been recorded and the conversion efficiency of the laser light into x-rays that contribute to exposure of the resist was measured to be 0.3% over 2pi sr. PMID- 21307443 TI - Synchrotron radiation white beam topography with an oscillating monochromator. AB - Drawbacks of white beam topography with synchrotron radiation, such as intense fluorescence background, thermal strain, and radiation damage, can be avoided by filtering the beam with an oscillating perfect crystal monochromator. The advantage of the white beam technique, namely the imaging of a sample of poor quality, is maintained. The image contrast is even improved due to the suppression of higher harmonics. Topographs of a LiF crystal demonstrate the feasibility of the method. PMID- 21307444 TI - Investigation of Damage to Multilayer Optics in X-Ray Laser Cavities: W/C, WRe/C, WC/C, Stainless-Steel/C, and Cr3C2/C Mirrors. AB - In many applications, multilayer mirrors are exposed to damaging fluences of x rays. In x-ray laser cavities intense optical and broad-band x radiation, from the x-ray laser plasma amplifier, can damage multilayer mirrors on time scales of hundreds of picoseconds. We describe experiments using short duration (500 ps) bursts of soft x rays from a laser produced gold plasma to damage multilayer mirrors designed to reflect wavelengths close to 45 A at normal incidence. The effect of the damaging x-ray flux on normal incidence reflectivity was time resolved for W/C, WRe/C, WC/C, 303-stainless-steel/C, and Cr3C2/C multilayers. The damage thresholds of the different mirrors were compared, and the Cr3C2/C mirrors were found to be the most resilient. The outer layers of the multilayers were observed to expand slowly as x rays were absorbed, and a more rapid expansion then preceded the total loss of reflectivity, at temperatures well below the melting temperature of the mirror components. It is believed that the dominant expansion mechanism is a change in the amorphous carbon layers to a more graphitic structure. The data are fit quite well by a model that assumes expansion of up to 25% in the thickness of the outermost carbon layers, followed by intermixing of the hotter layers. The rapid expansion has been observed to occur in times from 40 to 150 ps and may be the fastest resolution to date of the phenomenon of graphitization. The integrated reflectivity of the mirrors was observed to increase by up to a factor of 2.5 as they damaged; this reflectivity increase may be consistent with a reduction in the layer roughness. PMID- 21307445 TI - A Soft X-Ray/EUV Reflectometer Based on a Laser Produced Plasma Source. AB - A soft x-ray reflectometer is described which is based on a laser-produced plasma source and is continuously tunable over the range 40 A < lambda < 400 A. The source is produced by focusing 0.532-MUm light from a Q-switched Nd:YAG laser on a solid target. The x-ray wavelength is defined using a high throughput spherical grating monochromator with moderate resolving power (lambda/Deltalambda ~ 100 to 500). A time-averaged monochromatized flux of more than 109 photons/s in a 1% bandwidth at 100 eV is obtained. Photon "shot noise" limited measurements are obtained by the use of an I0 detector to normalize out the shot-to-shot variations in source intensity. Measurements with submillimeter spot sizes are readily obtainable. Various detectors have been used and the advantages and disadvantages of each are discussed. The higher order contamination of the monochromator output has been analyzed using a second grating for the purpose of making measurement corrections. The reflectometer thus provides the capability for precision absolute measurements of the reflectance of gratings and multilayer mirrors, the transmittance of thin film filters, or other properties of x-ray optical elements. PMID- 21307446 TI - Magnetic form factor of nickel determined by white beam x-ray diffraction. AB - The magnetic form factor of nickel has been measured, as a fraction of the charge form factor for {h00} and {hhh} reflections up to (10 00) and (666), by an x-ray energy dispersive white beam technique that uses elliptically polarized synchrotron radiation and single crystal samples. At low sin(theta)/lambda the results are in good agreement with theory and with the values determined from neutron studies. The measurements extend beyond the current range of neutron data and indicate that significant magnetic diffraction effects are observable at sin(theta)/lambda > 1.5 A-1 if photons with energies above 26 keV can be used. PMID- 21307447 TI - X-Ray Microscopy at Suboptical Resolution: Direct Observation of the 65-nm Periodicity in Collagen Fibrils. AB - Using a Fresnel zone plate we demonstrate for the first time the direct visualization by x-ray microscopy of suboptical regularity in a biological specimen, namely the 65-nm axial periodicity of tendon collagen. This resolution test demonstrates a resolving power of about 20lambda; a resolving power of <10lambda is in prospect. PMID- 21307448 TI - The Anisotropy of X-Ray Reflection and Scattering from Hexagonal BN. AB - B K-reflection spectra for grazing incidence angles (theta0 = 4 degrees , 8 degrees ), calculated absorption spectra, and angle-dependent scattering distributions at different grazing incidence angles and different wavelengths from hexagonal BN have been described. The reflection and scattering from a surface cut parallel and perpendicular to the c-axis of the crystal have been studied. The strong anisotropy of ultrasoft x-ray reflection and scattering has been discovered. PMID- 21307450 TI - Flux maximization techniques for compton backscatter depth profilometry. AB - Resolution in x-ray backscatter imaging has often been hampered by low fluxes. But, for a given set of resolution requirements and geometric constraints, it is possible to define a maximization problem in the geometric parameters for which the solution is the maximum flux possible in those circumstances. In this way, resolution in noncritical directions can be traded for improved resolution in a desired direction. Making this the thickness, or surface normal direction, makes practicable the depth profiling of layered structures. Such techniques were applied to the problem of imaging the layered structure of corroding aircraft sheet metal joints using Compton backscatter. PMID- 21307449 TI - Characterization of a Flat-Field Grazing-Incidence XUV Spectrometer. AB - We describe a XUV spectrometer for the study of dense hot microplasmas at wavelengths between ~50 and ~300 A. It uses a commercially fabricated grazing incidence flat-field reflection grating with 1200 grooves per millimeter. The spectral resolution was optimized by imaging the source on a narrow slit with the help of a curved grazing incidence mirror. The instrument was tested with a laser produced plasma as a source. The limit of the resolving power due to imaging aberrations of the flat-field grating ranges from 1500 at 50 A to 3600 at 200 A and has been achieved with a 5-MUm slit. We also measured and calculated the grating efficiencies for the first to fifth diffraction order as a function of wavelength. PMID- 21307451 TI - Interference Suppression of X-Ray Scattering under Total External Reflection from Rough Surfaces. AB - Destructive interference of waves scattered from both interfaces of a thin film deposited onto a rough substrate is theoretically shown to lead to considerable suppression (up to some orders) of x-ray scattering intensity. The conditions that are necessary for the suppression of scattering are discussed. PMID- 21307452 TI - Picosecond X-Ray Pulses Generated in a Diode Driven by 193-nm Picosecond Laser Pulses. AB - A new technique for the generation of picosecond x-ray pulses is presented. Picosecond laser pulses are used to generate ultrashort electron pulses in a conventional x-ray diode in which the cathode is replaced by a photocathode. In the experiments presented, 9-ps UV pulses are employed to produce characteristic x-ray pulses with duration in range of 20-90 ps at a repetition rate of 300 Hz. This technique is inherently capable of subpicosecond x-ray pulses and synchronization of the x-ray pulses with the laser pulses or other ultrafast devices with picosecond accuracy. PMID- 21307453 TI - Analysis of Impurity Content and Transport in Tokamak Plasmas Using Low Resolution XUV Spectra. AB - Two experiments were performed to determine whether impurity content and transport information could be extracted from low-resolution XUV spectra recorded from a simple spectroscopic diagnostic that utilized a flat multilayer mirror as the dispersive element. The first experiment, at the DIII-D tokamak, compared MLM spectra to higher-resolution spectra and found that the low-resolution MLM spectra were sufficient to distinguish changes in impurity emission patterns. The results demonstrated the feasibility of building simple MLM-based diagnostics for impurity monitors in the harsh environment of future tokamaks. The second experiment, at the Texas Experimental tokamak, compared MLM spectra to those produced by an impurity transport code coupled to a collisional-radiative model. The comparison showed that it is possible to distinguish changes in impurity transport from low-resolution MLM spectra. PMID- 21307454 TI - A phase-space approach to x-ray optics. AB - The basic concepts and properties of some phase-space mathematical functions, in particular of the Wigner distribution function, are reviewed. Then, the propagation and diffraction of x rays are considered from the point of view of the Wigner function, resulting in a simple method consisting in coordinate shifts in phase space, which can be easily implemented in a personal computer. The applications of this tool to x-ray technology are also discussed. PMID- 21307455 TI - Soft X Rays in the 21st Century Editor's Introduction. PMID- 21307456 TI - Large-area pressure-enduring entrance windows for soft x-ray regime. AB - A technology capable of producing large-area pressure-tolerant x-ray entrance windows of submicrometer thickness is presented. It is based on successive tungsten griddings to support a multilayered membrane consisting of polyimide, aluminum, and aluminum nitride. The aspects of design and fabrication processes are discussed with emphasis on the window foil fabrication. The performance of the windows is presented in terms of x-ray transmission, gas leak, pressure endurance, and radiation hardness properties. PMID- 21307457 TI - The New NIST/ARPA National Soft X-Ray Reflectometry Facility. AB - We have recently begun a series of upgrades to the NIST/ARPA National Reflectometry Facility at the Synchrotron Ultraviolet Radiation Facility. The facility currently consists of a new monochromator and the original sample manipulator which allows us to measure optical components less than 10 cm in diameter. The monochromator offers high throughput and modest resolution over the wavelength range 3.5-40 nm. In the next year we will be installing a sample manipulator that will be able to accommodate the much larger optics that will be used in future x-ray projection lithography and astronomy instruments. We offer preliminary measurements of the throughput and resolution of the new monochromator. PMID- 21307458 TI - Application of scanning microradiography and x-ray microtomography to studies of bones and teeth. AB - In scanning microradiography (SMR), a thin section is stepped across a 15-MUm diameter X-ray beam and the transmitted intensity measured at each point. This technique has permitted more accurate measurements of the spatial variation of the mineral concentration in sections of dentin and enamel than conventional photographic microradiography. Moreover, because the section is not in close contact with an emulsion, SMR allows continuous study while the specimen is bathed in a reaction solution. The present studies have been particularly directed to gaining an understanding of the formation and repair of carious lesions in teeth: one particular puzzle is subsurface demineralization, in which the initial loss of mineral appears to take place some 20 to 50 MUm below the tooth surface. SMR studies are reported here on the demineralization in dilute acids and the subsequent partial remineralization in supersaturated calcium phosphate solutions in model systems for dental caries. In order to develop a theoretical model for de- and remineralization of carious lesions, it is necessary to quantify transport processes within the tooth. To this end, we are developing a method of measuring effective diffusion coefficients of strongly X ray-absorbing ions in water within permeable solids in which the diffusion coefficient varies with position. The method uses sequential concentration/distance profiles determined by SMR. As a test, diffusion coefficients of potassium iodide in water within a permeable glass frit have been measured. X-ray microtomography (XMT) can be carried out by adding an axis of rotation to the SMR apparatus. Using this method, linear absorption coefficients, and hence mineral concentrations, can be measured in 15 X 15 X 15-MUm3 voxels. This has advantages over SMR in that superposition within the depth of the section and errors in determining its thickness are avoided. XMT studies of de- and remineralization similar to those described above for SMR, and also XMT studies of the variation in mineral concentration in the cortical bone of a rat femur along its length, are reported. PMID- 21307459 TI - Diffraction-limited large x-ray optics. AB - It is shown that the technologies required to produce large normal-incidence multilayer x-ray mirrors with diffraction-limited resolution are now available. Applications of these mirrors in x-ray astronomy and x-ray lithography are discussed. PMID- 21307460 TI - Digitization and image processing methods for enhancement and quantification of grazing-incidence x-ray topographs. AB - The conventional photographic prints obtained from double crystal x-ray topography are often hard to interprete and reproduce. Photographic enhancement methods require skillful work by an experienced photographer. They are time consuming and the image information is difficult to present quantitatively. Alternatively, image processing methods may be applied by digitization of the original topographic recording. Image processing computer programs may be applied, e.g., for image enhancement and for quantification of image information. This paper's main interest is related to-obtaining a sufficiently high magnification ratio;-correcting for intensity variations within the image; applying spatial filtering techniques in order to reduce film grain noise; improving contrast, and-retrieving quantative information on image details.The application of such image processing routines is exemplified on topographs obtained by a double-crystal diffractometer set to the (+, -) asymmetric asymmetric setting. A silicon single crystal was used as the monochromator, while the sample was a silicon single crystal which had undergone both surface damage and metallic contamination before the application of Rapid Thermal Annealing (RTA). Hence, well-defined microdefects are found within the sample. These computer-processed images are compared with corresponding images enhanced by conventional techniques. The results provide indications of which enhancement procedures should be applied for qualitative image improvement and for quantification of image details within different types of topographic recordings. PMID- 21307461 TI - High-Performance Mo/Si and W/B4C Multilayer Mirrors for Soft X-Ray Imaging Optics. AB - Soft x-ray projection lithography and microscopy require a high throughput and diffraction-limited performance of a multielement imaging system. To meet these requirements for a specific design it is necessary to (1) achieve high normal incidence reflectivity on each optical element while optimizing the d-spacing variation across the surface of the optical element and (2) match the rf-spacing on each optical element to that of the others according to the ray-tracing design. A technique used to achieve normal incidence reflectivity greater than 60% at 13 nm for Mo/Si and greater than 2.7% at the "water window" region for W/B4C coatings is discussed. In addition, methods to obtain a rf-spacing uniformity of +/-0.4% and to match the d-spacing between imaging mirrors with an accuracy of +/-0.5% are considered. A method for characterizing multilayer coatings on curved surfaces, using cylindrical witness optics with precalculated shape and radius of curvature to simulate final optics, and a manufacturing method for witness optics are also presented. PMID- 21307462 TI - Developments in x-ray detectors and associated electronics: a review of the technology and possible future trends. AB - The detection of low-energy x rays in a precise and efficient manner is now routinely performed with a range of solid state detectors. These devices have been developed continuously over the past 30 years to the point where current performance closely matches theoretical predictions for resolution and efficiency. To achieve these goals parallel developments in field effect transistors and amplifiers were also required. To fully understand the problems associated with the development and use of these detectors it is necessary to discuss both the generation of x rays and the way in which x rays interact with the available detector materials. The energy range considered is 0-100 keV and a comparison between the successful lithium drifted silicon detector and the more recently re-developed high-purity germanium detectors for these low energy applications is given. PMID- 21307463 TI - Coherent compton x-ray sources. AB - Coherent x rays can be produced by scattering of laser light by a beam of relativistic electrons, provided that the electron beam is density modulated or the scattering is done at, or near, 90 degrees . Since the coherent scattering is proportional to N2, where N is the number of electrons, and the incoherent scattering is proportional to N, also a modest degree of coherence can substantially increase the x-ray yield. The theory of laser-electron-beam scattering is reviewed and compared with the emission of radiation by an electron beam in an undulator. Examples of the practical implementation of an intense source of coherent x rays are discussed. PMID- 21307464 TI - Ultrashort ultraviolet free-electron lasers. AB - In this work we combine elements of chirped pulse amplification (CPA) techniques, now familiar in solid-state lasers, with an amplifier based upon a seeded free electron laser (FEL). The resulting device would produce amplified pulses of unprecedented brevity at wavelengths shorter than can be currently obtained by any tunable laser system. We use a subharmonically seeded FEL to illustrate the concept. Radiation from a Ti:sapphire laser is frequency-tripled and stretched optically to provide a coherent seed pulse for the FEL. When coupled to an electron beam inside a magnetic wiggler, the seed radiation introduces an additional energy modulation on the electron bunch, which has been prepared with an energy chirp to match the chirp in the optical pulse. The energy modulated electrons are then spatially bunched in a dispersion magnet and introduced to a wiggler configured to be resonant to a harmonic of the seed laser, providing additional frequency multiplication. The coherent radiation produced by these electrons is amplified as it traverses the wiggler and recompressed optically. The preservation of phase coherence provided by this scheme results in a device which can yield 4-fs pulses with 0.3 mJ at a central wavelength of ca. 88 nm, easily the shortest duration amplified pulses produced by any laser. In this paper, we discuss various aspects of the concept, including the generation of short pulses, temporal stretching and compression, and potential applications of the device. The phase distortion during the wide bandwidth FEL amplification is discussed in detail, and is shown to be within the bounds required to produce a 4 fs pulse upon compression. PMID- 21307465 TI - On some methods of x-ray production from relativistic electron beams. AB - We discuss the production of x rays from relativistic electron beams using synchrotron radiation, free electron lasers, and Compton backscattering of intense laser beams. We review the characteristics, and compare the flux and brightness, of x rays produced from these three processes. We show that free electron lasers can produce coherent x ray pulses in the keV region with a brightness much larger than that of synchrotron radiation facilities, and that in the 10-keV region Compton backscattering systems can be competitive with synchrotron radiation. We describe some of the existing or planned free electron lasers and Compton backscattering facilities. PMID- 21307466 TI - Nondestructive evaluation of millimeter scale engineered structures using synchrotron x-ray microtomography. AB - Synchrotron x-ray microtomography has matured into a practical tool for the metrology of small specimens, featuring a spatial resolution of a few micrometers. In this paper, the author examines the practice of monochromatic x ray tomography, emphasizing the characteristics of synchrotron radiation sources that have enabled the evolution of this new imaging technology. These principles are illustrated using reconstructions of millimeter scale engineered structures fabricated from low atomic weight materials. These structures include spherical shells, considered as model inertial confinement fusion targets, and examples of laser-welded aluminum alloys. PMID- 21307467 TI - Application of graphite mosaic monochromator crystals for x-ray transport. AB - The Vanderbilt University Free-Electron Laser Program is developing the capability to create near-monochromatic x rays for medical imaging and other purposes. For this experiment we feed back the normal infrared FEL light to collide with the electron beam. This causes Compton backscattering of the incident photons which creates x rays. This paper is particularly focused on the x-ray beam transport to be used with this experiment. This transport must redirect the x-ray beam to match a beam chase located in the accelerator vault ceiling at a 40 degrees angle to the x-ray creation axis. It has been determined that the most efficient way to form this transport is by using multiple reflections from mosaic graphite crystals. Samples of these crystals have been obtained and reflection characteristics are being measured. Flat crystals have been investigated at this point. Curved crystals have also been obtained and these will be measured soon. All of these results will dictate the final form of the beam transport. PMID- 21307468 TI - X-ray sources based on subpicosecond-laser-produced plasmas. AB - The production of an efficient user friendly ultrafast x-ray source requires an understanding of the role of the various factors which affect the x-ray emission. Here we examine several issues which control the source brightness and the pulse duration. Picosecond time-resolved, high spectral resolution spectroscopy is used to study plasmas produced by a subpicosecond laser pulse with intensity between 1016 W/cm2 and 5 * 1018 W/cm2. PMID- 21307469 TI - Use of monochromatic x rays in medical diagnosis and therapy what is it going to take? PMID- 21307470 TI - A Figure of Merit Comparison between Bremsstrahlung and Monoenergetic X-Ray Sources for Angiography. AB - A figure of merit (FOM) has been developed which embodies parameters related to image quality in the numerator and radiation integral dose to the patient in the denominator. In this manner, maximizing image quality and minimizing radiation dose amounts to maximizing the FOM. Furthermore, the FOM is designed to be independent of x-ray exposure (number of photons used), and this eliminates one important parameter in an optimization scenario. Monoenergetic x-ray beams (0% bandwidth) are compared with conventional Bremsstrahlung x-ray sources from a tungsten target, for angiographic imaging systems using 144 mg/cm2 Csl image intensifiers as the detector. Thus the results are applicable to both digital subtraction angiography (DSA) and digital fluoroscopic procedures involving iodine-based contrast (e.g., roadmapping). The results demonstrate improvement factors (the ratio of the best FOM of the monoenergetic beam over the best FOM of the polyenergetic beam) ranging from 2.3 to 1.4. The improvement factors averaged over four iodine contrast thicknesses (50, 100, 500, and 1000 mg/cm2) were 1.61 (sigma = 0.159) for the 10 cm thick patient, 1.68 (sigma= 0.172) for the 20 cm thick patient, and 1.82 (sigma= 0.186) for the 30 cm thick patient. The conclusions are that monoenergetic x-ray beams are capable of delivering the same image quality at about half the radiation dose to the patient compared to conventional X-ray tubes. PMID- 21307472 TI - Large area image plane sensors for radiography. AB - This paper investigates the feasibility of using large semiconductor image plane arrays (incorporating detector and readout functions) for radiology. It is anticipated that this approach will offer higher sensitivity and spatial resolution than many alternatives. The disadvantage is a smaller object field than can be imaged with film or by using optics after conversion of x rays to visible radiation. Semiconductor image plane arrays (detector plus multiplexing functions) should have utility because of the potential for higher sensitivity and spatial resolution compared with either computed radiography (photostimulable phosphors) or film cassettes. The major limitation is limited image plane size because of the maximum size of the silicon wafers. PMID- 21307471 TI - Current Status of the VU MFEL Compton X-Ray Program. AB - The Vanderbilt University medical FEL (free electron laser) Compton x-ray program is close to being operational. The FEL modifications necessary for this new capability are near completion. The transport and detection systems for electron and IR beams have been designed, delivered, and tested. We initially expect to produce 108 x-ray photons per second in the 15- to 20-keV region. PMID- 21307473 TI - Optical analysis of an ultra-high resolution two-mirror soft x-ray microscope. AB - Promoted by the successful application of multilayer coated optics in soft x-ray imaging experiments in solar physics and projection lithography, several groups have designed, analyzed, fabricated, and are testing Schwarzschild multilayer soft x-ray microscopes. Simulations have indicated that diffraction limited performance of a spherical Schwarzschild microscope operating near 100 A will be limited to systems with a small numerical aperture of approximately 0.15 and a corresponding resolution, based on the Rayleigh criterion, of 3.3 times the wavelength of the incident radiation. In principle, a two aspherical mirror Head microscope, which satisfies the constant optical path length condition and the Abbe sine condition, should achieve diffraction limited performance for very large numerical apertures. For a practical soft x-ray microscope, surface contour errors, microroughness, reflectance of multilayer coatings, and variation of the angle of incidence over the multilayer substrates become significant factors in degrading system resolution and must be controlled before an ultra-high resolution, two-mirror microscope will be realized. For a 30x reflecting microscope with a numerical aperture ranging from 0.15 to 0.35, the effects on resolution of surface contour errors, tilts, and misalignments of the optics have been studied. Graded spacing of the multilayer coatings on the mirror substrates are required of a fast, two-mirror microscope. PMID- 21307474 TI - Goldhelox: a soft x-ray solar telescope. AB - The Goldhelox Project is the construction and use of a near-normal incidence soft x-ray robotic solar telescope by undergraduate students at Brigham Young University. Once it is completed and tested, it will be deployed from a Get-Away Special (GAS) canister in the bay of a space shuttle. It will image the sun at a wavelength of 171-181A with a time resolution of 1 sec and a spatial resolution of 2.5 arcsec. The observational bandpass was chosen to image x-rays from highly ionized coronal Fe lines. The data will be an aid in better understanding the beginning phases of solar flares and how flaring relates to the physics of the corona-chromosphere transition region. Goldhelox is tentatively scheduled to fly on a space shuttle sometime in 1995 or 1996. This paper outlines the project goals, basic instrument design, and the unique aspects of making this an undergraduate endeavor. PMID- 21307475 TI - Soft x-ray instrumentation and its applications at the advanced photon source. AB - Knowledge of the intermediate energy range from 0.5-4 keV, bridging the "soft" and "hard" x-ray regions, is relatively underdeveloped. However, recent developments in the techniques of microscopy and magnetic circular dichroism have emphasized the need to operate in this energy range for microelectronic, biological, and materials science related experiments. The strong dipole-allowed 3d to 4f transitions in rare-earth magnetic materials fall in this region, as do the K-shells of many of the second and third row elements of the periodic table. Two beamlines to be constructed at the Advanced Photon Source (APS) have been designed to cover this energy region. The proposed undulator source, the beamline layout, and the experimental programs for these beamlines are described. PMID- 21307476 TI - A capillary discharge as a potential x-ray laser driver. AB - This paper describes a combined theoretical and experimental approach to understanding the capillary spark discharge with specific application to use as a soft x-ray or extreme ultraviolet laser source. Atomic physics calculations have identified several potential laser lines in a collisionally pumped neon-like or nickel-like plasma, and magnetohydrodynamic (MHD) modeling has shown that a capillary discharge device should be capable of producing the correct plasma conditions to achieve a population inversion in some of these lines. An experiment is constructed to evaluate the accuracy of the MHD model and investigate the potential of observing inversion in a neon-like argon or a nickel like krypton plasma. PMID- 21307477 TI - The use of soft x rays to study the ultrastructure of living biological material. AB - Imaging biological specimens with soft x rays offers several potential benefits over electron microscopy, and these are briefly reviewed. The disadvantages, most notably radiation-induced structural changes, have been investigated and images of irradiated algal cells (Chlorella) are presented. In soft x-ray contact microscopy the image is recorded rapidly to avoid both natural and radiation induced movement and this technique has been used to study the ultrastructural effects of electron microscopy fixatives. In the epidermal hairs of tomato plants there are numerous strands of cytoplasm which, by light microscopy, appear to traverse the vacuole but are rarely seen by electron microscopy. However, by soft x-ray contact microscopy these strands and the organelles within them can be successfully imaged. Moreover, examination by soft x-ray contact microscopy of the cytoplasm in a fixed material shows that these strands are not present in chemically fixed material. This paper also reports the use of soft x-ray contact microscopy to examine the abscission cells found within the protonema of a moss (Bryum tenuisetum) and compares the images to those obtained by light and electron microscopy. PMID- 21307478 TI - Study of the inner structure of co/c and ni/c multilayers prepared by pulsed laser evaporation method. AB - In the present work we have used the EXAFS and SAXS methods to study the inner structure of "classical" Co/C and Ni/C multilayers. This enabled us to study in detail the structure of a multilayer as a function of the thickness of a metal layer within the multilayer. On the basis of these data a model for multilayer growth produced with pulsed laser evaporation technology is proposed. PMID- 21307479 TI - Monochromatic backlighting as a laser-fusion diagnostic. AB - The case of an x-ray radiographed (backlit) image of a CH-shell laser-fusion target to be imploded by the Omega Upgrade laser system is studied. The goal is to obtain information on the conditions at peak compression, where the experimental constraints due to target self-emission and required spatial resolution are maximal. Particular attention is devoted to the problem of discriminating against the target self-emission. It is shown that a way to selectively image the target with radiation from a backlight source is to obtain a monochromatic image at a single spectral line emitted by the backlighter. Two experimental configurations are discussed: (a) an x-ray microscope with a flat crystal monochromator, and (b) pinhole imaging in conjunction with a curved crystal monochromator. Useful images are obtained with simple CH-shell targets and without the need for a short-pulse backlighter beam. PMID- 21307480 TI - An Elliptical Crystal Spectrometer Suitable for EXAFS Studies of Laser Compressed Materials and for High Resolution X-Ray Spectroscopy. AB - Using an x-ray spectrometer with an elliptically curved crystal it is possible to study absorption spectra from a target placed at one focus of the ellipse using a backlighting source placed at the other focus. This principle has been used to develop a spectrometer for EXAFS studies of laser compressed materials. The backlighting source is placed at one focus of the ellipse and the laser compressed EXAFS sample at the other. Using this technique a small area of the EXAFS target can be probed, thereby minimizing any spatial variations in the compressed plasma due to nonuniformities in the laser beams. Also, the dispersive nature of the crystal ensures that it acts as a bandpass filter, so that the EXAFS sample is not probed by other x-ray wavelengths which may cause unwanted heating. Another advantage is that compressed and uncompressed EXAFS spectra can be compared on a single shot. The optical properties of the spectrometer are discussed analytically and using a computer ray-tracing program. The development and alignment of the elliptical spectrometer are discussed, and its performance using both x-ray film and a CCD detector is evaluated. The use of the elliptical spectrometer as a high-resolution x-ray instrument is presented. PMID- 21307481 TI - Subnanosecond In-Line Soft X-Ray Holography Using Germanium Laser in the 20 nm Wavelength Region. AB - Near- and far-field characteristics of a germanium soft x-ray laser at the wavelengths of 23.2-23.6 nm (J = 2-1 transitions) and 19.6 nm (J = 0-1 transition) are given for quantitative evaluation of the germanium laser for holographic applications. In-line Gabor holography of simple structured objects, such as thin opaque fibers and a standard electron microscope test specimen, is demonstrated. The holograms were recorded on PMMA (polymethyl methacrylate) photoresists and llford Q-plates. The holograms recorded on PMMA were retrieved with an atomic force microscope. The object image was reconstructed by numerical reconstruction with phase retrieval algorithm, resulting in a clear, ghost-free image with sharp edges which infer sub-MUm resolution. Future directions for x ray laser holography are briefly discussed. PMID- 21307482 TI - Microstructural and chemical characterization of the inconel/ti(n) thin film and multilayer system. AB - Single layer and multilayer films of titanium and Inconel 600 (76 at.% Ni, 16 at.% Cr, 8 at.% Fe) have been prepared by sputtering in argon/nitrogen atmospheres, with nitrogen partial pressures ranging from 0% to 40%. The microstructure and chemistry of the sputtered films were characterized using transmission/high-resolution electron microscopy, x-ray diffraction, x-ray photoelectron spectroscopy, secondary ion mass spectroscopy, electron probe microanalysis, and ion beam analysis with MeV helium beams. The microstructure depended on deposition power and individual layer thickness, as well as the sputtering atmosphere composition. Metal nitrides were formed in single layers of both materials whereas, for multilayers, nitrogen was preferentially incorporated into the titanium layer. PMID- 21307483 TI - Erratum. PMID- 21307484 TI - Theoretical and experimental investigation of x-ray diffraction by a lamellar multilayer amplitude grating. AB - We present experimental and theoretical studies of the diffraction by an x-ray lamellar multilayer amplitude grating. The main diffraction properties of such a device are given. Experimental efficiency curves are obtained at 800 eV photon energy using synchrotron radiation. The features observed in these curves are identified and interpreted by means of two theoretical methods. Particular emphasis is given to structures observed for the first time which had been theoretically predicted. PMID- 21307485 TI - Engineering aspects of a kinestatic charge detector. AB - The engineering aspects of a nine-channel digital radiographic system developed for bioimaging research, based on high gas pressure ionography and kinestatic principles, are presented. The research imaging system uses a pulsed x-ray beam which allows one to study simultaneously the ionic signal characteristics at 10 different ionization sites along the drift axis. This research imaging detector system allows one to investigate methods to improve the detection and image quality parameters as part of the development of a large scale prototype medical imaging system. PMID- 21307486 TI - Production of ultra thin silicon foils. AB - Ultra thin silicon foils with thicknesses below 100 nm and large diameters have been produced. Foils with a thickness of 50-60 nm have been used as supporting foils for zone plates and as vacuum windows withstanding a pressure difference of 1 atm. PMID- 21307487 TI - Performance Model for High Spatial Resolution Csl Scintillator Screens Coupled to CCD Detectors. AB - A performance model for an x-ray imaging camera that is currently being developed at York University for the recording of crystallographic diffraction patterns produced by synchrotron radiation is presented. The camera is based on charge coupled device (CCD) sensors which are coupled to a CsI(Tl) x-ray scintillator screen using 3:1 reducing fiber optic tapers. The model predicts the accuracy to which diffraction spot intensities can be measured over a range of incident x-ray flux. The effect of the point spread function of the scintillator and optics and the typical expected diffraction spot geometry is included in the model and shown to have the most significant effect on the system performance for low spot intensities, limiting the camera's effective dynamic range. However, it is shown that quantum limited performance for incident dose fluxes as low as 100 photons per spot can be readily achieved in this design. Finally, the camera performance is predicted for x-ray energies above the scintillator K absorption edges (>33 keV). The effects of energy loss through scintillation K shell fluorescent escape photons reduces the camera's detective quantum efficiency. PMID- 21307488 TI - Ray tracing for crystal-diffraction spectrometers with position-sensitive detectors. AB - Ray tracing calculations for crystal-diffraction spectrometers with position sensitive detectors are done. After describing fundamentals of the ray tracing formalism, the paper presents selected results for a given spectrometer geometry. The developed method allows a three-dimensional representation of diffraction reflections as well as a matrix display of the recorded events in the detector plane. Applying the formalism of Monte Carlo simulation it is possible to calculate other important quantities, such as the resolving power and luminosity of the analyzed spectrometer. PMID- 21307489 TI - Entrance window design parameters for high-pressure gas x-ray imaging detectors. AB - Gas ionization x-ray detectors operating at pressures up to 100 atm offer inherently high spatial and contrast resolution. However, incorporating the detector x-ray entrance window in a conventional pressure vessel designed for such pressures can result in high primary beam loss in the window and a much reduced overall detective quantum efficiency. The design of a gas chamber cover plate for a strip beam detector which mechanically isolates the x-ray entrance window from the lateral tensile stresses in the chamber body is described. A number of test windows of this design, varying in three geometric parameters thickness, window curvature, and fillet radius-were fabricated from wrought aluminum [6061-T651 ] and subjected to pressures of up to 400 atm for the purpose of selecting an optimum window for a prototype digital x-ray imaging detector. The experimental data indicate that windows can be designed for a detector admitting a 1.0 cm wide x-ray beam that have rupture pressures exceeding 500 atm while maintaining x-ray transmittances of as much as 93.4% for a 120 kVp tungsten anode spectrum. PMID- 21307490 TI - Power loading limitations in soft x-ray projection lithography. AB - Soft x-ray projection lithography (SXPL) is an attractive technique for the fabrication of high-speed, high-density integrated circuits. In an SXPL stepper, the x-ray imaging mirrors consist of multilayer coatings deposited onto high precision substrates. The stepper is intended to fabricate ultra-high spatial resolution structures with a minimum feature size of <0.1 MUm. To achieve this resolution, the imaging mirrors must maintain a very precise surface figure while being exposed to x radiation. Failure to achieve and maintain the mirror surface figure will distort the wavefront propagating through the imaging system and will degrade system resolution. The required surface figure accuracy for each imaging mirror depends upon the required resolution, the wavelength, and the optical design. For conventional SXPL stepper designs, the total (peak-to-valley) surface figure error budget per mirror is approximately +/-1 nm. Due to material properties at soft x-ray wavelengths and practical fabrication considerations, x ray multilayer mirrors have limited reflectivities. A fraction of the incident x radiation is absorbed in the multilayer coating. This absorbed radiation constitutes a thermal load on the mirror, thereby distorting its shape and compromising the accuracy of its surface figure. In this paper, we analyze the thermally induced distortion on the imaging optics and conclude that the maximum allowable thermal distortion limits the maximum allowable x-ray power transported to the wafer and limits the minimum acceptable multilayer mirror reflectivity. The penalty for either insensitive x-ray resists or inefficient mirror reflectivity is a decrease in system throughput which cannot be compensated with increased source power either collected by condenser optics or generated by the source. PMID- 21307491 TI - Comparison of ultrathin x-ray window designs. AB - In order to fabricate entrance windows for soft x-ray detectors, various technologies have been developed. Depending on the x-ray-detector type and the environment in which the windows are used, entrance windows must meet several, often contradictory, requirements: while good pressure tolerance and durability as well as gas tightness require thicker structures, good x-ray transmission can only be achieved with thin membranes. In this paper, the suitability of different window types for various applications is discussed. The applicability discussion is based on the results of tests performed on prototype windows, as well as on calculated and measured x-ray transmission properties. A comparative study of endurance vs transmission properties of some candidate membrane materials is also presented. Test results include pressure tolerance and leakage rates as well as some measurements of radiation damage to the window materials. The window technologies presented include coated polyimide membranes with two different supporting schemes as well as submicrometer beryllium membranes. PMID- 21307492 TI - The effect of linear interpolation of the filtered projections on image noise in x-ray computed tomography. AB - Measured values for image noise variance in x-ray computed tomography were found to be less than half of the values predicted by published formulas. This phenomenon had previously been attributed qualitatively to the use of linear interpolation of the filtered projections in the back projection process. An analysis of the reconstruction process has allowed the derivation of a formula for image noise variance which incorporates the effect of this interpolation, giving results which are less than 50% of the previously predicted values. This formula has been tested with images of a perspex rod produced by an x-ray microtomography scanner and with a similar image derived from mathematically modeled projection data. The predicted noise variance was within 1% of the measured values for both the simulated and the experimental data. PMID- 21307493 TI - Grazing x-ray reflectometry data processing by fourier transform. AB - Grazing x-ray reflectometry allows analysis of thin-layer stacks. The fitting of the reflectivity curve by a trial and error method can determine the parameters of the films. The Fourier analysis of the experimental reflectivity curve can directly give a rough determination of the profile index. Such results can be useful in choosing a starting model. With the choice of an appropriate model a fit to the reflectivity curve can be undertaken to determine the parameters of the stack. The Fourier analysis method can only be used if the reflectivity data undergo a transformation to produce a periodic curve. Associated artifacts are studied and discussed. Each Fourier peak is associated with two interfaces. The interface roughness spreads the Fourier peaks, adding the squared roughness values. The sample's absorption of the x-rays does not limit the Fourier analysis. PMID- 21307494 TI - Application of structural phase transitions in x-ray spectroscopy. AB - A method is proposed for measuring different energy ranges of x-ray radiation with the same spectrometer crystal employing structural phase transitions. When the crystal temperature is varied beyond the phase transition temperature, the crystal symmetry is altered predictably and reversibly. Thus, with no change in the angle of glancing incidence, the x-ray beam hits in different crystal phases different lattice planes which correspond to different energy ranges. The advantage is that neither large motions nor exchanging the spectrometer crystal is necessary during observations. PMID- 21307495 TI - Characterization of a Si(Li) Detector for PIXE Analysis. AB - The characterization of a Si(Li) detector used for PIXE analysis is presented. The main detector parameters are indicated, and the different methods of determining them are examined. Also, the detection efficiency has been measured in the 1.4-100 keV photon energy range, using calibrated radioactive sources and PIXE, to obtain and compare the fitted parameters. Finally, the fit of an analytic function to the measured efficiency values and the efficiency in parametric form are compared, and the advantages observed for each are noted. PMID- 21307496 TI - X-UV Index of Refraction of Dense and Hot Plasmas. AB - In a dense and hot plasma the refractive index in the X-UV range takes into account not only the effect of free electrons, but also the effect of electrons bound by atoms. The refractive index is calculated by the Kramer-Kronig relations using the total opacity of the medium including bound-bound, free-bound, and free free atomic transitions. A simple method of calculation of the emission and absorption coefficients is presented. These parameters are of great interest when one wants to study radiative transfer in a dense and hot material. The computer program used allows one to obtain either in LTE or in NLTE the values of these coefficients for every material and for a wide range of mass density and temperature, using a screened hydrogenic model. Applications are presented first to generate opacity tables and second to generate the index of refraction of aluminum for a wide range of mass density and temperature. PMID- 21307497 TI - Long-Duration Soft X-Ray Pulses by XeCl Laser Driven Plasmas and Applications. AB - We report the characterization of a soft x-ray plasma source generated by a long pulse XeCl excimer laser system. The output energy is 4 J at a wavelength of 308 nm in a 100-ns pulse. The intensity of radiation on target is estimated to be 4 * 1012 W cm-2. X-ray emission spectra of the plasma have been recorded using a double focusing spatial resolution spectrometer with a spherical mica crystal. From these measurements, the plasma temperature and electron density have been estimated. Various applications of such a plasma source have been investigated. First images of whole intact living cells from our system, imaged using the technique of soft x-ray contact microscopy, utilizing x rays in the "water window" region (280-530 eV), are shown. The suitability of the source for other applications, for example, x-ray lithography and radiation damage studies, to living cells are discussed. Possible improvements to the x-ray source for the various applications are proposed. PMID- 21307498 TI - Plasma x-ray sources powered by megajoule magnetocumulative generators. AB - We have performed experiments using magnetocumulative generators (MCGs) to power three different types of high-energy-density plasma discharges suitable for intense x-ray generation. They include the H-pressed discharge, the capillary z pinch, and the theta-pinch. The MCGs were operated with, and without, plasma opening switches. The characteristic currents were approximately 10 MA and characteristic time scales approximately 1 MUs. In this paper we describe the characteristics of these experiments. PMID- 21307499 TI - A 10-TW Pulsed Facility "PIRIT" for Investigation of Short-Wave Radiation Generation. AB - The results of experiments with a plasma x-ray source in the PIRIT-2000 facility are presented in this paper. The facility is designed with module capacitive energy storage energizing vacuum inductive storage. The formation of a rapidly growing current pulse as well as its commutation on a load was carried out by a plasma opening switch. A vacuum diode as well as various types of plasma loads can be used for the generation of a high-power x-ray flux. The storage energy of a 54-module capacitive storage is up to 2 MJ, its inductance is 15 nH, and its output voltage is 500 kV. The peak current in the plasma load constituted 4 MA with a 150-ns rise time. The maximum integral energy output of x radiation measured by an open thermocouple calorimeter was as high as 100 kJ, while the primary storage energy was 1 MJ. The plasma load usage at a current of 4 MA ensured a 100-kJ generation in x-ray radiation and the density of the radiation flux at a distance of 1 m from the source was as much as 0.8 J/cm2, while near the source it was 10 J/cm2. PMID- 21307500 TI - Plasma x-ray radiation source. AB - This paper gives the results of studies on a plasma x-ray source, which enables one to obtain a 2.5-krad radiation dose per pulse over an area of 100 cm2 in the quantum energy range from 20 to 500 keV. Pulse duration is 100 ns. Spectral radiation distributions from a diode under various operation conditions of a plasma are obtained. A Marx generator served as an initial energy source of 120 kJ with a discharge time of T/4 = 10-6 s. A short electromagnetic pulse (10-7 s) was shaped using plasma erosion opening switches. PMID- 21307501 TI - Thermal Stability of Normal Incidence Multilayer Mirrors for the X-Ray Wavelength near Carbon K-Edge. AB - Annealing effects in the short-period multilayers Cr3C2/C, TiC/C, Cr3C2/(B + C), and CrB2/C were studied in a wide temperature range ~200-1200 degrees C by x-ray scattering and cross-sectional electron microscopy. It was shown that the thermodynamic equilibrium of the layer materials at their interfaces and stabilization of layer structure by impurities and heat treatment are effective approaches to short-period multilayers with enhanced thermal stability of their structure and optical properties. PMID- 21307502 TI - Double shell liners as an active medium for x-ray lasers. AB - The operation of x-ray lasers has been successfully demonstrated in laser produced plasmas. Pulsed-power-driven plasmas of imploding liners offer potentially higher overall efficiencies and less expensive drivers as compared with laser-produced plasmas. Stabilization of a liner implosion is the main problem to be solved to achieve x-ray lasing in liners. Stable liner implosions can be obtained using some methods of liner stabilization. A helical driving magnetic field, a double shell liner structure, and initial axial magnetic field were used to stabilize liner implosions on the SNOP-3 generator (Imax ? 1.1 MA, tau ? 100 ns). Using a capillary discharge in Fe2O3 to form the inner shell, a stable pinch of iron-bearing plasma with a diameter 150-200 MUm and an ion density of (2-4) * 1020 cm-3 was observed. Comparison with theoretical calculations shows that it is possible to create conditions conducive to lasing in neon-like iron using double shell liner implosions On the SNOP-3 generator. PMID- 21307503 TI - Wave-front distortion of high-order harmonic beams caused by intensity-dependent emission phases. AB - We have measured the far-field angular distribution of high-order harmonic beams generated in low-density gas at the focus of an intense laser beam. The experimental setup created conditions where the harmonics could be thought of as emerging from a two-dimensional plane at the focus rather than from a three dimensional interaction region. Under these conditions, harmonic light scattered into broad angles indicates that intrinsic phases develop at the atomic level between the laser field and the emitted individual harmonics and that this phenomenon has a strong dependence on the laser intensity. Because the laser intensity varies radially in the focus, intensity-dependent phases cause the emerging harmonic beams to have distorted wave fronts which result in broad scattering. These conclusions are in agreement with theoretical calculations and have interesting implications. PMID- 21307504 TI - Bragg x-ray optics for imaging spectroscopy of plasma microsources. AB - Bragg x-ray optics based on crystals with transmission and reflection properties bent on cylindrical or spherical surfaces are discussed. Applications of such optics for obtaining one- and two-dimensional monochromatic images of different plasma sources in the wide spectral range 1-20 A are described. Samples of spectra obtained with spectral resolution of up to lambda/Deltalambda ~ 10,000 and spatial resolution of up to 18 MUm are presented. PMID- 21307505 TI - Multiple reflections in single crystals as a tool for x-ray spectroscopy. AB - The process of multiple x-ray reflections in single crystals is presented as a tool for x-ray spectroscopy. Among the possible applications it is shown that monochromatic spatial resolution of the x-ray source may be obtained through this process. With this method the distribution of variously ionized ions in laser produced plasmas may be determined. Absolute wavelength values of x-ray transitions can be obtained. The x-ray emission qualities of x-ray tubes can be determined. PMID- 21307506 TI - A crystal camera for ultra-small-angle x-ray scattering using synchrotron radiation. AB - We describe a novel USAXS camera that combines the use of synchrotron radiation with collimation by perfect-crystal optics. The outstanding result is that high measuring intensities and extreme angular resolution are achieved even with a point-focusing geometry. Along the principles of the original design (U. Bonse and M. Hart, Z. Phys. 189, 151 (1966)) which had to be operated at an x-ray tube, we employ two sets of pairs of multiply reflecting channel-cut crystals diffracting in the horizontal and vertical planes. The collimation characteristics thus obtained are equivalent to the point-focusing geometry of conventional SAXS cameras based on slit collimation. We present results from samples of polystyrene spheres which were used for test measurements performed with synchrotron radiation of DORIS at HASYLAB/DESY in Hamburg. Taking into account the number of reflections within the channel-cut crystals, the theoretical resolution was calculated and found to agree well with that derived from measured scattering patterns. Structures as large as about 1.3 MUm could easily be identified from the scattering curves. As expected with point-focusing geometry, desmearing of raw data was unnecessary. PMID- 21307507 TI - ReflEXAFS Spectroscopy of Thin Fe/Sc Multilayers. AB - For two three-layer systems, Sc/Fe/Sc and Fe/Sc/Fe, the fine structure in specular reflected x rays above the Fe K-edge has been investigated experimentally. Computer simulation of ReflEXAFS formation on multilayered structures has been done. Estimates of each layer's thickness and density as well as of local atomic order in Fe layers have been obtained. The possibility of ultrathin-layer investigations (down to a few angstroms) has been analyzed. PMID- 21307508 TI - Structural Changes Study of Co/C and Ni/C Multilayers upon Annealing. AB - A detailed study of structural changes occurring in films and on boundaries in multilayers upon annealing with EXAFS, WAXS, and SAXS methods was performed. The optimum temperature of annealing for the Ni/C and Co/C multilayers obtained by the pulsed laser evaporation method was found. PMID- 21307509 TI - Whispering gallery mirrors for the soft x-ray region: properties and applications. AB - Basic properties of whispering gallery mirrors in the soft x-ray region are considered. The following applications of whispering gallery optics are discussed: increasing the utilization efficiency of point source radiation, deflecting a synchrotron radiation beam to the vertical plane and transporting it to another horizontal level, resonators for soft x-ray lasers, and using the whispering gallery effect to investigate the roughness of concave surfaces. PMID- 21307510 TI - The Structure of W/C (0.15 < gamma < 0.8) Multilayers Annealed in Argon or Air. AB - We report the effect that thermal annealing in inert and oxidizing atmospheres, and with and without encapsulating layers, has on the structure of tungsten/carbon [W/C] multilayer thin films. This study focuses on the tungsten component and deals mainly with multilayers where the ratio of thickness of tungsten layers is equal to or greater than for the carbon layers (that is, gamma <= 0.5). This is in contrast to prior studies where the tungsten layer thickness was generally held constant and the carbon layer was varied. Thermal annealing in inert atmospheres produces reactions and other structural changes in the tungsten and carbide layers which depend on the as-deposited multilayer structure which depends, in turn, on the thickness of the tungsten layer. In samples where both the tungsten and carbide fractions of the multilayer are completely amorphous as deposited, which is the case for thin tungsten layers (thickness of tungsten (tw) < 4 nm/period), the reactions in the tungsten layer forming crystalline tungsten and tungsten carbide occur at annealing temperatures above 900 degrees C. The layer pair spacing, or period, (d), in this group shows an expansion of up to 10 15% of the original value as has been reported in the past. Changes in both the tungsten and carbide layers, and their interfaces, contribute to changes in d spacing and relative thickness of the high and low Z components. When the tungsten layer thickness exceeds 4 nm per period the tungsten is partially crystallized in as-prepared samples. In such multilayers interfacial reactions, producing an oriented partially crystalline W2C/C superlattice, occur at temperatures of 600 degrees C and below. The fact that W2C crystallites in one period can form a structure which is correlated to W2C crystallites in neighboring layers is somewhat surprising, since layers are presumably still separated by amorphous carbon which is still visible via Raman. The expansion of the layer pair spacing is relatively small (<5%) in this group and, more importantly, mostly involves increases in the thickness of the high Z components. Samples annealed in air at temperatures below 300 degrees C are progressively destroyed by the oxidation of both tungsten and carbide layers. Encapsulation of similar multilayers with a thin (30 nm) dielectric layer of any of several types can retard oxidation to 600 degrees C. The silicon-containing encapsulants generally perform better. Failure at this temperature is seen to occur from pinhole formation. PMID- 21307511 TI - Applications and measurements of polycapillary x-ray optics. AB - The recent invention of Kumakhov polycapillary x-ray and neutron optics has expanded the ways x-ray beams can be controlled. X rays incident on the interior of glass tubes at small angles can be guided down the tubes by total external reflection. Now, arrays of curved tapered capillaries can be used to focus, collimate, and filter x-ray radiation. Extensive research is being conducted on the performance and potential applications of these optics. Potential medical applications include mammography, digital energy subtraction angiography, and focused beam therapy. Other applications are x-ray lithography, x-ray astronomy, crystal diffraction, x-ray fluorescence, and neutron prompt gamma analysis. PMID- 21307512 TI - Phosphors for luminescent image plates. AB - This is a review of the properties of some photostimulable phosphors for luminescent image plates as applied to digital radiography. In particular, the properties of BaFBr:Eu and other barium fluorohalides that are useful for this application are considered. The main emphasis of the review is on the effect of the preparative conditions and the origin of the photostimulated luminescence and its features under VUV excitation. PMID- 21307513 TI - An analysis of biological hard tissues using the tomographic reconstruction error formula. AB - A variety of teeth and bone specimens have been scanned using the constant statistics tomographic scanner developed at the London Hospital Medical College. Each data set has been reconstructed with several Hamming filters, and for a geometric resolution ranging from 20 to 50 micrometers. The reconstructions have been studied using the approximate error formula for the convolution backprojection algorithm. Some inferences are made on the relative structure of the cross sections. PMID- 21307514 TI - Dielectronic Spectra for Ne-like Ions from F-like Low-Lying States. AB - Energy levels, radiative decay, and Auger rates have been calculated for dielectronic recombination of seven Ne-like ions, ranging from Fel7+ to Ag38+, from the n = 2 F-like shell into the n = 3 one, by use of the multiconfiguration AUTOLSJ code in intermediate coupling. Rate coefficients have then been computed versus the electronic temperature, the nuclear charge of the involved element, the final Ne-like state, and the population distribution among the initial 3 F like levels. Dielectronic spectra have also been obtained. PMID- 21307515 TI - Luminosity of bragg crystal diffraction spectrometers with flat and focusing crystals. AB - Analytical approximations for calculations of the luminous efficiency of Bragg crystal diffraction spectrometers with flat and focussing crystals are derived. The given approximative formulas are in good agreement with ray-tracing calculations presented in an earlier work. Influences of the geometric source dimensions on the luminous efficiency are discussed for both spectrometer types mentioned. PMID- 21307516 TI - High-resolution x-ray computed tomography using a solid-state linear detector. AB - In this paper we present an original low cost acquisition system for computed tomographic imaging. On the first hand, the use of a linear detector consisting of sensitive elements 0.225 mm * 0.5 mm in size allows one to obtain a resolution of about 150 MUm after magnification. Image quality has been assessed in terms of spatial resolution and contrast sensitivity by imaging test objects. The images of in vitro vertebrae acquired by this experimental system show great improvement compared to the images acquired by a conventional medical scanner. On the other hand, an even better resolution (25 MUm) has been obtained by using an x-ray sensitive Vidicon camera, and an industrial application is presented with advanced composite materials. PMID- 21307517 TI - Pinch plasma source for x-ray microscopy with nanosecond exposure time. AB - The strong demand for bright, compact, and inexpensive sources for x-ray microscopy has stimulated the development of flash x-ray sources. In this paper, the requirements for such a source are analyzed under boundary conditions given by the concept of an imaging x-ray microscope using mirror condenser and Fresnel zone plates for high-resolution imaging. It is found that the Lyman-alpha (1s-2p) line of hydrogen-like nitrogen (N VII) at lambda = 2.48 nm emitted from a nonequilibrium plasma of about 200 eV temperature and 1020 cm-3 electron density is best suited. These conditions are achieved in medium-current pinch-plasma devices. Using detailed numerical simulation of the physical processes of such a device, optimization criteria for the integrated spectral brightness (ISB) are found. Measurements of the ISB confirm these optimization criteria. The results show that the spectral emission characteristics of an optimized pinch plasma souce are compatible with the demands of the mentioned x-ray microscopy concept. These emission characteristics are compared with laser-produced plasma sources. Using the optimized source with an ISB exceeding 0.6 MUJ/(MUm2 sr) in a 10-20 ns pulse, wet biological samples are imaged with about 0.1 MUm lateral resolution. PMID- 21307518 TI - Evolution of structure, phase composition, and x-ray reflectivity of multilayer mirrors mo-(B + C) after annealing at 250-1100 degrees c. AB - Structural, phase, and chemical stabilities of x-ray multilayer mirrors Mo-(B + C) with periods in the range 8-11.5 nm were studied at temperatures of 250-1100 degrees C by small-angle and large-angle x-ray diffraction and electron microscopy methods. Two amorphizations at ~450 and ~750 degrees C and two crystallizations at ~650 and ~850 degrees C of Mo-based layers were observed, which were due to the formation of the molybdenum carbides MoC (hex), gamma-MoC, and Mo2C instead of the metal Mo, and to the formation of the molybdenum borides MoB2 and Mo2B5 instead of molybdenum carbides, respectively. Both amorphizations of Mo-based layers were accompanied by smoothing of interfaces and by an increase of the multilayer x-ray reflectivity at lambda = 0.154 nm. Both crystallizations of Mo-based layers promoted the development of interface roughness and a decrease of multilayer x-ray reflectivity. The destruction of Mo-(B + C) multilayers at ~ 1100 degrees C was caused by the recrystallization of Mo2B5 layers. PMID- 21307519 TI - Two-period multilayer mirrors for the soft x-ray region. AB - The problem of multilayer mirrors which are capable of reflecting x-ray radiation at two given wavelengths is discussed. Three kinds of two-period multilayers are considered and a comparison of their properties in the soft x-ray region is presented. The scheme of a soft x-ray scanning microscope based on a Schwarzschild objective with a two-period multilayer coating is proposed for chemical microanalysis of biological samples. PMID- 21307520 TI - Non-destructive and Quantitative Investigation of Jingdezhen Blue and White Porcelains Using EDXRF. AB - The fabrication of the calibration source is a critical part for the non destructive and quantitative investigation of blue and white porcelains using EDXRF. In order to minimize the effects on the results due to the matrix difference between the samples and the calibration source, broken porcelain pieces of the Ming and Qing dynasties with matrix conditions similar to those of the measured samples are used directly as calibration sources. The 13 trace elements, viz. Ti, Mn, Fe, Co, Ni, Cu, Zn, Ga, Pb, Rb, Sr, Y, and Zr, have been quantitatively measured for 20 imperial blue and white porcelains of the Qing dynasty and for 11 contemporary Jingdezhen porcelains. The data are then analyzed by the principal component analysis method. The clustering of the data and the identification of the porcelains are then investigated. PMID- 21307521 TI - Diagnosis of high-temperature implosions using low- and high-opacity krypton lines. AB - High-temperature laser target implosions can be achieved by using relatively thin shell targets, and they can be diagnosed by doping the fuel with krypton and measuring K-shell and L-shell lines. Electron temperatures of up to 5 keV at modest compressed densities (~ 1-5 g/cm3) are predicted for such experiments, with ion temperatures peaking above 10 keV at the center. It is found that the profiles of low-opacity (optically thin) lines in the expected density range are dominated by the Doppler broadening and can provide a measurement of the ion temperature if spectrometers of spectral resolution Deltalambda/lambda >= 1000 are used. For high-opacity lines, obtained with a higher krypton fill pressure, the measurement of the escape factor can yield the rhoR of the compressed fuel. At higher densities, Stark broadening of low-opacity lines becomes important and can provide a density measurement, whereas lines of higher opacity can be used to estimate the extent of mixing. PMID- 21307522 TI - Enhanced X-Ray Detectors Using Polar Dopants for KCD Digital Radiography. AB - The goal of this study is to develop high resolution imaging detectors with applications in digital radiography and computed tomography. A physical treatment aimed at a better understanding of the line-spread function response of kinestatic charge detector (KCD) gas media, using dopants with permanent electric dipoles, is presented. Experimental results were obtained by operating a KCD krypton-filled detector at pressures up to 60 atm and constant electric field-to gas density ratio doped with small amounts of polar or nonpolar polyatomic molecules with low or high ionization potential. The results clearly indicate that the addition of dopants having both low ionization potential and high dipole moment significantly enhance the imaging signal quality. An analysis of the experimental results aimed at providing a plausible interpretation of the reported observations is offered. PMID- 21307523 TI - A comparison of the ball, wire, edge, and bar/space pattern techniques for modulation transfer function measurements of linear x-ray detectors. AB - Actual assessment of the modulation transfer function (MTF) of a physical system requires objective experimental data to be obtained. This paper presents four practical methods for measuring the MTF of a linear x-ray detector. These methods are based on using the ball, wire, edge, and bar/space pattern as stimuli. The measurement procedure and experimental conditions are described in detail. The MTF results obtained with these different techniques are analyzed and compared. PMID- 21307524 TI - Effects of a near-surface transition layer on x-ray reflection and scattering. AB - The influence of smooth (not step-like) variation of the dielectric function near a surface on the reflectivity and scattering of x rays is investigated theoretically with the model function epsilon(z) = 1 - 0.5(1 - epsilon+)(l + tanh(z/(2L))) taken as an example. It is shown that the presence of the transition layer can essentially change the shape of the differential scattering intensity diagram, especially when the incidence angle of the x-ray beam is greater than the critical angle of the total external reflection (TER). The results of measurements of the x-ray reflection coefficient and the differential scattered intensity are discussed. The model of the near-surface transition layer is shown to describe quantitatively the specific features of experimental curves for the incident beam beyond the TER region, whereas these experimental data cannot be explained in the framework of a step-like model of the dielectric function, taking into account the scattering from surface roughness. PMID- 21307525 TI - Soft x-ray emission from millimeter-wave electron cyclotron resonance discharge. AB - This work is devoted to the experimental investigation of incoherent soft x-ray radiation from an electron cyclotron resonance discharge with pumping by a millimeter-wave beam from a gyrotron. The basic contribution to the x-ray spectrum was shown to be produced by a plasma emission in the wavelength region 4.5-12 nm. The power of the x-ray emission from the ECR discharge was about 35 kW, and the efficiency of conversion of the gyrotron radiation into an x-ray emission exceeded 25%. PMID- 21307526 TI - Effects of the microstructuring process on diffraction properties of bragg fresnel lenses. AB - The effects appearing in a crystal microstructuring by reactive ion etching on diffraction properties of Bragg-Fresnel lenses were studied. Possible deviations of the real zone structures from ideal ones were considered. The influence of the Fresnel zone displacements due to sidewall undercutting effects and due to a mask erosion was analyzed. Technological tolerances for a different zone profile shape were defined. PMID- 21307527 TI - Action Constant for Bremsstrahlung from Electron-and-Nucleus Collisions. AB - The analysis of bremsstrahlung events presented in this paper is based on conservation of energy. It develops an action constant that applies to any nucleus. The constant differs from Planck's constant; it is needed to obtain a relation for the bremsstrahlung power radiated from a plasma per unit volume. The equation agrees with experimental tests and leads to the conclusion that magnetically confined plasmas cannot produce self-sustaining fusion power. PMID- 21307528 TI - The X-Ray CCDs Developed for the Joint European X-Ray Telescope. AB - The charge coupled devices (CCDs) developed for the Joint European X-ray Telescope (JET-X) are described in detail. A history of the development program and device performance is given. We present results from a comprehensive study to characterize the x-ray response of the flight model focal plane detectors. The goal of the program is to calibrate the efficiency, energy resolution, gain, etc. down to a precision of ~1%. Final calibration data sets will be based on combinations of measurements and calculations. For example, the CCD quantum efficiency will be composed of discrete line measurements made at the University of Leicester test facility and calculation and synchrotron measurements from the Daresbury Synchrotron Radiation Source (SRS). The absolute normalizations will be provided by x-ray long beam pipe measurements at the Max Planck Institut fur Extraterrestrische Physik (MPE) Panter test facility in Munich. Using the available data, it is shown that it is possible to calibrate the quantum efficiency, the FWHM energy resolution, and the system gain of the flight devices to better than 1%. PMID- 21307530 TI - International conference on soft x-rays in the 21st century. PMID- 21307529 TI - The spin dependent momentum density of hexagonal close packed cobalt. AB - Directional-spin-dependent Compton profiles of ferromagnetic hexagonal close packed cobalt metal have been measured with 117 keV and 167 keV circularly polarized synchrotron radiation at the new ESRF high energy beamline. Significantly improved resolution was achieved at the higher energy. The results have been compared with the profile predicted from an augmented plane wave (APW) calculation of the electron momentum density in the hexagonal phase. No significant difference was found between the c-axis and the basal plane magnetic profiles. The experiments show that there is substantially more 3d spin density at high momentum than in the model calculation. After correcting for this deficiency we find that the 4s-p component of the momentum density remains significantly different than predicted. PMID- 21307531 TI - Detection and Electrical Properties of Cd1-xZnxTe Detectors at Elevated Temperatures. AB - We have studied the behavior of Cd1-xZnxTe detectors in the temperature range 24 70 degrees C. The detector count rate stability and leakage currents are presented as a function of voltage, time, and temperature. Detector polarization due to bulk and surface effects leading to a decreased leakage current was observed. At 70 degrees C, the position of the 32 keV photopeak of 133Ba was stable with time. The peak position varies within only 3 keV, and the peak quality factor varied between 0.31 and 0.41, for a 24 h period of operation at a 60 V bias. The net count to total count ratio was also stable, with values varying between 0.56 and 0.59. The net count to total count ratio decreased from 0.78 at 25 degrees C to 0.71 at 60 degrees C. The conclusion is that Cd1-xZnxTe is a promising material for gamma ray detection at temperatures above room temperature. PMID- 21307532 TI - X-ray diffraction imaging using perfect crystals. AB - The imaging properties of perfect crystals, used for controlling and directing x ray beams in imaging systems, are analyzed using optical transfer functions. The optical transfer functions are related to the point-spread functions for the crystal imaging system and are derived from a one-dimensional Fourier transform of the Takagi-Taupin equations. Images obtained using diffracting crystals as optical elements are simulated for the Laue and Bragg geometries using a Fourier transform method and the imaging characteristics of each of these crystal configurations are analyzed. It is demonstrated that the perfect crystals act as spatial filters of the object wave. PMID- 21307533 TI - Line spread function study of kinestatic charge detectors operating at high gas pressures. AB - A systematic study of the line spread function (LSF) in the drift direction of a high-pressure ionization chamber for x-ray detection and imaging is presented. Experimental results, obtained by operating a KCD krypton-filled detector at pressures up to 60 atm and constant electric field-to-gas pressure ratio, indicate that the width of the LSF increases with the drift distance and decreases with increasing pressure, both effects being quite large. The hypothesis of this paper is that, at sufficiently high pressures, formation of clusters of molecular ions with a unique or narrowed mobility distribution take place by means of energy exchange mechanisms. Therefore, the LSF of the ionic signal becomes narrower and the FWHM of the ionic signal improves significantly with increasing gas pressure. This research is aimed at investigating methods to improve the spatial resolution as part of the development of a large field-of view prototype digital radiographic scanner operating on kinestatic charge detection principles. PMID- 21307534 TI - Calibrated time-resolved transmission grating spectrometer for the study of ultrafast x-ray sources. AB - A transmission grating spectrometer has been coupled to a high-temporal resolution soft x-ray streak camera for the study of picosecond laser-plasma x ray sources. A procedure to deconvolve the overlapping contributions of diffraction orders and to calibrate the instrument has been established in order to obtain absolute time-resolved x-ray emission spectra in the 0.1-1.2 keV spectral region. The deconvolution and calibration techniques are presented along with measurements establishing the temporal resolution of this diagnostic at ~2 ps. Examples of calibrated spectra of laser-plasma x-ray sources created by 400 fs laser pulses at intensities of 1018 W/cm2 are also shown. PMID- 21307535 TI - X-Ray Focusing Optics and Its Applications in XRMF and XRL. AB - A brief review of the research on capillary x-ray focusing optics (the x-ray lens) at the X-Ray Optics Laboratory of the Institute of Low Energy Nuclear Physics at Beijing Normal University is presented. As a new tool for controlling powerful wide-bandwidth x-ray beams, the x-ray lens has very broad applications in both pure and applied sciences and in industry. Research toward developing such optics continues to grow in Russia, United States, and China. Some applications of x-ray lenses have also been developed. The preliminary results of theoretical and experimental studies on applications of x-ray lenses in x-ray microfluorescence and deep submicron lithography are quite encouraging. These achievements anticipate the appearance of a new generation of x-ray equipment. PMID- 21307536 TI - X-Ray Interferometry at ESRF Using Two Coherent Beams from Fresnel Mirrors. AB - Using two small flat mirrors under grazing incidence, we have produced interference patterns from partially coherent x-ray beams at the European Synchrotron Radiation Facility. By piezoelectrically orienting one mirror around the horizontal plane, both the vertical and horizontal transverse coherence distances of the radiation have been measured. The experimental setup can be used to characterize the coherence properties along x-ray synchrotron beamlines. PMID- 21307537 TI - Influence of the Number of Bilayers on the Optical Performances of X-UV Multilayer Interferential Mirrors. AB - The influence of the number of bilayers on the optical performances of actual X UV multilayer interferential mirrors (MIMs) has been studied in order to emphasize the experimental restrictions in the designing of "thick" mirrors used for the development of etched multilayer gratings. Several sets of samples (W/C, Mo/Si) with increasing number of bilayers have been manufactured in the very same conditions by means of a sputtering technique. X-ray diffraction characterization at Cu-Kalpha radiation (lambda = 1.54018 A) exhibits technical constraints in the achievement of multilayer structures with large number of bilayers. We obtain a gradual loss of reflectivity for deposition times greater than 1h 30 min to 2h without significant drift of the MIM's geometrical parameters (period and division parameter). In the same time, absolute reflectivity measurements at Cu Lalpha radiation (lambda = 1.333 nm) emphasize satisfying optical and spectroscopic performances of W/C thick samples ( 150 bilayers). PMID- 21307538 TI - Optimization of Cd1-xZnxTe Detectors for Digital Radiography. AB - In this study, measurements of the electrical and detection parameters of the Cd1 xZnxTe detectors, within the x-ray diagnostic energy range, have been performed with the aim of optimizing the image quality parameters of these solid-state ionization detectors. Namely, the leakage current and system capacitance of the x ray imaging system have been measured as they relate to signal parameters. Similarly, the detected signal and noise contributions were measured and related to the radiation exposure and tube current setting. Furthermore, the detector contrast has been experimentally determined. The experimental results indicate that Cd1-xZnxTe detectors have low leakage current, high resistivity, and high detector contrast resolution. Therefore, they appear to be very attractive for imaging applications with applications in x-ray digital radiography. PMID- 21307539 TI - X-Ray Crystal Spectroscopy of Sub-picosecond Laser-Produced Plasmas beyond 50 keV. AB - The interaction of a sub-picosecond (sub-ps) laser with a high-Z target produces a hard x-ray continuum, but to our knowledge no high-resolution study of the line emission is known. We present here crystal spectroscopy as a tool for the observation of energetic line x-radiation from a sub-ps laser-produced plasma. Reflection properties of flat and bent crystals for x-ray spectroscopy are analyzed theoretically for both the Bragg and the Laue geometries and optimized for a crystal spectroscopy of hard (>50 keV) x-radiation. The crystal setup is optimized for spectroscopic applications with regard to high throughput and spectral resolution. The characteristic tantalum Kalpha,beta- and Lalpha,beta line emissions from a sub-ps laser-produced plasma is observed for the first time. A resolving power of about 450 is achieved which is much higher than that for comparable absorption filter techniques (E/DeltaE ~ 15). PMID- 21307540 TI - Method of eigenvectors for numerical studies of multilayer gratings. AB - A new approach to numerical studies of lamellar multilayer gratings is developed. It stands out against the existing modal and differential methods by its applicability to thick multilayer gratings with a small grating period, and also to the case of grazing incidence of radiation. The diffraction properties of multilayer gratings are calculated for x rays with the angles of incidence down to zero. Reflection curves are calculated for multilayer gratings with the grating periods down to 5 nm and the number of bilayers up to 1000. The diffraction pictures are developed for all the range of x-ray radiation (soft and hard x rays). It is directly demonstrated that the multilayer grating can be regarded as a two-dimensional crystal. Numerical calculations based on the newly proposed method were used for the interpretation of experimental data on the performance of the Ni/C multiplayer grating. PMID- 21307541 TI - Soft X Rays in the 21st Century II. PMID- 21307542 TI - Anecdotes about the Early Days of X-Ray Optics. AB - An anecdotal description of the trials and tribulations encountered by the first investigators in the field of x-ray optics starting in the late 1940s and how they managed to overcome them is provided. Some of the players, in addition to the author, included Paul Kirkpatrick, Hussein El Sum, and Howard Pattee of Stanford. At the University of Redlands we became interested in producing an x ray microscope based on the concepts of holography which Dennis Gabor had demonstrated. This led to correspondence with Gabor and the opportunity to meet him and many other investigators at the first International Conference on X-Ray Microscopy and Microradiography held in Cambridge, England, in 1956. With the help of V.E. Cosslett and William Nixon, a point-focus x-ray tube was obtained by the University of Redlands for its experiments in x-ray holography in the1950s. PMID- 21307543 TI - Projected advances in laboratory soft x-ray systems and their applications. AB - Advances in x-ray laser plasma sources and zone plate optics since the early 1980s are reviewed. The improvements are projected into the early years of the 21st century and it is demonstrated that applications such as x-ray microscopy will become increasingly amenable to small scale laboratory systems. PMID- 21307544 TI - Silicon drift detectors with on-chip electronics for x-ray spectroscopy. AB - The silicon drift detector (SDD) is a semiconductor device based on high resistivity silicon fully depleted through junctions implanted on both sides of the semiconductor wafer. The electrons generated by the ionizing radiation are driven by means of a suitable electric field from the point of interaction toward a collecting anode of small capacitance, independent of the active area of the detector. A suitably designed front-end JFET has been directly integrated on the detector chip close to the anode region, in order to obtain a nearly ideal capacitive matching between detector and transistor and to minimize the stray capacitances of the connections. This feature allows it to reach high energy resolution also at high count rates and near room temperature. The present work describes the structure and the performance of SDDs specially designed for high resolution spectroscopy with soft x rays at high detection rate. Experimental results of SDDs used in spectroscopy applications are also reported. PMID- 21307545 TI - Fabrication of Radiation Entrance Windows with Optimized sub-100 eV Transmission Properties. PMID- 21307546 TI - New Concepts for X-Ray, Soft X-Ray, and EUV Optical Instrumentation Including Applications in Spectroscopy, Plasma Diagnostics, and Biomedical Microscopy: A Status Report. AB - In this article, we review current progress in the development of several techniques for extreme ultraviolet, soft x-ray, and x-ray optical instrumentation. Applications of these concepts include diagnostics of hot plasmas, spectroscopic studies of the interaction of multicharged ion beams with matter (atoms, ions, molecules, microstructures, surfaces, solids), and biomedical x-ray microscopy. Novel applications of components include the use of glass capillary converters (GCCs) and multilayer mirrors (MLMs) or crystals. GCC devices provide guiding, focusing, and polarization analysis of short wavelength radiation over a wide bandwidth. The MLM or crystal optical elements can be used for dispersing, focusing, and polarization-sensitive studies of radiation within a narrow bandwidth. In this report we focus on the development and testing of optical diagnostic devices for the short wavelength spectral region 0.1 nm < lambda < 100 nm. PMID- 21307547 TI - Reactive gas magnetron sputtering of lithium hydride and lithium fluoride thin films. AB - We report the preparation and structural characterization of lithium hydride and lithium fluoride thin films. These materials, due to their low absorption in the soft x-ray range, may have a role as spacer layers in multilayer mirrors. Theoretical reflection calculations suggest that an epitaxial crystalline multilayer stack of a nitride and a lithium compound spacer layer could produce respectable reflectance for short soft x-ray wavelengths (lambda < 10 nm). Lithium targets were magnetron sputtered in the presence of hydrogen or ammonia to prepare the LiH films and nitrogen trifluoride to prepare the LiF films. The films were deposited on room temperature Si (100) or MgO (100) substrates. A near IR-Visible-UV spectrometer indicated a drop in reflectance at ~250 nm for a 100 nm-thick LiH film. This corresponds to a 5-eV band gap (characteristic of LiH). UV fluorescence indicated characteristic LiH defect bands at 2.5, 3.5, and 4.4 eV. The UV fluorescence characterization also indicated a possible lithium oxide (Li2O) contamination peak at 3.1 eV in some of our thin films. Film surface morphology, examined by scanning electron microscopy, appeared extremely rough. The roughness size varied with reactive gas pressure and the type of substrate surface. A LiH/MoN multilayer was constructed, but no significant d spacing peak was seen in a low angle CuKalpha XRD scan. It is believed that the roughness of the LiH film prevented smooth, uniform planar growth of the multilayer stack. Possible reasons of rough growth are briefly discussed. PMID- 21307548 TI - Focusing Properties of X-Ray Spectrometers with 2D-Curved Crystals for Extended X Ray Sources of Hot Plasmas. AB - The focusing properties of very large (~33 * 33 cm2) spherically and toroidally curved crystals with a radius of curvature of ~10 m were determined numerically with an x-ray tracing code and are compared to those of cylindrically bent crystals. Large spherically and toroidally curved crystals are of interest for the diagnostic of future large tokamak fusion experiments and possibly for other extended x-ray sources. Compared with cylindrically bent crystals-which are now widely used for the plasma diagnostic in tokamak experiments, in particular, for Doppler-broadening measurements to determine the central ion temperature-2D curved crystal spectrometers can provide a significant enhancement of the intensity due to the additional focusing of the sagittal rays. PMID- 21307549 TI - Time-Resolved, Multi-frame X-Ray Imaging of Laser-Produced Plasmas. AB - A novel x-ray imaging system based on a microchannel-plate combined with a multi pinhole camera has been employed to study x-ray emission from laser-produced plasmas in the 0.5-3 keV photon energy range. In particular, the interaction of intense laser radiation with such plasmas, under conditions relevant to inertial confinement fusion, was monitored by recording a sequence of consecutive x-ray images with a temporal resolution of 140 ps and a spatial resolution of 10 MUm. These images provide valuable information on the main physical mechanisms involved in the interaction process, including collisional absorption of the incident laser energy and electron thermal conduction. PMID- 21307550 TI - Electric Field Dependence on Charge Collection of CdZnTe X-Ray Detectors. AB - In this study, the electric field dependence on the charge collection process of CdZnTe detectors, at different x-ray tube settings, within the x-ray diagnostic energy range, is investigated. In addition, the detector contrast at different applied bias voltages and x-ray tube settings have been experimentally determined. The experimental results suggest that an efficient charge collection process is obtained by increasing the applied bias voltage. Once the applied bias voltage is sufficiently high, charge collection becomes complete and the detector operates in the saturation region. This is a prerequisite for high contrast and spatial resolution. As a result, the detector contrast is enhanced significantly. Therefore, CdZnTe detectors appear to be potential candidates for digital radiographic applications. PMID- 21307551 TI - Investigation of crystal perfection by measuring the collimating slit image widening in diffracted synchrotron radiation. AB - The development and experimental study of a method for determining the degree of surface and volume perfection of crystals by measuring the widening of the collimating slit image in synchrotron radiation beams diffracted by an (n, +n) spectrometer are presented. PMID- 21307552 TI - An experimental and theoretical study of pendellosung fringes in synchrotron section topographs of silicon wafers. AB - X-ray section topographs of nearly perfect Czochralski-grown wafers were made with synchrotron radiation having a continuous spectrum. An intensity curve measured from the x-ray film is compared to the calculated curve obtained using the dynamical theory of x-ray diffraction. A computer simulation of the topograph is also presented. A good agreement between theory and experiment is found except in the middle part of the topograph. PMID- 21307553 TI - Soft X-Ray Contact Microscopy of Biological Specimens: Aluminum-Coated Silicon Nitride Windows as XUV Filters. AB - The optimum wavelengths for soft x-ray contact microscopy of biological specimens are between 2.2 and 4.4 nm as, relative to water, this gives maximum contrast between carbon- and oxygen-containing constituents. Irradiation outside of this so-called "water window" interferes with either the resolution and/or the contrast that can be obtained. The previous belief that silicon nitride windows act as an effective filter for the longer wavelength, XUV radiation generated from laser-produced plasmas is shown to be suspect. However, in this study the use of aluminum-coated windows, which effectively exclude these longer wavelengths, still permits successful imaging of biological specimens. The added strength imparted to coated windows also ensures their survival during the imaging process, thereby demonstrating that the tissues can remain hydrated at the time that the image is formed in the photosensitive resist material used in this technique. PMID- 21307554 TI - DuMond Diagram Mappings for Multi Asymmetric Crystal Monochromators. AB - A set of transformation equations is derived to map DuMond diagrams between crystal faces in a multi-crystal system. The equations are constructed from the Bragg equation linearized about some angle and include the effects of refraction and asymmetry of the crystal faces. The equations form the basis of a ray tracing program for x rays to aid in the design of monochromators. PMID- 21307555 TI - Synchrotron white beam topographic imaging in grazing bragg-laue geometries. AB - The technique of synchrotron white beam topographic imaging in grazing Bragg-Laue geometries has been developed at the Stony Brook synchrotron topography station (beamline X-19C) at the National Synchrotron Light Source. This technique enables both general quality characterization and imaging of defects in subsurface regions of thickness which can range from hundreds of angstroms to hundreds of micrometers as determined by the effective penetration depth of the x rays. This penetration depth, which is shown in most cases to be determined by the kinematical theory of x-ray diffraction, can be conveniently varied in a controlled manner by simple manipulation of the diffraction geometry, thereby enabling a depth profiling of the defect content. The fundamentals of the technique are described, and its advantages and disadvantages compared to existing techniques are discussed. Brief examples of the application of the technique in the characterization of defects in both single crystals and heteroepitaxial systems are given, and the general applicability of the technique is discussed. PMID- 21307556 TI - X-ray standing wave analysis of highly perfect cu crystals and electrodeposited submonolayers of cd and tl on cu surfaces. AB - Experimental requirements for measuring the structure and coverage of adsorbates in the monolayer regime on single crystals with x-ray standing wavefields are discussed in detail along with a thorough description of the theory. The near surface region of Cu crystals was probed depth selectively by detecting K as well as L fluorescence as a function of fluorescence escape angle. The effects of crystalline imperfections and of dispersive crystal arrangements on the spatial resolution of standing wave measurements are described. Copper crystals with (111) and (100) surface orientation were used as substrates for electrodeposition of Cd and Tl from an aqueous electrolyte using cyclic voltammetry. Submonolayer amounts of Cd and Tl deposited in the underpotential range were investigated on the emerged electrodes with x-ray standing waves keeping the samples under atmospheric pressure, in air, or in inert atmosphere. PMID- 21307557 TI - The detective quantum efficiency of television x-ray detectors. AB - Television area x-ray detectors measure the incident x-ray flux as a function of position. The detective quantum efficiency (DQE) expresses the precision of the flux measurement relative to that of an ideal detector. The gain, quantum efficiency, and statistical and noise properties of x-ray convertors, image intensifiers, fiber optics or lenses, and CCD sensors or vidicon tubes are described and used to develop a formulation of the DQE for a general television detector. PMID- 21307558 TI - Microfocus x-ray spectra measurement. AB - The applied equipment, the experimental procedures, and the results obtained in the experimental measurement of x-ray spectra from a microfocus x-ray unit are described. The measured spectra of x rays passing through different absorbers are compared to calculated spectra, based on calculation of the linear absorption coefficient, MU, and the spectrum of the incident radiation. The nice fit between the measured and the calculated spectra testifies to the applicability of the presented method for determination of the linear attenuation coefficient. Such calculations form the basis for a more accurate experimental determination of the contrast reducing build-up factor in industrial radiography. PMID- 21307559 TI - Multilayer x-ray mirror calibration by an energy dispersive method using an x-ray tube and a si(li) detector: absolute reflectivity, energy band pass, and overlapping order determination. AB - We describe under which conditions the x-ray energy dispersive method permits absolute reflectivity, energy band pass, and overlapping order determination on artificial multilayers. For such measurements a Si (Li) detector and a simple x ray tube are used. Examples of experimental results on W/Si and Mo/Si x-ray mirrors are given for the photon energy range from 5 to 40 KeV. PMID- 21307560 TI - Wafer cost analysis for a soft x-ray projection lithography system. AB - We present a baseline analysis of issues affecting the economic viability of Soft X-Ray Projection Lithography (SXPL). This analysis is intended to serve as a starting point, and to provide an initial assessment of the relative importance of cost factors in a SXPL system. We presume a "conventional" SXPL system design and focus on wafer exposure costs. A baseline model for system component costs and performance specifications is presented, and the dependence of wafer exposure cost on elements of the model is analyzed. Within the guidelines of our model, we find that direct cost items (e.g., cost of the laser driver) are not nearly as critical as technical performance parameters (e.g., mirror reflectivity) in determining wafer exposure costs. PMID- 21307561 TI - The yoneda effect in the region of ultrasoft x-ray radiation. AB - An experimental confirmation of the Yoneda effect in the region of ultrasoft x ray radiation has been obtained. The angle-dependent scattering distributions from hexagonal BN at different glancing incidence angles and different wavelengths are described. The influence of surface treatment on anomalous scattering parameters is demonstrated. Some theoretical predictions are tested qualitatively. PMID- 21307562 TI - Dynamic x-ray diffraction by a multilayer mirror modulated with a transverse acoustic wave. AB - Dynamic diffraction of an x-ray plane wave by a multilayer mirror modulated with a transverse acoustic wave is analyzed on the basis of rigorous multiwave mode theory. Particular attention is given to the case when lambdas > tau. where lambdas is the acoustic wavelength and tau is the extinction length. It has been derived that with increasing sound amplitude, splitting arises in every point of the kinematic branch interaction for both lambdas < tau and lambdas > tau. Accordingly the rocking curve takes the form of separate rows of peaks of Bragg diffraction into separate orders, the widths of the peaks being smaller than the width of the Bragg mirror image without modulation. The widths decrease with increasing modulation amplitude. PMID- 21307563 TI - Raman spectroscopic analysis of mo/si multilayers. AB - Raman spectra are reported from MoSi2 polycrystalline powder and soft x-ray Mo/Si multilayers. The sharp lines at 323 and 438 cm-1 are all due to crystalline MoSi2. These lines in the powder sample intensify with annealing. The Raman spectra of as-deposited multilayers shows a broad asymmetric peak, highest at about 480 cm-1. We attribute this to alpha-Si which is highly disordered. In contrast to alpha-Si in semiconductor/semiconductor and semiconductor/dielectric multilayers, in the Mo/Si samples the Raman signal can vanish after modest heating. This provides evidence that the composition of the silicon component of the multilayer changes even with 200 degrees C annealing. Further annealing also produces the signature for crystalline MoSi2 in the multilayer samples. This is the first report of the characterization of Mo/Si soft x-ray multilayers by Raman spectroscopy, and it indicates that Raman spectroscopy may be an effective technique for characterizing these soft x-ray multilayers and may be useful in studying their interfaces. PMID- 21307564 TI - Soft x-rays in the 21st century. PMID- 21307566 TI - Production of anti-amyloid beta antibodies in mice fed rice expressing amyloid beta. AB - The main signs of Alzheimer's disease (AD) are cognitive impairment and senile plaques composed of amyloid beta (Abeta) observed in patients' brains. Therefore, therapy for AD focuses on the removal of Abeta. We developed an "edible vaccine" that employs intestinal immunity with little to no side effects. Rice was utilized as an edible vaccine. It expressed GFP-Abeta42. Abeta rice was administered orally to wild-type (WT) mice causing production of anti-Abeta antibodies. Since Abeta rice was mixed with the cholera toxin B subunit (CTB), antibody against the rice seed protein was also produced. Then, mice were caused to develop immune tolerance against the rice seed protein by oral administration of Abeta rice mixed with CTB. The results indicated that only anti-Abeta antibodies were produced. PMID- 21307567 TI - An in vitro effect of coffee on the antigen-specific immune responses of naive splenocytes. AB - Coffee is a globally consumed beverage with potential health benefits. However, there are few reports about the effects of coffee on immunological functions. We previously reported that in an allergic mouse model, coffee intake prevented allergy development through augmentation of interleukin (IL)-12p40. In order to investigate the anti-allergic activity of coffee, we examined the effect of coffee on antigen (Ag)-specific responses of immune cells in vitro. Coffee treatment suppressed proliferation and IL-2 secretion of mouse splenocytes in the same way as splenocytes from mice administered coffee orally. However, IL-12p40 secretion decreased significantly as a result of in vitro coffee treatment, which was contrary to the results obtained from experiments of mice administered coffee orally. Therefore, modification associated with oral administration might influence the anti-allergic activity of coffee. PMID- 21307568 TI - Attractive reactivity of a natural product, zerumbone. AB - Zerumbone is a cyclic seaquiterpene and, a potential resource for natural materials-related diversity-oriented synthesis (NMRDOS). Zerumbone, the main component of the essential oil of a wild ginger, Zingiber zerumbet Smith, showed strong reactivity with good chemo-, regio-, and stereoselectivity. To build the foundations for the industrial use of zerumbone, we examined conjugate addition, transannular reactions, ring cleavage, ring expansion, and asymmetric induction. The biological activity of zerumbone derivatives was also studied. PMID- 21307569 TI - Bacillus thuringiensis Cry toxins bound specifically to various proteins via domain III, which had a galactose-binding domain-like fold. AB - Cry toxins have been reported to bind not only to receptors on insect cells but also to several unrelated proteins. In this study, we investigated the binding properties of Bacillus thuringiensis Cry toxins, focusing on domain III, a Cry toxin region with a structure that of the galactose-binding domain-like. Cry1Aa, Cry1Ac, and Cry8Ca specifically bound to several proteins unrelated to insect midgut cells. Cry1Aa binding to Cry toxin-binding proteins was inhibited by a monoclonal antibody, 2C2, indicating that Cry1Aa binds to these Cry toxin-binding proteins through domain III. Cry1Aa binding to Bombyx mori aminopeptidase N and other Cry toxin-binding proteins was inhibited by carbonic anhydrase, a Cry toxin binding protein. The binding regions of carbonic anhydrase and Bombyx mori aminopeptidase N were narrowed to regions of less than 20 amino acids that did not have any similarity, suggesting that Cry toxin domain III has a binding pocket for multiple proteins. PMID- 21307570 TI - A mechanistic analysis of enzymatic degradation of organohalogen compounds. AB - Enzymes that catalyze the conversion of organohalogen compounds have been attracting a great deal of attention, partly because of their possible applications in environmental technology and the chemical industry. We have studied the mechanisms of enzymatic degradation of various organic halo acids. In the reaction of L-2-haloacid dehalogenase and fluoroacetate dehalogenase, the carboxylate group of the catalytic aspartate residue nucleophilically attacked the alpha-carbon atom of the substrates to displace the halogen atom. In the reaction catalyzed by DL-2-haloacid dehalogenase, a water molecule directly attacked the substrate to displace the halogen atom. In the course of studies on the metabolism of 2-chloroacrylate, we discovered two new enzymes. 2-Haloacrylate reductase catalyzed the asymmetric reduction of 2-haloacrylate to produce L-2 haloalkanoic acid in an NADPH-dependent manner. 2-Haloacrylate hydratase catalyzed the hydration of 2-haloacrylate to produce pyruvate. The enzyme is unique in that it catalyzes the non-redox reaction in an FADH(2)-dependent manner. PMID- 21307571 TI - The vitamin D3 1alpha-hydroxylase gene and its regulation by active vitamin D3. AB - Vitamin D has a pivotal role in a many biological processes, including the maintenance of calcium homeostasis, cell differentiation and proliferation. Most of these actions are mediated by transcriptional regulation of target genes through vitamin D receptor (VDR), a member the steroid/thyroid hormone receptor superfamily. Thus, it is important to understand vitamin D biosynthesis into an active form that regulates VDR transcriptional functions. The active form of vitamin D, 1alpha,25(OH)(2)D(3), derived by vitamin D3 1alpha hydroxylase, 1alpha(OH)ase in renal proximal tubule cells is a ligand for VDR. We have identified the 1alpha(OH)ase gene, which uses a novel expression cloning method derived from VDR deficient mice that have excess amounts of active vitamin D3 in the serum. Identification of 1alpha(OH)ase gene had lead us to understand not only the biological significance of active vitamin D3 synthesis, but also a novel mechanism of VDR-mediated transcriptional regulation. The gene expression of 1alpha(OH)ase is positively and negatively regulated by parathyroid hormone (PTH) and active vitamin D3 respectively. In this review, we describe switching between positive and negative transcriptional modulation by the VDR, together with recent findings on the mechanisms of VDR-mediated epigenetic regulation in the 1alpha(OH)ase gene. PMID- 21307572 TI - Development of a novel PPARgamma ligand screening system using pinpoint fluorescence-probed protein. AB - The activation of peroxisome-proliferator-activated receptor-gamma (PPARgamma), which plays a central role in adipocyte differentiation, depends on ligand dependent co-activator recruitment. In this study, we developed a novel method of PPARgamma ligand screening by measuring the increase in fluorescent polarization accompanied by the interaction of a fluorescent co-activator and PPARgamma. Sterol receptor co-activator-1 (SRC-1), a major PPARgamma co-activator, was probed by fluorescent TAMRA by the Amber codon fluorescence probe method. Polarization was increased by adding PPARgamma ligands to a solution containing labeled SRC-1 (designated TAMRA-SRC-S) and PPARgamma. The disassociation constants (Kd) of the PPARgamma synthesized ligands, pioglitazone (221 nM), troglitazone (83.0 nM), and 15-deoxy-Delta12,14-prostaglandin J(2) (15d DeltaPGJ(2)) (156 nM), were determined by this method. Farnesol (2.89 uM) and bixin (21.1 uM), which we have reported to be PPARgamma ligands, increased the fluorescent polarization. Their Kd values were in agreement with the ED(50) values obtained in the luciferase assay. The results indicate that the method is valuable for screening natural PPARgamma ligands. PMID- 21307573 TI - A calcium-dependent xylan-binding domain of alkaline xylanase from alkaliphilic Bacillus sp. strain 41M-1. AB - Xylanase J of alkaliphilic Bacillus sp. strain 41M-1 contains a carbohydrate binding module family 36 xylan-binding domain (XBD). Mutational analysis of the XBD revealed that Tyr237, Asp313, Trp317, and Asp318 were involved in Ca(2+) dependent xylan-binding, and that Asp313 and Asp318 were especially important. PMID- 21307575 TI - Evaluation of methods of determining humic acids in nucleic acid samples for molecular biological analysis. AB - It is important in molecular biological analyses to evaluate contamination of co extracted humic acids in DNA/RNA extracted from soil. We compared the sensitivity of various methods for measurement of humic acids, and influences of DNA/RNA and proteins on the measurement. Considering the results, we give suggestions as to choice of methods for measurement of humic acids in molecular biological analyses. PMID- 21307574 TI - The crystal structure of SDR-type pyridoxal 4-dehydrogenase of Mesorhizobium loti. AB - Pyridoxal 4-dehydrogenase catalyzes the irreversible oxidation of pyridoxal to 4 pyridoxolactone and is involved in degradation pathway I of pyridoxine, a vitamin B(6) compound. Its crystal structure was elucidated for the first time. Molecular replacement with (S)-1-phenylthanol dehydrogenase (PDB code 2EW8) was adopted to determine the tertiary structure of the NAD(+)-bound enzyme. PMID- 21307576 TI - Fatigue-alleviating effect on mice of an ethanolic extract from Rubus coreanus. AB - The fatigue-alleviating effects on mice of Rubus coreanus were investigated by using an adjustable-current water pool. The mice were exhaustively exercised for 2 consecutive days, and those administered with the 80% ethanol extract (RCE) of R. coreanus displayed a lower reduction (20%) in swimming time on day 2 than the control group (41% reduction). RCE significantly prevented the depletion of hepatic antioxidants during exercise-induced fatigue. These results suggest that RCE alleviated fatigue by elevating the antioxidative potential. PMID- 21307577 TI - Solubilization and structural stability of bacteriorhodopsin with a mild nonionic detergent, n-Octyl-beta-thioglucoside. AB - Solubilization and structural stability of a membrane protein bacteriorhodopsin (bR) with n-octyl-beta-thioglucoside (OTG) was investigated in comparison with a previous study on bR solubilized with n-octyl-beta-glucoside (OG). Highly efficient and stable solubilization of bR with OTG was accomplished above the OTG concentration of about 15 mM. In comparison with OG-solubilized bR, the structural stability of OTG-solubilized bR was high in the dark and under light illumination. These results indicate that OTG is a detergent superior to OG for solubilizing bR molecules. PMID- 21307578 TI - Characteristic coloring curve for white bread during baking. AB - The effect of heating conditions on the crust color formation was investigated during the baking of white bread. The surface temperatures were monitored with thermocouples attached to the inside surface of the loaf pan cover. The trace of the surface color in the L(*)a(*)b(*) color coordinate system is defined as the characteristic coloring curve. The overall baking process was classified into the following four stages based on the characteristic coloring curve: i) pre-heating (surface temperature < 110 degrees C), ii) Maillard reaction (110-150 degrees C), iii) caramelization (150-200 degrees C), and iv) over-baking (surface temperature>200 degrees C). A linear relationship was observed between the L(*) decrease and the increase in weight loss of a sample at each oven air temperature. The L(*) value appeared to be suitable as an indicator to control the surface color by baking conditions. PMID- 21307579 TI - Pictet-spengler reaction using ion-exchange resin as a catalyst and support for 'catch and release' purification. AB - The Pictet-Spengler reaction between tryptamine and aldehydes was catalyzed by Dowex 50W-X4 acidic ion-exchange resin. The products were obtained from the resin in high purity by 'catch and release' without the need for separate chromatographic purification. PMID- 21307580 TI - Long-term cultured human skin mast cells are suitable for pharmacological studies of anti-allergic drugs due to high responsiveness to FcepsilonRI cross-linking. AB - Human skin mast cells proliferated in the presence of interleukin (IL)-4+SCF (expanding 18-fold in 8 weeks) and acquired profound responsiveness towards high affinity IgE receptor (FcepsilonRI) cross-linking, liberating about 75% of their histamine. In a proof-of-concept, we found that these cells are useful for pharmacological testing. Even a subtle inhibition of degranulation can be visualized. This model might prove valuable in tests of novel anti-allergic drugs. PMID- 21307581 TI - Potential of D-erythro-C14-Sphingosine as an adjuvant for a fungal pesticide of Nomuraea rileyi. AB - D-erythro-C(14)-Sphingosin (C(14)-Sph) was isolated as the germination accelerating factor in Nomuraea rileyi in our previous study. This activity was expected to support fungal infection by reduction of the infection time between conidial adhesion and invasion into the insect. In this study, we estimated the effect of C(14)-Sph with regard to the infection time. Conidia activated by C(14) Sph shortened the time to about half, indicating the potential of C(14)-Sph as an adjuvant for fungal pesticide of N. rileyi. PMID- 21307582 TI - Atg22p, a vacuolar membrane protein involved in the amino acid compartmentalization of Schizosaccharomyces pombe. AB - The fission yeast Schizosaccharomyces pombe has a homolog of the budding yeast Atg22p, which is involved in spore formation (Mukaiyama H. et al., Microbiology, 155, 3816-3826 (2009)). GFP-tagged Atg22p in the fission yeast was localized to the vacuolar membrane. Upon disruption of atg22, the amino acid levels of the cellular fraction as well as the vacuolar fraction decreased. The uptake of several amino acids, such as lysine, histidine, and arginine, was impaired in atg22Delta cells. S. pombe Atg22p plays an important role in the compartmentalization of amino acids. PMID- 21307583 TI - A cysteine endopeptidase ("dionain") is involved in the digestive fluid of Dionaea muscipula (Venus's fly-trap). AB - The carnivorous plant Dionaea muscipula (Venus's flytrap) secretes proteinases into the digestive fluid to digest prey proteins. In this study, we obtained evidence that the digestive fluid contains a cysteine endopeptidase, presumably belonging to the papain family, through inhibitor studies and partial amino acid sequencing of the major SDS-PAGE band protein. The name "dionain" is proposed for the enzyme. PMID- 21307584 TI - Characterization of O-GlcNAcylation in starfish (Asterina pectinifera) development from fertilization to bipinnaria larva. AB - Though O-linked beta-N-acetylglucosaminylation (O-GlcNAcylation) of nucleocytoplasmic proteins has been found in many multicellular organisms, its presence or absence in Echinodermata is unknown. Here we report the occurrence of O-GlcNAcylation in starfish (Asterina pectinifera) oocytes and the apparent O GlcNAcylation pattern in starfish early development. O-GlcNAcylation might participate in the regulation of starfish development at the mid-blastula stage and thereafter. PMID- 21307585 TI - Effect of Lactobacillus pentosus S-PT84 ingestion on IFN-alpha production from plasmacytoid dendritic cells by virus stimulation. AB - We investigated the effect of ingesting Lactobacillus pentosus S-PT84 on the interferon-alpha (IFN-alpha) production from splenocytes and plasmacytoid dendritic cells by virus stimulation. IFN-alpha production by the Lactobacillus pentosus S-PT84 ingestion group was significantly greater under the virus infected condition than that by the control group. Lactobacillus pentosus S-PT84 could enhance the production of IFN-alpha which is known as an important cytokine for preventing virus infection. It may therefore become a prophylactic tool against such virus infection. PMID- 21307586 TI - A new, convenient cell-based screening method for small-molecule glycolytic inhibitors. AB - To counteract active glycolysis in tumors, we developed a new, convenient cell based screening system to identify an inhibitor of glycolysis. Using this system, we searched for an inhibitor in the synthetic Carbasugar library and found two candidates. It was found that both inhibited glycolysis by suppressing the glucose uptake step in tumor cells. PMID- 21307587 TI - Novel synthesis of optically active bishomotyrosine derivatives using the Friedel Crafts reaction in triflic acid. AB - We report here a novel synthesis of optically active bishomotyrosine. The bishomotyrosine skeleton was constructed by using a Friedel-Crafts reaction between phenol and optically active N-Tfa-Glu(Cl)-OMe in triflic acid under the mild condition. Reduction and subsequent deprotection then afforded bishomotyrosine derivatives without any loss of optical purity. PMID- 21307588 TI - A new pathway for poly(3-hydroxybutyrate) production in Escherichia coli and Corynebacterium glutamicum by functional expression of a new acetoacetyl-coenzyme A synthase. AB - A biosynthetic pathway for poly(3-hydroxybutyrate) [P(3HB)] was developed in Escherichia coli and Corynebacterium glutamicum by an acetoacetyl-coenzyme A (CoA) synthase (AACS) recently isolated from terpenoid-producing Streptomyces sp. strain CL190. Expression of AACS led to significant productions of P(3HB) in E. coli (10.5 wt %) and C. glutamicum (19.7 wt %). PMID- 21307589 TI - Isolation and characterization of CcAbf62A, a GH62 alpha-L-arabinofuranosidase, from the basidiomycete Coprinopsis cinerea. AB - A cDNA encoding a putative extracellular alpha-L-arabinofuranosidase was cloned from the basidiomycete Coprinopsis cinerea (CcAbf62A). CcAbf62A belongs to glycoside hydrolase family 62 (GH62), but is phylogenetically distinct from previously characterized GH62 enzymes. The recombinant CcAbf62A, expressed in Pichia pastoris, released L-arabinose from both wheat arabinoxylan and oat-spelt xylan. The enzyme activity for wheat arabinoxylan was increased by the addition of CcEst1, a carbohydrate esterase from C. cinerea. PMID- 21307590 TI - Contamination of chitin oligosaccharides in a laminarioligosaccharide preparation can cause a confused interpretation of its elicitor activity. AB - Chitinase treatment of a commercial laminarioligosaccharide preparation from a mushroom resulted in a loss of previously reported elicitor activity in rice cells, indicating that the activity was attributable not to the laminarioligosaccharide but rather to the contaminating chitin fragments. This suggests that the elicitor activity of laminarioligosacchraides from such sources containing chitinaceous substances should be carefully interpreted. PMID- 21307591 TI - Linoleic acid isomerase in Lactobacillus plantarum AKU1009a proved to be a multi component enzyme system requiring oxidoreduction cofactors. AB - Linoleic acid isomerase in Lactobacillus plantarum was found to be a novel multi component enzyme system widespread in membrane and soluble fractions. The isomerization reaction involved a hydration step, 10-hydroxy-12-octadecenoic acid production from linoleic acid, as part of the reaction, and the hydration reaction was catalyzed by the membrane fraction. Both membrane and soluble fractions were required for the whole isomerization reaction, i.e., conjugated linoleic acid (CLA) production from linoleic acid, and for CLA production from 10 hydroxy-12-octadecenoic acid, a reaction intermediate. The multi-component enzyme system was inhibited by o-phenanthroline, and divalent metal ions such as Ni(2+) and Co(2+) restored activity. Metal oxides such as VO(4)(3+), MoO(4)(2+), and MnO(4)(2+) enhanced activity. The multi-component enzyme systems required oxidoreduction cofactors such as NADH together with FAD or NADPH for total activity. PMID- 21307592 TI - Antioxidative ability of chicken myofibrillar protein developed by glycosylation and changes in the solubility and thermal stability. AB - Myofibrillar protein prepared from chicken breast muscle was incubated with several concentrations of glucose or maltose for 6 h at 60 degrees C and 35% relative humidity in order to obtain glycosylated chicken protein. When the ratio of the weights of the myofibrillar protein and glucose or maltose had respectively reached 1:6 or 1:3-5, the solubility of each type of glycosylated chicken protein in a 0.1 M NaCl solution was exceeded by about 60%, although the myofibrillar protein was insoluble in a low ionic strength solution. Moreover, when the myofibril and maltose reaction (myofibril:maltose = 1:4) was extended to 36 h, the glycosylated protein did not undergo denaturation when held at 50 degrees C for 2 h, while it also exhibited an antioxidative function against superoxide anion radicals. PMID- 21307593 TI - N-terminal region of chitinase I of Bacillus circulans KA-304 contained new chitin-biding domain. AB - Chitinase I (CHI1) of Bacillus circulans KA-304 forms protoplasts from Schizophyllum commune mycelia when the enzyme is combined with alpha-1,3 glucanase of B. circulans KA-304. CHI1 consists of an N-terminal unknown region and a C-terminal catalytic region classified into the glycoside hydrolase family 19 type. An N-terminal region-truncated mutant of CHI 1 (CatCHI1), which was expressed in Escherichia coli Rosetta-gami B (DE3), lost colloidal chitin- and powder chitin-binding activities. The colloidal chitin- and the powder chitin hydrolyzing activities of CatCHI1 were lower than those of CHI1, and CatCHI1 was not effective in forming the protoplast. A fusion protein of the N-terminal region of CHI1 and green fluorescent protein (Nterm-GFP) was expressed in E. coli, and the fusion protein was adsorbed to colloidal chitin, powder chitin, and chitosan. Fluorescence microscopy analysis showed that Nterm-GFP bound to the S. commune cell-wall. PMID- 21307594 TI - Quinotrierixin inhibited ER stress-induced XBP1 mRNA splicing through inhibition of protein synthesis. AB - Quinotrierixin was isolated from microbes as an inhibitor of ER stress-induced XBP1 mRNA splicing, but its mode of action was unclear. We found that quinotrierixin is an inhibitor of protein synthesis, and that the required dose range of quinotrierixin to inhibit ER stress-induced XBP1 mRNA splicing was similar to that to inhibit protein synthesis. Furthermore, we also found that quinotrierixin inhibited the ER stress-induced increases of unfolded protein response-related genes such as GRP78, CHOP, EDEM, ERdj4, and p58(IPK). Thus, we showed that quinotrierixin inhibited the ER stress-induced unfolded protein response, possibly due to its inhibitory activity of protein synthesis. PMID- 21307595 TI - Inhibition of heat tolerance and nuclear import of Gts1p by Ssa1p and Ssa2p. AB - The Saccharomyces cerevisiae gene GTS1 is pleiotropic. GTS1 induction produces a variety of biological phenomena represented by heat tolerance. To clarify the interaction partners of Gts1p, tandem affinity purification and immunoprecipitation were performed. Ssa1p and Ssa2p, members of the 70-kDa heat shock protein family, were identified. Co-expression of SSA1 or SSA2 inhibited Gts1p nuclear import. As compared to the wild type, the SSA1 and SSA2 double deletion mutant showed enhancement of Gts1p-mediated heat tolerance in the stationary phase, although neither of the single deletions affected heat tolerance, irrespective of GTS1 induction. These results indicate that the heat tolerance function of Gts1p is regulated by Ssa1p and Ssa2p. Furthermore, time dependent production of Ssa1p and Ssa2p revealed that Gts1p controls the production of Ssa1p and Ssa2p, and that the total amounts of Ssa1p and Ssa2p are important in inhibiting the unique function of Gts1p. PMID- 21307596 TI - Impact of omega-5 gliadin on wheat-dependent exercise-induced anaphylaxis in mice. AB - The effects of omega-5 gliadin on wheat-dependent exercise-induced anaphylaxis (WDEIA) were investigated by using a mouse model. The gliadin fraction was prepared as a 70% ethanol-soluble solution, and omega-5 gliadin was purified by chromatography. Purified omega-5 gliadin was run on SDS-PAGE gel to reveal three bands with a molecular mass of 53-60 kDa and had the characteristic N-terminal sequence of omega-5 gliadin. The mice were sensitized to the gliadin fraction, and the anaphylactic response was assessed by measuring the body temperature and voluntary physical activity. An oral administration of omega-5 gliadin evoked a significant drop in both the body temperature and voluntary physical activity, similar to the effects of the whole gliadin fraction. ELISA and immunoblotting analyses revealed that the IgE expression from sensitized mice reacted most strongly to omega-5 gliadin. Taken together, these results indicate omega-5 gliadin to be a major allergen responsible for stimulating WDEIA in mice, with the characteristic potential for stimulating IgE production. PMID- 21307597 TI - Ecl1, a regulator of the chronological lifespan of Schizosaccharomyces pombe, is induced upon nitrogen starvation. AB - In fission yeast, ecl1(+) was identified as a novel factor that extends chronological lifespan when overexpressed. Ecl1 is a small protein consisting of 80 amino acids localized mainly in the nucleus. However, the mechanism by which it affects chronological lifespan has not been elucidated clearly. Here we analyzed the expression profile of Ecl1, especially as to cell cycle and growth phase, and found that it is induced upon nitrogen starvation. Then we analyzed the relevance of factors, Atf1, Ste11, and Tor1, which are known to be involved in the signaling of nitrogen starvation. Though the nitrogen starvation-induced expression of Ecl1 did not change in the atf1Delta mutant, induction in both the ste11Delta mutant and the tor1Delta mutant showed a delay. Based on these observations, the regulation of Ecl1 is discussed. PMID- 21307598 TI - Characterization of a novel histone H3K36 methyltransferase setd3 in zebrafish. AB - Post-translational modifications of histones have been demonstrated to play important roles in the regulation of chromatin structure and transcriptional regulation. In histone modification, methylated lysine has an important role in transcriptional regulation. The evolutionarily conserved SET domain was first identified in Drosophila proteins: Suppressor of variegation (Su(var)3-9), Enhancer of zeste (E(z)), and Trithorax. SET domain-containing proteins have histone methyltransferase (HMTase) activity via the SET domain. Using a bioinformatics approach, we identified and cloned zebrafish setd3 containing SET and Rubis-subs-bind domains. In this study, we report that setd3 had lysine specificity toward histone H3K36. Methylation of histone H3K36 is known as one of the transcriptional activation markers. It transiently transfected setd3 activated general transcription in reporter assays. Overexpression of setd3 decreased cell viability and activated caspase-3, indicating possible roles in apoptotic cell death and cell cycle regulation. PMID- 21307599 TI - Causes of the production of multiple forms of beta-galactosidase by Bacillus circulans. AB - The presence of multiple types of beta-galactosidases in a commercial enzyme preparation from Bacillus circulans ATCC 31382 and differences in their transgalactosylation activity were investigated. Four beta-galactosidases, beta Gal-A, beta-Gal-B, beta-Gal-C, and beta-Gal-D, which were immunologically homologous, were isolated and characterized. The N-terminal amino acid sequences of all of the enzymes were identical and biochemical characteristics were similar, except for galactooligosaccharide production. beta-Gal-B, beta-Gal-C, and beta-Gal-D produced mainly tri- and tetra saccharides at maximum yields of 20 30 and 9-12%, while beta-Gal-A produced trisaccharide with 7% with 5% lactose as substrate. The Lineweaver-Burk plots for all of the enzymes, except for beta-Gal A, showed biphasic behavior. beta-Gal-A was truncated to yield multiple beta galactosidases by treatment with protease isolated from the culture broth of B. circulans. Treatment of beta-Gal-A with trypsin yielded an active 91-kDa protein composed of 21-kDa and 70-kDa proteins with characteristics similar to those for beta-Gal-D. PMID- 21307600 TI - Odorant transfer characteristics of white bread during baking. AB - The potent odorants in the crust and crumb of white bread were identified and quantified by gas chromatography-mass spectrometry and gas chromatography/olfactometry. The weight loss ratio of the samples baked at 220 degrees C was controlled in the range of 0-28%. The odorants were classified into 5 types by the transfer characteristics: i) All amounts of odorant transferred from the crust to external space (type-I). ii) All transferred from the crust to the crumb and external space (type-II). iii) Certain amount remaining in the crust and the rest transferred to the crumb and external space (type-III). iv) All transferred from the crumb to external space (type-IV). v) Certain amount remaining in the crumb and the rest transferred to the crust and external space (type-V). The odorants of type-IV were not apparent after the crust had formed. The results indicate that the crust could be a barrier to prevent the odorants from being transferred to external space. PMID- 21307601 TI - Characterization of a cryptic plasmid, pSM103mini, from polyethylene-glycol degrading Sphingopyxis macrogoltabida strain 103. AB - A cryptic plasmid, pSM103mini, was found in polyethylene-glycol degrading bacterium Sphingopyxis macrogoltabida, strain 103. The plasmid was 4,328-bp long and its GC content was 57.5%. It contained four open reading frames, but only two of them showed significant similarity to reported proteins. ORF3 and ORF4 were assumed to encode resolvase and replication protein (RepA) respectively. Downstream of ORF4 we found complex repeat sequences. These together with ORF3 and 4 were necessary and sufficient for plasmid maintenance in strain 103, as analyzed by constructing deletion plasmids. The pHSG398-fused plasmid (pHSG SM103mini) functioned as a shuttle vector between strain 103 and Escherichia coli. The plasmid constructed was maintained in strain 103 and its close relative, S. macrogoltabida strain 203, but not efficiently in PEG-degrading S. terrae. PMID- 21307602 TI - Expression and characterization of full-length Ampullaria crossean endoglucanase EG65s and their two functional modules. AB - Three endoglucanase cDNAs, eg65a, eg65b, and eg65c, were cloned from the mollusk Ampullaria crossean in previous work. To characterize the full-length enzymes as well as their individual functional modules via heterologous expression analysis, the three full-length putative endoglucanases (rEG65a, rEG65b, and rEG65c) and the corresponding catalytic modules (EG65a-CM, EG65b-CM, and EG65c-CM) were expressed in Pichia pastoris GS115, and the three corresponding carbohydrate binding modules (EG65a-CBM, EG65b-CBM, and EG65c-CBM) were expressed in Escherichia coli BL21 (DE3). The properties of recombinant rEG65b, EG65a-CM, EG65b-CM, and EG65c-CM were characterized. Binding assays of CBMs with insoluble polysaccharides indicated that both EG65b-CBM and EG65c-CBM bound to phosphoric acid swollen cellulose (PASC), Avicel, and oat-spelt xylan, while EG65a-CBM did not. The relative equilibrium constants (K(r)) of EG65b-CBM and EG65c-CBM were determined by absorption isotherm measurements. In this study, the CBMs of animal cellulases were expressed and characterized for the first time. PMID- 21307603 TI - Culture-independent phylogenetic analysis of the microbial community in industrial sugarcane bagasse feedstock piles. AB - Sugarcane bagasse is an important lignocellulosic by-product with potential for conversion to biofuels and chemicals in biorefinery. As a step towards an understanding of microbial diversity and the processes existing in bagasse collection sites, the microbial community in industrial bagasse feedstock piles was investigated. Molecular biodiversity analysis of 16S rDNA sequences revealed the presence of a complex bacterial community. A diverse group of mainly aerobic and facultative anaerobic bacteria was identified reflecting the aerobic and high temperature microenvironmental conditions under the pile surface. The major bacterial taxa present were identified as Firmicutes, Alpha- and Gammaproteobacteria, Acidobacteria, Bacteroidetes, and Actinobacteria. Analysis of the eukaryotic microbial assemblage based on an internal transcribed spacer revealed the predominance of diverse cellulolytic and hemicellulolytic ascomycota. A microbial interaction model is proposed, focusing on lignocellulose degradation and methane metabolism. The insights into the microbial community in this study provide a basis for efficient utilization of bagasse in lignocellulosic biomass-based industries. PMID- 21307604 TI - Development of a Sleeping Beauty-based telomerase gene delivery system for hepatocytes. AB - Telomerase is a particular reverse transcriptase that not only synthesizes and maintains the telomere but also promotes the proliferation of resting cells and prevents cellular senescence. The advantages of the Sleeping Beauty transposon system include prolonged transgene expression without eliciting an immunogenic response, no possibility of RCV and ease of construction. Tissue-specific therapeutic gene expression is extremely important in gene therapy, because non specific expression can cause an immune response of the transduced cells that can severely limit the stability of the transgene. The SB system containing the telomerase gene controlled by two chimeric transthyretin (TTR) gene promoters/enhancers, the human alcohol dehydrogenase gene promoter (ADHp), and the SV40 viral enhancer (SV40VE) was constructed in order to activate hepatocyte cell growth. The higher expression was achieved using these elements and FACS analysis showed that this system was effective in hepatocyte targeted gene therapy. Our new SB mediated telomerase delivery system for hepatocytes can be used in human gene therapy applications. PMID- 21307605 TI - Characterization of a new (R)-hydroxynitrile lyase from the Japanese apricot Prunus mume and cDNA cloning and secretory expression of one of the isozymes in Pichia pastoris. AB - PmHNL, a hydroxynitrile lyase from Japanese apricot ume (Prunus mume) seed was purified to homogeneity by ammonium sulfate fractionation and chromatographic steps. The purified enzyme was a monomer with molecular mass of 58 kDa. It was a flavoprotein similar to other hydroxynitrile lyases of the Rosaceae family. It was active over a broad temperature, and pH range. The N-terminal amino acid sequence (20 amino acids) was identical with that of the enzyme from almond (Prunus dulcis). Based on the N-terminal sequence of the purified enzyme and the conserved amino acid sequences of the enzymes from Pr. dulcis, inverse PCR method was used for cloning of a putative PmHNL (PmHNL2) gene from a Pr. mume seedling. Then the cDNA for the enzyme was cloned. The deduced amino acid sequence was found to be highly similar (95%) to that of an enzyme from Pr. serotina, isozyme 2. The recombinant Pichia pastoris transformed with the PmHNL2 gene secreted an active enzyme in glycosylated form. PMID- 21307606 TI - Conditions for the formation of dilysyl-dipyrrolones A and B, and novel yellow dipyrrolone derivatives formed from xylose and amino acids in the presence of lysine. AB - Foods derived from plants contain pentose in addition to hexose. It is well known that pentose contributes more to browning by the Maillard reaction than hexose does. We have recently found novel yellow compounds formed from xylose and lysine under weakly acidic conditions, named dilysyldipyrrolones (dilysyl-DPLs) A and B. We indicate in this study that dilysyl-DPLs were specifically formed under weakly acidic conditions from pentose, but not hexose. Moreover, we found novel DPL derivatives which were formed from xylose and such amino acids as alanine, arginine, aspartic acid, glutamic acid, isoleucine, leucine, phenylalanine, serine, and valine in the presence of lysine. PMID- 21307607 TI - Proteomic analysis of importin alpha-interacting proteins in adult mouse brain. AB - Many transport factors, such as importins and exportins, have been identified, and the molecular mechanisms underlying nucleocytoplasmic transport have been characterized. The specific molecules that are carried by each transport factor and the temporal profiles that characterize the movements of various proteins into or out of the nucleus, however, have yet to be elucidated. Here, we used a proteomic approach to identify molecules that are transported into the nuclei of adult mouse brain cells via importin alpha5. We identified 48 proteins in total, among which we chose seven to characterize more extensively: acidic (leucine rich) nuclear phosphoprotein 32 family member A (Anp32a), far upstream element binding protein 1 (FUBP1), thyroid hormone receptor beta1 (TRbeta1), transaldolase 1, CDC42 effector protein 4 (CDC42-ep4), Coronin 1B, and brain specific creatine kinase (CK-B). Analyses using green fluorescent protein (GFP) fused proteins showed that Anp32a, FUBP1, and TRbeta1 were localized in the nucleus, whereas transaldolase 1, CDC42-ep4, CK-B, and Coronin 1B were distributed in both the cytoplasm and nucleus. Using a digitonin-permeabilized in vitro transport assay, we demonstrated that, with the exception of CK-B, these proteins were transported into the nucleus by importin alpha5 together with importin beta and Ran. Further, we found that leptomycin B (LMB) treatment increased nuclear CK-B-GFP signals, suggesting that CK-B enters the nucleus and is then exported in a CRM1-dependent manner. Thus, we identified a comprehensive set of candidate proteins that are transported into the nucleus in a manner dependent on importin alpha5, which enhances our understanding of nucleocytoplasmic signaling in neural cells. PMID- 21307608 TI - Upregulation of circulating IL-15 by treadmill running in healthy individuals: is IL-15 an endocrine mediator of the beneficial effects of endurance exercise? AB - The beneficial effects of endurance exercise include insulin-sensitization and reduction of fat mass. Limited knowledge is available about the mechanisms by which endurance exercise exerts the salutary effects. Myokines, cytokines secreted by skeletal muscle, have been recognized as a potential mediator. Recently, a role of skeletal muscle-derived interleukin-15 (IL-15) in improvement of fat-lean body mass composition and insulin sensitivity has been proposed. Yet, previous studies have reported that endurance training does not increase production or secretion of IL-15 in skeletal muscle. Here, we show that in opposition to previous findings, 30-min treadmill running at 70% of age-predicted maximum heart rate resulted in a significant increase in circulating IL-15 level in untrained healthy young men. These findings suggest that IL-15 might play a role in the systemic anti-obesogenic and insulin-sensitizing effects of endurance exercise, not only as a paracrine and autocrine but also as an endocrine factor. PMID- 21307609 TI - Docosahexaenoic acid content in plasma phospholipids and desaturase indices in obese children. AB - AIMS: In obesity, fatty acid composition is altered with reduced docosahexaenoic acid (DHA) levels. Desaturating enzymes, stearoyl-CoA desaturase (SCD), delta-6 desaturase (D6D) and delta-5 desaturase (D5D) modulate fatty acid composition and are thus associated with the development of metabolic syndrome. The aim of this study was to identify the relationships among DHA content, desaturase indices and the components of metabolic syndrome in childhood obesity. METHODS: Thirty-two obese children (27 male, 5 female) aged 12.0+/-2.6 years (mean+/-SD), with a relative body weight greater than 120% of the standard weight for sex, age and height, were recruited. Fatty acid composition of plasma phospholipids was analyzed by gas chromatography, and the desaturase indices were assessed: SCD (16:1n-7/16:0 and 18:1n-9/18:0), D6D (20:3n-6/18:2n-6) and D5D (20:4n-6/20:3n-6). RESULTS: No sex difference was observed in fatty acid composition. DHA content tended to have an inverse association with body mass index (BMI) (r=-0.337, p=0.0592), and correlated significantly with very low-density lipoprotein triglyceride (r=-0.558, p=0.0057). In addition, DHA content had significant negative relationships with SCD indices (SCD16; r=-0.373, p=0.0357 and SCD18; r= 0.580, p=0.0005), which correlated positively with BMI(r=0.439, p=0.0120, r=0.353, p=0.0473, respectively), but had no association with D5D or D6D. CONCLUSIONS: DHA content in obese children was independent of the desaturation of alpha-linolenic acid. Reduced DHA content was associated with increased SCD index, and might contribute to the development of metabolic syndrome. Dietary management including fatty acids is suggested to be important to prevent and better manage obesity. PMID- 21307610 TI - Lifestyle and cardiovascular disease in Japan. AB - The aim was to give on overview of the profile of cardiovascular disease, vascular pathology and the relationships between lifestyle and cardiovascular disease in Japanese. Compared with the United States and Europe, the higher mortality from stroke and lower mortality from coronary heart disease constitute a unique cardiovascular profile for Japan. A selective review of population-based pathology, trend and prospective cohort studies was performed to clarify the characteristics of cardiovascular disease and vascular pathology, trends in the incidence and mortality of cardiovascular disease, and the relationships between lifestyle and cardiovascular disease among Japanese adults. Since the 1970s, mortality from coronary heart disease as well as stroke has declined substantially in Japan, probably due to a major decline in blood pressure levels and for men a more recent decline in smoking, in spite of an increase in body mass index and total cholesterol levels. However, the decline in mortality was smaller and plateaued in middle-aged men aged 30-49 in the metropolitan cities of Tokyo and Osaka. The incidence of coronary heart disease has increased among middle-aged men residing in the suburbs of Osaka. As for the associations between lifestyle and cardiovascular disease, higher sodium, lower calcium and lower animal protein content in the diet and for men higher alcohol consumption may account for the higher prevalence of hypertension and higher risk of stroke for Japanese than for western populations. On the other hand, lower saturated fat (meat) and higher n3 polyunsaturated fat (fish) in the Japanese diet may contribute to the lower prevalence of hypercholesterolemia and lower risk of coronary heart disease among Japanese. Japan is unique among developed countries in that coronary heart disease mortality has been low and has continued to decline, while stroke mortality has declined substantially. However, a recent trend for coronary heart disease incidence to increase among urban men is a cause for concern as a potential source of future problems for public health and clinical practice in Japan. PMID- 21307611 TI - Glucose-6-phosphate dehydrogenase (G6PDH) deficiency in a patient with ST-segment elevation acute myocardial infarction successfully treated by simple thrombectomy. AB - We report the case of an 82-year-old Sardinian woman affected by "favism" (i.e. intolerance to fava beans) with chest pain associated with persistent massive ST elevation in V2-V6 leads, admitted to our department after transfer from a rural hospital without catheterization facilities. On immediate transfer to the catheterization laboratory for primary percutaneous intervention (PCI), coronary angiogram showed proximal left anterior descending (LAD) thrombotic occlusion. In consideration of her history of glucose-6 phosphate dehydrogenase deficiency and "loss of consciousness" at a young age after taking aspirin, which contraindicated aspirin therapy, we treated this patient using a new, two-step strategy, with an emergency minimalist intervention using manual thrombectomy and intracoronary glycoprotein IIb/IIIa (GPIIbIIIa) inhibition with abciximab. Subsequent angiography control confirmed the persistence of Thrombolysis in Myocardial Infarction Trial (TIMI) grade 3 flow and the presence of an intermediate proximal LAD coronary lesion, which was not treated, also due to the persisting contraindication to aspirin. In our opinion, minimalist intervention with a thrombectomy device (especially in patients characterized by a high intracoronary thrombus burden) and/or with the use of a small balloon or gentle dilation, sustained by maximized antithrombotic therapy may represent an interesting and rational approach, allowing interventionalists to postpone stenting in the setting of primary PCI in special cases. PMID- 21307612 TI - Human mesenchymal stromal cells (MSCs) reduce neointimal hyperplasia in a mouse model of flow-restriction by transient suppression of anti-inflammatory cytokines. AB - AIM: Mesenchymal stromal cells from human bone marrow (hMSCs) were observed to produce therapeutic benefits in some models for cardiac and vascular injuries but their mode of action was not defined. We tested the effects of hMSCs in models for restricted vascular flow. METHODS: We made model for restricted vascular flow produced by permanent ligation of a carotid artery and injected hMSCs to clarify the effects of hMSCs to vascular lesions. RESULTS: Seven, 14, and 28 days after infusion of hMSCs into the cardiac left ventricle of the mice, there was a significant reduction in neointimal hyperplasia (p<0.05). Seven days after administration of the hMSCs, macrophages infiltration into the ligated artery and serum levels of monocyte chemoattractive protein-1 (MCP-1/CCL-2) (p<0.05) were reduced. However, no hMSCs were detected in the lesions by sensitive PCR assays. We then observed that the serum level of MCP-1 was a potential biomarker for the therapeutic effects of hMSCs in a mouse model for high-fat-diet. CONCLUSIONS: These results indicated the administration of hMSCs decreased the initial and excess inflammatory responses to carotid artery ligation. The decrease in inflammatory response apparently decreased the subsequent neointimal hyperplasia. PMID- 21307613 TI - Atrial fibrillation is a major risk factor for stroke, especially in women: the Jichi Medical School cohort study. AB - BACKGROUND: Only a few population-based cohort studies have investigated the impact of atrial fibrillation (AF) on stroke in Japan. METHODS: A total of 10 929 participants (4147 men and 6782 women) were included in this population-based prospective cohort study. Baseline data, including electrocardiograms (ECGs) to ascertain AF status, were obtained from April 1992 through July 1995 in 12 areas in Japan. Cox proportional hazards models were used to analyze the association of AF with stroke. RESULTS: A total of 54 participants had AF (0.49%). The mean follow-up period was 10.7 years, during which 405 strokes were identified; 12 of these occurred in participants with AF. The crude incidence of stroke in participants with and without AF was 14.9 and 4.5 per 1000 person-years in men, respectively, and 39.3 and 2.7 per 1000 person-years in women. After adjusting for geographical area, sex, age, smoking status, drinking status, obesity, hypertension, dyslipidemia, and diabetes mellitus, the hazard ratios (95% confidence interval) of AF in all participants and in male and female participants were 4.11 (2.28-7.41), 2.12 (0.77-5.84), and 10.6 (5.01-22.4), respectively. The population attributable fraction (PAF) of stroke caused by AF was 2.2%; the PAFs were 1.0% and 3.6% in men and women, respectively. CONCLUSIONS: The present Japanese population-based prospective cohort study showed that AF is a major risk factor for stroke, especially in women. PMID- 21307614 TI - Sleep, serotonin, and suicide in Japan. AB - This article reviews evidence supporting the hypothesis that suicide rates in Japan could be reduced by elevating serotonin levels via increasing the average duration of sleep. Seven major relevant findings were apparent in the literature: 1) Sleep loss is associated with suicide, but the direction of causality is equivocal. 2) Decreased serotonergic activity may be involved in suicidal behavior. 3) Sleep debt may decrease serotonergic activity. 4) The suicide rate in Japan has remained at a heightened level for the past 12 years. 5) The average sleep duration in Japan has decreased over the past 40 years. 6) The average sleep duration in Japan is among the lowest in the world. 7) The average sleep duration in Japan plateaued in 1995 and has been relatively stable since. From the research reviewed, two major problematic issues were apparent: 1) Most people in Japan receive inadequate sleep. 2) Individuals whose sleep is inadequate are unlikely to be sufficiently physically active to stimulate serotonergic systems to a desirable level. I propose that public health initiatives encouraging a longer duration of sleep may provide a relatively simple way of addressing the disturbing current trend in Japan. The combination of actigraph and brain serotonin level measurement could allow large population-based cohort studies to be designed, to elucidate the causal links between sleep duration, serotonin levels, and suicide rates. PMID- 21307615 TI - Effects of parametric speaker sound on physiological functions during mental task. AB - In recent years, parametric speakers have been used in various circumstances. However, nothing has yet been demonstrated about the safety of parametric speakers for the human body. Therefore, we studied their effects on physiological functions. Nine male subjects participated in this study. They completed three consecutive sessions: a 20-min quiet period as a baseline, a 45-min mental task period with a general speaker or a parametric speaker, and a 20-min recovery period. We measured electrocardiogram (ECG), photoplethysmogram (PTG), electroencephalogram (EEG), blood pressure (BP), and baroreflex sensitivity (BRS). Two experiments, one with a general speaker (the general condition), the other with a parametric speaker (the parametric condition), were conducted at the same time of day on separate days. To examine the effects of the parametric speaker, a two-way repeated measures ANOVA (speaker factor and time factor) was conducted. We found that sympathetic nervous activity and second derivative of PTG in task period and recovery period during the parametric condition were significantly lower than those indications during the general condition. Furthermore, Delta parasympathetic nervous activity during the parametric condition in task period and recovery period tended to be smaller than that during the general condition. The results suggested that the burden of the parametric speaker is lower than that of the general speaker for physiological functions, especially those of the cardiovascular system. Furthermore, we verified that the reaction time with the parametric speaker is shorter than that with the general speaker. PMID- 21307616 TI - The relationship between psychosocial stress, age, BMI, CRP, lifestyle, and the metabolic syndrome in apparently healthy subjects. AB - The aim of this cross-sectional study was to examine the factors which may be associated with the metabolic syndrome by exploring the relationship between psychosocial stress, age, body mass index (BMI), C-reactive protein (CRP), lifestyle factors, and the components of the metabolic syndrome, such as glycated hemoglobin (HbA1c), fasting blood sugar (FBS), body fat percentage, and triglyceride concentration, among apparently healthy subjects. Psychosocial stress was measured by the use of the inventory to measure psychosocial stress (IMPS). One thousand four hundred and ninety-nine people out of 1,941 public school workers admitted to a hospital for a medical check-up responded to the IMPS, yielding a response rate of 77.2%. A total of 1,201 workers excluding 298 who were taking medication for various diseases were analyzed with the use of hierarchical multiple regression models. It was found that IMPS-measured stress score, age, BMI, and smoking habit were associated with an increase in glycated hemoglobin among men, while alcohol consumption was associated with a decrease in glycated hemoglobin. Stress score, age, BMI, and alcohol consumption were found to be associated with an increase in FBS among men, while smoking and exercise habits were associated with a decrease in FBS. CRP was found to be associated with an increase in body fat percentage among men, though stress score was not associated with an increase in body fat percentage. Stress score, age, and BMI were associated with an increase in triglyceride concentration among women. The findings of the present study seem to be in line with the hypothesis that psychosocial stress plays an important role in developing the metabolic syndrome, which may be associated with inflammatory processes in the vascular wall, resulting in atherosclerosis and cardiovascular disease. PMID- 21307617 TI - Change in PGC-1alpha expression in rat skeletal muscle after low-intensity prolonged swimming exercise. AB - After 6-h low-intensity swimming exercise (LIE), peroxisome proliferator activated receptor gamma coactivator -1alpha (PGC-1alpha) in whole and nuclear fractions in rat skeletal muscle was higher than the control rats' muscles up to 18 h after LIE. However, no study has reported change in PGC-1alpha content after that. Therefore, we measured PGC-1alpha in whole and nuclear fractions in rat skeletal muscle up to 24 h after LIE. Furthermore, we evaluated change in the mRNA of delta-aminolevulinate synthase (ALAS), a mitochondrial protein, to clarify in which fraction of PGC-1alpha has a physiological role as a transcriptional coactivator for enhancing the mitochondrial oxidative enzymes after exercise. We measured PGC-1alpha protein content in whole and nuclear fractions in the epitrochlearis (EPI) muscle of male Sprague-Dawley rats (age: 6 w; body weight: 180-200 g) after LIE by Western-blot analysis. The ALAS mRNA content was quantified by RT-PCR. The PGC-1alpha contents in whole fractions in the rat EPI muscle were 73% and 75% higher than that of the control rats' muscle, 18 h and 24 h after LIE, respectively. The PGC-1alpha content in nuclear fractions in the muscle and ALAS mRNA was higher than that of the control rats' muscle by 58% and 25%, respectively, while they returned to the control level 24 h after LIE. The present investigation demonstrated that the time-course of PGC 1alpha content in nuclear fractions in the EPI muscle was the same as the ALAS mRNA, suggesting that PGC-1alpha in the nucleus may have a physiological function as a transcriptional coactivator for enhancing mitochondrial protein expression after exercise. PMID- 21307618 TI - The effect of intense interval cycle-training on unloading-induced dysfunction and atrophy in the human calf muscle. AB - We investigated whether intense interval training on a cycle ergometer would prevent loss of muscle strength and atrophy in the human calf during unilateral lower limb suspension (ULLS). The present study involved 11 healthy men. We defined unloading leg and contralateral leg as ULLS-leg and CONT-leg, respectively. The subjects were divided into 2 groups: one with single-leg cycling training (Tr-UL, n=6); the other as a control (UL, n=5). The Tr-UL group performed an intense 25-min interval cycling training up to 80% of peak oxygen uptake on alternate days during 20-d ULLS. It was found that: 1) in maximal voluntary contraction (MVC) and the cross-sectional area of the planter flexor, there was a significant time- (pre-ULLS and post-ULLS) by-leg (ULLS-leg and CONT leg) interaction; 2) in voluntary activation during MVC evaluated by the twitch interpolation technique, no significant time-by-leg interaction was detected but the trend of change from before to after ULLS tended to be different between ULLS leg and CONT-leg; and 3) regarding ULLS-leg, the change in any parameters was not significantly different between the Tr-UL and UL groups. These results suggest that unloading induces dysfunction and atrophy in the human calf and that high intensity interval training on a cycle ergometer cannot significantly prevent unloading-induced deconditioning in the human calf. PMID- 21307619 TI - Age-related pathophysiological changes in rats with unilateral renal agenesis. AB - Affected rats of the unilateral urogenital anomalies (UUA) strain show renal agenesis restricted to the left side. To determine whether unilateral renal agenesis is a risk factor for the progression of renal insufficiency, we studied age-related pathophysiological alterations in affected rats. Although body growth and food intake were normal, polydipsia and polyuria with low specific gravity were present at 10 weeks and deteriorated further with age. Blood hemoglobin concentrations were normal, though there was slight erythropenia with increased MCV and MCH. Although hypoalbuminemia, hypercholesterolemia, azotemia, and hypermagnesemia were manifested after age 20 weeks, neither hyperphosphatemia nor hypocalcemia was observed. Plasma Cre and UN concentrations gradually increased with age. Cre clearance was almost normal, whereas fractional UN excretion was consistently lower than normal. Proteinuria increased with age, and albumin was the major leakage protein. In addition to cortical lesions, dilated tubules, cast formation, and interstitial fibrosis were observed in the renal medulla of 50 week-old affected rats. Renal weight was increased 1.7-fold and glomerular number 1.2-fold compared with normal rats. These findings show that the remaining kidney in UUA rats is involved not only in compensatory reactions but experiences pathophysiological alterations associated with progressive renal insufficiency. PMID- 21307620 TI - Genetic comparison of Brucella canis isolates by the MLVA assay in South Korea. AB - The multiple-locus VNTR analysis (MLVA) assay is a method frequently employed as a molecular epidemiological tool for Brucella genetic fingerprinting. The purpose of this study was to assess the genotyping of 77 B. canis isolates from 14 different dog breeding farms in Korea by the MLVA assay and to compare the epidemiological relationships between the Korean isolates and foreign ones. Simpson's diversity index for 17 loci showed a range from 0 to 0.846 in 77 B. canis isolates. B. canis isolates in Korea were observed to have high genetic diversity at the most variable loci and were divided into 30 distinct genotypes by phylogenetic analysis. Some B. canis isolates were closely related to previously typed isolates in other countries. The MLVA assay can be helpful to analyze the epidemiological correlation of B. canis isolates in domestic pet animals and to track the geographic origin by comparing the genetic patterns with foreign isolates. Therefore, the MLVA assay will be useful as a tool for control and preventive measures of canine brucellosis. PMID- 21307621 TI - [The progress of antiviral therapy for chronic hepatitis B]. PMID- 21307622 TI - [Treatment of patients with lamivudine-resistant chronic hepatitis B]. PMID- 21307623 TI - [Efficacy of entecavir and adefovir combination therapy in patients with chronic hepatitis B refractory to lamivudine and adefovir combination therapy]. PMID- 21307624 TI - [Efficacy and treatment strategy for drug resistances of nucleos(t)ide analogues for chronic hepatitis B]. PMID- 21307625 TI - [Sequential therapy with a nucleos(t)ide analogue and interferon in patients with chronic hepatitis B: efficacy and limitations]. PMID- 21307626 TI - [Dynamic computed tomography is useful for the diagnosis and colonoscopic treatment of colonic diverticular bleeding]. AB - We investigated whether emergency dynamic computed tomography (CT) is helpful to identify bleeding colonic diverticulum treatable by colonoscopy. We enrolled 95 consecutive patients given diagnoses of colonic diverticular bleeding at Hiroshima City Hospital in the present study, of whom 60 underwent CT before colonoscopy (CT group), and 35 underwent colonoscopy alone (CS group). In the CT group, bleeding diverticula were identified and treated by colonoscopy in 31 of 32 (96.9%) patients in whom extravasation was detected by CT. The interval between bleeding being recognized and CT (median 1.0 hours) in patients in whom extravasation was detected by CT was shorter than that in whom extravasation was not detected (median 5.0 hours). To identify and treat bleeding diverticula by colonoscopy, the use of emergency dynamic CT prior to colonoscopy is recommended. PMID- 21307627 TI - [Tuberculous pleuritis with onset of refractory pleural effusion after chemoradiotherapy for esophageal cancer]. AB - A 75-year-old man received chemoradiotherapy (CRT) for stage IVa esophageal cancer and complete response (CR) was obtained. However, he was referred to our department for recurrence in an area of esophagus not included in the previously irradiated field. Left pleural effusion increased after admission. Tuberculous pleuritis was eventually diagnosed by thoracoscopic pleural biopsy. It is necessary to accurately diagnose the cause of pleural effusion after CRT, because treatment strategies greatly depend on it. It is also necessary to consider the possible onset of tuberculous pleuritis, in particular, in patients with a history of tuberculosis infection. PMID- 21307628 TI - [Recurrent advanced gastric cancer diagnosed 20 years after partial gastrectomy]. AB - A 67-year-old woman underwent partial gastrectomy (por2+sig, stage IIIA) for gastric cancer. She was admitted to our hospital because of swelling of her left neck lymph nodes 20 years after surgery. A biopsy specimen revealed poorly differentiated adenocarcinoma with signet-ring cell carcinoma. We diagnosed recurrence of gastric cancer and gave chemotherapy, but she died of myelosuppression and disseminated intravascular coagulation 2 years later. On autopsy, we examined all organs except the brain, but the primary lesion was not recognized. We concluded that this case was late recurrence after partial gastrectomy for advanced gastric cancer. PMID- 21307629 TI - [A case of sclerosing cholangitis caused by oral chemotherapy with S-1]. AB - We report a case of sclerosing cholangitis caused by oral chemotherapy with S-1. A 79-year-old woman with a history of hypertension presented with epigastric discomfort. Upper gastrointestinal endoscopy revealed advanced gastric cancer in the gastric antrum and abdominal computed tomography showed multiple lymph node metastasis. The patient underwent chemotherapy with S-1. Since 2 months later, blood chemistry analysis showed liver dysfunction and hyperbilirubinemia, and chemotherapy was discontinued. Endoscopic retrograde cholangiopancreatography revealed stenosis of the bile duct at the hepatic hilum. There was no evidence of tumor in the liver. We diagnosed chemotherapy-induced sclerosing cholangitis (CISC) caused by S-1. Although treatment with ursodeoxycholic acid and corticosteroids was temporarily effective, she eventually died of CISC and gastric cancer. To the best of our knowledge, this is the first case report of CISC caused by S-1. We present this rare condition with a review of the literature. PMID- 21307630 TI - [A case of parahiatal hernia with vomiting, and a review of the literature]. AB - A parahiatal hernia, that occurs from muscular diaphragmatic defects causing separation from the esophageal hiatus, is rare. We treated a 68-year-old Japanese woman with the symptom of vomiting. Based on imaging studies (upper gastrointestinal studies, gastroscopy, contrast-enhanced computed tomography) we diagnosed parahiatal hernia. On laparoscopic surgery, the hernial orifice was separated from the esophageal hiatus and the crus of the diaphragm was between the hiatus and the orifice. We closed the hernial orifice with mesh. Parahiatal hernia is rare and is difficult to diagnose preoperatively. We present a case and the clinical discuss the characteristics and management of this rare disease. PMID- 21307631 TI - [A case of granulocyte colony-stimulating factor-producing adenosquamous carcinoma of the liver accompanied by an adenocarcinoma of the ascending colon and urothelial carcinoma of the urinary bladder]. AB - An 83-year-old man was admitted with renal dysfunction, anemia, and peripheral leukocytosis. His peripheral leukocyte count was 41000/ul. A computed tomography scan revealed a solid cystic mass in the liver, mural thickening in the ascending colon and nodules in the right lower lung field. Colonoscopy revealed ascending colon cancer, and analysis of the biopsy specimens revealed well-differentiated adenocarcinoma. However, although a liver abscess was suspected, pus and bacteria were not found in the cystic lesion of the liver mass, the solid lesion of the mass was diagnosed as carcinoma. The serum concentration of granulocyte colony stimulating factor (G-CSF) was elevated to 256 pg/ml. Because his general condition worsened, we could not treat these tumors, but he died 38 days after admission. Autopsy revealed adenosquamous carcinoma of the liver, well differentiated adenocarcinoma of the ascending colon, urothelial carcinoma of the urinary bladder, and metastatic squamous cell carcinoma of the lung. Immunohistochemical analysis revealed positive staining for G-CSF in the liver tumor sample. PMID- 21307632 TI - [A case with chronic hepatitis C who developed liver cirrhosis due to liver dysfunction caused by pegylated interferon plus ribavirin treatment despite negativity of serum HCV RNA, during therapy]. AB - We report a case of chronic hepatitis C in whom liver cirrhosis was later diagnosed following abnormality of ALT levels during pegylated interferon alpha2a and ribavirin treatment. A 62-year-old woman with chronic hepatitis C was treated with pegylated interferon alpha2a plus ribavirin for 72 weeks. Her HCV RNA became negative 16 weeks after the start of treatment and continued to be negative for most of the treatment duration. Her AST/ALT, ALP/gamma-GTP levels became elevated soon after the initiation of treatment and thereafter remained unchanged. However, most of these levels normalized after the end of treatment. Post treatment liver biopsy showed liver cirrhosis, probably due to the interferon treatment itself. This unusual therapeutic outcome should be considered if the levels of hepatic dysfunction during interferon treatment are severe. PMID- 21307633 TI - [A rare case of gallbladder cancer with giardiasis]. AB - A 72-year-old man was referred to our hospital for suspected gallbladder cancer. We performed cholecystectomy with liver bed resection and lymph node dissection. Intraoperative cytological examination of the bile juice revealed some trophozoites of Giardia lamblia, and pathological examination revealed gallbladder cancer. Therefore, we diagnosed giardiasis associated with gallbladder cancer. We administered 750 mg per day metronidazole for 10 days. The patient was a farmer by occupation and used animal manure for agricultural purposes; he also consumed his own harvest, which was recognized as the infection route for his giardiasis. We reviewed the literature and found very few cases of giardiasis associated with gallbladder cancer. PMID- 21307634 TI - Measurement of nasal nitric oxide is useful for the diagnosis of sinusitis induced prolonged cough. AB - Upper airway cough syndrome (UACS), the most common cause of prolonged cough, is diagnosed based on clinical findings without specific diagnostic test. The concentration of nitric oxide in nasal cavity air (nNO) is influenced by allergic rhinitis and/or sinusitis, both of which are common causes of UACS. We measured nNO levels in patients with UACS and those with other causes. We also examined the usefulness of measuring nNO for differentiating patients with sinusitis from those without sinusitis. The study included 93 adult patients with prolonged cough lasting more than threeweeks. Etiologies of cough were identified and nNO was measured at the initial investigation. UACS was diagnosed in 58 patients (62.4%), and sinusitis was identified in 11 (19.0%) of the 58 patients with UACS. Levels of nNO in UACS did not differ from non-UACS etiologies (316.2+/-129.2 vs. 334.9+/-88.2 ppb; p=0.452), suggesting that the measurement of nNO could not discriminate UACS from other etiologies of prolonged cough. However, patients with sinusitis showed significantly decreased nNO levels (190.1+/-114.8ppb) compared with patients with UACS without sinusitis (345.7+/-114.6ppb; p<0.001) and non-UACS patients (334.9+/-88.2 ppb; p<0.001). In a receiver operating characteristic curve analysis for the diagnosis of sinusitis in prolonged cough, the best sensitivity (73.2%) and specificity (81.8%) were obtained with a nNO cutoff value of 279.0 ppb. These findings imply that the measurement of nNO could be useful for diagnosis of prolonged cough associated with sinusitis. PMID- 21307635 TI - Heterogeneity of pericentric inversions of the human y chromosome. AB - Pericentric inversions of the human Y chromosome (inv(Y)) are the result of breakpoints in Yp and Yq. Whether these breakpoints occur recurrently on specific hotspots or appear at different locations along the repeat structure of the human Y chromosome is an open question. Employing FISH for a better definition and refinement of the inversion breakpoints in 9 cases of inv(Y) chromosomes, with seemingly unvarying metacentric appearance after banding analysis, unequivocally resulted in heterogeneity of the pericentric inversions of the human Y chromosome. While in all 9 inv(Y) cases the inversion breakpoints in the short arm fall in a gene-poor region of X-transposed sequences proximal to PAR1 and SRY in Yp11.2, there are clearly 3 different inversion breakpoints in the long arm. Inv(Y)-types I and II are familial cases showing inversion breakpoints that map in Yq11.23 or in Yq11.223, outside the ampliconic fertility gene cluster of DAZ and CDY in AZFc. Inv(Y)-type III shows an inversion breakpoint in Yq11.223 that splits the DAZ and CDY fertility gene-cluster in AZFc. This inversion type is representative of both familial cases and cases with spermatogenetic impairment. In a further familial case of inv(Y), with almost acrocentric morphology, the breakpoints are within the TSPY and RBMY repeat in Yp and within the heterochromatin in Yq. Therefore, the presence of specific inversion breakpoints leading to impaired fertility in certain inv(Y) cases remains an open question. PMID- 21307636 TI - Abiotic stress and induced DNA hypomethylation cause interphase chromatin structural changes in rice rDNA loci. AB - Global climate change, i.e. higher and more variable temperatures, and a gain in soil salinity are increasing plant stress with direct consequences on crop yield and quality levels. Rice productivity is strongly affected by abiotic stress conditions. The regulation of chromatin structure in response to environmental stress is poorly understood. We investigated the interphase chromatin organization from rice plants in non-stress versus stress conditions. We have used a cytogenetic approach, based on fluorescence in situ hybridization (FISH) with 45S, 5S rDNA and centromeric probes on rice tissue sections. The abiotic stress conditions included cold, heat and mild salinity and were applied during seed germination. In contrast to cold, saline and heat stresses caused extensive decondensation of 45S rDNA chromatin and also an increase in the distance between the 2 homologous 5S rDNA loci. 5-Azacytidine (5-AC), a DNA hypomethylating drug, greatly increased 45S rDNA chromatin decondensation and interestingly was able to induce polarization of centromeres in rice interphase nuclei. The abiotic stresses tested did not perturb the spatial position of centromeres, typically with circular arrangement around the nucleolus. The results suggest a role for chromatin plasticity in a world of climate changes. PMID- 21307637 TI - Plasticity and imaging research in healthy aging: core ideas and profile of the International Normal Aging and Plasticity Imaging Center (INAPIC). AB - The key objective of the International Normal Aging and Plasticity Imaging Center (INAPIC) at the University of Zurich is to facilitate research on normal healthy behavioral and neural development and aging to explore the potential for plasticity and compensation across the lifespan. The INAPIC invites international research groups to submit proposals for collaborative projects on these subjects. It is unique in Europe in giving partner groups 'plug and play' access to state of-the-art neuroimaging techniques, technical support, and assistance in data collection. This article introduces the core ideas of the INAPIC, its key research areas, and the available infrastructure. PMID- 21307638 TI - New prospects for hepatocellular carcinoma therapy: microwave ablation working together with cellular immunotherapy. PMID- 21307640 TI - Sphingosine kinase: a promising cancer therapeutic target. PMID- 21307639 TI - Targeting NFKB mediated breast cancer chemoresistance through selective inhibition of sphingosine kinase-2. AB - Resistance to chemotherapy remains a significant obstacle in the treatment of hormone- independent breast cancer. Recent evidence suggests that altered sphingolipid signaling through increased sphingosine kinase activity may be an important mediator of breast cancer drug resistance. Sphingosine kinase-1 (Sphk1) is a proposed key regulator of breast cancer tumorigenesis, proliferation and resistance. There is, however, conflicting data on the role of sphingosine kinase 2 (Sphk2) in cancer biology and resistance, with some suggesting that Sphk2 has an opposing role to that of Sphk1. Here, we studied the effects of the novel selective Sphk2 inhibitor, ABC294640 (3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl) amide), on human breast cancer. ABC294640 blocked both viability and survival at low micromolar IC(50) concentrations in the endocrine therapy-resistant MDA-MB-231 and chemoresistant MCF-7TN-R cell systems. Treatment with the inhibitor significantly reduced proliferation, as seen in immunofluorescence staining of Ki-67 in vitro. Interestingly, pharmacological inhibition of Sphk2 induced apoptosis through the intrinsic programmed cell death pathway. Furthermore, ABC294640 also diminished NF-KB survival signaling, through decreased activation of the Ser536 phosphorylation site on the p65 subunit. Xenografts of MCF-7TN-R cells growing in immunocompromised mice were utilized to validate the therapeutic efficacy of the sphingosine kinase-2 inhibitor. Treatment with 50 mg of ABC294640/kg completely blocked tumor volume in this model. These results indicate that pharmacological inhibition of Sphk2 with the orally bioavailable selective inhibitor, ABC294640, has therapeutic potential in the treatment of chemo- and endocrine therapy- resistant breast cancer. PMID- 21307641 TI - A new perspective on Estrogen Receptor beta in breast cancer progression. PMID- 21307642 TI - Doxorubicin toxicity can be ameliorated during antioxidant L-carnitine supplementation. AB - Doxorubicin is an antibiotic broadly used in treatment of different types of solid tumors. The present study investigates whether L-carnitine, antioxidant agent, can reduce the hepatic damage induced by doxorubicin. Male Wistar albino rats were divided into six groups: group 1 were intraperitoneal injected with normal saline for 10 consecutive days; group 2, 3 and 4 were injected every other day with doxorubicin (3 mg/kg, i.p.), to obtain treatments with cumulative doses of 6, 12, and 18 mg/kg. The fifth group was injected with L-carnitine (200 mg/kg, i.p.) for 10 consecutive days and the sixth group was received doxorubicin (18 mg/kg) and L-carnitine (200 mg/kg). High cumulative dose of doxorubicin (18 mg/kg) significantly increase the biochemical levels of alanine transaminase , alkaline phosphatase, total bilirubin, total carnitine, thiobarbituric acid reactive substances (TBARs), total nitrate/nitrite (NOx) p < 0.05 and decrease in glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GSHPx), glutathione-s-transferase (GST),glutathione reductase (GR) and catalase (CAT) activity p < 0.05. The effect of doxorubicin on the activity of antioxidant genes was confirmed by real time PCR in which the expression levels of these genes in liver tissue were significantly decrease compared to control p < 0.05. Interestingly, L-carnitine supplementation completely reverse the biochemical and gene expression levels induced by doxorubicin to the control values. In conclusion, data from this study suggest that the reduction of antioxidant defense during doxorubicin administration resulted in hepatic injury could be prevented by L-carnitine supplementation by decreasing the oxidative stress and preserving both the activity and gene expression level of antioxidant enzymes. PMID- 21307643 TI - Long term ethanol consumption leads to lung tissue oxidative stress and injury. AB - BACKGROUND: Alcohol abuse is a systemic disorder. The deleterious health effects of alcohol consumption may result in irreversible organ damage. By contrast, there currently is little evidence for the toxicity of chronic alcohol use on lung tissue. Hence, in this study we investigated long term effects of ethanol in the lung. RESULTS: Though body weight of rats increased significantly with duration of exposure compared to its initial weight, but there was no significant change in relative weight (g/100 g body weight) of lung due to ethanol exposure. The levels of thiobarbituric acid reactive substances (TBARS), nitrite, protein carbonyl, oxidized glutathione (GSSG), redox ratio (GSSG/GSH) and GST activity elevated; while reduced glutathione (GSH) level and activities of glutathione reductase (GR), glutathione peroxidase (GPx), catalase, superoxide dismutase (SOD) and Na(+)K(+) ATPase reduced significantly with duration of ethanol exposure in the lung homogenate compared to the control group. Total matrix metalloproteinase activity elevated in the lung homogenate with time of ethanol consumption. Histopathologic examination also demonstrated that severity of lung injury enhanced with duration of ethanol exposure. METHODS: 16-18 weeks old male albino Wistar strain rats weighing 200-220 g were fed with ethanol (1.6 g/ kg body weight/ day) up to 36 weeks. At the end of the experimental period, blood samples were collected from reteroorbital plexus to determine blood alcohol concentration, and the animals were sacrificed. Various oxidative stress related biochemical parameters, total matrix metalloproteinase activity and histopathologic examinations of the lung tissues were performed. CONCLUSIONS: Results of this study indicate that long term ethanol administration aggravates systemic and local oxidative stress, which may be associated with lung tissue injury. PMID- 21307644 TI - Resveratrol and red wine function as antioxidants in the nervous system without cellular proliferative effects during experimental diabetes. AB - Chronic hyperglycemia increases oxidative stress status and has been associated with neurological complications in diabetic individuals. This study compared the antioxidant properties of red wine or resveratrol in different brain areas of diabetic and non-diabetic rats, and investigated the effect of them on hippocampal cell proliferation in hippocampal dentate gyrus of diabetic rats. Streptozotocin-induced diabetic and control rats were treated with red wine (4 mL/kg), resveratrol (20 mg/kg), or saline, by oral gavage, for 21 days. Lipid peroxidation (TBARS), catalase and superoxide dismutase were measured to evaluate the oxidative stress and the BrdU-positive cells were assessed to measure changes in cellular proliferation. In diabetic animals, resveratrol showed antioxidant property in the hippocampus and in the striatum, while red wine had an antioxidant effect only in the hippocampus. Neither red wine nor resveratrol reversed the lower hippocampal cell proliferation in diabetic rats. Daily doses of red wine or resveratrol have an antioxidant effect in rats depending on the brain area and the glycemic status. PMID- 21307645 TI - Retinal redox stress and remodeling in cardiometabolic syndrome and diabetes. AB - Diabetic retinopathy (DR) is a significant cause of global blindness; a major cause of blindness in the United States in people aged between 20-74. There is emerging evidence that retinopathy is initiated and propagated by multiple metabolic toxicities associated with excess production of reactive oxygen species (ROS). The four traditional metabolic pathways involved in the development of DR include: increased polyol pathway flux, advanced glycation end-product formation, activation of protein kinase C isoforms, and hexosamine pathway flux. These pathways individually and synergistically contribute to redox stress with excess ROS resulting in retinal tissue injury resulting in significant microvascular blood retinal barrier remodeling. The toxicity of hyperinsulinemia, hyperglycemia, hypertension, dyslipidemia, increased cytokines and growth factors, in conjunction with redox stress, contribute to the development and progression of DR. Redox stress contributes to the development and progression of abnormalities of endothelial cells and pericytes in DR. This review focuses on the ultrastructural observations of the blood retinal barrier including the relationship between the endothelial cell and pericyte remodeling in young nine week old Zucker obese (fa/fa) rat model of obesity; cardiometabolic syndrome, and the 20 week old alloxan induced diabetic porcine model. Preventing or delaying the blindness associated with these intersecting abnormal metabolic pathways may be approached through strategies targeted to reduction of tissue inflammation and oxidative - redox stress. Understanding these abnormal metabolic pathways and the accompanying redox stress and remodeling may provide both the clinician and researcher a new concept of approaching this complicated disease process. PMID- 21307647 TI - Lipopolysaccaride induces autophagic signaling in macrophages via a TLR4, heme oxygenase-1 dependent pathway. AB - Toll-like receptor (TLR) signaling is an important part of the innate immune response. One of the downstream responses to TLR4 signaling upon lipopolysaccharide (LPS) stimulation is the induction of autophagy, which is a key response to multiple stressors. An additional adaptive signaling molecule that is involved in the response to stress is heme oxygenase-1 (HO-1). HO-1 signaling is essential to limit inflammation and restore homeostasis. We found that LPS induced autophagic signaling in macrophages via a TLR4, HO-1 dependent pathway in macrophages. These data add to the developing contribution of autophagic signaling as part of the inflammatory response. PMID- 21307648 TI - Probiotic factors partially improve parameters of 5-fluorouracil-induced intestinal mucositis in rats. AB - Certain live bacteria have demonstrated preliminary indications of efficacy for the treatment of chemotherapy-induced intestinal mucositis. However, probiotic derived supernatants (SN) have yet to be investigated in the mucositis setting. We evaluated SN from Escherichia coli Nissle 1917 (EcN) and Lactobacillus fermentum BR11 (BR11) for their capacity to decrease 5-Fluorouracil (5-FU) induced damage in vivo. Female Dark Agouti rats were gavaged with 1 mL of either SN or vehicle daily (days 0-8) and intraperitoneally injected with 5-FU (150 mg/kg) on day 5 to induce mucositis. On day 9, animals were culled and intestinal tissues collected. Significantly lower histological damage scores were apparent in the jejunum of 5-FU treated rats receiving SN compared to 5-FU controls. Myeloperoxidase levels in the jejunum of 5-FU treated rats were increased in vehicle and BR11 SN treatments compared to untreated controls, whereas no significant increase was observed after EcN SN treatment. 5-FU treatment significantly reduced villus height and crypt depth in the jejunum compared to normal controls; however no significant reduction in these parameters was observed in 5-FU treated rats receiving either SN. We conclude that bacterial SN, especially EcN, partially protect the intestine from 5-FU mucositis. Further studies are required to define specific mechanisms by which SN exert their beneficial effects. PMID- 21307649 TI - The humoral response to Gardasil over four years as defined by total IgG and competitive Luminex immunoassay. AB - Safe and effective vaccines against anogenital human papillomaviruses (HPV) are now available. These vaccines, composed of virus-like particles (VLPs) made from the L1 major capsid protein of specific HPV types, induce a polyclonal antibody response directed against specific conformational and linear epitopes displayed on the VLP. Numerous studies indicated the importance of neutralizing antibodies in protection from infection. However, our understanding of the antibody responses to these vaccines is not complete, and there is no established immune correlate of protection nor antibody threshold that correlates with protection against HPV infection or disease. In the current study, antibody responses of young women to Gardasil(r), the quadrivalent HPV 6, 11, 16 and 18 L1 VLP vaccine (qHPV), were assessed through 48 months (M) in total IgG and competitive Luminex immunoassays (total IgG LIA and cLIA). The total IgG LIA was developed as a research assay to evaluate preclinical multivalent HPV VLP vaccine formulations. The cLIA simultaneously evaluates the antibody response to a unique conformational, neutralizing epitope on each of the four HPV types present in the quadrivalent vaccine; HPV 6, 11, 16 and 18. The same sera from women vaccinated with the qHPV vaccine were tested in both the total IgG LIA and the cLIA assays. The proportion of vaccinated women achieving seropositivity and the anti-HPV VLP total IgG and cLIA geometric mean titers (GMTs) were summarized at M7, M24, M48 based on the serostatus cut-points defined for each immunoassay. Overall, greater than 99% of subjects seroconverted to all four vaccine types in both assays; GMTs peaked at M7. For all four HPV types, regardless of the immunoassay used, the most significant decline in GMTs was observed between M7 and M24. By M24, the antibody titers had reached a plateau and minimal declines in antibody titers were observed between M24 and M48 for all four HPV types in both immunoassays. Testing the same sera, seropositivity for M48 HPV18 remained high (96.7%) in the total IgG LIA, but was 64.8% in the cLIA. The current study illustrates potential important differences in serologic assays utilized in the clinical trials of the two currently available HPV VLP vaccines (quadrivalent and bivalent). Differences in seropositivity status are attributed to the measurement parameters and sensitivity of the individual immunoassays and do not indicate reduced anti-HPV18 protective antibodies. PMID- 21307650 TI - Immunogenicity of a scalable inactivated rotavirus vaccine in mice. AB - Inactivated rotavirus vaccine is a safe and effective potential vaccine for the prevention of rotavirus infection among children, but no approved licensed vaccine is available now. In this study, a scalable inactivated rotavirus vaccine, prepared in Vero cells cultured by microcarrier fermentation, inactivated by formalin and absorbed by Al(OH)(3) adjuvant, was vaccinated into the six weeks-old female Balb/c mice by intramuscular injection. After twice immunization at interval of three weeks, both humoral and cell-mediated immune responses were assessed by ELISA, microneutralization assay and EISPOT assay. The results indicated that the scalable inactivated rotavirus vaccines induced not only high serum IgG antibody and neutralizing antibody responses, but Th1 and Th2 cytokine-secreting cell responses in mice immunized by the inactivated rotavirus vaccines. These results suggest that the scalable inactivated rotavirus vaccine has good immunogenicity, which provided the base for the scaled development of inactivated rotavirus vaccine in the future. PMID- 21307651 TI - Pertussis booster vaccine in China. PMID- 21307646 TI - Mammalian target of rapamycin: hitting the bull's-eye for neurological disorders. AB - The mammalian target of rapamycin (mTOR) and its associated cell signaling pathways have garnered significant attention for their roles in cell biology and oncology. Interestingly, the explosion of information in this field has linked mTOR to neurological diseases with promising initial studies. mTOR, a 289 kDa serine/threonine protein kinase, plays an important role in cell growth and proliferation and is activated through phosphorylation in response to growth factors, mitogens, and hormones. Growth factors, amino acids, cellular nutrients, and oxygen deficiency can down-regulate mTOR activity. The function of mTOR signaling is mediated primarily through two mTOR complexes: mTORC1 and mTORC2. mTORC1 initiates cap-dependent protein translation, a rate-limiting step of protein synthesis, through the phosphorylation of the targets eukaryotic initiation factor 4E-binding protein 1 (4EBP1) and p70 ribosomal S6 kinase (p70S6K). In contrast, mTORC2 regulates development of the cytoskeleton and also controls cell survival. Although closely tied to tumorigenesis, mTOR and the downstream signaling pathways are significantly involved in the central nervous system (CNS) with synaptic plasticity, memory retention, neuroendocrine regulation associated with food intake and puberty, and modulation of neuronal repair following injury. The signaling pathways of mTOR also are believed to be a significant component in a number of neurological diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, tuberous sclerosis, neurofibromatosis, fragile X syndrome, epilepsy, traumatic brain injury, and ischemic stroke. Here we describe the role of mTOR in the CNS and illustrate the potential for new strategies directed against neurological disorders. PMID- 21307652 TI - Long term protection against cervical infection with the human papillomavirus: review of currently available vaccines. AB - Two vaccines against HPV are commercially available: an HPV-16/18 (bivalent) and an HPV-6/11/16/18 (quadrivalent) vaccine. Vaccination programs have been and will be implemented before the full duration of protection is known. Whether booster doses will be required is also unknown at this time. Meanwhile, predictions rely upon phase III studies and mathematical modelling. In a head to head study, the bivalent vaccine induced a higher, more sustained immune response than the quadrivalent vaccine. Immunogenicity of the bivalent vaccine against HPV-16 and HPV-18 has been demonstrated up to 8.4 years. For the quadrivalent vaccine, immunogenicity data up to 5 years show that the immune response against HPV-18 wanes after approximately 4 years. Efficacy against infection and cervical lesions associated with HPV-16/18 has been shown up to 8.4 and 5 years with the bivalent and quadrivalent vaccine, respectively. Cross-protection against non vaccine types appears stronger with the bivalent vaccine. However, both vaccines may provide sufficient immunogenicity to confer long-term protection. Ongoing monitoring is essential. PMID- 21307653 TI - The clinical use of adjuvants in pneumococcal vaccination: current status and future perspectives. PMID- 21307654 TI - Vaccine safety in special populations. PMID- 21307655 TI - Co-administration of a novel Haemophilus influenzae type b and Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine does not interfere with the immune response to antigens contained in infant vaccines routinely used in the United States. AB - An investigational combined Haemophilus influenzae type b (Hib) and Neisseria meningitidis serogroups C and Y tetanus toxoid conjugate vaccine (HibMenCY-TT) has been developed to protect infants from invasive disease caused by Hib and these meningococcal serogroups without adding injections to the immunization schedule. Incorporation of this novel vaccine into the US vaccination schedule will require demonstration of a lack of immunologic interference with other routine pediatric vaccines. This study assessed the immune response to 7-valent pneumococcal conjugate vaccine (PCV7) and combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus vaccine (DTaP-HepB-IPV) when separately co-administered with HibMenCY-TT as compared to a US-licensed H. influenzae type b tetanus toxoid conjugate vaccine (Hib-TT) at 2, 4, 6 (N=606) and 12-15 months of age (N=366). HibMenCY-TT was non-inferior to Hib-TT in terms of antibody responses to all Streptococcus pneumoniae serotypes contained in PCV7 and the diphtheria, tetanus, pertussis, hepatitis B and poliovirus antigens contained in DTaP-HepB-IPV one month after the third vaccine dose, and the anti tetanus geometric mean antibody concentration (GMC) was significantly higher in the HibMenCY-TT group than in the Hib-TT group. In an exploratory analysis, no significant differences in the proportion of subjects with anti-pneumococcal antibody concentrations >=0.2 ug/ml or anti-pneumococcal GMC were seen between the two groups after the fourth vaccine dose. A schedule of HibMenCY-TT given concomitantly with PCV7 and DTaP-HepB-IPV would be expected to protect infants against all of the targeted diseases. PMID- 21307656 TI - Malignant characteristics of circulating tumor cells and corresponding primary tumor in a patient with esophageal squamous cell carcinoma before and after surgery. AB - We report the malignant characteristics of circulating tumor cells (CTCs) and the corresponding molecular features of the primary tumor in a patient with esophageal squamous cell carcinoma (ESCC). A 70-year-old male patient was diagnosed with TNM stage T3N0M0 ESCC. Before surgery, seven intact CTCs and 12 CTCs with a fragmented membrane were detected in 7.5 mL of peripheral blood by immunofluorescence staining. One week after radical resection of the primary tumor, four CTCs were identified in 7.5ml peripheral blood. All CTCs were confirmed as having a malignant phenotype by chromosomal analysis and routine cell staining. Ninety percent of the CTCs were found to have polysomic chromosomes 8 and 20 by fluorescence in situ hybridization (FISH). Immunofluorescence analysis showed that all of the primary tumor cells detected were cytokeratin8/18/19 (CK8/18/19)-positive, but only 1% were CD133-positive. The serum CA19-9 and CEA level were normal in the process of diseases. The patient died 6 months after surgery as a result of lung metastases and other complications. The results of this study suggest that the dynamics and malignant characteristics of both CTCs and the corresponding primary tumor during the disease process may predict tumor burden and the risk of relapse and metastasis. PMID- 21307657 TI - The state of art patent search with an example of human vaccines. PMID- 21307658 TI - Uptake of 2009 H1N1 vaccine among adolescent females. AB - BACKGROUND: The public health response to the threat of pandemic influenza A (H1N1) virus during the 2009-2010 influenza season was extensive. To better understand the lower than expected vaccine uptake, we aimed to characterize correlates of 2009 H1N1 vaccination among adolescent females in the U.S. and examine accessibility of the vaccine to parents. METHODS: We collected data from a national sample of mothers of adolescent females ages 11-14 years (n=944) during December 2009 using an online survey. RESULTS: Overall, 22% (221/944) of mothers indicated their daughters had received 2009 H1N1 vaccine. H1N1 vaccination was higher among daughters who had received 2009 seasonal influenza vaccine (49% vs. 11%, OR=7.00, 95% CI: 4.18-11.73) or whose mothers expressed higher trust in their daughters' healthcare providers (26% vs. 11%, OR=2.28, 95% CI: 1.10-4.73). Among mothers of unvaccinated daughters, 20% (150/723) indicated they wanted to get their daughters 2009 H1N1 vaccine but were unable to. Vaccination among daughters and accessibility of the vaccine to parents did not differ by race, socioeconomic status, or health insurance status. DISCUSSION: One explanation for the lower than expected uptake of 2009 H1N1 vaccine is that many parents were unable to get their daughters the vaccine despite wanting to do so. Concomitant administration with seasonal influenza vaccine may increase uptake of novel influenza vaccines. PMID- 21307660 TI - Wild-type and mutant p53 proteins interact with mitochondrial caspase-3. AB - Caspases play a key role in the apoptotic pathway by virtue of their ability to cleave key protein substrates within the dying cell. Caspases are produced as inactive zymogens, and need to become proteolytically processed in order to become active. A key executioner caspase, caspase-3, has previously been found to exist in both the cytosol and the mitochondria. At the mitochondria, caspase-3 is associated with both the inner and outer mitochondrial membranes, where it interacts with heat shock proteins Hsp60 and Hsp10. Like caspase-3, a small portion of the p53 tumor suppressor protein is localized to mitochondria, particularly after genotoxic stress. p53 interacts with various members of the Bcl2 family at the mitochondria, and this interaction is key to its ability to induce apoptosis. In this study, we sought to determine the identity of other mitochondrial p53-interacting proteins. Using immunoprecipitation from purified mitochondria followed by mass spectrometry we identified caspase-3 as a mitochondrial p53-interacting protein. Interestingly, we find that tumor-derived mutant forms of p53 retain the ability to interact with mitochondrial caspase-3. Further, we find evidence that these mutant forms of p53 may interfere with the ability of procaspase-3 to become proteolytically activated by caspase-9. The combined data suggest that tumor-derived mutants of p53 may be selected for in tumor cells due to their ability to bind and inhibit the activation of caspase-3. PMID- 21307659 TI - Resistance to HER2-directed antibodies and tyrosine kinase inhibitors: mechanisms and clinical implications. AB - The antibody trastuzumab and the tyrosine kinase inhibitor lapatinib are approved by the FDA for the treatment of HER2-overexpressing breast cancer. These anti HER2 drugs are changing the natural history of HER2-overexpressing breast cancer. However, therapeutic resistance to trastuzumab or lapatinib, as either single agents or in combination with chemotherapy in the metastatic setting, typically occurs within months of starting therapy. Several mechanisms of trastuzumab resistance have been reported that include signaling from other HER receptors, signaling from receptor tyrosine kinases (RTKs) outside of the HER (ErbB) family, increased phosphatidylinositol 3-kinase signaling, and the presence of truncated forms of HER2. Mechanisms of resistance to lapatinib also point to increased phosphatidylinositol 3-kinase signaling as well as derepression/activation of compensatory survival pathways. In this review, we discuss how these models and mechanisms enhance our understanding of the clinical resistance to HER2-directed therapies. PMID- 21307661 TI - Does GABA increase the efficiency of symbiotic N2 fixation in legumes? AB - The ability to regulate the rates of metabolic processes in response to changes in the internal and/or external environment is a fundamental feature which is inherent in all organisms. This adaptability is necessary for conserving the stability of the intercellular environment (homeostasis) which is essential for maintaining an efficient functional state in the organism. Symbiotic nitrogen fixation in legumes is an important process which establishes from the complex interaction between the host plant and microorganism. This process is widely believed to be regulated by the host plant nitrogen demand through a whole plant N feedback mechanism in particular under unfavorable conditions. This mechanism is probably triggered by the impact of shoot-borne, phloem-delivered substances. The precise mechanism of the potential signal is under debate, however, the whole phenomenon is probably related to a constant amino acid cycling within the plant, thereby signaling the shoot nitrogen status. Recent work indicating that there may be a flow of nitrogen to bacteroids is discussed in light of hypothesis that such a flow may be important to nodule function. Large amount of gamma aminobutyric acid (GABA) are cycled through the root nodules of the symbiotic plants. In this paper some recent evidence concerning the possible role of GABA in whole-plant-based up regulation of symbiotic nitrogen fixation will be reviewed. PMID- 21307662 TI - Prolonged root hypoxia effects on ethylene biosynthesis and perception in tomato fruit. AB - The effects of root hypoxia on ethylene biosynthesis and perception have been documented in many vegetative organs, but not extensively in fruit. Therefore, in the present study, the effects of root hypoxia on ethylene biosynthesis and perception were investigated in tomato (Solanum lycopersicum L.) fruit at five stages of the maturation phase. Our results showed that root hypoxia do not affect ethylene biosynthesis in fruit, but stimulates its reception from other plant part, as indicated by the increase in the expression of ethylene receptors ETR 1 and 3. PMID- 21307664 TI - Focus on biospecimens: the issue is the tissue. observations on the "NCI-NIST fitness-for-purpose quality assessment and standards development workshop," October 2010. PMID- 21307665 TI - Mutations in the RAS/RAF/MAP kinase pathway commonly occur in gallbladder adenomas but are uncommon in gallbladder adenocarcinomas. AB - The role of gallbladder adenomas in the pathogenesis of gallbladder carcinoma is still controversial. Comparison of the genetic abnormalities seen in adenomas may provide insight into the potential role of gallbladder adenomas as precursor lesions to gallbladder carcinoma. The purpose of this study was to evaluate gallbladder carcinomas, gallbladder adenomas, and high-grade dysplastic lesions for the BRAF and the KRAS mutations and the mismatch repair protein abnormalities. We analyzed 29 gallbladder carcinomas (9 papillary and 20 nonpapillary adenocarcinomas), 16 adenomas (6 pyloric, 3 intestinal, 3 biliary, 3 mixed pyloric-biliary, and 1 mixed pyloric-intestinal), and 5 cases of high-grade dysplasia for activating missense mutations in KRAS codons 12 and 13 and BRAF V600E mutations. Mismatch repair protein immunohistochemistry for MLH1, MSH2, MSH6, and PMS2 was also carried out. KRAS mutations were infrequently identified in gallbladder carcinoma (2/29, 7%) and high-grade dysplastic lesions (0/5, 0%). Compared with gallbladder carcinoma and high-grade dysplastic lesions, gallbladder adenomas frequently showed KRAS codon 12 mutations (5/16, 31%) (P=0.02). Adenomas with pyloric-type histology harbored KRAS mutations more often (4/10, 40%) than other histologic subtypes (1/6, 17%). Adenomas rarely showed BRAF mutations (1/16, 6%), and no cases of gallbladder carcinoma or high-grade dysplasia were positive for BRAF mutations. Both the adenomas and the carcinomas displayed intact expression of mismatch repair proteins by immunohistochemistry. The presence of frequent mutations in the RAS/RAF/MAPK pathway in the gallbladder adenomas compared with the gallbladder carcinomas suggest that the adenomas and the gallbladder carcinomas arise through distinctly different molecular pathways. PMID- 21307667 TI - Current world literature. PMID- 21307669 TI - Current world literature. PMID- 21307671 TI - Current world literature. PMID- 21307673 TI - Advancement in hypertension pathogenesis: some new concepts. PMID- 21307674 TI - Current world literature. PMID- 21307677 TI - Current world literature. PMID- 21307676 TI - First-line treatment for advanced nonsmall cell lung cancer harboring activating epidermal growth factor receptor mutation: epidermal growth factor receptor tyrosine kinase inhibitors or chemotherapy? PMID- 21307679 TI - Neuro-ophthalmic disease and optical coherence tomography: glaucoma look-alikes. AB - PURPOSE OF REVIEW: The use of optical coherence tomography (OCT)-measured retinal nerve fiber layer (RNFL) thickness in neuro-ophthalmic disease has grown since its first use in glaucoma and retinal diseases. OCT-measured RNFL in nonglaucomatous optic neuropathies shows thinning, which may mimic those seen in glaucoma. This article aims to provide insight regarding the use of OCT in nonglaucomatous optic neuropathies and sheds light on common patterns of RNFL loss in different nonglaucomatous optic neuropathies. RECENT FINDINGS: RNFL thinning is most likely to occur in the temporal peripapillary quadrant than in other quadrants in nonglaucomatous optic neuropathies. The pattern of RNFL thinning in ischemic optic neuropathy and optic nerve head drusen is more likely to mimic the pattern found in glaucoma due to the superior and inferior quadrant predilection. OCT-measured RNFL thickness in Alzheimer's disease reveals thinning superiorly and inferiorly, whereas superior and temporal thinning is seen in Parkinson's disease. The thinning observed in neurodegenerative diseases is believed to be multifactorial including causes such as axonal degeneration and retrograde degeneration. However, more studies are needed to further study these changes. SUMMARY: OCT is a valuable tool in evaluating the peripapillary RNFL in both glaucomatous and nonglaucomatous optic neuropathies. This technology may be used for both research and clinical purposes to assess disease progression in optic neuropathies and diseases that affect the central nervous system. OCT measured RNFL thickness remains complimentary to the clinical examination skills in the evaluation of nonglaucomatous optic neuropathies. PMID- 21307680 TI - Current world literature. PMID- 21307681 TI - Black widow spider bite: a case study. AB - This article is a case study of a patient cared for in the hours before her death. After the patient's death, we learned the patient died of a black widow spider bite. This article sheds light on the potential seriousness of this venom and allows for more rapid detection and treatment of those who are unfortunate enough to be bitten. The authors have documented the sequence of events for the patient, outlined the care the patient received, examined the pathophysiology of the body to a spider bite, and then made a passionate appeal for other nurses who work in critical care to do the same with patients in similar situations. PMID- 21307683 TI - Amiodarone-induced hypothyroidism and other adverse effects. AB - Amiodarone is a class III antiarrhythmic agent that is frequently prescribed today for the treatment of ventricular and atrial arrhythmias. Amiodarone has many adverse effects, and one of them is thyroid dysfunction. Advanced practice and staff nurses need to be vigilant, recognizing early signs and symptoms of thyroid dysfunction to prevent adverse drug reactions. Often, the signs and symptoms of amiodarone-induced hypothyroidism are overlooked because of the complexity of the patient's condition. The purpose of this article was to review a case study, present differential diagnoses and testing, discuss risk factors associated with amiodarone-induced hypothyroidism, discuss its pathogenesis, and review clinical management. PMID- 21307684 TI - Bedbugs: not back by popular demand. AB - Unfortunately, bedbugs are back and are found in many different places such as homes, hotels, hospitals, movie theaters, and clothing stores. Bedbugs are not related to lower socioeconomic status and are an equal-opportunity problem. This article describes bedbugs, inspection and treatment, and nursing interventions when bedbugs are found. PMID- 21307685 TI - Patients unsatisfied with palliative care: improving documentation that focuses on patients' needs. AB - As patients and families make the critical decision to end their life, the question becomes: What are we as nurses doing to focus on the needs of the patient and family? There is a lack of documentation when it comes to families (or the patient) making a decision for the withdrawal of life support, which may lead to a breakdown in communication between the family and medical professionals. Improving the documentation process can improve the nurse-patient relationship and communication as well as help put the family and patients at ease with their decision. PMID- 21307687 TI - Candidly critical, Part 5: but for the grace of god. AB - This is the fifth in a series of articles depicting real-life situations in critical care nursing. PMID- 21307691 TI - Greek intensive and emergency care nurses' perception of their public image: a phenomenological approach. AB - The public image of the nurse constitutes an important factor for recruitment into the profession, retention, and also for work satisfaction. The aim of this qualitative study was to disclose the way nurses internalize their professional public image and professional worth, as well as nurses' feelings about that image. Findings showed that although nurses have made a tremendous effort to improve the public image of their profession, negative nursing stereotypes still persist. Therefore, nurses have to actively participate in policy making and enhance their educational and cultural profile through the media. PMID- 21307692 TI - A randomized controlled trial of a discharge nursing intervention to promote self regulation of care for early discharge interventional cardiology patients. AB - This randomized controlled trial examined a discharge nursing intervention aimed at promoting self-regulation of care for early discharge interventional cardiology patients. The purpose of this study was to compare medication adherence, patient satisfaction, use of urgent care, and illness perception in patients with cardiovascular disease undergoing interventional revascularization procedures who receive usual care and those who receive a discharge nursing intervention. PMID- 21307695 TI - Professionalism. PMID- 21307697 TI - Confocal laser endomicroscopy: is it prime time? PMID- 21307698 TI - Improving detection during colonoscopy: multiple pathways for investigation. PMID- 21307699 TI - Iatrogenic radial nerve injury with cannulated fixation of medial epicondyle fractures in the pediatric humerus: a report of 2 cases. AB - Surgical treatment for medial epicondylar fractures is controversial, and indications depend on variety of variables, including the degree of displacement and future goals of the patient. If surgery is to be performed, typically open reduction of the medial epicondylar fragment, with visualization of the ulnar nerve, and fixation is undertaken. Pins, screws, and cannulated screws have all been described for fixation. The use of cannulated screw systems, especially when coupled with fluoroscopy, has many advantages, and is generally considered a safe way to place a screw accurately while minimizing the surgical exposure. Unfortunately, there are also inherent risks with a cannulated screw system that often go unrecognized, such as guide pin bending, breakage or unrecognized advancement. The complications are rarely reported, and recognition is critical to avoid future complications. This is the first study to report a radial nerve injury after the use of cannulated screw systems in 2 patients with a pediatric medial epicondyle fracture fixation. This study highlights the danger of these systems for this fracture fixation, and we discuss the potential techniques to avoid this complication. Our purpose in publishing this series of cases is to shed light on a complication, in the hope that its exposure will help prevent such complications in the future. LEVEL OF EVIDENCE: IV, Case Series. PMID- 21307700 TI - We hereby thank the author of the letter commenting on our study "displaced radial neck fractures in children, association of the Metaizeau and Bohler surgical techniques.". PMID- 21307701 TI - Fusion of double-layered patella using a single small fragment partially threaded screw: a case report. AB - BACKGROUND: The double-layered patella (DLP) was first described by Buttner in 1925 and is now considered pathognomonic for multiple epiphyseal dysplasia. In this study, we describe the case of an 11-year-old girl with multiple epiphyseal dysplasia and right-sided DLP. METHODS: The patient presented with intermittent unilateral anterior knee pain and swelling. There was a reproducible high-pitched click with every step. Imaging showed a DLP in good alignment. Surgical management comprised open debridement and fixation of the 2 patellar layers using one 3.5 mm (removed-) partially threaded AO small fragment screw. RESULTS: Standard radiographs of the right knee, 3 years postoperatively, showed sound union of the 2 patellae. The patient now plays sports, and recent examination showed a full range of movement with no instability, effusion, or tenderness. CONCLUSIONS: We conclude that surgical fusion of the patellar fragments in DLP using a single small fragment partially threaded screw provides excellent outcome at 3 years follow-up. CLINICAL RELEVANCE: This case report shows a comparatively simple and economical surgical solution to the problem of DLP. PMID- 21307702 TI - Impact of fractures on school attendance. AB - BACKGROUND: The purpose of this study was to determine the average prevalence of children across the nation who experience difficulty in attending school after an acute orthopaedic injury. METHODS: A survey was created to obtain information on school absence for children with acute orthopaedic injuries. All members of the Pediatric Orthopaedic Society of North America were invited to complete the survey. RESULTS: The survey was sent by e-mail to 936 members of the Pediatric Orthopaedic Society of North America. A total of 283 surgeons from 45 states responded to the survey, which resulted in a response rate of 30.2%. The survey found a correlation with difficulty in attending school with a cast and the size of the population served. Communities with the larger populations are less likely to permit children to attend school with a cast. The most common reasons given by schools for a child not being permitted to attend school with a cast were concern for the safety of the child and inability to accommodate the needs of the child. CONCLUSIONS: Most physicians participating in the survey reported no difficulty with their patients attending school with a cast. There was more difficulty with children in attending school with a cast in metropolitan areas and in communities with greater than 1 million people. To decrease or to eliminate absence from school, it may be best to identify schools in a physician's community that do not allow attendance of children with a cast. Once individual schools are identified, advocacy can be targeted. At the very least, when it is known which schools are involved, the surgeon can anticipate difficulties and plan accordingly. As a child's absence from school has substantial negative consequences, we strongly support intervention to enable injured children to appropriately return to a regular educational setting in a timely manner. Future studies with school participation would help to identify reasons for school absence after a musculoskeletal injury. LEVEL OF EVIDENCE: Level V, Prognostic. PMID- 21307703 TI - Diagnostic algorithm for a validated displacement grading of pediatric supracondylar fractures. AB - BACKGROUND: The first AO comprehensive pediatric long bone fracture classification system has been established following a structured path of development and validation with experienced pediatric surgeons. METHODS: A follow up series of agreement studies was applied to specify and evaluate a grading system for displacement of pediatric supracondylar fractures. An iterative process comprising an international group of 5 experienced pediatric surgeons (Phase 1) followed by a pragmatic multicenter agreement study involving 26 raters (Phase 2) was used. The last evaluations were conducted on a consecutive collection of 154 supracondylar fractures documented by standard anteroposterior and lateral radiographs. RESULTS: Fractures were classified according to 1 of 4 grades: I=incomplete fracture with no or minimal displacement; II=Incomplete fracture with continuity of the posterior (extension fracture) or anterior cortex (flexion fracture); III=lack of bone continuity (broken cortex), but still some contact between the fracture planes; IV=complete fracture with no bone continuity (broken cortex), and no contact between the fracture planes. A diagnostic algorithm to support the practical application of the grading system in a clinical setting, as well as an aid using a circle placed over the capitellum was proposed. The overall kappa coefficients were 0.68 and 0.61 in the Phase 1 and Phase 2 studies, respectively. In the Phase 1 study, fracture grades I, II, III, and IV were classified with median accuracies of 91%, 82%, 83%, and 99.5%, respectively. Similar median accuracies of 86% (Grade I), 73% (Grade II), 83% (Grade III), and 92% were reported for the Phase 2 study. Reliability was high in distinguishing complete, unstable fractures from stable injuries [ie, kappa coefficients of 0.84 (Phase 1) and 0.83 (Phase 2) were calculated]; in Phase 2, surgeons' accuracies in classifying complete fractures were all above 85%. CONCLUSIONS: With clear and unambiguous definition, this new grading system for supracondylar fracture displacement has proved to be sufficiently reliable and accurate when applied by pediatric surgeons in the framework of clinical routine as well as research. LEVEL OF EVIDENCE: Diagnostic study, Level II. PMID- 21307704 TI - Intra-articular radial head fracture in the skeletally immature patient: progressive radial head subluxation and rapid radiocapitellar degeneration. AB - BACKGROUND: Intra-articular fractures of the radial head in skeletally immature patients are rare. Most studies in the literature group intra-articular radial head fractures with the more common extra-articular, metaphyseal fractures of the radial neck; considered as a group, outcomes are favorable. In this study, we specifically evaluate a group of skeletally immature patients with intra articular radial head fractures, and a rapid progression of posterior subluxation of the radial head with the development of joint arthrosis. METHODS: A chart review identified 7 patients who were referred for management of an intra articular radial head fracture that had failed initial nonoperative management. All the elbows progressed to posterior radiocapitellar subluxation and joint degeneration within 4 months after initial injury. We cataloged clinical, radiographic, and intraoperative findings. RESULTS: The average age at the time of injury was 10 years and 6 months (range, 8 to 13 y). Five patients were male and 2 were female. Five patients had Salter-Harris III fractures of the radial epiphysis, while 2 had Salter-Harris IV injuries. The radiocapitellar articulation was reduced on the initial injury films, but all the elbows showed progressive radiocapitellar subluxation and arthrosis, whereas the ulnohumeral articulation remained unaffected. Motion was decreased in all patients with an average arc of extension-flexion of 38 degrees to 127 degrees and an average arc of rotation of 84 degrees. Six patients underwent salvage surgery. CONCLUSIONS: Skeletally immature patients with an intra-articular radial head fracture are at risk for progressive radial head subluxation and radiocapitellar arthrosis. LEVEL OF EVIDENCE: Retrospective Case Series, Level IV. PMID- 21307705 TI - Biomechanical analysis of lateral humeral condyle fracture pinning. AB - BACKGROUND: The purpose of this study was to determine the optimum pin configuration and the number of pins needed to stabilize the Milch type II lateral humeral condyle fractures in a pediatric bone model. METHODS: Forty synthetic pediatric humeri were sectioned through the lateral distal humerus to simulate a Milch type II lateral condyle fracture. Each fracture was stabilized with 0.062-in K-wires in 1 of 5 configurations: 2 convergent pins, 2 parallel pins, 2 divergent 30-degree pins, 2 divergent 60-degree pins, and 3 divergent pins (n=8/group). Models were tested in extension, flexion, varus, and valgus by applying a translational force through the distal fragment at 0.5 mm/sec oscillating between 5 N and 50 N for 10 cycles. For internal and external rotation, constructs were tested at 0.5 degree/sec between +/-1 Nm more than 10 cycles. The maximum force and torque values were also recorded. For bending loads, stiffness was calculated between 0.5 and 5 mm of displacement, whereas torsional stiffness was calculated between 1 degree and 10 degrees of rotation. Data for stiffness were analyzed with a 1-way analysis of variance and a 2-sample t test (P<0.05). RESULTS: Among 2-pin configurations, divergent (60 degrees) pins provided statistically greater stability than less divergent pins in torsional loading, and greater stability than parallel pins in valgus loading. Three divergent pins had statistically greater stability than all the 2-pin configurations in valgus and torsional loading, and tended to provide more secure fixation in varus loading. CONCLUSIONS: For 2-pin constructs, maximizing pin divergence at the fracture site provided greater stability in torsional loading and valgus loading. The addition of a third pin in a divergent orientation increases stability compared with 2-pin constructs in valgus, internal, and external rotation loading. CLINICAL RELEVANCE: Bicortical pins placed with maximum divergence and spread at the fracture site maximizes stability for 2-pin constructs in Milch type II lateral condyle fractures. If the stability of the fracture is questionable after 2 pins are inserted, the addition of a divergent third pin enhances the stability. PMID- 21307706 TI - Rapid remineralization of the distal radius after forearm fracture in children. AB - BACKGROUND: Bone mineral content (BMC) and density (BMD) have been shown to diminish after fracture and immobilization in adults. Distal radius fractures are common in children, and unlike adults, there is a low incidence of refracture. The primary aim of this study was to assess the change in radial BMC and BMD after upper extremity fracture and casting in healthy pediatric patients. METHODS: Patients were recruited at the time of distal radius fractures casting. The nonfractured (non-Fx) distal radius was initially scanned by dual energy x ray absorptiometry (baseline), and then both arms were scanned at the time of cast removal (CastOff), and 4, 8, 12, 24, and 52 weeks post CastOff. RESULTS: Twenty-one patients were enrolled (13 male, 13 Caucasian; 10.4+/-2.5 y) with an average length of casting of 38+/-11 days. Eighteen patients (86%) completed all protocol requirements. At CastOff, there was no significant difference in total BMC or BMD between the Fx and non-Fx arms. From CastOff to 24 weeks, the overall change in BMC and BMD for the non-Fx arm was +4.2% and +0.2%, respectively, whereas for the Fx arm, the change was +8.3% and +3.4%, respectively. By 24 weeks, the difference in the overall change in BMD between the Fx and non-Fx arms was statistically significant (greater than instrumental error; P<0.05). However, by 52 weeks, these differences were no longer significant. The increased mineralization was unrelated to age, sex, arm dominance, or calcium intake. CONCLUSIONS: These data show that there is rapid remineralization after a simple forearm fracture in children, with a transient elevation in BMD in the Fx arm after casting. This novel finding suggests that bone may be stronger around the site of fracture and could significantly change how we counsel young patients recovering from forearm fracture. Future research should focus on children immobilized for varying lengths of time and those with repeat fractures, using volumetric techniques of bone geometry and strength assessment. LEVEL OF EVIDENCE: CASE SERIES: Therapeutic Studies-investigating the results of treatment, Level IV. PMID- 21307707 TI - A prospective study on the effectiveness of cotton versus waterproof cast padding in maintaining the reduction of pediatric distal forearm fractures. AB - BACKGROUND: Distal forearm fractures, one of the most common fractures seen in the pediatric population, are regularly treated by closed reduction and casting. Our study investigates the effectiveness of Gore-Tex-lined casting in maintaining the reduction of 100% displaced distal forearm fractures compared with traditional cotton-lined casts. METHODS: We screened all patients from February 2007 to July 2009 who presented to Children's Hospital in Birmingham, AL with a distal radius fracture. Only patients with 100% displaced distal radius fractures were eligible to be assigned to either the cotton-lined or Gore-Tex-lined cast groups. Power analysis was performed to identify an adequate patient sample size. The mean maximum change between initial post-reduction x-rays and follow-up x rays for anterior-posterior (AP) angulation, AP displacement, lateral angulation, and lateral displacement of the radius were calculated for both cotton and Gore Tex groups. The rate of subsequent intervention and/or unacceptable results for each group was also analyzed. RESULTS: Seven hundred and twenty-two patients were treated with distal radius fractures at our hospital with 59 patients eligible for inclusion in our study. Thirty-six of our patients were treated with cotton lined casts, and 23 patients were treated with Gore-Tex-lined cast. The mean maximum change in AP angulation, AP displacement, lateral angulation, and lateral displacement of the radius after initial reduction was 9.2 degrees, 6.9%, 13.9 degrees, and 13.6%, respectively, for the cotton-lined cast group and 7.7 degrees, 6.1%, 14.6 degrees, and 9.6%, respectively, for the Gore-Tex-lined cast group. There were no statistical differences between the means of the 4 measurements (P=0.33, 0.69, 0.73, and 0.10, respectively). There were also no significant differences between groups for final AP and lateral angulation and displacement. Subgroup analysis showed no significant differences in all measurements between cotton and Gore-Tex groups. CONCLUSION: Gore-Tex and cotton lined casts are equally effective in their ability to maintain the reduction of 100% displaced distal forearm fractures. Thus, Gore-Tex-lined casts can be offered to pediatric patients immediately after closed reduction of distal radius fractures of any severity. LEVEL OF EVIDENCE: Therapeutic level II. PMID- 21307708 TI - Bone bruises and meniscal tears on MRI in skeletally immature children with tibial eminence fractures. AB - BACKGROUND: Earlier studies have found that tibial eminence fractures (TEFs) in children are rarely associated with additional injuries. In skeletally immature patients with this fracture, the rate of meniscal injury is reported to be less than 5%. Most earlier studies that evaluate TEFs are based on conventional radiographic findings and do not address injuries to the subchondral bone and soft tissues of the knee. Therefore, the purpose of this study was to assess additional injuries, specifically bone bruises and meniscal tears identified by magnetic resonance imaging (MRI) in skeletally immature patients who have sustained a TEF. METHODS: This study is a retrospective evaluation of 20 skeletally immature children with TEFs who have undergone MRI examinations of the knee. Sixteen boys and 4 girls, ranging in age from 7 to 17 years (mean age, 12 y) were included. The TEFs were classified by the modified Meyers McKeever system. The MRI examinations were reviewed for the presence and location of associated subchondral bone contusions and meniscal injuries. RESULTS: Distribution of the TEF types was: type I, n=6 (30%); type II, n=3 (15%); type III, n=11 (55%); and type IV, n=0. Subchondral bone contusions were seen in 18 children (90%). These were in the lateral femoral condyle (80%), lateral tibial plateau (75%), medial femoral condyle (60%), and medial tibial plateau (30%). Meniscal tears were present in 8 patients (40%), divided equally between the medial and lateral meniscus. CONCLUSIONS: TEFs in children are associated with a high rate of bone contusion and meniscal injury. The pattern of injuries observed in this series suggests that a mechanism of injury similar to that of adult anterior cruciate ligament tears might also be responsible for TEFs in skeletally immature children. In addition, we found that the incidence of associated meniscal injury is higher than previously reported. MRI examinations may play an important role in the evaluation for additional injuries in these children. LEVEL OF EVIDENCE: Level IV-Case series. PMID- 21307709 TI - Radiographic assessment of bone remodelling in slipped upper femoral epiphyses using Klein's line and the alpha angle of femoral-acetabular impingement: a retrospective review. AB - BACKGROUND: Bone remodelling in patients with earlier slipped upper femoral epiphysis (SUFE) has been shown to have a generally positive effect on both clinical and radiologic parameters. This study aims to further assess the effect of bone remodelling on the femoral head-neck relationship in SUFE patients, with the aid of 2 radiographic measurements not earlier used for this assessment. METHODS: A retrospective review of radiographs was performed on all patients surgically managed for SUFE at a tertiary institution between 2000 and 2006. The postoperative and the most recent review radiographs were used for analysis. Alpha angles of Notzli (generally used to measure cam-type femoral-acetabular impingement) and displacement from Klein's line were measured as markers of femoral head-neck relationship. RESULTS: A total of 59 hips were evaluated with a median mean follow-up time of 17.7 months. Patients had mild-to-moderate SUFE. The postoperative alpha angle mean reduced by 17.7 degrees (95% confidence interval: 13.6-21.8, P<0.001) at follow up. The displacement from Klein's line improved by a mean of 4.8 mm (95% confidence interval: 3.9-5.8 mm, P<0.001), over the review period. CONCLUSIONS: The femoral head-neck relationship, measured by both the Notzli alpha angle and the displacement from Klein's line, becomes significantly closer to normal after in situ pinning of mild-to-moderate SUFE, compatible with favorable bone remodelling. Both of these indices show promise for use in prospective study and standardized clinical follow up of patients with SUFE, and could be especially useful in assessing for future femoral-acetabular impingement. LEVEL OF EVIDENCE: III. PMID- 21307710 TI - Revised modified Oxford bone score: a simpler system for prediction of contralateral involvement in slipped capital femoral epiphysis. AB - BACKGROUND: The decision to prophylactically treat the uninvolved hip in slipped capital femoral epiphysis (SCFE) remains controversial. The modified Oxford bone score (mOBS) is predictive of future contralateral involvement in slipped capital femoral epiphysis. The scoring method for this system is challenging to remember because out-of-context irrational number sequences and total score range (16 to 26) are used. This study was performed to evaluate intraobserver and interobserver reliability of the mOBS and to determine whether revising the scoring sequence to 0 to 2 for all 5 categories (total score range: 0 to 10) would be easier for orthopedic surgeons to remember. METHODS: Six orthopedic surgeons scored 30 normal pelvis radiographs using the mOBS (original or revised scoring system) on 2 separate occasions, at least 2 weeks apart, with the aid of reference diagrams and an explanatory key. At a later date, the observers were asked to complete blank reference diagrams from memory for both scoring systems (16 to 26 and 0 to 10). RESULTS: Intraobserver reliability was analyzed for each parameter independently and as a total score. Overall, intraobserver reliability was excellent, with total scores being within 1 and 2 points of each other 80.5% and 94.9% of the time, respectively. Interobserver reliability was very good, with total scores within 1 and 2 points of each other 69.6% and 87% of the time, respectively. None of the 6 observers were able to complete the blank mOBS key correctly from memory, despite being reminded of the 16 to 26-point range. Five of the 6 were able to correctly complete the revised key using the 0 to 10 point range system. CONCLUSIONS: The mOBS is a useful method to estimate risk of contralateral slip, with excellent intraobserver and very good interobserver reliability. Difficulty in remembering the original scoring scheme because of its illogic sequences in the modified method limits its clinical applicability. Revision of the mOBS to a consistent 0 to 2 (range: 0 to 10) system greatly enhanced the observers ability to recall the scoring system. LEVEL OF EVIDENCE: Level II - development of diagnostic criteria with reference to "gold" standard. PMID- 21307711 TI - The effect of hip position upon the location of the sciatic nerve: an MRI Study. AB - BACKGROUND: Allowance for the positional changes of the sciatic nerve is important when considering the safest position of the leg to perform hip operations, specifically the ischial osteotomy during a pelvic triple or periacetabular osteotomy. As for its proximity to the osteotomy site the sciatic nerve can be injured during these operations with the consequence of severe functional impairment. This is the first in-vivo study that demonstrates the effect of hip position upon the location of the sciatic nerve. METHODS: We determined how altering the position of the hip moves the nerve toward or away from the infracotyloid groove, the desired starting point of the ischial osteotomy site just inferior to the acetabulum when performing a pelvic triple or periacetabular osteotomy. Magnetic resonance imaging scans of the left hip in 3 different positions (neutral/supine, 30 to 45 degrees flexion, 30 to 45 degrees flexion/abduction/external rotation) were performed in 11 healthy children (5 boys and 6 girls, age 7 to 17 y) without prior hip surgery. The distance between the sciatic nerve and the infracotyloid groove was measured on the magnetic resonance images. Distance ratios based on the neutral position were calculated for flexion and flexion/abduction/external rotation for each of the participants. RESULTS: The sciatic nerve moves toward the ischium osteotomy site in hip flexion without abduction (mean flexion: neutral ratio 0.79, P<0.01). However the nerve moves away from the osteotomy site when the hip is 30 to 45 degrees flexed, abducted, and externally rotated (mean flexion/abduction/external rotation: neutral ratio 1.34), meaning the distance from nerve to infracotyloid groove increases significantly (P<0.01). The mean distances were 14.8 mm (11 to 20 mm) in neutral, 11.8 mm (9 to 16 mm) in flexion, and 20.0 mm (9 to 30 mm) in flexion/abduction/external rotation. CONCLUSIONS: The likely safest position of the hip/leg to perform the ischium osteotomy as part of a pelvic triple or periacetabular osteotomy is in flexion, abduction, and external rotation. In this position the osteotomy can be performed via a medial or anterior approach with the nerve the furthest away from the osteotomy site. LEVEL OF EVIDENCE: Level II. PMID- 21307712 TI - Thoracoscopy in children less than 20 kg for the management of spinal disorders: efficacy at long-term follow-up. AB - BACKGROUND: Thoracoscopy is now considered a safe and feasible method for surgical management of spinal disorders in both adults and children. Nevertheless, a weight less than 20 kg has been reported as a relative contraindication because of the small volume of the thoracic cage and the anticipated difficulties of single-lung ventilation. The aim of this study was to evaluate the feasibility, as well as the safety and efficacy, of thoracoscopic procedures in such patients. METHODS: This study was a retrospective analysis of a consecutive group of patients less than 20 kg weight, who underwent a thoracoscopy between 1998 and 2005. Results were evaluated radiologically, and intraoperative and postoperative complications were reported. A minimum 2-year follow-up was required. RESULTS: Seventeen patients were included. Age at surgery averaged 3 years and 4 months (+/-1.25). The mean weight was 13.3 kg (+/-2.8). Fourteen of the patients had congenital scoliosis, 9 due to hemivertebrae and 5 due to segmentation failures. The other 3 suffered from evolutive kyphosis, 2 caused by Pott disease, and 1 caused by congenital anterior failure of segmentation. The mean follow-up was 6 years and 9 months (+/-1.5). Lung exclusion time averaged 114 minutes (+/-20). The intended procedure was possible in all cases and no conversion to open thoracotomy was required. The mean operating time was 139 minutes (+/-10). A posterior arthrodesis was associated and performed during the same anesthesia in 15 cases. The selective breathing was efficient and well tolerated in all cases. No intraoperative respiratory complication was observed. For patients with congenital scoliosis, the average improvement of the main curve between preoperative and latest follow-up was 55%, with an average Cobb angle improvement of 19.1 degrees (+/-10.5). For the 3 cases of kyphosis, the curve progression stopped, with a mean reduction of the regional kyphosis of 6 degrees (+/-11.5). Fusion was obtained radiologically in all cases. CONCLUSIONS: This study confirms the feasibility, safety, and efficacy of thoracoscopy for the management of spinal disorders in children less than 20 kg weight. Thoracoscopy can still be considered as an option in very young children, even though the small chest cavity creates additional technical challenges and the diminutive bronchial tree necessitates a dedicated method of single-lung ventilation. LEVEL OF EVIDENCE: IV. PMID- 21307713 TI - Measuring quality of life in children with early onset scoliosis: development and initial validation of the early onset scoliosis questionnaire. AB - BACKGROUND: Treatment of children with early onset scoliosis (EOS) seeks to improve natural history and health related quality of life (QOL). QOL measurement presents a significant challenge given the young age, comorbidities, and heterogeneity of this population. The purpose of this study is to develop a disease specific measure reflecting issues of importance to EOS patients and caretakers that is responsive to clinical and treatment changes. METHODS: Review of the literature and relevant measures informed development of semistructured qualitative interviews. Interviews of caregivers of EOS patients were interpreted through the framework technique. A masterlist of 75 items was created and responses were scaled on a 5-point Likert scale. Psychometric analysis was carried out to group items into domains, to maintain score distribution, to create a responsive instrument, and to identify question redundancy. RESULTS: Content validation showed 8 items with low content validity indices (<0.70). Item distribution analysis showed 19 items with skewed distribution. Item reliability showed redundant items within domains (r>=0.5). Construct validity showed unique domains measuring intended issues of interest. The resulting Early Onset Scoliosis Questionnaire (EOSQ) includes 33 items in 13 domains: General Health, Pain, Physical Function, Pulmonary Function, Daily Living, Fatigue, Emotion, Surgical Concerns, Satisfaction, Transfer, Financial Burden, Parental Burden, and Treatment Outcomes. CONCLUSIONS: The EOSQ reflects QOL and caregiver burden in the EOS population. The EOSQ will expand options for outcome assessment in this unique population. PMID- 21307714 TI - Surgical treatment for scoliosis in patients with Shprintzen-Goldberg syndrome. AB - BACKGROUND: Shprintzen-Goldberg syndrome (SGS) is characterized by craniosynostosis and marfanoid habitus. The clinical findings of SGS include neurological, cardiovascular, connective tissue, and skeletal abnormalities. Among these skeletal findings, developmental scoliosis is recognized in half of all patients with SGS. However, no earlier reports have described the surgical treatment of scoliosis associated with SGS. METHODS: Four patients (2 boys and 2 girls; mean age at the time of surgery, 7.3+/-4.4 y) with SGS who underwent surgical treatment for progressive scoliosis were reviewed. The radiologic findings, operative findings, and perioperative complications were evaluated. RESULTS: The mean preoperative Cobb angle was 102.8+/-16.9 degrees. The curve patterns were a double curve in 2 cases and a triple curve in 2 cases. Local kyphosis at the thoracolumbar area was recognized in all the cases with a mean kyphosis angle of 49+/-16 degrees. Growing rod procedures were performed in 2 patients, and posterior correction and fusion were performed in 2 patients. The mean correction rate was 45% in the patients who underwent the growing rod procedures at the time of growing rod placement and 51% in the patients who underwent posterior correction and fusion. Dislodgement of the proximal anchors occurred in 3 of the 4 patients. One patient developed pseudoarthrosis. Two patients developed deep wound infections, and implant removal was necessary in 1 patient. CONCLUSIONS: Surgical treatment for scoliosis in patients with SGS was associated with a high incidence of perioperative and postoperative complications including implant dislodgements and deep wound infections attributable to poor bone quality and a thin body habitus, which are characteristic clinical features of this syndrome. Careful preoperative surgical planning and postoperative care are critical for the surgical treatment of scoliosis associated with SGS, especially in infants requiring multiple surgeries. LEVEL OF EVIDENCE: Level IV. PMID- 21307715 TI - EMG and MRI are independently related to shoulder external rotation function in neonatal brachial plexus palsy. AB - BACKGROUND: Few studies exist with regard to the ability of electromyography (EMG) and volumetric magnetic resonance imaging (MRI) of the infraspinatus muscle to complement the physical assessment of active global shoulder external rotation (GER) in the neonatal brachial plexus palsy (NBPP) population. Therefore, the purpose of this study was to evaluate the relationships of EMG and MRI with active GER based on analysis of the infraspinatus muscle. METHODS: Seventy-four NBPP patients (mean age, 5 y 1 m; range, 1 y 1 m to 13 y 3 m) who had undergone physical examination of the shoulder, EMG evaluation of the infraspinatus muscle, and shoulder MRI were included in this study. The outcome variable active GER was dichotomized into <0 degree active GER (poor) and >=0 degree active GER (good). The interference pattern on EMG of the infraspinatus muscle was graded on a 6 point scale and dichotomized into <=4 and >=5. On shoulder MRI, infraspinatus muscle volume was measured. The infraspinatus muscle interference pattern and volume were compared with active GER. RESULTS: Interference pattern on EMG of the infraspinatus muscle was significantly related to the Mallet Score (P=0.0022), with a poor interference pattern associated with an approximately 7 times higher likelihood [odds ratio=7.391; 95% confidence interval (2.054, 26.588)] of poor active GER. Infraspinatus muscle volume decrease on MRI was also significantly related to active GER (P=0.0413), with each percent volume decrease corresponding to an increase of 0.094 in the odds of having a poor Mallet Score for active GER [odds ratio=1.094; 95% confidence interval (1.004, 1.193)]. CONCLUSIONS: The interference pattern of the infraspinatus muscle on EMG and the infraspinatus muscle volume on MRI are strongly related to active GER as assessed by the Mallet Score. Integrating clinical assessment with electrophysiological and imaging findings may improve the accuracy in evaluating shoulder dysfunction in NBPP and provide improved guidance in selecting interventions specific to the patient's pattern of deficits. LEVEL OF EVIDENCE: Diagnostic study, level II. PMID- 21307716 TI - Subtalar fusion in cerebral palsy patients: results of a new technique using corticocancellous allograft. AB - BACKGROUND: Valgus deformity of the hindfoot in cerebral palsy (CP) patients is common and causes functional deterioration and shoe fitting problems together with skin ulcerations. Our aims in this study are, to present an intra-articular technique of subtalar fusion using allograft and internal fixation to achieve stabilization and second to report the results and clinical outcome of a series of intra-articular subtalar arthrodesis performed in CP children. METHODS: We performed a retrospective review of radiographs and medical records of 145 children with CP who underwent intra-articular subtalar fusion from January 1994 to December 2004. The subtalar joint was fixed through the anterior facet with a cannulated screw whereas the anterior aspect of the calcaneus was parallel to the anterior aspect of the head of the talus. Tricortical iliac crest allograft was placed into the sinus tarsi and the denuded posterior facet area. Results are grouped as good, satisfactory, and poor according to the radiographic and clinical outcomes. RESULTS: The mean age at the time of surgery was 12.7 years (range: 5 to 20 y) and the average follow-up was 4.8 years (range: 2 to 11 y). Good results were obtained in 242 feet (96%). Satisfactory results were obtained in 6 feet (2%) which were painless pseudoarthrosis of subtalar joint in 2 feet and screw removal was required in 4 feet because of pain. Nonunion of thesubtalar joint together with recurrence of deformity was observed in 5 feet (2%) which is accepted as poor result and required revision surgery. No deep infections, implant failure, allograft failure were observed in a mean of 4.8 years. CONCLUSIONS: Our described technique of intra-articular subtalar joint fusion is safe and reliable in CP children with high rate of satisfactory results. LEVEL OF EVIDENCE: Therapeutic studies-Level IV. PMID- 21307717 TI - Dexamethasone therapy for septic arthritis in children: results of a randomized double-blind placebo-controlled study. AB - BACKGROUND: We evaluated the effect of adding dexamethasone to antibiotic therapy in the clinical course of septic arthritis in children. METHODS: A randomized double-blind placebo-controlled trial was performed. The study group included 49 children with septicarthritis. In addition to antibiotic therapy given, patients were randomly assigned to receive intravenous dexamethasone 0.15 mg/kg every 6 hours for 4 days or placebo. The groups were compared for clinical and laboratory parameters, length of hospital stay, and late sequelae. RESULTS: Mean age was 33+/-42 months (range: 6 to 161 mo). There was no significant difference between the dexamethasone and placebo groups in age, duration of symptoms, joint affected, or levels of acute phase reactants. Bacteria were isolated from joint fluid in 17 patients (35%) and from blood in 4 patients. Compared with the placebo group, patients treated with dexamethasone had a significantly shorter duration of fever (P=0.021; mean first day without fever 1.68 vs 2.83) and local inflammatory signs (P=0.021; mean first day without pain 7.18 vs 10.76), lower levels of acute phase reactants (P=0.003; mean last day of erythrocyte sedimentation rate>25 mm/h 3.76 vs 8.40), shorter duration of parenteral antibiotic treatment (P=0.007; mean of 9.91 d vs 12.60 d), and shorter hospital stay. No side effects of treatment were recorded in either group. CONCLUSIONS: A 4-day course of dexamethasone given at the start of antibiotic treatment in children with septic arthritis, is safe, and leads to a significantly more rapid clinical improvement, shortening duration of hospitalization compared with those treated with antibiotics alone. LEVEL OF EVIDENCE: I. PMID- 21307718 TI - Prevalence of stump overgrowth in pediatric burn patient amputations. AB - BACKGROUND: Pediatric patients sometimes require amputation as part of their life saving burn care. Bone overgrowth is known to occur in these amputation patients at rates of 4% to 43% depending on the study. METHODS: We conducted a retrospective study of all patients who underwent amputation at a children's burn center for a 45-year span. There were 18,880 burn patients during this time frame and 149 pediatric patients with amputation who survived long-term were studied. Burn types included flame, electrical, scald, thermal, and combination types in order of prevalence. We studied bone overgrowth as defined as those children requiring revision surgery. RESULTS: One hundred forty-nine patients underwent a total of 259 amputations. The average age at the time of amputation was 7.48 years. Stump overgrowth occurred in 15 patients (10.1%) or 15 of the 259 amputations (5.8%) overall. Bone overgrowth occurred in 11 of 104 flame burn patients (10.6%), 3 of 32 electrical burns (9.4%), and 1 of 9 scald burns (11.1%). Many patients had multiple amputations so the incidence for amputations was 6.1% (11 of 179) for flame, 5.4% (3 of 56) for electrical, and 5.9% (1 of 17) for scald burns. The mean time to overgrowth from primary amputation to revision surgery was 41.5 months. Overgrowth was more common in the lower extremities (17 of 104, or 16.3%) than in the upper extremities (3 of 153, or 2%). CONCLUSIONS: Bony overgrowth after amputation in pediatric burn patients occurs at a rate of 10.1% of patients or 5.8% of amputations. Younger children are more likely to have overgrowth. The type of burn does not influence overgrowth and lower extremity amputations are more likely to show overgrowth than upper extremities. LEVEL OF EVIDENCE: Level IV, case series. PMID- 21307719 TI - Ruptured abdominal aortic aneurysm. PMID- 21307720 TI - Service: 2010 Western Trauma Association presidential address. AB - Service is central to the mission of a trauma surgeon and inextricably interwoven into our professional lives and activities. It is important to recognize the role that professional associations play in leveraging service as well as the need to continue to cultivate the ethic of service in medical education and in our training programs. PMID- 21307721 TI - Sew it up! A Western Trauma Association multi-institutional study of enteric injury management in the postinjury open abdomen. AB - BACKGROUND: Use of damage control surgery techniques has reduced mortality in critically injured patients but at the cost of the open abdomen. With the option of delayed definitive management of enteric injuries, the question of intestinal repair/anastomosis or definitive stoma creation has been posed with no clear consensus. The purpose of this study was to determine outcomes on the basis of management of enteric injuries in patients relegated to the postinjury open abdomen. METHODS: Patients requiring an open abdomen after trauma from January 1, 2002 to December 31, 2007 were reviewed. Type of bowel repair was categorized as immediate repair, immediate anastomosis, delayed anastomosis, stoma and a combination. Logistic regression was used to determine independent effect of risk factors on leak development. RESULTS: During the 6-year study period, 204 patients suffered enteric injuries and were managed with an open abdomen. The majority was men (77%) sustaining blunt trauma (66%) with a mean age of 37.1 years+/-1.2 years and median Injury Severity Score of 27 (interquartile range=20 41). Injury patterns included 81 (40%) small bowel, 37 (18%) colonic, and 86 (42%) combined injuries. Enteric injuries were managed with immediate repair (58), immediate anastomosis (15), delayed anastomosis (96), stoma (10), and a combination (22); three patients died before definitive repair. Sixty-one patients suffered intra-abdominal complications: 35 (17%) abscesses, 15 (7%) leaks, and 11 (5%) enterocutaneous fistulas. The majority of patients with leaks had a delayed anastomosis; one patient had a right colon repair. Leak rate increased as one progresses toward the left colon (small bowel anastomoses, 3% leak rate; right colon, 3%; transverse colon, 20%; left colon, 45%). There were no differences in emergency department physiology, injury severity, transfusions, crystalloids, or demographic characteristics between patients with and without leak. Leak cases had higher 12-hour heart rate (148 vs. 125, p=0.02) and higher 12-hour base deficit (13.7 vs. 9.7, p=0.04), suggesting persistent shock and consequent hypoperfusion were related to leak development. There was a significant trend toward higher incidence of leak with closure day (chi for trend, p=0.01), with closure after day 5 having a four times higher likelihood of developing leak (3% vs. 12%, p=0.02). CONCLUSIONS: Repair or anastomosis of intestinal injuries should be considered in all patients. However, leak rate increases with fascial closure beyond day 5 and with left-sided colonic anastomoses. Investigating the physiologic basis for intestinal vulnerability of the left colon and in the open abdomen is warranted. PMID- 21307722 TI - Over reliance on computed tomography imaging in patients with severe abdominal injury: is the delay worth the risk? AB - BACKGROUND: Computed tomography (CT) has a high sensitivity and specificity for detecting abdominal injuries. Expeditious abdominal imaging in "quasi-stable" patients may prevent negative laparotomy. However, the significance of potential delay to laparotomy secondary to abdominal imaging remains unknown. We sought to analyze whether the use of abdominal CT (ABD CT) in patients with abdominal injury requiring laparotomy results in a significant delay and a higher risk of poor outcome. METHODS: A retrospective analysis of data from the National Trauma Data Bank (version 7.1) was performed. Inclusion criteria were adult patients (age>14 years), a scene admission (nontransfer), hypotension on arrival (emergency department systolic blood pressure<90 mm Hg), an abdominal Abbreviated Injury Scale (AIS) score>3, and undergoing a laparotomy within 90 minutes of arrival. Patients with severe brain injury (head AIS score>3) were excluded. The independent mortality risk associated with a preoperative ABD CT was determined using logistic regression after controlling important confounders. RESULTS: This cohort of patients (n=3,218) was significantly injured with a median Injury Severity Score of 25 ([interquartile range, 16-34]). Patients who underwent ABD CT had similar Glasgow Coma Scale scores, a lower head AIS, longer time delays to the operating room, and a higher crude mortality (45% vs. 30%; p=0.001). Logistic regression revealed that ABD CT was independently associated with more than a 70% higher risk of mortality (odds ratios, 1.71; 95% CI, 1.2-2.2; p<0.001). When stratified by injury mechanism, intubation status and whether or not a head CT was performed, the mortality risk remained significantly increased for each subgroup. When the laparotomy was able to occur within 30 minutes of arrival, an ABD CT was independently associated with more than a sevenfold higher risk of mortality (odds ratios, 7.6; p=0.038). CONCLUSION: Delay secondary to abdominal imaging in patients who require operative intervention results in an independent higher risk of mortality. ABD CT imaging is an important and useful tool after injury; however, these results suggest that delay caused by overreliance on ABD CT may result in poor outcome in specific patients. Clinicians who take care of critically injured patients should be aware of and understand these potential risks. PMID- 21307723 TI - Quality of life after abdominal wall reconstruction following open abdomen. AB - BACKGROUND: Management of intra-abdominal hypertension with an open abdomen and planned ventral hernia results in decreased mortality. But, delayed abdominal wall reconstruction (DAWR) is necessary. Results after DAWR demonstrate acceptable recurrence, morbidity, and mortality rates. However, little is known about quality of life (QOL) after DAWR. The purpose of this study was to analyze QOL after DAWR. METHODS: Patients who had DAWR>15 years were identified from operative logs of a trauma center. Patients were contacted, and a QOL assessment was administered in person or via telephone. The QOL assessment contained the Short-Form 36-Item Health Survey 1.0, the Posttraumatic Stress Disorder (PTSD) Checklist-Civilian Version, and the Centers for Epidemiologic Studies Depression Scale. RESULTS: The QOL assessment was completed by 41 of 152 patients. The indication for open abdomen was injury in 37 (90%) and emergency operation in 4 (10%). Time to follow-up ranged from 9 months to 14.6 years after DAWR. Of 31 patients working before DAWR, 23% had not returned to work secondary to DAWR. Also, 65% screened positive for depression and 23% screened positive for PTSD. Compared with population norms Physical Component Scores were significantly lower for the study population (41.1+/-13.2, p<0.05). CONCLUSION: Patients who undergo DAWR have decreased physical functioning and have a high prevalence of PTSD and depression. Consideration should be given to screening for depression and PTSD in this patient population. PMID- 21307724 TI - Body adipose content is independently associated with a higher risk of organ failure and nosocomial infection in the nonobese patient postinjury. AB - OBJECTIVE: Obesity defined by a body mass index (BMI) >30 kg/m is associated with increased morbidity and mortality following trauma. Evidence suggests that obesity represents a state of chronic inflammation and that the adipose tissue content may affect the intensity and resolution of inflammatory response. We sought to avoid the confounding effects attributable to obesity and determine the association of BMI and outcomes following injury in nonobese patients. METHODS: Data were obtained from a multicenter prospective cohort study evaluating outcomes in blunt-injured adults with hemorrhagic shock. Only patients with a BMI>=18.5 and<30 were analyzed. Those with isolated traumatic brain injury and cervical cord injury and those who survived<24 hours were excluded. Logistic regression was used to evaluate the effects of BMI on mortality, multiple organ failure (MOF, multiple organs dysfunction score [MODS]>5), and nosocomial infection (NI) after adjusting for differences in demographics, injury severity, early resuscitation needs, shock parameters, and comorbidities. RESULTS: Overall mortality, MOF, and NI rates for the study cohort (n=820) were 13%, 37%, and 46%, respectively. Median Injury Severity Score was 33 (interquartile range, 22-41). Median BMI for the study cohort was 25 (interquartile range, 23-27). As BMI increased, maximum organ dysfunction scores also significantly increased for cardiac, respiratory, and renal systems. Logistic regression revealed no significant association with mortality (odds ratio [OR]=0.95; 95% confidence interval [CI], 0.9-1.0); however, BMI was independently associated with a higher risk of MOF (OR=1.09; 95% CI, 1.02-1.06) and NI (OR=1.07; 95% CI, 1.01-1.13). For every single-point increase in BMI, the risk of MOF and NI increase by 9% and 7%, respectively. CONCLUSION: The risk of MOF and NI increases as BMI increases in the nonobese injured patient. These results suggest that body adipose content may be associated with the magnitude of or extent of the inflammatory response postinjury. Further studies are needed to elucidate the mechanism responsible for this association. PMID- 21307725 TI - Occupant and crash characteristics for case occupants with cervical spine injuries sustained in motor vehicle collisions. AB - BACKGROUND: Motor vehicle collisions (MVCs) are the leading cause of spine and spinal cord injuries in the United States. Traumatic cervical spine injuries (CSIs) result in significant morbidity and mortality. This study was designed to evaluate both the epidemiologic and biomechanical risk factors associated with CSI in MVCs by using a population-based database and to describe occupant and crashes characteristics for a subset of severe crashes in which a CSI was sustained as represented by the Crash Injury Research Engineering Network (CIREN) database. METHODS: Prospectively collected CIREN data from the eight centers were used to identify all case occupants between 1996 and November 2009. Case occupants older than 14 years and case vehicles of the four most common vehicle types were included. The National Automotive Sampling System's Crashworthiness Data System, a probability sample of all police-reported MVCs in the United States, was queried using the same inclusion criteria between 1997 and 2008. Cervical spinal cord and spinal column injuries were identified using Abbreviated Injury Scale (AIS) score codes. Data were abstracted on all case occupants, biomechanical crash characteristics, and injuries sustained. Univariate analysis was performed using a chi analysis. Logistic regression was used to identify significant risk factors in a multivariate analysis to control for confounding associations. RESULTS: CSIs were identified in 11.5% of CIREN case occupants. Case occupants aged 65 years or older and those occupants involved in rollover crashes were more likely to sustain a CSI. In univariate analysis of the subset of severe crashes represented by CIREN, the use of airbag and seat belt together (reference) were more protective than seat belt alone (odds ratio [OR]=1.73, 95% confidence interval [CI]=1.32-2.27) or the use of neither restraint system (OR=1.45, 95% CI=1.02-2.07). The most frequent injury sources in CIREN crashes were roof and its components (24.8%) and noncontact sources (15.5%). In multivariate analysis, age, rollover impact, and airbag-only restraint systems were associated with an increased odds of CSI. Using the population-based National Automotive Sampling System's Crashworthiness Data System data, 0.35% of occupants sustained a CSI. In univariate analysis, older age was noted to be a significant risk factor for CSI. Airbag-only restraint systems and both rollover and lateral crashes were also identified as risk factors for CSI. In addition, increasing delta v was highly associated with CSIs. In multivariate analysis, similar risk factors were noted. Of all the restraint systems, seat belt use without airbag deployment was found to be the most protective restraint system (OR=0.29, 95% CI=0.16-0.50), whereas airbag-only restraint was associated with the highest risk of CSI (OR=3.54, 95% CI=2.29-5.46). CONCLUSIONS: Despite advances in automotive safety, CSIs sustained in MVC continue to occur too often. Older case occupants are at an increased risk of CSI. Rollover crashes and severe crashes led to a much higher risk of CSI than other types and severity of MVCs. Seat belt use is very effective in preventing CSI, whereas airbag deployment may increase the risk of occupants sustaining a CSI. More protection for older occupants is needed and protection in both rollover and lateral crashes should remain a focus of the automotive industry. The design of airbag restraint systems should be evaluated so that they are not causative of serious injury. In addition, engineers should continue to focus on improving automotive design to minimize the risk of spinal injury to occupants in high severity crashes. PMID- 21307726 TI - Helicopters improve survival in seriously injured patients requiring interfacility transfer for definitive care. AB - BACKGROUND: Helicopter transport (HT) is frequently used for interfacility transfer of injured patients to a trauma center. The benefits of HT over ground transport (GT) in this setting are unclear. By using a national sample, the objective of this study was to assess whether HT impacted outcomes following interfacility transfer of trauma patients. METHODS: Patients transferred by HT or GT in 2007 were identified using the National Trauma Databank (version 8). Injury severity, resource utilization, and survival to discharge were compared. Stepwise logistic regression was used to determine whether transport modality was a predictor of survival after adjusting for covariates. Regression analysis was repeated in subgroups with Injury Severity Score (ISS)<=15 and ISS>15. RESULTS: There were 74,779 patients transported by helicopter (20%) or ground (80%). Mean ISS was higher in patients transported by helicopter (17+/-11 vs. 12+/-9; p<0.01) as was the proportion with ISS>15 (49% vs. 28%; odds ratio [OR], 2.53; 95% confidence interval [CI], 2.43-2.63). Patients transported by helicopter had higher rates of intensive care unit admission (54% vs. 29%; OR, 2.86; 95% CI, 2.75-2.96), had shorter transport time (61+/-55 minutes vs. 98+/-71 minutes; p<0.01), and had shorter overall prehospital time (135+/-86 minutes vs. 202+/-132 minutes; p<0.01). HT was not a predictor of survival overall or in patients with ISS<=15. In patients with ISS>15, HT was a predictor of survival (OR, 1.09; 95% CI, 1.02-1.17; p=0.01). CONCLUSIONS: Patients transported by helicopter were more severely injured and required more hospital resources than patients transported by ground. HT offered shorter transport and overall prehospital times. For patients with ISS>15, HT was a predictor of survival. These findings should be considered when developing interfacility transfer policies for patients with severe injuries. PMID- 21307727 TI - Does the rural trauma team development course shorten the interval from trauma patient arrival to decision to transfer? AB - BACKGROUND: The Rural Trauma Team Development Course (RTTDC) was developed by the ad hoc Rural Trauma Committee of the American College of Surgeons, Committee on Trauma to address the increased mortality of the rural trauma patient. The effectiveness of the RTTDC in shortening the interval from patient arrival to decision to transfer and the effect on the transfer process of communication training emphasizing team building is the focus of this study. METHOD: Rural level III and level IV trauma centers (N=18) were enrolled in a multiinstitutional 3-month longitudinal study of transferred trauma patients. Results were compared with institutions having hosted RTTDC versus those institutions not yet exposed to the course. RESULTS: One-way analysis of variance was conducted. Results indicated that RTTDC training alone and RTTDC including communication training resulted in a statistically significantly shorter (p<0.05) time for decision to transfer. Transferring squad arrival time was also significantly reduced (p<0.01) as was the number of transferring squads contacted (p<0.01). No differences were observed among the trauma facilities and the number of receiving facilities contacted, (p=0.64) or in the time required to find an accepting facility (p=0.72). CONCLUSION: The RTTDC alone and with the embedded communication module significantly reduce delays in the transfer process of the rural trauma patient. PMID- 21307728 TI - The secrets women keep: intimate partner violence screening in the female trauma patient. AB - BACKGROUND: Although intimate partner violence (IPV) is the leading cause of serious injury and the second leading cause of death among reproductive age women in America, effective screening is difficult. Our institution currently screens for IPV during the floor intake assessment by having a registered nurse (RN) ask three unscripted questions about physical, verbal, and sexual abuse during a battery of 81 questions. The patients are frequently in pain, medicated, distraught, or intoxicated, and the RN is juggling multiple responsibilities. We also use a protocol-driven alcohol abuse screen on every trauma admission known as "Screening, Brief Intervention, and Referral for Treatment" (SBIRT). It is conducted by trained counselors when any effects of alcohol are gone in a distraction-free setting after patients have had time to ruminate on their admission. We hypothesized that linking the validated partner violence screening (PVS) to SBIRT would result in higher rates of positive IPV screens than after RN screens. METHODS: This prospective trial was conducted at an urban Level I center. English- and Spanish-speaking female trauma patients underwent the three question, nonvalidated RN-screen on floor arrival per the local standard of care. Before discharge, they then underwent SBIRT screening per trauma service protocol, after which SBIRT administered the PVS as our investigative intervention. All screens were native language. SBIRT screeners were blinded to the results of the earlier RN screen. If an SBIRT or RN screen was not performed for any reason, it was categorized as a negative screen. Admissions to the surgical intensive care unit had both screens delayed until floor transfer. McNemar's exact test was used for paired categorical data and Fisher's exact test otherwise. Significance was set at an alpha of 0.05. RESULTS: One hundred twenty five consecutive female inpatients (mean age, 40.9 years+/-17.7 years; Injury Severity Score, 9.8+/-7.5) were enrolled, with 14 (11.2%) screening positive for one or both methods. The SBIRT-linked screen was significantly better at detecting IPV than the RN screen (p=0.01). No association was found between the likelihood of giving a discordant response to the two IPV screens and acute alcohol intoxication or polysubstance abuse at the time of admission, being a Spanish-only speaker, or if the initial admission was directly to the surgical intensive care unit. Despite being mandatory on intake, 23 of 125 patients (18.4%) had no RN screen performed, with 2 of these patients screening positive for IPV by SBIRT personnel. CONCLUSION: Linking an IPV screen to an established alcohol abuse screen results in higher rates of detection of IPV than screening by RNs at intake assessment. At our institution, adoption of this practice should result in detecting and referring ~85 additional female trauma inpatients per year for IPV services. PMID- 21307729 TI - Is early venous thromboembolism prophylaxis safe in trauma patients with intracranial hemorrhage. AB - BACKGROUND: Patients with traumatic brain injuries (TBIs) are at high risk for venous thromboembolic sequelae; however, prophylaxis is often delayed because of the perceived risk of intracranial hemorrhagic exacerbation. The goal of this study was to determine whether enoxaparin for early venous thromboembolism (VTE) prophylaxis is safe for hemodynamically stable patients with TBIs. METHODS: This is a retrospective cohort study from a Level I Trauma Center of patients with TBIs receiving early (0-72 hours) or late (>72 hours) VTE prophylaxis. Inclusion criteria included evidence of acute intracranial hemorrhagic injury (IHI) on admission computed tomography, head/neck abbreviated injury score>=3, age>=16 years, and hospital length of stay>=72 hours. Exclusion criteria included intracranial pressure monitor/ventriculostomy, current systemic anticoagulation, pregnancy, coagulopathy, history of DVT, ongoing intra-abdominal hemorrhage 24 hours postadmission, and preexisting inferior vena cava filter. Progression of IHI defined as lesion expansion/new IHI on repeat computed tomography. RESULTS: Totally, 669 patients were identified: 268 early (40.1%) and 401 late (59.9%), with a mean injury severity score of 27.8+/-10.2 and 29.4+/-11, respectively. Head neck abbreviated injury score of 3 (47% vs. 34%), 4 (42% vs. 46%), 5 (11% vs. 19%), and 6 (0% vs. 1%) were reported for the early and late treatment groups, respectively. Mean time to prophylaxis was 2.77 days+/-0.49 days and 5.31 days+/-1.97 days. IHI progression before prophylaxis was 9.38% versus 17.41% (p<0.001) and after prophylaxis was 1.46% versus 1.54% (p>0.9). Proportions of proximal DVT were 1.5% versus 3.5% (p=0.117) and pulmonary embolism were 1.5% versus 2.2% (p=0.49). There were no differences in injury severity score, age, and pelvic and/or long bone fractures. CONCLUSIONS: We found no evidence that early VTE prophylaxis increases the rate of IHI progression in hemodynamically stable patients with TBIs. The natural rate of IHI progression observed is comparable with previous studies. Although not powered to detect differences in the incidence of DVT and pulmonary embolism, the data trend toward increased proportions of both VTE outcomes in the late group. PMID- 21307730 TI - A decade's experience with balloon catheter tamponade for the emergency control of hemorrhage. AB - BACKGROUND: Balloon catheter tamponade is a valuable technique for arresting exsanguinating hemorrhage. Indications include (1) inaccessible major vascular injuries, (2) large cardiac injuries, and (3) deep solid organ parenchymal bleeding. Published literature is limited to small case series. The primary goal was to review a recent experience with balloon catheter use for emergency tamponade in a civilian trauma population. METHODS: All patients requiring emergency use of a balloon catheter to tamponade exsanguinating hemorrhage (1998 2009) were included. Patient demographics, injury characteristics, technique, and outcomes were analyzed. RESULTS: Of the 44 severely injured patients (82% presented with hemodynamic instability; mean base deficit=-20.4) who required balloon catheter tamponade, 23 of the balloons (52%) remained indwelling for more than 6 hours. Overall mortality depended on the site of injury/catheter placement and indwelling time (81% if <6 hours; 52% if >=6 hours; p<0.05). Physiologic exhaustion was responsible for 76% of deaths in patients with short-term balloons. Mortality among patients with prolonged balloon catheter placement was 11%, 50%, and 88% for liver, abdominal vascular, and facial/pharyngeal injuries, respectively. Mean indwelling times for iliac, liver, and carotid injuries were 31 hours, 53 hours, and 78 hours, respectively. Overall survival rates were 67% (liver), 67% (extremity vascular), 50% (abdominal vascular), 38% (cardiac), and 8% (face). Techniques included Foley, Fogarty, Blakemore, and/or Penrose drains with concurrent red rubber Robinson catheters. Initial tamponade of bleeding structures was successful in 93% of patients. CONCLUSIONS: Balloon catheter tamponade can be used in multiple anatomic regions and for variable patterns of injury to arrest ongoing hemorrhage. Placement for central hepatic gunshot wounds is particularly useful. This technique remains a valuable tool in a surgeon's armamentarium. PMID- 21307731 TI - Defining the limits of resuscitative emergency department thoracotomy: a contemporary Western Trauma Association perspective. AB - BACKGROUND: Since the promulgation of emergency department (ED) thoracotomy>40 years ago, there has been an ongoing search to define when this heroic resuscitative effort is futile. In this era of health care reform, generation of accurate data is imperative for developing patient care guidelines. The purpose of this prospective multicenter study was to identify injury patterns and physiologic profiles at ED arrival that are compatible with survival. METHODS: Eighteen institutions representing the Western Trauma Association commenced enrollment in January 2003; data were collected prospectively. RESULTS: During the ensuing 6 years, 56 patients survived to hospital discharge. Mean age was 31.3 years (15-64 years), and 93% were male. As expected, survival was predominant in those with thoracic injuries (77%), followed by abdomen (9%), extremity (7%), neck (4%), and head (4%). The most common injury was a ventricular stab wound (30%), followed by a gunshot wound to the lung (16%); 9% of survivors sustained blunt trauma, 34% underwent prehospital cardiopulmonary resuscitation (CPR), and the presenting base deficit was >25 mequiv/L in 18%. Relevant to futile care, there were survivors of blunt torso injuries with CPR up to 9 minutes and penetrating torso wounds up to 15 minutes. Asystole was documented at ED arrival in seven patients (12%); all these patients had pericardial tamponade and three (43%) had good functional neurologic recovery at hospital discharge. CONCLUSION: Resuscitative thoracotomy in the ED can be considered futile care when (a) prehospital CPR exceeds 10 minutes after blunt trauma without a response, (b) prehospital CPR exceeds 15 minutes after penetrating trauma without a response, and (c) asystole is the presenting rhythm and there is no pericardial tamponade. PMID- 21307732 TI - Meditation on mortality: lessons from a life in surgery. PMID- 21307733 TI - Computed tomography alone may clear the cervical spine in obtunded blunt trauma patients: a prospective evaluation of a revised protocol. AB - BACKGROUND: Cervical spine (CS) clearance in obtunded blunt trauma patients (OBTPs) remains controversial. When computed tomography (CT) of the CS is negative for injury, debate continues over the role of magnetic resonance imaging (MRI). Use of MRI in OBTPs is costly, time-consuming, and potentially dangerous. Our study evaluated the safety of a protocol to discontinue the cervical collar in OBTPs based on CT scan alone. METHODS: A prospective study was performed from October 2006 to September 2008 at a regional Level I trauma center on OBTPs with gross movement of all extremities. After a CT of the CS was read as negative for injury, the CS was cleared and the collar was removed. Patients were then followed prospectively for related complications. RESULTS: One hundred ninety seven patients had their collars removed and CS cleared at a mean of 3.3 days. There were 144 males (73%), and the average age was 47.1 years. Sixty-two percent of patients were reexamined by a physician when no longer obtunded and found to have no CS signs or symptoms. Five patients (2.5%), when no longer obtunded, had persistent pain for which MRI CS was negative for injury. Coroner reports and autopsies were reviewed for missed spinal cord injuries in the 13% who died before reexamination. One of these patients had an autopsy report of an isolated CS ligamentous injury, deemed to be stable by our attending neurosurgeon. We followed up an additional 12% by phone or chart review, with no report of new onset neurologic deficit. The remaining 11% were lost to follow-up, but no patient contacted our hospital to report deterioration in function. One patient (0.5%) developed a minor CS decubitus ulceration. CONCLUSION: Removal of CS precautions in OBTPs with gross movement of all extremities is safe and efficacious if CT CS is negative for injury. Supplemental MRI CS is not needed in this patient population. PMID- 21307734 TI - Open tibia fractures: timely debridement leaves injury severity as the only determinant of poor outcome. AB - BACKGROUND: Recent retrospective studies suggest that the time to debridement of open tibia fractures is not a major determinant of outcome. The aim of this prospective study was to determine the modifiable independent predictors of poor outcomes. METHODS: A 36-month prospective observational study ending in December 2009 was performed on consecutive open tibia shaft fracture patients (age >18 years) admitted to a Level 1 trauma center. Demographics, mechanism, Injury Severity Score, fracture type/grade, local contamination, time to debridement, time to antibiotics, and interventions were prospectively recorded. Outcome measures were as follows: length of stay, deep infection, secondary procedures, and presence of union at 6 months and 12 months. Univariate, multivariate, and logistic regression analyses were performed. RESULTS: Eighty-nine consecutive patients (74% male, age 41 years+/-17 years, Injury Severity Score 15+/-3, and 37% multiple injured) met inclusion criteria. The mean time to surgical debridement and operative stabilization was 8 hours+/-4 hours (48% within 6 hours). The average length of stay was 21 days+/-13 days. Fifteen patients (17%) had deep infection and 5 (6%) required amputation (1 acute and 4 late because of the infection). The 6-month and 12-month union rates were 39% and 67%, respectively. Fifty-six patients (63%) required further procedures (a total of 312). The multivariate regression model (18 variables) showed no independent significant predictors for deep infection or nonunion at 6 months and 12 months (multiple injuries and smoking were closest to reach significance, p=0.08). CONCLUSION: Timely management of open tibia fractures (mean, 8 hours) eliminates time to debridement and contamination as predictors of poor outcome. Patient factors and local and general injury severity determine the outcomes. Aiming for the earliest safe time to debridement minimizes the negative effects of modifiable factors on the outcome. PMID- 21307735 TI - Aberrant obturator artery is a common arterial variant that may be a source of unidentified hemorrhage in pelvic fracture patients. AB - BACKGROUND: Similar to all pelvic arteries, the aberrant obturator artery (AOA) and its branches are at risk for injury when the pelvic ring is fractured; however, because of its unique origin, bleeding from this artery may be unrecognized and, thus, treatment ineffective. The purpose of this study was to describe the incidence of the AOA using angiography and determine the sensitivity of 64-slice computed tomography angiography (CTA) at identifying the AOA. METHODS: Imaging from patients undergoing pelvic angiography, for any reason, during 2009 was retrospectively reviewed to determine the incidence of the AOA. The angiographically determined arterial anatomy was the compared with CTA findings. RESULTS: Pelvic angiography, performed in 174 patients, identified the AOA in 60.0% of males, 52.3% of females, 55.1% of all patients, and 38.4% of hemipelvises. The sensitivity/specificity of CTA at identifying the AOA is 90.0%/100% and 63.6%/92.3% in nonpelvic fracture and pelvic fracture patients, respectively; the sensitivity difference being significant (p=0.0351). Three of the 13 (23.1%) AOA identified in pelvic fracture patients demonstrated extravasation when the inferior epigastric artery was cannulated; however, flush angiography failed to demonstrate the extravasation. CONCLUSIONS: The AOA is a common arterial variant occurring in more than half of the population and, if present in pelvic fracture patients, commonly injured. Although CTA is effective at identifying the AOA in nonpelvic trauma patients, it is not as effective in pelvic fracture patients. Failure to consider this arterial variant may result in untreated arterial bleeding with the attendant consequences. PMID- 21307736 TI - Combination of arthrolysis by lateral and medial approaches and hinged external fixation in the treatment of stiff elbow. AB - BACKGROUND: Various methods are available to treat the stiff elbow. However, there is no consensus on which one is most useful. This study involves the effects of combination of arthrolysis by lateral and medial approaches and hinged external fixation in the treatment of stiff elbow. PATIENTS: We treated 12 patients with stiff elbows using a combination of arthrolysis by lateral and medial approaches and hinged external fixation. The arthrolysis was applied to the elbow for complete soft-tissue release, and the hinged external fixation mainly for rehabilitation and stability of the elbow after arthrolysis. With the help of the hinged external fixation, nonsurgical treatment including exercises was effectively performed to maintain the stability and the results of arthrolysis. Before surgery, the mean extension was -35 degrees and the mean flexion 70 degrees. One patient had a loss of 70 degrees in pronation. RESULTS: Satisfactory follow-up was given to 11 patients with the mean length of 15 month. The mean postoperative extension was -8 degrees whereas flexion 122 degrees. Two of 11 patients had a transient ulnar paresthesia and returned to normal after 8 month follow-up. The loss of pronation in one patient reduced to 30 degrees afterward. There were no complicating infections. All patients reported satisfactory effect. CONCLUSION: The combination of arthrolysis by lateral and medial approaches and hinged external fixation in the treatment of stiff elbow is safe and effective. PMID- 21307737 TI - Percutaneous aspiration irrigation drainage technique in the management of septic arthritis in children. AB - BACKGROUND: Septic arthritis in childhood is a therapeutic emergency. The authors present their experience using an intermediate technique with the advantages of the percutaneous aspiration irrigation drainage: joint aspiration, irrigation, and declivious drainage. METHODS: All children were treated by joint aspiration under fluoroscopic control, large volume irrigation, and declivious nonsuction drainage associated with immobilization and intravenous antibiotics during 8 days to 10 days. The draining system was removed when clinical improvement (namely apyrexia) and the decrease of biological inflammatory response were obtained. A late follow-up phone interview was made for each patient. Fifty-two patients were included in this study, with a mean age of 4.3 years. The most common sites of arthritis were the hip (19 of 52, 36%) and the knee (17 of 52, 32%), but ankle (8 of 52, 15%), shoulder (12%), and elbow (3%) were also involved. RESULT: Apyrexia was obtained after a mean period of 2 days. The mean draining duration was 4.5 days. On the last follow-up visit (at 21 months on average; range, 12-56 months), all patients except one were totally painless and had no limitation of physical activity. CONCLUSION: Percutaneous aspiration irrigation drainage assured very good results in this study population, with rapid clinical and biological improvement and the absence of long-term sequelae. The advantages of this technique include permanent joint access and control of synovial effusions, with only one general anesthesia and minimal iatrogenic morbidity. PMID- 21307738 TI - Identifying risk for massive transfusion in the relatively normotensive patient: utility of the prehospital shock index. AB - BACKGROUND: In the prehospital environment, the failure of medical providers to recognize latent physiologic derangement in patients with compensated shock may risk undertriage. We hypothesized that the shock index (SI; heart rate divided by systolic blood pressure [SBP]), when used in the prehospital setting, could facilitate the identification of such patients. The objective of this study was to assess the association between the prehospital SI and the risk of massive transfusion (MT) in relatively normotensive blunt trauma patients. METHODS: Admissions to a Level I trauma center between January 2000 and October 2008 with blunt mechanism of injury and prehospital SBP>90 mm Hg were identified. Patients were categorized by SI, calculated for each patient from prehospital vital signs. Risk ratios (RRs) and 95% confidence intervals (CI) for requiring MT (>10 red blood cell units within 24 hours of admission) were calculated using SI>0.5 to 0.7 (normal range) as the referent for all comparisons. RESULTS: A total of 8,111 patients were identified, of whom 276 (3.4%) received MT. Compared with patients with normal SI, there was no significant increased risk for MT for patients with a SI of <=0.5 (RR, 1.41; 95% CI, 0.90-2.21) or>0.7 to 0.9 (RR, 1.06; 95% CI, 0.77 1.45). However, a significantly increased risk for MT was observed for patients with SI>0.9. Specifically, patients with SI>0.9 to 1.1 were observed to have a 1.5-fold increased risk for MT (RR, 1.61; 95% CI, 1.13-2.31). Further increases in SI were associated with incrementally higher risks for MT, with an more than fivefold increase in patients with SI>1.1 to 1.3 (RR, 5.57; 95% CI, 3.74-8.30) and an eightfold risk in patients with SI>1.3 (RR, 8.13; 95% CI, 4.60-14.36). CONCLUSION: Prehospital SI>0.9 identifies patients at risk for MT who would otherwise be considered relatively normotensive under current prehospital triage protocols. The risk for MT rises substantially with elevation of SI above this level. Further evaluation of SI in the context of trauma system triage protocols is warranted to analyze whether it triage precision might be augmented among blunt trauma patients with SBP>90 mm Hg. PMID- 21307739 TI - Admission ionized calcium levels predict the need for multiple transfusions: a prospective study of 591 critically ill trauma patients. AB - BACKGROUND: Deaths from uncontrolled exsanguinating hemorrhage occur rapidly postinjury. Any successful resuscitation strategy must also occur early, underscoring the importance of rapid identification of patients at risk for multiple transfusions. Previous studies have shown low ionized calcium (iCa) levels to be associated with hypotension and function as a predictor of mortality. We hypothesized that admission iCa levels could potentially predict the need for multiple transfusions in critically ill trauma patients. METHODS: Admission iCa was collected prospectively on all trauma activations during a 9 month period. Youden's index was used to determine the appropriate cutpoint for iCa. Outcomes (mortality, multiple transfusions [>=5 units packed red blood cells in 24 hours] and massive transfusion [>=10 units packed red blood cells in 24 hours]) were compared using Wilcoxon rank-sum and chi tests where appropriate. Multivariable logistic regression was performed to determine whether iCa was an independent predictor of multiple transfusions. RESULTS: A total of 591 patients were identified: 461 (78%) men and 130 (22%) women. Cutpoint was identified as 1.00. iCa was <1.00 (lo-Cal) in 332 patients and>=1.00 (hi-Cal) in 259 patients. Mortality was significantly increased in the lo-Cal group (15.5% vs. 8.7%, p=0.036). In addition, both multiple transfusions (17.1% vs. 7.1%, p=0.005) and massive transfusion (8.2% vs. 2.2%, p=0.017) were significantly increased in the lo-Cal group. Multivariable logistic regression analysis identified iCa<1 as an independent predictor of the need for multiple transfusions after adjusting for age and injury severity (odds ratio=2.294, 95% confidence interval=1.053-4.996). CONCLUSIONS: Low iCa levels at admission were associated with increased mortality as well as an increased need for both multiple transfusions and massive transfusion. In fact, multivariable logistic regression analysis identified low iCa levels as an independent predictor of multiple transfusions. Admission iCa levels may facilitate the rapid identification of patients requiring massive transfusion, allowing for earlier preparation and administration of appropriate blood products. PMID- 21307740 TI - Emergency department crystalloid resuscitation of 1.5 L or more is associated with increased mortality in elderly and nonelderly trauma patients. AB - BACKGROUND: Recent evidence suggests a survival advantage in trauma patients who receive controlled or hypotensive resuscitation volumes. This study examines the threshold crystalloid volume that is an independent risk factor for mortality after trauma. METHODS: This study analyzed prospectively collected data from a Level I Trauma Center between January 2000 and December 2008. Demographics and outcomes were compared in elderly (>=70 years) and nonelderly (<70 years) trauma patients who received crystalloid fluid in the emergency department (ED) to determine a threshold volume that was an independent predictor for mortality. RESULTS: A total of 3,137 patients who received crystalloid resuscitation in the ED were compared. Overall mortality was 5.2%. Mortality among the elderly population was 17.3% (41 deaths), whereas mortality in the nonelderly population was 4% (116 deaths). After multivariate logistic regression analysis, fluid volumes of 1.5 L or more were significantly associated with mortality in both elderly (odds ratio [OR]: 2.89, confidence interval [CI] [1.13-7.41], p=0.027) and nonelderly patients (OR: 2.09, CI [1.31-3.33], p=0.002). Fluid volumes up to 1 L were not associated with significantly increased mortality. At 3 L, mortality was especially pronounced in the elderly (OR: 8.61, CI [1.55-47.75] p=0.014), when compared with the nonelderly (OR=2.69, CI [1.53-4.73], p=0.0006). CONCLUSION: ED volume replacement of 1.5 L or more was an independent risk factor for mortality. High-volume resuscitations were associated with high-mortality particularly in the elderly trauma patient. Our finding supports the notion that excessive fluid resuscitation should be avoided in the ED and when required, operative intervention or intensive care admission should be considered. PMID- 21307741 TI - Refractory postinjury thrombocytopenia is associated with multiple organ failure and adverse outcomes. AB - BACKGROUND: Postinjury multiple organ failure (MOF) remains the leading cause of morbidity and late mortality after severe trauma. Our previous work consistently identified an association between thrombocytopenia and progression to MOF. In addition, recent studies suggest that platelets play a critical role in postinjury hyperinflammation. Therefore, we hypothesized that postinjury thrombocytopenia is a marker for progression to MOF. METHODS: One thousand four hundred fifteen critically injured surgical intensive care unit patients surviving>48 hours were prospectively collected over 12 years. Variables studied included age, Injury Severity Score (ISS), red blood cell (RBC)/12 h, MOF (Denver MOF score), death, infectious complications, and noninfectious complications. Thrombocytopenia was defined as platelets<80k. Logistic regression was applied to identify independent predictors of MOF and death. RESULTS: Mean+/-standard error of the mean ISS, age, and RBC were 29.3+/-11.3; 37.4 years+/-16.6 years; and 4.4 units+/-5 units. MOF developed in 346 patients (24%) and 118 patients (8%) died. Thrombocytopenia occurred in 35% of patients within 48-hour postinjury and was associated with a significant increase in ISS, RBC transfused, and age. Logistic regression confirmed that thrombocytopenia was a major independent risk factor for all adverse outcomes with an odds ratio of 2.4 for developing MOF and 3.4 for death. After adjustment for these factors, a relative increase in platelet count from day 3 to day 10 was associated with a significantly lower likelihood of MOF and death. CONCLUSION: Early postinjury thrombocytopenia is an independent risk factor for MOF, death, and other complications. Following platelet count dynamics over the first several days postinjury can help predict which high-risk patient will develop these adverse outcomes. PMID- 21307742 TI - Selective nonoperative management of anterior abdominal stab wounds: 1992-2008. AB - BACKGROUND: The use of selective nonoperative management for anterior abdominal stab wounds has evolved into a readily accepted practice. Multiple reports have shown this strategy to be both safe and effective. However, there is a paucity of long-term studies. METHODS: A retrospective review was performed of all trauma patients presenting for anterior abdominal stab wounds at a Level I trauma center during a 17-year time period. Primary outcomes were the percentage of patients undergoing an exploratory laparotomy and the negative laparotomy rate. RESULTS: A total of 7,033 patients sustained a stab wound with 1,961 involving the anterior abdomen. The percentage of patients undergoing exploratory laparotomy decreased during the study period from 64.8% to 37.6% (overall 45.8%). The negative laparotomy rate decreased from 21.3% to 8.6% (overall 18.7%). The negative laparotomy rate of patients who underwent exploratory laparotomy immediately did not change over time (13.8%), whereas the negative laparotomy rate of those patients who underwent exploratory laparotomy in a delayed fashion decreased from 25.0% to 6.25%. The overall mortality was 1.9%, with 6.2% mortality for patients undergoing an immediate laparotomy, 0.7% for patients undergoing a delayed laparotomy, and 0.0% for patients managed nonoperatively (p<0.04). The mean length of hospital stay was 6.6 days+/-0.5 days, with a mean of 9.4 days+/-0.9 days in patients undergoing an immediate laparotomy, 8.1 days+/-0.5 days in patients undergo a delayed laparotomy, and 3.8 days+/-0.2 days in patients managed nonoperatively (p<0.001). CONCLUSIONS: Selective nonoperative management for stab wounds to the anterior abdomen is associated with a decreased operative rate and decreased negative laparotomy rate over time. Selective nonoperative management is both safe and effective for anterior abdominal stab wounds. PMID- 21307743 TI - Posttraumatic contrast-induced acute kidney injury: minimal consequences or significant threat? AB - BACKGROUND: Recent enthusiasm for the use of iodinated contrast media and progressive adaption of modern imaging techniques suggests an increased risk of contrast-induced acute kidney injury (CIAKI) in trauma patients. We hypothesized that CIAKI incidence would be higher than that previously reported. METHODS: A 1 year retrospective review of our prospective database was performed. Low-osmolar, nonionic, iodinated intravascular (IV) contrast was used exclusively. CIAKI was defined as serum creatinine>0.5 mg/dL, or >25% increase from baseline within 72 hours of admission. The association between CIAKI and risk factors was explored. RESULTS: Of 3,775 patients, 1,184 (31.4%) received IV contrast and had baseline and follow-up serum creatinine. Median age was 38 years (range, 18-95 years) and median Injury Severity Score (ISS) was 16. A total of 8% of patients had history of diabetes mellitus. CIAKI was identified in 78 (6.6%). One patient required long-term hemodialysis. In univariable analysis, age>65 years (p=0.01), history of diabetes mellitus (p=0.01), initial creatinine>1.5 mg/dL (p=0.01), ISS>=16 (p=0.04), and initial systolic blood pressure<90 mm Hg (p=0.01) were identified as risk factors for CIAKI. Of note, no association with the dose of IV contrast>=250 mL and CIAKI was identified (p=0.95). A multiple logistic regression model identified higher age, male gender, systolic blood pressure<90 mm Hg, and higher ISS as risk factors for CIAKI. In-hospital mortality was significantly higher in the CIAKI group (9.0% vs. 3.2%, p=0.02). After adjusting for covariates, CIAKI was not significantly associated with in-hospital mortality. CONCLUSION: Current trauma management places patients at substantial risk for CIAKI, and risk stratification can be assessed by common clinical criteria. IV contrast dose alone is not an independent associated risk factor. How these data would be extrapolated to an older cohort remains to be determined. PMID- 21307744 TI - The significance of a serum creatinine in defining renal function in seriously injured and septic patients. AB - BACKGROUND: Most current analyses of multiple organ failure after injury use the serum creatinine (SCr) as a surrogate for defining renal insufficiency (RI) or renal failure (RF). This study correlates SCr with glomerular filtration rate, renal perfusion, and renal excretion in injured and septic patients. METHODS: The 289 injured patients were in shock for an average of 32 minutes and received an average of 13.9 transfusions by the end of the operation. The 34 septic patients were in shock for an average of 23 minutes and received 8.4 crystalloid during operation. The renal studies included (SCr), inulin clearance (CIn), and creatinine clearance (CCr), renal plasma flow (CPAH), renal blood flow, and the clearance of sodium (CNa++), osmolar clearance (COsm), and urine output. All clearance studies followed the classic methodologies described by Homer Smith, including weight-guided leading dose, steady-state serum levels, and urine collections made exactly 15 minutes after serum collections. RESULTS: The average SCr in 289 trauma and septic patients was 1.23 mg/dL and 1.3 mg/dL, respectively. The average CCr was 106 mL/min and 103 mL/min, whereas the average CIn was 96 mL/min and 95 mL/min, respectively. The CIn correlated (p<0.0005) with CCr in all patients, whereas the CIn was lower than CCr due to the tubular excretion of creatinine. For the group of patients with RI (CIn between 10 and 30 mL/min) and nonoliguric RF (CIn<10 mL/min), the average CCr was 3.1. Other values in this subgroup included an average CCr 23.6 mL/min, CIn 14.6 mL/min, CPAH 69.9 mL/min, renal blood flow 138 mL/min, CNa 0.7 mL/min, COsm 1.5 mL/min, and urine output 1.4 mL/min. Although nephrectomy in 15 of 36 patients with renal injury or death in 21 patients was associated with a higher SCr, the relationship between SCr and renal function studies remained the same as with survivors and patients without renal injury. The best SCr value for defining RI was 2.4 mg/dL and for RF was 3.1 mg/dL. CONCLUSION: Based on these findings, one can recommend that when SCr data are extracted from large trauma registries, the definition of RI should be inferred when the SCr exceeds 2.4 mg/dL, and RF should be diagnosed when the SCr exceeds 3.1 mg/dL. PMID- 21307745 TI - Routine or protocol evaluation of trauma patients with suspected syncope is unnecessary. AB - BACKGROUND: Syncope is a commonly suspected cause of injury. Patients often undergo extensive testing without proven benefit. In this study, we investigated the utility of an inpatient syncope workup. METHODS: A retrospective review was performed of all admissions to a Level I trauma center after fall or motor vehicle collision in patients older than 50 years and in whom syncope was suspected for the 3-year period ending December 2008. Demographics, diagnostic workup, number of abnormal results, and the frequency of subsequent interventions were recorded. RESULTS: Two thousand one hundred seventy-one patients fulfilled study entry criteria; syncope was suspected in 302. The syncope and nonsyncope groups, respectively, were similar in age (76.9 years+/-12 years vs. 74.8 years+/ 13 years) and female gender (58.3% vs. 58.4%) but differed in Injury Severity Score (7.4+/-5.7 vs. 9.7+/-7.7; p<0.01). Diagnostic workup commonly included electrocardiogram (89.4%), cardiac enzymes (88.7%), echocardiogram (78.8%), and carotid duplex or computed tomography angiography (64.9%). Significant abnormal results were uncommon: cardiac enzymes (2.9%), echocardiogram (3.8%), and carotid imaging (4.6%). Overall only 42 patients (13.9%) required further intervention, and in 29 patients (69%), the intervention was based on the initial history, physical examination, or admitting electrocardiogram. CONCLUSION: Routine inpatient syncope workup has a low yield. Our data suggests that the diagnostic workup should be ordered based on clinical information rather than a standardized workup for all patients with suspected syncope. PMID- 21307746 TI - Early prognosis after severe traumatic brain injury with minor or absent computed tomography scan lesions. AB - BACKGROUND: To assess the prognostic value of corpus callosum lesions (CCL) and brain stem lesions (BSL) in diffuse axonal injury (DAI) patients. METHODS: From December 1989 to December 2008, 102 consecutive patients with pure DAI were admitted to our neurosurgical intensive care unit. Age, gender, Acute Physiology and Chronic Health Evaluation score, Glasgow Coma Score (GCS), pupillary light reactivity on admission, brain magnetic resonance imaging (MRI) 24 hours to 72 hours after trauma and sepsis, shock, adult respiratory distress syndrome, renal failure, neurosurgery, high intracranial pressure during the 6 months posttrauma were studied with multiple logistic regression, and Cox's proportional hazards, respectively, considering the Glasgow Outcome Scale and the time to recovery of consciousness as outcome variables. RESULTS: Four variables predicted unfavorable Glasgow Outcome Scale (likelihood ratio p<0.0001; Area Under the Receiver Operator Curve (AUROC)=0.92; Naglekerke's R=0.64; Goodness-of-Fit p=0.8679): age (5-year odds ratio [OR], 1.44; 95% CI, 1.14-1.82; p=0.002), bilateral absence of light reflexes (OR, 11.11; 95% CI, 2.19-57.67; p=0.004), multiplicity of CCL (OR, 29.23; 95% CI, 7.06-121.01; p<0.001), and multiplicity of BSL (OR, 9.43; 95% CI, 2.44-36.42; p=0.001). Four variables affected time to recovery of consciousness: age (hazard ratio, 0.98; 95% CI, 0.97-0.99; p=0.009), bilateral absence of light reflexes (hazard ratio, 0.51; 95% CI, 0.27-0.97; p=0.041), multiplicity of CCL (hazard ratio, 0.40; 95% CI, 0.25-0.66; p<0.001), and total GCS on admission (hazard ratio, 1.45; 95% CI, 1.23-1.71; p<0.001). CONCLUSIONS: In DAI patients, bad outcome is predicted by age, bilateral absence of pupillary light reflexes, multiplicity of CCL, and BSL on MRI. Time to recovery of consciousness is predicted by age, bilateral absence of light reflexes, multiplicity of CCL on MRI, and GCS on admission. PMID- 21307747 TI - Missed injuries in the era of the trauma scan. AB - BACKGROUND: A rapid computed tomography technique or "trauma scan" (TS) provides high-resolution studies of the head, cervical spine, chest, abdomen, and pelvis. We sought to determine whether TS has decreased missed injuries. A previous study of TS found a 3% missed rate. METHODS: After institutional review board approval, trauma patients from January 2001 through December 2008 were reviewed for delayed diagnosis (DD) of injury to the head, cervical spine, chest, abdomen, or pelvis. Missed extremity injuries were excluded. Injury Severity Score, length of stay, type of injury, outcomes, and days to detection were captured. RESULTS: Of 26,264 patients reviewed, 90 patients had DD, with an incidence of 0.34%. DD most commonly presented on day 2. Injuries included 16 bowel/mesentery, 12 spine, 11 pelvic, 8 spleen, 6 diaphragm, 5 clavicle, 4 scapula, 4 cervical spine, 4 intracranial, 4 sternum, 3 maxillofacial, 3 liver, 2 heart/aorta, 2 vascular, 2 urethra/bladder, 2 pneumothorax, and 2 pancreas/common bile duct. DD resulted in 1 death, 6 prolonged intensive care unit stays, 19 operative interventions, and 38 additional interventions. CONCLUSIONS: TS is an effective way of evaluating trauma patients for intracranial, cervical spine, chest, abdomen, and pelvic injuries that have the potential to impact morbidity and mortality. The incidence of injuries missed in these crucial areas has been reduced at our institution by the use of this radiographic modality. The most common missed injury remains bowel, and so a high index of suspicion and the tertiary survey must remain a mainstay of therapy. PMID- 21307748 TI - Blood levels, apoptosis, and homing of the endothelial progenitor cells after skin burns and escharectomy. AB - BACKGROUND: Skin burns are an acute trauma involving an extensive vascular damage and an intense inflammatory response. Bone marrow-derived circulating endothelial progenitor cells (EPC) are known to migrate to sites of neovascularization in response to mediators (vascular endothelial growth factor and stromal cell derived factor-1) released after trauma and ischemia, to contribute to wound healing, and to increase neovascularization of animal prefabricated flaps. Recent data showed an increase in EPC number in burned patients and a positive correlation between EPC number and total body surface area (TBSA) burnt, but data were limited to the first 5 days after thermal injury. METHODS: By using flow cytometry, we studied EPC (CD34, CD133, CD45, and KDR cells) blood levels, apoptosis, and homing (stromal cell-derived factor-1 receptor expression and CXC chemokine receptor 4) in a 1-month follow-up postburn in 25 patients with >=15% TBSA burnt, at least grade II burns and escharectomy performed at days 5 to 6, with respect to 31 controls. RESULTS: EPC count at admission showed a positive linear correlation with TBSA burnt. The EPC blood levels of the patients were low (50.7 cells/mL+/-61.8 cells/mL) immediately after thermal injury, then increased with two peaks, at day 1 (188.3 cells/mL+/-223.2 cells/mL) and day 12 (253.1 cells/mL+/-430.7 cells/mL) with respect to controls (95.2 cells/mL+/-28.5 cells/mL, p<0.05), and then returned to normal levels in 1 month. EPC apoptotic rate and inflammatory parameters paralleled EPC blood count. No significant variations were found in CXC chemokine receptor 4 expression. CONCLUSIONS: Thermal injury and escharectomy seem to induce an intense response in EPC production. In particular, escharectomy could improve physiologic wound repair by increasing EPC levels. PMID- 21307749 TI - Transfusion-related acute lung injury in a rat model of trauma-hemorrhage. AB - BACKGROUND: Major trauma often causes hemorrhage and predisposes to transfusion related acute lung injury (TRALI). TRALI is a leading cause of transfusion related deaths; however, its pathophysiology is uncertain. In the existing two event models of TRALI, infection (lipopolysaccharide injection) is followed by the infusion of aged blood products. Our objective was to develop a trauma relevant two-event model of TRALI by examining the effect of aged packed red blood cells (PRBC) on lung injury in rats with trauma-hemorrhage. METHODS: Male Lewis rats were used. Rat PRBC were prepared similar to human PRBC. Recipients were implanted with femoral arterial and venous catheters (isoflurane anesthesia) and then subjected to 30% controlled arterial hemorrhage after 16-hour recovery. After a 60-minute shock period, rats were resuscitated with crystalloid and PRBC (0-35 days old; 3:1 ratio) and followed for up to 6 hours. Lung edema was evaluated by Evans blue dye (EBD), protein, and cytokine-induced neutrophil chemoattractant-1 (CINC-1) accumulation in bronchoalveolar lavage fluid, and arterial blood gases were measured (iSTAT). RESULTS: CINC-1 levels increased over time in our PRBC stored for over 21 days. Transfusion survival was reduced, and Evans blue dye, protein, and CINC-1 accumulation in bronchoalveolar lavage fluid were increased in rats transfused with 28-day-old and 35-day-old PRBC compared with the 0-day group. Arterial PO2 and O2 saturation were decreased in rats transfused with 28-day-old and 35-day-old PRBC. However, pH and PCO2 were not different between groups. CONCLUSIONS: These results suggest that transfusion of 28-day-old and 35-day-old PRBC reliably promotes lung edema in a rat model of catheter surgery and hemorrhage. We propose that this model can be used as a trauma-relevant two-event model of TRALI. PMID- 21307750 TI - Role of beta-catenin in regulating microvascular endothelial cell hyperpermeability. AB - BACKGROUND: Paracellular microvascular hyperpermeability occurs mainly because of the disruption of the endothelial adherens junction complex. Vascular endothelial cadherin that consists of an extracellular and intracellular domain to confer cell-cell contact is linked to the actin cytoskeletal assembly through beta catenin. Our objective was to determine the functional role of beta-catenin during paracellular hyperpermeability and to evaluate whether exogenous beta catenin would protect against vascular leak. METHODS: beta-Catenin siRNA (2.5 MUg/mL) was administered to Sprague-Dawley rats through tail vein. FITC-albumin extravasation of the mesenteric postcapillary venules was evaluated after 48 hours using intravital microscopy. Parallel studies using rat lung microvascular endothelial cell monolayers were transfected with beta-catenin siRNA, and hyperpermeability was determined using monolayers after 48 hours. The effectiveness of beta-catenin siRNA was tested using immunofluorescence and Western blot. To study the protective effect of beta-catenin, rat lung microvascular endothelial cell monolayers were transfected with a beta-catenin gene expression construct for 48 hours or a recombinant beta-catenin protein (1 MUg/mL) for 2 hours, followed by transfection with proapoptotic BAK peptide (5 MUg/mL), a known inducer hyperpermeability. RESULTS: beta-Catenin siRNA induced a significant increase in vascular hyperpermeability in vivo (p<0.05) and monolayer permeability (in vitro; p<0.05). beta-Catenin siRNA significantly altered the adherens junction complex and decreased beta-catenin protein levels. beta-Catenin gene expression construct or recombinant beta-catenin protein attenuated BAK induced monolayer hyperpermeability significantly (p<0.05). CONCLUSION: Posttranscriptional gene silencing of beta-catenin leads to vascular hyperpermeability in vivo and monolayer hyperpermeability in vitro. The enhancement of beta-catenin gene expression at the adherens junction or exogenous introduction of beta-catenin protein shows protection against vascular hyperpermeability. PMID- 21307752 TI - A novel approach to continuous airway humidity for endotracheal tube or tracheostomy patients: combination of oxygen-driven jet nebulization and flow regulation. PMID- 21307751 TI - Intravenous injection of mesenteric lymph produced during hemorrhagic shock decreases RBC deformability in the rat. AB - OBJECTIVE: To test the hypothesis that gut-derived factors carried in trauma hemorrhagic shock (T/HS) lymph are sufficient to induce red blood cells (RBC) injury, to investigate their potential mechanisms of action, and to define the time post-T/HS that these factors appear in the lymph. METHODS: Mesenteric lymph collected from T/HS or trauma-sham shock (T/SS) rats over different time periods was injected intravenously into male rats at a rate of 1 mL/h for 3 hours. RBC deformability was measured using laser-assisted ektacytometer to calculate the elongation index. From the shear-stress elongation curve, the stress required for the erythrocytes to reach 50% of their maximal elongation was also determined. RBC deformability was measured before lymph infusion and at 1 hour and 3 hours after the initiation of lymph infusion. The effect of the lymph samples (5% v/v) was also determined in vitro by incubating naive whole blood with the lymph samples. The potential role of T/HS lymph-induced RBC oxidant injury mediated by inducible nitric oxide synthase (iNOS)-generated oxidants and/or white blood cells (WBC) was investigated using iNOS inhibitors and WBC depletion, respectively. In all the in vivo studies, five to seven rats were studied per group. RESULTS: The intravenous injection of T/HS lymph but not T/SS lymph caused in vivo RBC injury. The biological activity of T/HS lymph varied over time with the RBC-injurious factors being produced only during the first 3 hours postshock. The in vivo inhibition of iNOS did not prevent lymph-induced RBC injury. T/HS lymph incubated in vitro with naive whole blood resulted in RBC injury, but this injury was not observed in blood depleted of WBC. CONCLUSIONS: These results indicate that T/HS lymph produced during the initial 3-hour postshock period is sufficient to induce RBC injury in otherwise normal rats and that the lymph induced RBC injury is not dependent on activation of the iNOS pathway but seems to require WBC. PMID- 21307753 TI - Candidemia in burn patients: figures and facts. PMID- 21307754 TI - Survival of a patient with trauma-induced mucormycosis using an aggressive surgical and medical approach. AB - BACKGROUND: Mucormycosis is a deadly angioinvasive fungal infection that is increasing in incidence. Gastrointestinal and abdominal involvement is rare, has higher mortality rates, and is frequently diagnosed late. METHODS: We report a patient who sustained multiple gunshot wounds to the chest and abdomen and subsequently developed omental and hepatic mucormycosis. He underwent 14 abdominal washouts and several liver debridements, and he received combination therapy with amphotericin B and micafungin. RESULTS: The patient survived the disease, with negative cultures and pathology at the last washout, and underwent skin grafting. He is clinically improved and remains on oral antifungals as an outpatient. CONCLUSIONS: Mucormycosis should be considered in trauma patients with persistent signs of infection after lavage and antibiotics, especially when necrosis or atypical wound presentations are noted. Approaches such as ours using aggressive surgical management and intensive antifungal administration should be instituted once the diagnosis is suspected. PMID- 21307755 TI - Practice management guidelines for management of hemothorax and occult pneumothorax. PMID- 21307756 TI - The Firle eye magnet during the industrial revolution. PMID- 21307757 TI - Traumatic type A dissection. PMID- 21307758 TI - Acute aortic rupture after a trans-spinal gunshot injury. PMID- 21307759 TI - Recombinant activated factor VII--"lifesaving or surgeon correcting"? PMID- 21307760 TI - Is routine chest X-ray necessary before chest tube removal? PMID- 21307761 TI - Open abdomen and pancreatitis. PMID- 21307764 TI - Peristaltic pneumatic compression of the legs reduces fluid demand and improves hemodynamic stability during surgery: a randomized, prospective study. AB - BACKGROUND: Perioperative fluid restriction might be beneficial in specific clinical settings. In this prospective, randomized and blinded study, we assessed whether peristaltic pneumatic compression of the legs can support restrictive fluid management strategies by reducing intraoperative fluid demand and improving hemodynamic stability. METHODS: Seventy patients scheduled for minor surgery were randomly assigned to receive either intraoperative peristaltic pneumatic compression or placebo compression. Both groups received fluid therapy according to a goal-directed protocol with a crystalloid base rate of 2 ml . kg-1 . h-1 and bolus infusions of 250 ml crystalloids triggered by hypotension, tachycardia, or high Pleth Variability Index. RESULTS: Patients treated with peristaltic pneumatic compression received less intravenous fluid: median (interquartile range) 286 (499) versus 921 (900) ml (P < 0.001), resulting in a median difference of 693 ml (95% CI, 495-922 ml) and a median difference of 8.4 ml/kg (95% CI, 5.3-11.5 ml; P < 0.001). After the anesthesia induction phase, median overall infusion rates were 12.2 (14.1) ml . kg-1 . h-1 in the control group and 1.9 (0.4) ml . kg-1 . h-1 in the pneumatic peristaltic compression group (P < 0.001). Among patients treated with pneumatic peristaltic compression, the median cumulative time of hypotension was shorter (0 [12.5] vs. 22.6 [22.8] min; P = 0.002), fewer hypotensive events were recorded (39 vs. 137; P = 0.001), and median lowest individual systolic pressure was higher (92 [8] vs. 85 [16] mmHg; P = 0.002). CONCLUSIONS: This study demonstrates that peristaltic pneumatic compression of the legs significantly improves hemodynamic stability and reduces fluid demand during minor surgery. PMID- 21307765 TI - Hypotension during fluid-restricted abdominal surgery: effects of norepinephrine treatment on regional and microcirculatory blood flow in the intestinal tract. AB - BACKGROUND: Vasopressors, such as norepinephrine, are frequently used to treat perioperative hypotension. Increasing perfusion pressure with norepinephrine may increase blood flow in regions at risk. However, the resulting vasoconstriction could deteriorate microcirculatory blood flow in the intestinal tract and kidneys. This animal study was designed to investigate the effects of treating perioperative hypotension with norepinephrine during laparotomy with low fluid volume replacement. METHODS: Twenty anesthetized and ventilated pigs were randomly assigned to a control or treatment (norepinephrine) group. Both groups received 3 ml . kg-1 . h-1 Ringer's lactate solution. In addition, the norepinephrine group received norepinephrine to stepwise increase blood pressure to 65 and 75 mmHg. Regional blood flow was measured in the splanchnic arteries. In the small bowel and colon, microcirculatory blood flow was measured using laser Doppler flowmetry. Intestinal tissue oxygen tension was measured with intramural Clark-type electrodes. RESULTS: Hepatosplanchnic and kidney blood flow remained unchanged after reversal of arterial hypotension to a mean arterial pressure of 75 mmHg with norepinephrine. For the norepinephrine group versus the control group, the mean +/- SD microcirculatory blood flow in the jejunum (96 +/- 41% vs. 93 +/- 18%) and colon (98 +/- 19% vs. 97 +/- 28%) and intestinal tissue oxygen tension (jejunum, 45 +/- 13 vs. 43 +/- 5 mmHg; colon, 50 +/- 10 vs. 45 +/- 8 mmHg) were comparable. CONCLUSIONS: In this model of abdominal surgery in which clinical conditions were imitated as close as possible, treatment of perioperative hypotension with norepinephrine had no adverse effects on microcirculatory blood flow or tissue oxygen tension in the intestinal tract. PMID- 21307766 TI - Pulmonary vasoconstrictive and bronchoconstrictive responses to anaphylaxis are weakened via beta2-adrenoceptor activation by endogenous epinephrine in anesthetized rats. AB - BACKGROUND: Patients treated with propranolol, a nonselective beta-adrenoceptor antagonist, have increased incidence and severity of anaphylaxis. We determined whether beta1- or beta2-adrenoceptor antagonist modulated pulmonary vasoconstriction and bronchoconstriction in rat anaphylactic hypotension. METHODS: Anesthetized ovalbumin-sensitized male Sprague-Dawley rats were randomly allocated to the following pretreatment groups (n = 7/group): (1) sensitized control (nonpretreatment), (2) propranolol, (3) the selective beta2-adrenoceptor antagonist ICI 118,551, (4) the selective beta1-adrenoceptor antagonist atenolol, and (5) adrenalectomy. Shock was induced by an intravenous injection of the antigen. Mean arterial pressure, pulmonary arterial pressure, left atrial pressure, central venous pressure, portal venous pressure, airway pressure, and aortic blood flow were continuously measured. RESULTS: In either sensitized control or atenolol-pretreated rats, mean arterial pressure and aortic blood flow decreased substantially, whereas pulmonary arterial pressure and airway pressure did not increase soon after antigen injection. In contrast, in rats pretreated with either propranolol, ICI 118,551, or adrenalectomy, airway pressure significantly increased by 14 cm H2O, and pulmonary arterial pressure by 7.5 mmHg after antigen injection. At 2.5 min after antigen injection, the plasma concentration of epinephrine increased 14-fold in the sensitized rats except for the adrenalectomy group. Portal venous pressure after antigen injection increased by 16 mmHg similarly in all sensitized rats. All of the sensitized control group and two of the atenolol group were alive for 60 min after antigen injection, whereas all rats of the propranolol, ICI 118,551, and adrenalectomy groups died within 50 min after antigen injection. CONCLUSIONS: The pulmonary vasoconstrictive and bronchoconstrictive responses to systemic anaphylaxis were weakened via beta2-adrenoceptor activation by epinephrine endogenously released from the adrenal gland in the anesthetized Sprague-Dawley rats. PMID- 21307767 TI - Inflammation confers dual effects on nociceptive processing in chronic neuropathic pain model. AB - BACKGROUND: Although inflammation induces pain, immune cells also produce mediators that can effectively counteract it. To further elucidate the role of the immune response, we analyzed the relationship of pain behavior, several inflammatory signals, and opioid peptides using partial sciatic nerve ligation in mice at different levels of immunocompromise. METHODS: Sciatic nerves of C57BL/6C, nonobese diabetic (NOD), or nonobese diabetic-severe combined immune deficiency (NOD-SCID) mice were partially ligated. Responses to mechanical and radiant heat stimuli were observed. Inflammation was detected by immunohistochemistry and flow cytometry. Inflammatory cytokines and opioid peptides were analyzed using real-time polymerase chain reaction and enzyme linked immunosorbent assay or immunostaining. RESULTS: Inflammation in immunocompromised mice was subordinate when compared with that seen in C57BL/6C mice. In addition, immunocompromised mice had less pain hypersensitivity at early stages. Whereas proinflammatory tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta), interleukin 6 (IL-6), and interferon-gamma (IFN gamma), as well as antiinflammatory interleukin 1 receptor antagonist (IL-1Ra), interleukin 4 (IL-4), interleukin 10 (IL-10), and interleukin 13 (IL-13) cytokine expression and protein were increased in C57BL/6C mice, they were lower in immunocompromised mice. Although enkephalin, dynorphin, and beta-endorphin messenger RNA expression also increased in C57BL/6C mice, peaking on day 14, this result was not observed in immunocompromised mice. CONCLUSION: The contribution of inflammation to nerve injury is complex with biphasic modulation. During the early phase, a wide range of proinflammatory cytokines are released, leading to enhanced pain. In contrast, the analgesic effect of opioid peptides and antiinflammatory cytokines was more predominate in the later phases of injury, leading to attenuated pain responses. PMID- 21307768 TI - Rats exposed to isoflurane in utero during early gestation are behaviorally abnormal as adults. AB - BACKGROUND: Preclinical evidence suggests that commonly used anesthetic agents induce long-lasting neurobehavioral changes when administered early in life, but there has been virtually no attention to the neurodevelopmental consequences for the fetus of maternal anesthesia. This study tested the hypothesis that fetal rats exposed to isoflurane during maternal anesthesia on gestational day 14, which corresponds to the second trimester in humans, would be behaviorally abnormal as adults. METHODS: Timed, pregnant rats were randomly assigned on gestational day 14 to receive 1.4% isoflurane in 100% oxygen (n = 3) or 100% oxygen (n = 2) for 4 h. Beginning at 8 weeks of age, male offspring (N = 12-14 in control and anesthesia groups, respectively) were evaluated for spontaneous locomotor activity, hippocampal-dependent learning and memory (i.e., spontaneous alternations, novel object recognition, and radial arm maze), and anxiety (elevated plus maze). RESULTS: Isoflurane anesthesia was physiologically well tolerated by the dams. Adult rats exposed prenatally to isoflurane were not different than controls on spontaneous locomotor activity, spontaneous alternations, or object recognition memory, but made more open arm entries on the elevated plus maze and took longer and made more errors of omission on the radial arm maze. CONCLUSIONS: Rats exposed to isoflurane in utero at a time that corresponds to the second trimester in humans have impaired spatial memory acquisition and reduced anxiety, compared with controls. This suggests the fetal brain may be adversely affected by maternal anesthesia, and raises the possibility that vulnerability to deleterious neurodevelopmental effects of isoflurane begins much earlier in life than previously recognized. PMID- 21307769 TI - ED(50) and ED(95) of intrathecal bupivacaine in morbidly obese patients undergoing cesarean delivery. AB - BACKGROUND: It has been suggested that morbidly obese parturients may require less local anesthetic for spinal anesthesia. The aim of this study was to determine the effective dose (ED(50)/ED(95)) of intrathecal bupivacaine for cesarean delivery in morbidly obese patients. METHODS: Morbidly obese parturients (body mass index equal to or more than 40) undergoing elective cesarean delivery were enrolled in this double-blinded study. Forty-two patients were randomly assigned to receive intrathecal hyperbaric bupivacaine in doses of 5, 6, 7, 8, 9, 10, or 11 mg (n = 6 per group) coadministered with 200 MUg morphine and 10 MUg fentanyl. Success (induction) was defined as block height to pinprick equal to or more than T6 and success (operation) as success (induction) plus no requirement for epidural supplementation throughout surgery. The ED(50)/ED(95) values were determined using a logistic regression model. RESULTS: ED(50) and ED(95) (with 95% confidence intervals) for success (operation) were 9.8 (8.6-11.0) and 15.0 (10.0-20.0), respectively, and were similar to corresponding values of a nonobese population determined previously using similar methodology. We were unable to measure ED(50)/ED(95) values for success (induction) because so few blocks failed initially, even at the low-dose range. There were no differences with regard to secondary outcomes (i.e., hypotension, vasopressor use, nausea, and vomiting). CONCLUSIONS: Obese and nonobese patients undergoing cesarean delivery do not appear to respond differently to modest doses of intrathecal bupivacaine. This dose-response study suggests that doses of intrathecal bupivacaine less than 10 mg may not adequately ensure successful intraoperative anesthesia. Even when the initial block obtained with a low dose is satisfactory, it will not guarantee adequate anesthesia throughout surgery. PMID- 21307770 TI - Practice guidelines for preoperative fasting and the use of pharmacologic agents to reduce the risk of pulmonary aspiration: application to healthy patients undergoing elective procedures: an updated report by the American Society of Anesthesiologists Committee on Standards and Practice Parameters. PMID- 21307771 TI - Physiological control of intraaorta pump based on heart rate. AB - Because of the special structures of intraaorta pump, the pressure and blood flow sensors cannot be implanted in the blood pump. Moreover, the cardiovascular pump is a very complex system that has no accurate model but much uncertainty and disturbance. Hence, the conventional control algorithm cannot achieve good performance. To overcome this problem, on one hand, a cardiovascular pump model is established. The heart rate in this model is chosen as a controlled variable that is a nonlinear function of the mean arterial pressure. On the other hand, a fuzzy logic feedback control algorithm, which maintains the actual heart rate tracking the desired heart rate, is designed. Computer simulations are performed to verify the robustness and dynamic characters of the controller. The simulation results demonstrate that the controller can maintain the actual heart rate tracking the desired one without static error. When the desired heart rate changed from 100 to 80 bpm, the settling time is <10 seconds. When the peripheral resistance increases from 1.0 to 0.7 mm Hg/ml, the settling time is <10 seconds. PMID- 21307772 TI - Transcatheter aortic valve replacement: where will we be in 5 years? AB - PURPOSE OF REVIEW: Transcatheter aortic valve implantation (TAVI) has developed in less than 2 decades to be a viable procedure, carving out a niche position in our armamentarium to treat high-risk patients with aortic valve disease. Rapid advances are occurring in prosthesis design, catheter delivery system, imaging, and the hybrid operating room. RECENT FINDINGS: The PARTNER (Placement of AoRTic traNscathetER valve) randomized trial, cohort B confirms the superiority of the transfemoral TAVI compared with standard medical therapy with regard to overall survival and cardiac functional status. Major stroke and vascular complications, however, remain higher in the transfemoral TAVI group. Large European registries of both the transapical and transfemoral TAVI are reporting improved procedural success and early survival. The CoreValve and SAPIEN valves remain the forerunners, with accumulating evidence for use, and published 3-year prosthesis durability data for the latter. SUMMARY: Evidence is accumulating in support of TAVI for high-risk nonoperative aortic stenosis. Even before the PARTNER cohort A results, comparing TAVI and conventional aortic valve replacement, become available, the next generation devices and technological improvements are well underway to make the procedure even more reproducible. PMID- 21307773 TI - Genetics of the myeloproliferative neoplasms. AB - PURPOSE OF REVIEW: Since the discovery of the JAK2V617F mutation in 2005, an increasing number of somatic and germline genetic events responsible for myeloproliferative neoplasm (MPN) pathogenesis have been uncovered. The purpose of this review is to outline the most recent discoveries of the genetic alterations found in patients with MPNs. RECENT FINDINGS: In addition to the JAK2V617F mutation, additional mutations in the JAK-STAT pathway have been discovered including a series of mutations in exon 12 of JAK2, the thrombopoietic receptor gene MPL, and in the gene encoding the JAK-STAT inhibitory adaptor protein LNK. Additionally, mutations in genes which appear to affect the epigenome of MPN patients have been discovered including mutations in TET2, IDH1/ 2, EZH2, and ASXL1. Lastly, some insights into the genetic events which contribute to transformation of a chronic MPN phenotype to acute myeloid leukemia have been elucidated, including deletion of the transcription factor Ikaros. SUMMARY: The spectrum of genetic abnormalities found in the classic MPNs has increased over the last 6 years and somatic mutations in JAK2, MPL, LNK, TET2, EZH2, ASXL1, and IDH1/2 have all been described. Despite this, the initiating genetic events responsible for the development of MPNs is still not totally understood. PMID- 21307774 TI - Spectral-domain optical coherence tomography for the diagnosis and follow-up of glaucoma. AB - PURPOSE OF REVIEW: As spectral-domain optical coherence tomography (SD-OCT) progressively replaces time-domain OCT (TD-OCT) in the clinical and research setting, several commercially available instruments and new software upgrades for glaucoma diagnosis and progression analysis have been developed. Over the last year, several studies have been performed to assess the diagnostic performance of most of these instruments necessitating a review of their findings. RECENT FINDINGS: When compared with the measurements provided by TD-OCT, the conventional peripapillary circular scans by SD-OCT, which aim to measure the retinal nerve fiber layer (RNFL) thickness, show higher repeatability and similar diagnostic sensitivity. New software capabilities, such as the RNFL deviation map of Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA) or the macular Ganglion Cell Complex scan of RTVue (Optovue, Fremont, CA), provide complementary information that enhances our ability to discriminate between healthy and glaucomatous eyes. SUMMARY: SD-OCT-based instruments represent a technological advancement in the diagnosis of glaucoma. Improved repeatability will facilitate more reliable follow-up and progression analysis. PMID- 21307775 TI - Effects of extreme tonotopic mismatches between bilateral cochlear implants on electric pitch perception: a case study. AB - OBJECTIVES: Recent studies suggest that pitch perceived through cochlear implants (CIs) changes with experience to minimize spectral mismatches between electric and acoustic hearing. This study aimed to test whether perceived spectral mismatches are similarly minimized between two electric inputs. DESIGN: Pitch perception was studied in a subject with a 10-mm CI in one ear and a 24-mm CI in the other ear. Both processors were programmed to allocate information from the same frequency range of 188-7938 Hz, despite the large differences in putative insertion depth and stimulated cochlear locations between the CIs. RESULTS: After 2 and 3 years of experience, pitch-matched electrode pairs between CIs were aligned closer to the processor-provided frequencies than to cochlear position. CONCLUSIONS: Pitch perception may have adapted to reduce perceived spectral discrepancies between bilateral CI inputs, despite 2-3 octave differences in tonotopic mapping. PMID- 21307776 TI - The erythropoietin receptor: molecular structure and hematopoietic signaling pathways. AB - The process of erythropoiesis in the fetal liver and adult bone marrow is regulated by the hormone erythropoietin (Epo), which is produced in the kidney at low levels under homeostatic conditions. Defects in Epo production result in severe anemia; use of recombinant hormone has improved the lives of patients with renal failure or anemia because of bone marrow suppression. Deletion of the Epo gene in mice leads to embryonic lethality at days 13 to 15, coincident with the establishment of definitive (adult-type) erythropoiesis and underscoring the absolute necessity of Epo function in vivo. Epo has proven to be a successful pharmaceutical agent, one of the early triumphs of recombinant protein technology. Because of its clinical importance, a great deal of attention has focused on the molecular mechanisms of Epo-regulated erythropoiesis. This review highlights the basic concepts of Epo signal transduction within the hematopoietic system, the major site of Epo action in vivo. PMID- 21307777 TI - Association among microalbuminuria and oxidative stress biomarkers in patients with type 2 diabetes. AB - AIM: Hyperglycemia in diabetes mellitus (DM) may be one of the most important factors responsible for the development of oxidative stress, which promotes the main complications in DM patients. Therefore, this study evaluated if the hyperglycemia could be related to oxidative stress biomarkers, lipid profile, and renal function in type 2 diabetes patients without clinic complications. METHODS: Plasmatic malondialdehyde (MDA), serum protein carbonyl (PCO), serum creatinine levels, microalbuminuria, glycated hemoglobin, and lipid profile were analyzed in 37 type 2 diabetic patients and 25 subjects with no diabetes. RESULTS: Serum creatinine levels were within the reference values, but microalbuminuria presented increased levels in all the patients compared with controls (P < 0.05) and above of the reference values. The MDA, PCO, low-density lipoprotein, and triglyceride levels showed positive correlation with microalbuminuria levels. Moreover, glycated hemoglobin presented positive correlation with MDA, PCO, and microalbuminuria levels. CONCLUSIONS: The hyperglycemia could be responsible for the increase of the microalbuminuria levels and for the oxidation process in lipids and proteins in DM patients. Therefore, we suggested that the microvascular lesion is a direct consequence from hyperglycemia and an indirect one from the increased oxidative stress. Malondialdehyde and protein carbonyl levels could be suggested as additional biochemical evaluation to verify tissue damage in type 2 DM patients. PMID- 21307780 TI - Reversed halo sign after radiofrequency ablation of a lung nodule. AB - We report a case of the "reversed halo sign" 6 weeks after radiofrequency ablation (RFA) of a lung neoplasm in an 80-year-old man. The "reversed halo sign," first described on computed tomography in cryptogenic organizing pneumonia, has later been described as being associated with a wide range of pulmonary pathologies, including paracoccidiodomycosis, tuberculosis, lymphomatoid granulomatosis, Wegener granulomatosis, invasive pulmonary fungal infections, and sarcoidosis. Although a number of computed tomography findings have been reported after RFA of both primary lung tumors and pulmonary metastases, this case demonstrates that the reversed halo sign may also occur after RFA. PMID- 21307778 TI - Molecular mechanism of vitamin D in the cardiovascular system. AB - Vitamin D deficiency is a global health problem that has various adverse consequences. Vitamin D is mainly synthesized in the skin by sunlight (UV light) irradiation; therefore, vitamin D status is influenced by geographic locations, seasonal changes, and skin pigmentations. The kidney is involved in the biosynthesis of 1,25-dihydroxyvitamin D and the reuptake of filtered 25 hydroxyvitamin D from the proximal tubules, thus, vitamin D deficiency is highly prevalent in patients with kidney disease who have renal insufficiency. There is a growing body of epidemiological and clinical evidence in the literature that links vitamin D deficiency to cardiovascular disease. The discovery of the vitamin D hormone functioning as an endocrine inhibitor of the renin-angiotensin system provides an explanation for this association. This review will discuss the mechanism underlying the connection between vitamin D and cardiovascular disease and its physiological and therapeutic implications. PMID- 21307779 TI - Effect of hyperglycemia on human monocyte activation. AB - Our recent study defined the chemokine-induced human monocyte signaling under normoglycemic condition. To explore the hyperglycemia-induced monocyte signaling, we performed adhesion, migration, and transmigration assays on human monocytes obtained from THP-1 cell line in the presence of normal (5 mM) and high (10 and 20 mM) glucose concentrations without chemokines. We observed augmented (P < 0.01) monocyte adhesion to human umbilical vein endothelial cell monolayer at 10 than 5 mM glucose with no further increase at 20-mM glucose concentration (P < 0.07 vs 10 mM; P < 0.01 vs 5 mM). But incremental increases in monocyte migration (P < 0.01), transmigration (P < 0.01), and stress fiber response (P < 0.01) were observed at 10- and 20-mM glucose concentrations in comparison to 5-mM glucose concentrations. We found gradational increase (P < 0.01) in phosphorylation of Akt(S473) and glycogen synthase kinase (GSK3beta(S9)) in hyperglycemia (10 and 20 mM) when compared with 5 mM glucose. Furthermore, hyperglycemia (both 10 and 20 mM)-treated monocyte showed up-regulated phosphorylation of p101 and p110gamma subunits of PI-3 kinase in comparison to 5 mM glucose. Hyperglycemia-induced monocyte migration was restored to basal levels in the presence of PI-3 kinase inhibitor, LY. These observations imply that modest hyperglycemia per se, as is commonly observed in diabetic individuals, is a potent stimulator of monocyte activity even without chemokines. PMID- 21307781 TI - Flat-panel detector computed tomography imaging: observer performance in detecting pulmonary nodules in comparison with conventional chest radiography and multidetector computed tomography. AB - PURPOSE: The aim of this study was to compare the detectability of lung nodules on images obtained with a flat-panel detector computed tomography (FPD-CT) system and by chest radiographs (CXRs) using receiver-operating characteristic (ROC) analysis. MATERIALS AND METHODS: FPD-CT was conducted with the patients in the sitting position. For the CXR study, the patients stood erect. Our study population consisted of 26 individuals ranging in age from 50 to 83 years. The reference standard was based on the interpretations obtained by consensus of 2 radiologists on multidetector CT images for the presence or absence of nodules. Four other radiologists independently assessed and recorded the absence or presence of lung nodules and their location on FPD-CT and CXR images. ROC analysis was used to evaluate lung nodule detectability by both imaging modalities. RESULTS: Two radiologists identified 34 nodules whose diameter was 5 to 42 mm (mean, 19.3 mm) in 23 of the 26 study participants on the multidetector CT images. Overall, analysis of variance for ROC analysis showed that FPD-CT was significantly better in detecting nodules than CXR (P=0.02). The estimated mean Az value was 0.9818+/-0.0083 with FPD-CT and 0.7610+/-0.0908 with CXR. The sensitivity for nodule detection on FPD-CT and CXR images was 79.4% and 33.8%, respectively. CONCLUSION: The detectability of pulmonary nodules was better on images of FPD-CT than on CXRs. PMID- 21307783 TI - Neurosurgery simulation. PMID- 21307784 TI - Spinal cord stimulation for thalamic or central pain. PMID- 21307785 TI - High-frequency pallidal stimulation for camptocormia in Parkinson disease: case report. AB - BACKGROUND AND IMPORTANCE: Camptocormia is characterized by abnormal flexion of the thoracolumbar spine that increases during upright posture and abates in the recumbent position and has been reported to occur in patients with Parkinson disease. Camptocormia causes significant spinal and abdominal pain, impairment of balance, and social stigma. CLINICAL PRESENTATION: A 57-year-old woman with Parkinson disease developed severe camptocormia, which did not improve with trials of antiparkinsonian and muscle relaxant medications. The patient was successfully treated with bilateral globus pallidus interna deep brain stimulation surgery under general anesthesia. High-frequency neuromodulation afforded relief of camptocormia and improvement in Parkinson disease symptoms. CONCLUSION: Camptocormia in Parkinson disease may represent a form of dystonia and can be treated effectively with chronic pallidal neuromodulation. PMID- 21307786 TI - Onyx pulmonary artery embolization after treatment of a low-flow dural arteriovenous fistula: case report. AB - BACKGROUND AND IMPORTANCE: Endovascular management of dural arteriovenous fistulas (DAVFs) has become an accepted primary and often definitive therapy. We present the first documented case of Onyx pulmonary embolism after embolization of a low-flow DAVF. CLINICAL PRESENTATION: A 63-year-old man presented with subarachnoid hemorrhage secondary to a DAVF. Computed tomographic angiography, magnetic resonance imaging, and initial conventional angiogram were negative. A repeat angiogram demonstrated a DAVF, which was cured with Onyx embolization. A routine chest computed tomography after intervention revealed an asymptomatic Onyx embolization cast in a subsegmental pulmonary artery. CONCLUSION: Endovascular treatment options include transarterial embolization with microcoils, polyvinyl alcohol particles, n-butyl-2cyanoacrylate, and Onyx (ev3 Neurovascular, Irvine, California). Complications associated with the use of Onyx are low but include embolizate pulmonary embolism. Patients often remain asymptomatic, but for symptomatic patients, conservative treatment options usually result in resolution of symptoms. PMID- 21307787 TI - Pott disease in a 13-month-old: case report. AB - BACKGROUND AND IMPORTANCE: Tuberculosis (TB) is a common disease worldwide that is caused by Mycobacterium tuberculosis. TB of the spine is the most common site of bony infection and is often referred to as Pott disease. To the best of our knowledge, our case represents the youngest patient with naturally acquired Pott disease in the United States. CLINICAL PRESENTATION: A 13-month-old boy presented with paraplegia and a known diagnosis of TB. His evaluation revealed a kyphotic gibbus deformity in the midthoracic region associated with severe spinal cord compression. The patient underwent urgent decompressive laminectomies, T2-T4 transpedicular corpectomies, placement of an anterior tibial strut graft, and posterior instrumentation with sublaminar wires and a Steinmann pin. At his 18 month follow-up, the patient was ambulating 5 steps at a time independently, and his kyphotic deformity showed no sign of progression. CONCLUSION: Pott disease can occur in very young children and presents a unique challenge when a patient presents with a neurological deficit and unstable deformity requiring surgical intervention. PMID- 21307788 TI - Community-associated methicillin-resistant Staphylococcus aureus-infected chronic scalp wound with exposed dura in a 10-year-old boy: vacuum-assisted closure is a feasible option: case report. AB - BACKGROUND AND IMPORTANCE: Since the introduction of vacuum-assisted closure (VAC) in 1997, it has been used successfully in treating difficult wounds, including spinal wounds and wounds in pediatric patients. There are no reports on VAC therapy in pediatric patients on the scalp, especially with exposed dura. This report describes a 10-year-old boy with a chronic wound of the scalp with exposed dura after multiple neurosurgical interventions who was treated successfully with VAC. CLINICAL PRESENTATION: A 10-year-old mentally disabled boy with Apert syndrome suffered from a chronic wound with community-associated methicillin-resistant Staphylococcus aureus (MRSA) infection after multiple neurosurgeon operations. For wound closure, VAC therapy was initiated on the bony defect with exposed dura. The wound healed successfully, and the MRSA disappeared. CONCLUSION: The aims of VAC therapy are formation of new granulation tissue, wound cleansing, and bacterial clearance. In this case, the VAC device was excellent for temporary coverage of the defect and for wound cleaning, and it allowed a thick bed of granulation tissue to form over the dura, even with minimal constant negative pressure. The application and management were feasible even in a mentally disabled child. With this experience, we are encouraged to use the VAC device in difficult wounds, even in the head and neck area in children, and to bring this treatment into the outpatient clinic. PMID- 21307789 TI - Navigated brain stimulation for preoperative cortical mapping in paretic patients: case report of a hemiplegic patient. AB - BACKGROUND AND IMPORTANCE: Navigated brain stimulation (NBS) is an emerging technology that can be used for preoperative mapping of the motor cortex. It combines conventional transcranial magnetic stimulation with neuronavigation and achieves high precision by taking into account all relevant physical factors. In contrast to functional imaging technologies, NBS does not rely on voluntary patient movements for cortical mapping. Thus, NBS can be used even on patients with severe motor impairment. CLINICAL PRESENTATION: This article presents the case of a hemiplegic elderly woman with a brain tumor in the motor cortex. Preoperative NBS surprisingly demonstrated intact corticospinal tracts in the hemiplegic patient. The results modified the surgical strategy. Direct cortical stimulation was performed intraoperatively. The direct cortical stimulation results were in agreement with the preoperative NBS findings, and the clinical success of the surgery exceeded expectations. CONCLUSION: NBS can be used for preoperative mapping in plegic patients. Even more important, this case report discusses why tumor resection surgery based on NBS may sometimes lead to substantially better clinical outcomes than surgery planned according to functional imaging technologies. PMID- 21307790 TI - Reactive expansive intracerebral process as a complication of endovascular coil treatment of an unruptured intracranial aneurysm: case report. AB - BACKGROUND AND IMPORTANCE: As a consequence of the increased use of endovascular coiling of intracranial aneurysms, a growing number of case reports on complications are being reported. This article presents a case with a previously undescribed complication of coil treatment: a reactive, noninfectious process after coiling of an unruptured intracranial aneurysm CLINICAL PRESENTATION: A 60 year-old hypertensive woman with hypoxic encephalopathy after respiratory arrest following a total thyroidectomy had extensive intentional myoclonus and reduced quality of life as sequelae. An asymptomatic 15-mm internal carotid artery bifurcation aneurysm was discovered on magnetic resonance imaging (MRI) 6 months after the thyroidectomy. After documented growth, the aneurysm was treated endovascularly with bare platinum Guglielmi detachable coils. Three months later, an expansion in the right frontal lobe cranially to the coiled aneurysm was observed. The lesion had grown at the 12-month postcoil MRI and, because of its increasing mass effect, was resected through a craniotomy 2 years after the coiling. As a result of lesion regrowth and cyst formation, she underwent a new craniotomy 5 years later with excision of the now 21-mm large coiled aneurysm, internal carotid artery clip reconstruction, and lesionectomy. Five months postoperatively, the process had not recurred. No signs of malignancy or infection were observed during the histological evaluation of the resected tissue. The tissue is described as a reactive, noninfectious process, most likely resulting from the coils acting as a foreign body. CONCLUSION: This article presents a case with a reactive expansive intracerebral process as a complication to endovascular coil treatment of an unruptured intracranial aneurysm. PMID- 21307791 TI - Relationship of growth to aneurysm rupture in asymptomatic aneurysms <= 7 mm: a systematic analysis of the literature. AB - BACKGROUND: The apparent paradox of natural history data suggesting low rupture risk of small asymptomatic aneurysms and the median size of aneurysm rupture remains unexplained. Aneurysm growth rates and their potential relationship with rupture risk have not been well examined in natural history studies. OBJECTIVE: To examine the question of whether small asymptomatic aneurysms <= 7 mm that are followed up over time rupture and to determine the relationship between aneurysm growth and rupture. METHODS: We reviewed all publications on unruptured aneurysms published from 1966 to 2009. We then selected all aneurysms <= 7 mm for which measurements were reported for at least 2 time points and for which initial asymptomatic status and ultimate outcome (rupture vs unruptured) were reported. Using the Mann-Whitney U test, we compared absolute diameter annual growth rate. RESULTS: Our search retrieved 64 aneurysms. Thirty aneurysms ruptured during follow-up, of which 27 were enlarged before rupture (90%). Thirty-four aneurysms did not rupture, of which 24 enlarged during follow-up (71%). There was a statistically significant trend toward larger absolute diameter growth for ruptured aneurysms vs unruptured aneurysms (3.89 +/- 2.34 vs 1.79 +/- 1.02 mm; P < .001), respectively. Annual growth rates for aneurysms for the 2 groups, however, were not statistically different (27.46 +/- 18.76 vs 32.00 +/- 29.30; P = .92). CONCLUSION: Small aneurysms are prone to growth and rupture. Aneurysm rupture is more likely to occur in aneurysms with larger absolute diameter growth, but rupture can also occur in the absence of growth. The annual growth rate in both groups suggests that rate of growth of aneurysms is highly variable and unpredictable, justifying treatment or close diagnostic follow-up. PMID- 21307792 TI - Anterior thoracolumbar corpectomies: approach morbidity with and without an access surgeon. AB - BACKGROUND: Anterior approaches for thoracolumbar corpectomies can have significant morbidity. Spine surgeons have historically performed their own anterior approaches, but recently access surgeons are being used more frequently. OBJECTIVE: To evaluate the morbidity rates of approaches performed by an access surgeon and by an approach-trained spinal neurosurgeon. METHODS: From 2004 to 2008, 46 patients undergoing anterior thoracolumbar corpectomies (levels T2-L5) by the senior author (D.C.) were identified and subdivided into 2 groups based on whether an access surgeon was involved. Nine patients were excluded, leaving 37 patients in the final analysis. Blood loss, operative times, length of hospital stay, complications, and neurological outcomes were evaluated. RESULTS: Eighteen patients had anterior spinal access by an approach-trained spinal neurosurgeon, and 19 patients underwent the approach by an access surgeon. Surgeries performed by the spinal neurosurgeon alone were comparable to those performed by an access surgeon with respect to operative time, days spent in the hospital, blood loss, complication rates, and improvement in neurological function. CONCLUSION: There appears to be no increased morbidity of anterior approaches performed by an approach-trained spinal neurosurgeon compared with approaches performed by an access surgeon in terms of operative time, complication rate, and improvement in neurological function. PMID- 21307793 TI - A review of laboratory and clinical data supporting the safety and efficacy of cyclosporin A in traumatic brain injury. AB - For decades, cyclosporin A (CsA) has proved to be safe and effective for use in transplantation. In the past 10 years, this agent has shown neuroprotective effects in animal models of traumatic brain injury (TBI). This review article provides a critical overview of the literature on CsA neuroprotective effects in animal studies and current findings of clinical trials in the treatment of TBI with an emphasis on the possible CsA molecular mechanism of action. Animal data provide compelling evidence of the therapeutic benefits of CsA in TBI, but the outcome indices are heterogeneous with respect to the animal model of TBI as well as the route, dose, and timing of CsA administration. Similarly, clinical studies (phase II trials) adapting almost identical patient inclusion criteria have demonstrated the safety of CsA use in TBI, but the clinical trials are also heterogeneous based on study design, especially with regard to the variable timing of CsA administration after TBI. In view of the translational shortcomings of the preclinical studies and the rather pilot nature of the limited clinical trials that recently reached phase III, we offer guidance on the future directions of laboratory investigations on CsA that could improve the safety and efficacy of this agent in subsequent larger clinical trials. PMID- 21307794 TI - Treatment of severe trigeminal headache in patients with pituitary adenomas. AB - BACKGROUND: The incidence of headache in patients with pituitary adenomas is high, and the underlying pathological mechanisms are not completely understood. OBJECTIVE: We tested the efficacy of percutaneous ganglion block and trigeminal rhizotomy in the treatment of severe trigeminal/autonomic headache associated with pituitary tumors. METHODS: Eleven patients treated surgically for pituitary adenomas in whom intractable trigeminal headaches developed were enrolled in the study and underwent ictal cerebral single-photon emission computed tomography before starting treatment. Initially, all patients underwent a 6-month medical treatment trial. Patients who did not experience improvement in headache severity, addressed by the Headache Impact Test-6 scale, underwent trigeminal percutaneous ganglion blockade. Two patients subsequently underwent trigeminal balloon rhizotomy. RESULTS: Among the 11 patients, 6 did not have improved Headache Impact Test-6 scale scores after 6 months of treatment with medications and underwent trigeminal ganglion blockade. Significant improvement in headache severity was noted in 3 of them. Long-term response was obtained in 1 patient, and the other 2, in whom the response was transient, were then successfully treated with trigeminal rhizotomy. Cerebral single-photon emission computed tomography showed increased uptake in the thalamus/hypothalamus region in patients who responded well to manipulation of the trigeminal-hypothalamic system. CONCLUSION: Percutaneous ganglion blockade and trigeminal rhizotomy may be promising alternative options for the treatment of severe headache in selected patients with pituitary adenomas. PMID- 21307795 TI - Seizures and the natural history of World Health Organization Grade II gliomas: a review. AB - OBJECTIVE: The majority of adults with low-grade gliomas have seizures. Despite the frequency of seizures as initial symptoms and symptoms of later disease, seizures in relation to the natural course of low-grade gliomas have received little attention. METHODS: In this review, we provide an update of the literature on the prognostic impact of preoperative seizures and discuss the tumor- and treatment-related factors affecting seizure control at later stages of the disease. RESULTS: Seizures occur most frequently at disease presentation and predict a more favorable outcome. Initial seizures are correlated with tumor location and possibly indirectly to the molecular profile of the tumor. About 50% of all patients with seizures at presentation continue to have seizures before surgery. Maximal tumor resection, including resection of epileptic foci, is a valuable strategy for improving seizure control. In addition, radiotherapy and chemotherapy, as single therapies or in combination with surgery, have shown beneficial effects in terms of seizure reduction. Recurrent seizures after macroscopically complete tumor resection may be a marker for accelerated tumor growth. Recurrent seizures after an initial transient stabilization after radiotherapy and/or chemotherapy may be a marker for anaplastic tumor transformation. CONCLUSION: Preoperative seizures likely reflect, apart from tumor location, intrinsic tumor properties as well. Change in seizure control in individual patients is frequently associated with altered tumor behavior. Including seizures and seizure control as clinical parameters is recommended in future trials of low-grade gliomas to further establish the prognostic value of these symptoms and to identify the factors affecting seizure control. PMID- 21307796 TI - Thrombospondin-1 modulates the angiogenic phenotype of human cerebral arteriovenous malformation endothelial cells. AB - BACKGROUND: The management of cerebral arteriovenous malformation (AVM) is challenging, and invasive therapies place vital intracranial structures at risk of injury. The development of noninvasive, pharmacologic approaches relies on identifying factors that mediate key angiogenic processes. Previous studies indicate that endothelial cells (ECs) derived from cerebral AVM (AVM-ECs) are distinct from control brain ECs with regard to important angiogenic characteristics. OBJECTIVE: To determine whether thrombospondin-1 (TSP-1), a potent angiostatic factor, regulates critical angiogenic features of AVM-ECs and to identify factors that modulate TSP-1 production in AVM-ECs. METHODS: EC proliferation, migration, and tubule formation were evaluated with bromodeoxyuridine incorporation, Boyden chamber, and Matrigel studies, respectively. TSP-1 and inhibitor of DNA binding/differentiation 1 (Id1) mRNA levels were quantified with microarray and quantitative real-time polymerase chain reaction analyses. TSP-1 protein expression was measured using Western blotting, immunohistochemical, and enzyme-linked immunosorbent assay techniques. The mechanistic link between Id1 and TSP-1 was established through small interfering RNA-mediated knockdown of Id1 in AVM-ECs followed by Western blot and enzyme-linked immunosorbent assay experiments assessing TSP-1 production. RESULTS: AVM-ECs proliferate faster, migrate more quickly, and form disorganized tubules compared with brain ECs. TSP-1 is significantly down-regulated in AVM ECs. The addition of TSP-1 to AVM-EC cultures normalizes the rate of proliferation and migration and the efficiency of tubule formation, whereas brain ECs are unaffected. Id1 negatively regulates TSP-1 expression in AVM-ECs. CONCLUSION: These data highlight a novel role for TSP-1 in the pathobiology of AVM angiogenesis and provide a context for its use in the clinical management of brain AVMs. PMID- 21307797 TI - A long peripheral nerve autograft model in the sheep forelimb. AB - BACKGROUND: Autologous nerve grafts remain the only proven means of bridging lengthy gaps in peripheral nerve. However, there is very little literature on a reliable long (> 5 cm) nerve autograft animal model. OBJECTIVE: To establish a reproducible long nerve gap and autograft animal model that is clinically relevant but not cost prohibitive. METHODS: The extent of nerve regeneration and electrophysiological recovery after segmental repair of a long nerve defect was evaluated with a sheep model. Thirteen Suffolk sheep were used. An 18-cm segment of radial sensory nerve was harvested from the forelimb, trimmed, divided into 2 equal segments of 7 cm each, and microsurgically repaired to a surgically created defect of 5 cm in the median nerve within the same forelimb. Electrophysiological studies were performed on 6 sheep at 6 months and 6 sheep at 9 months. Samples of the grafted segments were obtained for histology, immunohistochemistry, and morphometric analyses. Electric studies were also performed on an uninjured median nerve of a control animal in tissue that was similarly harvested and processed. RESULTS: At 6 and 9 months, all sheep had recordable robust nerve action potentials. Nerve conduction velocity and amplitude were slightly decreased compared with control, but the difference was statistically insignificant. Histomorphometric assessment demonstrated that the autografts contained a large number of regenerating axons through graft fascicles in all animals. CONCLUSION: The median nerve in the sheep forelimb is a reproducible and reliable model for assessing regeneration through long peripheral nerve grafts. PMID- 21307799 TI - Differential efficacy of electric motor cortex stimulation and lesioning of the dorsal root entry zone for continuous vs paroxysmal pain after brachial plexus avulsion. AB - BACKGROUND: Pain after traumatic brachial plexus avulsion (BPA) has 2 distinct patterns: continuous burning pain and paroxysmal shooting pain. Lesioning of the dorsal root entry zone (DREZotomy) is more effective for paroxysmal than continuous pain. It is unknown, however, whether electric motor cortex stimulation (EMCS) has a differential effect on continuous vs paroxysmal BPA pain. OBJECTIVE: To analyze the differential effect of EMCS and DREZotomy on continuous vs paroxysmal BPA pain in a series of 15 patients. METHODS: Fifteen patients with intractable BPA pain underwent DREZotomy alone (n = 7), EMCS alone (n = 4), or both procedures (n = 4). Pain intensity was evaluated with the Visual Analog Scale, and separate ratings were recorded for paroxysmal and continuous pain. Pain relief was categorized as excellent (> 75% pain relief), good (50% 75%), or poor (< 50%). Favorable outcome was defined as good or better pain relief. RESULTS: Eight patients had EMCS; 7 were followed up for an average of 47 months. Of those 7 patients, 3 (42%) with continuous pain had favorable outcomes compared with no patients with paroxysmal pain. Eleven patients had DREZotomy; 10 were followed up for an average of 31 months. Of those 10 patients, 7 (70%) with paroxysmal pain had favorable outcomes compared with 2 (20%) with continuous pain. CONCLUSION: EMCS was ineffective for paroxysmal pain but moderately effective for continuous pain. DREZotomy was highly effective for paroxysmal pain but moderately effective for continuous pain. It may be prudent to use EMCS for residual continuous pain after DREZotomy. PMID- 21307798 TI - Induction of angiogenesis and modulation of vascular endothelial growth factor receptor-2 by simvastatin after traumatic brain injury. AB - BACKGROUND: Our previous studies demonstrated that simvastatin reduced neuronal death, increased neurogenesis, and promoted functional recovery after traumatic brain injury (TBI). OBJECTIVE: To investigate the effect of simvastatin on angiogenesis after TBI and the related signaling pathways. METHODS: Saline or simvastatin (1 mg/kg) was administered orally to rats starting at day 1 after TBI or sham surgery and then daily for 14 days. Rats were sacrificed at 3 and 14 days after treatment. Brain sections and tissues were prepared for immunohistochemical staining, enzyme-linked immunosorbent assay, and Western blot analysis. Cultured rat brain microvascular endothelial cells were subjected to oxygen-glucose deprivation followed by immunocytochemical staining with phallotoxins and vascular endothelial growth factor receptor-2 (VEGFR-2). Western blot analysis was carried out to examine the simvastatin-induced activation of the v-akt murine thymoma viral oncogene homolog (Akt) signaling pathway. The expression of VEGFR-2 was detected by enzyme-linked immunosorbent assay. RESULTS: Simvastatin significantly increased the length of vascular perimeter, promoted the proliferation of endothelial cells, and improved the sensorimotor function after TBI. Simvastatin stimulated endothelial cell tube formation after oxygen-glucose deprivation in vitro. VEGFR-2 expression in both brain tissues and cultured rat brain microvascular endothelial cells was enhanced after simvastatin treatment, which may be modulated by activation of Akt. Akt-dependent endothelial nitric oxide synthase phosphorylation was also induced by simvastatin in vivo and in vitro. CONCLUSION: Simvastatin augments TBI-induced angiogenesis in the lesion boundary zone and hippocampus and improves functional recovery. Simvastatin also promotes angiogenesis in vitro. These beneficial effects on angiogenesis may be related to simvastatin-induced activation of the VEGFR-2/Akt/endothelial nitric oxide synthase signaling pathway. PMID- 21307800 TI - Neuroprotection with intraventricular brain-derived neurotrophic factor in rat venous occlusion model. AB - BACKGROUND: The increasing number of neurosurgical procedures for elderly patients and the development of skull base neurosurgery have increased interest in cerebral venous injury that might occur in a neurosurgical setting. Brain derived neurotrophic factor (BDNF) may have neuroprotective effects against cerebral venous ischemia. OBJECTIVE: To investigate the intraventricular effects of BDNF infusion on infarct size, suppression of apoptosis, and regional cerebral blood flow (rCBF) in cerebral venous ischemic lesions in a rat 2-vein occlusion model. METHODS: Thirty-three male Wistar rats were randomly divided into BDNF treated and vehicle control groups; each group was further randomly divided into 2-day and 7-day postocclusion groups. BDNF (2.1 MUg/day) or vehicle was delivered continuously via intraventricular infusion pumps. Two adjacent contralateral cortical veins were then photochemically occluded. Two and 7 days after occlusion, we histologically measured ratios of infarct volume to contralateral hemisphere volume and counted (2-day group) terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick-end labeling (TUNEL)-positive apoptotic cells in the penumbra. rCBF was measured via full-field laser perfusion imaging. RESULTS: The mean infarct volume after venous occlusion was significantly smaller in BDNF-treated rats than in controls at 2 days (1.49 +/- 1.44% vs 3.66 +/- 1.51%; P < .05) and 7 days (0.93 +/- 0.47% vs 1.69 +/- 0.58%; P < .05). Two days after occlusion, there were significantly fewer TUNEL-positive apoptotic cells in the BDNF-treated rats (17.0 +/- 15.1) than in the controls (39.0 +/- 19.6; P < .05). There were no differences in rCBF. CONCLUSION: After 2-vein occlusion, continuous intraventricular administration of BDNF protected the cerebral cortex against apoptosis and reduced infarct size without affecting rCBF. PMID- 21307801 TI - Packed red blood cell transfusion and decreased mortality in intracerebral hemorrhage. AB - BACKGROUND: Accumulating data suggest that anemia worsens outcomes in critically ill patients, including those with subarachnoid and intracerebral hemorrhage (ICH). Although packed red blood cell (PRBC) transfusion appears to increase brain tissue oxygen, it is unknown whether such transfusions, which are commonly administered in patients with intracranial hemorrhage, alter outcome. OBJECTIVE: Following up on our observation that anemia is associated with poor outcome in patients with ICH, we investigated whether PRBC transfusion was associated with any benefit. METHODS: Five hundred forty-six consecutive subjects were identified from an ongoing single-center, prospective cohort study of nontraumatic ICH over a 6-year period. Clinical and radiographic characteristics, laboratory values including admission and daily mean hemoglobin values, and all instances of PRBC transfusion were recorded. Aggressiveness of care was assessed by whether the patient had a "do not resuscitate" order activated during hospitalization. The primary endpoint was 30-day survival. RESULTS: Anemia was present in 144 of 546 patients (26%) on admission and developed subsequently in an additional 250, leaving just 152 of 546 patients (28%) who never developed anemia. PRBC transfusion was administered to 100 patients (18%) during their hospital stay, 98% of whom were anemic. In multivariable analysis, PRBC transfusion was associated with improved survival at 30 days (odds ratio: 2.76; 95% confidence interval: 1.45-5.26; P = .002). CONCLUSION: Anemia develops in the majority of patients with ICH at some point during their hospitalization. PRBC transfusion was associated with improved outcome in these patients. PMID- 21307802 TI - Pediatric heart murmurs: evaluation and management in primary care. AB - The ability of the NP to discern pediatric heart murmurs is critical for accurate assessment of etiology, appropriate diagnostic testing, and prudent referral when indicated. This review includes an overview of cardiac assessment, distinguishing features of innocent and pathologic murmurs, differential diagnosis of murmurs, and current referral recommendations. PMID- 21307803 TI - Gait disorder in older adults: is it NPH? AB - In normal pressure hydrocephalus (NPH), there is enlargement of the brain's ventricular system due to an excess of cerebrospinal fluid. The triad of symptoms in NPH are gait disorder, cognitive impairment, and urinary continence problems. NPs need to consider the possibility of NPH in older adults with a hypokinetic gait. PMID- 21307804 TI - Building healthy bodies one child at a time. PMID- 21307805 TI - Trichoadenoma of the external auditory canal. PMID- 21307806 TI - Reliability of magnetic resonance imaging performed after intratympanic administration of gadolinium in the identification of endolymphatic hydrops in patients with Meniere's disease. AB - OBJECTIVE: To evaluate the reliability of magnetic resonance imaging performed after intratympanic gadolinium administration in evidencing endolymphatic hydrops in patients with Meniere's disease (MD). PATIENTS: A total of 26 patients (18 male and 8 female subjects, aged 25-78 yr; median age, 56 yr) with definite MD and 12 subjects (8 male and 4 female subjects, aged 31-75 yr; median age, 51 yr) with various unilateral non-MD disorders of the inner ear were examined. INTERVENTION: A 0.6-ml solution of gadobutrol (1 mmol/ml), diluted 1:7 in saline, was injected in the affected ear through the inferior-posterior quadrant of the tympanic membrane, using a 22-gauge spinal needle. In 9 MD patients, the contralateral ear also was injected. The patient was kept with the head rotated 45 degrees contralaterally for 30 minutes after each injection. Twenty-four hours later, a 3-dimensional fluid-attenuated inversion recovery magnetic resonance imaging using a 3 Tesla unit was performed. MAIN OUTCOME MEASURE: Perilymphatic enhancement was evaluated in different portions of the labyrinth in MD ears and compared with the outcomes obtained in the non-MD ears. RESULTS: All MD ears showed impaired perilymphatic enhancement of variable degrees. No enhancement defects could be observed in all examined contralateral unaffected ear of the patients with MD, as well as in 11 of the 12 ears of the subjects with various unilateral non-MD disorders. CONCLUSION: Perilymphatic enhancement defect of variable degrees is observed in the pathologic ear of every patient with MD. The consistency of this phenomenon in MD ears and the complete enhancement in most of the ears without MD safely enable to attribute these findings to endolymphatic hydrops. It is likely in the near future that imaging may be used to achieve a certain diagnosis of MD in life. PMID- 21307807 TI - Evaluation of an electrode prototype for atraumatic cochlear implantation in hearing preservation candidates: preliminary results from a temporal bone study. AB - OBJECTIVES: This study aimed to evaluate an atraumatic prototype electrode carrier for cochlear implantation, the FLEX electrode. This electrode is designed to preserve hearing and to achieve a 360-degree insertion. STUDY DESIGN: A cross sectional human temporal bone study was conducted. SETTING: Preliminarily, the prototype electrode was inserted in a scala tympani model to measure the insertion force. Thirteen human temporal bones were acquired postmortem and implanted with the new device using the round window approach. Three of them were implanted under radiologic control to demonstrate the insertion path. After embedding, the remaining 10 temporal bones were sectioned undecalcified and examined macroscopically and histologically. MAIN OUTCOME MEASURES: The insertion force was measured to determine intracochlear resistance peaks. The insertion angle was measured, and the degree of intracochlear trauma was determined. RESULTS: The round window approach caused cochlear trauma in 1 of 10 specimens. An exact 360-degree insertion was achieved in 7 of 10 specimens (mean overall insertion angle, 360 degrees). Radiologic examination and insertion force measurements revealed the smooth and atraumatic insertion. CONCLUSION: The new prototype electrode carrier is suitable for clinical application. It can be handled easily and allows atraumatic 360-degree insertion of all electrode contacts. Therefore, this electrode concept allows good coverage of the cochlea for electrical and additional acoustic stimulation. PMID- 21307808 TI - Murine middle ear inflammation and ion homeostasis gene expression. AB - HYPOTHESIS: Ion homeostasis genes are responsible for the movement of ions and water in the epithelium of the middle ear. BACKGROUND: It is not well known to what extent disruption of ion homeostasis is a factor in the accumulation of middle ear fluid during otitis media. METHODS: Balb/c mice were transtympanically injected with heat-killed Hemophilus influenza bacteria. Untreated and saline injected mice were used as controls. Mice were euthanized at 6, 24, and 72 hours and 1 week after injection, the bullae harvested, and total ribonucleic acid isolated from the middle ear tissues. Ion homeostasis genes were analyzed with real-time quantitative reverse transcription-polymerase chain reaction from the following gene families: Na,K-ATPase, claudins, K transport channels, epithelial Na channels, gap junctions, and aquaporins. Inflammatory genes also were analyzed to document inflammation. RESULTS: All inflammatory genes analyzed were significantly upregulated, more at 6 hours than at 24 hours, with the exception of vascular endothelial growth factor and Mapk8. Most middle ear ion homeostasis genes experienced downregulation because of inflammation. This was most prominent in the aquaporin and Na,K-ATPase genes. Significant upregulation was seen in several genes in response to inflammation and saline independently. CONCLUSION: The innate immune response to bacteria in the middle ear induces expression of several inflammatory genes. Coinciding with this inflammation is the downregulation of numerous ion homeostasis genes that are involved in ion and water transport and maintenance of tight junctions. This may explain the fluid accumulation within the middle ear seen with both acute and chronic otitis media. PMID- 21307809 TI - Arkansas BAHA experience: transcalvarial fixture placement using osseointegration surgical hardware. AB - OBJECTIVE: To determine what factors increase the likelihood of osseointegration failure and implant extrusion with the use of osseointegration surgical hardware, for bone-anchored hearing aids (BAHAs), in children and adults. PATIENTS: A total of 60 patients (42 pediatric [<=19 yr] and 18 adult patients [34-69 yr]) who received osseointegration surgical hardware for a BAHA at Arkansas Children's Hospital from October 2003 to May 2009 or at the University of Arkansas for Medical Sciences from November 2005 to May 2009, respectively. INTERVENTION: BAHA placement using 3- and 4-mm fixtures. MAIN OUTCOME MEASURES: Osseointegration failure with implant extrusion. RESULTS: Fifty-seven loaded fixtures in the pediatric population, and 20 were placed in the adults. We had a 21% pediatric and 0% adult osseointegration failure rate. CONCLUSION: Young age, syndromic status, and failure to penetrate the inner table of the cranium increased the risk of osseointegration failures in children. In some cases, skull thickness provides an inadequate amount of bone for 4-mm fixture placement requiring placement of a 3-mm fixture instead. In these cases, transcalvarial placement of the implanted fixture may decrease the extrusion rate as 3-mm fixtures have been associated with increased rates of implant extrusion. The 3-mm fixtures that were placed in a transcalvarial fashion had a decreased extrusion rate compared with 3 mm fixtures that were surrounded by bone and did not penetrate the inner table of the cranium. Individual patient factors out of the surgeon's control likely play a large role in osseointegration failures as well. This clinical case report encourages transcalvarial fixture insertion when using 3-mm fixtures during placement of osseointegration surgical hardware for BAHAs. PMID- 21307810 TI - Medullary infarction after vertebral artery dissection presenting as acute peripheral vertigo. PMID- 21307811 TI - Sarcoidosis of the middle ear and chronic suppurative otitis media: coexisting conditions? PMID- 21307812 TI - Epithelial migration on the external ear canal wall in normal and pathologic ears. AB - HYPOTHESIS: Epithelial migration on the external auditory canal (EAC) wall is abnormal in ears with keratosis obturans (KO). BACKGROUND: Earlier studies of epithelial migration have focused on the tympanic membrane with scattered information available for epithelial migration on canal walls. This study was undertaken to observe the epithelial migration on the EAC wall in normal ears and in ears with KO. METHODS: Twenty-five subjects with normal ears and 4 with KO were recruited for the study. Colored ink dots were placed around the tympanic annulus at the 12, 3, 6, and 9 o'clock positions. Migration patterns and the rate of travel of these ink dots were examined and photographed until the ink dots reached the bony cartilaginous junction. RESULTS: Fifteen healthy subjects and 1 with bilateral KO completed the study. The ink dots migrated laterally, with a rate of migration in normal ears between 42 and 205 MUm/d. The mean rates for each quadrant, measured clockwise from the 12 o'clock position, were 104.93, 89.80, 72.67, and 109.93 MUm/d, respectively. The pathologic ears exhibited a rate between 88 and 140 MUm/d, and at approximately 4 to 12 weeks after ink application, areas of abnormal desquamation were apparent at the inferior quadrant, leading to a halt in the migration of the ink dot once it reached these sites. CONCLUSION: Epithelial migration occurred in an almost linear pattern in all quadrants, but the speed of migration was relatively slower in the anterior and inferior quadrants of a normal EAC. In the single KO patient, there were areas of normal migration and areas of abnormal keratin resurfacing at the inferior quadrant, which interfered with the migration of ink dots. PMID- 21307813 TI - Vibrant Soundbridge surgery in patients with severe external otitis: complications of a transcanal approach. AB - OBJECTIVE: To evaluate the transcanal surgical implantation of the semi implantable Vibrant Soundbridge (VSB) device in patients with severe external otitis. STUDY DESIGN: Retrospective analysis. METHODS: Long-term postoperative complications and postoperative hearing thresholds were evaluated in 13 adults with bilateral sensorineural hearing loss (average of between 40 and 55 dB HL) and therapy-resistant external otitis after implantation of the VSB by a transcanal surgical method. RESULTS: Postoperative audiometry findings were comparable with those reported after the transmastoidal posterior tympanotomy approach. In 2 patients, the chorda tympani was intentionally sacrificed to maximize the size of the facial recess. Seven postoperative complications occurred in 6 patients (46%) during a mean follow-up period of 51 months: extrusion of the conducting wire into the ear canal (n=5), collapse of the cartilaginous part of the ear canal (n=1), and tympanic membrane perforation (n=1). In the revision operations that added additional layers of fascia for the patients with wire extrusions, repeated extrusion occurred in 3 of 4 cases. CONCLUSION: The transcanal approach for the implantation of the VSB has led to postoperative complications different from those reported after the transmastoidal posterior tympanotomy approach. External otitis should be considered as a contraindication for VSB surgery by the transcanal approach. PMID- 21307814 TI - Cone-beam volumetric tomography for applications in the temporal bone. AB - HYPOTHESIS: Cone beam volumetric tomography (CBVT) has better spatial resolution compared with multi slice computed tomography (MSCT) in temporal bone imaging for superior canal dehiscence (SCD). BACKGROUND: Imaging of SCD has traditionally used MSCT, but the ability to resolve thin bone next to low-radiodensity brain and inner ear fluids at the interface of the superior canal (SC) with the middle cranial fossa can be adversely affected by partial volume averaging, errors in registration of successive slices, and other factors. CBVT may offer advantages in these regards and may have better spatial resolution for this application. METHODS: Five cadaveric temporal bones were scanned using both CBVT and MSCT. The information content at the interface of the SC and the middle cranial fossa was measured for each method using spatial differential transformations. The ability of each method to resolve progressively smaller interfaces between bone and fluid was measured by creating a spatial grating model from a human temporal bone. RESULTS: The information content and spatial resolution were superior for CBVT compared with MSCT. CONCLUSION: The gold standard for diagnosis of SCD has been MSCT, but CBVT may offer improvements in information content and spatial resolution at the interface of the SC and the middle cranial fossa. PMID- 21307815 TI - Spoken word recognition in adolescent cochlear implant users during quiet and multispeaker babble conditions. AB - OBJECTIVE: To assess overall speech intelligibility in adolescent cochlear implant speakers during quiet and multispeaker babble conditions. STUDY DESIGN: A cross-sectional assessment of intelligibility incorporating group (auditory-oral versus total communication speakers), sentence context (high versus low contexts), and background conditions (quiet versus multispeaker babble). SETTING: A camp designed to assess adolescents over a concentrated period. PARTICIPANTS: Fifty-seven adolescents who participated in an earlier study when they were 8 to 9 years old examining functional outcomes of speech perception, speech production, and language were asked to participate in follow-up study. METHODS: Speech intelligibility was assessed by asking the adolescents to repeat sentences. Sentences were digitally edited and played to normal hearing listeners who either provided broad transcriptions of sound accuracy or wrote down the words they understood when the sentences were presented in quiet and in multispeaker babble. MAIN OUTCOME VARIABLE: The dependent variables were percent correct consonants, vowels, and total words identified. RESULTS: Very few substitutions or omissions occurred, resulting in high levels of accuracy for consonants and vowels. Speech intelligibility in quiet was significantly greater than in the multispeaker babble condition. Multispeaker babble decreased performance uniformly across sentence context for the 2 groups. CONCLUSION: Accurate consonant production based on measures of substitutions and omissions fails to account for distortions and allophonic variations. Reductions in speech intelligibility relative to the phoneme correct productions suggest that the allophonic variations related to distortions may influence naive listener's ability to understand the speech of profoundly deaf individuals. PMID- 21307816 TI - No effects of anti-motion sickness drugs on vestibular evoked myogenic potentials outcome parameters. AB - OBJECTIVE: To investigate the effects of meclizine (50 mg), baclofen (10 mg), cinnarizine (20 mg) + dimenhydrinate (40 mg), and promethazine (25 mg) + dextro amphetamine (5 mg) on the parameters of the vestibular evoked myogenic potential (VEMP) test. STUDY DESIGN: Double-blind placebo-controlled prospective randomized trial. SETTING: University hospital. SUBJECTS: Twenty-four (first block: baclofen versus placebo) and 20 healthy male subjects (second block: meclizine, cinnarizine + dimenhydrinate and promethazine + dextro-amphetamine versus placebo). INTERVENTIONS: VEMP test. MAIN OUTCOME MEASURES: Threshold, p13 and n23 latencies, p13-n23 latency difference, p13-n23 peak-to-peak amplitude, mean rectified voltage of the sternocleidomastoid muscle contraction and the corrected amplitude. RESULTS: There were no clinically significant pharmacologic effects on the VEMP outcome parameters. However, there was a statistically significant left right asymmetry after intake of the combination promethazine + d-amphetamine for the parameters p13 and latency difference. CONCLUSION: The absence of clinically significant effects can be explained by the predominant presence of the target receptors for the applied drugs in the medial vestibular nucleus, which receives the lowest grade of saccular projections. It also can be hypothesized that the VEMP methodology and techniques in general do not allow determining pharmacologic effects in a healthy group of subjects because of a too small discriminative power. The left-right asymmetry can be explained by a depressive action of the drugs on the central compensation mechanisms. Because there were no significant differences between the VEMP parameters obtained after intake of the placebos of both blocks, we concluded that there were no training effects. PMID- 21307817 TI - Diagnostic findings in stapes revision surgery--a retrospective of 26 years. AB - OBJECTIVE: The aim of the study is to obtain a detailed overview of the revision findings after stapes operations and to draw conclusions on a stapes prosthesis that can be recommended. STUDY DESIGN: : Retrospective case series. SETTING: Tertiary otologic referral center. METHODS: Approximately 12,000 middle ear operations within a period of 26 years were evaluated. The findings of the revisions were classified into surgeon related, prosthesis related, and other causes. RESULTS: Three hundred forty-three stapes revisions were done. Many different prostheses were found: the most common were Schuknecht prostheses and Teflon platinum, gold, and titanium pistons. Polyethylene strut, Teflon wire pistons, Shea (Teflon) pistons, and other techniques, such as columella or malleovestibulopexy, were rarely found.There are specific findings correlating to certain prostheses: Schuknecht prostheses were too short in 50% of the revisions (surgeon related), Teflon platinum caused necrosis or arrosion of the long incudal process (prostheses related) in 69%, and gold caused reparative granuloma sometimes combined with necosis of the incus in 70% (prostheses related). There was no specific diagnostic finding with titanium pistons, neither surgeon nor material related. CONCLUSION: An analysis of revision findings over an extended observation period can enable middle-ear surgeons to improve their surgical techniques and to select the best suited prosthesis. Self-fabricated stapes prostheses (e.g., Schuknecht) do not conform to required quality standards and should not be used. GoPi, which is no longer available, and TPlPi showed prosthesis-related diagnostic findings. The titanium prostheses used by the authors have proven to be excellently compatible and can therefore be recommended as safe stapes prostheses. PMID- 21307818 TI - High rate of coronary artery abnormalities in adolescents and young adults infected with human immunodeficiency virus early in life. AB - We completed a cross-sectional study of individuals infected with human immunodeficiency virus in early childhood using cardiac magnetic resonance imaging and magnetic resonance angiography. Coronary artery abnormality (CAA) was defined by the presence of luminal narrowing and irregularity of the coronary vessel wall. More than 50% of participants (14/27) had evidence of CAA. Individuals had a high rate of CAA, suggesting possible early atherosclerosis. PMID- 21307819 TI - Transplacental transfer of paclitaxel, docetaxel, carboplatin, and trastuzumab in a baboon model. AB - BACKGROUND: The paucity of data on fetal effects of prenatal exposure to chemotherapy prompted us to study the transplacental transport of commonly used anticancer agents in a pregnant baboon model. METHODS: Single or combination chemotherapy with paclitaxel, docetaxel, carboplatin, and trastuzumab was administered to 9 baboons at a mean (SD) gestational age of 117 (26) days (paclitaxel, 100 mg/m2 [n = 2]; docetaxel, 100 mg/m2 [n = 2]; paclitaxel, 175 mg/m2 with carboplatin, area under the curve of 6 at standard dosage [n = 2] and 50% dosage [n = 1]; docetaxel, 75 mg/m2 with carboplatin, area under the curve 6 [n = 1]; and docetaxel, 75 mg/m2 with trastuzumab, 8 mg/kg [n = 1]). Serial fetal and maternal blood samples, amniotic fluid, maternal urine, and fetal and maternal tissue samples were collected for the first 76 hours after drug infusion. Levels of carboplatin were determined by atomic absorption spectrometry, docetaxel and paclitaxel by high-performance liquid chromatography, and trastuzumab by enzyme-linked immunosorbent assay. RESULTS: Fetal plasma concentrations of carboplatin averaged 57.5% (14.2%) of maternal concentrations (n = 7). Fetal plasma concentrations were 1.5% (0.8%) of maternal concentrations (n = 7). Immediately after ending the infusion, paclitaxel was not detectable in fetal tissues, whereas, after 3 hours, fetal tissues contained 15% of maternal tissue concentrations.Docetaxel could not be detected in fetal blood samples (n = 9). In the first 3 hours after docetaxel infusion, fetal tissues contained 5.0% to 50.0% of maternal tissue concentrations, whereas equal fetal and maternal tissue concentrations were found after 26 and 76 hours.The transplacental passages of trastuzumab were 85.0% and 3.0%, 2 and 26 hours after trastuzumab infusion, respectively. After 26 hours, amniotic fluid contained 36.4% of the fetal plasma concentration. Fetal tissue concentrations varied between 5.0% and 14.0% of the maternal concentration. CONCLUSION: Variable plasma and/or tissue concentrations of taxanes, carboplatin, and trastuzumab were encountered in the fetal compartment. These data are important when cancer treatment is considered during pregnancy and underline the need for long-term follow-up of children after prenatal exposure to these cytotoxic agents. PMID- 21307820 TI - A convenient and safe O-methylation of flavonoids with dimethyl carbonate (DMC). AB - Dietary flavonoids exhibit beneficial health effects. Several epidemiological studies have focused on their biological activities, including antioxidant, antibacterial, antiviral, anti-inflammatory and cardiovascular properties. More recently, these compounds have shown to be promising cancer chemopreventive agents in cell culture studies. In particular, O-methylated flavonoids exhibited a superior anticancer activity than the corresponding hydroxylated derivatives being more resistant to the hepatic metabolism and showing a higher intestinal absorption. In this communication we describe a convenient and efficient procedure in order to prepare a large panel of mono- and dimethylated flavonoids by using dimethyl carbonate (DMC), an ecofriendly and non toxic chemical, which plays the role of both solvent and reagent. In order to promote the methylation reaction under mild and practical conditions, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was added in the solution; methylated flavonoids were isolated in high yields and with a high degree of purity. This methylation protocol avoids the use of hazardous and high toxic reagents (diazomethane, dimethyl sulfate, methyl iodide). PMID- 21307821 TI - Material binding peptides for nanotechnology. AB - Remarkable progress has been made to date in the discovery of material binding peptides and their utilization in nanotechnology, which has brought new challenges and opportunities. Nowadays phage display is a versatile tool, important for the selection of ligands for proteins and peptides. This combinatorial approach has also been adapted over the past decade to select material-specific peptides. Screening and selection of such phage displayed material binding peptides has attracted great interest, in particular because of their use in nanotechnology. Phage display selected peptides are either synthesized independently or expressed on phage coat protein. Selected phage particles are subsequently utilized in the synthesis of nanoparticles, in the assembly of nanostructures on inorganic surfaces, and oriented protein immobilization as fusion partners of proteins. In this paper, we present an overview on the research conducted on this area. In this review we not only focus on the selection process, but also on molecular binding characterization and utilization of peptides as molecular linkers, molecular assemblers and material synthesizers. PMID- 21307822 TI - Special issue: nano-catalysts and nano-technologies for green organic synthesis. AB - Catalysis by transition-metal nanoparticles has undergone an explosive growth during the past decade. This special issue presents the general trends in the current research in this field, the present situation concerning scope and limitations, as well as the future perspectives. Original contributions are also presented on the applications of nano-catalysts to the green synthesis. PMID- 21307823 TI - Discordant results from reverse sequence syphilis screening--five laboratories, United States, 2006-2010. AB - CDC recommends syphilis serologic screening with a nontreponemal test, such as the rapid plasma reagin (RPR) or Venereal Disease Research Laboratory (VDRL) test, to identify persons with possible untreated infection; this screening is followed by confirmation using one of several treponemal tests. Recently, the availability of automatable treponemal enzyme and chemiluminescence immunoassays (EIA/CIA) has led some laboratories to adopt a reverse sequence of screening in which a treponemal EIA/CIA is performed first, followed by testing of reactive sera with a nontreponemal test. To better understand the performance of reverse sequence screening for syphilis, CDC analyzed data from five laboratories that used reverse sequence screening during 2006-2010. This report describes the results of that analysis, which indicated that among sera reactive on initial screening with a treponemal EIA/CIA, 56.7% had a nonreactive RPR test. Among these discordant sera, 31.6% also were nonreactive by treponemal testing using Treponema pallidum particle agglutination (TP-PA) or fluorescent treponemal antibody absorbed (FTA-ABS) tests. Among discordant sera, the rate of nonreactive confirmatory treponemal tests was 2.9 times higher in a population with low prevalence of syphilis, suggesting that the low-prevalence population had a higher percentage of false-positive test results. Although CDC continues to recommend the traditional algorithm with reactive nontreponemal tests confirmed by treponemal testing, in this report CDC offers additional recommendations if reverse sequence syphilis screening is used. PMID- 21307824 TI - Decrease in smoking prevalence--Minnesota, 1999-2010. AB - Following the landmark 1998 settlement of the lawsuit, State of Minnesota versus Philip Morris, Inc., et al., Minnesota implemented a series of tobacco control efforts to limit the harm caused by tobacco use. In 2001, quitline services for tobacco users without health insurance coverage for cessation services were introduced and statewide mass media campaigns publicizing them were initiated. In 2005, Minnesota imposed a $0.75 per pack tax on cigarettes, followed in 2009 by a $0.62 per pack increase in federal excise tax, contributing in large part to a more than $2 increase in the average price of cigarettes. In 2007, a comprehensive, statewide smoke-free law was passed. Using surveillance data from the Minnesota Adult Tobacco Survey (MATS) and cigarette pack sales data, this report examines the effects of these tobacco-related public health efforts. Compared with a 15% decline in national adult smoking prevalence since 1999, adult smoking prevalence in Minnesota decreased 27.1%, from 22.1% in 1999 to 16.1% in 2010. During the same period, per capita cigarette sales in Minnesota decreased 40%. In addition, in 2010 compared with 1999, a higher percentage of adults reported that smoking was restricted in their homes (87.2% versus 64.5%), and adults were less likely to report exposure to secondhand smoke (45.6% versus 67.2%). In the past decade, Minnesota has benefited from sustained tobacco control. Future progress in decreasing adult smoking and reducing exposure to secondhand smoke will depend on a concerted effort across the public health community to keep tobacco control a priority. PMID- 21307825 TI - Examination of the telomere G-overhang structure in Trypanosoma brucei. AB - The telomere G-overhang structure has been identified in many eukaryotes including yeast, vertebrates, and Trypanosoma brucei. It serves as the substrate for telomerase for de novo telomere DNA synthesis and is therefore important for telomere maintenance. T. brucei is a protozoan parasite that causes sleeping sickness in humans and nagana in cattle. Once infected mammalian host, T. brucei cell regularly switches its surface antigen to evade the host's immune attack. We have recently demonstrated that the T. brucei telomere structure plays an essential role in regulation of surface antigen gene expression, which is critical for T. brucei pathogenesis. However, T. brucei telomere structure has not been extensively studied due to the limitation of methods for analysis of this specialized structure. We have now successfully adopted the native in-gel hybridization and ligation-mediated primer extension methods for examination of the telomere G-overhang structure and an adaptor ligation method for determination of the telomere terminal nucleotide in T. brucei cells. Here, we will describe the protocols in detail and compare their different advantages and limitations. PMID- 21307826 TI - Environmentally induced heritable changes in flax. AB - Some flax varieties respond to nutrient stress by modifying their genome and these modifications can be inherited through many generations. Also associated with these genomic changes are heritable phenotypic variations. The flax variety Stormont Cirrus (Pl) when grown under three different nutrient conditions can either remain inducible (under the control conditions), or become stably modified to either the large or small genotroph by growth under high or low nutrient conditions respectively. The lines resulting from the initial growth under each of these conditions appear to grow better when grown under the same conditions in subsequent generations, notably the Pl line grows best under the control treatment indicating that the plants growing under both the high and low nutrients are under stress. One of the genomic changes that are associated with the induction of heritable changes is the appearance of an insertion element (LIS 1) while the plants are growing under the nutrient stress. With respect to this insertion event, the flax variety Stormont Cirrus (Pl) when grown under three different nutrient conditions can either remain unchanged (under the control conditions), have the insertion appear in all the plants (under low nutrients) and have this transmitted to the next generation, or have the insertion (or parts of it) appear but not be transmitted through generations (under high nutrients). The frequency of the appearance of this insertion indicates that it is under positive selection, which is also consistent with the growth response in subsequent generations. Leaves or meristems harvested at various stages of growth are used for DNA and RNA isolation. The RNA is used to identify variation in expression associated with the various growth environments and/or t he presence/absence of LIS-1. The isolated DNA is used to identify those plants in which the insertion has occurred. PMID- 21307827 TI - An isolated retinal preparation to record light response from genetically labeled retinal ganglion cells. AB - The first steps in vertebrate vision take place when light stimulates the rod and cone photoreceptors of the retina. This information is then segregated into what are known as the ON and OFF pathways. The photoreceptors signal light information to the bipolar cells (BCs), which depolarize in response to increases (On BCs) or decreases (Off BCs) in light intensity. This segregation of light information is maintained at the level of the retinal ganglion cells (RGCs), which have dendrites stratifying in either the Off sublamina of the inner plexiform layer (IPL), where they receive direct excitatory input from Off BCs, or stratifying in the On sublamina of the IPL, where they receive direct excitatory input from On BCs. This segregation of information regarding increases or decreases in illumination (the On and Off pathways) is conserved and signaled to the brain in parallel. The RGCs are the output cells of the retina, and are thus an important cell to study in order to understand how light information is signaled to visual nuclei in the brain. Advances in mouse genetics over recent decades have resulted in a variety of fluorescent reporter mouse lines where specific RGC populations are labeled with a fluorescent protein to allow for identification of RGC subtypes and specific targeting for electrophysiological recording. Here, we present a method for recording light responses from fluorescently labeled ganglion cells in an intact, isolated retinal preparation. This isolated retinal preparation allows for recordings from RGCs where the dendritic arbor is intact and the inputs across the entire RGC dendritic arbor are preserved. This method is applicable across a variety of ganglion cell subtypes and is amenable to a wide variety of single-cell physiological techniques. PMID- 21307828 TI - In vivo andin vitro studies of adaptor-clathrin interaction. AB - A major endocytic pathway initiates with the formation of clathrin-coated vesicles (CCVs) that transport cargo from the cell surface to endosomes. CCVs are distinguished by a polyhedral lattice of clathrin that coats the vesicle membrane and serves as a mechanical scaffold. Clathrin coats are assembled during vesicle formation from individual clathrin triskelia , the soluble form of clathrin composed of three heavy and three light chain subunits. Because the triskelion does not have the ability to bind to the membrane directly, clathrin-binding adaptors are critical to link the forming clathrin lattice to the membrane through association with lipids and/or membrane proteins. Adaptors also package transmembrane protein cargo, such as receptors, and can interact with each other and with other components of the CCV formation machinery. Over twenty clathrin adaptors have been described, several are involved in clathrin mediated endocytosis and others localize to the trans Golgi network or endosomes. With the exception of HIP1R (yeast Sla2p), all known clathrin adaptors bind to the N terminal -propeller domain of the clathrin heavy chain. Clathrin adaptors are modular proteins consisting of folded domains connected by unstructured flexible linkers. Within these linker regions, short binding motifs mediate interactions with the clathrin N-terminal domain or other components of the vesicle formation machinery. Two distinct clathrin-binding motifs have been defined: the clathrin box and the W-box. The consensus clathrin-box sequence was originally defined as L[L/I][D/E/N][L/F][D/E] but variants have been subsequently discovered. The W-box conforms to the sequence PWxxW (where x is any residue). Sla1p (Synthetic Lethal with Actin binding protein-1) was originally identified as an actin associated protein and is necessary for normal actin cytoskeleton structure and dynamics at endocytic sites in yeast cells. Sla1p also binds the NPFxD endocytic sorting signal and is critical for endocytosis of cargo bearing the NPFxD signal. More recently, Sla1p was demonstrated to bind clathrin through a motif similar to the clathrin box, LLDLQ, termed a variant clathrin-box (vCB), and to function as an endocytic clathrin adaptor. In addition, Sla1p has become a widely used marker for the endocytic coat in live cell fluorescence microscopy studies. Here we use Sla1p as a model to describe approaches for adaptor-clathrin interaction studies. We focus on live cell fluorescence microscopy, GST-pull down, and co immunoprecipitation methods. PMID- 21307829 TI - A mouse model of in utero transplantation. AB - The transplantation of stem cells and viruses in utero has tremendous potential for treating congenital disorders in the human fetus. For example, in utero transplantation (IUT) of hematopoietic stem cells has been used to successfully treat patients with severe combined immunodeficiency. In several other conditions, however, IUT has been attempted without success. Given these mixed results, the availability of an efficient non-human model to study the biological sequelae of stem cell transplantation and gene therapy is critical to advance this field. We and others have used the mouse model of IUT to study factors affecting successful engraftment of in utero transplanted hematopoietic stem cells in both wild-type mice and those with genetic diseases. The fetal environment also offers considerable advantages for the success of in utero gene therapy. For example, the delivery of adenoviral, adeno-associated viral, retroviral, and lentiviral vectors into the fetus has resulted in the transduction of multiple organs distant from the site of injection with long-term gene expression. in utero gene therapy may therefore be considered as a possible treatment strategy for single gene disorders such as muscular dystrophy or cystic fibrosis. Another potential advantage of IUT is the ability to induce immune tolerance to a specific antigen. As seen in mice with hemophilia, the introduction of Factor IX early in development results in tolerance to this protein. In addition to its use in investigating potential human therapies, the mouse model of IUT can be a powerful tool to study basic questions in developmental and stem cell biology. For example, one can deliver various small molecules to induce or inhibit specific gene expression at defined gestational stages and manipulate developmental pathways. The impact of these alterations can be assessed at various timepoints after the initial transplantation. Furthermore, one can transplant pluripotent or lineage specific progenitor cells into the fetal environment to study stem cell differentiation in a non-irradiated and unperturbed host environment. The mouse model of IUT has already provided numerous insights within the fields of immunology, and developmental and stem cell biology. In this video-based protocol, we describe a step-by-step approach to performing IUT in mouse fetuses and outline the critical steps and potential pitfalls of this technique. PMID- 21307830 TI - Contrast enhanced vessel imaging using microCT. AB - Microscopic computed tomography (microCT) offers high-resolution volumetric imaging of the anatomy of living small animals. However, the contrast between different soft tissues and body fluids is inherently poor in micro-CT images (1). Under these circumstances, visualization of blood vessels becomes a nearly impossible task. To overcome this and to improve the visualization of blood vessels exogenous contrast agents can be used. Herein, we present a methodology for visualizing the vascular network in a rodent model. By using a long-acting aqueous colloidal polydisperse iodinated blood-pool contrast agent, eXIA 160XL, we optimized image acquisition parameters and volume-rendering techniques for finding blood vessels in live animals. Our findings suggest that, to achieve a superior contrast between bone and soft tissue from vessel, multiple-frames (at least 5-8/ frames per view), and 360-720 views (for a full 360 degrees rotation) acquisitions were mandatory. We have also demonstrated the use of a two dimensional transfer function (where voxel color and opacity was assigned in proportion to CT value and gradient magnitude), in visualizing the anatomy and highlighting the structure of interest, the blood vessel network. This promising work lays a foundation for the qualitative and quantitative assessment of anti angiogenesis preclinical studies using transgenic or xenograft tumor-bearing mice. PMID- 21307831 TI - Determination of DNA methylation of imprinted genes in Arabidopsis endosperm. AB - Arabidopsis thaliana is an excellent model organism for studying epigenetic mechanisms. One of the reasons is the loss-of-function null mutant of DNA methyltransferases is viable, thus providing a system to study how loss of DNA methylation in a genome affects growth and development. Imprinting refers to differential expression of maternal and paternal alleles and plays an important role in reproduction development in both mammal and plants. DNA methylation is critical for determining whether the maternal or paternal alleles of an imprinted gene is expressed or silenced. In flowering plants, there is a double fertilization event in reproduction: one sperm cell fertilizes the egg cell to form embryo and a second sperm fuses with the central cell to give rise to endosperm. Endosperm is the tissue where imprinting occurs in plants. MEDEA, a SET domain Polycomb group gene, and FWA, a transcription factor regulating flowering, are the first two genes shown to be imprinted in endosperm and their expression is controlled by DNA methylation and demethylation in plants. In order to determine imprinting status of a gene and methylation pattern in endosperm, we need to be able to isolate endosperm first. Since seed is tiny in Arabidopsis, it remains challenging to isolate Arabidopsis endosperm and examine its methylation. In this video protocol, we report how to conduct a genetic cross, to isolate endosperm tissue from seeds, and to determine the methylation status by bisulfite sequencing. PMID- 21307832 TI - Expired CO2 measurement in intubated or spontaneously breathing patients from the emergency department. AB - Carbon dioxide (CO2) along with oxygen (O2) share the role of being the most important gases in the human body. The measuring of expired CO2 at the mouth has solicited growing clinical interest among physicians in the emergency department for various indications: (1) surveillance et monitoring of the intubated patient; (2) verification of the correct positioning of an endotracheal tube; (3) monitoring of a patient in cardiac arrest; (4) achieving normocapnia in intubated head trauma patients; (5) monitoring ventilation during procedural sedation. The video allows physicians to familiarize themselves with the use of capnography and the text offers a review of the theory and principals involved. In particular, the importance of CO2 for the organism, the relevance of measuring expired CO2, the differences between arterial and expired CO2, the material used in capnography with their artifacts and traps, will be reviewed. Since the main reluctance in the use of expired CO2 measurement is due to lack of correct knowledge concerning the physiopathology of CO2 by the physician, we hope that this explanation and the video sequences accompanying will help resolve this limitation. PMID- 21307833 TI - Microtiter dish biofilm formation assay. AB - Biofilms are communities of microbes attached to surfaces, which can be found in medical, industrial and natural settings. In fact, life in a biofilm probably represents the predominate mode of growth for microbes in most environments. Mature biofilms have a few distinct characteristics. Biofilm microbes are typically surrounded by an extracellular matrix that provides structure and protection to the community. Microbes growing in a biofilm also have a characteristic architecture generally comprised of macrocolonies (containing thousands of cells) surrounded by fluid-filled channels. Biofilm-grown microbes are also notorious for their resistance to a range of antimicrobial agents including clinically relevant antibiotics. The microtiter dish assay is an important tool for the study of the early stages in biofilm formation, and has been applied primarily for the study of bacterial biofilms, although this assay has also been used to study fungal biofilm formation. Because this assay uses static, batch-growth conditions, it does not allow for the formation of the mature biofilms typically associated with flow cell systems. However, the assay has been effective at identifying many factors required for initiation of biofilm formation (i.e, flagella, pili, adhesins, enzymes involved in cyclic-di-GMP binding and metabolism) and well as genes involved in extracellular polysaccharide production. Furthermore, published work indicates that biofilms grown in microtiter dishes do develop some properties of mature biofilms, such a antibiotic tolerance and resistance to immune system effectors. This simple microtiter dish assay allows for the formation of a biofilm on the wall and/or bottom of a microtiter dish. The high throughput nature of the assay makes it useful for genetic screens, as well as testing biofilm formation by multiple strains under various growth conditions. Variants of this assay have been used to assess early biofilm formation for a wide variety of microbes, including but not limited to, pseudomonads, Vibrio cholerae, Escherichia coli, staphylococci, enterococci, mycobacteria and fungi. In the protocol described here, we will focus on the use of this assay to study biofilm formation by the model organism Pseudomonas aeruginosa. In this assay, the extent of biofilm formation is measured using the dye crystal violet (CV). However, a number of other colorimetric and metabolic stains have been reported for the quantification of biofilm formation using the microtiter plate assay. The ease, low cost and flexibility of the microtiter plate assay has made it a critical tool for the study of biofilms. PMID- 21307834 TI - Isolation and in vitro activation of Caenorhabditis elegans sperm. AB - Males and hermaphrodites are the two naturally found sexual forms in the nematode C. elegans. The amoeboid sperm are produced by both males and hermaphrodites. In the earlier phase of gametogenesis, the germ cells of hermaphrodites differentiate into limited number of sperm--around 300--and are stored in a small 'bag' called the spermatheca. Later on, hermaphrodites continually produce oocytes. In contrast, males produce exclusively sperm throughout their adulthood. The males produce so much sperm that it accounts for > 50% of the total cells in a typical adult worm. Therefore, isolating sperm from males is easier than from that of hermaphrodites. Only a small proportion of males are naturally generated due to spontaneous non-disjunction of X chromosome. Crossing hermaphrodites with males or more conveniently, the introduction of mutations to give rise to Him (High Incidence of Males) phenotype are some of strategies through which one can enrich the male population. Males can be easily distinguished from hermaphrodites by observing the tail morphology. Hermaphrodite's tail is pointed, whereas male tail is rounded with mating structures. Cutting the tail releases vast number of spermatids stored inside the male reproductive tract. Dissection is performed under a stereo microscope using 27 gauge needles. Since spermatids are not physically connected with any other cells, hydraulic pressure expels internal contents of male body, including spermatids. Males are directly dissected on a small drop of 'Sperm Medium'. Spermatids are sensitive to alteration in the pH. Hence, HEPES, a compound with good buffering capacity is used in sperm media. Glucose and other salts present in sperm media help maintain osmotic pressure to maintain the integrity of sperm. Post-meiotic differentiation of spermatids into spermatozoa is termed spermiogenesis or sperm activation. Shakes, and Nelson previously showed that round spermatids can be induced to differentiate into spermatozoa by adding various activating compounds including Pronase E. Here we demonstrate in vitro spermiogenesis of C. elegans spermatids using Pronase E. Successful spermiogenesis is pre-requisite for fertility and hence the mutants defective in spermiogenesis are sterile. Hitherto several mutants have been shown to be defective specifically in spermiogenesis process. Abnormality found during in vitro activation of novel Spe (Spermatogenesis defective) mutants would help us discover additional players participating in this event. PMID- 21307835 TI - A high throughput screen for biomining cellulase activity from metagenomic libraries. AB - Cellulose, the most abundant source of organic carbon on the planet, has wide ranging industrial applications with increasing emphasis on biofuel production (1). Chemical methods to modify or degrade cellulose typically require strong acids and high temperatures. As such, enzymatic methods have become prominent in the bioconversion process. While the identification of active cellulases from bacterial and fungal isolates has been somewhat effective, the vast majority of microbes in nature resist laboratory cultivation. Environmental genomic, also known as metagenomic, screening approaches have great promise in bridging the cultivation gap in the search for novel bioconversion enzymes. Metagenomic screening approaches have successfully recovered novel cellulases from environments as varied as soils (2), buffalo rumen (3) and the termite hind-gut (4) using carboxymethylcellulose (CMC) agar plates stained with congo red dye (based on the method of Teather and Wood (5)). However, the CMC method is limited in throughput, is not quantitative and manifests a low signal to noise ratio (6). Other methods have been reported (7,8) but each use an agar plate-based assay, which is undesirable for high-throughput screening of large insert genomic libraries. Here we present a solution-based screen for cellulase activity using a chromogenic dinitrophenol (DNP)-cellobioside substrate (9). Our library was cloned into the pCC1 copy control fosmid to increase assay sensitivity through copy number induction (10). The method uses one-pot chemistry in 384-well microplates with the final readout provided as an absorbance measurement. This readout is quantitative, sensitive and automated with a throughput of up to 100X 384-well plates per day using a liquid handler and plate reader with attached stacking system. PMID- 21307836 TI - High sensitivity 5-hydroxymethylcytosine detection in Balb/C brain tissue. AB - DNA hydroxymethylation is a long known modification of DNA, but has recently become a focus in epigenetic research. Mammalian DNA is enzymatically modified at the 5(th) carbon position of cytosine (C) residues to 5-mC, predominately in the context of CpG dinucleotides. 5-mC is amenable to enzymatic oxidation to 5-hmC by the Tet family of enzymes, which are believed to be involved in development and disease. Currently, the biological role of 5-hmC is not fully understood, but is generating a lot of interest due to its potential as a biomarker. This is due to several groundbreaking studies identifying 5-hydroxymethylcytosine in mouse embryonic stem (ES) and neuronal cells. Research techniques, including bisulfite sequencing methods, are unable to easily distinguish between 5-mC and 5-hmC . A few protocols exist that can measure global amounts of 5-hydroxymethylcytosine in the genome, including liquid chromatography coupled with mass spectrometry analysis or thin layer chromatography of single nucleosides digested from genomic DNA. Antibodies that target 5-hydroxymethylcytosine also exist, which can be used for dot blot analysis, immunofluorescence, or precipitation of hydroxymethylated DNA, but these antibodies do not have single base resolution.In addition, resolution depends on the size of the immunoprecipitated DNA and for microarray experiments, depends on probe design. Since it is unknown exactly where 5 hydroxymethylcytosine exists in the genome or its role in epigenetic regulation, new techniques are required that can identify locus specific hydroxymethylation. The EpiMark 5-hmC and 5-mC Analysis Kit provides a solution for distinguishing between these two modifications at specific loci. The EpiMark 5-hmC and 5-mC Analysis Kit is a simple and robust method for the identification and quantitation of 5-methylcytosine and 5-hydroxymethylcytosine within a specific DNA locus. This enzymatic approach utilizes the differential methylation sensitivity of the isoschizomers MspI and HpaII in a simple 3-step protocol. Genomic DNA of interest is treated with T4-BGT, adding a glucose moeity to 5 hydroxymethylcytosine. This reaction is sequence-independent, therefore all 5-hmC will be glucosylated; unmodified or 5-mC containing DNA will not be affected. This glucosylation is then followed by restriction endonuclease digestion. MspI and HpaII recognize the same sequence (CCGG) but are sensitive to different methylation states. HpaII cleaves only a completely unmodified site: any modification (5-mC, 5-hmC or 5-ghmC) at either cytosine blocks cleavage. MspI recognizes and cleaves 5-mC and 5-hmC, but not 5-ghmC. The third part of the protocol is interrogation of the locus by PCR. As little as 20 ng of input DNA can be used. Amplification of the experimental (glucosylated and digested) and control (mock glucosylated and digested) target DNA with primers flanking a CCGG site of interest (100-200 bp) is performed. If the CpG site contains 5 hydroxymethylcytosine, a band is detected after glucosylation and digestion, but not in the non-glucosylated control reaction. Real time PCR will give an approximation of how much hydroxymethylcytosine is in this particular site. In this experiment, we will analyze the 5-hydroxymethylcytosine amount in a mouse Babl/C brain sample by end point PCR. PMID- 21307837 TI - A mission in evolution: the International Society of Nephrology in the past 10 years--2001-2010. AB - The International Society of Nephrology is now 50 years old! It has dedicated the year 2010 to celebrate its Gold Anniversary in many ways, including documentation of its progress during the past decade, following an earlier article addressing the period 1960-2000. The present article describes the changing mission of the Society in the direction of achieving its ultimate vision of "global elimination of kidney disease." While maintaining its leadership in the promotion of science, it became the prime driving force in capacity building for the diagnosis, prevention and management of kidney disease in the developing world. The society has recently modified its directive from addressing only the physicians providing renal care to supporting other health care providers, and sharing in community education on how to avoid kidney disease. This required the acquisition of new skills in publishing, marketing, politics and fund-raising, which could only be handled by professional management, which the Society has utilized since 2003. It also necessitated enlargement of the leadership circle to include members from all over the world, for which reason the constitution had to be amended twice during the past decade, and the bylaws re-written in 2007. The pride that International Society of Nephrology takes from its scientific and outreach achievements is the fuel that drives its machinery to endless horizons in the humanitarian arena. PMID- 21307838 TI - Improved performance of urinary biomarkers of acute kidney injury in the critically ill by stratification for injury duration and baseline renal function. AB - To better understand the diagnostic and predictive performance of urinary biomarkers of kidney injury, we evaluated gamma-glutamyltranspeptidase (GGT), alkaline phosphatase (AP), neutrophil-gelatinase-associated lipocalin (NGAL), cystatin C (CysC), kidney injury molecule-1 (KIM-1), and interleukin-18 (IL-18) in a prospective observational study of 529 patients in 2 general intensive care units (ICUs). Comparisons were made using the area under the receiver operator characteristic curve (AUC) for diagnosis or prediction of acute kidney injury (AKI), dialysis, or death, and reassessed after patient stratification by baseline renal function (estimated glomerular filtration rate, eGFR) and time after renal insult. On ICU entry, no biomarker had an AUC above 0.7 in the diagnosis or prediction of AKI. Several biomarkers (NGAL, CysC, and IL-18) predicted dialysis (AUC over 0.7), and all except KIM-1 predicted death at 7 days (AUC between 0.61 and 0.69). Performance was improved by stratification for eGFR or time or both. With eGFR <60 ml/min, CysC and KIM-1 had AUCs of 0.69 and 0.73, respectively, within 6 h of injury, and between 12 and 36 h, CysC (0.88), NGAL (0.85), and IL-18 (0.94) had utility. With eGFR >60 ml/min, GGT (0.73), CysC (0.68), and NGAL (0.68) had the highest AUCs within 6 h of injury, and between 6 and 12 h, all AUCs except AP were between 0.68 and 0.78. Beyond 12 h, NGAL (0.71) and KIM-1 (0.66) performed best. Thus, the duration of injury and baseline renal function should be considered in evaluating biomarker performance to diagnose AKI. PMID- 21307841 TI - Mesenchymal stromal cells as treatment for chronic GVHD. PMID- 21307840 TI - Lower estimated glomerular filtration rate and higher albuminuria are associated with all-cause and cardiovascular mortality. A collaborative meta-analysis of high-risk population cohorts. AB - Screening for chronic kidney disease is recommended in people at high risk, but data on the independent and combined associations of estimated glomerular filtration rate (eGFR) and albuminuria with all-cause and cardiovascular mortality are limited. To clarify this, we performed a collaborative meta analysis of 10 cohorts with 266,975 patients selected because of increased risk for chronic kidney disease, defined as a history of hypertension, diabetes, or cardiovascular disease. Risk for all-cause mortality was not associated with eGFR between 60-105 ml/min per 1.73 m2, but increased at lower levels. Hazard ratios at eGFRs of 60, 45, and 15 ml/min per 1.73 m2 were 1.03, 1.38 and 3.11, respectively, compared to an eGFR of 95, after adjustment for albuminuria and cardiovascular risk factors. Log albuminuria was linearly associated with log risk for all-cause mortality without thresholds. Adjusted hazard ratios at albumin-to-creatinine ratios of 10, 30 and 300 mg/g were 1.08, 1.38, and 2.16, respectively compared to a ratio of five. Albuminuria and eGFR were multiplicatively associated with all-cause mortality, without evidence for interaction. Similar associations were observed for cardiovascular mortality. Findings in cohorts with dipstick data were generally comparable to those in cohorts measuring albumin-to-creatinine ratios. Thus, lower eGFR and higher albuminuria are risk factors for all-cause and cardiovascular mortality in high risk populations, independent of each other and of cardiovascular risk factors. PMID- 21307839 TI - Myofibroblast differentiation during fibrosis: role of NAD(P)H oxidases. AB - Progression of fibrosis involves interstitial hypercellularity, matrix accumulation, and atrophy of epithelial structures, resulting in loss of normal function and ultimately organ failure. There is common agreement that the fibroblast/myofibroblast is the cell type most responsible for interstitial matrix accumulation and consequent structural deformations associated with fibrosis. During wound healing and progressive fibrotic events, fibroblasts transform into myofibroblasts acquiring smooth muscle features, most notably the expression of alpha-smooth muscle actin and synthesis of mesenchymal cell-related matrix proteins. In renal disease, glomerular mesangial cells also acquire a myofibroblast phenotype and synthesize the same matrix proteins. The origin of interstitial myofibroblasts during fibrosis is a matter of debate, where the cells are proposed to derive from resident fibroblasts, pericytes, perivascular adventitial, epithelial, and/or endothelial sources. Regardless of the origin of the cells, transforming growth factor-beta1 (TGF-beta1) is the principal growth factor responsible for myofibroblast differentiation to a profibrotic phenotype and exerts its effects via Smad signaling pathways involving mitogen-activated protein kinase and Akt/protein kinase B. Additionally, reactive oxygen species (ROS) have important roles in progression of fibrosis. ROS are derived from a variety of enzyme sources, of which the nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase family has been identified as a major source of superoxide and hydrogen peroxide generation in the cardiovasculature and kidney during health and disease. Recent evidence indicates that the NAD(P)H oxidase homolog Nox4 is most accountable for ROS-induced fibroblast and mesangial cell activation, where it has an essential role in TGF-beta1 signaling of fibroblast activation and differentiation into a profibrotic myofibroblast phenotype and matrix production. Information on the role of ROS in mesangial cell and fibroblast signaling is incomplete, and further research on myofibroblast differentiation during fibrosis is warranted. PMID- 21307842 TI - The medial prefrontal and orbitofrontal cortices differentially regulate dopamine system function. AB - The prefrontal cortex (PFC) is essential for top-down control over higher-order executive function. In this study we demonstrate that the medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC) differentially regulate VTA dopamine neuron activity, and furthermore, the pattern of activity in the PFC drastically alters the dopamine neuron response. Thus, although single-pulse activation of the mPFC either excites or inhibits equivalent numbers of dopamine neurons, activation of the OFC induces a primarily inhibitory response. Moreover, activation of the PFC with a pattern that mimics spontaneous burst firing of pyramidal neurons produces a strikingly different response. Specifically, burst like activation of the mPFC induces a massive increase in dopamine neuron firing, whereas a similar pattern of OFC activation largely inhibits dopamine activity. Taken together, these data demonstrate that the mPFC and OFC differentially regulate dopamine neuron activity, and that the pattern of cortical activation is critical for determining dopamine system output. PMID- 21307843 TI - fMRI of cocaine self-administration in macaques reveals functional inhibition of basal ganglia. AB - Disparities in cocaine-induced neurochemical and metabolic responses between human beings and rodents motivate the use of non-human primates (NHP) to model consequences of repeated cocaine exposure in human subjects. To characterize the functional response to cocaine infusion in NHP brain, we employed contrast enhanced fMRI during both non-contingent injection of drug and self administration of cocaine in the magnet. Cocaine robustly decreased cerebral blood volume (CBV) throughout basal ganglia and motor/pre-motor cortex and produced subtle functional inhibition of prefrontal cortex. No brain regions exhibited significant elevation of CBV in response to cocaine challenge. Theses effects in NHP brain are opposite in sign to the cocaine-induced fMRI response in rats, but consistent with previous measurements in NHP based on glucose metabolism. Because the striatal ratio of D2 to D1 receptors is larger in human beings and NHP than rats, we hypothesize that the inhibitory effects of D2 receptor binding dominate the functional response in primates, whereas excitatory D1 receptor stimulation predominates in the rat. If the NHP accurately models the human response to cocaine, downregulation of D2 receptors in human cocaine abusing populations can be expected to blunt cocaine-induced functional responses, contributing to the weak and variable fMRI responses reported in human basal ganglia following cocaine infusion. PMID- 21307844 TI - Regulation of MiR-124, Let-7d, and MiR-181a in the accumbens affects the expression, extinction, and reinstatement of cocaine-induced conditioned place preference. AB - Molecular adaptations underlying drug seeking and relapse remain largely unknown. Studies highlight post-transcriptional modifications mediated by microRNAs (miRNAs) in addiction and other neurological disorders. We have previously shown that chronic cocaine suppresses miR-124 and let-7d and induces the expression of miR-181a in mesolimbic pathway. To further address the role and target gene regulation network of these miRNAs in vivo in cocaine addiction, we developed lentiviral vector (LV)-expressing miRNAs and their corresponding silencers for stable and regulatable miRNA expression. We tested in vivo miRNA gain and loss of function on cocaine-induced conditioned place preference (CPP) by localized LV miRNA regulation in the nucleus accumbens (NAc). LV-miR-124 and let-7d expression in the NAc attenuates cocaine CPP, whereas LV-miR-181a enhances it. Silencing miRNAs by corresponding LV-miRNA silencers expressing perfect miRNA target sequences inversed this effect on cocaine CPP. Doxycycline treatment for switching off silencer expression abolished the observed behavioral changes. Behavioral changes mediated by LV-miRNA regulation resulted in dynamic alterations in transcription factors, receptors, and other effector genes involved in cocaine-induced plasticity. Our results describe a complex regulatory pathway mediated by miRNAs in cocaine-mediated neuronal adaptations. PMID- 21307845 TI - KCNJ6 is associated with adult alcohol dependence and involved in gene * early life stress interactions in adolescent alcohol drinking. AB - Alcohol abuse and dependence have proven to be complex genetic traits that are influenced by environmental factors. Primate and human studies have shown that early life stress increases the propensity for alcohol abuse in later life. The reinforcing properties of alcohol are mediated by dopaminergic signaling; however, there is little evidence to indicate how stress alters alcohol reinforcement. KCNJ6 (the gene encoding G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2)) is a brain expressed potassium channel with inhibitory effects on dopaminergic tone. The properties of GIRK2 have been shown to be enhanced by the stress peptide corticotrophin-releasing hormone. Therefore, we sought to examine the role of KCNJ6 polymorphisms in adult alcohol dependence and stress-related alcohol abuse in adolescents. We selected 11 SNPs in the promoter region of KCNJ6, which were genotyped in 1152 adult alcohol dependents and 1203 controls. One SNP, rs2836016, was found to be associated with alcohol dependence (p=0.01, false discovery rate). We then assessed rs2836016 in an adolescent sample of 261 subjects, which were characterized for early life stress and adolescent hazardous drinking, defined using the Alcohol Use Disorders Identification Test (AUDIT), to examine gene-environment interactions. In the adolescent sample, the risk genotype of rs2836016 was significantly associated with increased AUDIT scores, but only in those individuals exposed to high levels of psychosocial stress in early life (p=0.01). Our findings show that KCNJ6 is associated with alcohol dependence and may moderate the effect of early psychosocial stress on risky alcohol drinking in adolescents. We have identified a candidate gene for future studies investigating a possible functional link between the response to stress and alcohol reinforcement. PMID- 21307846 TI - Cannabidiol reduces the anxiety induced by simulated public speaking in treatment naive social phobia patients. AB - Generalized Social Anxiety Disorder (SAD) is one of the most common anxiety conditions with impairment in social life. Cannabidiol (CBD), one major non psychotomimetic compound of the cannabis sativa plant, has shown anxiolytic effects both in humans and in animals. This preliminary study aimed to compare the effects of a simulation public speaking test (SPST) on healthy control (HC) patients and treatment-naive SAD patients who received a single dose of CBD or placebo. A total of 24 never-treated patients with SAD were allocated to receive either CBD (600 mg; n=12) or placebo (placebo; n=12) in a double-blind randomized design 1 h and a half before the test. The same number of HC (n=12) performed the SPST without receiving any medication. Each volunteer participated in only one experimental session in a double-blind procedure. Subjective ratings on the Visual Analogue Mood Scale (VAMS) and Negative Self-Statement scale (SSPS-N) and physiological measures (blood pressure, heart rate, and skin conductance) were measured at six different time points during the SPST. The results were submitted to a repeated-measures analysis of variance. Pretreatment with CBD significantly reduced anxiety, cognitive impairment and discomfort in their speech performance, and significantly decreased alert in their anticipatory speech. The placebo group presented higher anxiety, cognitive impairment, discomfort, and alert levels when compared with the control group as assessed with the VAMS. The SSPS-N scores evidenced significant increases during the testing of placebo group that was almost abolished in the CBD group. No significant differences were observed between CBD and HC in SSPS-N scores or in the cognitive impairment, discomfort, and alert factors of VAMS. The increase in anxiety induced by the SPST on subjects with SAD was reduced with the use of CBD, resulting in a similar response as the HC. PMID- 21307847 TI - Development of protective immunity to Salmonella, a mucosal pathogen with a systemic agenda. AB - Salmonella infections can cause a range of intestinal and systemic diseases in human and animal hosts. Although some Salmonella serovars initiate a localized intestinal inflammatory response, others use the intestine as a portal of entry to initiate a systemic infection. Considerable progress has been made in understanding bacterial invasion and dissemination strategies, as well as the nature of the Salmonella-specific immune response to oral infection. Innate and adaptive immunity are rapidly initiated after oral infection, but these effector responses can also be hindered by bacterial evasion strategies. Furthermore, although Salmonella resides within intramacrophage phagosomes, recent studies have highlighted a surprising collaboration of CD4 Th1, Th17, and B-cell responses in mediating resistance to Salmonella infection. PMID- 21307848 TI - Apoptosis is an innate defense function of macrophages against Mycobacterium tuberculosis. AB - Two different forms of death are commonly observed when Mycobacterium tuberculosis (Mtb)-infected macrophages die: (i) necrosis, a death modality defined by cell lysis and (ii) apoptosis, a form of death that maintains an intact plasma membrane. Necrosis is a mechanism used by bacteria to exit the macrophage, evade host defenses, and spread. In contrast, apoptosis of infected macrophages is associated with diminished pathogen viability. Apoptosis occurs when tumor necrosis factor activates the extrinsic death domain pathway, leading to caspase-8 activation. In addition, mitochondrial outer membrane permeabilization leading to activation of the intrinsic apoptotic pathway is required. Both pathways lead to caspase-3 activation, which results in apoptosis. We have recently demonstrated that during mycobacterial infection, cell death is regulated by the eicosanoids, prostaglandin E(2) (proapoptotic) and lipoxin (LX)A(4) (pronecrotic). Although PGE(2) protects against necrosis, virulent Mtb induces LXA(4) and inhibits PGE(2) production. Under such conditions, mitochondrial inner membrane damage leads to macrophage necrosis. Thus, virulent Mtb subverts eicosanoid regulation of cell death to foil innate defense mechanisms of the macrophage. PMID- 21307849 TI - Telomere dysfunction induces metabolic and mitochondrial compromise. AB - Telomere dysfunction activates p53-mediated cellular growth arrest, senescence and apoptosis to drive progressive atrophy and functional decline in high turnover tissues. The broader adverse impact of telomere dysfunction across many tissues including more quiescent systems prompted transcriptomic network analyses to identify common mechanisms operative in haematopoietic stem cells, heart and liver. These unbiased studies revealed profound repression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha and beta (PGC-1alpha and PGC-1beta, also known as Ppargc1a and Ppargc1b, respectively) and the downstream network in mice null for either telomerase reverse transcriptase (Tert) or telomerase RNA component (Terc) genes. Consistent with PGCs as master regulators of mitochondrial physiology and metabolism, telomere dysfunction is associated with impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species. In the setting of telomere dysfunction, enforced Tert or PGC-1alpha expression or germline deletion of p53 (also known as Trp53) substantially restores PGC network expression, mitochondrial respiration, cardiac function and gluconeogenesis. We demonstrate that telomere dysfunction activates p53 which in turn binds and represses PGC-1alpha and PGC-1beta promoters, thereby forging a direct link between telomere and mitochondrial biology. We propose that this telomere-p53-PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction. PMID- 21307850 TI - Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. AB - Individuals with congenital or acquired prolongation of the QT interval, or long QT syndrome (LQTS), are at risk of life-threatening ventricular arrhythmia. LQTS is commonly genetic in origin but can also be caused or exacerbated by environmental factors. A missense mutation in the L-type calcium channel Ca(V)1.2 leads to LQTS in patients with Timothy syndrome. To explore the effect of the Timothy syndrome mutation on the electrical activity and contraction of human cardiomyocytes, we reprogrammed human skin cells from Timothy syndrome patients to generate induced pluripotent stem cells, and differentiated these cells into cardiomyocytes. Electrophysiological recording and calcium (Ca(2+)) imaging studies of these cells revealed irregular contraction, excess Ca(2+) influx, prolonged action potentials, irregular electrical activity and abnormal calcium transients in ventricular-like cells. We found that roscovitine, a compound that increases the voltage-dependent inactivation of Ca(V)1.2 (refs 6-8), restored the electrical and Ca(2+) signalling properties of cardiomyocytes from Timothy syndrome patients. This study provides new opportunities for studying the molecular and cellular mechanisms of cardiac arrhythmias in humans, and provides a robust assay for developing new drugs to treat these diseases. PMID- 21307851 TI - Geometric frustration in compositionally modulated ferroelectrics. AB - Geometric frustration is a broad phenomenon that results from an intrinsic incompatibility between some fundamental interactions and the underlying lattice geometry. Geometric frustration gives rise to new fundamental phenomena and is known to yield intriguing effects such as the formation of exotic states like spin ice, spin liquids and spin glasses. It has also led to interesting findings of fractional charge quantization and magnetic monopoles. Mechanisms related to geometric frustration have been proposed to understand the origins of relaxor and multiferroic behaviour, colossal magnetocapacitive coupling, and unusual and novel mechanisms of high-transition-temperature superconductivity. Although geometric frustration has been particularly well studied in magnetic systems in the past 20 years or so, its manifestation in the important class formed by ferroelectric materials (which are compounds with electric rather than magnetic dipoles) is basically unknown. Here we show, using a technique based on first principles, that compositionally graded ferroelectrics possess the characteristic 'fingerprints' associated with geometric frustration. These systems have a highly degenerate energy surface and display critical phenomena. They further reveal exotic orderings with novel stripe phases involving complex spatial organization. These stripes display spiral states, topological defects and curvature. Compositionally graded ferroelectrics can thus be considered the 'missing link' that brings ferroelectrics into the broad category of materials able to exhibit geometric frustration. Our ab initio calculations allow deep microscopic insight into this novel geometrically frustrated system. PMID- 21307852 TI - Cell biology: Ageing theories unified. PMID- 21307856 TI - The Soliga, an isolated tribe from Southern India: genetic diversity and phylogenetic affinities. AB - India's role in the dispersal of modern humans can be explored by investigating its oldest inhabitants: the tribal people. The Soliga people of the Biligiri Rangana Hills, a tribal community in Southern India, could be among the country's first settlers. This forest-bound, Dravidian speaking group, lives isolated, practicing subsistence-level agriculture under primitive conditions. The aim of this study is to examine the phylogenetic relationships of the Soligas in relation to 29 worldwide, geographically targeted, reference populations. For this purpose, we employed a battery of 15 hypervariable autosomal short tandem repeat loci as markers. The Soliga tribe was found to be remarkably different from other Indian populations including other southern Dravidian-speaking tribes. In contrast, the Soliga people exhibited genetic affinity to two Australian aboriginal populations. This genetic similarity could be attributed to the 'Out of Africa' migratory wave(s) along the southern coast of India that eventually reached Australia. Alternatively, the observed genetic affinity may be explained by more recent migrations from the Indian subcontinent into Australia. PMID- 21307853 TI - Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. AB - Under physiological conditions the gut-associated lymphoid tissues not only prevent the induction of a local inflammatory immune response, but also induce systemic tolerance to fed antigens. A notable exception is coeliac disease, where genetically susceptible individuals expressing human leukocyte antigen (HLA) HLA DQ2 or HLA-DQ8 molecules develop inflammatory T-cell and antibody responses against dietary gluten, a protein present in wheat. The mechanisms underlying this dysregulated mucosal immune response to a soluble antigen have not been identified. Retinoic acid, a metabolite of vitamin A, has been shown to have a critical role in the induction of intestinal regulatory responses. Here we find in mice that in conjunction with IL-15, a cytokine greatly upregulated in the gut of coeliac disease patients, retinoic acid rapidly activates dendritic cells to induce JNK (also known as MAPK8) phosphorylation and release the proinflammatory cytokines IL-12p70 and IL-23. As a result, in a stressed intestinal environment, retinoic acid acted as an adjuvant that promoted rather than prevented inflammatory cellular and humoral responses to fed antigen. Altogether, these findings reveal an unexpected role for retinoic acid and IL-15 in the abrogation of tolerance to dietary antigens. PMID- 21307857 TI - A commentary on Identification of novel MLC1 mutations in Chinese patients with megalencephalic leukoencephalopathy with subcortical cysts (MLC). PMID- 21307858 TI - Polymorphisms of the PTGDR and LTC4S influence responsiveness to leukotriene receptor antagonists in Korean children with asthma. AB - Activation of the prostaglandin D2 receptor (PTGDR) may contribute to pulmonary vasodilation, bronchoconstriction, recruitment of eosinophils, basophils and T lymphocytes, and enhanced synthesis of leukotriene C4. We investigated whether polymorphisms of the leukotriene C4 synthase (LTC4S) -444A/C and PTGDR -441T/C were associated with clinical phenotypes and responsiveness to leukotriene receptor antagonist (LTRA) in Korean asthmatic children. We enrolled 270 normal and 870 asthmatic children. We prescribed montelukast (5 mg per day) to 100 of asthmatic children, and analyzed the responsiveness to LTRA by exercise challenge tests. Polymorphisms were genotyped by PCR-restriction fragment length polymorphism. As the number of minor alleles of the PTGDR -441T/C and LTC4S 444A/C polymorphisms increased, the log total eosinophil counts increased in atopic asthmatic children (P-value=0.03). We found a significant association between responsiveness to montelukast and the PTGDR polymorphism (P-value=0.038). However, the LTC4S -444A/C and PTGDR -441T/C were not associated with the susceptibility for asthma (LTC4S, AA versus AC+CC, adjusted odds ratio of 0.98 (95% confidence interval, 0.73-1.31); PTGDR, TT versus TC+CC, adjusted odds ratio of 0.90 (95% confidence interval, 0.68-1.19)) or clinical phenotypes (P value>0.05). The effects of the PTGDR and LTC4S polymorphisms on the enhancement of eosinophil counts were additive in the Korean children with asthma. In addition, the PTGDR polymorphism seems to be associated with the responsiveness to LTRA. Therefore, therapies that target the PTGDR may be useful for modulating the responsiveness to LTRA. PMID- 21307859 TI - Epidemiology of human papillomavirus genotypes in pregnant Japanese women. AB - To investigate the pre-vaccination epidemiology of genital human papillomavirus (HPV) infections and genotypes in pregnant Japanese women, we performed Pap smear tests and HPV genotype testing in patients attending Nagasaki University Hospital and collaborating hospitals from August 2007 to July 2010. Serial uterine cervical specimens were obtained from 151 pregnant women. The HPV test was positive on the first visit in 54 women (35.8%; 54/151, average age 30). A total of 49 women (32.5%; 49/151) were infected by at least one high-risk HPV and 5 women were infected by only low-risk HPV. The three most prevalent high-risk HPV genotypes were HPV 52 (31.5%; 17/54), HPV 16 (29.6%; 16/51) and HPV 31 (13.0%; 7/51). The HPV infection pattern (negative, single infection and multiple infection) differed significantly according to the pregnancy trimester (chi(2) test; P<0.01(Pearson)). Among HPV-infected pregnant Japanese women, HPV52 was the most common genotype. The second most common genotype was HPV16, and these two genotypes accounted for ~60% of HPV-positive pregnant women. Infection with multiple HPV genotypes was observed more frequently in the first trimester of pregnancy and the pattern of infection changed significantly depending on pregnancy stage. PMID- 21307860 TI - Hypophosphatasia now draws more attention of both clinicians and researchers: a commentary on Prevalence of c. 1559delT in ALPL, a common mutation resulting in the perinatal (lethal) form of hypophosphatasias in Japanese and effects of the mutation on heterozygous carriers. PMID- 21307861 TI - Association of the arginine vasopressin receptor 1A (AVPR1A) haplotypes with listening to music. AB - Music is listened in all cultures. We hypothesize that willingness to produce and perceive sound and music is social communication that needs musical aptitude. Here, listening to music was surveyed using a web-based questionnaire and musical aptitude using the auditory structuring ability test (Karma Music test) and Carl Seashores tests for pitch and for time. Three highly polymorphic microsatellite markers (RS3, RS1 and AVR) of the arginine vasopressin receptor 1A (AVPR1A) gene, previously associated with social communication and attachment, were genotyped and analyzed in 31 Finnish families (n=437 members) using family-based association analysis. A positive association between the AVPR1A haplotype (RS1 and AVR) and active current listening to music (permuted P=0.0019) was observed. Other AVPR1A haplotype (RS3 and AVR) showed association with lifelong active listening to music (permuted P=0.0022). In addition to AVPR1A, two polymorphisms (5-HTTLPR and variable number of tandem repeat) of human serotonin transporter gene (SLC6A4), a candidate gene for many neuropsychiatric disorders and previously associated with emotional processing, were analyzed. No association between listening to music and the polymorphisms of SLC6A4 were detected. The results suggest that willingness to listen to music is related to neurobiological pathways affecting social affiliation and communication. PMID- 21307862 TI - Functional analysis of recently identified mutations in eukaryotic translation initiation factor 2BE (eIF2BE) identified in Chinese patients with vanishing white matter disease. AB - Vanishing white matter disease (VWM) is the first human hereditary disease known to be caused by defects in initiation of protein synthesis. Gene defects in each of the five subunits of eukaryotic translation initiation factor 2B (eIF2B alpha E) are responsible for the disease, although the mechanism of the pathogenesis is not well understood. In our previous study, four novel eIF2BE mutations were found in Chinese patients: p.Asp62Val, p.Cys335Ser, p.Asn376Asp and p.Ser610 Asp613del. Functional analysis was performed on these mutations and the recently reported p.Arg269X. Our data showed that all resulted in a decrease in the guanine nucleotide exchange (GEF) activity of the eIF2B complex. p.Arg269X and p.Ser610-Asp613del mutants displayed the lowest activity, followed by p.Cys335Ser, p.Asn376Asp and p.Asp62Val. p.Arg269X and p.Ser610-Asp613del could not produce stable eIF2BE, leading to almost complete loss-of-function. No evidence was obtained for the three missense mutations in changes in eIF2BE protein level or eIF2BESer(540) phosphorylation, and disruption of holocomplex assembly, or binding to eIF2. All patients in our study had the classical phenotype. p.Asp62Val and p.Asn376Asp mutations caused only mildly decreased GEF activity, were probably responsible for relatively mild phenotype in cases of classical VWM. PMID- 21307863 TI - Genetic and clinical analysis in a Chinese parkinsonism-predominant spinocerebellar ataxia type 2 family. AB - Parkinson's disease is a degenerative central nervous system disorder that often impairs motor skills, speech and other functions. We discovered a large Chinese family showing primarily parkinsonism symptoms with autosomal dominant inheritance. Six affected individuals in the family showed typical parkinsonism symptoms, including pill-rolling tremor. Two other affected individuals showed cerebellar ataxia symptoms. A whole-genome scan using the 50K single nucleotide polymorphism array with three different linkage methods detected two positive regions on chromosome 12q24.1 and 5q13.3. The ATXN2 gene, responsible for spinocerebellar ataxia type 2 (SCA2) was located precisely in the center of the positive region on chromosome 12. Further analysis of SCA2 revealed heterozygous pathological CAG expansions in the family. The affected individuals' symptoms were typical of parkinsonism, but complex. Inverse correlation between CAG repeat size and age of onset is not obvious in this pedigree. This parkinsonism predominant SCA2 family shared the same disease gene locus with other 'standard' SCA2 families, but it is possible that variations in one or more modifier genes might account for the parkinsonism-predominant SCA2 predisposition observed in this pedigree. PMID- 21307864 TI - A commentary on the Soliga, an isolated tribe from Southern India: genetic diversity and phylogenetic affinities. PMID- 21307865 TI - Clinical and molecular genetic analysis in Chinese patients with distal myopathy with rimmed vacuoles. AB - Distal myopathy with rimmed vacuoles (DMRVs) is an autosomal recessive vacuolar myopathy that has been reported in different ethnic populations with the common mutations of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene. We presented the clinical, pathological and genetic characteristics of eight Chinese DMRV patients from six unrelated families. Six previously reported Chinese DMRV patients from four unrelated families were also reviewed for comparison in GNE mutations. In the present eight patients with DMRV, direct sequencing analysis revealed one homozygous mutation of c.1760T>C (p.I587T) and seven compound heterozygous mutations in the GNE gene. The latter included two known mutations, c.1892C>T (p.A631V) and c.527A>T (p.D176V), and three novel mutations, c.1523T>C (p.L508S), c.103G>A (p.E35K) and c.153A>G (p.I51M). The allelic frequency of c.1523T>C (p.L508S) was 25% in the Chinese patients with DMRV. Our findings expand the genetic spectrum of DMRV and indicate that the common mutations of GNE gene in DMRV may be variable among different ethnic populations. PMID- 21307866 TI - Clinical application of fetal sex determination using cell-free fetal DNA in pregnant carriers of X-linked genetic disorders. AB - As the first step in prenatal diagnosis of X-linked genetic disorders, chorionic villus sampling (CVS) for fetal sex determination is generally performed at 11-13 weeks of gestation. However, as the procedure-related miscarriage rate of CVS is 0.5-1.0%, non-invasive methods such as PCR of cell-free fetal DNA (cff-DNA) in maternal plasma are preferable. Here, we determined fetal sex at 9-12 weeks of gestation using PCR of cff-DNA in three pregnant carriers of Duchenne muscular dystrophy. The fetal sex was accurately determined in all three cases, as confirmed by ultrasound and amniocentesis at 16 weeks (for the two female fetuses) and CVS at 12 weeks (for the one male fetus). This procedure could avoid unnecessary CVS in female fetuses. PMID- 21307867 TI - Molecular characterization of phenylketonuria and tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Japan. AB - Phenylketonuria (PKU) is a heterogeneous metabolic disorder caused by a deficiency in hepatic phenylalanine hydroxylase (PAH). On the basis of phenotype/genotype correlations, determination of phenylketonuric genotype is important for classification of the clinical phenotype and treatment of PKU, including tetrahydrobiopterin therapy. We characterized the genotypes of 203 Japanese patients with PKU and hyperphenylalaninemia using the following systems: (1) denaturing high-performance liquid chromatography with a GC-clamped primer; (2) direct sequencing; and, (3) multiplex ligation-dependent probe amplification. Of 406 mutant alleles, 390 (96%) were genotyped; 65 mutations were identified, including 22 new mutations. R413P, R241C, IVS4-1g>a, R111X and R243Q were prevalent mutations. Mutations prevalent in the Japanese cohort are also common in Korean and Northern Chinese populations, suggesting same origin. The spectrum of prevalent mutations was not significantly different among six Japanese districts, indicating that Japan comprises a relatively homogeneous ethnic group. We classified the mutations by clinical phenotypes and in vivo PAH activity and estimated the mutations with potential tetrahydrobiopterin (BH(4)) responsiveness. The frequency of BH(4) responsiveness based on the genotype was 29.1% in Japanese PKU patients. A catalog of PKU genotypes would be useful for predicting clinical phenotype, deciding on the subsequent treatment of PKU including BH(4) therapy, and genetic counseling in East Asia. PMID- 21307868 TI - Olmesartan improves endothelial function in hypertensive patients: link with extracellular superoxide dismutase. AB - Endothelial dysfunction in essential hypertension is an independent predictor for future cardiovascular events. Although inhibition of the renin-angiotensin system (RAS) reportedly improves endothelial function through its effects on oxidative stress and inflammation, questions remain regarding the factors that are pivotal for improvement of endothelial function by RAS inhibition. We therefore performed a prospective, randomized crossover trial in which an angiotensin II type 1 receptor antagonist, olmesartan and calcium channel blocker, amlodipine, were compared in 31 essential hypertensive patients. Results showed that, although both treatments achieved comparable lowering of blood pressure (BP), olmesartan, but not amlodipine, significantly improved endothelial function as evaluated by flow-mediated vasodilation (FMD) in the brachial artery. Although no significant changes in diabetic and lipid parameters were observed with either drug, olmesartan slightly decreased estimated glomerular filtration rate, which, surprisingly, translated into decreased microalbuminuria. In a similar vein, olmesartan reduced serum C-reactive protein and increased urine antioxidant levels compared with baseline, and reduced urine 8-epi-prostaglandin F2alpha levels compared with both baseline and amlodipine. Finally, although overall changes in plasma extracellular superoxide dismutase (EC-SOD) levels were not modulated by either treatment, for olmesartan there was a positive correlation between changes in FMD and those in EC-SOD levels. In conclusion, olmesartan improved endothelial function in hypertensive patients independent of its BP lowering effect, which was due, at least in part, to its antioxidative property. Therefore, olmesartan might provide a greater long-term benefit for hypertensive patients with impaired endothelial function than amlodipine. PMID- 21307869 TI - Are blood pressure and diabetes additive or synergistic risk factors? Outcome in 8494 subjects randomly recruited from 10 populations. AB - It remains unknown whether diabetes and high blood pressure (BP) are simply additive risk factors for cardiovascular outcome or whether they act synergistically and potentiate one another. We performed 24-h ambulatory BP monitoring in 8494 subjects (mean age, 54.6 years; 47.0% women; 6.9% diabetic patients) enrolled in prospective population studies in 10 countries. In multivariable-adjusted Cox regression, we assessed the additive as opposed to the synergistic effects of BP and diabetes in relation to a composite cardiovascular endpoint by testing the significance of appropriate interaction terms. During 10.6 years (median follow-up), 1066 participants had a cardiovascular complication. Diabetes mellitus as well as the 24-h ambulatory BP were independent and powerful predictors of the composite cardiovascular endpoint. However, there was no synergistic interaction between diabetes and 24-h, daytime, or nighttime, systolic or diastolic ambulatory BP (P for interaction, 0.07?P?0.97). The only exception was a borderline synergistic effect between diabetes and daytime diastolic BP in relation to the composite cardiovascular endpoint (P=0.04). In diabetic patients, with normotension as the reference group, the adjusted hazard ratios for the cardiovascular endpoint were 1.35 (95% confidence interval (CI), 0.87-2.11) for white-coat hypertension, 1.78 (95% CI, 1.22-2.60) for masked hypertension and 2.44 (95% CI, 1.92-3.11) for sustained hypertension. The hazard ratios for non-diabetic subjects were not different from those of diabetic patients (P-values for interaction, 0.09?P?0.72). In conclusion, in a large international population-based database, both diabetes mellitus and BP contributed equally to the risk of cardiovascular complications without evidence for a synergistic effect. PMID- 21307871 TI - Does a replacement or revision of an inflatable penile prosthesis lead to decreased patient satisfaction? AB - To analyze the reason for replacement, revision and overall satisfaction of a cohort who underwent surgical replacement of an inflatable penile prosthesis (IPP). A cohort of 105 patients who underwent IPP replacement from 2005-2007 was retrieved from the prosthesis database. Approximately 21.9% (23) underwent replacement or revision of their prosthesis because of complications, and were further analyzed. Reason for removal was stratified into infectious and non infectious (erosion, non-function and patient discomfort). Age, race (African American vs non-African American), smoking history, hypertension, diabetes, coronary artery disease and hyperlipidemia were stratified by reason for removal. Finally, we contacted patients and recorded subjective satisfaction with their IPP. The reason for removal was most commonly because of a non-functional IPP (47.8%), followed by infection (30.4%), erosion (17.4%) and patient discomfort (4.3%). Age and race did not show a significant difference when analyzing reason for replacement (P > 0.05). Patients who were smokers (P = 0.907) had hypertension (P = 0.554), diabetes (P = 0.591) or hyperlipidemia (P = 0.219) did not have significantly higher infection rates. Approximately 58.3% were satisfied with their prosthesis, 75% would have the surgery performed again and 91.7% would still recommend prosthesis surgery. Device malfunction was the primary reason for replacement/removal at our institution. Despite the complications of prosthesis reoperation, the majority of patients were still satisfied with their prosthesis, would have the surgery performed again and would recommend prosthesis surgery to a friend. PMID- 21307870 TI - Stable EET urea agonist and soluble epoxide hydrolase inhibitor regulate rat pulmonary arteries through TRPCs. AB - Epoxyeicosatrienoic acids (EETs), cytochrome P450-derived metabolites of arachidonic acid, have been reported to increase intracellular calcium concentration in aortic vascular smooth muscle cells (SMCs). As EETs are labile, we synthesized a new stable urea EET analog with agonist and soluble epoxide hydrolase (sEH) inhibitor properties. We refer to this analog, 12-(3 hexylureido)dodec-8-enoic acid, as 8-HUDE. Measuring tension of vascular rings, intracellular calcium signaling by confocal laser scanning microscopy and gene expression by reverse-transcription-PCR and western blots, we examined the effects of 8-HUDE on pulmonary vascular tone and calcium signaling in rat pulmonary artery (PA) SMCs (PASMCs). 8-HUDE increased the tension of rat PAs to 145% baseline, whereas it had no effect on the tension of mesenteric arteries (MAs). The 8-HUDE-induced increase in vascular tone was abolished by removal of extracellular Ca(2+) or by pretreatment with either La(3+) or SKF96365, which are inhibitors of canonical transient receptor potential channels (TRPCs). Furthermore, 8-HUDE-evoked increases in [Ca(2+)](i) in PASMCs could be blunted by inhibition of TRPC with SKF96365, removal of extracellular calcium or depletion of intracellular calcium stores with caffeine, cyclopiazonic acid or 2 aminoethoxydiphenyl borate, but not by the voltage-activated calcium channel blocker nifedipine. In addition to immediate effects on calcium signaling, 8-HUDE upregulated the expression of TRPC1 and TRPC6 at both mRNA and protein levels in rat PASMCs, whereas it suppressed the expression of sEH. Our observations suggest that 8-HUDE increases PA vascular tone through increased release of calcium from intracellular stores, enhanced [Ca(2+)](i) influx in PASMCs through store operated Ca(2+) channels and modulated the expression of TRPC and sEH proteins in a proconstrictive manner. PMID- 21307872 TI - Radioprotective effects of Bmi-1 involve epigenetic silencing of oxidase genes and enhanced DNA repair in normal human keratinocytes. AB - Normal human keratinocytes (NHKs) undergo premature senescence following exposure to ionizing radiation (IR). This study investigates the effect of Bmi-1, a polycomb group protein, on radiation-induced senescence response. When exposed to IR, NHK transduced with Bmi-1 (NHK/Bmi-1) showed reduced senescent phenotype and enhanced proliferation compared with control cells (NHK/B0). To investigate the underlying mechanism, we determined the production of reactive oxygen species (ROS), expression of ROS-generating enzymes, and DNA repair activities in cells. ROS level was increased upon irradiation but notably reduced by Bmi-1 transduction. Irradiation led to strong induction of oxidase genes, e.g., Lpo (lactoperoxidase), p22-phox, p47-phox, and Gp91, in NHK/B0 but their expression was almost completely silenced in NHK/Bmi-1. Induction of oxidase genes upon irradiation was linked with loss of trimethylated histone 3 at lysine 27 (H3K27Me3), but NHK/Bmi-1 expressed a higher level of H3K27Me3 compared with NHK/B0. Bmi-1 transduction suppressed IR-associated induction of jumanji domain containing 3 while enhancing the expression of EZH2, thereby preventing the loss of H3K27Me3 in the irradiated cells. Furthermore, NHK/Bmi-1 demonstrated increased repair of IR-induced DNA damage compared with NHK/B0. These results indicate that Bmi-1 elicits radioprotective effects on NHK by mitigating the genotoxicity of IR through epigenetic mechanisms. PMID- 21307873 TI - Protease sensitivity of corneodesmosin variants encoded by the six more common CDSN haplotypes. PMID- 21307874 TI - Essential role of the keratinocyte-specific endonuclease DNase1L2 in the removal of nuclear DNA from hair and nails. AB - Degradation of nuclear DNA is a hallmark of programmed cell death. Epidermal keratinocytes die in the course of cornification to function as the dead building blocks of the cornified layer of the epidermis, nails, and hair. Here, we investigated the mechanism and physiological function of DNA degradation during cornification in vivo. Targeted deletion of the keratinocyte-specific endonuclease DNase1-like 2 (DNase1L2) in the mouse resulted in the aberrant retention of DNA in hair and nails, as well as in epithelia of the tongue and the esophagus. In contrast to our previous studies in human keratinocytes, ablation of DNase1L2 did not compromise the cornified layer of the epidermis. Quantitative PCRs showed that the amount of nuclear DNA was dramatically increased in both hair and nails, and that mitochondrial DNA was increased in the nails of DNase1L2 deficient mice. The presence of nuclear DNA disturbed the normal arrangement of structural proteins in hair corneocytes and caused a significant decrease in the resistance of hair to mechanical stress. These data identify DNase1L2 as an essential and specific regulator of programmed cell death in skin appendages, and demonstrate that the breakdown of nuclear DNA is crucial for establishing the full mechanical stability of hair. PMID- 21307875 TI - Superficial spreading-like melanoma in Arf(-/-)::Tyr-Nras(Q61K)::K14-Kitl mice: keratinocyte Kit ligand expression sufficient to "translocate" melanomas from dermis to epidermis. PMID- 21307876 TI - Does inflammation have a role in the pathogenesis of venous ulcers? A critical review of the evidence. AB - Chronic venous disease, a disorder involving venous return from the legs, is a growing epidemic in the developed world. Numerous studies have been conducted in the past two decades in an attempt to elucidate its underlying pathophysiology. Many theories have been proposed to address the profound inflammatory dysregulation, with the majority focusing on fibrin trap, inflammatory trap, cytokines, growth factors, and matrix metalloproteinases. Although many of these theories have obtained great momentum, much of the data are contradictory. Moreover, many treatments built on these theories have claimed overwhelming success despite insufficient evidence. At the same time, there are few reviews that critically analyze and evaluate these data. Therefore, in this paper, we will provide summaries of the background data and evolution of these theories and examine their supporting evidence. PMID- 21307877 TI - Tumor-associated macrophages in the cutaneous SCC microenvironment are heterogeneously activated. AB - Tumor-associated macrophages (TAMs) may have an important role in tumor immunity. We studied the activation state of TAMs in cutaneous SCC, the second most common human cancer. CD163 was identified as a more abundant, sensitive, and accurate marker of TAMs when compared with CD68. CD163(+) TAMs produced protumoral factors, matrix metalloproteinases 9 and 11 (MMP9 and MMP11), at the gene and protein levels. Gene set enrichment analysis (GSEA) was used to evaluate M1 and M2 macrophage gene sets in the SCC genes and to identify candidate genes in order to phenotypically characterize TAMs. There was coexpression of CD163 and alternatively activated "M2" markers, CD209 and CCL18 (chemokine (C-C motif) ligand 18). There was enrichment for classically activated "M1" genes in SCC, which was confirmed in situ by colocalization of CD163 and phosphorylated STAT1 (signal transducer and activator of transcription 1), IL-23p19, IL-12/IL-23p40, and CD127. Also, a subset of TAMs in SCC was bi-activated as CD163(+) cells expressed markers for both M1 and M2, shown by triple-label immunofluorescence. These data support heterogeneous activation states of TAMs in SCC, and suggest that a dynamic model of macrophage activation would be more useful to characterize TAMs. PMID- 21307878 TI - Contribution of transcript stability to a conserved procyanidin-induced cytokine response in gammadelta T cells. AB - gammadelta T cells function in innate and adaptive immunity and are primed for secondary responses by procyanidin components of unripe apple peel (APP). In this study, we investigate the effects of APP and purified procyanidins on gammadelta T-cell gene expression. A microarray analysis was performed on bovine gammadelta T cells treated with APP; increases in transcripts encoding granulocyte-monocyte colony stimulating factor (GM-CSF), IL-8 and IL-17, but not markers of TCR stimulation such as IFNgamma, were observed. Key responses were confirmed in human, mouse and bovine cells by reverse transcription-PCR and/or ELISA, indicating a conserved response to procyanidins. In vivo relevance of the cytokine response was shown in mice following intraperitoneal injection of APP, which induced production of CXCL1/KC and resulted in neutrophil influx to the blood and peritoneum. In the human T-cell line, MOLT-14, GM-CSF and IL-8 transcripts were increased and stabilized in cells treated with crude APP or purified procyanidins. The ERK1/2 MAPK pathway was activated in APP-treated cells, and necessary for transcript stabilization. Our data describe a unique gammadelta T-cell inflammatory response during procyanidin treatment and suggest that transcript stability mechanisms could account, at least in part, for the priming phenotype. PMID- 21307879 TI - The lupus phenotype in B6.NZBc1 congenic mice reflects interactions between multiple susceptibility loci and a suppressor locus. AB - Lupus susceptibility loci on chromosome 1 have an important role in the development of autoimmunity in the New Zealand Black (NZB) mouse. We have previously shown that C57BL/6 congenic mice with an introgressed homozygous NZB chromosome 1 interval extending from ~35 to 106 cM develop anti-nuclear antibodies and mild glomerulonephritis. In this study, we produced subcongenic mouse strains to localize the susceptibility loci in this interval and investigate how they promote autoimmunity. Our results indicate at least four susceptibility alleles and a suppressor allele. One allele is located in the 96 100 cM region and is sufficient to breach tolerance to chromatin. Addition of a second locus in the 88-96 cM interval enhances anti-dsDNA antibody production and promotes renal disease, which together with a third susceptibility allele in the 70-88 interval results in significant mortality. We further demonstrate the presence of a suppressor locus in the 35-70 or 100-102 cM interval that abrogates these phenotypes and an additional susceptibility allele in the 102-106 cM interval that restores a milder autoimmune phenotype. Several of these loci alter T-cell function. Thus, there is substantial genetic complexity in the NZB 35-106 cM interval, with disease reflecting a balance between susceptibility and suppressor loci. PMID- 21307880 TI - Long-term effect of early intervention with single intravitreal injection of bevacizumab followed by panretinal and macular grid photocoagulation in central retinal vein occlusion (CRVO) with macular edema: a pilot study. AB - PURPOSE: To evaluate the effect of single-dose intravitreal bevacizumab followed by panretinal and macular grid laser, early in the course of central retinal vein occlusion (CRVO). METHODS: It is a prospective, non-randomized, interventional study of nine eyes of nine patients with <10 days origin of CRVO who received 2.5 mg (0.1 ml) intravitreal bevacizumab, followed 3 weeks later by panretinal and macular grid photocoagulation. Its effect on visual acuity and anatomical features of CRVO were studied. RESULTS: Nine eyes of nine patients (male : female = 8 : 1, mean age 54 years), with <10 days (average 2.67 days) onset of CRVO, received intravitreal bevacizumab within 7 days of presentation (average 3.1 days) followed 3 weeks later by panretinal with macular grid laser. Presenting mean baseline visual acuity was 20/320 (1.2 logarithm of the minimum angle of resolution (LOGMAR) units). All the patients showed rapid improvement in the form of rapid clearance of retinal hemorrhages, decreased optic disc swelling and venous dilation, and tortuosity. Mean final visual acuity was 20/63 (0.5 LOGMAR units). No patient showed conversion from non-ischemic to ischaemic CRVO, recurrence of macular edema, and disc collateral formation. CONCLUSION: Early intravitreal bevacizumab followed by panretinal and macular grid laser may provide visually and anatomically favourable results in a case of CRVO. It may also obviate the need for repeated injection. It requires a large randomized study to substantiate the results. PMID- 21307882 TI - Common matrix metalloproteinase 2 gene haplotypes may modulate left ventricular remodelling in hypertensive patients. AB - Matrix metalloproteinases (MMPs) are involved in cardiac remodelling. We examined whether MMP-2 genetic polymorphisms are associated with hypertension and left ventricular (LV) remodelling in hypertensive patients. We studied 160 hypertensive patients and 123 healthy controls. Echocardiography was performed in all patients and the C(-1306)T (rs243865) and C(-735)T (rs 2285053) MMP-2 polymorphisms were analysed. Haplo.stats analysis was used to evaluate whether MMP-2 haplotypes are associated with hypertension and with extremes in LV mass index (LVMI). Multiple linear regression analysis was performed to assess whether MMP-2 genotypes or haplotypes affect LVMI and other echocardiography parameters. The C(-1306)T 'CC' genotype was associated with reduced LVMI and LV end-diastolic diameter (EDD) (P=0.0365 and P=0.0438, respectively). The haplotype 'C, C' was associated with reduced LVMI and EDD (P=0.0278 and P=0.0322, respectively). The comparison of upper and lower extremes of the LVMI phenotype showed that the 'C, C' haplotype was more common in the lower LVMI group (P=0.0060), whereas the 'T, C' haplotype was more common in the higher quartile of LVMI (P=0.0187), and this haplotype was associated with increased risk of higher LVMI values (odds ratio=3.5121, 95% confidence interval=1.3193-9.3494). The findings suggest that MMP-2 polymorphisms affect hypertension-induced LV remodelling. PMID- 21307883 TI - A systematic review and meta-analysis of elevated blood pressure and consumption of dairy foods. AB - Hypertension is a public health priority in developed countries and worldwide, and is strongly associated with increased risk and progression of cardiovascular and renal diseases. A systematic review and meta-analysis were conducted to examine the association between dairy food intake during adulthood and the development of elevated blood pressure (EBP), specifically comparing the association of EBP with consumption of low-fat dairy foods versus high-fat dairy foods, as well as cheese versus fluid dairy foods (milk or yogurt). Seven databases were searched and five cohort studies selected for inclusion, involving nearly 45,000 subjects and 11,500 cases of EBP. Meta-analysis of consumption of dairy foods and EBP in adults gave a relative risk (RR) of 0.87 (95% confidence interval (CI) 0.81-0.94). Separation of high- and low-fat dairy foods, however, indicated a significant association with low-fat dairy foods only (RR of 0.84 (95% CI 0.74-0.95)). Additional analyses showed no association between EBP and cheese, although fluid dairy foods were significantly associated with a reduced development in EBP (RR of 0.92 (95% CI 0.87-0.98)). Little heterogeneity was observed among the data presented. This meta-analysis supports the inverse association between low-fat dairy foods and fluid dairy foods and risk of EBP. Understanding these relationships can aid in the development of public health messages involving dairy foods, and supports current recommendations. PMID- 21307884 TI - Is DHAS related to hypertension? Perhaps, but it is still impossible to be certain. PMID- 21307885 TI - Polyunsaturated fatty acid intake and blood pressure in adolescents. AB - Evidence that intake of polyunsaturated fatty acids (PUFAs) may modify blood pressure (BP) is generally limited to middle-aged or hypertensive populations. This study examined cross-sectional associations between BP and dietary intake of PUFAs in 814 adolescents aged 13-15 years participating in the Western Australian Pregnancy Cohort (Raine) Study. Fatty acid intakes were assessed using 3-day diet records and resting BP was determined using multiple oscillometric readings. In multivariate regression models, systolic BP was inversely associated with intakes of polyunsaturated (b=-0.436, P<0.01), omega-3 (b=-2.47, P=0.02), omega-6 (b= 0.362, P=0.04) and long chain omega-3 fatty acids (b=-4.37, P=0.04) in boys. Diastolic BP and mean arterial pressure were inversely associated with intakes of long chain omega-3 fatty acids in boys (b=-3.93, P=0.01, b=-4.05, P=0.01, respectively). For specific long-chain omega-3s, significant inverse associations were observed between eicosapentaenoic acid (EPA) and docosahexaenoic acid, such as systolic BP decreasing by 4.7 mm Hg (95% CI -9.3 to -0.1) for a quarter gram increase in EPA, but no significant associations were observed with docosapentaenoic acid. No significant associations were observed in girls, or with the omega-6 to omega-3 ratio. Our results suggest that gender may moderate relationships between fatty acid intake and BP in adolescence. PMID- 21307886 TI - Cortisol, dehydroepiandrosterone sulphate, their ratio and hypertension: evidence of associations in male veterans from the Vietnam Experience Study. AB - Although clinical observations implicate cortisol in hypertension, the epidemiological evidence is less compelling. Little is known about the relationship between dehydroepiandrosterone sulphate (DHEAS) and hypertension, and nothing about the association with the cortisol:DHEAS ratio. The present analyses of data obtained from Vietnam-era US veterans examined the associations between cortisol, DHEAS, their ratio and hypertension. Participants were 4180 male veterans. From military files, telephone interviews and a medical examination, sociodemographic and health data were collected. At medical examination, a fasted morning blood sample was collected to assay serum cortisol and DHEAS, blood pressure measured and body mass index (BMI) determined. Hypertension was defined by having one of the following: a reported physician diagnosis, taking antihypertensive medication, an average systolic blood pressure >= 140 mm Hg and an average diastolic blood pressure >= 90 mm Hg. Cortisol and the cortisol:DHEAS ratio were positively associated with hypertension (P < 0.001), whereas DHEAS was negatively associated; the latter relationship was attenuated to non-significance (P = 0.06) in models that adjusted for age, sociodemographics, place of service, health behaviours and BMI. The present analyses provide confirmation of a positive association between cortisol and the cortisol:DHEAS ratio and population hypertension. PMID- 21307887 TI - Adenovirus-mediated delivery of CD46 attenuates the alternative complement pathway on RPE: implications for age-related macular degeneration. AB - Activation of the alternative pathway of the complement system has been implicated in the pathogenesis of age-related macular degeneration. Membrane attack complex (MAC) has been identified mainly on the Bruch's membrane and drusen underlying the retinal pigment epithelium (RPE). Membrane cofactor protein (CD46) preferentially regulates the alternative pathway of complement. The aim of this study was to evaluate the potential of increasing CD46 expression on RPE cells using an adenovirus as a gene therapy approach to reduce alternative pathway-mediated damage to RPE cells. We generated a recombinant adenovirus vector expressing human CD46 (hCD46) and delivered the vector to murine hepatocytes and RPE cells in vitro. After incubation in human serum in conditions in which the classical pathway of complement was blocked, we measured alternative pathway-mediated damage of these cells by quantifying lysis and MAC formation. Adenovirus expressing hCD46 was delivered to the subretinal space of adult mice, and 1 week later, ocular flat mounts were challenged with human serum and the levels of complement-mediated damage was quantified. Adenovirus-mediated delivery of hCD46 localizes to the basal and lateral surfaces of RPE cells where it offers protection from alternative pathway-mediated damage, but not classical, allowing the classical pathway to function unhindered. PMID- 21307890 TI - A fair share. PMID- 21307889 TI - Phase I/II trial of a dendritic cell vaccine transfected with DNA encoding melan A and gp100 for patients with metastatic melanoma. AB - This trial tested a dendritic cell (DC) therapeutic cancer vaccine in which antigen is loaded using a novel non-viral transfection method enabling the uptake of plasmid DNA condensed with a cationic peptide. Proof of principle required the demonstration of diverse T lymphocyte responses following vaccination, including multiple reactivities restricted through both major histocompatibility complex (MHC) class I and II. Patients with advanced melanoma were offered four cycles of vaccination with autologous DC expressing melan A and gp100. Disease response was measured using Response Evaluation Criteria in Solid Tumours. Circulating MHC class I- and II-restricted responses were measured against peptide and whole antigen targets using interferon-gamma ELIspot and enzyme-linked immunosorbent assay assays, respectively. Responses were analyzed across the trial population and presented descriptively for some individuals. Twenty-five patients received at least one cycle. Vaccination was well tolerated. Three patients had reduction in disease volume. Across the trial population, vaccination resulted in an expansion of effector responses to both antigens, to the human leukocyte antigen A2-restricted modified epitope, melan A ELAGIGILTV, and to a panel of MHC class I and II-restricted epitopes. Vaccination with mature DC non-virally transfected with DNA encoding antigen had biological effect causing tumour regression and inducing diverse T lymphocyte responses. PMID- 21307888 TI - Potent, tumor-specific gene expression in an orthotopic hepatoma rat model using a Survivin-targeted, amplifiable adenoviral vector. AB - Ideal cancer gene therapies should have high tumor specificity and efficacy, and allow systemic administration to target metastases. We recently developed a bi directional, two-step transcriptional amplification (TSTA) system driven by the tumor-specific Survivin promoter (pSurv) to amplify the correlated expression of both the reporter gene firefly luciferase (FL) and therapeutic gene tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Here, we compare the specificity and potency of an adenovirus carrying this system (Ad-pSurv-TSTA TRAIL-FL) to a nonspecific vector (Ad-pCMV-FL) in an orthotopic hepatocellular carcinoma (HCC) rat model after systemic administration. At 24 h after injection of Ad-pCMV-FL, bioluminescence imaging revealed a trend (P=0.30) towards greater FL expression in liver versus tumor. In striking contrast, Ad-pSurv-TSTA-TRAIL-FL showed increased FL activity within the tumor compared with the liver (P<0.01), a strong trend towards reduced liver expression compared with Ad-pCMV-FL (P=0.07), and importantly, similar FL levels within tumor compared with Ad-pCMV-FL (P=0.32). Hence, this vector shows potent, tumor-specific transgene expression even after extensive liver transduction and may be of significant value in avoiding hepatotoxicity in HCC patients. Future studies will explore the benefits of tumor-specific TRAIL expression in this model, the potential to target metastases and the extension of this vector for the treatment of other Survivin positive tumors is warranted. PMID- 21307891 TI - Letting the bugs out of the bag. PMID- 21307892 TI - Best is yet to come. PMID- 21307905 TI - Egypt's youth 'key to revival'. PMID- 21307893 TI - Pharmaceutical industry must take its medicine. PMID- 21307906 TI - University seeks to emerge from shooting's shadow. PMID- 21307907 TI - Science gender gap probed. PMID- 21307908 TI - Pfizer slashes R&D. PMID- 21307910 TI - Gene reading steps up a gear. PMID- 21307911 TI - Stem cells: the crusader. PMID- 21307912 TI - Evolution: a can of worms. PMID- 21307913 TI - Too many roads not taken. PMID- 21307914 TI - Anthropologists unite! PMID- 21307920 TI - Pick sanitation over vaccination in Haiti. PMID- 21307921 TI - Harnessing value of dispersed critiques. PMID- 21307922 TI - Biomarkers: call on industry to share. PMID- 21307923 TI - Biomarkers: better donor protection. PMID- 21307924 TI - Jack oliver (1923-2011). PMID- 21307925 TI - Quantum control: Squinting at quantum systems. PMID- 21307926 TI - Animal behaviour: the nexus of sex and violence. PMID- 21307928 TI - Palaeoclimatology: Core data from the Antarctic margin. PMID- 21307929 TI - Structural biology: a new look for the APC. PMID- 21307930 TI - Organic chemistry: Metals are not the only catalysts. PMID- 21307931 TI - Initial impact of the sequencing of the human genome. AB - The sequence of the human genome has dramatically accelerated biomedical research. Here I explore its impact, in the decade since its publication, on our understanding of the biological functions encoded in the genome, on the biological basis of inherited diseases and cancer, and on the evolution and history of the human species. I also discuss the road ahead in fulfilling the promise of genomics for medicine. PMID- 21307932 TI - A decade's perspective on DNA sequencing technology. AB - The decade since the Human Genome Project ended has witnessed a remarkable sequencing technology explosion that has permitted a multitude of questions about the genome to be asked and answered, at unprecedented speed and resolution. Here I present examples of how the resulting information has both enhanced our knowledge and expanded the impact of the genome on biomedical research. New sequencing technologies have also introduced exciting new areas of biological endeavour. The continuing upward trajectory of sequencing technology development is enabling clinical applications that are aimed at improving medical diagnosis and treatment. PMID- 21307933 TI - Charting a course for genomic medicine from base pairs to bedside. AB - There has been much progress in genomics in the ten years since a draft sequence of the human genome was published. Opportunities for understanding health and disease are now unprecedented, as advances in genomics are harnessed to obtain robust foundational knowledge about the structure and function of the human genome and about the genetic contributions to human health and disease. Here we articulate a 2011 vision for the future of genomics research and describe the path towards an era of genomic medicine. PMID- 21307934 TI - The genomic complexity of primary human prostate cancer. AB - Prostate cancer is the second most common cause of male cancer deaths in the United States. However, the full range of prostate cancer genomic alterations is incompletely characterized. Here we present the complete sequence of seven primary human prostate cancers and their paired normal counterparts. Several tumours contained complex chains of balanced (that is, 'copy-neutral') rearrangements that occurred within or adjacent to known cancer genes. Rearrangement breakpoints were enriched near open chromatin, androgen receptor and ERG DNA binding sites in the setting of the ETS gene fusion TMPRSS2-ERG, but inversely correlated with these regions in tumours lacking ETS fusions. This observation suggests a link between chromatin or transcriptional regulation and the genesis of genomic aberrations. Three tumours contained rearrangements that disrupted CADM2, and four harboured events disrupting either PTEN (unbalanced events), a prostate tumour suppressor, or MAGI2 (balanced events), a PTEN interacting protein not previously implicated in prostate tumorigenesis. Thus, genomic rearrangements may arise from transcriptional or chromatin aberrancies and engage prostate tumorigenic mechanisms. PMID- 21307935 TI - Functional identification of an aggression locus in the mouse hypothalamus. AB - Electrical stimulation of certain hypothalamic regions in cats and rodents can elicit attack behaviour, but the exact location of relevant cells within these regions, their requirement for naturally occurring aggression and their relationship to mating circuits have not been clear. Genetic methods for neural circuit manipulation in mice provide a potentially powerful approach to this problem, but brain-stimulation-evoked aggression has never been demonstrated in this species. Here we show that optogenetic, but not electrical, stimulation of neurons in the ventromedial hypothalamus, ventrolateral subdivision (VMHvl) causes male mice to attack both females and inanimate objects, as well as males. Pharmacogenetic silencing of VMHvl reversibly inhibits inter-male aggression. Immediate early gene analysis and single unit recordings from VMHvl during social interactions reveal overlapping but distinct neuronal subpopulations involved in fighting and mating. Neurons activated during attack are inhibited during mating, suggesting a potential neural substrate for competition between these opponent social behaviours. PMID- 21307936 TI - Structural basis for the subunit assembly of the anaphase-promoting complex. AB - The anaphase-promoting complex or cyclosome (APC/C) is an unusually large E3 ubiquitin ligase responsible for regulating defined cell cycle transitions. Information on how its 13 constituent proteins are assembled, and how they interact with co-activators, substrates and regulatory proteins is limited. Here, we describe a recombinant expression system that allows the reconstitution of holo APC/C and its sub-complexes that, when combined with electron microscopy, mass spectrometry and docking of crystallographic and homology-derived coordinates, provides a precise definition of the organization and structure of all essential APC/C subunits, resulting in a pseudo-atomic model for 70% of the APC/C. A lattice-like appearance of the APC/C is generated by multiple repeat motifs of most APC/C subunits. Three conserved tetratricopeptide repeat (TPR) subunits (Cdc16, Cdc23 and Cdc27) share related superhelical homo-dimeric architectures that assemble to generate a quasi-symmetrical structure. Our structure explains how this TPR sub-complex, together with additional scaffolding subunits (Apc1, Apc4 and Apc5), coordinate the juxtaposition of the catalytic and substrate recognition module (Apc2, Apc11 and Apc10 (also known as Doc1)), and TPR-phosphorylation sites, relative to co-activator, regulatory proteins and substrates. PMID- 21307937 TI - Programmable nanowire circuits for nanoprocessors. AB - A nanoprocessor constructed from intrinsically nanometre-scale building blocks is an essential component for controlling memory, nanosensors and other functions proposed for nanosystems assembled from the bottom up. Important steps towards this goal over the past fifteen years include the realization of simple logic gates with individually assembled semiconductor nanowires and carbon nanotubes, but with only 16 devices or fewer and a single function for each circuit. Recently, logic circuits also have been demonstrated that use two or three elements of a one-dimensional memristor array, although such passive devices without gain are difficult to cascade. These circuits fall short of the requirements for a scalable, multifunctional nanoprocessor owing to challenges in materials, assembly and architecture on the nanoscale. Here we describe the design, fabrication and use of programmable and scalable logic tiles for nanoprocessors that surmount these hurdles. The tiles were built from programmable, non-volatile nanowire transistor arrays. Ge/Si core/shell nanowires coupled to designed dielectric shells yielded single-nanowire, non-volatile field effect transistors (FETs) with uniform, programmable threshold voltages and the capability to drive cascaded elements. We developed an architecture to integrate the programmable nanowire FETs and define a logic tile consisting of two interconnected arrays with 496 functional configurable FET nodes in an area of ~960 MUm(2). The logic tile was programmed and operated first as a full adder with a maximal voltage gain of ten and input-output voltage matching. Then we showed that the same logic tile can be reprogrammed and used to demonstrate full subtractor, multiplexer, demultiplexer and clocked D-latch functions. These results represent a significant advance in the complexity and functionality of nanoelectronic circuits built from the bottom up with a tiled architecture that could be cascaded to realize fully integrated nanoprocessors with computing, memory and addressing capabilities. PMID- 21307938 TI - Asymmetric additions to dienes catalysed by a dithiophosphoric acid. AB - Chiral Bronsted acids (proton donors) have been shown to facilitate a broad range of asymmetric chemical transformations under catalytic conditions without requiring additional toxic or expensive metals. Although the catalysts developed thus far are remarkably effective at activating polarized functional groups, it is not clear whether organic Bronsted acids can be used to catalyse highly enantioselective transformations of unactivated carbon-carbon multiple bonds. This deficiency persists despite the fact that racemic acid-catalysed 'Markovnikov' additions to alkenes are well known chemical transformations. Here we show that chiral dithiophosphoric acids can catalyse the intramolecular hydroamination and hydroarylation of dienes and allenes to generate heterocyclic products in exceptional yield and enantiomeric excess. We present a mechanistic hypothesis that involves the addition of the acid catalyst to the diene, followed by nucleophilic displacement of the resulting dithiophosphate intermediate; we also report mass spectroscopic and deuterium labelling studies in support of the proposed mechanism. The catalysts and concepts revealed in this study should prove applicable to other asymmetric functionalizations of unsaturated systems. PMID- 21307939 TI - Holocene Southern Ocean surface temperature variability west of the Antarctic Peninsula. AB - The disintegration of ice shelves, reduced sea-ice and glacier extent, and shifting ecological zones observed around Antarctica highlight the impact of recent atmospheric and oceanic warming on the cryosphere. Observations and models suggest that oceanic and atmospheric temperature variations at Antarctica's margins affect global cryosphere stability, ocean circulation, sea levels and carbon cycling. In particular, recent climate changes on the Antarctic Peninsula have been dramatic, yet the Holocene climate variability of this region is largely unknown, limiting our ability to evaluate ongoing changes within the context of historical variability and underlying forcing mechanisms. Here we show that surface ocean temperatures at the continental margin of the western Antarctic Peninsula cooled by 3-4 degrees C over the past 12,000 years, tracking the Holocene decline of local (65 degrees S) spring insolation. Our results, based on TEX(86) sea surface temperature (SST) proxy evidence from a marine sediment core, indicate the importance of regional summer duration as a driver of Antarctic seasonal sea-ice fluctuations. On millennial timescales, abrupt SST fluctuations of 2-4 degrees C coincide with globally recognized climate variability. Similarities between our SSTs, Southern Hemisphere westerly wind reconstructions and El Nino/Southern Oscillation variability indicate that present climate teleconnections between the tropical Pacific Ocean and the western Antarctic Peninsula strengthened late in the Holocene epoch. We conclude that during the Holocene, Southern Ocean temperatures at the western Antarctic Peninsula margin were tied to changes in the position of the westerlies, which have a critical role in global carbon cycling. PMID- 21307940 TI - Acoelomorph flatworms are deuterostomes related to Xenoturbella. AB - Xenoturbellida and Acoelomorpha are marine worms with contentious ancestry. Both were originally associated with the flatworms (Platyhelminthes), but molecular data have revised their phylogenetic positions, generally linking Xenoturbellida to the deuterostomes and positioning the Acoelomorpha as the most basally branching bilaterian group(s). Recent phylogenomic data suggested that Xenoturbellida and Acoelomorpha are sister taxa and together constitute an early branch of Bilateria. Here we assemble three independent data sets-mitochondrial genes, a phylogenomic data set of 38,330 amino-acid positions and new microRNA (miRNA) complements-and show that the position of Acoelomorpha is strongly affected by a long-branch attraction (LBA) artefact. When we minimize LBA we find consistent support for a position of both acoelomorphs and Xenoturbella within the deuterostomes. The most likely phylogeny links Xenoturbella and Acoelomorpha in a clade we call Xenacoelomorpha. The Xenacoelomorpha is the sister group of the Ambulacraria (hemichordates and echinoderms). We show that analyses of miRNA complements have been affected by character loss in the acoels and that both groups possess one miRNA and the gene Rsb66 otherwise specific to deuterostomes. In addition, Xenoturbella shares one miRNA with the ambulacrarians, and two with the acoels. This phylogeny makes sense of the shared characteristics of Xenoturbellida and Acoelomorpha, such as ciliary ultrastructure and diffuse nervous system, and implies the loss of various deuterostome characters in the Xenacoelomorpha including coelomic cavities, through gut and gill slits. PMID- 21307941 TI - 9p21 DNA variants associated with coronary artery disease impair interferon-gamma signalling response. AB - Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in the 9p21 gene desert associated with coronary artery disease (CAD) and type 2 diabetes. Despite evidence for a role of the associated interval in neighbouring gene regulation, the biological underpinnings of these genetic associations with CAD or type 2 diabetes have not yet been explained. Here we identify 33 enhancers in 9p21; the interval is the second densest gene desert for predicted enhancers and six times denser than the whole genome (P < 6.55 * 10( 33)). The CAD risk alleles of SNPs rs10811656 and rs10757278 are located in one of these enhancers and disrupt a binding site for STAT1. Lymphoblastoid cell lines homozygous for the CAD risk haplotype show no binding of STAT1, and in lymphoblastoid cell lines homozygous for the CAD non-risk haplotype, binding of STAT1 inhibits CDKN2BAS (also known as CDKN2B-AS1) expression, which is reversed by short interfering RNA knockdown of STAT1. Using a new, open-ended approach to detect long-distance interactions, we find that in human vascular endothelial cells the enhancer interval containing the CAD locus physically interacts with the CDKN2A/B locus, the MTAP gene and an interval downstream of IFNA21. In human vascular endothelial cells, interferon-gamma activation strongly affects the structure of the chromatin and the transcriptional regulation in the 9p21 locus, including STAT1-binding, long-range enhancer interactions and altered expression of neighbouring genes. Our findings establish a link between CAD genetic susceptibility and the response to inflammatory signalling in a vascular cell type and thus demonstrate the utility of genome-wide association study findings in directing studies to novel genomic loci and biological processes important for disease aetiology. PMID- 21307942 TI - lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3' UTRs via Alu elements. AB - Staufen 1 (STAU1)-mediated messenger RNA decay (SMD) involves the degradation of translationally active mRNAs whose 3'-untranslated regions (3' UTRs) bind to STAU1, a protein that binds to double-stranded RNA. Earlier studies defined the STAU1-binding site within ADP-ribosylation factor 1 (ARF1) mRNA as a 19-base-pair stem with a 100-nucleotide apex. However, we were unable to identify comparable structures in the 3' UTRs of other targets of SMD. Here we show that STAU1 binding sites can be formed by imperfect base-pairing between an Alu element in the 3' UTR of an SMD target and another Alu element in a cytoplasmic, polyadenylated long non-coding RNA (lncRNA). An individual lncRNA can downregulate a subset of SMD targets, and distinct lncRNAs can downregulate the same SMD target. These are previously unappreciated functions of non-coding RNAs and Alu elements. Not all mRNAs that contain an Alu element in the 3' UTR are targeted for SMD even in the presence of a complementary lncRNA that targets other mRNAs for SMD. Most known trans-acting RNA effectors consist of fewer than 200 nucleotides, and these include small nucleolar RNAs and microRNAs. Our finding that the binding of STAU1 to mRNAs can be transactivated by lncRNAs uncovers an unexpected strategy that cells use to recruit proteins to mRNAs and mediate the decay of these mRNAs. We name these lncRNAs half-STAU1-binding site RNAs (1/2-sbsRNAs). PMID- 21307943 TI - Genomics: Genomes in three dimensions. PMID- 21307945 TI - Systematic mentoring on three continents. PMID- 21307949 TI - Restoring tacrolimus-induced impaired barrier function. PMID- 21307951 TI - Atopic dermatitis diagnostic criteria and outcome measures for clinical trials: still a mess. AB - The past 2 decades have seen a heightened interest in atopic dermatitis-related research, leading to an exponential increase in publications. However, large numbers of diagnostic criteria and outcome measures hamper study comparability. The Harmonizing Outcome Measures for Eczema (HOME) initiative addresses the urgent need for consensus, but more work will be required. PMID- 21307952 TI - Prospects for skin cancer treatment and prevention: the potential contribution of an engineered virus. AB - Nonmelanoma skin cancers are among the most common human malignancies. Although typically not lethal, they are responsible for tissue deformity and substantial morbidity, particularly in high-risk populations. Solar UVB radiation-a major etiologic factor for this kind of malignancy-produces DNA lesions such as cyclobutane pyrimidine dimers and 6-4 photoproducts in skin. These lesions are removed through nucleotide excision repair because humans lack a DNA glycosylase required to initiate base excision repair of pyrimidine-pyrimidine photoproducts but produce all the other proteins required for this process. In this issue, Johnson et al. show that a DNA glycosylase derived from Chlorella virus and engineered to enhance tissue penetration and nuclear localization can remove UVB induced DNA lesions in a human skin equivalent model and that the protein can be incorporated into a topical formulation for the prevention and treatment of UVB induced DNA damage. These results suggest that such an enzyme may be incorporated into regimens for the chemoprevention of skin cancers. PMID- 21307953 TI - Peeling skin syndrome: genetic defects in late terminal differentiation of the epidermis. AB - In this issue, Israeli and colleagues confirm that homozygous mutations in corneodesmosin (CDSN) cause type B peeling skin syndrome (PSS), an autosomal recessive skin disorder. The deletion mutation described resulted in a frameshift, producing a downstream premature stop codon and early truncation of the protein. The recently described CDSN nonsense mutation in another PSS family also resulted in protein truncation and nonsense-mediated mRNA decay. Type B generalized PSS can now be clearly distinguished from acral PSS, caused by mutations in transglutaminase 5. This directly affects cornified envelope cross linking rather than corneodesmosome adherence. These observations provide new insight into the molecular defects underlying two closely related forms of PSS. PMID- 21307954 TI - Comparative metagenomics of microbial traits within oceanic viral communities. AB - Viral genomes often contain genes recently acquired from microbes. In some cases (for example, psbA) the proteins encoded by these genes have been shown to be important for viral replication. In this study, using a unique search strategy on the Global Ocean Survey (GOS) metagenomes in combination with marine virome and microbiome pyrosequencing-based datasets, we characterize previously undetected microbial metabolic capabilities concealed within the genomes of uncultured marine viral communities. A total of 34 microbial gene families were detected on 452 viral GOS scaffolds. The majority of auxiliary metabolic genes found on these scaffolds have never been reported in phages. Host genes detected in viruses were mainly divided between genes encoding for different energy metabolism pathways, such as electron transport and newly identified photosystem genes, or translation and post-translation mechanism related. Our findings suggest previously undetected ways, in which marine phages adapt to their hosts and improve their fitness, including translation and post-translation level control over the host rather than the already known transcription level control. PMID- 21307956 TI - Mitochondrial genomes reveal slow rates of molecular evolution and the timing of speciation in beavers (Castor), one of the largest rodent species. AB - BACKGROUND: Beavers are one of the largest and ecologically most distinct rodent species. Little is known about their evolution and even their closest phylogenetic relatives have not yet been identified with certainty. Similarly, little is known about the timing of divergence events within the genus Castor. METHODOLOGY/PRINCIPAL FINDINGS: We sequenced complete mitochondrial genomes from both extant beaver species and used these sequences to place beavers in the phylogenetic tree of rodents and date their divergence from other rodents as well as the divergence events within the genus Castor. Our analyses support the phylogenetic position of beavers as a sister lineage to the scaly tailed squirrel Anomalurus within the mouse related clade. Molecular dating places the divergence time of the lineages leading to beavers and Anomalurus as early as around 54 million years ago (mya). The living beaver species, Castor canadensis from North America and Castor fiber from Eurasia, although similar in appearance, appear to have diverged from a common ancestor more than seven mya. This result is consistent with the hypothesis that a migration of Castor from Eurasia to North America as early as 7.5 mya could have initiated their speciation. We date the common ancestor of the extant Eurasian beaver relict populations to around 210,000 years ago, much earlier than previously thought. Finally, the substitution rate of Castor mitochondrial DNA is considerably lower than that of other rodents. We found evidence that this is correlated with the longer life span of beavers compared to other rodents. CONCLUSIONS/SIGNIFICANCE: A phylogenetic analysis of mitochondrial genome sequences suggests a sister-group relationship between Castor and Anomalurus, and allows molecular dating of species divergence in congruence with paleontological data. The implementation of a relaxed molecular clock enabled us to estimate mitochondrial substitution rates and to evaluate the effect of life history traits on it. PMID- 21307957 TI - Functional magnetic resonance imaging reveals different neural substrates for the effects of orexin-1 and orexin-2 receptor antagonists. AB - Orexins are neuro-modulatory peptides involved in the control of diverse physiological functions through interaction with two receptors, orexin-1 (OX1R) and orexin-2 (OX2R). Recent evidence in pre-clinical models points toward a putative dichotomic role of the two receptors, with OX2R predominantly involved in the regulation of the sleep/wake cycle and arousal, and the OX1R being more specifically involved in reward processing and motivated behaviour. However, the specific neural substrates underlying these distinct processes in the rat brain remain to be elucidated. Here we used functional magnetic resonance imaging (fMRI) in the rat to map the modulatory effect of selective OXR blockade on the functional response produced by D-amphetamine, a psychostimulant and arousing drug that stimulates orexigenic activity. OXR blockade was produced by GSK1059865 and JNJ1037049, two novel OX1R and OX2R antagonists with unprecedented selectivity at the counter receptor type. Both drugs inhibited the functional response to D-amphetamine albeit with distinct neuroanatomical patterns: GSK1059865 focally modulated functional responses in striatal terminals, whereas JNJ1037049 induced a widespread pattern of attenuation characterised by a prominent cortical involvement. At the same doses tested in the fMRI study, JNJ1037049 exhibited robust hypnotic properties, while GSK1059865 failed to display significant sleep-promoting effects, but significantly reduced drug seeking behaviour in cocaine-induced conditioned place preference. Collectively, these findings highlight an essential contribution of the OX2R in modulating cortical activity and arousal, an effect that is consistent with the robust hypnotic effect exhibited by JNJ1037049. The subcortical and striatal pattern observed with GSK1059865 represent a possible neurofunctional correlate for the modulatory role of OX1R in controlling reward-processing and goal-oriented behaviours in the rat. PMID- 21307962 TI - Regional deposition of particles in an image-based airway model: large-eddy simulation and left-right lung ventilation asymmetry. AB - Regional deposition and ventilation of particles by generation, lobe and lung during steady inhalation in a computed tomography (CT) based human airway model are investigated numerically. The airway model consists of a seven-generation human airway tree, with oral cavity, pharynx and larynx. The turbulent flow in the upper respiratory tract is simulated by large-eddy simulation. The flow boundary conditions at the peripheral airways are derived from CT images at two lung volumes to produce physiologically-realistic regional ventilation. Particles with diameter equal to or greater than 2.5 microns are selected for study because smaller particles tend to penetrate to the more distal parts of the lung. The current generational particle deposition efficiencies agree well with existing measurement data. Generational deposition efficiencies exhibit similar dependence on particle Stokes number regardless of generation, whereas deposition and ventilation efficiencies vary by lobe and lung, depending on airway morphology and airflow ventilation. In particular, regardless of particle size, the left lung receives a greater proportion of the particle bolus as compared to the right lung in spite of greater flow ventilation to the right lung. This observation is supported by the left-right lung asymmetry of particle ventilation observed in medical imaging. It is found that the particle-laden turbulent laryngeal jet flow, coupled with the unique geometrical features of the airway, causes a disproportionate amount of particles to enter the left lung. PMID- 21307958 TI - Comprehensive genotyping in two homogeneous Graves' disease samples reveals major and novel HLA association alleles. AB - BACKGROUND: Graves' disease (GD) is the leading cause of hyperthyroidism and thyroid eye disease inherited as a complex trait. Although geoepidemiology studies showed relatively higher prevalence of GD in Asians than in Caucasians, previous genetic studies were contradictory concerning whether and/or which human leukocyte antigen (HLA) alleles are associated with GD in Asians. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a case-control association study (499 unrelated GD cases and 504 controls) and a replication in an independent family sample (419 GD individuals and their 282 relatives in 165 families). To minimize genetic and phenotypic heterogeneity, we included only ethnic Chinese Han population in Taiwan and excluded subjects with hypothyroidism. We performed direct and comprehensive genotyping of six classical HLA loci (HLA-A, -B, -C, DPB1, -DQB1 and -DRB1) to 4-digit resolution. Combining the data of two sample populations, we found that B*46:01 (odds ratio under dominant model [OR] = 1.33, Bonferroni corrected combined P [P(Bc)] = 1.17 x 10-2), DPB1*05:01 (OR = 2.34, P(Bc) = 2.58 x 10-10), DQB1*03:02 (OR = 0.62, P(Bc) = 1.97 x 10-2), DRB1*15:01 (OR = 1.68, P(Bc) = 1.22 x 10-2) and DRB1*16:02 (OR = 2.63, P(Bc) = 1.46 x 10 5) were associated with GD. HLA-DPB1*05:01 is the major gene of GD in our population and singly accounts for 48.4% of population-attributable risk. CONCLUSIONS/SIGNIFICANCE: These GD-associated alleles we identified in ethnic Chinese Hans, and those identified in other Asian studies, are totally distinct from the known associated alleles in Caucasians. Identification of population specific association alleles is the critical first step for individualized medicine. Furthermore, comparison between different susceptibility/protective alleles across populations could facilitate generation of novel hypothesis about GD pathophysiology and indicate a new direction for future investigation. PMID- 21307963 TI - Transplantation. PMID- 21307964 TI - Humoral Antibodies in Patients After Renal Homotransplantation. AB - Humoral antibodies have been demonstrated by antiglobulin consumption tests to be present in the serum of virtually all patients after renal homotransplantation. The most completely characterized was a gammaG immunoglobulin distinct from the Forssman antibody which reacts against sheep but not against human red cell antigens, and which absorbs selectively against panels of human liver, kidney or white blood cells. This antibody appeared within a few days or weeks after transplantation, usually shortly after a rejection episode, and was more or less continuously detectable thereafter. The antibody was found in all of 10 patients studied during the first 4 post-transplant months, and in 13 of 14 patients tested from 4 months to more than 2 years after operation. Preliminary observations are included on another humoral antibody which does not react with sheep RBC stromata, but which can also be measured with a modified antiglobulin consumption test. The latter antibody was less commonly demonstrable, but it also exhibited specific absorption characteristics when tested against a panel of leukocytes obtained from volunteers. The implications of these findings are discussed in relation to the possible value of such sera for histocompatibility typing, as well as the possible role of such antibodies in promoting homograft enhancement. PMID- 21307965 TI - In Vitro Immunosuppressive Effects of FK506 in Combination With Other Drugs. PMID- 21307966 TI - Adaptive Accelerated Molecular Dynamics (Ad-AMD) Revealing the Molecular Plasticity of P450cam. AB - An extended accelerated molecular dynamics (AMD) methodology called adaptive AMD is presented. Adaptive AMD (Ad-AMD) is an efficient and robust conformational space sampling algorithm that is particularly-well suited to proteins with highly structured potential energy surfaces exhibiting complex, large-scale collective conformational transitions. Ad-AMD simulations of substrate-free P450cam reveal that this system exists in equilibrium between a fully and partially open conformational state. The mechanism for substrate binding depends on the size of the ligand. Larger ligands enter the P450cam binding pocket, and the resulting substrate-bound system is trapped in an open conformation via a population shift mechanism. Small ligands, which fully enter the binding pocket, cause an induced fit mechanism, resulting in the formation of an energetically stable closed conformational state. These results are corroborated by recent experimental studies and potentially provide detailed insight into the functional dynamics and conformational behavior of the entire cytochrome-P450 superfamily. PMID- 21307967 TI - Glucose control and opportunities for health care improvement in a hospital setting. AB - We initiated a study at Baylor Jack and Jane Hamilton Heart and Vascular Hospital to compare the sliding scale insulin (SSI) protocol used in 2006 with the SSI protocol currently used to treat diabetic patients admitted for procedures or surgery. An audit of patients' records revealed greater variation in staff compliance with the current protocol than with the previous one. In addition, it seemed that more patients were refusing insulin coverage under the current protocol than under the prior version. Although the study was aborted, the initial findings motivated us to identify obstacles to glucose control and to launch a health care improvement initiative to increase compliance with the SSI protocol. As a result of this process, the hospital has made several changes, including re-educating staff nurses, initiating competency checks of protocol interpretation, promoting patient education, and implementing early identification of inconsistent glucose control. PMID- 21307968 TI - Aortic valve replacement for stenosis with or without coronary artery bypass grafting after 2 previous isolated coronary artery bypass grafting operations. AB - Aortic valve replacement following an earlier coronary artery bypass grafting (CABG) procedure is fairly common. When this situation occurs, the type of valve dysfunction is usually stenosis (with or without regurgitation), and whether it was missed at the time of the earlier CABG or developed subsequently is usually unclear. We attempted to determine the survival in patients who had had aortic valve replacement after 2 previous CABG procedures. We describe 12 patients who had aortic valve replacement for aortic stenosis; rather than one previous CABG operation, all had had 2 previous CABG procedures. Only one patient died in the early postoperative period after aortic valve replacement, and the remaining 11 were improved substantially: all have lived at least 11 months, and one is still alive at over 101 months after aortic valve replacement. Aortic valve replacement remains beneficial for most patients even after 2 previous CABG procedures. PMID- 21307969 TI - Unusual origin of type 1 atrioventricular block with comments on Wenckebach's contribution. AB - We present a case that demonstrates the rare occurrence of type 1 second-degree atrioventricular block (Wenckebach or Mobitz type 1 block) as a result of block in the infranodal conduction system. This extremely rare occurrence often predicts progression to complete heart block and necessitates cardiac pacing. It also demonstrates the value of an electrophysiological study and exercise stress testing to identify the level of block, predict prognosis, and plan a management strategy. PMID- 21307970 TI - Anomalous origin of the right coronary artery from the left sinus of Valsalva associated with syncope in a young athlete. PMID- 21307971 TI - Acquired atheromatous coarctation of the aortic arch. AB - A 58-year-old woman with a past medical history significant for tobacco use presented with shortness of breath. Physical examination revealed a 30 mm Hg difference in upper-extremity blood pressures (right arm greater than left), elevated jugular venous pressure, and leg edema. A two-dimensional echocardiogram revealed an ejection fraction of 20%. During angiography a heavily calcified lesion was noted in the aortic arch, across which a significant gradient was measured. Computed tomographic scanning identified a focal calcified area in the aortic arch and diffuse atherosclerosis elsewhere. Acquired thromboatheromatous coarctation of the aorta is an uncommon entity found in patients who smoke and are hypertensive. It is almost always seen in conjunction with severe peripheral vascular disease, which this patient had. She was started on heart failure therapy and referred for surgical repair. PMID- 21307972 TI - The humanities are the hormones. PMID- 21307973 TI - Raising the bar: Mary Elizabeth Garrett, M. Carey Thomas, and The Johns Hopkins Medical School. PMID- 21307974 TI - Yale, Skull and Bones, and the beginnings of Johns Hopkins. PMID- 21307975 TI - The pithotomy club: R.I.p. PMID- 21307977 TI - The Elder Justice Act: a big step towards protecting older Americans. PMID- 21307976 TI - Biopsy-proven mantle cell lymphoma in brain parenchyma. AB - Brain parenchymal involvement by mantle cell lymphoma is rare and confers a grim prognosis. More commonly, patients with central nervous system manifestations of mantle cell lymphoma have leptomeningeal involvement on radiographic studies with malignant cells found in the cerebrospinal fluid. Risk factors for central nervous system involvement include a high proliferation index, bone marrow involvement, and blastoid morphology. We present an unusual case of a biopsy proven mantle cell lymphoma mass lesion in the brain parenchyma as the presentation of relapse 6 months after diagnosis. PMID- 21307978 TI - Building better cancer vaccines: researchers on the Baylor Dallas campus are using diverse approaches to optimize immune response. PMID- 21307979 TI - Headaches of increasing intensity for a week after using crack cocaine. PMID- 21307980 TI - Facts and ideas from anywhere. PMID- 21307981 TI - Genetic susceptibility to autoimmune liver disease. AB - Autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) are considered as putative autoimmune diseases of the liver. Whereas strong evidence that bacterial infection may trigger PBC exists, the etiologies for PSC and AIH remain unknown. Although there have been significant discoveries of genetic polymorphisms that may underlie the susceptibility to these liver diseases, their associations with environmental triggers and the subsequent implications have been difficult to elucidate. While single nucleotide polymorphisms within the negative costimulatory molecule cytotoxic T lymphocyte antigen 4 (CTLA-4) have been suggested as genetic susceptibility factors for all three disorders, we discuss the implications of CTLA-4 susceptibility alleles mainly in the context of PBC, where Novosphingobium aromaticivorans, an ubiquitous alphaproteobacterium, has recently been specifically associated with the pathogenesis of this devastating liver disease. Ultimately, the discovery of infectious triggers of PBC may expand the concept of genetic susceptibility in immune-mediated liver diseases from the concept of aberrant immune responses against self-antigens to insufficient and/or inappropriate immunological defense mechanisms allowing microbes to cross natural barriers, establish infection and damage respective target organs. PMID- 21307982 TI - Radiofrequency ablation of liver tumors: Actual limitations and potential solutions in the future. AB - Over the past decade, radiofrequency ablation (RFA) has evolved into an important therapeutical tool for the treatment of non resectable primary and secondary liver tumors. The clinical benefit of RFA is represented in several clinical studies. They underline the safety and feasibility of this new and modern concept in treating liver tumors. RFA has proven its clinical impact not only in hepatocellular carcinoma (HCC) but also in metastatic disease such as colorectal cancer (CRC). Due to the increasing number of HCC and CRC, RFA might play an even more important role in the future. Therefore, the refinement of RFA technology is as important as the evaluation of data of prospective randomized trials that will help define guidelines for good clinical practice in RFA application in the future. The combination of hepatic resection and RFA extends the feasibility of open surgical procedures in patients with extensive tumors. Adverse effects of RFA such as biliary tract damage, liver failure and local recurrence remain an important task today but overall the long term results of RFA application in treating liver tumors are promising. Incomplete ablation of liver tumors due to insufficient technology of ablation needles, tissue cooling by the neighbouring blood vessels, large tumor masses and ablation of tumors in close vicinity to heat sensitive organs remain difficult tasks for RFA. Future solutions to overcome these limitations of RFA will include refinement of ultrasonographic guidance (accuracy of probe placement), improvements in needle technology (e.g. needles preventing charring) and intraductal cooling techniques. PMID- 21307983 TI - Multicentric occurrence of hepatocellular carcinoma with nonalcoholic steatohepatitis. AB - AIM: To reveal the manner of hepatocellular carcinoma (HCC) development in patients with nonalcoholic steatohepatitis (NASH) focusing on multicentric occurrence (MO) of HCC. METHODS: We compared clinicopathological characteristics between patients with and without MO of HCC arising from NASH background. The clinical features were implicated with reference to the literature available. RESULTS: MO of HCC was identified with histological proof in 4 out of 12 patients with NASH-related HCC (2 males and 2 females). One patient had synchronous MO; an advanced HCC, two well-differentiated HCCs and a dysplastic nodule, followed by the development of metachronous MO of HCC. The other three patients had multiple advanced HCCs accompanied by a well-differentiated HCC or a dysplastic nodule. Of these three patients, one had synchronous MO, one had metachronous MO and the other had both synchronous and metachronous MO. There were no obvious differences between the patients with or without MO in terms of liver function tests, tumor markers and anatomical extent of HCC. On the other hand, all four patients with MO of HCC were older than 70 years old and had the comorbidities of obesity, type 2 diabetes mellitus (T2DM), hypertension and cirrhosis. Although these conditions were not limited to MO of HCC, all the conditions were met in only one of eight patients without MO of HCC. Thus, concurrence of these conditions may be a predisposing situation to synchronous MO of HCC. In particular, old age, T2DM and cirrhosis were suggested to be prerequisite for MO because these factors were depicted in common among two other cases with MO of HCC under NASH in the literature. CONCLUSION: The putative predisposing factors and necessary preconditions for synchronous MO of HCC in NASH were suggested in this study. Further investigations are required to clarify the accurate prevalence and predictors of MO to establish better strategies for treatment and prevention leading to the prognostic improvement in NASH. PMID- 21307985 TI - A patient-centric, provider-assisted diabetes telehealth self-management intervention for urban minorities. AB - This article describes the design and implementation of an online diabetes self management intervention for a sample of inner-city African Americans with diabetes. Study participants were randomly assigned to the treatment (26) and control (21) conditions. The results indicate that treatment group participants were more likely to achieve positive outcomes in terms of lowered hemoglobin A1c and body mass index measurements than were control group members. These findings support the development of telehealth interventions to promote effective chronic disease management in medically underserved communities. PMID- 21307986 TI - A peach of a telehealth program: Georgia connects rural communities to better healthcare. AB - This article presents Georgia's telehealth response to some of the significant healthcare challenges and disparities facing the rural citizens of this state. When compared to their urban and suburban counterparts, rural communities have fewer healthcare providers, and residents must travel longer distances to reach them. Georgia's statewide telemedicine network, the Georgia Partnership for TeleHealth (GPT), uses information technology to improve the efficiency and quality of healthcare and health outcomes for underserved populations in Georgia. PMID- 21307984 TI - First multicenter study for risk factors for hepatocellular carcinoma development in North Africa. AB - AIM: To assess the role of the major risk factors for hepatocellular carcinoma (HCC) development in the western part of North Africa. METHODS: A multicenter case control study was conducted in Tunisia, Morocco and Algeria in collaboration with Pasteur Institutes in these countries. A total of 164 patients with HCC and 250 control subjects without hepatic diseases were included. Prevalences of HBsAg, anti-hepatitis C virus (HCV) and diabetes were assessed. HCV and HBV genotyping were performed for anti-HCV and HBsAg positive patients. RESULTS: The mean age of patients was 62 +/- 10 years old for a 1.5 M:F sex ratio. Sixty percent of HCC patients were positive for anti-HCV and 17.9% for HBsAg. Diabetes was detected in 18% of cases. Odd ratio (OR) and 95% confidence intervals (CI) were 32.0 (15.8 - 65.0), 7.2 (3.2 - 16.1) and 8.0 (3.1 - 20.0) for anti-HCV, HBsAg and diabetes respectively. Multivariate analysis indicated that the three studied factors were independent. 1b HCV genotype and D HBV genotype were predominant in HCC patients. HCV was the only risk factor significantly associated with an excess of cirrhosis (90% vs 68% for all other risk factors collectively, P = 0.00168). Excessive alcohol consumption was reliably established for 19 (17.6%) cases among the 108 HCC patients for whom data is available. CONCLUSION: HCV and HBV infections and diabetes are the main determinants of HCC development in North Africa. An active surveillance and secondary prevention programs for patients with chronic hepatitis and nutrition associated metabolic liver diseases are the most important steps to reduce the risk of HCC in the region. PMID- 21307987 TI - Innovation in Indian healthcare: using health information technology to achieve health equity for American Indian and Alaska Native populations. AB - The US Indian health system utilizes a diverse range of health information technology and innovative tools to enhance health service delivery for American Indians and Alaska Natives. This article provides an overview of efforts and experience using such tools to achieve health equity for American Indian and Alaska Native communities. Specific attention is given to the Indian Health Service Electronic Health Record and to two examples of telehealth innovation. PMID- 21307988 TI - Role of mobile health in the care of culturally and linguistically diverse US populations. AB - Emerging trends in the health-related use of cell phones include the proliferation of mobile health applications for the care and monitoring of patients with chronic diseases and the rise in cell phone usage by Latinos and African Americans in the United States. This article reviews public policy in four areas with the goal of improving the care of patients belonging to culturally and linguistically diverse populations: 1) mobile health service access and the physician's duty of care, 2) affordability of and reimbursement for health related services via mobile phone, 3) protocols for mobile health enabled patient health data collection and distribution, and 4) cultural and linguistic appropriateness of health related messages delivered via cell phone. The review demonstrates the need for policy changes that would allow for reimbursement of both synchronous and asynchronous patient-provider communication, subsidize broadband access for lower-income patients, introduce standards for confidentiality of health data transmitted via cell phone as well as amplify existing cultural and linguistic standards to encompass mobile communication, and consider widespread public accessibility when certifying new technologies as "medical devices." Federal and state governments must take prompt action to ensure that the benefits of mobile health are accessible to all Americans. PMID- 21307989 TI - Use of health information technology among racial and ethnic underserved communities. AB - This article examines the potential role of health IT in addressing healthcare disparities among racial and ethnic minority populations. An overview of health IT utilization among healthcare providers notes certain characteristics that may disproportionately affect minority populations. Current and emerging health IT use among racial and ethnic minority populations is examined, highlighting areas in which technology use in these populations differs from that of nonminority populations and emphasizing the importance of new social media applications in healthcare education and delivery. Following a discussion of adoption and utilization barriers for providers as well as for patients and caregivers, specific opportunities to address healthcare disparities through health IT use are identified at the provider, patient/caregiver, and healthcare system levels. The article identifies several technical, practical, and human challenges to health IT adoption and stresses the need for the healthcare system to embrace the full spectrum of emerging health IT opportunities to address healthcare disparities. PMID- 21307990 TI - The care of patients with colon cancer: current treatment, and evaluation of new surgical approaches. AB - BACKGROUND: Multi-center observational studies in surgery can yield important findings, as long as they are appropriately designed and monitored and employ modern methods of statistical analysis. METHODS: In a multi-center quality assurance study carried out in 346 German hospitals from 2000 to 2004, data were collected from a total of 31 055 patients who underwent surgery for colon carcinoma. The current, overall state of medical care for this disease was analyzed, with particular attention to aspects of quality assurance. RESULTS: 46.7% of the patients were in the advanced, prognostically unfavorable stages UICC III and IV and had an overall 5-year survival of 53.8% in stage III and 9.8% in stage IV. Laparoscopic intention-to-treat procedures were performed on 1401 patients (4.7%), of whom 20.6% required conversion to laparotomy. The patients who required conversion to laparotomy had a worse overall outcome. 28 271 patients were treated with tumor resection and primary anastomosis; in this group, 3% (n = 844) developed an anastomotic leak. Logistic regression analysis identified the following risk factors for anastomotic leakage: duration of surgery, ileus, tumor localization in the left colon, and single-layer suturing. CONCLUSION: This multi-center observational study yields valid findings about the epidemiology and overall quality of medical care for colon carcinoma in Germany. PMID- 21307991 TI - Unemployment, social support and health problems: results of the GEDA study in Germany, 2009. AB - BACKGROUND: It is well documented that the unemployed have more health problems than the employed, and that social support facilitates coping with unemployment. The association of unemployment and social support with health was examined on the basis of representative data derived from a German study. METHODS: The GEDA study (Gesundheit in Deutschland Aktuell [Current Health in Germany]) was conducted in 2008/09 by the Robert Koch Institute, the nationwide governmental public health agency in Germany. For this paper, we analyzed data from the GEDA study that were obtained from 12022 persons aged 30 to 59. We used health indicators taken from the Four-Item Healthy Days Core Module of the Centers for Disease Control (CDC), and we measured social support on the Oslo Three-Item Social Support Scale. We report the findings on impairment in three distinct areas (physical, emotional, and functional) and the results of a multivariate statistical analysis. RESULTS: Unemployed persons aged 30 to 59 years suffer physical, emotional, and functional impairment more commonly than employed persons. Men and women with little social support are more likely to be impaired in these three areas whether they are employed or not. Regression analysis reveals that unemployment and social support have significant, independent effects on both the incidence of such impairments (OR(unemployed)= 1.2-1.7, OR(supported)= 0.4-0.9) and on their duration (IRR(unemployed)= 1.3-1.8, IRR(supported)=0.6-0.8) after age, income, and education have been controlled for. CONCLUSION: Physicians should be mindful of the deleterious effect of unemployment on health and should encourage unemployed patients to participate in social networks, as the evidence shows that social support can have health benefits. PMID- 21307993 TI - All that aches is not arthritis. AB - This article is the result of a round table discussion at the Charlton Family Centre in Hamilton about a patient presenting with musculoskeletal pain. It demonstrates how the participants approached the case and the problem solving processes involved during the discussion. The article is not a guide to the differential diagnosis of musculoskeletal pain. PMID- 21307992 TI - Lichen sclerosus in boys. AB - BACKGROUND: Lichen sclerosus (LS) is a sclerosing skin disease. When it appears in boys, it nearly always affects the penis and usually causes phimosis requiring surgical treatment. The clinical significance of this disease in boys is inadequately recognized. METHODS: The etiology, clinical manifestations, diagnosis, and treatment of LS in boys are presented in the light of a review of selected literature. We also present our own experience with this disease in an ambulatory pediatric surgery practice. RESULTS: LS has long been recognized as a disease of the prepubertal male genitalia (in such cases, the condition is also called "balanitis xerotica obliterans"). It is thought to be the main cause of acquired phimosis, and it can also involve the meatus and urethra as it progresses. Its possible association with squamous cell carcinoma of the penis remains unclear. Its etiology is unknown; its pathophysiological mechanism involves T-lymphocyte-mediated inflammation. The treatment of choice is complete circumcision. There is still controversy regarding the conservative treatment of LS with topical steroids. CONCLUSION: LS is much more common in boys than is generally assumed. Lichen sclerosus should be suspected in any case of acquired phimosis. Treatment with complete circumcision does not necessarily bring about a definitive cure. Further research on the pathogenesis of this disease is needed. PMID- 21307994 TI - Newer drugs for arthritis. AB - The major area of new drug discoveries for the treatment of arthritis is in non steroidal anti-inflammatory agents (NSAIA). Unfortunately, as yet no new and safe drug of major significance has appeared. Aspirin still ranks high beside the newcomers. Indomethacin, ibuprofen, naproxen, fenoprofen and tolmetin are described and their roles in therapy are discussed. A further group of older drugs receiving new application in the treatment of arthritis is presented. These include penicillamine and the immunosuppressive drugs. Gold and chloroquin are also discussed to put these agents in their proper perspective. PMID- 21307995 TI - [Not Available]. PMID- 21307996 TI - Interpreting blood tests in rheumatology. AB - The diagnosis of most rheumatic conditions is based on clinical findings. Blood tests help to narrow down the differential diagnosis in a problem rheumatologic case, and may help determine the activity and severity of the disease being followed, but should not be relied upon in isolation. PMID- 21307997 TI - The rheumatoid arthritic at home. AB - Most management of rheumatoid arthritis must take place in the patient's own home with only intermittent professional help. With good planning and instruction it is possible to create in the home a milieu appropriate not only for possible inducement of remission, but also for continuing care during even protracted disability.The mainstay of treatment in all stages of this disease is the achievement of a right balance between rest and activity. In the initial stages, proper rest and support, including splinting of the joints with other simple measures, will greatly relieve pain and help control the inflammatory process. A variety of therapeutic exercises can reduce the likelihood of secondary immobility and promote restoration of strength and function.For the patient in whom the disease has become chronic and disabling a wide variety of self-help devices can be prescribed, together with appropriate home modifications. PMID- 21307998 TI - Fibrositis syndrome. PMID- 21307999 TI - Voluntary review in family practice. AB - Compulsory examinations and reviews are becoming an increasingly important part of the physician's professional life. Four examples of voluntary review procedures for family physicians are described. Implementation of regular voluntary review processes could offset the imposition of such procedures through legislation. PMID- 21308000 TI - Efficacy of allopurinol in single daily dose. AB - Allopurinol 300 mg once daily was compared with allopurinol, 100 mg tid in 17 patients with gouty arthritis and/or gouty nephrolithiasis. Weekly serum uric acid levels showed small but statistically significant differences between dosage regimens in four patients. Two acute attacks of gouty arthritis occurred in two different patients during once daily dosing of the allopurinol. There were no side effects attributable to the once daily dosage regimen. PMID- 21308002 TI - Concept Systems and Ontologies: Recommendations for Basic Terminology. AB - This essay concerns the problems surrounding the use of the term "concept" in current ontology and terminology research. It is based on the constructive dialogue between realist ontology on the one hand and the world of formal standardization of health informatics on the other, but its conclusions are not restricted to the domain of medicine. The term "concept" is one of the most misused even in literature and technical standards which attempt to bring clarity. In this paper we propose to use the term "concept" in the context of producing defined professional terminologies with one specific and consistent meaning which we propose for adoption as the agreed meaning of the term in future terminological research, and specifically in the development of formal terminologies to be used in computer systems. We also discuss and propose new definitions of a set of cognate terms. We describe the relations governing the realm of concepts, and compare these to the richer and more complex set of relations obtaining between entities in the real world. On this basis we also summarize an associated terminology for ontologies as representations of the real world and a partial mapping between the world of concepts and the world of reality. PMID- 21308001 TI - Hippocampal oscillations in the rodent model of schizophrenia induced by amygdala GABA receptor blockade. AB - Brain oscillations are critical for cognitive processes, and their alterations in schizophrenia have been proposed to contribute to cognitive impairments. Network oscillations rely upon GABAergic interneurons, which also show characteristic changes in schizophrenia. The aim of this study was to examine the capability of hippocampal networks to generate oscillations in a rat model previously shown to reproduce the stereotypic structural alterations of the hippocampal interneuron circuit seen in schizophrenic patients. This model uses injection of GABA-A receptor antagonist picrotoxin into the basolateral amygdala which causes cell type specific disruption of interneuron signaling in the hippocampus. We found that after such treatment, hippocampal theta rhythm was still present during REM sleep, locomotion, and exploration of novel environment and could be elicited under urethane anesthesia. Subtle changes in theta and gamma parameters were observed in both preparations; specifically in the stimulus intensity-theta frequency relationship under urethane and in divergent reactions of oscillations at the two major theta dipoles in freely moving rats. Thus, theta power in the CA1 region was generally enhanced as compared with deep theta dipole which decreased or did not change. The results indicate that pathologic reorganization of interneurons that follows the over-activation of the amygdala-hippocampal pathway, as shown for this model of schizophrenia, does not lead to destruction of the oscillatory circuit but changes the normal balance of rhythmic activity in its various compartments. PMID- 21308003 TI - SOAs for Scientific Applications: Experiences and Challenges. AB - Over the past several years, with the advent of the Open Grid Services Architecture (OGSA) (19) and the Web Services Resource Framework (WSRF) (25), Service-oriented Architectures (SOA) and Web service technologies have been embraced in the field of scientific and Grid computing. These new principles promise to help make scientific infrastructures simpler to use, more cost effective to implement, and easier to maintain. However, understanding how to leverage these developments to actually design and build a system remains more of an art than a science. In this paper, we present some positions learned through experience that provide guidance in leveraging SOA technologies to build scientific infrastructures. In addition, we present the technical challenges that need to be addressed in building an SOA, and as a case study, we present the SOA that we have designed for the National Biomedical Computation Resource (NBCR) (9) community. We discuss how we have addressed these technical challenges, and present the overall architecture, the individual software toolkits developed, the client interfaces, and the usage scenarios. We hope that our experiences prove to be useful in building similar infrastructures for other scientific applications. PMID- 21308004 TI - Reduction of electro-optic half-wave voltage of 0.93Pb(Zn(1/3)Nb(2/3))O(3) 0.07PbTiO(3) single crystal through large piezoelectric strain. AB - The influence of converse piezoelectric effect on the electro-optic coefficient of single domain relaxor-based 0.93Pb(Zn(1/3)Nb(2/3))O(3)-0.07PbTiO(3) (PZN 0.07PT) has been quantified under ambient conditions. It was found that the large piezoelectric constants d(31) and d(33) have significant influence to the half wave voltage of electro-optic modulators. For single domain PZN-0.07PT crystal, Vpi13T is reduced by a factor of 8 and Vpi13L can be decreased by more than an order of magnitude due to the large piezoelectric effect. Compared to commonly used electro-optic crystal LiNbO(3) and BaTiO(3), PZN-xPT single crystal is much superior for optic phase modulation applications because they have much higher linear electro-optic coefficients and much lower half-wave voltage when piezoelectric strain influence is considered. PMID- 21308005 TI - Maternal Behavior and Children's Early Emotion Regulation Skills Differentially Predict Development of Children's Reactive Control and Later Effortful Control. AB - The role of maternal behavior and children's early emotion regulation skills in the development of children's reactive control, specifically behavioral impulsivity, and later effortful control was examined in a sample of 435 children. HLM analyses indicated significant growth in reactive control across the toddlerhood to early childhood period. Emotion regulation at age-2 positively predicted initial levels of children's reactive control abilities while maternal overcontrol/intrusiveness predicted lower levels of reactive control growth. Maternal behaviors at age-2 predicted children's effortful control abilities at age-5.5. Emotion regulation did not predict effortful control abilities. Maternal behavior and children's early emotion regulation skills may differentially facilitate the development of reactive and effortful control abilities. PMID- 21308006 TI - Coming to the medical olympics? PMID- 21308007 TI - Treating myocardial infarctions in the home. PMID- 21308008 TI - Make nutrition relevant! PMID- 21308009 TI - On donor kidneys. PMID- 21308010 TI - Nasal foreign bodies. PMID- 21308011 TI - Diagnosis and management of inflammatory bowel disease. AB - The onset of ulcerative colitis is characterized by diarrhea and bleeding, while granulomatous ileocolitis may be similar or more obscure with abdominal pain, bowel obstruction, loss of weight, iritis, arthritis or hypoalbuminemia. The diagnosis in ulcerative colitis is made by sigmoidoscopy and barium enema, while small bowel follow through is necessary in ileocolitis. Ulcerative colitis is treated by adrenocorticosteroids as retention enemas when limited to the left colon, intravenous ACTH or steroids in severe pancolitis and oral steroids in others. Sulphasalazine is used in addition to steroids in acute cases and as maintenance to prevent exacerbations. Proctocolectomy is indicated in those with severe disease with complications not responding to steroids. The treatment of Crohn's disease is similar but complicated by small bowel involvement and recurrence after surgery. PMID- 21308012 TI - Viral hepatitis: new aspects of an old disease. AB - The new classification and nomenclature of viral hepatitis and serological markers of hepatitis viruses are presented. Modes of infection, clinical aspects and sequelae of viral hepatitis are outlined. The clinical significance of Australia antigen (HBsAg) is explained, stressing its prognostic value. The problem of asymptomatic HBsAg carriers is discussed and practical guidelines for the prevention of viral hepatitis outlined. The treatment of fulminant hepatitis is unsatisfactory and development of an artificial liver support system is badly needed. Future modes of immunization are listed. PMID- 21308013 TI - The kock pouch: a continent ileostomy with no appliance. AB - In this new operation, a pouch or reservoir is fashioned out of terminal ileum with a valve mechanism at its exit to the skin surface. This allows storage of the liquid bowel contents in an expandable container with no leakage of stool or gas and therefore no skin problems. There is no need for appliances or bags, no embarrassment from the involuntary noise and smell of flatus through the ileostomy. The stoma is created flush and within the bikini line. The patient catheterizes the pouch on an average of three times a day.Not only does this procedure solve many of the complications of a conventional ileostomy, but it helps decrease the amount of emotional trauma suffered by the young ileostomist, greatly improving the quality of life. PMID- 21308014 TI - Functional gastrointestinal disease. AB - Despite their prevalence, functional disturbances of the gastrointestinal tract in response to stress are often disregarded or unrecognized. The nature of these disturbances, particularly the irritable bowel syndrome, is discussed and an outline of treatment programs given, stressing the need for psychotherapy. PMID- 21308015 TI - The etiological significance of related diseases. AB - If disease patterns emerge which show that certain diseases can be related, this is a valuable pointer to a common cause. This article traces the principle of interpreting disease relationships, illustrated by several common conditions of western civilization, for which the common cause is postulated as being removal of fiber from the diet. PMID- 21308016 TI - Cold feet: an unusual case of paresthesia. PMID- 21308017 TI - [Not Available]. PMID- 21308018 TI - Common skin diseases in children. AB - Six common pediatric skin problems are discussed through the use of case histories. Problems of differential diagnosis are outlined, and the various steps and pitfalls in therapy itemized. PMID- 21308019 TI - Skin reactions to cold. AB - Although skin reactions to cold are seen surprisingly infrequently in Canada, it is important to manage them correctly when they do occur. Frostbite, cold urticarias, Raynaud's disease and phenomenon, and several miscellaneous changes are discussed. PMID- 21308021 TI - Self evaluation program. PMID- 21308020 TI - Perioral dermatitis. AB - Perioral dermatitis is a new dermatological entity which occurs mostly in young women as a papular or papulovesicular erythematous skin eruption usually involving the nasolabial folds, upper lip and the chin, with a clear zone around the vermilion border of the lips. The cause of perioral dermatitis is not known, but several factors seem capable of triggering or inducing its onset, e.g. photosensitivity, prolonged use of topical fluorinated steroids, oral contraceptives, etc. The use of tetracyclines, 250 mg QID two hours before meals and preferably not in conjunction with iron supplements for three or four months, invariably results in good response with clearing of perioral dermatitis. PMID- 21308022 TI - Extended family crisis. AB - What is family medicine? What does a family physician do that defines the discipline? Focusing on an illustrative case history, this new section is designed to answer those questions, showing how the family physician intervenes in a given situation. PMID- 21308023 TI - The Art of Local Treatment (Or Laying it on Right). AB - The principles of formulating a topical prescription are given. Indications for the use of the range of applications in the treatment of skin disease are described. Techniques of local application, dressing materials, and methods are reviewed. PMID- 21308024 TI - Differential diagnosis of some common skin lesions: a morphological viewpoint. AB - Illustrative skin lesions are described and depicted in order to show the importance of seeing in making a diagnosis. Seeing is being neglected in the art and science of medicine - it needs to be revived. PMID- 21308025 TI - [Not Available]. PMID- 21308026 TI - [Not Available]. PMID- 21308027 TI - Early diagnosis of abdominal pain. AB - Differential diagnosis of abdominal pain is vitally important in sorting out those patients who should be sent for immediate surgery and those who can be treated at home, or observed for a period. Careful history and examination are mandatory, since the patient may find the pain difficult to describe and the signs may be minimal. PMID- 21308028 TI - Septicemia. AB - Certain factors which are major determinants in the survival of the septic patient - age, underlying disease, infecting organism - are beyond the physician's control. Others, however, we can have some impact on. These include initial vigorous supportive treatment, early and appropriate antibiotic administration and timely surgical intervention. In the following discussion current understanding of the pathophysiology of sepsis is outlined, together with a practical approach to the problem of patient management. PMID- 21308029 TI - The unconscious diabetic. AB - A rapid accurate diagnosis is essential when faced with a patient in diabetic coma. This article describes differential diagnoses, gives a flow chart of procedures to follow in diabetic coma, outlines methods of therapy and warns against the pitfalls attendant upon this condition. PMID- 21308030 TI - Anaphylaxis. PMID- 21308031 TI - The case for keeping the family physician in the emergency department. AB - For several reasons, emergency department utilization has shot up in the last few years, most notably in the area of non-urgent care. The College of Family Physicians has been concerned with the status and education of family physicians working in emergency departments and has formed an ad hoc Committee on the Emergency Care Physician. The committee's findings and recommendations are documented in this article. PMID- 21308032 TI - Rushing Roulette: The State of Canada's Ambulance Services. AB - In a Canada-wide survey, CANADIAN FAMILY PHYSICIAN found a startling divergence in provincial standards for ambulance crews and vehicles.While some provinces had developed a well-integrated ambulance system with central dispatching, rigorous standards for attendants and advanced paramedical training programs, in some the ambulances are run almost entirely by local undertakers. PMID- 21308033 TI - The terminal patient. AB - What is family medicine? What does a family physician do that defines the discipline? Focusing on an illustrative case history, this new section is designed to answer those questions, showing how the family physician intervenes in a given situation. PMID- 21308034 TI - [Not Available]. PMID- 21308035 TI - [Not Available]. PMID- 21308036 TI - [Not Available]. PMID- 21308037 TI - Respiratory Failure: What is It and How Do I Treat it? PMID- 21308038 TI - Occupational chest problems. AB - The interaction between chest problems and occupational environments occurs in a field wider than industry. Some common examples are described to show where the family physician's index of suspicion should be raised concerning occupational relationships of such problems. PMID- 21308040 TI - Recent therapy for reversible airway disease. AB - The current therapy for extrinsic and intrinsic asthma, together with that of 'wheezing bronchitis', is presented, with special attention to bronchodilators and adrenocorticosteroids. PMID- 21308039 TI - A study of inhaled beclomethasone dipropionate therapy in asthma. AB - Fourteen patients with asthma have been followed in a long term clinical trial of the inhaled synthetic corticosteroid, beclomethasone dipropionate. All the patients were corticosteroid-dependent, with significant corticosteroid adverse effects. Twelve of the patients were able to stay on long term beclomethasone dipropionate therapy. Eight were able to discontinue use of systemic corticosteroids. There was a statistically significant reduction in the use of systemic corticosteroids (P<0.01) for the group when they were transferred to beclomethasone dipropionate. There was also an improvement of corticosteroid adverse effects in ten patients, but no significant change in their symptom scores. Several points of caution are stressed concerning long term clinical use of this promising drug. PMID- 21308041 TI - Why make housecalls? PMID- 21308042 TI - Mortality and morbidity in an employed population. AB - The major health problems of an employed male population in a steel plant were identified. Five groups of conditions (arteriosclerotic and degenerative heart disease, non-occupational accidents, occupational accidents and illness, respiratory disease, and mental illness) accounted for 70 percent of all deaths and 58 percent of total illness absence.Since many of these conditions are potentially preventable or amenable to early intervention, effective means of identifying individuals at risk and of providing suitable prevention or intervention programs are necessary. PMID- 21308043 TI - The problem of chronic care. AB - With increasing numbers of elderly people requesting some sort of institutional care, doctors must be familiar with the types of facilities available in their communities for these patients. A study is presented illustrating how the lack of readily available extended care facilities is leading to inappropriate and costly use of acute hospital beds. The levels of care available in Ontario under the Extended Care Plan are reviewed and their costs to the patient are specified in hopes that physicians will be better equipped to guide their patients in an appropriate choice of institution. PMID- 21308044 TI - [Not Available]. PMID- 21308045 TI - [Not Available]. PMID- 21308046 TI - Take aim and fire: laboratory investigations and the family physician. AB - This article discusses the attitude of the family physician to laboratory investigation and puts forward a plea for the rational, economical, directed use of such investigations - the rifle bullet as opposed to the scatter-gun technique. As well as outlining the principles, their application to each section of the clinical laboratory is described in some depth. A request for laboratory investigation is a request for consultation and the full value of investigation cannot be achieved without such consultation. PMID- 21308047 TI - The practicality and significance of microbiological culturing in family practice. AB - Many recommendations from microbiologists and infectious diseases physicians are suitable for hospital infectious diseases practice but are very difficult to employ in family practice. This paper bears that situation in mind when outlining worthwhile cultures for diseases commonly seen by family physicians. PMID- 21308048 TI - Who should investigate infertility? AB - The author outlines step by step the investigation of the infertile couple. Careful attention is given to efficient use of time so that infertility investigation is within the realm of the family physician. PMID- 21308049 TI - Diagnostic procedures in parasitic diseases. AB - This article offers some guidelines for investigating patients with suspected tropical and parasitic diseases. The common symptoms of tropical diseases as seen in Canadians returning from the tropics are discussed and diagnostic approaches suggested. Simple office laboratory procedures for the diagnosis of the common intestinal and blood parasites are outlined. The value and pitfalls of serological tests in parasitic diseases are discussed. PMID- 21308050 TI - Self evaluation program. PMID- 21308051 TI - Nuclear medicine and diseases of the chest. AB - Nuclear medicine encompasses the diagnostic use of unsealed sources of radiation in patient care, and is largely a diagnostic specialty. A variety of methods exist to assist in the diagnosis and management of patients with chest disease. Already the application of pulmonary perfusion scintigraphy makes a major contribution to the diagnosis of pulmonary thromboembolism in the face of the often unhelpful chest radiograph, or if pulmonary angiography is contraindicated or unavailable. The rationale, applications and limitations of appropriate radionuclide methodologies such as pulmonary perfusion and ventilation scintigraphy, angiography, bone and tumor scintigraphy and radioimmunoassay are described. PMID- 21308052 TI - Occupation hearing loss and the primary care physician. AB - Industrial noise has become a major concern among both health and safety professionals. The primary care physician is in a position to initiate preventive action by ensuring early detection of hearing deficiencies. PMID- 21308054 TI - [Not Available]. PMID- 21308053 TI - Congenital dislocation of the hip. AB - The implications of a diagnosis of congenital dislocation of the hip and the importance of the role of the family physician in early detection and treatment are identified.A review of the salient clinical features of congenital dislocation of the hip is undertaken. The results of a survey carried out in the author's practice on an unusual incidence of congenital dislocated hip are reviewed. PMID- 21308055 TI - [Not Available]. PMID- 21308056 TI - Getting into the System: The Physician's Staff and Waiting Room. AB - This article represents a panel discussion with the staff of the Family Practice Unit at the Plains Health Centre, Regina, Sask. It outlines those things found helpful in presenting a positive image to the patient by a physician and his staff - telephone contacts, waiting rooms, patient flow, and common complaints. PMID- 21308057 TI - What really goes on in the psychiatric consultation. AB - The general hospital context within which the need for a psychiatric consultation emerges is briefly described. The forms that such requests assume are classified. The communicative distortions observed in this process are understood as a solution of compromise dictated by role perception, organizational communication style and the actual needs of the professionals requesting the consultation. Solutions to the creation of this communicative impasse are offered. PMID- 21308058 TI - The consultation process. AB - This article is a discussion between two family doctors and three consultants about the problems of consultation from both points of view. Some suggestions are made as to how we might improve the quality of this part of our medical practice. PMID- 21308059 TI - Overcoming language barriers. AB - Many family physicians in Canada experience language and cultural barriers between themselves and their patients. Several aspects of the ensuing problems are described and some practical suggestions for solutions are made. The importance of health education for new Canadians in the family physician's office as well as through the media and community projects is stressed. PMID- 21308060 TI - The problem of the population at risk. AB - Until we know numbers of patients at risk, their ages and sexes, we can do very little epidemiological research in family practice.This pilot study sought to establish whether family physicians could define their populations at risk, whether volunteer recording would work, and whether medicare-generated data could be used. PMID- 21308061 TI - Chronic obesity in a family. AB - Under threat by the family practice nurse and physician of future disinterest in their obesity problem, a family who had been refractory to all previous weight loss programs worked out a program based on behavior modification principles. The program that evolved provided them through their weight loss with a way of deriving pleasure from the competition with each other and from their joint dislike of the person who recorded their weight each week. All members have lost weight continuously over a three month period. PMID- 21308062 TI - Improving Communications: Use of the PHN In Family Practice. AB - One hundred and eight patient referrals to the public health nursing staff of the Regional Municipality of Waterloo were made between May 1, 1974 and April 30, 1975. The role of the public health nurse (PHN) seconded to an urban family practice in a group affiliation is discussed, with emphasis on the types of problems referred and the advantages of secondment for the doctor, the nurse and the patient. PMID- 21308063 TI - Library services for family physicians. AB - Family physicians have special information needs. Local access to the family medicine literature can be improved by encouraging hospital and medical centre libraries to consider using the Suggested Core Library List for Family Medical Centres (included at the end of the article) and by following the basic steps listed here in using a medical library. PMID- 21308064 TI - Suggested core library list for family medical centres, 1976. PMID- 21308065 TI - [Not Available]. PMID- 21308066 TI - WONCA- Qu'est-ce que ca peut bien etre? PMID- 21308067 TI - Reactions of canadian women to the pap test and breast self-examination. AB - The Canadian Cancer Society's public education program is based on the premise that early detection of cancer, followed by immediate treatment, saves lives. To promote this program the Society has developed the Seven Steps to Health which include "Have a Pap test" and "Do a monthly breast self-examination." To evaluate the effect of these two 'steps' on the female population of Canada, a public opinion poll was conducted which included a national random sample of women representative of age, educational and socio-economic levels and occupation. The poll showed that 76 percent of Canadian women have had at least one Pap test and 63 percent do breast self-examination regularly or occasionally. Significant relationships were revealed between social factors and participation in these health measures and reasons are elicited for non-participation. PMID- 21308068 TI - Are hysterectomies necessary? AB - Hysterectomy is a most useful surgical procedure. However, its indiscriminate performance has made this procedure suspect and it is being scrutinized at all levels of health care. Recent studies show that hysterectomy should be carried out for medical reasons ascertained by the gynecologist and not at the whim of a patient.The Hysterectomy Committee of the College of Physicians and Surgeons of Saskatchewan studied hysterectomies in Saskatchewan over the period 1970-1975. This committee consisted of two obstetrician gynecologists, a surgical pathologist, a social worker, a systems analyst, a medical student, a physician from the Medical Care Insurance Commission of Saskatchewan and a family physician. PMID- 21308069 TI - Treating anxious women today - a therapeutic. AB - Women seek help for psychological reasons earlier than men do, and most of these women initially present to their family physician.The author discusses the role of the family physician in the treatment of the anxious woman patient, and emphasizes the need for social awareness in dealing with such problems. PMID- 21308070 TI - Evaluating the cervix. AB - The colposcope is a stereoscopic microscope mounted on a tripod and is capable of magnifying the cervix ten to 45 times. Differential diagnosis of a diseased cervix is easily obtained through using the colposcope. A diagnosis of epidermization, ectopy, atypical epithelial changes and their extent can be established immediately. Use of colposcopy should diminish the use of tissue biopsy for benign cervical lesions and will modify the treatment of cervical dysplasia and carcinoma in situ by preserving the uterus in many cases. PMID- 21308071 TI - Selection of the family physician. AB - This study was conducted to examine the characteristics of 'initial visits' by patients, contrasted with 'average visits', to discover what is needed to establish a satisfactory patient-physician relationship leading to long term continuous care.In the initial visit, the patient presents with a relatively simple problem which will enable the physician to demonstrate his ability without unduly taxing his skills. This suggests that patients create an opportunity for a thorough face-to-face contact to provide an opportunity for the physician to display his ability so that the patient's desire for a long term relationship can be achieved. The study also suggests that patients' expectations have changed in proportion to changes in the mode of medical practice. PMID- 21308072 TI - Microcephaly and vulnerability of the brain in the etiology of cerebral palsy. AB - A review of data showed that of 100 children referred with a diagnosis or suspected diagnosis of cerebral palsy (CP), 37 children had microcephaly, defined as a head with a circumference of two standard deviations (SD) or more below the mean for age and sex. Is such a finding of any significance in the etiology of cerebral palsy? PMID- 21308073 TI - Prevention, assessment and treatment of decubitus ulcers. AB - Decubitus ulcers are not uncommon in chronically ill and disabled people who are bedridden. Prevention is better than cure, but the chief ingredient in both is avoidance of excess pressure on the tissues, especially over bony prominences. If an ulcer does occur, it requires scrutiny, appropriate therapy with the agents listed and repeated re-examination. PMID- 21308074 TI - Caring for the patient with breast cancer. AB - The management of the patient with cancer of the breast is a challenge to the family physician. Foremost is the need to educate the patient about self examination and the physician's role in providing a thorough clinical evaluation and the appropriate use of mammography. Once a diagnosis is established the patient requires counselling and referral to the needed specialists. Finally, the family physician is in a key position to coordinate the necessary services, provide access to rehabilitation programs and offer the necessary psychological support to the patient and her family. PMID- 21308076 TI - Characteristics of an effective medical teacher. PMID- 21308075 TI - Agony in academia: a play. PMID- 21308077 TI - [Not Available]. PMID- 21308078 TI - [Not Available]. PMID- 21308079 TI - [Not Available]. PMID- 21308080 TI - Examination of the mouth. AB - In an examination of the mouth, a definite order should be followed, finishing with the presenting lesion. This article lists the most frequent local or systemic origins of oral lesions, and makes a plea for better recording of oral abnormalities. PMID- 21308081 TI - Congenital abnormalities of the mouth. AB - The spectrum of congenital malformations in the mouth is broad. The incidence of any one condition is not great, with the exception of the anomalies of cleft lip and cleft palate. Most of these oral malformations can produce urgent problems in neonatal management for the physician, including the care of the distraught parents. Considerable plastic and reconstructive surgery is involved in the subsequent management. The modern key to the complete successful management of these patients is the participation of a multidiscipline team. PMID- 21308082 TI - Oral infections. AB - THIS ARTICLE REVIEWS AND DISCUSSES RECOGNITION AND MANAGEMENT OF EIGHT COMMON PRIMARY INFECTIONS OF THE MOUTH: thrush, perleche, warts, necrotizing gingivitis, aphthous ulcers, herpes simplex, herpangina and syphilis. PMID- 21308083 TI - Cancer of the mouth and lip. AB - Cancer of the lip and oral cavity are discussed, with emphasis on incidence, etiology, early diagnosis, treatment, curability, complications and after-care. PMID- 21308084 TI - Medical Management of Recurrent ENT Problems in Childhood. AB - Many children, particularly preschoolers, present with frequent symptoms associated with ear, nose and throat illness. Tonsillectomy-adenoidectomy (T&A) is widely employed in an attempt to alleviate these symptoms, although there is little valid evidence that long-lasting improvement occurs. Because of the high cost in dollars and morbidity associated with T & A, the author presents alternative practical ways of managing recurrent non-specific respiratory infections, recurrent acute otitis media and serous otitis media, recurrent upper airway obstruction and recurrent streptococcal sore throat. With appropriate medical management and patient compliance, very few children should require T & A. PMID- 21308085 TI - Hungary: home of the specialist. PMID- 21308086 TI - Budapest - twin city with a split personality. PMID- 21308088 TI - [Not Available]. PMID- 21308087 TI - A boy with abdominal pain. PMID- 21308089 TI - [Not Available]. PMID- 21308090 TI - Survey of a rural practice: rainy river 1975. AB - A study of family practice in a small rural community in northwestern Ontario was conducted over a one year period from January 1, 1975 - December 31, 1975.An attempt was made to define the population at risk and, in addition to recording morbidity in terms of illness episodes, study was made of referral patterns in the practice, the use of a small hospital staffed solely by a family physician, and differences in morbidity between Indian and non-Indian patients. PMID- 21308092 TI - Getting it Together: Health Care in a Rural Community. AB - In 1972, with the aid of a Local Initiatives Program grant, a group from Simon Fraser University studied the community of Port Alice, B.C., and the surrounding area. They concluded that health care for the community would have to involve the citizens themselves, and would necessitate regionalization and integration of all services in order to be effective. This paper summarizes and abstracts from the group's final report those findings which are applicable to many rural communities. The support of the study group, particularly Dr. Robert Horsfall of the Department of Geography, SFU, is gratefully acknowledged. PMID- 21308091 TI - The armstrong project: what have we learned? AB - In December 1974 the first volunteer went to staff the Armstrong Project - a joint effort of the Ontario Ministry of Health and the CFPC Ontario Chapter to provide health care for the province's most underserviced area. This article describes the experiences of the physicians who have served there. PMID- 21308093 TI - Screening for hypertension in the emergency department. AB - Because of the 10 percent incidence of hypertension in the adult population it is important to find an effective method for hypertension screening. A protocol is presented to screen for hypertension in the emergency department of a general hospital. Of 100 patients screened in our emergency, four asymptomatic hypertensives were found. Also, nine patients with a previous history of hypertension were found to be inadequately treated. PMID- 21308094 TI - Teaching family medicine. AB - Students should study the family system just as they would an organ system, making use of family studies and home visits. A comparison of private and academic faculty revealed the need to instruct private practitioners on patient selection and teaching methodology. Experience has shown that patients from the lower socioeconomic classes tend to allow the student to participate more in their family life and health care and that, in return, the student is often able to assist these patients in some way. Faculty must guide, monitor, and assist students with problems. Audit of students' and patients' reports on and evaluations of the family study will provide valuable information for planning future programs or revamping continuing ones. PMID- 21308095 TI - Medicine - as practiced on the north sea. PMID- 21308096 TI - Potential child abuse. PMID- 21308098 TI - CME and the Rural Physician. PMID- 21308097 TI - Preceptorships for undergraduates: an evaluation. PMID- 21308099 TI - [Not Available]. PMID- 21308100 TI - [Not Available]. PMID- 21308101 TI - Are you hooked, doctor?: addiction among physicians. AB - In an issue devoted to addictions one dare not overlook the fact that physicians are unfortunately a very addiction-prone group. This paper touches upon the origins, symptoms, and signs of a number of addictions common among physicians. First are the socially respectable addictions of work, food and tobacco. Then a look is taken at the socially unacceptable addictions through a variety of mood altering drugs from alcohol to narcotics. Most physicians are very keen on maintaining their freedom. One of the greatest threats to the freedom of many physicians is the development of an addiction. PMID- 21308102 TI - The phenomenon of tobacco smoking. AB - The social acceptance of tobacco prevents recognition of the fact that most regular smokers are addicted to nicotine. We have no facilities for dealing with this problem and there are no specific treatments; but group techniques may help some smokers to quit. Education and research may eventually provide solutions; but to date they have not been effective. Realistic expectations and acceptance of his limitations will permit the family physician to save time and energy when he is confronted by a persistent smoker. PMID- 21308103 TI - Narcotic addiction. AB - This article presents the major features of narcotic addictions, focusing on the role of methadone as a means of controlling or removing the addiction.It concludes with some observations on society's attitude towards addicts, addictions and programs for control of addiction. PMID- 21308104 TI - Young people and non-medical drug usage. AB - In our experience with young people at the Halifax Youth Clinic, we have found that the majority seen use drugs non-medically. A group with whom we have had a significant amount of experience are solvent users. For these youths, drug usage contributes to physical and sociopsychological problems, both on a short-term and long term basis. PMID- 21308105 TI - Contributing factors in pain relief for cancer patients. AB - Twenty-eight cancer patients in whom pain was a problem were interviewed over a seven week period. At the end of the period, 11 patients were still suffering the same amount of pain (moderate to severe pain as measured by the Distress Score Method of Marks and Sacher). The reasons for this include medication, the patients' attitude to drugs, mental confusion and other psychosocial problems. We propose that most of the problems would be solved by individualizing therapy and giving drugs regularly in adequate dosage. PMID- 21308106 TI - Psychopharmacology in family practice: a guide to usage. AB - Psychopharmacology is made needlessly complicated by the numerous basic psychotropic drugs and all their available proprietory variations. In the face of this artificial complexity, the family practitioner needs to know well the uses and side effects of only a few basic drugs. A guide to usage is provided, to outline the basic needs in a family practice. PMID- 21308108 TI - [Not Available]. PMID- 21308107 TI - The team approach to health care in the home. AB - This article describes a program for health care in the home, centred on the activities of a community nurse practitioner working with several physicians. Problems and benefits of the experience are identified. Potential of improved functioning in the home, better level of health and cost savings with regard to hospital stay are suggested as possible benefits of this approach. Enough soft data have been accumulated to proceed with more formal investigation. PMID- 21308109 TI - [Not Available]. PMID- 21308110 TI - Do MDs' Prescribing Habits Contribute Greatly To Drug Abuse? PMID- 21308111 TI - Proteomics analysis identifies PARK7 as an important player for renal cell resistance and survival under oxidative stress. AB - Renal fibrosis is a process that is characterized by declining excretory renal function. The molecular mechanisms of fibrosis are not fully understood. Oxidative stress pathways were reported to be involved in renal tissue deterioration and fibrosis progression. In order to identify new molecular targets associated with oxidative stress and renal fibrosis, differential proteomics analysis was performed with established renal cell lines (TK173 and HK 2). The cells were treated with oxidative stress triggering factor H(2)O(2) and the proteome alterations were investigated. Two dimensional protein maps were generated and differentially expressed proteins were processed and identified using mass spectrometry analysis combined with data base search. Interestingly the increase of ROS in the renal cell lines upon H(2)O(2) treatment was accompanied by alteration of a large number of proteins, which could be classified in three categories: the first category grouped the proteins that have been described to be involved in fibrogenesis (e.g. ACTA2, VIN, VIM, DES, KRT, COL1A1, COL4A1), the second category, which was more interesting involved proteins of the oxidative stress pathway (PRDX1, PRDX2, PRDX6, SOD, PARK7, HYOU1), which were highly up-regulated under oxidative stress, and the third category represented proteins, which are involved in different other metabolic pathways. Among the oxidative stress proteins the up-regulation of PARK7 was accompanied by a shift in the pI as a result of oxidation. Knockdown of PARK7 using siRNA led to significant reduction in renal cell viability under oxidative stress. Under H(2)O(2) treatment the PARK7 knockdown cells showed up to 80% decrease in cell viability and an increase in apoptosis compared to the controls. These results highlight for the first time the important role of PARK7 in oxidative stress resistance in renal cells. PMID- 21308112 TI - Epitaxial growth and electrochemical properties of Li4Ti5O12 thin-film lithium battery anodes. AB - Epitaxial Li(4)Ti(5)O(12) thin-films were successfully synthesized on SrTiO(3) single-crystal substrates with (111), (110), and (100) lattice plane orientations using pulsed laser deposition (PLD). Thin-film X-ray diffraction (XRD) revealed that the Li(4)Ti(5)O(12) films had the same orientation as the SrTiO(3) substrates: Li(4)Ti(5)O(12) (111) on SrTiO(3) (111), Li(4)Ti(5)O(12) (110) on SrTiO(3) (110), and Li(4)Ti(5)O(12) (100) on SrTiO(3) (100). These epitaxial films contained island structures, and the morphology of the (111), (110), and (100) films, observed by field emission scanning electron microscopy (FE-SEM), exhibited angular, needle-like, and circular shapes, respectively. The electrochemical properties of 20 nm thick Li(4)Ti(5)O(12) (111) and (110) films were investigated by cyclic voltammetry. Reversible intercalation proceeded through both lattice planes due to the three-dimensional diffusion pathway of lithium in the spinel framework. Reduction peaks in the first cathodic scan appeared at different positions from those in subsequent scans, suggesting a surface reconstruction at the Li(4)Ti(5)O(12) surface due to interfacial reactions. PMID- 21308114 TI - Preferential suppression of high-energy upconverted emissions of Tm3+ by Dy3+ ions in Tm3+/Dy3+/Yb3+-doped LiYF4 colloidal nanocrystals. AB - The intensity of high energy UV and blue upconverted emissions of Tm(3+) ions in Tm(3+)/Yb(3+) co-doped LiYF(4) colloidal nanocrystals was selectively reduced compared to the NIR emission at 802 nm. This was achieved by doping a small amount of Dy(3+) ions into the host matrix. PMID- 21308119 TI - New high-nuclearity manganese clusters containing mixed chelating ligands: syntheses, crystal structures and magnetochemical characterization. AB - Two polynuclear mixed-valence manganese clusters, [Mn(13)] and [Mn(16)], containing mixed chelating ligands were synthesized and structurally characterized. The alternating current (AC) susceptibilities of both complexes reveal nonzero frequency-dependent out-of-phase (chi(M)'') signals. PMID- 21308113 TI - Molecular imaging of cell-based cancer immunotherapy. AB - Cell-based cancer immunotherapy represents a new and powerful weapon in the arsenal of anticancer treatments. Non-invasive monitoring of the disposition, migration and destination of therapeutic cells will facilitate the development of cell based therapy. The therapeutic cells can be modified intrinsically by a reporter gene or labeled extrinsically by introducing imaging probes into the cells or on the cell surface before transplant. Various advanced non-invasive molecular imaging techniques are playing important roles in optimizing cellular therapy by tracking cells and monitoring the therapeutic effects of transplanted cells in vivo. This review will summarize the application of multiple molecular imaging modalities in cell-based cancer immunotherapy. PMID- 21308120 TI - "Nanocatalyst ? reagent-on-a-polymer film": a new polymer-supported system for (electro-)catalytic reactions. AB - Poly(3,4-ethylenedioxythiophene) has been used to immobilize both the metal particle catalyst and the reagent, (cyano-)borohydride, by simple doping and chemical reduction. These films have shown catalytic activity in the hydrogenation of nitrophenol and electro-oxidation of methanol, formic acid and borohydride. PMID- 21308121 TI - Flame synthesis of few-layered graphene/graphite films. AB - We report a fast (in 10-40 s) flame synthesis of high quality few-layered graphene/graphite films, offering the advantages of simplicity, high efficiency, energy saving, low cost and the ability to extend to continuous and mass production of graphene. PMID- 21308122 TI - Synergy between the metal nanoparticles and the support for the hydrogenation of functionalized carboxylic acids to diols on Ru/TiO2. AB - Ruthenium nanoparticles supported on titania are over three times more active than conventional ruthenium on carbon for the hydrogenation of lactic acid. This superior catalytic activity can be due to a combined action of small ruthenium nanoparticles and the titania support. PMID- 21308123 TI - Multiplex cancer cell detection by SERS nanotags with cyanine and triphenylmethine Raman reporters. AB - SERS nanotags have been prepared to accomplish the multiplex detection of cancer cells. Herein we evaluated the adequacy of lipoic acid-containing cyanine derivatives (Cy3LA and Cy5LA) to function as multiplex partners with a triphenylmethine Raman reporter (B2LA) under a single excitation wavelength. SERS experiments enabled the multiplex recognition of two different cancer cells with antibody-conjugated nanotags that were derivatized with optimized cyanine and triphenylmethine reporters. PMID- 21308124 TI - A synthetic approach to a fullerene-rich dendron and its linear polymer via ring opening metathesis polymerization. AB - Through the esterification of an acyl chloride functionalized fullerene precursor with dendritic alcohol, a fullerene-rich dendron containing a norbornene unit at the focal point is prepared for ring-opening metathesis polymerization to obtain its linear polymer with a unimodal and narrow molar mass distribution (PDI = 1.08) by a progressive addition of catalysts. PMID- 21308125 TI - High-performance hydrogen fuel cell using nitrate reduction reaction on a non precious catalyst. AB - The H(2)-NO(3)(-) electrochemical cell using nitrate reduction on a non-precious cathode catalyst shows much improved efficiency despite ~75% reduction of Pt metal loading as compared to typical PEMFCs using typical ORR on precious catalysts. PMID- 21308126 TI - Carrier-mediated electrodialysis. AB - Supported liquid membranes containing valinomycin or a calix[4]arene carrier can support electrodialysis under an imposed transmembrane potential. Under optimal conditions both transmembrane flux and carrier-based cation selectivity are enhanced relative to simple dialysis mediated by the same carriers. PMID- 21308127 TI - Thermodynamic stability of Hoogsteen and Watson-Crick base pairs in the presence of histone H3-mimicking peptide. AB - We found that Hoogsteen base pairs were stabilized by molecular crowding and a histone H3-mimicking peptide, which was not observed for Watson-Crick base pairs. Our findings demonstrate that the type of DNA base pair is critical for the interaction between DNA and histones. PMID- 21308128 TI - Assessment on the distribution and partitioning characteristics of polycyclic aromatic hydrocarbons (PAHs) in Lake Baiyangdian, a shallow freshwater lake in China. AB - The characteristics of polycyclic aromatic hydrocarbons (PAHs) in water, suspended particulate matter (SPM), sediments, and hydrophytes from Lake Baiyangdian, a shallow freshwater lake in China were studied. The low-molecular weight PAHs (2-3 ring PAHs) predominated (61.2 to 84.5%) in all samples. Principal component analysis (PCA) of individual PAHs and the ratios of selected PAHs showed that the PAHs in the lake were mainly petrogenic inputs. The solid liquid distribution coefficient (K(d)) in the water phase was much higher than the bioconcentration factor (BCF), and the leaf concentration factor (LCF) was higher than the root concentration factor (RCF) and stem concentration factor (SCF) in plant-sediment phase. Good linear log/log relationships were observed between the equilibrium partitioning coefficient (K(oc)) and the octanol-water partitioning coefficient (K(ow)), between RCF and K(ow), and between LCF and the octanol-air partitioning coefficient (K(oa)). These results indicated that PAHs accumulated more easily in SPM than in submerged aquatic plants, and some low molecular-weight PAHs could accumulate and be translocated in the lake's media. Media characteristics, contamination sources, and physicochemical properties all affect the partitioning of PAHs among water, SPM, sediments, and hydrophytes. PMID- 21308129 TI - Design of H2O2-dependent oxidation catalyzed by hemoproteins. AB - The monooxygenese activity of cytochrome P450 is successfully introduced into myoglobin by rational design of its active site. Introduction of an aromatic ring, tryptophan, near the heme by site-directed mutagenesis resulted in the hydroxylation of tryptophan at the C6 position by using an almost stoichiometric amount of H(2)O(2). We also altered the substrate specificity of H(2)O(2) dependent P450 by employing a simple substrate trick. Although P450(BSbeta) exclusively catalyzes peroxygenation of long-alkyl-chain fatty acids, oxidation of non-natural substrates such as styrene, ethylbenzene, and 1-methoxynaphthalen are catalyzed by P450(BSbeta) in the presence of decoy molecules having a carboxyl group. Advantageously, the substrate specificity of P450(BSbeta) can be altered by simply adding the decoy molecule without replacing any amino acid residues. Moreover, the stereoselectivity can be controlled by changing the structure of the decoy molecule. The crystal structure analysis of the decoy molecule bound-form of P450(BSbeta) shows that P450(BSbeta) accepts the decoy molecule, whose carboxylate is located at the same position to that of long-alkyl chain fatty acid. PMID- 21308130 TI - Straightforward preparation of biologically active 1-aryl- and 1-heteroarylpropan 2-amines in enantioenriched form. AB - Because of the importance of developing stereoselective syntheses for single enantiomers, a selected panel of racemic biologically active 1-aryl- and 1 heteroarylpropan-2-amines has been prepared, followed by a study of their behavior in enzymatic kinetic resolution (KR) processes. For this purpose, lipase B from Candida antarctica (CAL-B) proved to be an ideal biocatalyst allowing the preparation of the corresponding enantioenriched (R)-amides and (S)-amines by aminolysis reactions. Likewise, dynamic kinetic resolutions (DKR) have been successfully achieved combining the use of CAL-B and Shvo's catalyst. This research constitutes the first example of a lipase-catalyzed DKR process of beta substituted isopropylamines. PMID- 21308131 TI - New strategy for controlling the oligothiophene aggregation mode utilizing the gel-to-sol phase transition induced by crown-alkali metal interactions. AB - A new functional low molecular-weight gelator (LMWG) based on crown-appended quaterthiophene was synthesized and investigated as a new alkali metal cation responsive material with enhanced fluorescence emission upon gel-to-sol phase transition. PMID- 21308132 TI - Synthesis, crystal structures, luminescent and magnetic properties of homodinuclear lanthanide complexes with a flexible tripodal carboxylate ligand. AB - Six new homodinuclear lanthanide(III) complexes with a flexible tripodal carboxylate ligand (H(3)L), of formulae [Ln(2)L(2)(DMF)(4)].4DMF (Ln = La (1), Nd (2), Eu (3), Gd (4), Tb (5), Dy (6), DMF = N, N-Dimethylformamide) have been synthesized. Among them, 1, 2, 3, 4, 6 were characterized by single-crystal X-ray diffraction, which crystallized in the monoclinic space group P2(1)/n with a = 13.309(2) A, b = 27.404(4) A, c = 16.686(3) A, beta = 105.115(2) and V = 5875.2(17) A(3) for 1, a = 13.3016(5) A, b = 27.1952(12) A, c = 16.6339(7) A, beta = 105.030(2) and V = 5811.3(4) A(3) for 2, a = 13.2797(10) A, b = 27.072(2) A, c = 16.6564(13) A, beta = 104.9390(10) and V = 5785.7(8) A(3) for 3, a = 13.2855(3) A, b = 27.0074(6) A, c = 16.6357(3) A, beta = 104.9790(10) and V = 5766.2(2) A(3) for 4, a = 13.2837(5) A, b = 26.9105(10) A, c = 16.6066(6) A, beta = 104.917(2) and V = 5736.3(4) A(3) for 6. The crystal structures reveal that these complexes are isostructural, and molecules are connected from 0D to 3D supramolecular structures by hydrogen bonds. All of them were characterized by elemental analysis, IR spectroscopy, XRD and TGA. Unusually, non-luminescent Tb(III) complex was obtained. The photophysical property of the Eu(III) complex and the magnetic property of Gd(III) complex are investigated and discussed in detail. PMID- 21308133 TI - Enhancement of photocurrent in dye sensitized solar cells incorporating a cyclometalated ruthenium complex with cuprous iodide as an electrolyte additive. AB - A new cyclometalated ruthenium complex, [Ru(6'-phenyl-4'-thiophen-2-yl [2,2']bipyridinyl-4-carboxylic acid)(4,4',4''-tricarboxy- 2,2':6',2'' terpyridine)]Cl, for Dye Sensitized Solar Cells (DSSCs) is proposed. We have investigated the use of cuprous iodide (CuI) as an electrolyte additive, which in turn has shown photocurrent enhancements of more than 25% in our dye based cells. Using an ionic liquid based electrolyte, an efficiency of eta = 5.7% has been accomplished under 1 sun irradiation. The origin of this photocurrent enhancement upon the CuI addition was studied by means of impedance spectroscopy and cyclic voltammetry under dark conditions. The reason behind such a photocurrent enhancement is attributed to an electrocatalytic effect of the CuI on the regeneration of the oxidized dye. Furthermore, the CuI addition did not affect the recombination processes between the injected electrons and the electrolyte nor the electron lifetime in the semiconductor TiO(2) film, which in turn resulted in no changes in the photovoltage. PMID- 21308134 TI - Imidotungsten(VI) complexes with chelating amino and imino phenolates. AB - The reaction of WOCl(4) with 2,4-di-tert-butyl-6-((isopropylamino)methyl)phenol followed by the reaction with phenyl isocyanate leads to the formation of imidotungsten(VI) complex [W(NPh)Cl(3)(OC(6)H(3)(CH(2)NH-i-Pr)-2-t-Bu(2)-4,6)] 4 with a chelating aminophenolate ligand. When the same procedure was applied using aminophenols with bulkier substituents in the amino group, the final product was an unexpected Schiff-base complex [W(NPh)Cl(3)(OC(6)H(3)(CH=NPh)-2-t-Bu(2)-4,6)] 5, where the ligand is derived from 2,4-di-tert-butyl-6 ((phenylimino)methyl)phenol. Complex 5 is also formed in the thermal degradation of 4. On the whole, 5 appears to be formed by a disproportionation of intermediate compounds, which are analogous to complex 4. The solid-state structures of 4 and 5 have been determined by X-ray crystallography whereas the solution structures were studied by (1)H and (13)C NMR. PMID- 21308135 TI - One to chelate them all: investigation of a versatile, bifunctional chelator for 64Cu, 99mTc, Re and Co. AB - We describe the synthesis of the dip (di-picolyl-carboxylate) bifunctional chelator system, capable of fast coordination of Cu(2+), (64)Cu(2+) and Co(2+), as well as the [M(CO)(3)](+)-core (M = (99m)Tc, Re); it displays a variety of binding modes--tridentate when protected, tetradentate when deprotected. Syntheses of both the benzyl-nitro derivative and the benzyl-amino derivatives are described. The latter was coupled to biotin to show the viability of the system for functionalization with biomolecules. Besides coordination chemistry with stable isotopes, we also present labelling data with (64)Cu and (99m)Tc, as well as in vitro stability studies. PMID- 21308136 TI - First examples of oxaphosphirane pentacarbonylchromium(0) and -molybdenum(0) complexes: synthesis, structures and reactions. AB - Synthesis of the first oxaphosphirane chromium(0) and molybdenum(0) complexes of the type [{(R(1)PCH(R(2))-O}M(CO)(5)] (R(1) = C(5)Me(5)) (8a-e, 15a-e) and (R(1) = CH(SiMe(3))(2)) (9a-e, 16a-e) via reaction of dichloro(organo)- (1, 2, 10, 11) and chloro(organo)phosphane complexes (3,4,12) with lithium bases and aldehydes 7a-e is reported. Furthermore, bicyclic 1,3-oxaphospholane complexes 17 and 18 have been obtained via O-protonation of oxaphosphirane complexes 8a and 15a with HCl. All complexes were characterized by NMR, IR spectroscopic, mass spectrometric investigations and, in addition, single-crystal X-ray structures of complexes 8a-e, 9a,c, 15a,b,e, 16a-c, 17, 18 are presented and discussed. PMID- 21308137 TI - Hexa- and octanuclear iron(III) salicylaldoxime clusters. AB - The syntheses, structures and magnetic properties of six iron complexes stabilised with the derivatised salicylaldoxime ligands Me-saoH(2) (2 hydroxyethanone oxime) and Et-saoH(2) (2-hydroxypropiophenone oxime) are discussed. The four hexanuclear and two octanuclear complexes of formulae [Fe(8)O(2)(OMe)(4)(Me-sao)(6)Br(4)(py)(4)].2Et(2)O.MeOH (1.2Et(2)O.MeOH), [Fe(8)O(2)(OMe)(3.85)(N(3))(4.15)(Me-sao)(6)(py)(2)] (2), [Fe(6)O(2)(O(2)CPh-4 NO(2))(4)(Me-sao)(2)(OMe)(4)Cl(2)(py)(2)] (3), [Fe(6)O(2)(O(2)CPh-4-NO(2))(4)(Et sao)(2)(OMe)(4)Cl(2)(py)(2)].2Et(2)O.MeOH (4.2Et(2)O.MeOH), [HNEt(3)](2)[Fe(6)O(2)(Me-sao)(4)(SO(4))(2)(OMe)(4)(MeOH)(2)] (5) and [HNEt(3)](2)[Fe(6)O(2)(Et-sao)(4)(SO(4))(2)(OMe)(4)(MeOH)(2)] (6) all are built from a series of edge-sharing [Fe(4)(MU(4)-O)](10+) tetrahedra. Complexes 1 and 2 display a new MU(4)-coordination mode of the oxime ligand and join a small group of Fe-phenolic oxime complexes with nuclearity greater than six. PMID- 21308138 TI - {Mn14W48} aggregate: the perspective of isopolyanions as ligands. AB - The assembly of a tetradeca-manganese magnetic cluster [Mn(14)W(48)O(192)H(20)](26-), containing two high spin Mn(7) cores and supported exclusively by isopolytungstate ligands, demonstrates the promising perspective of using "defect" isopolyanions as ligands/synthons to construct large aggregated structures and model the surface deposition of molecular magnets. PMID- 21308139 TI - Biomimetic smart nanopores and nanochannels. AB - Nature provides a huge range of biological materials, just as ion channels, with various smart functions over millions of years of evolution, and which serve as a big source of bio-inspiration for biomimetic materials. In this critical review, a strategy for the design and synthesis of biomimetic smart nanopores and nanochannels is presented and put into context with recent progress in this rapidly growing field from biological, inorganic, organic to composite nanopore and nanochannel materials, which can respond to single/multiple external stimuli, e.g., pH, temperature, light, and so on. This review is intended to utilize a specific responsive behavior for regulating ionic transport properties inside the single nanopore or nanochannel as an example to demonstrate the feasibility of the design strategy, and provide an overview of this fascinating research field (109 references). PMID- 21308140 TI - Saharan dust contribution to PM10, PM2.5 and PM1 in urban and suburban areas of Rome: a comparison between single-particle SEM-EDS analysis and whole-sample PIXE analysis. AB - From February 15th to April 15th 2009, a period characterised by two episodes of Saharan dust outbreaks in Italy, particulate matter (PM) samples were collected at two stations (urban and suburban) in Rome. Some samples were selected and analysed using the SEM-EDS technique to characterise PM, focussing especially on the mineral contribution. Samples were representative both of days affected by Saharan dust episodes and days without this contribution. Cluster analysis allowed the attribution of each of about 67,000 analysed particles to one of the seven main statistical groups based on their composition. Characteristics of the particulate components identified using SEM-EDS analysis were verified by PIXE analysis carried out on filters collected in a suburban area. Ultimately, the contribution of crustal particles was revealed to be consistently high, highlighting the importance of local and regional mineral contributions, as well as those of Saharan origin. Therefore, quantifying all mineral contributions to resuspended particulate could lead to significant reductions of the PM level also on days not influenced by Saharan dust, thus limiting conditions when PM10 daily limit value (DLV) established by European legislation is exceeded. PMID- 21308141 TI - On the directionality of anion-pi interactions. AB - The directionality of two important noncovalent interactions involving aromatic rings (namely anion-pi and cation-pi) is investigated. It has been recently published that the anion-pi interactions observed in X-ray structures where the anion is located exactly over the center of the ring are scarce compared to cation-pi interactions. To explain this behavior, we have analyzed how the interaction energy (RI-MP2/aug-cc-pVDZ level of theory) is affected by moving the anion from the center of the ring to several directions in anion-pi complexes of chloride with either hexafluorobenzene or trifluoro-s-triazine. We have compared the results with the directionality of the cation-pi interaction in the sodium benzene complex. The results are useful to explain the experimental differences between both ion-pi interactions. We have also computed the van der Waals radii of several halide anions and we have compared them to the neutral halogen atoms. PMID- 21308142 TI - Synthesis of a family of 3-alkyl- or 3-aryl-substituted 1,2-dihydroquinazolinium salts and their isomerization to 4-iminium-1,2,3,4-tetrahydroquinolines. AB - A straightforward synthesis of substituted 1,2-dihydroquinazolinium triflates (3) is reported by reaction of 2-imino-substituted anilines with a range of carbonyl compounds in the presence of triflic acid via intermediate iminium salts. Similar reactions with di- or trialdehydes and triflic acid give bis- or tris-(1,2 dihydroquinazolinium) salts. Some 4-methyl substituted 1,2-dihydroquinazolinium salts rearrange, under various conditions, to their corresponding 4-iminium 1,2,3,4-tetrahydroquinolinium isomers (7). Most of salts 3 derived from ketones are rather unstable, which prevents their isolation or full characterization. The crystal structures of various 3 and 7 salts have been determined. PMID- 21308143 TI - 10th anniversary issue: France. PMID- 21308144 TI - Human telomeric G-quadruplexes undergo dynamic conversion in a molecular crowding environment. AB - We provide a novel insight into dynamic conversion of the human telomeric G quadruplexes and particularly a step-to-step transformation pathway of the long sequence containing two quadruplex units in K(+) solution in a molecular crowding environment, implying a possible behavior of the human telomeric DNA under physiological conditions. PMID- 21308145 TI - Porous upconversion materials-assisted near infrared energy harvesting by chlorophylls. AB - A facile approach has been developed to prepare a porous upconversion material, which converts near infrared to red light. As the red emission matches well with the absorption maximum of chlorophylls, NIR energy can be transferred to the biomolecules. PMID- 21308146 TI - Electronic structure and chemical bond in naphthalene and anthracene. AB - We investigated the electronic structure of crystalline naphthalene and anthracene within the framework of density functional theory including van der Waals interactions (DFT-D). It is established that for better agreement with experimental values it is necessary to use the increased values of the van der Waals radii, which is caused by an overestimated value of the van der Waals interactions in crystalline linear oligoacenes. Utilization of the DFT-D leads to a correct account of the dispersion forces, which results in a high precision of the computed lattice parameters and cohesive energy. Based on the relaxed crystal structures, we have computed the total and deformation electron density and determined the mechanism of chemical bonds formation in crystals of naphthalene and anthracene. It has been established that the chemical bond in molecular crystals is formed under the influence of not only intramolecular but also intermolecular interactions. On the basis of the Mulliken population analysis it was revealed that two C(3) atoms in naphthalene (or C(3) and C(4) in anthracene) have a positive charge and the population of the rest of the carbon atoms increased, as compared with isolated molecule. PMID- 21308147 TI - A four-gene signature predicts disease progression in muscle invasive bladder cancer. AB - There are no reliable criteria to handle disease progression of muscle invasive bladder cancer (MIBC), which strongly influences patient survival. Therefore, an accurate predicting method to identify progressive MIBC patients is greatly needed. The aim of this study was to identify a genetic signature associated with disease progression in MIBC. To address this issue, we analyzed three independent cohorts (a training set, test set 1 and test set 2) comprising a total of 128 MIBC patients. Microarray gene expression profiling, including gene network analysis, was performed in the training set to identify a gene expression signature associated with disease progression. The prognostic value of the signature was validated in test set 1 and test set 2 by microarray and real-time reverse transcriptase polymerase chain reaction (RT-PCR), respectively. The determination of gene expression patterns by microarray data analysis identified 1,320 genes associated with disease progression. Gene network analysis of the 1,320 genes suggested that IL1B, S100A8, S100A9 and EGFR were important mediators of MIBC progression. We validated this putative four-gene signature in two independent cohorts (log-rank test, P < 0.05 each, respectively) and estimated the predictive value of the signature by multivariate Cox regression analysis (hazard ratio [HR], 6.24; 95% confidence interval [CI], 1.58-24.61; P = 0.009). Finally, signature-based stratification demonstrated that the four-gene signature was an independent predictor of MIBC progression. In conclusion, a molecular signature defined by four genes represents a promising diagnostic tool for the identification of MIBC patients at high risk of progression. PMID- 21308148 TI - Milk fat globule-EGF factor 8 is a critical protein for healing of dextran sodium sulfate-induced acute colitis in mice. AB - Milk fat globule-EGF factor 8 (MFG-E8) has been shown to play an important role in maintaining the integrity of the intestinal mucosa and to accelerate healing of the mucosa in septic mice. Herein, we (a) analyzed the expression of MFG-E8 in the gut of wild-type (WT) C57BL/6 (MFG-E8(+/+)) mice with and without dextran sulfate sodium (DSS)-induced colitis, (b) characterized the pathological changes in intestinal mucosa of MFG-E8(+/+) and MFG-E8(-/-) mice with DSS-induced colitis and (c) examined the therapeutic role of MFG-E8 in inflammatory bowel disease by using DSS-induced colitis model. Our data documented that there was an increase in colonic and rectal MFG-E8 expression in MFG-E8(+/+) mice during the development of DSS colitis. MFG-E8 levels in both tissues decreased to below baseline during the recovery phase in mice with colitis. Changes in MFG-E8 gene expression correlated to the levels of inflammatory response and crypt-epithelial injury in both colonic and rectal mucosa in MFG-E8(+/+) mice. MFG-E8(-/-)mice developed more severe crypt-epithelial injury than MFG-E8(+/+) mice during exposure to DSS with delayed healing of intestinal epithelium during the recovery phase of DSS colitis. Administration of MFG-E8 during the recovery phase ameliorated colitis and promoted mucosal repair in both MFG-E8(-/-) and MFG E8(+/+) mice, indicating that lack of MFG-E8 causes increased susceptibility to colitis and delayed mucosal healing. These data suggest that MGF-E8 is an essential protective factor for gut epithelial homeostasis, and exogenous administration of MFG-E8 may represent a novel therapeutic target in inflammatory bowel disease. PMID- 21308149 TI - Impact of genotyping on outcome of prostatic biopsies: a multicenter prospective study. AB - Single nucleotide polymorphisms (SNPs) have been associated with prostate cancer (PCa) risk and tumor aggressiveness in retrospective studies. To assess the value of genotyping in a clinical setting, we evaluated the correlation between three genotypes (rs1447295 and rs6983267[8q24] and rs4054823[17p12]) and prostatic biopsy outcome prospectively in a French population of Caucasian men. Five hundred ninety-eight patients with prostatic-specific antigen (PSA) >4 ng/mL or abnormal digital rectal examination (DRE) participated in this prospective, multicenter study. Age, familial history of PCa, body mass index (BMI), data of DRE, International Prostate Symptom Score (I-PSS) score, PSA value and prostatic volume were collected prospectively before prostatic biopsy. Correlation between genotypes and biopsy outcome (positive or negative) and Gleason score (<=6 or >6) were studied by univariate and multivariable analysis. rs1447295 and rs6983267 risk variants were found to be associated with the presence of PCa in univariate analysis. rs6983267 genotype remained significantly linked to a positive biopsy (odds ratio [OR] = 1.66, 95% confidence interval [CI]: 1.06-2.59, P = 0.026) in multivariable analysis, but rs1447295 genotype did not (OR = 1.47, 95% CI: 0.89 2.43, P = 0.13).When biopsy outcome was stratified according to Gleason score, risk variants of rs1447295 were associated with aggressive disease (Gleason score >=7) in univariate and multivariable analysis (OR = 2.05 95% CI: 1.10-3.79, P = 0.023). rs6983267 GG genotype was not related to aggressiveness. The results did not reach significance concerning rs4054823 for any analysis. This inaugural prospective evaluation thus confirmed potential usefulness of genotyping PCa assessment. Ongoing clinical evaluation of larger panels of SNPs will detail the actual impact of genetic markers on clinical practice. PMID- 21308152 TI - Electronic medical files for patients: some steps towards the future. PMID- 21308151 TI - HDAC inhibition in rheumatoid arthritis and juvenile idiopathic arthritis. AB - Rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) are heterogeneous autoimmune diseases characterized by chronic joint inflammation. Methotrexate is used as the gold standard to treat rheumatoid arthritis, yet there are many patients in whom the disease cannot be controlled or who experience unacceptable intolerance. Most of the biologics currently used are effective, but mostly if combined with methotrexate. Long-term possible side effects, such as impaired host defense mechanisms against infection and lymphoma, are distinct disadvantages and a major concern of anticytokine therapies. Parenteral administration is a problem, particularly in children. Thus, there is a need to explore new treatment options. Here we review the properties of histone deacetylase inhibitors (HDACi) as they apply to rheumatoid arthritis by looking at effects on cytokine production, T-cell differentiation and the function of macrophages, dendritic cells, osteoblasts, osteoclasts and synovial fibroblasts. We also review the safety and efficacy of givinostat (ITF 2357) in the treatment of systemic onset juvenile idiopathic arthritis (SOJIA) and its influence on the cytokine networks in SOJIA. Givinostat is an orally active HDACi which was given to children with SOJIA. After 12 wk of treatment, there were significant benefits, particularly in reducing the pain and arthritic component of the disease and decreasing the neutrophilia. CD40L, IL-1alpha and IFNgamma in whole blood lysates decreased at wks 2 and 4 compared with baseline levels. The clinical data are consistent with those from animal models of rheumatoid arthritis and suggest that trials with HDACi are promising as a safe oral alternative to anticytokines and methotrexate. PMID- 21308150 TI - Histone deacetylase inhibitors in the treatment of muscular dystrophies: epigenetic drugs for genetic diseases. AB - Histone deacetylases inhibitors (HDACi) include a growing number of drugs that share the ability to inhibit the enzymatic activity of some or all the HDACs. Experimental and preclinical evidence indicates that these epigenetic drugs not only can be effective in the treatment of malignancies, inflammatory diseases and degenerative disorders, but also in the treatment of genetic diseases, such as muscular dystrophies. The ability of HDACi to counter the progression of muscular dystrophies points to HDACs as a crucial link between specific genetic mutations and downstream determinants of disease progression. It also suggests the contribution of epigenetic events to the pathogenesis of muscular dystrophies. Here we describe the experimental evidence supporting the key role of HDACs in the control of the transcriptional networks underlying the potential of dystrophic muscles either to activate compensatory regeneration or to undergo fibroadipogenic degeneration. Studies performed in mouse models of Duchenne muscular dystrophy (DMD) indicate that dystrophin deficiency leads to deregulated HDAC activity, which perturbs downstream networks and can be restored directly, by HDAC blockade, or indirectly, by reexpression of dystrophin. This evidence supports the current view that HDACi are emerging candidate drugs for pharmacological interventions in muscular dystrophies, and reveals unexpected common beneficial outcomes of pharmacological treatment or gene therapy. PMID- 21308153 TI - Positivity of HIV, hepatitis B and hepatitis C in patients enrolled in a confidential self-exclusion system of blood donation: a cross-sectional analytical study. AB - CONTEXT AND OBJECTIVE: Selection of healthy blood donors is essential to ensure blood safety. A confidential self-exclusion (CSE) system was designed so that high-risk donors could confidentially exclude their blood from use in transfusions. This study aimed to compare the demographic characteristics and the results from human immunodeficiency virus (HIV), hepatitis B surface (HBS) and hepatitis C virus (HCV) screening tests on donors who opted to get into and out of CSE. DESIGN AND SETTING: Analytical cross-sectional study on all volunteer donors at Shiraz Blood Transfusion Organization from March 21, 2006, to March 21, 2008. METHODS: The results from the abovementioned tests were compared between donors who opted into and out of CSE. RESULTS: 100,148 donors in 2006 and 104,271 in 2007 gave blood. Among these donors, respectively, 829 (0.82%) and 592 (0.57%) opted for the CSE. The prevalence of HIV antibodies, HBS antigens and HCV antibodies in CSE donors was significantly higher than in donors who did not choose CSE (p < 0.05). The prevalence of at least one of these three infections among CSE donors was 3.12% in 2006 and 3.04% in 2007, and was significantly higher than the prevalence among non-CSE donors (0.58% and 0.57%, respectively). CONCLUSION: Because of the higher prevalence of HBS, HCV and HIV positivity in blood donors who chose the CSE option, offering CSE to blood donors could be a potentially useful method for improving blood safety, since it could increase the detection of infected blood during the window period. PMID- 21308154 TI - Evaluation of calcium and folic acid supplementation in prenatal care in Sao Paulo. AB - CONTEXT AND OBJECTIVE: Preeclampsia and neural tube defects can be prevented during pregnancy. Today, there is level I evidence showing that calcium supplementation during pregnancy may prevent preeclampsia and that use of folic acid may prevent neural tube defects. The aim here was to evaluate the proportion of patients undergoing prenatal follow-up who had received a prescription for calcium and/or folic acid supplementation, and their adherence to the use of these two substances. DESIGN AND SETTING: Cross-sectional study at two hospitals in the Greater Sao Paulo region, Brazil (Faculdade de Medicina da Fundacao ABC, Santo Andre, and "Dr. Mario de Moraes Altenfelder Silva" Municipal Teaching and Maternity Hospital, Vila Nova Cachoeirinha). METHODS: Early primigravidae, late primigravidae and pregnant women with chronic hypertension, diabetes mellitus or kidney disease who had already had their first prenatal consultation were included. RESULTS: Out of 250 pregnant women interviewed, 10.40% had received a prescription for calcium supplementation and 80.76% of them reported taking it in tablet form. Regarding folic acid, 48% of the women said that they had received a prescription for this and 64.16% reported that they had started to use it during the periconceptional period. CONCLUSIONS: Calcium supplementation and periconceptional use of folic acid seem not to be prescribed routinely by physicians. This should motivate the implementation of educational programs for obstetricians on the use of interventions based on the best available evidence. PMID- 21308155 TI - A computed tomography scoring system to assess pulmonary disease among premature infants. AB - CONTEXT AND OBJECTIVE: High-resolution computed tomography (HRCT) is considered to be the best method for detailed pulmonary evaluation. The aim here was to describe a scoring system based on abnormalities identified on HRCT among premature infants, and measure the predictive validity of the score in relation to respiratory morbidity during the first year of life. DESIGN AND SETTING: Prospective cohort study in Instituto Fernandes Figueira, Fundacao Oswaldo Cruz. METHODS: Scoring system based on HRCT abnormalities among premature newborns. The affected lung area was quantified according to the number of compromised lobes, in addition to bilateral pulmonary involvement. Two radiologists applied the score to 86 HRCT scans. Intraobserver and interobserver agreement were analyzed. The score properties were calculated in relation to predictions of respiratory morbidity during the first year of life. RESULTS: Most of the patients (85%) presented abnormalities on HRCT, and among these, 56.2% presented respiratory morbidity during the first year of life. Scores ranged from zero to 12. There was good agreement between observers (intraclass correlation coefficient, ICC = 0.86, confidence interval, CI: 0.64-0.83). The predictive scores were as follows: positive predictive value 81.8%, negative predictive value 56.3%, sensitivity 39.1%, and specificity 90.0%. CONCLUSION: The scoring system is reproducible, easy to apply and allows HRCT comparisons among premature infants, by identifying patients with greater likelihood of respiratory morbidity during the first year of life. Its use will enable HRCT comparisons among premature infants with different risk factors for respiratory morbidity. PMID- 21308156 TI - Pectoralis major myocutaneous flaps for head and neck reconstruction: factors influencing occurrences of complications and the final outcome. AB - CONTEXT AND OBJECTIVE: Pedicled flaps play an important role in cancer treatment centers, particularly in developing and emerging countries. The aim of this study was to identify factors that may cause complications and influence the final result from reconstructions using pectoralis major myocutaneous flaps (PMMFs) for head and neck defect repair following cancer resection. DESIGN AND SETTING: Cross sectional study at the Hospital de Ensino Padre Anchieta of Faculdade de Medicina do ABC (FMABC). METHODS: Data on 58 patients who underwent head and neck defect reconstruction using PMMFs were reviewed. The final result from the reconstruction (success or failure) and the complications observed were evaluated in relation to the patients' ages, area reconstructed, disease stage, previous oncological treatment and need for blood transfusion. RESULTS: There were no total flap losses. The reconstruction success rate was 93.1%. Flap-related complications occurred in 43.1% of the cases, and half of them were considered major. Most of the complications were successfully treated. Defects originating in the hypopharynx were correlated with the development of major complications (p = 0.02) and with reconstruction failure (p < 0.001). Previous oncological treatment negatively influenced the reconstruction success (p = 0.04). CONCLUSIONS: Since the risk factors for developing major complications and reconstruction failure are known, it is important to heed the technical details and provide careful clinical support for patients in a more critical condition, so that better results from using PMMFs can be obtained. PMID- 21308157 TI - Clinical characteristics associated with hepatic steatosis on ultrasonography in patients with elevated alanine aminotransferase. AB - CONTEXT AND OBJECTIVE: The main causes of hepatic steatosis (HS) are alcoholic liver disease and nonalcoholic fatty liver disease (NAFLD). Although liver biopsy is the gold standard for NAFLD diagnosis, the finding of abnormal aminotransferases in abstinent individuals, without known liver disease, suggests the diagnosis of NAFLD in 80-90% of the cases. Identification of clinical factors associated with HS on abdominal ultrasound may enable diagnoses of fatty liver non-invasively and cost-effectively. The aim here was to identify clinical variables associated with HS in individuals with elevated alanine aminotransferase (ALT) levels. DESIGN AND SETTING: Cross-sectional study in a single tertiary care center. METHODS: Individuals with elevated ALT, serologically negative for hepatitis B and C, were evaluated by reviewing medical files. Patients who did not undergo abdominal ultrasonography were excluded. RESULTS: Among 94 individuals included, 40% presented HS on ultrasonography. Compared with individuals without HS, those with fatty liver were older (P = 0.043), with higher body mass index (BMI) (P = 0.003), diabetes prevalence (P = 0.024), fasting glucose levels (P = 0.001) and triglycerides (P = 0.003). Multivariate analysis showed that BMI (odds ratio, OR = 1.186; 95% confidence interval, CI: 1.049-1.341; P = 0.006) and diabetes mellitus (OR = 12.721; 95% CI: 1.380-117.247; P = 0.025) were independently associated with HS. CONCLUSIONS: Simple clinical findings such as history of diabetes and high BMI may predict the presence of HS on ultrasonography in individuals with elevated ALT and negative serological tests for hepatitis. PMID- 21308158 TI - Relationship between infectious agents for vulvovaginitis and skin color. AB - CONTEXT AND OBJECTIVE: Many factors influence occurrences of vulvovaginitis. The aims here were to assess skin color and age-related differences in the vaginal flora and occurrences of vulvovaginitis. DESIGN AND SETTING: Cross-sectional study; tertiary referral hospital (Universidade Federal do Triangulo Mineiro, Uberaba). METHODS: Healthy women who underwent routine outpatient gynecological assessments were assessed for vulvovaginitis and vaginal flora and then divided into whites (n = 13,881) and nonwhites (n = 5,295). Statistical analysis was performed using the X2 test, logistic regression and odds ratios. RESULTS: The vaginal microflora was skin-color dependent, with greater occurrence of clue cells, Trichomonas vaginalis and coccobacilli in nonwhite women (p < 0.0001). Doderlein bacilli and cytolytic flora were more prevalent in white women (p < 0.0001 and p < 0.05, respectively). The vaginal microflora was age-dependent within the skin color groups. Among the nonwhite women, clue cells were more prevalent in women aged 21 to 50 years; Trichomonas in women up to 40 years and coccobacili in women between 21 and 40 years (P < 0.05). During the proliferative and secretory phases, the nonwhite women were more likely to present clue cells, Trichomonas, Candida and coccobacilli (OR, proliferative phase: 1.31, 1.79, 1.6 and 1.25 respectively; secretory phase: 1.31, 2.88, 1.74 and 1.21 respectively), while less likely to present Doderlein flora (OR, proliferative phase: 0.76; secretory phase: 0.66), compared with white women, irrespective of age. CONCLUSIONS: There are differences in vulvovaginitis occurrence relating to skin color, which may be associated with variations in vaginal flora. PMID- 21308159 TI - Lifestyle, health characteristics and alcohol abuse in young adults who are non daily smokers. AB - CONTEXT AND OBJECTIVES: Despite the decline in the prevalence of tobacco use in many countries, including Brazil, there are growing numbers of smokers who continue to smoke at a low daily rate, or less frequently (non-daily smokers). This group needs to be better characterized in order to direct preventive actions and public health policies. The aim here was to compare lifestyle, health characteristics and alcoholism problems among young adult smokers, non-daily smokers and non-smokers. DESIGN AND SETTING: This was a cross-sectional study in which volunteers from the university community and its surrounds in Santa Maria, State of Rio Grande do Sul, Brazil, were included between October 2007 and January 2008. METHODS: Out of 1240 volunteers initially contacted in a university cafeteria, a total of 728 participants of mean age 22.45 +/- 3.32 years were selected for final analysis. Data were collected using structured questionnaires. RESULTS: In general, it was observed that the non-daily smokers showed intermediate characteristics in relation to the smokers and non-smokers. However, there was a significant association between non-daily smoking and alcohol abuse. The non-daily smokers presented an odds ratio of 2.4 (95% confidence interval: 1.10-5.48) in relation to the daily smokers and an odds ratio of 3.3 (confidence interval: 1.7-6.5) in relation to the non-smokers, with regard to presenting a positive CAGE test, thereby indicating alcohol abuse or dependence. CONCLUSION: The study suggested that non-daily smoking and alcohol consumption were concomitant behaviors. PMID- 21308160 TI - Marfan's syndrome: an overview. AB - Marfan's syndrome is an autosomal dominant condition with an estimated prevalence of one in 10,000 to 20,000 individuals. This rare hereditary connective tissue disorder affects many parts of the body. The diagnosis of Marfan's syndrome is established in accordance with a review of the diagnostic criteria, known as the Ghent nosology, through a comprehensive assessment largely based on a combination of major and minor clinical manifestations in various organ systems and the family history. Aortic root dilation and mitral valve prolapse are the main presentations among the cardiovascular malformations of Marfan's syndrome. The pathogenesis of Marfan's syndrome has not been fully elucidated. However, fibrillin-1 gene mutations are believed to exert a dominant negative effect. Therefore, Marfan's syndrome is termed a fibrillinopathy, along with other connective tissue disorders with subtle differences in clinical manifestations. The treatment may include prophylactic beta-blockers and angiotensin II-receptor blockers in order to slow down the dilation of the ascending aorta, and prophylactic aortic surgery. Importantly, beta-blocker therapy may reduce TGF beta activation, which has been recognized as a contributory factor in Marfan's syndrome. The present article aims to provide an overview of this rare hereditary disorder. PMID- 21308161 TI - Surgical treatment of lone atrial fibrillation. AB - Currently, off-pump video-assisted thoracoscopic epicardial pulmonary vein isolation offers an attractive alternative to on-pump Maze procedures for surgical treatment of lone atrial fibrillation. Nevertheless, on-pump Maze procedures through a mid-sternotomy approach still play an important role in patients with lone atrial fibrillation on many occasions, especially in patients with failed percutaneous pulmonary vein alone. The aim of this article was to give a brief review of the surgical strategies for treating lone atrial fibrillation, and present the possible indications for on-pump Maze procedures through a mid-sternotomy approach. PMID- 21308162 TI - Synchronous thyroid and colon metastases from epidermoid carcinoma of the lung: case report. AB - CONTEXT: Non-small cell lung cancer (NSCLC) progresses to distant metastases in most cases. The most frequent sites for distant metastases are the bones, central nervous system, adrenal glands and liver. Dissemination to the skin, myocardium, thyroid gland and intestine may occur, but is rare. CASE REPORT: We describe a case of squamous cell carcinoma in the lungs, with metastases in the colon and thyroid, in a 66-year-old female patient. The lesion was unresectable and chemotherapy was started. The patient evolved with intestinal subocclusion, and colonoscopy showed the presence of a polyp. Biopsy and immunohistochemical analysis on the polyp showed that it was compatible with squamous cell carcinoma of pulmonary origin. At a follow-up consultation, the patient presented a thyroid nodule. A aspiration biopsy and cellblock immunohistochemistry confirmed the squamous cell carcinoma of pulmonary origin. After third-line chemotherapy, the patient progressed with acute obstructive abdomen due to a retroperitoneal mass. She underwent exploratory laparotomy and died due to surgical complications. Metastases to the thyroid and colon are rarely reported in cases of epidermoid carcinoma of the lungs. Gastrointestinal involvement in pulmonary metastases may affect the stomach, small intestine and colon, and cases of bleeding and perforation have already been reported. Although richly vascularized, the thyroid is an infrequent site for metastases. Such sites reflect poor prognoses for the clinical evolution. We did not find any previous reports in the literature, on lung cancer with metastases concomitantly in the colon and thyroid, in a single patient. PMID- 21308163 TI - Rituximab monotherapy for splenic marginal zone lymphoma with villous lymphocytes: report on long-term disease control for two patients with recurrence after splenectomy. AB - CONTEXT: Splenic marginal zone lymphoma (SMZL) is a lymphoproliferative B-cell disorder that has a favorable prognosis, with estimated overall five-year survival of 70%. The majority of symptomatic patients undergo splenectomy, while a few receive first-line chemotherapy, especially with purine analogues. There are no specific treatment guidelines for patients for whom splenectomy fails to provide a cure. It is still unclear whether these patients should undergo cytotoxic chemotherapy, considering they have now a relapsed lymphoma (which is theoretically more aggressive), or whether they should be spared from treatments of greater toxicity, given that their disease usually develops with a more indolent course, even when it recurs. CASE REPORT: Here, we present two patients whose disease recurred after splenectomy and for whom rituximab monotherapy provided satisfactory treatment. From these cases, it can be suggested that postponement of cytotoxic treatments may be possible in at least some situations. It needs to be emphasized that the evidence to support this approach is based only on case reports, since there are no randomized clinical trials on this subject. PMID- 21308166 TI - Asthma cases in childhood attributed to atopy in tropical area in Brazil. AB - OBJECTIVE: This study aimed to explore the association between asthma and atopy in a cohort of children living in a large urban center in Brazil. Atopy was defined by the presence of allergen-specific IgE in serum or by a positive skin prick test. METHODS: In a sample of 1 445 Brazilian children, the association between the prevalence of asthma, skin prick test positivity, and allergen specific IgE in serum was investigated. RESULTS: The prevalence of asthma was 22.6%. The presence of serum allergen-specific IgE was frequent in asthmatics and nonasthmatics, and the prevalence of asthma increased only with levels of allergen-specific IgE > 3.5 kilounits/L. The proportion of asthma attributable to atopy was estimated to be 24.5% when atopy was defined by the presence of allergen-specific IgE. With a given level of specific IgE, no association between skin test reactivity and asthma was observed. Skin prick tests were less sensitive than specific IgE for detection of atopy. CONCLUSIONS: Most asthma cases in an urban underprivileged setting in Brazil were not attributable to atopy. This observation has important implications for understanding the risk factors for the asthma epidemic in Latin America. PMID- 21308167 TI - [Direct costs of medical care for patients with type 2 diabetes mellitus in Mexico micro-costing analysis]. AB - OBJECTIVE: Estimate the direct cost of medical care incurred by the Mexican Social Security Institute (IMSS, Instituto Mexicano del Seguro Social) for patients with type 2 diabetes mellitus (DM2). METHODS: The clinical files of 497 patients who were treated in secondary and tertiary medical care units in 2002 2004 were reviewed. Costs were quantified using a disease costing approach (DCA) from the provider's perspective, a micro-costing technique, and a bottom-up methodology. Average annual costs by diagnosis, complication, and total cost were estimated. RESULTS: Total IMSS DM2 annual costs were US$452 064 988, or 3.1% of operating expenses. The annual average cost per patient was US$3 193.75, with US$2 740.34 per patient without complications and US$3 550.17 per patient with complications. Hospitalization and intensive care bed-days generated the greatest expenses. CONCLUSIONS: The high cost of providing medical care to patients with DM2 and its complications represents an economic burden that health institutions should consider in their budgets to enable them to offer quality service that is both adequate and timely. Using the micro-costing methodology allows an approximation to real data on utilization and management of the disease. PMID- 21308168 TI - [Analysis of protection or risk factors for dental fluorosis in 6 to 8 year-old children in Fortaleza, Brazil]. AB - OBJECTIVE: To investigate protection or risk factors for dental fluorosis in permanent teeth of 6 to 8 year-old children in a neighborhood of Fortaleza, Brazil. METHODS: This case-control study included 57 controls and 67 children with fluorosis affecting superior and inferior incisors teeth as determined by the Dean classification criteria. Presence of fluorosis was considered as the dependent variable. Data concerning independent variables were obtained through interviews with the parents. Fisher's exact test was used to determine associations between fluorosis and the independent variables. Odds ratios (OR) were calculated to investigate associations and likelihood of fluorosis in the case group, with 95% significance level. RESULTS: Fluorosis was significantly associated with type of housing (owned, rented or squatted), but not with the source of drinking water or use of fluoridated toothpaste and fluoride supplements. Univariate analysis showed that the risk of fluorosis was higher in children who began drinking powdered milk mixed with water before 2 years of age (OR = 4.53; IC95%: 1.07-26.74) and in those who did not breastfeed (OR = 6.66; IC95%: 1.61-38.62). In the multivariate analysis, only breastfeeding was associated with fluorosis (4.54; IC95%: 1.21-16.66). CONCLUSIONS: Breastfeeding was a protection factor against fluorosis. More specific categorization criteria must be established to investigate relationships between fluorosis and socioeconomic class. PMID- 21308169 TI - Maternal behavior and experience, care access, and agency as determinants of child diarrhea in Bolivia. AB - OBJECTIVE: In Latin America and the Caribbean, Bolivia has the third highest rate of mortality among children under five years of age (57 per 1 000), with 14.0% of under-five deaths attributable to diarrhea. Because a child's world is predominantly controlled by and experienced through his or her mother, this investigation aims to understand what maternal dimensions may determine child diarrhea. METHODS: Variables were selected from the 2003 Bolivia Demographic and Health Survey to create indices of three maternal dimensions using principal components analysis: behavior and experience, access to care, and agency. The three indices were included in a logistic regression model while controlling for economic status, maternal education, and residence type. RESULTS: A total of 4 383 women who had children less than 5 years old were included in the final sample and 25.0% of mothers reported that their most recent born child had experienced an episode of diarrhea in the 2 weeks before the survey. Mothers with high levels of maternal agency or of high economic status were significantly less likely to report their child experienced an episode of diarrhea than women of low levels. Women with primary education were significantly more likely to report that their child experienced diarrhea than women with no education. CONCLUSIONS: High levels of agency have a significant protective effect even when controlling for other factors. Increasing maternal agency could have a positive impact on child health in Bolivia, and future work should aim to understand what accounts for different levels of agency and how it may be strengthened. PMID- 21308170 TI - Quality of previous diabetes care among patients receiving services at ophthalmology hospitals in Mexico. AB - OBJECTIVE: To survey a large sample of type 2 diabetes mellitus (T2DM) patients in Mexico City to determine if patient experience, access to basic services, treatment, and outcomes differed between those with social security coverage and those without. METHODS: From 2001-2007 a total of 1 000 individuals with T2DM were surveyed in outpatient clinics of the three largest public ophthalmology hospitals in Mexico City. Patients reported information about their health status and receipt of basic diabetes services, such as laboratory glycemic monitoring and diabetes education. Rates were compared between those with (n = 461) and without (n = 539) social security. RESULTS: Almost half of the patients (46%) in these public facilities were social security patients that were unable to access other services and had to pay out-of-pocket for care. Half of respondents were originally identified as potentially diabetic based on symptom complaints (51%), including 11% with visual impairment. Most patients (87.9%) reported that their glycemic level was being monitored exclusively via fasting blood glucose testing or random capillary blood glucose tests; only 5.3% reported ever having a glycated hemoglobin test. While nearly all respondents reported an individual physician encounter ever, only 39% reported ever receiving nutrition counseling and only 21% reported attending one or more sessions of diabetes education in their lifetime. Processes of care and outcomes were no different in patients with and those without social security coverage. CONCLUSIONS: In Mexico, the quality of diabetes care is poor. Despite receiving social security, many patients still have to pay out-of-pocket to access needed care. Without policy changes that address these barriers to comprehensive diabetes management, scientific achievements in diagnosis and pharmacotherapy will have limited impact. PMID- 21308171 TI - [Local governance in the decentralized health care system in Brazil]. AB - OBJECTIVE: To analyze the changes in local health care governance resulting from the decentralization process associated with the Unified Health System (SUS) in Brazil between 1996 and 2006. METHODS: A questionnaire was answered in 1996 and again in 2006 by all city officials involved in health care management in Brazil. Information was collected on the innovative characteristics of administrative practices in terms of three dimensions: social, management, and care. The present article analyzes the results relating to the social dimension (relationship between municipal officials and the various community actors) according to four attributes: preparing the budget (degree of influence of various actors), establishing priorities, accountability, and flow of information to the community. RESULTS: The influence of municipal secretaries of health and health councils on budget preparation has increased, with a decrease of local politician influence. In prioritizing health issues, local politicians and spontaneous demands have also become less influential, with strengthening of the influence of technical opinions and proposals by health councils and conferences. Public disclosure of results has become institutionalized as a result of the diversification of stakeholders (especially municipal secretaries and health councils) and of the methods available for disclosure, even though balance sheets are still the most common type of information disclosed (which imply technical knowledge for interpretation of results). Finally, the information conveyed to the community still mainly refers to health actions and campaigns and functioning of health services, even though a larger amount of innovative information is being communicated. This was observed in all regions and in cities of all sizes, with a more progressive trend in the South of Brazil. CONCLUSIONS: The relationship between government and society has changed toward a more democratic standard of local governance, despite the maintenance of centralized government decision-making practices. The process of decentralization still faces important obstacles to the establishment of a more participative model, with enhanced social control, accountability and interaction between government and society. PMID- 21308172 TI - [Opportunity cost for men who visit family medicine units in the city of Queretaro, Mexico]. AB - OBJECTIVE: To determine the opportunity cost for men who seek care in the family medicine units (FMU) of the Mexican Social Security Institute (IMSS, Instituto Mexicano del Seguro Social) in the city of Queretaro. METHODS: A sample was selected of 807 men, ages 20 to 59 years, who sought care through the family medicine, laboratory, and pharmacy services provided by the FMU at the IMSS in Queretaro. Patients referred for emergency services and those who left the facilities without receiving care were excluded. The sample (n = 807) was calculated using the averages for an infinite population formula, with a confidence interval of 95% (CI95%) and an average opportunity cost of US$5.5 for family medicine, US$3.1 for laboratory services, and US$2.3 for pharmacy services. Estimates included the amount of time spent on travel, waiting, and receiving care; the number of people accompanying the patient, and the cost per minute of paid and unpaid job activities. The opportunity cost was calculated using the estimated cost per minute for travel, waiting, and receiving care for patients and their companions. RESULTS: The opportunity cost for the patient travel was estimated at US$0.97 (CI95%: 0.81-1.15), while wait time was US$5.03 (CI95%: 4.08-6.09) for family medicine, US$0.06 (CI95%: 0.05-0.08) for pharmacy services, and US$1.89 (CI95%: 1.56-2.25) for laboratory services. The average opportunity cost for an unaccompanied patient visit varied between US$1.10 for pharmacy services alone and US$8.64 for family medicine, pharmacy, and laboratory services. The weighted opportunity cost for family medicine was US$6.24. CONCLUSIONS: Given that the opportunity cost for men who seek services in FMU corresponds to more than half of a minimum salary, it should be examined from an institutional perspective whether this is the best alternative for care. PMID- 21308173 TI - Treatment of type 2 diabetes in Latin America: a consensus statement by the medical associations of 17 Latin American countries. Latin American Diabetes Association. AB - Latin America faces unique challenges in the treatment of type 2 diabetes mellitus. The Asociacion Latinoamericana de Diabetes (Latin American Diabetes Association, ALAD) brought together medical associations in 17 countries in Latin America to produce a consensus statement regarding the treatment of type 2 diabetes. The goal of the document is to provide practical recommendations that will guide clinicians through a simple decision-making process for managing patients. The cornerstone elements for therapeutic decision making are: severity of hyperglycemia, clinical condition of the patient (stable or with metabolic decompensation), and body mass index. The consensus includes a section devoted specifically to patients with obesity. Information is presented as highly relevant clinical questions. The algorithm is based on the scientific recommendations of the 2006 ALAD guidelines (a document prepared using an evidence-based approach) and data from recent randomized controlled studies. PMID- 21308174 TI - Caribbean Wellness Day: mobilizing a region for chronic noncommunicable disease prevention and control. AB - The member states of the Caribbean Community (CARICOM) have the highest prevalence of chronic noncommunicable diseases (CNCDs) in the Americas. The CARICOM heads of government issued the Port-of-Spain Declaration "Uniting to Stop the Epidemic of Chronic Non-Communicable Diseases in the Caribbean," mandating intersectoral, population-based approaches and commemoration of the summit on the second Saturday in September as "Caribbean Wellness Day (CWD)." CWD, inaugurated in September 2008, is designed to strengthen public, private, and civil society partnerships and to promote multicountry, multisectoral activities in support of wellness. By 2009, the second year of the celebrations, 18 of the 20 CARICOM countries embraced and celebrated with multifaceted, multifocal activities, using this as a catalyst for sustained physical activities, healthy food choices, and health screening in a smoke-free environment. Organizational support and Caribbean branding of products came from the Pan American Health Organization/World Health Organization and CARICOM. Outcomes will be measured by input and process indicators and CNCD risk factor surveillance. PMID- 21308175 TI - [Generic drugs in Brazil: historical overview and legislation]. AB - The Brazilian generic drugs policy was implemented in 1999 with the aim of stimulating competition in the market, improve the quality of drugs and improve the access of the population to drug treatment. The process of implementing this policy allowed the introduction and discussion of concepts that had never before been used in the context of drug registration in Brazil: bioavailability, bioequivalence, pharmaceutical equivalence, generic drugs, biopharmaceutical classification system, biowaiver. The present article provides definitions for these concepts in the context of Brazilian legislation as well as a historical and chronological description of the implementation of the generic drugs policy in Brazil, including a list of current generic drug legislation. This article contributes to the understanding of the Brazilian generic drugs policy and facilitates the search for information concerning the legal requirements for registration of drugs in Brazil. PMID- 21308176 TI - [Mortality from ischemic heart disease in Chile: who, how many, and where]. AB - OBJECTIVE: To describe the characteristics of mortality from ischemic heart disease in Chile and its trend over time, and to identify the factors associated with extra-hospital mortality from this pathology between 1997 and 2007. METHODS: A time-series study was conducted using the mortality database of the Department of Health Statistics and Information for 1997 to 2007. Of the total of 917,029 deaths reported in this period, those whose primary cause was ischemic heart disease (ICD-10 codes I20-I25) were selected. Crude and adjusted rates were calculated by age and sex in order to analyze the trend. Mortality characteristics were analyzed by the place of death, evaluating potential factors associated with extra-hospital mortality (death at home or elsewhere outside a hospital or clinic). The factors considered, using binomial regression, were age, rurality, marital status, education, and sex, as well as the effect of the incorporation of acute myocardial infarction into the explicit health guarantees law. RESULTS: During the period in question, 87,342 deaths from ischemic heart disease were reported, 57.7% of which were in males and 59.5% outside the hospital. The age-standardized mortality rate declined from 52.9 to 40.4 per 100,000 population. Factors related to extra-hospital mortality in men were rurality, relative risk (RR) 1.24 (1.21-1.27); age of over 70 years, RR 1.03 (1.01-1.05); and being single, RR 1.10 (1.08-1.12). In women, the respective values were rurality, 1.13 (1.10-1.18); advanced age, 1.31 (1.27-1.36); and being single, 1.07 (1.04-1.09). Passage of the explicit health guarantees law was associated with an increase in the percentage of in-hospital deaths in women, RR 0.95 (0.92-0.97). CONCLUSIONS: Mortality from ischemic heart disease in Chile has declined. The majority of deaths from this cause occur outside hospitals or clinics. The factors associated with extra-hospital mortality in both sexes were advanced age, being single, and rurality. PMID- 21308177 TI - Economic impact of fatal and nonfatal road traffic injuries in Belize in 2007. AB - OBJECTIVE: To estimate the economic cost of road traffic injuries in Belize in 2007. METHODS: A cross-sectional study was conducted using secondary cost data, assuming the health system and social perspectives. Epidemiologic information was obtained from the mortality database, the national hospital discharge database, and administrative records from police and the Ministry of Health. A health provider survey was carried out in order to estimate the postdischarge ambulatory utilization figures. Direct cost was estimated with the World Health Organization WHO-CHOICE (CHOosing Interventions that are Cost Effective) database. Prehospital costs were obtained from the Belize emergency response team. After estimating years of potential life lost using the Belize life expectancy for 2008 and methodology proposed by the Pan American Health Organization, the indirect cost associated with premature death was estimated with the human capital approach. Total estimation of road traffic injuries' economic costs used a decision tree model approach. Multiway sensitivity analysis was used to incorporate uncertainty in the estimations. RESULTS: Sixty-one people died due to road traffic injuries during 2007, 338 were hospitalized, and 565 people were estimated to be slightly injured. A total of 2,501 years of potential life were lost in Belize due to premature death, with a total economic cost of US$11,062,544. This figure represents 0.9% of the Belize gross domestic product. Direct cost was estimated at US$163,503, of which 2.4% was spent on fatalities, 46.7% on the severely injured, and 50.9% on the slightly injured. CONCLUSIONS: The economic cost estimations make clear the need to prevent road traffic injuries with a strategic and multisectoral approach that focuses on addressing the main problems identified. PMID- 21308178 TI - [Exposure to contaminated water: perceptions and practices in a neighborhood in the city of Manaus, Brazil]. AB - OBJECTIVE: To investigate the modes of water supply and the perception concerning the problems caused by this water among residents of a neighborhood without public supply of water, settled in an area previously used as a garbage dump in the city of Manaus, Brazil. METHODS: One hundred and sixty-two semi-structured household interviews were conducted. In addition, a focal group with teachers from a local public school and a meeting with residents were held. The instruments employed focused on the perception and modes of water use and on the process of exposure to chemical contaminants through water. RESULTS: Untreated well water was used by most families. This water was considered to be "good" by 64.8% of the individuals interviewed. Most residents (88.3%) declared knowledge about the garbage dump. Of these, 77.6% stated that the garbage dump caused health and environmental problems. However, qualitative analysis of the responses revealed that the residents were not aware of contamination by chemical elements or of the consequences of such contamination. The activities carried out with teachers revealed that they were partially aware of the problem, but did not design interventions to address the issue. In a meeting with neighborhood residents, the presence of social activism concerning the problem was identified, but it did not extend beyond the neighborhood or reach governmental spheres. CONCLUSIONS: The study identified a situation of critical exposure that tends to be maintained as a result of misperceptions and lack of social mobilization. The dissemination of research results to teachers and residents was useful to empower subjects. PMID- 21308179 TI - Health status of southern Arizona border counties: a Healthy Border 2010 midterm review. AB - OBJECTIVE: The region on the United States (US) side of the US-Mexico border consists of 44 counties in four states; populations on both sides of the border have similar health problems. Healthy Border 2010: An Agenda for Improving Health on the US-Mexico Border (HB 2010) is a binational agenda of health promotion and disease prevention for individuals in the region. This study reports on the health status of the four southern Arizona border counties. METHODS: Data on health indicators for Cochise, Pima, Santa Cruz, and Yuma Counties were collected from the Arizona Department of Health Services Vital Records and Statistics. Progress was calculated as a percentage made toward or away from the 2010 target. Comparisons were made between the border counties and Arizona. RESULTS: Progress toward the HB 2010 targets varied among the border counties. All border counties made progress toward the targets with the cervical cancer, hepatitis A, and teenage birthrate objectives. Most border counties moved toward the goals for breast cancer, diabetes mortality, tuberculosis, motor vehicle crashes, infant mortality from congenital abnormalities, and prenatal care. Border counties moved away from the target with the human immunodeficiency virus and infant mortality objectives. CONCLUSIONS: Assessment of the HB 2010 objectives provided a comprehensive description of the health status of the population. Although the southern Arizona border counties have shown improvement in some areas, monitoring is still needed to identify the disparities that remain. PMID- 21308180 TI - [Malaria in Cruzeiro do Sul (Western Brazilian Amazon): analysis of the historical series from 1998 to 2008]. AB - OBJECTIVE: To describe the epidemiological characteristics of malaria and its main determinants in the municipality of Cruzeiro do Sul, State of Acre, Brazil, between 1998 and 2008. METHODS: This descriptive, retrospective study was carried out with secondary data available from the malaria information systems developed by the Brazilian Ministry of Health (SISMAL/SIVEP-Malaria). The data were analyzed using the TABLEAU(r) software. Geospatial data were obtained to assess the distribution of malaria cases. RESULTS: The annual parasite incidence (API) of 27 cases/1,000 population in 1998 reached 571.5 cases/1,000 population in 2006, the year in which the city recorded its largest epidemics, following the establishment of a state program that encouraged the digging of tanks for fish farming in 2005. Rural sites had the highest number of cases. However, peri-urban locations with fish tanks had higher APIs than peri-urban areas without tanks. Following the strengthening of control actions by the National Malaria Control Program, the API in Cruzeiro do Sul dropped to 152.9 cases/1,000 population in 2008. CONCLUSIONS: The type of economic activity fostered in peri-urban areas characterized by unstable malaria transmission, which are typical of Latin America, must be very well planned. Malaria control in Cruzeiro do Sul relied on integrated strategies implemented simultaneously by federal, state, and city governments, as recommended by the National Malaria Control Program. It is important to underscore the usefulness of a reliable information system such as SIVEP-Malaria to estimate the burden of disease and efficiently monitor the impact of interventions. PMID- 21308181 TI - Sexual risk behavior among military personnel stationed at border-crossing zones in the Dominican Republic. AB - OBJECTIVE: To estimate the prevalence of sexual risk behaviors among military personnel stationed along major border-crossing zones between the Dominican Republic and Haiti. METHODS: From November 2008 to January 2009, behavioral surveys were administered to 498 active duty military personnel stationed along the three largest border-crossing zones on the western border of the Dominican Republic. Participants were selected using systematic random sampling and asked about their sexual behavior over the past 12 months, alcohol use, and mental health. RESULTS: Forty-one percent reported having casual sex during the past 12 months, 37% of men had a history of having sex with a commercial sex worker (19% during the past 12 months), and 7% of men reported a history of having sex with a transmigrating Haitian (6% during the past 12 months). Among sexually non monogamous respondents (51%), inconsistent condom use exceeded 60% for those engaging in anal, vaginal, or oral sex. Fifteen percent reported using sexual coercion during the past 12 months. CONCLUSIONS: Sexual risk behaviors were prevalent among military personnel stationed along border-crossing zones between the Dominican Republic and Haiti. Prevention programs targeted at military personnel in this region should incorporate sexual coercion and mental health as key elements of their HIV prevention programs. PMID- 21308182 TI - Mortality trends from diabetes mellitus in the seven socioeconomic regions of Mexico, 2000-2007. AB - OBJECTIVE: To determine trends in mortality from diabetes mellitus nationwide according to federative entity, socioeconomic region, and sex and to establish the association between education level, federation entity of residence, and socioeconomic region and mortality from diabetes in Mexico during the years 2000 2007. METHODS: Records of mortality associated with diabetes for 2000-2007 were obtained from the National Information System of the Secretariat of Health. This information is generated by the National Institute of Statistics, Geography and Informatics through death certificates. Codes of International Classification of Diseases, 10th Revision, that correspond to the basic cause of death from diabetes mellitus were identified. Rates of mortality by federative entity and socioeconomic region were calculated, along with the strength of association (obtained by Poisson regression) between federative entity of residence, socioeconomic region, and education level and mortality from diabetes. The seven socioeconomic regions elaborated by the National Institute of Statistics, Geography and Informatics include the 32 federative entities according to indicators related to well-being such as education, occupation, health, housing, and employment. RESULTS: Individuals who did not complete elementary school had a higher risk of dying from diabetes (relative risk [RR] 2.104, 95% confidence interval [CI] 2.089-2.119). The federative entity and socioeconomic region with the strongest association with mortality from diabetes were Mexico City (RR 2.5, CI 2.33-2.68 for 2000; RR 2.06, CI 1.95-2.18 for 2007) and region 7 (RR 2.47, CI 2.36-2.57 for 2000; RR 2.05, CI 1.98-2.13 for 2007). CONCLUSIONS: Mortality rates increased from 77.9 to 89.2 per 100,000 inhabitants in the period 2000-2007. Women had higher mortality than men. Individuals who did not complete elementary school had a higher risk of dying from diabetes (RR 2.104, CI 2.089-2.119). Mexico City as federative entity and socioeconomic region 7 presented the strongest association with mortality from diabetes. PMID- 21308183 TI - [Methodology for evaluating cost-effectiveness in primary health care centers in Chile]. AB - OBJECTIVE: Present a methodology for evaluating cost-effectiveness in primary health care centers (PHCs) in Chile based on the family health care model promoted in Chile and evaluate the results of the first two years of operation of the first pilot center to work under this new primary-care model. METHODS: A cost effectiveness study with a social perspective and a one-year time frame was conducted. In order to compare the university health center in question with the control (a municipal health center), a Family Health Center Composite Quality Index (FHCCQI) was devised. It combines technical indicators and user perceptions of the health centers in six areas: access, continuity of medical care, a preventive and promotional clinical approach, problem-solving capability, participation, and a biopsychosocial and family approach. In order to calculate the costs, the centers' expenses, the savings realized in the rest of the health system, and patients' out-of-pocket expenditures were considered. The incremental cost-effectiveness ratio (ICR) was estimated and a sensitivity analysis was performed. RESULTS: The university health center was 13.4% more expensive (an additional US$8.93 per annum per enrollee) and was more effective (FHCCQI 13.3% greater) than the municipal one. Accordingly, the ICR is US$0.67 for each additional percentage point of FHCCQI increase. CONCLUSIONS: According to the PHC evaluation model that was implemented, the centers that follow the Chilean family health care model are more effective than traditional PHC centers, as measured by both technical indicators and user ratings. PMID- 21308184 TI - [Selenium in serum and plasma: epidemiology and reference values]. AB - OBJECTIVE: To review and analyze the literature on selenium (Se) levels in human serum and plasma; to describe some variations; to obtain reference values for the countries of Europe and Latin America, and to provide an information framework for future studies on the subject. METHODS: Scientific literature was reviewed to gather information on selenium serum or plasma levels in people identified as "healthy." The LILACS, SciELO, and PubMed Medline databases were consulted. The search for information could be from any date (up to January 2010) and in any language. Weighted arithmetic means and standard deviations were calculated. RESULTS: For Europe, 161 reports published between 1972 and 2009 were found, covering 49,869 healthy adults, 28 countries, and 8 regions. Serum/plasma Se levels ranged from 48.2 to 124.00 ug/L. Weighted values for Europe were 85.19+/ 14.58 (CI 95% for the weighted average, 85.124-85.256). The averages by country, region, and measurement technique were statistically different, with significant differences associated with sex and age. Twenty-three of the studies involved individuals under 19 years of age in 10 European countries. The weighted values for this population were 74.21+/-9.50 ug/L (CI 95%, 73.95-74.46). Only 11 studies from Latin America were available. Serum/plasma Se was 91.51+/-18.78 Ig/L in adults; 93.25+/-39.20 in children under 15; and 130+/-30 in newborns less than 25 hours old. CONCLUSIONS: Se serum/plasma levels in Europe showed statistically significant differences by sex and age. Se levels were higher in Latin American adults and children than in Europeans, but the Latin American data are based on few people. The technique for measuring Se in serum/plasma appears to have a significant influence. Properly planned and designed population studies should be conducted in Latin America in order to establish regional reference values for Se in serum and plasma. PMID- 21308185 TI - [Green, healthy environments: training of community health agents in the city of Sao Paulo, Brazil]. AB - The aim of this article is to describe the training of community health agents (ACSs) in the context of an intersectorial initiative (Green, Healthy Environments Project: Building Integrated Public Policies in the City of Sao Paulo). The initiative was developed by four city departments--Environment, Health, Social Support and Development, and Education--in collaboration with the city's 31 superintendencies and five regional health administrations. In addition to these municipal bodies, a network of partners was established, including institutions involved in multilateral international technical cooperation and academic institutions. The training of ACSs and social support agents, and the development of community programs that take into account local potential and characteristics was the main objective of the network. The locally integrated management for the development of an agenda of protection and promotion of green, healthy environments was carried out inside the previously existing networks operating in the territories close to public primary care health units serving populations covered by the Family Health Strategy. There currently are 705 programs created by the Green, Healthy Environments Project. These programs serve as evidence of the positive results obtained locally through intersectorial management efforts. PMID- 21308186 TI - [Parasitic zoonoses: a public health problem in Peru]. PMID- 21308187 TI - [Household factors associated with the presence of human hydatid disease in three rural communities of Junin, Peru]. AB - INTRODUCTION: Hydatid disease, a zoonosis caused by the larval stage of the parasite Echinococcus granulosus, is a public health problem at national level, especially in those regions dedicated to raising livestock. By now, there are many factors, at individual level, that have been associated to the infection by E. granulosus; nevertheless there is not any previous report that explore the association between household characteristics and the presence of the disease among household members. OBJECTIVE: To explore the association between household characteristics and the presence of hydatid disease among household members. MATERIAL AND METHODS: We performed a cross-sectional study in the households of 3 rural communities located in Junin, we evaluated the association between household characteristics and the presence of hydatid disease by multiple logistic regression (MLR). RESULTS: From 417 evaluated households, 56 (13%) of them had at least one positive case among its members. Multivariate analysis showed that households with three or more members, located in the community with the lowest quintile of poverty, that reported raising livestock, and with evaluation coverage greater than 25% were more likely to have at least one positive case among its members. CONCLUSION: The observed characteristics be taken into account in the preliminary definition of high-risk subgroups, optimizing the use of resources and improving the effectiveness of screening programs. PMID- 21308188 TI - [State of the quality of drinking water in households in children under five years in Peru, 2007-2010]. AB - OBJECTIVE: To evaluate the proportion of children under five with access to quality water and its behavior according to geographical location, water supply and poverty status. MATERIAL AND METHODS: Continuous survey (repeated cross), with multistage random sampling, being the universe children under five years living in Peru. We evaluated the presence of free chlorine in drinking water samples in the dwellings of 3570 children (Metropolitan Lima 666, Rest of Coast 755, Urban Sierra 703, Rural Sierra 667, and Jungle 779). We evaluated the presence of total coliforms and E. coli in water samples of 2310 households (445 Metropolitan Lima, Rest of Coast 510, Urban Sierra 479, Rural Sierra Selva 393 and 483). RESULTS: The national proportion of children under five years living in households with adequate free chlorine in drinking water reaches 19.5% of the total, while water free of coliforms and E. coli is 38.3%. There is a marked difference in results by area of residence (the most affected areas were rural Sierra and Jungle), public network at home inside the dwelling and income quintiles. CONCLUSION: Children under five years living in households belonging to the rural areas and extreme poverty, have a great disadvantage to access quality water consumption. This situation represents a serious problem for the control of diarrheal diseases and children malnutrition. PMID- 21308189 TI - [Comunicable diseases, mental health and exposure to environmental pollutants in population living near Las Bambas mining project before exploitation phase, Peru 2006]. AB - OBJECTIVE: To determine the prevalence of communicable diseases, mental health and environmental pollutants exposure in population living near Las Bambas mining project before exploitation phase. MATERIAL AND METHODS: Cross sectional study performed in 453 subjects (children and adults) living in three Apurimac region districts: Haquira, Chalhuahuacho and Progreso. Psychomotor development, intelligence quotient, anxiety and depression levels and the presence of communicable diseases (viral hepatitis B, C and delta, syphilis and HIV) were evaluated, as well as heavy metals (lead in blood, and cadmium, arsenic and mercury in urine samples) and serum cholinesterase levels. RESULTS: Mean age was 29 +/- 17.25 years, 59.2% were female and a range of 6 to 15 years of living in the area was found. No cases of HIV, hepatitis C and delta were found, 1.4% were positive for syphilis and in relation to hepatitis B, we found 1,7% of subjects positive to total anti HBc and 0.5% positive for HBsAg. Heavy metal testing identified people with exceeding limits of mercury in 1.8% arsenic in 4.6%, lead in 24.3% and cadmium in 43.9%. Besides, 29.1% of the population had cholinesterase levels below normal range. Among children, 12.5% were at psychomotor development levels of risk; 2.1% and 3.1% suffered from mild and borderline intellectual disability (mental retardation), respectively. 34.3% of subjects older than 12 had anxiety and 17.5% depression. CONCLUSIONS: Evidence of heavy metal environmental pollution and presence of communicable diseases in this population were already found. Future careless mining activity could worsen the current health situation. PMID- 21308190 TI - [Prevalence and associated factors with depressive symptoms in Health Sciences students from a private university in Lima, Peru 2010]. AB - INTRODUCTION: Depressive symptoms in health sciences students are common, these might be potentially detrimental. OBJECTIVES: To determine the prevalence of depressive symptoms and its associated factors in students from the Health Sciences Faculty of the Universidad Peruana de Ciencias Aplicadas in Lima (Peru), June 2010. MATERIALS AND METHODS: Cross-sectional analytic study; a pre-consented survey was applied to the population 590/869 students. Zung's abbreviated scale was used to measure depressive symptoms. To evaluate de associated factors, logistic regression was used, p<0.05 was considered statistically significant. RESULTS: The mean age was 18.97 +/- 2.45 years and 71.1% were women, 19.6% were migrants and 62.5% were medical students. The prevalence of depressive symptoms was 31.2% in the whole population and in medical students was 33.6%. Depressive symptoms were not associated in bivariate analysis with sex, career, having failed a course, living alone or being a migrant (p>0.05). In the multivariate analysis, significant statistical association was found between depressive symptoms and dissatisfaction with the own academic performance (OR=2.13 CI95%1.47 3.08), dissatisfaction with the current economic status (OR=1.93 CI95%1.24-2.99) and living with a relative external to the nuclear family (OR=1.62 CI95%1.07 2.45). CONCLUSION: A high prevalence of depressive symptoms was found, especially in medical students; being dissatisfaction with academic performance, economic status and living with a relative external to the nuclear family associated factors that could be taken into account in order to build preventive programs. PMID- 21308191 TI - [Vasodilator effect mediated by nitric oxide of the Zea mays L (andean purple corn) hydroalcoholic extract in aortic rings of rat]. AB - OBJECTIVE: To evaluate the vasodilator response of the hydroalcoholic extract of Zea mays L. (Andean purple corn) and to determine if this response is mediated by nitric oxide (NO). MATERIAL AND METHODS: We obtained an extract by maceration for eight days of Andean purple corn cobs in 70% ethanol and subsequent concentration of the product. Thoracic aortic rings were evaluated in an isolated organ chamber, bathed with Krebs-Hensleit solution (KH), and vasomotor activity was recorded with an isometric tension transducer. Basal contraction was produced with 120 mM KCl and then, we proceeded to determinate the vasodilator effect of 3 doses of the extract: 0.1, 0.5, and 1.0 mg/mL. We used L-NG-Nitroarginin methyl ester (L-NAME) to verify that the vasodilation depends on nitric oxide sinteasa (NOs). Then we compared the inhibition of vascular contraction after incubation for 30 minutes, with purple corn extract and captopril 10-5 M. RESULTS: We observed a reduction in maximum contraction (100%) to 85.25 +/- 2.60%, 77.76 +/- 3.23%, and 73.3 +/- 4.87% for doses of 0.1, 0.5 and 1,0 mg/mL respectively. The vasodilation was inhibited by prior incubation with L-NAME. Andean purple corn extract did not inhibit vascular contraction as captopril did (reduction to 75.27 +/- 8.61%). CONCLUSION: The hydroalcoholic extract of Zea mays L produces NO dependent vasodilation. PMID- 21308192 TI - [Molecular cloning and characterization in silico of phospholipase A(2) transcript isolated from Lachesis muta peruvian snake venom]. AB - OBJECTIVE: Isolate and characterize in silico gene phospholipase A(2) (PLA(2)) isolated from Lachesis muta venom of the Peruvian Amazon. MATERIAL AND METHODS: Technique RT-PCR from total RNA was using specific primers, the amplified DNA product was inserted into the pGEM vector for subsequent sequencing. By bioinformatic analysis identified an open reading frame of 414 nucleotides that encoded 138 amino acids including a signal peptide of 16 aminoacids, molecular weight and pI were 13,976 kDa and 5.66 respectively. RESULTS: The aminoacid sequence was called Lm-PLA(2)-Peru, contains an aspartate at position 49, this aminoacid in conjunction with other conserved residues such as Tyr-28, Gly-30, Gly-32, His-48, Tyr52, Asp99 are important for enzymatic activity. The comparison with the amino acid sequence data banks showed of similarity between PLA(2) from Lachesis stenophrys (93%) and other PLA(2) snake venoms and over 80% of other sPLA(2) family Viperidae venoms. A phylogenetic analysis showed that Lm-PLA(2) Peru grouped with other acidic [Asp(49)] sPLA(2) previously isolated from Bothriechis schlegelii venom showing 89 % nucleotide sequence identity. Finally, the computer modeling indicated that enzyme had the characteristic structure of sPLA(2) group II that consisted of three alpha-helices, a beta-wing, a short helix and a calcium-binding loop. CONCLUSION: The nucleotide sequence corresponding to the first transcript of gene from PLA(2) cloned of Lachesis muta venom, snake from the Peruvian rainforest. PMID- 21308193 TI - [Use of standardized blood smear slide sets for competency assessment in the malaria microscopic diagnosis in the Peruvian Amazon]. AB - OBJECTIVES: To assess the competency of microscopists for malaria diagnosis using standardized slide sets in the Peruvian Amazon. MATERIAL AND METHODS: Cross sectional study carried out in 122 first level health facilities of the Peruvian Amazon, between July and September 2007. Within the frame of the project "Control Malaria in the border areas of the Andean Region: A community approach" (PAMAFRO), we evaluated the malaria diagnosis performance in 68 microscopists without expertise (< 1 year of expertise) and 76 microscopists with expertise (> 1 year) using standardized sets of 20 blood smear slides according to the World Health Organization (WHO) recommendations. A correct diagnosis (correct species identification) was defined as "agreement", a microscopist was qualified as an "expert" if they have an agreement >=90% (>= 18 slides with correct diagnosis), as a "referent" with an agreement between 80% and <90%, "competent" if they are between 70 and <80% and "in training" if they have <70%. RESULTS: Microscopists with expertise (68.6%) had more agreement than those without expertise (48.2%). The competency assessment was acceptable (competent, referent, or experts levels) in 11.8% of the microscopists without expertise and in 52.6% from those with expertise. The agreement was lower using blood smear slides with P. falciparum with low parasitaemia, with P. malariae and with mixed infections. CONCLUSIONS: Is the first assessment, we found only one of three microscopists from the Peruvian Amazon is competent fro malaria diagnosis according to the WHO standards. From this baseline data, we have to continue working in order to improve the competency assessment of the microscopists within the frame of a quality assurance system. PMID- 21308194 TI - [Application of conventional and multiplex PCR assays for identification of isolates of Leptospira spp. in Colombia]. AB - Serological identification of Leptospira ssp isolates is difficult to achieve. Thus, molecular testing may be of great interest thanks to its high discrimination power, reproducibility and easy interpretation. OBJECTIVE: To implement and validate conventional and multiplex PCR methods (using primers directed against lipl32 and secY/flaB genes, respectively). To assess the capacity of PCR methods to identify pathogenic and saprophytic species of Leptospira ssp. MATERIAL AND METHODS: 22 international reference strains and 12 colombian isolates were used. DNA was extracted with a commercial kit (Wizard). Specificity and sensitivity of both PCR methods were evaluated. RESULTS: The maximum dilution of DNA samples allowing the detection of Leptospira ssp was determined to be 1:10000 for the PCR lipL32 and 1:100/1:1000 for the multiplex PCR secY/flaB. Both PCR didn't detect DNA from microorganisms unrelated to Leptospira ssp. The lipL32 PCR specifically amplified a 423 bp fragment from all pathogenic Leptospira reference strains, while the secY/flaB PCR amplified both 285 bp (secY) and 793 bp (flaB) fragments from 18 reference strains. The lipL32 PCR detected 7/12 colombian isolates, while secY/flaB PCR detected both secY and flaB genes from 6/12 isolates. CONCLUSIONS: Best results were obtained with the lipL32 PCR, which displayed a better sensitivity and a better capacity to detect different strains than the multiplex PCR. The secY primers showed a poor specificity to pathogenic species and a poor sensitivity. Thus, lipL32 primers show high potential for molecular diagnosis of Leptospira spp in clinical and environmental samples. PMID- 21308195 TI - [High frequency of dyslipidemia and impaired fasting glycemia in a high altitude Peruvian population]. AB - We performed a cross sectional study in Lari (3600 m), a highland rural community from Arequipa, Peru. We evaluated a body mass index (BMI), glycemia and lipid profile in 74 over 18 year persons. The mean age was 51.7 +/- 18.0 years, 62.2% were women, mean of BMI was 25.6 +/- 3.7. Prevalence of hypercholesterolemia was 40.6%, "low HDL" in 77% of the population (93.5% in women vs 50% in men, p <0.001) and elevated level of LDL was 71.7%. The prevalence of impaired fasting glycemia was 27%. In conclusion, we found high prevalence of impaired fasting glycemia, hypercholesterolemia and especially "low HDL" in high altitude rural natives. These findings must be considered to realize interventions in high altitude populations to avoid future cardiovascular complications. PMID- 21308196 TI - [Taeniosis prevalence and human cysticercosis seroprevalence in Pampa Cangallo, Ayacucho, Peru 2008]. AB - To estimate the taeniosis prevalence and human cysticercosis seroprevalence in a rural town from the Peruvian central Andes (Pampa Cangallo, Ayacucho), we performed a cross sectional study in 2008, included 368 people between 5 and 70 years. Fast sedimentation technique and direct examination of stool samples were used to taeniosis diagnosis, and ELISA are used as screening test to cysticercosis, positives cases were confirmed with immunoblot. We found five positives cases to Taenia sp. eggs, which represents a 1.4% (95%CI: 0.2 - 2.5%) of a taeniosis prevalence, being individuals between the 20 to 49 years those which presented high proportion. We found 3.3% (95%CI: 1.5 - 5.1%) of cysticercosis prevalence for 12 positives cases, being most frequent in women. No association with evaluated factors was found. Though the prevalence is low, the existence of the taeniosis and cysticercosis is confirmed in this population, by what there is suggested the establishment of prevention and control strategies, emphatically in the community education. PMID- 21308197 TI - [Evaluation of an ELISA test with Fasciola hepatica metabolic antigen for diagnosis of human fascioliasis in Cajamarca, Peru]. AB - Metabolic (excretion/secretion) antigen was obtained from sheep infected with Fasciola hepatica, with a 1005 MUg/MUL of protein concentration, composed principally by proteins of molecular weight between 1.2 and 170 KDa. Bands of 170, 150, 31, 24, 18-14 and 10 kDa were detected. With this antigen an ELISA test was developed and the cut off was determined in 0.140. We evaluated 33 serums of patient with fascioliasis confirmed by visualization of eggs in feces, 177 serums of persons without fascioliasis from endemic rural areas of Cajamarca and 88 serums of patients with others parasitic and bacterial infections. We found a 97.0% of sensitivity, 96.6 specificity, 78.1% predictive positive value, 99.6 % predictive negative value. In 9/88 serums was found cross reactions. We recommended the implementation and use of this test for the fascioliasis diagnosis. PMID- 21308198 TI - [Lophomonas sp. in respiratory tract secretions in hospitalized children with severe lung disease]. AB - Lophomonas sp. is a habitual parasite of the intestinal tract of the cockroaches and that is not recognized as pathogenic human being. Nevertheless, in the world literature are few reports of Lophomonas sp. in respiratory tract secretions in patients with severe pulmonary disease, mostly in adults. We present evidences of Lophomonas sp. in the respiratory low tract of children attended in the national reference center of paediatric diseases of Lima, Peru, in the period 2009- 2010. We found six cases, 4/23 from broncoalveolar lavage and 2/794 from tracheal aspirate samples of children. Five of them had pneumonia and one atelectasis, four were hospitalized in the intensive care unit. Increase knowledge about the presence of this organism in respiratory infections is needed, as its real pathogenic role. PMID- 21308199 TI - [Is it safe for human and animal health to use Salmonella-based rodenticides?]. AB - We conducted a systematic search of the literature to identify publications on the safety of exposure to Salmonella-based rodenticides by humans and animals. We included full-text publications that described the methods and presented their results satisfactorily. Of 545 publications retrieved, 47 were reviewed in full text and from those 12 were selected. Six reports featured cases of salmonellosis in humans, with fatal cases, associated with exposure to previous versions of this type of rodenticide. A clinical trial reported an increased frequency of diarrhea and fever in the group that ingested Biorat (r) (the current commercial form) containing Salmonella, however the difference from the control group was not significant, but the trial had methodological problems. Strains of Salmonella enteritidis from an earlier version of the rat poison (Ratin(r)) and those in the current version correspond to the same variety (Danyzs) and phage type (6a), and were found to be closely related using the technique of pulsed field gel electrophoresis (PFGE). No pathogenic effects of this Salmonella were reported in different animal species tested; however, we found limitations in the methodology. We conclude that the Salmonella enteritidis contained in earlier rat poison formulations produced illness in humans so that its commercialization was prohibited, and that there would be a potential risk with the present formulation because it contains a very similar bacteria, and because there is not sufficient evidence to guarantee its safety. Well-designed studies still need to be done by institutions that do not have a conflict of interest before it can be applied in the areas of public health and agriculture. PMID- 21308200 TI - [Neurocysticercosis diagnosis and management in Peru]. AB - Neurocysticercosis (NCC) is the most common parasitic disease of the central nervous system and is caused by larvae of the tapeworm Taenia solium. NCC is endemic in almost all developing countries. It presents as intraparenchymal forms associated with seizures or as extraparenchymal forms associated with intracranial hypertension. The clinical and epidemiological suspicion are important but the diagnosis is made primarily by images and confirmed by serology. Computed tomography (CT) and magnetic resonance imaging tests are used. Immunodiagnosis by Western Blot, which is currently perform in the Instituto Nacional de Ciencias Neurologicas in serum and cerebrospinal fluid serves as confirmatory test. Treatment involves symptomatic measures (control of seizures or intracranial hypertension) and anticysticercal medications (albendazole and praziquantel). Anticysticercal treatment should be used under hospital conditions because of secondary effects. PMID- 21308201 TI - [Epidemiology and control of cysticercosis in Peru]. AB - Neurocysticercosis, the infection of the human central nervous system by the larval stage of the cestode Taenia solium, is an important cause of epilepsy and other neurological manifestations in Peru and most developing countries. Since 1987, the Cysticercosis Working Group in Peru has performed a series of epidemiological studies which led to estimate the impact and to better understand the transmission of Taenia solium. This information was later applied to the design and execution of a control program in Tumbes, in the Northern Coast of Peru. This paper reviews the main epidemiological findings, as well as the conceptual framework of the elimination program and the tools used. Advances in the control of taeniasis/cysticercosis in our country open the road towards its elimination and potential eradication. PMID- 21308202 TI - [The Southern Cone Sub-Regional Project on Cystic Echinococcosis Control and Surveillance]. AB - Southern Cone Sub-Regional Project on Cystic Echinococcosis Control and Surveillance: Argentina, Brasil, Chile and Uruguay, is a joint and collaborative tool with the aim of promoting the implementation or the strengthening of programs for disease control. The paper describes the background, the institutional aspects that regulates the structure and functions, as well as the guidelines defined in the technical and operational project. The article emphasize the achievements through Projects of Technical Cooperation among Countries, and the development of integrated and innovative approaches for prevention and control of the disease and training of human resources of the control programs. Some of the challenges are: to achieve the sustainability of the project, implementation of technical groups for analysis and assessment at request of the countries, improvement of the regional information systems, to continue training human resources of the control programs and to expand and strengthen the technical cooperation among countries. PMID- 21308203 TI - [Human and animal fascioliasis in Peru: impact in the economy of endemic zones]. AB - Fasciola hepatica is the causative agent of fasciolosis in Peru; the disease is an important public health problem by the high prevalence of the human infection affecting mainly children and a major veterinary problem by the high rates of infected livestock. The human disease is endemic in the Sierra and the Coast but sporadic in the Amazonia, and reported in 18 Departments, while the animal infection in 21 of 24 Departments of Peru. Transmission occurs in Andean rural populations engaged in agriculture, but recently an increasing number of people became infected in the cities. The epidemiological situation in Peru includes i) Departments with non-autochtonous cases, where infection occurs by consumption of contaminated vegetables brought from endemic areas or infection is acquired by visit to endemic areas; ii) Departments with hypoendemic and mesoendemic villages, where transmission occurs by ingest of contaminated vegetables and prevalence <=10%; and iii) Departments with hyper-endemic villages with human prevalence >10 %, with an intense transmission by consumption of contaminated vegetables. The disease affects bovine, sheep, goat, swine, equine, South American camelids, rabbits and guinea pigs. The negative impact of fasciolosis in the livestock economy is not lesser than US$ 50 million per year, estimation based on the prevalence and the number of condemned livers in the abattoirs. It is difficult to estimate the economic impact of this infection in the human health due to its status of neglected disease, but fasciolosis is hyper-endemic in the poorest Andean areas of Peru where the situation has to be recognized as a public health emergency. PMID- 21308204 TI - [Diagnosis of human toxocarosis]. AB - Human toxocarosis is an important parasitic zoonosis caused by larval stages of Toxocara species, the roundworms from dogs and cats. Larval migration through different soft tissues in the human generates several clinical entities in the patient, such as visceral larva migrans, ocular toxocarosis, and neurotoxocarosis. Definitive diagnosis by histopathological methods is very difficult or almost impossible and, nowadays, the diagnosis is usually made by clinical signs/symptoms, epidemiological background of the patient and the use of hematological and immunological tests which finally help to confirm the clinical suspicion of the illness. The purpose of this paper was to update the available knowledge on the use of different tools for both the diagnosis and following up of human toxocarosis. PMID- 21308205 TI - [Towards a national commission on health research ethics in Peru: reflections on the routes and processes comparing viewpoints]. AB - We performed a review of the constitution processes and functions of national commissions on health research ethics in Latin America and Europe countries, which are characterized by its relation with the legislation and governmental structures in health sector, but, especially, in almost totality of cases for being linked by the functioning of the Research Ethics Committees. On the basis of this review there are realized an initial balance sheet and perspectives of the conformation of a National Commission on Health Research Ethics in Peru. PMID- 21308206 TI - [Experiences in the training of health human resources for the integral care of the victims of violence in a suburban area of Lima, Peru]. AB - In the year 2003, in the Faculty of Medicine of the Universidad Nacional Mayor de San Marcos, the Permanent Program of Training for the Integral Attention of the Victims of Violence was created, has been training human resources for the comprehensive health care to victims of violence. In this sense, we was considered necessary to develop a methodology for health professionals, identifying their training needs and the conditions under how they work. It is in this context, that the year 2004, a base line study was delineated in the Microrred de Salud Huaycan, in the east of Lima city; that included diverse stages with a multisectorial approach with the aim to identify the training needs of the health professionals, as well as the evaluation of the logistic and administrative support for the development of training activities to diverse levels. In this paper, the procedures and principal results are exposed, in a succinct way. There was demonstrated that the population of Huaycan were affected by the sequels of the political violence; nevertheless, the health services have severe limited resources to give appropriate health care to victims of violence. The health professionals require an intensive training on this issue. An adequate logistic and administrative conditions allowed to carry out an appropriate training program. We suggest that this methodology will facilitate to construct products and instruments for a suitable and specific training for the integral health care to the victims of the violence. PMID- 21308207 TI - [Idiopathic chronic granulomatous mastitis: a case report]. AB - Idiopathic chronic granulomatous mastitis is a rare disease in women at the reproductive life with clinic, mammographic, echographic and cytological characteristics suggestive of breast cancer. We report a case of breast pathology in a 35 years old woman who had a sensitiveness and eritematous tumor localized in the left breast. With the diagnosis of "mastitis", she was treated with antibiotics and corticoids for two weeks. Because the lesion and the sensitiveness persist and the mammographic and ecographic controls were suggestive of malignancy, the tumor was surgically removing. The histopathological diagnosis was idiopatic chronic granulomatous mastitis. PMID- 21308208 TI - [Jose Casimiro Ulloa Bucelo (1829-1891), paladin of the medical guild]. PMID- 21308209 TI - [Pictures of parasites causing fascioliasis, cysticercosis, hydatid disease and toxocarosis]. PMID- 21308210 TI - [About the withdrawal of sibutramine in Peru]. PMID- 21308211 TI - [Considering scientific publications for the entry to the medical residency in Peru]. PMID- 21308212 TI - [Public use of existing datasets as initiative to boost health research production in Peru]. PMID- 21308213 TI - [Actions to promote medical research in Peru]. PMID- 21308214 TI - [Impact of a dengue epidemic outbreak on the Google searches in Peru]. PMID- 21308215 TI - [The real significance of being bitten by a hematophagous bat in indigenous communities in the remote Peruvian Amazon]. PMID- 21308216 TI - Challenge for the Brazilian Nursing: creating a national alliance between their organizations. PMID- 21308217 TI - [The nurse and patient's nudity]. AB - This is a qualitative study about the relationship among nurses of a university hospital and their patients when they need to undress those patients to take care. The purpose was to analyze speech of seven nurses in this situation. The information was taken by transcribing the semi-structured interviews which were analyzed according Michel Foucault's thought. The results demonstrated that the relationship among nurses and patients at the time when nudity is needed to perform nursing care is full of power, to which the nurses don't feel always prepared. Also the nurses don't think that, acting as they act, they exert power over the patients. It is suggested to Nursing schools to perform seminars about the care with the naked body. PMID- 21308218 TI - [Use of medical supplies in surgical center after implementation of an automated management system]. AB - The study had the objective to compare the efficiency of the Automated System of Management of Hospital Medical Materials as opposed to the traditional system in relation to the consumption of stock of materials. It involved a comparative analysis with a quantitative approach adopted in the Surgical Center of the University Hospital of the University of Sao Paulo. The study dealt with 293 items of hospital medical materials during the month-periods of February to May of 2007 and of 2008. The results showed that the use of materials in 2008 decreased by 8.13% as compared to 2007. The volume of materials in stock in 2008 was reduced by 26.22% also in the same period, and the cost of these materials stocked in 2008 showed a 12.46% decrease. PMID- 21308219 TI - [Nursing diagnoses in in-rooming units]. AB - The use of nursing diagnoses in the rooming unit aims to guide nursing actions, qualifying the assistance. The aim was to identify the Nursing Diagnoses (ND) according to the taxonomy NANDA II 2007/2008, in newborns, and to describe the facts related to it and the risk factors. It is an exploratory descriptive study, conducted with 35 newborns, in January 2008. After physical examination, one identified the ND. The data were organized in charts. Out of the results the most common diagnoses were efficient and inefficient breastfeeding, risk of infection and damaged skin integrity. The use of ND makes nursing service more structured, favoring the nurse's autonomy in the care rendered to the newborn. PMID- 21308220 TI - [Mental health in Family Health Strategy: evaluation of matrix support]. AB - The objective of this article is to assess the matrix support under the perspective of 14 professionals of a family care unit, in an evaluative and qualitative study based on Fourth Generation Evaluation. The data were collected in observations and interviews, and were analyzed by the Constant Comparative Method, focusing on the inclusion of mental health actions in the Family Health Strategy. Professionals from these studied teams assessed the need for care support as well as technical orientations from teams that specialized in mental health as to carry out mental health actions in the territory, which could be implemented by the matrix support. We assessed that this form of organization is important when building mental health actions in the territory. PMID- 21308221 TI - [Nursing diagnosis "altered urinary elimination" in persons with diabetes mellitus]. AB - This is a exploratory descriptive study, to identify and describe the nursing diagnoses in people with diabetes mellitus and nursing diagnosis Urinary elimination altered. Data were collected by the researcher using the technique of physical examination and interview addressed. After collecting data, it is the identification of the nursing diagnoses appointed according to the NANDA Taxonomy II, using Risner's reasoning diagnostic process. Interviews of 31 persons, it was 10 (32%) subjects who had the nursing diagnosis of impaired urinary elimination. Know the related factors and defining characteristics of this diagnosis allows the nurse trace of nursing interventions to preserve renal function, and hence to diabetic nephropathy. PMID- 21308222 TI - [Hospital clinical experience: meanings for Family Health resident nurses]. AB - This qualitative research in phenomenological design aimed at understanding the meaning of hospital clinical experience in the nurse's training in a Multiprofessional Family Health Residency. The study was developed in a teaching institution. Data collection was based on interviews and had as study population eight resident nurses. I investigated the residents' experience according to their speeches, by making the following guiding question: "Talk about your hospital experience, how does it show itself in your training as a resident"? One open category emerged from the subject' description: Causing to approach the hospital experience and the Primary Health Care. Among the meanings attributed to the hospital experience, there is the need and relevance as an integrant part of the curriculum vitae of the Multiprofessional Family Health Residency for the nurses. PMID- 21308223 TI - [Gender analysis in acquiring cancer]. AB - The objective of this study was to understand the process of the sicked of cancer, in men and women, the perspective of the gender. To four women and three men, carriers of cancer of colon and rectum who were in ambulatorial treatment, in an Institution of Private Health, the city of Fortaleza-CE, in the month of July of 2008 had participated as informing. The information had been collected by half-structuralized interview being organized in categories in agreement analysis of studious content and analyzed consonant of the thematic one of gender. The categories that had emerged had been: The sicked of cancer: spallings and limitations in the life; a life in transformation: of the threats to the overcomings. The depositions all elucidate the process of sicked of cancer and the perception of gender on this event beyond disclosing that the stereotype created by the society concerning sort also are expressed the behavior presented for the people who sicked of cancer. PMID- 21308224 TI - [Perception of the nursing team about causes of errors in the administration of medication]. AB - The nursing staff, responsible for the last stages of the administration of medications can detect failures and avoid them. The security in the administration of medicines is essential, therefore it is necessary to identify the types of errors and the risk factors in the occurrence of failure. This study sought to identify the causes of errors in administering medication and preventive measures. This is a quantitative, descriptive and exploratory research. Fifty-two professionals participated in this research. The administration of drugs is one of the most important activities of nursing, so the awareness of all the nursing staff that there will be no punishment in the occurrence of error should be made clear. PMID- 21308225 TI - [Difficulties faced by family members of elderly with chronic diseases to access Basic Health Unit]. AB - The individual's aging process is being the target of attention in Brazil, what requires from the public health services a specific preparation to face this reality. The study aimed at to identify the difficulties lived by the families of elderly with chronic conditions looking for assistance in the Basic Health Units. As a methodological referential the Data Based Theory was used, and the Symbolic Interactionism was used as a theoretical referential. Eight families of seniors suffering from chronic disease took part in the research. The families mention problems of non-continuity of the programs accomplished by the BHU when the political administration is changed, as well as the frequent changes of the health team members, leading to the discontinuity of the treatment and the breaking of bonds between population and professionals of health. PMID- 21308226 TI - [Education process of nurse leaders]. AB - Qualitative study, descriptive and exploratory which aimed to ascertain the role of an institution of higher education and hospital training and continuing education of nurse-leaders. Was developed during the months of February and March 2008, with the participation of eleven nurses from a large hospital in the southern region of Rio Grande do Sul. For data collection was carried out semi structured interviews and focus groups. Using the Content Analysis for the treatment of data, two categories emerged: the role of higher education institution in the training of nurses, leaders and role of the hospital in continuing education of nurses-leaders. There is the existence of gaps related to the teaching of leadership and development of competence in the hospital context. PMID- 21308227 TI - [Selfcare of diabetic nephropathy]. AB - One aimed to describe the selfcare of diabetic nephropathy. Descriptive study assisted in july-august/2004 a Reference Unit for diabetes mellitus in Fortaleza, CE, Brazil. It is a, performed at the referral Secundary diabetes mellitus in Fortaleza-CE with 30 patients, across the medical files, semistructured interview and observation no participant. Predominance the female gender; 51 to 60 age; low education, monthly income of a minimum wage, nephropathy diabetes bearers type 2 associate the arterial hypertension. As to the orientations about selfcare, they are carried out by nurses and doctors. The diet and the psychological factor represented bearers the biggest obstacles to the treatment and the financial factor the main and limiting cause to its execution. We concluded that it is necessary a more intense education, contextualized with the reality in order to contribute to the diabetic nephropathy bearer's self sufficiency and quality of life enhancement. PMID- 21308228 TI - [Let us care with plays?]. AB - Given the importance of play in the everyday life of hospitalized children, the purpose of the study was to identify the perception of the nursing team in the preparation of children and adolescents for hospital procedures at university hospital in Aracaju. We used exploratory search with a qualitative approach with the nursing staff of the pediatric unit. It is that professionals do not perform the techniques with the plays in their daily activities, but know the importance of this resource. For evidence, it is necessary to insert the toy in the treatment of pediatric nursing care. Beware of play is one of the most efficient means of assisting a child in hospital. PMID- 21308229 TI - [Autonomy in intensive care unit: let us start by caring ourselves]. AB - This study, a qualitative investigation anchored in Foucaltian analysis with approximations to post-structuralist theory, explores the question of autonomy as one of the tensions of nursing performance/knowledge which can be discursively articulated to bioethics and to techno biomedicine. From such perspective, from the multiples vies that may emerge to completing a critical reading of the analyzed texts (articles produced by nurses) and of the interviews with intensive care nurses, the theme of autonomy was analytically explored from the concept of self care, unfolding itself into categories which express privileging: morals as obedience to the Law; conduct and morals concerning technical knowledge; self governing in its confront with technique. These are configured as ethical possibilities for the intensive care nurse/subject, not as sequential or competitive stages, but connected and confluent in the experience of the current historical period. PMID- 21308230 TI - [Symbolical violence in the access of disabled persons to basic health units]. AB - A descriptive study which aimed to characterize the conditions of people with disabilities (PD) in the Basic Health Units-UBS. Data were collected in January 2009 in 20 UBSF. It was used digital camera and check list based on the 9050-NBR ABNT. The results showed: Access town - no traffic lights (100%) of lanes for pedestrians (100%), bumpy sidewalks (90%); Access in UBS: non-standard ports (30%) staircases without banisters (20%); floor outside the standard (75%), in disagreement with standard mobile (20%), drinking at odds with standard (55%), making it difficult to people with disabilities to use a filter (30%), has no drinking or filters (15%); telephones installed inadequately (55%); inaccessible restrooms (96%). Access to UBS of PD is permeated by the symbolic violence. PMID- 21308231 TI - [Orotracheal aspiration in babies: implications in physiological parameters and nursing interventions]. AB - This study aimed to investigate the interventions performed by nurses in response to changes expressed by the babies in use of oxygenotherapy hospitalized at the neonatal intensive care unit during the implementation of the procedures aspiration of tracheal tube and upper airway. Quantitative study, conducted with 56 babies. The aspiration led to increased heart rate and pulse and decreased respiratory rate after the procedure, causing falls in oxygen saturation and extremes peaks in pulse during implementation. It was predominant the non performance of specific intervention that had as objective the improvement of the parameters of the baby. It was concluded that the study was important for bringing benefits to identifying and interpreting the changes expressed by the babies. PMID- 21308232 TI - [Geoprocessing of data as a management tool in a family health unit]. AB - This paper presents the results of geoprocessing data from a Family Health Unit in Curitiba-PR. A research dealt with both descriptive and operational aspects, using the Geographical Information System (GIS). It gathered available information from the Health Unit, identified which data is relevant for public health assessments, organized it in a database targeted for geoprocessing, and finally generated thematic maps. The paper focuses on cases of high-risk pregnancies and high-risk newborns. The thematic maps show the geographical distribution of the incidence and concentration of such cases, as well as correlations between them. Finally, the paper shows that georeferenced maps of public health issues support a better focused planning and management of health services offered to the local population. PMID- 21308233 TI - [Adhesion to leprosy treatment: inherent difficulties of the patients]. AB - This research, carried in Guaiuba, Ceara, Brazil aimed to identify the difficulties for the treatment compliance of leprosy patients, relating the associated factors. This is a qualitative study; data was collected from a home visit in January 2009 using an interview guideline containing seven guiding questions. Diagnosed leprosy patients with history of non compliance to treatment participated of the study. It was used Roper, Logan and Tierney's Model of Life Activities. The speeches of the subjects were classified according to twelve life activities. The model utilization made possible a holistic approach on the barriers lived by leprosy patients in the compliance to drug treatment, in order to know the life activities of these patients to a possible adaptation of the actions addressed to this clientele. PMID- 21308234 TI - [Prevalence and features of falls of institutionalized elders]. AB - This retrospective study seeks to check the prevalence of falls in older people from a long-term care institution for elderly people, in Sao Paulo, to describe the fallers and the events. We analyzed 121 medical records and 87 fall reports, between August 2006 and August 2007. There were 114 falls suffered by 45 ancians, a prevalence of 37,2%. The majority of fallers are women, average age 83,75 years. We found recurrent falls, various diagnoses and polipharmacy. The majority occurred in own height, in their bedroom, producing mainly hematomas. There is a need of implementation of fall preventive guidelines, due to the importance of this issue and its repercussions to the functional status of the institutionalized elderly. PMID- 21308235 TI - [Precocious skin-to-skin contact between mother and child: meanings to mothers and contributions for nursing]. AB - That was a convergent-care study, carried out in a maternity ward in the Southern Region of Brazil from April to May 2009, with the purpose to comprehend the meanings of premature mother-child skin-to-skin contact and relevant nursing contributions. Data were collected through participant observation and interviews involving nine mothers. Four categories were identified: a) predelivery orientation surrounding premature mother-child skin-to-skin contact; b) establishing premature mother-child skin-to-skin contact; c) meanings of premature mother-child skin-to-skin contact for the mother; and d) nursing contributions in establishing premature mother-child skin-to-skin contact. It was concluded that the meanings of premature mother-child skin-to-skin contact attributed by these mothers is positive, and that nursing's contribution in establishing such contact is significant. PMID- 21308236 TI - [Coverage characterization of pre-natal in Maranhao State, Brazil]. AB - The purpose of the study was to characterize the coverage of prenatal care in the State of Maranhao. A population-based study, descriptive in 30 municipalities of the State of Maranhao, with 2075 women of childbearing age, with previous pregnancy, from July 2008 to Januray 2009. The results demonstrated that the units of family health accounted for 45.9% of the care of pregnant women and that 46.8% reported carrying out consultations six or more prenatal care during last pregnancy and 64.6% started prenatal in the first three months of pregnancy. The coverage of prenatal care, without regard to adequacy, was 85.6%, however, when considering the coverage of adequate prenatal as established by Brazilian Health Ministry was 43.4%. Although coverage of prenatal above 80%, less than half is considered adequate, showing a gap in primary care quality. PMID- 21308237 TI - [Identity's configuration of nurses of a mobile emergency care service]. AB - This study considers the configuration of the identity of nurses working in a Mobile Emergency Care Service, based on the model of Dubar. This is a qualitative study, in which data were collected mainly through interviews, with nurses and other team members, and analyzed according to the technique of content analysis. About the identity of the nurse, the results point to a different subject, experienced, lonely, closer to the welfare activities, in search of training and recognition, wrapped in complex labor relations. Due the limitations of research and the issues that emerged in the research process, suggestions for future research are aligned at the end of the article. PMID- 21308238 TI - [Theoretical training for nurses in cardiac arrest attendance]. AB - OBJECTIVES OF THE STUDY: to apply a theoretical qualification program for nurses in cardiopulmonary resuscitation and compare the theoretical knowledge group-A control with group-B-experimental. This program comprised three stages: Stage-I, evaluation pre-theoretical qualification; Stages-II and III, evaluation of the recent (one week after stage-I) and later (three months after stage-I) qualification. The sample was composed of 21 nurses in Group-A and 38 in Group-B. The mean performance score in Group-A varied in a progressive form: 6.45; 6.66 and 7.10; in Group-B, in an oscillating form: 6.48; 8.36 and 8.0; stages II and III (p<0,001). It was concluded that: Group-B has been superior to Group-A. However, the performance of Group-B stage-II was superior to stage-III, while in the Group-A it was observed a gradual improvement. PMID- 21308239 TI - [Attitudes of clinical nurses toward personal characteristics of alcoholics patients]. AB - The purpose of this exploratory study was to discover nurses' attitudes towards the perceptions of personal characteristics of alcoholics. Nurses' attitudes were measuared using the Seaman-Manello Scale, the sample consisted of 171 nurses who work in a university general hospital located in the State of Sao Paulo, Brazil. The results evidenced that more than half of the sample (52.4%) had a professional experience with alcoholics. Nurses see the alcoholic patients as unhappy, lonely, sensitive people, who doubt their own value and have serious emotional problems. It is concluded that nurses' attitudes toward personal characteristics of alcoholic patients tend to be positive and suggests greater attention to professional training in recognition and approach of the alcoholic in general hospitals. PMID- 21308240 TI - [Theoric-phylosophic conceptions about aging, old age, aged and gerontogeriatric nursing]. AB - Objective of this essay was to lead a reflection/critics about the theoretical and philosophical ideas on the concepts of aging/elderly/old age, and gerontogeriatric nursing. Benchmarks of nursing, gerontology and the complexity of Morin as theoretical were used. The gerontology is still a new science in Brazil, emerging, rising, and walking to the need to implement actions aimed at improving the quality of life of those who are older and a guarantee of autonomy and independence of that part of the old already. There is a need to establish terms that approximate to give a common language among health workers/nurses that act, to act in that area or those who are concerned to use appropriate terms in reference to gerontology. PMID- 21308241 TI - [Analysis of scientific production on the usage of contraceptive methods by adolescents]. AB - The purpose fo the study was to analyze national scientific production on the contraceptives in adolescence. A quantitative descriptive research through systematic revision was performed in CAPES' database from 1997 to 2007. Out of the 43 ABSTRACTs, 35 were dissertations (81.4%) and eighth (18.4%) were doctoral theses. From 1997 to 2002 there was a wide number of publications. The health area presented 58.1% and the qualitative studies were predominant (48.8%). When it comes to the focus, the knowledge and usage of contraceptives and the opinions and/or perceptions on sexual and reproductive health of adolescents were highlighted. The professionals from several fields are concerned about discussing the theme, suggesting strategies of how adolescents should live their sexual and reproductive lives in a healthy way. PMID- 21308242 TI - [Analysis of clinical nurses' publications in national journals]. AB - This research study identified clinical nurses' publications. A literature review was carried out in three national periodicals between 2000 and 2007, totalizing 1918 articles. Data demonstrated that clinical nurses' authorship or co authorship of 162 articles (8.5%); titling was not identified in 75 publications; doctors published the most along with nurses; areas with the highest number of articles were health and nursing education, adult and elderly health. It was concluded that nurses have easier access to publish in research groups; resuming practice, even after post-graduation, they do not keep up scientific production. This entire professional category must double efforts to broaden their participation in periodicals. PMID- 21308243 TI - [Brazilian studies on nephrology produced in nursing thesis and dissertations]. AB - The purpose was to evaluate the scientific production in Brazilian nursing about nephrology in theses and dissertations published from 2001 to 2007. A bibliometric study was carried out with the nursing thesis and dissertations according to the Center of Studies and Researches in Nursing catalog. It was found 50 works on nephrology, predominating: 45 (90%) dissertations; 30 (60%) in the state of Sao Paulo; 18 (36%) in clinics of dialysis; 39 (78%) samples were patients. Considering the types of study, it predominated: 26 (52%) exploratory, 28 (56%) survey and 27 (54%) quantitative. Concerning the theme, hemodialysis predominated with 21 (42%) publications. Scientific researches on this theme make possible a multi and interdisciplinary assistance to these clients, in an individualized, systematized and humanized way. PMID- 21308244 TI - [Role of nursing in physical rehabilitation]. AB - This study reviews the literature concerning improvement of rehabilitation nurse role, suggesting paths to reach this goal and evoking a still poorly discussed area. Some questions were raised to provoke reflection and discussion. It is evident, based on the literature, that nurses have a total role in rehabilitation, however the boundaries are not clearly defined. Professional nurses must must join rehabilitation practice with permanent education, that will contribute for a more efficient and influence in processes and rehabilitation services. PMID- 21308245 TI - [From management competencies to nurse managerial competencies]. AB - This article is a literature review that aimed to collect more information about the competencies management, understand the concepts of profile and competencies in the managing people; understand the issue of professional competence and its relationship with the organization's competencies; and finally identify the managerial competencies necessary to work of the nurse on the aspect of the labor market. The literature showed that the concept of competence shows great results when applied in the people management arena. It also can provide in the context of health services, benefits for the organizations and for the professionals and patients. For that, it's required that health services to take the ownership of this knowledge as possibility to achieve better results, as well as educational institutions and nurses that seek for information and training to achieve the challenges of the profession and the labor market. PMID- 21308246 TI - [Conception of body in Merleau-Ponty and women who were mastectomized]. AB - Breast cancer has been the responsible for the largest mortality rate in the world, becoming one of the great concerns in health, regarding woman's health. Related to the therapeutics, although wide approaches of interventions that make possible better cure perspectives exist, the mastectomy is as treatment base. Article of philosophic reflection, had as study women's that lived the mastectomy aiming at to reflect the conception of these women's body starting from the work Phenomenology of the Perception of Merleau-Ponty object and of authors that work with the theme regarding the woman mastectomized. PMID- 21308247 TI - [Permanent care: 24 hours nursing care, our way to take care]. AB - Theoretical-reflexive study motivated by the epistemology of Gaston Bachelard and by the project "Thousand and one ways to take care in Nursing" by Maria Jose Coelho. We had as objective to trace new ways to take care in dialysis nursing, creating a system of cares offered to chronic kidney patients. Seven nursing cares that involve care of people in dialysis treatment were described: reception; bonding; specialized techniques; support to self-care; assessment of the treatment, facing the unstimulating routine; and citizenship rescue. Permanent care emerged, understood as an articulate and complementary relation between the scientific knowledge present in nursing care and the valorization of the other's essence, as a complex being in its whole. PMID- 21308248 TI - [Reflections about death: a challenge for nursing]. AB - This reflection proposes a reinsertion on the death theme, in a more present form, in the daily routine of the nurse and its similar, starting with a historic on death, focusing on the transfer of it, that occurred in the bedroom of the moribund, to the hospital bedroom. Soon after, some considerations about the reason to fear death and the need of discussing it, as well as a reflexion on the planning of actions looking as much as to care as to confort the dying patient. With that, it is easy to realize the relevance of the come back of the approach of the subject in the professional daily basis, considering the need to demystify it, to allow that nurses and its similars plan actions of confort to the dying patient. PMID- 21308251 TI - New perspectives and directions in schizophrenia therapeutics: advances related to non-dopaminergic systems. PMID- 21308252 TI - Strategy and plan of action on mental health for the Region of Americas. PMID- 21308253 TI - Principles to guide mental health policies in low- and middle-income countries. PMID- 21308254 TI - What are the principles that should guide mental health policies in low- and middle-income countries? PMID- 21308255 TI - HIV risk behavior of psychiatric patients with mental illness: a sample of Brazilian patients. AB - OBJECTIVE: The prevalence of HIV among psychiatric patients is higher than general population rates worldwide. Many risk behaviors have been identified in studies from both developing and developed countries, though sampling limitations restrict the generalizability of their results. The objective of this study was to report findings from the first national sample of psychiatric patients about lifetime practice of unsafe sex and associated factors. METHOD: A national multicenter sample of adults with mental illness was randomly selected from 26 public mental health institutions throughout Brazil. Sociodemographic, sexual behavior and clinical data were obtained from person-to-person interviews and blood was collected for serology testing. Logistic regression was used for analysis. RESULTS: The overall prevalence of lifetime unprotected sex was 80.3%. Married, older, female patients, those with multiple partners and living with children or partners only and those with less severe psychiatric diagnosis more often practised unsafe sex. DISCUSSION: Risk behavior assessment is a critical tool for clinicians to be able to determine needed HIV-related services for their clients and ensure appropriate follow-through with care and prevention. Interventions that address situational risks in psychiatric patients' lives institutional and individual- and increase their ability to make informed decisions about their sexual health are urgently needed. PMID- 21308256 TI - Alcohol, drugs, and risky sexual behavior are related to HIV infection in female adolescents. AB - OBJECTIVE: To examine associations between risk factors for HIV infection in a sample of young women who sought HIV testing in a city of southern Brazil. METHOD: Cross-sectional study with a consecutive convenience sample of 258 female adolescents aged 13 to 20 years evaluated in an anonymous testing site for HIV and sexually transmitted diseases in Brazil. Risk behavior for HIV was assessed with the Brazilian version of the Risk Assessment Battery and HIV status was assessed through ELISA (Enzyme Linked Immunosorbent Assay). RESULTS: Overall seropositivity rate was 7.4%. HIV-seropositive patients had significantly more sexual intercourse in exchange for money, higher rates of pregnancy and abortion, as well as earlier sexual debut. In multiple analyses with the inclusion of two composite variables (sex risk and drug risk), only drug risk was associated with positive HIV status (OR=4.178; IC 95%=1.476-11.827). CONCLUSION: Our findings suggest that high HIV seropositivity among female adolescents seeking HIV testing in Brazil directly reflects the need for effective interventions specifically designed to prevent risk behaviors in order to halt the spread of HIV infection. PMID- 21308257 TI - Depressed mood and poor quality of life in male patients with chronic renal failure undergoing hemodialysis. AB - OBJECTIVE: To assess mood and quality of life in male hemodialysis patients, and to correlate mood swings with the different domains of the quality of life questionnaire. METHOD: Forty-seven male patients undergoing regular hemodialysis for more than six months were included in the study. The Hamilton Rating Scale for Depression and the Kidney Disease Quality of Life Questionnaire, in a version translated into and adapted to Portuguese, were used. RESULTS: The patients' age was 39.4+/-8.9 years (median+/-SD). Depression was observed in 32 (68.1%) patients according to the Hamilton Rating Scale for Depression. A significant negative correlation was found between the results from the Hamilton Rating Scale for Depression and the following parameters of the specific dimensions of the Kidney Disease Quality of Life Questionnaire: list of symptoms and problems (rs= 0.399; p=0.005), quality of social interaction (rs=-0.433; p=0.002), and quality of sleep (rs=-0.585; p<0.001). Among the generic domains, mood showed a significant negative correlation with general health (rs=-0.475; p<0.001), emotional well-being (rs=-0.354; p=0.015), social functioning and energy/fatigue (rs=-0.518; p<0.001). The other parameters of the Kidney Disease Quality of Life Questionnaire did not show significant correlations with the Hamilton Rating Scale for Depression. CONCLUSION: Mood showed a negative correlation with the various scores of quality of life assessed by the Kidney Disease Quality of Life Questionnaire, suggesting a possible influence of mood on the quality of life of chronic renal patients undergoing hemodialysis. PMID- 21308258 TI - Posture and body image in individuals with major depressive disorder: a controlled study. AB - OBJECTIVE: In this study, we aimed to quantify posture and body image in patients with major depressive disorder during episodes and after drug treatment, comparing the results with those obtained for healthy volunteers. METHOD: Over a 10-week period, we evaluated 34 individuals with depression and 37 healthy volunteers. Posture was assessed based on digital photos of the subjects; CorelDRAW software guidelines and body landmarks were employed. Body image was evaluated using the Body Shape Questionnaire. RESULTS: During depressive episodes (in comparison with the post-treatment period), patients showed increased head flexion (p<0.001), increased thoracic kyphosis (p<0.001), a trend toward left pelvic retroversion (p=0.012) and abduction of the left scapula (p=0.046). During remission, patient posture was similar to that of the controls. At week 1 (during the episode), there were significant differences between the patients and the controls in terms of head flexion (p<0.001) and thoracic kyphosis (p<0.001); at weeks 8-10 (after treatment), such differences were seen only for shoulder position. The mean score on the Body Shape Questionnaire was 90.03 during the depressive episode, compared with 75.82 during remission (p=0.012) and 62.57 for the controls. CONCLUSION: During episodes of depression, individuals with major depressive disorder experience changes in posture and mild dissatisfaction with body image. The findings demonstrate that the negative impact of depression includes emotional and physical factors. PMID- 21308259 TI - Assessment of executive functions in obese individuals with binge eating disorder. AB - OBJECTIVE: The aim of this study was to assess executive functions of obese individuals with binge eating disorder. METHOD: Thirty-eight obese individuals with binge eating disorder were compared to thirty-eight obese controls without binge eating disorder in terms of their executive functions. All individuals were assessed using the following instruments: Digit Span, Trail Making Tests A and B, Stroop Test and the Wisconsin Card Sorting Test. In addition, four subtests from the Behavioral Assessment of the Dysexecutive Syndrome Battery were also used, namely the Zoo Map Test, the Modified Six Elements Test, the Action Program Test and the Rule Shift Cards Test. RESULTS: When compared to obese controls, obese individuals with binge eating disorder presented significant impairment in the following tests: Digit Span backward, Zoo Map Test, Modified Six Elements Test, and Action Program Test. Subjects with binge eating disorder also showed significant more set shifting and perseverative errors in the Wisconsin Card Sorting Test. In other measures such as the Digit Span Forward, the Trail Making Test, the Stroop Test and the Rule Shift Cards Test, obese subjects with binge eating disorder did not differ significantly from obese subjects without binge eating disorder. CONCLUSION: These results suggest that, in the present sample, obese individuals with binge eating disorder presented executive deficits, especially impairments relating to problem-solving, cognitive flexibility and working memory. PMID- 21308260 TI - Survey on the use of psychotropic drugs by twelve military police units in the municipalities of Goiania and Aparecida de Goiania, state of Goias, Brazil. AB - OBJECTIVE: To determine the prevalence of psychotropic drug use among military police officers in the state of Goias, Brazil. METHOD: Study carried out at twelve military police units located in the municipalities of Goiania and Aparecida de Goiania between March to October 2008. Volunteers (n=221) were interviewed about drug use using a questionnaire especially designed by the Centro Brasileiro de Informacoes sobre Drogas Psicotropicas (CEBRID). Descriptive statistics was used to determine the prevalence of licit and illicit drug use in the study sample. RESULTS: The frequency of use was divided into: 1) lifetime use: tobacco-39.9%, alcohol-87.8%, cannabis-8.1%, cocaine-1.8%, stimulants-7.2%, solvents-10.0%, sedatives, anxiolytics, antidepressants-6.8%, LSD-0.5%, Bentyl(r) 0.5%, anabolic steroids-5.4%; 2) use in the previous year: tobacco-15.4%, alcohol 72.9%, stimulants-6.3%, solvents-0.5%, sedatives, anxiolytics, antidepressants 3.7%; 3) use in the previous 30 days: tobacco-14.5%, alcohol-57.5%, stimulants 5.0%, solvents-0.5, sedatives, anxiolytics, antidepressants-3.7%. CONCLUSION: The high prevalence rate of psychotropic drug use found amoung military police officers in two cities of the state of Goias in Brazil can be considered an important factor with potential influence on job activities. PMID- 21308261 TI - The influence of the comorbidity between depression and alcohol use disorder on suicidal behaviors in the Sao Paulo Epidemiologic Catchment Area Study, Brazil. AB - OBJECTIVE: To investigate in a community sample the association of suicide related cognitions and behaviors ("thoughts of death", "desire for death", "suicidal thoughts", and "suicidal attempts") with the comorbidity of depressive disorders (major depressive episode or dysthymia) and alcohol or substance use disorders. METHOD: The sample was 1464 subjects interviewed in their homes using the Composite International Diagnostic Interview to generate DSM-III-R diagnosis. Descriptive statistics depicted the prevalence of suicide-related cognitions and behaviors by socio-demographic variables and diagnoses considered (major depressive episode, dysthymia, alcohol or substance use disorders). We performed a multivariate logistic regression analysis to estimate the effect of comorbid major depressive episode/dysthymia and alcohol or substance use disorders on each of the suicide-related cognitions and behaviors. RESULTS: The presence of major depressive episode and dysthymia was significantly associated with suicide related cognitions and behaviors. In the regression models, suicide-related cognitions and behaviors were predicted by major depressive episode (OR=range 2.3 9.2) and dysthymia (OR=range 5.1-32.6), even in the presence of alcohol use disorders (OR=range 2.3-4.0) or alcohol or substance use disorders (OR=range 2.7 2.8). The interaction effect was observed between major depressive episode and alcohol use disorders, as well as between dysthymia and gender. Substance use disorders were excluded from most of the models. CONCLUSION: Presence of major depressive episode and dysthymia influences suicide-related cognitions and behaviors, independently of the presence of alcohol or substance use disorders. However, alcohol use disorders and gender interact with depressive disorders, displaying a differential effect on suicide-related cognitions and behaviors. PMID- 21308262 TI - Vocal analysis of suicidal movie characters. AB - OBJECTIVE: The aim of this study was to describe the auditory-perceptive evaluation and the psychodynamic aspects of voice samples among suicidal movie characters. METHOD: Voice samples of 48 characters (27 male, 21 female), extracted from 36 movies produced between 1968 and 2006, were analyzed. The samples were evaluated through a specific protocol focusing on the auditory perceptive evaluation (voice quality, resonance, pitch, loudness, modulation, pauses, articulation and rhythm) and the psychodynamic aspects of voice. RESULTS: 85.5% of the samples exhibited abnormal findings in at least five parameters of the auditory-perceptive analysis, such as breathiness (n=42; 87.5% of the samples), hoarseness (n=39; 81.2%) and strain (n=29; 60.4%), as well as laryngopharingeal resonance (n=39; 81.2%), either high pitch (n=14; 29.2%), or decreased loudness (n=31; 64.6%). With respect to the psychodynamic aspects, dismay was detected in 50% (n=24) of the samples, hopelessness in 47.9% (n=23), resignation in 37.5% (n=18), and sadness in 33.3% (n=16). CONCLUSION: Our findings suggest the existence of specific patterns used by actors during the interpretation of suicidal characters. The replication of these findings among real patients may contribute to improvement in the evaluation of potential suicidal patients, as well as the implementation of preventive measures. PMID- 21308263 TI - Reliability and validity of a Brazilian version of the Hypomania Checklist (HCL 32) compared to the Mood Disorder Questionnaire (MDQ). AB - OBJECTIVE: Bipolar disorders are often not recognized and undertreated. The diagnosis of current or past episodes of hypomania is of importance in order to increase diagnostic certainty. The Hypomania Checklist-32 is a self-applied questionnaire aimed at recognizing these episodes. As part of the international collaborative effort to develop multi-lingual versions of the Hypomania Checklist 32, we aimed to validate the Brazilian version and to compare its psychometric properties with those of the Mood Disorder Questionnaire. METHOD: Adult outpatients with bipolar disorder I (n=37), bipolar disorder II (n=44) and major depressive disorder (n=42) of a specialized mood disorder unit were diagnosed according to DSM-IV-TR using a modified version of the SCID. We analyzed the internal consistency and discriminative ability of the Hypomania Checklist-32 Brazilian version in relation to the Mood Disorder Questionnaire. RESULTS: The internal consistency of the Brazilian Hypomania Checklist-32, analyzed using Cronbach's alpha coefficient, was 0.86. A score of 18 or higher in the Hypomania Checklist-32 Brazilian version distinguished between bipolar disorder and major depressive disorder, with a sensitivity of 0.75 and a specificity of 0.58, compared to 0.70 and 0.58, respectively, for the Mood Disorder Questionnaire (score>7). The Hypomania Checklist-32 Brazilian version showed a dual factor structure characterized by "active/elated" and "risk-taking/irritable" items. Hence, the Hypomania Checklist-32 Brazilian version was found to have a higher sensitivity but the same specificity as the Mood Disorder Questionnaire. CONCLUSION: The Brazilian version of the Hypomania Checklist-32 has adequate psychometric properties and helps discriminating bipolar disorder from major depressive disorder (but not bipolar disorder I from bipolar disorder II) with good sensitivity and specificity indices, similar to those of the Mood Disorder Questionnaire. PMID- 21308264 TI - Validity of the Mood Disorder Questionnaire in a Brazilian psychiatric population. AB - OBJECTIVE: Bipolar spectrum disorders are prevalent and frequently underdiagnosed and undertreated. This report describes the development and validation of the Brazilian version of the Mood Disorder Questionnaire, a screening instrument for bipolar spectrum disorders, in an adult psychiatric population. METHOD: A total of 114 consecutive patients attending an outpatient psychiatric clinic completed the Brazilian version of the Mood Disorder Questionnaire. A research psychiatrist, blind to the Mood Disorder Questionnaire results, interviewed patients by means of the mood module of the Structured Clinical Interview for DSM IV ('gold standard'). RESULTS: The internal consistency of the Brazilian Mood Disorder Questionnaire, evaluated with Cronbach's alpha coefficient was 0.76 (95% CI; 0.69-0.92). Principal component analysis with varimax rotation indicated an 'irritability-racing thoughts' factor and 'energized-activity' factor, which explained 39.1% of variance. On the basis of the SCID, 69 (60.5%) individuals received a diagnosis of bipolar disorders. A Brazilian Mood Disorder Questionnaire screening score of 8 or more items yielded sensitivity of 0.91 (95% CI; 0.85-0.98), specificity of 0.70 (95% CI; 0.62-0.75), a positive predictive value of 0.82 (95% CI; 0.75-0.88) and a negative predictive value of 0.84 (95% CI; 0.77-0.90). CONCLUSION: The present data demonstrate that the Brazilian Mood Disorder Questionnaire is a valid instrument for the screening of bipolar disorders. The instrument needs to be validated in other settings (e.g., in general practice). PMID- 21308265 TI - [Medicinal plants for the treatment of generalized anxiety disorder: a review of controlled clinical studies]. AB - OBJECTIVE: This work aimed to identify controlled trials, which evaluated effectiveness of herbal medicines in subjects suffering generalized anxiety disorder. METHOD: Controlled studies (randomized, comparative with placebo and/or standard drug, double-blind) were sought through electronic and hand-searches. The word strategy used "plant OR phytomed* OR extract OR herbal OR medicinal (OR specific name plants)" e "anxie* OR anxioly* OR tranquil* OR GAD", limited to "human OR clinical trial OR randomized controlled trial OR meta-analysis OR review". The search was restricted to English language. RESULTS: Piper methysticum presented an unequivocal anxiolytic effect, but most studies also included patients with other anxiety disorders (e.g. phobias). Isolated studies with Ginkgo biloba, Galphimia glauca, Matricaria recutita, Passiflora incarnata and Valeriana officinalis showed a potential use for anxious diseases. Despite this low number of studies, Ginkgo biloba and Matricaria recutita showed an effect size (Cohen's d=0.47 to 0.87) similar or higher to standard anxiolytics drugs (benzodiazepines, buspirone and antidepressants-0.17 to 0.38). No additional study with other plants was found. CONCLUSION: Despite the therapeutic potential of medicinal plants in generalized anxiety disorder, very few controlled trials assessing herbal medicines in generalized anxiety disorder were found. Additionally, these studies present serious flaw design. PMID- 21308266 TI - Mind-body interventions for the treatment of insomnia: a review. AB - OBJECTIVE: As insomnia is highly prevalent, and side effects of medication are well-known, mind-body interventions are increasingly being sought. The objective of this study is to present a narrative review regarding the effects of mind-body interventions for the treatment of insomnia. METHOD: A PubMed search was conducted including only randomized, controlled trials in which the main objective was to treat insomnia. DISCUSSION: Twelve studies were selected. In three of the studies, objective parameters (polysomnography) were analyzed. Mind body interventions were able to improve sleep efficiency and total sleep time. Most can ameliorate sleep quality; some can reduce the use of hypnotic drugs in those who are dependent on these drugs. CONCLUSION: According to the studies we selected, self-reported sleep was improved by all mind-body treatments, among them yoga, relaxation, Tai Chi Chih and music. Cognitive behavioral therapy seems to be the most effective mind-body intervention. Cognitive behavioral therapy was the only intervention that showed better results than medication. However, considering that only five of the twelve studies chosen reached a score of 3 in the Jadad scale, new studies with a higher methodological quality have to be conducted especially in mind-body interventions that belong to the complementary or alternative medicine field. PMID- 21308267 TI - [Guidelines of the Brazilian Medical Association for the diagnosis and differential diagnosis of social anxiety disorder]. AB - OBJECTIVE: Social anxiety disorder is the most common anxiety disorder. The condition has a chronic course usually with no remission and is frequently associated with significant functional and psychosocial impairment. The Brazilian Medical Association, with the project named Diretrizes ('Guidelines', in English), endeavors to develop diagnostic and treatment protocols for the most common disorders. This work presents the most relevant findings regarding the guidelines of the Brazilian Medical Association concerning the diagnosis and differential diagnosis of social anxiety disorder. METHOD: We used the methodology proposed by the Brazilian Medical Association for the Diretrizes project. The search was performed on the online databases Medline (PubMed), Scopus, Web of Science, and Lilacs, with no time restraints. Searchable questions were structured using PICO format (acronym for "patient or population"; "intervention, indicator or exposition"; "control or comparison" and; "outcome or ending"). RESULTS: We present data regarding the clinical manifestations of social anxiety disorder, impairments and implications related to the condition, differences between the generalized and specific subtypes, and the relationship with depression, drug dependence and abuse, and other anxiety disorders. Additionally, the main differential diagnoses are discussed. CONCLUSION: The guidelines are intended to serve as references to the general practitioner and the specialist as well, facilitating the diagnosis of social anxiety disorder. PMID- 21308268 TI - [Marital problems and other factors associated with postpartum psychiatric disorders]. PMID- 21308269 TI - Bipolar disorder and multiple sclerosis: comorbidity and risk factors. PMID- 21308270 TI - [What is the real association between cognitive disfunction and cannabis?]. PMID- 21308271 TI - Specific reading disability in Brazilian Portuguese: evidence for a multiple cognitive deficit model. PMID- 21308272 TI - Psychiatry in Russia: economic upturn must bring improvements. PMID- 21308273 TI - Evidence of persistent executive function deficits in cannabis dependence after one month of abstinence. PMID- 21308274 TI - [Depression during pregnancy in the Brazilian public health care system]. PMID- 21308276 TI - [Sexual homicide: case report of a forensic psychiatric evaluation]. PMID- 21308277 TI - Mania switch induced by amantadine in bipolar disorder: report of three cases. PMID- 21308282 TI - Comparison of debris extruded apically and working time used by ProTaper Universal rotary and ProTaper retreatment system during gutta-percha removal. AB - OBJECTIVE: The aim of this study was to evaluate the in vitro action of ProTaper retreatment files and ProTaper Universal in the retreatment of mandibular premolars. MATERIAL AND METHODS: The amount of debris extruded apically was measured and the time to reach the working length and to complete the removal of gutta-percha was observed. Thirty teeth had their canals prepared using ProTaper Universal files and were obturated by the single cone technique. The teeth were then stored at 37oC in a humid environment for 7 days. During the use of the rotary instruments for root canal filling removal, the apical portions of the teeth were attached to the open end of a resin tube to collect the apically extruded debris. RESULTS: ProTaper Universal files were significantly faster (p=0.0011) than the ProTaper retreatment files to perform gutta-percha removal, but no significant difference was found between the files regarding the time to reach the working length or the amount of apical extrusion. CONCLUSIONS: ProTaper Universal rotary had better results for endodontic retreatment, and both techniques promote similar apical extrusion of debris. PMID- 21308283 TI - Effect of cavity preparation on the flexural strengths of acrylic resin repairs. AB - OBJECTIVE: To investigate the effect of cavity preparation on the flexural strength of heat-curing denture resin when repaired with an auto-curing resin. MATERIAL AND METHODS: Ninety-six rectangular specimens (64 x 10 x 2.5 mm) prepared from heat-curing denture base resin (Meliodent) were randomly divided into four groups before repair. One group was left intact as control. Each repair specimen was sectioned into two; one group was repaired using the conventional repair method (Group 1). Two groups had an additional transverse cavity (2 x 3.5 x 21.5 mm) prepared prior to the repair; one repaired with (Group 2) and one without glass-fiber reinforcement (Group 3). A three-point flexural bending test according to the ISO 1567:1999 specification 8 for denture base polymers was carried out on all groups after 1, 7 and 30 days of water immersion. Statistical analysis was carried out using two-way ANOVA, Kruskal Wallis and post-hoc Mann Whitney tests. RESULTS: The highest flexural strength was observed in the control group. Control and conventional repairs group (Group 1) showed reduction in the flexural strength 30 days after water immersion. No significant change in the strength was observed for Groups 2 and 3 where the repair joints were similarly prepared with additional transverse cavity. CONCLUSION: Repaired specimens showed lower flexural strength values than intact heat-curing resin. Cavity preparation had no significant effect on the flexural strength of repair with water immersion. PMID- 21308284 TI - Antimicrobial resistance of aerobes and facultative anaerobes isolated from the oral cavity. AB - OBJECTIVES: This study evaluated the resistance to antimicrobials of aerobes and facultative anaerobes isolated from patients wearing complete dentures, patients with gingivitis and periodontitis, and periodontally health subjects. MATERIAL AND METHODS: Three hundred and four isolates were tested. The minimal inhibitory concentrations of the drugs were evaluated through the agar dilution method using Mueller-Hinton agar. RESULTS: The most active antimicrobial drugs were the carbapenems (meropenem and imipenem), and resistance to these drugs was restrict to 1.6-2.3% of the isolates, as well as ciprofloxacin and rifampin. Microbial resistance to ampicillin, amoxicillin/clavulanic acid, cefoxitin, cephalothin, amikacin, chloramphenicol and nalidixic acid was particularly high. In most cases, the resistance to beta-lactams was mediated by the production of hydrolytic enzymes, especially in gram-negative enteric rods, while enterococci did not evidence production of these enzymes. The association amoxicillin/clavulanic acid was not effective in 28.3% of the tested isolates. CONCLUSIONS: The results of this investigation confirmed that the oral cavity of patients with periodontitis and gingivitis, and particularly edentulous patients wearing complete dentures could harbor microorganisms with several antimicrobial resistance markers, and these microorganisms are frequently implicated in multiresistant, systemic, oral or nosocomial infections. PMID- 21308285 TI - Clinical and antimicrobial efficacy of NitrAdine TM-based disinfecting cleaning tablets in complete denture wearers. AB - OBJECTIVE: This study evaluated the efficacy of NitrAdine TM-based disinfecting cleaning tablets for complete denture, in terms of denture biofilm removal and antimicrobial action. MATERIAL AND METHODS: Forty complete denture wearers (14 men and 26 women) with a mean age of 62.3 +/- 9.0 years were randomly assigned to two groups and were instructed to clean their dentures according to two methods: brushing (control) - 3 times a day with denture brush and tap water following meals; brushing and immersion (Experimental) - brushing the denture 3 times a day with denture brush and tap water following meals and immersion of the denture in NitrAdine TM-based denture tablets (Medical Interporous TM). Each method was used for 21 days. Denture biofilm was disclosed by a 1% neutral red solution and quantified by means of digital photos taken from the internal surface before and after the use of the product. Microbiological assessment was conducted to quantify Candida sp. RESULTS: An independent t-test revealed a significant lower biofilm percentage for the experimental group (4.7, 95% CI 2.4 to 7.9) in comparison with the control group (mean 37.5, 95% CI 28.2 to 48.1) (t38=7.996, p<0.001). A significant reduction of yeast colony forming units could be found after treatment with Medical Interporous TM denture tablets as compared to the control group (Mann-Whitney test, Z=1.90; p<0.05). CONCLUSION: The present findings suggest that NitrAdine TM-based disinfecting cleaning tablets are efficient in removal of denture biofilm. In addition, a clear antimicrobial action was demonstrated. Therefore, they should be recommended as a routine denture maintenance method for the prevention of the development of microbial biofilm induced denture stomatitis. PMID- 21308286 TI - Effect of lipstick on composite resin color at different application times. AB - OBJECTIVES: The aim of this study was to evaluate the influence of the contact of two lipsticks, one with common fixer and one with ultra fixer, on the color of a composite resin immediately, 30 min and 24 h after photoactivation. MATERIAL AND METHODS: Ninety specimens were prepared with a composite resin, Filtek-Z350. Specimens were polished and divided into 9 groups (n=10) according to time elapsed after photoactivation (A- immediately; B- 30 min; C- 24 h) and the contact with lipstick (UF- lipstick with ultra fixer; F- lipstick with common fixer). The control group was represented by specimens that did not have any contact with lipstick (C- without lipstick). Color measurements of the specimens were carried out using a spectrophotometer (Easyshade - CIE L* a* b* system). For UF and F groups, the baseline color of the specimens was measured immediately before pigmentation and the lipsticks were applied dry after 1 hour. The excess lipstick was removed with absorbent paper and final color checking was performed, including the control group. Differences between the final and baseline color measurements were calculated and data were analyzed statistically by the Kruskal Wallis test at 5%. RESULTS: The means between the differences of color values were: AUF: 16.0; AF: 12.4; AC: 1.07; BUF: 9.51; BF: 8.3; BC: 0.91; CUF: 17.7; CF: 12.41; CC: 0.82. CONCLUSION: Groups where lipstick was applied showed greater staining than the control group at the three evaluation times. The lipstick with ultra fixer stained more than the lipstick with common fixer. Time elapsed between photoactivation and contact with lipstick had a similar influence on the groups that received lipstick application. PMID- 21308287 TI - Survey on the occurrence of dental trauma and preventive strategies among Brazilian professional soccer players. AB - OBJECTIVES: The aims of this study were to verify the occurrence of dental injuries in professional Brazilian soccer players, the level of knowledge of the teams' medical departments about mouthguards, and the conducts adopted in cases of dental trauma during the match. MATERIAL AND METHODS: Closed questionnaires were sent to the physicians in charge of the medical departments of the 40 teams enrolled in the first and second divisions of the Brazilian professional soccer league in 2007. The data obtained were subjected to descriptive analysis to determine absolute and relative frequencies of answers for each one of the questions. RESULTS: Physicians from 38 (95%) of the 40 teams in the first and second divisions answered the questionnaires and 71.1% reported the occurrence of some type of dental injury during soccer practice, dental fractures (74.1%) and avulsions (59.3%) being the most prevalent ones. Regarding emergency conducts, approximately 50% answered that a successful replantation could be obtained in periods from 6 to 24 h after injury, and 27.8% were not able to answer this question. Regarding mouthguard use, 48.6% of the physicians did not know about mouthguards, and only 21.6% usually recommended their use by the soccer players. Among the physicians who do not recommend the use of mouthguards, 50% justified that it was not necessary. Almost 50% of the medical departments do not have a dentist as part of the health professional staff. CONCLUSIONS: It was possible to conclude that dental injuries are common during professional soccer practice and that there is a lack of information in the medical departments related to the emergency conducts and prevention of dental trauma. PMID- 21308288 TI - Influence of powder/liquid ratio on the radiodensity and diametral tensile strength of glass ionomer cements. AB - Clinicians tend to make reductions in glass ionomer power/liquid (P/L) ratios since some materials are difficult to mix and flow into small cavities, grooves or pits. In general, changing the P/L ratio decreases the physical and mechanical properties of conventional glass ionomer cements (GICs) and resin modified glass ionomer cements (RMGICs), but alterations seem to depend on their composition. OBJECTIVE: To determine the influence of P/L ratio on the radiodensity and diametral tensile strength (DTS) of glass ionomer cements. MATERIAL AND METHODS: There were 2 factors under study: P/L ratio (manufacturer's recommended P/L ratio and a 50% reduced P/L ratio), and materials (Vitro Molar, Vitro Fil, Vitro Cem conventional GICs and Vitro Fil LC, Ortho Glass LC RMGICs. Five 1-mm-thick samples of each material-P/L ratio were produced for radiodensity evaluation. Samples were x-ray exposed onto Digora phosphor plate and radiodensity was obtained using the software Digora for Windows 2.5 Rev 0. For DTS, five (4.0 x 8.0 mm) cylinder samples of each material were tested (0.5 mm/min). Data were subjected to one- and two-way ANOVA (5x2) followed by Tukey's HSD test, or Kruskal-Wallis and Dunn's method. For paired comparisons, t-test or Mann-Whitney test were used (alpha=0.05). RESULTS: There was a significant interaction (P=0.001) for the studied factors (materials vs. P/L ratio). Reduced P/L ratio resulted in significantly lower DTS for the RMGICs, but radiodensity was affected for all materials (P<0.05). CONCLUSIONS: Reduced P/L ratio affected properties of the tested glass ionomer cements. RMGICs were more susceptible to lower values of DTS, but radiodensity decreased for all materials following P/L ratio reduction. PMID- 21308289 TI - Effect of chemical degradation followed by toothbrushing on the surface roughness of restorative composites. AB - OBJECTIVES: The aim of the present study was to assess the effect of the exposure to food-simulating liquids prior to brushing simulation on the surface roughness of five composite materials (Quixfil, Filtek Supreme, Esthet-X, Filtek Z250, Tetric Ceram). MATERIAL AND METHODS: Twenty cylinders (5 mm diameter and 4 mm height) of each composite were randomly allocated to 4 groups (n=5), according to the food-simulating liquid in which they were immersed for 7 days at 37 degrees C: artificial saliva, heptane, citric acid, and ethanol. After this period, the top surface of composite cylinders was submitted to 7,500 brushing cycles (200 g load). Measurements of the surface roughness (Ra, microm) were carried out before and after the exposure to the chemicals/brushing simulation. Changes on the morphology of composite surfaces were observed through scanning electron microscopy (SEM). RESULTS: The statistical analysis (ANOVA with cofactor / Tukey's test, alpha=5%) detected a significant interaction between solutions and composite resins. Esthet-X, Filtek Z250 and Tetric Ceram were not affected by the food-simulating liquids/toothbrushing. Citric acid and ethanol increased the surface roughness of Quixfil and Filtek Supreme, respectively. SEM images corroborate the surface roughness findings, demonstrating the negative effect from chemical solutions and mechanical abrasion. CONCLUSIONS: The surface roughness of composite resin materials are differently affected by the food simulating solutions, depending on the immersion media. PMID- 21308290 TI - Evaluating resin-enamel bonds by microshear and microtensile bond strength tests: effects of composite resin. AB - OBJECTIVES: The aims of this study were to evaluate the effect of resin composite (Filtek Z250 and Filtek Flow Z350) and adhesive system [(Solobond Plus, Futurabond NR (VOCO) and Adper Single Bond (3M ESPE)] on the microtensile (MUTBS) and microshear bond strength (MUSBS) tests on enamel, and to correlate the bond strength means between them. MATERIAL AND METHODS: Thirty-six extracted human molars were sectioned to obtain two tooth halves: one for MUTBS and the other one for MUSBS. Adhesive systems and resin composites were applied to the enamel ground surfaces and light-cured. After storage (37(0)C/24 h) specimens were stressed (0.5 mm/min). Fracture modes were analyzed under scanning electron microscopy. The data were analyzed using two-way ANOVA and Tukey's test (alpha=0.05). RESULTS: The correlation between tests was estimated with Pearson's product-moment correlation statistics (alpha =0.05). For both tests only the main factor resin composite was statistically significant (p<0.05). The correlation test detected a positive (r=0.91) and significant (p=0.01) correlation between the tests. CONCLUSIONS: The results were more influenced by the resin type than by the adhesives. Both microbond tests seem to be positive and linearly correlated and can therefore lead to similar conclusions. PMID- 21308291 TI - Non-surgical instrumentation associated with povidone-iodine in the treatment of interproximal furcation involvements. AB - OBJECTIVE: The aim of this controlled clinical trial was to evaluate the effect of topically applied povidone-iodine (PVP-I) used as an adjunct to non-surgical treatment of interproximal class II furcation involvements. MATERIAL AND METHODS: Thirty-two patients presenting at least one interproximal class II furcation involvement that bled on probing with probing pocket depth (PPD) >= 5 mm were recruited. Patients were randomly chosen to receive either subgingival instrumentation with an ultrasonic device using PVP-I (10%) as the cooling liquid (test group) or identical treatment using distilled water as the cooling liquid (control group). The following clinical outcomes were evaluated: visible plaque index, bleeding on probing (BOP), position of the gingival margin, relative attachment level (RAL), PPD and relative horizontal attachment level (RHAL). BAPNA (N-benzoyl-L-arginine-p-nitroanilide) testing was used to analyze trypsin like activity in dental biofilm. All parameters were evaluated at baseline and 1, 3 and 6 months after non-surgical subgingival instrumentation. RESULTS: Six months after treatment, both groups had similar means of PPD reduction, RAL and RHAL gain (p>0.05). These variables were, respectively, 2.20 +/- 1.10 mm, 1.27 +/ 1.02 mm and 1.33 +/- 0.85 mm in the control group and 2.67 +/- 1.21 mm, 1.50 +/- 1.09 mm and 1.56 +/- 0.93 mm in the test group. No difference was observed between groups at none of the posttreatment periods, regarding the number of sites showing clinical attachment gain >= 2 mm. However, at 6 months posttreatment, the test group presented fewer sites with PPD >= 5 mm than the control group. Also at 6 months the test group had lower BAPNA values than control group. CONCLUSION: The use of PVP-I as an adjunct in the non-surgical treatment of interproximal class II furcation involvements provided limited additional clinical benefits. PMID- 21308292 TI - Biaxial flexural strength of Turkom-Cera core compared to two other all-ceramic systems. AB - Advances in all-ceramic systems have established predictable means of providing metal-free aesthetic and biocompatible materials. These materials must have sufficient strength to be a practical treatment alternative for the fabrication of crowns and fixed partial dentures. OBJECTIVES: The aim of this study was to compare the biaxial flexural strength of three core ceramic materials. MATERIAL AND METHODS: Three groups of 10 disc-shaped specimens (16 mm diameter x 1.2 mm thickness - in accordance with ISO-6872, 1995) were made from the following ceramic materials: Turkom-Cera Fused Alumina [(Turkom-Ceramic (M) Sdn Bhd, Puchong, Selangor, Malaysia)], In-Ceram (Vita Zahnfabrik, Bad Sackingen, Baden Wurttemberg, Germany) and Vitadur-N (Vita Zahnfabrik, Bad Sackingen, Baden Wurttemberg, Germany), which were sintered according to the manufacturer's recommendations. The specimens were subjected to biaxial flexural strength test in an universal testing machine at a crosshead speed of 0.5 mm/min. The definitive fracture load was recorded for each specimen and the biaxial flexural strength was calculated from an equation in accordance with ISO-6872. RESULTS: The mean biaxial flexural strength values were: Turkom-Cera: 506.8 +/- 87.01 MPa, In-Ceram: 347.4 +/- 28.83 MPa and Vitadur-N: 128.7 +/- 12.72 MPa. The results were analyzed by the Levene's test and Dunnett's T3 post-hoc test (SPSS software V11.5.0 for Windows, SPSS, Chicago, IL, USA ) at a preset significance level of 5% because of unequal group variances (P<0.001). There was statistically significant difference between the three core ceramics (P<0.05). Turkom-Cera showed the highest biaxial flexural strength, followed by In-Ceram and Vitadur-N. CONCLUSIONS: Turkom-Cera core had significantly higher flexural strength than In Ceram and Vitadur-N ceramic core materials. PMID- 21308293 TI - Immunohistochemical expression of vascular endothelial growth factor and matrix metalloproteinase-9 in radicular and residual radicular cysts. AB - OBJECTIVE: This study assessed and compared the immunoexpression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) in radicular cysts (RCs) and residual radicular cysts (RRCs), relating them to the angiogenic index and the intensity of the inflammatory infiltrate. MATERIAL AND METHODS: Twenty RCs and 10 RRCs were evaluated by immunohistochemistry using anti VEGF and anti-MMP-9 antibodies. The angiogenic index was determined by microvessel count (MVC) using anti-von Willebrand factor antibody. RESULTS: The expression of both VEGF and MMP-9 was higher in RCs than in RRCs. RCs and RRCs presented strong epithelial expression of VEGF, irrespective of the intensity of the inflammatory infiltrate. Lesions with strong expression of MMP-9 showed significantly higher number of immunopositive cells for VEGF (p<0.05) and higher MVC (p<0.05). Lesions with dense inflammatory infiltrate exhibited significantly higher MVC (p<0.05) and higher number of immunopositive cells for VEGF (p<0.05). There was a positive correlation between both MVC (p<0.05) and the quantity of immunopositive cells for VEGF (p<0.05), with intensity of the inflammatory infiltrate. In addition, it was observed a positive correlation between the number of immunopositive cells for VEGF and MVC (p<0.05). CONCLUSIONS: VEGF and MMP-9 might play important roles in the angiogenesis in RCs and RRCs. In these lesions, the expression of these molecules and the MVC is closely related to the intensity of the inflammatory infiltrate. The expression of VEGF in the epithelial lining of RCs and RRCs might be important for the enlargement of these lesions. PMID- 21308294 TI - Removal efficiency of propolis paste dressing from the root canal. AB - OBJECTIVES: The aim of this study was to investigate through scanning electron microscopy (SEM) the cleaning of root canal walls after the use of experimental propolis or calcium hydroxide root canal dressings. MATERIAL AND METHODS: Twenty single-rooted teeth were used. After conventional cleaning and shaping procedures and removal of the smear layer with 17% EDTA, the teeth were divided into four groups according to the medication used (N=5): Group I (control) - No drug, Group II - Calcium hydroxide dressing, Group III - Propolis paste A70D and Group IV - Propolis paste D70D. The medications were introduced into the root canals and maintained for 7 days, then removed with a K-file and 5 mL of 1% sodium hypochlorite irrigation. Finally, the canals were flushed with 2 mL of 17% EDTA for 3 min. For SEM analysis, the roots were cleaved and microphotographs from the middle third of the root canal were taken at 750x. The cleaning of the root canal walls was determined by the number of open dentinal tubules as verified with the software Image Tool 3.1. The statistical analysis was performed by ANOVA and Tukey's test (p<0.05). RESULTS: The results showed no statistically significant difference between the calcium hydroxide and propolis groups. CONCLUSIONS: The experimental propolis pastes presented acceptable physical characteristics to be used as intracanal medicaments. PMID- 21308295 TI - Mesiodistal root angulation of permanent teeth in children with mixed dentition and normal occlusion. AB - OBJECTIVE: There is little information regarding the mesiodistal angulation of permanent teeth in mixed dentition. The aim of this study was to evaluate mesiodistal root angulation of permanent incisors, canines and first molars of 100 Brazilian children, using a new horizontal reference plane based on the midpoint of the intercuspation of primary canines and permanent first molars in panoramic radiographs during the mixed-dentition phase. MATERIAL AND METHODS: Children were equally divided between the genders with a mean age of 8.9 years (SD=0.76), normal occlusion and no eruptive disturbances. RESULTS: The angulation of the permanent maxillary first molars was close to the vertical, whereas the mandibular molars presented approximately 25 degrees of distal root angulation. The maxillary canines were the most distally angulated teeth, whereas the permanent mandibular canines were vertically positioned. The evaluation of the anterior maxillary area showed vertical position of permanent lateral, and central incisors with a slight distal angulation, whereas the permanent mandibular incisors tended to a mesial radicular convergence. CONCLUSIONS: The proposed reference line could be useful in mixed dentition root angulation evaluation; there was a slight asymmetry in the mesiodistal angulation among homologous teeth, and also a small variation between the male and the female groups, but no difference between 8-and 10-year-old children. PMID- 21308296 TI - Treatment with paracetamol, ketorolac or etoricoxib did not hinder alveolar bone healing: a histometric study in rats. AB - Prostaglandins control osteoblastic and osteoclastic function under physiological or pathological conditions and are important modulators of the bone healing process. The non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) activity and consequently prostaglandins synthesis. Experimental and clinical evidence has indicated a risk for reparative bone formation related to the use of non-selective (COX-1 and COX-2) and COX-2 selective NSAIDs. Ketorolac is a non-selective NSAID which, at low doses, has a preferential COX-1 inhibitory effect and etoricoxib is a new selective COX-2 inhibitor. Although literature data have suggested that ketorolac can interfere negatively with long bone fracture healing, there seems to be no study associating etoricoxib with reparative bone formation. Paracetamol/acetaminophen, one of the first choices for pain control in clinical dentistry, has been considered a weak anti-inflammatory drug, although supposedly capable of inhibiting COX-2 activity in inflammatory sites. OBJECTIVE: The purpose of the present study was to investigate whether paracetamol, ketorolac and etoricoxib can hinder alveolar bone formation, taking the filling of rat extraction socket with newly formed bone as experimental model. MATERIAL AND METHODS: The degree of new bone formation inside the alveolar socket was estimated two weeks after tooth extraction by a differential point-counting method, using an optical microscopy with a digital camera for image capture and histometry software. Differences between groups were analyzed by ANOVA after confirming a normal distribution of sample data. RESULTS AND CONCLUSIONS: Histometric results confirmed that none of the tested drugs had a detrimental effect in the volume fraction of bone trabeculae formed inside the alveolar socket. PMID- 21308297 TI - Experimental periodontal disease treatment by subgingival irrigation with tetracycline hydrochloride in rats. AB - OBJECTIVE: The aim of this study was to compare subgingival irrigation with tetracycline hydrochloride (TTC-HCL) as adjunctive treatment to scaling and root planning (SRP) on induced periodontitis in rats. MATERIAL AND METHODS: In 60 rats, periodontal disease was ligature-induced at the mandibular left first molar. After 7 days, the ligature was removed and all animals were submitted to SRP, and divided into 2 groups according to the following treatment: C (n=30) - subgingival irrigation with 1 mL of saline; T (n=30) - subgingival irrigation with 1 mL of TTC-HCL (50 mg/mL). Ten animals in each group were euthanized at 7, 15 and 30 days posttreatment. The histometric values were statistically analyzed (p<0.05). RESULTS: In the histometric analysis, at 7, 15 and 30 days, Group T (0.72 +/- 0.05 mm2, 0.57 +/- 0.14 mm2, 0.62 +/- 0.07 mm2), showed less bone loss (p<0.05) than Group C (1.35 +/- 0.25 mm2; 1.40 +/- 0.31 mm2; 1.29 +/- 0.27 mm2), respectively. CONCLUSIONS: Subgingival irrigation with TTC-HCL was an effective adjunctive treatment for periodontal disease induced in rats. PMID- 21308298 TI - Chromatic stability of acrylic resins of artificial eyes submitted to accelerated aging and polishing. AB - Esthetics and durability of materials used to fabricate artificial eyes has been an important issue since artificial eyes are essential to restore esthetics and function, protect the remaining tissues and help with patients' psychological therapy. However, these materials are submitted to degrading effects of environmental agents on the physical properties of the acrylic resin. OBJECTIVE: This study assessed the color stability of acrylic resins used to fabricate sclera in three basic shades (N1, N2 and N3) when subjected to accelerated aging, mechanical and chemical polishing. MATERIAL AND METHODS: Specimens of each resin were fabricated and submitted to mechanical and chemical polishing. Chromatic analysis was performed before and after accelerated aging through ultraviolet reflection spectrophotometry. RESULTS: All specimens revealed color alteration following polishing and accelerated aging. The resins presented statistically significant chromatic alteration (p<0.01) between the periods of 252 and 1008 h. CONCLUSIONS: Both polishing methods presented no significant difference between the values of color derivatives of resins. PMID- 21308299 TI - Goldenhar syndrome: clinical features with orofacial emphasis. AB - OBJECTIVES: Goldenhar syndrome (GS) is a relatively common developmental disorder characterized by craniofacial anomalies in association with vertebral, cardiac, renal, and central nervous system defects. This paper describes GS features with special emphasis on oral characteristics. MATERIAL AND METHODS: The clinical features of 6 patients with GS aged 3 months to 12 years are described, and a brief review of the literature about this genetic disorder is presented. RESULTS: All patients demonstrated the classical triad of GS, including mandibular hypoplasia resulting in facial asymmetry, ear and/or eye malformation, and vertebral anomalies. In addition, renal and gastrointestinal abnormalities were observed in 2 patients. Regarding the oral involvement, 2 patients presented cleft lip and palate, and 1 patient had temporomandibular joint malformation. Malocclusion was found in all patients. CONCLUSION: Our orofacial findings correlate with the reported cases in the literature, and point out that after diagnosis GS patients need to be examined for systemic abnormalities. PMID- 21308300 TI - Sexually transmitted diseases during pregnancy: a synthesis of particularities. AB - Sexually transmitted diseases (STDs) have a significant prevalence in both the general population and pregnant women. Accordingly, we consider the physiological changes of the maternal organism that can alter the clinical course of these diseases. In addition, obstetric and neonatal complications may occur, resulting in increased maternal and infant morbidity and mortality. We explore features of the natural course and treatment during pregnancy of the major STDs: soft chancre, donovanosis, gonorrhea, chlamydia, viral hepatitis, genital herpes, human papillomavirus (HPV) infection, lymphogranuloma venereum, syphilis, and vulvovaginitis. We believe that health professionals should pay careful attention to STDs, particularly in relation to early diagnosis and precautions on the use of drugs during pregnancy. Prevention and partner treatment to achieve effective results are also extremely relevant. PMID- 21308301 TI - Acne in adult women: epidemiological, diagnostic and therapeutic aspects. AB - BACKGROUND: Adult female acne (AFA) is a dermatosis of increasing incidence; hyperandrogenism is present in many cases, but there are patients without hormonal abnormalities. OBJECTIVE: To analyze the prevalent characteristics in adult women with acne without hyperandrogenism. MATERIAL AND METHODS: A survey of 226 medical records with AFA complaints was conducted; of these, 116 (51.3%) had a normal hormonal profile and were, therefore, included in the study. We investigated age, ethnicity, clinical profile of acne, complementary exams, previous treatment, prescribed treatment and evolution. RESULTS: The mean age was 33.9 years and the predominant clinical grade of acne was moderate inflammatory (grade 2). The face was the most affected area. Topical retinoids were the most prescribed drugs, and systemic medication was prescribed to 53.4% of the patients. Total regression was observed in 31 patients (26.7%) within 12 weeks of treatment. Adverse reactions to topical treatment occurred in 21.5% of the patients. CONCLUSION: The clinical manifestations of AFA in patients without hyperandrogenism are moderate, with predominance of inflammatory lesions. Treatment is similar to that of acne vulgaris; however, special attention should be taken with more irritating medication since this group appears to be more predisposed to skin irritations. PMID- 21308302 TI - Clinical aspects of patients with pityriasis versicolor seen at a referral center for tropical dermatology in Manaus, Amazonas, Brazil. AB - BACKGROUND: Pityriasis versicolor (tinea versicolor) is a chronic superficial mycosis caused by yeasts of the Malassezia spp. genus commensal of the keratinized layers of the skin. Under conditions not yet understood, it becomes pathogenic determining the clinical manifestations of the disease. It is a recurrent skin condition and persistent hypopigmentation may remain after treatment, causing social problems to those affected. OBJECTIVE: To describe the clinical and epidemiological features of patients diagnosed with tinea versicolor treated at a referral center for dermatology (Alfredo da Matta Foundation). METHODS: Case-studies in which cutaneous manifestations and epidemiological characteristics of patients diagnosed with tinea versicolor treated at Alfredo da Matta Foundation were detailed. RESULTS: One hundred and sixteen patients were included in the study from January to August 2008. Most subjects were male, of mixed ethnicity and young age. Most were students who were predisposed to the development of macules. The majority had extensive injuries and past history of the disease. CONCLUSION: The results revealed a high proportion of individuals with extensive clinical manifestations and duration of the disease. PMID- 21308303 TI - Epidemiological aspects of patients with ungual and cutaneous lesions caused by Scytalidium spp. AB - BACKGROUND: Dermatomycoses caused by non-dermatophyte filamentous fungi are rare infections, except for onychomycosis, whose prevalence has increased over the past few years. Among these etiologic agents, we highlight Scytalidium dimidiatum and S. hyalinum, emergent fungi that cause mycoses that affect the nails and skin. OBJECTIVE: To investigate the characteristics of onychomycosis and other mycoses caused by the fungi Scytalidium spp, using sex, age and site of infection as parameters. METHODS: Eighty-one samples were evaluated showing positive culture for Scytalidium spp, obtained from 74 patients referred to the Laboratory of Investigation in Dermatology (ID) located in the city of Rio de Janeiro, RJ, between 1997 and 2006. The samples were submitted to diagnostic confirmation through direct exam and culture. RESULTS: The prevalence of onychomycosis caused by Scytalidium spp. was of 0,87%. The most prevalent age was between 41-60 years (48.64%). Regarding the site of infection, the feet (91.36%) were most affected, with predominance of the left hallux. Hyaline hyphae were the most common structures in direct examination and the species S. dimidiatum was the most frequent in culture. CONCLUSION: Onychomycosis caused by Scytalidium spp. is rare and S. dimidiatum was the most isolated species in this laboratory during the period of the study. PMID- 21308304 TI - A comparison between the concentration of mast cells in squamous cell carcinomas of the skin and oral cavity. AB - FUNDAMENTS: The lethality of squamous cell carcinomas (SCC) of the skin is considered low. SCC in the mouth is usually associated with poor prognosis. Current evidence suggests that mast cells in the normal tissue contribute to the tumorigenesis of SCC, probably by promoting angiogenesis. OBJECTIVE: The aim of this study was to compare the concentration of mast cells in SCC of the mouth and skin and evaluate whether there is a correlation with the degree of differentiation of these tumors. MATERIAL AND METHODS: Thirty cases of SCC of the skin and 34 of the mouth were investigated. Toluidine blue staining was used to identify mast cells in blocks containing the central portion of the neoplasm. RESULTS: A concentration of between 0 and 10 mast cells was found in one single case of SCC of the skin and there were no cases of SCC of the mouth with concentrations of mast cells in the tumor >201. In the majority of cases of SCC of the mouth (47%; n=16), mast cell concentration was between 0 and 10, with a concentration >51 mast cells in 80% of cases of SCC of the skin. All the cases of SCC of the mouth with a concentration of mast cells between 100 and 200 and 80% of those with a concentration of 51-99 were located on the lip. The concentration of mast cells was unrelated to the degree of differentiation of the tumor. CONCLUSION: The concentration of mast cells is lower in SCC of the mouth except when the tumor is located on the lip. This may reflect a lower need for cell activation in the microenvironment to improve vascularization in oral cancer. PMID- 21308305 TI - Epidemiology of basal cell carcinomas in Tubarao, Santa Catarina (SC), Brazil between 1999 and 2008. AB - BACKGROUND: Skin cancer is the most frequent type of neoplasm in Brazil. There are no data on the incidence of basal cell carcinoma in the Southern region of Santa Catarina. OBJECTIVE: To establish epidemiological data on basal cell carcinoma in Tubarao, Santa Catarina, between 1999 and 2008. METHODS: A cross sectional study was conducted in which anatomopathological reports of basal cell carcinoma from the laboratories of Tubarao, Santa Catarina, were analyzed. We considered the following variables: year of diagnosis, age, gender, city of origin, tumor site, histological subtype, lesion diameter, margin involvement, and relapse. RESULTS: Reports of 3,253 subjects most frequently between the ages of 61 and 80 years diagnosed with basal cell carcinoma were obtained. The incidence of basal cell carcinoma was 164.5 cases per 100,000 inhabitants in 1999 and 295.2 per 100,000 in 2008, showing an increase of 80%. Most lesions occurred in the cephalic region and nodular was the most common histological subtype. There was an association between males and basal cell carcinoma of the torso and ear, and between females and basal cell carcinoma of the nose. The sclerodermiform subtype was the most aggressive in relation to margin involvement. CONCLUSION: There was a prevalence of involved margins following resection in 27% of lesions. Based on multivariate analysis, lesions of 2 cm in diameter were 5.5 times more likely to present margin involvement, and basal cell carcinoma of the face was 1.8 times more likely to occur (p <0.0001). PMID- 21308306 TI - Study of direct immunofluorescence, immunofluorescence mapping and light microscopy in porphyria cutanea tarda. AB - BACKGROUND: Even though porphyria cutanea tarda is the most frequent type of porphyria, there are few studies about its cutaneous physiopathology. OBJECTIVE: To evaluate skin changes in porphyria cutanea tarda using light microscopy and direct immunofluorescence before and after treatment with chloroquine. To perform antigen immunomapping of bullae to study their level of cleavage. METHODS: Light microscopy and direct immunofluorescence of 28 patients are reported in three different phases: 23 patients with active porphyria before treatment (Phase A), 7 patients with clinical remission during treatment (Phase B), and 8 patients with biochemical remission (Phase C). Immunomapping was performed on 7 patients. RESULTS: In active porphyria, direct immunofluorescence showed homogenous and intense fluorescence on the inside and on the walls of blood vessels as well as in the dermal-epidermal junction. In clinical remission (Phase B) and biochemical remission (Phase C), the deposit of immunoglobulins was maintained, but the deposit of complement was reduced in most cases. Immunomapping revealed no standard cleavage plane. CONCLUSION: No correlation was observed between clinical response and immunoglobulin deposits. The reduction of complement favors the hypothesis that activation of the complement cascade represents an additional pathway that leads to endothelial damage. PMID- 21308307 TI - UVB susceptibility as a risk factor to the development of lepromatous leprosy. AB - BACKGROUNDS: Ultraviolet radiation B (UVRB) is the most important environmental factor capable of altering the immune function of human skin. OBJECTIVE: To evaluate the association of the phenotypes of susceptibility or resistance to ultraviolet radiation B (UVRB) and the polar forms of leprosy. MATERIAL AND METHODS: We evaluated 38 patients with lepromatous leprosy (LL) and 87 patients with tuberculoid (TT) leprosy, according to the classification by Ridley and Jopling (1966). All the patients were submitted to a test to determine the phenotypes of susceptibility or resistance to UVRB through the application of a 2% dinitrochlorobenzene (DNCB) disc to a previously irradiated area with twice the minimal erythema dose (MED). After 21 days, a similar disc soaked in 0.05% DNCB was applied to the scapular area (unexposed to UVRB) to check for sensitiveness, with reading of the results after 48 hours. The patients that showed a positive reaction to DNCB were considered resistant (UVB-R) and those who did not show any reaction were considered susceptible (UVB-S). RESULTS: The frequency of UVB-S individuals was 63.2% (24 patients) in the LL group and 34.4% (30 patients) in the TT group (OR=3.26; IC=1.36 - 7.87; x(2)=7.73; p=0.005). CONCLUSION: Our results suggest that UVB-susceptibility is a risk factor to the development of lepromatous leprosy (LL). PMID- 21308308 TI - UVB: susceptibility in malignant melanoma. AB - BACKGROUND: It is well established that UV radiation provokes an immunological depletion in the skin, enabling the development of malignant cutaneous tumors. Most nonmelanoma skin cancer patients are considered to be UVB-susceptible. OBJECTIVE: To study the behavior of UVB- susceptibility in malignant melanoma (MM) patients and whether this is a risk factor to the development of MM. METHODS: Eighty-eight volunteers were selected and divided into two groups: healthy control group (n = 61) and MM group (n = 27), which were identified according to the following clinical criteria: histopathological type, level of invasion, skin phototype, sex and age. Susceptibility to ultraviolet B (UVB) radiation was measured by the onset of a contact hypersensitivity reaction to diphenylcyclopropenone among individuals sensitized in previously irradiated areas. RESULTS: Susceptibility to UVB radiation was 81.5 in the MM group and 31.2% in the control group. The risk of an UVB-susceptible individual to develop MM was 9.7 times higher than when UVB resistant. CONCLUSION: UVB susceptibility should be considered an important risk factor to the development of this type of cancer. PMID- 21308309 TI - Biostimulation effects of low-power laser in the repair process. AB - The wound healing process has always been an excellent subject for researchers. The use of low-power laser on wounds during the postoperative phase has increased the speed of the healing process. It has been implied that low power radiation affects cellular metabolic processes and promotes beneficial biological effects (analgesic, anti-inflammatory, and healing). Laser biostimulation appears to influence the behavior of the repair process. This paper aims at reviewing the most interesting aspects of the use of low-power laser in the tissue-repair process. PMID- 21308310 TI - Immunological mapping in hereditary epidermolysis bullosa. AB - Immunological mapping, an immunofluorescence technique, is currently the method most used to diagnose and differentiate the principal types of hereditary epidermolysis bullosa, since this technique is capable of determining the level of cleavage of this mechanobullous disease. PMID- 21308311 TI - Dysplastic nevus (atypical nevus). AB - Atypical nevum (dysplastic) is considered an important factor associated with increased risk of developing cutaneous melanoma. It is believed that atypical nevi are precursor lesions of cutaneous melanoma. They may be present in patients with multiple melanocytic nevi (atypical nevus syndrome) or isolated and in small numbers in a non-familial context. The disease usually begins at puberty and predominates in young people. It has a predilection for sun-exposed areas, especially the trunk. The major challenge in relation to atypical nevi lies in the controversy of defining its nomenclature, clinical diagnosis, dermoscopic criteria, histopathological diagnosis and molecular aspects. This review aims at bringing knowledge, facilitating comprehension and clarifying doubts about atypical nevus. PMID- 21308312 TI - Does incomplete excision of basal cell carcinoma of the eyelid mean tumor recurrence? AB - INTRODUCTION: Basal cell carcinoma is the most common tumor of the eyelid. In this region, reconstruction is complex and damage to healthy tissue should be minimal. OBJECTIVE: To define the relationship between margin clearance at excision and the recurrence rate of basal cell carcinoma of the eyelid. METHODS: This prospective study was conducted with 111 patients submitted to surgery for basal cell carcinoma of the eyelid between 2001 and 2003 and followed up for a period of five years. The patients were evaluated according to age, tumor site, recurrence rate and margin clearance at excision. RESULTS: No significant association was found between incomplete tumor excision and recurrence except in patients under 56 years of age, female patients and in the case of tumors of the medial canthus. CONCLUSION: A risk of recurrence in incompletely excised basal cell carcinomas of the eyelid was only confirmed in younger patients, females and for tumors of the medial canthus. PMID- 21308313 TI - Frontal fibrosing alopecia: case report. AB - Frontal fibrosing alopecia is a kind of progressive and frequently irreversible cicatricial alopecia marked by a lichenoid infiltrate in histology. Since its first description, in 1994, in Australia, some cases have been documented all over the world. The article reports, for the second time in the medical literature, a Brazilian case and reviews the main aspects of this dermatosis. PMID- 21308314 TI - Calcinosis cutis universalis associated with systemic lupus erythematosus: an exuberant case. AB - Calcinosis cutis is an uncommon disease of unclear pathophysiology that is often disabling. It is characterized by the formation of calcium deposits in the skin or subcutaneous tissue. It is classified into four subtypes: dystrophic, metastatic, idiopathic or iatrogenic. It may be seen in a variety of systemic diseases such as hyperparathyroidism and hypervitaminosis D, but is most commonly found in dermatomyositis, scleroderma and overlap syndromes and is a rare complication of systemic lupus erythematosus. The management of secondary complications and the success of therapy are constant challenges in the follow-up of these cases. PMID- 21308315 TI - Dermatophytosis caused by Tricophyton rubrum as an opportunistic infection in patients with Cushing disease. AB - Trichophyton rubrum is a common agent found in superficial mycoses, which present ample non-inflammatory lesions, with chronic evolution, especially in immunocompromised patients. The hypercortisolism in Cushing's syndrome increases the risk of infections as a result of the immunosuppressive effect of glucocorticoids. The reported cases here refer to two different types of dermatophytosis caused by Trichophyton rubrum in patients with Cushing's disease, resistant to antifungal treatment. The disease remitted after the levels of cortisol went back to normal. PMID- 21308316 TI - Febrile ulceronecrotic Mucha-Habermann disease in adult patient successfully treated with systemic corticosteroid. AB - The Febrile Ulceronecrotic Mucha-Habermann (FUMHD) disease is a rare variant of pityriasis lichenoides et varioliformis acuta (PLEVA). Its etiology still remains unknown and it is characterized by a sudden onset of ulceronecrotic skin lesions associated with systemic symptoms. It is reported here the case of a male patient with a sudden and acute evolution of macules and papules, ulceronecrotic and vesicle-bullous lesions associated with systemic symptoms. The patient was treated with prednisone 0.5 mg/kg/day with a dramatic response. The FUMHD is a severe variant of PLEVA and its diagnosis is clinical and histopathological. Many treatments such as methotrexate, corticosteroids and PUVA have been described. However, none of them has been settled. PMID- 21308317 TI - Milia en plaque. AB - Milia en plaque is a rare type of primary milia. Issues related to esthetics and differential diagnoses represent a concern to patients and a challenge for physicians. In this paper, a case of milia en plaque is reported and a review of the literature is described. PMID- 21308318 TI - Childhood pustular psoriasis: case report. AB - Generalized pustulous psoriasis is a rare type of psoriasis first described in 1910 by Von Zumbusch. This disease tends to have a more benign development in children when compared to its development in adults. However, in its serious form it may represent a risk to the patient's life. Maybe, due to being such a rare disease no therapeutic option has so far consistently proved to be both effective and safe. Isolated reports suggest that retinoid is the best choice of drug in these cases. However, it is difficult to manage this drug in early infancy. The present report describes a serious case of this rare disease in an infant with a satisfactory response and good tolerance to the use of dapsone. PMID- 21308319 TI - Sarcoidosis on skin scars: a case report. AB - Sarcoidosis is a systemic inflammatory disorder of unknown origin, in which non caseating granulomas (small inflammatory nodules) are found in the affected organs. Cutaneous involvement occurs in 25% of cases with a wide range of clinical presentation. The onset of scars is unusual although clinically characteristic of cutaneous sarcoidosis. Most patients with scar sarcoidosis have a systemic disease. It is reported the case of a 65 year-old woman that developed scar nodules 20 years after she had had surgical procedures without systemic manifestations. It is worth mentioning the importance of investigating sarcoidosis with inflammatory alterations in praevia scars. PMID- 21308320 TI - Four cases of Muckle-Wells syndrome within the same family. AB - Muckle-Wells syndrome is a rare autosomal dominant disease that belongs to a group of hereditary febrile syndromes. It is characterized by recurrent and self limited episodes of fever, urticaria, arthralgia, myalgia and conjunctivitis since childhood, which are related to exposure to cold temperatures. Lately, progressive sensorineural hearing loss occurs. Amyloidosis is the main complication and can be found in about 25% of the cases. It has been demonstrated that there is an association with mutations in the NLRP3 gene, which codifies cryopyrin, a protein responsible for regulating the production of proinflammatory cytokines, such as interleukin-1Beta. The authors report four cases of the disease within a family. PMID- 21308321 TI - Acquired unilateral nevoid telangiectasia in a healthy men. AB - Unilateral nevoid telangiectasia is a rare vascular dermatosis, characterized by areas of superficial telangiectases distributed in a linear unilateral pattern. It was described in 1899 by Zeisler and Blascko. Several theories where developed in order to explain its etiopathogenesis. The most widely accepted is the one which establishes its probable association with an increase in the estrogen levels. There are two types: congenital and acquired. The latter is associated with hepatopathies in male patients. The acquired form is rarely observed in healthy men, with a few cases reported in the medical literature, and its etiology is unknown. This study reports the case of a healthy young man with acquired unilateral nevoid telangiectasia, without any comorbidities, clinical and /or laboratory findings indicative of hyperestrogenism. PMID- 21308322 TI - Heparin-induced thrombocytopenia and warfarin-induced skin necrosis: case report. AB - This paper describes a case of heparin-induced thrombocytopenia complicated by warfarin-induced skin necrosis in a 74-year old female patient hospitalized with diagnoses of a hip fracture, deep vein thrombosis and pulmonary thromboembolism. Warfarin-induced skin necrosis is a rare complication of anticoagulant therapy, with high morbidity and mortality that may be associated with heparin-induced thrombocytopenia. PMID- 21308323 TI - Blepharitis and trichomegaly induced by cetuximab. AB - This report describes the case of a 41-year old woman in treatment for advanced colorectal cancer who developed severe bilateral blepharitis and trichomegaly after the second dose of cetuximab. Cetuximab-related eyelid toxicity has been described previously; however, its pathogenesis has not yet been clearly established. PMID- 21308324 TI - Borderline lepromatous leprosy. AB - It is presented a case of borderline lepromatous leprosy with 4 years of evolution and cutaneous lesions of difficult diagnosis in the National Health System. The histopathological evaluation, which was essential for the diagnosis, showed disorganized granulomatous structures and multiple alcohol -acid resistant bacilli. Cases like the one described here are responsible for the contamination of cohabitants and the appearance of new cases of leprosy. PMID- 21308325 TI - Case for diagnosis. Erythromelanosis follicularis faciei et colli. AB - Erythromelanosis follicularis faciei et colli is a rare disease of unknown etiology characterized by symmetric erythematous brownish hyperpigmentation on the frontal, malar and temporal areas associated with involvement of the pilary follicle. It is common to present pilar keratosis on the shoulders and neck. The three main clinical characteristics are: erythema (with or without telangiectasias), discrete follicular papules and brownish hyperpigmentation. PMID- 21308326 TI - Case for diagnosis. Mycosis fungoides. AB - An 18-year old female patient presented with a single, erythematous, desquamative plaque. The clearly outlined lesion was situated in the abdominal region. The patient reported that it had been present for the past year and that she had used no previous medication. Histopathology showed lymphocytic infiltration with atypia, principally affecting the superficial dermis with epidermotropism and mild spongiosis. Immunophenotyping revealed a predominance of CD3-positive cells, confirming the diagnosis of mycosis fungoides. PMID- 21308327 TI - Lyme borreliosis. AB - Borreliosis is an infectious disease caused by spirochetes of the genus Borrelia. Lyme borreliosis, also known as Lyme disease, is a non-contagious infectious disease caused by spirochetes belonging to the complex Borrelia burgdorferi sensu lato and more often transmitted by the bite of infected ticks of the genus Ixodes.The disease is characterized by a varied clinical profile, which can trigger cutaneous, articular, neurological and cardiac manifestations. PMID- 21308328 TI - Quality of life in leprosy: a comparative analysis between patients in the Amazon region and patients in Santo Andre in the ABC region of Sao Paulo, Brazil. AB - This study analyzed the quality of life of individuals with leprosy and compared quality of life indexes of patients in two different socioeconomic scenarios. The study was conducted at the leprosy clinic of the ABC School of Medicine, Sao Paulo, Brazil and during visits to the populations living along the Purus River in the Brazilian state of Amazonas. The Dermatology Life Quality Index (DLQI) was used to evaluate the patients. Quality of life was found to be impaired in 76.9% of the patients evaluated in the Amazon compared to 19% of the patients in Santo Andre. In the group of patients in the Amazon who had sequelae of the disease, quality of life was impaired. PMID- 21308329 TI - Superficial mycoses in Paraiba: a comparative analysis and bibliographical revision. AB - A survey of the incidence of clinically diagnosed cases of superficial mycosis was carried out using individual report cards in four Family Health units in Patos-PB, in 2007. We had a sample of 197 positive records with Pityriasis and Tinea as the most incident mycoses. There was a higher prevalence among female patients who were between 11 - 20 years of age. A high number of non-identified infections was found: 46,19%. The identification of the agents of such non identified infections is not possible as they are not infections of compulsory notification. PMID- 21308330 TI - Prevalence of skin diseases at a healthcare clinic in a small Brazilian town. AB - Doctors who are not specialists in dermatology often have difficulty diagnosing and managing prevalent skin diseases. The objective of this study was to evaluate the prevalence of skin diseases during a three-day healthcare clinic conducted with the population of a small town on the island of Marajo where no medical care had been available for months prior to the study. At these medical consultations, 36.5% of patients were seeking help for dermatological problems. This paper describes the diagnoses made in these cases. Knowledge of dermatology has been shown to be crucial in the clinical practice of physicians who are not dermatologists. PMID- 21308331 TI - Do you know this syndrome? Sjogren-Larsson syndrome. AB - We report a typical case of Sjogren-Larsson syndrome in a male patient, aged 20. The Sjogren-Larsson syndrome is a neurocutaneous, autosomal recessive and disabling condition, characterized by congenital ichthyosis, spastic paraplegia and mental retardation. It is caused by deficiency of the microsomal enzyme fatty aldehyde dehydrogenase. It has no cure, but most patients survive up to an adult age. Treatment should be multidisciplinary and dermatological therapy aims at relieving the persistent itching and ichthyosis. PMID- 21308334 TI - Case 1/2011: 15-year-old male adolescent with congenital tricuspid insufficiency simulating Ebstein's anomaly. PMID- 21308335 TI - Use of intracardiac echocardiography in the electrophysiology laboratory. AB - The intracardiac echocardiography (ICE) offers a detailed visualization of the cardiac structures, in association with hemodynamic information, allowing the precise and real-time positioning of the catheters, decreasing the time of exposure to fluoroscopy and the monitoring of acute complications during the electrophysiological procedure (i.e., formation of thrombi, pericardial effusion, cardiac tamponade), Consequently, its use has progressively increased, mainly in the ablation of atrial fibrillation and ventricular arrhythmias. It has shown to be very useful in the ablation of atrial fibrillation by providing anatomic data on the left atrium and pulmonary veins, helping in transseptal punctures, locating the ostium and antrum of the pulmonary veins, monitoring tissue injury during radiofrequency (RF) use, preventing esophageal injury by monitoring the injuries caused by RF on the left atrial posterior wall and assessing the pulmonary vein flow. PMID- 21308336 TI - Long distance runner with dilated cardiomyopathy and excellent performance. PMID- 21308337 TI - Constrictive pericarditis with extensive calcification. AB - A patient with signs and symptoms of right heart failure of unknown etiology was referred to a referral hospital in the eastern area of the city of Sao Paulo with a diagnosis of calcified constrictive pericarditis and was treated by surgery. This pathology is characterized by an irreversible process of pericardium calcification, and surgery is the only alternative to control the symptoms and improve patients' quality of life. This case drew special attention due to the extensive calcification involving the interventricular septum. The unusual aspect of the images has made the diagnosis difficult and raised doubts about the existence of an associated disease. PMID- 21308339 TI - Nitric oxide and the cardiovascular system: cell activation, vascular reactivity and genetic variant. AB - Nitric oxide (NO), primarily identified as an endothelium-derived relaxing factor, is a free radical that signals different biological processes. The identification of NO synthase (NOS) isoforms and the subsequent characterization of the mechanisms of cell activation of the enzymes permitted the partial understanding of both the physiological interactions and of the mechanisms of the diseases in which NO is involved. Mainly expressed in the vascular endothelium, the endothelial NOS isoform (eNOS) plays an important role in the regulation of vascular reactivity and in the development and progression of atherosclerosis. The purpose of this review is to contextualize the reader about the eNOS structure and its mechanisms of cell activation. In view of the advances in molecular biology, we will also address the known mechanisms of gene expression regulation and the role of variants on the genetic code of eNOS associated with cardiovascular phenotypes. Although the importance of NO as an atheroprotective molecule is recognized, our focus will be the review of the literature on NO and its participation in the modulation of the muscle vasodilatation phenotype. PMID- 21308340 TI - Alternative endocardial sites for artificial cardiac stimulation. AB - The conventional right ventricular stimulation can be associated with deleterious effects on cardiac function. The need for a more physiological artificial cardiac stimulation is undoubtedly one of the most important points in the area of cardiac electrotherapy. The programming algorithms for the maintenance of adequate atrioventricular conduction, the stimulation of alternative endocardial sites and the cardiac resynchronization therapy are used with the objective of attaining these goals. The stimulation of the bundle of His and the septal stimulation have been studied as alternative endocardial sites for the positioning of the electrode on the right ventricle. The septal stimulation represents a simple and practical alternative, with no additional costs involved and with potential benefits in decreasing the deleterious effects of the right ventricular stimulation. However, this alternative site involves a heterogeneous group of patients and presents conflicting results regarding its long-term clinical benefit. This article reviews the scientific evidence on the alternative sites for right ventricular stimulation, with emphasis on the safety of the procedure, the measurement of the electrophysiological parameters, assessment of the left ventricular function and the clinical follow-up of patients. PMID- 21308341 TI - The classic always has something extra. PMID- 21308342 TI - Aortic stenosis and the elderly. PMID- 21308343 TI - Education and telephone monitoring by nurses of patients with heart failure: randomized clinical trial. AB - BACKGROUND: Nursing approaches to manage patients with heart failure (HF) showed benefits in reducing the morbidity and mortality. However, combining intra hospital education with telephone contact after hospital discharge has been little explored. OBJECTIVE: To compare two nursing intervention groups among patients hospitalized due to decompensated HF: the intervention group (IG) received educational nursing intervention during hospitalization followed by telephone monitoring after discharge and the control group (CG) received in hospital intervention only. Outcomes were levels of HF and self-care knowledge, the frequency of visits to the emergency room, rehospitalizations and deaths in a three-month period. METHODS: Randomized clinical trial. We studied adult HF patients with left ventricle ejection fraction (LVEF) < 45% who could be contacted by telephone after discharge. HF awareness was evaluated through a standardized questionnaire that also included questions regarding self-care knowledge, which was answered during the hospitalization period and three months later. For patients in the IG group contacts were made using phone calls and final interviews were conducted in both groups at end of the study. RESULTS: Forty-eight patients were assigned to the IG and 63 to the CG. Mean age (63 +/- 13 years) and L (around 29%) were similar in the two groups. Scores for HF and self-care knowledge were similar at baseline. Three months later, both groups showed significantly improved HF awareness and self-care knowledge scores (P < 0.001). Other outcomes were similar. CONCLUSION: An in-hospital educational nursing intervention benefitted all HF patients in understanding their disease, regardless of telephone contact after discharge. PMID- 21308344 TI - Comparison between cardiac troponin I and CK-MB mass in acute coronary syndrome without st elevation. AB - BACKGROUND: There is uncertainty as to the comparative prognostic value between cardiac troponin I (cTnI) and CK-MB in acute coronary syndrome (ACS). OBJECTIVE: To compare the prognostic value between cTnI and CK-MB mass in patients with ACS without ST-segment elevation. METHODS: 1,027 patients were analyzed in a prospective way in a tertiary cardiology center. Combinations of biomarkers were examined: normal cTnI, normal CK-MB mass (65.5%), normal cTnI, elevated CK-MB mass (3.9%), elevated cTnI, normal CK-MB mass (8.8%), elevated cTnI, elevated CK MB mass (20.7%). A multivariate analysis of clinical, electrocardiographic and laboratory variables determined the independent prognostic value of biomarkers for the event of death or (re)infarction within 30 days. RESULTS: Patients with at least one elevated biomarker were older (p = 0.02) and males (p < 0.001). The previous use of aspirin (p = 0.001), beta-blockers (p = 0.003) or statin (p = 0.013) was most frequent among those without elevated cTnI. Patients with both biomarkers elevated had more ST-segment depression (p < 0.001) or elevated creatinine (p < 0.001). In a multivariate analysis with the inclusion of cTnI, the CK-MB mass was not an independent variable for the event of death or (re) infarction within 30 days (odds ratio [OR] 1.16, p = 0.71). When cTnI was not included, we had the following values: age (OR 1.07; p < 0.001); male (OR 1.09; p = 0.77); diabetes mellitus (OR 1.95; p = 0.02); previous stroke (OR 3.21; p = 0.008); creatinine level (OR 1.63; p = 0.002); CK-MB mass (OR 1.96; p = 0.03). C statistic 0.77 (p < 0.001). CONCLUSION: With a dose of cTnI, CK-MB mass may be dispensable for prognostic evaluation. If cTnI is unavailable, CK-MB mass is acceptable for making a decision on treatment options. PMID- 21308345 TI - Investigation of ion channel gene variants in patients with long QT syndrome. AB - BACKGROUND: The long QT syndrome (LQTS) is an inherited arrhythmia syndrome with increased QT interval and risk of sudden death. Mutations in genes KCNQ1, KCNH2 and SCN5A account for 90% of cases with genotype determined, and genotyping is informative for genetic counseling and better disease management. OBJECTIVE: Molecular investigation and computational analysis of gene variants of KCNQ1, KCNH2 and SCN5A associated with LQTS, in families with the disease. METHODS: The coding regions of genes KCNQ1, KCNH2 and SCN5A in patients with LQTS and their family members were sequenced and analyzed using Geneious ProTM software. RESULTS: Two families with clinical criteria for LQTS were investigated. The proband of Family A had QTC = 562 ms, Schwartz Score = 5.5. The genotyping identified the G1714A mutation in the KCNH2 gene. QTC = 521 +/- 42 ms was observed in family members carrying the mutation against QTC = 391 +/- 21 ms for non-carriers. The proband of Family B had QTc = 551 ms, Schwartz Score = 5.5. The genotyping identified the G1600T mutation, in the same gene. The analysis of family members revealed QTC = 497 +/- 42 ms in mutation carriers, compared with QTC = 404 +/- 29 ms in non-carriers. CONCLUSION: Two gene variants previously associated with LQTS were found in two families clinically diagnosed with LQTS. The prolongation of the QT interval was observed in all family members carrying the mutations. A strategy was developed to identify variants of genes KCNQ1, KCNH2 and SCN5A, making it possible to train technical staff for future application to diagnosis routine. PMID- 21308346 TI - Recovering missing data: estimating position and size of caudal vertebrae in Staurikosaurus pricei Colbert, 1970. AB - Missing data is a common problem in paleontology. It makes it difficult to reconstruct extinct taxa accurately and restrains the inclusion of some taxa on comparative and biomechanical studies. Particularly, estimating the position of vertebrae on incomplete series is often non-empirical and does not allow precise estimation of missing parts. In this work we present a method for calculating the position of preserved middle sequences of caudal vertebrae in the saurischian dinosaur Staurikosaurus pricei, based on the length and height of preserved anterior and posterior caudal vertebral centra. Regression equations were used to estimate these dimensions for middle vertebrae and, consequently, to assess the position of the preserved middle sequences. It also allowed estimating these dimensions for non-preserved vertebrae. Results indicate that the preserved caudal vertebrae of Staurikosaurus may correspond to positions 1-3, 5, 7, 14 19/15-20, 24-25/25-26, and 29-47, and that at least 25 vertebrae had transverse processes. Total length of the tail was estimated in 134 cm and total body length was 220-225 cm. PMID- 21308347 TI - Speeds and stance of titanosaur sauropods: analysis of Titanopodus tracks from the Late Cretaceous of Mendoza, Argentina. AB - Speed estimations from trackways of Titanopodus mendozensis Gonzalez Riga and Calvo provide information about the locomotion of titanosaurian sauropods that lived in South America during the Late Cretaceous. Titanopodus ichnites were found at Agua del Choique, a newly discovered track site in the Loncoche Formation, Late Campanian-Early Maastrichtian of Mendoza, Argentina. This speed study follows the hypothesis of dynamic similarity proposed by Alexander. As a refinement of this method, a complementary equation is presented here based on an articulated titanosaurian specimen collected in strata that are regarded as correlative to those that have yielded Titanopodus tracks (Allen Formation, Neuquen Basin). This analysis indicates that hip height can be estimated as 4.586 times the length of the pes track in derived titanosaurs. With an estimation of the hip height and the stride measurements, the speed is calculated. The study of two wide-gauge trackways indicates that Titanopodus ichnites were produced by medium-sized titanosaurs (hip height of 211-229 cm) that walked at 4.7-4.9 km/h towards the south and southwest, following, in part, a sinuous pathway. These speeds and some taphonomic features of tracks (prominent rims, distorted elongated shapes)indicate the capacity of derived titanosaurs for walking effectively over a very wet and slippery substrate. In the ichnological record, the walking speeds of Titanopodustrackmakers are somewhat faster than those previously inferred for most sauropods. PMID- 21308348 TI - Notes on the axial skeleton of the titanosaur Bonitasaura salgadoi (Dinosauria Sauropoda). AB - Sauropod axial anatomy is particularly important in understanding morphological features and phylogenetic analyses. Spatial arrangement of zygapophyses and rib articulations, as well as their complex laminar development, help to recognize the relative position of isolated vertebral elements. The presence of anterior, mid and posterior elements along the cervical, dorsal and caudal series in Bonitasaura salgadoi allows the analysis of several anatomical characteristics. These include the pattern of neurocentral closure with unfused, partially fused and completely fused elements in a peculiar temporal sequence, as well as several neural spine modifications and the laminar arrangement. The variations in neural spine morphology include a lateral expansion of the distal tip in cervico-dorsal region, different lateral constituents of these lateral expansions, and a marked deviation in spine angulation. The spinal inclination allows the division into three easily recognizable vertebral regions separated by two landmarks, which adds support in the determination of an accurate vertebral position for isolated elements. Finally, an analysis of the vertebral laminae reveals the importance of examining vertebral series in order to recognize laminar homologies and developmental series. Two vertebral laminae are analyzed here. PMID- 21308349 TI - Elevation and characteristics of Rab30 and S100a8/S100a9 expression in an early phase of liver regeneration in the mouse. AB - Recent studies have revealed that cytokines, including TNFalpha and IL-6 play key roles in the priming phase of liver regeneration. However, further knowledge of molecular events in the priming phase is needed for more comprehensively understanding the initiation of liver regeneration. In the present study, we attempted to identify additional genes involved in an early phase (2-6 h post partial hepatectomy, PH). The expression of 71 genes was shown to be up-regulated more than 3-fold in the liver at 2 h and 6 h post PH, as compared to 0 h (normal livers) using microarray analysis. Among them, Rab30 and S100a8/S100a9, were identified as novel genes up-regulated over 20-fold at 2 h post PH as compared to normal liver, and were further examined by RT-qPCR to confirm microarray results. Rab30 showed no significant up-regulation in organs other than the liver, whereas S100a8/S100a9 showed significant up-regulation in other organs, such as the lung and spleen at 6 h post PH as compared to those of sham-operated mice, indicating the existence of a different up-regulation machinery between Rab30 and S100a8/S100a9. Their expression was further investigated in the liver at various developmental stages. Rab30 was shown to be expressed only in newborn liver, whereas S100a8/S100a9 was highly expressed in embryo stages, and exhibited the highest levels in newborn liver. These findings imply that Rab30 and S100a8/S100a9 are possibly involved in the functional switch from hematopoiesis support to metabolism in the newborn stage, but might play different roles in liver development. In conclusion, Rab30 and S100a8/S100a9 were indicated to play roles in the initiation of liver regeneration as well as possibly in the functional switch of the liver in the newborn stage. PMID- 21308350 TI - Diverse inhibition of plasminogen activator inhibitor type 1 by theaflavins of black tea. AB - Fruits, vegetables, spices and a variety of teas are suggested for the prevention of many diseases. They encompass active, non-nutritional ingredients called nutraceuticals which are defined as food products that provide health benefits. Many nutraceuticals have been tested to identify inhibitors of plasminogen activator inhibitor (PAI-1). PAI-1 is the major and fast acting physiological inhibitor of fibrinolysis. However, preclinical studies of PAI-1 inhibitors have revealed an additional role of PAI-1 in the pathogenesis of vascular remodeling, renal injury, diabetes, obesity, Alzheimer's disease and cancer. Thus PAI-1 is a potential therapeutic target in some of these diseases. Our previous study revealed that a black tea extract (containing mostly theaflavins) inhibits PAI-1. In this study we report results for four pure (>98%) theaflavins. Inactivation of PAI-1 was tested by clot formation and by its lysis using thromboelastometry and measurements of human plasma turbidity. Among four tested theaflavins, theaflavin 3'-gallate was the most potent in PAI-1 inhibition trailed by theaflavin-3,3' digallate, while the other two i.e., theaflavin and theaflavin-3-gallate did not show inhibitory activity. PMID- 21308351 TI - Involvement of riboflavin kinase expression in cellular sensitivity against cisplatin. AB - Flavin adenine dinucleotide (FAD) is an essential coenzyme for glutathione reductase (GR) which catalyzes the reduction of oxidized glutathione to regenerate the reduced form involved in protection against oxidative stress. Riboflavin kinase (RFK) also known as flavokinase is involved in the first step of bioactivation of riboflavin (RF) to form flavin mononucleotide (FMN) which can be subsequently converted to FAD in an ATP-dependent reaction catalyzed by FAD synthetase (FADS). We investigated the involvement of RFK in cisplatin resistance using human prostate cancer PC3 cells. RFK overexpression renders cells resistant not only to cisplatin but also to hydrogen peroxide (H2O2) and diamide. Furthermore, knockdown of RFK expression induced apoptosis. We demonstrated that overexpression of RFK increased the levels of FAD, FMN and total glutathione and the expression of GR and glutathione S-transferase-pi (GSTpi). RFK expression is up-regulated in cisplatin-resistant P/CDP6 cells in addition to FAD, total glutathione level, GR and GSTpi. Knockdown of RFK expression also sensitized both PC3 and P/CDP6 cells to cisplatin. Moreover, cellular levels of RFK expression correlate well with Gleason score, known as a good indicator of patient prognosis. The present study suggests that RFK expression is involved not only in cellular protection from oxidative stress but also in malignant progression of prostate cancer. PMID- 21308352 TI - Expression of angiopoietin-like 4 (ANGPTL4) in human colorectal cancer: ANGPTL4 promotes venous invasion and distant metastasis. AB - There is strong evidence that the angiopoietin family is involved in the regulation of tumour progression. Recently, it has been reported that angiopoietin-like 4 (ANGPTL4) expression in cancer cells promotes the metastatic process by increasing vascular permeability. The present study was conducted to examine ANGPTL4 expression and its association with clinicopathological factors and prognosis in human colorectal cancers. We examined 144 cases of surgically resected human colorectal adenocarcinomas by immunohistochemistry, RT-PCR and Western blot analysis. Also, overall survival was investigated. Among 144 cases of adenocarcinoma, 95 cases (66.0%) showed positive staining in the cytoplasm of the carcinoma cells for ANGPTL4. Histologically, well, moderately, poorly differentiated adenocarcinoma or mucinous carcinoma showed 55.2, 79.3, 61.5 or 44.4% expression of ANGPTL4, respectively. The expression of ANGPTL4 was correlated with the depth of tumour invasion (p<0.0005), Vienna classification (category 3-5)(p<0.00005), venous invasion (p<0.0005) and Duke's classification (p<0.005). However, ANGPTL4 expression was not correlated with overall survival. However, all patients (100%) with distant metastasis showed immunopositivity for ANGPTL4. The mRNA and the protein expression of ANGPTL4 were shown in four resected samples and cultured cell lines by RT-PCR or western blot analysis. These findings suggest that ANGPTL4 is one of the factors involved in the progression of human colorectal cancer, especially venous invasion and distant metastasis. PMID- 21308353 TI - Impact of CD44+CD24- cells on non-sentinel axillary lymph node metastases in sentinel node-positive breast cancer. AB - Although complete axillary lymph node dissection (ALND) is the standard for evaluating axillary status after the identification of a positive sentinel lymph node (SLN) in breast cancer; approximately 40-60% of SLN-positive patients have negative non-SLN. In this study, to explore putative breast cancer stem cells with CD44+CD24- in the SLN, we retrospectively analyzed the expression of CD44+CD24- on metastatic tumor cells within SLNs as a predictive factor for positive non-SLNs (NSLNs). We tested 271 patients for SLNs using serial sectioning with cytokeratin immunohistochemistry (IHC) and hematoxylin-eosin staining and identified 67 patients who had a positive SLN biopsy and complete ALND. CD44 and CD24 expression was detected using double-staining IHC. Twenty eight (41.8%) out of 67 patients had positive NSLN metastases. Seven positive SLNs with micrometastases were not available for the evaluation of CD24 and CD44 expression. Out of the remaining 60 patients, 19 (31.7%), 44 (73.83%) and 37 (61.7%) patients had CD24+, CD44+ and CD44+CD24- metastatic tumor cells in SLNs, respectively. Positive NSLN metastasis was significantly associated with the primary tumor size (P=0.004), CD24- expression (P=0.04), CD44+ expression (P=0.01) and CD44+CD24- expression (P=0.02). This report provides the first evidence of the existence of a putative stem-like phenotype within the SLN, which is significantly associated with positive NSLN in early breast cancer patients. PMID- 21308354 TI - Combined effects of klotho and soluble CD40 ligand on A549 lung cancer cells. AB - Although the roles of soluble CD40 ligand (sCD40L) or the klotho gene in lung cancer cells have been studied, little is known about the functions of klotho combined with sCD40L in lung cancer. The present study was designed to investigate the biological effects of klotho combined with sCD40L on the A549 lung cancer cell line (CD40 positive) and their possible mechanisms. Lung cancer A549 cells were chosen as target cells and CD40 signals were stimulated by soluble CD40 ligand (sCD40L). In this study, we found that klotho, soluble CD40 ligand and their combination can increase cell proliferation inhibition and the apoptosis rate in A549 cells by inhibiting the cell cycle, up-regulating Bax gene expression and (or) down-regulating Bcl-2 gene expression; and their combination has a stronger effect on A549 cell apoptosis and proliferation inhibition compared to klotho or sCD40L alone. These data suggest that the combination of klotho and sCD40L may provide an efficient method to treat non-small cell lung cancer. PMID- 21308355 TI - [Hotline for malignant hyperthermia. New telephone number for the German nationwide 24 h service center: 08221/9600]. PMID- 21308356 TI - [Graft-versus-host disease (GvHD) - an update. Part 2: prognosis and therapy of GvHD]. AB - Graft-versus-host disease (GvHD) remains one of the major complications after allogeneic stem cell transplantation (SCT) and is responsible for morbidity, mortality and decrease in quality of life of patients after SCT. The most important preventive approach is the selection of a donor with best possible HLA compatibility between donor and recipient. Basic prophylaxis of acute GvHD begins already prior to transplantation and usually consists of cyclosporine with or without methotrexate. In the past few years, many new therapies have been introduced for the treatment of acute and chronic GvHD. Extracorporeal photopheresis (ECP), for example, represents a promising treatment option for acute and chronic GvHD with very few side effects. For chronic GvHD mTOR inhibitors (sirolimus, everolimus) may replace calcineurin-inhibitors with the advantage of not inducing malignant skin tumors. Guidelines are available ort he management of acute and chronic GvHD. While pathophysiology, classification and skin manifestations of GvHD have been already presented in the first part of this article, this second part covers the prognosis, prevention and treatment of GvHD. PMID- 21308357 TI - [Huntington's chorea mimicking adult attention deficit hyperactivity disorder]. PMID- 21308358 TI - [Comprehensive stroke unit]. AB - The concept of a "comprehensive stroke unit" (in German: Erweiterte Stroke-Unit) is an additional structural option for those stroke units already certified in Germany. Its aim is to complement the semi-intensive management of stroke unit patients in Germany by early mobilisation and neuropsychological rehab procedures. This concept is recommended in many European countries as well. It is based on the proof of efficacy of the combined treatment package in several randomised controlled trials. According to the Helsingborg Declaration, every stroke patient in Europe should have access to a chain of care best provided by a comprehensive stroke unit. Both early mobilisation and rehabilitation treatment can be integrated and continued without creating an interface between the acute stroke unit and the general neurological or medical ward. The monitoring beds of the acute stroke unit and the non-monitoring "enhanced care" beds are located within the same geographical area of the hospital and are run as a comprehensive stroke care entity. Continuous management of the acute stroke patients by the same team on the same unit means an increase in quality of care, better usage of staff resources and an additional gain in time. The scientific background of the advantages of a comprehensive stroke unit is described as are the structural and staff requirements. The clientel particularly benefiting from treatment on wards with enhanced care beds is described, and the spectrum of treatment services is defined. This concept will be used as the basis for an add-on qualification of already certified German stroke units. An important step was to fit the requirements of the comprehensive stroke unit to the already existing facilities and their infrastructures. From an economic point of view, the comprehensive stroke unit is expected to be cost-effective, either balanced or even positive. PMID- 21308359 TI - Impact of dexmedetomidine on early extubation in pediatric cardiac surgical patients. AB - PURPOSE: To evaluate the impact of dexmedetomidine on early extubation in post operative pediatric cardiac patients compared to patients on standard sedation regimens without dexmedetomidine. METHODS: Retrospective study comparing dexmedetomidine infusion (DEX) to our standard sedation regimens (control). RESULTS: A total of 269 patients were included (control: n = 180; DEX: n = 89). The mean duration of DEX was 34 +/- 2 h. Extubation was achieved in the operating room in 42% of the control group and 42% of the DEX group. Extubation within 24 h of surgery was achieved in 75% of the control group and 76% of the DEX group. Ventilator time in the DEX group was 35 +/- 29 h compared to 29 +/- 35 h in the control group. The mean cardiovascular intensive care unit (CV ICU) and hospital length of stays were 3 +/- 2 and 8 +/- 4 days in the DEX group and 3 +/- 3 and 8 +/- 5 days in the control group. Reintubation rates in the CV ICU were not significantly different. DEX patients received significantly less total intraoperative fentanyl and midazolam but significantly more midazolam rescue doses than the control group in the postoperative period. Post-extubation ventilation was clinically similar in the DEX group as measured by 1 h post extubation PaCO2 levels. CONCLUSIONS: Dexmedetomidine did not significantly impact the postoperative course of children compared to standard practice as measured by success of early extubation, ventilator time, and length of stay. PMID- 21308360 TI - The Crystalloid versus Hydroxyethyl Starch Trial: protocol for a multi-centre randomised controlled trial of fluid resuscitation with 6% hydroxyethyl starch (130/0.4) compared to 0.9% sodium chloride (saline) in intensive care patients on mortality. AB - PURPOSE: The intravenous fluid 6% hydroxyethyl starch (130/0.4) (6% HES 130/0.4) is used widely for resuscitation but there is limited information on its efficacy and safety. A large-scale multi-centre randomised controlled trial (CHEST) in critically ill patients is currently underway comparing fluid resuscitation with 6% HES 130/0.4 to 0.9% sodium chloride on 90-day mortality and other clinically relevant outcomes including renal injury. This report describes the study protocol. METHODS: CHEST will recruit 7,000 patients to concealed, random, parallel assignment of either 6% HES 130/0.4 or 0.9% sodium chloride for all fluid resuscitation needs whilst in the intensive care unit (ICU). The primary outcome will be all-cause mortality at 90 days post-randomisation. Secondary outcomes will include incident renal injury, other organ failures, ICU and hospital mortality, length of ICU stay, quality of life at 6 months, health economic analyses and in patients with traumatic brain injury, functional outcome. Subgroup analyses will be conducted in four predefined subgroups. All analyses will be conducted on an intention-to-treat basis. RESULTS AND CONCLUSIONS: The study run-in phase has been completed and the main trial commenced in April 2010. CHEST should generate results that will inform and influence prescribing of this commonly used resuscitation fluid. PMID- 21308362 TI - Low calcidiol levels and risk of progression of aortic calcification. AB - In this observational study, we found a positive relationship between low calcidiol levels and the risk of aortic calcification progression. A 10-ng/mL increase of calcidiol was associated with a decrease in the risk of progression by 44%. This figure was higher than that observed if we increased age by 10 years. INTRODUCTION: The aim of this study was to investigate the relationship between serum calcidiol levels and the onset and progression of aortic calcifications in a community-based sample of ambulatory subjects. METHODS: Three hundred two men and women aged 50 and over underwent two lateral X-rays and were followed up for 4 years. Abdominal aortic calcifications were classified as absent, mild-moderate, and severe. The biochemical measurements of serum calcium, phosphorus, parathyroid hormone, total alkaline phosphatase, tartrate-resistant acid phosphatase, creatinine, calcidiol, calcitriol, and osteocalcin were determined. Subjects who had received anti-osteoporotic treatments were excluded from the analysis. RESULTS: Subjects with progression of aortic calcifications had significantly lower serum calcidiol levels than those without progression. In the multivariate analysis, using the agreed upon serum levels for calcidiol (>30 ng/mL) as the reference, those subjects with calcidiol levels between 10 and 20 ng/mL showed a higher risk of progression of aortic calcification (odds ratio (OR) = 3.95; 95% confidence interval (CI) = 1.16 to 13.40). An even higher OR was observed in subjects with calcidiol values <10 ng/mL (OR = 4.10; 95% CI = 1.12 to 14.99). In addition, an increase by 1 ng/mL in osteocalcin levels was associated with a 17% reduction of the risk of aortic calcification progression. CONCLUSIONS: An increase by 10 ng/mL of calcidiol was associated with a decrease in the risk of aortic calcifications progression by 44%. This figure was even higher than that observed if we increased age by 10 years. Levels of calcidiol higher than 30 ng/mL seem to be desirable to reduce the progression of aortic calcification and to maintain bone turnover. PMID- 21308363 TI - Determinants of forearm strength in postmenopausal women. AB - Bone strength at the ultradistal radius, quantified by micro-finite element modeling, can be predicted by variables obtained from high-resolution peripheral quantitative computed tomography scans. The specific formula for this bone strength surrogate (-555.2 + 8.1 * [trabecular vBMD] + 19.6 * [cortical area] + 4.2 * [total cross-sectional area]) should be validated and tested in fracture risk assessment. INTRODUCTION: The purpose of this study was to identify key determinants of ultradistal radius (UDR) strength and evaluate their relationships with age, sex steroid levels, and measures of habitual skeletal loading. METHODS: UDR failure load (~strength) was assessed by micro-finite element (MUFE) modeling in 105 postmenopausal controls from an earlier forearm fracture case-control study. Predictors of bone strength obtained by high resolution peripheral quantitative computed tomography (HRpQCT) in this group were then evaluated in a population-based cohort of 214 postmenopausal women. Sex steroids were measured by mass spectrometry. RESULTS: A surrogate variable ( 555.2 + 8.1 * [trabecular vBMD] + 19.6 * [cortical area] + 4.2 * [total cross sectional area]) predicted UDR strength modeled by MUFE (R(2) = 0.81), and all parameters except total cross-sectional area declined with age. Evaluated cross sectionally, the 21% fall in predicted bone strength between ages 40-49 years and 80+ years more resembled the change in trabecular volumetric bone mineral density (vBMD) (-15%) than that in cortical area (-41%). In multivariable analyses, measures of body composition and physical activity were stronger predictors of UDR trabecular vBMD, cortical area, total cross-sectional area, and predicted bone strength than were sex steroid levels, but bio-available estradiol and testosterone were correlated with body mass. CONCLUSIONS: Bone strength at the UDR, as quantified by MUFE, can be predicted from variables obtained by HRpQCT. Predicted bone strength declines with age with changes in UDR trabecular vBMD and cortical area, related in turn to reduced skeletal loading and sex steroid levels. The predicted bone strength formula should be validated and tested in fracture risk assessment. PMID- 21308364 TI - Densitometry, radiography, and histological assessment of collagen as methods to evaluate femoral bones in an experimental model of osteoporosis. AB - SUMMARY: All methods to detect experimental loss of bone present technique limitations. The sensitivities of image and histological analyses to detect the effects of teriparatide in rats with bone loss after ovariectomy were evaluated. All methods were qualitatively valid. INTRODUCTION: The standardization of methods to assess bone loss after ovariectomy is crucial to establish the degree of experimental osteoporosis. In general, methods per image or histological techniques are used. To validate these two ways to determine the degree of bone loss in ovariectomized rats, we evaluated the sensitivities of bone densitometry, conventional radiography, and histological analysis of the area occupied by collagen, detecting the effects of teriparatide treatment in the femur of ovariectomized rats with bone loss. METHODS: Wistar rats were divided into three groups: a control group, in which the animals were only subjected to laparotomy; an ovariectomized group, in which bilateral removal of the ovaries was performed; and an ovariectomized + teriparatide group, in which bilateral removal of the ovaries was performed, and the animals were treated with 3 MUg/100 g/day of teriparatide. Three months following the ovariectomy, bone densitometry, radiographic densitometry, and histological analysis of the area occupied by collagen fibers were carried out in the femur diaphysis. RESULTS: The bone densitometry revealed 11.2% reduction in femur density; in the conventional radiography, the loss of bone mass was 14.5%, and with the histological analysis, a 40.9% reduction in the area occupied by collagen was detected in the femur diaphysis. CONCLUSIONS: In conclusion, histological analysis could not be quantitatively compared with the methods of bone densitometry and conventional radiography; however, all of these methods were qualitatively valid for assessing the loss of bone stemming from ovariectomy and the therapeutic effect of teriparatide in the prevention of osteoporosis. PMID- 21308365 TI - GRAND: the German retrospective cohort analysis on compliance and persistence and the associated risk of fractures in osteoporotic women treated with oral bisphosphonates. AB - This database analysis of over 4,000 German women prescribed oral bisphosphonates between December 2004 and November 2007 showed that compliance and persistence with oral bisphosphonates in German women with osteoporosis were inadequate. INTRODUCTION: GRAND is a database analysis designed to investigate persistence and compliance with oral bisphosphonate regimens, and their association with fracture incidence, in women with osteoporosis. METHODS: Diagnostic, treatment and fracture data were obtained from the IMS Disease Analyzer patient database in Germany. Women with osteoporosis prescribed one of six specified oral bisphosphonates between December 2004 and November 2007 with no similar prescription for at least 1 year beforehand were eligible for analysis. Those treated with intravenous bisphosphonates were excluded. Persistence (prescription refill gap of <= 30 days or change of treatment frequency) and compliance (medication possession ratio) were measured for 2 years from therapy start. RESULTS: Data from 4,147 women were evaluable, with a median oral bisphosphonate treatment duration of 145.5 days. Persistence rates after 1 and 2 years were 27.9% and 12.9%, respectively, and 66.3% of women were compliant. As expected, persistence rates were higher when the refill gap was increased to 60 or 90 days. No significant differences in 1-year persistence between patients on weekly or monthly treatment regimens were observed (28.6% and 29.4%, respectively), although 1-year persistence with daily treatment was only 7.2%. After 24 months of therapy, compliant women had fewer fractures than non-compliant women (88.1% and 85.0% fracture-free, respectively; p = 0.0147). In multivariate Cox regression analysis, treatment compliance was the only factor that significantly decreased fracture risk (p = 0.0034). CONCLUSIONS: Compliance and persistence with oral bisphosphonates in German women with osteoporosis were inadequate. Better compliance and persistence can prevent fractures in these women. PMID- 21308366 TI - Balicatib, a cathepsin K inhibitor, stimulates periosteal bone formation in monkeys. AB - Balicatib, an inhibitor of the osteoclastic enzyme cathepsin K, was tested in ovariectomized monkeys, a model for osteoporosis. As expected, ovariectomy induced bone mass changes were partially prevented by balicatib treatment. Bone turnover was significantly decreased at most sites, but unlike most bone resorption inhibitors, periosteal bone formation rates were increased. INTRODUCTION: Selective inhibitors of the osteoclastic enzyme cathepsin K have potential in osteoporosis treatment. This study evaluated the efficacy of balicatib (AAE581), a novel inhibitor of human cathepsin K, on bone mass and dynamic histomorphometric endpoints in ovariectomized monkeys. METHODS: Eighty adult female Macaca fascicularis underwent bilateral ovariectomies and were dosed twice daily by oral gavage with balicatib at 0, 3, 10, and 50 mg/kg for 18 months (groups O, L, M, H, respectively). Approximately 1 month after treatment initiation, the 50 mg/kg dose was decreased to 30 mg/kg. Twenty animals underwent sham-ovariectomies (group S). Bone mass was measured at 3-6 month intervals. At 18 months, vertebra and femur were collected for histomorphometry. RESULTS: In both spine and femur, group O animals lost bone mineral density (BMD), and all other groups gained BMD between 0 and 18 months. In balicatib-treated animals, BMD change in the spine was intermediate between group S and O, with groups L and M significantly different from group O. In femur, all three doses of balicatib significantly increased BMD gain relative to group O, and group mean values were also higher than group S. Most histomorphometric indices of bone turnover in vertebra and femoral neck were significantly lower than group O with balicatib treatment, except that periosteal bone formation rates (Ps.BFR) were significantly higher. Ps.BFR in mid-femur was also significantly increased by treatment. CONCLUSIONS: Balicatib partially prevented ovariectomy-induced changes in bone mass, inhibited bone turnover at most sites, and had an unexpected stimulatory effect on periosteal bone formation. PMID- 21308367 TI - Nanoparticles in cigarette smoke; real-time undiluted measurements by a scanning mobility particle sizer. AB - Cigarette smoke is a complex mixture of smoke constituents, often characterised by size-resolved particle distributions. Since descriptions of ultrafine particles <50 nm are absent, our aim was to explore the existence of these nanoparticles in fresh and undiluted cigarette smoke. We measured undiluted smoke particles real-time by a scanning mobility particle sizer with Faraday cup electrometer, integrated in our custom-made smoking machine. Cigarettes were smoked by 2 s puffs, 30 s puff intervals and 50 ml puff volume. We tested six different cigarettes (1-10 mg tar per cigarette) at ten particle size-ranges between 6 and 50 nm, and repeated measurements five times. The formation of nanoparticles in fresh cigarette smoke was observed over the entire range between 6 and 50 nm, and reproduced in all cigarettes. The highest mean yield was 8.8 * 10(9) (SD = 1.1 * 10(9)) particles per cigarette at the largest particle size range by high-tar cigarettes. Nanoparticle counts appear to increase with particle size, claimed tar values and blocking of filter ventilation holes, and inversely with butt length. Fresh undiluted cigarette smoke contains large amounts of potentially toxic nanoparticles <50 nm. We recommend to further study nanoparticles in the characterisation of cigarette smoke. PMID- 21308368 TI - Matrix-assisted laser desorption ionization imaging mass spectrometry in lipidomics. AB - The relevant structural, energetics, and regulatory roles of lipids are universally acknowledged. However, the high variability of lipid species and the large differences in concentrations make unraveling the role played by the different species in metabolism a titanic task. A recently developed technique, known as imaging mass spectrometry, may shed some light on the field, as it enables precise information to be obtained on the location of lipids in tissues. A review of the state of the art of the technique is presented in this manuscript, including detailed analysis of sample-preparation steps, data handling, and the identification of the species mapped so far. PMID- 21308369 TI - Statistical evaluation of environmental contamination, distribution and source assessment of heavy metals (aluminum, arsenic, cadmium, and mercury) in some lagoons and an estuary along the coastal belt of Ghana. AB - An environmental pollution investigation was carried out to determine the concentrations of aluminum (Al), arsenic (As), cadmium (Cd), and mercury (Hg) (heavy metals) in the surface water and river water bed sediments of lagoons and estuaries along the coastal belt of Ghana. The study assessed the environmental pollution situation and evaluated their sources and distribution of these metals. The total concentrations of Al, As, Cd, and Hg were determined by the neutron activation analysis technique. Water and sediment samples were collected from the Benya, Fosu, and Narkwa lagoons in the Central Region and from the Pra estuary in the western part of Ghana. Some indices, such as contamination factor, pollution load index, contamination degree, and geoaccumulation index, were used to assess eco-environmental quality of the sampling sites. The analysis indicated that the Fosu lagoon was fairly polluted with Cd. The investigation indicated a highly localized distribution pattern closely associated with the two pollution sources (garbage/solid waste dumps and industrial activities) along the coastal belt. The resulting environmental deterioration required a concerted evaluative effort by all stakeholders. PMID- 21308370 TI - Prognostic value of interim FDG PET/CT in Hodgkin's lymphoma patients treated with interim response-adapted strategy: comparison of International Harmonization Project (IHP), Gallamini and London criteria. AB - PURPOSE: Interim 2-[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) has shown to be an accurate predictor of prognosis in Hodgkin's lymphoma (HL). However, FDG PET response criteria are a matter of ongoing debate. The aim of this study was to confirm the prognostic value of interim PET/CT in HL patients treated with an interim response-adapted strategy and to compare the respective performances of different published criteria. METHODS: Newly diagnosed patients with HL underwent interim PET/CT after four courses of Adriamycin, bleomycin, vinblastine and dacarbazine (ABVD). The treatment strategy was adapted according to prognostic factors at diagnosis and interim PET/CT and CT results. PET images were prospectively interpreted visually: a negative result was defined as no residual uptake above local background. All other findings were considered as positive. Retrospectively, interim PET/CT was analysed according to International Harmonization Project (IHP), Gallamini and London criteria RESULTS: The analysis included 90 patients; 6 of 31 patients with positive interim PET/CT and 7 of 59 patients with negative interim result presented treatment failure. The negative predictive value (NPV) and positive predictive value (PPV) for predicting 2-year progression-free survival (PFS) was 95 and 16%, respectively. With the other criteria, NPV remained very high (from 95 to 96%). The PPV increased from 19 to 45% according to the threshold used. Interim PET/CT was significantly correlated with PFS with Gallamini (p = 0.01) and London criteria (p < 0.0001). CONCLUSION: Our study confirms the high NPV of interim PET/CT for predicting treatment outcome in HL and a probably better prognostic value using a higher threshold for positivity even after four cycles of chemotherapy as used in Gallamini and London criteria. PMID- 21308371 TI - 18F-FDG PET independently predicts survival in patients with cholangiocellular carcinoma treated with 90Y microspheres. AB - PURPOSE: (90)Y radioembolization has emerged as a valuable therapy for intrahepatic cholangiocellular carcinomas (ICC). We aimed to evaluate the prognostic power of FDG PET/CT and that of pretherapeutic scintigraphy with (99m)Tc-labelled macroagglutinated albumin (MAA), an index of tumour vascularization. METHODS: The study group comprised 26 consecutive patients suffering from nonresectable ICC. Before treatment with radioembolization, all patients underwent MRI of the liver, as well as MAA scintigraphy, which was followed immediately by SPECT(/CT) to quantify the liver-lung shunt fraction. Using image fusion, regions of interest were drawn around the tumours and the entire liver, and the tumour-to-liver quotient was calculated. In addition, FDG PET/CT was performed at baseline and 3 months after radioembolization, and the percentage changes in peak (DeltaSUV(max)) and mean (DeltaSUV(mean)) FDG uptake and in metabolic tumour volume (DeltaVol(2SD)) relative to baseline were calculated. Treatment response at 3 months was also assessed using contrast enhanced MRI and CT on the basis of standard criteria. RESULTS: Of 23 patients in whom follow-up MRI was available, 5 (22%) showed a partial response, 15 (65%) stable disease and 3 (13%) progressive disease. The change in all FDG values significantly predicted survival by Kaplan-Meier analysis after radioembolization; DeltaVol(2SD) responders had a median survival of 97 weeks versus 30 weeks in nonresponders (P = 0.02), whereas DeltaSUV(max) and DeltaSUV(mean) responders had a median survival of 114 weeks (responder) versus 19 weeks (nonresponder) and 69 weeks in patients with stable disease (P < 0.05). Pretherapeutic MAA scintigraphy or MRI did not predict survival, nor did the presence of extrahepatic metastases, or prior therapies. Only DeltaVol(2SD) was significantly associated with survival by univariate analysis (hazard ratio 0.25; P = 0.04) and multivariate analysis (hazard ratio 0.20, P = 0.04). CONCLUSION: FDG PET/CT was able to predict patient outcome after radioembolization treatment, with the change in metabolically active tumour volume at 3 months being the best independent predictor. High tumour vascularization, as indicated by MAA scintigraphy, was not a prerequisite for successful radioembolization and was even associated with a tendency towards shorter survival. PMID- 21308372 TI - FDG PET evaluation of early axillary lymph node response to neoadjuvant chemotherapy in stage II and III breast cancer patients. AB - PURPOSE: Regional axillary lymph node status has remained the single most independent variable to predict prognosis both in terms of disease recurrence and survival. This study aimed to prospectively assess sequential [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) findings as early predictors of axillary lymph node response to neoadjuvant chemotherapy in stage II and III breast cancer patients. METHODS: Images were acquired with a PET/CT scanner in 52 patients after administration of FDG (5 MBq/kg) at baseline and after the first, second, third and sixth course of chemotherapy before surgery. Clinical examination and ultrasound (US) were used to assess the size of axillary nodes. Decrease in the standardized uptake value (SUV) with PET corrected or not for partial volume effects was compared to the pathological response. RESULTS: The sensitivity, specificity and accuracy of axillary node staging was higher with PET (75, 87 and 80%) than with US (50, 83 and 65%), and even more so when PET images were corrected for partial volume effects (86, 83 and 84%). While FDG uptake did not vary much in non-responders, as confirmed by histopathological analysis, it markedly decreased to baseline levels in responders (p < 10(-5)). Fifty per cent of baseline SUV was considered the best cutoff value to distinguish responders from non-responders. The sensitivity, specificity, negative predictive value and accuracy of FDG PET after one course of chemotherapy were, respectively, 96, 75, 95 and 84%. CONCLUSION: The pathological status of regional axillary lymph nodes in stage II and III breast cancer patients could be accurately predicted after one course of neoadjuvant chemotherapy based on FDG PET images. PMID- 21308373 TI - The effect of patient positioning aids on PET quantification in PET/MR imaging. AB - OBJECTIVES: Clinical PET/MR requires the use of patient positioning aids to immobilize and support patients for the duration of the combined examination. Ancillary immobilization devices contribute to overall attenuation of the PET signal, but are not detected with conventional MR sequences and, hence, are ignored in standard MR-based attenuation correction (MR-AC). We report on the quantitative effect of not accounting for the attenuation of patient positioning aids in combined PET/MR imaging. METHODS: We used phantom and patient data acquired with positioning aids on a PET/CT scanner (Biograph 16, HI-REZ) to mimic PET/MR imaging conditions. Reference CT-based attenuation maps were generated from measured (original) CT transmission images (origCT-AC). We also created MR like attenuation maps by following the same conversion procedure of the attenuation values except for the prior delineation and subtraction of the positioning aids from the CT images (modCT-AC). First, a uniform (68)Ge cylinder was positioned centrally in the PET/CT scanner and fixed with a vacuum mattress (10 cm thick) and, in a repeat examination, with MR positioning foam pads. Second, 16 patient datasets were selected for subsequent processing. All patients were regionally immobilized with positioning aids: a vacuum mattress for head/neck imaging (nine patients) and a foam mattress for imaging of the lower extremities (seven patients). PET images were reconstructed following CT-based attenuation and scatter correction using the original and modified (MR-like) CT images: PET(origCT-AC) and PET(modCT-AC), respectively. PET images following origCT-AC and modCT-AC were compared visually and in terms of mean differences of voxels with a standardized uptake value of at least 1.0. In addition, we report maximum activity concentration in lesions for selected patients. RESULTS: In the phantom study employing the vacuum mattress the average voxel activity in PET(modCT-AC) was underestimated by 6.4% compared to PET(origCT-AC), with 3.4% of the PET voxels being underestimated by 10% or more. When the MR foam pads were not accounted for during AC, PET(modCT-AC) was underestimated by 1.1% on average, with none of the PET voxels being underestimated by 10% or more. Evaluation of the head/neck patient data showed a decrease of 8.4% ([(68)Ga]DOTATOC) and 7.4% ([(18)F]FDG) when patient positioning aids were not accounted for during AC, while the corresponding decrease was insignificant for the lower extremities. CONCLUSION: Depending on the size and density of the positioning aids used, a regionally variable underestimation of PET activity following AC is observed when positioning aids are not accounted for. This underestimation may become relevant in combined PET/MR imaging of patients with neuropsychiatric indications, but appears to be of no clinical relevance in imaging the extremities. PMID- 21308374 TI - Quantification of neutrophil migration into the lungs of patients with chronic obstructive pulmonary disease. AB - OBJECTIVE: To quantify neutrophil migration into the lungs of patients with chronic pulmonary obstructive disease (COPD). METHODS: Neutrophil loss via airways was assessed by dedicated whole-body counting 45 min, 24 h and 2, 4, 7 and 10 days after injection of very small activities of (111)In-labelled neutrophils in 12 healthy nonsmokers, 5 healthy smokers, 16 patients with COPD (of whom 7 were ex-smokers) and 10 patients with bronchiectasis. Lung accumulation of (99m)Tc-labelled neutrophils was assessed by sequential SPECT and Patlak analysis in six COPD patients and three healthy nonsmoking subjects. RESULTS: Whole body (111)In counts, expressed as percentages of 24 h counts, decreased in all subjects. Losses at 7 days (mean +/- SD) were similar in healthy nonsmoking subjects (5.5 +/- 1.5%), smoking subjects (6.5 +/- 4.4%) and ex smoking COPD patients (5.8 +/- 1.5%). In contrast, currently smoking COPD patients showed higher losses (8.0 +/- 3.0%) than healthy nonsmokers (p = 0.03). Two bronchiectatic patients lost 25% and 26%, indicating active disease; mean loss in the remaining eight was 6.9 +/- 2.5%. The rate of accumulation of (99m)Tc neutrophils in the lungs, determined by sequential SPECT, was increased in COPD patients (0.030-0.073 min(-1)) compared with healthy nonsmokers (0-0.002 min(-1); p = 0.02). CONCLUSION: In patients with COPD, sequential SPECT showed increased lung accumulation of (99m)Tc-labelled neutrophils, while whole-body counting demonstrated subsequent higher losses of (111)In-labelled neutrophils in patients who continued to smoke. Sequential SPECT as a means of quantifying neutrophil migration deserves further evaluation. PMID- 21308375 TI - Bone Morphogenic Protein--mRNA upregulation after exposure to low frequency electric field. AB - PURPOSE: For many years, our laboratory has been investigating different biological substrates for the effects of electromagnetic stimulation proposed in orthopaedic treatments. The results show an acceleration of differentiation at the expense of proliferation. This study using microarray analysis is focused on the cellular mechanisms involved. METHODS: A microarray analysis (Affymetrix) allowing the screening of the expression of 38,500 genes was used on epidermal cells sampled from three different human donors and distributed within each donor in seven groups of 12 explants, stimulated at different times, to compare control. Modifications of the expression of BMP-2, 4 and 7 were studied at days four, seven and 12. RESULTS: The expression of BMP-2 was significantly increased at day 12 on the stimulated samples. J(4) and J(7) did not show any significant difference nor did the expression of BMP-4 and 7 at the different times. CONCLUSION: The results obtained in previous experiments on cellular substrates, bone embryonic tissue and clinical series were all consistent with the increase of BMP-2. Other publications have confirmed an increase of BMP-2 under electric or electromagnetic stimulation. The increase of BMP-2 appears as an effect of the electromagnetic field stimulations applied in orthopaedics. This observation contributes towards possible indications and a better understanding of the cellular mechanism. PMID- 21308376 TI - Nutrient response modeling in Falls of the Neuse Reservoir. AB - In order to study system responses of Falls of the Neuse Reservoir (Falls Lake) to varied nutrient loadings, a coupled three-dimensional hydrodynamic and eutrophication model was applied. The model was calibrated using 2005 and 2006 intensive survey data, and validated using 2007 survey data. Compared with historical hydrological records, 2005 and 2007 were considered as dry years and 2006 was recognized as a normal year. Relatively higher nutrient fluxes from the sediment were specified for dry year model simulations. The differences were probably due to longer residence time and hence higher nutrient retention rate during dry years in Falls Lake. During the normal year of 2006, approximately 70% of total nitrogen (TN) and 80% of total phosphorus (TP) were delivered from the tributaries; about 20% (TN and TP) were from the sediment bottom. During the dry years of 2005 and 2007, the amount of TN released from sediment was equivalent to that introduced from the tributaries, indicating the critical role of nutrient recycling within the system in dry years. The model results also suggest that both nitrogen and phosphorus are limiting phytoplankton growth in Falls Lake. In the upper part of the lake where high turbidity was observed, nitrogen limitation appeared to dominate. Scenario model runs also suggest that great nutrient loading reductions are needed for Falls Lake to meet the water quality standard. PMID- 21308377 TI - Wet/dry mapping: using citizen scientists to monitor the extent of perennial surface flow in dryland regions. AB - Wet/dry mapping provides a low-cost, comprehensive snapshot for monitoring flow conditions in rivers with interrupted perennial (spatially intermittent) surface flow. When used in conjunction with more traditional point-specific stream flow or groundwater measurements, it provides a better understanding of hydrologic systems at the broad landscape or watershed scale. Through use of trained volunteers, we mapped reaches with surface water during the driest time of year to track annual variation in length and location of perennial flow. Data from 12 years of wet/dry mapping on the San Pedro River in Arizona, USA, showed 62 reaches with surface flow in every year, totaling 32% of the river length through the San Pedro Riparian National Conservation Area. They also show areas with high year-to-year variation in flow length, which indicate changes in local groundwater conditions and may provide early warning of ecological changes. Data and maps from this project have been useful for a wide variety of conservation, management, and research efforts. PMID- 21308378 TI - Feasibility of simultaneous PET/MR imaging in the head and upper neck area. AB - OBJECTIVE: The aim of this pilot study was to test and demonstrate the feasibility of simultaneous positron emission tomography (PET) and magnetic resonance imaging (MRI) of the head and upper neck area using a new hybrid PET/MRI system. METHODS: Eight patients with malignant head and neck tumours were included in the pilot study. Directly after routine PET/CT imaging with a whole body system using the glucose derivative 2-[18F]fluoro-2deoxy-D-glucose (FDG) as a radiotracer additional measurements were performed with a prototype PET/MRI system for simultaneous PET and MR imaging. Physiological radiotracer uptake within regular anatomical structures as well as tumour uptake were evaluated visually and semiquantitatively (metabolic ratios) in relation to cerebellar uptake on the PET/MRI and PET/CT systems. RESULTS: The MR datasets showed excellent image quality without any recognisable artefacts caused by the inserted PET system. PET images obtained with the PET/MRI system exhibited better detailed resolution and greater image contrast in comparison to those from the PET/CT system. An excellent agreement between metabolic ratios obtained with both PET systems was found: R = 0.99 for structures with physiological tracer uptake, R = 0.96 for tumours. CONCLUSION: Simultaneous PET/MRI of the head and upper neck area is feasible with the new hybrid PET/MRI prototype. PMID- 21308379 TI - Septic cardiomyopathy: hemodynamic quantification, occurrence, and prognostic implications. AB - INTRODUCTION: In sepsis, severe reduction of afterload may often mask cardiac impairment. By establishing the parameter "afterload-related cardiac performance (ACP)" we wanted to determine the extent, frequency, and prognostic relevance of septic cardiomyopathy. METHODS: Over a 12 months period, all patients of our medical intensive care ward were included into the study when they were classified as having "septic MODS" (sepsis score >=12 as long as APACHE II score was >=20). Hemodynamic assessments were performed using a pulmonary artery catheter. RESULTS: A total of 524 patients were screened, and from these 39 had septic MODS. In survivors, APACHE II score values declined from day 0 (day of diagnosis, 27.6 +/- 8.0) to day 4 (17.8 +/- 8.0), while in non-survivors, score values remained high (day 0: 31.8 +/- 5.7; day 4: 33.2 +/- 6.7; p < 0.001). Hemodynamic measurements showed an inverse correlation of cardiac output (CO(measured)) and SVR which can be described as CO = beta (0) * SVR( beta1). The upper limit of 80% tolerance range of CO was defined as the "normal" CO values (CO(normal)). The parameter "afterload-related cardiac performance (ACP)" was calculated as ACP (%) = CO(measured)/CO(normal) * 100. It turned out that ACP shows a stronger correlation with APACHE II- and sepsis-score than CO, cardiac index (CI), cardiac power (CPO), or cardiac power index (CPI). Furthermore, ACP correlated with sepsis-induced myocardial damage as indicated by elevations of troponin I and significantly differed between surviving (86.9 +/- 1.6%) and non surviving patients (69.2 +/- 1.4%; p < 0.0001). While 75% of the surviving patients showed an ACP >60%, 38% of the non-survivors had a moderate (ACP 40-60%) and 25% a severe impairment of cardiac function (ACP < 40%). CONCLUSION: By using the parameter "afterload-related cardiac performance, ACP", the impairment of cardiac function can be reliably quantified showing that septic cardiomyopathy occurs frequently and is of prognostic relevance in patients with septic MODS. PMID- 21308380 TI - Diagnosis and management of acute pharyngitis in a paediatric population: a cost effectiveness analysis. AB - Acute pharyngitis is one of the most frequent causes of primary care physician visits; however, there is no agreement about which is the best strategy to diagnose and manage acute pharyngitis in children. The aim of the current study was to evaluate the cost-effectiveness of the recommended strategies to diagnose and manage acute pharyngitis in a paediatric population. A decision tree analysis was performed to compare the following six strategies: "treat all", "clinical scoring", "rapid test", "culture", "rapid test + culture" and "clinical scoring + rapid test". The cost data came from the Spanish National Health Service sources. Cost-effectiveness was calculated from the payer's perspective. Effectiveness was measured as the proportion of patients cured without complications from the disease and did not have any reaction to penicillin therapy; a sensitivity analysis was performed. The findings revealed that the "clinical scoring + rapid test" strategy is the most cost-effective, with a cost-effectiveness ratio of 50.72 . This strategy dominated all others except "culture", which was the most effective but also the most costly. The sensitivity analysis showed that "rapid test" became the most cost-effective strategy when the clinical scoring sensitivity was <91% and its specificity was <=9%. In conclusion, the use of a clinical scoring system to triage the diagnoses and performing a rapid antigen test for those with a high score is the most cost-effective strategy for the diagnosis and management of acute pharyngitis in children. When the clinical scoring system has a low diagnostic accuracy, testing all patients with rapid test becomes the most cost-effective strategy. PMID- 21308381 TI - Implications for kidney disease in obese children and adolescents. AB - Increasing attention has been focused on the implications of obesity in adults on the development of kidney disease, but data on the obese pediatric population are lacking. The aim of this study was to investigate whether changes in various renal function indexes/markers, as expressed by the glomerular filtration rate [GFR, as estimated by the Schwartz formula (eGFR)], serum cystatin C (CysC) level, albumin excretion rate (AER), and modifications in nitric oxide (NO; an important modulator of renal function and morphology), urinary isoprostanes (markers of oxidative stress), and blood pressure (BP), can be detected in obese children and adolescents when compared to normal weight controls. Blood and urinary samples were collected to evaluate markers of renal function, serum and urinary NO, and urinary isoprostanes in 107 obese Caucasian subjects and 50 controls. Ambulatory BP monitoring (ABPM) was performed in all cases. Obesity was expressed by the body mass index standard deviation score (SDS-BMI), and insulin resistance by the homeostasis model assessment of insulin resistance (HOMA-IR). CysC and eGFR did not significantly differ between the two groups; AER was increased in obese children. CysC and GFR were related to HOMA-IR, and AER was related to HOMA-IR and SDS-BMI. Obese subjects had reduced NO levels and increased urinary isoprostanes and BP measurements; all three parameters were related to SDS-BMI and insulin resistance. ABPM showed an increased incidence of hypertension and non-dipping in the obese group. Based on our comparison of obese and nonobese children, we conclude that renal involvement is not an early clinically evident manifestation of adiposity in childhood, since no overt changes in eGFR and only a mild albuminuria were detected. A longer exposure to obesity is probably needed before renal function impairment appears. PMID- 21308382 TI - Importance of model fitting when a non-commercial TCI system was used: taking Kataria's parameter as an example. PMID- 21308383 TI - S-Propargyl-cysteine (SPRC) attenuated lipopolysaccharide-induced inflammatory response in H9c2 cells involved in a hydrogen sulfide-dependent mechanism. AB - The present study attempts to investigate the effects of S-propargyl-cysteine (SPRC), a sulfur-containing amino acid, on lipopolysaccharide (LPS)-induced inflammatory response in H9c2 cardiac myocytes. We found that SPRC prevented nuclear factor-kappaB (NF-kappaB) activation assessed by NF-kappaB p65 phosphorylation and IkappaBalpha degradation, suppressed LPS-induced extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and intracellular reactive oxygen species (ROS) production. Furthermore, incubation of H9c2 cells with SPRC induced phosphorylation of Akt in a time- and concentration-dependent manner. In addition, SPRC attenuated LPS-induced mRNA and protein expression of tumor necrosis factor-alpha (TNF-alpha), and mRNA expression of intercellular adhesion molecule-1 (ICAM-1) and inducible nitric oxide synthase (iNOS). The effects of SPRC were abolished by cystathionine gamma lyase [CSE-an enzyme that synthesizes hydrogen sulfide (H(2)S)] inhibitor, DL: propargylglycine (PAG), SPRC-induced Akt phosphorylation and TNF-alpha release was also abolished by the phosphoinositide 3-kinase (PI3K) inhibitor LY294002. Furthermore, SPRC also increased LPS-induced down-regulation expression of CSE and H(2)S level in H9c2 cells. PAG abolished SPRC-induced up-regulation of H(2)S level. Therefore, we concluded that SPRC produced an anti-inflammatory effect in LPS-stimulated H9c2 cells partly through the CSE/H(2)S pathway by impairing IkappaBalpha/NF-kappaB signaling and by activating PI3K/Akt signaling pathway. PMID- 21308384 TI - Autotrophic, sulfur-oxidizing actinobacteria in acidic environments. AB - Some novel actinobacteria from geothermal environments were shown to grow autotrophically with sulfur as an energy source. These bacteria have not been formally named and are referred to here as "Acidithiomicrobium" species, as the first of the acidophilic actinobacteria observed to grow on sulfur. They are related to Acidimicrobium ferrooxidans with which they share a capacity for ferrous iron oxidation. Ribulose bisphosphate carboxylase/oxygenase (RuBisCO) is active in CO(2) fixation by Acidimicrobium ferrooxidans, which appears to have acquired its RuBisCO-encoding genes from the proteobacterium Acidithiobacillus ferrooxidans or its ancestor. This lateral transfer of RuBisCO genes between a proteobacterium and an actinobacterium would add to those noted previously among proteobacteria, between proteobacteria and cyanobacteria and between proteobacteria and plastids. "Acidithiomicrobium" has RuBisCO-encoding genes which are most closely related to those of Acidimicrobium ferrooxidans and Acidithiobacillus ferrooxidans, and has additional RuBisCO genes of a different lineage. 16S rRNA gene sequences from "Acidithiomicrobium" species dominated clone banks of the genes extracted from mixed cultures of moderate thermophiles growing on copper sulfide and polymetallic sulfide ores in ore leaching columns. PMID- 21308385 TI - Predictive factors of neutralizing antibodies development in relapsing-remitting multiple sclerosis patients on interferon Beta-1b therapy. AB - The identification of predictive factors of NAbs development might have a relevant impact on clinical practice. Our objective is to look after predictive factors of NAbs development in MS IFN Beta-1b-treated patients. Database was screened for patients on IFN Beta-1b treatment with an Expanded Disability Status Scale (EDSS) at a baseline between 1 and 3.5, disease duration shorter than 15 years, and NAbs analysis performed every 6 months. The NAbs positive status was analysed in relation to baseline clinical, neuropsychological and brain imaging measures. Forty-nine patients were included. Sixteen patients had become NAbs positive at some point on IFN therapy (35%). NAbs producers differed from not producers for higher incidence of cognitive deficit and higher lesion load (OR = 5.0 and 5.6, respectively). Our study suggests that NAbs development might be a marker of a more aggressive disease and that worse outcome in NAbs producers might be biased by baseline condition. PMID- 21308386 TI - Prevalence of pilus-encoding islets and clonality of pneumococcal isolates from children with acute otitis media. AB - We characterized the prevalence of pilus islets 1 (PI-1) and 2 (PI-2) and the clonality of Streptococcus pneumoniae isolates taken from children with acute otitis media (AOM) to study the association between pilus existence and AOM disease potential prior to pneumococcal conjugate vaccine and increased antimicrobial resistance. The study material consisted of 75 pneumococcal isolates cultured from the middle ear fluid and/or nasopharyngeal aspirate of 56 children with AOM in Finland during the period 1990-1992. Isolates were studied for antimicrobial susceptibility and were serotyped, genotyped by multilocus sequence typing (MLST), and tested for the presence of pneumococcal PI-1 and PI-2 genes. All isolates were susceptible to penicillin, 14 different serotypes were found, and 20% of the isolates were positive for PI-1 genes. PI-2 genes were not found. MLST showed high heterogeneity: 52 AOM isolates belonged to 18 known clonal complexes (CC). PI-1 was associated with serotypes 6A, 6B, and 9V, and genotype CC490. In the time prior to 7-valent pneumococcal conjugate vaccine (PCV7) and increased antimicrobial resistance, pneumococcal AOM isolates carried PI-1 genes at a rather low prevalence. PI-2 genes were not detected. PI-1 was related to serotype rather than genotype. The importance of PI-1 in AOM infections and its association with the spread of antimicrobial resistance requires further research. PMID- 21308387 TI - Churg-Strauss syndrome complicated by central retinal artery occlusion: case report and a review of the literature. AB - A 68-year-old man was admitted with rapid visual loss. Churg-Strauss syndrome (CSS) was diagnosed, based upon the symptoms of asthma, eosinophilia, interstitial pneumonitis, and positive myeloperoxidase-anti neutrophil cytoplasmic antibody (MPO-ANCA). Light reflexes were absent and vision was completely lost in both eyes. Bilateral central retinal artery occlusion (CRAO) was observed by fluorescence angiography. Steroid pulse along with an anticoagulant improved the visual acuity to light perception and hand motion. CSS associated CRAO should be considered when acute visual loss occurs. PMID- 21308388 TI - Tocilizumab, a humanized anti-interleukin-6 receptor antibody, ameliorated clinical symptoms and MRI findings of a patient with ankylosing spondylitis. AB - Ankylosing spondylitis (AS) is a chronic inflammatory osteoarticular disease. Although the etiology remains unknown, proinflammatory cytokines, such as tumor necrosis factor alpha and interleukin-6, have been implicated in the development of AS. Here, we report that a patient with AS, whose disease had been refractory to conventional treatment regimens and who needed to receive continuous corticosteroid, responded well to tocilizumab. While further clinical evaluation is required, tocilizumab may be an optional treatment for AS. PMID- 21308389 TI - A case of lupus-associated pancreatitis with ruptured pseudoaneurysms. AB - Pancreatitis is a relatively rare complication in systemic lupus erythematosus (SLE). Herein we report a case of SLE with the initial development of acute pancreatitis, subsequently complicated by bleeding pseudoaneurysms. A 55-year-old Japanese woman was admitted to our hospital for the treatment of SLE. During the course of treatment, she complained of upper abdominal pain. An abdominal computed tomography (CT) scan showed that the pancreas was diffusely enlarged, and she was diagnosed with acute pancreatitis. Her pancreatitis was resistant to glucocorticoid therapy and was subsequently associated with pancreatic pseudocysts and recurrent rupture of the pseudoaneurysms. After surgical drainage of the hemorrhagic pseudocysts, the patient's clinical condition gradually improved with intensive therapies. Our case indicates that lupus pancreatitis can be associated with the potentially fatal complication of recurrent bleeding of pseudoaneurysms. PMID- 21308390 TI - Early mobilization after uncomplicated medial subtalar dislocation provides successful functional results. AB - BACKGROUND: Subtalar dislocation is a rare injury, with the medial type occurring in the majority of cases. The period of postreduction immobilization is a matter of controversy. Most studies set the period of immobilization between 4 and 8 weeks. The hypothesis in this study is that a period of 2-3 weeks of immobilization in a cast, followed by early mobilization, could provide better functional results than longer periods of immobilization. MATERIALS AND METHODS: During a period of 4 years, eight patients (six men, two women) with mean age of 37.2 years and uncomplicated medial subtalar dislocation were treated in our institution. Immediate reduction under sedation and cast immobilization was provided in all cases. Our rehabilitation protocol consisted of two completed weeks of immobilization and thereafter ankle range-of-motion exercises and partial weight-bearing mobilization. Patients were followed up for a mean period of 3 years. Clinical results were evaluated using the AOFAS Ankle-Hindfoot scale. RESULTS: All patients achieved almost normal ankle range of motion and good clinical outcome (mean AOFAS score 92.25). No radiographic evidence of arthritis or avascular necrosis of the talus was detected. Two patients complained of mild pain of the hindfoot. All patients returned to daily routine activities in about 2 months from injury. CONCLUSIONS: Immediate reduction and early mobilization could be key factors for uneventful recovery of uncomplicated medial subtalar dislocation. Multicenter clinical trials are needed for further validation of our initial results. LEVEL OF EVIDENCE: III, prospective clinical series study. PMID- 21308391 TI - A three-dimensional random network model of the cytoskeleton and its role in mechanotransduction and nucleus deformation. AB - We have developed a three-dimensional random network model of the intracellular actin cytoskeleton and have used it to study the role of the cytoskeleton in mechanotransduction and nucleus deformation. We use the model to predict the deformation of the nucleus when mechanical stresses applied on the plasma membrane are propagated through the random cytoskeletal network to the nucleus membrane. We found that our results agree with previous experiments utilizing micropipette pulling. Therefore, we propose that stress propagation through the random cytoskeletal network can be a mechanism to effect nucleus deformation, without invoking any biochemical signaling activity. Using our model, we also predict how nucleus strain and its relative displacement within the cytosol vary with varying concentrations of actin filaments and actin-binding proteins. We find that nucleus strain varies in a sigmoidal manner with actin filament concentration, while there exists an optimal concentration of actin-binding proteins that maximize nucleus displacement. We provide a theoretical analysis for these nonlinearities in terms of the connectivity of the random cytoskeletal network. Finally, we discuss laser ablation experiments that can be performed to validate these results in order to advance our understanding of the role of the cytoskeleton in mechanotransduction. PMID- 21308392 TI - The application of muscle wrapping to voxel-based finite element models of skeletal structures. AB - Finite elements analysis (FEA) is now used routinely to interpret skeletal form in terms of function in both medical and biological applications. To produce accurate predictions from FEA models, it is essential that the loading due to muscle action is applied in a physiologically reasonable manner. However, it is common for muscle forces to be represented as simple force vectors applied at a few nodes on the model's surface. It is certainly rare for any wrapping of the muscles to be considered, and yet wrapping not only alters the directions of muscle forces but also applies an additional compressive load from the muscle belly directly to the underlying bone surface. This paper presents a method of applying muscle wrapping to high-resolution voxel-based finite element (FE) models. Such voxel-based models have a number of advantages over standard (geometry-based) FE models, but the increased resolution with which the load can be distributed over a model's surface is particularly advantageous, reflecting more closely how muscle fibre attachments are distributed. In this paper, the development, application and validation of a muscle wrapping method is illustrated using a simple cylinder. The algorithm: (1) calculates the shortest path over the surface of a bone given the points of origin and ultimate attachment of the muscle fibres; (2) fits a Non-Uniform Rational B-Spline (NURBS) curve from the shortest path and calculates its tangent, normal vectors and curvatures so that normal and tangential components of the muscle force can be calculated and applied along the fibre; and (3) automatically distributes the loads between adjacent fibres to cover the bone surface with a fully distributed muscle force, as is observed in vivo. Finally, we present a practical application of this approach to the wrapping of the temporalis muscle around the cranium of a macaque skull. PMID- 21308393 TI - External tissue support and fluid-structure simulation in blood flows. AB - The objective of this work is to address the formulation of an adequate model of the external tissue environment when studying a portion of the arterial tree with fluid-structure interaction. Whereas much work has already been accomplished concerning flow and pressure boundary conditions associated with truncations in the fluid domain, very few studies take into account the tissues surrounding the region of interest to derive adequate boundary conditions for the solid domain. In this paper, we propose to model the effect of external tissues by introducing viscoelastic support conditions along the artery wall, with two-possibly distributed-parameters that can be adjusted to mimic the response of various physiological tissues. In order to illustrate the versatility and effectiveness of our approach, we apply this strategy to perform patient-specific modeling of thoracic aortae based on clinical data, in two different cases and using a distinct fluid-structure interaction methodology for each, namely an Arbitrary Lagrangian-Eulerian (ALE) approach with prescribed inlet motion in the first case and the coupled momentum method in the second case. In both cases, the resulting simulations are quantitatively assessed by detailed comparisons with dynamic image sequences, and the model results are shown to be in very good adequacy with the data. PMID- 21308394 TI - Predicting isometric force from muscular activation using a physiologically inspired model. AB - Motivated by biochemical processes during muscular contraction, a model is constructed that predicts isometric force from surface electromyographic signals (sEMG). The model is experimentally validated and then it is used to predict contractions from sEMG data. The calculated simulations reveal a highly non linear relationship between sEMG and isometric force. PMID- 21308395 TI - Proteomic approach to enhance doxorubicin production in panK-integrated Streptomyces peucetius ATCC 27952. AB - Biosynthesis of polyketide compounds depends upon the starter and extender units of coenzyme A derivatives of carboxylic acids present in the host organism. To increase the coenzyme A (CoA) pool, pantothenate kinase (panK) gene from Escherichia coli was integrated into S. peucetius ATCC 27952 (panK-integrated strain, BG200), which resulted in increase in aglycone polyketide epsilon rhodomycinone (RHO), but decrease in the desired product, i.e., doxorubicin (DXR). To reduce RHO accumulation by synthesizing daunorubicin (DNR) from RHO more efficiently, glycosyltransferase (dnrQS) was overexpressed (pIBR25::dnrQS in panK-integrated strain, BG201). However, DnrQS overexpression still resulted in less production of DXR compared with the parental strain. To understand the results in detail by investigating the proteome changes in the panK-integrated strain, two-dimensional (2D) gel electrophoresis was performed. Among the several proteins that are up- or downregulated in BG200, efflux protein DrrA was our main target of interest, because it is directly related to DXR/DNR production in S. peucetius. DXR transporter DrrAB was additionally introduced in BG200 to enhance secretion of toxic DXR. Compared with S. peucetius ATCC 27952, BG204 (pIBR25::drrAB in panK-integrated strain), produced two times higher amount of DXR, which is 9.4-fold higher than that of panK-integrated strain BG200. The results show that the proteomic approach is quite useful in host development of Streptomyces and understanding cell physiology for antibiotic production. PMID- 21308397 TI - Bevacizumab can induce reactivity to VEGF-C and -D in human brain and tumour derived endothelial cells. AB - Though clinical trials demonstrated effectiveness of the anti-VEGF antibody bevacizumab (Avastin) in adjuvant therapies for some solid tumours, there are rather few experimental data about cellular effects of bevacizumab on tumour cells and tumour associated endothelial cells. Recent reports demonstrate resistance mechanisms and secondary re-angiogenesis after a transient normalization of tumour vessels. Therefore we investigated the influence of bevacizumab on human glioma cells and human brain derived as well as tumour derived endothelial cells focussing on the role of VEGF-C and -D as potential alternative pro-angiogenic factors. Bevacizumab treatment showed no influence on proliferation after short term exposure (1-5 days) but slowed down endothelial cell proliferation by 25-30% after 14 days treatment. There was no significant induction of apoptosis after short or long term exposure. Tube formation capabilities were significantly impaired by bevacizumab with a continuing effect after 14 days of treatment even after omitting the antibody. VEGF-C and -D had no effect on endothelial cells in untreated or short term treatment groups. However, cells developed responsiveness to these factors in terms of increased proliferation and tube formation after 14 days bevacizumab treatment. Furthermore, bevacizumab induced expression of VEGF-C and -D in glioma cells. Treatment with bevacizumab may induce alterations in human brain and tumour endothelial cells leading to escape mechanisms from anti-VEGF therapy. VEGF-C and -D thus might act as alternative pro-angiogenic factors during anti-VEGF therapy. PMID- 21308398 TI - Outcome of 11 children with ependymoblastoma treated within the prospective HIT trials between 1991 and 2006. AB - Ependymoblastoma is a rare malignant brain tumor of early childhood. Data on clinical behavior and optimal treatment strategies are scarce. We report on 11 consecutively treated children with centrally confirmed diagnosis of CNS ependymoblastoma, registered between February 1994 and October 2006 to the prospective GPOH-HIT multicenter brain tumor trials, and treated by multimodal regimens. Median age at diagnosis was 3.5 years (range, 1.8-5.6 years), and the median follow-up of survivors was 5.9 years (range, 2.2-12.7 years). Initial stage was M0 in 9, and M0/1 (no cerebrospinal fluid examination done) in 2 patients. Gross-total tumor resection was achieved in 7 patients, incomplete resection in 4 patients. Further primary therapy included chemotherapy in all patients, craniospinal radiotherapy in 5 patients and high-dose chemotherapy in 2 patients. Tumor response to chemotherapy was observed in 1 of 4 evaluable patients. Tumor progression occurred in 7 patients after a median time of 5.0 months (range, 2.5-19.2 months). Five-year progression-free survival was 36.4% (+/-14.5%), 5-year overall survival 30.3% (+/-15.9%). Of 4 survivors, 3 had gross total tumor resection, and all were treated by either craniospinal radiotherapy and/or high-dose chemotherapy with autologous blood stem cell rescue. Prognosis of children with ependymoblastoma is poor, but sustained remissions have been achieved after multimodal treatment. Considerable diagnostic discrepancies between local and central pathologists underscore the importance of central review. Further studies are needed to improve survival of children with this rare malignant central nervous system tumor. PMID- 21308400 TI - X-ray diffraction and SEM study of kidney stones in Israel: quantitative analysis, crystallite size determination, and statistical characterization. AB - Urinary calculi have been recognized as one of the most painful medical disorders. Tenable knowledge of the phase composition of the stones is very important to elucidate an underlying etiology of the stone disease. We report here the results of quantitative X-ray diffraction phase analysis performed on 278 kidney stones from the 275 patients treated at the Department of Urology of Hadassah Hebrew University Hospital (Jerusalem, Israel). Quantification of biominerals in multicomponent samples was performed using the normalized reference intensity ratio method. According to the observed phase compositions, all the tested stones were classified into five chemical groups: oxalates (43.2%), phosphates (7.7%), urates (10.3%), cystines (2.9%), and stones composed of a mixture of different minerals (35.9%). A detailed analysis of each allocated chemical group is presented along with the crystallite size calculations for all the observed crystalline phases. The obtained results have been compared with the published data originated from different geographical regions. Morphology and spatial distribution of the phases identified in the kidney stones were studied with scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS). This type of detailed study of phase composition and structural characteristics of the kidney stones was performed in Israel for the first time. PMID- 21308399 TI - Plant aquaporins with non-aqua functions: deciphering the signature sequences. AB - Research in recent years on plant Major Intrinsic Proteins (MIPs), commonly referred to as 'aquaporins', has seen a vast expansion in the substrates found to be transported via these membrane channels. The diversity in sizes, chemical nature and physiological significance of these substrates has meant a need to critically analyse the possible structural and biochemical properties of MIPs that transport these, in order to understand their roles. In this work we have undertaken a comprehensive analysis of all plant MIPs, coming from different families, that have been proven to transport ammonia, boron, carbon dioxide, hydrogen peroxide, silicon and urea. The sequences were analysed for all primary selectivity-related motifs (NPA motifs, ar/R filter, P1-P5 residues). In addition, the putative regulatory phosphorylation and glycosylation sites and mechanistic regulators such as loop lengths have been analysed. Further, nine specificity-determining positions (SDPs) were predicted for each group. The results show the ar/R filter residues, P2-P4 positions and some of the SDPs are characteristic for certain groups, and O-glycosylation sites are unique to a subgroup while N-glycosylation was characteristic of the other MIPs. Certain residues, especially in loop C, and structural parameters such as loop lengths also contribute to the uniqueness of groups. The comprehensive analysis makes significant inroads into appraising the intriguing diversity of plant MIPs and their roles in fundamental life processes, and provides tools for plant selections, protein engineering and transgenics. PMID- 21308401 TI - Bioelements and mineral matter in human livers from the highly industrialized region of the Upper Silesia Coal Basin (Poland). AB - Contents of mineral substance, silica, and a range of bioelements and toxic elements (Mg, Na, K, Ca, Ba, Zn, Cr, P Al, Cd, Mn Cu, Ni, Pb, Sr, Fe) in 38 livers of donors from the Upper Silesia Coal Basin (southern Poland) are presented. Elements were determined by inductively coupled plasma-atomic emission spectrometry (ICP-AES) with the exception of silica that was estimated colorimetrically. Concentrations, concentration variability, and correlations between selected liver components determined for the total population are related to donor age, gender, and lesion occurrence. Correlations between particular elements were found using correlation coefficient values and the Fisher transformation. Mineral substance in the livers lies in the range 0.40-5.03 wt%. With increasing donor age, mineral-matter content decreases to a minimum for the 40-60 years of age range. Microbioelement contents show a similar tendency, while microbioelements and toxic elements reach maximum contents in donors aged 60-80 years. All elements show content decreases in livers from the oldest group (>80 years). Silica contents increase with age. Variability of element contents is lowest in the older subpopulations. Livers with lesions show lower element contents and variability. The results are compared to literature data for regions of Poland assumed to be of low pollution and to data from comparable regions in Japan and Hungary. Up to our knowledge, this paper is the first work describing the total contents, as distinct from contents of selected elements, of mineral substance in human livers. PMID- 21308403 TI - Individuals at the center of biology: Rudolf Leuckart's Polymorphismus der Individuen and the ongoing narrative of parts and wholes. With an annotated translation. AB - Rudolf Leuckart's 1851 pamphlet Ueber den Polymorphismus der Individuen (On the polymorphism of individuals) stood at the heart of naturalists' discussions on biological individuals, parts and wholes in mid-nineteenth-century Britain and Europe. Our analysis, which accompanies the first translation of this pamphlet into English, situates Leuckart's contribution to these discussions in two ways. First, we present it as part of a complex conceptual knot involving not only individuality and the understanding of compound organisms, but also the alternation of generations, the division of labor in nature, and the possibility of finding general laws of the organic world. Leuckart's pamphlet is important as a novel attempt to give order to the strands of this knot. It also solved a set of key biological problems in a way that avoided some of the drawbacks of an earlier teleological tradition. Second, we situate the pamphlet within a longer trajectory of inquiry into part-whole relations in biology from the mid eighteenth century to the present. We argue that biological individuality, along with the problem-complexes with which it engaged, was as central a problem to naturalists before 1859 as evolution, and that Leuckart's contributions to it left a long legacy that persisted well into the twentieth century. As biologists' interests in part-whole relations are once again on the upswing, the longue duree of this problem merits renewed consideration. PMID- 21308404 TI - Synthesis of novel tricalcium phosphate-bioactive glass composite and functionalization with rhBMP-2. AB - A functionalization is required for calcium phosphate-based bone substitute materials to achieve an entire bone remodeling. In this study it was hypothesized that a tailored composite of tricalcium phosphate and a bioactive glass can be loaded sufficiently with rhBMP-2 for functionalization. A composite of 40 wt% tricalcium phosphate and 60 wt% bioactive glass resulted in two crystalline phases, wollastonite and rhenanite after sintering. SEM analysis of the composite's surface revealed a spongious bone-like morphology after treatment with different acids. RhBMP-2 was immobilized non-covalently by treating with chrome sulfuric acid (CSA) and 3-aminopropyltriethoxysilane (APS) and covalently by treating with CSA/APS, and additionally with 1,1'-carbonyldiimidazole. It was proved that samples containing non-covalently immobilized rhBMP-2 on the surface exhibit significant biological activity in contrast to the samples with covalently bound protein on the surface. We conclude that a tailored composite of tricalcium phosphate and bioactive glass can be loaded sufficiently with BMP-2. PMID- 21308405 TI - Immunolocalization and activity of the MMP-9 and MMP-2 in odontogenic region of the rat incisor tooth after post shortening procedure. AB - MMP-9 and MMP-2 are metalloproteinases which degrade the denatured collagen fibers. However, there is no report about roles of these MMPs in the odontogenic region of the adult rat incisor tooth under different eruption conditions. Male Wistar rats were divided in a normofunctional group (NF) in which their lower teeth remained in a normal eruption. In a hypofunctional group (HP) rats underwent shortening of their lower left incisor tooth every 2 days during 12 days. The eruption rate as well as the expression and activities of MMP-9 and MMP 2 were evaluated using imunohistochemistry and zymography. Although the shortening increased the eruption rate, no changes in the MMP-9 and MMP-2 were observed. We conclude that in adult rats, in opposite to development of tooth, the MMP-9 and MMP-2 present in the odontogenic region does not seem to play a direct role in the remodeling matrix, even after post-shortening procedures which to lead an acceleration of the eruption process in the incisor. PMID- 21308406 TI - Immunohistochemical localization of four and a half LIM domains 2 in the odontoblasts of mature human teeth. AB - Four and a half LIM domains 2 (FHL2) participates in cell differentiation and cancer development of various tissues, possessing dual functions either as an activator or as a repressor depending on the protein partners involved. Recent studies show that FHL2 plays an important role in osteoblast differentiation and bone formation. The present study was to investigate the expression and localization of FHL2 in human pulp-dentin complex by immunohistochemistry. Our results showed that in sound mature human teeth, FHL2 was expressed in odontoblasts and some endothelial cells of blood vessels. Moreover, in carious teeth FHL2 immunoreactivity was detected in odontoblasts, odontoblast-like cells and endothelial cells of blood vessels. FHL2 was mainly distributed in cytosol of the odontoblast cell bodies and partly located in nuclei of odontoblasts, but not in the odontoblast processes. Our data suggest a role of FHL2 in odontoblast differentiation and dentin formation both in normal and in carious teeth. PMID- 21308407 TI - Does social support mediate the moderating effect of intrinsic religiosity on the relationship between physical health and depressive symptoms among Jews? AB - Previous research in the general population suggests that intrinsic religiosity moderates (mitigates) the effect of poor physical health on depression. However, few studies have focused specifically on the Jewish community. We therefore examined these variables in a cross-sectional sample of 89 Orthodox and 123 non Orthodox Jews. Based on previous research suggesting that non-Orthodox Judaism values religious mental states (e.g., beliefs) less and a collectivist social religiosity more, as compared to Orthodox Judaism, we hypothesized that the moderating effect of intrinsic religiosity would mediated by social support among non-Orthodox but not Orthodox Jews. As predicted, results indicated that the relationship between physical health and depression was moderated by intrinsic religiosity in the sample as a whole. Furthermore, this effect was mediated by social support among non-Orthodox Jews, but not among the Orthodox. The importance of examining religious affiliation and potential mediators in research on spirituality and health is discussed. PMID- 21308408 TI - Interpersonal influences on patients' surgical decision making: the role of close others. AB - Patients make medical decisions in consultation with their partner, family, and friends. However, little is known about the ways in which these close others influence their decisions, particularly with respect to discrete decisions such as those related to medical treatments. This cross-sectional study investigated their influence on the surgical decisions of inflammatory bowel disease patients referred for surgery to remove their colon (N = 91). Guided by research on social control and classic research on power and influence in close relationships, we identified four types of close other decision influence: persuasion, assistance with understanding, indirect influence, and negative influence. Linear logistic and regression analyses showed that patients were more likely to have surgery when their close other used persuasion, and they reported lower decisional conflict when their close other helped them understand the decision. Patients were less likely to have surgery and reported greater decisional conflict when their close other used negative influence tactics. Findings demonstrate the importance of considering social context when investigating patient decision making. PMID- 21308409 TI - IL-15 and IL-2 increase Cetuximab-mediated cellular cytotoxicity against triple negative breast cancer cell lines expressing EGFR. AB - Triple negative breast cancer (TNBC) patients are not likely to benefit from anti estrogen or anti-HER2 therapy and this phenotype is associated with a more aggressive clinical course and worse clinical outcome. Taking into account the limited treatment possibilities in TNBC, the aim of the present work was to study a potential therapy based on Cetuximab-mediated immune activity by natural killer (NK) cells. We performed in vitro studies on human breast cancer (BC) cell lines, IIB-BR-G, and the in vivo metastatic variant IIB-BR-G MT. The immunohistochemical analysis showed a TNBC phenotype with high but different levels of EGFR expression on each cell line, measured by flow cytometry. DNA sequencing showed that both cell lines have a mutated K-RAS status, 38 G > A at codon 13. Consequently, Cetuximab did not inhibit cellular proliferation or induce apoptosis. We investigated if Cetuximab could trigger immune mechanisms, and we determined that both cell lines treated with 1 MUg/ml Cetuximab were susceptible to antibody dependent cellular cytotoxicity (ADCC), mediated by peripheral blood mononuclear cells (PBMC). At 50:1 effector:target ratio, lytic activity was 34 +/ 2% against IIB-BR-G and 27 +/- 6% against IIB-BR-G MT cells. PBMC pretreatment with IL-2 allowed reaching 65 +/- 3% of Cetuximab-mediated ADCC against IIB-BR-G and 63 +/- 6.5% against IIB-BR-G MT. Furthermore, IL-15 pretreatment increased the ADCC up to 71 +/- 3% in IIB-BR-G and 79 +/- 3.5% in IIB-BR-G MT. We suggest that NK cells are the effectors present in PBMC since they were able to induce ADCC at lower effector:target ratios. Besides, IL-2- and mainly IL-15-induced upregulation of NK activating receptors CD16 and NKG2D and enhanced IFN-gamma production. EGFR-expressing TNBC could be killed by Cetuximab-mediated ADCC at clinically achievable concentrations. IL-15 could advantageously replace IL-2 in most of its immunologic activities, stimulating the ability to produce IFN-gamma, and paralleling the up-regulation of activating receptors. PMID- 21308410 TI - Rhizobium sphaerophysae sp. nov., a novel species isolated from root nodules of Sphaerophysa salsula in China. AB - Four gram-negative, aerobic, motile, non-spore, forming rods with a wide pH and temperature range for growth (pH 7.0-11.0, optimum pH 8.0; 20-45 degrees C, optimum 28 degrees C) strains were isolated from root nodules of Sphaerophysa salsula and characterized by means of a polyphasic approach. Phylogenetic analysis based on 16S rRNA gene sequences revealed that the four strains formed a new lineage related to the genus Rhizobium and the sequence similarities between the isolate and the most related type strain Rhizobium giardinii was 96.5%. These strains also formed a distinctive group from the reference strains for defined Rhizobium species based on housekeeping gene sequences (atpD and recA), BOX-PCR fingerprinting, phenotypic features and symbiotic properties. The representative strain CCNWGS0238(T) has DNA-DNA relatedness of less than 33.4% with the most closely related species R. giardinii. It is therefore proposed as a new species, Rhizobium sphaerophysae sp. nov., with isolate CCNWGS0238(T) (=ACCC17498(T) = HAMBI3074(T)) as the type strain. PMID- 21308411 TI - Crassulacean acid metabolism in the context of other carbon-concentrating mechanisms in freshwater plants: a review. AB - Inorganic carbon can be in short supply in freshwater relative to that needed by freshwater plants for photosynthesis because of a large external transport limitation coupled with frequent depleted concentrations of CO(2) and elevated concentrations of O(2). Freshwater plants have evolved a host of avoidance, exploitation and amelioration strategies to cope with the low and variable supply of inorganic carbon in water. Avoidance strategies rely on the spatial variation in CO(2) concentrations within and among lakes. Exploitation strategies involve anatomical and morphological features that take advantage of sources of CO(2) outside of the water column such as the atmosphere or sediment. Amelioration strategies involve carbon-concentrating mechanisms based on uptake of bicarbonate, which is widespread, C(4)-fixation, which is infrequent, and crassulacean acid metabolism (CAM), which is of intermediate frequency. CAM enables aquatic plants to take up inorganic carbon in the night. Furthermore, daytime inorganic carbon uptake is generally not inhibited and therefore CAM is considered to be a carbon-conserving mechanism. CAM in aquatic plants is a plastic mechanism regulated by environmental variables and is generally downregulated when inorganic carbon does not limit photosynthesis. CAM is regulated in the long term (acclimation during growth), but is also affected by environmental conditions in the short term (response on a daily basis). In aquatic plants, CAM appears to be an ecologically important mechanism for increasing inorganic carbon uptake, because the in situ contribution from CAM to the C-budget generally is high (18-55%). PMID- 21308412 TI - An alphaproteobacterium capable of both aerobic and anaerobic anoxygenic photosynthesis but incapable of photoautotrophy: Charonomicrobium ambiphototrophicum, gen. nov., sp. nov. AB - A facultatively aerobic deep brown coccoid to ovoid bacterium, strain EG17(T), was isolated from a saline effluent stream in the NaCl-dominated brine spring system known as East German Creek in the province of Manitoba, Canada. The strain produced BChl a incorporated into a functional reaction center and two light harvesting complexes with absorption peaks at 802, 850, and 879 nm. EG17(T) is the first reported anoxygenic phototroph capable of photoheterotrophic growth under both oxic and anoxic conditions. It yielded proportionally the greatest aerobic photosynthetic biomass under oligotrophic conditions. The results of 16S rRNA gene sequence comparisons revealed that EG17(T) was related most closely to the aerobic anoxygenic phototrophs Roseibacterium elongatum (98.3%) and quite distantly to both Dinoroseobacter shibae (95.2%) and Roseicyclus mahoneyensis (94.7%). The DNA G + C content was 65.6 mol%. On the basis of the unique dual aerobic/anaerobic photosynthetic capability, the distinctive spectrophotometric absorption of the photosynthetic apparatus, diagnostic physiological and biochemical traits, and the moderate phylogenetic separation between EG17(T) and its nearest relatives, it is concluded that this microorganism should be classified as a novel genus and species, Charonomicrobium ambiphototrophicum gen. nov., sp. nov., with EG17(T) as the type strain. PMID- 21308413 TI - Should people with unhealthy lifestyles pay higher health insurance premiums? AB - This commentary sets the article by Dubois on the ethical justification for charging higher insurance premiums for people with unhealthy lifestyles in the context of US health care reform. It reviews the relevance and strength of normative concerns identified by Dubois about the acceptability of such differentiated "means-tested" plans. It identifies key issues involving whether certain health behaviors matter ethically, and if so, the grounds that would justify an obligation for people to take action. The article frames the answer in terms of the need to achieve an ethically acceptable balance between the principle of equality and principle of merit and concludes with four ethical standards to focus the terms of the debate. PMID- 21308414 TI - Dimensionality and measurement invariance in the Satisfaction with Life Scale in Norway. AB - PURPOSE: Results from previous studies examining the dimensionality and factorial invariance of the Satisfaction with Life Scale (SWLS) are inconsistent and often based on small samples. This study examines the factorial structure and factorial invariance of the SWLS in a Norwegian sample. METHODS: Confirmatory factor analysis (AMOS) was conducted to explore dimensionality and test for measurement invariance in factor structure, factor loadings, intercepts, and residual variance across gender and four age groups in a large (N = 4,984), nationally representative sample of Norwegian men and women (15-79 years). RESULTS: The data supported a modified unidimensional structure. Factor loadings could be constrained to equality between the sexes, indicating metric invariance between genders. Further testing indicated invariance also at the strong and strict levels, thus allowing analyses involving group means. The SWLS was shown to be sensitive to age, however, at the strong and strict levels of invariance testing. CONCLUSION: In conclusion, the results in this Norwegian study seem to confirm that a unidimensional structure is acceptable, but that a modified single-factor model with correlations between error terms of items 4 and 5 is preferred. Additionally, comparisons may be made between the genders. Caution must be exerted when comparing age groups. PMID- 21308415 TI - Does the subjective quality of life of children with specific learning disabilities (SpLD) agree with their parents' proxy reports? AB - PURPOSE: The aim of the present study was to investigate agreement between child parent proxy reports on quality of life (QoL) in children with specific learning disabilities (SpLD) and in a control group of typically developing children. METHODS: One hundred and sixteen children aged 8-14 years with SpLD, and 312 same age typically developing children with their parents (one or both), respectively, completed the child and parent versions of the KINDL(R) questionnaire. Values were analyzed with ANOVA and intra-class correlation coefficient (ICC). RESULTS: Significant mean differences were found between children with SpLD and their mother's proxy ratings. So, mothers reported significantly lower scores in the dimension of everyday functioning in school, but significantly higher scores regarding the child's physical and emotional well-being. For typically developing children, significant differences between children and parents' proxy ratings were found in physical well-being and self-esteem with both parents reporting higher scores. Concerning ICC, correlations were few and low in the SpLD group but more robust in the typically developing child-parent proxy ratings with values ranging from 0.22 to 0.46. CONCLUSION: In the case of SpLD, the child's problem area, which is reflected in the KINDL(R) dimension of everyday functioning in school, seems to be an issue of controversial value that may be differentially perceived by children and their mothers. Further, it can be argued that as mothers seemed to perceive in a more negative way the child's QoL at school, they were at the same time attempting to counterbalance their reactions by overestimating the child's physical and emotional well-being. Besides differences, there is a tendency even low for mothers and children with SpLD to converge toward similar perceptions regarding the child's physical and emotional well-being and satisfaction with friends that is showing some rather common understanding of the child's overall well-being and his/her relationships with peers. In the control group, agreement between children and parents seems to be more even and evident. Proxy assessments in children with SpLD and their parents may be useful for planning targeted support interventions for these families. PMID- 21308416 TI - Low intensity microwave radiation as modulator of the L-lactate dehydrogenase activity. AB - In this study, we investigated experimentally the possibility of modulating protein activity by low intensity microwaves by measuring alternations of L: Lactate Dehydrogenase enzyme (LDH) activity. The LDH enzyme solutions were irradiated by microwaves of the selected frequencies and powers using the Transverse Electro-Magnetic (TEM) cell. The kinetics of the irradiated LDH was measured by continuous monitoring of nicotine adenine dinucleotide, reduced (NADH) absorbance at 340 nm. A comparative analysis of changes in the activity of the irradiated LDH enzyme versus the non-radiated enzyme was performed for the selected frequencies and powers. It was found that LDH activity can be selectively increased only by irradiation at the particular frequencies of 500 MHz [electric field: 0.02 V/m (1.2 * 10-6 W/m2)-2.1 V/m (1.2 * 10-2 W/m2)] and 900 MHz [electric field: 0.021-0.21 V/m (1.2 * 10-4 W/m2)]. Based on results obtained it was concluded that LDH enzyme activity can be modulated by specific frequencies of low power microwave radiation. This finding can serve to support the hypothesis that low intensity microwaves can induce non-thermal effects in bio-molecules. PMID- 21308417 TI - Airflow analysis in the alveolar region using the lattice-Boltzmann method. AB - A validated lattice-Boltzmann code has been developed based on the Bhatnagar Gross-Krook formulation to simulate and analyze transient laminar two-dimensional airflow in alveoli and bifurcating alveolated ducts with moving walls, representative of the human respiratory zone. A physically more realistic pressure boundary condition has been implemented, considering a physiological Reynolds number range, i.e., 0 < Re < 11, which covers the inhalation scenarios from resting mode to moderate exercise. Axial velocity contours, vortex propagation, and streamlines as well as mid-plane pressure variations in different alveolar geometries and shapes are illustrated and discussed. The results show that the influence of the geometric structure on the airflow fields in the human alveolar region is very important. Furthermore, the effect of a moving alveolus wall is significant, i.e., the vortices in the duct or alveolar sacs may change in size. In summary, for a given set of realistic inlet conditions, the airflow velocity and vortical flows are greatly dependent on the different alveolar sac shapes, local geometric structures, and sac expansion rates. The pressure distributions are less influenced by the alveolus shape and wall movement. The present results provide new physical insight and are important for the simulation of particle transport/deposition in the deep lung region. PMID- 21308419 TI - Temporary increase of PPAR-gamma and transient expression of UCP-1 in stromal vascular fraction isolated human adipocyte derived stem cells during adipogenesis. AB - In this study, cells from the stromal vascular fraction of human subcutaneous tissues were induced to differentiate toward adipose cells in vitro for 2 weeks. During adipogenic differentiation, we followed the chronological changes in their morphology with Coherent anti-Stokes Raman scattering (CARS) microscopy and checked the PPAR-gamma and UCP-1 expression with RT-PCR. On day 4 after inducing adipogenic differentiation, CARS imaging showed multiple small lipid droplets (LD) distributed peripherally along the cellular membrane. PPAR-gamma began to express at this time and increased until day 14 at a steady rate. On day 7, the cells appeared as brown adipocytes with numerous small LD throughout the cytoplasm, and the mRNA level of UCP-1 rose abruptly by 6- to 7-fold. After an additional 7 days, CARS imaging showed the development of a large LD, which is characteristic of white adipocytes, and the mRNA level of UCP-1 slumped significantly. These results demonstrate the possibility that ADSC pass through a brown adipocyte-like stage while differentiating into white adipocytes. PMID- 21308421 TI - Perioperative outcomes of laparoscopic adjustable gastric banding in mildly obese (BMI < 35 kg/m2) compared to severely obese. AB - Laparoscopic adjustable gastric banding (LAGB) has become a standard restrictive procedure in the USA for the treatment of severe obesity (body mass index, BMI > 35 kg/m(2)). Mildly obese individuals (BMI < 35 kg/m(2)) are also at increased risk from obesity-related conditions. Recently, an FDA panel supported its use in this subgroup. We compared the perioperative outcomes of LAGB in mildly and severely obese. Thirty consecutive patients (mildly obese n=10; severely obese n=20) that underwent preoperative medical weight loss followed by LAGB procedures were prospectively evaluated. Outcome variables included: operative room (OR) time, intraoperative estimated blood loss (EBL), length of hospital (LOS), and intensive care unit (ICU) stay, reoperations, readmissions, 30-day morbidity and mortality. Demographic data was comparable between groups. BMI was significantly higher in the severely obese compared to mildly obese (44.0 +/- 5 vs. 33.6 +/- 1 kg/m(2)). OR time, EBL, LOS, and ICU admissions were similar between BMI groups. There were no reoperations or 30-day mortality in either group. Minor morbidity was only observed in the severely obese group. BMI correlated with OR time and EBL. In mildly obese, LAGB is as safe as in the severely obese with no perioperative morbidity. The perioperative outcomes and hospital resource utilization are comparable between BMI groups. Lower BMI is associated with lower operative times and blood loss. PMID- 21308420 TI - Dietary monounsaturated fatty acids are protective against metabolic syndrome and cardiovascular disease risk factors. AB - Over 50 years of research has sought to define the role dietary fat plays in cardiovascular disease (CVD) risk. Although optimal dietary fat quantity has been keenly pursued over past decades, attention has recently centered on the value of dietary fat quality. The purpose of the present review is to provide a critical assessment of the current body of evidence surrounding efficacy of dietary monounsaturated fatty acids (MUFA) for reduction of traditional risk factors defining metabolic syndrome (MetS) and CVD. Due to existing and emerging research on health attributes of MUFA rich diets, and to the low prevalence of chronic disease in populations consuming MUFA rich Mediterranean diets, national dietary guidelines are increasingly recommending dietary MUFA, primarily at the expense of saturated fatty acids (SFA). Consumption of dietary MUFA promotes healthy blood lipid profiles, mediates blood pressure, improves insulin sensitivity and regulates glucose levels. Moreover, provocative newer data suggest a role for preferential oxidation and metabolism of dietary MUFA, influencing body composition and ameliorating the risk of obesity. Mounting epidemiological and human clinical trial data continue to demonstrate the cardioprotective activity of the MUFA content of dietary fat. As the debate on the optimal fatty acid composition of the diet continues, the benefit of increasing MUFA intakes, particularly as a substitute for dietary SFA, deserves considerable attention. PMID- 21308422 TI - Synonymous codon usage, GC(3), and evolutionary patterns across plastomes of three pooid model species: emerging grass genome models for monocots. AB - We have analyzed factors affecting the codon usage pattern of the chloroplasts genomes of representative species of pooid grass family. Correspondence analysis of relative synonymous codon usages (RSCU) showed that genes on secondary axis were correlated with their GC(3S) values (all r > 0.3, p < 0.05), indicating mutational bias as an important selective force that shaped the variation in the codon usage among chloroplast genes. The Nc-plot showed that although a majority of the points with low-Nc values were lying below the expected curve, a few genes lied on the expected curve. Nc plot clearly showed that mutational bias plays a major role in codon biology across the monocot plastomes. The hydrophobicity and aromaticity of encoded proteins of each species were found to be other factors of codon usage variation. In the view of above light, besides natural selection, several other factors also likely to be involved in determining the selective constraints on codon bias in plastomes of pooid grass genomes. In addition, five codons (B. distachyon), seven codons (H. vulgare), and four codons (T. aestivum) were identified as optimal codons of the three grass chloroplasts. To identify genes evolving under positive selection, rates of nonsynonymous substitutions (Ka) and synonymous substitutions (Ks) were computed for all groups of orthologous gene pairs. PMID- 21308423 TI - Renal nerve ablation for resistant hypertension. PMID- 21308425 TI - Transitions of care in heart failure: the case for comparative effectiveness research. PMID- 21308426 TI - Illness beliefs about cancer among healthy adults who have and have not lived with cancer patients. AB - BACKGROUND: Illness representations have been proposed as key determinants for facing health risks and managing disease, and consequently for health outcomes. PURPOSE: This study aims to know and compare non-specialised illness representations of cancer among adults who had not suffered from cancer and who had/had not lived with cancer patients. METHOD: The revised Illness Perception Questionnaire was adapted to assess illness perceptions among healthy people. Cancer representations were explored in a community-based sample of adults of both genders from different educational backgrounds and who had differing experience with cancer, none being a patient. RESULTS: The participants' beliefs about cancer included both biomedical and folk knowledge. Compared to age, sex, and educational level, family experience with cancer (having lived or not with a patient) had the strongest impact on the contents of the representations on cancer. Further, people with a family experience with the disease, compared to those not having a relative diagnosed with cancer, reported significantly more symptoms and stronger emotional impact. CONCLUSIONS: This study allowed us to establish the perceptions on cancer of non-patients with no specialised knowledge. Findings may help in designing and implementing tailored preventive interventions taking into account family experience with the disease, as well as interventions aimed at enhancing family and social care and support given to cancer patients. PMID- 21308427 TI - Physiological considerations related to the pediatric airway. PMID- 21308428 TI - The criterion-calibration model of cue interaction in contingency judgments. AB - Siegel, Allan, Hannah, and Crump (2009) demonstrated that cue interaction effects in human contingency judgments reflect processing that occurs after the acquisition of information. This finding is in conflict with a broad class of theories. We present a new postacquisition model, the criterion-calibration model, that describes cue interaction effects as involving shifts in a report criterion. The model accounts for the Siegel et al. data and outperforms the only other postacquisition model of cue interaction, Stout and Miller's (2007) SOCR model. We present new data from an experiment designed to evaluate a prediction of the two models regarding reciprocal cue interaction effects. The new data provide further support for the criterion-calibration model. PMID- 21308429 TI - [Hot Topics from the ESC-Congress 2010 in Stockholm]. PMID- 21308430 TI - [6th report of the German Association of Cardiologists in private practice (BNK) on quality assurance in cardiac catheterization and coronary intervention 2006 2009]. PMID- 21308431 TI - [Tracheoesophageal fistula]. AB - Congenital deformities, various forms of trauma, foreign bodies, granulomatous infection and tumors are the most common causes of tracheoesophageal fistulas. This is a rare but life-threatening complication with mortality rates up to 60% due to chronic aspiration and innominate artery arrosion and bleeding. Bronchoscopy should be done promptly if a fistula is suspected, followed by esophagoscopy. Radiologic examinations are only helpful for operational planning. Surgical treatment is mandatory for benign fistulas with excellent short-term and long-term results. However, for malignant fistulas the survival time is often only weeks to months and are best treated by palliative stenting, which offers a short-term improvement in the quality of life. PMID- 21308432 TI - [Injuries of the midfoot]. AB - Injuries of the midfoot comprise fractures, dislocations and/or fracture dislocations of the Chopart and Lisfranc joint lines. Fracture dislocations, in particular, represent prognostically severe lesions which may compromise foot function to a substantial degree. A number of injuries of the midfoot (up to one quarter) are still primarily overlooked. As such, a diagnostic algorithm is essential for the adequate detection of the injury components and planning of the therapeutic approach. Standard x-rays in three planes (dorso-plantar, lateral and lateral oblique views) represent the diagnostic basis which is supplemented by CAT scanning and multiplanar reconstruction, especially in cases where a potential midfoot lesion is suspected. MRI may be helpful in mainly ligamentous injuries only. Latent instability may be revealed by dynamic assessment employing stress fluoroscopy. Chronic instability may be detected by weight-bearing radiographs displaying manifest displacement and malalignment under load. The principal strategy of treatment includes anatomical reconstruction of the joint structures, the geometric proportions of the medial, central and lateral foot columns and the diagnostics and treatment of ligamentous instabilities. PMID- 21308433 TI - Fighting spinal cord complication during surgery for thoracoabdominal aortic disease. AB - Paraplegia or paraparesis after otherwise successful thoracic or thoracoabdominal aortic reconstruction is a devastating complication for both patient and physician. Various strategies have been developed to minimize the incidence of neurological complications after aortic surgery. The incidence of spinal cord ischemia and subsequent neurological complications has been correlated with (1) the duration and severity of ischemia, (2) failure to establish a spinal cord blood supply, and (3) reperfusion injury. Preoperative identification of the arteria radicularis magna, the artery of Adamkiewicz, facilitates identification of critical intercostal vessels for reimplantation, resulting in reestablishing spinal cord blood flow. Techniques for monitoring spinal cord function using evoked potentials have been developed, and surgical techniques have evolved to reduce the duration of ischemia. Furthermore, sequentially sacrificing all the intercostal arteries while maintaining collateral circulation to the cord has produced good outcomes. The severity of ischemia can be minimized by using cerebrospinal fluid drainage, hypothermia, distal bypass, managing the blood pressure, and adjunctive pharmacological therapy. Reperfusion injury can be reduced with the use of antioxidant therapy. Recent advances in endovascular stentgrafting have reduced the incidence of postoperative spinal complications, especially among high-risk patients. PMID- 21308434 TI - Tissue-engineered airway and "in situ tissue engineering". AB - Since the 1980s, tissue engineering has become one of the major areas of endeavor in medical research, applying the principles of biology and engineering to the development of functional substitutes for damaged tissue. Using this technology, various attempts have been made to create and apply a tissue-engineered prosthetic trachea, or airway. In addition to the conventional tissue engineering approach, a new substantially different concept has been advocated in Japan since 2000. This is "in situ tissue engineering," where a tissue is created not in vitro but in vivo, exploiting the potential of the living body for wound healing. An artificial trachea created by in situ tissue engineering has already been applied in human patients for reconstruction of airway defects, and promising results have been obtained. This article reviews recent progress in the relatively new field of airway reconstruction employing tissue engineering. PMID- 21308435 TI - Intraoperative direct hemoperfusion with a polymyxin-B immobilized fiber column for treatment of infective endocarditis. AB - PURPOSE: Endotoxin adsorption treatment (direct hemoperfusion using a polymyxin-B immobilized fiber column, or PMX-DHP) is now considered a useful option for treating severe sepsis. However, the efficacy of PMX-DHP for infective endocarditis (IE), in which the causative microorganisms are usually gram positive cocci, remains unclear. In the present study, we investigated the impact of intraoperative PMX-DHP on clinical parameters during the treatment of IE. METHODS: From November 2006 to December 2009, a total of 11 patients with active IE underwent emergent surgery using intraoperative PMX-DHP. The perioperative courses of these patients were compared with those of seven patients who underwent emergent surgery for active IE with the conventional method from January 2003 to October 2006. RESULTS: PMX-DHP was associated with a significant decrease in the postoperative catecholamine dose and duration. Intubation time and intensive care unit length of stay for the PMX-DHP group was significantly shorter than that for the conventional therapy group. There was also a significant difference in the number of failed organs postoperatively between the two groups. CONCLUSION: Intraoperative PMX-DHP demonstrated several positive effects, such as a drastic decrease in the doses of inotropic agents and shortening of the duration of mechanical ventilation, in patients who underwent emergent surgery for active IE. Intraoperative PMX-DHP can be a useful option for the treatment of critically ill patients with IE. PMID- 21308436 TI - Pulmonary hydatid cyst: analysis of 1024 cases. AB - PURPOSE: Pulmonary hydatid cyst, a parasitic disease, is a health care problem in developing countries. In this study, we evaluated outcomes of patients with pulmonary hydatid disease who were treated in our department. METHODS: Patients admitted with a pulmonary hydatid cyst from 1981 to 2008 were enrolled in this study. Their demographic data, the sites and number of cysts, diagnostic methods, type of operation, outcomes, and recurrence rate were statistically analyzed. RESULTS: Among the 1024 patients, the mean+/-SD age was 30.6+/-16.1 years, and the male/female ratio was 1.09. The most common symptom was a cough (55.1%). Only 1% of the patients were asymptomatic. Altogether, 53.8% had right-side involvement, 40.0% had left-side involvement, and 6.2% had bilateral disease. The inferior lobe was the lobe most common involved. The cyst was intact in 539 (52.6%) patients; and the others were complicated or perforated. The most common surgical technique entailed removing the cyst membrane without resecting the pericyst and closing the airways (67.2%). The cyst was enucleated in 21.2%; and parenchymal resection was performed in 10.3%. The mortality rate was 0.2%, and morbidity occurred in 8.4% of patients. The most common complications were residual spaces with prolonged air leak and wound infection. The recurrence rate was 2.5%, with most of the recurrences (82.6%) managed by surgery. CONCLUSION: The best treatment for pulmonary hydatid cyst disease is surgery, which is associated with low mortality and morbidity rates. The most common and acceptable treatment is extraction of the cyst membrane without manipulating the pericyst and closure of small airways. Pulmonary resection should be reserved for complicated forms of the disease. PMID- 21308437 TI - Surgical treatment for chronic type A aortic dissection and aortic regurgitation in a patient with a tracheostoma. AB - We successfully performed aortic root replacement and partial aortic arch replacement by a T-shaped sternotomy at the second intercostal space in a patient who had undergone tracheotomy for respiratory insufficiency and cardiac failure caused by methicillin-resistant Staphylococcus aureus pneumonia during preservation treatment of chronic type A aortic dissection and aortic regurgitation. PMID- 21308438 TI - Cardiogenic shock without cardiac tamponade caused by a subepicardial hematoma after percutaneous coronary intervention. AB - A 73-year-old man complaining of pain on effort was admitted to a hospital for a percutaneous coronary intervention (PCI) because of severe stenosis of the mid right coronary artery. During PCI, a coronary artery was ruptured, and the patient suddenly went into shock. Percutaneous pericardiocentesis was successfully performed, and cardiac tamponade was relieved. Despite the echocardiographic finding of no cardiac tamponade, the patient remained in the shock state. An emergency operation was performed. There was little pericardial effusion, but a large subepicardial and intramyocardial hematoma was present and was being compressed by the pericardium. Pericardial incision and off-pump coronary artery bypass grafting were performed. The patient was discharged on the 12th postoperative day. Decompression of the subepicardial hematoma by pericardiotomy ameliorated the condition of the patient, who was in cardiogenic shock. We thus report a rare case of subepicardial hematoma resulting in shock during PCI in which cardiac tamponade was not observed. PMID- 21308439 TI - Minimally invasive mitral valve replacement in a patient with previous omphalocele repair and severe scoliosis. AB - Mitral valve surgery in a patient with severe chest deformity and poor respiratory function can be associated with a high risk due to difficult access and postoperative respiratory failure. A 45-year-old man with scoliosis and respiratory dysfunction who had undergone previous omphalocele repairs presented with severe mitral regurgitation. Mitral valve replacement via right mini thoracotomy was successfully performed. The minimally invasive approach was considered useful in this patient with anatomical difficulty and respiratory dysfunction. PMID- 21308440 TI - Surgical repair of an idiopathic pulmonary artery aneurysm. AB - We report a rare case of idiopathic pulmonary artery aneurysm (PAA) in a 56-year old woman without any causative conditions, such as congenital heart disease, inflammation, pulmonary artery hypertension, or systemic vasculitis. She presented with sudden back pain, and examination revealed the PAA. She electively underwent resection of the aneurysm and graft replacement. Pathology examination revealed cystic medial necrosis, which was considered the underlying pathology of the aneurysm. PMID- 21308441 TI - Endovascular management for ruptured Stanford B acute aortic dissection. AB - Surgery for a complicated Stanford B acute aortic dissection, such as rupture or malperfusion, is still a challenge. We undertook endovascular therapy for ruptured Stanford B acute aortic dissection in two patients. A homemade stent graft was deployed in an 84-year-old woman with a massive mediastinal hematoma; and an aortic extender of Excluder was used for a 76-year-old man with left hemothorax. Both patients recovered without major complications. Careful follow up is mandatory. Endovascular therapy for a ruptured Stanford B acute aortic dissection seems feasible and efficient. PMID- 21308442 TI - Spindle cell carcinoma of the lung. AB - We report a rare case of spindle cell carcinoma in the lung. A 73-year-old woman was admitted because of a lung tumor, which was indicated during a group examination. Chest computed tomography revealed a tumor located in the right lung accompanied by spiculation. Right upper lobectomy with lymph nodal dissection was performed. Histological findings revealed only spindle-shaped tumor cells, and immunohistochemical stain showed that they were cytokeratin-positive. We diagnosed it as a pulmonary spindle cell carcinoma. PMID- 21308443 TI - Thoracoscopic resection of a thoracic duct cyst that developed during follow-up for a thymic cyst. AB - A 29-year-old man had been diagnosed with an anterior mediastinal cyst 6 years earlier and was undergoing follow-up. At a follow-up visit, a newly developed cystic lesion was found in the middle mediastinum; therefore, the anterior mediastinal cyst and the middle mediastinal cyst were resected by thoracoscopic surgery. It was observed that the middle mediastinal cyst originated from the thoracic duct, and the thoracic duct was clipped. Pathologically, the diagnosis was a thymic cyst of the anterior mediastinum and a thoracic duct cyst of the middle mediastinum. The patient developed chylothorax after surgery, and a second thoracoscopic operation was performed. It revealed that part of the clipping of the caudal thoracic duct was incomplete, and leakage of chyle was observed. Hence, the clipping was performed again. The course after the second surgery was good. Thoracic duct cysts are rare even among mediastinal cysts and thus require caution due to their tendency to expand. PMID- 21308444 TI - Primary lung cancer arising from the wall of a giant bulla in which positron emission tomography was useful for preoperative diagnosis. AB - We report a case of lung cancer arising from the wall of a giant bulla. A 58-year old man consulted a physician because of bloody sputum. Chest computed tomography (CT) revealed a left upper giant bulla with partial thickness of the wall. Cytology of both sputum and transbronchial brushing was negative at that time. After 6 months follow-up CT scans showed more thickness of the wall, and positron emission tomography (PET) revealed high accumulation of fluorodeoxyglucose in the thickened wall. Because lung cancer was highly suspected, we performed an operation without a definitive diagnosis. The postoperative pathological diagnosis was large cell carcinoma arising from the wall of a giant bulla. Because a preoperative diagnosis is difficult in the case of lung carcinoma associated with bullous disease due to the lack of a characteristic radiological appearance and the difficulty of pathological examination, we emphasize that PET is a useful diagnostic tool. PMID- 21308445 TI - Endobronchial hamartoma with obstructive pneumonia due to Nocardia asiatica. AB - A 60-year-old man who had diabetes had a history of hospitalization for pneumonia in the right lower lobe at the age of 57 years. He visited our facility complaining of fever and cough. He was admitted owing to pneumonia in the right lung. Computed tomography and bronchoscopy performed after admission revealed a tumor in the right basal bronchus. Nocardia asiatica was detected in a sputum culture. Complete resection of the bronchial tumor could not be achieved with a high-frequency snare, although the patient was preoperatively diagnosed as having hamartoma. The patient subsequently underwent resection of the right lower lobe due to his deteriorated clinical condition. The postoperative course was favorable, and there has been no recurrence of nocardiosis or bronchial hamartoma for 3 years. PMID- 21308446 TI - Primary mediastinal chondrosarcoma with Horner's syndrome. AB - Chondrosarcomas are uncommon tumors of the mediastinum. Cases reported in the literature are chondrosarcomas originating from osteocartilaginous structures; primary chondrosarcomas that have no anatomical relation with cartilaginous structures are rare. They present with myriad symptoms depending on compression of the adjacent structures; but Horner's syndrome, as a symptom, has not been described before. We report a rare case of a large primary mediastinal chondrosarcoma that presented with Horner's syndrome. PMID- 21308447 TI - Giant cell tumors that originated in the sternum. AB - Giant cell tumors originating from the sternum are rare. We report a case of a giant cell tumor of the sternum with radiological evidence of aggressiveness. A 34 year-old woman noted a mass in the anterior chest wall that had been slowly growing over 1 year. After incision biopsy revealed a diagnosis of a giant cell tumor she was treated by surgical resection (subtotal sternectomy) and reconstruction with methylmethacrylate. The tumor was 14*9*8 cm, and histological study confirmed that it was a giant cell tumor. Although giant cell tumors are benign, they are locally aggressive lesions and must be considered in the differential diagnosis in patients with a sternal mass. PMID- 21308448 TI - Clinical Trial Report: TMC278 (Rilpivirine) Versus Efavirenz as Initial Therapy in Treatment-Naive, HIV-1-Infected Patients. PMID- 21308449 TI - Novel approaches to oral immunization for hepatitis B. AB - Hepatitis B is a necroinflammatory liver disease manifested with subacute to acute symptoms, liver cirrhosis, and mortality. Parenteral alum-adsorbed hepatitis B surface antigenic (HBsAg) vaccination, although available, poses serious concerns regarding inability to induce both cell-mediated and mucosal immune response. In this context, oral delivery may be a prospective solution to the issues associated with conventional vaccination. However, the strategy is detrimental to the antigenic substances, suffers various physical/chemical barriers, and impedes poor transcytosis via mucosal route. Therefore, surface engineered novel carrier-based approaches are reportedly promising for effective HBsAg oral vaccine delivery. This review focuses on the efforts for developing oral mucosal vaccine against hepatitis B, with considerable attention on novel drug delivery systems for spatial distribution of antigenic substance to the immune effector cells and organs. PMID- 21308450 TI - Probiotics and prebiotics for the prevention of necrotizing enterocolitis. AB - Necrotizing enterocolitis (NEC) continues to be a major cause of morbidity and mortality in premature infants. Although the pathogenesis of NEC remains unclear, abnormal bacterial colonization has been postulated as playing a central role. Various factors impact bacterial colonization following delivery. Compared to term infants, the bacterial colonization pattern in prematurely born infants is markedly different, with a greater predilection for colonization with pathogenic bacteria. Probiotic and prebiotic administration offers the opportunity to manipulate the intestinal bacterial environment, favoring the growth of commensal bacteria. Experimental data from animal studies and data from human trials suggest that probiotics decrease the incidence of NEC. These preliminary studies support the need for a large, randomized, controlled trial to further investigate the role of probiotics in the prevention of NEC. PMID- 21308451 TI - Current Status of Nonantibiotic and Adjunct Therapies for Clostridium difficile Infection. AB - Clostridium difficile infection (CDI) is a leading cause of nosocomial infections and the most important cause of health care-associated diarrhea worldwide. Standard treatment of CDI consists of modifying underlying antibiotic exposure, aggressive supportive measures, and therapy with specific antibiotics, most commonly metronidazole or vancomycin. This general approach to CDI has remained largely unchanged for decades. In an effort to improve outcomes and reduce recurrences of CDI, interest has been renewed in the development of nonantibiotic and adjunct approaches to therapy. In this review, we highlight some of these recent, resurrected, and novel nonantibiotic treatments. PMID- 21308452 TI - Current concepts of the intestinal microbiota and the pathogenesis of infection. AB - The human gastrointestinal tract is populated by a vast and diverse community of microbes. This gut microbiota participates in host metabolism, protects from invading microbes, and facilitates immune system development and function. In this review, we consider the contributions of intestinal microbes to the pathogenesis of infectious diseases. Key concepts of colonization resistance, host-commensal microbe interaction in immunity, antibiotics and gut bacterial communities, viral-gut bacterial interactions, and evolving methods for studying commensal microbes are explored. PMID- 21308453 TI - Update on strongyloidiasis in the immunocompromised host. AB - Immunocompromised persons are the most vulnerable population at risk for developing life-threatening clinical syndromes associated with strongyloidiasis, such as hyperinfection syndrome (HS) or dissemination. This review focuses on describing Strongyloides infection in the immunocompromised host, including immune response against this infection, analyzing the cases with HS published during the past 4 years in the United States, and describing the most sensitive diagnostic tools and the most effective treatment for each clinical syndrome. Strongyloidiasis is becoming an important parasitic disease in the United States, especially in the immunocompromised immigrant population. Because the transplant population is particularly at risk for developing HS, both recipients and donors should be screened for Strongyloides. Clinicians should also be aware that the development of HS can follow unexpectedly a few days after appropriate anthelminthic therapy. Highly sensitive screening tests are still not available in the major tertiary medical centers. Parenteral ivermectin has been used in some severe cases. Further therapy developments and improving diagnostic tools are warranted. PMID- 21308454 TI - Current Views on the Pathophysiology of GB Virus C Coinfection with HIV-1 Infection. AB - GB virus C (GBV-C), a member of the Flaviviridae family of viruses, recently received considerable attention largely owing to its potential role in decelerating HIV-1 disease progression by interfering with HIV replication. With similar transmission features, GBV-C is parenterally transmitted, similar to the serum hepatitis viruses and HIV-1, and replicates in hemopoietic cells and T lymphocytes in particular, with no observable disease pathology. Progressive T cell depletion and subsequent immune abrogation being the cardinal features of HIV-1 infection, accumulating evidence indicates that GBV-C effectively overturns HIV's chances of exploiting the T-cell machinery and leads to enhanced survival rates of HIV-infected subjects. Much effort has been devoted to understanding the beneficial role of GBV-C in HIV disease. This review discusses recently proposed mechanisms underlying the pathophysiology of GBV-C coinfection in HIV disease. PMID- 21308455 TI - Posttransplant lymphoproliferative disease in liver transplant patients. AB - Posttransplant lymphoproliferative disorders (PTLD) are a life-threatening complication following solid organ transplantation. Many posttransplant lymphomas develop from the uncontrolled proliferation of Epstein-Barr virus (EBV)-infected B-cells, whereas EBV-negative PTLDs were increasingly recognized within the past decade. Major risk factors for the development of PTLDs after liver transplantation are immunosuppressive therapy and the type of underlying disease: viral hepatitis, autoimmune liver disease, or alcoholic liver cirrhosis contribute to an increased risk for PTLD. Therapeutic regimens include reduction of immunosuppression, the anti-CD20 antibody rituximab, and chemotherapy, as well as new approaches using interferon-alpha and anti-interleukin-6 antibodies. Despite the different therapeutic regimens, mortality from PTLD remains high. Therefore, it is of major importance to identify patients at risk at an early stage of the disease. In this review, risk factors for PTLD development after liver transplantation, clinical presentation, diagnosis, and therapy are discussed. PMID- 21308456 TI - When to start antiretroviral therapy. AB - Antiretrovirals perform superbly in combating HIV infection. But when to initiate therapy in asymptomatic, nonpregnant, hepatitis-free, HIV-infected persons is not securely established. Of two completed randomized trials using modern therapy, a Haitian trial demonstrated a benefit to initiating therapy between 200 and 350 CD4 cells/mm(3) as compared with less than 200 CD4 cells/mm(3) and an international trial demonstrated a benefit to starting at greater than 350 CD4 cells/mm(3) as compared with less than 250 CD4 cells/mm(3). Many observational cohorts support initiating treatment at less than 350 CD4 cells/mm(3). Of these, three large studies supported initiation at less than 350 cells/mm(3), less than 450 CD4 cells/mm(3), and less than 500 CD4 cells/mm(3), respectively, but only the last supported starting at higher counts. Such studies are not probative, given the problem of confounding. No conventional antiretroviral regimen is free of long-term adverse effects, especially over decades of use. All are expensive and require expensive monitoring. When resources are restricted, initiation of antiretrovirals for persons with high CD4 count diverts treatment from more needy persons. Pathophysiological considerations favor universal treatment because antiretrovirals mitigate systemic inflammation, which aggravates atherosclerosis. There are suggestions that HIV hastens the natural decline of cognitive, renal, and pulmonary function as well as bone mineral loss; the mechanism(s) are uncertain, as is the ability of antiretrovirals to counteract the probable acceleration. The four major guideline panels, although all have issued updates in the past year, are not consistent in recommendations for treatment of HIV infected persons with counts greater than 350 CD4 cells/mm(3). PMID- 21308457 TI - Comprehensive Approaches to the Diagnosis and Treatment of HIV Infection in the Community: Can "Seek and Treat" Really Deliver? AB - For every two people starting on combination antiretroviral therapy (cART), five become infected with HIV. Current prevention strategies are inadequate, and it has been hypothesized that cART itself could be used as a tool for prevention, in combination with enhanced testing and access to treatment-the "seek and treat" approach. Ecologic and modeling data support this strategy, but many questions remain: how to optimize HIV testing, cART uptake and adherence, how to deal with treatment failure and toxicity, and how to implement integrated prevention strategies and deal with key comorbidities. Pilot studies (eg, HIV Prevention Trials Network 065) are underway to validate the approach under controlled circumstances before it is integrated into public health policy. As we redefine the potential benefits of cART on a broader scale, let us not sacrifice the gains that have been made until we are more certain of the potential benefits of the "seek and treat" strategy. PMID- 21308458 TI - Growing Old with HIV. AB - The intersection of chronic HIV infection, its treatment, and lifestyle with aging has become a topic of considerable fascination during this, the third decade of the AIDS epidemic. An understanding of the pathophysiology of this intersection may provide valuable insights into our general understanding of human aging. This review summarizes the results of recent publications that may have considerable impact on screening and management strategies in the aging HIV infected population. PMID- 21308459 TI - The Rapidly Evolving Research on Vitamin D Among HIV-Infected Populations. AB - With ongoing improvement in antiretroviral therapy, mortality among HIV-infected persons has dramatically decreased. For HIV-infected persons who remain engaged in care on suppressive therapy, life expectancy approaches that of the general population. Additionally, we have seen increases in comorbidities traditionally associated with aging: diabetes, hypertension, dyslipidemia, ischemic heart disease, and osteoporosis. Vitamin D deficiency has also been identified as a highly prevalent entity among HIV-infected populations. The association of vitamin D deficiency with several of these comorbidities and its impact on immune function provide the impetus for well-designed studies to evaluate the impact of vitamin D supplementation on HIV disease and antiretroviral therapy. This review summarizes the role of vitamin D in several disease states that are prevalent among HIV populations, with a specific focus on bone health and the interactions with antiretroviral medications. PMID- 21308460 TI - Inflammatory Markers Associated with Coronary Heart Disease in Persons with HIV Infection. AB - Coronary heart disease (CHD) is an inflammatory process that takes decades to develop. In HIV-seronegative persons, high-sensitivity C-reactive protein is a biologic marker of CHD risk. HIV infection induces chronic inflammation, despite adequate suppression of HIV replication with antiretroviral therapy, resulting in elevations of several biologic markers associated with CHD risk in HIV seronegative persons. Indeed, the SMART study demonstrated that interruption in antiretroviral therapy is associated with higher mortality and CHD events postulated to be related to inflammatory mediators such as interleukin-6 and D dimer. Specific antiretroviral agents (eg, abacavir) have been associated with higher rates of myocardial infarctions and elevations in markers of inflammation such as interleukin-6 and D-dimer in persons with CHD events. This article reviews the current understanding of biomarkers of inflammation associated with the development of CHD in the setting of HIV infection and the use of antiretroviral therapy. PMID- 21308461 TI - Prospects for development of a vaccine to prevent and control vaginal candidiasis. AB - A vaccine against recurrent vulvovaginal candidiasis (RVVC) would benefit a large number of women who suffer from this debilitating syndrome. To date, several antigen formulations have been tested with modest results. In this article, we review the latest vaccine study reported in the literature. The candidate is a beta-glucan conjugate administered with a human compatible adjuvant. Results in a mouse model of vaginitis were again modest for protection. However, the study included live animal imaging to quantify fungal burden; animals were challenged with a Candida strain carrying a gene encoding a glycophosphatidylinositol (GPI) linked cell wall protein and luciferase. Fungal burden was expressed as photons following substrate administration. Protection appeared to be mediated by beta glucan antibodies. Although modest protection was observed, the imaging system was less variable than semi-quantitative plate counts of vaginal lavage fluid. Despite these advances in evaluating protection, a vaccine candidate against RVVC worthy of clinical testing remains elusive. PMID- 21308463 TI - [Polysegmental Dynesys system]. AB - INTRODUCTION: The advantages of using the Dynesys System are claimed to be sufficient and polysegmental dorsal stabilization of the spine while preserving a certain amount of motion. MATERIALS AND METHODS: In this study 20 patients with a polysegmental spinal pathology were treated with polysegmental decompression and using the Dynesys Dynamic Stabilization system. None of the patients had had spinal surgery previously. Bone density was measured in all patients preoperatively. RESULTS: All 20 patients were followed up for an average of 11.8 months postoperatively. The ability to walk was improved from 581.5 m to 1640.0 m after surgery. Complications observed were one leakage of the dura and one hypertensive crisis. Implant loosening was observed in one female patient, which was revised and dorso-ventral fusion was carried out. CONCLUSIONS: The use of the Dynesys Dynamic Stabilization system is a reasonable treatment in patients with polysegmental pathology of the spine. However, the system does not allow restoration of extensive malalignments or deformities of the spine. PMID- 21308464 TI - [Revision strategies for ventral implant failure in the lumbar spine exemplified by stand-alone cages]. AB - This article gives a review of the possible revision strategies after repeated operative treatment of degenerative spinal diseases using stand-alone cages. Own clinical experiences and reports from the literature were taken into consideration. Dorsal stabilization is the main consideration for all access routes even if it can be discussed, albeit controversially, whether ventral removal of an installed cage is justified, because this contains a significantly higher perioperative risk. The increased risk of neurological complications by dorsal revision and for vascular complications by ventral access, especially at the L4/5 level must be particularly considered. Clinical data and own experience have shown that in the majority of cases an additional dorsal stabilization should be favored for revision surgery. Currently large clinical studies which deal with the revision problematic of stand-alone cages with respect to the access route are still lacking. PMID- 21308465 TI - [Endoscopic nucleotomy - Renaissance of a procedure. State of the art]. AB - Since the introduction of percutaneous nucleotomy two lines of development have been followed. On the one hand the blindly driven intradiscal tissue active methods and on the other hand endoscopically controlled minimally invasive tissue methods. The first group diminished the acceptance of intradiscal applications due to few reproducible results. Due to high resolution endoscopy with coaxial endoscopes, the second group developed into effective minimally invasive forms of surgery with well defined indications and reproducible results and challenges conventional techniques in the range of intradiscal and extradiscal indications. PMID- 21308466 TI - Enhancement of cue-induced reinstatement of cocaine-seeking in rats by yohimbine: sex differences and the role of the estrous cycle. AB - RATIONALE: Previous studies have shown that female rats exhibit enhanced cocaine seeking across several phases of the addiction cycle when compared to males. Drug seeking in females is also estrous cycle dependent and inversely associated with plasma progesterone. Although sex and estrous cycle-dependent differences have been reported in the reinstatement of cocaine-seeking triggered by cocaine injections or drug-paired cues, it is not yet known what role the estrous cycle may have on stress-induced reinstatement, either alone or in combination with drug-paired cues. OBJECTIVES: Here, we examined male and female rats for reinstatement of extinguished cocaine-seeking produced by cocaine-paired cues or the stress-activating drug, yohimbine. METHODS: Male and female Sprague-Dawley rats self-administered intravenous cocaine (0.5 mg/kg/infusion) paired with a light + tone stimulus for 10-14 days. Lever responding was then allowed to extinguish, with subsequent reinstatement testing occurring 30 min following an injection of yohimbine (1.25 or 2.5 mg/kg, intraperitoneal) or vehicle either in the presence or absence of the conditioned stimulus. RESULTS: While males and females showed similar cue- and yohimbine-induced reinstatement (3-4 times over "No Cue"-vehicle responding), combining these stimuli resulted in a robust enhancement in cocaine-seeking in both groups, with a greater increase in females (10-12 vs. 14-15 times over "No Cue"-vehicle responding for the males and females, respectively). When examined as a function of the estrous cycle, females in proestrus demonstrated higher levels of responding during yohimbine + cues reinstatement. CONCLUSIONS: This cycle-dependent enhanced sensitivity to stress enhancement of cocaine-paired cues may generalize to greater relapse susceptibility under stressful conditions. PMID- 21308467 TI - Changes in plasma and platelet BDNF levels induced by S-citalopram in major depression. AB - BACKGROUND: Neuroplastic processes are thought to be involved in the pathophysiology of major depression. It has been reported that serum brain derived neurotrophic factor (BDNF) is decreased in depressed patients. OBJECTIVES: Compare BDNF levels in depressed patients and healthy controls in platelet poor plasma and in washed platelets. Observe the effects of 8- and 24 week treatment with S-citalopram on these levels. METHODS: We assessed the levels of BDNF in platelet poor plasma and in washed platelets from 18 major depression patients, and compared them with 14 healthy controls. Blood samples were obtained from patients before and during treatment (8 and 24 weeks) with a selective serotonin reuptake inhibitor, S-citalopram. RESULTS: A significant decrease in severity of depressive symptoms was observed from the first month of treatment with S-citalopram, and symptoms continued decreasing until the 6th month. Plasma BDNF levels in untreated patients appeared significantly increased (p<0.01) but reached values similar to those of controls at the 24th week. In contrast, levels of platelet BDNF appeared significantly decreased (p<0.05), but treatment also normalized levels so that values obtained were equivalent to those of controls. CONCLUSIONS: Untreated depressed patients showed increased plasma BDNF levels and decreased platelet BDNF levels, as compared with control subjects, and tend to normalize during treatment with S-citalopram for 24 weeks, with BDNF reaching levels similar to those in healthy controls at the 24th week in both samples. We observed that improvement in depressive symptoms was accompanied by normalization of plasma and platelet BDNF levels. PMID- 21308468 TI - Diffusion-weighted MRI, dynamic susceptibility contrast MRI and ultrasound perfusion quantification of denervated muscle in rabbits. AB - OBJECTIVE: The purpose of this study was to assess denervated muscle perfusion using dynamic susceptibility contrast MRI (DSCMRI) and contrast-enhanced ultrasound (CEUS), and to measure denervated muscle apparent diffusion coefficient (ADC) on b1000 diffusion-weighted MRI (DWMRI) at 3 T in order to clarify whether muscle denervation leads to an increase in the extracellular extravascular space, or an increase in blood flow-or both. MATERIALS AND METHODS: Axotomy of the right sciatic nerve of six white rabbits was performed at day 0. At day 9, hind limb muscles MRI and CEUS were performed to assess the consequences of denervation and both semimembranosus muscles of each rabbit were explanted for histological studies. Signal intensity on T2- and T1-weighted MRI, ADC on DWMRI, maximum signal drop (MSD) on DSCMRI and the area under the curve (AUC) on CEUS were measured over circular regions of interest (ROI), in both semimembranosus muscles. Non-parametric Wilcoxon matched-pairs tests were used to assess the mean differences between denervated and normal muscles. RESULTS: T2 fat-saturated (FS) MRI studies showed a strong signal in the right semimembranosus muscles compared with the left side, and gadolinium enhancement was observed on T1 FS MRI. Denervated muscles show a significant increase in ADC on DWMRI (p < 0.01) and a significant signal enhancement on DSCMR imaging (p < 0.05) and on first-pass CEUS (p < 0.05). CONCLUSION: The results of this study- based on perfusion- and diffusion-weighted images--suggest that, after denervation, both increased blood flow through muscle tissue and expansion of the extracellular water volume are present. PMID- 21308469 TI - Functional analysis of the DAT gene promoter using transient Catharanthus roseus and stable Nicotiana tabacum transformation systems. AB - The Catharanthus roseus DAT gene encodes the enzyme acetyl-CoA:deacetylvindoline 4-O-acetyltransferase involved in the last step of the indole alkaloid pathway leading to vindoline. This gene is characterized by specific cell type expression in idioblasts and laticifers. To understand the specific transcriptional regulation mechanism(s) of DAT, several DAT promoter GUS constructs were cloned into pCAMBIA1305.1. Agroinfiltration of different explant types of C. roseus resulted in organ-specific accumulation of GUS, albeit at various levels. Heterologous accumulation of GUS in transgenic tobacco revealed both general and non-specific expression with the exception of a stomata-specific expression when 2.3 kb of the DAT promoter was coupled with a portion of the DAT ORF. These results suggest that in addition to the 2.3 kb upstream of the DAT transcriptional start site, additional cis-acting elements may be responsible for the specific spatial expression of DAT in vivo. Furthermore, hairy roots transformed with DAT promoter GUS constructs demonstrated GUS expression in root tissues (visualized through GUS enzyme activity), even though DAT is repressed in non-transformed roots. PMID- 21308470 TI - Influence of mitochondria on gene expression in a citrus cybrid. AB - The production of cybrids, combining nucleus of a species with alien cytoplasmic organelles, is a valuable method used for improvement of various crops. Several citrus cybrids have been created by somatic hybridization. These genotypes are interesting models to analyze the impact of cytoplasmic genome change on nuclear genome expression. Herein, we report genome-wide gene expression analysis in leaves of a citrus cybrid between C. reticulata cv 'Willowleaf mandarin' and C. limon cv 'Eureka lemon' compared with its lemon parent, using a Citrus 20K cDNA microarray. Molecular analysis showed that this cybrid possesses nuclear and chloroplast genomes of Eureka lemon plus mitochondria from Willowleaf mandarin and, therefore, can be considered as a lemon bearing foreign mitochondria. Mandarin mitochondria influenced the expression of a large set of lemon nuclear genes causing an over-expression of 480 of them and repression of 39 genes. Quantitative real-time RT-PCR further confirmed the credibility of microarray data. Genes over-expressed in cybrid leaves are predominantly attributed to the functional category "cellular protein metabolism" whereas in the down-regulated none functional category was enriched. Overall, mitochondria replacement affected different nuclear genes including particularly genes predicted to be involved in mitochondrial retrograde signaling. Mitochondria regulate all cell structures even chloroplast status. These results suggest that nuclear gene expression is modulated with respect to new information received from the foreign organelle, with the final objective to suit specific needs to ensure better cell physiological balance. PMID- 21308472 TI - Acute onset intramedullary spinal cord abscess with spinal artery occlusion: a case report and review. AB - Intramedullary spinal cord abscess (ISCA) without meningitis is an extremely rare entity in the central nervous system, and it is often difficult to diagnose immediately, and no definitive imaging findings have been established. We experienced the case of a 61-year-old male who presented with a sudden onset back pain without fever following rapidly worsening paraparesis for 3 days, who subsequently become unable to walk. According to the initial MRI and 3D-CTA, the presumptive diagnosis was spinal infarction due to spinal artery embolism. However, his symptoms did not improve, despite the gradual changes in MRI following antiplatelet therapy. He underwent a biopsy in an attempt to prevent the lesion from progressing toward the upper spinal cord. The pathological examination revealed an intramedullary abscess, so we performed a midline myelotomy and drained the pus from the abscess. After surgery, MRI showed improvement, but the patient's paraplegia persisted. To the best of our knowledge, this is the first case report of spinal cord abscess with the confirmation of spinal artery occlusion on angiography, which could have been caused by a bacterial embolism. We herein discuss its possible etiology and also review recent reports on ISCA. PMID- 21308471 TI - Micromechanical regulation in cardiac myocytes and fibroblasts: implications for tissue remodeling. AB - Cells of the myocardium are at home in one of the most mechanically dynamic environments in the body. At the cellular level, pulsatile stimuli of chamber filling and emptying are experienced as cyclic strains (relative deformation) and stresses (force per unit area). The intrinsic characteristics of tension generating myocytes and fibroblasts thus have a continuous mechanical interplay with their extrinsic surroundings. This review explores the ways that the micromechanics at the scale of single cardiac myocytes and fibroblasts have been measured, modeled, and recapitulated in vitro in the context of adaptation. Both types of cardiac cells respond to externally applied strain, and many of the intracellular mechanosensing pathways have been identified with the careful manipulation of experimental variables. In addition to strain, the extent of loading in myocytes and fibroblasts is also regulated by cues from the microenvironment such as substrate surface chemistry, stiffness, and topography. Combinations of these structural cues in three dimensions are needed to mimic the micromechanical complexity derived from the extracellular matrix of the developing, healthy, or pathophysiologic heart. An understanding of cardiac cell micromechanics can therefore inform the design and composition of tissue engineering scaffolds or stem cell niches for future applications in regenerative medicine. PMID- 21308473 TI - Does lateral vertebral translation correspond to Cobb angle and relate in the same way to axial vertebral rotation and rib hump index? A radiographic analysis on idiopathic scoliosis. AB - The deformity in idiopathic scoliosis (IS) is three dimensional in nature and effective correction involves all three planes. Even though the vertebral translation (VT) is an accepted element in the deformity along with vertebral rotation(VR) as reported by Asher and Cook (Spine (Phila Pa 1976) 20(12):1386 1391, 1995), Kotwicki et al. (Study Health Technol Inf 123:164-168, 2006) and Kotwicki and Napiontek (Pediatr Orthop 28(2):225-229, 2008), rib hump (rib hump index (RI)) and Cobb angle as reported by Aaro and Dahlborn (Spine (Phila Pa 1976) 6(6):567-572, 1981), it was assumed that VT was represented by adequately by Cobb angle and it was not analysed individually. We hypothesized that the Cobb angle and the VT measured in axial plane on CT scan and may not represent the same measurement and factors like coronal plane vertebral tilt,VR and vertebral deformation might affect them in different ways. Hence, VT should be considered as a separate variable and its relationship with VR, RI and Cobb angle should be investigated. Since the newer implants depend on curve translation and derotation for correction studying the role of VT and the relationships is important. VT, VR and RI were measured in CT scans of 75 patients with IS and correlated with Cobb angle. Regression analysis was used to identify the influence of the variables on each other. All the variables significantly correlated with one another but the correlation of Cobb and VT is not perfectly linear and it cannot be used to represent VT. VT influences RI much more than Cobb angle or VR. VT, therefore, merits further study treating it as an independent variable. PMID- 21308474 TI - Early development of gaze following into distant space in juvenile Greylag geese (Anser anser). AB - Visual co-orientation with another's gaze direction (gaze following) may provide important information about the location of food, social interactions or predators. Gaze following has been shown in a variety of mammals, but only in few bird species, and has not been tested in precocial birds at all. It has been suggested that gaze following is an anti-predator behaviour, and in Common ravens (Corvus corax) and rooks (C. frugilegus), it emerges shortly after fledging, at a time when young birds leave the predator-safe nest. However, if gaze following is adaptive, the developmental pattern should differ between altricial and precocial birds. Greylag geese (Anser anser) are highly social birds with a precocial development. Goslings move and feed independently within 24 h post-hatching, and they are highly vulnerable to aerial predators. We therefore predicted that greylag geese are capable of gaze following and that they develop this skill already pre-fledging. We experimentally tested 19 hand-raised greylag goslings for their ability to follow a conspecific's gaze when they were between 10 days and 6 weeks old. In line with our predictions, first responses were already detectable in 10-day-old goslings. Our results therefore not only demonstrate that greylag geese follow the gaze of conspecifics into distant space, but that they also develop this ability much earlier than altricial birds. PMID- 21308475 TI - Wallenberg's syndrome and symptomatic trigeminal neuralgia. AB - Symptomatic trigeminal neuralgia due to a brainstem infarction is said to be rare. However, facial pain is not uncommon in Wallenberg's syndrome. Facial pain related to a Wallenberg's syndrome may be either persistent of intermittent, and occasionally occurs in brief attacks. Here, we report a patient with a right lateral medullary infarction who started having first division trigeminal neuralgia 1 month after the stroke. The pain paroxysms were suppressed with gabapentin. PMID- 21308476 TI - Pattern of health services use by immigrants from different regions of the world residing in Spain. AB - OBJECTIVE: To determine immigrants' frequency of use of four health services by place of origin and compare it with that of the Spanish population. METHODS: Based on the 2006 National Health Survey in Spain, we estimated the frequency of use of four health services in men and women from: Spain, Western countries, Eastern Europe, Latin America, North Africa, Sub Saharan Africa and Asia/Oceania. These results were compared with the Spanish population by calculating odds ratios adjusted for age, socioeconomic position, health status, and type of health coverage. RESULTS: Immigrant men generally use health services less frequently than Spanish nationals. The main exceptions are Latin American men, who more often use emergency services (OR 1.68, 95% CI 1.41-1.99) and Sub-Saharan men, who use specialists more frequently (OR 2.93, 1.70-5.05). Immigrant women use health services about as frequently as Spanish women. The main exceptions are North African women, who less frequently use specialists (OR 0.39, 0.22-0.71) and Sub-Saharan women who more frequently use GPs (OR 4.06, 2.21-7.44), specialists (OR 2.29, 1.06-4.95) and emergency services (OR 2.92, 1.49-5.72). CONCLUSIONS: Health services use by the immigrant population in Spain differs by gender and place of origin. PMID- 21308477 TI - Time series analysis of Japanese encephalitis and weather in Linyi City, China. AB - OBJECTIVES: To examine the relationship between meteorological factors and epidemiological pattern of Japanese encephalitis in Linyi City during 1956-2004. METHODS: Autoregressive integrated moving average (ARIMA) models were used to evaluate the relationship between monthly JE incidence and weather factors. Logarithmic transformation was applied to the JE incidence series to assure the normality and homogeneity of variance of the residuals. The effect of mass vaccination on JE incidence was also evaluated using a transfer function in the time series analysis. RESULTS: The analysis suggested that monthly average temperature [beta = 0.0574, 95% confidence interval (CI) = (0.0172, 0.0976)] and relative humidity [beta = 0.0082, 95% CI = (0.0004, 0.0158)] were positively associated with the logarithmic incidence of Japanese encephalitis after adjusting for mass vaccination in this area. CONCLUSIONS: Weather variables might be treated as possible predictors of Japanese encephalitis incidence for regions with similar geographic, weather, and socio-economic conditions to Linyi, China. PMID- 21308478 TI - Therapy innovations: tyrosine kinase inhibitors for the treatment of pancreatic neuroendocrine tumors. AB - Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) show limited sensitivity to cytotoxic agents, requiring the search for novel therapies. Recently, data from a phase III trial demonstrated that sunitinib produces a clinically significant improvement in progression-free survival in patients with unresectable, advanced, or metastatic GEP-NETs. Based on this finding, sunitinib became the first targeted drug approved for the treatment of GEP-NETs, paving the way for the approval of other anticancer agents in this drug-orphan disease. To date, results of trials involving other multitargeted tyrosine kinase inhibitors, such as sorafenib, the monoclonal antibody bevacizumab, and insulin-like growth factor 1 receptor inhibitors, have also shown promising results, and some are already being studied in phase III trials. This review updates the results of ongoing trials using inhibitors of growth factors and tyrosine kinase receptors involved in the carcinogenesis of GEP-NETs. PMID- 21308479 TI - The heparanase system and tumor metastasis: is heparanase the seed and soil? AB - Tumor metastasis, the leading cause of cancer patients' death, is still insufficiently understood. While concepts and mechanisms of tumor metastasis are evolving, it is widely accepted that cancer metastasis is accompanied by orchestrated proteolytic activity executed by array of proteases. While matrix metalloproteinases (MMPs) attracted much attention, other proteases constitute the tumor milieu, of which a large family consists of cysteine proteases named cathepsins. Like MMPs, some cathepsins are often upregulated in cancer and, once secreted or localized to the cell surface, can degrade components of the extracellular matrix. In addition, cathepsin L is held responsible for processing and activation of heparanase, an endo-beta-glucuronidase capable of cleaving heparan sulfate side chains of heparan sulfate proteoglycans, activity that is strongly implicated in cell dissemination associated with tumor metastasis, angiogenesis, and inflammation. In this review, we discuss recent progress in heparanase research focusing on heparanase-related molecules namely, cathepsin L and heparanase 2 (Hpa2), a heparanase homolog. PMID- 21308480 TI - Role of hyaluronan and CD44 in reactive oxygen species-induced mucus hypersecretion. AB - Mucus hypersecretion is an important manifestation in patients with chronic inflammatory airway diseases. Mucin 5AC (MUC5AC) is a major component of airway mucus. MUC5AC expression is regulated by epidermal growth factor receptor (EGFR) which can be activated by reactive oxygen species (ROS). Hyaluronan (HA), a linear glycosaminoglycan with molecular weights ranging from 2 * 10(5) to 1 * 10(7), is expressed in airway epithelium and can be depolymerized by ROS into hyaluronan fragments. The mechanisms through which fragmented HA exerts its biologic functions have been elucidated by interactions with its receptor CD44. The aim of our study was to examine the role of HA and CD44 in ROS-induced EGFR activation and MUC5AC expression. We exposed NCI-H292 cells to ROS generated by xanthine/xanthine oxidase (X/XO). ROS-induced EGFR phosphorylation, which was activated by tissue kallekrein (TK) activation and EGF release. We found ROS promoted CD44 co-immunoprecipitation with EGFR and MUC5AC up-regulation. These effects were mimicked by hyaluronan fragments. All the effects were inhibited by blocking CD44 or EGFR, suggesting that CD44 plays a critical role in ROS-induced MUC5AC up-regulation. These results show that ROS depolymerizes hyaluronan into fragments, and these fragments bind their receptor CD44 to induce TK activation, which cleaves EGF precursors into mature EGF to activate its receptor EGFR. Furthermore, we provide evidence that hyaluronan fragments are sufficient to induce CD44/EGFR interaction and EGFR signaling which lead to MUC5AC expression. The results indicate that the regulation of ROS-induced MUC5AC expression by hyaluronan and CD44 may provide important insights in the mechanism of mucus hypersecretion. PMID- 21308481 TI - Extracellular ATP signaling during differentiation of C2C12 skeletal muscle cells: role in proliferation. AB - Evidence shows that extracellular ATP signals influence myogenesis, regeneration and physiology of skeletal muscle. Present work was aimed at characterizing the extracellular ATP signaling system of skeletal muscle C2C12 cells during differentiation. We show that mechanical and electrical stimulation produces substantial release of ATP from differentiated myotubes, but not from proliferating myoblasts. Extracellular ATP-hydrolyzing activity is low in myoblasts and high in myotubes, consistent with the increased expression of extracellular enzymes during differentiation. Stimulation of cells with extracellular nucleotides produces substantial Ca(2+) transients, whose amplitude and shape changed during differentiation. Consistently, C2C12 cells express several P2X and P2Y receptors, whose level changes along with maturation stages. Supplementation with either ATP or UTP stimulates proliferation of C2C12 myoblasts, whereas excessive doses were cytotoxic. The data indicate that skeletal muscle development is accompanied by major functional changes in extracellular ATP signaling. PMID- 21308482 TI - Why simulation-based team training has not been used effectively and what can be done about it. AB - Advanced medical education simulators are broadly used today to train both technical/procedural and team-based skills. While there is convincing evidence of the benefits of training technical skills, this is not the case for team-based skills. Research on medical expertise could drive the creation of a new regime of simulation-based team training. The new regime includes first the understanding of complex systems such as the hospital and the operating room; then the performance of work-place assessment; thirdly, the deliberate training of weaknesses and team performance skills; and lastly the understanding of the underlying mechanisms of team competence. A new regime of deliberate training proposed by the author, which would need to be evaluated and validated, could elucidate the underlying mechanisms of team competence while providing evidence of the effect of simulation-based team training. PMID- 21308483 TI - Dissection properties and mechanical strength of tissue components in human carotid bifurcations. AB - Carotid artery dissections can be triggered by several factors. The underlying biomechanical phenomena and properties are unclear. This study investigates the dissection properties of 62 human carotid bifurcations using two experimental methods: direct tension and peeling tests. Direct tension tests study the mechanical strength of the tissue components in radial direction, while peeling tests quantify the fracture energy required to propagate a dissection in a tissue. Results show that the interface between the healthy adventitia and media has the highest radial failure stress (132 +/- 20 kPa, mean +/- SD, n = 25), whereas the lowest value occurs between the diseased intima and media (104 +/- 24 kPa, n = 18). The radial tissue strength at the bifurcation is the highest compared with locations that are away from the central region of the bifurcation. Force/width values required to separate the individual layers and to dissect the media in the circumferential direction are always lower than related values in the axial direction, suggesting anisotropic dissection properties. Dissection energies per reference area generated during the peeling tests are also lower for strips in the circumferential direction than for axial strips, and they vary significantly with the location, as shown for the media. Histological investigations demonstrate that interfacial ruptures mainly occur in the media in both types of tests and are 2-5 elastic lamellae away from the external and internal elastic laminae. A remarkably "rougher" dissection surface is generated during axial peeling tests when compared with tests performed in the circumferential direction. PMID- 21308484 TI - Areola and nipple-areola-sparing mastectomy for breast cancer treatment and risk reduction: report of an initial experience in a community hospital setting. AB - BACKGROUND: The use of areola-sparing (AS) or nipple-areola-sparing (NAS) mastectomy for the treatment or risk reduction of breast cancer has been the subject of increasing dialogue in the surgical literature over the past decade. We report the initial experience of a large community hospital with AS and NAS mastectomies for both breast cancer treatment and risk reduction. METHODS: A retrospective chart review was performed of patients undergoing either AS or NAS mastectomies from November 2004 through September 2009. Data collected included patient sex, age, family history, cancer type and stage, operative surgical details, complications, adjuvant therapies, and follow-up. RESULTS: Forty-three patients underwent 60 AS and NAS mastectomies. Forty-two patients were female and one was male. The average age was 48.7 years (range, 28-76 years). Forty mastectomies were for breast cancer treatment, and 20 were prophylactic mastectomies. The types of cancers treated were as follows: invasive ductal (n = 19), invasive lobular (n = 5), ductal carcinoma-in situ (n = 15), and malignant phyllodes (n = 1). Forty-seven mastectomies (78.3%) were performed by inframammary incisions. All patients underwent immediate reconstruction with either tissue expanders or permanent implants. There was a 5.0% incidence of full thickness skin, areola, or nipple tissue loss. The average follow-up of the series was 18.5 months (range, 6-62 months). One patient developed Paget's disease of the areola 34 months after an AS mastectomy (recurrence rate, 2.3%). There were no other instances of local recurrence. CONCLUSIONS: AS and NAS mastectomies can be safely performed in the community hospital setting with low complication rates and good short-term results. PMID- 21308485 TI - Hepatocellular carcinoma expressing cholangiocyte phenotype is a novel subtype with highly aggressive behavior. AB - BACKGROUND: The pathobiological features and surgical outcomes of patients with classical hepatocellular carcinoma (HCC)-expressing cholangiocyte markers that we named dual-phenotype HCC (DPHCC) remain unclear. The purpose of this study was to assess the association between the phenotype and surgicopathologic features of DPHCC. METHODS: A retrospective single-center study was performed on the surgicopathologic features of DPHCC from 1530 consecutive surgical specimens. Immunohistochemical staining was performed with antibodies to hepatocytes (Hep Par 1/pCEA) and cholangiocytes (cytokeratin 19 [CK19]/mucin core protein-1 [MUC 1]). RESULTS: DPHCC accounted for 10.1% (n = 155) of total HCCs. The serum alfa fetoprotein and CA19-9 were elevated in 87.7% (n = 136) and 20.7% (n = 32) of patients, respectively; the former had close correlation with the immunostaining of CK19 (P < 0.01). The combination of immunostaining intensities of CK19 and MUC 1 was significantly associated with tumor size, microvascular invasion, and satellite nodule formation (P < 0.05-0.01). Compared to patients with pure HCC, those with DPHCC had significantly lower overall survival (30.4 +/- 3.7 vs. 43.6 +/- 3.9 months, P < 0.05) and recurrence-free survival (13.2 +/- 2.0 vs. 23.4 +/- 2.5 months, P < 0.01), respectively. Multivariate Cox regression analyses identified CK19-positive expression to be an independent prognostic factor for both overall survival and recurrence-free survival. CONCLUSIONS: DPHCC is a novel surgicopathologic entity that has a highly aggressive behavior and worse postoperative prognosis than pure HCC. Because the morphological features between DPHCC and conventional HCC overlap, we recommend that CK19 be routinely used in the pathological diagnosis of HCC for screening DPHCC. PMID- 21308486 TI - Disparities in reconstruction rates after mastectomy: patterns of care and factors associated with the use of breast reconstruction in Southern California. AB - BACKGROUND: Many factors influence whether breast cancer patients undergo reconstruction after mastectomy. We sought to determine the patterns of care and variables associated with the use of breast reconstruction in Southern California. MATERIALS AND METHODS: Postmastectomy reconstruction rates were determined from the California Office of Statewide Health Planning and Development (OSHPD) inpatient database from 2003 to 2007. International Classification of Disease-9 codes were used to identify patients undergoing reconstruction after mastectomy. Changes in reconstruction rates were examined by calendar year, age, race, type of insurance, and type of hospital using a chi square test. Univariate and multivariate odds ratios (OR) with 95% confidence intervals (95% CI) were estimated for relative odds of immediate reconstruction versus mastectomy only. RESULTS: In multivariate analysis, calendar year, age, race, type of insurance, and type of hospital were statistically significantly associated with use of reconstruction. The proportion of patients undergoing reconstruction rose from 24.8% in 2003 to 29.2% in 2007. Patients with private insurance were 10 times more likely to undergo reconstruction than patients with Medi-Cal insurance (OR 9.95, 95% CI 8.46-11.70). African American patients were less likely (OR 0.58, 95% CI 0.46-0.73) and Asian patients one-third as likely (OR 0.37, 95% CI 0.29-0.47) to undergo reconstruction as Caucasians patients Most reconstructive procedures were performed at teaching hospitals and designated cancer centers. CONCLUSIONS: Although the rate of postmastectomy reconstruction is increasing, only a minority of patients undergo reconstruction. Age, race, type of insurance, and type of hospital appear to be significant factors limiting the use of reconstruction. PMID- 21308487 TI - Dynamic sentinel node biopsy for inguinal lymph node staging in patients with penile cancer: a systematic review and cumulative analysis of the literature. AB - BACKGROUND: Dynamic sentinel node biopsy (DSNB) is used to evaluate the nodal status of patients with clinically node-negative penile carcinoma. Its use is not widespread, and the majority of patients with clinically node-negative disease undergo an elective inguinal lymph node dissection (ILND). However, a prophylactic bilateral ILND is a procedure with approximately 50% of morbidity. The purpose of this review is to evaluate the accuracy of DSNB in penile cancer. METHODS: This is a systematic review and cumulative analysis of studies published between 1966 and 2010. The Medline, Embase, Cancerlit, and American Society of Clinical Oncology abstract databases were searched for published studies on penile cancer and DSNB. The outcomes assessed were: sensitivity, specificity, likelihood ratios, and summary receiver operating characteristics (ROC) curves. RESULTS: Ten articles covering 519 participants were included in the cumulative analysis. The pooled sensitivities and specificities for sentinel node biopsy for detection of metastasis were 77.1 and 100% versus ILND and 87.9 and 100% versus wait and see program. The false-negative rate founded was 3.1% in the ILND group and 3.5% in the wait and see group. CONCLUSIONS: The use of dynamic sentinel lymph node biopsy to detect lymph node metastasis in specialized centers appears to be justified. Addiction of other techniques to DSNB to reduce false-negative results is awaited and must be confirmed by future studies. PMID- 21308488 TI - Evaluating systemic stress response in single port vs. multi-port laparoscopic cholecystectomy. AB - BACKGROUND AND AIMS: Acute-phase proteins and inflammatory cytokines mediate measurable responses to surgical trauma, which are proportional to the extent of tissue injury and correlate with post-operative outcome. By comparing systemic stress following multi-port (LC) and single-incision laparoscopic cholecystectomy (SILC), we aim to determine whether reduced incision size induces a reduced stress response. METHODS: Thirty-five consecutive patients were included, 11 underwent SILC (mean +/- SEM; age 44.8 +/- 3.88 year; BMI 27 +/- 1.44 kg/m(2)) and 24 underwent LC (56.17 +/- 2.80 year; 31.72 +/- 1.07 kg/m(2), p < 0.05). Primary endpoint measures included levels of interleukin-6 and C-reactive protein measured pre- and post-operatively. Length-of-stay (LOS) and postoperative morbidity were secondary endpoints. RESULTS: No statistically significant differences were found between SILC and LC for interleukin-6 and C-reactive protein levels, LOS and duration of surgery. There was also no correlation between systemic stress response and operative parameters. There were no intra operative complications. CONCLUSION: SILC appears to be a safe, feasible technique with potential advantages of cosmesis, reduced incisional pain, and well-being recommending its use. These data indicate no difference in systemic stress and morbidity between SILC and LC. A larger, multi-centred, randomised prospective trial is warranted to further investigate and confirm this finding. PMID- 21308489 TI - Arsenic trioxide induces apoptosis of p53 null osteosarcoma MG63 cells through the inhibition of catalase. AB - This study is aimed at investigating the effect of arsenic trioxide (ATO) on p53 null human osteosarcoma MG63 cells and the mechanisms underlying the effect. Apoptotic cells were detected by flow cytometry with Annexin-V-FITC/PI dual staining. Intracellular ROS was measured by flow cytometry using a cell-based ROS assay kit. Catalase activity and mRNAs were analyzed by ELISA and real-time qRT PCR, respectively. Apoptosis and intracellular ROS of MG63 cells increased in a dose-dependent manner following arsenic treatments. Both were prevented by the presence of the anti-oxidative reagent N-acetyl-L: -cysteine (NAC) or catalase (CAT). Furthermore, the activity and mRNA of catalase were decreased strikingly following arsenic exposure. The present study indicates that p53 null osteosarcoma MG63 cells are susceptible to the ATO; the inhibition of catalase and the resulted intracellular ROS accumulation are an important molecular mechanism under which ATO induces apoptosis of p53-deficient osteosarcoma cells. PMID- 21308490 TI - Heart fatty acid-binding protein may not be an early biomarker for anthracycline induced cardiotoxicity in rabbits. AB - The objective of this study was to investigate the feasibility of using serum heart fatty acid-binding protein (H-FABP) concentrations as an early biomarker for doxorubicin-induced myocardial damage. Forty-four male rabbits were randomly divided into a control (8 rabbits) or one of four doxorubicin groups (8 rabbits in each group). Rabbits in the control group received saline, whereas rabbits in the doxorubicin group received 2 mg/kg doxorubicin weekly for 1-8 weeks. Rabbits in the doxorubicin groups received doxorubicin 2 mg/kg for one (Group 1, 8 rabbits), two (Group 2, 8 rabbits), four (Group 3, 9 rabbits), or eight (Group 4, 11 rabbits) weeks. Echocardiography was performed to measure left ventricular ejection fraction (LVEF), shortening fraction (FS), and E/A ratio. Cardiotoxicity scores were assessed by light microscopy using Billingham's method and also by electron microscopy. Serum H-FABP concentrations were quantified by a rabbit specific enzyme-linked immunosorbent assay. Decreased LVEF, FS, and E/A ratio were detected in Group 4 (P < 0.05). Billingham cardiomyopathy scores of the rabbits in Group 3 were significantly higher (P < 0.05) than those of rabbits in the control group or Groups 1 or 2. Billingham cardiomyopathy scores in Group 4 were the highest of all groups (P < 0.05). Myocardial injury was demonstrable by electron microscopy in rabbits in Groups 2, 3, and 4. Compared with the control group, serum H-FABP concentrations increased only in Group 4 (P < 0.05). Serum H FABP concentrations may not be a sensitive method for assessing early cardiotoxicity of doxorubicin. PMID- 21308491 TI - Heterogeneity of human monocytes: an optimized four-color flow cytometry protocol for analysis of monocyte subsets. AB - Monocytes are central mediators in the development of atherosclerotic plaques. They circulate in blood and eventually migrate into tissue including the vessel wall where they give rise to macrophages and dendritic cells. The existence of monocyte subsets with distinct roles in homeostasis and inflammation suggests specialization of function. These subsets are identified based on expression of the CD14 and CD16 markers. Routinely applicable protocols remain elusive, however. Here, we present an optimized four-color flow cytometry protocol for analysis of human blood monocyte subsets using a specific PE-Cy5-conjugated monoclonal antibody (mAb) to HLA-DR, a PE-Cy7-conjugated mAb to CD14, a FITC conjugated mAb to CD16, and PE-conjugated mAbs to additional markers relevant to monocyte function. Classical CD14(+)CD16(-) monocytes (here termed "Mo1" subset) expressed high CCR2, CD36, CD64, and CD62L, but low CX(3)CR1, whereas "nonclassical" CD14(lo)CD16(+) monocytes (Mo3) essentially showed the inverse expression pattern. CD14(+)CD16(+) monocytes (Mo2) expressed high HLA-DR, CD36, and CD64. In patients with stable coronary artery disease (n = 13), classical monocytes were decreased, whereas "nonclassical" monocytes were increased 90% compared with healthy subjects with angiographically normal coronary arteries (n = 14). Classical monocytes from CAD patients expressed higher CX(3)CR1 and CCR2 than controls. Thus, stable CAD is associated with expansion of the nonclassical monocyte subset and increased expression of inflammatory markers on monocytes. Flow cytometric analysis of monocyte subsets and marker expression may provide valuable information on vascular inflammation. This may translate into the identification of monocyte subsets as selective therapeutic targets, thus avoiding adverse events associated with indiscriminate monocyte inhibition. PMID- 21308492 TI - Importance of a multidisciplinary approach for the treatment of Barrett's esophagus. AB - Barrett's esophagus is a consequence of gastroesophageal reflux disease. Today, it is the most common cause of esophageal adenocarcinoma. Cancer is usually the end results of a cascade of events whereby metaplasia changes into low- and high grade dysplasia and eventually cancer. Today, we have the unique opportunity to block this cascade and avoid the development of esophageal cancer. A multidisciplinary approach with a team composed of radiologists, gastroenterologists, pathologists, and surgeons allows individualization of care and the best results. PMID- 21308493 TI - Antimicrobial therapy of otitis media reduces the incidence of mastoiditis. PMID- 21308494 TI - TLR, NLR Agonists, and Other Immune Modulators as Infectious Disease Vaccine Adjuvants. AB - Vaccines based on attenuated or killed viruses and bacteria are highly effective in preventing infection with a range of pathogens, but can have safety issues. Therefore, a move is underway toward the development of subunit vaccines based on recombinant proteins or naked DNA. However, protein subunit vaccines are typically poorly immunogenic when administered alone and therefore require coadministration with adjuvants to boost the immune response. For many decades, very little progress was made in understanding the mechanism of action of adjuvants, but recently several significant breakthroughs have occurred in this area. The binding of pathogen-derived molecules to different immune sensors, including Toll-like receptors (TLR), nucleotide-binding oligomerization domain like receptors (NLR), and retinoic acid-inducible gene (RIG)-1-like receptors (RLR), activates important innate immune pathways and provides not only an understanding of how current vaccines and adjuvants work, but also potential targets for novel adjuvant development. PMID- 21308495 TI - The role of antibiotics in the management of patients with acute necrotizing pancreatitis. AB - Our understanding of the role of antibiotics in the management of patients with pancreatic necrosis has changed over the past 5 years. Initial studies suggested that antibiotics were useful in preventing infection of necrosis, septic complications, and mortality in patients with acute pancreatitis; however, more recent, better-designed studies established that prophylactic antibiotics are not helpful. In the absence of infection, sterile necrosis is treated conservatively. With insufficient evidence to recommend antibiotics, these agents should be reserved to treat established infection of pancreatic necrosis. Infected necrosis is treated by targeting microbes with pancreatic-penetrating antibiotics (eg, carbapenems, quinolones in combination with metronidazole, or high-dose cephalosporins). If the patient with infected necrosis remains septic or deteriorates, surgical intervention should be performed urgently. Stable patients with infected necrosis can be managed more conservatively in a closely monitored environment. Recent studies suggest that many patients can clear the infection with antibiotics, but even if they do not clear the infection, delay in surgery decreases the mortality rate. Delaying surgery by using antibiotics may allow use of less invasive procedures if drainage is needed. The timing and method of interventions must be individualized based on the patient's condition, anatomic complications, patient's preference after informed consent, and expertise available at the institution. PMID- 21308496 TI - Current Views on the Clinical Relevance of Blastocystis spp. AB - Blastocystis is an enteric protistan parasite of uncertain clinical relevance. Recent studies indicate that the parasite is a species complex and humans are potentially hosts to nine Blastocystis subtypes, most of which are zoonotic. Subtype 3 is the most common in prevalence studies, followed by subtype 1. Laboratory diagnosis is challenging; the currently recommended diagnostic approach is trichrome staining of direct smears coupled with stool culture. Polymerase chain reaction testing from stools or culture is useful for determining Blastocystis subtype information. The controversial pathogenesis of Blastocystis is attributed to subtype variations in virulence; although current studies seem to support this idea, evidence suggests other factors also contribute to the clinical outcome of the infection. Clinical signs and symptoms of blastocystosis include abdominal pain, diarrhea, bloating, and flatulence. Extraintestinal manifestations, predominantly cutaneous, also were reported. In vitro and animal studies shed new light on the pathobiology of Blastocystis. PMID- 21308497 TI - Drug-resistant tuberculosis in sub-saharan Africa. AB - Drug-resistant tuberculosis (DRTB) is an emerging infectious disease threat to sub-Saharan Africa (SSA), particularly in the regions hit hardest by the HIV epidemic. Numerous challenges face clinicians and public health officials tasked with combating DRTB in SSA. These include difficulties providing effective diagnosis, treatment, and prevention of this illness. Furthermore, combating DRTB requires addressing various legal and ethical complexities. A sustained commitment to investigating as well as implementing new diagnostic, therapeutic, and preventative interventions is essential to defeating this threat. PMID- 21308498 TI - Non-AIDS-Defining Malignancies in Patients with HIV in the HAART Era. AB - The introduction of highly active antiretroviral therapy (HAART) has drastically changed the scope and spectrum of diseases associated with HIV, shifting from AIDS-related to non-AIDS-related diseases. Studies linking HIV/AIDS databases to cancer registries have shown a dramatic decrease in AIDS-related malignancies and a steady increase in non-AIDS-defining malignancies (NADM). We review the causes underlying the rise in incidence of NADM and the clinical presentation, pathology, and treatment outcomes of the four most commonly encountered NADM in the HAART era. Meta-analysis of published studies show an increase in NADM over the general population, mostly among infection-related cancers such as anal cancer, Hodgkin lymphoma, and liver cancer. Among the non-infection-related cancers, lung and skin cancers predominate. The overall effect of HAART on NADM is unsettled. As HIV-infected individuals survive longer, better screening strategies are needed to detect cancer earlier, and prospective data are needed to assess the impact of HAART on cancer outcomes. PMID- 21308499 TI - The HIV-Infected Adolescent. AB - HIV-infected adolescents represent a unique, yet diverse, population requiring specialized medical and psychosocial HIV care. Perinatally infected and behaviorally infected adolescents often have differing therapeutic needs, but may share common difficulties, including medication nonadherence, high-risk sexual behavior, psychosocial stressors, and concomitant psychiatric disorders. Addressing these needs within a culturally sensitive framework and in the context of a population-specific approach to treatment is paramount to optimizing care. Harm reduction for this group to maximize their health and limit HIV transmission to others is also critical with respect to the rising incidence of newly diagnosed HIV-positive adolescents. Implementing a formal, multidisciplinary program that involves individual youths and their families for improved transition to adult HIV care will afford such adolescents a better chance for a healthy adulthood. PMID- 21308500 TI - Renal Transplantation in HIV-Positive Recipients. AB - About 1% of all patients with end-stage renal disease in the United States are infected with HIV. With the introduction of highly active antiretroviral therapy (HAART), HIV death rates have declined 80%, and chronic diseases resulting from HIV have replaced opportunistic infections as the leading cause of death among HIV-infected patients. Traditionally, HIV infection has been considered an absolute contraindication to solid-organ transplantation. However, in the context of improved survival, the role for kidney transplantation among HIV-positive patients is currently being revisited. This article discusses long-term outcomes after kidney transplantation in the HAART era and management strategies for the HIV-positive kidney transplant recipient. PMID- 21308501 TI - The next era of HCV antiviral therapy finally begins: part 1. PMID- 21308502 TI - The next era of HCV antiviral therapy finally begins: part 2. PMID- 21308503 TI - The role of adenovirus in respiratory tract infections. AB - Adenovirus plays a significant role in respiratory tract disease in pediatric and adult patients. It has been linked to outbreaks and epidemics in various patient populations, resulting in considerable morbidity and mortality. In this article, we discuss the epidemiology, pathogenesis, respiratory tract illnesses and complications, and roles of potential treatment options. The role of the past oral adenovirus vaccine and the military implications of its withdrawal from routine use in military recruits is discussed as well. PMID- 21308504 TI - Topical antibiotic therapy of chronic rhinosinusitis. AB - Many different treatment options for chronic rhinosinusitis (CRS) exist, but questions remain regarding the best options. Although oral and intravenous antimicrobial therapies have traditionally been prescribed to manage CRS, topical administration of these agents has gained increasing popularity over the past few years. Topical antimicrobial agents are preferable because of their ability to localize delivery to the sinonasal mucosa and minimize the systemic effects seen with oral agents. This quality is especially important in treatment of biofilms, where higher concentrations of antibiotics are usually required. This article gives a brief overview of CRS and provides a summary of recent studies using topical agents for treatment of bacterial and fungal sinusitis. PMID- 21308505 TI - Recent advances in the understanding and management of kawasaki disease. AB - Kawasaki disease (KD) is an acute systemic inflammatory illness of childhood that can result in coronary artery aneurysms, myocardial infarction, and sudden death. Clinical and epidemiologic data point to an unknown infectious agent as the cause. We discovered that an oligoclonal IgA immune response is present in arterial tissue in acute KD. Synthetic versions of prevalent IgA antibodies in the KD arterial wall identify cytoplasmic inclusion bodies in acute KD ciliated bronchial epithelium and other inflamed KD tissues. Light and electron microscopic studies show that the inclusion bodies are consistent with aggregates of viral protein and RNA, and are likely formed by the KD etiologic agent. KD susceptibility is likely to be polygenic. Treatment of gammaglobulin nonresponders usually consists of additional intravenous immunoglobulin, methylprednisolone, and/or infliximab. Additional data regarding KD pathogenesis are urgently needed to provide other targets for therapy for those patients at highest risk of developing coronary artery abnormalities. PMID- 21308506 TI - Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infection (PANDAS): a Controversial Diagnosis. AB - Despite more than a decade of studying pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS), it is still not possible to confirm its existence and whether it is a poststreptococcal autoimmune disorder. Many controversies remain: the diagnostic criteria have not been validated, evidence of autoimmunity remains inconclusive, evidence of a genetic predisposition is weak, and streptococcal infections are common in childhood and could represent only a trigger of exacerbations of tics and obsessive-compulsive disorder. Patients who fit the PANDAS criteria appear to represent a subgroup of children with chronic tic disorder and/or obsessive compulsive disorder who may experience symptom exacerbations after group A beta hemolytic streptococci infections; however, those infections are not the sole or even the most common antecedent of exacerbations. There is not enough evidence to support PANDAS as a unique clinical entity. PMID- 21308507 TI - beta-Lactamase-Producing Bacteria in Upper Respiratory Tract Infections. AB - beta-Lactamase-producing bacteria (BLPB) can play an important role in respiratory infections. They can have a direct pathogenic impact in causing the infection as well as an indirect effect through their ability to produce the enzyme beta-lactamase. BLPB not only may survive penicillin therapy, but as demonstrated by in vitro and in vivo studies, can also protect other penicillin susceptible bacteria from penicillin by releasing the free enzyme into their environment. The clinical in vitro and in vivo evidence supporting the role of these organisms in the increased failure rate of penicillin in eradication of these infections and the implication of that increased rate on the management of infections is discussed. PMID- 21308508 TI - Epidemic of Sexually Transmitted Hepatitis C Virus Infection Among HIV-Infected Men. AB - Sexual contact is thought to be an inefficient mode of hepatitis C virus (HCV) transmission. However, reports of sexually transmitted HCV infection among HIV infected men who have sex with men (MSM) began to appear in 2004. The patients were of early middle age with well-controlled HIV infection, participated in unprotected receptive sex, and frequently used noninjection recreational drugs. Molecular studies showed evidence of clusters of transmission between patients in different countries in Europe. Spontaneous clearance was relatively rare, but treatment with pegylated interferon and ribavirin resulted in cure in about two thirds of patients. Of concern was the finding of moderately advanced fibrosis during the early stages of HCV infection. HIV-infected MSM are a new risk group for HCV infection and so should be screened regularly for HCV infection. PMID- 21308509 TI - Partner Concurrency and the STD/HIV Epidemic. AB - Conceptually and theoretically, it is easy to see how short gaps and concurrent partnerships fuel the spread of sexually transmitted infections (STI) and HIV in populations. The consequences of concurrency are bounded by the duration of the infectious period and by the relationships between concurrent partnerships and other dimensions of sexual behavior. Consequently, it is difficult to predict how concurrent partnerships or short gaps may be related to the spread of STI and HIV in a particular epidemiologic context in empirical reality. In recent years, analyses of sexual behavior data collected through nationally representative surveys revealed similar prevalences of concurrent sexual partnerships in Western populations. The association between concurrent sexual partnerships and STI/HIV risk is complicated. At the population level, recent findings suggest that the ecological association between polygyny and HIV prevalence is negative at the country level and at the sub-national level. To address the need for agreed-upon standard definitions and measures of concurrent sexual partnerships, which will facilitate comparisons across time and settings, the Joint United Nations Program on HIV/AIDS (UNAIDS) Reference Group on Estimates, Modelling, and Projections convened a meeting in April 2009. The recommendations developed at this meeting include suggestions for a definition, indicators, and measures of concurrency. PMID- 21308510 TI - Evaluation and Management of Syphilis in the HIV-Infected Patient. AB - Rates of syphilis continue to increase in the United States and HIV-infected patients make up a large proportion of cases. The interaction between syphilis and HIV is complex and still incompletely understood. Although diagnosis and management of HIV-infected patients with syphilis is, in general, similar to HIV uninfected patients, the former may be at increased risk for complications. Recent data suggest that HIV-induced immunosuppression may alter the course of syphilis and that highly active antiretroviral therapy may have a beneficial effect on syphilis outcomes. Prevention strategies consisting of sexual risk assessments, condom use, treatment of infected partners, yearly screening for syphilis of all HIV-infected patients, and enhanced clinical and serologic follow up of treated HIV-infected patients are critical components of a comprehensive approach to care. PMID- 21308511 TI - Episodic acyclovir therapy as part of syndromic management among men presenting with genital ulcer disease: is there benefit? PMID- 21308512 TI - Clinical trial report-polymyxin B hemoperfusion: effective, or not? PMID- 21308513 TI - Role of echocardiogram in decision making for surgery in endocarditis. AB - Infective endocarditis is a serious disease that carries significant morbidity and mortality. Adequate treatment is based on a high degree of clinical suspicion, accurate microbiologic diagnosis, and high-quality imaging. Echocardiography has been shown to be a fundamental tool for diagnosis and management. Currently accepted Duke criteria include blood cultures and echocardiography. Transthoracic and transesophageal echocardiography play a critical role in the decision-making process, especially when surgical treatment is contemplated. Because infective endocarditis is considered a medical and surgical disease, and considering that the current rate of surgery is about 50%, echocardiography has definite value in preoperative diagnosis and surgical planning, intraoperative confirmation of lesions and quality of repair or replacement before and after cardiopulmonary bypass, and postoperative assessment. PMID- 21308514 TI - Early identification of sepsis. AB - Early diagnosis is crucial to reduce morbidity and mortality from sepsis. Clinical suspicion is the first step to diagnosis, and necessitates meticulous history taking and complete clinical examination. Special attention should be paid to identifying foci of infection. Biomarkers of host response-including acute phase proteins, procalcitonin, and various cytokines-may be useful in the diagnosis and management of patients with sepsis. Rapid and reliable detection of pathogens and their antibiotic susceptibility patterns is also of utmost importance. Many new techniques have been developed to shorten the time required for pathogen detection, including nucleic acid-based technologies (eg, polymerase chain reaction, microarrays, and hybridization). The detection of pathogen related antigens is another approach that is useful in the diagnosis of fungal infections, targeting fungal cell wall components such as galactomannan and (1 >3)-beta-D-glucan. PMID- 21308515 TI - Early antimicrobial therapy in severe sepsis and septic shock. AB - The advent of modern antimicrobial therapy following the discovery of penicillin during the 1940s yielded remarkable improvements in the case fatality rates of serious infections, including septic shock. Since then, pathogens have continuously evolved under selective antimicrobial pressure, resulting in a lack of additional significant improvement in clinical effectiveness of antimicrobial therapy of septic shock despite ever more broad-spectrum and potent drugs. In addition, although substantial effort and money were expended on the development of novel nonantimicrobial therapies of sepsis in the past 30 years, clinical progress in this regard has been limited. This article explores the possibility that the key to significant improvement in the outcome of septic shock may lie, in great part, with improvements in delivery of existing antimicrobials. Recognizing the role of delays in administration of antimicrobial therapy in the poor outcomes of septic shock is central to this effort. PMID- 21308516 TI - Principles of source control in the early management of sepsis. AB - Source control refers to the spectrum of physical measures that are undertaken to control a focus of infection, and to facilitate restoration of optimal anatomy and physiology. These measures are classified as drainage-the evacuation of infected liquid through the creation of a controlled sinus or fistula, debridement-the physical removal of necrotic infected tissue, device removal, and the definitive measures that comprise the process of reconstruction and rehabilitation. Effective and timely source control is critical to the successful management of life-threatening infection. This article reviews the principles of diagnosis and source-control management, and their application to common infections that result in severe sepsis and septic shock. PMID- 21308517 TI - Early fluid resuscitation. AB - Solid evidence exists that fluid therapy must be started as a first-line treatment in all patients with septic shock as soon as hypotension is detected, with the goal of rapidly restoring tissue perfusion. Crystalloids or colloids can be used for initial fluid therapy, and albumin should be reserved for patients with patent or supposed hypoalbuminemia. Once fluid administration is started, its effect must be carefully monitored. In the early stages, appropriate monitoring should ensure that fluid resuscitation actually increases cardiac preload, mean arterial pressure, and tissue oxygenation. In later stages, monitoring should help to avoid fluid overload. For this purpose, the end-point of fluid therapy should not be the static values of preload indicators, but rather the disappearance of indicators of preload responsiveness. Finally, the risk of fluid overload must always be kept in mind, especially in case of lung injury. PMID- 21308518 TI - Adjunct therapy for sepsis: how early? AB - Sepsis is a leading cause of death worldwide. The management of patients is primarily based on curing the infectious process with anti-infective drugs and/or surgical drainage. Simultaneously, treatment includes optimization of oxygen use by tissues via appropriate oxygen therapy and respiratory and hemodynamic management. At best, initiating appropriate anti-infective and symptomatic treatments should lead to patient improvement within a few hours. Activated protein C and hydrocortisone are the only two available adjunct therapies for sepsis. These treatments should optimally be started within 24 hours of the onset of shock. They should be initiated in those patients who did not adequately respond after 6 hours of optimal anti-infective and symptomatic treatments. PMID- 21308519 TI - The resuscitation package in sepsis. AB - Sepsis and its attendant complications are commonly encountered in the intensive care unit. Early recognition of sepsis is critical because it allows for rapid deployment of a multifaceted resuscitation package. The cornerstones of sepsis management are antibiotic therapy, source control, and hemodynamic resuscitation. In select patients, ancillary therapies are indicated, such as activated protein C, corticosteroids, and glycemic control. Given the complexity of sepsis management, optimal care can be delivered as a bundle-a protocol encompassing the above interventions. The evidence behind the various components of sepsis management are reviewed here. PMID- 21308520 TI - Nonbacterial myositis. AB - Infectious myositis is defined as an infection of a skeletal muscle. Infectious myositis is most commonly caused by bacteria; however, a variety of viral, parasitic, and fungal agents may also cause myositis. The pathogenesis of nonbacterial infectious myositis is via direct or hematogenous infection of the musculature or immune mechanisms. Symptoms typically include muscular pain, tenderness, swelling, and/or weakness. The diagnosis of the specific microbe is often suggested by the presence of concordant clinical signs and symptoms, a detailed medical and travel history, and laboratory data. For example, immunocompromised hosts have a heightened risk of fungal myositis, whereas the presence of a travel history to an endemic location and/or eosinophilia may suggest a parasitic cause. Definitive diagnosis requires detecting the organism by specific laboratory testing including serologies, histopathology, and/or cultures. Treatment entails antimicrobial agents against the pathogen, with consideration for surgical drainage for focal purulent collections within the musculature. PMID- 21308521 TI - Clostridial myonecrosis: new insights in pathogenesis and management. AB - Clostridial myonecrosis remains an important cause of human morbidity and mortality worldwide. Although traumatic gas gangrene can be readily diagnosed from clinical findings and widely available technologies, spontaneous gas gangrene is more insidious, and gynecologic infections due to Clostridium sordellii progress so rapidly that death often precedes diagnosis. In each case, extensive tissue destruction and the subsequent systemic manifestations are mediated directly and indirectly by potent bacterial exotoxins. The management triumvirate of timely diagnosis, thorough surgical removal of necrotic tissue, and treatment with antibiotics that inhibit toxin synthesis remains the gold standard of care. Yet, despite these measures, mortality remains 30% to 100% and survivors often must cope with life-altering amputations. Recent insights regarding the genetic regulation of toxin production, the molecular mechanisms of toxin-induced host cell dysfunction, and the roles of newly described toxins in pathogenesis suggest that novel prevention, diagnostic, and treatment modalities may be on the horizon for these devastating infections. PMID- 21308522 TI - Staphylococcal toxic shock syndrome: mechanisms and management. AB - Staphylococcal toxic shock syndrome is a rare complication of Staphylococcus aureus infection in which bacterial toxins act as superantigens, activating very large numbers of T cells and generating an overwhelming immune-mediated cytokine avalanche that manifests clinically as fever, rash, shock, and rapidly progressive multiple organ failure, often in young, previously healthy patients. The syndrome can occur with any site of S. aureus infection, and so clinicians of all medical specialties should have a firm grasp of the presentation and management. In this article, we review the literature on the pathophysiology, clinical features, and treatment of this serious condition with emphasis on recent insights into pathophysiology and on information of relevance to the practicing clinician. PMID- 21308523 TI - Clinical Trials Report: Progress Toward an Effective Malaria Vaccine: RTS,S/ASO1B and RTS,S/ASO2A. PMID- 21308524 TI - Update on dengue: epidemiology, virus evolution, antiviral drugs, and vaccine development. AB - Dengue virus is the most widespread geographically of the arboviruses and a major public health threat in the tropics and subtropics. Scientific advances in recent years have provided new insights about the pathogenesis of more severe disease and novel approaches into the development of antiviral compounds and dengue vaccines. Phylogenetic studies show an association between specific subtypes (within serotypes) and severity of dengue. The lack of association between maternal antibodies and development of severe dengue in infants in a recent study has called for the rethinking or refinement of the current antibody-dependent enhancement theory of dengue hemorrhagic syndrome in infancy. Such studies should stimulate new directions of research into mechanisms responsible for the development of severe dengue. The life cycle of dengue virus readily shows that virus entry and replication can be targeted by small molecules. Advances in a mouse model (AG 129 mice) have made it easier to test such antiviral compounds. The efforts to find specific dengue inhibitors are intensifying and the tools to evaluate the efficacy of new drugs are now in place for rapid translation into trials in humans. Furthermore, several dengue vaccine candidates are in development, of which the chimeric dengue/yellow fever vaccine has now entered phase 3 trials. Until the availability of a licensed vaccine, disease surveillance and vector population control remain the mainstay of dengue prevention. PMID- 21308525 TI - Drug-Resistant Malaria: The Era of ACT. AB - As drug-resistant falciparum malaria has continued to evolve and spread worldwide, artemisinin-based combination therapies (ACT) have become the centerpiece of global malaria control over the past decade. This review discusses how advances in antimalarial drug resistance monitoring and rational use of the array of ACTs now available can maximize the impact of this highly efficacious therapy, even as resistance to artemisinins is emerging in Southeast Asia. PMID- 21308526 TI - New vaccines for Japanese encephalitis. AB - Epidemics of encephalitis occurring throughout much of Asia are caused by Japanese encephalitis virus (JEV), a flavivirus maintained in a zoonotic cycle and transmitted by the mosquito, Culex tritaeniorhynchus. Resident populations, including short-or long-term visitors to enzootic regions, are at risk for Japanese encephalitis (JE) infection and disease. For the past several decades, effective killed viral vaccines prepared in tissue culture or mouse brain have been used to immunize travelers and residents of affected countries. Cost, efficacy, and safety concerns led to the development of a single-dose live attenuated virus vaccine (SA14-14-2) and more recently, to the licensure in the United States, Europe, and Australia of a purified inactivated, tissue culture based JE vaccine (IC51; Intercell AG, Vienna, Austria) and the soon-to-be licensed live-attenuated yellow fever-JE chimeric vaccine (ChimeriVax-JE; Sanofi Pasteur, Lyon, France). Safe and effective JE vaccines are now available to the entire at-risk population and should greatly diminish the burden of disease. PMID- 21308527 TI - Influenza in travelers: epidemiology, risk, prevention, and control issues. AB - Influenza is the most frequent travel related infection preventable by universally available vaccines, but preventive measures were neglected until recently. Since the spread of pandemic (H1N1) 2009, various public health measures have been promoted first to contain, then to mitigate, the pandemic. Some of these measures contradicted recommendations issued by the World Health Organization and were of questionable efficacy. However, travelers may benefit from targeted recommendations on influenza risk reduction (eg, by social distancing or immunization). These recommendations are particularly indicated for those with an increased personal risk profile and for those likely to be exposed to influenza patients. PMID- 21308528 TI - Dermatologic presentations of tropical diseases in travelers. AB - Dermatoses are one of the three most common presenting health care problems in returning travelers. The spectrum of travel-related dermatoses is broad, and includes tropical, cosmopolitan, and environmental skin diseases. Bacterial infections are the main cause of skin consultations in returning travelers. Most of these infections are not specific to the tropics and are the consequences of arthropod bites. Conversely, tropical skin infections are less commonly observed. Knowledge of imported dermatoses among Western physicians is limited, even though it is becoming increasingly important that doctors be able to recognize and differentiate between the diverse varieties of diseases. This review highlights the most recent developments regarding dermatologic presentations of tropical diseases in travelers in order to provide more effective pre-travel counseling and an up-to-date aid to post-travel diagnosis and treatment. PMID- 21308529 TI - Global Impact of Multidrug-Resistant Pulmonary Tuberculosis Among HIV-Infected and Other Immunocompromised Hosts: Epidemiology, Diagnosis, and Strategies for Management. AB - Multidrug-resistant (MDR) tuberculosis (TB), or TB caused by strains of Mycobacterium tuberculosis resistant to at least isoniazid and rifampicin, represents a major threat to global TB control. Comprising more than 5% of all TB cases annually worldwide, these cases require treatment duration of 2 years on average with expensive and toxic second-line anti-TB drugs. Cure rates are far lower and mortality far higher than for drug-susceptible TB, particularly if patients are coinfected with HIV. Use of rapid diagnostic tools and assessment of risk factors for MDR TB, as well as rapid initiation of MDR TB treatment as recommended by the World Health Organization, including use of appropriate empiric regimens as necessary, is essential to achieving good outcomes from treatment. Rapid initiation of antiretroviral therapy (ART) for those with HIV coinfection, as well as strategic management of overlapping side effects from ART and first and second-line drugs for treating MDR TB to maintain patients on treatment are critical to patient survival and achieving good treatment outcomes. Employing sensible infection control practices in the context of diagnosis and treatment is essential to reducing transmission of MDR TB strains among patient populations and healthcare personnel. PMID- 21308530 TI - Pulmonary nontuberculous mycobacterial disease: new insights into risk factors for susceptibility, epidemiology, and approaches to management in immunocompetent and immunocompromised patients. AB - Nontuberculous mycobacteria (NTM) are ubiquitous in the environment and cause a wide range of diseases in humans. Pulmonary involvement, the most common disease manifestation of NTM infection, is being increasingly encountered in clinical settings. In addition, specific phenotypic and genetic characteristics of persons predisposed to contract pulmonary NTM disease are now beginning to be recognized. Prior to treatment, patients should meet clinical and microbiologic criteria for NTM disease. Treatment involves prolonged courses of antibiotics in various combination regimens that are often discontinued because of serious side effects. In some cases, complete cure of pulmonary disease is difficult to achieve. Rather, clinical improvement may be a more feasible goal. Surgical treatment is warranted for select patients. PMID- 21308531 TI - H1N1 Influenza Pandemic of 2009 Compared With Other Influenza Pandemics: Epidemiology, Diagnosis, Management, Pulmonary Complications, and Outcomes. AB - Influenza pandemics are complex events that have occurred frequently throughout human history, three during the past century alone. Now the world is facing the first 21st century pandemic, and the comparison among them is essential to identify common epidemiologic patterns, clinical characteristics, and outcomes. The evolution of medicine, including diagnostic and treatment options, the critical care advances, and global responses are new interventions that could modify the general outcome of the pandemic. Learning from past and current events could lead to a plan for prompt and efficient response in future pandemics and may be help us to predict the unpredictable. PMID- 21308532 TI - What's Behind the Increasing Rates of Coccidioidomycosis in Arizona and California? AB - The number of cases of symptomatic coccidioidomycosis reported in the endemic regions of California and Arizona has increased over the past two decades. In California, the southern San Joaquin Valley has seen a dramatic increase, with rates of symptomatic illness of more than 150 per 100,000 of population in Kern County. In Arizona, almost 5,000 cases are now reported yearly. In contrast to California, the coccidioidal endemic region in Arizona is also the most populous region of the state, and Arizona now accounts for 60% of all cases reported in the United States. Reasons for these increases appear to be multifactorial. Possible etiologies include climate change, changes in local exposure, an increase in the number of individuals susceptible to infection living in the endemic region, and increased testing and reporting. None of these factors are mutually exclusive and none has been clearly established as the etiology for the increase. PMID- 21308533 TI - Aspergillus infections in the head and neck. AB - Aspergillus is a chronic colonizer as well as a nidus of infection in the sinuses and ears. In the sinuses, the severity of the disease is classified by the invasiveness of the infection. Invasive fungal sinusitis varies in its presentation based upon the infective organism and shows reduced morbidity if identified early, which requires a high index of suspicion. Allergic fungal sinusitis was recently further classified using a radiologic staging system and was proven to have symptomatic improvement with the concomitant use of surgery and immunotherapy. Finally, fungal ball appears to be a chronic problem that is usually cured with surgery. Aspergillus in the ear is a relatively common problem often related to prolonged antibiotic use and almost always successfully treated with topical antifungals. PMID- 21308535 TI - Clinical trial report: is it safe to continue anticoagulation therapy in patients with infective endocarditis? PMID- 21308534 TI - Diagnosing Vaginal Infections: It's Time to Join the 21st Century. AB - Vaginal infections are one of the most common reasons for medical healthcare visits in the United States and Western Europe. These diseases are also significantly associated with HIV acquisition in resource-constrained settings throughout the world. However, despite ample opportunity to improve diagnosis, and therefore management, of vaginitis and vaginosis, the healthcare community continues to rely on diagnostic methods with poor performance characteristics. This state of affairs results in part from the lack of a public health mandate to reduce the burden of these infections in women. Without such a mandate, there is a lack of funding for reimbursement for more sensitive and specific diagnostic assays. Sensitive assays do exist for these infections, and their use should be encouraged when appropriate for clinical care. PMID- 21308536 TI - Clinical trial report: treatment of cryptococcal meningitis in the developing world. PMID- 21308537 TI - Clinical and microbiologic features of multivalvular endocarditis. AB - Multivalvular endocarditis accounts for 15% of all endocarditis. The mechanisms of spread of the infection differs whether endocarditis is only left-sided (involving both the mitral and aortic valves) or bilateral. In left-sided bivalvular endocarditis, it is often a secondary mitral lesion following a primary aortic endocarditis. Multivalvular endocarditis often results in severe and extensive cardiac lesions, well described at echocardiography and frequently responsible for severe heart failure. Patients often need surgery, which consists of radical debridement of all the infected tissue with reconstruction using different types of prostheses; therefore, the surgery may be very complex. The goal should be an early diagnosis of endocarditis to avoid spread of the infection to more than one valve, to improve the prognosis for those patients. PMID- 21308538 TI - Molecular methods for diagnosis of infective endocarditis. AB - Infective endocarditis (IE) is a life-threatening disease associated with high mortality. Conventional microbiologic diagnosis is based mainly on culture dependent methods that often fail because of previous antibiotic therapy or the involvement of fastidious or slowly growing microorganisms. In recent years, molecular techniques entered the field of routine diagnostics. Amplification based methods proved useful for detection of microorganisms in heart valve tissue. More recently, they were applied to blood samples from patients with IE. Direct detection of microorganisms in valve specimens by fluorescence in situ hybridization allowed identification of the causative agent and simultaneous visualization of complex microbial communities. These techniques will gain more importance in the near future, provided that procedures are standardized and results are interpreted with caution. With this review, we intend to give an overview of the impact and limitations of molecular techniques for the diagnosis of IE, including a focus on recent developments. PMID- 21308539 TI - Is there a role for antiplatelet therapy in infective endocarditis? A review of current scientific evidence. AB - Recently, interest has emerged regarding adjuvant antiplatelet therapy in infective endocarditis (IE) and its impact on clinical outcomes. Despite ongoing research, the role of antiplatelet therapy in this setting remains unclear. Generally, investigations of IE are limited by the low incidence of the disease, practical issues related to diagnosis, and the highly variable latency period between symptom onset and definitive diagnosis. This article reviews the rationale for using antiplatelet therapy in the setting of IE and the contemporary literature that investigates its use. PMID- 21308540 TI - Mycobacterial prosthetic valve endocarditis. AB - Prosthetic valve endocarditis (PVE) due to mycobacteria is a rare but frequently fatal complication that may occur early after the surgical procedure, or even years later. Infection has been described with both mechanical and biologic valvular prosthesis. The most commonly implicated mycobacterial species belong to the rapid-grower group (M. chelonei, M. fortuitum, and M. abscessus) of nontuberculous mycobacteria (NTM). The source of infection in this context is thought to be nosocomial, likely related to preoperative or intraoperative contamination of the prosthesis by contact with aqueous solutions containing the organisms. These infections are difficult to diagnose because blood cultures are often negative. Clinically, it is important to recognize the possibility of NTM PVE in the differential diagnosis of culture-negative patients who develop signs and symptoms of endocarditis, whether they present early or late in onset after the surgical procedure. These patients should be treated with surgical removal of the infected valve, followed by adequate antimicrobial therapy based on the susceptibility of the species isolated from the valve or perivalvular tissue culture. In a significant number of patients, however, an unstable hemodynamic condition ensues, precluding surgical intervention, and therefore leading to a high mortality rate. PMID- 21308541 TI - Modulation of brain injury as a target of adjunctive therapy in bacterial meningitis. AB - Despite effective antimicrobial therapy, mortality and morbidity from bacterial meningitis remain unacceptably high. Meningitis deaths occur as a consequence of intracranial and systemic complications. The neurologic and otologic sequelae reflect structural injury to brain and cochlear tissues. Over the past decade, experimental studies have demonstrated that meningitis-related vascular and cortical injury is largely caused by the massive neutrophilic inflammatory reaction, whereas hippocampal and cochlear injury is driven by both the host response and bacterial toxins. The benefit of adjunctive corticosteroid therapy proves the principle that the key to improve clinical outcome is combining antibiotics with drugs directed against pathophysiologically relevant targets; its limitations in efficacy and applicability highlight the need for novel adjunctive therapies. Promising targets were identified recently through animal studies, and include limiting the release of toxic bacterial products (by using nonbacteriolytic antibiotics) and interfering with the generation of host-derived cytotoxins (by using neutrophil apoptosis-inducing agents). PMID- 21308542 TI - Treatment of Drug-resistant Pneumococcal Meningitis. AB - The approach to therapy in patients with pneumococcal meningitis has changed considerably over the past 20 years. Given the emergence of pneumococcal strains that are intermediately susceptible or highly resistant to penicillin, penicillin is not recommended as empiric therapy for presumed pneumococcal meningitis; the combination of vancomycin and a third-generation cephalosporin (either cefotaxime or ceftriaxone) should be used, pending isolation of the organism and in vitro susceptibility testing. For patients with pneumococcal meningitis caused by highly penicillin- or cephalosporin-resistant strains, the addition of rifampin can be considered if the organism is susceptible in vitro, the expected clinical or bacteriologic response is delayed, or the pneumococcal isolate has a cefotaxime or ceftriaxone minimal inhibitory concentration greater than 4 MUg/mL. Meropenem is not a good option for monotherapy of highly penicillin- or cephalosporin-resistant strains, but use of a fluoroquinolone with in vitro activity against Streptococcus pneumoniae (specifically moxifloxacin) is an option in patients failing standard therapy; if used, however, it should be combined with a third-generation cephalosporin or vancomycin. Newer glycopeptides, daptomycin, and linezolid require further study to determine their efficacy in patients with pneumococcal meningitis. PMID- 21308543 TI - Mycoplasma pneumoniae: Innocent Bystander or a True Cause of Central Nervous System Disease? AB - The consistency with which Mycoplasma pneumoniae has been implicated as a cause of encephalitis, and the increased incidence of central nervous system (CNS) disease observed during M. pneumoniae respiratory outbreaks, support the role of M. pneumoniae as a CNS pathogen. Three pathophysiologic mechanisms have been proposed: direct infection, autoimmunity, and vascular occlusion. Recent evidence demonstrating the organism's ability to survive intracellularly, presence of its DNA in the serum of individuals with acute encephalitis, case reports in which the organism is detected in brain parenchyma or cerebrospinal fluid (CSF), and animal data demonstrating CNS invasion by several Mycoplasma species support the contention that M. pneumoniae is capable of direct infection of the CNS. Because of limitations of current serologic assays and difficulty in interpreting the significance of positive polymerase chain reaction results in regard to acuity of infection and viability of the organism, the diagnosis of M. pneumoniae associated CNS disease should be based on a combination of positive tests and exclusion of alternative diagnoses. PMID- 21308544 TI - Approach to the diagnosis and management of tuberculous meningitis. AB - Meningitis caused by Mycobacterium tuberculosis remains an important cause of morbidity and mortality worldwide, and presents particular challenges in terms of diagnosis and management. The nonspecific clinical presentation of tuberculous meningitis (TBM) has led researchers to develop newer molecular methods of making the diagnosis. Several of these methods have excellent sensitivity and specificity, although many are not yet available for clinical use. Successful treatment of TBM requires a combination of antimicrobial agents, with vigilance regarding the possibility of disease caused by resistant organisms. Adjunctive corticosteroids also have a role in treating this potentially devastating infection, as can neurosurgery. With proper therapy, morbidity and mortality can be minimized in patients with TBM. PMID- 21308545 TI - Cryptococcal meningitis: current approaches to management in patients with and without AIDS. AB - Cryptococcal meningitis is a life-threatening fungal infection of the central nervous system (CNS). Its management is characterized by the administration of initial combination antifungal therapy by following the principles of induction, consolidation, and maintenance therapy with aggressive management of elevated intracranial pressure (ICP). These tenets apply to patients with and without AIDS. Recent prospective trials on combination antifungal therapy, and the timing of the initiation of highly active antiretroviral therapy (HAART), suggest amphotericin B plus flucytosine and initiation of HAART are optimal therapy for management of patients with AIDS and cryptococcal meningitis. The paucity of prospective data on the management of cryptococcal meningitis in patients without AIDS is the most challenging aspect of formulating treatment guidelines, but the principles of induction, consolidation, and maintenance still apply. Combination antifungal therapy with a lipid formulation of amphotericin B plus flucytosine is generally indicated for this group, especially for those with a predisposition to renal dysfunction. Future research targeting this population may further inform recommendations. PMID- 21308546 TI - Mycoplasma genitalium: Is It a Sexually Transmitted Pathogen? AB - Mycoplasma genitalium is an emerging pathogen that has been detected in the male and female reproductive tracts. It is an established cause of nongonococcal urethritis and evidence linking it to cervicitis, endometritis, and tubal factor infertility is accumulating. Whether a pathogen is sexually transmitted has important implications for clinical management because partner management strategies are an essential part of the treatment plan for sexually transmitted infections. However, mere detection in the genital tract and associations with reproductive tract disease are insufficient to conclude that an organism is sexually transmitted. Therefore, to assess whether M. genitalium is sexually transmitted, we evaluated the literature in terms of associations with established risk factors for other sexually transmitted infections, comparisons of sexually experienced individuals to nonsexually experienced individuals, consideration of other modes of transmission, assessment of concordant infection status among sexual partners, and examination of molecular strain typing in concordantly infected partners. PMID- 21308547 TI - In Vitro Susceptibility Testing in Fungi: What is its Role in Clinical Practice? AB - An increasing number of patients are undergoing transplantation procedures or receiving aggressive immunosuppression and chemotherapy. The growing population of immunocompromised hosts has led to a rise in the prevalence of invasive fungal infections due to yeasts and molds. The introduction of new antifungal agents and recent reports of resistance emerging during treatment of fungal infections have highlighted the need for in vitro susceptibility testing. Various testing procedures have been proposed, including macrodilution and microdilution, agar diffusion, disk diffusion, and Etest (AB Biodisk, Solna, Sweden). Establishing clinical correlation with antifungal susceptibility testing, however, is a huge challenge because susceptibility techniques do not take into account the dynamic and complex biology of fungi exposed to an antifungal in vivo. This paper reviews the available methods for antifungal susceptibility testing of yeasts and filamentous fungi and the data regarding the clinical implications of in vitro testing. PMID- 21308548 TI - Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease: an emerging fungal disease. AB - Invasive pulmonary aspergillosis (IPA) is a necrotizing pneumonia caused by airborne opportunistic fungi of Aspergillus species. Patients with advanced-stage chronic obstructive pulmonary disease (COPD) have emerged to be at risk for IPA as a result of the overall improvement of long-term management of the disease. IPA is among the most severe infectious event that may occur during the course of COPD resulting from profound immune impairment and associated with poor outcome. Many aspects of the development of IPA in COPD patients differ from hematologic patients, explaining various patterns of IPA in an expanded population of immunocompromised patients. Therefore, it is legitimate to focus on the literature-based data available regarding the factors involved in the development of IPA in this setting as well as the use and interpretation of diagnosis criteria, and the treatment options. PMID- 21308549 TI - Role of Mycoplasma and ureaplasma species in female lower genital tract infections. AB - Genital mycoplasmas are commonly found in the female genital tract. Despite ongoing debate, the evidence that they cause lower genital tract disease in women remains sparse. The data that Mycoplasma genitalium is primarily transmitted sexually are accumulating, but its role as a cause of symptomatic urethritis or cervicitis is open to debate. Although Mycoplasma hominis may be a co-factor in bacterial vaginosis, it has otherwise not been implicated as a cause of lower tract disease. Now that Ureaplasma urealyticum has been divided into U. urealyticum and Ureaplasma parvum, their role in causing urethritis and cervicitis remains even more unclear. To date, no convincing evidence exists that antimicrobial therapy should be directed solely at these organisms when treating women with urethritis, bacterial vaginosis, trichomoniasis, or cervicitis. PMID- 21308550 TI - Recent advances in the treatment of mucormycosis. AB - In recent years, substantial advances have been achieved in the treatment of mucormycosis. It is now clear that early initiation of therapy results in substantially better outcomes, underscoring the need to maintain a high index of suspicion and aggressively biopsy potential lesions. Increasing data support the need for surgical excision of infected and/or necrosed tissue whenever feasible. Based on their superior safety and efficacy, lipid formulations of amphotericin B have become the standard treatment for mucormycosis. Posaconazole may be useful as salvage therapy, but cannot be recommended as primary therapy for mucormycosis based on available data. Pre-clinical and limited retrospective clinical data suggest that combination therapy with lipid formulations of amphotericin and an echinocandin improves survival during mucormycosis. A definitive trial is needed to confirm these results. The use of the iron chelator, deferasirox, as adjunctive therapy also improved outcomes in animal models of mucormycosis. However, its efficacy was not confirmed in a recent, phase 2 clinical trial. Additional study is required of the potential for abrogation of iron acquisition as adjunctive treatment of mucormycosis. Combination polyene-posaconazole therapy was of no benefit in pre-clinical studies. Adjunctive therapy with recombinant cytokines, hyperbaric oxygen, and/or granulocyte transfusions can be considered in selected patients. Large-scale, prospective, randomized clinical trials are needed to define optimal management strategies for mucormycosis. PMID- 21308551 TI - Advances and prospects for molecular diagnostics of fungal infections. AB - The polymerase chain reaction (PCR) methods published for the diagnosis of invasive fungal infections are still not included in the revised European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group definitions of IA. This could be achieved with consensual PCR procedures. A checklist of items has been proposed to improve the reliability of the results and clinicians' confidence in them, with emphasis on limiting false-positive results from contamination with either previously amplified products or environmental commensals. Internal amplification controls are mandatory to expose false-negative results. However, our ignorance of the origin and the kinetics of fungal DNA during an infection hamper the choice of the best specimen and DNA extraction protocol. Evidence is increasing that serum could be a good compromise between sensitivity and ease of DNA extraction. Once a technical consensus is achieved, clinical studies should be initiated to integrate quantitative PCR in the diagnostic armamentarium. PMID- 21308552 TI - Echinocandin antifungal drug resistance in Candida species: a cause for concern? AB - The echinocandins, the newest generation of antifungal agents, are inhibitors of beta-1,3-D-glucan synthesis, an action that damages fungal cell walls. Despite a relatively broad spectrum of activity, these drugs are rapidly fungicidal against most Candida spp and have established noninferiority over existing antifungal drugs in the treatment of invasive candidiasis. Clinical resistance to this class of agent is rare, although point mutations in the target Fksp have been shown to confer in vitro resistance to echinocandins in a range of Candida spp, which can result in clinical failures. In addition, the echinocandin treatment can induce a salvage mechanism involving the compensatory upregulation of chitin synthesis in the cell wall. Further elucidation of the echinocandin resistance mechanisms could be exploited to envisage new therapeutic strategies for the treatment of life-threatening Candida infections. PMID- 21308553 TI - Challenges and prospects of adoptive immunotherapy in prevention and treatment of opportunistic mycoses in hematologic transplant recipients. AB - Invasive fungal infections remain a serious and life-threatening complication in patients undergoing hematopoietic stem cell transplantation. Since it became clear that lymphocytes, in particular lymphocytes from the T helper 1 (T(H)1) subset, play a critical secondary defense against fungal pathogens, the adoptive transfer of functionally active antifungal T(H)1 cells might be an attractive option to restore adaptive antifungal immune effector mechanisms. Major advances have been made in the generation and characterization of antifungal T cells, which are active against medical important fungi such as Aspergillus spp and Candida spp. However, given the paucity of large homogenous patient populations, major challenges remain in evaluating the clinical usefulness of adoptive antifungal immunotherapy, which should be performed in international collaborative trials. PMID- 21308554 TI - Management of urinary tract infections associated with nephrolithiasis. AB - Nephrolithiasis is a common clinical entity, and the incidence of renal stones appears to be increasing in the United States. Infection with uropathogens that produce urease can lead to the development of stones (infection stones), which serve as a continued source of recurrent infection and can lead to chronic kidney disease. Other than treating infection, medical management has little role in the treatment of infection stones; complete eradication of the stones with percutaneous nephrolithotomy or extracorporeal shock wave lithotripsy is required. Stones of metabolic origin can cause obstruction in the ureter and predispose to the development of urinary tract infection (UTI). Recognizing obstruction and initiating prompt drainage of the collecting system is important in the successful management of nephrolithiasis complicated by UTI. These patients are often at high risk of infection with an antimicrobial-resistant pathogen, so careful consideration of antimicrobial therapy is required, especially for patients who present with severe sepsis. PMID- 21308555 TI - Treatment of resistant enterococcal urinary tract infections. AB - Enterococcus spp have emerged as important pathogens in urinary tract infection (UTI), especially in hospitalized patients. Resistance to multiple antibiotics, including vancomycin, has become common, particularly in infections involving Enterococcus faecium. The management of UTIs caused by Enterococcus spp has become challenging given the presence of underlying comorbidities in these patients and the limited therapeutic options available to treat multidrug resistant (MDR) Enterococcus. Routine therapy for asymptomatic bacteriuria with MDR-Enterococcus is not recommended. Removal of indwelling urinary catheters should be considered. Appropriate antibiotic therapy selection should be guided by urine culture and susceptibility results. Data are limited on the treatment of UTIs caused by MDR-Enterococcus. Potential oral agents active against MDR Enterococcus that may be considered for acute uncomplicated UTI include nitrofurantoin, fosfomycin, and fluoroquinolones. Potential parenteral agents for the treatment of pyelonephritis and complicated UTIs caused by MDR-Enterococcus include daptomycin, linezolid, and quinipristin-dalfopristin. Aminoglycosides or rifampin may be considered as adjunctive therapy in serious infections. PMID- 21308556 TI - Vulvovaginal Candidiasis Caused by Non-albicans Candida Species: New Insights. AB - Non-albicans Candida species have increasingly been identified as the cause of vulvovaginitis. In vitro and in vivo data indicate that the various non-albicans Candida species identified in the lower genital tract differ considerably with regard to epidemiology, virulence or vaginal pathogenicity, and antimycotic drug susceptibility. Clinical experience indicates reduced virulence of these organisms in the lower genital tract, and their causal role in a symptomatic patient requires careful case-by-case determination rather than routine administration of antimycotic therapy. Accordingly, vaginal Candida isolates deserve species identification and consideration of pathogenic potential and antifungal susceptibility before therapeutic decisions are made. PMID- 21308557 TI - The role of second-generation antifungal triazoles for treatment of the endemic mycoses. AB - Endemic fungi are geographically restricted to certain areas of the United States where they are typically found in soil. They often cause asymptomatic or self limited flu-like infections in humans. Occasionally, they cause serious human disease including acute or chronic pneumonias, or bone, skin, or central nervous system disease. Amphotericin B and first-generation triazoles are standard therapy for serious endemic fungal infections. Adverse effects, drug intolerance, and rare refractory infections may limit their use; therefore, experience is increasing using newer triazoles (voriconazole and posaconazole) to potentially circumvent these problems. This article reviews the basic scientific information and clinical experience using triazoles for treating endemic fungal infections. PMID- 21308558 TI - Clinical spectrum of desquamative inflammatory vaginitis. AB - Desquamative inflammatory vaginitis (DIV) is a rare chronic clinical syndrome of unknown etiology characterized by profuse purulent vaginal discharge, diffuse exudative vaginitis, epithelial cell exfoliation, and pain. A diagnosis of DIV is often missed by even experienced practitioners owing to its rarity and its clinical and laboratory presentation similar to other inflammatory vulvovaginal disorders. Although DIV is difficult to treat and often requires long-term therapy for maintenance, successful therapy has been reported with topical steroids and clindamycin. PMID- 21308559 TI - Spinal epidural abscess: current diagnosis and management. AB - Spinal epidural abscess (SEA) is an uncommon condition that warrants urgent diagnosis and treatment, because early pharmacotherapy significantly improves prognosis and prompt surgical decompression is often necessary to prevent or minimize neurologic complications. Increased awareness is critical; any of the characteristic clinical findings, especially in the presence of risk factors and elevated inflammatory markers, should lead to heightened suspicion for SEAs and its consideration on differential diagnosis, even in the absence of neurologic deficits. A multidisciplinary approach is essential for successful management of SEAs; along with infectious disease specialists and neurosurgeons/orthopedic spine surgeons, primary care, emergency medicine, and internal medicine clinicians are more likely to see patients with SEAs at earlier stages and play a pivotal role in early diagnosis and treatment. A combination of targeted antibiotic therapy and prompt surgical decompression is recommended in most cases, although medical management alone can be effective in select patients under close monitoring. PMID- 21308560 TI - Going home after Hurricane Katrina: Determinants of return migration and changes in affected areas. AB - This article examines the decision of Hurricane Katrina evacuees to return to their pre-Katrina areas and documents how the composition of the Katrina-affected region changed over time. Using data from the Current Population Survey, we show that an evacuee's age, family income, and the severity of damage in an evacuee's county of origin are important determinants of whether an evacuee returned during the first year after the storm. Blacks were less likely to return than whites, but this difference is primarily related to the geographical pattern of storm damage rather than to race per se. The difference between the composition of evacuees who returned and the composition of evacuees who did not return is the primary force behind changes in the composition of the affected areas in the first two years after the storm. Katrina is associated with substantial shifts in the racial composition of the affected areas (namely, a decrease in the percentage of residents who are black) and an increasing presence of Hispanics. Katrina is also associated with an increase in the percentage of older residents, a decrease in the percentage of residents with low income/education, and an increase in the percentage of residents with high income/education. PMID- 21308561 TI - The spatial dynamics of stratification: metropolitan context, population redistribution, and black and Hispanic homeownership. AB - Racial and ethnic inequality in homeownership remains stubbornly wide, even net of differences across groups in household-level sociodemographic characteristics. This article investigates the role of contextual forces in structuring disparate access to homeownership among minorities. Specifically, I combine household- and metropolitan-level census data to assess the impact of metropolitan housing stock, minority composition, and residential segregation on black and Hispanic housing tenure. The measure of minority composition combines both the size and rate of growth of the coethnic population to assess the impact on homeownership inequality of recent trends in population redistribution, particularly the increase in black migration to the South and dramatic dispersal of Hispanics outside traditional areas of settlement. Results indicate remarkable similarity between blacks and Hispanics with respect to the spatial and contextual influences on homeownership. For both groups, homeownership is higher and inequality with whites is smaller in metropolitan areas with an established coethnic base and in areas in which their group is less residentially segregated. Implications of recent trends in population redistribution for the future of minority homeownership are discussed. PMID- 21308562 TI - The residential segregation of mixed-nativity married couples. AB - This article examines the ways in which mixed-nativity marriage is related to spatial assimilation in metropolitan areas of the United States. Specifically, we examine the residential patterns of households with a mixed-nativity-and, in some cases, interracial-marriage to determine whether they are less segregated from the native-born than entirely foreign-born households. Using restricted-use data from the 2000 census, we find that compared with couples in which both spouses are foreign-born, mixed-nativity couples tend to be less segregated from various native-born racial and ethnic groups. Further, among both foreign-born Asians and Hispanics, those with a native-born non-Hispanic white spouse are considerably less segregated from native-born white households than from other foreign-born Asian and Hispanic households. We also find that even though nativity status matters for black couples in a manner consistent with assimilation theory, foreign-born and mixed-nativity black households still each display very high levels of segregation from all other native-born racial/ethnic groups, reaffirming the power of race in determining residential patterns. Overall, our findings provide moderate support for spatial assimilation theory and suggest that cross-nativity marriages often facilitate the residential integration of the foreign-born. PMID- 21308563 TI - Divorce as risky behavior. AB - Given that divorce often represents a high-stakes income gamble, we ask how individual levels of risk tolerance affect the decision to divorce. We extend the orthodox divorce model by assuming that individuals are risk averse, that marriage is risky, and that divorce is even riskier. The model predicts that conditional on the expected gains to marriage and divorce, the probability of divorce increases with relative risk tolerance because risk averse individuals require compensation for the additional risk that is inherent in divorce. To implement the model empirically, we use data for first-married women and men from the 1979 National Longitudinal Survey of Youth to estimate a probit model of divorce in which a measure of risk tolerance is among the covariates. The estimates reveal that a 1-point increase in risk tolerance raises the predicted probability of divorce by 4.3% for a representative man and by 11.4% for a representative woman. These findings are consistent with the notion that divorce entails a greater income gamble for women than for men. PMID- 21308564 TI - Do siblings' fertility decisions influence each other? AB - Individuals' fertility decisions are shaped not only by their own characteristics and life course paths but also by social interaction with others. However, in practice, it is difficult to disentangle the role of social interaction from other factors, such as individual and family background variables. We measure social interaction through the cross-sibling influences on fertility. Continuous time hazard models are estimated separately for women's first and second births. In addition to individual socioeconomic variables, demographic variables, and an unobserved factor specific to each sibling pair, siblings' birth events and their timing enter as time-varying covariates. We use data from longitudinal population wide Norwegian administrative registers. The data cover more than 110,000 sibling pairs and include the siblings' fertility, education, income, and marital histories. Our results indicate that cross-sibling influences are relatively strong for the respondents' first births but weak for the second parity transition. PMID- 21308565 TI - Gender and migration from Albania. AB - This article examines the dynamics and causes of the shift in the gender composition of migration, and more particularly, in women's access to migration opportunities and decision-making. Our analysis focuses on Albania, a natural laboratory for studying international migration where out-migration was essentially nonexistent from the end of World War II to the end of the 1980s. Interest in the Albanian case is heightened because of the complex layers of inequality existing at the time when migration began: relatively low levels of inequality within the labor market and educational system-a product of the Communist era-while household relations remained heavily steeped in tradition and patriarchy. We use micro-level data from the Albania 2005 Living Standards Measurement Study, including migration histories for family members since migration began. Based on discrete-time hazard models, the analysis shows a dramatic increase in male migration and a gradual and uneven expansion of the female proportion of this international migration. Female migration, which is shown to be strongly associated with education, wealth, and social capital, appears responsive to economic incentives and constraints. Using information on the dependency of female migration to the household demographic structure as well as the sensitivity of female migration to household-level shocks, we show how household-level constraints and incentives affect male and female migration differently. Throughout this period, however, women's migration behavior appears more directly aligned with household-level factors, and there is little evidence to suggest that increased female migration signals rising behavioral independence among Albanian women. PMID- 21308566 TI - Family life course transitions and rural household economy during China's market reform. AB - This article investigates the effect of family life course transitions on labor allocation strategies in rural Chinese households. We highlight three types of economic activity that involve reallocation of household labor oriented toward a more diversified, nonfarm rural economy: involvement in wage employment, household entrepreneurship, and/or multiple activities that span economic sectors. With the use of data from the China Health and Nutrition Survey (CHNS 1997, 2000, and 2004), our longitudinal analyses of rural household economic activity point to the significance of household demography, life course transitions, and local economic structures as factors facilitating household labor reallocation. First, as expected, a relatively youthful household structure is conducive to innovative economic behavior. Second, household entrances and exits are significant, but their impacts are not equal. Life events such as births, deaths, marriage, or leaving home for school or employment affect household economy in distinctive ways. Finally, the reallocations of household labor undertaken by households are shaped by local economic structures: in particular, the extent of village-level entrepreneurial activity, off-farm employment, and out-migration. PMID- 21308567 TI - Kinship institutions and sex ratios in India. AB - This article explores the relationship between kinship institutions and sex ratios in India at the turn of the twentieth century. Because kinship rules vary by caste, language, religion, and region, we construct sex ratios by these categories at the district level by using data from the 1901 Census of India for Punjab (North), Bengal (East), and Madras (South). We find that the male-to female sex ratio varied positively with caste rank, fell as one moved from the North to the East and then to the South, was higher for Hindus than for Muslims, and was higher for northern Indo-Aryan speakers than for the southern Dravidian speaking people. We argue that these systematic patterns in the data are consistent with variations in the institution of family, kinship, and inheritance. PMID- 21308568 TI - Standardization of pathways to adulthood? An analysis of Dutch cohorts born between 1850 and 1900. AB - This article examines pathways to adulthood among Dutch cohorts born in the second half of the nineteenth century. Although largely overlooked by previous studies, theory suggests that life courses of young adults born during this period were already influenced by a process of standardization, in the sense that their life courses became more similar over time. Using data from a Dutch registry-based sample, we examine household trajectories: that is, sequences of living arrangements of young adults aged 15-40. Our study shows that for successive cohorts, household trajectories became more similar. We identified six types of trajectories: early death, life-cycle service, early family formation, late family formation, singlehood, and childless but with partner. Overtime, early family formation gradually became the "standard" trajectory to adulthood. However, late family formation and singlehood, common pathways within the preindustrial western European marriage pattern, remained widespread among cohorts born in the late nineteenth century. Laboring class youths, farmers' daughters, young people of mixed religious background, and urban-born youngsters were the nineteenth century forerunners of a standard pathway to adulthood. PMID- 21308569 TI - Unhealthy and uninsured: exploring racial differences in health and health insurance coverage using a life table approach. AB - Millions of people in the United States do not have health insurance, and wide racial and ethnic disparities exist in coverage. Current research provides a limited description of this problem, focusing on the number or proportion of individuals without insurance at a single time point or for a short period. Moreover, the literature provides no sense of the joint risk of being uninsured and in need of medical care. In this article, we use a life table approach to calculate health- and insurance-specific life expectancies for whites and blacks, thereby providing estimates of the duration of exposure to different insurance and health states over a typical lifetime. We find that, on average, Americans can expect to spend well over a decade without health insurance during a typical lifetime and that 40% of these years are spent in less-healthy categories. Findings also reveal a significant racial gap: despite their shorter overall life expectancy, blacks have a longer uninsured life expectancy than whites, and this racial gap consists entirely of less-healthy years. Racial disparities in insurance coverage are thus likely more severe than indicated by previous research. PMID- 21308570 TI - Obtaining multistate life table distributions for highly refined subpopulations from cross-sectional data: A Bayesian extension of Sullivan's method. AB - Multistate life table methods are often used to estimate the proportion of remaining life that individuals can expect to spend in various states, such as healthy and unhealthy states. Sullivan's method is commonly used when panels containing data on transitions are unavailable and true multistate tables cannot be generated. Sullivan's method requires only cross-sectional mortality data and cross-sectional data indicating prevalence in states of interest. Such data often come from sample surveys, which are widely available. Although the data requirements for Sullivan's method are minimal, the method is limited in its ability to produce estimates for subpopulations because of limited disaggregation of data in cross-sectional mortality files and small cell sizes in aggregated survey data. In this article, we develop, test, and demonstrate a method that adapts Sullivan's approach to allow the inclusion of covariates in producing interval estimates of state expectancies for any desired subpopulation that can be specified in the cross-sectional prevalence data. The method involves a three step process: (1) using Gibbs sampling to sample parameters from a bivariate regression model; (2) using ecological inference for producing transition probability matrices from the Gibbs samples; (3) using standard multistate calculations to convert the transition probability matrices into multistate life tables. PMID- 21308573 TI - Disease modeling using pluripotent stem cells: making sense of disease from bench to bedside. AB - New advances in human stem cell biology now permit the derivation of disease specific induced pluripotent (iPS) stem cell lines, so-called "disease-in-a-dish" (DIAD) models. This is a promising approach for the study of disease phenotypes at the cellular and molecular level, both because such human cell lines may produce more faithful experimental models of disease than can be produced using non-human organisms, and because reprogrammed cell lines can provide a virtually infinite supply of cells without requiring additional tissue donation. However, expectations placed on this emerging technology privilege the laboratory over the clinic as the site for making sense of disease, thereby distracting from the socially embedded meanings of disease and reorienting how the goals of medicine are imagined. Here we identify and review the implications of this area of research for clinical approaches to disease. We argue that there is a central place for the larger medical community and patients in the very construction of experimental research programs and the expectations placed thereon. By attending to the constellation of social factors that inform understanding, treatments and experiences of disease, DIAD projects can be more effectively placed in the service of clinical goals, in both their research design and in the forms of innovation they claim to anticipate. PMID- 21308574 TI - Inducing occlusion effect in Y-shaped vessels using high-intensity focused ultrasound: finite element analysis and phantom validation. AB - High-intensity focused ultrasound (HIFU) surgery offers a truly non-invasive treatment method with no skin incision, but precise targeting of tumour tissues for thermotherapy. Clinical experience reveals that the efficacy of tumour destruction not only involves in coagulating necrosis, but also involves in damaging the tumour vessels, which play an important role in tumour progression. These vessels take the elevated temperature away by perfusion, resulting in uncertainty of the occlusion effect during HIFU treatment. In this study, a Y shaped vessel model comprising common and tumour vessels and an indirect fabrication method are proposed. The physical properties of the fabricated vessel phantom are measured and compared with human tissue. Simulation is performed using finite element modelling according to the tissue parameter, perfusion rate of the tumour vessel and treatment parameters including power intensity and exposure duration. The phantom experiments are carried out with perfusion of egg white to validate the threshold time prediction obtained from the simulation results. Our findings reveal that the threshold time obtained from experiments is consistent with the simulated one. PMID- 21308575 TI - Identity, desire and truth: homosociality and homoeroticism in Mexican migrant communities in the USA. AB - This paper examines the construction of a homoerotic social scene among Mexican migrants in California. It analyses the discourses of migrant men in the cities of San Diego and Fresno who identify themselves as heterosexual and have not had sexual experiences with men and those of members of civil society organisations doing HIV prevention work with migrant men, to show how an identity-based model of sexuality used by the HIV prevention organisations is counter to the strategic, non-identity-based model constructed by migrant men. With this incongruence as its starting point, the paper offers a critique both of the epistemological factors underlying the category of 'men who have sex with men' and the logic running through HIV prevention discourses that adhere to the Foucauldian notion of the deployment of sexuality, which demands both truth and coherence in subjects' sexuality. PMID- 21308576 TI - Predictors of vaginal practices for sex and hygiene in KwaZulu-Natal, South Africa: findings of a household survey and qualitative inquiry. AB - Vaginal practices in sub-Saharan Africa may increase HIV transmission and have important implications for development of microbicides and future HIV prevention technologies. It remains unclear which women undertake vaginal practices and what factors predict prevalence, practice type and choice of products. Using cross sectional data from mixed research methods, we identify factors associated with vaginal practices among women in KwaZulu-Natal, South Africa. Data were gathered through focus group discussions, in-depth and key-informant interviews, followed by a province-wide, multi-stage cluster household survey, using structured questionnaires in face-to-face interviews with 867 women. This paper details six types of vaginal practices, which--despite their individual distinctiveness and diverse motivations--may be clustered into two broad groups: those undertaken for purposes of 'hygiene' (genital washing, douching and application) and those for 'sexual motivations' (application, insertion, ingestion and incisions). Multivariate analysis found significant associations between 'hygiene' practices and media access, religiosity and transactional sex. 'Sexual' practices were associated with partner concurrency, religiosity and use of injectable hormonal contraceptives. Future interventions relating to vaginal practices as well as microbicides need to reflect this characterisation of practices as sexual- and/or hygiene-related. PMID- 21308577 TI - Let's talk about sex: helping substance abuse counsellors address HIV prevention with men who have sex with men. AB - Integrating HIV prevention into substance abuse counselling is recommended to ameliorate the health outcomes of men who have sex with men. However, culture based countertransferences (CBCs) may hamper this effort. Using a case illustration, this paper will explain the manifestation of CBCs held among substance abuse counsellors and how they hinder counsellors' work with men who have sex with men. The following CBCs will be explored: distancing, topic avoidance, heteronormativity, assumptions and denying client strengths. These CBCs allow counsellors to avoid discussions about sexual practices and curtail HIV prevention counselling, while undermining the counsellor-client relationship. Based on the empirical literature on HIV and substance abuse prevention with men who have sex with men, we provide recommendations to help counsellors overcome CBCs and integrate HIV prevention consistently with men who are in treatment for substance abuse. PMID- 21308578 TI - A new malaria protocol in a Congolese refugee camp in West Tanzania. AB - The objective of this study was to evaluate the impact of a new malaria protocol introduced in 2007 at Nyarugusu Refugee Camp. In accordance with this protocol, the delivery of a diagnostic test (rapid diagnostic test or microscopy) was made compulsory prior to the administration of antimalarial drugs (ACTs: artemisinin based combination therapies). We collected camp clinic records on outpatient malaria diagnoses from 2004 through 2007 and compared the morbidity percentages attributed to malaria during these years, as well as the actual incidence of malaria in 2006 and 2007. Our analyses demonstrate that malaria accounted for 45.8% of all morbidity in 2004 (64,557 malaria cases out of 1,40,669 total morbidity), followed by corresponding figures of 47.8% for 2005 (94,389 malaria cases out of 1,97,400) and 47.9% for 2006 (60,760 malaria cases out of 1,26,754); however, the values dropped sharply to 22.8% in 2007 (20,136 malaria cases out of 88,254). We found a similar drastic drop in the incidence of malaria from an average of 182.415 cases/1000 inhabitants/month in 2006 to only 35.635 cases/1000 inhabitants/month in 2007. The results of our study suggest that because of the overlap of symptoms from malarial and non-malarial febrile illnesses, diagnosing malaria on clinical and epidemiological bases may lead to its overdiagnosis. This could result in both the overprescription of antimalarials and the underdiagnosis and inappropriate treatment of non-malarial febrile processes. The use of affordable and available tests can increase the accuracy of malaria diagnoses, so that only real malaria cases would be treated as such. This would help curb the uncontrolled administration of antimalarials to prevent the development of resistance to new malarial treatments and thus decrease treatment expenses. This way, financial, material and human resources can be allocated to other health issues that currently go unnoticed. PMID- 21308579 TI - Not all nutrition claims are perceived equal: anchoring effects and moderating mechanisms in food advertising. AB - Despite the increased use of health claims in food advertising, few studies have investigated how specific nutrition claims have differential effects depending on how they are presented. In this context, the current study tests the anchoring hypothesis. Anchoring refers to a common human tendency to evaluate information differently depending on the presence or absence of a numerical "anchor" or reference point. Two (pilot and main) experimental studies explore anchoring effects on audience response to food advertising both directly and moderated by cognitive, motivational, and message factors. The pilot study finds that food product ads employing nutrition claims with an anchor rather than without an anchor generate two results: First, participants perceive the product to have lower fat/lower calorie contents (anchoring hypothesis); second, they prefer the messages with an anchor over those without an anchor. The main study reports that when anchoring is successfully evoked, it produces favorable attitudes toward the ad, favorable attitudes toward the brand, and purchase intention-but only when moderated by health orientation, claim believability, and nutrition knowledge. Practical implications are provided with respect to regulatory guidelines and effective communication strategies for promoting low-fat and low-calorie products in food advertising. PMID- 21308580 TI - Are nonparticipants in prosocial behavior merely innocent bystanders? AB - Latane and Darley's (1970) bystander intervention theory was used to model individuals' participation in two prosocial behaviors (organ donation, green living). It is argued that nonparticipants in prosocial helping are innocent bystanders who likely fail to notice the need, do not interpret the cause as an emergency, do not accept responsibility for the need to help, and have little knowledge on how to help. Data in study 1 (n = 494) indicate support for the proposed innocent bystander path model (notice event -> interpret event as emergency -> accept responsibility -> knowledge of how to help) in organ donation. Study 2 (n = 519) replicated the model in the context of green living and additionally found a direct path from noticing the event to knowledge of how to help. Implications of framing nonparticipation in prosocial behaviors as innocent bystander effects are discussed in context of campaign communication. PMID- 21308581 TI - Non-group a streptococci as common isolates from throat culture among college students with pharyngitis. PMID- 21308582 TI - The utility of a gender-specific definition of binge drinking on the AUDIT. AB - OBJECTIVE: Although binge drinking is commonly defined as the consumption of at least 5 drinks in 1 sitting for men and 4 for women, the Alcohol Use Disorders Identification Test (AUDIT) defines binge drinking as the consumption of 6 or more drinks in 1 sitting for both men and women. This study examined the effect of using gender-specific binge drinking definitions on overall AUDIT scores. PARTICIPANTS: Participants were 331 college men and 1224 college women. METHODS: Participants completed a self-report questionnaire, which included the AUDIT. RESULTS: Findings showed that defining binge drinking as 4 or more drinks for women, rather than 6 or more, does impact their AUDIT scores and could affect the percentage of women classified as hazardous users. Among men, AUDIT scores were unaffected by the use of a gender-specific definition of binge drinking. CONCLUSIONS: Results suggest that the AUDIT might be underidentifying hazardous users among college women. PMID- 21308583 TI - Influenza-like illness among university students: symptom severity and duration due to influenza virus infection compared to other etiologies. AB - OBJECTIVE: University students with influenza-like illness (ILI) were assessed to determine whether symptom severity, duration, or missed days of school or work varied according to etiology. PARTICIPANTS: Sixty persons presenting to a university health clinic with ILI symptoms during 3 consecutive influenza seasons completed baseline survey and viral testing; 51 (85%) completed follow-up. METHODS: Influenza viral culture and polymerase chain reaction and respiratory virus immunofluorescence assay testing were performed. Information collected at baseline and follow-up included symptom occurrence, severity, duration, and numbers of days of work and school missed. RESULTS: Influenza virus was confirmed in 63% of participants. Influenza-positive individuals were no more likely to report any symptom or miss more days of school or work. Self-reported severity and durations of symptoms were similar between groups. CONCLUSIONS: Students with influenza-associated ILI were similar to those with noninfluenza ILI with respect to severity, duration, and numbers of days of school and work missed. PMID- 21308584 TI - Referent group proximity, social norms, and context: alcohol use in a low-use environment. AB - OBJECTIVE: The purpose of this study was to investigate the relationship between perceived normative use of alcohol and reported consumption in an environment where relatively little alcohol use occurs. PARTICIPANTS: A total of 585 undergraduate students completed an online survey on alcohol use in March 2006. METHODS: Participants reported personal alcohol use and perceptions of use by "friends," "the average student," and "the average student who drinks." RESULTS: Due to the large number of students reporting zero alcohol use, zero-inflated negative binomial regression was used to analyze the data. Results showed that perceptions of use and beliefs about the acceptability of use by proximal groups were strongly and positively correlated with personal alcohol use. Perceptions of distal groups were either not correlated or were correlated negatively with personal use. CONCLUSION: These findings suggest that the use of distal referent groups for a social norms campaign in a low-use environment may have paradoxical effects. PMID- 21308585 TI - Canadian campus smoking policies: investigating the gap between intent and outcome from a student perspective. AB - BACKGROUND: Young adults remain the earliest legal target for the tobacco industry. Against this, the existence of smoking policies would appear to offer some protection to students on campus. However, little research has been conducted into the outcomes of such policies from a student perspective. METHODS: The authors conducted 8 focus groups at 4 selected Canadian undergraduate campuses to investigate student perceptions and behaviors resulting from campus smoking policies. RESULTS: Results indicated that student smoking behaviors are minimally impacted by campus smoking policies due to seriously compromised implementation and enforcement. CONCLUSIONS: These findings imply that the presence of campus smoking policies and claims of "smoke-free" campuses should not be misinterpreted as achievement and without renewed focus and adequate tobacco control infrastructure, it will remain possible for young adults to initiate and maintain tobacco smoking on campus. PMID- 21308586 TI - A description of disordered eating behaviors in Latino males. AB - OBJECTIVE: To explore disordered eating and eating disorders (EDs) in Latino males. PARTICIPANTS: Participants are 722 male college students from a larger prevalence study conducted in the University of Puerto Rico system. METHODS: Participants were selected from a list of sections of required courses for first year students on each campus. Self-report instruments were used to explore ED symptoms (the Eating Attitudes Test [EAT-26] and the Bulimia Test-Revised [BULIT 26-R] and the Beck Depression Inventory depression (BDI). RESULTS: Overall, 2.26% scored above the cut-off point on the BULIT-R and 5.08% score above the cut-off point on the EAT-26. Of the males, 4.43% reported sufficient frequency and severity to approximate DSM-IV criteria for bulimia nervosa. Depression symptomatology was found in those who scored above the cut-off point on both instruments of EDs. CONCLUSION: College health practitioners should be aware of disordered eating in Latino males and include them in efforts to detect disordered eating behaviors in college students. PMID- 21308587 TI - Sexual coercion, verbal aggression, and condom use consistency among college students. AB - OBJECTIVE: The relationship between condom use and 2 less visible categories of intimate partner violence (IPV), sexual coercion and verbal aggression, was examined among college students. METHODS: In March 2007 a random cross-sectional sample of undergraduates from the southeast region of the United States was taken to collect information about sexual coercion and verbal aggression, in addition to condom use consistency. Alcohol use was also assessed. RESULTS: Of the 142 participants, 31.7% reported being victims of sexual coercion, and 78% reported having verbally aggressive partners. Participants who reported experiencing sexual coercion in their relationship were significantly less likely to consistently use condoms. Additionally, alcohol use before or during episodes of verbal aggression was negatively associated with condom use. Alcohol use was also significantly associated with heightened incidents of coercion and aggression. CONCLUSIONS: Results indicate that among college students, the presence of sexual coercion adversely affects condom use, as does alcohol use. PMID- 21308588 TI - Disregulated alcohol-related behavior among college drinkers: associations with protective behaviors, personality, and drinking motives. AB - OBJECTIVE: This study investigated the psychometric properties of the Disregulated Alcohol-Related Behaviors Inventory (DARBI), a measure of harmful alcohol-related behavior, and the relationship between protective behavior use and scores on the DARBI and several other measures. PARTICIPANTS: Participants were 281 undergraduate volunteers (60% female) enrolled in introductory psychology sections in Summer and Fall 2007. METHODS: Participants completed the DARBI along with paper-and-pencil self-report measures of broad personality domains, trait resilience, protective behavior use, and drinking motivations and consequences. RESULTS: The DARBI's internal consistency was good (alpha = .85). DARBI scores correlated negatively with conscientiousness scores but positively with neuroticism, the Michigan Alcohol Screening Test (MAST), Rutgers Alcohol Problem Index (RAPI), and positive-reinforcement motives scores. The self reported use of protective behaviors related negatively to DARBI, MAST, RAPI, and enhancement motives scores. Protective behavior use was unrelated to broad personality domains. CONCLUSIONS: The DARBI may prove a useful tool in campus interventions. Further research should determine the dispositional and situational determinants of protective behavior use. PMID- 21308589 TI - Primary care screening of depression and treatment engagement in a university health center: a retrospective analysis. AB - OBJECTIVES: This retrospective study analyzed a primary care depression screening initiative in a large urban university health center. Depression detection, treatment status, and engagement data are presented. PARTICIPANTS: Participants were 3,713 graduate and undergraduate students who presented consecutively for primary care services between January and April 2006. METHODS: A standardized 2 tiered screening approach for an inception cohort of students utilizing primary services. Primary care providers were trained to triage students with depressive symptoms. RESULTS: Six percent of participants had clinically significant depressive symptoms (CSD). Severe depressive symptoms were found in less than 1.0% of participants. Male rates of severe depressive symptoms were more than double that of females. Only 35.7% of untreated depressed participants started treatment within 30 days following identification. CONCLUSIONS: Systematic primary care depression screening in a college health center is a promising approach to identify untreated students with depression. More study is needed to improve rates of treatment engagement. PMID- 21308590 TI - Knowledge, beliefs, and behaviors: examining human papillomavirus-related gender differences among African American college students. AB - OBJECTIVE: Given recent approval for administration of a human papillomavirus (HPV) vaccine to men, it is important to assess the HPV-related perspectives of men and women. The purpose of this study was to examine gender differences in HPV knowledge, beliefs, and vaccine acceptance among college students attending 3 historically black colleges/universities in the Southeast. PARTICIPANTS AND METHODS: A nonprobability sample of 575 students completed a self-report questionnaire. RESULTS: Males were significantly less likely to have heard of HPV, scored lower in HPV knowledge, were less likely to perceive HPV health outcomes as severe and that there was a benefit to vaccinate, reported fewer cues for vaccine acceptance, and perceived more barriers to vaccination compared to females (all p < .05). CONCLUSIONS: The gender disparities demonstrated in this study highlight the need to increase HPV-related communication/education to include men and to extend HPV research to a broader segment of the college population. PMID- 21308591 TI - How college students conceptualize and practice responsible drinking. AB - OBJECTIVE: This study sought to employ a mixed-methods approach to (a) qualitatively explore responsible drinking beliefs and behaviors among a sample of college students, and (b) quantitatively assess the prevalence of those behaviors. PARTICIPANTS: Convenience samples, drawn from currently enrolled students attending a large public university in Texas, comprised 13 participants in the qualitative phase and a random sample of 729 students for the quantitative phase. METHODS: A partially mixed sequential dominant status design (qual -> QUAN) was employed. RESULTS: PARTICIPANTS associated 7 distinct themes with drinking responsibly; however, embedded inside these themes were numerous potentially harmful elements. Quantitative findings supported the qualitative themes, also highlighting gender and ethnic differences. Males believed responsible drinking behaviors should occur with significantly less frequency than females, whereas Whites attached less relative necessity to certain responsible drinking behaviors. CONCLUSION: This study represents an initial attempt to determine specific, evidence-based characteristics of responsible drinking. PMID- 21308592 TI - Prevalence of metabolic syndrome and individual criteria in college students. AB - Metabolic syndrome (MetS) is present in young adults and because coronary heart disease (CHD) is likely, screening to determine MetS prevalence and its criteria is critical. OBJECTIVE: To determine MetS prevalence and most prevalent criteria in a sample of first-year college students. PARTICIPANTS: First-year college students between 18 and 24 years of age (n = 189). METHODS: Metabolic syndrome was defined using the updated 2001 National Cholesterol Education Programs Adult Treatment Panel III. Anthropometrics and blood pressure were obtained. Lipid and glucose concentrations were determined. RESULTS: Overall prevalence of MetS was 3.7%. Prevalence of 1 or 2 MetS criteria was 28.0% and 7.4%, respectively. Low high-density lipoprotein cholesterol (20.1%) and elevated triacylglycerol (17.5%) concentrations were the most prevalent criteria. CONCLUSIONS: Young adults have and are at risk of developing MetS. Identification of MetS early in life is critical and screening young adults will aid in targeted intervention development to decrease CHD risk. PMID- 21308593 TI - Alcohol-related vehicular death rates for college students in the Commonwealth of Virginia. AB - OBJECTIVE: Determine rate of college student alcohol-related vehicular traffic fatalities in Virginia during 2007. PARTICIPANTS: 17- to 24-year-old cohort [corrected] at colleges and universities in Virginia. METHODS: Institutions with membership in the American College Health Association were invited to participate in a survey. Data collected from institutional reports of student deaths due to vehicular accidents. RESULTS: Twenty-four institutions were invited to participate. Sixteen responded (response rate = 67%), comprising total enrollment of 117,100 for 17- to 24-year-olds (56% of total college population in state). Five traffic deaths were reported, representing 4.3 deaths per 100,000 students. Based on statewide statistics that estimate alcohol contributes to 38.9% of traffic deaths, rate of alcohol-related motor vehicle deaths is 1.7 deaths per 100,000 college students in Virginia, which is 89% lower than leading national estimates. CONCLUSIONS: These findings suggest that past estimates of alcohol related vehicular deaths among college students are overstated. PMID- 21308594 TI - Health administrator perspectives on human immunodeficiency virus/acquired immunodeficiency syndrome prevention and services at historically black colleges and universities. AB - OBJECTIVE: Due to the disproportionate impact of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) among African American young adults, the authors explored (1) number of historically black college and university (HBCU) campuses with existing HIV prevention policies and services and (2) perceived barriers for implementing HIV prevention services. METHODS: Semistructured telephone surveys were conducted with health administrators from 25 HBCUs. RESULTS: Twenty-four of 25 (96%) health administrators responded. Twelve of 24 administrators (50%) reported having no formal HIV prevention policies or services on campus, 11 of 24 (46%) described having formal HIV prevention policies and services (eg, condom distribution, HIV testing), and 1 was unsure. Seven of 11 (64%) administrators who reported having policies or services indicated that the availability of condoms on campus facilitated HIV/AIDS prevention by promoting safer sex. Perceived barriers to more effectively providing services included negative student attitudes regarding HIV and lack of support from school administration and parents. CONCLUSION: There are inadequate HIV/AIDS prevention services on some HBCU campuses. PMID- 21308595 TI - Heavy drinking on college campuses: no reason to change minimum legal drinking age of 21. AB - The recent Amethyst Initiative argues that a minimum legal drinking age (MLDA) of 21 has created a culture of heavy alcohol use on college campuses by making drinking clandestine and extreme. This group and others argue that lowering the MLDA will reduce the problem of "binge drinking" on college campuses. However, such a policy change would remove one of the most researched and supported policies in the nation's alcohol control arsenal. There is little evidence that other interventions or policies are capable of working on the same broad level as MLDA 21, and there could also be a deleterious ripple effect in related legislation because MLDA 21 works in conjunction with other drinking laws. In addition, historic and international experiences with a lowered MLDA indicate there are serious social and public health consequences. Instead of removing efficacious interventions, we must remain committed to implementing and enforcing evidence-based practices and legislation. PMID- 21308596 TI - The importance of the suspended solids parameter on the quantitative analysis of di-n-butyl phthalate in a wastewater treatment system. AB - The present study has investigated the influence of the filtration step of the liquid-liquid extraction (LLE) on the quantitative analysis of di-n-butyl phthalate (DnBP) in the wastewater treatment system of the University of Caxias do Sul (WWTS-UCS). During five months, five wastewater samples from the inflow and outflow points were collected and submitted to LLE with and without the filtration step. The organic extracts were analyzed by Gas Chromatography with Flame Ionization Detection (GC/FID). The DnBP removal in the filtered samples was 36%, and the median DnBP concentration at the outflow point was 17.45 MUg/mL. For the unfiltered samples, the DnBP removal was 39%, and the median DnBP concentration at the outflow point was 21.45 MUg/mL. According to these results, an important fraction of the contaminant is retained in the LLE filtration step leading to considerable errors in the quantification of the target compounds. PMID- 21308597 TI - Disinfection performances of stored acidic and neutral electrolyzed waters generated from brine solution. AB - The feasibility of storing two electrolyzed waters (EW), acidic (AEW) and neutral (NEW), were elucidated through Escherichia coli O157:H7 and Salmonella typhii inactivation experiments. Free chlorine (FC) loss, pH and oxidation-reduction potentials were monitored for 30 days. Initial activities of fresh EWs were determined at 5 mg Cl(2).min/L for 8 Log(10) inactivations of both strains. However, stored EWs exhibited activity declines which were associated to FC losses. All FC loss rates were first-order; AEWs underwent two phases of decays while NEWs had single decay rate constants. Two FC loss mechanisms were identified: chlorine (Cl(2)) volatilization and hypochlorous acid (HOCl) decomposition, wherein Cl(2) volatilization occurred at a faster rate. Chlorine volatilization was primarily influenced by storage condition as indicated by intensive FC losses on EWs stored in open vessels. Under the same storage conditions (open or closed), Cl(2)-rich AEW experienced higher FC losses which indicated the higher stability of HOCl-rich NEW. Overall, FC losses could be minimized if (1) samples are stored in closed vessels and (2) Cl(2) is not the main chlorine component. NEW in closed vessel is the most feasible system for EW storage; its initial activity (8 Log(10) inactivation) was preserved for up to 17 days. PMID- 21308598 TI - Molecular analysis of bacterial communities in uranium ores and surrounding soils from Banduhurang open cast uranium mine, India: A comparative study. AB - Bacterial community structure of heavy metal rich- uranium ores and surrounding soils was explored using 16S rRNA gene based clone library analysis and denaturing gradient gel electrophoresis (DGGE) to provide baseline microbial diversity data on autochthonous communities. Sequence analysis of major ribotypes and/or DGGE bands revealed Proteobacteria and Acidobacteria as the two most frequently present bacterial phyla across the samples, although relative abundance of each phyla and identity of their members at lower taxonomic level showed marked difference. Gammaproteobacteria (Pseudomonas and Escherichia) was most abundant in U-ore samples along with the lineages of beta-Proteobacteria (Burkholderia and Janthinobacterium), alpha-Proteobacteria (Brevundimonas), Bacteroidetes (Spingobacterium), Firmicutes (Peptoniphilus), Actinobacteria (Corynebacterium), uncultured -Acidobacteria, -Chloroflexi and -Cyanobacterium. In contrast to this soil communities were represented by mixed populations predominated by uncultured Acidobacteria along with Gammaproteobacteria (Succinivibrio, Cellovibrio and Legionella), beta-Proteobacteria (Rhodocyclus), alpha-Proteobacteria (Methylocystis and Phenylobacterium), delta-Proteobacteria, unclassified bacteria, uncultured Bacteroidetes, Firmicutes (Bacillus), Cyanobacteria (Scytonema), Actinobacteria (Actinomadura) and candidate division TM7. Principle Component Analyis (PCA) of geochemical data and UPGMA cluster analysis of DGGE profiles were in close agreement showing characteristic relatedness of samples obtained from either ores or soils. Our analysis indicated that soils surrounding the ore deposit bear specific geochemical as well as microbiologial characteristics distinct from the ore deposit and therefore these data obtained at the onset of mining could serve as a baseline of information to gauge the subsequent environmnetal impact of U-mining. PMID- 21308599 TI - Bacterial diversity dynamics in a long-term petroleum-contaminated soil. AB - Bacterial diversity dynamics were investigated in the soil samples in different distances and depths from/at a long-term petroleum-contaminated site. Microbial activity in the soil samples showed ATP values closely correlated with organic matter content (OC) and total petroleum hydrocarbon (TPH). Bacterial community diversity (H) and evenness (J) using PCR-DGGE (polymerase chain reaction denaturing gradient gel electrophoresis) and PCR-T-RFLP (terminal restriction fragment length polymorphism) results showed positive correlation with concentration of TPH or OC, but tmoA (toluene monooxygenase gene)-based bacterial H and J using a PCR-T-RFLP result did not. No significant difference of H and J values in the bacterial and the tmoA communities was observed. The bacterial community structure characterized by PCR-DGGE and PCR-T-RFLP techniques showed similarity according to soil sampling distance rather than soil sampling depth. Canonical correspondence analysis demonstrated that OC including TPH had the most significant effect on the bacterial community diversity at the long-term petroleum-contaminated site. PMID- 21308600 TI - Chemical-physical properties of spinel CoMn2O4 nano-powders and catalytic activity in the 2-propanol and toluene combustion: Effect of the preparation method. AB - Spinel-type CoMn(2)O(4)nano-powders are prepared using sol-gel auto combustion (SGC) and co-precipitation (CP) methods and their catalytic activities are evaluated in combustion of 2-propanol and toluene. The chemical-physical properties of the oxides are characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), N(2)-adsorption-desorption, temperature programmed reduction (TPR) and scanning electron microscopy (SEM). After calcination at 700 degrees C, CoMn(2)O(4)-SGC shows higher amounts of the normal type spinel phase and is more crystalline than CoMn(2)O(4)-CP. Higher calcination temperatures (850 degrees C) do not affect very much the weight percentage of the normal-type spinel phase; although the crystal size slightly increased. The TPR analysis evidences a large number of Mn(3+) cations in CoMn(2)O(4)-SGC compared to CoMn(2)O(4)-CP. This difference, together with the higher surface area, could justify the higher activity of CoMn(2)O(4)-SGC in both the investigated reactions. PMID- 21308601 TI - Application of 2III7-3 fractional factorial experimental design to enhance enzymatic activities of Pleurotus ostreatus with high concentrations of polychlorinated biphenyls. AB - A 2(III)(7-3) fractional factorial experimental design was used to establish 16 culture media, with and without PCBs to enhance the activities of laccase (Lac), manganese peroxidase (MnP), and versatile peroxidase (VP) produced by the white rot fungus Pleurotus ostreatus. The culture was added to 10,000 mg L(-1) of transformer oil, containing 71% of the identified Arochlor 1242. The culture conditions were established with eight variables at two values (levels); pH (4 and 6), agitation (100 and 200 rpm), CuSO(4) (150 and 250 mg L(-1)), MnSO(4) (50 and 200 mg L(-1)), Tween 80 (13 and 3500 mg L(-1)), wheat straw (0 and 2.5 g L( 1)), sugarcane bagasse (0 and 2.5 g L(-1)),and Arochlor 1242 (0 and 7100 mg L( 1)) at 4, 8, 12, 16 and 20 days old culture. Laccase activity was enhanced at a high value of pH and low value of agitation (P<0.001) and correlated positively (R(2)= 0.9; alpha=0.05) with the removal of polychlorinated biphenyls (PCBs). VP activity was enhanced 27-fold with PCBs, Tween 80 and pH. The MnP activity was increased 1.2-fold with PCBs. The fractional factorial experimental design methodology allowed us to determine the P. ostreatus culture media conditions to enhance Lac and VP activities for efficient removal of Arochlor 1242 (one of the most recalcitrant organochloride pollutants). The factors that shown the greatest effect on Lac activity were: pH, agitation and high concentrations of Arochlor 1242. PMID- 21308602 TI - An experimental study on the bio-surfactant-assisted remediation of crude oil and salt contaminated soils. AB - The effect of bio-surfactant (rhamnolipid) on the remediation of crude oil and salt contaminated soil was investigated in this study. The experimental results indicated that there was a distinct decline of total petroleum hydrocarbon (TPH) concentration within the soil when using rhamnolipid during a remediation period of 30 days, with maximum TPH reduction of 86.97%. The most effective remediation that was observed was with rhamnolipid at a concentration of 2 CMC in soil solution, and a first-order TPH degradation rate constant of 0.0866 d(-1). The results also illustrated that salts in soil had a negative impact on TPH reduction, and the degradation rate was negatively correlated with NaCl concentration in soil solution. The analysis of soil TPH fractions indicated that there was a significant reduction of C13-C30 during the remediation process when using bio-surfactant. PMID- 21308603 TI - Microbial characterization of the biofilms developed for treating ampicillin bearing wastewater. AB - In this study, biofilms were developed in three airlift reactors to treat wastewaters with ampicillin (AMP) of 0, 4 and 8 mg L(-1), respectively. During 60 days of operation, AMP was not found to inhibit the biofilm growth. Denaturing gradient gel electrophoresis (DGGE) and 16S rRNA gene sequencing were used to characterize the bacterial community of these biofilms. It was found that the community diversity was lowered, whereas the community stability was enhanced in the biofilm supplemented with AMP as compared to the biofilm free of AMP. Community members were particularly examined in the biofilms developed with 8 mg L(-1) AMP at different stages. Phylogenetic classification revealed that all the identified bacteria fell into four divisions: beta-Proteobacteria, alpha Proteobacteria, gamma-Proteobacteria and Bacteroides. The dominant genus was Acidovorax sp. with an abundance of about 35%. Further analyses on the identification results showed that the quantitative change of AMP-degrading bacteria in the biofilms developed with AMP was positively related to the AMP biodegradation performance. PMID- 21308604 TI - A combined treatment of landfill leachate using calcium oxide, ferric chloride and clinoptilolite. AB - The aim of this research was development of appropriate procedure for treatment of landfill leachate taken from old sanitary landfill Piskornica (Koprivnica, Croatia). Due to complex nature of the effluent a combined treatment approach was applied. Samples were treated with calcium oxide followed by ferric chloride and finally with clinoptilolite. The optimum amount of treating agents and contact time were determined. Application of calcium oxide (25 g/L, 20 min. contact time) resulted in the reduction of color, turbidity, suspended solids and ammonia for 94.50%, 96.55%, 95.66% and 21.60%, respectively, while the removal efficiency of Cr (VI), Fe, Ni, Cu, Zn and Pb was 75.00%, 95.34%, 56.52%, 78.72%, 73.02% and 100.00%, respectively. After addition of ferric chloride (570 mg Fe(3+)/L, 20 min. contact time) removal efficiency of color, turbidity, suspended solids and ammonia increased to 96.04%, 99.27%, 98.61%, and 43.20%, respectively. Removal of ammonia (81.60%) increased significantly after final adsorption onto clinoptilolite (25 g/L, 4 h contact time). Removal of COD after successive treatment with calcium oxide, ferric chloride and clinoptilolite was 64.70%, 77.40% and 81.00%, respectively. PMID- 21308605 TI - Health communication: beyond recognition to impact. PMID- 21308606 TI - Handedness and schizotypy in non-psychotic relatives of patients with schizophrenia. AB - Existing studies have found the relationship between handedness and schizotypy to be inconsistent, and had limited generalisability since only highly homogeneous groups have been investigated. This study aimed to examine the relation between handedness and the four schizotypal factors identified from a previous confirmatory factor analysis in a population of high familial loading for schizophrenia. Study participants consisted of non-psychotic first-degree relatives (850 parents and 334 siblings) of sib-pairs who were co-affected with schizophrenia. All participants were interviewed with the Diagnostic Interview for Genetic Studies, which contains a section of the modified Structured Interview for Schizotypy, and the Annett handedness questionnaire. Both categorical and continuous indicators for handedness were examined. Non-right handed siblings of schizophrenia patients displayed more positive schizotypal features than their right-handed counterparts when the two-way Annett's handedness classification was adopted. No association was found when handedness was treated as continuous. The relationship between handedness and schizotypy was insignificant for parents probably due to the strong social pressure against left handedness. We concluded that categorical non-right-handedness was associated with positive schizotypy in non-psychotic siblings of schizophrenia patients. The results indicate that an atypical cerebral lateralisation underlying non-right handedness may be also a contributing factor to positive schizotypy. PMID- 21308607 TI - Stepfamily childbearing in Sweden: quantum and tempo effects, 1950-99. AB - Several studies have demonstrated that stepfamily couples have a higher risk of childbearing than couples in a stable union with the same total number of children. Analysing retrospective data from a nationally representative sample of Swedish adults, we find that the risk of a second or third birth is higher when it is the first or second child in a new union. We also find a faster pace of childbearing after stepfamily formation than after a shared birth. The risk of a second birth (in total) is only a little higher in the first two years after stepfamily formation than in the first two years after a shared birth, and thereafter the risk is lower for stepfamilies. The risk of a third birth (in total) is particularly high early in the stepfamily union and remains higher than that of couples with two shared children for at least five years. The stepfamily difference was lower after than before 1980, when the Swedish government introduced parental leave incentives for short birth intervals. PMID- 21308608 TI - [Maternal education and phonological processing in preschool children]. AB - BACKGROUND: 1.: Children's language skills seem to depend on their mothers' level of academic education; 2.: phonological processing, i. e. processing information in terms of acoustic signals with linguistic content, seems to act as an accelerator in the development of language skills. Based on these premises the aim of this study was to evaluate whether there is a correlation between the maternal level of academic education and low level phonological processing skills in children. MATERIAL AND METHODS: 203 preschool-children aged 5;0 to 5;11 years were enrolled in this study. Low level phonological processing was probed using minimal pairs for both words and nonwords (logatoms). The items were chosen with respect to age appropriate vocabulary, phoneme features, phoneme contrast and phoneme position. RESULTS: Children, whose mothers were more highly educated, showed better results in low level phonological processing tasks than children of mothers with lower levels of academic education. DISCUSSION: Our results confirm the hypothesis that there is a correlation between a mother's level of academic education and the phonological processing skills of her child. This could also explain why children whose parents possess a higher level of education often demonstrate better linguistic skills. However, further studies are needed to clarify whether other factors act as a dependant variable. PMID- 21308609 TI - [Hypertonic (3%) vs. isotonic brine nosespray--a controlled study]. AB - PURPOSE: In several in-vitro research studies was shown that hypertonic salt water solution has an enhancing effect on mucociliary beat frequency. Nevertheless nose sprays with isotonic salt water solution are more popular on the market. They are sold as wellness products but also for care and cure of various nose diseases. METHODS: In a randomized double-blind trial with n = 20 healthy volunteers the effect of a 7-day application of hypertonic sodium chloride solution (3% NaCl) measured by saccharine-clearance-test (SCT), rhinomanometry and questionnaires was evaluated in comparison to a isotonic salt solution (0,9% NaCl). RESULTS: The SCT showed in both groups no significant change. In rhinomanometry a significant higher rate of airflow could be measured after a 7 day period of applicating hypertonic spray. The volunteers evaluated the hypertonic solution as "more effective" in regard their nasal airflow. CONCLUSION: Although in this RCT an effect on mucociliary clearance could not be detected after a 7 day application of salt water nose spray, a hypertonic spray showed objectively and subjectively a significant influence on nasal airflow. This effect could be of interest eg. in reducing the use of decongestive nose sprays. PMID- 21308610 TI - [A rare type of an acute neck swelling]. PMID- 21308611 TI - Sustainable medicines and global health care. AB - The global population has now exceeded 7 billion, and forests and other resources around the world are being irreversibly depleted for energy, food, shelter, material goods, and drugs to accommodate population needs. For most of the world's population, plants, based on many well-established systems of medicine, in either crude or extract form, represent the foundation of primary health care for the foreseeable future. Contemporary harvesting methods for medicinal plants are severely depleting these critical indigenous resources. However, maintaining and enhancing the availability of quality medicinal agents on a sustainable basis is an unappreciated public health care concept. To accomplish these goals for future health care, and restore the health of the Earth, a profound paradigm shift is necessary: ALL medicinal agents should be regarded as a sustainable commodity, irrespective of their source. Several approaches to enhancing the availability of safe and efficacious plant-based medicinal agents will be presented including integrated strategies to manifest the four pillars (information, botany, chemistry, and biology) for medicinal plant quality control. These integrated initiatives involve information systems, DNA barcoding, metabolomics, biotechnology, nanotechnology, in-field analysis of medicinal plants, and the application of new detection techniques for the development of medicinal plants with enhanced levels of safe and reproducible biological agents. PMID- 21308612 TI - Intestinal permeability of the constituents from the roots of Saposhnikovia divaricata in the human Caco-2 cell monolayer model. AB - The bidirectional intestinal permeability of the active constituents from the roots of Saposhnikovia divaricata, including four coumarins, anomalin (1), 5 methoxy-7-(3,3-dimethylallyloxy)coumarin (2), decursin (3), and decursinol angelate (4), as well as four chromones, cimifugin (5), prim-O-glucosylcimifugin (6), 3'- O-angeloylhamaudol (7), and sec-O-glucosylhamaudol (8), was studied by using the Caco-2 cell monolayer. These compounds were assayed by HPLC, and their transport parameters, including apparent permeability coefficients (P(app)), were then calculated. The bidirectional P(app) values of the compounds were compared with those of the markers, propranolol and atenolol. Compounds 1-5 and 7 were assigned to well-absorbed compounds, while 6 and 8 were assigned to moderately absorbed compounds. The transport of 1-7 increased linearly as a function of time up to 180 min and concentration within the test range of 10-200 uM, thus their passive diffusion mechanism was proposed. The results provided some useful information for predicting the intestinal absorption in vivo of these compounds. PMID- 21308613 TI - Inhibitory effects of Terminalia chebula extract on glycation and endothelial cell adhesion. AB - Terminalia chebula Retz. has been used in India for a long time to treat many diseases, and its extract was reported to have antidiabetic activity in vivo. In this study, T. chebula methanolic extract (TCE) containing 2.7 % chebulic acid was evaluated for its preventive effects against the formation of advanced glycation end products (AGEs) and endothelial cell dysfunction. When the effects of TCE on AGE formation and on protein crossing-linking by glycation with D threose and lens crystallines were examined, TCE showed inhibitory activity in a dose-dependent manner, and the concentration of 1000 ug/mL presented an activity similar to that of 5 mM aminoguanidine as a positive control. Upon investigating the protective activity of TCE against AGE-induced vascular endothelium dysfunction, human umbilical vein endothelial cells (HUVEC) incubated with 100 ug/mL of AGEs had significantly enhanced reactive oxygen species (ROS) formation, whereas the treatment of T. chebula reduced AGE-induced ROS generation. The incubation of HUVEC with 100 ug/mL of AGEs caused a considerable increase in THP 1 monocytic cell adhesion, but this adhesion was reduced by the treatment of TCE. These results suggest that TCE is a potential agent for alleviating diabetic complications. PMID- 21308614 TI - Screening and bioguided fractionation of Amaryllidaceae species with anti Trichomonas vaginalis activity. AB - The Amaryllidaceae family is known by its ornamental and medicinal value and has attracted considerable attention due to the content of alkaloids of its species, which showed interesting biological properties. The present study evaluated the anti-Trichomonas vaginalis activity of eighteen extracts (12.5 to 0.19 mg/mL) and six isolated alkaloids (125 to 1.9 ug/mL) from Amaryllidaceae species. The alkaloids diminished the trophozoites viability (from 15 to 40 %). The extracts from Hippeastrum breviflorum demonstrated the highest anti-T. vaginalis activity (viability was 60 % reduced), and a bioguided study was conducted. Six fractions with antiprotozoal activity had lycorine and lycosinine as major components suggesting a synergistic effect, taking into account the higher anti-T. vaginalis activity of extracts when compared to isolated alkaloids. Our results point out the antiprotozoal potential of the Amaryllidaceae species against T. vaginalis. This parasite causes trichomonosis, the most prevalent nonviral sexually transmitted diseases (STD) worldwide and a public health problem that requires new therapeutic alternatives as well bioactive natural products. PMID- 21308615 TI - Arctigenin isolated from the seeds of Arctium lappa ameliorates memory deficits in mice. AB - The seeds of Arctium lappa L. (AL, family Asteraceae), the main constituents of which are arctiin and arctigenin, have been used as an herbal medicine or functional food to treat inflammatory diseases. These main constituents were shown to inhibit acetylcholinesterase (AChE) activity. Arctigenin more potently inhibited AChE activity than arctiin. Arctigenin at doses of 30 and 60 mg/kg (p. o.) potently reversed scopolamine-induced memory deficits by 62 % and 73 %, respectively, in a passive avoidance test. This finding is comparable with that of tacrine (10 mg/kg p. o.). Arctigenin also significantly reversed scopolamine induced memory deficits in the Y-maze and Morris water maze tests. On the basis of these findings, arctigenin may ameliorate memory deficits by inhibiting AChE. PMID- 21308616 TI - Hepatoprotective and antioxidant arylbenzofurans and flavonoids from the twigs of Morus mesozygia. AB - The chemical investigation of the twigs of Morus mesozygia resulted in the isolation of three new prenylated 2-arylbenzofurans, named moracin KM, LM, and SC (1-3), nine known 2-arylbenzofurans (4-12), and two known flavonoids (13-14). The structures of the new compounds were established as [2'',3'':6,7]-(6-(S) hydroxymethyl-6-methylpyrano)-2-(3,5-dihydroxyphenyl)benzofuran-5-ol (1), [2'',3'':6,7]-(4,7-dihydro-6-methyloxepine)-2-(3-hydroxy-5 methoxyphenyl)benzofuran-5-ol (2), and [2'',3'':6,7]-(6,6-dimethylpyrano)-2-(3,5 dihydroxyphenyl)benzofuran (3). One of the new compounds, moracin LM (2), displayed modest antioxidant activity, whereas known compounds 4, 13, and 14 showed significant hepatoprotective and antioxidant activities. PMID- 21308618 TI - [Professor Ali El Okbi, a surgeon and activist]. PMID- 21308619 TI - [Management of the first hour of the pediatric septic shock patient]. AB - BACKGROUND: The pediatric septic shock mortality in Tunisia remains high (50%) and was markedly higher than in western countries (10%). The decrease in septic shock mortality has been obtained with the advent of the early goal directed therapy. AIM: The aim of this paper is to propose to the first line practitioners in Tunisia, during the first hour after establishing the diagnosis of septic shock practical clinical guidelines based on earlier consensus recommendations. METHODS: Literature review. RESULTS: Septic shock must be rapidly suspected and early recognized. Adequate oxygenation and prompt correction of hemodynamic derangements has been shown to improve outcome through aggressive volume resuscitation, early empiric antibiotherapy and early initiation of vasopressor agents. Frequent reassessment has been emphasized to ensure appropriate management. This treatment must take into consideration the resources available in our area. We can reasonably hope to decrease mortality of patients with septic shock if the first line physicians keep in mind specific therapeutic goals. PMID- 21308620 TI - [The fracture risk assessment tool (FRAXTM), where are we in Tunisia?]. AB - BACKGROUND: The fracture risk assessment tool (FRAXTM), published in February 2008, is developed based on the use of clinical risk factors with or without bone mineral density tests. AIM: To calculate the FRAX tool in a cohort of Tunisian patients in whom bone mineral density (BMD) was assessed by dual X ray absorptiometry (DXA); to correlate this score to osteoporotic fracture and to BMD assessment and to propose a threshold for therapeutic intervention. METHODS: In a cross sectional study of 582 patients older than 40 years, in whom a BMD measurement by DXA has been performed between January 2006 and December 2009, clinical risk factor for osteoporotic fracture and the occurrence of a prior fragility fracture were assessed. The French version of the FRAX tool was used. Threshold for pharmacological intervention was evaluated by ROC curve. RESULTS: Patients were aged 62.3 +/- 10.4 years. They were female in 91.2% of cases. BMD measurement was under 2.5 standard deviation in 53.2%. Osteopenia was noted in 29.2% of cases and BMD was normal in 17.4 % of cases. Osteoporotic fractures were observed in 38.2% of cases. Major osteoporotic fractures (FOM) (hip, vertebra, radius occurred in 82% of cases. The FRAX(r) score calculated with T-score was 8.55 +/- 8.54% for the FOM and 3.02 +/- 6.37% for femoral neck (FN), while it was 7.81 +/- 6.45% for the FOM and 2.58 +/- 3.97% for the FN if calculated without T score with a significant difference (p <10-3). For the patients having T-score under 2.5 SD, FRAX score was 11.39 +/- 10.32% for the FOM and 4.74 +/- 8.13% for the FN if calculated with T-score and it was 9.18 +/- 6.95 % for the FOM and 3.19 +/- 4.11 % if calculated without T-score. The score FRAX was correlated to BMD (r=0,53, p <10-3) and to fracture prevalence (p < 10-3). The threshold of therapeutic intervention was fixed to 30% for the FOM and 7% for the FN. CONCLUSION: Our study confirms the usefulness of the FRAX score in the prediction of fracture risk in Tunisian population. The determination of therapeutic threshold intervention requires other prospective and larger studies with medico economic analyses. PMID- 21308621 TI - [Therapeutic compliance in primary open angle glaucoma]. AB - BACKGROUND: Compliance with medical treatment is a public health problem. It denotes the patient's perception of the disease and the treatment prescribed by doctors. It concerns one out of two patients. It may happen to any patient at one or another. It is secondary for reasons that are numerous and modifiable in time. It results from problems related to the patient as much as to the doctor. It represents an obstacle to paying for chronic diseases such as chronic open-angle glaucoma, hence the importance given to it in the recent years. AIM: To evaluate the compliance of adult patients suffering from early open-angle glaucoma and to determine the influential factors. METHODS: We conducted a survey at the ophthalmology department of Ibn El Jazzar Hospital among 132 adults being treated for early open-angle glaucoma. The evaluation was done on the basis of patient's medical files and a questionnaire from January 2007 to June of the same year. It ranges between good, average or bad depending on the frequency of the patient's visits to doctors, regularity of treatment and compliance with the doctor's prescription. RESULTS: 40.15% of the patients have positively complied with the prescriptions. This improvement has mainly been due to the following factors: The patient's good knowledge of the disease and its treatment; use of antiseptic eye lotion with the utmost effectiveness for the least instillation and side effects; patient's mastery of drop usage; doctor's intensive care required for some particular cases. CONCLUSION: Our results need to be confirmed by other studies. It's very important to consider all the determining factors in order to improve patient's compliance. PMID- 21308622 TI - [Changes in serum lipids in patients with colorectal cancer]. AB - AIM: To evaluate and assess disruptions of serum lipids at patients having a colorectal cancer. METHODS: Our prospective study interested 30 patients, from 26 to 93 year old, presenting a colorectal cancer confirmed histologically, examined during the period going from March 2003 to April 2004. Thirty healthy controls were examined in parallel. All patients undergo three blood samples respectively in preoperative, 48h and 6 months after surgical operation. The analyses carried out were determination of a total serum cholesterol, HDL (high density lipoprotein) and LDL (low density lipoprotein) cholesterol, serum triglyceride and serum apoprotein (AI and B) RESULTS: We noticed a decrease of total serum cholesterol level in 43% of the cases associated to the reduction of the HDL and the LDL cholesterol in respectively 30% and 76% of cases. The mean values of total serum cholesterol, HDL and LDL cholesterol rates were significantly lower for patients compared to those of controls (p respectively : 0.001; 0.04 and 0.001). Moreover, the level of total serum cholesterol varied significantly with tumor localization ( p= 0,02). CONCLUSION: Serum lipid disruptions affect essentially total cholesterol, HDL and LDL cholesterol. It would be therefore interesting to evaluate their rate at the basal state in order to follow their evolution after treatment in colorectal cancer. PMID- 21308623 TI - [Necrotizing otitis externa: report of 36 cases]. AB - BACKGROUND: Necrotizing otitis externa is a potentially lethal form of otitis externa which occurs mainly in elderly diabetic. AIM: To study the clinical, diagnostic and therapeutic aspects of necrotizing otitis externa and to describe the outcomes of this disease. METHODS: We report in this retrospective study, a series of 36 patients treated in our department for necrotizing otitis externa over a period of 9 years. RESULTS: Our series consisted of 34 diabetics. The average age of our patients was 62 years. The diagnosis was based on clinical, biological and bacteriological data and on imaging findings. A medical treatment based on a systemic antibiotic therapy combining a third generation cephalosporin to a fluoroquinolone was prescribed in 24 cases and to an aminoglycoside in 12 cases. In addition, a local treatment was performed daily and included meticulous cleaning of the external auditory canal and topical application of antimicrobial agents. Surgical debridement of infected soft tissues and bone sequestra was indicated in 8 cases because of the lack of improvement with medical treatment. Only one patient underwent hyperbaric oxygen therapy. The cure rate was estimated at 86%. Only one death was noted. CONCLUSION: Necrotizing otitis externa is a severe infection. Its prognosis has improved markedly since the advent of antibiotics effective on Pseudomonas aeruginosa. Its management must be started without delay and its treatment must be prolonged. PMID- 21308624 TI - [Depression in chronic hemodialysis patients: report of 106 cases]. AB - BACKGROUND: Depression is the most common psychiatric disorder in chronic hemodialysis patients and is associated with mortality. AIM: To evaluate the prevalence of the depression in patients undergoing chronic hemodialysis, and to identify the correlated factors. METHODS: The study population included 106 patients on chronic hemodialysis. The Hospital-Anxiety and Depression Scale was used to diagnosis depression. RESULTS: The prevalence of the depression among the patients surveyed was 46.2%. Among 8 factors correlated with the depression at the univariate analysis, only 2 factors were still strongly correlated at the multivariate analysis: professional inactivity (OR = 6.54; p = 0.01) and anxiety (OR = 1.,5; p = 0.00). CONCLUSION: According to our study, professional inactivity and/or anxiety should make looking for depression in order to optimize the management of the patients on chronic hemodialysis. PMID- 21308625 TI - Primary hyperoxaluria type 1 in Tunisian children. AB - BACKGROUND: Primary hyperoxaliuria type 1 is an autosomal recessive disorder characterized by increasing urinary excretion of calcium oxalate, recurrent urolithiasis, nephrocalcinosis, and accumulation of insoluble oxalate throughout the body. This inborn error of metabolism appears to be a common cause of end stage renal disease in Tunisia. AIMS: To review the clinical, biological and radiological futures of primary hyperoxaluria type 1 and to correlate these aspects with the development of end-stage renal disease. METHODS: we retrospectively reviewed 44 children with Primary hyperoxaliuria type I who were treated in our department during a period of 15 years between 1995 and 2009. The diagnosis was established by quantitative urinary oxalate excretion. In patient with renal impairment, the diagnosis was made by infrared spectroscopy of stone or by renal biopsy. RESULTS: Male to female ratio was 1.2. The median age at diagnosis was 5.75 years. About 43 % of those were diagnosed before the age of 5 years. Initial symptoms were dominated by uraemia. Four patients were asymptomatic and diagnosed by sibling screening of known patients. Nephrocalcinosis was present in all patients. It is cortical in 34%, medullary in 32% and global in 34%. At diagnosis, twelve children were in end-stage renal disease (27%). Pyridoxine response, which is defined by a reduction in urine oxalate excretion of 60% or more, was found in 27%. CONCLUSION: In the majority of patients, the clinical expression of Primary hyperoxaliuria type 1 is characterized by nephrocalcinosis, urolithiasis and renal failure. Pyridoxine sensitivity is associated with better outcome. PMID- 21308626 TI - [Fine-wire localizations in non palpable breast lesions]. AB - BACKGROUND: Breast cancer represents a major health problem in Tunisia. Mammography allows screening and early diagnosis of breast cancer. The Harpoon allows the location of these small lesions in order to have a histological study and to adapt the management. AIM: To demonstrate on one hand, the feasibility and the safeness of the fine-wire localizations of breast lesions due to the collaboration of radiologists and gynecologists, and on the other hand, to show the possibility of outpatient management in these cases. METHODS: Our study is a retrospective study reporting 45 patients who had fine wire breast lesion localization, in the department "C" of the center of maternity and neonatology of Tunis, during a period of 5 years and a half. RESULTS: The rate of malignant lesions was 22.4 % among the patients who had screening mammographies with nine breast cancers among which two bifocal. The rate of in situ cancer was 33.3 % and invasive cancers 66.6 % allowing a less aggressive treatment of a third of the patients. The 38 patients were taken in charge in ambulatory reducing the cost of hospitalization. In our series, we didn't have any complication during the insertion of the harpoon. CONCLUSION: Fine wire breast lesion localization with harpoon is an easy elegant method, under expert hands, allowing a rapid diagnosis compulsory in breast cancers. PMID- 21308627 TI - [Early diagnosis of anastomotic dehiscence after colonic surgery]. AB - BACKGROUND: Anastomotic leaks are often responsible for severe sepsis can lead to death. Rapid diagnosis and early intervention are needed to improve prognosis. AIM: To identify predictors of early diagnosis of anastomotic leakage after colonic resection followed by immediate anastomosis without protective stoma to ensure a rapid therapeutic care and improve prognosis. METHODS: This retrospective study involved patients who had a colonic resection over a period from 1st January 1998 to December 31st, 2009. The diagnosis of anastomotic dehiscence was selected on clinical, radiological and / or surgery. Statistical analysis was undertaken to identify clinical and biological changes leading to early diagnosis. The significance level was set at 0.05. RESULTS: Anastomotic leaks were identified in 28 patients, a rate of 8.9%. Revision surgery was indicated in 23 patients. Univariate analysis identified 3 preoperative factors associated with anastomotic dehiscence (ASA score, the urgency of intervention, and neoplastic etiology), and 5 postoperative factors (parietal complications, respiratory problems, the cardiac disorders, neurological disorders, and bloating). Multivariate analysis identified only three factors related to the anastomotic dehiscence, they were respiratory symptoms, bloating, and neurological disorders. The median length of stay was 15.6 days (5-84). The mortality rate was 1.2%. It was higher in patients with leakage (7.4%) than in patients without leakage (0.7%). CONCLUSION: Better knowledge of these early clinical and laboratory manifestations related to anastomotic leaks, can ask the early indication of a radiological drainage or reoperation, which can improve the prognosis of this dreaded disease. PMID- 21308628 TI - Assessment of quality of life in asthmatics in Tunisia: a prospective study of 85 cases. AB - BACKGROUND: Asthma is a frequent pathology all over the world. The patient well being becomes an aim to achieve in th management of a patient with asthma. Thus, the factors affecting quality of life (QOL) in these patients should be determined. Moreover, as QOL is affected by the socio-cultural and psychological context of each patient, QOL should be assessed in the country where the patient lives. AIM: To determine the factors influencing QOL in our country: Tunisia: a Mediterranean, Arabic and developing country. METHODS: Eighty five adult patients with asthma were included prospectively. The questionnaire of the alteration of QOL in asthmatics in Tunisia (AQLAT) was used. RESULTS: QOL was moderately altered. The score didn't differ between men and women and was not correlated with age. In students, the QOL was less altered than in non students. Patients with severe asthma had a significantly more altered QOL than those with mild to moderate asthma. Nevertheless, there was no correlation between the oldness of asthma and the AQLAT. Besides, the QOL didn't differ in patients with controlled asthma and those with uncontrolled one. CONCLUSION: A good analysis of the factors determining QOL is patients with asthma would allow a more efficient care of them. PMID- 21308629 TI - Cardiac injury in traumatic subarachnoid hemorrhagea: prospective study in 35 patients. AB - BACKGROUND: Various electrocardiographic abnormalities have been noted since 1954 in patients with head trauma complicated by subarachnoid hemorrhage (SAH). However, very few studies have interested to these ECG modifications in the case of post traumatic SAH (t-SAH) AIM: To assess the incidence of ECG abnormalities during the first five days after admission and the predictive value of these cardiac complications on the mortality in t-SAH. METHODS: This prospective study included 35 patients out of 125 with traumatic SAH diagnosed in the emergency unit in Rabta's hospital (2001-2009). Patients with cardio vascular history, thoracic trauma, non neurological coma and vascular-related neurological coma were excluded. An electrocardiogram monitoring was performed. A brain CT scan was performed in admission, 48 h after and case of neurological aggravation. Serum cardiac troponin IC levels were determined on hospital admission and then on the third and fifth days of hospitalization. The statistical analysis was based on the non-parametric variance test of Kruskal-Wallis to compare the means; on the chi 2 and Fisher tests to compare percentage, with a significant result at 0.05 percentile and on the Odds ratio nonparametric factors for death. Association between 2 quantitative variables have been analyzed by Pearson coefficient of correlation. RESULTS: Mean age of the 35 patients was 39 +/- 17 years. Sex ratio was 4 in favor of men. The prevalence of electrocardiographic changes was of 57% (20 patients). Serum Troponin I level showed a peak on the 3rd day then it decreased. The majority of electrical abnormalities occurred during the third after admission and are associated to a markedly increased Troponin I plasma level and to the highest rate of mortality. Statistical analysis showed a significant correlation between T wave changes and the increase of serum Tn IC level (p= 0; 0002). The relative risk of mortality was higher than 7.2 times in cases with increase serum TnIc level. CONCLUSION: We demonstrated that ECG changes were common in patients with t SAH and the major predictive factors of mortality were the increase of serum TnIC and T wave changes. PMID- 21308630 TI - [Ochronosis: report of two familial cases]. AB - BACKGROUND: Ochronosis of alkaptonuria is a rare hereditary autosomal recessive disease in which there is an absence of homogentisic acid oxidase resulting in accumulation of homogentisic acid in tissues. AIM: To report a new case of alkaptonuria CASE REPORT: A 49-year-old man had been followed for 4 years for chronic lombalgia and arthropaty of two knees. He is married to his cousin and father of 4 girls. His parents are also cousins. The clinical examination has found a cutaneuous pigmentation and a lumbar stiffness. At biological checking, creatininemia was at 190 MUmol/L and there are not inflammatory indicators. The radiography have shown a discal dorsolumbar calcifications, anterior inter somatic bridges and bilateral arthritis of knees without articular chondrocalcinosis. The diagnosis of ochronosis have been suspected and confirmed by the blackness of urine and the dosage of alkaptonuria. The patient has been treated symptomatiquely. Familial investigation have revealed that his daughter suffered from the same disease with the notion of blackness of urine. She is 12 year old and she's asymptomatic on the osteoarticular level. CONCLUSION: Alkaptonuria causes a degenerative arthropaty which can endanger functional prognosis. Early diagnosis and scanning of this innate error of metabolism by genetic study play a fundamental interest, especially for molecular and genetic advisement. PMID- 21308631 TI - Volvulus of the small intestine associated with left paraduodenal hernia: a case report. AB - AIM: To report a rare case of a left paraduodenal hernia presenting as volvulus of the small intestine associated to an intestinal malrotation. CASE REPORT: A 2 months-old girl presented with history of bilious vomiting, sonography showed signs of volvulus and emergency laparotomy was performed and confirmed left paraduodenal hernia containing a part of the ileon, coecum with right colon and volvulus of the small intestine out of the hernia sac. CONCLUSION: Paraduodenal hernia is an uncommon cause of small bowel volvulus. It can be suspected by clinical and radiological findings, surgery is always required to prevent small bowel necrosis and to repair the defect. PMID- 21308632 TI - [Duodenal duplication revealed by acute pancreatitis. A case report]. AB - BACKGROUND: Duodenum duplications are uncommon congenital anomalies. Most symptomatic cases are diagnosed in childhood and usually present with obstructive or bleeding symptoms. Acute pancreatitis is rarely attributed to these cysts. AIM: To report a new case of duodenum duplication revealed by acute pancreatitis. CASE REPORT: This 3 year old child presented with an acute pancreatitis. Abdominal ultrasonography and Computer tomography were performed showing a cystic mass depending of the 2nd duodenum. Diagnosis of duodenal duplication is made in laparotomy. A surgical resection of the duplication was performed respecting the papilla. Microscopic examination of the specimen confirmed the duodenal duplication. The patient was asymptomatic after the intervention. CONCLUSION: Duodenum duplications are uncommon congenital anomalies. Acute pancreatitis might be revealing presentation. PMID- 21308633 TI - [Acute peritonitis complicating Crohn's disease: epidemiologic and physiopathological characteristics]. AB - BACKGROUND: An uncommon event in the natural course of Crohn's disease is the spontaneous perforation. It's the most serious intestinal complication. AIM: To report the incidence of this complication and to discuss the mechanism of the perforation. OBSERVATIONS: We report, retrospectively, 4 cases (3 men and one woman; median age: 30 years) of peritonitis complicating Crohn's disease and study their clinical characteristics intra operatively findings and course evolution. Steroid therapy was administrated to all patients before the perforation. The perforation sites are on the ileum in three cases and on the jejunum in one case. The treatment consists in a resection of the perforated intestine with stoma in all cases. CONCLUSION: Perforation in Crohn's disease is a rare event. The exact mechanism of the perforation is still unknown and many hypotheses are presented. PMID- 21308634 TI - [Sugar tumor]. AB - BACKGROUND: Clear cell tumor of the lung is a rare and very unusual benign pulmonary tumor. This tumor is called sugar tumor because of the abundance of glycogen on its cells. AIM: To report a case of sugar tumor and discuss clinical, evolutive features and diagnosis difficulties of this tumor. CASE REPORT: A case of 75 years old woman presenting as a round pulmonary opacity. Computed tomography (CT) scans showed in the left lower lobe a solitary pulmonary solid tumor with central calcifications. The patient underwent tumor resection. Pathologic examination, including immunohistochemical studies, revealed a benign clear cell tumor, so-called "sugar tumor". CONCLUSION: It's the second case reported in Tunisia. This very rare tumor of the lung is characterized by some immunohistological features. Its evolution is favourable after surgery. PMID- 21308635 TI - [Early neonatal infection caused by Streptococcus pneumonias: report of 3 cases]. AB - BACKGROUND: S pneumoniae is a rare cause (1-8 %) of maternofetal infection causing an important morbi-mortality in the newborn and the mother. AIM: To report 3 cases of early neonatal infection due to S pneumonia. CASES REPORT: Three cases of early neonatal infection due to S pneumoniae are reported. The three newborns were at term or near term babies with a vaginal delivery in two cases and a caesarean section in one case. They presented severe symptoms, with a progressive onset after birth, leading to hypoxemic pneumonia in one case and to septic shock in two newborns associated with meningitis in one case. S pneumoniae was isolated in the blood culture in two patients with positive soluble antigens in the cerebrospinal fluid in one case and positive peripheral bacteriological swabs in the other case. In the third case, S pneumoniae was isolated in the tracheal sample of the newborn and his mother. S pneumoniae was sensitive to ampicillin in two patients and of decreased sensitivity to ampicillin in one patient. The clinical course was favourable in the three patients after hospitalization in the intensive care unit. CONCLUSION: Early neonatal infections caused by S pneumonia are rare and are an important cause of morbi-mortality in the newborn and the mother. PMID- 21308636 TI - [TINU syndrome and lymphoid interstitial alveolitis: a new observation]. AB - BACKGROUND: TINU syndrome is a rare entity known Dobrin disease, combining uveitis mostly bilateral and recurrent with acute tubulo interstitial nephritis (AIN) occurring in young adults. The etiology and pathogenesis of this syndrome remain unknown. AIM: To report a new case of TINU syndrome and to discuss its etiopathogenesis. CASE REPORT: This 33 year old women is hospitalized for exploration of acute renal failure, in a context of deterioration of general condition, associated with a unilateral anterior uveitis. The bronchoalveolar lavage showed lymphoid interstitial alveolitis with CD4 and the renal biopsy found lesions characteristic of AIN. Evolution under corticoid treatment was favorable. CONCLUSION: Lymphoid interstitial alveolitis associated with TINU syndrome has been reported only twice before. The discovery of a TINU syndrome must practice bronchoalveolar lavage in search of sub clinical pulmonary involvement. PMID- 21308637 TI - Prenatal diagnosis of esophageal atresia. PMID- 21308638 TI - [Idiopathic infarction of the greater omentum]. PMID- 21308639 TI - [Sternal tuberculosis]. PMID- 21308640 TI - [Papillary carcinoma in a thyroglossal duct cyst]. PMID- 21308641 TI - [Shock, acute respiratory distress syndrome and compartment syndrome following a viper bite]. PMID- 21308642 TI - Report of two cases of primary amelanotic and melanotic anorectal malignant melanoma. PMID- 21308643 TI - Improvement in likelihood to donate blood after being offered a topical anesthetic. AB - BACKGROUND: While there are many reasons people choose not to donate blood, pain sustained during the venipuncture portion of the blood donation process is likely one deterrent to volunteer donation. The purpose of this study was to survey the improvement in likelihood of donation if participants were given the option of a topical anesthetic cream prior to venipuncture. STUDY DESIGN AND METHODS: Over a three month period 316 adults (convenience sample) completed a one page survey consisting of twelve questions pertaining to blood donation. Participants were asked about their likelihood of donating blood in the near future (No Possibility, Possible, Likely, Certain). They were then informed of the possibility of using a topical anesthetic cream prior to donation. Subsequently, their likelihood of donating blood was reassessed. RESULTS: Fifty (16%) subjects reported an increased likelihood of donating blood if offered a topical anesthetic (p<0.0001). Of these respondents reporting an increase in donation likelihood, eleven improved by 2 or more likelihood categories. Amongst the 169 participants who never donated blood, 34 (20%) reported an increased likelihood of donation after being told about the topical anesthetic cream, compared to 16 (10%) of the 147 subjects who had previously donated blood (p=0.02). CONCLUSION: The findings of this study suggest that providing a topical anesthetic had a positive effect on the study participants' likelihood of donating blood. This improvement was greater amongst those who have never donated blood. PMID- 21308644 TI - Case report and management of suspected acute appendicitis in pregnancy. AB - Suspected cases of acute appendicitis in pregnancy are considered surgical emergencies due to the potentially devastating outcomes for both mother and unborn child if the appendix perforates. Acute appendicitis is also the number one cause of non-traumatic acute abdomen in pregnancy, as well as the number one cause of fetal death. We present a case report with a typical presentation of suspected acute appendicitis in a pregnant woman. The work up and diagnostic tools available are discussed at length, as well as the finer points in treatment of this population. PMID- 21308646 TI - The role of morbidity and mortality (M&M) conferences in medical education. PMID- 21308645 TI - Access to care: the physician's perspective. AB - Private practice physicians in Hawaii were surveyed to better understand their impressions of different insurance plans and their willingness to care for patients with those plans. Physician experiences and perspectives were investigated in regard to reimbursement, formulary limitations, pre authorizations, specialty referrals, responsiveness to problems, and patient knowledge of their plans. The willingness of physicians to accept new patients from specific insurance company programs clearly correlated with the difficulties and limitations physicians perceive in working with the companies (p<0.0012). Survey results indicate that providers in private practice were much more likely to accept University Health Alliance (UHA) and Hawaii Medical Services Association (HMSA) Commercial insurance than Aloha Care Advantage and Aloha Quest. This was likely related to the more favorable impressions of the services, payments, and lower administrative burden offered by those companies compared with others. PMID- 21308647 TI - Envision our state with "no more cancer". PMID- 21308648 TI - Neuronal NOS expression in rat's cuneate nuclei following passive forelimb movements and median nerve stimulation. AB - Nitric oxide (NO) synthase (NOS) has been observed in the Cuneate Nuclei (CN), suggesting a role for NO in the modulation of their neurons' activity. The present study was undertaken to evaluate whether passive movement of forelimb as well as electric stimulation of medial nerve modulate the expression of neuronal isoform of NOS (nNOS) within CN. The experiments were carried out on 21 male Wistar rats, by using two different protocols. In the first group of rats the median nerve was stimulated with high frequency trains (phasic stimulation) or at constant frequency (tonic stimulation); as a control, in the third group, no stimulus was delivered. Moreover, in the second group of rats, we imposed to the animal's left forepaw circular paths at a roughly constant speed (continuous movement), or rapid flexions and extensions of the wrist (sudden movement); as a control, in the third group, no movement was imposed. After the experimental session, free-floating frontal sections of medulla oblongata were processed for nNOS or glutamate (GLU) immunohistochemistry. Phasic stimulation of the median nerve or sudden movements of the forelimb determines a significant decrement of the nNOS-positive neurons within the ipsilateral CN, whereas no effects were observed on GLU positive cells. We have also found a peculiar topographical distribution within IN of nNOS-positive neurons: positive cells were clustered at periphery of some "niches" having circular or elliptical form, with GLU positive cells at center. PMID- 21308649 TI - SUMO-1 interacts with mutant ataxin-1 and colocalizes to its aggregates in Purkinje cells of SCA1 transgenic mice. AB - Spinocerebellar ataxia type 1 (SCA1) is one of several progressive neurodegenerative diseases caused by the expanded polyglutamine tract in ataxin 1, the SCA1 gene product. In SCA1 patients and transgenic mice, the affected neuronal cells contain a large ubiquitin-positive aggregate which is derived from the mutant ataxin-1. Small ubiquitin-like modifier-1 (SUMO-1) is one of the most intriguing ubiquitin-like modifiers being conjugated to target proteins and modulating a number of cellular pathways. Recent findings that the aggregates from several neurodegenerative diseases are SUMO-1-positive prompted us to examine the implication of SUMO-1 in SCA1 pathogenesis. In our yeast two-hybrid experiments using mutant ataxin-1 as bait, we identified a SUMO-1 protein that directly binds to ataxin-1 protein. Interestingly, we found that most of the mutant ataxin-1-derived aggregates were SUMO-1-positive both in Purkinje cells of SCA1 transgenic mice and in HeLa cells, but not wild-type ataxin-1 in HeLa cells. In addition, the aggregates in Purkinje cells of SCA1 transgenic mice were positive against both anti-SUMO-1 and anti-ubiquitin antibodies. These results show that the SUMO-1 protein interacts with mutant ataxin-1 and colocalizes with its aggregates which suggests the involvement of the SUMO-1 system in the pathogenesis of SCA1 disease. PMID- 21308650 TI - Activation-dependent descending reflex evacuation motority of anal canal in rat model. AB - The evacuative motor responses of the anal canal and recto-anal reflexes during defecation were studied in an isolated rat recto-anal model preparation using (i) partitioned organ bath, (ii) electrical stimulation, (iii) balloon distension and (iv) morphological techniques. Electrical field stimulation applied to the anal canal or to the distal part of the rectum elicited tetrodotoxin (10(-7) M) sensitive frequency-dependent local or descending contractions of the anal canal and the local responses were bigger in amplitude (14.9 +/- 1.35 mN) than the descending contractions (5.3 +/- 0.7 mN at frequency of 5 Hz, p < 0.05). The balloon-induced distension of the distal rectum evoked descending responses of the anal canal consisting of a short contraction (1.50 +/- 0.18 mN) followed by deep relaxation (3.12 +/- 0.34 mN). In the presence of atropine (3 x 10(-7) M) the electrically-elicited (5 Hz) local or descending contractions of the anal canal were suppressed and a relaxation revealed. The initial contraction component of the distension-induced response was decreased while the relaxation was not changed. During atropine treatment, spantide (10(-7) M) lowered even more the contractile component of the anal canal response. NG-nitro-L-arginine (5 x 10(-4) M) enhanced the contraction, prevented the atropine-dependent relaxation of the electrically-elicited response and inhibited the distension-induced relaxation. L-Arginine (5 x 10(-4) M) suppressed the contraction and extended the relaxation. ChAT-, substance P- and NADPH-diaphorase-positive perikarya and nerve fibers were observed in myenteric ganglia of the anal canal. The results suggest activation-dependent descending reflex motority of the anal canal involving electrical stimulation-displayed cholinergic and tachykininergic and distension manifested nitrergic neuro-muscular communications. PMID- 21308651 TI - Field hockey players have different values of ulnar and tibial motor nerve conduction velocity than soccer and tennis players. AB - The aim of this study was to describe motor nerve conduction velocity in upper and lower extremities in sportsmen. Fifteen high-level field hockey players, seventeen soccer players and ten tennis players were recruited from the Polish National Field Hockey League, Polish Soccer League Clubs, and Polish Tennis Association clubs,respectively. The control group comprised of seventeen healthy, non-active young men. Nerve conduction velocities of ulnar and tibial nerve were assessed with NeuroScreen electromyograph (Toennies, Germany) equipped with standard techniques of supramaximal percutaneus stimulation with constant current and surface electrodes. No significant differences in motor nerve conduction velocities were found between dominant and non-dominant limbs in each studied group. Ulnar nerve conduction velocity measured from above elbow to below elbow was significantly lower only in the field hockey players' dominant limb. Tibial conduction velocity of the field hockey players' non-dominant lower limb was higher in comparison to the tennis players and the control group. There was no significant correlation between body mass and NCV as well as between height of subjects and NCV in both athletes or non-athletes. A slight trend towards a lower TCV values in athletes with longer duration of practicing sport was found. It was most pronounced in the non-dominant lower extremity of field hockey players. PMID- 21308652 TI - Central antalgic activity of resveratrol. AB - A single dose of resveratrol (25 MUg/10MUl) was injected directly into the right lateral cerebral ventricle (icv) of Wistar rats via an implanted cannula in order to study the analgesic properties of the compound. A control group of rats received 10 MUl NaCl 0.9%. The lengthening of the time to reaction to painful stimuli was assessed in the radiant heat tail-flick latency time test. In this study, the response to painful stimuli of the animals treated with resveratrol had a bimodal profile with hypoalgesia or hyperalgesia. In the selected experimental conditions, resveratrol had a definite analgesic effect; the increase in time to reaction ranged from 100-120% (8 rats) to 600-700% (9 rats). In this experiment resveratrol exerts evident central antalgic effects in the majority of rats, which are related to the individual level of excitation and vigilance at baseline. Antinociceptive induced by resveratrol icv injection was maximal at 4-10 min and lasted no longer than 15 min. The effect of resveratrol to produce analgesia after a single icv injection may be interesting for preventing chronic pain. PMID- 21308653 TI - Ligation induced matrix-metalloproteinase-9 activity in peripheral frog nervous system. AB - Matrix metalloproteinases (MMPs) are endopeptidases that cleave matrix, soluble and membrane-bound proteins and are regulated by their endogenous inhibitors the tissue inhibitors of MMPs (TIMPs). MMP-2 and MMP-9 are two of the MMPs which are essential to contribute to inflammatory and degenerative processes in injured nerves. The aim of the present study was to examine expression and activities of MMP-2 and MMP-9 in the injured and control groups frog sciatic nerves using gelatin zymography. Our investigation demonstrated for the first time as far as we know the expression of MMP-2 and MMP-9 in frog sciatic nerve. The expression and activity of MMP-9 were increased two fold on average following ligation. By contrast, MMP-2 activities remained unchanged. These findings suggest that we can consider MMP-9 as a marker for degenerative changes that follow nerve ligation in frog nerve. PMID- 21308654 TI - Investigating paraoxonase-1 gene Q192R and L55M polymorphism in patients with renal cell cancer. AB - Increased oxidative stress can help promote carcinogenesis, including development of renal cell carcinoma. The enzyme protects low-density lipoproteins from oxidation and can be a factor in this process. PON1 Q192R and L55M paraoxonase gene polymorphisms were assessed in 60 renal cell carcinoma patients and 60 healthy controls. Genotypes were examined by PCR; the restriction enzyme AlwI was used to examine the Q192R polymorphism and Hsp92II for the L55M polymorphism. Significant differences in the PON1 Q192R polymorphism were found between patients and controls. The Q allele was more frequent in the patient group than in controls, while the R allele was more frequent in the control group. No significant differences were found in the L55M polymorphism. Additionally, there were no significant differences in L and M allele frequencies. We conclude that the R allele may protect against renal cell carcinoma. PMID- 21308655 TI - Genetic diversity in local and commercial dry bean (Phaseolus vulgaris) accessions based on microsatellite markers. AB - Dry beans are considered to be a crop of great socio-economic importance, because they are an inexpensive source of nutrients and because their cultivation requires considerable manual labor. Studies of genetic diversity have been very important for genetic improvement programs, because they give parameters for the identification of genitors that can provide large heterosis effects and improved segregation in recombinants, increasing the probability of obtaining superior genotypes in the progeny. We evaluated the genetic diversity of 57 dry bean accessions, including 31 local accessions, propagated by small-scale farmers, 20 accessions supplied by the Brazilian Agricultural Research Agency, and six commercial accessions, using 16 microsatellite primers. Among these primers, 13 were found to be polymorphic, giving 29 polymorphic alleles. The largest number of alleles per locus was observed for primer BM141, which had four alleles. The polymorphic information content varied from 0.11 to 0.51, observed for loci BM212 and BM141, respectively. The lowest degree of dissimilarity (0.0) was found between the accession Iapar 81 and the accessions E03, E04, E09, and E13 and between the accession pairs E08 with E16 and Iapar 31 with E06. The highest degree of dissimilarity was found between the accessions Carioca and E22 (1.0). Grouping analysis revealed four groups, according to the place of origin. This tendency was also found in the principal coordinate analysis. The local genotypes were found to have relatively high genetic diversity, while the EMBRAPA and commercial cultivars had a relatively narrow genetic basis. PMID- 21308656 TI - Single-primer PCR correction: a strategy for false-positive exclusion. AB - Polymerase chain reaction (PCR) technology plays an important role in molecular biology research, but false-positive and nonspecific PCR amplification have plagued many researchers. Currently, research on the optimization of the PCR system focuses on double-primer-based PCR products. This research has shown that PCR amplification based on single-primer binding to the DNA template is an important contributing factor to obtaining false-positive results, fragment impurity, and nonspecific fragment amplification, when the PCR conditions are highly restricted during PCR-based target gene cloning, detection of transgenic plants, simple-sequence repeat marker-assisted selection, and mRNA differential display. Here, we compared single- and double-primer amplification and proposed "single-primer PCR correction"; improvements in PCR that eliminate interference caused by single-primer-based nonspecific PCR amplification were demonstrated and the precision and success rates of experiments were increased. Although for some kinds of experiments, the improvement effect of single-primer PCR correction was variable, the precision and success rate could be elevated at 12-50% in our experiment by this way. PMID- 21308657 TI - An optimized preparation method to obtain high-quality RNA from dry sunflower seeds. AB - In an attempt to isolate high-quality, intact total RNA from sunflower (Helianthus annuus) seeds for investigation of the molecular mechanisms of mutations, we tested various procedures, using kits, including RNAiso Plus, RNAiso Plus+RNAiso-mate for Plant Tissue, Trizol, and the Qi method, but no high quality total RNA of high integrity was obtained with any of these methods, probably due to the high content of polyphenols, polysaccharides, and secondary metabolites in mature sunflower seeds. Modifications were made to the Qi method. To avoid polyphenol oxidation, frozen dry seeds free of the seedcase were ground in a mortar with an equal amount of PVP30, and the fine ground powder was transferred to an extraction buffer with 2% PVP30 (w/v), 5% beta-mercaptoethanol (v/v) and LiCl (8 M). A sample homogenate was extracted with chloroform prior to acidic phenol-chloroform extraction. The total RNA was precipitated with 1/4 volume of NaAc and 2 volumes of absolute ethanol to prevent contamination by polysaccharides. The yield of total RNA was 29.95 MUg/100 mg husked dry seeds; the ratios of A260/A230 and A260/A280 were 2.44 and 2.09, respectively. Electrophoretic analysis clearly showed 28S and 18S ribosomal RNA bands. Using the extracted RNA, a fragment of the actin gene was successfully expressed by RT PCR. This modified protocol is suitable for isolating high-quality total RNA from sunflower seeds for molecular research. PMID- 21308658 TI - Meiotic behavior in nonaploid accessions of Brachiaria humidicola (Poaceae) and implications for breeding. AB - Brachiaria humidicola is a grass adapted to seasonally swampy grasslands in Africa; two cultivars, 'common' and Llanero, are widely used in Brazilian pastures. New cultivars are in great demand in order to diversify current production systems to achieve improved quality and yield. Cytological analyses of 55 accessions of this species available from the Embrapa Beef Cattle germplasm collection revealed that 27 are apomictic and have 2n = 54 chromosomes. Chromosome pairing as bi- to nonavalent associations at diakinesis indicated a basic chromosome number in this species of x = 6, as found in other closely related Brachiaria species. Thus, these 27 accessions are nonaploid (2n = 9x = 54). Abnormalities were found in the meiosis of these accessions, at variable frequencies. The most common abnormalities were those related to irregular chromosome segregation, which led to unbalanced gamete formation; but chromosome stickiness, cell fusion, and absence of cytokinesis were also recorded. Although some accessions have a low frequency of meiotic abnormalities, ensuring potentially good pollen viability, these cannot be used in hybridization due to a lack of sexual accessions with the same ploidy level. PMID- 21308659 TI - Glomerular filtration rate in general small animal practice. AB - Quantitative evaluation of renal function in small animal general practice has remained essentially unchanged for decades. Glomerular filtration rate (GFR) is considered the gold standard for evaluating functional renal mass in veterinary medicine. For practical and financial reasons, GFR testing was previously available only at referral veterinary hospitals. Newer techniques for estimating GFR now allow the routine performance of this test in any small animal practice. PMID- 21308660 TI - Septic peritonitis. AB - Bacterial septic peritonitis is a serious condition that requires immediate treatment. The pathogenesis is complex, and the list of diagnostic differentials is extensive. The keys to successful treatment are early recognition of the condition and elimination of the causative organism. Multiple options for draining the peritoneal cavity exist, and further studies are necessary to establish specific, evidence-based guidelines. The prognosis is generally guarded in dogs and cats. Much depends on whether the patient develops concurrent sepsis, systemic inflammatory response syndrome, or multiple organ dysfunction syndrome. PMID- 21308661 TI - Meniscal injury in dogs with cranial cruciate ligament rupture. AB - Meniscal damage is common in dogs with naturally occurring rupture of the cranial cruciate ligament (CrCL). Appropriate diagnosis and treatment of meniscal injuries is critical to avoid chronic lameness in these patients. Given the frequency, expense, and clinical importance of meniscal injuries, a thorough understanding of the meniscus is important for general practitioners and veterinary surgeons alike. Research over the past 7 years has produced an abundance of new information regarding the importance of meniscal pathology, diagnostic methods, and potential treatment options at the time of CrCL surgery. This manuscript highlights recent advances that can benefit clinical practitioners and summarizes research developments that promise new therapies in the near future. PMID- 21308662 TI - Fluid therapy in equine patients: small-volume fluid resuscitation. AB - Fluid therapy is an important component of resuscitation and treatment of critically ill equine patients. However, the decision of which fluid type to use in certain critical situations is somewhat controversial. This article focuses on the potential benefits of performing small-volume resuscitation in critically ill horses by combining hypertonic saline with a colloid (e.g., hetastarch). PMID- 21308663 TI - Skin distribution of imidacloprid by microautoradiography after topical administration to beagle dogs. AB - To investigate the cutaneous distribution, localization, and persistence of imidacloprid in dogs, Advantage Topical Solution labeled with carbon 14 ((14)C) was topically applied as a single treatment at label rates and application pattern based on body weight to two adult beagles. One dog (8.5 kg) received 1.0 mL of the test solution at a single spot in the interscapular area (14 mg active ingredient/kg body weight); the second dog (12.3 kg) was treated with 2.5 mL of the test solution at four sites, each site receiving approximately 0.625 mL, along the dorsal thoracic and lumbar spine area (21 mg active ingredient/kg body weight). Samples of hair, skin surface residue, and skin taken from the application sites and/or distal body regions of the dogs at four intervals between 7 and 56 days after treatment demonstrated the migration of (14)C radioactivity from the application sites to distal areas of the canine haircoat and skin. The (14)C radioactivity concentrations in the skin biopsy and stratum corneum samples diminished steadily over 56 days after treatment. Microautoradiography of the skin showed focal concentrations of radioactivity in the superficial epidermis, hair follicles, and sebaceous glands. The presence of imidacloprid-derived radioactivity within hair follicles and sebaceous glands and on the skin surface is in good agreement with the reported efficacy of imidacloprid against fleas on dogs and cats for up to 1 month despite posttreatment bathing, shampooing, and/or swimming. PMID- 21308664 TI - Treatment of Hepatozoon americanum infection: review of the literature and experimental evaluation of efficacy. AB - There is no labeled treatment for dogs with American canine hepatozoonosis (ACH), but the drug therapies discussed in this article, although not rapidly curative, may be successful in alleviating acute clinical signs, prolonging life, reducing the number of clinical relapses, and enhancing quality of life. This article also describes a pilot trial conducted to assess the efficacy of a novel treatment approach with ponazuril as a stand-alone parasiticide administered for 4 weeks without follow-up decoquinate treatment. Although extended ponazuril treatment in combination with NSAID administration did ameliorate acute clinical signs associated with ACH, the parasite was not completely cleared with this treatment protocol alone. Long-term decoquinate therapy remains a critical component of successful treatment of ACH. PMID- 21308666 TI - The outcomes of critically ill patients with acute kidney injury receiving renal replacement therapy. AB - INTRODUCTION: Acute kidney injury (AKI) is common among critically ill patients and associated with a high mortality. We report here on the outcomes of patients with AKI who received renal replacement therapy (RRT) on our intensive care unit (ICU). We were interested in which parameters measured at the time of ICU admission were predictive of mortality and the long term renal sequelae for these patients. PATIENTS AND METHODS: All ICU patients in a large UK teaching hospital who received RRT for AKI over a 6-year period were identified and reviewed retrospectively. RESULTS: There were 5582 admissions to ICU during this period of which 821 (14.7%) received RRT for AKI. The mean age was 59 years with ICU and hospital mortality rates of 55% and 66% respectively. Logistic regression analysis indicated that being older (OR 1.02 (1.01-1.03)) or having a lower pH (OR 0.07 (0.02-0.27)) or hemoglobin (OR 0.82 (0.74-0.91)) at the time of admission were predictive of mortality. Less than 7% of survivors were RRT dependant at hospital discharge and the majority had pre-existing renal impairment. For those patients with data available, there was a significant rise in the serum creatinine by 12 months post discharge (p<0.001). CONCLUSIONS: The mortality for critically ill patients receiving RRT for AKI is high, with two thirds dying before hospital discharge. The requirement for long-term dialysis was 6.5% of survivors in our series which is much lower than that published elsewhere. Survivors of AKI who regained independent renal function had evidence of lasting renal injury. PMID- 21308667 TI - Ex vivo examination of the biocompatibility of biodegradable magnesium via microdialysis in the isolated perfused bovine udder model. AB - PURPOSE: Being biodegradable, magnesium is considered a promising future implant material but very little is known about the biocompatibility for the tissues in direct contact with it. In this study, the degradation of pure magnesium implants in the skin of an isolated bovine udder was examined over a period of five hours. METHODS: Microdialysis technique was used in order to investigate the reactions at the interface of implant and tissue. Pure titanium implants served as control. Degradation behavior and biocompatibility were evaluated via extracellular magnesium ion concentration and PGE2 and TNF alpha served as indicators of inflammation. RESULTS: Concentrations of 5.5 mmol/l Mg2+ were detected at the beginning, which decreased to a plateau of about 3.5 mmol/l after approximately two and a half hours. PGE2 and TNF alpha concentrations indicated no major inflammatory tissue response to the degradation. CONCLUSIONS: These results give an idea of the ion burden at the implantation site of degrading magnesium and suggest good biocompatibility even at the tissue-implant interface. PMID- 21308668 TI - [Endometriosis: aetiopathogenetic basis]. AB - Endometriosis, defined by the presence of endometrial tissue outside the uterine cavity, is a common condition affecting 10% of women in the reproductive age. Menstrual factors reported to increase risk include dysmenorrhea, early menarche, and shorter cycle lengths. The theory of retrograde menstruation with implantation of endometrial fragments, in conjunction with peritoneal factors to stimulate cell growth is the most widely accepted. There is a growing body of evidence that immunological factors and angiogenesis play a key role in the pathogenesis of endometriosis. In women with endometriosis, there appears to be an alteration in the function of peritoneal macrophages, natural killer cells and lymphocytes, with production of growth factors and inflammatory mediators in the peritoneal fluid. Survival, adhesion, proliferation, invasion and vascularization of endometrial tissue in abdominal cavity may be the consequence of retrograde menstruation and referred to as implantation theory. PMID- 21308669 TI - [Endometriosis: necessary and sequential therapeutic procedures and guidelines]. AB - OBJECTIVES: To define the actual guidelines about the therapy of endometriosis. METHODS: A brief review of the literature for the correct diagnosis of endometriosis and the medical and surgical approach. RESULTS: It is well accepted that the gold standard of endometriosis diagnosis is the direct vision of the disease with laparoscopy or the presence of endometriosis implants in vagina or cervix. Staging must be performed along with the distribution, and depth and bowel involvement must be noted. Symptoms intensity is not related to the degree of endometriosis. Therapy, medical or surgical, should be chosen in relation to symptoms and the disease degree, keeping in mind that surgery is the approach that may offer better results. CONCLUSIONS: The direct vision of the disease is the only method to obtain the correct diagnosis and an accurate staging. However, ultrasound can be helpful in cases of pelvic localization and in the follow-up of the disease. Moreover, MRI can be employed, especially in cases with particular endometriosis implant, e.g. gluteus muscle. Surgery offers the best results but some medical therapy, especially hormonal therapy, is often employed for the relief of pains. PMID- 21308670 TI - [Indications and limits to endourologic procedures for endometriosis of the urinary tract]. AB - INTRODUCTION: The incidence of Urinary tract endometriosis (UTE) ranges from 1% to 3%; bladder is the most affected organ (85% of UTE), followed by ureter (12 - 14% of UTE), for which we distinguish an intrinsic very rare form and an extrinsic variety most frequently occurring in advanced pelvic endometriosis. MATERIALS AND METHODS: From 1997 to 2010, 33 surgical procedures for urologic endometriosis were performed, involving the urinary tract, in 28 patients with mean age of 31 years (25-43). The localization of endometriosis were: 7 cases in the bladder, 2 cases in the vesicoureteral tract, and 19 cases of ureteral tract only. Of these, two cases were diagnosed with an intrinsic localization. RESULTS: Overall, we performed 3 TURB, 5 partial cystectomies (2 with open surgical approach and 3 by laparoscopy procedure), 12 laparoscopic ureterolysis and simultaneous protection of the upper urinary tract with stent, 9 cases of ureterocystoneostomy (UCNS) according to Lich-Gregoire procedure, and 3 according to Boari-Kuess procedure. Of the 12 patients who underwent ureterolysis with laparoscopic and stenting procedure, five cases required a UCNS according to Lich Gregoire technique for persistent ureteral obstruction. CONCLUSIONS: The limits of endoscopic procedures in endometriosis of the urinary tract are correlated both to the degree of extension and the localization of the disease. It is mandatory to achieve an interdisciplinary consensus in order to ensure the disease removal and the simultaneous functional results of the upper urinary tract. PMID- 21308671 TI - [High alpha-fetoprotein persistence after orchiectomy. On a case of uncommon etiology]. AB - BACKGROUND: The following report describes a case of inherited elevation of alpha fetoprotein (AFP) in a young male suspected for testicular cancer. AFP shows very high values during fetal life. After birth the synthesis of AFP decreases dramatically, and only trace amounts are detected in the adult. From this age on, serum AFP can rise above normal in some diseases, e.g. liver disorders, and in some kind of tumors. A condition in which persistent high levels of AFP are found, named Hereditary Persistence of AFP (HPAFP), was first reported in 1983 by Ferguson-Smith, and then recorded in the literature only on eleven occasions till 2004. The occurrence of HPAFP may be underestimated. HPAFP can be easily confirmed by testing AFP levels in blood-related family members. METHODS: An elevated serum AFP (about 20 ug/mL) was found in a 27-year-old white man with an unremarkable medical history, who was concerned to have left testicular cancer. By our examination, his left testis was markedly reduced in size. beta-HCG, LDH, and liver function were normal. Surgical inguinal exploration with testis and spermatic cord excision was carried out. Postoperative repeated AFP levels remained persistently elevated, in the range from 20 to 30 ug/mL. Careful evaluation for occult cancer showed no abnormality. Histology showed necrotic tissue and could not make a reliable diagnosis. A literature search was done using PubMed by key word "alpha-fetoprotein" and "elevation". Thinking of a hereditary trait, we decided to screen patient's blood-related family members. RESULTS: AFP was found to be elevated in another four out of six relatives within three generations, unrelated to any disease. This pedigree was consistent with an autosomal dominant inheritance pattern. CONCLUSIONS: HPAFP could mislead the physician. Failure to recognize HPAFP can lead to unsuitable treatments. The existence of this clinically benign condition needs to be considered in both children and adults with unexplained and persistent elevation of AFP, e.g. those diagnosed or suspected for germ cell tumor. PMID- 21308672 TI - [Diagnosis and treatment of octogenarian neoplastic patients: bladder cancers]. AB - Age is a risk factor for the occurrence of bladder cancer and bladder cancer is a disease of the elderly. The choice of treatment relays on the staging into non invasive and muscle-invasive bladder cancer. Non-invasive bladder cancer is usually treated with transurethral resection of the bladder (TURB) followed by intravesical therapy with BCG or chemotherapeutic agents. The gold standard in the treatment of muscle-invasive bladder cancer is radical cystectomy. The elderly and, in particular, the octogenarian have a worse tolerance for aggressive therapies, due to the higher incidence of side effects and complications. This problem could significantly occur for intravesical BCG therapy and for radical cystectomy. When the urologist faces the treatment of an octogenarian affected by bladder cancer, he should answer many questions: 1. In case of a non-invasive bladder cancer, is it possible to use the same drugs that we use for younger patients (BCG vs chemotherapeutic agents)? Should the timing and the kind of follow-up be the same? 2. Should the octogenarian affected by muscle-invasive bladder cancer undergo radical cystectomy or a less invasive treatment? What kind of diversion should be preferred? Is it possible to propose an orthotopic neobladder to an octogenarian patient? The choice of the treatment should be made on the basis of a careful evaluation of the patient, considering not only the patient's age but also comorbidities and life expectancy. PMID- 21308673 TI - [A case of chronic schistosomiasis four years after infestation]. AB - Authors present a case of bilharziosis incidentally diagnosed in a patient undergoing TURB for suspected bladder cancer. The patient, who in 2005 had gone to Malaysia, had been suffering from recurrent hemorrhagic cystitis since 2007, which were treated with antibiotic therapy. In November 2009 he presented to our observation for persistent hematuria, underwent ultrasound examination, fibroscopy and TURB diagnostics for suspicious lesions. The histopathology diagnosis found granulomatous lesions with typical parasites eggs due to schistosomiasis eggs. As a consequence of that, the patient underwent medical therapy. The pathologist's role becomes nullifying not only for the diagnosis of parasitic infections but also for the exclusion or evidence of urothelial squamous neoplasia. The low incidence of this rare parasitic disease in European tourists and the presence of immigrants in our country require to spread the knowledge of these parasites and the most simple tests for early detection. PMID- 21308674 TI - [Three cases of renal cell carcinoma with sarcomatoid differentiation]. AB - Renal cell carcinoma with sarcomatoid differentiation has an incidence of 4-6%. It occurs more frequently with clinical advanced presentation in relation to the greater biological aggressiveness. This variant was also found both in transplanted kidneys and in patients with von Hippel-Lindau syndrome. The authors present three cases of cancer all clinically evolving to rapidly progressive conditions. The pathologic staging was, respectively: Case 1 pT4 N0 M0 G4 case, Case 2 P G4 T3a N2 M0, Case 3 pT3a N0 M1 G4. The clinical responses related to protocols with VEGF drugs that seem to have better clinical response compared to immunotherapy are still being studied. From the pathologic point of view it is necessary, for all renal cell cancers, to search and identify the sarcomatoid components that, although poorly represented, give a negative prognosis. PMID- 21308675 TI - [Laparoscopic removal of voluminous right seminal vesicle neoplasm]. AB - INTRODUCTION: We present the case of a male adnexal tumor of probable Wolffian origin occurred to the right seminal vesicle of a 47-year-old man. MATERIALS AND METHODS: The patient presented with a 2-month history of hematospermia. The diagnosis was achieved by transrectal ultrasound, CT of the abdomen and pelvis, and biopsy of both prostate and seminal vesicle. The patient was counseled for laparoscopic excision of the right seminal vesicle. RESULTS: The right seminal vesicle, along with the tumor and the right vas deferens, were excised and clear margins were ensured by frozen section. Total operative time was 180 with 200 mL blood loss. The patient's recovery was uncomplicated and he was discharged on the fourth post-operative day. The histologic examination demonstrated a male adnexal tumor of probable Wolffian origin, which is a rare low-grade malignant neoplasm that has been previously described in the broad ligament, ovaries and retroperitoneum of females. The patient is free of relapse at a 20-month follow up. CONCLUSIONS: This is the second report of this entity in a male. The laparoscopic approach for the excision of seminal vesicle neoplasms is a good treatment for its obvious benefits of minimal blood loss, short hospital stay and quick return to normal activity. The magnifications of the anatomical details of the pelvic floor help the surgeon in the dissection of the seminal vesicle from the other structures. PMID- 21308676 TI - [Long-term results of laparoscopic retroperitoneal lymph node dissection (RPLND) in low-stage nonseminomatous germ-cell testicular tumors (NSGCTT) performed by a senior surgeon: 1999-2003]. AB - BACKGROUND: Laparoscopic RPLND for low-stages NSGCTT is controversial: it is performed and recommended by excellent laparoscopic surgeons, but it is not widely used. The aim of this paper is to evaluate the results achieved by a senior surgeon, expert in open RPLND, who was introduced to laparoscopic surgery by excellent laparoscopists (LN, CU, GJ). PATIENTS AND METHODS: of the 48 operated patients, 36 had primary RPLND for clinical stage I disease (22 TIN0, 7 TxN0, 5 T2-3 N0 and 2 TIS1 N0) and 12 had post-chemotherapy surgery for IIA and IIB retroperitoneal nodes with normalized AFP and HCG. L-RPLND was performed with 4 ports and the en bloc removal of unilateral retroperitoneal nodes with the spermatic vessels. No post-operative adjuvant chemotherapy was planned for patients with documented nodal metastases as for open RPLND since 1985. RESULTS: Average operative time was 3.30' for the 36 clinical stage I patients and 4 hours for post-chemotherapy surgery. Blood loss was minimal in all cases, because of early conversion to open surgery in all patients with no immediate hemostasis at L-RPLND. Metastases were found in 6 (17%) out of the 36 clinical stage I patients: none in the 22 pTI, 1 in the 7 Tx, 3 in the 5 pT2-3 and in 2 of the 2 pT1S1 patients. Residual teratoma was found in 6 of the 12 patients who received neo-adjuvant chemotherapy for clinical stage IIA or IIB disease. The other 6 had fibrosis-necrosis. Further metastases developed in 2 of the 30 patients with negative nodes: 1 in the lung in a pT1, and 1 in a pT2 patient with increasing markers. Surprisingly, the first two pT2-3 patients with positive nodes developed liver metastases in a few months after L-RPLND. Consequently, all following patients with active metastases at L-RPLND received 2 courses of adjuvant PEB. All 4 patients who relapsed were cured, are alive and disease-free. CONCLUSIONS: L-RPLND is a very demanding operation, which appears to be more a staging procedure than a curative operation. It is ideal for pT1 clinical stage I and for post-chemotherapy stages IIA& B with residual teratoma and normalized markers, but wait & see in good risk and open RPLND in high risk patients are very competing. Only few reports compared laparoscopic versus open RPLND, but not in a randomized study. PMID- 21308677 TI - [RIRS through semi-rigid ureteroscope and holmium laser in the treatment of ureteral stones retropulsion]. AB - Retrograde displacement of ureteral stones into the renal cavities during ureteroscopic lithotripsy represents a frequent and adverse event that leads to additional procedures (ESWL, PCNL, Retrograde Intra-renal lithotripsy with flexible instruments, DJ stent placement and subsequent EWSL) to obtain full clearence of calculi. All these procedures require a further time of treatment. Between 1/2008 and 3/2009, a total of 48 patients harbouring proximal (21 cases) and distal (27 cases) ureteral stones underwent Holmium Laser lithotripsy. In 3 patients previous percutaneous nephrostomy was performed to drain the excretory way. In 12 cases (25%) stone retropulsion occurred; in 3 patients in the upper calix and in 5 in the renal pelvis. Only in 4 cases the stone migrated in the lower or medium calix. In 8 cases we attempted the immediate treatment of intrarenal displaced stones by advancing the semi-rigid instrument into the renal cavities. In 2 cases the treatment aborted because of the shortness of ureteroscope. The instillation of lubricating lidocaine jelly prevented in 3 cases furher displacement of stone. Washing with saline solution through nephrostomic catheter allowed an effective mobilization of stone and an easy lasertripsy. RIRS was successful in 4 cases. When flexible devices or immediate ESWL are not available, rigid or semi-rigid retrograde lithotripsy with holmium laser immediately performed after ureteral stone displacement represents a safe and effective method to treat displaced stones. Several tricks are required to obtain a good stone-free rate. PMID- 21308678 TI - [Neuroendocrine small-cell bladder cancer: our experience]. AB - INTRODUCTION: Neuroendocrine bladder cancer is extremely rare, with an estimated incidence of 0.35-0.70% of all bladder tumors. The small-cell carcinoma represents the most frequent histologic variant described. Small-cell carcinoma is an epithelial tumor associated with a more aggressive behavior and poorer prognosis than transitional cell bladder carcinoma. The overall survival rate at 5 years does not exceed 8%. At the time of presentation 59% of patients have clinical stage >T2 and 56% show metastatic disease. In 50% of the patients, fatal progression occurs within 6 months. Local recurrence after radical surgery occurred in 50-70% of cases. PATIENTS AND METHODS: We report three cases of pure neuroendocrine small-cell bladder cancer. Hematuria was the most common presenting symptom. Local advanced disease was present in all the cases with stage >T2, metastatic disease in 1 case, lymph node involvement and ureteral bilateral obstruction in 2. Two patients were treated by radical cystectomy, bilateral pelvic limph node resections and urinary derivation. Platinum-based adjuvant chemotherapy was proposed but only two patients received the treatment. One patient with liver metastasis was managed only by extensive TUR and support regimen. RESULTS: In 2 patients residual or relapsed cancer reappered within 2 months after surgery. All of the three patients died of metastatic disease at 5, 7, and 13 months. Median overall survival was 7 months. The most common site of relapse and spread of disease was the peritoneum and intestinal tract, and the reason of death was uncontrolled acute hemorrhage from gastro-intestinal district. CONCLUSIONS: In the absence of a prospective study, and because of the rarity of the disease, the best treatment for small-cell bladder cancer remains uncertain. Neoadjuvant chemotherapy with platinum regimen plus aggressive surgical approach will be the treatment of choice. The association of chemotherapy and radiotherapy should also be considered. PMID- 21308679 TI - [Urethral recurrence of invasive carcinoma following BCG treatment for bladder Ca in situ]. AB - CIS is a flat, high-grade, non-invasive microscopic urothelial carcinoma. It is considered a precursor of invasive bladder cancer. CIS is classified as primary, secondary or concurrent, when occurred as isolated CIS without cuncurrent papillary tumors, or detected during the follow-up of patients with a previous papillary tumor, or finally in the presence of bladder neoplasm. BCG is widely established as the treatment of choice for CIS with a success rate of approximately 70%. BCG reduces the risk of progression of CIS into invasive carcinoma in 30 to 50% of cases. Direct and prolonged contact between the urothelium and BCG is a prerequisite for successful therapy. Discovery of CIS in the prostatic or membranous urethra represents an ominous sign. CIS may be present only in the epithelial lining of the prostatic urethra or in the ducts, or in the worst case it may be found in the prostatic tissue stroma. Urethral involvement by CIS is at high risk of tumor progression and development of metastases due to reduced thickness of lamina propria and absence of muscolaris mucosa. 83 patients, enrolled from 1/1996 to 12/2005 at our urological department with CIS: primary (focal and multifocal) in 25, secondary in 7 and cuncurrent in 51 (associated with T1bG3 cancer in 37 cases), and urethral CIS in 5 and conservatively treated by TUR and intravescical instillations of BCG, 4 developed afterwords only invasive cancer of the urethra in the absence of bladder involvement. In 2 cases cancer arised from the prostatic fossa after TURP, in 1 from membranous urethra and in the last from prostatic ducts. Among the 4 patients, 3 were treated by cystoprostatourethrectomy and Platinum-based chemotherapy, 1 refused surgical treatment. Two patients died for disseminated disease. 1 patient is alive at 60-month's follow-up. In the last patient cancer relapsed at 36-month's follow-up. We conclude that prostatic/urethral involvement during follow-up after successful intravesical treatment with BCG in CIS represents a high risk of developing invasive and incontrolled cancer. A careful watch is recommended in these patients. PMID- 21308681 TI - Amplification of cytokine production through synergistic activation of NFAT and AP-1 following stimulation of mast cells with antigen and IL-33. AB - IL-33 is associated with atopic and autoimmune diseases and, as reported here, it interacts synergistically with Ag to markedly enhance production of inflammatory cytokines in rodent mast cells even in the absence of degranulation. Investigation of the underlying mechanisms revealed that synergy in signaling occurred at the level of TGF-beta-activated kinase 1, which was then transmitted downstream through JNK, p38 MAP kinase, and AP-1. Stimulation of the Ca(2+) /calcineurin/NFAT pathway by Ag, which IL-33 did not, was critical for the synergy between Ag and IL-33. For example, selective stimulation of the NFAT pathway by thapsigargin also markedly enhanced responses to IL-33 in a calcineurin-dependent manner. As indicated by luciferase-reporter assays, IL-33 failed to stimulate the transcriptional activities of NFAT and AP-1 but augmented the activation of these transcription factors by Ag or thapsigargin. Robust stimulation of NF-kappaB transcriptional activity by IL-33 was also essential for the synergy. These and pharmacologic data suggested that the enhanced production of cytokines resulted in part from amplification of the activation of AP-1 and NFAT as well as co-operative interactions among transcription factors. IL-33 may retune mast cell responses to Ag toward enhanced cytokine production and thus determine the symptoms and severity of Ag-dependent allergic and autoimmune diseases. PMID- 21308682 TI - Ly6C supports preferential homing of central memory CD8+ T cells into lymph nodes. AB - Ly6C is a murine cell-surface antigen expressed by plasma cells, subsets of myeloid cells and many T cells, including memory T cells. We previously documented that Ly6C crosslinking induces LFA-1 clustering on naive CD8(+) T cells. Here, we show that in vitro and in vivo differentiation of naive CD8(+) T cells into central (Tcm) but not effector (Tem) memory T cells enhances Ly6C expression, and its crosslinking induces strong LFA-1 clustering on Tcm. Blocking Ly6C function inhibits in vivo Tcm homing to LNs as efficiently as blocking L selectin but it does not potentiate the inhibition provided by blocking either L selectin or LFA-1 function. Thus, Ly6C, L-selectin and LFA-1 all appear to be part of a common homing pathway. In vitro, Ly6C crosslinking enhances Tcm adherence to ICAM-1 in the presence of CCL21. In summary, Tcm homing involves Ly6C, in addition to L-selectin and LFA-1, and appears to potentiate firm adhesion of Tcm to ICAM-1 in synergy with a chemokine. We propose that Ly6C augments Tcm compartmentalization into LNs during their homing. PMID- 21308683 TI - Hypermethylation of tumor-related genes in Tunisian patients with gastric carcinoma: clinical and biological significance. AB - BACKGROUND: Promoter hypermethylation is an alternative mechanism of gene silencing in cancers including gastric carcinoma (GC). Its affects genes with crucial functions as tumor suppressor. METHODS: DNA methylation in the promoter of P16INK4a, DAPK, retinoic acid receptor beta (RARbeta2), RASSF1A, and CDH1 genes was investigated in 79 Tunisian patients with GC using methylation-specific PCR. RESULTS: The methylation frequencies vary from 31.6% for P16INK4a to 65.8% for RARbeta2. Hypermethylation of DAPK and CDH1 was associated with tumor grade and age (P = 0.04 and 0.034) respectively, while hypermethylation of RASSF1A correlated with TNM stage (P = 0.027). The distribution of the methylated DNA at P16INK4a, DAPK, and CDH1 promoters were different in the intestinal and diffuse histotypes of GC according to TNM. Moreover, the survival rate of patients with P16INK4a methylated status was shorter than that of patients with the unmethylated status (P log rank = 0.009). On the other hand, the hypermethylation of RARbeta2 correlated with COX-2 expression (P = 0.001). CONCLUSION: We showed that methylation of P16INK4a is predictive of poor prognosis and could be a useful marker. Moreover, the association between RARbeta2 methylation and COX-2 expression suggests a functional link between these two proteins in gastric carcinogenesis. PMID- 21308684 TI - Serum soluble vascular adhesion protein-1 is a valuable prognostic marker in gastric cancer. AB - BACKGROUND: Vascular adhesion protein-1 (VAP-1) regulates leukocyte tissue infiltration. Elevated serum soluble VAP-1 (sVAP-1) levels occur in certain diseases having an inflammatory component. We previously showed in colorectal cancer that sVAP-1 expression is significantly higher relative to controls, and this decreased expression is associated with poor prognosis and lymph node and liver metastasis. However, sVAP-1 expression has not been described for gastric cancer. This study determines the relationship between preoperative serum sVAP-1 levels and clinicopathological features and prognosis in gastric cancer. METHODS: Preoperative serum was collected from 107 gastric cancer patients and 33 normal controls. sVAP-1 levels were assayed by enzyme-linked immunosorbent assay. RESULTS: The mean sVAP-1 level for cancer patients was significantly higher relative to controls, and decreased with disease progression. Tumor size, serosal invasion, lymph node metastasis, peritoneal dissemination, and TNM classification was significantly correlated with sVAP-1 level. sVAP-1 is also an independent predictive marker for lymph node metastasis. Patients having low sVAP-1 levels had significantly poorer prognosis relative to patients having elevated sVAP-1 in all or stages I-III gastric cancer patients, respectively. CONCLUSIONS: Low sVAP 1 levels are associated with poor prognosis in gastric cancer. Determining sVAP-1 levels may be valuable for predicting prognosis and lymph node metastasis. PMID- 21308685 TI - Clinicopathologic characteristics and prognosis of signet ring cell carcinoma of the stomach: results from a Chinese mono-institutional study. AB - BACKGROUND: Signet ring cell carcinoma (SRC) of the stomach is a histological type based on microscopic characteristics, and its clinicopathologic characteristics and prognosis are still controversial. METHODS: A retrospective analysis was under taken for 2,315 patients with gastric cancer who had undergone gastrectomy from 1980 to 2004. Among them, 211 patients had SRC and were compared with 2,104 patients with non-signet ring cell carcinoma (NSRC). RESULTS: Significant differences were noted in age, gender, and depth of tumor invasion between patients with SRC and NSRC of early gastric carcinoma. There were statistically significant differences in age, gender, macroscopic appearance, tumor size, depth of tumor invasion, peritoneal dissemination, and curability between patients with SRC and NSRC of advanced gastric carcinoma. In early gastric carcinoma, patients with SRC had a significantly better survival rate than those with NSRC, and the signet ring cell histology was an independent predictive factor. In advanced gastric carcinoma, there was no significant difference of survival rate between SRC and NSRC, and the signet ring cell histology was not an independent predictive factor. CONCLUSIONS: SRC is a distinct type of gastric carcinoma in terms of clinicopathologic characteristics and prognosis. PMID- 21308686 TI - CASP8 -652 6N del and CASP8 IVS12-19G>A gene polymorphisms and susceptibility/prognosis of ESCC: a case control study in northern Indian population. AB - BACKGROUND: Caspase8 influences carcinogenesis through regulation of apoptosis, hyperproliferation, and metastasis. Role of genetic variations in caspase8 has been explored in various cancers; however, their predictive and prognostic role in esophageal cancer is poorly understood. METHODS: We investigated the association of two potential caspase8 polymorphisms: CASP8 -652 6N del and CASP8 IVS12-19 G>A polymorphisms with susceptibility and survival of 259 esophageal squamous cell carcinoma (ESCC) cases and 259 cancer-free controls from northern Indian population using PCR/PCR RFLP method. RESULTS: CASP8 IVS12-19 AA genotype was found to be associated with significant increased risk of ESCC (odds ratio (OR) 3.28, 95% confidence interval (CI) 1.04-10.29) specifically in male subjects (OR 3.71, 95% CI 1.01-13.35) with lower third tumor anatomical location (OR 6.00, 95% CI 1.60-22.55). Kaplan-Meier and Cox Regression analysis showed lower median survival (7.13 months vs. 25.21 months) and greater hazard of death (HR 3.40, 95% CI 1.38-7.90) with CASP8 IVS12-19 AA genotype in ESCC cases compared to IVS12-19 GG genotype. However, no association of CASP8 -652 6N del polymorphism with susceptibility and prognosis of ESCC was observed. CONCLUSION: CASP8 IVS12-19 G>A but not CASP8 -652 6N del polymorphism may modulate risk of ESCC and its survival outcome in northern Indian population. PMID- 21308687 TI - Antibody microarray-based technology to rapidly define matrix metalloproteinase (MMP) signatures in patients undergoing resection for primary gastric carcinoma. PMID- 21308688 TI - Impact of dietary carotenoid and packaging during frozen storage on the quality of rainbow trout (Oncorhynchus mykiss) fed carotenoids. AB - BACKGROUND: The storage life of frozen salmonids is often limited primarily by oxidation and flesh discolouration due to carotenoid degradation. The objective of this research was to determine the carotenoid changes and therefore the muscle colour modifications during 6 months of frozen storage (-18 degrees C) of whole rainbow trout fed astaxanthin (100 ppm) or canthaxanthin (80 ppm), kept under two different packagings: plastic film and cardboard box. RESULTS: After 6 months of frozen storage, the carotenoid type effect was seen for dry matter while there was no packaging material effect on carotenoid, total lipids, and TBARS contents of trout fillets. The time under frozen storage had an effect on carotenoid and TBARS fillet concentration. The carotenoid-type effect was noted for the four colour parameters (lightness difference, chroma difference, hue angle difference, and total colour difference) of rainbow trout fillet, while the packaging material effect was observed only for chroma. Frozen storage time had an effect on the four colour parameters of rainbow trout fillet. CONCLUSION: Carotenoid and packaging material effects were more marked for colour parameters than for biochemical parameters. In this study, as fish were frozen and stored as whole fish, fish skin provided good protection against oxidation. PMID- 21308689 TI - Rheological interactions between Lallemantia royleana seed extract and selected food hydrocolloids. AB - BACKGROUND: Lallemantia royleana (Balangu) is a mucilaginous endemic plant which is grown in different regions of world. The flow behaviour of Balangu seed extract (BSE) and its mixture with xanthan, guar and locust bean gums at 1:3, 1:1 and 3:1 ratios, in addition to control samples (0% BSE), were evaluated. To describe the rheological properties of samples, the power law model was fitted on apparent viscosity-shear rate data. To evaluate the interaction between BSE and selected hydrocolloids in dilute solutions, the relative viscosity was also investigated. RESULTS: There was no significant difference between the consistency coefficient of guar and locust bean solutions and their blends substituted with 250 g kg(-1) BSE. The BSE-xanthan mixture at 1:3 and 1:1 ratios had consistency index equal to xanthan solution. BSE-locust bean gum at all ratios, BSE-xanthan at 1:3 ratio and BSE-guar gum at 1:1 and 3:1 ratios indicated relative viscosity lower than values calculated assuming no interaction. The intrinsic viscosity value of BSE was determined 3.50 dL g(-1) . CONCLUSION: The apparent viscosities of BSE, selected hydrocolloids and their blends were the same at a shear rate of 293 s(-1) and the commercial gums can be substituted by 250 g kg(-1) and 500 g kg(-1) BSE. PMID- 21308690 TI - Phenolic acid concentrations in organically and conventionally cultivated spring and winter wheat. AB - BACKGROUND: Organic crops are often thought to contain more phenolic secondary metabolites than conventional ones. This study evaluated the influence of organic and conventional farming on concentrations of phenolic acids in spring and winter wheat cultivars. RESULTS: Five phenolic acids were identified: ferulic, sinapic, p-coumaric, vanillic and p-hydroxybenzoic acid. Ferulic acid was the main phenolic acid in the grain of all tested wheat varieties. Significant differences among the examined cultivars in concentration of particular compounds were observed. Concentrations of phenolic acids varied significantly in organic and conventional wheat. Levels of ferulic and p-coumaric acids, as well as the total phenolic acid content were higher in organic crops. Concentrations of sinapic acid in spring wheat, as well as vanillic and p-hydroxybenzoic acid levels in both types of wheat were significantly higher in conventional grains. The 1000 kernel weight (TKW) of spring and winter wheat was significantly lower in organic crops. CONCLUSION: Organically produced spring and winter wheat had significantly higher concentrations of ferulic and p-coumaric acid as well as the total phenolic acid content than conventional wheat, though the differences in the levels of phenolics were not large. However, these differences are probably caused mainly by smaller size of organic wheat kernels (lower TKW). PMID- 21308691 TI - Reduction of greenhouse gas emissions from feed supply chains by utilizing regionally produced protein sources: the case of Austrian dairy production. AB - BACKGROUND: The aim of this study was to analyse the potential greenhouse gas emissions (GHGE) for regionally alternative produced protein-rich feedstuffs (APRFs) which are utilized for dairy cattle in Austria in comparison to solvent extracted soybean meal (SBME). In addition to GHGE from agriculture and related upstream supply chains, the effects of land use change were calculated and were included in the results for GHGE. Furthermore, mixtures of APRFs were evaluated which provided energy and utilizable protein equivalent to SBME. RESULTS: Highest GHGE were estimated for SBME, mainly due to land use change-related emissions. Medium GHGE were found for distillers' dried grains with solubles, for seed cake and solvent-extracted meal from rapeseed and for lucerne cobs. Cake and solvent extracted meal from sunflower seed as well as faba beans were loaded with lowest GHGE. Substituting SBME by nutritionally equivalent mixtures of APRFs, on average, resulted in a reduction of GHGE of 42% (22-62%). CONCLUSION: Utilization of locally produced APRFs shows clear advantages in terms of GHGE. Balanced mixtures of APRFs may offer specific benefits, as they allow for a combination of desirable nutritional value and reduced GHGE. PMID- 21308692 TI - Implantable mechanical circulatory support: demystifying patients with ventricular assist devices and artificial hearts. AB - Engineering advancements have expanded the role for mechanical circulatory support devices in the patient with heart failure. More patients with mechanical circulatory support are being discharged from the implanting institution and will be seen by clinicians outside the immediate surgical or heart-failure team. This review provides a practical understanding of device design and physiology, general troubleshooting, and limitations and complications for implantable left ventricular assist devices (pulsatile-flow and continuous-flow pumps) and the total artificial heart. PMID- 21308693 TI - High-sensitivity detection using isotachophoresis with variable cross-section geometry. AB - We present a theoretical and experimental study on increasing the sensitivity of ITP assays by varying channel cross-section. We present a simple, unsteady, diffusion-free model for plateau mode ITP in channels with axially varying cross section. Our model takes into account detailed chemical equilibrium calculations and handles arbitrary variations in channel cross-section. We have validated our model with numerical simulations of a more comprehensive model of ITP. We show that using strongly convergent channels can lead to a large increase in sensitivity and simultaneous reduction in assay time, compared to uniform cross section channels. We have validated our theoretical predictions with detailed experiments by varying channel geometry and analyte concentrations. We show the effectiveness of using strongly convergent channels by demonstrating indirect fluorescence detection with a sensitivity of 100 nM. We also present simple analytical relations for dependence of zone length and assay time on geometric parameters of strongly convergent channels. Our theoretical analysis and experimental validations provide useful guidelines on optimizing chip geometry for maximum sensitivity under constraints of required assay time, chip area and power supply. PMID- 21308694 TI - Retention behavior and selectivity of a latex nanoparticle pseudostationary phase for electrokinetic chromatography. AB - The retention characteristics and separation selectivity of a novel latex nanoparticle (NP) pseudostationary phase (PSP) for electrokinetic chromatography have been characterized. The anionic NPs have very low or no affinity for cationic solutes, but show significant interactions and retention based on hydrophobic interactions. Retention factors of alkyl-phenyl ketones increase linearly with the concentration of the NPs and have zero or near zero y intercepts as expected for electrokinetic chromatography with non-micellar PSPs. The retention factors of these solutes and representative pharmaceuticals decrease logarithmically with increases in the concentration of ACN in the background electrolyte, as expected for reversed-phase retention. Linear solvation energy relationship analysis indicates that the NPs are less cohesive than would be expected for polymeric PSPs with similar structure but that the overall separation selectivity can be expected to be similar to polymer PSPs with similar backbone chemistry. The results indicate that the hydrophobic core of the NPs is non-cohesive and is highly accessible to solutes, whereas the ionic head groups are not as accessible and do not contribute substantially to retention or selectivity. PMID- 21308696 TI - High-resolution electrophoretic simulations: performance characteristics of one dimensional simulators. AB - Three comprehensive one-dimensional simulators were used on the same PC to simulate the dynamics of different electrophoretic configurations, including two migrating hybrid boundaries, an isotachophoretic boundary and the zone electrophoretic separation of ten monovalent anions. Two simulators, SIMUL5 and GENTRANS, use a uniform grid, while SPRESSO uses a dynamic adaptive grid. The simulators differ in the way components are handled. SIMUL5 and SPRESSO feature one equation for all components, whereas GENTRANS is based on the use of separate modules for the different types of monovalent components, a module for multivalent components and a module for proteins. The code for multivalent components is executed more slowly compared to those for monovalent components. Furthermore, with SIMUL5, the computational time interval becomes smaller when it is operated with a reduced calculation space that features moving borders, whereas GENTRANS offers the possibility of using data smoothing (removal of negative concentrations), which can avoid numerical oscillations and speed up a simulation. SPRESSO with its adaptive grid could be employed to simulate the same configurations with smaller numbers of grid points and thus is faster in certain but not all cases. The data reveal that simulations featuring a large number of monovalent components distributed such that a high mesh is required throughout a large proportion of the column are fastest executed with GENTRANS. PMID- 21308695 TI - 10,000-fold concentration increase in proteins in a cascade microchip using anionic ITP by a 3-D numerical simulation with experimental results. AB - This paper describes both the experimental application and 3-D numerical simulation of isotachophoresis (ITP) in a 3.2 cm long "cascade" poly(methyl methacrylate) (PMMA) microfluidic chip. The microchip includes 10 * reductions in both the width and depth of the microchannel, which decreases the overall cross sectional area by a factor of 100 between the inlet (cathode) and outlet (anode). A 3-D numerical simulation of ITP is outlined and is a first example of an ITP simulation in three dimensions. The 3-D numerical simulation uses COMSOL Multiphysics v4.0a to concentrate two generic proteins and monitor protein migration through the microchannel. In performing an ITP simulation on this microchip platform, we observe an increase in concentration by over a factor of more than 10,000 due to the combination of ITP stacking and the reduction in cross-sectional area. Two fluorescent proteins, green fluorescent protein and R phycoerythrin, were used to experimentally visualize ITP through the fabricated microfluidic chip. The initial concentration of each protein in the sample was 1.995 MUg/mL and, after preconcentration by ITP, the final concentrations of the two fluorescent proteins were 32.57 +/- 3.63 and 22.81 +/- 4.61 mg/mL, respectively. Thus, experimentally the two fluorescent proteins were concentrated by over a factor of 10,000 and show good qualitative agreement with our simulation results. PMID- 21308697 TI - Cell-cycle-dependent active thermal bystander effect (ATBE). AB - OBJECTIVE: To determine whether the active thermal bystander effect (ATBE) is cell-cycle dependent. MATERIALS AND METHODS: Dividing cells were directly heated for 10 minutes and co-cultured for 24 hours with different bystander cells. We compared the ATBE for dividing and non-dividing human fibroblasts, as well as for dividing human white preadipocytes (HWP) and non-dividing, mature differentiated human white adipocytes. ATBE was assessed as loss of cell viability of the bystander cells by using the MTT assay. Cell-cycle analysis was performed by using flow cytometry. RESULTS: Dividing fibroblasts and preadipocytes showed a significant ATBE (P < 0.008 and P < 0.05) with loss of cell viability of about 10% in the temperature range of 40-48 degrees C. There was no significant difference between the extent of the bystander effect for these two cell populations (P = 0.30). In contrast, non-dividing fibroblasts and mature adipocytes did not generate any ATBE within this temperature range. There was a statistically significant difference in ATBE between dividing and non-dividing cell subpopulations for both fibroblasts (P = 0.003) and preadipocytes (P < 0.001) compared to their non-dividing counterparts. CONCLUSION: These results suggest that the ATBE is a cell-cycle-dependent process which requires actively dividing cells as receiving bystander cells. The cell-cycle dependency of the ATBE could have useful clinical applications in selectively targeting fast growing cells such as tumor cells. Whether the yield of the ATBE can be amplified by synchronizing the exposure to the ATBE with specific phases of the cell cycle remains subject to further investigation. PMID- 21308698 TI - Quercetin inhibits invasion, migration and signalling molecules involved in cell survival and proliferation of prostate cancer cell line (PC-3). AB - Urokinase-type plasminogen activator (uPA) is a serine protease that is involved in cancer progression, especially invasion and metastasis including prostate cancer. uPA activation is mediated by transactivation of uPAR and epidermal growth factor receptor (EGF-R) in prostate cancer progression. Prostate cancer (PC-3) cells have highly invasive capacity and they express uPA and uPAR gene. PC 3 cells are treated with quercetin, which inhibits invasion and migration of PC-3 cells. Quercetin downregulates uPA, uPAR and EGF, EGF-R mRNA expressions. Quercetin inhibits cell survival factor beta-catenin, NF-kappaB and also proliferative signalling molecules such as p-EGF-R, N-Ras, Raf-1, c.Fos c.Jun and p-c.Jun protein expressions. But quercetin increased p38 mitogen-activated protein kinase protein expression. Our results suggest that quercetin inhibit migration and invasion of prostate cancer cells. It shows the value for treatment of invasive and metastasis type of prostate cancer. PMID- 21308699 TI - Long-term exposure to incense smoke alters metabolism in Wistar albino rats. AB - The burning of incense is an important source of indoor air pollution in Asia. We assessed the effect of long-term exposure to incense smoke on the body weight and levels of circulating glucose, triglycerides, total cholesterol, HDL-cholesterol, insulin, adiponectin and leptin in Wistar albino rats. Two groups of rats were used. First group (n = 12) was exposed daily to incense smoke for 4 months at the rate of 4 g day(-1) in the exposure chamber. Another group of rats (n = 12), was used as non-exposed control. Blood samples were collected from all animals after 4, 8, 12 and 16 weeks of exposure. Serum glucose, triglycerides, total cholesterol and HDL-cholesterol, LDL-cholesterol insulin, adiponectin and leptin were measured. Our results showed that incense smoke exposure was associated with decreased weight gain and the adverse metabolic changes of increased triglycerides and decreased HDL-cholesterol concentrations. Exposure to incense was also associated with a transient increase of leptin levels. Taken together, these data suggest that incense smoke influences metabolism adversely in rats. The effect of incense smoke on human health and the underlying mechanisms need to be studied further. PMID- 21308700 TI - Comparative study on enantiomeric excess of main akannin/shikonin derivatives isolated from the roots of three endemic Boraginaceae plants in China. AB - This work systematically investigated the enantiomeric excess (e.e.) of main components isolated from the roots of three endemic Boraginaceae plants distributed extensively in China, named Arnebia euchroma (Royle) Johnst (A.e.), Lithospermum erythrorhizon Sieb. et Zucc. (L.e.) and Onosma confertum W. W. Smith (O.c.), and the optical purity of their hydrolysis products separately, by means of three different approaches. The influence of HCl on the e.e. values of the major constituents was also studied. Analysis of the absolute configurations and e.e. values of all the derivatives acquired was performed by CD and chiral-HPLC respectively. The results of the main constituents demonstrated that A.e. mainly yields S-form naphthoquinone derivatives, while the R-form is predominant in the derivatives of L.e. and O.c. The optical purity of alkannin and shikonin and their derivatives was not influenced by acid treatment in the course of separation and hydrolysis. Additionally, it was found that 100% e.e. of shikinon could be acquired from a specific shikinon ester derivative, beta,beta dimethylacrylshikonin occurring in the roots of O.c., as did 100% e.e. of alkannin from beta,beta-dimethylacrylalkannin contained in the roots of A.e. PMID- 21308701 TI - A liquid chromatography-mass spectrometry method for nicotine and cotinine; utility in screening tobacco exposure in patients taking amiodarone. AB - A liquid chromatographic mass spectrometric (LC-MS) assay for the quantification of nicotine and cotinine in human specimens was developed. Human serum and urine (100 MUL) were subjected to liquid-liquid extraction. For glucuronidated cotinine, serum was alkalinized and hydrolyzed before extraction. The dried samples were reconstituted and run using gradient flow reverse-phase liquid chromatography with MS detection. The ions utilized for quantification of nicotine, cotinine and milrinone (internal standard) were 162.8, 176.9 and 211.9 m/z, respectively. The mean recoveries were over 80% for cotinine and nicotine with excellent linearity between nominal concentrations and peak area ratios, over a wide concentration range. The percentage coefficient of variation and mean error of the inter- and intra-day validations were <15% for nicotine and cotinine. Analysis of serum from cardiac patients receiving amiodarone suggested that a number of patients were either active smokers or exposed to second-hand smoke. Significant concentrations of nicotine and cotinine were measured in the urine of a known smoking volunteer. The method was highly specific, sensitive and applicable as a tool in detecting and monitoring the passive exposure to tobacco smoke using small specimen volumes (0.1 mL). PMID- 21308702 TI - An improved LC-MS/MS method for the determination of taspoglutide in plasma and urine using orthogonal HILIC-RP column switching, ultra-performance LC separation and 'wrong-way-round' electrospray ionization. AB - The synthetic peptide drug taspoglutide, developed for treatment of diabetes, must be quantified at low pg/mL levels in biological samples. This manuscript describes the improvement of a previous method, featuring orthogonal hydrophilic interaction to reversed-phase chromatography column switching and tandem mass spectrometric detection. Signal-to-noise ratio was enhanced and isobaric interferences were reduced by ultra-performance separation using a basic mobile phase in 'wrong-way-round' ionization mode and monitoring a selective fragment ion. Tedious solid-phase extraction cleanup was abandoned in favor of simple protein precipitation. Urine required the addition of surfactants to prevent adsorptive drug loss. Dissociation of complexes with possibly formed anti-drug antibodies was achieved with formic acid. Lower limits of quantitation (LLOQ) were 4 pg/mL in human plasma and 10 pg/mL in urine using a 250 MUL sample, and an LLOQ of 50 pg/mL was obtained in animal plasma using 50 MUL. Precision, accuracy and incurred samples reproducibility fulfilled regulatory requirements. Simultaneous determination of unlabeled and stable isotope labeled taspoglutide, interesting for clearance studies in which both compounds are co-administered, was realized using a structural analog as internal standard. The described method offered excellent sensitivity with low sample consumption, reasonable throughput, moderate costs and high robustness for routine analysis. PMID- 21308703 TI - Celecoxib determination in different layers of skin by a newly developed and validated HPLC-UV method. AB - A simple, rapid and sensitive analytical procedure for the measurement of celecoxib (CXB) levels in skin samples after in vitro penetration studies was developed and validated. In vitro permeability studies in porcine skin were performed for quantification of CXB at different layers of skin, the stratum corneum (SC) and epidermis plus dermis (EP + D) as well as in the acceptor solution (AS) to assess CXB permeation through skin. CXB was quantified by HPLC using a C18 column and UV detection at 251 nm. The mobile phase was methanol water 72:28 (v/v) and the flow-rate was 0.8 mL/min. The CXB retention time was 5 min. The assay was linear for CBX in the concentration range of 0.1-3.0 MUg/mL in the AS (drug permeated through skin) and 5.0-50.0 MUg/mL for drug retained in SC and [EP + D] in vitro. The linear correlation coefficients for the different calibration curves were equal or greater than 0.99. Intra- and inter-assay variabilities were below 8.0%. Extraction of CXB from skin samples showed recoveries higher than 95.0% after 15 min of ultrasonic sound and centrifugation at 2500 rpm for 3 min. The method was considered appropriate for the assay of CXB in skin samples, after in vitro cutaneous penetration studies. PMID- 21308704 TI - Simultaneous determination of fluoxetine and its major active metabolite norfluoxetine in human plasma by LC-MS/MS using supported liquid extraction. AB - A rapid, sensitive and selective bioanalytical method was developed for the simultaneous determination of fluoxetine and its primary metabolite norfluoxetine in human plasma. Sample preparation was based on supported liquid extraction (SLE) using methyl tert-butyl ether to extract the analytes from human plasma. Chromatography was performed on a Synergi 4 MU polar-RP column using a fast gradient. The ionization was optimized using ESI (+) and selectivity was achieved by tandem mass spectrometric analysis using MRM functions, m/z 310 -> 44 for fluoxetine, m/z 296 -> 134 for norfluoxetine and m/z 315 -> 44 for fluoxetine-d5 (internal standard). The method is linear over the range of 0.05-20 ng/mL (using a human plasma sample volume of 0.1 mL) with a coefficient determination of greater than 0.999. The method is accurate and precise with intra-batch and inter batch accuracy (%bias) of < +/- 15% and precision (%CV) of <15% for both analytes. A run time of 4 min means a high throughput of samples can be achieved. To our knowledge, this method appears to be the most sensitive one reported so far for the quantitation of fluoxetine and norfluoxetine and can be used for routine therapeutic drug monitoring or pharmacokinetic studies. PMID- 21308705 TI - High-performance liquid chromatographic determination of anti- hypertensive drugs on dried blood spots using a fluorescence detector--method development and validation. AB - A selective and sensitive high-performance liquid chromatography method with fluorescence detection for simultaneous determination of irbesartan, losartan and valsartan on dried blood spots (DBS) has been developed and validated. It involves solvent extraction of a punch of DBS followed by reversed-phase liquid chromatography on a Lichrospher((r)) 100 RP-18e column. Fluorescence detection was performed at 259 and 385 nm as excitation and emission wavelengths, respectively. The detection limits of irbesartan, losartan and valsartan were 1.8, 3.6 and 1.8 ng/mL respectively. The mean recoveries of irbesartan, losartan and valsartan were 98.68, 98.42 and 97.81%, respectively. The mean inter-day and intra-day precisions of irbesartan, losartan and valsartan were 2.07 and 1.34%, 1.42 and 1.48%, and 3.20 and 2.15% respectively. The proposed method was simple and rapid. Design of experiments was used to evaluate the robustness of the method. PMID- 21308706 TI - Determination of dimethyl fumarate in desiccant and antimould sachets by reversed phase liquid chromatography. AB - A method for the determination of dimethyl fumarate (DMF) in desiccant and antimould sachets, employed for protecting consumer products from humidity and mould, has been developed. The method is based on a solid-liquid extraction followed by HPLC-UV analysis. The method was validated with respect to recovery, linearity, limits of detection and quantitation and precision. The recovery was 98%. The correlation coefficient value (r) was equal to 0.94. Both intra- and inter-day precisions were studied at several concentration levels, being satisfactory in all cases (RSD < 5). Limits of detection and quantification values were in the low microgram per gram level, thus allowing the determination of DMF at concentrations below the limit established (0.1 mg/kg) by the recent EU Directive (Decision 2009/251/EC). The proposed procedure was applied for the determination of the target compound in 41 desiccant and antimould samples. DMF was detected in 39.0% of samples and its content in many samples exceeded the legal limits. The results of our analysis highlight the high risk of exposure to this powerful allergic sensitizer for consumers. PMID- 21308707 TI - Quantification of urapidil, alpha-1-adrenoreceptor antagonist, in plasma by LC MS/MS: validation and application to pharmacokinetic studies. AB - A sensitive high-performance liquid chromatography-positive ion electrospray tandem mass spectrometry method was developed and validated for the quantification of urapidil in plasma. Following liquid-liquid extraction, the analyte was separated using an isocratic mobile phase on a reverse-phase column and analyzed by MS/MS in the multiple reaction monitoring mode using the respective [M + H](+) ions, m/z 388 to 205 for urapidil and m/z 452 to 344 for the internal standard. The assay exhibited a linear dynamic range of 0.1-500 ng/mL for urapidil in plasma. Acceptable precision (<7%) and accuracy (100 +/- 8%) were obtained for concentrations over the standard curve range. The method was successfully applied to quantify urapidil concentrations in a preclinical pharmacokinetic study after a single oral administration of urapidil at 3 mg/kg to rats. Following oral administration the maximum mean concentration in plasma (C(max); 616 +/- 73 ng/mL) was achieved at 0.5 h (T(max)) and area under curve (AUC(0-24)) was 1841 +/- 308 ng h/mL. The half-life (t(1/2)) and clearance (Cl) were 2.47 +/- 0.4 h and 1660 +/- 276 mL/h/kg, respectively. Moreover, it is plausible that the assay method in rat plasma would facilitate the adaptability of urapidil quantification in human plasma for clinical trials. PMID- 21308708 TI - Application of LC-MS/MS method for the in vivo metabolite determination of oleuropein after intravenous administration to rat. AB - A highly sensitive, specific and simple LC-MS/MS method was developed to investigate in vivo bio-transformation of oleuropein in rat. Rat urine samples collected after the intravenous administrations were determined using liquid chromatography coupled to tandem mass spectrometry with electrospray ionization in the negative-ion mode. The assay procedure involves a simple liquid-liquid extraction of parent oleuropein and the metabolite from rat urine with ethyl acetate. Chromatographic separation was operated with 0.1% formic acid aqueous and methanol in gradient program at a flow rate of 0.80 mL/min on an RP-C(18) column with a total run time of 30 min. This method has been successfully applied to simultaneous determination of oleuropein and its metabolite in rat urine. Oxygenation was found to be the major metabolic pathway of the oleuropein in rat after intravenous administration. PMID- 21308709 TI - A sensitive and specific liquid chromatography/tandem mass spectrometry method for determination of pinaverium bromide in human plasma: application to a pharmacokinetic study in healthy volunteers. AB - A sensitive and specific method using liquid chromatography-electrospray tandem mass spectrometry (LC-MS/MS) for the determination of pinaverium bromide in human plasma was developed and validated. Pinaverium bromide and an internal standard (paclitaxel) were isolated from plasma samples by precipitating plasma, and determined by LC-MS/MS in multiple-reaction monitoring mode. The main metabolite of pinaverium bromide and endogenous substances in plasma did not show any interference. The calibration curve was linear over the plasma concentration range of 10.0-10000.0 pg/mL with a correlation coefficient of 0.9979. The relative standard derivations intra- and inter-day at 30.0, 300.0 and 8000.0 pg/mL in plasma were less than 15%. The absolute recoveries of pinaverium bromide and the internal standard were 99.7-111.7 and 106.2%, respectively. The lower limit of quantitation was 10 pg/mL. The analytical method was successfully applied to study the pharmacokinetics of pinaverium bromide tablets in healthy Chinese volunteers. PMID- 21308710 TI - Distribution of the lymphatic vessels in the prostatic fascia. AB - BACKGROUND: The prostatic fascia-preserving procedure is effective for the early recovery of erectile function after radical prostatectomy; however, the long-term influence of on cancer control was unknown. This study clarified the distribution of lymphatic vessels in the prostatic fascia. MATERIAL AND METHODS: The lymphatic vessels were analyzed in 10 prostates obtained from fixed Japanese cadavers (aged, 71-90 years old). Specimens were taken from the apex, the middle part, and the base of the right-hand side of the prostate. Lymphatic vessels were detected by immunohistochemical stain using an antibody specific for the lymphatic endothelial cells (clone D2-40). The lymphatic vessels were counted in the prostate capsule and the prostatic fascia of each section by light microscopy at low power (100*). RESULTS: The median number of lymphatic vessels in the prostatic capsule per prostatic half was 21.0, 14.0, and 21.0 in the apex, middle, and base part of the prostate, respectively. In the prostatic facia the median number of lymphatic vessels per prostatic half was 8.0, 3.0, and 13.0 in the apex, middle, and the base part of the prostate, respectively. In the apex and the middle part the lymphatic vessels in the prostatic fascia were fewer than those in the prostatic capsule. However, in the base part the number of lymphatic vessels in the prostatic fascia was similar to that in the prostatic capsule. CONCLUSIONS: The present study suggested the surgeon to pay more attention for the dissection of the fascia at the base of the prostate. PMID- 21308711 TI - Androgen receptor regulates expression of the MUC1-C oncoprotein in human prostate cancer cells. AB - BACKGROUND: The MUC1 heterodimeric oncoprotein is aberrantly overexpressed in human prostate cancers with more aggressive pathologic and clinical features. However, the signals that regulate MUC1 expression in prostate cancer cells are not well understood. METHODS: MUC1 expression was studied in androgen-dependent and -independent prostate cancer cell lines by quantitative RT-PCR, immunoblotting and assessment of MUC1 promoter activation. Chromatin immunoprecipitation (ChIP) studies were performed to assess androgen receptor (AR) occupancy on the MUC1 promoter. Post-transcriptional regulation of MUC1 expression was assessed by miR-125b-mediated effects on activity of the MUC1 3' untranslated region (3'UTR). RESULTS: The present studies demonstrate that AR occupies a consensus AR element on the MUC1 promoter in androgen-dependent LNCaP, but not in androgen-independent DU145 and PC3, prostate cancer cells. The results further show that AR downregulates MUC1 gene transcription. Stable introduction of exogenous AR in PC3 (PC3/AR) cells and then silencing of AR confirmed AR mediated repression of the MUC1 promoter. AR signaling has also been shown to drive miR-125b expression. The present studies further demonstrate that miR-125b suppresses MUC1 translation in LNCaP cells and that an anti-sense miR-125b upregulates expression of MUC1 protein. In addition, stable expression of miR 125b in DU145 cells resulted in decreases in MUC1 levels. CONCLUSIONS: These findings demonstrate that AR signaling regulates MUC1 expression by transcriptional and posttranscriptional mechanisms in prostate cancer cells. PMID- 21308712 TI - G-protein alpha-s and -12 subunits are involved in androgen-stimulated PI3K activation and androgen receptor transactivation in prostate cancer cells. AB - BACKGROUND: The androgen receptor (AR) is a ligand-dependent transcription factor that mediates androgenic hormone action in cells. We recently demonstrated the involvement of phosphoinositide 3-OH kinase (PI3K) p110beta in AR transactivation and gene expression. In this study, we determined the upstream signals that lead to PI3K/p110beta activation and AR transactivation after androgen stimulation. METHODS: Human prostate cancer LAPC-4 and 22Rv1 cell lines were used for the experiments. AR transactivation was assessed using an androgen responsive element driven luciferase (ARE-LUC) assay. Cell proliferation was examined using BrdU incorporation and MTT assays. Target genes were silenced using small interfering RNA (siRNA) approach. Gene expression was evaluated at the mRNA level (real-time RT-PCR) and protein level (Western blot). PI3K kinase activities were measured using immunoprecipitation-based in vitro kinase assay. The AR-DNA-binding activity was determined using chromatin-immunoprecipitation (ChIP) assay. RESULTS: First, at the cellular plasma membrane, disrupting the integrity of caveolae microdomain with methyl-beta-cyclodextrin (M-beta-CD) abolished androgen induced AR transactivation and gene expression. Then, knocking down caveolae structural proteins caveolin-1 or -2 with the gene-specific siRNAs significantly reduced androgen-induced AR transactivation. Next, silencing Galpha(s) and Galpha(12) genes but not other G-proteins blocked androgen-induced AR transactivation and cell proliferation. Consistently, overexpression of Galpha(s) or Galpha(12) active mutants enhanced androgen-induced AR transactivation, of which Galpha(s) active mutant sensitized the AR to castration-level of androgen (R1881). Most interestingly, knocking down Galpha(s) but not Galpha(12) subunit significantly suppressed androgen-stimulated PI3K p110beta activation. However, ChIP analysis revealed that both Galpha(s) or Galpha(12) subunits are involved in androgen-induced AR interaction with the AR target gene PSA promoter region. CONCLUSION: These data suggest that caveolae-associated G-protein alpha subunits are involved in AR transactivation by modulating the activities of different PI3K isoforms. PMID- 21308714 TI - High-dose-rate brachytherapy boost to the dominant intra-prostatic tumor region: hemi-irradiation of prostate cancer. AB - BACKGROUND: To assess the feasibility, toxicity, and outcome of prostate hemi irradiation with a high-dose-rate brachytherapy (HDR-BT) boost for patients presumed to harbor dominant intra-prostatic tumors in a single lobe. METHODS: After 3D conformal external radiotherapy (3DCRT) to 64-64.4 Gy, 77 patients with non-metastatic locally aggressive prostate cancer have been treated from 2000 to 2004, with HDR-BT using temporary open MRI-guided (192) Ir implants, to escalate the dose in the boost region. Twenty patients (26%) had one lobe involvement (i.e., one sided endorectal MRI, rectal examination, and biopsies) and were boosted to one side of the gland only. A dose of 12, 14, and 16 Gy in two fractions was delivered to 5, 6, and 9 patients, respectively. RESULTS: After a median follow-up 69 months, no differences in late rectal toxicity were observed between the unilaterally and bilaterally irradiated cohorts. Although, grade 2 late urinary toxicity was worse in the hemi-irradiated group (P = 0.03), severe grade >=3 late urinary toxicity at 5 years was not different: 10% versus 8.8% in the unilaterally and bilaterally irradiated cohorts, respectively. Grade 4 late urinary toxicity, however, was exclusively observed in patients boosted to both lobes (5/57, 8.8%). Five-year biochemical relapse-free survival was 79.7% versus 70.5% for the unilateral and bilateral boost groups, respectively (P = 0.99). CONCLUSION: Prostate hemi-irradiation with a HDR-BT boost to the dominant tumor region may be considered when rectal examination, MRI, and biopsies suggest one lobe involvement. Nevertheless, strict dosimetric optimization is needed in order to further reduce the risk of late severe toxicity. PMID- 21308713 TI - Increased cancer cell proliferation in prostate cancer patients with high levels of serum folate. AB - BACKGROUND: A recent clinical trial revealed that folic acid supplementation is associated with an increased incidence of prostate cancer (Figueiredo et al., J Natl Cancer Inst 2009; 101(6): 432-435). As tumor cells in culture proliferate directly in response to available folic acid, the goal of our study was to determine if there is a similar relationship between patient folate status, and the proliferative capacity of tumors in men with prostate cancer. METHODS: Serum folate and/or prostate tissue folate was determined in 87 randomly selected patients undergoing surgery for prostate cancer, and compared to tumor proliferation in a subset. RESULTS: Fasting serum folate levels were positively correlated with prostate tumor tissue folate content (n = 15; r = 0.577, P < 0.03). Mean serum folate was 62.6 nM (7.5-145.2 nM), 39.5% of patients used supplements containing folic acid (n = 86). The top quartile of patients had serum folates above 82 nM, six times the level considered adequate. Of these, 48% reported no supplement use. Among 50 patients with Gleason 7 disease, the mean proliferation index as determined by Ki67 staining was 6.17 +/- 3.2% and 0.86 +/- 0.92% in the tumors from patients in the highest (117 +/- 15 nM) and lowest (18 +/- 9 nM) quintiles for serum folate, respectively (P < 0.0001). CONCLUSIONS: Increased cancer cell proliferation in men with higher serum folate concentrations is consistent with an increase in prostate cancer incidence observed with folate supplementation. Unexpectedly, more than 25% of patients had serum folate levels greater than sixfold adequate. Nearly half of these men reported no supplement use, suggesting either altered folate metabolism and/or sustained consumption of folic acid from fortified foods. PMID- 21308715 TI - Reduced levels of 5-alpha reductase 2 in adult prostate tissue and implications for BPH therapy. AB - BACKGROUND: 5-alpha reductase 2 (5-AR 2) is a key enzyme that is responsible of proper development of prostate tissue. Inhibition of 5-AR 2 has proven to be efficacious for management of urinary symptoms secondary benign prostatic hyperplasia (BPH). However, some patients are resistant to the therapeutic effects of 5-AR 2 inhibitor. We wished to determine why some benign non-cancerous adult human prostates do not express 5-AR 2, and hypothesized that methylation of 5-AR 2 promoter region correlated with low expression of 5-AR 2 protein. METHODS: The transition zone of 42 human prostate tissues after radical prostatectomy was used for evaluation. Initially, 21 paraffin embedded samples were used to assess immunoreactivity to 5-AR 2 antibody in non-cancerous BPH samples. In the next 21 samples, fresh frozen prostate transition zone samples without cancer were assessed for immunoreactivity and methylation of the 5-AR 2 promoter using methyl specific PCR. RESULTS: We show that 6/21 (29%) of benign human prostate samples did not express the 5-AR 2 protein. Moreover, the promoter region of 5-AR 2 contains a CpG island that is methylated in benign prostate epithelial cells in culture and also in 39% (7/18) human prostate tissues. We show a strong correlation between methylation of the 5-AR 2 promoter region and absence of 5-AR 2 protein expression (P = 0.0025, Fisher's exact test). CONCLUSIONS: Methylation of 5-AR 2 promoter may account for low or absent expression of 5-AR 2 in some human adult prostate tissues. PMID- 21308716 TI - Risk factors for incidental prostate cancer-who should not undergo vaporization of the prostate for benign prostate hyperplasia? AB - BACKGROUND: Vaporization of the prostate (e.g., using laser devices) for treatment of benign prostatic hyperplasia does not allow for subsequent histological examination. Therefore, patients should be counseled about the risk of missing an incidental prostate cancer (incPCa). In this study the risk of an incPCa was determined based on all preoperative parameters. METHODS: Thousand three hundred and fifty seven (04/2004-09/2008) patients underwent transurethral resection of the prostate (TURP) in our department. Cases with less than 10 g removed tissue, PSA >20 ng/ml or with known PCa were excluded. Data of the remaining 1,000 consecutive patients were collected retrospectively and statistically analyzed using SAS. RESULTS: Mean age was 69.4 (36-96) years, mean PSA 4.41 (0.08-19.5) ng/ml, mean weight of removed tissue 30.9 (10-110) g. An incPCa was detected in 111 cases. Thirty-four out of these were considered to be clinically relevant (relPCa; stage T1b and/or Gleason sum >=7). In univariate analysis age, volume of the prostate and body mass index correlated with incPCa while age, volume of the prostate and PSA correlated with relPCa. Predictive parameters for a multivariate logistic regression model are age and body mass index for incPCa and age, prostate volume, and number of prior biopsies for relPCa. CONCLUSIONS: More than 1 in 10 patients undergoing TURP has an incPCa and 3.4% have a relPCa. Patients should be counseled carefully about the risk of missing especially relPCa when undergoing vaporization of the prostate. Our model significantly improves prediction of relPCa compared to PSA and digital examination alone. PMID- 21308717 TI - Biological properties of androgen receptor pure antagonist for treatment of castration-resistant prostate cancer: optimization from lead compound to CH5137291. AB - BACKGROUND: Castration-resistant prostate cancer (CRPC) is still dependent on androgen receptor (AR) signaling. We previously reported that a novel nonsteroidal AR pure antagonist, CH4933468, which is a thiohydantoin derivative with a sulfonamide side chain, provided in vitro proof of concept but did not in vivo. METHODS: We developed other derivatives, CH5137291, CH5138514, and CH5166623, and their pharmacological properties were compared with CH4933468 and bicalutamide. Agonist/antagonist activities in AR-mediated transactivation, cell proliferation against LNCaP and LNCaP-BC2, and AR translocation were evaluated. Agonist metabolite was monitored in liver microsomes and in pharmacokinetics experiments. Antitumor activities in CRPC xenograft models were examined using LNCaP-BC2 and VCaP-CRPC. RESULTS: All CH compounds completely inhibited AR mediated transactivation and proliferation of LNCaP and LNCaP-BC2. In contrast bicalutamide showed a partial inhibition of AR-mediated transactivation and a proliferation of LNCaP-BC2. AR translocation to nucleus was inhibited by CH compounds, but stimulated by bicalutamide. In the LNCaP-BC2 xenograft model, however, only CH5137291 showed significant inhibition of plasma PSA level and antitumor activity. The other three CH compounds were metabolized to their core structure which had agonist activity. CH5137291 also exhibited antitumor activity in a VCaP-CRPC xenograft model, but bicalutamide did not. CONCLUSIONS: The molecular mechanism of the CH compounds, inhibition of AR translocation, was different from bicalutamide and this action could contribute to AR pure antagonist activity. Agonist metabolite diminished the antitumor activity of AR pure antagonist. CH5137291 exhibited antitumor activity in LNCaP-BC2 and VCaP CRPC xenograft models, suggesting that the compound has potential for the treatment of CRPC. PMID- 21308718 TI - Construction of tissue micro array from prostate needle biopsies using the vertical clustering re-arrangement technique. AB - BACKGROUND: Tissue microarray (TMA) allows for simultaneous rapid expression analysis of multiple molecular targets in many tissue specimens. TMA's are specifically in demand for the screening for diagnostic and prognostic markers in prostate cancer (PC). Consequently, TMAs from prostate needle biopsy (PNB) material taken at diagnosis before any treatment commenced are in demand. However, since PNB contain only limited amount of tumor arranged within a very thin tissue core, TMA construction from PNB is problematic. METHODS: Archival PNB from 30 PC patients with variable Gleason scores (6-10) and % of cores involvement (30-90%) were used. Following selection of representative cores, the paraffin blocks were melted. Each core was sectioned into equal parts of 3-4 mm in length. For each case, a group of fragments was then re-embedded in a vertical orientation. Using Manual TMA Apparatus, 2 mm cores from each of the vertically rearranged fragments were harvested. Sections (4 um) were stained with H&E and with high-molecular weight cytokeratin (HMWCK), PIN-cocktail (p63 + p504S), and PSA immunohistochemical stains. RESULTS: A TMA from PNB with a capacity of 80 serial 4 um sections was constructed. In all cases, identical tumor and neighboring tissue morphology (atrophic changes and high-grade prostatic intra epithelial neoplasia) with no loss of tissue was evident. CONCLUSIONS: The vertical clustering re-arrangement (VCR) technique is suitable for large scale construction of TMA blocks from PNB maintaining the morphological and immunohistochemical characteristics of the original samples. This method is promising both in terms of archival tissue preservation and biomarkers research. PMID- 21308719 TI - SOCS-3 antagonizes pro-apoptotic effects of TRAIL and resveratrol in prostate cancer cells. AB - BACKGROUND: Therapy for advanced prostate cancer is only palliative and its improvement could be achieved by sensitization to pro-apoptotic agents to which resveratrol belongs. We investigated the interaction between the tumor-selective apoptosis inducer tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and suppressor of cytokine signaling (SOCS-3), an antiapoptotic molecule which is up-regulated in prostate cancer. METHODS: Expression of SOCS-3 and TRAIL (death) receptors was determined by Western blot after treatment with TRAIL in prostate cancer cell lines. Binding of SOCS-3 to death receptors was investigated by immunoprecipitation. Apoptosis rate was determined by a propidium iodide assay after treatment by TRAIL and resveratrol. RESULTS: SOCS-3, whose expression was differentially regulated by TRAIL in androgen-insensitive prostate cell lines, binds to death receptor 4. Overexpression of SOCS-3 reduced apoptosis in TRAIL- and resveratrol-treated DU145 cells and SOCS-3 siRNA increased apoptosis in TRAIL treated PC-3 and LNCaP-IL-6+ cells. CONCLUSIONS: Our results strongly suggest that SOCS-3 is one of the proteins which influence the ability of TRAIL and resveratrol to cause programmed cell death in prostate cancer. PMID- 21308720 TI - Associations between arachidonic acid metabolism gene polymorphisms and prostate cancer risk. AB - BACKGROUND: The arachidonic acid (AA) pathway is suspected to be involved in the development of various cancers, including prostate cancer. However, the role of single nucleotide polymorphisms (SNPs) of AA pathway genes remains unclear. The purpose of this case-control study was to evaluate the association between prostate cancer risk and 14 such SNPs in the PTGS2, PTGES2, ALOX5, ALOX5AP, and LTA4H genes. METHODS: Genotyping was conducted on 585 white prostate cancer cases and 585 healthy, age-matched controls. The best genetic model for each SNP was determined using Akaike's information criterion. Odds ratios for the association between each SNP and prostate cancer risk were calculated, both overall and stratified by obesity (BMI >= 30). Haplotype analysis was conducted for the PTGES2 SNPs. RESULTS: LTA4H rs1978331 was inversely associated with prostate cancer risk overall (unadjusted, overdominant model OR = 0.68, 95% CI: 0.51-0.91 for TC vs. TT/CC). Among non-obese individuals, the GG genotype of PTGES2 rs10987883 was associated with an increased risk for prostate cancer (unadjusted, recessive model OR = 3.23, 95% CI: 1.27-8.23). CONCLUSIONS: Our results indicate that SNPs in certain AA metabolism genes may influence prostate cancer susceptibility. Furthermore, it is possible that obesity, which induces a chronic state of low-level inflammation in addition to several metabolic sequelae, may modify the impact of these SNPs. These findings should be confirmed in a larger study with power to detect differential effects by obesity. PMID- 21308722 TI - Intrapericardial steroid treatment for recurrent pericardial effusion in a patient with acute lymphoblastic Leukaemia. AB - Intrapericardial corticosteroid therapy for pericardial effusion is an uncommon practice. We had an initial experience with this therapeutic measure but this was our first attempt in the context of malignant diseases and paraneoplastic syndrome. A patient with relapsed Acute Lymphoblastic Leukemia and recurrent pericardial effusion presented. She had been treated by pericardiocenthesis and systemic corticosteroids on two occasions. Following the second pericardiocenthesis and pericardial drainage, methylprednisolone was injected into the pericardium prior to withdrawal of the draining catheter. The patient had a dramatic clinical improvement with a short hospital stay and a lower dose of systemic steroids. We conclude that Intrapericardial steroids injection may be beneficial for patients with paraneoplastic syndrome and pericardial effusion. PMID- 21308721 TI - Docetaxel-mediated apoptosis in myeloid progenitor TF-1 cells is mitigated by zinc: potential implication for prostate cancer therapy. AB - BACKGROUND: Docetaxel-based combination chemotherapy is approved by the FDA for the treatment of metastatic castration-resistant prostate cancer. Unfortunately, docetaxel's efficacy is significantly limited by its considerable toxicity on hematopoietic progenitor cells, thus necessitating dose reduction or even discontinuation of the chemotherapy. Induction of pre-mitotic arrest protects cells against docetaxel-mediated toxicity and affords therapeutic opportunities. METHODS: Cell cycle progression was examined by propidium iodide staining. Zinc uptake was determined by FluoZin-3 AM staining. Apoptotic DNA fragmentation was detected using APO-BRDU kit. RESULTS: In the course of our current work, we treated the myeloid progenitor TF-1 cells and the castration-resistant PC-3 and DU-145 prostate cancer cells with physiologically relevant concentrations of zinc. In doing so, we were able to prevent docetaxel-mediated mitotic arrest in zinc accumulating myeloid progenitor TF-1 cells but not in castration-resistant PC-3 and DU-145 prostate cancer cells. Moreover, pre-treatment with zinc abolished docetaxel-induced apoptosis in TF-1 cells, whereas such treatment had no effect on apoptosis in PC-3 and DU-145 prostate cancer cells. CONCLUSIONS: Our results suggest that zinc can protect myeloid progenitor cells against docetaxel induced toxicity without compromising the drug's anti-tumor activity. PMID- 21308723 TI - Assessment of evaluation criteria for survival prediction from genomic data. AB - Survival prediction from high-dimensional genomic data is dependent on a proper regularization method. With an increasing number of such methods proposed in the literature, comparative studies are called for and some have been performed. However, there is currently no consensus on which prediction assessment criterion should be used for time-to-event data. Without a firm knowledge about whether the choice of evaluation criterion may affect the conclusions made as to which regularization method performs best, these comparative studies may be of limited value. In this paper, four evaluation criteria are investigated: the log-rank test for two groups, the area under the time-dependent ROC curve (AUC), an R2 measure based on the Cox partial likelihood, and an R2-measure based on the Brier score. The criteria are compared according to how they rank six widely used regularization methods that are based on the Cox regression model, namely univariate selection, principal components regression (PCR), supervised PCR, partial least squares regression, ridge regression, and the lasso. Based on our application to three microarray gene expression data sets, we find that the results obtained from the widely used log-rank test deviate from the other three criteria studied. For future studies, where one also might want to include non likelihood or non-model-based regularization methods, we argue in favor of AUC and the R2-measure based on the Brier score, as these do not suffer from the arbitrary splitting into two groups nor depend on the Cox partial likelihood. PMID- 21308724 TI - Measures of prediction error for survival data with longitudinal covariates. PMID- 21308725 TI - Discrimination measures for survival outcomes: connection between the AUC and the predictiveness curve. AB - Finding out biomarkers and building risk scores to predict the occurrence of survival outcomes is a major concern of clinical epidemiology, and so is the evaluation of prognostic models. In this paper, we are concerned with the estimation of the time-dependent AUC--area under the receiver-operating curve- which naturally extends standard AUC to the setting of survival outcomes and enables to evaluate the discriminative power of prognostic models. We establish a simple and useful relation between the predictiveness curve and the time dependent AUC--AUC(t). This relation confirms that the predictiveness curve is the key concept for evaluating calibration and discrimination of prognostic models. It also highlights that accurate estimates of the conditional absolute risk function should yield accurate estimates for AUC(t). From this observation, we derive several estimators for AUC(t) relying on distinct estimators of the conditional absolute risk function. An empirical study was conducted to compare our estimators with the existing ones and assess the effect of model misspecification--when estimating the conditional absolute risk function--on the AUC(t) estimation. We further illustrate the methodology on the Mayo PBC and the VA lung cancer data sets. PMID- 21308726 TI - Correction of confounding bias in non-randomized studies by appropriate weighting. AB - In non-randomized studies, the assessment of a causal effect of treatment or exposure on outcome is hampered by possible confounding. Applying multiple regression models including the effects of treatment and covariates on outcome is the well-known classical approach to adjust for confounding. In recent years other approaches have been promoted. One of them is based on the propensity score and considers the effect of possible confounders on treatment as a relevant criterion for adjustment. Another proposal is based on using an instrumental variable. Here inference relies on a factor, the instrument, which affects treatment but is thought to be otherwise unrelated to outcome, so that it mimics randomization. Each of these approaches can basically be interpreted as a simple reweighting scheme, designed to address confounding. The procedures will be compared with respect to their fundamental properties, namely, which bias they aim to eliminate, which effect they aim to estimate, and which parameter is modelled. We will expand our overview of methods for analysis of non-randomized studies to methods for analysis of randomized controlled trials and show that analyses of both study types may target different effects and different parameters. The considerations will be illustrated using a breast cancer study with a so-called Comprehensive Cohort Study design, including a randomized controlled trial and a non-randomized study in the same patient population as sub cohorts. This design offers ideal opportunities to discuss and illustrate the properties of the different approaches. PMID- 21308727 TI - A novel set of structures within the elasmobranch, ovarian follicle. AB - Elasmobranch fishes produce some of the largest oocytes known, exceeding 10 cm in diameter. Using various microscopy techniques we investigated the structural adaptations which facilitate the production of these large egg cells in three species of shark: the Atlantic sharpnose shark, Rhizoprionodon terraenovae, dusky smoothound, Mustelus canis and the little gulper shark, Centrophorus uyato. The ovarian follicle of elasmobranchs follows the typical vertebrate pattern, with one notable exception; the zona pellucida reaches extreme widths, over 70 MUm, during early oogenesis. Contact between the follicle cells and the oocyte across the zona pellucida is necessary for oogenesis. We describe here a novel set of large, tube-like structures, which we named follicle cell processes that bridge this gap. The follicle cell processes are more robust than the microvilli associated with the follicle cells and the oocyte plasma membrane and much longer. During early oogenesis the follicle increases in size relatively quickly resulting in a wide zona pellucida. At this stage the follicle cell processes appear taut, uniform and radially oriented. As oogenesis continues the zona pellucida narrows and the follicle cell processes change their orientation, appearing to wrap around the oocyte. The presence of the contractile protein actin within the follicle cell processes and their change in orientation may well be an adaptation for maintaining the integrity of these large oocytes. The follicle cell processes also contain electron dense material, identical to material found within the follicle cells, suggesting a role in the transport of metabolites to the developing oocyte. PMID- 21308728 TI - Sex steroid and thyroid hormone receptor expressions in the thyroid of the American alligator (Alligator mississippiensis) during different life stages. AB - The expression of estrogen receptors, ESR1 (ERalpha) and ESR2 (ERbeta), and androgen receptors (AR) in the thyroid gland has been reported in few vertebrate species other than a few mammals. This study reports the presence of sex steroid hormone receptors and thyroid receptors (ERalpha, ERbeta, AR, TRalpha, and TRbeta) in the thyroid gland of the American alligator at several life stages. It provides a semiquantification and distribution of ERalpha in the thyroid follicle cells using an immunohistochemical approach as well as reports quantitative differences in mRNA expression of ERalpha, ERbeta, TRalpha, TRbeta, and AR in the same tissue using quantitative real time-PCR (Q-PCR) with primers designed specifically for alligators. The thyroid tissue of the American alligator expresses ERalpha, ERbeta, and AR at all of the life stages examined here although no statistically significant differences were observed between male and female in thyroid mRNA expression for any of the genes analyzed. No sexual dimorphism was observed in ERalpha immunostaining. No statistical analysis across life stages were performed due to confounding factor of season. PMID- 21308729 TI - The role of retinoic acid receptor inhibitor LE135 on the osteochondral differentiation of human bone marrow mesenchymal stem cells. AB - The present study aimed to investigate the role of a retinoic acid receptor-beta (RARbeta) inhibitor LE135 on TGF-beta induced chondrogenesis of human bone marrow mesenchymal stem cells (hMSCs). Pellet culture with exogenous transforming growth factor-beta (TGF-beta), and a mechanically loaded scaffold system were used to provide two culture models. All samples were cultured for 8 days and changes in early gene expression were determined. Glycosaminoglycan and mRNA expression data showed that LE135 itself did not induce any chondrogenic response in either pellet culture or scaffold culture of hMSCs. LE135 actually inhibited the chondrogenic response caused by exogenous TGF-beta, or endogenous TGF-beta induced by mechanical load, while the expression of genes normally associated with osteogenesis was not affected. This suggests that the inhibitor LE135 affects the osteochondral differentiation pathway at a different stage, inhibiting chondrogenic gene expression while having no effect on genes normally associated with the osteogenic phenotype. Alternatively, it might be that different cells were proceeding down different lineages. Some cells were undergoing chondrogenesis and this was affected by LE135, while other cells underwent osteogenic differentiation and were not affected by LE135. PMID- 21308730 TI - Inhibition of thyroid-restricted genes by follicular thyroglobulin involves iodinated degree. AB - Follicular thyroglobulin (TG) reflects the storage of both iodine and thyroid hormone. This is because it is a macromolecular precursor of thyroid hormone and organic iodinated compound in follicular lumen. Thus, it may have an important feedback role in thyroid function. In this study, monolayer cells were cultured and follicles were reconstituted with primary pig thyroid cells in vitro. Reconstituted follicles were treated with iodine and methimazole (MMI), a drug that blocks iodine organification and reduces the degree of TG iodination in follicular lumen. The high degree of iodinated TG in follicular lumen was observed to inhibit thyroid-restricted gene expression. To confirm this finding, monolayer thyroid cells were treated with a different degree of TG iodination at the same concentration. These iodinated TG were extracted from reconstituted follicles of different groups. In this manner, this study provides firsthand evidence suggesting that follicular TG inhibits the expressions of thyroid restricted genes NIS, TPO, TG, and TSHr. PMID- 21308731 TI - Identification of a sequence in the matricellular protein SPARC that interacts with the scavenger receptor stabilin-1. AB - SPARC (osteonectin/BM-40), a secreted matricellular protein that promotes cellular deadhesion and motility in wound healing, carcinogenesis, and inflammation, binds to the scavenger receptor stabilin-1 in alternatively activated macrophages and undergoes endocytosis and clearance from the extracellular space. Both SPARC and stabilin-1 are expressed by endothelial cells during inflammation, but their interaction in this context is unknown. We have identified a binding site on SPARC for stabilin-1 by a solid-state peptide array coupled with a modified enzyme-linked immunosorbent assay. A monoclonal antibody that recognizes the identified binding site was also characterized that could be an inhibitor for the SPARC-stabilin-1 interaction in macrophages or endothelial cells. PMID- 21308732 TI - Effects of Cissus quadrangularis on the proliferation, differentiation and matrix mineralization of human osteoblast like SaOS-2 cells. AB - Osteoporosis is a public health problem which is associated with significant morbidity and mortality. The repair of bone defect is still a big challenge for orthopedic surgeons. Traditional use of Cissus quadrangularis (C. quadrangularis) in the treatment of bone disorders has been documented. The present study was employed to delineate the effects of ethanolic extract of C. quadrangularis on the proliferation, differentiation and matrix mineralization of human osteoblast like SaOS-2 cells. Lactate dehydrogenase assayed in the conditioned medium of control and C. quadrangularis treated cells did not differ significantly indicating that ethanolic extract of C. quadrangularis is nontoxic to osteoblastic cells. [(3)H] Thymidine incorporation assay revealed that C. quadrangularis treatment has increased the DNA synthesis of human osteoblastic SaOS-2 cells indicating increased proliferation of these cells. The data on alizarin red and ALP staining revealed increased matrix mineralization of human osteoblast like SaOS-2 cells. The study also revealed that the anabolic actions of ethanolic extract of C. quadrangularis in human osteoblast like cells are mediated through increased mRNA and protein expression of Runx2, a key transcription factor involved in the regulation of bone matrix proteins. Chromatin immunoprecipitation analysis revealed increased transcriptional activity of Runx2 on the promoter of osteocalcin after C. quadrangularis treatment. These results indicate positive regulation of C. quadrangularis on the proliferation, differentiation, and matrix mineralization of human osteoblast like SaOS-2 cells. PMID- 21308733 TI - Effects of p-CREB-1 on transforming growth factor-beta3 auto-regulation in hepatic stellate cells. AB - Previous studies have demonstrated that transforming growth factor-beta3 (TGF beta3) protected liver against fibrosis in vivo and vitro, but its regulation is poorly understood. In addition, the cAMP-responsive element (CRE) in TGF-beta3 promoter is recognized as an important regulatory site for TGF-beta3 auto regulation. Thus, we hypothesize that transcription factor CRE-binding protein-1 (CREB-1) regulates the auto-induction of TGF-beta3 in hepatic stellate cells (HSCs). We used exogenous TGF-beta3 to activate the signal pathway of TGF-beta3 auto-regulation in HSCs, results indicated that exogenous TGF-beta3 could up regulate the protein and mRNA expressions of TGF-beta3, and provoke the phosphorylation of CREB-1 on Ser-133, besides, it could induce the DNA binding activity of p-CREB-1 and activate TGF-beta3 promoter as well. Additionally, we used pGenesil-1.1-shRNA-CREB-1 and pRSV-CREB-1 expression vector to silence and up-regulate CREB-1 gene expression respectively, and the results indicated that inhibition of CREB-1 suppressed exogenous TGF-beta3 stimulation of TGF-beta3 mRNA and protein expressions in HSCs, whereas up-regulation of CREB-1 induced this stimulation. Our results indicate that exogenous TGF-beta3 up-regulates the activity of TGF-beta3 promoter by activating CREB-1, then induces the mRNA and protein expressions of TGF-beta3. Especially, p-CREB-1 is a critical transcription factor in mediating TGF-beta3 auto-induction. PMID- 21308734 TI - Inhibitory effect of curcumin on oral carcinoma CAL-27 cells via suppression of Notch-1 and NF-kappaB signaling pathways. AB - Curcumin has been reported to inhibit cell growth and induce apoptosis in oral cancer cells. Although many studies have been done to uncover the mechanisms by which curcumin exerts its antitumor activity, the precise molecular mechanisms remain to be unclear. In the present study, we assessed the effects of curcumin on cell viability and apoptosis in oral cancer. For mechanistic studies, we used multiple cellular and molecular approaches such as gene transfection, real-time RT-PCR, Western blotting, invasion assay, and ELISA. For the first time, we found a significant reduction in cell viability in curcumin-treated cells, which was consistent with induction of apoptosis and also associated with down-regulation of Notch-1 and nuclear factor-kappaB (NF-kappaB). Taken together, we conclude that the down-regulation of Notch-1 by curcumin could be an effective approach, which will cause down-regulation of NF-kappaB, resulting in the inhibition of cell growth and invasion. These results suggest that antitumor activity of curcumin is mediated through a novel mechanism involving inactivation of Notch-1 and NF-kappaB signaling pathways. PMID- 21308735 TI - Creatine kinase brain overexpression protects colorectal cells from various metabolic and non-metabolic stresses. AB - Creatine kinase brain (CKB) is one of three cytosolic isoforms of creatine kinase that is predominantly expressed in the brain. The enzyme is overexpressed in a wide variety of cancers, with the exception of colon cancer, where it is downregulated. The significance of this downregulation remains poorly understood. Here, we demonstrate that overexpression of CKB-C283S, a dominant-negative construct that lacks the kinase function but retains its ability to dimerize, causes remarkable changes in cell shape, adhesion, and invasion. Furthermore, it results in increased expression of stromal cell markers such as PAGE4 and SNAIL, suggesting an epithelial-to-mesenchymal transition (EMT) in these cells. In cells transfected with a CKB-expressing construct, CKB localizes not only to the cytosol but also to the nucleus, indicating a structural or kinase role unrelated to ATP storage. Furthermore, overexpression of CFP-tagged wild-type (WT) CKB in Caco-2 colon cancer cells dramatically increased the number of cells in G2/M but had little effect on cell proliferation. Taken together, these data demonstrate that the downregulation of CKB may play an important role in colon cancer progression by promoting EMT. PMID- 21308736 TI - Euphorbia factor L1 reverses ABCB1-mediated multidrug resistance involving interaction with ABCB1 independent of ABCB1 downregualtion. AB - Euphorbia factor L1 (EFL1) belongs to diterpenoids of genus Euphorbia. In this article, its reversal activity against ABCB1-mediated MDR in KBv200 and MCF-7/adr cells was reported. However, EFL1 did not alter the sensitivity of KB and MCF-7 cells to chemotherapeutic agents. Meanwhile, EFL1 significantly increased accumulation of doxorubicin and rhodamine 123 in KBv200 and MCF-7/adr cells, showing no significant influence on that of KB and MCF-7 cells. Furthermore, EFL1 could enhance the ATP hydrolysis activity of ABCB1 stimulated by verapamil. At the same time, EFL1 inhibited the efflux of ABCB1 in KBv200 and MCF-7/adr cells. In addition, EFL1 did not downregulate expression of ABCB1 in KBv200 and MCF 7/adr cells either in mRNA or protein level. PMID- 21308737 TI - CAT-1-mediated arginine uptake and regulation of nitric oxide synthases for the survival of human breast cancer cell lines. AB - Growth of the human MCF-7 breast cancer cell line is highly dependent on L arginine. We have reported that L-arginine, released from extracellular substrates by prolactin (PRL)- and 17beta-estradiol (E2)-induced carboxypeptidase D in the cell membrane, promotes nitric oxide (NO) production for MCF-7 cell survival. Arginine uptake is mediated by members of the cationic amino acid transporter (CAT) family and may coincide with induction of nitric oxide synthase (NOS) for the production of NO. The present study investigated the CAT isoforms and PRL/E2 regulation of CAT and NOS in breast cancer cell lines. Using RT-PCR analysis, CAT-1, CAT-2A, and CAT-2B transcripts were detected in MCF-7, T47D, and MDA-MB-231 cells. The CAT-4 transcript was detected in MDA-MB-231 only. CAT-3 was not detected in any of these cells. PRL and E2 did not significantly alter levels of CAT-1 mRNA and protein, nor CAT-2A and CAT-2B mRNAs in MCF-7 and T47D cells. PRL and E2 also had no effect on the overall uptake of L-[2,3,4,5-H(3)] arginine into these cells. However, confocal immunofluorescent microscopy showed that PRL and E2 upregulated eNOS and iNOS proteins, which distributed in the cytoplasm and/or nucleus of MCF-7 cells. Knockdown of CAT-1 gene expression using small interfering RNA significantly decreased L-[2,3,4,5-H(3)]-arginine uptake, decreased viability and increased apoptosis of MCF-7 and T47D cells. In summary, several CAT isoforms are expressed in breast cancer cells. The CAT-1 isoform plays a role in arginine uptake and, together with PRL/E2-induced NOS, contribute to NO production for the survival of MCF-7 and T47D cells. PMID- 21308738 TI - Electrophysiological characterization of potassium conductive pathways in Trypanosoma cruzi. AB - Potassium channels (K(+) channels) are members of one of the largest and most diverse families of membrane proteins, widely described from bacteria to humans. Their functions include voltage-membrane potential maintenance, pH and cell volume regulation, excitability, organogenesis and cell death. K(+) channels are involved in sensing and responding to environmental changes such as acidification, O(2) pressure, osmolarity, and ionic concentration. Trypanosoma cruzi is a parasitic protozoan, causative agent of Chagas disease (American trypanosomiasis) an endemic pathology in Latin America, where up 200,000 new cases are reported annually. In protozoan parasites, the presence of K(+) channels has been suggested, but functional direct evidence supporting this hypothesis is limited, mainly due to the difficulty of employing conventional electrophysiological methods to intact parasites. In T. cruzi, K(+) conductive pathways are thought to contribute in the regulatory volume decrease observed under hypoosmotic stress, the steady state pH and the compensatory response to extracellular acidification and the maintenance of plasma membrane potential. In this work we describe the isolation of plasma membrane enriched fractions from T. cruzi epimastigotes, their reconstitution into giant liposomes and the first functional characterization by patch-clamp of K(+) conductive pathways in protozoan parasites. PMID- 21308739 TI - Interference with ER-alpha enhances the therapeutic efficacy of the selective CDK inhibitor roscovitine towards ER-positive breast cancer cells. AB - In recent years many risk factors for the development of breast cancer that are linked to estrogens have been identified, and roscovitine (ROSC), a selective cyclin-dependent kinase (CDK) inhibitor, has been shown to be an efficient inhibitor of the proliferation of human breast cancer cells. Therefore, we have examined the possibility that interference with estrogen signaling pathways, using tamoxifen (TAM), a selective estrogen receptor modulator (SERM), could modulate the efficacy of treatment with ROSC. In conjunction with TAM, ROSC exhibited enhanced anti-proliferative activity and CDK inhibition, particularly in estrogen-dependent MCF-7 cells. The interaction between both drugs was synergistic. However, in ER-alpha-negative cells the interaction was antagonistic. Exposure of MCF-7 cells to ROSC abolished the activating phosphorylation of CDK2 and CDK7 at Ser(164/170). This in turn prevented the phosphorylation of the carboxyl-terminal repeat domain of RNA Polymerase II and ER-alpha at Ser(118), resulting in the down-regulation of the latter. Concomitantly, wt p53 was strongly activated by phosphorylation at Ser(46). Our results demonstrate that ROSC negatively affects the functional status of ER alpha, making it potentially useful in the treatment of estrogen-dependent breast cancer cells. PMID- 21308740 TI - The presence of extracellular matrix alters the chondrocyte response to endoplasmic reticulum stress. AB - The objective of this study was to test the hypothesis that extracellular matrix (ECM) would alter the endoplasmic reticulum (ER) stress response of chondrocytes. Chondrocytes were isolated from calf knees and maintained in monolayer culture or suspended in collagen I to form spot cultures (SCs). Our laboratory has shown that bovine chondrocytes form cartilage with properties similar to native cartilage after 2-4 weeks in SCs. Monolayer cultures treated with ER stressors glucose withdrawal (-Glu), tunicamycin (TN), or thapsigargin (TG) up-regulated Grp78 and Gadd153, demonstrating a complete ER stress response. SCs were grown at specific times from 1 day to 6 weeks before treatment with ER stressors. Additionally, SCs grown for 1, 2, or 6 weeks were treated with increasing concentrations of TN or TG. Western blotting of SCs for Grp78 indicated that increased ECM accumulation results in delayed expression; however, Grp78 mRNA is up-regulated in response to ER stressors even after 6 weeks in culture. SCs treated with ER stressors did not up-regulate Gadd153, suggesting that the cells experienced ER stress but would not undergo apoptosis. In fact, SCs undergo apoptosis upon ER stress treatment after 0-1 day of growth; however, after 4 days and to 6 weeks, apoptosis in treated samples was not different than controls. Pro survival molecules Bcl-2 and Bag-1 were up-regulated upon ER stress in SCs. These results suggest that presence of ECM confers protection from ER stressors. Future studies involving chondrocyte physiology should focus on responses in conditions more closely mimicking the in vivo cartilage environment. PMID- 21308741 TI - Expression of CD34 in hematopoietic cancer cell lines reflects tightly regulated stem/progenitor-like state. AB - Hematopoietic cancer stem cells preserve cellular hierarchy in a manner similar to normal stem cells, yet the underlying regulatory mechanisms are poorly understood. It is known that both normal and malignant stem/progenitor cells express CD34. Here, we demonstrate that several cell lines (HL-60, U266) derived from hematopoietic malignancies contain not only CD34(-) but also CD34(+) subpopulations. The CD34(+) cells displayed a stem/progenitor-like phenotype since, in contrast to CD34(-) cells, they frequently underwent cellular division and rapidly formed colonies in methylcellulose-based medium. Strikingly, a constant fraction of the CD34(+) and CD34(-) cell subpopulations, when separated, rapidly switched their phenotype. Consequently, both separated fractions could generate tumors in immunocompromised NOD/LtSz-scid/scid mice. Cultures in vitro showed that the proportion of CD34(+) stem/progenitor-like cells in the population was decreased by cell-cell contact and increased by soluble factors secreted by the cells. Using cytokine arrays, we identified some of these factors, notably thymopoietin that was able to increase the proportion of CD34(+) cells and overall colony-forming capacity in tested cell lines. This action of thymopoietin was conserved in mononuclear cells from bone marrow. Therefore, we propose that hematopoietic cancer cell lines containing subpopulations of CD34(+) cells can provide an in vitro model for studies of cancer stem/progenitor cells. PMID- 21308742 TI - Y-box protein-1 is a transcriptional regulator of BMP7. AB - Bone morphogenetic protein-7 (BMP7) is an endogenous antifibrogenic protein in the kidney which is down regulated in experimental chronic kidney diseases such as obstructive and diabetic nephropathy in parallel with progressively increasing TGFbeta. In vitro studies were performed in Madin-Darby Canine Kidney (MDCK) cells to identify transcriptional regulators of BMP7. Experiments with various BMP7 promoter fragments (465-4,267 bp) identify small proximal promoter segments that are transcriptionally activated by high glucose (3.2-fold) but down regulated by TGFbeta (0.2-fold) compared to normal glucose. Protein binding to these DNA segments is increased by high glucose and decreased by TGFbeta in a time-dependent, progressive manner. Analysis of BMP7 promoter-binding proteins with liquid chromatography/tandem mass spectrometry (LC/MS/MS) identifies seven unique, partially overlapping peptides, spanning 25% of the amino acid sequence of Y-box protein-1 (YB1). EMSA-Western blot combination experiments confirm that YB1 is a BMP7 promoter-binding protein. YB1 knock-down reduces transcriptional responses to high glucose and TGFbeta by about one-half, respectively. In addition, high glucose induces but TGFbeta reduces nuclear translocation of YB1 from the cytoplasm. These studies identify YB1 as a transcriptional activator of BMP7 and helps to explain the progressive decline in renal BMP7 in diabetic nephropathy and other kidney diseases. PMID- 21308743 TI - 13 years of cultured limbal epithelial cell therapy: a review of the outcomes. AB - The cornea is the clear tissue at the front of the eye which enables the transmission of light to the retina for normal vision. The surface of the cornea is composed of an epithelium which is renewed by stem cells located at the periphery of the cornea, a region known as the limbus. These limbal stem cells can become deficient as a result of various diseases of the eye's surface, resulting in the blinding disease of limbal stem cell deficiency. The treatment of this disease is often difficult and complex. In 1997, it was proposed that a small amount of limbal tissue containing limbal stem cells could be culture expanded and then transplanted. Since then various case reports and case series have been reported showing promising results. Here, we review the outcomes of this procedure over the past 13 years with the aim of highlighting the best culture and surgical techniques to date. PMID- 21308744 TI - Retinol (vitamin A) maintains self-renewal of pluripotent male germline stem cells (mGSCs) from adult mouse testis. AB - Studies have shown that male germline stem cells (mGSCs), which are responsible for maintaining spermatogenesis in the male, could be obtained from mouse and human testis. However, the traditional cultural methods were mostly dependent on serum and feeder, and the initial mGSCs were either obtained from neonatal mice or the detailed description of its potency and origin was not provided. Here we reported a novel (retinol (RE) serum-free and feeder-free) system for the successful culture of adult germline stem cells from adult Kunming mice (8-24 weeks) testis. The isolated mGSCs cultured in RE serum-free and feeder-free medium maintained the typical morphology of undifferentiated embryonic stem cells (ESCs), and they proliferated well in RE medium analyzed by proliferation assay, RT-PCR, microarray, and Western blotting. These cells also showed typical properties of ESCs (alkaline phosphatase (AP) positive, expressions of Oct4, Sox2, Nanog, and SSEA1, with the capacity to form teratomas and differentiate into various types of cells within three germ layers). Taken together, we conclude that RE promotes the self-renewal of mGSCs and maintains the pluripotency of mGSCs, the RE serum-free and feeder-free system may be useful for the culture of pluripotent stem cell lines from adult testis tissues, which provides a new resource for tissue engineering and therapy for infertility. PMID- 21308745 TI - Destabilization of CARP mRNAs by aloe-emodin contributes to caspase-8-mediated p53-independent apoptosis of human carcinoma cells. AB - Using short hairpin RNA against p53, transient ectopic expression of wild-type p53 or mutant p53 (R248W or R175H), and a p53- and p21-dependent luciferase reporter assay, we demonstrated that growth arrest and apoptosis of FaDu (human pharyngeal squamous cell carcinoma), Hep3B (hepatoma), and MG-63 (osteosarcoma) cells induced by aloe-emodin (AE) are p53-independent. Co-immunoprecipitation and small interfering RNA (siRNA) studies demonstrated that AE caused S-phase cell cycle arrest by inducing the formation of cyclin A-Cdk2-p21 complexes through extracellular signal-regulated kinase (ERK) activation. Ectopic expression of Bcl X(L) and siRNA-mediated Bax attenuation significantly inhibited apoptosis induced by AE. Cyclosporin A or the caspase-8 inhibitor Z-IETD-FMK blocked AE-induced loss of mitochondrial membrane potential and prevented increases in reactive oxygen species and Ca(++). Z-IETD-FMK inhibited AE-induced apoptosis, Bax expression, Bid cleavage, translocation of tBid to mitochondria, ERK phosphorylation, caspase-9 activation, and the release of cytochrome c, apoptosis inducing factor (AIF), and endonuclease G from mitochondria. The stability of the mRNAs encoding caspase-8 and -10-associated RING proteins (CARPs) 1 and 2 was affected by AE, whereas CARP1 or 2 overexpression inhibited caspase-8 activation and apoptosis induced by AE. Collectively, our data indicate AE induces caspase-8 mediated activation of mitochondrial death pathways by decreasing the stability of CARP mRNAs in a p53-independent manner. PMID- 21308747 TI - Protein phosphatase 1-dependent dephosphorylation of Akt is the prime signaling event in sphingosine-induced apoptosis in Jurkat cells. AB - Sphingosine (SPH) is an important bioactive lipid involved in mediating a variety of cell functions including apoptosis. However, the signaling mechanism of SPH induced apoptosis remains unclear. We have investigated whether SPH inhibits survival signaling in cells by inhibiting Akt kinase activity. This study demonstrates that treatment of Jurkat cells with SPH leads to Akt dephosphorylation as early as 15 min, and the cells undergo apoptosis after 6 h. This Akt dephosphorylation is not mediated through deactivation of upstream kinases, since SPH does not inhibit the upstream phosphoinositide-dependent kinase 1 (PDK1) phosphorylation. Rather, sensitivity to the Ser/Thr protein phosphatase inhibitors (calyculin A, phosphatidic acid, tautomycin, and okadaic acid) indicates an important role for protein phosphatase 1 (PP1) in this process. In vitro phosphatase assay, using Akt immunoprecipitate following treatment with SPH, reveals an increase in Akt-PP1 association as determined by immunoprecipitation analysis. Moreover, SPH-induced dephosphorylation of Akt at Ser(473) subsequently leads to the activation of GSK-3beta, caspase 3, PARP cleavage, and ultimately apoptosis. Pre-treatment with caspase 3 inhibitor z-VAD fmk and Ser/Thr phosphatase inhibitor abrogates the effect of SPH on facilitating apoptosis. Altogether, these results demonstrate that PP1-mediated inhibition of the key anti-apoptotic protein, Akt, plays an important role in SPH-mediated apoptosis in Jurkat cells. PMID- 21308746 TI - Role of C/EBP-beta, p38 MAPK, and MKK6 in IL-1beta-mediated C3 gene regulation in astrocytes. AB - Complement component C3, the central player in the complement cascade and the pro inflammatory cytokine IL-1beta is expressed by activated glial cells and may contribute to neurodegeneration. This study examines the regulation of the expression of C3 by IL-1beta in astroglial cells focusing on the role of the upstream kinase MKK6, p38-alpha MAPK, and C/EBP-beta isoforms (LAP1, LAP2, or LIP) in astroglial cells. Activation of human astroglial cell line, U373 with IL 1beta, led to the induction of C3 mRNA and protein expression as determined by real-time RT-PCR and Western blot analysis, respectively. This induction was suppressed by the pharmacological inhibitor of p38 MAPK (i.e., SB202190-HCl), suggesting the involvement of p38 MAPK in C3 gene expression. IL-1beta also induced C3 promoter activity in U373 cells in a MAP kinase- and C/EBP-beta dependent manner. Cotransfection of C3 luciferase reporter construct with constitutively active form of the upstream kinase in the MAP kinase cascade, that is, MKK6 (the immediate upstream activator of p38 kinase) resulted in marked stimulation of the promoter activity, whereas overexpression of a dominant negative forms of MKK6 and p38alpha MAPK inhibited C3 promoter activity. Furthermore, a mutant form of C/EBP-beta, LAP(T235A) showed reduction in IL-1beta mediated C3 promoter activation. These results suggest that the p38alpha, MAPK, and MKK6 play prominent roles in IL-1beta and C/EBP-beta-mediated C3 gene expression in astrocytes. PMID- 21308748 TI - Obstetric vesico-vaginal fistula repair: should we trim the fistula edges? A randomized prospective study. AB - OBJECTIVE: To test the hypothesis that not trimming the edges of the vesico vaginal fistula (VVF) during its surgical repair has an advantage in the outcome as compared to the classical teaching of trimming the fistula. METHODOLOGY: Sixty four females with obstetric VVF were randomized into two groups. Both groups were treated with vaginal anatomical closure in three layers with Martius flap inter positioning. Fistulae of the first group were closed without trimming the edges of the bladder while the second group was subject to trimming of the bladder edges. RESULTS: There were no statistically significant differences between both groups regarding pre-operative patient demographics and fistula characteristics. Cure rates were 75% and 67.6% in the non-trimming and the trimming groups, respectively. This was not statistically different. When patients were stratified according to the number of previous repairs, 100% patients in both groups were cured in cases of primary repair of the fistula. Lower cure rates were shown with increasing number of previous repairs. Recurrent fistulae after our repair were not statistically different in site and number in both groups. Nevertheless, fistulae after trimming tends to get larger than the original ones as compared to the non-trimming group which tends to get smaller. This is statistically different. CONCLUSION: Although there is no statistically significant difference between both groups regarding the cure rate in both fresh cases or recurrent ones, there is an advantage of not trimming the fistula since trimmed fistula tends to get larger, should recurrence occur after trimming. PMID- 21308749 TI - Ultrasound estimated bladder weight in men attending the uroflowmetry clinic. AB - AIMS: To determine if measurements of ultrasound estimated bladder weight (UEBW) provide an additional diagnostic tool when assessing men with lower urinary tract symptoms (LUTS) in the uroflowmetry clinic. METHODS: One hundred men with LUTS attending the uroflowmetry clinic underwent transabdominal ultrasound measurement of bladder weight, using the BVM 9500 bladder scanner (Verathon Medical, Bothell, WA). These data were explored for any correlation between measurements of maximum flow rate (Q(max)) with UEBW, age, height, weight, body mass index (BMI), ICIQ M LUTS score, M-LUTS voiding score, M-LUTS incontinence score, IPSS, IPSS quality of life score, voided volume, and post-void residual urine. Based on previously reported probabilities of bladder outlet obstruction (BOO), patients were grouped for analysis (Group 1 = Q(max) <10, Group 2 = Q(max) 10-15, Group 3 = Q(max) >15). A one-way ANOVA was undertaken to assess any difference in mean UEBW between the three groups. RESULTS: Statistically significant negative correlations between Q(max) and age (r = -0.308, P = 0.002), M-LUTS voiding score (r = -0.298, P = 0.003), IPSS (r = -0.295, P = 0.003), and post-void residual (r = -0.213, P = 0.033) were observed. A statistically significant positive correlation between Q(max) and voided volume (r = 0.503, P < 0.01) was observed. No association between Q(max) and UEBW was observed (r = 0.12, P = 0.243). Mean UEBW for the three groups was remarkably similar. One-way ANOVA identified there was no statistically significant effect of UEBW on Q(max) F(2, 97) = 0.175, P = 0.840. CONCLUSION: Mean UEBW did not differ significantly between the three Q(max) groups. Further work is required to investigate the relationship of Q(max) and UEBW in men with urodynamic confirmation of either BOO or detrusor underactivity. PMID- 21308750 TI - The effect of biological and synthetic meshes on vaginal smooth muscle cell proliferation. AB - AIMS: To compare the effects of polypropylene mesh or porcine dermal acellular collagen matrix mesh with and without estradiol supplementation on vaginal smooth muscle cells (VaSMC) proliferation. RESULTS: Under in vitro culture conditions, VaSMC proliferation was significantly higher in the porcine dermal acellular collagen matrix mesh exposed cells compared to the type I polypropylene mesh exposed cells (relative cell number, mean +/- SD, 0.27 +/- 0.03 vs. 0.21 +/- 0.01, P = 0.03). Under estradiol supplementation cell proliferation in the porcine mesh exposed cells remained significantly higher compared to the polypropylene mesh exposed cells (relative cell number, mean +/- SD, 0.27 +/- 0.04 vs. 0.15 +/- 0.03, P < 0.01). CONCLUSION: The decreased rate of erosion found with the utilization of biological absorbable mesh in vaginal reconstructive surgery may partially be explained by the significantly increased VaSMC proliferation with porcine dermal acellular collagen mesh compared to polypropylene mesh. PMID- 21308751 TI - A comparison of students' and jury panelists' decision-making in split recovery cases. AB - This study was designed to assess jury decision-making for 289 participants reading a medical malpractice vignette as a function of participant type (undergraduate students or jury panelists), punitive damage award apportionment (none, half, or all to the plaintiff), and compensation previously assigned to the plaintiff (low, medium, or high). We found several sample differences. Overall, jury panelists awarded more money for punitive damages. Jury panelists were also more affected by compensatory-relevant information when making punitive decisions, including assigning punitive damages and rating the fairness of the traditional apportionment scheme, where the plaintiff receives all of the money. Compared with students, more jury panelists were in favor of the plaintiff receiving the entire punitive award. Most students endorsed split recovery. The authors suggest that psycholegal research conducted solely with student samples, rather than community members, may misestimate the likely behavior of actual juries. The implications of the study for split recovery policy are also discussed. PMID- 21308752 TI - How reason for surgery and patient weight affect verdicts and perceptions in medical malpractice trials: a comparison of students and jurors. AB - Jurors' decision-making processes are often influenced by extra-legal factors, including judgments of defendants and plaintiffs. Two studies comparing the decisions of university students with those of community jurors sought to determine if extra-legal factors such as individual differences (including identity as a student or juror participant), the reason for surgery (medically necessary vs. elective), the type of surgery (e.g., gastric bypass, nasal reconstruction) or weight of the patient influenced jurors' decisions and perceptions in medical malpractice suits, such that participants would hold negative perceptions of overweight patients or patients who undergo elective surgeries. Results indicate that students and jurors differ in perceptions of the patient's injury and perceptions of risk, which explains some of the variance in liability verdicts. Students were more likely to find doctors liable, but also were more likely to assign responsibility to patients than were jurors. Patients who had undergone elective surgery were seen as more responsible for their situation - and their doctors were assigned less responsibility - than those who had undergone a medically necessary surgery. Tests of weight bias showed that jurors found overweight patients less responsible for their situation than patients of normal weight, but students showed the opposite pattern. Theoretical explanations are explored and implications discussed. PMID- 21308753 TI - Lack of association between adolescent idiopathic scoliosis and previously reported single nucleotide polymorphisms in MATN1, MTNR1B, TPH1, and IGF1 in a Japanese population. AB - Adolescent idiopathic scoliosis (AIS) is a spinal deformity most commonly arising in apparently healthy girls around puberty. AIS has a strong genetic predisposition. Several genetic associations between AIS and single nucleotide polymorphisms (SNPs) have been reported; common SNPs in the genes for matrilin 1 (MATN1), melatonin receptor 1B (MTNR1B), tryptophan hydroxylase 1 (TPH1), and insulin-like growth factor 1 (IGF1) are reported to be associated with AIS in Chinese. However, these associations have not been replicated so far. To confirm the associations, we compared these SNPs with AIS predisposition and curve severity in a population of Japanese females consisting of 798 AIS patients and 1,239 controls. All the subjects were genotyped using the PCR-based Invader assay. We found no association of any of the SNPs with AIS predisposition or curve severity. Considering the statistical power and sample size of the present study, we concluded that these SNPs are not associated with either AIS predisposition or curve severity in Japanese. PMID- 21308754 TI - Comparative in vivo study of injectable biomaterials combined with BMP for enhancing tendon graft osteointegration for anterior cruciate ligament reconstruction. AB - This study was to compare effect of osteointegration of grafted tendon in bone tunnels between injected calcium phosphate cement (ICPC) and injected fibrin sealant (IFS) combined with bone morphogenetic protein (BMP) after anterior cruciate ligament (ACL) reconstruction. ACL reconstruction was performed bilaterally in 51 rabbits. ICPC-BMP composite was injected into one knee, with the contralateral knee IFS-BMP composite. The rabbits were killed at postoperative weeks 2, 6, and 12 for testing. Histological observations showed the ICPC composite gradually increased the new bone formation during the whole healing process, while the IFS composite had a burst effect on enhancing the healing of tendon-to-bone at 2 and 6 weeks. By 12 weeks, there was more new cartilage and new bone in the interface in the ICPC-bBMP group. Micro-CT showed that the values of BMD in the ICPC-bBMP group were lower than those in the IFS bBMP group at 6 weeks, while the values in the ICPC-bBMP group were higher than those in the IFS-bBMP group at 12 weeks (p > 0.05). Fluorescent labels showed that the rate of new bone formation of IFS-BMP composite was significantly higher than that of ICPC composite at 6 weeks (3.45 +/- 0.62 um/day vs. 2.93 +/- 0.51 um/day), but the rate was decreased compared with ICPC composite at 12 weeks (2.58 +/- 0.72 um/day vs. 3.05 +/- 0.68 um/day; p < 0.05). Biomechanically, the ultimate failure load in the ICPC-BMP group was always higher than that in the IFS-BMP group. It is evident that the ICPC composite achieved a more prolonged osteogenic effect than that by IFS composite. PMID- 21308755 TI - Restoration of anterior-posterior rotator cuff force balance improves shoulder function in a rat model of chronic massive tears. AB - The rotator cuff musculature imparts dynamic stability to the glenohumeral joint. In particular, the balance between the subscapularis anteriorly and the infraspinatus posteriorly, often referred to as the rotator cuff "force couple," is critical for concavity compression and concentric rotation of the humeral head. Restoration of this anterior-posterior force balance after chronic, massive rotator cuff tears may allow for deltoid compensation, but no in vivo studies have quantitatively demonstrated an improvement in shoulder function. Our goal was to determine if restoring this balance of forces improves shoulder function after two-tendon rotator cuff tears in a rat model. Forty-eight rats underwent detachment of the supraspinatus and infraspinatus. After four weeks, rats were randomly assigned to three groups: no repair, infraspinatus repair, and two tendon repair. Quantitative ambulatory measures including medial/lateral forces, braking, propulsion, and step width were significantly different between the infraspinatus and no repair group and similar between the infraspinatus and two tendon repair groups at almost all time points. These results suggest that repairing the infraspinatus back to its insertion site without repair of the supraspinatus can improve shoulder function to a level similar to repairing both the infraspinatus and supraspinatus tendons. Clinically, a partial repair of the posterior cuff after a two-tendon tear may be sufficient to restore adequate function. An in vivo model system for two-tendon repair of massive rotator cuff tears is presented. PMID- 21308756 TI - Does high-flexion total knee arthroplasty promote early loosening of the femoral component? AB - High-flexion knee replacements have been developed to accommodate a large range of motion (RoM > 120 degrees ). Knee implants that allow for higher flexion may be more sensitive to femoral loosening as the knee load is relatively high during deep knee flexion, which could result in an increased failure potential at the implant-cement interface of the femoral component. A 3D finite element knee model was developed including a posterior-stabilized high-flexion knee replacement to analyze the stress state at the femoral implant-cement interface during a full squatting movement (RoM <= 155 degrees ). During deep flexion (RoM > 120 degrees ), tensile and shear stress concentrations were found at the implant-cement interface beneath the proximal part of the anterior flange. Particularly, the shear stresses at this interface location increased during high flexion, from a peak stress of 4.03 MPa at 90 degrees to 6.89 MPa at 140 degrees of flexion. Tensile stresses were substantially lower, having a peak stress of 0.72 MPa at 100 degrees of flexion. Using data from earlier interface strength experiments, none of the interface beneath the anterior flange was predicted to fail in the normal flexion range (RoM <= 120 degrees ), whereas the prediction increased to 2.2% of the interface during deeper knee flexion. Thigh-calf contact reduced the knee forces, interface load, and failure risk beyond 140-145 degrees of flexion. Based on the more critical stresses at the femoral fixation site between 120 degrees and 145 degrees of flexion, we conclude that the femoral component has a higher risk of loosening at high-flexion angles. PMID- 21308757 TI - Toll-like receptors and their adaptors are regulated in macrophages after phagocytosis of lipopolysaccharide-coated titanium particles. AB - Macrophages phagocytose metallic wear particles and produce mediators, which can induce cellular host response and aseptic implant loosening. Lipopolysaccharide (LPS) on the wear debris can stimulate macrophages via Toll-like receptor 4 (TLR4) and enhance the response. However, the precise functional role and interaction of TLRs and their adaptor molecules is still unclear. Rat bone marrow macrophages were stimulated with titanium particle (Ti) coated by LPS (Ti/LPS+) and LPS-free Ti (Ti/LPS-). mRNA levels of cytokines, TLRs and their adaptor molecules were measured using real time PCR. mRNA levels of TNF-alpha, IL-1beta, and IL-6 increased in Ti/LPS+ than Ti/LPS-. In contrast, mRNA levels of TLR4, TLR5, and TLR9 decreased in Ti/LPS+ compared to Ti/LPS-. mRNA levels of MyD88, IRAK1, IRAK4 decreased gradually, and TRAF6 underwent an initial transient increase, followed by suppression in Ti/LPS+. However, mRNA levels of TLR2 and IRAK2 increased after phagocytosis of Ti/LPS+ than Ti/LPS-. The increased expressions of proinflammatory cytokines found in Ti/LPS+ indicated that their productions cytokines could be enhanced by phagocytosis of LPS-coated particles. Subsequent down-regulation of TLR4, TLR5, TLR9, MyD88, IRAK1, and IRAK4 suggests that self-protective mechanisms to regulate excessive host responses are activated in macrophages. Increase of TLR2 and IRAK2 and a transient increase of TRAF6 in Ti/LPS+ suggest that another possible pathway to modulate TLR-mediated cellular response to prolong inflammatory response in foreign body reaction of aseptic loosening. This down- and/or up-regulation of the potential TLR-mediated responses to LPS-coated particles reflects the proactive behavior of effector cells. PMID- 21308758 TI - Don't hedge your bets: hedgehog signaling as a central mediator of endochondral bone development and cartilage diseases. AB - Cell differentiation and patterning are vital processes in the development of the appendicular skeleton. The hedgehog (Hh) signaling pathway plays a central role in regulating the anterior-posterior axis of the distal limb as well as the length of endochondral bones. Ligand-induced Hh signaling inhibits the processing of the Gli transcription factors from activator to repressor isoforms. In the growth plate, Indian hedgehog inhibits Gli processing, resulting in accumulation of Gli activators that induce chondrocyte maturation and hypertrophic differentiation. Parathyroid hormone-like hormone promote and Gli processing to repressor forms, thus regulating the rate of hypertrophic differentiation. In cartilage diseases such as osteoarthritis and cartilage tumors, there is a recapitulation of developmental processes that involve increased Hh signaling. Studies have shown that pharmacological inhibitors of Hh signaling can attenuate the progression osteoarthritis and cartilage tumor growth. Thus, Hh blockade can serve as a potential therapy for the treatment of various cartilage diseases. PMID- 21308759 TI - Adolescents after Pemberton's osteotomy for developmental dysplasia of the hip displayed greater joint loading than healthy controls in affected and unaffected limbs during gait. AB - Patients after reduced developmental dysplasia of the hip (DDH) are at higher than normal risk of developing avascular necrosis (AVN) of the femoral head and degenerative hip osteoarthritis (OA) that are closely related to abnormal loadings. We aimed to determine the lower limb loadings in adolescents after Pemberton's osteotomy for unilateral DDH. Eleven females (age: 10.6 +/- 1.0 years), who had received Pemberton's osteotomy for unilateral DDH at 1.6 +/- 0.5 years of age, and 12 age-matched healthy controls were studied using gait analysis. Compared to the normal controls, the patients were displayed greater peak axial forces at the hip, knee, and ankle in both limbs, with greater loading rates in the ground reaction force (GRF) and at the hips (p < 0.05 for all comparisons). The increased rates of repetitive loading around heel strike in both hips suggest that patients treated for unilateral DDH using Pemberton's osteotomy may be at higher risk of premature hip OA. The increased axial forces at the affected hip may be a contributing factor to the development of AVN of the femoral head in these patients, especially when incomplete coverage, insufficient congruency, and/or damaged articular surfaces remain after the osteotomy. Therefore, monitoring the loading condition at the hip is necessary for a more accurate assessment of the risk of developing joint pathology in patients after reduced DDH. PMID- 21308760 TI - Expression of trypsin-like serine peptidases in pre-imaginal stages of Aedes aegypti (Diptera: Culicidae). AB - This study reports the biochemical characterization and comparative analyses of highly active serine proteases in the larval and pupal developmental stages of Aedes aegypti (Linnaeus) using substrate-SDS-PAGE. Zymographic analysis of larval stadia detected proteolytic activity in 6-8 bands with apparent molecular masses ranging from 20 to 250 kDa, with activity observed from pH 5.5 to 10.0. The pupal stage showed a complex proteolytic activity in at least 11 bands with apparent Mr ranging from 25 to 250 kDa, and pH optimum at 10.0. The proteolytic activities of both larval and pupal stages were strongly inhibited by phenyl-methyl sulfonyl fluoride and N-alpha-Tosyl-L-lysine chloromethyl ketone hydrochloride, indicating that the main proteases expressed by these developmental stages are trypsin-like serine proteases. The enzymes were active at temperatures ranging from 4 to 85 degrees C, with optimal activity between 37 and 60 degrees C, and low activity at 85 degrees C. Comparative analysis between the proteolytic enzymes expressed by larvae and pupae showed that substantial changes in the expression of active trypsin-like serine proteases occur during the developmental cycle of A. aegypti. PMID- 21308761 TI - Characterization of mosquito CYP6P7 and CYP6AA3: differences in substrate preference and kinetic properties. AB - Cytochrome P450 monooxygenases are involved in insecticide resistance in insects. We previously observed an increase in CYP6P7 and CYP6AA3 mRNA expression in Anopheles minimus mosquitoes during the selection for deltamethrin resistance in the laboratory. CYP6AA3 has been shown to metabolize deltamethrin, while no information is known for CYP6P7. In this study, CYP6P7 was heterologously expressed in the Spodoptera frugiperda (Sf9) insect cells via baculovirus mediated expression system. The expressed CYP6P7 protein was used for exploitation of its enzymatic activity against insecticides after reconstitution with the An. minimus NADPH-cytochrome P450 reductase enzyme in vitro. The ability of CYP6P7 to metabolize pyrethroids and insecticides in the organophosphate and carbamate groups was compared with CYP6AA3. The results revealed that both CYP6P7 and CYP6AA3 proteins could metabolize permethrin, cypermethrin, and deltamethrin pyrethroid insecticides, but showed the absence of activity against bioallethrin (pyrethroid), chlorpyrifos (organophosphate), and propoxur (carbamate). CYP6P7 had limited capacity in metabolizing lambda-cyhalothrin (pyrethroid), while CYP6AA3 displayed activity toward lambda-cyhalothrin. Kinetic properties suggested that CYP6AA3 had higher efficiency in metabolizing type I than type II pyrethroids, while catalytic efficiency of CYP6P7 toward both types was not significantly different. Their kinetic parameters in insecticide metabolism and preliminary inhibition studies by test compounds in the flavonoid, furanocoumarin, and methylenedioxyphenyl groups elucidated that CYP6P7 had different enzyme properties compared with CYP6AA3. (c) 2011 Wiley Periodicals, Inc. PMID- 21308762 TI - Lipid accumulation and utilization by oocytes and eggs of Rhodnius prolixus. AB - Insect eggs must contain the necessary nutrients for embryonic growth. In this article, we investigated the accumulation of triacylglycerol (TAG) in growing oocytes and its utilization during embryonic development. TAG makes up about 60% of the neutral lipids in oocytes and accumulates as oocytes grow, from 2.2 +/- 0.1 ug in follicles containing 1.0 mm length oocytes to 10.2 +/- 0.8 ug in 2.0 mm length oocytes. Lipophorin (Lp), the hemolymphatic lipoprotein, radioactively labeled in free fatty acid (FFA) or diacylglycerol (DAG), was used to follow the transport of these lipids to the ovary. Radioactivity from both lipid classes accumulated in the oocytes, which was abolished at 4 degrees C. The capacity of the ovary to receive FFA or DAG from Lp varied according to time after a blood meal and reached a maximum around the second day. (3) H-DAG supplied by Lp to the ovaries was used in the synthesis of TAG as, 48 hr after injection, most of the radioactivity was found in TAG (85.7% of labeling in neutral lipids). During embryogenesis, lipid stores were mobilized, and the TAG content decreased from 16.4 +/- 2.1 ug/egg on the first day to 10.0 +/- 1.3 ug on day 15, just before hatching. Of these, 7.4 +/- 0.9 ug were found in the newly emerged nymphs. In unfertilized eggs, the TAG content did not change. Although the TAG content decreased during embryogenesis, the relative lipid composition of the egg did not change. The amount of TAG in the nymph slowly decreased during the days after hatching. PMID- 21308763 TI - High-level expression of the Geranylgeranyl diphosphate synthase gene in the frontal gland of soldiers in Reticulitermes speratus (Isoptera: Rhinotermitidae). AB - Defensive strategies of termite soldiers are roughly classified as either mechanical, using mandibles and/or the whole head, or chemical, using frontal gland secretion. Soldiers of the genus Nasutitermes (Termitidae, Nasutitermitinae), which is one of the most derived termite genera, use only chemical defenses, and diterpene defensive secretions were suggested to be synthesized through geranylgeranyl diphosphate (GGPP). On the other hand, soldiers of the genus Reticulitermes (Rhinotermitidae, Heterotermitinae) mainly use mechanical defenses, but also use supplementary chemical defenses involving frontal gland secretions, including diterpene alcohol. In this study, to confirm whether the GGPP is used for diterpene synthesis in a representative of an earlier-branching termite lineage, the GGPP synthase gene (RsGGPPS) was identified in the rhinotermitid Reticulitermes speratus (Kolbe). The relative expression level of RsGGPPS in soldiers was three-fold higher than in workers. Furthermore, RsGGPPS gene expression was detected in epithelial class 1 gland cells around the frontal-gland reservoir. Although GGPP is used for various essential cellular roles in animals, RsGGPPS is suggested to be used not only for these essential roles but also for diterpene synthesis in order to produce defensive secretions. Chemical structures of the diterpene identified from Reticulitermes and Nasutitermes are extremely different from each other, and the two genera are phylogenetically distant from each other. Thus, these two lineages may have independently acquired the abilities of diterpene synthesis from GGPP. PMID- 21308764 TI - Latent class model with familial dependence to address heterogeneity in complex diseases: adapting the approach to family-based association studies. AB - Clinical diagnoses of complex diseases may often encompass multiple genetically heterogeneous disorders. One way of dissecting this heterogeneity is to apply latent class (LC) analysis to measurements related to the diagnosis, such as detailed symptoms, to define more homogeneous disease sub-types, influenced by a smaller number of genes that will thus be more easily detectable. We have previously developed a LC model allowing dependence between the latent disease class status of relatives within families. We have also proposed a strategy to incorporate the posterior probability of class membership of each subject in parametric linkage analysis, which is not directly transferable to genetic association methods. Under the framework of family-based association tests (FBAT), we now propose to make the contribution of an affected subject to the FBAT statistic proportional to his or her posterior class membership probability. Simulations showed a modest but robust power advantage compared to simply assigning each subject to his or her most probable class, and important power gains over the analysis of the disease diagnosis without LC modeling under certain scenarios. The use of LC analysis with FBAT is illustrated using autism spectrum disorder (ASD) symptoms on families from the Autism Genetics Research Exchange, where we examined eight regions previously associated to autism in this sample. The analysis using the posterior probability of membership to an LC detected an association in the JARID2 gene as significant as that for ASD (P = 3 * 10(-5)) but with a larger effect size (odds ratio = 2.17 vs. 1.55). PMID- 21308765 TI - Relationship between genomic distance-based regression and kernel machine regression for multi-marker association testing. AB - To detect genetic association with common and complex diseases, two powerful yet quite different multimarker association tests have been proposed, genomic distance-based regression (GDBR) (Wessel and Schork [2006] Am J Hum Genet 79:821 833) and kernel machine regression (KMR) (Kwee et al. [2008] Am J Hum Genet 82:386-397; Wu et al. [2010] Am J Hum Genet 86:929-942). GDBR is based on relating a multimarker similarity metric for a group of subjects to variation in their trait values, while KMR is based on nonparametric estimates of the effects of the multiple markers on the trait through a kernel function or kernel matrix. Since the two approaches are both powerful and general, but appear quite different, it is important to know their specific relationships. In this report, we show that, under the condition that there is no other covariate, there is a striking correspondence between the two approaches for a quantitative or a binary trait: if the same positive semi-definite matrix is used as the centered similarity matrix in GDBR and as the kernel matrix in KMR, the F-test statistic in GDBR and the score test statistic in KMR are equal (up to some ignorable constants). The result is based on the connections of both methods to linear or logistic (random-effects) regression models. PMID- 21308766 TI - Estimation of odds ratios of genetic variants for the secondary phenotypes associated with primary diseases. AB - Genetic association studies for binary diseases are designed as case-control studies: the cases are those affected with the primary disease and the controls are free of the disease. At the time of case-control collection, information about secondary phenotypes is also collected. Association studies of secondary phenotype and genetic variants have received a great deal of interest recently. To study the secondary phenotypes, investigators use standard regression approaches, where individuals with secondary phenotypes are coded as cases and those without secondary phenotypes are coded as controls. However, using the secondary phenotype as an outcome variable in a case-control study might lead to a biased estimate of odds ratios (ORs) for genetic variants. The secondary phenotype is associated with the primary disease; therefore, individuals with and without the secondary phenotype are not sampled following the principles of a case-control study. In this article, we demonstrate that such analyses will lead to a biased estimate of OR and propose new approaches to provide more accurate OR estimates of genetic variants associated with the secondary phenotype for both unmatched and frequency-matched (with respect to the secondary phenotype) case control studies. We also propose a bootstrapping method to estimate the empirical confidence intervals for the corrected ORs. Using simulation studies and analysis of lung cancer data for single-nucleotide polymorphism associated with smoking quantity, we compared our new approaches to standard logistic regression and to an extended version of the inverse-probability-of-sampling-weighted regression. The proposed approaches provide more accurate estimation of the true OR. PMID- 21308767 TI - Sample size requirements to detect gene-environment interactions in genome-wide association studies. AB - Many complex diseases are likely to be a result of the interplay of genes and environmental exposures. The standard analysis in a genome-wide association study (GWAS) scans for main effects and ignores the potentially useful information in the available exposure data. Two recently proposed methods that exploit environmental exposure information involve a two-step analysis aimed at prioritizing the large number of SNPs tested to highlight those most likely to be involved in a GE interaction. For example, Murcray et al. ([2009] Am J Epidemiol 169:219-226) proposed screening on a test that models the G-E association induced by an interaction in the combined case-control sample. Alternatively, Kooperberg and LeBlanc ([2008] Genet Epidemiol 32:255-263) suggested screening on genetic marginal effects. In both methods, SNPs that pass the respective screening step at a pre-specified significance threshold are followed up with a formal test of interaction in the second step. We propose a hybrid method that combines these two screening approaches by allocating a proportion of the overall genomewide significance level to each test. We show that the Murcray et al. approach is often the most efficient method, but that the hybrid approach is a powerful and robust method for nearly any underlying model. As an example, for a GWAS of 1 million markers including a single true disease SNP with minor allele frequency of 0.15, and a binary exposure with prevalence 0.3, the Murcray, Kooperberg and hybrid methods are 1.90, 1.27, and 1.87 times as efficient, respectively, as the traditional case-control analysis to detect an interaction effect size of 2.0. PMID- 21308768 TI - Gene-environment interplay in common complex diseases: forging an integrative model-recommendations from an NIH workshop. AB - Although it is recognized that many common complex diseases are a result of multiple genetic and environmental risk factors, studies of gene-environment interaction remain a challenge and have had limited success to date. Given the current state-of-the-science, NIH sought input on ways to accelerate investigations of gene-environment interplay in health and disease by inviting experts from a variety of disciplines to give advice about the future direction of gene-environment interaction studies. Participants of the NIH Gene-Environment Interplay Workshop agreed that there is a need for continued emphasis on studies of the interplay between genetic and environmental factors in disease and that studies need to be designed around a multifaceted approach to reflect differences in diseases, exposure attributes, and pertinent stages of human development. The participants indicated that both targeted and agnostic approaches have strengths and weaknesses for evaluating main effects of genetic and environmental factors and their interactions. The unique perspectives represented at the workshop allowed the exploration of diverse study designs and analytical strategies, and conveyed the need for an interdisciplinary approach including data sharing, and data harmonization to fully explore gene-environment interactions. Further, participants also emphasized the continued need for high-quality measures of environmental exposures and new genomic technologies in ongoing and new studies. PMID- 21308769 TI - Power in the phenotypic extremes: a simulation study of power in discovery and replication of rare variants. AB - Next-generation sequencing technologies are making it possible to study the role of rare variants in human disease. Many studies balance statistical power with cost-effectiveness by (a) sampling from phenotypic extremes and (b) utilizing a two-stage design. Two-stage designs include a broad-based discovery phase and selection of a subset of potential causal genes/variants to be further examined in independent samples. We evaluate three parameters: first, the gain in statistical power due to extreme sampling to discover causal variants; second, the informativeness of initial (Phase I) association statistics to select genes/variants for follow-up; third, the impact of extreme and random sampling in (Phase 2) replication. We present a quantitative method to select individuals from the phenotypic extremes of a binary trait, and simulate disease association studies under a variety of sample sizes and sampling schemes. First, we find that while studies sampling from extremes have excellent power to discover rare variants, they have limited power to associate them to phenotype-suggesting high false-negative rates for upcoming studies. Second, consistent with previous studies, we find that the effect sizes estimated in these studies are expected to be systematically larger compared with the overall population effect size; in a well-cited lipids study, we estimate the reported effect to be twofold larger. Third, replication studies require large samples from the general population to have sufficient power; extreme sampling could reduce the required sample size as much as fourfold. Our observations offer practical guidance for the design and interpretation of studies that utilize extreme sampling. PMID- 21308770 TI - Determination of (3)J((1)H3'-(31)P) couplings in a DNA oligomer with enhanced sensitivity employing a constant-time TOCSY difference experiment. AB - A constant-time TOCSY difference experiment for the determination of (3)J((1)H3' (31)P) coupling constants in non-isotope-labelled DNA oligonucleotides is presented. The method is tested on a DNA octamer and compared with the established constant-time NOESY difference method. Each (3)J((1)H3'-(31)P) coupling constant is determined from amplitude changes caused by phosphorous decoupling, which are observable on multiple cross-peaks, thus leading to a high accuracy of the value of the (3)J((1)H3'-(31)P) coupling constant. The new experiment delivers up to three times the sensitivity compared with previously reported methods. PMID- 21308771 TI - The orally bioavailable met inhibitor PF-2341066 inhibits osteosarcoma growth and osteolysis/matrix production in a xenograft model. AB - Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents. Ninety percent of patients who present with metastatic and 30% to 40% of patients with nonmetastatic disease experience relapse, creating an urgent need for novel therapeutic strategies. The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are important for mitosis, motility, and cell survival. Upregulation of Met/HGF signaling via receptor overexpression, amplification, or mutation drives the proliferation, invasiveness, and metastasis of a variety of cancer cells, including OS, prompting the development of Met/HGF inhibitors. OS cells depend on Met overexpression because introduction of dominant-negative Met inhibits in vivo tumorigenicity. Despite the importance of Met/HGF signaling in the development and maintenance of OS, the potential efficacy of pharmacologic Met inhibition in OS has been addressed only in in vitro studies. PF-2341066 is an orally bioavailable, selective ATP-competitive Met inhibitor that showed promising results recently in a phase I clinical trial in non-small cell lung cancer (NSCLC) patients. We tested the ability of PF 2341066 to inhibit malignant properties of osteosarcoma cells in vitro and orthotopic xenograft growth in vivo. In vitro, PF-2341066 inhibited osteosarcoma behavior associated with primary tumor growth (eg, proliferation and survival) as well as metastasis (eg, invasion and clonogenicity). In nude mice treated with PF 2341066 via oral gavage, the growth and associated osteolysis and extracortical bone matrix formation of osteosarcoma xenografts were inhibited by PF-2341066. PF 2341066 may represent an effective new systemic therapy for localized and potentially disseminated osteosarcoma. PMID- 21308772 TI - Inhibitory effects of iron on bone morphogenetic protein 2-induced osteoblastogenesis. AB - Postmenopausal osteoporosis is characterized by an imbalance of bone resorption exceeding bone formation, resulting in a net loss of bone mineral density (BMD). Estrogen deficiency is known to promote bone resorption. However, the causative factors that impair bone formation have not been identified. Women after menopause experience not only estrogen deficiency but also iron accumulation as a result of cessation of menstruation. In this study we investigated whether increased iron plays a role in osteoporosis. By growing primary mouse osteoclast and osteoblast progenitor cells as well as immortalized cell lines in the presence of iron, we found that increased iron had minimal effects on osteoclast cell differentiation. Interestingly, iron, particularly in its inorganic form, and to a lesser extent ferritin and transferrin all suppressed alkaline phosphatase (ALP) activities in osteoblasts. Moreover, iron downregulated mRNA levels of several other osteoblastogenic markers such as Runx2, osterix, osteopontin, and osteocalcin. To further show that this in vitro finding is relevant to the in vivo condition, we demonstrated that iron-accumulated mice with intact ovaries exhibited a significant decrease in BMD. Although iron inhibited preosteoblast cell differentiation, it did enhance preosteoblast cell proliferation, as evidenced by increased cell growth and expression of cell cycle regulator genes such as CDK4, CDK6, cyclin D1, and cyclin D3 and G(2) /M phase cell population. Taken together, our results suggest that increased iron could be a factor that slows down bone formation in postmenopausal women. PMID- 21308773 TI - Bone mineral accrual in 4- to 10-year-old precompetitive, recreational gymnasts: a 4-year longitudinal study. AB - Competitive female gymnasts have greater bone mineral measures than nongymnasts. However, less is known about the effect of recreational and/or precompetitive gymnastics participation on bone development. The purpose of this study was to investigate whether the differences previously reported in the skeleton of competitive female gymnasts are also demonstrated in young children with a current or past participation history in recreational or precompetitive gymnastics. One hundred and sixty-three children (30 gymnasts, 61 ex-gymnasts, and 72 nongymnasts) between 4 and 6 years of age were recruited and measured annually for 4 years (not all participants were measured at every occasion). Total-body (TB), lumbar spine (LS), and femoral neck (FN) bone mineral content (BMC) were measured by dual-energy X-ray absorptiometry (DXA). Multilevel random effects models were constructed and used to predict differences in TB, LS, and FN BMC between groups while controlling for differences in body size, physical activity, and diet. Gymnasts had 3% more TB and 7% more FN BMC than children participating in other recreational sports at year 4 (p < .05). No differences were found at the LS between groups, and there were no differences between ex gymnasts' and nongymnasts' bone parameters (p > .05). These findings suggest that recreational and precompetitive gymnastics participation is associated with greater BMC. This is important because beginner gymnastics skills are attainable by most children and do not require a high level of training. Low-level gymnastics skills can be implemented easily into school physical education programs, potentially affecting skeletal health. PMID- 21308774 TI - Skeletal recovery after weaning does not require PTHrP. AB - Mice lose 20% to 25% of trabecular bone mineral content (BMC) during lactation and restore it after weaning through unknown mechanisms. We found that tibial Pthrp mRNA expression was upregulated fivefold by 7 days after weaning versus end of lactation in wild-type (WT) mice. To determine whether parathyroid hormone related protein (PTHrP) stimulates bone formation after weaning, we studied a conditional knockout in which PTHrP is deleted from preosteoblasts and osteoblasts by collagen I promoter-driven Cre (Cre(ColI) ). These mice are osteopenic as adults but have normal serum calcium, calcitriol, and parathyroid hormone (PTH). Pairs of Pthrp(flox/flox) ;Cre(ColI) (null) and WT;Cre(ColI) (WT) females were mated and studied through pregnancy, lactation, and 3 weeks of postweaning recovery. By end of lactation, both genotypes lost lumbar spine BMC: WT declined by 20.6% +/- 3.3%, and null decreased by 22.5% +/- 3.5% (p < .0001 versus baseline; p = NS between genotypes). During postweaning recovery, both restored BMC to baseline: WT to -3.6% +/- 3.7% and null to 0.3% +/- 3.7% (p = NS versus baseline or between genotypes). Similar loss and full recovery of BMC were seen at the whole body and hind limb. Histomorphometry confirmed that nulls had lower bone mass at baseline and that this was equal to the value achieved after weaning. Osteocalcin, propeptide of type 1 collagen (P1NP), and deoxypyridinoline increased equally during recovery in WT and null mice; PTH decreased and calcitriol increased equally; serum calcium was unchanged. Urine calcium increased during recovery but remained no different between genotypes. Although osteoblast-derived PTHrP is required to maintain adult bone mass and Pthrp mRNA upregulates in bone after weaning, it is not required for recovery of bone mass after lactation. The factors that stimulate postweaning bone formation remain unknown. PMID- 21308775 TI - Trabecular bone microstructure and local gene expression in iliac crest biopsies of men with idiopathic osteoporosis. AB - Male idiopathic osteoporosis (MIO) is a metabolic bone disease that is characterized by low bone mass, microstructural alterations, and increased fracture risk in otherwise healthy men. Although the detailed pathophysiology of MIO has yet to be clarified, evidence increasingly suggests an osteoblastic defect as the underlying cause. In this study we tested the hypothesis that the expression profile of certain osteoblastic or osteoblast-related genes (ie, WNT10B, RUNX2, Osterix, Osteocalcin, SOST, RANKL, and OPG) is different in iliac crest biopsies of MIO patients when compared with healthy controls. Furthermore, we investigated the relation of local gene expression characteristics with histomorphometric, microstructural, and clinical features. Following written informed consent and diligent clinical patient characterization, iliac crest biopsies were performed in nine men. While RNA extraction, reverse-transcription, and real-time polymerase chain reactions (PCRs) were performed on one biopsy, a second biopsy of each patient was submitted for histomorphometry and micro computed tomography (uCT). Age-matched bone samples from forensic autopsies served as controls. MIO patients displayed significantly reduced WNT10B, RUNX2, RANKL, and SOST expression. Performing uCT for the first time in MIO biopsies, we found significant decreases in trabecular number and connectivity density. Trabecular separation was increased significantly, but trabecular thickness was similar in both groups. Histomorphometry revealed decreased BV/TV and osteoid volume and fewer osteoclasts in MIO. By providing evidence for reduced local WNT10B, RUNX2, and RANKL gene expression and histomorphometric low turnover, our data support the osteoblast dysfunction model discussed for MIO. Further, MIO seems to lead to a different microstructural pathology than age-related bone loss. PMID- 21308776 TI - DLK1 is a novel regulator of bone mass that mediates estrogen deficiency-induced bone loss in mice. AB - Delta-like 1/fetal antigen 1 (DLK1/FA-1) is a transmembrane protein belonging to the Notch/Delta family that acts as a membrane-associated or a soluble protein to regulate regeneration of a number of adult tissues. Here we examined the role of DLK1/FA-1 in bone biology using osteoblast-specific Dlk1-overexpressing mice (Col1-Dlk1). Col1-Dlk1 mice displayed growth retardation and significantly reduced total body weight and bone mineral density (BMD). Micro-computed tomographis (uCT) scanning revealed a reduced trabecular and cortical bone volume fraction. Tissue-level histomorphometric analysis demonstrated decreased bone formation rate and enhanced bone resorption in Col1-Dlk1 mice compared with wild type mice. At a cellular level, Dlk1 markedly reduced the total number of bone marrow (BM)-derived colony-forming units fibroblasts (CFU-Fs), as well as their osteogenic capacity. In a number of in vitro culture systems, Dlk1 stimulated osteoclastogenesis indirectly through osteoblast-dependent increased production of proinflammatory bone-resorbing cytokines (eg, Il7, Tnfa, and Ccl3). We found that ovariectomy (ovx)-induced bone loss was associated with increased production of Dlk1 in the bone marrow by activated T cells. Interestingly, Dlk1(-/-) mice were significantly protected from ovx-induced bone loss compared with wild-type mice. Thus we identified Dlk1 as a novel regulator of bone mass that functions to inhibit bone formation and to stimulate bone resorption. Increasing DLK1 production by T cells under estrogen deficiency suggests its possible use as a therapeutic target for preventing postmenopausal bone loss. PMID- 21308777 TI - Phospho-Smad1 modulation by nedd4 E3 ligase in BMP/TGF-beta signaling. AB - A considerable number of studies have focused on the regulation of mothers against decapentaplegic homologue (Smad)-dependent or -independent pathways in the signaling by each transforming growth factor beta (TGF-beta) superfamily member in diverse biologic contexts. The sophisticated regulation of the actions of these molecules and the underlying molecular mechanisms still remain elusive. Here we show new mechanisms of ambilateral R (receptor-regulated)-Smad regulation of bone morphogenetic protein 2 (BMP-2)/TGF-beta1 signals. In a specific context, both signals regulate the nonclassic Smads pathway reciprocally, BMP-2 to Smad2/3 and TGF-beta1 to Smad1/5/8, as well as their own classic linear Smad pathway. Interestingly, in this study, we found that C-terminal phosphorylated forms of each pathway Smad degraded rapidly 3 hours after stimulation of nonclassic signals but are dramatically restored by treatment with via proteasomal inhibition. Furthermore, an E3 ligase, neural precursor cell expressed, developmentally down-regulated 4 (Nedd4), also was found as one of the important modulators of the p-Smad1 in both BMP-2 and TGF-beta1 action. Overexpressed Nedd4 suppressed the BMP-induced osteoblast transdifferentiation process of premyoblast C2C12 cells or alkaline phosphatase (ALP) level of human osteosarcoma cells and promoted TGF-beta1-induced degradation of p-Smad1 via physical interaction and polyubiquitination. Conversely, siNedd4 potentiated BMP signals through upregulation of p-Smad1 and ALP activity, the effect of which led to an increased the rate of P(i) -induced calcification of human vascular smooth muscle cells. These new insights about proteasomal degradation-mediated phosphorylated nonclassic Smad regulation of BMP-2/TGF-beta1 could, in part, help to unravel the complex mechanisms of abnormal nonosseous calcification by the aberrant activity of BMP/TGF-beta/Smads. PMID- 21308778 TI - Telomerase-deficient mice exhibit bone loss owing to defects in osteoblasts and increased osteoclastogenesis by inflammatory microenvironment. AB - Telomere shortening owing to telomerase deficiency leads to accelerated senescence of human skeletal (mesenchymal) stem cells (MSCs) in vitro, whereas overexpression leads to telomere elongation, extended life span, and enhanced bone formation. To study the role of telomere shortening in vivo, we studied the phenotype of telomerase-deficient mice (Terc(-/-)). Terc(-/-) mice exhibited accelerated age-related bone loss starting at 3 months of age and during 12 months of follow-up revealed by dual-energy X-ray absorptiometric (DXA) scanning and by micro-computed tomography (uCT). Bone histomorphometry revealed decreased mineralized surface and bone-formation rate as well as increased osteoclast number and size in Terc(-/-) mice. Also, serum total deoxypyridinoline (tDPD) was increased in Terc(-/-) mice. MSCs and osteoprogenitors isolated from Terc(-/-) mice exhibited intrinsic defects with reduced proliferating cell number and impaired osteogenic differentiation capacity. In addition, the Terc(-/-) -MSC cultures accumulated a larger proportion of senescent beta-galactosidase(+) cells and cells exhibiting DNA damage. Microarray analysis of Terc(-/-) bone revealed significant overexpression of a large number of proinflammatory genes involved in osteoclast (OC) differentiation. Consistently, serum obtained from Terc(-/-) mice enhanced OC formation of wild-type bone marrow cultures. Our data demonstrate two mechanisms for age-related bone loss caused by telomerase deficiency: intrinsic osteoblastic defects and creation of a proinflammatory osteoclast-activating microenvironment. Thus telomerization of MSCs may provide a novel approach for abolishing age-related bone loss. PMID- 21308779 TI - Interferon-gamma plays a role in bone formation in vivo and rescues osteoporosis in ovariectomized mice. AB - Interferon gamma (IFN-gamma) is a cytokine produced locally in the bone microenvironment by cells of immune origin as well as mesenchymal stem cells. However, its role in normal bone remodeling is still poorly understood. In this study we first examined the consequences of IFN-gamma ablation in vivo in C57BL/6 mice expressing the IFN-gamma receptor knockout phenotype (IFNgammaR1(-/-)). Compared with their wild-type littermates (IFNgammaR1(+/+)), IFNgammaR1(-/-) mice exhibit a reduction in bone volume associated with significant changes in cortical and trabecular structural parameters characteristic of an osteoporotic phenotype. Bone histomorphometry of IFNgammaR1(-/-) mice showed a low-bone turnover pattern with a decrease in bone formation, a significant reduction in osteoblast and osteoclast numbers, and a reduction in circulating levels of bone formation and bone-resorption markers. Furthermore, administration of IFN-gamma (2000 and 10,000 units) to wild-type C57BL/6 sham-operated (SHAM) and ovariectomized (OVX) female mice significantly improved bone mass and microarchitecture, mechanical properties of bone, and the ratio between bone formation and bone resorption in SHAM mice and rescued osteoporosis in OVX mice. These data therefore support an important physiologic role for IFN-gamma signaling as a potential new anabolic therapeutic target for osteoporosis. PMID- 21308780 TI - Mortality risk for operated and nonoperated vertebral fracture patients in the medicare population. AB - Vertebral compression fractures (VCFs) are associated with increased mortality risk, but the association between surgical treatment and survivorship is unclear. We evaluated the mortality risk for VCF patients undergoing conservative treatment (nonoperated), kyphoplasty, and vertebroplasty. Survival of VCF patients in the 100% U.S. Medicare data set (2005-2008) was estimated by the Kaplan-Meier method, and the differences in mortality rates at up to 4 years were assessed by Cox regression (adjusted for comorbidities) between operated and nonoperated patients and between kyphoplasty and vertebroplasty patients. An instrumental variables analysis was used to evaluate mortality-rate difference between kyphoplasty and vertebroplasty patients. A total of 858,978 VCF patients were identified, including 119,253 kyphoplasty patients and 63,693 vertebroplasty patients. At up to 4 years of follow-up, patients in the operated cohort had a higher adjusted survival rate of 60.8% compared with 50.0% for patients in the nonoperated cohort (p < .001) and were 37% less likely to die [adjusted hazard ratio (HR) = 0.63, p < .001]. The adjusted survival rates for VCF patients following vertebroplasty or kyphoplasty were 57.3% and 62.8%, respectively (p < .001). The relative risk of mortality for kyphoplasty patients was 23% lower than that for vertebroplasty patients (adjusted HR = 0.77, p < .001). Using physician preference as an instrument, the absolute difference in the adjusted survival rate at 3 years was 7.29% higher in patients receiving kyphoplasty than vertebroplasty (p < .001), compared with a crude absolute rate difference of 5.09%. This study established the mortality risk associated with VCFs diagnosed between 2005 and 2008 with respect to different treatment modalities for elderly patients in the entire Medicare population. PMID- 21308781 TI - The comparison of aripiprazole and risperidone augmentation in selective serotonin reuptake inhibitor-refractory obsessive-compulsive disorder: a single blind, randomised study. AB - OBJECTIVE: To investigate the comparative efficacy of aripiprazole and risperidone as augmenting agents in the treatment of obsessive-compulsive disorder (OCD) patients who did not show a >=35% decrease in the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) after 12-week monotherapy with selective serotonin reuptake inhibitors (SSRIs). METHODS: The study consists of two different periods of treatment: a 12-week prospective period to determine resistance to SSRI treatment and an 8-week single-blind addition period for refractory patients only. Ninety patients were randomly assigned to receive one of the SSRI treatments. Sixty-nine patients (76.6%) completed the 12-week SSRI monotherapy period. Forty-one patients (59.4%) were considered refractory and were randomised to receive either risperidone (20 patients, 3 mgr daily) or aripiprazole (21 patients, 15 mgr daily) as augmentation to SSRI treatment. Sixteen patients (76.2%) in the aripiprazole group and 18 patients (84%) in the risperidone group completed the 8-week treatment period. RESULTS: Eight patients (50%) in aripiprazole and 13 patients (72.2%) in risperidone group met response criteria of Y-BOCS decrease >=35% at the end of the study. The risperidone group showed a significant improvement in Y-BOCS obsession scores compared with aripiprazole. CONCLUSIONS: The present findings suggest that risperidone may be more effective than aripiprazole. PMID- 21308782 TI - Novel combination strategy to optimize treatment for PTSD. AB - Post-traumatic stress disorder (PTSD) is increasingly recognized as a serious and potentially debilitating condition in combat veterans returning from Iraq and Afghanistan. Exposure to a potentially life-threatening event such as military combat may be followed by PTSD. Despite recent advances in pharmacotherapy for PTSD, monotherapy with the currently available medications is only partially effective, as demonstrated in large clinical trials of combat veterans with PTSD. This underscores the need to investigate novel combination strategies to enhance treatment response in PTSD. The alpha-1 adrenergic receptor (AR) antagonist, prazosin, appears promising in recent studies for its capacity to reduce trauma related nightmares (a group B night-time intrusion symptom) and insomnia (a group D night-time arousal symptom), while recent evidence supports using the beta-AR antagonist, propranolol, to dampen the emotional content of traumatic memories (daytime intrusion symptoms including flashbacks, intrusive recollections of traumatic event, and heightened physiological reactivity/ responsivity to trauma reminders). In this review, we present data supporting the potential utility of combined drug regimen (prazosin and propranolol) acting through different noradrenergic mechanisms, with the potential to target more than one set of PTSD symptoms to optimize PTSD treatment. PMID- 21308783 TI - Venlafaxine modulates depression-induced behaviour and the expression of Bax mRNA and Bcl-xl mRNA in both hippocampus and myocardium. AB - OBJECTIVES: Major depressive disorder is associated with progressive brain changes and is frequently comorbid with cardiovascular disease. There may be shared pathophysiological pathways between cerebral and myocardial dysfunction that impact on apoptosis related proteins. Our aim was to examine behaviour changes of rats with chronic mild stress (CMS), explore the expression of Bax and Bcl-xl in the hippocampus and myocardium, and additionally evaluate the effects of venlafaxine on these molecular mechanisms. METHODS: Rats were randomly divided into three groups. The behaviour was assessed using the open field and sucrose consumption tests. Gene expression was measured by RT-PCR. RESULTS: In CMS, there was a significant reduction of movements and sucrose consumption, an increased Bax level and a decreased Bcl-xl level in both the hippocampus and myocardium. The venlafaxine group showed an increase in movements and sucrose consumption, as well as upregulated expression of Bcl-xl and downregulated expression of Bax in both the hippocampus and myocardium. CONCLUSIONS: These results demonstrate that in CMS, there is an increase in pro-apoptotic pathways that is reversed by venlafaxine. This suggests that there are shared active biochemical pathways that may play a role in the process of neuroprogression that is seen in depression and cardiovascular disorders. PMID- 21308784 TI - Pain treatment of agitation in patients with dementia: a systematic review. AB - BACKGROUND: Advancing age is associated with high prevalence of both dementia and pain. Dementia is frequently accompanied by distressing behavioral and psychological symptoms, including agitation and aggression, particularly in nursing home patients. The etiology of agitation is multifactorial. It has been suggested that un-diagnosed and untreated pain may contribute to agitation in people with dementia. If this is correct, individual pain treatment could be of benefit in ameliorating agitation and other behavioral changes in people with dementia. OBJECTIVE: The objective of this paper is to conduct a systematic review of studies of whether pain medication can improve agitation in people with dementia. METHODS: A systematic search of the PubMed and Cochrane databases for the period 1992-2010 was performed, using dementia, agitation, aggression, depression, behavioral disturbances, behavioral and psychological symptoms (BPSD), pain, pain assessment, pain treatment, pain management, and analgesics as search terms. Inclusion criteria were: prospective studies including patients with dementia, interventions focusing on pain reduction, inclusion of a control condition, and outcome measures including agitation or other related behavioral disturbances. RESULTS: Only three controlled trials were identified; all were cross-over trials, and two included small sample sizes (<50). Findings were inconsistent, and although some correlations were reported, these did not support the hypothesis that pain management reduced agitation. CONCLUSION: There is a profound dearth of rigorous studies of the effect of pain treatment in patients with dementia and agitation. The available studies do not support the hypothesis that pain management reduces agitation in nursing-home patients with dementia. Randomized, controlled parallel-group studies are needed. PMID- 21308785 TI - Caregiver support groups in patients with dementia: a meta-analysis. AB - OBJECTIVES: Meta-analysis studies of specific types of support groups are limited. We conducted a review and assessment of the effectiveness of support groups for caregivers of demented patients, and examined the impact of support group characteristics. METHODS: A search of multiple, electronic databases including the Cochrane Library, Medline, PUBMED, and others was conducted; studies published between 1998 and 2009 were collected. Thirty quantitative journal articles that were true and quasi-experimental controlled trials on support groups for non-professional caregivers, including mutual support, psychoeducational, and educational groups were analyzed. Outcome indicators were psychological well-being, depression, burden, and social outcomes. RESULTS: Support groups showed a significant positive effect on caregivers' psychological well-being (Hedge's g = -0.44, 95% CI = -0.73, -0.15), depression (Hedge's g = 0.40, 95% CI = -0.72, -0.08), burden (Hedge's g = -0.23, 95% CI = -0.33, -0.13), and social outcomes (Hedge's g = 0.40, 95% CI = 0.09, 0.71). The use of theoretical models, and length and intensity of group sessions had a significant impact on the effect sizes for psychological well-being and depression. Ratio of female participation (for psychological well-being and depression) and average age (social outcomes) were significant predictor variables. CONCLUSIONS: Support groups benefit caregivers and findings of this meta-analysis serve as immediate guidance for group facilitators. Future research should include additional outcome variables with our defined factors on effectiveness collected as demographic characteristic data for comparison. A more comprehensive understanding of the effectiveness of support groups is indicated to enhance outcomes for caregivers and patients. PMID- 21308786 TI - Tobacco use and dementia: evidence from the 1066 dementia population-based surveys in Latin America, China and India. AB - OBJECTIVES: To assess the association between tobacco consumption and dementia using the same methodology in seven developing countries, testing the specific hypotheses that higher exposure to tobacco is associated with a higher prevalence of dementia, that the association is limited to smoked tobacco and is stronger for vascular dementia compared to Alzheimer's disease. METHODS: Cross-sectional surveys conducted on individuals aged 65+. A total of 15 022 residents in specified catchment areas were assessed face-to-face using a standardised protocol, which included dementia diagnosis and detailed information on past and current tobacco consumption, and on important potential confounders of this association. RESULTS: A high proportion of participants were never smokers (52% in Dominican Republic to 83% in Peru), most of those who ever used tobacco in China and India were still smoking at age 65 and above (80% and 84%, respectively). There was a positive association between history of tobacco smoke exposure (pack years up to age 50) and dementia (pooled PR = 1.003; 95%CI 1.001 1.005), Alzheimer's disease (pooled PR = 1.007; 95% CI, 1.003-1.011) and Vascular Dementia (pooled PR = 1.003; 95% CI = 1.001-1.005). These associations were attenuated but remained significant if exposure after the age of 50 was included. In India there was no association between smokeless tobacco and dementia. CONCLUSIONS: Dementia in developing countries appears to be positively associated with history of tobacco smoking but not smokeless tobacco use. Selective quitting in later life may bias estimation of associations. PMID- 21308787 TI - The rising demand for consultation-liaison psychiatry for older people: comparisons within Liverpool and the literature across time. AB - OBJECTIVES: To compare the rate of referrals of older people for consultation liaison psychiatry services over time within Liverpool and with the literature. METHODS: All referrals to the liaison psychiatry service for older people in Liverpool between 1999 and 2004 were used to calculate referral rates and compared with data from the same hospital from 1981 to 1989 previously published. Data related to referral rates was extracted from other published studies to allow cross-national comparisons over time. RESULTS: Between 1999 and 2004 there were 2760 referrals to the Liverpool liaison psychiatry service for older people producing an average annual referral rate of 2.89%. This compares to a referral rate of 0.7% in 1981 and 1.34% in 1989. Comparison with studies from the UK, North America, Europe, Singapore and Taiwan shows an increasing trend across a 30 year period. The rate of referral increases with increasing age up to age 90. CONCLUSION: Trends indicate increasing rates of referral of older people to consultation-liaison psychiatry services with greater representation of the older old. Similar effects are likely to be experienced in all nations with an ageing population. Liaison psychiatry services will need professionals trained in old age psychiatry if the needs of this increasing elderly population are to be addressed. PMID- 21308788 TI - Antipsychotic medication is associated with selective alterations in ventricular cerebrospinal fluid Abeta 40 and tau in patients with intractable unipolar depression. AB - OBJECTIVE: Alterations in plasma and in lumbar cerebrospinal fluid amyloid-B peptide (Abeta) levels have been reported in Alzheimer's disease. Studies have also suggested similar changes in depressed patients. No information is available on the impact of psychotropic drugs on this in patients with depression. We therefore quantified Abeta in ventricular cerebrospinal fluid (CSF) in a population of patients with treatment-resistant depression, with and without antipsychotic medication. METHOD: A cross-sectional study of 32 patients undergoing subcaudate tractotomy for major (unipolar) depressive disorder. Ventricular CSF concentrations of Abeta peptide 1-40 and 1-42, also p-tau and total tau were determined by Western blotting or enzyme-linked immunosorbent assay. RESULTS: Patients taking antipsychotic medication in the 2 weeks prior to surgery demonstrated significantly higher levels of Abeta 1-40 (mean +/- SD: 727.3 +/- 382.3 vs. 440.9 +/- 337.2 pg/ml; p = 0.032, Student's t-test) but unaltered Abeta 1-42 (mean 72.1 +/- 67.5 vs. 60.0 +/- 56.7 pg/ml; p = 0.587) compared to a matched sample not treated with antipsychotic drugs. The same group demonstrated elevated total tau (mean 945.0 +/- 422.2 vs. 534.3 +/- 388.3 pg/ml; p = 0.010) but not p-tau (mean 98.6 +/- 71.5 vs. 88.1 +/- 70.5 pg/ml; p = 0.694). No similar effect was found with lithium, antidepressants, carbamazepine or benzodiazepines. CONCLUSIONS: This preliminary study suggests antipsychotic drugs, widely used in patients with severe depression across all age ranges, may be associated with alteration of Abeta 1-40 and total tau, indices strongly linked with progressive organic brain disease. Further confirmatory work is needed. PMID- 21308789 TI - The effectiveness of behavioural therapy for the treatment of depression in older adults: a meta-analysis. AB - OBJECTIVE: To systematically review the effectiveness of behavioural therapy in depressed older adults. METHODS: Electronic databases were searched to July 2009. Reference lists of systematic reviews and identified studies from the search strategy were also screened. Randomised controlled trials (RCTs) of behavioural therapy compared with waiting list controls or other psychotherapies in older adults (aged >=55 years) with clinical depression were included. One author independently identified studies for inclusion. Two authors extracted data and assessed the included studies for risk of bias. Estimates of depression were combined using a random effects model and the I(2) statistic to examine heterogeneity. RESULTS: Four RCTs were included in the meta-analysis. For post treatment self-rated depression symptoms, behavioural therapy was not significantly more effective than a waiting list control [standardised mean difference (SMD) of -0.52, 95% confidence interval (CI) -1.35 to 0.30, p = 0.21, n = 117], cognitive therapy (SMD of 0.23, 95% CI -0.24 to 0.70, p = 0.33, n = 134) or brief psychodynamic therapy (SMD of -0.37, 95% CI -0.84 to 0.11, p = 0.13, n = 69). For post-treatment clinician-rated depression, behavioural therapy was not significantly more effective than cognitive therapy or brief psychodynamic therapy but was significantly more effective than a waiting list control (weighted mean difference (WMD) of -5.68, 95% CI -7.71 to -3.66, p < 0.001, n = 117). CONCLUSIONS: Behavioural therapy in depressed older adults appears to have comparable effectiveness with alternative psychotherapies. Further research is recommended with the need for larger sample sizes, more clarity on trial design and the intervention, longer term follow-up and concomitant economic evaluations. PMID- 21308790 TI - The association between intensive care unit admission and subsequent depression in patients with diabetes. AB - OBJECTIVE: To examine whether intensive care unit (ICU) admission is independently associated with increased risk of major depression in patients with diabetes. METHODS: This prospective cohort study included 3596 patients with diabetes enrolled in the Pathways Epidemiologic Follow-Up Study, of whom 193 had at least one ICU admission over a 3-year period. We controlled for baseline depressive symptoms, demographics, and clinical characteristics. We examined associations between ICU admission and subsequent major depression using logistic regression. RESULTS: There were 2624 eligible patients who survived to complete follow-up; 98 had at least one ICU admission. Follow-up assessments occurred at a mean of 16.4 months post-ICU for those who had an ICU admission. At baseline, patients who had an ICU admission tended to be depressed, older, had greater medical comorbidity, and had more diabetic complications. At follow-up, the point prevalence of probable major depression among patients who had an ICU admission was 14% versus 6% among patients without an ICU admission. After multivariate adjustment, ICU admission was independently associated with subsequent probable major depression (Odds Ratio 2.07, 95% confidence interval (1.06-4.06)). Additionally, baseline probable major depression was significantly associated with post-ICU probable major depression. CONCLUSIONS: ICU admission in patients with diabetes is independently associated with subsequent probable major depression. Additional research is needed to identify at-risk patients and potentially modifiable ICU exposures in order to inform future interventional studies with the goal of decreasing the burden of comorbid depression in older patients with diabetes who survive critical illnesses. PMID- 21308791 TI - One-year cholesterol lowering treatment reduces medial temporal lobe atrophy and memory decline in stroke-free elderly with atrial fibrillation: evidence from a parallel group randomized trial. AB - OBJECTIVES: In elderly patients with atrial fibrillation (AF), medial temporal lobe (MTL) atrophy and white matter lesions (WML) may account for the cognitive decline. Though a combination therapy of statins with cholesterol lowering agents like ezetimibe may be beneficial in patients with AF, its effects on MTL structure and WML remains unknown. METHODS: A parallel group double-blinded randomized trial was performed during 1 year whereby elderly stroke-free AF patients either received placebo or atorvastatin and ezetimibe on top oral anticoagulation therapy. Neuropsychological performance and inflammatory markers in the blood were assessed at baseline and 1 year later together with amygdala and hippocampal volume as well as WML. RESULTS: Sixty-three patients were assessed for eligibility, but 29 patients had to be excluded so that 34 patients were randomized to both groups. In the treatment group, the systemic level of inflammation was significantly decreased after 1 year and an improvement in cognitive speed as well as short- and long-term memory was observed. While there was no significant difference in MTL volume at baseline, the placebo group exhibited more atrophy for right amygdala and left hippocampus at follow-up. Finally, descriptive data showed a slight decline of WML volume in the treatment group. CONCLUSIONS: In spite of limitations due to small sample size, our data suggest that intensive cholesterol lowering therapy in AF patients may slow cognitive decline and atrophy of the MTL. Though these results have to be replicated in a larger sample, they offer potential for future interventions. PMID- 21308792 TI - Depression subtypes and 5-years risk of mortality in aged 70 years: a population based cohort study. AB - AIMS: To estimate the mortality risk related to different mood disorders in a geriatric sample of subjects aged 70 years and over without dementia. METHOD: All non-demented subjects at baseline who participate on a second phase of a population-based cohort study were included. Adjusted Cox proportional hazards models were used to determine the association between depression and 5-year survival of 451 elderly people without dementia originally recruited for a representative community dementia cohort study. Baseline evaluation included the Cambridge Mental Disorders of the Elderly Examination Schedule. Depressive disorders (major and minor episode) were assessed according DSM-IV criteria and classified according the age of onset (late vs. early). The late-onset depression was classified according to the presence or absence of depression-executive dysfunction syndrome (DEDS). RESULTS: The initial cohort size was 451 subjects, among which 10.9% (n = 49) suffered a major depressive episode and 10.4% (n = 47) a minor depressive disorder. Among the total affective disorders, 77.9% (n = 74) were late-onset depressions and 29.5% (n = 28) had executive dysfunction. After 5 years, the vital status of 94% (n = 424) of the participants was known and the mortality was 18.9% (n = 80). Late-onset major depressive episode with executive dysfunction was related to mortality after adjustment by age, gender, marital status, level of education, comorbidity (or health global status) and cognitive impairment (HR = 3.70; 95% CI = 1.55-8.83). The executive dysfunction was found to be an independent mortality risk factor (HR = 2.05; 95% CI = 1.15-3.64). CONCLUSIONS: There is a statistically significant association between mortality and late-onset major depression with executive dysfunction. PMID- 21308793 TI - Combination strategies for repair, plasticity, and regeneration using regulation of gene expression during the chronic phase after spinal cord injury. AB - Although recovery after spinal cord injury (SCI) is rare in humans, recent literature indicates that some patients do recover sensorimotor function years after the trauma. This study seeks to elucidate the genetic underpinnings of SCI repair through the investigation of neurodegenerative and regenerative associated genes involved in the response to SCI during the chronic phase in adult rats. Intervention on the level of gene regulation focused on enhancing naturally attempting SCI regenerative genes has the potential to promote SCI repair. Our aim was to analyze gene expression characteristics of candidate genes involved in the neuro-degenerative and -regenerative processes following various animal models of SCI. We compiled data showing gene expression changes after SCI in adult rats and created a chronological time-line of candidate genes differentially expressed during the chronic phase of SCI. Compiled data showed that SCI induced a transient upregulation of endogenous neuro-regenerative genes not only within a few hours but also within a few days, weeks, and months after SCI. For example, gene controlling growth-associated protein-43 (GAP-43), brain derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and others, showed significant changes in mRNA accumulation in SCI animals, from 48 hours to 12 weeks after SCI. Similarly, inhibitory genes, such as RhoA, LINGO-1, and others, were upregulated as late as 4 to 14 days after injury. This indicates that gene specific regulation changes, corresponding to repair and regenerative attempts, are naturally orchestrated over time after injury. These delayed changes after SCI give ample time for therapeutic gene modulation through upregulation or silencing of specific genes responsible for the synthesis of the corresponding biogenic proteins. By following the examination of differential gene regulation during the chronic phase, we have determined times, successions, co-activations, interferences, and dosages for potential therapeutic synchronized interventions. Finally, local cellular specificities and their neuropathophysiologies have been taken into account in the elaboration of the combination treatment strategy we propose. The interventions we propose suggest the delivery of exogenous therapeutic agents to upregulate or downregulate chosen genes or the expression of the downstream proteins to revert the post-traumatic stage of SCI during the chronic phase. The proposed combination and schedule of local cell-specific treatment should enhance intrinsic regenerative machinery and provide a promising strategy for treating patients sustaining chronic SCI. PMID- 21308794 TI - Phenotypic disruption to orofacial movement topography in conditional mutants with generalized CamKIIa/Cre D1Tox versus striatal-specific DARPP-32/Cre D1Tox ablation of D1 dopamine receptor-expressing cells. AB - Orofacial movements were quantified in (a) DARPP-32/Cre D1Tox mutants, having progressive loss of D1 dopamine receptor expressing striatal medium spiny neurons and (b) CamKIIa/Cre D1Tox mutants, having progressive, generalized loss of forebrain D1 receptor expressing cells. Horizontal jaw movements and tongue protrusions were reduced in DARPP-32/Cre but not in CamKIIa/Cre mutants; head and vibrissae movements were increased in DARPP-32/Cre but decreased in CamKIIa/Cre mutants. In drug challenge studies, tongue protrusions were increased in CamKIIa/Cre mutants following vehicle, suggesting a stress-related phenotype. These findings indicate that mice with progressive loss of striatal-specific D1 receptor expressing cells have an orofacial phenotype that may be modulated by the loss of extrastriatal D1 receptor expressing cells. As progressive loss of D1 dopamine receptor-expressing cells is a hallmark feature of Huntington's disease (HD), these findings may inform the functional role of loss of this cell population in the overall pathobiology of HD. PMID- 21308795 TI - Hypocretin1/OrexinA-containing axons innervate locus coeruleus neurons that project to the Rat medial prefrontal cortex. Implication in the sleep-wakefulness cycle and cortical activation. AB - The Hypocretin1/OrexinA (Hcrt1/OxA) neuropeptides are found in a group of posterolateral hypothalamus neurons and are involved in sleep-wakefulness cycle regulation. Hcrt1/OxA neurons project widely to brainstem aminergic structures, such as the locus coeruleus (LC), which are involved in maintenance of wakefulness and EEG activation through intense projections to the medial prefrontal cortex (mPFC). Moreover, defects of the Hcrt1/OxA system are linked to narcolepsy, a disorder characterized by excessive diurnal hypersomnia and REM state disturbance. We aimed to determine whether Hcrt1/OxA neurons innervate LC neurons (noradrenergic and nonnoradrenergic) that project to the mPFC, thereby sustaining behavioral wakefulness. To assess this, we used retrograde tracing from mPFC injections and either Hcrt1/OxA or tyrosine hydroxylase (TH) immunohistochemical labeling in single sections of rat LC. The retrograde tracer Fluorogold (FG) was microinjected into mPFC and, at optimal survival periods, sections through the LC were processed for dual immunolabeling of anti-FG and either anti-Hcrt1/OxA or anti-TH antisera. Many LC neurons projecting to mPFC were nonnoradrenergic. Electron microscopy revealed a prominent localization of Hcrt1/OxA in unmyelinated axons and axon boutons (varicosities and axon terminals) within the LC. Hcrt1/OxA-immunoreactive axon boutons frequently apposed (104/1907) or made asymmetric excitatory-type synapses (60/1907) with FG immunolabeled dendrites, indicating that Hcrt1/OxA can modulate the activity of LC neurons with cortical projections. Our results show that Hcrt1/OxA hypothalamic neurons likely excite LC neurons that project to the mPFC, and thus activate EEG and facilitate wakefulness. In narcoleptics, who are deficient in Hcrt1/OxA, impairment of this Hcrt1/OxA hypothalamic input to LC might contribute to the appearance of excessive daytime sleepiness. PMID- 21308796 TI - Methamphetamine-mediated modulation of MOR expression in the SH-SY5Y neuroblastoma cell line. AB - Methamphetamine (METH) has been shown to induce oxidative stress in SH-SY5Y cells, a neuroblastic, dopaminergic cell line model. In neuronal cells, oxidation of dopamine by auto-oxidative or enzymatic mechanisms leads to the production of reactive oxygen species (ROS). Neuronal cells treated with METH accumulate dopamine, which can ultimately lead to increased levels of ROS. ROS has been shown to mediate the expression of the mu-opioid receptor (MOR). The goal of this in vitro study was to examine the effects of METH on the accumulation of intracellular ROS in SH-SY5Y cells, which could, in turn, modulate MOR expression. Confocal laser scanning microscopy (CLSM) indicated that METH induced intracellular accumulation of ROS, detected as increased fluorescence of rhodamine 123, in a dose- and time-dependent manner. Moreover, accumulation of ROS preceded METH-induced expression of the MOR, which was attenuated by the free radical chelator, vitamin E. Additionally, increased MOR expression was noted following hydrogen peroxide treatment, indicating a role for ROS in mediating MOR expression. Taken together, our data show that METH's effect on MOR expression is dependent upon sublethal levels of intracellular ROS, which suggests a possible coupling of METH- and opiate-mediated intracellular signaling. PMID- 21308797 TI - The effects of nicotine and cigarette smoke on the monoamine transporters. AB - Cigarette smoking is the leading cause of preventable illness worldwide; however, smoking addiction remains poorly understood and cessation therapies based on nicotine replacement have limited success. The monoamine transporters are the primary mechanism for regulating the levels of dopamine, serotonin and norepinephrine in the synapse, and have been implicated in addiction and associated behaviors. Furthermore, the non-nicotinic smoking cessation therapy bupropion acts at least in part by blocking the dopamine and norepinephrine transporters. Despite this, little work has been conducted into the effects of nicotine and cigarette smoke on the monoamine transporters. This review will outline research that has been conducted to date on cigarette smoke, nicotine and the monoamine transporters. This will include monoamine transporter regulation by nicotine and cigarette smoke, genetic associations of the transporters with smoking behavior, and the potential for monoamine transporters to be targets in the development of smoking cessation pharmacotherapies. PMID- 21308798 TI - Progesterone influences postischemic synaptogenesis in the CA1 region of the hippocampus in rats. AB - Synaptogenesis is considered necessary for learning and memory. Recently, it has been suggested that progesterone (PROG) effects synaptogenesis of the cerebellar Purkinje cell, helps alleviate symptoms of multiple sclerosis and helps arrest spinal cord neurodegeneration. However, it is unclear whether PROG influences synaptic plasticity in central nervous system neurons after global cerebral ischemia. The purpose of the present study was to reveal PROG's influence on postischemic synaptogenesis in the CA1 region of the hippocampus in rats. Global cerebral ischemia was induced in male Sprague-Dawley rats by the 4-vessel occlusion (4-VO) method. To determine the amount of synaptogenesis, growth associated protein 43 (GAP-43) and synaptophysin (SYP) expression were examined by immunohistochemical, reverse transcription-polymerase chain reaction (RT-PCR) and western blot techniques. Histological and behavioral tests were used to indicate the effect of PROG on global cerebral ischemia. Recovery times were 3, 7, 14, 21, and 35 days after surgery. We found that PROG increased the expression of GAP-43 and SYP. In addition, there was a significant increase in neuronal cell density and improvement ability to remain on an accelerating rotarod observed in the 4-VO rats treated with PROG compared to vehicle. We propose that PROG helped enable synaptogenesis in the CA1 region of therat hippocampus after global cerebral ischemia in rats. PMID- 21308799 TI - Absolute abundances and affinity states of dopamine receptors in mammalian brain: A review. AB - The abundances of dopamine (DA) D(1) and D(2) receptors have been assayed with radioligands in membrane preparations and by autoradiography in vitro, and also in living brain using positron emission tomography (PET). This review compares the saturation binding parameters (B(max) and K(D) ) obtained in striatum by these several methods, and in different species. Some uncertainty in quantitation is derived from the incomplete specificities of commonly used ligands, especially Sch 23,390 for D(1) sites and spiperone for D(2) -like sites. In striatal membrane preparations, the D(1) B(max) ranges from 10 to 139 pmol g(-1) tissue, whereas the D(2) B(max) ranges from 8 to 42 pmol g(-1) tissue. Receptor concentrations in human material, despite the more extended post mortem interval, are roughly similar to those reported in rodent and nonhuman primate. Estimates of B(max) by quantitative autoradiography are generally five times higher than corresponding results for similar ligands in membrane preparations. The saturation binding parameters in living striatum have been estimated by serial PET studies with ligands over a range of specific activities. The few PET estimates of D(1) B(max) , (40-80 pmol g(-1) ) and numerous PET estimates of D(2) B(max) (20-40 pmol g(-1) ) are in general agreement with membrane estimates, but fall far short of the mean of autoradiographic results in vitro. Apparent affinities for D(1) and D(2) ligands in vivo are typically 10 times lower than for corresponding in vitro studies, presumably because the unbound ligand concentration is not corrected for the free fraction in living brain tissue. The disparate B(max) results by method suggest the presence of a large reservoir or reserve of D(1) and D(2) receptors in intact brain sections, which are unavailable to PET ligands in vivo, and which may be lost during the preparation of washed membranes. A subset of receptors existing in a high affinity state for agonists is detected in washed membrane preparations, in which the coupling to intracellular G-proteins may have become artificially limiting. However, in most PET and autoradiographic studies in vitro, agonist and antagonist ligands have similar B(max) . Discrepancies in the literature highlight the need for a better understanding of affinity states in vivo and trafficking of G-protein coupled receptors between plasma membrane and intracellular compartments. PMID- 21308802 TI - Serotonergic projections and serotonin receptor expression in the reticular nucleus of the thalamus in the rat. AB - The reticular nucleus (RT) of the thalamus, a thin sheet of GABAergic neurons located between the external medullary lamina and the internal capsule of the thalamus, has functionally distinct afferent and efferent connections with thalamic nuclei, the neocortex, the basal forebrain and the brainstem. RT is critically positioned to rhythmically pace thalamocortical networks leading to the generation of spindle activity during the early phases of sleep and during absence (spike-wave) seizures. Serotonin, acting on 5-HT(1A) receptors on parvalbumin-containing cells of RT, has been implicated in this rhythmicity. However, the precise source(s) of 5-HT afferents to the RT remains to be determined. In the present study, we injected the retrograde tracer, Fluorogold, into dorsal and ventral regions of RT to determine the origins of raphe input to RT. We further characterized the distribution of 5-HT fibers to RT by using immunohistochemistry for 5-HT and for the 5HT transporter (SERT) detection. Finally, we described the presence of the two major postsynaptic 5-HT receptors in RT, 5-HT(1A) and 5-HT(2A) receptors. Our results show that the dorsal raphe nucleus and the supralemniscal nucleus (B9) of the midbrain are the principal sources of raphe projections to RT. In addition, serotonergic fibers (5-HT and SERT positive) were richly distributed throughout RT, and 5-HT(1A) and 5-HT(2A) receptors were highly expressed on RT neurons and dendrites. These findings suggest a significant 5-HT modulatory influence on GABAergic neurons of RT in the control of rhythmical (or spindle) activity in thalamocortical systems directly associated with sleep and possibly with absence seizures. PMID- 21308801 TI - [(76) Br]BMK-152, a nonpeptide analogue, with high affinity and low nonspecific binding for the corticotropin-releasing factor type 1 receptor. AB - Corticotropin-releasing factor (CRF), a neuropeptide, regulates endocrine and autonomic responses to stress through G-protein coupled receptors, CRF(1) or CRF(2) . A PET ligand able to monitor changes in CRF(1) receptor occupancy in vivo would aid in understanding the pathophysiology of stress-related diseases as well as in the clinical development of nonpeptide antagonists with therapeutic value. We have radiolabeled the CRF(1) receptor ligand, [8-(4-bromo-2,6 dimethoxyphenyl)-2,7-dimethylpyrazolo[1,5-alpha][1,3,5]triazin-4-yl]-N,N-bis-(2 methoxyethyl)amine (BMK-152) (ClogP = 2.6), at both the 3 and 4 position with [(76) Br]. Using in vitro autoradiography saturation studies the 4-[(76) Br]BMK 152 exhibited high affinity binding to both rat (K(d) = 0.23 +/- 0.07 nM; n = 3) and monkey frontal cortex (K(d) = 0.31 +/- 0.08 nM; n = 3) consistent with CRF(1) receptor regional distribution whereas with the 3-[(76) Br]BMK-152, the K(d) s could not be determined due to high nonspecific binding. In vitro autoradiography competition studies using [(125) I]Tyr(0) -o-CRF confirmed that 3-Br-BMK-152 (K(i) = 24.4 +/- 4.9 nM; n = 3) had lower affinity (70-fold) than 4-Br-BMK-152 (K(i) = 0.35 +/- 0.07 nM; n = 3) in monkey frontal cortex and similiar studies using [(125) I]Sauvagine confirmed CRF(1) receptor selectivity. In vivo studies with P-glycoprotein (PGP) knockout mice (KO) and their wild-type littermates (WT) showed that the brain uptake of 3-[(76) Br]BMK/4-[(76) Br]BMK was increased less than twofold in KO versus WT indicating that 3-[(76) Br]BMK-152/4-[(76) Br]BMK was not a Pgp substrate. Rat brain uptakes of 4-[(76) Br] BMK-152 from ex vivo autoradiography studies showed regional localization consistent with known published CRF(1) receptor distribution and potential as a PET ligand for in vivo imaging of CRF(1) receptors. PMID- 21308803 TI - Imaging of alcohol-induced dopamine release in rats:preliminary findings with [(11) C]raclopride PET. AB - Microdialysis studies report that systemic alcohol increases extracellular dopamine (DA) in the rat striatum. The present study examined whether changes in striatal DA could be detected in rats using small animal positron emission tomography (PET). PET images were acquired in 44 alcohol-naive male Wistar and alcohol-preferring (P) rats. Subjects received up to three [(11) C]raclopride scans (rest, alcohol, and saline). Animals were anesthetized with isoflurane and secured on a stereotactic-like holder during all scans. Blood samples were collected from the tail or lateral saphenous vein of 12 animals 10 min after tracer injection for determination of blood alcohol concentration (BAC). Time activity curves were extracted from the striatum and the cerebellum and binding potential (BP(ND) ) was calculated as a measure of D(2) receptor availability. Wistars given 1.0 g kg(-1) alcohol (20%v/v) i.v. or 3.0 g kg(-1) alcohol (20%v/v) i.p. showed significant alcohol-induced decreases in BP(ND) . In P rats (given 1.5, 2.25, or 3.0 g kg(-1) alcohol), no individual group showed a statistical effect of alcohol on BP(ND) , but taken together, all P rats receiving i.p. alcohol had significantly lower BP(ND) than rest or saline scans. Large decreases in BP(ND) were primarily observed in rats with BAC above 200 mg%. Also, a significant difference was found between baseline BP(ND) of Wistars who had undergone jugular catheterization surgery for i.v. alcohol administration and those who had not. Preliminary results suggest that alcohol-induced DA release in the rat striatum is detectable using small animal PET given sufficiently large cohorts and adequate blood alcohol levels. PMID- 21308804 TI - Cyclosporine a mediates pathogenesis of aggressive cutaneous squamous cell carcinoma by augmenting epithelial-mesenchymal transition: role of TGFbeta signaling pathway. AB - Organ transplant recipients (OTRs) develop multiple aggressive and metastatic non melanoma skin cancers (NMSCs). Yet, the underlying mechanism remains elusive. Employing a variety of immune-compromised murine models, immunoblotting, immunohistochemical and immunofluorescence techniques, we show that human squamous xenograft tumors in nude mice grow faster and become significantly larger in size following treatment with the immunosuppressive drug, cyclosporine A (CsA). Re-injected tumor cells isolated from CsA-treated xenografts continued to form larger tumors in nude mice than those from vehicle-controls and retained the CsA-signatures of calcineurin signaling inhibition. Similar results were obtained when these tumors were grown in SCID-beige mice or in immuno-competent mice inoculated with syngeinic tumor cells. Consistently, tumors in the CsA group manifested enhanced cellular proliferation and decreased apoptosis. Tumors in CsA treated animals also showed an augmented epithelial-mesenchymal transition (EMT) characterized by an increased expression of fibronectin, alpha-SMA, vimentin, N cadherin, MMP-9/-2, snail and twist with a concomitant decrease in E-cadherin. CsA-treated xenograft tumors manifested increased TGFbeta1 expression and TGFbeta dependent signaling characterized by increased nuclear p-Smad 2/3. Our data demonstrate that CsA alters the phenotype of skin SCCs to an invasive and aggressive tumor-type by enhancing expression of proteins regulating EMT acting through the TGFbeta1 signaling pathway providing at least one unique mechanism by which multiple aggressive and metastatic NMSCs develop in OTRs. PMID- 21308805 TI - From molecular to macroscopic engineering: shaping hydrogen-bonded organic nanomaterials. AB - The self-assembly and self-organization behavior of chromophoric acetylenic scaffolds bearing 2,6-bis(acetylamino)pyridine (1, 2) or uracyl-type (3-9) terminal groups has been investigated by photophysical and microscopic methods. Systematic absorption and luminescence studies show that 1 and 2, thanks to a combination of solvophilic/solvophobic forces and pi-pi stacking interactions, undergo self-organization in apolar solvents (i.e., cyclohexane) and form spherical nanoparticles, as evidenced by wide-field optical microscopy, TEM, and AFM analysis. For the longer molecular module, 2, a more uniform size distribution is found (80-200 nm) compared to 1 (20-1000 nm). Temperature scans in the range 283-353 K show that the self-organized nanoparticles are reversibly formed and destroyed, being stable at lower temperatures. Molecular modules 1 and 2 were then thoroughly mixed with the complementary triply hydrogen-bonding units 3-9. Depending on the specific geometrical structure of 3-9, different nanostructures are evidenced by microscopic investigations. Combination of modules 1 or 2 with 3, which bears only one terminal uracyl unit, leads to the formation of vesicular structures; instead, when 1 is combined with bis-uracyl derivative 4 or 5, a structural evolution from nanoparticles to nanowires is observed. The length of the wires obtained by mixing 1 and 4 or 1 and 5 can be controlled by addition of 3, which prompts transformation of the wires into shorter rods. The replacement of linear system 5 with the related angular modules 6 and 7 enables formation of helical nanostructures, unambiguously evidenced by AFM. Finally, thermally induced self-assembly was studied in parallel with modules 8 and 9, in which the uracyl recognition sites are protected with tert butyloxycarbonyl (BOC) groups. This strategy allows further control of the self assembly/self-organization process by temperature, since the BOC group is completely removed on heating. Microscopy studies show that the BOC-protected ditopic modules 8 self-assemble and self-organize with 1 into ordered linear nanostructures, whereas BOC-protected tritopic system 9 gives rise to extended domains of circular nano-objects in combination with 1. PMID- 21308806 TI - Synthesis and reactivity of 4,5-[1,2-dicarba-closo-dodecaborano(12)]-1,3 diselenacyclopentane: opening of the icosahedron to give a zwitterionic intermediate and conversion into 7,8-dicarba-nido-undecaborate(1-). AB - The reaction of the 1,2-diselenolato-1,2-dicarba-closo-dodecaborane(12) dianion [1,2-(1,2-C(2)B(10)H(10))Se(2)](2-) with dichloromethane (CH(2)Cl(2) or CD(2)Cl(2)) in the presence of donor solvents gave 4,5-[1,2-dicarba-closo dodecaborano(12)]-1,3-diselenacyclopentane, the title compound, which was characterized by X-ray structural analysis and NMR spectroscopy ((1)H, (11)B, (13)C, and (77)Se). In the presence of pyridine, opening of the icosahedron took place, and a zwitterionic intermediate was isolated and fully characterized in the solid state by X-ray diffraction and in solution by multinuclear magnetic resonance techniques. Although such types of intermediates, prior to deboronation of the ortho-carborane cage, have been proposed several times, this is first example for which the structure has been confirmed unambiguously. This intermediate possesses a nido structure and contains a 7,8-dicarba-nido undecaborate(1-) anion and a boronium cation, the latter with two pyridine rings linked to the boron atom, which has been extruded from the cage. It was shown that this process is reversible as long as the deboronation is not complete. The formation of the intermediate is accompanied by deboronation, which leads to the 7,8-dicarba-nido-undecaborate(1-) anion. The latter was prepared independently by conventional routes from the title compound, isolated as crystalline material as the tetrabutyl ammonium salt, and characterized by X-ray structural analysis and multinuclear magnetic resonance spectroscopy ((1)H, (11)B, (13)C, and (77)Se). PMID- 21308807 TI - Complexation equilibria involving salts in non-aqueous solvents: ion pairing and activity considerations. AB - Complexation of anions, cations and even ion pairs is now an active area of investigation in supramolecular chemistry; unfortunately it is an area fraught with complications when these processes are examined in low polarity organic media. Using a pseudorotaxane complex as an example, apparent K(a2) values (=[complex]/{[salt](o)-[complex]}{[host](o)-[complex]}) for pseudorotaxane formation from dibenzylammonium salts (2-X) and dibenzo-[24]crown-8 (1, DB24C8) in CDCl(3)/CD(3)CN 3:2 vary with concentration. This is attributable to the fact that the salt is ion paired, but the complex is not. We report an equilibrium model that explicitly includes ion pair dissociation and is based upon activities rather than molar concentrations for study of such processes in non-aqueous media. Proper analysis requires both a dissociation constant, K(ipd), for the salt and a binding constant for interaction of the free cation 2(+) with the host, K(a5); K(a5) for pseudorotaxane complexation is independent of the counterion (500 M(-1)), a result of the complex existing in solution as a free cation, but K(ipd) values for the salts vary by nearly two orders of magnitude from trifluoroacetate to tosylate to tetrafluoroborate to hexafluorophosphate anions. The activity coefficients depend on the nature of the predominant ions present, whether the pseudorotaxane or the ions from the salt, and also strongly on the molar concentrations; activity coefficients as low as 0.2 are observed, emphasizing the magnitude of their effect. Based on this type of analysis, a method for precise determination of relative binding constants, K(a5), for multiple hosts with a given guest is described. However, while the incorporation of activity coefficients is clearly necessary, it removes the ability to predict from the equilibrium constants the effects of concentration on the extent of binding, which can only be determined experimentally. This has serious implications for study of all such complexation processes in low polarity media. PMID- 21308808 TI - Computational studies on azaphosphiridines, or how to effect ring-opening processes through selective bond activation. AB - The relative energies of azaphosphiridine and its isomers, the ring stability towards valence isomerization, and the ring strain, as well as the kinetics and thermodynamics of possible ring-opening reactions of P(III) derivatives (1-5) and P(V) chalcogenides (6-9; O to Te), were studied at high levels of theory (up to CCSD(T)). The barrier to inversion at the nitrogen atom in the trimethyl substituted P(III) derivative 5 increases from 12.11 to 15.25 kcal mol(-1) in the P-oxide derivative 6 (P(V)); the relatively high barrier to inversion at the phosphorus in 5 (75.38 kcal mol(-1)) points to a configurationally stable center (MP2/def2-TZVPP//BP86/def2-TZVP). The ring strain for azaphosphiridine 5 (av. 22.6 kcal mol(-1)) was found to increase upon P-oxidation (6) (30.8 kcal mol(-1); same level of theory). Various ring-bond-activation processes were studied: N protonation of P(III) (5) and P(V) (6, 7) derivatives leads to highly activated species that readily undergo P-N bond cleavage. In contrast, metal chlorides such as LiCl, CuCl, CuCl(2), BeCl(2), BCl(3), AlCl(3), TiCl(3), and TiCl(4) show little P-N bond activation in 5 and 7. Remarkably, TiCl(3) selectively activates the C-N bond, and induces stronger bond activation for P(V) (6, 7) than for P(III) azaphosphiridines (5). The ring-expanding rearrangement of P(V) azaphosphiridines 6-9 to yield P(III) 1,3,2-chalcogena-azaphosphetidines 32 a-d is predicted to be preferred for the heavier chalcogenides 7-9, but not for the P oxide 6. The first comparative analysis of three bond strength parameters is presented: 1) the electron density at bond critical points, 2) Wiberg's bond index, and 3) the relaxed force constant. This reveals the usefulness of these parameters in assessing the degree of ring bond activation. PMID- 21308809 TI - Chemical ecology of tannins: recent developments in tannin chemistry reveal new structures and structure-activity patterns. AB - Tannins are chemically complex plant polyphenols and only little is known of their true molecule-specific anti-herbivore activities. Here we will show that modern tannin chemistry is able to reveal fully new types of tannins in plants together with new types of biological activities for the tannins. Most of these new findings relate to ellagitannins, one of the least studied and underestimated classes of bioactive plant polyphenols. PMID- 21308810 TI - The "bridge" game: role of the fourth player in chiral recognition. AB - A new team player: The "three-point interaction" model, which is usually employed to rationalize chiral recognition, does not account for the amazing enantioselectivity measured for the receptors of many proteic acceptors. Gas phase experiments have indicated that at least a fourth "player" must be considered: the rigidity that a receptor opposes to distortions of its cavity resulting from noncovalent interactions with a chiral molecule (see picture). PMID- 21308811 TI - Stereoelectronic requirements for optimal hydrogen-bond-catalyzed enolization. AB - Protein crystallographic analysis of the active sites of enolizing enzymes and structural analysis of hydrogen-bonded carbonyl compounds in small molecule crystal structures, complemented by quantum chemical calculations on related model enolization reactions, suggest a new stereoelectronic model that accounts for the observed out-of-plane orientation of hydrogen-bond donors (HBDs) in the oxyanion holes of enolizing enzymes. The computational results reveal that the lone-pair directionality of HBDs characteristic for hydrogen-bonded carbonyls is reduced upon enolization, and the enolate displays almost no directional preference for hydrogen bonding. Positioning the HBDs perpendicular to the carbonyl plane induces strain in the catalyst-substrate complex, which is released upon enolization, resulting in more favorable kinetics and thermodynamics than the in-plane arrangement of HBDs. PMID- 21308812 TI - LiB12PC, the first boron-rich metal boride with phosphorus--synthesis, crystal structure, hardness, spectroscopic investigations. AB - We present synthesis, crystal structure, hardness, and IR/Raman and UV/Vis spectra of a new compound with the mean composition LiB(12)PC. Transparent single crystals were synthesised from Ga, Li, B, red phosphorus and C at 1500 degrees C in boron nitride crucibles welded in Ta ampoules. Depending on the type of boron used for the synthesis we obtained colourless, brown and red single crystals with slightly different P/C ratios. Colourless LiB(12)PC crystallizes orthorhombic in the space group Imma (No. 74) with a=10.188(2) A, b=5.7689(11) A, c=8.127(2) A and Z=4. Brown LiB(12)P(0.89)C(1.11) is very similar, but with a lower P content. Red single crystals of LiB(12)P(1.13)C(0.87) have a larger unit cell with a=10.4097(18) A, b=5.9029(7) A, c=8.2044(12) A. EDX measurements confirm that the red crystals contain more phosphorus than the other ones. The crystal structure is characterized by a covalent network of B(12) icosahedra connected by exohedral B-B bonds and P-P, P-C or C-C units. Li atoms are located in interstitials. The structure is closely related to MgB(7), LiB(13)C(2) and ScB(13)C. LiB(12)PC fulfils the electron counting rules of Wade and also Longuet-Higgins. Measurements of Vickers micro-hardness (H(V)=27 GPa) revealed that LiB(12)PC is a hard material. The optical band gaps obtained from UV/Vis spectra match the colours of the crystals. Furthermore we report on the IR and Raman spectra. PMID- 21308813 TI - Unraveling low-barrier hydrogen bonds in complex systems with a simple quantum topological criterion. PMID- 21308814 TI - Disproportionation for growing copper nanowires and their controlled self assembly facilitated by ligand exchange. AB - The coating makes the wire bundle: High-quality free-standing copper nanowires have been successfully produced by disproportionation of Cu(+) in oleylamine. This provides an effective way to prepare high-quality copper nanowires, but also enriches synthetic routes to other nanostructures. These copper nanowires can self-assemble by surface ligand exchange of oleylamine with trioctylphosphine. PMID- 21308815 TI - One-pot triple functionalization of carbon nanotubes. AB - Carbon nanotubes (CNTs) are very promising as carriers for the delivery of bioactive molecules. The multifunctionalization of CNTs is necessary to impart multimodalities for the development of future CNT-based multipotent therapeutic constructs. In this context, we report the first example of covalent trifunctionalization of different types of CNTs. Our strategy is a simple and efficient methodology based on the simultaneous functionalization of the nanotube surface with three different active groups. The reaction is performed in one step by arylation with diazonium salts generated in situ. The CNTs are functionalized with benzylamine moieties blocked with three different protecting groups that can be selectively removed under specific conditions. The trifunctionalized CNTs were characterized by TEM, thermogravimetric analysis, and Raman and UV/Vis/NIR spectroscopy, while the amine loading was determined by using the Kaiser test. The sequential removal of the protecting groups of the amine functions allows the grafting of the molecules of interest on the nanotube surface to be controlled. PMID- 21308816 TI - Concise synthesis of pyrrolidine and indolizidine alkaloids by a highly convergent three-component reaction. AB - The synthesis of pyrrolidine and indolizidine derivatives through radical carboazidation of alkenes with alpha-iodoketones, followed by reductive amination, is described. When properly substituted, further lactamization afforded pyrrolizidinones in good yield. This carboazidation/reductive amination sequence was efficiently applied to the total synthesis of three different simple alkaloids, including (+/-)-monomorine I. PMID- 21308817 TI - How the colourless 'nonfluorescent' chlorophyll catabolites rust. PMID- 21308818 TI - Supramolecular control of single-crystal-to-single-crystal transformation through selective guest exchange. AB - Guest-switchable crystals: A solid-state guest exchange of the tetraphosphonate cavitand Tiiii[H,CH(3),Ph] as host promotes single-crystal-to-single-crystal transformations (see graphic). The strong preference for methanol over water is observed in all three phases (gas, liquid, solid), thus demonstrating the fundamental role played by the preorganized cavity through synergistic H-bonds and C-H???pi interactions. PMID- 21308819 TI - Organocatalytic Michael-alkylation cascade: the enantioselective nitrocyclopropanation of oxindoles. PMID- 21308820 TI - Infusions and decoctions of mixed herbs used in folk medicine: synergism in antioxidant potential. AB - Infusions (herbal teas) and decoctions are used frequently to administer oral doses of herbs. Although some herbs are used as single ingredients, they are often prepared as mixtures, as reported by numerous ethnobotanical surveys. The present work was carried out to identify the different types of interaction (synergistic, additive and antagonistic effects) which may be found in the antioxidant activity of preparations from mixtures of the popular herbs Aloysia citrodora (lemon verbena), Foeniculum vulgare (fennel) and Mentha spicata (spearmint). Herbs were prepared using traditional methods, and the effects after different periods of storage, up to 120 days, were also evaluated. Antioxidant activity was evaluated using DPPH radical scavenging activity, reducing power and inhibition of lipid peroxidation by the beta-carotene - linoleate system and the TBARS assay. Known antioxidant compounds such as total phenolics, flavonoids, ascorbic acid and reducing sugars were also determined. Spearmint was found to be present in the herb mixtures with the greatest antioxidant activity and these also had the highest flavonoid content. The most potent antioxidant activity was found in combinations of different herbs, suggesting synergistic effects. PMID- 21308821 TI - Angelica acutiloba root attenuates insulin resistance induced by high-fructose diet in rats. AB - Angelica acutiloba root (Japanese Dong Quai), used for treatment of gynecological disorders, is currently cultivated in Taiwan. The present study evaluated the preventative effect of Angelica acutiloba root (Japanese Dong Quai) on the induction of insulin resistance. Insulin resistance was induced in rats by feeding a high fructose diet for 6 weeks. Thereafter, the rats were maintained on the same diet and treated with oral A. acutiloba root extract or pioglitazone once daily for 8 weeks. At the end of treatment, the degree of basal insulin resistance was measured by homeostasis model assessment (HOMA-IR). Insulin sensitivity was calculated using the composite whole body insulin sensitivity index (ISIcomp). Protein expression was evaluated by immunoblotting. A. acutiloba (300 mg/kg/day) displayed similar characteristics to pioglitazone (20 mg/kg/day) in reducing HOMA-IR and elevating ISIcomp. Elevated glycosylated hemoglobin levels and hyperinsulinemia were ameliorated by A. acutiloba treatment without hepatotoxic or nephrotoxic effects. A. acutiloba treatment improved dyslipidemia, induced lipoprotein lipase activity and enhanced hepatic glycogen accumulation. Further, A. acutiloba treatment enhanced the action of insulin on muscle glucose transporter subtype 4 translocation and attenuated hepatic phosphoenolpyruvate carboxykinase expression. The findings suggest that A. acutiloba may be an effective ethnomedicine for improving insulin sensitivity. PMID- 21308822 TI - Antidyslipidemic activity of hot-water extracts from leaves of Cinnamomum osmophloeum Kaneh. AB - The antidyslipidemic activity of hot-water extracts of Cinnamomum osmophloeum leaves (COE) were evaluated on hamsters fed a high-fat diet. Oral administration of COE to hyperlipidemic hamsters reduced the total cholesterol (TC), triglyceride (TG) and low-density lipoprotein (LDL-C) levels. Compared with hyperlipidemic hamsters, the plasma TC and TG levels of hamsters fed with COE at a dosage of 100 mg/kg body weight for 5 and 10 weeks were significantly reduced to 12.63% and 34.25%, and 33.88% and 36.88%, respectively. Plasma LDL-C was also reduced to 27.77% after 10 weeks feeding with the same regimen. Standard diagnostic tests indicated that the extracts did not cause damage to hamster liver or kidneys. Based on these results, it is concluded that COE possesses antidyslipidemic activity. The composition of COE was characterized. Two main compounds, kaempferol 3-O-beta-D-apiofuranosyl-(1 -> 2)-alpha-L-arabinofuranosyl 7-O-alpha-L-rhamnopyranoside (1) and kaempferitrin (2) were identified in the hot water extracts. Their contents were 7.56% and 9.95%, respectively. PMID- 21308823 TI - In vitro antiinflammatory activity of a new sesquiterpene lactone isolated from Siegesbeckia glabrescens. AB - A new sesquiterpene lactone was isolated from Siegesbeckia glabrescens as an inhibitor of nitric oxide and prostaglandin E2 synthesis in the LPS-activated RAW264.7 macrophage cell line. It dose-dependently decreased the protein and mRNA levels of inducible nitric oxide synthase and cyclooxygenase-2. Reporter gene assay revealed that the compound attenuated the LPS-induced DNA transcriptional activity of nuclear factor-kappa B (NF-kappaB). In addition, it inhibited the nuclear translocation of the p65 subunit of NF-kappaB by blocking the inhibitory kappa B-alpha degradation. This compound from Siegesbeckia glabrescens might be beneficial for the treatment of inflammation-related diseases. PMID- 21308824 TI - Effect of cinnamoyl and flavonol glucosides derived from cherry blossom flowers on the production of advanced glycation end products (AGEs) and AGE-induced fibroblast apoptosis. AB - Cherry blossom flowers are familiar to the Japanese, and some species of the flowers soaked in salty vinegar are used as processed foods. The constituents of aqueous ethanol extract from cherry blossom (Prunus lannesiana) flowers (CBE) were examined and cinnamoyl and flavonol glucosides were isolated. To elucidate the pharmacological functions of CBE and its constituents, their effects on the production of advanced glycation end products (AGEs) and on AGE-induced fibroblast damage were examined. CBE and 1-O-(E)-caffeoyl-beta-D-glucopyranoside (CaG), a principal compound in CBE, significantly suppressed the production of AGEs derived from glucose and albumin at 100 MUg/mL. Among the flavonol glucosides, quercetin 3-O-beta-D-glucopyranoside (QG) exhibited potent suppressive activity (IC50 : 30 MUg/mL). CBE and CaG suppressed glyoxal-induced AGE production in fibroblasts at 10 MUg/mL, but QG did not. In addition, CBE and CaG recovered collagen lattice formation consisting of collagen and glycated fibroblasts at 10 MUg/mL. Moreover, CBE and its constituents, except kaempferol 3 O-(6"-malony)-beta-D-glucopyranoside, significantly suppressed fibroblast apoptosis induced by carboxymethyl lysine-collagen at 10 MUg/mL. These results show that cinnamoyl and flavonol glucosides of cherry blossom flowers suppress AGE production and AGE-induced fibroblast apoptosis. Cherry blossom flowers may be effective against skin AGE production and fibroblast damage by AGEs. PMID- 21308825 TI - Appetite control and glycaemia reduction in overweight subjects treated with a combination of two highly standardized extracts from Phaseolus vulgaris and Cynara scolymus. AB - The management of overweight may include the use of dietary supplements targeted to favour the increase of the satiation associated with a decrease in blood glucose and lipid levels. The aim of this study was to evaluate the efficacy of a dietary supplementation with an extract from Phaseolus vulgaris and Cynara scolymus, on satiation, the glucose and lipid pattern. A randomized, double blind, placebo-controlled clinical trial was performed in 39 overweight subjects (20 supplemented group, 19 placebo group) for 2 months. The modification of satiation, by Haber's scale, was the primary end-point, and the variation of the glucose and lipid pattern, of the anthropometric parameters and of the psychodynamic tests score were the secondary end-points. At the end of treatment, the net change of the Haber's mean score increased significantly in the intervention group. The net change of the glycaemia and of the dietary restriction score of the three factor eating questionnaire (TFEQ), were reduced significantly only in the intervention group. Moreover, in the supplemented group, the homeostasis model assessment, the body mass index and the susceptibility-to-hunger score of the TFEQ, decreased significantly after intervention; these parameters did not change in the controls. This treatment appears potentially useful in the management of overweight and dysglycaemia. PMID- 21308826 TI - High-field MRS of the human brain at short TE and TR. AB - In vivo MRS of the human brain at 7 tesla allows identification of a large number of metabolites at higher spatial resolutions than currently possible at lower field strengths. However, several challenges complicate in vivo localization and artifact suppression in MRS at high spatial resolution within a clinically feasible scan time at 7 tesla. Published MRS sequences at 7 tesla suffer from long echo times, inherent signal-to-noise ratio (SNR) loss, large chemical shift displacement artifacts or long repetition times because of excessive radiofrequency (RF) power deposition. In the present study a pulse-acquire sequence was used that does not suffer from these high field drawbacks. A slice selective excitation combined with high resolution chemical shift imaging for in plane localization was used to limit chemical shift displacement artifacts. The pulse-acquire approach resulted in a very short echo time of 1.4 ms. A cost function guided shimming algorithm was developed to constrain frequency offsets in the excited slice, therefore adiabatic frequency selective suppression could be employed to minimize artifacts from high intensity lipids and water signals in the excited slice. The high sensitivity at a TR of 1 s was demonstrated both on a supraventricular slice as well as in an area very close to the skull in the frontal cortex at a nominal spatial resolution of 0.25 cc within a feasible scan time. PMID- 21308827 TI - Evaluation of the impact of a consultation in a secure setting. AB - BACKGROUND: Organisational consultation is widespread in the National Health Service (NHS), but little is known about its impact. AIMS: To evaluate the impact of a psychodynamically informed consultation to a high-security hospital ward. METHOD: This prospective study compared measures before and after the consultation with similarly timed measures on a comparison ward in the hospital, matched for patient characteristics, but not exposed to the consultation. The intention was to compare the consultation with 'treatment as usual', but the study became a comparison of interventions after a programme to facilitate staff patient communication was instituted by management on the comparison ward. Measures included the Ward Atmosphere Scale (WAS) and an index of burnout. Interactions between staff and patients were observed and rated for content and quality. RESULTS: Most scales on two of three dimensions of the WAS improved on both wards, as did the quality of staff-patient contact. Change at the levels of behaviour and attitude strengthens confidence that a shift occurred in a positive direction. CONCLUSIONS: The overall importance of professional supportive attention to staff in such settings was established. Although there was little evidence here for a distinct advantage of one intervention style, the results were encouraging for the consultation, because ward atmosphere and staff-patient interaction were not a direct target for change. Further study is needed to test the possibility that specific interventions may carry specific advantage in other settings or with other patient groups. The nature and quality of institutional support for such research itself needs strengthening. In this case, the institutions' intention to assist was robust, but real understanding and/or sustained ability to facilitate it is lacking. This problem is hardly unique to this setting. PMID- 21308828 TI - Persistent pulsation in a fetal great vessel after complete cardiac arrest. PMID- 21308829 TI - Online evaluation of fetal second-trimester four-chamber view images: a comparison of six evaluation methods. AB - OBJECTIVE: To compare six online evaluation methods for auditing routine second trimester four-chamber view still images. METHODS: We evaluated three different scoring grids (subjective, five-item score and seven-item score), which were applied with or without access to online help, resulting in a total of six evaluation methods. For the subjective scoring grid, images were rated as excellent, good, fair, poor or very poor. For the five-item score, 1 point was allocated for visualization (vs non-visualization or non-evaluable) of each of: heart crux, atria, ventricles, apex and aorta, yielding a score of 0-5. For the seven-item score, 1 point was allocated for clear (vs unclear) visualization of each of: moderator band at the apex, interventricular septum, atrioventricular valves, non-linear insertion of atrioventricular valves (normal offset), septum primum, aorta and pulmonary vein. Each evaluation method was used via the Internet by three randomly selected reviewers, who evaluated the same set of 80 images. Reviewers were experienced in fetal ultrasound, but were not involved in the design of the study. Interrater agreement was the main outcome. RESULTS: The five-item scoring grid with online help achieved the best interrater agreement (interrater intraclass correlation coefficient = 0.7). CONCLUSIONS: Evaluation of the second-trimester sonographic four-chamber view is apparently best achieved with a simple five-item scoring grid. PMID- 21308830 TI - Relationship between fetal head station established using an open magnetic resonance imaging scanner and the angle of progression determined by transperineal ultrasound. AB - OBJECTIVE: We investigated the correlation between the angle of progression measured by transperineal ultrasound and fetal head station measured by open magnetic resonance imaging (MRI), the gold standard, in pregnant women at full term. METHODS: Thirty-one pregnant women at full term with a fetus in the occipitoanterior position were enrolled. First, the distance between the leading part of the skull and the interspinal plane was obtained using an open MRI system with the patient in a supine position. Immediately after MRI, the angle of progression was obtained by transperineal ultrasound without changing the woman's posture. RESULTS: There was a significant correlation between the angle of progression determined by transperineal sonography and the distance between the presenting fetal part and the level of the maternal ischial spines (y = - 0.51x + 60.8, r(2) = 0.38, P < 0.001). None of the fetal heads was engaged at the time of MRI and ultrasound examinations. CONCLUSIONS: The present study demonstrated a predictable relationship between the angle of progression obtained by transperineal ultrasound and the traditional scale used to quantify fetal head descent. Based on our results, station 0 would correspond to a 120 degrees angle of progression. However, this correlation is based on statistical assumptions only and has to be proven in future studies. PMID- 21308831 TI - Birth-weight prediction using three-dimensional sonographic fractional thigh volume at term in a Chinese population. AB - OBJECTIVES: To develop and validate new birth-weight prediction models in Chinese pregnant women using fractional thigh volume. METHODS: Healthy late third trimester fetuses within 5 days of delivery were prospectively examined using two (2D) and three- (3D) dimensional ultrasonography. Measurements were performed using 2D ultrasound for standard fetal biometry and 3D ultrasound for fractional thigh volume (TVol) and middle thigh circumference. The intraclass correlation coefficient (ICC) was used to analyze the inter- and intraobserver reliability of the 3D ultrasound measurements of 40 fetuses. Five birth-weight prediction models were developed using linear regression analysis, and these were compared with previously published models in a validation group. RESULTS: Of the 290 fetuses studied, 100 were used in the development of prediction models and 190 in the validation of prediction models. The inter- and intraobserver variability for TVol and middle thigh circumference measurements was small (all ICCs >= 0.95). The prediction model using TVol, femur length (FL), abdominal circumference (AC) and biparietal diameter (BPD) provided the most precise birth-weight estimation, with a random error of 4.68% and R(2) of 0.825. It correctly predicted 69.5 and 95.3% of birth weights to within 5 and 10% of actual birth weight. By comparison, the Hadlock model with standard fetal biometry (BPD, head circumference, AC and FL) gave a random error of 6.41%. The percentage of birth-weight prediction within 5 and 10% of actual birth weight was 46.3 and 82.6%, respectively. CONCLUSION: Consistent with studies on Caucasian populations, a new birth-weight prediction model based on fractional thigh volume, BPD, AC and FL, is reliable during the late third trimester in a Chinese population, and allows better prediction than does the Hadlock model. PMID- 21308832 TI - Cervical varices complicated by thrombosis in pregnancy. AB - We present a case of a 36-year-old pregnant woman with varicose veins of the uterine cervix diagnosed during the second trimester. The cervical tissue was completely replaced with dilated venous plexus. Therapeutic decisions were further complicated by the presence of blood clots within the dilated vessels. Pregnancy proceeded uneventfully, no bleeding occurred and the patient underwent a planned Cesarean delivery. This is the first reported case in the medical literature where the rare phenomenon of cervical varices was accompanied by thrombosis. PMID- 21308833 TI - Umbilical artery pulsatility index and fetal abdominal circumference in isolated gastroschisis. AB - OBJECTIVES: To investigate changes in abdominal circumference (AC) and umbilical artery pulsatility index (UA-PI) with gestation in fetuses with isolated gastroschisis, and to determine whether a relationship exists between UA-PI and fetal AC. METHODS: Data from 58 pregnancies with isolated gastroschisis diagnosed at between 24 and 36 weeks' gestation were included in the study. Z-scores were calculated with respect to expected UA-PI values in normal pregnancies after log transformation. AC-Z-scores were calculated with respect to expected size in normal pregnancies according to a standard chart. Functional linear discriminant analysis (FLDA) was applied to generate 50(th), 5(th) and 95(th) percentile curves for changes in both AC and UA-PI with gestational age in fetuses with gastroschisis. These curves were compared with the standard curves, as were the means. UA-PI was also plotted against AC. For this relationship, a robust Spearman correlation coefficient was obtained with FLDA. RESULTS: In fetuses with gastroschisis, there was a highly significant negative correlation between UA-PI and AC, normalized for gestation using Z-scores (median correlation coefficient, 0.289; median P = 0.000023). Moreover, compared with standard curves AC was lower and UA-PI higher in the gestational-age range studied. Both the AC and UA PI curves showed a significantly different rate of change with gestation compared with the normal ranges. The mean values for fetuses with gastroschisis compared with the standard AC and UA-PI range curves were significantly different for AC throughout gestation, and for UA-PI from 32 weeks' gestation. CONCLUSIONS: In fetal gastroschisis, it is well known that AC tends to be smaller, though UA-PI has not been reported to be abnormal in any consistent way. There is a clear relationship between the fetus's AC for gestation and UA-PI, which is not the case for normally grown fetuses. The data suggest that the growth restriction seen in gastroschisis may be explained by hypoxia, and not simply by the classical explanation of extra-abdominal displacement of the abdominal viscera. PMID- 21308834 TI - Effect of antenatal corticosteroid treatment on the fetal lung: a magnetic resonance imaging study. AB - OBJECTIVES: To investigate the effect of antenatal corticosteroid treatment on the fetal lung using magnetic resonance imaging. METHODS: Prospective evaluation of 30 consecutive singleton pregnancies that received antenatal corticosteroid treatment (12 mg betamethasone i.m. on admission and 24 h later) because of threatened preterm birth. Fetal lungs were assessed using T2-weighted single-shot fast spin-echo images of a whole-body 1.5-T superconducting unit twice: less than 24 h and more than 48 h after the first course of betamethasone. Lung volumes and lung-liver signal-intensity ratios were compared between the two time points. RESULTS: Nine patients had to be excluded from the analysis because they did not complete the study protocol as required. Ten female and 11 male fetuses with a gestational age between 23.4 and 32.6 weeks were included in the final analysis. The mean gestational age of included fetuses was 27.5 +/- 2.8 weeks. Using a linear regression model, a significant influence of gestational age on ln fetal lung volume (r(2)=0.414; P<0.0001) and lung-liver signal-intensity ratios (r(2)=0.271, P<0.0001) was found. Between the two evaluated time points, a significant increase in lung-liver signal-intensity ratios (2.34 +/- 0.72 vs. 3.22 +/- 1.12, P<0.0001), but not in mean lung volumes (46.6 +/- 20.7 cm(3) vs. 48.8 +/- 16.0 cm(3) , P=0.292), was observed. CONCLUSION: We demonstrate a significant increase in lung-liver signal-intensity ratios after antenatal corticosteroid treatment for induction of lung maturation which most likely reflects changing properties of the fetal lung parenchyma. This could potentially be useful in non-invasively assessing the effect of antenatal corticosteroid treatment on the lungs of fetuses at risk for preterm birth. PMID- 21308835 TI - Abnormalities of the upper extremities on fetal magnetic resonance imaging. AB - OBJECTIVE: In view of the increasing use of fetal magnetic resonance imaging (MRI) as an adjunct to prenatal ultrasonography, we sought to demonstrate the visualization of upper extremity abnormalities and associated defects on MRI, with regard to fetal outcomes and compared with ultrasound imaging. METHODS: This retrospective study included 29 fetuses with upper extremity abnormalities visualized with fetal MRI following suspicious ultrasound findings and confirmed by postnatal assessment or autopsy. On a 1.5-Tesla unit, dedicated sequences were applied to image the extremities. Central nervous system (CNS) and extra-CNS anomalies were assessed to define extremity abnormalities as isolated or as complex, with associated defects. Fetal outcome was identified from medical records. MRI and ultrasound findings, when available, were compared. RESULTS: Isolated upper extremity abnormalities were found in three (10.3%) fetuses. In 26 (89.7%) fetuses complex abnormalities, including postural extremity disorders (21/26) and structural extremity abnormalities (15/26), were demonstrated. Associated defects involved: face (15/26); musculoskeletal system (14/26); thorax and cardio/pulmonary system (12/26); lower extremities (12/26); brain and skull (10/26); and abdomen (8/26). Of the 29 cases, 18 (62.1%) pregnancies were delivered and 11 (37.9%) were terminated. MRI and US findings were compared in 27/29 cases: the diagnosis was concordant in 14 (51.9%) of these cases, and additional findings were made on MRI in 13/27 (48.1%) cases. CONCLUSIONS: Visualization of upper extremity abnormalities on fetal MRI enables differentiation between isolated defects and complex ones, which may be related to poor fetal prognosis. MRI generally confirms the ultrasound diagnosis, and may provide additional findings in certain cases. PMID- 21308836 TI - A new method for analysis of non-pregnant uterine peristalsis using transvaginal ultrasound. AB - OBJECTIVES: To develop an objective method for analysis of uterine peristalsis using transvaginal sonography (TVS). METHODS: We performed computerized analysis of 2-5-min video recordings of TVS imaging of a midsagittal cross-section of the uterus during the proliferative and early secretory phases of 18 healthy volunteers aged 28-41 years. The contours of the fluid-endometrial interface (FEI) and the endometrium-myometrium interface (EMI) were detected in each frame, and the data from all frames were used to explore the dynamic motility characteristics of these interfaces at fixed distances from the fundus. RESULTS: The mean +/- SD dominant frequency of peristalsis of the EMI along the midsagittal cross-section was 0.049 +/- 0.01 Hz and that of the cavity center was 0.043 +/- 0.02 Hz. The maximal amplitudes of the EMI were about 1 +/- 0.25 mm, located between 7 and 17 mm from the fundus. The amplitudes of the FEI were in the range 0.05-0.2 mm. The amplitude of the cavity centerline movement was 0.94 +/- 0.34 mm, located at the extremes of the unperturbed curve. CONCLUSIONS: This study provides a simple tool for analysis of uterine peristalsis characteristics using ultrasound data. This is possible at the EMI even when the FEI is invisible or incomplete, such as during the luteal phase, when an intrauterine contraceptive device is in place, and during diagnostic or medical intervention. PMID- 21308837 TI - Prediction of delivery mode with transperineal ultrasound in women with prolonged first stage of labor. AB - OBJECTIVE: To investigate if fetal head-perineum distance and angle of progression measured with two-dimensional (2D) and three-dimensional (3D) transperineal ultrasound could predict outcome of labor in primiparous women with prolonged first stage of labor. METHODS: This was a prospective observational study of 110 primiparous women with singleton cephalic presentation at term diagnosed with prolonged first stage of labor. Digital assessment of fetal station was related to the ischial spine. Fetal head descent was measured with transperineal ultrasound as the shortest distance from the fetal head to the perineum, and the angle between the pubic symphysis and the fetal head. Receiver operating characteristics (ROC) curves were constructed and 2D and 3D data acquisitions were compared. The stored 3D volumes were assessed by an examiner blinded to all other data. Vaginal delivery vs. Cesarean section was the primary outcome. RESULTS: Cesarean section was performed in 25% of the women. Areas under the ROC curves for prediction of vaginal delivery were 81% (95% confidence interval (CI), 71-91%) (P < 0.01) and 76% (95% CI, 66-87%) (P < 0.01) for fetal head-perineum distance and angle of progression, respectively, as measured by 2D ultrasound and 66% (95% CI, 54-79%) for digital assessment of fetal station (P = 0.01). In 50% of women fetal head-perineum distance was <= 40 mm and 93% (95% CI, 83-97%) of them delivered vaginally vs. 18% (95% CI, 5-48%) with distance > 50 mm. In 48% of women the angle of progression was >= 110 degrees and 87% (95% CI, 75-93%) of them delivered vaginally vs. 38% (95% CI, 21-57%) with angle < 100 degrees . Results from 2D and 3D acquisitions were similar. CONCLUSION: Fetal head-perineum distance and angle of progression measured with 2D or 3D ultrasound can predict labor outcome, with similar predictive values for the two techniques. PMID- 21308838 TI - The thymic-thoracic ratio in fetal heart defects: a simple way to identify fetuses at high risk for microdeletion 22q11. AB - OBJECTIVES: To establish reference ranges for the fetal thymic-thoracic ratio (TT ratio) and to compare results with those from fetuses with congenital heart defects (CHD) with and without microdeletion 22q11 (del.22q11), a condition known to be associated with a hypoplastic thymus. METHODS: TT-ratio was defined as the quotient of the anteroposterior thymic to the intrathoracic mediastinal diameters measured in the three vessels and trachea view. This ratio was measured in a prospective cross-sectional study of 302 normal healthy fetuses between 15 and 39 weeks' gestation. The study group comprised two groups: one group (CHDn) consisted of 90 fetuses with CHD and a normal karyotype with no del.22q11 and the other group (CHD(22)) included 20 fetuses with CHD and a normal karyotype but with proven del.22q11. RESULTS: The TT-ratio of the normal fetuses did not show any statistically significant change during gestation, with a mean value of 0.44. The values of all 90 fetuses of the CHDn group were within the normal range and no different from normal fetuses. However, 19 of the 20 (95%) fetuses in the CHD(22) group had a significantly smaller TT-ratio (P < 0.001) compared with both the CHDn group and the normal fetuses, having a mean value of 0.25. CONCLUSIONS: The TT-ratio is reliable and easy to obtain during fetal echocardiography. Fetuses with CHD and a low TT-ratio can be considered at high risk of having microdeletion del.22q11. PMID- 21308839 TI - Smaller fetal thymuses in pre-eclampsia: a prospective cross-sectional study. AB - OBJECTIVE: To determine whether the thymus is smaller in fetuses of pre-eclamptic mothers than in those of normal controls. METHODS: This was a cross-sectional, prospective, comparative study of sonographically determined fetal thymus measurements in 39 pregnancies with pre-eclampsia and 70 healthy pregnancies. RESULTS: Both the diameter and the perimeter of the fetal thymus were smaller in pregnancies with pre-eclampsia than in healthy controls. The means of the thymus diameters were 28.6 +/- 5.9 and 32.9 +/- 4.5 mm and of thymus perimeters 80.9 +/- 16.5 and 93.1 +/- 16.6 mm for pre-eclamptic and healthy pregnancies, respectively (P < 0.001). General linear models showed that smaller fetal thymuses in pre eclampsia were independent of gestational age, estimated fetal weight, small for gestational age status and antenatal steroid use. CONCLUSIONS: Pre-eclampsia is associated with smaller fetal thymuses. PMID- 21308840 TI - Narrowed beam width in newer ultrasound machines shortens measurements in the lateral direction: fetal measurement charts may be obsolete. AB - OBJECTIVES: Fetal ultrasound measurements are made in axial, lateral and oblique directions. Lateral resolution is influenced by the beam width of the ultrasound system. To improve lateral resolution and image quality, the beam width has been made narrower; consequently, measurements in the lateral direction are affected and apparently made shorter, approaching the true length. The aims of this study were to explore our database to reveal time-dependent shortening of ultrasound measurements made in the lateral direction, and to assess the extent of beam width changes by comparing beam-width measurements made on old and new ultrasound machines. METHODS: A total of 41,941 femur length measurements, collected during the time-period 1987-2005, were analyzed, with time as a covariate. Using three ultrasound machines from the 1990s and three newer machines from 2007, we performed 25 series of blinded beam-width measurements on a tissue-mimicking phantom, measuring at depths of 3-8 cm with a 5-MHz transducer. RESULTS: Regression analysis showed time to be a significant covariate. At the same gestational age, femur length measurement was 1.15 (95% CI, 1.08-1.23) mm shorter in the time-period 1999-2005 than in the time-period 1987-1992. Overall, the beam width was 1.08 (95% CI, 0.50-1.65) mm narrower with the new machines than with the old machines. CONCLUSIONS: Technical improvements in modern ultrasound machines that have reduced the beam width affect fetal measurements in the lateral direction. This has clinical implications and new measurement charts are needed. PMID- 21308841 TI - Prenatal evaluation of the position of the fetal conus medullaris. AB - OBJECTIVES: To determine the position of the fetal conus medullaris during pregnancy in relation to the last vertebral body and to examine its use in detecting skin-covered spinal dysraphism. METHODS: This was a retrospective study involving 300 consecutive ultrasound examinations between 15 weeks of gestation and term. Two operators independently assessed images of the spine to determine whether the conus medullaris and the last vertebral body could be visualized in a single image in a midsagittal plane. The distance between these two landmarks (the conus distance) was measured twice by both operators who were not aware of any previous measurements. Intra- and interobserver variability was assessed by 95% limits of agreement. Linear regression analysis was used to determine the relevant contributors to the conus distance and a normal range was computed based on the best-fit model. The normal results were compared with five cases of prenatally detected skin-covered spinal dysraphism. RESULTS: In 84.7% of the 300 cases, both operators were able to visualize the conus medullaris and the last vertebral body. Ninety-five percent limits of agreement for the intraobserver variability in measurement of conus distance were +/- 1.9 mm. For the interobserver variability, they were - 3.7 and 2.5 mm. We found a linear relationship between conus distance and gestational age, biparietal diameter and abdominal circumference. The strongest relationship was observed for femur length (conus distance = - 8.2 + femur length (mm)). In the five abnormal cases, conus distance was well below the 5(th) percentile. CONCLUSIONS: Determination of conus distance allows for an objective and feasible assessment of the conus medullaris position. This parameter promises to be useful in the prenatal detection of skin covered spinal dysraphism. PMID- 21308842 TI - First-trimester ultrasound determination of chorionicity in twin pregnancy. AB - OBJECTIVE: To determine the accuracy of ultrasound at 11-14 weeks' gestation in the diagnosis of chorionicity in twin pregnancy. METHODS: This was a retrospective observational study of data obtained between 1999 and 2010. At the first-trimester routine ultrasound scan, chorionicity was assigned according to the number of placental masses and T or lambda-signs for a single placental mass. Chorionicity was confirmed by histology or discordant sex at birth. RESULTS: A total of 648 pregnancies were assigned chorionicity by first-trimester ultrasound during the study period. Chorionicity was ascertained in 613 cases, either by histology (n = 340) or discordant sex (n = 273). Chorionicity was correctly assigned by ultrasound at 11-14 weeks in 612 of 613 pregnancies (accuracy 99.8%). Sensitivity and specificity for determining monochorionicity were 100% and 99.8%, respectively. CONCLUSIONS: First-trimester ultrasound can be used to determine chorionicity reliably by noting the number of placental masses and T or lambda signs. Determination of twin chorionicity is important and should be completed in the first trimester. PMID- 21308843 TI - Appearance of the fetal posterior fossa at 11 + 3 to 13 + 6 gestational weeks on transabdominal ultrasound examination. AB - OBJECTIVES: To describe the sonographic appearance of the structures of the posterior cranial fossa in fetuses at 11 + 3 to 13 + 6 weeks of pregnancy and to determine whether abnormal findings of the brain and spine can be detected by sonography at this time. METHODS: This was a prospective study including 692 fetuses whose mothers attended Innsbruck Medical University Hospital for first trimester sonography. In 3% (n = 21) of cases, measurement was prevented by fetal position. Of the remaining 671 cases, in 604 there was either a normal anomaly scan at 20 weeks or delivery of a healthy child and in these cases the transcerebellar diameter (TCD) and the anteroposterior diameter of the cisterna magna (CM), measured at 11 + 3 to 13 + 6 weeks, were analyzed. In 502 fetuses, the anteroposterior diameter of the fourth ventricle (4V) was also measured. In 25 fetuses, intra- and interobserver repeatability was calculated. RESULTS: We observed a linear correlation between crown-rump length (CRL) and CM (CM = 0.0536 * CRL - 1.4701; R2 = 0.688), TCD (TCD = 0.1482 * CRL - 1.2083; R2 = 0.701) and 4V (4V = 0.0181 * CRL + 0.9186; R2 = 0.118). In three patients with posterior fossa cysts, measurements significantly exceeded the reference values. One fetus with spina bifida had an obliterated CM and the posterior border of the 4V could not be visualized. CONCLUSIONS: Transabdominal sonographic assessment of the posterior fossa is feasible in the first trimester. Measurements of the 4V, the CM and the TCD performed at this time are reliable. The established reference values assist in detecting fetal anomalies. However, findings must be interpreted carefully, as some supposed malformations might be merely delayed development of brain structures. PMID- 21308844 TI - Protein disulfide isomerase isomerizes non-native disulfide bonds in human proinsulin independent of its peptide-binding activity. AB - Protein disulfide isomerase (PDI) supports proinsulin folding as chaperone and isomerase. Here, we focus on how the two PDI functions influence individual steps in the complex folding process of proinsulin. We generated a PDI mutant (PDI aba'c) where the b' domain was partially deleted, thus abolishing peptide binding but maintaining a PDI-like redox potential. PDI-aba'c catalyzes the folding of human proinsulin by increasing the rate of formation and the final yield of native proinsulin. Importantly, PDI-aba'c isomerizes non-native disulfide bonds in completely oxidized folding intermediates, thereby accelerating the formation of native disulfide bonds. We conclude that peptide binding to PDI is not essential for disulfide isomerization in fully oxidized proinsulin folding intermediates. PMID- 21308845 TI - A secretory system for bacterial production of high-profile protein targets. AB - Escherichia coli represents a robust, inexpensive expression host for the production of recombinant proteins. However, one major limitation is that certain protein classes do not express well in a biologically relevant form using standard expression approaches in the cytoplasm of E. coli. To improve the usefulness of the E. coli expression platform we have investigated combinations of promoters and selected N-terminal fusion tags for the extracellular expression of human target proteins. A comparative study was conducted on 24 target proteins fused to outer membrane protein A (OmpA), outer membrane protein F (OmpF) and osmotically inducible protein Y (OsmY). Based on the results of this initial study, we carried out an extended expression screen employing the OsmY fusion and multiple constructs of a more diverse set of human proteins. Using this high throughput compatible system, we clearly demonstrate that secreted biomedically relevant human proteins can be efficiently retrieved and purified from the growth medium. PMID- 21308846 TI - Crystal structure of the sensory domain of Escherichia coli CadC, a member of the ToxR-like protein family. AB - The membrane-integral transcriptional activator CadC comprises sensory and transcriptional regulatory functions within one polypeptide chain. Its C-terminal periplasmic domain, CadC(pd), is responsible for sensing of environmental pH as well as for binding of the feedback inhibitor cadaverine. Here we describe the crystal structure of CadC(pd) (residues 188-512) solved at a resolution of 1.8 A via multiple wavelength anomalous dispersion (MAD) using a ReCl(6)(2-) derivative. CadC(pd) reveals a novel fold comprising two subdomains: an N terminal subdomain dominated by a beta-sheet in contact with three alpha-helices and a C-terminal subdomain formed by an eleven-membered alpha-helical bundle, which is oriented almost perpendicular to the helices in the first subdomain. Further to the native protein, crystal structures were also solved for its variants D471N and D471E, which show functionally different behavior in pH sensing. Interestingly, in the heavy metal derivative of CadC(pd) used for MAD phasing a ReCl(6)(2-) ion was found in a cavity located between the two subdomains. Amino acid side chains that coordinate this complex ion are conserved in CadC homologues from various bacterial species, suggesting a function of the cavity in the binding of cadaverine, which was supported by docking studies. Notably, CadC(pd) forms a homo-dimer in solution, which can be explained by an extended, albeit rather polar interface between two symmetry-related monomers in the crystal structure. The occurrence of several acidic residues in this region suggests protonation-dependent changes in the mode of dimerization, which could eventually trigger transcriptional activation by CadC in the bacterial cytoplasm. PMID- 21308847 TI - Electron transfer flavoprotein domain II orientation monitored using double electron-electron resonance between an enzymatically reduced, native FAD cofactor, and spin labels. AB - Human electron transfer flavoprotein (ETF) is a soluble mitochondrial heterodimeric flavoprotein that links fatty acid beta-oxidation to the main respiratory chain. The crystal structure of human ETF bound to medium chain acyl CoA dehydrogenase indicates that the flavin adenine dinucleotide (FAD) domain (alphaII) is mobile, which permits more rapid electron transfer with donors and acceptors by providing closer access to the flavin and allows ETF to accept electrons from at least 10 different flavoprotein dehydrogenases. Sequence homology is high and low-angle X-ray scattering is identical for Paracoccus denitrificans (P. denitrificans) and human ETF. To characterize the orientations of the alphaII domain of P. denitrificans ETF, distances between enzymatically reduced FAD and spin labels in the three structural domains were measured by double electron-electron resonance (DEER) at X- and Q-bands. An FAD to spin label distance of 2.8 +/- 0.15 nm for the label in the FAD-containing alphaII domain (A210C) agreed with estimates from the crystal structure (3.0 nm), molecular dynamics simulations (2.7 nm), and rotamer library analysis (2.8 nm). Distances between the reduced FAD and labels in alphaI (A43C) were between 4.0 and 4.5 +/- 0.35 nm and for betaIII (A111C) the distance was 4.3 +/- 0.15 nm. These values were intermediate between estimates from the crystal structure of P. denitrificans ETF and a homology model based on substrate-bound human ETF. These distances suggest that the alphaII domain adopts orientations in solution that are intermediate between those which are observed in the crystal structures of free ETF (closed) and ETF bound to a dehydrogenase (open). PMID- 21308848 TI - Crystal structure of a soluble form of human monoglyceride lipase in complex with an inhibitor at 1.35 A resolution. AB - A high-resolution structure of a ligand-bound, soluble form of human monoglyceride lipase (MGL) is presented. The structure highlights a novel conformation of the regulatory lid-domain present in the lipase family as well as the binding mode of a pharmaceutically relevant reversible inhibitor. Analysis of the structure lacking the inhibitor indicates that the closed conformation can accommodate the native substrate 2-arachidonoyl glycerol. A model is proposed in which MGL undergoes conformational and electrostatic changes during the catalytic cycle ultimately resulting in its dissociation from the membrane upon completion of the cycle. In addition, the study outlines a successful approach to transform membrane associated proteins, which tend to aggregate upon purification, into a monomeric and soluble form. PMID- 21308849 TI - Crystal structure of the Nogo-receptor-2. AB - The inhibition of axon regeneration upon mechanical injury is dependent on interactions between Nogo receptors (NgRs) and their myelin-derived ligands. NgRs are composed of a leucine-rich repeat (LRR) region, thought to be structurally similar among the different isoforms of the receptor, and a divergent "stalk" region. It has been shown by others that the LRR and stalk regions of NgR1 and NgR2 have distinct roles in conferring binding affinity to the myelin associated glycoprotein (MAG) in vivo. Here, we show that purified recombinant full length NgR1 and NgR2 maintain significantly higher binding affinity for purified MAG as compared to the isolated LRR region of either NgR1 or NgR2. We also present the crystal structure of the LRR and part of the stalk regions of NgR2 and compare it to the previously reported NgR1 structure with respect to the distinct signaling properties of the two receptor isoforms. PMID- 21308850 TI - An occupational therapy programme in a religious community in South Africa: a historical narrative. AB - The purpose of this paper was to describe an occupational therapy programme that addressed the needs of younger nuns as they faced the difficulties of caring for older nuns in a Dominican old-age home in South Africa. Weekly occupational therapy group sessions with the younger sisters over a 1-year period enabled them to cope with an elderly population who were struggling to adapt to life in an old age home. Activity groups and individual sessions were run concurrently with the older sisters. Aspects addressed included: dealing with loss, exploring meaningful activity, communication, healthy lifestyles, community involvement and life review. No formal outcome measures were used. Informal evidence of the effectiveness of the programme is the occupationally healthy community observed 20 years later. The younger enablers are now the care receivers and play an integral part in sustaining the programme. Although the Dominican community has specific needs and practices, there is a parallel to other groups of older adults adjusting to a care setting. This programme can serve as a model to facilitate the quality of life of caregivers and residents. The programme outcomes support the principles of occupational science by demonstrating the importance of engaging in meaningful activities to maintain health and well-being. PMID- 21308851 TI - The duplicated rainbow trout (Oncorhynchus mykiss) T-box transcription factors 1, tbx1a and tbx1b, are up-regulated during testicular development. AB - Tbx1 is a member of the T-box transcription factor gene family involved in embryogenesis and organogenesis. Recently, within a pan-genomic screen using rainbow trout (Oncorhynchus mykiss) cDNA microarrays, we identified a tbx1 homolog with testicular over-expression during sex differentiation. Here, we characterized two very similar rainbow trout tbx1 paralogs, tbx1a and tbx1b. In adult tissues, tbx1a expression is restricted to the gonads, with high expression in the testis, while tbx1b is more widely expressed in gonads, gills, brains, muscle, and skin. During gonadal differentiation, both genes are differentially expressed in favor of testis formation shortly after hatching. These genes are expressed in somatic cells surrounding germ cells of the differentiating testis, while no or only weak expression was observed in the differentiating ovary. tbx1a and tbx1b were also both down-regulated in the differentiating testis during feminization with estrogens and up-regulated in the differentiating ovary during masculinization with an aromatase inhibitor. These results suggest that tbx1a and tbx1b are probably involved in the regulation of testicular differentiation in rainbow trout. Since Tbx1 is known to interact with the retinoic acid (RA) signaling pathway, we also examined the effect of RA on the rainbow trout tbx1 expression pattern. Expression of tbx1a and tbx1b was down-regulated in RA treated male gonads, suggesting that tbx1 interacts with the RA signaling pathway and thus could be involved in the control of rainbow trout gonadal differentiation. PMID- 21308852 TI - Lipovitellin constitutes the protein backbone of glycoproteins involved in sperm egg interaction in the amphibian Discoglossus pictus. AB - Our knowledge of the molecules that interact with sperm at the egg membrane is restricted to a short list. In the eggs of Discoglossus pictus, fusion with sperm is limited to a differentiated structure, the dimple, offering several advantages for detecting molecules involved in fertilization. Previous studies have identified fucosylated glycoproteins of 200, 260, and 270 kDa located at the surface of the dimple that are able to bind sperm in vitro. Here, we show that dimple glycoproteins and a protein represented by a 120-kDa band released following gel-into-gel SDS-PAGE of both glycoproteins share the same N-terminal amino acid sequence, which itself is similar to the N-termini of Xenopus liver synthesized vitellogenin (VTG) and the lipovitellin 1. MALDI/MS mass spectrometry indicated that the 120-kDa band is part of both gps 200 and 270/260. A 117-kDa major protein of the egg lysate exhibits the same MALDI/MS spectrum, and LC-MSMS indicates that this is a lipovitellin 1 (DpLIV) that coincides with the 120-kDa band and is responsible for the formation of the 200-270-kDa dimers. Therefore, lipovitellin 1 constitutes the protein backbone of the dimple glycoconjugates. In vitro assays using polystyrene beads coated with DpLIV or with its dimers indicate that significant sperm binding occurs only with DpLIV dimers. In amphibians, VTG is taken up by the oocyte, where it releases lipovitellins destined to form yolk. In Discoglossus, our data suggest that yolk proteins are also synthesized by the oocyte. The dimple forms in the ovulated oocyte following the exocytosis of vesicles that likely expose DpLIVs at their membrane. Indeed, in whole mounts of immunostained eggs, anti-vitellogenin antibodies label only the surface of the dimple. PMID- 21308853 TI - Early avian follicular development is characterized by changes in transcripts involved in steroidogenesis, paracrine signaling and transcription. AB - The mechanisms associated with follicular activation and early growth are not well understood in avian species. Level of mRNA transcripts involved in steroidogenesis (STAR, HSD3B, CYP11A1, CYP19), paracrine signaling (AMH, BMP2, BMP4, BMP6, KITL, WNT4, and PCSK6) and transcription (SMAD1, SMAD2, SMAD3, SMAD5, SMAD9, FOXL3, FOXL2, NR5A1 (SF1), and WT1) were determined in small avian follicles 0.5, 1, and 2 mm in diameter after oocyte removal. STAR, HSD3B, CYP11A1, CYP19, PCSK6, FOXO3, and KITL mRNA increased 2- to 45-fold, while FOXL2, WT1, and WNT4 decreased 30-90% and NR5A1 did not change as follicles developed from 0.5 to 2 mm. Phosphorylated SMAD2, SMAD3, SMAD1/5/9 and FOXO3 proteins were found in both granulosa cells and oocytes of small (<0.5 mm) and larger (>1 mm) follicles. In contrast, non-phosphorylated FOXO3 protein was found in oocyte and granulosa cells of small follicles, but only in the oocyte of larger follicles. Culture of small avian follicles on the chorioallantoic membrane of chick embryos (in ovo) for 7 days caused changes in transcript levels that were similar to changes observed in vivo. The collective findings suggest that the growth of avian follicles from 0.5 to 2 mm is marked by an increase in steroidogenic capacity, and changes in paracrine signaling that may be important during early avian follicular development. Thus, a number of candidate marker genes were identified, and a method of follicle culture was developed to study early follicular development in a model avian species. PMID- 21308854 TI - Nxf3 is expressed in Sertoli cells, but is dispensable for spermatogenesis. AB - In eukaryotes, mRNA is actively exported to the cytoplasm by a family of nuclear RNA export factors (NXF). Four Nxf genes have been identified in the mouse: Nxf1, Nxf2, Nxf3, and Nxf7. Inactivation of Nxf2, a germ cell-specific gene, causes defects in spermatogenesis. Here we report that Nxf3 is expressed exclusively in Sertoli cells of the postnatal testis, in a developmentally regulated manner. Expression of Nxf3 coincides with the cessation of Sertoli cell proliferation and the beginning of their differentiation. Continued expression of Nxf3 in mature Sertoli cells of the adult is spermatogenesis stage-independent. Nxf3 is not essential for spermatogenesis, however, suggesting functional redundancy among Nxf family members. With its unique expression pattern in the testis, the promoter of Nxf3 can be used to drive postnatal Sertoli cell-specific expression of other proteins such as Cre recombinase. PMID- 21308855 TI - Association of polypharmacy with nutritional status, functional ability and cognitive capacity over a three-year period in an elderly population. AB - PURPOSE: To determine the association of polypharmacy with nutritional status, functional ability and cognitive capacity among elderly persons. METHODS: This was a prospective cohort study of 294 survivors from the population-based Geriatric Multidisciplinary Strategy for the Good Care of the Elderly (GeMS) Study, with yearly follow-ups during 2004 to 2007. Participants were the citizens of Kuopio, Finland, aged 75 years and older at baseline. Polypharmacy status was categorized as non-polypharmacy (0-5 drugs), polypharmacy (6-9 drugs) and excessive polypharmacy (10+ drugs). A linear mixed model approach was used for analysis the impact of polypharmacy on short form of mini nutritional assessment (MNA-SF), instrumental activities of daily living (IADL) and mini-mental status examination (MMSE) scores. RESULTS: Excessive polypharmacy was associated with declined nutritional status (p = 0.001), functional ability (p < 0.001) and cognitive capacity (p < 0.001) when compared to non-polypharmacy group. Age, institutional living, poor self-reported health and time of measuring were also associated with the three outcome measures. In the excessive polypharmacy group, the proportion of malnourished or at risk of it increased from 31% to 50%, having difficulties in daily tasks from 48% to 74% and impaired cognition from 36% to 54% during the follow-up. The mixed model analysis revealed that polypharmacy status was not able to predict the progress of MNA-SF, IADL and MMSE scores over a three-year time. CONCLUSIONS: Excessive polypharmacy is associated with decline in nutritional status, functional ability and cognitive capacity in elderly persons. However, the changes in nutrition, physical functionality and cognition over a three-year period cannot be predicted by polypharmacy status. PMID- 21308856 TI - A uniform time trade off method for states better and worse than dead: feasibility study of the 'lead time' approach. AB - The way time trade off (TTO) values are elicited for states of health considered 'worse than being dead' has important implications for the mean values used in economic evaluation. Conventional approaches to TTO, as used in the UK's 'MVH' value set, are problematic because they require fundamentally different trade offs tasks for the valuation of states better and worse than dead. This study aims to refine and test the feasibility of a new approach described by Robinson and Spencer (2006. Health Economics 15: 393-402), and to explore the characteristics of the valuation data it generates. The approach introduces a 'lead time' into the TTO, producing a uniform procedure for generating values either >0 or<0. We used this lead time TTO to value 10 moderate to severe EQ-5D states using a sample of the general public (n=109). We conclude that the approach is feasible for use in valuation studies and appears to overcome the discontinuity in values around 0 evident in conventional methods. However, further research is required to resolve the issue of how to handle participants who 'use up' all lead time; to develop ways of controlling for individual time preferences; and to better understand the implications for valuations of states better than dead. PMID- 21308857 TI - The detection and management of emotional distress in cancer patients: the views of health-care professionals. AB - OBJECTIVE: Emotional distress (ED) is an under-diagnosed problem in cancer patients and over the last decade a number of national guidelines have recommended an assessment and management model based on appropriate health professional response to a hierarchy of patient need. This study explores the views of cancer professionals regarding their current roles and responsibilities in the detection and management of ED, use of screening tools and access to expert psychological support. METHODS: Interviews with 23 professionals were conducted [6 clinical nurse specialists (CNS), 8 oncologists, 4 surgeons and 5 ward sisters] from hospitals in Yorkshire, UK. Data were evaluated using framework analysis. RESULTS: Detection of ED was seen to be the responsibility of the whole cancer team though nurses, particularly CNSs, are heavily depended upon to assess and manage distress. Experience of screening tools was limited and a number of reservations were expressed about routine implementation. A wide range of services are used to support distressed patients but a lack of referral guidance and access to specialist psychological care were reported to be a significant barrier to effective management. CONCLUSIONS: Cancer professionals describe working within the fundamental principles of the guidance frameworks; however, access to specialist support do not appear to meet recommendations, leaving the CNS with considerable responsibility for the detection and management of ED. Support for ED may be improved by the introduction of routine screening along with appropriate training and implementation of referral guidelines to assist professionals in accessing specialist psychology services. PMID- 21308858 TI - Cancer Care Ontario's experience with implementation of routine physical and psychological symptom distress screening. AB - OBJECTIVE: In late 2006, Cancer Care Ontario launched a quality improvement initiative to implement routine screening with the Edmonton Symptom Assessment System (ESAS) for cancer patients seen in fourteen Regional Cancer Centres throughout the province. METHODS: A central team: created a provincial project plan and management and evaluation framework; developed common tools and provided expert coaching and guidance, provincial data analysis, progress reporting and program evaluation. Regional Steering Committees and Improvement teams were accountable for planning and coordination within each region and supported by a funded Regional Improvement Coordinator. A hybrid model for quality improvement facilitated process improvements and uptake of screening. RESULTS: Challenges to implementation included: lack of consensus on the chosen screening tool, lack of guidance for assessment or management of high scores, concern of inadequate time or resources to address issues identified by the screening, data entry was labour intensive, resistance to change and challenges to the traditional care model. Essential components for success were: centralized project management, a person dedicated to implementation of the project locally, clinical champions, clearly identified aims, monthly regional data reporting and implementation of quality improvement methodologies with expectations for performance. To achieve screening aims many centres engaged all members of the team, examined the roles of the different members and reorganized workflow and responsibilities and changed booking times. In March 2010, approximately 25,000 ESAS's were completed in the regional cancer centres across Ontario, with 60% of lung cancer patients and almost 40% of all other cancer patients who visited the Regional Cancer Centres screened. CONCLUSION: Routine physical and psychological distress screening is possible within regional cancer centres. Although considerable effort and investment is required, it is worthwhile as it helps create a culture that is more patient-centered. PMID- 21308859 TI - No improvement in distress and quality of life following psychosocial cancer rehabilitation. A randomised trial. AB - OBJECTIVE: Rehabilitation programmes are intended to help cancer patients achieve optimal functioning and live independently. We evaluated whether a psychosocial rehabilitation course was effective in relieving cancer patients' distress and improving their well-being. METHODS: Patients with breast, prostate or colorectal cancer diagnosed within 2 years who had finished primary treatment were randomised to usual care or a 6-day residential course of lectures, discussions and peer groups on issues related to treatment and living with cancer. Changes in self-reported distress (POMS-Sf) and quality of life (EORTC QLQ-C30) from baseline to 1 and 6 months' follow-up were measured. Analyses were adjusted for baseline scores of outcome, cancer site, time since diagnosis, gender, age and education. RESULTS: Of 507 patients, 452 were included in the analyses, 404 completed the 1-month and 394 the 6-month assessment. Patients in the control group showed greater decreases in total mood disturbance and subscales of the POMS-Sf and showed more improvement in emotional, cognitive and social functioning at both 1 and 6 months and in role functioning at 6 months than the intervention group. A similar pattern was observed in analyses of breast cancer patients only. CONCLUSION: A 6-day residential rehabilitation course did not relieve cancer patients' distress or improve their well-being. PMID- 21308860 TI - The factor structure of the revised Illness Perception Questionnaire in a population of oesophageal cancer survivors. AB - OBJECTIVES: To determine whether the proposed seven-factor structure of the Illness Perception Questionnaire-Revised (Timeline Acute/Chronic, Timeline Cyclical, Consequences, Personal Control, Treatment Control, Illness Coherence and Emotional Representations) is appropriate among a population of oesophageal cancer survivors. METHODS: Everyone registered with the Oesophageal Patients' Association in the UK (n = 2185) was mailed a questionnaire booklet, which included the Illness Perception Questionnaire-Revised. Responses from 587 oesophageal cancer survivors (27%) were subjected to a confirmatory factor analysis. RESULTS: The proposed seven-factor structure provided a reasonable fit of the data. Modification indices suggested that a significantly better fit could be provided if one of the items on the Timeline Acute/Chronic factor loaded on the Treatment Control factor and an error covariance was added between two other items on the Timeline Acute/Chronic factor. CONCLUSIONS: The model fit for the seven-factor structure proposed by Moss-Morris et al. (Psychol Health 2002;17:1 16) was found to be adequate in our study. However, the structure of the timeline acute/chronic factor needs to be considered, particularly when the IPQ-R is to be used among older people with a potentially life-threatening illness or those receiving palliative care. PMID- 21308861 TI - Inhibition of ataxia telangiectasia- and Rad3-related function abrogates the in vitro and in vivo tumorigenicity of human colon cancer cells through depletion of the CD133(+) tumor-initiating cell fraction. AB - The identification of novel approaches to specifically target the DNA-damage checkpoint response in chemotherapy-resistant cancer stem cells (CSC) of solid tumors has recently attracted great interest. We show here in colon cancer cell lines and primary colon cancer cells that inhibition of checkpoint-modulating phosphoinositide 3-kinase-related (PIK) kinases preferentially depletes the chemoresistant and exclusively tumorigenic CD133(+) cell fraction. We observed a time- and dose-dependent disproportionally pronounced loss of CD133(+) cells and the consecutive lack of in vitro and in vivo tumorigenicity of the remaining cells. Depletion of CD133(+) cells was initiated through apoptosis of cycling CD133(+) cells and further substantiated through subsequent recruitment of quiescent CD133(+) cells into the cell cycle followed by their elimination. Models using specific PIK kinase inhibitors, somatic cell gene targeting, and RNA interference demonstrated that the observed detrimental effects of caffeine on CSC were attributable specifically to the inhibition of the PIK kinase ataxia telangiectasia- and Rad3-related (ATR). Mechanistically, phosphorylation of CHK1 checkpoint homolog (S. pombe; CHK1) was significantly enhanced in CD133(+) as compared with CD133(-) cells on treatment with DNA interstrand-crosslinking (ICL) agents, indicating a preferential activation of the ATR/CHK1-dependent DNA-damage response in tumorigenic CD133(+) cells. Consistently, the chemoresistance of CD133(+) cells toward DNA ICL agents was overcome through inhibition of ATR/CHK1 signaling. In conclusion, our study illustrates a novel target to eliminate the tumorigenic CD133(+) cell population in colon cancer and provides another rationale for the development of specific ATR-inhibitors. PMID- 21308862 TI - Self-renewal versus lineage commitment of embryonic stem cells: protein kinase C signaling shifts the balance. AB - The intricate molecular mechanisms that regulate ESC pluripotency are incompletely understood. Prior research indicated that activation of the Janus kinase-signal transducer and activator of transcription (STAT3) pathway or inhibition of extracellular signal-regulated kinase/glycogen synthase kinase 3 (ERK/GSK3) signaling maintains mouse ESC (mESC) pluripotency. Here, we demonstrate that inhibition of protein kinase C (PKC) isoforms maintains mESC pluripotency without the activation of STAT3 or inhibition of ERK/GSK3 signaling pathways. Our analyses revealed that the atypical PKC isoform, PKCzeta plays an important role in inducing lineage commitment in mESCs through a PKCzeta-nuclear factor kappa-light-chain-enhancer of activated B cells signaling axis. Furthermore, inhibition of PKC isoforms permits derivation of germline-competent ESCs from mouse blastocysts and also facilitates reprogramming of mouse embryonic fibroblasts toward induced pluripotent stem cells. Our results indicate that PKC signaling is critical to balancing ESC self-renewal and lineage commitment. PMID- 21308864 TI - Transforming growth factor beta-mediated Sox10 suppression controls mesenchymal progenitor generation in neural crest stem cells. AB - During vertebrate development, neural crest stem cells (NCSCs) give rise to neural cells of the peripheral nervous system and to a variety of mesenchymal cell types, including smooth muscle, craniofacial chondrocytes, and osteocytes. Consistently, mesenchymal stem cells (MSCs) have recently been shown to derive in part from the neural crest (NC), although the mechanisms underlying MSC generation remains to be identified. Here, we show that transforming growth factor beta (TGFbeta)-mediated suppression of the NCSC transcription factor Sox10 induces a switch in neural to mesenchymal potential in NCSCs. In vitro and in vivo, TGFbeta signal inactivation results in persistent Sox10 expression, decreased cell cycle exit, and perturbed generation of mesenchymal derivatives, which eventually leads to defective morphogenesis. In contrast, TGFbeta-mediated downregulation of Sox10 or its genetic inactivation suppresses neural potential, confers mesenchymal potential to NC cells in vitro, and promotes cell cycle exit and precocious mesenchymal differentiation in vivo. Thus, negative regulation of Sox10 by TGFbeta signaling promotes the generation of mesenchymal progenitors from NCSCs. Our study might lay the grounds for future applications demanding defined populations of MSCs for regenerative medicine. PMID- 21308863 TI - Wnt and Notch pathways have interrelated opposing roles on prostate progenitor cell proliferation and differentiation. AB - Tissue stem cells are capable of both self-renewal and differentiation to maintain a constant stem cell population and give rise to the plurality of cells within a tissue. Wnt signaling has been previously identified as a key mediator for the maintenance of tissue stem cells; however, possible cross-regulation with other developmentally critical signaling pathways involved in adult tissue homeostasis, such as Notch, is not well understood. By using an in vitro prostate stem cell colony ("prostasphere") formation assay and in vivo prostate reconstitution experiments, we demonstrate that Wnt pathway induction on Sca-1(+) CD49f(+) basal/stem cells (B/SCs) promotes expansion of the basal epithelial compartment with noticeable increases in "triple positive" (cytokeratin [CK] 5(+), CK8(+), p63(+)) prostate progenitor cells, concomitant with upregulation of known Wnt target genes involved in cell-cycle induction. Moreover, Wnt induction affects expression of epithelial-to-mesenchymal transition signature genes, suggesting a possible mechanism for priming B/SC to act as potential tumor initiating cells. Interestingly, induction of Wnt signaling in B/SCs results in downregulation of Notch1 transcripts, consistent with its postulated antiproliferative role in prostate cells. In contrast, induction of Notch signaling in prostate progenitors inhibits their proliferation and disrupts prostasphere formation. In vivo prostate reconstitution assays further demonstrate that induction of Notch in B/SCs disrupts proper acini formation in cells expressing the activated Notch1 allele, Notch-1 intracellular domain. These data emphasize the importance of Wnt/Notch cross-regulation in adult stem cell biology and suggest that Wnt signaling controls the proliferation and/or maintenance of epithelial progenitors via modulation of Notch signaling. PMID- 21308865 TI - CD24: a novel surface marker for PDX1-positive pancreatic progenitors derived from human embryonic stem cells. AB - Human ESCs provide a promising cell resource for the treatment of type I diabetes mellitus. Although PDX1-positive pancreatic progenitors can be efficiently generated from human ESCs by stepwise induction, further in vitro differentiation into functional, mature beta cells is not efficient or reproducible. Purification of pancreatic progenitor cells could facilitate the identification of signals that regulate beta cell differentiation and maturation. Here, we report the identification of a novel surface marker for PDX1-positive pancreatic progenitors based on an in vitro human ESC differentiation system. By costaining PDX1 and a panel of cell surface antigens at the pancreatic progenitor stage of human ESC differentiation, we discovered a positive marker, CD24. CD24-positive cells coexpressed most of the key transcription factors of pancreatic progenitors, and the expression of important pancreatic genes was greatly enriched in CD24 positive cells compared with the CD24-negative cells. In addition, CD24-positive cells could differentiate into insulin-producing cells but CD24-negative cells could not. These results indicate that CD24 could be a surface marker for PDX1 positive pancreatic progenitors derived from human ESCs. Enrichment of pancreatic progenitors with this marker will facilitate the investigation of beta cell maturation during the human ESC differentiation. PMID- 21308866 TI - Specific glycosaminoglycans modulate neural specification of mouse embryonic stem cells. AB - Mouse embryonic stem (mES) cells express a low sulfated form of heparan sulfate (HS). HS chains displayed by ES cells and their progeny become more complex and more sulfated during progression from pluripotency to neuroectodermal precursors. Sulfated epitopes are important for recognition and binding of a variety of ligands including members of the fibroblast growth factor (FGF) family. We demonstrated previously that mES cells lacking HS cannot undergo neural specification but this activity can be recovered by adding soluble heparin, a highly sulfated glycosaminoglycan (GAG). Therefore, we hypothesized that soluble GAGs might be used to support neural differentiation of HS competent cells and that the mechanisms underlying this activity might provide useful information about the signaling pathways critical for loss of pluripotency and early lineage commitment. In this study, we demonstrate that specific HS/heparin polysaccharides support formation of Sox1(+) neural progenitor cells from wild type ES cells. This effect is dependent on sulfation pattern, concentration, and length of saccharide. Using a selective inhibitor of FGF signal transduction, we show that heparin modulates signaling events regulating exit from pluripotency and commitment to primitive ectoderm and subsequently neuroectoderm. Interestingly, we were also able to demonstrate that multiple receptor tyrosine kinases were influenced by HS in this system. This suggests roles for additional factors, possibly in cell proliferation or protection from apoptosis, during the process of neural specification. Therefore, we conclude that soluble GAGs or synthetic mimics could be considered as suitable low-cost factors for addition to ES cell differentiation regimes. PMID- 21308867 TI - Concise review: induced pluripotent stem cells and lineage reprogramming: prospects for bone regeneration. AB - Bone tissue for transplantation therapies is in high demand in clinics. Osteodegenerative diseases, in particular, osteoporosis and osteoarthritis, represent serious public health issues affecting a respectable proportion of the elderly population. Furthermore, congenital indispositions from the spectrum of craniofacial malformations such as cleft palates and systemic disorders including osteogenesis imperfecta are further increasing the need for bone tissue. Additionally, the reconstruction of fractured bone elements after accidents and the consumption of bone parts during surgical tumor excisions represent frequent clinical situations with deficient availability of healthy bone tissue for therapeutic transplantations. Epigenetic reprogramming represents a powerful technology for the generation of healthy patient-specific cells to replace or repair diseased or damaged tissue. The recent generation of induced pluripotent stem cells (iPSCs) is probably the most promising among these approaches dominating the literature of current stem cell research. It allows the generation of pluripotent stem cells from adult human skin cells from which potentially all cell types of the human body could be obtained. Another technique to produce clinically interesting cell types is direct lineage reprogramming (LR) with the additional advantage that it can be applied directly in vivo to reconstitute a damaged organ. Here, we want to present the two technologies of iPSCs and LR, to outline the current states of research, and to discuss possible strategies for their implementation in bone regeneration. PMID- 21308868 TI - Concise review: aldehyde dehydrogenase bright stem and progenitor cell populations from normal tissues: characteristics, activities, and emerging uses in regenerative medicine. AB - Flow cytometry has been used to detect cells that express high levels of the aldehyde dehydrogenase activity in normal tissues. Such ALDH bright (ALDHbr) cell populations have been sorted from human cord blood, bone marrow, mobilized peripheral blood, skeletal muscle, and breast tissue and from the rodent brain, pancreas, and prostate. A variety of hematopoietic, endothelial, and mutiltipotential mesenchymal progenitors are enriched in the human bone marrow, cord, and peripheral blood ALDHbr populations. Multipotential neural progenitors are enriched in rodent brain tissue, and tissue-specific progenitors in the other tissue types. In xenograft models, uncultured human bone marrow and cord ALDHbr cells home to damaged tissue and protect mice against acute ischemic injury by promoting angiogenesis. Uncultured cord ALDHbr cells also deploy to nonhematopoietic tissues and protect animals in CCl4 intoxication and chronic multiorgan failure models. Mouse ALDHbr cells and cells derived from them in culture protect animals in a chronic neurodegenerative disease model. Purifying ALDHbr cells appears to increase their ability to repair tissues in these animal models. Clinical studies suggest that the number of ALDHbr cells present in hematopoietic grafts or circulating in the blood of cardiovascular disease patients is related to clinical outcomes or disease severity. ALDHbr cells have been used to supplement unrelated cord blood transplant and to treat patients with ischemic heart failure and critical limb ischemia. ALDH activity can play several physiological roles in stem and progenitor cells that may potentiate their utility in cell therapy. PMID- 21308869 TI - An innovative short-term, intensive, family-based treatment for adolescent anorexia nervosa: case series. AB - OBJECTIVE: In order to improve the dissemination of new expert-based treatments for adolescents with anorexia nervosa, we have developed an innovative 1-week intensive family-based evaluation and treatment programme. Ages of the adolescents in the programme ranged from 10 to 18 years (mean = 15.0, SD = 2.1). We report the outcomes of the first 19 cases. METHOD: Data were obtained from a retrospective chart review and a follow-up of cases at 52 to 738 days (mean = 278.4, SD = 193.8) post-treatment. The primary outcome measure was ideal body weight (IBW) percentage. RESULTS: At admission, the duration of illness ranged from less than 1 to 8 years (mean 2.1, SD = 1.7). Admission IBW ranged from 69.3 to 99.1% (mean = 84.3%, SD = 8.7). Follow-up IBW ranged from 84.4 to 134.6% (mean = 99.3%, SD = 11.8). All but one patient reported a sustained gain in weight post treatment (mean = 15.0, SD = 14.5). DISCUSSION: These data provide further support for the notion that short-term family-based therapy may be useful for weight restoration and maintenance in some adolescents with anorexia nervosa. PMID- 21308870 TI - A case series investigating distinct neuropsychological profiles in children and adolescents with anorexia nervosa. AB - A number of specific deficits in neuropsychological functioning in anorexia nervosa (AN) have been identified. However, it is not known whether these specific deficits cluster together to form one or more clear neuropsychological profiles. We present a case series of nine participants who were recruited as part of a wider, ongoing investigation of the neuropsychological profile of eating disorders (the Ravello Profile). Results show that there was a wide range of different neuropsychological profiles at initial assessment. This suggests a spectrum of neuropsychological strengths and weaknesses that would otherwise be masked in a cohort analysis. It is anticipated that factor and cluster analytic studies will establish one or more common profiles of neuropsychological deficits in AN. PMID- 21308871 TI - Decision-making impairments in women with binge eating disorder in comparison with obese and normal weight women. AB - OBJECTIVE: The purpose of the current study was to examine decision making in female patients with binge eating disorder (BED) in comparison with obese and normal weight women. METHOD: In the study, 20 patients with BED, 21 obese women without BED and 34 healthy women participated. Decision making was assessed using the Iowa Gambling Task (IGT). Several questionnaires were administered measuring binge eating severity, sensitivity for punishment and reward, and self-control. RESULTS: The findings indicated that the BED and obese group performed poorly on the IGT. Participants who have BED and are obese did not improve their choice behaviour over time, whereas participants with normal weight showed a learning effect. An association between IGT performance and binge eating severity was found. CONCLUSION: This study demonstrates that patients with BED display decision-making deficits on the IGT comparable with other forms of disordered eating. Future research should focus on unravelling the processes underlying the deficits. PMID- 21308872 TI - Psychometric evaluation of SAFA P test for eating disorders in adolescents: comparative validation with EDI-2. AB - OBJECTIVE: This study evaluates the psychometric properties of self-administered psychiatric scale for children and adolescents with psychogenic eating disorders (SAFA P)--a brief self-report designed to screen and assess eating disorders (ED) in children and adolescents. Although SAFA P belongs to a broad battery of tests (SAFA) that explores different psychiatric conditions, it has not undergone appropriate validation until now. METHOD: We administered SAFA P and Eating Disorder Inventory 2 (EDI-2) to 87 ED patients, with an average age of 15.4 +/- 1.6 years. RESULTS: The internal reliability of SAFA P is good (Cronbach alpha = .776). Convergent validity with EDI-2 was assessed: both SAFA P subscale P1 (p < .005) and EDI-2 subscale bulimia (p < .001) showed a statistically significant difference among the three diagnostic categories (anorexia nervosa, bulimia nervosa and eating disorder not otherwise specified). Sensibility and specificity range from 62 to 91%, depending on the subscales. McNemar's test did not reveal statistically significant differences in assessing the concordance of the two measures. Statistically significant correlations were found between specific couples of subscales (p < .001). CONCLUSIONS: Cross-validation with EDI-2 showed good results. SAFA P may be an alternative, useful and reliable instrument for assessing cursory ED in childhood and adolescence. PMID- 21308873 TI - General method for selective labelling of double-chain cysteine-rich peptides with a lanthanide chelate via solid-phase synthesis. AB - The use of lanthanides in preference to radioisotopes as probes for various biological assays has gained enormous popularity. The introduction of lanthanide chelates to peptides/proteins can be carried out either in solution using a commercially available labelling kit or by solid-phase peptide synthesis using an appropriate lanthanide chelate. Herein, a detailed protocol for the latter is provided for the labelling of peptides or small proteins with diethylenetriamine N, N, N", N"-tetra-tert-butyl acetate-N'-acetic acid (DTPA) chelate or other similar chelates on a solid support using a chimeric insulin-like peptide composed of human insulin-like peptide 5 (INSL5) A-chain and relaxin-3 B-chain as a model peptide. Copyright (c) 2011 European Peptide Society and John Wiley & Sons, Ltd. PMID- 21308874 TI - Epitope motif of an anti-nitrotyrosine antibody specific for tyrosine-nitrated peptides revealed by a combination of affinity approaches and mass spectrometry. AB - Nitration of tyrosine residues has been shown to be an important oxidative modification in proteins and has been suggested to play a role in several diseases such as atherosclerosis, asthma, lung and neurodegenerative diseases. Detection of nitrated proteins has been mainly based on the use of nitrotyrosine specific antibodies. In contrast, only a small number of nitration sites in proteins have been unequivocally identified by MS. We have used a monoclonal 3-NT specific antibody, and have synthesized a series of tyrosine-nitrated peptides of prostacyclin synthase (PCS) in which a single specific nitration site at Tyr-430 had been previously identified upon reaction with peroxynitrite17. The determination of antibody-binding affinity and specificity of PCS peptides nitrated at different tyrosine residues (Tyr-430, Tyr-421, Tyr-83) and sequence mutations around the nitration sites provided the identification of an epitope motif containing positively charged amino acids (Lys and/or Arg) N-terminal to the nitration site. The highest affinity to the anti-3NT-antibody was found for the PCS peptide comprising the Tyr-430 nitration site with a K(D) of 60 nM determined for the peptide, PCS(424-436-Tyr-430NO(2) ); in contrast, PCS peptides nitrated at Tyr-421 and Tyr-83 had substantially lower affinity. ELISA, SAW bioaffinity, proteolytic digestion of antibody-bound peptides and affinity-MS analysis revealed highest affinity to the antibody for tyrosine-nitrated peptides that contained positively charged amino acids in the N-terminal sequence to the nitration site. Remarkably, similar N-terminal sequences of tyrosine-nitration sites have been recently identified in nitrated physiological proteins, such as eosinophil peroxidase and eosinophil-cationic protein. PMID- 21308875 TI - The action of fish peptide Orpotrin analogs on microcirculation. AB - In order to investigate the relationship between the primary structure of Orpotrin, a vasoactive peptide previously isolated from the freshwater stingray Potamotrygon gr. orbignyi, and its microcirculatory effects, three Orpotrin analogs were synthesized. The analogs have a truncated N-terminal with a His residue deletion and two substituted amino acid residues, where one Nle is substituted for one internal Lys residue and the third analog has a substitution of a Pro for an Ala (Orp-desH(1) , Orp-Nle and Orp-Pro/Ala, respectively). Only Orp-desH(1) could induce a lower vasoconstriction effect compared with the natural Orpotrin, indicating that besides the N-terminal, the positive charge of Lys and the Pro residues located at the center of the amino acid chain is crucial for this vasoconstriction effect. Importantly, the suggestions made with bioactive peptides were based on the molecular modeling and dynamics of peptides, the presence of key amino acids and shared activity in microcirculation, characterized by intravital microscopy. Moreover, this study has demonstrated that even subtle changes in the primary structure of Orpotrin alter the biological effects of this native peptide significantly, which could be of interest for biotechnological applications. PMID- 21308876 TI - Analysis of the interacting surface of maurotoxin with the voltage-gated Shaker B K(+) channel. AB - Maurotoxin (MTX) is a 34-residue toxin that was isolated initially from the venom of the scorpion Scorpio maurus palmatus. Unlike the other toxins of the alpha KTx6 family (Pi1, Pi4, Pi7, and HsTx1), MTX exhibits a unique disulfide bridge organization of the type C(1) ?C(5) , C(2) ?C(6) , C(3) ?C(4) , and C(7) ?C(8) (instead of the conventional C(1) ?C(5) , C(2) ?C(6) , C(3) ?C(7) , and C(4) ?C(8) , herein referred to as Pi1-like) that does not prevent its folding along the classic alpha/beta scaffold of scorpion toxins. MTX(Pi1) is an MTX variant with a conventional pattern of disulfide bridging without any primary structure alteration of the toxin. Here, using MTX and/or MTX(Pi1) as models, we investigated how the type of folding influences toxin recognition of the Shaker B potassium channel. Amino acid residues of MTX that were studied for Shaker B recognition were selected on the basis of their homologous position in charybdotoxin, a three disulfide-bridged scorpion toxin also active on this channel type. These residues favored either an MTX- or MTX(Pi1) -like folding. Our data indicate clearly that Lys(23) and Tyr(32) (two out of ten amino acid residues studied) are the most important residues for Shaker B channel blockage by MTX. For activity on SKCa channels, the same amino acid residues also affect, directly or indirectly, the recognition of SK channels. The molecular modeling technique and computed docking indicate the existence of a correlation between the half cystine pairings of the mutated analogs and their activity on the Shaker B K(+) channel. Overall, mutations in MTX could, or could not, change the reorganization of disulfide bridges of this molecule without affecting its alpha/beta scaffold. However, changing of the peptide backbone (cross linking disulfide bridges from MTX-like type vs MTX(Pi1) -like type) appears to have less impact on the molecule activity than mutation of certain key amino acids such as Lys(23) and Tyr(32) in this toxin. PMID- 21308877 TI - Synthesis, biological activity and solution structure of new analogues of the antimicrobial Gramicidin S. AB - Gramicidin S (GS) is a cyclo-decapeptide antibiotic isolated from Bacillus brevis. The structural studies have shown that GS forms a two-stranded antiparallel beta-sheet imposed by two II' beta-turns. Despite its wide Gram+ and Gram- antimicrobial spectrum, GS is useless in therapy because of its high hemotoxicity in humans. It was found, however, that the analogues of GS-14 (GS with 14 amino acid residues) attained a better antimicrobial selectivity when their amphipatic moments were perturbed. In this study, we report effects of similar perturbations imposed on GS cyclo-decapeptide analogues. Having solved their structures by NMR/molecular dynamics and having tested their activities/selectivities, we have concluded that the idea of perturbation of the amphipatic moment does not work for GS-10_0 analogues. An innovative approach to the synthesis of head-to-tail cyclopeptides was used. PMID- 21308878 TI - Charge inversion at position 68 of the glucagon and glucagon-like peptide-1 receptors supports selectivity in hormone action. AB - Glucagon and glucagon-like peptide-1 (GLP-1)are two structurally related hormones that acutely regulate glucose control in opposite directions through homologous receptors. The molecular basis for selectivity between these two hormones and their receptors is of physiological and medicinal importance. The application of co-agonists to enhance body weight reduction and correct multiple abnormalities associated with the metabolic syndrome has recently been reported. Substitution of amino acids 16, 18, and 20 in glucagon with those found in GLP-1 and exendin-4 were identified as partial contributors to balanced, high potency receptor action. The amidation of the C-terminus was an additional glucagon-based structural change observed to be of seminal importance to discriminate recognition by both receptors. In this work, the molecular basis for receptor selectivity associated with differences in C-terminal peptide sequence has been determined. A single charge inversion in glucagon and GLP-1 receptor sequence at position 68* was determined to significantly alter hormone action. Changing E68* in GLP-1R to the corresponding Lys of GCGR reduced receptor activity for natural GLP-1 hormones by eightfold. The enhanced C-terminal positive charges in GLP-1 peptides favor the native receptor's negative charge at position 68*, while the unfavorable interaction with the C-terminal acid of native glucagon is minimized by amidation. The extension of these observations to other glucagon-related hormones such as oxyntomodulin and exendin, as well as other related receptors such as GIPR, should assist in the assembly of additional hormones with broadened pharmacology. PMID- 21308879 TI - Influenza virus H5N1 hemagglutinin (HA) T-cell epitope conjugates: design, synthesis and immunogenicity. AB - The influenza virus, major surface glycoprotein hemagglutinin (HA) is one of the principal targets for the development of protective immunity. Aiming at contributing to the development of a vaccine that remains the first choice for prophylactic intervention, a reconstituted model of HA, mimicking its antigenic properties was designed, synthesized and tested in mice for the induction of protective immunity. Four helper T lymphocyte [HTL (T(1) , T(3) , T(7) and T(8) )] and four cytotoxic lymphocyte [CTL (T(2) , T(4) , T(5) and T(6) )] epitopes were coupled in two copies each to an artificial carrier, SOC(4) , which was formed by the repeating tripeptide Lys-Aib-Gly. The helical conformation of the SOC(4) -conjugates preserves the initial topology of the attached epitopes, which is critical for their immunogenic properties. Survival of immunized animals, ranged from 30 to 50%, points out the induction of protective immunity by using the SOC(4) -conjugates. PMID- 21308880 TI - Predictors of fibrostenotic Crohn's disease. AB - Intestinal fibrosis is a common and serious complication of Crohn's disease (CD) and as it can occur at any time during the disease course, it is crucial to identify patients at risk. The aim is not only to understand the pathophysiology of fibrogenesis but to be able to accurately inform subjects about their disease course, design future trials of potentially useful antifibrotic therapies, and, most important, identify those CD patients at risk, with the view to early, more aggressive medical therapy. This review summarizes the current status of our understanding and ability to predict fibrostenosing CD. The review encompasses three distinct areas: genetic variants, clinical phenotypes, and serologic markers in order to develop a conceptual framework for an understanding of fibrostenotic CD. It also aims to highlight where our knowledge is insufficient in order to identify areas that require future research. PMID- 21308881 TI - STAT6 activation in ulcerative colitis: a new target for prevention of IL-13 induced colon epithelial cell dysfunction. AB - BACKGROUND: Interleukin 13 (IL-13) is upregulated in ulcerative colitis (UC) and increases colon epithelial permeability by inducing apoptosis and expression of the pore-forming tight junction protein claudin-2. IL-13 induces activation of signal transducer and activator of transcription 6 (STAT6). However, the STAT6 phosphorylation status in patients with UC is unknown, as is the effect of STAT6 inhibition on colonic epithelium exposed to IL-13. The study aims were to determine if mucosal STAT6 phosphorylation is increased in patients with UC, and if STAT6 inhibition attenuates IL-13-induced colon epithelial cell dysfunction. METHODS: Immunohistochemical staining for phosphorylated (p) STAT6 was performed on colonic tissue from newly diagnosed pediatric subjects with UC (early UC) or Crohn's disease (CD), colectomy tissue from adults with UC (advanced UC), and controls. Colon HT-29 and T84 cells were transfected with STAT6 small interfering RNA (siRNA), or treated with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor that inhibits STAT6, prior to IL-13 treatment. RESULTS: The median score for epithelial pSTAT6 was 0 in control subjects, 2 in early UC (versus control P = 0.019), 4 in advanced UC (P = 0.003), and 0 in CD (P = 0.4). Cell transfection with STAT6 siRNA prevented IL-13-induced apoptosis and claudin 2 expression. SAHA inhibited IL-13-induced STAT6 phosphorylation, apoptosis, and claudin-2 expression, and mitigated IL-13-induced reductions in transepithelial resistance. CONCLUSIONS: UC is associated with increased colonic epithelial STAT6 phosphorylation, and STAT6 inhibition prevents IL-13-induced apoptosis and barrier disruption. These data identify STAT6 as a novel target for UC treatment and support further study of SAHA as a therapeutic agent. PMID- 21308882 TI - Treatment-emergent suicidal ideation during 4 months of acute management of unipolar major depression with SSRI pharmacotherapy or interpersonal psychotherapy in a randomized clinical trial. AB - BACKGROUND: To date, few randomized controlled trials (RCTs) of major depression have examined suicidal ideation as an outcome measure. Our aim is to determine the incidence of treatment-emergent suicidal ideation (ESI) and behaviors during the acute phase of treatment with an SSRI antidepressant or interpersonal psychotherapy (IPT) in patients with unipolar major depression. METHODS: In a two site RCT, 291 adult outpatients with nonpsychotic major depression and a Hamilton Depression Rating Scale (HDRS) score >=15 were randomly allocated to IPT or SSRI. Participants who did not remit with monotherapy received augmentation with the other treatment. ESI was defined as a post-baseline HDRS suicidality item score >=2 or a post-baseline Quick Inventory of Depressive Symptomatology (QIDS) score >=2 in patients with a baseline score <=1. RESULTS: Of the 231 participants who had no suicidal ideation at baseline, 32 (13.8%) subsequently exhibited ESI on at least one post-baseline visit. Time to suicidal ideation was significantly longer in patients allocated to SSRI compared to those allocated to IPT (HR = 2.21, 95% CI 1.04-4.66, P = .038), even after controlling for treatment augmentation, benzodiazepine use, and comorbidity with anxiety disorders. Worsening of suicidal ideation occurred in 7/60 patients who had suicidal ideation at baseline. In the large majority of cases, suicidal ideation was successfully managed with the study protocol. CONCLUSIONS: In the context of careful monitoring and frequent contact, selective serotonin reuptake inhibitor (SSRI) was associated with a lower risk of ESI than IPT and both SSRI and IPT appeared to be safe treatments for patients with past suicide attempts, none of whom exhibited ESI during the study. PMID- 21308883 TI - Separation anxiety disorder in OCD. AB - BACKGROUND: A history of separation anxiety disorder (SAD) is frequently reported by patients with obsessive-compulsive disorder (OCD). The purpose of this study was to determine if there are clinical differences between OCD-affected individuals with, versus without, a history of SAD. METHODS: Using data collected during the OCD Collaborative Genetic Study, we studied 470 adult OCD participants; 80 had a history of SAD, whereas 390 did not. These two groups were compared as to onset and severity of OCD, lifetime prevalence of Axis I disorders, and number of personality disorder traits. RESULTS: OCD participants with a history of SAD were significantly younger than the non-SAD group (mean, 34.2 versus 42.2 years; P<.001). They had an earlier age of onset of OCD symptoms (mean, 8.0 versus 10.5 years; P<.003) and more severe OCD, as measured by the Yale-Brown Obsessive Compulsive Scale (mean, 27.5 versus 25.0; P<.005). In addition, those with a history of SAD had a significantly greater lifetime prevalence of agoraphobia (odds ratio (OR) = 2.52, 95% confidence interval (CI) = 1.4-4.6, P<.003), panic disorder (OR = 1.84, CI = 1.03-3.3 P<.04), social phobia (OR = 1.69, CI 1.01-2.8, P<.048), after adjusting for age at interview, age at onset of OCD, and OCD severity in logistic regression models. There was a strong relationship between the number of dependent personality disorder traits and SAD (adjusted OR = 1.42, CI = 1.2-1.6, P<.001). CONCLUSIONS: A history of SAD is associated with anxiety disorders and dependent personality disorder traits in individuals with OCD. PMID- 21308884 TI - Predictors of treatment outcome in modular cognitive therapy for obsessive compulsive disorder. AB - BACKGROUND: The present study sought to identify predictors of outcome for a comprehensive cognitive therapy (CT) developed for patients with obsessive compulsive disorder (OCD). METHODS: Treatment was delivered over 22 sessions and included standard CT methods, as well as specific strategies designed for subtypes of OCD including religious, sexual, and other obsessions. This study of 39 participants assigned to CT examined predictors of outcomes assessed on the Yale-Brown Obsessive Compulsive Scale. A variety of baseline symptom variables were examined as well as treatment expectancy and motivation. RESULTS: Findings indicated that participants who perceived themselves as having more severe OCD at baseline remained in treatment but more severe symptoms were marginally associated with worse outcome for those who completed therapy. Depressed and anxious mood did not predict post-test outcome, but more Axis I comorbid diagnoses (mainly major depression and anxiety disorders), predicted more improvement, as did the presence of sexual (but not religious) OCD symptoms, and stronger motivation (but not expectancy). A small rebound in OCD symptoms at 1 year follow-up was significantly predicted by higher scores on personality traits, especially for schizotypal (but not obsessive-compulsive personality) traits. CONCLUSIONS: Longer treatment may be needed for those with more severe symptoms at the outset. CT may have positive effects not only on OCD symptoms but also on comorbid depressive and anxious disorders and associated underlying core beliefs. Findings are discussed in light of study limitations and research on other predictors. PMID- 21308885 TI - The effect of Avoidant Personality Disorder on the persistence of Generalized Social Anxiety Disorder in the general population: results from a longitudinal, nationally representative mental health survey. AB - BACKGROUND: The primary objective of this study was to prospectively examine the role of Avoidant Personality Disorder (AvPD) as a determinant in the outcome of Generalized Social Anxiety Disorder (GSAD) using Wave 2 of the National Epidemiologic Survey of Alcohol and Related Conditions 3 years later. METHOD: This study analyzed data from Waves 1 and 2 of the NESARC (n = 34,653). GSAD was operationalized based on the DSM-IV definitions of this SAD subtype. RESULTS: Logistic regression analyses indicated that AvPD significantly predicted the persistence of GSAD, even after adjusting for a number of important sociodemographic variables and other psychiatric comorbidity. AvPD did not significantly predict outcome in non-generalized SAD. CONCLUSIONS: AvPD can influence the course of GSAD in adulthood. Specific personality dimensions may underlie and explain the similarities between AvPD and GSAD. Self-criticism could be a shared feature of both AvPD and GSAD and could represent an important psychological marker of poor prognosis in comorbid GSAD and AvPD. PMID- 21308886 TI - Neural correlates of anxiety sensitivity during masked presentation of affective faces. AB - BACKGROUND: Anxiety Sensitivity (AS), the tendency to fear the thoughts, symptoms, and social consequences associated with the experience of anxiety, is associated with increased risk for developing anxiety disorders. Some evidence suggests that higher scores on the Anxiety Sensitivity Index (ASI), a measure of the AS construct, are associated with activation of the anterior insular cortex during overt emotion perception. Although the ASI provides subscale scores measuring Physical, Mental Incapacitation, and Social Concerns of AS, no study has examined the relationship between these factors and regional brain activation during affect processing. We hypothesized that insular responses to fear-related stimuli would be primarily related to the Physical Concerns subscale of the ASI, particularly for a sample of subjects with specific phobias. METHODS: Adult healthy controls (HC; n = 22) and individuals with specific phobia, small animal subtype (SAP; n = 17), completed the ASI and underwent functional magnetic resonance imaging while engaged in a backward-masked affect perception task that presents emotional facial stimuli below the threshold of conscious perception. RESULTS: Groups did not differ in ASI, state or trait anxiety scores, or insula activation. Total ASI scores were positively correlated with activation in the right middle/anterior insula for the combined sample and for the HC and SAP groups separately. Multiple regression analysis revealed that the relationship between AS and insular activation was primarily accounted for by Physical Concerns only. CONCLUSIONS: Findings support the hypothesized role of the right anterior insula in the visceral/interoceptive aspects of AS, even in response to masked affective stimuli. PMID- 21308887 TI - Recovery from PTSD following Hurricane Katrina. AB - BACKGROUND: We examined patterns and correlates of speed of recovery of estimated posttraumatic stress disorder (PTSD) among people who developed PTSD in the wake of Hurricane Katrina. METHOD: A probability sample of prehurricane residents of areas affected by Hurricane Katrina was administered a telephone survey 7-19 months following the hurricane and again 24-27 months posthurricane. The baseline survey assessed PTSD using a validated screening scale and assessed a number of hypothesized predictors of PTSD recovery that included sociodemographics, prehurricane history of psychopathology, hurricane-related stressors, social support, and social competence. Exposure to posthurricane stressors and course of estimated PTSD were assessed in a follow-up interview. RESULTS: An estimated 17.1% of respondents had a history of estimated hurricane-related PTSD at baseline and 29.2% by the follow-up survey. Of the respondents who developed estimated hurricane-related PTSD, 39.0% recovered by the time of the follow-up survey with a mean duration of 16.5 months. Predictors of slow recovery included exposure to a life-threatening situation, hurricane-related housing adversity, and high income. Other sociodemographics, history of psychopathology, social support, social competence, and posthurricane stressors were unrelated to recovery from estimated PTSD. CONCLUSIONS: The majority of adults who developed estimated PTSD after Hurricane Katrina did not recover within 18-27 months. Delayed onset was common. Findings document the importance of initial trauma exposure severity in predicting course of illness and suggest that pre- and posttrauma factors typically associated with course of estimated PTSD did not influence recovery following Hurricane Katrina. PMID- 21308888 TI - Vigilant and avoidant attention biases as predictors of response to cognitive behavioral therapy for social phobia. AB - BACKGROUND: Attention bias for socially threatening information, an empirically supported phenomenon, figures prominently in models of social phobia. However, all published studies examining this topic to date have relied on group means to describe attention bias patterns; research has yet to examine potential subgroups of attention bias among individuals with social phobia (e.g., vigilant or avoidant). Furthermore, almost no research has examined how attention biases in either direction may predict change in symptoms as a result of treatment. METHODS: This study (N = 24) compared responses to cognitive behavioral therapy (CBT) for social phobia between individuals with avoidant and vigilant biases for threatening faces at pretreatment. RESULTS: Participants with avoidant biases reported significantly and clinically higher symptom levels at posttreatment than did those with vigilant biases. CONCLUSIONS: These findings suggest that an avoidant attention bias may be associated with reduced response to CBT for social phobia. PMID- 21308889 TI - Stressful life events at onset of obsessive-compulsive disorder are associated with a distinct clinical pattern. AB - BACKGROUND: Environmental stressors are considered to play an important role in the triggering of mental disorders such as obsessive-compulsive disorder (OCD). Although there is extensive literature on traumatic life events, little is known about the role of nontraumatic but nonetheless stressful life events (SLEs) in OCD. The aim of this study was to establish whether OCD preceded by an SLE presents a different clinical pattern compared to non-SLE-preceded OCD. METHODS: We interviewed 412 OCD patients to assess both SLEs at onset of OCD and other clinical variables, including OCD symptom dimensions. Logistic regression was then applied to explore the relationship between clinical variables and OCD preceded by an SLE. RESULTS: The SLE-preceded OCD group showed a later onset of the disorder (OR = 1.04, P = .015), a history of complicated birth (OR = 5.54, P<.001), less family history of OCD (OR = 0.42, P = .014), and the presence of contamination/cleaning symptoms (OR = 1.99, P = .01). CONCLUSIONS: Patients with OCD onset close to an SLE and those without an SLE close to OCD onset show a distinct clinical pattern. PMID- 21308890 TI - The role of values-consistent behavior in generalized anxiety disorder. AB - BACKGROUND: Theory and research suggest that generalized anxiety disorder (GAD) is associated with diminished quality of life and restriction in valued action. The purpose of this study was to examine the relevance of values-consistent behavior (valued action) in understanding the impairment in quality of life in GAD. METHOD: Treatment-seeking clients with a principal diagnosis of GAD (n = 30) were compared with demographically matched nonanxious controls (n = 30) using self-report measures. RESULTS: Participants with GAD reported significantly less valued action compared with controls, and within the GAD group, diminished valued action was not fully explained by depression comorbidity. Valued action was significantly correlated with measures of experiential avoidance, distress about emotions, and quality of life. Further, consistent with a theoretical model of GAD, restrictions in valued action contributed unique variance to diminished quality of life over and above the contributions of gender, GAD severity, experiential avoidance, distress about emotions, and depression comorbidity. Finally, an acceptance-based behavioral therapy significantly improved self reports of valued action for GAD clients with 40% achieving clinically significant change in this domain. CONCLUSION: The findings provide preliminary support for the relevance of valued action in understanding the functional impairment associated with GAD, and the beneficial effects of an acceptance-based behavior therapy in increasing valued action. PMID- 21308891 TI - Diagnosing social anxiety disorder in the presence of obesity: implications for a proposed change in DSM-5. AB - BACKGROUND: The proposed draft of the DSM-5 from the Anxiety Disorder Workgroup recommends allowing the diagnosis of social anxiety disorder (SAD) in individuals with medical conditions, if the anxiety is considered to be excessive. Although prior research has examined diagnosing SAD in individuals with stuttering, such research has not yet been conducted in obese individuals. METHODS: This study compared demographic and clinical characteristics of obese individuals diagnosed with DSM-IV SAD (n = 135), modified SAD (clinically significant social anxiety related to weight only; n = 40), and a group of obese individuals with no history of psychiatric disorders (n = 616). All participants were seeking psychiatric clearance for bariatric surgery and completed a comprehensive diagnostic interview. RESULTS: The two social anxiety groups differed from the no disorder group on adolescent and past 5 years social functioning, and overall current functioning. Individuals with modified SAD had a later onset of their social anxiety, yet reported greater impairment in social life and distress about their social anxiety compared to the DSM-IV SAD group. CONCLUSIONS: Although both of the social anxiety groups differed from the no disorder group on social and overall functioning, there were few differences between those with DSM-IV SAD and modified SAD. This suggests that obese individuals with social anxiety related to weight only may experience comparable severity of anxiety to those with DSM-IV SAD, and supports adoption of the DSM-5 Workgroup's recommendation to change criterion H. PMID- 21308892 TI - Mangiferin: A xanthone attenuates mercury chloride induced cytotoxicity and genotoxicity in HepG2 cells. AB - Mangiferin (MGN), a dietary C-glucosylxanthone present in Mangifera indica, is known to possess a spectrum of beneficial pharmacological properties. This study demonstrates antigenotoxic potential of MGN against mercuric chloride (HgCl2) induced genotoxicity in HepG2 cell line. Treatment of HepG2 cells with various concentrations of HgCl2 for 3 h caused a dose-dependent increase in micronuclei frequency and elevation in DNA strand breaks (olive tail moment and tail DNA). Pretreatment with MGN significantly (p < 0.01) inhibited HgCl2 -induced (20 uM for 30 h) DNA damage. An optimal antigenotoxic effect of MGN, both in micronuclei and comet assay, was observed at a concentration of 50 uM. Furthermore, HepG2 cells treated with various concentrations of HgCl2 resulted in a dose-dependent increase in the dichlorofluorescein fluorescence, indicating an increase in the generation of reactive oxygen species (ROS). However, MGN by itself failed to generate ROS at a concentration of 50 uM, whereas it could significantly decrease HgCl2 -induced ROS. Our study clearly demonstrates that MGN pretreatment reduced the HgCl2-induced DNA damage in HepG2 cells, thus demonstrating the genoprotective potential of MGN, which is mediated mainly by the inhibition of oxidative stress. PMID- 21308893 TI - ImKTx1, a new Kv1.3 channel blocker with a unique primary structure. AB - Toxins from the venoms of scorpion, snake, and spider are valuable tools to probe the structure-function relationship of ion channels. In this investigation, a new toxin gene encoding the peptide ImKTx1 was isolated from the venom gland of the scorpion Isometrus maculates by constructing cDNA library method, and the recombinant ImKTx1 peptide was characterized physiologically. The mature peptide of ImKTx1 has 39 amino acid residues including six cross-linked cysteines. The electrophysiological experiments showed that the recombinant ImKTx1 peptide had a pharmacological profile where it inhibited Kv1.3 channel currents with IC(50) of 1.70 n+/- 1.35 uM, whereas 10 uM rImKTx1 peptide inhibited about 40% Kv1.1 and 42% Kv1.2 channel currents, respectively. In addition, 10 uM rImKTx1 had no effect on the Nav1.2 and Nav1.4 channel currents. Multiple sequence alignments showed that ImKTx1 had no homologous toxin peptide, but it was similar with Ca(2+) channel toxins from scorpion and spider in the arrangement of cysteine residues. These results indicate that ImKTx1 is a new Kv1.3 channel blocker with a unique primary structure. Our results indicate the diversity of K(+) channel toxins from scorpion venoms and also provide a new molecular template targeting Kv1.3 channel. PMID- 21308894 TI - Neurodegeneration by activated microglia across a nanofiltration membrane. AB - Microglia have been implicated in the pathogenesis of several neurodegenerative diseases, but their precise role remains elusive. Although neuron loss in the presence of lipopolysaccharide-stimulated microglia has been well documented, a novel coculture paradigm was developed as a new approach to assess the diffusible, soluble mediators of neurodegeneration. Isolated microglia were plated on membrane inserts that were coated with a layer of cellulose acetate. The cellulose acetate-coated membranes have nanofiltration properties, in that only molecules with masses less than 350 Da can pass through. Products released from activated microglia that were separated from primary ventral mesencephalon cells beneath the nanofiltering membrane were able to kill the dopamine neurons. Microglial cytokines cannot diffuse through this separating membrane. Addition of a nitric oxide synthase inhibitor prevented the loss of the dopamine neurons. These data describe a novel coculture system for studying diffusible factors and further support nitric oxide production as an important mediator in microglia induced neuron death. PMID- 21308895 TI - Study on the binding of cerium to bovine serum albumin. AB - The interaction of Ce(3+) to bovine serum albumin (BSA) has been investigated mainly by fluorescence spectra, UV-vis absorption spectra, and circular dichroism (CD) under simulative physiological conditions. Fluorescence data revealed that the quenching mechanism of BSA by Ce(3+) was a static quenching process, the binding constant is 6.70 * 10(5) , and the number of binding site is 1. The thermodynamic parameters (DeltaH = -29.94 kJ mol(-1) , DeltaG = -32.38 kJ mol(-1) , and DeltaS = 8.05 J mol(-1) K(-1) ) indicate that electrostatic effect between the protein and the Ce(3+) is the main binding force. In addition, UV-vis, CD, and synchronous fluorescence results showed that the addition of Ce(3+) changed the conformation of BSA. PMID- 21308896 TI - Trans fat diet causes decreased brood size and shortened lifespan in Caenorhabditis elegans delta-6-desaturase mutant fat-3. AB - Trans-fatty acids (TFAs) enter the diet through industrial processes and can cause adverse human health effects. The present study was aimed to examine the effects of dietary cis- and trans-fatty acids on the model organism Caenorhabditis elegans. Cis- or trans-18:1n9 triglycerides (25 MUM) caused no apparent changes in the numbers of viable progeny of wild-type N2 animals. However, in fat-3 mutants lacking delta-6-desaturase, the trans-isomer caused modest decreases in lifespan and progeny after three generations. Long-chain polyunsaturated fatty acids (PUFA) profiles were significantly altered in fat-3 mutants compared to wild type but were not altered after exposure to dietary cis- or trans-18:1n9. Genome-wide expression analysis of fat-3 mutants revealed hundreds of changes. Several genes involved in fat metabolism (acs-2, fat-7, mdt 15) were significantly increased by cis- or trans-18:1n9 without discrimination between isomers. These results provide support for the hypothesis that dietary trans fats are detrimental to development and aging. PMID- 21308897 TI - Effect of mitochondrial dysfunction and oxidative stress on endogenous levels of coenzyme Q(10) in human cells. AB - Little is known about the regulation of endogenous CoQ(10) levels in response to mitochondrial dysfunction or oxidative stress although exogenous CoQ(10) has been extensively used in humans. In this study, we first demonstrated that acute treatment of antimycin A, an inhibitor of mitochondrial complex III, and the absence of mitochondrial DNA suppressed CoQ(10) levels in human 143B cells. Because these two conditions also enhanced formation of reactive oxygen species (ROS), we further investigated whether oxidative stress or mitochondrial dysfunction primarily contributed to the decrease of CoQ(10) levels. Results showed that H(2)O(2) augmented CoQ(10) levels, but carbonyl cyanide-p trifluoromethoxyphenylhydrazone (FCCP), a chemical uncoupler, decreased CoQ(10) levels in 143B cells. However, H(2)O(2) and FCCP both increased mRNA levels of multiple COQ genes for biosynthesis of CoQ(10) . Our findings suggest that ROS induced CoQ(10) biosynthesis, whereas mitochondrial energy deficiency caused secondary suppression of CoQ(10) levels possibly due to impaired import of COQ proteins into mitochondria. PMID- 21308898 TI - Visualization of intracellular trafficking of Math1 protein in different cell types with a newly-constructed nonviral gene delivery plasmid. AB - BACKGROUND: In recent years, Math1 gene therapy was indicated to be the future therapy for deafness in combination with other growth factors. However, Math1 delivery using adenovirus-mediated gene delivery or electroporation was impractical. The contribution of Math1 in the combined procedure was not clearly elucidated using the existing plasmids. Nonviral gene delivery vectors are expected to be extremely safe and convenient. The present study aimed to construct the pCDNA6.2/C-EmGFP-Math1 plasmid and evaluate its transfection efficiency and intracellular trafficking of Math1 protein corresponding to transcription regulation function. METHODS: After constructing the pCDNA6.2/C EmGFP-Math1 expression plasmid, the plasmid was transfected into different cell lines and primary cochlear cells using Lipofectamine 2000. Transfection efficiencies of the plasmid were evaluated. Transfection efficiencies using liposome nanoparticles containing Math1 plasmid were also assessed. Intracellular trafficking of Math1 was monitored using confocal microscopy. RESULTS: Different cell types can be transfected with high transfection efficiencies by the pcDNA6.2/C-EmGFP-Math1 plasmid using Lipofectamine 2000. Liposome nanoparticles containing the Math1 plasmid expressed the gene with variable efficiencies, depending on the particle size, surface charge and PEGylation status. Unique intracellular trafficking of Math1 was demonstrated in different cell types. CONCLUSIONS: The newly-constructed plasmid pcDNA6.2/C-EmGFP-Math1 was suitable for nonviral gene delivery of Math1. Unique intracellular trafficking of Math1 with dynamics from the cytoplasm to the nucleus was demonstrated. The modification of mesenchymal stem cells by Math1 gene delivery and by brain derived neurotrophic factor and glial cell line-derived neurotrophic factor treatments can potentially be applied to cell replacement for the treatment of cochlear spiral ganglion cell loss in deafness. PMID- 21308899 TI - Amphiphilic, low molecular weight poly(ethylene imine) derivatives with enhanced stability for efficient pulmonary gene delivery. AB - BACKGROUND: Poly(ethylene imine) (PEI) is a widely used transfection reagent for mammalian cells, but in vivo application of PEI 25 kDa is restricted by its toxicity. Low molecular weight (LMW) PEI is less toxic, but also less efficient than its high molecular weight equivalent, and prone to aggregation. METHOD: A set of polymers was synthesized by coupling poly(ethylene glycol) (PEG) that contained either C(16/18) -chains (Cx-EO) or butyl-poly(propylene oxide)-co poly(ethylene glycol) (ButPP). Critical micelle concentration (CMC) was determined for copolymers. Polyplexes were characterized by DNA binding ability, polyplex size and aggregation, hemolysis, and cytotoxicity. Transfection efficiency was tested in vitro and in vivo in mouse lungs. RESULTS: Copolymers formed stable complexes with DNA, and showed enhanced complex stability in isotonic solution for at least 1 h. CMC was determined for Cx-EO-PEI 4.7 and 8.3 at 0.0019 and 0.0037 mM, respectively; membrane activity in a haemolysis assay was demonstrated for ButPP-PEI: both factors possibly enhance endosomal escape effect after PEGylation. IC(50) values of all synthesized polymers were in the range 6-33 ng/ml. Transfection efficiency of unmodified LMW-PEIs was equivalent or better than that of PEI 25 as a result of aggregation in vitro. Cells treated with polyplexes of amphiphilic polymers showed reduced transfection compared to PEI 25. After instillation in mouse lungs, highest transfection efficiency was demonstrated with Cx-EO copolymer of lowest molecular weight PEI. CONCLUSIONS: A new set of polymers with low toxicity and high stability was synthesized, which contains promising candidates for pulmonary gene transfer, as documented by in vivo experiments in mice. PMID- 21308902 TI - Ben L. Feringa. PMID- 21308903 TI - A cavity-shaped diphosphane displaying "oschelating" behavior. PMID- 21308904 TI - Formation of a dinuclear mercury(II) complex with a regular bis-strapped porphyrin following a tunable cooperative process. PMID- 21308905 TI - Photon-quantitative reaction of a dithiazolylarylene in solution. PMID- 21308906 TI - Hybrid ferritin nanoparticles as activatable probes for tumor imaging. PMID- 21308907 TI - [Cu(HF2)2 (pyrazine)]n: a rectangular antiferromagnetic lattice with a spin exchange path made up of two different FHF- bridges. PMID- 21308908 TI - Zinc-triggered hydrogelation of a self-assembling beta-hairpin peptide. PMID- 21308909 TI - An asymmetric organocatalytic one-pot strategy to octahydroacridines. PMID- 21308910 TI - On the surface chemistry of iron oxides in reactive gas atmospheres. PMID- 21308911 TI - (Pro2 H+)2 (TCNQ.-)2?TCNQ: an amino acid derived semiconductor. PMID- 21308912 TI - Superstructures and SERS properties of gold nanocrystals with different shapes. PMID- 21308913 TI - Soluble Prussian blue nanoworms from the assembly of metal-organic block ionomers. PMID- 21308914 TI - Anodization of gold in oxalate solution to form a nanoporous black film. PMID- 21308915 TI - Effects of neighboring glycans on antibody-carbohydrate interaction. PMID- 21308916 TI - On the roles of protic solvents in imidazolidinone-catalyzed transformations. PMID- 21308917 TI - Silica-nanoparticle coatings by adsorption from lysine-silica-nanoparticle Sols on inorganic and biological surfaces. PMID- 21308918 TI - Self-seeding in one dimension: an approach to control the length of fiberlike polyisoprene-polyferrocenylsilane block copolymer micelles. PMID- 21308919 TI - Ruthenium(II) polyimine complexes with a long-lived 3IL excited state or a 3MLCT/3 IL equilibrium: efficient triplet sensitizers for low-power upconversion. PMID- 21308920 TI - Divergolides A-D from a mangrove endophyte reveal an unparalleled plasticity in ansa-macrolide biosynthesis. PMID- 21308921 TI - Self-adjuvanting multicomponent cancer vaccine candidates combining per glycosylated MUC1 glycopeptides and the Toll-like receptor 2 agonist Pam3CysSer. PMID- 21308922 TI - Reversible and quantitative denaturation of amphiphilic oligo(azobenzene) foldamers. PMID- 21308923 TI - A smart polysaccharide/drug conjugate for photodynamic therapy. PMID- 21308924 TI - Multicompartment polymersomes from double emulsions. PMID- 21308925 TI - Hidden noninnocence: theoretical and experimental evidence for redox activity of a beta-diketiminate1- ligand. PMID- 21308926 TI - Solid-state ion channels for potentiometric sensing. PMID- 21308927 TI - Repeatable photoinduced self-healing of covalently cross-linked polymers through reshuffling of trithiocarbonate units. PMID- 21308928 TI - Enantioselective construction of bridged multicyclic skeletons: intermolecular [2+2+2] cycloaddition/intramolecular Diels-Alder reaction cascade. PMID- 21308929 TI - Trinucleating copper: synthesis and magnetostructural characterization of complexes supported by a hexapyridyl 1,3,5-triarylbenzene ligand. PMID- 21308930 TI - alpha,beta-Unsaturated acyl azoliums from N-heterocyclic carbene catalyzed reactions: observation and mechanistic investigation. PMID- 21308932 TI - Fiber supercapacitors made of nanowire-fiber hybrid structures for wearable/flexible energy storage. PMID- 21308931 TI - Lewis acid activated synthesis of highly substituted cyclopentanes by the N heterocyclic carbene catalyzed addition of homoenolate equivalents to unsaturated ketoesters. PMID- 21308933 TI - Deacylative allylation of nitroalkanes: unsymmetric bisallylation by a three component coupling. PMID- 21308934 TI - Tetrasubstituted olefins through the stereoselective catalytic intermolecular conjugate addition of simple alkenes to alpha,beta-unsaturated carbonyl compounds. PMID- 21308935 TI - Magnetic memory effect in a transuranic mononuclear complex. PMID- 21308936 TI - Towards a further generation of high-energy carbon-based capacitors by using redox-active electrolytes. PMID- 21308938 TI - The catalytic asymmetric Knoevenagel condensation. PMID- 21308937 TI - Rhodium-catalyzed synthesis of 2,3-disubstituted indoles from beta,beta disubstituted stryryl azides. PMID- 21308940 TI - Structural diversity and flexibility of MgO gas-phase clusters. PMID- 21308939 TI - An oxocobalt(IV) complex stabilized by Lewis acid interactions with scandium(III) ions. PMID- 21308941 TI - Elusive diazirinone, N2CO. PMID- 21308943 TI - FRET and FCS--friends or foes? AB - Fluorescence correlation spectroscopy (FCS) and Forster resonance energy transfer (FRET) are both scientific concepts that are frequently discussed in the context of single-molecule fluorescence techniques. In contrast to FCS, FRET is strictly not a technique but a photophysical phenomenon, which can be employed in combination with any method that probes fluorescence intensity or lifetime. Thus, the combination of FCS with FRET is possible and-although these concepts are quite often treated as alternative approaches, particularly for the analysis of biological systems-also quite attractive. However, under certain circumstances, for example, for applications of fluorescence cross-correlation spectroscopy, FRET effects can cause significant complications for quantitative data analysis, and careful calibration has to be carried out to avoid FRET-induced artifacts. This can be most elegantly done if alternating excitation schemes such as PIE (pulsed interleaved excitation) are employed. In this minireview, we discuss the potential and the caveats of FCS combined with FRET and give a short record on successful and promising applications. PMID- 21308944 TI - Single-molecule FRET ruler based on rigid DNA origami blocks. AB - Fluorescence resonance energy transfer (FRET) has become a work-horse for distance measurements on the nanometer scale and between single molecules. Recent model systems for the FRET distance dependence such as polyprolines and dsDNA suffered from limited persistence lengths and sample heterogeneity. We designed a series of rigid DNA origami blocks where each block is labeled with one donor and one acceptor at distances ranging between 2.5 and 14 nm. Since all dyes are attached in one plane to the top surface of the origami block, static effects of linker lengths cancel out in contrast to commonly used dsDNA. We used single molecule spectroscopy to compare the origami-based ruler to dsDNA and found that the origami blocks directly yield the expected distance dependence of energy transfer since the influence of the linkers on the donor-acceptor distance is significantly reduced. Based on a simple geometric model for the inter-dye distances on the origami block, the Forster radius R(0) could directly be determined from the distance dependence of energy transfer yielding R(0)=5.3+/ 0.3 nm for the Cy3-Cy5 pair. PMID- 21308946 TI - Induction of oxidative stress in liver and kidney of rats exposed to Nigerian bonny light crude oil. AB - The local population of Niger-Delta in the Southern part of Nigeria have used bonny light crude oil (BLCO) as a remedy for various ailments and are exposed to some extent to this widespread environmental contaminant or its metabolites through the food chain. BLCO's hepatorenal toxicity was studied using oxidative stress indices to elucidate the precise nature and mechanism of action. BLCO was orally administered at concentrations of 0, 200, 400, and 800 mg kg-1 to adult male rats for 7 days. After exposure, kidney weight was unaffected, but liver weight decreased significantly at 800 mg kg-1 only compared with control. BLCO exposure resulted in dose-dependent elevation of serum aminotransferases, total bilirubin, urea, and creatinine. Activities of superoxide dismutase and catalase decreased significantly, whereas gamma-glutamyltransferase activity and the level of glutathione increased significantly in BLCO-treated animals compared with control in both liver and kidney of rat. Renal activities of glucose-6 phosphatase and 5'-nucleotidase markedly decreased in a dose-dependent manner in BLCO-exposed rats. In addition, the levels of hydrogen peroxide and lipid peroxidation significantly increased, dose dependently, in liver and kidney of BLCO-treated rats compared with control. BLCO-treated rats showed marked degeneration of kidney evident in cortical hemorrhages, tubular necrosis, protein casts, and cellular infiltration. However, no treatment-related liver histopathology was observed. The results suggested that BLCO elicits disruption of antioxidant status and concomitant elevation of hydrogen peroxide and lipid peroxidation differentially in liver and kidney of rats. The hepatorenal toxicity of BLCO could be due to induction of oxidative stress in liver and kidney. PMID- 21308945 TI - A FRET sensor for non-invasive imaging of amyloid formation in vivo. AB - Misfolding and aggregation of amyloidogenic polypeptides lie at the root of many neurodegenerative diseases. Whilst protein aggregation can be readily studied in vitro by established biophysical techniques, direct observation of the nature and kinetics of aggregation processes taking place in vivo is much more challenging. We describe here, however, a Forster resonance energy transfer sensor that permits the aggregation kinetics of amyloidogenic proteins to be quantified in living systems by exploiting our observation that amyloid assemblies can act as energy acceptors for variants of fluorescent proteins. The observed lifetime reduction can be attributed to fluorescence energy transfer to intrinsic energy states associated with the growing amyloid species. Indeed, for a-synuclein, a protein whose aggregation is linked to Parkinson's disease, we have used this sensor to follow the kinetics of the self-association reactions taking place in vitro and in vivo and to reveal the nature of the ensuing aggregated species. Experiments were conducted in vitro, in cells in culture and in living Caenorhabditis elegans. For the latter the readout correlates directly with the appearance of a toxic phenotype. The ability to measure the appearance and development of pathogenic amyloid species in a living animal and the ability to relate such data to similar processes observed in vitro provides a powerful new tool in the study of the pathology of the family of misfolding disorders. Our study confirms the importance of the molecular environment in which aggregation reactions take place, highlighting similarities as well as differences between the processes occurring in vitro and in vivo, and their significance for defining the molecular physiology of the diseases with which they are associated. PMID- 21308947 TI - Toxicity evaluation of verapamil and tramadol based on toxicity assay and expression patterns of Dhb, Vtg, Arnt, CYP4, and CYP314 in Daphnia magna. AB - In this study, the toxicities of two pharmaceuticals, verapamil and tramadol were evaluated in Daphnia magna using the conventional toxicity tests (acute and chronic test) and the expression patterns of five stress responsive genes. In the chronic toxicity test, several parameters, such as the survival percentage, the body length of D. magna, the time of first reproduction, and the number of offspring per female, were adversely affected during the exposure to 4.2 mg L(-1) verapamil and 34 mg L(-1) tramadol. During the 24-h short-term exposure, verapamil particularly caused a downregulated expression of the CYP4 and CYP314 genes, whereas tramadol upregulated the expression of the CYP314 gene. Neither pharmaceutical affected the expression of Dhb, Arnt, and Vtg. However, during the 21-day long-term exposure, both verapamil and tramadol significantly reduced the expression level of the Vtg gene, a biomarker of the reproduction ability in an oviparous animal, whereas neither affected the other genes. PMID- 21308948 TI - Medical care of type 2 diabetes in German disease management programmes: a population-based evaluation. AB - OBJECTIVE: Type 2 diabetes disease management programmes (DDMPs) are offered by German social health insurance to promote healthcare consistent with evidence based medical guidelines. The aim of this study was to compare healthcare quality and medical endpoints between diabetes management programme participants and patients receiving usual care designated as controls. METHODS: All patients with type 2 diabetes (age range: 36-81) in a cross-sectional survey of a cohort study, performed by the Cooperative Health Research in the Region of Augsburg, received a self-administered questionnaire regarding their diabetes care. Physical examination and laboratory tests were also performed. The analysis only included patients with social health insurance and whose participation status in a diabetes disease management program was validated by the primary physician (n = 166). Regression analyses, adjusting for age, sex, education, diabetes duration, baseline waist circumference and clustering regarding primary physician were conducted. RESULTS: Evaluation of healthcare processes showed that those in diabetes disease management programmes (n = 89) reported medical examination of eyes and feet and medical advice regarding diet [odds ratio (OR): 2.39] and physical activity (OR: 2.87) more frequently, received anti-diabetic medications (OR: 3.77) and diabetes education more often (OR: 2.66) than controls. Both groups had satisfactory HbA(1c) control but poor low-density lipoprotein cholesterol control. Blood pressure goals (<140/90 mmHg) were achieved more frequently by patients in diabetes disease management programmes (OR: 2.21). CONCLUSIONS: German diabetes disease management programmes are associated with improved healthcare processes and blood pressure control. Low-density lipoprotein cholesterol control must be improved for all patients with diabetes. Further research will be required to assess the long-term effects of this diabetes disease management programme. PMID- 21308949 TI - Flow system for the automatic screening of the effect of phenolic compounds on the luminol-hydrogen peroxide-peroxidase chemiluminescence system. AB - In this work, an automated flow-based procedure for the screening of the effect of the different phenolic compounds on the chemiluminescence (CL) luminol hydrogen peroxide-horseradish peroxidase (HRP) system is presented. This procedure involves the combination of multisyringe flow injection analysis (MFSIA) and sequential injection analysis (SIA) techniques and exploits the ability of the different subgroups of phenols, such as cholorophenols, nitrophenols, methylphenols and polyphenols, to enhance or inhibit the described CL system. The implementation of this reaction in the SIA-MSFIA system enabled favourable and precise conditions to evaluate the effect of phenolic compounds, as it involves an in-line reaction between the phenolic derivative, hydrogen peroxide and peroxidase and subsequent oxidized HRP intermediates generation prior to the fast reaction with the chemiluminogenic reagent. Several studies were then performed with the aim of establishing the appropriate flow system configuration and reaction conditions. It was shown that phenol and chlorophenols produce an enhanced CL response and nitrophenols, methylphenols and polyphenols are inhibitors within the range of concentrations studied (1-100 mg/L). Based on these studies, the developed method was applied to the determination of total polyphenol and phenol content in wine/grape seeds and water samples, respectively, and the results obtained showed good agreement with those furnished by the corresponding Folin-Ciocalteu and 4-aminoantipyrine reference methods. The developed approach is further pursued by designing an automated generic tool for performing studies of peroxidase-catalysed CL reactions of luminol focused on the detection of compounds that will affect the rate of those reactions. PMID- 21308950 TI - Low pesticide rates may hasten the evolution of resistance by increasing mutation frequencies. AB - At very low pesticide rates, a certain low proportion of pests may receive a sublethal dose, are highly stressed by the pesticide and yet survive. Stress is a general enhancer of mutation rates. Thus, the survivors are likely to have more than normal mutations, which might include mutations leading to pesticide resistance, both for multifactorial (polygenic, gene amplification, sequential allelic mutations) and for major gene resistance. Management strategies should consider how to eliminate the subpopulation of pests with the high mutation rates, but the best strategy is probably to avoid too low application rates of pesticides from the outset. PMID- 21308951 TI - Resistance to HPPD-inhibiting herbicides in a population of waterhemp (Amaranthus tuberculatus) from Illinois, United States. AB - BACKGROUND: A population of waterhemp in a seed maize production field in central Illinois, United States, was not adequately controlled after post-emergence applications of herbicides that inhibit 4-hydroxyphenylpyruvate dioxygenase (HPPD). RESULTS: Progeny from the field population survived following treatment with mesotrione, tembotrione or topramezone applied to the foliage either alone or in combination with atrazine in greenhouse experiments. Dose-response experiments indicated that the level of resistance to the HPPD inhibitor mesotrione is at least tenfold relative to sensitive biotypes. CONCLUSION: These studies confirm that waterhemp has evolved resistance to HPPD-inhibiting herbicides. PMID- 21308952 TI - Development of strategies for monitoring indoxacarb and gel bait susceptibility in the German cockroach (Blattodea: Blattellidae). AB - BACKGROUND: Advion((r)) cockroach gel bait (6 g kg(-1) indoxacarb) is in widespread use for Blattella germanica (L.) control in the United States. However, baseline susceptibility levels to indoxacarb in German cockroach field populations are not known. Hence, this research sought to develop monitoring strategies to estimate the susceptibility of German cockroach populations to indoxacarb. RESULTS: Four bioassays were evaluated: topical lethal dose (LD), formulated gel bait lethal time (LT), vial lethal concentration (LC) and gel bait matrix LD. Of these methods, the vial LC and gel bait matrix LD bioassays were the most economical and relevant assessment strategies. For indoxacarb susceptibility monitoring, a two-tiered approach was developed that utilizes diagnostic concentrations and doses in vial LC (30 and 60 ug vial(-1) ) and gel bait matrix LD (1.0, 1.5 and 2.5 ug insect(-1) ) formats. CONCLUSIONS: A two tiered susceptibility monitoring strategy was developed that includes testing field populations at diagnostic concentrations and doses in first-tier vial LC bioassays and second-tier gel bait matrix LD bioassays. The vial method facilitates rapid identification of field strains with reduced susceptibility. The feeding bioassay effectively simulates field exposure to Advion((r)) and therefore has utility for secondary confirmation of susceptibility shifts and identification of behavioral resistance (i.e. bait aversion). PMID- 21308953 TI - Reduced metribuzin pollution with phosphatidylcholine-clay formulations. AB - BACKGROUND: Metribuzin is a widely used herbicide that has been identified as a groundwater contaminant. In this study, slow-release formulations of metribuzin were designed by encapsulating the active ingredient in phosphatidylcholine (PC) vesicles and adsorbing the vesicles onto montmorillonite. RESULTS: The maximum active ingredient content in the slow-release formulations was 246 g kg(-1) . Infrared spectroscopy results revealed that the hydrophobic interactions between metribuzin and the alkyl chains on PC were necessary for encapsulation. In addition, water bridges connecting the herbicide and the PC headgroup enhanced the solubility of metribuzin in PC. Adsorption experiments in soils were performed to evaluate the relationship between sorption and leaching. Funnel experiments in a sandy soil revealed that the herbicide was not irreversibly retained in the formulation matrix. In soil column experiments, PC-clay formulations enhanced herbicide accumulation and biological activity in the top soil layer relative to a commercial formulation. PC-clay formulations also reduced the dissipation of metribuzin by a factor of 1.6-2.5. CONCLUSIONS: A reduction in the recommended dose of metribuzin can be achieved by employing PC clay formulations, which reduces the environmental risk associated with herbicide applications. Moreover, PC and montmorillonite are non-toxic and do not negatively affect the environment. PMID- 21308954 TI - Synthesis of D-glucosamine quaternary ammonium derivatives and evaluation of their antifungal activity together with aminodeoxyglucose derivatives against two wood fungi Coriolus versicolor and Poria placenta: structure-activity relationships. AB - BACKGROUND: Structure-activity relationships are often reported in scientific studies. These may be employed in searching for new acceptable biocides to use against harmful microorganisms, because the biocides used hitherto encounter various problems, including lack of efficiency, high toxicity and persistence. Nowadays, scientists are trying to find new, environmentally acceptable biocides to replace these earlier biocides. Different compounds from renewable materials have been studied and have shown pronounced antifungal activity against wood fungi. These include aminopolysaccharide derivatives and different quaternary ammonium polymers. A biological study carried out with these products indicated a possible relationship between amino groups and differences in biological activity observed. RESULTS: In this study, an amino group was successively fixed to different carbon atoms of glucose, and glucosamine was also modified by both N alkylation and quaternisation. The impact of the amino group position on antifungal activity against two wood decay fungi was investigated. The amino group at the anomeric position showed the highest antifungal activity against both Coriolus versicolor Quel. and Poria placenta (Fr.) Cooke. Furthermore, the positive impact of both N-alkylation and quaternisation on the growth of both strains was demonstrated. CONCLUSION: The anomeric position of the amino group and the N-alkylation and quaternisation of amino sugars considerably increase the antifungal activity of these compounds. PMID- 21308955 TI - Effect of pesticide fate parameters and their uncertainty on the selection of 'worst-case' scenarios of pesticide leaching to groundwater. AB - BACKGROUND: For the registration of pesticides in the European Union, model simulations for worst-case scenarios are used to demonstrate that leaching concentrations to groundwater do not exceed a critical threshold. A worst-case scenario is a combination of soil and climate properties for which predicted leaching concentrations are higher than a certain percentile of the spatial concentration distribution within a region. The derivation of scenarios is complicated by uncertainty about soil and pesticide fate parameters. As the ranking of climate and soil property combinations according to predicted leaching concentrations is different for different pesticides, the worst-case scenario for one pesticide may misrepresent the worst case for another pesticide, which leads to 'scenario uncertainty'. RESULTS: Pesticide fate parameter uncertainty led to higher concentrations in the higher percentiles of spatial concentration distributions, especially for distributions in smaller and more homogeneous regions. The effect of pesticide fate parameter uncertainty on the spatial concentration distribution was small when compared with the uncertainty of local concentration predictions and with the scenario uncertainty. CONCLUSION: Uncertainty in pesticide fate parameters and scenario uncertainty can be accounted for using higher percentiles of spatial concentration distributions and considering a range of pesticides for the scenario selection. PMID- 21308956 TI - Genetic identity of the Bemisia tabaci species complex and association with high cotton leaf curl disease (CLCuD) incidence in Pakistan. AB - BACKGROUND: The cotton whitefly, Bemisia tabaci (Gennadius), is a cryptic species complex, and members of the complex have become serious pests in Pakistan because of their feeding and their ability to transmit cotton leaf curl virus (CLCuV). Here, an analysis was made of the identity of B. tabaci collected from cotton and a range of non-cotton hosts in the cotton-growing zones in Punjab and Sindh, the main cotton-producing provinces of Pakistan, using a portion of the mitochondrial cytochrome oxidase 1 gene. The geographic distribution of the different members of the complex was then compared with the incidence of CLCuD. RESULTS: Using the Dinsdale nomenclature, the results revealed three putative species, Asia 1, Asia II 1 and Middle East-Asia Minor 1. Asia II 1 (also referred to in the literature as biotypes K, P, PCG-1, PK1, SY and ZHJ2) was only recorded from Punjab cotton plants, whereas Asia 1 (also referred to in the literature as biotypes H, M, NA and PCG-2) was found in both Sindh and Punjab. Middle East-Asia Minor 1 (commonly known as biotype B and B2) was found only in Sindh. Moreover, Asia II 1 was associated with high incidences of CLCuD, whereas regions where Middle East-Asia Minor 1 was present had a lower incidence. Phylogenetic analysis showed that the Middle East-Asia Minor 1 population in Sindh formed a distinct genetic subgroup within the putative species, suggesting that the Sindh province of Pakistan may form part of its home range. So far, no individuals from the putative species Mediterranean (commonly known as biotypes Q, J and L) have been found in Pakistan. CONCLUSIONS: The capacity to manage pests and disease effectively relies on knowledge of the identity of the agents causing the damage. In the case of CLCuD in Pakistan, this knowledge has been obscured to some extent because of the inconsistent approach to identifying and distinguishing the different B. tabaci associated with CLCuD. The situation has now been clarified, and a strong association between disease incidence and vector identity and abundance has been shown. Given this advance, future research can now focus on factors that influence the capacity of different vector species to transmit the viruses that cause CLCuD, the reason for differences in vector abundance and the lack of geographic overlap between the cryptic vector species. This knowledge will contribute to the development of improved methods with which to manage the disease in Pakistan. PMID- 21308957 TI - Efficacy of non-toxic surfaces to reduce bioadhesion in terrestrial gastropods. AB - BACKGROUND: Invasive species are described as the greatest threat to biodiversity, after habitat destruction and climate change, potentially imposing economic impacts and indigenous species impairment. Commonly applied chemical controls present the potential for legacy contamination and non-target organism injury. This study investigated the effects of different substrates and novel topographical surfaces on the behavioral and mechanical associations of the terrestrial gastropod Otala lactea. RESULTS: The gastropod preferentially aestivated on rough glass (61% increase, P < 0.01) relative to smooth glass but avoided a cross-patterned surface tessellation on silicone (82% reduction, P < 0.01) relative to smooth silicone. Significant deviations in turning behavior were found on the cross-patterned topographical surface and hydrophobic Teflon surfaces. The strongest correlation with gastropod adhesion strength to surfaces was found for surface elastic modulus (R = 0.88, P = 0.03), followed by hydrophobicity (R = - 0.71, P = 0.14), but no relationship with roughness (P = 0.36). CONCLUSION: Preliminary data suggest surface roughness controlled aestivation behavior while elastic modulus (surface flexibility) controlled adhesion strength. In spite of greater adhesion to high-modulus materials, surface modulus was not a statistically significant controlling factor on gastropod aestivation preference. Understanding and exploiting the behavioral and mechanistic cues that organisms use while attaching to surfaces may lead to more environmentally benign control approaches. PMID- 21308958 TI - Biological characterization of sulfoxaflor, a novel insecticide. AB - BACKGROUND: The commercialization of new insecticides is important for ensuring that multiple effective product choices are available. In particular, new insecticides that exhibit high potency and lack insecticidal cross-resistance are particularly useful in insecticide resistance management (IRM) programs. Sulfoxaflor possesses these characteristics and is the first compound under development from the novel sulfoxamine class of insecticides. RESULTS: In the laboratory, sulfoxaflor demonstrated high levels of insecticidal potency against a broad range of sap-feeding insect species. The potency of sulfoxaflor was comparable with that of commercial products, including neonicotinoids, for the control of a wide range of aphids, whiteflies (Homoptera) and true bugs (Heteroptera). Sulfoxaflor performed equally well in the laboratory against both insecticide-susceptible and insecticide-resistant populations of sweetpotato whitefly, Bemisia tabaci Gennadius, and brown planthopper, Nilaparvata lugens (Stal), including populations resistant to the neonicotinoid insecticide imidacloprid. These laboratory efficacy trends were confirmed in field trials from multiple geographies and crops, and in populations of insects with histories of repeated exposure to insecticides. In particular, a sulfoxaflor use rate of 25 g ha(-1) against cotton aphid (Aphis gossypii Glover) outperformed acetamiprid (25 g ha(-1) ) and dicrotophos (560 g ha(-1) ). Sulfoxaflor (50 g ha(-1) ) provided a control of sweetpotato whitefly equivalent to that of acetamiprid (75 g ha(-1) ) and imidacloprid (50 g ha(-1) ) and better than that of thiamethoxam (50 g ha(-1) ). CONCLUSION: The novel chemistry of sulfoxaflor, its unique biological spectrum of activity and its lack of cross-resistance highlight the potential of sulfoxaflor as an important new tool for the control of sap-feeding insect pests. PMID- 21308959 TI - Characterisation of spinosad resistance in the housefly Musca domestica (Diptera: Muscidae). AB - BACKGROUND: Spinosad, a relatively new, effective and safe pesticide, has been widely used in pest control over the last 10 years. However, different levels of resistance to this insecticide have developed in some insects worldwide. RESULTS: After continuous selection for 27 generations, a strain (SpRR) of the housefly developed 247-fold resistance to spinosad compared with the laboratory susceptible strain (CSS). The estimated realised heritability (h(2) ) of spinosad resistance was 0.14. There was no significant difference in the LD(50) values and slopes between reciprocal progenies F(1) and F(1) ', and values of 0.33 (F(1) ) and 0.30 (F(1) ') were obtained for the degree of dominance. Chi-square analysis from responses of self-bred (F(2) ) and backcrosses (BC(1) and BC(2) ) were highly significant, suggesting that the resistance was probably controlled by more than one gene. Synergists piperonyl butoxide (PBO), diethyl maleate (DEM) and S,S,S-tributyl phosphorotrithioate (DEF) affected the toxicity of spinosad at a low level, and demonstrated that metabolic-mediated detoxification was not an important factor in conferring resistance to spinosad in the SpRR strain. CONCLUSION: It was concluded that spinosad resistance in the housefly was autosomal and incompletely dominant, and the resistance was probably controlled by more than one gene. These results provide the basic information for designing successful management programmes for the control of houseflies. PMID- 21308960 TI - Synergistic and antagonistic interactions of terpenes against Meloidogyne incognita and the nematicidal activity of essential oils from seven plants indigenous to Greece. AB - BACKGROUND: Biorational means for phytonematode control were studied within the context of an increasingly ecofriendly pest management global approach. The nematicidal activity and the chemical composition of essential oils (EOs) isolated from seven plants grown in Greece and ten selected compounds extracted from them against second-stage juveniles (J2) of Meloidogyne incognita (Kof. & White) Chitwood were evaluated using juvenile paralysis experiments. Additionally, synergistic and antagonistic interactions between nematicidal terpenes were studied using an effect addition model, with the comparison made at one concentration level. RESULTS: The 96 h EC(50) values of Foeniculum vulgare Mill., Pimpinella anisum L., Eucalyptus meliodora A Cunn ex Schauer and Pistacia terebinthus L. were 231, 269, 807 and 1116 ug mL(-1) , respectively, in an immersion bioassay. Benzaldehyde (9 ug mL(-1) ) was the most toxic compound, followed by gamma-eudesmol (50 ug mL(-1) ) and estragole (180 ug mL(-1) ), based on 96 h EC(50) values. The most potent terpene pairs between which synergistic actions were found, in decreasing order, were: trans-anethole/geraniol, trans anethole/eugenol, carvacrol/eugenol and geraniol/carvacrol. CONCLUSION: This is the first report on the activity of F. vulgare, P. anisum, E. meliodora and P. terebinthus, and additionally on synergistic/antagonistic nematicidal terpene interactions, against M. incognita, providing alternative methods for nematode control. PMID- 21308961 TI - Toxicity of thiamethoxam to Tetranychus urticae Koch and Phytoseiulus persimilis Athias-Henriot (Acari Tetranychidae, Phytoseiidae) through different routes of exposure. AB - BACKGROUND: Knowledge of the impact of insecticides on Tetranychus urticae Koch and its predator Phytoseiulus persimilis Athias-Henriot is crucial for IPM. This study evaluates the effect of thiamethoxam on T. urticae and its predator by considering different routes of exposure (topical, residual and contaminated food exposures) and their combinations. RESULTS: Thiamethoxam effects on T. urticae were higher when residual and contaminated food exposures were considered. The total effect was higher than 90% where contaminated food exposure was involved. On P. persimilis, the total effect was higher in residual and contaminated prey exposures compared with topical exposure, and all combinations of routes of exposure attained a total effect higher than 90%. CONCLUSION: Thiamethoxam was found to be toxic to T. urticae and P. persimilis; however, the impact of the insecticide depended on the routes of exposure and their combinations. Lethal and sublethal effects occurred in residual and contaminated food exposures, while only sublethal effects occurred in topical exposure of predators and prey. The toxicity of thiamethoxam on prey and predator increased with the number of exposure routes involved. By limiting exposure to thiamethoxam to ingestion of contaminated food only, the impact of the pesticide was more favourable to P. persimilis than to its prey. PMID- 21308962 TI - Contradictions in host plant resistance to pests: spider mite (Tetranychus urticae Koch) behaviour undermines the potential resistance of smooth-leaved cotton (Gossypium hirsutum L.). AB - BACKGROUND: Two-spotted spider mites (Tetranychus urticae Koch) oviposit near leaf veins or in leaf folds on the undersides of cotton (Gossypium hirsutum L.) leaves where the humid boundary layer offers protection from desiccation. The authors predicted that the boundary layer of glabrous cotton leaves should be shallower than that of hairy leaves, providing some resistance to mites. The dynamics of mite populations, leaf damage, leaf gas exchange and crop yield on two leaf hair isolines (smooth versus hairy) in two genetic backgrounds was assessed. RESULTS: Mite colonies developed faster on the hairy leaf isolines, but leaf damage per mite was higher in smooth leaf isolines, indicating more intense damage. A 50% reduction in photosynthesis on the hairy isolines required 1.8 times more mites than smooth leaves. The yield of cotton was reduced in + mite treatments, but the magnitude of reduction was similar for hairy and smooth isolines. CONCLUSION: Paradoxically, the relative inhospitality of glabrous leaves may have induced mites to concentrate in protected leaf sections, causing more localised and more severe damage, negating the yield benefits from fewer mites. These results highlight interactions between leaf microenvironment, pest behaviour and plant productivity that may have implications for other instances of plant resistance. PMID- 21308963 TI - Insecticide resistance of the oriental fruit fly, Bactrocera dorsalis (Hendel) (Diptera: Tephritidae), in mainland China. AB - BACKGROUND: In order to investigate the extent of resistance of oriental fruit fly, Bactrocera dorsalis (Hendel), which is a widespread pest throughout tropical, subtropical and temperate fruit crops, 25 populations of this insect were collected from 13 sites in mainland China in 2007 and 2008. In addition, resistant strains were established that showed increasing development of resistance. RESULTS: Compared with the susceptible strain, one population of B. dorsalis expressed high resistance (RR = 70.4-fold), 16 populations expressed medium resistance (11.5-fold < RR < 25.8-fold) and eight populations had low resistance or remained susceptible (1.4-fold < RR < 8.9-fold) to trichlorphon. As regards beta-cypermethrin, one population showed high resistance (RR = 44.0 fold), nine populations expressed medium resistance (12.2-fold < RR < 28.4-fold), 14 populations expressed low or minor resistance (3.0-fold < RR < 9.7-fold) and one population remained susceptible (RR = 1.1-fold). As regards avermectin, five populations had developed high resistance (44.3-fold < RR < 104-fold), seven populations expressed medium resistance (11.4-fold < RR < 38.6-fold) and three populations expressed low or minor resistance (3.5-fold < RR < 5.6-fold). A continuous resistance selection in the laboratory strain showed that the resistance ratios to trichlorphon, beta-cypermethrin and avermectin were 71.6 fold, 333-fold and 70.4-fold respectively. CONCLUSION: The data provided a comprehensive survey of insecticide resistance in Bactrocera dorsalis in mainland China. All results suggested that early resistance management programmes should be established for restoring the efficacy of pesticide-based control measures. PMID- 21308964 TI - Corn poppy (Papaver rhoeas) cross-resistance to ALS-inhibiting herbicides. AB - BACKGROUND: Papaver rhoeas (L.) has evolved resistance to tribenuron in winter wheat fields in northern Greece owing to multiple Pro(197) substitutions. Therefore, the cross-resistance pattern to other sulfonylurea and non sulfonylurea ALS-inhibiting herbicides of the tribenuron resistant (R) and susceptible (S) corn poppy populations was studied by using whole-plant trials and in vitro ALS catalytic activity assays. RESULTS: The whole-plant trials revealed that tribenuron R populations were also cross-resistant to sulfonylureas mesosulfuron + iodosulfuron, chlorsulfuron and triasulfuron. The whole-plant resistance factors (RFs) calculated for pyrithiobac, imazamox and florasulam ranged from 12.4 to > 88, from 1.5 to 28.3 and from 5.6 to 25.4, respectively, and were lower than the respective tribenuron RF values (137 to > 2400). The ALS activity assay showed higher resistance of the ALS enzyme to sulfonylurea herbicides (tribenuron > chlorsulfuron) and lower resistance to non-sulfonylurea ALS-inhibiting herbicides (pyrithiobac > florasulam ~ imazamox). CONCLUSION: These findings indicate that Pro(197) substitution by Ala, Ser, Arg or Thr in corn poppy results in a less sensitive ALS enzyme to sulfonylurea herbicides than to other ALS-inhibiting herbicides. The continued use of sulfonylurea herbicides led to cross-resistance to all ALS-inhibiting herbicides, making their use impossible in corn poppy resistance management programmes. PMID- 21308965 TI - Insecticidal and repellent activities of insecticide-sucrose solutions to Culex pipiens molestus (Diptera: Culicidae) under laboratory and field conditions. AB - BACKGROUND: Culex pipiens molestus Forskal has been reported as a dominant species in underground structures of urban areas in the Republic of Korea (ROK) during all seasons and becomes bothersome to humans in late autumn and winter. Most Cx. pipiens molestus in septic tanks are controlled in the ROK using larvicides such as Bt and IGR. However, there are a number of problems associated with larvicides, such as high cost and requirement for frequent use. In the present work, a new control method for Cx. pipiens molestus in septic tanks by using mixtures of sucrose solution with insecticides was investigated. RESULTS: The insecticidal and repellent activities of ten insecticides were evaluated for best control of Cx. pipiens molestus in septic tanks. Firstly, differences in susceptibilities to insecticides were evaluated in topical assays by forced direct contact bioassay and in a screened wire cage by free direct contact bioassay. The difference in insecticide susceptibility in the mosquitoes was the result of repellency by the insecticides. In three septic tanks, the density of Culex mosquitoes was sharply reduced by a deltamethrin-sucrose solution kit. CONCLUSIONS: The results demonstrated the potential for mosquito control by deltamethrin-sucrose solution, and the study offers basic information related to mosquito control in septic tanks. PMID- 21308966 TI - Field evaluation of synthetic sex pheromone traps for the cocoa mirid Sahlbergella singularis (Hemiptera: Miridae). AB - BACKGROUND: Field trapping experiments were conducted to evaluate the attractiveness of five different pheromone blends as well as the impact of trap design on attractiveness towards cocoa mirids, Sahlbergella singularis Hagl. and Distantiella theobroma (Dist.), in Cameroon. RESULTS: A total of 361 adults of S. singularis (359 males and two females) were caught. The highest numbers of mirids were found in traps with pheromone blends that combined a monoester and a diester, compared with traps with the diester or the monoester individually and control traps with no pheromone. Rectangular traps caught significantly more mirids compared with delta traps. The mean number of 5.1 mirids trap-1 year-1 caught in rectangular traps was significantly higher compared with the 1.8 mirids trap-1 year-1 for the delta traps. CONCLUSION: The data revealed that rectangular traps containing pheromone blends combining both the monoester and the diester have a good potential to lure and trap adult males of S. singularis on cocoa farms. The pheromone blends used were specific for S. singularis, and the use of pheromone traps appears to be a promising strategy for incorporation into integrated pest management strategies for the monitoring or even the control of S. singularis in cocoa plantations. PMID- 21308969 TI - Nanostructure control in polymer solar cells by self-organization. AB - Recently, polymer solar cells (PSCs) based on "bulk heterojunctions" using a simple mixture of electron donor and acceptor materials in thin films have been extensively studied. Although relatively high power conversion efficiencies have been achieved by using this approach, further improvement is necessary to precisely construct stable, reproducible nanostructures that are suitable for both efficient charge separation and transport inside such films. For this purpose, it is highly desirable to utilize a bottom-up approach, such as the self organized formation of inorganic and organic nanostructures. In this review, an overview of our recent studies on the control of nanostructures in PSCs is presented. PMID- 21308970 TI - Enantioselective epoxidation of electron-deficient olefins: an organocatalytic approach. AB - Versatile synthetic intermediates--alpha,beta-epoxyketones and alpha,beta epoxyaldehydes--can be obtained through asymmetric organocatalytic epoxidation of alpha,beta-unsaturated ketones and aldehydes. This Review focuses on some recent advances in these epoxidation reactions with respect to scope and limitations with polyamino acids, phase-transfer catalysts (PTCs), amines, and guanidines as chiral organocatalysts. Furthermore, recent results obtained with chiral peroxides are discussed. PMID- 21308972 TI - The longest quinoidal oligothiophene: a Raman story. AB - The main research on the family of aromatic and quinoidal oligothiophenes is described, with a focus on their longest members. We have described how the comprehensive understanding of the vibrational Raman spectra of oligothiophenes in a variety of situations permitted the elucidation of properties of fundamental importance, not only for basic research in molecular physics and in physical chemistry, but also for applications. We have written the Raman story that brought us to the elucidation of the biradicaloid nature of the longest quinoidal oligothiophene. PMID- 21308973 TI - Fabrication of the smallest organic nanocolloids by a top-down method based on laser ablation. AB - Stable aqueous colloids of 10-nm sized organic nanoparticles were tailored by laser ablation of microcrystalline quinacridone in water. The nanocolloids were flaky in shape and had the dimension of a width of 13 (+/-5) nm and a height of 1.4 (+/-0.5) nm. The formation mechanism is discussed in terms of laser-induced fragmentation of organic solids and the potential application of aqueous organic nanocolloids free from any additives and chemicals is considered. PMID- 21308974 TI - Additional results for 'Sequential design approaches for bioequivalence studies with crossover designs'. AB - In 2008, this group published a paper on approaches for two-stage crossover bioequivalence (BE) studies that allowed for the reestimation of the second-stage sample size based on the variance estimated from the first-stage results. The sequential methods considered used an assumed GMR of 0.95 as part of the method for determining power and sample size. This note adds results for an assumed GMR = 0.90. Two of the methods recommended for GMR = 0.95 in the earlier paper have some unacceptable increases in Type I error rate when the GMR is changed to 0.90. If a sponsor wants to assume 0.90 for the GMR, Method D is recommended. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 21308975 TI - Assessing the trend of gastroschisis prevalence in China from 1996 to 2007 using two analytical methods. AB - BACKGROUND: In recent years, the prevalence of gastroschisis has increased remarkably in some areas and remained unchanged in other areas; however, in general, there is a recent increasing trend compared to the 1970s and 1980s. In this study, we explored the time trend of gastroschisis prevalence in China during 1996 to 2007. METHODS: Data were retrieved from the hospital-based national monitoring database maintained by the Chinese Birth Defects Monitoring Network (CBDMN). The monitored subjects were infants born on the 28th gestational week or later, including live births and stillbirths. The maximal time for the diagnosis of a congenital malformation was the seventh day after birth. The secular trends on the overall prevalence and the different feature-specific prevalence of gastroschisis in China were analyzed using the linear chi-square test and the Poisson regression model. RESULTS: The overall prevalence of gastroschisis in China was 2.54 per 10,000 births during 1996 to 2007. Except for the prevalence of gastroschisis that significantly increased among infants whose mothers were 20 to 24 years old (p=0.0498 for the linear chi-square test, p=0.0032 for the Poisson regression model analysis) and significantly decreased among infants whose mothers were 30 to 34 years old (p=0.0177 for the Poisson regression model analysis), no significant changes were found in the overall and remaining feature-specific prevalences. CONCLUSION: The overall prevalence of gastroschisis in China did not change remarkably during 1996 to 2007; but the prevalence of gastroschisis significantly increased among infants whose mothers were 20 to 24 years old and decreased among infants whose mothers were 30 to 34 years old. PMID- 21308976 TI - Agrin function associated with ocular development is a target of ethanol exposure in embryonic zebrafish. AB - BACKGROUND: Alcohol (ethanol) is a teratogen known to affect the developing eyes, face, and brain. Among the ocular defects in fetal alcohol spectrum disorder (FASD) are microphthalmia and optic nerve hypoplasia. Employing zebrafish as an FASD model provides an excellent system to analyze the molecular basis of prenatal ethanol exposure-induced defects because embryos can be exposed to ethanol at defined developmental stages and affected genetic pathways can be examined. We have previously shown that disruption of agrin function in zebrafish embryos produces microphthalmia and optic nerve hypoplasia. METHODS: Zebrafish embryos were exposed to varying concentrations of ethanol in the absence or presence of morpholino oligonucleotides (MOs) that disrupt agrin function. In situ hybridization was used to analyze ocular gene expression as a consequence of ethanol exposure and agrin knockdown. Morphologic analysis of zebrafish embryos was also conducted. RESULTS: Acute ethanol exposure induces diminished agrin gene expression in zebrafish eyes and, importantly, combined treatment with subthreshold levels of agrin MO and ethanol produces pronounced microphthalmia, markedly reduces agrin gene expression, and perturbs Pax6a and Mbx gene expression. Microphthalmia produced by combined agrin MO and ethanol treatment was rescued by sonic hedgehog (Shh) mRNA overexpression, suggesting that ethanol mediated disruption of agrin expression results in disrupted Shh function. CONCLUSIONS: These studies illustrate the strong potential for using zebrafish as a model to aid in defining the molecular basis for ethanol's teratogenic effects. The results of this work suggest that agrin expression and function may be a target of ethanol exposure during embryogenesis. PMID- 21308977 TI - VACTERL association and mitochondrial dysfunction. AB - BACKGROUND: VACTERL association includes the presence of malformations affecting the vertebrae, anus, heart, trachea and esophagus, kidneys, and limbs. The causes remain largely unknown, but rare patients with mitochondrial dysfunction have been reported. Although clinical signs and symptoms consistent with possible mitochondrial disease are not uncommon in patients with VACTERL association, the necessary testing to confirm mitochondrial dysfunction is infrequently performed. METHODS: We describe a patient with relatively classic signs of VACTERL association who had an onset of clinical signs of mitochondrial dysfunction at 13 months of age. These signs included progressive muscle weakness, autonomic dysregulation, episodic hypoglycemia, and exocrine pancreatic dysfunction. The patient was later shown to have evidence of mitochondrial dysfunction (cytochrome c oxidase deficiency). CONCLUSIONS: Abnormal mitochondrial function may be associated with VACTERL association, and clinicians who encounter patients with VACTERL association should have a low threshold for considering mitochondrial dysfunction. PMID- 21308978 TI - Racial differences in gene-specific DNA methylation levels are present at birth. AB - BACKGROUND: DNA methylation patterns differ among children and adults and play an unambiguous role in several disease processes, particularly cancers. The origin of these differences is inadequately understood, and this is a question of specific relevance to childhood and adult cancer. METHODS: DNA methylation levels at 26,485 autosomal CpGs were assayed in 201 newborns (107 African American and 94 Caucasian). Nonparametric analyses were performed to examine the relation between these methylation levels and maternal parity, maternal age, newborn gestational age, newborn gender, and newborn race. To identify the possible influences of confounding, stratification was performed by a second and third variable. For genes containing CpGs with significant differences in DNA methylation levels between races, analyses were performed to identify highly represented gene ontological terms and functional pathways. RESULTS: 13.7% (3623) of the autosomal CpGs exhibited significantly different levels of DNA methylation between African Americans and Caucasians; 2% of autosomal CpGs had significantly different DNA methylation levels between male and female newborns. Cancer pathways, including four (pancreatic, prostate, bladder, and melanoma) with substantial differences in incidence between the races, were highly represented among the genes containing significant race-divergent CpGs. CONCLUSIONS: At birth, there are significantly different DNA methylation levels between African Americans and Caucasians at a subset of CpG dinucleotides. It is possible that some of the epigenetic precursors to cancer exist at birth and that these differences partially explain the different incidence rates of specific cancers between the races. PMID- 21308979 TI - Polymorphisms in CHDH gene and the risk of tooth agenesis. AB - BACKGROUND: Tooth agenesis is one of the most common anomalies of human dentition and is due to a complex and not fully elucidated etiology. The purpose of this study was to evaluate the possibility that polymorphic variants of genes encoding the main folate and choline metabolism enzymes might be associated with the risk of hypodontia in the Polish population. METHODS AND RESULTS: We analyzed 21 polymorphisms of 13 candidate genes and found that single nucleotide polymorphisms (SNPs) in the CHDH gene are significantly correlated with the risk of dental agenesis. The strongest association was found for the SNP located in the intronic sequence of CHDH. Individuals carrying one copy of the rs6445606 C allele had an over two-fold decreased risk of having hypodontia (odds ratio [OR]CTvsTT=0.434; 95% confidence interval [CI], 0.2724-0.6915; p=0.0004; pcorr=0.0084). A reduced risk of tooth agenesis was also observed in individuals with one or two copies of the rs6445606 C allele compared to T allele carriers (ORCT+CCvsTT=0.524; 95% CI, 0.3386-0.8097; p=0.0035; pcorr=0.0735). Moreover, the gene-gene interaction analysis revealed a significant epistatic interaction between CHDH (rs6445606) and PLD2 (rs3764897) in the susceptibility to hypodontia (p=0.004). CONCLUSION: Our study identified CHDH and PLD2 as novel candidate genes, the nucleotide variants of which could be associated with the risk of tooth agenesis. PMID- 21308981 TI - Roles of genipin crosslinking and biomolecule conditioning in collagen-based biopolymer: Potential for vascular media regeneration. AB - The vascular media, a layer of the blood vessel wall containing smooth muscle cells (SMCs), are often the target functional tissue in the construction of artificial vessel. It contributes to mechanical properties and biological functions of vessels. The present study aimed to study effects of crosslinking and biomolecule conditions in the development of mechanically strong and stable, biologically functional constructs with potential for vascular media regeneration. Genipin was used to crosslink collagen-chitosan-elastin (CCE) constructs. Results revealed that mechanical strength, stiffness, and stability of CCE constructs significantly increased with genipin concentration, but crosslinking significantly inhibited SMC contraction of and invasion in gel constructs. No contraction or invasion was observed in those crosslinked with genipin at 5 mM or above. attenuated total reflectance Fourier transform infrared results showed crosslinking changed functional groups on CCE depending on genipin concentration. To enhance biological activities on crosslinked constructs, soluble molecule factors were incorporated, and their effects on SMC activities were evaluated. These conditions include heparin, platelet-derived transforming growth factor (PDGF), high-concentrated fetal bovine serum (h-FBS), a mixture of heparin and PDGF, and a mixture of h-FBS and PDGF. The h-FBS and PDGF mixture was found to stimulate a 3.2-fold increase in SMC contraction of the crosslinked gels. It was also found that PDGF and h-FBS, separately and in combination, induced SMC invasion in the crosslinked gels, while heparin attenuated PDGF induced SMC invasion. Our study suggests that designing high-performance acellular constructs to encourage tissue regeneration should use a combination of crosslinking condition and biomolecule factor, striking a balance between mechanical properties and biological functions. PMID- 21308980 TI - A semi-degradable composite scaffold for articular cartilage defects. AB - Few options exist to replace or repair damaged articular cartilage. The optimal solution that has been suggested is a scaffold that can carry load and integrate with surrounding tissues; but such a construct has thus far been elusive. The objectives of this study were to manufacture and characterize a nondegradable hydrated scaffold. Our hypothesis was that the polymer content of the scaffold can be used to control its mechanical properties, while an internal porous network augmented with biological agents can facilitate integration with the host tissue. Using a two-step water-in-oil emulsion process a porous polyvinyl alcohol (PVA) hydrogel scaffold combined with alginate microspheres was manufactured. The scaffold had a porosity of 11-30% with pore diameters of 107-187 MUm, which readily allowed for movement of cells through the scaffold. Alginate microparticles were evenly distributed through the scaffold and allowed for the slow release of biological factors. The elastic modulus (Es ) and Poisson's ratio (upsilon), Aggregate modulus (Ha ) and dynamic modulus (ED ) of the scaffold were significantly affected by % PVA, as it varied from 10 to 20% wt/vol. Es and upsilon were similar to that of articular cartilage for both polymer concentrations, while Ha and ED were similar to that of cartilage only at 20% PVA. The ability to control scaffold mechanical properties, while facilitating cellular migration suggest that this scaffold is a potentially viable candidate for the functional replacement of cartilage defects. PMID- 21308982 TI - The influence of surface energy of titanium-zirconium alloy on osteoblast cell functions in vitro. AB - The success of an implant used for bone regeneration and repair is determined by the events that take place at the cell-material interface. An understanding of these interactions in vitro gives insights into the formulation of ideal conditions for their effective functioning in vivo. Thus, it is not only important to understand the physico-chemical properties of the materials but, also necessary to assess the cellular responses to them to determine their long term stability and efficacy as implants. In the present study, we have compared the physico-chemical and biological properties of titanium (Ti) and two Ti-based alloys, namely: Ti- Zirconium (TiZr) and Ti-Niobium (TiNb). The morphology, chemical analysis, surface roughness, and contact angle measurements of the alloys were assessed by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), profilometer, and contact angle goniometer, respectively whereas the biological properties of the materials were evaluated by measuring the adhesion, proliferation, and differentiation of MC3T3-E1 osteoblast cells on the surfaces of these alloys. Our results indicate that the biological properties of osteoblasts were better on TiZr surface than on TiNb surface. Furthermore, the surface energy and substrate composition influenced the superior biological activity of the TiZr alloy. PMID- 21308983 TI - Structure and properties of biomedical films prepared from aqueous and acidic silk fibroin solutions. AB - Silk fibroin films are promising materials for a range of biomedical applications. To understand the effects of casting solvents on film properties, we used water (W), formic acid (FA), and trifluoroacetic acid (TFA) as solvents. We characterized molecular weight, secondary structure, mechanical properties, and degradation behavior of cast films. Significant degradation of fibroin was observed for TFA-based film compared to W and TA-based films when analyzed by SDS PAGE. Fibroin degradation resulted in a significant reduction in tensile strength and modulus of TFA-based films. Compared to water, TFA-based films demonstrated lower water solubility (19.6% vs. 62.5% in 12 h) despite having only a marginal increase in their beta-sheet content (26.9% vs. 23.7%). On the other hand, FA based films with 34.3% beta-sheet were virtually water insoluble. Following solubility treatment, beta-sheet content in FA-based films increased to 50.9%. On exposure to protease XIV, water-annealed FA-based films lost 74% mass in 22 days compared to only 30% mass loss by ethanol annealed FA films. This study demonstrated that a small variation in the beta-sheet percentage and random coil conformations resulted in a significant change in the rates of enzymatic degradation without alteration to their tensile properties. The film surface roughness changed with the extent of enzymatic hydrolysis. PMID- 21308984 TI - Probing orientation of immobilized humanized anti-lysozyme variable fragment by time-of-flight secondary-ion mass spectrometry. AB - As methods to orient proteins are conceived, techniques must also be developed that provide an accurate characterization of immobilized protein orientation. In this study, X-ray photoelectron spectroscopy (XPS), surface plasmon resonance (SPR), and time-of-flight secondary ion mass spectrometry (ToF-SIMS) were used to probe the orientation of a surface immobilized variant of the humanized anti lysozyme variable fragment (HuLys Fv, 26 kDa). This protein contained both a hexahistidine tag and a cysteine residue, introduced at opposite ends of the HuLys Fv, for immobilization onto nitrilotriacetic acid (NTA) and maleimide oligo(ethylene glycol) (MEG)-terminated substrates, respectively. The thiol group on the cysteine residue selectively binds to the MEG groups, while the his-tag selectively binds to the Ni-loaded NTA groups. XPS was used to monitor protein coverage on both surfaces by following the change in the nitrogen atomic %. SPR results showed a 10-fold difference in lysozyme binding between the two different HuLys Fv orientations. The ToF-SIMS data provided a clear differentiation between the two samples due to the intensity differences of secondary ions originating from asymmetrically located amino acids in HuLys Fv (histidine: 81, 82, and 110 m/z; phenylalanine: 120 and 131 m/z). An intensity ratio of the secondary ion peaks from the histidine and phenylalanine residues at either end of the protein was then calculated directly from the ToF-SIMS data. The 45% change in this ratio, observed between the NTA and MEG substrates with similar HuLys Fv surface coverages, indicates that the HuLys Fv fragment has opposite orientations on two different surfaces. PMID- 21308985 TI - Controlled curing of adhesive complex coacervates with reversible periodate carbohydrate complexes. AB - Periodate oxidation of carbohydrates with vicinal hydroxyl groups and aromatic ortho-dihydroxyphenyl groups has been employed extensively to initiate crosslinking or conjugation reactions in adhesive biomaterials. Periodate forms stable tridentate complexes with carbohydrates containing three appropriately configured hydroxyls, such as 1,2-O-isopropylidene-a-D-glucofuranose, that are not appreciably oxidized relative to carbohydrates with vicinal hydroxyls and ortho-dihydroxyphenyl groups. In the presence of 1,2-O-Isopropylidene-a-D glucofuranose the rate of periodate oxidation of dihydroxy containing compounds is controlled by the rates of association and dissociation of the periodate carbohydrate complex. By varying the ratio of 1,2-O-isopropylidene-a-D glucofuranose to periodate the curing rate of adhesive complex coacervates was varied over a wide range. PMID- 21308986 TI - An in vitro study of blood compatibility of vascular grafts made of bacterial cellulose in comparison with conventionally-used graft materials. AB - In this study we analyzed the blood compatibility of bacterial cellulose (BC) as a new biosynthetic material for use as a vascular graft. As reference materials we used expanded polytetrafluoroethylene (ePTFE) and poly(ethylene terephthalate) (PET) vascular grafts. These materials are in clinical use today. Tubes with inner diameters of both 4 (not PET) and 6 mm were tested. Heparin-coated PVC tubes (hepPVC) were used as a negative control. Platelet consumption and thrombin antithrombin complex (TAT) were used as parameters of coagulation and for complement activation, sC3a and sC5b-9 were used. The investigated parameters were measured after 1-h exposure to freshly drawn human blood supplemented with a low dose of heparin in a Chandler loop system. The results showed that BC exhibits no significant difference in platelet consumption, as compared with PET (6 mm), ePTFE and hepPVC. The PET material consumed more platelets than any of the other materials. The TAT generation for 4 mm tubes was not significantly different between BC and the other materials. For 6 mm tubes, however, differences were observed between hepPVC and PET (p < 0.0001); BC and hepPVC (p = 0.0016); ePTFE and PET (p < 0.0001); BC and ePTFE (p = 0.0029); BC and PET (p = 0.0141). Surprisingly, considering the low platelet consumption, the complement activation parameters (sC3a and sC5b-9) were much higher for BC, as compared with the other materials for both 4 and 6 mm tubes. PMID- 21308987 TI - Lysinuric protein intolerance: reviewing concepts on a multisystem disease. AB - Lysinuric protein intolerance (LPI) is an inherited aminoaciduria caused by defective cationic amino acid transport at the basolateral membrane of epithelial cells in intestine and kidney. LPI is caused by mutations in the SLC7A7 gene, which encodes the y(+)LAT-1 protein, the catalytic light chain subunit of a complex belonging to the heterodimeric amino acid transporter family. LPI was initially described in Finland, but has worldwide distribution. Typically, symptoms begin after weaning with refusal of feeding, vomiting, and consequent failure to thrive. Hepatosplenomegaly, hematological anomalies, neurological involvement, including hyperammonemic coma are recurrent clinical features. Two major complications, pulmonary alveolar proteinosis and renal disease are increasingly observed in LPI patients. There is extreme variability in the clinical presentation even within individual families, frequently leading to misdiagnosis or delayed diagnosis. This condition is diagnosed by urine amino acids, showing markedly elevated excretion of lysine and other dibasic amino acids despite low plasma levels of lysine, ornithine, and arginine. The biochemical diagnosis can be uncertain, requiring confirmation by DNA testing. So far, approximately 50 different mutations have been identified in the SLC7A7 gene in a group of 142 patients from 110 independent families. No genotype-phenotype correlation could be established. Therapy requires a low protein diet, low-dose citrulline supplementation, nitrogen-scavenging compounds to prevent hyperammonemia, lysine, and carnitine supplements. Supportive therapy is available for most complications with bronchoalveolar lavage being necessary for alveolar proteinosis. PMID- 21308988 TI - Disorders of creatine transport and metabolism. AB - Creatine is a nitrogen containing compound that serves as an energy shuttle between the mitochondrial sites of ATP production and the cytosol where ATP is utilized. There are two known disorders of creatine synthesis (both transmitted as autosomal recessive traits: arginine: glycine amidinotransferase (AGAT) deficiency; OMIM 602360; and guanidinoacetate methyltransferase (GAMT) deficiency (OMIM 601240)) and one disorder of creatine transport (X-linked recessive SLC6A8 creatine transporter deficiency (OMIM 300036)). All these disorders are characterized by brain creatine deficiency, detectable by magnetic resonance spectroscopy. Affected patients can have mental retardation, hypotonia, autism or behavioral problems and seizures. The diagnosis of these conditions relies on the measurement of plasma and urine creatine and guanidinoacetate. Creatine levels in plasma are reduced in both creatine synthesis defects and guanidinoacetate is increased in GAMT deficiency. The urine creatine/creatinine ratio is elevated in creatine transporter deficiency with normal plasma levels of creatine and guanidinoacetate. The diagnosis is confirmed in all cases by DNA testing or functional studies. Defects of creatine biosynthesis are treated with creatine supplements and, in GAMT deficiency, with ornithine and dietary restriction of arginine through limitation of protein intake. No causal therapy is yet available for creatine transporter deficiency and supplementation with the guanidinoacetate precursors arginine and glycine is being explored. The excellent response to therapy of early identified patients with GAMT or AGAT deficiency candidates these condition for inclusion in newborn screening programs. PMID- 21308989 TI - Hypermethioninemias of genetic and non-genetic origin: A review. AB - This review covers briefly the major conditions, genetic and non-genetic, sometimes leading to abnormally elevated methionine, with emphasis on recent developments. A major aim is to assist in the differential diagnosis of hypermethioninemia. The genetic conditions are: (1) Homocystinuria due to cystathionine beta-synthase (CBS) deficiency. At least 150 different mutations in the CBS gene have been identified since this deficiency was established in 1964. Hypermethioninemia is due chiefly to remethylation of the accumulated homocysteine. (2) Deficient activity of methionine adenosyltransferases I and III (MAT I/III), the isoenzymes the catalytic subunit of which are encoded by MAT1A. Methionine accumulates because its conversion to S-adenosylmethionine (AdoMet) is impaired. (3) Glycine N-methyltrasferase (GNMT) deficiency. Disruption of a quantitatively major pathway for AdoMet disposal leads to AdoMet accumulation with secondary down-regulation of methionine flux into AdoMet. (4) S adenosylhomocysteine (AdoHcy) hydrolase (AHCY) deficiency. Not being catabolized normally, AdoHcy accumulates and inhibits many AdoMet-dependent methyltransferases, producing accumulation of AdoMet and, thereby, hypermethioninemia. (5) Citrin deficiency, found chiefly in Asian countries. Lack of this mitochondrial aspartate-glutamate transporter may produce (usually transient) hypermethioninemia, the immediate cause of which remains uncertain. (6) Fumarylacetoacetate hydrolase (FAH) deficiency (tyrosinemia type I) may lead to hypermethioninemia secondary either to liver damage and/or to accumulation of fumarylacetoacetate, an inhibitor of the high K(m) MAT. Additional possible genetic causes of hypermethioninemia accompanied by elevations of plasma AdoMet include mitochondrial disorders (the specificity and frequency of which remain to be elucidated). Non-genetic conditions include: (a) Liver disease, which may cause hypermethioninemia, mild, or severe. (b) Low-birth-weight and/or prematurity which may cause transient hypermethioninemia. (c) Ingestion of relatively large amounts of methionine which, even in full-term, normal-birth weight babies may cause hypermethioninemia. PMID- 21308990 TI - Minimally stable nanoparticle-based colorimetric assay for simple, rapid, and sensitive antibody structure and activity evaluation. AB - A gold nanoparticle-based colorimetric antibody structure and activity evaluation method is developed without using complicated and expensive instrumentation. In this assay, a minimum number of antibodies to stabilize nanoparticles are conjugated to gold nanoparticles to prepare minimally stable nanoparticle probes, and the addition of salt rapidly induced particle aggregation and a color change of the solution from red to blue (25-min assay time). It is found that the solution color change is affected by the degree of structural denaturation of antibodies, and the conformational change of antibodies affects the modification of antibodies to nanoparticles and particle stability. Importantly, the colorimetric method can be applied to different types of antibodies (IgG, IgA, and IgM) and it shows comparable or better structural sensitivity than conventional circular dichroism spectroscopy. Moreover, immunoassay results show that these structural changes of antibodies are highly correlated with their antigen-binding activities. Rapid particle aggregation and high structural sensitivity are achieved in this assay because particles are modified with a minimum number of antibodies to stabilize particles in solution. This nanoparticle-based colorimetric method could be useful in evaluating the structural and activity changes of an array of antibodies in an easy, rapid, and sensitive manner. PMID- 21308991 TI - Perfusion conditioning of hydroxyapatite-chitosan-gelatin scaffolds for bone tissue regeneration from human mesenchymal stem cells. AB - Tissue-engineered bone grafts require an osteogenic cell source and a scaffold capable of supporting tissue regeneration. Hydroxyapatite (H), chitosan (C), and gelatin (G), when combined, produce a biomimetic scaffold with a chemical similarity to the main structural components of natural bone tissue. In this study a phase-separation technique was used to produce a porous 3D HCG scaffold, containing a network of cross-linked chitosan and gelatin fibrils coated in hydroxyapatite, with pore size readily controlled by freezing temperature. The HCG scaffolds were then seeded with human mesenchymal stem cells (hMSCs), using a depth filtration system after preconditioning with serum-containing medium for 7 days under either static or perfusion conditions. The effects of static and perfusion media preconditioning on protein adsorption, surface morphology, hMSC attachment, proliferation and osteogenic differentiation were examined. Perfusion preconditioning, as opposed to static preconditioning, enhances adsorption of ECM proteins, which in turn promotes hMSC proliferation and osteogenic differentiation. The results demonstrate the importance of convective flow in modulating the 3D HCG microenvironment and highlight its profound influence on 3D construct development. PMID- 21308992 TI - The role of shear stress on mechanically stimulated engineered vascular substitutes: influence on mechanical and biological properties. AB - Vascular tissue engineering represents a promising field in the replacement of diseased vessels. The biological properties of three-dimensional (3D) collagen scaffolds indicate this material as a valid choice for vascular tissue engineering. Unfortunately, mechanical properties still remain unsatisfactory, due to a low burst pressure resistance and a plastic deformation. The use of a bioreactor to apply appropriate mechanical stresses have already shown a remodelling effect on the extracellular matrix and the behaviour of cells. In this study, we have shown the effect of the mechanical stress on elastin synthesis, which has a direct effect on the mechanical properties of the tissue engineered vessel. We measured and compared the stress-strain curves, the elastic modulus and tenacity of a collagen tubular scaffold in the presence of C2C12 murine myoblasts cells, before and after the maturation in the bioreactor, applying a shear stress of 5 dynes/cm(2) for 3 days. Interesting evidence concerning the extracellular matrix structure, which significantly modify the biomechanical characteristics of the cellular scaffold, were observed, underlying the importance of focusing more effort in the research field of physiologically guided 3D tissue-engineered substitutes. PMID- 21308993 TI - The cytoskeletal and signaling mechanisms of axon collateral branching. AB - During development, axons are guided to their appropriate targets by a variety of guidance factors. On arriving at their synaptic targets, or while en route, axons form branches. Branches generated de novo from the main axon are termed collateral branches. The generation of axon collateral branches allows individual neurons to make contacts with multiple neurons within a target and with multiple targets. In the adult nervous system, the formation of axon collateral branches is associated with injury and disease states and may contribute to normally occurring plasticity. Collateral branches are initiated by actin filament- based axonal protrusions that subsequently become invaded by microtubules, thereby allowing the branch to mature and continue extending. This article reviews the current knowledge of the cellular mechanisms of the formation of axon collateral branches. The major conclusions of this review are (1) the mechanisms of axon extension and branching are not identical; (2) active suppression of protrusive activity along the axon negatively regulates branching; (3) the earliest steps in the formation of axon branches involve focal activation of signaling pathways within axons, which in turn drive the formation of actin-based protrusions; and (4) regulation of the microtubule array by microtubule-associated and severing proteins underlies the development of branches. Linking the activation of signaling pathways to specific proteins that directly regulate the axonal cytoskeleton underlying the formation of collateral branches remains a frontier in the field. PMID- 21308994 TI - Cystic fibrosis transmembrane conductance regulator modulates synaptic chloride homeostasis in motoneurons of the rat spinal cord during neonatal development. AB - Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated Cl(-) channel functional in neonatal rat spinal motoneurons. The present study investigated the developmental (P1-P8) expression of CFTR, its impact on motoneuron excitability and Cl(-) homeostasis in relation to canonical Cl(-) transporters. The Cl(-) outward transporter KCC2 gene was upregulated in females over males and increased from P1 to P8. The gene activities of the Cl(-) inward transporter NKCC1 and CFTR were positively correlated and grew between P1 and P8. P1 motoneuronal somata were immunopositive for CFTR whose expression later (P8) extended to cell processes. KCC2 immunopositivity outlined somata and cell processes at P1 and P8. Electrophysiological recording with sharp electrodes showed that the CFTR blocker glibenclamide increased motoneuron input resistance, suggesting functional CFTR in P1-P8 motoneurons. Whole cell patch-clamping of spinal motoneurons to study CFTR contribution to postnatal synaptic Cl(-) regulation indicated that glibenclamide or the selective CFTR blocker diphenylamine-2,2'-dicarboxylic acid produced a negative shift in GABA/glycine reversal potential (E(GABA/Gly) ) of spontaneously occurring synaptic events measured after block of excitatory transmission. A similar effect on E(GABA/Gly) was induced by the NKCC1 inhibitor bumetanide. A 3D reconstructed motoneuron model suggested that CFTR activity contributes to set the E(GABA/Gly) positive to the resting potential. The functional outcome of these Cl(-) mediated synaptic events depended not only on the postnatal age of the animal but also on their timing with respect to the excitatory synaptic signals. We propose that CFTR operated together with NKCC1 to produce depolarizing GABA/glycine mediated synaptic events. PMID- 21308995 TI - Emodin prolongs recipient survival time after orthotopic liver transplantation in rats by polarizing the Th1/Th2 paradigm to Th2. AB - Advances in immunosuppressive drugs have improved the short-term survival of liver transplantation. However, drug toxicities have been a serious problem in patients after long-term administration. Therefore, it is necessary to develop a novel immunosuppressant with low-toxicity. We investigated the immunosuppressive effects of Emodin on acute graft rejection following liver transplantation in rats. The recipient rats of orthotopic liver transplantation were divided into groups as follows: isograft+NS group, allograft+NS group, and allograft+emodin group. The survival time of the recipients in each group was recorded. Histopathological changes in the liver, as well as serum concentrations of IL-2, TNF-alpha, and IL-10 and their expressions in liver tissue were determined. Our results showed that Emodin treatment prolonged liver allograft survival time and inhibited histopathologic changes of acute graft rejection. The rejection activity index in groups isograft+NS, allograft+NS, and allograft+emodin were 1.52 +/- 0.37, 6.95 +/- 0.75, and 4.23 +/- 0.51, respectively (P < 0.01, isograft+NS group vs. allograft+emodin group and allograft+NS group vs. allograft+emodin group). The serum levels of IL-2 and TNF-alpha were down regulated but that of IL-10 was up-regulated by Emodin. Serum levels of IL-2 and TNF-alpha were higher in allograft+NS group than the allograft+emodin group, but that of IL-10 showed opposite effects (P < 0.05 or 0.01). Changes in the expression of these cytokines in transplanted liver tissue were consistent with changes in serum concentrations. These results demonstrate that Emodin has therapeutic potentials for alleviating acute rejection following liver transplantation in rats and prolonging liver allograft survival. The mechanisms underlying this effect may be associated with polarizing the Th1/Th2 paradigm to Th2. PMID- 21308996 TI - Fate map of serotonin transporter-expressing cells in developing mouse thyroid. AB - A Cre/loxP-based fate mapping approach was used to follow the regions of the mouse thyroid labeled by the serotonin transporter SERT. Reporter gene expression (lacZ) is activated by Cre expression from the SERT locus in SERT(Cre/+) ;ROSA26R compound mouse embryos. Cell labeling, first detected in the thyroid primordium at the E10.5 prenatal stage, was followed until the postnatal day P30. The co localization of lacZ staining in the same cells that express the transcription factors Nkx2.1 and Pax8 at the E12.5 stage confirms their identity as thyroid cell precursors. SERT immunohistochemistry on thyroid sections of E18.5 embryos showed SERT expression in thyroid follicular cells. Western blotting analysis confirmed the expression of the protein in adult thyroid tissue and cultured FRTL 5 cells. These results describe the fate of SERT-expressing cells during thyroid development, suggesting an active role of SERT in the development and functions of mammalian thyroid. They also highlight the possibility to use the SERT-Cre mouse line as a good Cre driver in early thyroid development. PMID- 21308997 TI - The utility of endobronchial ultrasound-guided transbronchial needle aspiration biopsy in the diagnosis of mediastinal lymphoproliferative disorders. AB - BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) biopsy is routinely used to stage lung cancer; however, its usefulness in diagnosing lymphoproliferative disorders has not been well established. In this retrospective study, we determined the utility of EBUS-TBNA in evaluating mediastinal lymphadenopathy in patients with suspected lymphoproliferative disorders. METHODS: The authors searched the pathology database at their institution to identify all patients who had undergone EBUS TBNA biopsy for possible lymphoproliferative disorders. The cytologic diagnoses were correlated with concurrent and subsequent biopsy findings and clinical follow-up data. RESULTS: Of 886 lymph nodes evaluated by EBUS-TBNA biopsy, 91 nodes from 33 patients (23 men and 10 women) were eligible. Fourteen patients had a history of lymphoma. Adequate material for diagnosis was obtained in 31 of 34 procedures (1 patient had 2 procedures). The cytologic diagnoses of the 31 adequate procedures included 19 with benign disease (8 reactive lymph nodes and 11 granulomatous inflammation), 8 with lymphoma (2 large B-cell, 2 small lymphocytic, 2 Hodgkin, 1 mantle cell, and 1 T-cell lymphoblastic), 2 with cells suspicious for Hodgkin lymphoma, and 2 cases with atypical cells. CONCLUSIONS: EBUS-TBNA proved to be useful for evaluating mediastinal lymphadenopathy in patients with suspected lymphoproliferative disorders. Its use may decrease the need for invasive diagnostic procedures. Immediate assessment is valuable in these cases because of the need to triage material for immunophenotyping or other studies to determine optimal and clinically meaningful diagnoses. PMID- 21308998 TI - Phonology and vocal behavior in toddlers with autism spectrum disorders. AB - The purpose of this study is to examine the phonological and other vocal productions of children, 18-36 months, with autism spectrum disorder (ASD) and to compare these productions to those of age-matched and language-matched controls. Speech samples were obtained from 30 toddlers with ASD, 11 age-matched toddlers and 23 language-matched toddlers during either parent-child or clinician-child play sessions. Samples were coded for a variety of speech-like and nonspeech vocalization productions. Toddlers with ASD produced speech-like vocalizations similar to those of language-matched peers, but produced significantly more atypical nonspeech vocalizations when compared to both control groups. Toddlers with ASD show speech-like sound production that is linked to their language level, in a manner similar to that seen in typical development. The main area of difference in vocal development in this population is in the production of atypical vocalizations. Findings suggest that toddlers with ASDs do not tune into the language model of their environment. Failure to attend to the ambient language environment negatively impacts the ability to acquire spoken language. PMID- 21309000 TI - Phytochemical and biological investigation of the extracts of Nigella sativa L. seed waste. AB - Different extracts of Nigella sativa L. seed waste; aqueous (AE) 200 mg/kg, ethanol 70% (EE) 250 mg/kg and hexane (HE) 10 mg/kg, were evaluated for their hepatoprotective activities. They were administered orally, once daily, for 5 consecutive days. On day 5, liver injury was induced in animals by a single i.p. injection of carbon tetrachloride (10 mg/kg b. w. of 0.25% (v/v). Hepatoxicity produced, was evaluated by both biochemical and histopathological investigations. The aqueous extract attenuated the CCl(4) -induced liver damage likely due to the decrease of proinflammatory cytokines and T-cell proliferation. This was noticed by a significant decrease in both serum and tissue cytokines; tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (INF-gamma) and interlukin-beta (IL 1beta), in the markers of liver functions; bilirubin and glutamic pyruvic transaminase (GPT) and in the oxidative stress markers; malondialdehyde (MDA) and glutathione content (GSH). Fractionation of this extract was performed and its component, protein, saponin, and polyphenol fractions were evaluated by appropriate analytical procedures. The crude protein of the seed waste reached 36.85% while protein fingerprint showed four bands ranging from 91.97 KD and 29.00 KD. The saponin content was evaluated through the determination of the haemolytic index and reached 15.56 mg/g dry powder. Finally, Folin Ciocalteu method was used for the determination of the total polyphenols. The same biochemical and histopathological studies were again performed on the different fractions of the aqueous extract; protein fraction (PF) 10 mg/kg, saponin fraction (SF) 5 mg/kg and polyphenol fraction (FF) 10 mg/kg. The biochemical changes were improved only by the protein fraction (PF) of the seed waste of Nigella sativa. This was manifested by a significant reduction in both serum and tissue cytokines in the liver markers and in the oxidative stress markers. Moreover, liver histopathology showed that (PF) reduced the incidence of liver lesions including hepatic cells cloudy swelling, lymphocytes infiltration, hepatic necrosis and fibrous connective tissue proliferation induced by CCl(4) in mice. From this study, it is concluded that the protein fraction of the aqueous extract of Nigella sativa seed waste exhibited a promising hepatoprotective effect in the management of different liver disorders. PMID- 21308999 TI - Contactin 4 as an autism susceptibility locus. AB - Structural and sequence variation have been described in several members of the contactin (CNTN) and contactin-associated protein (CNTNAP) gene families in association with neurodevelopmental disorders, including autism. Using array comparative genome hybridization (CGH), we identified a maternally inherited ~535 kb deletion at 3p26.3 encompassing the 5' end of the contactin 4 gene (CNTN4) in a patient with autism. Based on this finding and previous reports implicating genomic rearrangements of CNTN4 in autism spectrum disorders (ASDs) and 3p- microdeletion syndrome, we undertook sequencing of the coding regions of the gene in a local ASD cohort in comparison with a set of controls. Unique missense variants were identified in 4 of 75 unrelated individuals with ASD, as well as in 1 of 107 controls. All of the amino acid substitutions were nonsynonomous, occurred at evolutionarily conserved positions, and were, thus, felt likely to be deleterious. However, these data did not reach statistical significance, nor did the variants segregate with disease within all of the ASD families. Finally, there was no detectable difference in binding of two of the variants to the interacting protein PTPRG in vitro. Thus, additional larger studies will be necessary to determine whether CNTN4 functions as an autism susceptibility locus in combination with other genetic and/or environmental factors. PMID- 21309001 TI - Simultaneous estimation of atorvastatin and its two metabolites from human plasma by ESI-LC-MS/MS. AB - A selective, sensitive, and fast high performance liquid chromatography (HPLC) method with mass spectrometric (MS) detection mode has been developed and validated completely in human plasma. Atorvastatin (ATO), p-hydroxy atorvastatin (p-HATO), o-hydroxy atorvastatin (o-HATO) and internal standard (IS) are extracted from human plasma via solid phase extraction (SPE) technique. After elution, the solution is evaporated, then reconstituted with 250 uL of Mobile Phase and analyzed using HPLC/MS/MS system. An isocratic mode is used to separate interference peaks using a Symmetry C-18, 75 * 4.6 mm ID, 3.5 u, column. The m/z of ATO, o-HATO and p-HATO are 559.2/440.2, 575.3/440.4 and 575.0/440.4 respectively. Linearity ranges are 0.05 to 252.92 ng/mL for ATO, p-HATO and o HATO respectively. Calibration functions, lower limit of quantitation (LLOQ), stability, intra- and inter-day reproducibility, accuracy, and recovery are estimated. This method is free from matrix effects and any abnormal ionization. This method was successfully applied to a single dose 80 mg tablet bioequivalence (BE) study of Atorvastatin. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 21309002 TI - Voltammetric determination of isoproterenol using multiwall carbon nanotubes ionic liquid paste electrode. AB - A sensitive and selective electrochemical method for the determination of isoproterenol (ISPT) was developed using multiwall carbon nanotubes and a room temperature ionic liquid (i.e. 1-butyl-3-methylimidazolium hexafluoro phosphate, ([C4mim]-[PF6])). This multiwall carbon nanotubes ionic liquid electrode (MWCNTILEE) is a very good alternative to previously described electrodes because the electrocatalytic effect is achieved without any electrode modification. The oxidation peak potentials in cyclic voltammogram of ISPT on MWCNTILEE was occurred around 470 mV vs Ag/AgCl (at pH 6.0) while this peak potential at carbon paste electrode was appeared around 605 mV at the same scan rate of 100 mV s-1. The electrochemical parameters such as diffusion coefficient and charge transfer resistance were determined using cyclic voltammetry and electrochemical impedance spectroscopy. Under the optimized conditions, the peak current was linear to ISPT concentration over the concentration range of 1.0 to 520 umol L-1 using differential pulse voltammetry. The detection limit was 0.85 umol L-1. The proposed method was successfully applied to the determination of ISPT in both ampoules and urine samples. PMID- 21309003 TI - Determinants of incident and persistent finger joint pain during a five-year followup among female dentists and teachers. AB - OBJECTIVE: To investigate the association of radiographic finger osteoarthritis (OA), hand use, and lifestyle factors with incident and persistent finger joint pain among female dentists and teachers. METHODS: Random samples of female dentists (n = 295) and teachers (n = 248) ages 45-63 years were examined by radiography for the presence of finger joint OA. Body weight was measured. Information on finger joint pain during the past 30 days, height, smoking, and leisure-time hand activity was collected by questionnaire. Five years later, 482 women (89%; 65% still active occupationally) responded to a survey on finger joint pain. RESULTS: The incidence and persistence of finger joint pain were higher among the subjects with OA compared to those without OA. The relative risk (RR) of incident pain in the first through the third fingers was 1.8 (95% confidence interval [95% CI] 1.2-2.7) in the right hand and the RR in the left hand was 3.0 (95% CI 2.0-4.6), allowing for age, occupation, and lifestyle factors. The corresponding figures for the fourth and fifth fingers were RR 2.3 (95% CI 1.4-3.8) in the right and RR 1.9 (95% CI 1.1-3.5) in the left hand. Regarding persistent pain, the RRs varied between 2.4 and 5.4. Body mass index, smoking, or leisure-time hand activity were not associated with pain. The dentists tended to have a higher incidence of pain in the first through the third fingers of the right hand compared with the teachers. CONCLUSION: Radiographic finger joint OA was a significant determinant of both persistent and incident finger joint pain in a 5-year followup among middle-aged women. Hand use may modify the association between radiographic OA and finger joint pain. PMID- 21309004 TI - A 26-year-old white man with a systemic lupus erythematosus flare and acute multiorgan ischemia: Vasculitis or thrombosis? PMID- 21309005 TI - Effects of rosuvastatin on vascular biomarkers and carotid atherosclerosis in lupus: a randomized, double-blind, placebo-controlled trial. AB - OBJECTIVE: To study the effect of rosuvastatin on vascular biomarkers and carotid intima-media thickness (IMT) in systemic lupus erythematosus (SLE). METHODS: SLE patients with inactive disease and subclinical atherosclerosis were randomized in a double-blinded manner to receive either rosuvastatin (10 mg/day) or matching placebo (half in each group were also randomly allocated low-dose aspirin). After 12 months, treatment was unblinded. Patients treated with rosuvastatin and aspirin were continued on the same medications for another 12 months. Plasma levels of homocysteine, high-sensitivity C-reactive protein (hsCRP), soluble vascular cell adhesion molecule 1, P-selectin, and thrombomodulin were measured at baseline, 6 months, and 12 months. Measurement of carotid IMT was repeated at 24 months. RESULTS: Seventy-two patients were studied (97% women, mean +/- SD age 50.8 +/- 9.7 years). Thirty-six patients were randomly assigned to each of the study arms (18 patients in each arm also received aspirin). Baseline clinical characteristics and medications were similar between the two groups. At 12 months, the mean low-density lipoprotein cholesterol (mean +/- SD 2.62 +/- 1.04 mmoles/liter to 1.69 +/- 0.72 mmoles/liter; P < 0.001) and median hsCRP levels (1.26 mg/liter, interquartile range [IQR] 2.3 to 0.88 mg/liter, IQR 1.1; P = 0.02) decreased significantly in the rosuvastatin group. There was no significant change in homocysteine, and aspirin use did not influence the levels of the biomarkers studied. A subgroup analysis of patients with a Systemic Lupus Erythematosus Disease Activity Index score <=2 revealed a significant decrease in hsCRP (1.20 mg/liter, IQR 2.3 to 0.92 mg/liter, IQR 1.1; P = 0.04) and thrombomodulin levels (0.76 ng/ml, IQR 1.2 to 0.67 ng/ml, IQR 1.0; P = 0.001) with rosuvastatin treatment. At 24 months, the IMT of the internal carotid arteries appeared to be decreased in patients treated with rosuvastatin, which was well tolerated. CONCLUSION: In stable SLE patients, low-dose rosuvastatin leads to a significant reduction in hsCRP and thrombomodulin levels, which may possibly help to reduce cardiovascular risk. PMID- 21309006 TI - Predicting outcomes of lupus nephritis with tubulointerstitial inflammation and scarring. AB - OBJECTIVE: In lupus nephritis, glomerular injury correlates poorly with progression to renal failure. While the tubulointerstitium is also commonly involved, the importance of such involvement is not well defined. Therefore, we developed a simple method to assess the prognostic utility of measuring tubulointerstitial inflammation (TI). METHODS: Sixty-eight systemic lupus erythematosus patients with lupus nephritis were enrolled. Tubulointerstitial lymphocytic infiltrates were quantitated both by anti-CD45 antibody staining and standard histochemical staining. Followup data were obtained and survival analysis was carried out to determine which histologic features were predictive of subsequent renal failure. RESULTS: By CD45 staining, TI was a common pathologic finding, with 72% of biopsies having moderate or severe involvement. The extent of TI correlated with serum creatinine, but not with double-stranded DNA antibodies, serum C3, or glomerular inflammation. TI severity, but not glomerular injury, identified patients at greater risk for renal failure (P = 0.02). A high National Institutes of Health (NIH) chronicity index also identified patients at risk for renal failure. However, when the glomerular and tubulointerstitial subcomponents of the NIH chronicity index were separated in a bivariate model, only tubulointerstitial chronicity provided prognostic information (hazard ratio [HR] 2.2, 95% confidence interval [95% CI] 1.3-3.6; P = 0.002 versus HR 1.0, 95% CI 0.7-1.5; P = 0.97 for glomerular chronicity). CONCLUSION: TI identifies lupus nephritis patients at greatest risk for progression to renal failure. The immunologic mechanisms underlying TI may provide novel targets for therapeutic intervention. PMID- 21309007 TI - Bias introduced by conditioning on an intermediate variable: Comment on the article by Zhang et al. PMID- 21309008 TI - Spectrum of orbital and ocular adnexal lesions: an analysis of 389 cases diagnosed by fine needle aspiration cytology. AB - The aim of the present study was to evaluate the scope and the limitations of fine needle aspiration cytology (FNAC) in orbital and ocular adnexal lesions. This study was a retrospective audit of 389 cases of orbital and ocular adnexal lesions subjected to FNAC over a period of 12 years (1998-2009). The cyto-smears were reviewed and the lesions were categorized under different diagnostic categories in adult and pediatric population. Three hundred and one adult patients (age >=15 years) and 88 pediatric patients (age <=14 years) constituted the study group. In the adult population, there were 23.3% cases of infectious and lymphoproliferative lesions and 12.6% of benign cysts. In the pediatric population, 18.2% cases had infectious and lymphoproliferative lesions and 8% had benign cysts. Various benign tumors (9.6% in adults) included pleomorphic adenoma, meningioma, and schwannoma. Benign vascular tumors predominated in the pediatric population. A majority of malignant tumors in adults were lymphoreticular malignancies (12.6%); non-Hodgkin's lymphoma being the most common followed by malignant epithelial tumors (10.3%). Nearly 3.6% cases of soft tissue/bone sarcomas and 6.3% of metastatic tumors were seen in adult population. However, most of the orbital tumors in the pediatric population were malignant small blue round cell tumors (33%). FNAC is a cost-effective technique with good diagnostic value in the assessment of ophthalmic lesions, especially when sampling and interpretation are performed by experienced personnel in the light of clinico-radiological information. PMID- 21309009 TI - Liver lesions in children and adolescents: cytopathologic analysis and clinical correlates in 44 cases. AB - The role of fine needle aspiration (FNA) as a first-line diagnostic modality is well-established for neoplastic and nonneoplastic liver masses in adults. However, cytopathologic analysis of such lesions in children and adolescents has not been well studied. An 18-year retrospective review of the cytopathology archives at The Johns Hopkins Hospital identified 44 cases of hepatic FNA in children and adolescents (i.e., 21 years and younger). The cytopathologic material was reviewed and correlated with subsequent surgical pathology diagnoses and/or clinical follow-up. Among the 44 FNAs studied, 40 (90.9%) were deemed diagnostic for evaluation and 4 (9.1%) were nondiagnostic. Twenty four (60%) of the diagnostic FNAs were neoplasms, 10 (25%) were nonneoplastic lesions, and 6 (15%) were "atypical" or "suspicious." There were 21 (87.5%) malignant and 3 (12.5%) benign tumors. Among the malignant cases, metastases/secondary tumors accounted for 12 (54.5%) followed by hepatocellular carcinoma (HCC)--7 (38.1%). The types of metastatic/secondary neoplasms were Wilms tumor (2), germ cell tumor (2), acute leukemias (2), and miscellaneous others (6). Among the nonneoplastic lesions focal nodular hyperplasia was most common--4 (40%). Among the "atypical" cases, 4 (66.6%) turned out to be benign on follow-up, 2 were HCC, and 1 was Hodgkin lymphoma. Immunoperoxidase (IPOX) studies were done in 20 (45.5%) cases to confirm the cytopathologic diagnoses. Overall, FNA showed a sensitivity of 95.2% and a specificity of 100% for a malignant diagnosis. PMID- 21309010 TI - An atypical morphologic presentation of Coccidioides spp. in fine-needle aspiration of lung. AB - Infection due to Coccidioides spp., a dimorphic fungal pathogen, usually presents as a chronic pulmonary disease, occasionally with pulmonary nodules. On cytology, large spherules filled with endospores are typically seen. We report an unusual case of coccidioidomycosis in a 39-year-old female from an area nonendemic for Coccidioides and without other known risk factors for infection. Fine-needle aspiration of the patient's cavitary lung lesion revealed Coccidioides spp., which demonstrated atypical delicate septate hyphal forms and chains of conidia, with none of the large spherules typical of Coccidioides spp. Atypical hyphal and other forms of Coccidioides spp. have been reported in several studies, primarily from biopsy or tissue resection specimens. However, this is the first case to our knowledge that the organism has presented solely as conidial and atypical hyphal forms in an aspirated specimen. Pathologists who are unfamiliar with this atypical hyphal formation may misdiagnose the organism as several different fungi, including Aspergillus spp. or Fusarium spp. It is important to differentiate among fungi, as antifungal treatments may vary. Cytologists should be aware of the diverse morphologies demonstrated by Coccidioides spp. and include this organism in their differential diagnosis, even in patients seemingly devoid of pertinent risk factors. PMID- 21309011 TI - Assisting cytopathology training in medically under-resourced countries: defining the problems and establishing solutions. AB - Cytology is able to deliver rapid accurate diagnoses with minimal equipment and laboratory infrastructure at minimal cost, and this is especially so for fine needle biopsy (FNB), which is a powerful diagnostic tool in medically resource poor environments, where histopathology laboratories are small in number and poorly supported financially. The crucial element in the development of cytology services is to train a sufficient number of well trained cytopathologists and cytotechnologists to create a 'critical mass' of personnel who not only provide routine diagnostic services, but also can train an ever expanding number of pathologists, cytotechnologists, and health workers. A review of practical programs to train cytopathologists and cytotechnologists in their own countries will be presented, including a recent series of FNB and cytology tutorials run in sub Saharan Africa. The need for local cytopathology programs and the potential for both local and visiting cytopathologists to provide a faculty will be discussed, as well as a range of possible programs which can bring African pathologists and trainee pathologists to Western institutions for periods of their training. Ideally, the regional Societies of Cytology, including the recently formed West African Society of Cytology, will establish their own diagnostic protocols, training programs, syllabuses, examinations and accreditation and career pathways for both cytopathologists and cytotechnologists, and organize tutorials where they will invite overseas faculty to contribute. Crucially, these new societies will empower cytopathologists and cytotechnologists to approach health services and governments to state the need for cytology services as a cost-effective accurate diagnostic service that enhances patient care. PMID- 21309012 TI - Reducing "atypical squamous cells" overdiagnosis on cervicovaginal smears by diligent cytology screening. AB - The frequency of possible reasons for "atypical squamous cells" (ASC) overdiagnosis on Papanicolaou (Pap) smears was analyzed. Pap smears of 199 women with negative biopsy outcome after an ASC diagnosis were reviewed. Special attention was paid to presence of reproductive tract infections (RTIs), perimenopausal cells (PM cells), immature metaplastic cells, hormone-related alterations, and drying artefacts. Comparisons were made using chi(2) test between the two ASC qualifiers and also between premenopausal and peri/postmenopausal women. Possible reasons for ASC overdiagnosis could be assigned on Pap smear review in 88/199 (44.2%) negative biopsies. Overall, PM cells were the most frequent reason for ASC overdiagnosis, being present in 35/199 (17.6%) smears. RTIs were the next most common cause (14.6%). PM cells were the most significant confounding factors for persistent ASC undetermined significance (ASC-US) over interpretation (20.2%) while in none of the cases these were interpreted as ASC-H (P = 0.004). Of these, 32 smears belonged to peri/postmenopausal women while only three to premenopausal women (P < 0.001). Immature metaplastic cells were significantly more frequent cause of ASC-H rather than ASC-US interpretation (P = 0.007). RTIs and drying artefacts were more frequently overcalled as ASC-US (in premenopausal women) while hormonal changes were interpreted as ASC-H. Hormone related changes, immature metaplastic cells and drying artefacts more commonly resulted in ASC interpretation in peri/ postmenopausal smears. The results of this study suggest that diligent screening can substantially reduce ASC overdiagnosis, thereby reducing the referrals/ follow ups. PMID- 21309013 TI - Challenging breast lesions: pitfalls and limitations of fine-needle aspiration and the role of core biopsy in specific lesions. AB - Core biopsy rapidly replaced fine needle aspiration (FNA) over the past decade in evaluation of diseases of the female breast in many centers in the USA. We continue to heavily utilize FNA for the initial evaluation of breast masses in our institution. In this article, we discuss the cytologic and core biopsy findings in challenging breast lesions such as papillary and mucinous proliferations, fibroepithelial neoplasms, and low grade cancers. We specifically focus on the pitfalls and limitations of both diagnostic modalities in these selected specific lesions. PMID- 21309014 TI - Fine needle aspiration cytology of insular carcinoma of thyroid. AB - Poorly differentiated (insular) thyroid carcinoma is defined as a thyroglobulin producing non-follicular non-papillary thyroid carcinoma, having an intermediate behavior between well-differentiated and anaplastic carcinomas. FNAC is widely used as aid for workup of thyroid gland lesion. However, scant information is available in the literature about cytologic findings of this rare entity. Ten cases of surgically resected insular carcinoma with a corresponding cytology were selected. The cytologic smears and histological sections were reviewed for presence of cytomorphologic features including cellularity, predominant cytoarchitectural pattern, additional cytologic co-patters pattern, cell size, cell shape, nuclear pleomorphism, nuclear/cytoplasmic (N/C) ratio, chromatin pattern, amount of cytoplasm, mitotic figures, colloid, background debris, nuclear grooves, and intranuclear pseudoinclusions. In all the cases, the cells were arranged predominantly in solid clusters. Focal microfollicular pattern was identified in five cases of which three cases showed presence of inspissated colloid within the follicles. Singly scattered malignant cells and bare nuclei were seen in all cases. Cells were monomorphic, round with high N/C ratio, finely granular chromatin and inconspicuous nucleoli. Background showed presence of cellular debris in two cases. Mitotic figures were obvious and atypical mitosis was also identified. Cellular smears composed of monomorphic population of small cells arranged in large clusters and sheets with high N/C ratio and high mitosis suggest the possibility of insular carcinoma. Background cellular debris/necrosis also supports the diagnosis. Cell block preparation in these cases may be of additional help in accurate diagnosis. PMID- 21309015 TI - Cytological significance of abnormal squamous cells in urinary cytology. AB - The aim of this study was to evaluate the significance of abnormal squamous cells (ASCs) in urinary cytology to clarify whether finding of ASCs could improve diagnostic accuracy. A total of 3,812 urine specimens were reviewed. We focused on three parameters of ASCs, necrotic debris, and ASC clusters, and linked them to histological diagnosis and clinical information. ASCs were identified in 34 (0.9%) specimens from 21 different patients. The incidence of ASCs was higher in females than in males. The 34 urine specimens were categorized as voided urine (16 cases), bladder-catheterized urine (17 cases), and bladder-washed fluid (1 case). Six (28.6%) of 21 patients were histologically diagnosed as having combined urothelial carcinoma and squamous cell carcinoma (SCC). Eight patients (38.1%) were histologically diagnosed as having SCC originating from sites other than the urinary tract; those urine specimens showed ASCs that were likely to have been exfoliated from malignant lesions. Necrotic debris and ASC clusters were identified in 12 specimens (35.3%) from 11 patients and 4 specimens (11.8%) from 4 patients, respectively, from a total of 34 specimens. Our results indicate that a great amount of care is needed for cytological diagnosis when attempting to recognize ASCs in urine specimens because ASCs were identified in not only SCC of the bladder but also in carcinoma or nonmalignant lesions of nonurinary tracts. Necrotic debris was found not only in patients who had malignant bladder tumors but also in those who had malignant lesions in locations other than the bladder. PMID- 21309016 TI - Mechanism of action of mercury on sperm morphology, adenosine triphosphate content, and motility in Perca fluviatilis (Percidae; Teleostei). AB - The main objectives of the present study were to investigate the performance of mercury chloride (HgCl2 ) on sperm function and structure, identify sites of action of HgCl2 , and investigate the mechanism of action of HgCl2 on fish (Perca fluviatilis L.) spermatozoa. Direct exposure of nonincubated sperm decreased sperm motility and velocity in a dose-dependent manner and was totally suppressed at 250 uM HgCl2 . Adenosine-5'-triphosphate (ATP) content of sperm after activation in an activation medium (AM) containing more than 25 uM HgCl2 did not differ compared with nonactivated sperm. Motility and velocity of demembranated sperm decreased after activation in an AM containing 62 uM HgCl2 , and was totally suppressed at 250 uM HgCl2 . Incubation of sperm in an immobilizing medium (IM) containing HgCl2 enhanced HgCl2 effects after sperm activation in an AM containing HgCl2 . Sperm motility of incubated sperm in an IM without HgCl2 was totally suppressed at 125 uM HgCl2 after 3 h incubation. In case of incubated sperm in an IM containing HgCl2 , sperm motility was totally suppressed at 31 uM HgCl2 . Adenosine-5'-triphosphate content of sperm was significantly lower in an IM containing HgCl2 greater than 3 uM compared with those of the control (no HgCl2 ) and lower HgCl2 concentrations. Damage to the plasma membrane and axoneme were observed in sperm incubated in an IM containing HgCl2 compared with the control, when HgCl2 concentration and incubation time increased. In conclusion, HgCl2 acts on sperm through disruption of function of the plasma membrane, axoneme, and ATP content. PMID- 21309017 TI - Use of butterflies as nontarget insect test species and the acute toxicity and hazard of mosquito control insecticides. AB - Honeybees are the standard insect test species used for toxicity testing of pesticides on nontarget insects for the U.S. Environmental Protection Agency (U.S. EPA) under the Federal Insecticide Fungicide and Rodenticide Act (FIFRA). Butterflies are another important insect order and a valued ecological resource in pollination. The current study conducted acute toxicity tests with naled, permethrin, and dichlorvos on fifth larval instar (caterpillars) and adults of different native Florida, USA, butterfly species to determine median lethal doses (24-h LD50), because limited acute toxicity data are available with this major insect group. Thorax- and wing-only applications of each insecticide were conducted. Based on LD50s, thorax and wing application exposures were acutely toxic to both caterpillars and adults. Permethrin was the most acutely toxic insecticide after thorax exposure to fifth instars and adult butterflies. However, no generalization on acute toxicity (sensitivity) of the insecticides could be concluded based on exposures to fifth instars versus adult butterflies or on thorax versus wing exposures of adult butterflies. A comparison of LD50s of the butterflies from this study (caterpillars and adults) with honeybee LD50s for the adult mosquito insecticides on a ug/organism or ug/g basis indicates that several butterfly species are more sensitive to these insecticides than are honeybees. A comparison of species sensitivity distributions for all three insecticides shows that permethrin had the lowest 10th percentile. Using a hazard quotient approach indicates that both permethrin and naled applications in the field may present potential acute hazards to butterflies, whereas no acute hazard of dichlorvos is apparent in butterflies. Butterflies should be considered as potential test organisms when nontarget insect testing of pesticides is suggested under FIFRA. PMID- 21309018 TI - Specific in vitro toxicity of crude and refined petroleum products: 3. Estrogenic responses in mammalian assays. AB - Current petroleum risk assessment considers only narcosis as the mode of action, but several studies have demonstrated that oils contain compounds with dioxin like, estrogenic or antiestrogenic, and androgenic or antiandrogenic activities. The present study is the third in a series investigating the specific toxic effects of 11 crude oils and refined products. By employing recombinant mammalian cells stably transfected with the human estrogen receptor alpha (ERalpha) or beta (ERbeta), and expressing the luciferase protein (ERalpha-U2OS-Luc and ERbeta-U2OS Luc assay), the estrogenicity or antiestrogenicity of oils was studied. All oils, except for two refined oils and one crude oil, induced estrogenic responses. The calculated estrogenic potencies of the oils were six to nine orders of magnitude lower than the potency of 17beta-estradiol (E2). Upon coexposure to a fixed concentration of E2 and increasing concentrations of oils, additive, antagonistic, and synergistic effects were revealed. One nautical fuel oil was tested in the human breast carcinoma cell line MCF-7, in which it induced cell proliferation up to 70% relative to the maximal induction by E2. At its minimum effect concentration of 25 mg/L, the oil was also capable of inducing mRNA expression of the estrogen-dependent protein pS2 by a factor of two. The present results indicate that oils naturally contain potentially endocrine-disrupting compounds that are able to influence the estrogenicity of other compounds and may cause biological responses beyond receptor binding. PMID- 21309019 TI - Toxicity and bioaccumulation of phenanthrene in Enchytraeus albidus (Oligochaeta: Enchytraeidae). AB - Polycyclic aromatic compounds, such as phenanthrene (PHE), tend to accumulate in the soil compartment, where they may be retained for many years because of their persistency and hydrophobicity. The toxicity and bioaccumulation of these chemicals in soil biota and potential biomagnification along the food chain is an issue of concern. The main goal of this study was to determine the toxicity and bioaccumulation of PHE in Enchytraeus albidus (Oligochaeta: Enchytraeidae) in a natural standard soil (LUFA 2.2) following standard test guidelines. Phenanthrene dose-relatedly affected the survival and reproduction of E. albidus with median lethal concentration and median effective concentration (EC50) values of 135 and 33 mg/kg dry soil, respectively. A toxicokinetics study, performed at a nontoxic soil concentration of 8 mg/kg, showed uptake and elimination rate constants of 4.91 kg soil per kilogram fresh weight animal per day and 0.236 per day, respectively and a bioaccumulation factor (BAF) of 20.8 kg soil per kilogram fresh weight animal. These results show that the three-week exposure in the toxicity test with E. albidus is sufficiently long to reach equilibrium, but also that PHE may accumulate to considerable levels, possibly causing a risk for predators. PMID- 21309020 TI - Can we reduce the number of fish in the OECD acute toxicity test? AB - OECD (Organisation for Economic Co-operation and Development) Guideline 203, Fish Acute Toxicity Test, states that the test should be performed using at least five concentrations in a geometric series with a separation factor not exceeding 2.2, with at least seven fish per concentration. However, the efficiency of this design can be questioned, because it often results in only one concentration that causes partial mortality (mortality >0% and <100%). We performed Monte Carlo computer simulations to assess whether more efficient designs could allow reductions in fish use. Simulations indicated that testing with six fish per concentration could yield 50% lethal concentration (LC50) estimates of quality similar to those obtained using seven fish. Experts attending a workshop organized to consider this finding and to identify the best methods for reducing fish use concluded that significant reductions could best be achieved by modifying the test paradigm. They suggested initiating testing using a 96-h fish embryo test instead of juvenile fish to cover the range from the upper threshold concentration (the lowest 50% effective concentration [EC50] in existing algae and daphnia studies) to the highest concentration with no mortality. This would be followed by a confirmatory limit test with juvenile fish at the highest concentration with no mortality or by a full test with juvenile fish, if a point estimate of the LC50 is required. PMID- 21309021 TI - Changes in agglomeration of fullerenes during ingestion and excretion in Thamnocephalus platyurus. AB - The crustacean Thamnocephalus platyurus was exposed to aqueous suspensions of fullerenes C(60) and C(70) . Aqueous fullerene suspensions were formed by stirring C(60) and C(70) as received from a commercial vendor in deionized water (termed aqu/C(60) and aqu/C(70) ) for approximately 100 d. The Z-average (mean hydrodynamic) diameters of aqu/C(60) and aqu/C(70) aggregates as measured by dynamic light scattering were 517 +/- 21 nm and 656 +/- 39 nm (mean +/- 95% confidence limit), respectively. Exposure of T. platyurus to fullerene suspensions resulted in the formation of dark masses in the digestive track visible under a stereo microscope (*40 magnification). Fullerene ingestion over 1 h of exposure was quantitatively determined after extraction and analysis by high performance liquid chromatography-mass spectrometry (HPLC-MS). One-hour exposures (at 3 mg/L and 6 mg/L) resulted in aqu/C(60) burdens of 2.7 +/- 0.4 ug/mg and 6.8 +/- 1.5 ug/mg wet weight, respectively. Thin-section transmission electron microscopy (TEM) images of aqu/C(60) -exposed T. platyurus showed the formation in the gut of fullerene agglomerates (5-10 um) that were an order of magnitude larger than the suspended fullerene agglomerates. Upon excretion, the observed fullerene agglomerates were in the 10- to 70-um size range and settled to the bottom of the incubation wells. In contrast to the control polystyrene microspheres, which dispersed after depuration, the aqu/C(60) agglomerates (greater than two orders of magnitude larger than the suspended fullerenes) remained agglomerated for up to six months. When exposed to fullerenes, T. platyurus shows the potential to influence agglomerate size and may facilitate movement of these nanoparticles from the water column into sediment. PMID- 21309022 TI - Validation of Ontario's new laboratory-based bioaccumulation methods with in situ field data. AB - To validate the standardization of a laboratory protocol for measuring bioaccumulation, laboratory-derived tissue residues and biota-sediment accumulation factors (BSAFs) were compared with historical field data from nine sites in Ontario, Canada. As a result of temporal discontinuity between the field and the laboratory studies, a priori considerations, such as changes in site conditions or concentrations of contaminants in sediment, were necessary to assess whether to compare absolute or relative measures of bioaccumulation. For the majority of sites, BSAFs for field-collected and laboratory-exposed fish were within a factor of 2. Biota-sediment accumulation factors for laboratory-exposed oligochaetes were typically greater than those for mussels caged in the field, by a factor of 2 to 9. Overall, the laboratory methods for all species generally overestimated the relative bioavailability of contaminants compared with field conditions by a factor of 1.1 to 9.2. Other than the great disparity observed for polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) between field and laboratory studies, on average the laboratory-derived BSAFs with Pimephales promelas and Lumbriculus variegatus overestimated those from field-collected fish and field-exposed mussels by factors of 1.6 and 3.6, respectively. The laboratory method reflects a potentially worst-case exposure scenario and provides an appropriately conservative estimate of bioaccumulation. Laboratory-based estimates can be comparable to bioaccumulation data from the field but may be confounded by species-specific differences in routes of exposure and bioaccumulation of certain compounds or other environmental and biological factors that should be considered in these comparisons. PMID- 21309023 TI - Effects of aging and mixed nonaqueous-phase liquid sources in soil systems on earthworm bioaccumulation, microbial degradation, sequestration, and aqueous desorption of pyrene. AB - The effects of loading and aging pyrene in soils in the presence of four environmentally common nonaqueous-phase liquids (NAPLs) (hexadecane, 2,2,4,4,6,8,8-heptamethylnonane [HMN], toluene, and dimethyl phthalate [DMP]) on its subsequent desorption from those soils, earthworm accumulation, biodegradation, and extractability were tested by using two dissimilar soils. The presence of each of the four NAPLs increased fractions and rates of pyrene desorption, and hexadecane slowed the effects of aging on these same parameters. Loading with hexadecane and HMN caused earthworm accumulation of pyrene to decrease. These results contrast with generally observed faster desorption rates resulting from NAPL addition, suggesting that additional factors (e.g., association of pyrene with NAPL phases and NAPL toxicities to earthworms) may impact bioaccumulation. The presence of HMN and toluene increased pyrene biodegradation, whereas hexadecane and DMP had the opposite effects. These results correlate with changes in the extractability of pyrene from the soils. After aging and biodegradation, hexadecane and DMP substantially increased pyrene residues extractable by methanol and decreased nonextractable fractions, whereas HMN and toluene had the opposite effects. PMID- 21309024 TI - Pesticide and toxicity reduction using an integrated vegetated treatment system. AB - The California, USA, central coast is one of the most productive agricultural areas in the world, and numerous stakeholders are working there to implement conservation practices to reduce contaminated runoff. Practices include vegetated treatment systems (VTS) designed to promote contaminant reduction and breakdown. The current study evaluated the effectiveness of a vegetated drainage ditch incorporating a sedimentation basin, a vegetated section, and a Landguard organophosphate-A (OP-A) enzyme dosing system. The VTS was constructed on a working farm and was designed to remove organophosphate and pyrethroid pesticides, the primary pesticides causing toxicity in Salinas Valley watersheds. The present study was conducted during five separate irrigation events on tailwater runoff containing mixtures of pesticides and suspended sediments. Water samples were collected at four stations within the system, and these were subjected to chemical analyses and tested for toxicity to Ceriodaphnia dubia. All inflow samples were highly toxic to C. dubia, and this was largely because of diazinon. Treatment of diazinon-contaminated runoff was only partially effective using aquatic vegetation. All diazinon remaining after vegetated treatment was effectively removed after treatment with the Landguard OP-A enzyme. Chemical analysis of the VTS water samples showed that pyrethroid and organochlorine pesticide concentrations in water were greatly reduced in the sedimentation section of the ditch, and these pesticides were further reduced in the vegetated section of the ditch. The overall conclusion from these analyses is that the VTS was effective at reducing the more hydrophobic organochlorine and pyrethroid pesticides from water. The water-soluble pesticide diazinon was not sufficiently removed during the VTS residence times observed in this study; however, residual diazinon was effectively removed using Landguard OP-A. PMID- 21309025 TI - Effect of humic substances on toxicity of inorganic oxidizer bioluminescent monitoring. AB - The current study deals with the effect of humic substances (HS) on toxicity of solutions of a model inorganic oxidizer, potassium ferricyanide. Chemical reactions responsible for toxicity changes are under consideration. The bioluminescent system of coupled enzymatic reactions catalyzed by bacterial luciferase and oxidoreductase was used as a bioassay. General and oxidative toxicity of ferricyanide solutions were evaluated. Ability of HS to decrease or increase general and oxidative toxicity of the solutions was revealed. Two types of chemical processes are supposed to be responsible for detoxification by HS: ferricyanide-HS complex formation and acceleration of endogenous redox reactions in the bioluminescent assay system. Decrease of oxidative toxicity of ferricyanide solution was observed under incubation with HS at all concentrations of HS used. Conditions for general toxicity decrease were prior incubation of ferricyanide with HS and low HS concentrations (< 10-4g/L). Acceleration of NADH auto-oxidation under higher HS concentrations was supposed to result in a toxicity increase. PMID- 21309026 TI - Survival and precopulatory guarding behavior of Hyalella azteca (Amphipoda) exposed to nitrate in the presence of atrazine. AB - Nitrate is one of the most commonly detected contaminants found in aquatic systems with other pesticides such as atrazine. The current study examined potential combined effects of nitrate and atrazine on adults of the freshwater amphipod Hyalella azteca, using survival and precopulatory guarding behavior as toxic endpoints. Although significant differences in acute toxicity with nitrate alone and in binary combination with atrazine (200 ug/L) in water-only tests were not consistently observed for each time point, potential biologically relevant trends in the data were observed. Posttest growth and behavioral observations (10 day period) conducted after 96-hour exposure suggested that atrazine and nitrate at these concentrations did not result in delayed effects on H. azteca. However, when test conditions were modified from standard toxicity tests by feeding amphipods, nitrate was found to be more toxic, with a reduction in median lethal concentration (LC50) values of approximately 80%. We also demonstrated that nitrate exhibits a dose-response effect on precopulatory guarding behavior of H. azteca, suggesting that reproductive effects may occur at environmentally relevant concentrations. PMID- 21309027 TI - Use of vegetated agricultural drainage ditches to decrease pesticide transport from tomato and alfalfa fields in California, USA. AB - Irrigation and storm water runoff from agricultural fields has the potential to cause impairment to downstream aquatic receiving systems. Over the last several years, scientists have discovered the benefit of using edge-of-field practices, such as vegetated agricultural drainage ditches, in the mitigation of pesticides and sediment. After demonstrating this practice's feasibility in California, field trials were initiated to document irrigation runoff pesticide mitigation in California alfalfa and tomato fields. In the alfalfa field, chlorpyrifos concentration was decreased by 20% from the inflow to the ditch outflow. Thirty two percent of the measured chlorpyrifos mass was associated with ditch plant material. In the tomato field, permethrin concentration was decreased by 67% and there was a 35% reduction in suspended sediment concentration from inflow to the ditch outflow. When surface water was not present in the ditch systems, the sediment was a significant repository for pesticides. Based on the field trials, vegetated agricultural drainage ditches can be successfully used as part of a suite of management practices to reduce pesticide and sediment runoff into aquatic receiving systems. PMID- 21309028 TI - Proteomics in aquatic amphipods: can it be used to determine mechanisms of toxicity and interspecies responses after exposure to atrazine? AB - Proteomics has gained popularity in the field of ecotoxicology as a holistic tool for unraveling novel mechanisms of toxicity and elucidating subtle effects of contaminant exposure. The holoarctic amphipod Diporeia spp. is declining at precipitous rates in the Great Lakes, and we are evaluating the use of the well studied amphipod model Hyalella azteca as a surrogate for Diporeia spp. This article presents proteomics data from both amphipod species exposed to atrazine (ATZ) and one of its metabolites, desethylatrazine (DEA; 3 and 30 ug/L for 21 and 42 d). We used a proteomics approach to determine whether these two species of amphipods responded similarly to the same chemicals and to understand better the mechanisms of toxicity of ATZ and DEA in aquatic invertebrates. We observed disruption in energy production and mitochondrial function as well as hormesis in exposed organisms. In addition, we identified a two proteins (GAPDH and HSP 90 kDa) that have been linked to hormonal disruptions, suggesting potential endocrine disruption. Finally, we found that H. azteca and Diporeia spp. responded with similar proteomic profiles after ATZ and DEA exposure, suggesting that H. azteca may be used as a surrogate model organism for Diporeia spp. PMID- 21309029 TI - Bacterial gene profiling assay applied as an alternative method for mode of action classification: pilot study using chlorinated anilines. AB - Polar narcotic structural analogues (e.g., chlorinated anilines with a differing degree of chlorosubstitution, such as aniline, 4-chloroaniline, 3,5 dichloroaniline, and 2,3,4-trichloroaniline) are assumed to induce their toxic effects via the same predominant mode of action (MOA; membrane damage) at equitoxic exposure concentrations. In this study, a bacterial gene profiling assay consisting of 14 general stress genes was used to test this hypothesis for these four compounds. Although we found a consistent induction of membrane damage, the response cascade and the extent of the response differed among the different chemical treatments. The higher chlorosubstituted anilines also triggered significantly more genes involved in other general stress MOA classes (oxidative stress and protein perturbation). These findings illustrate that, along with the commonly used physicochemistry-based MOA categorization methods, alternative tests such as the bacterial gene profiling assay can yield valuable biological information on the MOA of a certain chemical or group of chemicals that is crucial in high-quality environmental risk assessment. In a second phase, the experimental gene profiling data sets of the chlorinated anilines were analyzed and weighed against existing data on other polar and non polar narcotic compounds to obtain a broader comparison in which the predefined chemical MOAs (narcosis and polar narcosis) were contrasted with the biological MOAs (gene expression profiles). Although additional optimization of the assay is needed, our results show that the bacterial gene profiling assay opens new perspectives for biology-based chemical grouping, thereby further enabling targeted MOA-based risk assessment. PMID- 21309030 TI - Describing structural changes by extending HGVS sequence variation nomenclature. AB - New technologies allow rapid discovery of novel sequence variants among which those involving complex structural rearrangements. The description of such complex variants challenges the existing standard sequence variation nomenclature of the Human Genome Variation Society (HGVS, http://www.hgvs.org/mutnomen), because this mainly focuses on simple variants. Here, we suggest several extensions of the HGVS nomenclature guidelines to facilitate unambiguous description of complex sequence variants at the DNA level. These include: (1) nesting to support description of changes within inversions and duplications, and (2) composite changes to support concatenation of inserted sequences. The advantage of these additions is that inversions and duplications with small differences and more complex variants can be described without reverting to the less informative indel description. In addition, they should provide sufficient flexibility and consistency, thereby limiting alternative interpretations and ambiguous descriptions. The specifications should allow easy implementation in sequence variant nomenclature checkers (e.g., Mutalyzer, http://www.mutalyzer.nl/). We are extending the functionality of Mutalyzer to incorporate the latest version of the HGVS sequence variation nomenclature guidelines. PMID- 21309031 TI - Homozygosity mapping on a single patient: identification of homozygous regions of recent common ancestry by using population data. AB - Homozygosity mapping has played an important role in detecting recessive mutations using families of consanguineous marriages. However, detection of regions identical and homozygosity by descent (HBD) when family data are not available, or when relationships are unknown, is still a challenge. Making use of population data from high-density SNP genotyping may allow detection of regions HBD from recent common founders in singleton patients without genealogy information. We report a novel algorithm that detects such regions by estimating the population haplotype frequencies (HF) for an entire homozygous region. We also developed a simulation method to evaluate the probability of HBD and linkage to disease for a homozygous region by examining the best regions in unaffected controls from the host population. The method can be applied to diseases of Mendelian inheritance but can also be extended to complex diseases to detect rare founder mutations that affect a very small number of patients using either multiplex families or sporadic cases. Testing of the method on both real cases (singleton affected) and simulated data demonstrated its superb sensitivity and robustness under genetic heterogeneity. PMID- 21309032 TI - BioGrid Australia facilitates collaborative medical and bioinformatics research across hospitals and medical research institutes by linking data from diverse disease and data types. AB - BioGrid Australia is a federated data linkage and integration infrastructure that uses the Internet to enable patient specific information to be utilized for research in a privacy protected manner, from multiple databases of various data types (e.g. clinical, treatment, genomic, image, histopathology and outcome), from a range of diseases (oncological, neurological, endocrine and respiratory) and across more than 20 health services, universities and medical research institutes. BioGrid has demonstrated an ability to facilitate powerful research into the causation of human disease and the prediction of disease and treatment outcomes. BioGrid has successfully implemented technology and processes that allow researchers to efficiently extract data from multiple sources, without compromising data security and privacy. This article reviews BioGrid's first seven years and how it has overcome 9 of its top 10 challenges. PMID- 21309033 TI - Dendritic cells from humans with hypomorphic mutations in IKBKG/NEMO have impaired mitogen-activated protein kinase activity. AB - The covalent attachment of lysine 63-linked polyubiquitin to the zinc-finger domain of IKBKG/NEMO (also known as IKKgamma) is necessary for full activation of NF-kappaB. Impairments of this biochemical mechanism explain the deleterious effects of hypomorphic NEMO mutations on NF-kappaB signaling function in humans suffering from X-linked ectodermal dysplasia and immunodeficiency. Nevertheless, the biological function of the NEMO zinc-finger domain in the regulation of mitogen-activated protein kinase (MAPK) activity is poorly understood. Here we show that dendritic cells from patients with EDI caused by a C-terminal E391X deletion of the zinc finger of NEMO exhibit impaired MAPK activation in response to lipopolysaccharide (LPS) stimulation. Interestingly, DCs from patients with a C417R missense mutation within the zinc finger domain of NEMO in which ubiquitination of NEMO is preserved are also defective in JNK and ERK activity following LPS stimulation. Our findings indicate that the structural integrity of the NEMO ZF domain is more important than its polyubiquitination for full activation of the MAPK. Furthermore, phosphorylation and polyubiquitination of upstream TAK1 were significantly reduced in the E391X zinc-finger deleted patients, indicating that the NEMO zinc finger may play an important role in assembling the proximal signaling complex for MAPK activation. PMID- 21309034 TI - Loss of dermatan-4-sulfotransferase 1 (D4ST1/CHST14) function represents the first dermatan sulfate biosynthesis defect, "dermatan sulfate-deficient adducted thumb-clubfoot syndrome". PMID- 21309035 TI - A SImplified method for Segregation Analysis (SISA) to determine penetrance and expression of a genetic variant in a family. AB - A method for SImplified rapid Segregation Analysis (SISA) to assess penetrance and expression of genetic variants in pedigrees of any complexity is presented. For this purpose the probability for recombination between the variant and the gene is zero. An assumption is that the variant of undetermined significance (VUS) is introduced into the family once only. If so, all family members in between two members demonstrated to carry a VUS, are obligate carriers. Probabilities for cosegregation of disease and VUS by chance, penetrance, and expression, may be calculated. SISA return values do not include person identifiers and need no explicit informed consent. There will be no ethical complications in submitting SISA return values to central databases. Values for several families may be combined. Values for a family may be updated by the contributor. SISA is used to consider penetrance whenever sequencing demonstrates a VUS in the known cancer-predisposing genes. Any family structure at hand in a genetic clinic may be used. One may include an extended lineage in a family through demonstrating the same VUS in a distant relative, and thereby identifying all obligate carriers in between. Such extension is a way to escape the selection biases through expanding the families outside the clusters used to select the families. PMID- 21309036 TI - Recurrence and variability of germline EPCAM deletions in Lynch syndrome. AB - Recently, we identified 3' end deletions in the EPCAM gene as a novel cause of Lynch syndrome. These truncating EPCAM deletions cause allele-specific epigenetic silencing of the neighboring DNA mismatch repair gene MSH2 in tissues expressing EPCAM. Here we screened a cohort of unexplained Lynch-like families for the presence of EPCAM deletions. We identified 27 novel independent MSH2-deficient families from multiple geographical origins with varying deletions all encompassing the 3' end of EPCAM, but leaving the MSH2 gene intact. Within The Netherlands and Germany, EPCAM deletions appeared to represent at least 2.8% and 1.1% of the confirmed Lynch syndrome families, respectively. MSH2 promoter methylation was observed in epithelial tissues of all deletion carriers tested, thus confirming silencing of MSH2 as the causative defect. In a total of 45 families, 19 different deletions were found, all including the last two exons and the transcription termination signal of EPCAM. All deletions appeared to originate from Alu-repeat mediated recombination events. In 17 cases regions of microhomology around the breakpoints were found, suggesting nonallelic homologous recombination as the most likely mechanism. We conclude that 3' end EPCAM deletions are a recurrent cause of Lynch syndrome, which should be implemented in routine Lynch syndrome diagnostics. PMID- 21309037 TI - Characterization of MSH2 variants by endogenous gene modification in mouse embryonic stem cells. AB - Mutations in the mismatch repair gene MSH2 underlie hereditary nonpolyposis colorectal cancer (Lynch syndrome). Whereas disruptive mutations are overtly pathogenic, the implications of missense mutations found in sporadic colorectal cancer patients or in suspected Lynch syndrome families are often unknown. Adequate genetic counseling of mutation carriers requires phenotypic characterization of the variant allele. We present a novel approach to functionally characterize MSH2 missense mutations. Our approach involves introduction of the mutation into the endogenous gene of murine embryonic stem cells (ESC) by oligonucleotide-directed gene modification, a technique we recently developed in our lab. Subsequently, the mismatch repair capacity of mutant ESC is determined using a set of validated functional assays. We have evaluated four clinically relevant MSH2 variants and found one to completely lack mismatch repair capacity while three behaved as wild-type MSH2 and can therefore be considered as polymorphisms. Our approach contributes to an adequate risk assessment of mismatch repair missense mutations. We have also shown that oligonucleotide-directed gene modification provides a straightforward approach to recreate allelic variants in the endogenous gene in murine ESC. This approach can be extended to other hereditary conditions. PMID- 21309038 TI - Induction of phenotype modifying cytokines by FERMT1 mutations. AB - Kindler syndrome (KS) is a progressive skin disorder caused by FERMT1 mutations. Early in life, KS manifests as a mechanobullous disease reflecting diminished cell adhesion, but the mechanisms of its later phenotypic features, progressive poikiloderma, and mucocutaneous fibrosis, remain elusive. The FERMT1 gene product and KS protein, kindlin-1, is an epithelial-specific phosphoprotein involved in integrin beta-1 activation, without an obvious link to dermal connective tissue. Here we show how lack of intracellular kindlin-1 in epidermal keratinocytes leads to profound changes in another skin compartment, the dermis. Kindlin-1-deficient keratinocytes respond to cell stress by upregulating the expression of cytokines such as IL-20, IL-24, TGF-beta2, IL1F5, PDGFB, and CTGF. These launch-via paracrine communication-an inflammatory response in the dermis, accompanied by the presence of TGF-beta, IL-6, and CTGF, activation of fibroblasts and their differentiation to myofibroblasts, which secrete and deposit increased amounts of extracellular matrix proteins. These data are concordant with a model wherein repeated cycles of epidermal cell stress, cytokine secretion, dermal inflammation, and profibrotic processes underlie mucocutaneous fibrosis in KS. PMID- 21309039 TI - Functional assessment of variants in the TSC1 and TSC2 genes identified in individuals with Tuberous Sclerosis Complex. AB - The effects of missense changes and small in-frame deletions and insertions on protein function are not easy to predict, and the identification of such variants in individuals at risk of a genetic disease can complicate genetic counselling. One option is to perform functional tests to assess whether the variants affect protein function. We have used this strategy to characterize variants identified in the TSC1 and TSC2 genes in individuals with, or suspected of having, Tuberous Sclerosis Complex (TSC). Here we present an overview of our functional studies on 45 TSC1 and 107 TSC2 variants. Using a standardized protocol we classified 16 TSC1 variants and 70 TSC2 variants as pathogenic. In addition we identified eight putative splice site mutations (five TSC1 and three TSC2). The remaining 24 TSC1 and 34 TSC2 variants were classified as probably neutral. PMID- 21309040 TI - Databases in the area of pharmacogenetics. AB - In the area of pharmacogenetics and personalized health care it is obvious that databases, providing important information of the occurrence and consequences of variant genes encoding drug metabolizing enzymes, drug transporters, drug targets, and other proteins of importance for drug response or toxicity, are of critical value for scientists, physicians, and industry. The primary outcome of the pharmacogenomic field is the identification of biomarkers that can predict drug toxicity and drug response, thereby individualizing and improving drug treatment of patients. The drug in question and the polymorphic gene exerting the impact are the main issues to be searched for in the databases. Here, we review the databases that provide useful information in this respect, of benefit for the development of the pharmacogenomic field. PMID- 21309041 TI - Sideroblastic anemia: molecular analysis of the ALAS2 gene in a series of 29 probands and functional studies of 10 missense mutations. AB - X-linked Sideroblastic Anemia (XLSA) is the most common genetic form of sideroblastic anemia, a heterogeneous group of disorders characterized by iron deposits in the mitochondria of erythroid precursors. XLSA is due to mutations in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene. Thirteen different ALAS2 mutations were identified in 16 out of 29 probands with sideroblastic anemia. One third of the patients were females with a highly skewed X-chromosome inactivation. The identification of seven novel mutations in the ALAS2 gene, six missense mutations, and one deletion in the proximal promoter extends the allelic heterogeneity of XSLA. Most of the missense mutations were predicted to be deleterious, and 10 of them, without any published functional characterization, were expressed in Escherichia coli. ALAS2 activities were assayed in vitro. Five missense mutations resulted in decreased enzymatic activity under standard conditions, and two other mutated proteins had decreased activity when assayed in the absence of exogenous pyridoxal phosphate and increased thermosensitivity. Although most amino acid substitutions result in a clearly decreased enzymatic activity in vitro, a few mutations have a more subtle effect on the protein that is only revealed by in vitro tests under specific conditions. PMID- 21309042 TI - Emerging landscape of genomics in the Electronic Health Record for personalized medicine. AB - The Information Technology (IT) roadmap for personalized medicine requires Electronic Health Records (EHRs), extension of Healthcare IT (HIT) standards, and understanding of how genetics/genomics should be integrated into the clinical applications. For reduced overall costs and development times, these three initiatives should run in parallel. EHRs must contain structured data and infrastructure that enables quality analysis, Clinical Decision Support (CDS) and messaging within the healthcare information network. Fortunately, as a result of sustained financial commitment to nongenetic-based healthcare, the industry has HIT data standards and understanding of EHR functionality that improves patient safety and outcomes while reducing overall healthcare costs. However, the HIT standards and EHR functional requirements, needed for personalized medicine, are only beginning to support simple genetic tests and need significant extension. In addition, our understanding of the clinical implications of genomic data is evolving and translation of new discovery into clinical care remains a challenge. Therefore, priority areas include CDS, educational resources, and knowledgebases for the EHR, clinical and research data warehouses, messaging frameworks, and continued review of healthcare policies and regulations supporting personalized medicine. Where core infrastructure remains to be developed and implemented, funding is needed for pilot projects, data standards, policy, and stakeholder collaboration. PMID- 21309043 TI - Prediction of single-nucleotide substitutions that result in exon skipping: identification of a splicing silencer in BRCA1 exon 6. AB - Missense, nonsense, and translationally silent mutations can inactivate genes by altering the inclusion of mutant exons in mRNA, but their overall frequency among disease-causing exonic substitutions is unknown. Here, we have tested missense and silent mutations deposited in the BRCA1 mutation databases of unclassified variants for their effects on exon inclusion. Analysis of 21 BRCA1 variants using minigene assays revealed a single exon-skipping mutation c.231G>T. Comprehensive mutagenesis of an adjacent 12-nt segment showed that this silent mutation resulted in a higher level of exon skipping than the 35 other single-nucleotide substitutions. Exon inclusion levels of mutant constructs correlated significantly with predicted splicing enhancers/silencers, prompting the development of two online utilities freely available at http://www.dbass.org.uk. EX-SKIP quickly estimates which allele is more susceptible to exon skipping, whereas HOT-SKIP examines all possible mutations at each exon position and identifies candidate exon-skipping positions/substitutions. We demonstrate that the distribution of exon-skipping and disease-associated substitutions previously identified in coding regions was biased toward top-ranking HOT-SKIP mutations. Finally, we show that proteins 9G8, SC35, SF2/ASF, Tra2, and hnRNP A1 were associated with significant alterations of BRCA1 exon 6 inclusion in the mRNA. Together, these results facilitate prediction of exonic substitutions that reduce exon inclusion in mature transcripts. PMID- 21309045 TI - Country of birth, socioeconomic factors, and risk factor control in patients with type 2 diabetes: a Swedish study from 25 primary health-care centres. AB - BACKGROUND: Few large-scale studies have examined the association between sociodemographic factors and the probability of reaching the recommended levels of haemoglobin A1c (HbA(1c)) and blood lipids in patients with type 2 diabetes. The aim was to investigate whether sociodemographic characteristics of patients with type 2 diabetes affected the odds that they would reach recommended levels of blood lipids and HbA(1c). METHODS: This study included 2912 men and 2136 women, in the age group of 35-74, with diagnosed type 2 diabetes from 25 primary health-care centres in Stockholm, Sweden. National population registers were linked to clinical data from electronic records and logistic regression was used to estimate odds ratios. RESULTS: Less than half of the men and women with diabetes reached the recommended levels of HbA(1c). Even fewer reached the recommended levels for total cholesterol and low-density lipoprotein cholesterol. The gender differences favoured women, for HbA(1c) and men, for blood lipids. Individuals with the lowest income levels were less likely to reach the recommended level of HbA(1c). Country of birth showed that immigrants from Middle Eastern countries and other countries had lower odds of reaching the recommended levels of HbA(1c). CONCLUSION: This study confirmed that risk factor control among patients with type 2 diabetes treated in primary health care is inadequate and that sociodemographic factors were associated with metabolic control. Future studies could include new strategies for the control of modifiable risk factors in patients with type 2 diabetes. PMID- 21309044 TI - New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations. AB - Autosomal dominant cutis laxa (ADCL) is characterized by a typical facial appearance and generalized loose skin folds, occasionally associated with aortic root dilatation and emphysema. We sequenced exons 28-34 of the ELN gene in five probands with ADCL features and found five de novo heterozygous mutations: c.2296_2299dupGCAG (CL-1), c.2333delC (CL-2), c.2137delG (CL-3), c.2262delA (monozygotic twin CL-4 and CL-5), and c.2124del25 (CL-6). Four probands (CL-1,-2, 3,-6) presented with progressive aortic root dilatation. CL-2 and CL-3 also had bicuspid aortic valves. CL-2 presented with severe emphysema. Electron microscopy revealed elastic fiber fragmentation and diminished dermal elastin deposition. RT PCR studies showed stable mutant mRNA in all patients. Exon 32 skipping explains a milder phenotype in patients with exon 32 mutations. Mutant protein expression in fibroblast cultures impaired deposition of tropoelastin onto microfibril containing fibers, and enhanced tropoelastin coacervation and globule formation leading to lower amounts of mature, insoluble elastin. Mutation-specific effects also included endoplasmic reticulum stress and increased apoptosis. Increased pSMAD2 staining in ADCL fibroblasts indicated enhanced transforming growth factor beta (TGF-beta) signaling. We conclude that ADCL is a systemic disease with cardiovascular and pulmonary complications, associated with increased TGF-beta signaling and mutation-specific differences in endoplasmic reticulum stress and apoptosis. PMID- 21309046 TI - Diabetes mellitus, other medical conditions and pancreatic cancer: a case-control study. AB - BACKGROUND: Diabetes and other medical conditions have been related to pancreatic cancer, but time risk quantification is unsettled. METHODS: We combined data from two case-control studies conducted in Italy, including 688 pancreatic cancer cases and 2204 controls. All subjects were interviewed by trained interviewers during their hospital stay. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using multiple logistic regression. RESULTS: Overall, 103 cases (15%) and 125 controls (5.7%) reported a history of diabetes. The OR for pancreatic cancer was more pronounced among those diagnosed with diabetes in the previous 2 years (OR = 5.17; 95% CI = 2.71-9.87) than among those with diabetes diagnosed more than 2 years ago (OR = 2.35; 95% CI = 1.70-3.26). The ORs remained significantly elevated 2-4 years (OR = 3.81; 95% CI = 2.07-7.04) and 5-9 years (OR = 3.75; 95% CI = 2.13-6.59) since diagnosis of diabetes, after which a non-significant 20% increased risk for pancreatic cancer was observed. As compared to non-diabetic non-smokers, the OR was 1.85 among non-diabetic current smokers, 2.17 among diabetic never/former smokers, and rose to 4.67 among diabetic current smokers, indicating a multiplicative effect between these two risk factors. Pancreatic cancer was significantly associated with pancreatitis, primarily among those diagnosed within 2 years (OR = 7.16; 95% CI = 2.25-22.78). In addition, the ORs were elevated for cholelithiasis (3.53; 95% CI = 1.67-7.45) and gastroduodenal ulcer (3.16; 95% CI = 1.14-8.73) only among those diagnosed within the past 2 years. CONCLUSIONS: Diabetes is associated with heightened risk of pancreatic cancer. The association is significant for diabetes diagnosed up to 10 years before pancreatic cancer. PMID- 21309047 TI - The role of metabolic and haemodynamic factors in podocyte injury in diabetes. AB - SUMMARY: Podocyte loss is a common feature in human diabetes as well as in experimental diabetes in rodents. Almost all components of the diabetic milieu lead to serious podocyte stress, driving the cells towards cell cycle arrest and hypertrophy, detachment and apoptosis. Common pathway components induced by high glucose and advanced glycation end-products are reactive oxygen species, cyclin dependent kinases (p27(Kip1)) and transforming growth factor-beta. In addition, mechanical stresses by stretch or shear forces, insulin deficiency or insulin resistance are independent components resulting in podocyte apoptosis and detachment. In this review, we discuss the common pathways leading to podocyte death as well as novel pathways and concepts of podocyte dedifferentiation and detachment that influence the progression of diabetic glomerulopathy. PMID- 21309048 TI - The potential of multimer technologies in type 1 diabetes prediction strategies. AB - Type 1 diabetes is an autoimmune disease which occurs in (human leukocyte antigen) genetically predisposed individuals as a consequence of the organ specific immune destruction of the insulin-producing beta cells in the islets of Langherans within the pancreas. Type 1 diabetes is the result of a breakdown in immune regulation that leads to expansion of autoreactive CD4+ and CD8+ T cells, autoantibody-producing B lymphocytes and activation of the innate immune system. Islet-related autoantibodies revealed themselves to be good predictors of future onset of the disease, although they are not directly pathogenetic; T cells instead play a dominant role in disease initiation and progression. In this review, we first discuss the approaches that several laboratories attempted to measure human islet autoantigen-specific T-cell function in type 1 diabetes. T cell assays could be used in combination with standardized autoantibody screenings to improve predictive strategies. They could also help to monitor in long-term follow-up the efficacy of tolerogenic immunotherapeutic strategies when established at the onset of the disease, and help to predict the recurrence of disease. Although some recent developments based on enzyme-linked immunosorbent spot and immunoblotting techniques have been able to distinguish with good sensitivity and specificity patients from controls, T-cell results, as revealed by international workshops, were indeed largely inconclusive. Nowadays, novel technologies have been exploited that could contribute to answering the tantalizing question of identifying autoreactive T cells. We particularly focus on and discuss MHC multimer tools and emphasize the advantages they can offer but also their weaknesses when used in combination with other T-cell assays. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 21309049 TI - Expanding the clinical use of standard OGTT: the percentage increment of 2 h with respect to fasting glucose as an index of beta-cell dysfunction. AB - AIMS: Since glucose levels during oral glucose tolerance test (OGTT) are determined both by insulin sensitivity and insulin secretion, we investigated whether the percentage increment (PG%) of 2-h plasma glucose (2hPG) over fasting plasma glucose (FPG) is related to validated indexes of insulin sensitivity and insulin secretion. METHODS: Using Stumvoll's formulas we calculated estimated insulin sensitivity index and first-phase insulin secretion in 1281 subjects who underwent a standard OGTT. The ratio first-phase insulin secretion/(1/estimated insulin sensitivity index) was considered a surrogate index of beta-cell function. For each subject we calculated PG% using the formula: [(2hPG - FPG)/FPG] * 100. For each glucose tolerance group we formed tertiles based on PG% values. RESULTS: In each glucose tolerance group, beta-cell function was better preserved in lower PG% tertiles, demonstrating a correlation between PG% and insulin resistance. CONCLUSIONS: By a simple calculation, our study allows, expansion of the clinical use of OGTT to recognize subjects liable to further worsening of glucose homeostasis, independent from glucose tolerance groupings. PMID- 21309050 TI - 24-Hour Fasting with Diabetes: guide to physicians advising patients on medication adjustments prior to religious observances (or outpatient surgical procedures). AB - Patients with diabetes may undergo an approximately 24-h fast for a voluntary religious observance or in preparation for a medical procedure. Commonly, patients will manage their diabetes before and during such fasting without guidelines from their doctors, often because they did not ask for advice. The physician should therefore take the lead in advising patients how to fast safely, in order to avoid the situation wherein the patient manages medication changes on his/her own. Furthermore, it sends a message to the patient that having diabetes does not preclude living a reasonably 'normal' life, even when it comes to religious observances. PMID- 21309051 TI - Decreased variation of inflammatory markers in gestational diabetes. AB - BACKGROUND: Gestational diabetes is a prediabetic state. Sub-clinical inflammation may play a role in the transition from gestational diabetes to type 2 diabetes; the role of the autonomic nervous system as a mediating system has been raised. We aimed to study the association of the sympathetic nervous system and sub-clinical inflammation in women with gestational diabetes. METHODS: We studied 41 Caucasian women with gestational diabetes and 22 healthy pregnant and 14 non-pregnant controls. We assayed plasma noradrenaline, insulin, C-reactive protein, interleukin-6, insulin growth factor-1, serum amyloid A, steroid hormone binding globulin, alpha-1 acid glycoprotein and cortisol at 2400, 0400 and 0700 h. RESULTS: No differences existed in the concentrations of inflammatory markers between gestational diabetes and normal pregnancy but women with gestational diabetes showed loss of variation in C-reactive protein and serum amyloid A. Levels of hormone-binding globulin were lower in hypertensive compared with normotensive women with gestational diabetes at all time points and lowest at midnight when alpha-1 acid glycoprotein levels were higher in hypertensive women. CONCLUSIONS: Gestational diabetes is associated with loss of natural variation of C-reactive protein and serum amyloid A, suggesting altered modulation of inflammation. Hypertension in gestational diabetes seems not to be associated with higher levels of inflammatory markers other than alpha-1 acid glycoprotein. PMID- 21309052 TI - High-protein low-carbohydrate diets: what is the rationale? AB - Dietary recommendations released by the large majority of international scientific committees and organizations suggest that the diet for the prevention and treatment of the most compelling health problems of our societies (obesity, diabetes, atherosclerosis, cardiovascular diseases and cancer) should be a diet moderately low in caloric content, low in fat content (particularly in saturated fat), poor in total cholesterol and rich in fibre. Despite this uniformity in official recommendations, alternative diets with low carbohydrate and high protein content continue to be extremely popular within consumers and patients. Recently, new studies seem to suggest that high-protein low-carbohydrate diets may have particularly positive effects on reducing body weight and other risk factors for heart disease. Gannon and Nuttall conducted direct comparisons of high-protein low-carbohydrate diets compared with high-carbohydrate low-protein diets in subjects with type 2 diabetes. They found that high-protein low carbohydrate diets reduced fasting plasma glucose, 24-h glucose area under the curve and haemoglobin A(1c). On the basis of these results, a joint committee of the American Diabetes Association, North American Society for the Study of Obesity and the American Society for Clinical Nutrition suggested that a low carbohydrate diet may be preferred to a low-fat diet for the induction of weight loss and glycaemic control in subjects with type 2 diabetes. What is the rationale? What mechanisms are involved? PMID- 21309053 TI - The emerging role of NO and IGF-1 in early renal hypertrophy in STZ-induced diabetic rats. AB - BACKGROUND: Diabetic nephropathy (DN) is a major complication of diabetes mellitus, and the most common cause of end-stage renal disease. DN is characterized by early hyperfiltration and renal hypertrophy, which are associated with increased renal insulin-like growth factor-1 (IGF-1) levels. The relationship between IGF-1 and nitric oxide (NO) in DN is not established. The aim of this study was to investigate the effects of NO system modulation on the IGF-1-mediated hypertrophy and hyperfiltration during the first week after diabetes induction. METHODS: Diabetes was induced in rats by streptozotocin (STZ) injection. Diabetic rats were treated with NO synthase inhibitor L-NG nitroarginine methyl ester (L-NAME). Various serum IGF-binding proteins (IGFBPs) and renal IGFBP1 expression was evaluated. Urine and plasma NO(2) + NO(3) level analysis was also performed. RESULTS: STZ induced hyperglycaemia decreased plasma insulin levels and brought about a decrease in body weight. L-NAME administration to diabetic rats significantly prevented renal hypertrophy and hyperfiltration. Serum IGFBP3, IGFBP4 and 30-kDa IGFBP fraction were all significantly reduced in diabetic rats, compared with those in non-diabetic control rats. However, the renal IGFBP1 mRNA expression in diabetic rats was significantly higher. These changes were accompanied by an increased in NO production. L-NAME administration prevented the serum IGFBP decline, without significantly affecting the renal IGFBP1 mRNA expression. CONCLUSIONS: We have shown that increased renal IGF-1 and increased NO production during the very early stages of STZ-induced DN are associated with renal hypertrophy and hyperfiltration in diabetic rats. Modulating the IGF-1 availability to the kidney by nitric oxide synthase inhibition significantly reduced renal hypertrophy and hyperfiltration during the first week of STZ-induced diabetes mellitus. PMID- 21309054 TI - Alterations of platelet biochemical and functional properties in newly diagnosed type 1 diabetes: a role in cardiovascular risk? AB - BACKGROUND: The involvement of platelets in the pathogenesis of diabetic vascular complications is supported by several studies. Type 1 diabetic (T1D) platelets show increased adhesiveness and aggregation related to a modification of nitric oxide synthase activity. Moreover, different cell types from diabetic patients showed a decreased membrane Na(+) /K(+) -ATPase activity, which might be involved in diabetic complications. The aim of this study was to investigate whether T1D at onset is able to induce alterations of platelet physicochemical and functional properties and whether these changes are affected by hyperglycaemia. METHODS: The study was performed on 50 young subjects: 30 patients (1-14 years) affected by T1D and 20 age- and gender-matched healthy subjects. We analyzed platelet membrane fluidity by fluorescent anisotropy of 1-(4-trimethylaminophenyl)-6 phenyl-1,3,5-hexatriene and 1,6-diphenyl-1,3,5-hexatriene, Na(+) /K(+) -ATPase, nitric oxide, and peroxynitrite production. RESULTS: In T1D subjects, we observed an increased fluidity in the plasma membrane outer part and greater rigidity in the internal part compared with that in controls. Na(+) /K(+) -ATPase activity and nitric oxide levels were significantly reduced, while peroxynitrite production was increased compared with that in controls. Moreover, correlations found between the above parameters were correlated with fasting glycaemia and haemoglobin A(1c). CONCLUSIONS: T1D patients exhibit structural and functional modifications of platelet membrane properties and alterations of nitric oxide metabolism due to diabetes per se and not to chronic hyperglycaemia, insulin therapy, or ageing. These results support the hypothesis that oxidative attack could be an important early event in the pathogenesis of diabetic complications. PMID- 21309055 TI - Insulin therapy has a complex relationship with measure of oxidative stress in type 2 diabetes: a case for further study. AB - BACKGROUND: Because pharmacotherapies in type 2 diabetes exert complex effects, we examined the different anti-diabetic strategies, especially the influence of insulin doses, on the activation of oxidative stress, a key player in atherosclerosis, ageing and the risk of cancer. METHODS: This observational study included 122 persons with type 2 diabetes, 61 treated with oral hypoglycaemic agents alone (group I), 61 treated with a combination of oral hypoglycaemic agents and insulin at either a low dose (<0.40 unit/kg/day, group IIa, n = 30) or high dose (>=0.40 unit/kg/day, group IIb, n = 31) of insulin. Oxidative stress was estimated from 24-h urinary excretion rates of 8-iso-prostaglandin F2alpha. Haemoglobin A(1c) (%) was also measured to assess overall diabetic control. RESULTS: The 24-h excretion rates of 8-iso-prostaglandin F2alpha [median (range) pmol/mmol of creatinine] were much lower in group IIa [68 (32-220)] than in either group I [120 (26-329) p < 0.001] or group IIb [101 (30-289) p = 0.026]. Considering groups IIa and IIb as a whole, a significant and positive relationship (p = 0.021) was observed between insulin dose and 8-iso prostaglandin F2alpha. Haemoglobin A(1c) was comparable in the three groups. CONCLUSIONS: The main benefit of insulin therapy is the restoration and maintenance of near normal glycaemia. However insulin at elevated doses can promote oxidative stress which is thought to be an important mediator of some of the deleterious effects of insulin. Our study shows that the link between insulin action and oxidative stress in type 2 diabetes is complex and warrants further study. PMID- 21309056 TI - Pulmonary fibrosis: a possible diabetic complication. AB - Diabetic complications affect many organs in diabetic patients. Emerging evidence indicates that diabetes can increase the risk of pulmonary dysfunction. Early epidemiological studies from different populations on whether diabetes was an independent risk for pulmonary dysfunction were inconclusive. Recent epidemiological studies and systematic reviews clearly indicate that diabetes is an independent risk factor for pulmonary dysfunction. Given that pulmonary fibrosis is an important predictor of mortality in people with this chronic disease, whether diabetes directly causes pulmonary fibrosis is an important unresolved clinical question. This review combines recent epidemiological data with findings from basic research to indicate that diabetes induces pulmonary fibrosis. We then discuss the possible underlying mechanisms for the histological and biochemical pathology. At the end of this review, we emphasize that diabetic pulmonary fibrosis as a potential diabetic complication warrants more attention. PMID- 21309057 TI - Cannabinoid/agonist WIN 55,212-2 reduces cardiac ischaemia-reperfusion injury in Zucker diabetic fatty rats: role of CB2 receptors and iNOS/eNOS. AB - BACKGROUND: Diabetes increases cardiac damage after myocardial ischaemia. Cannabinoids can protect against myocardial ischaemia/reperfusion injury. The aim of this study was to examine the cardioprotective effect of the cannabinoid agonist WIN 55,212-2 (WIN) against ischaemia/reperfusion injury in an experimental model of type 2 diabetes. We performed these experiments in the Zucker diabetic fatty rat, and focused on the role of cannabinoid receptors in modulation of cardiac inducible nitric oxide synthase (iNOS)/endothelial-type nitric oxide synthase (eNOS) expression. METHODS: Male 20-week-old Zucker diabetic fatty rats were treated with vehicle, WIN, the selective CB1 or CB2 receptor antagonists AM251 and AM630, respectively, AM251 + WIN or AM630 + WIN. Hearts were isolated from these rats, and the cardiac functional response to ischaemia/reperfusion injury was evaluated. In addition, cardiac iNOS and eNOS expression were determined by western blot. RESULTS: WIN significantly improved cardiac recovery after ischaemia/ reperfusion in the hearts from Zucker diabetic fatty rats by restoring coronary perfusion pressure and heart rate to preischaemic levels. Additionally, WIN decreased cardiac iNOS expression and increased eNOS expression after ischaemia/reperfusion in diabetic hearts. WIN induced cardiac functional recovery was completely blocked by the CB2 antagonist AM630. However, changes in NOS isoenzyme expression were not affected by the CB antagonists. CONCLUSIONS: This study shows a cardioprotective effect of a cannabinoid agonist on ischaemia/reperfusion injury in an experimental model of a metabolic disorder. The activation mainly of CB2 receptors and the restoration of iNOS/eNOS cardiac equilibrium are mechanisms involved in this protective effect. These initial studies have provided the basis for future research in this field. PMID- 21309058 TI - Direct effects of FGF21 on glucose uptake in human skeletal muscle: implications for type 2 diabetes and obesity. AB - BACKGROUND: Fibroblast growth factor (FGF) 21, a novel member of the FGF family, plays a role in a variety of endocrine functions, including regulation of glucose and lipid metabolism. The role of FGF21 in skeletal muscle is currently not known. METHODS: Serum levels and skeletal muscle mRNA of FGF21 were determined in normal glucose tolerant (n = 40) and type 2 diabetic (T2D; n = 40) subjects. We determined whether FGF21 has direct effects on glucose metabolism in cultured myotubes (n = 8) and extensor digitorum longus skeletal muscle. RESULTS: Serum FGF21 levels increased 20% in T2D versus normal glucose tolerant subjects (p < 0.05), whereas skeletal muscle mRNA expression was unaltered. Fasting insulin, homeostatic model assessment of insulin resistance (HOMA-IR), waist circumference, and body mass index (BMI) significantly correlated with serum FGF21 levels in T2D (p < 0.01), but not in normal glucose tolerant subjects. Serum FGF21 concentrations were greater in T2D patients in the highest tertile of fasting insulin (p < 0.05) and BMI (p < 0.05). Stepwise regression analysis identified BMI as the strongest independent variable correlating with FGF21. FGF21 exposure increased basal and insulin-stimulated glucose uptake in human myotubes, coincident with increased glucose transporter 1 mRNA, and enhanced glucose transporter 1 abundance at the plasma membrane. In isolated extensor digitorum longus muscle, FGF21 potentiated insulin-stimulated glucose transport, without altering phosphorylation of Akt or AMP-activated protein kinase. CONCLUSIONS: Plasma FGF21 is increased in T2D patients, and positively correlated with fasting insulin and BMI. However, FGF21 has direct effects in enhancing skeletal muscle glucose uptake, providing additional points of regulation that may contribute to the beneficial effects of FGF21 on glucose homeostasis. Whether increased plasma FGF21 in T2D is a compensatory mechanism to increase glucose metabolism remains to be determined. PMID- 21309059 TI - Independent and combined associations of abdominal obesity and seated resting heart rate with type 2 diabetes among older Chinese: the Guangzhou Biobank Cohort Study. AB - BACKGROUND: Central obesity and poor physical fitness predict the development of type 2 diabetes and cardiovascular mortality among Caucasian populations. We studied the independent and combined effect of abdominal obesity and seated resting heart rate used as an indicator of physical fitness, on the presence of type 2 diabetes among 30 519 older residents of Guangzhou, Southern China. METHODS: Participants were stratified into four groups, based on the Asian criteria for abdominal obesity (>=90/>= 80 cm in men/women) and the 75% cut-off point for seated resting heart rate (>=83 beats per min). The association with type 2 diabetes was assessed using multivariable logistic regression. RESULTS: A total of 3777 (12.7%) volunteers were diagnosed with type 2 diabetes, which was independently associated with seated resting heart rate and, in particular, increasing levels of abdominal obesity (p < 0.001). An odds ratio of 3.93 (95% confidence interval = 3.48-4.43) was identified for type 2 diabetes in participants who were obese with a seated resting heart rate >= 83 beats per min after adjusting for potential confounders. CONCLUSIONS: Higher seated resting heart rate, a marker of poor physical fitness, independently doubles the risk of type 2 diabetes. The strength of this association is further increased when abdominal obesity is considered. PMID- 21309060 TI - Long-term diabetic complications may be ameliorated by targeting Rho kinase. AB - This review addresses the roles of Rho/Rho-kinase (ROCK) pathway in the pathogenesis of diabetes complications. Diabetes can cause many serious complications and can result in physical disability or even increased mortality. However, there are not many effective ways to treat these complications. The small guanosine-5'-triphosphate-binding protein Rho and its downstream target Rho kinase mediate important cellular functions, such as cell morphology, motility, secretion, proliferation, and gene expression. Recently, the Rho/Rho-kinase pathway has attracted a great deal of attention in diabetes-related research. These studies have provided evidence that the activity and gene expression of Rho kinase are upregulated in some tissues in animal models of type 1 or type 2 diabetes and in cell lines cultured with high concentrations of glucose. Inhibitors of Rho-kinase could prevent or ameliorate the pathological changes in diabetic complications. The inhibitory effects of statins on the Rho/Rho-kinase signalling pathway may also play a role in the prevention of diabetic complications. However, the precise molecular mechanism by which the Rho/Roh kinase pathway participates in the development or progression of diabetic complications has not been extensively investigated. This article evaluates the relationship between Rho/Roh-kinase activation and diabetic complications, as well as the roles of Roh-kinase inhibitors and statins in the complications of diabetes, with the objective of providing a novel target for the treatment of long-term diabetic complications. PMID- 21309061 TI - Contributions of dysglycaemia, obesity, and insulin resistance to impaired endothelium-dependent vasodilation in humans. AB - BACKGROUND: Individual effects of hyperglycaemia and obesity to impair vascular health are recognized. However, the relative contributions of dysglycaemia versus other obesity-related traits to vascular dysfunction have not been systematically evaluated. METHODS: We undertook a cross-sectional evaluation of factors contributing to vascular function in 271 consecutive subjects, categorized as non obese normal glucose tolerant (n = 115), non-obese dysglycaemic (n = 32), obese normal glucose tolerant (n = 57), obese dysglycaemic (n = 38), or type 2 diabetic (n = 29). Vascular function was measured invasively as leg blood flow responses to methacholine chloride, an endothelium-dependent vasodilator. Categorical and continuous analyses were carried out to assess the contributions of hyperglycaemia to vascular dysfunction. RESULTS: Even among normoglycaemic subjects, obese subjects had impaired vascular function compared to non-obese subjects (p = 0.004). Vascular function was also impaired in non-obese dysglycaemic subjects (p = 0.04 versus non-obese normoglycaemic subjects), to a level comparable to normoglycaemic obese subjects. Within obese subject groups, gradations of dysglycaemia including the presence of diabetes were not associated with further worsening of these vascular responses beyond the effect of obesity alone (p = not significant comparing all obese groups, p < 0.001 versus lean normoglycaemic subjects). After univariate and multivariable modelling analyses we found that effects of glycaemia were less powerful than effects of insulin resistance and obesity on vascular dysfunction. CONCLUSIONS: Dysglycaemia contributes to impaired vascular function in non-obese subjects, but obesity and insulin resistance are more important determinants of vascular function in obese and diabetic subjects. PMID- 21309062 TI - Predictors of response to dipeptidyl peptidase-4 inhibitors: evidence from randomized clinical trials. AB - AIM: Dipeptidyl peptidase-4 (DPP-4) inhibitors are used in the treatment of type 2 diabetes. Available sub-group analysis of clinical trials does not allow a clear identification of predictors of therapeutic response to these drugs. The aim of this study is the assessment of predictors of response to DPP-4 inhibitors. MATERIALS AND METHODS: A meta-analysis was performed, exploring correlation between 24-week effects on HbA(1c) of maximal doses of DPP-4 inhibitors, compared either with placebo or with other active drugs, matches to baseline characteristics of patients enrolled in 63 randomized clinical trials, either published or unpublished but disclosed on different websites were studied. RESULTS: DPP-4 inhibitors significantly reduce HbA(1c) at 24 weeks [by 0.6 (0.5 0.7)%] when compared with placebo; no difference in HbA(1c) was observed in comparisons with thiazolidinediones and alpha-glucosidase inhibitors, whereas sulfonylureas and metformin produced a greater reduction of HbA(1c) , at least in the short term. DPP-4 inhibitors produced a smaller weight gain than thiazolidinediones, and showed a lower hypoglycaemia risk than sulfonylureas. The placebo-subtracted effect of DPP-4 inhibitors on HbA(1c) was greater in older patients and in those with lower fasting plasma glucose at baseline. Similar results were obtained in comparisons with thiazolidinediones and metformin. CONCLUSIONS: Although drugs for type 2 diabetes are studied in heterogeneous samples of patients, their efficacy can be predicted by some clinical parameters. DPP-4 inhibitors appear to be more effective in older patients with mild/moderate fasting hyperglycaemia. These data could be useful for a better definition of the profile of patients who are likely to benefit most from these drugs. PMID- 21309063 TI - Effects of insulin and oral anti-diabetic agents on glucose metabolism, vascular dysfunction and skeletal muscle inflammation in type 2 diabetic subjects. AB - BACKGROUND: To test potential differences between the actions of anti-diabetic medications, we examined the effects of oral hypoglycaemic agents versus glargine apidra insulin therapy in T2DM. METHODS: T2DM subjects were randomized to either oral hypoglycaemic agents (pioglitazone, metformin and glipizide, n = 9) or insulin therapy (n = 12) for 6 months. Carotid intimal media thickness, vascular reactivity (flow-mediated vasodilatation; percent change in brachial artery basal diameter post-ischaemia) and sublingual nitrate were measured with ultrasonography. Euglycemic hyperinsulinemic (80 mU/m(2) ) clamp with [3]-3H glucose and muscle biopsies were performed. RESULTS: Fasting plasma glucose (~257 to ~124 mg/dL, oral hypoglycaemic agents and ~256 to ~142 mg/dL, IT) and HbA(1c) (~10.3 to ~6.4%, OHA and ~10.7 to ~7.1%, IT) improved comparably. Endogenous glucose production (~2.1 to ~1.7 mg/kg/min, oral hypoglycaemic agents and ~2.3 to ~2.0 mg/kg/min, insulin therapy) and endogenous glucose production suppression by insulin (~0.4 to ~0.3 mg/kg min, oral hypoglycaemic agents and ~0.5 to ~0.7 mg/kg min, insulin therapy) were different. Total glucose disposal * 100 increased in the oral hypoglycaemic agents group (~5.2 to ~8.1; p = 0.03), but not in insulin therapy (~6.0 to ~5.4 mg/kg/min/uU/mL * 100). OHA reduced CIMT (~0.080 to ~0.068 cm; p < 0.05), whereas insulin therapy did not (~0.075 to ~0.072 cm). After sublingual nitrate, brachial artery basal diameter increased in the OHA group (~8.7 to ~18.2%), but not in insulin therapy (~11.2 to ~15.0%; p < 0.02). Except for plasma adiponectin (~7 to ~15, oral hypoglycaemic agents versus ~6 to ~10, IT), changes in inflammatory markers in the circulation and in muscle (IkappaBalpha, super-oxidase dismutase 2, monocyte-chemo-attractant protein 1, p ERK and JNK) were equivalent. CONCLUSIONS: Oral hypoglycaemic agents and insulin therapy treated patients achieved adequate glycemic control and the effects on circulating and muscle inflammatory biomarkers were similar, but only oral hypoglycaemic agents improved insulin sensitivity, vascular function and carotid intimal media thickness. These findings in a small sample suggest that the use of oral hypoglycaemic agents provides additional benefits to patients with T2DM. PMID- 21309064 TI - Molecular genetics of supernumerary tooth formation. AB - Despite advances in the knowledge of tooth morphogenesis and differentiation, relatively little is known about the aetiology and molecular mechanisms underlying supernumerary tooth formation. A small number of supernumerary teeth may be a common developmental dental anomaly, while multiple supernumerary teeth usually have a genetic component and they are sometimes thought to represent a partial third dentition in humans. Mice, which are commonly used for studying tooth development, only exhibit one dentition, with very few mouse models exhibiting supernumerary teeth similar to those in humans. Inactivation of Apc or forced activation of Wnt/beta(catenin signalling results in multiple supernumerary tooth formation in both humans and in mice, but the key genes in these pathways are not very clear. Analysis of other model systems with continuous tooth replacement or secondary tooth formation, such as fish, snake, lizard, and ferret, is providing insights into the molecular and cellular mechanisms underlying succesional tooth development, and will assist in the studies on supernumerary tooth formation in humans. This information, together with the advances in stem cell biology and tissue engineering, will pave ways for the tooth regeneration and tooth bioengineering. PMID- 21309065 TI - The eye as an organizer of craniofacial development. AB - The formation and invagination of the optic stalk coincides with the migration of cranial neural crest (CNC) cells, and a growing body of data reveals that the optic stalk and CNC cells communicate to lay the foundations for periocular and craniofacial development. Following migration, the interaction between the developing eye and surrounding periocular mesenchyme (POM) continues, leading to induction of transcriptional regulatory cascades that regulate craniofacial morphogenesis. Studies in chick, mice, and zebrafish have revealed a remarkable level of genetic and mechanistic conservation, affirming the power of each animal model to shed light on the broader morphogenic process. This review will focus on the role of the developing eye in orchestrating craniofacial morphogenesis, utilizing morphogenic gradients, paracrine signaling, and transcriptional regulatory cascades to establish an evolutionarily-conserved facial architecture. We propose that in addition to the forebrain, the eye functions during early craniofacial morphogenesis as a key organizer of facial development, independent of its role in vision. PMID- 21309066 TI - Sox9 function in craniofacial development and disease. AB - The Sox family of transcriptional regulators has been implicated in the control of a broad array of developmental processes. One member of this family SOX9 was first identified as a candidate gene for campomelic dysplasia (CD), a human syndrome affecting skeletal, and testis development. In these patients most endochondral bones of the face fail to develop resulting in multiple defects such as micrognathia, cleft palate, and facial dysmorphia. In this review we describe Sox9 expression during embryonic development and summarize loss of function experiments in frog, fish, and mouse embryos highlighting the role of Sox9 in regulating morphogenesis of the face. We also discuss the mutations in and around SOX9 responsible for craniofacial defects in CD patients. PMID- 21309067 TI - Generation and characterization of iUBC-KikGR photoconvertible transgenic mice for live time-lapse imaging during development. AB - A transgenic mouse line named iUBC-KikGR was generated, which expresses the photoconvertible fluorescent protein Kikume Green-Red (KikGR) under the control of the human Ubiquitin C promoter. KikGR is natively a green fluorophore, which can be converted into a red fluorophore upon exposure to UV light. KikGR is expressed broadly throughout transgenic embryos from the two-cell stage onward and in the adult. Specificity of photoconversion can range from the entire embryo to a region of an organ, to a few individual cells, depending on the needs of the experimenter. Cell movements, tissue reorganization, and migration can then be observed in real time by culturing the tissue of interest as an explant on the microscope stage. The iUBC-KikGR transgenic line represents a singular genetic reagent, which can be used for fate mapping, lineage tracing, and live visualization of cell behaviors and tissue movements in multiple organs at multiple time points. PMID- 21309068 TI - Generation of two modified mouse alleles of the Hic1 tumor suppressor gene. AB - HIC1 (hypermethylated in cancer 1) is a tumor suppressor gene located on chromosome 17p13.3, a region frequently hypermethylated or deleted in human neoplasias. In mouse, Hic1 is essential for embryonic development and exerts an antitumor role in adult animals. Since Hic1-deficient mice die perinatally, we generated a conditional Hic1 null allele by flanking the Hic1-coding region by loxP sites. When crossed to animals expressing Cre recombinase in a cell-specific manner, the Hic1 conditional mice will provide new insights into the function of Hic1 in developing and mature tissues. Additionally, we used gene targeting to replace sequence-encoding amino acids 186-893 of Hic1 by citrine fluorescent protein cDNA. We demonstrate that the distribution of Hic1-citrine fusion polypeptide corresponds to the expression pattern of wild-type Hic1. Consequently, Hic1-citrine "reporter" mice can be used to monitor the activity of the Hic1 locus using citrine fluorescence. PMID- 21309069 TI - Unsuspected effects of a lung-specific Cre deleter mouse line. AB - Cre-expressing mouse lines constitute an important asset to mammalian genetics, allowing the deletion of genes in a spatio-temporal specific manner. Our study on Hox gene function in lung development has led us to use a lung endoderm-specific deletion with the Sftpc-cre mouse line expressing the Cre recombinase gene under the control of human surfactant protein C regulatory sequences. In control experiments, the Cre recombinase faithfully activated the Rosa26-lacZ reporter gene in lung epithelium. However as early as e15.5, lungs from Sftp-Cre(+) embryos showed abnormal dilated cysts. This unexpected phenotype was also observed in mice carrying the conditional lung epithelial Hoxa5 deletion, indicating some bias due to Cre deleterious effects. Excessive apoptosis, likely due to Cre toxicity, could explain the abnormal cysts. Our findings illustrate the need for appropriate control experiments and careful interpretation of data to discriminate between the phenotype due to the targeted mutation and the confounding effects of the Cre recombinase. PMID- 21309070 TI - Reptilian tooth development. AB - Dental patterns in vertebrates range from absence of teeth to multiple sets of teeth that are replaced throughout life. Despite this great variation, most of our understanding of tooth development is derived from studies on just a few model organisms. Here we introduce the reptile as an excellent model in which to study the molecular basis for early dental specification and, most importantly, for tooth replacement. We review recent snake studies that highlight the conserved role of Shh in marking the position of the odontogenic band. The distinctive molecular patterning of the dental lamina in the labial-lingual and oral-aboral axes is reviewed. We explain how these early signals help to specify the tooth-forming and non-tooth forming sides of the dental lamina as well as the presumptive successional lamina. Next, the simple architecture of the reptilian enamel organ is contrasted with the more complex, mammalian tooth bud and we discuss whether or not there is an enamel knot in reptilian teeth. The role of the successional lamina during tooth replacement in squamate reptiles is reviewed and we speculate on the possible formation of a vestigial, post-permanent dentition in mammals. In support of these ideas, we present data on agamid teeth in which development of a third generation is arrested. We suggest that in diphyodont mammals, similar mechanisms may be involved in reducing tooth replacement capacity. Finally, we review the location of label-retaining cells and suggest ways in which these putative dental epithelial stem cells contribute to continuous tooth replacement. PMID- 21309071 TI - Mouse resources for craniofacial research. AB - The mouse, as a genetically defined and easily manipulated model organism, has played a critical role in unraveling the mechanisms of craniofacial development and dysmorphology. While numerous gene knockout strains that display craniofacial abnormalities and essential recombinase tool strains with craniofacial-specific expression have been generated, many are absent from public repositories. Large scale, international resource-generating initiatives promise to address this concern, providing a comprehensive set of targeted mutations and a suite of new Cre driver strains. In addition, panels of genetically defined strains provide tools to dissect the multigenic, complex nature of craniofacial development, adding to the foundation of information gained from single gene studies. Continued progress will require awareness and access to these essential mouse resources. In this review, current mouse resources, large-scale efforts, and potential future directions will be outlined and discussed. PMID- 21309072 TI - Rho signaling pathway and apical constriction in the early lens placode. AB - Epithelial invagination in many model systems is driven by apical cell constriction, mediated by actin and myosin II contraction regulated by GTPase activity. Here we investigate apical constriction during chick lens placode invagination. Inhibition of actin polymerization and myosin II activity by cytochalasin D or blebbistatin prevents lens invagination. To further verify if lens placode invaginate through apical constriction, we analyzed the role of Rho ROCK pathway. Rho GTPases expression at the apical portion of the lens placode occurs with the same dynamics as that of the cytoskeleton. Overexpression of the pan-Rho inhibitor C3 exotoxin abolished invagination and had a strong effect on apical myosin II enrichment and a mild effect on apical actin localization. In contrast, pharmacological inhibition of ROCK activity interfered significantly with apical enrichment of both actin and myosin. These results suggest that apical constriction in lens invagination involves ROCK but apical concentration of actin and myosin are regulated through different pathways upstream of ROCK. genesis 49:368-379, 2011. PMID- 21309073 TI - Pax6 regulates craniofacial form through its control of an essential cephalic ectodermal patterning center. AB - Normal patterning and morphogenesis of the complex skeletal structures of the skull requires an exquisite, reciprocal cross-talk between the embryonic cephalic epithelia and mesenchyme. The mesenchyme associated with the jaws and the optic and olfactory capsules is derived from a Hox-negative cranial neural crest (CNC) population that acts much as an equivalence group in its interactions with specific local cephalic epithelial signals. Craniofacial pattern and morphogenesis is therefore controlled in large part through the regulation of these local cephalic epithelial signals. Here, we demonstrate that Pax6 is essential to the formation and maturation of the complex cephalic ectodermal patterning centers that govern the development and morphogenesis of the upper jaws and associated nasal capsules. Previous examinations of the craniofacial skeletal defects associated with Pax6 mutations have suggested that they arise from an optic-associated blockage in the migration of a specific subpopulation of midbrain CNC to the lateral frontonasal processes. We have addressed an alternative explanation for the craniofacial skeletal defects. We show that in Pax6(SeyN/SeyN) mutants regional CNC is present by E9.25 while there is already specific disruption in the early ontogenetic elaboration of cephalic ectodermal expression, associated with the nascent lambdoidal junction, of secreted signaling factors (including Fgf8 and Bmp4) and transcription factors (including Six1 and Dlx5) essential for upper jaw and/or nasal capsular development. Pax6 therefore regulates craniofacial form, at stages when CNC has just arrived in the frontonasal region, through its control of surface cephalic ectodermal competence to form an essential craniofacial patterning center. PMID- 21309074 TI - A mart-1::Cre transgenic line induces recombination in melanocytes and retinal pigment epithelium. AB - The number of transgenic mouse lines expressing Cre in either type of pigment cells (melanocytes and retinal pigment epithelium, RPE) is limited, and the available lines do not always offer sufficient specificity. In this study, we addressed this issue and we report on the generation of a MART-1::Cre BAC transgenic mouse line, in which the expression of Cre recombinase is controlled by regulatory elements of the pigment cell-specific gene MART-1 (mlana). When MART-1::Cre BAC transgenic mice were bred with the ROSA26-R reporter line, beta galactosidase expression was observed in RPE from E12.5 onwards, and in melanocyte precursors from E17.5, indicating that the MART-1::Cre line provides Cre recombinase activity in pigment-producing cells rather than in a particular lineage. In addition, breeding of this mouse line to mice carrying a conditional allele of RBP-Jkappa corroborated the reported phenotypes in both pigment cell lineages, inducing hair greying and microphthalmia. Our results thus suggest, that the MART-1::Cre line may serve as a novel and useful tool for functional studies in melanocytes and the RPE.genesis 49:403-409, 2011. PMID- 21309075 TI - A resilience perspective on biofuel production. AB - The recent investment boom and collapse of the corn ethanol industry calls into question the long-term sustainability of traditional approaches to biofuel technologies. Compared with petroleum-based transportation fuels, biofuel production systems are more closely connected to complex and variable natural systems. Especially as biofeedstock production itself becomes more independent of fossil fuel-based supports, stochasticity will become an increasingly important, inherent feature of biofuel feedstock production systems. Accordingly, a fundamental change in design philosophy is necessary to ensure the long-term viability of the biofuels industry. To respond effectively to unexpected disruptions, the new approach will require systems to be designed for resilience (indicated by diversity, efficiency, cohesion, and adaptability) rather than more narrowly defined measures of efficiency. This paper addresses important concepts in the design of coupled engineering-ecological systems (resistance, resilience, adaptability, and transformability) and examines biofuel conversion technologies from a resilience perspective. Conversion technologies that can accommodate multiple feedstocks and final products are suggested to enhance the diversity and flexibility of the entire industry. PMID- 21309076 TI - Predictive modeling of selenium accumulation in brine shrimp in saline environments. AB - Great Salt Lake, Utah, is a large, terminal, hypersaline lake consisting of a northern more saline arm and a southern arm that is less saline. The southern arm supports a seasonally abundant fauna of low diversity consisting of brine shrimp (Artemia franciscana), 7 species of brine flies, and multiple species of algae. Although fish cannot survive in the main body of the lake, the lake is highly productive, and brine shrimp and brine fly populations support large numbers of migratory waterfowl and shorebirds, as well as resident waterfowl, shorebirds, and gulls. Selenium and other trace elements, metals, and nutrients are contaminants of concern for the lake because of their concentrations in municipal and industrial outfalls and runoff from local agriculture and the large urban area of Salt Lake City. As a consequence, the State of Utah recently recommended water quality standards for Se for the southern arm of Great Salt Lake based on exposure and risk to birds. The tissue-based recommendations (as measured in bird eggs) were based on the understanding that Se toxicity is predominately expressed through dietary exposure, and that the breeding shorebirds, waterfowl, and gulls of the lake are the receptors of most concern. The bird egg-based recommended standards for Se require a model to link bird egg Se concentrations to their dietary concentrations and water column values. This study analyzes available brine shrimp tissue Se data from a variety of sources, along with waterborne and water particulate (potential brine shrimp diet) Se concentrations, in an attempt to develop a model to predict brine shrimp Se concentrations from the Se concentrations in surrounding water. The model can serve as a tool for linking the tissue-based water quality standards of a key dietary item to waterborne concentrations. The results were compared to other laboratory and field-based models to predict brine shrimp tissue Se concentrations from ambient water and their diet. No significant relationships were found between brine shrimp and their dietary Se, as measured by seston concentrations. The final linear and piecewise regression models showed significant positive relationships between waterborne and brine shrimp tissue Se concentrations but with a very weak predictive ability for waterborne concentrations<10 ug/L. PMID- 21309077 TI - Assessing the roles of environmental factors in coastal fish production in the northern Baltic Sea: a Bayesian network application. AB - Environmental conditions play a crucial role in the distribution and abundance of fish species in any area. Much research has been attributed to the requirements and tolerance limits of commercially exploited fish species. It is rare, however, that studies have been able to address the relative importance of potentially restrictive environmental factors; extensive enough to allow for estimation of the effect of several environmental factors through the fishes' life span. The coastline of Finland in the northern Baltic Sea offers a unique natural experimental setting that can be used to assess the relative importance of various environmental factors for the species occupying it. The area includes major variations in several crucial environmental factors: salinity, temperature regime, represented by winter ice duration, coastline characteristics, and eutrophic status. Furthermore, Finland has collected extensive and spatially representative data of water quality and environmental factors, as well as a long and extraordinarily spatially detailed data set of commercial catches of several fish species. In this article, we make an attempt to correlate the environmental data to the commercial catches of fish species, assuming that the commercial catches reflect, to some reasonable degree, the productivity of that species in that area (compared to other areas and combinations of environmental factors, not to other species). We use a Bayesian network approach to examine the sensitivity of the species to the environmental factors. PMID- 21309078 TI - Toward sustainability: a case study demonstrating transdisciplinary learning through the selection and use of indicators in a decision-making process. AB - The purpose of this article is to use a case study example to demonstrate how a transparent, transdisciplinary approach to decision making allows the US Environmental Protection Agency Region III (USEPA Region III) to fulfill its decision-making responsibilities while taking critical steps toward engaging in sustainability discussions. The case study goals were to use information about environmental condition to inform staff and fiscal resource prioritization and allocation for the federal 2010 fiscal year. This article will use a select group of 3 indicators to show 1) that data are not the same as indicators, 2) the feasibility of using disparate data in the same analysis, and 3) specific discussions about indicators can lead to transdisciplinary learning, supporting more informed decision making. We show that, when used in a transdisciplinary learning process, these indicator lessons provide a stepping stone for organizations like USEPA Region III to consider sustainability as more than just a lofty, ethical concept. Instead, these kinds of organizations can more routinely and substantively address sustainability through a progression of individual decisions. We discuss how sustainability can be linked to decision making through a process that requires stakeholders to articulate and confront their values. In this process, selecting indicators and understanding what those choices imply regarding the issues that are highlighted and the population affected is part of the assessment of environmental condition, which is the focus of the case study. PMID- 21309079 TI - Use of multicriteria involvement processes to enhance transparency and stakeholder participation at Bergen Harbor, Norway. AB - Use of participatory stakeholder engagement processes could be important to reduce the risk of potential conflicts in managing contaminated sites. Most stakeholder engagement techniques are qualitative in nature and require experienced facilitators. This study proposes a multicriteria involvement process to enhance transparency and stakeholder participation and applies it to a contaminated sediment management case study for Bergen Harbor, Norway. The suggested multicriteria involvement process builds on the quantitative principles of multicriteria decision analysis and also incorporates group interaction and learning through qualitative participatory methods. Three different advisory groups consisting of local residents, local stakeholders, and nonresident sediment experts were invited to participate in a stakeholder engagement process to provide consensual comparative advice on sediment remediation alternatives. In order for stakeholders or residents to be able to embrace a complex decision such as selection of remediation alternatives, the involvement process with lateral learning, combined with multicriteria decision analysis providing structure, robustness and transparent documentation was preferable. In addition, a multicriteria involvement process resulted in consistent ranking of remediation alternatives across residents, stakeholder, and experts, relative to individual intuitive ranking without the multicriteria involvement process. PMID- 21309080 TI - Imaging circuit formation in zebrafish. AB - The study of nervous system development has been greatly facilitated by recent advances in molecular biology and imaging techniques. These approaches are perfectly suited to young transparent zebrafish where they have allowed direct observation of neural circuit assembly in vivo. In this review we will highlight a number of key studies that have applied optical and genetic techniques in zebrafish to address questions relating to axonal and dendritic arbor development,synapse assembly and neural plasticity. These studies have revealed novel cellular phenomena and modes of growth that may reflect general principles governing the assembly of neural circuits. PMID- 21309081 TI - Development of the cerebellum and cerebellar neural circuits. AB - The cerebellum, a structure derived from the dorsal part of the most anterior hindbrain, is important for integrating sensory perception and motor control. While the structure and development of the cerebellum have been analyzed most extensively in mammals,recent studies have shown that the anatomy and development of the cerebellum is conserved between mammals and bony fish (teleost) species, including zebrafish. In the mammalian and teleost cerebellum,Purkinje and granule cells serve, respectively, as the major GABAergic and glutamatergic neurons. Purkinje cells originate in the ventricular zone (VZ), and receive inputs from climbing fibers. Granule cells originate in the upper rhombic lip (URL) and receive inputs from mossy fibers. Thus, the teleost cerebellum shares many features with the cerebellum of other vertebrates, and isa good model system for studying cerebellar function and development. The teleost cerebellum also has features that are specific to teleosts or have not been elucidated in mammals, including eurydendroid cells and adult neurogenesis. Furthermore, the neural circuitry in part of the optic tectum and the dorsal hindbrain closely resembles the circuitry of the teleost cerebellum; hence,these are called cerebellum-like structures. Here we describe the anatomy and development of cerebellar neurons and their circuitry, and discuss the possible roles of the cerebellum and cerebellum-like structures in behavior and higher cognitive functions. We also consider the potential use of genetics and novel techniques for studying the cerebellum in zebrafish. PMID- 21309082 TI - The role of selective transport in neuronal polarization. AB - Neurons are functionally and morphologically polarized and possess two distinct types of neurites: axons and dendrites. Key molecules for axon formation are transported along microtubules and accumulated at the distal end of the nascent axons. In this review, we summarize recent advances in the understanding of the mechanisms involved in selective transport in neurons. In addition, we focus on motor proteins, cargo, cargo adaptors, and the loading and unloading of cargo. PMID- 21309083 TI - Otx genes in neurogenesis of mesencephalic dopaminergic neurons. AB - Mesencephalic-diencephalic dopaminergic (mdDA) neurons play a relevant role in the control of movement, behavior, and cognition. Indeed loss and/or abnormal functioning of mdDA neurons are responsible for Parkinson's disease as well as for addictive and psychiatric disorders. In the last years a wealth of information has been provided on gene functions controlling identity, fate, and proliferation of mdDA progenitors. This review will focus on the role exerted by Otx genes in early decisions regulating sequential steps required for the neurogenesis of mesencephalic dopaminergic (mesDA) neurons. In this context, the regulatory network involving Otx functional interactions with signaling molecules and transcription factors required to promote or prevent the development of mesDA neurons will be analyzed in detail. PMID- 21309084 TI - Megakaryocyte lineage-specific class VI beta-tubulin suppresses microtubule dynamics, fragments microtubules, and blocks cell division. AB - Class VI beta-tubulin (beta6) is the most divergent tubulin produced in mammals and is found only in platelets and mature megakaryocytes. To determine how this unique tubulin isotype affects microtubule assembly and organization, we expressed the cDNA in tissue culture cells under the control of a tetracycline regulated promoter. The beta6 coassembled with other endogenous beta-tubulin isotypes into a normal microtubule array; but once the cells entered mitosis it caused extensive fragmentation of the microtubules, disrupted the formation of the spindle apparatus, and allowed entry into G1 phase without cytokinesis to produce large multinucleated cells. The microtubule fragments persisted into subsequent cell cycles and accumulated around the membrane in a marginal band like appearance. The persistence of the fragments could be traced to a pronounced suppression of microtubule dynamic instability. Impairment of centrosomal nucleation also contributed to the loss of a normal microtubule cytoskeleton. Incorporation of beta6 allowed microtubules to resist the effects of colcemid and maytansine, but not vinblastine or paclitaxel; however, cellular resistance to colcemid or maytansine did not occur because expression of beta6 prevented cell division. The results indicate that many of the morphological features of megakaryocyte differentiation can be recapitulated in non-hematopoietic cells by beta6 expression and they provide a mechanistic basis for understanding these changes. PMID- 21309085 TI - Long-term immunologically competent human peripheral lymphoid tissue cultures in a 3D bioreactor. AB - Peripheral lymphoid organs (PLOs), the primary sites of development of adaptive immune responses, display a complex structural organization reflecting separation of cellular subsets (e.g., T and B lymphocytes) and functional compartments which is critical for immune function. The generation of in vitro culture systems capable of recapitulating salient features of PLOs for experimental, biotechnological, and clinical applications would be highly desirable, but has been hampered so far by the complexity of these systems. We have previously developed a three-dimensional bioreactor system for long-term, functional culture of human bone marrow cells on macroporous microspheres in a packed-bed bioreactor with frequent medium change. Here we adapt the same system for culture of human primary cells from PLOs (tonsil) in the absence of specific exogenous growth factors or activators. Cells in this system displayed higher viability over several weeks, and maintain population diversity and cell surface markers largely comparable to primary cells. Light microscopy showed cells organizing in large diverse clusters within the scaffold pores and presence of B cell-enriched areas. Strikingly, these cultures generated a significant number of antibody-producing B cells when challenged with a panel of diverse antigens, as expected from a lymphoid tissue. Thus the three-dimensional tonsil bioreactor culture system may serve as a useful model of PLOs by recapitulating their structural organization and function ex vivo. PMID- 21309086 TI - Abstracts of the Urological Society of Australia and New Zealand 64th Annual Scientific Meeting. Christchurch, New Zealand. February 21-24, 2011. PMID- 21309087 TI - Increasing diversity and range of functions ascribed to RNAs are having an impact on your field. From the editors. PMID- 21309088 TI - Plasticity: a total makeover. PMID- 21309089 TI - Neuroimmunology: MicroRNAs keep microglia quiet. PMID- 21309090 TI - Synaptic plasticity: breaking the learning barrier with ACh. PMID- 21309091 TI - Neurogenesis: food signals wake sleeping stem cells. PMID- 21309092 TI - Abstracts of CardioRhythm 2011. February 25-27, 2011. Hong Kong. PMID- 21309093 TI - The reproductive life plan as a strategy to decrease poor birth outcomes. AB - The purpose of this article is to discuss the importance of implementing a life course perspective model that includes a reproductive life plan to improve health outcomes, especially in populations at risk for adverse outcomes. A reproductive life plan is a comprehensive strategy that can be incorporated into nursing practice at all levels to improve birth outcomes. Health care providers, especially nurses, should incorporate reproductive life planning into their daily encounters with patients. PMID- 21309094 TI - Reward: a dopaminergic dichotomy. PMID- 21309095 TI - Developmental neuroscience: asymmetric inhibition. PMID- 21309097 TI - Neurodegenerative disease: meet the mediator, but not as you know it. PMID- 21309096 TI - Systems neuroscience: the stress of dieting. PMID- 21309098 TI - Glia: aquaporin: not so swell? PMID- 21309099 TI - Abstracts of the 3rd Australian Lung Cancer Conference (ALCC). Melbourne, Australia. October 6-9, 2010. PMID- 21309100 TI - Abstracts of Excellence in Rheumatology. February 17-19, 2011. Istanbul, Turkey. PMID- 21309101 TI - Abstracts of Cardiovascular Research Technologies (CRT) 2010. February 21-23. Washington, DC, USA. PMID- 21309102 TI - Behavioral neurobiology of anxiety and its treatment. Preface. PMID- 21309103 TI - Anxiety disorders diagnosis: some history and controversies. AB - Treatment of and research on anxiety disorders depends on the adequate conceptualization and measurement of these conditions. We review the history of the nosology of anxiety disorders and note that divisions of "neurosis" have inadvertently taken attention away from what is shared among conditions now classified separately. We note the changes in the definition of agoraphobia over time and the striking differences between DSM-IV and ICD-10 definitions. We mention ongoing controversies in the diagnoses of posttraumatic stress disorder, acute stress disorder, and generalized anxiety disorder. Finally, we discuss controversies surrounding the proper placement of obsessive-compulsive disorder and putatively related conditions in future diagnostic classifications. We hope that reviewing controversial aspects of diagnosis is useful to clinicians and researchers interested in the neurobiology of anxiety disorders. PMID- 21309104 TI - Epidemiology of anxiety disorders. AB - This chapter presents an overview of the descriptive epidemiology of anxiety disorders based on recently completed surveys of the general population. The overall prevalence of anxiety disorders is shown to be quite high, but with considerable variation from the most prevalent (specific phobias) to the least prevalent (agoraphobia without a history of panic disorder) disorders. Age-of onset (AOO) of anxiety disorders is typically in childhood or adolescence and the course is often chronic-recurrent. Anxiety disorders are highly comorbid with each other and with other mental disorders. Because of their early AOO, they are often the temporally primary disorders in comorbid profiles, raising the question whether early interventions to treat anxiety disorders might have a positive effect on the onset, persistence, or severity of secondary disorders such as mood and substance use disorders. This possibility has not yet been extensively explored but warrants further study given the high societal costs of anxiety disorders. PMID- 21309105 TI - Comorbidity in anxiety disorders. AB - Ever since Feinstein coined the term "comorbidity", referring to the presence of any additional coexisting ailment in a patient with a particular index disease (J Chronic Dis 23:455-468, 1970), aspects of the phenomenon have been extensively studied. The aims of this chapter are: (1) to summarize the evidence of psychiatric comorbidity in anxiety disorders from adult population-based studies; (2) to present findings from the National Comorbidity Survey Replication (NCS-R); (3) to summarize evidence of psychiatric comorbidity in anxiety disorders from child and adolescent population-based samples; (4) to provide a summary of evidence on comorbidity from family and genetic studies; and (5) to examine patterns of comorbidity between anxiety disorders and medical conditions. Throughout each of these aims, implications of the comorbidity are explored, including whether these patterns reflect a need for redefining the disorders or rather an etiologic or even causal path. PMID- 21309106 TI - Genetics. AB - The present state of knowledge on the genetics of anxiety disorders, in particular panic disorder, comprising clinical and molecular genetic studies, interaction analyses, as well as meta-analyses of single association studies will be presented in detail. A particular focus will be on the most robust findings in panic disorder to date in the serotonergic, noradrenergic, and dopaminergic system, such as the catechol-O-methyltransferase (COMT) gene. Additionally, findings on the adenosine receptor 2A (A2A) gene, which has been reported to be associated with panic disorder and also with anxiety levels after caffeine administration in a gene--environment interactional model, will be discussed. Furthermore, the first imaging genetic findings in panic disorder, social phobia, and anxiety-related traits using fMRI and PET techniques in combination with molecular genetic association analyses are reviewed, taking into account the present intermediate phenotype discussion in the investigation of complex genetic disorders. Finally, the first exemplary pharmacogenetic studies in panic disorder and generalized social phobia will be presented. The pathomechanism of anxiety disorders and in particular panic disorder is considered to be multifactorial with converging evidence for a pivotal role of genetic factors in particular, which will be presented in detail in this chapter. PMID- 21309107 TI - Neuroanatomy of anxiety. AB - The evolutionary approach to human anxiety is based on the defensive responses that nonhuman animals show to fear-provoking stimuli. Studies performed mostly on rodents have related areas such as the medial prefrontal cortex, amygdaloid and hypothalamic nuclei, hipoccampal formation, and midbrain central gray to these responses. It is clear, however, that animals show different and sometimes opposite responses according to the threatening stimulus. These responses include immediate reactions such as freezing or flight, behavioral inhibition or avoidance, which are organized by at least partially distinct brain systems. As discussed in this chapter, several pieces of evidence indicate that these brain systems are similar in rodents and primates. In addition, recent neuroimaging studies also suggest dysfunctions in these systems are probably related to anxiety disorders in humans. PMID- 21309108 TI - Stress and the neuroendocrinology of anxiety disorders. AB - Stress is a risk factor for depressive and anxiety disorders. Changes in lifestyle patterns that are associated with increased stress therefore place a greater burden on mental health. Stress challenges the organism's homeostatic mechanisms, triggering a cascade of events that should, normally, maintain or allow a return to equilibrium. Stressful events are perceived by sensory systems in the brain, facilitating evaluation and comparison of the existing and previous stimuli as well as the activation of hormones responsible for energy mobilization. The limbic system coordinates the release of corticosteroids, the primary stress hormones, by modulating activation of the hypothalamic paraventricular nucleus (PVN). The amygdala, a limbic structure related to emotional behavior, has a putative role in the evaluation of emotional events and formation of fearful memories; it is also a target of the neurochemical and hormonal mediators of stress. Clinical and experimental data have correlated changes in the structure/function of the amygdala with emotional disorders such as anxiety. In this chapter we review the neuroendocrinology of the stress response, focusing on the role of the limbic system in its establishment and supplementing that information with new experimental data that demonstrates the relationship between stress and anxiety disorders; we also discuss the structural changes that occur in the amygdala after stress. PMID- 21309109 TI - Animal models of anxiety and anxiolytic drug action. AB - Animal models of anxiety attempt to represent some aspect of the etiology, symptomatology, or treatment of human anxiety disorders, in order to facilitate their scientific study. Within this context, animal models of anxiolytic drug action can be viewed as treatment models relevant to the pharmacological control of human anxiety. A major purpose of these models is to identify novel anxiolytic compounds and to study the mechanisms whereby these compounds produce their anxiolytic effects. After a critical analysis of "face," "construct," and "predictive" validity, the biological context in which animal models of anxiety are to be evaluated is specified. We then review the models in terms of their general pharmacological profiles, with particular attention to their sensitivity to 5-HTIA agonists and antidepressant compounds. Although there are important exceptions, most of these models are sensitive to one or perhaps two classes of anxiolytic compounds, limiting their pharmacological generality somewhat, but allowing in depth analysis of individual mechanisms of anxiolytic drug action (e.g., GABAA agonism). We end with a discussion of possible sources of variability between models in response to 5-HTIA agonists and antidepressant drugs. PMID- 21309110 TI - Genetic approaches to modeling anxiety in animals. AB - Anxiety disorders are a growing health problem world-wide. However, the causative factors, etiology, and underlying mechanisms of anxiety disorders, as for most psychiatric disorders, remain relatively poorly understood. The current status of clinical research indicates that anxiety traits and anxiety disorder in man have a genetic component, and therefore genetic modeling in animals is a logical approach to gain a greater insight into their neurobiology. However, it is also clear that the nature of these genetic contributions is highly complex. Moreover, the success of this approach is largely contingent upon the utility of available behavioral paradigms for modeling anxiety-related behaviors in mice. Animal genetic models provide a unique and comprehensive methodological tool to aid discovery into the etiology, neurobiology, and ultimately, the therapy of human anxiety disorders. The approach, however, is challenged with a number of complexities. In particular, the heterogeneous nature of anxiety disorders in man coupled with the associated multifaceted and descriptive diagnostic criteria, create challenges in both animal modeling and in clinical research. In this article, we describe some of the powerful modem genetic techniques that are uniquely amenable to the laboratory mouse and thus provide a strategy for approaching some of these challenges. Moreover, we focus on recent advances which have highlighted the relative contribution of genetic modeling in animals to the understanding of underlying neurobiology and genetic basis of anxiety disorders. PMID- 21309111 TI - Behavioral correlates of anxiety. AB - The tripartite model of anxiety includes three response domains: cognitive (most often identified by self report), behavioral, and physiological. Each is suggested to bring a separate element of response characteristics and, in some cases, potentially independent underlying mechanisms to the construct of anxiety. In this chapter, commonly used behavioral correlates of anxiety in human research, including startle reflex, attentional bias, and avoidance tasks, as well as future tasks using virtual reality technology will be discussed. The focus will be in evaluating their translational utility supported by (1) convergent validity with other measures of anxiety traits or anxiety disorders, (2) their use in identifying neural and genetic mechanisms of anxiety, and (3) ability to predict treatment efficacy. PMID- 21309112 TI - Challenging anxiety: a focus on the specificity of respiratory symptoms. AB - Physiological symptoms are characteristic features of anxiety states. Presumably, specific psychophysiological profiles differentiate between anxiety disorders, which would offer potential for diagnostic purposes. Abundant evidence points to a causal relationship between panic disorder and instability of respiratory regulation. However, the specificity of most measures that indicate aberrant functioning of the respiratory system in PD can be questioned. Possibly, the traditional measures of respiratory functioning are too restricted. The underlying respiratory vulnerability in PD seems to constitute a subtle, unstable trait, which calls for more sensitive and sophisticated measures of respiratory variability and chaos. To increase the probability of finding parameters with diagnostic specificity, the application of disorder specific challenge paradigms is recommended. PMID- 21309113 TI - Functional neuroanatomy of anxiety: a neural circuit perspective. AB - Anxiety is a commonly experienced subjective state that can have both adaptive and maladaptive properties. Clinical disorders of anxiety are likewise also common, and range widely in their symptomatology and consequences for the individual. Cognitive neuroscience has provided an increasingly sophisticated understanding of the processes underlying normal human emotion, and its disruption or dysregulation in clinical anxiety disorders. In this chapter, I review functional neuroimaging studies of emotion in healthy and anxiety disordered populations. A limbic-medial prefrontal circuit is emphasized and an information processing model is proposed for the processing of negative emotion. Data on negative emotion processing in a variety of anxiety disorders are presented and integrated within an understanding of the functions of elements within the limbic-medial prefrontal circuit. These data suggest that anxiety disorders may be usefully conceptualized as differentially affecting emotional reactivity and regulatory processes--functions that involve different neurobiological mechanisms. While the neural bases of several anxiety disorders are increasingly better understood, advances have lagged significantly behind in others. Nonetheless, the conceptual framework provided by convergent findings in studies of emotional processing in normative and anxiety-disordered populations promises to yield continued insights and nuances, and will likely provide useful information in the search for etiology and novel treatments. PMID- 21309114 TI - Pharmacological enhancement of behavioral therapy: focus on posttraumatic stress disorder. AB - Improved efficacy in the treatment of posttraumatic stress disorder (PTSD) and other anxiety disorders is urgently needed. Traditional anxiety treatments of hypnosis and psychodynamic therapy may be of some help, but uncontrolled studies lead to inconclusive results on the efficacy of these treatment techniques. There is a larger literature supporting the efficacy of cognitive-behavioral procedures with PTSD, including prolonged exposure therapy, eye movement desensitization and reprocessing, and anxiety management techniques. The cutting-edge technology of virtual reality-based exposure therapy for PTSD is particularly exciting. To further build on effective psychosocial treatments, current pharmacological augmentation approaches to emotional learning are being combined with psychotherapy. In particular, D-cycloserine, a partial NMDA agonist, has shown to be effective in facilitating the exposure/extinction therapy to improve the efficacy of treating anxiety disorders, and may guide the way for new pharmacological enhancements of behavioral therapy. PMID- 21309115 TI - The pharmacology of anxiety. AB - Understanding the neurochemistry of anxiety is of fundamental importance in the development and use of novel anxiolytics. Through measuring peripheral markers of brain biochemistry, direct pharmacological challenges and brain neuroimaging techniques our understanding of this field has increased substantially in the past few decades. We review the four most studied neurotransmitter systems with respect to in anxiety disorders: gamma amino-butyric acid, serotonin, noradrenaline and dopamine. We have focussed upon clinical studies to highlight the current techniques used to determine brain neurochemistry in vivo. Future research in this field will greatly benefit from recent advances in neuroimaging techniques and the discovery of novel ligands targeting specific receptors. PMID- 21309116 TI - GABAA receptor alpha2/alpha3 subtype-selective modulators as potential nonsedating anxiolytics. AB - Nonselective benzodiazepines exert their pharmacological effects via GABAA receptors containing either an alpha1, alpha2, alpha3, or alpha5 subunit. The use of subtype-selective tool compounds along with transgenic mice has formed the conceptual framework for defining the requirements of subtype-selective compounds with potentially novel pharmacological profiles. More specifically, compounds which allosterically modulate the alpha2 and/or alpha3 subtypes but are devoid of, or have much reduced, effects at the alpha1 subtype are hypothesized to be anxioselective (i.e., anxiolytic but devoid of sedation). Accordingly, three compounds, MRK-409, TPA023 and TPA023B, which selectively potentiated the effects of GABA at the alpha2 and alpha3 compared to alpha1 subtypes were progressed into man. All three compounds behaved as nonsedating anxiolytics in preclinical (rodent and primate) species but, surprisingly, MRK-409 produced sedation in man at relatively low levels of occupancy (< 10%). This sedation liability of MRK-409 in man was attributed to its weak partial agonist efficacy at the alpha1 subtype since both TPA023 and TPA023B lacked any alpha1 efficacy and did not produce overt sedation even at relatively high levels of occupancy (> 50%). The anxiolytic efficacy of TPA023 was evaluated in Generalized Anxiety Disorder and although these clinical trials were terminated early due to preclinical toxicity issues, the combined data from these incomplete studies demonstrated an anxiolytic-like effect of TPA023. This compound also showed a trend to increase cognitive performance in a small group of schizophrenic subjects and is currently under further evaluation of its cognition-enhancing effects in schizophrenia as part of the TURNS initiative. In contrast, the fate of the back-up clinical candidate TPA023B has not been publicly disclosed. At the very least, these data indicate that the pharmacological profile of compounds that differentially modulate specific populations of GABAA receptors is distinct from classical benzodiazepines and should encourage further preclinical and clinical investigation of such compounds, with the caveat that, as exemplified by MRK-409, the preclinical profile might not necessarily translate into man. PMID- 21309117 TI - Antidepressant treatment in anxiety disorders. AB - Antidepressant drug treatment is the clinical standard of care for all types of anxiety disorders. Broad efficacy of selective serotonin reuptake inhibitors suggests the importance of enhanced serotonergic function of the anxiolytic properties of current antidepressants. However, analysis of the preclinical evidence indicates that most conventional "anxiolytic" drug tests are not sensitive to antidepressants. Such dissociation is not surprising because of the traditional approach to validation of preclinical tests that is to a large extent based on establishing face validity as well as sensitivity to benzodiazepine anxiolytics. The present review argues for extending the cognitive model of antidepressant drug action to cover their anxiolytic properties as well. Such an approach is based on ambiguity or uncertainty in a broad sense as the hallmark of human stress that has different expressions ready for experimental modeling. These possibilities include schedule-induced behaviors that are directly based on intermittent reinforcement, conditioning to ambiguous stimuli, social stress where agonistic confrontations are possible but not predictable or controlled by the subject, and an even larger class of behaviors that are critically dependent on the inhibition of the prepotent responses in exchange for the ambiguous possibility of a later gain in reinforcement. Interestingly, in all these cases, antidepressant drug treatment is clearly effective in preclinical laboratory settings. One of the cognitive functions that appears to be affected by antidepressant drugs is inhibitory control. Inhibition of prepotent responding has beneficial effects in the "uncertainty" stress situations discussed above and therefore it is this cognitive function that may be critical for anxiolytic effects of antidepressants and novel anxiolytic drug development. PMID- 21309118 TI - Metabotropic glutamate receptors: their therapeutic potential in anxiety. AB - Psychiatric and neurological disorders are linked to changes in synaptic excitatory processes with a key role for glutamate, that is, the most abundant excitatory amino-acid. Molecular cloning of the metabotropic glutamate (mGlu) receptors has led to the identification of eight mGlu receptors, which, in contrast to ligand-gated ion channels (responsible for fast excitatory transmission), modulate and fine-tune the efficacy of synaptic transmission. mGlu receptors are G protein-coupled and constitute a new group of "drugable" targets for the treatment of various CNS disorders. The recent discovery of small molecules that selectively bind to receptors of Groups I (mGlu1 and mGlu5) and II (mGlu2 and mGlu3) allowed significant advances in our understanding of the roles of these receptors in brain function and dysfunction including anxiety. Although investigation of the role of the Group III (mGlu4, 6, 7, and 8) receptors is less advanced, the generation of genetically manipulated animals and recent advances in the identification of subtype-selective compounds have revealed some first insights into the therapeutic potential of this group of receptors. PMID- 21309119 TI - Developing small molecule nonpeptidergic drugs for the treatment of anxiety disorders: is the challenge still ahead? AB - Neuropeptide systems have been considered a major opportunity for the development of novel treatment approaches for anxiety disorders based on preclinical evidence and neurochemical alterations seen in anxiety disorders. This excitement was further facilitated by the fact that drugs acting at these systems, such as CRF1 antagonists, NK1 antagonists, NK3 antagonists or CCK2 antagonists, may have unique properties not seen with drugs affecting more classical mechanisms involved in anxiety. Consequently, there have been major efforts to develop such small-molecule, nonpeptide receptor ligands. A number of these molecules have been tested in the clinic, either in trials where levels of anxiety served as a secondary measure, or in a few studies with patients suffering from anxiety disorders. But unfortunately, and despite all the efforts of the field as a whole, we still lack convincing clinical proof-of-concept for any of the neuropeptidergic approaches in patients. It must, therefore, be concluded that neuropeptide targets remain a promising approach for the development of the next generation drugs to treat anxiety disorders, but that they continue to be high risk targets for drug development. PMID- 21309120 TI - Cannabinoids and anxiety. AB - The term cannabinoids encompasses compounds produced by the plant Cannabis sativa, such as delta9-tetrahydrocannabinol, and synthetic counterparts. Their actions occur mainly through activation of cannabinoid type 1 (CB1) receptors. Arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol (2-AG) serve as major endogenous ligands (endocannabinoids) of CB1 receptors. Hence, the cannabinoid receptors, the endocannabinoids, and their metabolizing enzymes comprise the endocannabinoid system. Cannabinoids induce diverse responses on anxiety- and fear-related behaviors. Generally, low doses tend to induce anxiolytic-like effects, whereas high doses often cause the opposite. Inhibition of endocannabinoid degradation seems to circumvent these biphasic effects by enhancing CB1 receptor signaling in a temporarily and spatially restricted manner, thus reducing anxiety-like behaviors. Pharmacological blockade or genetic deletion of CB1 receptors, in turn, primarily exerts anxiogenic-like effects and impairments in extinction of aversive memories. Interestingly, pharmacological blockade of Transient Receptor Potential Vanilloid Type-1 (TRPV1) channel, which can be activated by anandamide as well, has diametrically opposite consequences. This book chapter summarizes and conceptualizes our current knowledge about the role of (endo)cannabinoids in fear and anxiety and outlines implications for an exploitation of the endocannabinoid system as a target for new anxiolytic drugs. PMID- 21309121 TI - Pharmacological treatment of generalized anxiety disorder. AB - Generalized anxiety disorder (GAD) is common in community and clinical settings. The individual and societal burden associated with GAD is substantial, but many of those who could benefit from treatment are not recognized or treated. Recent evidence-based guidelines for the pharmacological management of patients with GAD have recommended initial treatment with either a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), on the basis of their proven efficacy and reasonable tolerability in randomized placebo controlled trials. However, there is much room for improvement in both the efficacy and the tolerability of treatment. Response rates to first-line treatment can be disappointing and it is hard to predict reliably which patients will respond well and which will have only a limited treatment response. Many patients worry about becoming dependent on medication, a substantial proportion experience troublesome adverse effects, and these problems limit the effectiveness of pharmacological treatments in clinical practice. The relative lack of longitudinal studies of clinical outcomes in GAD, and the small number of placebo-controlled relapse prevention studies lead to uncertainty about the optimal duration of treatment after a satisfactory initial response. There have been few investigations of the further management of patients who have not responded to first-line treatment and there is a pressing need for further augmentation studies in patients who have not responded to an SSRI or SNRI, or to other initial pharmacological approaches. Future treatment guidelines for GAD will be influenced by emerging data for established and novel pharmacological approaches, and possibly through the more accurate identification of certain patient subgroups who are likely to respond preferentially to particular interventions. PMID- 21309122 TI - Pharmacologic treatment of panic disorder. AB - Comprehensive management of panic disorder involves a wide array treatments and interventions to reduce symptoms and increase functionality. This chapter provides an overview of the pharmacologic treatment of panic disorder including aspects of assessment, treatment selection and the biologic mechanisms of the illness. PMID- 21309123 TI - Pharmacotherapy of social anxiety disorder. AB - A range of medications have been shown effective for the treatment of social anxiety disorder. The largest trials to date have been with various selective serotonin reuptake inhibitors (SSRIs). Several of these agents have been registered for the treatment of social anxiety disorder with agencies such as the FDA or EMEA, meta-analyses confirm their efficacy and safety, and expert consensus guidelines have often recommended them as a first-line pharmacotherapy of choice. Despite such advances, there are many unanswered questions in the pharmacotherapy of social anxiety disorder, including the optimal pharmacotherapy of patients refractory to first-line intervention, and the optimal sequencing of pharmacotherapy and psychotherapy. Translational research has already had an impact on concepts of treatment, and may ultimately lead to novel interventions. PMID- 21309124 TI - Pharmacotherapy of post-traumatic stress disorder. AB - Post-traumatic stress disorder (PTSD) is a prevalent psychiatric disorder that may result in significant social and occupational debilitation unless symptoms are recognized and treated appropriately. Considerable research effort has been devoted over the last 20 years to developing effective pharmacological treatments for this illness. At this time, the bulk of the agents investigated include antidepressants, anticonvulsants, atypical antipsychotics, benzodiazepines, and antiadrenergic agents. Herein, we review the existing evidence base for these different classes of psychotropics in PTSD. Emphasis is placed on discussion of evidence stemming from randomized placebo-controlled clinical trials wherever possible. A brief description of novel agents that have shown initial promise for PTSD treatment is also provided. PMID- 21309125 TI - Pharmacological treatment of obsessive-compulsive disorder. AB - Obsessive-compulsive disorder (OCD) is a disabling neuropsychiatric disorder. Two treatments have been proven efficacious for the symptoms of OCD: pharmacological treatment with serotonin reuptake inhibitors and cognitive-behavioral therapy (CBT) consisting of exposure and response prevention. This chapter will focus on pharmacological treatments. The only medications which have proved effective for OCD in multisite randomized controlled trials are serotonin reuptake inhibitors, which include clomipramine (a noradrenergic and serotonergic reuptake inhibitor) and the selective serotonin reuptake inhibitors. General guidelines for the use of these medication will be presented, focusing on key issues that arise in clinical practice such as what dose to use, time to response, management of side effects, and duration of treatment. Because many OCD patients will have either a partial response or no response to these medications, evidence-based strategies for managing both partial responders and nonresponders will be described, including the evidence supporting augmentation with other medications or with CBT, and switching to other medications. Finally, novel strategies which are based on an increased understanding of the brain mechanisms underlying OCD and which are under investigation will be reviewed. PMID- 21309126 TI - For the patient. Crowded households and obesity in young black and white adults. PMID- 21309127 TI - For the patient. A breast cancer screening clinic for underserved women. PMID- 21309128 TI - For the patient. Medication assistance programs are used less by African Americans than whites with limited incomes. PMID- 21309129 TI - Biphasic insulin treatment in type 2 diabetes patients. PMID- 21309130 TI - Surgical vascular access in the porcine model for long-term repeated blood sampling. AB - A simple technique for implanting a long-term jugular catheter in piglets under general anesthesia is described. We report our experience in 10 young female pigs with a body weight of 20-30 Kg. The surgical procedure involves implantation of a jugular central venous catheter (11Fr polyurethane) tunneled in the subcutaneous fat layer of the neck. This procedure may be performed in about 15 minutes. The maintenance of the catheter is described which allows several daily blood samples to be taken. This procedure reduces both the stress in piglets and the chance of catheter dislodgement due to the animals scratching or rubbing. Blood sampling can be easily performed with a low incidence of infection or thrombosis. PMID- 21309134 TI - Abstracts of the American Society for Radiation Oncology 52nd Annual Meeting. San Diego, California, USA. October 31-November 4, 2010. PMID- 21309135 TI - Erythrophagocytosis by neutrophils. PMID- 21309140 TI - ERS Meeting Report. Metabolic aspects of obstructive sleep apnoea syndrome. AB - Insulin resistance is often associated with obstructive sleep apnoea syndrome (OSAS) and could contribute to cardiovascular risk in OSAS. Sleep loss and intermittent hypoxia could contribute to the pathogenesis of the metabolic alterations associated with obesity, a common feature of OSAS. The biology of the adipocyte is being increasingly studied, and it has been found that hypoxia negatively affects adipocyte function. In November 2007, the European Respiratory Society and two EU COST Actions (Cardiovascular risk in OSAS (B26) and Adipose tissue and the metabolic syndrome (BM0602), held a Research Seminar in Dusseldorf, Germany, to discuss the following: 1) the effects of hypoxia on glucose metabolism and adipocyte function; 2) the role of inflammatory activation in OSAS and obesity; 3) the alarming rates of obesity and OSAS in children; 4) the harmful effects of the metabolic syndrome in OSAS; 5) the effects of OSAS treatment on metabolic variables; and 6) the relationship between daytime sleepiness and hormonal and inflammatory responses. Insulin resistance in skeletal muscle, the role of the endocannabinoid system and novel pharmacological approaches to treat insulin resistance were also discussed. As obesity and hypoxia could be the basic links between OSAS and adipocyte dysfunction, further research is needed to translate these new data into clinical practice. PMID- 21309141 TI - [What do we know about trachoma in the economically weakest infantile population of Kara in Togo?]. AB - PURPOSE: To describe the distribution of the trachoma in the infantile population of Kara region. MATERIALS AND METHODS: A descriptive cross sectional investigation has been achieved in 6 sanitary districts of Kara's region in November 2009. In each of the 2 villages of the sanitary area of every peripheral health unit (PHU), 15 schoolchildren aged of 6 to 9 years then 35 children of the community aged of 1 to 5 years have been examined to search signs of trachoma with the help of a lamp wipes coupled of a binocular loupe (2.5X magnification). RESULTS: To the total 10,100 children have been examined in 202 villages of the sanitary areas of 101 PHU. Among the 7070 children aged of 1-5 years, 289 presented trachomatous inflammation follicular (TF) and 131 trachomatous inflammation intense (TI), corresponding to a prevalence rate of 5.94%. Among the 3030 schoolchildren, 68 presented TF and 62 TI corresponding to 4.29% prevalence rate. The prevalence rate of the active trachoma was of 5.44% in the infantile population of this region. CONCLUSION: This investigation could confirm that active trachoma still exists in this region. Another investigation will be carried out to determine the prevalence of trachoma among the adult subjects in order to have a more complete data base in view of further action for trachoma elimination in this region. PMID- 21309142 TI - [Sneddon Syndrome and antiphospholipid antibodyies: an etiology of later al homonymous hemianopia]. AB - Sneddon's syndrome is a particular and rare entity that mostly affects young women and whose diagnosis is based on the coexistence of a cuteaneous livedo and a cerebrovascular ischemic attack. It had be considered as being an expression of an occlusive vasculitis or of antiphospholipid antibody syndrome. We report the case of a 20-year-old female, who had developed a left homonymous hemianopia after ischemic encephalopathy. Visual field examination confirmed the presence of a complete left homonymous hemianopia. Cerebral Magnetic Resonance Imaging revealed right occipital cerebrovascular ischemic lesions. Sneddon's syndrome diagnosis was considered on the presence of cutaneous livedo reticularis and associated cerebral ischemic events. With medical treatment, a small functional improvement could be noticed but without net improvement in the visual field defect. PMID- 21309143 TI - [The six keys of the monitoring of the glaucoma patient]. AB - Treatment of glaucoma aims at preserving the visual function and the Quality of Life (QoL) of the patients. To slow down the progression of the disease, the IOP should be decreased to a level where the risk of further deterioration is reduced to a minimum. Rates of progression vary between patients. Detection of glaucoma progression should be based on the assessment of structure and function. When making a treatment plan, one should take into consideration the rate of progression and the impact of visual field deterioration on the QoL. Therefore, a careful and reliable baseline examination is crucial. Furthermore, yearly documentation of the optic disc and frequent examinations of the visual field, especially during the first two years of follow-up, are mandatory to evaluate how aggressive the treatment should be. Slowing down progression of the disease is closely related to a good communication with the patient, the quality of the information provided, and the tolerance of the medications, all keys to a good adherence. Other risk factors than IOP should be looked for and treated if possible, especially when worsening of glaucoma damage is observed despite apparently good IOP control and compliance. Modern monitoring of the glaucoma patient can be summarized in six keys. Current limitations of this approach will be briefly discussed. PMID- 21309144 TI - [Characteristics of the genetic structure of parasite and host populations by the example of helminthes from moor frog Rana arvalis Nilsson]. AB - The genetic structure of populations of four helminth species from moor frog Rana arvalis, in comparison with the population-genetic structure of the host, has been studied with the gel-electrophoresis method. As compared with the host, parasites are characterized by more distinct deviation from the balance of genotypic frequencies and higher level of interpopulation genetic differences. The genetic variability indices in the three of four frog helminthes examined are lower than those in the host. Moreover, these indices are lower than the average indices typical of free-living invertebrates; this fact contradicts the opinion on polyhostality of these helminthes and their wide distribution. PMID- 21309146 TI - [Ecological-faunistical review of fish parasites in the Umbozero Lake (the Kola Peninsula)]. AB - Data on fish infestation by parasites in the Umbozero Lake are given. 90 species of parasites were identified including 16 species of Myxosporea, 2 Suctoria, 18 Peritricha, 12 Monogenea, 13 Cestoda, 18 Trematoda, 5 Nematoda, 2 Acanthocephala, 2 Hirudinea, and 2 species of Crustacea. Character of parasites' distribution in fishes of this lake and ecological peculiarities in the host-parasite system are demonstrated. PMID- 21309145 TI - [Diagnostic features of Microsomacanthus microsoma (Creplin, 1829), type species of the genus Microsomacanthus Lopez-Neyra, 1942, as the base for the revision of the genus]. AB - The genus Microsomacanthus was created by Lopez-Neyra (1942). Its type species, Taenia microsoma Creplin, 1829, was described from the common eider Somateria mollissima and remained a collective species until Fuhrmann (1913) revealed its diagnostic features on the original material. Simultaneously he described two new species of "microsoma-Gruppe", Microsomacanthus jaegerskioeldi (Fuhrmann, 1913) and M. diorchis (Fuhrmann, 1913). Fuhrmann stressed that under the name of Hymenolepis microsoma Cohn (1901) gave a description of quite different species (a parasite of the freshwater duck Anas penelope). Much earlier Leuckart (1879) used the same name for the denomination of a certain larval form from freshwater snails, without any experimental verification. Fuhrmann (1932), in conflict with himself, synonymized Taenia microsoma Creplin, 1829 and Hymenolepis microsoma sensu Cohn, 1901 and thus caused new inadequacy. Spassky et Spasskaja (1954) confirmed the validity of the genus Microsomacanthus Lopez-Neyra, 1942 and supplemented its diagnosis with such significant criteria as the number of rostellar hooks (10) and the absence of any accessory structures in the copulatory apparatus. Intermediate hosts of M. microsoma proved to be gammarids (Belopolskaya, 1952). Nevertheless Yamaguti (1959) synonymized a larval form from pond snails (Monocercus lymnaei Villot, 1883) with Microsomacanthus microsoma, meanwhile Hymenolepis microsoma sensu Cohn, 1901 was shown to be a synonym of Microsomacanthus compressa (Linton, 1892). The life cycle of the latter species includes copepods as intermediate hosts and freshwater gastropods as storage (reservoir) ones. Schmidt (1986) and Czaplinski and Vaucher (1994) chose M. compressa as an illustrative example of the genus Microsomacanthus instead of its type species. The diagnostic features of the genus remain vague, so the list of its synonyms attained as much as 17. Fuhrmann's material on M. microsoma, as well as on the two other species of "microsoma-Gruppe", deposited in the Museum of Natural History (Geneva) was reinvestigated. The diagnostic features of the group formulated by Fuhrmann (1913) were confirmed and enlarged. Large assemblage of species corresponding to M. microsoma by morphology (small gonads, early resorption of testes, formation of eggpacket in the uterus) and biology (gammarids as intermediate hosts) is established. This group is taken as the nominotypical subgenus Microsomacanthus (Microsomacanthus). For the antithetic group which life cycle corresponds to that of M. compressa (a species with comparatively large gonads, with testes persisting till the maturation of female gonads and eggs disseminating one by one from the uterus) we erect a new taxon, Microsomacanthus (Leucartcohnacanthus subgen. nov. Microsomacanthus paracompressa (Czaplinski, 1956) is selected as its type species. Representatives of both subgenera of the genus Microsomacanthus may have rostellar hooks of the same length. Literary data on their larval forms were often based on misidentification. PMID- 21309147 TI - [Helminthes of wild birds in Bashkortostan]. AB - Results of the helminthological dissection of 312 wild birds of 83 species from five orders were considered. Diagrams reflecting these data show the state of infestation for the orders and, separately, infestation of families in the order Passeriformes. Indices of infestation for these orders and families are also given. PMID- 21309148 TI - [Characteristic of reproductive structure in the hemipopulation of a bat parasitizing nematode Thominx neopulchra (Nematoda, Capillariidae)]. AB - Features of reproductive structure of the Thominx neopulchra hemipopulation from Daubenton's bat from Zhiguli State Reserve are studied. It is established, that females and males of Th. neopulchra have different dynamics of coming in the host population. Males of the parasite invade the of Daubenton's bat population during all the year, while females infest the host only from May to November. Maturing of helminthes become slowed in winter period. Only about a half of of the host population is involved in the forming of the reproductive structure of Th. neopulchra hemipopulation. PMID- 21309149 TI - [Taenia martis (Cestoda, Taeniidae) from vertebrates in the Republic of Belarus]. AB - Infestation of vertebrate animals with the cestode Taenia martis and its larvae was investigated in south-west Belarus during 2001-2008. Obligatory definitive host (common marten) and intermediate hosts (red-backed vole, yellow-necked mouse, striped field mouse, and red squirrel) of this helminth were established for the Republic of Belarus. Description and figure of the T. martis larva is given. PMID- 21309150 TI - [Ecological characteristics and distribution of the mosquito Aedes communis (De Geer, 1776) in the Northwestern part of European Russia]. AB - According to recent data, Aedes communis is a polytopic species inhabiting both zonal and intrazonal biotopes. It has a wide Holarctic nemoral-tundra-steppe range, which can be characterized as European-Asiatic-North-American. In the North-West of the European part of Russia, A. communis occurs in early spring and summer, being a monocyclic species. It is distributed everywhere, both in zones of tundra and forest-tundra and in all taiga subzones. Aedes communis is a psychrophilic species, but attacks of its females were recorded under the temperatures from 2.5 to 28 degrees C. The species occurs in biotopes of different types, but in the taiga zone it is distributed mainly in swampy coniferous forests and, particularly, in fir-woods where its quantity is steadily high, amounting to 70% and more of the mosquito females collections. When fir woods are cut down, A. communis develops in the reservoirs situated in the small leaved forests forming in taiga after deforestation. PMID- 21309151 TI - [Chewing lice (Mallophaga) on birds in the Central Ciscaucasia]. AB - Mallophaga parasitizing wild and domestic birds in the Central Ciscaucasia were studied; 8805 chewing lice specimens were collected and identified. At present, 102 species of Mallophaga are known from this territory, including 15 species recorded in the Central Ciscaucasia for the first time. Most of the chewing lice species in the region under study are parasites of Passeriformes. Species diversity of chewing lice connected with each of other 12 bird orders is several times lesser. The exchange of chewing lice between some species of hosts, particularly between domestic and wild birds, seems possible. PMID- 21309152 TI - [Changes in the behaviour of Moina macrocopa (Crustacea: Cladocera) under the influence of Gurleya sp. (Microsporidia: Gurleyidae)]. AB - It is established, that infestation with Gurleya sp. (Microsporidia, Gurleyidae) changes the behaviour of its host Moina macrocopa (Straus, 1820), a crustacean inhabiting pools. Heavily infested host individuals attach to surface film of water before their death by senescence. As a consequence, their dead bodies filled with spores of the parasite adhere to objects dipped in water that probably facilitates the transfer of spores by birds and cattle to other pools. Weakly infested or uninfested individuals drown after the end of their ontogenesis. Distribution of the microsporidian spores by two different ways (with attached dead bodies of the hosts or with bottom sediments) makes invasion of a new host more probable. PMID- 21309153 TI - [Russian experience with international health cooperation at early stages of its development]. AB - It is a historical review of the development of international health cooperation and participation of Russia at its early stages. Detailed information is presented concerning joint work for control of malaria and other parasitic infections with WHO, CMEA countries, developed and developing states. The important role of E.I. Martsinovsky Institute of Medical Parasitology and Tropical Medicine in combating infections and in health protection at large is emphasized. Current collaboration and its prospects are briefly discussed. PMID- 21309154 TI - [University hygiene school of I.M.Sechenov Moscow Medical Academy]. AB - Different aspects of evolvement and development of university hygiene in this country are considered. The first studies on learning environment, living conditions and health status of students were conducted in the late 19th and early 20th centuries in main Russian scientific centres. Researchers and specialists of their hygiene departments greatly contributed to the development of this discipline. Systematic studies date back to the foundation of the university hygiene laboratory at I.M.Sechenov Moscow Medical Academy. Today the laboratory focuses on the complex problem "Lifestyle and health status of main participants of the educational process, students and professors". PMID- 21309155 TI - [Management as a key professional competence of preventive medicine specialists]. AB - The paper deals with the strategy of training specialists in preventive medicine and improvement of their professional skills for the management of activities aimed at the maintenance of adequate population health status and prevention of adverse effects of environmental factors. Integration of managerial issues into curricula and teaching courses for preventive medicine specialists may be instrumental in upgrading their professional level. PMID- 21309156 TI - [Demographic structure and dynamics of morbidity due to anthroponosis infections]. AB - A fall in the incidence of both preventable and non-preventable or partly preventable infections with different modes of transmission has recently been documented in Russia and worldwide; it parallels marked changes in the demographic structure of the population. Simulation based on parasite-host mathematical models confirmed that demographic structure is a key factor responsible for the incidence of anthroponosis infections producing long-standing or lifelong immunity. It was shown that differences in the frequency of these diseases between countries may be due to different age structure of their populations. The lowered incidence of preventable and non-preventable infections in Russia appears to be associated with changes in the country's demographics. We have developed prognosis of further dynamics of anthroponosis diseases that predicts reversal of the mean morbidity rate toward that recorded in the 1980s and the shift of its higher values to senior age-groups. PMID- 21309157 TI - [Architectonics of gastrointestinal microbial community]. AB - Architectonics of gastrointestinal microbial community in colonic mucosa and feces was studied in patients with different gastrointestinal pathologies and without them. The study model was comprised of Bifidobacteria, Lactobacteria, E.coli, Enterococci, Staphylococci, and Candida. Communities of mucosal and fecal microbes appear to be organized in a definite manner, with most microorganisms forming either indigenous or indigenous-transient associations. Multicomponent indigenous-transient associations prevail in fecal communities, few-component indigenous one or individual microbes in parietal colonic mucin. The structure of community from colonic mucosa overlying a tumour proved identical with that from the apparently normal tissue whereas the community from an inflammed site was structurally closer to the fecal one. PMID- 21309158 TI - [Comparative studies of microbial strains used in biotechnology for the elaboration of biosafety standards]. AB - Comparative studies of different microbial strains used in biotechnology as potentially hazardous for human health agents demonstrated their ability to cause adverse effects such as toxicity, immunotropic action, sensitization, and alteration of normal intestinal microflora in rats. It was shown that certain microscopic fungi of genera Aspergillus, Penicillum, and Candida as well as some gram-negative bacteria can affect the immune system and disturb the balance of microflora in rat intestines. Actinomycetes were found to produce minimal adverse effects. These observations can be used to elaborate hygienic safety standards for the work with industrial microorganisms and thereby reduce or minimize the risk of occupational infection and immune disorders. PMID- 21309159 TI - [Approaches to improvement of laboratory diagnosis of infectious diseases]. AB - Modern routine and novel techniques for diagnostics of infectious diseases and identification of intoxication syndrome markers are reviewed. Also presented are results of original studies of mixed intestinal infections and methods of their rapid differential diagnostics. PMID- 21309160 TI - [Effect of HBc-antigen expression on replication of recombinant Salmonella strains in vivo and in vitro]. AB - The development of therapeutic vaccines against chronic hepatitis B is a major challenge facing modern medicine. HBc antigen-expressing DNA-vaccines designed to be transported into the organism by attenuated Salmonella appear to be good candidates for the purpose. Expression of HBc-antigen was earlier shown to lead to the loss of ability of attenuated Salmonella bearing the DNA-vaccine to multiply in the host lymphoid tissue of mice after per rectum immunization and in human monocyte culture. The aim of the study was to assess the influence of HBc antigen expression on replication of a virulent strain of wild-type Salmonella serotype Enteritidis in the murine lymphoid tissue after per rectum infection and in human blood monocytes. HBc expression was shown to inhibit propagation of Salmonella in both model systems despite its high virulence. PMID- 21309161 TI - [Reoccurrence of histomonosis in turkey breeder farm]. AB - Histomonosis is a severe disease caused by the protozoan parasite Histomonas (H.) meleagridis, which can lead to high losses in turkeys. The present report describes the reoccurrence of histomonosis in a turkey breeder farm. The first outbreak occurred in 2005 in 17 weeks old hens, the second in 2009 in 8 weeks old hens. The disease remained restricted in one house and one compartment, respectively. Mortality rose to 26 and 65% respectively within few days in spite of therapy with various compounds. Both flocks had to be euthanized. In both cases H. meleagridis belonging to genotype A was detected. The source of infection remained unclear in both cases. PMID- 21309162 TI - [Examination of the prevalence of skin injuries in debeaked fattened turkeys]. AB - Within the framework of a cooperative research project, turkey health as well as numerous aspects of animal welfare were examined in various intensive commercial farms with varying rearing forms. The present study demonstrates the prevalence of skin injuries concerning living animals as well as carcasses of slaughtered turkeys of both sexes. Although all turkeys were debeaked, prevalences of skin injuries at a value of 12.8% with male turkeys and 13.8% with female turkeys could be found at the age of 16 weeks. Within the scope of medically inspections skin injuries were mainly established in the head region, especially the snood as well as in the region of the back. By means of their clinical picture pecking wounds and scratch injuries could be distinguished. Skin lesion produced primary as a result of scratching the skin surface, could be enlarged by the animal itself or by conspecifics by beak pecking, especially after bleeding, in spite of debeaked upper beak. Injuries in the head region, especially of the snood, could be explained mainly as a result of pecking by conspecifics by reason of their clinical picture and were found mainly in male turkeys. Skin injuries in the region of the back, especially at the coxal tuberosity, were identified primarily as scratch marks. They were found mainly in female turkeys. A statistically significant correlation of the injury prevalence to particular husbandry parameters discussed in the literature as "predisposing" or "limiting" factors (e.g., population density, light regime or offer of employment material) could not be established in this study. At the meat inspection fresh scratching injuries at the chest and the hind legs were diagnosed most often. Especially fresh injuries of the carcass point to a misguided behaviour of the staff concerning animal handling during loading and transport which is not conform to animal welfare. PMID- 21309163 TI - [Comparative behaviour studies in horses infested with flying insects treated with insecticide or repellent substances]. AB - The aim of this study was to estimate the effects of flying insects (Order Diptera) on the behaviour of grazing horses in relation to the use of insecticide and repellent substances. The investigations were done between June and August in 2008 in 3 periods of 7 days each. As insecticide and repellent two substances were used: "Well-care emulsion" (Co. Essex Tierarznei, Munchen, GER) containing Permethrin and "Bremsen-Frei-Plus" (Co. Dr. Schaette AG, Bad Waldsee, GER) based on etheric oils. Both groups were compared with a non treated control group in a crossover-design. Each group (n = 3-5) was used alternately as control and treatment group. Several climate parameters were taken during the study. Furthermore, the number of insects per animal was estimated at certain times. Once per observation period insects were caught using Malaise traps and differentiated by species. The proportion of horse relevant species of the genera Diptera, especially Culex pipiens and Musca autumnalis, caught was 9% on an average. There was no correlation between the number of Tabanidae caught in the Malaise traps and the number observed near by the horses. Behaviour parameters like tailswishing, headshaking, stamping, skintwitching, snapping at the body, and moving were observed more frequently with increasing insect infestation. When horses were infested with a high number of flying insects, feeding activity was significant lower, whereas locomotion activity was significant higher. Both substances had positive effects for about 50 hours after application with no apparent difference between the substances. However, a lower frequency of headshaking and tailswishing could be observed in the Permethrin treated horses. PMID- 21309164 TI - [Pathogenesis of classical swine fever--similarities to viral haemorrhagic fevers: a review]. AB - In spite of differences in etiology, viral haemorrhagic diseases share similarities in their pathogenesis. Characteristic for these diseases are thrombocytopenia, petechia and increased vascular leakage. Most lesions can be attributed to cytokine-mediated interactions triggered by infected and activated monocytes and macrophages, rather than by virus-induced direct cell damage. Causative agents of viral hemorrhagic diseases are enveloped RNA viruses. In most cases, they are transmitted to humans from their animal hosts by rodents or arthropod vectors (Arboviruses). Due to the clinical picture, the acute lethal form of classical swine fever (CSF) is also considered as a viral haemorrhagic disease. CSF is caused by an RNA virus in the family Flaviviridae, and members of the Suidae family are the only ones clinically affected. It is a highly contagious, therefore notifiable disease. In contrast to other viral hamorrhagic diseases, it is mainly transmitted oro-nasally by contact with infected pigs, or by contaminated items (semen, swill feed, clothing). The present survey summarizes analogies between classical representatives of viral haemorrhagic fevers, and recapitulates current knowledge concerning the pathogenesis of classical swine fever. PMID- 21309165 TI - [Control of bovine viral diarrhea/mucosal disease in the district of Kamenz on a voluntary basis--ways, successes, limitations]. AB - In 69 dairy and beef herds in the district of Kamenz, Saxony, with a total number of 21,783 and 89.6% of the district's cattle, a voluntary BVDV eradication protocol was implemented from 2000 to 2007. The aim was to achieve eradication as comprehensive as possible and to prepare the herds for the mandatory eradication program. Essential preconditions for the accreditation of a herd as "free of BVD virus" were the antigen test of all cattle and their offspring for 12 months including completeness check and a negative serological random sampling of young cattle. Mean eradication period of infected herds lasted 45.6 months, herd size, and the number of newly purchased cattle were found to have a significant influence. In five infected farms calf losses significantly decreased after termination of the eradication. further examination of the 126 antigen test positive animals from 15 herds resulted in 87 persistently infected (PI) and 15 transiently infected (TI) individuals, 24 animals missed the second test. Furthermore, out of the 87 PI's 30 individuals (34%) had antibodies against BVDV. Eight farms vaccinated their whole herd, seven only the young stock before first breeding, and 54 herds did not vaccinate, respectively. Concluding from this study, the epidemiological particularities of the farms should be taken in account. Testing of all cattle in a minimum of time including, official monitoring of immediate culling of PI's, immediate epidemiological research, and serological monitoring of the eradication process is necessary. PMID- 21309166 TI - [General practitioners of the future: between peace and anxiety. Reflections from young physicians and general internists]. PMID- 21309167 TI - [Cardiology]. AB - The present review provides a selected choice of clinical research in the field of interventional cardiology, electrophysiology and cardiac imaging. We also focused on the new guidelines published by the European society of cardiology in 2010 (revascularization, atrial fibrillation and device therapy in heart failure). PMID- 21309168 TI - [Addiction]. AB - The news in addiction medicine for 2010 include somatic, neuroscientific as well as psychotherapeutic aspects. First are considered the risks of cardiac arythmy with methadone as long as the racemate form is prescribed in Switzerland. Then the neurosciences bring their usual novelties in the field of the addictions, this year in relational neuroscience and in the relationship between trauma and addiction. At last a contribution bridges the notion of low threshold treatment with the psychodynamic approach. PMID- 21309169 TI - [Management of prolactinomas: what's new in 2010?]. AB - Prolactinomas represent the most frequent pituitary adenomas. Dopaminergic agonists, especially cabergoline, are the first choice treatment. The efficacy of cabergoline in the normalization of prolactin level and in the tumoral volume reduction is well documented. Following more than two years of cabergoline treatment, in case the level of prolactin is normalized and the MRI shows no tumor residue, the medication can be withdrawn with chance of remission. Valvular heart disease has been associated with cabergoline in patients with Parkinson's disease. However due to the lack of systematic data on the subject, cabergoline is still prescribed in case of prolactinoma. Echocardiography could be proposed as a follow up diagnostics to the subjects treated with high dose of cabergoline for a long period. PMID- 21309170 TI - [Highlights in gastroenterology and hepatology 2010]. AB - This review highlights recent advances in gastroenterology and hepatology, including the treatment of Crohn's disease, of eosinophilic esophagitis, of chronic hepatitis C, and of hepatic encephalopathy as well as the role of high resolution manometry in the investigation of esophageal motility disorders. These new developments will be summarized and discussed critically, with a particular emphasis on their potential implications for current and future clinical practice. PMID- 21309171 TI - [Review in geriatric medicine]. AB - In 2010, a study emphasizes the difficulty to predict disability trajectories in the last year of life. A meta analysis shows the effectiveness of post-acute geriatric rehabilitation in reducing functional decline after hospitalisation. Several studies evaluated pneumococcal and herpes zoster vaccines' efficacy. A short and simple intervention is effective in reducing benzodiazepine use. The effect of vitamine D on falls and fractures has been further evaluated in several studies. Diagnostic criteria for dementias, including Alzheimer's disease, are moving to better acknowledge their preclinical stages. PMID- 21309172 TI - [H1N1 (continued), multiresistant Enterobacteriacea, new diagnostic tools]. AB - The pandemic was declared over in October 2010. In this article we review some publications that describe the specificity of the 2009 A(H1N1) virus or suggest new approaches to design more efficacious and better accepted vaccines. Antibiotics resistance continue to increase with the emergence of enterobacteria resistant to almost all available agents. Use of old drugs like fosfomycin is reconsidered. 2010 has also brought progress in the diagnosis of infectious diseases. PMID- 21309173 TI - [Emergency medicine: update 2010]. AB - Several scores with predictive value for morbidity or mortality have been published this year. Their current purpose is to improve the direction of admissions and lengths of stay in hospital. Their use permits more directed care, especially for the elderly, and therefore could improve the proper orientation and admission of patients. Also this year, certain procedures are undergoing evaluation, namely: new assays for troponin, and non-contrast CT in the diagnosis of acute appendicitis. Furthermore in the therapeutic realm: the importance of cardiac massage and the advantages of therapeutic hypothermia in cardiac arrest, and the efficacy of oxygen therapy in cluster headache. PMID- 21309174 TI - [Updates in peritoneal dialysis and renal transplantation]. AB - Loss of the association between cuff number and peritonitis may be related to implementation of new strategies of prevention. Daily application of antibiotic prophylaxis at the peritoneal dialysis exit site is a very effective one. Update of peritoneal dialysis-related infections recommendations published by the international society of peritoneal dialysis presents some evolutions in diagnosis techniques and treatments. Renal transplant recipients under belatacept have significant better renal function and less cardio-vascular risk factors compared to patients under cyclosporine A. Six month administration of anti-CMV prophylaxis in seronegative recipients has shown less CMV disease at 12 month follow-up. The correction of anemia up to 13-15 g/dl was associated with a better quality of life and a better graft function at 2 years follow up. PMID- 21309175 TI - [Therapeutic advances in neurology]. AB - This article summarizes the main therapeutic advances of 2010 in the field of neurology. It focuses on aspects that are likely to change the care of patients in clinical practice. Among these, we discuss the new oral treatments that have proved to be effective in multiple sclerosis, the results of two large studies comparing endarterectomy and stenting in carotid stenosis, novel therapeutic approaches for the treatment of non-motor symptoms in Parkinson's disease as well as the results of several pharmacological studies in the field of epilepsy. PMID- 21309176 TI - [Drug control of appetite]. AB - The control of the appetite by drugs (sensation of hunger, satiation and satiety) is crucial in the management of obesity. Numerous drugs in this domain were forbidden these last years because of serious side effects. New researches allow the development of new substances presenting fewer side effects either by better specificity on receptors (locarserin), or by new mechanism of action (GLP-1, leptin, anti Ghrelin). The appetite is settled by a complex neurohormonal mechanism. To act on some systems at the same time, the development of products "polypill" combining naltroxone-bupropion, phentermine-topiramate or amylin leptine give encouraging results. However the dominant mechanism of the appetite dysregulation needs to be better understood. PMID- 21309177 TI - [Pediatrics. Developmental care in neonatology]. AB - Developmental care is a multidisciplinary approach aiming at improving the premature newborn's well-being through individualized observation and care, and at limiting environmental nociceptive stimuli. The aim is to lessen neonatal morbidity and enhance long-term psychomotor development in this population of high-risk newborns. PMID- 21309178 TI - [Pediatrics. The PAT: a simple and rapid tool for the assessment of the severely ill or injured child]. AB - The Pediatric Assessment Triangle (PAT) has become the cornerstone for the assessment and treatment of a critically ill or injured infant/young child. Now incorporated to the PALS course, it can be taught to all levels of health care providers in charge of severly-ill children. The PAT is a rapid and simple observational tool suitable for pediatric assessment regardless of complaint or underlying diagnosis. It can be introduced in every emergency department, especially those having relatively infrequent encounters with very sick children. Implementation of such a tool needs formal theoritical and practical education skills, rapid availability of experienced pediatric seniors and spaces specifically intented for children. PMID- 21309179 TI - [Pediatrics. Upper limb treatment in congenital hemiparesis: progress and perspectives]. AB - Congenital hemiparesis is one of the most frequent pediatric motor disorders. Upper limb rehabilitation of the hemiparetic child has considerably evolved during the last decade by the use of focal chemical denervation (intramuscular botulinum toxin) and the introduction of novel rehabilitation techniques such as constraint induced movement therapy or robotic reeducation. PMID- 21309180 TI - [Pediatrics. Fecal calprotectin in children: use and interpretation]. AB - Fecal calprotectin is a small protein released mainly by neutrophils. It is recognized as a reliable, easy and non-invasive biomarker of gastro-intestinal inflammation. Normal values vary with age, with higher cut-off values during the first year of life (<350 microg/g) than in children (<275 microg/g) or adults (<50 microg/g). Fecal calprotectin can be a useful tool in initial evaluation of recurrent abdominal pain, helping to distinguish between functional gastro intestinal disorders, where it is normal, and inflammatory bowel disease (IBD). It is not a specific marker of IBD but is increased in other situations of gastro intestinal inflammation. In patients with IBD, fecal calprotectin is used to monitor treatment response. PMID- 21309181 TI - [Pharmacovigilance update]. AB - Main pharmacovigilance updates are reviewed. Rosiglitazone and sibutramine have been suspended due to cardiovascular risks. The safety profile of H1N1 vaccines is similar to the established profile of seasonal influenza vaccines. Paroxetine reduces the benefit of tamoxifen. The use of serotoninergic antidepressants in pregnancy is still disputed. The risk of venous thromboembolism could be higher with oral combined contraceptives containing drospirenone compared to those containing levonorgestrel. Prolonged QT and PR intervals have been observed with saquinavir. The correct use of transdermal patches is reviewed with the example of rivastigmine. Aseptic meningitis is a rare adverse reaction of lamotrigine. An increased risk of fractures after long term use of proton pump inhibitors is suspected. PMID- 21309182 TI - [Rheumatology. TNF alpha-inhibitors: infection risks? Practical recommendations]. AB - Anti-TNF alpha are immunomodulatory treatments prescribed for some rheumatologic inflammatory diseases (ex: spondylarthropathy, rheumatoid polyarthritis). The randomised studies suggested that anti-TNF alpha therapy is associated with an overall risk of infectious diseases. The results of the observational studies are more reassuring. In this article, we will describe some results of theses studies and propose some practical recommendations in use of the anti-TNF alpha therapy. PMID- 21309183 TI - [Urology in 2010]. AB - In 2010, therapeutic acquisitions in urology mainly allowed optimizing the management of benign prostatic hypertrophy, overactive bladder, localized and metastatic prostate and renal cancers. PMID- 21309184 TI - [Breaking bad news: "EPICES", a French style as a learning method]. AB - Breaking bad news is a daily task for doctors and nurses. These health professionals may feel powerless to achieve this task and to deal with the emotions that arise in the patient when they are doing so. The interdisciplinary approach and a specific training are essential resources to feel more comfortable in this context. "EPICES", the French translation of the mnemonic acronym "SPIKES", of Buckman, gives a guide for this sensitive practice. PMID- 21309185 TI - [Assisted suicide, state of necessity and exception for euthanasia. Discussion of the recent Neuchatel ruling ]. PMID- 21309186 TI - [How, soon, the economy of amniocentesis?]. PMID- 21309187 TI - [Who are these women who "murder" from birth?]. PMID- 21309189 TI - [2011, a little outrage ]. PMID- 21309188 TI - [The leader Henry IV of France (1553-1610) is found ]. PMID- 21309190 TI - [Scientific training and professional practice in Vicente Cervantes Mendo's Spain.]. AB - Vicente Cervantes Mendo (Ledrada, Salamanca, 1758 - Mexico, 1829) was a famous Spanish Mexican scientists; he is today heritage of Spain and Mexico. As a continuation of two recent articles on his life at Spain, the present study deals with his scientific formation at madrid, as pharmacist and as botanist, as well as on his professional activity. Two documents of Casimiro Gomez Ortega, principal professor of the Real Jardin Botanico de Madrid, dated in 1786 and related with the "Real Expedicion Botanica a Nueva Espana (1787-1803)," have served to establish conclusions which clarify the subjects studied and correct mistakes. PMID- 21309191 TI - [The takeover process of the "Real Tribunal del Protoalbeitarato" by the faculty of Veterinary of Madrid (1792-1855)]. AB - The absorption of the "Real Tribunal del Protoalbeitarato" by the Veterinary Science School of Madrid shows several singularities in relation to the equivalent process in medicine and pharmacy. The conflict and the hegemony of the "Real Tribunal" during almost sixty years from the creation of the Veterinary Science School (1792), has been studied by the traditional historiography with a view fundamentally focused on veterinary aspects. In this article, the process of absorption is investigated in full detail. Also, the relevance of political motivations and their predominance over technical, sanitary or professional motivations are shown. So, the game of institutions and agents which are external to the veterinary science are analysed; specially, the outstanding role performed by the XV Marquis of Cerralbo. PMID- 21309192 TI - [Protomedicato and pharmacy in Castile at the end of the sixteenth century: "Catalogo de las Cosas que los Boticarios han de tener en sus Boticas" (Catalogue of the things that apothecaries must have in their shops), by Andres Zamudio de Alfaro, Protomedico General (1592-1599)]. AB - In this article we present a catalogue of medicinal products preserved in a manuscript copy among the papers of a druggist who died in Madrid in 1599. This catalogue, whose title expresses its normative character, contains 423 entries and is signed by Andres Zamudio de Alfaro, Protomedico General of Castile from 1592 until his death in 1599. It was presumably issued by the Real Tribunal del Protomedicato during the last decade of the sixteenth century for the use of the protomedicos and examiners who carried out official visits to apothecaries under the aegis of the Tribunal, in accordance with the royal decrees of 1588 and 1593, and was also distributed among the apothecaries themselves and their suppliers, such as the druggist who possessed the copy edited here. The document offers valuable evidence of the policy of normalization of medical, and specifically pharmaceutical, practice imposed during this period by the State through the Protomedicato. PMID- 21309193 TI - Medicare beneficiary access to primary care physicians--better in rural, but still worrisome. AB - Primary care is the foundation of the rural U.S. health care system. Thus, the willingness of rural primary care physicians to accept new Medicare patients is critically important to the Medicare program and to rural America's elderly. But universally consistent access to primary care physicians for Medicare beneficiaries may be in jeopardy. The American Academy of Family Physicians (AAFP) reports that the percentage of family physicians accepting new Medicare patients declined from 84% in 2000 to 73% in 2008. Urban family physicians accepted new Medicare patients at a lower rate (70%) than did rural family physicians (83%). In this policy brief, we use results from a large national physician survey to assess U.S. primary care physician and general surgeon willingness to accept Medicare patients. We also assess physician-reported reasons for not accepting Medicare patients. PMID- 21309195 TI - Maternal morbidity in cases of placenta accreta managed by a multidisciplinary care team compared with standard obstetric care. AB - OBJECTIVE: To compare maternal morbidity in cases of placenta accreta managed by a multidisciplinary care team with similar cases managed by standard obstetric care. METHODS: This was a retrospective cohort study of all cases of placenta accreta identified in the State of Utah from 1996 to 2008. Cases of placenta accreta were identified using International Classification of Diseases (ICD-9) codes for placenta accreta, placenta previa, and cesarean hysterectomy. Maternal morbidity was compared for cases managed by a multidisciplinary care team in two tertiary care centers and similar cases managed at 26 other hospitals using multivariable logistic regression analysis. RESULTS: One-hundred forty-one cases of placenta accreta were identified including 79 managed by a multidisciplinary care team and 62 cases managed by standard obstetric care. Women managed by a multidisciplinary care team were less likely to require large-volume blood transfusion (4 or more units of packed red blood cells) (43% compared with 61%, P=.031) and reoperation within 7 days of delivery for bleeding complications (3% compared with 36%, P<.001) compared with women managed by standard obstetric care. Women with suspected placenta accreta managed by a multidisciplinary team were less likely to experience composite early morbidity (prolonged maternal admission to the intensive care unit, large-volume blood transfusion, coagulopathy, ureteral injury, or early reoperation) than women managed by standard obstetric care (47% compared with 74%, P=.026). The odds ratio of composite early morbidity in women managed by a multidisciplinary team was 0.22, (95% confidence interval, 0.07- 0.70) in the multivariable model. CONCLUSION: Maternal morbidity is reduced in women with placenta accreta who deliver in a tertiary care hospital with a multidisciplinary care team. LEVEL OF EVIDENCE: II PMID- 21309196 TI - [My encounter with pharmacology]. PMID- 21309194 TI - The relationship between maternal glycemia and perinatal outcome. AB - OBJECTIVE: To examine the relationship between varying degrees of maternal hyperglycemia and pregnancy outcomes. METHODS: This was a secondary analysis of a treatment trial for mild gestational diabetes including four cohorts: 1) 473 women with untreated mild gestational diabetes; 2) 256 women with a positive 50-g screen and one abnormal oral glucose tolerance test (OGTT) value; 3) 675 women with a positive screen and no abnormal OGTT values; and 4) 437 women with a normal 50-g screen. Groups were compared by test of trend for a composite perinatal outcome (neonatal hypoglycemia, hyperbilirubinemia, elevated cord C peptide level, and perinatal trauma or death), frequency of large for gestational age neonates, shoulder dystocia, and pregnancy-related hypertension. Three-hour OGTT levels (fasting, 1-, 2-, and 3-hour) levels were divided into categories and analyzed for their relationship to perinatal and maternal outcomes. RESULTS: There were significant trends by glycemic status among the four cohorts for the composite and all other outcomes (P<.001). Analysis for trend according to OGTT categories showed an increasing relationship between fasting and all postload levels and the various outcomes (P<.05). Fasting glucose 90 mg/dL or greater and 1 hour 165 mg/dL or greater were associated with an increased risk for the composite outcome (odds ratios and 95% confidence intervals of 2.0 [1.03-4.15] and 1.46 [1.02-2.11] to 1.52 [1.08-2.15] for the fasting and 1 hour, respectively). A 1 hour glucose 150 mg/dL or greater was associated with an increased risk for large for gestational age (odds ratios, 1.8 [1.02-3.18] to 2.35 [1.35-4.14]); however, 2- and 3-hour glucose levels did not increase the risk for the composite or large for gestational age until well beyond current gestational diabetes diagnostic thresholds. CONCLUSION: A monotonic relationship exists between increasing maternal glycemia and perinatal morbidity. Current OGTT criteria require reevaluation in determining thresholds for the diagnosis and treatment of gestational diabetes. LEVEL OF EVIDENCE: II PMID- 21309197 TI - [The 29th National Congress of the Italian Society of Surgical Endocrinology, Mondello (Palermo), June 24-26, 2010]. PMID- 21309198 TI - [Dr. Luboslav Starka, 80-year-old]. PMID- 21309199 TI - Medical ethics: as theme issue on EMA annual conference. PMID- 21309200 TI - Caregivers' child malaria treatment practice in Gilgel Gibe field research center, south west Ethiopia. AB - BACKGROUND: Reduction of malarial morbidity and mortality in children greatly depends on caregivers' response to childhood malaria. OBJECTIVE: The study was conducted to assess caregivers'practice related to the treatment of childhood malaria. METHODS: The study was conducted in 9 Kebeles surrounding Gilgel Gibe Dam from November to December 2005 employing a cross-sectional design. A sample of 588 households in which children between the age of 2 months and 59 months resided were randomly selected from urban, semi urban and rural strata. The primary caregivers in each sampled households were interviewed using structured questionnaire. FINDINGS: Most (79.2%) of the caregivers reported that their under five child has been affected by malaria at least once in their lifetime. The common first modalities of treatment for the child's last malarial episode were home treatment (52.3%) and treatment seeking from formal sectors (43.7%). The commonest type of home care was treatment with antimalarials (71.3%). Early treatment seeking was higher among those who started home antimalarial treatment (30%) as compared to those who sought treatment from formal sectors (19.7%). Higher socioeconomic status was found to be associated with early treatment seeking. CONCLUSION: The study has identified high prevalence of home treatment with antimalarials and late onset of treatment seeking by caregivers for children with malaria. This lays a good ground and calls for implementation of home malaria management strategy. PMID- 21309201 TI - Impact of HIV/AIDS on labor productivity in Akaki fiber products factory, Ethiopia. AB - BACKGROUND: HIV/AIDS has become a full-blown development crisis affecting all sectors of the economy in most developing countries. Its social and economic consequences are felt widely not only in health but in education, industry, agriculture as well as transport. OBJECTIVE: The study attempted to estimate the changes in worker's output and attendance associated with advancing HIV infection, and direct costs incurred by a fiber products factory due to illness and death related to HIV/AIDS. METHODS: The study is a retrospective cohort with accounting method of cost estimation. The study subjects were factory workers enrolled in a cohort study of HIV incidence and progression in Akaki, Ethiopia since February 1997. RESULTS: The mean incentive earnings were not significantly different between HIV positives and negatives at baseline (in 1997). However, in the following years (1998, 1999 and 2000) the incentive earnings of HIV positives were significantly lower than the incentive earnings of HIV negatives. Trend analysis showed that advancing HIV infection, as measured by drop in CD4 count and increasing viral load, is associated with reduction in productivity and increased sick leave days. CONCLUSION: The study has shown that there is a direct negative impact of HIV infection on the productivity of factory workers and recommends institution of ART centers and programs in work places to mitigate the socio economic impact of the pandemic. PMID- 21309202 TI - Differentials in measures of dietary quality among adolescents in Jimma zone, Southwest Ethiopia. AB - BACKGROUND: nutritionally adequate, safe and good quality diet is essential for human health, school performance, and employment output. Dietary diversity, consumption of animal source food and food variety score are commonly used measures of dietary quality. This study aimed to assess gender & sociodemographic differentials in measures of dietary quality among male and female adolescents. METHODS: As part of the Jimma Family Longitudinal Study of Youth households with a youth between 13-17 years were randomly sampled from Jimma Town, the small towns and nearby rural Kebeles. Dietary diversity was assessed by asking youth about the consumption of 32 different food items included in the survey, which were regrouped into four major food groups. The four groups included animal source foods (10 items), fruits-vegetables (11 items), cereals (7 items) and legumes-nuts (2 items). From these food groups, measures of dietary diversity, food variety score, and animal source food consumption were calculated Logistic regression model was done using SPSS for windows version 12.0.1 to determine the odds ratios and predicted probabilities of consuming diversified diet. RESULTS: Overall, 826 (39.7%), 819 (39.4%) and 955 (45.9%) of adolescents had low quality diet as measured by dietary diversity, consumption of animal source food and food variety score, respectively. Predictors of a diversi-fied diet consumption were male gender, (1.3 OR, 95% CI 1.1, 1, 5), living in small towns (1.7 OR (95% 1.3, 2.1) and being a member of household in the high-income quartile (2.1 OR 95% CI 1.5, 2.8). Intake of animal source foods was associated with the highest level of education achieved in the household (1.4 OR 95% CI: 1.1, 1.8), being male (1.3 OR 95% CI: 1.1, 1.5), being in a households with highest income quartile (2.3 OR 95% CI: 1.6, 3.1). Adolescents who lived in households with the highest income quartile and those who lived in the small towns were 1.6 and 1.4 times more likely to have high food variety score. CONCLUSION: Large proportion of adolescents consumed low quality diets, which may effect on their education and work productivity and contribute to an intergenerational cycle of malnutrition. Interventions designed to improve dietary quality should target female adolescents, those in the poorest households, and households with low levels of education. Rural areas should also be targeted Thus targeted interventions to promote dietary quality and programmatic interventions to increases schooling may positively influence dietary quality in this area. PMID- 21309203 TI - A retrospective analysis of prevalence and antimicrobial susceptibility patterns of Staphylococcus aureus in Gondar teaching hospital, 2001-2005. AB - BACKGROUND: The current anti-staphylococcal therapy is increasingly compromised by the emergence and spread of resistant strains. The presence of multi-drug resistant bacteria is a great threat and because of the increasing members of resistant strains with time, updated information on prevalence and sensitivity of local major pathogens is of paramount importance. OBJECTIVES: To determine the prevalence of S. aureus infections among outpatients and inpatients and the drug resistance patterns of the isolates to the commonly used antimicrobials. MATERIALS AND METHODS: The study is a laboratory based retrospective analysis of different bacteriological specimens which were processed for culture and antimicrobial susceptibility testing in the bacteriology laboratory of the University of Gondar Teaching hospital from September 2001 to August 2005. RESULTS: Of the 616 isolates of S. aureus from different clinical specimens, the highest rate of isolation was from pus cultures (38.5%) followed by urine (32.5%). The isolates showed high level of drug resistance against tetracycline (68.3%), penicillin (54.9%), ampicillin (49.7%), trimethoprim-sulfamethoxazole (48.2%), and chloramphenicol (44.2%) but a moderate degree of resistance to erythromycin (21.6%) and gentamicin (19.6%). Resistance to ciprofloxacin was found only in 6.8% of the isolates. The isolates also showed increased resistance to the antibiotics tested with passage of time (from 2001 through 2005) and higher resistance was observed among ward isolates compared to the outpatients. CONCLUSION: Our results demonstrate the existence of multidrug resistant strains of S. aureus in Gondar indicating a strong need to ease selective antibiotic pressure to limit spread of drug resistance in the region. A continuous surveillance of antimicrobial susceptibility patterns and strong antibiotic policies are needed in order to minimize the emergence and spread of resistant pathogenic bacteria. PMID- 21309204 TI - Methicillin-resistant strains of Staphylococcus aureus and coagulase-negative staphylococus from clinical isolates at Felege Hiwot Refferal Hospital, North West Ethiopia. AB - OBJECTIVES: Methicillin-resistant staphylococci are one of the major causes of nosocomial infection. The aim of this study was to determine Methicillin resistant strain of staphylococci and its antibiotic resistance. MATERIALS AND METHODS: Across--sectional study was done on 162 S. aureus and 59 coagulase negative staphylococci from 151 inpatients and 70 outpatients at Felege Hiwot Referral Hospital from 1st April to June 31, 2006. Methicillin resistance was identified by detecting penicillin binding protein 2' (PBP2') using PBP2' Latex (Oxoid Ltd, Basingstoke, UK) and cefoxitin (30 microg) disc-diffusion method RESULTS: The isolation rate of methicillin-resistant staphylococci (MRSA and MRCoNS) was found to be 55% and 78% respectively. MRSA and MRCoNS showed higher rates of multi-drug resistance against other commonly prescribed antibiotics such as penicillin G 89 (100%), ceftriaxon 85 (99.5%) tetracycline 80 (89.88%), erythromycin 69 (77.5%), ciprofloxacin 67 (75.3%) and gentamicin 63 (70.78%) compared to methicillin-susceptible staphylococci (MSSA & MSCoNS). The overall prevalence of MRSA and MRCONS was 59.7% of which 72.8% was from inpatients and 31.4% outpatients. CONCLUSION: High rates of MRSA and MRCON with its multi-drug resistance will pose a big challenge in therapy of MRSA and MRCON infection, thus, empirical therapy of this infection should include glycopeptid drugs and further studies on prevention and control of MRSA and MRCoNS infection in hospital need to be conducted PMID- 21309205 TI - Frequency of isolation and antimicrobial susceptibility pattern of bacterial isolates from blood culture, Gondar University teaching hospital, Northwest Ethiopia. AB - BACKGROUND: Bacterial bloodstream infections cause substantial morbidity and mortality, with up to one-quarter of affected patients dying as a result of their infection. Up-to-date information on blood culture isolates and their antimicrobial susceptibility pattern is very important as guide for immediate prescription of antimicrobial agents and monitoring of emergence of drug resistant strains. OBJECTIVE: To determine the frequency of blood culture isolation and antimicrobial susceptibility pattern of isolates in Gondar University teaching hospital. METHODS: This was retrospective analysis of records of blood culture results for febrile patients seen at Gondar University teaching hospital, bacteriology section from March 2001 to April 2005. RESULTS: During the four years period, blood cultures were done for a total of 472 febrile patients. Among these, 233 (49.4%) were females and 239 (50.6%) were males. The median age was 20.5 years (age range of 2 hours to 78 years). Out of these, total of 114 bacterial strains were isolated with culture positivity rate of 24.2%. Coagulase negative Staphylococci (CoNS) were isolated with the highest frequency in 38 (33.3%), followed by Staphylococcus aureus in 34 (29.8%), Salmonella species other than Salmonella typhi in 12 (10.5%), Klebsiella species in 10 (8.8%), Streptococcus pneumoniae in 6 (5.3%), Salmonella typhi in 4 (3.5%), Enterobacter species in 3 (2.6%), Escherichia coli in 2 (1.7%). The gram positive and gram negative bacteria constituted 80 (70.2%) and 34 (29.8%) of the culture isolates, respectively. Culture positivity rates vary as for neonates, 63% (17 out of 27);followed by 25.6% (36 out of 141) in children and 20% (61 out of 304) in adults. The isolates especially gram negative bacteria showed multiple drug resistance, to Ampicillin and penicillin. However, ciprofloxacin is fairly effective against both gram negative and gram positive isolates. CONCLUSION: An effective documented data may serve as a guide for initial empirical treatment of bloodstream infections but in view of these findings the presented data is only imperative to do large-scale prospective and quantitative studies. More importantly, an ongoing surveillance for antimicrobial susceptibility is of the essence to enhance efforts to identify resistance and attempt to limit its spread. PMID- 21309206 TI - The risk factors for machine injury of the upper limb case-crossover study in Tikur Anbessa University Hospital, Addis Ababa, Ethiopia. AB - INTRODUCTION: Machinery is the single most common cause of acute occupational hand injury in our hospital. OBJECTIVE: To identify the pattern and determine the causes of acute upper limb injury resulting from the use of machines. MATERIAL AND METHODS: Case-crossover study design was used. Two hundred and nine (97%) of all 216 patients who had an acute upper limb injury when using a machine and who presented to Tikur Anbessa hospital between November 2004 and October 2005 were examined RESULT: The majority of our patients were young (mean age 28.5 years), male (95%) and working in manufacturing industry 181 (87%). Ninety (43%) were machine operator, and had worked less than one year 122 (58%) with short term contract 120 (57%). The majority were not trained formally either for the task they were doing 168 (80%), or for safety measures 178 (85%). A safety guard was present only in a few machines 31 (15%) and half of these were being used. Most of the injuries occurred shortly after lunch. Very many of the injuries were severe with a resulting amputation 47% and fracture 35%. The mean permanent disability was 20%. Doing unfamiliar tasks was associated with the highest relative risk (increase by 14 fold) followed by being rushed (RR = 12), being distracted (RR = 8), using alfunctioning equipment (RR = 8) and using unaccustomed technique to do a task (RR = 6). Wearing gloves decreased the risk by 83%. Job category, work experience, training on the task and safety training significantly modified the transient risk factors. CONCLUSION: the incidence of occupational upper limb machinery injuries could be reduced by avoiding transient risk factors and by providing safety training. PMID- 21309207 TI - Surgical lymph node biopsies in a rural Ethiopian hospital: histopathologic diagnoses and clinical characteristics. AB - OBJECTIVE: To assess the clinical features and histological diagnoses of patients with lymphadenopathy in a rural general hospital. BACKGROUND: Gambo Rural General Hospital, located between the Arsi and East Shoa regions, 250 km south of Addis Ababa (Ethiopia), and the Department of Pathology, Faculty of Medicine, Addis Ababa University, Addis Ababa, Ethiopia for the pathology examination carried out between December 2003 and July 2005. METHOD: Retrospective cross-sectional survey. RESULTS: 308 patients with enlarged superficial lymph nodes with surgical lymph node excision. The most common diagnoses were tuberculosis lymphadenitis (TB-L) (74.4%), followed by non-specific reactive lymphadenitis (10.2%), malignant secondary lymphadenopathy (7.5%), and lymphomas (7.1%). In the multivariate analysis, TB-L was significantly associated with previous antibiotic treatment for more than 20 days (adjusted odds ratio (aOR): 3.70; 95% CI: 1.43 9.59) (p = 0.007), and female sex (OR: 2.07; 95% CI: 1.09-3.9). Non-specific reactive lymphadenitis was significantly associated with paediatric cases (aOR: 4.42; 95% CI: 1.78-10.87) (p = 0.001). CONCLUSION: These results show that tuberculosis is a major problem in this area. PMID- 21309208 TI - Patterns of pre hospital fatal injuries in Mekelle, Ethiopia. AB - OBJECTIVE: To assess the pattern of pre hospital fatal injuries and determine the age, sex and types of injury for all victims brought dead to Mekelle hospital MATERIALS AND METHODS: A retrospective descriptive audit of all victims brought dead to Mekelle hospital due to trauma was carried out to assess the magnitude and pattern of pre hospital fatal injuries between September 1, 2004 to Jun. 30, 2006. These include all victims brought dead following road traffic accidents, suicidal, homicidal, drowning, burns and also deaths from other accidental causes. The source and the study group are (N = 120 deaths) involved in accidental injuries. Case notes were obtained from written police reports and medical records office and were analyzed for age, sex and type of injury. RESULTS: There were 120 deaths caused by fatal accidents before arrival to Mekelle hospital. There were 95 (79.2%) male and 25 (20.8%) female victims. Peak incidence of pre hospital fatal deaths were in the 10-29 year age group accounting for 54.9% of the cases. In the study the median age was 25 years and the range from 4 to 70 years. Road traffic accident was the leading causes of fatal injuries, accounting for 46.6 % of all fatal deaths followed by physical assaults (28.3%), suicidal hanging (10.8%), electrical burns (5.0%) and bullet injuries (4.1%). CONCLUSION: Overall this study has shown that pre hospital fatal injuries commonly occurred in the younger age group. Majority were caused by road traffic accidents with males predominantly affected PMID- 21309209 TI - Vaginal calculus following severe form of female genital mutilation: a case report. AB - We present a case of vaginal calculus formation following an initial insult of female genital mutilation (FGM) and crocodile bite to the external genital. A literature review made with regards to acute and late complication of female genital mutilation. Female genital cutting existed as early as the 5th century B.C. This ritualistic practice has affected the physical, mental, and social well being of women and undermined the basic reproductive and sexual health rights of the female population. Worldwide, 85-114 million girls and young women are subjected to this dreadful practice. It is mostly practiced in Africa and Middle East. Various authors classify female genital cutting differently. The World Health Organization classifies FGM in to FOUR types. Female genital mutilation is associated with immediate, intermediate and long-term complications (1-4). The complications are strongly related to the variant of the mutilation, especially of the third and the fourth types where introcision or vaginal scraping is performed. Vaginal calculus formation is a rare phenomenon. Our patient had a total obliteration of the introitus, vaginal calculus formation and urethra vaginal fistula, which were surgically managed and corrected PMID- 21309210 TI - Oral rehabilitation of a patient with hypoplastic amelogenesis imperfecta: a case report. AB - To report a case of oral rehabilitation of a patient diagnosed with hypoplastic amelogenesis imperfecta. A 18-year-old female with hypoplastic amelogenesis imperfecta presented for prosthodontic treatment to eliminate tooth sensitivity while enhancing esthetics and restoring masticatory function. Treatment included, lengthening of the maxillary and mandibular clinical crowns, and placement of metal-ceramic fixed partial dentures. The 1-year recall examination revealed no pathology associated with the rehabilitation, and the patient's esthetic and functional expectations were satisfied. For successful prosthodontic therapy, the clinician should be aware of all condition of patient. PMID- 21309211 TI - Viral hepatitis: epidemiology, treatment, prevention. PMID- 21309212 TI - Accumulation of pest insects on eucalyptus in California: random process or smoking gun. AB - Eucalyptus spp., native to Australia, have been introduced into many parts of the world as important timber and ornamental trees. Although the trees have important silvicultural qualities, they also have generated intense dissatisfaction, particularly among groups of individuals in California. The trees have benefited from the lack of insect pests and diseases in their adventive ranges but that has changed over the past four decades. In California, two species of insect herbivores were introduced between the time trees were first introduced to the state in the middle of the 19th century and 1983. Between 1983 and 2008, an additional 16 Australian insect pests of eucalyptus have become established in the state. The modes or routes of introduction have never been established. However, examinations of different temporal and spatial patterns suggest that the introductions were nonrandom processes. It is possible that they occurred because of increased trade or movement of people, but the hypothesis that there were intentional introductions also must be considered. The rapid accumulation of introduced herbivores on an ornamental plant system in a single state is a cautionary example of what could happen if a major food or fiber crop were intentionally targeted. PMID- 21309213 TI - Factors affecting ionizing radiation phytosanitary treatments, and implications for research and generic treatments. AB - Phytosanitary irradiation (PI) treatments are promising measures to overcome quarantine barriers to trade and are currently used in several countries. Although PI has advantages compared with other treatments one disadvantage bedevils research, approval, and application: organisms may remain alive after importation. Although this does not preclude their use as a phytosanitary treatment, it does leave the treatment without an independent verification of efficacy and places a greater burden for assuring quarantine security on the research supporting the treatment. This article analyses several factors that have been hypothesized to affect PI efficacy: low oxygen, pest stage, host, dose rate, and temperature. Of these factors, the first is known to affect efficacy, whereas host and dose rate probably need more research. The International Plant Protection Convention considered several PI treatments for its international standard on phytosanitary treatments and did not approve some at first because of perceived problems with the research or the presence of live adults after irradiation. Based on these concerns recommendations for research and dealing with the issue of live adults postirradiation are given. Generic PI treatments are suggested. PMID- 21309214 TI - Overview of pesticide residues in stored pollen and their potential effect on bee colony (Apis mellifera) losses in Spain. AB - In the last decade, an increase in honey bee (Apis mellifera L.) colony losses has been reported in several countries. The causes of this decline are still not clear. This study was set out to evaluate the pesticide residues in stored pollen from honey bee colonies and their possible impact on honey bee losses in Spain. In total, 1,021 professional apiaries were randomly selected. All pollen samples were subjected to multiresidue analysis by gas chromatography-mass spectrometry (MS) and liquid chromatography-MS; moreover, specific methods were applied for neonicotinoids and fipronil. A palynological analysis also was carried out to confirm the type of foraging crop. Pesticide residues were detected in 42% of samples collected in spring, and only in 31% of samples collected in autumn. Fluvalinate and chlorfenvinphos were the most frequently detected pesticides in the analyzed samples. Fipronil was detected in 3.7% of all the spring samples but never in autumn samples, and neonicotinoid residues were not detected. More than 47.8% of stored pollen samples belonged to wild vegetation, and sunflower (Heliantus spp.) pollen was only detected in 10.4% of the samples. A direct relation between pesticide residues found in stored pollen samples and colony losses was not evident accordingly to the obtained results. Further studies are necessary to determine the possible role of the most frequent and abundant pesticides (such as acaricides) and the synergism among them and with other pathogens more prevalent in Spain. PMID- 21309215 TI - Incidence of Candidatus Liberibacter asiaticus infection in abandoned citrus occurring in proximity to commercially managed groves. AB - Huanglongbing is one of the most devastating diseases of citrus (Citrus spp.). One management tactic against huanglongbing is aggressive management of the vector, the Asian citrus psyllid (Diaphorina citri Kuwayama), with insecticide applications. However, D. citri in abandoned groves are not controlled and therefore pose a risk of reinfestation for nearby commercial citrus. These abandoned groves could serve as a reservoir for the vector, as well as a source of the presumed causal agent for huanglongbing in Florida, Candidatus Liberibacter asiaticus (Las). The current study was conducted to determine the degree to which Las is present in abandoned Florida citrus groves and to compare relative inoculum levels in nearby managed and abandoned groves during times of the year when D. citri are abundant (June, July, and August). In addition, the movement of Las by dispersing D. citri adults from inner and edge rows of abandoned grove plots to the corresponding rows of managed plots was quantified during the same 3 mo. The results of the current study confirmed the presence of Las in both D. citri and plant tissue in abandoned groves at statistically equivalent levels to those in nearby managed groves. The mean number of D. citri adults dispersing from abandoned to managed grove plots ranged from 7.25 +/- 1.70 to 70.25 +/- 21.25 per 4-d intervals. Of those, the mean number of dispersing D. citri adults that were carrying the Las pathogen ranged from 1.00 +/- 0.58 to 1.50 +/- 0.50. Our results indicate that abandoned citrus groves are a significant source of Ca. Las and that dispersing D. citri move this pathogen into nearby managed groves. PMID- 21309216 TI - Evaluation of chemical controls and entomopathogenic nematodes for control of Phyllophaga white grubs in a Fraser fir production field. AB - The results of 2 yr of field trials evaluating various chemical and biological controls of Phyllophaga anxia (LeConte) white grubs in a Fraser fir [Abies fraseri (Pursh) Poir] Christmas tree production field are reported here. Chemical insecticides evaluated included bifenthrin, chlorantraniliprole, thiamethoxam, and time-released imidacloprid tablets (Coretect, Bayer CropScience, Research Triangle Park, NC). Entomopathogenic nematodes evaluated included Heterorhabditis bacteriophora (Poinar) and Steinernema carpocapsae (Weiser). Overall, the chemical controls provided the best root protection and grub control. Targeted treatments of an insecticide in the root zone may provide adequate tree protection and can be a way to reduce overall insecticide input compared with banded sprays. The nematode H. bacteriophora provided limited root protection and grub control, whereas S. carpocapsae did not provide effective control. Differences in efficacy and persistence of the two entomopathogenic nematode species can be attributed to the biology and environmental preferences of these organisms. PMID- 21309217 TI - Toxicity of phosphine to Carposina niponensis (Lepidoptera: Carposinadae) at low temperature. AB - Carposina niponensis Matsumura (Lepidoptera: Carposinadae), is widely distributed in pome fruit production areas in China and presents a problem in some export markets because it is considered a quarantine pest by some countries. Methyl bromide is the only fumigant used for fumigation of apples (Malus spp.) for export. However, phosphine is a candidate replacement that can be applied directly at low temperature. Here, laboratory tests showed that tolerance of different stages of C. niponensis to phosphine fumigation at 0 degrees C differed greatly; first-second-instar larvae were the least tolerant stage and the mature fifth instars were the most tolerant stage. In the mature larvae, fumigation tests, with a range of phosphine concentrations from 0.42 to 1.95 mg/liters and exposure periods of 24 h to 14 d at 0 degrees C indicated narcosis when phosphine concentration was > or = 1.67 mg/liter and that a 15.52-8.14-d fumigation period was required to achieve 99% mortality with different phosphine concentrations. The expression of C(0.7)T = k was obtained, which indicated that exposure time was much more important than concentration of phosphine in mortality of mature larvae of C. niponensis. All results suggested that phosphine fumigation at low temperature offers promising control of C. niponensis infestation in pome fruit. PMID- 21309218 TI - Development of allele-specific single-nucleotide polymorphism-based polymerase chain reaction markers in cytochrome oxidase I for the differentiation of Bactrocera papayae and Bactrocera carambolae (Diptera: Tephritidae). AB - Differentiation of Bactrocera papayae Drew & Hancock and Bactrocera carambolae Drew & Hancock (Diptera: Tephritidae) based on morphological characters has often been problematical. We describe here a single-nucleotide polymorphism (SNP)-based polymerase chain reaction (PCR) assay to differentiate between these two species. For detection of SNPs, fragments derived from each species were amplified using two primer pairs, COIF/COIR and UEA7/UEA10, sequenced, and aligned to obtain a contiguous 1,517-bp segment. Two new sets of primers were designed based on the 11 SNPs identified in the region. Results of the SNP-PCR test using any one of these species-specific primer sets indicate that these two species could be differentiated on basis of presence or absence of a band in the gel profile. We also tested the SNP-PCR primers on Bactrocera umbrosa F., Bactrocera cucurbitae Coquillett, Bactrocera latifrons Hendel, and Bactrocera tau (Walker) but did not detect any band in the gel, indicating the likelihood of a false positive for B. papayae is nil. This SNP-PCR method is efficient and useful, especially for immature life stages or when only adult body parts of the two species are available for identification, as encountered often in quarantine work. PMID- 21309219 TI - Effect of cold storage on larval and adult Anastrepha ludens (Diptera: Tephritidae) viability in commercially ripe, artificially infested Persea americana 'Hass'. AB - Commercially ripe 'Hass' avocados, Persea americana Mill, artificially exposed to wild Anastrepha ludens (Loew) (Diptera: Tephritidae) females 24 h after harvest were placed in a cold storage facility to determine the effect of low temperature on larval survival and adult viability. Fruit were left for 3, 6, 9, and 12 d in a cold room at 5 degrees C followed by a 20-25-d period at ambient temperature to allow for larval development and pupation. Hass avocados and grapefruit, Citrus paradisi Macfadyen, maintained at ambient temperature served as controls. Overall, only 0.23% of the Hass avocados and 19.30% of the grapefruit were infested. The number of infested fruit increased with decreasing exposure time to cold. Puparia from cold-treated Hass avocados were significantly smaller than those stemming from cold-treated grapefruit. Hass avocados exposed for 12 d to 5 degrees C yielded no puparia, and those exposed for 6 and 9 d yielded 22 and two puparia, respectively, but no adults. Although Hass avocados exposed to cold temperature for 3 d yielded adults that reached sexual maturity (N = 16), females laid inviable eggs. Grapefruit exposed to cold for 12 d yielded normal-sized puparia (but no adults), whereas those exposed over 9 d yielded females able to lay viable eggs. We conclude that exposing fruit to cold storage after packing and during transport represents an effective risk-mitigating procedure in the highly improbable event that a gravid A. ludens female might lay eggs in a commercially ripe Hass avocado that had been left unprotected in a packinghouse. PMID- 21309220 TI - Development and population growth of Lygus hesperus on selected weed hosts, artificial diet and cotton in the laboratory. AB - Laboratory studies were conducted to obtain basic biological information of Lygus hesperus Knight (Hemiptera: Miridae) on alfalfa (Medicago sativa L.), pigweed (Amaranthus palmeri S. Wats.), Russian thistle (Salsola iberica Sennen and Pau), green bean (Phaseolus vulgaris L.), artificial diet, and cotton (Gossypium hirsutum L.) square and cotton boll at 27 degrees C. The nymphal developmental duration was 28.8 d on cotton bolls, nearly twice longer, compared with approximately 15 d in other hosts. The nymphal survivorship was significantly lowest on the cotton boll (18%), whereas the survivorship in other hosts ranged from 33% (cotton square) to 93% (green bean). The average total nymphal survivorship was approximately 60% and the most nymphal mortalities occurred on the first three instars. The life-table parameters were obtained only in cotton square, artificial diet, green bean, and alfalfa. The average adult longevity in artificial diet was the shortest (18.7 d),with the longest longevity observed (36.1 d) on green beans. The intrinsic rates of population increase (r(m)) were much higher in artificial diet (0.0771) and green beans (0.0671) than in alfalfa (0.0327) and cotton square (0.0317). Although statistically significant, the difference in r(m) values between alfalfa and cotton square was very small, indicating the similarity in reproductive suitability of cotton square and alfalfain a no-choice test. Thus, even though cotton is not a preferred host, when blooming alfalfa and roadside weeds are mowed in the Texas High Plains during June-July, it is the most likely time that Lygus bugs may move from alfalfa and other host plants into adjacent cotton fields and become effective pest of actively fruiting cotton. PMID- 21309221 TI - Bottom-up effect of different host plants on Plutella xylostella (Lepidoptera: Plutellidae): a life-table study on canola. AB - The effects of 10 commercial canola, Brassica napus L., cultivars widely grown in Iran--'SLM(046),' 'Opera,' 'Okapi,' 'RGS(003),' 'Modena,' 'Sarigol,' 'Zarfam,' 'Licord,' 'Hayula(420),' and 'Talaye'--on the demographic parameters of diamondback moth, Plutella xylostella L. (Lepidoptera-Plutellidae), were determined. The experiments were conducted in a growth chamber at 25 +/- 1 degrees C, 65 +/- 2% RH, and a photoperiod of 16:8 (L:D) h. The comparison of intrinsic rate of natural increase (r(m)), net reproductive rate (R0), and the survival rate of adult stage of P. xylostella on 10 canola cultivars suggested that this pest performed best on SLM(046). The r(m) value of P. xylostella ranged between 0.241 on RGS(003) and 0.304 on SLM(046). The R0, finite rate of increase (lambda), mean generation time (T), and doubling time (DT) values of P. xylostella on SLM(046) were 52, 1.35, 13.4, and 2.35 and on RGS(003) were 31, 1.27, 14.4, and 2.94, respectively. The Weibull model adequately described the shape of the survivorship curve of adult P. xylostella from life-table data. A significant fit was obtained with the Weibull model for P. xylostella in all experimental canola cultivars. As a result, SLM(046), Opera, and Hayula(420) were the most suitable hosts and had least negative impact on life-history statistics of the pest. PMID- 21309222 TI - Effects of temperature and humidity on emergence dynamics of Plutella xylostella (Lepidoptera: Plutellidae). AB - The effects of temperature and humidity on the emergence patterns of diamondback moth, Plutella xylostella (L.) (Lepidoptera: Plutellidae), were studied at four temperatures (20, 25, 28, and 33 degrees C),three relative humidities (50, 70, and 90%) and a photoperiod of 14:10 (L:D) h. Both sexes emerged primarily in the late afternoon to early morning, and the peaks of emergence varied depending on temperature and humidity. Females emerged significantly earlier than males. Incubation at 33 degrees C and 90% RH had a significant effect on the emergence rate, but no significant interaction was found between temperature and humidity. Emergence duration was 25.3 h for both sexes at 90% RH, with emergence duration at 33 degrees C lower than the other treatments. The sex ratios of diamondback moth under different temperature and humidity treatments were approximately 1:1, and there were no significant effects of temperature and humidity or interactions between these two factors. PMID- 21309223 TI - Assessment of effect of partial sterility on mating performance in sweetpotato weevil (Coleoptera: Curculionidae). AB - The sterile insect technique (SIT) is widely used to suppress or eradicate target pest insect populations. Although the effectiveness of SIT depends on the ability of released sterile males to mate with and inseminate wild females, the use of gamma radiation to induce sterility negatively impacts reproductive cells as well as somatic cells. Consequently, sterilization by irradiation drastically diminishes mating performance over time. In the current study, we evaluated the effect of irradiation dose intensity on fertility, mating propensity, and mating competitiveness in sweetpotato weevil, Cylas formicarius elegantulus (Summers) (Coleoptera: Curculionidae), for 16 d after irradiation. Although the mating propensity of males irradiated with 200 Gy, the dose currently used to induce complete sterility of C. f. elegantulus in the SIT program in Okinawa Prefecture, was equal to that of nonirradiated weevils for the first 6 d, the mating propensity of males irradiated with doses between of 75 and 150 Gy was maintained for the first 12 d. The potential fertilization ability of weevils was highly depressed compared with the control weevils, even in those treated with 75 Gy. Mating performance was severely compromised in weevils that were irradiated with a dose of 100 Gy or more. These results demonstrate that partial sterilization can be highly advantageous in eradication programs for the sweetpotato weevil. We discuss the advantages of the application of partial irradiation in insect eradication programs. PMID- 21309224 TI - Capture probability of released males of two Bactrocera species (Diptera: Tephritidae) in detection traps in California. AB - The genus Bactrocera (Diptera: Tephritidae) includes approximately 70 polyphagous species that are major pests of fruit and vegetable crops. Most Bactrocera species have limited geographic distributions, but several species are invasive, and many countries operate continuous trapping programs to detect infestations. In the United States, California maintains approximately 25,000 traps (baited with male lures) specifically for Bactrocera detection distributed over an area of approximately 6,400 km2 (2,500 miles2) in the Los Angeles area. Although prior studies have used male lures to describe movement of Bactrocera males, they do not explicitly relate capture probability with fly distance from lure-baited traps; consequently, they do not address the relative effectiveness of male lures in detecting incipient populations of Bactrocera species. The objective of this study was to measure the distance-dependent capture probability of marked, released males of Bactrocera dorsalis (Hendel) and Bactrocera cucurbitae (Coquillett) (methyl eugenol- and cue lure-responding species, respectively) within the detection trapping grid operating in southern California. These data were then used to compute simple probability estimates for detecting populations of different sizes of the two species. Methyl eugenol was the more powerful attractant, and based on the mark-recapture data, we estimated that B. dorsalis populations with as few as approximately 50 males would always (>99.9%) be detected using the current trap density of five methyl eugenol-baited traps per 2.6 km2 (1 mile2). By contrast, we estimated that certain detection of B. cucurbitae populations would not occur until these contained approximately 350 males. The implications of the results for the California trapping system are discussed, and the findings are compared with mark-release-recapture data obtained for the same two species in Hawaii. PMID- 21309225 TI - Antixenosis in maize reduces feeding by western corn rootworm larvae (Coleoptera: Chrysomelidae). AB - SUM2162 is the first known example of a naturally occurring maize, Zea mays L., genotype with antixenosis (nonpreference) resistance to western corn rootworm, Diabrotica virgifera virgifera LeConte (Coleoptera: Chrysomelidae), larval feeding. Behavioral responses of neonate western corn rootworm larvae were evaluated in laboratory bioassays with seven maize genotypes selected for native resistance to rootworm feeding damage. Two susceptible maize genotypes and one transgenic (Bacillus thuringiensis) maize genotype were included as controls. In soil bioassays with cut roots, no larvae entered the roots of the resistant variety SUM2162, but at least 75% of the larvae entered the roots of every other maize type. Larvae made significantly fewer feeding holes in the roots of SUM2162 than in all the other maize genotypes, except the isoline control. In feeding bioassays, larval feeding varied significantly among maize genotypes, but there was no significant difference between the resistant varieties and the susceptible controls. There were no significant differences among any of the genotypes in host recognition (search) behavior of larvae after exposure to the roots. Little variation in feeding stimulant blends was observed among maize genotypes, indicating minimal contribution to the observed antixenosis. PMID- 21309226 TI - Reducing the impact of pesticides on biological control in Australian vineyards: pesticide mortality and fecundity effects on an indicator species, the predatory mite Euseius victoriensis (Acari: Phytoseiidae). AB - Laboratory bioassays on detached soybean, Glycine max (L.) Merr., leaves were used to test 23 fungicides, five insecticides, two acaricides, one herbicide, and two adjuvants on a key Australian predatory mite species Euseius victoriensis (Womersley) in "worst-case scenario" direct overspray assays. Zero- to 48-h-old juveniles, their initial food, and water supply were sprayed to runoff with a Potter tower; spinosad and wettable sulfur residues also were tested. Tests were standardized to deliver a pesticide dose comparable with commercial application of highest label rates at 1,000 liter/ha. Cumulative mortality was assessed 48 h, 4 d, and 7 d after spraying. Fecundity was assessed for 7 d from start of oviposition. No significant mortality or fecundity effects were detected for the following compounds at single-use application at 1,000 liter/ha: azoxystrobin, Bacillus thuringiensis (Bt) subsp. kurstaki, captan, chlorothalonil, copper hydroxide, fenarimol, glyphosate, hexaconazole, indoxacarb, metalaxyl/copper hydroxide, myclobutanil, nonyl phenol ethylene oxide, phosphorous acid, potassium bicarbonate, pyraclostrobin, quinoxyfen, spiroxamine, synthetic latex, tebufenozide, triadimenol, and trifloxystrobin. Iprodione and penconazole had some detrimental effect on fecundity. Canola oil as acaricide (2 liter/100 liter) and wettable sulfur (200 g/100 liter) had some detrimental effect on survival and fecundity and cyprodinil/fludioxonil on survivor. The following compounds were highly toxic (high 48-h mortality): benomyl, carbendazim, emamectin benzoate, mancozeb, spinosad (direct overspray and residue), wettable sulfur (> or = 400 g/100 liter), and pyrimethanil; pyrimethanil had no significant effect on fecundity of surviving females. Indoxacarb safety to E. victoriensis contrasts with its toxicity to key parasitoids and chrysopid predators. Potential impact of findings is discussed. PMID- 21309227 TI - Impact of brown stink bug (Heteroptera: Pentatomidae) feeding on corn grain yield components and quality. AB - Brown stink bug, Euschistus servus (Say) (Heteroptera: Pentatomidae), damage on developing corn, Zea mays L., ears was examined in 2005 and 2006 by using eight parameters related to its yield and kernel quality. Stink bug infestations were initiated when the corn plants were at tasseling (VT), mid-silking (R1), and blister (R2) stages by using zero, three, and six in 2005 or zero, one, two, and four bugs per ear in 2006, and maintained for 9 d. The percentage of discolored kernels was affected by stink bug number in both years, but not always affected by plant growth stage. The growth stage effect on the percentage of discolored kernels was significant in 2006, but not in 2005. The percentage of aborted kernels was affected by both stink bug number and plant growth stage in 2005 but not in 2006. Kernel weight was significantly reduced when three E. sercus adults were confined on a corn ear at stage VT or R1 for 9 d in 2005, whereas one or two adults per ear resulted in no kernel weight loss, but four E. servus adults did cause significant kernel weight loss at stage VT in 2006. Stink bug feeding injury at stage R2 did not affect kernel damage, ear weight or grain weight in either year. The infestation duration (9 or 18 d) was positively correlated to the percentage of discolored kernels but did not affect kernel or ear weight. Based on the regression equations between the kernel weight and stink bug number, the gain threshold or economic injury level should be 0.5 bugs per ear for 9 d at stage VT and less for stage R1. This information will be useful in developing management guidelines for stink bugs in field corn during ear formation and early grain filling stages. PMID- 21309228 TI - A technique using reusable components for hand-infesting cornstalks with European corn borer (Lepidoptera: Crambidae) larvae. AB - Field trials were conducted in 2005 and 2006 to evaluate the use of reusable wire nuts and nonreusable gelatin capsules for hand-infesting cornstalks with European corn borer, Ostrinia nubilalis (Hubner), (Lepidoptera: Crambidae) larvae. The reusable technique, which consists of a modified WingGard plastic wire connector (i.e., wire nut) as a containment device for larvae, was compared over three plant growth stages to a gelatin capsule technique. In 2005 and 2006, the wire nut technique resulted in significantly higher number of wire nuts still intact (i.e., undamaged, with or without a larva) on the stalk at 72 h after infestation compared with the gelatin capsule technique. In addition, the wire nut technique resulted in significantly higher number of tunnels per stalk compared with the gelatin capsule technique at all three corn growth stages during both years. In 2005, the mean +/- SEM number of tunnels per stalk was 0.53 +/- 0.03 in the wire nut technique compared with 0.13 +/- 0.03 tunnels per stalk in the gelatin capsule technique. In 2006, the mean number of tunnels per stalk was 0.45 +/- 0.03 in the wire nut technique compared with 0.08 +/- 0.02 tunnels per stalk in the gelatin capsule technique. In addition, the relative net precision in the wire-nut technique was approximately 2 times higher compared with the gelatin capsule technique. PMID- 21309229 TI - Influence of preceding crop on wireworm (Coleoptera: Elateridae) abundance in the coastal plain of North Carolina. AB - Three studies were conducted to determine the effect of preceding crop on wireworm (Coleoptera: Elateridae) abundance in the coastal plain of North Carolina. In all three studies, samples of wireworm populations were taken from the soil by using oat, Avena sativa L., baits. Treatments were defined by the previous year's crop and were chosen to reflect common crop rotations in the region. Across all three studies, eight wireworm species were recovered from the baits: Conoderus amplicollis (Gyllenhal), Conoderus bellus (Say), Conoderus falli (Lane), Conoderus lividus (Degeer), Conoderus scissus (Schaeffer), Conoderus vespertinus (F.), Glyphonyx bimarginatus (Schaeffer), and Melanotus communis (Gyllenhal). The effect of corn, Zea mays L.; cotton, Gossypium hirsutum L.; fallow; soybean, Clycine max (L.) Merr.; sweet potato, Ipomoea batatas (L.) Lam.; and tobacco (Nicotiana spp.) was evaluated in a small-plot replicated study. M. communis was the most frequently collected species in the small-plot study and was found in significantly higher numbers following soybean and corn. The mean total number of wireworms per bait (all species) was highest following soybean. A second study conducted in late fall and early spring assessed the abundance of overwintering wireworm populations in commercial fields planted to corn, cotton, peanut (Arachis hypogaea L.), soybean, sweet potato, and tobacco in the most recent previous growing season. C. lividus was the most abundant species, and the mean total number of wireworms was highest following corn and soybean. A survey was conducted in commercial sweet potato in late spring and early summer in fields that had been planted to corn, cotton, cucurbit (Cucurbita pepo L.), peanut, soybean, sweet potato, or tobacco in the most recent previous growing season. C. vespertinus was the most abundant species, and the mean total number of wireworms per bait was highest following corn. PMID- 21309230 TI - Test of nonhost angiosperm volatiles and verbenone to protect trap trees for Sirex noctilio (Hymenoptera: Siricidae) from attacks by bark beetles (Coleoptera: Scolytidae) in the northeastern United States. AB - Sirex noctilio F. (Hymenoptera: Siricidae) is an invasive woodwasp, currently established in northeastern North America. In other regions of the world, stressed trap trees are used to monitor populations of S. noctilio and to provide inoculation points for the biological control nematode Deladenus siricidicola Bedding. However, the operational use of trap trees for S. noctilio in North America may be compromised by the large community of native organisms that inhabit stressed and dying pine trees. Common bark beetles such as Ips pini (Say) and Ips grandicollis (Eichhoff) (Coleoptera: Scolytidae) could potentially compete with S. noctilio and associates for resources on trap trees, possibly reducing the efficacy of trap trees as habitats for the woodwasp. In an attempt to develop a technology to mitigate this potential issue, three common semiochemical interruptants--conophthorin, green leaf volatile mix, and verbenone -were tested for effectiveness in reducing arrivals of I. pini and I. grandicollis on trap trees treated with herbicides in northeastern United States. In addition, the effects of these compounds were determined independently with pheromone-baited multiple-funnel traps. None of the interruptants reduced numbers of I. pini or I. grandicollis either arriving on trap trees or caught in pheromone-baited traps. However, verbenone increased catches of I. grandicollis in traps baited with its pheromone, ipsenol. The mix of green leaf volatiles reduced catches of a native ambrosia beetle, Gnathotrichus materiarius (Fitch), whereas verbenone reduced trap catches of an exotic ambrosia beetle, Xylosandrus germanus (Blandford). Catches of X. germanus in traps adjacent to trap trees were enhanced with conophthorin. PMID- 21309231 TI - Mating behaviors of Cydia pomonella (Lepidoptera: Tortricidae) as influenced by sex pheromone in electrostatic powder. AB - Entostat is an electrostatically charged wax powder that can adhere strongly to insect cuticle, making it an ideal carrier to deliver pheromone for pheromone based confusion techniques. We investigated the attractiveness of Cydia pomonella (L.) (Lepidoptera: Tortricidae) males treated with pheromone-laden Entostat powder to naive conspecifics as well as mating behaviors of males after such treatment in a laboratory flight tunnel. Male moths exposed to Entostat containing 1% E,E-8,10-dodecadien-1-ol (codlemone) acquired and retained the largest amount of the powder and became more attractive as point sources to naive moths compared with those treated with powder containing 5 or 10% codlemone. All Entostat-exposed males remained as attractive as a 0.1-mg codlemone lure for up to 24 h in flight tunnel investigations. Male moth orientation to normally attractive sources of codlemone was completely disrupted directly after treatment with Entostat powder. Males' ability to orient to 0.1-mg lures recovered progressively over a 6-d postexposure interval; however, their responses never reached the levels observed with untreated control moths. Entostat-exposed moths retained detectable amounts of codlemone up to 4 d. Our laboratory flight tunnel results suggest that the mode of action of Entostat powder as an autodissemination control tactic may be due to creating both attractive false point sources after exposure to the powder as well as directly inhibiting contaminated males' capability to orient to pheromone. PMID- 21309232 TI - Effect of insect density, plant age, and residue duration on acetamiprid efficacy against swede midge. AB - The Swede midge, Contarinia nasturtii Kieffer (Diptera: Cecidomyiidae), a common insect pest in Europe, is a newly invasive pest in North America that constitutes a major threat to crucifer vegetable and field crops. Chemical control of Swede midge with synthetic insecticides under laboratory conditions indicated that insecticides generally could provide very effective control; however, insecticide treatments in the field were rarely able to maintain damage levels within marketable limits. In the current study, factors affecting insecticide efficacy were investigated using a neonicotinoid insecticide, acetamipird, as a foliar spray on cauliflower plants. Our results indicated that Swede midge density did not affect the efficacy of acetamirpid, although it significantly increased the subsequent Swede midge population on the unsprayed cauliflower plants. Additionally, cauliflower plant age did not significantly affect spray coverage and acetamipird efficacy on Swede midge. However, acetamiprid only provided 6-d control of Swede midge and its efficacy was reduced by up to 50% 9 d after spraying. Implications of our results on the development of an overall integrated pest management (IPM) program for Swede midge also are discussed. PMID- 21309233 TI - Foraging population and territory estimates for Microcerotermes diversus (Isoptera: Termitidae) through mark-release-recapture in Ahwaz (Khouzestan, Iran). AB - Microcerotermes diversus Silvestri (Isoptera: Termitidae), an important pest in Ahwaz (Khouzestan, Iran), causes serious economic damage to wooden products in buildings. In this study, we determined the foraging populations and territories of this species using mark-release-recapture techniques. Based on both the weighted mean model and Lincoln index methods, mean termite foraging population estimates for two colonies, A and B, were 2,984,489 +/- 258,802 and 326,134 +/- 8,713, respectively. Estimates with the Lincoln index were 2,731,229 +/- 813,081 for colony A and 321,493 +/- 138,499 for colony B. Estimated horizontal foraging territories for colonies A and B were 25.59 and 44.16 m2, respectively. The maximum and minimum linear foraging distances were 5.40 and 2.14 m for colony A and 9.14 and 1.86 m for colony B, respectively. Our data expand the knowledge about the biology, ecology and behavior of M. diversus. PMID- 21309234 TI - Comparative toxicity and repellency of microencapsulated and other liquid insecticide formulations to the German cockroach (Dictyoptera: Blattellidae). AB - Responses of German cockroaches, Blattella germanica (L.) (Dictyoptera: Blattellidae), to microencapsulated (ME) formulations of six insecticides (bifenthrin, chlorpyrifos, cyfluthrin, deltamethrin, lambda-cyhalothrin, and permethrin) were compared with emulsifiable concentrates (EC) (chlorpyrifos, cyfluthrin, deltamethrin, and permethrin) or ready-to-use (RTU) formulations (bifenthin and lambda-cyhalothrin). Two rates were tested per comparison. Baseline toxicity (LT50 value) was determined by continuous exposure to residual deposits. Repellency, toxicity (LT50), and performance index (PI) values were determined using Ebeling choice boxes. Baseline toxicity of the permethrin formulations was similar, but all other active ingredients had significant toxicity differences at one or both formulation x dose comparisons. Baseline toxicity and repellency were negatively correlated. Choice box LT50 and the time to reach 50% of the maximum PI were positively correlated. The maximum PI was positively correlated (P < 0.06) with baseline LT50 and negatively correlated (P < 0.07) with repellency. Chlorpyrifos had the lowest repellency except for the EC at 0.25%. Bifenthrin ME and lambda-cyhalothrin ME had greater PI values than comparative RTU formulations. Cyfluthrin EC at 0.03% and deltamethrin ME at 0.01% had significantly lower PI values than comparison treatments. Permethrin PI value for the EC at 0.03% exceeded that for the ME, but at 0.05% the ME had a significantly greater PI. These data demonstrate the difficulty in making generalizations about the relative performance of ME compared with EC or RTU formulations. Variable results observed within, and between, formulations may be influenced by application rate, formulation type, other formulation components, and the toxicity-repellency of the active ingredient. PMID- 21309235 TI - A test of seasonal responses to sugars in four populations of the termite Reticulitermes flavipes. AB - Several studies have shown that Reticulitermes termites prefer food with certain types of sugars. However, the specific sugars that were preferred by the termites in each study differed. The difference between the results of these studies might be explained by differences between populations or changes in feeding responses during the active season. To address these variables, we examined the feeding response to a food source food containing glucose, sucrose, or xylose versus a food source without sugar in several populations of termites and observed whether these responses changed during the year. Termites were collected from colonies from four field sites in Missouri during the spring (May and June), summer (July and August), and fall (September and October) and tested for their response to all three sugars under laboratory conditions. Results show there are distinct differences in response to sugars between populations but only a slight seasonal effect. PMID- 21309236 TI - Toxicity and inhibition of feeding and tunneling response of naphthalene and 10 derivatives on the formosan subterranean termite (Isoptera: Rhinotermitidae). AB - In laboratory choice tests with either filter paper treatment or sand treatment, naphthalene and 10 derivatives were evaluated for their effects on the behavior of the Formosan subterranean termite, Coptotermes formosanus Shiraki (Isoptera: Rhinotermitidae). After 24-h exposure, workers avoided 50-microg/cm2-treated filter paper with 1'- and 2'-acetonaphthone. By day 8, feeding activity on filter paper treated with 1- and 2-methoxynaphthalene, 1'- and 2'-acetonaphthone were significantly reduced compared with the controls. Naphthalene and six other derivatives were not effective at 50-microg/cm2-treated filter paper. After 12-d exposure, tunnels constructed in sand treated with 1- and 2-methoxynaphthalene (0 3 cm2), 1'- and 2'-acetonaphthone (2-9 cm2), 2-naphthalene methanol (14-19 cm2), or 2-isopropylnaphthalene (16-19 cm2) at the rate of 100 mg/kg sand were significantly less than the controls (34 cm2). Consumption on filter paper placed on sand treated with 1- and 2-methoxynaphthalene and 1'- and 2'-acetonaphthone was significantly reduced (0-7 mg) compared with the controls (33-54 mg). 1 Methoxynaphthalene was the only treatment that caused significantly less feeding activity in the untreated sand chamber (0-6 mg) compared with the control (63-128 mg). PMID- 21309237 TI - Control of subterranean termites (Isoptera: Rhinotermitidae) infesting power poles. AB - A trial was conducted to determine the efficacy of termiticidal dusts (arsenic trioxide, triflumuron, and Metarhizium anisopliae), a timber fumigant (dazomet) and liquid termiticides (bifenthrin, chlorfenapyr, chlorpyrifos, fipronil, and imidacloprid) for controlling subterranean termites (Isoptera: Rhinotermitidae) infesting in-service power poles in New South Wales, Australia. Dusts were applied to parts of the pole where termites were present. Fumigant was inserted into holes drilled into the base of the pole. Liquid termiticides were mixed with soil around the base of the pole and injected into internal voids if present. Poles were inspected for up to 5 yr, and the time taken for reinfestation to occur was recorded. Before the start of the trial, the major Australian pole owners were surveyed to obtain an estimate of the annual national cost of termite infestation to the power supply industry. The annual costs of termite treatment and replacing damaged poles were estimated at AU$2 million and AU$13 million, respectively. Infestation rates were lower for all treatments compared with controls within the first 12 mo of the study. Dazomet, arsenic trioxide, fipronil, and chlorpyrifos were the most efficacious treatments. Efficacy was positively related to the amount of termiticide applied and negatively related to the infestation severity but was unaffected by geographical location. Survival curves were calculated of the time elapsed before the recurrence of termite infestations (survival absence of reinfestation). Survival was highest for poles treated with liquid termiticides. PMID- 21309238 TI - Characteristics of resistance to Bacillus thuringiensis toxin Cry2Ab in a strain of Helicoverpa punctigera (Lepidoptera: Noctuidae) isolated from a field population. AB - In 1996, the Australian cotton industry adopted Ingard that expresses the Bacillus thuringiensis (Bt) toxin gene cry1Ac and was planted at a cap of 30%. In 2004-2005, Bollgard II, which expresses cry1Ac and cry2Ab, replaced Ingard in Australia, and subsequently has made up >80% of the area planted to cotton, Gossypium hirsutum L. The Australian target species Helicoverpa armigera (Hubner) and Helicoverpa punctigera (Wallengren) are innately moderately tolerant to Bt toxins, but the absence of a history of insecticide resistance indicates that the latter species is less likely to develop resistance to Bt cotton. From 2002-2003 to 2006-2007, F2 screens were deployed to detect resistance to CrylAc or Cry2Ab in natural populations of H. punctigera. Alleles that conferred an advantage against CrylAc were not detected, but those that conferred resistance to Cry2Ab were present at a frequency of 0.0018 (n = 2,192 alleles). Importantly, the first isolation of Cry2Ab resistance in H. punctigera occurred before significant opportunities to develop resistance in response to Bollgard II. We established a colony (designated Hp4-13) consisting of homozygous resistant individuals and examined their characteristics through comparison with individuals from a Bt susceptible laboratory colony. Through specific crosses and bioassays, we established that the resistance present in Hp4-13 is due to a single autosomal gene. The resistance is fully recessive. Homozygotes are able to survive a dose of Cry2Ab toxin that is 15 times the reported concentration in field grown Bollgard II in Australia (500 microg/ml) and are fully susceptible to Cry1Ac and to the Bt product DiPel. These characteristics are the same as those described for the first Cry2Ab resistant strain of H. armigera isolated from a field population in Australia. PMID- 21309239 TI - Responses of susceptible and cyfluthrin-resistant broiler house populations of lesser mealworm (Coleoptera: Tenebrionidae) to gamma-cyhalothrin. AB - Gamma-Cyhalothrin was proposed as an agent for management of lesser mealworm, Alphitobius diaperinus (Panzer) (Coleoptera: Tenebrionidae), in Australian broiler houses. From 2007 to 2009, baseline susceptibility of 20 Australian broiler farm beetle populations plus an insecticide-susceptible laboratory population was determined for gamma-cyhalothrin by using topical application. In addition, repeat testing and regression analyses of specific beetle populations to gamma-cyhalothrin showed that topical application was a very reliable and repeatable testing method. The 21 populations were tested with a cyfluthrin discriminating concentration (based on LC(99.9), 0.0007% [AI]) to identify possible cross-resistance. Across all populations, there was a significant linear relationship between the gamma-cyhalothrin LC50 value and mortality induced by the cyfluthrin LC(99.9). Full cyfluthrin baseline studies of seven populations indicated that gamma-cyhalothrin was twice as toxic as cyfluthrin, even against susceptible beetles and resistance ratios at the cyfluthrin LC50 and LC(99.9), varied considerably, with maxima of 56.6 and 83.6 respectively. Corresponding ratios for gamma-cyhalothrin for the same populations were 8.6 (LC50) and 7.9 (LC(99.9)). There were no significant correlations between beetle weights and gamma-cyhalothrin LC50 or LC(99.9), values. A discriminating concentration of 0.005% (AI) gamma-cyhalothrin was chosen to detect any future changes in susceptibility. Results of this study suggest that cyfluthrin can confer cross resistance to gamma-cyhalothrin in A. diaperinus, but the magnitude of this resistance is unpredictable. Thus, widespread and frequent cyfluthrin use in broiler houses in eastern Australia, which has selected for cyfluthrin resistance, also has resulted in reduced susceptibility to gamma-cyhalothrin. Due to its higher relative toxicity, gamma-cyhalothrin is still potentially useful for management of lesser mealworm, but due to cross-resistance issues, adoption of gamma-cyhalothrin for broiler house use will require a cautious and judicious approach. PMID- 21309240 TI - Life-stage variation in insecticide resistance of the western flower thrips (Thysanoptera: Thripidae). AB - The life-stage variations in insecticide resistance of western flower thrips, Frankliniella occidentalis (Pergande) (Thysanoptera: Thripidae), to selective insecticides (acrinathrin, formetanate, and methiocarb) were studied using resistant laboratory strains. In each strain, the second-instar larva was less susceptible to the insecticides tested than the adults. The lower the resistance level of the adults, the higher the difference between larva and adult susceptibility: 32-fold to methiocarb, 15.4-fold to formetanate, and 180-fold to acrinathrin in the reference strain. In laboratory-selected resistant strains, these differences were much lower: 5.8-fold to methiocarb, 4.8-fold to formetanate, and 2.0-fold to acrinathrin. In selected strains, higher resistance levels for each insecticide were found, both for larvae and adults, compared with the reference strain. These results show that after insecticide resistance selection in adults, the resistance is carried over to the larvae, but at lower levels. PMID- 21309241 TI - Vip3Aa tolerance response of Helicoverpa armigera populations from a Cry1Ac cotton planting region. AB - Transgenic cotton, Gossypium hirsutum L., that expresses the Bacillus thuringiensis (Bt) Cry1Ac toxin, holds great promise in controlling target insect pests. Evolution of resistance by target pests is the primary threat to the continued efficacy of Bt cotton. To thwart pest resistance evolution, a transgenic cotton culitvar that produces two different Bt toxins, cry1Ac and vip3A genes, was proposed as a successor of cry1Ac cotton. This article reports on levels of Vip3Aa tolerance in Helicoverpa armigera (Hubner) (Lepidoptera: Noctuidae) populations from the Cry1Ac cotton planting region in China based on bioassays of the F1 generation of isofemale lines. In total, 80 isofemale families of H. armigera from Xiajin county of Shandong Province (an intensive Bt cotton planting area) and 93 families from Anci county of Hebei Province (a multiple-crop system including corn [Zea mays L.] , soybean [Glycine max (L.) Merr.], peanut (Arachis hypogaea L.), and Bt cotton) were screened with a discriminating concentration of both Cry1Ac- and Vip3A-containing diets in 2009. From data on the relative average development rates and percentage of larval weight inhibition of F1 full-sib families tested simultaneously on Cry1Ac and Vip3Aa, results indicate that responses to Cry1Ac and Vip3Aa were not genetically correlated in field population ofH. armigera. This indicates that the threat of cross-resistance between Cry1Ac and Vip3A is low in field populations of H. armigera. Thus, the introduction of Vip3Aa/Cry1Ac-producing lines could delay resistance evolution in H. armigera in Bt cotton planting area of China. PMID- 21309242 TI - Extraordinary resistance to insecticides reveals exotic Q biotype of Bemisia tabaci in the New World. AB - A strain of the whitefly Bemisia tabaci (Gennadius) possessing unusually high levels of resistance to a wide range of insecticides was discovered in 2004 in the course of routine resistance monitoring in Arizona. The multiply resistant insects, collected from poinsettia (Euphorbia pulcherrima Willd. ex Klotzsch) plants purchased at a retail store in Tucson, were subjected to biotype analysis in three laboratories. Polyacrylamide gel electrophoresis of naphthyl esterases and sequencing of the mitochondrial cytochrome oxidase I gene (780 bp) confirmed the first detection of the Q biotype of B. tabaci in the New World. This U.S. Q biotype strain, referred to as Poinsettia'04, was highly resistant to two selective insect growth regulators, pyriproxyfen and buprofezin, and to mixtures of fenpropathrin and acephate. It was also unusually low in susceptibility to the neonicotinoid insecticides imidacloprid, acetamiprid, and thiamethoxam, relative to B biotype whiteflies. In 100 collections of whiteflies made in Arizona cotton (Gossypium spp.), vegetable, and melon (Cucumis melo L.) fields from 2001 to 2005, no Q biotypes were detected. Regions of the United States that were severely impacted by the introduction of the B biotype of B. tabaci in the 1980s would be well advised to promote measures that limit movement of the Q biotype from controlled environments into field systems and to formulate alternatives for managing this multiply-resistant biotype, in the event that it becomes more widely distributed. PMID- 21309243 TI - Mortality of western corn rootworm larvae on MIR604 transgenic maize roots: field survivorship has no significant impact on survivorship of F1 progeny on MIR604. AB - Mortality of western corn rootworm, Diabrotica virgifera virgifera LeConte, larvae due to MIR604 transgenic corn, Zea mays L., expressing the modified Cry3A (mCry3A) protein relative to survivorship on corn with the same genetic background without the gene (isoline corn) was evaluated at three Missouri sites in both 2005 and 2006. We made these comparisons by using wild-type western corn rootworm at three different egg densities (6,000, 3,000, and 1,500 eggs per m) so that the role of density-dependent mortality would be known. The mortality due to the mCry3A protein was 94.88% when averaged across all environments and both years. Fifty percent emergence of beetles was delayed approximately 5.5 d. Beetles were kept alive and their progeny evaluated on MIR604 and isoline corn in the greenhouse to determine whether survivorship on MIR604 in the field for one generation increased survivorship on MIR604 in the greenhouse in the subsequent generation. There was no significant difference in survivorship on MIR604 in greenhouse assays between larvae whose parents survived isoline and larvae whose parents survived MIR604 in the field the previous generation, indicating that many susceptible beetles survived MIR604 in the field the previous season along with any potentially resistant beetles. The data are discussed in terms of rootworm insect resistance management. PMID- 21309244 TI - Putative polymerase chain reaction markers for insecticide resistance in the leafminer Liriomyza trifolii (Diptera: Agromyzidae) to cyromazine and abamectin. AB - In this study, random amplified polymorphic DNA polymerase chain reaction (RAPD PCR) was used to identify polymorphic genomic DNA that would discriminate among cyromazine-resistant, abamectin-resistant, and susceptible Liriomyza trifolii (Burgess) (Diptera: Agromyzidae) leafminers. Using a reference strain that was susceptible to both cyromazine and abamectin, and a cyromazine-resistant strain and an abamectin-resistant strain, 400 oligonucleotides were assayed using RAPD PCR. We found that two oligonucleotides, B10 and G16, amplified unique bands in the cyromazine-resistant strain but not in the reference or abamectin-resistant strains. Three oligonucleotides, K04, J13, and I02, showed polymorphisms unique to the abamectin-resistant strain but not in the reference or cyromazine resistant strain. Leaf dip bioassays and RAPD-PCR were performed on two additional reference strains, seven strains from commercial ornamental production greenhouses, and one field strain. The two reference strains were negative for the resistance-correlated oligonucleotides. Of the seven strains from ornamental greenhouses, leaf dip bioassays showed that five had some level of resistance to both abamectin and cyromazine, whereas two were susceptible. The field strain was susceptible to both cyromazine and abamectin. In RAPD-DNA analyses, the five strains with abamectin resistance were positive for the three abamectin resistance-correlated oligonucleotides K04, J13, and I02. In the cases of cyromazine resistance, the five strains with cyromazine resistance were positive for the two cyromazine resistance-correlated oligonucleotides B10 and G16. The field strain and two greenhouse strains that were susceptible in leaf dip bioassays were negative for all three abamectin resistance-correlated oligonucleotides. The field strain and one greenhouse strain were negative for the two cyromazine resistance-correlated oligonucleotides; however, one greenhouse strain that was susceptible to cyromazine in leaf dip bioassay tested positive for one of the cyromazine resistance-correlated oligonucleotides. This method can be used to quickly identify cyromazine resistance, abamectin resistance, or both in leafminers, enabling a grower to choose an effective insecticide for leafminer control in a timely manner. PMID- 21309245 TI - Genetic diversity and population structure of Panonychus citri (Acari: Tetranychidae), in China based on mitochondrial COI gene sequences. AB - The citrus red mite, Panonychus citri (McGregor) (Acari: Tetranychidae), is regarded as one of the most important citrus pests in many countries, such as Japan, Spain, and China. In this study, the mitochondrial cytochrome oxidase subunit I gene was used to analyze genetic diversity and population structure of 15 P. citri populations collected from three citrus (Citrus spp.) planting regions of China. Our analysis found that these populations had relatively low genetic diversities. Bayesian tree and haplotype network showed that the 22 haplotypes of P. citri formed two lineages with low Bayesian posterior probabilities (0.55 and 0.63), and haplotypes in a sample were scattered throughout the Bayesian tree, indicating that there may be no significant genealogical structure among populations. However, when Yuxi and Danjiangkou populations (both without H7 haplotype) were excluded from the analysis, analysis of molecular variance found a weak, but significant, geographic structuring. Mantel test indicated a significant and positive correlation between genetic and geographical distances, reflecting certain degree of isolation by distance. The genetic differentiation based on pairwise F(ST) was not significant between most populations, and some F(ST) were even negative, indicating remarkable gene flow among these populations. The weak population structure of P. citri in this study was probably influenced by high gene flow between some populations due to long distance dispersal of this species, which may be largely relied on the movement of plants between populations. The mismatch distribution analysis showed that no signal of population growth, but the Fu's F(S) value was significantly negative for total populations and the star-like shape of haplotype network, suggesting a history of population expansion of P. citri in China. PMID- 21309246 TI - Genetic variation of Anastrepha suspensa (Diptera: Tephritidae) in Florida and the Caribbean using microsatellite DNA markers. AB - Anastrepha suspensa (Loew) (Diptera: Tephritidae), the Caribbean fruit fly, is indigenous to Florida and the Greater Antilles where it causes economic losses in fruit crops, including citrus. Because of the geographic separation of many of its native locations and anecdotal descriptions of regional differences in host preferences, there have been questions about the population structure of A. suspensa. Seven DNA microsatellite markers were used to characterize the population genetic structure of A. suspensa, in Florida and the Caribbean from a variety of hosts, including citrus. We genotyped 729 A. suspensa individuals from Florida, Puerto Rico, Cayman Island, Dominican Republic, and Jamaica. The investigated seven loci displayed from 5 to 19 alleles, with expected heterozygosities ranging from 0.05 to 0.83. There were five unique alleles in Florida and three unique alleles in the Caribbean samples; however, no microsatellite alleles were specific to a single host plant. Genetic diversity was analyzed using F(ST) and analysis of molecular variance and revealed low genetic diversity between Florida and Caribbean samples and also between citrus and noncitrus samples. Analyses using migrate revealed there is continuous gene flow between sampling sites in Florida and the Caribbean and among different hosts. These results support previous comparisons based on the mitochondrial cytochrome oxidase I locus indicating there is no genetic differentiation among locations in Florida and the Caribbean and that there is no separation into host races. PMID- 21309247 TI - Influence of poplar clones on fertility life-table parameters of Chaitophorus leucomelas (Hemiptera: Aphididae). AB - The aphid Chaitophorus leucomelas Koch (Hemiptera: Aphididae) is one of the most important pests of poplar (Populus spp.) plantations in Iran. In this study, development, reproduction, and life history of the aphid were assessed on 11 poplar clones; belong to three species, Populus nigra L., Populus deltoides Bartram ex Marshall, and Populus. euramericana Guinier. The experiments were carried out under controlled conditions at 24 +/- 1 degrees C, 50-60% RH, and a photoperiod of 12:12 (L:D) h. The developmental time at immature stage ranged from 10 to 12 d. Nymphs reproduced per female were ranged from 49 to 98 nymphs on Populus deltoides var. missoriensis and P. deltoides 72/51, respectively. The intrinsic rate of natural increase (r(m)) varied from 0.176 to 0.264 d(-1) among poplar clones. The r(m) values of the aphids were adversely affected in P. euramericana 242 in comparison with P. nigra 56/72 and P. nigra 63/135. In addition, the jackknife estimates of net reproductive rate (R0) indicated the presence of resistance among poplar clones. R0 ranged from 16.48 on P. nigra var. betulifoli to 47.53 on P. nigra 63/135. Mean generation times (T) was last 17.56 d on P. euramericana 242 to 14.51 d on P. deltoides 69/55. However, doubling time (DT) was 3.87 d on P. euramericana var. grandis to 2.63 d on P. nigra 63/135. The finite rate of increase (lambda) was 1.192 on resistant clone (P. euramericana 242) and 1.302 on susceptible clone (P. nigra 63/135). These results indicate that variation in life-table parameters could be an important component of variation in resistance to C. leucomelas in poplar. PMID- 21309248 TI - Virulence in Hessian fly (Diptera: Cecidomyiidae) field collections from the southeastern United States to 21 resistance genes in wheat. AB - Genetic resistance in wheat, Triticum aestivum L., is the most efficacious method for control of Hessian fly, Mayetiola destructor (Say) (Diptera: Cecidomyiidae). However, because of the appearance of new genotypes (biotypes) in response to deployment of resistance, field collections of Hessian fly need to be evaluated on a regular basis to provide breeders and producers information on the efficacy of resistance (R) genes with respect to the genotype composition of Hessian fly in regional areas. We report here on the efficacy of 21 R genes in wheat to field collections of Hessian fly from the southeastern United States. Results documented that of the 21 R genes evaluated only five would provide effective protection of wheat from Hessian fly in the southeastern United States. These genes were H12, H18, H24, H25, and H26. Although not all of the 33 identified R genes were evaluated in the current study, these results indicate that identified genetic resistance to protect wheat from Hessian attack in the southeastern United States is a limited resource. Historically, R genes for Hessian fly resistance in wheat have been deployed as single gene releases. Although this strategy has been successful in the past, we recommend that in the future deployment of combinations of highly effective previously undeployed genes, such as H24 and H26, be considered. Our study also highlights the need to identify new and effective sources of resistance in wheat to Hessian fly if genetic resistance is to continue as a viable option for protection of wheat in the southeastern United States. PMID- 21309249 TI - Relationship between external stink bug (Hemiptera: Pentatomidae) boll-feeding symptoms and internal boll damage with respect to cotton lint gin-out and fiber quality. AB - Cotton, Gossypium hirsutum L., bolls from 17 field locations in northeastern North Carolina and southeastern Virginia, having 20% or greater internal boll damage, were studied to determine the relationship between external feeding symptoms and internal damage caused by stink bug (Hemiptera: Pentatomidae) feeding. In 2006 and 2007, two cohorts of 100 bolls each were sampled at all field locations. The first cohort was removed as bolls reached approximately quarter size in diameter (2.4 cm). External and internal symptoms of stink bug feeding were assessed and tabulated. Concurrent to when the first cohort was collected, a second cohort of quarter-size-diameter bolls was identified, tagged, examined in situ for external feeding symptoms (sunken lesions), and harvested at the black seed coat stage. Harvested bolls were assessed for internal damage and locks were categorized (undamaged, minor damage, or major damage), dried, and ginned. Lint samples from each damage category were submitted for high volume instrument and advanced fiber information system quality analyses. Significant, moderately strong Pearson correlation coefficients existed between number of external stink bug feeding lesions and internal damage. Pearson correlation of total external lesions with total internal damage was stronger than any correlation among the other single components compared. Predictability plots indicated a rapid increase in relationship strength when relating external stink bug lesions to internal damage as the number of external lesions increased. Approximately 90% predictability of internal damage was achieved with four (2006) or six (2007) external lesions per boll. Gin-turnout and fiber quality decreased with increasing intensity of internal stink bug damage. PMID- 21309250 TI - Realistic global scouting for pests and diseases on cut rose crops. AB - Scouting is considered an essential component of integrated pest management strategies, but most of the techniques, which involve visual assessment, remain too time-consuming for application on a commercial scale. The global scouting method proposed here for greenhouse rose (Rosa spp.) crops combines several rapid visual methods for common pests and diseases, in a single sampling process. A 2 min observation time per sampling unit is required, with two observers. The sampling unit consists of a single stem with its flower and the corresponding basal foliage. A 90-unit regular grid (1 U/6.4 m2) was used, with weekly assessments, including a spatial distribution approach, for pest monitoring. Different grid sizes were simulated and tested with reference data, to determine whether to decrease the number of sampling units. A grid size of 1 U/21 m2 was found to be acceptable, with no significant loss of information. A more realistic and cheaper sampling strategy of this type is more likely to be accepted by growers, increasing the efficiency of crop monitoring and leading to more rational decisions. PMID- 21309251 TI - Temperature preference and respiration of acaridid mites. AB - The thermal preferences in a grain mass and respiration at various temperatures in mites (Acari: Acarididae) of medical and economical importance [Acarus siro (L. 1758), Dermatophagoides farinae Hughes 1961, Lepidoglyphus destructor (Schrank 1871), and Tyrophagus putrescentiae (Schrank 1781)] were studied under laboratory conditions. Based on the distribution of mites in wheat, Triticum aestivum L., grain along a thermal gradient from 10 to 40 degrees C, L. destructor, D. farinae, and A. siro were classified as eurythermic and T. putrescentiae as stenothermic. The lowest preferred temperature was found for D. farinae (28 degrees C), followed by A. siro (28.5 degrees C), L. destructor (29.5 degrees C), and T. putrescentiae (31.5 degrees C). The relationship between the respiration rate and the temperature was similar for all four mite species. The highest respiration was found in the range from 31 to 33 degrees C. This is approximately 2 degrees C higher than the preferred temperature of these species. The lower temperature threshold of respiration ranged from 1 to 5 degrees C and the upper threshold ranged from 45 to 48 degrees C. Acclimatization of A. siro to temperature regimes of 5, 15, and 35 degrees C resulted in thermal preferences between 9 and 12 degrees C, 9 and 20 degrees C, and 28 and 35 degrees C, respectively. The respiration rate of acclimatized specimens increased with the temperature, reaching a maximum at 29.0 degrees C for mites acclimatized at 5 and 15 degrees C and a maximum at 33.7 degrees C for those acclimatized at 30 degrees C. PMID- 21309252 TI - Assessing permethrin resistance in the stable fly (Diptera: Muscidae) in Florida by using laboratory selections and field evaluations. AB - Insecticide resistance in the stable fly, Stomoxys calcitrans (L.) (Diptera: Muscidae),has been demonstrated previously, but mostly with insecticides that are no longer used, such as the organochlorines. Resistance to commonly used pyrethroids has been evaluated twice, but only in the midwestern United States. Stable fly susceptibility to a commonly used pyrethroid, permethrin, was determined in Florida to assess the possibility of resistance development. Diagnostic concentration evaluations of three stable fly field strains demonstrated a maximum of 57 and 21% survival to permethrin residues of 3x and 10x the LC99 of a susceptible strain, respectively. Stable flies from an equine facility with no reported insecticide use demonstrated approximately 20% survival with a 3x diagnostic concentration. Despite a distance of 91-km between field collection sites, survival profiles of field-collected stable fly strains were similar. Although an established stable fly colony collected from a local dairy previously expressed low level resistance to permethrin residues, five generations of laboratory permethrin selection increased resistance 15-fold. PMID- 21309253 TI - Western moral theory of the inalienable right to life and liberty is enforced by the Thirteenth Amendment. Preface. PMID- 21309254 TI - The question of the constitutional case against suicide: an historiographical and originalist inquiry into the degree to which the theory of the inalienable right to life and liberty is enforced by the Thirteenth Amendment. AB - This article completes a study that the author foreshadowed in his previous articles. The Western moral theory that defends the inalienable right to life and liberty--and that therefore forbids all forms of suicide and slavery--is now well known to the author's readers. What is not well known is an answer to the question of whether this theory, in its totality, was part of the original intent of the Thirteenth Amendment to the Constitution of the United States. The theory of the inalienable right to life and liberty was supported by many political philosophers in the seventeenth and eighteenth centuries. Those philosophers and their theory did shape a good deal of the thought of the men who made the Thirteenth Amendment a part of the Constitution. The anti-suicide implication of the theory, however, was not present in the minds of the framers and ratifiers of the Thirteenth Amendment, and therefore was not part of their intent. PMID- 21309255 TI - Pathology of the endometrium. Introduction. PMID- 21309256 TI - Endometrial hyperplasia. AB - Endometrial hyperplasia is a heterogeneous set of pathologic lesions that range from mild, reversible glandular proliferations to direct cancer precursors. These lesions comprise a continuum of morphologic appearances, with the earliest proliferation represented by crowded glands with simple tubular architecture lined by cells resembling proliferative endometrium, whereas advanced proliferations in this continuum are characterized by crowded glands with complex architecture, often containing cells with nuclear atypia resembling low-grade endometrioid adenocarcinoma. The former "early" proliferations may be isolated to an endometrial polyp, but advanced proliferations are generally more diffusely present throughout the endometrium. There are at least three major classification systems for endometrial carcinoma precursor lesions, each of which trend toward overlap at the complex end of the spectrum. Although some classifications are based on a series of molecular genetic alterations (which may or may not translate into biologically or clinically relevant risk lesions), each classification scheme ultimately uses a series of histologic features, usually a combination of architecture and cytology, to establish a diagnosis of hyperplasia. Because different pathologists may apply different histologic criteria for endometrial hyperplasia depending on the classification system used, this article will provide an overview of the classifications used in current daily practice, present the histologic criteria and relative merits of each classification system, and discuss common and not so common causes of misclassification. PMID- 21309257 TI - Endometrial intraepithelial neoplasia. AB - Endometrial intraepithelial neoplasia (EIN) is a monoclonal premalignant endometrial glandular lesion that precedes the development of endometrioid-type endometrial adenocarcinoma. EIN arises through complex interactions involving the sequential accumulation of genetic damage in endometrial glands and the positive selective pressure of unopposed estrogen. Recent data have revealed a preclinical latent precursor lesion composed of mutated but morphologically nondescript glands that may persist for years in normal-appearing premenopausal cycling endometrium. This latent precursor shares many of the molecular features of EIN and endometrial adenocarcinoma, including frequent inactivation of both the tumor suppressor gene PTEN and the paired box-containing gene PAX2. Upon progression to EIN, the distinctive appearance of crowded and cytologically altered glands heralds a 45-fold increased risk of developing endometrial adenocarcinoma. To preserve the high predictability of EIN for concurrent/ subsequent adenocarcinoma, strict adherence to defined diagnostic criteria is essential. These criteria, as well as potential diagnostic pitfalls and their resolution, are discussed herein. PMID- 21309258 TI - Endometrioid carcinoma of the endometrium: pathologic and molecular features. AB - Endometrioid carcinoma of the endometrium is the most common type of endometrial carcinoma. The microscopic appearance of the tumor resembles that of the proliferative endometrium, with a variable degree of glandular complexity and cellular pleomorphism. Several subtypes have been described, including the presence of squamous differentiation, villoglandular pattern, secretory features and ciliated cells. Recently recognized subtypes are the tumors that arise in the setting of hereditary nonpolyposis colon cancer syndrome, tumors with small nonvillous papillae, presence of microglandular pattern, sertoliform features, and dedifferentiated carcinomas. The main differential diagnosis includes endocervical adenocarcinoma, atypical polypoid adenomyoma, malignant mixed Mullerian tumors, and metastatic tumors to the endometrium. The main prognostic factors are stage, histologic grade, myometrial, cervical and vascular invasion. There are several pathologic features that should be recognized to avoid underestimation of these prognostic factors, such as presence of MELF pattern of myometrial invasion, and invasion of the cervical stroma with a deceptive pattern of spread. Six different molecular features are frequent in this type of tumor, including microsatellite instability, and mutations in PTEN, k-RAS, PIK3CA, FGFR2 and CTNNB1. PMID- 21309259 TI - Nonendometrioid endometrial carcinomas. AB - Clinicopathologic studies support a classification of endometrial carcinoma into two main categories (type I and type II). Type I cancers consist of endometrioid and mucinous carcinomas, with the former being the most common, whereas serous and clear cell carcinomas are the so-called "prototype" of type II cancers. Nonendometrioid carcinomas account for approximately 10% of endometrial carcinomas and differ from endometrioid carcinomas in terms of patient demographics, morphologic features, and biological behavior. Molecular studies have provided further insights into the differing alterations involved in the development and progression of these tumors. This review summarizes the characteristic clinical, morphologic, immunophenotypic, and molecular features of the various subtypes of nonendometrioid carcinomas and also highlights relevant conditions (both nonneoplastic and neoplastic) that should be considered in the differential diagnosis of these tumors. PMID- 21309260 TI - Endometrial carcinomas with ambiguous features. AB - Endometrial carcinomas are a heterogenous group of tumors that show variable histologies, molecular abnormalities and clinical outcomes. The idea of rigid distinctions between tumor types is appealing to pathologists, gynecologists, researchers and patients, but in a recent study where high grade endometrial carcinomas were reviewed by three experienced gynecologic pathologists, diagnostic agreement about tumor type was reached in only approximately one half of cases. In general, biologically and clinically validated diagnostic criteria are lacking for high grade endometrial carcinomas and for those that appear mixed epithelial. Until such criteria are developed, it remains important to define which morphologic patterns convey accurate clinical and biological information and which do not or might not. "Endometrial carcinomas with ambiguous features," the focus of this review, are tumors with comparatively uninformative morphologic features. Some publications indicate that gland forming and papillary endometrial carcinomas that appear morphologically low grade or ambiguous are really high grade. There are also indications that high grade endometrial carcinomas are biologically heterogeneous and that the morphologic clues we currently use to distinguish one subtype from another fail to correlate with biological data. Many tumors that appear morphologically mixed are, in fact, not biologically or clinically confused: most represent biologically "pure" tumors with variant morphology. Interesting associations between the presence of Lynch Syndrome (hereditary nonpolyposis colorectal carcinoma syndrome) and ambiguous morphology have been discussed in the literature. An apparent relationship between morphologic ambiguity and malignant mixed Mullerian tumor (MMMT) also exists. The identity of some morphologically ambiguous endometrial carcinoma can be elucidated with immunohistochemistry or other ancillary techniques at present, but the nature of many still remains undefined. This review presents the concept of morphologically ambiguous endometrial carcinomas, proposes morphological gold standard diagnostic criteria for tumors that are not ambiguous (an effort that helps define tumors that are ambiguous), provides a relevant literature review and offers practical guidance for sorting through diagnostically challenging cases. PMID- 21309261 TI - Pathologic and molecular features of uterine carcinosarcomas. AB - Uterine carcinosarcomas (UCSs), formerly known as malignant mixed mullerian tumors, are uncommon neoplasias that account for <5% of uterine malignancies. Traditionally, UCSs have been considered a subtype of sarcoma and the staging system and adjuvant oncological treatments used have been similar to those used for high-grade uterine sarcomas. However, there is now enough clinical, pathologic, and biological evidence to consider UCSs more closely related to high grade endometrial carcinomas. Thus, these tumors should be staged based on the surgicopathologic staging system used for endometrial carcinomas. Morphologically, UCSs are heterogeneous biphasic tumors composed of an admixture of malignant (endometrioid and nonendometrioid) epithelial and (homologous and heterologous) mesenchymal elements in different proportions. UCSs predominantly metastasize as carcinomas and they are associated with a poor prognosis. Although stage is a consistent prognostic factor, the significance of several histopathological features, such as myometrial invasion, lymphovascular space involvement, type of carcinomatous component, extent of the sarcomatous component, and the presence of heterologous elements, remains controversial and probably differs among different stages. Although the diagnosis of UCS is not difficult in most cases, the differential diagnosis may include entities such as undifferentiated or dedifferentiated carcinoma, endometrioid adenocarcinoma with spindle cell elements, sarcomatous overgrowth in a low-grade mullerian adenosarcoma, and pure malignant mesenchymal tumors. Genetic and molecular studies have confirmed the clonal origin of most UCSs and have shown these tumors to be similar to those observed in high-grade/nonendometrioid carcinomas, with p53 mutations being the most common molecular alteration. Finally, from a biological standpoint, the process by which epithelial malignant cells of UCS transdifferentiate to malignant mesenchymal cells could be considered a true example of epithelial mesenchymal transition in human neoplasias. PMID- 21309262 TI - Miscellaneous disorders involving the endometrium. AB - In this review, selected miscellaneous disorders of the endometrium, mostly benign but some malignant, are discussed. Topics covered include criteria for adequacy as well as common artifacts in endometrial biopsy specimens, endometritis, exogenous hormone and drug (including tamoxifen) effects on the endometrium, and endometrial metaplasias. Various issues relating to endometrial polyps are also covered, as are metastatic neoplasms involving the endometrium. PMID- 21309263 TI - An autopsy case of butane gas abuse. AB - A case of fatal butane gas poisoning in a young female is presented. Quantitative toxicological analysis showed that the concentration of butane in the femoral blood was 6.8 microl/ml, and isobutane and propane were also identified. Severe congestion of the lungs and deposition of lipofuscin in the myocardium were also observed. We concluded that the cause of death of the victim was due to cardiac arrhythmia induced by the butane gas abuse. PMID- 21309264 TI - The effect of the home shooting percussion pistol on skull substitute bones. AB - The aim of this paper was to determine if the saloon percussion pistol, considered to be a non-lethal weapon, can in fact be dangerous to life even if the neucranium is hit elsewhere than the so-called "locus minoris resistentiae" areas. In the face of specialist opinion that states that life-threatening or serious injury can occur only after a shot to the sensitive parts of the head (eyes, ears, sinus, nasal and oral cavity), it was experimentally determined on replacement materials that if the gun is loaded with just 100mg of gun powder a 4.5mm calibre bullet always penetrates the cranium. Saloon percussion pistols can be dangerous to life in situations that nobly expected till now. PMID- 21309265 TI - The role of molecular biology in detection and monitoring of prostate cancer. AB - The study of molecular markers in various types of human carcinomas, as well as in carcinoma of prostate, is focused on genes responsible for the formation of carcinoma. Mutation, amplification or other changes in these genes or in their protein products are being examined and compared with traditional prognostic markers. These genes can be characterized as oncogenes, tumor suppressor genes or genes for other significant cell functions. However, studies are often limited by heterogenity and multifocality of tumors, especially in prostate cancer. In this review, we offer a survey of some of the most frequent diagnostic and prognostic parameters of molecular biology research in relation to prostate cancer. PMID- 21309266 TI - Prolonged treatment of chronic renal insufficiency, acquired cystic kidney disease, simultaneous precancerous lesions and multiple tumors of left kidney. AB - PURPOSE OF THE INVESTIGATION: Description of precancerous lesions and kidney tumors developing in a patient with chronic uremia treated by long-term hemodialysis. MOST IMPORTANT METHODS: Light microscopy, polarization and immunohistochemistry with CK1/CK3, CK5/6, CK7, CK8, CK20, EMA, Renal cell, CD10, Ki-67, PCNA, p53 and E-cadherin antibodies were used. MAIN FINDINGS: After 11 years of hemodialysis treatment of end-stage diabetic nephropathy and chronic tubulointerstitial nephritis an urgent left-sided nephrectomy was performed because of pain and massive intrarenal bleeding. Biopsy revealed acquired cystic kidney disease associated with multiple precancerous lesions, several small papillary adenomas and a multifocal renal cell carcinoma with conventional and papillary structures with admixture of small foci of highly cellular sarcomatoid features. Severe vascular nephrosclerosis and uremic oxalosis were additional findings. The upper pole of the kidney was massively hemorrhagic. PRINCIPAL CONCLUSIONS: This case illustrates the association of chronic renal insufficiency, uremic oxalosis, long-term hemodialysis, acquired cystic kidney disease and development of variable precursor intratubular and intracystic lesions progressing to several papillary adenomas and multifocal renal cell carcinomas with variegated microscopic structures in one kidney. PMID- 21309267 TI - Written in the stars. Introducing our five-star rating system. PMID- 21309268 TI - Portable/transport ventilators. Breath easier. AB - Many of today's portable ventilators come "fully loaded" with advanced capabilities formerly available only on full-size models. However, more is not always better. in some settings, a simpler, less expensive unit is often preferred. we'll help you choose a model that matches your users' needs. PMID- 21309269 TI - Field equations. Cost-saving tips for magnetic resonance systems. PMID- 21309270 TI - Someone to watch over me. Monitoring project that won Health Devices Achievement Award is featured in Anesthesiology. PMID- 21309271 TI - Reducing the risk of burns and shocks during lontophoresis. AB - Although uncommon, burns and shocks can occur during iontophoresis treatments. A thorough understanding of the proper operation of iontophoresis equipment, along with proper preparation of the treatment site, can significantly reduce the likelihood of injuries. PMID- 21309272 TI - Choosing not to follow recommendations in medical device recalls, notifications, or alerts. PMID- 21309273 TI - FDA extends transition period for Steris System 1. PMID- 21309274 TI - The 2010 Gold Medal for distinguished service--Dr. John S. Findley. PMID- 21309275 TI - Access to care. PMID- 21309276 TI - Restorative dentistry for the pediatric patient. AB - The American Academy of Pediatric Dentistry sponsored the Pediatric Restorative Dentistry Consensus Conference in 2002. This paper will review the consensus statements that were issued as a result of the conference. Since the conference there have been advances in procedures, materials, and techniques that need to be considered in terms of some of the consensus statements. The introduction of the First Dental Home, interim therapeutic restoration and nanotechnology are examples of some of the materials and techniques that are now part of everyday pediatric dentistry. This paper will discuss the updates as it relates to each of the 2002 consensus statements. PMID- 21309277 TI - Indirect pulp therapy: an alternative to pulpotomy in primary teeth. AB - Preservation of the primary teeth until their normal exfoliation is essential for normal oral function and facial growth of the child. To that end, treatment of primary teeth with large carious lesions approximating the pulp should be aimed at preserving the tooth. Currently, the pulpotomy is the most frequently used pulp treatment for cariously involved primary teeth. The purpose of this manuscript is to describe the use of an alternative to the pulpotomy, indirect pulp therapy (IPT), for the treatment of vital, primary teeth with carious involvement approaching the pulp. Accurate diagnosis of the vitality status of the pulp is critical to the success of IPT and involves careful radiographic and clinical assessment of the teeth to be sure they are healthy or at worst, reversibly inflamed. The indications for IPT are the same as for pulpotomy. The technique involves one appointment, requires that some carious dentin be left to avoid pulp exposure and requires the placement of a biologically sealing base and sealing final restoration. Teeth treated with IPT have success rates at least as good as those treated with pulpotomies, and IPT offers an acceptable alternative to pulpotomy as a treatment for vital, asymptomatic, cariously involved primary teeth. PMID- 21309278 TI - Comprehensive oral rehabilitation with general anesthesia and prosthetic care in the primary dentition: a case report. AB - This case report describes the oral rehabilitation of a 5-year-old male referred by a general dentist to a pediatric dentist due to acute psychological stress to dental treatment and extensive dental caries. The patient's dental restorations and extractions were completed under general anesthesia. Maxillary and mandibular prostheses were completed in the outpatient clinical setting. The treatment plan for this child provided options to improve appearance, self-image and oral function. PMID- 21309279 TI - Infant oral exam and first dental home. AB - The purpose of this article is to familiarize general practitioners with the components of a dental home including an infant oral exam, and to the First Dental Home initiative, which is unique to the State of Texas. This article encourages the general practitioners to actively participate in providing care for young children under the age of 3. Components of an infant oral examination are described here with emphasis on knee-to-knee or lap exam, caries risk assessment, preventive treatment, age-appropriate anticipatory guidance, and parent education. The First Dental Home is uniquely designed to help pediatric clients 6 months through 35 months of age to establish a dental home. The objectives, goal and components of FDH are discussed in detail. PMID- 21309280 TI - Dental implants. PMID- 21309281 TI - A better freedom-of-choice plan, and how your patients and practice can benefit from it. PMID- 21309282 TI - Oral and maxillofacial pathology case of the month. Paraneoplastic pemphigus. PMID- 21309283 TI - Angiography contrast injector safety. Visualizing the marketplace. AB - The most common risk associated with angiography contrast injectors is air embolism. Injector manufacturers have attempted to address this concern by adding air detection systems and other safety features. Find out which injectors do the best job of protecting patients. PMID- 21309284 TI - At your service. The ins and outs of servicing equipment in-house. AB - Are you thinking about shifting some of your servicing efforts from outside sources to your clinical engineering staff? We outline the most important issues you need to consider and explain why adequate manufacturer support could be crucial. PMID- 21309285 TI - Digital microscopy. Bringing new technology into focus. AB - Digital microscopy enables the scanning of microscope slides so that they can be viewed, analyzed, and archived on a computer. While the technology is not yet widely accepted by pathologists, a switch to digital microscopy systems seems to be inevitable in the near future. PMID- 21309286 TI - Hazard report. Unfamiliarity with differences in the way ventilators set pressure control values may lead to lung injuries. AB - Variations in ventilator designs may result in different inspiratory pressures being delivered at seemingly identical settings during delivery of pressure controlled breaths. Because a lack of familiarity with these design variations may lead to the setting of excessive pressures that could result in lung injuries, staff need to be trained to understand how the units they use work. PMID- 21309287 TI - Hazard report. FDA orders recall of Baxter Colleague infusion pumps; hospitals may continue use for now. PMID- 21309288 TI - Hazard report. Electri-cord and interpower power cords. PMID- 21309289 TI - The hunt for 1LT Kenneth R. Shoemaker Jr., CRNA. AB - Little was known about 1LT Kenneth R. Shoemaker Jr, 1 of 2 nurse anesthetists killed during the Vietnam War, outside of his family and friends. This column examines the life, death, and legacy of Shoemaker as seen through the eyes of his family, former classmates, and fellow nurse anesthetists who served in Vietnam. PMID- 21309290 TI - Crew resource management or crisis resource management: which term is correct? PMID- 21309291 TI - Use of dexmedetomidine and ketamine infusions during scoliosis repair surgery with somatosensory and motor-evoked potential monitoring: a case report. AB - Dexmedetomidine and ketamine infusions were the main anesthetic for a 15-year-old girl, who underwent scoliosis repair surgery with intraoperative wake-up test, somatosensory evoked potential (SSEP), and motor-evoked potential (MEP) monitoring. To achieve maintenance of anesthesia, dexmedetomidine and ketamine were administered concomitantly. The dexmedetomidine dose ranged from 0.9 to 1.2 microg/kg per hour throughout the case, and the ketamine dose ranged from 0.4 to 0.6 mg/kg per hour. The analgesic properties of dexmedetomidine and ketamine were complimented by the continuous fentanyl infusion at 1 to 2 microg/kg per hour. The sympatholytic properties of dexmedetomidine were balanced with the sympathomimetic properties of ketamine, and the patient required minimal vasoactive support (only 250 microg of phenylephrine was administered over the course of 12 hours of anesthetic care). This anesthetic regimen, as well as 60% nitrous oxide and 40% oxygen, provided satisfactory conditions for the intraoperative neurophysiologic monitoring. This case report discusses the use of dexmedetomidine and ketamine infusions as an alternative to propofol-based total intravenous anesthesia during scoliosis repair surgery with intraoperative SSEP and MEP monitoring. PMID- 21309292 TI - The effect of ellagic acid on platelet activation as measured by the quantification of P-selectin using flow cytometry. AB - The purpose of this study was to investigate the effects of ellagic acid on platelet expression via the cyclooxygenase (COX) pathway by examining its effects on platelet activation and comparing them with known COX inhibitors in male Sprague-Dawley rats. Ellagic acid is a major compound found in certain fruits and nuts. It has been attributed as having anti-inflammatory, free radical scavenging, and coagulation properties as well as effects on tumor genesis in multiple forms of cancer. We assessed the similarities of ellagic acid to known COX-2 specific and nonspecific COX inhibitors by examining their effects on platelet activation via use of P-selectin flow cytometry. Compared with the vehicle group, both the ellagic acid (P = .035) and the ketorolac (P = .038) groups demonstrated a significant decrease in platelet activation (P = .026). Furthermore, compared with all other groups, ellagic acid plus ketorolac group showed a significant decrease in platelet activation (P = .01). Our findings suggest that ellagic acid is likely a nonspecific COX inhibitor. It also suggests that combining ellagic acid with a known nonspecific COX inhibitor such as ketorolac may cause a significant decrease in platelet activity and an increase in blood loss. PMID- 21309293 TI - Bilateral tension pneumothoraces and subcutaneous emphysema following colonoscopic polypectomy: a case report and discussion of anesthesia considerations. AB - A 78-year-old man presented preoperatively with severe abdominal pain, dyspnea, and subcutaneous emphysema in his face, neck, and chest approximately 8 hours after colonoscopy with a sigmoid polypectomy. A pneumoperitoneum, free air in the mesentery, pneumoretroperitoneum, pneumomediastinum, and bilateral pneumothoraces were diagnosed using radiography and computed axial tomography. He emergently underwent an exploratory laparotomy with colostomy following bilateral chest tube placement. At laparotomy, a perforation of the posterior sigmoid colon was identified at the site of earlier polypectomy. The patient remained intubated and mechanically ventilated for 3 days postoperatively. Perforations of the colon during colonoscopies are the most serious complication of the procedure. Continued insufflation of air or carbon dioxide into a perforated colon can result in extraluminal gas that can result in life-threatening tension pneumothoraces. This case examines the consequences of colonic perforation and the anesthetic management for the definitive surgical treatment of a posterior sigmoid wall perforation. Anesthesia providers' awareness of the risk factors for colonic perforation due to colonoscopy, early signs and symptoms of perforation, and knowledge of the surgical and anesthetic management of perforation could lead to early recognition and intervention and likely to improved patient outcomes. PMID- 21309294 TI - Use of propofol and emergence agitation in children: a literature review. AB - Emergence agitation (EA) is an important issue in pediatric anesthesia. This phenomenon arises more frequently with the use of inhalational agents. Three commonly used general anesthesia techniques in children were evaluated as to the associated incidence of emergence reactions. An extensive literature review was performed to evaluate these anesthetic practices and the occurrence of EA in young children. Relevant literature was obtained from multiple sources, including professional journals, professional websites, and textbooks. Three categories of anesthesia techniques were reviewed: sevoflurane inhalational general anesthetic, Emerpropofol as an adjunct to sevoflurane general anesthetic, and propofol total intravenous anesthesia (TIVA) techniques. Several variables within each category were evaluated with respect to the outcome of EA: prevention, intraoperative adjuncts, type of surgery, and patient-related factors. According to the literature evidence base, there is an advantage to either propofol TIVA or adjunctive propofol with sevoflurane (compared with sevoflurane alone). We conclude, based on the current evidence, that the use of propofol is associated with a reduction in the incidence of emergence agitation. PMID- 21309295 TI - Exploring student nurse anesthetist stressors and coping using grounded theory methodology. AB - The purpose of this qualitative study was to examine the challenges that recent graduates of nurse anesthesia programs coped with during their anesthesia curriculum from their perspective. The initial research questions for this study were: From the graduates'perspective, what were the stressors that they encountered during their nurse anesthesia program? And how did they successfully negotiate those stressors in order to graduate from their program? This phenomenon was studied using grounded theory methodology. The data were collected by individual, semistructured, in-depth interviews with 12 recent nurse anesthesia program graduates, from 5 different nurse anesthesia programs, who have been out of school for less than 2 years. This exploration into student nurse anesthetist stress and coping articulates 3 phases of development as these students progressed through their program. The phases are transitioning in (first 9 months of program), finding their way (9 to 18 months into program), and transitioning out (18 to 28 months into program). Coping mechanisms employed by the participants were problem focused, emotion focused, and a combination of the 2. Recommendations for action and future research are discussed. PMID- 21309296 TI - Ventricular assist devices and anesthetic implications for noncardiac procedures. AB - Approximately 5 million Americans experience heart failure, which affects 10 in every 1000 people older than 65 years. Ventricular assist devices (VADs) are a type of mechanical circulatory support that aids in systemic perfusion by maintaining unidirectional flow while reducing the oxygen demand of the failing ventricle. There are 3 generations of VADs in circulation used as a bridge to transplantation, a bridge to recovery, or as destination therapy. Due to the increasing use of these devices, it is likely that anesthetists will encounter patients with these devices more frequently, which requires adequate preoperative discussion with the care team. Intraoperatively, it is important to realize that patients with VADs are at higher risk for aspiration, to recognize electromagnetic interference from surgical devices, to maintain hemodynamic stability, and to monitor coagulation status. With proper knowledge, and adequate preoperative preparation and intraoperative care, anesthetists should be able to achieve safe and successful patient outcomes through anesthesia care. PMID- 21309297 TI - Kinetics and kinematics analysis of incremental cycling to exhaustion. AB - Technique changes in cyclists are not well described during exhaustive exercise. Therefore the aim of the present study was to analyze pedaling technique during an incremental cycling test to exhaustion. Eleven cyclists performed an incremental cycling test to exhaustion. Pedal force and joint kinematics were acquired during the last three stages of the test (75%, 90% and 100% of the maximal power output). Inverse dynamics was conducted to calculate the net joint moments at the hip, knee and ankle joints. Knee joint had an increased contribution to the total net joint moments with the increase of workload (5-8% increase, p < 0.01). Total average absolute joint moment and knee joint moment increased during the test (25% and 39%, for p < 0.01, respectively). Increases in plantar flexor moment (32%, p < 0.01), knee (54%, p < 0.01) and hip flexor moments (42%, p = 0.02) were found. Higher dorsiflexion (2%, for p = 0.03) and increased range of motion (19%, for p = 0.02) were observed for the ankle joint. The hip joint had an increased flexion angle (2%, for p < 0.01) and a reduced range of motion (3%, for p = 0.04) with the increase of workload. Differences in joint kinetics and kinematics indicate that pedaling technique was affected by the combined fatigue and workload effects. PMID- 21309298 TI - Elite golfers' kinematic sequence in full-swing and partial-swing shots. AB - The aim of this study was to investigate whether kinematic proximal-to-distal sequencing (PDS) and speed-summation are common characteristics of both partial and full-swing shots in golf players of different skill levels and genders. A total of 45 golfers participated, 11 male tournament professionals, 21 male and 13 female elite amateurs. They performed partial shots with a wedge to targets at three submaximal distances, 40, 55 and 70 m, and full-swing shots with a 5 iron and a driver for maximal distance. Pelvis, upper torso and hand movements were recorded in 3D with an electromagnetic tracking system (Polhemus Liberty) at 240 Hz and the magnitude of the resultant angular velocity vector of each segment was computed. The results showed a significant proximal-to-distal temporal relationship and a concomitant successive increase in maximum (peak) segment angular speed in every shot condition for both genders and levels of expertise. A proximal-to-distal utilization of interaction torques is indicated. Using a common PDS movement strategy in partial and full-swing golf shots appears beneficial from mechanical and control points of view and could serve the purpose of providing both high speed and accuracy. PMID- 21309299 TI - Effects of mat characteristics on plantar pressure patterns and perceived mat properties during landing in gymnastics. AB - Shock absorption and stability during landings is provided by both, gymnast ability and mat properties. The aims of this study were to determine the influence of different mat constructions on their energy absorption and stability capabilities, and to analyse how these properties affect gymnast's plantar pressures as well as subjective mat perception during landing. Six mats were tested using a standard mechanical drop test. In addition, plantar pressures and subjective perception during landing were obtained from 15 expert gymnasts. The different mats influenced plantar pressures and gymnasts' subjective perception during landing of gymnasts. Significant correlations between plantar pressures at the medial metatarsal and lateral metatarsal zones of the gymnasts' feet with the different shock absorption characteristics of the mats were found. However, subjective perception tests were not able to discriminate mat functionality between the six mats as no significant correlations between the mechanical mat properties with the subjective perception of these properties were found. This study demonstrated that plantar pressures are a useful tool for discriminating different landing mats. Using similar approaches, ideally including kinematics as well, could help us in our understanding about the influences of different mats upon gymnast-mat interaction. PMID- 21309300 TI - Choice of sprint start performance measure affects the performance-based ranking within a group of sprinters: which is the most appropriate measure? AB - Sprint start performance has previously been quantified using several different measures. This study aimed to identify whether different measures could influence the performance-based ranking within a group of 12 sprinters, and if so, to identify the most appropriate measure. None of the 10 performance measures ranked all sprinters in the same order; Spearman's rho correlations between different block phase measures ranged from 0.50 to 0.94, and between block phase measures and those obtained beyond block exit from 0.66 to 0.85. Based on the consideration of what each measure quantifies, normalised average horizontal external power was identified as the most appropriate, incorporating both block velocity and the time spent producing this velocity. The accuracy with which these data could be obtained in an externally valid field setting was assessed against force platform criterion data. For an athlete producing 678 +/- 40 W of block power, a carefully set-up manual high-speed video analysis protocol produced systematic and random errors of +5 Wand +/- 24 W, respectively. Since the choice of performance measure could affect the conclusions drawn from a technique analysis, for example the success of an intervention, it is proposed that external power is used to quantify start performance. PMID- 21309301 TI - Biomechanical analysis of the different classifications of the Functional Movement Screen deep squat test. AB - The purpose of this study is to examine the peak sagittal plane joint angles and joint moments of the lower extremity during the deep squat (DS) movement of the Functional Movement Screen (FMS) to assess differences between the classifications (1,2,3). Twenty-eight participants volunteered for the study and were screened to assess their FMS score on the DS task. All participants underwent a quantitative movement analysis performing the FMS DS movement at a self-selected speed. The participants in Group 3 exhibited greater dorsiflexion excursion compared to those in Group 1. Participants in Group 3 had greater peak knee flexion and knee flexion excursion than those in Group 2 who exhibited more than the participants in Group 1. Group 3 also exhibited a greater peak knee extension moment compared to Group 1. At the hip, Groups 3 and 2 exhibited greater peak hip flexion, hip flexion excursion and peak hip extension moment compared to Group 1. Thus, it appears that individuals who score differently on the deep squat as determined by the FMS exhibit differences in mechanics that may be beneficial in assessing strategies for interventions. Future research should assess how fundamental changes in mobility and stability independently affect DS performance. PMID- 21309302 TI - Kinematic differences of elite and high-performance tennis players in the cross court and down the line forehand. AB - This study identified and compared the full body kinematics of different skill levels in the forehand groundstroke when balls were hit cross court and down the line. Forty-three three-dimensional retroreflective marker trajectories of six elite and seven high-performance players were recorded using an eight-camera 400 Hz, Vicon motion analysis system. The six highest horizontal velocity forehands with reliable kinematics of all participants were analysed for each specific situation (a total of 156 analysed shots). Significant differences (p < 0.01) and large effect sizes were observed between elite and high-performance players in linear velocity of the shoulder (2.0 vs. 1.2 m/s), angular velocity of the pelvis (295 vs. 168 degrees/s), and angular velocity of the upper trunk (453 vs. 292 degrees/s) at impact. The elite group showed a tendency towards higher racquet velocities at impact (p < 0.05). No significant differences were found in angular displacement of the racquet, hip alignment, or shoulder alignment at the completion of the backswing; nor did angular displacement vary significantly at impact. Irrespective of the group, different shoulder, hip, and racquet angles were found at impact, depending on the situation. The results should assist coaches when striving to improve their players' forehand. PMID- 21309304 TI - In a heartbeat. Our review of two intrapartum fetal monitors. AB - Intrapartum fetal monitors help clinicians determine the well-being of the fetus during labor. However, with at least two heart rates involved (the mother's and the fetus's), the possibility exists that the measurements will be misrepresented. We evaluate two intrapartum monitors, basing our ratings primarily on their capability to alert the user to possible misrepresentation of fetal heart rates. PMID- 21309303 TI - Effect of skill decomposition on racket and ball kinematics of the elite junior tennis serve. AB - Whole body kinematics of the tennis serve have been reported extensively in the literature, yet comparatively less information exists regarding the kinematic characteristics of the swing and toss. In attempting to develop consistency in placement of the toss and racket trajectory, coaches will often decompose the serve and practice it in separate parts. A 22-camera VICON MX motion analysis system, operating at 250 Hz, captured racket, ball and hand kinematics of the serves of five elite junior players under three conditions. The conditions were flat first serves (FS) directed to a 1 x 1 m target bordering the 'T' of the deuce service box, a ball toss (BT) in isolation and a free swing (SW) in isolation. Players were instructed to perform BT and SW as in the FS. Paired t tests assessed within-group differences in hand, racket and ball kinematics between the discrete skill and the two decomposed conditions. Vertical displacement of the ball at its zenith increased significantly during BT compared with the FS and temporal associations between racket and ball motion during the FS (r = 0.861) were affected during task decomposition. This study questions the pervasive use of task decomposition in the development of the tennis serve. PMID- 21309305 TI - Best practices for health technology management. Valuable lessons from the 2010 Health Devices Achievement Award finalists. AB - The annual health devices achievement award competition provides a valuable opportunity for us to learn about--and share--some of the outstanding technology management initiatives implemented by our members. This year's top submissions describe best practices and effective techniques that other healthcare facilities can emulate to improve patient safety, reduce costs, and facilitate better strategic management of health technology. PMID- 21309306 TI - Clearing up confusion about the Steris System 1E. ECRI Institute's perspective on its appropriate use. AB - Recent statements by FDA about the appropriate use of the Steris System 1 E have created uncertainty in hospitals looking to replace the STERIS SYSTEM 1. We've spoken with FDA and steris and reviewed the evidence. Here's why we think the SS1 E can be considered for use in your facility. PMID- 21309307 TI - Moog Curlin 6000 CMS infusion pumps may falsely indicate hardware failures and stop therapy. AB - Due to a software issue, the Moog Curlin 6000 CMS infusion pump may activate an error code associated with a hardware failure (error code 45) when no such failure exists. When this occurs, the unit will stop infusing, and the user may be unable to restart it. Moog has announced plans to release new software in the coming weeks to address this problem. Until the software is available, facilities whose units exhibit this error code should contact Moog for guidance. PMID- 21309308 TI - ECRI institute recommends reporting EMI events. AB - Electromagnetic interference (EMI), though rare, can have a detrimental effect on the performance of electronic medical devices, potentially posing a patient safety risk. We encourage healthcare facilities to report EMI events (both known and suspected) to external entities such as device manufacturers, regulatory bodies (e.g., the U.S. Food and Drug Administration [FDA]), and ECRI Institute. Reporting such events will allow these organizations to analyze a greater number of reports in order to recognize trends that can help identify the susceptibility of devices to this problem; this information can then be disseminated to the healthcare community. PMID- 21309309 TI - Survey results: hospitals' status regarding steris system 1 replacement. PMID- 21309315 TI - Unions prepare for difficult decision over increment freeze. PMID- 21309316 TI - Magic moments. AB - Every year volunteer nurses accompany children with life-limiting conditions and their families on a trip to Walt Disney World, Florida. PMID- 21309317 TI - Hope is key to recovery. AB - With increasing numbers of people surviving cancer, there is a need to focus on how they can be supported once they have completed treatment. PMID- 21309318 TI - Helping hands. AB - Hand eczema can seriously affect nurses' lives, but new treatments are available. PMID- 21309319 TI - Sick day scrutiny. AB - NHS trusts are introducing a variety of initiatives to reduce staff sickness absence and save money. PMID- 21309320 TI - Acute pain management following Roux-en-Y gastric bypass surgery. AB - Obesity is a growing public health problem. This article provides an overview of the health implications associated with obesity. It describes laparoscopic Roux en-Y gastric bypass surgery, an invasive intervention for the management of obesity. Strategies for achieving effective pain management following this procedure are discussed. PMID- 21309321 TI - Patient-reported outcome measures: implications for nursing. AB - The Patient Reported Outcome Measures (PROMs) Programme, which was implemented by the NHS in 2009, gives prominence to patients' views about their health. Self reported measures of health are now being sought from all patients before and after four elective procedures--hip and knee replacement surgery, hernia repair and varicose veins surgery. This information will be used to assess changes in health and provides routine information on NHS patients' health outcomes for the first time. The information will be used to identify and reward good performance by providers; help patients to make choices and clinicians to monitor and improve quality; and inform commissioners' decisions about which services to prioritise. The aim of this article is to inform nurses about PROMs and encourage them to engage with it. PMID- 21309322 TI - MRSA: implications for hospitals and nursing homes. AB - Meticillin-resistant Staphylococcus aureus (MRSA) is a major infection prevention and control challenge globally. In the UK, the occurrence of MRSA has fuelled public concern about hospital safety and had a major effect on health policy. Guidelines emphasise the importance of surveillance, decolonisation strategies, standard infection prevention and control precautions, and antibiotic stewardship to reduce the risk of transmission. PMID- 21309323 TI - Unintentional injury. PMID- 21309324 TI - Degrees of success. PMID- 21309325 TI - You can bank on it. PMID- 21309326 TI - Care in a cold climate. PMID- 21309327 TI - The real emergency. Getting rid of 24-hour shifts. PMID- 21309328 TI - Water work made easy. Helpful tips for boluses and drips. PMID- 21309329 TI - A bolt from the blue. The storm's over, but for a teenage golf course worker, the danger's not. PMID- 21309331 TI - Bougie it! The gum elastic bougie is a viable adjunct for the difficult endotracheal intubation. PMID- 21309330 TI - Assessing mental status. With these challenging patients, you'll need facts, not opinions. AB - A patient with diminished mental status must be evaluated carefully to rule out organic or traumatic reasons for the condition, as well as to identify possible causes, such as drug ingestion. PMID- 21309332 TI - When life gives you lemons...Assessment of difficult laryngoscopy in emergency airway management. PMID- 21309333 TI - Wheezing in the pediatric patient. A review of prehospital management of two childhood diseases--bronchiolitis and asthma. AB - A wheeze is a high-pitched, musical, continuous sound that originates from oscillations in narrowed airways. Wheezing is most often the result of bronchiolitis in infants and asthma in older children. This article will discuss the similarities and differences between these two childhood diseases, along with management of the infant or child with wheezing. PMID- 21309334 TI - Respecting the game. Aiding others is a privilege, and EMS demands more humility than hubris. PMID- 21309335 TI - Potato perspectives. IT's hard to know what the implications are for the future at the moment any technological or consumer innovation emerges. PMID- 21309336 TI - Gold from the mine. Healthcare IT and clinician leaders make evidence-based care a reality. AB - Healthcare IT leaders nationwide are moving forward steadily to introduce evidence-based care tools into clinician workflows, both with regard to the development of order sets in computerized physician order entry (CPOE) systems, as well as in the context of the medical diagnosis process. As they advance in these areas, they are finding that building everything from scratch is simply too labor-intensive a prospect. And as hospitals and medical groups turn increasingly to the commercially sponsored offerings available, they are finding the insertion of evidence-based decision support to be a plus in winning doctors over to CPOE adoption. PMID- 21309337 TI - Business intelligence effort get a boost. The meaningful use framework highlights the value of data warehouses and BI tools. AB - As patient care organizations nationwide prepare to report on meaningful use quality measures, those with enterprise data warehouses may find they have a head start. The more advanced among them are establishing workgroups to create dashboards to analyze progress and identify gaps that need addressing. PMID- 21309338 TI - Paperless strategies rely on document imaging. Document imaging provides a bridge to the paperless hospital. AB - Hospitals that have tried to shed their reliance on paper have found the task fraught with challenges. Some have found that document imaging provides a useful interim step in meeting their goal. PMID- 21309339 TI - Community-based information exchange. Community-based hies are a model of interoperability among clinical information systems. AB - Many health providers have focused on community-based health information exchanges (HIEs) as a useful platform to help them take the next steps in implementing electronic health information. Recent research by a healthcare technology advisory firm is an attempt to characterize various HIE models, with an eye on achieving that goal. PMID- 21309340 TI - Revenue cycle management automation. An interview with Paul Conocenti, Senior Vice President, Vice Dean AND CIO, NYU Langone Medical Center. Interview by Mark Hagland. PMID- 21309341 TI - Meaningful use: an assessment. An interview with David Blumenthal, M.D., National Coordinator for Health Information Technology, Office of the National Coordinator. Interview by Mark Hagland. PMID- 21309342 TI - Could SGR imperil HITECH for MDs? An interview with William F. Jessee, M.D., President and CEO, MGMA. Interview by Mark Hagland. PMID- 21309343 TI - Portal/EHR interoperability: one practice's struggle. North Carolina practice faces challenge connecting patient portal to EHR. PMID- 21309344 TI - First impressions matter especially in an interview. Six common mistakes hiring managers should avoid in their search for the best talent. PMID- 21309345 TI - Outbreak: the changing epidemiology of HAIs and CAIs. PMID- 21309346 TI - Advances in technology improving safety and efficiency in blood-sample draw. PMID- 21309347 TI - Challenges of the oncology draw. PMID- 21309348 TI - Form an effective compliance program. PMID- 21309349 TI - Drawing from intraosseous vascular access. PMID- 21309350 TI - Permissive hypercapnia: finding its place in clinical care. PMID- 21309352 TI - Integrate the LIS for the lab's future. PMID- 21309351 TI - Darkfield microscopy for point-of-care syphilis diagnosis. PMID- 21309353 TI - POCT key to widespread access to healthcare. PMID- 21309354 TI - COLA CEO leads quest for quality. PMID- 21309355 TI - Radiation in cardiac CT: predictors of higher dose and its reduction over time. AB - INTRODUCTION: Cardiac CT provides noninvasive information on cardiac anatomy, particularly in coronary artery disease. However, exposure to radiation has been identified as a limitation of this exam. The aim of this study was to evaluate variations in radiation dose over time and to identify variables associated with use of higher radiation doses. METHODS: A prospective registry of 643 patients who underwent 64-slice dual source cardiac CT scan (Dual source CT--Somaton Definition, Siemens-Medical) during 2007 and 2008 was analyzed. RESULTS: The sample was divided into quartiles according to the chronological order of the exams. There was a progressive reduction in median radiation dose in the quartiles analyzed (Q1: 8.9 [5.9-14.1], Q2: 6.6 [5.5-10.7], Q3: 6.4 [5.3-8.7], Q4: 6.1 [5.2-7.9] mSv), significant when the first quartile was compared with the others (p < 0.05). Along with this reduction, was a progressive increase in the use of a tube voltage of 100 kV (p < 0.001). Predictors of a higher radiation dose were higher body mass index, previous cardiac surgery, atrial fibrillation during acquisition, longer acquisition time and use of a tube voltage of 120 kV. When one or more of these variables were present (one third of the population), the radiation dose was significant higher (12.1 [9.5-14.8] vs. 5.7 [5.0-6.7] mSv, p < 0.001). PMID- 21309357 TI - Cardiac computed tomography and radiation: balancing benefit and risk. PMID- 21309356 TI - Coronary computed tomography angiography in a single cardiac cycle with a mean radiation dose of approximately 1 mSv: initial experience. AB - INTRODUCTION: The aim of this study was to evaluate the radiation dose, image quality and acquisition time of coronary computed tomography angiography (CCTA) using a 128-slice dual source scanner with prospective ECG-triggered high-pitch spiral acquisition (Flash Spiral). METHODS: A series of 20 consecutive patients in sinus rhythm, with no contraindications to administration of iodinated contrast media and beta-blockers and no history of coronary revascularization, underwent CCTA either to rule out coronary artery disease (CAD) or to evaluate known or suspected CAD. Image quality was evaluated using a four-point scale (1 excellent, 4 poor). Data on acquisition time and radiation dose were recorded. RESULTS: Mean acquisition time was 292 +/- 21 milliseconds. The mean effective radiation dose was 0.99 mSv +/- 0.34 mSv. All of the 266 coronary artery segments analyzed were of diagnostic image quality. CONCLUSION: CCTA using a 128-slice dual source scanner with prospective ECG-triggered high-pitch spiral acquisition provides single cardiac cycle acquisition with high image quality at mean effective radiation doses of approximately 1 mSv. PMID- 21309358 TI - Global cardiovascular risk stratification of hypertensive patients followed in Portugal in primary care or in hospital care according to the 2007 ESH/ESC guidelines. AB - INTRODUCTION: Hypertension is one of the major risk factors for cardiovascular (CV) disease. Our aim was to assess and stratify the CV risk of two cohorts of hypertensive patients in Portugal attended in primary care (PC) or in outpatient hospital care (HC) using the global CV risk stratification model of the 2007 ESH/ESC guidelines. METHODS: We retrospectively analyzed the clinical data of hypertensive patients (aged 18-75 years) enrolled in other population studies and attended in PC (n = 2299, 66 +/- 11 years, 64% women) or in HC (n = 2028, 51 +/- 14 years, 54.7% women). Global risk stratification was performed according to the 2007 ESH/ESC guidelines. RESULTS: In patients attended in PC (67% treated with antihypertensive drugs, 31% with BP < 140/90 mmHg, 22% with dyslipidemia and 16% with diabetes), added global CV risk was average or low in 26%, moderate in 31%, high in 27% and very high in 16%; in patients attended in HC (77% treated with antihypertensive drugs, 16% with BP <140/90 mmHg, 47% with dyslipidemia and 26% with diabetes), added global CV risk was average or low in 16%, moderate in 30%, high in 28% and very high in 26%. CONCLUSIONS: The majority of hypertensiv patients attended in PC or HC have a high or very high global CV risk according to the 2007 ESH/ECS guidelines. Thus, global CV risk stratification should be undertaken in all hypertensive patients, as well as the implementation and reinforcement of strategies aimed at adequate control of hypertension and of all other modifiable CV risk factors. PMID- 21309359 TI - Percutaneous aortic valve implantation. AB - INTRODUCTION: Percutaneous aortic valve implantation is an emerging procedure for the treatment of patients with severe aortic stenosis. METHODS: The procedure was performed in patients with severe symptomatic aortic stenosis, who had been refused for aortic valve replacement surgery. A self-expanding bioprosthesis within a nitinol frame delivered by an 18F catheter was used. Most of the procedures were performed through a femoral artery approach and under local anesthesia and sedation. RESULTS: Thirty-two patients were treated, mean age 80 years, with various comorbidities and mean logistic EuroSCORE of 22%. The procedure was successful in all patients, with a significant improvement in transvalvular gradients. Two patients died due to procedure-related complications. The most common complications were vascular access related and high-degree atrioventricular block requiring permanent pacemaker. No events were reported after one month follow-up, with most patients showing improvement in functional capacity. After 23 months of follow-up (mean 13 months) five additional deaths had occurred. No prosthesis-related events were observed. CONCLUSIONS: Percutaneous aortic valve implantation is safe and improves quality of life in patients with severe symptomatic aortic stenosis. It may be an alternative therapeutic option for patients with high risk features for aortic replacement surgery. PMID- 21309360 TI - Patent foramen ovale closure with the BioSTAR bioabsorbable implant. AB - The authors present the case of a 35-year-old woman admitted to her local hospital with right upper limb paresis, which led to a diagnosis of ischemic stroke, confirmed by brain magnetic resonance imaging (MRI). Investigation of the embolic source by transesophageal echocardiography (TEE) revealed a patent foramen ovale (PFO), with spontaneous right-to-left shunt. In May 2009 percutaneous closure of the PFO was performed with a BioSTAR bioabsorbable implant, under TEE and fluoroscopic control. Transthoracic echocardiography was performed one, three and six months after the procedure, and TEE was repeated after nine months, in each case showing correct implant positioning, with no residual leak. The patient has been asymptomatic since the stroke episode. The authors discuss the importance of bioabsorbable implants for PFO closure, and their advantages over the previously used permanent synthetic implants. PMID- 21309361 TI - Recurrent orthodeoxia and patent foramen ovale. AB - BACKGROUND: Patent foramen ovale (PFO) occurs in 25% of healthy adults. It can lead to paradoxical embolization, migraine and respiratory failure (RF). The authors present a case of RF and orthodeoxia due to a right-to-left shunt via a PFO without previous elevation of right atrial pressure. Closure of the PFO effectively resolved the RF. CASE REPORT: A 52-year-old man, with IgA-k multiple myeloma diagnosed one year before, was admitted for severe hypoxemic RF, with orthodeoxia and poor response to oxygen supplementation, after placement of a central venous catheter (CVC) in the right subclavian vein. The patient reported paresthesia and nonspecific visual changes after manipulation of the CVC. The RF suggested a shunt between the pulmonary and systemic circulations. There was no clinical or radiological evidence of an intrapulmonary shunt. Contrast echocardiography showed a right-to-left shunt and transesophageal echocardiography revealed a PFO. Cardiac catheterization, after spontaneous resolution of the RF, showed no shunt. A week later, severe RF recurred. Complete resolution of respiratory dysfunction and neurological symptoms was seen after PFO closure. DISCUSSION: RF due to an intracardiac shunt without increased right sided pressure is hemodynamically difficult to interpret. A few reports (in adults) relate this entity to anatomical anomalies, which can lead to a shunt by directing blood flow preferentially to the PFO. Examples include right diaphragmatic paresis and ectasia of the ascending aorta, which were observed in this patient. The role of the CVC, which was placed immediately before the RF, is uncertain. Complete therapeutic success after closure of the PFO supports the diagnosis. CONCLUSION: Correct evaluation of RF (by investigating orthodeoxia and response to oxygen therapy) enables the suspicion of a shunt, which can be confirmed through simple, safe and cost-effective exams. Intracardiac shunt without increased right-sided pressure should be considered because it can be successfully treatment. PMID- 21309362 TI - Behind heart failure syndrome: remember AL amyloidosis. Two case-reports. AB - Amyloidosis is a systemic disease that is a consequence of extracellular deposition of insoluble fibrils composed of subunits of low molecular weight (5 25 kD) derived from a variety of plasma proteins. Identification of the amyloidogenic protein determines the type of amyloidosis. In primary systemic amyloidosis (classically called AL amyloidosis), the amyloid protein is composed of light chains resulting from plasma-cell dyscrasia. Cardiac manifestations are the most common clinical presentation of this type of amyloidosis, occurring in 50% of patients. The authors describe two cases in which hospitalization was due to decompensated heart failure, which were similar in their etiology (multiple myeloma/amyloid cardiomyopathy) and evolution (sudden death). The authors wish to draw attention to an entity that is rarely encountered in clinical practice and that requires a high index of suspicion. PMID- 21309363 TI - Atrial flutter after pulmonary vein isolation. PMID- 21309364 TI - Complication after endoluminal stent grafting of a thoracic aneurysm [126]. PMID- 21309365 TI - Special issue on work-related injuries and illnesses and the role of occupational therapy: implications of a systematic literature review for practice, research, education, and policy. PMID- 21309366 TI - Methodology for the systematic reviews on occupational therapy for individuals with work-related injuries and illnesses. AB - Systematic reviews of literature relevant to individuals with work-related injuries and illnesses are important to the practice of occupational therapy. This article describes the four questions that served as the focus for the systematic reviews of the effectiveness of occupational therapy interventions for individuals with work-related injuries and illnesses of the low back; hand, wrist, and forearm; elbow; and shoulder. The article includes the background for the reviews; the process followed for each question, including search terms and search strategy; the databases searched; and the methods used to summarize and critically appraise the literature. The final number of articles included in each systematic review; a summary of the results; the strengths and limitations of the findings; and the implications for practice, education, and research are presented. PMID- 21309367 TI - Occupational therapy interventions for shoulder conditions: a systematic review. AB - The objectives of this systematic review were (1) to identify, evaluate, and synthesize the research literature of relevance to occupational therapy regarding interventions for work-related shoulder conditions and (2) to interpret and apply the research literature to occupational therapy. Twenty-two studies were reviewed for this study-16 of Level I evidence, 2 of Level II evidence, and 4 of Level III evidence. In this systematic review, limited evidence from Level I studies was found to support exercise for shoulder pain; manual therapy and laser for adhesive capsulitis; conservative management of shoulder instability; early intervention without immobilization for specific, nondisplaced proximal humerus fractures; and exercise, joint mobilizations, and laser for patients with shoulder impingement. Further prospective studies are necessary for the delineation of specific surgical and therapeutic variables that facilitate positive outcomes in the treatment of patients with shoulder conditions. PMID- 21309368 TI - Systematic review and analysis of work-related injuries to and conditions of the elbow. AB - This systematic review of literature examines and synthesizes research findings related to interventions for people with work-related elbow injuries, particularly epicondylitis. It was carried out as part of the Evidence-Based Literature Review Project of the American Occupational Therapy Association. The 11 articles included in this review suggest multiple approaches to intervention but do not provide sufficient evidence to determine which methods or approaches are best practice. Research has provided little evidence to support the use of commonly prescribed interventions for epicondylitis, the most frequently reported work-related elbow injury. Collectively, the evidence to support the use of splinting, exercise, or physical agent modalities is weak and provides little guidance for approaching management of elbow injuries. The implications for education and research are discussed, as is the application of the evidence to clinical practice in occupational therapy. PMID- 21309369 TI - Occupational therapy interventions for work-related injuries and conditions of the forearm, wrist, and hand: a systematic review. AB - A systematic review of the literature related to effective occupational therapy interventions in rehabilitation of individuals with work-related forearm, wrist, and hand injuries and illnesses was conducted as part of the Evidence-Based Literature Review Project of the American Occupational Therapy Association. This review provides a comprehensive overview and analysis of 36 studies that addressed many of the interventions commonly used in hand rehabilitation. Findings reveal that the use of occupation-based activities has reasonable yet limited evidence to support its effectiveness. This review supports the premise that many client factors can be positively affected through the use of several commonly used occupational therapy-related modalities and methods. The implications for occupational therapy practice, research, and education and limitations of reviewed studies are also discussed. PMID- 21309370 TI - Effective occupational therapy interventions in the rehabilitation of individuals with work-related low back injuries and illnesses: a systematic review. AB - A systematic review of the literature related to effective occupational therapy interventions in rehabilitation of individuals with work-related low back injuries and illnesses was carried out as part of the Evidence-Based Literature Review Project of the American Occupational Therapy Association. This review evaluated research on a broad range of occupational therapy-related intervention procedures and approaches. Findings from the review indicate that the evidence is insufficient to support or refute the effectiveness of exercise therapy and other conservative treatments for subacute and chronic low back injuries. The research reviewed strongly suggests that for interventions to be effective, occupational therapy practitioners should use a holistic, client-centered approach. The research supports the need for occupational therapy practitioners to consider multiple strategies for addressing clients' needs. Specifically, interventions for individuals with low back injuries and illnesses should incorporate a biopsychosocial, client-centered approach that includes actively involving the client in the rehabilitation process at the beginning of the intervention process and addressing the client's psychosocial needs in addition to his or her physical impairments. The implications for occupational therapy practice, research, and education are also discussed. PMID- 21309371 TI - Creating a clinically useful data collection form for the DASH questionnaire. AB - PURPOSE: We generated a clinically useful data collection form for the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire. This data collection form is designed to aid in measuring change and goal setting. METHOD: Rasch analysis was used to generate three data collection forms for constructs on the DASH (gross motor, fine motor, and symptoms; N = 960). A form was completed to represent the findings from 1 study participant. Admission and discharge data were illustrated for one of the three sections (gross motor activity). Possible goals were indicated on the admission form. The discharge form illustrates whether these goals have been achieved. RESULTS: Figures illustrate the utility of the forms in observing functional change from admission to discharge and how the forms aid in goal setting. CONCLUSION: Use of the data collection form has many positive implications. This type of form could aid in goal setting and treatment planning. PMID- 21309372 TI - Cognitive approach to improving participation after stroke: two case studies. AB - Despite the need for occupational therapy to emphasize client-specific occupational performance, primary emphasis in stroke rehabilitation continues to be on the remediation of client factors and self-care. Such practice leaves many survivors of stroke with continuing performance deficits. Two case studies demonstrate a novel, alternative approach. The Cognitive Orientation to Daily Occupational Performance (CO-OP) treatment is a performance-based, problem solving approach to developing functional skills that are client centered. CO-OP was used to guide treatment with 2 older women. The findings suggest that the approach has the potential to successfully help clients with stroke achieve their everyday occupational goals and support continued research in this area. This work will lead to a pilot randomized controlled trial. PMID- 21309373 TI - Evaluating driving as a valued instrumental activity of daily living. AB - The purpose of this translational research article is to illustrate how general practice occupational therapists have the skills and knowledge to address driving as a valued occupation using an algorithm based on the Occupational Therapy Practice Framework: Domain and Process (2nd ed.; American Occupational Therapy Association, 2008b). Evidence to support the model is offered by a research study. Participants were compared on their performance of complex instrumental activities of daily living (IADLs) and a behind-the-wheel driving assessment. A significant relationship was found between the process skills from the performance assessment and whether the driver passed, failed, or needed restrictions as indicated by the behind-the-wheel assessment. The evidence suggests that occupational therapists using observational performance evaluation of IADLs can assist in determining who might be an at-risk driver. The algorithm addresses how driver rehabilitation specialists can be used most effectively and efficiently with general practice occupational therapy practitioners meeting the needs of senior drivers. PMID- 21309374 TI - Effectiveness of sensory integration interventions in children with autism spectrum disorders: a pilot study. AB - The purpose of this pilot study was to establish a model for randomized controlled trial research, identify appropriate outcome measures, and address the effectiveness of sensory integration (SI) interventions in children with autism spectrum disorders (ASD). Children ages 6-12 with ASD were randomly assigned to a fine motor or SI treatment group. Pretests and posttests measured social responsiveness, sensory processing, functional motor skills, and social-emotional factors. Results identified significant positive changes in Goal Attainment Scaling scores for both groups; more significant changes occurred in the SI group, and a significant decrease in autistic mannerisms occurred in the SI group. No other results were significant. The study discusses considerations for designing future outcome studies for children with ASD. PMID- 21309375 TI - Factors associated with therapists' involvement in children's transition to preschool. AB - We identified factors associated with occupational therapists' involvement as children receiving early intervention services transition into preschool. A survey was sent to members of the American Occupational Therapy Association's School System Special Interest Section. The highest ranked factor for respondents in early intervention was understanding their role (mean [M]= 4.96, standard deviation [SD] = 1.26, n = 78) and for respondents in preschool programs it was having preschool staff value their participation (M = 4.84, SD = 1.46, n = 248). Preschool occupational therapists' relationship with early intervention providers, employer-based supports, and knowledge of the transition process were significantly associated with their involvement in two transition planning areas: collaboration with early intervention programs (p < .001) and family support (p < .001). Findings suggest that practices that enhance relationships among programs influence occupational therapist involvement. Implications for formal training to support involvement in the transition process are discussed. PMID- 21309376 TI - Computer-based rhythm and timing training in severe, stroke-induced arm hemiparesis. AB - OBJECTIVE: We pilot tested the efficacy of computer-based training implementing rhythm and timing in chronic, severe, stroke-induced hemiparesis. METHOD: Two chronic stroke patients were administered the upper-extremity section of the Fugl Meyer Impairment Scale (FM), the Arm Motor Ability Test (AMAT), Stroke Impact Scale (SIS), and Canadian Occupational Performance Measure (COPM). We then administered the computer-based intervention for 60 min, 3 days/wk for 4 wk. One week after intervention, we administered the FM, AMAT, COPM, and SIS. RESULTS: After intervention, participants exhibited reduced arm impairment (indicated by FM scores of + 2.0 and +4.0) and increases in average functional ability (+0.85 and +1.1 points on the AMAT), perceived quality of life (+2.0 and +32.0 points on the SIS), and perception of overall recovery (+10.0 points for each participant on the SIS). CONCLUSION: This study provides preliminary evidence suggesting efficacy of computer-based rhythm and timing in chronic stroke. PMID- 21309377 TI - Caregiver awareness of prone play recommendations. AB - We examined caregiver awareness of the American Academy of Pediatrics' prone play recommendation, determined the primary sources of the recommendation, and examined why some infants are not provided "tummy time." Of caregivers, 25% were not aware of prone play recommendations, and one-fourth of that group was not aware of potential complications from limited tummy time. The primary sources of prone play information and potential complications were printed materials, then pediatricians. Of infants, 53% received < or = 30 min; 35% were intolerant of the prone position. This study indicates that many caregivers are not aware of tummy time and complications that can occur if it is not provided. Health care professionals, including therapists, must educate parents on the importance of prone play and provide information on how to increase infant tolerance for prone play time. PMID- 21309379 TI - How to speak 'Texican'. PMID- 21309378 TI - Is occupational therapy adequately meeting the needs of people with chronic pain? PMID- 21309380 TI - Quo vadis home care and hospice. PMID- 21309381 TI - Home care and hospice in the wake of health care reform: maximizing opportunities, minimizing risk. PMID- 21309382 TI - Successful leaders share their wisdom with home care and hospice executives. PMID- 21309383 TI - George W. Bush headlines NAHC annual meeting speakers. PMID- 21309384 TI - Home care & hospice exposition delivers the goods, high expectations for next year in Las Vegas. PMID- 21309385 TI - Representative Eddie Bernice Johnson, former home care nurse, lauds NAHC and promises action. PMID- 21309387 TI - Chip Bell shares the keys to superlative customer service. PMID- 21309386 TI - Congressman Mike Ross speaks of his advocacy on behalf of aged, infirm, and disabled Americans who need home care and hospice services. PMID- 21309388 TI - John Gray: men-women communication often faulty, yet becomes even more important as they age and need care. PMID- 21309389 TI - IHCTAA, CCHIT cite progress on certification and adoption of health IT. PMID- 21309390 TI - National caring awards honor Mother Teresa in her centennial year. PMID- 21309391 TI - Spreading holiday cheer the techie way. PMID- 21309392 TI - Healing wounds. PMID- 21309393 TI - Inventing the home care organization of the future. PMID- 21309394 TI - Will therapeutic interchange be put off limits by states? PMID- 21309395 TI - Europe, U.S. cooperate on drug regulation. PMID- 21309396 TI - California still golden for pharmacists. PMID- 21309397 TI - UnitedHealthcare's bold effort to deal with cancer drug costs. PMID- 21309398 TI - It's time to get aggressive on patient safety. Interview by John Marcille. PMID- 21309399 TI - ACOs will depend on HIEs, with an assist from plans. PMID- 21309400 TI - Can self-management programs ease chronic conditions? PMID- 21309401 TI - Vision plans hope to gain access to state insurance exchanges. PMID- 21309402 TI - Managing fibromyalgia. PMID- 21309403 TI - Obesity blamed for kids' rising Rx drug use. PMID- 21309404 TI - Aetna's unusual Medicare plan uses ACO-style approach. PMID- 21309405 TI - FDA to act on benlysta, rare new drug for lupus. PMID- 21309406 TI - Reform expected to add 1.1% to plan costs. PMID- 21309407 TI - A new concept for stage grouping of gastric cancer according to dynamic stage migration with time: a survival-period perspective. AB - The aim of this study was to clarify the mechanism of "dynamic stage migration with time". Nine hundred thirty-nine patients with gastric cancer were evaluated in the study. Patients who survived for more than 1, 2, 3, 4, and 5 years after the initial operation were selected. The 6-, 7-, 8-, 9-, and 10-year survival rates from the time of surgery were evaluated for every tumor depth (t)/nodular status (n) group in every stage. The longer the patients survived after the initial operation, the closer the next 5 year survival of patients in the t2n0 group came to that of patients in the t1n0 group; the closer that of t2n1 patients came to that of t1n1; and the closer those of t3n2, t2n2, t2n3, and t3n1 patients came to that of t3n0 patients. A stage grouping at some years after the initial operation is expected to differ from that estimated just after surgery because of the heterogeneity of the disease. PMID- 21309408 TI - Serum p53 antibody is a useful tumor marker of early colorectal cancer. AB - The aim of this study was to evaluate the significance of preoperative serum p53 antibodies (Abs) in patients with colorectal cancer. Between 2007 and 2008, serum p53 Abs were measured by enzyme-linked immunoabsorbent assay in 100 consecutive patients with colorectal cancer. Relationships between clinicopathologic features and the preoperative presence of serum p53 Abs were evaluated. Serum p53 Abs were positive in approximately 30%, regardless of the depth of tumor invasion--sm (submucosa), mp (muscularis propria), or ss (subserosa). Two patients among 23 T1 patients (9%) had lymph node metastasis. These 2 patients belonged to a group of 7 patients who were determined positive for serum p53 Abs (29%), although none of 16 patients negative for serum p53 Abs had lymph node metastasis, regardless of vascular invasion. Preoperative serum p53 Abs do not seem to be a marker of tumor progression but may be a useful marker for detecting high risk of lymph node metastasis in T1 colorectal cancer. PMID- 21309410 TI - Early readmission is a predictor of overall survival following isolated lung transplantation. AB - Causes of early readmissions following lung transplantation are not well understood, and the impact is poorly reported. We reviewed 221 consecutive lung transplantations and identified patients readmitted within 90 days. A case control analysis was performed to determine the characteristics that predict readmission and the impact of readmission on survival. Ninety (44%) of the 205 operative survivors required a total of 125 readmissions during the 90 days after transplantation. Twenty-eight patients (13.7%) required multiple readmissions. Causes for readmissions were pulmonary complication (59%), gastrointestinal (18%), cardiac (5%), metabolic (2.5%), neurological (2.5%), hematological (2%), and miscellaneous (11%). The sex, native disease, or type of transplant did not predict readmission. Requirement of cardiopulmonary bypass for transplantation showed a trend toward significance (P = 0.08). The 90-day conditional survival at 1, 3, and 5 years for those patients readmitted within 90 days were 76%, 59%, and 52%, respectively, compared to 93%, 80%, and 76% for patients not readmitted (P = 0.01). Requirement for readmission within 90 days following transplantation is associated with increased mortality. Sex, native disease, and type of transplant are not predictors of readmission or survival. PMID- 21309409 TI - Thyroid surgery without cut and tie: the use of Ligasure for total thyroidectomy. AB - Total thyroidectomy is the surgical preferred procedure for the treatment of benign and malignant disease. The purpose of this research was to evaluate total thyroidectomy operation by Ligasure in comparison with total thyroidectomy by the traditional technique that uses clamp and tie. We evaluated 256 patients. In 144 patients (56%), we used Ligasure without tie for total thyroidectomy; in the remaining 112 patients (44%), we used clamp and tie. The middle values of the variables examined were inferior (P < 0.0005) in the Ligasure group compared with the clamp and tie group. Only the middle value of operating room costs was higher in the first group than in the second, balanced by a decreased hospital stay of two days. Ligasure can be safely used for total thyroidectomy, because there is a meaningful difference in the distribution of variance between the two groups. There are decreasing risks of parathyroid gland and laryngeal nerve injury in the Ligasure group. PMID- 21309411 TI - Kidney transplantation in a patient with aortic bi-iliac endovascular graft: case report and literature review. AB - Arterial hypertension is a leading cause of both vascular diseases and chronic renal failure. With the increasing incidence of patients suffering from hypertensive vascular disease, namely aorto-iliac atherosclerosis and aneurysms, more candidates are referred for kidney transplantation (KT). Staged or simultaneous surgical repair of aorto-iliac lesions with KT have long been described and studied. In this report, we discuss the case of a patient with infrarenal abdominal aortic aneurysm, having an endovascular bifurcated aortic bi iliac stent (EVBAIS) introduced, who underwent a KT 3 months after his vascular surgery without any postoperative complication. This case, as well as other previous studies, supports the fact that the presence of an EVBAIS does not contraindicate KT. PMID- 21309412 TI - Combination of hiatal hernia with nonspecific esophageal motility disorder (NEMD) successfully treated with thoracic and abdominal surgery: report of a case. AB - A 74-year-old woman was admitted to Gunma University Hospital because of dysphagia symptoms. A gastrointestinal contrast study demonstrated a large esophageal hiatal sliding hernia affecting the passage of barium at the lower end of the esophagus. Manometric studies showed hypotensive pressure in the lower esophageal sphincter (LES) and relaxation failure of the LES during swallowing. We diagnosed a combination of sliding hiatal hernia with nonspecific esophageal motility disorder (NEMD). Thoracoscopically assisted Heller myotomy and Dor fundoplication by abdominal open surgery were then performed. The patient is currently well and is free from dysphagia symptoms. Treatment with combination thoracoscopic and abdominal open surgery was effective. We report here the first case of combined hiatal hernia with NEMD treated by thoracoscopic and abdominal open surgery. PMID- 21309413 TI - The use of the radial recurrent fasciocutaneous flap in interposition arthroplasty of elbow ankylosis case report and review of literature. AB - Elbow ankylosis and its management remain a challenge in the developing countries like Nigeria because of many factors, including the absence of elbow replacement surgery. Current operative management, which is interposition arthroplasty with fascia lata or arthrodesis in a more functional position, is commonly complicated with donor site morbidity and restricted functionality, respectively. We report the use of the regional radial recurrent fasciocutaneous flap of the arm as an interposition material for an ankylosed elbow after excision of the bone block, with no donor site morbidity and improved range of elbow motion. At 4 years postoperatively, patient is very satisfied with functionality. Additionally, this method of managing elbow ankylosis uses a vascularized and durable flap, is cheap, and has less operation time, and thus is highly recommended. PMID- 21309414 TI - Profile of pediatric abdominal surgical emergencies in a developing country. AB - We aim to determine the profile and determinants of outcome of pediatric abdominal surgical emergencies in southeastern Nigeria. We prospectively analyzed 115 children with abdominal surgical emergencies managed at the University of Nigeria Teaching Hospital, Enugu, Nigeria, from January 2008 to June 2009. The emergencies were typhoid intestinal perforation (TIP) 22 (19.1%), intussusception 20 (17.4%), obstructed hernia 17 (14.8%), neonatal intestinal obstruction 11 (9.6%), appendicitis 11 (9.6%), trauma 8 (6.9%), ruptured omphalocele/gastroschisis 8 (6.9%), Hirschsprung's disease 7 (6.1%), adhesive bowel obstruction 7 (6.1%), and malrotation 4 (3.5%). The mean time to diagnosis was 3.5 days (range, 4 hours to 12 days). Ninety-three cases had an emergency operation, while 22 were managed nonoperatively. After a mean hospital stay of 10.8 days (range, 2-38 days), 35 (37.6%) of the operated patients had one or more postoperative complications. There were 10 (8.7%) deaths. Overall, TIP had a higher postoperative complication rate (P < 0.001), while neonates had a higher mortality (P < 0.001). Delayed presentation and lack of neonatal and pediatric intensive care facilities were daunting challenges. A pediatric abdominal surgical emergency in our setting has high morbidity and mortality. Efforts geared towards improvement in time to diagnosis and perioperative care may result in better outcomes. PMID- 21309415 TI - Hemosuccus pancreaticus caused by a primary splenic artery aneurysm as a rare cause of gastrointestinal bleeding: report of a case. AB - Hemosuccus pancreaticus is a rare complication of chronic pancreatitis. It is defined as hemorrhage from the papilla of Vater via the pancreatic duct. A 77 year-old man presented with a history of intermittent episodes of hematemesis and abdominal pain. Upper gastrointestinal endoscopy showed no obvious bleeding point, but clots were seen in the stomach and duodenum. Computed tomography (CT) showed a splenic artery aneurysm, and we diagnosed hemosuccus pancreaticus caused by rupture of the aneurysm into the main pancreatic duct. We performed distal pancreatectomy, during which we found the splenic artery aneurysm with thrombus in the pancreatic tail. Angiography of the resected specimen showed the splenic artery aneurysm and the communication with the main pancreatic duct. Microscopic examination revealed a true aneurysm of the splenic artery. Interventional radiology is commonly performed for diagnosis and treatment, but arterial embolization has a high recurrence rate. Thus, surgery is still required for hemosuccus pancreaticus. PMID- 21309416 TI - Expansion of CD25+CD4+ regulatory T cells by natural mature dendritic cells. AB - Because of the anergy of CD25+CD4+ regulatory T cells, it is unclear how the number of these regulatory T cells is sustained and expanded in normal physiologic circumstances. In the present study, we examined the effect of natural allogeneic mature dendritic cells (DCs) on the proliferation and function of CD25+CD4+ T cells. Our data showed that natural allogeneic mature DCs stimulated CD25+CD4+ T-cell growth vigorously, whereas immature DCs had little effect on the proliferation of CD25+CD4+ T cells. After expansion by mature DCs, CD25+CD4+ T cells maintained their expression of Foxp3 and suppressed the proliferation of CD25- CD4+ T cells similar to freshly isolated CD25+CD4+ T cells. Our results introduce a potentially critical role played by natural allogeneic mature DCs, which exist in normal physiologic circumstances, in controlling CD25+CD4+ regulatory T-cell expansion and function. PMID- 21309417 TI - Sliding inguinal hernia with incarceration of urinary bladder diverticulum in a child. AB - Although inguinal herniorrhaphy is generally safe, certain complications can occur even with an experienced pediatric surgeon. We present a case of sliding right inguinal hernia with incarceration of urinary bladder diverticulum in a 2 year-old boy. A small perforation at the anterior wall of the urinary bladder, peritonitis, and kinking of the sigmoid colon occurred after the herniorrhaphy. He received exploratory laparotomy for repairing the urinary bladder perforation hole and drainage of the ascites. An anal tube was inserted to keep the sigmoid colon patent. The patient recovered from this insult gradually with an uneventful postoperative course 10 months after the operation, until the writing of this study. Surgeons should be aware of the possibility of urinary bladder diverticulum incarceration at the inguinal canal and should perform the operation meticulously. PMID- 21309418 TI - A case of appendiceal Crohn's disease in which a laparoscopic appendectomy was performed. AB - A 74-year-old female had occasionally experienced right lower abdominal pain in the past. She underwent a barium enema examination during a medical checkup, which revealed a wall irregularity around the appendix, but the appendix itself was not visualized. The patient was referred to our hospital for possible appendiceal neoplasm. Colonoscopy revealed a tumor-like protrusion with marked redness at the entrance to the appendix. Pathologic analysis of biopsy specimens revealed only inflammatory cells. Differential diagnosis of appendiceal Crohn's disease or appendiceal neoplasm was made, and laparoscopic appendectomy was performed. Pathologic examination revealed inflammation in all layers of the appendiceal wall and noncaseating epithelioid cell granuloma, and a diagnosis of appendiceal Crohn's disease was made. The postoperative course was uneventful, and the patient was discharged from the hospital 3 days after surgery. No sign of recurrence has been observed up to now, 6 months after surgical treatment. PMID- 21309419 TI - Changes of glomerular filtration after nephrectomy in living donor. AB - A possible complication after donor nephrectomy is a decrease in glomerular filtration rate. The goal of our investigation is to estimate the function of the remaining donor kidney in the first 6 months after nephrectomy using the equations Cockcroft-Gault, Modification of Diet in Renal Disease 1 (MDRD1) and MDRD2. In addition to basic age and sex data, we collected standard biochemical data from blood: creatinine, blood urea nitrogen, and albumin. Blood samples and diuresis were taken at -1, 0, 1, 2, 3, 7, and 14 days, and after 6 months. Our results show that glomerular filtration rate decreases after nephrectomy and stabilizes after 6 months in values significantly lower compared with predonation values. Both MDRD estimations show that these donors after nephrectomy are patients in the third degree of chronic kidney disease, and we can predict that older donors and those with comorbidities very soon will need a treatment for chronic kidney disease. For glomerular filtration rate estimation, we recommend the MDRD2 equation. All donors must have long-term follow-up and treatment, because there is a possibility of eventual cardiovascular and metabolic diseases. PMID- 21309420 TI - The herbal medicine daikenchuto ameliorates an impaired anorectal motor activity in postoperative pediatric patients with an anorectal malformation--a pilot study. AB - Fecoflowmetry (FFM) has been introduced to simulate natural anorectal evacuation. So far, few reports have described the effect of the herbal medicine Daikenchuto (DKT) on impaired anorectal motor function. The aim of this pilot study was to assess anorectal motor function by FFM in postoperatively impaired patients with an anorectal malformation (ARM) before and after administration of DKT. Six postoperative patients with ARM (mean age, 7.8 years) who complained of intractable constipation with soiling in spite of administration of magnesia as a laxative were assessed over an extended period. These patients received 0.3 g/kg/d of DKT for an average of 128 days. Evacuative rate and maximum fecal stream flow were seen to increase significantly after administration of DKT when compared with values before administration of DKT. In conclusion, DKT had a favorable clinical effect on anorectal motor function in postoperative patients with ARM. PMID- 21309421 TI - A case of fulminant amebic colitis with multiple large intestinal perforations. AB - Amebic colitis normally causes mucous and bloody diarrhea stool as predominant symptoms, thus leading to a course of chronic colitis. However, though rare, there exists a fulminating type that causes intestinal perforations due to wide necrosis of the large intestine. We encountered a case of fulminant amebic colitis that lead to death due to multiple large intestinal perforations. The patient was a 72-year-old female. The patient was admitted to our hospital with symptoms of fever, abdominal pain, and diarrhea. She continued to have a fever of over 38 degrees C and increased left abdominal pain. An abdominal computed tomography scan revealed free gas on the abdominal side of the kidney. Therefore, gastrointestinal perforations were diagnosed and surgery was performed. In surgery, many perforated parts were observed from the appendix to the descending colon, and subtotal colectomy was performed. However, sepsis and disseminated intravascular coagulation occurred, and the patient died on the eighth postoperative day. PMID- 21309422 TI - Malignant granular cell tumor in the gluteal region with unusual pathologic features. AB - Malignant granular cell tumors (MGCTs) are very rare soft tissue sarcomas. Definite criteria for pathologic diagnosis and the optimal treatment strategy have not been fully established. Here, we describe a 76-year-old woman with a huge MGCT in the right gluteal region, who developed a local recurrence and died from that tumor 14 months after undergoing an operation for the primary tumor. Although microscopic examination revealed that round and granular tumor cells staining for S-100 protein were dominant, components of the spindle cell sarcoma reacting with alpha smooth muscle actin were partially observed. MGCT is believed to originate from Schwann cells; however, pathologic findings in our case showed both Schwannian and non-Schwannian features. This is the first report on MGCT with these 2 features appearing simultaneously. PMID- 21309423 TI - Recidive of renal cell carcinoma tumor thrombus in inferior vena cava via lumbar vein. AB - Renal cell carcinoma (RCC) develops tumor thrombus in the renal vein and inferior vena cava (IVC) in 10% of cases. Surgical treatment is radical nephrectomy and thrombectomy of the IVC. Local recidive can develop in the lumbar fossa, lymph nodes, and the IVC. We report a 58-year-old patient admitted to the Clinic for Urology at the Military Medical Academy, Belgrade, Serbia, in February 2009 with RCC of the left kidney and tumor thrombus in the IVC. After ultrasonography exam and multislice computed tomography scan, we performed radical nephrectomy and thrombectomy of the IVC (level II). Four months after the operation, ultrasound exam and cavography showed intracaval and paracaval recidive tumor masses in the renal part of the IVC. On operation we removed intraluminal IVC thrombus, which arises from the lumbar vein on the IVC posterior wall, with paracaval thrombus in the lumbar vein. We conclude that RCC tumor thrombus can spread from the kidney to the IVC through the lumbar vein. PMID- 21309427 TI - Ardent campaigners. AB - For some nurses, their commitment to caring goes beyond the bedside into trying to make things better for everyone. PMID- 21309428 TI - Freedom to innovate. AB - Clinicians discuss the benefits and challenges of the community foundation trust model for delivering healthcare services in England. PMID- 21309429 TI - Use of ketamine in uncontrolled acute and procedural pain. AB - This article explores the role of ketamine in pain management. Ketamine is an analgesic used to treat uncontrolled acute and procedural pain. It has protective properties and can prevent patients from developing persistent pain. In sub anaesthetic analgesic doses, ketamine is a safe drug and produces minimal side effects. PMID- 21309430 TI - Discussing sexuality with patients in a motor neurone disease clinic. AB - Sexual relationships remain an important aspect of life for people living with motor neurone disease. This article explores the use of the Extended-PLISSIT model when discussing relationships and sexual function with patients and their partners in a motor neurone disease clinic. The model provides a structured approach to assist discussions with patients as well as promoting reflection and exchange of knowledge in the multidisciplinary team. It is a useful model when addressing issues that are sometimes difficult to discuss. PMID- 21309431 TI - Hepatitis C virus infection: risk factors, diagnosis and management. AB - This article focuses on the risk factors, diagnosis and management of patients with chronic hepatitis C virus infection. It describes treatment options and the role of the nurse in caring for patients who are undergoing therapy. PMID- 21309432 TI - Vital signs. PMID- 21309433 TI - Paper trail of evidence. PMID- 21309434 TI - Stand and deliver. PMID- 21309435 TI - All kinds of voices. PMID- 21309436 TI - Girls with attention-deficit/hyperactivity disorder: EEG differences between DSM IV types. AB - This study investigated EEG differences between the Combined and Inattentive types of Attention-Deficit/Hyperactivity Disorder (AD/HD) in girls. Thirty girls with AD/HD of the Combined type, 30 girls with the inattentive type, and 30 controls (aged 8-12 years) had a resting eyes-closed EEG recorded from 21 electrodes. The EEG was Fast Fourier Transformed and estimates for total power, and absolute and relative power in the delta, theta, alpha and beta frequency bands, were analyzed in nine cortical regions. Across the scalp, girls with AD/HD had elevated total power, elevated absolute delta and theta, reduced relative delta and beta, and increased relative theta compared with controls. Compared with the Inattentive group, the Combined group had greater right hemisphere absolute theta and greater midline posterior absolute beta activity. The Combined group also had reduced right hemisphere relative delta, greater left hemisphere relative theta, reduced midline posterior relative alpha and reduced central relative beta activity. In conclusion, girls with AD/HD had increased slow wave (delta and theta) activity and reduced beta activity, which are robust results in the predominantly-male AD/HD literature, and exhibited the elevated theta/beta abnormality. The lack of global differences between DSM-IV AD/HD types differs from previous studies of boys and mixed-sex groups. The present results highlight the homogeneity of EEG profiles in AD/HD girls, which could be due to sex-bias in the diagnostic criteria. This study is the first to investigate EEG differences between the Inattentive and Combined types of AD/HD with a purely female sample. PMID- 21309437 TI - Fuzzy synchronization likelihood with application to attention deficit/hyperactivity disorder. AB - Synchronization as a measure of quantification of similarities in dynamic systems is an important concept in many scientific fields such as nonlinear science, neuroscience, cardiology, ecology, and economics. When interdependencies and connections of coupled dynamic systems are not directly accessible and measurable such as those of the neurons of the brain, quantification of similarities between their time series outputs is the best possible way to detect the existent interdependencies among them. In recent years, Synchronization Likelihood (SL) has been used as one of the most suitable algorithms in highly nonlinear and non stationary systems. In this method, the likelihood of patterns is measured statistically, and then it is determined which patterns of the time series are similar to each other considering a threshold. But the degree of similarities is not considered in the decision. In this paper, a new measure of synchronization, fuzzy SL, is presented using the theory of fuzzy logic and Gaussian membership functions. The new fuzzy SL is compared with the conventional SL using both a standard problem from the chaos literature and a complicated real life neurological diagnostic problem, that is, the EEG-based diagnosis of Attention Deficit/Hyperactivity Disorder (ADHD). The results of ANOVA analysis indicate the interdependencies measured by the fuzzy SL are more reliable than the conventional SL for discriminating ADHD patients from healthy individuals. PMID- 21309438 TI - Rapid automatized naming and lexical decision in children from an electrophysiological perspective. AB - Rapid Automatized Naming (RAN) deficits have been associated with less developed orthographic abilities that may affect lexical decisions. The effects of Spanish speaking children's RAN performance on lexical decisions were evaluated by analyzing ERP and behavioral measures. Based upon their naming speed in four RAN tasks, 28 normal IQ, right-handed, 7-year-old children were selected and divided uniformly into two groups: average-naming (AN), and slow-naming (SN). ERPs were obtained during a lexical decision task consisting of 100 strings of four sequentially-presented letters that completed words (50 trials) or pseudowords (also 50 trials). The SN group showed major reading difficulties when compared to the AN group, as well as a significantly lower number of correct responses and slower reaction times in the lexical task. Two main ERP components were observed: parietal N320, interpreted as analogous to N170/N200; and a subsequent P3-like component (P500) with a higher amplitude for pseudowords, which probably reflects higher cognitive demands. Better reading comprehension and fewer misread pseudowords correlated with minor N320 latencies, while lower N320 amplitudes for words correlated with faster reading speeds, lower naming times and fewer errors while reading a text. The present results suggest that naming speed and ERP seem to be valuable in distinguishing early orthographic stored code retrieval abilities through a lexical decision task. Moreover, RAN and ERP emerge as accurate tools for evaluating reading processes in the early stages of reading acquisition. PMID- 21309439 TI - The use of permutation entropy to characterize sleep electroencephalograms. AB - This work proposes the use of Permutation Entropy (PE), a measure of time-series complexity, to characterize electroencephalogram (EEG) signals recorded during sleep. Such a measure could provide information concerning the different sleep stages and, thus, be utilized as an additional aid to obtain sleep staging information. PE has been estimated for artifact-free 30s segments from more than 80 hours of EEG records obtained from 16 subjects during all-night recordings, from which the mean PE for each sleep stage was obtained. It was found that different sleep stages are characterized by significantly different PE values, which track the physiological changes in the complexity of the EEG signals observed at the different sleep stages. This finding encourages the use of PE as an additional aide to either visual or automated sleep staging. PMID- 21309440 TI - Amygdalar hyperactivity, a fear-related link between panic disorder and mesiotemporal epilepsy. AB - The sudden onset, short duration and stereotyped features of panic attacks, and the fear aura of seizures starting at the mesial aspects of the temporal lobe, suggest common mechanisms underlying panic disorder (PD) and mesiotemporal epilepsy (MTLE). However, current consensus emphasizes the importance of differentiating the two entities based on 1) intact consciousness in panic attacks, 2) poor response to antiepileptics, and 3) unsuccessful electrophysiological attempts to demonstrate a relationship. We report two cases with a diagnosis of PD that had been partially responsive to first line treatments. During the EEG session, both patients developed panic symptoms with minimal EEG changes in response to paper bag-hyperventilation (PB-HV), and several minutes later presented a clear ictal EEG pattern associated with very different clinical symptoms, but both with strong fear content. Z-scored LORETA analysis showed increased current source densities (CSD) at the right amygdala in both subjects during the induced panic symptoms. Several areas were involved during the seizure, different in each subject. Yet, a very significant increase at the amygdala was found in both cases. The LORETA Z-scored source correlation (LSC) analysis also showed similar abnormal patterns during the panic symptoms in both patients, and marked differences during the seizure. These findings show a major role of amygdalar hyperactivity in both fear-related conditions for the two patients, and are discussed in relation to existing models of PD in general. Abnormal overactivation at mesiotemporal regions is poorly represented at the surface recordings but can be detected by the appropriate analytical techniques. PMID- 21309441 TI - Low-frequency repetitive transcranial magnetic stimulation for the treatment of refractory partial epilepsy. AB - Seventeen refractory partial epilepsy patients were enrolled in an open-label study to evaluate the antiepileptic effect of low-frequency repetitive transcranial magnetic stimulation (rTMS). Seven of the patients had not obtained seizure-free status after epileptogenic focus resection surgery before they were enrolled in the study. All patients were treated with low-frequency rTMS which included 3 sessions per day (0.5 Hz, 90% RMT and 500 pulses each session) and lasted for 2 weeks. Seizure frequency, seizure days and epileptic discharges in the EEG obtained before, during and after stimulation were compared. The psychological conditions of all individual patients were evaluated with Symptom Checklist-90 (SCL-90) before and after rTMS treatment. Mean seizure frequencies per week significantly decreased in the following 4-week rTMS treatment period compared with the pretreatment period (14.09 vs. 5.63, p < 0.05, mean reduction of 60.02% in seizure frequency). Mean seizure days per week during the treatment period and the post-treatment period were lower than that of the pretreatment period (5.18 vs. 2.99 p < 0.05, mean reduction of 42.5% in seizure days). Mean epileptic discharges in the EEG decreased significantly during the treatment period compared to that of the pre-treatment period (78.60 vs. 66.09, p < 0.05, mean reduction of 15.9% in epileptic spikes discharges) in all 17 patients. Fourteen patients completed the test of Symptom Checklist-90 effectively. The scales of Global Severity Index, Depression, Anxiety, Phobic anxiety, Paranoid ideation, Psychoticism, Somatization, Obsession-compulsion, Interpersonal sensitivity, Hostility in patients decreased respectively at the post-treatment periods compared with those of the pre-treatment periods (P < 0.05). Low frequency rTMS may have a significant antiepileptic effect in patients with refractory partial epilepsy. Additionally, our results indicate rTMS treatment can improve the psychological condition of these patients. PMID- 21309442 TI - Individualized alpha activity and frontal asymmetry in major depression. AB - Lateralized differences in frontal alpha power in individuals with major depressive disorder (MDD) are thought to reflect an aberrant affective processing style. However research into anterior alpha asymmetry and MDD has often produced conflicting results. The current study aimed to investigate whether individualized alpha bandwidths provide a more sensitive measure of anterior alpha asymmetry in MDD than the traditional fixed 8-13 Hz alpha band. Resting EEG was recorded from 34 right-handed female participants (18 controls, 16 MDD). Each participant's Individual Alpha Frequency was used to delineate a broad individualized alpha band and three individualized narrow alpha sub-bands: lower alpha1, lower alpha 2 and upper alpha. Activity within the broad and narrow individualized bandwidths and within the traditional fixed alpha band were used to compare a) controls and acutely depressed individuals and b) medicated and unmedicated MDD participants. Individualizing and subdividing the alpha bandwidth did not add appreciably to the sensitivity of anterior alpha asymmetry in MDD as no significant differences in lateralized alpha power between controls and MDD participants were observed in any alpha bandwidth. This finding was consistent under two reference schemes and across multiple scalp locations. Within the MDD group, antidepressant use was associated with significantly greater right than left hemispheric power in the lower alpha 1 band. The relevance of this finding is discussed in relation to the electrophysiological correlates of antidepressant medication use, lateralized differences in affective processing and treatment resistant MDD. PMID- 21309443 TI - Decreased delta event-related synchronization in patients with early vascular dementia. AB - Electroencephalogram (EEG) activity, recorded while performing an "odd ball" detection task, was compared between patients with early vascular dementia (VD), healthy young controls and healthy elderly controls performing the same task. The data were analyzed using the event-related synchronization/desynchronization (ERS/ERD) method. VD patients, compared with controls, showed decreased ERS effects in the delta frequency band (0.5-3.5Hz) of EEG after the target stimulus appeared in frontal, central and parietal regions. Similarly, elderly controls also showed a decreased ERS compared with young controls only in central and parietal regions. As part of this analysis, we introduce a novel quantitative index, the Event-related Energy Change Progression (EECP), which provides a reliable measure that distinguishes these groups and thereby provides a promising marker for early diagnosis of VD. PMID- 21309444 TI - QEEG-guided neurofeedback for recurrent migraine headaches. AB - Seventy-one patients with recurrent migraine headaches, aged 17-62, from one neurological practice, completed a quantitative electroencephalogram (QEEG) procedure. All QEEG results indicated an excess of high-frequency beta activity (21-30 Hz) in 1-4 cortical areas. Forty-six of the 71 patients selected neurofeedback training while the remaining 25 chose to continue on drug therapy. Neurofeedback protocols consisted of reducing 21-30 Hz activity and increasing 10 Hz activity (5 sessions for each affected site). All the patients were classified as migraine without aura. For the neurofeedback group the majority (54%) experienced complete cessation of their migraines, and many others (39%) experienced a reduction in migraine frequency of greater than 50%. Four percent experienced a decrease in headache frequency of < 50%. Only one patient did not experience a reduction in headache frequency. The control group of subjects who chose to continue drug therapy as opposed to neurofeedback experienced no change in headache frequency (68%), a reduction of less than 50% (20%), or a reduction greater than 50% (8%). QEEG-guided neurofeedback appears to be dramatically effective in abolishing or significantly reducing headache frequency in patients with recurrent migraine. PMID- 21309445 TI - To report or not to report: a psychosocial investigation aimed at improving early detection of avian influenza outbreaks. AB - The aim of this study was to identify difficulties and barriers to reporting clinically suspect situations, possibly caused by avian influenza (AI), and to explore possible incentives to reporting such situations, with the ultimate aim of facilitating early detection of AI outbreaks. Focus group sessions were held with policy-makers from the competent authority, representatives of veterinary practitioners and poultry farmers. Personal interviews with a group of poultry farmers and practitioners were held to ascertain the difficulties and barriers they perceived and their proposed solutions. An electronic questionnaire was put on the websites of a poultry farmer union and the Royal Dutch Veterinary Association to investigate perceptions and attitudes concerning AI-suspect situations in The Netherlands. Six themes emerged identifying factors that hinder the reporting of a clinically suspect situation: lack of knowledge and uncertainty about clinical signs of AI; guilt, shame and prejudice; negative opinion of control measures; dissatisfaction with post-reporting procedures; lack of trust in veterinary authorities; lack of transparency in reporting procedures and uncertainty about the notification process. Recommendations to facilitate early detection of AI are discussed. PMID- 21309446 TI - The OIE World Animal Health Information System: the role of OIE Reference Laboratories and Collaborating Centres in disease reporting. AB - One of the main objectives of the World Organisation for Animal Health (OIE) is to ensure transparency in and knowledge of the world animal health situation. To achieve this objective, the OIE relies on its network of Member Countries, which is complemented by the activities of 221 Reference Laboratories (RLs) and Collaborating Centres. The RL mandate states that, in the case of positive results for diseases notifiable to the OIE, the laboratory should inform the OIE Delegate of the Member Country from which the samples originated and send a copy of the information to OIE Headquarters. However, since 2006 the OIE has received a lower than expected number of notifications from RLs, which implies eitherthat the majority of samples are sent to national laboratories or that some RLs are not fully complying with their mandate. The OIE sent a questionnaire to RLs in preparation for the Second Global Conference of OIE Reference Laboratories and Collaborating Centres (Paris, France, 21-23 June 2010). Two main factors emerged: the need for RLs to clarify their role and responsibilities in disease reporting and the need for an awareness campaign to sensitise national Veterinary Services to the importance of conducting more surveillance (and consequently of submitting samples to RLs) for all OIE-listed diseases. Reference laboratories indicated two main reasons for not sharing more data on positive samples with the OIE: i) a perceived contradiction between their mandate as OIE RLs and the standards of the International Organization for Standardization (ISO) dealing with confidentiality; and ii) certain Member Countries or stakeholders asking RLs not to share positive results with the OIE, for political or economic reasons. The OIE has put forward proposals to help RLs resolve these problems in future. The use of ISO standards must be clarified and there must be improved communication between the OIE and its RLs. A lack of transparency about a significant disease event can jeopardise the biosecurity of several countries, an entire region or even the whole world. The reference status of a non-transparent RL could be questioned. PMID- 21309447 TI - Assessment of exposure to bovine spongiform encephalopathy in a hypothetical country. AB - The authors present a basic quantitative spreadsheet model to evaluate the risk of bovine spongiform encephalopathy (BSE) within a national setting. The model is based on information from BSE risk assessments undertaken in Latin American countries. The analysis focuses on the level of regulatory implementation and its impact over different time periods and estimates the potential impact if one BSE infected animal is introduced into the production cycle. The information is consolidated so that the results of the evaluation can be presented for a hypothetical country, 'Country X'. Evaluating the BSE cycle within a country may help in making decisions on where preventive or control measures should be placed and/or enforced. Such an evaluation may also be used as the exposure assessment of a risk assessment, recommended by the World Organisation for Animal Health to determine the BSE risk status of a given country. PMID- 21309448 TI - Development of a semi-quantitative evaluation system for surveillance of bovine spongiform encephalopathy, using the analytic hierarchy process. AB - Evaluating surveillance results is important in estimating the risk of bovine spongiform encephalopathy (BSE) cases in a particular country, or in countries from which products are imported. Although various methods have been proposed for quantitative evaluation of surveillance results, no methods focusing on surveillance from a qualitative perspective have yet been established. The authors have developed an objective method for evaluating the qualitative aspects of BSE surveillance, based on the analytic hierarchy process. Factors related to surveillance credibility were selected through expert meetings and arranged in a hierarchical structure. These evaluation factors were also weighted, so that a points system could be used for evaluation. As a result, 13 evaluation factors comprising three-layer hierarchies were generated. When surveillance in Japan before and after a BSE case was evaluated using this evaluation system, an improvement in the quality of the surveillance was observed after the outbreak. Although this study suggests that the selection of the experts had a significant effect on the outcome, the authors believe that this method will also be applicable for establishing qualitative evaluation systems for other diseases. PMID- 21309449 TI - Mapping cattle trade routes in southern Somalia: a method for mobile livestock keeping systems. AB - The Somali economy is the only one in the world in which more than half the population is dependent on nomadic pastoralism. Trade typically involves drovers trekking animals over long distances to markets. A pilot approach for mapping trade routes was undertaken, using the Afmadow to Garissa routes in southern Somalia. The methodology included conducting a workshop with traders to gather preliminary information about the most-used routes and general husbandry practices and training selected drovers to collect data about key features along the routes, using hand-held global positioning system (GPS) devices, radio collar GPS and pictorial data forms. Collected data were then integrated into geographic information systems for analysis. The resultant spatial maps describe the Afmadow to Garissa routes, the speed of livestock movement along these routes and relevant environmental and social features affecting this speed. These data are useful for identifying critical control points for health screening along the routes, which may enable the establishment of a livestock certification system in nomadic pastoral environments. PMID- 21309450 TI - A sero-survey of rinderpest in nomadic pastoral systems in central and southern Somalia from 2002 to 2003, using a spatially integrated random sampling approach. AB - A cross-sectional sero-survey, using a two-stage cluster sampling design, was conducted between 2002 and 2003 in ten administrative regions of central and southern Somalia, to estimate the seroprevalence and geographic distribution of rinderpest (RP) in the study area, as well as to identify potential risk factors for the observed seroprevalence distribution. The study was also used to test the feasibility of the spatially integrated investigation technique in nomadic and semi-nomadic pastoral systems. In the absence of a systematic list of livestock holdings, the primary sampling units were selected by generating random map coordinates. A total of 9,216 serum samples were collected from cattle aged 12 to 36 months at 562 sampling sites. Two apparent clusters of RP seroprevalence were detected. Four potential risk factors associated with the observed seroprevalence were identified: the mobility of cattle herds, the cattle population density, the proximity of cattle herds to cattle trade routes and cattle herd size. Risk maps were then generated to assist in designing more targeted surveillance strategies. The observed seroprevalence in these areas declined over time. In subsequent years, similar seroprevalence studies in neighbouring areas of Kenya and Ethiopia also showed a very low seroprevalence of RP or the absence of antibodies against RP. The progressive decline in RP antibody prevalence is consistent with virus extinction. Verification of freedom from RP infection in the Somali ecosystem is currently in progress. PMID- 21309451 TI - Methodology of the biological risk classification of animal pathogens in Belgium. AB - Since many micro-organisms are a biological hazard, they have been categorised into risk groups by many countries and organisations and classification lists have been developed. Current classification systems rely on criteria defined by the World Health Organization, which cover the severity of the disease the micro organism might cause, its ability to spread and the availability of prophylaxis or efficient treatment. Animal pathogens are classified according to the definitions of the World Organisation for Animal Health, which also consider economic aspects of disease. In Europe, classification is often directly linked to containment measures. The Belgian classification system, however, only considers the inherent characteristics of the micro-organism, not its use, making the risk classification independent of containment measures. A common classification list for human and animal pathogens has been developed in Belgium using as comprehensive an approach as possible. The evolution of scientific knowledge will demand regular updating of classification lists. This paper describes the Belgian risk classification system and the methodology that was used for its peer-reviewed revision (with a focus on animal pathogens). PMID- 21309452 TI - Animal production food safety: priority pathogens for standard setting by the World Organisation for Animal Health. AB - In this short study, expert opinion and a literature review were used to identify the pathogens that should be prioritised by the World Organisation for Animal Health (OIE) for the development of future standards for animal production food safety. Prioritisation was based on a pathogen's impact on human health and amenability to control using on-farm measures. As the OIE mandate includes alleviation of global poverty, the study focused on developing countries and those with 'in-transition' economies. The regions considered were Eastern Europe, Asia, the Middle East, Africa and South America. Salmonella (from species other than poultry) and pathogenic Escherichia coli were considered to be top priorities. Brucella spp., Echinococcus granulosus and Staphylococcus aureus were also mentioned by experts. As Salmonella, and to a lesser extent pathogenic E. coli, can be controlled by on-farm measures, these pathogens should be considered for prioritisation in future standard setting. On-farm control measures for Brucella spp. will be addressed in 2010-2011 in a review of the OLE Terrestrial Animal/Health Code chapter on brucellosis. In Africa, E. granulosus, the causative agent of hydatidosis, was estimated to have the greatest impact of all pathogens that could potentially be transmitted by food (i.e. via contamination). It was also listed for the Middle East and thought to be of importance by both South American experts consulted. Taenia saginata was thought to be of importance in South America and Africa and by one expert in the Middle East. PMID- 21309453 TI - Canine leishmaniosis and euthanasia in Italy: a critical legal-ethical analysis. AB - The increasing awareness that control of zoonotic visceral leishmaniosis (ZVL) depends on effective control of canine leishmaniosis has promoted research into leishmanial infection in dogs, but has also encouraged the indiscriminate elimination of seropositive dogs. Public health campaigns in various parts of the world (e.g. in Brazil and China) are designed to reduce the incidence of human ZVL by targeting/killing dogs. However, not all situations are the same; in Italy, for example, there would be little support for this type of control measure because attitudes towards animals are different. Moreover, research has suggested that the destruction of seropositive dogs is a relatively ineffective control measure. In this context, the authors reflect on some epidemiological, ethical and juridical aspects, aiming to contribute to the discussion and to find more feasible solutions. PMID- 21309454 TI - An analysis of the 1978 African swine fever outbreak in Brazil and its eradication. AB - The aim of this paper is to evaluate the African swine fever (ASF) outbreak that began in 1978 in Paracambi municipality, Rio de Janeiro State, Brazil, and the steps taken by the Brazilian authorities to eradicate the disease. The presence of ASF in the country was confirmed by isolating the virus, and its pathogenicity was certified by the laboratory of the Plum Island Disease Center, New York, United States. Even before the laboratory results became available, the Brazilian Agriculture Ministry declared an Animal Health Emergency, in which the official Veterinary Services adopted rapid control measures to restrain and eradicate the disease. These control measures contributed to the reorganisation of the national swine industry and stimulated the use of high-technology production techniques, as well as an improvement in herd health consciousness. All this contributed to Brazil becoming the largest meat exporter in the world. PMID- 21309455 TI - Influence of the incubation temperature and the batch components on the sensitivity of an enzyme-linked immunosorbent assay to detect Aujeszky's disease virus glycoprotein E (gE). AB - Although licensed batches of an enzyme-linked immunosorbent assay (ELISA) for Aujeszky's disease virus (ADV) were used, and the assays were performed within an ISO/IEC 17025 accredited quality control system, certain routine runs of the ADV ELISA were not validated using the quality system criteria, even when all technical parameters were controlled. Incubation at different temperatures and batch composition were identified as parameters that could result in non validated assays/runs. Therefore, the effect of incubation temperature and batch composition on the analytical sensitivity of the ELISA was investigated. The World Organisation for Animal Health (OIE) standard reference serum ADV1 was diluted 1:8 and tested in 94 different glycoprotein E ELISA runs performed with different batches and different incubation temperatures. The incubation temperature and batch components had a significant influence on the qualitative result for the OIE standard reference serum. An incubation temperature of at least 22 degrees C was recommended, based on the results of this analysis. Which of the batch components caused these differences in sensitivity was not investigated further. PMID- 21309456 TI - Bluetongue control strategy, including recourse to vaccine: a critical review. AB - The bluetongue (BT) epidemic that has prevailed in Europe since 2000 is the first example of continental spread of the BT virus (BTV) in large naive populations of susceptible animals. Based on the results of intensive surveillance and research in countries of the southern Mediterranean that were affected by the infection early on in the epidemic, a new strategy for prevention and control of the disease was developed to limit direct losses and to reduce the consequences due to movement restrictions. The basic innovations that were introduced were the use of mass vaccination of all domestic ruminant species to limit the spread of BTV and the use of intensive active surveillance to limit, as far as possible, the zone where movement restrictions must be applied. The novel strategy that was adopted dramatically reduced the number of clinical outbreaks in southern Europe and the Mediterranean Basin and ensured safer animal trade. In 2006, the first BTV-8 epidemic occurred, this time in north-western Europe. During this epidemic, affected countries adopted a 'wait and see' approach. No vaccination was implemented until 2008 and, in many instances, the movement of animals was authorised within restricted areas, thereby facilitating the spread of infection. The delay in administering vaccination was due to the decision to avoid the use of modified live virus vaccines, although this type of vaccine performed satisfactorily in the previous BT epidemics in southern Europe. Bluetongue has demonstrated that the infectious agents present in southern Africa can easily spread to the Mediterranean Basin, which should be considered a single entity as far as the epidemiology of animal diseases is concerned. Therefore, any effective strategy for the prevention and control of animal disease in Europe must take into account this reality and recognise the need for regional surveillance networks that include all the countries that border the Mediterranean. PMID- 21309457 TI - Toward a global foot and mouth disease vaccine bank network. AB - A network of foot and mouth (FMD) vaccine banks has been initiated with the support of vaccine bank managers and technical advisors that participated in a workshop held at the Institute for Animal Health, Pirbright, in the United Kingdom in April 2006. Terms of Reference that provide guidance for coordinated activities are under consultation. Practical and economic benefits can be realised from collaboration, which will be achieved through mutually acceptable mechanisms for the exchange of information and materials relevant to vaccine banks and their management. If administrative and technical hurdles can be overcome, the network has the potential to contribute significantly to the improved control of FMD worldwide. A 'global' and interactive vaccine bank association could be created by agreeing a system of resource sharing that could orchestrate additional emergency cover with vaccine or antigen from the reserves of network members. PMID- 21309458 TI - Water requirements for livestock production: a global perspective. AB - Water is a vital but poorly studied component of livestock production. It is estimated that livestock industries consume 8% of the global water supply, with most of that water being used for intensive, feed-based production. This study takes a broad perspective of livestock production as a component of the human food chain, and considers the efficiency of its water use. Global models are in the early stages of development and do not distinguish between developing and developed countries, or the production systems within them. However, preliminary indications are that, when protein production is adjusted for biological value in the human diet, no plant protein is significantly more efficient at using water than protein produced from eggs, and only soybean is more water efficient than milk and goat and chicken meat. In some regions, especially developing countries, animals are not used solely for food production but also provide draught power, fibre and fertiliser for crops. In addition, animals make use of crop by-products that would otherwise go to waste. The livestock sector is the fastest-growing agricultural sector, which has led to increasing industrialisation and, in some cases, reduced environmental constraints. In emerging economies, increasing involvement in livestock is related to improving rural wealth and increasing consumption of animal protein. Water usage for livestock production should be considered an integral part of agricultural water resource management, taking into account the type of production system (e.g. grain-fed or mixed crop livestock) and scale (intensive or extensive), the species and breeds of livestock, and the social and cultural aspects of livestock farming in various countries. PMID- 21309459 TI - Mysterious mortality in camels (Camelus dromedarius) in Borana, Ethiopia: evidence of its association with reproductive age groups. AB - In May and June of 2007, sudden death was observed in camels in southern pastoral areas of Oromia, Ethiopia. It significantly (p < 0.001) affected reproductive age groups of both male and female camels (in females and males, 63.9% and 10.8% of those in reproductive age groups were affected, respectively). Pregnant females (37.6%) were affected significantly more often (p < 0.001) than non-pregnant females. Absence of rigor mortis and absence of blood clotting, together with the death of pregnant and lactating camels, were common findings during different outbreaks, but no aetiological agent such as Bacillus anthracis was isolated. In addition to loss of milk in lactating camels and loss of the calf in pregnant individuals, the average value of the dead camels was 2377.6 birr (approximately US$264). A multifactorial cause of mortality is hypothesised. Hence, research to develop an intervention, with increased input of financial resources and time, is required urgently so that the cause of the problem can be discovered and the disease can be controlled. PMID- 21309460 TI - Parasitic zoonoses in India: an overview. AB - Parasitic zoonotic diseases are prevalent throughout India at varying rates. First reports of zoonotic parasites and new emerging diseases have been recorded in both the human and animal populations in recent decades. The prevalence of zoonotic parasites is likely to be an underestimate, owing to the lack of proper surveillance and the shortage of information about the existence of asymptomatic animal carriers. Emergence of diseases such as human echinococcosis/hydatidosis, neurocysticercosis, cryptosporidiosis and toxoplasmosis in those with acquired immune deficiency syndrome, together with the re-emergence of cutaneous leishmaniosis, poses a serious threat in India and the prevention and control of these parasitic zoonoses, and others, is a great challenge. PMID- 21309461 TI - Swine vesicular disease in northern Italy: diffusion through densely populated pig areas. AB - At the end of 2006, a recrudescence of swine vesicular disease (SVD) was recorded in Italy and the disease spread widely throughout the northern regions. Lombardy, a densely populated pig area, was most affected and the presence of the disease caused heavy economic losses to the entire pig industry. Although SVD is considered only moderately contagious, the epidemic in the north was characterised by a rapid spread of the condition. Numerous difficulties were encountered in eradicating it. Over the past decade, there has been a significant increase in the population of pigs in Lombardy, concentrated mainly in a few areas which were the most severely affected during the 2006 to 2007 SVD epidemic. Increases in both the pig population and animal movements, combined with weak biosecurity measures, increased the spread rate of the disease and hampered eradication activities. PMID- 21309462 TI - Seroepidemiological survey of trypanozoon infection in horses in the suspected dourine-infected Bale highlands of the Oromia region, Ethiopia. AB - This paper presents the results of a seroepidemiological survey of trypanozoon infection in horses carried out between September 2007 and June 2008. The survey was conducted to determine the seroprevalence of anti-trypanozoon antibodies in 880 serum samples collected randomly from selected horse-breeding districts of the Bale highlands of Ethiopia. The seroprevalence of trypanozoon infection was found to be 173 (19.66%) and 140 (15.91%) for the CATT/T. evansi and LATEX/T. evansi tests, respectively. The high seroprevalence of trypanozoon infection strongly indicates that the infection is endemic. Neither test can differentiate between anti-trypanozoon antibodies caused by infection with T. equiperdum (the causative agent of dourine) and those of T. evansi (the causative agent of surra). The findings of the present study suggest that field-applicable screening serological tests such as the CATT/T. evansi and LATEX/T. evansi could be useful for epidemiological studies and the control of trypanozoon infection. PMID- 21309463 TI - An outbreak of peste des petits ruminants in migratory flocks of sheep and goats in Egypt in 2006. AB - An outbreak of peste des petits ruminants (PPR) was recorded in Kalubia province, Egypt in 2006, affecting a large population of migratory goats and sheep over a huge geographical area. Epidemiological, clinical and laboratory investigations were performed. Diseased animals showed pyrexia, erosive stomatitis, enteritis and bronchopneumonia. Clinical manifestations were more severe in goats. The overall morbidity, cumulative mortality and case fatality rates were 26.1%, 10.5% and 40.2%, respectively, and were significantly higher in young animals. Post mortem examination showed emaciation, congested mucous membranes, lymphadenopathy, hepatosplenomegaly, haemorrhagic necrosis of the abomasal and intestinal mucosa, pleurisy and lung consolidation. Forty oculonasal swabs and 243 serum samples from diseased animals were tested for PPR antigen and antibodies using immunocapture and competitive enzyme-linked immunosorbent assays (ELISA), respectively. PPR antigen was detected in 30/40 (75%) of the swabs. PPR virus was identified in inoculated Vero cells using immunocapture ELISA and fluorescent antibody technique (FAT); 33/40 (82.5%) and 36/40 (90%) samples were positive, respectively. Of 243 sera, 154 (63.4%) contained PPR antibodies. Circulation of PPR among the migratory sheep and goat flocks was demonstrated. Strict serosurveillance and monitoring of PPR with vaccination of migratory flocks at borders is required for effective control of the disease. PMID- 21309464 TI - Brucellosis in camels, cattle and humans: associations and evaluation of serological tests used for diagnosis of the disease in certain nomadic localities in Sudan. AB - Brucellosis was studied in 2,225 camels, 20 camel nomads and 33 abattoir workers in certain nomadic localities in Sudan, using serum and milk samples. Lymph nodes, testicular tissues and udder tissues from positive camels and hygroma aspirates from three affected cows were used for isolation of Brucella. Serum samples were examined by Rose Bengal plate test (RBPT), modified RBPT (mRBPT), serum agglutination test (SAT) and competitive enzyme-linked immunosorbent assay (cELISA), and milk by the milk ring test. Overall seroprevalence in camels (milk and serum samples) was 37.5%. The seroprevalence in males was 28.2% and in females 40.1%. Twelve (60%) of the 20 nomads and three (9%) of the 33 abattoir workers had positive antibody titres. Brucella abortus biovar 6 was isolated from two camels and three cows. Two isolates, one from each species, were atypical. The bacteriological findings suggested that camels were infected from cattle, the primary hosts of B. abortus. The mRBPT was suitable for screening camel sera for brucellosis, but the cELISA detected 2.1% more positives. The SAT antibody concentrations ranged between < 13 and 3,282 IU/ml. PMID- 21309465 TI - Footrot on a sheep breeding farm in the Himalayan state of Jammu and Kashmir. AB - In the present study ovine footrot was detected clinically on a sheep farm in the Himalayan state of Jammu and Kashmir. Dichelobacter nodosus was confirmed by culture and polymerase chain reaction (PCR) using species-specific 16S ribosomal RNA primers. When cultured, the organism appeared as flat colourless colonies having a fine granulated structure with irregular margins, and showing characteristic Gram-negative rods with swollen ends. Detection by PCR from cultured bacteria resulted in amplification of a 783 base pairs (bp) product. Serogrouping by multiplex PCR using group (A-I)-specific primers revealed the presence of serogroup B-specific bands of 283 bp. PMID- 21309466 TI - Molecular epidemiology and in vitro antimicrobial susceptibility of Salmonella isolated from poultry in Kashmir. AB - A total of 480 samples, comprising 429 faecal samples from healthy adult birds and 51 tissue samples from dead birds, were collected from four government poultry farms in the Kashmir valley from September 2007 to April 2008. In all, 33 Salmonella isolates were obtained. Of these, 28 (84.85%) isolates were Salmonella Gallinarum, 3 (9.09%) were Salmonella Enteritidis and the remaining 2 (6.06%) were Salmonella Typhimurium. All the isolates harboured the invA, sefA, stn and spvC virulence-specific genes. However, the sopB gene was found in only 90.9% of the isolates. Pulsed-field gel electrophoresis analysis of representative isolates revealed that the majority were related but a few belonged to different clones. The majority of the isolates were resistant to cefpodoxime, nalidixic acid and sulphadiazine and sensitive to chloramphenicol, cefotaxime and tetracycline. Isolation of multidrug-resistant Salmonella, including the zoonotically important serovars, revealed a potential threat not only to poultry but also to human health in Kashmir. PMID- 21309467 TI - Investigation of haemorrhagic enteritis in pygmy hogs (Sus salvanius) from India. AB - The pygmy hog is a representative of the smallest and rarest wild species of known living Suidae. This paper reports the investigation of haemorrhagic enteritis encountered amongst the pygmy hogs at the Research and Breeding Centre of the Pygmy Hog Conservation Programme, Guwahati, Assam, India. Three out of 68 pygmy hogs died of enteric infection. Post-mortem examination and bacteriological investigation of two out of the three animals that died revealed clostridial infection. The isolates harboured two plasmids of molecular weight 42.8 kilobases (kb) and 51.9 kb. Clostridium perfringens Type A positive for the beta2 toxin (cpb2) gene was detected by polymerase chain reaction. Sequence analysis of the partial alpha toxin (cpa) gene showed 98% to 100% homology with isolates from different geographical locations. PMID- 21309468 TI - Detection of bovine herpesvirus 1 sequences in yaks (Bos grunniens) with keratoconjunctivitis, using a highly sensitive nested polymerase chain reaction. AB - Thirty-seven yaks (Bos grunniens) with keratoconjunctivitis and 22 healthy yaks were used to investigate the role of bovine herpesvirus 1 (BoHV-1) in keratoconjunctivitis in yaks. Nucleic acid sequences of BoHV-1 glycoproteins B and E were detected in conjunctival swabs from all yaks with keratoconjunctivitis using a nested polymerase chain reaction (PCR). In 21 yaks, BoHV-1 sequences were detected along with Moraxella bovis (M. bovis) and Neisseria spp. The amplified BoHV-1 sequences were identical, and no nucleotide variation was observed when compared with a BoHV-1 reference strain using single-strand conformation polymorphism analysis of the amplified DNA sequences. Interestingly, BoHV-1 sequences could not be detected in samples from healthy yaks. However, conjunctival swabs from two healthy yaks (9.09%) yielded M. bovis and Neisseria spp. Samples from 35 yaks with keratoconjunctivitis showed positive reactions in an avidin biotin enzyme-linked immunosorbent assay for BoHV-1 antibodies; all the healthy yaks were seronegative. This is the first report of a possible association of BoHV-1 with keratoconjunctivitis in yaks. PMID- 21309469 TI - Mycobacterium fortuitum from lesions of slaughtered pigs in Ibadan, Nigeria. AB - To ascertain the cause of tuberculous-like lesions in pigs slaughtered in a local abattoir in Ibadan (south-western Nigeria), a total of 516 pigs were inspected over a period of four months, 18 of which had gross lesions suggestive of tuberculosis at post-mortem. Mycobacterial culture and molecular typing (GenoType Mycobacterium CM [Common Mycobacteria] assay) analysis were used to identify and confirm the mycobacteria species responsible for these lesions. Results show that 2.3% (12/516) of the animals screened were infected with mycobacteria; Mycobacterium fortuitum was confirmed in 33.3% (4/12) of these cases. As far as the authors are aware, this is the first report confirming the isolation of M. fortuitum in slaughtered pigs in Nigeria. There is a need to improve on necessary preventive and control measures that will reduce potential sources of mycobacterial infections in pig-rearing herds. These infections may also have public health implications, especially to workers in the pig industry. PMID- 21309470 TI - An overview of cyclophilins in human cancers. AB - Cyclophilins (Cyps) belong to a group of proteins that have peptidyl-prolyl cis trans isomerase (PPIase) and molecular chaperone activities. Originally, Cyps were identified as the intracellular receptors for the immunosuppressive drug cyclosporin A. Cyps are found in all prokaryotes and eukaryotes, and have been structurally conserved throughout evolution, implying their importance in cellular function. There are seven major Cyp isoforms in humans. CypA is up regulated in many human cancers, and there is a strong correlation between over expression of the CYPA gene and malignant transformation in some cancers. Moreover, CypA is directly under the transcriptional control of two critical transcription factors for cancer development: p53 and hypoxia inducible factor la. This review discusses the general biological functions of Cyps under a variety of stress conditions, and the importance and diverse roles of overexpression of CYP genes in human cancers, with a particular emphasis on CYPA. These oncogenic properties suggest that CypA is a promising target for cancer therapy. PMID- 21309471 TI - Oestrogen receptor-alpha polymorphism and risk of fracture: a meta-analysis of 13 studies including 1279 cases and 6069 controls. AB - A meta-analysis was performed to evaluate the effect of oestrogen receptor-alpha (ESR1) gene PvuII polymorphism on fracture risk. It included published data from relevant studies (up to May 2010) identified from Medline, Embase and Current Contents. The 13 included studies contained 1279 fracture cases and 6069 controls. The combined results based on these studies showed no relationship between ESR1 gene PvuII polymorphism and fracture risk. No significant difference in genotype distribution was found when stratifying by race. When stratifying by fracture type, it was found that vertebral fracture cases had a significantly higher frequency of the PvuII pp genotype than controls in five studies (552 cases and 2350 controls). This meta-analysis suggests a modest but statistically significant association between the ESR1 PvuII pp genotype and vertebral fracture. PMID- 21309472 TI - Delayed treatment of delirium increases mortality rate in intensive care unit patients. AB - Delirium in the intensive care unit (ICU) is a serious complication associated with a poor outcome in critically ill patients. In this prospective observational study of the effect of a delay in delirium therapy on mortality rate, 418 ICU patients were regularly assessed using the Delirium Detection Score (DDS). The departmental standard required that if delirium was diagnosed (DDS >7), therapy should be started within 24 h. In total, 204 patients (48.8%) were delirious during their ICU stay. In 184 of the delirious patients (90.2%), therapy was started within 24 h; in 20 patients (9.8%), therapy was delayed. During their ICU stay, patients whose delirium treatment was delayed were more frequently mechanically ventilated, had more nosocomial infections (including pneumonia) and had a higher mortality rate than patients whose treatment was not delayed. Thus, it would appear that a delay in initiating delirium therapy in ICU patients was associated with increased mortality. PMID- 21309473 TI - Real-time imaging and detection of intracranial haemorrhage by electrical impedance tomography in a piglet model. AB - The aim of this study was to use electrical impedance tomography (EIT) to detect and image acute intracranial haemorrhage (ICH) in an animal model. Blood was infused into the frontal lobe of the brains of anaesthetized piglets and impedance was measured using 16 electrodes placed in a circle on the scalp. The EIT images were constructed using a filtered back-projection algorithm. The mean of all the pixel intensities within a region of interest--the mean resistivity value (MRV)--was used to evaluate the relative impedance changes in the target region. A symmetrical index (SI), reflecting the relative impedance on both sides of the brain, was also calculated. Changes in MRV and SI were associated with the injection of blood, demonstrating that EIT can successfully detect ICH in this animal model. The unique features of EIT may be beneficial for diagnosing ICH early in patients after cranial surgery, thereby reducing the risk of complications and mortality. PMID- 21309474 TI - Computer-assisted decision support for changing practice in severe sepsis and septic shock. AB - Computer-assisted decision support systems (CDSS) are designed to improve infection management. The aim of this prospective, clinical pre- and post intervention study was to investigate the influence of CDSS on infection management of severe sepsis and septic shock in intensive care units (ICUs). Data were collected for a total of 180 days during two study periods in 2006 and 2007. Of the 186 patients with severe sepsis or septic shock, 62 were stratified into a low adherence to infection management standards group (LAG) and 124 were stratified into a high adherence group (HAG). ICU mortality was significantly increased in LAG versus HAG patients (Kaplan-Meier analysis). Following CDSS implementation, adherence to standards increased significantly by 35%, paralleled with improved diagnostics, more antibiotic-free days and a shortened time until antibiotics were administered. In conclusion, adherence to infection standards is beneficial for patients with severe sepsis or septic shock and CDSS is a useful tool to aid adherence. PMID- 21309475 TI - Differential effects of esomeprazole on the antiplatelet activity of clopidogrel in healthy individuals and patients after coronary stent implantation. AB - Clopidogrel plus aspirin is a standard antiplatelet aggregation regimen in cardiovascular diseases, especially after implantation of a coronary stent. Interaction between clopidogrel and proton pump inhibitors theoretically reduces clopidogrel's antiaggregation effect, but the evidence is controversial. A total of 30 healthy subjects and 74 patients with a coronary stent were given a 300 mg loading dose of aspirin and 300 mg clopidogrel and then 100 mg aspirin/75 mg clopidogrel daily for 14 days. Subgroups were concomitantly treated or not treated with esomeprazole (20 mg/day). Clopidogrel significantly reduced adenosine diphosphate-induced platelet aggregation in healthy and stent-implanted subjects on days 7 and 14. Healthy subjects receiving esomeprazole showed a significantly higher platelet aggregation rate than those not receiving esomeprazole, but esomeprazole had no effect in patients with a stent. Aspirin plus clopidogrel did not result in significant gastrointestinal complications. These differential effects of esomeprazole on the antiplatelet activity of clopidogrel in healthy individuals and patients after coronary stent implantation merit further investigation. PMID- 21309476 TI - Combining intrathecal bupivacaine and meperidine during caesarean section to prevent spinal anaesthesia-induced hypotension and other side-effects. AB - This study compared intrathecal hyperbaric bupivacaine with low-dose intrathecal plain bupivacaine plus different doses of meperidine (pethidine), administered sequentially, with regard to blood pressure stability, post-operative analgesia and incidence of side-effects in 80 parturients undergoing caesarean section. Patients were randomly assigned to one of four groups (n=20 each group): the HB group received 10 mg hyperbaric bupivacaine intrathecally; the BM35, BM30 and BM25 groups received 5 mg plain bupivacaine plus 35, 30 or 25 mg of meperidine intrathecally, respectively. The incidence of hypotension in the BM25 group was significantly lower than in the HB group. Nausea and vomiting were less prevalent in the BM25 group than in the HB and BM35 groups. In conclusion, sequential administration of 5 mg plain bupivacaine and 25 mg meperidine intrathecally provided better blood pressure stability and a lower incidence of side-effects than bupivacaine alone, without affecting quality of anaesthesia or surgical and patient satisfaction. PMID- 21309477 TI - Control of the haemodynamic response to surgical stimuli in semi-closed circuit or closed circuit anaesthesia using a multifunctional anaesthesia system. AB - This study compared the ability of the Zeus multifunctional anaesthesia system to control haemodynamic response to surgical stimulation in semi-closed (SCA) or closed circuit anaesthesia (CCA) modes. Fifty patients undergoing gynaecological surgery were randomly assigned to SCA or CCA. Anaesthesia was induced with 2 mg propofol and 0.9 mg/kg rocuronium, intravenously, and maintained using sevoflurane (minimum alveolar concentration [MAC], 1.0) using 2 l/min oxygen plus 2 l/min nitrous oxide (SCA 4 l/min group) or 50% oxygen plus 50% nitrous oxide (CCA group). An increase in mean arterial pressure (MAP) > 20% above baseline in response to surgical stimulation provoked a stepwise increase in sevoflurane (1.3 MAC and then 1.6 MAC), followed by fentanyl 1 pg/kg intravenously (rescue drug). The time required for MAP to return to within 10% of baseline was significantly shorter in the CCA group (6.4 +/- 3.6 min) compared with the SCA 4 l/min group (10.2 +/- 6.0 min). The percentage of patients requiring fentanyl was significantly greater in the SCA 4 l/min group than in the CCA group. In conclusion, CCA controlled acute haemodynamic responses to surgical stimuli more successfully and rapidly than SCA 4 l/min, using a multifunctional anaesthesia machine. PMID- 21309478 TI - Association between epidermal growth factor +61 G/A polymorphism and glioma risk in a Chinese Han population. AB - The association between the +61 G/A polymorphism of the epidermal growth factor (EGF) gene and glioma risk remains controversial and unclear. The objective of this study was to investigate the association between the EGF +61 G/A polymorphism and glioma risk in a Chinese Han population. Peripheral blood samples were extracted from 160 glioma patients and 320 control subjects. Genotyping was performed using a polymerase chain reaction-restriction fragment length polymorphism method. Glioma patients had a significantly higher frequency of the AA genotype (odds ratio [OR] 1.93, 95% confidence intervals [CI] 1.08, 3.44) than control subjects and the frequency of the AA genotype was significantly higher in glioblastoma patients than in patients with other gliomas (OR 2.19, 95% CI 1.05, 4.57). Patients with grade IV gliomas had a significantly higher frequency of the AA genotype (OR 2.25, 95% CI 1.08, 4.71) than patients with lower grade gliomas. This study demonstrated that the EGF +61 AA genotype is associated with an increased risk of glioma in a Chinese Han population. PMID- 21309479 TI - ADP-ribosylation factor guanine nucleotide-exchange factor 2 (ARFGEF2): a new potential biomarker in Huntington's disease. AB - Microarray searches have revealed potential genetic biomarkers in a wide variety of human diseases. Identification of biomarkers for disease status is particularly important in chronic neurodegenerative diseases where brain tissue cannot be sampled. A previous study identified 12 genes from microarray analysis as associated with Huntington's disease, although the relationships had not been validated. We used new machine learning approaches to reanalyse those microarray data and to rank the identified potential genetic biomarkers. We then performed quantitative reverse transcription-polymerase chain reaction analysis on a subset of the candidate genes in blood samples from an independent cohort of 23 Huntington's disease patients and 23 healthy controls. Our highest ranked genes did not overlap with the 12 previously identified, but two were significantly up regulated in the Huntington's disease group: ARFGEF2 and GOLGA8G. Little is known about the latter, but the former warrants further analysis as it is known to be associated with intracellular vesicular trafficking, disturbances of which characterize Huntington's disease. PMID- 21309480 TI - Apoptosis-mediated cytotoxic effects of ibandronic acid on hormone- and drug refractory prostate cancer cells and human breast cancer cells. AB - Over 80% of patients with advanced breast and prostate cancer ultimately develop bone metastases. Ibandronic acid has proven efficacy for treatment of bone metastasis secondary to breast cancer. This study was designed to investigate the cytotoxic and apoptotic effects of ibandronic acid on hormone- and drug refractory prostate carcinoma DU-145 and human breast cancer MCF-7 cell lines. Cytotoxicity was evaluated using an XTT cell proliferation kit, and apoptosis was assessed by enzyme-linked immunosorbent assay (histone-DNA fragmentation) and measurement of caspase 3/7 activity. With increasing concentrations of ibandronic acid there was a dose- and time-dependent decrease in cell numbers. MCF-7 cells were more resistant than DU-145 cells (half maximal inhibitory concentrations of 122 and 90 microM, respectively). Ibandronic acid induced apoptosis in both cell lines. The study showed an apoptosis-mediated cytotoxic effect for ibandronic acid (in addition to the already known osteoclast inhibiting effect) in breast cancer patients with bone metastases; which was also observed in prostate cancer cells. Further clinical studies involving breast and prostate cancer patients with bone metastases are warranted to confirm these findings. PMID- 21309481 TI - Inhibition of the signal transducers and activators of transcription (STAT) 3 signalling pathway by AG490 in laryngeal carcinoma cells. AB - Signal transducers and activators of transcription (STAT) are important in the development of laryngeal carcinomas and are potential novel molecular targets for therapy to improve survival of patients with this cancer. This study was designed to investigate the influence of the janus activated kinase (JAK)/STAT inhibitor AG490 on proliferation and apoptosis of Hep-2 human laryngeal cancer cells and whether there was any inhibition by AG490 of the JAK/STAT3 signalling pathway. AG490 inhibited cell proliferation in dose- and time-dependent manners and induced apoptosis in Hep-2 cells, with the number of apoptotic cells increasing with time. AG490 inhibited G1 to S cell cycle transition and induced G1 cell cycle arrest as well as significantly down-regulating STAT3, phosphorylated STAT3 and survivin in Hep-2 cells. This study showed that AG490 significantly inhibited proliferation and induced apoptosis of laryngeal carcinoma cells through down regulation of STAT3 and survivin, suggesting a potential target for laryngeal carcinoma treatment. PMID- 21309482 TI - Local delivery of recombinant human bone morphogenetic protein-2 increases axonal regeneration and the expression of tau protein after facial nerve injury. AB - This study explored the function and possible mechanism of bone morphogenetic protein-2 (BMP-2) in the healing of injured peripheral nerves in vivo. Rabbit facial nerves were injured by clamping and then treated with recombinant human BMP-2 (rhBMP-2) or phosphate-buffered saline (control) by injecting once during surgery and twice a day post-injury for 7 days. Facial nerve fragments within 5 mm of the clamping point were examined at different times post-surgery. Axon structures visualized by Bielschowsky staining were similar in experimental and control nerves 2 and 6 weeks post-injury. At 4 weeks post-injury, cross-section images of facial nerves showed that axons treated with rhBMP-2 were denser and thicker, and levels of tau protein were increased. It is concluded from these data that rhBMP-2 may affect injured facial nerve regeneration by inducing more neurons to return to embryonic patterns of tau gene expression. PMID- 21309483 TI - Cyclooxygenase-2 and survivin in superficial urothelial carcinoma of the bladder and correlation with intratumoural microvessel density. AB - This study was designed to investigate the protein levels of cyclooxyogenase-2 (COX-2) and survivin in superficial urothelial carcinoma (UC) and their correlation with microvessel density (MVD). High-grade UC was positive for both COX-2 and survivin protein, and the proportion of tumours positive for both proteins increased with increasing tumour grade. The presence of COX-2 protein was significantly correlated with the presence of survivin protein. Both COX-2 and survivin positivity were significantly correlated with MVD in all patients regardless of tumour grade, but there was no correlation between MVD and COX-2 and survivin positivity by individual tumour grade. Although there was no significant difference in the proportion of COX-2-positive tumours when patients were stratified by tumour stage, a significantly higher proportion of patients with pT1 stage tumours were survivin-positive compared with patients with pTa stage tumours. COX-2 and survivin positivity were significantly correlated in all patients regardless of tumour grade or stage. COX-2 and survivin were significantly correlated in patients with pTa, but there was no correlation in pT1 tumours. These findings demonstrate that together, COX-2, survivin and MVD may play an important role in UC. PMID- 21309484 TI - The effects and mechanism of xenogeneic adipocyte vaccine for the prevention of obesity in rats. AB - The objectives of this study were to observe the effects of immunization with mouse mature adipocytes for the prevention of obesity in rats and to investigate their mechanism of action. Mouse mature adipocytes (3T3-L1) were injected as a vaccine into the abdominal cavity of rats. Control rats were injected with fibroblast cell lines (MRC-5 or NIH/3T3) or with 0.9% saline. Rats were fed a high calorie diet and body weight changes were used to evaluate obesity prevention. Immunohistochemical and immunofluorescence assays were used to investigate the mechanism of action. Results showed that obesity in rats can be prevented by immunization with xenogeneic mature mouse adipocytes. Body weight gain was inhibited in rats in the treatment group but not in the control groups and was statistically significant between the groups over the 19-week observation period. The assays demonstrated the presence of autoantibodies in rat adipocytes. It was concluded that vaccines of xenogeneic adipocytes can effectively prevent obesity in rats. PMID- 21309485 TI - Trauma scores and neuron-specific enolase, cytokine and C-reactive protein levels as predictors of mortality in patients with blunt head trauma. AB - This study evaluated serum neuron-specific enolase (NSE), cytokine and high sensitivity C-reactive-protein (hs-CRP) levels, along with the Glasgow Coma Scale (GCS) and Revised Trauma Score (RTS), as predictors of mortality in the early posttraumatic period, in 100 Turkish patients with blunt head trauma. Overall patient mortality was 27%. There was a significant association between age and mortality, and mortality was negatively correlated with GCS and RTS. Head injury severity (GCS) was significantly related to NSE, hs-CRP, interleukin (IL)-6, IL-8 and tumour necrosis factor (TNF)-alpha levels. Mortality correlated positively with IL-6, IL-8, TNF-alpha and hs-CRP levels. NSE, hs-CRP, IL-6, IL-8 and TNF alpha levels were significantly higher in non-survivors compared with survivors. GCS score < or =8, younger age and NSE levels were significant independent predictors of mortality. During the early post-traumatic period, NSE may be an objective alternative criterion to the GCS, in the management of patients with blunt head trauma. PMID- 21309486 TI - Regenerated host axons form synapses with neurons derived from neural stem cells transplanted into peripheral nerves. AB - It is reported that neural stem cells (NSC) can arrest denervated muscle atrophy and promote nerve regeneration when transplanted into injured peripheral nerves, and that regenerated host axons can form synapses with transplanted and differentiated NSC. In this study, F344 rat nerve segments and F344 rat NSC were transplanted into host green fluorescence protein (GFP) transgenic F344 rats. This allowed transplanted F344 rat tissue to be used as a nonluminous background for the clear visualization of regenerated host GFP axons. Regenerated host axons grew into the transplanted F344 nerve segment 2 weeks after nerve anastomosis. Immunohistochemical staining and confocal microscope analysis revealed that regenerated host axons formed synapses with NSC-derived neurons. The findings confirmed that regenerated peripheral axons form synapses with neurons in peripheral nerves, possibly forming the basis for clinical application in peripheral nerve injury. PMID- 21309487 TI - High-risk human papillomavirus reduces the expression of microRNA-218 in women with cervical intraepithelial neoplasia. AB - This study was designed to investigate whether there is a correlation between the down-regulation of microRNA-218 (miR-218) and the presence of human papillomavirus (HPV) infection in the pathogenesis of cervical cancer. The participants comprised 78 women with cervical intraepithelial neoplasia (CIN); 22 (28.2%) had CIN 1, 27 (34.6%) had CIN 2 and 29 (37.2%) had CIN 3. MiR-218 expression was determined by reverse transcriptase polymerase chain reaction and HPV genotypes in tissue specimens were identified with a microarray test kit. The findings showed that miR-218 levels in patients with high-risk HPV infection were lower than in those infected with low-risk or intermediate-risk HPV, or in those who were HPV-free. MiR-218 levels in patients with high-risk CIN were lower than in those with low-risk CIN. We concluded that infection with high-risk HPV lowered the expression of miR-218 and that down-regulation of miR-218 was involved in the pathogenesis of cervical cancer. PMID- 21309488 TI - The influence of diabetes on the relationship between N-terminal pro-B-type natriuretic peptide and body mass index. AB - This study evaluated the influence of diabetes on the relationship between N terminal pro-B-type natriuretic peptide (NT-proBNP) and body mass index (BMI). Simultaneous NT-proBNP and echocardiographic Doppler examinations were performed in 1117 patients with dyspnoea undergoing cardiac catheterization. Patients were divided into BMI > or =25 kg/m2 (obese), 23-25 kg/m2 (overweight) and <23 kg/m2 (non-obese) groups. In the 803 non-diabetic patients, mean plasma NT-proBNP levels in non-obese, overweight and obese patients showed a significant negative correlation with BMI (862.3 +/- 228.8 pg/ml, 611.5 +/- 149.7 pg/ml, 278.3 +/- 172.5 pg/ml, respectively). In the 314 patients with diabetes, there was no correlation between BMI and NT-proBNP. This study demonstrated that obese patients had reduced concentrations of NT-proBNP compared with non-obese patients, despite having higher left ventricular filling pressures. NT-proBNP was not reduced in obese patients with diabetes. These results suggest that factors other than cardiac status impact on NT-proBNP concentration. PMID- 21309489 TI - Effect of remifentanil on arterial oxygenation during one-lung ventilation. AB - This study was designed to assess the dose-related effects of remifentanil on arterial oxygenation during one-lung ventilation (OLV) under total intravenous anaesthesia with propofol. A total of 104 patients scheduled for elective lung resection surgery requiring OLV were randomly assigned to one of four groups with a target effect-site concentration (Ce) of remifentanil of 0.5, 1, 2 or 4 ng/ml. Patients were anaesthetized with propofol and remifentanil in 100% oxygen. Arterial blood gas analysis was performed after 15 min of two-lung ventilation (TLV15, baseline) and after 15 and 30 min of OLV (OLV15 and OLV30). Mean arterial oxygen tension (PaO2) decreased significantly at OLV15 and OLV30 compared with baseline in all groups, but was comparable in the four groups at each time point, suggesting that remifentanil infusion with a Ce < or =4 ng/ml can be successfully used for anaesthesia with propofol during OLV in lung surgery without any significant changes in PaO2. PMID- 21309490 TI - Evaluation of iloprost to prevent vasospasm in coronary artery bypass grafts. AB - This study assessed the efficacy of iloprost in relieving vasospasm in coronary artery bypass grafts. Radial artery (RA), left internal thoracic artery (LITA) and saphenous vein (SV) grafts were taken from 20 patients (13 men and seven women, mean age 63.8 years [range 48-74 years]) scheduled to undergo coronary artery bypass grafting. Ten 3 mm vascular rings were cut from each graft and kept under tension for at least 60 min. They were kept alive with 37 degrees C oxygenated Krebs solution. Smooth muscle contraction was achieved with phenylephrine before iloprost was administered every 2 min, starting at a concentration of 10(-9) mol/l and increasing in logarithmic increments to a concentration of 10(-5) mol/l. The vasodilation response to iloprost started in all samples at a concentration of 10(-9) mol/l and increased with each incremental increase in iloprost concentration up to 10(-5) mol/l. These data suggest that local administration of iloprost has a role in relieving graft vasospasm during harvesting and preparation for coronary artery bypass grafting. PMID- 21309491 TI - Autonomic changes in preoperative uncomplicated diabetic patients with postural changes. AB - Diabetic autonomic neuropathy is a critical complication frequently encountered in anaesthetic and surgical practice. Power spectral analysis is a noninvasive tool for monitoring frequency analysis of heart rate variability (HRV) and autonomic control of the heart. This study examined HRV changes in preoperative diabetic patients without overt signs of autonomic dysfunction and in matched controls (n=18 per group). HRV values at -15 degrees, 0 degrees, 15 degrees, 45 degrees and sitting positions were compared between groups and for each position. HRV in diabetic patients was lower than in controls at all positions (absolute units). Low-frequency power (normalized units) and the low-frequency/high frequency ratio increased significantly at 45 degrees and in sitting positions in controls but not in diabetic patients. Pre-existing autonomic derangements in diabetic patients without overt clinical symptoms can be aggravated by high degree tilting or sitting positions. Consequently, great care should be taken during the intra- and perioperative management of these patients. PMID- 21309492 TI - The role of serum D-dimer level in the diagnosis of patients admitted to the emergency department complaining of chest pain. AB - This study investigated D-dimer levels in 241 patients admitted to the emergency department with sudden-onset chest pain. The patient group included those diagnosed with acute coronary syndrome (ACS; i.e., unstable angina pectoris [USAP], non-ST elevated myocardial infarction [NSTEMI], ST-elevated myocardial infarction [STEMI]); the control group included those diagnosed with non-cardiac chest pain. Mean serum levels of D-dimer, creatine kinase-MB (CK-MB) and troponin I (TPI) were compared between the groups. Levels of D-dimer, CK-MB and TPI in the patient group were significantly higher than in the control group. There were also significantly higher D-dimer, CK-MB and TPI levels in the STEMI and NSTEMI patient subgroups compared with the control group. Only the D-dimer level was significantly higher in the USAP subgroup versus the control group. The sensitivity and specificity of D-dimer for ACS were 83.7% and 95.4%, respectively, suggesting that evaluating D-dimer levels might be useful in the emergency room for diagnosing ACS and predicting mortality in patients presenting with acute chest pain. PMID- 21309493 TI - The effect of flurbiprofen as prophylactic analgesic before hysterosalpingography. AB - Hysterosalpingography (HSG) is associated with pain during the four-step procedure. This prospective, double-blind, randomized, placebo-controlled study was conducted to investigate the effect of the analgesic flurbiprofen, administered prior to HSG, in 60 women. Thirty women were randomized to receive 100 mg of flurbiprofen, orally, 1 h prior to HSG and a further 30 women were randomized to receive placebo. Injection of contrast medium was more painful than the other steps in the HSG procedure in both groups; however, there was no significant between-group difference in terms of pain experienced in the individual steps of HSG. Pain scores at 5 and 30 min after the procedure were compared between the two groups. There was a significant decrease in the visual analogue scale pain score in the flurbiprofen-treated group compared with the placebo-treated group at both time points. Thus, the authors recommend flurbiprofen as a prophylactic analgesic to be administered before HSG procedures. PMID- 21309494 TI - Assessment of the risk of rupture of intracranial aneurysms using three dimensional cerebral digital subtraction angiography. AB - The aim of this study was to develop an improved binary logistic regression model for predicting the risk of intracranial aneurysm rupture. A cohort of patients (n=37) with aneurysms underwent three-dimensional digital subtraction angiography examination to measure several morphological parameters of the aneurysm. The aspect ratio (height/neck size) and the size ratio (length/mean diameter of parent vessel) were also calculated. All the morphological parameters combined with the aneurysm location and the patient's baseline data were used to derive a backward binary logistic regression model. In order to validate the model, it was applied to another independent cohort of 19 patients with aneurysms. The model had sensitivity, specificity and accuracy of 84.6%, 66.7% and 78.9%, respectively. This binary logistic regression model of aneurysm rupture risk identified the status of an aneurysm with high accuracy and could form the basis of more complex models in the future. PMID- 21309495 TI - The analgesic effect of remifentanil on prevention of withdrawal response associated with the injection of rocuronium in children: no evidence for a peripheral action. AB - Remifentanil pre-treatment has been reported to decrease the incidence of rocuronium injection-associated withdrawal movement. This study was designed to explore the site of action of remifentanil for reducing withdrawal response during rocuronium injection in children. Ninety-six paediatric patients were randomly assigned to three groups. After induction of anaesthesia with 5 mg/kg 2.5% thiopental sodium, 2 ml saline (placebo group) or 0.5 microg/kg remifentanil (group R), was injected intravenously 1 min before 0.6 mg/kg rocuronium. In a third group (group R'), the venous retention of 0.5 microg/kg remifentanil was maintained for 30 s followed by tourniquet release and injection of 0.6 mg/kg rocuronium. Withdrawal response was graded using a four-point scale. The incidence of withdrawal movement after rocuronium administration was 94%, 22% and 81% in the placebo, R, and R' groups, respectively. This study demonstrated that the pre-treatment effect of remifentanil for reducing rocuronium-associated withdrawal response occurs mainly through a central action. PMID- 21309496 TI - The Kruppel-like factor 6 genotype is associated with gastric cancer in a Chinese population. AB - Association of the IVS1 -27G/A polymorphism of Kruppel-like factor 6 (KLF6) with gastric cancer was examined in a Chinese population comprising 300 gastric cancer patients and 300 healthy controls. Single-nucleotide polymorphism analysis was performed by amplifying intron 1 of KLF6 and sequencing the products. The KLF6 genotype IVS1 -27AA was significantly less frequent in gastric cancer patients than in controls and significantly less frequent in patients with advanced (stage III/IV) gastric cancer than in those with early (stage I/II) cancer. Stratification by location, Lauren's classification and histological differentiation revealed no significant differences in genotype distribution. Thus, in this Chinese population the KLF6 IVS1 -27AA genotype was associated with a decreased risk of gastric cancer and with cancer stage. Further study is required to clarify the mechanisms involved and, potentially, to facilitate the design of effective clinical trials. PMID- 21309497 TI - Endocrine disorders in a specialist hospital in Jamaica. AB - The objective of this study was to define the types of disease seen at the only endocrine clinic in Jamaica. The diagnoses of all patients attending the endocrinology clinic of the University Hospital of the West Indies over a 7-year period were analysed. Of the 1503 patients attending 263 weekly endocrinology clinics, 1251 patients had thyroid-related diseases, of which 684 patients had thyrotoxicosis and 233 patients had hypothyroidism. There were 17 pituitary tumours, eight cases of Cushing's syndrome and four of acromegaly. Cases of Sheehan's syndrome (n=11), hypopituitarism (n=17), hypoadrenalism (n=13), hypogonadism (n=9), primary hyperparathyroidism (n=3) and phaeochromocytoma (n=3) were rare. Thyroid disease was the most common diagnosis. New emerging endocrine disorders that are public health problems, such as obesity (n 21) and hyperlipidaemia (n=1), were rare. More traditional diseases, such as Sheehan's syndrome have become rare with improvements in obstetric care. PMID- 21309498 TI - Effect of number of pregnancies on bone mineral density. AB - This study investigated the effect of the number of pregnancies on bone mineral density (BMD) in 320 post-menopausal women aged between 49 and 64 years. Cases were selected from people with similar lifestyles and stratified into five groups according to the number of pregnancies. Each group was divided into two subgroups according to the duration of the menopause (3-5 years versus 6-10 years). Lumbar (L2-L4) and femoral neck BMD were measured by dual-energy X-ray absorptiometry and T-score values were used in the statistical evaluation. No significant difference was found between the number of pregnancies and BMD within each group based on the same menopause duration, but a significant correlation was found in most groups based on menopause duration: T-scores decreased as menopause duration increased. Changes in BMD are likely to be related to menopause duration, rather than the number of pregnancies. PMID- 21309499 TI - Correlation between serum 25-hydroxyvitamin D levels and quadriceps muscle strength in elderly cretans. AB - Vitamin D deficiency is associated with osteomalacic myopathy, and muscle weakness related to vitamin D deficiency has been implicated as a possible risk factor for falls in the elderly. This study investigated the possible correlation between serum 25-hydroxyvitamin D (25[OH]D) concentration and quadriceps muscle strength in ambulatory community dwelling Cretan men (n=13) and women (n=35) aged > or = 65 years. Quadriceps muscle strength was measured isometrically using Cybex 6000 apparatus. The mean serum 25(OH)D concentration was significantly higher in men than in women (76.00 versus 49.11 nmol/l, respectively). Serum 25(OH)D values were < 50 nmol/l in 15% of men and in 60% of women. Serum 25(OH)D concentration correlated positively with quadriceps muscle strength. In conclusion, vitamin D deficiency was common in the study participants despite the high levels of sunlight in Crete. Serum 25(OH)D levels were positively correlated with muscle strength. PMID- 21309500 TI - The frequency of HLA class I and II alleles in Turkish childhood acute leukaemia patients. AB - In this study, blood samples were taken from 200 patients with childhood acute leukaemias, including acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML), and from 100 healthy volunteers (controls). The frequency of the human leucocyte antigen (HLA)-DRB1*04 allele was significantly higher, and the frequencies of the HLA-A23 and HLA-B7 antigens were significantly lower, in patients with ALL compared with controls. Among patients with AML, the frequency of the HLA-B49 antigen and the HLA-DRB1*15 allele were significantly higher, whereas the frequencies of the HLA-A11 and HLA-B38 antigens were significantly lower compared with controls. The frequency of the HLA-DRB1*04 allele was also significantly higher in male patients with ALL and AML, whereas the HLA-DRB1*13 allele was found significantly less frequently in male AML and female ALL patients than in controls. To date, this is the only study to evaluate the associations between HLA molecules and leukaemia in a Turkish population with acute childhood leukaemia. PMID- 21309501 TI - Perioperative risk factors for pulmonary complications after liver transplantation. AB - Using monofactorial and multivariate logistic regression analyses, the correlation of perioperative risk factors with postoperative pulmonary complications (PPCs) within 1 month after orthotopic liver transplantation (OLT) was investigated. Data on 107 patients (median age 46.8 years, 72% male) with end stage liver disease who received OLT were retrospectively analysed. The incidence of PPCs was 60.7%. Overall mortality was 13.1% and pulmonary causes accounted for 85.7% of deaths. Mortality was 18.5% and 4.8% for patients with and without pulmonary complications, respectively. Independent risk factors for PPCs were a preoperative model for end-stage liver disease (MELD) score > or =25, intraoperative fluid transfusion volume > 10 1 and intraoperative blood transfusion volume > 4 l. A fluid balance of < or = -300 ml for > or =2 days of the first 3 days after surgery was protective. Other variables studied did not predict PPCs. It was concluded that improving the patient's preoperative medical condition, restricting intraoperative transfusion volumes and maintaining a negative fluid balance in the first 3 days after operation may decrease PPCs. PMID- 21309502 TI - A case of lichen ruber planus in a patient with familial multiple sclerosis. AB - Multiple sclerosis and lichen ruber planus are clinically and histologically distinct complex disorders of putative autoimmune aetiology that are fairly commonly observed in isolation but rarely found in combination. Only two previous reports have described lichen skin disorders in association with multiple sclerosis. The present report describes the case of a 51-year-old Caucasian woman exhibiting both familial multiple sclerosis and lichen ruber planus. This combination may have occurred by chance or it might imply that these disorders share common mechanisms in their pathogenesis. PMID- 21309503 TI - Large phyllodes tumour of the seminal vesicle: case report and literature review. AB - A rare case of phyllodes tumour arising in the seminal vesicle is reported here. A 59-year-old male presented with lower abdominal discomfort and symptoms of bladder outlet obstruction for 1 year. Transrectal ultrasonography and pelvic computed tomography and magnetic resonance imaging demonstrated a large mass posterior to the bladder and anterior to the rectum. Tumour excision and right seminal vesiculectomy were performed via a transvesical approach. The left seminal vesicle, bladder and prostate were not involved. The patient had an uneventful post-operative course and recovered well. There was no evidence of recurrence or metastasis during 22 months of regular follow up. The diagnosis, histological classification, treatment and prognosis of this case are presented together with a review of the literature. It is suggested that the behaviour of phyllodes tumour of the seminal vesicle is related to its histological parameters. PMID- 21309504 TI - Solitary intracranial plasmacytoma located in the spheno-clival region mimicking chordoma: a case report. AB - Solitary intracranial plasmacytoma (SIP) is very rare. This case report presents serial findings of SIP located in the spheno-clival region in a 54-year old female who presented with an inferior hemianopia in the right eye and an enlarged physiological blind spot in both eyes. Based on the initial diagnosis of a spheno clival region chordoma, the tumour was partially resected by the nasal-sphenoidal sinus approach. Subsequently, the correct diagnosis of SIP was made based on the pathology and immunohistochemical staining of the tumour. The patient was treated using a whole skull-base radiation therapy protocol with 45 Gy and she was in good physical condition during the subsequent 22 months. The findings of a series of similar case reports documenting SIP in 20 cases published from 1976 to 2008 are also reviewed. Based on these case reports, the key features of SIP, including their clinical manifestations, clinical imaging characteristics, treatment and prognosis, are described. PMID- 21309505 TI - Post-operative implantation metastasis of craniopharyngioma: a case report. AB - Craniopharyngiomas are histologically benign epithelial tumours arising from squamous epithelial remnants of Rathke's pouch, which have a tendency to invade surrounding structures and recur after apparently complete resection. They represent the most frequent non-glial tumour in children, accounting for approximately 5% of paediatric brain neoplasms. Total resection of a craniopharyngioma may be difficult, and recurrence has been reported in 25-70% of patients. Recurrence often occurs at the primary site, although a few cases of ectopic recurrence along surgical or needle tracts have been reported. Here a case of metastatic adamantinomatous-type craniopharyngioma attributed to direct implantation by surgical procedure is presented, along with a review of the current literature on craniopharyngiomas. PMID- 21309506 TI - Bioinspired material based on femtosecond laser machining of cast sheet micromolding as a pattern transfer process. AB - We present herein a simple, fast, and easy-to-use process to replicate poly(methyl methacrylate) (PMMA) plates generating surface effects. First, a femtosecond laser has been used to fabricate, with sufficient accuracy, a periodic pattern on a glass plate at the microscale. This glass plate, used as a master, can be structured on a large distance with a good control of its roughness. Then, the polymer plates were obtained by bulk polymerization without any solvents with a good replication from the cast sheet process, which has been industrially performed for years. Thus, the modification of this process, environmentally friendly, lets us foresee new applications for commodity polymers by introducing visual iridescent properties and hydrophobicity exaltation. PMID- 21309507 TI - Low frequency vibrational modes of room temperature ionic liquids. AB - The vibrational spectra of four ionic liquids, sharing the same imidazolium cation but containing different anions-[bmim][NO(3)], [bmim][BF(4)], [bmim][PF(6)], and [bmim][NTf(2)]-have been obtained using normal-mode analysis within the harmonic approximation and from velocity autocorrelation functions from a molecular dynamics trajectory generated using empirical force fields. The vibrational density of states obtained from the two methods agree well. The low frequency modes (<100 cm(-1)) exhibit a red shift with an increase in the anion size. Deuteration of the ring hydrogens leads to a negligible change in this region of the spectrum. The participation ratio of low frequency modes is large, implying that they are not localized to a few atoms. The low frequency band arises primarily from short-range interionic interactions, and the exact peak position is modulated by the cation-anion hydrogen bond strength. Results obtained from these force-field-based calculations are confirmed by ab initio molecular dynamics simulations of crystalline [bmim][PF(6)]. PMID- 21309508 TI - Net air emissions from electric vehicles: the effect of carbon price and charging strategies. AB - Plug-in hybrid electric vehicles (PHEVs) may become part of the transportation fleet on time scales of a decade or two. We calculate the electric grid load increase and emissions due to vehicle battery charging in PJM and NYISO with the current generation mix, the current mix with a $50/tonne CO(2) price, and this case but with existing coal generators retrofitted with 80% CO(2) capture. We also examine all new generation being natural gas or wind+gas. PHEV fleet percentages between 0.4 and 50% are examined. Vehicles with small (4 kWh) and large (16 kWh) batteries are modeled with driving patterns from the National Household Transportation Survey. Three charging strategies and three scenarios for future electric generation are considered. When compared to 2020 CAFE standards, net CO(2) emissions in New York are reduced by switching from gasoline to electricity; coal-heavy PJM shows somewhat smaller benefits unless coal units are fitted with CCS or replaced with lower CO(2) generation. NO(X) is reduced in both RTOs, but there is upward pressure on SO(2) emissions or allowance prices under a cap. PMID- 21309509 TI - Detection of sulfur dioxide by cavity ring-down spectroscopy. AB - Sulfur dioxide (SO(2)) is a major air pollutant that can contribute to the production of particulate sulfate and increase the acidity in the environment. SO(2) is detected by cavity ring-down spectroscopy (CRDS) utilizing the SO(2) absorption in the 308 nm region. A ferrous sulfate scrubber and a sodium carbonate annular denuder are used to reduce background interferences and to obtain quantitative values of SO(2). The method is characterized using SO(2) standards in the laboratory and compared to a commercial pulsed fluorescence analyzer (PFA). A limit of detection of 3.5 ppb/10 s (S/N = 2) is demonstrated. Ambient measurements are attempted to demonstrate this technique. PMID- 21309510 TI - Metabolism of a new herbicide, [(14)c]pyribenzoxim, in rice. AB - The in vivo metabolism of a new herbicide pyribenzoxim (benzophenone Omicron-[2,6 bis(4,6-dimethoxypyrimidin-2-yloxy)benzoyl]oxime) in rice was carried out using container trials. Two radiolabeled forms of [carbonyl-(14)C]pyribenzoxim (P1) and [ring-(14)C(U)]pyribenzoxim (P2) were treated separately as formulations for foliar treatment by single applications of 50 g of active ingredient (ai)/ha at the 4-6 leaves stage. At 0, 7, 30, and 60 days after treatment (DAT), samples of panicle, foliage/rest of plant, and roots were taken for analysis. Upon harvest (120 DAT), rice plants were separated into grain, husk, straw, and root parts. Total radioactive residues (TRRs) at each sampling date were determined to show that the final radioactive residues at harvest were low in grain, husk, straw, and roots, accounting for <17 ppb. The concentration of final residues in the rice plant decreased rapidly, and less than 0.1% of initial TRRs remained at harvest. At 7 DAT, metabolite 1 [M1, 2,6-bis(4,6-dimethoxypyrimidin-2 yloxy)benzoic acid] and two unknown compounds (other-1 and other-2) were detected in foliage extract, accounting for 3.5% TRRs (21.0 ppb), 3.1% TRRs (19.0 ppb), and 9.0% TRRs (54.3 ppb), respectively, while 26.1% of M1 was observed in solvent wash. Any other metabolites were not detected in the plant, including expected metabolite M3 (benzophenone oxime). On the basis of the results obtained, a metabolic pathway of pyribenzoxim in a rice plant was proposed. PMID- 21309511 TI - Dynamic hydrogen-bonding network in the distal pocket of the nitrosyl complex of Pseudomonas aeruginosa cd1 nitrite reductase. AB - cd(1) nitrite reductase (NIR) is a key enzyme in the denitrification process that reduces nitrite to nitric oxide (NO). It contains a specialized d(1)-heme cofactor, found only in this class of enzymes, where the substrate, nitrite, binds and is converted to NO. For a long time, it was believed that NO must be released from the ferric d(1)-heme to avoid enzyme inhibition by the formation of ferrous-nitroso complex, which was considered as a dead-end product. However, recently an enhanced rate of NO dissociation from the ferrous form, not observed in standard b-type hemes, has been reported and attributed to the unique d(1) heme structure (Rinaldo, S.; Arcovito, A.; Brunori, M.; Cutruzzola, F. J. Biol. Chem. 2007, 282, 14761-14767). Here, we report on a detailed study of the spatial and electronic structure of the ferrous d(1)-heme NO complex from Pseudomonas aeruginosa cd(1) NIR and two mutants Y10F and H369A/H327A in solution, searching for the unique properties that are responsible for the relatively fast release. There are three residues at the "distal" side of the heme (Tyr(10), His(327), and His(369)), and in this work we focus on the identification and characterization of possible H-bonds they can form with the NO, thereby affecting the stability of the complex. For this purpose, we have used high field pulse electron-nuclear double resonance (ENDOR) combined with density functional theory (DFT) calculations. The DFT calculations were essential for assigning and interpreting the ENDOR spectra in terms of geometric structure. We have shown that the NO in the nitrosyl d(1)-heme complex of cd(1) NIR forms H-bonds with Tyr(10) and His(369), whereas the second conserved histidine, His(327), appears to be less involved in NO H-bonding. This is in contrast to the crystal structure that shows that Tyr(10) is removed from the NO. We have also observed a larger solvent accessibility to the distal pocket in the mutants as compared to the wild-type. Moreover, it was shown that the H-bonding network within the active site is dynamic and that a change in the protonation state of one of the residues does affect the strength and position of the H-bonds formed by the others. In the Y10F mutant, His(369) is closer to the NO, whereas mutation of both distal histidines displaces Tyr(10), removing its H-bond. The implications of the H-bonding network found in terms of the complex stability and catalysis are discussed. PMID- 21309512 TI - Rhodium phosphine-pi-arene intermediates in the hydroamination of alkenes. AB - A detailed mechanistic study of the intramolecular hydroamination of alkenes with amines catalyzed by rhodium complexes of a biaryldialkylphosphine is reported. The active catalyst is shown to contain the phosphine ligand bound in a kappa(1), eta(6) form in which the arene is pi-bound to rhodium. Addition of deuterated amine to an internal olefin showed that the reaction occurs by trans addition of the N-H bond across the C?C bond, and this stereochemistry implies that the reaction occurs by nucleophilic attack of the amine on a coordinated alkene. Indeed, the cationic rhodium fragment binds the alkene over the secondary amine, and the olefin complex was shown to be the catalyst resting state. The reaction was zero-order in substrate, when the concentration of olefin was high, and a primary isotope effect was observed. The primary isotope effect, in combination with the observation of the alkene complex as the resting state, implies that nucleophilic attack of the amine on the alkene is reversible and is followed by turnover-limiting protonation. This mechanism constitutes an unusual pathway for rhodium-catalyzed additions to alkenes and is more closely related to the mechanism for palladium-catalyzed addition of amide N-H bonds to alkenes. PMID- 21309513 TI - A quantitative analysis of the effect of nucleotides and the M domain on the association equilibrium of ClpB. AB - ClpB is a hexameric molecular chaperone that, together with the DnaK system, has the ability to disaggregate stress-denatured proteins. The hexamer is a highly dynamic complex, able to reshuffle subunits. To further characterize the biological implications of the ClpB oligomerization state, the association equilibrium of the wild-type (wt) protein and of two deletion mutants, which lack part or the whole M domain, was quantitatively analyzed under different experimental conditions, using several biophysical [analytical ultracentrifugation, composition-gradient (CG) static light scattering, and circular dichroism] and biochemical (ATPase and chaperone activity) methods. We have found that (i) ClpB self-associates from monomers to form hexamers and higher-order oligomers that have been tentatively assigned to dodecamers, (ii) oligomer dissociation is not accompanied by modifications of the protein secondary structure, (iii) the M domain is engaged in intersubunit interactions that stabilize the protein hexamer, and (iv) the nucleotide-induced rearrangement of ClpB affects the protein oligomeric core, in addition to the proposed radial extension of the M domain. The difference in the stability of the ATP- and ADP bound states [DeltaDeltaG(ATP-ADP) = -10 kJ/mol] might explain how nucleotide exchange promotes the conformational change of the protein particle that drives its functional cycle. PMID- 21309514 TI - Carcinoembryonic antigen admittance biosensor based on Au and ZnO nanoparticles using FFT admittance voltammetry. AB - In this work, a highly sensitive carcinoembryonic antigen fast Fourier transform admittance biosensor is introduced. The proposed biosensor is based on bilayer films of ZnO/Au nanoparticles as an immobilization matrix. These layers are prepared by self-assembly and deposition method on a gold electrode surface, respectively. Carcinoembryonic antibody (anti-CEA) was immobilized on gold nanoparticles and positively charged horseradish peroxidase (HRP) was used to block sites against nonspecific binding. The admittance biosensor was developed based on fast Fourier transform continuous square wave voltammetry, which produces a sensitive, fast (less than 20 s) and reliable response for determination of carcinoembryonic antigen. The technique was applied as a detector in a flow injection system. The admittances reduction current of the biosensor decreases linearly in two concentrations ranges of CEA from 0.1 to 70 ng/mL and from 70 to 200 ng/mL with a detection limit of 0.01 ng/mL in presence of 0.5 mM H(2)O(2) as an eluent solution. PMID- 21309515 TI - pH-dependent chirality of L-proline studied by Raman optical activity and density functional theory calculation. AB - The characteristic pyrrolidine ring structure of proline (Pro) and its conformational flexibility are important to its biological function in peptides and proteins. Properties of Pro in aqueous solution vary with the acid-base conditions. In this work, Raman optical activity (ROA) spectroscopy is used to carefully study the chirality of L-Pro in aqueous solution with different pH values. Raman shifts and ROA intensities are found to be directly correlated with the acidic or basic environment. Pyrrolidine ring torsions and carbonyl group twists differ in cation, zwitterion, and anion forms (denoted as ProCA, ProZW, and ProAN, respectively), as confirmed by the agreement between the experimental results and density functional theory (DFT) calculation. From analysis of vibrational modes and group couple matrices (GCMs), the local carbonyl group stretching modes may reflect electronic structure changes, and the couplings between the three CH2 group with others mainly contribute to the ROA intensities in the low wavenumber region (1400-700 cm(-1)). The dramatic changes of the distributions and dispersion of the ROA intensities indicate that an acidic or basic environment not only leads to the simple abstraction or addition of a proton but also changes the electron delocalization throughout the molecule. Isolation of the two symmetric anisotropic invariants shows the predominant contributions of the electric dipole-magnetic dipole invariant to the ROA signals in L-Pro. These results will be useful for interpreting the ROA spectra of proteins and at least proline-rich peptides. PMID- 21309516 TI - Long-term-stable ether-lipid vs conventional ester-lipid bicelles in oriented solid-state NMR: altered structural information in studies of antimicrobial peptides. AB - Recently, ether lipids have been introduced as long-term stable alternatives to the more natural, albeit easier degradable, ester lipids in the preparation of oriented lipid bilayers and bicelles for oriented-sample solid-state NMR spectroscopy. Here we report that ether lipids such as the frequently used 14-O PC (1,2-di-O-tetradecyl-sn-glycero-3-phosphocholine) may induce significant changes in the structure and dynamics, including altered interaction between peptides and lipids relative to what is observed with the more conventionally used DMPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine) bilayers. Such effects are demonstrated for the antimicrobial peptide novicidin, for which 2D separate local-field NMR and circular dichroism experiments reveal significant structural/conformational differences for the peptide in the two different lipid systems. Likewise, we observe altered secondary structure and different temperature-dependent membrane anchoring for the antimicrobial peptide alamethicin depending on whether the peptide is reconstituted into ester or ether lipids. Such observations are not particularly surprising considering the significant difference of the lipids in the phosphorus headgroup and they may provide important new insight into the delicate peptide-membrane interactions in the systems studied. In contrast, these observations reinforce the need to carefully consider potential structural changes in addition to long-term stability prior to the selection of membrane environment of membrane proteins in the analysis of their structure and dynamics. In more general terms, the results underscore the necessity in structural biology to address both the protein and its environments in studies relating structure to function. PMID- 21309518 TI - Elaiomycins B and C: alkylhydrazide antibiotics from Streptomyces sp. BK 190. AB - Two novel alkyhydrazides, elaiomycins B and C, together with the azoxy antibiotic elaiomycin were isolated from Streptomyces sp. BK 190. The structures were established by 1D- and 2D-NMR spectroscopy including (15)N NMR studies and high resolution orbitrap-ESI-mass spectrometry. PMID- 21309519 TI - Stereocontrolled synthesis of (+)-methoxyphenylkainic acid and (+)-phenylkainic acid. AB - The efficient total syntheses of (+)-methoxyphenylkainic acid (3) and (+) phenylkainic acid (4) were achieved using a rhodium carbenoid-mediated intermolecular C-H insertion reaction. Complete stereoselective construction of the kainoid skeleton was accomplished by utilizing the stereochemistry at the C-4 position as a pivotal stereogenic center. PMID- 21309520 TI - Autoxidative annulation cascade of the alpha-cyano beta-TMS-capped alkynyl cycloalkanone system. AB - The autoxidative annulation cascade promoted by an alpha-cyano beta-TMS-capped alkynyl cycloalkanone system under catalysis with pyridine in one oxygen atmosphere has proven to be highly viable. On the basis of this newly developed protocol, a variety of highly functionalized bicyclic frameworks can be effectively constructed. PMID- 21309521 TI - O-substituted alkyl aldehydes for rhodium-catalyzed intermolecular alkyne hydroacylation: the utility of methylthiomethyl ethers. AB - Combining alpha-methylthiomethyl (MTM) ether substituted aldehydes and 1-alkynes in the presence of [Rh(dppe)]ClO(4) results in efficient intermolecular alkyne hydroacylation to deliver alpha-O-MTM-substituted enone products. The product MTM ethers can be converted to the free hydroxyl group either in situ, by the addition of water to the completed reaction, or in a separate operation, by the action of silver nitrate. PMID- 21309522 TI - 6,13-dibromopentacene [2,3:9,10]-bis(dicarboximide): a versatile building block for stable pentacene derivatives. AB - 6,13-Dibromopentacene [2,3:9,10]-bis(dicarboximide) (1) was synthesized for the first time by using in situ generated benzo[1,2-c:4,5-c']difuran as a key intermediate. Compound 1 exhibits good photostability in comparison to other pentacene derivatives and it can be further functionalized by Pd-catalyzed coupling reactions to give a series of soluble and stable functional pentacenes. PMID- 21309523 TI - Organocatalytic sequential Michael reactions: stereoselective synthesis of multifunctionalized tetrahydroindan derivatives. AB - Multifunctionalized tetrahydroindan derivatives with four stereocenters were constructed via two sequential Michael reactions between cyclic gamma,delta unsaturated-beta-ketoester and nitroalkenes initiated with 0.5-2 mol % of cinchona alkaloid based bifunctional organocatalysts and then with 1 equiv of tetramethylguanidine for cyclization. The desired products could be obtained in high yields (up to 99% yield) with excellent enantioselectivities (95-99% ee) as well as diastereoselectivities (up to >99:1 dr) even on a gram scale. PMID- 21309524 TI - Hammett analysis of a family of carbene-carbene complex equilibria. AB - p-X-substituted phenylchlorocarbenes (X = NO(2), CF(3), Cl, H, Me, and MeO) form pi-type complexes with trimethoxybenzene in pentane. The carbenes and complexes are in equilibrium, and logarithms of the measured equilibrium constants are well correlated by Hammett sigma(p) constants with rho = 2.48. The carbene complexes are characterized by UV-vis spectroscopy, and computational analysis is afforded by DFT calculations. PMID- 21309525 TI - A short asymmetric route to the bromophycolide A and D skeleton. AB - An asymmetric synthesis of the bromophycolide D ring system has been achieved in seven steps from a known geranylgeranylated benzoate, via bromonium-promoted transannular cyclization of a macrocyclic intermediate. PMID- 21309526 TI - alpha,beta-Divinyl tetrahydropyrroles as chiral chain diene ligands in rhodium(I) catalyzed enantioselective conjugated additions. AB - A series of alpha,beta-divinyl tetrahydropyrroles, synthesized by asymmetric allylic C-H bond activation/conjugated diene addition reaction of ene-2-dienes, were found to be very efficient chiral chain diene ligands in the rhodium catalyzed conjugated addition of organoboronic acids to various alpha,beta unsaturated compounds, achieving the desired chiral adducts with good to excellent yields and ee values. PMID- 21309527 TI - Copper(II)-catalyzed conversion of bisaryloxime ethers to 2-arylbenzoxazoles via C-H functionalization/C-N/C-O bonds formation. AB - A copper(II)-catalyzed conversion of bisaryloxime ethers to 2-arylbenzoxazoles has been developed. The reaction involves a cascade C-H functionalization and C N/C-O bond formation under oxygen atmosphere. PMID- 21309528 TI - Stereospecific ring expansion of chiral vinyl aziridines. AB - In this report, it is demonstrated that chiral vinyl aziridines can be stereospecifically ring expanded. This synthetic approach allows controlled access to chiral 2,5-cis- or 2,5-trans-3-pyrroline products from starting materials with the appropriate aziridine geometry. Twenty three ring expansion examples, most of which feature a stereospecific cyclization, are presented. PMID- 21309529 TI - Nickel-catalyzed Negishi cross-coupling reactions of secondary alkylzinc halides and aryl iodides. AB - A general Ni-catalyzed process for the cross-coupling of secondary alkylzinc halides and aryl/heteroaryl iodides has been developed. This is the first process to overcome the isomerization and beta-hydride elimination problems that are associated with the use of secondary nucleophiles, and that have limited the analogous Pd-catalyzed systems. The impact of salt additives was also investigated. It was found that the presence of LiBF(4) dramatically improves both isomeric retention and yield for challenging substrates. PMID- 21309530 TI - Lewis acid catalyzed carbon-carbon bond cleavage of aryl oxiranyl diketones: synthesis of cis-2,5-disubstituted 1,3-dioxolanes. AB - Carbonyl ylide is one of the most important intermediates which can undergo a series of 1,3-dipolar cycloaddition reactions. The C-C heterolysis of oxirane is believed to be the most atom-economic and straightforward way to generate carbonyl ylide. However, this chemistry was only achieved under photochemical and thermal conditions in past years. In this work, the one-step diastereoselective synthesis of cis-2,5-disubstituted 1,3-dioxolanes via [3 + 2] cycloadditions of aldehydes and carbonyl ylide, which is obtained from Lewis acid catalyzed C-C bond heterolysis of aryl oxiranyl diketones at ambient temperature, is described. PMID- 21309531 TI - Nanopore analysis of beta-amyloid peptide aggregation transition induced by small molecules. AB - beta-Amyloid 42 (Abeta42) is the predominant form of the amyloid peptide, which is found in the plaques of the brains of Alzheimer's (AD) patients and is one of the most abundant components in amyloid aggregates. Information of the Abeta42 aggregation states is essential for developing an understanding of the pathologic process of amyloidoses. Here, we used alpha-hemolysin (alpha-HL) pores to probe the different aggregation transition of Abeta42 in the presence of beta cyclodextrin (beta-CD), a promoter of Abeta42 aggregations, and in the presence of Congo red (CR), an inhibitor of aggregations. Analyzing the characteristic transit duration times and blockade currents showed that beta-CD and CR have opposite effects on the aggregation of Abeta42. Translocation events of the monomeric Abeta42 peptide were significantly lower in amplitude currents than protofilaments, and protofilaments were captured in the alpha-HL nanopore with a longer duration time. CR binds to Abeta42 and its peptide fibrils by reducing the aggregated fibrils formation. In this process it is assumed CR interferes with intermolecular hydrogen bonding present in the aggregates. In contrast to CR, beta-CD promotes the aggregation of Abeta42. These differences can readily be analyzed by monitoring the corresponding characteristic blockade events using a biological alpha-HL nanopore. PMID- 21309532 TI - Capillary electrophoretic analysis reveals subcellular binding between individual mitochondria and cytoskeleton. AB - Interactions between the cytoskeleton and mitochondria are essential for normal cellular function. An assessment of such interactions is commonly based on bulk analysis of mitochondrial and cytoskeletal markers present in a given sample, which assumes complete binding between these two organelle types. Such measurements are biased because they rarely account for nonbound "free" subcellular species. Here we report on the use of capillary electrophoresis with dual laser induced fluorescence detection (CE-LIF) to identify, classify, count, and quantify properties of individual binding events of the mitochondria and cytoskeleton. Mitochondria were fluorescently labeled with DsRed2 while F-actin, a major cytoskeletal component, was fluorescently labeled with Alexa488 phalloidin. In a typical subcellular fraction of L6 myoblasts, 79% of mitochondrial events did not have detectable levels of F-actin, while the rest had on average ~2 zmol of F-actin, which theoretically represents a ~2.5 MUm long network of actin filaments per event. Trypsin treatment of L6 subcellular fractions prior to analysis decreased the fraction of mitochondrial events with detectable levels of F-actin, which is expected from digestion of cytoskeletal proteins on the surface of mitochondria. The electrophoretic mobility distributions of the individual events were also used to further distinguish between cytoskeleton-bound from cytoskeleton-free mitochondrial events. The CE LIF approach described here could be further developed to explore cytoskeleton interactions with other subcellular structures, the effects of cytoskeleton destabilizing drugs, and the progression of viral infections. PMID- 21309533 TI - A copper(I) isonitrile complex as a heterogeneous catalyst for azide-alkyne cycloaddition in water. AB - A structurally well-defined copper(I) isonitrile complex is shown to be an efficient, heterogeneous catalyst for the Huisgen azide-alkyne 1,3-dipolar cycloaddition under mild conditions in water. Notably, this catalyst can also be utilized in a three-component reaction of halides, sodium azide and alkynes to form 1,4-disubstituted 1,2,3-triazoles in high yields. Furthermore, it can be readily recovered by precipitation and filtration and recycled for at least five runs without significant loss of activity. PMID- 21309534 TI - Computer-readable DNAzyme assay on disc for ppb-level lead detection. AB - A method for the convenient detection of lead at the parts-per-billion (ppb) level has been developed; it uses a conventional compact disc (CD) as the platform for preparing DNAzyme assays and an unmodified optical drive of ordinary desktop/laptop computers as the readout device. In particular, by immobilization of Pb(2+)-specific DNAzyme sensing constructs on the "transparent side" of a conventional CD-R via mild surface reactions, the Pb(2+) concentration can be determined by a free diagnostic program that checks the error distribution on the CD (i.e., it extracts the number of errors in a prerecorded audio file). The reading errors increase monotonically over a wide range of Pb(2+) concentrations (from 10 nM to 1 mM), and the selectivity is confirmed by testing several other divalent cations (Zn(2+), Ba(2+), Mg(2+), Ca(2+), Cu(2+), and Hg(2+)). PMID- 21309535 TI - Protein-repellent silicon nitride surfaces: UV-induced formation of oligoethylene oxide monolayers. AB - The grafting of polymers and oligomers of ethylene oxide onto surfaces is widely used to prevent nonspecific adsorption of biological material on sensors and membrane surfaces. In this report, we show for the first time the robust covalent attachment of short oligoethylene oxide-terminated alkenes (CH(3)O(CH(2)CH(2)O)(3)(CH(2))(11)-(CH?CH(2)) [EO(3)] and CH(3)O(CH(2)CH(2)O)(6)(CH(2))(11)-(CH?CH(2)) [EO(6)]) from the reaction of alkenes onto silicon-rich silicon nitride surfaces at room temperature using UV light. Reflectometry is used to monitor in situ the nonspecific adsorption of bovine serum albumin (BSA) and fibrinogen (FIB) onto oligoethylene oxide coated silicon-rich silicon nitride surfaces (EO(n)-Si(x)N(4), x > 3) in comparison with plasma-oxidized silicon-rich silicon nitride surfaces (SiO(y)-Si(x)N(4)) and hexadecane-coated Si(x)N(4) surfaces (C(16)-Si(x)N(4)). A significant reduction in protein adsorption on EO(n)-Si(x)N(4) surfaces was achieved, adsorption onto EO(3)-Si(x)N(4) and EO(6)-Si(x)N(4) were 0.22 mg m(-2) and 0.08 mg m(-2), respectively. The performance of the obtained EO(3) and EO(6) layers is comparable to those of similar, highly protein-repellent monolayers formed on gold and silver surfaces. EO(6)-Si(x)N(4) surfaces prevented significantly the adsorption of BSA (0.08 mg m(-2)). Atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS), X-ray reflectivity and static water contact angle measurements were employed to characterize the modified surfaces. In addition, the stability of EO(6)-Si(x)N(4) surfaces in phosphate-buffered saline solution (PBS) and alkaline condition (pH 10) was studied. Prolonged exposure of the surfaces to PBS solution for 1 week or alkaline condition for 2 h resulted in only minor degradation of the ethylene oxide moieties and no oxidation of the Si(x)N(4) substrates was observed. Highly stable antifouling coatings on Si(x)N(4) surfaces significantly broaden the application potential of silicon nitride-coated microdevices, and in particular of microfabricated filtration membranes. PMID- 21309537 TI - Metallophilic bonding and agostic interactions in gold(I) and silver(I) complexes bearing a thiotetrazole unit. AB - Gold(I) and silver(I) complexes of 1-methyl-5-thio-tetrazole (1) have been prepared and the coordination chemistry of this ligand toward metal-phosphine frameworks has been explored. As indicated by IR and Raman data, ligand 1 is deprotonated and the resulted anion acts as a bidentate (S,N)-tetrazole-5 thiolato unit in the new gold(I) complexes, [Au(SCN(4)Me)(PPh(3))] (2), [{Au(SCN(4)Me)}(2)(MU-dppm)] (3), and [{Au(SCN(4)Me)}(2)(MU-dppe)] (4), while it is coordinated only through the sulfur atom as its neutral tetrazole-5-thione form in the silver(I) derivative, [Ag(HSCN(4)Me)(PPh(3))](2)(OTf)(2) (5). Further characterization of the new compounds was performed using multinuclear ((1)H, (13)C, (31)P, (19)F) NMR spectroscopy, mass spectrometry, and DSC measurements. Single-crystal X-ray diffraction studies revealed basically linear P-M-S arrangements in complexes 3-5. The bidentate (S,N) coordination pattern results in a T-shaped (S,N)PAu core in 3 and 4, whereas, in 5, a similar coordination geometry is achieved in the dimer association based on S-bridging ligand 1. Herein, weak (C)H...Au and (C)H...Ag agostic interactions were observed. An intramolecular Au...Au contact occurs in 3, while in 4 intermolecular aurophilic bonds lead to formation of a chain polymer. An intermolecular Ag...Ag contact is also present in the dimer unit of 5. Low-temperature (31)P NMR data for 5 evidenced the presence of monomer and dimer units in solution. Theoretical calculations on model of the complexes 2 and 4 are consistent with the geometries found by X-ray diffraction studies. PMID- 21309538 TI - Cation-cation "attraction": when London dispersion attraction wins over Coulomb repulsion. AB - London forces are omnipresent in nature and relevant to molecular engineering. Proper tuning of their energetic contribution may stabilize molecular aggregates, which would be otherwise highly unstable by virtue of other overwhelming repulsive terms. The literature contains a number of such noncovalently bonded molecular aggregates, of which the "binding mode" has never been thoroughly settled. Among those are the emblematic cationic complexes of tetrakis(isonitrile)rhodium(I) studied by a number of researchers. The propensity of these complexes to spontaneously produce oligomers has been an "open case" for years. For the dimer [(PhNC)(4)Rh](2)(2+), one of the archetypes of such oligomers, density functional theory methods (DFT-D3) and wave function based spin-component-scaled second-order Moller-Plesset perturbation theory (SCS-MP2) quantum chemical calculations indicate that when the eight isonitrile ligands arrange spatially in an optimal pi-stacked fashion, the energy due to dispersion not only overcomes coulombic repulsion but also the entropy penalty of complex formation. This central role of long-range electron correlation explains such cation-cation attractive interactions. Furthermore, the present findings relativize the role of the metal-metal "d(8)-d(8)" interactions, which are present on a relatively small scale compared to the effects of the ligands; d(8) d(8) interactions represent about 10-15% of the total dispersion contribution to the binding energy. PMID- 21309539 TI - Electronic--mechanical coupling in graphene from in situ nanoindentation experiments and multiscale atomistic simulations. AB - We present the in situ nanoindentation experiments performed on suspended graphene devices to introduce homogeneous tensile strain, while simultaneously carrying out electrical measurements. We find that the electrical resistance shows only a marginal change even under severe strain, and the electronic transport measurement confirms that there is no band gap opening for graphene under moderate uniform strain, which is consistent with our results from the first-principles informed molecular dynamics simulation. PMID- 21309540 TI - Photodissociation of CH3I: a full-dimensional (9D) quantum dynamics study. AB - The photodissociation of methyl iodide in the A band is studied by full dimensional (9D) wave packet dynamics calculations using the multiconfigurational time-dependent Hartree approach. The potential energy surfaces employed are based on the diabatic potentials of Xie et al. [J. Phys. Chem. A 2000, 104, 1009] and the vertical excitation energy is taken from recent ab initio calculations [Alekseyev et al. J. Chem. Phys.2007, 126, 234102]. The absorption spectrum calculated for exclusively parallel excitation agrees well with the experimental spectrum of the A band. The electronic population dynamics is found to be strongly dependent on the motion in the torsional coordinate related to the H(3) C-I bend, which presumably is an artifact of the diabatic model employed. The calculated fully product state-selected partial spectra can be interpreted based on the reflection principle and suggests strong coupling between the C-I stretching and the H(3)-C-I bending motions during the dissociation process. The computed rotational and vibrational product distributions typically reproduce the trends seen in the experiment. In agreement with experiment, a small but significant excitation of the total symmetric stretching and the asymmetric bending modes of the methyl fragment can be seen. In contrast, the umbrella mode of the methyl is found to be too highly excited in the calculated distributions. PMID- 21309541 TI - Study on potassium iso-propylxanthate and its decomposition products: experimental 13C CP/MAS NMR combined with DFT calculations. AB - Solid-state (13)C NMR is believed to be a valuable tool for studying adsorption and speciation of xanthates on sulfide mineral surfaces, but to do that, model compounds of possible xanthate species need to be investigated. (13)C NMR chemical shift tensors for molecular fragments of potassium iso-propylxanthate and six of its decomposition products have been determined by combining DFT calculations and (13)C CP/MAS NMR experiments. DFT calculations were performed in NWChem using GIAO method for the NMR shielding tensor calculations. The results of the calculations are in good agreement with experimental data. In the -XCYZ moiety (X, Y, Z = O, S), the more sulfur atoms, the more deshielded the chemical shift becomes and the larger the span of the chemical shift tensor. The delta11 principal value has the largest influence on the span, decreasing when the number of sulfur atoms decreases and the number of oxygen atoms increases. The significant differences in chemical shifts make it possible to distinguish between different species and, hence, in future studies, interpret surface speciation. The tensor parameters can also aid in the interpretation. PMID- 21309542 TI - Solvation dynamics by coherence period resolved transient grating. AB - We report a third-order nonlinear time-domain method, coherence period (tau) resolved transient grating (TRTG), that gives accurate solvation dynamics free from population relaxation in a short data acquisition time. The validity of TRTG is established by theory and experiment. The TRTG signal is shown to follow the transition frequency correlation function by an analytic expression based on the response function theory for delta function pulses and by model numerical calculations including finite pulse durations. TRTG is demonstrated for two cyanine dyes IR144 and IR125 in methanol by using a diffractive-optics based four wave mixing apparatus. Solvation dynamics in methanol obtained from the TRTG are consistent with those reported previously confirming the validity of TRTG. PMID- 21309543 TI - Maximum-score diversity selection for early drug discovery. AB - Diversity selection is a common task in early drug discovery. One drawback of current approaches is that usually only the structural diversity is taken into account, therefore, activity information is ignored. In this article, we present a modified version of diversity selection, which we term Maximum-Score Diversity Selection, that additionally takes the estimated or predicted activities of the molecules into account. We show that finding an optimal solution to this problem is computationally very expensive (it is NP-hard), and therefore, heuristic approaches are needed. After a discussion of existing approaches, we present our new method, which is computationally far more efficient but at the same time produces comparable results. We conclude by validating these theoretical differences on several data sets. PMID- 21309544 TI - Postprocessing of docked protein-ligand complexes using implicit solvation models. AB - Molecular docking plays an important role in drug discovery as a tool for the structure-based design of small organic ligands for macromolecules. Possible applications of docking are identification of the bioactive conformation of a protein-ligand complex and the ranking of different ligands with respect to their strength of binding to a particular target. We have investigated the effect of implicit water on the postprocessing of binding poses generated by molecular docking using MM-PB/GB-SA (molecular mechanics Poisson-Boltzmann and generalized Born surface area) methodology. The investigation was divided into three parts: geometry optimization, pose selection, and estimation of the relative binding energies of docked protein-ligand complexes. Appropriate geometry optimization afforded more accurate binding poses for 20% of the complexes investigated. The time required for this step was greatly reduced by minimizing the energy of the binding site using GB solvation models rather than minimizing the entire complex using the PB model. By optimizing the geometries of docking poses using the GB(HCT+SA) model then calculating their free energies of binding using the PB implicit solvent model, binding poses similar to those observed in crystal structures were obtained. Rescoring of these poses according to their calculated binding energies resulted in improved correlations with experimental binding data. These correlations could be further improved by applying the postprocessing to several of the most highly ranked poses rather than focusing exclusively on the top-scored pose. The postprocessing protocol was successfully applied to the analysis of a set of Factor Xa inhibitors and a set of glycopeptide ligands for the class II major histocompatibility complex (MHC) A(q) protein. These results indicate that the protocol for the postprocessing of docked protein-ligand complexes developed in this paper may be generally useful for structure-based design in drug discovery. PMID- 21309545 TI - Double-transduced MDCKII cells to study human P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) interplay in drug transport across the blood brain barrier. AB - P-glycoprotein (P-gp/ABCB1) and breast cancer resistance protein (BCRP/ABCG2) combination knockout mice display disproportionately increased brain penetration of shared substrates, including topotecan and several tyrosine kinase inhibitors, compared to mice deficient for only one transporter. To better study the interplay of both transporters also in vitro, we generated a transduced polarized MDCKII cell line stably coexpressing substantial levels of human ABCB1 and ABCG2 (MDCKII-ABCB1/ABCG2). Next, we measured concentration-dependent transepithelial transport of topotecan, sorafenib and sunitinib. By blocking either one or both of the transporters simultaneously, using specific inhibitors, we aimed to mimic the ABCB1-ABCG2 interplay at the blood-brain barrier in wild-type, single or combination knockout mice. ABCB1 and ABCG2 contributed to similar extents to topotecan transport, which was only partly saturable. For sorafenib transport, ABCG2 was the major determinant at low concentrations. However, saturation of ABCG2-mediated transport occurred at higher sorafenib concentrations, where ABCB1 was still fully active. Furthermore, sunitinib was transported equally by ABCB1 and ABCG2 at low concentrations, but ABCG2-mediated transport became saturated at lower concentrations than ABCB1-mediated transport. The relative impact of these transporters can thus be affected by the applied drug concentrations. A comparison of the in vitro observed (inverse) transport ratios and cellular accumulation of the drugs at low concentrations with in vivo brain penetration data from corresponding Abcb1a/1b-/-, Abcg2-/- and Abcb1a/1b;Abcg2-/- mouse strains revealed very similar qualitative patterns for each of the tested drugs. MDCKII-ABCB1/ABCG2 cells thus present a useful in vitro model to study the interplay of ABCB1 and ABCG2. PMID- 21309546 TI - Assessing the toxicity of naphthenic acids using a microbial genome wide live cell reporter array system. AB - Mixtures of naphthenic acids (NAs), which include cyclopentyl and cyclohexyl carboxylic acids, have been suggested to be toxic components in oils spills, effluents from the petrochemical industry and in oil sands process waters (OSPW). The present study demonstrated, for the first time, an application of a high throughput live bacterial cell array in a genome-scale investigation of the toxic mechanisms of environmental chemicals, a commercial NAs technical mixture extracted from crude oil. Real time gene profiling of time- and concentration- dependent responses of live cells exposed to NAs for three hours was conducted using a library of 1800 fluorescent transcriptional reporters for Escherichia coli (E. coli) growing in 384-well plates. The response patterns obtained after exposure to NAs suggested that the primary cellular responses were up-regulation of genes in the pentose phosphate pathway, involved in the molecular function of NADP or NADPH binding, and down-regulation of the ATP-binding cassette (ABC) transporter complex. Transcriptional networks that were significantly modulated by NAs included those that were regulated by transcriptional factors such as CRP , RecA-, and GadE. Down-regulation of the SOS response pathway suggested that DNA damage might not be the direct result of NAs within the first three hours of exposure. However, CRP-dependent genes modulated by exposure to NAs indicated that the cellular level of cyclic AMP was altered immediately upon exposure of cells to NAs. Furthermore, the linear range of the concentration-response curve of the selected gene reporters encompassed a range of concentrations between 10 and 1000 mg NAs/L, which covers concentrations typically observed in the environment and makes this assay system ideal for the detection of environmental NAs. PMID- 21309547 TI - Kinetics of the reactions of OH radicals with 2- and 3-methylfuran, 2,3- and 2,5 dimethylfuran, and E- and Z-3-hexene-2,5-dione, and products of OH + 2,5 dimethylfuran. AB - Furan and alkylfurans are present in the atmosphere from direct emissions and in situ formation from other volatile organic compounds. The OH radical-initiated reactions of furan and alkylfurans have been proposed as relatively clean in situ sources of unsaturated 1,4-dicarbonyls, some of which are otherwise not readily available. Using a relative rate method, rate constants at 296 +/- 2 K for the gas-phase reactions of OH radicals with 2- and 3-methylfuran, 2,3- and 2,5 dimethylfuran, and Z- and E-3-hexene-2,5-dione have been measured, of (in units of 10(-11) cm(3) molecule(-1) s(-1)): 2-methylfuran, 7.31 +/- 0.35; 3 methylfuran, 8.73 +/- 0.18; 2,3-dimethylfuran, 12.6 +/- 0.4; 2,5-dimethylfuran, 12.5 +/- 0.4; Z-3-hexene-2,5-dione, 5.90 +/- 0.57; and E-3-hexene-2,5-dione, 4.14 +/- 0.02. Products of the OH radical-initiated reaction of 2,5-dimethylfuran were investigated, with 3-hexene-2,5-dione being formed with molar yields of 24 +/- 3% in the presence of NO and 34 +/- 3% in the absence of NO. Direct air sampling atmospheric pressure ionization mass spectrometry showed the formation of additional products of molecular weight 114, attributed to CH(3)C(O)CH ? CHC(O)OH and/or 5-hydroxy-5-methyl-2-furanone, and 128, attributed to CH(3)C(O)OC(CH(3)) = CHCHO. PMID- 21309548 TI - Coupling sodium dodecyl sulfate-capillary polyacrylamide gel electrophoresis with matrix-assisted laser desorption ionization time-of-flight mass spectrometry via a poly(tetrafluoroethylene) membrane. AB - Sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis (PAGE) is a fundamental analytical technique for proteomic research, and SDS-capillary gel electrophoresis (CGE) is its miniaturized version. Compared to conventional slab gel electrophoresis, SDS-CGE has many advantages such as increased separation efficiency, reduced separation time, and automated operation. SDS-CGE is not widely accepted in proteomic research primarily due to the difficulties in identifying the well-resolved proteins. MALDI-TOF-MS is an outstanding platform for protein identifications. Coupling the two would solve the problem but is extremely challenging because the MS detector has no access to the SDS-CGE resolved proteins and the SDS interferes with MS detection. In this work we introduce an approach to address these issues. We discover that poly(tetrafluoroethylene) (PTFE) membranes are excellent materials for collecting SDS-CGE-separated proteins. We demonstrate that we can wash off the SDS bound to the collected proteins and identify these proteins on-membrane with MALDI-TOF-MS. We also show that we can immunoblot and Coomassie-stain the proteins collected on these membranes. PMID- 21309549 TI - Atomic-resolution imaging of spin-state superlattices in nanopockets within cobaltite thin films. AB - Certain cobalt oxides are known to exhibit ordered Co spin states, as determined from macroscopic techniques. Here we report real-space atomic-resolution imaging of Co spin-state ordering in nanopockets of La(0.5)Sr(0.5)CoO(3-delta) thin films. Unlike the bulk material, where no Co spin-state ordering is found, thin films present a strain-induced domain structure due to oxygen vacancy ordering, inside of which some nanometer sized domains show high-spin Co ions in the planes containing O vacancies and low-spin Co ions in the stoichiometric planes. First principles calculations provide support for this interpretation. PMID- 21309550 TI - High-performance, low-voltage, and easy-operable bending actuator based on aligned carbon nanotube/polymer composites. AB - In this work, we show that embedding super-aligned carbon nanotube sheets into a polymer matrix (polydimethylsiloxane) can remarkably reduce the coefficient of thermal expansion of the polymer matrix by two orders of magnitude. Based on this unique phenomenon, we fabricated a new kind of bending actuator through a two step method. The actuator is easily operable and can generate an exceptionally large bending actuation with controllable motion at very low driving DC voltages (<700 V/m). Furthermore, the actuator can be operated without electrolytes in the air, which is superior to conventional carbon nanotube actuators. Proposed electrothermal mechanism was discussed and confirmed by our experimental results. The exceptional bending actuation performance together with easy fabrication, low voltage, and controllable motion demonstrates the potential ability of using this kind of actuator in various applicable areas, such as artificial muscles, microrobotics, microsensors, microtransducers, micromanipulation, microcantilever for medical applications, and so on. PMID- 21309551 TI - Tunneling magnetoresistance with sign inversion in junctions based on iron oxide nanocrystal superlattices. AB - Magnetic tunnel junctions sandwiching a superlattice thin film of iron oxide nanocrystals (NCs) have been investigated. The transport was found to be controlled by Coulomb blockade and single-electron tunneling, already at room temperature. A good correlation was identified to hold between the tunnel magnetoresistance (TMR), the expected magnetic properties of the NC arrays, the charging energies evaluated from current-voltage curves, and the temperature dependence of the junction resistance. Notably, for the first time, a switching from negative to positive TMR was observed across the Verwey transition, with a strong enhancement of TMR at low temperatures. PMID- 21309552 TI - Synthesis and optical properties of triphenylene-based dendritic donor perylene diimide acceptor systems. AB - A donor-acceptor charge transfer system based on two discotic mesogens has been synthesized. The donor is either a triphenylene (POG0) or a triphenylene-based conjugated dendron (POG1), while the acceptor is a perylene diimide (PDI) core. The donors are covalently linked to the bay positions of the PDI core through an ether linkage. In chloroform, due to the short donor-acceptor distance and the matching frontier orbital levels, photoinduced charge transfer from either the donor excitation or the acceptor excitation are both thermodynamically and kinetically favored, resulting in efficient quenching of both donor and acceptor fluorescence. In a less polar solvent, hexane, while charge transfer is still the dominant mechanism for decay of the excited electronic state of POG1, photoinduced charge transfer is no longer energetically favorable for POG0 when the acceptor PDI core is excited, making the PDI core of POG0 weakly fluorescent in chloroform but strongly so in hexane. In solid film, POG0 is highly aggregated through both PDI-PDI and triphenylene-triphenylene homotopic stacking. POG1, on the other hand, aggregates through triphenylene dendrons with limited PDI-PDI core stacking, presumably due to the steric hindrance caused by bulky triphenylene moieties which block the access to the PDI core. The efficient photoinduced charge transfer, coupled with the homotopic stacking that forms separated electron-transporting PDI-stacked columns and hole transporting triphenylene-stacked columns, suggests that the reported donor-acceptor systems based on dual-discotic mesogens are potentially new efficient photovoltaic materials. PMID- 21309553 TI - Synthesis and growth mechanism of iron oxide nanowhiskers. AB - Iron oxide nanowhiskers with dimensions of approximately 2 * 20 nm were successfully synthesized by selectively heating an iron oleate complex. Such nanostructures resulted from the difference in the ligand coordination microenvironments of the Fe(III) oleate complex, according to our electronic structure calculations and thermogravimetric analysis. A ligand-directed growth mechanism was subsequently proposed to rationalize the growth process. The formation of the nanowhiskers provides a unique example of shape-controlled nanostructures, offering additional insights into nanoparticle synthesis. PMID- 21309554 TI - Disappearance and recovery of luminescence in Bi3+, Eu3+ codoped YPO4 nanoparticles due to the presence of water molecules up to 800 degrees C. AB - YPO(4) nanoparticles codoped with Eu(3+) (5 at. %) and Bi(3+) (2-10 at. %) have been synthesized by a simple coprecipitation method using a polyethylene glycol glycerol mixture, which acts as capping agent. It has been found that the incorporation of Bi(3+) ions into the YPO(4):Eu(3+) lattice induces a phase transformation from tetragonal to hexagonal, and also a significant decrease in Eu(3+) luminescence intensity was observed. This is related to the association of the water molecules in the hexagonal phase of YPO(4) in which the nonradiative process from the surrounding water molecules around Eu(3+) is dominating over the radiative process. On annealing above 800 degrees C, luminescence intensity recovers due to significant removal of water. 900 degrees C annealed Bi(3+) codoped YPO(4):Eu(3+) shows enhanced luminescence (2-3 times) as compared to that of YPO(4):Eu(3+). When sample was prepared in D(2)O (instead of H(2)O), 4-fold enhancement in luminescence was observed, suggesting the extent of reduction of multiphonon relaxation in D(2)O. This study illustrates the stability of water molecules even at a very high temperature up to 800 degrees C in Eu(3+) and Bi(3+) codoped YPO(4) nanoparticles. PMID- 21309555 TI - Stepwise synthesis of giant unilamellar vesicles on a microfluidic assembly line. AB - Among the molecular milieu of the cell, the membrane bilayer stands out as a complex and elusive synthetic target. We report a microfluidic assembly line that produces uniform cellular compartments from droplet, lipid, and oil/water interface starting materials. Droplets form in a lipid-containing oil flow and travel to a junction where the confluence of oil and extracellular aqueous media establishes a flow-patterned interface that is both stable and reproducible. A triangular post mediates phase transfer bilayer assembly by deflecting droplets from oil, through the interface, and into the extracellular aqueous phase to yield a continuous stream of unilamellar phospholipid vesicles with uniform and tunable size. The size of the droplet precursor dictates vesicle size, encapsulation of small-molecule cargo is highly efficient, and the single bilayer promotes functional insertion of a bacterial transmembrane pore. PMID- 21309556 TI - Tunable tunneling electroresistance in ferroelectric tunnel junctions by mechanical loads. AB - Combining nonequilibrium Green function's approach with density functional theory, effects of the applied mechanical loads on polarization, electrostatic potential, and tunneling conductance of a ferroelectric tunneling junction (FTJ) have been investigated. Using the first principle calculations, we show that compressive strains can induce and enhance the polarization in ferroelectric tunnel barriers, and practically achieve ferroelectricity in two unit cell thickness under a -2.2% compressive strain. More importantly, mechanical strains can significantly change the effective electrostatic potential in FTJ and thus control its tunneling conductance, which is defined as giant piezoelectric resistance (GPR) effect. Our calculations indicate that GPR effect is particularly significant near the paraelectric/ferroelectric phase transition, and increases exponentially with the barrier thickness. Furthermore, it is also found that defects of oxygen vacancies and nitrogen doping have little impact on GPR ratio of strained FTJ. Because of its high-sensitivity to external mechanical loads, FTJ with GPR effect should be adequate for applications in agile mechanical sensors, transducers, and other multifunctional devices. PMID- 21309557 TI - Thermionic field emission transport in carbon nanotube transistors. AB - With experimental and analytical analysis, we demonstrate a relationship between the metal contact work function and the electrical transport properties saturation current (Isat) and differential conductance (sigmasd=?Isd/?Vsd) in ambient exposed carbon nanotubes (CNT). A single chemical vapor deposition (CVD) grown 6 mm long semiconducting single-walled CNT is electrically contacted with a statistically significant number of Hf, Cr, Ti, Pd, and Au electrodes, respectively. The observed exponentially increasing relationship of Isat and sigmasd with metal contact work function is explained by a theoretical model derived from thermionic field emission. Statistical analysis and spread of the data suggest that the conduction variability in same CNT devices results from differences in local surface potential of the metal contact. Based on the theoretical model and methodology, an improved CNT-based gas sensing device layout is suggested. A method to experimentally determine gas-induced work function changes in metals is also examined. PMID- 21309558 TI - Thermal transport in nanoporous silicon: interplay between disorder at mesoscopic and atomic scales. AB - We present molecular and lattice dynamics calculations of the thermal conductivity of nanoporous silicon, and we show that it may attain values 10-20 times smaller than in bulk Si for porosities and surface-to-volume ratios similar to those obtained in recently fabricated nanomeshes. Further reduction of almost an order of magnitude is obtained in thin films with thickness of 20 nm, in agreement with experiment. We show that the presence of pores has two main effects on heat carriers: appearance of non-propagating, diffusive modes and reduction of the group velocity of propagating modes. The former effect is enhanced by the presence of disorder at the pore surfaces, while the latter is enhanced by decreasing film thickness. PMID- 21309559 TI - Nontrivial redox behavior of nanosized cobalt: new insights from ambient pressure X-ray photoelectron and absorption spectroscopies. AB - The reduction and oxidation of carbon-supported cobalt nanoparticles (3.50+/-0.22 nm) and a Co (0001) single crystal was investigated by ambient pressure X-ray photoelectron (APPES) and X-ray absorption (XAS) spectroscopies, applied in situ under 0.2 mbar hydrogen or oxygen atmospheres and at temperatures up to 620 K. It was found that cobalt nanoparticles are readily oxidized to a distinct CoO phase, which is significantly more stable to further oxidation or reduction compared to the thick oxide films formed on the Co(0001) crystal. The nontrivial size dependence of redox behavior is followed by a difference in the electronic structure as suggested by theoretical simulations of the Co L-edge absorption spectra. In particular, contrary to the stable rocksalt and spinel phases that exist in the bulk oxides, cobalt nanoparticles contain a significant portion of metastable wurtzite-type CoO. PMID- 21309560 TI - Large-area graphene single crystals grown by low-pressure chemical vapor deposition of methane on copper. AB - Graphene single crystals with dimensions of up to 0.5 mm on a side were grown by low-pressure chemical vapor deposition in copper-foil enclosures using methane as a precursor. Low-energy electron microscopy analysis showed that the large graphene domains had a single crystallographic orientation, with an occasional domain having two orientations. Raman spectroscopy revealed the graphene single crystals to be uniform monolayers with a low D-band intensity. The electron mobility of graphene films extracted from field-effect transistor measurements was found to be higher than 4000 cm(2) V(-1) s(-1) at room temperature. PMID- 21309561 TI - Contrasting the individual reactive pathways in protein unfolding and disulfide bond reduction observed within a single protein. AB - Identifying the dynamics of individual molecules along their reactive pathways remains a major goal of modern chemistry. For simple chemical reactions, the transition state position is thought to be highly localized. Conversely, in the case of more complex reactions involving proteins, the potential energy surfaces become rougher, resulting in heterogeneous reaction pathways with multiple transition state structures. Force-clamp spectroscopy experimentally probes the individual reaction pathways sampled by a single protein under the effect of a constant stretching force. Herein, we examine the distribution of conformations that populate the transition state of two different reactions; the unfolding of a single protein and the reduction of a single disulfide bond, both occurring within the same single protein. By applying the recently developed static disorder theory, we quantify the variance of the barrier heights, sigma(2), governing each distinct reaction. We demonstrate that the unfolding of the I27 protein follows a nonexponential kinetics, consistent with a high value of sigma(2) ~ 18 (pN nm)(2). Interestingly, shortening of the protein upon introduction of a rigid disulfide bond significantly modulates the disorder degree, spanning from sigma(2) ~ 8 to ~21 (pN nm)(2). These results are in sharp contrast with the exponential distribution of times measured for an S(N)2 chemical reaction, implying the absence of static disorder sigma(2) ~ 0 (pN nm)(2). Our results demonstrate the high sensitivity of the force-clamp technique to capture the signatures of disorder in the individual pathways that define two distinct force-induced reactions, occurring within the core of a single protein. PMID- 21309562 TI - Helical encapsulation of graphene nanoribbon into carbon nanotube. AB - Molecular dynamics (MD) simulations were performed to study interaction between the graphene nanoribbon (GNR) and single-wall carbon nanotube (SWCNT). The GNR enters the SWCNT spontaneously to display a helical configuration which is quite similar to the chloroplast in the spirogyra cell. This unique phenomenon results from the combined action of the van der Waals potential well and the pi-pi stacking interaction. The size of SWCNT and GNR should satisfy some certain conditions in the helical encapsulation process. A DNA-like double helix would be formed inside the SWCNT with the encapsulation of two GNRs. A water cluster enclosed in the SWCNT has great effect on the formation of the GNR helix in the tube. Furthermore, we also studied the possibility that the spontaneous encapsulation of GNR is used for substance delivery. The expected outcome of these properties is to provide novel strategies to design nanoscale carriers and reaction devices. PMID- 21309563 TI - Thermal stability of ascorbic acid and ascorbic acid oxidase in african cowpea leaves ( Vigna unguiculata ) of different maturities. AB - Cowpea, an African leafy vegetable ( Vigna unguiculata ), contains a high level of vitamin C. The leaves harvested at 4-9 weeks are highly prone to vitamin C losses during handling and processing. Therefore, the purpose of this research was to study the effect of thermal treatment on the stability of ascorbic acid oxidase (AAO), total vitamin C content (l-ascorbic acid, l-AA), and dehydroascorbic acid (DHAA) and l-AA/DHAA ratio in cowpea leaves harvested at different maturities (4, 6, and 8 weeks old). The results showed that AAO activity, total vitamin C content, and l-AA/DHAA ratio in cowpea leaves increased with increasing maturity (up to 8 weeks). Eight-week-old leaves were the best source of total vitamin C and showed a high ratio of l-AA/DHAA (4:1). Thermal inactivation of AAO followed first-order reaction kinetics. Heating at temperatures above 90 degrees C for short times resulted in a complete AAO inactivation, resulting in a protective effect of l-AA toward enzyme-catalyzed oxidation. Total vitamin C in young leaves (harvested at 4 and 6 weeks) was predominantly in the form of DHAA, and therefore temperature treatment at 30-90 degrees C for 10 min decreased the total vitamin C content, whereas total vitamin C in 8-week-old cowpea leaves was more than 80% in the form of l-AA, so that a high retention of the total vitamin C can be obtained even after heating and/or reheating (30-90 degrees C for 10 min) before consumption. The results indicated that the stability of total vitamin C in situ was strongly dependent on the plant maturity stage and the processing conditions applied. PMID- 21309564 TI - Simple and rapid method for the analysis of phenolic compounds in beverages and grains. AB - A new method for the detection of phenolics in food systems was developed. This method is based on interactions of phenolics with Fast Blue BB diazonium salt in alkali pH, forming azo complexes, with the absorbance measured at 420 nm after 60 min. The linear regression correlations (R(2)) of gallic acid calibration standards were >0.99. The phenolic content (gallic acid equivalent) of samples analyzed yielded higher ratios (1.7-6.6) of the total phenolics by Fast Blue BB to Folin-Ciocalteu methods in most beverages and grain samples, but in flaxseed and some juice blends, the ratios were <1. The lower ratios suggest the presence of non-phenolic reducing constituents measured with the Folin-Ciocalteu method as "total phenolics". This method is simple and inexpensive and can be used to rapidly assess the total phenolics of foods and beverages. PMID- 21309565 TI - High-quality thin graphene films from fast electrochemical exfoliation. AB - Flexible and ultratransparent conductors based on graphene sheets have been considered as one promising candidate for replacing currently used indium tin oxide films that are unlikely to satisfy future needs due to their increasing cost and losses in conductivity on bending. Here we demonstrate a simple and fast electrochemical method to exfoliate graphite into thin graphene sheets, mainly AB stacked bilayered graphene with a large lateral size (several to several tens of micrometers). The electrical properties of these exfoliated sheets are readily superior to commonly used reduced graphene oxide, which preparation typically requires many steps including oxidation of graphite and high temperature reduction. These graphene sheets dissolve in dimethyl formamide (DMF), and they can self-aggregate at air-DMF interfaces after adding water as an antisolvent due to their strong surface hydrophobicity. Interestingly, the continuous films obtained exhibit ultratransparency (~96% transmittance), and their sheet resistance is <1k Omega/sq after a simple HNO3 treatment, superior to those based on reduced graphene oxide or graphene sheets by other exfoliation methods. Raman and STM characterizations corroborate that the graphene sheets exfoliated by our electrochemical method preserve the intrinsic structure of graphene. PMID- 21309566 TI - Nitrogen-promoted self-assembly of N-doped carbon nanotubes and their intrinsic catalysis for oxygen reduction in fuel cells. AB - Nitrogen atoms were found to exhibit a strong ability to promote the self assembly of nitrogen-doped carbon nanotubes (NCNTs) from gaseous carbons, without an assistance of metal atoms. On the basis of this discovery, pure metal-free CNTs with a nitrogen-doping level as high as 20 atom % can be directly synthesized using melamine as a C/N precursor. This offers a novel pathway for carbon nanotube synthesis. Furthermore, the metal-free and intact characteristics of the NCNT samples facilitate a clear verification of the intrinsic catalytic ability of NCNTs. The results show that the NCNTs intrinsically display excellent catalytic activity for oxygen reduction in fuel cells, comparable to traditional platinum-based catalysts. More notably, they exhibit outstanding stability, selectivity, and resistance to CO poisoning, much superior to the platinum-based catalysts. PMID- 21309567 TI - Inelastic electron tunneling spectroscopy of gold-benzenedithiol-gold junctions: accurate determination of molecular conformation. AB - The gold-benzenedithiol-gold junction is the classic prototype of molecular electronics. However, even with the similar experimental setup, it has been difficult to reproduce the measured results because of the lack of basic information about the molecular confirmation inside the junction. We have performed systematic first principles study on the inelastic electron tunneling spectroscopy of this classic junction. By comparing the calculated spectra with four different experimental results, the most possible conformations of the molecule under different experimental conditions have been successfully determined. The relationship between the contact configuration and the resulted spectra is revealed. It demonstrates again that one should always combine the theoretical and experimental inelastic electron tunneling spectra to determine the molecular conformation in a junction. Our simulations have also suggested that in terms of the reproducibility and stability, the electromigrated nanogap technique is much better than the mechanically controllable break junction technique. PMID- 21309568 TI - A convergent synthesis of the C1-C16 segment of goniodomin A via palladium catalyzed organostannane-thioester coupling. AB - A convergent synthesis of the C1-C16 segment of goniodomin A, an actin-targeting marine polyether macrolide natural product, has been achieved via a 2-fold application of palladium-catalyzed organostannane-thioester coupling. PMID- 21309569 TI - Nature of electron transport by pyridine-based tripodal anchors: potential for robust and conductive single-molecule junctions with gold electrodes. AB - We have designed and synthesized a pyridine-based tripodal anchor unit to construct a single-molecule junction with a gold electrode. The advantage of tripodal anchoring to a gold surface was unambiguously demonstrated by cyclic voltammetry measurements. X-ray photoelectron spectroscopy measurements indicated that the pi orbital of pyridine contributes to the physical adsorption of the tripodal anchor unit to the gold surface. The conductance of a single-molecule junction that consists of the tripodal anchor and diphenyl acetylene was measured by modified scanning tunneling microscope techniques and successfully determined to be 5 +/- 1 * 10(-4)G(0). Finally, by analyzing the transport mechanism based on ab initio calculations, the participation of the pi orbital of the anchor moieties was predicted. The tripodal structure is expected to form a robust junction, and pyridine is predicted to achieve pi-channel electric transport. PMID- 21309570 TI - Epitaxy of rodlike organic molecules on sheet silicates--a growth model based on experiments and simulations. AB - During the last years, self-assembled organic nanostructures have been recognized as a proper fundament for several electrical and optical applications. In particular, phenylenes deposited on muscovite mica have turned out to be an outstanding material combination. They tend to align parallel to each other forming needlelike structures. In that way, they provide the key for macroscopic highly polarized emission, waveguiding, and lasing. The resulting anisotropy has been interpreted so far by an induced dipole originating from the muscovite mica substrate. Based on a combined experimental and theoretical approach, we present an alternative growth model being able to explain molecular adsorption on sheet silicates in terms of molecule-surface interactions only. By a comprehensive comparison between experiments and simulations, we demonstrate that geometrical changes in the substrate surface or molecule lead to different molecular adsorption geometries and needle directions which can be predicted by our growth model. PMID- 21309571 TI - Supramolecular AA-BB-type linear polymers with relatively high molecular weights via the self-assembly of bis(m-phenylene)-32-crown-10 cryptands and a bisparaquat derivative. AB - Two novel bis(m-phenylene)-32-crown-10-based cryptands, one bearing covalent linkages and the other metal-complex linkages, were designed and prepared. By self-assembly of these biscryptands, which can be viewed as AA monomers, and a bisparaquat, which can be viewed as a BB monomer, AA-BB-type linear supramolecular polymers with relatively high molecular weights were successfully prepared. PMID- 21309572 TI - Hierarchical gold-decorated magnetic nanoparticle clusters with controlled size. AB - We present a new route to stable magnetic-plasmonic nanocomposite materials with exceptional control over composite size and very high monodispersity. The method involves the assembly of magnetic iron oxide nanoparticles, of any size in the superparamagnetic size range, whose steric repulsion is gradually reduced by competitive stabilizer desorption arising from the presence of a tertiary silica phase. Subsequent addition of gold nanoparticles results in hierarchical assemblies in the form of gold-decorated magnetic nanoparticle clusters, in a range of possible sizes from 20 to 150 nm, selected by the timing of the addition. This approach adds plasmonic and chemical functionality to the magnetic clusters and improves the physical robustness and processability of the suspensions. Most critically, detailed NMR relaxation analysis demonstrates that the effect of the gold NPs on the interaction between bulk solvent and the magnetic moments of the cluster is minimal and that the clusters remain superparamagnetic in nature. These advantages enhance the potential of the materials as size-selected contrast agents for magnetic resonance imaging. The possibility of generalizing the approach for the production of hierarchical assemblies of variable composition is also demonstrated. PMID- 21309573 TI - Rhodium-catalyzed enantioselective addition of boronic acids to N benzylnicotinate salts. AB - The highly enantioselective catalytic asymmetric addition of aryl and alkenylboronic acids to N-benzylnicotinate salt 1 is described. The dihydropyridine 2 reaction products can be converted to synthetically useful piperidines. Application of the methodology to the preparation of enantioenriched quaternary chiral centers is also discussed. PMID- 21309574 TI - Flavonoids from Radix Astragali induce the expression of erythropoietin in cultured cells: a signaling mediated via the accumulation of hypoxia-inducible factor-1alpha. AB - Radix Astragali (RA) is commonly used as a health food supplement to reinforce the body vital energy. Flavonoids, including formononetin, ononin, calycosin, and calycosin-7-O-beta-d-glucoside, are considered to be the major active ingredients within RA. Here, we provided different lines of evidence that the RA flavonoids stimulated the expression of erythropoietin (EPO), the central regulator of red blood cell mass, in cultured human embryonic kidney fibroblasts (HEK293T). A plasmid containing hypoxia response element (HRE), a critical regulator for EPO transcription, was tagged upstream of a firefly luciferase gene, namely, pHRE Luc, which was being transfected into fibroblasts. The application of RA flavonoids onto the transfected cells induced the transcriptional activity of HRE. To account for the transcriptional activation after the treatment of flavonoids, the expression of hypoxia-inducible factor-1alpha (HIF-1alpha) was markedly increased: The increase was in both mRNA and protein levels. In addition, the degradation of HIF-1alpha was reduced under the effect of flavonoids. The regulation of HIF-1alpha therefore could account for the activation of EPO expression mediated by the RA flavonoids. The current results therefore reveal the function of this herb in enhancing hematopoietic functions. PMID- 21309575 TI - Kinetic study of the quenching reaction of singlet oxygen by Pyrroloquinolinequinol (PQQH(2), a reduced form of Pyrroloquinolinequinone) in micellar solution. AB - A kinetic study of the quenching reaction of singlet oxygen ((1)O(2)) with pyrroloquinolinequinol (PQQH(2), a reduced form of pyrroloquinolinequinone (PQQ)), PQQNa(2) (disodium salt of PQQ), and seven kinds of natural antioxidants (vitamin C (Vit C), uric acid (UA), epicatechin (EC), epigallocatechin (EGC), alpha-tocopherol (alpha-Toc), ubiquinol-10 (UQ(10)H(2)), and beta-carotene (beta Car)) has been performed. The second-order rate constants k(Q) (k(Q) = k(q) + k(r), physical quenching and chemical reaction) for the reaction of (1)O(2) with PQQH(2), PQQNa(2), and seven kinds of antioxidants were measured in 5.0 wt % Triton X-100 micellar solution (pH 7.4), using UV-visible spectrophotometry. The k(Q) values decreased in the order of beta-Car > PQQH(2) > alpha-Toc > UA > UQ(10)H(2) > Vit C ~ EGC > EC ? PQQNa(2). PQQH(2) is a water-soluble antioxidant. The singlet oxygen-quenching activity of PQQH(2) was found to be 6.3, 2.2, 6.1, and 22 times as large as the corresponding those of water-soluble antioxidants (Vit C, UA, EGC, and EC). Further, the activity of PQQH(2) was found to be 2.2 and 3.1 times as large as the corresponding activity of lipid-soluble antioxidants (alpha-Toc and UQ(10)H(2)). On the other hand, the activity of PQQH(2) is 6.4 times as small as that of beta-Car. It was observed that the chemical reaction (k(r)) is almost negligible in the quenching reaction of (1)O(2) by PQQH(2). The result suggests that PQQH(2) may contribute to the protection of oxidative damage in biological systems, by quenching (1)O(2). PMID- 21309576 TI - Discovery of sulfated sterols from marine invertebrates as a new class of marine natural antagonists of farnesoid-X-receptor. AB - We report the biochemical characterization of sulfated polyhydroxysterols isolated from marine invertebrates as potent antagonists of farnesoid-X-receptor (FXR), a ligand-regulated transcription factor involved in the regulation of lipid and glucose homeostasis in mammals. Molecular characterization of a library of sulfated polyhydroxysteroids resulted in the identification of a first FXR antagonist. In contrast to partial antagonists, this compound was endowed with an antagonistic activity on the expression of a subset of FXR-regulated genes in liver cells and abrogated the release of nuclear coreceptor from the promoter of these genes. The putative binding mode to FXR, obtained through docking calculations, suggested the crucial role played by the bent shape of the molecule as well as the presence of one hydroxyl group in its side chain. This compound is a major tool to explore the effect of FXR inhibition in pharmacological settings. PMID- 21309577 TI - Design, synthesis, and biological evaluation of new cinnamic derivatives as antituberculosis agents. AB - Tuberculosis, HIV coinfection with TB, emergence of multidrug-resistant TB, and extensively drug-resistant TB are the major causes of death from infectious diseases worldwide. Because no new drug has been introduced in the last several decades, new classes of molecules as anti-TB drugs are urgently needed. Herein, we report the synthesis and structure-activity relationships of a series of thioester, amide, hydrazide, and triazolophthalazine derivatives of 4-alkoxy cinnamic acid. Many compounds exhibited submicromolar minimum inhibitory concentrations against Mycobacterium tuberculosis strain (H(37)Rv). Interestingly, compound 13e, a 4-isopentenyloxycinnamyl triazolophthalazine derivative, was found to be 100-1800 times more active than isoniazid (INH) when tested for its ability to inhibit the growth of INH-resistant M. tuberculosis strains. The results also revealed that 13e does not interfere with mycolic acid biosynthesis, thereby pointing to a different mode of action and representing an attractive lead compound for the development of new anti-TB agents. PMID- 21309578 TI - Influence of end-capping on the self-assembly of model amyloid peptide fragments. AB - The influence of charge and aromatic stacking interactions on the self-assembly of a series of four model amyloid peptides has been examined. The four model peptides are based on the KLVFF motif from the amyloid beta peptide, Abeta(16-20) extended at the N terminus with two beta-alanine residues. We have studied NH(2) betaAbetaAKLVFF-COOH (FF), NH(2)-betaAbetaAKLVF-COOH (F), CH(3)CONH betaAbetaAKLVFF-CONH(2) (CapF), and CH(3)CONH-betaAbetaAKLVFF-CONH(2) (CapFF). The former two are uncapped (net charge +2) and differ by one hydrophobic phenylalanine residue; the latter two are the analogous capped peptides (net charge +1). The self-assembly characteristics of these peptides are remarkably different and strongly dependent on concentration. NMR shows a shift from carboxylate to carboxylic acid forms upon increasing concentration. Saturation transfer measurements of solvent molecules indicate selective involvement of phenylalanine residues in driving the self-assembly process of CapFF due presumably to the effect of aromatic stacking interactions. FTIR spectroscopy reveals beta-sheet features for the two peptides containing two phenylalanine residues but not the single phenylalanine residue, pointing again to the driving force for self-assembly. Circular dichroism (CD) in dilute solution reveals the polyproline II conformation, except for F which is disordered. We discuss the relationship of this observation to the significant pH shift observed for this peptide when compared the calculated value. Atomic force microscopy and cryogenic TEM reveals the formation of twisted fibrils for CapFF, as previously also observed for FF. The influence of salt on the self-assembly of the model beta sheet forming capped peptide CapFF was investigated by FTIR. Cryo-TEM reveals that the extent of twisting decreases with increased salt concentration, leading to the formation of flat ribbon structures. These results highlight the important role of aggregation-induced pK(a) shifts in the self-assembly of model beta-sheet peptides. PMID- 21309579 TI - A unified, probabilistic framework for structure- and ligand-based virtual screening. AB - We present a probabilistic framework for interpreting structure-based virtual screening that returns a quantitative likelihood of observing bioactivity and can be quantitatively combined with ligand-based screening methods to yield a cumulative prediction that consistently outperforms any single screening metric. The approach has been developed and validated on more than 30 different protein targets. Transforming structure-based in silico screening results into robust probabilities of activity enables the general fusion of multiple structure- and ligand-based approaches and returns a quantitative expectation of success that can be used to prioritize (or deprioritize) further discovery activities. This unified probabilistic framework offers a paradigm shift in how docking and scoring results are interpreted, which can enhance early lead-finding efforts by maximizing the value of in silico computational tools. PMID- 21309580 TI - IR spectra of flavins in solution: DFT/MM description of redox effects. AB - The functional reactions in blue light photoreceptors generally involve transiently reduced flavins exhibiting characteristic infrared (IR) spectra. To approach a theoretical understanding, here we apply density functional theory (DFT) to flavin radicals embedded in a molecular mechanics (MM) model of an aqueous solution. Combining a DFT/MM approach with instantaneous normal-mode analyses (INMA), we compute the IR solution spectra of anionic and neutral flavin radicals. For a set of mid-IR marker bands, we identify those changes of spectral locations, intensities, and widths, which are caused by sequentially adding an electron and a proton to the oxidized flavin. Comparisons with experimental IR solution spectra of flavin radicals show the accuracy of our DFT/MM-INMA approach and allow us to assign the observed bands. The room temperature ensembles of solvent cages required for the INMA calculations of the IR spectra are generated in an MM setting from molecular dynamics (MD) simulations. For the solvated flavin radicals, these MD simulations employ MM force fields derived from DFT/MM calculations. PMID- 21309581 TI - More than 100,000 detectable peptide species elute in single shotgun proteomics runs but the majority is inaccessible to data-dependent LC-MS/MS. AB - Shotgun proteomics entails the identification of as many peptides as possible from complex mixtures. Here we investigate how many peptides are detectable by high resolution MS in standard LC runs of cell lysate and how many of them are accessible to data-dependent MS/MS. Isotope clusters were determined by MaxQuant and stringently filtered for charge states and retention times typical of peptides. This resulted in more than 100,000 likely peptide features, of which only about 16% had been targeted for MS/MS. Three instrumental attributes determine the proportion of additional peptides that can be identified: sequencing speed, sensitivity, and precursor ion isolation. In our data, an MS/MS scan rate of 25/s would be necessary to target all peptide features, but this drops to less than 17/s for reasonably abundant peptides. Sensitivity is a greater challenge, with many peptide features requiring long MS/MS injection times (>250 ms). The greatest limitation, however, is the generally low proportion of the target peptide ion intensity in the MS/MS selection window (the "precursor ion fraction" or PIF). Median PIF is only 0.14, making the peptides difficult to identify by standard MS/MS methods. Our results aid in developing strategies to further increase coverage in shotgun proteomics. PMID- 21309582 TI - Automated synthesis of a 184-member library of thiadiazepan-1,1-dioxide-4-ones. AB - The construction of a 225-member (3 * 5 * 15) library of thiadiazepan-1,1-dioxide 4-ones was performed on a Chemspeed Accelerator (SLT-100) automated parallel synthesis platform, culminating in the successful preparation of 184/225 sultams. Three sultam core scaffolds were prepared based upon the utilization of an aza Michael reaction on a multifunctional vinyl sulfonamide linchpin. The library exploits peripheral diversity in the form of a sequential, two-step [3 + 2] Huisgen cycloaddition/Pd-catalyzed Suzuki-Miyaura coupling sequence. PMID- 21309583 TI - Molecular transport through surfactant-covered oil-water interfaces: role of physical properties of solutes and surfactants in creating energy barriers for transport. AB - Mechanisms of molecular transport across oil-water interfaces covered by nonionic surfactants are investigated using coarse-grained molecular dynamics simulations. Resistance of the surfactant monolayer to the solute transport is shown to be controlled by dense regions in the monolayer. The dense regions are formed on both sides of the dividing surface and the barrier to the solute transport is created by those of them experiencing unfavorable interactions with the solute. Resistance to the transport of a hydrophobic (hydrophilic) solute increases with the excess density of the head (tail) group region of the monolayer, which in turn increases with the length of the surfactant head (tail) group. Barriers for solute transport through surfactant monolayers are also influenced by the solute size. However, the extent of this influence is determined by the monolayer thickness and the solute structure and composition. For example, it is shown that resistance offered by thin monolayers to transport of linear oligomers is relatively insensitive to the solute length. The barrier sensitivity to the length of these solutes increases with the monolayer thickness. In addition to the static barriers, the solute transport is shown to be affected by dynamic barriers due to a nonadiabatic coupling of the monolayer surface with the solute position and configuration. This coupling leads to deviations of the system dynamics from the minimum energy path. The deviations are most significant in the neighborhood of the static energy barrier, which effectively leads to an increase of the barrier for the solute transport. PMID- 21309584 TI - An in-depth analysis of polymer-analogous conjugation using DMTMM. AB - Combinatorial libraries have become increasingly popular in the field of functional biomaterials. One approach for creating diverse polymer libraries is polymer-analogous conjugation of functional groups to polymer scaffolds. In this study, we show that a water-soluble condensing agent, 4-(4,6-dimethoxy-1,3,5 triazin-2-yl)-4-methylmorpholinium chloride (DMTMM), can be employed to conjugate two disparate model ligands, d-(+)-galactosamine (Gal) and agmatine (Agm), to the side chains of either poly(methacrylic acid) (pMAA) or poly(acrylic acid) (pAA) at various substitution ratios. The degree of substitution was found to be directly influenced by media pH, polymer concentration, structure of ligands, and polymer precursor. A nearly 2-fold increase in conjugation efficiencies for both ligands to pAA was achieved as compared to pMAA under identical conditions reaching up to 56% and 78% of Gal and Agm of total content, respectively. These two structurally similar polymers showed remarkably different performances, which reveals that the selection of a polymer precursor is crucial for the optimal design of polymeric libraries, particularly when complex structural ligands are involved. The approach employed provides a basis from which larger and more diverse combinatorial libraries of functionalized polymers with multiple moieties can be generated. PMID- 21309585 TI - Polymer-supported organotin reagent for prosthetic group labeling of biological macromolecules with radioiodine. AB - In this study, we investigated the use of poly-mer-bound precursor for generating a radiolabeled prosthetic group to be used for conjugate labeling of biological macromolecules. For the approach, a trialkyltin chloride in which the tin was bound to a hydrophilic PEG-based resin support via one of the alkyl groups was synthesized. This resin was then used to prepare a resin-bound trialkyltin benzoic acid, which in some cases was further derivatized on-resin by converting it to a succinimidyl ester. Exposure of the resin-bound compounds to electrophilic radioiodine (125I) in either an aqueous or methanol solvent liberated either free radiolabeled [125I]iodobenzoic acid or its succinimidyl ester without co-release of the resin-bound precursors. Radiochemical yield was between 35% and 75%, depending on the solvent system and precursor. As example applications for the released compounds, the amine-reactive N-succinimidyl [125I]iodobenzoate prosthetic group was used for conjugate radiolabeling of a peptide, tomato plant systemin, and two proteins, albumin and IgG antibody. These results demonstrate that resin-bound organotin precursors in which the compound to be labeled is tethered to the support via the tin group to be substituted can be used to produce radioiodine-labeled aromatic prosthetic groups in good specific activity without the need for HPLC purification. This solid-phase approach is potentially adaptable to kit-formulation for performing conjugate radiolabeling of biological macromolecules. PMID- 21309586 TI - Spectroscopic ellipsometry study on refractive index spectra of colloidal beta FeOOH nanorods with their self-assembled thin films. AB - We prepared monodisperse colloidal beta-FeOOH (square prismatic crystalline) nanorods. Self-assembled dry thin films of the rods were formed on quartz substrates by evaporating drops of repulsive-rod suspensions. Using spectroscopic ellipsometry, the complex refractive index spectra of the beta-FeOOH nanorod films were deduced, which are further corrected on the basis of absorption spectra measured for beta-FeOOH nanorod suspensions, with aid of the Kramers Kronig relation and an optical two-phase mixing model. Simultaneously, in this correction process, the rod volume fraction in the films and the complex mean refractive index spectra of purely the rod were extracted together. The real part of the refractive index spectra of the beta-FeOOH rod, n'(c)(lambda), shows a maximal value of 2.365 (aver.) at 410 nm (lambda(m)) (hence a normal dispersion at lambda > lambda(m) and an anomalous dispersion at lambda < lambda(m)). At lambda = 589.3 nm (lambda(D) for "sodium light"), the n'(c)(lambda) value is consistent with refractive indices predicted by Gladstone-Dale's and Anderson's refractivity formulas with the density of the beta-FeOOH rod, 3.638 +/- 0.104 g/cm(3), measured in this work. PMID- 21309587 TI - Interaction between DNA and microcystin-LR studied by spectra analysis and atomic force microscopy. AB - Microcystin-LR (MC-LR) is one of the hepatotoxins produced by cyanobacteria in the eutrophicated fresh water. In this work, the minor groove binding mode of MC LR to plasmid DNA was explored by using UV and fluorescence spectra, and the binding characteristics of MC-LR for plasmid DNA were calculated via the fluorescence quenching of ethidium bromide (EB) and mole ratio method. Furthermore, atomic force microscopy (AFM) was used to observe DNA morphology change in the presence of MC-LR. With the increasing concentration of MC-LR, circle DNA strands twined gradually to rod condensates. The possible reason for the condensation might be the masking of the electrostatic repulsion between DNA double strands by MC-LR. The present study might provide useful information for the pathopoiesis mechanism of MC-LR. More, because the condensation of DNA could affect the progresses of gene expression and protein transcription, it may implicate another trend to explore the nosogenesis of MC-LR. PMID- 21309588 TI - Electro-Marangoni effect in thin liquid films. AB - The present paper reports a new drainage model accounting for the electro Marangoni effect in thin liquid films stabilized by ionic surfactants. It was shown that the liquid outflow during the film drainage drifts charges from the diffuse part of the electrical double layer toward the film rim and thus generates a streaming potential along the film plane. This creates reverse fluxes near the film surfaces due to the requirement for zero electric current in the film. In a previous paper on this model (Tsekov et al. Langmuir, 2010, 26, 4703), the immobile surfaces were assumed. Here, the film surfaces were considered mobile, and surface velocity is controlled by an electro-Marangoni number. It was also shown that the motion of the charges makes the film surfaces more mobile, and they flow in reverse direction to the overall liquid outflow. The theory was validated by experimental data on drainage of planar foam films stabilized by cationic (tetrapentyl ammonium bromide) and anionic (sodium dodecyl sulfate) surfactants. A good agreement between the theoretical prediction and experimental data was found. PMID- 21309589 TI - Influence of the impact velocity and size of the film formed on bubble coalescence time at water surface. AB - Phenomena occurring during bubble collisions with a water/air interface were studied. The bubble impact velocity was tuned by the following: (i) changing the bubble diameter and (ii) adjusting the distance between the bubble formation point and the water free surface (at the bubble acceleration stage). It was found that the bubble bouncing and the coalescence time, i.e., the time from the moment of the bubble's first collision to its rupture, increased with the impact velocity. The coalescence time varied from a few to ca. 120 ms when the bubble impact velocity was changed from 8.0 to 36.7 cm/s. It was found that a prolongation of the coalescence time was related to size of the liquid film formed during the bubble collision. Higher impact velocity means larger deformation of the bubble shape and larger radius of the liquid film formed. It was shown that the bubble bounces when the thinning water film between the bubble and the air/water interface does not reach its rupture thickness during the collision time. PMID- 21309590 TI - Bunodosine 391: an analgesic acylamino acid from the venom of the sea anemone Bunodosoma cangicum. AB - A new acylamino acid, bunodosine 391 (BDS 391), was isolated from the venom of the sea anemone Bunodosoma cangicum. The structure was elucidated by spectroscopic analyses (2D NMR, ESIMS/MS) and verified by its synthesis. Intraplantar injection of BDS 391 into the hind paw of a rat induced a potent analgesic effect. This effect was not altered by naloxone (an opioid receptor antagonist), but was completely reversed by methysergide (a serotonin receptor antagonist), indicating that the effect is mediated by activation of serotonin receptors. PMID- 21309591 TI - Antiproliferative triterpenes from the leaves and twigs of Juglans sinensis on HSC-T6 cells. AB - Bioassay-guided fractionation of an 80% MeOH extract of leaves and twigs of Juglan sinensis has resulted in the isolation of four new triterpenes (1-4) and 17 known triterpenes (5-21). The new compounds were determined to be 1-oxo 3beta,23-dihydroxyolean-12-en-28-oic acid 28-O-beta-D-glucopyranoside (1), 1-oxo 3beta-hydroxyolean-18-ene (2), 3beta,23-dihydroxyurs-12-en-28-oic acid 28-O-beta D-glucopyranoside (3), and 3beta,22alpha-dihydroxyurs-12-en-28-oic acid 28-O-beta D-glucopyranoside (4) by spectroscopic analysis. Compounds 2, 13, 15, and 21 showed antiproliferative activities (14.2, 14.8, 15.6, and 11.0% at 100 MUM, respectively) in HSC-T6 cells. Flow cytometry assays revealed that these compounds inhibited HSC-T6 proliferation by inducing apoptosis. PMID- 21309592 TI - New synthetic triterpenoids: potent agents for prevention and treatment of tissue injury caused by inflammatory and oxidative stress. AB - We review the original rationale for the development and the chemistry of a series of new synthetic oleanane triterpenoids (SO), based on oleanolic acid (1) as a starting material. Many of the new compounds that have been made, such as 2 cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid ("CDDO", 8), are highly potent (activities found at levels below 1 nM) anti-inflammatory agents, as measured by their ability to block the cellular synthesis of the enzyme inducible nitric oxide synthase (iNOS) in activated macrophages. Details of the organic synthesis of new SO and their chemical mechanisms of biological activity are reviewed, as is formation of biotin conjugates for investigation of protein targets. Finally, we give a brief summary of important biological activities of SO in many organ systems in numerous animal models. Clinical investigation of a new SO (methyl 2 cyano-3,12-dioxooleana-1,9(11)dien-28-oate, "CDDO-Me", bardoxolone methyl, 13) is currently in progress. PMID- 21309593 TI - Cyclopropyl and isopropyl derivatives of 11-cis and 9-cis retinals at C-9 and C 13: subtle steric differences with major effects on ligand efficacy in rhodopsin. AB - Retinal is the natural ligand (chromophore) of the vertebrate rod visual pigment. It occurs in either the 11-cis (rhodopsin) or the 9-cis (isorhodopsin) configuration. In its evolution to a G protein coupled photoreceptor, rhodopsin has acquired exceptional photochemical properties. Illumination isomerizes the chromophore to the all-trans isomer, which acts as a full agonist. This process is extremely efficient, and there is abundant evidence that the C-9 and C-13 methyl groups of retinal play a pivotal role in this process. To examine the steric limits of the C-9 and C-13 methyl binding pocket of the binding site, we have prepared C-9 and C-13 cyclopropyl and isopropyl derivatives of its native ligands and of alpha-retinal at C-9. Most isopropyl analogues show very poor binding, except for 9-cis-13-isopropylretinal. Most cyclopropyl derivatives exhibit intermediate binding activity, except for 9-cis-13-cyclopropylretinal, which presents good binding activity. In general, the binding site shows preference for the 9-cis analogues over the 11-cis analogues. In fact, 13 isopropyl-9-cis-retinal acts as a superagonist after illumination. Another surprising finding was that 9-cyclopropylisorhodopsin is more like native rhodopsin with respect to spectral and photochemical properties, whereas 9 cyclopropylrhodopsin behaves more like native isorhodopsin in these aspects. PMID- 21309594 TI - Regulation of integrin alphaIIbbeta3 ligand binding and signaling by the metal ion binding sites in the beta I domain. AB - The ability of alphaIIbbeta3 to bind ligands and undergo outside-in signaling is regulated by three divalent cation binding sites in the beta I domain. Specifically, the metal ion-dependent adhesion site (MIDAS) and the synergistic metal binding site (SyMBS) are thought to be required for ligand binding due to their synergy between Ca(2+) and Mg(2+). The adjacent to MIDAS (ADMIDAS) is an important ligand binding regulatory site that also acts as a critical link between the beta I and hybrid domains for signaling. Mutations in this site have provided conflicting results for ligand binding and adhesion in different integrins. We have mutated the beta3 SyMBS and ADMIDAS. The SyMBS mutant abolished ligand binding and outside-in signaling, but when an activating glycosylation mutation in the alphaIIb Calf 2 domain was introduced, the ligand binding affinity and signaling were restored. Thus, the SyMBS is important but not absolutely required for integrin bidirectional signaling. The ADMIDAS mutants showed reduced ligand binding affinity and abolished outside-in signaling, and the activating glycosylation mutation could fully restore integrin signaling of the ADMIDAS mutant. We propose that the ADMIDAS ion stabilizes the low-affinity state when the integrin headpiece is in the closed conformation, whereas it stabilizes the high-affinity state when the headpiece is in the open conformation with the swung-out hybrid domain. PMID- 21309595 TI - Spatial and temporal trends of perfluorinated compounds in Beluga Whales (Delphinapterus leucas) from Alaska. AB - Wildlife from remote locations have been shown to bioaccumulate perfluorinated compounds (PFCs) in their tissues. Twelve PFCs, consisting of perfluorinated carboxylic (PFCA) and sulfonic (PFSA) acids as well as the perfluorooctane sulfonate (PFOS) precursor perfluorooctane sulfonamide (PFOSA), were measured in livers of 68 beluga whales (Delphinapterus leucas) collected from two subpopulations, Cook Inlet and eastern Chukchi Sea, in Alaska between 1989 and 2006. PFOS and PFOSA were the dominant compounds measured in both beluga stock populations, with overall median concentrations of 10.8 ng/g and 22.8 ng/g, respectively. Long-chain perfluorocarboxylates, PFCAs (9 to 14 carbons), were detected in more than 80% of the samples. Perfluoroundecanoic acid (PFUnA) and perfluorotridecanoic acid (PFTriA) made up a large percentage of the PFCAs measured with median concentrations of 8.49 ng/g and 4.38 ng/g, respectively. To compare differences in location, year, sex, and length, backward stepwise multiple regression models of the individual and total PFC concentrations were used. Spatially, the Cook Inlet belugas had higher concentrations of most PFCAs and PFOS (p < 0.05); however, these belugas had a lower median concentration of PFOSA when compared to belugas from the eastern Chukchi Sea (p < 0.05). Temporal trends indicated most PFCAs, PFHxS, PFOS, and PFOSA concentrations increased from 1989 to 2006 (p < 0.05). Males had significantly higher concentrations of PFTriA, SigmaPFCA, and PFOS (p < 0.05). Perfluorononanic acid (PFNA) and PFOS showed a significant decrease in concentration with increasing animal length (p < 0.05). These observations suggest the accumulation of PFCs in belugas is influenced by year, location, sex, and length. PMID- 21309596 TI - Interfacial pH: a critical factor for osteoporotic bone regeneration. AB - Osteoporosis is a disease attributed to an imbalance in communication between osteoblasts and osteoclasts, possibly arising from a locally acidic microenvironment which hinders normal cell function. However, to date, little or no attention has been paid to these cells' milieu in respect of implant materials. Although it has been claimed for a few biomaterials that they stimulate bone formation, seldom has their surface behavior been invoked to explain behavior. With degradation, ion concentrations and pH at the material's surface must vary and thus may affect osteoblast response directly. On degradation of a recently developed biomaterial, Sr-containing CaSiO3, the interfacial pH was found to be appreciably higher than that of the bulk medium and the "standard" physiological value of 7.4. At these high values (pH > 8), both the proliferation and alkaline phosphatase (ALP) activity of osteoblasts was significantly enhanced, with a maximum response at 10% Sr substitution for Ca. This shows that the chemistry of the solid-liquid interface is a critical factor in bone regeneration, although this has generally been overlooked. Thus, the interfacial pH in particular is to be considered, rather than the bulk value, and this may be of importance in many related contexts in bone-tissue engineering. PMID- 21309597 TI - A model for the enantioselectivity of imine reactions catalyzed by BINOL phosphoric acid catalysts. AB - BINOL-phosphoric acid catalysts have been used successfully in many reactions involving imines. In this paper, we present a model, based on DFT calculations, for describing the degree and sense of the enantioselectivity of these reactions that is able to predict the correct enantioselectivity for the reactions in more than 40 recent publications. We rationalize the different factors on which the enantioselectivity depends, focusing on the E- or Z-preference of the transition structures and the orientation of the catalyst with respect to the electrophile. PMID- 21309598 TI - Cadmium sulfide and cadmium phosphide thin films from a single cadmium compound. AB - Aerosol-assisted chemical vapor deposition of Cd[(SP(i)Pr(2))(2)N](2) leads to the growth of cadmium sulfide and/or phosphide thin films on glass. Decomposition of the precursor has been studied by pyrolysis-gas chromatography/mass spectrometry and modeled by density functional theory. PMID- 21309599 TI - Ring-closing and dehydrogenation reactions of highly excited cis-stilbene: ultrafast spectroscopy and structural dynamics. AB - The ultrafast dynamics of highly excited cis-stilbene (CS) in a molecular beam is explored using femtosecond time-resolved mass spectrometry and structure sensitive photoelectron spectroscopy. cis-Stilbene is initially pumped by a 6 eV photon to the 7(1)B state and the reaction is followed by ionization with a time delayed 3 eV probe pulse. Upon excitation, cis-stilbene rapidly decays to the 3(1)B state, where it undergoes a ring-closing reaction to form 4a,4b dihydrophenanthrene (DHP). Whereas 14% of the ionized CS molecules dissociate one hydrogen atom to form hydrophenanthrene, the ionized DHP molecules completely dehydrogenate in the ion state to produce hydrophenanthrene and phenanthrene with a 1:1 ratio. We determined the lifetimes of the 7(1)B state and the 3(1)B state of CS to be 167 and 395 fs, respectively. PMID- 21309600 TI - Mechanism and direct kinetics study on the homogeneous gas-phase formation of PBDD/Fs from 2-BP, 2,4-DBP, and 2,4,6-TBP as precursors. AB - This study investigated the homogeneous gas-phase formation of polybrominated dibenzo-p-dioxin/dibenzofurans (PBDD/Fs) from 2-BP, 2,4-DBP, and 2,4,6-TBP as precursors. First, density functional theory (DFT) calculations were carried out for the formation mechanism. The geometries and frequencies of the stationary points were calculated at the MPWB1K/6-31+G(d,p) level, and the energetic parameters were further refined by the MPWB1K/6-311+G(3df,2p) method. Then, the formation mechanism of PBDD/Fs was compared and contrasted with the PCDD/F formation mechanism from 2-CP, 2,4-DCP, and 2,4,6-TCP as precursors. Finally, the rate constants of the crucial elementary reactions were evaluated by the canonical variational transition-state (CVT) theory with the small curvature tunneling (SCT) correction over a wide temperature range of 600-1200 K. Present results indicate that only BPs with bromine at the ortho position are capable of forming PBDDs. The study, together with works already published from our group, clearly shows an increased propensity for the dioxin formations from BPs over the analogous CPs. Multibromine substitutions suppress the PBDD/F formations. PMID- 21309601 TI - Occurrence and transport of tetracycline, sulfonamide, quinolone, and macrolide antibiotics in the Haihe River Basin, China. AB - The occurrence and transport of 12 antibiotics (from the tetracycline, sulfonamide, quinolone, and macrolide families) was studied in a 72-km stretch of the Haihe River, China, and in six of its tributaries. Aqueous and sediment samples were analyzed by HPLC-MS/MS. Sulfonamides were detected at the highest concentrations (24-385 ng/L) and highest frequencies (76-100%). Eight of the 12 antibiotics likely originated from veterinary applications in swine farms and fishponds, and concentrations at these sources (0.12-47 MUg/L) were 1-2 orders of magnitude higher than in the effluent of local wastewater treatment plants. Sulfachloropyridazine (SCP) was detected in all swine farm and fishpond samples (maximum concentration 47 MUg/L), which suggests its potential usefulness to indicate livestock source pollution in the Haihe River basin. Hydrological and chemical factors that may influence antibiotic distribution in the Haihe River were considered by multiple regression analysis. River flow rate exerted the most significant effect on the first-order attenuation coefficient (K) for sulfonamides, quinolones, and macrolides, with higher flow rates resulting in higher K, probably due to dilution. For tetracyclines, sediment total organic matter and cation exchange capacity exerted a greater impact on K than flow rate, indicating that adsorption to sediments plays an important role in attenuating tetracycline migration. Overall, the predominance of sulfonamides in the Haihe River underscores the need to consider regulating their veterinary use and improving the management and treatment of associated releases. PMID- 21309602 TI - Liquid scintillation spectrometry of tritium in studying lysozyme behavior in aqueous/organic liquid systems. The influence of the organic phase. AB - Liquid scintillation spectrometry of tritium in the application of the scintillation phase method was used for studying the adsorption of lysozyme at the liquid/liquid interface and its distribution in the bulk of the system. The goal of this research was to reveal the influence of the nature of the organic phase on the distribution and adsorption ability of the protein when it is placed in a system containing two immiscible liquids. Based on the radiochemical assay distribution coefficients and adsorption isotherms obtained for aqueous/octane, aqueous/p-xylene and aqueous/octanol systems, it was concluded that the interaction of the protein with the interface plays a dominant role in protein behavior in aqueous/organic liquid systems. PMID- 21309603 TI - Role of specific amine surface configurations for grafted surfaces: implications for nanostructured CO2 adsorbents. AB - Amine-grafted porous materials that capture CO2 from emission streams have been considered to be potential alternatives to the more energy-intensive liquid amine systems currently employed. An underappreciated fact in the uptake mechanism of these materials is that under dry, anhydrous conditions each CO2 molecule must react with two adjacent amine groups to adsorb onto the surface, which makes the configuration of amine groups on the surface critically important. Using this chemical mechanism, we developed a semiempirical adsorption isotherm equation that allows straightforward computation of the adsorption isotherm from an arbitrary surface configuration of grafted amines for honeycomb, square, and triangular lattices. The model makes use of the fact that the distribution of amines with respect to the number of nearest neighbors, referred to as the z histogram, along with the amine loading and equilibrium constant, uniquely determine the adsorption characteristics to a very good approximation. This model was used to predict the range of uptakes possible just through surface configuration, and it was used to fit experimental data in the literature to give a meaningful equilibrium constant and show how efficiently amines were utilized. We also demonstrate how the model can be utilized to design more efficient nanostructured adsorbents and polymer-based adsorbents. Recommendations for exploiting the role of surface configuration include the use of linear instead of branched polyamines, higher amine grafting densities, the use of flexible, less bulky, long, and rotationally free amine groups, and increased silanol densities. PMID- 21309604 TI - Passivation of metal surface states: microscopic origin for uniform monolayer graphene by low temperature chemical vapor deposition. AB - Scanning tunneling microscopy (STM) and density functional theory (DFT) calculations were used to investigate the surface morphology and electronic structure of graphene synthesized on Cu by low temperature chemical vapor deposition (CVD). Periodic line patterns originating from the arrangements of carbon atoms on the Cu surface passivate the interaction between metal substrate and graphene, resulting in flawless inherent graphene band structure in pristine graphene/Cu. The effective elimination of metal surface states by the passivation is expected to contribute to the growth of monolayer graphene on Cu, which yields highly enhanced uniformity on the wafer scale, making progress toward the commercial application of graphene. PMID- 21309605 TI - Charge control of surface dangling bonds using nanoscale Schottky contacts. AB - Titanium silicide (TiSi2) nanoscale Schottky contacts were prepared on hydrogen terminated n-type Si (100) surfaces. The Schottky contact created a region of upward band bending surrounding the TiSi2 contacts. The surface band bending was observed as a sloping surface depression using the scanning tunneling microscope. Scanning tunneling spectroscopy measurements also show shifted I/V data consistent with upward band bending. Charge control of dangling bonds was accomplished through a distance relationship between the dangling bond and the TiSi2 contact. The lowered chemical potential in the near contact region removes the ability of dangling bonds to become negatively charged while dangling bonds outside the close contact region remain fully charged. Methods to actively control dangling bond charge states are discussed. PMID- 21309606 TI - Self-assembly of short abeta(16-22) peptides: effect of terminal capping and the role of electrostatic interaction. AB - We report the characterization of self-assembly of two short beta-amyloid (Abeta) peptides (16-22), KLVFFAE and Ac-KLVFFAE-NH2, focusing on examining the effect of terminal capping. At pH 2.0, TEM and AFM imaging revealed that the uncapped peptide self-assembled into long, straight, and unbranched nanofibrils with a diameter of 3.8 +/- 1.0 nm while the capped one formed nanotapes with a width of 70.0 +/- 25.0 nm. CD analysis indicated the formation of beta-sheet structures in both aggregated systems, but the characteristic CD peaks were less intense and less red-shifted for the uncapped than the capped one, indicative of weaker hydrogen bonding and weaker pi-pi stacking. Fluorescence and rheological measurements also confirmed stronger intermolecular attraction associated with the capped nanotapes. At acidic pH 2, each uncapped KLVFFAE molecule carries two positive charges at the N-terminus, and the strong electrostatic repulsion favors interfacial curving and twisting within the beta-sheet, causing weakening of hydrogen bonds and pi-pi stacking. In contrast, capping reduces the charge by half, and intermolecular electrostatic repulsion is drastically reduced. As a result, the lateral attraction of beta-sheets favors stronger lamellar structuring, leading to the formation of rather flat nanotapes. Flat tapes with similar morphological structure were also formed by the capped peptide at pH 12.0 where the charge on the capping end was reversed. This study has thus demonstrated how self-assembled nanostructures of small peptides can be manipulated through simple molecular structure design and tuning of electrostatic interaction. PMID- 21309607 TI - Kinetics of nonequilibrium electron transfer in photoexcited ruthenium(II) cobalt(III) complexes. AB - Kinetics of photoinduced electron transfer reactions in [Ru(II)(L-L)Co(III)](5+) complexes have been investigated in the framework of the stochastic point transition model. The model involves the medium and intramolecular nuclear reorganization as well as fast relaxation of intramolecular high frequency vibrations and description of the medium relaxation in terms of two time scales. The model has allowed reproducing the experimental data (Torieda, H.; Nozaki, K.; Yoshimura, A.; Ohno, T. J. Phys. Chem. A2004, 108, 4819) of forward and backward electron transfer kinetics, including the low yield of electron transfer products and its variation with solvent. These results have lent support to the important role of hot backward electron transfer in the formation of low yield of electron transfer products. The experimentally observed significant decrease of the product yield in more viscous solvents has been shown to be a direct consequence of the hot transition efficiency increase. A weak opposite dependence, also revealed in experiments, has been elucidated in terms of two time scales of the solvent relaxation. Solvent relaxation is well-known to involve at least two stages: the inertial one (fast) and the diffusive one (slower) with the time scales weakly dependent on and proportional to solvent viscosity, respectively. When hot transitions are terminated at the stage of the inertial relaxation, the yield of the electron transfer products is nearly independent of the diffusive time scale; otherwise a strong increase of the yield in more viscous solvents should be observed. PMID- 21309608 TI - Selective screening of tyrosine-nitrated peptides in tryptic mixtures by in source photodissociation at 355 nm in matrix-assisted laser desorption ionization. AB - Nitration of tyrosine residues in proteins is an important post-translational modification related to various diseases such as Alzheimer's. In this work, efficient and selective photodissociation (PD) at 355 nm was observed for [M + H](+), [M + H - 16](+), and [M + H - 32](+) generated by matrix-assisted ultraviolet laser desorption ionization (UV-MALDI) of tyrosine-nitrated peptides (nitropeptides). Product ion spectra obtained by post-source PD at this wavelength contained useful information on the amino acid sequence. The spectra for nitropeptides obtained with 355 nm irradiation inside the ion source (MALDI/in-source PD) displayed characteristic triplet patterns due to PD of the above ions. For peptides displaying prominent signal in a MALDI mass map of a tryptic mixture, which are mostly those with arginine at the C-terminus, in source PD allowed positive identification of their tyrosine-nitrated forms. Identification of such nitropeptides was possible at the 10 fmol level (in tryptic digest of 100 fmol BSA). PMID- 21309609 TI - Rh-catalyzed carbonylation of arylzinc compounds yielding symmetrical diaryl ketones by the assistance of oxidizing agents. AB - Carbonylative homocoupling of arylzinc compounds 1 using 1 atm of CO and 1,2 dibromoethane as an oxidant was achieved in the presence of Rh-dppf catalyst, affording symmetrical diaryl ketones in good yields. Under similar conditions, Pd or Ni catalysts induced oxidative homocoupling of 1 to yield biaryls instead. The beneficial catalysis by Rh in the carbonylation was presumed to stem from the facility by which the migration of the aryl ligand to CO at the Rh(3+) intermediate occurred. PMID- 21309610 TI - Study of the structural and electronic properties of valproic acid and new derivatives used as anticonvulsant agents. AB - The conformational and electronic characteristics of the polar O(9)?C(8)-X(10) moiety in the anticonvulsant valproic acid (Vpa) drug and some of their amides and ester derivatives are analyzed at the B3LYP level using the 6-31+G(d,p) and 6 311++G(d,p) 6d,10f basis sets. Exploring the delocalization of the electron density of the O(9)?C(8)-X(10) moiety by means of ELF, NBO, and AIM calculations, we found that the bending away from coplanarity of the atoms in O(9)?C(8)-X(10) is accompanied by a three-dimensional arrangement of donor and acceptor proton units closing nearly planar pseudorings of four, five, and six members arising from stabilizing interactions around the O(9)?C(8)-X(10) backbone. From the structure-property relationship analysis, we explain the origin of the change in the structural parameters and atomic charges in the polar moiety. PMID- 21309611 TI - Carbon sequestration may have negative impacts on ecosystem health. PMID- 21309612 TI - Increasing forest carbon sequestration through cooperation and shared strategies between China and the United States. PMID- 21309613 TI - Proteomic analysis of pancreatic ductal adenocarcinoma cells reveals metabolic alterations. AB - In this present work, we characterized the proteomes of pancreatic ductal adenocarcinoma (PDAC) cells and normal pancreatic duct cells by mass spectrometry using LTQ-Orbitrap, and identified more than 1200 proteins from each sample. On the basis of spectra count label-free quantification approach, we identified a large number of differentially expressed metabolic enzymes and proteins involved in cytoskeleton, cell adhesion, transport, transcription, translation, and cell proliferation as well. The data demonstrated that metabolic pathways were altered in PDAC, consistent with Warburg effect. Our analysis provides a potentially comprehensive picture of metabolism in PDAC, which may serve as the basis of new diagnostic and treatment of PDAC. PMID- 21309614 TI - Including indirect medical care costs from survivor years of life in economic evaluations. PMID- 21309615 TI - Sample size and power for cost-effectiveness analysis (part 1). AB - Basic sample size and power formulae for cost-effectiveness analysis have been established in the literature. These formulae are reviewed and the similarities and differences between sample size and power for cost-effectiveness analysis and for the analysis of other continuous variables such as changes in blood pressure or weight are described. The types of sample size and power tables that are commonly calculated for cost-effectiveness analysis are also described and the impact of varying the assumed parameter values on the resulting sample size and power estimates is discussed. Finally, the way in which the data for these calculations may be derived are discussed. PMID- 21309616 TI - Posaconazole: a pharmacoeconomic review of its use in the prophylaxis of invasive fungal disease in immunocompromised hosts. AB - Posaconazole (Noxafil(r)) is an oral, second-generation, extended-spectrum triazole whose approved indications include prophylaxis of invasive fungal disease (IFD) in immunocompromised patients. In pivotal head-to-head trials, posaconazole was significantly more effective in preventing IFD than standard azole therapy (i.e. oral fluconazole or itraconazole) in chemotherapy-induced neutropenic patients with acute myelogenous leukaemia (AML) or myelodysplastic syndromes (MDS) and was noninferior to treatment with fluconazole in patients with graft-versus-host disease (GVHD) who were receiving intensive immunosuppressive therapy following haematopoietic stem cell transplantation. In both indications, prophylactic posaconazole was associated with significantly lower rates of IFD-related mortality. The overall tolerability profile of posaconazole was generally similar to that of the other prophylactic treatments. The large body of modelled cost-effectiveness analyses from a healthcare payer perspective on the use of prophylactic posaconazole suggest that it is a dominant or cost-effective option relative to prophylaxis with standard azole therapy in neutropenic patients with AML/MDS, and fluconazole in patients with GVHD. Based on clinical trial data in these patient groups, antifungal prophylaxis with posaconazole was predicted to be a dominant or cost-effective option relative to prophylaxis with standard oral azoles, with regard to the incremental cost per QALY gained, life-year (LY) gained and/or other outcomes in cost-effectiveness analyses in numerous countries. In those analyses in which posaconazole did not dominate the comparator, posaconazole was considered cost effective, as the incremental cost per QALY or LY gained with posaconazole was lower than assumed willingness-to-pay thresholds. Sensitivity analyses consistently demonstrated that these results were robust to plausible changes in key model assumptions. In conclusion, prophylactic treatment with posaconazole is clinically effective in preventing IFD in neutropenic patients with AML/MDS and patients with GVHD. Available pharmacoeconomic data from several countries, despite some inherent limitations, support the use of posaconazole as a dominant or cost-effective prophylactic antifungal treatment relative to prophylaxis with standard oral azoles in these patient populations at high risk of developing IFD. PMID- 21309617 TI - Identification of personal lubricants that can cause rectal epithelial cell damage and enhance HIV type 1 replication in vitro. AB - Over-the-counter personal lubricants are used frequently during vaginal and anal intercourse, but they have not been extensively tested for biological effects that might influence HIV transmission. We evaluated the in vitro toxicity anti HIV-1 activity and osmolality of popular lubricants. A total of 41 lubricants were examined and compared to Gynol II and Carraguard as positive and negative controls for toxicity, respectively. Cytotoxicity was assessed using the XTT assay. The MAGI assay with R5 and X4 HIV-1 laboratory strains was used to evaluate antiviral activity. The effect of the lubricants on differentiated Caco 2 cell monolayers (transepithelial electrical resistance, TEER) was also measured. None of the lubricants tested showed significant activity against HIV 1. Surprisingly, four of them, Astroglide Liquid, Astroglide Warming Liquid, Astroglide Glycerin & Paraben-Free Liquid, and Astroglide Silken Secret, significantly enhanced HIV-1 replication (p<0.0001). A common ingredient in three of these preparations is polyquaternium-15. In vitro testing of a chemically related compound (MADQUAT) confirmed that this similarly augmented HIV-1 replication. Most of the lubricants were found to be hyperosmolar and the TEER value dropped approximately 60% 2 h after exposure to all lubricants tested. Cells treated with Carraguard, saline, and cell controls maintained about 100% initial TEER value after 2-6 h. We have identified four lubricants that significantly increase HIV-1 replication in vitro. In addition, the epithelial damage caused by these and many other lubricants may have implications for enhancing HIV transmission in vivo. These data emphasize the importance of performing more rigorous safety testing on these products. PMID- 21309619 TI - Does personality disorder co-morbidity impact treatment outcome for patients with major depression? A multi-level analysis. AB - In literature, there exists disagreement regarding the impact of comorbid personality disorder(s) (PD[s]) on treatment outcome for patients with major depressive disorder (MDD). The aim of this paper was to investigate whether statistical heterogeneity and inter-dependency are potential moderators of the effect of co-morbid PDs on outcome for patients with MDD. Clinician-rated MADRS scores and DSM-IV Axis II personality disorder diagnoses were obtained from 562 outpatients with MDD who received 6 months of combined psycho- and pharmacotherapy. Single-level regression showed significantly worse treatment outcome among patients with co-morbid PD, as compared to patients with no PD. After controlling for statistical heterogeneity and interdependency, treatment outcome was no longer significantly worse for patients with co-morbid PD. In conclusion, heteroscedasticity and inter-dependency should be considered as potentially compelling explanations for inconsistencies in findings on treatment outcome for depressed patients with co-morbid PDs. PMID- 21309618 TI - Size and surface charge of gold nanoparticles determine absorption across intestinal barriers and accumulation in secondary target organs after oral administration. AB - It is of urgent need to identify the exact physico-chemical characteristics which allow maximum uptake and accumulation in secondary target organs of nanoparticulate drug delivery systems after oral ingestion. We administered radiolabelled gold nanoparticles in different sizes (1.4-200 nm) with negative surface charge and 2.8 nm nanoparticles with opposite surface charges by intra oesophageal instillation into healthy adult female rats. The quantitative amount of the particles in organs, tissues and excrements was measured after 24 h by gamma-spectroscopy. The highest accumulation in secondary organs was mostly found for 1.4 nm particles; the negatively charged particles were accumulated mostly more than positively charged particles. Importantly, 18 nm particles show a higher accumulation in brain and heart compared to other sized particles. No general rule accumulation can be made so far. Therefore, specialized drug delivery systems via the oral route have to be individually designed, depending on the respective target organ. PMID- 21309620 TI - Interpersonal competence across domains: relevance to personality pathology. AB - Interpersonal problems are significant markers of personality disorders (PDs). There is little research examining the specific interpersonal problems which lead to social impairment in PD. This study used canonical correlation analyses to examine the relationship between interpersonal competence and PDs, first as categorized by DSM-IV diagnoses, then as categorized by empirically-derived factors, in a sample at risk for recurrence of major depression. The most significant sources of shared variance were social inhibition and self-disclosure competence. The empirically-derived PD categories accounted for more variance in interpersonal competence than the DSM-IV diagnostic categories. Social skills training in initiation and self-disclosure may be useful for treating individuals with PD who experience interpersonal problems. Empirically-derived categories of PD symptoms may capture interpersonal problems experienced by individuals with PD which DSM-IV categories do not. PMID- 21309621 TI - Sexually coercive tactics used by university students: a clear role for primary psychopathy. AB - Current research suggests that people with psychopathic traits engage in sexual coercion as an alternative mating strategy. Research overlooks the relation between psychopathic traits and coercive behavior in male and female samples that engage in dating quite frequently. Male and female university students reported on their current relationship styles and their use of minor and severe sexually coercive tactics. Results indicate that primary psychopathy (using the Levenson's SRPS), but not secondary psychopathy, predicts the use of all measures of sexual coercion for both females and males, although males were more likely to exploit an intoxicated partner than females. Additionally, females with high levels of primary psychopathy were more likely to use physical forms of coercion. The findings show that the primary psychopathy features (callousness, charm, and selfishness) predict a shortterm mating strategy that focuses on gaining sex through minor forms of coercion and manipulation. PMID- 21309622 TI - Extended Schema Mode conceptualizations for specific personality disorders: an empirical study. AB - The aim of this study was to investigate newly formulated schema mode models for cluster-C, paranoid, histrionic and narcissistic personality disorders. In order to assess 18 hypothesized modes, the Schema Mode Inventory (SMI) was modified into the SMI-2. The SMI-2 was administered to a sample of 323 patients (with a main diagnosis on one of the PDs mentioned) and 121 nonpatients. The SMI-2 was successful in distinguishing patients and controls. Newly formulated modes proved to be appropriate for histrionic, avoidant, and dependent PD. The modification of the Overcontroller mode into the Perfectionistic and Suspicious Overcontroller mode was valuable for characterizing paranoid and obsessive-compulsive PD. The results support recent theoretical developments in Schema Therapy, and are useful for application in clinical practice. PMID- 21309623 TI - Parental burden associated with borderline personality disorder in female offspring. AB - To identify aspects of parental burden associated with borderline personality disorder (BPD), an anonymous internet survey linked to BPD support websites was developed for parents to complete on their BPD offspring and unaffected siblings. The questions cover aspects of the child's life from pregnancy through young adulthood, and query about the impact of the child's BPD on six domains of the parent's life, including physical and emotional health, marriage, job, standard of living, social life, and career trajectory. Additionally, financial burden was assessed with questions pertaining to insurance and out-of pocket costs associated with the BPD disorder. BPD offspring were identified by meeting diagnostic criteria embedded within the survey and having been given a diagnosis of BPD by a professional at some point in their life. We report on 233 female offspring meeting strict criteria for BPD. Parents of daughters with BPD endorsed varying levels of impact on the six domains comprising burden with the largest impact on emotional health which was impacted in over 88% of the respondents. Over 50% of parents endorsed four or greater of the six burden items. Particular aspects of the offspring's BPD symptom profile correlated with intensity of parental burden included including problems in adolescence with acting out behavior (p < .000), property destruction (.003), delusional symptoms (.007), and hallucinatory symptoms (.008). A subgroup of respondents provided data on specific financial expenses. The average and median out-of-pocket expense was $60,087, and $10,000. Insurance costs totaled an average of $108,251 with a mean of $20,000. The average cost per year after diagnosis was $14,606 out-of-pocket and $45,573 billed to insurance. The median cost per year after diagnosis was $3,667 out-of-pocket, and $12,500 billed to insurance. After adjusting for household income, a female proband who had been raped incurred roughly $40,000 more in BPD-related costs, while a diagnosis of conduct disorder led to about $50,000 in additional costs. Parents of female offspring with BPD experience burden in multiple domains of their life and many have incurred substantial financial expense. Increasing awareness of co-morbid conditions in the BPD proband that significantly increase parental burden may be indicators for the provision of increased family support. PMID- 21309624 TI - Cortical correlates of impaired self-regulation in personality disordered patients with traits of psychopathy. AB - Psychopathic personality disordered patients would, by virtue of a failure to self-regulate, be expected to show diminished amplitudes of feedback-related brain potentials. Among a sample of personality disordered patients detained at different levels of security, those who met a Psychopathy Checklist (PCL) criterion of 25 or above were identified (N = 27). Their event-related brain potentials (ERPs), together with those of their nonpsychopathic counterparts (N = 22) and healthy male controls (N = 20), were measured while they performed a visual Go/No Go task, with feedback given for correct and incorrect performance. Psychopathic patients showed a significantly reduced amplitude of an early frontal negative ERP component maximally evoked by negative feedback, and a high rate of errors of commission. Findings are consistent with the idea that psychopathic patients' unsuccessful attempts to self-regulate reflect a cognitive deficit characterised by a failure to attend and respond to a mismatch between expected and obtained outcomes. PMID- 21309625 TI - Assessment of abnormal personality in childhood: a Delphi survey of questionnaire data. AB - As an investigation into the feasibility of recording personality status from questionnaire data in younger people we used a three phase Delphi survey to assess items from the Christchurch Health and Development Study, administered at ages 12 to 16 years. Twelve experts took part in Phase I, and 22 in Phases II and III, 16 of whom were experts in adult personality disorder (PD), and 6 were experts who work with children. In total, 189 questions (55% of the total (238) in the questionnaires) were identified as possibly being related to personality abnormality in one or more clusters with high consensus. Experts who work with children were less likely to label features as related to personality than experts in PD (p < 0.001), and the four personality factors (equivalent to Mulder and Joyce's antisocial, asocial, asthenic, and anankastic) chosen for assessment showed variable agreement. Confirmatory factor analysis showed the best fitting model of the data was a 3 factor solution involving asocial/asthenic, antisocial, and anankastic factors. This represents the first attempt to use existing recorded data to code personality status and the results of this Delphi survey give some grounds for optimism that this approach has potential in the early identification of personality features. PMID- 21309626 TI - Severity of childhood attention-deficit hyperactivity disorder--a risk factor for personality disorders in adult life? AB - Some evidence points to an increased rate of cluster B and C personality disorders (PDs) in adult ADHD patients. In order to assess axis II disorders comprehensively we used the diagnostic instrument of the WHO. In sixty adult out patients with ADHD according to DSM-IV criteria PDs were assessed with the International PD Examination (IPDE) and severity of childhood ADHD with the Wender-Utah-Rating Scale (WURS). We found at least one PD in 25% of cases. Cluster C PDs were most common (36.6%) followed by Cluster B (23.3%) and A (8.3%). Avoidant (21.7%) and borderline (18.3%) were the most frequent single PD entities. ADHD patients with PD suffered from significantly more severe childhood ADHD compared to those without co-occurring PD. Applying the IPDE we confirmed a high number of PDs among adult ADHD patients. Our findings point to a higher vulnerability for the development of PDs in patients with severe childhood ADHD. PMID- 21309627 TI - Personality disorder diagnostic thresholds correspond to different levels of latent pathology. AB - To meet a diagnosis for a particular personality disorder (PD), among other requirements, a person must exhibit a specified minimum number of the features outlined for that PD, otherwise referred to as the diagnostic threshold. Despite many years of research on the DSM PDs, there is little empirical basis for the chosen thresholds. The present study used mechanisms of item response theory (IRT) to link the diagnostic thresholds of six PDs to their corresponding level of latent PD pathology. Consistent with our hypothesis, analyses of the data from 41,227 participants revealed that PD diagnostic thresholds corresponded to a wide range of latent pathology. For example, the diagnostic threshold for schizoid PD corresponded to 1.54 SDs of pathology whereas the threshold for dependent PD corresponded to 2.72 SDs of pathology. The current analyses have demonstrated for the first time that the latent pathology associated with each PD threshold varies widely, and thus has quantified what others accurately have speculated. Implications and considerations for the future directions of PD classification are discussed. PMID- 21309628 TI - Brief report--associations of personality disorder with early separation anxiety in patients with adult separation anxiety disorder. AB - A recent study has suggested a link between early separation anxiety and personality disorder. It is possible that this relationship is mediated or confounded by the presence of adult separation anxiety disorder (ASAD). In a clinic study of 397 anxiety patients, we found that ASAD patients with heightened early separation anxiety had higher rates of any Cluster C personality disorder compared to ASAD patients without elevated early separation anxiety, and higher rates of any Cluster B or C personality disorder compared to anxiety patients with low early separation anxiety and no ASAD. Although cross-sectional in design, the study supports a direct link between early separation anxiety and some adult personality disorders, irrespective of the type of adult anxiety disorder present, including ASAD. PMID- 21309629 TI - Assessment of nuchal translucency thickness and the fetal anatomy in the first trimester of pregnancy by two- and three-dimensional ultrasonography: a pilot study. AB - AIM: To evaluate the use of three-dimensional ultrasonography (3D) as an alternative for examining fetal anatomy and nuchal translucency (NT) in the 1(st) trimester of pregnancy. METHOD: Prospective study of 199 low risk pregnant women undergoing 1(st) trimester ultrasound scan for fetal anomalies. The NT and fetal anatomy were evaluated by three-dimensional (3D) ultrasonography after the standard two-dimensional (2D) examination. The gold standard in this study was the 2D ultrasonography. RESULTS: In some of the evaluated parameters the 3D method approaches the conventional 2D results. These parameters are the crown rump length (CRL), the skull - brain anatomy (93.5%), the spine (85.4%), the upper (88.4%) and lower limbs (87.9%) and the examination of the fetal abdomen (98.5%). Some of the anatomic parameters under evaluation revealed a statistically significant difference in favor of the 2D examination. During the 3D examination the nasal bone was identified in 62.1% of the cases, the stomach in 85.9%, and the urinary bladder in 57.3% of the cases. The NT was assessed accurately in half of the cases compared to 2D examination. CONCLUSION: The 3D ultrasound is insufficient for the detailed fetal anatomy examination during the 1(st) trimester of pregnancy. Nevertheless, the method might be improved in order to be considered as a screening method. PMID- 21309630 TI - Reply: A great lack of knowledge regarding umbilical cord blood banking among pregnant women in Berlin, Germany. PMID- 21309631 TI - Risk groups and maternal-neonatal complications of preeclampsia--current results from the national German Perinatal Quality Registry. AB - AIMS: We investigated risk factors and neonatal outcomes of preeclampsia. METHODS: We analyzed data of the German Perinatal Quality Registry 2006 that contains the complete national birth cohort of 668,085 newborn infants and 647,392 mothers from 917 German obstetric clinics. RESULTS: The prevalence of preeclampsia in 2006 was at 2.31%. Higher maternal age, gestational diabetes, no previous as well as multiple births, pre-pregnancy obesity and above-average weight gain during pregnancy were significantly associated with preeclampsia. A positive relationship between social burden (e.g., low social status, psychosocial stress) and the risk of preeclampsia appeared. Smoking appeared to be negatively correlated. Neonatal complications associated with preeclampsia in the study were small babies, acute respiratory distress syndrome, postpartum neonatal hypoglycemia and low Apgar scores. We did not observe an increased rate of stillbirths with preeclampsia pregnancies. CONCLUSIONS: Further studies and interventions regarding prenatal care should not focus only on how better diagnostic and treatment procedures can be implemented but also on how these diagnostic and treatment procedures can reach high-risk groups. PMID- 21309632 TI - C-reactive protein levels at pre-/post-indicated cervical cerclage predict very preterm birth. AB - AIMS: To investigate the relation between serum levels of C-reactive protein (CRP) at pre-/post-cerclage points and preterm birth at <33 weeks of gestation in women with indicated cervical cerclage (CC). METHODS: Fifty-eight women with CC indicated for a short or soft cervix, but no visible or protruding fetal membranes into the vagina, between 17 and 26 weeks of gestation, were reviewed. Serum CRP levels were examined three times: just before cerclage, and on day 1 and day 2 post-cerclage. RESULTS: Serum CRP levels on day 1 and day 2, but not just before cerclage, predicted the occurrence of very preterm birth. In women with cervical dilatation of <3.0 cm, serum CRP levels on post-cerclage day 1 were associated with the increase of very preterm birth [CRP >=1.5 mg/dL vs. <1.5 mg/dL: 4/5 (80%) vs. 8/31 (26%), P=0.033]. In women with cervical dilatation of <3.0 cm, serum CRP >=3.0 mg/dL on post-cerclage day 2 was also associated with the increase of very preterm birth. CONCLUSION: In women with indicated CC between 17 and 26 weeks of gestation, increased levels of serum CRP on post cerclage day 1 or 2 might be ominous signs for very preterm birth. PMID- 21309633 TI - miRNA expression profiling in formalin-fixed and paraffin-embedded placental tissue samples from pregnancies with severe preeclampsia. AB - AIMS: Micro RNAs (miRNAs) are small, single-strand RNAs, playing an important role in post-transcriptional gene regulation. The placenta is considered to play a key role in pathogenesis of preeclampsia. The purpose of this study was to demonstrate deregulation of miRNAs in placentas with preeclampsia using formalin fixed and paraffin-embedded (FFPE) tissues. METHODS: Expression levels of 162 miRNAs were measured in FFPE placental tissues (5 with severe preeclampsia, 5 from a control group) using a quantitative qPCR based technique. RESULTS: Six miRNAs were more than 2-fold over-expressed in severe preeclampsia: let-7b, miRNA 302*, miRNA-104, miRNA-128a, miRNA-182* and miRNA-133b. Gene ontology analyses were performed using the algorithms "TargetScanS", "microRNA", and "PicTar". CONCLUSIONS: Two of the up-regulated miRNAs (miRNA-182* and miRNA-133b) are putative regulators of the transcript variants 1 and 2 of the BCL2-like gene, which controls apoptosis. miRNA-182* is also a probable angiogenesis regulator via angiogenin and VEGF-B. Apoptosis and angiogenesis are major mechanisms presumed to be involved in the pathogenesis of preeclampsia. Moreover, usability of qPCR technique based miRNA profiling for FFPE tissues was proofed. Hence FFPE tissue is the most widely used material for retrospective clinical studies, this method has a great property for future investigations in placenta research. PMID- 21309634 TI - Neurobehavioral continuity from fetus to neonate. AB - Neurobehavior represents development of the central nervous system (CNS). Fetuses and newborns exhibit a large number of endogenously generated motor patterns, among which general movements are often investigated pre- and post-natally. Spontaneous activity is probably a more sensitive indicator of brain dysfunction than reactivity to sensory stimuli while testing reflexes. Nutritional stress at critical times during fetal development can have persistent and potentially irreversible effects particularly on brain growth and function. Unfavorable intrauterine environment can affect adversely brain growth. All endogenously generated movement patterns from un-stimulated CNS might be observed as early as from the seven to eight weeks' gestation, with a rich repertoire of movements within the next two or three weeks, continuing for five to six months postnatally. It is still uncertain whether a new scoring system for prenatal neurological assessment will be adequate for the distinction between normal and abnormal fetuses in low-risk pregnancies. The continuity of behavioral patterns from prenatal to postnatal life might answer these intriguing questions. PMID- 21309635 TI - Critical analysis of literature on low-dose synergy for use in screening chemical mixtures for risk assessment. AB - There is increasing interest in the use of tiered approaches in risk assessment of mixtures or co-exposures to chemicals for prioritization. One possible screening-level risk assessment approach is the threshold of toxicological concern (TTC). To date, default assumptions of dose or response additivity have been used to characterize the toxicity of chemical mixtures. Before a screening level approach could be used, it is essential to know whether synergistic interactions can occur at low, environmentally relevant exposure levels. Studies demonstrating synergism in mammalian test systems were identified from the literature, with emphasis on studies performed at doses close to the points of departure (PODs) for individual chemicals. This search identified 90 studies on mixtures. Few included quantitative estimates of low-dose synergy; calculations of the magnitude of interaction were included in only 11 papers. Quantitative methodology varied across studies in terms of the null hypothesis, response measured, POD used to test for synergy, and consideration of the slope of the dose-response curve. It was concluded that consistent approaches should be applied for quantification of synergy, including that synergy be defined in terms of departure from dose additivity; uniform procedures be developed for assessing synergy at low exposures; and the method for determining the POD for calculating synergy be standardized. After evaluation of the six studies that provided useful quantitative estimates of synergy, the magnitude of synergy at low doses did not exceed the levels predicted by additive models by more than a factor of 4. PMID- 21309636 TI - Dihydroartemisinin induces caspase-8-dependent apoptosis in murine GT1-7 hypothalamic neurons. AB - The cytotoxicity of dihydroartemisinin (DHART; an active metabolite of artemisinin or ART) was investigated using murine GT1-7 hypothalamic neurons. A decrease in neuronal cell viability was observed in DHART-treated cells typically after 6 h of incubation. When neuronal cells were exposed to DHART for 24 h, the value of IC50 was found to be 24 +/- 3.2 uM (n = 6). Based on acridine orange/ethidium bromide (dual) staining and increases in oligonucleosomal fragmentation, the cell death at lower concentrations of DHART (<= 20 uM) was suggestive of apoptotic in nature. On the other hand, at higher concentrations of DHART (>= 50 uM), the cell death appeared to be predominantly necrotic. A potentiation of cytotoxic effects was seen in Fe(II)-containing medium whereas inclusion of deferoxamine (chelator of Fe) attenuated such effects. This would imply that the cleavage of the endoperoxide bridge of DHART by Fe(II) and the subsequent formation of O- and C-centered radical(s) are important determinants of the cytotoxicity that was observed. The activities of caspase-3/7, caspase-8 and caspase-9 were maximally seen at 12-h after exposure to DHART. Inhibitors of caspase-8 (C8I) but not caspase-9 (C9I) reduced the DHART-induced increase in caspase-3/7 activity. A relatively higher activity of caspase-8 to that of caspase-9 and the inhibition of caspsase-3/7 activity by C8I suggest that DHART induces caspase-8-mediated apoptosis involving the extrinsic pathway. Taken together, this study demonstrates that DHART and, possibly, other ART derivatives have considerable neurotoxic potential and facilitate our understanding of these agents. PMID- 21309637 TI - Infectious endocarditis caused by Escherichia coli. AB - Although Escherichia coli is among the most common causes of Gram-negative bacteraemia, infectious endocarditis (IE) due to this pathogen is rare. A 67-y old male without a previous medical history presented with a new mitral regurgitation murmur and persisting E. coli bacteraemia in spite of broad spectrum intravenous antibiotics. Transthoracic and transoesophageal echocardiography revealed a severe mitral endocarditis. E. coli DNA was identified from the mitral valve and the vegetation, and no other pathogen was found. The case was further complicated by spondylodiscitis and bilateral endophthalmitis. Extra-intestinal pathogenic E. coli (ExPEC) are able to colonize tissue outside the gastrointestinal tract and contain a variety of virulence factors that may enable the pathogens to invade and induce infections in the cardiac endothelia. In these cases echocardiography as the imaging technology is of paramount importance for the correct diagnosis and treatment. PMID- 21309638 TI - Failure of combination oral oseltamivir and inhaled zanamivir antiviral treatment in ventilator- and ECMO-treated critically ill patients with pandemic influenza A (H1N1)v. AB - OBJECTIVE: The objective of this study was to describe the clinical course of severe and complicated pandemic (H1N1)v infection treated with oral oseltamivir and inhaled zanamivir in a series of intensive care patients. METHODS: We investigated a case series of patients with respiratory failure and a positive (H1N1)v real-time reverse transcriptase polymerase chain reaction (rRT-PCR). Treatment consisted of oseltamivir tablets 75 mg * 4 daily in a nasogastric tube plus zanamivir intravenous (i.v.) solution 25 mg * 4 daily as inhalation. Ventilator inspiratory plateau airway pressure in the ventilator was kept below 30 cmH2O, PaO2 above 8 kPa and pH above 7.30. If this could not be achieved, inhalational nitric oxide (NO) was added or extracorporeal membrane oxygenation (ECMO) was initiated. RESULTS: Twenty-one patients were admitted, with a median age of 50 y (range 6-69 y). Five patients (23.8%) died in the intensive care unit (ICU) and 1 patient died 2 weeks after ICU discharge. Nine patients received ECMO treatment, of whom 3 died during ECMO (33.3%; 3/9) and 1 at 2 weeks after. The mortality in patients not receiving ECMO treatment was 16.6% (2/12). Sixteen patients (76%) were influenza PCR-positive on day 7 after the start of antiviral treatment. Irreversible presumed lung fibrosis complicated with pneumothorax was common. A high Murray score at admission was significantly associated with a fatal outcome. CONCLUSIONS: The mortality in these patients was high despite combined antiviral treatment with oseltamivir and zanamivir. Patients shed virus for a long time despite intensive therapy. Optimal management of patients with bilateral pneumonia and respiratory failure caused by (H1N1)v still needs to be determined. PMID- 21309639 TI - An examination of the pairing between narrative and occupational science. AB - In this paper the author proposes a possible typology of the use of narrative in occupational science based on an analysis of journal articles from occupational therapy and occupational science literature. The resulting typology identifies usages of narrative that fall into three categories: (a) everyday life, (b) clinical reasoning, and (c) research methodology. The theoretical and methodological interrelations among these categories are explored. This typology contributes to a clearer conceptualization of the various uses of narrative, minimizes terminological confusion, and suggests new extensions through which narrative can be used to study occupation. Recommendations for how this typology can be used to diminish confusion and encourage dialogue are provided. PMID- 21309640 TI - A method to measure hearing aid directivity index and polar pattern in small and reverberant enclosures. AB - OBJECTIVE: The directivity index (DI) and polar pattern of directional hearing aids are typically measured in an anechoic chamber, which is expensive and not commonly found. This article proposes a quasi-anechoic technique to measure hearing aid directivity in small and reverberant enclosures using the root-mean square amplitude of the first 3 ms of the hearing aid's response to the input signal. DESIGN: The hearing aid's planar DI and polar pattern were measured using the proposed method in an audiologic booth with low reverberation, a room with moderate reverberation, and an anechoic chamber. The measurement was repeated four times for each aid in each environment. The results were compared to the directivity obtained in the anechoic chamber using two benchmark measurements. STUDY SAMPLE: Eight hearing aids with a fixed directional mode were tested. RESULTS AND CONCLUSIONS: The results revealed that the error of the proposed method in DI was smaller than 0.3 dB in 94% of the measurement conditions. The standard deviation of the DI was smaller than 0.1 dB in 94% of the conditions. These results suggest that the proposed quasi-anechoic method provides an accurate and repeatable way to assess non-adaptive directional microphone hearing aids in small non-anechoic enclosures. PMID- 21309641 TI - Effects of speech signal content and speaker gender on acceptance of noise in listeners with normal hearing. AB - OBJECTIVE: The purpose of this research was to determine if the content and/or speaker gender of a running speech sample affected the acceptance of background noise within a participant. DESIGN: A male and a female recording of the Arizona Travelogue (Cosmos Inc.) and the ipsilateral competing message (ICM) from the synthetic sentence identification with ICM were created and used as the experimental speech signals. Two acceptable noise level measurements were obtained and averaged for each condition. Twenty-one participants rated interest level in the speech sample for each condition. STUDY SAMPLE: Forty-three listeners with normal hearing participated. RESULTS: Interest level was significantly greater for the ICM than the Arizona Travelogue speech samples, and was significantly greater for female samples. Neither the content of the sample nor the gender of the speaker significantly affected the most comfortable level or the acceptable noise level. CONCLUSIONS: Findings suggest that the acceptable noise level can be measured using various types of speech signals for normal hearing listeners. PMID- 21309642 TI - Tinnitus and its risk factors in the Beaver Dam offspring study. AB - OBJECTIVE: To assess the prevalence of tinnitus along with factors potentially associated with having tinnitus. DESIGN: Data were from the Beaver Dam Offspring Study, an epidemiological cohort study of aging. STUDY SAMPLE: After a personal interview and audiometric examination, participants (n = 3267, ages 21-84 years) were classified as having tinnitus if in the past year they reported having tinnitus of at least moderate severity or that caused difficulty in falling asleep. RESULTS: The prevalence of tinnitus was 10.6%. In a multivariable logistic regression model adjusting for age and sex, the following factors were associated with having tinnitus: hearing impairment (Odds Ratio (OR) = 3.20), currently having a loud job (OR = 1.90), history of head injury (OR = 1.84), depressive symptoms (OR = 1.82), history of ear infection (men, OR = 1.75), history of target shooting (OR = 1.56), arthritis (OR = 1.46), and use of NSAID medications (OR = 1.33). For women, ever drinking alcohol in the past year was associated with a decreased risk of having tinnitus (OR = 0.56). CONCLUSIONS: These results suggest that tinnitus is a common symptom in this cohort and may be associated with some modifiable risk factors. PMID- 21309643 TI - The mental health of deaf adolescents with cochlear implants compared to their hearing peers. AB - OBJECTIVE: To measure the mental health status of deaf adolescents with cochlear implants (CI). STUDY SAMPLE AND DESIGN: We used the "Strengths and Difficulties Questionnaire" (SDQ) to assess the mental health problems of 32 adolescents with CI (mean age 15.0 years) and 212 normal hearing peers (mean age 15.0 years). RESULTS: Parent and teacher ratings for the CI subjects (ES emotional symptoms, HA inattention-hyperactivity, CP conduct-problems and PBS pro-social behavior) did not differ significantly from the results of normal hearing peers. However, teachers rated significantly more cases as having peer problems (PP) and more cases as having very high (clinical) total difficulty scores (TDS) in the CI group. The SDQ results of the CI users correlated significantly with poor results in auditory performance and special school education. The age at CI implantation was not found to be a correlated with emotional, behavioral and social problems. CONCLUSIONS: Our findings indicate that the mental health of deaf adolescents with CI is comparable to that of normal hearing peers. PMID- 21309644 TI - CSF and serum hCG in patients without gestational and neoplastic hCG-secretion. AB - BACKGROUND: The measurement of human chorionic gonadotropin (hCG) in cerebrospinal fluid (CSF) is important for the diagnosis of intracranial or intraspinal trophoblastic tumours. The current study was performed to establish reference values for hCG in CSF and to explore the relationship of CSF hCG and serum hCG in patients who are not pregnant or do not have trophoblastic tumours. MATERIAL AND METHODS: CSF samples were obtained from 369 inpatients admitted because of various neurological diseases, excluding pregnancy, trophoblastic tumours and other malignant tumours. In 271 of the 369 patients, paired samples of CSF and serum were obtained. Both CSF hCG and serum hCG were measured. The 97.5th percentile and maximum value of CSF hCG were obtained. The CSF hCG and serum hCG concentrations in each of the 271 paired samples were compared. RESULTS: The 97.5th percentile and maximum value of CSF hCG concentration for overall participants were 1.00 and 5.00 IU/L, respectively. The CSF hCG concentration was found to be higher than the simultaneous serum hCG concentration in 81.9% (222/271) of the participants. CONCLUSIONS: The reference value determined in this study of CSF hCG in men is significantly lower than that usually used in clinical practice. A CSF hCG concentration higher than the simultaneous serum hCG concentration but lower than the upper reference limit does not necessarily suggest abnormal intrathecal hCG-secretion. PMID- 21309645 TI - Piperacillin and vancomycin induced severe thrombocytopenia in a hospitalized patient. AB - In hospitalized patients with complex medical problems on numerous drugs, thrombocytopenia may have a multiple confounding etiology. Keeping this in mind, it is of utmost importance to monitor the platelet count regularly during hospitalization and on subsequent follow-up visits, even after the most probable etiology has been identified/most likely causative drug has been withdrawn. Isolated thrombocytopenia with no evidence of microangiopathic hemolysis on the peripheral blood smear in an acutely ill hospitalized patient implicated sepsis, disseminated intravascular coagulation and drugs as the most probable causes. Our patient represents an uncommon case of antibiotic-induced severe immune thrombocytopenia, as he developed both vancomycin-dependent and piperacillin dependent antibodies, while being treated for cellulitis (vancomycin-specific antibodies of the IgG isotype, and both IgG and IgM antibodies specific for piperacillin were identified in laboratory testing). Vancomycin was stopped before the reports were available. Following this, the patient's platelet count showed a transient upward trend, but then the thrombocytopenia worsened drastically reaching a nadir of 10,000/uL. The platelet count returned to normal only after piperacillin/tazobactam was stopped after a week, thus establishing it as the cause of the more severe thrombocytopenia, which occurred later on; this was subsequently confirmed by the laboratory results. Vancomycin is an established cause of drug-induced immune thrombocytopenias, especially in acutely ill, hospitalized or elderly patients, whereas incidents of piperacillin/tazobactam-induced immune thrombocytopenia are uncommon. In case clinical suspicion is high, workup should include immunoprecipitation and flow cytometry studies to confirm antiplatelet antibodies. PMID- 21309647 TI - Likelihood of a subsequent chemotherapy-induced nausea and vomiting (CINV) event in patients receiving low, moderately or highly emetogenic chemotherapy (LEC/MEC/HEC). AB - OBJECTIVE: To assess the likelihood of subsequent chemotherapy-induced nausea and vomiting (CINV) events following a first chemotherapy administration CINV event in patients receiving single-day low, moderately, or highly emetogenic chemotherapy (LEC, MEC, or HEC). METHODS: A retrospective analysis was conducted utilizing Georgia Cancer Specialists, Florida Cancer Specialists, and ACORN electronic medical records databases (April 2006 through July 2009). Patients were included who received more than one single-day LEC, MEC, or HEC administration (oral or intravenous) with no chemotherapy 3 months prior to the first LEC, MEC, or HEC administration. Two cohorts, patients with a first administration CINV and no first administration CINV, were created and followed for 6 months. A multivariate logistic regression assessed the likelihood of subsequent CINV, controlling for age, gender, Charlson comorbidity index, cancer type, number of chemotherapy administrations, gap between LEC, MEC, or HEC administrations, and number of different LEC, MEC, or HEC agents administered. RESULTS: A total of 10,586 patients met the inclusion criteria (LEC = 3099; MEC = 5172; HEC = 2315). Of those patients, 4.4% (n = 136), 7.8% (n = 402), and 13.8% (n = 320) experienced a CINV event with their initial single-day LEC, MEC, or HEC administration, respectively. The unadjusted subsequent CINV rate was higher in the cohorts with first LEC, MEC, or HEC administration CINV for all groups receiving LEC (33.1% vs. 16.0%; p < 0.0001), MEC (46.5% vs. 18.9%; p < 0.0001), or HEC (59.1% vs. 26.9%; p < 0.0001). After controlling for covariates, patients with first LEC, MEC, or HEC administration CINV were 3.1, 3.8, and 3.7 times more likely to have a subsequent CINV compared to patients without a first LEC, MEC, or HEC administration CINV (Odds Ratio: 3.05 [95% CI: 2.08-4.48, p < 0.0001]; 3.77 [95% CI: 3.04-4.68, p < 0.0001]; and 3.70 [95% CI: 2.88-4.74, p < 0.0001], respectively). CONCLUSION: In this retrospective analysis, patients receiving single-day LEC, MEC, or HEC who had a prior CINV were at increased risk of subsequent CINV. Further studies assessing increased risk of a subsequent CINV events are warranted given this study represents an assessment of electronic medical record data within select community-based populations under usual care. PMID- 21309648 TI - Palliative and terminal care at home as portrayed in Dutch newspapers in 2009 compared to 2000. AB - BACKGROUND: Terminal care at home is receiving increased attention from the Dutch media, which is relevant for primary care providers. OBJECTIVES: To explore the portrayal of terminal care at home in newspapers in the Netherlands in 2000 and in 2009. METHOD: We performed a systematic analysis of documents retrieved from the LexisNexis Academic NL database. We compared data regarding the 'point of reference' (or 'frame') and the 'moral judgments' in articles appearing in the first six months of 2009 to the same period in 2000. RESULTS: In the year 2000, the framing of articles in regional newspapers appeared to be predominantly consumer-oriented (66%) and in national newspapers predominantly contextual (63%). The moral judgment in the regional articles was predominantly positive (66%), in the national newspapers predominantly negative (58%). In 2009, articles in regional and national newspapers were categorized mainly as consumer-oriented (73% and 55%, respectively), and new themes appeared, i.e. self care and medical topics. For moral judgment, again regional articles were mainly positive (76%) and national articles were mainly negative (39%) and neutral (31%). CONCLUSION: Regarding the theme 'terminal care at home' as published in Dutch newspapers in 2009 as compared to 2000, the diversity of the framing was more prominent and over all moral judgments were more positive, particularly in regional newspapers. Health care providers should realize that the portrayal of palliative and terminal care at home may differ depending on the type of newspaper--regional or national. PMID- 21309649 TI - Examining changes in self-perceived quality of life in children and adolescents with physical disability using a longitudinal design. AB - PURPOSE: The study aimed to investigate the changes in self-perceived quality of life (QOL) of children and adolescents with physical disability (PD). METHOD: Two hundred students aged 10-18 with PD were recruited from primary and high schools in Taiwan to participate in this longitudinal study. The Student Version of the Comprehensive Quality of Life Scale (COMQOL-S) was used to measure self perceived QOL, which was recorded at baseline, and 6, 12 and 18 months post baseline. Statistically, linear mixed models were used to compare the QOL scores among the four time points. RESULTS: At the second, third and fourth visit, 192, 151 and 128 participants completed COMQOL-S, respectively. Significant changes over time were found in overall objective and subjective OQL scores (slope = 0.8, p = 0.002 and slope = -1.3, p < 0.001, respectively). Specifically, significant reductions of the subjective QOL scores over the period of the four visits were observed in five domains, namely, Productivity (slope = -1.7, p = 0.005), Intimacy (slope = -1.6, p = 0.004), Safety (slope = -1.6, p = 0.008), Place in community (slope = -1.4, p = 0.019) and Emotional wellbeing (slope = -2.5, p < 0.001). Age was negatively correlated with the change of overall subjective score. Positive correlation was found between the change in mean objective scores and mean subjective scores in the Intimacy and Productivity domains. CONCLUSIONS: Even though the conditions of material wellbeing and health can be kept steady, the overall QOL of children and adolescents with PD could still decline over time. This might be attributable to the fact that social life becomes more sophisticated when children become older. PMID- 21309650 TI - The important predictors of cycling use in three groups of knee patients. AB - PURPOSE: Cycling is a popular international professional and recreational sport performed by both sexes and all age groups. Regular exercise is important for the elderly population and it has been shown that cycling is of great value for the osteoarthritis and knee arthroplasty patients. The purpose of this study was to evaluate the predictors of cycle use in three groups of knee patients. METHOD: We included 298 patients, 93 patients had osteoarthritis of the knee, 118 received a total knee arthroplasty and 87 had a meniscal and/or ligamentous injury. Patients were evaluated at the outpatient clinic and asked to complete the SF36-, Oxford 12-item-, IKDC-questionnaire and a specific cycling questionnaire. RESULTS: As the patient gets older, the chances of being able to cycle decrease by 5% every year. The chance to be able to cycle is 1.98 times higher for a male patient compared to a female patient. The chances of experiencing pain while cycling increases by 8% per unit rise of BMI. CONCLUSION: Age and sex, and not the clinical diagnosis, are the predictors of the ability of a patient to cycle. An increased BMI is the only risk factor found for experiencing pain while cycling. PMID- 21309651 TI - Living with a craniofacial condition: development of the Craniofacial Experiences Questionnaire (CFEQ) for adolescents and their parents. AB - OBJECTIVE: To develop a new instrument (the Craniofacial Experiences Questionnaire, CFEQ) to measure both stressors and positive aspects of living with a craniofacial condition from adolescent and parent perspectives, and to examine its validity and reliability. A secondary aim was to explore experiences reported according to age, gender, and diagnosis. DESIGN: Self-report and parent report questionnaires (CFEQ, Youth Self Report [YSR], Child Behavior Checklist [CBCL], Behavioral and Emotional Rating Scale [BERS]) were completed by adolescents with congenital craniofacial conditions and their parents. PARTICIPANTS: Fifty adolescents with craniofacial conditions and 55 of their parents. RESULTS: Internal reliability of the stressor and positive aspects scales was acceptable (.81 to .92) but was lower for some stressor subscales (.50 .86). Higher stressor scale scores were related to poorer adjustment (CBCL r = .55, YSR r = .37). There were no consistent differences in the stressful or positive experiences of young people with craniofacial conditions according to gender or age. There were no differences in stressors reported according to diagnosis. CONCLUSIONS: The CFEQ shows promise as a clinical and research tool for investigating the stressors and positive experiences of young people with craniofacial conditions. Consistent with the literature on chronic pediatric conditions, there were few differences in experiences of young people according to diagnosis. Furthermore, the lack of gender or age differences supports the need for clinicians to comprehensively assess the experiences of young people regardless of demographic variables. PMID- 21309652 TI - Influence of timing of hard palate repair in a two-stage procedure on early speech development in Danish children with cleft palate. AB - OBJECTIVE: To investigate the influence of timing of hard palate closure on early speech development from 18 months to 3 years of age. DESIGN: A prospective, randomized clinical trial. PARTICIPANTS: Thirty-four children with unilateral cleft lip and palate (UCLP) with velum closure at 4 months of age, and hard palate closure at 12 months (early hard palate repair, EarlyHPR) or 36 months (late hard palate unrepaired, LateHPU) by random assignment. Thirty-five control children were matched for gender and age. METHODS: All children were video recorded during a play interaction with a parent at 18 months of age. These recordings were transcribed according to the International Phonetic Alphabet. At 36 months a single word naming test was administered. RESULTS: At 18 months the LateHPU group produced fewer labial stops and more velar stops than the EarlyHPR group. Unlike the EarlyHPR group, the LateHPU group produced fewer vocalizations, consonants, and consonants permissible in word-initial position than the control group. Additionally, both cleft palate groups had a smaller productive vocabulary than the control group, but unlike the EarlyHPR group, the LateHPU group produced a smaller number of word tokens in social interaction than the control group. By 3 years of age, the LateHPU group had a (severely) restricted phonological system and produced more cleft speech characteristics than the EarlyHPR group. CONCLUSIONS: Surgical timing of hard palate repair in a two-stage procedure appears to have an influence on early speech development in children with cleft palate. PMID- 21309653 TI - A novel delivery system of probiotic drop and its effect on dental caries risk factors in cleft lip/palate children. AB - OBJECTIVE: The aim of the present study was to investigate the effect of the probiotic bacterium Lactobacillus reuteri on the levels of salivary mutans streptococci and lactobacilli in children with cleft lip/palate who used the novel drop containing L. reuteri. MATERIAL AND METHODS: The study group consisted of 19 operated cleft lip/palate children aged 4 to 12 years. The study had a double-blind, randomized crossover design, and the experimental period consisted of four consecutive time periods. During periods 2 and 4, consisting of 25 days each, parents were instructed that their children should consume 5 drops per day (0.15 to 0.20 g) of probiotic or placebo drops produced by the same manufacturer. The probiotic drop, BioGaia Reuteri drops, contained L. reuteri DSM 17938 and L. reuteri ATCC PTA 5289 (>=1 * 10(8) CFU/5 drops). The counts of salivary mutans streptococci and lactobacilli were evaluated using the CRT tests. The data were processed with NCSS 2007 software using chi-square and McNemar tests. RESULTS: There was no statistically significant (p > .05) reduction of salivary mutans streptococci and lactobacilli after 25 days of consumption of both drops. CONCLUSIONS: The novel drop containing L. reuteri may not reduce the levels of salivary mutans streptococci and lactobacilli in cleft lip/palate children. PMID- 21309654 TI - Oral and craniofacial findings of Binder syndrome: two case reports. AB - Binder syndrome is a malformative midfacial alteration, known also as maxillonasal dysplasia or maxillonasal dysostosis. In this article, two cases of affected patients are reported, and the features of the condition are reviewed. One case presents a cleft lip. Hypotheses about etiology, pathogenesis, and classification of the syndrome are illustrated. This work provides a contribution for the delineation of a differential diagnostic procedure. PMID- 21309655 TI - Multidisciplinary approach for esthetic, functional, and quality-of-life outcome in soft palate cleft patient. AB - The fabrication of a Suersen obturator prosthesis with titanium framework is described in the case of a 43-year-old man with congenital absence of the soft palate. The patient revealed an open soft palate, bilateral cleft lip and palate, Angle Class III dental malocclusion, and anterior and posterior crossbite. He was treated with a multidisciplinary approach. A Dolder bar was fabricated between the maxillary canines, and telescopic crowns were prepared for maxillary premolars. Angle Class III tooth relation was readjusted to tooth-tooth relation; closure of the nasopharynx and oropharynx was performed by Suersen method, which improves speech. PMID- 21309656 TI - Assessment of renal artery stenosis using both resting pressures ratio and fractional flow reserve: relationship to angiography and ultrasonography. AB - BACKGROUND. Clinical benefit from renal artery revascularization remains controversial, probably because of inaccurate stenosis severity assessment. Objective. The aim of the study was to evaluate resting translesional pressures ratio and renal fractional flow reserve (rFFR) in relation to angiography and Doppler duplex ultrasonography in patients with at least moderate renal artery stenosis (RAS). METHODS. 44 hypertensive patients (48% of males, mean age 65 years) with at least moderate RAS were investigated. Translesional systolic pressure gradient (TSPG), resting Pd/Pa ratio (the ratio of mean distal to lesion and mean proximal pressures) and hyperemic rFFR - after intrarenal administration of papaverine - were evaluated. Quantitative angiographic analysis of stenosis severity was performed including minimal lumen diameter (MLD) and percent diameter stenosis (DS) assessment. Renal/aortic ratio (RAR), resistive index (RI) and deltaRI (side-to side difference) were obtained in Doppler-duplex ultrasonography. The predictive value of selected variables was calculated using receiver-operating characteristics curves. RESULTS. Mean Pd/Pa ratio was 0.86 +/- 0.12 and decreased to 0.79 +/- 0.13 after papaverine administration. Both Pd/Pa ratio and rFFR strongly correlated with TSPG (r = -0.92, p < 0.0001 and r = 0.88, p < 0.0001, respectively) and moderately with MLD (r = 0.62, p < 0.0001 and r = 0.66, p < 0.0001) and DS (r = -0.63, p < 0.0001 and r = -0.70, p < 0.0001). To identify more than 70% RAS, considered severe, the most predictive cut-off values were 0.93 for Pd/Pa ratio and 0.80 for rFFR. CONCLUSIONS. Mean Pd/Pa ratio and rFFR strongly correlated with angiographic data and in less pronounced manner with ultrasound parameters reflecting intrarenal blood flow. The best accuracy cut-off points for severe RAS predicting were 0.93 and 0.80, respectively. PMID- 21309659 TI - Handwriting in adults with Down syndrome. AB - BACKGROUND: Although there is growing awareness about the potential for people with Down syndrome (DS) to become literate, we know little about the characteristics of handwriting within this population. METHODS: Thirty-three participants took part in this experiment. Eleven adults with DS and 22 typically developing individuals (11 children matched on mental age and 11 adults matched on chronological age) performed a copy task. A French adaptation of the Concise Evaluation Scale for Children's Handwriting (BHK) was used to assess speed and quality. RESULTS: Handwriting of adults with DS was relatively similar to that of the mental age control group, but comparisons with the chronological age control group showed differences on quality and spatial organisation. CONCLUSIONS: Results revealed that adults with DS are capable of producing acceptable writing. Observed differences could be explained by the mode of movement control involved in production. Implications for future research and education are discussed. PMID- 21309658 TI - Effects of high and low glycemic load meals on energy intake, satiety and hunger in obese Hispanic-American youth. AB - Some short-term pediatric studies have suggested beneficial effects of low glycemic load (LGL) meals on feelings of hunger and on energy intake. However, the effects of LGL diets have not been systematically studied in obese Hispanic children, who stand to benefit from successful interventions. OBJECTIVE: To examine the effects of LGL and high-GL (HGL) meals on appetitive responses and ad libitum energy intake of obese Hispanic youth. METHODS: A total of 88 obese Hispanic youth aged 7-15 years were enrolled in a community-based obesity intervention program and randomly assigned to consume meals designed as either LGL (n = 45) or HGL (n = 43). After 12 weeks, participants were admitted for a 24 hour metabolic study. Following the morning test meal, subjects serially reported hunger, fullness, and satiety using a visual analog scale. Blood insulin and glucose were measured. After 5 hours, participants were fed another test meal and given a snack platter from which to eat ad libitum. All test food was weighed and the energy, macronutrients, and glycemic load (GL) of consumed foods were calculated. RESULTS: The HGL group had significantly higher insulin (p = 0.0005) and glucose (p = 0.0001) responses to the breakfast meal compared with the LGL group. There were no significant between-group differences in energy consumed from the snack platter (1303 vs. 1368 kcal, p = 0.5), or in the subjective feelings of hunger (p = 0.3), fullness (p = 0.5) or satiety (p = 0.3) between the two groups. CONCLUSIONS: Our study provides no evidence that, for obese Hispanic youth, changing the GL of the diet affects short-term hunger, fullness, satiety, or energy intake. ClinicalTrials.gov Identifier: NCT01068197. PMID- 21309660 TI - Reflections on a participatory project: the rewards and challenges for the lead researchers. AB - BACKGROUND: Participatory action research (PAR) offers potential for people with an intellectual disability to have an active voice in service provision. However, ensuring their meaningful engagement is not without challenges. Guided by PAR, a recent project to develop a quality of life tool provided learning opportunities for the lead researchers. This paper addresses 3 issues raised by Ramcharan, Grant, and Flynn (2004) in relation to participation of people with intellectual disability in research. METHOD: Informed by reflective practice, this paper draws on a combination of field notes and written reports to critically examine the 3 issues related to effective participation. RESULTS: Although the project achieved its goal of people with intellectual disability authoring a quality of life tool, there was variation in participants' contribution. With both data collection and analysis, prior experience and confidence influenced the participation of co researchers. The financial and the practical support of the contracting organisation were crucial to enabling people to take part. CONCLUSIONS: For researchers interested in PAR, planning well whilst maintaining flexibility would appear to be key to achieving maximum participation. PMID- 21309662 TI - Acute nose-only inhalation exposure of rats to di- and triphosgene relative to phosgene. AB - Groups of young adult Wistar rats were acutely exposed to trichloromethyl chloroformate (diphosgene) and bis(trichloromethyl) carbonate (triphosgene) vapor atmospheres using a directed-flow nose-only mode of exposure. The exposure duration used was 240 min. The median lethal concentration (LC50) of diphosgene and triphosgene was 13.9 and 41.5 mg/m3, respectively. Based on the molar exposure concentrations, the LC50s of phosgene (previously published), diphosgene, and triphosgene were 0.07, 0.07, and 0.14 mmol/m3, respectively. Although the principal toxic mode of action of the volatile diphosgene was similar to phosgene gas, the vapor phase of triphosgene appeared to be different to that of phosgene and diphosgene based on a more persistent occurrence of signs of respiratory distress and a biphasic onset of mortality. While all substances caused mortality within 1 day postexposure, triphosgene induced a second phase of mortality 11?14 days postexposure. The vapor saturation concentration of triphosgene at ambient temperature is ?100 times its LC50. In summary, triphosgene-induced lung injury patterns are different from that of phosgene and diphosgene. More research is needed to close the substantial data gaps of triphosgene. PMID- 21309663 TI - Inspiratory and expiratory aerosol deposition in the upper airway. AB - Aerosol deposition efficiency (DE) in the extrathoracic airways during mouth breathing is currently documented only for the inspiratory phase of respiration, and there is a need for quantification of expiratory DE. Our aim was to study both inspiratory and expiratory DE in a realistic upper airway geometry. This was done experimentally on a physical upper airway cast by scintigraphy, and numerically by computational fluid dynamic simulations using a Reynolds Averaged Navier?Stokes (RANS) method with a k-? SST turbulence model coupled with a stochastic Lagrangian approach. Experiments and simulations were carried out for particle sizes (3 and 6 MUm) and flow rates (30 and 60 L/min) spanning the ranges of Stokes (Stk) and Reynolds (Re) number pertinent to therapeutic and environmental aerosols. We showed that inspiratory total deposition data obtained by scintigraphy fell onto a previously published deposition curve representative of a range of upper airway geometries. We also found that expiratory and inspiratory DE curves were almost identical. Finally, DE in different compartments of the upper airway model showed a very different distribution pattern of aerosol deposition during inspiration and expiration, with preferential deposition in oral and pharyngeal compartments, respectively. These compartmental deposition patterns were very consistent and only slightly dependent on particle size or flow rate. Total deposition for inspiration and expiration was reasonably well-mimicked by the RANS simulation method we employed, and more convincingly so in the upper range of the Stk and Re number. However, compartmental deposition patterns showed discrepancies between experiments and RANS simulations, particularly during expiration. PMID- 21309664 TI - Short-term inhalation of stainless steel welding fume causes sustained lung toxicity but no tumorigenesis in lung tumor susceptible A/J mice. AB - Debate exists as to whether welding fume is carcinogenic, but epidemiological evidence suggests that welders are an at-risk population for development of lung cancer. Our objective was to expose, by inhalation, lung tumor susceptible (A/J) and resistant C57BL/6J (B6) mice to stainless steel (SS) welding fume containing carcinogenic metals and characterize the lung-inflammatory and tumorigenic response. Male mice were exposed to air or gas metal arc (GMA)-SS welding fume at 40 mg/m(3)*3 h/day for 6 and 10 days. At 1, 4, 7, 10, 14, and 28 days after 10 days of exposure, bronchoalveolar lavage (BAL) was done. Lung cytotoxicity, permeability, inflammatory cytokines, and cell differentials were analyzed. For the lung tumor study, gross tumor counts and histopathological changes were assessed in A/J mice at 78 weeks after 6 and 10 days of exposure. Inhalation of GMA-SS fume caused an early, sustained macrophage and lymphocyte response followed by a gradual neutrophil influx and the magnitudes of these differed between the mouse strains. Monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-2 (MIP-2), and tumor necrosis factor-alpha (TNF-alpha) were increased in both strains while the B6 also had increased interleukin-6 (IL-6) protein. BAL measures of cytotoxicity and damage were similar between the strains and significantly increased at all time points. Histopathology and tumorigenesis were unremarkable at 78 weeks. In conclusion, GMA-SS welding fume induced a significant and sustained inflammatory response in both mouse strains with no recovery by 28 days. Under our exposure conditions, GMA-SS exposure resulted in no significant tumor development in A/J mice. PMID- 21309665 TI - Gastroesophageal junction carcinoma multimodal treatment: standards, debate and new therapeutic options. PMID- 21309667 TI - XELOX in colorectal cancer: a convenient option for the future? AB - XELOX is a 3-weekly chemotherapy combination of oral capecitabine and intravenous oxaliplatin. The central hypothesis that led to its development was that it would provide a convenient and cost-effective alternative to intravenous fluorouracil based chemotherapy doublets, without compromising on anti-tumor efficacy. Recently its role in colorectal cancer has become more established in both the metastatic and adjuvant setting. Ongoing investigation of XELOX continues in a number of directions: its combination with novel biological agents, its efficacy and safety in the elderly, and the development of biomarkers that can predict its anti-tumor effect. This article provides a comprehensive and up-to-date synopsis of all pertinent clinical studies detailing this regimen and its promise for the future. PMID- 21309668 TI - Annual update of pediatric digestive diseases. AB - The 24th Annual Meeting of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition provided a comprehensive overview of pediatric digestive diseases. The meeting and its adjunct events, including a postgraduate course and 1-day symposium, enabled a diverse group of physicians, trainees and nurses to have the opportunity to discuss the latest developments in pediatric gastrointestinal, liver and nutritional disorders. PMID- 21309669 TI - Risk factors and diagnosis of flat adenomas of the colon. AB - In addition to histology, size and location, a morphologic description can be ascribed to polyps and adenomas. Traditionally, adenomas have been described as sessile and pedunculated, but it is now accepted that they can also present as flat or even depressed. Although first recognized in 1985, flat adenomas have become more common in Western published literature and in endoscopic reports. The Japanese Research Society Classification describes flat adenomas as lesions with a height that is less than one half of the diameter, while the Paris classification divides polyps into protruding and nonprotruding. The clinical significance of flat adenomas includes their potential malignancy, difficulty in detection and possible role in interval cancers. Serrated polyps represent a subset of polyps that have all the features that make flat lesions clinically important. Due to the relatively recent recognition of these lesions, as well as the technology required to detect them, the prevalence and malignant potential of these lesions in Western patients are still unknown. Finally, the best techniques and equipment for detecting flat polyps are also not established. In this article, we examine the issue of flat polyps and their significance in colorectal cancer screening with regard to prevalence, risk factors and methods for detecting flat polyps. PMID- 21309670 TI - Targeting the innate immune system in pediatric inflammatory bowel disease. AB - The pathogenesis of inflammatory bowel disease (IBD) is complex and involves both innate and adaptive immune responses. This article addresses, in a selective and speculative fashion, the topic of how the various components of the intestinal innate immune system can be manipulated for the purpose of developing new therapeutic approaches. These various components include: agents that stimulate mucosal innate immune responses, such as food components and the gut microbiota; cells that directly respond to these stimuli, including epithelial cells, macrophages and dendritic cells; and molecules that mediate innate immune responses, such as Toll-like receptors and protein kinases. Downregulation of excessive innate immune responses makes therapeutic sense in both pediatric and adult IBD. However, because IBD is complex and characteristically chronic, major alterations of adaptive immunity are also involved in the mediation of inflammation. Thus, novel and truly effective approaches to treat IBD will undoubtedly require intervening in the innate as well as the adaptive branches of the mucosal immunity. PMID- 21309672 TI - Dysplasia and cancer in inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) is a chronic gastrointestinal disease associated with an increased risk of colorectal cancer (CRC). Although CRC occurs in a minority of IBD patients (1%), it carries a high mortality and accounts for 20% of IBD-related mortality. Established risk factors for the development of CRC in IBD include disease duration of 8 years or more, family history of CRC, extensive colitis and primary sclerosing cholangitis. Meticulous colonoscopy and anti inflammatory medications can reduce the risk of developing CRC. The future of IBD surveillance involves the use of novel endoscopic techniques (chromoendoscopy, narrow-band imaging, confocal laser endomicroscopy and autofluorescence) to enhance colonoscopic accuracy, in concert with chemopreventative medications to help reduce the risk of CRC in IBD. PMID- 21309673 TI - Vitamin D and colon cancer. AB - A wealth of scientific evidence supports a role for vitamin D in decreasing colorectal cancer incidence, and possibly mortality. This reduction in risk is related to inhibition of cellular proliferation and stimulation of differentiation. The minimal amount and duration needed to bring about these effects necessitate additional studies. Furthermore, a critical evaluation of physiologically relevant biomarkers of vitamin D status, including 25 hydroxyvitamin D, is needed. Several dietary components and the balance between energy intake and expenditure influence vitamin D metabolism. Scientists need to identify confounders and modifiers of the biological response to vitamin D, including dietary factors, lifestyle factors such as exercise, race or ethnicity, and genetic background. PMID- 21309671 TI - The role of experimental models in developing new treatments for irritable bowel syndrome. AB - Irritable bowel syndrome (IBS) is characterized by chronic, recurrent abdominal pain and altered bowel habits and is currently defined by symptom criteria and the absence of detectable organic disease. The underlying pathophysiology remains incompletely understood. Despite considerable efforts by the scientific community and the pharmaceutical industry to develop novel pharmacological treatments aimed at chronic visceral pain, the traditional approach to identifying and evaluating novel drugs for this target have largely failed to translate into effective IBS treatments. However, several novel drugs aimed at normalizing bowel movements have produced clinical effects, not only on the primary target, but also on pain and discomfort. While some of the commonly used experimental animal models for the pain dimension of IBS have some face and construct validity, the predictive validity of most of the models is either unknown, or has been disappointing. A reverse translational approach is proposed, which is based on identification and characterization of brain endophenotypes in patients, followed by translation of these endophenotypes for pharmacological studies in rodent models. PMID- 21309674 TI - Celiac disease and health-related quality of life. AB - Celiac disease is a particularly common life-long disorder with a prevalence of approximately 1-2% in Western populations. In recent years the health-related quality of life has become an important issue in this context, and most studies carried out so far have shown diminished quality of life in untreated patients compared with healthy controls. Furthermore, there has generally been a beneficial response to treatment with a gluten-free diet. However, the majority of trials have been carried out among adults with gastrointestinal disease, while in fact several extraintestinal and atypical forms of celiac disease might be even more common than the classical disorder. In addition, only a small proportion of these studies have been conducted among children. This article highlights the studies of health-related quality of life and celiac disease conducted to date. Particular attention is paid to the extraintestinal and atypical forms of the disorder. PMID- 21309675 TI - Recent advances in imaging hepatic fibrosis and steatosis. AB - Liver disease is an increasing cause of morbidity and mortality worldwide. Currently, the gold standard for diagnosis and assessment of parenchymal disease is histopathological assessment of a percutaneous or transjugular liver biopsy. The risks and limitations of this technique are well recognized and as a result, significant effort has gone into the development of novel noninvasive methods of diagnosis and longitudinal assessment. Imaging techniques have improved significantly over the past decade and new technologies are beginning to enter clinical practice. Ultrasound, computed tomography and MRI are the main modalities currently used, but novel MRI-based techniques will have an increasing role. While there has been extensive research into the imaging of focal liver disease, the evidence base for imaging in diffuse disease has also undergone recent rapid development, particularly in the assessment of fibrosis and steatosis. Both of these abnormalities of the parenchyma can lead to cirrhosis and/or hepatocellular carcinoma and represent an important opportunity for detection of early liver disease. We discuss the recent advances in liver imaging techniques and their role in the diagnosis and monitoring of diffuse liver disease, with a focus on their current and potential clinical relevance and whether they may replace or augment liver biopsy. We also discuss techniques currently under development and their potential clinical applications in the future. PMID- 21309676 TI - Advances in the regulation of liver regeneration. AB - Liver regeneration is known to be a process involving highly organized and ordered tissue growth triggered by the loss of liver tissue, and remains a fascinating topic. A large number of genes are involved in this process, and there exists a sequence of stages that results in liver regeneration, while at the same time inhibitors control the size of the regenerated liver. The initiation step is characterized by priming of quiescent hepatocytes by factors such as TNF-alpha, IL-6 and nitric oxide. The proliferation step is the step during which hepatocytes enter into the cell cycle's G1 phase and are stimulated by complete mitogens including HGF, TGF-alpha and EGF. Hepatic stimulator substance, glucagon, insulin, TNF-alpha, IL-1 and IL-6 have also been implicated in regulating the regeneration process. Inhibitors and stop signals of hepatic regeneration are not well known and only limited information is available. Furthermore, the effects of other factors such as VEGF, PDGF, hypothyroidism, proliferating cell nuclear antigen, heat shock proteins, ischemic-reperfusion injury, steatosis and granulocyte colony-stimulating factor on liver regeneration are also systematically reviewed in this article. A tissue engineering approach using isolated hepatocytes for in vitro tissue generation and heterotopic transplantation of liver cells has been established. The use of stem cells might also be very attractive to overcome the limitation of donor liver tissue. Liver specific differentiation of embryonic, fetal or adult stem cells is currently under investigation. PMID- 21309677 TI - Global epidemiology of Barrett's esophagus. AB - Barrett's esophagus (BE) is defined as a metaplastic change of the distal esophageal epithelium from squamous to columnar type epithelium with the presence of intestinal metaplasia. There is a striking geographic variation in the prevalence rates of BE. Most epidemiological data on BE are derived from patients undergoing endoscopy and do not reflect prevalence rates in the general population. BE is much more common in the West when compared with Asia and Africa. Although BE is less common in Asia, the demographics are similar to the West, being predominantly found in older men with longer duration of reflux symptoms. Some studies from the West have suggested an increase in prevalence rates of BE. An increase in prevalence rates will have significant implications for health resource utilization and costs, due to the small but significant risk of developing esophageal adenocarcinoma. Endoscopic surveillance with the aim of detecting early lesions has been advocated. Compared with conventional white light endoscopy with blind four-quadrant biopsies, the use of image-enhanced endoscopy, including chromoendoscopy, may improve detection of subtle mucosal irregularities and facilitate targeted biopsies. However, a truly cost-effective surveillance strategy remains to be determined. PMID- 21309680 TI - Electrophysiology and functional MRI in post-acute mild traumatic brain injury. AB - Symptoms persisting beyond the acute phase (>2 months) after a mild traumatic brain injury (MTBI) are often reported, but their origin remains controversial. Some investigators evoke dysfunctional cerebral mechanisms, while others ascribe them to the psychological consequences of the injury. We address this controversy by exploring possible cerebral dysfunction with functional magnetic resonance imaging (fMRI) and event-related potentials (ERP) in a group of patients during the post-acute phase. Fourteen MTBI symptomatic patients (5.7+/-2.9 months post injury) were tested with fMRI and ERP using a visual externally ordered working memory task, and were compared with 23 control subjects. Attenuated blood oxygen level dependent (BOLD) signal changes in the left and right mid-dorsolateral prefrontal cortex (mid-DLPFC), the putamen, the body of the caudate nucleus, and the right thalamus were found in the MTBI group compared with the control group. Moreover, symptom severity and BOLD signal changes were correlated: patients with more severe symptoms had lower BOLD signal changes in the right mid-DLPFC. For ERP, a group*task interaction was observed for N350 amplitude. A larger amplitude for the working memory task than for the control task was found in control subjects, but not in MTBI subjects, who had weak amplitudes for both tasks. This study confirms that persistent symptoms after MTBI cannot be uniquely explained by psychological factors, such as depression and/or malingering, and indicates that they can be associated with cerebral dysfunction. ERP reveals decreased amplitude of the N350 component, while fMRI demonstrates that the more severe the symptoms, the lower the BOLD signal changes in the mid-DLPFC. PMID- 21309681 TI - E-selectin is a viable route of infection for polymer-coated adenovirus retargeting in TNF-alpha-activated human umbilical vein endothelial cells. AB - BACKGROUND: E-selectin is an attractive endothelial cell surface marker in inflammation and cancer. PURPOSE: We sought to investigate retargeting of adenovirus via E-selectin as a viable pathway of infection in tumor necrosis factor-alpha (TNF-alpha)-activated human umbilical vein endothelial cells (HUVECs). METHODS: E1, E3-deleted Ad5 expressing cytomegalovirus immediate-early (CMV IE) promoter-driven luciferase (Adluc) was coated with an amino-reactive multivalent hydrophilic polymer based on poly [N-(2-hydroxypropyl) methacrylamide] to generate pHPMA-adenovirus (pcAdluc). This was then retargeted by covalent attachment of a mouse antihuman E-selectin monoclonal antibody (MHES mAb), purified from the H18/7 hybridoma cell line (MHESpcAdluc). RESULTS: MHESpcAdluc was efficiently taken up into HUVECs, generating a high level of transduction in TNF-alpha-treated E-selectin positive cells but not in untreated receptor-negative cells. Specific retargeting of MHESpcAdluc was demonstrated through reduced transduction of stimulated HUVEC when incubated in the presence of free E-selectin antibodies. DISCUSSION AND CONCLUSION: Our results suggest that E-selectin could be a valuable target for gene transfer strategies internalizing polymer-coated modified adenovirus particles through a viable receptor-mediated endocytosis pathway, generating adequate levels of transgene expression per virus genome copy without compromising the specific activity of the parental virus. PMID- 21309682 TI - Lung epithelial binding peptide-linked high mobility group box-1 A box for lung epithelial cell-specific delivery of DNA. AB - High mobility group box-1 A box (HMGB1A) is an anti-inflammatory peptide originating from HMGB1. A previous report demonstrated that recombinant HMGB1A could deliver DNA into cells. Lung epithelial-specific gene delivery is required for the gene therapy of various lung diseases such as acute lung injury. In this study, a lung epithelial-specific DNA carrier was produced by linking the lung epithelial binding peptide (LEBP) to HMGB1A. An LEBP-linked HMGB1A (LEBP-HMGB1A) expression vector, pET21a-LEBP-HMGB1A, was constructed. LEBP-HMGB1A was expressed in BL21 strain and purified by consecutive applications of nickel affinity chromatography and cationic exchange chromatography. In a gel retardation assay, LEBP-HMGB1A completely retarded DNA at a 5:1 weight ratio (peptide:DNA). LEBP HMGB1A/DNA complexes were prepared at various weight ratios, to which a fixed amount of polyethylenimine (2 kDa, PEI2k) was added to increase the proton buffering effect of the complex. LEBP-HMGB1A had the highest transfection efficiency to L2 lung epithelial cells at a 20:1 weight ratio (peptide:DNA). At this ratio, LEBP-HMGB1A had a higher transfection efficiency than poly-L-lysine (PLL) as well as HMGB1A without LEBP. A cytotoxicity assay showed that LEBP HMGB1A was not toxic to L2 cells. Therefore, LEBP-HMGB1A may be useful in developing gene therapies for lung diseases. PMID- 21309683 TI - The Global Sepsis Alliance: building new collaborations to confront an under recognized threat. PMID- 21309657 TI - Apixaban in patients with atrial fibrillation. AB - BACKGROUND: Vitamin K antagonists have been shown to prevent stroke in patients with atrial fibrillation. However, many patients are not suitable candidates for or are unwilling to receive vitamin K antagonist therapy, and these patients have a high risk of stroke. Apixaban, a novel factor Xa inhibitor, may be an alternative treatment for such patients. METHODS: In a double-blind study, we randomly assigned 5599 patients with atrial fibrillation who were at increased risk for stroke and for whom vitamin K antagonist therapy was unsuitable to receive apixaban (at a dose of 5 mg twice daily) or aspirin (81 to 324 mg per day), to determine whether apixaban was superior. The mean follow up period was 1.1 years. The primary outcome was the occurrence of stroke or systemic embolism. RESULTS: Before enrollment, 40% of the patients had used a vitamin K antagonist. The data and safety monitoring board recommended early termination of the study because of a clear benefit in favor of apixaban. There were 51 primary outcome events (1.6% per year) among patients assigned to apixaban and 113 (3.7% per year) among those assigned to aspirin (hazard ratio with apixaban, 0.45; 95% confidence interval [CI], 0.32 to 0.62; P<0.001). The rates of death were 3.5% per year in the apixaban group and 4.4% per year in the aspirin group (hazard ratio, 0.79; 95% CI, 0.62 to 1.02; P=0.07). There were 44 cases of major bleeding (1.4% per year) in the apixaban group and 39 (1.2% per year) in the aspirin group (hazard ratio with apixaban, 1.13; 95% CI, 0.74 to 1.75; P=0.57); there were 11 cases of intracranial bleeding with apixaban and 13 with aspirin. The risk of a first hospitalization for cardiovascular causes was reduced with apixaban as compared with aspirin (12.6% per year vs. 15.9% per year, P<0.001). The treatment effects were consistent among important subgroups. CONCLUSIONS: In patients with atrial fibrillation for whom vitamin K antagonist therapy was unsuitable, apixaban reduced the risk of stroke or systemic embolism without significantly increasing the risk of major bleeding or intracranial hemorrhage. (Funded by Bristol-Myers Squibb and Pfizer; ClinicalTrials.gov number, NCT00496769.). PMID- 21309684 TI - The history of surgical infections. PMID- 21309686 TI - General health-related quality of life and oral health impact among Australians with cleft compared with population norms; age and gender differences. AB - OBJECTIVE: To evaluate general health-related quality of life (HRQoL) and oral health impact among adults treated for cleft to determine age and gender differences, and to compare against population norms. DESIGN: Cross-sectional prospective study. PARTICIPANTS/SETTING: Nonsyndromic cleft patients treated by the Australian Craniofacial Unit from 1975 to 2009 were recruited (n = 112). Response rate was 79% (n = 88). Main outcome measures : HRQoL was measured by the Short Form (SF)-36 questionnaire. Oral health impact was measured by the Oral Health Impact Profile (OHIP)-14 questionnaire. State-based and national norms were used for comparative purposes. RESULTS: There were no significant age or sex differences in the cleft sample's SF-36 and OHIP-14 scores. When compared against South Australian 2002 state-level norms, cleft participants scored higher on physical function and physical role function but lower on vitality and mental health. The prevalence of having experienced one or more of OHIP-14 items "fairly often" or "very often" was 2.7 times higher than national-level estimates, while extent was 2.8 times and severity 1.7 times higher. CONCLUSIONS: The oral health impact among cleft patients included in our study was poor compared with population-level estimates. The HRQoL showed mixed results, with the vitality and mental health components being poorer in the cleft group compared with population level estimates. These results indicate that treatment for orofacial clefting does not entirely remove the factors contributing to poor HRQoL and oral health. PMID- 21309687 TI - Lung exposure of titanium dioxide nanoparticles induces innate immune activation and long-lasting lymphocyte response in the Dark Agouti rat. AB - Nanomaterial of titanium dioxide (TiO(2)) is manufactured in large-scale production plants, resulting in risks for accidental high exposures of humans. Inhalation of metal oxide nanoparticles in high doses may lead to both acute and long-standing adverse effects. By using the Dark Agouti (DA) rat, a strain disposed to develop chronic inflammation following exposure to immunoactivating adjuvants, we investigated local and systemic inflammatory responses after lung exposure of nanosized TiO(2) particles up to 90 days after intratracheal instillation. TiO(2) induced a transient response of proinflammatory and T-cell activating cytokines (interleukin [IL]-1alpha, IL-1beta, IL-6, cytokine-induced neutrophil chemoattractant [CINC]-1, granulocyte-macrophage colony-stimulating factor [GM-CSF], and IL-2) in airways 1-2 days after exposure, accompanied by an influx of eosinophils and neutrophils. Neutrophil numbers remained elevated for 30 days, whereas the eosinophils declined to baseline levels at Day 8, simultaneously with an increase of dendritic cells and natural killer (NK) cells. The innate immune activation was followed by a lymphocyte expansion that persisted throughout the 90-day study. Lymphocytes recruited to the lungs were predominantly CD4(+) helper T-cells, but we also demonstrated presence of CD8(+) T-cells, B-cells, and CD25(+) T-cells. In serum, we detected both an early cytokine expression at Days 1-2 (IL-2, IL-4, IL-6, CINC-1, IL-10, and interferon gamma [IFN-gamma] and a second response at Day 16 of tumor necrosis factor-alpha (TNF-alpha), indicating systemic late-phase effects in addition to the local response in airways. In summary, these data demonstrate a dynamic response to TiO(2) nanoparticles in the lungs of DA rats, beginning with an innate immune activation of eosinophils, neutrophils, dendritic cells, and NK cells, followed by a long-lasting activation of lymphocytes involved in adaptive immunity. The results have implications for the assessment of risks for adverse and persistent immune stimulation following nanoparticle exposures in sensitive populations. PMID- 21309689 TI - Detection of visual deficits in aging DBA/2J mice by two behavioral assays. AB - PURPOSE: The DBA/2J mice have been used as an animal model for human pigmentary glaucoma. However, these mice develop various degrees of disease symptoms at different ages, making it difficult to detect pathological changes of retinal degeneration at glaucoma onset. The purpose of this study is to develop a non invasive assay to identify individual mice that develop visual deficits. MATERIALS AND METHODS: We apply two behavioral tests, a swimming test of visual discrimination and a test of optomotor response, to identify glaucomatous DBA/2J mice. We then examine whether the elevation of intraocular pressure (IOP), the common risk factor for glaucoma, affects visual performances of the DBA/2J mice. We further compare the retinal ganglion cell death, one of the signature glaucoma symptoms, in mice with normal behavior with those with poor visual performances. RESULTS: Our data demonstrate that (1) the onset of visual deficits in DBA/2J mice is around 7 months of age; (2) within each age group, there are various degrees of visual deficits; and (3) the percentage of mice exhibiting visual deficits increases with age and their visual capacities decrease gradually. Furthermore, the poor visual performances of DBA/2J mice do not correlate with the elevation of IOP. Importantly, compared to mice with normal visual performances in the same age group, mice with poor visual performances exhibit significant loss of retinal ganglion cells. CONCLUSIONS: Our studies establish a reliable behavioral assay to identify glaucomatous DBA/2J mice, thus making it possible to examine subtle pathological changes and molecular mechanisms in glaucoma pathogenesis with a relatively small number of samples. PMID- 21309688 TI - NBHA reduces acrolein-induced changes in ARPE-19 cells: possible involvement of TGFbeta. AB - PURPOSE: Acrolein, a toxic, reactive aldehyde formed metabolically and environmentally, has been implicated in the damage to and dysfunction of the retinal pigment epithelium (RPE) that accompanies age-related macular degeneration (AMD). Our purpose was to investigate the potential of acrolein to influence the release of transforming growth factor beta-2 (TGFbeta2) and vascular endothelial growth factor (VEGF), to assess the ability of N benzylhydroxylamine (NBHA) to prevent the effect of acrolein on cytokine release and reduction of viable cells, and to explore the pathway by which acrolein might be causing the increase of VEGF. MATERIALS AND METHODS: Confluent ARPE-19 cells were treated with acrolein and/or NBHA. They were also pretreated with SIS3, a specific inhibitor of SMAD 3, and ZM39923, a JAK3 inhibitor, before being treated with acrolein. Viable cells were counted; ELISA was used to measure the TGFbeta2 and/or VEGF in the conditioned media. RESULTS: Acrolein was shown to reduce the number of viable ARPE-19 cells and to upregulate the release of the proangiogenic cytokines TGFbeta2 and VEGF. Co-treatment with 200 MUM NBHA significantly reduced the effects of acrolein on viable cell number and TGFbeta2 release. Pretreatment of the cells with SIS3 partially blocked the action of acrolein on decreased viable cell number and VEGF upregulation, suggesting that part of the effects of acrolein are mediated by the increased levels of TGFbeta and its signaling. CONCLUSIONS: Our results suggest that the action of acrolein on the reduction of viability and VEGF increase by ARPE-19 cells is partially mediated by TGFbeta2. By reducing the effects of acrolein, NBHA and SIS3 could be potential pharmacological agents in the prevention and progression of acrolein-induced damage to the RPE that relates to AMD. PMID- 21309690 TI - Splicing factor polymorphisms, the control of VEGF isoforms and association with angiogenic eye disease. AB - PURPOSE: Alternative splicing of the last exon (exon 8) of vascular endothelial growth factor (VEGF) pre-mRNA is a key element in the balance of pro- and anti angiogenic VEGF isoforms in exudative age-related macular degeneration (exAMD) and proliferative diabetic retinopathy (PDR). Three splicing factors, SRp40, ASF/SF2, and SRp55 are predicted to control alternative splicing by binding to exonic splice enhancers (ESE) in VEGF exon 8. This pilot study examines whether there is an association between angiogenic eye disease and splicing factor polymorphisms, and whether there are sequence variations in the alternative splice sites of the VEGF gene. MATERIALS AND METHODS: A case:control pilot study comparing 163 individuals with angiogenic eye disease (94 exAMD and 69 PDR patients) with 95 age-matched controls. Splicing factor polymorphisms were genotyped by Restriction Fragment Length Polymorphism (RFLP) and sequencing, and the VEGF alternatively spliced region was assessed by denaturing High Performance Liquid Chromatography (dHPLC) using a transgenomic WAVE heteroduplex analyzer. RESULTS: No variations were observed in the alternatively spliced region of VEGF exon 8. ASF/SF2 polymorphisms showed no association with exAMD or PDR. For PDR, we observed a trend in SRp40 (rs6573908) where the 5136CC genotype was more frequent in controls (p = 0.0517) and a significant association of the SRp55 (rs2235611), where the 2994C allele was more common in the PDR group (p = 0.03). This remained strong, but not significant, after logistic regression for age, sex, disease type, and duration (p = 0.06). CONCLUSIONS: The lack of variation in the VEGF alternatively spliced region suggests the importance of sequence conservation in this area in maintaining the balance of pro- and anti-angiogenic VEGF isoforms. The link between PDR and the SRp55 2994 polymorphism suggests a disease-specific association between factors controlling VEGF splicing and ocular angiogenesis. PMID- 21309691 TI - Periocular allergic contact dermatitis following topical Mitomycin C eye drop application. AB - A 63-year-old women had an extensive limbal papilliform tumoural lesion of her left eye. Mitomycin C (MMC) was applied to the area at a dose of 0.2 mg/ml after total surgical excision of the lesion. The lesion was diagnosed as invasive squamous cell carcinoma on histopathology and topical 0.02% MMC was prescribed four times daily to the left eye. A severe per ocular contact dermatitis of the left eye developed two days after starting MMC. The patch test result was positive. The per ocular dermatitis resolved after discontinuation of the topical MMC and treatment with a topical corticosteroid. PMID- 21309692 TI - Reactive astrocytes inhibit the survival and differentiation of oligodendrocyte precursor cells by secreted TNF-alpha. AB - Axonal demyelination is a consistent pathological characteristic of spinal cord injury (SCI). Although an increased number of oligodendrocyte progenitor cells (OPCs) is observed in the injured spinal cord, they fail to convert into mature oligodendrocytes. However, little is known about the underlying mechanism. In our study, we identified a link between inhibition of OPC survival and differentiation and reactive astrocytes in glial scar that was mediated by tumor necrosis factor-alpha (TNF-alpha). Initially, both glial scar tissue and reactive astrocyte-conditioned medium were shown to inhibit OPC differentiation. Reverse transcriptase polymerase chain reaction (RT-PCR) and immunochemistry revealed that OPCs expressed type 1 TNF-alpha receptor (TNF-R1). When TNF-alpha or TNF-R1 was neutralized with antibody, the effect of reactive astrocyte-conditioned medium or recombinant TNF-alpha protein on OPC differentiation was markedly attenuated. In addition, reactive astrocyte-conditioned medium was also shown to induce OPC apoptosis. All these findings provide the first evidence that reactive astrocytes release TNF-alpha to inhibit OPC survival and prevent them from differentiating into mature oligodendrocytes, suggesting a mechanism for the failure of remyelination after SCI. PMID- 21309693 TI - Visualization of Connexin 43-positive cells of glioma and the periglioma zone by means of intravenously injected monoclonal antibodies. AB - The selectivity of monoclonal antibodies against the E2 extracellular fragment of connexin 43 (Cx43) for a glioma focus was studied in in vivo experiments on animals with intracranial C6 glioma. Antibodies labeled with two alternative labels, the radioisotope (125)I and the fluorophore Alexa 660, were intravenously injected to rats with 18-day gliomas. Seventy-two hours after injection, (125)I labeled antibodies accumulated in the hemisphere where the glioma was located to a concentration of 0.27 +/- 0.01% of the injected dose per gram of wet weight, which exceeded their accumulation in the liver, spleen, and other organs. Fluorescent-labeled antibodies against the Cx43 fragment E2 specifically visualized cells in the peritumoral astroglial bank (a zone of active invasion of glioma cells). Double immunofluorescent visualization using antibodies against the Cx43 fragment E2 and glial fibrillar acidic protein (GFAP) showed that only a small proportion of the cells that bound the antibodies injected into the blood circulation were reactive astrocytes, whereas most of these cells were GFAP negative and morphologically corresponded to astroblasts. These results suggest that antibodies against the extracellular Cx43 fragment E2 can be used for targeted transport of diagnostic and therapeutic drugs to the peritumoral invasion zone of high-grade gliomas. PMID- 21309694 TI - Cyclic neutropenia in a cleft lip and palate patient: a case report. AB - Cleft lip and palate is the most common congenital anomaly. Its association with hematologic disorders is rarely reported. Cyclic neutropenia is a rare blood disorder that may occur spontaneously or has a genetic predisposition. Periodicity/recurrence of cyclic neutropenia has a cyclical pattern reoccurring in multiples of 7 days, usually at 21- or 28-day intervals between attacks, with the patient being fairly asymptomatic. There is no case in the literature that has reported the presence of cyclic neutropenia in cleft patients. We report a case of cleft patient associated with cyclic neutropenia. The clinical features, diagnosis, and course of management are described. PMID- 21309695 TI - Zinc for attention-deficit/hyperactivity disorder: placebo-controlled double blind pilot trial alone and combined with amphetamine. AB - OBJECTIVE: To explore effects of zinc supplementation in American children with attention-deficit/hyperactivity disorder (ADHD). Mideastern trials reported significant benefit from 13-40 mg elemental zinc as the sulfate. METHOD: We randomly assigned 52 children aged 6-14 with DSM-IV ADHD to zinc supplementation (15 mg every morning [qAM] or two times per day [b.i.d.] as glycinate, n = 28) or matched placebo (n = 24) for 13 weeks: 8 weeks monotherapy and then 5 weeks with added d-amphetamine (AMPH). AMPH dose was weight-standardized for 2 weeks and then clinically optimized by week 13. Zinc glycinate was chosen as having less gastrointestinal discomfort than sulfate. Hypotheses were that zinc would improve inattention more than placebo by effect size of d > 0.25 at 8 weeks; zinc+AMPH would improve ADHD symptoms more than placebo+AMPH by d > 0.25, and optimal dose of AMPH with zinc would be 20% lower than with placebo. An interim analysis requested by the National Institute of Mental Health resulted in an increased dosage, so that 20 received 15 mg/day qAM and 8 received 30 mg/day (15 mg b.i.d.) RESULTS: Only the third hypothesis was upheld: Optimal mg/kg AMPH dose with b.i.d. zinc was 37% lower than with placebo. Other clinical outcomes were equivocal, sometimes favoring zinc, sometimes placebo, but objective neuropsychological measures mostly favored b.i.d. zinc (d = 0.36-0.7). Safety tests and adverse events were not different between groups. Copper and iron blood indices were not impaired by 8 weeks of 30 mg/day zinc. CONCLUSION: Doses up to 30 mg/day of zinc were safe for at least 8 weeks, but clinical effect was equivocal except for 37% reduction in amphetamine optimal dose with 30 mg/day zinc (not with 15 mg). Possible reasons for difference from mideastern reports include endemic diets, population genetics, relative rate of zinc deficiency, difference in background nutrition, insufficient dosage or absorption, or wrong anion (sulfate may be necessary for reported benefit). Dose may be especially important: All visually impressive advantages over placebo appeared only with 15 mg b.i.d. rather than once a day. Future research should use larger doses than 15 mg/day, provide a basic recommended daily allowance/intake multivitamin/mineral supplement for all to standardize background nutrition, select participants for low zinc, and consider the issue of anion interaction. PMID- 21309696 TI - Safety and efficacy of donepezil in children and adolescents with autism: neuropsychological measures. AB - OBJECTIVE: There has been recent interest in the use of cognitive enhancing drugs, such as cholinesterase inhibitors, as a possible treatment for executive functioning (EF) deficits in autism spectrum disorder (ASD). The goal of this study was to assess the tolerability, safety, and efficacy of donepezil on EF in a sample of children and adolescents with ASD. METHOD: Thirty-four children and adolescents with ASD (age range 8-17 years; IQ >75) were enrolled in a 10-week, double-blind, placebo-controlled trial of donepezil (doses of 5 and 10 mg), followed by a 10-week open label trial for placebo nonresponders. RESULTS: The effect of donepezil treatment on EF was examined. Despite improvement on a number of EF measures, no statistically significant between-group differences were found (with gains observed for both the placebo and donepezil groups). CONCLUSIONS: The results suggest that short-term treatment with donepezil may have limited impact on cognitive functioning in ASD. Future controlled trials may need to consider a longer treatment period to detect significant gains on EF measures. PMID- 21309697 TI - Predictors of nonresponse to psychosocial treatment in children and adolescents with disruptive behavior disorders. AB - OBJECTIVE: A crucial issue in youths with disruptive behavior disorders, including oppositional defiant disorder and conduct disorder, is the refractoriness to treatments. A multimodal approach with individual therapy to improve social skills and self-control and family and school interventions is the best psychosocial treatment. Predictors of poor response to psychosocial treatment remain understudied. We aimed at exploring whether callous (lack of empathy and guilt) and unemotional (shallow emotions) (CU) trait and type of aggression (predatory vs. affective) can affect response to psychosocial treatment in referred youths with disruptive behavior disorders. METHODS: The sample consisted of 38 youths (28 boys and 10 girls, age range: 6-14 years, mean age: 13.1 +/- 2.6 years) diagnosed as having oppositional defiant disorder or conduct disorder according to Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria and a clinical interview (Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children Present and Lifetime Version), who completed a 6-month therapeutic program at our hospital. Patients were assessed according to severity and improvement (Clinical Global Impressions-Severity score [CGI-S] and CGI-Improvement score), functional impairment (Children's Global Assessment Scale [C-GAS]), type of aggression, predatory versus affective (Aggression Questionnaire), and CU dimension (Antisocial Process Screening Device and the Inventory of CU Traits). RESULTS: Among the 38 patients, 21 (55.3%) were responders and 17 (44.7%) were nonresponders, according to CGI-Improvement score and CGI-S. Nonresponders were more impaired at the baseline according to CGI-S and C-GAS. Nonresponders presented higher scores of predatory aggression, whereas affective aggression did not differ between groups. Nonresponders presented higher scores in CU trait of Antisocial Process Screening Device and in Inventory of CU total score (callous trait), but these differences did not survive Bonferroni correction. CONCLUSIONS: Severity at the baseline and predatory aggression are negative predictors of psychosocial treatment, but the role of the callous trait needs more exploration in larger samples. Further research may increase our diagnostic and prognostic capacities, thus improving our treatment strategies. PMID- 21309699 TI - New onset of psychotic symptoms in an adolescent with pervasive developmental disorder, not otherwise specified. PMID- 21309700 TI - Atypical Stevens-Johnson syndrome in an adolescent treated with duloxetine. PMID- 21309701 TI - Activation of PI3 kinase/Akt signaling in chronic subdural hematoma outer membranes. AB - Chronic subdural hematoma (CSDH) is an angiogenic disease that is recognized as a cause of treatable dementia with unknown pathogenesis. Vascular endothelial growth factor (VEGF), a potent growth factor regulating angiogenesis through the phosphatidylinositol 3-kinase (PI3-kinase)/Akt pathway, has been implicated in its etiology. The status of this signaling pathway in CSDH outer membranes was examined in the present study, using outer membranes obtained during trepanation surgery. Expressions of PI3-kinase, PKB-kinase, Akt, phosphorylated Akt at Ser(473) (p-Akt), endothelial nitric oxide synthase (eNOS), vascular endothelial cadherin (VE-cadherin), and actin were examined by Western blot analysis, together with their immunohistochemistry. PI3-kinase, Akt, eNOS, and VE-cadherin were detected in all cases. The magnitude of the expression of p-Akt varied among cases; however, the localization was revealed to be present in endothelial cells of vessels in CSDH outer membranes, together with VEGF and VE-cadherin detected in endothelial cells of vessels. These findings suggest that the PI3-kinase/Akt signaling is activated in CSDH outer membranes, and indicate the possibility that the PI3 kinase/Akt pathway might be activated by VEGF and play a critical role in the angiogenesis of CSDH. PMID- 21309702 TI - Carbon dioxide (CO2) laser-assisted microdiscectomy for extraforaminal lumbar disc herniation at the L5-S1 level. AB - OBJECTIVE: The purpose of this study was to analyze the surgical outcomes of carbon dioxide (CO(2)) laser-assisted microdiscectomy for extraforaminal lumbar disc herniations (EFLDH) at the L5-S1 level. BACKGROUND DATA: Microdiscectomy via the lateral transmuscular route is beneficial for treating EFLDH at the L5-S1 level. However, this technique may not effectively remove concomitant foraminal lumbar disc herniation (FLDH), resulting in persistent leg pain and a necessity for revision surgery. CO(2) laser-assisted microdiscectomy could be an effective alternative, as it enables effective decompression of EFLDH as well as of the accompanying FLDH, despite a narrow operative window. METHODS: Thirty-one consecutive patients with EFLDH at the L5-S1 level who underwent CO(2) laser assisted microdiscectomy via the lateral transmuscular route were prospectively enrolled. Clinical outcomes were assessed 1 year after surgery by using the visual analogue scale (VAS) scores, Oswestry Disability Index (ODI), and patient's subjective satisfaction rate. RESULTS: Of the 31 patients, 10 were male and 21 were female, with a mean age at surgery of 62.2 years. All patients showed improvement in leg pain immediately after surgery. Transient dysesthesia developed in one patient. Of the 28 patients (90.3%) followed for a 1-year period, the mean VAS for back pain and leg pain, as well as the mean ODI, decreased significantly from 5.2, 8.3, and 60.7% to 2.6, 1.8, and 18.1%, respectively. The mean subjective satisfaction rate was 75.7%. Clinical success was observed in 27 patients (96.4%), and reherniation occurred in one patient (3.6%). No patient underwent reoperation for reherniation or segmental instability. CONCLUSIONS: CO(2) laser-assisted microdiscectomy for EFLDH at the L5-S1 level showed satisfactory surgical results at the 1-year follow-up. PMID- 21309703 TI - Laser photobiomodulation of gene expression and release of growth factors and cytokines from cells in culture: a review of human and animal studies. AB - AIM: The aim of this paper was to review experimental studies of laser irradiation of human and animal cells in culture to assess the photobiomodulatory effects of such irradiation on gene expression and release of growth factors and CYTOKINES. BACKGROUND: Previous studies have reported that the release of certain growth factors and cytokines by various types of cells can be modulated by laser irradiation. A review of recent studies may provide further insight into the clinical effects brought about by laser irradiation of cells and tissues, including changes in inflammation and cellular proliferation. METHODS: A systematic review was completed of original research papers investigating the effects of laser phototherapy on gene expression and release of these mediators from human and animal cells in culture (January 2002 to September 2009). Relevant papers were retrieved primarily from PubMed and Medline databases. The search terms were "growth factors", "cytokines", "laser therapy", "laser irradiation", "laser phototherapy," and "phototherapy". RESULTS: A total of 17 relevant papers were included in the review, comprising studies on a variety of cell types. Considerable variation occurred in research design, methodology, and irradiation parameters employed, limiting comparison of research findings between studies. Results demonstrated that laser irradiation at green, red, or infrared wavelengths at a range of dosage parameters can cause significant changes in the cellular gene expression and release of these mediators, and that such effects depend upon wavelength and radiant exposure. CONCLUSION: Findings from the reviewed studies clearly demonstrate the ability of laser irradiation to modulate gene expression and the release of growth factors and cytokines from cells in culture. Further work is indicated at the clinical level to elucidate the putative clinical relevance of these cellular-level effects. PMID- 21309704 TI - Repair of choanal atresia and oro-nasal fistula in one sitting. AB - A seven month-old girl with bilateral choanal atresia presented to our institution with oro-nasal fistula secondary to a previous atresia repair. Examination revealed obstruction of both choanae and the presence of a fistula located in the hard palate. Endoscopic repair of the atresia and a two-layer closure of the fistula were carried out in one sitting. Follow-up of the patient for 6 months showed patent choanae and a healed palatal fistula. PMID- 21309705 TI - The relationship between out-of-hospital airway management and outcome among trauma patients with Glasgow Coma Scale Scores of 8 or less. AB - BACKGROUND: Airway management remains a fundamental component of optimal care of the severely injured patient, with endotracheal intubation representing the definitive strategy for airway control. However, multiple studies document an association between out-of-hospital intubation and increased mortality for severe traumatic brain injury. OBJECTIVES: To explore the relationship between out-of hospital intubation attempts and outcome among trauma patients with Glasgow Coma Scale (GCS) scores <= 8 across sites participating in the Resuscitation Outcomes Consortium (ROC). METHODS: The ROC Epistry-Trauma, an epidemiologic database of prehospital encounters with critically injured trauma victims, was used to identify emergency medical services (EMS)-treated patients with GCS scores <= 8. Multiple logistic regression was used to explore the association between intubation attempts and vital status at discharge, adjusting for the following covariates: age, gender, GCS score, hypotension, mechanism of injury, and ROC site. Sites were then stratified by frequency of intubation attempts and chi square test for trend was used to associate the frequency of intubation attempts with outcome. RESULTS: A total of 1,555 patients were included in this analysis; intubation was attempted in 758 of these. Patients in whom intubation was attempted had higher mortality (adjusted odds ratio [OR] 2.91, 95% confidence interval [CI] 2.13-3.98, p < 0.01). However, sites with higher rates of attempted intubation had lower mortality across all trauma victims with GCS scores <= 8 (OR 1.40, 95% CI 1.15-1.72, p < 0.01). CONCLUSIONS: Patients in whom intubation is attempted have higher adjusted mortality. However, sites with a higher rate of attempted intubation have lower adjusted mortality across the entire cohort of trauma patients with GCS scores <= 8. Coma Scale score. PMID- 21309706 TI - Incidence and predictors of acute kidney injury in an urban cohort of subjects with HIV and hepatitis C virus coinfection. AB - Coinfection with hepatitis C (HCV) significantly increases the risk of acute and chronic renal disease in HIV-infected individuals. However, the burden of acute kidney injury (AKI) directly attributable to HIV among HCV-infected individuals and associated risk factors are not well understood. Within a prospective cohort, AKI episodes were identified by a rise in creatinine of 0.5 mg/dL. Incidence of first AKI events was calculated for HIV/HCV coinfected versus HCV monoinfected subjects, and multivariable analyses using Cox proportional hazards were performed to identify predictors of AKI. Throughout the study period, 35% HIV/HCV coinfected and 17% HCV monoinfected subjects developed AKI, with incidence of 8.74/100 person-years and 3.53/100 person-years, respectively (hazard ratio (HR) 2.48; [95% confidence interval (CI) 1.50, 3.74]). In multivariable analysis, HIV coinfection (HR 2.19 [1.33, 3.62]), decompensated cirrhosis (HR 6.64 [3.81, 11.6]), and cocaine use (HR 2.06 [1.15, 3.71]) were independently associated with AKI. HCV genotype, HCV viral load, hazardous drinking, and heroin use were not associated with AKI. Study limitations included potential misclassification bias of HCV-infected individuals as serial HIV antibody testing was not routinely performed after study entry, and inability to adjust for tenofovir use in multivariable analysis. In conclusion, among subjects with HCV infection, decompensated cirrhosis, HIV coinfection, and cocaine use are associated with increased risk of AKI. These findings highlight the importance of preventing and treating cirrhosis, controlling HIV coinfection, and reducing cocaine use in HIV/HCV coinfected persons. PMID- 21309707 TI - Radiation metabolomics. 4. UPLC-ESI-QTOFMS-Based metabolomics for urinary biomarker discovery in gamma-irradiated rats. AB - Radiation metabolomics has aided in the identification of a number of biomarkers in cells and mice by ultra-performance liquid chromatography-coupled time-of flight mass spectrometry (UPLC-ESI-QTOFMS) and in rats by gas chromatography coupled mass spectrometry (GCMS). These markers have been shown to be both dose- and time-dependent. Here UPLC-ESI-QTOFMS was used to analyze rat urine samples taken from 12 rats over 7 days; they were either sham-irradiated or gamma irradiated with 3 Gy after 4 days of metabolic cage acclimatization. Using multivariate data analysis, nine urinary biomarkers of gamma radiation in rats were identified, including a novel mammalian metabolite, N-acetyltaurine. These upregulated urinary biomarkers were confirmed through tandem mass spectrometry and comparisons with authentic standards. They include thymidine, 2' deoxyuridine, 2'deoxyxanthosine, N(1)-acetylspermidine, N acetylglucosamine/galactosamine-6-sulfate, N-acetyltaurine, N-hexanoylglycine, taurine and, tentatively, isethionic acid. Of these metabolites, 2'-deoxyuridine and thymidine were previously identified in the rat by GCMS (observed as uridine and thymine) and in the mouse by UPLC-ESI-QTOFMS. 2'Deoxyxanthosine, taurine and N-hexanoylglycine were also seen in the mouse by UPLC-ESI-QTOFMS. These are now unequivocal cross-species biomarkers for ionizing radiation exposure. Downregulated biomarkers were shown to be related to food deprivation and starvation mechanisms. The UPLC-ESI-QTOFMS approach has aided in the advance for finding common biomarkers of ionizing radiation exposure. PMID- 21309708 TI - The need for a trans-disciplinary, global health framework. AB - BACKGROUND: Health research consists of multiple disciplines that conceptualize and operationalize health in different ways, making integration of knowledge difficult. To help researchers and practitioners study and intervene on complex health processes, comprehensive integrative frameworks linking multiple disciplines and bodies of knowledge must be developed. AIM: This research article presents a conceptual framework of health integrating multiple elements from biomedical, psychosocial, behavioral, and spiritual research. We integrate different perspectives using a trans-disciplinary approach. METHODS: The framework includes discipline-specific constructs and domains, outlines their interactions, and links them to a global or holistic concept of health. In this context, health is an emergent individual experience transcending objective and subjective classifications of health and disease. CONCLUSIONS: Integration of evidence and knowledge from multiple sources should enhance our understanding of health processes and should yield new means of improving human health in the future. PMID- 21309709 TI - Efficacy and safety of Derris scandens Benth extracts in patients with knee osteoarthritis. AB - OBJECTIVES: The objectives of this study were to determine the efficacy and safety of Derris scandens Benth extracts in pain reduction and functional improvement in patients with knee osteoarthritis (OA). DESIGN: This was a prospective, randomized, controlled trial, single-blinded (assessor). SETTINGS: The study was conducted at the Rehabilitation Medicine Department, Siriraj Hospital. SUBJECTS: One hundred and seven (107) patients with primary OA knee who had pain score of >= 5 were recruited. INTERVENTIONS: Patients were randomized to receive naproxen 500 mg/day or Derris 800 mg/day for 4 weeks. OUTCOME MEASUREMENTS: Western Ontario McMaster Osteoarthritis Index (WOMAC) scores and 6 minute walking distance were the outcome measurements. RESULTS: Fifty-five (55) and 52 patients were randomized to Derris and naproxen groups, respectively. The mean differences of all WOMAC scores between 2 groups at week 4 adjusted by week 0 were within +/- 1 point. The mean scores of the aforementioned outcomes at weeks 0, 2, and 4 were significantly improved compared to the baseline values. There was no difference of WOMAC scores between groups. The gastrointestinal irritation and dyspepsia were observed more often in the naproxen than in the Derris group. CONCLUSIONS: Derris scandens Benth extracts were efficacious and safe for the treatment of knee OA. PMID- 21309710 TI - Identification of organic compounds in San Diego de los Banos Peloid (Pinar del Rio, Cuba). AB - BACKGROUND: Natural organic compounds with biologic activity have extensive use in the treatment of many diseases, and are of great interest both as natural products and as precursors for synthetic strategies. Thermal muds ("peloids") are a typical example of natural products that contain organic compounds with biologic activity, which allows their use in the treatment of different pathologies. More recently, these thermal muds have found an increasing use in relaxation therapies in health spas. MATERIALS AND METHODS: This study was performed to characterize the organic composition of San Diego de los Banos peloid (Pinar del Rio, Cuba). For this purpose, a procedure for the extraction and chromatographic analysis has been developed, taking into account sample preparation, elimination of interferences, chromatographic separation of the organic compounds, and identification by mass spectrometry. RESULTS: More than 50 compounds were identified in the San Diego de los Banos peloid, mainly of natural origin. Among them were found alkanes, the 4 phenyl valeric acid, 5 isopentyl picolinic acid, 3 hydroxylauric acid, (5alpha, 3beta) 3-hydroxy-11-androstanone, the 5alpha-2-en-11 androstenone, squalene, terpinol (alpha terpineol), menthol derivatives (1 butyn 3 one 1 yl menthol), the palmitic, oleic, and eicosanoic acids, and the isoprenoid phytane. These compounds have reportedly shown biologic activity in their isolated form as antioxidant, analgesic, anti-inflammatory, immune stimulant, antineoplastic, detoxicant, membrane regulator, and hormones. CONCLUSIONS: These results provide strong evidence for medical interpretation of the well-known therapeutic action of San Diego de los Banos peloid in the treatment of inflammatory and dermatological diseases, as analgesic, in male and female infertility therapies, and with cosmetic purposes. Furthermore, this systematic work contributes to the fundamental understanding of pelotherapy, giving some scientific basis for its future development. PMID- 21309711 TI - A systematic review on the anxiolytic effects of aromatherapy in people with anxiety symptoms. AB - PURPOSE: We reviewed studies from 1990 to 2010 on using aromatherapy for people with anxiety or anxiety symptoms and examined their clinical effects. METHODS: The review was conducted on available electronic databases to extract journal articles that evaluated the anxiolytic effects of aromatherapy for people with anxiety symptoms. RESULTS: The results were based on 16 randomized controlled trials examining the anxiolytic effects of aromatherapy among people with anxiety symptoms. Most of the studies indicated positive effects to quell anxiety. No adverse events were reported. CONCLUSIONS: It is recommended that aromatherapy could be applied as a complementary therapy for people with anxiety symptoms. Further studies with better quality on methodology should be conducted to identify its clinical effects and the underlying biologic mechanisms. PMID- 21309712 TI - Functional characterization and high-throughput screening of positive allosteric modulators of alpha7 nicotinic acetylcholine receptors in IMR-32 neuroblastoma cells. AB - alpha7 nicotinic acetylcholine receptors (nAChRs) are characterized by relatively low ACh sensitivity, rapid activation, and fast desensitization kinetics. ACh/agonist evoked currents at the alpha7 nAChR are transient, and, typically, calcium flux responses are difficult to detect using conventional fluorometric assay techniques. One approach to study interactions of agonists with the alpha7 nAChR is by utilizing positive allosteric modulators (PAMs). In this study, we demonstrate that inclusion of type II PAMs such as PNU-120596, but not type I, can enable detection of endogenous alpha7 nAChR-mediated calcium responses in human neuroblastoma (IMR-32) cells. Using this approach, we characterized the pharmacological profile of nicotine, epibatidine, choline, and other nAChR agonists such as PNU-282987, SSR-180711, GTS-21, OH-GTS21, tropisetron, NS6784, and A-582941. The rank order potency of agonists well correlated with alpha7 nAChR binding affinities measured in brain membranes. Inhibition of calcium response by methyllycaconitine in the presence of increasing concentrations of PNU-282987 or PNU-120596 revealed that the IC(50) value of methyllycaconitine was sensitive to varying concentrations of the agonist, but not that of the PAM. This format demonstrated the feasibility of this approach for high-throughput screening to identify small molecule, PAMs, which were further confirmed in electrophysiological assays of human alpha7 nAChR expressed in oocytes. PMID- 21309713 TI - The zebrafish: a powerful platform for in vivo, HTS drug discovery. AB - The zebrafish (Danio rerio) is an emerging vertebrate model for drug discovery that permits whole animal drug screens with excellent throughput, combined with ease of use and low cost. This review will begin with a discussion on the background, suitability, and advantages of this vertebrate model system and then, citing specific examples, will describe the utility of zebrafish at specific stages in the drug development pipeline. We will end with a synopsis of recent drug screens based on morphological disruptions, genetic disease models, fluorescent markers, behavioral changes, and specific targets. The numerous advantages of this whole animal approach provide new promise for the discovery of safe, specific, and powerful new drugs. PMID- 21309714 TI - A study of the etiology of congenital hypothyroidism in the Niigata prefecture of Japan in patients born between 1989 and 2005 and evaluated at ages 5-19. AB - BACKGROUND: The prevalence of congenital hypothyroidism (CH) increased during the period 1994-2002 in Japan. The reasons for these recently described increases in the prevalence of CH remain unclear. Moreover, the proportion of patients with different etiologies CH in the more recently diagnosed patients has not been established. In this study, we determined the etiologies of CH that were detected by neonatal screening in Niigata refecture, Japan. METHODS: A total of 100 patients having a diagnosis of CH (41 men and 59 women, aged 5-19 years old) were evaluated. To determine the etiology of CH, the patients underwent a 123I thyroidal radioiodine uptake test, a scintigram, a saliva to plasma radioiodine ratio analysis, a perchlorate discharge test, thyroid ultrasonography, measurements of thyroidal function and thyroglobulin, and a thyrotropin (TSH) releasing hormone tolerance test. RESULTS: Patients with overt CH (n=34, elevated TSH levels with low free thyroxine levels) made up 34% of the total group, 56% of the patients had subclinical CH (n=56, elevated TSH levels with normal free thyroxinelevels), and 10% had normal thyroid function. These were patients who were considered to have transient hypothyroidism or hyperthyrotropinemia. Thyroid dysgenesis was the diagnosis in 73% of patients with overt CH, and the most of these had ectopic thyroid tissue. In contrast, thyroid dysgenesis was the diagnosis in only 36% of the patients with subclinical CH. CONCLUSIONS: Only 50% of our patients with CH detected by neonatal screening had thyroid dysgenesis. With an increase in the percentage of patients with subclinical hypothyroidism, the prevalence of thyroid dyshormogenesis has increased. Studies of the frequency and etiology of CH should consider overt and subclinical CH separately. PMID- 21309715 TI - Gingival crevicular fluid and serum visfatin concentration: their relationship in periodontal health and disease. AB - BACKGROUND: Visfatin is a pleiotropic mediator that acts as growth factor, cytokine, and enzyme involved in energy including nicotinamide adenine dinucleotide metabolism and was recently demonstrated to exert several proinflammatory functions. The purpose of this study is to determine the presence of visfatin in gingival crevicular fluid (GCF) and serum samples and to find out their association, if any. METHODS: At the beginning of the study, 40 individuals (20 males and 20 females; age range: 23 to 53 years) were selected and divided into three groups based on the gingival index, probing depths, clinical attachment levels, and radiologic parameters (bone loss). Group 1 (10 patients with healthy periodontium; age range: 25-36 years), group 2 (15 patients with gingivitis; age range: 25-36 years), and group 3 (15 patients with chronic periodontitis; age range: 23-53 years) GCF (by microcapillary pipettes) and serum (by venipuncture) samples were collected to estimate levels of visfatin using an enzyme-linked immunosorbent assay kit. RESULTS: Mean visfatin concentrations increased in GCF and serum with the severity of disease from healthy to gingivitis to periodontitis groups and differed significantly (P <0.05). However, it was found that GCF values were higher than serum values. The highest to lowest visfatin concentrations were found in groups 3 through 1, respectively. Visfatin in GCF and serum correlated positively with periodontal parameters in the chronic periodontitis group. CONCLUSIONS: The results suggest that GCF and serum visfatin concentrations increase with the severity of periodontal disease. Hence, visfatin values were considered an inflammatory marker in periodontal disease in GCF and serum. Visfatin also deserves further consideration as a therapeutic target. PMID- 21309716 TI - Attachment formation after transplantation of teeth cultured with enamel matrix derivative in dogs. AB - BACKGROUND: Implantation of cultured cells may be applied for periodontal regeneration in the future. However, a donor is essential in each case and tooth extraction is required to obtain the periodontal ligament-derived cell. We developed a novel regenerative technique combining tissue culture and transplantation of teeth. The purpose of this study is to evaluate the effect of enamel matrix derivative (EMD) on periodontal healing using this technique in dogs. METHODS: A total of 32 incisors from seven beagle dogs were used. The periodontal ligament and cementum 5 mm from the coronal part of the roots were removed, whereas those in the apical part were preserved. Teeth were transplanted after the following treatments: 1) culture with application of EMD to the root surface for 6 weeks (n = 11); 2) culture without application of EMD for 6 weeks (n = 11); and 3) immediately transplanted without culture as control (n = 10). Eight weeks after transplantation, periodontal healing was analyzed. RESULTS: The downgrowth of junctional epithelium on the roots of the EMD and culture groups was significantly smaller than that in the control group (P <0.01). Most of the root-planed surfaces in the EMD group were covered with new cementum (72.2% +/- 8.6%). This was significantly greater than that in the culture (29.1% +/- 22.9%) and control groups (0.3% +/- 1.1%). CONCLUSIONS: Transplantation of tissue cultured teeth decreased epithelial downgrowth and increased connective tissue attachment on the root-planed surface. Furthermore, EMD could remarkably increase the new connective tissue attachment in this periodontal regenerative technique. PMID- 21309717 TI - Effects of luteolin on the release of nitric oxide and interleukin-6 by macrophages stimulated with lipopolysaccharide from Prevotella intermedia. AB - BACKGROUND: Although a range of biologic and pharmacologic activities of luteolin has been reported, little is known about its potential as an agent to treat periodontal disease. In the present study, we investigated whether luteolin could downregulate the production of proinflammatory mediators in murine macrophage like RAW264.7 cells stimulated with lipopolysaccharide (LPS) from Prevotella intermedia (Pi), a major cause of inflammatory periodontal disease, and we attempted to elucidate the possible mechanisms of action. METHODS: LPS was prepared from lyophilized Pi ATCC 25611 cells by the standard hot phenol-water method. Culture supernatants were collected and assayed for nitric oxide (NO) and interleukin (IL)-6. We used real-time polymerase chain reaction to detect inducible NO synthase (iNOS) and IL-6 mRNA expression. iNOS expression, phosphorylation of JNK and p38, IkappaB-alpha degradation, nuclear translocation of nuclear factor-kappaB (NF-kappaB) subunits, and signal transducer and activator of transcription-1 (STAT1) phosphorylation were characterized via immunoblotting. DNA-binding of NF-kappaB was also analyzed. RESULTS: Luteolin strongly suppressed the production of NO and IL-6 at both gene transcription and translation levels in Pi LPS-activated RAW264.7 cells. Mitogen-activated protein kinase pathways were not involved in the inhibition of Pi LPS-induced NO and IL-6 release by luteolin. Luteolin did not reduce NF-kappaB transcriptional activity at the level of IkappaB-alpha degradation. Luteolin blocked NF-kappaB signaling through inhibition of nuclear translocation and DNA binding activity of NF-kappaB p50 subunit and suppressed STAT1 signaling. CONCLUSIONS: Although further research is encouraged to clarify the detailed mechanism of action, flavonoid luteolin may contribute to blockade of the host-destructive processes mediated by these two proinflammatory mediators and could have potential use in the treatment of inflammatory periodontal disease. PMID- 21309718 TI - Effect of non-surgical treatment on chronic and aggressive periodontitis: clinical, immunologic, and microbiologic findings. AB - BACKGROUND: Our goal was to examine differences in clinical, microbiologic, and immunologic responses to non-surgical mechanical therapy in patients with generalized chronic periodontitis (GCP) and generalized aggressive periodontitis (GAgP). METHODS: Twenty patients with GCP and 14 patients with GAgP were evaluated. Clinical data, gingival crevicular fluid (GCF), and subgingival plaque samples were collected at baseline and 3 months after non-surgical periodontal treatment. Levels of 40 subgingival species were measured using checkerboard DNA DNA hybridization. GCF interleukin (IL)-1beta, -4, and -8 and interferon-gamma (IFN-gamma) were analyzed using a multiplexed bead immunoassay, and elastase activity was measured using an enzymatic assay. The significance of changes with time was examined using the Wilcoxon rank sum test. Changes in clinical, microbiologic, and immunologic parameters after therapy were compared between groups using the Mann-Whitney U test. RESULTS: After periodontal therapy, we found significant improvements for all clinical parameters in both groups. We also observed significant reductions in elastase activity in shallow and deep sites from the GAgP group and in deep sites from the GCP group. Microbiologic data showed significant reductions in proportions of orange and red complexes and an increase in proportions of Actinomyces species in both clinical groups. When the clinical, microbiologic, and immunologic responses after therapy were compared between groups, only minor differences were found. CONCLUSION: This study fails to show any significant differences between severe forms of GCP and GAgP in response to non-surgical periodontal treatment. PMID- 21309719 TI - Interleukin-10 genotypes of the -1087 single nucleotide polymorphism influence sp1 expression in periodontitis lesions. AB - BACKGROUND: Interleukin (IL)-10 is an important cytokine in immune regulation, and the -1087 IL-10 single nucleotide polymorphism (SNP) is associated with chronic periodontitis. The binding of the transcription factor Sp1 to the -1087 position in the IL-10 promoter upregulates IL-10 gene expression, especially in patients with the GG genotype. A correlation between the -1087 GG genotype and high IL-10 and Sp1 gene expressions was found. METHODS: Twenty-five individuals with severe generalized chronic periodontitis were genotyped for the -1087 IL-10 gene polymorphism. SV40 promoter factor 1/specificity protein 1 (Sp1) and IL-10 mRNA were analyzed using a real-time polymerase chain reaction. The amount of Sp1 positive cells and Sp1-positive B cells, as well as the amount of Sp1 protein, in periodontitis lesions were assessed using immunohistochemistry and an in situ proximity ligation assay. RESULTS: The mRNA expression of Sp1 and IL-10 in patients with the GG genotype was four times higher than that in patients with the AA genotype. Proportions of Sp1-positive cells overall and Sp1-positive B cells were larger in patients with the GG genotype than in patients with the AA genotype. CONCLUSION: The transcription factor Sp1 was present in large amounts in periodontitis lesions, and the local expression of Sp1 was related to the 1087 IL-10 SNP. PMID- 21309720 TI - Biomechanical behavior of oral soft tissues. AB - BACKGROUND: Little attention has been given to understanding the variation in biomechanical behavior of oral soft tissues, and this represents an obstacle for the development of biomaterials that perform with appropriate biomechanical characteristics. With this as our motivation, a uniaxial mechanical analysis was performed on lingual and buccal aspects of the attached gingiva, alveolar mucosa, and buccal mucosa to gain insight into human tissue performance and site-specific mechanical variation. METHODS: A discrete quantitative mechanical evaluation of each soft tissue region using tensile, dynamic compression, and stress relaxation analysis was conducted to correlate tissue structure with function as assessed histologically. RESULTS: Results confirm the keratinized gingiva to have increased tensile strength (3.94 +/- 1.19 MPa) and stiffness (Young modulus of 19.75 +/- 6.20 MPa) relative to non-keratinized mucosal regions, where densely arranged elastin fibers contribute to a tissue with increased viscoelastic properties. Dynamic compression analysis indicated the instantaneous modulus (E(int)), steady modulus (E(s)), and peak stress increased with loading frequency and strain amplitude, with the highest values found in the buccal attached gingiva. CONCLUSION: These investigations quantify the biomechanical properties of oral soft tissues and show region-to-region variation that details structure function relationships and provides key parameters to aid development of biomaterials that perform with appropriate biomechanical properties. PMID- 21309721 TI - Molecular analysis of the RET proto-oncogene key exons in patients with medullary thyroid carcinoma: a comprehensive study of the Iranian population. AB - BACKGROUND: Germ-line mutations of RET proto-oncogene are the known cause of hereditary medullary thyroid carcinoma (MTC), which account for approximately 25% of all MTC cases and occur as multiple endocrine neoplasia type 2 syndromes. Here, we present the first comprehensive genetic screening and analysis of MTC among Iranian families. METHODS: A total of 55 patients with MTC (male to female ratio=1:1.6; average age of disease onset = 33 +/- 13 years) from 53 independent families participated in this study. All of the patients had undergone total thyroidectomy between 1999 and 2006, and 51 of them were clinically characterized as apparently sporadic cases. Genomic DNA samples were obtained and following highly-specific polymerase chain reaction amplification of the 6 RET key exons (10, 11, 13, 14, 15, and 16) were subjected to direct DNA sequencing without a requirement for a purification step. RESULTS: Sequence analysis revealed that 9 (17.6%) of the apparently sporadic cases (from 8 kindreds) carried an RET germ line mutation. Of the seven different mutations identified among all of the families studied, five were in the cysteine codons, with Cys634Arg having the highest prevalence (45.5%) among the afflicted families. Mutation carriers have an earlier age of onset (21 +/- 6) versus the sporadic cases (37 +/- 12). CONCLUSIONS: This is the first comprehensive genetic screening and analysis of MTC among Iranian families. The results further confirm the need and advantages of DNA sequencing for identification of hereditary MTC cases. There does not seem to be a meaningful correlation between single nucleotide polymorphism patterns and the average age of disease onset. Geographical distribution of the sporadic cases, however, shows a significant concentration toward the Northern regions of the country, noticeably the provinces situated directly to the south of the Caspian Sea. PMID- 21309722 TI - A diffuse sclerosing variant of papillary thyroid carcinoma: clinical and pathologic features and outcomes of 34 consecutive cases. AB - BACKGROUND: The diffuse sclerosing variant of papillary thyroid carcinoma (DSPC) is a relatively rare variant of papillary thyroid cancer. Large studies of patients with DSPC have been infrequently performed, and controversy still exists concerning some DSPC features and outcomes. The aim of the present study was to retrospectively evaluate the clinicopathologic features and outcomes in a series of 34 consecutive patients with DSPC and to compare them with a larger group of 245 consecutive patients with the classic variant of papillary thyroid carcinoma (cPTC) that were evaluated in the same period. PATIENTS AND METHODS: Clinical and histological features (sex, age, tumor size,multifocality, bilaterality, extra thyroid extension, and local and distant metastases) were recorded in all patients, as well as any persistent or recurrent disease and the patients' disease status at last observation. Patients with cPTC were classified as either low (122) or high risk (123). DSPC and high-risk patients were all treated with the same protocol, including 131I treatment. All patients were included in a Cox regression model analysis to investigate the effect of each variable on the hazard ratio. RESULTS: As expected, multifocality, bilaterality, and extra thyroid extension were more frequently noted at presentation, and the pT1 category of TNM classification was less frequently noted in DSPC and high-risk patients with cPTC compared with low-risk patients with cPTC. No significant difference was found between patients with DSPC and those with high-risk cPTC, except that extra thyroid extension was found more frequently in the patients with DSPC. Using multivariate analysis, diffuse sclerosing variant was an independent variable for predicting a high risk of persistent and recurrent disease during initial follow-up. However, at a later time, and after further treatment, the disease status was not different between patients with DSPC and those with high-risk cPTC, and only the presence of distant metastases affected the final outcome. CONCLUSIONS: DSPC is a thyroid papillary carcinoma variant characterized by high aggressiveness. In patients with DSPC, the outcome is worse than in patients with low-risk cPTC; and, at presentation, characteristics are somewhat worse than for patients with high-risk cPTC.At medium term, the outcome is similar to that observed in patients with high-risk cPTC, provided aggressive treatment is used (additional surgical intervention, when required, and/or 131I radiotherapy). PMID- 21309723 TI - The variable presentations of anaplastic spindle cell squamous carcinoma associated with tall cell variant of papillary thyroid carcinoma. AB - BACKGROUND: In 1976, Hawk and Hazard described the tall cell variant (TCV) of papillary thyroid carcinoma (PTC). While the lesions they described had cytologic features of papillary carcinoma, they showed more aggressive behavior with a greater propensity for extrathyroid extension and lymphovascular invasion than classic PTC. In 1991, Bronner and LiVolsi described a series of patients with TCV that progressed to spindle cell squamous carcinoma (SCSC), a unique form of anaplastic thyroid carcinoma. This study describes the variable clinical and pathologic presentations in 31 patients with anaplastic SCSC arising in association with TCV. METHODS: The surgical pathology archives as well as the personal consultation files of one of the authors (V.A.L.) were reviewed to retrieve cases of SCSC arising in association with TCV. The available clinical as well as pathologic information on all patients was reviewed. RESULTS: A total of 31 patients with SCSC arising in association with TCV were retrieved from our files. The average age at primary presentation was 67 (range 32-92) with a female to-male ratio of 2:1. Three clinical scenarios for SCSC associated with TCV were identified. These were type I, consisting of TCV with SCSC at the time of presentation (18 patients); type II, consisting of SCSC arising as a recurrence in patients with a known history of TCV (5 patients); and type III, consisting of SCSC presenting as a primary laryngeal squamous cell carcinoma in a patient with or without a known history of TCV (8 patients). The type III cases were of most concern since they often were confused with primary laryngeal squamous cell carcinoma and most often were diagnosed after laryngectomy. CONCLUSIONS: SCSC of the thyroid is almost exclusively associated with TCV and can have variable clinical presentations. SCSC is most commonly seen associated with a primary diagnosis of TCV. SCSC may be seen, however, in patients with recurrent PTC and most importantly may present in a fashion similar to primary laryngeal SCSC. Therefore, caution should be exercised in evaluating laryngeal squamous lesions in patients with known history of TCV and without known risks factors for head and neck carcinogenesis. PMID- 21309724 TI - Consistent injury to medium spiny neurons and white matter in the mouse striatum after prolonged transient global cerebral ischemia. AB - A reproducible transient global cerebral ischemia (tGCI) mouse model has not been fully established. Although striatal neurons and white matter are recognized to be vulnerable to ischemia, their injury after tGCI in mice has not been elucidated. The purpose of this study was to evaluate injuries to striatal neurons and white matter after tGCI in C57BL/6 mice, and to develop a reproducible tGCI model. Male C57BL/6 mice were subjected to tGCI by bilateral common carotid artery occlusion (BCCAO). Mice whose cortical cerebral blood flow after BCCAO decreased to less than 13% of the pre-ischemic value were used. Histological analysis showed that at 3 days after 22 min of BCCAO, striatal neurons were injured more consistently than those in other brain regions. Quantitative analysis of cytochrome c release into the cytosol and DNA fragmentation in the striatum showed consistent injury to the striatum. Immunohistochemistry and Western blot analysis revealed that DARPP-32-positive medium spiny neurons, the majority of striatal neurons, were the most vulnerable among the striatal neuronal subpopulations. The striatum (especially medium spiny neurons) was susceptible to oxidative stress after tGCI, which is probably one of the mechanisms of vulnerability. SMI-32 immunostaining showed that white matter in the striatum was also consistently injured 3 days after 22 min of BCCAO. We thus suggest that this is a tGCI model using C57BL/6 mice that consistently produces neuronal and white matter injury in the striatum by a simple technique. This model can be highly applicable for elucidating molecular mechanisms in the brain after global ischemia. PMID- 21309725 TI - Short-term moderate hypocapnia augments detection of optimal cerebral perfusion pressure. AB - An autoregulation-oriented strategy has been proposed to guide neurocritical therapy toward the optimal cerebral perfusion pressure (CPPOPT). The influence of ventilation changes is, however, unclear. We sought to find out whether short term moderate hypocapnia (HC) shifts the CPPOPT or affects its detection. Thirty patients with traumatic brain injury (TBI), who required sedation and mechanical ventilation, were studied during 20 min of normocapnia (5.1+/-0.4 kPa) and 30 min of moderate HC (4.4+/-3.0 kPa). Monitoring included bilateral transcranial Doppler of the middle cerebral arteries (MCA), invasive arterial blood pressure (ABP), and intracranial pressure (ICP). Mx -autoregulatory index provided a measure for the CPP responsiveness of MCA flow velocity. CPPOPT was assessed as the CPP at which autoregulation (Mx) was working with the maximal efficiency. During normocapnia, CPPOPT (left: 80.65+/-6.18; right: 79.11+/-5.84 mm Hg) was detectable in 12 of 30 patients. Moderate HC did not shift this CPPOPT but enabled its detection in another 17 patients (CPPOPT left: 83.94+/-14.82; right: 85.28+/-14.73 mm Hg). The detection of CPPOPT was achieved via significantly improved Mx-autoregulatory index and an increase of CPP mean. It appeared that short-term moderate HC augmented the detection of an optimum CPP, and may therefore usefully support CPP-guided therapy in patients with TBI. PMID- 21309726 TI - Biokinetic analysis of ubiquitin C-terminal hydrolase-L1 (UCH-L1) in severe traumatic brain injury patient biofluids. AB - Ubiquitin C-terminal hydrolase-L1 (UCH-L1) is a neuron-specific enzyme that has been identified as a potential biomarker of traumatic brain injury (TBI). The study objectives were to determine UCH-L1 exposure and kinetic metrics, determine correlations between biofluids, and assess outcome correlations in severe TBI patients. Data were analyzed from a prospective, multicenter study of severe TBI (Glasgow Coma Scale [GCS] score <= 8). Cerebrospinal fluid (CSF) and serum data from samples taken every 6 h after injury were analyzed by enzyme-linked immunosorbent assay (ELISA). UCH-L1 CSF and serum data from 59 patients were used to determine biofluid correlations. Serum samples from 86 patients and CSF from 59 patients were used to determine outcome correlations. Exposure and kinetic metrics were evaluated acutely and up to 7 days post-injury and compared to mortality at 3 months. There were significant correlations between UCH-L1 CSF and serum median concentrations (r(s)=0.59, p<0.001), AUC (r(s)=0.3, p=0.027), Tmax (r(s)=0.68, p<0.001), and MRT (r(s)=0.65, p<0.001). Outcome analysis showed significant increases in median serum AUC (2016 versus 265 ng/mL*min, p=0.006), and Cmax (2 versus 0.4 ng/mL, p=0.003), and a shorter Tmax (8 versus 19 h, p=0.04) in those who died versus those who survived, respectively. In the first 24 h after injury, there was a statistically significant acute increase in CSF and serum median Cmax((0-24h)) in those who died. This study shows a significant correlation between UCH-L1 CSF and serum median concentrations and biokinetics in severe TBI patients, and relationships with clinical outcome were detected. PMID- 21309727 TI - Coagulation disorders in traumatic brain injury. PMID- 21309728 TI - Improved neopterin ELISA kit: a good compromise between HPLC results and clinical practice. PMID- 21309729 TI - Identification of Bcl-2/IgH fusion sequences using real-time PCR and chip-based microcapillary electrophoresis. AB - BACKGROUND: The determination of polymerase chain reaction (PCR) amplification product sizes of the Bcl-2/IgH fusion gene from follicular lymphoma (FL) provides evidence of clonal identity. METHODS: The present study describes detection of Bcl-2/IgH fusion gene clonality utilizing a small, simple microcapillary electrophoretic chip combined with a real-time PCR method. RESULTS: The microcapillary electrophoretic chip system effectively detects size differences among the Bcl-2/IgH fusion gene amplification products of FL from patient samples; something that is not possible using traditional gel electrophoresis. We also describe the potential of this system to utilize formalin-fixed, paraffin embedded tissue samples sectioned on charged slides. CONCLUSIONS: The simple detection of Bcl-2/IgH fusion gene clonality using a microcapillary electrophoretic chip provides reliable information for monitoring minimal residual disease of FL, and can be an effective tool for use in clinical laboratories. PMID- 21309730 TI - HIV-associated immune activation: from bench to bedside. AB - HIV infection is associated with a state of chronic, generalized immune activation that has been shown in many studies to be a key predictor of progression to AIDS. Consistent with this model, nonpathogenic SIV infections of natural hosts, such as the sooty mangabeys, are characterized by low levels of immune activation during the chronic phase of infection. The molecular, cellular, and pathophysiological mechanisms underlying the HIV-associated immune activation are complex and still poorly understood. There is, however, growing consensus that both viral and host factors contribute to this phenotype, with emphasis on the role played by the mucosal immune dysfunction (and consequent microbial translocation) as well as the pattern of in vivo-infected CD4(+) T cells. The observation that antiretroviral therapy (ART)-induced suppression of HIV replication does not fully resolve immune activation provided the rationale for a number of exploratory studies of potential immune modulatory treatments to be used in HIV-infected individuals in addition to standard ART. This review provides an update on the causes and consequences of the HIV-associated immune activation, and a summary of the immune modulatory approaches that are currently under clinical investigation. PMID- 21309732 TI - Correlation of EPHX1, GSTP1, GSTM1, and GSTT1 genetic polymorphisms with antioxidative stress markers in chronic obstructive pulmonary disease. AB - This study was undertaken to ascertain if a relationship existed between oxidative status and polymorphisms of microsomal epoxide hydrolase X1 (EPHX1), glutathione S-transferase P1 (GSTP1), GSTM1, and GSTT1 in chronic obstructive pulmonary disease (COPD). Erythrocyte glutathione peroxidase (GSH-px), glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT), and plasma GST activities and total antioxidant status (TAS) as antioxidative stress markers were determined and compared either with individual and combined genotypes of EPHX1 exon 3, GSTP1 exon 5, GSTM1, and GSTT1 polymorphisms in COPD patients and healthy controls from the central area of Tunisia. Statistical data processing revealed significantly lower GSH-px, GR, SOD, CAT, GST, and TAS values in COPD patients in comparison to the control group (P < .001). As for genotypes, there was a no significant association in each of the 6 parameters and individual genotypes (P > .05). A significant correlation between the studied parameters and combined null GSTM1/null GSTT1 (GSH-px: P < .001, GR: P = .026, CAT: P = .018, GST: P = .022, TAS: P = .046), His113His EPHX1/null GSTM1 (GSH-px: P = .001, GST: P = .0012, TAS: P = .013), His113His EPHX1/Val105Val GSTP1 (GSH-px: P = .048, CAT: P = .026, GST: P = .031), and null GSTM1/Val105Val GSTP1 (GSH-px: P = .011, GR: P = .0028, GST: P = .0054, TAS: P = .032) was found in patients. In conclusion, combined genetic polymorphisms of GSTM1, GSTT1, GSTP1, and EPHX1 may have favorable effects on redox balance in COPD patients. PMID- 21309731 TI - Exogenous administration of vascular endothelial growth factor prior to human respiratory syncytial virus a2 infection reduces pulmonary pathology in neonatal lambs and alters epithelial innate immune responses. AB - Human respiratory syncytial virus (RSV) affects thousands of children every year. Vascular endothelial growth factor (VEGF) is a regulator of vasculogenesis, pulmonary maturation, and immunity. In order to test the extent to which VEGF may alter RSV infection, 4 groups of lambs received either human recombinant VEGF (rhVEGF) or phosphate-buffered saline (PBS) pretreatment followed by inoculation with human RSV strain A2 or sterile medium. Lambs in each group were sacrificed at 2, 4, and 6 days post infection. Expression of surfactant protein-A (SP-A), surfactant protein-D (SP-D), sheep beta-defensin-1 (SBD-1), tumor necrosis factor alpha (TNFalpha), interleukin (IL)-6, IL-8, interferon beta, and endogenous VEGF were measured to determine effect of rhVEGF pretreatment. RSV lambs pretreated with rhVEGF had reduced viral mRNA and decreased pulmonary pathology at day 6. Pretreatment with rhVEGF increased mRNA expression of SP-A, SBD-1, and TNFalpha, with alteration of expression in RSV lambs. Endogenous VEGF mRNA levels were increased at day 2 regardless of pretreatment. Pretreatment with rhVEGF increased pulmonary cellular proliferation in RSV lambs at day 4 post infection. Overall, these results suggest that pretreatment with rhVEGF protein may have therapeutic potential to decrease RSV viral load, decrease pulmonary lesion severity, and alter both epithelial innate immune responses and epithelial cell proliferation. PMID- 21309733 TI - Presence of task-1 channel in the laryngeal mucosa in the newborn lamb. AB - Nearly 40 potassium channels have been described in respiratory epithelial cells. Of these are found several members of the 4-transmembrane domain, 2-pore K(+) channel family (K2P family), namely Twik-1 and -2, Trek-1 and -2, Task-2, -3, and -4, Thik-1, and KCNK7. The aim of this study was to verify whether the Twik related acid-sensitive K(+) channel, subtype 1 (Task-1) (also known as KCNK3), is present in the laryngeal mucosa in the newborn lamb. Through the use of immunohistochemistry and nested polymerase chain reaction (PCR) amplification, results indicate that Task-1 protein and mRNA are present in the laryngeal mucosa, in both the ciliated, pseudostratified columnar (respiratory) epithelium and the nonkeratinized, stratified squamous epithelium. The complete ovine Task-1 protein sequence showed high homology levels with previously reported mouse, bovine, and human Task-1 sequences. This includes a complete homology for the C terminal amino acid sequence, which is mandatory for protein trafficking to the cell membrane. These results represent the first demonstration that Task-1, a pH sensitive channel responsible for setting membrane potential, is present in the laryngeal mucosa of a newborn mammal. PMID- 21309734 TI - Comparison of functional, biochemical, and morphometric alterations in the lungs of 4 rat strains and hamsters following repeated intratracheal instillation of crocidolite asbestos. AB - Four rat strains and hamsters were exposed to 0.7 mg crocidolite asbestos/g lung once/week for 3 weeks by intratracheal instillation (IT). Pulmonary function, biochemistry, and morphometry were evaluated at 3 and 6 months after IT. Each rat strain, but not the hamster, exhibited elevated lung volumes. Quasistatic compliance in rats and hamsters was reduced 15%-40% and 25%-50%, respectively. Diffusing capacity for carbon monoxide was elevated in the rats, but in hamsters, it was reduced at both time points. Hydroxyproline was increased in the rat strains but not in hamsters. Lung protein/dry weight was not altered in most of the rat strains and in hamsters at both time points. The linear mean intercept value was increased in Fischer 344 (F344) rats (3 and 6 months) and Long Evans rats (6 months), whereas in hamsters only at 6 months. Surface area was unchanged in both species. Specific density for parenchymal tissue was reduced for F344 rats at both time points, but alveolar density values did not change overall relative to species and time. The correlated functional and morphological changes in the hamster appeared more consistent with human asbestosis. Divergent lung responses in different species and strains should be considered when selecting laboratory animal models for studies related to asbestos exposure. PMID- 21309735 TI - Predictive role of arterial carboxyhemoglobin concentrations in ovine burn and smoke inhalation-induced lung injury. AB - Inhalation injury frequently occurs in burn patients and contributes to the morbidity and mortality of these injuries. Arterial carboxyhemoglobin has been proposed as an indicator of the severity of inhalation injury; however, the interrelation between arterial carboxyhemoglobin and histological alterations has not yet been investigated. Chronically instrumented sheep were subjected to a third degree burn of 40% of the total body surface area and inhalation of 48 breaths of cotton smoke. Carboxyhemoglobin was measured immediately after injury and correlated to clinical parameters of pulmonary function as well as histopathology scores from lung tissue harvested 24 hours after the injury. The injury was associated with a significant decline in pulmonary oxygenation and increases in pulmonary shunting, lung lymph flow, wet/dry weight ratio, congestion score, edema score, inflammation score, and airway obstruction scores. Carboxyhemoglobin was negatively correlated to pulmonary oxygenation and positively correlated to pulmonary shunting, lung lymph flow, and lung wet/dry weight ratio. No significant correlations could be detected between carboxyhemoglobin and histopathology scores and airway obstruction scores. Arterial carboxyhemoglobin in sheep with combined burn and inhalation injury are correlated with the degree of pulmonary failure and edema formation, but not with certain histological alterations including airway obstruction scores. PMID- 21309736 TI - Chronic allergen challenge induces pulmonary extramedullary hematopoiesis. AB - Allergic inflammation is associated with increased generation and trafficking of inflammatory cells, especially eosinophils, to sites of inflammation. The effect of acute versus chronic airway allergen challenge on hematopoietic activity in the bone marrow (BM) and lungs was investigated using murine models of allergic airway inflammation. Acute allergen challenge induced proliferation of BM cells and significantly increased generation of eosinophil, but not multipotent, granulocyte-macrophage (GM), or B-lymphocyte progenitor cells. However, no hematopoietic activity was observed in the lungs. With chronic challenge, BM cells failed to proliferate, but exhibited increased capacity to generate multipotent as well as eosinophil, GM, and B-lymphocyte progenitors. In addition, increased generation of eosinophil- and GM-specific progenitors was observed in the lungs. Although no differences were observed in their ability to roll on BM endothelium in vitro or in vivo, CD34-enriched hematopoietic/stem progenitor cells (HSPCs) from chronic-, but not acute-, challenged mice demonstrated reduced migration across BM endothelial cells associated with decreased CXCR4 expression. Overall, these studies demonstrate that chronic allergen exposure can alter BM homing due to decreased transendothelial migration enabling noninteracting HSPCs to egress out of the BM and recruit to sites of inflammation such as the airways, resulting in extramedullary hematopoiesis. PMID- 21309737 TI - Differential expression of monocyte/macrophage- selective markers in human idiopathic pulmonary fibrosis. AB - Idiopathic interstitial pneumonias are a group of idiopathic interstitial lung diseases of which idiopathic pulmonary fibrosis (IPF) is the lesion of usual interstitial pneumonia. Although the pathogenic mechanisms remain incompletely understood, disease-specific changes in blood, a readily accessible biospecimen, have not been fully characterized. To identify biomarkers from blood and sera, the immune status of IPF patients and control subjects without structural lung disease was quantified by measuring cell surface markers, mRNA levels, and serum proteins. Statistically significant differences in cellular and molecular markers were observed between the 2 groups. The cytokine receptor IL-17RB was significantly higher in CD14+ peripheral blood mononuclear cells (PBMCs) from IPF patients, whereas expression of the chemokine receptor CXCR4 was lower. Gene expression analyses identified 18 differentially expressed genes out of 195 selected. Of these, EMR1, CCR3, UPAR, FCGR2A, OPN, CEACAM3, CD16a, CD18, CD11b, LTF, and LCN2 were up-regulated, whereas IL-17RB, IL-10, PDGFA, CD301/Clec10a, CD25/IL-2RA, IL-23p19, and IL-15 were down-regulated in IPF. Differentially regulated genes were in the functional areas of inflammation and cell signaling. Serum levels of UPAR and OPN were higher in IPF. These observations reveal significant differences in cell and molecular markers involved in monocyte/macrophage activation and migration, and suggest a role for IL-17RB in IPF. PMID- 21309738 TI - Anti-inflammatory effects of anti-hypertensive agents: influence on interleukin 1beta secretion by peripheral blood polymorphonuclear leukocytes from patients with essential hypertension. AB - The effects of clinically relevant concentrations of anti-hypertensive agents on lipopolysaccharide (LPS)-induced interleukin-1beta (IL-1beta) secretion by polymorphonuclear leukocytes (PMNs) were investigated in vitro. Lipopolysaccharide-induced secretion of IL-1beta by PMNs from 15 hypertensive and 15 normotensive subjects after incubation with losartan, captopril, amlodipine, atenolol, and hydrochlorothiazide were assessed. IL-1beta secretion by PMNs markedly increased in hypertensive patients versus normotensive subjects. Losartan, captopril, and amlodipine caused a concentration-dependent attenuation of IL-1beta levels in both groups. Losartan, captopril, and amlodipine demonstrated marked in vitro anti-inflammatory effects at clinically relevant serum concentrations but atenolol and hydrochlorothiazide did not. PMID- 21309739 TI - Using random forest algorithm to predict beta-hairpin motifs. AB - A novel method is presented for predicting beta-hairpin motifs in protein sequences. That is Random Forest algorithm on the basis of the multi characteristic parameters, which include amino acids component of position, hydropathy component of position, predicted secondary structure information and value of auto-correlation function. Firstly, the method is trained and tested on a set of 8,291 beta-hairpin motifs and 6,865 non-beta-hairpin motifs. The overall accuracy and Matthew's correlation coefficient achieve 82.2% and 0.64 using 5 fold cross-validation, while they achieve 81.7% and 0.63 using the independent test. Secondly, the method is also tested on a set of 4,884 beta-hairpin motifs and 4,310 non-beta-hairpin motifs which is used in previous studies. The overall accuracy and Matthew's correlation coefficient achieve 80.9% and 0.61 for 5-fold cross-validation, while they achieve 80.6% and 0.60 for the independent test. Compared with the previous, the present result is better. Thirdly, 4,884 beta hairpin motifs and 4,310 non-beta-hairpin motifs selected as the training set, and 8,291 beta-hairpin motifs and 6,865 non-beta-hairpin motifs selected as the independent testing set, the overall accuracy and Matthew's correlation coefficient achieve 81.5% and 0.63 with the independent test. PMID- 21309740 TI - Prediction of rat protein subcellular localization with pseudo amino acid composition based on multiple sequential features. AB - The study of rat proteins is an indispensable task in experimental medicine and drug development. The function of a rat protein is closely related to its subcellular location. Based on the above concept, we construct the benchmark rat proteins dataset and develop a combined approach for predicting the subcellular localization of rat proteins. From protein primary sequence, the multiple sequential features are obtained by using of discrete Fourier analysis, position conservation scoring function and increment of diversity, and these sequential features are selected as input parameters of the support vector machine. By the jackknife test, the overall success rate of prediction is 95.6% on the rat proteins dataset. Our method are performed on the apoptosis proteins dataset and the Gram-negative bacterial proteins dataset with the jackknife test, the overall success rates are 89.9% and 96.4%, respectively. The above results indicate that our proposed method is quite promising and may play a complementary role to the existing predictors in this area. PMID- 21309741 TI - An antifungal peptide with antiproliferative activity toward tumor cells from red kidney beans. AB - A 7.3-kDa antifungal peptide was purified from dried red kidney beans. The purification procedure entailed ion exchange chromatography on DEAE-cellulose, affinity chromatography on Affi-gel blue gel, ion exchange chromatography on CM cellulose, followed by fast protein liquid chromatography-gel filtration on Superdex 75. The peptide was unadsorbed on DEAE-cellulose but adsorbed on Affi gel blue gel and CM-cellulose. It exhibited a molecular mass of 7.3 kDa in gel filtration and also in SDS-polyacrylamide gel electrophoresis, indicating that it is a single-chained protein. The N-terminal sequence of the peptide was DGVCFGGLANGDRT. The peptide exerted an antifungal action on Fusarium oxysporum with an IC50 of 3.8+/-0.4 uM (mean+/-SD, n=3). It also inhibited mycelial growth in Mycosphaerella arachidicola. It suppressed growth of lymphoma MBL2 cells and leukemia L1210 cells with an IC50 of 5.2+/-0.4 uM and 7.6+/-0.6 uM, respectively. HIV-1 reverse transcriptase was inhibited with an IC50 of 40+/-3.2 uM. However, no activity was demonstrated toward other viral enzymes. PMID- 21309742 TI - Study of prolactin permeation through the pericardium and its bioavailability. AB - The prolactin (PRL) permeation through the pericardium depending on the species of origin (porcine, bovine and ovine) was studied, and the parameters of its bioavailability were calculated. An in vitro model using pericardium as a natural membrane and Frantz cell method was applied. Significant differences in permeation were observed depending on the species of origin. Within 5 h, 17.5% of bovine PRL, 27.2% of porcine PRL and 90.3% of ovine PRL permeated the pericardium. The amount of permeated ovine PRL was 3.3-fold higher than porcine PRL and 5.2-fold higher than bovine PRL. The maximum concentration of permeated PRL was reached in the thirtieth minute of the experiment and was the highest for ovine PRL (C(max) = 677.21 ug/cm2) and the lowest for bovine PRL (C(max) = 259.97 ug/cm2). Bioavailability of PRL through the pericardium is 3.3-fold greater for ovine PRL in comparison to porcine or bovine PRL. The relative extent of bioavailability for bovine and ovine prolactin versus the porcine PRL standard was 85.6% and 229.3%, respectively. PMID- 21309743 TI - Targeting insulin amyloid assembly by aminosugars and their derivatives. AB - The use of small carbohydrates that stabilize proteins from misfolding is important from pharmaceutical point of view. We have investigated the role of small isomeric amino sugars on the in vitro aggregation of insulin amyloid. Using mass spectrometry, we screened 6 isomeric aminosugars for their role on inhibition of insulin amyloid formation and the results were compared with transmission electron microscopy imaging. We found that three N-acetylamino sugars promote insulin fibril formation. Among three isomeric aminosugars studied, only galactosamine showed few fibrils whereas other two isomers showed enhanced fibrils. The results demonstrated here may contribute to future designing of small amine derivatised galactose sugars as amyloid inhibitors and understanding their action. PMID- 21309744 TI - Novel pharmacotherapies for diabetic retinopathy: current and future perspectives. PMID- 21309745 TI - The popularity of "legal highs". PMID- 21309746 TI - C-terminal provasopressin (copeptin) as a prognostic marker after acute non-ST elevation myocardial infarction: Leicester Acute Myocardial Infarction Peptide II (LAMP II) study. AB - Copeptin, the 39-amino-acid C-terminal portion of provasopressin, has been shown to be an independent predictor for adverse events following STEMI (ST elevation myocardial infarction). We hypothesized that plasma copeptin was an independent predictor for adverse outcomes following acute NSTEMI (non-STEMI) and evaluated whether copeptin added prognostic information to the GRACE (Global Registry of Acute Coronary Events) score compared with NT-proBNP (N-terminal pro-B-type natriuretic peptide). Plasma copeptin and NT-proBNP were measured in 754 consecutive patients admitted to the hospital with chest pain and diagnosed as having NSTEMI in this prospective observational study. The end point was all cause mortality at 6 months. Upper median levels of copeptin were strongly associated with all-cause mortality at 6 months. Copeptin was a significant predictor of time to mortality {HR (hazard ratio), 5.98 [95% CI (confidence interval, 3.75-9.53]; P < 0.0005} in univariate analysis and remained a significant predictor in multivariate analysis [HR, 3.03 (05% CI, 1.32-6.98); P = 0.009]. There were no significant differences between the area under ROC (receiver operating characteristic) curves of copeptin, NT-proBNP and the GRACE score. Copeptin improved accuracy of risk classification when used in combination with the GRACE score as determined by net reclassification improvement, whereas NT-proBNP did not. The relative utility of the GRACE score was increased more by copeptin than by NT-proBNP over a wide range of risks. Plasma copeptin is elevated after NSTEMI, and higher levels are associated with worse outcomes. Copeptin used in conjunction with the GRACE score improves risk stratification enabling more accurate identification of high-risk individuals. PMID- 21309747 TI - Beyond the endoplasmic reticulum: atypical GRP78 in cell viability, signalling and therapeutic targeting. AB - GRP78 (glucose-regulated protein of 78 kDa) is traditionally regarded as a major ER (endoplasmic reticulum) chaperone facilitating protein folding and assembly, protein quality control, Ca(2+) binding and regulating ER stress signalling. It is a potent anti-apoptotic protein and plays a critical role in tumour cell survival, tumour progression and angiogenesis, metastasis and resistance to therapy. Recent evidence shows that GRP78 can also exist outside the ER. The finding that GRP78 is present on the surface of cancer but not normal cells in vivo represents a paradigm shift on how GRP78 controls cell homoeostasis and provides an opportunity for cancer-specific targeting. Cell-surface GRP78 has emerged as an important regulator of tumour cell signalling and viability as it forms complexes with a rapidly expanding repertoire of cell-surface protein partners, regulating proliferation, PI3K (phosphoinositide 3-kinase)/Akt signalling and cell viability. Evidence is also emerging that GRP78 serves as a receptor for viral entry into host cells. Additionally, a novel cytosolic form of GRP78 has been discovered prominently in leukaemia cells. These, coupled with reports of nucleus- and mitochondria-localized forms of GRP78, point to the previously unanticipated role of GRP78 beyond the ER that may be critical for cell viability and therapeutic targeting. PMID- 21309748 TI - Biological signalling activity measurements using mass spectrometry. AB - MS (mass spectrometry) techniques are rapidly evolving to high levels of performance and robustness. This is allowing the application of these methods to the interrogation of signalling networks with unprecedented depth and accuracy. In the present review we discuss how MS-based multiplex quantification of kinase activities and phosphoproteomics provide complementary means to assess biological signalling activity. In addition, we discuss how a wider application of these analytical concepts to quantify kinase signalling will result in a more comprehensive understanding of normal and disease biology at the system level. PMID- 21309749 TI - Molecular targets of oxidative stress. AB - Aerobic life requires organisms to resist the damaging effects of ROS (reactive oxygen species), particularly during stress. Extensive research has established a detailed picture of how cells respond to oxidative stress. Attention is now focusing on identifying the key molecular targets of ROS, which cause killing when resistance is overwhelmed. Experimental criteria used to establish such targets have differing merits. Depending on the nature of the stress, ROS cause loss of essential cellular functions or gain of toxic functions. Essential targets on which life pivots during ROS stress include membrane lipid integrity and activity of ROS-susceptible proteins, including proteins required for faithful translation of mRNA. Protein oxidation also triggers accumulation of toxic protein aggregates or induction of apoptotic cell death. This burgeoning understanding of the principal ROS targets will offer new possibilities for therapy of ROS related diseases. PMID- 21309750 TI - The Cdc42-associated kinase ACK1 is not autoinhibited but requires Src for activation. AB - The non-RTK (receptor tyrosine kinase) ACK1 [activated Cdc42 (cell division cycle 42)-associated kinase 1] binds a number of RTKs and is associated with their endocytosis and turnover. Its mode of activation is not well established, but models have suggested that this is an autoinhibited kinase. Point mutations in its SH3 (Src homology 3)- or EGF (epidermal growth factor)-binding domains have been reported to activate ACK1, but we find neither of the corresponding W424K or F820A mutations do so. Indeed, deletion of the various ACK1 domains C-terminal to the catalytic domain are not associated with increased activity. A previous report identified only one major tyrosine phosphorylated protein of 60 kDa co purified with ACK1. In a screen for new SH3 partners for ACK1 we found multiple Src family kinases; of these c-Src itself binds best. The SH2 and SH3 domains of Src interact with ACK1 Tyr518 and residues 623-652 respectively. Src targets the ACK1 activation loop Tyr284, a poor autophosphorylation site. We propose that ACK1 fails to undergo significant autophosphorylation on Tyr284 in vivo because it is basophilic (whereas Src is acidophilic). Subsequent ACK1 activation downstream of receptors such as EGFR (EGF receptor) (and Src) promotes turnover of ACK1 in vivo, which is blocked by Src inhibitors, and is compromised in the Src-deficient SYF cell line. The results of the present study can explain why ACK1 is responsive to so many external stimuli including RTKs and integrin ligation, since Src kinases are commonly recruited by multiple receptor systems. PMID- 21309751 TI - Cell-surface nucleolin is involved in lipopolysaccharide internalization and signalling in alveolar macrophages. AB - C23 (nucleolin) shuttling between the nucleus, cytoplasm and cell surface has been implicated in controlling regulatory processes and may play a role in pathogen infection and autoimmune diseases. It has been reported that cell surface-expressed C23 on THP-1 monocytes is involved in the inflammatory response induced by LPS (lipopolysaccharide). This study investigates whether C23 is a membrane receptor for LPS during LPS-induced AMs (alveolar macrophages) activation. First, using immunofluorescence and microscopy, we detected the expression of C23 on the surface of AMs. Second, using LPS affinity columns, we demonstrated that C23 directly binds to LPS. Third, we found that LPS colocalized with C23 on both the cell surface and in the cytoplasm. Finally, knockdown of C23 expression on the cell surface using siRNA (small interfering RNA) led to significant reductions in the internalization of LPS, in LPS-induced NF-kappaB (nuclear factor kappaB)-DNA binding and in the protein expression of TNF (tumour necrosis factor)-alpha and IL-6 (interleukin-6). These findings provide evidence that cell-surface C23 on AMs may serve as a receptor for LPS and are essential for internalization and transport of LPS. Furthermore, C23 participates in the regulation of LPS-induced inflammation of AMs, which indicates that cell-surface C23 is a new and promising therapeutic target for the treatment of bacterial infections. PMID- 21309752 TI - Eicosanoid formation by a cytochrome P450 isoform expressed in the pharynx of Caenorhabditis elegans. AB - Caenorhabditis elegans harbours several CYP (cytochrome P450) genes that are homologous with mammalian CYP isoforms important to the production of physiologically active AA (arachidonic acid) metabolites. We tested the hypothesis that mammals and C. elegans may share similar basic mechanisms of CYP dependent eicosanoid formation and action. We focused on CYP33E2, an isoform related to the human AA-epoxygenases CYP2C8 and CYP2J2. Co-expression of CYP33E2 with the human NADPH-CYP reductase in insect cells resulted in the reconstitution of an active microsomal mono-oxygenase system that metabolized EPA (eicosapentaenoic acid) and, with lower activity, also AA to specific sets of regioisomeric epoxy- and hydroxy-derivatives. The main products included 17,18 epoxyeicosatetraenoic acid from EPA and 19-hydroxyeicosatetraenoic acid from AA. Using nematode worms carrying a pCYP33E2::GFP reporter construct, we found that CYP33E2 is exclusively expressed in the pharynx, where it is predominantly localized in the marginal cells. RNAi (RNA interference)-mediated CYP33E2 expression silencing as well as treatments with inhibitors of mammalian AA metabolizing CYP enzymes, significantly reduced the pharyngeal pumping frequency of adult C. elegans. These results demonstrate that EPA and AA are efficient CYP33E2 substrates and suggest that CYP-eicosanoids, influencing in mammals the contractility of cardiomyocytes and vascular smooth muscle cells, may function in C. elegans as regulators of the pharyngeal pumping activity. PMID- 21309753 TI - Clinicopathological and prognostic significance of Bmi-1 expression in human cervical cancer. AB - OBJECTIVE: To investigate the clinical significance of Bmi-1 expression as a prognostic marker for cervical cancer. Design. Retrospectively collected data from a population-based cohort. SETTING: Jiangsu Province Hospital. Population. Eighty-eight women diagnosed with cervical carcinoma between 2000 and 2003. METHODS: RT-PCR assay was performed to determine Bmi-1 mRNA expression in 18 cervical cancer and noncancerous tissue samples and immunohistochemistry to detect Bmi-1 protein expression in 88 cervical cancer samples. The correlation between Bmi-1 expression and clinicopathological factors was analyzed. Additionally, statistical analyses were applied to test for prognostic associations. RNA interference was used to downregulate Bmi-1 expression in a cervical cancer cell line (HeLa). In vitro cytotoxicity was measured by the methylthiazoletetrazolium and colony formation assays. Effects of Bmi-1 inhibition on in vivo growth of cancer cells was detected by the tumorigenicity assay. Cell cycle distribution and cell apoptosis were measured by flow cytometry. MAIN OUTCOME MEASURES: The levels of Bmi-1 mRNA and protein expression in tissues were evaluated by RT-PCR and Western Blot assays. RESULTS: The level of Bmi-1 mRNA expression in cervical cancer tissues was significantly higher than that in corresponding noncancerous tissues. High Bmi-1 expression was significantly correlated with poor tumor differentiation, advanced International Federation of Gynecology and Obstetrics stage and positive lymph node metastasis. Patients with high Bmi-1 expression showed shorter overall survival than those with low expression. Univariate and multivariate analyses showed that high Bmi-1 expression was an independent prognostic factor. CONCLUSIONS: RNA interference mediated Bmi-1 inhibition could inhibit in vitro and in vivo growth, enhance apoptosis and induce cell cycle arrest of cervical cancer cells. Bmi-1 might be an independent prognostic marker for cervical cancer patients. PMID- 21309754 TI - Vitamin D receptor gene as a candidate gene for Parkinson disease. AB - Vitamin D and vitamin D receptor (VDR) have been postulated as environmental and genetic factors in neurodegeneration disorders including multiple sclerosis (MS), Alzheimer disease (AD), and recently Parkinson disease (PD). Given the sparse data on PD, we conducted a two-stage study to evaluate the genetic effects of VDR in PD. In the discovery stage, 30 tagSNPs in VDR were tested for association with risk as a discrete trait and age-at-onset (AAO) as a quantitative trait in 770 Caucasian PD families. In the validation stage, 18 VDR SNPs were tested in an independent Caucasian cohort (267 cases and 267 controls) constructed from a genome-wide association study (GWAS). In the discovery dataset, SNPs in the 5' end of VDR were associated with both risk and AAO with more significant evidence of association with AAO (P= 0.0008-0.02). These 5' SNPs were also associated with AD in another study. In the validation dataset, SNPs in the 3' end of VDR were associated with AAO (P= 0.003) but not risk. The 3' end SNP has been associated with both MS and AD in previous studies. Our findings suggest VDR as a potential susceptibility gene and support an essential role of vitamin D in PD. PMID- 21309756 TI - Prevalence of clinically relevant UGT1A alleles and haplotypes in African populations. AB - Variation of a short (TA)(n) repeat sequence (rs8175347) covering the TATA box of UGT1A1 (UDP-glucuronosyltransferase1A1) is associated with hyperbilirubinaemia (Gilbert's syndrome) and adverse drug reactions, and is used for dosage advice for irinotecan. Several reports indicate that the low-activity (risk) alleles ((TA)(7) and (TA)(8) )) are very frequent in Africans but the patterns of association with other variants in the UGT1A gene complex that may modulate these responses are not well known. rs8175347 and two other clinically relevant UGT1A variants (rs11692021 and rs10929302) were assayed in 2616 people from Europe and Africa. Low-activity (TA)(n) alleles frequencies were highest in equatorial Africa, (TA)(7,) being the most common in Cameroon, Ghana, southern Sudan, and in Ethiopian Anuak. Haplotypic diversity was also greatest in equatorial Africa, but in Ethiopia was very variable across ethnic groups. Resequencing of the promoter of a sample subset revealed no novel variations, but rs34547608 and rs887829 were typed and shown to be tightly associated with (TA)(n) . Our results illustrate the need for investigation of the effect of UGT1A variants other than (TA)(n) on the risk of irinotecan toxicity, as well as hyperbilirubinaemia due to hemolytic anaemia or human immunodeficiency virus protease inhibitors, so that appropriate pharmacogenetic advice can be given. PMID- 21309755 TI - Genetic mapping of vascular calcified plaque loci on chromosome 16p in European Americans from the diabetes heart study. AB - A linkage peak for carotid artery calcified plaque (CarCP) on chromosome 16p (LOD 4.39 at 8.4 cM) in families with type 2 diabetes mellitus (T2DM) from the Diabetes Heart Study (DHS) has been refined. Fine mapping encompassed 104 single nucleotide polymorphisms (SNPs) in 937 subjects from 315 families; including 45 SNPs in six candidate genes (CACNA1H, SEPX1, ABCA3, IL32, SOCS1, CLEC16A). Linkage and association analyses using variance components analysis adjusting for age, gender, body mass index (BMI), and diabetes status refined the CarCP linkage into two distinct peaks (LODs: 3.89 at 6.9 cM and 4.86 at 16.0 cM). Evidence of linkage for coronary calcified plaque (LOD: 2.27 at 19 cM) and a vascular calcification principle component (LOD: 3.71 at 16.0 cM) was also observed. The strongest evidence for association with CarCP was observed with SNPs in the A2BP1 gene region (rs4337300 P= 0.005) with modest evidence of association with SNPs in CACNA1H (P= 0.010-0.033). Bayesian quantitative trait nucleotide (BQTN) analysis identified a SNP, rs1358489, with either a functional effect on CarCP or in linkage disequilibrium (LD) with a functional SNP. This study refined the 16p region contributing to vascular calcification. The causal variants remain to be identified, but results are consistent with a linkage peak that is due to multiple common variants, though rare variants cannot be excluded. PMID- 21309757 TI - Association of polymorphisms in the solute carrier organic anion transporter family member 1B1 gene with essential hypertension in the Uyghur population. AB - Solute carrier organic anion transporter family member 1B1 (SLCO1B1) is an important hepatic uptake transporter that can transport a wide variety of endogenous compounds, including thyroid hormones and prostaglandin E2. Dysregulation of thyroid hormones and prostaglandin E2 plays a role in the development of hypertension, suggesting that SLCO1B1 might contribute to the aetiology of essential hypertension (EH). In this study, we selected five single nucleotide polymorphisms (SNPs) at the SLCO1B1 gene promoter or coding regions and performed a case-control association study involving 731 unrelated Uyghur subjects, including 374 hypertensive and 357 normotensive individuals, to investigate the potential genetic contribution of SLCO1B1 to the aetiology of EH. Of the five polymorphisms, only one (i.e., rs4149014) showed correlation with EH. The minor allele of SNP rs4149014 at the SLCO1B1 promoter showed association with increased risk for EH (adjusted OR 1.88; 95% CI 1.36-2.60; P= 1.22 * 10(-4)). This study provides preliminary genetic evidence for the role of variant of SLCO1B1 in the susceptibility to human EH in Uyghurs. PMID- 21309758 TI - The Rho kinase inhibitor Fasudil up-regulates astrocytic glutamate transport subsequent to actin remodelling in murine cultured astrocytes. AB - BACKGROUND AND PURPOSE: Glutamate transporters play a major role in maintaining brain homeostasis and the astrocytic transporters, EAAT1 and EAAT2, are functionally dominant. Astrocytic excitatory amino acid transporters (EAATs) play important roles in various neuropathologies wherein astrocytes undergo cytoskeletal changes. Astrocytic plasticity is well documented, but the interface between EAAT function, actin and the astrocytic cytoskeleton is poorly understood. Because Rho kinase (ROCK) is a key determinant of actin polymerization, we investigated the effects of ROCK inhibitors on EAAT activity and astrocytic morphology. EXPERIMENTAL APPROACH: The functional activity of glutamate transport was determined in murine cultured astrocytes after exposure to the ROCK inhibitors Fasudil (HA-1077) and Y27632 using biochemical, molecular and morphological approaches. Cytochemical analyses assessed changes in astrocytic morphology, F-/G-actin, and localizations of EAAT1/2. RESULTS: Fasudil and Y27632 increased [(3)H]-D-aspartate (D-Asp) uptake into astrocytes, and the action of Fasudil was time-dependent and concentration-related. The rapid stellation of astrocytes (glial fibrillary acidic protein immunocytochemistry) induced by Fasudil was accompanied by reduced phalloidin staining of F-actin and increased V(max) for [(3)H]-D-Asp uptake. Immunoblotting after biotinylation demonstrated that Fasudil increased the expression of EAAT1 and EAAT2 on the cell surface. Immunocytochemistry indicated that Fasudil induced prominent labelling of astrocytic processes by EAAT1/2. CONCLUSION AND IMPLICATIONS: These data show for the first time that ROCK plays a major role in determining the cell surface expression of EAAT1/2, providing new evidence for an association between transporter function and astrocytic phenotype. ROCK inhibitors, via the actin cytoskeleton, effect a consequent elevation of glutamate transporter function - this activity profile may contribute to their beneficial actions in neuropathologies. PMID- 21309760 TI - Unilateral cerebral palsy: a population-based study of gait and motor function. AB - AIM: To investigate the spectrum and relationships between gait patterns and motor function in a population-based cross study of children with unilateral cerebral palsy (CP). METHOD: Children identified with unilateral CP born in Victoria, Australia, from 1990 to 1992 were eligible to participate. Characteristics were reported using the Winters, Gage, and Hicks (WGH) classification for gait patterns, the Gross Motor Function Classification System (GMFCS) and Functional Mobility Scale (FMS) for gross motor function, and Manual Ability Classification System (MACS) and House classification for upper-limb function. RESULTS: A recruitment rate of 71% was achieved (42 males, 27 females; mean age 11 y 4 mo, SD 2 y 4 mo). Children were classified in levels I and II of the GMFCS and levels I, II, and III of the MACS whereas there was a greater range of scores using the FMS and House classification. The association was moderate between categorizations of lower-limb and upper-limb involvement (Kendall's tau(b) =0.46-0.47, p < 0.001), accounting for around 21% of the explained variance. The proportions of gait-pattern groups in the current cohort were rather similar to the original WGH cohort (chi(2) =7.07, degrees of freedom [df]=3, p = 0.070). INTERPRETATION: Unilateral CP embraces a wide spectrum of clinical phenotypes. There were only moderate associations between categorizations of upper- and lower-limb function, supporting the need for separate classification systems of upper- and lower-limb functioning in this diverse group of children. PMID- 21309761 TI - CDKL5 gene-related epileptic encephalopathy: electroclinical findings in the first year of life. AB - AIM: Cyclin-dependent kinase-like 5 (CDKL5) gene abnormalities cause an early onset epileptic encephalopathy. We performed video-electroencephalography (video EEG) monitoring early in the course of CDKL5-related epileptic encephalopathy in order to examine the early electroclinical characteristics of the condition. METHOD: We used video-EEG to monitor six infants (five females, one male) with CDKL5-related epileptic encephalopathy (five mutations; one deletion), at ages 45 days to 12 months and followed them up to the ages of 14 months to 5 years (mean age 23 mo). We focused our analysis on the first year of life. The results were evaluated against those of a comparison group of nine infants (aged below 1y) with epileptic encephalography who had tested negative for CDKL5 mutations and deletions. RESULTS: One infant exhibited normal background activity, three exhibited moderate slowing, and two exhibited a suppression burst pattern. Two participants had epileptic spasms and four had a stereotyped complex seizure pattern, which we defined as a 'prolonged' generalized tonic-clonic event consisting of a tonic-tonic/vibratory contraction, followed by a clonic phase with series of spasms, gradually translating into repetitive distal myoclonic jerks. Seizure duration ranged from 2 to 4 minutes. The EEG correlate of each clinical phase included an initial electrodecremental event (tonic vibratory phase), irregular series of sharp waves and spike slow waves (clonic phase with series of spasms), and bilateral rhythmic sharp waves (time locked with myoclonus). INTERPRETATION: Infants with CDKL5-related early epileptic encephalopathy can present in the first year of life with an unusual electroclinical pattern of 'prolonged' generalized tonic-clonic seizures. PMID- 21309759 TI - Pharmacological relevance and potential of sphingosine 1-phosphate in the vascular system. AB - Sphingosine-1-phosphate (S1P) was identified as a crucial molecule for regulating immune responses, inflammatory processes as well as influencing the cardiovascular system. S1P mediates differentiation, proliferation and migration during vascular development and homoeostasis. S1P is a naturally occurring lipid metabolite and is present in human blood in nanomolar concentrations. S1P is not only involved in physiological but also in pathophysiological processes. Therefore, this complex signalling system is potentially interesting for pharmacological intervention. Modulation of the system might influence inflammatory, angiogenic or vasoregulatory processes. S1P activates G-protein coupled receptors, namely S1P(1-5) , whereas only S1P(1-3) is present in vascular cells. S1P can also act as an intracellular signalling molecule. This review highlights the pharmacological potential of S1P signalling in the vascular system by giving an overview of S1P-mediated processes in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). After a short summary of S1P metabolism and signalling pathways, the role of S1P in EC and VSMC proliferation and migration, the cause of relaxation and constriction of arterial blood vessels, the protective functions on endothelial apoptosis, as well as the regulatory function in leukocyte adhesion and inflammatory responses are summarized. This is followed by a detailed description of currently known pharmacological agonists and antagonists as new tools for mediating S1P signalling in the vasculature. The variety of effects influenced by S1P provides plenty of therapeutic targets currently under investigation for potential pharmacological intervention. PMID- 21309762 TI - Reliability of a shuttle run test for children with cerebral palsy who are classified at Gross Motor Function Classification System level III. AB - For children and adolescents with cerebral palsy (CP) classified as Gross Motor Function Classification System (GMFCS) level III there is no running-based field test available to assess their cardiorespiratory fitness. The current study investigated whether a shuttle run test can be reliably (test-retest) performed in a group of children with spastic diplegia (eight male, five female) classified as GMFCS level III. Thirteen children (mean age 12 y, SD 3 y) had to walk/run in squares of 7.5m delimited by cones. The auditory signals from the GMFCS II compact disc (as used in a previous reliability and validation study) were used during the test, resulting in a starting speed of 1.5 km/hour with a graded increase in speed of 0.19 km/hour per minute (shuttle). Intraclass correlation coefficients (two-way mixed) for achieved shuttles were 0.98. The standard error of measurement was 0.48 levels and the smallest detectable change was 1.32 shuttles. The results are the first indication that the shuttle run test protocol could be reliably performed in this population. PMID- 21309763 TI - Standardized tests of handwriting readiness: a systematic review of the literature. AB - AIM: To establish if there are psychometrically sound standardized tests or test items to assess handwriting readiness in 5- and 6-year-old children on the levels of occupations activities/tasks and performance. METHOD: Electronic databases were searched to identify measurement instruments. Tests were included in a systematic review if: (1) participants are 5 and 6 years old, (2) the focus was on handwriting readiness, and (3) the measurement was standardized. In the second step a further electronic search was undertaken for selected relevant measurement instruments to evaluate the content, psychometric properties, and feasibility of these instruments. RESULTS: The search identified 1113 citations. In the final selection 39 articles with information about 12 tests were included. The content, feasibility, and psychometric properties of these 12 tests were evaluated and none of the instruments was satisfactory, according to the specific criteria. INTERPRETATION: None of the instruments include all necessary components to evaluate writing readiness. Therefore, the development of an all encompassing assessment is necessary to test handwriting readiness and to make tailored interventions possible. PMID- 21309764 TI - Identification of a core set of exercise tests for children and adolescents with cerebral palsy: a Delphi survey of researchers and clinicians. AB - AIM: Evidence-based recommendations regarding which exercise tests to use in children and adolescents with cerebral palsy (CP) are lacking. This makes it very difficult for therapists and researchers to choose the appropriate exercise related outcome measures for this group. This study aimed to identify a core set of exercise tests for children and adolescents with CP. METHOD: Fifteen experts (10 physical therapists/researchers and five exercise physiologists; three from the Netherlands, two from the USA, one from the UK, five from Canada, and four from Australia) participated in a Delphi survey which took four stages to achieve a consensus. Based on the information that was collected during the survey, a core set of measures was identified for levels I to IV of the Gross Motor Function Classification System (GMFCS). RESULTS: For children with CP classified at GMFCS levels I and II, tests were identified for two motor skills (walking and cycling). For the subgroup of children with CP classified at GMFCS level III, the tests that were identified related to walking, cycling, and arm cranking. For children with CP classified at GMFCS level IV, the tests included in the core set were related to cycling and arm cranking. INTERPRETATION: The core set will help physical therapists, exercise physiologists, and other health professionals who work with children and adolescents with CP to decide which test(s) to use in clinical practice or research. This will facilitate comparability of results across studies and clinical programmes. PMID- 21309765 TI - Hereditary motor sensory neuropathy (type 1) presenting with transient and persistent central nervous system manifestations: a novel genetic mutation. PMID- 21309766 TI - Treating inflammation in childhood neurodegenerative disorders. AB - Inflammation of the central nervous system is a prominent feature in many childhood neurodegenerative conditions, with various studies demonstrating the upregulation of the innate and adaptive immune system. Recent evidence also suggests that this inflammatory process can contribute to further neurodegeneration. Furthermore, immunosuppression in mouse models of a few lysosomal storage disorders has demonstrated that attenuation of this immune response can influence the clinical and neuropathological progression. However, there are significant challenges before this finding translates to patient care. Treating inflammation in neurodegenerative conditions requires the identification of the time point when inflammation becomes pathogenic, after which the safest therapeutic strategies are required to target the various components and confounders of inflammation. Nevertheless, as the progress made towards effective gene-, cellular-, and enzyme-based therapy in most of these disorders has been disappointing, treating pathogenic inflammation may offer the clinician another therapeutic strategy in managing these devastating disorders. PMID- 21309767 TI - Visual assessment in children with cerebral palsy: implementation of a functional questionnaire. AB - AIM: The aim of this study was to evaluate an interdisciplinary visual assessment for multiply challenged children diagnosed with cerebral palsy (CP). METHOD: A comprehensive ophthalmological assessment together with a visual classification scale (VCS) and a questionnaire evaluating daily visual function were completed regarding 77 children (41 females, 36 males; age range 3-20y; mean age 8 y 3 mo [SD 4 y 3 mo]; Gross Motor Function Classification System [GMFCS] level V; Manual Ability Classification System level V) who were diagnosed with CP (79.2% spastic quadriplegia, 6.5% athetoid quadriplegia, 10.4% mixed type, 3.9% hemiplegia). All participants had severe to profound motor and intellectual disability and an inability to communicate consistently through either verbal or assisted communication. The interrater and test-retest reliability of the questionnaire and its validity in comparison with the VCS were examined. In addition, the contribution of ophthalmological testing in predicting daily visual function was assessed. RESULTS: The ophthalmological examination revealed three diagnostic subgroups: a group with cerebral visual impairment (CVI), a group with optic atrophy, and a group without visual impairment. The questionnaire was found to have high values of interrater reliability (interclass correlation coefficient [ICC]=0.873; 95% confidence interval [CI] 0.762-0.935) and test-retest reliability (ICC=0.988; 95% CI 0.964-0.996). Validity was established for the questionnaire factors: task-orientated visual function (r=0.802; 95% CI 0.669 0.885) and basic visual skills (r=0.691; 95% CI 0.504-0.816). The questionnaire provided information about daily visual performance not available from one-time ophthalmological testing, particularly for participants diagnosed with CVI. The visual performance scale significantly predicted daily visual function for all groups. INTERPRETATION: This study highlights the benefits of implementing a diagnostic performance scale as well as a reliable functional questionnaire to achieve a precise visual assessment of children with severe neurological impairment. PMID- 21309768 TI - Influence of oscillating flow on hyporheic zone development. AB - The hyporheic zone is an ecologically important ecotone that describes the extent to which nutrient-rich surface waters penetrate the shallow subsurface adjacent to a flowing surface water body. Although steady-state models satisfactorily explain the incursion of surface water into the subsurface as a function of head gradients developed across streambed riffles, they fail to account for the depth that surface water is observed to penetrate the subsurface or for the extent to which the hyporheic zone develops adjacent to the stream channel. To investigate these issues, transient flow modeling has been conducted at the riffle scale and supported by data for an instrumented site in northern Ontario where stream-stage fluctuations are strictly regulated. Model results show that daily stream-stage fluctuations between 0.6 and 4 m produce oscillating solute flow paths that typically reduce residence times of water and solutes in the hyporheic zone from 60 days or more under steady-state conditions to less than 1 day. Furthermore, similar stream-stage fluctuations increase the depth that solutes pervade the subsurface and banks lateral to the stream from around 1 m under steady-state conditions to as much as 2 and 10 m, respectively. The results demonstrate that the transient flow conditions triggered in the subsurface by variable stream stage can exert a strong influence on hyporheic zone development and have important implications for the hyporheos. The results are especially important for hyporheic communities that may survive gradual changes to their living conditions by migrating to more hospitable aquatic habitats, but are unable to respond to rapid changes provoked by more extreme hydrological events. PMID- 21309769 TI - Estimation of groundwater residence time using the 36Cl bomb pulse. AB - We propose a methodology for estimating the residence time of groundwater based on bomb-produced (36)Cl. Water samples were collected from 28 springs and 2 flowing wells located around Mt. Fuji, Central Japan. (36)Cl/Cl ratios in the water samples, determined by accelerator mass spectrometry (AMS), were between 43 * 10(-15) and 412 * 10(-15). A reference time series of the above-background (i.e., bomb-derived) (36)Cl concentration was constructed by linearly scaling the background-corrected Dye-3 data according to the estimated total bomb-produced (36)Cl fallout in the Mt. Fuji area. Assuming piston flow transport, estimates of residence time were obtained by comparing the measured bomb-derived (36)Cl concentrations in spring water with the reference curve. The distribution of (36)Cl-based residence times is basically consistent with that of tritium-based estimates calculated from data presented in previous studies, although the estimated residence times differ between the two tracers. This discrepancy may reflect chlorine recycling via vegetation or the relatively small change in fallout rate, approximately since 1975, which would give rise to large uncertainties in (36)Cl-based estimates of recharge for the period, approximately since 1975. Given the estimated ages for groundwater from flowing wells, dating based on a (36)Cl bomb pulse may be more reliable and sensitive for groundwater recharged before 1975, back as far as the mid-1950s. PMID- 21309770 TI - The effect of cleft lip on cognitive development in school-aged children: a paradigm for examining sensitive period effects. AB - BACKGROUND: Our previous investigation showed that infants with cleft lip who had undergone late (three-month) surgical repair (but not those with early, neonatal, repair) had significantly poorer cognitive development at 18 months than a group of unaffected control children. These differences were mediated by the quality of early mother-infant interactions. The present study examined whether this pattern persisted into later childhood. METHOD: At 7 years, 93 index (44 early, and 49 late repair) and 77 control children were followed up and their cognitive development assessed (IQ, language and school achievements). RESULTS: Index children (particularly those with late lip repair) scored significantly lower than controls on tests of cognitive development. Group differences in Verbal IQ were mediated by 2 months' maternal sensitivity; this was associated with 7-year Verbal IQ, even after controlling for later mother-child interactions. CONCLUSIONS: Social interactions in the first few months may be of especial importance for child cognitive development. Interventions for infants with cleft lip should be directed at fostering the best possible parental care in infancy. PMID- 21309774 TI - A fresh take on whole blood. PMID- 21309771 TI - Annual Research Review: New frontiers in developmental neuropharmacology: can long-term therapeutic effects of drugs be optimized through carefully timed early intervention? AB - Our aim is to present a working model that may serve as a valuable heuristic to predict enduring effects of drugs when administered during development. Our primary tenet is that a greater understanding of neurodevelopment can lead to improved treatment that intervenes early in the progression of a given disorder and prevents symptoms from manifesting. The immature brain undergoes significant changes during the transitions between childhood, adolescence, and adulthood. Such changes in innervation, neurotransmitter levels, and their respective signaling mechanisms have profound and observable changes on typical behavior, but also increase vulnerability to psychiatric disorders when the maturational process goes awry. Given the remarkable plasticity of the immature brain to adapt to its external milieu, preventive interventions may be possible. We intend for this review to initiate a discussion of how currently used psychotropic agents can influence brain development. Drug exposure during sensitive periods may have beneficial long-term effects, but harmful delayed consequences may be possible as well. Regardless of the outcome, this information needs to be used to improve or develop alternative approaches for the treatment of childhood disorders. With this framework in mind, we present what is known about the effects of stimulants, antidepressants, and antipsychotics on brain maturation (including animal studies that use more clinically-relevant dosing paradigms or relevant animal models). We endeavor to provocatively set the stage for altering treatment approaches for improving mental health in non-adult populations. PMID- 21309775 TI - Between the trash can and the freezer: donor education and the fate of cord blood. PMID- 21309776 TI - Bias in transfusion research: from study design to result reporting. PMID- 21309778 TI - Cord blood banking and transplantation at the Mexican Institute of Social Security: the first 5 years. AB - BACKGROUND: In January 2005, the Cord Blood Bank (CBB) at the Mexican Institute of Social Security initiated activities. Herein, we describe the experience generated during this period (January 1, 2005-December 31, 2009). STUDY DESIGN AND METHODS: Good manufacturing practices and standard operating procedures were used to address donor selection, as well as umbilical cord blood (UCB) collection, processing, and cryopreservation. Based mainly on HLA and nucleated cell content, specific UCB units were thawed, processed, and released for transplantation. RESULTS: A total of 589 UCB units were stored, representing 54% of the total number of units collected. Forty-eight units (8.14% of the stored units) were released for transplantation of 36 patients. Twenty-six patients (72% of cases) corresponded to patients with acute leukemia, five (14%) to patients with marrow failure, and the rest (five; 14%) to patients with hemoglobinopathies and other syndromes. The median number of nucleated cells infused per patient was 6.71 * 10(7) /kg and the median number of CD34+ cells was 4.8 * 10(5) /kg. Current engraftment data indicate that engraftment occurred in 56%, and no engraftment in 44%, of cases. Engraftment was more frequent (59%) in patients that received more than 3 * 10(7) total nucleated cells (TNCs)/kg body weight, than in those receiving fewer than 3 * 10(7) TNCs/kg (40%). Myeloid engraftment was observed 7 to 54 days posttransplant (median, 23 days), whereas platelet engraftment was detected on Days 12 to 87 posttransplant (median, 38 days). To date, the disease-free survival rate was 41% and the overall survival was 47%, with survival periods of 126 to 1654 days. CONCLUSION: Although the experience presented herein is still limited and the period of analysis is still short, the results obtained during these 5 years are encouraging. PMID- 21309779 TI - Characterization of Jk(a+(weak)): a new blood group phenotype associated with an altered JK*01 allele. AB - BACKGROUND: The clinically important Kidd (JK) blood group system is considered to be relatively uncomplicated, both serologically and genetically. The JK*01 and JK*02 alleles give rise to Jk(a) and Jk(b) antigens, respectively, and silenced alleles result in Jk(a-b-). Other inherited variants analogous to Fy(x) and weak D phenotypes have not been characterized for JK, although recent abstracts indicate their presence. STUDY DESIGN AND METHODS: Six index samples from individuals whose RBCs reacted variably or weakly with different sources of anti Jk(a) and 300 controls of the four known JK phenotypes were investigated by standard serology, flow cytometry, Western blotting, and the urea hemolysis test. Molecular analysis, including allele-specific polymerase chain reaction (PCR), DNA sequencing, and transcript analysis by real-time PCR, was performed. RESULTS: All Jk(a+(w)b-) and Jk(a+(w)b+) index samples were homo- or heterozygous for an altered JK*01 allele carrying 130G>A (Glu44Lys) and the JK*02-associated silent SNPs 588G and Intron 9 -46g. Blood donor screening indicated an allele frequency of 0.042. Titration and flow cytometry with anti-Jk(a) gave lower values in index samples compared to controls, as did anti-Jk3 titers. Donors with 130A also showed significantly decreased Jk(a) density by flow cytometry versus 130G. Western blotting with anti-UT-B demonstrated weaker reactivity with Jk(a+(w)) membranes while JK mRNA levels could not discriminate index samples from controls. The urea hemolysis test was only moderately affected in two Jk(a+(w)b-) samples. CONCLUSIONS: A new phenotype with weakened Jk(a) expression on RBCs is associated with a JK*01-like allele, which may constitute a risk for hemolytic transfusion reactions if antigen-positive units are missed by routine serology. PMID- 21309772 TI - Annual Research Review: Transgenic mouse models of childhood-onset psychiatric disorders. AB - Childhood-onset psychiatric disorders, such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), mood disorders, obsessive compulsive spectrum disorders (OCSD), and schizophrenia (SZ), affect many school age children, leading to a lower quality of life, including difficulties in school and personal relationships that persist into adulthood. Currently, the causes of these psychiatric disorders are poorly understood, resulting in difficulty diagnosing affected children, and insufficient treatment options. Family and twin studies implicate a genetic contribution for ADHD, ASD, mood disorders, OCSD, and SZ. Identification of candidate genes and chromosomal regions associated with a particular disorder provide targets for directed research, and understanding how these genes influence the disease state will provide valuable insights for improving the diagnosis and treatment of children with psychiatric disorders. Transgenic mouse models are one important approach in the study of human diseases, allowing for the use of a variety of experimental approaches to dissect the contribution of a specific chromosomal or genetic abnormality in human disorders. While it is impossible to model an entire psychiatric disorder in a single mouse model, these models can be extremely valuable in dissecting out the specific role of a gene, pathway, neuron subtype, or brain region in a particular abnormal behavior. In this review we discuss existing transgenic mouse models for childhood-onset psychiatric disorders. We compare the strength and weakness of various transgenic mouse models proposed for each of the common childhood-onset psychiatric disorders, and discuss future directions for the study of these disorders using cutting-edge genetic tools. PMID- 21309780 TI - Time to rethink clinically important outcomes in platelet transfusion trials. PMID- 21309781 TI - Core temperature changes in red blood cells. PMID- 21309782 TI - Viable hematopoietic progenitor cells in frozen femoral heads from living donors for orthopedic surgery. PMID- 21309783 TI - Alternate analysis strategies for retrospective assessment of outcomes with a male donor-only plasma policy. PMID- 21309785 TI - Pathogen reduction technique for fresh-frozen plasma, cryoprecipitate, and plasma fraction minipools prepared in disposable processing bag systems. PMID- 21309787 TI - A retrospective study of patch tests in Chongqing, China from 2004 to 2009. AB - BACKGROUND: There has been no previous report on allergens responsible for dermatitis in southwest China. OBJECTIVE: To investigate the prevalence of contact allergy in southwest China, we retrospectively analysed the patch testing results in our department from 2004 to 2009. METHODS: A total of 2758 patients were patch tested with the Chinese baseline series of contact allergens (Beijing Medical University), the most common baseline series used in China. The results from patch tests were collected, analysed, and compared with clinical findings. RESULTS: Of 2758 patients tested, 1826 (66.2%) were allergic to one or more common allergens. Five hundred (27.4%) patients had more than two contact allergies. One patient showed positive reactions to seven allergens. The most common allergens among the 1826 patients with positive reactions were nickel sulfate (39.5%), potassium dichromate (13.5%), thiomersal (11.6%), fragrance mix (6.9%), and rubber mix IV (5.8%). Nickel sensitivity was more common in female patients, and potassium dichromate sensitivity was more common in male patients (p < 0.001). CONCLUSION: Contact allergy in southwest China has particular characteristics, and these findings should be helpful in the development of strategies to reduce contact allergy in this geographical region. PMID- 21309788 TI - Textile allergy--the Melbourne experience. AB - BACKGROUND: Textile allergy is a well-established entity, but there are relatively few Australian reports in this area. OBJECTIVES: To report the combined experience of textile contact dermatitis from the general and occupational contact dermatitis clinics at the Skin and Cancer Foundation, Melbourne, Victoria, Australia. PATIENTS/METHODS: On the basis of the clinical suspicion of textile allergy, 2069 patients were tested with a textile series. RESULTS: One hundred and fifty-seven (7.6%) patients reacted to any of the textile-related allergens. The most common allergen was Basic Red 46 (20.2% of the positive reactions), followed by Disperse Blue 106 and Disperse Blue 124 (11.8% and 11.2%, respectively). Reactions to formaldehyde and formaldehyde releasing chemicals accounted for 30.6% of the concomitant reactions, and reactions to p-phenylenediamine accounted for 12.6% of the concomitant reactions. The use of Disperse Blue mix yielded only 12.2% of patients sensitive to either of these two allergens, and it is not endorsed as a screening agent for textile dye allergy. CONCLUSION: Textile allergy is not uncommon. In Melbourne, Basic Red 46 in inexpensive, dark-coloured, acrylic-blend, men's work socks is the most important cause. It is important to test with samples of patients' clothing. PMID- 21309789 TI - The different decomposition properties of diazolidinyl urea in cosmetics and patch test materials. AB - BACKGROUND: Diazolidinyl urea is a formaldehyde-releasing compound that releases formaldehyde through its decomposition. However, there have been few reports about the decomposition properties of diazolidinyl urea in cosmetics and patch test materials. OBJECTIVES: The aim of this study was to show how diazolidinyl urea decomposes in cosmetics and patch test vehicles, and to determine which cosmetic compounds should be evaluated in patch test studies of diazolidinyl urea. METHOD: We fractionated diazolidinyl urea-dissolving buffers or diazolidinyl urea-containing cosmetics with high-performance liquid chromatography-photodiode array detector (HPLC-PDA), and characterized them in liquid chromatography-mass spectrometry (LC-MS) and (1) H-nuclear magnetic resonance studies. Diazolidinyl urea-containing cosmetics and diazolidinyl urea patch test materials were also analysed with HPLC-PDA and LC-MS. RESULTS: Diazolidinyl urea was decomposed to (4-hydroxymethyl-2,5-dioxo-imidazolidine-4 yl)-urea (HU) and (3,4-bis-hydroxymethyl-2,5-dioxo-imidazolidine-4-yl)-urea (3,4 BHU) in most of the cosmetic samples tested. The peak patterns of the patch test materials analysed with the HPLC-PDA were different from those of the cosmetic samples. CONCLUSIONS. The diazolidinyl urea-derived decomposition products differed between the cosmetics and patch test preparations. To test the contact sensitivity of the diazolidinyl urea present in cosmetics, patch tests with HU and 3,4-BHU in petrolatum should be performed. PMID- 21309790 TI - Kiwifruit Act d 11 is the first member of the ripening-related protein family identified as an allergen. AB - BACKGROUND: Kiwifruit is an important cause of food allergy. A high amount of a protein with a molecular mass compatible with that of Bet v 1 was observed in the kiwifruit extract. OBJECTIVE: To identify and characterize kirola, the 17-kDa protein of green kiwifruit (Act d 11). METHODS: Act d 11 was purified from green kiwifruit. Its primary structure was obtained by direct protein sequencing. The IgE binding was investigated by skin testing, immunoblotting, inhibition tests, and detection by the ISAC microarray in an Italian cohort and in selected Bet v 1 sensitized Austrian patients. A clinical evaluation of kiwi allergy was carried out. RESULTS: Act d 11 was identified as a member of the major latex protein/ripening-related protein (MLP/RRP) family. IgE binding to Act d 11 was shown by all the applied testing. Patients tested positive for Act d 11 and reporting symptoms on kiwifruit exposure were found within the Bet v 1-positive subset rather than within the population selected for highly reliable history of allergic reactions to kiwifruit. Epidemiology of Act d 11 IgE reactivity was documented in the two cohorts. IgE co-recognition of Act d 11 within the Bet v 1 like molecules is documented using the microarray IgE inhibition assay. CONCLUSIONS: Act d 11 is the first member of the MLP/RRP protein family to be described as an allergen. It displays IgE co-recognition with allergens belonging to the PR-10 family, including Bet v 1. PMID- 21309791 TI - Hydraulic conductivity of red oak (Quercus rubra L.) leaf tissue does not respond to light. AB - The permeability of leaf tissue to water has been reported to increase under illumination, a response reputed to involve aquaporins. We studied this 'light response' in red oak (Quercus rubra L.), the species in which the phenomenon was first detected during measurements of leaf hydraulic conductance with the high pressure flow meter (HPFM). In our HPFM measurements, we found that pre conditioning leaves in darkness was not sufficient to bring them to their minimum conductance, which was attained only after an hour of submersion and pressurization. However, pre-conditioning leaves under anoxic conditions resulted in an immediate reduction in conductance. Leaves light- and dark-acclimated while on the tree showed no differences in the time course of HPFM measurement under illumination. We also studied the effect of light level and anoxia on rehydration kinetics, finding that anoxia slowed rehydration, but light had no effect either in the lab (rehydration under low light, high humidity) or on the tree (acclimation under high light, 10 min of dark prior to rehydration). We conclude that the declines in conductance observed in the HPFM must involve a resistance downstream of the extracellular air space, and that in red oak the hydraulic conductivity of leaf tissue is insensitive to light. PMID- 21309792 TI - Decrease in leaf sucrose synthesis leads to increased leaf starch turnover and decreased RuBP regeneration-limited photosynthesis but not Rubisco-limited photosynthesis in Arabidopsis null mutants of SPSA1. AB - We investigated the individual effect of null mutations of each of the four sucrose-phosphate synthase (SPS) genes in Arabidopsis (SPSA1, SPSA2, SPSB and SPSC) on photosynthesis and carbon partitioning. Null mutants spsa1 and spsc led to decreases in maximum SPS activity in leaves by 80 and 13%, respectively, whereas null mutants spsa2 and spsb had no significant effect. Consistently, isoform-specific antibodies detected only the SPSA1 and SPSC proteins in leaf extracts. Leaf photosynthesis at ambient [CO2] was not different among the genotypes but was 20% lower in spsa1 mutants when measured under saturating [CO2] levels. Carbon partitioning at ambient [CO2] was altered only in the spsa1 null mutant. Cold treatment of plants (4 degrees C for 96 h) increased leaf soluble sugars and starch and increased the leaf content of SPSA1 and SPSC proteins twofold to threefold, and of the four null mutants, only spsa1 reduced leaf non structural carbohydrate accumulation in response to cold treatment. It is concluded that SPSA1 plays a major role in photosynthetic sucrose synthesis in Arabidopsis leaves, and decreases in leaf SPS activity lead to increased starch synthesis and starch turnover and decreased Ribulose 1,5-bisphosphate regeneration-limited photosynthesis but not ribulose 1.5-bisphosphate carboxylase/oxygenase (Rubisco)-limited photosynthesis, indicating a limitation of triose-phosphate utilization (TPU). PMID- 21309793 TI - Climate-related trends in sapwood biophysical properties in two conifers: avoidance of hydraulic dysfunction through coordinated adjustments in xylem efficiency, safety and capacitance. AB - In the Pacific north-west, the Cascade Mountain Range blocks much of the precipitation and maritime influence of the Pacific Ocean, resulting in distinct climates east and west of the mountains. The current study aimed to investigate relationships between water storage and transport properties in populations of Douglas-fir (Pseudotsuga menziesii) and ponderosa pine (Pinus ponderosa) adapted to both climates. Sapwood thickness, capacitance, vulnerability to embolism, and axial and radial conductivity were measured on samples collected from trunks of mature trees. The sapwood of ponderosa pine was three to four times thicker than Douglas-fir. Radial conductivity was higher in west-side populations of both species, but axial conductivity was higher in the east-side populations and in Douglas-fir. Eastern populations of both species had sapwood that was more vulnerable to embolism than west-side populations. Sapwood capacitance was similar between species, but was about twice as great in east-side populations (580 kg m-3 MPa-1) as in west-side populations (274 kg m-3 MPa-1). Capacitance was positively correlated with both mean embolism pressure and axial conductivity across species and populations, suggesting that coordinated adjustments in xylem efficiency, safety and water storage capacity may serve to avoid embolism along a gradient of increasing aridity. PMID- 21309794 TI - Transgenic poplars with reduced lignin show impaired xylem conductivity, growth efficiency and survival. AB - We studied xylem anatomy and hydraulic architecture in 14 transgenic insertion events and a control line of hybrid poplar (Populus spp.) that varied in lignin content. Transgenic events had different levels of down-regulation of two genes encoding 4-coumarate:coenzyme A ligase (4CL). Two-year-old trees were characterized after growing either as free-standing trees in the field or as supported by stakes in a greenhouse. In free-standing trees, a 20 to 40% reduction in lignin content was associated with increased xylem vulnerability to embolism, shoot dieback and mortality. In staked trees, the decreased biomechanical demands on the xylem was associated with increases in the leaf area to sapwood area ratio and wood specific conductivity (k(s)), and with decreased leaf-specific conductivity (k(l)). These shifts in hydraulic architecture suggest that the bending stresses perceived during growth can affect traits important for xylem water transport. Severe 4CL-downregulation resulted in the patchy formation of discoloured, brown wood with irregular vessels in which water transport was strongly impeded. These severely 4CL-downregulated trees had significantly lower growth efficiency (biomass/leaf area). These results underscore the necessity of adequate lignification for mechanical support of the stem, water transport, tree growth and survival. PMID- 21309795 TI - Circadian photosynthetic reductant flow in the dinoflagellate Lingulodinium is limited by carbon availability. AB - Circadian rhythms are the observed outputs of endogenous daily clocks and are thought to provide a selective advantage to cells adapted to daily light/dark cycles. However, the biochemical links between the clock and the overt rhythms in cell physiology are generally not known. Here, we examine the circadian rhythm in O2 evolution by cultures of the dinoflagellate Lingulodinium, a rhythm previously ascribed to rhythmic electron flow through photosystem II. We find that O2 evolution rates increase when CO2 concentrations are increased, either following addition of DIC or a rapid decrease in culture pH. In medium containing only nitrate as an electron acceptor, O2 evolution rates mirror the circadian rhythm of nitrate reductase activity in the cells. Furthermore, competition between photosynthetic electron flow to carbon and to nitrate varies in its relative efficiency through the day-night cycle. We also find, using simultaneous and continuous monitoring of pH and O2 evolution rates over several days, that while culture pH is normally rhythmic, circadian changes in rates of O2 evolution depend not on the external pH but on levels of internal electron acceptors. We propose that the photosynthetic electron transport rhythm in Lingulodinium is driven by the availability of a reductant sink. PMID- 21309796 TI - Proton-coupled high-affinity phosphate transport revealed from heterologous characterization in Xenopus of barley-root plasma membrane transporter, HvPHT1;1. AB - High-affinity phosphate transporters mediate uptake of inorganic phosphate (P(i) ) from soil solution under low P(i) conditions. The electrophysiological properties of any plant high-affinity P(i) transporter have not been described yet. Here, we report the detailed characterization of electrophysiological properties of the barley P(i) transporter, HvPHT1;1 in Xenopus laevis oocytes. A very low K(m) value (1.9 um) for phosphate transport was observed in HvPHT1;1, which falls within the concentration range observed for barley roots. Inward currents at negative membrane potentials were identified as nH+ :P(i)- (n > 1) co transport based on simultaneous P(i) radiotracer uptake, oocyte voltage clamping and pH dependence. HvPHT1;1 showed preferential selectivity for P(i) and arsenate, but no transport of the other oxyanions SO42- and NO3-. In addition, HvPHT1;1 locates to the plasma membrane when expressed in onion (Allium cepa L.) epidermal cells, and is highly expressed in root segments with dense hairs. The electrophysiological properties, plasma membrane localization and cell-specific expression pattern of HvPHT1;1 support its role in the uptake of P(i) under low P(i) conditions. PMID- 21309798 TI - Potential hazards of viewing 3-D stereoscopic television, cinema and computer games: a review. AB - The visual stimulus provided by a 3-D stereoscopic display differs from that of the real world because the image provided to each eye is produced on a flat surface. The distance from the screen to the eye remains fixed, providing a single focal distance, but the introduction of disparity between the images allows objects to be located geometrically in front of, or behind, the screen. Unlike in the real world, the stimulus to accommodation and the stimulus to convergence do not match. Although this mismatch is used positively in some forms of Orthoptic treatment, a number of authors have suggested that it could negatively lead to the development of asthenopic symptoms. From knowledge of the zone of clear, comfortable, single binocular vision one can predict that, for people with normal binocular vision, adverse symptoms will not be present if the discrepancy is small, but are likely if it is large, and that what constitutes 'large' and 'small' are idiosyncratic to the individual. The accommodation convergence mismatch is not, however, the only difference between the natural and the artificial stimuli. In the former case, an object located in front of, or behind, a fixated object will not only be perceived as double if the images fall outside Panum's fusional areas, but it will also be defocused and blurred. In the latter case, however, it is usual for the producers of cinema, TV or computer game content to provide an image that is in focus over the whole of the display, and as a consequence diplopic images will be sharply in focus. The size of Panum's fusional area is spatial frequency-dependent, and because of this the high spatial frequencies present in the diplopic 3-D image will provide a different stimulus to the fusion system from that found naturally. PMID- 21309799 TI - Statistical guidelines for clinical studies of human vision. AB - Statistical analysis of data can be complex and different statisticians may disagree as to the correct approach leading to conflict between authors, editors, and reviewers. The objective of this article is to provide some statistical advice for contributors to optometric and ophthalmic journals, to provide advice specifically relevant to clinical studies of human vision, and to recommend statistical analyses that could be used in a variety of circumstances. In submitting an article, in which quantitative data are reported, authors should describe clearly the statistical procedures that they have used and to justify each stage of the analysis. This is especially important if more complex or 'non standard' analyses have been carried out. The article begins with some general comments relating to data analysis concerning sample size and 'power', hypothesis testing, parametric and non-parametric variables, 'bootstrap methods', one and two-tail testing, and the Bonferroni correction. More specific advice is then given with reference to particular statistical procedures that can be used on a variety of types of data. Where relevant, examples of correct statistical practice are given with reference to recently published articles in the optometric and ophthalmic literature. PMID- 21309800 TI - A novel instrument for logging nearwork distance. AB - PURPOSE: To validate a novel ultrasonic sensor for logging reading distances. In addition, this device was used to compare the habitual reading distances between low and high myopes. METHODS: First, the stability and sensitivity of the ultrasonic device were determined by repeated measures using artificial targets. Then, thirty Hong Kong Chinese (20-30 years) were recruited, of whom fifteen were considered to be high myopes (mean +/- S.D. = -8.7 +/- 0.5 D) and 15 to be low to non-myopes (mean +/- S.D. = -2.0 +/- 0.2 D). Each subject read a newspaper with their habitual visual aid continuously for 10 min in two sessions at their preferred working distance(s). The reading distances were recorded continuously using a novel nearwork analyzer. The modal working distance was considered as the 'habitual' reading distance. In addition, habitual reading distance was reported orally by each subject. RESULTS: The nearwork analyzer gave accurate and repeatable measurements over a range of distances and angles. Using this instrument, high myopes were found to have a significantly shorter reading distance than low myopes or non-myopes (mean +/- S.D. = 35.9 +/- 9.8 cm vs 50.9 +/- 24.8 cm; two-sample t-test, p = 0.04, df = 18). The reading distances reported orally by the subjects were not correlated with those recorded by the nearwork analyzer. CONCLUSIONS: The nearwork analyzer was found to be an effective tool for measuring nearwork reading distance in a small group of emmetropic and myopic adults over a 10 min interval. Differences between the reading distance between high myopes and low/non-myopes was detected by the device. Further study is needed to determine if a closer working distance is a cause or effect of myopia development. PMID- 21309801 TI - Effect of near adds on the variability of accommodative response in myopic children. AB - PURPOSE: Higher variability of accommodative response (VAR) has been reported in myopes and speculated to be a possible risk factor for the progression of myopia. We investigated whether near adds of +2D and -2D were capable of altering accommodative variability and also determined the influence of near phoria and viewing condition (binocular vs monocular) on the VAR in myopic and emmetropic children. METHODS: Twenty-seven myopic and 25 emmetropic children between 7 and 14 years were examined. All children were classified into 'normophores' (0 to 4 exo), exophores (>6 exo) or esophores (>2 eso) based on their near phoria. Binocular and monocular steady-state measures of accommodation were obtained for 5 s using a PowerRefractor (Multichannel Co) while children fixated a high contrast target (33 cm) with distance correction, and then with +2D add and -2D add over the corrective lenses. The variation in accommodative responses (VAR) was defined as the standard deviation of the accommodative response during the 5 s period. RESULTS: Myopic children showed higher VAR through their distance spectacle corrections compared to emmetropes (emmetropes=0.23 +/- 0.03D, myopes=0.37 +/- 0.07D, p < 0.001). Plus adds significantly reduced the VAR in myopic children to the level of emmetropes (emmetropes=0.2 +/- 0.03D, myopes=0.19 +/- 0.02D, p>0.9). Introduction of a -2D add significantly increased the VAR in both refractive groups; however, myopes showed greater VAR compared to emmetropes (emmetropes=0.39 +/- 0.03D, myopes=0.53 +/- 0.07D, p < 0.001). Near phoria or binocular viewing did not alter the magnitude of fluctuations in either refractive group. VAR significantly correlated with the monocular accommodative error in both refractive groups (emmetropes r2 = 0.34; p < 0.0001; myopes: r2 = 0.35; p < 0.001). Pupil size, while varying with add type, did not confound the VAR. CONCLUSIONS: The near steady state accommodative response of young myopes shows greater variability than non-myopes. This difference is maintained when accommodative responses are increased beyond the vergence plane using -2D adds. However, accommodative fluctuations were reduced to emmetropic levels when the stimulus to accommodation is reduced using a +2D add. The resulting VAR through adds appear to follow that expected from variations in accommodative demands and hence properties of the accommodative controller. Vergence postures (eso and exo phoria) do not appear to influence the VAR with and without near adds. PMID- 21309802 TI - Spectacle prescribing II: practitioner experience is linked to the likelihood of suggesting a partial prescription. AB - PURPOSE: A follow up study to investigate whether UK optometrists partially prescribe significant changes in refractive correction to assist patient adaptation and whether various aspects of practitioner profiles are linked to the nature of these prescribing decisions. METHOD: A case scenario type questionnaire was distributed by post and via the internet to UK optometrists. Five case scenarios were described that included information on patient age, symptoms, habitual refractive correction (if any), subjective refraction and any other relevant clinical information. In each case respondents were asked to indicate and justify what refractive correction they would prescribe. RESULTS: A total of 592 questionnaires were completed. Between 41% and 84% prescribed the subjective refraction result depending on the scenario. The likelihood of partial prescribing increased by 34% for every 10 years following qualification and thus after a typical 40 year career, respondents were now over three times more likely to partially prescribe. There were no other links with the propensity to partially prescribe. CONCLUSION: The subjective refraction result exerted a strong hold on the reported prescribing outcome, particularly for newly qualified optometrists. Partial prescribing was increasingly proposed the greater the number of years the respondent had been qualified. This suggests that with increasing exposure to patients who return dissatisfied with their spectacles, a greater appreciation of partial prescribing is gained. This link seems to be an important finding that provides significant support for the prescribing rules suggested by textbooks, which are not yet supported by research evidence. PMID- 21309803 TI - Decision making in chronic glaucoma--optometrists vs ophthalmologists in a shared care service. AB - PURPOSE: Shared care schemes have become popular in glaucoma management in the UK over the past 20 years. Published audits of decision making processes by non ophthalmologists working in such schemes are however rare. Our aim was to audit the appropriateness of optometrists' decision-making when working in an in-house shared care glaucoma scheme. METHODS: A single masked comparison study utilising retrospective consensus decisions by two ophthalmologists compared with 'live' optometrist decisions from three optometrists who reviewed patients with glaucoma, suspect glaucoma and ocular hypertension. RESULTS: Comparisons were made on management decisions on 140 consecutive eligible patients. There were high degrees of agreement (>88%) in terms of visual field interpretation, medical and surgical management decisions, timing of next appointment and ordering of visual field tests. Accuracy of communication with primary physicians was excellent with two optometrists but sub-optimal in a third. CONCLUSION: An audit model of decision-making in shared care is demonstrated that in this case supported the apprenticeship model of training utilised in the clinic. PMID- 21309804 TI - A comparison of the NCT Reichert R7 with Goldmann applanation tonometry and the Reichert ocular response analyzer. AB - PURPOSE: The aim of this study was to evaluate the accuracy of intraocular pressure (IOP) values from the new non-contact tonometer (NCT) Reichert R7 by comparing results with those from Goldmann applanation tonometry (GAT) and the Reichert Ocular Response Analyzer (ORA). Other ocular dimensions were assessed to evaluate their potential influence on the IOP values obtained. METHODS: Ninety two right eyes from 92 adults aged between 21 and 59 years (mean 34.9 +/- 11.7 years) were enrolled in this study. IOP was measured with R7, ORA and GAT. All measurements were taken between 14:00 and 16:00 in the afternoon. Corneal resistance factor (CRF) and corneal hysteresis were measured with the Reichert ORA. The spherical equivalent refractive error was obtained using an open field auto-refractor (WAM5500; Grand Seiko) and corneal curvature, anterior chamber depth, corneal diameter and axial length were assessed with an optical coherence biometer (IOL Master; Zeiss Meditec, CA, USA). RESULTS: The mean values for IOP measurements were 15.20 +/- 3.37 mmHg (R7), 13.49 +/- 3.55 mmHg (GAT), 15.01 +/- 3.38 mmHg (ORA IOPcc) and 14.44 +/- 3.47 mmHg (ORA IOPg). With the exception of the CRF (rho = 0.72 p < 0.001) the correlations between ocular parameters and IOP obtained with the R7 were neither statistically nor clinically significant. CONCLUSIONS: The new NCT, R7 overestimated the IOP compared with GAT in normal, healthy eyes by about 1.7 mmHg on average (95% confidence range of approximately 2 to +6 mmHg). The measures provided by the R7 were significantly influenced by the stiffness of the corneal tissue as measured by the ORA CRF value but not by other dimensional parameters of the eye. PMID- 21309805 TI - Effectiveness of vision therapy for convergence dysfunctions and long-term stability after vision therapy. AB - BACKGROUND: Symptomatic convergence insufficiency (CI) is a common binocular dysfunction. It is often associated with accommodative insufficiency (AI). Optimum therapy for this condition was recently shown to be in-clinic vision therapy (VT). More scientific studies are needed to assess the effectiveness of VT and verify these evidence-based results. METHODS: Fifty-seven children aged 9 13 years were diagnosed with symptomatic CI (n = 27) or combined symptomatic CI and AI (n = 30). They were independently divided into a treatment and a control group, matched by age and gender. The treatment group received 12 weeks of VT while the control group received no therapy. A quality of life instrument documented the symptomatic patients and charted improvement in symptoms after therapy. Clinical aspects were also assessed to determine the treatment effects on clinical findings. Twenty children in the treatment group completed a 1 year follow-up examination. RESULTS: Symptom scores and clinical measures of the treatment and control groups were not significantly different at baseline (p > 0.05), but showed significant differences after completion of 12 weeks of treatment (p < 0.001). No significant changes of either symptoms or signs were evident for the control group. One year follow-up examination revealed that most children maintained the improved symptom and clinical measures after VT. CONCLUSION: This study supports the notion that VT is a successful method of treating CI and CI combined with AI. PMID- 21309806 TI - Randomised controlled study comparing comfort-related outcomes between two rigid gas permeable (RGP) lenses with different sessile drop contact angles. AB - PURPOSE: To compare comfort-related outcomes when wearing rigid gas permeable (RGP) contact lenses made of two different materials and using two cleaning regimes. METHODS: In a double-masked lens material cross-over study, subjects (n = 28 who completed the study) were refitted with new lenses made from (A) Boston XO material in one eye and made from (B) ONSI-56 material in the other eye. The lenses made from materials A and B were worn on the right eye and the left eye following the pattern AB-BA-AB (or vice versa) during the first, second, and third 5 week trial periods respectively. Miraflow cleaner (1st and 2nd period) was replaced by Boston Advance cleaner in the 3rd period. Comfort-related outcomes were assessed by a numerical rating scale (NRS) after each period. Subjects rated six comfort-related factors: satisfaction, sharpness of vision, end of day comfort, maximum comfortable wearing time, maximum wearing time and foreign body feeling. Additionally we obtained subjects' preferences for type of lens and lens cleaner during an exit interview. The sessile drop method was used to measure static contact angles. RESULTS: The mean of the contact angle measured for the Boston XO material was 93.3 degrees and for the ONSI-56 material was 75.8 degrees . Mean 'end of the day comfort', 'satisfaction' and 'lens feeling' scores reached statistical significance (anova periods 1, 2 and 3, p's: 0.005, 0.028, 0.046, n = 23) with marginal differences in favour of those eyes that had worn lenses made of the ONSI-56 material (differences in mean scores on a 1-10 NRS never exceeded 0.7, 0.5 and 0.2 points in periods 1, 2, 3 respectively). At the exit interview 60% of the subjects (n = 17) were not able to express a preference for wearing either of the lenses, while 29% reported some preference for lenses made of the ONSI-56 material (n = 8) and 11% for wearing lenses made of the Boston XO material (n = 3) within one or more periods. CONCLUSIONS: The differences in comfort-related outcomes between contact lenses made from two different materials, with sessile contact angles that differed by 17.5 degrees , were small. Although some observed comfort differences reached statistical significance, none of these differences were sufficiently large to support a clinically significant difference in comfort between the two materials. We recommend that both the sessile drop and the captive bubble contact angles, measured according to current standards, are made available to practitioners. PMID- 21309807 TI - Plant systems biology: network matters. AB - Systems biology is all about networks. A recent trend has been to associate systems biology exclusively with the study of gene regulatory or protein interaction networks. However, systems biology approaches can be applied at many other scales, from the subatomic to the ecosystem scales. In this review, we describe studies at the sub-cellular, tissue, whole plant and crop scales and highlight how these studies can be related to systems biology. We discuss the properties of system approaches at each scale as well as their current limits, and pinpoint in each case advances unique to the considered scale but representing potential for the other scales. We conclude by examining plant models bridging different scales and considering the future prospects of plant systems biology. PMID- 21309808 TI - Implant-induced intraperitoneal inflammatory angiogenesis is attenuated by fluvastatin. AB - 1. Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA) inhibitors, exert anti-inflammatory, anti-oxidant and anti-angiogenic effects. These effects are associated with downregulation of pro-inflammatory/pro-angiogenic molecules and upregulation of endothelial nitric oxide synthase (e-NOS) expression/nitric oxide (NO) production. 2. Using the murine sponge model to induce chronic intraperitoneal inflammatory response, we evaluated the inflammatory components, angiogenic and NO production of the fibrovascular tissue, and their modulation by fluvastatin. 3. Our results showed that fluvastatin (0.6 and 6 mg/kg per day) inhibited haemoglobin (Hb) content 4.9+/-0.4 (n=15; control) vs 2.2+/-0.2 (n=6; fluvastatin 0.6) and 1.8+/-0.2 (n=6; fluvastatin 6.0) and the number of vessels in the treated group when compared with the control group. The inflammatory component, as assessed by myeloperoxidase and N-acetyl-beta-d-glucosaminidase activities and by the pro-inflammatory cytokines, tumour necrosis factor-alpha (TNF-alpha) and Monocyte chemotactic protein-1 (MCP-1)/CCL2/JE levels, was also decreased by the compound. In the treated group, inhibition of both enzyme activities was 54% and 57%, respectively. The levels of the cytokines (TNF-alpha and CCL2/JE) intra-implant were decreased relative to the control. In these implants, fluvastatin was also able to increase NO production, as detected with an NO-sensitive electrode. 4. The inhibitory function of fluvastatin on key components of intraperitoneal inflammatory angiogenesis shown in the present study is clearly associated with the modulatory effects of this statin on vascular endothelial growth factor, TNF-alpha and NO production. PMID- 21309810 TI - Everyday clinical experience of alitretinoin in the treatment of severe chronic hand eczema: seven case studies. AB - Chronic hand eczema (CHE) is a debilitating and distressing disease for patients, the physical symptoms of which are compounded by psychosocial problems. Alitretinoin is an endogenously occurring physiological vitamin A derivative (retinoid) that possesses strong anti-inflammatory and immunomodulatory activity. It is currently the only licensed product for severe CHE unresponsive to treatment with potent topical corticosteroids, and has been proven to be highly effective in clinical trials with two-thirds of patients who responded to treatment remaining in remission at 6 months. For those that did relapse, a second study showed they could be successfully retreated with a further 3-6 month course of alitretinoin. Seven case studies of alitretinoin have been provided by consultant dermatologists showing its use in normal UK clinical practice. The cases chosen demonstrate the efficacy of alitretinoin across several different subtypes of CHE, and the positive effects the treatment brought to patients' quality of life. PMID- 21309809 TI - Epigenetics: deciphering its role in diabetes and its chronic complications. AB - 1. Increasing evidence suggests that epigenetic factors might regulate the complex interplay between genes and the environment, and affect human diseases, such as diabetes and its complications. 2. Clinical trials have underscored the long lasting beneficial effects of strict glycaemic control for reducing the progression of diabetic complications. They have also shown that diabetic complications, such as diabetic nephropathy, a chronic kidney disorder, can continue even after blood glucose normalization, suggesting a metabolic memory of the prior glycaemic state. 3. Dysregulation of epigenetic post-transcriptional modifications of histones in chromatin, including histone lysine methylation, has been implicated in aberrant gene regulation associated with the pathology of diabetes and its complications. Genome-wide studies have shown cell-type specific changes in histone methylation patterns under diabetic conditions. In addition, studies in vascular cells have shown long lasting changes in epigenetic modifications at key inflammatory gene promoters after prior exposure to diabetic conditions, suggesting a possible mechanism for metabolic memory. 4. Recent studies have shown roles for histone methylation, DNA methylation, as well as microRNA in diabetic nephropathy. Whether these epigenetic factors play a role in metabolic memory of diabetic kidney disease is less well understood. 5. The incidence of diabetes is growing rapidly, as also the cost of treating the resulting complications. A better understanding of metabolic memory and the potential involvement of epigenetic mechanisms in this phenomenon could enable the development of new therapeutic targets for the treatment and/or prevention of sustained diabetic complications. PMID- 21309811 TI - Case study 1--A 54-year-old male gardener with chronic hand eczema. PMID- 21309812 TI - Case study 2--A 33-year-old female horse trainer with long-standing hand and foot eczema. PMID- 21309813 TI - Case study 3--A 41-year-old male with hyperkeratotic changes to the hands and feet. PMID- 21309814 TI - Case study 4--A 35-year old male handyman with pompholyx blisters. PMID- 21309815 TI - Case study 5--A 50-year-old female politician with long-standing chronic hand eczema affecting her quality of life. PMID- 21309816 TI - Case study 6--A 56-year-old male civil engineer with chronic hand eczema presenting as fissures and inflammation. PMID- 21309817 TI - Case study 7--A 39-year-old male IT worker with a 3 year history of chronic hand eczema. PMID- 21309818 TI - A closer look at self-reported suicide attempts: false positives and false negatives. AB - The validity of self-reported suicide attempt information is undermined by false positives (e.g., incidences without intent to die), or by unreported suicide attempts, referred to as false negatives. In a sample of 1,385 Austrian adults, we explored the occurrence of false positives and false negatives with detailed, probing questions. Removing false positives decreased the rate of suicide attempters from 4.3% to 2.7%. Probing questions also revealed 0.8% false negatives. We recommend using probing questions with both those who report a suicide attempt and those who do not report a suicide attempt to increase the validity of self-reported suicide-related information. PMID- 21309819 TI - Risk factors of attempted suicide in bipolar disorder. AB - Suicide rates of bipolar patients are among the highest of any psychiatric disorder, and improved identification of risk factors for attempted and completed suicide translates into improved clinical outcome. Factors that may be predictive of suicidality in an exclusively bipolar population are examined. White race, family suicide history, and history of cocaine abuse were predictive of suicidal histories. Gender, nicotine use, medical comorbidity, and history of alcohol and other drug abuse were not, although a trend was noted for a history of benzodiazepine abuse. Attempts, although less common among African Americans, were equally as violent. Likewise, attempts were as violent among females as males, in distinction to general population studies. PMID- 21309820 TI - Effects of race and precipitating event on suicide versus nonsuicide death classification in a college sample. AB - Race group differences in suicide death classification in a sample of 109 Black and White university students were examined. Participants were randomly assigned to read three vignettes for which the vignette subjects' race (only) varied. The vignettes each described a circumstance (terminal illness, academic failure, or relationship difficulties) that preceded the vignette subject's ambiguously premature death. Participants were asked to describe "what happened." Black participants were significantly less likely than White participants to attribute a vignette target's death to suicide and also less likely to report that suicide is acceptable. Implications for future research and prevention efforts are discussed. PMID- 21309821 TI - Systemic vulnerabilities to suicide among veterans from the Iraq and Afghanistan Conflicts: review of case reports from a National Veterans Affairs Database. AB - While suicide among recently returned veterans is of great concern, it is a relatively rare occurrence within individual hospitals and clinics. Root cause analysis (RCA) generates a detailed case report that can be used to identify system-based vulnerabilities following an adverse event. Review of a national database of RCA reports may identify common vulnerabilities and assist in the development of more robust prevention strategies. Our objective was to identify and compare common themes among reports of suicide among veterans of Operations Iraqi Freedom and Enduring Freedom (OIF/OEF) in the Veterans Affairs system. Common themes among root causes of suicide as identified in RCA reports were collected and compared as the primary outcome--systematic vulnerabilities. Actions recommended within the reports were coded as the secondary outcome- prevention strategies. Fifty-one RCA reports of OIF/OEF suicides were identified by our search. Coding generated 16 common categories among 132 root causes, and 13 categories among 108 recommended actions. Assessment of suicidal risk, coordination of care, timely access to care, and communication among providers were the most common root causes. Actions identified by RCA teams to reduce suicide included improving referral processes, staff education in suicide assessment, and follow-up with suicidal veterans. Review of multiple RCA reports can identify organizational vulnerabilities detected at the local level that may be applicable system wide. Attention to improving suicide assessment, coordination of care, and timely access may have the largest impact on reducing suicide among OIF/OEF veterans. PMID- 21309822 TI - Race, urban context, and Russian roulette: findings from the National Violent Death Reporting System, 2003-2006. AB - Previous work on Russian roulette has focused on data from large cities. It is unclear if the epidemiological patterns based on large cities will replicate for the nation as a whole, and if the influence of minority status will be moderated by urban context. The present investigation fills these gaps by providing descriptive epidemiological data on Russian roulette for 17 states, and testing a hypothesis on urbanism as a moderator of the race-Russian roulette relationship. Data were taken from the National Violent Death Reporting System (2003-2006). They refer to 71 Russian roulette cases and a matched control group of 284 males who committed suicide by a gunshot wound to the head. Russian roulette suicides were more apt to be of minority status, younger, had a lower incidence of mental health problems, and were more likely to be utilizing alcohol than the controls. Differentiating the sample into larger and smaller urban areas, it was found that the risk of Russian roulette for African Americans was higher in larger urban areas. Epidemiological patterns in previous research on large city samples are largely replicated. The moderating influence of urban context is related to differential opportunity structures for risk-taking behavior. PMID- 21309823 TI - Suicides in users of mental health care services: treatment characteristics and hindsight reflections. AB - The current study aims to describe the patient and treatment characteristics of a sample of 505 suicides by mental health care patients, and to determine how clinicians view the care provided and what they learned. The results indicate that the quality of mental health care for suicidal patients could be improved by focusing on communication among clinicians, continuity of care, suicide risk assessment procedures, and the involvement of relatives. PMID- 21309824 TI - Friendship factors and suicidality: common and unique patterns in Mexican American and European American youth. AB - Research suggests a link between friendships and suicidality among U.S. youth, but this link has not been confirmed across ethnicities. The relationship between friendships and suicidality among Mexican American and European American adolescents was examined in this study. Specifically, the role of friendship problems (i.e., social isolation, poor quality friendships) and problematic friends (i.e., friends who were disconnected from school, delinquent friends) was explored. Participants were 648 community youth. Friends' school disconnection was related to Mexican American girls' suicidal ideation, while friends' delinquency was associated with European American youth suicidal behavior. Friendship factors were no longer associated with suicidality after controlling for suicidality correlates such as depression. These findings indicate that the relationship between friendships and suicidality varies by gender and ethnicity. They also suggest a dominant role of depression. PMID- 21309825 TI - Suicide, schizophrenia, and schizoid-type psychosis: role of life events and childhood factors. AB - The first objective was to identify the provoking events of suicide in patients with schizophrenia or schizoid-type disorder, and to assess the humiliation component of these events. The second objective was to verify if quality of care during childhood is a vulnerability factor for suicide in patients with schizophrenia or schizoid-type psychosis. Thirty-three cases of suicide with a diagnosis of schizophrenia or schizoid-type psychosis were compared with 34 living patients with a similar diagnosis. The psychological autopsy method was used. The assessments were made with the Structured Clinical Interview for the Diagnostic and Statistical Manual for Axis I mental disorders, the Life Events and Difficulties Schedule, and the Child Experiences and Child Abuse Interview. The suicide group (SG) experienced more often a recent severe event, usually of a humiliation nature, than the control group (CG). It also experienced more severe events associated with aggressive behavior or with psychiatric impairment. Contrary to expectations, the CG had worse scores than the SG for quality of care during childhood. In conclusion, suicide in schizophrenia is related both to environmental stress and to psychiatric impairment. PMID- 21309826 TI - Community responses to a suicidal crisis: implications for suicide prevention. AB - We conducted a cross-sectional, random-digit-dial survey to evaluate public responses to a hypothetical question: "If someone you knew was suicidal, what would you do first?" Younger people were more likely to call a suicide hotline, and less likely to go to an emergency room (ER) or call 911; immigrants (in the U.S. < 15 years) were more likely to call 911, and less likely to call a suicide hotline; African Americans were more likely to go to the ER and call 911; Hispanics were more likely to call 911 but less likely to call a suicide hotline. These results suggest that public messages about hotlines and emergency options for suicidal patients need to be tailored to relevant population characteristics including age, education, ethnicity, and language preferences. PMID- 21309827 TI - Connect: an effective community-based youth suicide prevention program. AB - Youth suicide prevention is an important public health issue. However, few prevention programs are theory driven or systematically evaluated. This study evaluated Connect, a community-based youth suicide prevention program. Analysis of pre and posttraining questionnaires from 648 adults and 204 high school students revealed significant changes in knowledge and attitudes about suicide, increased belief in the usefulness of mental health care, and reduction of stigma associated with seeking help. Adults' preparedness to help also increased significantly as did the likelihood that youth participants would seek adult assistance if they were concerned about a peer. Implications of findings are discussed. PMID- 21309828 TI - The construction of self-injury in the clinical literature: a sociological exploration. AB - This article presents a sociologically informed critique of a range of academic literatures relating to self-injury. It is noted how a lack of consensus on definitional issues, together with the inaccurate portrayal of the "typical self injurer" in the clinical literature, has impeded the development of a sound understanding of self-injury. Some of the more problematic explanations for self injury are explored. The individualistic focus of existing research is found to be inadequate, since it fails to account for the social context in which self injury occurs. Social scientific approaches critically examine psychiatric and psychological constructions of self-injury, explore wider social and cultural meanings of the behavior, and examine its distribution across different social groups. The inclusion of social scientific perspectives into current debates will greatly improve understanding of self-injury. PMID- 21309829 TI - Estimating the population of survivors of suicide: seeking an evidence base. AB - Shneidman (1973) derived an estimate of six survivors for every suicide that, in the ensuing years, has become an assumed fact underlying public health messaging campaigns in support of suicide prevention and postvention programs worldwide, in spite of it lacking either empirical testing or validation. This report offers a first test designed to derive estimates of suicide survivors and raises an array of empirical questions needing further study to reasonably address the impact of suicide on others. PMID- 21309830 TI - Treatment following a near fatal suicide attempt. PMID- 21309831 TI - Self-harming behavior and suicidality: suicide risk assessment. PMID- 21309832 TI - Diabetes, cardiovascular disease and the nurse specialist. PMID- 21309833 TI - Nurse-led interventions used to improve control of high blood pressure in people with diabetes: a systematic review and meta-analysis. AB - BACKGROUND: Previous reviews demonstrate uncertainty about the effectiveness of nurse-led interventions in the management of hypertension. No specific reviews in diabetes have been identified. We have systematically reviewed the evidence for effectiveness of nurse-led interventions for people with diabetes mellitus. METHODS: In this systematic review and meta-analysis, searches of Medline, Embase, CINAHL and the Cochrane Central Trials register were undertaken to identify studies comparing any intervention conducted by nurses in managing hypertension in diabetes with usual doctor-led care. Additional citations were identified from papers retrieved and correspondence with authors. Outcome measures were absolute systolic and diastolic blood pressure, change in blood pressure, proportions achieving study target blood pressure and proportions prescribed anti-hypertensive medication. RESULTS: Eleven studies were identified. Interventions included adoption of treatment algorithms, nurse-led clinics and nurse prescribing. Meta-analysis showed greater reductions in blood pressure in favour of any nurse-led interventions (systolic weighted mean difference -5.8 mmHg, 95% CI -9.6 to -2.0; diastolic weighted mean difference 4.2 mmHg, 95% CI -7.6 to -0.7) compared with usual doctor-led care. No overall superiority in achievement of study targets or in the use of medication was evident for any nurse-based interventions over doctor-led care. CONCLUSIONS: There is some evidence for improved blood pressure outcomes with nurse-led interventions for hypertension in people with diabetes compared with doctor-led care. Nurse-based interventions require an algorithm to structure care and there is some preliminary evidence for better outcomes with nurse prescribing. Further work is needed to elucidate which nurse-led interventions are most effective. PMID- 21309834 TI - Factors associated with medication adherence to oral hypoglycaemic agents in different ethnic groups suffering from type 2 diabetes: a systematic literature review and suggestions for further research. AB - AIMS: To synthesize knowledge regarding the different factors that may influence adherence to oral hypoglycaemic agents in different ethnic groups through a systematic review of the literature. METHODS: Thirteen databases were searched and 1201 articles were screened by two authors independently from each other. Different quantitative study designs were included if the study population included at least one ethnic group other than White people, medication adherence was a dependent variable and a clear description was given of the method used to measure medication adherence. RESULTS: Demographic, disease-related and treatment related, socio-economic and cultural factors were associated with medication adherence in the populations that were studied. However, to synthesize results, the number of studies was too small and the included studies differed too much with respect to their study designs and the ethnic groups that were studied. We discuss several methodological challenges with respect to measuring medication adherence, measuring ethnicity and study designs that need to be resolved to make future studies comparable. We propose methodological improvements for future research. CONCLUSION: Although medication adherence is an essential part of the diabetic regimen, little is known about the association between ethnicity and medication adherence and the underlying factors that could explain this association. More research is needed in which important methodological challenges will have to be faced. PMID- 21309835 TI - Type 2 diabetes mellitus and risk of malignancy: is there a strategy to identify a subphenotype of patients with increased susceptibility to endogenous and exogenous hyperinsulinism? AB - AIMS: To give an overview on the relationship between diabetes mellitus and increased cancer risk. METHODS: We identified studies evaluating the association between diabetes mellitus, its treatment with insulin and insulin analogues and malignancies, paying special attention to studies on in vitro and in vivo effects of the long-acting analogue insulin glargine. RESULTS: Even although the pathophysiological mechanisms underlying the relationship between elevated cancer risk and Type 2 diabetes mellitus are not completely understood, hyperinsulinaemia in the presence of insulin resistance appears to be a key factor. Because of the mitogenic actions of insulin at high concentrations, hyperinsulinaemia may favour tumorigenesis. In line with this, an insulin-based therapy is associated with an increased cancer risk, whereas an insulin sensitizing treatment results in a cancer risk reduction. Furthermore, alterations of the insulin receptor profile on tumour cells may contribute to an enhanced susceptibility towards insulin. Studies on the analogue insulin glargine have been controversial. In vitro data pointed to an elevated mitogenicity of insulin glargine, whereas in vivo data did not confirm cancerogenous effects. Moreover, recently published clinical studies on the association of insulin glargine (Lantus(r)) and cancer suggest that treatment with insulin glargine is not associated with increased cancer risk. CONCLUSIONS: The relationship between elevated cancer risk and Type 2 diabetes mellitus has been shown by numerous epidemiological studies, with endogenous and exogenous hyperinsulinaemia in the presence of insulin resistance as potential underlying pathophysiological mechanisms. Recent clinical studies do not support an increased cancer risk in patients treated with insulin glargine. PMID- 21309836 TI - Effect of subsequent pregnancies on the risk of developing diabetes following a first pregnancy complicated by gestational diabetes: a population-based study. AB - AIMS: Women with gestational diabetes mellitus have a high risk of developing Type 2 diabetes, secondary to post-partum progression of the chronic pancreatic beta-cell defect that underlies their presenting with dysglycaemia in pregnancy. Insulin-sensitizing therapy can decrease this risk of Type 2 diabetes, partly by offloading the secretory demand placed on the beta-cells. Conversely, however, it is not known whether the considerable secretory demands posed by the physiologic insulin resistance of a subsequent pregnancy could accelerate the progression to Type 2 diabetes. Thus, we sought to determine whether subsequent pregnancies are associated with the risk of developing diabetes following gestational diabetes. METHODS: Using a population-based administrative database, we identified all women in Ontario, Canada, whose first pregnancy was between April 2000 and March 2007 and was complicated by gestational diabetes (n = 16,817). This cohort was followed for a median 4.5 years for subsequent pregnancies and the development of diabetes. RESULTS: During follow-up, 2731 women (16.2%) developed diabetes. Gestational diabetes recurred in 41.5% of subsequent pregnancies. Interestingly, after covariate adjustment, a subsequent pregnancy was associated with a reduced risk of diabetes (adjusted hazard ratio (HR) = 0.68, 95%CI 0.60-0.76; P < 0.0001). Specifically, whereas each subsequent gestational diabetes pregnancy was associated with a modestly increased risk of diabetes (adjusted HR = 1.16, 95%CI 1.01-1.34; P = 0.03), each non-gestational diabetes pregnancy was associated with a significantly reduced risk of diabetes (adjusted HR=0.34, 95%CI 0.27-0.41; P < 0.0001). CONCLUSIONS: A subsequent pregnancy is not necessarily associated with an increased risk of Type 2 diabetes following gestational diabetes. Instead, the absence of recurrent gestational diabetes in a subsequent pregnancy may identify a lessened risk of developing Type 2 diabetes in this high-risk patient population. PMID- 21309838 TI - Plasma levels of glucagon like peptide-1 associate with diastolic function in elderly men. AB - AIMS: Congestive heart failure is a major cause of morbidity and mortality in diabetes. Besides the glycaemic effects of glucagon-like peptide 1 (GLP-1) mimetics, their effects on the heart are of interest. METHODS: We aimed to investigate longitudinal relationships between plasma levels of fasting GLP-1 (fGLP-1), 60-min oral glucose tolerance test-stimulated GLP-1 levels (60GLP-1), and the dynamic GLP-1 response after oral glucose tolerance test (DeltaGLP-1 = 60GLP-1 - fGLP-1) and incidence of hospitalized congestive heart failure, during a follow-up time of a maximum of 9.8 years in 71-year-old men. We also investigated, cross-sectionally, the association between GLP-1 and left ventricular function as estimated by echocardiography. R: During the follow-up period, 16 of 290 participants with normal glucose tolerance experienced a congestive heart failure event (rate 0.7/100 person-years at risk), as did eight of 136 participants (rate 0.8/100 person-years at risk) with impaired glucose tolerance and nine of 72 participants (rate 1.7/100 person-years at risk) with Type 2 diabetes mellitus. Although GLP-1 concentrations did not predict congestive heart failure (fGLP-1: HR 0.98, 95% CI 0.4-2.4; 60GLP-1: HR 1.1, 95% CI 0.4-2.6; DeltaGLP-1: HR 0.9, 95% CI 0.3-2.3), there was an association between left ventricular diastolic function (E/A ratio) and fGLP-1 (r = 0.19, P = 0.001), 60GLP-1 (r = 0.20, P < 0.001) and DeltaGLP-1 (r = 0.18, P = 0.004). There was a lack of differences in plasma levels of GLP-1 between the groups with Type 2 diabetes and normal glucose tolerance. CONCLUSIONS: There were no longitudinal associations between GLP-1 levels and incidence of hospitalization for congestive heart failure. However, without any causality proven, GLP-1 levels did correlate, cross-sectionally, with left ventricular diastolic function in this cohort, suggesting that pathways including GLP-1 might be involved in the regulation of cardiac diastolic function. PMID- 21309839 TI - Modification and validation of the Revised Diabetes Knowledge Scale. AB - OBJECTIVES: To develop a simplified true/false response format of the Revised Diabetes Knowledge Scale and assess scaling assumptions, reliability and validity of the binary response format (the Simplified Diabetes Knowledge Scale) and compare with a multiple-choice version. METHODS: Ninety-nine respondents attending an outpatient clinic completed the multiple-choice version of the Revised Diabetes Knowledge Scale and the simplified version of the Revised Diabetes Knowledge Scale. The response patterns and psychometric properties of both questionnaires were assessed in order to test the construct validity of the simplified version. RESULTS: The mean age of the respondents was 57 years (range 21-83 years) and 64% were men. Respondents attained an average score of 65% on the Simplified Diabetes Knowledge Scale, compared with 62% on the Revised Diabetes Knowledge Scale. Overall, the Simplified Diabetes Knowledge Scale appeared to be somewhat easier to complete compared with the Revised Diabetes Knowledge Scale, as indicated by the number of missing responses. CONCLUSIONS: The Simplified Diabetes Knowledge Scale provides researchers with a brief and simple diabetes knowledge questionnaire with favourable psychometric properties. The scale may require further updating to include other items relevant to diabetes education. This simplified version will now undergo translation and validation for use among minority ethnic groups resident in the UK. PMID- 21309837 TI - Characterizing sudden death and dead-in-bed syndrome in Type 1 diabetes: analysis from two childhood-onset Type 1 diabetes registries. AB - AIMS: Type 1 diabetes mellitus increases the risk for sudden unexplained death, generating concern that diabetes processes and/or treatments underlie these deaths. Young (< 50 years) and otherwise healthy patients who are found dead in bed have been classified as experiencing 'dead-in-bed' syndrome. METHODS: We thus identified all unwitnessed deaths in two related registries (the Children's Hospital of Pittsburgh and Allegheny County) yielding 1319 persons with childhood onset (age < 18 years) Type 1 diabetes diagnosed between 1965 and 1979. Cause of death was determined by a Mortality Classification Committee (MCC) of at least two physician epidemiologists, based on the death certificate and additional records surrounding the death. RESULTS: Of the 329 participants who had died, the Mortality Classification Committee has so far reviewed and assigned a final cause of death to 255 (78%). Nineteen (8%) of these were sudden unexplained deaths (13 male) and seven met dead-in-bed criteria. The Mortality Classification Committee adjudicated cause of death in the seven dead-in-bed persons as: diabetic coma (n =4), unknown (n=2) and cardiomyopathy (n=1, found on autopsy). The three dead-in bed individuals who participated in a clinical study had higher HbA(1c) , lower BMI and higher daily insulin dose compared with both those dying from other causes and those surviving. CONCLUSIONS: Sudden unexplained death in Type 1 diabetes seems to be increased 10-fold and associated with male sex, while dead in-bed individuals have a high HbA(1c) and insulin dose and low BMI. Although sample size is too small for definitive conclusions, these results suggest specific sex and metabolic factors predispose to sudden unexplained death and dead-in-bed death. PMID- 21309840 TI - Progression to insulin deficiency in Korean patients with Type 2 diabetes mellitus positive for anti-GAD antibody. AB - AIMS: To investigate the rate of progression to insulin deficiency in Korean patients with Type 2 diabetes mellitus positive for anti-GAD antibody (GADA) and to determine the factors related to progression to insulin deficiency. METHODS: We retrospectively analysed data on 87 GADA-positive and 87 age- and sex-matched GADA-negative patients with Type 2 diabetes. GADA-positive patients were further subclassified into high-titre (>= 250 WHO units/ml) (n = 24) and low-titre (< 250 WHO units/ml) (n = 63) subgroups. Cox proportional hazard analysis was used to identify factors associated with progression to insulin deficiency. RESULTS: Over a period of 6 years, two of 87 (2.3%) GADA-negative and 37 of 87 (42.5%) GADA positive patients had progressed to insulin deficiency. The rate of progression to insulin deficiency was higher in the high-titre than in the low-titre subgroup (75.0 vs. 30.2%). Multivariate analysis in GADA-positive patients showed that high-titre GADA and low BMI at diagnosis were independent factors significantly related to progression to insulin deficiency. CONCLUSIONS: The presence of GADA predicted the progression to insulin deficiency in Korean patients with Type 2 diabetes. In GADA-positive patients, high-titre GADA and low BMI were associated with this progression. PMID- 21309841 TI - Improved quality of Type 2 diabetes care following electronic feedback of treatment status to general practitioners: a cluster randomized controlled trial. AB - AIMS: To evaluate the effect of an electronic feedback system to general practitioners on quality of Type 2 diabetes care. METHODS: A cluster randomized, controlled trial with 15 months follow-up. Eighty-six general practices (158 general practitioners) in a Danish county caring for 2458 people 40-70 years old with Type 2 diabetes were randomized to receive or not to receive electronic feedback on quality of care. People with Type 2 diabetes were identified using a validated algorithm. Primary end-points were processes of care according to guidelines on prescriptions redeemed for Type 2 diabetes treatments, measuring of glycated haemoglobin and cholesterol and visits to ophthalmologists. Secondary end-points were changes in level of glycated haemoglobin and serum cholesterol. Data were analysed using generalized linear models accounting for clustering at practice level. RESULTS: During follow-up, people with Type 2 diabetes in the intervention group more often redeemed recommended prescriptions than people in the control group, respectively, as follows: oral antidiabetic treatment (32.8 vs. 12.0%, P =0.002), insulin treatment (33.8 vs. 12.4%, P < 0.001), lipid-lowering medication (38.3 vs. 18.6%, 0.004) and blood pressure medication (27.6 vs. 16.3%, P = 0.026). There were no differences in mean glycated haemoglobin and serum cholesterol between the two groups. CONCLUSIONS: Electronic feedback to general practitioners on the quality of Type 2 diabetes care resulted in significantly improved quality regarding processes of care according to guidelines. It was not possible to demonstrate any effect on secondary end-point measures within the follow-up period. Electronic feedback on quality of diabetes care can be effective in improving adherence to treatment according to evidence-based guidelines. PMID- 21309842 TI - Liraglutide improves treatment satisfaction in people with Type 2 diabetes compared with sitagliptin, each as an add on to metformin. AB - AIMS: Patient-reported outcomes from clinical trials offer insight into the impact of disease on health-related quality of life, including treatment satisfaction. This patient-reported outcomes evaluation was a substudy of a 26 week randomized, open-label trial comparing the once-daily injectable human GLP-1 analogue liraglutide with once-daily oral sitagliptin, both added to metformin. The patient reported outcomes substudy aimed to evaluate treatment satisfaction using the Diabetes Treatment Satisfaction Questionnaire (DTSQ) at baseline and 26 weeks. METHODS: In the main 26-week randomized, open-label study (n =658), liraglutide, 1.2 or 1.8 mg, injected with a pen, led to greater HbA1c reduction than oral sitagliptin, 100 mg once daily, both added to metformin = 1500 mg daily: mean HbA1c reduction was 1.5, 1.2 and 0.9% (7, 10 and 14 mmol/mol) for liraglutide 1.8 mg, 1.2 mg and sitagliptin, respectively (P < 0.0001 for both liraglutide doses vs. sitagliptin) and liraglutide patients lost more weight (3 vs.1 kg; P < 0.0001). In this patient-reported outcomes substudy (liraglutide 1.8 mg, n = 171; 1.2 mg, n = 164; sitagliptin, n = 170) DTSQ scores were analyzed by ANCOVA with treatment and country as fixed effects and baseline value as covariate. RESULTS: Overall treatment satisfaction, calculated by adding satisfaction scores for 'current treatment', 'convenience', 'flexibility', 'understanding', 'recommend', and 'continue', improved in all groups at 26 weeks; greater improvement with liraglutide (4.35 and 3.51 vs. 2.96; P = 0.03 for liraglutide 1.8 mg vs. sitagliptin) may reflect greater HbA1c reduction and weight loss. Patients perceived themselves to be hyperglycaemic significantly less frequently with liraglutide 1.8 mg (difference = -0.88; P < 0.0001) and 1.2 mg ( -0.49; P = 0.01). Perceived frequency of hypoglycaemia was similar across all groups. CONCLUSIONS: Injectable liraglutide may lead to greater treatment satisfaction than oral sitagliptin, potentially by facilitating greater improvement in glycaemic control, weight loss and/ or perception of greater treatment efficacy. PMID- 21309843 TI - Deprivation impedes success of insulin intensification in children and adolescents with Type 1 diabetes; longitudinal linear mixed modelling of a retrospective observational cohort. AB - AIMS: To examine the relationship between social deprivation, intensification of insulin therapy (>= three injections per day) and diabetes control in children and adolescents. METHODS: We performed a longitudinal observational study of 283 children and adolescents with Type 1 diabetes from three UK paediatric centres from 2005 to 2007. We used linear mixed modelling to identify the contribution of the Index of Multiple Deprivation 2004, insulin regimen and demographic factors in explaining longitudinal differences in HbA(1c) levels. RESULTS: Overall mean HbA(1c) levels were 8.9% [sd 1.4, 74 mmol/mol (8 mmol/mol)]. Prescribing of intensive therapy increased from 49.2 to 70.1% (chi(2) = 32.9, P < 0.001), but there was no corresponding improvement in HbA(1c) levels. Those from more educationally deprived backgrounds were less likely to be started on intensive therapy (P = 0.04). In linear mixed modelling, factors independently associated with poor metabolic control were greater social deprivation (P = 0.01), particularly lower educational levels (P = 0.006), and non-White ethnicity (P = 0.04). Nested terms analysis showed that increased deprivation interacted with non-White ethnicity (P = 0.009) and with intensive insulin therapy (P = 0.03) to result in poorer metabolic control. In a subgroup intensified from conventional regimens during follow-up (n = 75), greater social deprivation was associated with least success of intensive therapy (P = 0.02). CONCLUSIONS: Social deprivation was associated with low uptake and poor success of insulin intensification and this appeared to be largely mediated via lower educational levels. PMID- 21309845 TI - Frequency of symptomatic and asymptomatic hypoglycaemia in Type 1 diabetes: effect of impaired awareness of hypoglycaemia. AB - AIMS: To characterize the frequency and the nature (symptomatic vs. asymptomatic) of hypoglycaemia in people with Type 1 diabetes with impaired awareness of hypoglycaemia. METHODS: A group of 19 patients with Type 1 diabetes with normal hypoglycaemia awareness were matched for age, sex, duration of diabetes and glycaemic control with 19 patients with impaired awareness of hypoglycaemia. Frequency of severe hypoglycaemia in the preceding year was estimated retrospectively. Capillary blood glucose was monitored prospectively four times daily, over a 4-week period. All blood glucose values < 3 mmol/l were recorded and classified by symptom response. RESULTS: The patients with impaired awareness of hypoglycaemia exhibited twice the frequency of all episodes of hypoglycaemia over the 4-week monitoring period than those with normal awareness (mean +/-sd 7.9 +/- 5.4 vs. 3.7 +/- 3.6, P = 0.003). No differences between the two subgroups were observed in the total number of symptomatic hypoglycaemia episodes (4.2 +/- 3.3 vs. 3.2 +/- 3.4, P = 0.25). The group with impaired awareness of hypoglycaemia had a sevenfold higher incidence of asymptomatic hypoglycaemia than those with normal awareness (3.7 +/- 5.3 vs. 0.5 +/- 1.2, P = 0.001); these episodes comprised 47% of all glucose values < 3.0 mmol/l in this group, compared with 14% in the normal awareness group. The annual prevalence of severe hypoglycaemia for patients with impaired awareness of hypoglycaemia was 53% compared with 5% for patients with normal awareness, and these patients had a significantly higher incidence of severe events (1.6 +/- 2.8 vs. 0.1 +/- 0.3, P = 0.001). CONCLUSIONS: Adults with Type 1 diabetes who have impaired awareness of hypoglycaemia are exposed to a much higher incidence of asymptomatic hypoglycaemia than those with normal awareness and are at higher risk of developing severe hypoglycaemia. PMID- 21309844 TI - Retinal microaneurysm count predicts progression and regression of diabetic retinopathy. Post-hoc results from the DIRECT Programme. AB - OBJECTIVE: To study the association between baseline retinal microaneurysm score and progression and regression of diabetic retinopathy, and response to treatment with candesartan in people with diabetes. METHODS: This was a multicenter randomized clinical trial. The progression analysis included 893 patients with Type 1 diabetes and 526 patients with Type 2 diabetes with retinal microaneurysms only at baseline. For regression, 438 with Type 1 and 216 with Type 2 diabetes qualified. Microaneurysms were scored from yearly retinal photographs according to the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Retinopathy progression and regression was defined as two or more step change on the ETDRS scale from baseline. Patients were normoalbuminuric, and normotensive with Type 1 and Type 2 diabetes or treated hypertensive with Type 2 diabetes. They were randomized to treatment with candesartan 32 mg daily or placebo and followed for 4.6 years. RESULTS: A higher microaneurysm score at baseline predicted an increased risk of retinopathy progression (HR per microaneurysm score 1.08, P < 0.0001 in Type 1 diabetes; HR 1.07, P = 0.0174 in Type 2 diabetes) and reduced the likelihood of regression (HR 0.79, P < 0.0001 in Type 1 diabetes; HR 0.85, P = 0.0009 in Type 2 diabetes), all adjusted for baseline variables and treatment. Candesartan reduced the risk of microaneurysm score progression. CONCLUSIONS: Microaneurysm counts are important prognostic indicators for worsening of retinopathy, thus microaneurysms are not benign. Treatment with renin-angiotensin system inhibitors is effective in the early stages and may improve mild diabetic retinopathy. Microaneurysm scores may be useful surrogate endpoints in clinical trials. PMID- 21309846 TI - Exercise treadmill testing in patients with claudication, with and without diabetes. AB - AIM: To compare symptoms and walking capacities of patients with and without diabetes reporting vascular-type claudication. METHODS: We recorded self-reported maximal walking distance, maximal walking distance on treadmill test (3.2 km h( 1) , 10% slope), exercise transcutaneous oxygen pressure DROP index [limb transcutaneous oxygen pressure (TcpO2) changes from rest minus chest TcpO2 changes from rest] and symptoms on treadmill in 230 patients with diabetes and 982 patients without diabetes. Exercise-induced proximal and distal symptoms were analysed in the perspective of underlying proximal and distal ischaemia (DROP value < negative 15 mmHg). RESULTS: Self-reported maximal walking distance did not differ between groups, whereas maximal walking distance on treadmill test was lower in patients with diabetes vs. patients without diabetes (261 +/- 257 and 339 +/- 326 m, respectively; P < 0.05 when adjusted for potential confounders). In patients with ischaemia, the number of ischaemic areas (proximal and/or distal on right and/or left) was comparable between the two groups. Patients with diabetes had more distal ischaemia than patients without diabetes (38 vs. 29%, respectively; P < 0.01), whereas proximal ischaemia was similar between groups. The prevalence of lower-limb exercise-related symptoms without ischaemia was comparable between groups. There were more symptoms other than lower-limb pain in patients with diabetes than patients without diabetes (29.6 vs. 18.3%, respectively; P < 0.01). CONCLUSIONS: Patients with diabetes show more severe limitation on the treadmill and more non-limb symptoms than patients without diabetes, although self-reported walking capacity is comparable between the two groups. Using TcpO2, we confirm that patients with diabetes reporting claudication show more distal ischaemia than patients without diabetes, with no difference at the buttock level. Treadmill testing is of interest in patients with peripheral artery disease and diabetes. PMID- 21309847 TI - Impact of personalized cardiovascular disease risk estimates on physical activity a randomized controlled trial. AB - AIM: Informing a person of their individual risk of developing a disease in the future may be sufficient to provide the person with the impetus to adopt risk reducing behaviours. The aim of this study was to determine if a personalised 10 year cardiovascular disease (CVD) risk estimate can increase physical activity and other risk reduction behaviours in adults at high risk of CVD. METHODS: Pilot 2 * 2 factorial randomised controlled trial conducted in Oxfordshire, UK including 194 adults at increased CVD risk (10-year CVD risk >= 20%) recruited from four general practices. Main outcome measure at one month was physical activity measured by accelerometer. RESULTS: Median (IQR) age was 62.3 (54.9, 66.1) years, 67% were men and 19% had known diabetes. Mean (SD) total accelerometer counts per day was 297 * 10(-3) (110 * 10(-3) ) and activity of moderate or greater intensity was undertaken for 53 (22) minutes per day. In the 185 (95%) participants attending follow-up an increase in physical activity was not seen. There was a non-significant 0.5% (p = 0.56) greater increase in accelerometer counts in those receiving personalised CVD risk estimates. No significant within or between group changes were seen at one month in estimated 10-year CVD risk. A net 7% decrease in mean LDL cholesterol (p = 0.004) was seen in the intervention group despite similar increases in new prescriptions for lipid lowering therapies. CONCLUSION: In adults at increased risk of CVD provision of personalised 10-year CVD risk estimates did not appear to increase physical activity or estimated CVD risk over a one-month period. PMID- 21309849 TI - From children to young adults: cystic fibrosis and siblingship: a longitudinal study. AB - AIM: To compare the results from our previous study in 1994/95 of children with cystic fibrosis (CF) at the age of 6-14 years and their healthy siblings with data from the same participants as young adults in regard to their self-esteem, life satisfaction and attitudes towards the CF siblingship situation. METHODS: Thirty-seven sibling pairs participated. Three instruments were used: The 'As I see myself' self-evaluation questionnaire; the 'Ladder of life', assessing life satisfaction; and the 'Sibling Mirror', reflecting a person's feelings, when one's sibling or oneself has CF. RESULTS: Contrary to 1994/95 study results, the female participants showed no signs of impaired self-esteem. Concerning life satisfaction, women in both groups and the men with CF have lower ratings than a healthy reference group. Individuals with CF look upon themselves today as independent, thoughtful and mature, but remember themselves as being active, spoiled or fussy. Healthy siblings consider themselves diplomatic, responsible, mature, important and loyal but remember themselves as angry, envious and neglected. CONCLUSION: The self-esteem of women in the sibling pairs (whether with CF or healthy sisters) has improved since their childhood. Overall, the results indicate that young adults with CF today are medically well controlled and psychosocially well adapted, albeit aware of their precarious future. PMID- 21309850 TI - The role of botanic gardens in the science and practice of ecological restoration. AB - Many of the skills and resources associated with botanic gardens and arboreta, including plant taxonomy, horticulture, and seed bank management, are fundamental to ecological restoration efforts, yet few of the world's botanic gardens are involved in the science or practice of restoration. Thus, we examined the potential role of botanic gardens in these emerging fields. We believe a reorientation of certain existing institutional strengths, such as plant-based research and knowledge transfer, would enable many more botanic gardens worldwide to provide effective science-based support to restoration efforts. We recommend botanic gardens widen research to include ecosystems as well as species, increase involvement in practical restoration projects and training practitioners, and serve as information hubs for data archiving and exchange. PMID- 21309851 TI - A landholder-based approach to the design of private-land conservation programs. AB - Many ecosystems exist primarily, or solely, on privately owned (freehold) or managed (leasehold) land. In rural and semirural areas, local and regional government agencies are commonly responsible for encouraging landholders to conserve native vegetation and species on these private properties. Yet these agencies often lack the capacity to design and implement conservation programs tailored to rural and semirural landholdings and instead offer one program to all landholders. Landholders may elect not to participate because the program is irrelevant to their property or personal needs; consequently, vegetation retention objectives may not be achieved. We differentiated landholders in Queensland, Australia, according to whether they derived income from the land (production landholders) or not (nonproduction landholders). We compared these two groups to identify similarities and differences that may inform the use of policy instruments (e.g., voluntary, economic, and regulatory) in conservation program design. We interviewed 45 landholders participating in three different conservation agreement programs (price-based rate [property tax] rebate; market based tender; and voluntary, permanent covenant). Production landholders were more likely to participate in short-term programs that offered large financial incentives that applied to <25% of their property. Nonproduction landholders were more likely to participate in long-term programs that were voluntary or offered small financial incentives that applied to >75% of their property. These results may be explained by significant differences in the personal circumstances of production and nonproduction landholders (income, education, health) and differences in their norms (beliefs about how an individual is expected to act) and attitudes. Knowledge of these differences may allow for development of conservation programs that better meet the needs of landholders and thus increase participation in conservation programs and retention of native vegetation. PMID- 21309852 TI - Rights, governance, and conservation of biological diversity. PMID- 21309853 TI - Effects of management of domestic dogs and recreation on carnivores in protected areas in northern California. AB - In developed countries dogs (Canis lupus familiaris) are permitted to accompany human visitors to many protected areas (e.g., >96% of protected lands in California, U.S.A.), and protected-area management often focuses on regulating dogs due to concerns about predation, competition, or transmission of disease and conflicts with human visitors. In 2004 and 2005, we investigated whether carnivore species richness and abundance were associated with management of domestic dogs and recreational visitation in protected areas in northern California. We surveyed for mammalian carnivores and human visitors in 21 recreation areas in which dogs were allowed offleash or onleash or were excluded, and we compared our observations in the recreation areas with observations in seven reference sites that were not open to the public. Carnivore abundance and species richness did not differ among the three types of recreation areas, but native carnivore species richness was 1.7 times greater (p < 0.01) and the relative abundances of native coyotes (Canis latrans) and bobcats (Lynx rufus) were over four times greater (p < 0.01) in the reference sites. Abundances of bobcats and all carnivores declined as the number of visitors increased. The policy on domestic dogs did not appear to affect species richness and abundance of mammalian carnivores. But the number of dogs we observed was strongly associated with human visitation (R(2) = 0.54), so the key factors associated with recreational effects on carnivores appear to be the presence and number of human visitors to protected areas. PMID- 21309854 TI - Does occlusion duration influence procedural and clinical outcome of patients who underwent percutaneous coronary intervention for chronic total occlusion? AB - BACKGROUND: Previous studies have reported that the indeterminable aging and long duration occlusion are associated with procedural failure and adverse long-term outcome. We aimed to investigate the clinical impact of occlusion duration in a consecutive series of patients who underwent percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) lesions. METHODS AND RESULTS: From October 2005 to June 2009, a total of 303 patients with 328 CTO lesions were consecutively treated achieving a success rate of 86.3%. The average of occlusion duration estimated in 62.5% of cases (known occlusion duration [KOD] patients, n = 188) was 29.8 +/- 41.3 months. In the remaining 37.5% of cases, the occlusion duration was indeterminate (indetermination of occlusion duration [IOD] patients, n = 115). No influence of duration in procedural outcome was observed. Moreover, no differences of 1-year major adverse cardiac events (MACE) were observed between KOD and IOD patients. The multivariate COX regression analysis identified diabetes mellitus and multivessel coronary disease as independent predictors of 12-month MACE (HR 5.023; 95% CI 0.164-9.653; P = 0.025 and HR 0.801; 95% CI 0.109 0.909, P = 0.033). The analysis did not show any influence of IOD and long occlusion duration in the occurrence of MACE. Predictors of angiographic failure recognized with multivariate binary logistic were vessel diameter <2.5 mm (OR 5.3; 95% CI 1.19-8.91; P = 0.02), CTO length >20 mm (OR 6.3; 95% CI 1.22-9.54; P = 0.02), and severe calcification (OR 3.2; 95% CI 1.62-5.51; P = 0.03). CONCLUSION: IOD and long duration of CTO do not affect procedural and clinical outcome of patients who underwent CTO PCI. This marks the importance of considering PCI treatment, a reliable strategy in cases of IOD or long occlusion duration. PMID- 21309855 TI - A meta-analysis of Th2 pathway genetic variants and risk for allergic rhinitis. AB - There is a significant genetic contribution to allergic rhinitis (AR). Genetic association studies for AR have been performed, but varying results make it challenging to decipher the overall potential effect of specific variants. The Th2 pathway plays an important role in the immunological development of AR. We performed meta-analyses of genetic association studies of variants in Th2 pathway genes and AR. PubMed and Phenopedia were searched by double extraction for original studies on Th2 pathway-related genetic polymorphisms and their associations with AR. A meta-analysis was conducted on each genetic polymorphism with data meeting our predetermined selection criteria. Analyses were performed using both fixed and random effects models, with stratification by age group, ethnicity, and AR definition where appropriate. Heterogeneity and publication bias were assessed. Six independent studies analyzing three candidate polymorphisms and involving a total of 1596 cases and 2892 controls met our inclusion criteria. Overall, the A allele of IL13 single nucleotide polymorphism (SNP) rs20541 was associated with increased odds of AR (estimated OR=1.2; 95% CI 1.1-1.3, p-value 0.004 in fixed effects model, 95% CI 1.0-1.5, p-value 0.056 in random effects model). The A allele of rs20541 was associated with increased odds of AR in mixed age groups using both fixed effects and random effects modeling. IL13 SNP rs1800925 and IL4R SNP 1801275 did not demonstrate overall associations with AR. We conclude that there is evidence for an overall association between IL13 SNP rs20541 and increased risk of AR, especially in mixed-age populations. PMID- 21309856 TI - Diagnosis of drug hypersensitivity in children and adolescents: discrepancy between physician-based assessment and results of testing. AB - BACKGROUND: Diagnosis of drug hypersensitivity is often based on history alone. But such a vague diagnosis may cause limitations of therapeutic options in the future. To confirm or rule out drug hypersensitivity, skin testing, in vitro studies, and challenge tests are necessary. However, the diagnostic value of this complex and time-consuming allergologic work-up, especially in children, remains controversial. OBJECTIVE: Aim of this retrospective analysis was to compare the results of diagnostic testing in children and adolescents with drug hypersensitivity diagnosed on clinical grounds, i.e., temporal relationship and observation of symptoms alone. METHODS: We studied 43 children and adolescents (23 females, 20 males, mean age 13) with a history of immediate or delayed hypersensitivity symptoms in temporal relation to drug treatment using standardized skin testing followed by oral challenges. Patients with suspected penicillin hypersensitivity were further evaluated with in vitro tests. RESULTS: Drug hypersensitivity was excluded in 40 patients by tolerated oral challenge tests with the incriminated drug. In two patients, positive challenge tests confirmed non-steroidal anti-inflammatory drug hypersensitivity. One patient with amoxicillin-associated exanthema developed positive late skin test reactions to aminopenicillins. CONCLUSION: In childhood and adolescence, allergologic testing in cases of suspected drug hypersensitivity is of importance both to establish a correct diagnosis and to prevent unjustified withholding of a drug or class of drugs. PMID- 21309857 TI - Training of trainers on epinephrine autoinjector use. AB - The majority of physicians do not know how to use epinephrine autoinjectors. This displays that current education of physicians on anaphylaxis is inadequate for a thorough practice. We hypothesize that a theoretical lecture together with a practical session on epinephrine autoinjector use will improve its proper use by physicians. Residents, specialists, and consultants from General Pediatrics excluding allergists and allergy fellows were included in this study. All physicians were given an eight-item questionnaire followed by a practical session scoring and timing ability to use epinephrine autoinjector trainer. This ensued with one-to-one hands-on training on correct autoinjector use. Finally, a joint theoretical lecture on anaphylaxis including re-demonstration of epinephrine autoinjector use was given. All physicians were scored a second time on use of epinephrine autoinjector 6 months later. One hundred fifty-one of 196 participants completed all steps of the study in four tertiary hospitals. Correct use of epinephrine autoinjector improved from 23.3% to 74.2%, mean score from 3.49 +/- 1.14 to 4.66 +/- 0.65, need for prospectus from 91.4% to 29.1%, and mean time to administer autoinjector from 28.01 +/- 6.22 s to 19.62 +/- 5.01 s (p < 0.001 for each). The rate of most common mistakes during autoinjector use decreased but the ranking did not change. An integrated theoretical and practical education increased correct of epinephrine autoinjector use by physicians. Ongoing mistakes despite this education may be related with its design. PMID- 21309858 TI - Effect of bovine bone and collagen membranes on healing of mandibular bone blocks: a prospective randomized controlled study. AB - AIM: The aim of the present study was to evaluate if the use of deprotenized bovine bone mineral (DBBM) and collagen barrier membranes (CM) in combination with mandibular bone block grafts could reduce bone block graft resorption during healing. METHODS: A prospective randomized controlled study has been designed. Twenty-two ridges presenting horizontal alveolar deficiency (crest width <4 mm) and at least two adjacent missing teeth were included in the study. In the control group, one or multiple mandibular blocks were used to gain horizontal augmentation of the ridge. In the test group, DBBM granules were added at the periphery and over the graft. The reconstructions were covered by two layers of CM. Implants were placed 4 months after grafting. Direct measurements of crest width were performed before and immediately after bone augmentation, and immediately before implant placement. RESULTS: Statistical analysis showed no significant differences in crest width between test and control groups at baseline and immediately after grafting. Mean augmentation at first surgery in the test group was 4.18 vs. 4.57 mm in the control group. Final gain obtained at the time of implant placement was 3.93 mm in the test and 3.67 mm in the control groups. The difference in mean graft resorption between test and control sites was statistically significant (0.25 mm in the test group vs. 0.89 mm in the control group, P=0.03). Complications seem to occur more often in the test group (complications recorded in three cases in the test group vs. one complication recorded in the control group). In all cases, implants could be placed in the planned sites and a total of 55 implants were placed (28 in the test group and 27 in the control group). All implants could be considered successfully integrated at the 24-month follow-up visit. CONCLUSION: The results from this study showed that the addition of bovine bone mineral and a CM around and over a mandibular bone block graft could minimize graft resorption during healing. On the other hand, the use of bone substitutes and barrier membranes in combination with block grafts increased the frequency of complications and the difficulty of their management. PMID- 21309859 TI - Vertical and horizontal ridge alterations after tooth extraction in the dog: flap vs. flapless surgery. AB - OBJECTIVE: To compare ridge alterations after flap and flapless tooth extraction in the vertical and horizontal dimension in the dog model. MATERIAL AND METHODS: This study was carried out on five Beagle dogs. Four extractions were performed in the lower jaw of each dog (two per side. Pm3, Pm4). At the time of tooth extraction, flap surgery was performed on one side (control group). On the contra lateral side, a flapless extraction was performed (test group). Mesial sockets were left untreated on both sides. After 3 months of healing, the dogs were sacrificed and prepared for histological analysis. RESULTS: Ten samples were evaluated on each group. The vertical difference in height between the buccal and lingual crest was 1.48 mm for the flap, and 1.22 mm for the flapless group. The horizontal dimension of the ridge was 4.41 mm (at 1 mm from the crest), 5.72 mm (at 3 mm from the crest) and 6.67 mm (at 5 mm form the crest) in the flap group. In the flapless group, the measurements were 4.5, 5.58 mm and 6.44 at 1, 3 and 5 mm from the crest, respectively. CONCLUSION: Evaluating ridge alterations in the vertical and horizontal dimension after 3 months of healing following tooth extraction, results for the flap and the flapless group were very similar. PMID- 21309860 TI - Outcome of surgical treatment of peri-implantitis: results from a 2-year prospective clinical study in humans. AB - AIM: The aim of the present study was to evaluate the outcome of a surgical procedure based on pocket elimination and bone re-contouring for the treatment of peri-implantitis. MATERIAL AND METHODS: The 31 subjects involved in this study presented clinical signs of peri-implantitis at one or more dental implants (i.e. >=6 mm pockets, bleeding on probing and/or suppuration and radiographic evidence of >=2 mm bone loss). The patients were treated with a surgical procedure based on pocket elimination and bone re-contouring and plaque control before and following the surgery. At the time of surgery, the amount of bone loss at implants was recorded. RESULTS: Two years following treatment, 15 (48%) subjects had no signs of peri-implant disease; 24 patients (77%) had no implants with a probing pocket depth of >=6 mm associated with bleeding and/or suppuration following probing. A total of 36 implants (42%) out of the 86 with initial diagnosis of peri-implantitis presented peri-implant disease despite treatment. The proportion of implants that became healthy following treatment was higher for those with minor initial bone loss (2-4 mm bone loss as assessed during surgery) compared with the implants with a bone loss of >=5 mm (74% vs. 40%). Among the 18 implants with bone loss of >=7 mm, seven were extracted. Between the 6-month and the 2-year examination, healthy implants following treatment tended to remain stable, while deepening of pockets was observed for those implants with residual pockets. CONCLUSION: The results of this study indicated that a surgical procedure based on pocket elimination and bone re-contouring and plaque control before and following surgery was an effective therapy for treatment of peri implantitis for the majority of subjects and implants. However, complete disease resolution at the site level seems to depend on the initial bone loss at implants. Implants with no signs of peri-implantitis following treatment tended to remain healthy during the 2-year period, while a tendency for disease progression was observed for the implants that still showed signs of peri-implant disease following treatment. PMID- 21309861 TI - Prophylactic agents and bacterial adherence to titanium. AB - AIMS: An evaluation was made of surface alterations of commercially pure titanium and Ti6Al4V alloy caused by fluoride at the concentration present in dentifrices and oral mouth washes (1500 ppm), and by prophylactic use of airborne particle abrasion with bicarbonate of soda. MATERIALS AND METHODS: For each material, 60 pre-fabricated disk-shaped test specimens with industrial metallographic finish, measuring 5 mm in diameter and 3 mm thick, were divided into four groups, according to the storage solutions: artificial saliva pH 7.0 (G1), fluoridated artificial saliva pH 5.5 (G2), airborne particle abrasion with bicarbonate of sodium (G3), airborne particle abrasion with bicarbonate of sodium followed by storage in fluoridated artificial saliva (G4). The surface roughness (Ra) was measured with a profilometer, before and after the storage periods. Afterwards, the test specimens were submitted to Streptococcus mutans adherence. RESULTS: A statistically significant reduction in surface roughness was observed in commercially pure titanium in G1, G4 and in Ti6Al4V alloy, G1, G2, G4, and no statistically significant reduction in G3. DISCUSSION: With a mean initial roughness surface of Ra=0.2 MUm, fluoride promoted homogenization. Microscopy images confirmed these results. In the groups without significant homogenization, S. mutans adherence was greater, whereas it was lower in the groups in which the test specimens were stored previously in fluoridated saliva. CONCLUSION: The greater homogenization that occurred, as well as the antimicrobial effect of fluoride, proved that bacterial adherence and effects of fluoride were both dependent on the roughness of the surface topography. PMID- 21309862 TI - External validation of the proposed T and N categories of squamous cell carcinoma of the penis. AB - OBJECTIVES: The aim of this study was to validate recently proposed modifications to the current TNM classification of penile squamous cell carcinoma (PSCC) by using data from four German urological centers. METHODS: We identified 89 patients treated for histologically confirmed PSCC between 1996 and 2008 and reclassified them according to the proposed TNM staging revisions. The proposed changes restricted T2 to tumoral invasion of the corpus spongiosum, whereas invasion of the corpus cavernosum was considered as T3. No changes were made to T1 and T4. Furthermore, N1 was limited to unilateral and N2 to bilateral inguinal lymph node involvement regardless of their number. Pelvic lymph node involvement and fixed lymph node were considered as N3 tumors. The range of follow up after initial treatment was 1-142 months (mean 38). RESULTS: Node-negative cases following the current classification were 65.2% (30/46), 48.5% (16/33) and 87.5% (7/8) for T1, T2 and T3, respectively. According to the proposed classification, N0 cases were markedly reduced in the T3 group (55.5%, 10/18) and relatively changed in the T2 group (56.5%, 13/23). T4 patients had no negative disease status. The 3-year disease-specific survival (DSS) rates for the proposed categories were 85.4%, 71.6% and 62.4% for T1, T2 and T3, respectively. For the current categories, the 3-year DSS rates were 85.4%, 66.9% and 100% for T1, T2 and T3, respectively. The 3-year DSS of the current N categories was 78.7%, 51% and 13.3% for N1, N2 and N3, respectively. According to the newly proposed categories, the 3-year DSS was 70%, 50% and 13.3% for N1, N2 and N3, respectively. CONCLUSION: Tumor and nodal staging of the newly proposed TNM classification show a more distinctive survival compared to the current one. However, a multi-institutional validation is still required to further corroborate the proposed modifications. PMID- 21309863 TI - Does obesity really protect against psychological distress? Examining the 'fat jolly' versus 'fat-sad' hypotheses using Mendelian randomization. PMID- 21309864 TI - The phosphomimetic mutation of an evolutionarily conserved serine residue affects the signaling properties of Rho of plants (ROPs). AB - Plant ROP (Rho of plants) proteins form a unique subgroup within the family of Rho-type small G-proteins of eukaryotes. In this paper we demonstrate that the phosphomimetic mutation of a serine residue conserved in all Rho proteins affects the signaling properties of plant ROPs. We found that the S74E mutation in Medicago ROP6 and Arabidopsis ROP4 prevented the binding of these proteins to their plant-specific upstream activator the plant-specific ROP nucleotide exchanger (PRONE)-domain-containing RopGEF (guanine nucleotide exchange factor) protein and abolished the PRONE-mediated nucleotide exchange reaction in vitro. Structural modeling supported the hypothesis that potential phosphorylation of the S74 residue interferes with the binding of the PRONE-domain to the adjacent plant-specific R76 residue which plays an important role in functional ROP-PRONE interaction. Moreover, we show that while the binding of constitutively active MsROP6 to the effector protein RIC (ROP-interactive CRIB-motif-containing protein) was not affected by the S74E mutation, the capability of this mutated protein to bind and activate the RRK1 kinase in vitro was reduced. These observations are in agreement with the morphology of tobacco pollen tubes expressing mutant forms of yellow fluorescent protein (YFP):MsROP6. The S74E mutation in MsROP6 had no influence on pollen tube morphology and attenuated the phenotype of a constitutively active form of MsROP6. The presented Medicago and Arabidopsis data support the notion that the phosphorylation of the serine residue in ROPs corresponding to S74 in Medicago ROP6 could be a general principle for regulating ROP activation and signaling in plants. PMID- 21309865 TI - Fatty acid elongase is required for shoot development in rice. AB - Organisms are covered extracellularly with cuticular waxes that consist of various fatty acids. In higher plants, extracellular waxes act as indispensable barriers to protect the plants from physical and biological stresses such as drought and pathogen attacks. However, the effect of fatty acid composition on plant development under normal growth conditions is not well understood. Here we show that the ONION1 (ONI1) gene, which encodes a fatty acid elongase (beta ketoacyl CoA synthase) involved in the synthesis of very-long-chain fatty acids, is required for correct fatty acid composition and normal shoot development in rice. oni1 mutants containing a reduced amount of very-long-chain fatty acids produced very small shoots, with an aberrant outermost epidermal cell layer, and ceased to grow soon after germination. These mutants also showed abnormal expression of a KNOX family homeobox gene. ONI1 was specifically expressed in the outermost cell layer of the shoot apical meristem and developing lateral organs. These results show that fatty acid elongase is required for formation of the outermost cell layer, and this layer is indispensable for entire shoot development in rice. PMID- 21309866 TI - Analysis of short-term changes in the Arabidopsis thaliana glycerolipidome in response to temperature and light. AB - Although the influence of temperature, particularly cold, on lipid metabolism is well established, previous studies have focused on long-term responses and have largely ignored the influence of other interacting environmental factors. Here, we present a time-resolved analysis of the early responses of the glycerolipidome of Arabidopsis thaliana plants exposed to various temperatures (4, 21 and 32 degrees C) and light intensities (darkness, 75, 150 and 400 MUmol m(-2) s(-1)), including selected combinations. Using a UPLC/MS-based lipidomic platform, we reproducibly measured most glycerolipid species reported for Arabidopsis leaves, including the classes phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI) phosphatidylglycerol (PG), monogalactosyldiacylglycerol (MGDG), digalactosyldiacylglycerol (DGDG) and sulfoquinovosyldiacylglycerol (SQDG). In addition to known lipids, we have identified previously unobserved compounds, such as 36-C PGs and eukaryotic phospholipids containing 16:3 acyl chains. Occurrence of these lipid species implies the action of new biochemical mechanisms. Exposition of Arabidopsis plants to various light and temperature regimes results in two major effects. The first is the dependence of the saturation level of PC and MGDG pools on light intensity, likely arising from light regulation of de novo fatty acid synthesis. The second concerns an immediate decrease in unsaturated species of PG at high temperature conditions (32 degrees C), which could mark the first stages of adaptation to heat-stress conditions. Observed changes are discussed in the context of current knowledge, and new hypotheses have been formulated concerning the early stages of the plant response to changing light and temperature conditions. PMID- 21309867 TI - Over-expression of PHO1 in Arabidopsis leaves reveals its role in mediating phosphate efflux. AB - Inorganic phosphate (Pi) homeostasis in multi-cellular eukaryotes depends not only on Pi influx into cells, but also on Pi efflux. Examples in plants for which Pi efflux is crucial are transfer of Pi into the xylem of roots and release of Pi at the peri-arbuscular interface of mycorrhizal roots. Despite its importance, no protein has been identified that specifically mediates phosphate efflux either in animals or plants. The Arabidopsis thaliana PHO1 gene is expressed in roots, and was previously shown to be involved in long-distance transfer of Pi from the root to the shoot. Here we show that PHO1 over-expression in the shoot of A. thaliana led to a two- to threefold increase in shoot Pi content and a severe reduction in shoot growth. (31) P-NMR in vivo showed a normal initial distribution of intracellular Pi between the cytoplasm and the vacuole in leaves over-expressing PHO1, followed by a large efflux of Pi into the infiltration medium, leading to a rapid reduction of the vacuolar Pi pool. Furthermore, the Pi concentration in leaf xylem exudates from intact plants was more than 100-fold higher in PHO1 over expressing plants compared to wild-type. Together, these results show that PHO1 over-expression in leaves leads to a dramatic efflux of Pi out of cells and into the xylem vessel, revealing a crucial role for PHO1 in Pi efflux. PMID- 21309868 TI - Root hair-specific expansins modulate root hair elongation in rice. AB - Root hair growth requires intensive cell-wall modification. This study demonstrates that root hair-specific expansin As, a sub-clade of the cell wall loosening expansin proteins, are required for root hair elongation in rice (Oryza sativa L.). We identified a gene encoding EXPA17 (OsEXPA17) from a rice mutant with short root hairs. Promoter::reporter transgenic lines exhibited exclusive OsEXPA17 expression in root hair cells. The OsEXPA17 mutant protein (OsexpA17) contained a point mutation, causing a change in the amino acid sequence (Gly104 >Arg). This amino acid alteration is predicted to disrupt a highly conserved disulfide bond in the mutant. Suppression of OsEXPA17 by RNA interference further confirmed requirement for the gene in root hair elongation. Complementation of the OsEXPA17 mutant with other root hair EXPAs (OsEXPA30 and Arabidopsis EXPA7) can restore root hair elongation, indicating functional conservation of these root hair EXPAs in monocots and dicots. These results demonstrate that members of the root hair EXPA sub-clade play a crucial role in root hair cell elongation in Graminaceae. PMID- 21309869 TI - The Arabidopsis trithorax-like factor ATX1 functions in dehydration stress responses via ABA-dependent and ABA-independent pathways. AB - Emerging evidence suggests that the molecular mechanisms driving the responses of plants to environmental stresses are associated with specific chromatin modifications. Here, we demonstrate that the Arabidopsis trithorax-like factor ATX1, which trimethylates histone H3 at lysine 4 (H3K4me3), is involved in dehydration stress signaling in both abscisic acid (ABA)-dependent and ABA independent pathways. The loss of function of ATX1 results in decreased germination rates, larger stomatal apertures, more rapid transpiration and decreased tolerance to dehydration stress in atx1 plants. This deficiency is caused in part by reduced ABA biosynthesis in atx1 plants resulting from decreased transcript levels from NCED3, which encodes a key enzyme controlling ABA production. Dehydration stress increased ATX1 binding to NCED3, and ATX1 was required for the increased levels of NCED3 transcripts and nucleosomal H3K4me3 that occurred during dehydration stress. Mechanistically, ATX1 affected the quantity of RNA polymerase II bound to NCED3. By upregulating NCED3 transcription and ABA production, ATX1 influenced ABA-regulated pathways and genes. ATX1 also affected the expression of ABA-independent genes, implicating ATX1 in diverse dehydration stress-response mechanisms in Arabidopsis. PMID- 21309870 TI - Alternative targeting of Arabidopsis plastidic glucose-6-phosphate dehydrogenase G6PD1 involves cysteine-dependent interaction with G6PD4 in the cytosol. AB - Arabidopsis peroxisomes contain an incomplete oxidative pentose-phosphate pathway (OPPP), consisting of 6-phosphogluconolactonase and 6-phosphogluconate dehydrogenase isoforms with peroxisomal targeting signals (PTS). To start the pathway, glucose-6-phosphate dehydrogenase (G6PD) is required; however, G6PD isoforms with obvious C-terminal PTS1 or N-terminal PTS2 motifs are lacking. We used fluorescent reporter fusions to explore possibly hidden peroxisomal targeting information. Among the six Arabidopsis G6PD isoforms only plastid predicted G6PD1 with free C-terminal end localized to peroxisomes. Detailed analyses identified SKY as an internal PTS1-like signal; however, in a medial G6PD1 reporter fusion with free N- and C-terminal ends this cryptic information was overruled by the transit peptide. Yeast two-hybrid analyses revealed selective protein-protein interactions of G6PD1 with catalytically inactive G6PD4, and of both G6PD isoforms with plastid-destined thioredoxin m2 (Trx(m2) ). Serine replacement of redox-sensitive cysteines conserved in G6PD4 abolished the G6PD4-G6PD1 interaction, albeit analogous changes in G6PD1 did not. In planta bimolecular fluorescence complementation (BiFC) demonstrated that the G6PD4-G6PD1 interaction results in peroxisomal import. BiFC also confirmed the interaction of Trx(m2) with G6PD4 (or G6PD1) in plastids, but co-expression analyses revealed Trx(m2) -mediated retention of medial G6PD4 (but not G6PD1) reporter fusions in the cytosol that was stabilized by CxxC113S exchange in Trx(m2) . Based on preliminary findings with plastid-predicted rice G6PD isoforms, we dismiss Arabidopsis G6PD4 as non-functional. G6PD4 orthologs (new P0 class) apparently evolved to become cytosolic redox switches that confer thioredoxin-relayed alternative targeting to peroxisomes. PMID- 21309871 TI - Arabidopsis chloroplast lipid transport protein TGD2 disrupts membranes and is part of a large complex. AB - In most plants the assembly of the photosynthetic thylakoid membrane requires lipid precursors synthesized at the endoplasmic reticulum (ER). Thus, the transport of lipids from the ER to the chloroplast is essential for biogenesis of the thylakoids. TGD2 is one of four proteins in Arabidopsis required for lipid import into the chloroplast, and was found to bind phosphatidic acid in vitro. However, the significance of phosphatidic acid binding for the function of TGD2 in vivo and TGD2 interaction with membranes remained unclear. Developing three functional assays probing how TGD2 affects lipid bilayers in vitro, we show that it perturbs membranes to the point of fusion, causes liposome leakage and redistributes lipids in the bilayer. By identifying and characterizing five new mutant alleles, we demonstrate that these functions are impaired in specific mutants with lipid phenotypes in vivo. At the structural level, we show that TGD2 is part of a protein complex larger than 500 kDa, the formation of which is disrupted in two mutant alleles, indicative of the biological relevance of this TGD2-containing complex. Based on the data presented, we propose that TGD2, as part of a larger complex, forms a lipid transport conduit between the inner and outer chloroplast envelope membranes, with its N terminus anchored in the inner membrane and its C terminus binding phosphatidic acid in the outer membrane. PMID- 21309873 TI - The impact of caregivers' singing on expressions of emotion and resistance during morning care situations in persons with dementia: an intervention in dementia care. AB - AIMS AND OBJECTIVES: The aim was to describe expressions of emotions and resistiveness to care among persons with dementia (PWD), during morning care situations without and with music therapeutic caregiving (MTC). BACKGROUND: Effective caregiving is dependent on the interpersonal relationship between nurse and patient. PWD suffer from major cognitive impairment, making interaction with others problematic. Such patients often react with problematic behaviours such as resistance and anger towards the care activity and the caregiver. Earlier research suggests that MTC - when caregivers sing for or together with PWD during caregiving - can reduce resistance and evoke positive emotions in PWD. DESIGN: This was an intervention study whereby MTC was implemented during morning care situations while PWD were being cared for. METHOD: The study included ten, 66-92 year-old men and women with severe dementia living in a nursing home in Sweden. Video observations of eight weekly sessions, consisting of four recordings of usual morning care and four recordings of morning care with MTC, provided data. The resistiveness to care scale and the observed emotion rating scale were used for analysis. RESULTS: Pull away was the most common resistant behaviour under both conditions. The PWDs' expressions of resistant behaviour, such as pull away, grab object and adduction, were significantly reduced under the intervention situation. Positively expressed emotions, specifically pleasure and general alertness, significantly increased under the MTC intervention compared with the 'usual' morning care sessions. CONCLUSIONS: MTC can be an effective nursing intervention to provide PWD a more pleasant experience of morning care situations as it decreases resistant behaviour and increases positive emotions. RELEVANCE TO CLINICAL PRACTICE: MTC offers a potential non-pharmacologic treatment that can be used in caring for PWD. PMID- 21309874 TI - Oral glucose for pain relief during eye examinations for retinopathy of prematurity. AB - AIM: The aim of this study was to determine whether oral glucose could have a pain-relieving effect during the eye examinations that premature neonates undergo in the screening for retinopathy of prematurity. BACKGROUND: Studies have shown that orally administered sweet-tasting solutions reduce signs of pain during painful procedures such as venepuncture and heel sticks on premature and full term infants. This effect has not yet been proven during the eye examinations for the screening of retinopathy of prematurity. Design. Randomised, controlled, double-blind study. METHOD: Thirty infants born before 32 weeks of gestation and/or weighing <1500 g at birth were randomised to receive 1 ml of either 30% glucose or sterile water before the eye examination. Examinations were videotaped, and the observer was blinded to the intervention. Pain responses were scored using the premature infant pain profile. Heart rate and crying time were also recorded. RESULTS: There were no statistically significant differences between the two groups, neither in premature infant pain profile score, heart rate changes nor crying time. CONCLUSION: This study does not support the pain relieving effect of orally administered glucose during eye examinations in preterm infants. RELEVANCE TO CLINICAL PRACTICE: Oral glucose should not be used as single measure for pain relief during eye examinations of preterm infants. Other comforting and pain-relieving measures should be used. PMID- 21309872 TI - A revised mineral nutrient supplement increases biomass and growth rate in Chlamydomonas reinhardtii. AB - Interest in exploiting algae as a biofuel source and the role of inorganic nutrient deficiency in inducing triacylglyceride (TAG) accumulation in cells necessitates a strategy to efficiently formulate species-specific culture media that can easily be manipulated. Using the reference organism Chlamydomonas reinhardtii, we tested the hypothesis that modeling trace element supplements after the cellular ionome would result in optimized cell growth. We determined the trace metal content of several commonly used Chlamydomonas strains in various culture conditions and developed a revised trace element solution to parallel these measurements. Comparison of cells growing in the revised supplement versus a traditional trace element solution revealed faster growth rates and higher maximum cell densities with the revised recipe. RNA-seq analysis of cultures growing in the traditional versus revised medium suggest that the variation in transcriptomes was smaller than that found between different wild-type strains grown in traditional Hutner's supplement. Visual observation did not reveal defects in cell motility or mating efficiency in the new supplement. Ni2+ inducible expression from the CYC6 promoter remained a useful tool, albeit with an increased requirement for Ni2+ because of the introduction of an EDTA buffer system in the revised medium. Other advantages include more facile preparation of trace element stock solutions, a reduction in total chemical use, a more consistent batch-to-batch formulation and long-term stability (tested up to 5 years). Under the new growth regime, we analyzed cells growing under different macro- and micronutrient deficiencies. TAG accumulation in N deficiency is comparable in the new medium. Fe and Zn deficiency also induced TAG accumulation, as suggested by Nile Red staining. This approach can be used to efficiently optimize culture conditions for other algal species to improve growth and to assay cell physiology. PMID- 21309875 TI - Adaptive evolution of the Populus tremula photoperiod pathway. AB - Perennial plants monitor seasonal changes through changes in environmental conditions such as the quantity and quality of light and genes in the photoperiodic pathway are known to be involved in controlling these processes. Here, we examine 25 of genes from the photoperiod pathway in Populus tremula (Salicaceae) for signatures of adaptive evolution. Overall, levels of synonymous polymorphism in the 25 genes are lower than at control loci selected randomly from the genome. This appears primarily to be caused by lower levels of synonymous polymorphism in genes associated with the circadian clock. Natural selection appears to play an important role in shaping protein evolution at several of the genes in the photoperiod pathways, which is highlighted by the fact that approximately 40% of the genes from the photoperiod pathway have estimates of selection on nonsynonymous polymorphisms that are significantly different from zero. A surprising observation we make is that circadian clock associated genes appear to be over-represented among the genes showing elevated rates of protein evolution; seven genes are evolving under positive selection and all but one of these genes are involved in the circadian clock of Populus. PMID- 21309876 TI - Smoking cessation intervention practices in Chinese physicians: do gender and smoking status matter? AB - Healthcare settings provide a major arena for administering smoking cessation interventions. However, few studies have reported differences in the frequency of practice in healthcare professionals by gender and smoking status. This might also be influenced by a difference in smoking prevalence by gender, especially in China and other developing countries. This study examined factors associated with the frequency of cessation intervention practices by smoking status among Chinese physicians in men and women. A cross-sectional survey was conducted in 2006 in physicians with direct patient contact from nine hospitals in Guangzhou with a response rate of 60.8%. Significantly more female physicians who were non-smokers (79.7%) reported "initiation and/or advice" smoking cessation interventions than male physicians who were smokers (71.2%) and non-smokers (71.6%). Factors significantly associated with "initiation and/or advice" were prior smoking cessation training (OR = 4.2, 95% CI 1.8-9.6) and lack of knowledge to help patients to quit (OR = 0.4, 95% CI 0.2-0.9) among male physicians who smoked; and organisational support (OR = 1.7, 95% CI 1.3-2.2) and successful past experience (OR = 0.4, 95% CI 0.2-1.0) among male physicians who did not smoke. Among female physicians who did not smoke, significant factors were agreeing that quitting smoking is the most cost-effective way to prevent chronic disease and cancer (OR = 3.0, 95% CI 1.4-6.1), helping patients stop smoking is part of expected role and responsibility (OR = 2.0, 95% CI 1.0-3.7), lack of knowledge to help patients to quit (OR = 0.5, 95% CI 0.2-1.0) and organisational support (OR = 1.3, 95% CI 1.0-1.6) for non-smoking female physicians. This study is the first to show that male physicians were less likely to provide smoking cessation counselling regardless of their smoking status while non-smoking female physicians were more active in advising patients on quitting. The findings highlight the need for developing tailored smoking cessation training programmes for physicians according to their smoking status and gender in China. PMID- 21309877 TI - Early functional echocardiogram and inhaled nitric oxide: usefulness in managing neonates born following extreme preterm premature rupture of membranes (PPROM). AB - AIM: Poor neonatal outcome of preterm premature rupture of membranes (PPROM) < 24 weeks' gestational age (GA) is probably a result of abnormalities in both airway and vascular developments, ventilation perfusion mismatch, and possibly persistent pulmonary hypertension of the newborn (PPHN). Perinatal mortality of 50-90% has been reported in the past, with recent literature reporting significant improvement in neonatal survival. We report our 8-year experience in this group of infants using early diagnostic functional echocardiography (fECHO), high-frequency ventilation (HFV) and inhaled nitric oxide (iNO). METHODS: The obstetric and neonatal databases were searched to identify babies with PPROM (< 20 weeks' gestation) or rupture earlier than 25 weeks for more than 14 days. RESULTS: Twenty-six infants were identified, of whom 20 were admitted to the neonatal intensive care unit (NICU; mean GA 27.8 weeks, mean birth weight (BW) 1207 g). Early echocardiographic data were available in 12/15 infants requiring mechanical ventilation of whom 10 had evidence of PPHN. All infants who received iNO therapy survived to discharge and only two infants died. Survival to discharge was 69% for the whole cohort of infants and 90% for infants admitted to the NICU. In contrast, for the cohort from pre-iNO and -HFV era, the overall survival to discharge was 62% and 66% for the infants admitted to the NICU. CONCLUSION: Premature infants with PPROM and presumed severe hypoxemic respiratory failure because of hypoplastic lungs often have significant PPHN and may show improvement in oxygenation after treatment with HFV and iNO. Early fECHO results in earlier identification and treatment of infants with PPHN in this high risk group. PMID- 21309878 TI - The placebo mystique: Implications for clinical trial methodology. AB - AIM: The World Medical Association Declaration of Helsinki states that the use of a placebo in a clinical trial can only be justified ethically when no proven active treatment is available as a comparison. Despite this, placebos remain a popular choice as controls in clinical trials. Recent literature reviews have suggested that reliance on placebos may, in part, be because of methodological misconceptions about the need for placebos to control for the 'placebo effect'. This study aimed to assess doctors' understanding of the requirements for placebo use in clinical trials. METHODS: Two hundred doctors working in tertiary hospitals in Melbourne, Australia were surveyed in regards to their understanding of the role of the placebo and placebo effects in clinical trials. There was a 72% response rate. Doctors were specifically asked if a placebo was required in a randomised clinical trial, in preference to another form of control, to control for the 'placebo effect'. RESULTS: The majority of respondents (62%) incorrectly believed that placebos are essential to control for the 'placebo effect' in a randomised clinical trial. CONCLUSIONS: Misconceptions about the methodological requirement for placebos in randomised controlled trials may influence researcher decisions to use placebo controls in unethical situations. PMID- 21309879 TI - Caustic ingestion and oesophageal damage in children: Clinical spectrum and feeding practices. AB - AIM: The study aims to evaluate the association of oesophageal damage with clinical data and feeding practices in children who suffered a caustic substance ingestion (CSI). METHODS: Cross-sectional design was used in this study. The setting was at a paediatric referral hospital in 2006. Ninety-four children with CSI were used as study samples, with mean age of 38.4 months, and 37.2% were females. The independent variable was oesophageal damage; the dependent variables were clinical data and feeding practices. RESULTS: Main symptoms included salivation, oropharyngeal burns and vomiting. On endoscopy, 84.6% had second- or third-degree burns. Oesophageal stricture occurred in 48.9%. Severe burns were associated with oesophageal stricture and ingestion of alkaline products; dysphagia was associated with oesophageal stricture. In about one fourth of the cases, a nutritional intervention with complete and balanced liquid diets was required to maintain the adequate daily recommended intake (DRI). CONCLUSIONS: Alkali ingestion was associated with severe burns and oesophageal stricture. The presence of oesophageal strictures and dysphagia required changes in the feeding practices in order to maintain an adequate nutritional status and/or to complete their DRI. PMID- 21309880 TI - Predictors of medication adherence in children receiving psychotropic medication. AB - AIM: Medication adherence is poor in many young people with chronic illness. However, little research has examined medication adherence in clinic samples of young people receiving psychotropic medication, and whether factors such as disorder or drug type influence adherence. This study aimed to examine medication adherence in children and adolescents receiving psychotropic medication. METHODS: Young people receiving psychotropic medication and their caregivers were recruited from pharmacy and mental health services within a large metropolitan hospital. A brief cross-sectional survey examined medication history, missed doses within the previous week and other clinical information. Multiple regression analysis examined whether child characteristics, drug type and regimen characteristics were associated with medication adherence. RESULTS: Poor adherence was associated with lack of parental involvement in medication routines (P < 0.05), use of complementary medicines (P < 0.01) and difficulty remembering doses (P < 0.01). Developmental diagnoses (P < 0.05), use of antipsychotics (P < 0.05) and use of concomitant non-psychotropic medication (P < 0.05) were predictors of good adherence. CONCLUSION: Encouraging parental involvement in medication routines may be a practical target for clinicians aiming to improve medication adherence in young people. Use of complementary medicines may indicate a group with a higher risk of poorer adherence. PMID- 21309881 TI - Norovirus as cause of benign convulsion associated with gastro-enteritis. AB - AIM: Rotavirus and norovirus gastro-enteritis (GE) are common in children. Complications, except severe dehydration, are rare. Rotavirus was known to cause seizures and even GE encephalopathy, but these complications are less described in norovirus infection. The objective of this study is to compare the demographic features, clinical manifestations including the incidence of afebrile seizure, and the outcomes in children with rotavirus and norovirus infections. METHODS: This is a retrospective review of children between age 1 month and 6 years admitted to the paediatric department of a regional hospital in Hong Kong with rotavirus and norovirus infections over a period of 3 years from 1 June 2006 to 31 May 2009. Their demographic data, clinical features, laboratory results and outcomes were compared and analysed. RESULTS: Two hundred and thirty-two children with rotavirus and 173 children with norovirus GE were admitted within the study period. Afebrile seizure commonly occurred in norovirus infection (8.67% vs. 1.29%, P < 0.001). Children with rotavirus infection had higher temperature and more diarrhoea episodes, while more blood-stained stool was noted in the norovirus group. Rotavirus-infected patients stayed longer in hospital. All of them had full recovery without any complication. Among the 18 patients who developed afebrile convulsions, 17 of them had neuroimaging performed, which was normal. Fourteen of them had electroencephalogram (EEG) performed, demonstrating normal or non-specific findings. None of them developed subsequent seizure attack after the GE episode. CONCLUSIONS: Norovirus is more commonly associated with benign convulsion in GE than rotavirus. We need to identify the presence of virus, in particular norovirus, in children with GE and afebrile generalised tonic-clonic seizure. Further neuro-investigations may not be necessary once the aetiology is established. Prognosis is excellent in this group of children and prophylactic anticonvulsant is not needed. PMID- 21309882 TI - Childhood outcomes of neonates diagnosed with portal vein thrombosis. AB - AIM: The study aims to determine childhood outcomes of neonates diagnosed with portal vein thrombosis (PVT). METHODS: A retrospective chart review of neonates diagnosed with PVT who had documented follow up (physical examination, laboratory tests or ultrasonographic examination) at the age of 2 years or beyond was conducted. RESULTS: Data were available for 70 children (71% of eligible neonates) at a median age of 5 years (range 2-8 years). Physical examination was unremarkable in all who were examined (n= 68). Twenty-five children had liver functions assessed and only mild abnormalities were detected in nine children. Six of 25 patients tested for thrombophilia showed abnormalities. Thirty-seven children had ultrasonographic follow up. Left lobar atrophy (LLA) was noted in 20 children (16 had isolated LLA, two had LLA and splenomegaly, and two had LLA and portal hypertension). Five children who had normal ultrasound examinations at discharge had splenomegaly (two with additional finding of LLA) at follow up. Two children with portal hypertension diagnosed during neonatal period needed porta caval shunting. CONCLUSION: Our results show that among patients, who had PVT as neonates, 28% still had asymptomatic LLA in childhood, 7% had slowly progressive splenomegaly and 3% required shunting because of progression of portal hypertension. Ultrasonographic follow up was the most sensitive method in detecting progression associated with neonatal PVT. Until more data are available, periodic long-term ultrasonographic follow up should be considered for neonates diagnosed with PVT. PMID- 21309883 TI - Impact of an oral health intervention on pre-school children < 3 years of age in a rural setting in Australia. AB - AIM: Australian pre-school children living in rural areas experience higher levels of dental caries than those in metropolitan areas. This may be because of a lack of community water fluoridation. The aim of this study was to evaluate the effectiveness of a community-based intervention to improve the oral health of children in non-fluoridated rural Victoria, Australia. METHODS: The study was conducted across three local government areas in Victoria, with two receiving the intervention and one remaining with standard care. Although multifaceted, the primary strategy of the intervention was the promotion of early exposure to fluoridated toothpaste, including the distribution, by maternal and child health nurses (MCHNs), of an oral health starter kit including toothpaste, toothbrush and information to parents at their child's 7-8-month health check. Children were followed up annually to the age of three. RESULTS: Infants in the intervention arm experienced less caries (cavitated and pre-cavitated lesions included) than infants in the control arm at the first and second examinations (3.1% with caries in the intervention vs. 6.9% in the control group at exam 1 (adjusted P= 0.07) and 10.8% vs. 19.5% at exam 2 (adjusted P= 0.11), respectively). However potential benefits disappeared at the third examination (29.5% vs. 28.9%, adjusted P= 0.67). CONCLUSIONS: This study suggests that an oral health promotion intervention delivered via local MCHNs promoting early exposure to fluoride may be successful in reducing caries in the second year of life but less so in older children when participants have less contact with MCHNs. PMID- 21309884 TI - Non-attendance to the paediatric clinics in a Malaysian tertiary hospital: a sizeable problem and identification of an efficacious intervention. AB - AIM: To determine the rate, causes and risk factors of non-attendance to the paediatric clinic in a tertiary hospital in Malaysia and to determine the efficacy of one telephone call to confirm a new appointment. METHODS: For all non attending patients, during a 2-month period, a pro forma was filled up based on patients' records. During a phone call, additional questions were asked, and a new appointment was offered. RESULTS: Of 1563 patients who had an appointment, 497 (31.8%) were non-attendees. Weather conditions, the sub-specialty and timing (morning or afternoon) had a significant effect on non-attendance. Forgetfulness was the main cause. Only 160 patients could be successfully contacted. Among the contactable patients, 55 already had an appointment, and 10 had reasons not to get a new appointment. Of the 95 remaining patients, 73 (76.8%) attended the new appointment. CONCLUSION: The non-attendance rate was high. One telephone call had a reasonable efficacy for the contactable patients, but because a high number of patients were not contactable, overall effectiveness was poor. PMID- 21309886 TI - Ultrastructure of Myxobolus brycon n. sp. (Phylum Myxozoa), parasite of the piraputanga fish Brycon hilarii (Teleostei) from Pantanal (Brazil). AB - Light and electron microscopy studies of a myxosporean, parasitizing the gill filaments of the freshwater fish Brycon hilarii (Valenciennes, 1850) (Characidae) collected in the Paraguay River (18 degrees 49'S, 57 degrees 39'W) (Pantanal), Brazil, is described. This parasite produces spherical to ellipsoidal polysporic histozoic plasmodia (Pmd) (up to ~180 MUm in diameter) delimited by a double membrane and with several pinocytic channels. The plasmodial cyst contained the youngest developmental stages at the cortical periphery and immature and mature spores more internally. The Pmd developed near the cartilaginous structure of the gill filament, forming a prominent deformation where the gill lamellae disappear. Pyriform spores measured 6.9+/-0.6 (range 6.5-7.2) MUm long, 4.2+/-0.5 (range 3.9 4.8) MUm wide, and 2.5+/-0.7 (range 1.9-2.8) MUm thick. The spores composed of two equal shell valves (~70 nm thick), adhering together along the straight suture line, surrounded two equal symmetric and elongated to pyriform polar capsules (PC) 4.2+/-0.6 (range 3.8-4.7) * 1.9+/-0.6 (1.7-2.5) MUm; each PC contained a coiled polar filament with eight or nine (rarely 10) turns and a binucleated sporoplasm cell. Dense irregular masses were observed among the polar filaments coils. An intercapsular appendix was not observed. The sporoplasm contained several globular sporoplasmosomes randomly distributed among an extensive rough endoplasmic reticulum system with numerous vesicles and cisternae. Based on the morphological and ultrastructural differences and specificity of the host, we establish the new species, Myxobolus brycon n. sp. PMID- 21309885 TI - Low defaecation frequency in Taiwanese adolescents: association with dietary intake, physical activity and sedentary behaviour. AB - AIM: The objectives of this study were to estimate the prevalence of constipation, defined as less than three defaecations per week, in Taiwanese adolescents and to examine its association with the intake of vegetables, fruits and fluids; time spent on sedentary behaviour; and time spent on moderate and vigorous physical activity. METHODS: This study used a questionnaire survey. The study participants were 14,626 adolescents in grades 7-12. Physical activity was measured using the International Physical Activity Questionnaire-Youth Show Card Version. Time spent on sedentary activity included studying, reading, sitting in vehicles and screen time. Consumption of fluid, fruits and vegetables was measured by asking participants to describe the average consumption of each type of food in the past 7 days. RESULTS: The prevalence of defaecation frequency of < 3 times a week was 9.3%. Multivariate logistic regression analysis showed that female sex (odds ratio (OR) = 2.2), worse health status (OR = 1.3), not being overweight/obese (OR = 0.7 and 0.3 for overweight and obesity), more time spent on sedentary activity (OR = 1.0) and low intake of fluids (< 1.8 L/day; OR = 1.2), fruits (< 1 portion; OR = 1.6), vegetables (< 1 portion or 100 g; OR = 1.4) and whole-grain products (OR = 1.2) were independently associated with increased risk of low defaecation frequency. CONCLUSIONS: The prevalence of low defaecation frequency was high in Taiwanese adolescents. Decreasing sedentary behaviour and increasing the intake of fluids, vegetables, fruits and whole-grain products among those adolescents with very low intake levels could be helpful in preventing and managing constipation, irrespective of body size and health status. PMID- 21309887 TI - Connecting public health law, practice, policy, and research. PMID- 21309888 TI - Lawyers, guns, and money: a plenary presentation from the conference "Using Law, Policy, and Research to Improve the Public's Health". PMID- 21309889 TI - Making the case for laws that improve health: the work of the Public Health Law Research National Program Office. PMID- 21309890 TI - What gets measured, gets changed: evaluating law and policy for maximum impact. PMID- 21309891 TI - Health in All Policies: addressing the legal and policy foundations of Health Impact Assessment. PMID- 21309892 TI - The potential of shared decision making to reduce health disparities. PMID- 21309893 TI - Environmental public health law: three pillars. PMID- 21309894 TI - State boards of health: governance and politics. PMID- 21309895 TI - Policy issues in American Indian health governance. PMID- 21309896 TI - Global public health legal responses to H1N1. PMID- 21309897 TI - Public health preparedness laws and policies: where do we go after pandemic 2009 H1N1 influenza? PMID- 21309899 TI - Five legal preparedness challenges for responding to future public health emergencies. PMID- 21309898 TI - Protecting the mental health of first responders: legal and ethical considerations. PMID- 21309900 TI - National health care reform and the public's health. PMID- 21309901 TI - Implementing health reform at the state level: access and care for vulnerable populations. PMID- 21309902 TI - Rhetorical federalism: the role of state resistance in health care decision making. PMID- 21309903 TI - Meaningful use and certification of health information technology: what about safety? PMID- 21309904 TI - Right to health litigation and HIV/AIDS policy. PMID- 21309905 TI - The role of federal preemption in injury prevention litigation. PMID- 21309906 TI - Regulating food retail for obesity prevention: how far can cities go? PMID- 21309907 TI - Pursuing health equity: zoning codes and public health. PMID- 21309908 TI - The Michigan BioTrust for Health: using dried bloodspots for research to benefit the community while respecting the individual. PMID- 21309909 TI - Becoming the standard: how innovative procedures benefitting public health are incorporated into the standard of care. PMID- 21309910 TI - Use of multiple channel pH monitoring for evaluation of ultra-distal reflux in patients after fundoplication for treatment of Barrett's esophagus. AB - Dysplasia and esophageal adenocarcinoma may arise in patients with Barrett's esophagus after fundoplication esophageal pH monitoring showing no acid in esophagus. This suggests the need to develop methodology to evaluate the occurrence of ultra-distal reflux (1cm above the LES). The objective of the study was to compare acid exposition in three different levels: 5cm above the upper border of the LES, 1cm above the LES and in the intrasphincteric region. Eleven patients with Barrett's esophagus after Nissen fundoplication with no clinical, endoscopic and radiologic evidence of reflux were selected. Four-channel pH monitoring took place: channel A, 5cm above the upper border of the LES; channel B, 1cm above the LES; channel C, intrasphincteric; channel D, intragastric. The results of channels A, B and C were compared. There was significant increase in number of reflux episodes and a higher fraction of time with pH <4.0 in channel B compared to channel A. There was significant decrease in fraction of time with pH <4.0 in channel B compared to channel C. Two cases of esophageal adenocarcinoma were diagnosed in the studied patients. The region 1cm above the upper border of the LES is more exposed to acid than the region 5cm above the upper border of the LES, although this exposure occurred in reduced levels. The region 1cm above the upper border of the LES is less exposed to acid than the intrasphincteric region. PMID- 21309911 TI - Use of a continuing medical education course to improve fellows' knowledge and skills in esophageal disorders. AB - Advanced esophageal endoscopic procedures such as stricture dilation, hemostasis tools, and stent placement as well as high-resolution manometry (HRM) interpretation are necessary skills for gastroenterology fellows to obtain during their training. Becoming proficient in these skills may be challenging in light of higher complication rates compared with diagnostic procedures and infrequent opportunities to practice these skills. Our aim was to determine if intensive training during a continuing medical education (CME) course boosts the knowledge and skills of gastroenterology fellows in esophageal diagnostic test interpretation and performance of therapeutic procedures. This was a pretest posttest design without a control group of a simulation-based, educational intervention in esophageal stricture balloon dilation and HRM interpretation. The participants were 24 gastroenterology fellows from 21 accredited US training programs. This was an intensive CME course held in Las Vegas, Nevada from August 7 to August 9, 2009. The research procedure had two phases. First, the subjects were measured at baseline (pretest) for their knowledge and procedural skill. Second, the fellows received 6 hours of education sessions featuring didactic content, instruction in HRM indications and interpretation, and deliberate practice using an esophageal stricture dilation model. After the intervention, all of the fellows were retested (posttest). A 17-item checklist was developed for the esophageal balloon dilation procedure using relevant sources, expert opinion, and rigorous step-by-step procedures. Nineteen representative HRM swallow studies were obtained from Northwestern's motility lab and formed the pretest and posttest in HRM interpretation. Mean scores on the dilation checklist improved 81% from 39.4% (standard deviation [SD]= 33.4%) at pretest to 71.3% (SD = 29.5%) after simulation training (P < 0.001). HRM mean examination scores increased from 27.2% (SD = 16.4%) to 46.5% (SD = 15.8%), representing a 71% improvement (P < 0.001). Pearson's correlations indicated there was no correlation between pretest performance, medical knowledge measured by United States Medical Licensing Examination examinations, prior clinical experience, or procedural self-confidence and posttest performance of esophageal dilation or HRM interpretation. The education program was rated highly. This study demonstrated that a CME course significantly enhanced the technical skills and knowledge of gastroenterology fellows in esophageal balloon dilation and HRM interpretation. CME courses such as this may be a valuable adjunct to standard fellowship training in gastroenterology. PMID- 21309912 TI - Reconstruction of hypopharyngeal and cervical esophageal defect after resection of hypopharyngeal carcinoma: a new technique based on the use of bilateral platysma myocutaneous flaps. AB - Commonly used procedures for reconstructing hypopharyngeal and cervical esophageal defects resulting from total laryngopharyngectomy (TL) are the gastric conduit or colon transposition as well as microvascularized free flaps. Herein we designed an alternative procedure utilizing bilateral platysma myocutaneous flaps (PMCFs) for the reconstruction of hypopharyngeal and cervical esophageal defects. This report summarizes the technical description of this procedure. TL and cervical esophagectomy were performed and bilateral PMCFs were harvested for reconstruction of hypopharyngeal and cervical esophageal defects in 25 patients aged between 46 and 73 years (mean 58.7 +/- 16.2 years). All these patients had advanced-stage (IV) cancer with involvement of the cervical esophagus. Operative time ranged from 176 to 382 minutes (average 243 +/- 91 minutes) and the mean intraoperative blood loss was 294 +/- 119mL. There were six cases of anastomotic leak (24.0%) and two of them (8.0%) developed anastomotic stricture. Neither flap necrosis nor postoperative death was observed. The majority of our patients (68.0%) were restored to a normal unrestricted oral diet after surgery. The 3 year and 5-year actuarial survival rates were approximately 54.7% and 26.1%, respectively. We conclude that reconstruction of the cervical esophagus with bilateral PMCFs is a valuable method for treating advanced hypopharyngeal carcinoma. PMID- 21309913 TI - A comparison of surgery and radiation therapy for cT1 esophageal squamous cell carcinoma. AB - Surgery and radiation therapy have been used to treat esophageal squamous cell carcinoma. However, treatment outcomes have not yet been extensively investigated. The aim of this study was to compare surgery and radiation therapy for clinical T1 esophageal squamous cell carcinoma. A total of 67 clinical T1 esophageal squamous cell carcinoma patients were treated between January 1997 and December 2005; 29 had undergone radical esophagectomy (surgery group) and 38 were treated with definitive radiation therapy (radiation group). The mean patient age was lower in the surgery group than in the radiation group. In surgery group, respiratory complications, anastomotic leaks, recurrent nerve palsies, and anastomotic stenosis occurred in 7, 8, 6, and 5 patients, respectively. In radiation group, leucopenia, esophagitis, pericarditis were observed in 15, 3, and 3 patients, respectively. The 5-year overall survival rate for the surgery group was 68.9%, and 74.3% for the radiation group. There were no significant difference between groups (P= 0.3780). The 5-year relapse-free survival rate in the surgery group was 61.8% and 38.8% in the radiation group. The relapse-free survival rate was significantly higher in the surgery group than in the radiation group (P= 0.0051). The 5-year overall and relapse-free survival rates for tumors invaded into but not through the muscularis mucosa were 83.3% and 75.0%, respectively, in the surgery group and 78.8% and 33.3%, respectively, in the radiation group. There were no significant differences. The 5-year overall survival rates for patients with tumors that invaded the submucosal layer was 64.9% in the surgery group and 66.5% in the radiation group. This difference was not significant (P= 0.8712). The 5-year relapse-free survival rate in the surgery group (56.0%) was significantly higher than that in the radiation group (41.8%; P= 0.0219). In conclusion, surgery may become a standard treatment for cT1 esophageal cancer that can offer longer relapse-free survival, particularly for patients with tumors that invade the submucosa. PMID- 21309914 TI - Lugol chromo-endoscopy versus narrow band imaging for endoscopic screening of esophageal squamous-cell carcinoma in patients with a history of cured esophageal cancer: a feasibility study. AB - To date, Lugol chromo-endoscopy is the reference technique to detect an esophageal neoplasia in patients with prior esophageal squamous-cell carcinoma (ESCC), but is not easy to perform without general anesthesia, which can limit its use in routine practice. The objective of this study were to compare the accuracy of white light, narrow band imaging (NBI), and Lugol to detect esophageal neoplasia in patients with a history of cured ESCC, in a prospective study. Thirty patients were prospectively included between June 2006 and June 2009. They all had a history of cured ESCC. Esophageal mucosa was examined first using white light, second NBI, and third after Lugol staining. Histology was obtained in all abnormalities detected by white light, NBI, and/or Lugol. Five neoplastic lesions in five different patients were identified at histology, four cancers, and one high-grade dysplasia. NBI and Lugol both detected all esophageal neoplastic lesions, whereas white light detected the four cancers but missed the high-grade dysplasia. In this feasibility study, NBI and Lugol both detected all identified esophageal neoplasia in very high-risk patients of ESCC. This result suggests that NBI could be used instead of Lugol to detect an esophageal neoplasia in patients with high risk of ESCC, but needs to be confirmed in a larger study. PMID- 21309915 TI - Outcomes of laparoscopic-assisted transhiatal esophagectomy for adenocarcinoma of the esophagus and esophago-gastric junction. AB - Esophagectomy is associated with substantial morbidity and mortality, yet it is the only modality that offers the possibility of cure for esophageal and gastroesophageal junction (E-GEJ) adenocarcinoma. Several minimally invasive techniques have been developed to decrease the morbidity of the operation, but to date, the results have not led to its wide adoption in part due to their complexity. We developed a technique of laparoscopic-assisted transhiatal esophagectomy (LA-THE) with the idea of preserving some of the advantages of the minimally invasive approach while eliminating the degree of complexity and the time required to complete the operation solely using laparoscopy. The course of all patients who underwent LA-THE for E-GEJ adenocarcinoma at the University of Washington Medical Center was determined by analysis of all hospital records to determine perioperative variables, complications, and survival. Patients were also given a follow-up survey in order to assess long-term health-related quality of life (Gastrointestinal Quality of Life Index or GIQLI). Seventy-two patients underwent LA-THE between 1995 and 2007. Median age was 64 years (range, 42-83 years), and the median body mass index was 28 (range 17-35). Twenty-eight tumors (39%) were categorized as Siewert I, 41 (57%) as Siewert II, and 3 (4%) as Siewert III. Median operative time was 299min (range, 212-700min). All the resections were R-0. The median number of lymph nodes harvested was 11 (range, 2 32). Using the Dindo-Clavien classification of surgical complication, we had a total of 48 postoperative complications in 37 patients: 26 (53%) grade I, 20 (41%) grade II, 1 (2%) grade IIIb, 1 (2%) grade IVb, and 1 (2%) grade V complications. Median length of hospital stay was 9 days (range, 7-58 days). One patient (1.4%) died within 30 days. Overall, 3- and 5-year survival (calculated Kaplan-Meier) was 68% and 63%, respectively. Forty-nine patients (90% of those still alive) answered the GIQLI survey. Median follow-up was 26 months (range, 6 144 months). The mean GIQLI score was 108 (range, 74-138) from a maximum possible value of 144. Our study shows that LA-THE is feasible, safe, and effective in the treatment of adenocarcinoma of the esophagus and GEJ and should probably be considered an alternative to open esophagectomy and other minimally invasive techniques in the treatment of this disease. PMID- 21309916 TI - Boerhaave's syndrome as the primary manifestation of adult eosinophilic esophagitis. Two case reports and a review of the literature. AB - Eosinophilic esophagitis (EoE) has been associated with an increased risk of esophageal mucosal tears induced by vomiting to dislodge impacted food or following endoscopic procedures. However, Boerhaave's syndrome or transmural perforation of the organ resulting from vomiting induced to dislodge impacted food has rarely been reported. In this article, we present two male adult patients with long-term esophageal symptoms who suffered from Boerhaave's syndrome after the impaction of food in the esophagus. Both patients required surgical management because of clinical and radiological signs of perforation. This rare complication of EoE has been documented in 11 other reports, predominantly affecting young men in whom EoE had not been previously diagnosed, despite the majority having esophageal symptoms and a history of atopy. There are only two published cases of esophageal perforation that presented in children, which were managed conservatively. Our two patients and 4 out of the 11 described in literature required surgery because of esophageal perforation. Our two cases involved closure of the perforation, while in three published reports, perforation resulted in a partial or complete esophagectomy. No cases have been published on Boerhaave's syndrome caused by EoE that ended in fatalities. It is important to note that esophageal perforation caused by vomiting is a potentially severe complication of EoE that is being increasingly described in literature. Therefore, patients with non-traumatic Boerhaave's syndrome should be assessed for EoE, especially if they are young men who have a prior history of dysphagia and allergic manifestations. PMID- 21309917 TI - Various doses of fractioned irradiation modulates multidrug resistance 1 expression differently through hypoxia-inducible factor 1alpha in esophageal cancer cells. AB - To evaluate the effect of different regimen of radiotherapy on multidrug resistance 1 (MDR1) expression and analyze the role hypoxia-inducible factor 1alpha (HIF1alpha) played in the whole process. Fifty-four cell lines established from 96 esophageal cancer biopsy samples were given various doses of fractioned irradiation. The mRNA and protein levels of HIF1alpha and MDR1 post-irradiation were measured by quantitative reverse transcription-polymerase chain reaction and Western blot analysis, respectively. HIF1alpha-siRNA was used to verify the effect of HIF1alpha on radiation-mediated MDR1 modulation. In esophageal cancer cells surviving 28 Gy irradiation (2 Gy/f, 14 fractions), MDR1 mRNA expression increased 65.27 +/- 5.58%, and HIF1alpha was elevated by 27.21 +/- 2.25%. Interestingly, their expression decreased by 54.38 +/- 11.53% and 32.08 +/- 4.75% after 7 Gy irradiation (0.5 Gy/f, 14 fractions). HIF1alpha expression showed a positive correlation with MDR1 expression in the whole process (P < 0.05). Silencing of HIF1alpha decreased MDR1 expression and blocked changes in MDR1 and HIF1alpha expression induced by fractioned irradiation. These results indicate that MDR1 is differentially modulated by different doses of fractionated radiation, which should be taken into account when combining radiotherapy and chemotherapy for patients with esophageal cancer. PMID- 21309918 TI - Circular stapled pyloroplasty: a fast and effective technique for pyloric disruption during esophagectomy with gastric pull-up. AB - The necessity of pyloroplasty after esophagectomy and gastric pull-up is debated. Disadvantages of a standard pyloroplasty include the potential for leak, shortening of the length of the graft, and complexity when done during a minimally invasive procedure. The aim of this study is to report our experience with a novel internal pyloroplasty technique using a circular stapler (CS pyloroplasty), which is applicable for both laparoscopic and open esophagectomy. The records of all patients who underwent an esophagectomy with gastric pull-up and pyloroplasty between 2002 and 2007 were reviewed. The CS pyloroplasty was performed through a lesser curve gastrotomy with a 21-mm CS, while the standard pyloroplasty entailed a longitudinal full thickness incision through the pylorus with mucosal closure in the same direction and a Graham patch. A CS pyloroplasty was performed in 144 and a standard pyloroplasty in 133 patients. The median patient age was 66years, and the median follow-up was 17months, and was similar for both types of pyloroplasty. Routine postoperative videoesophagram was significantly more likely to show a delay in contrast transit through the pylorus after standard pyloroplasty (16% standard vs. 8% CS pyloroplasty, P= 0.03). Significantly more patients had postoperative endoscopy after standard pyloroplasty (40% standard vs. 24% CS pyloroplasty, P= 0.004), but the frequency of pyloric dilatation was similar. There were no leaks with either technique. A circular stapled pyloroplasty is as efficacious as a standard pyloroplasty after esophagectomy with gastric pull-up. Potential advantages include the ease and simplicity of the procedure along with virtually no risk of a leak and no graft shortening. The technique is amenable to both open and minimally invasive procedures. PMID- 21309919 TI - Adenocarcinoma of the esophagus presenting as choroidal metastasis. AB - Adenocarcinoma of the esophagus is an exceedingly rare cause of choroidal metastasis. We report the case of a 48-year-old Caucasian male with a 2-month history of decreased vision and dysphagia. Ophthalmologic examination revealed bilateral choroidal masses and an exudative retinal detachment in the left eye. Gastroduodenoscopy revealed a circumferential mass in the distal esophagus at 30 cm extending into and involving the gastroesophageal junction. Endoscopic biopsy disclosed an invasive, poorly differentiated adenocarcinoma. Systemic workup revealed widespread metastatic changes in the pericardium, liver, and left adrenal gland, and a right pleural effusion. The patient's condition rapidly deteriorated, and he passed away 40 days after initial presentation. To our knowledge, this represents the first case of choroidal metastasis as the initial manifestation of esophageal adenocarcinoma. PMID- 21309920 TI - Preoperative physical activity levels and postoperative pulmonary complications post-esophagectomy. AB - Postoperative pulmonary complications (PPCs) after esophagectomy have been reported to occur in 15-30% of patients and are the most common causes of major morbidity and mortality. Risk factors for the development of PPCs include impairment in lung function, cardiac reserve, aerobic capacity, and body composition. Physical activity is associated with these factors but has not been examined in relation to the risk of developing a PPC. The aim of this cross sectional study was to investigate if there was a difference in physical activity levels, lung function, and body composition in patients who developed a PPC post esphagectomy compared with those who did not. Consecutive patients were studied preoperatively: (i) lung function with a portable micro-medical spirometer; (ii) body composition analysis using a Tanita BC 418 machine (Tanita Corp., Tokyo, Japan); and (iii) physical activity with an accelerometer (RT3, (StayHealthy, Monrovia, CA, USA)). Thirty-seven patients were studied, mean age 61 +/- 9 years. PPCs developed in 10 patients (27%). Smoking status, lung function, and body composition were similar in both groups. For physical activity, there were significant differences in the time spent sedentary (20.0 +/- 1.5 h/day [PPC], 18.4 +/- 2.1 h/day [non-PPC]; P < 0.05) and in moderate activity (20 +/- 13.7 min/day [PPC], 36 +/- 20.7 min/day [non PPC]; P < 0.01). Patients who developed a PPC engaged in less physical activity than those who did not; hence, targeting physical activity preoperatively may result in less PPCs. PMID- 21309921 TI - Diffuse esophageal spasm: the surgical approach. AB - Diffuse esophageal spasm (DES) is a rare primary motility disorder of unknown cause, that can be found in patients complaining of chest pain and dysphagia and in whom ischemic heart disease and GERD have been excluded. The manometric hallmark of DES is the presence of simultaneous contractions in the distal esophagus alternating with a normal peristalsis. Even at specialized esophageal motility laboratories, DES is considered an uncommon diagnosis. In this review, the authors discuss the clinical and diagnostic aspects of this disease, as well as the possible therapeutic options (medical, endoscopic or surgical therapy). Surgery (esophageal myotomy performed through a thoracotomy or with a thoracoscopic access) seems to have a better outcome than medical or endoscopic treatment, and it is considered "the last resource" in these patients. However, satisfactory results are reported, from highly skilled centers, in only about 70% of treated cases, certainly inferior to those achieved in other esophageal disorders. The role of surgery in this disease requires therefore further study, even if controlled trials are probably difficult to perform, due to the rarity of the disease. PMID- 21309922 TI - Long-term outcomes of late course accelerated hyper-fractionated radiotherapy for localized esophageal carcinoma in Mainland China: a meta-analysis. AB - Published data on the long-term survival results of patients with localized esophageal carcinoma receiving late course accelerated hyper-fractionated radiotherapy (LCAF RT) versus conventional fractionated radiotherapy (CF RT) are inconclusive. In order to derive a more precise estimation of the both treatment regimes, a meta-analysis based on systematic review of published articles was performed. A meta-analysis was performed using trials identified through Pubmed and Chinese national knowledge infrastructure. Results in 5-year survival and 5 year local control were collected from randomized trials comparing LCAF RT with CF RT. Review Manager (The Cochrane Collaboration, Oxford, England) and Stata software (Stata Corporation, College Station, TX, USA) were used for data management. A total of 11 trials were involved in this analysis with 572 cases and 567 controls. Our results showed that LCAF RT, compared with CF RT, significantly improved the 5-year survival (odds ratio [OR]= 2.93, 95% confidence interval [CI]: 2.15-4.00, P < 0.00001) and 5-year local control (OR = 3.96, 95% CI: 2.91-5.38, P < 0.00001). LCAF RT was more therapeutically beneficial than CF RT in the localized esophageal carcinoma. PMID- 21309923 TI - Palliative interventions and prognosis in patients with advanced esophageal cancer. AB - In a retrospective review, in order to describe the palliative care and prognosis of patients with advanced cancer of the esophagus, the clinical characteristics and the treatment modalities applied were explored in relation to survival and symptom relief for 261 patients treated without curative potential. The data were obtained from a study of all patients with cancer of the esophagus treated at the Norwegian Radium Hospital in the 10-year period from 1990 to 1999. Medical data of the patients were reviewed and missing clinical information was retrieved from local hospitals and general practitioners. The patients were divided into three groups based upon the overall survival from start of treatment to death. Survival <=3 months is in this paper, defined as 'short,' while survival > 6 months is defined as 'long.' Median survival for the total group of patients was 4 months. The 1-, 2-, and 3-year survival was 8%, 3%, and 1%, respectively. Patients with short survival (n= 107) had more advanced disease, lower performance status, and more dysphagia, weight loss, and pain and used more analgesics than patients with long survival (n= 91). Tumor characteristics such as localization, tumor length, and histology were not significantly associated with survival. This result was confirmed in a logistic regression analysis (with backward stepwise elimination) including sex, age, clinical stage, tumor length, tumor localization, histology, performance status, dysphagia, weight loss, and pain, where clinical stage, performance status, weight loss, and pain were included in the final model. A large variety of first-line palliative treatments were applied within the studied time period; external radiotherapy +/- brachytherapy (n= 149), brachytherapy alone (n= 44), endoluminal stent (n= 28), laser evaporization (n= 8), chemotherapy (n= 5), and best supportive care only (n= 27). There were no clear differences in the effect on dysphagia between the modalities. Fourteen percent of the patients had treatment related complications. In conclusion, symptoms, performance status, and use of analgesics seemed to better prognosticate survival than tumor characteristics other than stage of disease. Our study reveals that knowledge about prognostic factors is crucial for the choice of palliative treatment. Even though all of the different treatment modalities seemed to provide relief of dysphagia, several other factors should be considered when deciding which treatment modality to offer. The time to onset of relief, duration of response, level of complications, and time spent in hospital should be a part of the decision-making process when selecting the appropriate treatment. PMID- 21309924 TI - The gene expression profile of cardia intestinal metaplasia is similar to that of Barrett's esophagus, not gastric intestinal metaplasia. AB - The etiology and significance of cardia intestinal metaplasia (CIM) is disputed. CIM may represent a form of Barrett's esophagus due to reflux or could reflect generalized gastric intestinal metaplasia due to Helicobacter pylori. The aim of this study was to utilize gene expression data to compare CIM to Barrett's and gastric intestinal metaplasia. Endoscopic biopsies were classified by endoscopic and histologic criteria as CIM (n= 33), Barrett's (n= 25), or gastric intestinal metaplasia of the antrum or body (n= 18). The squamocolumnar and gastroesophageal junctions were aligned in CIM patients and patients with diffuse gastric intestinal metaplasia were excluded. H. pylori was tested for in the biopsies of all patients. After laser-capture microdissection, quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to measure the mRNA expression of a panel of nine genes that has been shown to differentiate Barrett's from other foregut mucosa. Cluster analysis with linear discriminant analysis of the expression data was used to classify each sample into groups based solely on similarity of gene expression. Cluster analysis was performed for three groups (CIM vs. Barrett's vs. gastric intestinal metaplasia) and two groups (CIM + Barrett's vs. gastric intestinal metaplasia). There was no difference in H. pylori infection among groups (P= 0.66). Clustering into three groups resulted in frequent misclassification between CIM and Barrett's while misclassification of gastric intestinal metaplasia was uncommon. The CIM and Barrett's groups were then combined for two group clustering and linear discriminant analysis correctly predicted 95% of CIM and Barrett's samples and 83% of gastric intestinal metaplasia samples based on gene expression alone. In conclusion, the gene expression profiles of CIM and Barrett's esophagus were similar in 95% of biopsies and differed significantly from that of gastric intestinal metaplasia. The indistinguishable gene expression profile of CIM and BE suggests that they may share a common etiology in the majority of patients with a similar biology, and calls into question the perception that CIM is an innocuous process. PMID- 21309925 TI - PCR for the diagnosis and species identification of microsporidia in patients with keratitis. AB - Corneal scrapings from 30 patients with microbial keratitis were subjected to microsporidial PCR. PCR was positive for microsporidia in ten of 30 patients. The species was identified as Vittaforma corneae by sequencing in all ten patients. The remaining 20 patients were negative for microsporidia and showed the growth of other organisms (Acanthamoeba, fungi or bacteria). PMID- 21309926 TI - Failure of complete recanalization is associated with poor outcome after cardioembolic stroke. AB - BACKGROUND: Recanalization is strongly associated with outcomes after thrombolytic treatment. Cardiac emboli are known as better response to fibrinolytic agents because they are fibrin-rich; however, cardioembolic stroke itself is associated with poor outcomes and high mortality. Completeness of recanalization may therefore affect the outcome of cardioembolic stroke. We investigated whether degree of recanalization influences outcomes following fibrinolytic therapy in cardioembolic stroke. METHODS: Consecutive stroke patients with relevant artery occlusions on baseline CT angiography who had received thrombolytic treatment were enrolled. Completeness of recanalization was assessed by the Thrombolysis in Myocardial Infarction (TIMI) grade, which was compared between patients with and without cardiac sources of embolism (CSE). We also investigated independent predictors of poor outcome (modified Rankin scale score 3-6) at 3 months. RESULTS: Of the 127 patients enrolled, 65 (51%) had one or more CSE. Although the overall recanalization rates (TIMI 2 or 3) in patients with CSE (65%) and patients without CSE (68%) were similar (P=0.710), patients with CSE were less likely to show complete recanalization (TIMI 3) compared with those without CSE (19% vs. 39%, P=0.011). Multivariate analysis revealed that CSE was associated with failure of complete recanalization (OR 2.809, 95% CI 1.097 7.192) and was an independent predictor of poor outcome at 3months (OR 3.629, 95% CI 1.205-8.869). CONCLUSIONS: In cardioembolic strokes, failure of complete recanalization following thrombolytic therapy was frequent and was associated with poor outcome after thrombolysis. PMID- 21309927 TI - The GABA-B positive modulator GS39783 decreases psychostimulant conditioned reinforcement and conditioned-reward. AB - Baclofen, a gamma-amino-butyric-acid (GABA)(B) receptor agonist, can reduce cue enhanced cocaine-seeking in rats and attenuate cue-evoked craving in cocaine addicts. However, baclofen also has sedative effects that might interfere with its efficacy in reducing cocaine's rewarding effects. The present study aimed at comparing the effects of baclofen with the GABA(B) -receptor positive allosteric modulator GS39783 on psychostimulant conditioned cues. Two identically trained groups of male Lister-Hooded rats were baselined on a new responding for a light stimulus previously paired with cocaine self-administration. One group was treated with the GABA(B) -receptor positive allosteric modulator GS39783 (0, 10, 30, 100 mg/kg, i.p.), the other with baclofen (0, 0.6, 1.25, 1.9, 2.5 mg/kg, i.p.). In another series of experiments, male Wistar rats received GS39783 (0, 10, 30, 100 mg/kg, i.p.) or baclofen (1.25 mg/kg) prior to the expression of a conditioned place preference (CPP) to amphetamine (2 mg/kg i.p.). Both GS39783 (30 and 100 mg/kg) and baclofen (2.5 mg/kg) significantly decreased responding for the cocaine cue; however, only GS39783 (30 mg/kg) reduced lever pressing responding without interfering with locomotor activity. Both GS39783 (30 and 100 mg/kg) and baclofen (1.25 mg/kg), significantly blocked the expression of amphetamine CPP without affecting locomotor activity. These findings suggest that GABA(B) positive allosteric modulators can modulate discrete and contextual psychostimulant conditioned stimuli in a manner dissociable from unwanted sedative effects and may offer a novel therapeutic approach to treat cravings and relapse to drug-taking triggered by stimuli associated with psychostimulant use. PMID- 21309928 TI - Low plasma antibodies specific for phosphatidylethanol in alcohol abusers and patients with alcoholic pancreatitis. AB - Phosphatidylethanol (PEth) is a group of alcohol-modified phospholipids present in cell membranes after heavy drinking. Our aim was to demonstrate the presence of human plasma antibodies binding to PEth and to address their specificity and value in detecting subjects engaged in heavy alcohol consumption. Antibodies to PEth were analyzed in plasma from heavy drinkers (n=20), patients with alcoholic pancreatitis (n=58) and control subjects (n=24), using chemiluminescent immunoassay. Heavy drinkers and patients with alcoholic pancreatitis demonstrated significantly lower levels of plasma IgG, IgA and IgM titers to PEth compared with controls (P<0.001). The specificity of the antibodies to PEth was demonstrated with competitive liquid phase immunoassays and flow cytometry. The plasma IgG, but not IgA or IgM, titers to PEth in heavy drinkers correlated with the whole blood PEth concentration determined by liquid chromatography-mass spectrometry (r=0.655, P=0.002). Compared with traditional markers for alcohol abuse (aspartate aminotransferase, gamma-glutamyl transpeptidase and mean corpuscular volume), receiver operating characteristic curve analysis showed that a low plasma IgA to PEth had the highest area under the curve (AUC 0.940, P<0.001). In conclusion, plasma IgG, IgA and IgM antibodies binding specifically to PEth were found in subjects of all study groups. Subjects with heavy alcohol consumption showed markedly lower plasma immunoglobulin levels to PEth, potentially making them useful as a biomarker to distinguish heavy from moderate alcohol use. PMID- 21309929 TI - Training minimal invasive approaches in hepatopancreatobilliary fellowship: the current status. AB - BACKGROUND: There has been an increasing role of advanced minimally invasive procedures in hepatopancreatobilliary (HPB) surgery. However, there are no set minimum laparoscopic case requirements. METHODS: A 14-question electronic survey was sent to 82 worldwide HPB fellowship programme directors. RESULTS: Forty-nine per cent (n=40) of the programme directors responded. The programmes were predominantly university based (83%). Programmes had either one (55%) or two fellows (40%) each year. Programmes (35-48%) had average annual volumes of 51-100 hepatic, 51-100 pancreatic and 25-50 biliary cases. For many programmes, <10% of hepatic (48%), pancreatic (40%) and biliary (70%) cases were done laparoscopically. The average annual fellow case volumes for hepatic, pancreatic and biliary surgeries were 25-50 (62%), 25-50 (47%) and <25 (50%), respectively. The average annual number of hepatic, pancreatic and biliary cases done laparoscopically by a fellow was 9, 9 and 4, which constitutes 36%, 36% and 16%, respectively, of the International Hepato-Pancreato-Billiary Association (IHPBA) requirement. CONCLUSION: We surmise that the low average number of surgeries performed by minimally-invasive techniques by HPB fellows is not sufficient in today's practice. Should there be an increase in the minimal number of hepatic, pancreatic and complex biliary cases to 50, 50, and 25, with at least 50% of these performed laparoscopically? PMID- 21309930 TI - Genexol inhibits primary tumour growth and metastases in gemcitabine-resistant pancreatic ductal adenocarcinoma. AB - INTRODUCTION: Gemcitabine, the current standard of care for pancreatic ductal adenocarcinoma (PDA), has a less than 10% partial response rate. Genexol-PM, a modified form of paclitaxel, has been shown to have antitumour effects in clinical trials of metastatic breast and small-lung-cell carcinoma. The aim of the present study was to determine if Genexol would be a beneficial treatment for gemcitabine-resistant PDA. MATERIALS AND METHODS: We measured the in vitro IC50s of gemcitabine and genexol in cell lines sensitive and resistant to gemcitabine. In vivo, animals with orthotopic pancreatic tumours, resistant to gemcitabine, were treated with phosphate-buffered saline (PBS), gemcitabine, Genexol or gemcitabine+Genexol. Tumour progression was monitored using red fluorescent protein imaging. RESULTS: We showed equivalent IC50s for gemcitabine-sensitive and gemcitabine-resistant cell lines when treated with genexol. In vivo treatment with genexol resulted in a greater per cent reduction in tumour size, less metastatic spread and longer survival compared with treatment with gemcitabine. DISCUSSION: Genexol proved to be an effective treatment for gemcitabine-resistant PDA. These data combined with the successful clinical use of genexol in Phase II trials of other malignancies suggests it maybe an effective treatment for pancreatic cancer, specifically for those patients resistant to gemcitabine. PMID- 21309931 TI - Integrated ablation and division device for liver resection. AB - BACKGROUND: Intraoperative blood loss during liver resection may be minimized by ablating the liver parenchyma using radiofrequency (RF) energy. However, it is difficult to estimate the depth of the avascular plane and more RF energy than necessary may be inadvertently used as a result of lack of feedback. METHODS: Laparoscopic liver resection was performed on a live porcine model to determine the feasibility and applicability of a model which integrates ablation and division in a single device. RESULTS: Liver resection was uncomplicated with minimal bleeding. The integration of the ablation and division mechanism resolved the difficulty of estimating the depth of the avascular plane after coagulation. The real-time feedback mechanism minimized liver damage by eliminating the application of unnecessary RF. CONCLUSIONS: The proposed model is functionally acceptable and represents a possible method of determining the depth of the avascular plane and the amount of RF energy required during liver resection. PMID- 21309932 TI - Influence of aberrant right hepatic artery on perioperative course and longterm survival after pancreatoduodenectomy. AB - OBJECTIVES: An aberrant right hepatic artery (aRHA) is the most frequently encountered vascular anomaly during pancreatoduodenectomy (PD). This study was performed to investigate the incidence of aRHA in a large series of PDs and to explore its relationship with complications and survival. METHODS: In a consecutive series of 790 PDs, aRHA could be identified or ruled out in 758 patients by reviewing operation reports. Patients with and without aRHA were compared. Main outcome measures were complications and survival (only in patients with a malignancy). RESULTS: The aRHA group consisted of 143 patients (19%). Characteristics of patients in the aRHA and normal RHA groups were comparable. There were no differences in surgical complications. The aRHA was preserved without damage in 130 patients (91%). Two patients in whom the aRHA was either sacrificed or damaged suffered complications (haemorrhage and intra-abdominal abscess in the right upper quadrant) that may have been related. Longterm survival in patients with a malignancy and an aRHA was not compromised. CONCLUSIONS: An aRHA is frequently encountered during PD. Preservation is generally feasible without compromising survival in patients with malignant tumours. Surgical morbidity is not higher in patients with an aRHA. Preservation is technically possible in most patients and does not negatively impact on outcomes. PMID- 21309933 TI - Irreversible electroporation of the liver and liver hilum in swine. AB - BACKGROUND: Irreversible electroporation (IRE) is a novel, non-thermal form of ablation. We studied the safety and efficacy of IRE for the ablation of liver tissue around the liver hilum. We also studied the ability of triphenyltetrazolium chloride staining (TTC) to predict the zone of ablation after IRE. METHODS: Eight swine underwent 20 ablations of the liver and liver hilum. Two monopolar probes were positioned 2 cm apart. IRE was performed using 90 pulses of 2500-3000 V/cm. IRE treatments were performed from 15 min to 14 days (n= 4) before sacrifice. RESULTS: All animals survived. No major complications were encountered. Ablation width ranged from 2.27 to 4.45 cm and ablation height ranged from 1.5 to 1.8 cm. TTC staining demonstrated the zone of ablation in all animals. Hepatocyte necrosis occurs immediately adjacent to large central veins without evidence of heat sink. Bile ducts, portal veins and hepatic arteries appear to be more resistant to the effects of IRE. CONCLUSIONS: IRE appears to be safe and effective for liver tissue ablation in the liver hilum. The portal structures appear more resistant to the effects of IRE. TTC staining can predict the zone of IRE ablation as early as 15 min after treatment. PMID- 21309934 TI - A retrospective analysis of benzodiazepine sedation vs. propofol anaesthesia in 252 patients undergoing endoscopic retrograde cholangiopancreatography. AB - BACKGROUND: Historically, hepatopancreatobiliary surgeons and gastroenterologists have undertaken endoscopic retrograde cholangiopancreatography (ERCP) using benzodiazepine sedation (BS). This is poorly tolerated by a substantial number of patients, which leads to its potential premature abandonment and subsequent additional investigations and therapeutics, and hence to the exposure of patients to avoidable risk and the health service to increased costs. Furthermore, concerns have been raised in the recent literature regarding safe sedation techniques. OBJECTIVES: The aim of this study was to compare the completion rates and safety profile of ERCP using BS vs. those of ERCP using light propofol anaesthesia (PA). METHODS: We carried out a retrospective, case-matched comparison analysis of consecutive patients who underwent ERCP with BS vs. PA, in the presence of an anaesthetist, over a 2-year period. Benzodiazepine sedation consisted of midazolam, fentanyl and buscopan. Propofol anaesthesia consisted of propofol, fentanyl and buscopan administered via a mouth guard in a non-intubated patient. Patient demographics, complications and completion rates were recorded. Procedural monitoring included pulse oximetry, non-invasive blood pressure, electrocardiography and end-tidal CO(2) . Statistical analyses used t-tests to compare continuous variables and chi-squared and Fisher's exact tests to compare categorical variables. A P-value of <0.05 was considered significant. RESULTS: Of 252 patients included in the study, 128 (50.8%) received BS and 124 (49.2%) received PA. Median ages in the BS and PA groups were 69 years (range: 20-99 years) and 65 years (range: 26-98 years), respectively (P= 0.07). Median hospital stays in the BS and PA groups were 1 day (range: day case to 61 days) and 1 day (range: day case to 38 days), respectively (P= 0.61). Incidences of mild anaesthesia-related complications in the BS and PA groups were 2.3% and 2.4%, respectively (P= 0.97). There were no severe anaesthesia-related complications. Incidences of mild procedural complications in the BS and PA groups were 2.3% and 1.6%, respectively (P= 0.68). One severe procedural complication occurred in the PA group. Incidences of incomplete ERCP procedures in the BS and PA groups were 10.9% (n= 14) and 4.0% (n= 5), respectively (odds ratio = 2.92, 95% confidence interval 1.02-8.38; chi-squared test, P= 0.04; Fisher's exact test, P= 0.03). CONCLUSIONS: Propofol anaesthesia for ERCP carried out in the presence of an anaesthetist is safe and may improve procedural completion rates. PMID- 21309935 TI - A comparison of the hospital costs of open vs. minimally invasive surgical management of necrotizing pancreatitis. AB - BACKGROUND: Infected necrotizing pancreatitis is a major burden for both the patient and the health care system. Little is known about how hospital costs break down and how they may have shifted with the increasing use of minimally invasive techniques. The aim of this study was to analyse inpatient hospital costs associated with pancreatic necrosectomy. METHODS: A prospective database was used to identify all patients who underwent an intervention for necrotizing pancreatitis. Costs of treatment were calculated using detailed information from the Decision Support Department. Costs for open and minimally invasive surgical modalities were compared. RESULTS: Twelve open and 13 minimally invasive necrosectomies were performed in a cohort of 577 patients presenting over a 50 month period. One patient in each group died in hospital. Overall median stay was 3.8 days in the intensive care unit (ICU) and 44 days on the ward. The median overall treatment cost was US$ 56,674. The median largest contributors to this total were ward (26.3%), surgical personnel (22.3%) and ICU (17.0%) costs. These did not differ statistically between the two treatment modalities. CONCLUSIONS: Pancreatic necrosectomy uses considerable health care resources. Minimally invasive techniques have not been shown to reduce costs. Any intervention that can reduce the length of hospital and, in particular, ICU stay by reducing the incidence of organ failure or by preventing secondary infection is likely to be cost-effective. PMID- 21309936 TI - Real-time three-dimensional guided ultrasound targeting system for microwave ablation of liver tumours: a human pilot study. AB - OBJECTIVES: This study aimed to evaluate a novel three-dimensional ultrasound (US) guidance system for use in hepatic microwave ablation (MWA). METHODS: An in vitro assessment was performed in which users with different degrees of experience were evaluated for accuracy in targeting phantom lesions embedded in agar using US alone, or US in conjunction with the InVisionTM System (IVS). An eight-patient pilot trial of the IVS was then performed in the setting of open hepatic MWA, in which lesions would otherwise have been targeted with conventional US. RESULTS: In vitro studies demonstrated that the IVS significantly improved targeting accuracy at all levels of operator experience (novice, beginner and expert). In the human trial, a total of 31 tumours were targeted and all lesions were hit in one pass, as assessed by independent US image observations. There were no adverse operative events; however, there was minor line-of-sight interference with the infra-red tracking mechanism when some lesions high on the dome of the liver were targeted. CONCLUSIONS: The IVS significantly increased the accuracy of complex targeting procedures of phantom lesions and enhanced targeting in an eight-patient clinical pilot study. During the accrual phase of this pilot study, the development of improved non-optical tracking hardware obviated the requirement to maintain a direct line of sight. The trial was then halted prematurely in order to focus on the application of the IVS utilizing this non-optical modality. PMID- 21309937 TI - Cirrhosis is not a contraindication to laparoscopic cholecystectomy: results and practical recommendations. AB - BACKGROUND: Gallstones appear more frequently in patients with cirrhosis and open cholecystectomy in this patient population is associated with higher morbidity and mortality. The aim of the present study was to evaluate experience with laparoscopic cholecystectomy in patients with cirrhosis and to provide recommendations for management. METHODS: Retrospective review of laparoscopic cholecystectomy in patients with cirrhosis from March 1999 to May 2008 was performed. Peri-operative characteristics and subgroup analysis were performed in patients with Child-Pugh's classes A, B and C cirrhosis. RESULTS: A total of 68 patients were reviewed in this study. In all, 69% of the patients were Child's class A. The most common indication for cholecystectomy was chronic/symptomatic cholelithiasis (68%). Compared with patients with Child's class B and C, laparoscopic cholecystectomy in patients with Child's class A was associated with significantly decreased operative time (P= 0.01), blood loss (P= 0.001), conversion to open cholecystectomy (P= 0.001) and length of hospital stay (P= 0.001). CONCLUSIONS: Laparoscopic cholecystectomy in patients with cirrhosis is feasible with no mortality and low morbidity, especially in patients with Child's class A cirrhosis. PMID- 21309938 TI - Comparison of the prognostic accuracy of the sixth and seventh editions of the TNM classification for intrahepatic cholangiocarcinoma. AB - BACKGROUND: The seventh TNM edition introduced a new, specific staging structure for intrahepatic cholangiocarcinoma (IHC). OBJECTIVE: To compare the accuracy of the sixth and the new seventh edition to predict survival after hepatectomy for IHC. METHODS: In all, 434 consecutive patients who underwent hepatectomy at 16 tertiary-care centres (1990-2008) were identified. End points were overall (OS) and recurrence-free survival (RFS) for both T cohorts and stage strata. RESULTS: After a median follow-up of 32.4 months, 3- and 5-year OS and RFS estimates were 47.1% and 32.9%, and 26.5% and 19.1%, respectively. Overall, both the editions were statistically significant discriminators of OS and RFS (P < 0.05). However, the survival curves of the new T2a and T2b cohorts appear superimposed. Conversely, the old T2 and T3 cohorts accurately stratify patients into distinct prognostic groups (P < 0.01). The seventh edition does not show monotonicity of gradients (the T4 category demonstrates significantly better OS and RFS compared with T2 patients). The seventh edition stage I and II are significantly different whereas the old stage I and II were not. CONCLUSIONS: The new seventh edition of the AJCC/UICC Staging System proved to be adequate although further studies are need to confirm its superiority compared with the previous edition. PMID- 21309939 TI - Effectiveness of epidural analgesia following open liver resection. AB - OBJECTIVES: Epidural analgesia is often considered the reference standard for pain relief following major abdominal surgery; however, the provision of analgesia in the context of liver surgery raises unique challenges. This study investigated the effectiveness of analgesia and the postoperative course of patients who did or did not receive epidural analgesia following liver resection. METHODS: Data were collected retrospectively on 177 patients who underwent open liver resection between June 2007 and June 2009. Patients were divided into two groups consisting, respectively, of those who received epidural analgesia (Epidural group, n= 148) and those who did not (No-Epidural group, n= 29). RESULTS: In the Epidural group, 27 patients (18%) required i.v. opiate analgesia on the day of surgery (DoS) or the first postoperative day (POD1). The Epidural group received significantly more i.v. colloid solution on the DoS (median: 1500 ml vs. 750 ml, range: 0-12,000 ml vs. 0-3500 ml; P= 0.004) and POD1 (median: 0 ml vs. 0 ml, range: 0-5000 ml vs. 0-1000 ml; P= 0.018), and total fluid on the DoS and POD1 combined (median: 6522 ml vs. 5453 ml, range: 2150-21 300 ml vs. 2875 15,886 ml; P= 0.032). CONCLUSIONS: Epidural analgesia provided inadequate postoperative pain relief in approximately 20% of liver resection patients and was associated with the administration of significantly greater volumes of i.v. colloid solution. PMID- 21309940 TI - Liver grafts from selected older donors do not have significantly more ischaemia reperfusion injury. AB - BACKGROUND: There is a general concern that aged organs are more susceptible to ischaemia. In the light of recent proposals to change the liver allocation system by expanding regional sharing, it is feared that increased cold ischaemia time of grafts from older donors may reduce graft survival. The aim of this study was to correlate donor age and the patterns of ischaemia reperfusion injury and synthetic function early after liver transplantation. METHODS: We performed a retrospective study of first transplants using a single-centre electronic database. Patterns of liver injury (based on transaminases and post-reperfusion biopsy), synthetic function (international normalized ratio [INR]), and graft and patient survival in recipients receiving liver grafts from donors aged >= 65 years (group 1, n= 50) were compared with equivalent patterns in a matched cohort of recipients transplanted with grafts from donors aged <65 years (group 2, n= 50). RESULTS: There was no significant difference in transaminase levels from day 0 to day 6 after transplantation. When groups 1 and 2 were subdivided into two subgroups based on the duration of graft cold ischaemia time (<8 h and >= 8 h), there was no statistical difference in transaminase levels during the first 7 days. There were two cases (4%) of primary non-function in group 1 and one (2%) in group 2. Initial poor function did not differ significantly between the groups (26% vs. 24%; P= 0.81). In addition, there was no difference in histological changes in post-reperfusion biopsies (21% vs. 34%; P= 0.078) and rate of acute rejection episodes in the first year (30% vs. 32%; P= 0.99). There was no significant difference between groups 1 and 2 in 1-year patient and graft survivals (78% vs. 90% [P= 0.17]; 88% vs. 94% [P= 0.48], respectively). CONCLUSIONS: Judiciously selected livers from aged donors are not associated with major increased susceptibility to ischaemia reperfusion injury. PMID- 21309941 TI - Re: Alanine transaminase rather than abdominal ultrasound alone is an important investigation to justify cholecystectomy in patients presenting with acute pancreatitis. PMID- 21309944 TI - Ghrelin receptor (GHS-R1A) antagonism suppresses both operant alcohol self administration and high alcohol consumption in rats. AB - The mechanisms involved in alcohol use disorders are complex. It has been shown that ghrelin is an important signal for the control of body weight homeostasis, preferably by interacting with hypothalamic circuits, as well as for drug reward by activating the mesolimbic dopamine system. The ghrelin receptor (GHS-R1A) has been shown to be required for alcohol-induced reward. Additionally, ghrelin increases and GHR-R1A antagonists reduce moderate alcohol consumption in mice, and a single nucleotide polymorphism in the GHS-R1A gene has been associated with high alcohol consumption in humans. However, the role of central ghrelin signaling in high alcohol consumption is not known. Therefore, the role of GHS R1A in operant self-administration of alcohol in rats as well as for high alcohol consumption in Long-Evans rats and in alcohol preferring [Alko alcohol (AA)] rats was studied here. In the present study, the GHS-R1A antagonist, JMV2959, was found to reduce the operant self-administration of alcohol in rats and to decrease high alcohol intake in Long-Evans rats as well as in AA rats. These results suggest that the ghrelin receptor signaling system, specifically GHS-R1A, is required for operant self-administration of alcohol and for high alcohol intake in rats. Therefore, the GHS-R1A may be a therapeutic target for treatment of addictive behaviors, such as alcohol dependence. PMID- 21309945 TI - A novel role for PSD-95 in mediating ethanol intoxication, drinking and place preference. AB - The synaptic signaling mechanisms mediating the behavioral effects of ethanol (EtOH) remain poorly understood. Post-synaptic density 95 (PSD-95, SAP-90, Dlg4) is a key orchestrator of N-methyl-D-aspartate receptors (NMDAR) and glutamatergic synapses, which are known to be major sites of EtOH's behavioral actions. However, the potential contribution of PSD-95 to EtOH-related behaviors has not been established. Here, we evaluated knockout (KO) mice lacking PSD-95 for multiple measures of sensitivity to the acute intoxicating effects of EtOH (ataxia, hypothermia, sedation/hypnosis), EtOH drinking under conditions of free access and following deprivation, acquisition and long-term retention of EtOH conditioned place preference (CPP) (and lithium chloride-induced conditioned taste aversion), and intoxication-potentiating responses to NMDAR antagonism. PSD 95 KO exhibited increased sensitivity to the sedative/hypnotic, but not ataxic or hypothermic, effects of acute EtOH relative to wild-type controls (WT). PSD-95 KO consumed less EtOH than WT, particularly at higher EtOH concentrations, although increases in KO drinking could be induced by concentration-fading and deprivation. PSD-95 KO showed normal EtOH CPP 1 day after conditioning, but showed significant aversion 2 weeks later. Lithium chloride-induced taste aversion was impaired in PSD-95 KO at both time points. Finally, the EtOH potentiating effects of the NMDAR antagonist MK-801 were intact in PSD-95 KO at the dose tested. These data reveal a major, novel role for PSD-95 in mediating EtOH behaviors, and add to growing evidence that PSD-95 is a key mediator of the effects of multiple abused drugs. PMID- 21309946 TI - Relationship between vulnerability to reinforcing effects of morphine and activity of the endogenous cholecystokinin system in Lewis and Fischer rats. AB - A great number of studies have shown the presence of physiological interactions between brain neurotransmitter systems in behavioural responses. This is the case for opioid, cholecystokinin (CCK) and dopamine systems. However, so far the role that the CCK system may play in vulnerability to consumption of drugs of abuse is not clear. This was investigated in this study using Lewis rats that are more sensitive to the reinforcing properties of drugs of abuse than Fischer rats. The extraneuronal CCK(8) levels and brain CCK(2) receptors were found higher in Fischer than in Lewis rats in the nucleus accumbens, one of the most important structures involved in drug consumption. Moreover, pharmacological modulation of the CCK system by administration of a selective CCK(2) agonist blocked, in the conditioned place preference, the reinforcing effects of morphine in Lewis rats, whereas a selective CCK(2) antagonist revealed reinforcing effects of the alkaloid in Fischer rats. These results obtained following systemic administrations of the CCK ligands were confirmed following microinjection into the nucleus accumbens. Thus, a low level of CCK efflux in the nucleus accumbens could be one of the many factors involved in drug reinforcing effects, whereas a high level of CCK efflux could attenuate it. PMID- 21309948 TI - Reversal of cocaine-conditioned place preference and mesocorticolimbic Zif268 expression by social interaction in rats. AB - Little is known how social interaction, if offered as an alternative to drug consumption, affects neural circuits involved in drug reinforcement and substance dependence. Conditioned place preference (CPP) for cocaine (15 mg/kg i.p.) or social interaction (15 minutes) as an alternative stimulus was investigated in male Sprague-Dawley rats. Four social interaction episodes with a male adult conspecific completely reversed cocaine CPP and were even able to prevent reacquisition of cocaine CPP. Social interaction also reversed cocaine CPP induced expression of the immediate-early gene zif268 in the nucleus accumbens shell, the central and basolateral amygdala and the ventral tegmental area. These findings suggest that social interaction, if offered in a context that is clearly distinct from the previously drug-associated ones, may profoundly decrease the incentive salience of drug-associated contextual stimuli. The novel experimental design facilitates the neurobiological investigation of this phenomenon which may be beneficial for human drug users in treatment. PMID- 21309947 TI - Neuroimmune regulation of alcohol consumption: behavioral validation of genes obtained from genomic studies. AB - Analysis of mouse brain gene expression, using strains that differ in alcohol consumption, provided a number of novel candidate genes that potentially regulate alcohol consumption. We selected six genes [beta-2-microglobulin (B2m), cathepsin S (Ctss), cathepsin F (Ctsf), interleukin 1 receptor antagonist (Il1rn), CD14 molecule (Cd14) and interleukin 6 (Il6)] for behavioral validation using null mutant mice. These genes are known to be important for immune responses but were not specifically linked to alcohol consumption by previous research. Null mutant mice were tested for ethanol intake in three tests: 24-hour two-bottle choice, limited access two-bottle choice and limited access to one bottle of ethanol. Ethanol consumption and preference were reduced in all the null mutant mice in the 24-hour two-bottle choice test, the test that was the basis for selection of these genes. No major differences were observed in consumption of saccharin or quinine in the null mutant mice. Deletion of B2m, Ctss, Il1rn, Cd14 and Il6 also reduced ethanol consumption in the limited access two bottle choice test for ethanol intake; with the Il1rn and Ctss null mutants showing reduced intake in all three tests (with some variation between males and females). These results provide the most compelling evidence to date that global gene expression analysis can identify novel genetic determinants of complex behavioral traits. Specifically, they suggest a novel role for neuroimmune signaling in regulation of alcohol consumption. PMID- 21309949 TI - COMT and ALDH2 polymorphisms moderate associations of implicit drinking motives with alcohol use. AB - Dual process models of addiction emphasize the importance of implicit (automatic) cognitive processes in the development and maintenance of substance use behavior. Although genetic influences are presumed to be relevant for dual process models, few studies have evaluated this possibility. The current study examined two polymorphisms with functional significance for alcohol use behavior (COMT Val158Met and ALDH2*2) in relation to automatic alcohol cognitions and tested additive and interactive effects of genotype and implicit cognitions on drinking behavior. Participants were college students (n = 69) who completed Implicit Association Tasks (IATs) designed to assess two classes of automatic drinking motives (enhancement motives and coping motives). Genetic factors did not show direct associations with IAT measures; however, COMT and ALDH2 moderated associations of implicit coping motives with drinking outcomes. Interaction effects indicated that associations of implicit motives with drinking outcomes were strongest in the context of genetic variants associated with relatively higher risk for alcohol use (COMT Met and ALDH2*1). Associations of genotype with drinking behavior were observed for ALDH2 but not COMT. These findings are consistent with the possibility that genetic risk or protective factors could potentiate or mitigate the influence of reflexive cognitive processes on drinking behavior, providing support for the evaluation of genetic influences in the context of dual process models of addiction. PMID- 21309950 TI - The SLC6A4 VNTR genotype determines transcription factor binding and epigenetic variation of this gene in response to cocaine in vitro. AB - We demonstrated that the genotype of the variable number tandem repeats (VNTRs) in the linked polymorphic region (LPR) of the 5' promoter and in the intron 2 (Stin2) transcriptional regulatory domains of the serotonin transporter SLC6A4 gene determined its promoter interactions with transcription factors and co activators in response to cocaine in the JAr cell line. The LPR variants contain 14 (short, s) or 16 (long, l) copies of a 22-23 bp repeat element, whereas the Stin2 VNTR exists as three variants containing 9, 10 or 12 copies of a 16-17 bp repeat. We observed a differential effect of cocaine on the association of the promoter with the transcription factor CTCF, which bound to both LPR alleles prior to cocaine exposure but only to the l-allele following exposure. Significantly, this differential effect of cocaine was correlated with the binding of the transcriptional regulator MeCP2 specifically to the s-allele and recruiting the histone deacetylase complex (HDAC). Concurrently, cocaine increased the association of positive histone marks over the SLC6A4 gene locus. At the Stin2 domain, we lost binding of the transcription factor YB-1, while CTCF remained bound. Our biochemical data are consistent with differential reporter gene activity directed by the individual or dual domains in response to cocaine in an Epstein-Barr virus-based episome model of stable transfections. These observations suggest that exposure of JAr cells to cocaine may result in differential binding of transcription factors and activators based on a specific genotype that might alter epigenetic parameters affecting gene expression after the initial challenge. PMID- 21309951 TI - Effect of morphine on conditioned place preference in rhesus monkeys. AB - In rodents, a conditioned place preference (CPP) can be induced by morphine. In the current study, we designed a biased place conditioning paradigm to test the rewarding effects of morphine in freely moving rhesus monkeys. Five monkeys were first placed in three serial rooms with the doors open between them for three days. After this habituation period, during which baseline preference for each of the two end rooms was measured, CPP conditioning occurred when the monkeys were injected intramuscularly with morphine at an increasing dose (1.5, 3, 4.5 mg/kg) before they entered the non-preferred room and on alternate days, with saline before they entered the preferred room. Morphine and saline treatment lasted for six days, respectively. CPP was tested 24 hours after the end of CPP training. The result showed that in all five monkeys, CPP was induced by the morphine treatment. The preference lasted for at least 15.3 +/- 1.7 months. PMID- 21309952 TI - MR spectroscopy in opiate maintenance therapy: association of glutamate with the number of previous withdrawals in the anterior cingulate cortex. AB - Pre-clinical research indicates that opioids reduce extracellular glutamate in acute opioid treatment, whereas during withdrawal, glutamatergic neurotransmission is increased and withdrawal symptoms can be blocked by glutamate receptor antagonists. The glutamate hypothesis of addiction suggests that withdrawal-associated hyperglutamatergic states destabilize the glutamatergic system chronically and contribute to relapse. magnetic resonance spectroscopy at three tesla optimized for glutamate assessment (TE 80 ms) was performed in the anterior cingulate gyrus (ACC) and frontal white matter (fWM) of 17 opiate-dependent patients during opiate maintenance therapy and 20 healthy controls. Controlling for age and gray matter content, glutamate in the ACC was positively associated with the number of previous withdrawals. For glutamate + glutamine (Glx), a significant group-age interaction was found. Whereas Glx declines with age in healthy controls, Glx increases with age in opiate-dependent patients. The number of previous withdrawals did not correlate with age. In fWM spectra, increased Cho concentrations were observed in opiate-dependent patients. Both new findings, the positive correlation of glutamate and previous withdrawals and increasing Glx with age in contrast to an age-dependent Glx decrease in controls indicate a destabilization of the glutamate system in opiate-dependent patients and support the glutamate hypothesis of addiction. Increased Cho concentrations in fWM corroborate findings of WM abnormalities in opioid dependent subjects. PMID- 21309954 TI - Sex and estrous cycle differences in cocaine-induced approach-avoidance conflict. AB - Human and animal research indicates that females may have a higher biological propensity for cocaine abuse than do males. Furthermore, reproductive status modulates the subjective effects of cocaine in women and self-administration rates in rats. Despite the attention that has been given to the modulation of appetitive responses by reproductive status and the well-known mixed positive and negative subjective effects of cocaine, it is unknown if similar effects are observed on aversive responses to cocaine. The present study examines the impact of sex and estrous cycle on approach-avoidance behavior for cocaine as measured in the runway self-administration model. Male and freely cycling female Sprague Dawley rats were trained to traverse a straight alley for single daily injections of 1.0 mg/kg intravenous cocaine over 21 trials. Relative to males, females had significantly longer start latencies but significantly faster approach and shorter run times during the first week of training. Further, estrus females displayed significantly fewer approach-avoidance retreats across all sessions relative to non-estrus females. These results suggest that females initially exhibit greater motivation for cocaine (faster approach) than do males and that the drug's anxiogenic properties have a reduced impact on the motivation to seek cocaine (fewer retreats) in females during the estrus phase relative to other reproductive phases. These findings indicate that both sex and reproductive status contribute to the motivation for cocaine and that sex differences in addiction vulnerability may be attributable in part to differences in the motivational impact of both the appetitive and aversive properties of cocaine. PMID- 21309955 TI - Alpha-synuclein and heroin craving in opiate-dependent patients on injectable heroin maintenance. AB - Research suggests that alpha-synuclein (SNCA) and NACP-Rep1, a polymorphic complex microsatellite repeat ~10 kb upstream of the SNCA gene translational start, may be involved in substance-use behaviors and craving. This study was the first to examine the effects of diacetylmorphine (DAM) on peripheral SNCA protein expression along with craving in opiate-dependent patients and to compare their NACP-Rep1 allele lengths with those of healthy controls. Using an experimental design, opiate-dependent patients on injectable heroin maintenance were investigated at four time points, twice pre- and post-injection of DAM. SNCA protein levels of 30 DAM-maintained patients were measured using enzyme-linked immunosorbent assay. Participant-rated effects were assessed in 42 patients by Tiffany's Heroin Craving Questionnaire (HCQ), Gossop's Short Opiate Withdrawal Scale and Visual Analogs. NACP-Rep1 alleles of 42 patients and 101 controls were analyzed. One-way repeated-measures ANOVAs provided significant overall effects for SNCA protein content (P = 0.028), craving (P < 0.001), withdrawal symptomatology (P < 0.001) and mood (P < 0.001), indicating that DAM injections may not only reduce craving but also SNCA protein expression. However, there was no association between protein expression and craving. Relative to controls, patients had significantly longer NACP-Rep1 alleles (P < 0.001). NACP-Rep1 allele lengths correlated positively with HCQ total scores averaged across all time points (r = 0.420; P = 0.006) as well as with post-DAM HCQ total scores in the morning (r = 0.488, P = 0.001) and afternoon (r = 0.423, P = 0.005). The findings provide evidence of a contributory role of SNCA and NACP-Rep1 for opiate dependence. PMID- 21309953 TI - Evidence that vasopressin V1b receptors mediate the transition to excessive drinking in ethanol-dependent rats. AB - Alcoholism is a devastating condition that represents a progression from initial alcohol use to dependence. Although most individuals are capable of consuming alcohol in a limited fashion, the development of alcohol dependence in a subset of individuals is often associated with negative emotional states (including anxiety and depression). Since the alleviation of this negative motivational state via excessive alcohol consumption often becomes a central goal of alcoholics, the transition from initial use to dependence is postulated to be associated with a transition from positive to negative reinforcement mechanisms. Vasopressin is a neuropeptide known to potentiate the effects of CRF on the HPA axis, and emerging evidence also suggests a role for centrally located vasopressin acting on V(1b) receptors in the regulation of stress- and anxiety like behaviors in rodents. The present study determined state-dependent alterations in vasopressin/V(1b) R signaling in an animal model of ethanol dependence. The V(1b) R antagonist SSR149415 dose-dependently reduced excessive levels of ethanol self-administration observed in dependent animals without affecting the limited levels of ethanol drinking in non-dependent animals. Ethanol self-administration reduced V(1b) receptor levels in the basolateral amygdala of non-dependent animals, a neuroadaptation that could theoretically facilitate the positive reinforcing effects of alcohol. In contrast, V(1b) R levels were seemingly restored in ethanol-dependent rats, a switch that may in part underlie a transition from positive to negative reinforcement mechanisms with dependence. Together, our data suggest a key role for vasopressin/V(1b) R signaling in the transition to ethanol dependence. PMID- 21309956 TI - Role of ghrelin in food reward: impact of ghrelin on sucrose self-administration and mesolimbic dopamine and acetylcholine receptor gene expression. AB - The decision to eat is strongly influenced by non-homeostatic factors such as food palatability. Indeed, the rewarding and motivational value of food can override homeostatic signals, leading to increased consumption and hence, obesity. Ghrelin, a gut-derived orexigenic hormone, has a prominent role in homeostatic feeding. Recently, however, it has emerged as a potent modulator of the mesolimbic dopaminergic reward pathway, suggesting a role for ghrelin in food reward. Here, we sought to determine whether ghrelin and its receptors are important for reinforcing motivation for natural sugar reward by examining the role of ghrelin receptor (GHS-R1A) stimulation and blockade for sucrose progressive ratio operant conditioning, a procedure used to measure motivational drive to obtain a reward. Peripherally and centrally administered ghrelin significantly increased operant responding and therefore, incentive motivation for sucrose. Utilizing the GHS-R1A antagonist JMV2959, we demonstrated that blockade of GHS-R1A signaling significantly decreased operant responding for sucrose. We further investigated ghrelin's effects on key mesolimbic reward nodes, the ventral tegmental area (VTA) and nucleus accumbens (NAcc), by evaluating the effects of chronic central ghrelin treatment on the expression of genes encoding major reward neurotransmitter receptors, namely dopamine and acetylcholine. Ghrelin treatment was associated with an increased dopamine receptor D5 and acetylcholine receptor nAChRbeta2 gene expression in the VTA and decreased expression of D1, D3, D5 and nAChRalpha3 in the NAcc. Our data indicate that ghrelin plays an important role in motivation and reinforcement for sucrose and impacts on the expression of dopamine and acetylcholine encoding genes in the mesolimbic reward circuitry. These findings suggest that ghrelin antagonists have therapeutic potential for the treatment of obesity and to suppress the overconsumption of sweet food. PMID- 21309958 TI - Emergence of context-associated GluR(1) and ERK phosphorylation in the nucleus accumbens core during withdrawal from cocaine self-administration. AB - Reexposure to cocaine-associated environments promotes relapse to cocaine seeking and represents a persistent impediment to successful abstinence. Neurobiological adaptations are thought to underlie the preservation of drug-seeking behavior during protracted withdrawal periods, possibly including changes associated specifically with cocaine-paired contexts. We measured GluR(1) (S845) and extracellular signal-regulated kinase (ERK) phosphorylation in rat striatal subregions in an animal model of cocaine relapse. Animals with cocaine self administration experience and their yoked partners were exposed to extinction conditions for one hour in the drug-paired environmental context after one day or three weeks withdrawal to measure protein phosphorylation induced by the cocaine paired context in the absence of cocaine reinforcement. GluR(1) (S845) (an index of protein kinase A (PKA) activity) and ERK phosphorylation increased in the nucleus accumbens core of self-administering but not yoked animals after three weeks (but not one day) withdrawal, indicating a time-dependent emergence of context-associated protein phosphorylation in this accumbens subregion. In comparison, animals trained to self-administer sucrose displayed a similar increase in ERK, but not GluR(1) (S845) , phosphorylation following reexposure to a sucrose-paired environment three weeks later, indicating that GluR(1) (S845) phosphorylation did not result solely from lever press behavior per se. In contrast, basal (home cage) GluR(1) (S845) phosphorylation was elevated in the nucleus accumbens shell and caudate-putamen after one day or three weeks cocaine withdrawal regardless of context exposure. These results suggest that time dependent emergence of context-associated GluR(1) (S845) phosphorylation in the nucleus accumbens core may contribute to the persistence of cocaine-seeking behavior, whereas ERK phosphorylation may be a consequence of this behavior. PMID- 21309957 TI - The delta opioid receptor antagonist, SoRI-9409, decreases yohimbine stress induced reinstatement of ethanol-seeking. AB - A major problem in treating alcohol use disorders (AUDs) is the high rate of relapse due to stress and re-exposure to cues or an environment previously associated with alcohol use. Stressors can induce relapse to alcohol-seeking in humans or reinstatement in rodents. Delta opioid peptide receptors (DOP-Rs) play a role in cue-induced reinstatement of ethanol-seeking; however, their role in stress-induced reinstatement of ethanol-seeking is not known. The objective of this study was to determine the role of DOP-Rs in yohimbine-stress-induced reinstatement of ethanol-seeking. Male, Long-Evans rats were trained to self administer 10% ethanol in daily 30-minute operant self-administration sessions using a FR3 schedule of reinforcement, followed by extinction training. Once extinction criteria were met, we examined the effects of the DOP-R antagonist, SoRI-9409 (0-5 mg/kg, i.p.) on yohimbine (2 mg/kg, i.p.) stress-induced reinstatement. Additionally, DOP-R-stimulated [(35) S]GTPgammaS binding was measured in brain membranes and plasma levels of corticosterone (CORT) were determined. Pre-treatment with SoRI-9409 decreased yohimbine stress-induced reinstatement of ethanol-seeking but did not affect yohimbine-induced increases in plasma CORT levels. Additionally, yohimbine increased DOP-R-stimulated (35) [S]GTPgammaS binding in brain membranes of ethanol-trained rats, an effect that was inhibited by SoRI-9409. This suggests that the DOP-R plays an important role in yohimbine-stress-induced reinstatement of ethanol-seeking behavior, and DOP-R antagonists may be promising candidates for further development as a treatment for AUDs. PMID- 21309959 TI - Short-term development of behavioral sensitization to amphetamine requires N methyl-D-aspartate- and nicotinic-dependent mechanisms in the nucleus accumbens. AB - Repeated administration of psychostimulant drugs, such as amphetamine, induces an enhanced behavioral response to subsequent drug challenge. This behavioral sensitization is proposed to model the increased drug craving observed in human psychostimulant abusers. Current thinking is that the ventral tegmental area, but not the nucleus accumbens, plays a critical role in the development of behavioral sensitization. Here, we report that the concomitant blockade of glutamatergic and nicotinic ionotropic receptors in the core of the nucleus accumbens blocks the development of behavioral sensitization to amphetamine and further abolishes the increase in extracellular dopamine release induced by amphetamine in the nucleus accumbens. These findings demonstrate that the development of behavioral sensitization to amphetamine depends, in addition to the well-known role of the ventral tegmental area, on glutamatergic and nicotinic-dependent mechanisms in the core of the nucleus accumbens and further indicate that the dopaminergic mesolimbic pathway must be viewed as a single coordinated system of critical importance in the development of behavioral sensitization to psychostimulant drugs. PMID- 21309961 TI - Dose effects associated with rivastigmine transdermal patch in patients with mild to-moderate Alzheimer's disease. AB - AIM: The cholinesterase inhibitor rivastigmine is available in both oral and transdermal forms. The efficacy of oral rivastigmine appears to be dose dependent. The current analysis investigates the effect of dose on the efficacy of the rivastigmine transdermal patch. METHODS: This was a retrospective analysis of a large, international, 24-week, randomised, placebo- and active-controlled trial (IDEAL, CENA713D2320) of rivastigmine in patients with mild-to-moderate Alzheimer's disease (AD). Patients received the 9.5 mg/24 h rivastigmine patch, the 17.4 mg/24 h rivastigmine patch, 12 mg/day rivastigmine capsules or placebo. Changes from baseline at week 24 on the AD Assessment Scale-cognitive subscale (ADAS-cog), AD Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) and the AD Cooperative Study-Activities of Daily Living (ADCS-ADL) scale were calculated based on the patient's mode and last prescribed patch dose. The analysis included the 4.6 mg/24 h and 13.3 mg/24 h patch doses, for which efficacy data have not previously been reported. RESULTS: Significant differences (p<0.05 vs. placebo) were seen on the ADAS-cog and ADCS-ADL for all mode rivastigmine patch doses (except 4.6 mg/24 h) and all last prescribed rivastigmine patch doses (except 4.6 mg/24 h and 13.3 mg/24 h). Patients with a last prescribed/mode patch dose of 9.5 mg/24 h and 13.3 mg/24 h showed significant improvements (p<0.05 vs. placebo) on the ADCS-CGIC. CONCLUSION: Rivastigmine patch doses higher than 9.5 mg/24 h may offer additional benefits. The 13.3 mg/24 h patch is worthy of further investigation. PMID- 21309960 TI - Innate difference in the endocannabinoid signaling and its modulation by alcohol consumption in alcohol-preferring sP rats. AB - The present study was undertaken to examine whether genetically predetermined differences in components of the endocannabinoid system were present in the brain of Sardinian alcohol-preferring (sP) and Sardinian alcohol-non-preferring (sNP) rats, a pair of rat lines selectively bred for opposite alcohol preference. The effects of acquisition and maintenance of alcohol drinking, alcohol withdrawal, and alcohol re-exposure on the endocannabinoid system was also assessed in the striatum of sP rats. The findings revealed significantly higher density of the CB1 receptors and levels of CB1 receptor mRNA, CB1 receptor-mediated G-protein coupling, and endocannabinoids in the cerebral cortex, hippocampus and striatum of alcohol-naive sP rats than sNP rats. A significantly lower expression of mFAAH enzyme was evident in the hippocampus of alcohol-naive sP rats. Alcohol drinking (during both acquisition and maintenance phases) in sP rats resulted in a significant reduction in striatal CB1 receptor-mediated G-protein coupling whereas alcohol withdrawal attenuated this effect. Alcohol consumption was also associated with markedly increased levels of endocannabinoids in the striatum. Co administration of the CB1 receptor antagonist, rimonabant (SR141716A) reduced alcohol intake, and reversed alcohol-induced changes in CB1 receptor-mediated G protein activation. These findings provided a new insight into a potential genetic basis of excessive alcohol consumption, suggesting innate differences in the endocannabinoid system might be associated with higher alcohol preference in sP rats. The data also indicate a modulation of CB1 receptor-mediated signaling following alcohol consumption, and further strengthen the potential of the endocannabinoid system as a target for the treatment of alcohol related behaviors. PMID- 21309962 TI - Outcomes in pediatric solid-organ transplantation. AB - LaR Pediatric solid-organ transplantation is an increasingly successful treatment for organ failure. Five- and 10-yr patient survival rates have dramatically improved over the last couple of decades, and currently, over 80% of pediatric patients survive into adolescence and young adulthood. Waiting list mortality has been a concern for liver, heart, and intestinal transplantation, illustrating the importance of transplant as a life-saving therapy. Unfortunately, the success of pediatric transplantation comes at the cost of long-term or late complications that arise as a result of allograft rejection or injury, immunosuppression related morbidity, or both. As transplant recipients enter adolescence treatment, non-adherence becomes a significant issue, and the medical and psychosocial impacts transition to adulthood not only with regard to healthcare but also in terms of functional outcomes, economic potential, and overall QoL. This review addresses the clinical and psychosocial challenges encountered by pediatric transplant recipients in the current era. A better understanding of pediatric transplant outcomes and adult morbidity and mortality requires further ongoing assessment. PMID- 21309963 TI - KIR/HLA-I mismatching and risk of relapse in paediatric patients undergoing non haploidentical allogeneic haematopoietic stem cell transplantation. AB - In HSCT setting, KIR-driven alloreactivity might be better predicted if the donor KIR genotype is considered in addition to the recipient HLA genotype. The prediction of NK cell alloreactivity relies on the missing ligand in the recipient, a scenario that can be found in HLA-identical and non-identical allotransplants. The aim of this study was to investigate at genetic level the prognostic impact of recipient HLA-I lacking for donor KIR on allotransplanted patients outcome. We analysed donors KIR genotype and HLA genotype of 60 paediatric patients who received related (n=15) or unrelated (n=45) transplantation. When patients were grouped based on the KIR gene type involved in the KIR/HLA-I mismatch, we did not observe any relapse in the group of patients characterized by mismatches involving only inhibitory KIR. On the contrary, all relapses were observed in patients showing at least one activating gene involved in the mismatch (p<0.05). Although the biological mechanism accounting for this putative genetic rule is still to be clarified, we suggest that a careful survey of KIR/HLA-I mismatching should be taken into account in the selection of donor in related and unrelated HSCT. PMID- 21309964 TI - Donor and recipient ACE I/D genotype are associated with loss of renal function in children following renal transplantation. AB - Genetic polymorphisms of the RAS correlate with allograft function. We therefore analyzed common RAS polymorphisms in kidney donors and in children following RTx to determine the relationship between genotype and decline in GFR, blood pressure, and LVM. A total of 107 children who underwent RTx were included: 70 male, 37 female, mean age 8.8+/-4.9 yr, mean follow up 5.4 yr. The following RAS polymorphisms were studied in all 107 recipients, 48 donors, and 120 healthy controls: Renin (Renin Mbol 18G/A), ACE I/D; angiotensinogen (AGT M235T), and angiotensin II receptor type-1 (AT1R A1166C). Only patients homozygous for the ACE D allele had a significantly steeper decline in GFR compared with homozygous carriers of the ACE I allele (slope DD: -4.3+/-0.8 vs. II: -1.3+/-1.1 mL/min/1.73 m2 per yr; p=0.035). In four cases, a DD recipient received a kidney from a DD donor, and these patients showed a more pronounced decline in GFR (-5.2+/-0.5 mL/min/1.73 m2 per yr; p=0.002). MABP was not different before vs. after RTx and was independent of ACE I/D genotype. LVMI increased significantly in the majority of patients (36.6+/-13.9 g/m2.7 six months before RTx vs. 46.4+/-15.3 g/m2.7 12 months after RTx, p=0.015). However, this difference disappeared after stratification by ACE I/D genotype. The ACE DD genotype is a potential marker for identifying patients at high risk of poor allograft outcome. PMID- 21309966 TI - Disseminated nocardiosis masking an atypical zygomycosis presentation in a kidney transplant recipient. AB - Immunosuppressive agents increase the vulnerability of solid organ transplant patients to opportunistic infections. An atypical clinical presentation of a bacterial and fungal co-infection makes diagnosis and treatment even more challenging in this population. A 54-year-old hypertensive woman underwent a cadaveric kidney transplant after years on hemodialysis. Her treatment included mycophenolate, tacrolimus, and prednisone. By post-transplant week 8, she had pneumonia followed by progressive visual changes and seizures. Diagnostic work up, consisting of magnetic resonance imaging of the brain and chest x-ray, showed several cerebral ring-enhancing lesions, and a pulmonary cavitary lesion. Disseminated nocardiosis was suspected and therapy was started. Skin biopsy was taken from a nodular lesion and culture confirmed Nocardia species infection. During hospitalization, neurological deficit persisted with worsening of brain lesions. She underwent excision of a brain abscess and the final pathologic report showed mucormycosis, revealing the patient's co-infection by 2 different pathogens. After therapy with liposomal amphotericin B and posaconazole, she has remained stable for more than 1 year. Disseminated nocardiosis masked and delayed the diagnosis and treatment of a more aggressive and worrisome organism. Mucormycosis, as a non-fatal isolated brain abscess without rhinal involvement, is an atypical presentation, and only a few cases have been reported. PMID- 21309967 TI - Successful pegylated interferon alpha2a monotherapy for hepatitis C virus infection in a transplanted patient who relapsed after the preceding course. PMID- 21309968 TI - Plant metallothioneins--metal chelators with ROS scavenging activity? AB - Metallothioneins (MTs) are ubiquitous cysteine-rich proteins present in plants, animals, fungi and cyanobacteria. In plants, MTs are suggested to be involved in metal tolerance or homeostasis, as they are able to bind metal ions through the thiol groups of their cysteine residues. Recent reports show that MTs are also involved in the scavenging of reactive oxygen species (ROS). The interplay between these roles is not entirely clear. Plants have many MT isoforms with overlapping expression patterns, and no specific role for any of them has been assigned. This review is focused on recent findings on plant MTs. PMID- 21309969 TI - The language of nitric oxide signalling. AB - Nitric oxide (NO) has recently joined the select circle of the ubiquitous molecules of plant signalling networks. Indeed, the last decade has produced a tremendous amount of data that evidence the diversity of physiological situations in which NO is involved in plants and the complexity of NO biology. These data also underline our difficulties in providing simple answers to the cardinal questions of where NO comes from and how the NO message is converted into a physiological response. The identification of NO primary targets and NO-regulated genes provides new opportunities to connect NO biochemistry and NO biology. This review summarises our current understanding of NO signalling, from the generation of the NO message to its execution into a cellular response. The review particularly considers whether and how NO may be responsible for specific signalling in different physiological processes. PMID- 21309970 TI - Effect of abandonment and plant classification on carbohydrate reserves of meadow plants. AB - We studied the effect of cessation of management on carbohydrate reserves of plants in meadows with different environmental characteristics and plant composition. We recorded storage carbohydrates and seasonal changes for 40 plant species. We asked whether there are differences in responses of carbohydrate reserves in forbs versus graminoids and in plants storing starch versus plants storing osmotically active carbohydrates. We analysed belowground organs before the meadows were mown and at the end of the vegetation season in mown versus recently abandoned plots. Whereas starch and fructans were widely distributed, raffinose family oligosaccharides were the main carbohydrate reserves of the Lamiaceae and Plantago lanceolata. Properties of carbohydrate reserves differed between forbs and graminoids but no difference was found between plants storing starch versus osmotically active carbohydrates. Graminoids had lower carbohydrate concentrations than forbs. We observed a positive effect of mowing on carbohydrate concentrations of graminoids in the dry, calcium-rich meadow and higher seasonal fluctuations of these values in the acid, wet meadow, suggesting that local factors and/or the species pool affect carbohydrate reserves. Despite local conditions, graminoids represent a distinct functional group in meadows from the point of view of their storage economy. We suggest that as well as growth, storage processes should also be considered for understanding the functioning of meadow plant communities. PMID- 21309971 TI - Drought advances spring growth phenology of the Mediterranean shrub Erica multiflora. AB - Current climate projections predict drier and warmer conditions in the Mediterranean basin over the next century. While advanced spring growth due to warming has been described in the literature, few data are available on the effects of drought on phenology. Hence, the phenology and growth of two Mediterranean shrubs, Erica multiflora and Globularia alypum, was studied in a rainfall exclusion field experiment to simulate spring drought in a natural shrubland. We estimated the onset of growth in spring by monitoring the appearance of new stems, and the end of growth in summer by following the elongation of stems. Drought treatment caused earlier onset of the spring growing season in E. multiflora, whereas no advance was observed in G. alypum. However, growth cessation was not affected in E. multiflora. Drought reduced the growth of both shrubs, as reflected in less stem elongation. The results show that a drier climate might affect not only growth but also spring phenology of some Mediterranean species. We suggest that a reduction in the cooling effect of transpiration may have analogous effects to warming and might advance the start of growth in E. multiflora, a species whose phenology has been described as warming-sensitive. The lengthening of the growing season resulting from advanced growth did not imply higher productivity, as growth was restricted by drought. PMID- 21309972 TI - Elevated CO2 effects on canopy and soil water flux parameters measured using a large chamber in crops grown with free-air CO2 enrichment. AB - An arable crop rotation (winter barley-sugar beet-winter wheat) was exposed to elevated atmospheric CO(2) concentrations ([CO(2) ]) using a FACE facility (Free Air CO(2) Enrichment) during two rotation periods. The atmospheric [CO(2) ] of the treatment plots was elevated to 550 ppm during daylight hours (T>5 degrees C). Canopy transpiration (E(C) ) and conductance (G(C) ) were measured at selected intervals (>10% of total growing season) using a dynamic CO(2) /H(2) O chamber measuring system. Plant available soil water content (gravimetry and TDR probes) and canopy microclimate conditions were recorded in parallel. Averaged across both growing seasons, elevated [CO(2) ] reduced E(C) by 9%, 18% and 12%, and G(C) by 9%, 17% and 12% in barley, sugar beet and wheat, respectively. Both global radiation (Rg) and vapour pressure deficit (VPD) were the main driving forces of E(C) , whereas G(C) was mostly related to Rg. The responses of E(C) and especially G(C) to [CO(2) ] enrichment were insensitive to weather conditions and leaf area index. However, differences in LAI between plots counteracted the [CO(2) ] impact on E(C) and thus, at least in part, explained the variability of seasonal [CO(2) ] responses between crops and years. As a consequence of lower transpirational canopy water loss, [CO(2) ] enrichment increased plant available soil water content in the course of the season by ca. 15 mm. This was true for all crops and years. Lower transpirational cooling due to a [CO(2) ]-induced reduction of E(C) increased canopy surface and air temperature by up to 2 degrees C and 0.5 degrees C, respectively. This is the first study to address effects of FACE on both water fluxes at canopy scale and water status of a European crop rotation. PMID- 21309973 TI - Stable isotope signatures confirm carbon and nitrogen gain through ectomycorrhizas in the ghost orchid Epipogium aphyllum Swartz. AB - Epipogium aphyllum is a rare Eurasian achlorophyllous forest orchid known to associate with fungi that form ectomycorrhizas, while closely related orchids of warm humid climates depend on wood- or litter-decomposer fungi. We conducted (13) C and (15) N stable isotope natural abundance analyses to identify the organic nutrient source of E. aphyllum from Central Norway. These data for orchid shoot tissues, in comparison to accompanying autotrophic plants, document C and N flow from ectomycorrhizal fungi to the orchid. DNA data from fungal pelotons in the orchid root cortex confirm the presence of Inocybe and Hebeloma, which are both fungi that form ectomycorrhizas. The enrichment factors for (13) C and (15) N of E. aphyllum are used to calculate a new overall average enrichment factor for mycoheterotrophic plants living in association with ectomycorrhizal fungi (epsilon(13) C +/- 1 SD of 7.2 +/- 1.6 0/00 and epsilon(15) N +/- 1 SD of 12.8 +/ 3.9 0/00). These can be used to estimate the fungal contribution to organic nutrient uptake by partially mycoheterotrophic plants where fully mycoheterotrophic plants are lacking. N concentrations in orchid tissue were unusually high and significantly higher than in accompanying autotrophic leaf samples. This may be caused by N gain of E. aphyllum from obligate ectomycorrhizal fungi. We show that E. aphyllum is an epiparasitic mycoheterotrophic orchid that depends on ectomycorrhizal Inocybe and Hebeloma to obtain C and N through a tripartite system linking mycoheterotrophic plants through fungi with forest trees. PMID- 21309974 TI - Herbivore-induced volatiles of cabbage (Brassica oleracea) prime defence responses in neighbouring intact plants. AB - When attacked by herbivores, plants release herbivore-induced plant volatiles (HIPV) that may function in direct defence by repelling herbivores or reducing their growth. Emission of HIPV may also contribute to indirect defence by attracting natural enemies of the herbivore. Here, cabbage (Brassica oleracea L.) plants (receiver plants) previously exposed to HIPV and subsequently induced through feeding by five Pieris brassicae L. caterpillars attracted more Cotesia glomerata L. parasitoids than control plants. HIPVs to which receiver plants had been exposed were emitted by B. oleracea infested with 50 P. brassicae caterpillars. Control plants had been exposed to volatiles from undamaged plants. In contrast, there were no differences in the attraction of wasps to receiver plants induced through feeding of one or ten larvae of P. brassicae compared to control plants. In addition, RT-PCR demonstrated higher levels of LIPOXYGENASE (BoLOX) transcripts in HIPV-exposed receiver plants. Exposure to HIPV from emitter plants significantly inhibited the growth rate of both P. brassicae and Mamestra brassicae caterpillars compared to growth rates of caterpillars feeding on control receiver plants. Our results demonstrate plant-plant signalling leading to priming of both indirect and direct defence in HIPV-exposed B. oleracea plants. PMID- 21309975 TI - Genetic dissection of Rhizobium-induced infection and nodule organogenesis in pea based on ENOD12A and ENOD5 expression analysis. AB - In legumes, perception of rhizobial lipochitooligosacharide-based molecules (Nod factors) and subsequent signal transduction triggers transcription of plant symbiosis-specific genes (early nodulins). We present genetic dissection of Nod factor-controlled processes in Pisum sativum using two early nodulin genes PsENOD12a and PsENOD5, that are differentially up-regulated during symbiosis. A novel set of non-nodulating pea mutants in fourteen loci was examined, among which seven loci are not described in Lotus japonicus and Medicago truncatula. Mutants defective in Pssym10, Pssym8, Pssym19, Pssym9 and Pssym7 exhibited no PsENOD12a and PsENOD5 activation in response to Nod factor-producing rhizobia. Thus, a conserved signalling module from the LysM receptor kinase encoded by Pssym10 down to the GRAS transcription factor encoded by Pssym7 is essential for Nod factor-induced gene expression. Of the two investigated genes, PsENOD5 was more strictly regulated; not only requiring the SYM10-SYM7 module, but also SYM35 (NIN transcription factor), SYM14, SYM16 and SYM34. Since Pssym35, Pssym14, Pssym34 and Pssym16 mutants show arrested infection and nodule formation at various stages, PsENOD5 expression seems to be essential for later symbiotic events, when rhizobia enter into plant tissues. Activation of PsENOD12a only requires components involved in early steps of signalling and can be considered as a marker of early symbiotic events preceding infection. PMID- 21309976 TI - Molecular cloning and characterisation of a pathogenesis-related protein CsPR10 from Crocus sativus. AB - Plants have developed many mechanisms to protect themselves against most potential microbial pathogens and diseases. Among these mechanisms, pathogenesis related proteins are produced as part of the active defence to prevent attack. In this study, a full-length cDNA encoding the CsPR10 protein was identified in fresh saffron stigmas (Crocus sativus). The deduced amino acid sequence from the nucleotide sequence of the coding region showed homology with PR10 proteins. The clone expressed as a protein in fusion with a GST tag produced a 47-kDa protein in E. coli. CsPR10 had ribonuclease activity, with features common to class II type ribonucleases; its specific activity was quantified as 68.8 U.mg(-1) protein, thus falling within the range of most PR10 proteins exhibiting RNase activity. Antifungal activity of CsPR10 was assayed against Verticillium dahliae, Penicillium sp. and Fusarium oxysporum. CsPR10 inhibited only F. oxysporum growth, and antifungal potency was reflected in a IC(50) of 8.3 MUm. Expression analysis showed the presence of high transcript levels in anther and tepal tissues, low levels in stigmas and roots, and no signal detected in leaves. This protein seems to be involved in the active defence response through activation of the jasmonic acid pathway. PMID- 21309977 TI - Highly efficient virus resistance mediated by artificial microRNAs that target the suppressor of PVX and PVY in plants. AB - MicroRNAs (miRNAs) processed from nuclear-encoded transcripts control expression of target transcripts by directing cleavage or translational inhibition. Artificial miRNAs (amiRNAs) that exploit this endogenous gene silencing mechanism can be designed to target any gene of interest and provide a highly specific approach for effective post-transcriptional gene silencing (PTGS) in plants. Here, using Arabidopsis thaliana miR159a, miR167b and miR171a precursors as backbones, we designed two types of amiRNA targeting sequence that encode the silencing suppressor HC-Pro of Potato virus Y (PVY) and the TGBp1/p25 (p25) of Potato virus X (PVX). The detected amiRNAs efficiently inhibited HC-Pro and p25 gene expression and conferred highly specific resistance against PVY or PVX infection in transgenic Nicotiana tabacum; this resistance was also maintained under conditions of increased viral pressure. Moreover, resistance was strongly influenced by the complementarity between the target sequence and amiRNA, and was well correlated to amiRNA expression level; the expression level of amiRNAs was also well related to the precursor backbones. We further showed that transgenic N. tabacum developed highly effective resistance to both PVY and PVX through expression of a dimeric amiRNA precursor. Together, our findings indicate that transgenic plants with multiple virus-specific resistance can be obtained through co-expression of several amiRNAs targeting multiple viruses. PMID- 21309978 TI - Arabidopsis shoot organogenesis is enhanced by an amino acid change in the ATHB15 transcription factor. AB - The hoc mutant displays high organogenic competence for in vitro shoot regeneration without addition of exogenous phytohormones. The genetic basis of this phenotype is investigated here. Using genetic mapping, the HOC locus was identified on chromosome 1. A point mutation was found in the At1g52150 gene, which encodes ATHB15/CORONA/INCURVATA4, a class III HD-ZIP transcription factor. The mutation replaced a serine with a cysteine in the MEKHLA domain of the protein. The wild-type ATHB15 gene was able to complement the hoc phenotype. Organogenesis response experiments revealed that hoc organogenic capacity was affected by the genetic background, and that it was not caused by a loss of ATHB15 function but by an effect of the mutation on protein function. PMID- 21309979 TI - Functional analysis of sucrose phosphate synthase (SPS) and sucrose synthase (SS) in sugarcane (Saccharum) cultivars. AB - Sucrose phosphate synthase (SPS; EC 2.4.1.14) and sucrose synthase (SS; EC 2.4.1.13) are key enzymes in the synthesis and breakdown of sucrose in sugarcane. The activities of internodal SPS and SS, as well as transcript expression were determined using semi-quantitative RT-PCR at different developmental stages of high and low sucrose accumulating sugarcane cultivars. SPS activity and transcript expression was higher in mature internodes compared with immature internodes in all the studied cultivars. However, high sugar cultivars showed increased transcript expression and enzyme activity of SPS compared to low sugar cultivars at all developmental stages. SS activity was higher in immature internodes than in mature internodes in all cultivars; SS transcript expression showed a similar pattern. Our studies demonstrate that SPS activity was positively correlated with sucrose and negatively correlated with hexose sugars. However, SS activity was negatively correlated with sucrose and positively correlated with hexose sugars. The present study opens the possibility for improvement of sugarcane cultivars by increasing expression of the respective enzymes using transgene technology. PMID- 21309980 TI - Variations in oil palm (Elaeis guineensis Jacq.) progeny response to high aluminium concentrations in solution culture. AB - Aluminium (Al) phytotoxicity is an important soil constraint that limits crop yield. The objectives of this study were to investigate how growth, physiology, nutrient content and organic acid concentration is affected by Al, and to assess the degree of Al tolerance in different oil palm progeny (OPP). Four OPPs ['A' (Angola dura * Angola dura), 'B' (Nigerian dura * Nigerian dura), 'C' (Deli dura * AVROS pisifera) and 'D' (Deli dura * Dumpy AVROS pisifera)] were grown in different Al concentrations (0, 100 and 200 MUm) in aerated Hoagland solution, pH 4.4, for 80 days. We observed a severe reduction (57.5%) in shoot dry weight, and root tips were reduced by 46.5% in 200 MUm Al. In 'B' and 'C', the majority of macro- and micronutrients in plants were reduced significantly by 200 MUm Al, with Mg being lowered by more than 50% in roots and shoots. The 200 MUm Al treatment resulted in a 56.50% reduction in total leaf area, a 20% reduction in net photosynthesis and a 17% reduction in SPAD chlorophyll value in the third leaf. Root tips (0-5 mm) showed a significant increase in oxalic acid content with increasing Al concentration (~ 5.86-fold); progeny 'A' had the highest concentration of oxalic acid. There was a significant interaction between Al concentration * OPP on total leaf number, root volume, lateral root length, Mg and K in root and shoot tissues, and Ca and N in shoots. The OPPs could be ranked in their tolerance to Al as: 'A' > 'D' > 'B' > 'C'. PMID- 21309981 TI - LeERF-1, a novel AP2/ERF family gene within the B3 subcluster, is down-regulated by light signals in Lithospermum erythrorhizon. AB - We previously showed that ethylene might be involved in the process of shikonin biosynthesis regulated by light signals. Here, we cloned a full-length cDNA of LeERF-1, a putative ethylene response factor gene, from Lithospermum erythrorhizon using the RACE (rapid amplification of cDNA ends) method. Phylogenetic analysis revealed that LeERF-1 was classified in the B3 subfamily, together with ERF1 and ORA59 of Arabidopsis. Heterologous expression of LeERF-1 in Arabidopsis showed that LeERF-1:eGFP fusion protein was precisely localised to the nucleus, implying that it might function as a transcription factor. Detailed expression analysis with real-time PCR showed that LeERF-1 was significantly down regulated by white, blue and red light, although the inhibitory effect of red light was relatively weak compared to other light conditions. Tissue-specific expression analysis also indicated that LeERF-1 was dominantly expressed in the roots, which grow in soil in darkness. These patterns are all consistent with the effects of different light signals on regulating formation of shikonin and its derivatives, indicating that LeERF-1 might be a crucial positive regulator, like other B3 subfamily proteins (such as ORCA3 and ORA59), in regulating biosynthesis of secondary metabolites. PMID- 21309982 TI - Transitions of gene expression induced by short-term blue light. AB - Blue light modulates many processes in plants and plant cells. It influences global and long-term responses, such as seedling development and phototropism, and induces short-term adaptations like stomatal opening and chloroplast movement. Three genes were identified as important for the latter process, namely PHOT1, PHOT2 and CHUP1. The former two phototropin blue light receptors act in perception of the blue light signal. The protein CHUP1 is localised to the outer envelope membrane of chloroplasts and is involved in chloroplast movement. To explore whether short-term reactions required for chloroplast movement are under transcriptional control, we analysed the transcriptome in wild-type Arabidopsis thaliana, phot1, phot2 and chup1 with different blue light treatments for 5 or 30 min. Blue light-induced changes in transcription depended on illumination time and intensity. Illumination with 100 MUmol.m(-2) . s(-1) blue light induced down regulation of several genes and might point to cascades that could be important for sensing low levels of blue light. Analysis of the transcriptome of the mutants in response to the different light regimes suggests that the transcriptional response to blue light in the wild-type can be attributed to phot1 rather than phot2, suggesting that blue light-induced alteration of expression is a function of phot1. In contrast, the blue light response at the transcriptional level of chup1 plants was unique, and confirmed the higher light sensitivity of this mutant. PMID- 21309983 TI - Over-expression of the Arabidopsis CBF1 gene improves resistance of tomato leaves to low temperature under low irradiance. AB - A known Arabidopsis cDNA clone, the CRT/DRE binding factor 1 (CBF1), was isolated and introduced into tomato plants. CBF1 is a member of the CBF gene family related to low temperature and enhanced low temperature tolerance in plants. In the present work, transcripts of CBF1 could be detected in transgenic tomato leaves, and the photochemical efficiency of PSII (F(v) /F(m)) and oxidisable P700 in the transgenic tomato over-expressing CBF1 were higher than in non-transformed plants under low temperature stress at low irradiance. Similarly, higher activity of superoxide dismutase (SOD), higher non-photochemical quenching (NPQ), and lower malondialdehyde (MDA) content were also detected in transgenic tomato leaves. These results suggest that CBF1 protein plays an important role in protection of PSII and PSI during low temperature stress at low irradiance. PMID- 21309984 TI - Genetic differentiation in the genus Lithops L. (Ruschioideae, Aizoaceae) reveals a high level of convergent evolution and reflects geographic distribution. AB - Southern Africa is one of the hot spots for plant biodiversity, with ca. 80% of species endemic to this area. Rapid and recent radiations in Southern African plant genera were triggered by fine-scale differences in climate, topography and geology. The genus Lithops (Ruschioideae, Aizoaceae) contains 37 species and is widely distributed in Southern Africa. Species delimitation within the genus is challenging because the limited number of morphological characters in these reduced succulents varies intensely between populations, presumably as adaptations to local geological environments. We analysed phylogenetic relationships within Lithops using non-coding chloroplast DNA (trnS-trnG intergenic spacer), nuclear ribosomal internal transcribed spacer (nrITS) sequences and AFLP data. Genetic variability of the sequence data was very low, but AFLP data detected nine clades within Lithops that do not fit current morphology-based taxonomy. Two of these clades are separated by their distribution on the northern and eastern border of the distribution area, and four clades are found in the Gariep Centre in the estuary of the Orange River. Morphological similarities, especially colour of leaves, evolved repeatedly within the clades, thus we hypothesise that closely related species became adapted to different soil types in a mosaic-like geological environment. One third of the species are found in the Gariep Centre, characterised by extremely diverse edaphic habitats. PMID- 21309985 TI - Genetic diversity and geographic differentiation in the alternative legume Tripodion tetraphyllum (L.) Fourr. in North African populations. AB - Wild legumes constitute an important component of widespread pastures in the Mediterranean basin. This region is experiencing remarkable effects from climate change, and continuous monitoring of species and population dynamics is important in order to plan and enact valuable conservation programmes. Tripodion tetraphyllum (L.) Fourr. [=Anthyllis tetraphylla L.] (2n=16), belongs to the tribe Loteae (Fabaceae), and could be very important for soil protection and sward improvement in abandoned or degraded Mediterranean areas. This alternative pasture legume is very closely related to Lotus japonicus and has some important characteristics for survival of the species in difficult and overgrazed Mediterranean areas. In this study, we have investigated the molecular diversity and population structure of T. tetraphyllum from North Africa using ISSR markers and plastidial microsatellites. To date, this is the first study concerning the genetic diversity and geographic differentiation of T. tetraphyllum. Ninety genotypes from three North African countries were analysed according to ISSRs, cpSSRs and one phenotypic trait. T. tetraphyllum shows a clear geographical structure, with differentiation associated with longitudinal differences; moreover, there is a general reduction in genetic diversity from Morocco to Tunisia. With all the markers used, strong differentiation was seen among collection sites. Our data highlight a genetic diversity gradient and cline of distribution, indicating that T. tetraphyllum has extended its area of distribution from Morocco to Tunisia. PMID- 21309986 TI - Chloroplast DNA phylogeography of the shrub Cistus ladanifer L. (Cistaceae) in the highly diverse Western Mediterranean region. AB - This study investigated the phylogeographic structure of Cistus ladanifer, in order to locate its Quaternary refugia, reconstruct its recolonisation patterns and assess the role of geographical features (mountain ranges, rivers and the Strait of Gibraltar) as barriers to its seed flow and expansion through the Western Mediterranean. Thirty-eight populations were screened for length variation of polymorphic chloroplast simple sequence repeats (cpSSRs). Statistical analyses included estimation of haplotypic diversity, hierarchical analysis of molecular variation (amova) and fixation indices. Mantel tests, SAMOVA and BARRIER analyses were applied to evaluate the geographical partitioning of genetic diversity across the entire species range. Pollen data from bibliography were used to complement molecular inferences. Chlorotype diversity within populations was similar throughout the natural range of C. ladanifer (mean haplotypic diversity=0.32). High differentiation among populations was estimated (G(ST)=0.60). Our data suggest that the barriers of the Strait of Gibraltar and the Betic ranges may have favoured the divergence during glacial periods of four different lineages of populations inferred with SAMOVA. The main northward colonisation of in the Iberian Peninsula occurred from refugia in southwest Iberia. This process may have been influenced by human activities (forest clearance, livestock grazing and even commerce) in the Iberian Peninsula. In contrast, populations in the Betic area have conserved a specific haplotype. PMID- 21309987 TI - Fine-scale spatial genetic structure and gene flow in a small, fragmented population of Sinojackia rehderiana (Styracaceae), an endangered tree species endemic to China. AB - Populations of Sinojackia rehderiana are highly threatened and have small and scattered distribution due to habitat fragmentation and human activities. Understanding changes in genetic diversity, the fine-scale spatial genetic structure (SGS) at different life stages and gene flow of S. rehderiana is critical for developing successful conservation strategies for fragmented populations of this endangered species. In this study, 208 adults, 114 juveniles and 136 seedlings in a 50 * 100-m transect within an old-growth forest were mapped and genotyped using eight microsatellite makers to investigate the genetic diversity and SGS of this species. No significant differences in genetic diversity among different life-history stages were found. However, a significant heterozygote deficiency in adults and seedlings may result from substantial biparental inbreeding. Significant fine-scale spatial structure was found in different life-history stages within 19 m, suggesting that seed dispersal mainly occurred near a mother tree. Both historical and contemporary estimates of gene flow (13.06 and 16.77 m) indicated short-distance gene dispersal in isolated populations of S. rehderiana. The consistent spatial structure revealed in different life stages is most likely the result of limited gene flow. Our results have important implications for conservation of extant populations of S. rehderiana. Measures for promoting pollen flow should be taken for in situ conservation. The presence of a SGS in fragmented populations implies that seeds for ex situ conservation should be collected from trees at least 19-m apart to reduce genetic similarity between neighbouring individuals. PMID- 21309988 TI - Production of prenylated flavonoids in tomato fruits expressing a prenyltransferase gene from Streptomyces coelicolor A3(2). AB - Flavonoids are natural compounds found in many plants, including the important fruit crop, tomato. Prenylated flavonoids consist of a large group of compounds, which often exhibit antitumour, antibacterial and/or anti-androgen activities. In this study, we engineered the biosynthesis of prenylated flavonoids using a Streptomyces prenyltransferase HypSc (SCO7190) possessing broad-range substrate specificity, in tomato as a host plant. LC/MS/MS analysis demonstrated the generation of 3'-dimethylallyl naringenin in tomato fruits when recombinant HypSc protein was targeted to the plastids, whereas the recombinant protein hardly produced this compound in vitro. This is the first report confirming the accumulation of a prenylated flavonoid using a bacterial prenyltransferase in transgenic plants, and our results suggest that the product specificities of prenyltransferases can be significantly influenced by the host plant. PMID- 21309990 TI - The advantages of eye photography for retinopathy of prematurity. PMID- 21309991 TI - Angle closure and the lens. PMID- 21309993 TI - Systematic screening for occult cancer in elderly patients with venous thromboembolism: a prospective study. AB - BACKGROUND: Cancer is an established risk factor for venous thromboembolism (VTE) and the incidence of cancer increases in the elderly. The benefit of screening for occult cancers in this population is still not clear. AIM: To evaluate a systematic screening programme for cancer in elderly patients with VTE. METHODS: This was a prospective study with a 12-month follow-up period. It was conducted in a single centre in consecutive patients over the age of 70 years who had a confirmed diagnosis of VTE. Predefined non-invasive screening techniques for cancer with clinical, laboratory (including tumour markers) and radiological investigations (abdominal ultrasound, chest X-ray and a thoraco-abdominopelvic computed tomography scan) were evaluated. RESULTS: Fifty patients with a median age of 80 years (range: 70 to 94 years) were included. One patient was diagnosed with chronic lymphocytic leukaemia at inclusion and cancers were found in three other patients during the follow-up period (rectosigmoid adenocarcinoma with hepatic metastases, hepatocellular carcinoma and gastric adenocarcinoma). Only one of the four cancers could have been treated at an earlier stage. The mortality rate of the entire cohort after 12 months was 28%. Two patients died as a direct consequence of cancer. DISCUSSION: In this study of elderly patients, a non-invasive screening strategy did not detect several cancers that were subsequently overt clinically. A full history, clinical examination and routine laboratory investigations might be the optimal first-line strategy to detect cancer after the diagnosis of VTE in elderly patients, but regular clinical examinations during follow up are warranted. PMID- 21309994 TI - Staphylococcus aureus bacteraemia at Alice Springs Hospital, Central Australia, 2003-2006. AB - BACKGROUND: Infectious diseases remain the leading cause of death at Alice Springs Hospital (ASH) and Staphylococcus aureus bacteraemia (SAB) is the second most common bloodstream infection. Non-multidrug-resistant, methicillin-resistant S. aureus (nmMRSA) is endemic to the region. AIMS: To determine whether differences exist between racial groups and resistance phenotypes in the clinical manifestations and outcomes of SAB at ASH. METHODS: A retrospective review of medical and pathology records for inpatients with SAB between 1 January 2003 and 31 December 2006. RESULTS: A total of 125 patients (indigenous, 111; non indigenous, 14) presented with SAB during the study period. Among indigenous patients, there were 95 adults and 16 children. No non-indigenous child was admitted with SAB. The mean annual incidence rate was 160.7/100 000 indigenous population and 8.1/100 000 non-indigenous population (incidence rate ratio 19.9) (P = 0.010). Isolates were predominantly methicillin-susceptible S. aureus (indigenous, 85; non-indigenous, 13). Twenty of 27 MRSA isolates were non multidrug-resistant. Indigenous adults were more likely to present with an infective focus (indigenous, 75; non-indigenous, 6) (P = 0.004). These were most often skin infections (skin abscesses, 31; scabies, 4). Twenty-seven indigenous adults self-discharged after receiving a median of only 5 days (inter-quartile range (IQR), 3-9) of antibiotic therapy. Ninety-day mortality rates for indigenous and non-indigenous adults were 14.7% and 14.3% respectively. The median age of death for indigenous adults was 50 years (IQR, 37-68). CONCLUSIONS: Indigenous Australians have the highest reported incidence rate of SAB worldwide. This reflects the socioeconomic disadvantage experienced by indigenous Australians whose living conditions predispose to pathogen transmission and limits opportunities to maintain adequate skin hygiene. PMID- 21309995 TI - Clinically important detection of infection as an 'incidental' finding during cancer staging using FDG-PET/CT. AB - BACKGROUND: FDG-PET/CT is widely used in the management of a variety of malignancies with excellent overall accuracy, despite the potential for false positive results related to infection and inflammation. AIM: As cancer patients can develop clinically inapparent infections, we evaluated the prevalence and nature of incidental findings reported to be suggestive of infections that had been identified during clinical cancer staging with FDG-PET/CT. METHODS: The study involved a retrospective analysis of 60 patients managed primarily at our facility from a total of 121 cases identified as having possible infection on clinical reporting of more than 4500 cancer staging investigations performed during the calendar year of 2008. RESULTS: Occult infections were uncommon overall (<=1%), but most often because of pneumonia (31.6%), upper respiratory tract infections (21.1%) or wound infections (15.8%). Abnormal scans contributed to patients' management in 52.7% of cases. Two out of 13 patients whose scan abnormalities were not investigated further had worsening changes on repeated scan and one of these patients had clinical deterioration. CONCLUSIONS: In patients with FDG-PET/CT scans suggestive of infection and in whom a final diagnosis could be reached, the positive predictive value for FDG-PET/CT scans was 89% suggesting that abnormal scans indicative of infection should be investigated further in this population. PMID- 21309996 TI - Asbestos-related disease. AB - Inhalation of airborne asbestos fibres causes several diseases. These include asbestosis, lung cancer, malignant mesothelioma as well as pleural effusion, discrete (plaques) or diffuse benign pleural fibrosis and rolled atelectasis. The lag time between exposure and the development of disease may be many decades, thus the health risks of asbestos continue to be relevant despite bans on the use of asbestos and improvements in safety regulations for those who are still exposed. Asbestos was mined and used extensively in Australia for over 100 years and Australia is now experiencing part of a worldwide epidemic of asbestos related disease. This review provides insight into the history and epidemiology of asbestos-related disease in Australia and discusses relevant clinical aspects in their diagnosis and management. The past and current medico-legal aspects of asbestos as well as currently evolving areas of research and future projections are summarized. PMID- 21309997 TI - Current use of aminoglycosides: indications, pharmacokinetics and monitoring for toxicity. AB - The new Australian Therapeutic Guidelines: Antibiotic, version 14 have revised the recommendations for the use and monitoring of aminoglycosides. The guidelines have clear distinctions between empirical and directed therapy as well as revised recommendations about the monitoring of aminoglycosides. This has led many clinicians to review their current practice with regard to the use of aminoglycosides. This review summarizes why aminoglycosides are still a valid treatment option and discusses the rationale for current dosing regimens in Gram negative infections. In particular it focuses on the various methods for monitoring aminoglycosides that are currently being used. The aminoglycoside monitoring methods can be categorized into three groups: linear regression analysis (one compartment model), population methods and Bayesian estimation procedures. Although the population methods are easy to use and require minimal resources they can recommend clinically inappropriate doses as they have constant pharmacokinetic parameters and are not valid in special population groups, that is, renal impairment. The linear regression and Bayesian methods recommend more accurate dosage regimens; however, they require additional resources, such as information technology and healthcare personnel with background training in pharmacokinetics. The Bayesian methods offer additional advantages, such as calculation of doses based on a single serum concentration and optimization of the patient's previous pharmacokinetic data, in order to determine subsequent dosage regimens. We recommend the Bayesian estimation procedures be used, wherever feasible. However, they require the expertise of healthcare practitioners with a good understanding of pharmacokinetic principles, such as clinical pharmacists/clinical pharmacologists, in order to make appropriate recommendations. PMID- 21309998 TI - Optimization of the expression of the HIV fusion inhibitor cyanovirin-N from the tobacco plastid genome. AB - Plants with transgenic plastid (chloroplast) genomes represent a promising production platform in molecular farming, mainly because of the plastids' potential to accumulate foreign proteins to very high levels and the increased biosafety conferred by the maternal mode of plastid inheritance. Although some transgenes can be expressed to extraordinarily high levels, the expression of others has been unsuccessful. Lack of detectable transgene expression is usually attributable to either RNA instability or protein instability. Here, we have investigated the possibilities to improve the production of a pharmaceutical protein that is difficult to express in chloroplasts: the HIV-1 fusion inhibitor cyanovirin-N (CV-N). Testing various N-terminal and C-terminal fusions to peptide sequences from two proteins known to accumulate to high levels in transgenic plastids (GFP and the protein antibiotic PlyGBS), we show that both low mRNA stability and low protein stability contribute to the lack of detectable CV-N expression in chloroplasts. Both problems can be alleviated by N-terminal fusions to the CV-N coding region, thus highlighting a suitable strategy for optimization of plastid transgene expression. PMID- 21310000 TI - Extreme 15N-enrichments in 2.72-Gyr-old sediments: evidence for a turning point in the nitrogen cycle. AB - Although nitrogen is a key element in organic molecules such as nucleic acids and proteins, the timing of the emergence of its modern biogeochemical cycle is poorly known. Recent studies on the antiquity of the nitrogen cycle and its interaction with free oxygen suggests the establishment of a complete aerobic N biogeochemical cycle with nitrification, denitrification, and nitrogen fixation at about 2.68 Gyr. Here, we report new bulk nitrogen isotope data for the 2.72 billion-year-old sedimentary succession of the Tumbiana Formation (Pilbara Craton, Western Australia). The nitrogen isotopic compositions vary widely from +8.60/00 up to +50.40/00 and are inversely correlated with the very low delta(13)C values of associated organic matter defining the Fortescue excursion (down to about -560/00). We propose that this (15)N-enrichment records the onset of nitrification coupled to the continuous removal of its derivatives (nitrite and nitrate) by denitrification. This finding implies an increase in the availability of electron acceptors and probably oxygen in the Tumbiana depositional environment, 300 million years before the oxygenation of the Earth's atmosphere. PMID- 21310001 TI - Characteristics of left ventricular rotational mechanics in patients with systemic amyloidosis, systemic hypertension and normal left ventricular mass. AB - INTRODUCTION: Recently, two-dimensional (2D) speckle-tracking echocardiography has enabled assessment of a particular behaviour of left ventricular (LV) motion defined as twisting/untwisting. The aim of our study is to evaluate whether in early stage of hypertension and systemic amyloidosis, subclinical alteration of LV twist and untwist is already present even if no LV hypertrophy is evidenced. METHODS: Forty-seven patients with light chain immunoglobulin amyloidosis (AL) entered the study and were classified having cardiac amyloidosis (CA) or not (NCA) if the mean value of LV wall thickness was >=12 mm or not. Twenty-two consecutive patients with history of arterial essential hypertension (Hyp Group) and no sign of LV hypertrophy were enrolled. A total of 26 asymptomatic healthy subjects, age-matched, were analysed as control group. All three groups of patients and healthy subjects underwent traditional and 2D speckle-tracking echocardiography evaluation. LV diameters, volumes, wall thickness, mass, ejection fraction, E/A and E/E' ratio were evaluated. RESULTS: Twisting and untwisting rates were significantly increased in NCA and Hyp group when compared with CA and control group. Moreover, despite similar LV mass and diastolic dysfunction degree, untwisting rate peak was significantly delayed in NCA when compared with Hyp group. In patients with CA, untwisting rate delay was similar to patients with NCA. CONCLUSION: Our results show that amyloidosis and systemic hypertension produce both LV twist and untwist rate enhancement before LV hypertrophy is developed. In patients with amyloidosis irrespectively of LV infiltration degree, a significant LV untwisting rate peak delay occurs suggesting that different aetiology of cardiac involvement could differently affect LV untwisting rate. PMID- 21310002 TI - Twenty-first century pain education: the rediscovery of compassion. PMID- 21310003 TI - CNTNAP2 variants affect early language development in the general population. AB - Early language development is known to be under genetic influence, but the genes affecting normal variation in the general population remain largely elusive. Recent studies of disorder reported that variants of the CNTNAP2 gene are associated both with language deficits in specific language impairment (SLI) and with language delays in autism. We tested the hypothesis that these CNTNAP2 variants affect communicative behavior, measured at 2 years of age in a large epidemiological sample, the Western Australian Pregnancy Cohort (Raine) Study. Singlepoint analyses of 1149 children (606 males and 543 females) revealed patterns of association which were strikingly reminiscent of those observed in previous investigations of impaired language, centered on the same genetic markers and with a consistent direction of effect (rs2710102, P = 0.0239; rs759178, P = 0.0248). On the basis of these findings, we performed analyses of four-marker haplotypes of rs2710102-rs759178-rs17236239-rs2538976 and identified significant association (haplotype TTAA, P = 0.049; haplotype CGAG, [corrected] P = .0014). Our study suggests that common variants in the exon 13-15 region of CNTNAP2 influence early language acquisition, as assessed at age 2, in the general population. We propose that these CNTNAP2 variants increase susceptibility to SLI or autism when they occur together with other risk factors. PMID- 21310004 TI - PGE(1) therapy for Martorell's ulcer. AB - Martorell's ulcer is a type of ischaemic ulcer of the lower leg, defined by severe pain and female-to-male predominance. The aim of this article is to assess the therapeutic effectiveness of PGE(1), both in pain control and in the healing times of Martorell's ulcers for patients already undergoing antihypertensive treatment. Between January 2004 and December 2008, we recruited 10 patients with Martorell's ulcers. These patients were organized into two groups (A and B). Group A included six patients who underwent only antihypertensive treatment with calcium channel blockers or angiotensin converting enzyme inhibitors. Group B consisted of four patients who underwent continuous administration of PGE(1) through a single-day elastomer (120 ug/24 hours) for 7 days. In both groups, we observed a progressive reduction in the surface area of Martorell's ulcers until complete recovery, but there was a significant difference with regards to healing time. We also observed a significant improvement in symptomatic pain after only 2 days of PGE(1) therapy. It has now been proved that antihypertensive treatment leads to ulcers healing but, according to our experience, intravenous infusion of prostaglandins improves peripheral perfusion and symptomatic pain and decreases healing time. PMID- 21310005 TI - Clinical challenge: cutaneous Kaposi's sarcoma of the lower extremity. AB - Kaposi's sarcoma (KS) typically presents as multiple bilateral cutaneous patches or plaques of the lower extremities. This malignancy, however, can evolve with atypical presentation masquerading as a chronic wound. Lesions can mimic venous stasis ulcers, arterial insufficiency, vascular ulcers or chronic-infected wounds. With acquired immune deficiency syndrome (AIDS)-associated KS, lesions are even more widespread, and can affect the respiratory tract, lymph nodes, gastrointestinal tract, spleen, liver and, rarely, bone. As the initial diagnosis of KS is generally determined clinically, a high index of suspicion is necessary for all patients with a known or suspected history of HIV/AIDS. Tissue biopsy with histological analysis is essential for all wound types in this patient subset, regardless of wound presentation. The purpose of this report is to review the pathogenesis as well as the typical and atypical presentations of KS with an example of a diagnostic dilemma. PMID- 21310006 TI - Epigallocatechin gallate elicits contractions of the isolated aorta of the aged spontaneously hypertensive rat. AB - The present study examined the effect of the green tea catechin epigallocatechin gallate (EGCG) on endothelium-dependent responses in the aorta of 36-week-old spontaneously hypertensive rats (SHR). Isometric tension was measured in isolated aortic rings. The release of prostanoid end products was determined using enzyme immunoassay kits and the intracellular reactive oxygen species (ROS) concentration using confocal microscopy. EGCG did not improve endothelium dependent relaxations evoked by acetylcholine, except in the presence of indomethacin. EGCG did not inhibit endothelium-dependent contractions induced by acetylcholine or ATP. At 10(-6) M and higher concentrations, EGCG caused increases in tension in the SHR aorta. The EGCG-induced contractions were accompanied by an increased production of ROS. The amount of prostanoid end products was increased significantly by EGCG, indicating that their production followed the activation of cyclooxygenase (COX). These prostanoids in turn stimulated thromboxane-prostanoid (TP) receptors and caused contractions. EGCG induced significantly smaller contractions in aortae of normotensive Wistar-Kyoto rats (WKY), accompanied with a lower production of ROS and a lesser release of prostanoids. These observations suggest that EGCG-induced contractions occur more readily in blood vessels of hypertensive than normotensive animals. The present findings indicate that the increased oxidative stress in the ageing hypertensive animals contributes to the loss of the beneficial effects and the enhancement of the adverse effects of EGCG. PMID- 21310007 TI - Megaloblastic pancytopenia vis-a-vis non-megaloblastic pancytopenia: is mean platelet volume useful discriminating indicator. AB - INTRODUCTION: Megaloblastic anaemia may present with pancytopenia and clinically mimic other causes of pancytopenia including myelodysplastic syndrome or aplastic anaemia. Bone marrow examination may be required for precise differentiation. The study was conducted to evaluate the role of mean platelet volume (MPV) to discriminate between pancytopenia due to megaloblastic anaemia or non megaloblastic causes. METHODS: A total of 268 cases of pancytopenia were divided into megaloblastic and non- megaloblastic group depending on clinical, laboratory and bone marrow examination. Mean MPV was statistically analyzed in both the groups along with comparison with healthy controls. RESULTS: The mean MPV in 88 cases of megaloblastic group (7.97 fl) was although statistically significantly higher than mean MPV in 180 cases of non-megaloblastic group (7.04 fl) with P value <0.05 but had limited sensitivity and specificity to discriminate megaloblastic and non-megaloblastic pancytopenia (cut off of 7.45 fl was 63.6% sensitive and 67.3% specific as observed by receptor operating characteristic curve analysis).The mean MPV in aplastic/hypocellular marrow and acute leukaemia category of non-megaloblastic group was significantly lower than megaloblastic group of pancytopenia (P value <0.05). MPV was also significantly lower in non megaloblastic pancytopenia as compared to controls (P < 0.001) while there was no statistical difference in MPV between megaloblastic pancytopenia and controls (P < 0.057). CONCLUSION: MPV has limited sensitivity and specificity to discriminate between megaloblastic and non-megaloblastic pancytopenia. Pancytopenia due to aplastic/hypocellular marrow and acute leukaemia has significantly lower MPV than megaloblastic group while other pancytopenic cases do not show any statistical difference in MPV from megaloblastic pancytopenia. PMID- 21310008 TI - Pro-oxidative/antioxidative imbalance: a key indicator of adverse outcome in hematopoietic stem cell transplantation. AB - INTRODUCTION: Pretransplantation iron overload (IO) is considered as a predictor of adverse outcome in hematopoietic stem cell transplantation (HSCT). Peroxidative tissue injury caused by IO leads to progressive organ dysfunction. METHODS: This is a retro-prospective study which explores the possible relationship between IO, oxidative stress and transplant outcome. Serum samples of 149 consecutive HSCT candidates were subjected to analysis of iron parameters, including nontransferrin bound iron (NTBI) and pro-oxidant/antioxidant status. RESULTS: Serum ferritin was found to be positively correlated with NTBI and negatively correlated with glutathione peroxidase (GPx) and superoxide dismutase (SOD). An inverse correlation of NTBI with SOD, total antioxidant potential (TAP) and malonyldialdehide (MDA) was also demonstrated. An adverse impact of serum ferritin level on early posttransplant complications including pulmonary toxicity, fungal infections and sinusoidal obstruction syndrome (SOS) was shown. A significant impact of NTBI on +30 day (P = 0.027) and +100 day survival (P = 0.028) was shown in auto-transplanted patients. MDA levels had a significant impact on +30 day and +100 day survival in autologous (P = 0.047; P = 0.026) and allogeneic (P = 0.053; P = 0.059) groups. GPx (P = 0.016) and MDA (P = 0.021) were identified as independent prognostic parameters for overall survival in allo transplanted patients. CONCLUSION: Pretransplantation IO might be a major contributor to adverse outcome in HSCT recipients through an impaired pro oxidative/antioxidative homeostasis. The reversible nature of IO and oxidative stress suggests that early preventive strategies might have a potential to improve transplant outcome. PMID- 21310010 TI - Generation of melanocytes from neural crest cells. AB - The neural crest is a transient structure in vertebrate embryos that generates multiple neural and mesenchymal cell types as well as melanocytes. Melanocytes in the skin either derive directly from neural crest cells populating the skin via a dorsolateral migratory pathway or arise by detaching from nerves innervating the skin. Several transcription factors, such as FoxD3, Sox10, Pax3, and Mitf, take part in a genetic network regulating melanocyte formation from the neural crest. The activity of these intrinsic factors is controlled and modulated by extracellular signals including canonical Wnt, Edn, Kitl, and other signals that remain to be identified. Here, we summarize the current view of how melanocytes are specified from the neural crest and put this process into the context of spatiotemporal lineage decisions in neural crest cells. PMID- 21310009 TI - Genetic tool development underpins recent advances in thermophilic whole-cell biocatalysts. AB - The environmental value of sustainably producing bioproducts from biomass is now widely appreciated, with a primary target being the economic production of fuels such as bioethanol from lignocellulose. The application of thermophilic prokaryotes is a rapidly developing niche in this field, driven by their known catabolic versatility with lignocellulose-derived carbohydrates. Fundamental to the success of this work has been the development of reliable genetic and molecular systems. These technical tools are now available to assist in the development of other (hyper)thermophilic strains with diverse phenotypes such as hemicellulolytic and cellulolytic properties, branched chain alcohol production and other 'valuable bioproduct' synthetic capabilities. Here we present an insight into the historical limitations, recent developments and current status of a number of genetic systems for thermophiles. We also highlight the value of reliable genetic methods for increasing our knowledge of thermophile physiology. We argue that the development of robust genetic systems is paramount in the evolution of future thermophilic based bioprocesses and make suggestions for future approaches and genetic targets that will facilitate this process. PMID- 21310011 TI - Performance of three biometry devices in patients with different grades of age related cataract. AB - PURPOSE: The new Lenstar biometry device was compared in a typical clinical setting to the IOL-Master and Visante-OCT. METHODS: Fifty-one eyes of 51 patients with age-related cataract were examined with Lenstar LS900 (Haag Streit AG) biometer, IOL-Master V.5 (Carl Zeiss Meditec AG) and Visante-OCT (Carl Zeiss Meditec AG) before cataract surgery. Central corneal thickness (CCT), anterior chamber depth (ACD), keratometry readings of flattest and steepest meridian (K), corneal radius (R) and axial length (AL) values were correlated. Cataracts were graded according to the Lens Opacities Classification System III (LOCS) regarding nuclear colour (NC), nuclear opalescence (NO), cortical (C) and posterior subcapsular (P) cataract. RESULTS: Mean values and standard deviations for AL, K and R was 23.66 +/- 1.23 mm and 23.67 +/- 1.26 mm, 43.24 +/- 1.69 dpt and 43.16 +/- 1.71 dpt, 7.68 +/- 0.29 mm and 7.70 +/- 0.28 mm with the IOL-Master and with the LS900, respectively (r = 0.99 and p = 0.76, r = 0.99 and p = 0.029, r = 0.89 and p = 0.14, respectively). Visante-OCT demonstrated highest values of three devices regarding to ACD followed by Lenstar LS900 and IOLMaster. Axial length measurements were unfeasible in 10% of the cases (five patients) and this significantly correlated with the presence of posterior subcapsular cataract of LOCS III grade 4.0 or higher. CONCLUSIONS: IOL-Master, Lenstar LS900 and AC-OCT proved to be excellent non-contact measurement methods in eyes with age-related cataract. Nevertheless, ultrasound biometry is still required for cases with dense posterior subcapsular cataract. PMID- 21310012 TI - Quality of life of eye amputated patients. AB - PURPOSE: To evaluate eye-amputated patients' health-related quality of life, perceived stress, self-rated health, job separation because of illness or disability and socioeconomic position. METHODS: Patients were recruited from a tertiary referral centre situated in Copenhagen. Inclusion criteria were eye amputation, i.e. evisceration, enucleation, orbital exenteration or secondary implantation of an orbital implant during the period 1996-2003, and participation in a previous investigation (2005). In total, 159 eye-amputated patients were included, and completed a self-administered questionnaire containing health related quality of life (SF-36), the perceived stress scale and answered questions about self-rated health, job changes because of illness or disability and socioeconomic status. These results were compared with findings from the Danish Health Interview Survey 2005. RESULTS: The eye-amputated patients had significantly (p < 0.05) lower scores (poorer health) on all SF-36 subscales and more perceived stress compared to the general population. In all, 43.3% of the patients rated their health as excellent or very good compared to 52.1% of the general population. In total, 25% of the study population has retired or changed to a part-time job because of eye disease. The percentage of eye amputated patients, who were divorced or separated, was twice as high as in the general population. CONCLUSION: The impact of an eye amputation is considerable. The quality of life, perceived stress and self-rated health of many eye-amputated patients are drastically changed. Eye amputation has a marked negative influence on job separation because of illness or disability and on socioeconomic position. PMID- 21310013 TI - Stimulation of adrenergic beta-receptors enhances mydriasis in a porcine eye model. AB - PURPOSE: To compare the mydriatic effect of intracamerally injected isoprenaline plus phenylephrine to phenylephrine alone and to epinephrine in a porcine eye model, aiming to eventually find the best combination of adrenergic substances for surgical mydriasis in humans. METHODS: In this study, we used 89 intact eyes from newly slaughtered pigs, pretreated with 2.0 mg of intracameral acetylcholine. After waiting 60 seconds for miosis to develop, 0.15 ml 0.3% isoprenaline and 0.15 ml 3.0% phenylephrine were injected sequentially with a 90 second interval in 21 eyes. In another 22 eyes, the same substances were given in the reverse order. In 20 eyes, 0.15 ml of 0.025% epinephrine was injected, and as a negative control 0.15 ml of balanced salt solution was injected in 26 eyes. The pupils were filmed during the treatments, and the mean pupil diameters were measured every 15 seconds from the video recordings. RESULTS: Phenylephrine injected after isoprenaline had a larger mydriatic effect than epinephrine (p < 0.01). Without isoprenaline pretreatment, the mydriatic effect of phenylephrine was significantly smaller than that of epinephrine (p < 0.05). Isoprenaline also exhibited a small mydriatic effect of its own. CONCLUSIONS: The beta-receptor stimulator isoprenaline enhances the mydriatic effect of intracameral phenylephrine, indicating a role for the beta-receptor in the mydriatic response. Mydriasis mediated by beta-receptors may explain why nonspecific adrenergic stimulators such as epinine and epinephrine can have larger mydriatic effects than the specific alpha(1)-receptor stimulator phenylephrine. PMID- 21310014 TI - A comparison of the effectiveness between amniotic membrane homogenate and transplanted amniotic membrane in healing corneal damage in a rabbit model. AB - PURPOSE: To determine whether amniotic membrane homogenate is as effective in healing corneal damage as amniotic membrane transplantation in a rabbit model. METHOD: The rabbits were divided into three groups. The cornea of one eye in each rabbit was incised resulting in a defect of approximately 8 mm in diameter. Amniotic membrane transplantation was performed in the first group, and amnion homogenate was administered four times a day in the second group. The third group was the control group. RESULTS: There were no differences in the diameter of the defects and the rate of corneal growth between the amnion transplant group and the amnion homogenate group. CONCLUSION: Amnion homogenate is as effective as transplanted amniotic membrane in promoting corneal healing in a rabbit model. PMID- 21310015 TI - Cytogenetics and prognosis for uveal melanoma in Korean patients. AB - PURPOSE: To determine the rate of mortality for uveal melanoma in the Korean population and assess whether it correlates with cytogenetic data, and clinical and histopathological factors. METHODS: A retrospective review of medical files from 33 uveal melanoma patients who underwent enucleation at Yonsei University, Seoul, Korea, between January, 1994 and December, 2009 was performed. Dual-colour fluorescence in situ hybridization was performed using centromeric probes for chromosome 3 and 8 in archived patient tissues. RESULTS: The mean age of patients was 53.2 years (range; 29-78), and the mean largest basal diameter was 11.8 mm (range; 6.0-18.1). Of the 20 tissue blocks with available cytogenetic data, there was monosomy 3 in seven (35%) and polysomy 8 in four (20%). The presence of monosomy 3 (p < 0.001), polysomy 8 (p < 0.001), ciliary body involvement (p < 0.001), a mitotic rate >=5/40 high-power fields (p = 0.006), closed extravascular matrix loop (p = 0.025), large basal tumour diameter (p = 0.029) and epithelioid cellularity (p = 0.038) predicted melanoma-related mortality. The median time from enucleation to liver metastasis was 16 months (range; 10-70), and the median survival after metastasis was 5 months (range; 1-9). The Kaplan--Meier survival curve estimated the metastatic death rate to be 22% for 5 years and 30% for 10 years. CONCLUSIONS: Korean patients with uveal melanoma are younger and appear to exhibit no worse prognosis than Caucasian. Cytogenetic abnormality of chromosome 3 and 8 highly predicted metastatic death. PMID- 21310016 TI - Braille use among Norwegian children from 1967 to 2007: trends in the underlying causes. AB - PURPOSE: The aim of the study was to estimate the occurrence, diagnoses and time trends among Norwegian children that have received education in braille from 1967 to 2007. METHODS: We used a retrospective population-based study design. The health care system is free for all inhabitants in Norway. We included all children that had received braille education the last four decades. From each student's record, we abstracted year born, country of birth, gender, year diagnosed, diagnosis, classification of visual impairment and type of reading media. RESULTS: We identified 287 children (137 girls and 150 boys) that had received braille education over the last 40 years. Of these, 262 (91.3%) children were born in Norway, 145 (53.7%) were diagnosed within the first year of life and 59 (20.6%) from age of one to five. The most frequent diagnoses were Retinopathy of Prematurity (ROP), Juvenile Ceroid Lipofuscinoses (JNCL), Lebers Congenital Amaurosis (LCA) and Retinitis Pigmentosa (RP). Among the children, 63% (N = 170) used braille only, 9% (N = 25) braille and print, but priority braille, and 27% (N = 73) braille and print, priority print. The number of children with ROP using braille had a peak in 1977, then the number declined. The number diagnosed with LCA increased from 1987 to 1992. The number of braille users among children diagnosed with JNCL tended to increase substantially after 1992. CONCLUSION: Braille education seemed to be dependent of trends in diagnoses as well as trends in recommendations from professional educators. PMID- 21310017 TI - The vitreomacular interface in retinal vein occlusion. AB - PURPOSE: To evaluate the posterior vitreous adhesion status in patients with a history of central or branch retinal vein occlusion and to compare the results with the natural time-course of posterior vitreous detachment in healthy age related controls. METHODS: A retrospective chart review in terms of the posterior vitreous adhesion status was performed in 132 patients (133 eyes) with a history of a central (CRVO) or branch (BRVO) retinal vein occlusion. All patients underwent vitrectomy. Based on the operation reports, the vitreous adhesion status was classified as attached, partially detached or completely detached. The results were compared to the natural time-course of posterior vitreous detachment development in healthy age-related controls. RESULTS: Eighty-one eyes met the inclusion and exclusion criteria. Fifty-two eyes (64%) had a history of CRVO and 29 eyes (36%) a history of BRVO, respectively. In the CRVO group, the posterior vitreous was attached in 47 eyes (90%) and completely detached in five eyes (10%). In the BRVO group, the posterior vitreous was attached in 27 eyes (93%), partially detached in 1 eye (3%) and completely detached in another eye (3%). A subdivision into age classes and a comparison with healthy age-related controls [data by Weber-Krause & Eckardt (1997) Ophthalmologe, 94, 619-623] showed in patients between 65 and 69 years of age an attached posterior vitreous cortex in 72% in healthy eyes, in 100% in CRVO (p = 0.109) and in 89% in BRVO (p = 0.440), in patients between 70 and 79 years of age an attached posterior vitreous cortex in 56% in healthy eyes, in 86% in CRVO (p = 0.010) and in 100% in BRVO (p = 0.038) and in patients between 80 and 89 years of age an attached posterior vitreous cortex in 43% in healthy eyes, in 100% in CRVO (p = 0.191) and in 67% in BRVO (p = 0.582) (Fisher's exact t-test). CONCLUSION: In patients with a history of CRVO or BRVO, the posterior vitreous cortex stays attached more frequently in all age groups in comparison with the healthy age-related controls. PMID- 21310018 TI - Favourable outcome after cataract surgery with IOL implantation in uveitis associated with juvenile idiopathic arthritis. AB - PURPOSE: Management of uveitic cataract in patients with juvenile idiopathic arthritis (JIA) is challenging, and intraocular lens (IOL) implantation is controversial. This study investigated the outcome after minimally invasive surgery with IOL implantation. METHODS: Retrospective analysis after phacoemulsification with in-the-bag IOL implantation was performed in 16 patients (17 operations) with ANA-positive JIA-associated chronic uveitis. In these patients, 25 G capsulectomy and anterior vitrectomy was performed and they received an intravitreal triamcinolone (TA) injection. RESULTS: Mean age at uveitis onset was 5 +/- 2 years, and surgery was performed at a mean age of 11 +/ 2.2 years. Preoperatively, uveitis was inactive in all patients, and visual acuity was logMAR 0.8 +/- 0.44; additional uveitis complications were present in all patients, and 15 patients were receiving systemic immunosuppression/biologicals. After surgery (mean follow-up 26.5 +/- 11.7 months), presence of cystoid macular oedema, papilloedema, ocular hypertension/glaucoma and hypotony did not increase compared with baseline. There was no significant worsening of AC inflammation (by cell numbers and laser flare values). IOL deposits persisted in four patients, and synechiae developed in eight. The visual acuity was improved (>=2 lines) in all patients (mean logMAR 0.3 +/- 0.24). Retrolental membrane formation was not noted. Secondary capsular opacification was observed in seven patients, requiring Nd:YAG capsulotomy in five of them. CONCLUSIONS: Phacoemulsification and in-the-bag IOL implantation may improve visual outcome in JIA-associated uveitis with minimally invasive surgical technique and intravitreal TA injection. Well-controlled uveitis with appropriate use of topical steroids and systemic immunosuppression or biologicals appears as a perioperative requirement. PMID- 21310019 TI - Whole-genome resequencing shows numerous genes with nonsynonymous SNPs in the Japanese native cattle Kuchinoshima-Ushi. AB - BACKGROUND: Because the Japanese native cattle Kuchinoshima-Ushi have been isolated in a small island and their lineage has been intensely protected, it has been assumed to date that numerous and valuable genomic variations are conserved in this cattle breed. RESULTS: In this study, we evaluated genetic features of this breed, including single nucleotide polymorphism (SNP) information, by whole genome sequencing using a Genome Analyzer II. A total of 64.2 Gb of sequence was generated, of which 86% of the obtained reads were successfully mapped to the reference sequence (Btau 4.0) with BWA. On an average, 93% of the genome was covered by the reads and the number of mapped reads corresponded to 15.8-fold coverage across the covered region. From these data, we identified 6.3 million SNPs, of which more than 5.5 million (87%) were found to be new. Out of the SNPs annotated in the bovine sequence assembly, 20,432 were found in protein-coding regions containing 11,713 nonsynonymous SNPs in 4,643 genes. Furthermore, phylogenetic analysis using sequence data from 10 genes (more than 10 kbp) showed that Kuchinoshima-Ushi is clearly distinct from European domestic breeds of cattle. CONCLUSIONS: These results provide a framework for further genetic studies in the Kuchinoshima-Ushi population and research on functions of SNP containing genes, which would aid in understanding the molecular basis underlying phenotypic variation of economically important traits in cattle and in improving intrinsic defects in domestic cattle breeds. PMID- 21310020 TI - Mechanisms involved in extraterritorial facial pain following cervical spinal nerve injury in rats. AB - BACKGROUND: The aim of this study is to clarify the neural mechanisms underlying orofacial pain abnormalities after cervical spinal nerve injury. Nocifensive behavior, phosphorylated extracellular signal-regulated kinase (pERK) expression and astroglial cell activation in the trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal dorsal horn (C1-C2) neurons were analyzed in rats with upper cervical spinal nerve transection (CNX). RESULTS: The head withdrawal threshold to mechanical stimulation of the lateral facial skin and head withdrawal latency to heating of the lateral facial skin were significantly lower and shorter respectively in CNX rats compared to Sham rats. These nocifensive effects were apparent within 1 day after CNX and lasted for more than 21 days. The numbers of pERK-like immunoreactive (LI) cells in superficial laminae of Vc and C1-C2 were significantly larger in CNX rats compared to Sham rats following noxious and non-noxious mechanical or thermal stimulation of the lateral facial skin at day 7 after CNX. Two peaks of pERK-LI cells were observed in Vc and C1-C2 following mechanical and heat stimulation of the lateral face. The number of pERK LI cells in C1-C2 was intensity-dependent and increased when the mechanical and heat stimulations of the face were increased. The decrements of head withdrawal latency to heat and head withdrawal threshold to mechanical stimulation were reversed during intrathecal (i.t.) administration of MAPK/ERK kinase 1/2 inhibitor PD98059. The area of activated astroglial cells was significantly higher in CNX rats (at day 7 after CNX). The heat and mechanical nocifensive behaviors were significantly depressed and the number of pERK-LI cells in Vc and C1-C2 following noxious and non-noxious mechanical stimulation of the face was also significantly decreased following i.t. administration of the astroglial inhibitor fluoroacetate. CONCLUSIONS: The present findings have demonstrated that mechanical allodynia and thermal hyperalgesia occur in the lateral facial skin after CNX and also suggest that ERK phosphorylation of Vc and C1-C2 neurons and astroglial cell activation are involved in orofacial extraterritorial pain following cervical nerve injury. PMID- 21310021 TI - Implementing accountability for reasonableness framework at district level in Tanzania: a realist evaluation. AB - BACKGROUND: Despite the growing importance of the Accountability for Reasonableness (A4R) framework in priority setting worldwide, there is still an inadequate understanding of the processes and mechanisms underlying its influence on legitimacy and fairness, as conceived and reflected in service management processes and outcomes. As a result, the ability to draw scientifically sound lessons for the application of the framework to services and interventions is limited. This paper evaluates the experiences of implementing the A4R approach in Mbarali District, Tanzania, in order to find out how the innovation was shaped, enabled, and constrained by the interaction between contexts, mechanisms and outcomes. METHODS: This study draws on the principles of realist evaluation -- a largely qualitative approach, chiefly concerned with testing and refining programme theories by exploring the complex interactions of contexts, mechanisms, and outcomes. Mixed methods were used in data collection, including individual interviews, non-participant observation, and document reviews. A thematic framework approach was adopted for the data analysis. RESULTS: The study found that while the A4R approach to priority setting was helpful in strengthening transparency, accountability, stakeholder engagement, and fairness, the efforts at integrating it into the current district health system were challenging. Participatory structures under the decentralisation framework, central government's call for partnership in district-level planning and priority setting, perceived needs of stakeholders, as well as active engagement between researchers and decision makers all facilitated the adoption and implementation of the innovation. In contrast, however, limited local autonomy, low level of public awareness, unreliable and untimely funding, inadequate accountability mechanisms, and limited local resources were the major contextual factors that hampered the full implementation. CONCLUSION: This study documents an important first step in the effort to introduce the ethical framework A4R into district planning processes. This study supports the idea that a greater involvement and accountability among local actors through the A4R process may increase the legitimacy and fairness of priority-setting decisions. Support from researchers in providing a broader and more detailed analysis of health system elements, and the socio-cultural context, could lead to better prediction of the effects of the innovation and pinpoint stakeholders' concerns, thereby illuminating areas that require special attention to promote sustainability. PMID- 21310022 TI - Studies on mechanisms of interferon-gamma action in pancreatic cancer using a data-driven and model-based approach. AB - BACKGROUND: Interferon-gamma (IFNgamma) is a multifunctional cytokine with antifibrotic and antiproliferative efficiency. We previously found that pancreatic stellate cells (PSC), the main effector cells in cancer-associated fibrosis, are targets of IFNgamma action in the pancreas. Applying a combined experimental and computational approach, we have demonstrated a pivotal role of STAT1 in IFNgamma signaling in PSC. Using in vivo and in vitro models of pancreatic cancer, we have now studied IFNgamma effects on the tumor cells themselves. We hypothesize that IFNgamma inhibits tumor progression through two mechanisms, reduction of fibrogenesis and antiproliferative effects on the tumor cells. To elucidate the molecular action of IFNgamma, we have established a mathematical model of STAT1 activation and combined experimental studies with computer simulations. RESULTS: In BALB/c-nu/nu mice, flank tumors composed of DSL 6A/C1 pancreatic cancer cells and PSC grew faster than pure DSL-6A/C1 cell tumors. IFNgamma inhibited the growth of both types of tumors to a similar degree. Since the stroma reaction typically reduces the efficiency of therapeutic agents, these data suggested that IFNgamma may retain its antitumor efficiency in PSC-containing tumors by targeting the stellate cells. Studies with cocultures of DSL-6A/C1 cells and PSC revealed a modest antiproliferative effect of IFNgamma under serum-free conditions. Immunoblot analysis of STAT1 phosphorylation and confocal microscopy studies on the nuclear translocation of STAT1 in DSL-6A/C1 cells suggested that IFNgamma-induced activation of the transcription factor was weaker than in PSC. The mathematical model not only reproduced the experimental data, but also underscored the conclusions drawn from the experiments by indicating that a maximum of 1/500 of total STAT1 is located as phosphorylated STAT1 in the nucleus upon IFNgamma treatment of the tumor cells. CONCLUSIONS: IFNgamma is equally effective in DSL-6A/C1 tumors with and without stellate cells. While its action in the presence of PSC may be explained by inhibition of fibrogenesis, its efficiency in PSC-free tumors is unlikely to be caused by direct effects on the tumor cells alone but may involve inhibitory effects on local stroma cells as well. To gain further insights, we also plan to apply computer simulations to the analysis of tumor growth in vivo. PMID- 21310023 TI - Optical nerve detection by diffuse reflectance spectroscopy for feedback controlled oral and maxillofacial laser surgery. AB - BACKGROUND: Laser surgery lacks haptic feedback, which is accompanied by the risk of iatrogenic nerve damage. It was the aim of this study to investigate diffuse reflectance spectroscopy for tissue differentiation as the base of a feedback control system to enhance nerve preservation in oral and maxillofacial laser surgery. METHODS: Diffuse reflectance spectra of nerve tissue, salivary gland and bone (8640 spectra) of the mid-facial region of ex vivo domestic pigs were acquired in the wavelength range of 350-650 nm. Tissue differentiation was performed using principal component (PC) analysis followed by linear discriminant analysis (LDA). Specificity and sensitivity were calculated using receiver operating characteristic (ROC) analysis and the area under curve (AUC). RESULTS: Five PCs were found to be adequate for tissue differentiation with diffuse reflectance spectra using LDA. Nerve tissue could be differed from bone as well as from salivary gland with AUC results of greater than 88%, sensitivity of greater than 83% and specificity in excess of 78%. CONCLUSIONS: Diffuse reflectance spectroscopy is an adequate technique for nerve identification in the vicinity of bone and salivary gland. The results set the basis for a feedback system to prevent iatrogenic nerve damage when performing oral and maxillofacial laser surgery. PMID- 21310024 TI - Canadian Emergency Department Triage and Acuity Scale: implementation in a tertiary care center in Saudi Arabia. AB - BACKGROUND: The Canadian Emergency Department Triage and Acuity Scale (CTAS) is a well recognized and validated triage system that prioritizes patient care by severity of illness. The aim of this study was to describe the results of Emergency Department (ED) waiting times after the implementation of the CTAS in a major tertiary care hospital emergency department outside of Canada. METHODS: A total of 1206 charts were randomly selected and retrospectively reviewed for triage performance. The indicators were: time to triage, triage duration, waiting time to be evaluated by a physician, and proportion of patients who left without being seen by a physician. Waiting times were stratified by triage level and reported as fractile response rates. RESULTS: The approximate time to triage was <= 10 minutes for 71% and <= 15 minutes for 82.8% of the patients. Fifty-three percent (53.5%) completed their triage process within 5 minutes. Waiting times evaluated by a physician was 100% within CTAS time objectives in category I patients, however, this was not the case for the other 4 categories. The overall left without being seen (LWBS) rate was 9.8%; 11.9% were in Level III, 20.3% in Level IV, and 67.8% in Level V. Median length of stay (LOS) was 144 minutes for the study sample as a whole. CONCLUSION: The CTAS may be adapted, with achievable objectives, in hospitals outside Canada as well. Time to see physician, total LOS, and LWBS are effective markers of ED performance and the quality of triage. Registration-to-physician time (RTP) and LOS profiles, stratified by triage level, are essential indicative markers for ED performance and should be used in improving patients flow through collaborative efforts. PMID- 21310025 TI - Hereditary angioedema: beyond international consensus - circa December 2010 - The Canadian Society of Allergy and Clinical Immunology Dr. David McCourtie Lecture. AB - BACKGROUND: The 2010 International Consensus Algorithm for the Diagnosis, Therapy and Management of Hereditary Angioedema was published earlier this year in this Journal (Bowen et al. Allergy, Asthma & Clinical Immunology 2010, 6:24 - http://www.aacijournal.com/content/6/1/24). Since that publication, there have been multiple phase III clinical trials published on either prophylaxis or therapy of hereditary angioedema and some of these products have changed approval status in various countries. This manuscript was prepared to review and update the management of hereditary angioedema. OBJECTIVE: To review approaches for the diagnosis and management of hereditary angioedema (HAE) circa December 2010 and present thoughts on moving from HAE management from international evidence-based consensus to facilitate more local health unit considerations balancing costs, efficacies of treatments, and risk benefits. Thoughts will reflect Canadian and international experiences. METHODS: PubMed searches including hereditary angioedema and diagnosis, therapy, management and consensus were reviewed as well as press releases from various pharmaceutical companies to early December 2010. RESULTS: The 2010 International Consensus Algorithms for the Diagnosis, Therapy and Management of Hereditary Angioedema is reviewed in light of the newly published phase III Clinical trials for prevention and therapy of HAE. Management approaches and models are discussed. CONCLUSIONS: Consensus approach and double blind placebo controlled trials are only interim guides to a complex disorder such as HAE and should be replaced as soon as possible with large phase IV clinical trials, meta analyses, data base registry validation of approaches including quality of life and cost benefit analyses, safety, and head-to-head clinical trials investigating superiority or non-inferiority comparisons of available approaches. Since not all therapeutic products are available in all jurisdictions and since health care delivery approaches and philosophy vary between countries, each health care delivery sector will likely devise their own algorithms based on local practicalities for implementing evidence-based guidelines and standards for HAE disease management. Quality-of-life and cost affordability benefit conclusions will likely vary between countries and health care units. Data base registries for rare disorders like HAE should be used to detect early adverse events for new therapies and to facilitate phase IV clinical trials and encourage superiority and non-inferiority comparisons of HAE management approaches. PMID- 21310026 TI - Large-scale seroprevalence analysis of human metapneumovirus and human respiratory syncytial virus infections in Beijing, China. AB - BACKGROUND: Human metapneumovirus (hMPV), a recently identified virus, causes acute respiratory tract infections (ARTIs) in infants and children. However, studies on the seroepidemeology of hMPV are very limited in China. To assess the seroprevalence of hMPV infection in China, we tested a total of 1,156 serum specimens for the presence of anti-hMPV IgG antibody in children and adults free of acute respiratory illness in Beijing, China by using hMPV nucleocapsid (N) protein as an antigen. As a control, we used the human serum antibody against the N protein of human respiratory syncytial virus (hRSV), the most important viral agent responsible for ARIs in children. RESULTS: The seropositive rate for hMPV increased steadily with age from 67% at 1-6 mo to 100% at age 20. However, the rate dropped slightly between 6 mo and 1 yr of age. The seropositive rate for hRSV also increased steadily with age from 71% at 1-6 mo to 100% at age 20. In children aged six months to six years, the seropositive rates for the anti-hRSV IgG antibody were significantly higher than those for hMPV. Additionally, IgG antibody titers to hMPV and hRSV were significantly higher in adults than in young children. Consistent with the seropositive rates, the geometric mean titer of anti-hMPV IgG antibody was lower than that of anti-hRSV IgG antibody in children aged six months to six years. CONCLUSIONS: Our results indicate that similar to hRSV, exposure to hMPV is ubiquitous in the Beijing population. However, the seroprevalence of anti-hMPV IgG antibody is lower than that of hRSV in children between six months and six years old, which suggests a different number of repeat infections or a different response to infections. PMID- 21310027 TI - The stigma of mental health problems and other barriers to care in the UK Armed Forces. AB - BACKGROUND: As with the general population, a proportion of military personnel with mental health problems do not seek help. As the military is a profession at high risk of occupational psychiatric injury, understanding barriers to help seeking is a priority. METHOD: Participants were drawn from a large UK military health study. Participants undertook a telephone interview including the Patient Health Questionnaire (PHQ); a short measure of PTSD (Primary Care PTSD, PC-PTSD); a series of questions about service utilisation; and barriers to care. The response rate was 76% (821 participants). RESULTS: The most common barriers to care reported are those relating to the anticipated public stigma associated with consulting for a mental health problem. In addition, participants reported barriers in the practicalities of consulting such as scheduling an appointment and having time off for treatment. Barriers to care did not appear to be diminished after people leave the Armed Forces. Veterans report additional barriers to care of not knowing where to find help and a concern that their employer would blame them for their problems. Those with mental health problems, such as PTSD, report significantly more barriers to care than those who do not have a diagnosis of a mental disorder. CONCLUSIONS: Despite recent efforts to de stigmatise mental disorders in the military, anticipated stigma and practical barriers to consulting stand in the way of access to care for some Service personnel. Further interventions to reduce stigma and ensuring that Service personnel have access to high quality confidential assessment and treatment remain priorities for the UK Armed Forces. PMID- 21310028 TI - RedundancyMiner: De-replication of redundant GO categories in microarray and proteomics analysis. AB - BACKGROUND: The Gene Ontology (GO) Consortium organizes genes into hierarchical categories based on biological process, molecular function and subcellular localization. Tools such as GoMiner can leverage GO to perform ontological analysis of microarray and proteomics studies, typically generating a list of significant functional categories. Two or more of the categories are often redundant, in the sense that identical or nearly-identical sets of genes map to the categories. The redundancy might typically inflate the report of significant categories by a factor of three-fold, create an illusion of an overly long list of significant categories, and obscure the relevant biological interpretation. RESULTS: We now introduce a new resource, RedundancyMiner, that de-replicates the redundant and nearly-redundant GO categories that had been determined by first running GoMiner. The main algorithm of RedundancyMiner, MultiClust, performs a novel form of cluster analysis in which a GO category might belong to several category clusters. Each category cluster follows a "complete linkage" paradigm. The metric is a similarity measure that captures the overlap in gene mapping between pairs of categories. CONCLUSIONS: RedundancyMiner effectively eliminated redundancies from a set of GO categories. For illustration, we have applied it to the clarification of the results arising from two current studies: (1) assessment of the gene expression profiles obtained by laser capture microdissection (LCM) of serial cryosections of the retina at the site of final optic fissure closure in the mouse embryos at specific embryonic stages, and (2) analysis of a conceptual data set obtained by examining a list of genes deemed to be "kinetochore" genes. PMID- 21310029 TI - Genetic predisposition to fracture non-union: a case control study of a preliminary single nucleotide polymorphisms analysis of the BMP pathway. AB - BACKGROUND: Despite the known multi-factorial nature of atrophic fracture non unions, a possible genetic predisposition for the development of this complication after long bone fractures remains unknown. This pilot study aimed to address this issue by performing a preliminary SNP analysis of specific genes known to regulate fracture healing. METHODS: A total of fifteen SNPs within four genes of the Bone Morphogenetic Protein (BMP) pathway (BMP-2, BMP-7, NOGGIN and SMAD6) were examined, in 109 randomly selected patients with long bone fractures as a result of motor vehicle accident, fall or direct blow. There were sixty-two patients with atrophic non-union and forty-seven patients (54 fractures) with uneventful fracture union. Overall SNPs frequencies were computed with respect to patient's age, gender, smoking habits, fracture-associated parameters and the use of nonsteroidal anti-inflammatory drugs (NSAIDs), and tested for their association to the impaired bone healing process, using binary logistic regression (STATA 11.1; StataCorp, Texas USA). RESULTS: Statistical analysis revealed age to be an important covariate in the development of atrophic non union (p = 0.01, OR 1.05 [per year]), and two specific genotypes (G/G genotype of the rs1372857 SNP, located on NOGGIN and T/T genotype of the rs2053423 SNP, located on SMAD6) to be associated with a greater risk of fracture non-union (p = 0.02, OR 4.56 and p = 0.04, OR 10.27, respectively, after adjustment for age). CONCLUSIONS: This is the first clinical study to investigate the potential existence of genetic susceptibility to fracture non-union. Even though no concrete conclusions can be obtained from this pilot study, our results indicate the existence of a potential genetically predetermined impairment within the BMP signalling cascade, initiated after a fracture and when combined with other risk factors could synergistically increase the susceptibility of a patient to develop non-union. Further research is desirable in order to clarify the genetic component and its role and interaction with other risk factors in the development of atrophic long bone non-union, as simple genetic testing may contribute to the early identification of patients at risk in the future and the on-time intervention at the biologic aspects of bone healing. PMID- 21310030 TI - Differential utilization of NF-kappaB RELA and RELB in response to extracellular versus intracellular polyIC stimulation in HT1080 cells. AB - BACKGROUND: Pattern recognition receptors (PRRs) for double-stranded RNA (dsRNA) are components of innate immunity that recognize the presence of viral infection and initiate efficient defense mechanisms. In addition to previously well characterized signaling pathways that are mediated by PKR and TLR3, new intracellular dsRNA sensors, that are members of CARD and DExD/H box helicase family, have been identified. However, the molecular mechanisms involved in the signaling pathways mediated by these new dsRNA sensors have not been extensively characterized. RESULTS: Here, we studied an intracellular dsRNA pathway in the human fibrosarcoma cell line HT1080, which is distinct from the TLR3-mediated extracellular dsRNA pathway. Particularly, the NF-kB subunits RELA and RELB were differentially utilized by these two dsRNA signaling pathways. In TLR3-mediated dsRNA signaling, siRNA knock-down studies suggested a limited role for RELA on regulation of interferon beta and other cytokines whereas RELB appeared to have a negative regulatory role. By contrast, intracellular dsRNA signaling was dependent on RELA, but not RELB. CONCLUSIONS: Our study suggests that extracellular and intracellular dsRNA signaling pathways may utilize different NF kB members, and particularly the differential utilization of RELB may be a key mechanism for powerful inductions of NF-kB regulated genes in the intracellular dsRNA signaling pathway. PMID- 21310031 TI - Transcriptome characterization and high throughput SSRs and SNPs discovery in Cucurbita pepo (Cucurbitaceae). AB - BACKGROUND: Cucurbita pepo belongs to the Cucurbitaceae family. The "Zucchini" types rank among the highest-valued vegetables worldwide, and other C. pepo and related Cucurbita spp., are food staples and rich sources of fat and vitamins. A broad range of genomic tools are today available for other cucurbits that have become models for the study of different metabolic processes. However, these tools are still lacking in the Cucurbita genus, thus limiting gene discovery and the process of breeding. RESULTS: We report the generation of a total of 512,751 C. pepo EST sequences, using 454 GS FLX Titanium technology. ESTs were obtained from normalized cDNA libraries (root, leaves, and flower tissue) prepared using two varieties with contrasting phenotypes for plant, flowering and fruit traits, representing the two C. pepo subspecies: subsp. pepo cv. Zucchini and subsp. ovifera cv Scallop. De novo assembling was performed to generate a collection of 49,610 Cucurbita unigenes (average length of 626 bp) that represent the first transcriptome of the species. Over 60% of the unigenes were functionally annotated and assigned to one or more Gene Ontology terms. The distributions of Cucurbita unigenes followed similar tendencies than that reported for Arabidopsis or melon, suggesting that the dataset may represent the whole Cucurbita transcriptome. About 34% unigenes were detected to have known orthologs of Arabidopsis or melon, including genes potentially involved in disease resistance, flowering and fruit quality. Furthermore, a set of 1,882 unigenes with SSR motifs and 9,043 high confidence SNPs between Zucchini and Scallop were identified, of which 3,538 SNPs met criteria for use with high throughput genotyping platforms, and 144 could be detected as CAPS. A set of markers were validated, being 80% of them polymorphic in a set of variable C. pepo and C. moschata accessions. CONCLUSION: We present the first broad survey of gene sequences and allelic variation in C. pepo, where limited prior genomic information existed. The transcriptome provides an invaluable new tool for biological research. The developed molecular markers are the basis for future genetic linkage and quantitative trait loci analysis, and will be essential to speed up the process of breeding new and better adapted squash varieties. PMID- 21310033 TI - Percutaneous endoscopic gastrojejunostomy for a patient with an intractable small bowel injury after repeat surgeries: a case report. AB - INTRODUCTION: The management of intestinal injury can be challenging, because of the intractable nature of the condition. Surgical treatment for patients with severe adhesions sometimes results in further intestinal injury. We report a conservative management strategy using percutaneous endoscopic gastrojejunostomy for an intractable small bowel surgical injury after repeated surgeries. CASE PRESENTATION: A 78-year-old Japanese woman had undergone several abdominal surgeries including urinary cystectomy for bladder cancer. After this operation, she developed peritonitis as a result of a small bowel perforation thought to be due to an injury sustained during the operation, with signs consistent with systemic inflammatory response syndrome: body temperature 38.5 degrees C, heart rate 92 beats/minute, respiratory rate 23 breaths/minute, white blood cell count 11.7 * 109/L (normal range 4-11 * 109/MUL). Two further surgical interventions failed to control the leak, and our patient's clinical condition and nutritional status continued to deteriorate. We then performed percutaneous endoscopic gastrojejunostomy, and continuous suction was applied as an alternative to a third surgical intervention. With this endoscopic intervention, the intestinal leak gradually closed and oral feeding became possible. CONCLUSION: We suggest that the technique of percutaneous endoscopic gastrojejunostomy combined with a somatostatin analog is a feasible alternative to surgical treatment for small bowel leakage, and is less invasive than a nasojejunal tube. PMID- 21310032 TI - Functional genomics of the horn fly, Haematobia irritans (Linnaeus, 1758). AB - BACKGROUND: The horn fly, Haematobia irritans (Linnaeus, 1758) (Diptera: Muscidae) is one of the most important ectoparasites of pastured cattle. Horn flies infestations reduce cattle weight gain and milk production. Additionally, horn flies are mechanical vectors of different pathogens that cause disease in cattle. The aim of this study was to conduct a functional genomics study in female horn flies using Expressed Sequence Tags (EST) analysis and RNA interference (RNAi). RESULTS: A cDNA library was made from whole abdominal tissues collected from partially fed adult female horn flies. High quality horn fly ESTs (2,160) were sequenced and assembled into 992 unigenes (178 contigs and 814 singlets) representing molecular functions such as serine proteases, cell metabolism, mitochondrial function, transcription and translation, transport, chromatin structure, vitellogenesis, cytoskeleton, DNA replication, cell response to stress and infection, cell proliferation and cell-cell interactions, intracellular trafficking and secretion, and development. Functional analyses were conducted using RNAi for the first time in horn flies. Gene knockdown by RNAi resulted in higher horn fly mortality (protease inhibitor functional group), reduced oviposition (vitellogenin, ferritin and vATPase groups) or both (immune response and 5'-NUC groups) when compared to controls. Silencing of ubiquitination ESTs did not affect horn fly mortality and oviposition while gene knockdown in the ferritin and vATPse functional groups reduced mortality when compared to controls. CONCLUSIONS: These results advanced the molecular characterization of this important ectoparasite and suggested candidate protective antigens for the development of vaccines for the control of horn fly infestations. PMID- 21310034 TI - Factors predicting the outcome of customised foot orthoses in patients with rheumatoid arthritis: a prospective cohort study. AB - BACKGROUND: Conservative management of foot problems in patients with rheumatoid arthritis (RA) may consist of the prescription of customised foot orthoses. Indications for foot orthoses are not clear and the effectiveness of the intervention is highly variable among patients. Knowledge on which patients benefit the most from foot orthoses can help to select patients eligible for this type of intervention. The objective of the present study was to determine clinical and demographic factors that predict the outcome of customised foot orthoses on pain and disability in patients with RA. METHODS: A total of 135 RA patients who were supplied with customised foot orthoses were included in this prospective cohort study. Pain and disability were measured before and after the intervention period using a Numeric Rating Scale (NRS) for foot pain, the Foot Function Index (FFI), the Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) and a 10-meter walking test. The intervention period consisted of one or more appointments with the podiatrist during which the foot orthoses were customised.Swollen foot joint count, foot deformity scores, forefoot peak pressure, disease duration, age, gender, body mass index and baseline values of the outcome measures were selected as potential factors predicting outcome. Multivariate linear regression analyses were performed to determine factors associated with change in pain and disability (at P < 0.05). RESULTS: Disease duration was negatively associated with the change scores in NRS foot pain (P = 0.018), WOMAC pain (P = 0.001), FFI disability (P = 0.003) and WOMAC physical function (P = 0.002). Age was negatively associated with the change score in 10 meter walking time (P = 0.008). For all outcome measures baseline values were positively associated with the change scores (P < 0.001). CONCLUSIONS: Shorter disease duration predicted greater improvements in self reported foot pain and disability, and younger age predicted greater improvements in walking time after intervention with foot orthoses. Also, higher baseline values of pain and disability predicted greater improvements. Referral for conservative management with foot orthoses in the early stage of RA seems important when aiming to achieve reduction in pain and improvement in daily activities. PMID- 21310035 TI - Solitary splenic metastasis from ovarian carcinosarcoma: a case report. AB - INTRODUCTION: Metastatic tumors to the spleen are rare but are usually found in conjunction with metastasis to other organs. The most common sources of splenic metastasis are breast, lung and colorectal cancers as well as melanoma and ovarian carcinoma. A solitary carcinosarcoma metastasis to the spleen of any origin is very rare. To the best of our knowledge, there are fewer than 30 reported cases of ovarian primary tumors with solitary metastasis to the spleen, and only three solitary primary carcinosarcomas to the spleen have been reported, of which one is female. We present what is, to the best of our knowledge, the first case of a solitary metastatic carcinosarcoma to the spleen arising from a primary ovarian carcinsarcoma. CASE PRESENTATION: A 72-year-old Hispanic woman status post-total abdominal hysterectomy for ovarian carcinosarcoma presented with complaints of early satiety and abdominal pain for the past two months with a 30-lb unintentional weight loss. An initial computed tomographic scan of her abdomen and pelvis revealed a 30 cm * 27 cm splenic mass with displacement of the left kidney, stomach and liver. The patient was found to have a solitary metastatic carcinosarcoma of the spleen with biphasic epithelial (carcinomatous) and mesenchymal (sarcomatous) elements consistent with carcinosarcoma. CONCLUSION: Carcinosarcoma of the spleen is a rare tumor. Carcinosarcomas are a biphasic neoplasm comprising malignant epithelial and mesenchymal components arising from a stem cell capable of differentiation. They can arise anywhere in the female genital tract, most commonly from the endometrium. Even though it is rare, carcinosarcomas can metastasize to the spleen. This unique case of a solitary splenic metastasis from ovarian carcinosarcoma has particular interest in medicine, especially for the specialties of surgical oncology, pathology and hematology/oncology. PMID- 21310036 TI - Small risk of developing symptomatic tick-borne diseases following a tick bite in The Netherlands. AB - BACKGROUND: In The Netherlands, the incidence of Lyme borreliosis is on the rise. Besides its causative agent, Borrelia burgdorferi s.l., other potential pathogens like Rickettsia, Babesia and Ehrlichia species are present in Ixodes ricinus ticks. The risk of disease associated with these microorganisms after tick-bites remains, however, largely unclear. A prospective study was performed to investigate how many persons with tick-bites develop localized or systemic symptoms and whether these are associated with tick-borne microorganisms. RESULTS: In total, 297 Ixodes ricinus ticks were collected from 246 study participants who consulted a general practitioner on the island of Ameland for tick bites. Ticks were subjected to PCR to detect DNA of Borrelia burgdorferi s.l., Rickettsia spp., Babesia spp. or Ehrlichia/Anaplasma spp.. Sixteen percent of the collected ticks were positive for Borrelia burgdorferi s.l., 19% for Rickettsia spp., 12% for Ehrlichia/Anaplasma spp. and 10% for Babesia spp.. At least six months after the tick bite, study participants were interviewed on symptoms by means of a standard questionnaire. 14 out of 193 participants (8.3%) reported reddening at the bite site and 6 participants (4.1%) reported systemic symptoms. No association between symptoms and tick-borne microorganisms was found. Attachment duration >=24 h was positively associated with reddening at the bite site and systemic symptoms. Using logistic regression techniques, reddening was positively correlated with presence of Borrelia afzelii, and having 'any symptoms' was positively associated with attachment duration. CONCLUSION: The risk of contracting acute Lyme borreliosis, rickettsiosis, babesiosis or ehrlichiosis from a single tick bite was <1% in this study population. PMID- 21310037 TI - The 'three Ps' of cancer survivorship care. PMID- 21310038 TI - Parenthood and factors that influence outdoor recreational physical activity from a gender perspective. AB - BACKGROUND: A physically active life promotes both physical and mental health, increasing well-being and quality of life. Physical activity (PA) performed outdoors has been found to be particularly good for promoting well-being. However, participation in PA can change during the course of a lifetime. Parenthood has been found to be a life event associated with decreased PA, especially among women, although studies in the field are sparse. The aim of this study was to investigate participation in outdoor recreational PA, and factors influencing participation among parents-to-be, with and without previous children, from a gender perspective. METHODS: This study included baseline data from parents-to-be, 224 women and 208 men, from the municipality of Karlskrona in south-east Sweden. Data collection was carried out during 2008-2009. We measured the self-reported amount of outdoor recreational PA undertaken during the last year and analysed the probability of participating in this PA using 25 variables covering individual and socioeconomic factors. RESULTS: Seventy-six per cent of the women and 65% of the men had participated in outdoor recreational PA, varying from several times per month to every day, over a 12-month period prior to one month before pregnancy. Participation in PA indoors and owning a dog or a horse emerged as the most important factors associated with the probability of participation in outdoor recreational PA. Men were affected by a greater number of factors than women, for example men who had a family situation that permitted outdoor recreational PA participated in activities to a greater extent than men without such a family situation. The physical aspect, i.e. improved physical condition, staying power and vigour, also played a significant role with regard to participation among men. CONCLUSIONS: Becoming a parent is a life-changing event that affects participation in PA. By offering family-oriented PA choices that involve both parents and children, midwives and health promoters can encourage parents to be active and to support each other. The promotion of outdoor recreational PA, which also has restorative effects on well-being, needs to focus on activities which are attractive and affordable for the majority of both women and men. PMID- 21310039 TI - Haplotype and isoform specific expression estimation using multi-mapping RNA-seq reads. AB - We present a novel pipeline and methodology for simultaneously estimating isoform expression and allelic imbalance in diploid organisms using RNA-seq data. We achieve this by modeling the expression of haplotype-specific isoforms. If unknown, the two parental isoform sequences can be individually reconstructed. A new statistical method, MMSEQ, deconvolves the mapping of reads to multiple transcripts (isoforms or haplotype-specific isoforms). Our software can take into account non-uniform read generation and works with paired-end reads. PMID- 21310041 TI - India-EU relations in health services: prospects and challenges. AB - BACKGROUND: India and the EU are currently negotiating a Trade and Investment Agreement which also covers services. This paper examines the opportunities for and constraints to India-EU relations in health services in the context of this agreement, focusing on the EU as a market for India's health services exports and collaboration. The paper provides an overview of key features of health services in the EU and India and their bearing on bilateral relations in this sector. METHODS: Twenty six semi-structured, in-person, and telephonic interviews were conducted in 2007-2008 in four Indian cities. The respondents included management and practitioners in a variety of healthcare establishments, health sector representatives in Indian industry associations, health sector officials in the Indian government, and official representatives of selected EU countries and the European Commission based in New Delhi. Secondary sources were used to supplement and corroborate these findings. RESULTS: The interviews revealed that India-EU relations in health services are currently very limited. However, several opportunity segments exist, namely: (i) Telemedicine; (ii) Clinical trials and research in India for EU-based pharmaceutical companies; (iii) Medical transcriptions and back office support; (iv) Medical value travel; and (v) Collaborative ventures in medical education, research, training, staff deployment, and product development. However, various factors constrain India's exports to the EU. These include data protection regulations; recognition requirements; insurance portability restrictions; discriminatory conditions; and cultural, social, and perception-related barriers. The interviews also revealed several constraints in the Indian health care sector, including disparity in domestic standards and training, absence of clear guidelines and procedures, and inadequate infrastructure. CONCLUSIONS: The paper concludes that although there are several promising areas for India-EU relations in health services, it will be difficult to realize these opportunities given the pre-dominance of public healthcare delivery in the EU and sensitivities associated with commercializing healthcare. Hence, a gradual approach based on pilot initiatives and selective collaboration would be advisable initially, which could be expanded once there is demonstrated evidence on outcomes. Overall, the paper makes a contribution to the social science and health literature by adding to the limited primary evidence base on globalization and health, especially from a developing-developed country and regional perspective. PMID- 21310040 TI - A method to study the effect of bronchodilators on smoke retention in COPD patients: study protocol for a randomized controlled trial. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common disease, associated with cardiovascular disease. Many patients use (long-acting) bronchodilators, whilst they continue smoking alongside. We hypothesised an interaction between bronchodilators and smoking that enhances smoke exposure, and hence cardiovascular disease. In this paper, we report our study protocol that explores the fundamental interaction, i.e. smoke retention. METHOD: The design consists of a double-blinded, placebo-controlled, randomised crossover trial, in which 40 COPD patients smoke cigarettes during both undilated and maximal bronchodilated conditions. Our primary outcome is the retention of cigarette smoke, expressed as tar and nicotine weight. The inhaled tar weights are calculated from the correlated extracted nicotine weights in cigarette filters, whereas the exhaled weights are collected on Cambridge filters. We established the inhaled weight calculations by a pilot study, that included paired measurements from several smoking regimes. Our study protocol is approved by the local accredited medical review ethics committee. DISCUSSION: Our study is currently in progress. The pilot study revealed valid equations for inhaled tar and nicotine, with an R2 of 0.82 and 0.74 (p < 0.01), respectively. We developed a method to study pulmonary smoke retentions in COPD patients under the influence of bronchodilation which may affect smoking-related disease. This trial will provide fundamental knowledge about the (cardiovascular) safety of bronchodilators in patients with COPD who persist in their habit of cigarette smoking. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00981851. PMID- 21310042 TI - Highly sensitive detection of the group A Rotavirus using Apolipoprotein H-coated ELISA plates compared to quantitative real-time PCR. AB - BACKGROUND: The principle of a capture ELISA is binding of specific capture antibodies (polyclonal or monoclonal) to the surface of a suitable 96 well plate. These immobilized antibodies are capable of specifically binding a virus present in a clinical sample. Subsequently, the captured virus is detected using a specific detection antibody. The drawback of this method is that a capture ELISA can only function for a single virus captured by the primary antibody. Human Apolipoprotein H (ApoH) or beta2-glycoprotein 1 is able to poly-specifically bind viral pathogens. Replacing specific capture antibodies by ApoH should allow poly specific capture of different viruses that subsequently could be revealed using specific detection antibodies. Thus, using a single capture ELISA format different viruses could be analysed depending on the detection antibody that is applied. In order to demonstrate that this is a valid approach we show detection of group A rotaviruses from stool samples as a proof of principle for a new method of capture ELISA that should also be applicable to other viruses. RESULTS: Stool samples of different circulating common human and potentially zoonotic group A rotavirus strains, which were pretested in commercial EIAs and genotyped by PCR, were tested in parallel in an ApoH-ELISA set-up and by quantitative real time PCR (qPCR). Several control samples were included in the analysis. The ApoH ELISA was suitable for the capture of rotavirus-particles and the detection down to 1,000 infectious units (TCID(50/ml)). Subsets of diagnostic samples of different G- and P-types were tested positive in the ApoH-ELISA in different dilutions. Compared to the qPCR results, the analysis showed high sensitivity, specificity and low cross-reactivity for the ApoH-ELISA, which was confirmed in receiver operating characteristics (ROC) analysis. CONCLUSIONS: In this study the development of a highly sensitive and specific capture ELISA was demonstrated by combining a poly-specific ApoH capture step with specific detection antibodies using group A rotaviruses as an example. PMID- 21310043 TI - The level of claudin-7 is reduced as an early event in colorectal carcinogenesis. AB - BACKGROUND: Compromised epithelial barriers are found in dysplastic tissue of the gastrointestinal tract. Claudins are transmembrane proteins important for tight junctions. Claudins regulate the paracellular transport and are crucial for maintaining a functional epithelial barrier. Down-regulation of the oncogenic serine protease, matriptase, induces leakiness in epithelial barriers both in vivo and in vitro. We found in an in-silico search tight co-regulation between matriptase and claudin-7 expression. We have previously shown that the matriptase expression level decreases during colorectal carcinogenesis. In the present study we investigated whether claudin-7 expression is likewise decreased during colorectal carcinogenesis, thereby causing or contributing to the compromised epithelial leakiness of dysplastic tissue. METHODS: The mRNA level of claudin-7 (CLDN7) was determined in samples from 18 healthy individuals, 100 individuals with dysplasia and 121 colorectal cancer patients using quantitative real time RT PCR. In addition, immunohistochemical stainings were performed on colorectal adenomas and carcinomas, to confirm the mRNA findings. RESULTS: A 2.7-fold reduction in the claudin-7 mRNA level was found when comparing the biopsies from healthy individuals with the biopsies of carcinomas (p < 0.001). Reductions in the claudin-7 mRNA levels were also detected in mild/moderate dysplasia (p < 0.001), severe dysplasia (p < 0.01) and carcinomas (p < 0.01), compared to a control sample from the same individual. The decrease at mRNA level was confirmed at the protein level by immunohistochemical stainings. CONCLUSIONS: Our results show that the claudin-7 mRNA level is decreased already as an early event in colorectal carcinogenesis, probably contributing to the compromised epithelial barrier in adenomas. PMID- 21310044 TI - Synchronous perforation of non-Hodgkin's lymphoma of the small intestine and colon: a case report. AB - INTRODUCTION: Primary non-Hodgkin's lymphoma of the small and large bowel presenting as a perforated viscus entity with peritonitis is extremely rare. A thorough literature review did not reveal any cases where primary lymphoma of the jejunum presented with perforation and peritonitis synchronously with primary lymphoma of the descending colon. CASE PRESENTATION: This report concerns a 64 year-old Caucasian woman admitted with severe abdominal pain and fever. An emergency laparotomy revealed a large mass with perforation in the proximal jejunum with intense mesenteric thickening and lymphadenopathy. The descending colon was edematous and covered with fibrinous exudate. Histopathological examination of the resected segment of jejunum revealed a T cell non-Hodgkin's lymphoma. On post-operative day 10, a computed tomography scan of our patient's abdomen and pelvis showed leakage of contrast into the pelvis. Re-exploration revealed perforation of the descending colon. The histopathology of the resected colon also showed T cell non-Hodgkin's lymphoma. Her post-operative course was complicated by acute renal and respiratory failure. The patient died on post operative day 21. CONCLUSIONS: Lymphoma of the small intestine has been reported to have a poor prognosis. The synchronous occurrence of lesions in the small intestine or colon is unusual, and impacts the prognosis adversely. Early diagnosis and treatment are important to improve the prognosis of bowel perforation in patients with non-Hodgkin's lymphoma. PMID- 21310045 TI - Gender-related differences in physiologic color space: a functional transcranial Doppler (fTCD) study. AB - Simultaneous color contrast and color constancy are memory processes associated with color vision, however, the gender-related differences of 'physiologic color space' remains unknown. Color processing was studied in 16 (8 men and 8 women) right-handed healthy subjects using functional transcranial Doppler (fTCD) technique. Mean flow velocity (MFV) was recorded in both right (RMCA) and left (LMCA) middle cerebral arteries in dark and white light conditions, and during color (blue and yellow) stimulations. The data was plotted in a 3D quadratic curve fit to derive a 'physiologic color space' showing the effects of luminance and chromatic contrasts. In men, wavelength-differencing of opponent pairs (yellow-blue) was adjudged by changes in the RMCA MFV for Yellow plotted on the Y axis, and the RMCA MFV for Blue plotted on the X-axis. In women, frequency differencing for opponent pairs (blue-yellow) was adjudged by changes in the LMCA MFV for Yellow plotted on the Y-axis, and the LMCA MFV for Blue plotted on the X axis. The luminance effect on the LMCA MFV in response to white light with the highest luminous flux, was plotted on the (Z - axis), in both men and women. The 3D-color space for women was a mirror-image of that for men, and showed enhanced color constancy. The exponential function model was applied to the data in men, while the logarithmic function model was applied to the data in women. Color space determination may be useful in the study of color memory, adaptive neuroplasticity, cognitive impairment in stroke and neurodegenerative diseases. PMID- 21310046 TI - A specific inhibitor of protein kinase CK2 delays gamma-H2Ax foci removal and reduces clonogenic survival of irradiated mammalian cells. AB - BACKGROUND: The protein kinase CK2 sustains multiple pro-survival functions in cellular DNA damage response and its level is tightly regulated in normal cells but elevated in cancers. Because CK2 is thus considered as potential therapeutic target, DNA double-strand break (DSB) formation and rejoining, apoptosis induction and clonogenic survival was assessed in irradiated mammalian cells upon chemical inhibition of CK2. METHODS: MRC5 human fibroblasts and WIDR human colon carcinoma cells were incubated with highly specific CK2 inhibitor 4,5,6,7 tetrabromobenzotriazole (TBB), or mock-treated, 2 hours prior to irradiation. DSB was measured by pulsed-field electrophoresis (PFGE) as well as gamma-H2AX foci formation and removal. Apoptosis induction was tested by DAPI staining and sub-G1 flow cytometry, survival was quantified by clonogenic assay. RESULTS: TBB treatment did not affect initial DNA fragmention (PFGE; up to 80 Gy) or foci formation (1 Gy). While DNA fragment rejoining (PFGE) was not inhibited by the drug, TBB clearly delayed gamma-H2AX foci disappearence during postirradiation incubation. No apoptosis induction could be detected for up to 38 hours for both cell lines and exposure conditions (monotherapies or combination), but TBB treatment at this moderately toxic concentration of 20 MUM (about 40% survival) enhanced radiation-induced cell killing in the clonogenic assay. CONCLUSIONS: The data imply a role of CK2 in gamma-H2AX dephosporylation, most likely through its known ability to stimulate PP2A phosphatase, rather than DSB rejoining. The slight but definite clonogenic radiosensitization by TBB does apparently not result from interference with an apoptosis suppression function of CK2 in these cells but could reflect inhibitor-induced uncoupling of DNA damage response decay from break ligation. PMID- 21310047 TI - In vitro impairment of whole blood coagulation and platelet function by hypertonic saline hydroxyethyl starch. AB - BACKGROUND: Hypertonic saline hydroxyethyl starch (HH) has been recommended for first line treatment of hemorrhagic shock. Its effects on coagulation are unclear. We studied in vitro effects of HH dilution on whole blood coagulation and platelet function. Furthermore 7.2% hypertonic saline, 6% hydroxyethylstarch (as ingredients of HH), and 0.9% saline solution (as control) were tested in comparable dilutions to estimate specific component effects of HH on coagulation. METHODS: The study was designed as experimental non-randomized comparative in vitro study. Following institutional review board approval and informed consent blood samples were taken from 10 healthy volunteers and diluted in vitro with either HH (HyperHaes, Fresenius Kabi, Germany), hypertonic saline (HT, 7.2% NaCl), hydroxyethylstarch (HS, HAES6%, Fresenius Kabi, Germany) or NaCl 0.9% (ISO) in a proportion of 5%, 10%, 20% and 40%. Coagulation was studied in whole blood by rotation thrombelastometry (ROTEM) after thromboplastin activation without (ExTEM) and with inhibition of thrombocyte function by cytochalasin D (FibTEM), the latter was performed to determine fibrin polymerisation alone. Values are expressed as maximal clot firmness (MCF, [mm]) and clotting time (CT, [s]). Platelet aggregation was determined by impedance aggregrometry (Multiplate) after activation with thrombin receptor-activating peptide 6 (TRAP) and quantified by the area under the aggregation curve (AUC [aggregation units (AU)/min]). Scanning electron microscopy was performed to evaluate HyperHaes induced cell shape changes of thrombocytes. STATISTICS: 2-way ANOVA for repeated measurements, Bonferroni post hoc test, p < 0.01. RESULTS: Dilution impaired whole blood coagulation and thrombocyte aggregation in all dilutions in a dose dependent fashion. In contrast to dilution with ISO and HS, respectively, dilution with HH as well as HT almost abolished coagulation (MCFExTEM from 57.3 +/- 4.9 mm (native) to 1.7 +/- 2.2 mm (HH 40% dilution; p < 0.0001) and to 6.6 +/ 3.4 mm (HT 40% dilution; p < 0.0001) and thrombocyte aggregation (AUC from 1067 +/- 234 AU/mm (native) to 14.5 +/- 12.5 AU/mm (HH 40% dilution; p < 0.0001) and to 20.4 +/- 10.4 AU/min (HT 40% dilution; p < 0.0001) without differences between HH and HT (MCF: p = 0.452; AUC: p = 0.449). CONCLUSIONS: HH impairs platelet function during in vitro dilution already at 5% dilution. Impairment of whole blood coagulation is significant after 10% dilution or more. This effect can be pinpointed to the platelet function impairing hypertonic saline component and to a lesser extend to fibrin polymerization inhibition by the colloid component or dilution effects.Accordingly, repeated administration and overdosage should be avoided. PMID- 21310048 TI - beta-TrCP is dispensable for Vpu's ability to overcome the CD317/Tetherin-imposed restriction to HIV-1 release. AB - BACKGROUND: The cellular transmembrane protein CD317/BST-2/HM1.24/Tetherin restricts HIV-1 infection by physically tethering mature virions to the surface of infected cells. HIV-1 counteracts this restriction by expressing the accessory protein Vpu, yet the mechanism of this antagonism is incompletely understood. beta-TrCP is the substrate recognition domain of an E3 ubiquitin ligase complex that interacts with the di-serine motif S52/S56 in the cytoplasmic tail of Vpu to target the CD4 receptor for proteasomal degradation. Recently, it has been suggested that beta-TrCP is also critically involved in Vpu's ability to overcome the CD317-mediated virion release block. RESULTS: To test this model, we analyzed the consequences of several experimental strategies to interfere with the Vpu beta-TrCP protein-protein interaction. Under these conditions, we studied effects of Vpu on expression and localization of CD317 and CD4, as well as on its ability to promote HIV-1 release. Our results demonstrate a strict requirement for Vpu's di-serine motif for degradation of CD4 and also CD317, reduction of cell surface exposure of CD317, and HIV-1 release enhancement. We further show a critical role of beta-TrCP2, but not of the structurally related beta-TrCP1 isoform, for Vpu mediated degradation of both receptors. Most importantly, Vpu remained active in downregulating CD317 from the cell surface and in overcoming the HIV-1 release restriction in beta-TrCP-depleted cells. CONCLUSIONS: These results demonstrate that beta-TrCP is not strictly required for Vpu's ability to counteract the CD317 imposed virion release block and support the relevance of cell surface down modulation of the restriction factor as a central mechanism of Vpu antagonism. Moreover, we propose the existence of a critical, yet to be identified cellular factor that interacts with Vpu via its di-serine motif to alter the trafficking of the restriction factor. PMID- 21310049 TI - The pivotal role of the intermediate fragment in initial operative treatment of olecranon fractures. AB - BACKGROUND: In order to improve initial operative treatment of complex olecranon fractures we searched for new determining details. We assumed that the intermediate fragment plays a decisive role for anatomic restoration of the trochlear notch and consecutive outcome of initial operative treatment. METHODS: 80 patients operated with diagnosis of complex olecranon fracture were identified in an 8-year-period from trauma unit files at two European Level 1 Trauma Centers. Retrospective review of all operative reports and radiographs/computer tomography scans identified patients with concomitance of an intermediate fragment. The Patient-Rated Elbow Evaluation Score was calculated for 45 of 80 patients at a minimum of 8 months postoperatively (range 8-84 months). RESULTS: 29 patients were treated with stable internal fixation with figure-of-eight tension band wire fixation and 51 patients with posterior plate osteosynthesis with/without intramedullary screw. An intermediate fragment was seen in 52 patients. In 29 of these 52 patients, the intermediate fragment was described in operative report. 24 of these 29 patients were treated with posterior plate osteosynthesis, and 5 patients with figure-of-eight tension band wiring. Complications included superficial infection (2 patients), secondary dislocation (3 patients) and heterotopic ossifications (1 patient). Functional outcome demonstrated a total PREE score of 9 points on average in 45 of 80 patients. CONCLUSION: An extraordinary amount of patients showed an intermediate fragment. Consideration, desimpaction and anatomic reduction of the intermediate fragment are necessary preconditions for anatomic restoration of the trochlear notch. There is no clear benefit for plating versus tension band wiring according to our data. In the operative report precise description of the fracture pattern including presence of an intermediate fragment is recommended. PMID- 21310050 TI - Cellulose accessibility limits the effectiveness of minimum cellulase loading on the efficient hydrolysis of pretreated lignocellulosic substrates. AB - A range of lignocellulosic feedstocks (including agricultural, softwood and hardwood substrates) were pretreated with either sulfur dioxide-catalyzed steam or an ethanol organosolv procedure to try to establish a reliable assessment of the factors governing the minimum protein loading that could be used to achieve efficient hydrolysis. A statistical design approach was first used to define what might constitute the minimum protein loading (cellulases and beta-glucosidase) that could be used to achieve efficient saccharification (defined as at least 70% glucan conversion) of the pretreated substrates after 72 hours of hydrolysis. The likely substrate factors that limit cellulose availability/accessibility were assessed, and then compared with the optimized minimum amounts of protein used to obtain effective hydrolysis. The optimized minimum protein loadings to achieve efficient hydrolysis of seven pretreated substrates ranged between 18 and 63 mg protein per gram of glucan. Within the similarly pretreated group of lignocellulosic feedstocks, the agricultural residues (corn stover and corn fiber) required significantly lower protein loadings to achieve efficient hydrolysis than did the pretreated woody biomass (poplar, douglas fir and lodgepole pine). Regardless of the substantial differences in the source, structure and chemical composition of the feedstocks, and the difference in the pretreatment technology used, the protein loading required to achieve efficient hydrolysis of lignocellulosic substrates was strongly dependent on the accessibility of the cellulosic component of each of the substrates. We found that cellulose-rich substrates with highly accessible cellulose, as assessed by the Simons' stain method, required a lower protein loading per gram of glucan to obtain efficient hydrolysis compared with substrates containing less accessible cellulose. These results suggest that the rate-limiting step during hydrolysis is not the catalytic cleavage of the cellulose chains per se, but rather the limited accessibility of the enzymes to the cellulose chains due to the physical structure of the cellulosic substrate. PMID- 21310051 TI - Oral ondansetron versus domperidone for symptomatic treatment of vomiting during acute gastroenteritis in children: multicentre randomized controlled trial. AB - BACKGROUND: Vomiting in children with acute gastroenteritis (AG) is not only a direct cause of fluid loss but it is also a major factor of failure of oral rehydration therapy (ORT). Physicians who provide care to paediatric patients in the emergency department (ED) usually prescribe intravenous fluid therapy (IVT) for mild or moderate dehydration when vomiting is the major symptom. Thus, effective symptomatic treatment of vomiting would lead to an important reduction in the use of IVT and, consequently, of the duration of hospital stay and of frequency of hospital admission. Available evidence on symptomatic treatment of vomiting shows the efficacy of the most recently registered molecule (ondansetron) but a proper evaluation of antiemetics drugs largely used in clinical practice, such as domperidone, is lacking. OBJECTIVES: To compare the efficacy of ondansetron and domperidone for the symptomatic treatment of vomiting in children with AG who have failed ORT. METHODS/DESIGN: Multicentre, double blind randomized controlled trial conducted in paediatric EDs. Children aged from 1 to 6 years who vomiting, with a presumptive clinical diagnosis of AG, and without severe dehydration will be included. After the failure of a initial ORS administration in ED, eligible children will be randomized to receive: 1) ondansetron syrup (0,15 mg/Kg of body weight); 2) domperidone syrup (0,5 mg/Kg of body weight); 3) placebo. The main study outcome will be the percentage of patients needing nasogastric or IVT after symptomatic oral treatment failure, defined as vomiting or fluid refusal after a second attempt of ORT. Data relative to study outcomes will be collected at 30 minute intervals for a minimum of 6 hours. A telephone follow up call will be made 48 hours after discharge. A total number of 540 children (i.e. 180 patients in each arm) will be enrolled. DISCUSSION: The trial results would provide evidence on the efficacy of domperidone, which is largely used in clinical practice despite the lack of proper evaluation and a controversial safety profile, as compared to ondansetron, which is not yet authorized in Italy despite evidence supporting its efficacy in treating vomiting. The trial results would contribute to a reduction in the use of IVT and, consequently, in hospital admissions in children with AG. The design of this RCT, which closely reflect current clinical practice in EDs, will allow immediate transferability of results. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01257672. PMID- 21310052 TI - Genomic organization and splicing evolution of the doublesex gene, a Drosophila regulator of sexual differentiation, in the dengue and yellow fever mosquito Aedes aegypti. AB - BACKGROUND: In the model system Drosophila melanogaster, doublesex (dsx) is the double-switch gene at the bottom of the somatic sex determination cascade that determines the differentiation of sexually dimorphic traits. Homologues of dsx are functionally conserved in various dipteran species, including the malaria vector Anopheles gambiae. They show a striking conservation of sex-specific regulation, based on alternative splicing, and of the encoded sex-specific proteins, which are transcriptional regulators of downstream terminal genes that influence sexual differentiation of cells, tissues and organs. RESULTS: In this work, we report on the molecular characterization of the dsx homologue in the dengue and yellow fever vector Aedes aegypti (Aeadsx). Aeadsx produces sex specific transcripts by alternative splicing, which encode isoforms with a high degree of identity to Anopheles gambiae and Drosophila melanogaster homologues. Interestingly, Aeadsx produces an additional novel female-specific splicing variant. Genomic comparative analyses between the Aedes and Anopheles dsx genes revealed a partial conservation of the exon organization and extensive divergence in the intron lengths. An expression analysis showed that Aeadsx transcripts were present from early stages of development and that sex-specific regulation starts at least from late larval stages. The analysis of the female-specific untranslated region (UTR) led to the identification of putative regulatory cis elements potentially involved in the sex-specific splicing regulation. The Aedes dsx sex-specific splicing regulation seems to be more complex with the respect of other dipteran species, suggesting slightly novel evolutionary trajectories for its regulation and hence for the recruitment of upstream splicing regulators. CONCLUSIONS: This study led to uncover the molecular evolution of Aedes aegypti dsx splicing regulation with the respect of the more closely related Culicidae Anopheles gambiae orthologue. In Aedes aegypti, the dsx gene is sex-specifically regulated and encodes two female-specific and one male-specific isoforms, all sharing a doublesex/mab-3 (DM) domain-containing N-terminus and different C termini. The sex-specific regulation is based on a combination of exon skipping, 5' alternative splice site choice and, most likely, alternative polyadenylation. Interestingly, when the Aeadsx gene is compared to the Anopheles dsx ortholog, there are differences in the in silico predicted default and regulated sex specific splicing events, which suggests that the upstream regulators either are different or act in a slightly different manner. Furthermore, this study is a premise for the future development of transgenic sexing strains in mosquitoes useful for sterile insect technique (SIT) programs. PMID- 21310053 TI - H9N2 influenza virus acquires intravenous pathogenicity on the introduction of a pair of di-basic amino acid residues at the cleavage site of the hemagglutinin and consecutive passages in chickens. AB - BACKGROUND: Outbreaks of avian influenza (AI) caused by infection with low pathogenic H9N2 viruses have occurred in poultry, resulting in serious economic losses in Asia and the Middle East. It has been difficult to eradicate the H9N2 virus because of its low pathogenicity, frequently causing in apparent infection. It is important for the control of AI to assess whether the H9N2 virus acquires pathogenicity as H5 and H7 viruses. In the present study, we investigated whether a non-pathogenic H9N2 virus, A/chicken/Yokohama/aq-55/2001 (Y55) (H9N2), acquires pathogenicity in chickens when a pair of di-basic amino acid residues is introduced at the cleavage site of its HA molecule. RESULTS: rgY55sub (H9N2), which had four basic amino acid residues at the HA cleavage site, replicated in MDCK cells in the absence of trypsin after six consecutive passages in the air sacs of chicks, and acquired intravenous pathogenicity to chicken after four additional passages. More than 75% of chickens inoculated intravenously with the passaged virus, rgY55sub-P10 (H9N2), died, indicating that it is pathogenic comparable to that of highly pathogenic avian influenza viruses (HPAIVs) defined by World Organization for Animal Health (OIE). The chickens inoculated with the virus via the intranasal route, however, survived without showing any clinical signs. On the other hand, an avirulent H5N1 strain, A/duck/Hokkaido/Vac-1/2004 (Vac1) (H5N1), acquired intranasal pathogenicity after a pair of di-basic amino acid residues was introduced into the cleavage site of the HA, followed by two passages by air sac inoculation in chicks. CONCLUSION: The present results demonstrate that an H9N2 virus has the potential to acquire intravenous pathogenicity in chickens although the morbidity via the nasal route of infection is lower than that of H5N1 HPAIV. PMID- 21310054 TI - Temporal lobe necrosis: a dwindling entity in a patient with nasopharyngeal cancer after radiation therapy. AB - INTRODUCTION: Our objective was to report a case of misdiagnosed temporal lobe necrosis (TLN) in a patient with nasopharyngeal cancer (NPC) after radiation therapy. CASE PRESENTATION: We report a case of a 45 years old Chinese woman who developed moderate to severe headache and dizziness 1 year after 2D radiation therapy for NPC. Subsequent MRI scanning revealed a big enhancing mass in the right temporal lobe. The initial diagnosis was metastatic or intracranial extension of NPC, or a primary intracranial malignancy. She was referred to the neurosurgery department where a maximal surgical resection of the lesion was performed. A diagnosis of TLN was made according to the final histology. CONCLUSION: TLN still matters in the IMRT era. The diagnostic quagmire of TLN lies in its close resemblance to neoplasm on clinical presentation and imaging. Reviewing the patient's treatment plan to scrutinize the dose to the temporal lobes is an important prerequisite for diagnosis. PMID- 21310055 TI - The ADP receptor P2Y1 is necessary for normal thermal sensitivity in cutaneous polymodal nociceptors. AB - BACKGROUND: P2Y1 is a member of the P2Y family of G protein-coupled nucleotide receptors expressed in peripheral sensory neurons. Using ratiometric calcium imaging of isolated dorsal root ganglion neurons, we found that the majority of neurons responding to adenosine diphosphate, the preferred endogenous ligand, bound the lectin IB4 and expressed the ATP-gated ion channel P2X3. These neurons represent the majority of epidermal afferents in hairy skin, and are predominantly C-fiber polymodal nociceptors (CPMs), responding to mechanical stimulation, heat and in some cases cold. RESULTS: To characterize the function of P2Y1 in cutaneous afferents, intracellular recordings from sensory neuron somata were made using an ex vivo preparation in which the hindlimb skin, saphenous nerve, DRG and spinal cord were dissected in continuum, and cutaneous receptive fields characterized using digitally-controlled mechanical and thermal stimuli in male wild type mice. In P2Y1-/- mice, CPMs showed a striking increase in mean heat threshold and a decrease in mean peak firing rate during a thermal ramp from 31-52 degrees C. A similar change in mean cold threshold was also observed. Interestingly, mechanical testing of CPMs revealed no significant differences between P2Y1-/- and WT mice. CONCLUSIONS: These results strongly suggest that P2Y1 is required for normal thermal signaling in cutaneous sensory afferents. Furthermore, they suggest that nucleotides released from peripheral tissues play a critical role in the transduction of thermal stimuli in some fiber types. PMID- 21310057 TI - Access to artesunate-amodiaquine, quinine and other anti-malarials: policy and markets in Burundi. AB - BACKGROUND: Malaria is the leading cause of morbidity and mortality in post conflict Burundi. To counter the increasing challenge of anti-malarial drug resistance and improve highly effective treatment Burundi adopted artesunate amodiaquine (AS-AQ) as first-line treatment for uncomplicated Plasmodium falciparum malaria and oral quinine as second-line treatment in its national treatment policy in 2003. Uptake of this policy in the public, private and non governmental (NGO) retail market sectors of Burundi is relatively unknown. This study was conducted to evaluate access to national policy recommended anti malarials. METHODS: Adapting a standardized methodology developed by Health Action International/World Health Organization (HAI/WHO), a cross-sectional survey of 70 (24 public, 36 private, and 10 NGO) medicine outlets was conducted in three regions of Burundi, representing different levels of transmission of malaria. The availability on day of the survey, the median prices, and affordability (in terms of number of days' wages to purchase treatment) of AS-AQ, quinine and other anti-malarials were calculated. RESULTS: Anti-malarials were stocked in all outlets surveyed. AS-AQ was available in 87.5%, 33.3%, and 90% of public, private, and NGO retail outlets, respectively. Quinine was the most common anti-malarial found in all outlet types. Non-policy recommended anti malarials were mainly found in the private outlets (38.9%) compared to public (4.2%) and NGO (0%) outlets. The median price of a course of AS-AQ was US$0.16 (200 Burundi Francs, FBu) for the public and NGO markets, and 3.5-fold higher in the private sector (US$0.56 or 700 FBu). Quinine tablets were similarly priced in the public (US$1.53 or 1,892.50 FBu), private and NGO sectors (both US$1.61 or 2,000 FBu). Non-policy anti-malarials were priced 50-fold higher than the price of AS-AQ in the public sector. A course of AS-AQ was affordable at 0.4 of a day's wage in the public and NGO sectors, whereas, it was equivalent to 1.5 days worth of wages in the private sector. CONCLUSIONS: AS-AQ was widely available and affordable in the public and NGO markets of hard-to-reach post-conflict communities in Burundi. However greater accessibility and affordability of policy recommended anti-malarials in the private market sector is needed to improve country-wide policy uptake. PMID- 21310058 TI - A human cancer-predisposing polymorphism in Cdc25A is embryonic lethal in the mouse and promotes ASK-1 mediated apoptosis. AB - BACKGROUND: Failure to regulate the levels of Cdc25A phosphatase during the cell cycle or during a checkpoint response causes bypass of DNA damage and replication checkpoints resulting in genomic instability and cancer. During G1 and S and in cellular response to DNA damage, Cdc25A is targeted for degradation through the Skp1-cullin-beta-TrCP (SCFbeta-TrCP) complex. This complex binds to the Cdc25A DSG motif which contains serine residues at positions 82 and 88. Phosphorylation of one or both residues is necessary for the binding and degradation to occur. RESULTS: We now show that mutation of serine 88 to phenylalanine, which is a cancer-predisposing polymorphic variant in humans, leads to early embryonic lethality in mice. The mutant protein retains its phosphatase activity both in vitro and in cultured cells. It fails to interact with the apoptosis signal regulating kinase 1 (ASK1), however, and therefore does not suppress ASK1 mediated apoptosis. CONCLUSIONS: These data suggest that the DSG motif, in addition to its function in Cdc25A-mediated degradation, plays a role in cell survival during early embyogenesis through suppression of ASK1-mediated apoptosis. PMID- 21310056 TI - Canadian clinical practice guidelines for acute and chronic rhinosinusitis. AB - This document provides healthcare practitioners with information regarding the management of acute rhinosinusitis (ARS) and chronic rhinosinusitis (CRS) to enable them to better meet the needs of this patient population. These guidelines describe controversies in the management of acute bacterial rhinosinusitis (ABRS) and include recommendations that take into account changes in the bacteriologic landscape. Recent guidelines in ABRS have been released by American and European groups as recently as 2007, but these are either limited in their coverage of the subject of CRS, do not follow an evidence-based strategy, or omit relevant stakeholders in guidelines development, and do not address the particulars of the Canadian healthcare environment.Advances in understanding the pathophysiology of CRS, along with the development of appropriate therapeutic strategies, have improved outcomes for patients with CRS. CRS now affects large numbers of patients globally and primary care practitioners are confronted by this disease on a daily basis. Although initially considered a chronic bacterial infection, CRS is now recognized as having multiple distinct components (eg, infection, inflammation), which have led to changes in therapeutic approaches (eg, increased use of corticosteroids). The role of bacteria in the persistence of chronic infections, and the roles of surgical and medical management are evolving. Although evidence is limited, guidance for managing patients with CRS would help practitioners less experienced in this area offer rational care. It is no longer reasonable to manage CRS as a prolonged version of ARS, but rather, specific therapeutic strategies adapted to pathogenesis must be developed and diffused.Guidelines must take into account all available evidence and incorporate these in an unbiased fashion into management recommendations based on the quality of evidence, therapeutic benefit, and risks incurred. This document is focused on readability rather than completeness, yet covers relevant information, offers summaries of areas where considerable evidence exists, and provides recommendations with an assessment of strength of the evidence base and degree of endorsement by the multidisciplinary expert group preparing the document.These guidelines have been copublished in both Allergy, Asthma & Clinical Immunology and the Journal of Otolaryngology-Head and Neck Surgery. PMID- 21310059 TI - Influence of genetic variability at the surfactant proteins A and D in community acquired pneumonia: a prospective, observational, genetic study. AB - INTRODUCTION: Genetic variability of the pulmonary surfactant proteins A and D may affect clearance of microorganisms and the extent of the inflammatory response. The genes of these collectins (SFTPA1, SFTPA2 and SFTPD) are located in a cluster at 10q21-24. The objective of this study was to evaluate the existence of linkage disequilibrium (LD) among these genes, and the association of variability at these genes with susceptibility and outcome of community-acquired pneumonia (CAP). We also studied the effect of genetic variability on SP-D serum levels. METHODS: Seven non-synonymous polymorphisms of SFTPA1, SFTPA2 and SFTPD were analyzed. For susceptibility, 682 CAP patients and 769 controls were studied in a case-control study. Severity and outcome were evaluated in a prospective study. Haplotypes were inferred and LD was characterized. SP-D serum levels were measured in healthy controls. RESULTS: The SFTPD aa11-C allele was significantly associated with lower SP-D serum levels, in a dose-dependent manner. We observed the existence of LD among the studied genes. Haplotypes SFTPA1 6A(2) (P = 0.0009, odds ration (OR) = 0.78), SFTPA(2) 1A(0) (P = 0.002, OR = 0.79), SFTPA1-SFTPA2 6A2-1A(0) (P = 0.0005, OR = 0.77), and SFTPD-SFTPA1-SFTPA(2)C-6A2-1A(0) (P = 0.00001, OR = 0.62) were underrepresented in patients, whereas haplotypes SFTPA2 1A(10) (P = 0.00007, OR = 6.58) and SFTPA1-SFTPA2 6A(3)-1A (P = 0.0007, OR = 3.92) were overrepresented. Similar results were observed in CAP due to pneumococcus, though no significant differences were now observed after Bonferroni corrections. 1A(10) and 6A-1A were associated with higher 28-day and 90-day mortality, and with multi-organ dysfunction syndrome (MODS) and acute respiratory distress syndrome (ARDS) respectively. SFTPD aa11-C allele was associated with development of MODS and ARDS. CONCLUSIONS: Our study indicates that missense single nucleotide polymorphisms and haplotypes of SFTPA1, SFTPA2 and SFTPD are associated with susceptibility to CAP, and that several haplotypes also influence severity and outcome of CAP. PMID- 21310060 TI - Bronchial artery embolization for management of massive cryptogenic hemoptysis: a case series. AB - INTRODUCTION: Hemoptysis constitutes a common and urgent medical problem. Swift and effective management is of crucial importance, especially in severe, life threatening cases. In cases of idiopathic hemoptysis, in which no underlying pulmonary pathology can be identified, treatment is challenging. We report our experience with bronchial artery embolization in the treatment of massive idiopathic hemoptysis. CASES PRESENTATION: We report three consecutive cases of acute severe idiopathic hemoptysis. Our patients (two men aged 51 and 56 years and one woman aged 46 years), were of Caucasian ethnicity. We discuss the results and management of the patients, and review the literature. All three patients were treated safely and successfully with transcatheter embolization of the bronchial arteries using tris-acryl gelatin microspheres. Hemoptysis was controlled. All cases were followed up for 12 months, and there was no recurrence of bleeding. CONCLUSION: Bronchial artery embolization is an effective tool for the evaluation and treatment of massive idiopathic hemoptysis. PMID- 21310061 TI - Inferring causal phenotype networks using structural equation models. AB - Phenotypic traits may exert causal effects between them. For example, on the one hand, high yield in dairy cows may increase the liability to certain diseases and, on the other hand, the incidence of a disease may affect yield negatively. Likewise, the transcriptome may be a function of the reproductive status in mammals and the latter may depend on other physiological variables. Knowledge of phenotype networks describing such interrelationships can be used to predict the behavior of complex systems, e.g. biological pathways underlying complex traits such as diseases, growth and reproduction. Structural Equation Models (SEM) can be used to study recursive and simultaneous relationships among phenotypes in multivariate systems such as genetical genomics, system biology, and multiple trait models in quantitative genetics. Hence, SEM can produce an interpretation of relationships among traits which differs from that obtained with traditional multiple trait models, in which all relationships are represented by symmetric linear associations among random variables, such as covariances and correlations. In this review, we discuss the application of SEM and related techniques for the study of multiple phenotypes. Two basic scenarios are considered, one pertaining to genetical genomics studies, in which QTL or molecular marker information is used to facilitate causal inference, and another related to quantitative genetic analysis in livestock, in which only phenotypic and pedigree information is available. Advantages and limitations of SEM compared to traditional approaches commonly used for the analysis of multiple traits, as well as some indication of future research in this area are presented in a concluding section. PMID- 21310062 TI - Expression of an endotoxin-free S-layer/allergen fusion protein in gram-positive Bacillus subtilis 1012 for the potential application as vaccines for immunotherapy of atopic allergy. AB - BACKGROUND: Genetic fusion of the major birch pollen allergen (Bet v1) to bacterial surface-(S)-layer proteins resulted in recombinant proteins exhibiting reduced allergenicity as well as immunomodulatory capacity. Thus, S layer/allergen fusion proteins were considered as suitable carriers for new immunotherapeutical vaccines for treatment of Type I hypersensitivity. Up to now, endotoxin contamination of the fusion protein which occurred after isolation from the gram-negative expression host E. coli had to be removed by an expensive and time consuming procedure. In the present study, in order to achieve expression of pyrogen-free, recombinant S-layer/allergen fusion protein and to study the secretion of a protein capable to self-assemble, the S-layer/allergen fusion protein rSbpA/Bet v1 was produced in the gram-positive organism Bacillus subtilis 1012. RESULTS: The chimaeric gene encoding the S-layer protein SbpA of Lysinibacillus sphaericus CCM 2177 as well as Bet v1 was cloned and expressed in B. subtilis 1012. For that purpose, the E. coli-B. subtilis shuttle vectors pHT01 for expression in the B. subtilis cytoplasm and pHT43 for secretion of the recombinant fusion protein into the culture medium were used. As shown by western blot analysis, immediately after induction of expression, B. subtilis 1012 was able to secret rSbpA/Bet v1 mediated by the signal peptide amyQ of Bacillus amyloliquefaciens. Electron microscopical investigation of the culture medium revealed that the secreted fusion protein was able to form self-assembly products in suspension but did not recrystallize on the surface of the B. subtilis cells. The specific binding mechanism between the N-terminus of the S-layer protein and a secondary cell wall polymer (SCWP), located in the peptidoglycan-containing sacculi of Ly. sphaericus CCM 2177, could be used for isolation and purification of the secreted fusion protein from the culture medium. Immune reactivity of rSbpA/Bet v1 could be demonstrated in immunoblotting experiments with Bet v1 specific IgE containing serum samples from patients suffering birch pollen allergy. CONCLUSIONS: The impact of this study can be seen in the usage of a gram positive organism for the production of pyrogen-free self-assembling recombinant S-layer/allergen fusion protein with great relevance for the development of vaccines for immunotherapy of atopic allergy. PMID- 21310063 TI - What's in a name; genetic structure in Solanum section Petota studied using population-genetic tools. AB - BACKGROUND: The taxonomy and systematic relationships among species of Solanum section Petota are complicated and the section seems overclassified. Many of the presumed (sub)species from South America are very similar and they are able to exchange genetic material. We applied a population genetic approach to evaluate support for subgroups within this material, using AFLP data. Our approach is based on the following assumptions: (i) accessions that may exchange genetic material can be analyzed as if they are part of one gene pool, and (ii) genetic differentiation among species is expected to be higher than within species. RESULTS: A dataset of 566 South-American accessions (encompassing 89 species and subspecies) was analyzed in two steps. First, with the program STRUCTURE 2.2 in an 'unsupervised' procedure, individual accessions were assigned to inferred clusters based on genetic similarity. The results showed that the South American members of section Petota could be arranged in 16 clusters of various size and composition. Next, the accessions within the clusters were grouped by maximizing the partitioning of genetic diversity among subgroups (i.e., maximizing Fst values) for all available individuals of the accessions (2767 genotypes). This two-step approach produced an optimal partitioning into 44 groups.Some of the species clustered as genetically distinct groups, either on their own, or combined with one or more other species. However, accessions of other species were distributed over more than one cluster, and did not form genetically distinct units. CONCLUSIONS: We could not find any support for 43 species (almost half of our dataset). For 28 species some level of support could be found varying from good to weak. For 18 species no conclusions could be drawn as the number of accessions included in our dataset was too low. These molecular data should be combined with data from morphological surveys, with geographical distribution data, and with information from crossing experiments to identify natural units at the species level. However, the data do indicate which taxa or combinations of taxa are clearly supported by a distinct set of molecular marker data, leaving other taxa unsupported. Therefore, the approach taken provides a general method to evaluate the taxonomic system in any species complex for which molecular data are available. PMID- 21310064 TI - Diagnostic value and clinical laboratory associations of antibodies against recombinant ribosomal P0, P1 and P2 proteins and their native heterocomplex in a Caucasian cohort with systemic lupus erythematosus. AB - INTRODUCTION: In this study, we sought to determine the diagnostic value and clinical laboratory associations of autoantibodies against recombinant ribosomal P0, P1 and P2 proteins and their native heterocomplex in systemic lupus erythematosus (SLE). METHODS: Autoantibodies against recombinant ribosomal P proteins (aRibPR0, aRibPR1 and aRibPR2) and antibodies against native ribosomal P heterocomplex (aRibPNH) were determined in sera from patients with SLE (n = 163), systemic sclerosis (n = 66), Sjogren's syndrome (n = 54), rheumatoid arthritis (n = 90) and healthy donors (n = 100) using enzyme-linked immunosorbent assay. Test results were correlated to medical records, including the American College of Rheumatology criteria, the Systemic Lupus Erythematosus Disease Activity Index 2000, laboratory data and medications of all SLE patients. RESULTS: Sensitivities of 22.0% for aRibPR0, 14.9% for aRibPR2, 14.3% for aRibPNH and 10.7% for aRibPR1 were obtained at a specificity of 99%. The assay for aRibPR0 detection demonstrated the best performance in receiver-operating characteristics analysis, with aRibPR0 detectable in 10% of anti-Smith antibody and anti-double-stranded DNA-negative sera at a specificity of 100%. ARibPR0 positivity was associated with lymphocytopenia. ARibPR1+ patients had significantly higher gamma-glutamyl transpeptidase (GGT) levels than their aRibPR1- counterparts. No specific damage occurred in aRibP+ lupus patients compared with a group of age-, sex- and nephritis-matched aRibP- lupus patients within 3 years. CONCLUSIONS: The determination of antibodies against ribosomal P proteins improves the diagnosis of SLE and should therefore be implemented in upcoming criteria for the diagnosis or classification of SLE. High titers of aRibPR0 can be associated with lymphocytopenia, and high titers of aRibPR1 can be associated with elevated GGT levels. So far, there is no evidence for a prognostic value of aRibPs for damage. PMID- 21310065 TI - The whole-organism heavy chain B cell repertoire from Zebrafish self-organizes into distinct network features. AB - BACKGROUND: The adaptive immune system is based on selected populations of molecularly distinct individual B and T cell clones. However, it has not been possible to characterize these clones in a comprehensive and informatics manner to date; attempts have been limited by the number of cells in the adaptive immune system and an inability to quantify them. Recently, using the Zebrafish (ZF) Danio rerio as a model organism and parallel sequencing as the quantifying technology, Weinstein et al. overcame this major hurdle and quantified the entire heavy chain B-cell repertoire in ZF. Here, we present a novel network analysis of the data from the Weinstein group, providing new insights into the network structure of the B-cell repertoire. RESULTS: Using a collection of computational methods, the IgM sequences from 14 fish were analyzed. This analysis demonstrated that the B-cell repertoire of the ZF is structured along similar lines to those previously detected in limited parts of the human B-cell immune system. The analysis confirms the validity of the global data and the evolutionary placement of the ZF based on known sequence motifs. Recombination events in the repertoire were quantified, and demonstrated a lack of shared recombined V, J groups across fish. Nevertheless, it was demonstrated that a similar network architecture is shared among fish. However, the network analysis identified two distinct populations within the group; these findings are compatible with the occurrence of an immune response in a subset of the fish. The emerging connectivity network was demonstrated and quantified, and mutation drifts within the groups were characterized. Dissection of sequence data revealed common network features of the B-cell repertoire as well as individual differences. CONCLUSION: The ZF B cell repertoire reveals an underlying order that is compatible with self organization representing every portion of the sequence-based network. This pattern varies in individual specimens, perhaps as a response to an immune challenge. However, a sequence-non-specific network that maintains a common architecture of sequence diversity was detected.The common feature among different individuals can be captured by the network architecture and characteristics, rather than specific clones. We believe that further study of the dynamics of this network could provide insight into modes of operation of the immune system. PMID- 21310066 TI - Overexpression of Sterol Carrier Protein 2 in patients with hereditary cholesterol gallstones. AB - BACKGROUND: Lithogenic bile is the major cause of cholesterol gallstone, but its pathogenesis is not well understood. The hypersecretion of biliary cholesterol is believed to be an important cause of lithogenic bile. Sterol Carrier Protein 2 (SCP2) participates in cholesterol trafficking and lipid metabolism in hepatocytes and may play a key role in cholesterol gallstone formation. METHODS: 21 cholesterol gallstone genealogies were studied to investigate the expression of SCP2 gene in liver tissue of hereditary and non-hereditary cholesterol gallstone patients as well as non-gallstone patients. The mRNA expression of liver SCP2 in 28 hereditary patients, 30 non-hereditary cholesterol gallstone patients and 32 non-gallstone patients was measured by Reverse Transcription Polymerase Chain Reaction (RT-PCR). The protein expression of liver SCP2 was also detected in all the patients by Western blotting. At the same time, the bile was also analyzed with biochemical techniques and the Cholesterol Saturation Index (CSI) was calculated. RESULTS: The mRNA and protein expression of SCP2 was significantly increased in cholesterol gallstone patients compared to those of non-gallstone patients. Moreover, SCP2 was expressed at higher levels in hereditary cholesterol gallstone patients than that of non-hereditary cholesterol gallstone patients. There was significant difference observed in CSI between cholesterol gallstone patients and non-gallstone patients, but not in CSI between hereditary and non-hereditary cholesterol gallstone patients. CONCLUSIONS: SCP2 was overexpressed in hereditary cholesterol gallstone patients compared to non hereditary cholesterol gallstone patients. This finding indicated that SCP2 might be one of the genetic factors contributing to cholesterol gallstone formation, which was always accompanied by the increase of bile lithogenicity. PMID- 21310067 TI - Inhibition of angiogenesis and suppression of colorectal cancer metastatic to the liver using the Sleeping Beauty Transposon System. AB - BACKGROUND: Metastatic colon cancer is one of the leading causes of cancer related death worldwide, with disease progression and metastatic spread being closely associated with angiogenesis. We investigated whether an antiangiogenic gene transfer approach using the Sleeping Beauty (SB) transposon system could be used to inhibit growth of colorectal tumors metastatic to the liver. RESULTS: Liver CT26 tumor-bearing mice were hydrodynamically injected with different doses of a plasmid containing a transposon encoding an angiostatin-endostatin fusion gene (Statin AE) along with varying amounts of SB transposase-encoding plasmid. Animals that were injected with a low dose (10 MUg) of Statin AE transposon plasmid showed a significant decrease in tumor formation only when co-injected with SB transposase-encoding plasmid, while for animals injected with a higher dose (25 MUg) of Statin AE transposon, co-injection of SB transposase-encoding plasmid did not significantly affect tumor load. For animals injected with 10 MUg Statin AE transposon plasmid, the number of tumor nodules was inversely proportional to the amount of co-injected SB plasmid. Suppression of metastases was further evident in histological analyses, in which untreated animals showed higher levels of tumor cell proliferation and tumor vascularization than animals treated with low dose transposon plasmid. CONCLUSION: These results demonstrate that hepatic colorectal metastases can be reduced using antiangiogenic transposons, and provide evidence for the importance of the transposition process in mediating suppression of these tumors. PMID- 21310068 TI - Reciprocal relationship between APP positioning relative to the membrane and PS1 conformation. AB - BACKGROUND: Several familial Alzheimer disease (FAD) mutations within the transmembrane region of the amyloid precursor protein (APP) increase the Abeta42/40 ratio without increasing total Abeta production. In the present study, we analyzed the impact of FAD mutations and gamma-secretase modulators (GSMs) that alter the Abeta42/40 ratio on APP C-terminus (CT) positioning relative to the membrane, reasoning that changes in the alignment of the APP intramembranous domain and presenilin 1 (PS1) may impact the PS1/gamma-secretase cleavage site on APP. RESULTS: By using a Forster resonance energy transfer (FRET)-based technique, fluorescent lifetime imaging microscopy (FLIM), we show that Abeta42/40 ratio-modulating factors which target either APP substrate or PS1/gamma-secretase affect proximity of the APP-CT to the membrane and change PS1 conformation. CONCLUSIONS: Thus, we propose that there is a reciprocal relationship between APP-CT positioning relative to the membrane and PS1 conformation, suggesting that factors that modulate either APP positioning in the membrane or PS1 conformation could be exploited therapeutically. PMID- 21310069 TI - Genetically altering the expression of neutral trehalase gene affects conidiospore thermotolerance of the entomopathogenic fungus Metarhizium acridum. AB - BACKGROUND: The entomopathogenic fungus Metarhizium acridum has been used as an important biocontrol agent instead of insecticides for controlling crop pests throughout the world. However, its virulence varies with environmental factors, especially temperature. Neutral trehalase (Ntl) hydrolyzes trehalose, which plays a role in environmental stress response in many organisms, including M. acridum. Demonstration of a relationship between Ntl and thermotolerance or virulence may offer a new strategy for enhancing conidiospore thermotolerance of entomopathogenic fungi through genetic engineering. RESULTS: We selected four Ntl over-expression and four Ntl RNA interference (RNAi) transformations in which Ntl expression is different. Compared to the wild-type, Ntl mRNA expression was reduced to 35-66% in the RNAi mutants and increased by 2.5-3.5-fold in the over expression mutants. The RNAi conidiospores exhibited less trehalase activity, accumulated more trehalose, and were much more tolerant of heat stress than the wild-type. The opposite effects were found in conidiospores of over-expression mutants compared to RNAi mutants. Furthermore, virulence was not altered in the two types of mutants compared to the wild type. CONCLUSIONS: Ntl controlled trehalose accumulation in M. acridum by degrading trehalose, and thus affected conidiospore thermotolerance. These results offer a new strategy for enhancing conidiospore thermotolerance of entomopathogenic fungi without affecting virulence. PMID- 21310070 TI - Granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) for sepsis: a meta-analysis. AB - INTRODUCTION: To investigate the effects of G-CSF or GM-CSF therapy in non neutropenic patients with sepsis. METHODS: A systematic literature search of Medline, Embase and Cochrane Central Register of Controlled Trials was conducted using specific search terms. A manual review of references was also performed. Eligible studies were randomized control trials (RCTs) that compared granulocyte colony stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) therapy with placebo for the treatment of sepsis in adults. Main outcome measures were all-cause mortality at 14 days and 28 days after initiation of G-CSF or GM-CSF therapy, in-hospital mortality, reversal rate from infection, and adverse events. RESULTS: Twelve RCTs with 2,380 patients were identified. In regard to 14-day mortality, a total of 9 death events occurred among 71 patients (12.7%) in the treatment group compared with 13 events among 67 patients (19.4%) in the placebo groups. Meta-analysis showed there was no significant difference in 28-day mortality when G-CSF or GM-CSF were compared with placebo (relative risks (RR) = 0.93, 95% confidence interval (CI): 0.79 to 1.11, P = 0.44; P for heterogeneity = 0.31, I2 = 15%). Compared with placebo, G-CSF or GM-CSF therapy did not significantly reduce in-hospital mortality (RR = 0.97, 95% CI: 0.69 to 1.36, P = 0.86; P for heterogeneity = 0.80, I2 = 0%). However, G-CSF or GM-CSF therapy significantly increased the reversal rate from infection (RR = 1.34, 95% CI: 1.11 to 1.62, P = 0.002; P for heterogeneity = 0.47, I2 = 0%). No significant difference was observed in adverse events between groups (RR = 0.93, 95% CI: 0.70 to 1.23, P = 0.62; P for heterogeneity = 0.03, I2 = 58%). Sensitivity analysis by excluding one trial did not significantly change the results of adverse events (RR = 1.05, 95% CI: 0.84 to 1.32, P = 0.44; P for heterogeneity = 0.17, I2 = 36%). CONCLUSIONS: There is no current evidence supporting the routine use of G CSF or GM-CSF in patients with sepsis. Large prospective multicenter clinical trials investigating monocytic HLA-DR (mHLA-DR)-guided G-CSF or GM-CSF therapy in patients with sepsis-associated immunosuppression are warranted. PMID- 21310071 TI - A rare case of giant leiomyosarcoma in a filarial scrotum: a case report. AB - Giant leiomyosarcoma of scrotum is a rare tumour. A case of scrotum leiomyosarcoma is presented in a 67 year old patient with scrotal filariasis which was managed successfully with total scrotectomy with bilateral orchidectomy, degloved penis reconstructed with rotation advancement supra pubic fasciocutaneous flap. We made a literature search proving the rarity of this lesion type. Only 36 cases have been described and the first case in a filarial scrotum. PMID- 21310072 TI - An automated growth enclosure for metabolic labeling of Arabidopsis thaliana with 13C-carbon dioxide - an in vivo labeling system for proteomics and metabolomics research. AB - BACKGROUND: Labeling whole Arabidopsis (Arabidopsis thaliana) plants to high enrichment with 13C for proteomics and metabolomics applications would facilitate experimental approaches not possible by conventional methods. Such a system would use the plant's native capacity for carbon fixation to ubiquitously incorporate 13C from 13CO2 gas. Because of the high cost of 13CO2 it is critical that the design conserve the labeled gas. RESULTS: A fully enclosed automated plant growth enclosure has been designed and assembled where the system simultaneously monitors humidity, temperature, pressure and 13CO2 concentration with continuous adjustment of humidity, pressure and 13CO2 levels controlled by a computer running LabView software. The enclosure is mounted on a movable cart for mobility among growth environments. Arabidopsis was grown in the enclosure for up to 8 weeks and obtained on average >95 atom% enrichment for small metabolites, such as amino acids and >91 atom% for large metabolites, including proteins and peptides. CONCLUSION: The capability of this labeling system for isotope dilution experiments was demonstrated by evaluation of amino acid turnover using GC-MS as well as protein turnover using LC-MS/MS. Because this 'open source' Arabidopsis 13C-labeling growth environment was built using readily available materials and software, it can be adapted easily to accommodate many different experimental designs. PMID- 21310073 TI - Bcr is a substrate for Transglutaminase 2 cross-linking activity. AB - BACKGROUND: Breakpoint cluster region (Bcr) is a multi-domain protein that contains a C-terminal GTPase activating protein (GAP) domain for Rac. Transglutaminase 2 (TG2) regulates Bcr by direct binding to its GAP domain. Since TG2 has transglutaminase activity that has been implicated in the response to extreme stress, we investigated if Bcr can also act as a substrate for TG2. RESULTS: We here report that activation of TG2 by calcium caused the formation of covalently cross-linked Bcr. Abr, a protein related to Bcr but lacking its N terminal oligomerization domain, was not cross-linked by TG2 even though it forms a complex with it. A Bcr mutant missing the first 62 amino acid residues remained monomeric in the presence of activated TG2, showing that this specific domain is necessary for the cross-linking reaction. Calcium influx induced by a calcium ionophore in primary human endothelial cells caused cross-linking of endogenous Bcr, which was inhibited by the TG2 inhibitor cystamine. Treatment of cells with cobalt chloride, a hypoxia-mimetic that causes cellular stress, also generated high molecular weight Bcr complexes. Cross-linked Bcr protein appeared in the TritonX-100-insoluble cell fraction and further accumulated in cells treated with a proteasome inhibitor. CONCLUSIONS: Bcr thus represents both an interacting partner under non-stressed conditions and a target of transglutaminase activity for TG2 during extreme stress. PMID- 21310074 TI - Progress towards the eradication of Tsetse from the Loos islands, Guinea. AB - BACKGROUND: The tsetse fly Glossina palpalis gambiensis is the main vector of sleeping sickness (Human African Trypanosomiasis - HAT) in West Africa, in particular in littoral Guinea where this disease is currently very active. The Loos islands constitute a small archipelago some 5 km from mainland Guinea, where G. p. gambiensis is well known as a nuisance and potential disease vector by inhabitants of the three main islands, Fotoba, Room, and Kassa. The National Control Program against HAT of Guinea has decided to eradicate tsetse in Loos islands in order to sustainably protect humans and economic activities. After baseline data collection, tsetse control began on the islands in 2006. On each of the three islands a specific combination of control methods was implemented according to the entomological situation found. RESULTS: Starting densities before control operations were 10, 3 and 1 tsetse/trap/day in Kassa, Room and Fotoba respectively, but by July 2010, tsetse were no longer caught in any of the sentinel traps used for monitoring. The reduction rate was faster where several control methods were implemented as a combination (impregnated traps and targets ITT, selective groundspraying, epicutaneous insecticide treatment of pigs, and impregnated fences around pig pens), whereas it was slower when ITT were used as the only control method. CONCLUSIONS: This 100% suppression is a promising step in the eradication process, but G. p. gambiensis may still occur at very low, undetectable, densities on the archipelago. Next step will consist in assessing a 0.05 probability of tsetse absence to ascertain a provisional eradication status. Throughout these operations, a key factor has been the involvement of local teams and local communities without whom such results would be impossible to obtain. Work will continue thanks to the partners involved until total eradication of the tsetse on Loos islands can be declared. PMID- 21310075 TI - Reduction of claustrophobia during magnetic resonance imaging: methods and design of the "CLAUSTRO" randomized controlled trial. AB - BACKGROUND: Magnetic resonance (MR) imaging has been described as the most important medical innovation in the last 25 years. Over 80 million MR procedures are now performed each year and on average 2.3% (95% confidence interval: 2.0 to 2.5%) of all patients scheduled for MR imaging suffer from claustrophobia. Thus, prevention of MR imaging by claustrophobia is a common problem and approximately 2,000,000 MR procedures worldwide cannot be completed due to this situation. Patients with claustrophobic anxiety are more likely to be frightened and experience a feeling of confinement or being closed in during MR imaging. In these patients, conscious sedation and additional sequences (after sedation) may be necessary to complete the examinations. Further improvements in MR design appear to be essential to alleviate this situation and broaden the applicability of MR imaging. A more open scanner configuration might help reduce claustrophobic reactions while maintaining image quality and diagnostic accuracy. METHODS/DESIGN: We propose to analyze the rate of claustrophobic reactions, clinical utility, image quality, patient acceptance, and cost-effectiveness of an open MR scanner in a randomized comparison with a recently designed short-bore but closed scanner with 97% noise reduction. The primary aim of this study is thus to determine whether an open MR scanner can reduce claustrophobic reactions, thereby enabling more examinations of claustrophobic patients without incurring the safety issues associated with conscious sedation. In this manuscript we detail the methods and design of the prospective "CLAUSTRO" trial. DISCUSSION: This randomized controlled trial will be the first direct comparison of open vertical and closed short-bore MR systems in regards to claustrophobia and image quality as well as diagnostic utility. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00715806. PMID- 21310076 TI - Modification of genetic regulation of a heterologous chitosanase gene in Streptomyces lividans TK24 leads to chitosanase production in the absence of chitosan. AB - BACKGROUND: Chitosanases are enzymes hydrolysing chitosan, a beta-1,4 linked D glucosamine bio-polymer. Chitosan oligosaccharides have numerous emerging applications and chitosanases can be used for industrial enzymatic hydrolysis of chitosan. These extracellular enzymes, produced by many organisms including fungi and bacteria, are well studied at the biochemical and enzymatic level but very few works were dedicated to the regulation of their gene expression. This is the first study on the genetic regulation of a heterologous chitosanase gene (csnN106) in Streptomyces lividans. RESULTS: Two S. lividans strains were used for induction experiments: the wild type strain and its mutant (DeltacsnR), harbouring an in-frame deletion of the csnR gene, encoding a negative transcriptional regulator. Comparison of chitosanase levels in various media indicated that CsnR regulates negatively the expression of the heterologous chitosanase gene csnN106. Using the DeltacsnR host and a mutated csnN106 gene with a modified transcription operator, substantial levels of chitosanase could be produced in the absence of chitosan, using inexpensive medium components. Furthermore, chitosanase production was of higher quality as lower levels of extracellular protease and protein contaminants were observed. CONCLUSIONS: This new chitosanase production system is of interest for biotechnology as only common media components are used and enzyme of high degree of purity is obtained directly in the culture supernatant. PMID- 21310077 TI - Novel therapies for resistant focal segmental glomerulosclerosis (FONT) phase II clinical trial: study design. AB - BACKGROUND: The lack of adequate randomized clinical trials (RCT) has hindered identification of new therapies that are safe and effective for patients with primary focal segmental glomerulosclerosis (FSGS), especially in patients who fail to respond to corticosteroids and immunosuppressive therapies. Recent basic science advances have led to development of alternative treatments that specifically target aberrant pathways of fibrosis which are relevant to disease progression in FSGS. There is a need for a flexible Phase II study design which will test such novel antifibrotic strategies in order to identify agents suitable for phase III testing. METHODS/DESIGN: The Novel Therapies for Resistant Focal Segmental Glomerulosclerosis (FONT) project is a multicenter Phase I/II RCT designed to investigate the potential efficacy of novel therapies for resistant FSGS. Adalimumab and galactose will be evaluated against conservative therapy consisting of the combination of lisinopril, losartan and atorvastatin. The sample size is defined to assure that if one of the treatments has a superior response rate compared to that of the other treatments, it will be selected with high probability for further evaluation. Comparison of primary and secondary endpoints in each study arm will enable a choice to be made of which treatments are worthy of further study in future Phase III RCT. DISCUSSION: This report highlights the key features of the FONT II RCT including the two-step outcome analysis that will expedite achievement of the study objectives. The proposed phase II study design will help to identify promising agents for further testing while excluding ineffective agents. This staged approach can help to prevent large expenditures on unworthy therapeutic agents in the management of serious but rare kidney diseases. PMID- 21310078 TI - Biochemical isolation and purification of ovulation-inducing factor (OIF) in seminal plasma of llamas. AB - BACKGROUND: The objective of the present study was to isolate and purify the protein fraction(s) of llama seminal plasma responsible for the ovulation inducing effect of the ejaculate. METHODS: Semen collected from male llamas by artificial vagina was centrifuged and the seminal plasma was harvested and stored frozen. Seminal plasma was thawed and loaded onto a Type 1 macro-prep ceramic hydroxylapatite column and elution was carried out using a lineal gradient with 350 mM sodium phosphate. Three protein fractions were identified clearly (Fractions A, B, and C), where a prominent protein band with a mass of 14 kDa was identified in Fraction C. Fraction C was loaded into a sephacryl gel filtration column for further purification using fast protein liquid chromatography (FPLC). Isocratic elution resulted in 2 distinct protein fractions (Fractions C1 and C2). An in vivo bioassay (n=10 to 11 llamas per group) was used to determine the ovarian effect of each fraction involving treatment with saline (negative control), whole seminal plasma (positive control), or seminal plasma Fractions A, B or C2. Ultrasonography was done to detect ovulation and CL formation, and blood samples were taken to measure plasma progesterone and LH concentrations. RESULTS: Ovulation and CL formation was detected in 0/10, 10/11, 0/10, 2/11, and 10/11 llamas treated with saline, whole seminal plasma, Fractions A, B and C2 respectively (P<0.001). A surge in circulating concentrations of LH was detected within 2 hours only in llamas treated with either whole seminal plasma or Fraction C2. Plasma progesterone concentration and CL diameter profiles were greatest (P<0.05) in llamas treated with Fraction C2. CONCLUSION: Ovulation inducing factor was isolated from llama seminal plasma as a 14 kDa protein molecule that elicits a preovulatory LH surge followed by ovulation and CL formation in llamas, suggesting an endocrine effect at the level of the hypothalamus (release of GnRH) or the pituitary (gonadotrophs). PMID- 21310079 TI - Inositol pentakisphosphate isomers bind PH domains with varying specificity and inhibit phosphoinositide interactions. AB - BACKGROUND: PH domains represent one of the most common domains in the human proteome. These domains are recognized as important mediators of protein phosphoinositide and protein-protein interactions. Phosphoinositides are lipid components of the membrane that function as signaling molecules by targeting proteins to their sites of action. Phosphoinositide based signaling pathways govern a diverse range of important cellular processes including membrane remodeling, differentiation, proliferation and survival. Myo-Inositol phosphates are soluble signaling molecules that are structurally similar to the head groups of phosphoinositides. These molecules have been proposed to function, at least in part, by regulating PH domain-phosphoinositide interactions. Given the structural similarity of inositol phosphates we were interested in examining the specificity of PH domains towards the family of myo-inositol pentakisphosphate isomers. RESULTS: In work reported here we demonstrate that the C-terminal PH domain of pleckstrin possesses the specificity required to discriminate between different myo-inositol pentakisphosphate isomers. The structural basis for this specificity was determined using high-resolution crystal structures. Moreover, we show that while the PH domain of Grp1 does not possess this high degree of specificity, the PH domain of protein kinase B does. CONCLUSIONS: These results demonstrate that some PH domains possess enough specificity to discriminate between myo-inositol pentakisphosphate isomers allowing for these molecules to differentially regulate interactions with phosphoinositides. Furthermore, this work contributes to the growing body of evidence supporting myo-inositol phosphates as regulators of important PH domain-phosphoinositide interactions. Finally, in addition to expanding our knowledge of cellular signaling, these results provide a basis for developing tools to probe biological pathways. PMID- 21310080 TI - A dual investigation of the effect of dietary supplementation with licorice flavonoid oil on anthropometric and biochemical markers of health and adiposity. AB - BACKGROUND: Licorice flavonoid oil (LFO) has been reported to minimize visceral adipose tissue gain in obese mice and to result in a decrease in body weight and body fat in humans; the effects of which may be more pronounced when administered in an overfed state. METHODS: We investigated the effects of LFO in two separate studies. Study 1 included a sample of overweight or grade I-II obese men and women (N = 22) who followed their usual dietary and physical activity programs. Study 2 included a sample of athletic men who followed their usual dietary and physical activity programs but consumed a daily supplemental meal (25% above daily energy requirements) in an attempt to induce a state of overfeeding. In both studies, subjects were randomly assigned (double-blind) to either LFO or a placebo for eight weeks, and anthropometric and multiple biochemical outcomes (e.g., markers of oxidative stress, markers of insulin sensitivity, blood lipids, etc.) were obtained before and following the intervention. RESULTS: No differences of statistical significance were noted between LFO and placebo for any measured variable in Study 1 or Study 2. When investigating the percent change from baseline for data in Study 2, although not of statistical significance, subjects in the LFO condition experienced less overall fat gain, as well as attenuation in the elevation in selected blood lipids (e.g., cholesterol, LDL-C, and triglycerides). CONCLUSION: These combined data indicate little effect of LFO supplementation within a sample of overweight/obese men and women or athletic men, with the possible exception of attenuation in body fat gain and selected components of the blood lipid panel in response to an overfeeding condition. PMID- 21310081 TI - Cumulative smoking exposure, duration of smoking cessation, and peripheral arterial disease in middle-aged and older Korean men. AB - BACKGROUND: We investigated the association of cumulative smoking exposure and duration of smoking cessation with peripheral arterial disease (PAD). METHODS: The study population consisted of 2517 community-dwelling Korean men aged 50 years and older. Information on smoking characteristics such as smoking status, pack-years of smoking, and years since quitting smoking was collected using a standardized questionnaire. PAD was defined as an ankle-brachial index (ABI) less than 0.90 in either leg. RESULTS: The odds ratio (OR, 95% confidence interval) of PAD was 2.31 (1.20-4.42) for former smokers and 4.30 (2.13-8.66) for current smokers, after adjusting for other cardiovascular risk factors. There was a significant dose-response relationship between pack-years of smoking and PAD. Compared with those who had never smoked, the multivariate-adjusted ORs of PAD for smokers of 0.1-20.0, 20.1-40.0, and >40.0 pack-years were 2.15 (1.06-4.38), 2.24 (1.08-4.65), and 2.93 (1.41-6.09), respectively. There was a significant decrease in PAD risk as the years since quitting smoking increased. The multivariate-adjusted ORs of PAD for 11-20 and >= 21 years smoking cessation were 0.41 (0.19-0.86) and 0.49 (0.24-0.98), compared with current smokers. CONCLUSIONS: Cumulative smoking exposure and duration of smoking cessation were significantly associated with PAD in middle aged and older Korean men. PMID- 21310082 TI - High prevalence of vitamin D insufficiency and its association with BMI-for-age among primary school children in Kuala Lumpur, Malaysia. AB - BACKGROUND: Deficiencies of micronutrients can affect the growth and development of children. There is increasing evidence of vitamin D deficiency world-wide resulting in nutritional rickets in children and osteoporosis in adulthood. Data on the micronutrient status of children in Malaysia is limited. The aim of this study was to determine the anthropometric and micronutrient status of primary school children in the capital city of Kuala Lumpur. METHODS: A cross sectional study of primary aged school children was undertaken in 2008. A total of 402 boys and girls aged 7-12 years, attending primary schools in Kuala Lumpur participated in the study. Fasting blood samples were taken to assess vitamin D [as 25(OH)D], vitamin B12, folate, zinc, iron, and ferritin and haemoglobin concentrations. Height-for-age and body mass index for age (BMI-for-age) of the children were computed. RESULTS: Most of the children had normal height-for-age (96.5%) while slightly over half (58.0%) had normal BMI-for-age. A total of 17.9% were overweight and 16.4% obese. Prevalence of obesity was significantly higher among the boys (25%) than in the girls (9.5%) (chi2 = 22.949; P < .001). Most children had adequate concentrations of haemoglobin, serum ferritin, zinc, folate and vitamin B12. In contrast, 35.3% of the children had serum 25(OH)D concentrations indicative of vitamin D deficiency(<= 37.5 nmol/L) and a further 37.1% had insufficiency concentrations (> 37.5-<= 50 nmol/L). Among the boys, a significant inverse association was found between serum vitamin D status and BMI-for-age (chi2 = 5.958; P = .016). CONCLUSIONS: This study highlights the presence of a high prevalence of sub-optimal vitamin D status among urban primary school children in a tropical country. In light of the growing problem of obesity in Malaysian children, these findings emphasize the important need for appropriate interventions to address both problems of obesity and poor vitamin D status in children. PMID- 21310083 TI - Knowledge-to-action processes in SHRTN collaborative communities of practice: a study protocol. AB - BACKGROUND: The Seniors Health Research Transfer Network (SHRTN) Collaborative is a network of networks that work together to improve the health and health care of Ontario seniors. The collaborative facilitates knowledge exchange through a library service, knowledge brokers (KBs), local implementation teams, collaborative technology, and, most importantly, Communities of Practice (CoPs) whose members work together to identify innovations, translate evidence, and help implement changes.This project aims to increase our understanding of knowledge-to action (KTA) processes mobilized through SHRTN CoPs that are working to improve the health of Ontario seniors. For this research, KTA refers to the movement of research and experience-based knowledge between social contexts, and the use of that knowledge to improve practice. We will examine the KTA processes themselves, as well as the role of human agents within those processes. The conceptual framework we have adopted to inform our research is the Promoting Action on Research Implementation in Health Services (PARIHS) framework. METHODS/DESIGN: This study will use a multiple case study design (minimum of nine cases over three years) to investigate how SHRTN CoPs work and pursue knowledge exchange in different situations. Each case will yield a unique narrative, framed around the three PARIHS dimensions: evidence, context, and facilitation. Together, the cases will shed light on how SHRTN CoPs approach their knowledge exchange initiatives, and how they respond to challenges and achieve their objectives. Data will be collected using interviews, document analysis, and ethnographic observation. DISCUSSION: This research will generate new knowledge about the defining characteristics of CoPs operating in the health system, on leadership roles in CoPs, and on the nature of interaction processes, relationships, and knowledge exchange mechanisms. Our work will yield a better understanding of the factors that contribute to the success or failure of KTA initiatives, and create a better understanding of how local caregiving contexts interact with specific initiatives. Our participatory design will allow stakeholders to influence the practical usefulness of our findings and contribute to improved health services delivery for seniors. PMID- 21310084 TI - Estimating developmental states of tumors and normal tissues using a linear time ordered model. AB - BACKGROUND: Tumor cells are considered to have an aberrant cell state, and some evidence indicates different development states appearing in the tumorigenesis. Embryonic development and stem cell differentiation are ordered processes in which the sequence of events over time is highly conserved. The "cancer attractor" concept integrates normal developmental processes and tumorigenesis into a high-dimensional "cell state space", and provides a reasonable explanation of the relationship between these two biological processes from theoretical viewpoint. However, it is hard to describe such relationship by using existed experimental data; moreover, the measurement of different development states is also difficult. RESULTS: Here, by applying a novel time-ordered linear model based on a co-bisector which represents the joint direction of a series of vectors, we described the trajectories of development process by a line and showed different developmental states of tumor cells from developmental timescale perspective in a cell state space. This model was used to transform time-course developmental expression profiles of human ESCs, normal mouse liver, ovary and lung tissue into "cell developmental state lines". Then these cell state lines were applied to observe the developmental states of different tumors and their corresponding normal samples. Mouse liver and ovarian tumors showed different similarity to early development stage. Similarly, human glioma cells and ovarian tumors became developmentally "younger". CONCLUSIONS: The time-ordered linear model captured linear projected development trajectories in a cell state space. Meanwhile it also reflected the change tendency of gene expression over time from the developmental timescale perspective, and our finding indicated different development states during tumorigenesis processes in different tissues. PMID- 21310085 TI - Expression of sphingosine kinase 1 in amoeboid microglial cells in the corpus callosum of postnatal rats. AB - Sphingosine kinase 1 (SphK1), a key enzyme responsible for phosphorylating sphingosine into sphingosine-1-phosphate (S1P) has been shown to be expressed in monocytes and monocyte-derived peripheral macrophages. This study demonstrates SphK1 immunoexpression in amoeboid microglial cells (AMC), a nascent monocyte derived brain macrophage in the corpus callosum of developing rat brain. SphK1 immunofluorescence expression, which appeared to be weak in AMC in normal brain, was markedly induced by lipopolysaccharide (LPS) or hypoxia treatment. Western blot analysis also showed increased expression level of SphK1 in the corpus callosum rich in AMC after LPS treatment. Detection of SphK1 mRNA and its upregulation after LPS treatment was confirmed in primary culture AMC by RT-PCR. Administration of N, N-dimethylsphingosine (DMS), a specific inhibitor of SphK1, effectively reduced upregulated SphK1 immunoexpression in AMC both in vivo and in vitro. This was corroborated by western blot which showed a decrease in SphK1 protein level of callosal tissue with DMS pretreatment. Remarkably, LPS-induced upregulation of the transcription factor NFkappaB was suppressed by DMS. We conclude that SphK1 expression in AMC may be linked to regulation of proinflammatory cytokines via an NFkappaB signaling pathway. PMID- 21310086 TI - Physician attitudes and treatment patterns for pancreatic cancer. AB - BACKGROUND: Surgery appears to be an underutilized treatment option for pancreatic cancer. Nihilistic physician attitudes may be partly responsible. The study objectives were to analyze physician attitudes towards this disease and determine treatment patterns and outcomes including rates of surgical referral. METHODS: A survey was administered to 420 physicians in Manitoba to document general knowledge and attitudes. Population based administrative data was accessed for all patients diagnosed with pancreatic cancer between 2004 and 2006 to examine treatment patterns and outcomes. RESULTS: 181 physicians responded to the survey. Most (73%) believed that surgical resection was worthwhile. Of the 413 Manitobans diagnosed with pancreatic cancer, only 11% underwent an attempt at surgical resection. There were 124 patients with stage I or II disease (i.e. potentially resectable), 85 of these patients received no treatment and 39% were not referred to a surgeon. These patients were older than those referred, but did not have more comorbidities. CONCLUSION: Most physicians were insightfully aware of both the survival benefit and potential risks of surgical resection. However, some did overestimate the surgical mortality and underestimate the associated survival benefit. Although advanced age may justly account for some of the patients not receiving a referral, it is reasonable to assume that nihilistic physician attitudes is contributing to the apparent underutilization of surgery for pancreatic cancer. Efforts should be made to ensure that eligible patients are at least offered surgery as a potential treatment option. PMID- 21310087 TI - Identification of errors introduced during high throughput sequencing of the T cell receptor repertoire. AB - BACKGROUND: Recent advances in massively parallel sequencing have increased the depth at which T cell receptor (TCR) repertoires can be probed by >3log10, allowing for saturation sequencing of immune repertoires. The resolution of this sequencing is dependent on its accuracy, and direct assessments of the errors formed during high throughput repertoire analyses are limited. RESULTS: We analyzed 3 monoclonal TCR from TCR transgenic, Rag-/- mice using Illumina(r) sequencing. A total of 27 sequencing reactions were performed for each TCR using a trifurcating design in which samples were divided into 3 at significant processing junctures. More than 20 million complementarity determining region (CDR) 3 sequences were analyzed. Filtering for lower quality sequences diminished but did not eliminate sequence errors, which occurred within 1-6% of sequences. Erroneous sequences were pre-dominantly of correct length and contained single nucleotide substitutions. Rates of specific substitutions varied dramatically in a position-dependent manner. Four substitutions, all purine-pyrimidine transversions, predominated. Solid phase amplification and sequencing rather than liquid sample amplification and preparation appeared to be the primary sources of error. Analysis of polyclonal repertoires demonstrated the impact of error accumulation on data parameters. CONCLUSIONS: Caution is needed in interpreting repertoire data due to potential contamination with mis-sequence reads. However, a high association of errors with phred score, high relatedness of erroneous sequences with the parental sequence, dominance of specific nt substitutions, and skewed ratio of forward to reverse reads among erroneous sequences indicate approaches to filter erroneous sequences from repertoire data sets. PMID- 21310088 TI - The efficacy and safety study of dietary supplement PURIAM110 on non-insulin taking Korean adults in the stage of pre-diabetes and diabetes mellitus: protocol for a randomized, double-blind, placebo-controlled, and multicenter trial-pilot study. AB - BACKGROUND: Diabetes has already become a threat to the nation and the individual due to its high prevalence rates and high medical expenses. Therefore, preventing diabetes at an earlier stage is very important. Despite advances in antidiabetic agents, we have not yet achieved any satisfying results in treating diabetes. Among various treatments, medicinal herbs and supplements for diabetes are reported to show generally good efficacy and safety data. In particular, PURIAM110, a compound from orange fruits and mulberry leaves, is supposed to prevent the progress of type II diabetes mellitus and improve diabetic symptoms. This is the first reported pilot study about the protective effect of the orange fruits and mulberry leaves mixture against pre-diabetes on Korean adults. Based on these positive results of herb-derived components, extended studies of dietary supplements have to be done to suggest confirmative evidences. METHODS/DESIGN: The efficacy and safety study of PURIAM110 is a double-blinded, placebo controlled, randomized, and multi-center clinical trial. A total of 45 subjects will participate in this study for 6 weeks. DISCUSSION: The present protocol will confirm the efficacy and safety of PURIAM110 for pre-diabetes, suggesting more basic knowledge to conduct further randomized controlled trials (RCT). In addition, PURIAM110 can be an alternative dietary supplemental remedy for diabetes patients. TRIAL REGISTRATION: ISRCTN: ISRCTN44779824. PMID- 21310089 TI - Molecular adaptation of a plant-bacterium outer membrane protease towards plague virulence factor Pla. AB - BACKGROUND: Omptins are a family of outer membrane proteases that have spread by horizontal gene transfer in Gram-negative bacteria that infect vertebrates or plants. Despite structural similarity, the molecular functions of omptins differ in a manner that reflects the life style of their host bacteria. To simulate the molecular adaptation of omptins, we applied site-specific mutagenesis to make Epo of the plant pathogenic Erwinia pyrifoliae exhibit virulence-associated functions of its close homolog, the plasminogen activator Pla of Yersinia pestis. We addressed three virulence-associated functions exhibited by Pla, i.e., proteolytic activation of plasminogen, proteolytic degradation of serine protease inhibitors, and invasion into human cells. RESULTS: Pla and Epo expressed in Escherichia coli are both functional endopeptidases and cleave human serine protease inhibitors, but Epo failed to activate plasminogen and to mediate invasion into a human endothelial-like cell line. Swapping of ten amino acid residues at two surface loops of Pla and Epo introduced plasminogen activation capacity in Epo and inactivated the function in Pla. We also compared the structure of Pla and the modeled structure of Epo to analyze the structural variations that could rationalize the different proteolytic activities. Epo expressing bacteria managed to invade human cells only after all extramembranous residues that differ between Pla and Epo and the first transmembrane beta-strand had been changed. CONCLUSIONS: We describe molecular adaptation of a protease from an environmental setting towards a virulence factor detrimental for humans. Our results stress the evolvability of bacterial beta-barrel surface structures and the environment as a source of progenitor virulence molecules of human pathogens. PMID- 21310090 TI - Characterization of a non-pathogenic H5N1 influenza virus isolated from a migratory duck flying from Siberia in Hokkaido, Japan, in October 2009. AB - BACKGROUND: Infection with H5N1 highly pathogenic avian influenza viruses (HPAIVs) of domestic poultry and wild birds has spread to more than 60 countries in Eurasia and Africa. It is concerned that HPAIVs may be perpetuated in the lakes in Siberia where migratory water birds nest in summer. To monitor whether HPAIVs circulate in migratory water birds, intensive surveillance of avian influenza has been performed in Mongolia and Japan in autumn each year. Until 2008, there had not been any H5N1 viruses isolated from migratory water birds that flew from their nesting lakes in Siberia. In autumn 2009, A/mallard/Hokkaido/24/09 (H5N1) (Mal/Hok/24/09) was isolated from a fecal sample of a mallard (Anas platyrhynchos) that flew from Siberia to Hokkaido, Japan. The isolate was assessed for pathogenicity in chickens, domestic ducks, and quails and analyzed antigenically and phylogenetically. RESULTS: No clinical signs were observed in chickens inoculated intravenously with Mal/Hok/24/09 (H5N1). There was no viral replication in chickens inoculated intranasally with the isolate. None of the domestic ducks and quails inoculated intranasally with the isolate showed any clinical signs. There were no multiple basic amino acid residues at the cleavage site of the hemagglutinin (HA) of the isolate. Each gene of Mal/Hok/24/09 (H5N1) is phylogenetically closely related to that of influenza viruses isolated from migratory water birds that flew from their nesting lakes in autumn. Additionally, the antigenicity of the HA of the isolate was similar to that of the viruses isolated from migratory water birds in Hokkaido that flew from their northern territory in autumn and different from those of HPAIVs isolated from birds found dead in China, Mongolia, and Japan on the way back to their northern territory in spring. CONCLUSION: Mal/Hok/24/09 (H5N1) is a non pathogenic avian influenza virus for chickens, domestic ducks, and quails, and is antigenically and genetically distinct from the H5N1 HPAIVs prevailing in birds in Eurasia and Africa. H5 viruses with the HA gene of HPAIV had not been isolated from migratory water birds in the surveillance until 2009, indicating that H5N1 HPAIVs had not become dominant in their nesting lakes in Siberia until 2009. PMID- 21310091 TI - In vitro study of the PLA2 inhibition and antioxidant activities of Aloe vera leaf skin extracts. AB - BACKGROUND: In the present work we determined the total phenolic content of Aloe vera leaf skin (AVLS) extracts by using various solvents (hexane, chloroform ethanol (1/1), ethyl acetate, butanol and water). We have also evaluated the antioxidant and the anti-PLA2 properties of these extracts by measuring their inhibition potency on the human pro-inflammatory phospholipase A2 (group IIA). RESULTS: The water extract exhibits the highest inhibitory effect with an IC50 = 0.22 mg/ml and interestingly no effect was observed on the digestive phospholipase A2 (group IB) even at a concentration of 5 mg/ml. Antioxidant activities were also analyzed and the most active extracts were observed when using chloroform ethanol (1/1) and ethyl acetate (IC50 = 0.274 and 0.326 mg/ml, respectively). Analysis of the total phenolic content reveals that the water extract, with the best anti-PLA2 effect, was poor in phenolic molecules (2 mg GAE/g). This latter value has to be compared with the chloroform-ethanol and the ethyl acetate extracts (40 and 23.8 mg GAE/g, respectively), mostly responsible for the antioxidant activity. CONCLUSION: A significant correlation was established between the total phenolic content and the antioxidant capacity but not with the anti PLA2 activity. Results from phytochemical screening suggest that the anti PLA2 molecules were probably catechin tannins compounds. PMID- 21310092 TI - Six rapid assessments of alcohol and other substance use in populations displaced by conflict. AB - BACKGROUND: Substance use among populations displaced by conflict is a neglected area of public health. Alcohol, khat, benzodiazepine, opiate, and other substance use have been documented among a range of displaced populations, with wide reaching health and social impacts. Changing agendas in humanitarian response including increased prominence of mental health and chronic illness-have so far failed to be translated into meaningful interventions for substance use. METHODS: Studies were conducted from 2006 to 2008 in six different settings of protracted displacement, three in Africa (Kenya, Liberia, northern Uganda) and three in Asia (Iran, Pakistan, and Thailand). We used intervention-oriented qualitative Rapid Assessment and Response methods, adapted from two decades of experience among non displaced populations. The main sources of data were individual and group interviews conducted with a culturally representative (non-probabilistic) sample of community members and service providers. RESULTS: Widespread use of alcohol, particularly artisanally-produced alcohol, in Kenya, Liberia, Uganda, and Thailand, and opiates in Iran and Pakistan was believed by participants to be linked to a range of health, social and protection problems, including illness, injury (intentional and unintentional), gender-based violence, risky behaviour for HIV and other sexually transmitted infection and blood-borne virus transmission, as well as detrimental effects to household economy. Displacement experiences, including dispossession, livelihood restriction, hopelessness and uncertain future may make communities particularly vulnerable to substance use and its impact, and changing social norms and networks (including the surrounding population) may result in changed - and potentially more harmful-patterns of use. Limited access to services, including health services, and exclusion from relevant host population programmes, may exacerbate the harmful consequences. CONCLUSIONS: The six studies show the feasibility and value of conducting rapid assessments in displaced populations. One outcome of these studies is the development of a UNHCR/WHO field guide on rapid assessment of alcohol and other substance use among conflict-affected populations. More work is required on gathering population-based epidemiological data, and much more experience is required on delivering effective interventions. Presentation of these findings should contribute to increased awareness, improved response, and more vigorous debate around this important but neglected area. PMID- 21310093 TI - Decentralization of the provision of health services to people living with HIV/AIDS in rural China: the case of three counties. AB - This study is based on a large-scale household survey and in-depth interviews of key informants that was conducted in villages in three counties of two provinces in China. We assess the new decentralized service provision system for people living with HIV/AIDS in rural populations in China. Since 2003, new social assistance schemes, and, more importantly, decentralization of routine treatment and care to community health stations, were progressively implemented in rural areas most affected by the HIV/AIDS epidemic. Though some problems remain, such as persistent discrimination towards infected patients and the lack of sufficient training of medical staff, the new decentralized pattern of service provision has lowered barriers to health access and alleviated economic pressure on affected households. PMID- 21310094 TI - Report from The International Society for Nomenclature of Paediatric and Congenital Heart Disease: cardiovascular catheterisation for congenital and paediatric cardiac disease (Part 2 - Nomenclature of complications associated with interventional cardiology). AB - Interventional cardiology for paediatric and congenital cardiac disease is a relatively young and rapidly evolving field. As the profession begins to establish multi-institutional databases, a universal system of nomenclature is necessary for the field of interventional cardiology for paediatric and congenital cardiac disease. The purpose of this paper is to present the results of the efforts of The International Society for Nomenclature of Paediatric and Congenital Heart Disease to establish a system of nomenclature for cardiovascular catheterisation for congenital and paediatric cardiac disease, focusing both on procedural nomenclature and the nomenclature of complications associated with interventional cardiology. This system of nomenclature for cardiovascular catheterisation for congenital and paediatric cardiac disease is a component of The International Paediatric and Congenital Cardiac Code. This manuscript is the second part of the two-part series. Part 1 covered the procedural nomenclature associated with interventional cardiology as treatment for paediatric and congenital cardiac disease. Part 2 will cover the nomenclature of complications associated with interventional cardiology as treatment for paediatric and congenital cardiac disease. PMID- 21310095 TI - Reassessing catastrophic health-care payments with a Nigerian case study. AB - Health financing reforms have recently received much attention in developing countries. However, out-of-pocket payments remain substantial. When such payments involve expenditures above some given proportion of household resources, they are often deemed 'catastrophic'. The research literature on defining catastrophe leaves open a number of important questions and as a result there still exists a lack of consensus on the issue. This paper argues that there is a need to examine the question of what might constitute fair indices of catastrophic payment, which explicitly recognize diminishing marginal utility of income as reflected in some principle of vertical equity. It proposes the use of rank-dependent weights to allow variations in threshold payment levels across individuals on the income ladder. These are then applied to a Nigerian data set. It emerged that the catastrophic headcount (positive gap) obtained using a fixed threshold - weighted or not by the concentration index - is lower (higher) than that predicted by the rank-dependent threshold. More fundamentally there is a need for more research effort to take the ideas in this paper further and examine in various different contexts what a fair construct of catastrophe might look like. PMID- 21310096 TI - Investigating the effects of syllable complexity in Russian-speaking children with SLI. AB - This study examined the effect of number of syllables and syllable structure on repetition of pseudo-words by Russian-speaking children with Specific Language Impairment (SLI) and typically developing (TD) children. One hundred and forty four pseudo-words, varying in length and syllable complexity, were presented to two groups of children: 15 children with SLI, age range 4 ; 0 to 8 ; 8, and 15 TD children matched in age to the SLI group. The number of errors in the repetition of pseudo-words was analyzed in terms of the number of syllables and syllable complexity. The results demonstrated that children with SLI have deficits in working memory capacity. In addition to the pseudo-word length, the repetition performance was affected by syllable structure complexity. PMID- 21310097 TI - Contending with foreign accent in early word learning. AB - By their second birthday, children are beginning to map meaning to form with relative ease. One challenge for these developing abilities is separating information relevant to word identity (i.e. phonemic information) from irrelevant information (e.g. voice and foreign accent). Nevertheless, little is known about toddlers' abilities to ignore irrelevant phonetic detail when faced with the demanding task of word learning. In an experiment with English-learning toddlers, we examined the impact of foreign accent on word learning. Findings revealed that while toddlers aged 2 ; 6 successfully generalized newly learned words spoken by a Spanish-accented speaker and a native English speaker, success of those aged 2 ; 0 was restricted. Specifically, toddlers aged 2 ; 0 failed to generalize words when trained by the native English speaker and tested by the Spanish-accented speaker. Data suggest that exposure to foreign accent in training may promote generalization of newly learned forms. These findings are considered in the context of developmental changes in early word representations. PMID- 21310098 TI - Infected tracheocoele (acquired tracheal diverticulum): case report and literature review. AB - BACKGROUND: Paratracheal air-filled cysts are rare. Tracheocoele or acquired tracheal diverticulum is the term given to these acquired abnormalities, which usually arise in adults. The majority is asymptomatic, being discovered as incidental findings on radiological imaging. METHODS: We report the case of a 72 year-old man with a previously identified tracheocoele which became symptomatic following an upper respiratory tract infection. A literature is presented and nomenclature is discussed. RESULTS: The clinical presentation, differential diagnosis and management of paratracheal air-filled cysts are discussed. CONCLUSION: While most of these rare abnormalities are discovered incidentally, this case illustrates the fact that significant symptoms can develop; excision should therefore be considered. PMID- 21310099 TI - Biofilms in chronic rhinosinusitis: systematic review and suggestions for future research. AB - BACKGROUND: A biofilm is a community of micro-organisms encased within a self produced, extracellular, polymeric substance. The role of biofilms as a major pathological aetiology in chronic rhinosinusitis would help explain the clinical manifestation of the disease. OBJECTIVES: To examine the current evidence, and to discuss possible future research directions, in relation to biofilms and chronic rhinosinusitis. STUDY DESIGN: Systematic literature review. EVALUATION METHOD: Two assessors independently undertook critical appraisal of the studies identified by the literature search. Significant findings were incorporated into this review. The primary outcome assessed was the presence of biofilm in human mucosal biopsy samples taken from patients with chronic rhinosinusitis, and from healthy controls. RESULTS: We identified 11 studies examining biofilm formation in human mucosal biopsy samples taken from patients with chronic rhinosinusitis. CONCLUSION: It is unlikely that biofilms occur in every case of chronic rhinosinusitis; consequently, the significance of 'biofilm detection' in some series should be considered carefully. Several authors have argued strongly for the use of confocal scanning laser microscopy with fluorescent in situ hybridisation probes as the 'gold standard' for biofilm imaging. This imaging modality should be combined with further investigation of the microbiology of chronic rhinosinusitis, and of the efficacy of traditional culture techniques used for pathogen identification. PMID- 21310100 TI - Surfers' awareness of the preventability of 'surfer's ear' and use of water precautions. AB - OBJECTIVE: To establish surfers' knowledge of the preventability of external auditory canal exostoses ('surfer's ear'), and their use of water precautions. METHOD: Survey of surfers conducted between December 2009 and March 2010 at beaches in Cornwall, UK. RESULTS: Ninety-two surfers were included (78 males and 14 females, mean age 27 years, standard deviation 7.9 years). Participants were grouped according to their awareness of the preventability of surfer's ear (55 aware, 37 unaware). These groups were comparable in age, surfing history and gender mix (p > 0.05). Surfers aware of the preventability of exostoses (66 per cent) were more likely to use water precautions than those who were not (38 per cent) (p < 0.01). Two surfers used water precautions regularly and 48 used them occasionally. Sixty-one of the 76 surfers who did not use water precautions (ear plugs) suggested they would consider doing so in the future. CONCLUSION: Awareness of the preventability of surfer's ear was associated with greater use of water precautions. Further research should explore reasons for the low uptake of such precautions. Most surfers not already using ear plugs would consider doing so in the future. PMID- 21310101 TI - Effect of chlorhexidine gluconate and benzydamine hydrochloride mouth spray on clinical signs and quality of life of patients with streptococcal tonsillopharyngitis: multicentre, prospective, randomised, double-blinded, placebo-controlled study. AB - OBJECTIVE: To assess the effect of chlorhexidine gluconate and benzydamine hydrochloride mouth spray, used in conjunction with antibiotic treatment, on the intensity of clinical signs and quality of life of patients with group A streptococcal tonsillopharyngitis. METHODS: Patients (n = 147) with streptococcal tonsillopharyngitis were recruited and randomly allocated to either the treatment group (penicillin plus chlorhexidine and benzydamine; n = 72) or control group (penicillin plus placebo; n = 75). Blinded assessments were conducted before and after 10 days' treatment, using an intensity rating scale for clinical sign severity, a visual analogue scale for subjective health state, the Short Form 36 Health Questionnaire for quality of life, and a customised questionnaire for side effects. RESULTS: The treatment group showed a statistically significant reduction in the intensity of clinical signs, compared with the control group. On treatment day 7, there was no significant difference in quality of life between the treatment and control groups. The treatment drugs were well tolerated, and no serious adverse events were observed. CONCLUSION: Chlorhexidine gluconate and benzydamine hydrochloride mouth spray, added to standard antibiotic treatment, significantly alleviate the intensity of clinical signs in patients with streptococcal pharyngitis. Further research is needed using larger sample sizes or alternative control groups. PMID- 21310102 TI - Shared environments: a multilevel analysis of community context and child nutritional status in Bangladesh. AB - OBJECTIVE: The goal of the present study was to examine the influence of community environment on the nutritional status (weight-for-age and height-for age) of children (aged 0-59 months) in Bangladesh. In addition, we tested the association between specific characteristics of community environments and child nutritional status. DESIGN: Cross-sectional survey. SETTING: The data are from the nationally representative 2004 Bangladesh Demographic and Health Survey. SUBJECTS: Respondents were ever-married women (aged 15-49 years) and their children (n 5731), residing in 361 communities. Child nutritional outcomes are physical measurements of weight-for-age and height-for-age in sd units. We considered the following attributes of community environments potentially related to child nutrition: (i) community water and sanitation infrastructure; (ii) availability of community health and education services; (iii) community employment and social participation; and (iv) education level of the community. RESULTS: Multilevel regression analysis showed that the spatial distribution of maternal and child covariates did not entirely explain the between-community variation in child nutritional status. The education level of the community emerged as the strongest community-level predictor of child height-for-age (highest v. lowest tertile, beta = 0.18 (SE 0.07)) and weight-for-age (highest v. lowest tertile, beta = 0.21 (SE 0.06)). In the height-for-age model, community employment and social participation also emerged as being statistically significant (highest v. lowest tertile, beta = 0.13 (SE = 0.06)). CONCLUSIONS: The community environment influences child nutrition in Bangladesh, and maternal- and child-level covariates may fail to capture the entire influence of communities. Interventions to reduce child undernutrition in developing countries should take into consideration the wider community context. PMID- 21310103 TI - Report from The International Society for Nomenclature of Paediatric and Congenital Heart Disease: cardiovascular catheterisation for congenital and paediatric cardiac disease (Part 1 - Procedural nomenclature). AB - Interventional cardiology for paediatric and congenital cardiac disease is a relatively young and rapidly evolving field. As the profession begins to establish multi-institutional databases, a universal system of nomenclature is necessary for the field of interventional cardiology for paediatric and congenital cardiac disease. The purpose of this paper is to present the results of the efforts of The International Society for Nomenclature of Paediatric and Congenital Heart Disease to establish a system of nomenclature for cardiovascular catheterisation for congenital and paediatric cardiac disease, focusing both on procedural nomenclature and on the nomenclature of complications associated with interventional cardiology. This system of nomenclature for cardiovascular catheterisation for congenital and paediatric cardiac disease is a component of The International Paediatric and Congenital Cardiac Code. This manuscript is the first part of a two-part series. Part 1 will cover the procedural nomenclature associated with interventional cardiology as treatment for paediatric and congenital cardiac disease. This procedural nomenclature of The International Paediatric and Congenital Cardiac Code will be used in the IMPACT RegistryTM (IMproving Pediatric and Adult Congenital Treatment) of the National Cardiovascular Data Registry(r) of The American College of Cardiology. Part 2 will cover the nomenclature of complications associated with interventional cardiology as treatment for paediatric and congenital cardiac disease. PMID- 21310104 TI - The Plan-a-Day approach to measuring planning ability in patients with schizophrenia. AB - Deficits in executive functioning are closely related to the level of everyday functioning in patients with schizophrenia. However, many existing neuropsychological measures are limited in their ability to predict functional outcome. To contribute towards closing this gap, we developed a computer-based test of planning ability ("Plan-a-Day") that requires participants to create daily activity schedules in a simulated work setting. Eighty patients diagnosed with schizophrenia were tested with Plan-a-Day and a battery of cognitive ability tests. Plan-a-Day showed satisfactory psychometric properties in terms of consistency, reliability, and construct validity. Compared to other neuropsychological tests used in this study, it also demonstrated incremental validity with regard to the Global Assessment of Functioning. The Plan-a-Day approach, therefore, seems to represent a valid alternative for measuring planning ability in patients with executive function deficits, occupying a middle ground between traditional neuropsychological tests and real-life assessments. PMID- 21310105 TI - A viscoelastic chitosan-modified three-dimensional porous poly(L-lactide-co epsilon-caprolactone) scaffold for cartilage tissue engineering. AB - Biomaterials have been playing important roles in cartilage regeneration. Although many scaffolds have been reported to enhance cartilage regeneration, none of the scaffolds available are optimal regarding mechanical properties, integration with host cartilage and providing proper micro-environment for chondrocyte attachment, proliferation and differentiation. In the current study, chitosan-modified poly(L-lactide-co-epsilon-caprolactone) (PLCL) scaffolds were fabricated to simulate the main biochemical components of cartilage, as well as their interaction with the aim to endow them with viscoelasticity similar to native cartilage. Porous PLCL scaffolds were fabricated with porogen-leaching, freeze-extraction and freeze-gelation before chitosan was cross-linked. The acquired porous scaffolds had pore sizes ranging from 200 to 500 MUm and about 85% porosity with good interconnection between individual pores. Chitosan was successfully cross-linked to PLCL scaffolds, as validated by ninhydrin staining and X-ray photoelectron spectroscopy (XPS). The viscoelasticity of the scaffolds was similar to that of bovine cartilage and they had a relatively good recovery ratio from compression deformation, while the Young's modulus was one order of magnitude less than cartilage. Not only could the chitosan-modified PLCL scaffolds promote cell adhesion and proliferation, but also they could significantly enhance excretion of aggrecan and type-II collagen, as testified by both histology and quantitative PCR, compared with PLCL scaffolds. With the fabrication of biomimetic scaffolds, it is possible to make scaffolds for cartilage tissue engineering, which are not only biocompatible, but also have mechanical properties similar to native cartilage. PMID- 21310106 TI - Transport of phospholipid in silicone hydrogel contact lenses. AB - Characterization of the transport and release of phospholipids from a silicone hydrogel contact lens is required to assess the possible use of these lenses for phospholipid delivery to increase patient comfort. Contact lenses of silicone hydrogel composition were loaded with varying amounts of radiolabeled 1,2 dimyristoyl-sn-glycero-3-phosphocholine (DMPC) from a solution of n-propanol. These lenses were eluted at 35 degrees C into artificial tear fluid (ATF) or ATF containing varying amounts of DMPC. The amount of DMPC loaded into a lens is a linear function of the time of exposure to the DMPC/propanol solution. The initial rate of elution into ATF appears to be diffusion controlled for at least 10 h and is proportional to the amount of DMPC loaded. The elution rate decreases as the DMPC concentration in the ATF increases. The ease of loading and the controllable release of DMPC from silicone hydrogels presents the possibility of using such lenses to counter eye discomfort caused by inherently low levels of phospholipid in tears. PMID- 21310107 TI - Critical surface energy of composite cement containing MDP (10 methacryloyloxydecyl dihydrogen phosphate) and chemical bonding to hydroxyapatite. AB - Self-adhesive composite cements are increasingly used for cementing inlays/onlays, intraradicular posts, crowns and laminate veneers. Wider clinical acceptance is driven by simpler and faster handling procedures, much like observed for self-etching adhesives. 10-Methacryloyloxydecyl dihydrogen phosphate (MDP) is a bi-functional monomer incorporated as the reactive ingredient in a contemporary self-adhesive cement. We have examined the surface free energy parameters of this cement and studied the mode of action of the cement on dentine substrate by contact angle measurements to determine the critical surface energy of the cement. Retention of the infrared absorption bands characteristic of the acrylate moieties on the surface of hydroxyapatite particles suggests that MDP contributes to the overall bonding to dentine by forming ionic chemical bonds with surface calcium ions in dentine crystalites. PMID- 21310108 TI - In vitro biocompatibility of new PVA-based hydrogels as vitreous body substitutes. AB - In order to synthesize injectable hydrogels suitable as vitreous body substitutes, a new method based on the use of trisodium trimetaphosphate (STMP) to cross-link PVA was recently proposed. Hydrogels with different molar ratios between STMP and PVA were realised. The aim of the present study was the evaluation of the biocompatibility of the different STMP/PVA hydrogels synthesised by analysing the effects of their in vitro interaction with cultures of mouse fibroblasts NIH3T3, primary human microvascular endothelial cells adult (HMVECad) and human lens cells. Cytotoxicity of hydrogels was first evaluated by analysing cell density and proliferation. Morphological and morphometric analysis of cell in contact with hydrogels was then performed using light microscopy and scanning electron microscopy, respectively. Moreover, cell adhesion and growth onto the hydrogels surface was evaluated and correlated to the amount of adsorbed proteins. At last, the biocompatibility of the sheared STMP/PVA 1:8 hydrogel was tested. The in vitro data of all the STMP/PVA hydrogels demonstrated their good biocompatibility, and indicated that the 1:8 sample was the most promising as vitreous body substitute. PMID- 21310109 TI - A thermo-sensitive NIPA-based co-polymer and monosize polycationic nanoparticle for non-viral gene transfer to smooth muscle cells. AB - Primary smooth muscle cells (SMC) isolated from the aorta of fetal calf were transfected with a green fluorescent protein (GFP)-encoding plasmid DNA, which was carried by a water-soluble and temperature-sensitive N-isopropylacrylamide based (NIPAAm-based)-co-polymer, either poly(N-isopropylacrylamide-co-2 methacryloamidohistidine) (poly(NIPAAm-co-MAH)) or monosized PEGylated nanoparticle poly(styrene/poly(ethylene glycol) ethyl ether methacrylate/N-(3 (dimethylamino)propyl) methacrylamide) (poly(St/PEG-EEM/DMAPM)). Poly(NIPAAm-co MAH) co-polymer was synthesized by solution polymerization of n isopropylacrylamide (NIPAAm) and 2-methacrylamidohistidine (MAH). Monosized cationic nanoparticles were produced by emulsifier-free emulsion polymerization of styrene, PEG ethyl ether methacrylate and N-[3-(dimethyl-amino) propyl] methacrylamide, in the presence of a cationic initiator, 2,2-azobis (2 methylpropionamidine) dihydrochloride. The structure of poly(St/PEG-EEM/DMAPM) and poly(NIPAAm-co-MAH) was confirmed by(1) H-NMR and FT-IR spectroscopy. Particle size/size distribution and surface charges of both carriers were measured by Zeta Sizer. The LCST behavior of poly(NIPAAm-co-MAH) co-polymer was followed spectrophotometrically. Poly(St/PEG-EEM/DMAPM) nanoparticles, with an average size of 78 nm and zeta potential of 54.4 mV, and an average size of 200 nm with a zeta potential of 54.2 mV, and poly(NIPAAm-co-MAH) were used in the transfection studies. The cytotoxicity of the vectors was tested using the MTT method. According to conditions for the transfection study (polymer/cell ratio and polymer-cell incubation period), cell loss was only 4 and 15% with poly(St/PEG-EEM/DMAPM) sized 78 and 200 nm, respectively. Poly(NIPAAm-co-MAH) cytotoxicity was insignificant. Poly(NIPAAm-co-MAH) uptake efficiency in SMCs was around 85%, but gene expression efficiency were low compared to poly(St/PEG EEM/DMAPM)/pEGFP-N2 conjugates because of the low zeta potential of the co polymer. Polymer uptake efficiencies of the nanoparticles were 90-95%. GFP expression efficiency was 68 and 64% after transfection with pEGFP-N2 conjugate with 78 and 200 nm sized poly(St/PEG-EEM/DMAPM) nanoparticles. PMID- 21310110 TI - Improvement of blood compatibility on polysulfone-polyvinylpyrrolidone blend films as a model membrane of dialyzer by physical adsorption of recombinant soluble human thrombomodulin (ART-123). AB - ART-123 is a recombinant soluble human thrombomodulin (hTM) with potent anticoagulant activity, and is available for developing antithrombogenic surfaces by immobilization. We focused on improving blood compatibility on the dialyzer surface by the physical adsorption of ART-123 as a safe yet simple method without using chemical reagents. The physical adsorption mechanism and anticoagulant activities of adsorbed hTM on the surface of a polysulfone (PSF) membrane containing polyvinylpyrrolidone (PVP) as a model dialyzer were investigated in detail. The PVP content of the PSF-PVP films was saturated at 20 wt% after immersion in Tris-HCl buffer, even with the addition of over 20 wt% PVP. The surface morphology of the PSF-PVP films was strongly influenced by the PVP content, because PVP covered the outermost surface of the PSF-PVP films. The adsorption speed of hTM slowed dramatically with increasing PVP content up to 10 wt%, but the maximum adsorption amount of hTM onto the PSF-PVP film surface was almost the same, regardless of the PVP content. The PSF-PVP film with the physically adsorbed hTM showed higher protein C activity as compared to the PSF film, it showed excellent blood compatibility due to the protein C activity and the inhibition properties of platelet adhesion. The physical adsorption of hTM can be useful as a safe yet simple method to improve the blood compatibility of a dialyzer surface. PMID- 21310111 TI - A calcium-cross-linked hydrogel based on alginate-modified atelocollagen functions as a scaffold material. AB - We have developed a scaffold material consisting of a covalently-bonded structure of alginate and atelocollagen (AtCol). Addition of calcium ions caused the material to form a hydrogel (alginate-modified AtCol gel). The condition of the alginate-modified AtCol gel could be controlled by the feed ratio of alginate and the activating reagent. Measurement of temporal stability in culture medium suggested that covalent bonding between alginate and AtCol might contribute to the structural stability of the alginate-modified AtCol gel. Culture with endothelial cells indicated that cell adhesiveness on the alginate-modified AtCol gel was similar to that on native collagen. Collagenase digestion revealed that the alginate-modified AtCol gel had considerable ability to retain basic fibroblast growth factor. Additionally, active cell migration into alginate modified AtCol was detected by in vitro assay using endothelial cells. These findings indicate that this gel material can be expected to function as a scaffold for inducing vascular in-growth. PMID- 21310112 TI - Preliminary evaluation of a new index to predict the outcome of a spontaneous breathing trial. AB - BACKGROUND: The available predictors of spontaneous-breathing-trial (SBT) success/failure lack accuracy. We devised a new index, the CORE index (compliance, oxygenation, respiration, and effort). OBJECTIVE: To compare the CORE index to the CROP index (compliance, rate, oxygenation, and pressure), airway-occlusion pressure 0.1 s after the start of inspiratory flow (P(0.1)), and rapid shallow breathing index (RSBI) for predicting SBT success/failure in a critical care environment. METHODS: With 47 mechanically ventilated patients recovering from respiratory failure, of various causes, we prospectively examined the SBT success/failure prediction accuracy and calculated receiver operating characteristic curves, sensitivity, specificity, and likelihood ratios of CORE, CROP, P(0.1), and RSBI. RESULTS: The specificities were CORE 0.95, P(0.1) 0.70, CROP 0.70, and RSBI 0.65. The sensitivities were CORE 1.00, CROP 1.00, P(0.1) 0.93, and RSBI 0.89. The areas under the receiver operating characteristic curve were CORE 1.00 (95% CI 0.92-1.00), CROP 0.91 (95% CI 0.79 0.97), P(0.1) 0.81 (95% CI 0.67-0.91), and RSBI 0.77 (95% CI 0.62-0.88). The positive likelihood ratios were CORE 20.0, CROP 3.3, P(0.1) 3.1, and RSBI 2.5. The negative likelihood ratios were CORE 0.0, CROP 0.0, P(0.1) 0.1, and RSBI 0.2. CONCLUSIONS: The CORE index was the most accurate predictor of SBT success/failure. PMID- 21310113 TI - Test/retest reliability of maximum mouth pressure measurements with the MicroRPM in healthy volunteers. AB - BACKGROUND: Respiratory muscle strength is an important part of lung function. Assessment of the respiratory muscles' ability to generate force is important for recognizing respiratory muscle weakness in both sick and healthy people. OBJECTIVE: To assess the test/retest reliability of the MicroRPM portable manometer's measurements of maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) in the sitting and standing positions; the number of expiratory maneuvers needed with the MicroRPM for reliability in MIP and MEP measurement; and the MicroRPM's test/retest reliability in other respiratory function indices, such as the maximum rate of pressure development (MRPD), the time constant of relaxation (tau), and the maximum relaxation rate (MRR). METHODS: We recruited 15 healthy volunteers (mean age 21.6 +/- 1.1 years). We assessed respiratory muscle strength on 3 separate occasions, each a week apart. We calculated reliability with the intraclass correlation coefficient (ICC), the standard error of measurement (SEM) and the smallest detectable difference (SDD). RESULTS: MicroRPM reliably measured MIP and MEP in both the sitting position (ICC 0.86-0.90, SEM 9-10, SDD 18-22) and standing position (ICC 0.78-0.83, SEM 12-14, SDD 23-26). After a 5-breath practice, 2 expiratory/inspiratory maneuvers on each testing occasion gave adequate MIP and MEP reliability (ICC > 0.90). MRR reliability was moderate to excellent (ICC 0.58-0.87), MRPD reliability was moderate (ICC 0.59-0.64), and tau reliability was insufficient (ICC 0.27-0.67). CONCLUSIONS: The MicroRPM reliably measures MIP and MEP, but its MRPD, MRR, and tau measurements should be considered with caution. PMID- 21310114 TI - Accuracy and reliability of extubation decisions by intensivists. AB - BACKGROUND: Mortality increases when extubations fail. Although predictors of extubation failure have been evaluated, physicians' reasoning to extubate a patient has received minimal attention. We hypothesized that the accuracy and reliability of physicians' extubation decisions are low. METHODS: We sent surveys to 55 physicians in the divisions of pulmonary and critical care medicine of 3 teaching hospitals in Chicago, Illinois. The survey comprised 32 clinical vignettes of real patients who were extubated after they tolerated a spontaneous breathing trial (16 failed extubations). Unaware of the outcomes of extubation, the physicians were asked if they would extubate each patient, and to give reasons if they opted not to. We quantified the agreement between and accuracy of the physicians' decisions, determined the patient characteristics that influence the extubation decision, and described the tradeoffs leading to that decision. RESULTS: Completed surveys were obtained from 45 physicians (82%). The physicians postponed extubation in 37% of the cases. Agreement between any 2 physicians was fair (mean +/- SD phi 0.34 +/- 0.15) and was highest between attending physicians from the same institution (0.37 +/- 0.15). In deciding to extubate a patient, 33% of the physicians relied on the breathing pattern on pressure support ventilation, 49% relied on the acid-base status, 13% relied on the mental status, and 8% relied on the amount of secretions. The accuracy of the physicians' extubation decisions was low (area under the receiver operating characteristic curve 0.35). The sensitivity of the physicians identifying the patients who were successfully extubated was 57%, and the specificity was 31%. A model that comprises the same variables that influenced the physicians was more accurate in predicting extubation outcome (area under the receiver operating characteristic curve 0.88). CONCLUSIONS: For a decision made on an almost daily basis in intensive care units, physicians' extubation decisions are inaccurate and only fairly reliable. PMID- 21310115 TI - Survival from severe pandemic H1N1 in urban and rural Turkey: a case series. AB - BACKGROUND: Pandemic influenza A (H1N1) was a serious health problem during the winter of 2009-2010 in Turkey. OBJECTIVE: To clarify the clinical and demographic characteristics of patients who needed intensive care in our region. METHODS: We conducted a prospective cohort study from November 2009 to February 2010 of demographic characteristics, clinical course, management strategies, 28-day mortality, and stay in the intensive care unit (ICU). RESULTS: During the study period, in our ICU we followed 18 patients (10 female) with H1N1. Their median (and IQR) age was 39 y (24-52 y), their median (and IQR) Acute Physiology and Chronic Health Evaluation (APACHE II) score was 16 (10-25), and 7 (39%) of them lived in rural places. All 18 patients had acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). The most common risk factors for severe H1N1 infection were obesity (33%), COPD (16%), and pregnancy (11%). Thirteen patients (72%) needed mechanical ventilation at ICU admission. Mortality was 50% (9/18) at day 28. Significantly more survivors were urban dwellers than rural (82% vs 0%, P < .001). There were also statistically significant differences between survivors and nonsurvivors in success of noninvasive ventilation, time to confirmation of the H1N1 virus after ICU admission, creatinine, lactate dehydrogenase, pH, P(aCO(2)), and P(aO(2))/F(IO(2)). CONCLUSIONS: The most common clinical presentation was ALI/ARDS in H1N1 patients who needed intensive care. Living in rural areas might have affected those patients' access to advanced ICU facilities and early ventilatory support. Failure of noninvasive ventilation, late diagnosis, late antiviral therapy, high APACHE II score, and living in a rural area were associated with mortality. PMID- 21310116 TI - MicroRNA expression profile in hyperoxia-exposed newborn mice during the development of bronchopulmonary dysplasia. AB - BACKGROUND: Bronchopulmonary dysplasia (BPD) is a chronic lung disease of preterm neonates; the underlying pathogenesis is not fully understood. MicroRNAs (length 21-25 nucleotides) are ribonucleic acid (RNA) molecules that have important functions in development, cellular differentiation, apoptosis, proliferation, and migration; very little is known regarding their role in developmental lung diseases. METHODS: We exposed neonatal mice to either room air or 60% oxygen, beginning at birth, and we used microRNA microarray and real-time polymerase chain reaction on lung samples. RESULTS: The hyperoxia-exposed mice developed a lung injury that mimicked human BPD. Fifty-one microRNAs shared similar profiles in the hyperoxia-exposed BPD lungs and the normal lungs, which indicates that those microRNAs might play a protective role during the septation process. In the BPD lungs, compared to the control lungs, 14 microRNAs were up-regulated, and 7 microRNAs were down-regulated, which indicates that these microRNAs might play an important role in the development of BPD. Some of the candidate microRNAs can regulate cell proliferation. CONCLUSIONS: To our knowledge, this study is the first to identify microRNAs associated with BPD development, which provides a clue for further investigation of their function in BPD development. PMID- 21310118 TI - Use of non-partitioned ventilator tubing results in dead-space ventilation hypercarbia. AB - We present a case of severe postoperative hypercarbia in a patient with severe COPD. Hypercarbia and respiratory acidosis continued to increase despite maximal ventilation, bronchodilator therapy, sedation, and paralysis. Mistaken use of non partitioned ventilator circuit was the cause of the hypercarbia. The ventilator's self-test function failed to detect the error. We changed to a partitioned-lumen circuit, with much less ventilation dead space, and the hypercarbia resolved immediately. PMID- 21310117 TI - Diagnostic accuracy of clinical pulmonary infection score for ventilator associated pneumonia: a meta-analysis. AB - OBJECTIVE: To assess the diagnostic accuracy of the clinical pulmonary infection score in the diagnosis of ventilator-associated pneumonia in mechanically ventilated patients. METHODS: We searched PubMed and the Cochrane database, and included only studies that compared clinical pulmonary infection score with quantitative microbiological analysis of samples for diagnosing ventilator associated pneumonia. We constructed 2-by-2 tables of diagnostic accuracy from each article, and meta-analyzed the results by pooling estimates of sensitivity, specificity, likelihood ratio for positive index test, likelihood ratio for negative index test, diagnostic odds ratio, and 95% confidence intervals. RESULTS: Thirteen studies met the inclusion criteria. The pooled estimates for sensitivity and specificity for clinical pulmonary infection score were 65% (95% CI 61-69%) and 64% (95% CI 60-67%), respectively. The combined diagnostic odds ratio was 4.85 (95% CI 2.42-9.71) and the area under the curve was 0.748 (95% CI 0.65-0.85). CONCLUSIONS: The diagnostic performance of the clinical pulmonary infection score for ventilator-associated pneumonia is moderate. However, the clinical pulmonary infection score is simple and easy to perform, and may still be useful in diagnosing ventilator-associated pneumonia. PMID- 21310119 TI - Epidemiology of allergic rhinitis caused by grass pollen or house-dust mites in Spain. AB - BACKGROUND: Although the prevalence of allergic rhinitis (AR) is increasing, relatively little is known about patient characteristics in Spain. The aim of this study was to investigate the clinical profile and therapeutic strategies in patients attending Spanish specialists for AR caused by grass pollen or house dust mites (HDMs). METHODS: This was a multicenter cross-sectional epidemiological study of consecutive patients aged >=5 years with confirmed diagnosis of AR caused by grass pollen or HDMs attending allergy specialists throughout Spain. Demographic and clinical data and information on treatment were collected. RESULTS: Data from 1043 patients were analyzed (524 with grass pollen allergy and 519 with HDM allergy; mean age, 27.1 years). Three-quarters had persistent AR as per the Allergic Rhinitis and Its Impact on Asthma (ARIA) definition, with disease duration of >2 years in 94.3% of those with pollen allergy and 85.5% of those with HDM allergy. Approximately 38% had concurrent asthma. Over one-half of the patients were considered to have gotten worse since the first onset of symptoms. In total, 51.5% did not achieve good disease control with pharmacotherapy and 47.7% were treated with immunotherapy (52.2% of HDM allergic patients and 43.2% of grass pollen-allergic patients). CONCLUSION: The duration of AR in patients attended for the first time by specialists is long and, in general, the disease does not improve over time and is often not well controlled with pharmacologic interventions. Less than one-half of patients receive allergen-specific immunotherapy that is more often prescribed in HDM allergy. PMID- 21310120 TI - [Advances in molecular biology of lung cancer]. PMID- 21310121 TI - [Screening and early diagnosis of lung cancer]. PMID- 21310122 TI - [PET in the diagnosis and treatment of lung cancer]. PMID- 21310123 TI - [Advances in the lung cancer biotherapy]. PMID- 21310124 TI - [Genetic susceptibilify of lung cancer and environmental carcinogensis]. PMID- 21310125 TI - [Current condition and advances in the target treatment of lung cancer]. PMID- 21310126 TI - [Advances in multimodality therapy of lung cancer]. PMID- 21310128 TI - [Controveries in treatment of resectable local advanced non-small cell lung cancer]. PMID- 21310127 TI - [Advances in surgical treatment for lung cancer]. PMID- 21310129 TI - [Advances in chemotherapy of lung cancer]. PMID- 21310130 TI - [Advance in radiotherapy of lung cancer]. PMID- 21310131 TI - [Identification of novel metastasis associated genes MAG-1 and MAG-2]. AB - BACKGROUND: To isolate and identify the genes related to cancer metastasis by comparison of two cell strains with different metastasis potentials subcloned from human lung giant cell carcinoma cell line. METHODS: Suppression subtractive hybridization (SSH) was used to compare the levels of gene expression between the two cell strains and SSH library was constructed. After screening the library by gene chip, the expressed sequence tags (ESTs) with different expressing level were sequenced and blasted with GenBank. RESULTS: Seventy-nine genes were obtained that were expressed much higher in PLA-801D than in PLA-801C, including two full-length cDNA. GenBank Accession numbers of the two cDNA, named MAG-1 and MAG-2, were BC006236 and BC002420, the 8.5 kb MAG-1 gene was composed of four exons and located on the chromosome of 4q21. The MAG-2 gene, which was made up by 9 exons, had a length of 5.2 kb and its location was 2q35. Both sequences had open reading frames (ORF) and promoters before the theoretical transcription start points. Using special software, the secondary structure of theoretical products of the two cDNAs was prognosticated, alpha-helix was the main proportion, but beta-pleated sheet and random coil were also included. CONCLUSIONS: The expression of MAG-1 and MAG-2 has significant differences in these two cell strains, so they might impact tumor metastasis in some ways that are still uncharted. PMID- 21310132 TI - [Establishment and their biological characteristics of clonal cell subpopulations (NL9980 and L9981) from a human lung large cell carcinoma cell line (WCQH-9801)]. AB - BACKGROUND: To explore the possibility of separating and establishing clonal cell subpopulations with different metastatic phenotype from a human lung large cell carcinoma cell line (WCQH-9801), to identify the difference of biological and molecular biology between NL9980 and L9981 cell lines. METHODS: Two sub-cell lines (NL9980 and L9981) were isolated and established from a human lung large cell carcinoma cell line (WCQH-9801) by the single cell cloning techniques. The RELP, mRNA and protein transcript expression were detected in NL9980 and L9981 cell lines by Southern blot, RT-PCR and Western blot. The biological characteristics of vivo and vitro were determined in NL9980 and L9981 cell lines by MTT, plate, Boyden chamber methods and animal models. RESULTS: (1)Two sub-cell lines, NL9980 and L9981 which had different metastatic phenotype, were successfully isolated and established from a human lung large cell carcinoma cell line (WCQH-9801). (2)The L9981 cell line had LOH of nm23-H1 gene, deletion of mRNA and protein expression of nm23-H1, but the NL9980 cell line had neither LOH of nm23-H1 nor deletion of mRNA and protein expression of nm23-H1. (3)The proliferation, clone formation and vitro invastion of L9981 cell line were significantly higher than those of NL9980 cell line. (4)The tumorigenicity and lung metastatic rate in nude mouse of L9981 cell line were remarkably higher than those of NL9980. (5) No significant difference of the chromosome number was observed between NL9980 and L9981 cell lines. CONCLUSIONS: (1)NL9980 and L9981 cell lines established from a human lung large cell carcinoma cell line have different biological and molecular characteristics. (2)The high invsaion and metastasis ability of L9981 cell line might be related to the LOH of nm23-H1 gene. PMID- 21310133 TI - [A study on effects of cisplatin and its mechanisms on human lung adenocarcinoma SLC-89 cells]. AB - BACKGROUND: To investigate the effects of cisplatin on proliferation, telomerase activity, cell cycle, p53, bcl-2 and proliferating cell nuclear antigen (PCNA) expressions of human lung adenocarcinoma SLC-89 cells induced by cisplatin and to find out the possible mechanisms. METHODS: SLC-89 cells were treated with cisplatin of different concentrations for 72 h. Then, the proliferation of the cells was measured by MTT method, telomerase activity was measured by telomeric repeat amplification protocol with ELISA (TRAP-ELISA), and cell cycle, p53, bcl-2 and PCNA expressions of the cells were detected by flow cytometry (FCM) respectively. RESULTS: Cisplatin could obviously inhibit the proliferation of the cells, and IC50 value for cisplatin treatment was 18.47 mg/L. Cisplatin could obviously down-regulate telomerase activity, decrease S phase cells, increase G0/G1 phase cells, decline the expressions of bcl-2 and PCNA proteins and induce the expression of p53 protein of SLC-89 cells in a concentration-dependent fashion. CONCLUSIONS: Cisplatin can obviously inhibit the proliferation of SLC 89, change the distribution of cell cycle, decline telomerase activity and expressions of bcl-2 and PCNA proteins, and induce expression of p53 protein, which may be the important mechanisms of cisplatin's anticancer action. PMID- 21310134 TI - [Study on the gene expression patterns of KANGLAITE in anti-lung metastasis of LA795 mouse]. AB - BACKGROUND: To screen the differential expression genes of KANLAITE in anti-tumor metastasis. METHODS: mRNA was extracted and purified from the lung of the mouse with LA795 lung metastasis, hybridized respectively on 4 096-gene chip. cDNA microarray was scanned for the fluorescent signals and analyzing difference expression. RESULTS: Twenty-seven differential expressed genes were obtained. Among these genes, 25 were up-regulated and 2 were down-regulated. Twelve of them were Mus musculus cDNA clone. Six genes related with genesis, development and metastasis of tumor. CONCLUSIONS: cDNA microarray for analysis of gene expression patterns is a powerful method to identify differential expressed genes. In this study, 6 genes are thought to be associated genes of KANGLAITE in anti-tumor metastasis. PMID- 21310135 TI - [Relationship between the expression of E-cadherin and MVD and its significance in lung cancer]. AB - BACKGROUND: To study the relationship between the expression of E-cadherin and MVD in lung cancer and its significance. METHODS: The expressions of E-cadherin and factor VIII were detected in 104 lung cancer tissues by immunohistochemical method, and MVD was calculated by image analysis system. RESULTS: The expression of E-cadherin was significantly related to the differentiation of lung cancer (P < 0.05). A negative correlation was observed between E-cadherin expression and MVD in lung cancer tissues (P= 0.047). CONCLUSIONS: Downexpression of E-cadherin and increase of MVD may play an important role in the invasion and metastasis of lung cancer, and may also be used as a useful marker for tumor prognosis. PMID- 21310136 TI - [Expression of CD44v3 and its prognostic value in non-small cell lung cancer]. AB - BACKGROUND: To study the expression of CD44v3 and its prognostic value in non small cell lung cancer (NSCLC). METHODS: CD44v3 expression was detected in 52 NSCLC tissues and 12 normal pulmonary tissues by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry (SP method). RESULTS: The positive expression rate of CD44v3 in NSCLC was 57.7% (SP method) and 71.2% (RT PCR), respectively. The positive rate of CD44v3 in squamous cell carcinoma was significantly higher than that in adenocarcinoma (P < 0.01). Higher expression of CD44v3 was demonstrated in poor differentiation compared with moderate and well differentiation (P < 0.05). The expression of CD44v3 was much higher in patients with lymph node metastasis than that in those without lymph node metastasis (P < 0.05). The expression rate of CD44v3 was remarkably higher in stage III than that in stage I-II. Multi-variate Logistic analysis showed the expression of CD44v3 and p-TNM stage were significantly prognostic factors (P < 0.05). CONCLUSIONS: Overexpression of CD44v3 is very common in lung cancer tissues. Detection of CD44v3 expression may be helpful to predict the prognosis of lung cancer patients. PMID- 21310137 TI - [The expression and its clinical significance of MMP-2 and MMP-9 in non-small cell lung cancer]. AB - BACKGROUND: To investigate the expression and its clinical significance of MMP-2 and MMP-9 in non-small cell lung cancer (NSCLC), so as to provide reference in diagnosis, treatment and determining prognosis of NSCLC. METHODS: MMP-2 and MMP-9 expression was detected in 32 lung cancer tissues, 32 paracancerous lung tissues and 10 benign pulmonary lesion tissues by immunohistochemical method with anti MMP-2 and anti-MMP-9 antibody. RESULTS: (1)Expression of MMP-2 (90%, 36/40) and MMP-9 (83%, 33/40) in cancer tissues was significantly higher than that in paracancerous tissues (22% and 13%) and benign pulmonary disease tissues (0) (P < 0.01). (2)Expression level of MMP-2 and MMP-9 was significantly related to lymph node metastasis and TNM staging, and histologic classification and differentiation (P < 0.05). CONCLUSIONS: MMP-2 and MMP-9 expression in NSCLC tissue is remarkably higher than that in paracancerous tissues and benign pulmonary tissues. Detaction of MMP-2 and MMP-9 expression in lung cancer tissue might be helpful to determine metastasis, staging of the cancer, and predict the prognosis of patients with NSCLC. PMID- 21310138 TI - [The impact on perioperative patients with non-small cell lung cancer by neoadjuvant chemotherapy]. AB - BACKGROUND: To investigate whether neoadjuvant chemotherapy (MVP) could influence the safety of perioperative patients with non-small cell lung cancer (NSCLC). METHODS: The regimen of chemotherapy was MVP (mitomycin+vindesine+cisplatin) for all patients. The patients undergoing 2 cycles of neoadjuvant chemotherapy, radical resection and 2 cycles of postoperative chemotherapy were compared with those undergoing similar resections and 4 cycles of similar postoperative chemotherapy. RESULTS: Of the 107 eligible patients, 66 patients were in the neoadjuvant-chemotherapy group and 41 in control group. There was no statistical difference between these two groups in the distributions of gender, age, tumor staging and pathology. The neoadjuvant-chemotherapy group had longer operative duration (P=0.262), more operative blood loss (P=0.704), more amount of operative transfusion (P=0.811) and total amount of perioperative transfusion (P=0.074), and less amount of post-operative drainage (P=0.061) than those of the control group, but no statistical difference was found among them. No statistical difference was detected between two groups in the mortality (P=0.674) and the morbidity such as arrhythmia (P=0.608), bronchial parietal fistula (P= 0.378 ), pneumonia (P=0.622) and respiratory failure (P=0.285). CONCLUSIONS: Neoadjuvant chemotherapy does not exert significant influence on the safety of perioperative patients with NSCLC. PMID- 21310139 TI - [Anaesthesia management of lobectomy combined with superior vena cava graft for lung cancer with superior vena cava syndrome]. AB - BACKGROUND: To introduce the experience of anaesthesia management of lobectomy combined with resection and reconstruction of superior vena cava (SVC) with graft in the treatment of lung cancer patients with superior vena cava syndrome. METHODS: Under intubation and general anaesthesia, lobectomy combined with resection and reconstruction of superior vena cava with graft was carried out in 18 lung cancer patients with superior vena cava syndrom. RESULTS: The anaesthesia was very stable and operation was smooth in all patients. All of the patients safely returned to intensive care unit. No symptom and sign of nervous system damage was found after anaesthesia consciousness in all patients. CONCLUSIONS: The key of anaesthesia management is to maintain a stable hemodynamics and to decrease the pressure of superior vena cava, which is the key point of brain protection. PMID- 21310140 TI - [A clinicopathologic study of 9 cases of primary pulmonary extranodal marginal zone B-cell lymphoma]. AB - BACKGROUND: To study the clinicopathologic and immunohistochemical features of primary pulmonary extranodal marginal zone B-cell lymphomas (MALT lymphomas). METHODS: Immunohistochemical staining for LCA, CD20, CD45RO, CD5, cyclinD1, Ki 67, immunoglobine light chain kappa and lambda, CK and NSE was carried out in 9 patients with primary pulmonary extranodal marginal zone B-cell lymphomas by the S-P methods. RESULTS: According to the histological pattern and immunohistochemical features, all patients were diagnosed as primary pulmonary extranodal marginal zone B-cell lymphomas. There were four males and five females with a median age of 51.5 years (range from 37 to 64 years). The tumor cells were positive for LCA and CD20, however, the positive rates of Ki-67 were low. The tumor cells expressed immunoglobine light chain restriction lambda in 5 cases , kappa in 1 case, both lambda and kappa in 1 case, and neither of them in 2 cases. The tumor cells were negative for CD45RO, CD5, cyclineD1, CK, NSE in all patients. CONCLUSIONS: Primary pulmonary extranodal marginal zone B-cell lymphomas are inert lymphomas which are easily misdiagnosed. The evaluation of pathologic features and immunohistochemistry are useful and practical in the diagnosis and differential diagnosis of primary pulmonary extranodal marginal zone B-cell lymphomas. PMID- 21310141 TI - [Gemcitabine plus cisplatin versus navelbine plus cisplatin in the treatment of advanced non-small cell lung cancer]. AB - BACKGROUND: To evaluate and compare the efficacy and toxicity between combination of gemcitabine and cisplatin (GC) and combination of navelbine and cisplatin (VC) in the treatment of patients with advanced non-small cell lung cancer (NSCLC). METHODS: Sixty-seven patients with locally advanced or metastatic NSCLC were enrolled into the study, with 32 patients in GC group and 35 in VC group. Patients' characteristics were similar between the two groups. They were given gemcitabine 1 000-1 250 mg/m2, or navelbine 25 mg/m2 on days 1 and 8, and cisplatin 80-100 mg/m2 on days 1-3. The chemotherapy was repeated every 3 weeks as a cycle. RESULTS: An objective response rate of 37.5% was observed in GC arm versus 34.3% in VC arm (P=0.59). The 1-year survival rate was 38.7% in GC compared to 34.3% in VC (P=0.48). The median survival duration was 9.5 months for GC arm and 8.6 months for VC arm. Myelosuppression was the major dose-limiting toxicity. The incidence of grade III/IV leukopenia was significantly higher in the VC group than that in DC group (P=0.01), while grade III/IV thrombocytopenia occurred more frequently in the GC group than that in VC group (P=0.015). CONCLUSIONS: The GC combination is as equally active and well tolerated as the VC combination in the treatment of patients with advanced NSCLC. PMID- 21310142 TI - Differential attraction of Aedes albopictus in the field to flowers, fruits and honeydew. AB - Sugar is the main source of energy for the activities of mosquitoes; however, information on the vital sugar feeding of Aedes albopictus in the field is scanty and often anecdotal. Using glue traps and baits, we evaluated the attraction of Ae. albopictus to 28 different, potential sugar sources. Control traps were baited with either sugar-water solution or water alone, and since there was no significant difference between these controls, the water control was used as the standard for comparison. The total catch amounted to 1347 females and 1127 males. An attraction index (mean number of mosquitoes attracted to the baits/mean number of mosquitoes attracted to the control) was used to compare the relative attraction of the baits. The attraction index of significantly attractive baits ranged from 2.5 to 50.0 and the index of others ranged from 0.50 to 2.75. None of the baits were repellent. Significantly high attraction was observed for four of six ornamental flowers (Tamarix chinensis, Vitex agnus-castus, Polygonum baldchuanicum, Buddleja davidii), four of eleven wild flowers (Prosopis farcta, Ziziphus spina-christi, Polygonum equisetiforme, Ceratonia siliqua), the only tested seed pod when damaged and fermenting (C. siliqua), and all five of the tested fruits: Opuntia ficus indica (sabra), Ficus carica (fig), Punica granatum (pomegranate, damaged), Eriobotyra japonica (loquat), and Rubus sanctus (raspberry). Unlike damaged, fermenting carob seed pods and pomegranates, the fresh fruits were not attractive. Attraction to foliage soiled with honeydew excretion of three different aphid species was also not significant. The potential to use attractive sugar sources for mosquito control is discussed. PMID- 21310143 TI - Antibody-free peptide substrate screening of serine/threonine kinase (protein kinase A) with a biotinylated detection probe. AB - Being different from anti-phosphotyrosine antibodies, anti-phosphoserine- or anti phosphothreonine-specific antibodies with high affinity for the detection of serine/threonine kinase substrates are not readily available. Therefore, chemical modification methods were developed for the detection of phosphoserine or threonine in the screening of protein kinase substrates based on beta-elimination and Michael addition. We have developed a biotin-based detection probe for identification of the phosphorylated serine or threonine residue. A biotin derivative induced a color reaction using alkaline phosphate-conjugated streptavidin that amplified the signal. It was effective for the detection and separation of the target peptide on the resin. The detection probe was successfully used in identifying PKA substrates from peptide libraries on resin beads. The peptide library was prepared as a ladder-type, such that the active peptides on the colored resin beads were readily sequenced with the truncated peptide fragments by MALDI-TOF/MS analysis after releasing the peptides from the resin bead through photolysis. PMID- 21310144 TI - Non-invasive screening of HLA-DPA1 and HLA-DPB1 alleles for persistent hepatitis B virus infection: susceptibility for vertical transmission and toward a personalized approach for vaccination and treatment. AB - BACKGROUND: Polymorphisms in the major histocompatibility complex (MHC) and non MHC genes were recently reported to be associated with persistent hepatitis B virus (HBV) infection and host response to hepatitis B vaccine in Asian populations. We aimed to confirm the associations in Chinese population and develop a non-invasive screening method for the risk loci. METHODS: We genotyped 2 risk alleles on the MHC loci, HLA-DPA1 (rs3077) and HLA-DPB1 (rs9277535), and 1 risk allele near a non-MHC gene, FOXP1 (rs6789153) using high-resolution melting curve analysis. With minimal processing steps and time, salivary DNA was extracted with a modified protocol of a blood kit. We compared the genotyping fidelity between peripheral blood DNA and salivary DNA. RESULTS: Both rs3077 and rs9277535, but not rs6789153, are significantly associated with CHB in Chinese population (p-value<0.001). High genotype concordance between different sources of genomic DNA was obtained. CONCLUSIONS: Genotyping salivary DNA using our modified methods provides a non-invasive fast screening for host susceptibility loci. The transmission mechanism of hepatitis B can now be modified by adding genetic susceptibility to the traditional vertical transmission model of hepatitis B. PMID- 21310145 TI - Genomically integrated transgenes are stably and conditionally expressed in neural crest cell-specific lineages. AB - Neural crest cells (NCCs) are a transient embryonic structure that gives rise to a variety of cells including peripheral nervous system, melanocytes, and Schwann cells. To understand the molecular mechanisms underlying NCC development, a gene manipulation of NCCs by in ovo electroporation technique is a powerful tool, particularly in chicken embryos, the model animal that has long been used for the NCC research. However, since expression of introduced genes by the conventional electroporation method is transient, the mechanisms of late development of NCCs remain unexplored. We here report novel methods by which late-developing NCCs are successfully manipulated with electroporated genes. Introduced genes can be stably and/or conditionally expressed in a NCC-specific manner by combining 4 different techniques: Tol2 transposon-mediated genomic integration (Sato et al., 2007), a NCC-specific enhancer of the Sox10 gene (identified in this study), Cre/loxP system, and tet-on inducible expression (Watanabe et al., 2007). This is the first demonstration that late-developing NCCs in chickens are gene manipulated specifically and conditionally. These methods have further allowed us to obtain ex vivo live-images of individual Schwann cells that are associated in axon bundles in peripheral tissues. Cellular activity and morphology dynamically change as development proceeds. This study has opened a new way to understand at the molecular and cellular levels how late NCCs develop in association with other tissues during embryogenesis. PMID- 21310146 TI - Dendritic changes in visual pathways in glaucoma and other neurodegenerative conditions. AB - Visual information is sent from the retina to central visual targets through the optic nerve formed of retinal ganglion cells' (RGCs) axons. In rodents, the superior colliculus (SC) is the major site of termination of retinal axons, whilst in primates and felines, it is the lateral geniculate nucleus (LGN). Glaucoma is a progressive optic neuropathy characterized by RGC death. There is increasing evidence that neuronal changes occur both in retina and central visual targets in glaucoma and other neurodegenerative diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Dendrites are fine neuronal processes which support postsynaptic contact elements and are responsible for receiving synaptic signals. The morphology of dendrites has a profound impact on integrating neuronal input to the central nervous system from peripheral targets. This review summarizes different dendritic changes that have been recorded in neurodegenerative processes including those occurring in development, ageing and diseases. The findings suggest dendritic pathology is an early sign in disease and underline the importance of synapto-dendritic structure, providing new insights into therapeutic strategies. PMID- 21310147 TI - Neuronal replacement in the injured olfactory bulb. AB - The adult forebrain subventricular zone contains neural stem cells that produce neurons destined for the olfactory bulb, where interneuron populations turnover throughout life. Forebrain injuries can stimulate production of these cells, and re-direct migrating precursors from the olfactory system to areas of damage, where their region-appropriate differentiation and long-term functional integration remain a matter for debate. Paradoxically, little is known about the ability of these progenitors to replace olfactory neurons lost to injury. Their innate capacity to generate bulb neurons may give them an advantage in this regard, and using injections of N-methyl-d-aspartate to kill mature olfactory bulb neurons, combined with bromodeoxyuridine labeling to monitor the fate of adult-born cells, we investigated the potential for injury-induced neurogenesis in this system. Widespread degeneration of bulb neurons did not affect the rate of cell proliferation in the subventricular zone, or cause neuroblasts to divert from their normal migratory route. However migration was slowed by the injury, leading to the accumulation and differentiation of neuroblasts as NeuN+ cells in the rostral migratory stream within 2 weeks of their birth. Despite this, a subset of new neurons successfully invaded the damaged bulb tissue, where they expressed neuronal markers including NeuN, calretinin, GABA, and tyrosine hydroxylase, with some surviving here for as long as 6 months. To test for functional integration of cells born post-injury, we also performed smaller NMDA lesions in restricted portions of the bulb granule cell layer and observed adult born NeuN+ cells in these areas within 5 weeks, and BrdU+ cells that expressed the immediate-early gene c-fos following odor stimulation. These data suggest that the normal neurogenic capacity of the adult subventricular zone can be adapted to replace subsets of olfactory neurons lost to injury. PMID- 21310148 TI - Toxoplasma gondii: protective immunity against experimental toxoplasmosis induced by a DNA vaccine encoding the perforin-like protein 1. AB - Toxoplasma gondii is an important zoonotic parasite infecting about one third of the world population, causing congenital infections and eye disease. T. gondii perforin-like protein 1 (TgPLP1) is believed to be involved in the acute virulence of T. gondii in mice, and is therefore of interest as a vaccine candidate. In this study, we constructed a DNA vaccine expressing TgPLP1, and evaluated the immune response in Kunming mice. The gene sequence encoding TgPLP1 was inserted into the eukaryotic expression vector pVAX I, and Kunming mice were immunized intramuscularly with the plasmid. After immunization, we evaluated the immune response using lymphoproliferative assay, cytokine and antibody measurements, and the survival times of mice challenged lethally with 1*10(3) tachyzoites of the virulent T. gondii RH strain. The results showed that pVAX/TgPLP1 alone or with pVAX/IL-18 developed specific anti-TLA (T. gondii lysate antigen) antibodies and specific lymphocyte proliferative responses. Co injection of pVAX/IL-18 significantly increased the production of IFN-gamma and IL-2. Further, challenge experiments showed that co-immunization of pVAX/TgPLP1 with pVAX/IL-18 significantly (P<0.05) increased survival time (12.7+/-1.2days) of immunized mice, compared with pVAX/TgPLP1 alone (11.3+/-0.9days). These results demonstrate that TgPLP1 is a potential vaccine candidate against toxoplasmosis, worth further evaluation in other animal hosts. IL-18 could enhance the immune effect of TgPLP1, prolonging the survival time of immunized mice. PMID- 21310149 TI - Mice lacking Ran binding protein 1 are viable and show male infertility. AB - The small GTPase Ran plays important roles in multiple aspects of cellular function. Maximal RanGAP activity is achieved with the aid of RanBP1 and/or presumably of RanBP2. Here, we show that RanBP1-knockout mice are unexpectedly viable, and exhibit male infertility due to a spermatogenesis arrest, presumably caused by down-regulation of RanBP2 during spermatogenesis. Indeed, siRNA mediated depletion of RanBP2 caused severe cell death only in RanBP1-deficient MEFs, indicating that simultaneous depletion of RanBP1 and RanBP2 severely affects normal cell viability. Collectively, we conclude that the dramatic decrease in "RanBP" activity impairs germ cell viability and affects spermatogenesis decisively in RanBP1-knockout mice. PMID- 21310150 TI - NDUFB7 and NDUFA8 are located at the intermembrane surface of complex I. AB - Complex I (NADH:ubiquinone oxidoreductase) is the first and largest protein complex of the oxidative phosphorylation. Crystal structures have elucidated the positions of most subunits of bacterial evolutionary origin in the complex, but the positions of the eukaryotic subunits are unknown. Based on the analysis of sequence conservation we propose intra-molecular disulfide bridges and the inter membrane space localization of three Cx(9)C-containing subunits in human: NDUFS5, NDUFB7 and NDUFA8. We experimentally confirm the localization of the latter two, while our data are consistent with disulfide bridges in NDUFA8. We propose these subunits stabilize the membrane domain of complex I. PMID- 21310151 TI - A way to sense light intensity: Multiple-excitation of the BLUF photoreceptor TePixD suppresses conformational change. AB - TePixD, a cyanobacterial sensor of blue light using flavin adenine dinucleotide (FAD) (BLUF) which exists in a decamer form, was found to exhibit photoreaction sensitive to light intensity. While the number of excited molecules increased monotonically as the laser power increased, the number of decamers exhibiting a global conformational change initially increased, and then decreased with the increase of excitation intensity. This unusual power dependence was analyzed based on a Poisson distribution equation, demonstrating that decamers containing more than one excited monomer subunit do not undergo conformational change. Our results suggest that TePixD functions not only as a photosensor, but also by sensing light intensity. PMID- 21310152 TI - Seasonal changes in courtship behavior, plasma androgen levels and in hypothalamic aromatase immunoreactivity in male free-living European starlings (Sturnus vulgaris). AB - In songbirds from temperate latitudes, singing during spring has an essential role in mate attraction, while during the non-breeding season it is connected to territorial aggression and/or maintaining dominance hierarchies or flock cohesion. Courtship behavior is regulated by plasma testosterone (T) levels. Other androgens, like dehydroepiandrosterone (DHEA) could be responsible for aggression. The aromatization of androgens in the brain is an essential step in mediating their effects on behavior. Our goal was to determine whether the seasonal changes in male courtship behavior (measured by average song bout length and wing-waving/flicking) are related to seasonal changes in androgen activity (measured by plasma T, DHEA levels) and aromatase (ARO) immunoreactivity in the preoptic area/medial preoptic nucleus (POA/POM) of free-living male starlings. DHEA increased during pair formation, decreased at nesting and remained at low levels. The number of ARO cells - in line with the T levels - increased during the courtship and nesting periods, but outside the breeding season it was low. Song bout length showed a similar pattern, namely the peak was reached during the courtship period, and after that males stopped singing when chicks started to hatch. Short and fast wing-flicking and wing-waving behavior was observed only during the breading season. Summarizing, we have found that song bout length of male starlings changes parallel with plasma T levels and ARO immunoreactivity in the POA/POM. Furthermore, DHEA levels were low during the sexually inactive period which suggests that other mechanisms could be involved in the aggressive non-courtship behavior/vocalization in these birds. PMID- 21310153 TI - Historical view of development of comparative endocrinology in Japan. AB - This article describing a brief history of development of comparative endocrinology in Japan is contributed to the journal General and Comparative Endocrinology, in commemoration of the 50th anniversary of its publication. It covers significant works in the field of comparative endocrinology that have been done by Japanese endocrinologists, focusing those achieved during the past 70 years. The contents were arranged according to the taxonomical order of the experimental animals with which individual researchers or research groups have contributed to the acquisition of important knowledge in comparative endocrinology. PMID- 21310154 TI - Molecular identification of genes involved in testicular steroid synthesis and characterization of the response to gonadotropic stimulation in the Senegalese sole (Solea senegalensis) testis. AB - In male teleosts, testicular steroids are essential hormones for the regulation of spermatogenesis and their production is regulated by pituitary gonadotropins. In the Senegalese sole (Solea senegalensis), an economically important flatfish with semi-cystic and asynchronous spermatogenesis, the gonadotropic regulation of spermatogenesis, particularly regarding the production and regulation of testicular steroids, are not well understood. For this reason, we first cloned and characterized the response of several key genes for the production and action of testicular steroids to the in vivo administration of human chorionic gonadotropin (hCG) and, second, we investigated the transcriptomic effects of hCG in the Senegalese sole testis. We succeeded in cloning the full-length cDNAs for Steroidogenic Acute Regulatory protein (StAR), 3beta-hydroxysteroid dehydrogenase (3beta-HSD), 17beta-HSD and 20beta-HSD and a partial cDNA for the nuclear progesterone receptor. In this study we also identified a transcript encoding a protein with homology to StAR, which we named StAR-like, that could represent a new member of the StAR-related lipid transfer (START) family. All the cloned genes were expressed in the testis and their expression levels were significantly increased by the in vivo administration of hCG. The plasma levels of testosterone and 11-ketotestosterone also increased in response to hCG administration, likely as a result of the induction of the expression of steroidogenic enzymes by hCG. Furthermore, gene expression analysis by microarray identified 90 differentially expressed genes in the testis in response to hCG administration, including genes potentially involved in steroidogenesis, progression of spermatogenesis and germ cell maturation and cytoskeletal organization. Our results have identified for the first time a number of key genes involved in the regulation of steroid production and spermatogenesis in the Senegalese sole testis that are under gonadotropic control. PMID- 21310155 TI - Identification of members of the gonadotropin-releasing hormone (GnRH), corticotropin-releasing factor (CRF) families in the genome of the holocephalan, Callorhinchus milii (elephant shark). AB - The gonadotropin-releasing hormone (GnRH) and corticotropin-releasing family (CRF) are two neuropeptides families that are strongly conserved throughout evolution. Recently, the genome of the holocephalan, Callorhinchus milii (elephant shark) has been sequenced. The phylogenetic position of C. milii, along with the relatively slow evolution of the cartilaginous fish suggests that neuropeptides in this species may resemble the earliest gnathostome forms. The genome of the elephant shark was screened, in silico, using the various conserved motifs of both the vertebrate CRF paralogs and the insect diuretic hormone sequences to identify the structure of the C. milii CRF/DH-like peptides. A similar approach was taken to identify the GnRH peptides using conserved motifs in both vertebrate and invertebrate forms. Two CRF peptides, a urotensin-1 peptide and a urocortin 3 peptide were found in the genome. There was only about 50% sequence identity between the two CRF peptides suggesting an early divergence. In addition, the urocortin 2 peptide seems to have been lost and was identified as a pseudogene in C. milii. In contrast to the number of CRF family peptides, only a GnRH-II preprohormone with the conserved mature decapeptide was found. This confirms early studies about the identity of GnRH in the Holocephali, and suggests that the Holocephali and Elasmobranchii differ with respect to GnRH structure and function. PMID- 21310156 TI - Context alters the ability of clitoral stimulation to induce a sexually conditioned partner preference in the rat. AB - We have shown previously that clitoral stimulation (CLS) of female rats induces significant conditioned place preference (CPP), indicating that it is rewarding. The present study asked whether CLS could induce a conditioned partner preference. In the first experiment, sexually naive females received 10 alternating trials of CLS and No-CLS in the presence of a male rat behind a wire mesh screen. For one group, CLS was made in the presence of the male scented with almond extract. On alternating trials, those females received sham CLS in the presence of an unscented male behind the screen. The order was reversed for the other group. After 5 trials in each condition, females were placed into an open field with two sexually vigorous males, one scented and the other unscented. Contrary to expectation, females displayed a preference for the male associated with sham CLS. The second experiment examined whether a partner preference could be conditioned by associating CLS with the almond odor alone. A new group of sexually naive females received the same CLS-odor, No-CLS-No Odor pairings as above, but with the odor presented on cotton gauze in the chamber. During the final open field test, those females selectively solicited the scented male. We conclude that CLS that induces CPP also induces conditioned partner preference. However, we propose that CLS in the presence of an inaccessible male created a sexual inhibitory state for female rats. PMID- 21310157 TI - Peripheral ghrelin stimulates feeding behavior and positive energy balance in a sciurid hibernator. AB - Hibernators exhibit a robust circannual cycle of body mass gain and loss primarily mediated by food intake, but the pathways controlling food intake in these animals have not been fully elucidated. Ghrelin is an orexigenic hormone that increases feeding in all mammals studied so far, but has not until recently been studied in hibernators. In other mammals, ghrelin stimulates feeding through phosphorylation and activation of AMP-activated protein kinase (AMPK). Activation of AMPK phosphorylates and deactivates acetyl Co-A carboxylase (ACC), a committed step in fatty acid synthesis. In order to determine the effects of exogenous ghrelin on food intake and metabolic factors (i.e. non-esterified fatty acids (NEFAs), and hypothalamic AMPK and ACC) in hibernators, ghrelin was peripherally injected into ground squirrels in all four seasons. Changes in food intake and body mass were recorded over a 2-6 hour period post injections, and squirrels were euthanized. Brains and blood were removed, and Western blots were performed to determine changes in phosphorylation of hypothalamic AMPK and ACC. A colorimetric assay was used to determine changes in concentration of serum NEFAs. We found that food intake, body mass, and locomotor activity significantly increased with ghrelin injections versus saline-injected controls, even in animals injected during their aphagic winter season. Injected ghrelin was correlated with increased phosphorylation of AMPK, but didn't have an effect on ACC in winter. Ghrelin-injected animals also had increased levels of serum NEFAs compared with saline controls. This study is the first to show an effect of injected ghrelin on a hibernator. PMID- 21310158 TI - The protective effect against Leishmania infection conferred by sand fly bites is limited to short-term exposure. AB - Under laboratory conditions, hosts exposed twice to sand fly saliva are protected against severe leishmaniasis. However, people in endemic areas are exposed to the vector over a long term and may experience sand fly-free periods. Therefore, we exposed mice long- or short-term to Phlebotomus duboscqi bites, followed by Leishmania major infection either immediately or after a sand fly-free period. We showed that protection against leishmaniasis is limited to short-term exposure to sand flies immediately before infection. Our results may explain the persistence of leishmaniasis in endemic areas and should be taken into account when designing anti-Leishmania vaccines based on sand fly saliva. PMID- 21310159 TI - Choice matters: incipient speciation in Gyrodactylus corydori (Monogenoidea: Gyrodactylidae). AB - We investigated how Gyrodactylus corydoriBueno-Silva and Boeger, 2009 exploits two sympatric host species, Corydoras paleatus (Jenyns, 1842) and Corydoras ehrhardti Steindachner, 1910. Specimens of G. corydori were collected from the Piraquara and Miringuava Rivers, State of Parana, Brazil, between 2005 and 2006. A total of 167 parasites was measured from both host species. Nine morphometric features of the haptoral sclerites were measured and analyzed by discriminant analysis, cluster analysis and multivariate analysis of variance. A fragment of the mitochondrial cytochrome oxidase I gene (COI) (~740 bp) and the rDNA internal transcribed spacers (ITS) (~1200 bp) of G. corydori were sequenced. Bayesian and parsimony analyses of COI recognized two genetically structured clades of G. corydori, which corresponded closely with the two species of Corydoras. Twenty eight haplotypes were detected (18 were exclusive to C. ehrhardti and seven were exclusive to C. paleatus). The same general pattern between parasites and host species was observed in the morphometric analyses. Nevertheless, poor correlation of genetic and morphometric variation strongly supports the plastic nature of the morphological variation of haptoral sclerites. The existence of two clades with limited gene flow would suggest that G. corydori already represents two cryptic species. However, the morphometric and molecular data showed that there is insufficient evidence to support two valid species. The low COI (0.1-6.2%) and ITS (0.09-3.5%) divergence within G. corydori suggest a recent separation of the lineages between distinct host species (less than 1 million years). As the hypothesis of secondary contact of the parasite demographic history was rejected, our results point to the possibility of sympatric incipient ongoing speciation of G. corydori to form distinct parasite lineages adapted to C. ehrhardti and C. paleatus. This may be a common event within the Gyrodactylidae, adding a yet unreported mode of adaptive speciation that helps to understand its rate of diversification. PMID- 21310160 TI - Construction of a genetic map for Theileria parva: identification of hotspots of recombination. AB - The tick-borne protozoan parasite Theileria parva is the causal agent of East Coast Fever (ECF), a severe lymphoproliferative disease of cattle in eastern, central and southern Africa. The life cycle of T. parva is predominantly haploid, with a brief diploid stage occurring in the tick vector that involves meiotic recombination. Resolved genetic studies of T. parva are currently constrained by the lack of a genome-wide high-definition genetic map of the parasite. We undertook a genetic cross of two cloned isolates of T. parva to construct such a map from 35 recombinant progeny, using a genome-wide panel of 79 variable number of tandem repeat markers. Progeny were established by in vitro cloning of cattle lymphocytes after infection with sporozoites prepared from Rhipicephalus appendiculatus ticks fed on a calf undergoing a dual infection with the two clonal parental stocks. The genetic map was determined by assigning individual markers to the four chromosome genome, whose physical length is approximately 8309 kilobasepairs (Kb). Segregation analysis of the markers among the progeny revealed a total genetic size of 1683.8 centiMorgans (cM), covering a physical distance of 7737.62 Kb (~93% of the genome). The average genome-wide recombination rate observed for T. parva was relatively high, at 0.22 cM Kb(-1) per meiotic generation. Recombination hot-spots and cold-spots were identified for each of the chromosomes. A panel of 27 loci encoding determinants previously identified as immunorelevant or likely to be under selection were positioned on the linkage map. We believe this to be the first genetic linkage map for T. parva. This resource, with the availability of the genome sequence of T. parva, will promote improved understanding of the pathogen by facilitating the use of genetic analysis for identification of loci responsible for variable phenotypic traits exhibited by individual parasite stocks. PMID- 21310161 TI - Preparation of fully synthetic histone H3 reveals that acetyl-lysine 56 facilitates protein binding within nucleosomes. AB - Posttranslational modification (PTM) of histones plays a central role in genome regulation. Engineering histones with defined PTMs on one residue or on multiple residues is crucial for understanding their function within nucleosomes and chromatin. We introduce a sequential native chemical ligation strategy that is suitable for the preparation of fully synthetic histone proteins, allowing for site-specific incorporation of varied PTMs throughout the sequence. We demonstrate this method with the generation of histone H3 acetylated at lysine 56 [H3(K56ac)]. H3(K56ac) is essential for transcription, replication, and repair. We examined the influence of H3(K56ac) on the targeting of a model DNA binding factor (LexA) to a site ~30 bp within the nucleosome. We find that H3(K56ac) increases LexA binding to its DNA target site by 3-fold at physiological ionic strength. We then demonstrate that H3(K56ac) facilitates LexA binding by increasing DNA unwrapping, not by nucleosome repositioning. Furthermore, we find that H3(K56Q) quantitatively imitates H3(K56ac) function. Together, these studies introduce powerful tools for the analysis of histone PTM functions. PMID- 21310162 TI - Melanoblast proliferation dynamics during mouse embryonic development. Modeling and validation. AB - In this paper, we are looking for mathematical modeling of mouse embryonic melanoblast proliferation dynamics, taking into account, the expression level of beta-catenin. This protein plays an important role into the whole signal pathway process. Different assumptions on some unobservable features lead to different candidate models. From real data measured, from biological experiments and from a priori biological knowledge, it was able to validate or invalidate some of the candidate models. Data assimilation and parameter identification allowed us to derive a mathematical model that is in very good agreement with biological data. As a result, the produced model can give tracks for biologists into their biological investigations and experimental evidence. Another interest is the use of this model for robust hidden parameter identification like double times or number of founder melanoblasts. PMID- 21310163 TI - Stem cell protein Piwil2 modulates chromatin modifications upon cisplatin treatment. AB - Piwil2 (mili in mouse or hili in humans), a member of the PIWI/Argonaute gene family, plays important roles in stem cell self-renewal, RNA silencing, and translational regulation in various organisms. Recent demonstration of stable Piwil2 expression in pre-cancerous stem cells and in various human and animal tumor cell lines suggests its association in tumorigenesis. Here, we show that cisplatin induces chromatin relaxation in Mili-wild type (WT) mouse embryonic fibroblasts (MEFs), but not in Mili-knockout (KO) MEFs. Moreover, in contrast to Mili-WT MEFs, Mili-KO MEFs showed a discernable H3 hypoacetylation response upon cisplatin treatment. Levels of the histone acetyltransferase (HAT), p300, were dramatically different due to a consistent cisplatin post-treatment decrease in Mili-WT and an increase in Mili-KO MEFs. Concomitant reduction of specific HAT activity of p300 could explain the decrease of H3 acetylation in Mili-KO MEFs. Our data also shows Mili is required for maintaining the euchromatic marks in MEFs upon cisplatin treatment. In addition, Mili-KO MEFs exhibited a significant deficiency in repairing cisplatin-induced DNA damage and displayed higher sensitivity to cisplatin. Further analysis revealed that Piwil2 was also enhanced in two completely different cisplatin-resistant ovarian cancer cell lines. Interestingly, knockdown of Piwil2 expression in these two cell lines also resulted in their enhanced sensitivity to cisplatin and decreased their efficiency for removing cisplatin-induced DNA intrastrand crosslinks (Pt-GG). The overall data showed that Piwil2 is a key factor in regulating chromatin modifications especially in response to cisplatin. To conclude, the overexpression of Piwil2 in some cancers could lead to cellular cisplatin resistance, possibly due to enhanced chromatin condensation affecting normal DNA repair. PMID- 21310164 TI - Therapeutic significance of NR2B-containing NMDA receptors and mGluR5 metabotropic glutamate receptors in mediating the synaptotoxic effects of beta amyloid oligomers on long-term potentiation (LTP) in murine hippocampal slices. AB - Soluble amyloid beta (Abeta) oligomers are widely accepted to be neurotoxic and lead to the memory loss and neuronal death observed in Alzheimer's disease (AD). Ample evidence suggests that impairment in glutamatergic signalling is associated with AD pathology. In particular, Abeta(1-42) is thought to affect N-methyl-d aspartate (NMDA) receptor function and abolish the induction of long-term potentiation (LTP), which is regarded to be a phenomenon relevant to memory formation. The involvement of glutamatergic signalling in the pathology of AD is underscored by the therapeutic success of memantine, an uncompetitive NMDA receptor antagonist, used to treat patients with moderate to severe AD. In this study we show that Abeta(1-42) oligomers applied to acute murine hippocampal slices prevented, in a concentration-dependent manner, the development of CA1-LTP after tetanic stimulation of the Schaffer collaterals with a half maximal inhibitory concentration of around 2 nM (before oligomerization). The highest concentration of Abeta(1-42) oligomers (50 nM before oligomerization) completely blocked LTP (105 +/- 1% potentiation versus 141 +/- 3% in control) whereas scrambled Abeta(1-42) (50 nM) was without effect (144 +/- 10% potentiation). Pre incubation with memantine (1 MUM) restored LTP in the presence of Abeta(1-42) (50 nM; 135 +/- 5% potentiation). NMDA receptors containing the NR2B subunit have been proposed to play a particularly important role in excitotoxicity, functioning as extracellular "death receptors". The metabotropic glutamate receptor 5 (mGluR5) is mechanistically coupled to postsynaptic NMDA receptors. As such, allosteric sites on both receptors offer alternative means to modulate NMDA receptor function. We therefore tested low concentrations (each 300 nM) of allosteric antagonists of NR2B (Ro 25-6981, [R-(R*,S*)]-alpha-(4-Hydroxyphenyl) beta-methyl-4(phenylmethyl)-1-piperidine propanol hydrochloride) and mGluR5 receptors (MPEP, 2-methyl-6-(phenylethynyl)-pyridine). Both compounds restored LTP in the presence of Abeta(1-42) oligomers (50 nM, fEPSPs were potentiated to 129 +/- 13% and 133 +/- 7% respectively). Finally, we demonstrated that slices from mice heterozygous for NR2B receptor) in the forebrain are not susceptible to the toxic effects of Abeta(1-42) oligomers but express normal LTP (138 +/- 6%). These experiments demonstrate that glutamate receptor antagonists delivered at concentrations which still allow physiological activities in vitro, are able to prevent Abeta(1-42) oligomer-induced synaptic toxicity and further support the glutamatergic system as a target for the development of improved symptomatic/neuroprotective treatments for AD. PMID- 21310165 TI - Neglect rehabilitation by prism adaptation: different procedures have different impacts. AB - Several studies point to prism adaptation as an effective tool for the rehabilitation of hemispatial neglect. However, some recent reports failed to show a significant amelioration of neglect after prism adaptation as compared to control treatments. This apparent contradiction might reflect important differences in the procedures used for treatment. Here we compare the effects of two treatments (performed for 10 sessions, over 2 weeks) in two groups of patients, based either on a Terminal (TPA) or a Concurrent (CPA) prism adaptation procedure. During TPA only the final part of the pointing movement is visible and prism adaptation relies most strongly on a strategic recalibration of visuomotor eye-hand coordinates. In contrast, during CPA the second half of the pointing movement is visible, and thus adaptation mainly consists of a realignment of proprioceptive coordinates. The present results show that both TPA and CPA treatments induced a greater improvement of neglect as compared to a control treatment of pointing without prisms. However, neglect amelioration was higher for patients treated with TPA than for those treated with CPA. At the same time, the TPA treatment induced a stronger deviation of eye movements toward the left, neglected, field as compared to the CPA treatment. Interestingly, in TPA patients the visuomotor and oculomotor effects of the treatment were directly related to the patients' ability to compensate for the optical deviation induced by prism during pointing (i.e., Error reduction effect). In summary, prism adaptation seems particularly effective for the recovery of visuo-spatial neglect when conducted with a procedure stressing a correction of visuomotor eye-hand coordinates, i.e., with a TPA procedure. The present observations may help to better understand the mechanisms underlying prism-induced recovery from neglect and the procedural basis for some of the contradictory results obtained when using this rehabilitative strategy. PMID- 21310166 TI - The immediacy of recollection: the use of the historical present in narratives of autobiographical episodes by patients with unilateral temporal lobe epilepsy. AB - Objectively measuring the experiential phenomenon of "reliving" a personal memory without relying on the retrieval of specific contents such as richness/vividness of perceptual details is difficult. There are, however, some circumstances in which an indirect measure that does not require conscious retrieval or deliberate assessment of such information, would be quite useful (e.g., in very young children, in patients with poor fluency or inappropriate use of rating scales). Here, we examined the use of the historical present (HP), defined as a present tense that refers to a past action, in autobiographical narratives. The HP indexes a sense of reliving because the memory of the event is vividly re experienced as occurring again in the current moment. We compared the use of the HP in narratives from neurologically intact controls and from patients with unilateral temporal lobe excisions or epilepsy (TLE). Results indicate that patients used fewer instances of the HP than healthy controls. Also, the use of the HP correlated positively with other measures of recollection, such as the total number of perceptual details contained in a narrative. We provide the first empirical evidence that a linguistic construct can be used to assess the conscious experience that accompanies recollection. PMID- 21310167 TI - Seized designer supplement named "1-Androsterone": identification as 3beta hydroxy-5alpha-androst-1-en-17-one and its urinary elimination. AB - New analogues of androgens that had never been available as approved drugs are marketed as "dietary supplement" recently. They are mainly advertised to promote muscle mass and are considered by the governmental authorities in various countries, as well as by the World Anti-doping Agency for sport, as being pharmacologically and/or chemically related to anabolic steroids. In the present study, we report the detection of a steroid in a product seized by the State Bureau of Criminal Investigation Schleswig-Holstein, Germany. The product "1 Androsterone" of the brand name "Advanced Muscle Science" was labeled to contain 100mg of "1-Androstene-3b-ol,17-one" per capsule. The product was analyzed underivatized and as bis-TMS derivative by GC-MS. The steroid was identified by comparison with chemically synthesized 3beta-hydroxy-5alpha-androst-1-en-17-one, prepared by reduction of 5alpha-androst-1-ene-3,17-dione with LS-Selectride (Lithium tris-isoamylborohydride), and by nuclear magnetic resonance. Semi quantitation revealed an amount of 3beta-hydroxy-5alpha-androst-1-en-17-one in the capsules as labeled. Following oral administration to a male volunteer, the main urinary metabolites were monitored. 1-Testosterone (17beta-hydroxy-5alpha androst-1-en-3-one), 1-androstenedione (5alpha-androst-1-ene-3,17-dione), 3alpha hydroxy-5alpha-androst-1-en-17-one, 5alpha-androst-1-ene-3alpha,17beta-diol, and 5alpha-androst-1-ene-3beta,17beta-diol were detected besides the parent compound and two more metabolites (up to now not finally identified but most likely C-18 and C-19 hydroxylated 5alpha-androst-1-ene-3,17-diones). Additionally, common steroids of the urinary steroid profile were altered after the administration of "1-Androsterone". Especially the ratios of androsterone/etiocholanolone and 5alpha-/5beta-androstane-3alpha,17beta-diol and the concentration of 5alpha dihydrotestosterone were influenced. 3alpha-Hydroxy-5alpha-androst-1-en-17-one appears to be suitable for the long-term detection of the steroid (ab-)use, as this characteristic metabolite was detectable in screening up to nine days after a single administration of one capsule. PMID- 21310168 TI - Effects of manganese on tyrosine hydroxylase (TH) activity and TH-phosphorylation in a dopaminergic neural cell line. AB - Manganese (Mn) exposure causes manganism, a neurological disorder similar to Parkinson's disease. However, the cellular mechanism by which Mn impairs the dopaminergic neurotransmitter system remains unclear. We previously demonstrated that caspase-3-dependent proteolytic activation of protein kinase C delta (PKCdelta) plays a key role in Mn-induced apoptotic cell death in dopaminergic neurons. Recently, we showed that PKCdelta negatively regulates tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, by enhancing protein phosphatase-2A activity in dopaminergic neurons. Here, we report that Mn exposure can affect the enzymatic activity of TH, the rate-limiting enzyme in dopamine synthesis, by activating PKCdelta-PP2A signaling pathway in a dopaminergic cell model. Low dose Mn (3-10MUM) exposure to differentiated mesencephalic dopaminergic neuronal cells for 3h induced a significant increase in TH activity and phosphorylation of TH-Ser40. The PKCdelta specific inhibitor rottlerin did not prevent Mn-induced TH activity or TH-Ser40 phosphorylation. On the contrary, chronic exposure to 0.1-1 MUM Mn for 24h induced a dose-dependent decrease in TH activity. Interestingly, chronic Mn treatment significantly increased PKCdelta kinase activity and protein phosphatase 2A (PP2A) enzyme activity. Treatment with the PKCdelta inhibitor rottlerin almost completely prevented chronic Mn-induced reduction in TH activity, as well as increased PP2A activity. Neither acute nor chronic Mn exposures induced any cytotoxic cell death or altered TH protein levels. Collectively, these results demonstrate that low dose Mn exposure impairs TH activity in dopaminergic cells through activation of PKCdelta and PP2A activity. PMID- 21310169 TI - Genotoxicity of carbon nanofibers: are they potentially more or less dangerous than carbon nanotubes or asbestos? AB - The production of carbon nanofibers and nanotubes (CNF/CNT) and their composite products is increasing globally. CNF are generating great interest in industrial sectors such as energy production and electronics, where alternative materials may have limited performance or are produced at a much higher cost. However, despite the increasing industrial use of carbon nanofibers, information on their potential adverse health effects is limited. In the current study, we examine the cytotoxic and genotoxic potential of carbon-based nanofibers (Pyrograf(r)-III) and compare this material with the effects of asbestos fibers (crocidolite) or single-walled carbon nanotubes (SWCNT). The genotoxic effects in the lung fibroblast (V79) cell line were examined using two complementary assays: the comet assay and micronucleus (MN) test. In addition, we utilized fluorescence in situ hybridization to detect the chromatin pan-centromeric signals within the MN indicating their origin by aneugenic (chromosomal malsegregation) or clastogenic (chromosome breakage) mechanisms. Cytotoxicity tests revealed a concentration- and time-dependent loss of V79 cell viability after exposure to all tested materials in the following sequence: asbestos>CNF>SWCNT. Additionally, cellular uptake and generation of oxygen radicals was seen in the murine RAW264.7 macrophages following exposure to CNF or asbestos but not after administration of SWCNT. DNA damage and MN induction were found after exposure to all tested materials with the strongest effect seen for CNF. Finally, we demonstrated that CNF induced predominantly centromere-positive MN in primary human small airway epithelial cells (SAEC) indicating aneugenic events. Further investigations are warranted to elucidate the possible mechanisms involved in CNF-induced genotoxicity. PMID- 21310170 TI - Vision-for-perception and vision-for-action: which model is compatible with the available psychophysical and neuropsychological data? AB - Westwood and Goodale (this issue) review the evidence for distinct visual streams for action and perception. They argue that, on balance, both the neuropsychological and psychophysical data support this distinction. They claim that critical results were either statistically inconclusive (because they consisted of negative evidence) or based on a suspect "calibration" procedure. Finally, they suggest that explanations dismissing the psychophysical evidence for the TVSH are contradicted by the neuropsychological evidence. We disagree with their assessment. 'Negative evidence' is not necessarily inconclusive. Problems raised by mixed evidence are best dealt with by conducting meta analytical studies, which so far are only in part consistent with the TVSH. Correction ("calibration") of illusion effects is critical for comparisons across stimuli, studies, and tasks. We furthermore argue that both psychophysical and neuropsychological evidence can be explained without assuming divergent pathways for perception and action. PMID- 21310171 TI - Oculomotor capture during real-world scene viewing depends on cognitive load. AB - It has been claimed that gaze control during scene viewing is largely governed by stimulus-driven, bottom-up selection mechanisms. Recent research, however, has strongly suggested that observers' top-down control plays a dominant role in attentional prioritization in scenes. A notable exception to this strong top-down control is oculomotor capture, where visual transients in a scene draw the eyes. One way to test whether oculomotor capture during scene viewing is independent of an observer's top-down goal setting is to reduce observers' cognitive resource availability. In the present study, we examined whether increasing observers' cognitive load influences the frequency and speed of oculomotor capture during scene viewing. In Experiment 1, we tested whether increasing observers' cognitive load modulates the degree of oculomotor capture by a new object suddenly appeared in a scene. Similarly, in Experiment 2, we tested whether increasing observers' cognitive load modulates the degree of oculomotor capture by an object's color change. In both experiments, the degree of oculomotor capture decreased as observers' cognitive resources were reduced. These results suggest that oculomotor capture during scene viewing is dependent on observers' top-down selection mechanisms. PMID- 21310173 TI - From mice to men: Biological factors in the development of sexuality. PMID- 21310172 TI - Sexual orientation and the auditory system. AB - The auditory system exhibits differences by sex and by sexual orientation, and the implication is that relevant auditory structures are altered during prenatal development, possibly by exposure to androgens. The otoacoustic emissions (OAEs) of newborn male infants are weaker than those of newborn females, and these sex differences persist through the lifespan. The OAEs of nonheterosexual females also are weaker than those of heterosexual females, suggesting an atypically strong exposure to androgens some time early in development. Auditory evoked potentials (AEPs) also exhibit sex differences beginning early in life. Some AEPs are different for heterosexual and nonheterosexual females, and other AEPs are different for heterosexual and nonheterosexual males. Research on non-humans treated with androgenic or anti-androgenic agents also suggests that OAEs are masculinized by prenatal exposure to androgens late in gestation. Collectively, the evidence suggests that prenatal androgens, acting globally or locally, affect both nonheterosexuality and the auditory system. PMID- 21310174 TI - Developmental, sexual and reproductive neuroendocrinology: historical, clinical and ethical considerations. AB - Different milestones have marked the development of the field of neuroendocrinology. This is an essay in which a new direction is proposed; one in which the field is marked more by a concern for ethical considerations than experimental procedures. Among the primary concerns is the need for a national registry for intersex and transsexual cases to follow how they are managed and to assess the long-term results. As in Europe, the data in the registries should be available to qualified and certified researchers and clinicians for analysis. A secondary focus is on the surgery often imposed in cases of intersex. Many current procedures have been found to have negative effects. The overall aim is to provide better management and treatment. Other topics are offered for ethical consideration. PMID- 21310176 TI - The influence of the different inductivity of acetyl phenyl-thiosemicarbazone chitosan on antimicrobial activities. AB - Ten different acetyl phenyl-thiosemicarbazone derivatives of chitosan were synthesized. Their structures were characterized by FT-IR and elemental analysis. The antimicrobial behaviors of CS and its derivatives against four species of bacteria and four crop-threatening pathogenic fungi were investigated in this paper. The results indicated that the antimicrobial activities of acetyl phenyl thiosemicarbazone derivatives are much better than that of pure CS. The minimum value of MIC and MBC of the derivatives against Escherichia coli was 7.03 and 225 MUg mL(-1), respectively. All of the derivatives had significant inhibiting effect on the investigated fungi in the concentration of 50-500 MUg mL(-1), and the maximum inhibitory index was 93.10%. The bioactivities of the derivatives have relationship with the grafted groups with different inductivity. PMID- 21310175 TI - Prediction of protein-protein interactions between human host and a pathogen and its application to three pathogenic bacteria. AB - Molecular understanding of disease processes can be accelerated if all interactions between the host and pathogen are known. The unavailability of experimental methods for large-scale detection of interactions across host and pathogen organisms hinders this process. Here we apply a simple method to predict protein-protein interactions across a host and pathogen organisms. We use homology detection approaches against the protein-protein interaction databases, DIP and iPfam in order to predict interacting proteins in a host-pathogen pair. In the present work, we first applied this approach to the test cases involving the pairs phage T4 -Escherichia coli and phage lambda -E. coli and show that previously known interactions could be recognized using our approach. We further apply this approach to predict interactions between human and three pathogens E. coli, Salmonella enterica typhimurium and Yersinia pestis. We identified several novel interactions involving proteins of host or pathogen that could be thought of as highly relevant to the disease process. Serendipitously, many interactions involve hypothetical proteins of yet unknown function. Hypothetical proteins are predicted from computational analysis of genome sequences with no laboratory analysis on their functions yet available. The predicted interactions involving such proteins could provide hints to their functions. PMID- 21310177 TI - Probabilistic neural networks for diagnosis of Alzheimer's disease using conventional and wavelet coherence. AB - Recently, the authors presented an EEG (electroencephalogram) coherence study of the Alzheimer's disease (AD) and found statistically significant differences between AD and control groups. In this paper a probabilistic neural network (PNN) model is presented for classification of AD and healthy controls using features extracted in coherence and wavelet coherence studies on cortical connectivity in AD. The model is verified using EEGs obtained from 20 AD probable patients and 7 healthy/control subjects based on a standard 10-20 electrode configuration on the scalp. It is shown that extracting features from EEG sub-bands using coherence, as a measure of cortical connectivity, can discriminate AD patients from healthy controls effectively when a mixed band classification model is applied. For the data set used a classification accuracy of 100% is achieved using the conventional coherence and a spread parameter of the Gaussian function in a particular range found in this research. PMID- 21310178 TI - Culturing conditions remarkably affect viability and organization of mouse subventricular zone in ex vivo cultured forebrain slices. AB - Mammalian neurogenic sites are good models for physiological neural cell renewal in the perspective of brain repair. Yet, investigating their stem cell niches is not easy since they are small areas deeply hidden in the brain hemispheres. Organotypic slices could be a useful tool since they substantially retain the three-dimensional tissue organization. The postnatal forebrain subventricular zone (SVZ), as a dynamic structure endowed with proliferation and migration, might undergo striking cellular changes in culture. Literature concerning this ex vivo approach applied to SVZ neurogenic activity and response to damage is scarce and heterogeneous, not considering the fine cellular composition of the slice and not taking into account the modifications occurring as a consequence of the culture conditions. Our aim was to describe in detail what happens in the SVZ when establishing an ex vivo model. We addressed the changes occurring in five day-old, postnatal mice forebrain organotypic slices cultured for several days in vitro, by using confocal and ultrastructural analyses. We found that during the first two days in vitro the slices undergo progressive structural disaggregation accompanied by remarkable increase in cell proliferation and death with respect to basal levels. In addition, these facts occur in parallel with strong activation of astrocytic cells and microglia. Our results highlight technical limits in the use of forebrain organotypic slices for studying the activity of SVZ neurogenic niche, indicating that they can be reliable for a very short time (1-2 days) and could be misleading when addressing lesion-induced responses. PMID- 21310179 TI - An extended model of intracranial latency facilitates non-invasive detection of cerebrovascular changes. AB - A method has been recently developed to reduce the confounding factors of extracranial origins on the intracranial latency (the time interval between the electrocardiogram QRS component and the initial inflection of the resulting pulse). Although, the proposed model was shown to portray a better characterization of cerebral vasculature, the parameters of the model and their physiological interpretations have not been fully explored. The present work improves the physiological understanding of these parameters, refines the model and extends its ability to monitor real-time changes in overall cerebrovascular resistance. We show that the slope of the linear model which relates the latency of arterial blood pressure to that of the cerebral blood flow velocity, could be a measure of resistance, and that the intercept is a function of slope and pre ejection period. A dataset of cerebral blood flow velocity and arterial blood pressure signals from 18 normal subjects at rest was used to validate the derived parameters of the model. Also, the results of further data processing verified our hypothesis that the slope of the model would significantly increase during a period of CO2 rebreathing, due to dilation of the vessels and reduction of cerebrovascular resistance (p <= 0.02). Finally as the slope of the proposed model is shown to be highly correlated with other conventional measures of cerebrovascular resistance, (resistance area product and critical closing pressure), we conclude that the derived slope metric is a measure of overall cerebrovascular resistance and therefore could be useful in guiding the non invasive cerebrovascular management of patients. PMID- 21310180 TI - Death of photoreceptors in organotypic retinal explant cultures: implication of rhodopsin accumulation and endoplasmic reticulum stress. AB - Here we suggest that endoplasmic reticulum (ER)-stress may be induced following aberrant rhodopsin accumulation in photoreceptors in explanted rat retinas. Rhodopsin accumulation was accompanied by increased phosphorylation of pancreatic ER-kinase and eukaryotic initiator factor 2alpha as well as increased levels of C/EBP homologous protein, glucose-regulated protein 78 and eventually increased cleaved caspase-12 and cleaved caspase-3. Glucose-regulated protein 78, pancreatic ER-kinase, caspase-12 and cleaved caspase-3 were present in photoreceptors, indicating that ER-stress and apoptosis are induced in this cell population. These results suggest that ER-stress and subsequent apoptosis is induced in healthy photoreceptors, presumably by aberrant accumulation of rhodopsin and the phosphorylation of eukaryotic initiator factor 2alpha. The explant culture system may allow investigations of neuroprotective strategies. PMID- 21310181 TI - Electrochemical detection of endogenous glutamate release from rat spinal cord organotypic slices as a real-time method to monitor excitotoxicity. AB - Excessive release of glutamate is believed to be a major component of cell damage following excitotoxicity associated with acute spinal cord injury. Using an in vitro model of excitotoxicity evoked by kainate on rat organotypic spinal slice cultures, we investigated the timecourse and extent of endogenous glutamate release following 1h application of kainate using a commercially available biosensor placed on the ventral horn area of such slices. The release of glutamate peaked 7 min from the start of kainate (0.5 mM) application and then slowly declined to baseline prior to kainate washout. A lower concentration of kainate (0.1 mM) induced a smaller release that developed more slowly. At the end of each experiment, the number of pyknotic nuclei was counted to quantify cell death that was found to be about 10% of the total population with no significant neuronal loss. This finding accords with previous studies showing that, on the basis of neuronal counts at various times after kainate application, neuronal death was delayed. The present data demonstrate that a glutamate biosensor can be employed for real-time monitoring of endogenous glutamate release from an in vitro model of acute spinal cord injury applied to organotypic slices. This method can, therefore, be useful to study the cellular action of neuroprotective drugs targeting glutamate release mechanisms. PMID- 21310182 TI - Autofluorescent cells in rat brain can be convincing impostors in green fluorescent reporter studies. AB - Cell transplant and gene therapies are promising approaches to many disorders of the nervous system. In studies involving cell transplants to the brain or nervous system, expression of green fluorescent protein (GFP) is commonly used to label cells, allowing their identification and histological assessment even after long post-operative survival times. Techniques employing viral tracing or reporter genes also commonly use GFP to label cells. Here, we document the presence of a subpopulation of green autofluorescent cells in the cortex and hippocampus of formaldehyde fixed, cryosectioned rat brains aged 3-9 months. Using standard microscopic fluorescence imaging techniques, we acquired clear images of green autofluorescent cells, complete with extensive processes, which appear to be well integrated into the host tissue. Treatment of brain sections with sodium borohydride followed by cupric sulfate in ammonium acetate buffer reduced background and cellular autofluorescence throughout sections but, especially in hippocampus, did not eliminate considerable green fluorescence in a subset of neurons. This autofluorescence was weak and would therefore pose a problem only when cells weakly express GFP or when few labeled cells survive. We suggest that investigators be aware of the potential for false positives, especially if the cells expressing GFP are expected to migrate widely from the transplant site. Parallel sections from naive brains should regularly be processed and imaged alongside experimental brain sections, and anti-GFP immunohistochemistry should be performed to ensure that true GFP+ signals are imaged instead of endogenous autofluorescent neurons. PMID- 21310183 TI - A humanised murine monoclonal antibody with broad serogroup specificity protects mice from challenge with Venezuelan equine encephalitis virus. AB - In murine models of Venezuelan equine encephalitis virus (VEEV) infection, the neutralising monoclonal antibody 1A3B-7 has been shown to be effective in passive protection from challenge by the aerosol route with serogroups I, II and Mucambo virus (formally VEE complex subtype IIIA). This antibody is able to bind to all serogroups of the VEEV complex when used in ELISA and therefore is an excellent candidate for protein engineering in order to derive a humanised molecule suitable for therapeutic use in humans. A Complementarity Determining Region (CDR) grafting approach using human germline IgG frameworks was used to produce a panel of humanised variants of 1A3B-7, from which a single candidate molecule with retained binding specificity was identified. Evaluation of humanised 1A3B-7 (Hu1A3B-7) in in vitro studies indicated that Hu1A3B-7 retained both broad specificity and neutralising activity. Furthermore, in vivo experiments showed that Hu1A3B-7 successfully protected mice against lethal subcutaneous and aerosol challenges with VEEV strain TrD (serogroup I). Hu1A3B-7 is therefore a promising candidate for the future development of a broad-spectrum antiviral therapy to treat VEEV disease in humans. PMID- 21310184 TI - Behavioral profile and Fos activation of serotonergic and non-serotonergic raphe neurons after central injections of serotonin in the pigeon (Columba livia). AB - Central injections of serotonin (5-HT) in food-deprived/refed pigeons evoke a sequence of hypophagic, hyperdipsic and sleep-like responses that resemble the postprandial behavioral sequence. Fasting-refeeding procedures affect sleep and drinking behaviors "per se". Here, we describe the behavioral profile and long term food/water intake following intracerebroventricular (ICV) injections of 5-HT (50, 150, 300 nmol/2 MUl) in free-feeding/drinking pigeons. The patterns of Fos activity (Fos+) in serotonergic (immunoreactive to tryptophan hydroxylase, TPH+) neurons after these treatments were also examined. 5-HT ICV injections evoked vehement drinking within 15 min, followed by an intense sleep. These effects did not extend beyond the first hour after treatment. 5-HT failed to affect feeding behavior consistently. The density of double-stained (Fos+/TPH+) cells was examined in 6 brainstem areas of pigeons treated with 5-HT (5-HTW) or vehicle. Another group received 5-HT and remained without access to water during 2h after treatment (5-HTO). In the pontine raphe, Fos+ density correlated positively to sleep, and increased in both the 5-HTW and 5-HTO animals. In the n. linearis caudalis, Fos+ and Fos+/TPH+ labeling was negatively correlated to sleep and was reduced in 5-HTO animals. In the A8 region, Fos+/TPH+ labeling was reduced in 5 HTW and 5-HTO animals, was positively correlated to food intake and negatively correlated to sleep. These data indicate that hyperdipsic and hypnogenic effects of ICV 5-HT in pigeons may result from the inhibition of a tonic activity of serotonergic neurons, which is possibly relevant to the control of postprandial behaviors, and that these relationships are shared functional traits of the serotonergic circuits in amniotes. PMID- 21310185 TI - Frequency-induced changes in interlimb interactions: increasing manifestations of closed-loop control. AB - In bimanual coordination, interactions between the limbs result in attraction to in-phase and antiphase coordination. Increasing movement frequency leads to decreasing stability of antiphase coordination, often resulting in a transition to the more stable in-phase pattern. It is unknown, however, how this frequency induced loss of stability is engendered in terms of the interlimb interactions underwriting bimanual coordination. The present study was conducted to help resolve this issue. Using an established method (based on comparison of various unimanual and bimanual tasks involving both passive and active movements), three sources of interlimb interaction were dissociated: (1) integrated timing of feedforward signals, (2) afference-based correction of relative phase errors, and (3) phase entrainment by contralateral afference. Results indicated that phase entrainment strength remained unaffected by frequency and that the stabilizing effects of error correction and integrated timing decreased with increasing frequency. Their contributions, however, reflected an interesting interplay as frequency increased. For moderate frequencies coordinative stability was predominantly secured by integrated timing processes. However, at high frequencies, the stabilization of the antiphase pattern required combined contributions of both integrated timing and error correction. In sum, increasing frequency was found to induce a shift from predominantly open-loop control to more closed-loop control. The results may be accounted for by means of an internal forward model for sensorimotor integration in which the sensory signals are compared to values predicted on the basis of efference copies. PMID- 21310186 TI - Effects of the cognition impairer MK-801 on learning and memory in mice and rats. AB - There is a great need for relevant animal models for investigating the effects of putative pro-cognitive compounds. Compounds that impair learning and/or memory processes without inducing adverse side effects are cognition impairers. Rats and mice with cognitive deficits induced by the prototypical N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 may provide a relevant animal model based on the mechanistic approach of blocking NMDA/glutamatergic signaling. Unfortunately, the dose range over which MK-801 induces cognitive impairment without causing sensory, locomotor, or toxicological side effects is small. We provide an overview of the effects of MK-801 in different cognitive tasks and assessed whether MK-801 reliably affects the cognitive performance of mice or rats in the spatial Morris task, T-maze alternation tasks, and non-spatial passive avoidance, social, and object recognition tasks. MK-801 disrupted or retarded memory acquisition in all tasks. The Morris task, once acquired, was insensitive to MK 801 at a dose up to 0.1 mg kg(-1) body weight. Retention deficits in the passive avoidance tests were not likely to be due to MK-801-induced changes in shock sensitivity, as measured by a shock threshold test. On the basis of published evidence and the present findings, we conclude that MK-801, administered s.c. or i.p. into rodents in doses up to 0.1 mg kg(-1), appears to fulfill the criteria of our definition of a cognition impairer in rodents, without causing sensorimotor impairments and/or signs of intoxication. In addition, MK-801 treated rodents appear to fulfill the criteria of a valid animal model of cognitive dysfunctions, with robust effects across species, housing conditions, and testing paradigms. PMID- 21310187 TI - Facilitation of tactile working memory by top-down suppression from prefrontal to primary somatosensory cortex during sensory interference. AB - Tactile working memory (WM) is improved by increasing top-down suppression of interfering sensory processing in S1 via a link from the middle frontal gyrus (MFG) to S1. Here we studied in healthy subjects whether the efficacy of top-down suppression varies with submodality of sensory interference. Navigated stimulation of the MFG-S1 link significantly improved tactile WM performance when accompanied by tactile but not visual interference of memory maintenance. PMID- 21310188 TI - The COGITAT holeboard system as a valuable tool to assess learning, memory and activity in mice. AB - The comprehensive and stress-free assessment of various aspects of learning and memory is a prerequisite to evaluate mouse models for neuropsychiatric disorders such as Alzheimer's disease or attention deficit/hyperactivity disorder (ADHD). COGITAT is an automated holeboard system allowing simultaneous assessment of spatial working and reference-memory performance which we have adapted in this study to enable its usage with mice. The holeboard apparatus consists of an open field chamber with a 25-hole floor insert, each hole being monitored by infrared light beams, located on three different levels, allowing the distinction between visits of holes, i.e. the animal reaches the bottom of the hole, or inspections, which means only superficial exploration of the hole. Across trials, animals learn a pattern of five baited holes. Here, we show that C57BL/6 mice readily acquire this task within 5 days when submitted to six trials per day. A number of individual parameters - overall exploratory activity, number of visits into or inspections of holes, number of baited, unbaited, or previously baited holes visited or inspected, reinspections of or revisits into any holes, number of pellets eaten, time to find pellets, and reference and working memory errors-are obtained simultaneously and results are immediately available after the end of each experiment. The muscarinic antagonist scopolamine impaired task performance, while the cognitive enhancer metrifonate (an acetylcholinesterase inhibitor) reduced error rates. Overall, our data indicate that this spatial learning task will be useful to characterize spatial memory in various genetic or pharmacological mouse models. PMID- 21310189 TI - Altered prefrontal and insular cortical thickness in adolescent marijuana users. AB - INTRODUCTION: There are limited data regarding the impact of marijuana (MJ) on cortical development during adolescence. Adolescence is a period of substantial brain maturation and cortical thickness abnormalities may be indicative of disruptions of normal cortical development. This investigation applied cortical surface based techniques to compare cortical thickness measures in MJ using adolescents compared to non-using controls. METHODS: Eighteen adolescents with heavy MJ use and 18 non-using controls similar in age received MRI scans using a 3T Siemens scanner. Cortical reconstruction and volumetric segmentation was performed with FreeSurfer. Group differences in cortical thickness were assessed using statistical difference maps covarying for age and gender. RESULTS: Compared to non-users, MJ users had decreased cortical thickness in right caudal middle frontal, bilateral insula and bilateral superior frontal cortices. Marijuana users had increased cortical thickness in the bilateral lingual, right superior temporal, right inferior parietal and left paracentral regions. In the MJ users, negative correlations were found between frontal and lingual regions for urinary cannabinoid levels and between age of onset of use and the right superior frontal gyrus. CONCLUSION: This is one of the first studies to evaluate cortical thickness in a group of adolescents with heavy MJ use compared to non-users. Our findings are consistent with prior studies that documented abnormalities in prefrontal and insular regions. Our results suggest that age of regular use may be associated with altered prefrontal cortical gray matter development in adolescents. Furthermore, reduced insular cortical thickness may be a biological marker for increased risk of substance dependence. PMID- 21310190 TI - Peptides from cytomegalovirus UL130 and UL131 proteins induce high titer antibodies that block viral entry into mucosal epithelial cells. AB - Cytomegalovirus infections are an important cause of disease for which no licensed vaccine exists. Recent studies have focused on the gH/gL/UL128-131 complex as antibodies to gH/gL/UL128-131 neutralize viral entry into epithelial cells. Prior studies have used cells from the retinal pigment epithelium, while to prevent transmission, vaccine-induced antibodies may need to block viral infection of epithelial cells of the oral or genital mucosa. We found that gH/gL/UL128-131 is necessary for efficient viral entry into epithelial cells derived from oral and genital mucosa, that short peptides from UL130 and UL131 elicit high titer neutralizing antibodies in rabbits, and that such antibodies neutralize viral entry into epithelial cells derived from these relevant tissues. These results suggest that single subunits or peptides may be sufficient to elicit potent epithelial entry neutralizing responses and that secretory antibodies to such neutralizing epitopes have the potential to provide sterilizing immunity by blocking initial mucosal infection. PMID- 21310191 TI - Enhanced pneumonia and disease in pigs vaccinated with an inactivated human-like (delta-cluster) H1N2 vaccine and challenged with pandemic 2009 H1N1 influenza virus. AB - Influenza is an economically important respiratory disease affecting swine world wide with potential zoonotic implications. Genetic reassortment and drift has resulted in genetically and antigenically distinct swine influenza viruses (SIVs). Consequently, prevention of SIV infection is challenging due to the increased rate of genetic change and a potential lack of cross-protection between vaccine strains and circulating novel isolates. This report describes a vaccine heterologous challenge model in which pigs were administered an inactivated H1N2 vaccine with a human-like (delta-cluster) H1 six and three weeks before challenge with H1 homosubtypic, heterologous 2009 pandemic H1N1. At necropsy, macroscopic and microscopic pneumonia scores were significantly higher in the vaccinated and challenged (Vx/Ch) group compared to non-vaccinated and challenged (NVx/Ch) pigs. The Vx/Ch group also demonstrated enhanced clinical disease and a significantly elevated pro-inflammatory cytokine profile in bronchoalveolar lavage fluid compared to the NVx/Ch group. In contrast, viral shedding and replication were significantly higher in NVx/Ch pigs although all challenged pigs, including Vx/Ch pigs, were shedding virus in nasal secretions. Hemagglutination inhibition (HI) and serum neutralizing (SN) antibodies were detected to the priming antigen in the Vx/Ch pigs but no measurable cross-reacting HI or SN antibodies were detected to pandemic H1N1 (pH1N1). Overall, these results suggest that inactivated SIV vaccines may potentiate clinical signs, inflammation and pneumonia following challenge with divergent homosubtypic viruses that do not share cross-reacting HI or SN antibodies. PMID- 21310192 TI - 17beta-Estradiol restores antibody responses to an influenza vaccine in a postmenopausal mouse model. AB - Post-menopausal women belong to an age group that is highly susceptible to influenza infection and its most serious complications. However, data on the immunogenicity of influenza vaccines in these women is limited. Therefore, the antibody response to influenza vaccination was assessed in a postmenopausal mouse model. An inactivated-detergent-split vaccine from the A/New Caledonia/20/99 (H1N1) influenza virus strain was given to three groups of mice: ovariectomized (OVEX), OVEX with 17beta-estradiol replacement (OVEX+E2), and sham-OVEX. The OVEX+E2 group produced influenza virus-specific serum antibodies, including neutralizing antibodies, at significantly higher levels (p<0.001) than did OVEX mice. These levels matched those observed in the sham-OVEX group, indicating that ovariectomy negatively modulates the antibody response to the influenza vaccine, whereas 17beta-estradiol replacement restores this response to levels observed in intact animals. Our findings suggest that immunogenicity and efficacy of influenza vaccines need to be evaluated in postmenopausal women, including women receiving hormone replacement therapy. PMID- 21310193 TI - Dense display of HIV-1 envelope spikes on the lambda phage scaffold does not result in the generation of improved antibody responses to HIV-1 Env. AB - The generation of strong, virus-neutralizing antibody responses to the HIV-1 envelope spike (Env) is a major goal in HIV-1 vaccine research. To try to enhance the Env-specific response, we displayed oligomeric gp140 on a virus-like scaffold provided by the lambda phage capsid. To do this, an in vitro complementation system was used to "decorate" phage particles with glycosylated, mammalian cell derived envelope oligomers. We compared the immune response to lambda phage particles displaying HIV-1 Env to that elicited by soluble oligomeric gp140 in rabbits. Env-binding antibody titers were higher in animals that received oligomeric gp140 as compared to Env decorated phage particles, as were virus neutralizing antibody responses. The Env decorated phage particles were, however, able to efficiently boost a protein-primed humoral response to levels equivalent to those elicited by high-dose adjuvanted Env oligomers. These results show that display of HIV-1 envelope spikes on the bacteriophage lambda capsid does not result in an improved, Env-specific humoral immune response. PMID- 21310194 TI - Plasma nociceptin/orphanin FQ levels are lower in patients with chronic ischemic cardiovascular diseases--A pilot study. AB - BACKGROUND: Clinical studies are limited regarding the role of human nociceptin/orphanin FQ (N/OFQ) in ischemic cardiovascular diseases, which are still the number one cause of death in the developed world. The aim of our study was to measure the plasma levels of N/OFQ in patients with chronic ischemic cardiovascular diseases in a pilot study. METHODS AND RESULTS: Our study population consisted of 22 patients presenting symptoms of stable angina pectoris (SAP): 12 severe Canadian Cardiovascular Society (CCS) III-IV functional class, and 10 with milder SAP (CCS II-III). 12 patients were also enrolled with chronic peripheral artery disease (9 with intermittent claudication; 3 with rest pain and gangrene). Patients were asked to avoid any exertion or given analgetics for their rest pain. Patients had no episodes of chest or limb pain in 1week before their fasting blood samples were taken and N/OFQ plasma levels were measured by radioimmunoassay. 14 healthy subjects without any cardiac risk factors served as a control group. CONCLUSIONS: N/OFQ levels were significantly lower in patient groups with severe vs. milder chronic angina (p<0.05) and vs. control subjects (p<0.01). Patients suffering from peripheral artery disease had also a lower plasma N/OFQ levels than in healthy controls (p<0.01). Our findings show that chronic ischemic conditions of atherosclerotic origin are associated with significantly lower plasma N/OFQ levels. PMID- 21310195 TI - Mechanism of 1alpha,25-dihydroxyvitamin D(3)-dependent repression of interleukin 12B. AB - Interleukin 12 (IL-12) is a heterodimeric, pro-inflammatory cytokine that plays a central role in activation and differentiation of CD4(+) T cells into interferon gamma secreting T-helper type 1 cells. IL-12B, a gene encoding the larger subunit of active IL-12, has been reported to be down-regulated by the nuclear hormone 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)), but the mechanism of the regulation is unknown. In this study, we have examined the molecular mechanism of transcriptional regulation of the IL-12B gene by 1alpha,25(OH)(2)D(3) in lipopolysaccharide (LPS)-treated human monocytes (THP-1). Quantitative RT-PCR showed that IL-12B mRNA displays a cyclical expression profile and is down regulated 2.8-fold during the first 8h and even 12.1-fold 24h after exposure to 1alpha,25(OH)(2)D(3). Gel shift and quantitative chromatin immunoprecipitation (ChIP) assays demonstrated vitamin D receptor (VDR) binding to genomic regions 480 and 6300bp upstream of the IL-12B transcription start site (TSS). Quantitative ChIP assays also revealed that together with VDR and its partner RXR the above regions recruited the co-repressor NCOR2/SMRT and histone deacetylase 3 leading to a decreased histone 4 acetylation and increased histone 3 trimethylation at the IL-12B promoter and its TSS. We suggest that these repressive epigenetic changes eventually cause down-regulation of IL-12 expression. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. PMID- 21310196 TI - An SV40 mutant defective in VP4 expression exhibits a temperature-sensitive growth defect. AB - On reexamination of temperature-sensitive D-type (tsD) mutants of simian virus 40 (SV40), we found that the tsD222 mutant is identical to the VP2 M228I mutant, which is defective in VP4 expression, at the nucleotide level. Although a previous study reported that lack of VP4 caused defects in viral dissemination in BSC-1 cells, this mutant showed a temperature-sensitive growth defect in CV-1 cells. tsD101:VP3 Q113K and tsD202:VP3 P108S exhibited a growth phenotype similar to that of tsD222, and they retained the VP4 open reading frame (ORF). These three mutants did not complement each other, suggesting that their defects were functionally indistinguishable. Transduction of the SV40 vector expressing wild type VP4 in tsD222-infected cells did not ameliorate the growth defect at the non permissive temperature. The results indicate that tsD mutation in minor capsid proteins has a more profound impact on viral propagation, and that lack of VP4 ORF seems to have little influence on viral growth. PMID- 21310197 TI - Severe stunting in blackgram caused by the Mungbean yellow mosaic virus (MYMV) KA27 DNA B component is ameliorated by co-infection or post-infection with the KA22 DNA B: MYMV nuclear shuttle protein is the symptom determinant. AB - Mungbean yellow mosaic virus-[India:Vigna] (MYMV-[IN:Vig]), a blackgram isolate of MYMV, has five variable and infective DNA B components of which KA22 and KA27 DNA Bs share only 72% nucleotide sequence identity between them. Agroinoculation of blackgram with partial dimers of DNA A and KA27 DNA B caused severe stunting and an inordinate delay in flowering. Interestingly, co-agroinoculation of KA27+KA22 DNA B components along with DNA A ameliorated severe stunting, rescued from the delay in flowering and caused the appearance of yellow mosaic symptom characteristic of KA22 DNA B. Post-agroinoculation of KA27 DNA B-infected blackgram plants with KA22 DNA B also resulted in the amelioration from severe stunting and in the alleviation from the delay in flowering. Alleviation from KA27 DNA B-type of symptom by co-infection or post-infection with KA22 DNA B did not result in a corresponding reduction in KA27 DNA B levels. Swapping of KA27 DNA B with the nuclear shuttle protein gene (NSP) of KA22 DNA B abolished severe stunting and caused the appearance of mild yellow symptom, suggesting that the NSP is the major symptom determinant in MYMV DNA B. PMID- 21310198 TI - Human cytomegalovirus immediate early gene expression in the osteosarcoma line U2OS is repressed by the cell protein ATRX. AB - The control of human cytomegalovirus (HCMV) immediate early (IE) gene expression in infected human fibroblasts was compared with that in the U2OS human osteosarcoma cells. Viral IE expression was stimulated by the virion protein pp71 and repressed by the cell protein hDaxx in fibroblasts, as expected from published data. Neither of these events occurred in infected U2OS cells, suggesting that this cell line lacks one or more factors that repress HCMV IE expression. The chromatin remodeling factor ATRX is absent from U2OS cells, therefore the effect of introducing this protein by electroporation of plasmid DNA was investigated. Provision of ATRX inhibited HCMV IE expression, and the presence of the HCMV-specified virion phosphoprotein pp71 overcame the repression. The experiments demonstrate that ATRX can act as a cellular intrinsic antiviral defense in U2OS cells by blocking gene expression from incoming HCMV genomes. In contrast, ATRX did not affect the replication of herpes simplex virus type 1, showing that there are differences in the way U2OS cells respond to the presence of the herpesviral genomes. PMID- 21310199 TI - Engineered Tobacco mosaic virus mutants with distinct physical characteristics in planta and enhanced metallization properties. AB - Tobacco mosaic virus mutants were engineered to alter either the stability or surface chemistry of the virion: within the coat protein, glutamic acid was exchanged for glutamine in a buried portion to enhance the inter-subunit binding stability (E50Q), or a hexahistidine tract was fused to the surface-exposed carboxy terminus of the coat protein (6xHis). Both mutant viruses were expected to possess specific metal ion affinities. They accumulated to high titers in plants, induced distinct phenotypes, and their physical properties during purification differed from each other and from wild type (wt) virus. Whereas 6xHis and wt virions contained RNA, the majority of E50Q protein assembled essentially without RNA into rods which frequently exceeded 2 MUm in length. Electroless deposition of nickel metallized the outer surface of 6xHis virions, but the central channel of E50Q rods, with significantly more nanowires of increased length in comparison to those formed in wtTMV. PMID- 21310200 TI - Portal vein thrombosis as complication of romiplostim treatment in a cirrhotic patient with hepatitis C-associated immune thrombocytopenic purpura. AB - BACKGROUND & AIMS: Thrombopoietin receptor agonists are a new class of compounds licenced for the treatment of immune thrombocytopenic purpura. They are currently being studied for patients with thrombopenia in advanced liver disease or under therapy for hepatitis C. There are indications that the risk for development of portal vein thrombosis in patients with advanced liver cirrhosis might be increased under therapy with thrombopoietin receptor agonists. We report a case of a patient with Child class B liver cirrhosis with concurrent immune thrombocytopenic purpura that developed portal vein thrombosis under therapy with the thrombopoietin receptor agonist romiplostim. METHODS: A 50-year-old woman with hepatitis C virus associated immune thrombocytopenic purpura and Child class B liver cirrhosis presented in our emergency with rapidly evolving hydropic decompensation and general malaise. For immune thrombocytopenic purpura, the patient was started on the thrombopoietin receptor agonist romiplostim nine months ago. RESULTS: During hospitalization, the platelet count was measured above 330,000/MUl and partial portal vein thrombosis was diagnosed by imaging studies. The thrombotic event was assumed to be associated with the romiplostim treatment for immune thrombocytopenic purpura via excessive elevation of platelet count. After anticoagulation with heparin and cessation of romiplostim treatment, complete recanalisation of the portal vein was achieved. CONCLUSIONS: We conclude that romiplostim should be used with precaution in patients with hepatitis C associated immune thrombocytopenic purpura and advanced liver cirrhosis as the risk for thrombotic complications may increase significantly. PMID- 21310201 TI - Development and validation of a short, consumer-oriented nutrition knowledge questionnaire. AB - A short scale was developed and validated that assesses consumers' knowledge about nutrition. Sixty-four nutrition knowledge items were derived from consumer interviews and expert recommendations about healthy eating. Items were administered as a postal survey to a sample of consumers randomly drawn from the directory (response rate=37%, N=1043). Twenty items were retained to build the final nutrition knowledge scale. Internal reliability, criterion and construct validity were acceptable. Associations of the scale with self-reported food consumption frequencies indicated limited correlation of nutrition knowledge with food choice. Widespread nutrition knowledge gaps in consumers were revealed. PMID- 21310202 TI - Effects of JBP485 on the expression and function of PEPT1 in indomethacin-induced intestinal injury in rats and damage in Caco-2 cells. AB - To investigate the effect of JBP485 (an anti-inflammatory dipeptide) on PEPT1 in indomethacin-induced intestinal injury in rats and damage in Caco-2 cells, the activity and expression of PEPT1 were examined. The effects of treatment with indomethacin and co-treatment with JBP485 were examined in terms of intestinal histological changes, MDA and MPO levels in rats; as well as LDH-release and oxidative stress in Caco-2 cells. Uptake of glycylsarcosine (Gly-Sar) by PEPT1 was determined by in vivo, in vitro and in situ studies. RT-PCR and Western blot were used to assess the expression of PEPT1 in rat intestine and Caco-2 cells. JBP485 caused a significant decrease in MDA and MPO levels, and improved the pathological condition of rat intestine, while attenuating Caco-2 cells damage induced by indomethacin. Uptake of Gly-Sar by PEPT1 was decreased by indomethacin treatment, whereas the Gly-Sar plasma concentration was markedly increased in JBP485 co-treated rats. Indomethacin down-regulated the expression of PEPT1 mRNA and protein in rat intestine and Caco-2 cells, and the effects were reversed after administration of JBP485. These results indicated that JBP485 not only improved intestinal injury and cell damage but also partially blocked the down regulation of PEPT1 expression and function induced by indomethacin. PMID- 21310203 TI - Oxytocin, but not arginine vasopressin is involving in the antinociceptive role of hypothalamic supraoptic nucleus. AB - Our previous study has demonstrated that the hypothalamic supraoptic nucleus (SON) plays a role in pain modulation. Oxytocin (OXT) and arginine vasopressin (AVP) are the important hormones synthesized and secreted by the SON. The experiment was designed to investigate which hormone was relating with the antinociceptive role of the SON in the rat. The results showed that (1) microinjection of L-glutamate sodium into the SON increased OXT and AVP concentrations in the SON perfusion liquid, (2) pain stimulation induces OXT, but not AVP release in the SON, and (3) intraventricular injection (pre-treatment) with OXT antiserum could inhibit the pain threshold increase induced by SON injection of L-glutamate sodium, but administration of AVP antiserum did not influence the antinociceptive role of SON stimulation. The data suggested that the antinociceptive role of the SON relates to OXT rather than AVP. PMID- 21310204 TI - Preliminary analgesic properties of deltorphin-5-methoxytryptamine chimeric opioid peptides. AB - To further understand the relationship between melatonin (MT) and deltorphins (Dels) in pain modulation, two chimeric peptides (Del I-5-methoxytryptamine and Del II-5-methoxytryptamine) both containing 5-methoxytryptamine at the carboxyl terminal of Dels mimicking MT were designed, synthesized and characterized by tail-flick assay in mice. Results showed that intracerebroventricular (i.c.v.) administration of Del I-5-methoxytryptamine (YaFDVVG-X, X is 5-methoxytryptamine, 5, 50 nmol/kg) or Del II-5-methoxytryptamine (YaFEVVG-X, X is 5 methoxytryptamine, 5, 50 nmol/kg) produced stronger analgesia than deltorphins (Del I or Del II alone), and acting even longer and stronger than cocktails containing Del I or Del II (50 nmol/kg) and MT (50 nmol/kg). Naloxone (i.p., 100 nmol/kg) could totally block the analgesic effects induced by the chimeric peptides, while luzindole (specific antagonist of melatonin receptor, i.p., 250 nmol/kg) could only partially inhibit the effects down to that induced by Dels alone. Interestingly, Del I-5-methoxytryptamine and Del II-5-methoxytryptamine act weaker with delta receptor than Dels in vitro but could induce much longer analgesia through co-activating delta opioid receptor and melatonin receptor. PMID- 21310205 TI - Predictive models for nanotoxicology: current challenges and future opportunities. AB - Characterizing the risks posed by nanomaterials is extraordinarily complex because these materials can have a wide range of sizes, shapes, chemical compositions and surface modifications, all of which may affect toxicity. There is an urgent need for a testing strategy that can rapidly and efficiently provide a screening approach for evaluating the potential hazard of nanomaterials and inform the prioritization of additional toxicological testing where necessary. Predictive toxicity models could form an integral component of such an approach by predicting which nanomaterials, as a result of their physico-chemical characteristics, have potentially hazardous properties. Strategies for directing research towards predictive models and the ancillary benefits of such research are presented here. PMID- 21310206 TI - Eye irritation potential: usefulness of the HET-CAM under the Globally Harmonized System of classification and labeling of chemicals (GHS). AB - Extensive research has been conducted over the past decades to develop alternatives to the rabbit eye irritation test (Draize test) used in a regulatory context to assess eye irritation potentials. Although no single in vitro test has emerged as being completely acceptable for full replacement, various tests are considered to be suitable and are regularly used to assess certain aspects. Amongst these, the Hen's Egg Test Chorioallantoic Membrane (HET-CAM) has gained regulatory acceptance in various countries to classify severe eye irritants. In this retrospective study, historical eye irritation data (in vivo and in vitro) from 137 samples (approx. 75% non-irritants; 25% (severe) irritants) tested both in the HET-CAM and Draize eye test was compared with regard to the predicted eye irritation classes under the GHS and the traditional EU classification system (DSD).The overall concordance was in the range of 80-90%. A high specificity (96 98%, depending on the classification system and the chosen discrimination) but rather low sensitivity (48-65%) was observed. The study indicates that HET-CAM results are useful as part of weight-of-evidence assessments or in tiered approaches to assess eye irritation potentials rather than as stand-alone classification method. PMID- 21310207 TI - The antihyperglycemic effect of curcumin in high fat diet fed rats. Role of TNF alpha and free fatty acids. AB - This study was conducted to investigate the effect of curcumin, obtained from Curcuma longa, in comparison with rosiglitazone on the progression of insulin resistance and type 2 diabetes mellitus (T2DM) and the mechanisms underlying this effect. Insulin resistance and T2DM was induced in male Sprague Dawley rats by high fat diet (HFD) feeding for 60 and for 75 days representing two regimens of the study, protection and treatment. Prophylactic oral administration of curcumin (80 mg/kg), rosiglitazone (1 mg/kg), their combination, or vehicle (in control groups) was started along with HFD feeding in different groups. Treatment is achieved by oral administration of the previously mentioned agents in the last 15 days of HFD feeding after induction of insulin resistance and T2DM in rats. Curcumin showed an anti-hyperglycemic effect and improved insulin sensitivity, and this action may be attributed at least in part to its anti-inflammatory properties as evident by attenuating TNF-alpha levels in HFD fed rats, and its anti-lipolytic effect as evident by attenuating plasma free fatty acids. The curcumin effects are comparable to those of rosiglitazone, which indicate that they may act similarly. Finally we can say that, curcumin could be a beneficial adjuvant therapy in patients with T2DM. PMID- 21310208 TI - The antioxidant activity of vitamin C, DPPD and L-cysteine against Cisplatin induced testicular oxidative damage in rats. AB - Oxidative stress has been proven to be involved in cisplatin (CP)-induced toxicity. The present study was designed to evaluate the antioxidant activity of Vit C, N,N'-diphenyl-p-phenylenediamine (DPPD) and L-cysteine against CP-induced testicular oxidative damage in rats. Our data indicated significant increases in lipid peroxides (LPO), total peroxides and superoxide anion levels in testes of rats treated with CP (2 mg/kg/week, for 4 weeks) that was associated with a significant reduction in the activity of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione S-transferase (GST). The contents of glutathione (GSH), Vit E and Vit C were significantly lower in CP treated testes compared with these of control. The co-administration of CP with DPPD or L cysteine significantly reduced the elevation in LPO, however the co administration of CP with Vit C, DPPD or L-cysteine reduced the effect of CP on superoxide anion and antioxidant enzymes and also on the antioxidants contents. The administration of Vit C, DPPD or L-cysteine before CP injection improved the histological pictures and reduced the number of apoptotic cells and DPPD was more efficient. In conclusion, DPPD is a potent antioxidant, against CP-induced testicular oxidative damage, as compared with Vit C and L-cysteine. PMID- 21310209 TI - Antioxidant activity, acetylcholinesterase inhibition, iridoid content and mutagenic evaluation of Leucosidea sericea. AB - Leucosidea sericea is an important medicinal plant widely used in traditional medicine in southern Africa. Leaf and stem petroleum ether (PE), dichloromethane (DCM) and 50% aqueous methanol (MeOH) extracts were investigated for antioxidant and acetylcholinesterase inhibitory activities. The safety of the extracts was evaluated using the Ames test. In addition, the iridoid content of L. sericea stems and leaves were quantified. For DPPH radical-scavenging activity, the stem MeOH extract (EC(50) value: 1.6 MUg/ml) was more potent than ascorbic acid (EC(50) value: 1.7 MUg/ml). In the beta-carotene-linoleic acid model system, antioxidant activity of the leaf DCM extract (89.8%) was not significantly different to that of butylated hydroxytoluene (BHT) (98.9%). All extracts showed a dose-dependent acetylcholinesterase inhibition; in terms of the IC(50) value, the leaf DCM extract (0.14 mg/ml) was the most potent sample. Total iridoid content was 35% higher in the stem extract than in the leaf extract. Based on the Ames test, L. sericea extracts were not mutagenic, either with or without S9 metabolic activation. These findings suggest the safety as well as the potential of L. sericea as a possible source of novel/alternative antioxidant and acetylcholinesterase inhibitory compounds. PMID- 21310210 TI - Preventing distraction: assessing stimulus-specific and general effects of the predictive cueing of deviant auditory events. AB - Rare irregular sounds (deviants) embedded into a regular sound sequence have large potential to draw attention to themselves (distraction). It has been previously shown that distraction, as manifested by behavioral response delay, and the P3a and reorienting negativity (RON) event-related potentials, could be reduced when the forthcoming deviant was signaled by visual cues preceding the sounds. In the present study, we investigated the type of information used in the prevention of distraction by manipulating the information content of the visual cues preceding the sounds. Cues could signal the specific variant of the forthcoming deviant, or they could just signal that the next tone was a deviant. We found that stimulus-specific cue information was used in reducing distraction. The results also suggest that early P3a and RON index processes related to the specific deviating stimulus feature, whereas late P3a reflects a general distraction-related process. PMID- 21310211 TI - Adaptor protein Lnk binds to PDGF receptor and inhibits PDGF-dependent signaling. AB - OBJECTIVE: Platelet-derived growth factor receptors alpha and beta (PDGFRA, PDGFRB) are frequently expressed on hematopoietic cells and regulate cellular responses such as proliferation, differentiation, survival, and transformation. Stimulation by autocrine loops or activation by chromosomal translocation makes them important factors in development of hematopoietic disorders. Interaction with the ligand PDGF results in activation of the tyrosine kinase domain and phosphorylation of tyrosine residues, thereby creating binding sites for molecules containing Src homology 2 domains. We hypothesized that one such protein may be Lnk, a negative regulator of cytokine receptors, including Mpl, EpoR, c-Kit, and c-Fms. MATERIALS AND METHODS: Interaction of Lnk with PDGFRA, PDGFRB, or leukemogenic FIP1L1-PDGFRA or TEL-PDGFRB was studied in cotransfected 293T cells. Effects of Lnk on PDGFR signaling were shown in 293T and NIH3T3 cells, whereas its influence on either PDGF-dependent or factor-independent growth was investigated using Ba/F3 or 32D cells expressing wild-type PDGFR, FIP1L1-PDGFRA, or TEL-PDGFRB. RESULTS: We show that Lnk binds to PDGFR after exposure of cells to PDGF. Furthermore, Lnk can bind the FIP1L1-PDGFRA fusion protein. Mutation or deletion of the Lnk Src homology 2 domain completely abolished binding of Lnk to FIP1L1-PDGFRA, but just partly prevented binding to PDGFRA or PDGFRB. Expression of Lnk inhibited proliferation of PDGF-dependent Ba/F3 cells and diminished phosphorylation of Erk in PDGF-treated NIH3T3. 32D cells transformed by either FIP1L1-PDGFRA or TEL-PDGFRB stopped growing when Lnk was expressed. CONCLUSIONS: Lnk is a negative regulator of PDGFR signaling. Development of Lnk mimetic drugs might provide a novel therapeutic strategy for myeloproliferative disorders. PMID- 21310212 TI - Treadmill step training-induced adaptive muscular plasticity in a chronic paraplegia model. AB - The purpose of this study was to provide evidence that treadmill step training is capable of attenuating muscle atrophy and may regulate brain derived neurotrophic factor (BDNF) in soleus muscle after complete spinal cord transection (SCT) at T8 T9 in rats. Five days after SCT, spinal animals started a 9-week step-training program on a treadmill with partial body weight support and manual step help. The muscular trophism was studied by analyzing muscle weight and myofiber cross sectional area of the soleus, while Western blot analysis was used to detect BDNF expression in the same muscle. Step training, initiated immediately after SCT in rats, may partially impede/revert muscular atrophy in chronic paralyzed soleus muscle. Moreover, treadmill step training promoted upregulation of the BDNF in soleus muscle, which was positively correlated with muscle weight and myofiber cross-sectional size. These findings have important implications for the comprehension of the neurobiological substrate that promotes exercise-induced effects on paralyzed skeletal muscle and suggests treadmill training is a viable therapeutic approach in spinal cord injuries. PMID- 21310213 TI - Left-lateralized early neurophysiological response for Chinese characters in young primary school children. AB - Adult readers consistently show an enhanced early event-related potential (ERP) response, N170, for visual words compared with other stimuli at left posterior electrodes. Developmental studies with words in alphabetic languages showed that this neurophysiological specialization for print develops rapidly from 6 to 10 years of age and becomes established around 10-11 years of age. Here we report for the first time the development of the word-related N170 in Chinese children learning to read Chinese, a logographic writing system radically different from alphabetic scripts in visual and linguistic features. We recorded ERP responses elicited by Chinese characters and line drawings of common objects in three groups of primary school children at 7, 9, and 11 years of age as well as college students. Results showed that the amplitude of N170 evoked by Chinese characters in the 7-year-old group was significantly larger than that in the 11-year-old group and the adult readers. Remarkably, all four age groups - even the youngest group - showed an increased and left-lateralized N170 response for Chinese characters, as compared with line drawings, suggesting that a relatively specialized mechanism for processing Chinese characters is already emergent by as early as 7 years of age. Our results, combined with studies of non-Chinese child readers suggest that the developmental pattern of word-related N170 is highly similar across different scripts, possibly reflecting increased visual processing expertise that children acquire through everyday reading. PMID- 21310214 TI - Colocalisation of plasma derived apo B lipoproteins with cerebral proteoglycans in a transgenic-amyloid model of Alzheimer's disease. AB - Alzheimer's disease (AD) is characterized by cerebral proteinaceous deposits comprised of amyloid beta (Abeta). Evidence suggests that enhanced blood-to-brain delivery of Abeta occurs when plasma concentration is increased, exacerbating amyloidosis. In blood, significant Abeta is associated with apolipoprotein (apo) B lipoproteins. In this study, immunofluorescent microscopy was utilised to explore if there is an association between apo B lipoproteins and proteoglycan expression within Abeta-rich plaques in transgenic-amyloid mice. Focal accumulation of apo B was found with Abeta-plaque in APP/PS1 mice. There was enrichment in the proteoglycans, agrin, perlecan, biglycan and decorin within the core of dense Abeta-plaque. Perlecan, biglycan and decorin were positively associated with apo B lipoprotein abundance within amyloid plaque consistent with a cause-for-retention effect. These findings show that proteoglycans are an integral component of Abeta deposits in APP/PS1 mice. This study suggests that some proteoglycans contribute to Abeta retention, whilst other proteoglycans have different functions in the aetiology of AD. PMID- 21310215 TI - Cognitive integration of asynchronous natural or non-natural auditory and visual information in videos of real-world events: an event-related potential study. AB - In this paper, we aim to study the cognitive integration of asynchronous natural or non-natural auditory and visual information in videos of real-world events. Videos with asynchronous semantically consistent or inconsistent natural sound or speech were used as stimuli in order to compare the difference and similarity between multisensory integrations of videos with asynchronous natural sound and speech. The event-related potential (ERP) results showed that N1 and P250 components were elicited irrespective of whether natural sounds were consistent or inconsistent with critical actions in videos. Videos with inconsistent natural sound could elicit N400-P600 effects compared to videos with consistent natural sound, which was similar to the results from unisensory visual studies. Videos with semantically consistent or inconsistent speech could both elicit N1 components. Meanwhile, videos with inconsistent speech would elicit N400-LPN effects in comparison with videos with consistent speech, which showed that this semantic processing was probably related to recognition memory. Moreover, the N400 effect elicited by videos with semantically inconsistent speech was larger and later than that elicited by videos with semantically inconsistent natural sound. Overall, multisensory integration of videos with natural sound or speech could be roughly divided into two stages. For the videos with natural sound, the first stage might reflect the connection between the received information and the stored information in memory; and the second one might stand for the evaluation process of inconsistent semantic information. For the videos with speech, the first stage was similar to the first stage of videos with natural sound; while the second one might be related to recognition memory process. PMID- 21310216 TI - Attentional modulation of the somatosensory mu rhythm. AB - Neural oscillations with a frequency of around 10 Hz are thought to be a ubiquitous phenomenon in sensory cortices, and it has been hypothesized that the level of 10 Hz activity is related to local cortical excitability. During spatial attention, the visual alpha rhythm has been found to be modulated according to the direction of attention. Specifically, the alpha rhythm desynchronizes over visual cortex contralateral to the direction of attention and synchronizes over visual cortex ipsilateral to the direction of attention, and these modulations have been associated with facilitation and inhibition of sensory processing. In the somatosensory domain, the reactivity of a similar rhythm, known as the mu rhythm, during attention tasks is a current topic of inquiry and somatotopic modulation of the mu rhythm by directed attention have been reported. In this paper, we investigate how lateralized spatial attention modulates the ongoing somatosensory mu rhythm, and how such modulation impacts sensory information processing. 128 channel EEG was recorded while subjects performed a somatosensory spatial attention task. In addition to analyses on scalp recorded data, a spatial filtering method was utilized to investigate spatial attention effects in the source space. The direction of spatial attention was found to have a significant somatotopic effect on the ongoing mu rhythm occurring in primary somatosensory cortex. Concurrently, the visual alpha rhythm was significantly elevated above the baseline level during somatosensory attention, demonstrating a cross-modal effect. Lastly, an analysis was performed to investigate the correlation between the level of prestimulus mu activity and subsequent stimulus evoked activity in primary somatosensory cortex. PMID- 21310218 TI - Changes in intracellular protein expression in cortex, thalamus and hippocampus in a genetic rat model of absence epilepsy. AB - Epilepsy is a chronic disorder characterized by repeated seizures resulting from abnormal activation of neurons in the brain. Although mutations in genes related to Na(+), K(+), Ca(2+) channels have been defined, few studies show intracellular protein changes. We have used proteomics to investigate the expression of soluble proteins in a genetic rat model of absence epilepsy "Genetic Absence Epilepsy Rats from Strasbourg (GAERS)". The advantage of this technique is its high throughput quantitative and qualitative detection of all proteins with their post translational modifications at a given time. The parietal cortex and thalamus, which are the regions responsible for the generation of absence seizures, and the hippocampus, which is not involved in this activity, were dissected from GAERS and from non-epileptic control rat brains. Proteins from each tissue sample were isolated and separated by two-dimensional gel electrophoresis. Spots that showed significantly different levels of expression between controls and GAERS were identified by nano LC-ESI-MS/MS. Identified proteins were: ATP synthase subunit delta and the 14-3-3 zeta isoform in parietal cortex; myelin basic protein and macrophage migration inhibitory factor in thalamus; and macrophage migration inhibitory factor and 0-beta 2 globulin in hippocampus. All protein expressions were up-regulated in GAERS except 0-beta globulin. These soluble proteins are related to energy generation, signal transduction, inflammatory processes and membrane conductance. These results indicate that not only membrane proteins but also cytoplasmic proteins may take place in the pathophysiology and can be therapeutic targets in absence epilepsy. PMID- 21310217 TI - Salicylate-induced peripheral auditory changes and tonotopic reorganization of auditory cortex. AB - The neuronal mechanism underlying the phantom auditory perception of tinnitus remains elusive at present. For over 25 years, temporary tinnitus following acute salicylate intoxication in rats has been used as a model to understand how a phantom sound can be generated. Behavioral studies have indicated that the pitch of salicylate-induced tinnitus in the rat is approximately 16 kHz. In order to better understand the origin of the tinnitus pitch measurements were made at the levels of auditory input and output; both cochlear and cortical physiological recordings were performed in ketamine/xylazine anesthetized rats. Both compound action potentials and distortion product otoacoustic emission measurements revealed a salicylate-induced band-pass-like cochlear deficit in which the reduction of cochlear input was least at 16 kHz and significantly greater at high and low frequencies. In a separate group of rats, frequency receptive fields of primary auditory cortex neurons were tracked using multichannel microelectrodes before and after systemic salicylate treatment. Tracking frequency receptive fields following salicylate revealed a population of neurons that shifted their frequency of maximum sensitivity (i.e. characteristic frequency) towards the tinnitus frequency region of the tonotopic axis (~16 kHz). The data presented here supports the hypothesis that salicylate-induced tinnitus results from an expanded cortical representation of the tinnitus pitch determined by an altered profile of input from the cochlea. Moreover, the pliability of cortical frequency receptive fields during salicylate-induced tinnitus is likely due to salicylate's direct action on intracortical inhibitory networks. Such a disproportionate representation of middle frequencies in the auditory cortex following salicylate may result in a finer analysis of signals within this region which may pathologically enhance the functional importance of spurious neuronal activity concentrated at tinnitus frequencies. PMID- 21310219 TI - Using differential reinforcement to improve equine welfare: shaping appropriate truck loading and feet handling. AB - Inappropriate behavior during common handling procedures with horses is often subject to aversive treatment. The present study replicated and extended previous findings using differential reinforcement to shape appropriate equine handling behavior. In Study 1, a multiple baseline across subjects design was used with four horses to determine first the effects of shaping target-touch responses and then successive approximations of full truck loading under continuous and intermittent schedules of reinforcement. Full loading responses were shaped and maintained in all four horses and occurrences of inappropriate behaviors reduced to zero. Generalization of the loading response was also observed to both a novel trainer and trailer. In Study 2, a changing criterion design was used to increase the duration of feet handling with one horse. The horse's responding reached the terminal duration criterion of 1min and showed consistent generalization and one week maintenance. Overall, the results of both studies support the use of applied equine training systems based on positive reinforcement for increasing appropriate behavior during common handling procedures. PMID- 21310220 TI - Complete mitochondrial genome sequences of three Crocodylus species and their comparison within the Order Crocodylia. AB - Crocodylus is the largest genus within the Order Crocodylia consisting of eleven species. This paper reports the complete mitochondrial genome sequences of three Crocodylus species, Crocodylus moreletii, Crocodylus johnstoni and Crocodylus palustris, and compares the newly obtained mitochondrial DNA sequences with other crocodilians, available in the public databases. The mitochondrial genomes of C. moreletii, C. johnstoni and C. palustris are 16,827 bp, 16,851 bp and 16,852 bp in length, respectively. These mitochondrial genomes consist of 13 protein coding genes, two ribosomal RNA genes, 22 transfer RNA genes and a non-coding region. The mitochondrial genomes of all the Crocodylus species, studied herein show identical characteristics in terms of nucleotide composition and codon usage, suggestive of the existence of analogous evolutionary patterns within the genus, Crocodylus. The synonymous and non-synonymous substitution rates for all the protein coding genes of Crocodylus were observed in between 0.001 and 0.275 which reveal the prevalence of purifying selection in these genes. The phylogenetic analyses based on complete mitochondrial DNA data substantiate the previously established crocodilian phylogeny. This study provides a better understanding of the crocodilian mitochondrial genome and the data described herein will prove useful for future studies concerning crocodilian mitochondrial genome evolution. PMID- 21310221 TI - Complete mitochondrial genomes of two Japanese precious corals, Paracorallium japonicum and Corallium konojoi (Cnidaria, Octocorallia, Coralliidae): notable differences in gene arrangement. AB - Precious coral are taxonomically a group of corals that belong to the family Coralliidae within the order Alcyonacea, subclass Octocorallia, and class Anthozoa, whose skeletal axes are used for jewelry. They are distributed in the Mediterranean Sea and in waters adjacent to Japan, Taiwan, Midway Island and the Hawaiian Islands. The genus Corallium of the family Coralliidae was recently divided into two genera, Corallium and Paracorallium, based on morphological observations, but insufficient molecular evidence to support this classification has been presented to date. We determined for the first time the complete mitochondrial genome sequence of two precious corals P. japonicum and C. konojoi, in order to clarify their systematic positions. The circular mitochondrial genomes of P. japonicum and C. konojoi are 18,913bp and 18,969bp in length, respectively, and encode 13 typical energy pathway protein coding genes (nad1-6, nad4L, cox1-3, cob, atp6 and atp8), two ribosomal RNA genes (rns and rnl), a transfer RNA (trnM) and a mismatch repair gene homologue msh1. The two genomes have an overall nucleotide sequence identity of 97.5%, which is comparable to that between Acanella eburnea and Keratoisidinae sp. belonging to Octocorallia. Surprisingly, however, their gene arrangements were not identical. Phylogenetic analyses using seven complete mitochondrial genome sequences belonging to species in the subclass Octocorallia indicated that within the subclass, at least three gene order rearrangement events occurred during evolution. Our results support the validity of the morphological classification that separated the family Coralliidae into two genera, Corallium and Paracorallium. PMID- 21310222 TI - Beads made of cyclodextrin and oil for the oral delivery of lipophilic drugs: in vitro studies in simulated gastro-intestinal fluids. AB - The aim of this work was to investigate the stability in vitro, in simulated gastro-intestinal fluids, of beads, made of alpha-cyclodextrin and soybean oil, and to study the release of progesterone, a model of lipophilic drug. This was evaluated over time by the monitoring of the proportion of intact beads, their volume and the percentage of progesterone dissolved. Their incubation in the simulated gastric fluid provoked a moderate reduction of their number (20%) and a decrease of their volume (50%) after 55 min. Whatever the intestinal medium subsequently introduced, bead number and volume decreased more until bead disintegration that appeared faster in sodium taurocholate rich-medium. In such fluid, the amount of progesterone dissolved increased rapidly between 65 and 180 min, with both beads and emulsion to be equal after 85 min. With soft capsules, the increase was more gradual. In sodium taurocholate free-medium, more progesterone was dissolved from the emulsion than from beads or soft capsules. The release of progesterone from beads resulted from the erosion of their matrix and its partition equilibrium between oily micro-droplets and aqueous phase. The original structure of beads confers to this multiparticulate system interesting properties for the oral delivery of lipophilic drugs. PMID- 21310223 TI - Evaluation of the physical properties and stability of two lipid drug delivery systems containing mefloquine. AB - Stability data is used to determine the change the product has undergone over a certain time period at specific temperatures. In the present study, the physical stability characterized by size, pH and entrapment efficacy of mefloquine loaded liposomes and PheroidTM vesicles were investigated. Size was accurately determined by flow cytometry. Entrapment efficacy, after unentrapped drug was removed was successfully determined by UV-spectrophotometry. The formulations contained 0.5% (m/v) mefloquine and results showed that mefloquine interfered with the formation of lipid bilayer of the liposomes. Liposomes increased in size from 5.22+/-0.03 MUm to 9.71+/-1.11 MUm with accelerated stability and large aggregates were observed. A notable difference in stability testing of PheroidTM vesicles was seen with no significant increase in size. Entrapment efficacy of 68.72+/-0.04% (5 degrees C), 67.45+/-2.92% (25 degrees C) and 67.45+/-2.92% (30 degrees C) were obtained at the different storage conditions. With these findings the mefloquine loaded PheroidTM vesicles are stable and should be used investigated for the possible increase in efficacy and bioavailability and decrease toxicity. PMID- 21310224 TI - Comparison of in vitro antioxidant activities and bioactive components of green tea extracts by different extraction methods. AB - In this study, in vitro antioxidant activities and bioactive components of green tea extracts (GTE) by ultrahigh pressure extraction and conventional extraction methods (microwave extraction, ultrasonic extraction, Soxhlet extraction and heat reflux extraction) were investigated. DPPH radical-scavenging and FTC method were applied to test the antioxidant activities. The bioactive components were determined by chemical methods. The results indicated that the GTE by ultrahigh pressure extraction exhibited the strongest antioxidant activities. The contents of polyphenols and catechins in the GTE by ultrahigh pressure extraction were significantly higher than those by other extraction methods, which was possibly responsible for the higher antioxidant activities of the GTE by ultrahigh pressure extraction. From the results we can draw the conclusion that not only the more bioactive components are obtained but also the extract has better free radical and reactive oxygen species scavenging activities through ultrahigh pressure extraction method. These findings further illustrate that ultrahigh pressure extraction has a bright prospect for extracting active ingredients from plant materials. PMID- 21310225 TI - Cryogenic transmission electron microscopy (cryo-TEM) for studying the morphology of colloidal drug delivery systems. AB - Cryogenic transmission electron microscopy (cryo-TEM) has evolved into an indispensable tool for the characterization of colloidal drug delivery systems. It can be applied to study the size, shape and internal structure of nanoparticulate carrier systems as well as the overall colloidal composition of the corresponding dispersions. This review gives a short overview over the instrumentation used in cryo-TEM experiments and over the sample preparation procedure. Selected examples of cryo-TEM studies on colloidal drug carrier systems, including liposomes, colloidal lipid emulsions, solid lipid nanoparticles, thermotropic and lyotropic liquid crystalline nanoparticles, polymer-based colloids and delivery systems for nucleic acids, are presented in order to illustrate the wealth of information that can be obtained by this technique. PMID- 21310227 TI - Induction of apoptosis by cordycepin via reactive oxygen species generation in human leukemia cells. AB - Cordycepin (3'-deoxyadenosin), a specific polyadenylation inhibitor, is the main functional component in Cordyceps militaris, one of the top three renowned traditional Chinese medicines. Cordycepin has been shown to possess many pharmacological activities including immunological stimulation, and anti bacterial, anti-viral, and anti-tumor effects. However, the mechanisms underlying its anti-cancer mechanisms are not yet understood. In this study, the apoptotic effects of cordycepin were investigated in human leukemia cells. Treatment with cordycepin significantly inhibited cell growth in a concentration-dependent manner by inducing apoptosis but not necrosis. This induction was associated with generation of reactive oxygen species (ROS), mitochondrial dysfunction, activation of caspases, and cleavage of poly(ADP-ribose) polymerase protein. However, apoptosis induced by cordycepin was attenuated by caspase inhibitors, indicating an important role for caspases in cordycepin responses. Administration of N-acetyl-l-cysteine, a scavenger of ROS, also significantly inhibited cordycepin-induced apoptosis and activation of caspases. These results support a mechanism whereby cordycepin induces apoptosis of human leukemia cells through a signaling cascade involving a ROS-mediated caspase pathway. PMID- 21310226 TI - Synaptic morphology and the influence of auditory experience. AB - The auditory experience is crucial for the normal development and maturation of brain structure and the maintenance of the auditory pathways. The specific aims of this review are (i) to provide a brief background of the synaptic morphology of the endbulb of Held in hearing and deaf animals; (ii) to argue the importance of this large synaptic ending in linking neural activity along ascending pathways to environmental acoustic events; (iii) to describe how the re-introduction of electrical activity changes this synapse; and (iv) to examine how changes at the endbulb synapse initiate trans-synaptic changes in ascending auditory projections to the superior olivary complex, the inferior complex, and the auditory cortex. PMID- 21310228 TI - The endocannabinoid anandamide downregulates IL-23 and IL-12 subunits in a viral model of multiple sclerosis: evidence for a cross-talk between IL-12p70/IL-23 axis and IL-10 in microglial cells. AB - Theiler's virus (TMEV) infection of the central nervous system (CNS) induces an immune-mediated demyelinating disease in susceptible mouse strains and serves as a relevant infection model for human multiple sclerosis (MS). The endocannabinoid system represents a novel therapeutic target for autoimmune and chronic inflammatory diseases due to its anti-inflammatory properties by regulating cytokine network. IL-12p70 and IL-23 are functionally related heterodimeric cytokines that play a crucial role in the pathogenesis of MS. In the present study we showed that the endocannabinoid anandamide (AEA) downregulated the gene expression of IL-12p70 and IL-23 forming subunits mRNAs in the spinal cord of TMEV-infected mice and ameliorated motor disturbances. This was accompanied by significant decreases on the serological levels of IL-12p70/IL-23 and more interestingly, of IL-17A. In contrast, serum levels of IL-10 resulted elevated. In addition, we studied the signalling pathways involved in the regulation of IL 12p70/IL-23 and IL-10 expression in TMEV-infected microglia and addressed the possible interactions of AEA with these pathways. AEA acted through the ERK1/2 and JNK pathways to downregulate IL-12p70 and IL-23 while upregulating IL-10. These effects were partially mediated by CB2 receptor activation. We also described an autocrine circuit of cross-talk between IL-12p70/IL-23 and IL-10, since endogenously produced IL-10 negatively regulates IL-12p70 and IL-23 cytokines in TMEV-infected microglia. This suggests that by altering the cytokine network, AEA could indirectly modify the type of immune responses within the CNS. Accordingly, pharmacological modulation of endocannabinoids might be a useful tool for treating neuroinflammatory diseases. PMID- 21310229 TI - The pineal complex of the European sea bass (Dicentrarchus labrax): I. histological, immunohistochemical and qPCR study. AB - The pineal organ of fish is a photosensory and neuroendocrine epithalamic structure that plays a key role in the temporal organisation of physiological and behavioural processes. In this study performed in the European sea bass, Dicentrarchus labrax, we provided an in-depth description of the macroscopic and microscopic anatomy of the pineal organ and identified the presence of photoreceptor and presumed melatonin-producing cells using histological and immunohistochemical techniques. In addition, we analysed in the pineal the day night expression (using quantitative real-time PCR) of two key enzymes in the melatonin-synthesising pathway; arylalkylamine-N-acetyltransferase 2 (AANAT2) and hydroxyindole-O-methyltransferase (HIOMT). The pineal complex of sea bass consisted of a narrow and short pineal stalk that adopts a vertical disposition, a small-sized pineal end vesicle firmly attached to the skull by connective tissue, a parapineal organ and a convoluted dorsal sac. Immunohistochemical study showed the presence of abundant serotonin-positive cells. Cone opsin-like and rod opsin-like photoreceptor cells were also evidenced in the pineal stalk and vesicle. Both Aanat2 and Hiomt were expressed in sea bass pineal organ. Aanat2 exhibited higher nocturnal transcript levels, while no significant day-night differences were found for Hiomt. These results, together with ongoing studies analysing neural and neurohormonal outputs from the pineal organ of sea bass, provide the basic framework to understand the transduction integration of light stimulus in this relevant species for marine aquaculture. PMID- 21310230 TI - Characterization of free radicals formed from COX-catalyzed DGLA peroxidation. AB - Like arachidonic acid (AA), dihomo-gamma-linolenic acid (DGLA) is a 20-carbon omega-6 polyunsaturated fatty acid and a substrate of cyclooxygenase (COX). Through free radical reactions, COX metabolizes DGLA and AA to form well-known bioactive metabolites, namely, the 1 and 2 series of prostaglandins (PGs1 and PGs2), respectively. Unlike PGs2, which are viewed as proinflammatory, PGs1 possess anti-inflammatory and anticancer activities. However, the mechanisms linking the PGs to their bioactivities are still unclear, and radicals generated in COX-DGLA have not been detected. To better understand PG biology and determine whether different reactions occur in COX-DGLA and COX-AA, we have used LC/ESR/MS with a spin trap, alpha-(4-pyridyl-1-oxide)-N-tert-butyl nitrone (POBN), to characterize the carbon-centered radicals formed from COX-DGLA in vitro, including cellular peroxidation. A total of five types of DGLA-derived radicals were characterized as POBN adducts: m/z 266, m/z 296, and m/z 550 (same as or similar to COX-AA) and m/z 324 and m/z 354 (exclusively from COX-DGLA). Our results suggest that C-15 oxygenation to form PGGs occurs in both COX-DGLA and COX-AA; however, C-8 oxygenation occurs exclusively in COX-DGLA. This new finding will be further investigated for its association with various bioactivities of PGs, with potential implications for inflammatory diseases. PMID- 21310231 TI - A critical life-supporting role for cystathionine gamma-lyase in the absence of dietary cysteine supply. AB - This study examined the important relationship between cystathionine gamma-lyase (CSE) functionality and cysteine supply for normal growth and life span. Mice with a targeted deletion of the CSE gene (CSE-KO) were fed a cysteine-limited diet and their growth and survival patterns as well as levels of cysteine, homocysteine, glutathione, and hydrogen sulfide (H2S) were measured. CSE-KO mice fed a cysteine-limited diet exhibited growth retardation; decreased levels of cysteine, glutathione, and H2S; and increased plasma homocysteine level. However, histological examinations of liver did not reveal any abnormality and plasma levels of aspartate aminotransferase, alanine aminotransferase, and albumin were normal in these animals. No CSE-KO mice survived after 12 weeks of feeding with the cysteine-limited diet. Supplementation of H2S to the CSE-KO mice failed to reverse the aforementioned abnormalities. On the other hand, supplementation of cysteine in the drinking water of the CSE-KO mice significantly increased plasma cysteine and glutathione levels. This eventually led to an increase in body weight and rescued the animals from death. In conclusion, CSE is critical for cysteine biosynthesis through the transsulfuration pathway and the combination of CSE deficiency and lack of dietary cysteine supply would threaten life sustainability. PMID- 21310232 TI - Oleoyl-estrone is a precursor of an estrone-derived ponderostat signal. AB - Oleoyl-estrone (OE) is a powerful anti-obesity compound that decreases food intake, decreases insulin resistance and circulating cholesterol. OE stimulates a severe loss of body fat by decreasing adipose tissue lipid synthesis and maintaining lipolysis. Therefore, the body economy loses lipid energy because energy expenditure is maintained. This study analyses the discrepancy between OE effects and the distribution of labelled OE in plasma. Estrone radioimmunoassay of organic solvent plasma extracts of rats treated with OE showed the massive presence of acyl-estrone, but saponification did not release estrone, but containing similar unknown compound. Analysis of label distribution in plasma after oral gavages of (3)H-OE showed the presence of a more hydrophilic compound than OE or any estrogen as well as (3)H(2)O, formed from (3)H-OE in the acidic stomach medium. OE was not attached to a specific transporter in plasma. Through serum HPLC analysis we found W, a labelled derivative more hydrophilic than OE or estrone. The results were confirmed using (14)C-OE. HPLC-MS/MS studies showed that plasma OE levels were one order of magnitude lower than those of W. When liver cell cytosols from rats laden with (3)H-OE were incubated with nuclei from untreated rats, the OE-derived label (i.e., Ws) was found attached to nuclear DNA. Neither estradiol nor estrone interfered with its binding. W is a fairly hydrophilic compound of low molecular weight containing the estrone nucleus, but it is not an ester because saponification or esterases do not yield estrone as OE does. It is concluded that OE acts through its conversion to W, its active form; which binds to a nuclear receptor different from that of estrogen. The estimated W serum levels are proportional to the pharmacological OE effects in vivo. We postulate W as a new type of hormone that exerts the full range of in vivo effects thus far attributed to OE. The full identification of W is anticipated to open the way for the development of new OE-like anti-obesity drugs. PMID- 21310233 TI - Identification of a new steroid degrading bacterial strain H5 from the Baltic Sea and isolation of two estradiol inducible genes. AB - The presence of steroid hormones in the aquatic environment is potentially threatening the population dynamics of all kinds of sea animals and public health. Environmental estrogens in water have been reported to be associated with abnormal sexual development and abnormal feminizing responses in some animals. New approaches for the bioremediation of steroid hormones from the environment are therefore urgently sought. We have previously isolated a steroid degrading bacterial strain (H5) from the Baltic Sea, at Kiel, Germany. In the present investigation, 16S rRNA analysis showed that marine strain H5 belongs to the genus Vibrio, family Vibrionaceae and class Gamma-Proteobacteria. To enable identification of steroid inducible genes from bacterial strain H5, a library was constructed of H5 chromosomal DNA fragments cloned into a fluorescent reporter (pKEGFP-2). A reporter plasmid pK3alpha-4.6-EGFP3 containing the estrogen inducible gene 3alpha-hydroxysteroid dehydrogenase/carbonyl reductase (3alpha HSD/CR) from Comamonas testosteroni (C. testosteroni) was created as a positive control. Steroid induction could be detected by a microplate fluorescence reader, when the plasmids were transformed into Escherichia coli (E. coli) HB101 cells. With our meta-genomic pKEGFP-2 approach, we identified two estradiol-inducible genes from marine strain H5, which are obviously involved in steroid degradation. Sequencing of the pKEGFP-2 inserts and data base research at NCBI revealed that one gene corresponds to 3-ketosteroid-delta-1-dehydrogenase from several Mycobacterium strains, while the other showed high similarity to carboxylesterase in Sebadella termitidis and Brachyspira murdochii. Both 3-ketosteroid-delta-1 dehydrogenase and carboxylesterase are one of the first enzymes in steroid degradation. In addition, we identified a strain H5 specific DNA sequence of 480bp which allows sensitive PCR detection and quantification of strain H5 bacteria in "unknown" seawater samples. Currently, the exact characterization and systematic classification of the marine steroid degrading bacterial strain H5 is envisaged, which might be used for the bioremediation of steroid contaminations in seawater. Article from a special issue on steroids and microorganisms. PMID- 21310234 TI - Impact of the lesion procedure on the profiles of motor impairment and molecular responsiveness to L-DOPA in the 6-hydroxydopamine mouse model of Parkinson's disease. AB - 6-Hydroxydopamine (6-OHDA) lesions are being used in the mouse for basic research on Parkinson's disease and L-DOPA-induced dyskinesia. We set out to compare unilateral lesion models produced by intrastriatal or intramesencephalic injections of a fixed 6-OHDA concentration (3.2 MUg/MUl) in C57BL/6 mice. In the first experiment, toxin injections were performed either at two striatal coordinates (1 or 2 MUl per site, termed "striatum(2 * 1 MUl)" and "striatum(2 * 2 MUl)" models), in the medial forebrain bundle (MFB), or in the substantia nigra pars compacta (SN) (1 MUl per site). All the four lesion models produced significant forelimb use asymmetry, but spontaneous turning asymmetry only occurred in the MFB and striatum(2 * 2 MUl) models. After the behavioral studies, the induction of phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK1/2) by acute L-DOPA (30 mg/kg) was used as a marker of post-synaptic supersensitivity. Striatal pERK1/2 expression was sparse in the SN and striatum(2 * 1 MUl) groups, but pronounced in the striatum(2 * 2 MUl) and MFB-lesioned mice. In further experiments, mice with MFB and striatal(2 * 2 MUl) lesions were used to compare behavioral and molecular responses to chronic L-DOPA treatment (12 days at 3 and 6 mg/kg/day). Maximally severe abnormal involuntary movements (AIMs) occurred in all MFB-lesioned mice, whereas only 35% of the mice with striatal lesions developed dyskinesia. Striatal tissue levels of dopamine were significantly lower in the dyskinetic animals (both MFB and striatum(2 * 2 MUl) groups) in comparison with the non-dyskinetic ones. Noradrenaline levels were significantly reduced only in MFB lesioned animals and did not differ among the dyskinetic and non-dyskinetic cases with striatal lesions. In all groups, the L DOPA-induced AIM scores correlated closely with the number of cells immunoreactive for tyrosine hydroxylase or FosB/?FosB in the striatum. In conclusion, among the four lesion procedures examined here, only the MFB and striatum(2 * 2 MUl) models yielded a degree of dopamine denervation sufficient to produce spontaneous postural asymmetry and molecular supersensitivity to L-DOPA. Both lesion models are suitable to reproduce L-DOPA-induced dyskinesia, although only MFB lesions yield a pronounced and widespread expression of post-synaptic supersensitivity markers in the striatum. PMID- 21310235 TI - Saccadic latency in Parkinson's disease correlates with executive function and brain atrophy, but not motor severity. AB - Brain regions related to saccadic control are affected by Parkinson's disease (PD) pathology and a relationship between abnormal saccades and cognitive features of PD has been suggested. We measured the latency of visually-evoked saccades, and correlated best-fit parameters in a LATER neuronal decision model MU and sigma (mean and SD of the distribution of reciprocal latency, i.e. speed of response), and sigma(E) (SD of the early component) with motor function, cognition and grey matter volume in 18 patients with PD and 17 controls. There was a negative correlation between verbal fluency and sigma; no correlation was found between motor function and any of the latency parameters. Higher MU (shorter latency) positively correlated with grey matter volume in the prefrontal cortex, the cerebellar vermis, and the fusiform gyrus. There was a negative correlation between sigma and grey matter volume in the frontal and parietal eye fields, the premotor cortex, and the lateral prefrontal cortex. sigma(E) negatively correlated with grey matter volume in the frontal eye fields and the middle frontal gyrus. Our behavioural and imaging findings point to an association between saccade latency, executive function and the structural integrity within a well-defined oculomotor network. PMID- 21310236 TI - The bone morphogenetic protein antagonist noggin protects white matter after perinatal hypoxia-ischemia. AB - Hypoxia-ischemia (HI) in the neonate leads to white matter injury and subsequently cerebral palsy. We find that expression of bone morphogenetic protein 4 (BMP4) increases in the neonatal mouse brain after unilateral common carotid artery ligation followed by hypoxia. Since signaling by the BMP family of factors is a potent inhibitor of oligodendroglial differentiation, we tested the hypothesis that antagonism of BMP signaling would prevent loss of oligodendroglia (OL) and white matter in a mouse model of perinatal HI. Perinatal HI was induced in transgenic mice in which the BMP antagonist noggin is overexpressed during oligodendrogenesis (pNSE-Noggin). Following perinatal HI, pNSE-Noggin mice had more oligodendroglial progenitor cells (OPCs) and more mature OL compared to wild type (WT) animals. The increase in OPC numbers did not result from proliferation but rather from increased differentiation from precursor cells. Immunofluorescence studies showed preservation of white matter in lesioned pNSE Noggin mice compared to lesioned WT animals. Further, following perinatal HI, the pNSE-Noggin mice were protected from gait deficits. Together these findings indicate that the BMP-inhibitor noggin protects from HI-induced loss of oligodendroglial lineage cells and white matter as well as loss of motor function. PMID- 21310237 TI - Repetitive nerve stimulation transiently opens the mitochondrial permeability transition pore in motor nerve terminals of symptomatic mutant SOD1 mice. AB - Mitochondria in motor nerve terminals temporarily sequester large Ca(2+) loads during repetitive stimulation. In wild-type mice this Ca(2+) uptake produces a small (<5 mV), transient depolarization of the mitochondrial membrane potential (Psi(m), motor nerve stimulated at 100 Hz for 5s). We demonstrate that this stimulation-induced Psi(m) depolarization attains much higher amplitudes in motor terminals of symptomatic mice expressing the G93A or G85R mutation of human superoxide dismutase 1 (SOD1), models of familial amyotrophic lateral sclerosis (fALS). These large Psi(m) depolarizations decayed slowly and incremented with successive stimulus trains. Additional Psi(m) depolarizations occurred that were not synchronized with stimulation. These large Psi(m) depolarizations were reduced (a) by cyclosporin A (CsA, 1-2 MUM), which inhibits opening of the mitochondrial permeability transition pore (mPTP), or (b) by replacing bath Ca(2+) with Sr(2+), which enters motor terminals and mitochondria but does not support mPTP opening. These results are consistent with the hypothesis that the large Psi(m) depolarizations evoked by repetitive stimulation in motor terminals of symptomatic fALS mice result from mitochondrial dysfunction that increases the likelihood of transient mPTP opening during Ca(2+) influx. Such mPTP openings, a sign of mitochondrial stress, would disrupt motor terminal handling of Ca(2+) loads and might thereby contribute to motor terminal degeneration in fALS mice. Psi(m) depolarizations resembling those in symptomatic fALS mice could be elicited in wild-type mice following a 0.5-1h exposure to diamide (200 MUM), which produces an oxidative stress, but these depolarizations were not reduced by CsA. PMID- 21310238 TI - Mitochondria, oligodendrocytes and inflammation in bipolar disorder: evidence from transcriptome studies points to intriguing parallels with multiple sclerosis. AB - Gene expression studies of bipolar disorder (BPD) have shown changes in transcriptome profiles in multiple brain regions. Here we summarize the most consistent findings in the scientific literature, and compare them to data from schizophrenia (SZ) and major depressive disorder (MDD). The transcriptome profiles of all three disorders overlap, making the existence of a BPD-specific profile unlikely. Three groups of functionally related genes are consistently expressed at altered levels in BPD, SZ and MDD. Genes involved in energy metabolism and mitochondrial function are downregulated, genes involved in immune response and inflammation are upregulated, and genes expressed in oligodendrocytes are downregulated. Experimental paradigms for multiple sclerosis demonstrate a tight link between energy metabolism, inflammation and demyelination. These studies also show variabilities in the extent of oligodendrocyte stress, which can vary from a downregulation of oligodendrocyte genes, such as observed in psychiatric disorders, to cell death and brain lesions seen in multiple sclerosis. We conclude that experimental models of multiple sclerosis could be of interest for the research of BPD, SZ and MDD. PMID- 21310239 TI - A transcriptomic analysis of type I-III neurons in the bed nucleus of the stria terminalis. AB - The activity of neurons in the anterolateral cell group of the bed nucleus of the stria terminalis (BNST(ALG)) plays a critical role in anxiety- and stress-related behaviors. Histochemical studies have suggested that multiple distinct neuronal phenotypes exist in the BNST(ALG). Consistent with this observation, the physiological properties of BNST(ALG) neurons are also heterogeneous, and three distinct cell types can be defined (Types I-III) based primarily on their expression of four key membrane currents, namely I(h), I(A), I(T), and I(K(IR)). Significantly, all four channels are multimeric proteins and can comprise of more than one pore-forming alpha subunit. Hence, differential expression of alpha subunits may further diversify the neuronal population. However, nothing is known about the relative expression of these ion channel alpha subunits in BNST(ALG) neurons. We have addressed this lacuna by combining whole-cell patch-clamp recording together with single-cell reverse transcriptase polymerase chain reaction (scRT-PCR) to assess the mRNA transcript expression for each of the subunits for the four key ion channels in Type I-III neurons of the BNST(ALG.) Here, cytosolic mRNA from single neurons was probed for the expression of transcripts for each of the alpha subunits of I(h) (HCN1-HCN4), I(T) (Ca(v)3.1 Ca(v)3.3), I(A) (K(v)1.4, K(v)3.4, K(v)4.1-K(v) 4.3) and I(K(IR)) (Kir2.1 Kir2.4). An unbiased hierarchical cluster analysis followed by discriminant function analysis revealed that a positive correlation exists between the physiological and genetic phenotype of BNST(ALG) neurons. Thus, the analysis segregated BNST(ALG) neurons into 3 distinct groups, based on their alpha subunit mRNA expression profile, which positively correlated with our existing electrophysiological classification (Types I-III). Furthermore, analysis of mRNA transcript expression in Type I-Type III neurons suggested that, whereas Type I and III neurons appear to represent genetically homologous cell populations, Type II neurons may be further subdivided into three genetically distinct subgroups. These data not only validate our original classification scheme, but further refine the classification at the molecular level, and thus identifies novel targets for potential disruption and/or pharmacotherapeutic intervention in stress-related anxiety-like behaviors. PMID- 21310240 TI - Imaging of nucleic acids with atomic force microscopy. AB - Atomic force microscopy (AFM) is a key tool of nanotechnology with great importance in applications to DNA nanotechnology and to the recently emerging field of RNA nanotechnology. Advances in the methodology of AFM now enable reliable and reproducible imaging of DNA of various structures, topologies, and DNA and RNA nanostructures. These advances are reviewed here with emphasis on methods utilizing modification of mica to prepare the surfaces enabling reliable and reproducible imaging of DNA and RNA nanostructures. Since the AFM technology for DNA is more mature, AFM imaging of DNA is introduced in this review to provide experience and background for the improvement of AFM imaging of RNA. Examples of imaging different structures of RNA and DNA are discussed and illustrated. Special attention is given to the potential use of AFM to image the dynamics of nucleic acids at the nanometer scale. As such, we review recent advances with the use of time-lapse AFM. PMID- 21310241 TI - A genetic and molecular toolbox for analyzing histone ubiquitylation and sumoylation in yeast. AB - Combinations of phosphorylation, acetylation, methylation, ubiquitylation, and sumoylation of histones comprise what is referred to as the "histone code". These marks influence processes from transcription to DNA replication, where gaining access to DNA organized in chromatin is necessary. Much emphasis has been placed on the role of histone ubiquitylation and sumoylation during the process of transcription. Histone H2B is monoubiquitylated at lysine 123 in budding yeast and influences gene activation. All four of the core histones are sumoylated on their amino terminal tails in this organism, and this serves to negatively regulate gene expression. Because antibodies specific for ubiquitylated or sumoylated yeast histones are not commercially available, and these marks are highly sensitive to proteolysis in native cell extracts, special genetic and molecular tools have been developed to monitor these dynamic and often rare modifications in vivo. Here, we describe some of these tools, with emphasis on how they can be used for transcriptional studies. PMID- 21310242 TI - Ani s 10, a new Anisakis simplex allergen: cloning and heterologous expression. AB - Anisakiasis is a human disease caused by accidental ingestion of larval nematodes belonging to the Anisakidae family. Anisakiasis is often associated with a strong allergic response. Diagnosis of A. simplex allergy is currently carried out by test based on the IgE reactivity to a complete extract of L3 Anisakis larvae although the specificity of these diagnostic tests is poor. Improving the specificity of the diagnostic test is possible using purified recombinant allergens. A new Anisakis allergen, named Ani s 10, was detected by immunoscreening an expression cDNA library constructed from L3 Anisakis simplex larvae. The new allergen was overproduced in Escherichia coli; it is a protein of 212 amino acids and it was localized as a 22 kDa protein band in an ethanol fractionated extract from the parasite. Ani s 10 has no homology with any other described protein, and its sequence is composed by seven almost identical repetitions of 29 amino acids each. A total of 30 of 77 Anisakis allergic patients (39%) were positive both to rAni s 10 and natural Ani s 10 by immunoblotting. The new allergen could be useful in a component-resolved diagnosis system for Anisakis allergy. PMID- 21310243 TI - A rapid procedure to purify Escherichia coli DNA topoisomerase I. AB - On the basis of the asymmetrical charge distribution of Escherichia coli DNA topoisomerase I, we developed a new procedure to purify E. coli DNA topoisomerase I in the milligram range. The new procedure includes using both cation- and anion exchange columns, i.e., SP-Sepharose FF and Q-Sepharose FF columns. The E. coli DNA topoisomerase I purified here is free of DNase contamination. The kinetic constants of the DNA relaxation reaction of E. coli DNA topoisomerase I were also determined. PMID- 21310244 TI - Epitope analysis of white spot syndrome virus of Penaeus monodon by in vivo neutralization assay employing a panel of monoclonal antibodies. AB - A panel of six monoclonal antibodies (MAbs) against the major envelope proteins VP18, VP26 and VP28 of white spot syndrome virus (WSSV) was evaluated for neutralization of the virus in vivo in Penaeus monodon. WSSV stock diluted to 1 x 10-6 resulting in 100% mortality on 12 day post injection (dpi) was used as optimum infectious dose of virus for challenge. Constant quantity (100 MUg/ml) of MAbs C-5, C-14, C-33, C-38, C-56 and C-72 was incubated separately with WSSV (1 x 10-6 dilution) at 27 degrees C for 90 min and injected to shrimp. WSSV infection was neutralized by the MAbs C-5, C-14 and C-33 with a relative percent survival (RPS) of 60, 80 and 60 on 12 dpi, respectively compared to 100% mortality in positive control injected with WSSV alone. MAbs C-38, C-56 and C-72 could neutralize WSSV infection with RPS on 12 dpi of 40, 30 and 30, respectively. Shrimp injected with WSSV (1 x 10-6 dilution) incubated with panel of the MAbs at 100 MUg/ml separately were subjected to nested PCR analysis at 0, 8, 12, 24, 36, 48 and 72 hour post injection (hpi) to provide further evidence for neutralization. MAbs C-5, C-14 and C-33 showed delay in WSSV positivity by 24 and 48 hpi by 2nd and 1st step PCR, respectively. MAbs C-38, C-56 and C-72 showed WSSV positivity by 12 and 24 hpi by 2nd and 1st step PCR, respectively. Shrimp injected with WSSV alone showed WSSV positivity by 8 and 12 hpi by 2nd and 1st step PCR, respectively. The study clearly shows that infectivity of WSSV could be delayed by MAbs C-14, C-5 and C-33. PMID- 21310245 TI - Gray matter density increase in the primary sensorimotor cortex in long-term essential blepharospasm. AB - In this study, we investigated gray matter density in essential blepharospasm (EB) patients, focusing on the duration of disease and severity of symptoms. We studied 32 patients (10 males and 22 females; age, 55.0 +/- 6.5years) with EB and 48 controls (15 males and 33 females; age, 54.4 +/- 10.3years) by using 3D T1 weighted magnetic resonance imaging and voxel-based morphometry. We defined an activity index (AI) that reflects the severity and duration of EB symptoms in each patient. The difference between the 2 groups was examined by statistical parametric mapping software (SPM8). After controlling for age, gray matter density increased in the bilateral primary sensorimotor cortex (S1M1) and cingulate gyrus. The gray matter density in the bilateral S1M1 was found to have a significant positive correlation with the duration of disease and a more robust correlation with AI. The correlation coefficients, after correcting for age, in the S1M1 and left cingulate gyrus were as follows: with duration, right S1M1, 0.72 (P<0.00001); left S1M1, 0.72 (P<0.00001); and left cingulate gyrus, 0.33 (not significant); and with AI, right S1M1, 0.81 (P<10(-7)); left S1M1, 0.74 (P<0.00001); and left cingulate gyrus, 0.43 (P<0.05). The increase in gray matter density in the S1M1 and cingulate gyrus might be a secondary effect caused by long-term hyperactivity in these areas instead of a predisposing factor. PMID- 21310246 TI - Segmentation of the thalamus in MRI based on T1 and T2. AB - Reliable identification of thalamic nuclei is required to improve positioning of electrodes in Deep Brain Stimulation (DBS), and to allow the role of individual thalamic nuclei in health and disease to be fully investigated. In this work, a previously proposed method for identifying sub-regions within the thalamus based on differences in their T1 and T2 values is explored in detail. The effect on the segmentation of T1 and T2 dependence weighted against priors for spatial position and extent was investigated. When T1 and T2 dependence was highly weighted, good distinction between identified regions was obtained in T1/T2 feature-space, but no contiguous anatomically distinct regions were identified within the thalamus. Incorporating spatial priors was necessary to ensure anatomically distinct regions were defined. Optimal values for segmentation parameters were obtained by assessing performance on a 'synthetic thalamus'. Using these optimum input parameters, within- and between-subjects reproducibility was assessed. Good reproducibility was obtained when six regions were specified to be identified in the thalamus. The six regions identified were similar in the majority of the normal subject group. However, intriguingly these regions were different from those obtained in the same subjects using a well-known connectivity-based segmentation technique. This method shows promise to identify intrathalamic structures on the basis of T1 and T2 signal. A comprehensive characterisation of thalamic nuclei may require a fully multi-modal approach. PMID- 21310247 TI - Generalised filtering and stochastic DCM for fMRI. AB - This paper is about the fitting or inversion of dynamic causal models (DCMs) of fMRI time series. It tries to establish the validity of stochastic DCMs that accommodate random fluctuations in hidden neuronal and physiological states. We compare and contrast deterministic and stochastic DCMs, which do and do not ignore random fluctuations or noise on hidden states. We then compare stochastic DCMs, which do and do not ignore conditional dependence between hidden states and model parameters (generalised filtering and dynamic expectation maximisation, respectively). We first characterise state-noise by comparing the log evidence of models with different a priori assumptions about its amplitude, form and smoothness. Face validity of the inversion scheme is then established using data simulated with and without state-noise to ensure that DCM can identify the parameters and model that generated the data. Finally, we address construct validity using real data from an fMRI study of internet addiction. Our analyses suggest the following. (i) The inversion of stochastic causal models is feasible, given typical fMRI data. (ii) State-noise has nontrivial amplitude and smoothness. (iii) Stochastic DCM has face validity, in the sense that Bayesian model comparison can distinguish between data that have been generated with high and low levels of physiological noise and model inversion provides veridical estimates of effective connectivity. (iv) Relaxing conditional independence assumptions can have greater construct validity, in terms of revealing group differences not disclosed by variational schemes. Finally, we note that the ability to model endogenous or random fluctuations on hidden neuronal (and physiological) states provides a new and possibly more plausible perspective on how regionally specific signals in fMRI are generated. PMID- 21310248 TI - Dissociation of mirroring and mentalising systems in autism. AB - The role of mirror neuron systems and mentalising systems in causing poor social and communication skills in individuals with autistic spectrum conditions is hotly debated. We studied 18 adults with autistic spectrum conditions in comparison to 19 age and IQ matched typical individuals. Behavioural assessments revealed difficulties in mental state attribution and action comprehension in the autism sample. We examined brain responses when observing rational and irrational hand actions, because these actions engage mirror and mentalising components of the social brain respectively. Both typical and autistic participants activated the left anterior intraparietal sulcus component of the mirror system when viewing hand actions compared to moving shapes. The typical but not autistic participants activated the posterior mid cingulate cortex/supplementary motor area and bilateral fusiform cortex when viewing hand actions. When viewing irrational hand actions, the medial prefrontal cortex of typical participants deactivated but this region did not distinguish the different stimuli in autistic participants. These results suggest that parietal mirror regions function normally in autism, while differences in action understanding could be due to abnormal function of cingulate, fusiform and medial prefrontal regions. Thus, brain regions associated with mirroring and mentalising functions are differentially affected in autistic spectrum conditions. PMID- 21310249 TI - Structural correlates of active-staining following magnetic resonance microscopy in the mouse brain. AB - Extensive worldwide efforts are underway to produce knockout mice for each of the ~25,000 mouse genes, which may give new insights into the underlying pathophysiology of neurological disease. Microscopic magnetic resonance imaging (MUMRI) is a key method for non-invasive morphological phenotyping, capable of producing high-resolution 3D images of ex-vivo brains, after fixation with an MR contrast agent. These agents have been suggested to act as active-stains, enhancing structures not normally visible on MRI. In this study, we investigated the structural correlates of the MRI agent Gd-DTPA, together with the optimal preparation and scan parameters for contrast-enhanced gradient-echo imaging of the mouse brain. We observed that in-situ preparation was preferential to ex-situ due to the degree of extraction damage. In-situ brains scanned with optimised parameters, enabled images with a high signal-to-noise-ratio (SNR ~30) and comprehensive anatomical delineation. Direct correlation of the MR brain structures to histology, detailed fine histoarchitecture in the cortex, cerebellum, olfactory bulb and hippocampus. Neurofilament staining demonstrated that regions of negative MR contrast strongly correlated to myelinated white matter structures, whilst structures of more positive MR contrast corresponded to areas with high grey matter content. We were able to identify many sub-regions, particularly within the hippocampus, such as the unmyelinated mossy fibres (stratum lucidum) and their region of synapse in the stratum pyramidale, together with the granular layer of the dentate gyrus, an area of densely packed cell bodies, which was clearly visible as a region of hyperintensity. This suggests that cellular structure influences the site-specific distribution of the MR contrast agent, resulting in local variations in T(2)*, which leads to enhanced tissue discrimination. Our findings provide insights not only into the cellular distribution and mechanism of MR active-staining, but also allow for three dimensional analysis, which enables interpretation of magnetic resonance microscopy brain data and highlights cellular structure for investigation of disease processes in development and disease. PMID- 21310250 TI - Molecular genetic analysis and ecological evidence reveals multiple cryptic species among thynnine wasp pollinators of sexually deceptive orchids. AB - Sexually deceptive Chiloglottis orchids lure their male thynnine wasp pollinators to the flower by emitting semiochemicals that mimic the specific sex pheromone of the wasp. Sexual deception is possible because chemical rather than visual cues play the key role in wasp mate search, suggesting that cryptic wasp species may be frequent. We investigated this prospect among Neozeleboria wasp pollinators of Chiloglottis orchids, drawing on evidence from molecular phylogenetic analysis at three genes (CO1, rhodopsin and wingless), population genetic and statistical parsimony analysis at CO1, orchid associations and their semiochemicals, and geographic ranges. We found a compelling relationship between genetically defined wasp groups, orchid associations, semiochemicals and geographic range, despite a frequent lack of detectable morphological differences. Our findings reveal multiple cryptic species among orchid pollinators and indicate that chemical changes are important for wasp reproductive isolation and speciation. The diversity of Neozeleboria may have enabled, rather than constrained, pollinator driven speciation in these orchids. PMID- 21310251 TI - Population genetic analysis and phylogeny reconstruction in Eucalyptus (Myrtaceae) using high-throughput, genome-wide genotyping. AB - A set of over 8000 Diversity Arrays Technology (DArT) markers was tested for its utility in high-resolution population and phylogenetic studies across a range of Eucalyptus taxa. Small-scale population studies of Eucalyptus camaldulensis, Eucalyptus cladocalyx, Eucalyptus globulus, Eucalyptus grandis, Eucalyptus nitens, Eucalyptus pilularis and Eucalyptus urophylla demonstrated the potential of genome-wide genotyping with DArT markers to differentiate species, to identify interspecific hybrids and to resolve biogeographic disjunctions within species. The population genetic studies resolved geographically partitioned clusters in E. camaldulensis, E. cladocalyx, E. globulus and E. urophylla that were congruent with previous molecular studies. A phylogenetic study of 94 eucalypt species provided results that were largely congruent with traditional taxonomy and ITS based phylogenies, but provided more resolution within major clades than had been obtained previously. Ascertainment bias (the bias introduced in a phylogeny from using markers developed in a small sample of the taxa that are being studied) was not detected. DArT offers an unprecedented level of resolution for population genetic, phylogenetic and evolutionary studies across the full range of Eucalyptus species. PMID- 21310252 TI - Association of knee and ankle osteoarthritis with physical performance. AB - OBJECTIVE: The direct measurement of the ability to perform physical tasks yields information about factors contributing to poor function and insights into strategies for preventing disability. Our goal was to evaluate the relationship of walking speed and balance tests with specific radiographic features of knee and ankle osteoarthritis (OA). METHODS: A timed eight foot walk and a standing balance test were performed by 138 participants of a longitudinal observational study of knee OA progression. Radiographic features of OA severity, joint space narrowing (JSN), a surrogate for cartilage loss and osteophyte (OST) formation, were assessed for the knee and ankle. The association of these performance measures with radiographic OA was evaluated using correlation analysis, adjusted for age, gender, body mass index (BMI), and number of comorbidities. RESULTS: Knee and ankle JSN, but not OST, was negatively associated with specific performance tests: walking speed was associated with knee JSN (Spearman rho = 0.20, P = 0.02) and balance was associated with ankle (subtalar joint) JSN (Spearman rho = -0.22, P = 0.01). These relationships remained significant upon further control for knee and ankle pain. CONCLUSIONS: Structural joint damage due to OA (JSN in contrast to OST) negatively impacted specific domains of physical performance. These results indicate that targeting specific joints for specific functional outcomes may be indicated, and suggest that prevention of cartilage damage in these joints is a sensible target for OA disease modification to prevent disability. PMID- 21310253 TI - IL-17RA aptamer-mediated repression of IL-6 inhibits synovium inflammation in a murine model of osteoarthritis. AB - OBJECTIVE: Generate DNA aptamers to inhibit IL-17RA-mediated synovial inflammation in an experimental mouse model of osteoarthritis (OA). METHODS: A novel cell-SELEX method was applied to obtain DNA aptamers specific for IL-17RA. A single-stranded (ss) DNA library with four(30) probes was synthesised. By incubating this library with NIH3T3 cells, we collected DNA ligands that could bind the cell surface. The collected ligands were incubated with IL-17RA deficient NIH3T3 cells, and unbound ssDNA was harvested from the supernatant for the next round of selection. After 12 cycles, specific aptamers against IL-17RA were generated. For animal experiments, a meniscectomy was performed on Balb/C mice to generate an animal model of OA. Mice received weekly intra-articular (i.a.) injections of aptamers or control treatments for 6 weeks. Synovial membranes were evaluated by histomorphology and the mRNAs of critical inflammatory cytokines were measured by quantitative reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: An aptamer termed RA10-6 was obtained that could efficiently block IL-17 binding to IL-17RA in a dose dependent manner in vitro. Histological examination and quantitative RT-PCR results showed that OA mice that injected with RA10-6, especially in combination with celecoxib demonstrated inhibition of synovial thickening and reduction in IL 6 levels in the synovial tissue. CONCLUSION: Our results suggest that RA10-6 can inhibit synovial inflammation by blocking IL-17/IL-17RA-mediated IL-6 expression. RA10-6 acted synergistically with celecoxib to inhibit IL-6 expression in synovial tissues. Thus, aptamers targeting IL-17RA might serve as potent adjunctive agents for the early treatment of OA. PMID- 21310255 TI - MDSC in autoimmunity. AB - Myeloid derived suppressor cells (MDSC) were first described nearly two decades ago. Until recently, however, descriptions of MDSC populations were found almost exclusively in animal models of cancer or in cancer patients. Over the last few years, an increasing number of reports have been published describing populations of myeloid cells with MDSC-like properties in murine models of autoimmune disease. In contrast to the proposed deleterious role of MDSC in cancer--where these cells likely inhibit tumor immunity--in the context of autoimmunity, MDSC have the potential to suppress the autoimmune response, thereby limiting tissue injury. A logical corollary of this hypothesis is that a failure of endogenous MDSC to appropriately control autoimmune T cell responses in vivo may actually contribute to the pathogenesis of autoimmune disease. PMID- 21310254 TI - Serious infection risk and immune recovery after double-unit cord blood transplantation without antithymocyte globulin. AB - Factors contributing to infection risk after cord blood transplantation (CBT) include the use of anti-thymocyte globulin (ATG), prolonged neutropenia, and failure to transfer immunity. In the present study, we investigated the potential of double-unit CBT without ATG to reduce the risk of infection and evaluated the nature of serious infections in the first year after CBT using this approach. Seventy-two predominantly adult patients underwent CBT for hematologic malignancies; of these, 52 patients received myeloablative conditioning, and 20 received nonmyeloablative conditioning. The peak incidences of bacterial infections (32%), fungal infections (14%), and bacterial/fungal pneumonias (10%) occurred in the first 30 days posttransplantation. Three such infections contributed to early mortality. The peak incidence of viral infections was 31-60 days posttransplantation, affecting 30% of patients. Cytomegalovirus (CMV) was the most common viral infection. CMV infections occurring before day 120 (n = 23) had no relationship with graft-versus-host disease (GVHD), whereas CMV infections occurring after day 120 (n = 5), along with all cases of Epstein-Barr virus viremia (n = 5) and adenoviral enteritis (n = 2), occurred exclusively in the context of GVHD therapy or corticosteroid use for another indication. Viral infections had the highest lethality: 2 were a direct cause of death, and 3 contributed to death. Patients exhibited steady immune recovery, achieving a median CD3(+)4(+) T cell count >200 cells/MUL by day 120 post-CBT, and no infection-related deaths occurred after day 120. Our results suggest that double unit CBT without ATG is associated with prompt T cell recovery, and, unlike in CBT incorporating ATG, infection is rarely a primary cause of death. However, CBT without ATG is associated with a significant risk of GVHD, and serious infections remain a challenge, especially in the setting of GVHD. New strategies are needed to further reduce infectious complications after CBT; these will require earlier neutrophil recovery and more effective prevention of GVHD, ideally without the profound T cell depletion associated with ATG therapy. PMID- 21310256 TI - CpG oligodeoxynucleotide synergizes innate defense regulator peptide for enhancing the systemic and mucosal immune responses to pseudorabies attenuated virus vaccine in piglets in vivo. AB - Oligonucleotides containing CpG motifs (CpG ODN) are strong adjuvants for humoral and cellular immune responses in mice, and innate defense-regulator peptides (IDRs) are known to facilitate the uptake of antigens into antigen presenting cells (APCs), but data on synergistic effects of CpG and IDRs in piglets are scarce. In this report, the combination of porcine-specific CpG ODN and HH2 (a kind of IDR which was selected for its better synergy with CpG ODN) was used as immunoadjuvant to enhance the immune responses of the newborn piglets to Pseudorabies attenuated virus (PRV) vaccine. The titers of specific antibodies and serum IgG1/IgG2 subtypes to PRV vaccine, interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), IL-12 and IL-4 were examined to identify the immune responses of the newborn piglets. The results showed that piglets immunized intranasally (IN) and subcutaneously (SC) with PRV vaccine and CpG-HH2 complex both presented high titers of PRV-specific antibodies and IgG2 isotype, a Th1-dominated (IFN-gamma and IL-12) cytokine profiles, high levels of IgA in saliva, broncheoalveolar lavage (BAL) and intestinal washings. The results suggested that, CpG-HH2 complex augmented systemic (IgG in serum) and mucosal (IgA in saliva, BAL and intestinal washings) immune responses against antigen. CpG-HH2 complex stimulated both T-helper type1 (Th1) (IgG2) and Th2 (IgA) responses when delivered IN, and IN route could induce stronger mucosal immune responses than SC route. All these data indicate that CpG-HH2 complex is a potential effective adjuvant for the PRV vaccine in newborn piglets. PMID- 21310257 TI - The role of PI3K/Akt pathway in beta-glucan-induced dendritic cell maturation. PMID- 21310258 TI - Bacterial glyoxalase enzymes. AB - The glyoxalase system is composed of two metalloenzymes, Glyoxalase I and Glyoxalase II. This system is important in the detoxification of methylglyoxal, among other roles. Detailed studies have determined that a number of bacterial Glyoxalase I enzymes are maximally activated by Ni(2+) and Co(2+) ions, but are inactive in the presence of Zn(2+). This is in contrast to the Glyoxalase I enzyme from humans, which is catalytically active with Zn(2+) as well as a number of other metal ions. The structure-activity relationships between these two classes of Glyoxalase I are serving as important clues to how the molecular structures of these proteins control metal activation profiles as well as to clarify the mechanistic chemistry of these catalysts. In addition, the possibility of targeting inhibitors against the bacterial versus human enzyme has the potential to lead to new approaches to combat bacterial infections. PMID- 21310259 TI - The glyoxalase system of malaria parasites--implications for cell biology and general glyoxalase research. AB - Malaria parasites of the genus Plasmodium have developed sophisticated mechanisms to benefit from the nutrient-rich environments of their hosts. For example, by hiding in red blood cells, they found a secure way to tap into the glucose supply of vertebrates. The high-power metabolism of Plasmodium leads not only to a significantly increased glucose consumption of infected erythrocytes, but also to an elevated production of D-lactate from methylglyoxal. The latter substance is a harmful by-product from glycolysis that is detoxified by the ubiquitous glyoxalase system. This system consists of reduced glutathione and two enzymes, the glyoxalases 1 and 2. Inhibition of the glyoxalases in the host/parasite unit is expected to be highly detrimental to the parasite. Moreover, by studying Plasmodium isozymes, physiological functions of the system beyond methylglyoxal conversion became prima facie obvious: (i) the two different active sites of glyoxalase 1 as well as the existence of (insular) glyoxalases in the apicoplast point to alternative substrates and metabolic pathways. (ii) The allostery of glyoxlase 1 and the monomer-dimer equilibrium of glyoxalase 2 suggest novel regulatory features of these enzymes. Here we review the current knowledge on the glyoxalase systems of the host/parasite unit, discuss their potential as drug target and summarize new hypotheses on glyoxalases with respect to general cell biology. PMID- 21310260 TI - Glyoxalase system in yeasts: structure, function, and physiology. AB - The glyoxalase system consists of glyoxalase I and glyoxalase II. Glyoxalase I catalyzes the conversion of methylglyoxal (CH(3)COCHO), a metabolite derived from glycolysis, with glutathione to S-D-lactoylglutathione, while glyoxalase II hydrolyses this glutathione thiolester to D-lactic acid and glutathione. Since methylglyoxal is toxic due to its high reactivity, the glyoxalase system is crucial to warrant the efficient metabolic flux of this reactive aldehyde. The budding yeast Saccharomyces cerevisiae has the sole gene (GLO1) encoding the structural gene for glyoxalase I. Meanwhile, this yeast has two isoforms of glyoxalase II encoded by GLO2 and GLO4. The expression of GLO1 is regulated by Hog1 mitogen-activated protein kinase and Msn2/Msn4 transcription factors under highly osmotic stress conditions. The physiological significance of GLO1 expression in response to osmotic stress is to combat the increase in the levels of methylglyoxal in cells during the production of glycerol as a compatible osmolyte. Deficiency in GLO1 in S. cerevisiae causes pleiotropic phenotypes in terms of stress response, because the steady state level of methylglyoxal increases in glo1Delta cells thereby constitutively activating Yap1 transcription factor. Yap1 is crucial for oxidative stress response, although methylglyoxal per se does not enhance the intracellular oxidation level in yeast, but it directly modifies cysteine residues of Yap1 that are critical for the nucleocytoplasmic localization of this b-ZIP transcription factor. Consequently, glyoxalase I can be defined as a negative regulator of Yap1 through modulating the intracellular methylglyoxal level. PMID- 21310261 TI - Methylglyoxal metabolism in trypanosomes and leishmania. AB - Methylglyoxal is a toxic by-product of glycolysis and other metabolic pathways. In mammalian cells, the principal route for detoxification of this reactive metabolite is via the glutathione-dependent glyoxalase pathway forming d-lactate, involving lactoylglutathione lyase (GLO1; EC 4.4.1.5) and hydroxyacylglutathione hydrolase (GLO2; EC 3.2.1.6). In contrast, the equivalent enzymes in the trypanosomatid parasites Trypanosoma cruzi and Leishmania spp. show >200-fold selectivity for glutathionylspermidine and trypanothione over glutathione and are therefore sensu stricto lactoylglutathionylspermidine lyases (EC 4.4.1.-) and hydroxyacylglutathionylspermidine hydrolases (EC 3.2.1.-). The unique substrate specificity of the parasite glyoxalase enzymes can be directly attributed to their unusual active site architecture. The African trypanosome differs from these parasites in that it lacks GLO1 and converts methylglyoxal to l-lactate rather than d-lactate. Since Trypanosoma brucei is the most sensitive of the trypanosomatids to methylglyoxal toxicity, the absence of a complete and functional glyoxalase pathway in these parasites is perplexing. Alternative routes of methylglyoxal detoxification in T. brucei are discussed along with the potential of exploiting trypanosomatid glyoxalase enzymes as targets for anti parasitic chemotherapy. PMID- 21310262 TI - Amphotericin B mediates killing in Cryptococcus neoformans through the induction of a strong oxidative burst. AB - We studied the effects of Amphotericin B (AmB) on Cryptococcus neoformans using different viability methods (CFUs enumeration, XTT assay and propidium iodide permeability). After 1h of incubation, there were no viable colonies when the cells were exposed to AmB concentrations >= 1 mg/L. In the same conditions, the cells did not become permeable to propidium iodide, a phenomenon that was not observed until 3h of incubation. When viability was measured in parallel using XTT assay, a result consistent with the CFUs was obtained, although we also observed a paradoxical effect in which at high AmB concentrations, a higher XTT reduction was measured than at intermediate AmB concentrations. This paradoxical effect was not observed after 3h of incubation with AmB, and lack of XTT reduction was observed at AmB concentrations higher than 1mg/L. When stained with dihydrofluorescein, AmB induced a strong intracellular oxidative burst. Consistent with oxidative damage, AmB induced protein carbonylation. Our results indicate that in C. neoformans, Amphotericin B causes intracellular damage mediated through the production of free radicals before damage on the cell membrane, measured by propidium iodide uptake. PMID- 21310263 TI - alpha-Synuclein overexpression impairs mitochondrial function by associating with adenylate translocator. AB - alpha-Synuclein (alpha-syn), a protein involved in the pathogenesis of Parkinson's disease (PD), is known to accumulate in mitochondria, disrupt mitochondrial function. However, the molecular mechanisms that link these pathological responses have not been investigated. In rats overexpressing alpha syn in the substantia nigra (SN) through adeno-associated virus (AAV) transduction, about 50% of tyrosine hydroxylase positive neurons were lost after 24 weeks. Overexpression of alpha-syn was also associated with morphological deformation of mitochondria and depolarization of the mitochondrial membrane potential (DeltaPsim). Both co-immunoprecipitation and confocal microscopy demonstrated that mitochondrial alpha-syn associated with adenylate translocator (ANT), a component of the mitochondrial permeability transition pore (mPTP). The depolarization of DeltaPsim was partially reversed in vitro by bongkrekic acid (BKA), an inhibitor of ANT, suggesting that the molecular association between alpha-syn and ANT facilitated DeltaPsim depolarization. Concomitant with alpha syn accumulation in mitochondria, abnormal mitochondrial morphology, DeltaPsim depolarization, and loss of TH-positive neurons, there was a decrease in apoptosis-inducing factor (AIF) within the mitochondrial matrix, suggesting possible translocation to the cytosol. Our findings suggest that overexpression of alpha-syn may cause mitochondrial defects in dopaminergic neurons of the substantia nigra through an association with adenylate translocator and activation of mitochondria-dependent cell death pathways. Disruption of normal mitochondrial function may contribute to the loss of dopaminergic neurons in Parkinson's disease. PMID- 21310264 TI - StarBRITE: the Vanderbilt University Biomedical Research Integration, Translation and Education portal. AB - StarBRITE is a one-stop, web-based research portal designed to meet the day-to day needs of the Vanderbilt University and Meharry Medical College research community during the planning and conduct of research studies. StarBRITE serves as the main online location for research support addressing issues such as identification and location of resources, identification of experts, guidance for regulatory applications and approvals, regulatory assistance, funding requests, research data planning and collection, and serves as a central repository for educational offerings. To date, there have been more than 590,038 StarBRITE hits by more than 6582 cumulative users. We present here StarBRITE design objectives, details about technical infrastructure and system components, status report and activity metrics for the first 2.75-years of operation, and a report of lessons learned during organizing, launching and refining the portal. PMID- 21310265 TI - Inferring cell cycle feedback regulation from gene expression data. AB - Feedback control is an important regulatory process in biological systems, which confers robustness against external and internal disturbances. Genes involved in feedback structures are therefore likely to have a major role in regulating cellular processes. Here we rely on a dynamic Bayesian network approach to identify feedback loops in cell cycle regulation. We analyzed the transcriptional profile of the cell cycle in HeLa cancer cells and identified a feedback loop structure composed of 10 genes. In silico analyses showed that these genes hold important roles in system's dynamics. The results of published experimental assays confirmed the central role of 8 of the identified feedback loop genes in cell cycle regulation. In conclusion, we provide a novel approach to identify critical genes for the dynamics of biological processes. This may lead to the identification of therapeutic targets in diseases that involve perturbations of these dynamics. PMID- 21310266 TI - Polystyrene nanoparticle trafficking across MDCK-II. AB - Polystyrene nanoparticles (PNP) cross rat alveolar epithelial cell monolayers via non-endocytic transcellular pathways. To evaluate epithelial cell type specificity of PNP trafficking, we studied PNP flux across Madin Darby canine kidney cell II monolayers (MDCK-II). The effects of calcium chelation (EGTA), energy depletion (sodium azide (NaN(3)) or decreased temperature), and endocytosis inhibitors methyl-beta-cyclodextrin (MBC), monodansylcadaverine and dynasore were determined. Amidine-modified PNP cross MDCK-II 500 times faster than carboxylate-modified PNP. PNP flux did not increase in the presence of EGTA. PNP flux at 4 degrees C and after treatment with NaN(3) decreased 75% and 80%, respectively. MBC exposure did not decrease PNP flux, whereas dansylcadaverine- or dynasore-treated MDCK-II exhibited ~80% decreases in PNP flux. Confocal laser scanning microscopy revealed intracellular colocalization of PNP with clathrin heavy chain. These data indicate that PNP translocation across MDCK-II (1) occurs via clathrin-mediated endocytosis and (2) is dependent on PNP physicochemical properties. We conclude that uptake/trafficking of nanoparticles (NPs) into/across epithelia depends both on properties of the NPs and on the specific epithelial cell type. PMID- 21310267 TI - Multistability in platelets and their response to gold nanoparticles. AB - The nanoparticle (NP) response of platelets is shown to be critically dependent on extent of preactivation of platelets by an agonist like ADP. A transition from de-aggregatory to aggregatory state is triggered in the presence of gold NPs (AuNP) only in such critical conditions. Adhered and suspended platelets respond differentially to NPs. Preactivation in the adhered state induced by shear force explains such observation. The NP effect is associated with enhanced release reaction, tyrosine phosphorylation and CD62P expression level. Unlike cancer cells, whose response is maximal when NP size is optimal (within the range 50 - 70 nm), the platelet response monotonically increases with reduction of the AuNP size. The uptake study, using quenching of quinacrine hydrochloride fluorescence by AuNP, indicates that accumulation 18 nm AuNP is several-fold higher than the 68 nm AuNP. It is further shown that AuNP response can provide a simple measure for thrombotic risk associated with nano-drugs. FROM THE CLINICAL EDITOR: Platelet aggregation can be triggered in the presence of gold nanoparticles (AuNP). Platelet response monotonically increases with reduction of the AuNP size. AuNP response can provide a simple measure for thrombotic risk associated with nano-drugs. PMID- 21310268 TI - Neonatal stress increases respiratory instability in rat pups. AB - Neonatal maternal separation (NMS) is a form of stress that has persistent, sex specific effects on respiratory control development. In adult male (but not female) rats, NMS increases the hypoxic ventilatory response and augments respiratory instability during sleep; however, the effects of NMS on respiratory control prior to puberty are unknown. This study tested the hypothesis that NMS augments respiratory instability and the O(2) chemosensitivity in 12 days old rats. Pups subjected to NMS were placed in an incubator 3h/day from P3 to P12. Controls were undisturbed. Breathing and apnea index were measured in normoxia with plethysmography. The ventilatory chemoreflex was assessed by measuring the increase in breathing frequency upon brief exposure to a hypoxic challenge ( [Formula: see text]; 5 min). In normoxia, NMS augments the coefficient of variation (CV; an index of respiratory instability) of respiratory frequency and the number of apneas; this effect was more pronounced in male pups. We conclude that disruption of respiratory regulation by NMS is already apparent at P12. Based on results showing that plasma corticosterone levels of NMS pups were still elevated one day after the last NMS episode and the lack of effect of NMS on the O(2) chemoreflex index, we propose that disruption of hypothalamic regulation contributes to respiratory instability in NMS pups. PMID- 21310269 TI - Improvement of Bacillus thuringiensis bioinsecticide production by sporeless and sporulating strains using response surface methodology. AB - Statistical experimental designs, involving a Plackett-Burman design followed by a rotatable central composite design were used to optimize the culture medium constituents for Bacillus thuringiensis bioinsecticide production. This was carried out by using firstly an asporogenic strain and extrapolated to some sporeless and sporulating strains. Initial screening of production parameters was performed and the variables with statistically significant effects on delta endotoxin production were identified: glucose, glycerol, yeast extract and MnSO(4). These variables were selected for further optimization by response surface methodology. The obtained results revealed that the optimum culture medium for delta-endotoxin production consists of 22.5 g/l of glucose, 4.8g/l of glycerol, 5.8 g/l of yeast extract and 0.008 g/l of MnSO(4). Under these conditions, delta-endotoxin production was 2,130 and 2,260 mg/l into 250 and 1,000 ml flask respectively, which represent more than 38% improvement in toxin production over the basal medium (1,636 mg/l). Such medium composition was shown to be suitable for overproducing delta-endotoxins by sporeless and sporulating strains. PMID- 21310270 TI - Alteration of plasma membrane-bound redox systems of iron deficient pea roots by chitosan. AB - Iron is essential for all living organisms and plays a crucial role in pathogenicity. This study presents the first proteome analysis of plasma membranes isolated from pea roots. Protein profiles of four different samples (+Fe, +Fe/Chitosan, -Fe, and -Fe/Chitosan) were compared by native IEF-PAGE combined with in-gel activity stains and DIGE. Using DIGE, 89 proteins of interest were detected in plasma membrane fractions. Data revealed a differential abundance of several spots in all samples investigated. In comparison to the control and -FeCh the abundance of six protein spots increased whereas 56 spots decreased in +FeCh. Altered protein spots were analyzed by MALDI-TOF-TOF mass spectrometry. Besides stress-related proteins, transport proteins and redox enzymes were identified. Activity stains after native PAGE and spectrophotometric measurements demonstrated induction of a ferric-chelate reductase (-Fe) and a putative respiratory burst oxidase homolog (-FeCh). However, the activity of the ferric-chelate reductase decreased in -Fe plants after elicitor treatment. The activity of plasma membrane-bound class III peroxidases increased after elicitor treatment and decreased under iron-deficiency, whereas activity of quinone reductases decreased mostly after elicitor treatment. Possible functions of proteins identified and reasons for a weakened pathogen response of iron deficient plants were discussed. PMID- 21310271 TI - Proteomics for development of vaccine. AB - The success of genome projects has provided us with a vast amount of information on genes of many pathogenic species and has raised hopes for rapid progress in combating infectious diseases, both by construction of new effective vaccines and by creating a new generation of therapeutic drugs. Proteomics, a strategy complementary to the genomic-based approach, when combined with immunomics (looking for immunogenic proteins) and vaccinomics (characterization of host response to immunization), delivers valuable information on pathogen-host cell interaction. It also speeds the identification and detailed characterization of new antigens, which are potential candidates for vaccine development. This review begins with an overview of the global status of vaccinology based on WHO data. The main part of this review describes the impact of proteomic strategies on advancements in constructing effective antibacterial, antiviral and anticancer vaccines. Diverse aspects of disease mechanisms and disease preventions have been investigated by proteomics. PMID- 21310272 TI - Compound heterozygous loss of Ext1 and Ext2 is sufficient for formation of multiple exostoses in mouse ribs and long bones. AB - Multiple Hereditary Exostoses (MHE) syndrome is caused by haploinsufficiency in Golgi-associated heparan sulfate polymerases EXT1 or EXT2 and is characterized by formation of exostoses next to growing long bones and other skeletal elements. Recent mouse studies have indicated that formation of stereotypic exostoses requires a complete loss of Ext expression, suggesting that a similar local loss of EXT function may underlie exostosis formation in patients. To further test this possibility and gain greater insights into pathogenic mechanisms, we created heterozygous Ext1(+/-) and compound Ext1(+/-)/Ext2(+/-) mice. Like Ext2(+/-) mice described previously (Stickens et al. Development 132:5055), Ext1(+/-) mice displayed rib-associated exostosis-like outgrowths only. However, compound heterozygous mice had nearly twice as many outgrowths and, more importantly, displayed stereotypic growth plate-like exostoses along their long bones. Ext1(+/ )Ext2(+/-) exostoses contained very low levels of immuno-detectable heparan sulfate, and Ext1(+/-)Ext2(+/-) chondrocytes, endothelial cells and fibroblasts in vitro produced shortened heparan sulfate chains compared to controls and responded less vigorously to exogenous factors such as FGF-18. We also found that rib outgrowths formed in Ext1(f/+)Col2Cre and Ext1(f/+)Dermo1Cre mice, suggesting that ectopic skeletal tissue can be induced by conditional Ext ablation in local chondrogenic and/or perichondrial cells. The study indicates that formation of stereotypic exostoses requires a significant, but not complete, loss of Ext expression and that exostosis incidence and phenotype are intimately sensitive to, and inversely related to, Ext expression. The data also indicate that the nature and organization of ectopic tissue may be influenced by site-specific anatomical cues and mechanisms. PMID- 21310273 TI - Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect. AB - Neuromuscular junctions (NMJs) are synapses that transmit impulses from motor neurons to skeletal muscle fibers leading to muscle contraction. Study of hereditary disorders of neuromuscular transmission, termed congenital myasthenic syndromes (CMS), has helped elucidate fundamental processes influencing development and function of the nerve-muscle synapse. Using genetic linkage, we find 18 different biallelic mutations in the gene encoding glutamine-fructose-6 phosphate transaminase 1 (GFPT1) in 13 unrelated families with an autosomal recessive CMS. Consistent with these data, downregulation of the GFPT1 ortholog gfpt1 in zebrafish embryos altered muscle fiber morphology and impaired neuromuscular junction development. GFPT1 is the key enzyme of the hexosamine pathway yielding the amino sugar UDP-N-acetylglucosamine, an essential substrate for protein glycosylation. Our findings provide further impetus to study the glycobiology of NMJ and synapses in general. PMID- 21310274 TI - A fast, powerful method for detecting identity by descent. AB - We present a method, fastIBD, for finding tracts of identity by descent (IBD) between pairs of individuals. FastIBD can be applied to thousands of samples across genome-wide SNP data and is significantly more powerful for finding short tracts of IBD than existing methods for finding IBD tracts in such data. We show that fastIBD can detect facets of population structure that are not revealed by other methods. In the Wellcome Trust Case Control Consortium bipolar disorder case-control data, we find a genome-wide excess of IBD in case-case pairs of individuals compared to control-control pairs. We show that this excess can be explained by the geographical clustering of cases. We also show that it is possible to use fastIBD to generate highly accurate estimates of genome-wide IBD sharing between pairs of distant relatives. This is useful for estimation of relationship and for adjusting for relatedness in association studies. FastIBD is incorporated in the freely available Beagle software package. PMID- 21310275 TI - Development and validation of a computational method for assessment of missense variants in hypertrophic cardiomyopathy. AB - Assessing the significance of novel genetic variants revealed by DNA sequencing is a major challenge to the integration of genomic techniques with medical practice. Many variants remain difficult to classify by traditional genetic methods. Computational methods have been developed that could contribute to classifying these variants, but they have not been properly validated and are generally not considered mature enough to be used effectively in a clinical setting. We developed a computational method for predicting the effects of missense variants detected in patients with hypertrophic cardiomyopathy (HCM). We used a curated clinical data set of 74 missense variants in six genes associated with HCM to train and validate an automated predictor. The predictor is based on support vector regression and uses phylogenetic and structural features specific to genes involved in HCM. Ten-fold cross validation estimated our predictor's sensitivity at 94% (95% confidence interval: 83%-98%) and specificity at 89% (95% confidence interval: 72%-100%). This corresponds to an odds ratio of 10 for a prediction of pathogenic (95% confidence interval: 4.0-infinity), or an odds ratio of 9.9 for a prediction of benign (95% confidence interval: 4.6-21). Coverage (proportion of variants for which a prediction was made) was 57% (95% confidence interval: 49%-64%). This performance exceeds that of existing methods that are not specifically designed for HCM. The accuracy of this predictor provides support for the clinical use of automated predictions alongside family segregation and population frequency data in the interpretation of new missense variants and suggests future development of similar tools for other diseases. PMID- 21310276 TI - Identification and characterization of an inborn error of metabolism caused by dihydrofolate reductase deficiency. AB - Dihydrofolate reductase (DHFR) is a critical enzyme in folate metabolism and an important target of antineoplastic, antimicrobial, and antiinflammatory drugs. We describe three individuals from two families with a recessive inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency due to a germline missense mutation in DHFR, resulting in profound enzyme deficiency. We show that cerebral folate levels, anemia, and pancytopenia of DHFR deficiency can be corrected by treatment with folinic acid. The characterization of this disorder provides evidence for the link between DHFR and metabolism of cerebral tetrahydrobiopterin, which is required for the formation of dopamine, serotonin, and norepinephrine and for the hydroxylation of aromatic amino acids. Moreover, this relationship provides insight into the role of folates in neurological conditions, including depression, Alzheimer disease, and Parkinson disease. PMID- 21310278 TI - Maternal mortality in the United States: a human rights failure. PMID- 21310277 TI - Dihydrofolate reductase deficiency due to a homozygous DHFR mutation causes megaloblastic anemia and cerebral folate deficiency leading to severe neurologic disease. AB - The importance of intracellular folate metabolism is illustrated by the severity of symptoms and complications caused by inborn disorders of folate metabolism or by folate deficiency. We examined three children of healthy, distantly related parents presenting with megaloblastic anemia and cerebral folate deficiency causing neurologic disease with atypical childhood absence epilepsy. Genome-wide homozygosity mapping revealed a candidate region on chromosome 5 including the dihydrofolate reductase (DHFR) locus. DHFR sequencing revealed a homozygous DHFR mutation, c.458A>T (p.Asp153Val), in all siblings. The patients' folate profile in red blood cells (RBC), plasma, and cerebrospinal fluid (CSF), analyzed by liquid chromatography tandem mass spectrometry, was compatible with DHFR deficiency. DHFR activity and fluorescein-labeled methotrexate (FMTX) binding were severely reduced in EBV-immortalized lymphoblastoid cells of all patients. Heterozygous cells displayed intermediate DHFR activity and FMTX binding. RT-PCR of DHFR mRNA revealed no differences between wild-type and DHFR mutation-carrying cells, whereas protein expression was reduced in cells with the DHFR mutation. Treatment with folinic acid resulted in the resolution of hematological abnormalities, normalization of CSF folate levels, and improvement of neurological symptoms. In conclusion, the homozygous DHFR mutation p.Asp153Val causes DHFR deficiency and leads to a complex hematological and neurological disease that can be successfully treated with folinic acid. DHFR is necessary for maintaining sufficient CSF and RBC folate levels, even in the presence of adequate nutritional folate supply and normal plasma folate. PMID- 21310279 TI - Expanding medical abortion: can medical abortion be effectively provided without the routine use of ultrasound? AB - Medical abortion studies have traditionally relied on ultrasound to confirm gestational age, intrauterine location and abortion completion. However, the routine dependence on ultrasound can limit access to safe services for women living in low resource settings that are often most in need of safe abortion care. This review discusses the literature surrounding the safe provision of medical abortion without the routine use of ultrasonography and concludes that clinicians can use the reported last menstrual period (LMP) and physical examination to reasonably estimate gestational age. Completed pregnancy expulsion can be confirmed primarily through history and physical examination with some studies indicating that urine pregnancy tests may also play a limited role. Central to the discussion of whether medical abortion can be provided in most low resource settings without the routine use of ultrasonography is the fact that the mifepristone-misoprostol regimen is a highly effective procedure for pregnancy termination through 63 days' gestation. PMID- 21310280 TI - The management of unacceptable bleeding patterns in etonogestrel-releasing contraceptive implant users. AB - The aim of this guidance is to review the management of unacceptable vaginal bleeding patterns in etonogestrel (ENG)-releasing contraceptive implant users concentrating, where possible, on the evidence for pharmacological treatments and identifying a pragmatic approach where this is not possible. This article was developed in accordance with methodology used for producing Royal College of Obstetricians and Gynaecologists' Green Top Guidelines. The Cochrane Library (including the Cochrane Database of Systematic Reviews, DARE and EMBASE) and Medline (1966-2010) were searched using the relevant MeSH terms, including all subheadings, and this was combined with a keyword search. Search words included "progestogen only contraceptives," "contraceptive implants," "progestogen implants," "etonogestrel implants," "irregular bleeding," "unpredictable bleeding," "bleeding irregularity" and "bleeding pattern," and the search was limited to humans and English language. Enquiries for relevant information were also made to the pharmaceutical industry and researchers for missing studies. Although this is not a systematic review, two of the authors (D.M., I.S.F.), qualitatively assessed those papers reporting quantitative results involving treatments given either to stop or prevent bleeding in ENG or levonorgestrel contraceptive implants users. PMID- 21310281 TI - Levonorgestrel-releasing and copper intrauterine devices and the risk of breast cancer. AB - BACKGROUND: This study compares the risk of breast cancer for levonorgestrel releasing intrauterine devices (LNG(IUD)) versus copper IUDs (CU(IUD)) in women younger than 50 years of age. STUDY DESIGN: Retrospective, population-based, case control study using cancer registers in Finland and Germany, powered to exclude a 1.5-fold risk of breast cancer. RESULTS: Analysis of 5113 breast cancer cases diagnosed 2000-2007 and 20,452 controls - matched by year of birth and area of residence - yielded relative risk estimates approaching unity with 95% CI crossing 1.0 for all comparisons, including ever-use of LNG(IUD) versus CU(IUD) (adjusted OR, 0.99; 95% CI, 0.88-1.12) and current use at time of diagnosis (adjusted OR, 0.85; 95% CI, 0.52-1.39), as well as for sub-analyses by country, age, tumor characteristics and period, recency and duration of use prior to diagnosis. CONCLUSION: This study does not indicate an increased risk of breast cancer for users of LNG(IUD). No indications for tumor promotion or tumor induction were found. PMID- 21310282 TI - The effect of depot medroxyprogesterone acetate (DMPA) on bone mineral density (BMD) and evaluating changes in BMD after discontinuation of DMPA in Chinese women of reproductive age. AB - BACKGROUND: Depot medroxyprogesterone acetate (DMPA) as a hormonal contraceptive is highly effective and widely used, but it may reduce bone mineral density (BMD) and increase the risk of osteoporosis. We compared BMD between users of intramuscular DMPA and nonhormonal subjects and evaluated the changes in BMD after discontinuation of DMPA. STUDY DESIGN: The study included 68 women aged between 25 and 40 years using DMPA for 24 months and 59 women aged between 25 and 40 years using nonhormonal contraception as nonusers of hormonal contraception. Sixty-one women in the DMPA group and 52 women in the nonusers of hormonal contraception group completed the 2-year post-treatment periods. BMD of the lumbar spine and femoral neck was measured every 12 months for 48 months using dual-energy X-ray absorptiometry, comparing mean BMD changes in DMPA users and discontinuers with nonusers. RESULTS: At 24 months of treatment, as compared to baseline, the mean BMD of DMPA users in lumbar spine and femoral neck decreased by 5.52% and 6.35%, respectively. Lumbar spine and femoral neck BMD in women who used DMPA significantly decreased compared to the nonusers (p<.001). At 24 months after DMPA discontinuation, the mean BMD values in DMPA users increased significantly. Although the values of the lumbar spine and femoral neck BMD in DMPA users were still 1.08% and 2.30%, respectively, below their baseline values, there were no significant difference when compared to nonusers (p>.05). CONCLUSION: These results show that BMD declined during use of DMPA in women aged 25 to 40 years. Bone loss occurring with DMPA use is reversible after DMPA discontinuation. PMID- 21310283 TI - Effects of an estrogen-free, desogestrel-containing oral contraceptive in women with migraine with aura: a prospective diary-based pilot study. AB - BACKGROUND: Migraine with aura (MA) is a contraindication to the use of combined oral contraceptives (COCs) because of the increased risk of ischemic stroke. Progestogen-only contraceptive pill (POP) is a safe alternative to COCs and it is preferable in women with cerebrovascular diseases or risk factors for stroke. STUDY DESIGN: Prospective diary-based pilot study. Thirty women with MA (n = 15 who have never used COCs and n = 15 who had previously used COCs were diagnosed according to the International Headache Society criteria. The observational period lasted 9 months during which women filled in a diary with the clinical characteristics of headache attacks. After a 3-month run-in period, each subject received an estrogen-free desogestrel (DSG) (75 mcg/day)-containing OC (Cerazette((r)); Schering-Plough, formerly NV Organon, Oss, The Netherlands). Follow-up evaluations were planned at the end of the third and sixth month of treatment. RESULTS: The number (mean+/-S.D.) of migraine attacks was significantly reduced both in previous COCs users (from 3.9+/-1.0 to 2.9+/-0.8; p<.001) and nonusers (from 3.2+/-0.9 to 2.6+/-1.3; p<.02) following 6 months of POP use in comparison with the run-in period. Duration of headache pain did not differ significantly in both groups throughout the study. Interestingly enough, a beneficial POP effect on the duration (mean+/-S.D.) of visual aura (from 16.3+/ 9.5 to 11.4+/-5.6 min) and on the total duration (mean+/-S.D.) of neurological symptoms (from 33.6+/-23.3 to 18.6+/-18.0 min) was only significantly reported by previous COCs users (p<.001, for both) by the end of the study period. The POP was well tolerated by each woman and the bleeding pattern was variable with a tendency towards infrequent bleeding. CONCLUSIONS: The present study supports the use of the POP containing desogestrel in a population of women with MA and underlines a positive effect on symptoms of aura, especially in MA sensitive to previous use of COCs. PMID- 21310284 TI - Pregnane progestin contraception in systemic lupus erythematosus: a longitudinal study of 187 patients. AB - BACKGROUND: Systemic lupus erythematosus (SLE) affects women of child-bearing age. Combined oral contraceptives can worsen the course and increase the risk of thrombosis. The objectives of this study were to provide an alternative contraception and thus evaluate the gynecological tolerability of pregnane progestins (PPs) in SLE patients. Systemic lupus erythematosus disease activity and vascular tolerance were also reported. STUDY DESIGN: We used two PP with antigonadotropic potencies, chlormadinone acetate (CMA, 10 mg/day) and cyproterone acetate (CPA, 50 mg/day), administered orally for contraception in 187 SLE patients observed for 46+/-34.6 months (mean+/-S.E.), i.e., 6854 women months. RESULTS: The gynecological tolerability was satisfactory: breakthrough bleeding was reported in 17.7% patients using CPA and 12.6% patients using CMA. No pregnancy was observed in the women followed in this cohort study. One deep vein thrombosis, one myocardial infarction, and one tibial posterior arterial occlusion were observed, giving an incidence for venous thromboembolism of 1.39/year*1000 women (95% CI 0-4.12) and for macroarterial disease an incidence of 2.79/year*1000 women (95% CI 0-6.65). Disease activity was less than before progestins. CONCLUSIONS: Pregnane progestin contraception is effective and well tolerated, thus providing SLE patients an excellent contraceptive alternative to the currently used methods. PMID- 21310285 TI - Postpartum contraception: needs vs. reality. AB - BACKGROUND: The postpartum time is a unique time to address patient's contraceptive needs and provide education. There are little data to suggest the best approach to provide information about contraception after delivery. STUDY DESIGN: Postpartum patients in an urban university hospital were asked to complete a written survey on postpartum contraception. Participants were asked about contraception counseling offered both antepartum and postpartum. Participants were also asked if they would have elected to have an intrauterine device (IUD) inserted immediately after delivery. Participants were contacted 4-6 months after delivery regarding ongoing contraceptive use. RESULTS: One hundred seventy-five surveys were completed; 77% (134) reported discussing contraception antepartum, and 87% (153), postpartum. Thirty percent of women reported discussing IUD insertion at an antepartum visit and 31% reported discussing it in the hospital prior to discharge. Twenty-three percent (39) of women would have elected immediate post-placental IUD placement if available. Of the 59 patients who were able to be contacted 4-6 months after delivery, 5% reported using an IUD. Twenty-two percent (13) of the participants contacted at follow-up still desired an IUD, of which 62% would have elected postplacental placement, if available. Twenty-nine percent of women reported using no contraceptive method and 32% reported using a method which is not highly effective. CONCLUSIONS: Prenatal visits and postpartum contact with providers create an opportunity to discuss family planning and contraception and most patients report receiving counseling. However, significantly fewer reported continued contraceptive use at 4-6 months postpartum. Initiation of postplacental IUD placement would be acceptable and would increase contraceptive use at 6 months postpartum. PMID- 21310286 TI - Levonorgestrel-releasing intrauterine system for the management of heavy menstrual bleeding in women with inherited bleeding disorders: long-term follow up. AB - BACKGROUND: There are currently limited data on the use of the levonorgestrel releasing intrauterine system (LNG-IUS) for the management of heavy menstrual bleeding (HMB) in women with inherited bleeding disorders (IBDs) particularly on its long-term (>12 months) efficacy. STUDY DESIGN: This study involves a case series of women with IBDs who received the LNG-IUS as treatment for HMB. Menstrual blood loss before its insertion and at the time of follow-up was assessed by the pictorial blood-loss assessment chart (PBAC) and hemoglobin (Hb) concentrations. A questionnaire was used to evaluate quality of life (QOL) during menstruation before and after insertion of the LNG-IUS. RESULTS: Twenty-six women were included. The median duration of LNG-IUS use at follow-up was 33 months (range, 14-103). The median PBAC score decreased from 255 (range, 134-683) to 35 (range, 0-89) with LNG-IUS use. The median Hb concentrations (11.2 to 13.2 g/dL) and QOL scores (median, 26 to 52) improved significantly with LNG-IUS use (p<.01). CONCLUSION: The LNG-IUS appears to be an effective long-term treatment for HMB in women with IBDs. PMID- 21310287 TI - Three new female condoms: which do South-African women prefer? AB - BACKGROUND: The widespread distribution of female condoms (FCs) in developing countries has been hindered by high unit cost, making new less expensive devices a priority for donor agencies. STUDY DESIGN: Randomized, crossover study assessing product preference, safety, acceptability and function of three new FCs (PATH Woman's Condom, FC2 and V-Amour) among 170 women in Durban, South Africa. A subsequent "simulated market" study provided participants with free choice of FCs and assessed condom uptake over 3 months. RESULTS: Of the 160 women who used at least one FC of each type, 47.5% preferred the PATH Woman's Condom (WC), 35.6% preferred FC2 and 16.3% preferred V-Amour (p<.001). Women rated the WC better than FC2 and V-Amour for appearance, ease of use and overall fit and better than V-Amour for feel. WC was rated worse than FC2 and V-Amour for lubrication volume. The simulated market demonstrated similar preferences. Total clinical failure rates (i.e., the types of failures that could result in pregnancy or STI) were low (<4%), regardless of condom type. CONCLUSIONS: Three new FC types functioned similarly and were generally acceptable. Most participants preferred WC and FC2 over V-Amour, and WC was preferred over FC2 in several acceptability measures. PMID- 21310288 TI - Study on the mechanical properties of Cu/LDPE composite IUDs. AB - BACKGROUND: The copper/low-density polyethylene composite (Cu/LDPE composite) intrauterine devices (IUDs), which can eliminate or lessen the side effects of existing IUDs, have been developed in our laboratory. As a novel type of copper containing IUDs, it is not clear whether the mechanical properties of the Cu/LDPE composite IUDs can meet the need of clinical use or not. Therefore, the mechanical properties of the Cu/LDPE composite IUDs have been studied in the present article. STUDY DESIGN: The influence of copper particle content and size on the mechanical properties of the Cu/LDPE composite IUDs was analyzed firstly to provide guidance for the material composition design of the Cu/LDPE composite IUDs, and then the BaSO(4)/LDPE composite, which has been applied as a framework of the existing copper-containing IUDs in clinical use for decades, has been used as reference to judge whether the mechanical properties of the Cu/LDPE composite IUDs can meet the need of clinical use or not. However, the mechanical properties of IUDs cannot be characterized directly. Therefore, the mechanical properties of both the Cu/LDPE composite IUDs and the framework of the existing copper containing IUDs were investigated by means of tensile test using standard tensile samples, and the fracture surface morphology of the tensile samples was characterized by scanning electron microscopy (SEM). RESULTS: Both the elongation at break and the tensile strength decrease with increasing of copper particle content and increase with increasing of the copper particle size, while the elastic modulus shows an opposite tendency. The tensile strength and elastic modulus of both the Cu/LDPE microcomposite IUDs and the Cu/LDPE nanocomposite IUDs with 25 wt.% of copper particles are higher than those of existing copper containing IUDs (TCu220C; its framework is made of the BaSO(4)/LDPE composite with 20 wt.% of BaSO(4)). CONCLUSIONS: The content and size of the copper particles have significant effect on the mechanical properties of Cu/LDPE composite IUDs. The mechanical properties of both the Cu/LDPE microcomposite IUDs and the Cu/LDPE nanocomposite IUDs with 25 wt.% of copper particles were superior to that of existing copper-containing IUDs, indicating that the novel Cu/LDPE composite IUDs can satisfy the requirement of mechanical properties in clinical application. PMID- 21310289 TI - Exploration of a new procedure for sterilization by intrauterine instillation of a methylcellulose gel. AB - BACKGROUND: Our goal was to evaluate a new gel and procedure for non-surgical sterilization. STUDY DESIGN: We injected a methylcellulose-based gel containing a radiographic contrast agent into the uteri of 15 women, varying the gel viscosity, volume injected, injection speed and continuity and duration of cervical blockage. We monitored gel distribution with fluoroscopy and spot imaging, and subjects' condition by interview and examination. RESULTS: The gel and procedure were safe and acceptable. The low-viscosity gel reached at least the ampullae of all tubes, but retention in the isthmuses was shorter than 5 min in more than 25% of tubes studied. The high-viscosity gel did not consistently pass into and through the fallopian tubes. CONCLUSIONS: This study did not identify a gel and insertion procedure that would reliably provide exposure of both fallopian tubes to a sclerosing agent for more than a brief period of time. PMID- 21310290 TI - Social support in the post-abortion recovery room: evidence from patients, support persons and nurses in a Vancouver clinic. AB - BACKGROUND: The benefits of social support in post-surgical recovery are well documented; social support decreases preoperative stress and postoperative recovery time. However, a paucity of studies have examined the effect of social support in the context of pregnancy termination. This study is the first to examine the effect of postoperative accompaniment from the patient, support person and nurses' perspective. STUDY DESIGN: This study was carried out in two phases. In Phase I, no accompaniment was allowed in the post-anesthesia recovery room (PAR); in Phase II, accompaniment was permitted. All participants completed pre- and postoperative questionnaires. RESULTS: The perception of accompaniment was overwhelmingly positive in patients and support people. Patients in Phase II demonstrated a high (over 95%) acceptance of accompaniment in the recovery room. It was found that 96.8% reported they would choose to be accompanied in the recovery room again if they had to have another abortion. Support persons felt very strongly that their presence was helpful to the patient. The decrease in pre to postoperative anxiety levels was significantly greater in those women who were accompanied. However, overall, nurses demonstrated a negative attitude towards accompaniment in the recovery room. CONCLUSION: In summary, the presence of a support person in the PAR was perceived in a positive manner by patients and support people. However, the reasoning behind the negative opinion of nurses requires further study before PAR accompaniment can be considered a possibility in the context of pregnancy termination. PMID- 21310291 TI - A family planning clinic partner violence intervention to reduce risk associated with reproductive coercion. AB - BACKGROUND: This study examined the efficacy of a family-planning-clinic-based intervention to address intimate partner violence (IPV) and reproductive coercion. STUDY DESIGN: Four free-standing urban family planning clinics in Northern California were randomized to intervention (trained family planning counselors) or standard of care. English-speaking and Spanish-speaking females ages 16-29 years (N = 906) completed audio computer-assisted surveys prior to a clinic visit and 12-24 weeks later (75% retention rate). Analyses included assessment of intervention effects on recent IPV, awareness of IPV services and reproductive coercion. RESULTS: Among women reporting past-3-months IPV at baseline, there was a 71% reduction in the odds of pregnancy coercion among participants in intervention clinics compared to participants in the control clinics that provided standard of care. Women in the intervention arm were more likely to report ending a relationship because the relationship was unhealthy or because they felt unsafe regardless of IPV status (adjusted odds ratio = 1.63; 95% confidence interval=1.01-2.63). CONCLUSIONS: Results of this pilot study suggest that this intervention may reduce the risk for reproductive coercion from abusive male partners among family planning clients and support such women to leave unsafe relationships. PMID- 21310292 TI - Ectopic pregnancy after levonorgestrel emergency contraception. AB - BACKGROUND: Although the possibility of ectopic pregnancy after intake of levonorgestrel (LNG) as an emergency contraceptive (EE) pill is well-known, the causality has not been well established. CASE: A 27-year-old nulliparous woman with regular menstrual periods took 1.5-mg LNG EE midcyclic 5 h after an unprotected intercourse. She had prolonged vaginal bleeding at the expected time. She consulted the general practitioner because of continuous vaginal bleeding for 4 weeks and lower abdominal pain. The pregnancy test was positive, and her symptoms and clinical findings suggested an ectopic pregnancy. At emergency surgery, she was found to have a left tubal pregnancy. CONCLUSION: The possible role of 1.5-mg LNG EE in causing ectopic pregnancy is discussed. A high serum LNG concentration decreases ciliary activity and tube motility, but further epidemiological studies are necessary to establish the risk of ectopic pregnancy following intake of LNG EE. PMID- 21310293 TI - Drosophila models of Parkinson's disease. AB - Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder principally affecting the dopaminergic neurons of the substantia nigra. The pathogenic mechanisms are unknown and there are currently no cure or disease modifying therapies. Recent genetic linkage studies have begun to identify single gene mutations responsible for rare heritable forms of PD and define genetic risk factors contributing to disease prevalence in sporadic cases. These findings provide an opportunity to gain insight into the molecular mechanisms of this disorder through the creation and analysis of appropriate genetic models. One model system that has proven surprisingly tractable for these studies is the fruit fly, Drosophila melanogaster. Analysis of a number of Drosophila models of PD has revealed some profound and sometimes surprising insights into PD pathogenesis. Moreover, these models can be used to investigate potential therapeutic strategies that may be effective in vivo, and tests have highlighted the efficacy of a number of neuroprotective compounds. Here, I review the methodologies employed in developing the various Drosophila models, and the recent advances that these models in particular have contributed to our understanding of the mechanisms that underlie PD pathogenesis and possible treatment strategies. PMID- 21310294 TI - Cell cycle regulated gene expression in yeasts. AB - The regulation of gene expression through the mitotic cell cycle, so that genes are transcribed at particular cell cycle times, is widespread among eukaryotes. In some cases, it appears to be important for control mechanisms, as deregulated expression results in uncontrolled cell divisions, which can cause cell death, disease, and malignancy. In this review, I describe the current understanding of such regulated gene expression in two established simple eukaryotic model organisms, the budding yeast Saccharomyces cerevisiae and the fission yeast Schizosaccharomyces pombe. In these two yeasts, the global pattern of cell cycle gene expression has been well described, and most of the transcription factors that control the various waves of gene expression, and how they are in turn themselves regulated, have been characterized. As related mechanisms occur in all other eukaryotes, including humans, yeasts offer an excellent paradigm to understand this important molecular process. PMID- 21310295 TI - RNA editing by mammalian ADARs. AB - The main type of RNA editing in mammals is the conversion of adenosine to inosine which is translated as if it were guanosine. The enzymes that catalyze this reaction are ADARs (adenosine deaminases that act on RNA), of which there are four in mammals, two of which are catalytically inactive. ADARs edit transcripts that encode proteins expressed mainly in the CNS and editing is crucial to maintain a correctly functioning nervous system. However, the majority of editing has been found in transcripts encoding Alu repeat elements and the biological role of this editing remains a mystery. This chapter describes in detail the different ADAR enzymes and the phenotype of animals that are deficient in their activity. Besides being enzymes, ADARs are also double-stranded RNA-binding proteins, so by binding alone they can interfere with other processes such as RNA interference. Lack of editing by ADARs has been implicated in disorders such as forebrain ischemia and Amyotrophic Lateral Sclerosis (ALS) and this will also be discussed. PMID- 21310296 TI - Cell entry of enveloped viruses. AB - Enveloped viruses penetrate their cell targets following the merging of their membrane with that of the cell. This fusion process is catalyzed by one or several viral glycoproteins incorporated on the membrane of the virus. These envelope glycoproteins (EnvGP) evolved in order to combine two features. First, they acquired a domain to bind to a specific cellular protein, named "receptor." Second, they developed, with the help of cellular proteins, a function of finely controlled fusion to optimize the replication and preserve the integrity of the cell, specific to the genus of the virus. Following the activation of the EnvGP either by binding to their receptors and/or sometimes the acid pH of the endosomes, many changes of conformation permit ultimately the action of a specific hydrophobic domain, the fusion peptide, which destabilizes the cell membrane and leads to the opening of the lipidic membrane. The comprehension of these mechanisms is essential to develop medicines of the therapeutic class of entry inhibitor like enfuvirtide (Fuzeon) against human immunodeficiency virus (HIV). In this chapter, we will summarize the different envelope glycoprotein structures that viruses develop to achieve membrane fusion and the entry of the virus. We will describe the different entry pathways and cellular proteins that viruses have subverted to allow infection of the cell and the receptors that are used. Finally, we will illustrate more precisely the recent discoveries that have been made within the field of the entry process, with a focus on the use of pseudoparticles. These pseudoparticles are suitable for high-throughput screenings that help in the development of natural or artificial inhibitors as new therapeutics of the class of entry inhibitors. PMID- 21310297 TI - Molecular signaling how do axons die? AB - Axons depend critically on axonal transport both for supplying materials and for communicating with cell bodies. This chapter looks at each activity, asking what aspects are essential for axon survival. Axonal transport declines in neurodegenerative disorders, such as Alzheimer's disease, amyotrophic lateral sclerosis, and multiple sclerosis, and in normal ageing, but whether all cargoes are equally affected and what limits axon survival remains unclear. Cargoes can be differentially blocked in some disorders, either individually or in groups. Each missing protein cargo results in localized loss-of-function that can be partially modeled by disrupting the corresponding gene, sometimes with surprising results. The axonal response to losing specific proteins also depends on the rates of protein turnover and on whether the protein can be locally synthesized. Among cargoes with important axonal roles are components of the PI3 kinase, Mek/Erk, and Jnk signaling pathways, which help to communicate with cell bodies and to regulate axonal transport itself. Bidirectional trafficking of Bdnf, NT-3, and other neurotrophic factors contribute to intra- and intercellular signaling, affecting the axon's cellular environment and survival. Finally, several adhesion molecules and gangliosides are key determinants of axon survival, probably by mediating axon-glia interactions. Thus, failure of long-distance intracellular transport can deprive axons of one, few, or many cargoes. This can lead to axon degeneration either directly, through the absence of essential axonal proteins, or indirectly, through failures in communication with cell bodies and nonneuronal cells. PMID- 21310299 TI - A high ratio of dietary n-6/n-3 polyunsaturated fatty acids is associated with increased risk of prostate cancer. AB - Experimental studies suggest omega-3 (n-3) polyunsaturated fatty acids (PUFA) suppress and n-6 PUFA promote prostate tumor carcinogenesis. Epidemiologic evidence remains inconclusive. The objectives of this study were to examine the association between n-3 and n-6 PUFA and prostate cancer risk and determine if these associations differ by race or disease aggressiveness. We hypothesize that high intakes of n-3 and n-6 PUFA will be associated with lower and higher prostate cancer risk, respectively. A case-control study comprising 79 prostate cancer cases and 187 controls was conducted at the Durham VA Medical Center. Diet was assessed using a food frequency questionnaire. Logistic regression analyses were used to obtain odds ratios (ORs) and 95% confidence intervals (95% CI) for the associations between n-3 and n-6 PUFA intakes, the dietary ratio of n-6/n-3 fatty acids, and prostate cancer risk. Our results showed no significant associations between specific n-3 or n-6 PUFA intakes and prostate cancer risk. The highest dietary ratio of n-6/n-3 was significantly associated with elevated risk of high-grade (OR, 3.55; 95% CI, 1.18-10.69; P(trend) = 0.03), but not low grade prostate cancer (OR, 0.95; 95% CI, 0.43-2.17). In race-specific analyses, an increasing dietary ratio of n-6/n-3 fatty acids correlated with higher prostate cancer risk among white men (P(trend) = 0.05), but not black men. In conclusion, our findings suggest that a high dietary ratio of n-6/n-3 fatty acids may increase the risk of overall prostate cancer among white men and possibly increase the risk of high-grade prostate cancer among all men. PMID- 21310300 TI - Little impact of resting energy expenditure on childhood weight and body composition: a longitudinal study (EarlyBird 47). AB - The role of resting energy expenditure (REE) in the development of obesity in children is controversial. Our aim was to test the hypothesis that REE has a meaningful impact on change in weight or body composition in healthy children. Resting energy expenditure by indirect calorimetry and body composition by dual energy x-ray absorptiometry were measured in 236 children (131 boys) on 7 annual occasions (7-13 years). The effect of REE at 7 years on change in weight and body composition was analyzed using linear mixed effects models. In neither sex was there an interaction between REE at 7 years and change in weight (P > .9). There were weak associations between REE at 7 years and change in body composition in boys but not in girls: for a 418 kJ (100 kcal) lower REE at 7 years, an increase in rate of change in fat mass of approximately 0.1 kg/y and in percentage of fat of 0.2% per year and a decrease in fat-free mass of 0.1 kg/y. Change in REE during follow-up was not significantly associated with body composition changes in either sex (P > .06). Thus, REE has little impact on the wide variation in weight gain at this age; although in boys, some fat was simply exchanged for lean, the effect was small. Resting energy expenditure does not appear to provide an explanation for childhood obesity. PMID- 21310298 TI - Restless genomes humans as a model organism for understanding host retrotransposable element dynamics. AB - Since their initial discovery in maize, there have been various attempts to categorize the relationship between transposable elements (TEs) and their host organisms. These have ranged from TEs being selfish parasites to their role as essential, functional components of organismal biology. Research over the past several decades has, in many respects, only served to complicate the issue even further. On the one hand, investigators have amassed substantial evidence concerning the negative effects that TE-mutagenic activity can have on host genomes and organismal fitness. On the other hand, we find an increasing number of examples, across several taxa, of TEs being incorporated into functional biological roles for their host organism. Some 45% of our own genomes are comprised of TE copies. While many of these copies are dormant, having lost their ability to mobilize, several lineages continue to actively proliferate in modern human populations. With its complement of ancestral and active TEs, the human genome exhibits key aspects of the host-TE dynamic that has played out since early on in organismal evolution. In this review, we examine what insights the particularly well-characterized human system can provide regarding the nature of the host-TE interaction. PMID- 21310301 TI - Relative and biomarker-based validity of a food frequency questionnaire that measures the intakes of vitamin B(12), folate, iron, and zinc in young women. AB - Folate, vitamin B(12), iron, and zinc are particularly important nutrients for women of childbearing age. We tested the hypothesis that an electronic, 235-item, semiquantitative food frequency questionnaire (FFQ) is a valid measure of dietary intake when compared with repeat dietary 24-hour recalls. Biomarkers of folate, vitamin B(12), iron, and zinc were determined because their measurement errors are unrelated to errors in dietary questionnaires. Female adults (N = 256) aged 18 to 35 years completed the FFQ, and a representative subset (n = 53) completed repeat dietary 24-hour recalls. The FFQ estimates (mean +/- SD) were 315 +/- 132 MUg for folate, 3.1 +/- 2.1 MUg for vitamin B(12), 15.4 +/- 5.6 mg for iron, and 15.1 +/- 6.4 mg for zinc. The percentage of women classified within the same +/-1 quartile for energy intake by the 2 methods was 77.3%. There was moderate agreement between the 2 dietary methods, and no systematic bias was noted for energy, folate, vitamin B(12), and zinc. The deattenuated energy-adjusted correlation coefficients ranged from 0.41 (dietary folate equivalents) to 0.60 (folate). Significant correlations between biomarker and nutrient intakes were found for folate (r = 0.37, P < .01) and vitamin B(12) (r = 0.27, P < .01). The electronic FFQ developed in the present study is a relatively valid tool that was able to adequately assess and rank individuals according to their nutrient intakes. PMID- 21310302 TI - Vitamin D insufficiency is common in patients with nonmetastatic prostate cancer. AB - Because an inverse relationship between serum 25-hydroxyvitamin D (25[OH]D) levels and the risk of prostate cancer has been suggested, it was hypothesized that vitamin D insufficiency would be common in patients with prostate cancer. To test the hypothesis, an exploratory study was conducted to examine serum 25(OH)D levels in a cohort of patients with nonmetastatic prostate cancer. The study aim was to assess the prevalence of vitamin D insufficiency in these patients. Vitamin D insufficiency was defined as serum 25(OH)D less than 75 nmol/L. Serum 25(OH)D levels measured prospectively at baseline and, then, yearly during a 5 year follow-up were analyzed. Various parameters were examined to assess their possible association with vitamin D insufficiency at baseline, using both a univariate analysis and a logistic regression model. Analyses including descriptive statistics for all variables were carried out with SAS version 9.1 (SAS Institute, Cary, NC). A total of 106 patients were available for analysis. The median age was 66.3 years. At baseline, mean and median vitamin D level was 72.4 and 70.0 nmol/L, respectively. Sixty-four patients (60.4%) met the definition of vitamin D insufficiency with serum 25(OH)D less than 75 nmol/L. Forty (37.7%), 20 (18.9%), and 2 patients (1.9%) had serum 25(OH)D less than 62.5, less than 50, and less than 25 nmol/L, respectively. On a logistic regression model, season was the only significant variable associated with vitamin D insufficiency. Of a total 477 serum 25(OH)D measurements from the baseline and yearly follow-ups, 187 (39.2%) met the definition of vitamin D insufficiency. In conclusion, vitamin D insufficiency was prevalent among patients with nonmetastatic prostate cancer. PMID- 21310303 TI - Calcium from plant sources is beneficial to lowering the risk of osteoporosis in postmenopausal Korean women. AB - Osteoporosis, which has become a serious public health concern, is influenced by diet, especially calcium intake. Dairy products are a good source of calcium, but plant calcium may also be important in populations that do not consume a large amount of milk. The purpose of the present study was to examine the hypothesis that calcium from vegetable sources is associated with osteoporosis risk and bone mineral density in postmenopausal Korean women with osteoporosis and age-matched controls (N = 144). The results of multivariate-adjusted regression analyses indicated that the intake of calcium, plant calcium, potassium, vitamin A, carotene, vitamin B(1), niacin, vitamin E, vitamin C, and vegetables was associated with significantly reduced risk of osteoporosis after adjusting for age, body mass index, hormone replacement therapy, and energy intake. In addition, intake of vegetables alone, as well as calcium, plant calcium, potassium, and antioxidant vitamins (vitamin C, vitamin E, beta-carotene), which are abundant in vegetables, was significantly and positively associated with bone mineral density. However, in this population of low-dairy consumers, intake of calcium from meat and dairy products was not related to risk of osteoporosis and bone mineral density. Our results suggest that high dietary intake of calcium, especially plant calcium, reduces the risk of osteoporosis and increased bone mineral density in postmenopausal Korean women. Vegetables may be an important source of calcium and may also provide vitamins and minerals that exert additional beneficial effects on the bone. PMID- 21310304 TI - Diets high in conjugated linoleic acid from pasture-fed cattle did not alter markers of health in young women. AB - Conjugated linoleic acid (CLA) purportedly alters body composition, glucose tolerance, hepatic function, lipoprotein distributions, and other markers of health. Results are often inconclusive or contradictory, and presently, no studies have investigated the effects of naturally incorporated CLA from pasture fed beef and dairy products on human health. We hypothesized that a diet comprised of foods naturally enriched with CLA from pasture-fed cattle would result in improved insulin sensitivity, body composition, circulating lipids, and other disease risk factors when compared to a diet comprised of commercial foods naturally low in CLA from grain-fed cattle. Eighteen healthy women 20 to 39 years of age consumed one of these 2 diets for 56 days. Balanced nutritionally complete diets comprised of 31% energy from lipid, 13% from protein, and 54% from carbohydrate were administered, with the primary difference being CLA content (CLA diet: 1.17 g/d; control diet: 0.35 g/d). The CLA diet did not result in any differences in insulin sensitivity, body composition, circulating blood lipids, or other measured disease risk factors as compared with the control diet. Thus, we conclude that a diet naturally enriched with over a 3-fold increase in CLA from pasture-fed cattle did not significantly alter selected health risk factors in healthy, premenopausal women as compared with a similar diet composed of foods from grain-fed cattle. PMID- 21310305 TI - Glucose and insulin do not decrease in a dose-dependent manner after increasing doses of mixed fibers that are consumed in muffins for breakfast. AB - Conventional wisdom suggests that fiber consumption leads to lower postprandial glucose and insulin response. We hypothesized that increasing doses of mixed, viscous fiber would lower glucose and insulin levels in a dose-dependent manner. Healthy men (n = 10) and women (n = 10) with a body mass index of 24 +/- 2 (mean +/- SEM) participated in this double-blind, crossover study. On 4 separate visits, fasting subjects consumed an approximately 2093 kJ (500 calorie) muffin with 0, 4, 8, or 12 g of mixed fibers. Blood was drawn to measure glucose and insulin at regular intervals throughout a 3-hour test period. Area under the curve (AUC) glucose was significantly lower after 0 g of fiber than after 4, 8, or 12 g of fiber (arbitrary AUC units +/- SEM: 25.3 +/- 5.2 vs 44.6 +/- 7.7, 49.7 +/- 7.9, 51.5 +/- 6.6, respectively; P < .006). Area under the curve glucose increased with increasing fiber doses (P for trend = .0003). Area under the curve insulin was higher after the 4-g dose than after the 0-, 8-, and 12-g doses (arbitrary AUC units +/- SEM: 84.4 +/- 8.0 vs 60.1 +/- 6.5, 69.4 +/- 8.7, 69.7 +/ 8.5, respectively; P < .05); it did not change in a dose-dependent manner. Area under the curve glucose and AUC insulin did not correlate with each other. Glucose and insulin did not decrease in a dose-dependent manner after 0, 4, 8, and 12 g of mixed fibers were consumed in muffins for breakfast. The lack of differences was largely based on the individual variation in glucose response. Caution should be used when making general claims about the expected impact of fiber on glucose and insulin levels. PMID- 21310306 TI - Prevalence and correlates of vitamin D deficiency in US adults. AB - Mounting evidence suggests that vitamin D deficiency could be linked to several chronic diseases, including cardiovascular disease and cancer. The purpose of this study was to examine the prevalence of vitamin D deficiency and its correlates to test the hypothesis that vitamin D deficiency was common in the US population, especially in certain minority groups. The National Health and Nutrition Examination Survey 2005 to 2006 data were analyzed for vitamin D levels in adult participants (N = 4495). Vitamin D deficiency was defined as a serum 25 hydroxyvitamin D concentrations <=20 ng/mL (50 nmol/L). The overall prevalence rate of vitamin D deficiency was 41.6%, with the highest rate seen in blacks (82.1%), followed by Hispanics (69.2%). Vitamin D deficiency was significantly more common among those who had no college education, were obese, with a poor health status, hypertension, low high-density lipoprotein cholesterol level, or not consuming milk daily (all P < .001). Multivariate analyses showed that being from a non-white race, not college educated, obese, having low high-density lipoprotein cholesterol, poor health, and no daily milk consumption were all significantly, independently associated with vitamin D deficiency (all P < .05). In summary, vitamin D deficiency was common in the US population, especially among blacks and Hispanics. Given that vitamin D deficiency is linked to some of the important risk factors of leading causes of death in the United States, it is important that health professionals are aware of this connection and offer dietary and other intervention strategies to correct vitamin D deficiency, especially in minority groups. PMID- 21310307 TI - Honey promotes lower weight gain, adiposity, and triglycerides than sucrose in rats. AB - Various dietary carbohydrates have been linked to obesity and altered adipose metabolism; however, the influences of honey vs common sweeteners have not been fully explored. We hypothesized that in comparison with sucrose, a honey-based diet would promote lower weight gain, adiposity, and related biomarkers (leptin, insulin, and adiponectin) as well as a better blood lipid profile. Thirty-six male Sprague-Dawley rats (228.1 +/- 12.5 g) were equally divided by weight into 2 groups (n = 18) and provided free access to 1 of 2 diets of equal energy densities differing only in a portion of the carbohydrate. Diets contained 20% carbohydrate (by weight of total diet) from either clover honey or sucrose. After 33 days, epididymal fat pads were excised and weighed, and blood was collected for analyses of serum concentrations of lipids, glucose, and markers of adiposity and inflammation. Body weight gain was 14.7% lower (P <= .05) for rats fed honey, corresponding to a 13.3% lower (P <= .05) consumption of food/energy, whereas food efficiency ratios were nearly identical. Epididymal fat weight was 20.1% lower (P <= .05) for rats fed honey. Serum concentrations of triglycerides and leptin were lower (P <= .05) by 29.6% and 21.6%, respectively, and non-high density lipoprotein cholesterol was higher (P <= .05) by 16.8% for honey-fed rats. No significant differences in serum total cholesterol, high-density lipoprotein cholesterol, adiponectin, C-reactive protein, monocyte chemoattractant protein-1, glucose, or insulin were detected. These results suggest that in comparison with sucrose, honey may reduce weight gain and adiposity, presumably due to lower food intake, and promote lower serum triglycerides but higher non-high-density lipoprotein cholesterol concentrations. PMID- 21310308 TI - Guidelines for the diagnosis and management of food allergy in the United States: summary of the NIAID-sponsored expert panel report. PMID- 21310309 TI - Simultaneous rupture of ventricular septum and papillary muscle as a mechanical complication of acute myocardial infarction. PMID- 21310310 TI - Adiponectin and vulnerable atherosclerotic plaques. AB - High-risk plaques that are vulnerable to rupture demonstrate distinct morphological characteristics. They are differentiated from the lesions responsible for stable coronary artery disease by their large necrotic cores, thin-inflamed fibrous caps, and positive remodeling. Adiponectin is an adipocytokine that is reduced in obesity and type 2 diabetes. Hypoadiponectinemia has been associated with an increased risk of coronary artery disease and acute coronary syndrome in several though not all studies. The involvement of adiponectin provides clues to the inflammatory and atherogenic mechanisms associated with pathological coronary disease progression. PMID- 21310311 TI - High versus standard clopidogrel maintenance dose after percutaneous coronary intervention and effects on platelet inhibition, endothelial function, and inflammation results of the ARMYDA-150 mg (antiplatelet therapy for reduction of myocardial damage during angioplasty) randomized study. AB - OBJECTIVES: This study was done to compare effects of high versus standard clopidogrel maintenance doses on platelet inhibition, inflammation, and endothelial function in patients undergoing percutaneous coronary intervention. BACKGROUND: Previous data suggested that clopidogrel has various biological actions in addition to antiplatelet effects. METHODS: Fifty patients were randomly assigned 1 month after intervention (T-0) to receive standard (75 mg/day; n = 25) or high (150 mg/day; n = 25) clopidogrel maintenance dose for 30 days (until T-1); at this time-point, cross-over was performed, and the assigned clopidogrel maintenance regimen was switched and continued for a further 30 days (until T-2). Platelet reactivity (expressed as P2Y(12) reaction units by the point-of-care VerifyNow assay [Accumetrics, San Diego, California]), endothelial function (evaluated by flow-mediated vasodilation), and high-sensitivity C reactive protein levels were measured at T-0, T-1, and T-2. RESULTS: Patients in the 150-mg/day arm had higher platelet inhibition (50 +/- 20% vs. 31 +/- 20% in the 75-mg/day group; p < 0.0001), better flow-mediated vasodilation (16.9 +/- 12.6% vs. 7.9 +/- 7.5%; p = 0.0001), and lower high-sensitivity C-reactive protein levels (3.6 +/- 3.0 mg/l vs. 7.0 +/- 8.6 mg/l; p = 0.016). Higher clopidogrel dose was associated with decreased proportion of patients with P2Y(12) reaction units >= 240 (12% vs. 32%; p = 0.001), flow-mediated vasodilation <7% (16% vs. 58%; p = 0.0003), and high-sensitivity C-reactive protein levels >3 mg/l (46% vs. 64%; p = 0.07). CONCLUSIONS: For patients undergoing percutaneous coronary intervention, the 150-mg/day clopidogrel maintenance dose is associated with stronger platelet inhibition, improvement of endothelial function, and reduction of inflammation, compared with the currently recommended 75-mg/day regimen; those effects might have a role in the clinical benefit observed with clopidogrel and may provide the rationale for using the higher maintenance regimen in selected patients. PMID- 21310312 TI - Prevalence and predictors of concomitant carotid and coronary artery atherosclerotic disease. AB - OBJECTIVES: The purpose of this research was to evaluate the relationship between coronary and carotid atherosclerotic disease using current guidelines for the definition of carotid artery stenosis (CAS). BACKGROUND: The reported prevalence of concomitant coronary and carotid atherosclerotic disease has varied among studies due to differences in study populations and methodologies used. METHODS: We performed a retrospective analysis of prospectively collected data obtained between January 2007 and May 2009 from consecutive patients undergoing same-day coronary angiography and carotid Doppler studies. Spearman correlations and multinomial logistic regression models were used to identify independent correlates of CAS. RESULTS: The study included 1,405 patients (age 65 +/- 11 years, 77.2% male), of whom 12.8% had significant CAS (peak systolic velocity [PSV] >125 cm/s) and 4.6% had severe CAS (PSV >230 cm/s). Mild CAS (PSV <125 cm/s and the presence of a sonographic atherosclerotic lesion) was present in 58%. The severity of CAS and the extent of coronary artery disease (CAD) were significantly correlated (r = 0.255, p < 0.001). Independent predictors of severe CAS defined by PSV were the presence of left-main or 3-vessel CAD, increasing age, a history of stroke, smoking status, and diabetes mellitus. CONCLUSIONS: The degree of internal carotid artery (ICA) stenosis is related to the extent of CAD, though the prevalence of clinically significant ICA stenosis is lower in specific CAD subsets than previously reported. PMID- 21310313 TI - The cost-effectiveness of C-reactive protein testing and rosuvastatin treatment for patients with normal cholesterol levels. AB - OBJECTIVES: We sought to evaluate the cost-effectiveness of applying the JUPITER (Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial results into clinical practice. BACKGROUND: The JUPITER trial found that rosuvastatin reduces vascular events in apparently healthy subjects with elevated high-sensitivity C-reactive protein (hs-CRP) but normal low-density lipoprotein (LDL) cholesterol levels. The implications of expanding treatment recommendations based on these results have not been evaluated. METHODS: We constructed a cost-effectiveness model of men >= 50 years and women >= 60 years with LDL cholesterol levels of <130 mg/dl and no known cardiovascular disease. We compared: 1) hs-CRP testing followed by rosuvastatin treatment for patients with hs-CRP levels >= 2.0 mg/l; and 2) usual care (i.e., no testing and no treatment). Estimates of treatment effectiveness were based on the JUPITER trial and were varied in sensitivity analyses. RESULTS: Among patients with LDL <130 mg/dl and hs-CRP levels >= 2.0 mg/l, rosuvastatin had an incremental cost-effectiveness of $25,198 per quality-adjusted life year (QALY) gained compared to usual care. If the effectiveness of rosuvastatin were 50% of that observed in JUPITER, the incremental cost-effectiveness ratio would increase to $50,871 per QALY. Implementing this strategy only in patients with a Framingham risk score >= 10% yielded an incremental cost-effectiveness of $14,205 per QALY. Among such intermediate-risk patients, a JUPITER-based strategy becomes cost-saving at a rosuvastatin price of < $0.86 per day. CONCLUSIONS: Rosuvastatin treatment for JUPITER-eligible patients appears to be cost-effective, particularly among those with a Framingham risk score >= 10%. PMID- 21310314 TI - The cost-effectiveness of rosuvastatin therapy JUPITER (justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin). PMID- 21310315 TI - Systematic review of the incidence of sudden cardiac death in the United States. AB - The need for consistent and current data describing the true incidence of sudden cardiac arrest (SCA) and/or sudden cardiac death (SCD) was highlighted during the most recent Sudden Cardiac Arrest Thought Leadership Alliance's (SCATLA) Think Tank meeting of national experts with broad representation of key stakeholders, including thought leaders and representatives from the American College of Cardiology, American Heart Association, and the Heart Rhythm Society. As such, to evaluate the true magnitude of this public health problem, we performed a systematic literature search in MEDLINE using the MeSH headings, "death, sudden" OR the terms "sudden cardiac death" OR "sudden cardiac arrest" OR "cardiac arrest" OR "cardiac death" OR "sudden death" OR "arrhythmic death." Study selection criteria included peer-reviewed publications of primary data used to estimate SCD incidence in the U.S. We used Web of Science's Cited Reference Search to evaluate the impact of each primary estimate on the medical literature by determining the number of times each "primary source" has been cited. The estimated U.S. annual incidence of SCD varied widely from 180,000 to >450,000 among 6 included studies. These different estimates were in part due to different data sources (with data age ranging from 1980 to 2007), definitions of SCD, case ascertainment criteria, methods of estimation/extrapolation, and sources of case ascertainment. The true incidence of SCA and/or SCD in the U.S. remains unclear, with a wide range in the available estimates that are badly dated. As reliable estimates of SCD incidence are important for improving risk stratification and prevention, future efforts are clearly needed to establish uniform definitions of SCA and SCD and then to prospectively and precisely capture cases of SCA and SCD in the overall U.S. population. PMID- 21310316 TI - The short QT syndrome: proposed diagnostic criteria. AB - OBJECTIVES: We aimed to develop diagnostic criteria for the short QT syndrome (SQTS) to facilitate clinical evaluation of suspected cases. BACKGROUND: The SQTS is a cardiac channelopathy associated with atrial fibrillation and sudden cardiac death. Ten years after its original description, a consensus regarding an appropriate QT interval cutoff and specific diagnostic criteria have yet to be established. METHODS: The MEDLINE database was searched for all reported cases of SQTS in the English language, and all relevant data were extracted. The distribution of QT intervals and electrocardiographic (ECG) features in affected cases were analyzed and compared to data derived from ECG analysis from general population studies. RESULTS: A total of 61 reported cases of SQTS were identified. Index events, including sudden cardiac death, aborted cardiac arrest, syncope, and/or atrial fibrillation occurred in 35 of 61 (57.4%) cases. The cohort was predominantly male (75.4%) and had a mean QT(c) value of 306.7 ms with values ranging from 248 to 381 ms in symptomatic cases. In reference to the ECG characteristics of the general population, and in consideration of clinical presentation, family history, and genetic findings, a highly sensitive diagnostic scoring system was developed. CONCLUSIONS: Based on a comprehensive review of 61 reported cases of the SQTS, formal diagnostic criteria have been proposed that will facilitate diagnostic evaluation in suspected cases of SQTS. Diagnostic criteria may lead to a greater recognition of this condition and provoke screening of at-risk family members. PMID- 21310317 TI - Cardiac resynchronization therapy is more effective in women than in men: the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy) trial. AB - OBJECTIVES: The purpose of this study was to investigate the factors related to sex-specific outcomes for death and heart failure events in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy) trial. BACKGROUND: In the MADIT-CRT trial, women seemed to achieve a better result from resynchronization therapy than men. METHODS: All 1,820 patients (453 female and 1,367 male) enrolled in the MADIT-CRT trial were included in this sex-specific outcome analysis that compared the effect of cardiac resynchronization therapy with defibrillator (CRT-D) relative to implanted cardioverter-defibrillator (ICD) on death or heart failure (whichever came first), heart failure only, and death at any time. RESULTS: Female patients were more likely to have nonischemic cardiomyopathy and left bundle branch block and less likely to have renal dysfunction than male patients. Overall, female patients had a better result from CRT-D therapy than male patients, with a significant 69% reduction in death or heart failure (hazard ratio: 0.31, p < 0.001) and 70% reduction in heart failure alone (hazard ratio: 0.30, p < 0.001). Women had a significant 72% reduction in all-cause mortality in the total population (hazard ratio: 0.28, p = 0.02) and significant 82% and 78% reductions in mortality in those with QRS >= 150 ms and with left bundle branch block conduction disturbance, respectively, with sex-by-treatment interactions for mortality reduction significant at p < 0.05 in each of these 3 patient groups. These beneficial CRT-D effects among women were associated with consistently greater echocardiographic evidence of reverse cardiac remodeling in women than in men. CONCLUSIONS: Women in the MADIT-CRT trial obtained significantly greater reductions in death or heart failure (whichever came first), heart failure alone, and all-cause mortality with CRT-D therapy than men, with consistently greater echocardiographic evidence of reverse cardiac remodeling in women than in men. (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy [MADIT-CRT]; NCT00180271). PMID- 21310318 TI - Myocardial fibrosis predicts appropriate device therapy in patients with implantable cardioverter-defibrillators for primary prevention of sudden cardiac death. AB - OBJECTIVES: The purpose of this study was to evaluate the association between regional myocardial fibrosis and ventricular arrhythmias in patients with cardiomyopathy. BACKGROUND: Patients with heart failure are at risk of sudden cardiac death (SCD). Current guidelines recommend implantable cardioverter defibrillator (ICD) devices for a subgroup based on impaired left ventricular function. A significant proportion of devices never discharge, hence a more accurate method for targeting those at risk is desirable. METHODS: We prospectively enrolled 103 patients meeting criteria for ICD implantation for primary prevention of SCD. Cardiac magnetic resonance imaging was performed before device implantation. Regional fibrosis was identified with late gadolinium enhancement (LGE). RESULTS: Median follow-up was 573 days (interquartile range: 379 to 863 days). The LGE identified regional fibrosis in 31 of 61 (51%) patients with nonischemic cardiomyopathy (NICM) and in all 42 patients with ischemic cardiomyopathy (ICM). There was a 29% (9 of 31) discharge rate in the NICM group with LGE compared with a 14% (6 of 42) discharge rate in the ICM group (p = NS). There were no ICD discharges in the NICM group without LGE, which was significantly lower than the rate observed in both the ICM patients (p = 0.04) and the NICM patients with LGE (p < 0.01). Left ventricular ejection fraction was similar in patients with and without device therapy (24 +/- 12% vs. 26 +/- 8%, p = NS) and those with or without LGE (25 +/- 9% vs. 26 +/- 9%, p = NS). CONCLUSIONS: Patients with advanced cardiomyopathy and myocardial fibrosis demonstrated by LGE on cardiac magnetic resonance imaging have a high likelihood of appropriate ICD therapy. Correspondingly, absence of LGE may indicate a lower risk for malignant ventricular arrhythmias. PMID- 21310319 TI - Imaging in electrical cardiac devices. PMID- 21310320 TI - Association of left atrial fibrosis detected by delayed-enhancement magnetic resonance imaging and the risk of stroke in patients with atrial fibrillation. AB - OBJECTIVES: This study tried to determine the association between left atrial (LA) fibrosis, detected using delayed-enhanced magnetic resonance imaging (DE MRI), and the CHADS(2) score (point system based on individual clinical risk factors including congestive heart failure, hypertension, age, diabetes, and prior stroke) variables, specifically stroke. BACKGROUND: In patients with atrial fibrillation (AF), conventional markers for the risk of stroke base their higher predictive effect on clinical features, particularly previous stroke history, and not individual LA pathophysiological properties. We aimed to determine the association between LA fibrosis, detected using DE-MRI, and the CHADS(2) score variables, specifically stroke. METHODS: Patients with AF who presented to the AF clinic and received a DE-MRI of the LA were evaluated. Their risk factor profiles, including a CHADS(2) score, were catalogued. The degree of LA fibrosis was determined as a percentage of the LA area. Any history of previous strokes, warfarin use, or cerebrovascular disease was recorded. RESULTS: A total of 387 patients, having a mean age of 65 +/- 12 years, 36.8% female, were included in this study. A history of previous stroke was present in 36 (9.3%) patients. Those patients with previous strokes had a significantly higher percentage of LA fibrosis (24.4 +/- 12.4% vs. 16.2 +/- 9.9%, p < 0.01). A larger amount of LA fibrosis was also seen in those patients with a higher CHADS(2) score (>= 2: 18.7 +/- 11.4 vs. <2: 14.7 +/- 9.2, p < 0.01). A logistic regression analysis of all variables except strokes (CHAD score) demonstrated that LA fibrosis independently predicted cerebrovascular events (p = 0.002) and significantly increased the predictive performance of the score (area under the curve = 0.77). CONCLUSIONS: Our preliminary, multicenter results suggest DE-MRI-based detection of LA fibrosis is independently associated with prior history of strokes. We propose that the amount of DE-MRI-determined LA fibrosis could represent a marker for stroke and a possible therapeutic target with potential applicability for clinical treatment for patients with AF. PMID- 21310321 TI - Impaired left ventricular stroke volume reserve during clinical dobutamine stress predicts future episodes of pulmonary edema. AB - OBJECTIVES: The purpose of this study was to determine whether dobutamine-induced abnormal stress changes in left ventricular stroke volume (LVSV) and aortic stiffness predict future pulmonary edema. BACKGROUND: Increased aortic stiffness that decreases LVSV during adrenergic stress may serve as a marker for future pulmonary edema (PE). METHODS: We measured LVSV, ventriculovascular stiffness (pulse pressure/LVSV(index)), and aortic distensibility at rest and during intravenous dobutamine administration using cardiovascular magnetic resonance. Personnel blinded to dobutamine cardiovascular magnetic resonance followed participants longitudinally over time to identify those admitted to the hospital with PE. Data for 44 participants who had a hospital admission for PE were compared with data for 72 participants of similar age, sex, and resting left ventricular ejection fraction who remained PE free. RESULTS: Expressed as median and interquartile range, participants with and without PE exhibited a decreased stress/rest LVSV ratio (0.9 [range 0.7 to 1.1] vs. 1.0 [range 0.9 to 1.2], respectively; p = 0.002), an increased ventriculovascular stiffness stress/rest ratio (1.4 [range 1.0 to 1.6] vs. 1.0 [range 0.8 to 1.3], respectively; p <= 0.001); and a decreased stress-induced measure of aortic distensibility (0.8 mm Hg(-3) [range 0.3 to 1.3 mm Hg(-3)] vs. 1.6 mm Hg(-3) [range 1.2 to 3.2 mm Hg( 3)], respectively; p = 0.002). After accounting for age, sex, left ventricular ejection fraction, risk factors for PE, and the presence of dobutamine-induced ischemia, LVSV reserve and the stress/rest ventriculovascular stiffness ratio still differed (p < 0.008 for both) in those with and without PE. CONCLUSIONS: In patients without inducible ischemia during dobutamine stress testing in whom one might otherwise assume a favorable prognosis, the failure to increase LVSV or an increase in ventriculovascular stiffness indicates patients at risk of subsequent PE. PMID- 21310322 TI - beta-trace protein and cystatin C as predictors of long-term outcomes in patients with acute heart failure. AB - OBJECTIVES: The purpose of this study was to evaluate the prognostic importance of novel markers of renal dysfunction among patients with acutely destabilized heart failure (ADHF). BACKGROUND: beta-trace protein (BTP) and cystatin C are newer biomarkers for renal dysfunction; the prognostic importance of these tests, particularly BTP, relative to standard measures of renal function remains unclear. METHODS: A total of 220 consecutive hospitalized patients with ADHF were prospectively studied. Blood samples were collected on presentation. In-hospital worsening renal function, as well as mortality and/or heart failure (HF) hospitalization, over a median follow-up period of 500 days was examined as a function of BTP or cystatin C concentrations; results were compared with creatinine, estimated glomerular filtration rate, and blood urea nitrogen. RESULTS: Neither BTP nor cystatin C was associated with worsening renal function during the index hospitalization. A total of 116 patients (53%) either died or were hospitalized for HF during follow-up. Those with adverse outcomes had higher BTP (1.04 mg/l [range 0.80 to 1.49 mg/l] vs. 0.88 mg/l [range 0.68 to 1.17 mg/l], p = 0.003) and cystatin C (1.29 mg/l [range 1.00 to 1.71 mg/l] vs. 1.03 mg/l [range 0.86 to 1.43 mg/l], p = 0.001). After multivariable adjustment, both BTP (hazard ratio: 1.41, 95% confidence interval: 1.06 to 1.88; p = 0.018) and cystatin C (hazard ratio: 1.50, 95% confidence interval: 1.13 to 2.01; p = 0.006) were significant predictors of death/HF hospitalization, whereas serum creatinine, estimated glomerular filtration rate, and blood urea nitrogen were no longer significant. In patients with an estimated glomerular filtration rate >60 ml/min/1.73 m(2), elevated concentrations of BTP and cystatin C were still associated with significantly higher risk of adverse clinical events (p < 0.05). Net reclassification index analysis suggested cystatin C and BTP deliver comparable information regarding prognosis. CONCLUSIONS: Among patients hospitalized with ADHF, BTP and cystatin C predict risk of death and/or HF hospitalization and are superior to standard measures of renal function for this indication. PMID- 21310323 TI - beta-trace protein versus cystatin C: which is a better surrogate marker of renal function versus prognostic indicator in cardiovascular diseases? PMID- 21310324 TI - Pentraxin 3 is a new inflammatory marker correlated with left ventricular diastolic dysfunction and heart failure with normal ejection fraction. AB - OBJECTIVES: This study investigated the clinical significance of plasma pentraxin 3 (PTX3) levels in patients with heart failure with normal ejection fraction (HFNEF) and whether PTX3 is produced from coronary circulation. BACKGROUND: Pentraxin 3 is a novel inflammatory marker and a member of pentraxin superfamily including C-reactive protein (CRP). The relationship between inflammatory markers and HFNEF remains unclear. METHODS: We measured peripheral blood levels of PTX3, high-sensitivity CRP, tumor necrosis factor-alpha, and interleukin-6 in 323 patients comprising 82 HFNEF, 70 heart failure (HF) with reduced EF, and 171 non HF patients. Levels of PTX3 were also measured at the aortic root and the coronary sinus in 75 patients. RESULTS: The levels of PTX3, tumor necrosis factor alpha, and interleukin-6, but not high-sensitivity CRP, were significantly higher in HFNEF patients than in non-HF patients. Multivariate logistic regression analysis identified only high levels of PTX3 as the independent inflammatory marker correlated with the presence of HFNEF in patients with normal left ventricular (LV) EF (odds ratio [OR]: 1.49, 95% confidence interval [CI]: 1.11 to 1.98, p < 0.01) and with the presence of left ventricular diastolic dysfunction (LVDD) in non-HF patients (OR: 1.23, 95% CI: 1.02 to 1.50, p < 0.05). Levels of PTX3 at the coronary sinus were significantly higher than at the aortic root in HFNEF patients (p < 0.05) and in non-HF patients with LVDD (p < 0.01), but not different in non-HF patients without LVDD (p = 0.33). CONCLUSIONS: Pentraxin 3 is significantly elevated in HFNEF patients and produced in the coronary circulation in patients with LVDD. Pentraxin 3, but not high-sensitivity CRP, is an independent inflammatory marker correlated with the presence of LVDD and HFNEF. (The Clinical Significance of Plasma Pentraxin 3 levels for Patients with Diastolic Heart Failure; UMIN000002170). PMID- 21310325 TI - Characteristic findings of coronary artery disease in Kawasaki disease. PMID- 21310326 TI - Mentors. PMID- 21310327 TI - Is cardiovascular mortality related to the season of birth?: evidence from more than 6 million cardiovascular deaths between 1992 and 2007. PMID- 21310329 TI - $1 billion to the National Heart, Lung, and Blood Institute: economic stimulus or bust? PMID- 21310330 TI - Neurophysiologic intraoperative monitoring in pediatrics. AB - Neurophysiologic intraoperative monitoring, using somatosensory, brainstem auditory, and visual evoked potentials, transcranial electric motor stimulation, and electromyography, is typically used during complex surgeries involving the motor and sensory cortex, brainstem, cranial nerves, spinal cord, nerve root, peripheral roots, brachial plexus, lumbar plexus, and peripheral nerves. The particular type of surgery and the neurologic structures at risk determine the type of monitoring chosen. Although many methods are the same in adult and pediatric patients, some differences in the pediatric population will be discussed here. In general, monitoring consists of two types. The first involves monitoring data which is obtained on an ongoing basis, with comparisons to data obtained at the outset of surgery (baseline). The second form of monitoring involves mapping neural structures, so that a neural structure in the field is identified accurately, to avoid injuring it, or to demonstrate its degree of neurophysiologic function or impairment. In this paper we discuss both forms of monitoring and their general applications, including unique features or modifications needed in the pediatric population. PMID- 21310331 TI - Cranial magnetic resonance imaging findings in children with nonsyndromic mitochondrial diseases. AB - Cranial magnetic resonance imaging findings suggestive of specific mitochondrial syndromes are reported. However, cranial magnetic resonance imaging features in children with nonsyndromic mitochondrial diseases are rarely described. From January 1992-September 2009, data from 33 patients with nonsyndromic mitochondrial diseases were collected. We investigated cranial magnetic resonance imaging features in children with nonsyndromic mitochondrial diseases, and identified potential diagnostic characteristics. Eleven of 33 patients (33.3%) demonstrated normal findings, and 22 (66.7%) demonstrated abnormal findings. The most common abnormal finding was cerebral atrophy, with or without other lesion sites (15/33; 45.5%). The second most common was bilateral basal ganglia involvement (6/33; 18.2%). Follow-up imaging was performed in 20 patients. Ten of these 20 (50.0%) demonstrated evolutionary changes, in which progressive global brain atrophy was evident. Three patients with normal results and one patient with cerebral atrophy on initial imaging demonstrated prominent signal changes over the basal ganglia, brainstem, gray matter, white matter, and bilateral cerebellar hemispheres on follow-up imaging. Imaging in children with nonsyndromic mitochondrial diseases may produce variable findings. Normal results and cerebral atrophy on the initial cranial magnetic resonance imaging are commonly evident in this patient group. PMID- 21310332 TI - Somatosensory evoked potentials in children with bilateral spastic cerebral palsy. AB - Alterations were monitored of somatosensory evoked potentials in children with bilateral spastic cerebral palsy and these findings correlated with relevant clinical and laboratory parameters. Fifty-one children with bilateral spastic cerebral palsy (31 boys, 20 girls; age range 24-168 months) participated in the study. Abnormal somatosensory evoked potentials latencies were recorded in 23 of 34 (67.6%) cortical recordings of the median nerve and in 38 of 51 (74.5%) cortical recordings of the tibial nerve. Abnormal tibial nerve somatosensory evoked potentials were strongly correlated with abnormal electroencephalogram (P=0.014), while impaired median nerve recordings were correlated with abnormal visual evoked potentials (P = 0.02) and a history of perinatal or neonatal infection (P=0.016). Furthermore, perinatal/neonatal infection adversely effected the recordings in both tibial and medial nerves in quadriplegic patients (P=0.023). Sensory impairment is strongly related with abnormal visual evoked potentials, abnormal electroencephalogram, and a history of perinatal or neonatal infection. PMID- 21310333 TI - Idiopathic childhood occipital epilepsy of Gastaut: report of 12 patients. AB - This study sought to present clinical and outcome data of patients with idiopathic childhood occipital epilepsy of Gastaut, to validate previously reported characteristics of this epilepsy. The study group was comprised of 12 affected children (three boys and nine girls), with a median age of onset at 10.3 years. Common ictal manifestations included elementary visual hallucinations (75.0%), blindness or blurring of vision (50.0%), headache (50.0%), and secondarily generalized tonic-clonic seizures (58.3%). Interictal electroencephalography revealed occipital spike-wave paroxysms reactive to eye closure and opening in all patients, accompanied by spike-wave activity in the extra-occipital areas in four (33.3%), and by generalized spike-wave discharges in two (16.7%). One patient exhibited the onset of occipital lobe seizures 1 year after manifesting absence epilepsy. Seizure remission occurred in 81.8% of cases, in half of which medication was discontinued by late adolescence. This study confirmed the previously delineated electroclinical features of epilepsy syndrome, with additional aspects including the frequent association of generalized tonic-clonic seizures and atypical evolution from childhood absence epilepsy. PMID- 21310334 TI - Attention-deficit hyperactivity disorder in children with benign epilepsy and their siblings. AB - This prospective study explores the prevalence and characteristics of attention deficit hyperactivity disorder in children with benign epilepsy, compared with its prevalence in their siblings. Among 40 patients with benign epilepsy, 28 (70%) were diagnosed with attention-deficit hyperactivity disorder: 19 with the inattentive type, one with the hyperactive type, and eight with the combined type. In the control group of 12 siblings, only two (16.7%) were diagnosed with attention-deficit hyperactivity disorder (P<0.03). A trend toward an increased risk for attentional difficulties was evident in children whose seizures were more resistant and required more than one antiepileptic drug for seizure control. Children with more epileptiform features in their electroencephalograms were also more subject to signs of attention deficit hyperactivity disorder. Larger scale studies are required to validate our findings. PMID- 21310335 TI - Effects of hydrocephalus after cerebellar tumor: a case-by-case approach. AB - Although hydrocephalus affects approximately 80% of children with a posterior fossa tumor, its impact on neurodevelopmental outcomes remains unclear. We investigated the effects of hydrocephalus severity on the development of cognitive, motor, academic, and attention skills in 15 children with cerebellar injury after treatment for a tumor sustained during preschool years. Significant impairment was indicated by scores 2 S.D.s or more below the test norm mean. Results indicated substantial intra-individual and interindividual variation, with little consistent influence of hydrocephalus severity on outcomes. Generally, children with moderate hydrocephalus were least impaired, but the child without hydrocephalus performed most poorly. Those who received a shunt generally performed higher on many of the cognitive, but not motor, tests. Thus, when considering differences within and across individuals, neither hydrocephalus severity nor shunt placement alone is a strong predictor of neurodevelopmental outcomes. PMID- 21310336 TI - Use of trihexyphenidyl in children with cerebral palsy. AB - A paucity of information exists regarding medications to treat dystonia in children with cerebral palsy. This study sought to review the benefits and tolerability of trihexyphenidyl in children with cerebral palsy, treated for dystonia or sialorrhea or both in a pediatric tertiary care hospital, through a retrospective chart review. In total, 101 patients (61 boys and 40 girls) were evaluated. The mean age at drug initiation was 7 years and 10 months (range, 1-18 years). The mean initial dose was 0.095 mg/kg/day. The dose was increased by 10 20% no sooner than every 2 weeks. The mean maximum dose reached was 0.55 mg/kg/day. Ninety-three patients (91%) tolerated the medication well, with a mean duration of treatment of 3 years and 7 months. Side effects occurred in 69% of subjects, the majority in patients aged >=7 years, and soon after treatment initiation. Sixty-four percent continued the treatment at study end. Ninety-seven patients reported benefits, including reduction of dystonia in upper (59.4%) and lower (37.6%) extremities, sialorrhea (60.4%), and speech issues (24.7%). The majority of patients tolerated trihexyphenidyl well on a schedule of gradual dose increases, and almost all demonstrated improvements in dystonia or sialorrhea or both. PMID- 21310337 TI - Sequence learning in cerebral palsy. AB - We investigated sequence-learning skills in 64 children with cerebral palsy (aged 4.01-14.7 years; 49 with bilateral, two with dystonic, and 13 with unilateral cerebral palsy), compared with a matched control group of typically developing children. Participants' motor and handling abilities were classified according to the Gross Motor Function Classification System and the Manual Ability Classification System. General cognitive, visuoperceptual, and constructive abilities were assessed. Participants performed an experimental computerized version of Corsi Span, followed by a normalized Supraspan sequence. Controls outperformed cerebral palsy participants in visual memory and accuracy. Participants with cerebral palsy were likelier to fail the test (cerebral palsy, 37.5%; control subjects, 5%) and obtain overall lower scores. Sequence learning skills were not related to motor and handling impairments. Failure to learn sequences resulted in an overall lower functioning profile regarding visuoperceptual, verbal, and performance abilities. The ability to fix sequences seemed to split the cerebral palsy group into an overall high-functioning group (successful in sequence learning) and low-functioning (failing) group. Results are discussed in light of a specific implicit memory impairment and the abnormal development of white matter frontostriatal and parietal connections. PMID- 21310338 TI - Ischemic stroke because of intracranial fibromuscular dysplasia. AB - Ischemic stroke in a 12-year-old African-American boy was caused by intracranial fibromuscular dysplasia. Imaging investigations included computed tomography and magnetic resonance angiography, before reaching a definitive diagnosis with a conventional cerebral angiogram. This pediatric case of intracranial fibromuscular dysplasia highlights the need to consider this rare disorder in the differential diagnosis of pediatric stroke and the role of imaging in establishing a diagnosis. The literature of fibromuscular dysplasia is reviewed, and other causes of pediatric stroke are discussed. PMID- 21310339 TI - Argininemia presenting with progressive spastic diplegia. AB - Argininemia is caused by a deficiency of arginase 1, which catalyzes the final step in the urea cycle, i.e., the cytosolic hydrolysis of arginine to ornithine and urea. In contrast to other urea cycle disorders, hyperammonemic encephalopathy is rarely observed in patients with argininemia. Rather, most exhibit an insidious onset and progression of neurologic manifestations, including spastic diplegia. We describe the first Korean patient with argininemia, manifesting as slowly progressive spastic diplegia. Our patient carries c.[32T>C]+[913G>A] (p.[Ile11Thr]+[Gly305Arg]) mutations in the ARG1 gene. The latter mutation was not previously reported. Although argininemia is a very rare disease, it is recognized as a pan-ethnic disorder. We conclude that argininemia should be considered more frequently in the differential diagnosis of a patient with slowly progressive neurologic manifestations, especially progressive spastic diplegia, even in a population where argininemia was previously unknown. PMID- 21310340 TI - Cryptic x; autosome translocation in a boy--delineation of the phenotype. AB - Chromosome X-to-autosome translocations [t(X;A)] are rare rearrangements with an estimated occurrence of 1 to 3 per 10,000 live births. Occurrences of Xq duplications have been observed in male and female subjects in whom the X chromosome segment escapes inactivation and results in functional disomy. We report a case of X;6 translocation in a 7-year-old boy with severe mental retardation, hypotonia, and recurrent respiratory tract infections. High resolution chromosome analyses (fluorescence in situ hybridization, multiplex ligation probe-dependent amplification, and whole-genome array) revealed a terminal duplication of chromosome X at q28-qter (approximately 3.246 Mb in size) involving gene MECP2 and a terminal deletion (approximately 1.89 Mb) with the breakpoint at 6q27. This is the second report of a boy with a cryptic unbalanced Xq-autosome translocation. This case increases our understanding of mental disability caused by terminal Xq duplication. PMID- 21310341 TI - Hypoplasia of the trapezius and history of ipsilateral transient neonatal brachial plexus palsy. AB - We present two children with hypoplasia of the left trapezius muscle and a history of ipsilateral transient neonatal brachial plexus palsy without documented trapezius weakness. Magnetic resonance imaging in these patients with unilateral left hypoplasia of the trapezius revealed decreased muscles in the left side of the neck and left supraclavicular region on coronal views, decreased muscle mass between the left splenius capitis muscle and the subcutaneous tissue at the level of the neck on axial views, and decreased size of the left paraspinal region on sagittal views. Three possibilities can explain the association of hypoplasia of the trapezius and obstetric brachial plexus palsy: increased vulnerability of the brachial plexus to stretch injury during delivery because of intrauterine trapezius weakness, a casual association of these two conditions, or an erroneous diagnosis of brachial plexus palsy in patients with trapezial weakness. Careful documentation of neck and shoulder movements can distinguish among shoulder weakness because of trapezius hypoplasia, brachial plexus palsy, or brachial plexus palsy with trapezius hypoplasia. Hence, we recommend precise documentation of neck movements in the initial description of patients with suspected neonatal brachial plexus palsy. PMID- 21310342 TI - Recovery after tetraplegia caused by dermal sinus infection: intramedullary abscess and tetraparesis. AB - Congenital dermal sinuses result from abnormal neurulation, and are uncommon. A spinal intramedullary abscess secondary to an infected dermoid cyst is very rare, and the functional prognosis is usually quite poor. We report on a 16-month-old child with tetraplegia secondary to intramedullary abscesses because of a dermoid cyst infection associated with a dermal sinus. The abscesses were drained, and the dermoid cyst was removed. Antibiotics were administered for 6 weeks after neurosurgery. The child was followed at a pediatric rehabilitation department. After 1 year, he was able to walk quickly and had regained appropriate upper limb motor function for his age. However, bladder sphincter dyssynergia persisted, requiring intermittent catheterization. This case highlights the importance of early diagnosis for surgical intervention and prolonged antibiotic therapy. Long term follow-up by a multidisciplinary team allowed for the effective management of related neurologic, orthopedic, and bladder disorders. PMID- 21310343 TI - Acute disseminated encephalomyelitis associated with acute rheumatic fever. AB - An 8-year-old boy developed acute disseminated encephalomyelitis, 2 weeks after an episode of acute rheumatic fever. The disease was succesfully treated with high-dose methylprednisolone. A wide range of neurologic disorders is associated with streptococcal disease. Poststreptococcal acute disseminated encephalomyelitis was previously reported in children, but to our knowledge, this is the first case report of rheumatic fever complicated by acute disseminated encephalomyelitis. This case supports the hypothesis that rheumatic fever, a late complication of streptococcal infections, may be associated with acute disseminated encephalomyelitis. PMID- 21310344 TI - Tacrolimus leukoencephalopathy--is it posterior reversible encephalopathy syndrome? PMID- 21310346 TI - Alveolar bone changes in autogenous tooth transplantation. AB - OBJECTIVE: To assess the alveolar bone formation after autogenous tooth transplantation by conventional radiographic method and digital subtraction radiography. STUDY DESIGN: This retrospective study was done in 54 of 136 patients who received the third molar tooth transplantation and attended the first week, as well as the 1-, 3-, 6-, 9-, and 12-month follow-up. Postoperative periapical radiographs were subsequently evaluated by direct visual interpretation and digital subtraction radiography. The data were analyzed by using McNemar test and 1-way repeated-measure analysis of variance as well as Bonferroni multiple comparison. RESULTS: Fifty-four cases of transplantation were studied. Most of them had normal wound healing. The direct radiographic interpretation and digital subtraction radiography found significant alveolar bone formation in the first-and the third-month follow-ups (P < .05). Lamina dura appeared in the third month and kept increasing until the sixth month. CONCLUSIONS: Postoperative radiographs revealed the distinctive bone formation up to the third month. The clinical and radiographic assessment found that the third molar transplants could bear a normal chewing load within 3 months. PMID- 21310347 TI - Pigmented villonodular synovitis of the temporomandibular joint: case report and review of the literature. AB - Pigmented villonodular synovitis (PVNS) is an aggressive proliferative lesion that usually involves the synovial tissues of big joints. To date, there are ~52 cases of PVNS affecting the temporomandibular joint reported in the English language literature, about one-third of them exhibiting intracranial involvement. We herein describe an additional case of PVNS of the temporomandibular joint with skull base invasion affecting a 26-year-old male patient and discuss its clinicopathologic features considering previously published cases. Histopathology and imaging evaluation are important for the diagnosis of PVNS, which should be included in the differential diagnosis of preauricular aggressive swellings. PMID- 21310348 TI - Juvenile mandibular chronic osteomyelitis: multimodality imaging findings. AB - BACKGROUND AND PURPOSE: Juvenile mandibular chronic osteomyelitis is a rare entity that predominantly affects children and adolescents, but little is known about the factors that contribute to the recurrent course and eventual resolution of this disease. Here, we describe new findings of soft tissue and mandibular nerve canal involvement. MATERIALS AND METHODS: Four patients with mandibular diffuse sclerosing osteomyelitis are presented; all were followed with CT, a few also with MRI and bone scan. We recorded imaging findings of lesion location, pattern of bone formation, presence and evolution of lytic lesions, mandibular nerve, and soft tissue involvement. RESULTS: In all patients we found enlargement of the mandibular nerve canal and soft tissue changes on CT and MRI (when available). All patients had ground glass bone patterns in conjunction with lamellated/onion skin new periosteal bone formation on CT, and all patients with follow-up CT had change in lytic lesion locations. CONCLUSION: Mandibular nerve canal enlargement, soft tissue abnormalities, and change in location of lytic lesions may represent a diagnostic pattern in mandibular diffuse sclerosing osteomyelitis (Garre) that was not previously entirely recognized as such. PMID- 21310349 TI - Accuracy of working length determination using 3 electronic apex locators and direct digital radiography. AB - OBJECTIVES: The objectives of this study were to assess the accuracy of working length determination using 3 electronic apex locators and direct digital radiography and to compare the results with those obtained using the visual method (control measurement). STUDY DESIGN: Twenty extracted human maxillary premolars were selected: 17 two-rooted and 3 single-rooted (total of 37 canals). Working length was measured using electronic apex locators Elements Diagnostic, Root ZX, and Just II. Subsequently, teeth were positioned in the alveolar bone of a dry skull and submitted to direct digital radiography. A variation of +/-1 mm was considered as acceptable. Results were analyzed using the Wilcoxon and the chi(2) tests. RESULTS: Results presented an accuracy of 94.6% for Elements Diagnostic, 91.9% for Root ZX, 73.0% for Just II, and 64.9% for direct digital radiography when considering the margin of +/-1 mm in relation to the control measurement. Comparisons with the actual control measurements resulted in accuracy results of 13.51%, 13.51%, 10.10%, and 2.70%, respectively. CONCLUSIONS: Root ZX and Elements Diagnostic are more accurate in determining working length when compared with Just II and Schick direct digital radiography. PMID- 21310350 TI - Effect of the angle of apical resection on apical leakage, measured with a computerized fluid filtration device. AB - OBJECTIVE: We determined the effect of the angle of apical resection on apical leakage using a computerized fluid filtration meter with a laser system and a digital air pressure regulator in 46 extracted single-rooted human teeth. Orthograde endodontic treatment was performed. The root canals were prepared up to a size 50 K-type file with 17% EDTA solution (Roth International, Chicago, IL) and 5% NaOCl solution as the irrigant. Gates Glidden burs (Maillefer Instruments, Ballaigues, Switzerland) were used to flare the coronal two thirds of the canal. All canals were dried with paper points and then obturated using cold lateral condensation (except for the positive controls) of gutta-percha points and AH plus (Dentsply DeTrey, Konstanz, Germany). All 40 roots were sectioned 3 mm from the apex. Forty teeth were assigned randomly into 1 of 4 experimental groups of 10 teeth each: in group 1, the teeth were resected apically (90 degrees angle) and the cavities were obturated with mineral trioxide aggregate (MTA); in group 2, after apical resection (90 degrees angle), a root-end cavity was prepared using ultrasonic diamond retrotips and the cavities were obturated with MTA; in group 3, the teeth were resected apically (~45 degrees angle) and the cavities were obturated with MTA; and in group 4, after apical resection (~45 degrees angle), a root-end cavity was prepared using ultrasonic diamond retrotips and the cavities were obturated with MTA. An additional 6 teeth were used as controls (3 each, negative and positive controls). Apical leakage was measured using a computerized fluid filtration meter with a laser system. RESULTS: The mean apical microleakage was 2.0 +/- 0.4 * 10(-4), 1.6 +/- 0.6 * 10(-4), 1.6 +/- 0.9 * 10( 4), and 1.8 +/- 0.7 * 10(-4) MUL/cmH(2)O/min(-1) at 1.2 atm, in groups 1 to 4, respectively. Although the mean apical microleakage was greater in group 1, the differences among the 4 groups were not statistically significant (P > .05). CONCLUSIONS: The results of these in vitro studies showed that when an adequate retrograde cavity depth is prepared, variation in the root-end cutting angle does not necessarily cause any difference in microleakage. PMID- 21310351 TI - Assuring dental student head and neck cancer screening competency. PMID- 21310352 TI - A slowly enlarging cheek mass. PMID- 21310354 TI - Expression of DNA damage response biomarkers during oral carcinogenesis. AB - Emerging evidence suggests that an intact DNA damage response (DDR) serves as a potent barrier to malignant transformation. Using immunohistochemistry and patient-derived biopsy samples, we investigated whether the same may hold true during oral carcinogenesis. DNA damage accumulates early in the development of oral squamous cell carcinoma (OSCC) as evidenced by the detection of surrogate DDR biomarkers gamma-H2A.X and phosphorylated CHK2-threonine-68 (phospho CHK2(Thr68)) in epithelial hyperplasias. However, whereas gamma-H2A.X expression peaked in dysplastic epithelium, its levels were significantly reduced in OSCCs (chi(2) = 7.655; P = .02). In contrast, there was a trend toward increased phospho-CHK2(Thr68) expression with increasing severity of the pathology. Nonetheless, combined expression of the biomarkers was significantly greater in the nontransformed tissues relative to OSCCs (chi(2) = 6.42; P = .04). Thus, our findings suggest that early therapeutic exploitation of the DDR may be worthy of investigation as a means by which to limit OSCC development. PMID- 21310353 TI - The presence of amyloid in abdominal and oral mucosal tissues in patients initially diagnosed with multiple myeloma: a pilot study. AB - OBJECTIVES: The aims of this study were to (1) determine the feasibility of tandem assessment of the presence of amyloid in subcutaneous abdominal fat by fine-needle aspiration and oral mucosal tissue biopsy in patients initially diagnosed with multiple myeloma (MM) and (2) determine the optimal site for detection of amyloid in the oral cavity (tongue compared with labial minor salivary glands) in the same cohort of patients. STUDY DESIGN: A prospective, cross-sectional study was performed on patients with newly diagnosed MM. Subjects completed an abdominal fat pad aspirate and biopsies of both the tongue and labial minor salivary glands (LMSGs). All specimens were analyzed for presence of amyloid via standard techniques. RESULTS: Eleven subjects completed the protocol. Amyloid was not detected in any abdominal fat pad specimens. Amyloid was not detected in any tongue specimens; however, 2 subjects demonstrated amyloid deposition in LMSGs. Neither of these subjects demonstrated evidence of systemic amyloidosis or recurrence of MM at least 3 years after completing the study protocol. CONCLUSIONS: The results of this study suggest that the labial minor salivary glands may be the optimal site to detect amyloid in patients with newly diagnosed MM. Additional studies are warranted to determine if amyloid in the LMSGs represents a high-risk prognostic factor for MM. PMID- 21310355 TI - The relationship between mouth opening and computerized tomographic features of posttraumatic bony ankylosis of the temporomandibular joint. AB - OBJECTIVE: The purpose of this paper was to investigate the relationship between mouth opening and computerized tomography (CT) features in patients with bony ankylosis of the temporomandibular joint. STUDY DESIGN: A series of morphologic parameters-the diameters of bony mass (D1), the width of bony fusion area (D2), the ratio of D2/D1, and the degree of calcification in bony fusion area (D3)-were measured by Mimics 10.0 software. Correlation analysis and stepwise multiple linear regression analysis were the statistical methods used. RESULTS: Nine patients (23.68%) with bony fusion area fully calcified were completely unable to open their mouth, whereas 29 patients (76.32%) with bony fusion area calcified incompletely had a slight degree of mouth opening. No correlation was found between mouth opening and D1. A negative correlation was observed between mouth opening and D2 (r = -0.670; P < .01), between mouth opening and D2/D1 (r = 0.697; P < .01), and between mouth opening and D3 (r = -0.744; P < .01). Multiple stepwise regression analysis identified D2 and D3 as predictive factors of residual mouth opening. CONCLUSIONS: D2 and D3 were independent factors affecting the mouth opening. The insufficient calcification of bony fusion area, which cannot fully limit the motion of ankylosed joint, may be an important cause of residual mouth opening in patients with complete bony ankylosis. PMID- 21310356 TI - Is failure of condylar neck osteosynthesis predictable based on orthopantomography? AB - BACKGROUND: Osteosynthesis failure rates of 11.3% with 1 miniplate, 6.7% with 2 miniplates, and 4.4% with a single Medartis condyle plate were reported in previous studies of our clinic. Current science is still focused on the osteosynthesis material. Besides clinical parameters, conventional radiographs are still the first choice to detect osteosynthesis failures. This study scrutinized several factors assessable in postoperative orthopantomographs which might elevate the risk of osteosynthesis failure. STUDY DESIGN: A total of 136 patients (22 with osteosynthesis failure, 114 without) with 151 mandibular condyle fractures were included in this study. Eight parameters were assessed in postoperative orthopantomographs. RESULTS: The best predictor of osteosynthesis failure was a simplified concept of ramus height. In cases of reduced or normal ramus height, the odds of osteosynthesis failure was significantly (P = .000001) reduced to a 10th. Isolated fractures were significantly more error prone (P = .0009). CONCLUSIONS: Postoperative orthopantomographs depict factors which increase the risk of osteosynthesis failure. PMID- 21310357 TI - Radiological and histologic studies of the mandibular cortex of ovariectomized monkeys. AB - OBJECTIVE: The objective was to study the radiological and histologic changes in the mandibular cortices of ovariectomized monkeys. STUDY DESIGN: Twelve female, adult, Cynomolgus monkeys (Macaca fascicularis) were used. Under anesthesia, 1 group was bilaterally ovariectomized (OVX), and the other (control group) underwent sham surgery. Seventy-six weeks after surgery, the monkeys were humanely killed, their mandibles were excised, and their mandibular inferior cortices (MIC) and adjacent cortices were examined histologically and with panoramic radiographs and micro computed tomography. RESULTS: Striped shadows were seen on the endosteal side of the OVX cortices on panoramic radiographs. Histologic observation revealed many enlarged pores with eroded surfaces and calcein labeling (indicating osteon remodeling) in the OVX cortices. CONCLUSIONS: In the MIC and adjacent cortices of OVX monkeys, enlarged Haversian canals were seen and there were indications of a high rate of bone turnover. The enlarged Haversian canals resulted in striped shadows and unclear endosteal margins on radiographic images. PMID- 21310368 TI - [Narrowband UV-B, monochromatic excimer laser, and photodynamic therapy in psoriasis: a consensus statement of the Spanish Psoriasis Group]. AB - Novel treatment strategies and new information concerning the management of moderate to severe psoriasis justify a reassessment of the role of the classic therapies in this setting. This consensus statement evaluates narrowband UV-B therapy, which is currently considered the phototherapy option of choice in psoriasis because of its risk-to-benefit ratio. The role of excimer laser and photodynamic therapies are also discussed. These targeted therapies are still only available in a small number of centers in Spain and are used principally in the treatment of localized and recalcitrant forms of psoriasis. We discuss the efficacy and safety of phototherapy as well as treatment regimens, combination therapy, and clinical considerations relating to the characteristics of the patient or the disease. PMID- 21310369 TI - [Septic emboli to the skin following angioplasty]. AB - Invasive vascular procedures have good efficacy and safety profiles and are now widely used for the diagnosis and treatment of many cardiovascular disorders. However, they do have potential complications that can occasionally be life threatening. We present a new case of infectious pseudoaneurysm following percutaneous transluminal coronary angioplasty and complicated by septic emboli to the skin. It is a rare condition characterized by persistent bacteremia, sepsis of unknown origin, and regional septic emboli. Histopathology of the skin lesions typically reveals gram-positive coccobacilli and septic vasculitis. The condition carries a significant morbidity and mortality, making early diagnosis essential. Both cholesterol and septic emboli should be considered in the differential diagnosis of skin lesions after invasive vascular procedures. PMID- 21310370 TI - Effect of exercise training on plasma levels and functional properties of high density lipoprotein cholesterol in the metabolic syndrome. AB - Intense lifestyle modifications can change the high-density lipoprotein (HDL) cholesterol concentration. The aim of the present study was to analyze the early effects of short-term exercise training, without any specific diet, on the HDL cholesterol plasma levels and HDL functional characteristics in patients with the metabolic syndrome (MS). We studied 30 sedentary subjects, 20 with and 10 without the MS. The patients with the MS underwent moderate intensity exercise training for 3 months on bicycle ergometers. Blood was sampled before and after training for biochemical analysis, paraoxonase-1 activity, and HDL subfraction composition and antioxidative capacity. Lipid transfer to HDL was assayed in vitro using a labeled nanoemulsion as the lipid donor. At baseline, the MS group had greater triglyceride levels and a lower HDL cholesterol concentration and lower paraoxonase-1 activity than did the controls. Training decreased the plasma triglycerides but did not change the low-density lipoprotein or HDL cholesterol levels. Nonetheless, exercise training increased the HDL subfractions' antioxidative capacity and paraoxonase-1 activity. After training, the MS group had compositional changes in the smallest HDL subfractions associated with increased free cholesterol and cholesterol ester transfers to HDL, reaching normal values. In conclusion, the present investigation has added relevant information about the dissociation between the quantitative and qualitative aspects of HDL after short-term exercise training without any specific diet in those with the MS, highlighting the importance of evaluating the functional aspects of the lipoproteins, in addition to their plasma levels. PMID- 21310371 TI - Screening for cognitive deficits using the Montreal cognitive assessment tool in outpatients >=65 years of age with heart failure. AB - There is strong evidence to suggest that heart failure (HF) is an independent risk factor for cognitive impairment (CI). The combination of CI and HF is associated with increased mortality, repeat hospitalization, and poor quality of life. The purpose of this pilot study was to determine the presence of CI in older patients with HF using the Montreal Cognitive Assessment (MoCA), a brief screening instrument for CI. We conducted a cross-sectional descriptive study using the MoCA in outpatients with HF who were >= 65 years of age. Forty-four patients (mean +/- SD 76 +/- 6.6 years of age) completed the MoCA. More than 70% of patients scored below the MoCA cutoff score of 26, suggesting the presence of CI. However, 91% of patients with New York Heart Association classes III to IV versus 52% of patients with classes I to II had a MoCA score < 26 (p = 0.004). Patients with a recent hospital admission were more likely to have a MoCA score < 26 versus patients without a recent hospital admission (89% vs 62%, respectively, p < 0.045). Cognitive domain subscores showing significant differences (p <0.01) were short-term memory, visuospatial function, executive function, and language. In conclusion, this study sample represented a group of older patients with HF and no suspected or documented CI, but screening with the MoCA detected CI in >70% of the sample. The presence of CI was significantly more common in patients with advanced HF symptoms or a recent hospitalization. Future studies need to determine if the MoCA can identify the presence of CI that is predictive of adverse clinical outcomes in the HF population. PMID- 21310372 TI - New method of intracoronary adenosine injection to prevent microvascular reperfusion injury in patients with acute myocardial infarction undergoing percutaneous coronary intervention. AB - The aim of our study was to examine the role of a new, simple protocol of intracoronary adenosine administration performed during primary angioplasty on the immediate angiographic results and clinical course. A prospective, single center, randomized, placebo-controlled trial of 70 consecutive patients (64 +/- 14 years, 54 men) with acute myocardial infarction with ST-segment elevation undergoing primary percutaneous coronary intervention (PCI) was conducted. Patients were randomized to 2 groups. Group 1 (n = 35) received intracoronary adenosine (1 to 2 mg) with a hand injection through the guiding catheter 2 times: immediately after crossing the lesion of the infarct-related artery with guidewire and then after the first balloon inflation. Group 2 (n = 35) received placebo. The baseline clinical and angiographic characteristics of the 2 groups were similar. Percutaneous coronary intervention resulted in Thrombolysis In Myocardial Infarction grade 3 flow after PCI in 32 patients (91.4%) in the adenosine group and 27 patients (77.1%) in the placebo group (p = 0.059). Myocardial blush grade 3 was observed at the end of PCI in 23 patients (65.7%) in the adenosine group and 13 (37.1%) in the placebo group (p < 0.05). Resolution of ST-segment elevation (> 50%) was more frequently observed in the adenosine than in the placebo group: 27 (77%) versus 15 (43%), respectively (p < 0.01). In conclusion, intracoronary adenosine administration improved the angiographic and electrocardiographic results in patients with acute myocardial infarction with ST segment elevation undergoing PCI. Adenosine administration seemed to be associated with a more favorable clinical course. PMID- 21310373 TI - Noninvasive detection of fetal trisomy 21 by sequencing of DNA in maternal blood: a study in a clinical setting. AB - OBJECTIVE: We sought to evaluate a multiplexed massively parallel shotgun sequencing assay for noninvasive trisomy 21 detection using circulating cell-free fetal DNA. STUDY DESIGN: Sample multiplexing and cost-optimized reagents were evaluated as improvements to a noninvasive fetal trisomy 21 detection assay. A total of 480 plasma samples from high-risk pregnant women were employed. RESULTS: In all, 480 prospectively collected samples were obtained from our third-party storage site; 13 of these were removed due to insufficient quantity or quality. Eighteen samples failed prespecified assay quality control parameters. In all, 449 samples remained: 39 trisomy 21 samples were correctly classified; 1 sample was misclassified as trisomy 21. The overall classification showed 100% sensitivity (95% confidence interval, 89-100%) and 99.7% specificity (95% confidence interval, 98.5-99.9%). CONCLUSION: Extending the scope of previous reports, this study demonstrates that plasma DNA sequencing is a viable method for noninvasive detection of fetal trisomy 21 and warrants clinical validation in a larger multicenter study. PMID- 21310374 TI - Eviscerated: a fall at home had astonishing consequences for an elderly patient. PMID- 21310375 TI - Amino Acid profiles in human tear fluids analyzed by high-performance liquid chromatography and electrospray ionization tandem mass spectrometry. AB - PURPOSE: To identify the 23 amino acid profiles in human tear fluids, and to evaluate whether the ocular disease conditions reflect the amino acid profiles. DESIGN: Laboratory investigation. METHODS: We evaluated the concentrations and relative composition of 23 amino acids in tear fluids obtained from 31 healthy volunteers using reversed-phase high-performance liquid chromatography and electrospray ionization tandem mass spectrometry, and compared them with those in plasma and aqueous humor. We also evaluated the tear-fluid amino acid profiles from 33 affected subjects. RESULTS: The amino acid profiles of the basal tear and reflex tear were found to be similar, and 4 distinct groups of healthy volunteers (male, female, young, and elderly) showed similar profiles. Absolute concentrations of taurine (Tau) and L-glutamine were significantly dominant in these tear fluids. The relative compositions of Tau, L-glutamic acid, L-arginine (Arg), and citrulline in the tear fluid were significantly higher than those in the plasma and aqueous humor. Analysis of the hierarchical clustering of the amino acid profiles clearly distinguished severe ocular surface diseases from non ocular surface diseases. The relative compositions of Tau, L-methionine, and Arg decreased in severe ocular surface disease subjects compared with non-ocular surface disease subjects. CONCLUSIONS: Tear-fluid amino acid profiles differ from those in plasma and aqueous humor. Steady-state tear-fluid amino acid profiles might reflect ocular-surface homeostasis and the observed changes of amino acids might have a close relation with the disease conditions on the ocular surface. PMID- 21310376 TI - Long-term change in corneal astigmatism after sutureless cataract surgery. AB - PURPOSE: To compare long-term change in corneal astigmatism with advancing age between eyes that underwent sutureless cataract surgery and those that did not undergo surgery. DESIGN: Case-control study. METHODS: A total of 153 eyes that underwent phacoemulsification with a horizontal incision more than 11 years ago (surgery group) and 153 age-matched control eyes that did not undergo surgery (nonsurgery group) were enrolled. The keratometric cylinder at baseline (at 1 year or more postoperatively in the surgery group) and at 5 and 10 years after baseline was examined. The corneal astigmatic change, as calculated using polar value analysis and vector decomposition analysis, between baseline and 5 years after baseline and between 5 and 10 years was compared between the groups. RESULTS: The mean corneal astigmatic change, specifically DeltaKP (90) in the polar analysis and against-the-rule component in the vector analysis, between baseline and 5 years and between 5 and 10 years showed an against-the-rule change in both groups. Using multivariate analysis, no significant difference was found in the corneal astigmatic change between the 2 groups at either time interval (P >= .126). Furthermore, the change between baseline and 5 years was similar to that between 5 and 10 years in both groups (P >= .315). CONCLUSIONS: Corneal astigmatism after sutureless cataract surgery shows a long-term against-the-rule change with advancing age, and this change is similar to that of normal cornea, suggesting that the against-the-rule change that occurs subsequently should be taken into consideration at the time of cataract surgery. PMID- 21310377 TI - Predictability of visual function and nerve fiber layer thickness by cross sectional areas of extraocular muscles in graves ophthalmopathy. AB - PURPOSE: To evaluate the predictability of visual function and peripapillary nerve fiber layer thickness by cross-sectional areas of extraocular muscles in patients with Graves ophthalmopathy. DESIGN: Interventional case series. METHODS: The data on a total of 76 patients with Graves ophthalmopathy were collected, and the cross-sectional areas of 4 rectus muscles were calculated using computed tomographic images. This study measured the correlation between the cross sectional area of all rectus muscles and the Hertel value, logarithm of the minimal angle of resolution (logMAR), mean deviation of retinal sensitivity, P(100) value of visual evoked potential, total error of the Farnsworth-Munsell 100-hue color sensation test, and total thickness of the peripapillary nerve fiber layer thickness by optical coherence tomography. RESULTS: The cross sectional area of all rectus muscles was significantly correlated with the mean deviation of retinal sensitivity (Pc = .08), the P(100) value of visual evoked potential (Pc < .01), and the total error of the 100-hue color sensation test (Pc < .01). However, the cross-sectional area of all rectus muscles was not significantly correlated with logMAR or proptosis, nor with the total thickness of the peripapillary nerve fiber layer. CONCLUSIONS: For patients with Graves ophthalmopathy, the cross-sectional area of all rectus muscles was significantly correlated with visual function. The enlargement of extraocular muscles can be an early sign of optic neuropathy prior to perceived clinical symptoms. Furthermore, it is possible to predict visual function change using the cross-sectional area of all rectus muscles. PMID- 21310378 TI - Management of traumatic severely subluxated cataracts. AB - PURPOSE: To determine outcome of cataract surgery in severely subluxated traumatic cataracts. DESIGN: Noncomparative case series. METHODS: Retrospective review of cataract surgery in all consecutive eyes with at least 6 clock hours of zonulysis, for patient demographics, presenting best-corrected visual acuity (BCVA) and postoperative BCVA at various time points, extent of zonulysis, and type and timing of insertion of capsular tension device. Main outcome measures were retention of the capsular bag and BCVA at last visit. Secondary outcome measures included IOL stability and centration, and perioperative complications. RESULTS: There were 41 eyes (41 patients). Mean age at time of surgery was 57 years and the mean duration of follow-up was 21.4 months. The capsular bag was preserved with aid of a Cionni modified capsular tension ring (CTR) in 36 eyes (87.8%) and a combination of a capsular tension segment (CTS) and CTR in 2 eyes. In 3 eyes with total zonulysis, the bag could not be preserved despite the use of a CTS in 2 eyes. Preoperatively only 9 of the 41 eyes (22.0%) had a BCVA of 20/40 or better, as compared to 38 eyes at the last visit (92.7%, P < .001, chi(2) test). Posterior capsule rupture occurred in 3 eyes, 2 of which occurred during fixation of the CTR. CONCLUSIONS: The capsular bag can be successfully preserved even in severely subluxated traumatic cataracts with the aid of fixated capsular tension devices. PMID- 21310379 TI - Tear osmolarity in the diagnosis and management of dry eye disease. AB - PURPOSE: To evaluate the use of tear osmolarity in the diagnosis of dry eye disease. DESIGN: A prospective, observational case series to determine the clinical usefulness of tear osmolarity and commonly used objective tests to diagnose dry eye disease. METHODS: A multicenter, 10-site study consisting of 314 consecutive subjects between 18 and 82 years of age. Bilateral tear osmolarity, tear film break-up time (TBUT), corneal staining, conjunctival staining, Schirmer test, and meibomian gland grading were performed. Diagnostic performance was measured against a composite index of objective measurements that classified subjects as having normal, mild or moderate, or severe dry eye. The main outcome measures were sensitivity, specificity, area under the receiver operating characteristic curve, and intereye variability. RESULTS: Of the 6 tests, tear osmolarity was found to have superior diagnostic performance. The most sensitive threshold between normal and mild or moderate subjects was found to be 308 mOsms/L, whereas the most specific was found at 315 mOsms/L. At a cutoff of 312 mOsms/L, tear hyperosmolarity exhibited 73% sensitivity and 92% specificity. By contrast, the other common tests exhibited either poor sensitivity (corneal staining, 54%; conjunctival staining, 60%; meibomian gland grading, 61%) or poor specificity (tear film break-up time, 45%; Schirmer test, 51%). Tear osmolarity also had the highest area under the receiver operating characteristic curve (0.89). Intereye differences in osmolarity were found to correlate with increasing disease severity (r(2) = 0.32). CONCLUSIONS: Tear osmolarity is the best single metric both to diagnose and classify dry eye disease. Intereye variability is a characteristic of dry eye not seen in normal subjects. PMID- 21310380 TI - Long-term anatomic and visual outcomes of initially closed macular holes. AB - PURPOSE: To evaluate the anatomic and visual outcomes in patients with initially closed macular holes after vitreoretinal surgery and with 1 to 7 years of follow up. DESIGN: Retrospective, noncomparative, consecutive case series. METHODS: Eighty-seven consecutive eyes of 79 patients with previous closure of the macular holes and with at least 1 year of follow-up were reviewed in this retrospective clinical study. Main outcome measures included the rate of macular hole reopening and visual acuity outcomes. RESULTS: The mean age of enrolled patients was 63.1 +/- 6.2 years (range, 49 to 74 years); the mean duration of macular hole was 5.6 +/- 9.7 months (range, 0.25 to 60 months); and the mean follow-up interval was 38.4 +/- 19.7 months (range, 12 to 86 months). All eyes underwent internal limiting membrane peeling during the vitrectomy, and 64 (73.6%) of 87 eyes underwent cataract extraction. No reopening of initially closed macular holes was observed in any eyes. Slight perifoveal epiretinal membranes were observed by optical coherence tomography in 32.2% of cases (28/87). The final best-corrected visual acuity improved to 0.47 +/- 0.39 logarithm of the minimal angle of resolution units, which was significantly higher than preoperative visual acuity of 1.01 +/- 0.36 logarithm of the minimal angle of resolution units (t = -12.532; P = .000). Multiple linear regression analysis demonstrated that the final best corrected visual acuity was affected by the macular hole stage, preoperative best corrected visual acuity, and cataract exaction (F = 19.858; P = .000). CONCLUSIONS: The stable closure of macular holes is achieved after vitrectomy with internal limiting membrane peeling. Phacoemulsification cataract surgery with intraocular lens implantation for improvement of visual function is not responsible for the reopening of previously closed macular holes. PMID- 21310381 TI - Oxygen therapy for acute ocular chemical or thermal burns: a pilot study. AB - PURPOSE: To evaluate the effect of systemic oxygen therapy in the management of acute ocular chemical and thermal burns. DESIGN: Prospective, nonrandomized, comparative, interventional case series. METHODS: Twenty-four eyes of 22 patients with grade III to IV acute ocular chemical and thermal burns received conventional medical therapy. The oxygen therapy group (13 eyes) additionally received 100% oxygen using a simple mask at a flow rate of 10 L/minute for 1 hour twice daily. Main outcome measures were time for healing of the corneal epithelial defect and improvement in perilimbal ischemia. Secondary outcome measures included visual acuity, corneal transparency and vascularization, and complications. RESULTS: Corneal epithelial defects healed within 15.23 +/- 3.94 days (range, 10 to 21 days) in the oxygen group versus 59.9 +/- 23.33 days (range, 28 to 95 days) in controls (P < .001). Vascularization of ischemic areas was complete in 14.54 +/- 2.70 days (range, 10 to 21 days) in the oxygen group versus 45.09 +/- 22.20 days (range, 25 to 105 days) in controls (P = .001). In the oxygen group, the cornea was more transparent and less vascularized 3 and 6 months after injury. Mean final visual acuity (logarithm of the minimal angle of resolution) was 0.40 +/- 0.52 (range, 0 to 1.3) versus 1.11 +/- 0.83 (range, 0.1 to 3) in the oxygen and control groups, respectively (P = .018). In the oxygen group, symblepharon or corneoscleral melting did not develop in any patient; however, in the control group, symblepharon developed in 3 eyes and corneoscleral melting developed in 1 patient. CONCLUSIONS: In the acute phase of ocular chemical or thermal burns, oxygen therapy improves limbal ischemia, accelerates epithelialization, increases corneal transparency, and decreases corneal vascularization. It also may improve visual acuity and reduce complications. PMID- 21310382 TI - Bilateral irreversible severe vision loss from cosmetic iris implants. AB - PURPOSE: To report a case of bilateral neovascular glaucoma with central retinal vein occlusions secondary to cosmetic iris implantation. DESIGN: Interventional case report. METHODS: setting: Tertiary care center; ophthalmology clinic. patient: A 25-year-old woman presented with persistent bilateral blurry vision after simultaneous bilateral cosmetic iris implantation. Examination showed best corrected visual acuity of hand motion in the right and 20/400 in the left eye with intraocular pressures (IOP) of 48 mm Hg in the right and 40 mm Hg in the left eye on maximal medical therapy. She had bilateral neovascularization of the iris and angle with synechial angle closure, surgical aniridia, central retinal vein occlusion, and end-stage glaucomatous optic neuropathy. She was diagnosed with neovascular glaucoma in both eyes, associated with cosmetic iris implants. intervention procedures: Humphrey 24-2 visual field testing, optic nerve coherence tomography, and fundus imaging were performed. After bilateral intravitreal bevacizumab and panretinal photocoagulation, Ahmed glaucoma drainage devices were implanted in both eyes. main outcome measures: IOP, anterior chamber inflammation, neovascularization. RESULTS: Despite aggressive treatment, severe permanent bilateral vision loss ensued. CONCLUSION: We strongly advise against the use of anterior chamber iris implants for cosmetic indications. Close monitoring of implanted individuals is necessary. Explantation should be considered at the earliest sign of adverse reaction. PMID- 21310383 TI - Higher-order aberration changes after Implantable Collamer Lens implantation for myopia. AB - PURPOSE: To investigate the changes in higher-order aberrations (HOAs) induced by implantation of Implantable Collamer Lenses (STAAR Surgical) and to explain them in relation to the surgical incision and optical properties. DESIGN: Prospective, observational case study. METHODS: This study included 56 eyes undergoing Implantable Collamer Lens insertion for myopic correction. The corneal incision size was determined according to the amount of astigmatism. HOAs were measured before surgery and 3 months after surgery in 25 eyes having small superior incision (<3.2 mm) surgery and in 31 eyes with large superior incision (3.2 to 4.5 mm) surgery. Changes in spherical aberration, coma, trefoil, and total HOAs (third to sixth order) were analyzed. Laboratory measurements of aberration profiles of Implantable Collamer Lenses with different optical powers were performed to validate clinical measurements. RESULTS: In the small-incision group, trefoil (Z(3)(-3)) and spherical aberration changed significantly (P=.004). In the large-incision group, in addition to trefoil and spherical aberration, total HOA changed significantly (mean change, 0.13 +/- 0.17; P=.001). Significant correlations were observed among the incision size, the astigmatism induced, and the trefoil induced. Induced trefoil showed a predominant pattern at the orientation of the incision meridian. Optical measurement of aberrations of the Implantable Collamer Lenses confirmed the postoperative negative spherical aberration. CONCLUSIONS: HOA changes after Implantable Collamer Lens insertion were increased trefoil and induced negative spherical aberration. These changes may be explained by the effect of the corneal incision and the negative spherical aberration in the Implantable Collamer Lens, respectively. PMID- 21310384 TI - The lifetime economic burden of keratoconus: a decision analysis using a markov model. AB - PURPOSE: To estimate the expected incremental lifetime cost of treatment of keratoconus compared to the expected cost of the treatment of myopia. DESIGN: Cost estimate from the patient's perspective using a Markov decision model. METHODS: We modeled a hypothetical cohort of people with clinically significant incident keratoconus as defined by the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study. We included costs of clinic visits, fitting fees, contact lenses, surgical procedures, and complications. Survival curves of corneal transplants and associated complications were modeled using data from the 2007 Australian Graft Registry. Medical treatment regimens after surgery were defined by expert opinion. RESULTS: The expected value of the lifetime cost of the treatment of keratoconus over myopia was $25 168 with a standard deviation of $16 247 and a median of $17 596. The factors that most influenced the lifetime cost were the probability of initial corneal transplant and a subsequent regraft. The cost of routine care had relatively little influence on the lifetime cost of care. CONCLUSIONS: The expected lifetime cost of treatment of keratoconus represents a significant cost to patients and payors. While the cost of routine care for keratoconus is not trivial, the primary factor influencing changes in the cost of care for keratoconus is the probability of corneal transplant. Combined with the significantly impaired vision-related quality of life and the relatively young onset of disease, the economic burden of the treatment of keratoconus represents a significant public health concern. PMID- 21310386 TI - Intraocular pressure measurements and biomechanical properties of the cornea in eyes after penetrating keratoplasty. AB - PURPOSE: To compare intraocular pressure (IOP) measurements obtained using the Goldmann applanation tonometer (GAT; Haag-Streit), the Tono-Pen XL (Reichert, Inc), and the ocular response analyzer (ORA; Reichert Ophthalmic Instruments), and to determine the influence of corneal factors on IOP measurements in eyes that had undergone penetrating keratoplasty (PK). DESIGN: Consecutive, prospective study. METHODS: Study population. Sixty-one eyes that underwent PK were enrolled in this study. Intervention. IOP was measured using the GAT, Tono Pen, and ORA. Corneal hysteresis and corneal resistance factor as provided by the ORA were recorded. Central corneal thickness was measured using an ultrasound pachymeter. Main outcome measures. IOP and corneal biomechanical factors. RESULTS: IOP measurements were obtained in an average of 65 months (range, 6 to 209 months) after PK surgery. ORA-derived IOP measurements (corneal-compensated IOP and Goldmann-correlated IOP) and Tono-Pen XL IOP all correlated in a significant manner to GAT IOP measurements. Corneal-compensated IOP and Tono-Pen XL IOP values were higher than GAT IOP (P < .001 and P = .001, respectively), whereas Goldmann-correlated IOP readings did not differ from GAT IOP readings (P = .054). Central corneal thickness did not correlate to any tonometry technique. In a regression analysis, corneal hysteresis and corneal resistance factor were found to play a role in IOP prediction. CONCLUSIONS: Central corneal thickness may be of less importance than corneal hysteresis and corneal resistance factor in IOP determination in eyes that have undergone PK, perhaps because of the lower modulus of elasticity in these eyes. GAT IOP seems to be lower than other tonometry techniques in eyes that have undergone PK. PMID- 21310385 TI - Transforming growth factor-beta signaling pathway activation in Keratoconus. AB - PURPOSE: To assess the presence of transforming growth factor-beta (TGFbeta) pathway markers in the epithelium of keratoconus patient corneas. DESIGN: Retrospective, comparative case series of laboratory specimens. METHODS: Immunohistochemistry results for TGFbeta2, total TGFbeta, mothers against decacentaplegic homolog (Smad) 2, and phosphorylated Smad2 was performed on formalin-fixed, paraffin-embedded sections of keratoconus patient corneas and normal corneas from human autopsy eyes. Keratoconus patient corneas were divided in two groups, depending on their severity based on keratometer readings and pachymetry. Autopsy controls were age-matched with the keratoconus cases. Immunohistochemistry signal quantification was performed using automated software. Real-time reverse-transcriptase polymerase chain reaction was performed on total ribonucleic acid of epithelium of keratoconus patient corneas and autopsy control corneas. RESULTS: Immunohistochemistry quantification showed a significant increase in mean signal in the group of severe keratoconus cases compared with normal corneas for TGFbeta2 and phosphorylated Smad2 (P < .05). Immunohistochemistry analysis using antibodies against total TGFbeta and Smad2 did not show any significant increase in the keratoconus cases versus the autopsy controls. Reverse-transcriptase polymerase chain reaction exhibited elevated messenger ribonucleic acid levels of Smad2 and TGFbeta2 in severe keratoconus corneal epithelium. CONCLUSIONS: This work shows increased TGFbeta pathway markers in severe keratoconus cases and provides the rationale for investigating TGFbeta signaling further in the pathophysiology of keratoconus. PMID- 21310387 TI - Impact of clinical factors on the long-term functional and anatomic outcomes of osteo-odonto-keratoprosthesis and tibial bone keratoprosthesis. AB - PURPOSE: To report the long-term functional and anatomic outcomes of osteo-odonto keratoprosthesis and tibial bone keratoprosthesis; to analyze the influence of clinical factors, such as surgical technique, primary diagnosis, age, and postoperative complications, on the final outcome. DESIGN: Retrospective cohort study. METHODS: setting: Centro de Oftalmologia Barraquer, between 1974 and 2005. PARTICIPANTS: Two hundred twenty-seven patients. intervention: Biological keratoprosthesis using osteo-odonto-keratoprosthesis or tibial bone keratoprosthesis. main outcome measures: Functional survival with success defined as best-corrected visual acuity >=0.05; anatomic survival with success defined as retention of the keratoprosthesis lamina. RESULTS: Osteo-odonto-keratoprosthesis and tibial bone keratoprosthesis have comparable anatomic survival at 5 and 10 years of follow-up, but osteo-odonto-keratoprosthesis has a significantly better functional success than tibial bone keratoprosthesis at the same time periods. Among the primary diagnoses, Stevens-Johnson syndrome, chemical burn, and trachoma have generally good functional and anatomic outcomes and the least favorable prognosis is for ocular cicatricial pemphigoid. Younger patients fared better than those in older age groups. The most frequent complications were extrusion (28%), retinal detachment (16%), and uncontrolled glaucoma (11%). The glaucoma group had the best anatomic success but the worst functional results, only exceeded by the retinal detachment group in terms of functional outcome. CONCLUSION: Clinical factors, such as surgical technique, primary diagnosis, age, and postoperative complications, can affect the long-term anatomic and functional successes of biological keratoprosthesis. Knowledge about the impact of each of these factors on survival can help surgeons determine the best approach in every particular case. PMID- 21310388 TI - In vivo analysis of stromal integration of multilayer amniotic membrane transplantation in corneal ulcers. AB - PURPOSE: To evaluate integration of amniotic membrane into the corneal stroma using laser scanning in vivo confocal microscopy and anterior segment optical coherence tomography (AS-OCT). DESIGN: Prospective noncomparative interventional case series. METHODS: Twenty-two eyes of 22 consecutive patients (mean age 53.9 +/- 9.2 years) presenting with noninfectious corneal ulcers and stromal thinning unresponsive to medical treatment were enrolled. Multiple layers of amniotic membrane were applied over the ulcer bed to fill the ulcer crater and held in place with an overlying amniotic membrane patch, which was anchored to the surrounding cornea with 10-0 nylon interrupted sutures. Outcome measures were healing of the corneal ulcers, corneal morphology and stromal thickness changes at the ulcer site as measured by AS-OCT and surface epithelialization, stromal repopulation, and structural modifications of the amniotic membrane grafts as evaluated by confocal microscopy. RESULTS: Follow-up extended to 12 months. Successful result was observed in 20 of 22 eyes (90.9%). AS-OCT showed that the mean residual stromal thickness at the ulcer bed was 222 +/- 70 MUm before surgery. The mean thickness of amniotic membrane layers at the same site was 394 +/- 80 MUm while the mean total corneal thickness was 623 +/- 51 MUm at day 1 post surgery. Thereafter a progressive reduction in thickness to 420 +/- 61 MUm at 6 months occurred, after which the thickness stabilized. Confocal microscopy showed that integration of the amniotic membrane tissues with corneal stroma was preceded by epithelialization over the amniotic membrane covering the ulcer. This occurred 15 +/- 5 days post surgery in the successful cases. Confocal microscopy also showed that the amniotic membrane patch was degraded during the first few weeks after surgery, while the integrated amniotic tissues underwent progressive modifications characterized by early loss of amniotic epithelial cells, changes in fibrillar structure, and migration into the amniotic stroma by corneal stroma derived cells. CONCLUSIONS: Multiple layers of amniotic membrane can integrate into the corneal stroma with resulting increase in corneal thickness. This appears to be related to re-epithelialization of the transplanted membrane. Integrated amnion within the stromal defect undergoes progressive changes including contraction of tissue and repopulation by corneal stroma-derived cells. PMID- 21310389 TI - Corneal nerve aberrations in bullous keratopathy. AB - PURPOSE: To study the corneal nerves in patients with chronic bullous keratopathy. DESIGN: Prospective observational case series with histologic evaluation. METHODS: We studied 25 eyes of 25 bullous keratopathy patients of different etiologies (17 female, 8 male; mean age, 76.3 years) as well as 6 eyes of 6 normal control subjects (5 male, 1 female; mean age, 38 years). All subjects were scanned by laser scanning confocal microscope. Five corneal buttons obtained following penetrating keratoplasty from 5 of the above patients and 6 normal control corneal buttons were stained as whole mounts with acetylcholinesterase (AChE) method for corneal nerve demonstration and scanned in multiple layers with digital pathology scanning microscope. RESULTS: The density, branching pattern, and diameter of sub-basal nerves were significantly lower in corneas with bullous keratopathy compared with normal corneas (density: 4.42 +/- 1.91 mm/mm(2) vs 20.05 +/- 4.24 mm/mm(2); branching pattern: 36.02% +/- 26.57% vs 70.79% +/- 10.53%; diameter: 3.07 +/- 0.64 MUm vs 4.57 +/- 1.12 MUm). Aberrations such as localized thickenings or excrescences, abnormal twisting, coiling, and looping of the (mid) stromal nerves were observed in the study group both by in vivo confocal microscopy and on histology. CONCLUSIONS: Striking alterations in corneal innervation are present in corneas with bullous keratopathy that are unrelated to any specific etiology of bullous keratopathy. This study provides histologic confirmation of novel in vivo confocal microscopy findings related to corneal nerves in bullous keratopathy. PMID- 21310390 TI - Pharmacotherapy for neovascular age-related macular degeneration: an analysis of the 100% 2008 medicare fee-for-service part B claims file. AB - PURPOSE: To describe the usage patterns of pharmacological treatments for neovascular age-related macular degeneration (AMD) in Medicare fee-for-service beneficiaries. DESIGN: Retrospective review of all Medicare fee-for-service Part B claims for neovascular AMD during 2008. METHODS: Medicare beneficiaries having undergone treatment were identified. The data collected for each visit for a given beneficiary included age, race, gender, Medicare region, state/zip code of residence, date of visit, whether or not the beneficiary had a treatment, the type and amount of drug, and dollars paid by Medicare. The main outcome measures were the number and rate of treatments, the types of drugs used for treatment, and the payments for these drugs. RESULTS: Of the 222 886 unique beneficiaries, 146 276 (64.4%) received bevacizumab and 80 929 (35.6%) received ranibizumab. A total of 824 525 injections were performed with 480 025 injections of bevacizumab (58%) and 336 898 injections of ranibizumab (41%). National rates of injections per 100 000 fee-for-service Part B Medicare beneficiaries for bevacizumab and ranibizumab were 1506 and 1057, respectively. Total payments by Medicare were $20 290 952 for bevacizumab and $536 642 693 for ranibizumab. In 39 out of 50 states, the rate of injection was higher for bevacizumab compared with ranibizumab. CONCLUSIONS: In 2008, bevacizumab was used at a higher rate than ranibizumab for the treatment of neovascular AMD. Even though bevacizumab accounted for 58% of all injections, Medicare paid $516 million more for ranibizumab than bevacizumab. These data suggest that despite its off-label designation, intravitreal bevacizumab is currently the standard-of-care treatment for neovascular AMD in the United States. PMID- 21310391 TI - Incidence, determinants, and prognostic impact of operative refusal or denial in octogenarians with severe aortic stenosis. AB - BACKGROUND: Aortic stenosis (AS) is a common valve disease in octogenarians. Previous studies have shown that aortic valve replacement (AVR) is frequently not performed in these patients. This study investigated the incidence, determinants, and prognostic impact of AVR refusal or denial in these patients. METHODS: Between 2000 and 2007, 163 octogenarians (mean age, 84 +/- 3 years) with severe AS and an indication for operation according to guidelines were prospectively included in an echocardiographic registry. Among these, 97 underwent AVR, and 66 were treated conservatively. RESULTS: Logistic regression analysis identified older age, a lower transaortic pressure gradient, a larger aortic valve area, and the presence of diabetes as independent predictors of AVR refusal or denial. Patients who underwent AVR had a 30-day mortality of 9%. Overall 5-year survival was 66% in AVR patients vs 31% in those treated conservatively (log rank p < 0.001 vs AVR). After adjustment for the propensity score, patients undergoing AVR still had a better outcome than conservatively treated patients (hazard ratio, 0.56; 95% confidence interval, 0.29 to 0.91; p = 0.022). In addition to the therapeutic decision, Cox regression analysis also identified low body weight, New York Heart Association class III/IV, and the logistic European System for Cardiac Operative Risk Evaluation as independent predictors of outcome in the overall series. CONCLUSIONS: About 40% of octogenarians with severe AS and a definite indication for operation either refuse or are denied AVR. AVR refusal or denial has a profound impact on long-term prognosis, resulting in a twofold excess mortality, even after adjustment for the propensity score. PMID- 21310392 TI - Polymorphisms in genes involved in folate metabolism and orofacial clefts. AB - BACKGROUND: Orofacial clefts (OFCs) are one of the most common birth defects in humans. Maternal use of folate antagonists including dihydrofolate reductase inhibitors has been associated with a higher risk of OFCs thus suggesting that folate-related metabolism and associated genes may be involved in pathogenesis of OFC. The association between folate intake and risk of OFCs however is inconsistent. OBJECTIVE: To review the published evidence that polymorphisms in genes that affect folate metabolism are associated with an increased risk of OFCs. METHODS: We reviewed articles published up until October 2010, on polymorphisms of genes related to folate and homocysteine metabolism and their associations with OFCs. Articles were identified via Medline searches. CONCLUSIONS: No consistent evidence emerged of a strong association between risk of OFCs and any known gene related to folate metabolism. Further, recent genome wide association studies have not identified associations between OFCs and folate related genes. Further studies are warranted to determine whether gene environment interactions, including gene-nutrient interactions and epigenetic modifications of genes affect the risk of OFCs. PMID- 21310394 TI - Efficacy and safety of transcranial direct current stimulation in major depression. PMID- 21310393 TI - Alterations of antioxidant biomarkers and type I collagen deposition in the parotid gland of streptozotocin-induced diabetic rats. AB - BACKGROUND AND OBJECTIVE: Acarbose is a competitive inhibitor of intestinal alpha glycosidases that slows the breakdown of sucrose and starch, thereby reducing glucose and fructose absorption. The aim of this study was to evaluate the effect of acarbose treatment on antioxidant parameters and deposition of type I collagen in the parotid glands of diabetic rats. METHODS: Diabetes mellitus was induced by intravenous injection of streptozotocin, and rats were divided into four groups: non-diabetic (NDM), diabetic (DM), diabetic treated with 25mg/kg acarbose (DMA) and non-diabetic treated with acarbose (NDMA). Changes in enzymatic antioxidant systems, such as the activity of SOD and GPx enzymes, were evaluated, and the specific staining pattern of the type I collagen fibres was investigated in the rat parotid glands. RESULTS: The DM group presented high levels of SOD and GPx enzymes, which were reduced by acarbose treatment. Tissue damage, which was indicated by an increased MDA concentration in the parotid glands of rats in the DM group, was also reversed in the DMA group. Moreover, type I collagen fibres from DM rats were more intensely stained than those of NDM rats. Acarbose treatment was effective in decreasing collagen deposition, which was shown by a decrease in staining intensity of approximately 25%. CONCLUSIONS: These results suggest that the diabetic state influences the type I collagen concentration in the parotid glands of rats. In addition, acarbose treatment was helpful in preventing the deposition of such fibres, as well the increase in oxidative stress induced by hyperglycemia. PMID- 21310395 TI - Age-related increase in inferior frontal gyrus activity and social functioning in autism spectrum disorder. AB - BACKGROUND: Hypoactivation of the inferior frontal gyrus during the perception of facial expressions has been interpreted as evidence for a deficit of the mirror neuron system in children with autism. We examined whether this dysfunction persists in adulthood, and how brain activity in the mirror neuron system relates to social functioning outside the laboratory. METHODS: Twenty-one adult males with autism spectrum disorders and 21 typically developing subjects matched for age, sex, and IQ were scanned in three conditions: observing short movies showing facial expressions, performing a facial movement, and experiencing a disgusting taste. Symptom severity and level of social adjustment were measured with the Autism Diagnostic Observation Schedule and the Social Functioning Scale. RESULTS: Inferior frontal gyrus activity during the observation of facial expressions increased with age in subjects with autism, but not in control subjects. The age related increase in activity was associated with changes in gaze behavior and improvements in social functioning. These age-related neurocognitive improvements were not found in a group of individuals with schizophrenia, who had comparable levels of social functioning. CONCLUSIONS: The results of this cross-sectional study suggest that mirror neuron system activity augments with age in autism and that this is accompanied by changes in gaze behavior and improved social functioning. It is the first demonstration of an age-related neurocognitive improvement in autism. Increased motor simulation may contribute to the amelioration in social functioning documented in adolescence and adulthood. This finding should encourage the development of new therapeutic interventions directed at emotion simulation. PMID- 21310396 TI - [Oesophagogastric anastomosis complications in the Ivor Lewis operation]. AB - INTRODUCTION: Oesophagectomy is the principal treatment for cancer of the oesophagus. The oesophagogastric anastomotic leak is a serious complication of the Ivor Lewis operation, and is associated with increased mortality. The objective of this study is to analyse its incidence, its diagnosis and treatment results. MATERIAL AND METHODS: A descriptive analysis of a consecutive series of oesophagectomies, carried out during a 5 year period, using the Ivor Lewis technique. All patients had hand sewn anastomosis. Data were collected on general morbidity, anastomosis leak, hospital mortality, survival, and stenosis of the anastomosis. RESULTS: A total of 41 intrathoracic anastomoses were performed. Complications, of any type, were observed in 49% of cases, of which 3 (7.3%) were anastomotic leaks, one of them asymptomatic. One patient was urgently reoperated, and two others were treated with drains and conservative treatment. The mortality of the series was 7.3%, none associated with the anastomotic leak. The survival at 5 years was 27%, and 34% of the patients developed stenosis of the anastomosis. CONCLUSIONS: Intrathoracic anastomosis after oesophagectomy, in our experience, can be performed with a low incidence of anastomotic leaks and without mortality due to this cause. Their treatment must be individualised and a considerable proportion do not require surgical intervention. PMID- 21310397 TI - Subcarinal collection following mediastinoscopy: a normal post-procedural CT finding. AB - AIM: To determine the frequency with which a subcarinal collection is present at computed tomography (CT) following mediastinoscopy and to determine the CT features of the collection. MATERIALS AND METHODS: All patients who underwent uncomplicated mediastinoscopy during a 1-year period were retrospectively identified. This list was cross-referenced to determine those patients who also underwent CT within 15 days after the procedure. Each post-mediastinoscopy CT examination was assessed in consensus by three fellowship-trained thoracic radiologists for the presence of subcarinal abnormalities, which were also characterized in terms of their size and density. Additional CT findings were recorded, including tracheobronchial wall thickening, paratracheal collections, mediastinal fat stranding, and mediastinal air. RESULTS: The study cohort included 10 patients (seven men and three women) with mean age of 65 years (range 49-81 years). CT was performed a mean of 11 days following mediastinoscopy. The most common CT finding was an oval subcarinal collection in nine of 10 cases (size 1.1-3.2 cm). In all nine cases, the subcarinal collections were consistently lower in attenuation than the subcarinal lymph node in the same region on the pre-procedure CT examination. Other CT findings included anterior tracheobronchial wall thickening (n=7); paratracheal collection (n=6); mediastinal fat stranding (n=6); and mediastinal air in (n=4) cases. CONCLUSION: A subcarinal collection was identified in 90% of cases following mediastinoscopy. Its rapid development and characteristic appearance help to distinguish it from a lymph node. PMID- 21310398 TI - Teleradiology: a modern approach to diagnosis, training, and research in child abuse? PMID- 21310399 TI - Phenotypes within sensory modulation dysfunction. AB - Sensory modulation disorder (SMD) is a severe inability to regulate responses to everyday sensory stimulation to which most people easily adapt. It is estimated to affect 5% to 16% of the general population of children. Although heterogeneity is seen in the presentation clinically, previous research has not empirically investigated whether the clinical heterogeneity of SMD can be classified into subtypes. This study explores a cohort of 98 children identified with SMD at the Department of Pediatric Rehabilitation by a member of the occupational therapy team at The Children's Hospital of Denver. Two subtypes of SMD were identified through cluster analysis based on data from 4 parent-report instruments. The first subtype is characterized by sensory seeking/craving, hyperactive, impulsive, externalizing (eg, delinquent, aggressive), unsocial, inadaptive, and impaired cognitive/social behavior. The second subtype is characterized by movement sensitivity, emotionally withdrawal, and low energy/weak behavior. Findings from this study present a step toward understanding and classifying the complexities of children with SMDs. PMID- 21310400 TI - Factors associated with adherence to treatment with olanzapine and other atypical antipsychotic medications in patients with schizophrenia. AB - OBJECTIVES: Poor treatment response is an important factor contributing to lack of treatment adherence. The goals of this research were to determine whether improvements in Positive and Negative Syndrome Scale (PANSS) symptom domains predict the likelihood of staying on treatment and whether differential responses to treatment with various atypical antipsychotics in specific symptom domains account for differences in discontinuation rates or treatment adherence. METHODS: We conducted a post-hoc analysis of pooled data from 5 randomized, double-blind, 24- to 28-week clinical trials in 1103 olanzapine-treated and 1090 risperidone-, quetiapine-, ziprasidone-, or aripiprazole-treated adult patients with schizophrenia. The 5 PANSS factors were tested as potential predictors of treatment adherence for all treatment groups combined. Treatment differences in the 5 PANSS factors and individual items were assessed between olanzapine and the other atypical antipsychotics combined. Secondary analyses repeated for the 21 Heinrichs Quality of Life Scale (QLS) items. RESULTS: Improvement in PANSS positive factor was the strongest predictor of treatment adherence, irrespective of medication (based on standardized scores, hazard ratio [HR], 1.58; 95% confidence interval [CI], +1.40 to +1.79; P < .001). Improvement in PANSS hostility (HR, 1.23; 95% CI, +1.11 to +1.37; P < .001) and depressive (HR, 1.15; 95% CI, +1.05 to +1.27; P = .002) factors was also a significant predictor; negative and disorganized thoughts factors were not. All QLS items had significant predictive effects. Olanzapine-treated patients showed significantly greater improvements than all other groups at week 24 on all 5 PANSS factors (P = .028 for negative; P < .001 for all others) and on 3 QLS items. CONCLUSION: Significant improvement in positive symptoms, regardless of treatment, followed by significant improvement in hostility and depressive symptoms, may best predict treatment adherence. Olanzapine-treated patients experienced significantly greater improvements in these specific symptoms than patients treated with the other atypical antipsychotics examined. These findings may further explain why olanzapine-treated patients continue treatment more often. PMID- 21310401 TI - Is there a relationship between attention deficit/hyperactivity disorder and manic symptoms among children with mental retardation of unknown etiology? AB - Mental retardation (MR) is common and lifelong. In children and adolescents with MR, the rate of attention deficit/hyperactivity disorder (ADHD) and bipolar disorder is higher than that in the general population. However, there are no previous sufficient data that exist in establishing a relationship between ADHD and manic symptoms. The aim of the present study was to examine the relationship between manic symptoms and ADHD as well as oppositional-defiant disorder (ODD) and conduct disorder (CD) in children with MR of unknown etiology (MR-UE). A total of 167 children with MR-UE attending a rehabilitation and training school in Erzurum, Turkey, were included in the study. We administered the Child Disruptive Behavior Screening and Rating Scale related to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition and the Young Mania Rating Scale-Parent Version (P-YMRS) to parents. The age range of children and adolescents with MR-UE was between 5 and 21 years, with a mean age of 11.13 +/- 3.75 years. In total, 5.8% of children and adolescents with MR-UE showed a border intelligence quotient (IQ), with 58.4% having a mild IQ, 29.2% having a moderate IQ, and 6.6% having severe IQ. According to the Child Disruptive Behavior Screening and Rating Scale related to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, 40.1% of children and adolescents with MR-UE had inattention, 19.9% had hyperactivity, 28.7% had ODD, and 13.3% had CD. A total of 7.2% of the children and adolescents with MR-UE had probable mania, and 1.8% had mania according to Young Mania Rating Scale-Parent Version. A positive correlation existed between the mean scores of Young Mania Rating Scale-Parent Version and the mean scores of inattention, hyperactivity, ODD, and CD (P = .000). Hyperactivity and ODD were predictors of being manic/probably manic. Diagnosing psychiatric disorders in children and adolescents with MR-UE is difficult but essential for better functioning. Manic symptoms and disruptive behaviors as well as ADHD symptoms were prevalent among children and adolescents with MR-UE and hyperactivity, and oppositional-defiant symptoms were predictors of manic symptoms in these patients. PMID- 21310403 TI - Perfluorinated acids and hypothyroxinemia in pregnant women. AB - Perfluorinated acids (PFAs) are prominent and widespread contaminants of human blood. In animal studies there is evidence that suggests certain PFAs can disrupt thyroid hormone homeostasis. A commonly reported condition in exposed animals is hypothyroxinemia, whereby serum free thyroxine (fT4) is decreased despite normal thyroid stimulating hormone (TSH) concentrations. We designed an individually matched case-control study to investigate whether exposure to perfluorooctanoate (PFOA), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS) was associated with hypothyroxinemia in pregnant women from Edmonton, Alberta, Canada, in 2005-2006, who underwent a "triple screen" blood test at 15-20 weeks gestation as part of ante-natal care. Thyroid hormones, fT4 and TSH, were measured in serum from 974 women, and from these we measured PFAs in the sera of 96 hypothyroxinemic cases (normal TSH, the lowest 10th percentile of fT4) and 175 controls (normal TSH, fT4 between the 50th and 90th percentiles) matched on age and referring physician. Analyses by conditional logistic regression indicated that the concentrations of PFAs in this population were not associated with hypothyroxinemia among pregnant women. The current findings do not support a causal link between PFA exposure and maternal hypothyroxinemia in the studied population. PMID- 21310402 TI - Uterine leiomyomata in a cohort of Great Lakes sport fish consumers. AB - Diet and endocrine disrupting persistent organic pollutants (POPs) have been associated with gynecologic conditions including uterine leiomyomata (UL), endometriosis, and ovarian cysts. Great Lakes sport fish consumption is a source of exposure to POPs such as p,p'-diphenyldichloroethene (DDE) and polychlorinated biphenyls (PCBs). This study was designed to examine retrospectively the effects Great Lakes sport fish consumption on the incidence of UL and to examine the effects of DDE and PCB serum levels on prevalent UL in women participating in the Great Lakes Fish Consumption Study. We hypothesized that associations of exposures with UL would be modified by breastfeeding status. Years of sport fish consumption, demographic, health, and reproductive data were assessed by survey. In a subgroup, serum was collected and tested for DDE and PCB levels. Effects of years of Great Lakes sport fish and sport fish consumption were modeled using time-dependent Cox proportional hazards regression and effects of POP exposures on UL were modeled using multiple logistic regression. Years of sport fish consumption were associated with UL, with an incidence rate ratio of 1.2 (95% CI 1.0-1.3) for each 10-year increment of fish consumption. Summary measures of POP exposures in the overall group were not associated with UL. In the subgroup of women who never breastfed and in whom PCB measurements were available, however, UL was significantly associated with PCBs and groupings of estrogenic, antiestrogenic, and dioxin-like PCBs. These findings support the possibility that PCB exposures from fish consumption may increase the risk of UL and highlight the importance of additional studies exploring biologic pathways by which they could be acting. PMID- 21310404 TI - Quintuplets after a transfer of two embryos following in vitro fertilization: a proved superfecundation. AB - OBJECTIVE: To report a genetically proved superfecundation of quintuplets after transfer of two embryos in IVF procedure and successful completion of the pregnancy after fetal reduction. DESIGN: Case report. SETTING: Academic reproductive medicine center. PATIENT(S): A 31-year-old woman, gravida 0, who underwent her second IVF cycle after three IUIs. INTERVENTION(S): After 5 years of primary infertility, three IUIs, and one IVF, the patient underwent her second IVF cycle with transfer of two fresh embryos on day 2. MAIN OUTCOME MEASURE(S): Development of five separate embryonic sacs. Fetal reduction to twins at 12 weeks of gestation. Successful pregnancy and delivery. Deoxyribonucleic acid analysis of the three reduced embryos, the live-born twins, and their parents. RESULT(S): Analysis of the seven DNA samples, because all were different, confirmed the superfecundation and disproved the zygote's division after transfer. Fetal growth restriction motivated preterm delivery by cesarean section. Both twins were in good health. CONCLUSION(S): Superfecundation can explain high-order multiple pregnancy and can be proved by DNA analysis. Couples must be informed because of the implications of fetal reduction for ethical issues, risks of pregnancy loss, fetal growth restriction, preterm delivery, and its consequences. PMID- 21310405 TI - Thrombocytes are effectors of the innate immune system releasing human beta defensin-3. AB - BACKGROUND: Thrombocyte concentrate i.e. platelet-rich plasma (PRP) has become a popular adjunct for many surgical procedures. It is believed to improve bone and soft tissue healing. Recently antimicrobial effects of the autologous preparation were reported by several groups. In this study we investigated the antimicrobial effect of PRP against gram-negative microbes which frequently cause severe complications in orthopaedic trauma surgery. METHODS: Platelet-rich plasma was produced from liquid preserved thrombocyte concentrates. ELISA, Western blot and immunohistochemistry were preformed to investigate the release and content of platelet concentrates. A radial diffusion assay was used to detect antimicrobial effects of PRP. RESULTS: We detected the human beta defensin-3 in bactericidal concentrations in platelet preparations by ELISA, Western blot and immunohistochemistry. In antimicrobial testing we demonstrated effective inhibition of Escherichia coli (ATCC 11303), Bacterium megaterium (ATCC 14581), Klebsiella pneumoniae (ATCC 13883), Enterococcus faecalis (ATCC 29212) and Proteus mirabilis (ATCC21100). CONCLUSION: With this study we demonstrate antimicrobial action of a popular adjunct for orthopaedic and trauma surgery against gram-positive and gram-negative bacteria. We have identified a possible mechanism of action via the secretion of HBD-3 as a first line defence in contaminated wounds and in elective application of PRP. This finding supports a broader spectrum of clinical indications for an autologous platelet preparation. PMID- 21310406 TI - Predicting failure after surgical fixation of proximal humerus fractures. AB - BACKGROUND: Several studies reported high failures rates after internal fixation of proximal humerus fractures. Loss of reduction and screw cut-out are the most common reasons for revision surgery. Several risk factors for failure have been described in the literature. The aim of the present study was to assess risk factors for failure after surgical fixation of unstable proximal humerus fractures in a multivariate setup. METHODS: Two different surgical techniques (PHILOS locking plate and Humerusblock) were used. In the PHILOS group, every kind of postoperative relative movement between the implant and the humeral head or shaft was defined as failure. In the Humerusblock group, postoperative movement between the humeral head and the shaft in terms of angulation or translational displacement was defined as failure. The following parameters were assessed: age, gender, cancellous bone mineral density (BMD) of the humeral head, fracture type, medial metaphyseal comminution, medial metaphyseal head extension, initial angulation of the humeral head in the frontal plane, initial anteversion of the humeral head, medial hinge displacement, maximum displacement of the tuberosities with respect to the head, surgical technique, anatomic reconstruction and restoration of the medial cortical support. RESULTS: The following parameters were found to have a significant influence on the failure rate: age, local BMD, anatomic reduction, and restoration of the medial cortical support. The failure rate significantly increased with the number of risk factors. CONCLUSION: Preoperative assessment of the local BMD and the patients' biological age as well as intraoperative anatomic reduction and restoration of the medial cortical support are the essentials for successful surgical fixation of proximal humerus fractures. Multifragmentary fracture patterns in old patients with low local BMD are prone for fixation failure. If the surgeon is not able to achieve anatomic reduction and restoration of the medial cortical support intraoperatively in this situation, adjustments such as augmentation or primary arthroplasty should be considered. PMID- 21310407 TI - Management of traumatic popliteal vein injuries. AB - PURPOSE: The aim of this study was to evaluate different repair methods of popliteal vein injuries, and to assess the relationship between early patency and surgical outcome. METHODS: Thirty patients with popliteal vein injuries underwent surgical repair procedure at our hospital from March 2000 to April 2010. Patients who were haemodynamically unstable and those with massive bleeding from limb wounds were taken directly to the operating room. Stable patients underwent preoperative colour-flow duplex ultrasonography (CFDU). RESULTS: Our study group consisted of 26 males and 4 females, ranging in age from 17 to 60 years with a mean age of 25.3 +/- 5.9 years. The mechanism of trauma was penetrating in 27 patients and blunt in the remaining 3 patients. Treatment included primary venous repair in 11 cases, end-to-end anastomosis in 8, interposition vein graft in 10, and interposition polytetrafluoroethylene (PTFE) graft in 1. There were 26 patients with associated arterial injury, of which 4 cases had primary repair, 9 had end-to-end anastomosis, 11 had saphenous vein graft interposition, and 2 had PTFE graft interposition. Associated bone fracture was seen in 6 patients. There were no deaths. One patient required a below-knee amputation. Postoperative CFDU revealed thrombosed venous repair in 7 cases without any sequelae. CONCLUSION: Popliteal venous injuries can be repaired with minimal downside and a good early patency rate. Additionally, transient venous patency allows for establishment of venous and lymphatic collateralisation. Alternatively, venous ligation should be considered only in unstable patients who refuse blood transfusion (Jehovah's witnesses). In these victims, adjuvant management may be required such as the use of fasciotomy and anticoagulation treatment. PMID- 21310408 TI - Staged abdominal repairs reduce long-term quality of life. AB - INTRODUCTION: Damage control surgery increasingly requires serial operations and a staged abdominal repair (STAR) for ultimate abdominal closure. The effects of multiple operations on quality of life are unknown. We hypothesized that this population of patients had a lower quality of life than the general U.S. population. METHODS: Patients requiring STAR for general surgical and trauma diagnoses during a 5-year period from January 2002 to December 2006 were identified from the operative database of a single institution. Demographic, illness, and injury information were obtained from record review. Survivors were 3-7 years from their hospitalization for STAR when they were contacted and the SF 12v2 was administered by phone. The physical (PCS) and mental component (MCS) scores were calculated and compared to US population norms and a population of trauma patients. The non-STAR trauma population completed the SF-12v2 six months after injury. RESULTS: A total of 27 patients with a mean age of 46.5 years (SD = 15.9) participated in the survey. The participants were interviewed a median of 4.7 years after injury. The mechanism of injury included 8 (29.6%) general surgical causes including 4 perforated viscus, 3 intra-abdominal infections, and 1 wound dehiscence from a urological procedure. The remaining 19 (70.4%) were trauma-related, including 13 blunt and 6 penetrating injuries. Patients who had undergone a STAR procedure reported lower levels of physical quality of life [z = -15.42, p<0.001] and mental quality of life [z = -6.79, p<0.001] compared to population norms for healthy adults. Also, STAR patients reported lower physical [z = -2.22, p<0.05] and mental [z = -2.59, p<0.05] quality of life as the non STAR trauma group. DISCUSSION: The number of patients undergoing STAR for a variety of reasons is increasing. Measurements of quality of life of STAR patients show that quality of life is reduced compared to a healthy U.S. adult population and to non-STAR trauma patients. CONCLUSIONS: The significant impact of severe abdominal injuries continues to affect the physical and mental health of patients years later. Injuries of this type are associated with lower quality of life than those observed in patients experiencing non-STAR trauma. PMID- 21310409 TI - Comparison of depressive symptoms during the early recovery period in patients with a distal radius fracture treated by volar plating and cast immobilisation. AB - INTRODUCTION: Patients with orthopaedic trauma experience substantial psychological and physical morbidities. The purpose of this study was to assess depressive symptoms in patients with a distal radius fracture, and to determine whether early use of the wrist after volar plating reduces depressive symptoms as compared with cast immobilisation during the early recovery period. MATERIALS AND METHODS: Twenty-six patients with a distal radius fracture, who underwent volar plating and were allowed immediate use of the wrist, and 24 patients treated by cast immobilisation for 6 weeks were prospectively compared with respect to depressive symptoms at week 0, and at 2, 6, 12 and 24 weeks after injury, using the Center for Epidemiologic Studies Depression Scale (CES-D). Physical morbidity was assessed using the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire and a pain Numerical Rating Scale (NRS). Multivariate analysis was performed to identify factors that independently predicted CES-D scores at each time point. RESULTS: No differences in the CES-D scores were found between the volar plating and the cast immobilisation groups, although volar plating group had marginally better CES-D scores at 24 weeks. Multivariate analysis indicated that CES-D scores at each time were independently associated with pain NRS scores at 0 and 24 weeks, and DASH scores at 6 weeks. CONCLUSION: Early use of the wrist after volar plating was not found to reduce depressive symptoms as compared with cast immobilisation in the early treatment period following a distal radius fracture. Pain was found to be an important predictor of depression, suggesting that caution is needed to address pain during the early rehabilitation period. PMID- 21310410 TI - Embolic complications after carotid artery stenting or carotid endarterectomy are associated with tissue characteristics of carotid plaques evaluated by magnetic resonance imaging. AB - BACKGROUND: Unstable carotid plaques are associated with an increased incidence of embolic complications after carotid artery stenting (CAS) or carotid endarterectomy (CEA). The aim of this study was to elucidate the relationship between the tissue components of carotid plaques and the incidence of new ipsilateral silent ischemic lesions (NISIL) after CAS or CEA. METHODS: We performed CAS in 56 patients and CEA in 25 patients. We also performed quantitative analyses of carotid plaque characteristics before treatment using T1 weighted black-blood magnetic resonance imaging (BB-MRI). The signal intensity ratio (SIR) was defined as the ratio of signal intensity evaluated by BB-MRI in carotid plaques to that of sternocleidomastoid muscle. According to criteria that we and other investigators previously reported, an SIR >= 1.25 was defined as "high". NISIL were evaluated by diffusion-weighted imaging of MRI before and after CAS or CEA. RESULTS: In the high SIR group, the incidence of NISIL was significantly greater after CAS than after CEA (61% vs 13%, respectively, p=0.006), whereas there were no significant difference in NISIL after the two procedures when the SIR was <1.25 (21% vs 0%). In multivariate regression analysis, the independent predictors of NISIL were CAS (p=0.002), symptomatic stenosis (p=0.036) and the SIR (p=0.049). CONCLUSIONS: Noninvasive quantitative tissue characterization of carotid plaques using BB-MRI is useful to determine the indication for CAS. PMID- 21310411 TI - Endothelial enriched microRNAs regulate angiotensin II-induced endothelial inflammation and migration. AB - Inflammation is observed at all stages of atherosclerosis. The initial stage of atherosclerosis is characterized by recruitment of leukocytes to activated endothelial cells (ECs). MicroRNAs (miRNAs) are a class of 19-25 nucleotides, non protein-coding RNAs that repress target gene expression by translational inhibition or mRNA degradation. The link between miRNA and endothelial functions is largely unknown. Northern blot showed that miR-155 and miR-221 were highly expressed in human umbilical vein endothelial cells (HUVECs) and vascular smooth muscle cells (VSMCs). Bioinformatics analysis proposed Ets-1, a key endothelial transcription factor for inflammation and tube formation, as a candidate target for miR-155 and miR-221/222 cluster. The effect was demonstrated by luciferase reporter assay and Western blot. By using Western blot, we also confirmed that angiotensin II type 1 receptor (AT1R) is a target of miR-155 in HUVECs. Quantitative PCR showed that Ets-1 and its downstream genes, including VCAM1, MCP1 and FLT1, were upregulated in angiotensin II-stimulated HUVECs, and this effect was partially reversed by overexpression of miR-155 and miR-221/222. In addition, cell adhesion assay revealed overexpression of miR-155 and miR-221/222 effectively decreased the adhesion of Jurkat T cells to Ang II-stimulated HUVECs. Besides, by targeting AT1R, miR-155 can also decrease the HUVECs migration in response to Ang II. In summary, HUVECs highly expressed miR-155 may co-target AT1R and Ets-1 while miR-221/222 targets Ets-1, which indirectly regulate the expression of several inflammatory molecules of ECs, and therefore attenuate the adhesion of Jurkat T cells to activated HUVECs and reduce HUVECs migration. These findings present possible therapeutic targets in atherosclerosis. PMID- 21310412 TI - Apolipoprotein E genotypes, circulating C-reactive protein and angiographic coronary artery disease: the Ludwigshafen Risk and Cardiovascular Health Study. AB - C-reactive protein (CRP) has been implicated in the development of atherosclerosis. The genetic polymorphism of apolipoprotein (apo) E is associated with the concentration of CRP. We analyzed the association between the apo E genotype, CRP and angiographic coronary artery disease (CAD). The concentration of CRP was similar in patients with stable CAD and in controls, but increased in patients presenting with acute coronary syndromes. In models adjusting for the main confounding variables, the alleles E4 and E2 were associated with decreased and increased concentrations of CRP, respectively, compared to the wild-type allele E3. In spite of this, the E2 allele was associated with a lower prevalence of angiographic CAD, while the slight over-representation of the E4 allele was statistically not significant. We conclude that the apo E genotype is associated with circulating CRP. A causal role of CRP in the development of CAD would be supported if genotypes that raise CRP in the long-term were themselves associated with CAD. As we found the opposite, we suggest that the association between CRP and cardiovascular events reflects confounding and reverse causation. PMID- 21310413 TI - Serum fetuin-A is correlated with metabolic syndrome in middle-aged and elderly Chinese. AB - OBJECTIVE: Fetuin-A is an important player in the enhancement of insulin resistance. We aimed to investigate the association of serum fetuin-A and metabolic syndrome (MetS) in a community based Chinese population. METHODS: A total of 5469 subjects aged 40 years or above were recruited from two urban communities in Shanghai. Demographic, anthropometric and biochemical features were collected according to a standard protocol. Serum fetuin-A levels were measured using ELISA and the modified NCEP-ATP III criteria were adopted to diagnose MetS. RESULTS: A higher level of serum fetuin-A was well associated with a variety of metabolic disorders and an increased prevalence of MetS. The relative risks for MetS were markedly elevated in a dose-dependent manner both before and after extended adjustment in total participants (adjusted odds ratios were 1.00, 1.11, 1.20 and 1.40 for fetuin-A quartiles 1, 2, 3 and 4, respectively; P value for trend = 0.0002). MetS risks were also significantly associated with serum fetuin-A in various subgroups of sex, age, body mass index and glycaemic status. Moreover, an elevated serum fetuin-A was also independently associated with MetS components including central obesity, high blood pressure, high blood glucose and high triglycerides. Stepwise regression analyses revealed fetuin-A as an independent determinant of insulin resistance measured by the index of homeostasis model (HOMA-IR) (beta = 0.064; P = 0.009). CONCLUSION: Serum fetuin-A levels were strongly and independently associated with MetS and its components in community-dwelling Chinese adults. PMID- 21310414 TI - Suppression of zinc finger protein 580 by high oxLDL/LDL-ratios is followed by enhanced expression of endothelial IL-8. AB - OBJECTIVE: The Interleukin 8 (IL-8) response of endothelial cells to lipoproteins has well known implications for the development and progression of atherosclerosis. In this study we sought for the role of zinc finger protein 580 (ZNF580) in the endothelial IL-8 response to lipoproteins. METHODS: In human umbilical vein endothelial cells (HUVEC) ZNF580 and IL-8 levels were examined by real-time-RT-PCR, immunoblotting and immunostaining or ELISA, respectively. RESULTS: ZNF580 is located in the nucleus and regulated by LDL and HDL depending on the oxLDL/LDL-ratio but not by TNFalpha. IL-8 expression profiles are inversely influenced by the oxLDL/LDL-ratio, both in vitro and in vivo. Knock down of ZNF580 enhances the expression and release of IL-8 and increases monocyte arrest under flow conditions in vitro. CONCLUSIONS: ZNF580 is a novel factor in the lipoprotein-dependent regulation of IL-8 and monocyte arrest. Therefore it may be a new potential target for intervention in atherosclerosis. PMID- 21310416 TI - Associations of the ATP-binding cassette transporter A1 R219K polymorphism with HDL-C level and coronary artery disease risk: a meta-analysis. AB - OBJECTIVE: Previous studies have evaluated the associations of the ATP-binding cassette transporter A1 (ABCA1) R219K polymorphism (rs2230806) with the level of high-density lipoprotein cholesterol (HDL-C) and the risk of developing coronary artery disease (CAD), but results from many small, underpowered studies are conflicting. The objective of this study was to overcome the limitations of individual study and provide solid epidemiologic evidence. METHODS: We conducted a systematic review and meta-analysis of available studies to clarify the associations of the ABCA1 R219K polymorphism with HDL-C level and CAD risk. RESULTS: Through retrieving PubMed, Embase, Web of Science, CBM and CNKI, we identified a total of 22 studies with 6597 cases and 15,369 controls for the association between the ABCA1 R219K polymorphism and CAD risk. The carriers of allele 219K were found to have a lower risk of CAD than the non-carriers: OR=0.76, 95% CI=0.68-0.85, P=3.78E-07, P(heterogeneity)=3.59E-08; meanwhile, 18 studies from 17 papers with 12,869 subjects were included in the association between the ABCA1 R219K polymorphism and the level of HDL-C. It was suggested that the carriers of KK genotype had higher level of HDL-C than those of RR genotype: SMD=0.19, 95% CI=0.06-0.32, P=0.005, P(heterogeneity)=3.19E-09. Subgroup analyzes by ethnicity certified that the effect on HDL level was just significant in Asians. Exclusion of the outlier studies effectively removed the heterogeneity and confirmed the total results. No publication bias was detected in this meta-analysis. CONCLUSIONS: The synthesis of available evidence demonstrates that the ABCA1 R219K polymorphism is associated with a higher HDL-C level in Asians and a protective role for CAD risk both in Asians and Caucasians. PMID- 21310415 TI - Burden of subclinical cardiovascular disease in "metabolically benign" and "at risk" overweight and obese women: the Study of Women's Health Across the Nation (SWAN). AB - BACKGROUND: Metabolically benign obese individuals have a 10-year cardiovascular disease (CVD) risk comparable to healthy normal weight individuals. However, the burden of subclinical CVD among metabolically benign obese is not well known. METHODS: In cross-sectional analyses of 475 mid-life women, we compared common carotid artery intima media thickness (CCA-IMT), aortic pulse wave velocity (aPWV) and coronary (CAC) and aortic calcification (AC) among three groups: healthy normal weight, metabolically benign overweight/obese (<3 metabolic syndrome components/elevated CRP), and at-risk overweight/obese (>=3 metabolic syndrome components/elevated CRP). RESULTS: The mean (SD) CCA-IMT and aPWV were lowest in the normal weight group (n=145), followed by the benign overweight/obese (n=260) and at-risk overweight/obese (n=70) groups [CCA-IMT: 0.64 (0.08) vs. 0.68 (0.09) vs. 0.73 (0.13) mm, p<0.001; aPWV: 731.0 (176.4) vs. 809.9 (182.3) vs. 875.7 (228.8) cm/s, p<0.001]. Similar results were found for the frequency (%) of women with increased CAC and AC [CAC: 13 (9%) vs. 53(20%) vs. 28(40%), p<0.001; AC: 47(32%) vs. 130 (50%) vs. 55(79%), p<0.001]. These differences remained significant after multivariable adjustment. Further adjustment for BMI attenuated the statistical significance of differences in aPWV and calcification between benign and at-risk overweight/obese women, but had little effect on the magnitude of these differences. CONCLUSIONS: Metabolically benign overweight/obese women have a significantly greater subclinical CVD burden than normal weight women, despite published data finding similar CVD event rates between the two groups. Prospective studies tracking the progression of subclinical atherosclerosis to clinical CVD in these women are needed. PMID- 21310417 TI - An APEX-based genotyping microarray for the screening of 168 mutations associated with familial hypercholesterolemia. AB - OBJECTIVE: Familial hypercholesterolemia (FH) is an inborn disorder of lipid metabolism characterised by elevated plasma concentrations of low-density lipoprotein cholesterol and total cholesterol. This imbalance results in accelerated atherosclerosis and premature coronary heart disease. The early identification and treatment of FH patients is extremely important because it leads to significant reduction of both coronary morbidity and mortality. FH is transmitted in an autosomal dominant manner and associated predominantly with mutations in the genes encoding the low-density lipoprotein receptor (LDLR) and its ligand apolipoprotein B (APOB). To date, more than 1000 sequence variants have been described in the LDLR gene. In marked contrast to LDLR, only one APOB mutation is prevalent in Europe. METHODS AND RESULTS: The aim of this study was, on the basis of data obtained by the molecular genetic analysis of 1945 Czech FH probands, to propose, generate, and validate a new diagnostic tool, an APEX (Arrayed Primer EXtension)-based genotyping DNA microarray called the FH chip. The FH chip contains the APOB mutation p.Arg3527Gln, all 89 LDLR point mutations and small DNA rearrangements detected in Czech FH patients, and 78 mutations frequent in other European and Asian FH populations. The validation phase revealed the sensitivity and specificity of this platform, 100% and 99.1%, respectively. CONCLUSIONS: This FH chip is a rapid, reproducible, specific, and cost-effective tool for genotyping, and in combination with MLPA (multiple ligation-dependent probe amplification) represents a reliable molecular genetic protocol for the large-scale screening of FH mutations in the Czech population. PMID- 21310418 TI - Effect of non-Newtonian and pulsatile blood flow on mass transport in the human aorta. AB - To investigate the effects of both non-Newtonian behavior and the pulsation of blood flow on the distributions of luminal surface LDL concentration and oxygen flux along the wall of the human aorta, we numerically compared a non-Newtonian model with the Newtonian one under both steady flow and in vivo pulsatile flow conditions using a human aorta model constructed from MRI images. The results showed that under steady flow conditions, although the shear thinning non Newtonian nature of blood could elevate wall shear stress (WSS) in most regions of the aorta, especially areas with low WSS, it had little effect on luminal surface LDL concentration (c(w)) in most regions of the aorta. Nevertheless, it could significantly enhance c(w) in areas with high luminal surface LDL concentration through the shear dependent diffusivity of LDLs. For oxygen transport, the shear thinning non-Newtonian nature of blood could slightly reduce oxygen flux in most regions of the aorta, but this effect became much more apparent in areas with already low oxygen flux. The pulsation of blood flow could significantly reduce c(w) and enhance oxygen flux in these disturbed places. In most other regions of the aorta, the oxygen flux was also significantly higher than that for the steady flow simulation. In conclusion, the shear shining non Newtonian nature of blood has little effect on LDL and oxygen transport in most regions of the aorta, but in the atherogenic-prone areas where luminal surface LDL concentration is high and oxygen flux is low, its effect is apparent. Similar is for the effect of pulsatile flow on the transport of LDLs. But, the pulsation of blood flow can apparently affect oxygen flux in the aorta, especially in areas with low oxygen flux. PMID- 21310419 TI - Relative movements between the tibia and femur induced by external plantar shocks are controlled by muscle forces in vivo. AB - The purpose of this study was to investigate the role of muscle activation on the relative motion between tibia and femur. Impacts were initiated under the heels of four volunteers in three different activation levels of muscles crossing the extended knee joint: 0%, 30% and 60% of previously performed maximal voluntary isometric contractions. Impact forces were measured and tibial and femoral accelerations and displacements were determined by means of accelerometry. The accelerometers were mounted on the protruding ends of intracortical pins, inserted into the distal aspect of the femur and proximal aspect of the tibia. Under the 0%-condition the impact force (475+/-64N) led to 2.3+/-1.2mm knee compression and to 2.4+/-1.9mm medio-lateral and 4.4+/-1.1mm antero-posterior shear. The impact forces increased significantly with higher activation levels (619+/-33N (30%), 643+/-147N (60%)), while the knee compression (1.5+/-1.2, 1.4+/ 1.3mm) and both medio-lateral shear (1.8+/-1.4, 1.5+/-1.1mm) and antero-posterior shear (2.6+/-1.3, 1.5+/-1.1mm) were significantly reduced. This study indicated that muscles are effective in controlling the relative motion between tibia and femur when the knee is subjected to external forces. PMID- 21310420 TI - Scaling of adult human body mass with height. PMID- 21310421 TI - Liquid chromatography-tandem mass spectrometry method for the determination of dye residues in aquaculture products: development and validation. AB - A method is described for the identification and the quantitative determination of the triphenylmethane dyes, malachite green (MG), crystal violet (CV), brilliant green (BG) and leuco malachite green (LMG) and leuco crystal violet (LCV). The analytes were isolated from the matrix by liquid-liquid extraction with acetonitrile. Determination was performed using LC-MS/MS with positive electrospray ionisation. 4 different deuterated internal standards were introduced to improve the quantitative performance of the method. The method has been validated in line with the EU criteria of Commission Decision 2002/657/EC in accordance with the minimum required performance limit (MRPL) set at 2 MUgkg(-1) for the sum of MG and LMG. For all the monitored compounds, accuracy, intra-day and inter-day precision were determined at each level of fortification (0.5, 0.75, 1.0 and 2.0 MUgkg(-1)). Decision limits CCalpha and detection capabilities CCbeta were calculated according to the standard ISO 11843-2. A study on the applicability of the method was conducted on various aquacultured species with the aim to assess the matrix effects. The presence of residues of leuco brilliant green in fish has also been confirmed from experimental study performed on trout treated with brilliant green, using LTQ-Orbitrap mass spectrometer. PMID- 21310422 TI - Characterization of hexavalent chromium interaction with Sargassum by X-ray absorption fine structure spectroscopy, X-ray photoelectron spectroscopy, and quantum chemistry calculation. AB - Hexavalent chromium represents higher toxicity in aqueous solutions. It can be removed by such low-cost biosorbents as Sargassum sp. In this study, X-ray absorption fine structure spectroscopy, X-ray photoelectron spectroscopy, and quantum chemistry (QC) calculation were used to study the interactions between hexavalent chromium and Sargassum sp. during the biosorption. It was found that most of the adsorbed Cr(VI) ions were reduced to Cr(III) after the biosorption. The electrons for the reduction of Cr(VI) were possibly supplied from the Sargassum biomass, some organic compounds of which were oxidized. Cr(III) ions were coordinated with the oxygen atoms from either carboxyl or hydroxyl functional groups to form an octahedral structural metal complex. The coordination numbers of the formed Cr complex were 4-6, and bond length of Cr-O was 1.98A. QC calculation proved the possible formation of the Cr(III) metal complex, and revealed that carboxyl from biomass could be strongly bound with Cr(III). A three-step removal mechanism of Cr(VI) by Sargassum was proposed. PMID- 21310423 TI - Colloidal and chemical aspects of nanosized hydrated zirconium dioxide synthesized via a sol-gel process. AB - The processes of coagulation and gelation of sols in zirconium oxychloride aqueous solutions and the properties of hydrated zirconium dioxide sols (pH, particles size, dynamic viscosity) depending on the aging conditions of partially neutralized zirconium oxychloride feedstock solution-zirconyl hydroxychloride used for the synthesis and molar ratio of initial reagents (Zr/NaOH, Zr/CH(3)COO( )) were first studied in the paper. The concentration and temperature limits of hydrated zirconium dioxide sols stability were determined. The coagulation constant, gelation activation energy, and gelation thermal effect values were found. PMID- 21310424 TI - The application of novel spindle-like polypyrrole hollow nanocapsules containing Pt nanoparticles in electrocatalysis oxidation of nicotinamide adenine dinucleotide (NADH). AB - Novel spindle-like polypyrrole hollow nanocapsules containing Pt nanoparticles (Pt NPs/PPy composite hollow nanospindles) were successfully prepared by using beta-akaganeite (beta-Fe(3+)O(OH,Cl)) nanospindles as templates and methanoic acid as a reducing agent. The beta-Fe(3+)O(OH,Cl) templates can be easily obtained in ethanol/water mixing solution in the presence of thiophene and FeCl(3).6H(2)O, and after coating by PPy shell, they can be gradually and completely etched during the reduction of H(2)PtCl(6) into Pt nanoparticles (Pt NPs) with the average size of 3.6 nm on spindle-like polypyrrole hollow nanocapsules, which could still keep their integrality of morphologies with the thickness of PPy shell of 18-20 nm. The investigation of Pt NPs/PPy composite hollow nanospindles modified glassy carbon electrode (GCE) for the application to detect nicotinamide adenine dinucleotide (NADH) with cyclic voltammetry (CV) and amperometry indicated good linearity and sensitivity of responses in the certain range of NADH concentration. The influence of Pt NPs content to the NADH oxidation current was also studied. This new kind of unique spindle-like noble metal/conducting polymer hollow nanostructured complex can be acted as a good steady electrode material for electrocatalytic oxidation of NADH. PMID- 21310425 TI - The use of dielectric spectroscopy for the characterisation of polymer-induced flocculation of core-shell particles. AB - Flocculation is an important process in separation science, but only few methods are available for on-line evaluation of the process. Recently, it has been shown that dielectric spectroscopy can be used to characterise the flocculation process of hard polystyrene particles. As many "real life" suspensions contain particles covered with a porous layer of organic material, it is of interest to investigate the potential of dielectric spectroscopy to characterise the flocculation of such suspensions as well. In this paper dielectric spectroscopy is used to investigate the flocculation process of core-shell particles. The flocculation process is characterised using a photometric dispersion analyser as a reference method, and the results are compared to the dielectric dispersions measured by dielectric spectroscopy. It is found that the use of the relaxation time of the dielectric dispersion for an evaluation of the flocculation process is commensurate with the use of the photometric dispersion analyser. Furthermore, the magnitude of the dielectric dispersion is observed to decrease as the charge of the core-shell particles is neutralised. Dielectric spectroscopy is thus found to have potential as an on-line flocculation monitor. PMID- 21310426 TI - Synthesis and application of colloidal nanocrystals of the MFI-type zeolites. AB - The colloidal dispersion containing the nanosized zeolites with the MFI topology has been successfully prepared. A pre-aging process of the mother gel at 80 degrees C for 24 h before the crystallization was important for the formation of the nanosized zeolites. We have also found that silicalite-1 nanocrystals av. 62 nm in size were formed by the addition of acidic amino acids into the mother gel. The particle size of the zeolites can be controlled ranging from 62 to 530 nm by changing the amount of water, aging process, crystallization time and temperature and the addition of organic molecules. Furthermore, nanosized titanium silicalite 1 (TS-1) with the size of 50-130 nm has been successfully synthesized by the addition of a Ti source into the synthesis gel of the silicalite-1 nanocrystals. The nanosized TS-1 exhibits a higher catalytic activity in the epoxidation of cyclohexene than the microsized ones. Finally, we demonstrate the preparation of thin films of the silicalite-1 and TS-1 nanocrystals onto a silicon substrate by a dip-coating technique. PMID- 21310427 TI - Thermodynamic quantities of surface formation of aqueous electrolyte solutions X. Aqueous solution of 2:1 valence-type salts. AB - The behaviors of a series of calcium halides and of alkali earth metal chlorides in the air/water surface region were studied in comparison with those of alkali metal halides by measuring the surface tension increments of solutions. The effect of salts with divalent cations on the surface tension increments is more pronounced than that of uni-univalent salts, but there are some similarities between these two types. It seems that the anions cause a marked effect on surface tension which is proportional to the magnitude of hydration in the bulk water. We also observed a decrease in the entropy change of surface formation with increasing concentration. The importance of an electrical double layer at the surface is discussed in relation to these surface tension increments. PMID- 21310428 TI - Effects of exposure to sulfur mustard on speech aerodynamics. AB - Sulfur mustard is an alkylating agent with highly cytotoxic properties even at low exposure. It was used widely against both military and civilian population by Iraqi forces in the Iraq-Iran war (1983-1988). Although various aspects of mustard gas effects on patients with chemical injury have been relatively well characterized, its effects on speech are still evolving. We evaluated aerodynamics of speech in male patients following sulfur mustard inhalation. In a case-control study patients with chemical injuries (n=19) along with age and sex matched healthy control group (n=20) were selected. Aerodynamic analyses were performed by using the Glasgow Airflow Measurement System (known as ST1 dysphonia). Results indicated that except mean flow rate, there were statistically significant differences in vital capacity, phonation time, phonation volume, vocal velocity index, total expired volume and phonation quotient of patients between experimental and control groups (P<0.05). This study demonstrated mustard gas can impair different parameters of speech aerodynamics. LEARNING OUTCOMES: As a result of this activity, the reader will be able to describe: (1) the evaluation of air flow in relation to speech system dysfunction and efficiency; (2) the effect of sulfur mustard known as mustard gas on respiratory physiology. PMID- 21310429 TI - Expression of genes encoding extracellular matrix macromolecules and metalloproteinases in avian tibial dyschondroplasia. AB - Avian tibial dyschondroplasia (TD) is a skeletal disease characterized by disruption of endochondral bone formation. The aim of this study was to determine the expression of extracellular matrix (ECM) macromolecules and ECM-degrading enzymes [matrix metalloproteinases (MMPs)] in the growth plates of normal and TD affected 3-week-old broiler chicks (Cobb strain). Protein levels were analyzed by immunoblotting and gelatin zymography and gene expression by polymerase chain reaction. Expression of genes encoding the ECM macromolecules (collagen types II, IX, X and XI; and aggrecan) was not altered in dyschondroplasia; however, there was down-regulation of genes encoding MMP-9, MMP-13, MMP-10 and MMP-11 in addition to reduced amounts of MMP-2 and MMP-13 proteins. In contrast, there was up-regulation of genes encoding MMP-7 and the vascular endothelial growth factor. These findings suggest that the accumulation of cartilage associated with the disease may be the result of decreased proteolysis due to the down-regulation of MMPs and not to an increased production of ECM macromolecules. PMID- 21310430 TI - Generalized encephalitozoonosis in a young kitten with cerebellar hypoplasia. AB - In recent years opportunistic infections due to microsporidial organisms have become increasingly important in immunocompromised people. Infected animals could serve as reservoirs of such infections. A case of generalized encephalitozoonosis in a young kitten is reported. Diagnosis was established by histopathological, immunohistochemical and molecular biological investigations demonstrating characteristic lesions and DNA of Encephalitozoon cuniculi in formalin-fixed and paraffin wax-embedded tissue sections. Infections due to E. cuniculi are not common in cats, but a potential role of domestic cats in transmission of the infectious agent cannot be excluded. PMID- 21310431 TI - Cutaneous myxosarcoma with pulmonary metastases in a dog. AB - The pathological findings in a 13-year-old dog with cutaneous myxosarcoma with pulmonary metastases are described. Grossly, there was a large subcutaneous mass in the right scapular region, a smaller nodule in the caudal abdominal region and a fibrotic mass at a fracture site in the right hindlimb. Radiographic examination revealed several pulmonary nodules. Microscopical evaluation revealed a myxosarcoma characterized by the proliferation of spindle to stellate cells with multiple prominent nucleoli and vascular invasion. The neoplastic cells were haphazardly arranged in a mucopolysaccharide matrix. Immunohistochemically, the neoplastic cells expressed vimentin, but not cytokeratin or glial fibrillary acidic protein. There was restricted expression of desmin, smooth muscle actin and S-100 protein. PMID- 21310432 TI - An unusual cause of chest pain in a child. PMID- 21310434 TI - Involvement of pontine transverse and longitudinal fibers in multiple system atrophy: a tractography-based study. AB - OBJECTIVE: Pathological studies showed both pontine transverse (cortico-ponto cerebellar) and longitudinal (corticospinal) fibers degenerate in MSA. The objective was to investigate the association between the development of cross sign, degenerations of pontine fibers, and the frequency of pyramidal signs in MSA. METHODS: Patients with MSA (n=26) and healthy subjects (n=27) were enrolled in this study. Whole pontine transverse and longitudinal fibers were individually traced by diffusion tensor tractography. FA was calculated along each entire tractography. Cross sign was graded as: 0, no cross sign; 1, anterior-posterior line only; and 2, complete cross sign. T2-hyperintense MCPs was graded as: 0, no change; 1, slight signal change; and 2, severe signal change. FA of pontine fibers in MSA patients and that in healthy subjects was statistically evaluated by ANOVA with an overall statistical significance level of 0.05. The frequency of pyramidal signs in MSA was compared between each cross and MCP grade. RESULTS: FA of pontine transverse fibers in MSA patients decreased with the development of cross sign. FA of Cross 2 was significantly lower than that of healthy subjects (p=0.003). As regards pontine longitudinal fibers, FA decreased when cross sign was completed. The frequency of pyramidal signs in MCP 2 and 1 was higher than that in MCP 0. CONCLUSION: Pontine transverse fibers degenerate as cross sign develop, and degenerations of pontine longitudinal fibers begin, or even accelerate when cross sign becomes apparent. Pyramidal signs are frequently present when T2-hyperintense MCPs are clearly observed. PMID- 21310435 TI - Melkersson-Rosenthal syndrome: an unusual cause of intermittent raised hemidiaphragm? PMID- 21310436 TI - Sorption of heavy oil onto Jiaozhou Bay sediment. AB - The sorption of heavy oil onto sediment collected from Jiaozhou Bay was studied in a series of kinetic and equilibrium experiments using NaCl solutions. The effects of temperature, salinity, and pH of the medium on sorption behavior were investigated. Sorption equilibrium of the heavy oil and sediment was established within 60 min. The process was shown to follow a pseudo-second-order kinetic rate model. The sorption rate decreased with increasing initial heavy oil concentration in the solution. Batch equilibrium experiments showed that the sorption isotherm could be described by the Freundlich model. The standard free energy change and enthalpy change at the temperatures studied (283, 288, 293, and 298 K) were negative. These findings indicated that the process was spontaneous and exothermic. Salinity, pH and temperature influenced sorption performance. Sorption was favored by higher concentrations of NaCl, by lower pH values and by lower temperatures. PMID- 21310437 TI - Species- and size-specific variability of mercury concentrations in four commercially important finfish and their prey from the northwest Atlantic. AB - Total mercury was analyzed as a function of body length, season, and diet in four commercially and recreationally important marine fish, bluefish (Pomatomus saltatrix), goosefish (Lophius americanus), silver hake (Merluccius bilinearis), and summer flounder (Paralichthys dentatus), collected from continental shelf waters of the northwest Atlantic Ocean. Mercury levels in the dorsal muscle tissue of 115 individuals ranged from 0.006 to 1.217 MUg/g (wet weight) and varied significantly among species. The relationship between predator length and mercury concentration was linear for bluefish and summer flounder, while mercury levels increased with size at an exponential rate for silver hake and goosefish. Mercury burdens were the highest overall in bluefish, but increased with size at the greatest rate in silver hake. Seasonal differences were detected for bluefish and goosefish with mercury levels peaking during summer and spring, respectively. Prey mercury burdens and predator foraging habits are discussed as the primary factors influencing mercury accumulation. PMID- 21310438 TI - Effects of alumina refinery wastewater and signature metal constituents at the upper thermal tolerance of: 1. The tropical diatom Nitzschia closterium. AB - Ecotoxicological studies, using the tropical marine diatom, Nitzschia closterium (72-h growth rate), were undertaken to assess potential issues relating to the discharge from an alumina refinery in northern Australia. The studies assessed: (i) the species' upper thermal tolerance; (ii) the effects of three signature metals, aluminium (Al), vanadium (V) and gallium (Ga) (at 32 degrees C); and (iii) the effects of wastewater (at 27 and 32 degrees C). The critical thermal maximum and median inhibition temperature for N. closterium were 32.7 degrees C and 33.1 degrees C, respectively. Single metal toxicity tests found that N. closterium was more sensitive to Al compared to Ga and V, with IC(50)s (95% confidence limits) of 190 (140-280), 19,640 (11,600-25,200) and 42,000 (32,770 56,000) MUg L(-1), respectively. The undiluted wastewater samples were of low toxicity to N. closterium (IC(50)s>100% wastewater). Environmental chemistry data suggested that the key metals and discharge are a very low risk to this species. PMID- 21310439 TI - Ecology of twelve species of Thyasiridae (Mollusca: Bivalvia). AB - Benthic samples from coastal locations off Southwestern Norway were examined and the specimens of Thyasiridae were identified to species. A multivariate analysis based on 13 parameters was carried out and the environmental preferences of all thyasirid species present were determined. The potential of the Thyasiridae as indicators of organic enrichment was investigated by using direct canonical correspondence analyses to identify correlations between selected environmental parameters and the collected biological data. The presence of Thyasira sarsi together with a low biodiversity is a good indicator of organic enrichment. High thyasirid species diversity seems to indicate good environmental conditions, and single thyasirid species that lack symbiotic bacteria might also be useful as indicators of good environmental conditions. PMID- 21310440 TI - Levels and spatial distribution of polycyclic aromatic hydrocarbons (PAHs) in superficial sediment from 15 Italian marine protected areas (MPA). AB - Surface sediment from 15 Italian marine protected areas (MPA) were analysed for polycyclic aromatic hydrocarbons (PAHs). The organic carbon percentage was also determined. Total PAH concentrations (ng g-1 d.w.) ranged from 0.71 (Penisola del Sinis) to 1550 (Miramare). Individual PAH analysis showed that three and four rings PAHs were the most frequently detected isomers and accounted for 60-70% of the PAH total concentrations. PAH ratio analysis showed a prevalence of pyrolytic PAH origin at most of the MPAs with exception of Porto Cesareo and Ustica where a petrogenic origin was detected. Results for organic carbon percentages ranged from 0.3% (Capo Rizzuto) to 2% (Punta Campanella). These results are comparable to other Mediterranean marine environments. However, our results shows that some MPAs, such as Miramare, Porto Cesareo, Isola Capo Rizzuto and Punta Campanella, are subject to strong pressure from urban and industrial activities where high PAH levels were detected. PMID- 21310441 TI - CYP1A mRNA expression in redeye mullets (Liza haematocheila) from Bohai Bay, China. AB - Induction of cytochrome P4501A (CYP1A) has been used as a biomarker in fish for monitoring aromatic and organic contaminants. In this study, a partial of CYP1A gene in redeye mullet (Liza haematocheila) was isolated and sequenced, and then a real-time quantitative reverse-transcription polymerase chain reaction assay was developed for quantification of CYP1A mRNA normalized to beta-actin. The developed method was applied to detect CYP1A mRNA expression in redeye mullets collected from Nandaihe (reference site) and Dashentang (impacted site) in Bohai Bay, China. CYP1A mRNA expression values were significantly elevated in redeye mullets from Dashentang compared to a reference site--Nandaihe, which was correlated with the contents of different environmentally relevant pollutants in tissues, particularly with PCBs and PBDEs. PMID- 21310442 TI - [Plasmacytoid dendritic cell neoplasm in a 71 year-old male]. PMID- 21310443 TI - Metabolic factors in the development of hepatic steatosis and altered mitochondrial gene expression in vivo. AB - The objective of the study was to understand the role in vivo of elevated plasma free fatty acids (FFA), insulin, and glucose levels in the development of steatosis and altered mitochondrial gene/protein expression. We studied 4 groups of Sprague-Dawley rats: (1) high-fat diet (HFD), (2) high-dose streptozotocin induced diabetes (T1DM), (3) low-dose streptozotocin-induced diabetic rats on an HFD (T2DM), and (4) controls. Liver histology and expression of genes/proteins related to mitochondrial fatty acid oxidation and biogenesis were analyzed. Despite an attempt to compensate by increasing expression of genes of fatty acid oxidation (carnitine palmitoyl transferase-1/medium chain acyl-CoA dehydrogenase), the HFD and diabetic groups developed marked steatosis and suffered a significant reduction in mitochondrial biogenesis gene expression (nuclear respiratory factor 1/transcriptional factor A, mitochondrial). In T2DM rats, the combination of high glucose and FFA unexpectedly did not lead to greater fat accumulation than HFD alone. Greater steatosis in HFD vs T2DM (P < .001) correlated with impairment in the gene expression of PPAR-alpha (ie, fatty acid oxidation) and PGC1alpha, a major coactivator for mitochondrial biogenesis. Steatosis was not severe in insulin-deficient T1DM rats despite very elevated FFA and glucose levels. Increased carnitine palmitoyl transferase-1/medium chain acyl CoA dehydrogenase/PPAR-alpha gene expression suggested inadequate adaptation to high FFA in both T1DM/T2DM rats. Hyperinsulinemia combined with elevated FFA is the key metabolic factor driving hepatic lipogenesis in vivo (HFD rats). Mitochondrial biogenesis (nuclear respiratory factor 1; transcriptional factor A, mitochondrial) is highly susceptible to FFA-induced steatosis. In contrast, hyperglycemia does not have an additive effect (T2DM) and leads to only a modest degree of steatosis in the absence of hyperinsulinemia, even when FFA are extremely elevated as in T1DM rats. PMID- 21310444 TI - Mitochondrial DNA copy number is modulated by genetic variation in the signal transducer and activator of transcription 3 (STAT3). AB - The regulation of mitochondrial DNA (mtDNA) copy number not only is critical for the maintenance of the normal mitochondrial function but has a strong clinical significance. A recent report revealed that the signal transducer and activator of transcription 3 (STAT3) is involved in the regulation of the mitochondrial function and is required for the optimal function of the electron transport chain. In this study, we explored whether gene variants in the STAT3 influence the leukocyte mtDNA copy number. Clinical data and blood samples were collected from 179 subjects (aged 52.8 +/- 0.9 years). Mitochondrial DNA quantification using nuclear DNA (nDNA) as a reference was carried out by a real-time quantitative polymerase chain reaction method; results are presented as the mtDNA/nDNA ratio. We selected 3 tag single nucleotide polymorphisms showing a minor allele frequency greater than 10% (rs2293152 C/G, rs6503695 C/T, and rs9891119 A/C), representing 24 polymorphic sites of the STAT3 (r(2) > 0.8). We observed a significant association between mtDNA/nDNA ratio and both rs6503695 and rs9891119, adjusted by age and homeostasis model assessment index. The proportion of the total variance of the mtDNA/nDNA ratio accounted for by the rs6503695 and rs9891119 genotypes was 4.7% and 6.53%, respectively. Common variation in the STAT3 may influence mtDNA copy number. PMID- 21310445 TI - [Breast magnetic resonance imaging: state of the art and clinical applications]. AB - Breast magnetic resonance imaging is a modality that is being progressively integrated into the breast radiologist's daily clinical practice. There is consensus on the minimal technical requirements that a breast MR exam should have in order to attain diagnostic quality. Diagnostic criteria are mainly based on the American College of Radiology's BI-RADS magnetic resonance imaging categories. Breast cancer staging is a main clinical application, but it is not universally accepted. Other applications are: response evaluation in patients treated with chemotherapy, screening in high-risk patients, cancer of unknown origin, assessment of a possible relapse and breast implant evaluation. PMID- 21310446 TI - [Isolated torsion of the Fallopian tube: a case report]. PMID- 21310447 TI - Effect of polymorphisms at the STAT5A and FGF2 gene loci on reproduction, milk yield and lameness of Holstein cows. AB - The objective of this study was to investigate the association of polymorphisms at the STAT5A and FGF2 gene loci with fertility, lactation milk yield and lameness in dairy cattle. Five hundred and eighteen primiparous Holstein cows were included in the study. Several reproductive traits were considered including conception rate (0/1) at first insemination, conception rate (0/1) in a 305-day lactation, number of inseminations per conception, interval (days) from calving to conception for cows that conceived in the first 305 days of lactation and age at first calving. Milk yield and lameness incidence were also recorded. Genotyping was performed using PCR-RFLP. The effect of allele substitution at each gene locus on reproductive traits, milk yield and lameness was assessed with single-trait mixed linear models. No significant associations were found between reproduction traits and any of the studied polymorphisms, apart from age at first calving, for which STAT5A polymorphism had a suggestive effect (P = 0.077). In addition, no significant effect of any polymorphism on lameness was found. Replacement of the C by G allele at the STAT5A locus was associated with a significant (P<0.05) increase in lactation milk yield, suggesting that this locus could be considered in gene assisted selection for the genetic improvement of milk production. PMID- 21310448 TI - Development of a minor groove binding probe based real-time PCR for the diagnosis and quantification of Leishmania infantum in dog specimens. AB - A new quantitative real-time PCR (qPCR) assay based on Taqman(r) technology and minor groove binding (MGB) probe was developed for the diagnosis of leishmaniosis and quantification of Leishmania infantum DNA in infected dogs. This method was based on the amplification of a 122bp fragment of the highly conserved kDNA minicircles of L. infantum. The reaction was performed using the StepOnePlusTM system with StepOne softwareTM. This assay was able to detect the presence of protozoan parasite DNA in amounts as low as 0.03 parasites per reaction. The standard curve designed for the quantification of parasites showed linearity over seven log DNA concentration range with a correlation coefficient >0.999 and both intra- and inter-assay variability demonstrated the high efficiency and reproducibility of the assay. The qPCR also proved to be successfully applicable to different clinical samples including blood, bone marrow, lymph node aspirates and conjunctival swabs. PMID- 21310449 TI - Factors affecting pharmacokinetics of benzimidazole anthelmintics in food producing animals: the consequences and potential risks. AB - Benzimidazoles are frequently and widely used veterinary anthelmintics. Unfortunately, an administration of these anthelmintics does not always result in the expected therapeutic success. Many host-related factors modify pharmacokinetic behavior and efficacy of a chosen anthelmintic. Pharmacokinetics of anthelmintics varies among animals of different species, sex and age. Also diseases, medication, feed and environmental conditions can significantly affect behavior of anthelmintics and resultant drug efficacy in animals. The presented review gathers information, gained in last 20 years, on factors which bring about the variability in performance of benzimidazole anthelmintics in food-producing animals. It is focused particularly on differences in absorption and metabolism of these anthelmintics as these stages of the pharmacokinetic process seem to be the most important for the overall anthelmintic efficacy. The consequences of abnormalities and alterations in pharmacokinetics of benzimidazole anthelmintics are summarized and discussed. PMID- 21310450 TI - Specific expression of osteopontin and S100A6 in hepatocellular carcinoma. AB - BACKGROUND: Our aim was to identify differential expression of genes in hepatocellular carcinoma (HCC) with the ultimate goal of discovering novel diagnostic and therapeutic targets. METHODS: We examined differences in gene expression between HCC and noncancerous liver tissue using a cDNA array with probes for 15,843 genes/clones. Two genes, osteopontin (OPN) and S100A6, were found to be >10-fold differentially expressed, and were selected for further immunohistochemical staining in 51 HCC and 10 nonmalignant liver specimens. The relation between OPN and S100A6 alterations and various clinicopathologic parameters was also evaluated. RESULTS: We found a total of 219 genes that were differentially expressed >3-fold. Of these, 109 were upregulated and 110 downregulated. Within this group, 123 genes, including 59 upregulated and 64 downregulated, had been identified previously. These known genes were mainly involved in cell migration, cytoskeleton dynamics, the signaling pathway and cell cycle, and metabolism. OPN expression and S100A6 expression were seen in 26 of 51 (51.0 %) and 16 of 51 (31.4 %) HCC samples, respectively. More importantly, proteins coded by these genes were not found in any noncancerous liver specimen by immunohistochemical analysis. Expression of these genes correlated with poor differentiation (OPN: P = .013; S100A6: P = .008). CONCLUSION: OPN, a secreted phosphoprotein that has been increasingly implicated in the progression and metastasis of cancer, and S100A6, a member of the S100 protein family that can perform cell proliferation, differentiation, migration, and cytoskeletal dynamics, may be promising diagnostic markers and therapeutic targets for HCC. In addition, the results encourage future studies involving the roles of these proteins in the development and progression of this cancer. PMID- 21310451 TI - A comparison of evaluation, time pressure, and multitasking as stressors of psychomotor operative performance. AB - BACKGROUND: There is gathering interest in determining the typical sources of stress for an operating surgeon and the effect that stressors might have on operative performance. Much of the research in this field, however, has failed to measure stress levels and performance concurrently or has not acknowledged the differential impact of potential stressors. Our aim was to examine empirically the influence of different sources of stress on trained laparoscopic performance. METHODS: A total of 30 medical students were trained to proficiency on the validated Fundamentals of Laparoscopic Surgery peg transfer task, and then were tested under 4 counterbalanced test conditions: control, evaluation threat, multitasking, and time pressure. Performance was assessed via completion time and a process measure reflecting the efficiency of movement (ie, path length). Stress levels in each test condition were measured using a multidimensional approach that included the State-Trait Anxiety Inventory (STAI) and the subject's heart rate while performing a task. RESULTS: The time pressure condition caused the only significant increase in stress levels but did not influence completion time or the path length of movement. Only the multitasking condition significantly increased completion time and path length, despite there being no significant increase in stress levels. Overall, the STAI and heart rate measures were not correlated strongly. CONCLUSION: Recommended measures of stress levels do not necessarily reflect the demands of an operative task, highlighting the need to understand better the mechanisms that influence performance in surgery. This understanding will help inform the development of training programs that encourage the complete transfer of skills from simulators to the operating room. PMID- 21310452 TI - Simultaneous restoration of voice function and digestive tract continuity in patients with synchronous primaries of hypopharynx and thoracic esophagus with pedicled ileocolon flap. AB - BACKGROUND: Defects involving hypopharynx, cervical, and thoracic esophagus are challenging to reconstruct, and the available procedures usually leave patients voiceless. We describe our experience with a modified pedicled ileocolon flap for the reconstruction of alimentary conduit and voice in patients undergoing hypopharyngo-laryngectomy and total esophagectomy. METHODS: Between January 1995 and December 2008, 7 patients underwent reconstruction of the digestive tract and voice function with a pedicled ileocolon flap because of extensive defects involving larynx, hyphopharynx, cervical, and thoracic esophagus. Patient's charts were reviewed and appropriate clinical data were evaluated. RESULTS: All patients were male with a mean age of 58 years. The continuity of the digestive tract was restored with ileum-colon (n = 1) or colon (n = 6). The voice tube was reconstructed with appendix (n = 1) or with terminal ileum (n = 6). The middle colic artery (n = 1) and left ascending colic artery (n = 6) were used as a pedicle. Five flaps were supercharged using ileocolic vessels. All the flaps survived completely. No intraoperative or in-hospital mortalities occurred. The mean hospital stay was 40 days. The mean follow-up was 22.4 months. Two patients died of local recurrence (1 patient) and distant metastasis (1 patient). One patient died of the complications of pre-existing disease. At the last follow-up, the median deglutition score was 5/7. The median speech score for intelligibility and fluency was 3, and 4 for loudness. The maximum phonation time was 7.57 s. The average sound pressure loudness and fundamental frequency were, respectively, 59 +/- 3 dB and 133 +/- 33 Hz. CONCLUSION: The pedicled ileocolon flap as used in this series proved to be a safe and reliable technique for simultaneous reconstruction of voice and digestive tract. PMID- 21310453 TI - Preoperative T staging of gastric cancer by multi-detector row computed tomography. AB - BACKGROUND AND PURPOSE: Preoperative T staging demands high accuracy, because it greatly influences subsequent therapies in advanced gastric cancer. PATIENTS AND METHODS: 616 patients with gastric cancer underwent multi-detector row computed tomography (MDCT) before operation. The results were compared with operative and pathologic findings. Especially, we evaluated the correlations among the diagnostic accuracy of T staging and various clinicopathologic parameters by focusing on 276 patients who had detectable lesions by MDCT. RESULTS: The overall diagnostic accuracy of preoperative T staging by MDCT was 90.9% (560/616). For each pathologic T stage, the accuracy was 95% for pT1, 76% for pT2-3, 92% for pT4a, and 75% for pT4b, respectively. Among the 276 patients, 239 (87%) were correctly staged by MDCT whereas 29 (11%) and 8 (3%) were over- or under-staged, respectively. Antral tumors (P = .045), and Borrmann type 1 tumors (P = .0001) were incorrectly T staged by MDCT, whereas differentiated type tumors tended to be over-staged. All patients with positive cytology (n = 12 cases) and peritoneal metastasis (n = 7 cases) diagnosed at laparotomy had been diagnosed as T4a or deeper by MDCT. The 5-year overall survival rates classified by preoperative T staging by MDCT (T1/T2-3/T4a/T4b) were 100%, 89%, 59%, and 31%, respectively, whereas those for each pT stage were 100%, 84%, 59%, and 19%. CONCLUSION: Preoperative T staging of gastric cancer by MDCT is highly accurate and could contribute to treatment strategies, particularly in advanced disease. PMID- 21310454 TI - When swallowing takes your breath. PMID- 21310455 TI - Safe and effective gene transfer by adeno-associated virus of neonatal thymus derived mesenchymal stromal cells. AB - Recently, human neonatal thymus-derived mesenchymal stromal cells (nTMSCs) have been recognized as a promising mesenchymal stem cell source for combined cell and gene therapy. While efficient gene transfer is crucial for optimizing therapeutic efficacy, almost no studies have yet reported on the characteristics of nTMSC in terms of genetic modification. The present study investigates and realizes the potential of self-complementary adeno-associated viruses (scAAVs) as an effective transduction tool for nTMSCs. Transduction efficiency (TE), cytotoxicity and functional characteristics were determined in nTMSCs isolated from thymic tissues and transduced with scAAV1-6 and -8 serotypes expressing GFP. Our study confirms MSC-typical characteristics in nTMSCs and additionally, suggests further therapeutic advantages of nTMSCs due to its particularities with lower levels of MHC class I protein and higher levels of CD31 and CD34 expression. Effective transduction by scAAV2 and scAAV5 was evident in the majority of nTMSCs that were GFP-positive at a multiplicity of infection (MOI) of 1000. TE was further improved by higher MOI treatments. Transduced cells also successfully maintained adipocyte and vessel-forming endothelial cell multi-potency and showed no evidence of gene delivery-related cytotoxicity. Collectively, the data strongly suggest that scAAVs are promising technical platforms for safe and effective transgene expression in nTMSCs. PMID- 21310456 TI - Ultrasonic scanning of straight micro tools in soft biological tissues: Methodology and implementation. AB - The acoustical behaviour of straight micro tools (SMT), such as sub-millimetre needles or electrodes, is delicate and their automated maintaining in the image plane displayed to the practitioner must handle the extremely varying signal they backscatter. Because of the complex nature of the scattering by a narrow rod target, the localization process has to face two main tasks before being able to conduct 3D location: the reduction of the apparent diameter when this latter is visible, and the detection of the instrument and its real depth of penetration. In this paper, a methodology based on these steps is proposed, along with preliminary implementations of each of the steps. This methodology exploit the acoustic duality of those SMT and treat different acoustic aspects separately: first the apparent diameter is reduced through a deconvolution process, associating the backscattering to a purely linear acoustic process without attenuation; second, the imaging is treated as a pure attenuation process, and the signal is summed post-ROI to achieve the detection. Finally, the complete localisation is achieved by combining the two first steps with a previously tested global 3D straight line location technique: the Parallel Integral Projection. Experiments are conducted in vitro with 700MUm graphite rods and 150MUm in diameter tungsten electrode crossing gelatine and cryogel phantoms, and ex vivo on a porcine liver to assess the efficiency of the proposed implementations and of the whole methodology. The volumes were acquired with a Kretztechnic 530D scanner customized so as to provide the raw RF data. Results show that the combination of the different step-methods reduces progressively the apparent diameter, and that the detection step is essential to the proper localization of the micro tool. The final resolution improvement is at least of 3 and estimated to be typically of 12, for a final estimated apparent diameter reaching the average 400MUm resolution cell in the porcine liver. PMID- 21310457 TI - Evolution of mosaically related tailed bacteriophage genomes seen through the lens of phage P22 virion assembly. AB - The mosaic composition of the genomes of dsDNA tailed bacteriophages (Caudovirales) is well known. Observations of this mosaicism have generally come from comparisons of small numbers of often rather distantly related phages, and little is known about the frequency or detailed nature of the processes that generate this kind of diversity. Here we review and examine the mosaicism within fifty-seven clusters of virion assembly genes from bacteriophage P22 and its "close" relatives. We compare these orthologous gene clusters, discuss their surprising diversity and document horizontal exchange of genetic information between subgroups of the P22-like phages as well as between these phages and other phage types. We also point out apparent restrictions in the locations of mosaic sequence boundaries in this gene cluster. The relatively large sample size and the fact that phage P22 virion structure and assembly are exceptionally well understood make the conclusions especially informative and convincing. PMID- 21310458 TI - Bioaugmented membrane bioreactor (MBR) with a GAC-packed zone for high rate textile wastewater treatment. AB - The long-term performance of a bioaugmented membrane bioreactor (MBR) containing a GAC-packed anaerobic zone for treatment of textile wastewater containing structurally different azo dyes was observed. A unique feeding strategy, consistent with the mode of evolution of separate waste streams in textile plants, was adopted to make the best use of the GAC-zone for dye removal. Dye was introduced through the GAC-zone while the rest of the colorless media was simultaneously fed through the aerobic zone. Preliminary experiments confirmed the importance of coupling the GAC-amended anaerobic zone to the aerobic MBR and also evidenced the efficacy of the adopted feeding strategy. Following this, the robustness of the process under gradually increasing dye-loading was tested. The respective average dye concentrations (mg/L) in the sample from GAC-zone and the membrane-permeate under dye-loadings of 0.1 and 1 g/L.d were as follows: GAC-zone (3, 105), permeate (0, 5). TOC concentration in membrane-permeate for the aforementioned loadings were 3 and 54 mg/L, respectively. Stable decoloration along with significant TOC removal during a period of over 7 months under extremely high dye-loadings demonstrated the superiority of the proposed hybrid process. PMID- 21310459 TI - Monitoring organic loading to swimming pools by fluorescence excitation-emission matrix with parallel factor analysis (PARAFAC). AB - Fluorescence Excitation-Emission Matrix spectroscopy combined with parallel factor analysis was employed to monitor water quality and organic contamination in swimming pools. The fluorescence signal of the swimming pool organic matter was low but increased slightly through the day. The analysis revealed that the organic matter fluorescence was characterised by five different components, one of which was unique to swimming pool organic matter and one which was specific to organic contamination. The latter component had emission peaks at 420 nm and was found to be a sensitive indicator of organic loading in swimming pool water. The fluorescence at 420 nm gradually increased during opening hours and represented material accumulating through the day. PMID- 21310460 TI - Spatial and temporal variability of 210Po and 210Pb in mussels (Mytilus galloprovincialis) at the Turkish coast of the Aegean Sea. AB - In this study, the activity concentrations of 210Po and 210Pb were determined in mussel samples (Mytilus galloprovincialis) collected from the Turkish coast of the Aegean Sea. The samples were collected seasonally for a period of two years (2004-2006) at six coastal stations (Canakkale, Dikili, Foca, Cesme, Didim, Bodrum). Mussels were separated into several groups according to their size (1 4,4-6,>6 cm). The results showed that 210Po concentrations in mussels varied between 53+/-4 and 1960+/-60 Bq kg(-1)dw. The highest activity 210Po concentrations were determined in winter samples of mussels with a shell length of 4-6 cm from Didim. In general, it was observed that the 210Pb concentration levels in mussels were lower than 210Po concentrations. The 210Po/210Pb activity concentration ratios exceeded unity for all mussel samples and averaged 26.0. The inter-site differences seen in 210Po concentrations can be due to both the natural background levels of sites and industrial activities. PMID- 21310461 TI - Effects of salinity, DOM and metals on the fate and microbial toxicology of propetamphos formulations in river and estuarine sediment. AB - Toxicity studies tend to use pure pesticides with single organisms. However, natural systems are complex and biological communities diverse. The organophosphate pesticide propetamphos (PPT) has been found exceeding regulatory limits (100 ng L(-1)) in rivers. We address whether solution properties affect the fate of Analar (Analar-PPT) or industrial PPT (PPT-Ind) propetamphos formulations and whether propetamphos and metal toxicant effects are additive, antagonistic or synergistic? The sorption, desorption, biodegradation and microbial toxicology of Analar-PPT and PPT-Ind were investigated in Conwy River and estuary sediment. Results showed elevated salinity enhanced PPT sorption, while higher salinities increased PPT-Ind retention. Higher dissolved organic matter (DOM) and low salinity slowed Analar-PPT biodegradation (1.9*10(-3)h(-1)). Analar-PPT and PPT-Ind biodegradation was further reduced by low salinity, high DOM and dissolved Zn and Pb (6.3*10(-4)h(-1), 1100 ht(1/2) for Analar-PPT; 7.5*10(-4)h(-1), 924 ht(1/2) for PPT-Ind). Toxicity effects of PPT, Zn and Pb in equitoxic ratio were higher for PPT-Ind (4.7 MUg PPT-Ind g(-1); 581 MUg Zn g(-1); 395 MUg Pb g(-1)) than for Analar-PPT (34.6 MUg PPT g(-1); 312 MUg Zn g(-1); 212 MUg Pb g(-1)) whilst a toxicant ratio 1:100:10 suggested small quantities of Analar-PPT (EC(10)=0.06 MUg g(-1)) affected microbial communities. The combined toxicity effect was more than additive. Thus, industrial formulations and pollutant mixtures should be considered when assessing environmental toxicity. PMID- 21310462 TI - Cellular uptake and mutagenic potential of metal oxide nanoparticles in bacterial cells. AB - Extensive production and consumption of nanomaterials such as ZnO and TiO(2) has increased their release and disposal into the environment. The accumulation of nanoparticles (NPs) in ecosystem is likely to pose threat to non-specific targets such as bacteria. The present study explored the effect of ZnO and TiO(2) NPs in a model bacterium, Salmonella typhimurium. The uptake of ZnO and TiO(2) bare NPs in nano range without agglomeration was observed in S. typhimurium. TEM analysis demonstrated the internalization and uniform distribution of NPs inside the cells. Flow cytometry data also demonstrates that both ZnO and TiO(2) NPs were significantly internalized in the S. typhimurium cells in a concentration dependent manner. A significant increase in uptake was observed in the S. typhimurium treated even with 8 and 80 ng mL(-1) of ZnO and TiO(2) NPs with S9 after 60 min, possibly the formation of micelles or protein coat facilitated entry of NPs. These NPs exhibited weak mutagenic potential in S. typhimurium strains TA98, TA1537 and Escherichia coli (WP2uvrA) of Ames test underscoring the possible carcinogenic potential similar to certain mutagenic chemicals. Our study reiterates the need for re-evaluating environmental toxicity of ZnO and TiO(2) NPs presumably considered safe in environment. PMID- 21310463 TI - Microbial toxicity of metal oxide nanoparticles (CuO, NiO, ZnO, and Sb2O3) to Escherichia coli, Bacillus subtilis, and Streptococcus aureus. AB - In this study, the microbial toxicities of metal oxide nanoparticles were evaluated for Escherichia coli, Bacillus subtilis, and Streptococcus aureus in laboratory experiments. The nanoparticles tested were CuO, NiO, ZnO, and Sb(2)O(3). The metal oxide nanoparticles were dispersed thoroughly in a culture medium, and the microorganisms were cultivated on Luria-Bertani agar plates containing different concentrations of metal oxide nanoparticles. The bacteria were counted in terms of colony forming units (CFU). The CFU was reduced in a culture medium containing metal oxide NP, and the dose-response relationship was characterized. CuO nanoparticles were found to be the most toxic among the tested nanoparticles, followed by ZnO (except S. aureus), NiO, and Sb(2)O(3) nanoparticles. We determined that the intrinsic toxic properties of heavy metals are also associated with the toxicity of metal oxide nanoparticles. Ion toxicity was also evaluated to determine the effects of metal ions dissolved from metal oxide NPs, and the toxicity induced from the dissolved ions was determined to be negligible herein. To the best of our knowledge, this is the first study of the toxicity of NiO and Sb(2)O(3) NPs on microorganisms. We also discuss the implications of our findings regarding the effects of the intrinsic toxic properties of heavy metals, and concluded that the apparent toxicities of metal oxide NPs can largely be understood as a matter of particle toxicity. PMID- 21310464 TI - Comparison of Northern Ireland radon maps based on indoor radon measurements and geology with maps derived by predictive modelling of airborne radiometric and ground permeability data. AB - Publicly available information about radon potential in Northern Ireland is currently based on indoor radon results averaged over 1-km grid squares, an approach that does not take into account the geological origin of the radon. This study describes a spatially more accurate estimate of the radon potential of Northern Ireland using an integrated radon potential mapping method based on indoor radon measurements and geology that was originally developed for mapping radon potential in England and Wales. A refinement of this method was also investigated using linear regression analysis of a selection of relevant airborne and soil geochemical parameters from the Tellus Project. The most significant independent variables were found to be eU, a parameter derived from airborne gamma spectrometry measurements of radon decay products in the top layer of soil and exposed bedrock, and the permeability of the ground. The radon potential map generated from the Tellus data agrees in many respects with the map based on indoor radon data and geology but there are several areas where radon potential predicted from the airborne radiometric and permeability data is substantially lower. This under-prediction could be caused by the radon concentration being lower in the top 30 cm of the soil than at greater depth, because of the loss of radon from the surface rocks and soils to air. PMID- 21310465 TI - Analysis of sperm aneuploidies and DNA fragmentation in patients with globozoospermia or with abnormal acrosomes. AB - OBJECTIVES: To evaluate the levels of DNA fragmentation and aneuploidy rate in ejaculated sperm of men with globozoospermia and men with a predominance of abnormal acrosomes. METHODS: The semen samples obtained from 2 globozoospermic men, 8 patients with a predominance of abnormal acrosomes, and 20 fertile men were analyzed using the fluorescence in situ hybridization and the terminal desoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick-end labeling assay. Dual fluorescence in situ hybridization for chromosomes 8 and 12, and triple fluorescence in situ hybridization for chromosomes X, Y, and 18 were performed. RESULTS: The patients with globozoospermia and those with a predominance of abnormal acrosomes had a significantly greater percentage of sperm with DNA fragmentation compared with the controls (P < .01). In addition, a modest increase in the frequency of sex chromosome aneuploidy and disomy 8 was found in these patients compared with the controls (P < .01). A significant correlation was established between the abnormal acrosome and chromosomal aneuploidy. CONCLUSIONS: The high level of DNA fragmentation, in addition to moderate chromosomal abnormalities, might contribute to the low fertilization rate and poor pregnancy prognosis reported in the present category of patients. PMID- 21310466 TI - Quantitative assessment of AKAP12 promoter methylation in human prostate cancer using methylation-sensitive high-resolution melting: correlation with Gleason score. AB - OBJECTIVES: To quantitatively investigate the A kinase anchoring protein 12 (AKAP12) gene promoter methylation and its association with clinicopathologic variables in human prostate cancer (PCa). The AKAP12 gene has shown reduced expression and marked hypermethylation in a variety of cancers. METHODS: The percentage levels of DNA methylation were measured in 78 PCa, 22 benign prostatic hyperplasia, and 22 normal adjacent tissue samples using an AKAP12 methylation sensitive high-resolution melting assay. AKAP12 gene expression was also examined in 4 human prostate carcinoma cell lines, PC-3, DU145, LNCaP, and 22RV1, using quantitative reverse transcriptase-polymerase chain reaction and methylation sensitive high-resolution melting analysis and after DNA methyltransferase inhibition with 5-aza-2'-deoxycytidine. RESULTS: Methylation (>1%) of the AKAP12 promoter region was present in 47 (60.2%) of the 78 PCa, 5 (22.7%) of the 22 benign prostatic hyperplasia, and 2 (9.1%) of the 22 adjacent normal tissue samples. AKAP12 methylation was significantly greater in the PCa than in the benign prostatic hyperplasia or adjacent tissue samples (P < .01). AKAP12 methylation was significantly greater in the PCa samples with higher Gleason scores (P = .03); however, no correlation was found with age, pT category, or serum prostate-specific antigen level. Reverse transcriptase-polymerase chain reaction demonstrated that PC-3 and DU-145 cells expressed AKAP12 RNA and LNCaP and 22RV1 did not. The AKAP12 locus was methylated in the LNCaP and 22RV1 cells. Treatment of LNCaP cells with 5-aza-2'-deoxycytidine markedly decreased the methylation levels and increased the expression of AKAP12. CONCLUSIONS: The results of the present study have demonstrated that AKAP12 promoter methylation is a frequent event in human PCa. AKAP12 methylation represents a potential molecular biomarker for predicting the malignancy of PCa. PMID- 21310467 TI - Inhibitory effect of standardized cannabis sativa extract and its ingredient cannabidiol on rat and human bladder contractility. AB - OBJECTIVES: To evaluate the effect of a Cannabis sativa extract enriched in cannabidiol (CBD) botanic drug substance (BDS) and pure CBD, on bladder contractility in vitro. Cannabis based-medicines, including CBD-enriched extracts, have been shown to reduce urinary urgency, incontinence episodes, frequency, and nocturia in patients with multiple sclerosis. METHODS: Strips were cut from male Wistar rats and the human bladder body and placed in organ baths containing Krebs solution. Contractions were induced by electrical field stimulation, acetylcholine, KCl, and alpha,beta-methylene adenosine triphosphate. RESULTS: CBD BDS significantly reduced the contractions induced by acetylcholine, but not those induced with electrical field stimulation, KCl, or alpha,beta methylene adenosine triphosphate in the isolated rat bladder. The inhibitory effect of CBD BDS was not significantly modified by the cannabinoid or opioid receptor antagonists or by modulators of calcium levels, but it was increased by ruthenium red and capsazepine, 2 transient receptor potential vanilloid type-1 blockers. In humans, CBD BDS and pure CBD significantly reduced acetylcholine induced contractions, an effect that was not changed by the transient receptor potential vanilloid type-1 blockers. CONCLUSIONS: Our data have suggested that CBD BDS reduces cholinergic-mediated contractility and that this effect is modulated by transient receptor potential vanilloid type-1 in rats but not in humans. CBD is the chemical ingredient of CBD BDS responsible for such activity. If confirmed in vivo, such results could provide a pharmacologic basis to explain, at least in part, the efficacy of Cannabis medicines in reducing incontinence episodes in patients with multiple sclerosis. PMID- 21310468 TI - Are chlamydial lipopolysaccharide-directed antibodies in seminal plasma or serum clinically significant during investigation of male infertility? AB - OBJECTIVES: To analyze the clinical relevance of chlamydial serology in seminal plasma (SP)/serum for male fertility. METHODS: We determined the IgG, IgA, and IgM class antibodies to Chlamydia trachomatis with a lipopolysaccharide-directed standard enzyme-linked immunosorbent assay in the serum of 173 asymptomatic subfertile couples and in the same-day SP in a prospective study. The semen quality evaluation was done using aliquots of the same ejaculate (eg, sperm analysis, leukocytes, bacterial cultures, sperm functional capacity). The medical history, clinical examination, postcoital testing, and determination of subsequent fertility were also done. RESULTS: The antichlamydial antibodies of the 3 classes were significantly interrelated, and SP Chlamydia IgA antibodies were significantly associated with the findings in the serum. The evidence for previous or persistent chlamydial infection was significantly more frequent in the female partners of men with Chlamydia antibodies in the serum and/or Chlamydia IgA antibodies in the SP. The chlamydial serology results in the SP/serum were not associated with the sperm quality, leukocytes, semen culture findings, or sperm functional capacity. CONCLUSIONS: The chlamydial serology results (ie, IgG, IgA, and IgM antibodies in SP/serum) determined using a lipopolysaccharide-directed enzyme-linked immunosorbent assay were not indicative of reduced sperm function or subsequent fertilizing capacity. PMID- 21310469 TI - Simplified technique for parastomal hernia repair after radical cystectomy and ileal conduit creation. AB - OBJECTIVE: To review the results of parastomal hernia repair with a simplified technique of translocation of the stoma with no need for a midline incision. METHODS: A total of 405 radical cystectomies with creation of an ileal conduit were reviewed at our institution. The primary goal of the review was to determine the incidence of parastomal hernias in a large series of cystectomies and their management at our institution. Surgical correction of parastomal hernia was indicated in case of pain, discomfort, risk of bowel obstruction, and/or distortion of the abdominal wall. The simplified technique includes an elliptical incision around the stoma and dissection of the hernia's sac down to the level of the fascia. The sac is incised and the peritoneum is entered. The ileal conduit is thereafter mobilized to guarantee sufficient length. This is crucial to be able to transpose the conduit 5-10 cm superiorly and to obtain a tension-free ileostomy. RESULTS: Sixty-three patients (16%) presented during the follow-up after ileal conduit a palpable defect or bulge adjacent to the stoma. The review highlighted 19 patients (4.69%) who developed a parastomal hernia and underwent surgical repair. Four cases (21%) recurred at a median follow-up of 55 months. Recurrence was not found to be related to gender, age, body mass index, protein level, radiotherapy, adjuvant chemotherapy, or previous abdominal surgery on univariate analysis. Postoperative complications included one wound infection (5.2%) and one stomal necrosis (5.2%). CONCLUSIONS: The technique herein proposed simplifies the management of parastomal hernia repair by avoiding a midline incision, which implies a reduction in surgical trauma with acceptable recurrence and postoperative complication rate. PMID- 21310470 TI - Mass circumcision with a novel plastic clamp technique. AB - OBJECTIVE: To evaluate the safety and efficacy of mass circumcision performed using a plastic clamp. METHODS: A total of 2013 males, including infants, children, adolescents, and adults were circumcised during a 7-day period by using a plastic clamp technique. Complications were analyzed retrospectively in regard to 4 different age groups. Postcircumcision sexual function and satisfaction rates of the adult males were also surveyed. RESULTS: The mean duration of circumcision was 3.6+/-1.2 minutes. Twenty-six males who were lost to follow-up were excluded from the study. The total complication rate was found to be 2.47% among the remaining 1987 males, with a mean age of 7.8+/-2.5 years. The highest complication rate (2.93%) was encountered among the children<2 years age, which was because of the high rate of buried penis (0.98%) and excessive foreskin (0.98%) observed in this group. The complication rates of older children, adolescents, and adults were slightly lower than the children<2 years age, at 2.39%, 2.51%, and 2.40%, respectively. Excessive foreskin (0.7%) was the most common complication observed after mass circumcision. Bleeding (0.6%), infection (0.55%), wound dehiscence (0.25%), buried penis (0.25%), and urine retention (0.1%) were other encountered complications. The erectile function and sexual libido in adolescents and adults was not affected by circumcision and a 96% satisfaction rate was obtained. CONCLUSIONS: Mass circumcision performed by a plastic clamp technique was found to be a safe and time-saving method of circumcising a large number of males at any age. PMID- 21310471 TI - Laparoscopic ureteroureterostomies for duplicated ureteral entrapment in a fractured spine. AB - An extremely rare case of ureteral entrapment caused by traumatic lumbar spine injury with a duplication anomaly is presented. The patient was successfully managed in a minimally invasive fashion with laparoscopic excision and ureteroureterostomy. PMID- 21310472 TI - Nuclear P27 expression in benign, borderline (LMP) and invasive tumors of the ovary and its association with prognosis: a gynecologic oncology group study. AB - OBJECTIVE: Nuclear p27 expression was examined in non-invasive and invasive ovarian tumors from a cross-sectional study, and clinical relevance of p27 was evaluated in the primary tumors from women participating in two randomized phase III treatment trials. METHODS: An immunohistochemistry assay was used to detect p27 in formalin-fixed paraffin-embedded ovarian tumors from 3 distinct sources. RESULTS: Among the initial 91 ovarian tumors tested, low p27 expression (<50% positive cells) was observed in 5.4% of non-invasive tumors versus 42.6% of invasive tumors (p<0.001). In 145 ovarian cancers with high-risk early stage disease, 16.5% exhibited low p27 expression, and categorized p27 was not associated with age, race, or performance status. Low expression of p27 was common in poorly differentiated tumors (35.7%) compared to moderately (15.0%) and well (9.5%) differentiated tumors (p=0.024) and rare in clear cell carcinomas (2.4%) compared to other histologies (p=0.014). In the 139 cancers with advanced disease, 60% displayed low p27 expression, and categorized p27 expression was not associated with age, race, performance status, tumor grade, histologic subtype, measurable disease status or survival. Exploratory analyses revealed an association of cyclin E to p27 ratio >1.0 with an increased risk of death (hazard ratio=1.53; p=0.017). CONCLUSIONS: Low p27 expression could be associated with malignant transformation of the ovarian epithelium and FIGO stage. A cyclin E to p27 ratio >1.0 may be associated with shorter survival in these patients. Further study is required to confirm the trend for increased recurrences with low p27 expression in early stage disease. PMID- 21310473 TI - Management of post-liver transplant-associated IgE-mediated food allergy in children. PMID- 21310475 TI - Circulating levels of 25-hydroxyvitamin D and human cathelicidin in healthy adults. PMID- 21310476 TI - Sex dependence of airflow limitation and air trapping in children with severe asthma. PMID- 21310477 TI - The adenylate cyclase toxin of Bacillus anthracis is a potent promoter of T(H)17 cell development. PMID- 21310478 TI - Can starvation influence cellular and biochemical parameters in the crab Carcinus aestuarii? AB - Crustacea experience periods of starvation during moulting or when limited food availability occurs. The effects of starvation on Crustacea physiological responses have been demonstrated, whereas the effects of starvation on Crustacea immune parameters remain to be more fully studied. In the present study the effects of starvation on immune parameters and antioxidant enzyme activities of the crab Carcinus aestuarii were evaluated for the first time. Treated crabs were starved for 7 days, whereas control crabs were fed daily with mussels. Total haemocyte count (THC), haemocyte diameter and volume, haemocyte proliferation, cell-free haemolymph (CFH) glucose and total protein levels, and phenoloxidase (PO) activity in both haemocyte lysate (HL) and CFH were measured in crabs. In addition, superoxide dismutase (SOD) and catalase (CAT) activities were evaluated in both gills and digestive gland from crabs, in order to evaluate whether starvation induced oxidative stress in C. aestuarii. THC increased significantly in starved crabs, with respect to controls, whereas no significant variations were observed in haemocyte diameter, volume and proliferation. In CFH of starved animals glucose concentration significantly increased, whereas total protein concentration significantly reduced. A significantly higher PO activity was recorded in HL from starved crabs, than in control crabs. Conversely, PO activity did not vary significantly in CFH. Starvation did not cause significant alterations in antioxidant enzyme activities in both gills and digestive gland. Results obtained demonstrated that starvation influenced crab immune parameters, but did not induce oxidative stress. Results also indicated that C. aestuarii can modulate its cellular and biochemical parameters in order to cope with starvation. PMID- 21310479 TI - Biodegradable block poly(ester-urethane)s based on poly(3-hydroxybutyrate-co-4 hydroxybutyrate) copolymers. AB - A series of block poly(ester-urethane)s (abbreviated as PU3/4HB) based on biodegradable poly(3-hydroxybutyrate-co-4-hydroxybutyrate) (P3/4HB) segments were synthesized by a facile way of melting polymerization using 1,6-hexamethylene diisocyanate (HDI) as the coupling agent and stannous octanoate (Sn(Oct)(2)) as catalyst, with different 4HB contents and segment lengths. The chemical structure, molecular weight and distribution were systematically characterized by (1)H nuclear magnetic resonance spectrum (NMR), Fourier transform infrared spectroscopy (FTIR) and gel permeation chromatography (GPC). The thermal property was studied by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). The hydrophilicity was investigated by static contact angle of deionized water and CH(2)I(2). DSC curves revealed that the PU3/4HB polyurethanes have their T(g) from -25.6 degrees C to -4.3 degrees C, and crystallinity from 2.5% to 25.3%, being almost amorphous to semi-crystalline. The obtained PU3/4HBs are hydrophobic (water contact angle 77.4 degrees -95.9 degrees ), and their surface free energy (SFE) were studied. The morphology of platelets adhered on the polyurethane film observed by scanning electron microscope (SEM) showed that platelets were activated on the PU3/4HB films which would lead to blood coagulation. The lactate dehydrogenase (LDH) assay revealed that the PU3/4HBs displayed higher platelet adhesion property than raw materials and biodegradable polymer polylactic acid (PLA) and would be potential hemostatic materials. Crystallinity degree, hydrophobicity, surface free energy and urethane linkage content play important roles in affecting the LDH activity and hence the platelet adhesion. CCK-8 assay showed that the PU3/4HB is non-toxic and well for cell growth and proliferation of mouse fibroblast L929. It showed that the hydrophobicity is an important factor for cell growth while 3HB content of the PU3/4HB is important for the cell proliferation. Through changing the composition and the chain-length of P3/4HB-diol prepolymers, the biocompatibility of the poly(ester-urethane)s can be tailored. PMID- 21310480 TI - The effects of combined micron-/submicron-scale surface roughness and nanoscale features on cell proliferation and differentiation. AB - Titanium (Ti) osseointegration is critical for the success of dental and orthopedic implants. Previous studies have shown that surface roughness at the micro- and submicro-scales promotes osseointegration by enhancing osteoblast differentiation and local factor production. Only relatively recently have the effects of nanoscale roughness on cell response been considered. The aim of the present study was to develop a simple and scalable surface modification treatment that introduces nanoscale features to the surfaces of Ti substrates without greatly affecting other surface features, and to determine the effects of such superimposed nano-features on the differentiation and local factor production of osteoblasts. A simple oxidation treatment was developed for generating controlled nanoscale topographies on Ti surfaces, while retaining the starting micro /submicro-scale roughness. Such nano-modified surfaces also possessed similar elemental compositions, and exhibited similar contact angles, as the original surfaces, but possessed a different surface crystal structure. MG63 cells were seeded on machined (PT), nano-modified PT (NMPT), sandblasted/acid-etched (SLA), and nano-modified SLA (NMSLA) Ti disks. The results suggested that the introduction of such nanoscale structures in combination with micro-/submicro scale roughness improves osteoblast differentiation and local factor production, which, in turn, indicates the potential for improved implant osseointegration in vivo. PMID- 21310481 TI - Vacuolar Ca(2+) uptake. AB - Calcium transporters that mediate the removal of Ca(2+) from the cytosol and into internal stores provide a critical role in regulating Ca(2+) signals following stimulus induction and in preventing calcium toxicity. The vacuole is a major calcium store in many organisms, particularly plants and fungi. Two main pathways facilitate the accumulation of Ca(2+) into vacuoles, Ca(2+)-ATPases and Ca(2+)/H(+) exchangers. Here I review the biochemical and regulatory features of these transporters that have been characterised in yeast and plants. These Ca(2+) transport mechanisms are compared with those being identified from other vacuolated organisms including algae and protozoa. Studies suggest that Ca(2+) uptake into vacuoles and other related acidic Ca(2+) stores occurs by conserved mechanisms which developed early in evolution. PMID- 21310482 TI - Reduced gain of excitation-contraction coupling in triadin-null myotubes is mediated by the disruption of FKBP12/RyR1 interaction. AB - Several studies have suggested that triadin (Tdn) may be a critical component of skeletal EC-coupling. However, using Tdn-null mice we have shown that triadin ablation results in no significant disruption of skeletal EC-coupling. To analyze the role of triadin in EC-coupling signaling here we used whole-cell voltage clamp and simultaneous recording of intracellular Ca2+ release to characterize the retrograde and orthograde signaling between RyR1 and DHPR in cultured myotubes. DHPR Ca2+ currents elicited by depolarization of Wt and Tdn-null myotubes displayed similar current densities and voltage dependence. However, kinetic analysis of the Ca2+ current shows that activation time constant of the slow component was slightly decreased in Tdn-null cells. Voltage-evoked Ca2+ transient of Tdn-null myotubes showed small but significant reduction in peak fluorescence amplitude but no differences in voltage dependence. This difference in Ca2+ amplitude was averted by over-expression of FKBP12.6. Our results show that bi-directional signaling between DHPR and RyR1 is preserved nearly intact in Tdn-null myotubes and that the effect of triadin ablation on Ca2+ transients appears to be secondary to the reduced FKBP12 binding capacity of RyR1 in Tdn null myotubes. These data suggest that skeletal triadins do not play a direct role in skeletal EC-coupling. PMID- 21310483 TI - DIGE-based proteomic analysis identifies nucleophosmin/B23 and nucleolin C23 as over-expressed proteins in relapsed/refractory acute leukemia. AB - Drug resistance is a challenge in treatment of acute leukemia. To investigate novel protein changes involved in resistance, protein expression profiles between leukemia cell line HL-60 and adriamycin-resistant HL-60 (HL-60/ADR) were compared based on a proteomic approach-2D-DIGE followed by MALDI-TOF/MS. 13 protein spots were identified as up-regulated and 3 down-regulated in HL-60/ADR. Nucleophosmin/B23 (NPM B23) and nucleolin C23 (C23) were selected and verified by western blot, which showed an obvious up-regulation in leukemia cells, especially in 3 resistant leukemia cell lines and in relapsed/refractory patients. To a conclusion, B23 and C23 may be involved in drug resistance and be useful in assessing the prognosis of leukemia. PMID- 21310484 TI - 7-b, a novel amonafide analogue, cause growth inhibition and apoptosis in Raji cells via a ROS-mediated mitochondrial pathway. AB - Previous studies have shown that 7-b (6-(dodecylamino)-2-(3-(4-methylpiperazin-1 yl)propyl)-1H-benzo-[de]isoquinoline-1,3(2H)-dione), a novel amonafide-based DNA intercalator, was generated as a new anticancer candidate. However, the effects induced by 7-b and the molecular mechanisms involved remain poorly understood in Burkitt's lymphoma. To shed light on these issues, we have investigated the effects of 7-b on proliferation, cell cycle progression, apoptosis activity and oxidative stress levels of lymphoma Raji cells in vitro. Our results showed that 7-b inhibited the proliferation of Raji cells and induced G1 cell cycle arrest in a dose-dependent manner. Moreover, 7-b treatment triggered programmed cell death, production of reactive oxygen species (ROS) and alteration of the mitochondrial membrane potential (Deltapsim). Altogether our results showed that 7-b mediated its growth inhibitory effects on Raji cells via the activation of a ROS-mediated mitochondrial pathway and cell cycle checkpoint signaling pathway which subsequently targeted p21. PMID- 21310485 TI - The effect of multi-walled carbon nanotubes on soil microbial activity. AB - Nanomaterials such as multi-walled carbon nanotubes (MWCNTs) are applied to various industrial products and thus may be released to soils, but their potential environmental impacts remain largely undetermined. We investigated the short-term effect of MWCNTs on the activity and biomass of microorganisms inhabiting two different soil types in an incubation study. Up to 5000 MUg MWCNT g(-1) soil was applied and the activities of 1,4-beta-glucosidase, cellobiohydrolase, xylosidase, 1,4-beta-N-acetylglucosaminidase, and phosphatase and microbial biomass were measured. In both soil types, most enzyme activities showed a tendency to be repressed under 500 MUg MWCNT g(-1) soil, and all enzymatic activities as well as microbial biomass C and N were significantly lowered under 5000 MUg MWCNT g(-1) soil. Our results suggest that high concentrations of MWCNTs could lower the microbial activity and biomass in soils, and they may serve as an important guideline in regulating the release of MWCNTs to the soil environment. PMID- 21310486 TI - Novel approach for assessing heavy metal pollution and ecotoxicological status of rivers by means of passive sampling methods. AB - In order to study the pollution of fluvial ecosystems, it is necessary to analyze not only the levels of chemical contaminants in water, but also those accumulated in the sediment matrix, as well as to assess its ecotoxicological status. Eleven Catalan (Spain) river sections (one sampling point per river) located near urban and industrial areas were sampled during winter of 2009. Water pollutants were collected by using passive samplers as Diffusive Gradient in Thin-Films (DGTs) and Semi-Permeable Membrane Devices (SPMDs). Point water samples were also collected. The concentrations of potentially toxic elements (PTE) in water, filtered water, DGTs and sediment samples were analyzed. Aqueous and organic solvent extracts of sediments samples and organic extracts of SPMDs were performed to assess acute toxicity to Vibrio fischeri by Microtox((r)), and chronic toxicity to the green alga Pseudokirschneriella subcapitata. Microtox((r)) test was also performed with DGT extracts. The results show that metals content of Catalan river waters are below the freshwater screening US EPA benchmarks, excepting some industrial areas (for Hg, Pb, and Zn). In contrast, sediments levels of some rivers were far above freshwater sediment screening US EPA benchmarks (for Zn, As, Cr, Pb, Ni, Hg, and Mn), particularly in the most industrialized areas. A good correlation was found between toxicity values of extracts (from sediments and DGTs) and PTE levels in sediments. The current results support the suitability of using combined point and passive sampling methods for assessing the chemical and ecotoxicological status of aqueous environments. PMID- 21310487 TI - The Isle Royale Wolf-Moose Project (1958-present) and the wonder of long-term ecological research. PMID- 21310488 TI - A bioinformatics pipeline to build a knowledge database for in silico antibody engineering. AB - A challenge to antibody engineering is the large number of positions and nature of variation and opposing concerns of introducing unfavorable biochemical properties. While large libraries are quite successful in identifying antibodies with improved binding or activity, still only a fraction of possibilities can be explored and that would require considerable effort. The vast array of natural antibody sequences provides a potential wealth of information on (1) selecting hotspots for variation, and (2) designing mutants to mimic natural variations seen in hotspots. The human immune system can generate an enormous diversity of immunoglobulins against an almost unlimited range of antigens by gene rearrangement of a limited number of germline variable, diversity and joining genes followed by somatic hypermutation and antigen selection. All the antibody sequences in NCBI database can be assigned to different germline genes. As a result, a position specific scoring matrix for each germline gene can be constructed by aligning all its member sequences and calculating the amino acid frequencies for each position. The position specific scoring matrix for each germline gene characterizes "hotspots" and the nature of variations, and thus reduces the sequence space of exploration in antibody engineering. We have developed a bioinformatics pipeline to conduct analysis of human antibody sequences, and generated a comprehensive knowledge database for in silico antibody engineering. The pipeline is fully automatic and the knowledge database can be refreshed anytime by re-running the pipeline. The refresh process is fast, typically taking 1min on a Lenovo ThinkPad T60 laptop with 3G memory. Our knowledge database consists of (1) the individual germline gene usage in generation of natural antibodies; (2) the CDR length distributions; and (3) the position specific scoring matrix for each germline gene. The knowledge database provides comprehensive support for antibody engineering, including de novo library design in selection of favorable germline V gene scaffolds and CDR lengths. In addition, we have also developed a web application framework to present our knowledge database, and the web interface can help people to easily retrieve a variety of information from the knowledge database. PMID- 21310489 TI - Differences in rates of glaucoma among Asian Americans and other racial groups, and among various Asian ethnic groups. AB - PURPOSE: To determine the incidence and prevalence of different glaucoma types among Asian Americans and other races, and evaluate the hazard for glaucoma among different races and Asian ethnicities. DESIGN: Retrospective, longitudinal, cohort study. PARTICIPANTS: A group of 2,259,061 eye care recipients, aged >= 40, who were enrolled in a US managed-care network in 2001-2007. METHODS: Incidence and prevalence rates of open-angle glaucoma (OAG), narrow-angle glaucoma (NAG), and normal-tension glaucoma (NTG) were calculated and stratified by race and Asian ethnicity. Cox regression was performed to assess the hazard of developing OAG, NAG, and NTG for Asian Americans and other races, and among different Asian ethnicities, with adjustment for potentially confounding variables. MAIN OUTCOME MEASURES: Multivariable adjusted hazard of OAG, NAG, and NTG among different races and Asian ethnicities. RESULTS: The OAG prevalence rate for Asian Americans, 6.52%, was similar to that of Latinos (6.40%) and higher than that of non-Hispanic whites (5.59%). The NAG and NTG prevalence rates were considerably higher among Asian Americans (3.01% and 0.73%, respectively) relative to other races. After adjustment for potential confounding factors, Asian Americans had a 51% increased hazard of OAG (adjusted hazard ratio [HR], 1.51 [95% confidence interval (CI), 1.42-1.60]), a 123% increased hazard of NAG (adjusted HR, 2.23; CI, 2.07-2.41), and a 159% increased hazard of NTG (adjusted HR, 2.59; CI, 2.22 3.02) compared with non-Hispanic whites. Vietnamese Americans (adjusted HR, 3.78; CI, 3.19-4.48), Pakistani Americans (adjusted HR, 2.45, CI 1.50-4.01), and Chinese Americans (adjusted HR, 2.31, CI 2.06-2.59) had considerably higher hazards of NAG, whereas Japanese Americans (adjusted HR, 4.37, CI 3.24-5.89) had a substantially higher hazard of NTG, compared with non-Asian Americans. CONCLUSIONS: Given the rapid rise in the number of Asian Americans in the US population, resources should be devoted to identifying and treating glaucoma in these patients. Eye-care providers should be aware of the increased risk for OAG, NAG, and NTG among Asian Americans relative to other races. Knowing Asian American patients' ancestral country of origin may permit more precise estimation of their risks for OAG, NAG, and NTG. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article. PMID- 21310490 TI - Prevalence and risks factors of age-related macular degeneration in Oklahoma Indians: the Vision Keepers Study. AB - OBJECTIVE: To determine the prevalence of age-related macular degeneration (AMD) and to identify its risk factors in an Oklahoma Indian population. DESIGN: Cross sectional study design. PARTICIPANTS: Included 1019 Oklahoma Indians who participated in baseline and second examinations of the Strong Heart Study. METHODS: Retinal photographs of at least 1 eye were obtained and graded for AMD by the University of Wisconsin Ocular Epidemiology Reading Center. Retinal photographs of 986 participants were considered gradable and were included in the study. MAIN OUTCOME MEASURES: Age-related macular degeneration (early and late). RESULTS: The overall prevalence of AMD in the study was 35.2%, including a prevalence of 0.81% for late AMD. The prevalence of early AMD increased from 30.6% in those aged 48 to 59 years to 46.1% in those 70 to 82 years of age. When potential risk factors were analyzed individually (univariate analyses), men with hypertension had a significantly higher prevalence of AMD (P = 0.02) than those without hypertension. In women, high-density lipoprotein cholesterol and sun exposure were associated positively with the prevalence of AMD (P = 0.01), whereas a history of using multivitamins was associated with lower AMD prevalence (P = 0.005). When multiple risk factors were analyzed simultaneously using logistic regression, only age showed significant association with AMD in both men (P = 0.02) and women (P<0.0001) and was the only significant risk factor in men. In women, multivitamin use and total cholesterol had a significant inverse association with AMD, whereas sun exposure and high-density lipoprotein cholesterol had a positive association. When men and women were combined, age and high-density lipoprotein cholesterol had significant positive associations, whereas total cholesterol, multivitamin use, and current alcohol use showed a significant inverse association with AMD. CONCLUSIONS: This study was the first to report a detailed prevalence of AMD in Oklahoma Indians and its risk factors. The prevalence seemed to be relatively high compared with that in other ethnic groups. Some of the modifiable risk factors identified confirmed previous findings and can be used to design preventive programs to reduce the burden of AMD, although longitudinal data are still needed. PMID- 21310491 TI - CLRN1 mutations cause nonsyndromic retinitis pigmentosa. AB - OBJECTIVE: To describe the mutations in the CLRN1 gene in patients from 2 consanguineous Pakistani families diagnosed with autosomal recessive retinitis pigmentosa (arRP). DESIGN: Case-series study. PARTICIPANTS: Affected and unaffected individuals of 2 consanguineous Pakistani families and 90 unaffected controls from the same population. Informed consent was obtained from participants and the protocol was approved by a local institutional review board. METHODS: Patients of 2 consanguineous families were genotyped with single nucleotide polymorphism microarrays for genome-wide linkage analysis. The search for potential candidate genes within the 8-Mb overlapping homozygous region in these families revealed the presence of CLRN1, a gene previously known to cause Usher's syndrome type III (USH3), which was analyzed by direct sequence analysis. The clinical diagnosis was based on the presence of night blindness, fundoscopic findings, and electroretinography (ERG) results. Additionally, pure tone audiometry was performed to rule out Usher's syndrome. MAIN OUTCOME MEASURES: Fundoscopy, single-nucleotide polymorphism microarray, DNA sequence analysis, ERG, and audiometry. RESULTS: Sequencing of CLRN1 revealed novel missense mutations (p.Pro31Leu and p.Leu154Trp) segregating in 2 families. Analysis of fundus photographs indicated attenuation of the retinal vessels, and bone spicule pigmentation in the periphery of the retina. The ERG responses were indicative of a rod-cone pattern of the disease. Audiometric assessment revealed no hearing impairment, thereby excluding Usher's syndrome. Subcellular localization studies demonstrated the retention of the mutant proteins in the endoplasmic reticulum, whereas the wild-type protein was mainly present at the cell membrane. CONCLUSIONS: The RP-associated mutations p.Pro31Leu and p.Leu154Trp may represent hypomorphic mutations, because the substituted amino acids located in the transmembrane domains remain polar, whereas more severe changes have been detected in patients with USH3. These data indicate that mutations in CLRN1 are associated not only with USH3, but also with nonsyndromic arRP. PMID- 21310492 TI - Genome-wide association study of diabetic retinopathy in a Taiwanese population. AB - PURPOSE: Diabetic retinopathy (DR) is a microvascular complication of diabetes with a complex multifactorial pathogenesis. The aim of this study was to identify the susceptibility genes that increase the risk of DR in type 2 diabetes (T2D) and to further elucidate the underlying mechanism of DR pathogenesis. DESIGN: A case-control study. PARTICIPANTS: We included 749 unrelated individuals with T2D (174 with DR and 575 without DR) and 100 nondiabetic controls. METHODS: We conducted a genome-wide association study using Illumina HumanHap550-Duo BeadChips. MAIN OUTCOME MEASURES: Compared with the genotypic distribution of single nucleotide polymorphisms (SNPs) between subjects with DR and without DR. RESULTS: Using statistical models, we selected a total of 12 SNPs with P-values <1 * 10(-6) that were associated with DR. After controlling for diabetes duration and hemoglobin A(1C), 9 of the 12 SNPs located on 5 chromosomal regions were found to be associated with DR. Five loci not previously associated with DR susceptibility were identified in and around the following genes: MYSM1 (Myb like, SWIRM, and MPN domains 1) located on chromosome 1p (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.03-2.20); PLXDC2 (plexin domain-containing 2) located on the chromosome 10p (OR, 1.67; 95% CI, 1.06-2.65); ARHGAP22 (Rho GTPase activating protein 22) located on chromosome 10q (OR, 1.65; 95% CI, 1.05-2.60); and HS6ST3 (heparan sulfate 6-O-sulfotransferase 3) located on chromosome 13q (OR, 2.33; 95% CI, 1.13-4.77). The SNPs rs13163610 and rs17376456 located in the unknown gene on chromosome 5q were also associated with DR (OR, 3.63; 95% CI, 1.38-9.58). CONCLUSIONS: We identified a genetic association for susceptibility to DR in 5 novel chromosomal regions and PLXDC2 and ARHGAP22, the latter 2 of which are genes implicated in endothelial cell angiogenesis and increased capillary permeability. These findings suggest unsuspected pathways in the pathogenesis of DR. PMID- 21310493 TI - Whole population trends in complications of cataract surgery over 22 years in Western Australia. AB - OBJECTIVE: To examine the trends in major complications of cataract surgery in the Western Australian population over 22 years. DESIGN: Population-based study. PARTICIPANTS: We included 129 982 cataract/lens surgery patients across 46 health facilities. METHODS: Using the Western Australian Data Linkage System, we identified all patients who underwent cataract/lens surgery in Western Australia between 1980 and 2001. Complications of interest were identified from those patients admitted to hospital or who underwent unplanned surgery after cataract surgery and were validated by medical record review. MAIN OUTCOME MEASURES: Admission for retinal detachment, dropped nucleus, wound dehiscence, pseudophakic corneal edema, intraocular lens (IOL) dislocation, and postoperative endophthalmitis requiring surgery. RESULTS: There were 129 982 cataract/lens procedures and 2087 (1.6%) complications. Complications fell almost 70% over the study period. Retinal detachment (n = 905; 0.70%) was most common, followed by IOL dislocation (n = 361; 0.28%), endophthalmitis (n = 228; 0.18%), wound dehiscence (n = 227; 0.17%), pseudophakic corneal edema (n = 207; 0.16%), and dropped nucleus (n = 159; 0.12%). The incidence of complications lessened over time, except for IOL dislocations, which has increased since 1995. Overall, the risk of complications after phacoemulsification halved since it was introduced in the late 1990s (incidence rate ratio, 0.52; 95% confidence interval, 0.37-0.74), whereas complications after extracapsular extraction (ECCE) have increased over recent years. CONCLUSIONS: Cataract surgery remains an extremely safe procedure with comparatively few major complications. Changes in operative techniques have been accompanied by a significant decrease in complication rates over time, although the increase in IOL dislocations and complications after ECCE warrants further study. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article. PMID- 21310494 TI - Thirty-Year follow-up of an African American family with macular dystrophy of the retina, locus 1 (North Carolina macular dystrophy). AB - PURPOSE: To describe clinical characteristics, including visual acuity (VA), genetic analysis, and management of complications, over a 30-year period in an African American family with macular dystrophy of the retina, locus 1 (MCDR1), commonly referred to as "North Carolina macular dystrophy." DESIGN: Observational, cohort study. PARTICIPANTS: Twelve family members from a 4 generation pedigree. METHODS: A total of 12 African American patients in an affected family were examined. Clinical examination was documented during 2 different follow-up periods from 1979 to 1982 in 10 patients and from 2005 to 2009 in 11 patients. Genetic analysis was performed in 4 affected members during this time. Foveal microperimetry, fundus autofluorescence, and spectral domain optical coherence tomography (OCT) data were also obtained. MAIN OUTCOME MEASURES: Change in VA of 8 members followed over 3 decades and clinical data and management of complications for all patients. RESULTS: Nine of 11 living family members had classic findings ranging from disease grade 2 (confluent foveal drusen, 8 eyes) to grade 3 (central coloboma-like lesion, 10 eyes). Two members developed choroidal neovascularization (CNV) requiring laser ablation, and 1 member developed non-clearing vitreous hemorrhage and underwent 25-gauge pars plana vitrectomy. Another family member developed exotropia and amblyopia in 1 eye by age 7 years. Those without CNV had no significant change in VA over 30 years. Linkage studies of 4 affected family members showed the same short tandem repeats on markers spanning D6S249 and D6S283 within the MCDR1 region of chromosome 6q16. Microperimetry analysis of an affected member with grade 3 MCDR1 revealed absent function in the region of the central coloboma-like lesions, corresponding to photoreceptor absence on OCT, although there were preserved foveal function and intact photoreceptors adjacent to the lesion. CONCLUSIONS: This African American family shares similar clinical findings as other MCDR1 pedigrees and the same haplotype as the originally described family from North Carolina. Clinical characteristics, including retinal features and stable VA in the absence of amblyopia and CNV, are similar to those in other reports. Eccentric viewing around impaired photoreceptors may explain good VA in patients with clinically severe-appearing macular lesions. Sequencing of the MCDR1 interval may help identify a protein responsible for early macular development. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 21310496 TI - Explosive anger in postconflict Timor Leste: interaction of socio-economic disadvantage and past human rights-related trauma. AB - BACKGROUND: Countries emerging from major conflict commonly experience recurrent periods of communal instability. A psychosocial theory, Adaptation and Development after Persecution and Trauma (ADAPT), suggests that experiences of past human rights abuses interact with socio-economic disadvantage in the postconflict period to generate or maintain explosive forms of anger. Previous research has supported a link between trauma exposure and anger but the role of ongoing socio-economic disadvantage requires further clarification. METHODS: The present study examined a structural equation model based on cross-sectional epidemiological data (n = 1245) collected in post-conflict Timor Leste in 2004. The model included four trauma dimensions derived from a prior factor analysis; a latent variable of post-conflict distress symptoms (derived from measures of PTSD and depression/anxiety); an index of socio-economic distress; and an indigenously based measure of explosive anger. RESULTS: The final model yielded a good fit (chi-square = 26.59 df = 20 p = 0.15 CFI = 0.99; TLI = 0.99; RMSEA = 0.016). Postconflict distress symptoms mediated the associations of trauma dimensions and socio-economic disadvantage with anger. Trauma dimensions associated with human rights violations and witnessing murder were partly mediated by ongoing socio economic disadvantage in the path to postconflict distress and anger. LIMITATIONS: Longitudinal studies will be needed to confirm the chronological sequencing of these relationships. CONCLUSIONS: The study offers empirical support for a link between past trauma related to human rights violations and ongoing socio-economic disadvantage in the path to distress and anger. PMID- 21310495 TI - Risk factors for suicide attempt in an Arab kindred. AB - OBJECTIVE: This explorative study examines correlates of suicidal behavior in an extended Arab kindred selected because of a high rate of suicidal behavior. METHODS: Family members (n=468) aged 15 through 55 were assessed using a comprehensive structured psychiatric interview, the Composite International Diagnostic Interview (CIDI), which covers a wide range of psychopathology, including a spectrum of suicidal thoughts and behaviors. In addition, self reported depression, anxiety, hopelessness, impulsivity and hostility, early childhood adversity, and suicidal behavior in first- and second-degree relatives were assessed. RESULTS: Significant associations were found between suicidal thoughts and behavior, and the presence of family history of suicide, all forms of psychopathology and suicidal behaviors. In addition, impulsivity and hostility were also significantly associated with suicidality. LIMITATION: The absence of similar assessments in comparison families, makes it difficult to assess why this family appears to be at higher risk for suicidal behavior. CONCLUSION: Risk correlates of suicidal behavior in the Arab kindred are similar to those reported from other parts of the world. These findings suggest that effective means of suicide prevention used in European populations may be successfully adapted to prevent suicide in this ethnic group as well. Since all forms of suicidal behavior in this population as well as in other Arab populations are increasing rapidly (Karam et al., 2008), these results have important implications for suicide prevention as well as for the understanding of the genetics of suicide. PMID- 21310497 TI - Treatment-seeking for social anxiety disorder in a general outpatient psychiatry setting. AB - Many individuals with social anxiety disorder (SAD) seek treatment principally for another psychiatric disorder, but when directly asked, a majority of these individuals also desire treatment for SAD. Several reasons may exist for why individuals with SAD do not seek treatment for it, such as the severity or functional impairment related to SAD. The aim of the current study was to examine factors related to SAD severity, impairment, and comorbidity, to gain a better understanding of what factors may be related to treatment-seeking for SAD. In 819 psychiatric outpatients with SAD, initial results showed that age, duration of SAD illness, number of social fears endorsed, Clinical Global Impression score, Sheehan Disability Scale ratings for social life and distress, presence of major depressive disorder, and presence of depressive disorder not otherwise specified (DDNOS) were associated with treatment-seeking for SAD status. However, a regression analysis found that DDNOS was the most robust predictor of treatment seeking for SAD status, followed by the number of feared social situations. Other factors should be examined in the future, such as knowledge of SAD and available treatment options. PMID- 21310499 TI - Gender difference in obesity management among Iranian patients with metabolic syndrome. PMID- 21310498 TI - Differences in muscle coactivation during postural control between healthy older and young adults. AB - The purpose of this study was to clarify the difference in muscle coactivation during postural control between older and young adults and to identify the characteristics of postural control strategies in older adults by investigating the relationship between muscle coactivation and postural control ability. Forty six healthy older adults (82.0+/-7.5 years) and 34 healthy young adults (22.1+/ 2.3 years) participated. The postural tasks selected consisted of static standing, functional reach, functional stability boundary and gait. Coactivation of the ankle joint was recorded during each task via electromyography (EMG). The older adults showed significantly higher coactivation than the young adults during the tasks of standing, functional reach, functional stability boundary (forward), and gait (p<0.01). Postural sway area (rho=0.42, p<0.05) and functional reach distance (rho=-0.52, p<0.05) significantly correlated with coactivation during the corresponding task in older adults, i.e., muscle coactivation was significantly higher in the elderly with low postural control ability than in the elderly with high balance ability. Increased muscle coactivation could be a necessary change to compensate for a deterioration in postural control accompanying healthy aging. Further research is needed to clarify in greater detail positive and negative effects of muscle coactivation on postural control. PMID- 21310500 TI - Deriving distributional weights for QALYs through discrete choice experiments. AB - This paper presents the first attempt to use a discrete choice experiment to derive distributional weights for quality adjusted life years (QALYs), based on characteristics (age and severity) of the beneficiaries. A novel approach using the Hicksian compensating variation is applied. Advantages include derivation of weights for QALYs, not just for life or life years saved, and investigation of the impact of the size of the health gain by allowing the gain to be traded against other characteristics. Results suggest one would generally not weight QALYs, except in a small number of specific cases and in those cases the weights are relatively small. Methodological challenges are highlighted as is a future research agenda. PMID- 21310502 TI - Treatment of diabetic foot ulcers: a comparative study of extracorporeal shockwave therapy and hyperbaric oxygen therapy. AB - OBJECTIVE: This study compared the effectiveness of extracorporeal shockwave therapy (ESWT) and hyperbaric oxygen therapy (HBOT) in chronic diabetic foot ulcers. PATIENTS AND METHODS: The ESWT group (39 patients/44 feet) received shockwave therapy twice per week for total six treatments. The HBOT group (38 patients/40 feet) received hyperbaric oxygen therapy daily for total 20 treatments. Evaluations included clinical assessment, blood flow perfusion scan and histopathological examination. RESULTS: The overall clinical results showed completely healed ulcers in 57% and 25% (P = 0.003); >= 50% improved ulcers in 32% and 15% (P = 0.071); unchanged ulcers in 11% and 60% (P < 0.001) and none worsened for the ESWT and the HBOT group respectively. The blood flow perfusion rates were comparable between the two groups before treatment (P = 0.245), however, significant differences were noted after treatment favoring the ESWT group (P = 0.002). Histopathological examination revealed considerable increases in cell proliferation and decreases in cell apoptosis in the ESWT group as compared to the HBOT group. CONCLUSION: ESWT is more effective than HBOT in chronic diabetic foot ulcers. ESWT-treated ulcers showed significant improvement in blood flow perfusion rate and cell activity leading to better healing of the ulcers relative to HBOT in chronic diabetic foot ulcers. PMID- 21310501 TI - Mining high-throughput experimental data to link gene and function. AB - Nearly 2200 genomes that encode around 6 million proteins have now been sequenced. Around 40% of these proteins are of unknown function, even when function is loosely and minimally defined as 'belonging to a superfamily'. In addition to in silico methods, the swelling stream of high-throughput experimental data can give valuable clues for linking these unknowns with precise biological roles. The goal is to develop integrative data-mining platforms that allow the scientific community at large to access and utilize this rich source of experimental knowledge. To this end, we review recent advances in generating whole-genome experimental datasets, where this data can be accessed, and how it can be used to drive prediction of gene function. PMID- 21310503 TI - The genes underlying the process of speciation. AB - The long-standing goal of finding genes causing reproductive isolation is being achieved. To better link the genetics with the process of speciation, we propose that 'speciation gene' be defined as any gene contributing to the evolution of reproductive isolation. Characterizing a speciation gene involves establishing that the gene affects a component of reproductive isolation; demonstrating that divergence at the locus occurred before completion of speciation; and quantifying the effect size of the gene (i.e. the increase in total reproductive isolation caused by its divergence). Review of a sample of candidate speciation genes found that few meet these criteria. Improved characterization of speciation genes will clarify how numerous they are, their properties and how they affect genome-wide patterns of divergence. PMID- 21310504 TI - Characterization of fracture aperture field heterogeneity by electrical resistance measurement. AB - We use electrical resistance measurements to characterize the aperture field in a rough fracture. This is done by performing displacement experiments using two miscible fluids of different electrical resistivity and monitoring the time variation of the overall fracture resistance. Two fractures have been used: their complementary rough walls are identical but have different relative shear displacements which create "channel" or "barrier" structures in the aperture field, respectively parallel or perpendicular to the mean flow velocity U(->). In the "channel" geometry, the resistance displays an initial linear variation followed by a tail part which reflects the velocity contrast between slow and fast flow channels. In the "barrier" geometry, a change in the slope between two linear zones suggests the existence of domains of different characteristic aperture along the fracture. These variations are well reproduced analytically and numerically using simple flow models. For each geometry, we present then a data inversion procedure that allows one to extract the key features of the heterogeneity from the resistance measurement. PMID- 21310505 TI - A stress responsive alternative splicing mechanism in Citrus clementina leaves. AB - Chitinases are often considered pathogenesis-related proteins since their activity can be induced by viral infections, fungal and bacterial cell wall components, and also by more general sources of stress such as wounding, salicylic acid, ethylene, auxins and cytokinins. In the present study, comparative proteomic analysis showed the defense-related acidic chitinase II to be specifically induced in Citrus clementina leaves infested by the two-spotted spider mite Tetranychus urticae or treated with MeJA. In parallel, changes in the mRNA profiles of two partially homologous chitinase forms were shown by RT-PCR. In particular, the appearance of an additional cDNA chitinase fragment in T. urticae-infested and MeJA-treated leaves was observed. This finding may indicate a specific regulatory mechanism of chitinase expression. We report evidence for alternative splicing in T. urticae-infested C. clementina, where a premature stop codon after the first 135 amino acids was introduced. We observed inducible chitinase activity after MeJA treatment, indicative of a rapid plant response to infestation. This work provides the first evidence of chitinase alternative splicing in C. clementina. In addition, the presence of the dual-band pattern for chitinase cDNA by RT-PCR may represent a suitable predictive marker for early diagnosis of plant biotic stress. PMID- 21310506 TI - Identification of an amino acid residue required for differential recognition of a viral movement protein by the Tomato mosaic virus resistance gene Tm-2(2). AB - The Tm-2 gene of tomato and its allelic gene, Tm-2(2), confer resistance to Tomato mosaic virus (ToMV) and encode a member of the coiled-coil/nucleotide binding-ARC/leucine-rich repeat (LRR) protein class of plant resistance (R) genes. Despite exhibiting only four amino acid differences between the products of Tm-2 and Tm-2(2), Tm-2(2) confers resistance to ToMV mutant B7, whereas Tm-2 is broken by ToMV-B7. An Agrobacterium-mediated transient expression system was used to study the mechanism of differential recognition of the movement proteins (MPs), an avirulence factor for ToMV resistance, of ToMV-B7 by Tm-2 and Tm-2(2). Although resistance induced by Tm-2 and Tm-2(2) is not usually accompanied by hypersensitive response (HR), Tm-2 and Tm-2(2) induced HR-like cell death by co expression with MP of a wild-type ToMV, a strain that causes resistance for these R genes, and Tm-2(2) but not Tm-2 induced cell death with B7-MP in this system. Site-directed amino acid mutagenesis revealed that Tyr-767 in the LRR of Tm-2(2) is required for the specific recognition of the B7-MP. These results suggest that the Tyr residue in LRR contributes to the recognition of B7-MP, and that Tm-2 and Tm-2(2) are involved in HR cell death. PMID- 21310507 TI - Coping with the death of a patient in the emergency department. PMID- 21310508 TI - Acute childhood arterial ischemic and hemorrhagic stroke in the emergency department. AB - STUDY OBJECTIVE: Little is known about the presenting features of acute ischemic and hemorrhagic stroke in children presenting to the emergency department (ED). Yet, initial clinical assessment is a key step in the management pathway of stroke. We describe the presentation in the ED of children with confirmed acute ischemic and hemorrhagic stroke subtypes. METHODS: We conducted a retrospective descriptive case series of consecutive patients aged 1 month to younger than 18 years and presenting to a single-center tertiary ED with radiologically confirmed acute ischemic stroke or hemorrhagic stroke during a 5-year period. Patients were identified by medical record search with International Classification of Diseases, 10th Revision codes for hemorrhagic stroke and through the hospital stroke registry for acute ischemic stroke. Signs, symptoms, and initial management were described. RESULTS: Fifty patients with acute ischemic stroke and 31 with hemorrhagic stroke were identified. Mean age was 8.7 years (SD 5.2), and 51% were male. Fifty-six percent were previously healthy. Median time from onset of symptoms to ED presentation was 21 hours (interquartile range 6 to 48 hours) for acute ischemic stroke and 12 hours (interquartile range 4 to 72 hours) for hemorrhagic stroke. Acute ischemic stroke presented with symptoms of focal limb weakness (64%; 95% confidence interval [CI] 49% to 77%), facial weakness (60%; 95% CI 45% to 73%), and speech disturbance (46%; 95% CI 31% to 60%). Few patients with acute ischemic stroke presented with vomiting and altered mental status. Most patients with acute ischemic stroke had a Glasgow Coma Scale (GCS) score of 14 or greater (86%; 95% CI 73% to 94%) and presented with at least 1 focal neurologic sign (88%; 95% CI 73% to 98%). Hemorrhagic stroke presented with headache (73%; 95% CI 54% to 87%), vomiting (58%; 95% CI 40% to 75%), and altered mental status (48%; 95% CI 30% to 67%). GCS score in hemorrhagic stroke was less than 14 in 38% and less than 8 in 19% (95% CI 7% to 37%). Less than one third of patients had focal limb weakness, facial weakness, or slurred speech. Nineteen percent of patients with hemorrhagic stroke were intubated in the ED and admitted to the ICU. None of the acute ischemic stroke patients were intubated in the ED, and 4% were admitted to the ICU. CONCLUSION: Diagnosis of stroke in children with acute ischemic stroke and hemorrhagic stroke was delayed. Acute ischemic stroke presented mainly with focal findings; hemorrhagic stroke, with headache, vomiting, and mental status change. PMID- 21310510 TI - Implications of conducting trend analyses of emergency department visits using publicly released masked design variables. AB - STUDY OBJECTIVE: We examine whether using public National Hospital Ambulatory Medical Care Survey (NHAMCS) data with masked design variables produces different estimates, standard errors, and confidence intervals (CIs) for the temporal trend of overall and injury-related emergency department (ED) visits compared with using unmasked data housed at the Centers for Disease Control and Prevention. METHODS: We obtained counts of ED visits with their standard errors for unmasked data from published summaries from 1999 through 2006. Public files with masked design variables were used to estimate visit counts and rates with standard errors for each year, using the Taylor series linearization method. Weighted least squares linear regressions were used for trend analysis to estimate the annual change in visits. RESULTS: Compared with using unmasked data, using masked data produced similar estimates of overall ED visit counts and rates for each year from 1999 through 2006 but overestimated standard errors by 27% on average (range 12% to 45%). According to unmasked data, overall ED visit counts increased by 1.973 million annually (standard error 0.747; 95% CI 0.505 to 3.440 million [corrected] ). With masked data, the estimated change was 1.977 million visits annually (standard error 0.894; 95% CI -0.221 to 3.733 million [corrected] ). As for injury-related ED visit counts, masked data overestimated the standard error by 16% for trend. Although neither unmasked nor masked data suggested a statistically significant annual increase of overall or injury-related ED visit rate, masked data overestimated the standard error by 16%. CONCLUSION: Using masked public data overestimated standard errors for trend of counts and rates for overall and injury-related ED visits and resulted in wider CIs. PMID- 21310509 TI - Use of a beta-hCG discriminatory zone with bedside pelvic ultrasonography. AB - STUDY OBJECTIVE: We seek to assess the performance of the beta human chorionic gonadotropin (beta-hCG) "discriminatory zone" when using bedside pelvic ultrasonography in the evaluation of symptomatic pregnant emergency department (ED) patients. METHODS: This was a cross-sectional study of bedside pelvic ultrasonography performed on consecutive pregnant patients in the first trimester who presented to the ED with abdominal pain or vaginal bleeding. Patients received pelvic ultrasonography, serum beta-hCG testing, and blinded formal radiologic ultrasonography. All patients were followed for 8 weeks to determine outcomes. The sensitivity and specificity of a discriminatory beta-hCG level of 3,000 mIU/mL for the diagnosis of ectopic pregnancy were calculated for patients without an intrauterine pregnancy visualized by bedside ultrasonography. RESULTS: Thirty-six faculty physicians performed bedside pelvic ultrasonography on 256 patients. There were 161 cases with a confirmed visualizable intrauterine pregnancy and 29 ectopic pregnancies. Bedside ultrasonography identified 115 intrauterine pregnancies. The range of beta-hCG for cases of confirmed visualizable intrauterine pregnancy with a nondiagnostic bedside ultrasonography was 15 mIU/mL to 123,368 mIU/mL (median 6,633; interquartile range 1,551 to 32,699). For patients with nondiagnostic bedside ultrasonography, using a discriminatory beta-hCG level of 3,000 mIU/mL to further assess for ectopic pregnancy showed sensitivity of 35% (95% confidence interval [CI] 18% to 54%) and specificity of 58% (95% CI 48% to 67%). Finally, the overall sensitivity of bedside pelvic ultrasonography for the detection of intrauterine pregnancy was 71% (95% CI 63% to 78%), and the specificity was 99% (95% CI 94% to 100%). CONCLUSION: When bedside pelvic ultrasonography does not demonstrate an intrauterine pregnancy, serum beta-hCG level is not helpful in differentiating intrauterine from ectopic pregnancy in symptomatic ED patients. PMID- 21310511 TI - [Variability in HIV viral tropism determination using different genotypic algorithms in patients infected with B versus non-B HIV-1 subtypes]. AB - BACKGROUND: Genotypic tools based on the analysis of the V3 region are seen as an alternative to phenotypic assays for viral tropism determination before prescribing maraviroc. The concordance between different genotypic algorithms has been evaluated in HIV+ patients infected with B versus non-B subtypes. METHODS: HIV-infected patients on regular follow up at Hospital Universitario de Santiago de Compostela (Spain) were selected. The env-V3 region was sequenced from plasma samples and viral tropism was estimated using 8 different genotypic algorithms. Concordance among predictors was statistically evaluated by the calculation of the kappa index. Phylogenetic analyses were performed to determine the genetic subtype. RESULTS: A total of 92 HIV-infected patients were selected, 72 B and 20 non-B subtypes. Regarding the B subtype group, significant kappa values were obtained among all 28 possible combinations between the genotypic predictors evaluated. The best concordance among non-related predictors was observed for webPSSM(SINSI)/Wetcat(PART) (k: 0.771) and webPSSM(SINSI)/geno2pheno (k: 0.574). Conversely, among non-B subtypes, a significative kappa index was only obtained for 13 combinations. Among non-B subtypes, the best concordance values were obtained for webPSSM(X4R5)/Wetcat(PART) (k: 0.600) and webPSSM(SINSI)/Charge rule (k: 0.590). CONCLUSION: A high concordance was observed between different genotypic algorithms to determine viral tropism among HIV-1 B subtypes infected patients, especially between webPSSM(SINSI) and geno2pheno or Wetcat. Conversely, the overall concordance among non-B subtypes was lower. This heterogeneity could be justified by the low prevalence of non B subtypes in the datasets in which the genotypic tropism predictors were trained. PMID- 21310512 TI - [Microbiological diagnosis of urinary tract infections]. AB - For the diagnosis of urinary tract infection (UTI), besides the quantification of bacteria in the urine, cellular elements contained in the urine, the collection method used and the clinical syndrome should also be considered. Therefore, the microbiological diagnosis of UTI should be performed by an experienced person who takes into account the diversity of situations that may influence the result of each of the cultures. The processing of urine samples depends on the number of samples received daily. In laboratories with a high number, it is impossible to culture each of them, so negative urines have to be ruled out by using automated systems and cultivate only those that are positive. This review includes an analysis of the methods currently available for this screening. It also includes procedures to be performed in special situations such as prostatitis, UTI caused by fastidious microorganisms and other kind of infections that may be diagnosed in a urine test. PMID- 21310513 TI - Pre-registration paid employment choice: the views of newly qualified nurses. AB - In Australia, nurse education was transferred from hospital based nursing schools to the higher education sector. This transfer resulted in a change for students, from hospital employee to an unpaid, supernumerary role during professional placements. The majority of undergraduate nursing students now combine part time employment with their studies, working mainly within health settings or service sectors such as hospitality and retail. The aims of this study were to identify if newly qualified registered nurses engaged in paid employment during their final year of undergraduate studies, the types of employment they chose, reasons for that choice, skills acquired and their views on any link between employment choice and transition to practice. Focus group interviews involving sixty seven new graduates were conducted. From the data, four organising themes were identified; financial independence and autonomy, confidence and experience, future opportunity and ease of transition. The global theme maximising opportunity describes nurse's views about their decisions on student employment. Participants had differing views on employment choice and transition to practice. Further research is needed in the area to identify whether there is any link between student employment choice and transition to practice. PMID- 21310514 TI - Effects of lateral cortical anchorage on the primary stability of implants subjected to controlled loads: an in vitro study. AB - Our aim was to evaluate the effects of lateral cortical anchorage on the primary stability of implants subjected to immediate loading. Implants were placed into bovine bones with monocortical anchorage (implant placed through the cortical bone of the crest) and bicortical anchorage (the crest cortical bone plus one cortical bone on the lateral side). Loads of 25N and 50N were applied to the implants in different cycles. The implant stability quotient (ISQ) was measured before and after the cyclic loadings. Under 25N load there was no difference in ISQ between 1800 cyclic loading and preloading, but the values decreased significantly after 3600 cyclic loading in both groups (p<0.05). Under a 50N load the ISQ value after 1800 and 3600 cyclic loading decreased in the monocortical group (p<0.05), but there was no difference between 1800 cyclic loading and preloading in the bicortical group, and the ISQ in the bicortical group was higher than in the monocortical group after 1800 cyclic loading (p<0.05). Our results suggest that the stability of implants with bicortical anchorage decreased more slowly under higher loads. PMID- 21310515 TI - Oral health and pathology: a macrophage account. AB - Macrophages are present in healthy oral mucosa and their numbers increase dramatically during disease. They can exhibit a diverse range of phenotypes characterised as a functional spectrum from pro-inflammatory to anti-inflammatory (regulatory) subsets. This review illustrates the role of these subsets in the oral inflammatory disease lichen planus, and the immunosuppressive disease oral squamous cell carcinoma (SCC). We conclude that the role of macrophages in driving progression in oral disease identifies them as potential therapeutic targets for a range of oral pathologies. PMID- 21310516 TI - Arsenic strongly associates with ferrihydrite colloids formed in a soil effluent. AB - Arsenic mobility may increase in liquid phase due to association with colloidal Fe oxides. We studied the association of As with Fe oxide colloids in the effluent from water-saturated soil columns run under anoxic conditions. Upon exfiltration, the solutions, which contained Fe2+, were re-aerated and ferrihydrite colloids precipitated. The entire amount of effluent As was associated with the ferrihydrite colloids, although PO4(3-), SiO4(4-), CO3(2-) and dissolved organic matter were present in the effluent during ferrihydrite colloid formation. Furthermore, no subsequent release of As from the ferrihydrite colloids was observed despite the presence of these (in)organic species known to compete with As for adsorption on Fe oxides. Arsenic was bound via inner-sphere complexation on the ferrihydrite surface. FTIR spectroscopy also revealed adsorption of PO4(3-) and polymerized silica. However, these species could not impede the quantitative association of As with colloidal ferrihydrite in the soil effluents. PMID- 21310517 TI - Identification of perfluoroalkyl acid sources in Swiss surface waters with the help of the artificial sweetener acesulfame. AB - Anthropogenic perfluorinated compounds (PFCs), especially the perfluoroalkyl acids (PFAAs) are ubiquitously found in surface waters around the globe. Emissions from households, industries and also atmospheric transport/deposition are discussed as the possible sources. In this study, these sources are evaluated using Switzerland as the study area. Forty-four surface water locations in different rivers and an Alpine lake were investigated for 14 PFAAs, four precursors and acesulfame, an artificial sweetener used as a population marker. Concentrations of individual PFAAs were generally low, between 0.02 and 10 ng/L. Correlation analysis showed that some PFAAs concentrations correlated well with population and less with catchment area, indicating that emissions from population, i.e., from consumer products, is the most important source to surface waters in Switzerland. The correlation with the population marker acesulfame confirmed this observation but highlighted also a few elevated PFAA levels, some of which could be attributed to industrial emissions. PMID- 21310518 TI - Effects of canopy-deposition interaction on H+ supply to soils in Pinus banksiana and Populus tremuloides ecosystems in the Athabasca oil sands region in Alberta, Canada. AB - Soil acidification has been of concern in the oil sands region in Alberta due to increased acid deposition. Using the canopy budget model, and accounting for H(+) canopy leaching by organic acids, we determined sources and sinks of H+ in throughfall in jack pine (Pinus banksiana) and trembling aspen (Populus tremuloides) stands in two watersheds from 2006 to 2009. In pine stands, H+ deposition was greater in throughfall than in bulk precipitation while the opposite was true in aspen stands. The annual H+ interception deposition was 148.8-193.8 and 49.7-70.0 molcha(-1) in pine and aspen stands, respectively; while the annual H+ canopy leaching was 127.1-128.7 and 0.0-6.0 molcha(-1), respectively. The greater H+ supply in pine stands was caused by greater interception deposition of SO4(2-) and organic acids released from the pine canopy. Such findings have significant implications for establishing critical loads for various ecosystems in the oil sands region. PMID- 21310519 TI - Promoting medical tourism to India: messages, images, and the marketing of international patient travel. AB - The practice of medical tourism depends on successfully informing potential patients about procedure options, treatment facilities, tourism opportunities, travel arrangements, and destination countries. The promotion of medical tourism includes a wide range of marketing materials such as flyers, booklets, and websites. Yet, there is a paucity of knowledge about the dissemination, content, and reception of these promotional materials. Drawing on a thematic content analysis of the promotional print material distributed at the first medical tourism trade show in Canada in 2009, the main purpose of this article is to identify and understand the messages and images that companies use to market India as a global destination. While researchers and news media frequently cite low cost procedures as a key determinant for international patient travel, particularly to developing nations, our analysis reveals few low cost-related images or messages in the promotional materials distributed at the trade show. To help explain this surprising disjuncture, we consider four related issues: (1) promotional materials may be designed to be circulated amongst potential patients' concerned family and friends who privilege knowing about things such as the use of advanced technologies; (2) developing nations need to portray safe and advanced treatment facilities in order to dispel potential patients' suspicions that their medical care is inferior; (3) companies may avoid making cost saving claims that cannot be fulfilled for all of their international patients, especially those traveling from developing nations; and (4) messages of low cost may detract from and even undermine messages about quality. We conclude by identifying numerous avenues for future research by social and health scientists, and by considering the implications of our findings for existing knowledge gaps and debates within health geography specifically. PMID- 21310520 TI - Repeated daclizumab administration to delay the introduction of calcineurin inhibitors in heart transplant patients with postoperative renal dysfunction. AB - Daclizumab is an interleukin-2 receptor antagonist which is used for induction therapy in heart transplant patients. It has few side effects and is associated with a low infection rate. Postoperative renal failure after heart transplantation is common and potentially fatal. The administration of calcineurin inhibitors in the postoperative period can aggravate the situation. We report the cases of six patients who underwent heart transplantation and developed acute renal failure in the immediate postoperative period. All were administered daclizumab weekly to avoid the introduction of calcineurin inhibitors and to facilitate recovery of renal function. Calcineurin inhibitors were introduced only once renal function had improved. Renal function recovered in all cases and there was a low complication rate. The administration of repeated doses of daclizumab to patients who experience acute postoperative renal failure after heart transplantation may provide an alternative therapeutic approach that enables calcineurin inhibitors to be avoided and, consequently, renal function to recover. PMID- 21310521 TI - Toddler parents training, understanding, and perceptions of CPR. AB - BACKGROUND: Little is known about parent CPR skills and their perceptions of its use, especially in the context of drowning incidents among young children where parents are often the first responder. The primary objective of the study was to examine parental understanding of child and adult CPR, extent of CPR training, and parental confidence to perform CPR. METHOD: Survey research using a self complete questionnaire was used to gather data from parents (n = 1716) whose 2-4 year-old toddlers were either attending early childhood centres (n = 781) or enrolled in swim schools (n = 935). Differences in parental CPR training, knowledge, levels of confidence in ability to perform CPR, and perceptions were measured by frequency, with regression tests used to discern differences by institution, gender, ethnicity, length of residency, and recency of CPR training. RESULTS: Almost two-thirds (64%) of parents reported that they had received formal CPR training in the past, yet few correctly reported the current ratios for either adult CPR (19%) or child CPR (12%). Most parents correctly agreed that, in child CPR, you must always give initial breaths before starting compressions (74%), but the majority incorrectly believed you should seek help before starting CPR (61%) and continue CPR for 5 min before stopping (59%). Most parents (56%) felt anxious about their ability to perform CPR on an adult, and even more (62%) felt anxious about their ability to perform child CPR. CONCLUSION: Our findings highlight the need for education interventions to address the substantial gaps in knowledge of CPR for all parents of young children. PMID- 21310522 TI - Dialectics, systems biology and embryonic induction. AB - A hallmark of embryonic development is the temporal-spatial continuum of cell cell interactions, which gives rise to the trajectory of progressive cell differentiations. Despite the great reductionists' success in dissecting the mechanistic basis of developmental processes, the call for more holistic system theories never ceased during the last century. Various system theories were proposed to provide a more adequate understanding of biological systems, including development. Although widely ignored by modern biology, the first systematic system theory was Hegel's dialectics. Here I examine the process of embryonic induction as elaborated by Hans Spemann in the light of dialectics. I conclude that embryonic induction and its underlying molecular mechanisms can be re-interpreted in terms of Hegel's dialectics. The example highlights that despite its shortcomings, dialectics can be of heuristic value as a theory of systems biology. PMID- 21310523 TI - Application of a value-based equivalency method to assess environmental damage compensation under the European Environmental Liability Directive. AB - The Environmental Liability Directive (ELD) establishes a framework of liability based on the 'polluter-pays' principle to prevent and remedy environmental damage. The ELD requires the testing of appropriate equivalency methods to assess the scale of compensatory measures needed to offset damage. The aim of this paper is to contribute to fill the existing knowledge gap on the application of the value equivalency approach for damage compensation in this context. We analyze the toxic spill damaging the Donana National Park (Spain) in 1998. The welfare losses associated with the resource damage are estimated using non-market valuation and compared to the value of the compensatory measures taken after the accident. Our results show that the in-kind compensation may have been insufficient to offset the welfare losses. We conclude that a more comprehensive knowledge of the human welfare effects caused by environmental damage is of substantial importance to determine compensatory remediation, as insufficient information in this respect can lead to erroneous decisions causing loss to society. PMID- 21310524 TI - Allocation of supplementary aeration stations in the Chicago waterway system for dissolved oxygen improvement. AB - The Chicago Waterway System (CWS), used mainly for commercial and recreational navigation and for urban drainage, is a 122.8 km branching network of navigable waterways controlled by hydraulic structures. The CWS receives pollutant loads from 3 of the largest wastewater treatment plants in the world, nearly 240 gravity Combined Sewer Overflows (CSO), 3 CSO pumping stations, direct diversions from Lake Michigan, and eleven tributary streams or drainage areas. Even though treatment plant effluent concentrations meet the applicable standards and most reaches of the CWS meet the applicable water quality standards, Dissolved Oxygen (DO) standards are not met in the CWS during some periods. A Use Attainability Analysis was initiated to evaluate what water quality standards can be achieved in the CWS. The UAA team identified several DO improvement alternatives including new supplementary aeration stations. Because of the dynamic nature of the CWS, the DUFLOW model that is capable of simulating hydraulics and water quality processes under unsteady-flow conditions was used to evaluate the effectiveness of new supplementary aeration stations. This paper details the use of the DUFLOW model to size and locate supplementary aeration stations. In order to determine the size and location of supplemental aeration stations, 90% compliance with a 5 mg/l DO standard was used as a planning target. The simulations showed that a total of four new supplementary aeration stations with oxygen supply capacities ranging from 30 to 80 g/s would be sufficient to meet the proposed target DO concentration for the North Branch and South Branch of the Chicago River. There are several aeration technologies, two of which are already being used in the CWS, available and the UAA team determined that the total capital costs of the alternatives range from $35.5 to $89.9 million with annual operations and maintenance costs ranging from $554,000 to $2.14 million. Supplemental aeration stations have been shown to be a potentially effective means to improve DO concentrations in the CWS and will be included in developing an integrated strategy for improving water quality in the CWS. PMID- 21310525 TI - A systematic review and meta-analysis of the relationship between hospital/surgeon volume and outcome for radical cystectomy: an update for the ongoing debate. AB - CONTEXT: There is an ongoing debate about centralisation of radical cystectomy (RC) procedures. OBJECTIVE: To conduct a systematic review of the literature on the volume-outcome relationship for RC for bladder cancer (BCa) with consideration for the methodologic quality of the available evidence and to perform a meta-analysis on the studies meeting predefined quality criteria. EVIDENCE ACQUISITION: A systematic search was performed to identify all articles examining the effects of procedure volume on clinical outcome for cystectomy. Reviews, opinion articles, and surveys were excluded. All articles were critically appraised for methodologic quality and risk of bias. Meta-analysis was performed to calculate the overall effect of higher surgeon or hospital volume on patient outcome. EVIDENCE SYNTHESIS: Ten studies of good methodologic quality were included for meta-analysis. Eight studies were based on administrative data, two studies on clinical data. The results showed a significant association between high-volume hospitals and low mortality. A meta-analysis of the seven studies on hospital mortality showed a pooled estimated effect of odds ratio (OR) 0.55 (range: 0.44-0.69). The result was moderate heterogeneity (I(2)=50). A large variation in cut-off points used was observed. Sensitivity analyses did not show different effects in any of the subgroup analyses. Also, no significant differences in effect sizes were observed for different cut-off points. The data were not suggestive for publication bias. One study showed a positive effect of hospital volume on survival (hazard ratio [HR]: 0.89; p=0.06). Two studies showed a beneficial effect of surgeon volume on mortality (OR: 0.55; OR: 0.64). Only one study on the impact of surgeon volume on survival was found; it showed no significant positive effect for higher volume (HR: 0.83; p=0.26). CONCLUSIONS: Postoperative mortality after cystectomy is significantly inversely associated with high-volume providers. However, additional quality criteria, such as infrastructure and level of specialisation, should be formulated to direct centralisation initiatives. The Dutch Association of Urology in 2010 implemented a national quality of care (QoC) registration programme for all patients treated by surgery for muscle-invasive BCa, including multiple parameters defining QoC. PMID- 21310526 TI - MicroRNA-542-5p as a novel tumor suppressor in neuroblastoma. AB - Several studies have implicated the dysregulation of microRNAs in neuroblastoma pathogenesis, an often fatal paediatric cancer arising from precursor cells of the sympathetic nervous system. Our group and others have demonstrated that lower expression of miR-542-5p is highly associated with poor patient survival, indicating a potential tumor suppressive function. Here, we demonstrate that ectopic over-expression of this miRNA decreases the invasive potential of neuroblastoma cell lines in vitro, along with primary tumor growth and metastases in an orthotopic mouse xenograft model, providing the first functional evidence for the involvement of miR-542-5p as a tumor suppressor in any type of cancer. PMID- 21310527 TI - UCH-L1 promotes cancer metastasis in prostate cancer cells through EMT induction. AB - Ubiquitin C-terminal hydrolse-L1 (UCH-L1) is a deubiquitinating enzyme (DUB) that cleaves the ubiquitin (ub) moiety from ub precursors or protein substrates. The correlation between UCH-L1 and cancer has been reported in various tissues, but the role of UCH-L1 in prostate cancer has not been thoroughly researched. Here we found that UCH-L1 is specifically highly expressed in the metastatic DU145 prostate cancer cell line, but not in the benign or weakly metastatic prostate cancer cells. To determine the role of UCH-L1 in prostate cancer metastasis, we constructed UCH-L1-knockdown DU145 and UCH-L1 or the active site mutant form of UCH-L1 (UCH-L1 C90S) expressing RWPE1 stable cells. Notably, the expression of UCH-L1 in RWPE1 cells promotes epithelial-to-mesenchymal transition (EMT), and this is an important process for cancer cell invasion and metastasis. On the contrary, knockdown of UCH-L1 in DU145 cells induces MET, the reverse program of EMT. Furthermore, the change of EMT status caused by altering the UCH-L1 level affects the migration and invasiveness of prostate cancer cells. Our results indicate that UCH-L1 promotes prostate cancer metastasis through EMT induction and UCH-L1 could be a novel diagnostic and therapeutic target for prostate cancer treatment. PMID- 21310528 TI - Ovarian cancer-associated fibroblasts contribute to epithelial ovarian carcinoma metastasis by promoting angiogenesis, lymphangiogenesis and tumor cell invasion. AB - Cancer-associated fibroblasts (CAFs) are thought to play an essential role in cancer initiation and development. However, little research has been done to evaluate the role of CAFs in epithelial ovarian cancer (EOC) development. To address this issue, ninety-one specimens were immunostained with alpha-smooth muscle actin (alpha-SMA) and fibroblast activation protein (FAP) antibodies to quantify CAFs, and antibodies D2-40 and CD34 to evaluate the lymphatic vessel density (LVD) and microvessel density (MVD) of the lesions. We found there were no alpha-SMA or FAP positive fibroblasts in normal ovary tissues. More CAFs were found in EOC than in borderline tumors and benign tumors (P<0.01). Abundant CAFs in EOC were associated with advanced-stage disease (P=0.002), the occurrence of lymph node metastases (P=0.02) and omentum metastases (P<0.0001), and increased LVD (P=0.002) and MVD (P=0.0004). CAFs isolated from EOC tissues induced more cancer cells to invade (P=0.003) and migrate (P=0.005) compared with normal fibroblasts (NFs) isolated from normal ovary tissues in vitro. Our data indicate that CAFs play a vital role in ovarian cancer progression and metastasis. Targeting CAFs as a therapeutic strategy against ovarian cancer is an intriguing concept that needs further study. PMID- 21310529 TI - Effect of shear force, solution pH and breakage period on characteristics of flocs formed by Titanium tetrachloride (TiCl4) and Polyaluminum chloride (PACl) with surface water treatment. AB - The growth, breakage and regrowth nature of flocs formed by Titanium tetrachloride (TiCl(4)) and polyaluminum chloride (PACl) was comparatively evaluated with surface water treatment. A series of jar experiments were conducted to investigate the impacts of different operating parameters such as shear force, solution pH and a breakage period on floc strength and re aggregation potential. Results indicated that the responses of flocs to different operating parameters depend on the coagulant used. The ability of floc to resist breakage decreased with the increase of shear force and breakage period. Floc strength properties were also measured in response to increasing shear force, with the results suggesting that the order of floc strength was TiCl(4)>PACl. Floc regrowth of the two coagulants after exposure to high shear was limited, and flocs formed by TiCl(4) displayed weaker recoverability. The flocs generated in acid conditions were more recoverable than those generated in alkaline conditions no matter which coagulant was used. PMID- 21310530 TI - Being present: the role of narrative medicine in reducing the unequal burden of pain. PMID- 21310532 TI - Current prevalence of Dirofilaria immitis in dogs, cats and humans from the island of Gran Canaria, Spain. AB - The island of Gran Canaria is a hyperendemic area for canine dirofilariasis. The aim of the present study was to provide data on Dirofilaria immitis in dogs, cats, and humans on this island in 2010. The data confirms the prevalence in the overall canine population (19%), with a considerably higher prevalence (43%) in the autochthonous breed of Canarian Warren hound. The prevalence in the feline population (33%) is higher than that of the canine population, and the existence of specific D. immitis antibodies in the inhabitants of the island of Gran Canaria (12%) is confirmed. In both cats and humans, the prevalence, according to the different climate areas on the island, is related to the prevalence of D. immitis in dogs in the same area, which shows the key epidemiological role played by the canine host with regard to the transmission to other hosts of D. immitis. PMID- 21310533 TI - Attributes, knowledge, beliefs, and behaviors relating to prevention of heartworm in dogs among members of a national hunting dog club. AB - The Food and Drug Administration Center for Veterinary Medicine (FDA/CVM) has cited an increasing number of reports of failure of heartworm prophylaxis in dogs. Failures may be due to resistance of L(3)-L(4) stage Dirofilaria immitis to the macrocyclic lactone class of compounds used for prophylaxis, lack of compliance with and understanding of administration of prophylactics, individual differences in drug absorption or metabolism, or a combination of these factors. Using the latest scientific information, the American Heartworm Society (AHS) and Companion Animal Parasite Council (CAPC) have developed guidelines for the diagnosis, prevention, and treatment of heartworm infection in dogs. This study summarizes the knowledge, beliefs, and behaviors relating to prevention of heartworm among members of a national hunting dog club, visitors to the club website, and attendees at club-sponsored events. These factors can have a direct effect on the success of heartworm prophylaxis. Results suggest that the dog owners lack confidence in the accuracy of the heartworm test to identify infection, the efficacy of products sold for prevention of heartworm, and the effectiveness of treatment to eliminate adult heartworms from infected dogs. Knowledge about when to begin heartworm preventive medication in a new puppy and the timing of heartworm tests was also lacking among a substantial number of respondents. In order to increase acceptance of prophylaxis and reduce the likelihood of a false conclusion of prophylactic failure, education of dog owners should focus on the need for an appropriately timed annual heartworm test and the importance of administering the last dose of monthly heartworm preventative after the last possible day of potential transmission. PMID- 21310534 TI - Genetic polymorphism in Dirofilaria immitis. AB - Dirofilaria immitis is the causative agent of heartworm disease. Reports of macrocyclic lactone inefficacy prompted an investigation of genetic polymorphism in D. immitis. Currently, there is a lack of genetic information for this parasite. Information on baseline levels of genetic heterogeneity in the dog heartworm would have important implications for the possible development of macrocyclic lactone resistance in D. immitis. Genetic variability was investigated to assess the extent of genetic polymorphism in D. immitis populations from the USA (field and laboratory samples) and Japan (field samples). Single nucleotide polymorphisms (SNPs) were investigated in a full length beta-tubulin gene and segments of genes encoding heat shock protein 60 (Hsp60), a P-glycoprotein (Pgp), sarco-endoplasmic reticulum Ca(2+)ATPase (Serca) and phosphofructokinase (PFK). Significant differences in SNP frequencies were found in all genes except PFK. A combined genotype built from two SNPs from beta tubulin, Hsp60, Pgp and Serca was analyzed in the US lab, US field and Japan field samples. Some combined genotypes were unique to each sample group while others were shared between groups. F coefficients calculated for 15 SNPs from beta-tubulin, Hsp60, Pgp and Serca were not in equilibrium. Differences in F coefficients were observed between the groups. D. immitis was found to be genetically heterogeneous. This genetic heterogeneity has implication for the development of genetically selected strains of the parasite. PMID- 21310535 TI - Dirofilaria immitis infection in dogs: cardiopulmonary biomarker levels. AB - Cardiopulmonary biomarkers are biological parameters that can be objectively measured and quantified as indicators of pathogenic processes (heartworm disease) or as indicators of response to therapeutic intervention. To determine levels of cardiopulmonary biomarkers in canine dirofilariasis, measurements of cardiac troponin T, cardiac troponin I, myoglobin, and D-dimer concentrations were performed for dogs with and without evidence of adult heartworm infection. The results showed that levels of cardiac troponin T were undetectable in all dogs studied while levels of cardiac troponin I were higher in dogs infected with Dirofilaria immitis. In healthy dogs, levels of myoglobin and D-dimer were below detection limits of the instrument and were significantly higher in heartworm infected dogs, notably in microfilaremic dogs. The results suggest the possibility of using troponin I and myoglobin as markers for cardiac damage and the D-dimer as a supportive tool for a diagnosis of pulmonary thromboembolism in dogs with cardiopulmonary dirofilariasis. PMID- 21310536 TI - Molecular discrimination of sheep and cattle isolates of Echinococcus granulosus by SSCP and conventional PCR in Turkey. AB - Cystic echinococcosis (CE), caused by hydatid cysts, is a widespread and hazardous disease in humans and animals worldwide. The aim of the current study was to investigate the genetic characteristics of sheep and cattle isolates of Echinococcus granulosus obtained from eastern Turkey using Single Stranded Conformation Polymorphism (SSCP) analysis and conventional PCR method. A total of 54 isolates collected from Erzurum and Elazig provinces of east-Turkey were examined. The 31 of these were obtained from liver of sheep while 23 cattle isolates (12 of liver and 11 of lung) were tested. After the total genomic DNA isolation 12S rRNA gene of all isolates were examined by PCR for the aim of genetic characterization by conventional PCR and mitochondrial CO1 gene for SSCP analysis. The 12S rRNA-PCR yielded 254 bp of amplification product with all samples analyzed. Thus, these samples were identified as G1-G3 cluster (E. granulosus sensu stricto). At least two major single stranded bands were resolved for G1-G3 cluster and G5 in SSCP analysis. While the resolution of more than two additional single stranded bands in SSCP indicated the existence of G7 genotype. The SSCP analysis was identified the G5 and G7 while failed to G1 and G3. The present SSCP analysis classified all 54 cyst isolates from sheep and cattle as E. granulosus sensu stricto (G1-G3 cluster). However, some sequenced samples for G1 and G3 showed the same band patterns by SSCP. PMID- 21310537 TI - Canine angiostrongylosis: the French heartworm: an emerging threat in North America. AB - Angiostrongylus vasorum, French heartworm, is a metastrongloid parasite found in the pulmonary arteries and right ventricle of wild and domestic canids and various other animals. The natural definitive hosts are species of foxes. The geographic distribution of the parasite includes various countries of Europe, Africa, South America, and North America. Angiostrongylosis is considered an emerging disease in dogs in Europe. In North America, autochthonous A. vasorum infection occurs only in the Canadian province of Newfoundland-Labrador. Computer modeling suggests there is a high probability that A. vasorum will spread to other parts of North America and will likely become endemic in the eastern half of the continent and in the states and provinces along the western coast. Animals acquire infection by the ingestion of gastropod or frog intermediate hosts that carry the infective 3rd-stage larvae. Frogs can also serve as paratenic hosts. Definitive antemortem diagnosis is by detection of L(1) in feces, sputum, or bronchoalveolar lavage samples. Baermann fecal examination is the most reliable method for fecal detection. However, false negative results can occur due to the typical erratic/sporadic fecal larval shedding pattern of A. vasorum. Recently, promising new methods for A. vasorum infection diagnosis have been reported involving polymerase chain reaction of blood and fecal samples and a sandwich ELISA for detection of circulating worm excretory/secretory antigen. Current treatment options include moxidectin, milbemycin oxime, and fenbendazole. PMID- 21310538 TI - Exploring the life cycle of Besnoitia besnoiti - experimental infection of putative definitive and intermediate host species. AB - The biology of Besnoitia besnoiti, the cause of bovine besnoitiosis, is poorly understood. Its definitive host is unknown, and information on potential intermediate hosts is scarce. In order to investigate potential definitive and intermediate hosts for European isolates of B. besnoiti, domestic dogs, cats, rabbits, guinea pigs (Cavia porcellus), gerbils (Meriones unguiculatus), common voles (Microtus arvalis) and NMRI-mice were inoculated with B. besnoiti isolated from naturally infected German cattle. Dogs and cats were fed 5*10(6)B. besnoiti tachyzoites (isolate Bb-GER1), or tissue cysts containing at least 2*10(7)B. besnoiti bradyzoites obtained from the skin of a naturally infected Limousin cow from the same herd where strain Bb-GER1 was isolated. Rodents and rabbits were subcutaneously inoculated with either 5*10(5) Bb-GER1 tachyzoites or 5*10(5) bradyzoites. Groups of 2-4 non-inoculated animals of each species were monitored as negative controls. Feces from all dogs and cats were daily examined by a sedimentation-flotation technique for at least 11 weeks after inoculation but no B. besnoiti oocysts were identified. Cats fed tachyzoites and dogs did not seroconvert, but specific antibodies to B. besnoiti tachyzoites were detected by IFAT (titer>=100) in 2 out of 3 cats fed tissue cysts since 5-7 weeks post infection. By immunoblot, these two cats exhibited a reaction pattern against tachyzoite antigens similar to that observed in naturally infected cattle. Antibodies against B. besnoiti tachyzoites were detected in all inoculated rodent species and rabbits by both, IFAT and immunoblot since 3 weeks post-inoculation. Rabbits and rodents, subcutaneously inoculated with same doses of inactivated bradyzoites remained serologically negative (IFAT titer<50). Clinical signs observed in the inoculated rabbits included fever, serous conjunctivitis and transient swelling of the testes. No clinical abnormalities were noticed in the other tested animal species. Voles developed pneumonia as observed by histological examination. B. besnoiti-DNA was detected by PCR in blood from rabbits, gerbils and voles at 9 days post-infection, and in skin, heart, lung, striated muscle and kidney tissues from voles at 19-21 weeks post-infection. Domestic dogs and cats could not be shown to be definitive hosts of B. besnoiti, but cats seroconverted after feeding on B. besnoiti tissue cysts indicating that B. besnoiti stages had invaded the cats' tissues. The molecular and serological results from this study indicate that European B. besnoiti isolates may infect cats, rabbits, guinea pigs, gerbils, mice and voles; however a persistence of the parasite could be demonstrated only in voles. PMID- 21310539 TI - Examining the effect of the Life Enhancement Treatment for Substance Use (LETS ACT) on residential substance abuse treatment retention. AB - Effective, parsimonious behavioral interventions that target reinforcement are needed for substance users with depression to improve mood as well as treatment retention. The Life Enhancement Treatment for Substance Use (LETS ACT; Daughters et al., 2008) is a behavioral activation-based approach tailored to increase levels of positive reinforcement among depressed substance users while in substance abuse treatment. The current study tested the efficacy of LETS ACT compared to a contact-time matched control condition, supportive counseling (SC), examining effects on depressed mood, substance abuse treatment retention, and behavioral activation outcomes. Fifty-eight adult substance users in residential substance abuse treatment presenting with depressive symptoms (BDI>=12) were randomly assigned to LETS ACT or SC. Assessments were administered at pre- and post-treatment and included assessment of DSM-IV psychiatric diagnoses, depression severity, treatment motivation, overall activation, environmental reward, and substance abuse treatment retention. Patients in LETS ACT had significantly higher rates of substance abuse treatment retention and significantly greater increases in activation on the Behavioral Activation for Depression Scale (BADS) compared to those in SC. Both groups had decreased depression severity at post-treatment, although the group by time interaction was not significant. This study was the first to compare LETS ACT to a contact-time matched control treatment to evaluate effects on substance abuse treatment retention and two distinct measures of behavioral activation: overall activation and environmental reward. Findings suggest preliminary support for the feasibility, tolerability, and efficacy of a brief behavioral activation-based protocol that may be particularly useful to improve substance abuse treatment retention. PMID- 21310540 TI - The theory of planned behavior and binge drinking among undergraduate students: assessing the impact of habit strength. AB - The present study sought to apply the theory of planned behavior (TPB) to the prediction of binge drinking intentions and behavior among undergraduate students and to test whether habit strength explains additional variance in binge drinking behavior. Undergraduate students (N=137) completed measures of the TPB (i.e., attitude, subjective norm, self-efficacy, perceived control, and intention) and habit strength (Self-Report Habit Index) in relation to binge drinking. Frequency of binge drinking was assessed one month later (n=109). The TPB explained 75% of the variance in binge drinking intentions, with attitude and self-efficacy making significant contributions, and 35% of the variance in binge drinking behavior at one-month follow-up, with only intention making a significant contribution. Habit strength explained additional variance in binge drinking behavior (?R(2)=.06), although intention remained as a significant predictor. The results suggest that binge drinking among undergraduate students is under the control of both intentional and habitual processes. Interventions to reduce binge drinking should therefore focus on the motivational determinants (e.g., perceived positive and negative consequences) of binge drinking as well as the environmental factors (i.e., contextual cues) that promote binge drinking. PMID- 21310541 TI - Modifications of evidence-based practices in community-based addiction treatment organizations: a qualitative research study. AB - This qualitative research effort explored implementation of evidence-based practices (EBPs) in 100 community-based addiction treatment organizations (CBOs) nationwide. The study describes CBO program director attitudes on: (1) satisfaction with EBPs they were mandated to implement; (2) the extent to which their organization modified the EBPs; (3) reasons for modifications; and, (4) the standards they used for modifications. Findings indicate that program directors were highly positive both about EBPs implemented and the modifications made to those EBPs. A broad range of modifications were identified; most common were adding or deleting intervention sessions in efforts to serve the needs of a specific client population. Given the addiction treatment field's lack of standards for modifying EBPs, it is not surprising that little consistency occurred in modification efforts. As government funders of addiction treatments require that CBOs implement EBPs, standards need to be created for modifying and adapting the EBPs while maintaining their fidelity. PMID- 21310542 TI - Can vitamin D delay the progression of ALS? AB - The pathogenesis of amyotrophic lateral sclerosis (ALS) is multifactorial and a treatment targeting only one aspect of the disease is unlikely to be beneficial. Vitamin D is safe and may delay progression of ALS by acting on several aspects of the disease. In this article we explore how vitamin D may promote VGEF, IGF-1 and axonal regeneration delaying ALS progression. In addition, we discuss how vitamin D may increase calcium binding protein in motor neuron cells conferring a greater resistance to the underlying disease process, as seen in the oculomotor nerve and Onuf's nucleus. Finally, we discuss vitamin D immunomodulator role, decreasing the reactive gliosis in ALS. PMID- 21310543 TI - Monitoring intestinal microbiota profile: a promising method for the ultraearly detection of colorectal cancer. AB - Colorectal cancer is one of the most common cancers and is very hard to be detected at an ultraearly stage because of lack of valuable predicating methods that often lead to treatment failure. Intestinal microbiota has long been considered to implicate in colorectal cancer pathology; and many recent reports point out a close linkage between the intestinal bacteria and the genesis of the tumor. Present studies indicate that the structure and characteristics of the intestinal microbiota are significantly altered in colorectal cancer, precancerous lesion, and high risk population compared with healthy controls and low risk population. Based on the current studies and theories, we postulate monitoring the intestinal bacterial profile by the molecular methods that could fulfill the ultraearly prediction about the degree of the risk developing into colorectal cancer. Further population-based epidemiological study is useful to reveal the characteristics of the intestinal microbiota in ultraearly colorectal cancer, which might provide some novel prophylactic and therapeutic strategies for the colorectal cancer. PMID- 21310544 TI - Lack of radiation dose or quality dependence of epithelial-to-mesenchymal transition (EMT) mediated by transforming growth factor beta. AB - PURPOSE: Epithelial-to-mesenchymal transition (EMT) is a phenotype that alters cell morphology, disrupts morphogenesis, and increases motility. Our prior studies have shown that the progeny of human mammary epithelial cells (HMECs) irradiated with 2 Gy undergoes transforming growth factor beta (TGF-beta) mediated EMT. In this study we determined whether radiation dose or quality affected TGF-beta-mediated EMT. METHODS AND MATERIALS: HMECs were cultured on tissue culture plastic or in Matrigel (BD Biosciences, San Jose, CA) and exposed to low or high linear energy transfer (LET) and TGF-beta (400 pg/mL). Image analysis was used to measure membrane-associated E-cadherin, a marker of functional epithelia, or fibronectin, a product of mesenchymal cells, as a function of radiation dose and quality. RESULTS: E-cadherin was reduced in TGF beta-treated cells irradiated with low-LET radiation doses between 0.03 and 2 Gy compared with untreated, unirradiated cells or TGF-beta treatment alone. The radiation quality dependence of TGF-beta-mediated EMT was determined by use of 1 GeV/amu (gigaelectron volt/atomic mass unit) (56)Fe ion particles at the National Aeronautics and Space Administration's Space Radiation Laboratory. On the basis of the relative biological effectiveness of 2 for (56)Fe ion particles' clonogenic survival, TGF-beta-treated HMECs were irradiated with equitoxic 1-Gy (56)Fe ion or 2-Gy (137)Cs radiation in monolayer. Furthermore, TGF-beta-treated HMECs irradiated with either high- or low-LET radiation exhibited similar loss of E-cadherin and gain of fibronectin and resulted in similar large, poorly organized colonies when embedded in Matrigel. Moreover, the progeny of HMECs exposed to different fluences of (56)Fe ion underwent TGF-beta-mediated EMT even when only one-third of the cells were directly traversed by the particle. CONCLUSIONS: Thus TGF-beta-mediated EMT, like other non-targeted radiation effects, is neither radiation dose nor quality dependent at the doses examined. PMID- 21310545 TI - The role of computed tomography in the management of the neck after chemoradiotherapy in patients with head-and-neck cancer. AB - PURPOSE: The aim of this study was to describe the outcome in patients with head and neck-squamous cell carcinoma (HNSCC) followed up without neck dissection (ND) after concomitant chemoradiotherapy (CRT) based on computed tomography (CT) response. The second objective was to establish CT characteristics that can predict which patients can safely avoid ND. METHODS AND MATERIALS: Between 1998 and 2007, 369 patients with node-positive HNSCC were treated with primary CRT at our institution. After a clinical and a radiologic evaluation based on CT done 6 to 8 weeks after CRT, patients were labeled with a complete neck response (CR) or with a partial neck response (PR). RESULTS: The median follow-up was 44 months. The number of patients presenting with N3, N2, or N1 disease were 54 (15%), 268 (72%), and 47 (13%), respectively. After CRT, 263 (71%) patients reached a CR, and 253 of them did not undergo ND. Ninety-six patients reached a PR and underwent ND. Of those, 34 (35%) had residual disease on pathologic evaluation. A regression of the diameter of >= 80% and a residual largest diameter of 15 mm of nodes had negative pathologic predictive values of 100% and 86%, respectively. The 3-year regional control and survival rates were not different between patients with CR who had no ND and patients with PR followed by ND. CONCLUSION: Node-positive patients presenting a CR as determined by CT evaluation 6 to 8 weeks after CRT had a low rate of regional recurrence without ND. This study also suggests that lymph node residual size and percentage of regression on CT after CRT may be useful criteria to guide clinical decisions regarding neck surgery. Those results can help diminish the number of ND procedures with negative results and their associated surgical complications. PMID- 21310546 TI - High-dose-rate monotherapy: safe and effective brachytherapy for patients with localized prostate cancer. AB - PURPOSE: High-dose-rate (HDR) brachytherapy used as the only treatment (monotherapy) for early prostate cancer is consistent with current concepts in prostate radiobiology, and the dose is reliably delivered in a prospectively defined anatomic distribution that meets all the requirements for safe and effective therapy. We report the disease control and toxicity of HDR monotherapy from California Endocurietherapy (CET) and William Beaumont Hospital (WBH) in low and intermediate-risk prostate cancer patients. METHODS AND MATERIALS: There were 298 patients with localized prostate cancer treated with HDR monotherapy between 1996 and 2005. Two biologically equivalent hypofractionation protocols were used. At CET the dose was 42 Gy in six fractions (two implantations 1 week apart) delivered to a computed tomography-defined planning treatment volume. At WBH the dose was 38 Gy in four fractions (one implantation) based on intraoperative transrectal ultrasound real-time treatment planning. The bladder, urethral, and rectal dose constraints were similar. Toxicity was scored with the National Cancer Institute Common Toxicity Criteria for Adverse Events version 3. RESULTS: The median follow-up time was 5.2 years. The median age of the patients was 63 years, and the median value of the pretreatment prostate-specific antigen was 6.0 ng/mL. The 8-year results were 99% local control, 97% biochemical control (nadir +2), 99% distant metastasis-free survival, 99% cause-specific survival, and 95% overall survival. Toxicity was scored per event, meaning that an individual patient with more than one symptom was represented repeatedly in the morbidity data table. Genitourinary toxicity consisted of 10% transient Grade 2 urinary frequency or urgency and 3% Grade 3 episode of urinary retention. Gastrointestinal toxicity was <1%. CONCLUSIONS: High disease control rates and low morbidity demonstrate that HDR monotherapy is safe and effective for patients with localized prostate cancer. PMID- 21310547 TI - Geometric and dosimetric approach to determine probability of late cardiac mortality in left tangential breast irradiation: comparison between wedged beams and field-in-field technique. AB - PURPOSE: To evaluate the probability of late cardiac mortality resulting from left breast irradiation planned with tangential fields and to compare this probability between the wedged beam and field-in-field (FIF) techniques and to investigate whether some geometric/dosimetric indicators can be determined to estimate the cardiac mortality probability before treatment begins. METHODS AND MATERIALS: For 30 patients, differential dose-volume histograms were calculated for the wedged beam and FIF plans, and the corresponding cardiac mortality probabilities were determined using the relative seriality model. As a comparative index of the dose distribution uniformity, the planning target volume (PTV) percentages involved in 97-103% of prescribed dose were determined for the two techniques. Three geometric parameters were measured for each patient: the maximal length, indicates how much the heart contours were displaced toward the PTV, the angle subtended at the center of the computed tomography slice by the PTV contour, and the thorax width/thickness ratio. RESULTS: Evaluating the differential dose-volume histograms showed that the gain in uniformity between the two techniques was about 1.5. With the FIF technique, the mean dose sparing for the heart, the left anterior descending coronary artery, and the lung was 15% (2.5 Gy vs. 2.2 Gy), 21% (11.3 Gy vs. 9.0 Gy), and 42% (8.0 Gy vs. 4.6 Gy) respectively, compared with the wedged beam technique. Also, the cardiac mortality probability decreased by 40% (from 0.9% to 0.5%). Three geometric parameters, the maximal length, angle subtended at the center of the computed tomography slice by the PTV contour, and thorax width/thickness ratio, were the determining factors (p = .06 for FIF, and p = .10 for wedged beam) for evaluating the cardiac mortality probability. CONCLUSION: The FIF technique seemed to yield a lower cardiac mortality probability than the conventional wedged beam technique. However, although our study demonstrated that FIF technique improved the dose coverage of the PTV, the restricted number of patients enrolled and the short follow-up did not allow us to evaluate and compare the breast cancer survival rates of the patients. PMID- 21310548 TI - Benchmarking dosimetric quality assessment of prostate intensity-modulated radiotherapy. AB - PURPOSE: To benchmark the dosimetric quality assessment of prostate intensity modulated radiotherapy and determine whether the quality is influenced by disease or treatment factors. PATIENTS AND METHODS: We retrospectively analyzed the data from 155 consecutive men treated radically for prostate cancer using intensity modulated radiotherapy to 78 Gy between January 2007 and March 2009 across six radiotherapy treatment centers. The plan quality was determined by the measures of coverage, homogeneity, and conformity. Tumor coverage was measured using the planning target volume (PTV) receiving 95% and 100% of the prescribed dose (V(95%) and V(100%), respectively) and the clinical target volume (CTV) receiving 95% and 100% of the prescribed dose. Homogeneity was measured using the sigma index of the PTV and CTV. Conformity was measured using the lesion coverage factor, healthy tissue conformity index, and the conformity number. Multivariate regression models were created to determine the relationship between these and T stage, risk status, androgen deprivation therapy use, treatment center, planning system, and treatment date. RESULTS: The largest discriminatory measurements of coverage, homogeneity, and conformity were the PTV V(95%), PTV sigma index, and conformity number. The mean PTV V(95%) was 92.5% (95% confidence interval, 91.3 93.7%). The mean PTV sigma index was 2.10 Gy (95% confidence interval, 1.90 2.20). The mean conformity number was 0.78 (95% confidence interval, 0.76-0.79). The treatment center independently influenced the coverage, homogeneity, and conformity (all p < .0001). The planning system independently influenced homogeneity (p = .038) and conformity (p = .021). The treatment date independently influenced the PTV V(95%) only, with it being better at the start (p = .013). Risk status, T stage, and the use of androgen deprivation therapy did not influence any aspect of plan quality. CONCLUSION: Our study has benchmarked measures of coverage, homogeneity, and conformity for the treatment of prostate cancer using IMRT. The differences seen between centers and planning systems and the coverage deterioration over time highlight the need for every center to determine their own benchmarks and apply clinical vigilance with respect to maintaining these through quality assurance. PMID- 21310549 TI - A clinical concept for interfractional adaptive radiation therapy in the treatment of head and neck cancer. AB - PURPOSE: To present an approach to fast, interfractional adaptive RT in intensity modulated radiation therapy (IMRT) of head and neck tumors in clinical routine. Ensuring adequate patient position throughout treatment proves challenging in high-precision RT despite elaborate immobilization. Because of weight loss, treatment plans must be adapted to account for requiring supportive therapy incl. feeding tube or parenteral nutrition without treatment breaks. METHODS AND MATERIALS: In-room CT position checks are used to create adapted IMRT treatment plans by stereotactic correlation to the initial setup, and volumes are adapted to the new geometry. New IMRT treatment plans are prospectively created on the basis of position control scans using the initial optimization parameters in KonRad without requiring complete reoptimization and thus facilitating quick replanning in daily routine. Patients treated for squamous cell head and neck cancer (SCCHN) in 2006-2007 were evaluated as to necessity/number of replannings, weight loss, dose, and plan parameters. RESULTS: Seventy-two patients with SCCHN received IMRT to the primary site and lymph nodes (median dose 70.4 Gy). All patients received concomitant chemotherapy requiring supportive therapy by feeding tube or parenteral nutrition. Median weight loss was 7.8 kg, median volume loss was approximately 7%. Fifteen of 72 patients required adaptation of their treatment plans at least once. Target coverage was improved by up to 10.7% (median dose). The increase of dose to spared parotid without replanning was 11.7%. Replanning including outlining and optimization was feasible within 2 hours for each patient, and treatment could be continued without any interruptions. CONCLUSION: To preserve high-quality dose application, treatment plans must be adapted to anatomical changes. Replanning based on position control scans therefore presents a practical approach in clinical routine. In the absence of clinically usable online correction methods, this approach allows significant improvement of target volume coverage and continuous parotid sparing without treatment delays. PMID- 21310550 TI - Association between maximal skin dose and breast brachytherapy outcome: a proposal for more rigorous dosimetric constraints. AB - PURPOSE: Multiple investigations have used the skin distance as a surrogate for the skin dose and have shown that distances <6 mm have been associated with late toxicity after MammoSite brachytherapy. No publications have yet described the relationship between the actual maximal skin dose and the outcome. The present study analyzed the maximal skin dose delivered and the occurrence of late toxicity in a large cohort of patients with prolonged follow-up. METHODS: A total of 96 patients treated with breast brachytherapy between 2000 and 2007 for whom complete planning and follow-up data were available were included in the present analysis. The median follow-up was 48 months (range, 24-111). Of the 96 patients, 40 were treated with multicatheter interstitial brachytherapy and 56 with MammoSite. A multivariate statistical analysis was performed to determine the relationship between several dosimetric parameters and patient outcome. RESULTS: The treatment was well tolerated, with 98% of patients experiencing good to excellent cosmesis. Significant late toxicity was uncommon. The maximal dose delivered to the skin was significantly associated with the incidence of any degree of telangiectasia (p = .009) and moderate to severe fibrosis (p = .010). The incidence of late toxicity was significantly increased when the dose to the skin was >4.05 Gy/fraction. CONCLUSION: The initial skin dose recommendations have been based on safe use and the avoidance of significant toxicity. The results from the present study have suggested that patients might further benefit if more rigorous constraints were applied and if the skin dose were limited to 120% of the prescription dose. PMID- 21310551 TI - Dronabinol for the treatment of cannabis dependence: a randomized, double-blind, placebo-controlled trial. AB - Cannabis dependence is a substantial public health problem. Behavioral treatments have shown promise, but there are no effective medications for cannabis dependence. The purpose of this study was to evaluate the safety and efficacy of dronabinol, a synthetic form of delta-9-tetrahydrocannabinol, a naturally occurring pharmacologically active component of marijuana, in treating cannabis dependence. 156 cannabis-dependent adults were enrolled in a randomized, double blind, placebo-controlled, 12-week trial. After a 1-week placebo lead-in phase, participants were randomized to receive dronabinol 20mg twice a day or placebo. Doses were maintained until the end of week 8 and then tapered off over 2 weeks. All participants received weekly motivational enhancement and relapse prevention therapy. Marijuana use was assessed using the timeline follow back method. There was no significant difference between treatment groups in the proportion of participants who achieved 2 weeks of abstinence at the end of the maintenance phase (dronabinol: 17.7%; placebo: 15.6%). Although both groups showed a reduction in marijuana use over time, there were no differences between the groups. Treatment retention was significantly higher at the end of the maintenance phase on dronabinol (77%), compared to placebo (61%) (P=.02), and withdrawal symptoms were significantly lower on dronabinol than placebo (P=.02). This is the first trial using an agonist substitution strategy for treatment of cannabis dependence. Dronabinol showed promise, it was well-tolerated, and improved treatment retention and withdrawal symptoms. Future trials might test higher doses, combinations of dronabinol with other medications with complementary mechanisms, or with more potent behavioral interventions. PMID- 21310552 TI - Predictors of methadone treatment retention from a multi-site study: a survival analysis. AB - BACKGROUND: Longer tenure in methadone treatment has been associated with positive outcomes such as reductions in drug use and crime, HIV seroconversion, and overdose death. METHODS: Retention in treatment was examined for 351 opioid dependent individuals who had been newly admitted to one of six methadone programs in Baltimore, Maryland. Cox proportional hazards regression was used to predict number of days retained in treatment to 90 days from baseline ASI Composite scores and Treatment Motivation scales. A second analysis predicted days in treatment to 365 days using the same baseline variables plus 3-month Motivation scales, Patient Satisfaction scales, and methadone dose in the 248 individuals who had remained in treatment at least 3 months. Analyses held constant gender, race, age, whether participants had a history of regularly smoking cocaine, whether participants were on parole/probation, and program site. RESULTS: Retention at 90 days was predicted by female gender, and greater baseline Treatment Readiness (p=.005) but lower Desire for Help (p=.010). Retention at 365 days was predicted by higher baseline ASI Medical Composite scores (p=.037) and lower Legal Composite scores (p=.039), higher 3-month Treatment Satisfaction scores (p=.008), and higher dose (p=.046). CONCLUSIONS: Greater satisfaction with treatment at 3 months was a significant predictor of retention at 12 months, indicating the importance of understanding the role satisfaction plays in determining retention. Greater severity of legal problems was associated with shorter retention, suggesting that program efforts to increase services to criminal justice patients (e.g., legal counseling) may constitute a useful addition to treatment. PMID- 21310553 TI - Ghrelin receptor antagonism attenuates nicotine-induced locomotor stimulation, accumbal dopamine release and conditioned place preference in mice. AB - BACKGROUND: The orexigenic peptide ghrelin activates the reward systems, specifically the cholinergic-dopaminergic reward link, suggesting that ghrelin may increase the incentive salience of motivated behaviours such as food seeking. Moreover, central ghrelin signalling, involving the growth hormone secretagogue receptor 1A (GHS-R1A), is required for the rewarding properties, as measured by locomotor stimulation, accumbal dopamine release and conditioned place preference, of alcohol, cocaine as well as amphetamine. As the target circuits for other drugs of abuse, including nicotine, in the brain includes this reward link, we sought to determine whether the central ghrelin signalling system is involved in nicotine's activation of this system. METHODS: This was investigated by studying the effects of peripheral administration of a GHS-R1A antagonist (JMV2959) on the nicotine-induced locomotor simulation, accumbal dopamine release and conditioned place preference. RESULTS: In the present study we found that the ability of nicotine to increase the locomotor activity, accumbal dopamine release and to condition place preference were reduced in mice treated with a GHS-R1A antagonist. CONCLUSION: Thus GHS-R1A appears to be required not only for alcohol, cocaine and amphetamine-induced reward, but also for reward induced by nicotine. Our data suggest that the central ghrelin signalling system may constitute a novel potential target for treatment of drug dependence. PMID- 21310554 TI - A qualitative study exploring the reason for low dosage of methadone prescribed in the MMT clinics in China. AB - OBJECTIVES: Dosage of methadone maintenance therapy (MMT) is an important factor influencing retention in methadone treatment. MMT clients in China received lower dosages of methadone compared with those provided in other countries. The objective of this study is to elucidate the reason for the low methadone dosage prescribed in MMT clinics in China. METHODS: Twenty-eight service providers were recruited from the MMT clinics in Zhejiang and Jiangxi Provinces, China. Qualitative in-depth interviews were conducted to ascertain the procedure for prescribing methadone in the MMT clinics. RESULTS: The average dosage prescribed in the 28 clinics was 35 mg/person/day. Four major themes resulting in low dosage of methadone were identified: (1) the service providers fear the liability resulting from large doses of methadone in combination with other substances which might result in overdose fatalities, (2) lack of understanding of harm reduction which resulted in low acceptance of the long term maintenance treatment approach, (3) break-down in communication between clients and service providers about dosage adjustment, and (4) dosage reduction is perceived by most service providers as an effective way to treat the side-effects associated with MMT. CONCLUSIONS: The findings of the study highlighted the necessity to formulate clear guidelines concerning individualized dosage management and to improve training among service providers' in MMT clinics in China. PMID- 21310555 TI - Genetic and immunobiological diversities of porcine reproductive and respiratory syndrome genotype I strains. AB - Genetic diversity of porcine reproductive and respiratory syndrome virus (PRRSV) has been based on ORF5/GP5 and ORF7/N protein variations. Complete viral genome studies are limited and focused on a single or a few set of strains. Moreover, there is a general tendency to extrapolate results obtained from a single isolate to the overall PRRSV population. In the present study, six genotype-I isolates of PRRSV were sequenced from ORF1a to ORF7. Phylogenetic comparisons and the variability degree of known linear B-epitopes were done considering other available full-length genotype-I sequences. Cytokine induction of all strains was also evaluated in different cellular systems. Non structural protein 2 (nsp2) was the most variable part of the virus with 2 out of 6 strains harboring a 74 aa deletion. Deletions were also found in ORF3 and ORF4. Phylogenetic analyses showed that isolates could be grouped differently depending on the ORF examined and the highest similarity with the full genome cluster was found for the nsp9. Interestingly, most of predicted linear B-epitopes in the literature, particularly in nsp2 and GP4 regions, were found deleted or varied in some of our isolates. Moreover, 4 strains, those with deletions in nsp2, induced TNF-alpha and 3 induced IL-10. These results underline the high genetic diversity of PRRSV mainly in nsp1, nsp2 and ORFs 3 and 4. This variability also affects most of the known linear B-epitopes of the virus. Accordingly, different PRRSV strains might have substantially different immunobiological properties. These data can contribute to the understanding of PRRSV complexity. PMID- 21310556 TI - Rapid test for the serodiagnosis of acute canine leptospirosis. PMID- 21310557 TI - A distinct CDV genotype causing a major epidemic in Alpine wildlife. AB - Canine distemper virus (CDV) infection represents an important conservation threat to many carnivore species and has contributed to the population decline of several wild terrestrial and aquatic mammalian species. Since 2006, the Alpine region of North-Eastern (NE) Italy has been experiencing a severe and widespread outbreak of CDV affecting the wild carnivore population. In this study we performed an extensive phylogenetic and molecular evolutionary analysis of CDV identified during the recent wildlife epidemic in the Alpine region. Our analysis yielded data on the evolutionary dynamics of the Alpine wildlife CDV epidemic and revealed the emergence and spread of a single genetic cluster of CDV. The wide distribution of the novel cluster combined with the identification of a specific amino acid mutation, which is believed to increase the ability of the virus to replicate in a wider host range, raises concerns over the possible implications of the spread of this virus on the conservation of endangered wildlife species. PMID- 21310558 TI - Bone loss during menopausal transition among southern Chinese women. AB - OBJECTIVES: Estrogen deficiency during menopausal transition is associated with rapid bone loss. The purpose of this study was to examine the time of onset, the rate, and predictors of menopausal bone loss. STUDY DESIGN: Prospective data were analyzed from 160 Chinese women between the ages of 45 to 55 years who participated in the Hong Kong Osteoporotic Study. MAIN OUTCOME MEASURES: All participants were studied yearly for 4 years. Demographic information, menstrual status according to the Stages of Reproductive Aging Workshop (STRAW), and lifestyle habits were recorded as well as bone mineral density (BMD) measured every visit. Baseline follicular stimulating hormone, sex hormone binding globulin, parathyroid hormones, C-terminal telopeptides of type 1 collagen, estradiol and testosterone were also measured. RESULTS: There was no significant bone loss at the spine, femoral neck and total hip in premenopausal women. Maximal bone loss occurred within the STRAW stage -2 and -1. Age at menopause, baseline age, body weight and FSH were independent predictors of bone loss. Subjects in the lowest quartile of baseline body weight (<50 kg) lost bone 2 times faster at spine compared with those in the highest quartile (>61 kg). Subjects in the highest quartile of baseline FSH (>40 IU/l) lost bone 1.3-2.3 times faster at all 3 sites compared with those in the lowest quartile (<5.8 IU/l). CONCLUSION: Strategies to retard bone loss should be stressed to middle aged women, especially those with lean body built or with early menopause, to prevent osteoporosis later on in life. PMID- 21310559 TI - Cardiovascular autonomic responsiveness in postmenopausal women with and without hot flushes. AB - OBJECTIVES: During menopausal transition autonomic balance is known to shift towards sympathetic dominance, but the role of vasomotor hot flushes in this phenomenon is not understood. We compared cardiovascular autonomic responsiveness between women with and without hot flushes. STUDY DESIGN AND MAIN OUTCOME MEASURES: One hundred fifty recently postmenopausal healthy women with varying degree of hot flushes (none, mild, moderate, severe) underwent comprehensive cardiovascular autonomic nervous testing (controlled and deep breathing, active orthostatic test, Valsalva manoeuvre and handgrip test) assessing both sympathetic and parasympathetic activity. The responses of heart rate, heart rate variability and blood pressure in these tests were evaluated. RESULTS: Responses in heart rate showed differences between the study groups only in the Valsalva manoeuvre where the tachycardia ratio in all symptomatic women was lower (p=0.041) than in women without hot flushes. Neither change in the heart rate variability analyses nor the blood pressure responses were affected by hot flush status. However, there was a non-significantly higher maximum systolic (140 (112 182)mmHg vs. 135 (102-208)mmHg) and diastolic blood pressure (94 (72-112)mmHg vs. 90 (66-122)mmHg) following the handgrip test in women without hot flushes vs. all the symptomatic women. CONCLUSIONS: Menopausal hot flushes seem to be associated with a possibly increased sympathetic preponderance without an effect on parasympathetic activity in cardiovascular autonomic responses. This may imply a potentially negative impact on cardiovascular health in women experiencing hot flushes. PMID- 21310560 TI - Obtaining absorption spectra from single textile fibers using a liquid crystal tunable filter microspectrophotometer. AB - Visible absorption spectra were recorded for single textile fibers using a microspectrophotometer based on a liquid crystal tunable filter. Spectra compared well with results from a conventional instrument. Some advantages include very fast and simple sample preparation and easy comparison of multiple fibers at the same time. Advantages over extraction-dependent methods include the fact that it is applicable to extremely small sample size, not susceptible to artifacts induced by variable extraction efficiencies, non-destructive, and much easier. Because an immense amount of information is collected in one experiment, good signal averaging is possible, along with multiple comparisons for each data set. The addition of a camera, computer, and liquid crystal tunable filter can transform a standard microscope into a microspectrophotometer capable of performing similar work. PMID- 21310561 TI - The effect of annealing on the variation of glass refractive index. AB - The variation of refractive index (RI) over a non-toughened, float pane of glass and a toughened, float pane of glass was investigated. The two panes of colourless, float glass were cut into 150 5 cm * 5 cm squares. The pre- and post annealing RI values from three random areas from each square were measured. Bayesian statistical hierarchical modelling of the results showed that for the non-toughened, float glass pane annealing increased the variability in RI by a factor of 1.29-1.58, with a mean of 1.43 (with 95% probability); and for the toughened, float pane of glass annealing decreased the variability in RI by a factor of 0.63-0.76, with a mean of 0.69 (with 95% probability). In addition it was found that although there were no systematic differences in DeltaRI across either pane of glass, there were observable differences across both panes of glass. These results provide information regarding the expected RI variation over entire panes of both non-toughened and toughened float window glass for both pre- and post-annealing RI measurements. PMID- 21310562 TI - Comparison between surgery and radiofrequency ablation for stage I non-small cell lung cancer. AB - Surgical resection remains as the treatment of choice for non-small cell lung cancer (NSCLC) and provides the best opportunity for cure and long-term survival. Minimally invasive percutaneous ablative therapies, such as radiofrequency ablation (RFA) for treating lung cancers, are currently being studied as treatment alternatives. But, to date, there is little information on comparison of therapeutic effects between surgery and RFA in patients with early stage lung malignancy. We aimed to investigate the clinical significance of RFA as an alternative curative modality for the early stage lung cancer through analyzing the long-term mortality of both treatment groups; surgery vs. RFA. Twenty-two patients of stage I NSCLC were included for this comparative analysis. To minimize confounding effects, we conducted a matching process. In which patients of RFA group (n = 8) were matched with patients of surgery group (n = 14) on the following variables; gender, age (+/- 3 years), tumor node metastasis stage, and calendar year of surgery or RFA (+/- 2 years). The mean survival duration of RFA group and surgery group were 33.18 +/- 7.90 and 45.49 +/- 7.21, respectively (months, p = 0.297). Log-rank analysis showed that there was no significant difference in overall survival (p = 0.054) between two groups. These results have shown that RFA can offer the survival comparable to that by surgery to stage I NSCLC patients, especially to the patients impossible for the surgery. This study provides an evidence for the use of RFA as a treatment alternative with low procedural morbidity for inoperable early-stage NSCLC patients. PMID- 21310563 TI - Dynamic 3D-MR-angiography for assessing rheumatoid disease of the hand--a feasibility study. AB - PURPOSE: To investigate highly temporally resolved MR-angiography (MRA) with time resolved imaging with stochastic trajectories (TWIST) of the hand as supplementary tool for dynamic assessment of synovitis and vascular pathologies in rheumatoid diseases. MATERIAL AND METHODS: A coronal dynamic TWIST-MRA sequence (0.7 mm * 0.7 mm * 1.4 mm, temporal resolution 2.5s, time of acquisition 4 min) of the predominantly affected hand of 17 patients with suspected rheumatoid disease was acquired after contrast administration (Multihance, Bracco Imaging SpA) at 3T (Magnetom VERIO, 8-channel-knee-coil, Siemens Healthcare). As standard of reference, contrast enhanced non fat-saturated coronal and fat saturated axial T1-w sequences were acquired. These static sequences and the dynamic TWIST-MRA-maximum-intensity-projections (MIP) were separately assessed by two readers in consensus, recording the number of synovial lesions (wrist, intercarpal, metacarpophaleangal/proximal/distal interphalangeal joints), signs of tenosynovitis and vasculitis. Diagnostic confidence was rated (4-point-scale: 4=excellent; 1=non-diagnostic). Statistical significance was tested using the Wilcoxon-rank-sum-test. RESULTS: An insignificantly lower number of synovial lesions (n=72 vs. 89; p=0.1) and only 3/9 cases with tenosynovitis were identified by the TWIST-MRA. For detected lesions, diagnostic confidence was comparable (MRA: 3.64; static T1-w post contrast: 3.47). In patients with high clinical activity dynamic MRA showed very early synovial enhancement. Only dynamic MRA detected 3 cases of vasculitis (subsequently confirmed with digital subtraction-angiography). CONCLUSION: TWIST-MRA facilitates fast detection of synovitis. Although dynamic MRA of the hand is inferior to static contrast enhanced sequences in assessing the number of synovitic and tenosynovitic lesions, its high temporal resolution allows for fast visual grading of disease activity and assessment of vasculitis without additional contrast material application. PMID- 21310564 TI - Evaluation of inflammatory status of atherosclerotic carotid plaque before thromboendarterectomy using delayed contrast-enhanced subtracted images after magnetic resonance angiography. AB - OBJECTIVE: To investigate the correlation among carotid plaque contrast enhancement (CPCE) at MRI, inflammatory cell infiltration (ICI) at histopathology, and carotid stenosis degree. MATERIALS AND METHODS: Twenty-eight patients (19 males; mean age 67+/-9 years) scheduled for thromboendarterectomy prospectively underwent 1.5-T MR imaging using: (a) axial T1-weighted gradient echo (T1wGRE) sequence centered on carotid bifurcations; (b) contrast-enhanced MR angiography (CE-MRA) with 0.1 mmol/kg of gadobenate dimeglumine; (c) enhanced axial T1wGRE sequence as in (a), 3 min after contrast injection. A three-point score system (absent, focal, wide) was used to assess CPCE on native and subtracted MRI images (c minus a) and ICI at histopathology. Carotid stenosis degree was determined on CE-MRA. RESULTS: Six CPCE studies were discarded due to patient movement. In the remaining 22 studies, CPCE was absent, focal and wide in 13, 6 and 3 cases, respectively; ICI was absent, focal and wide in 13, 7 and 2 cases, respectively (k=0.57). On CE-MRA 21/28 stenoses were severe and 7/28 moderate. There was no correlation either with ICI (p=1.000, n=28) or CPCE (p=0.747, n=22). CONCLUSION: The correlation between CPCE and ICI suggests a role for CPCE as an independent marker of plaque inflammation. PMID- 21310565 TI - Radiation doses from phantom measurements at high-pitch dual-source computed tomography coronary angiography. AB - OBJECTIVE: To compare radiation doses delivered at prospectively ECG-triggered sequential- (SEQ), retrospectively ECG-gated spiral- (RETRO) and prospectively ECG-triggered high-pitch spiral- (HP) computed tomography coronary angiography (CTCA) protocols, as well as catheter coronary angiography (CCA) using an anthropomorphic phantom. MATERIALS AND METHODS: An anthropomorphic Alderson phantom equipped with 50 thermoluminescent dosimeters (TLDs) was scanned using different CTCA protocols and an uncomplicated diagnostic CCA examination was simulated. Absorbed doses were experimentally determined and effective doses calculated using the dose-length product (DLP) for CTCA and the dose-area product (DAP) for CCA, as well as according to International Commission on Radiation Protection (ICRP) publications 60 and 103. RESULTS: Effective organ doses were significantly lower for HP protocols (100kV: 0.17+/-0.26mSv; 120kV: 0.26+/ 0.39mSv) compared to SEQ protocols (100kV: 0.50+/-0.79mSv; 120kV: 0.90+/-1.41mSv; each p<0.05) and compared to RETRO protocols (100kV: 1.59+/-2.12mSv; 120kV: 2.75+/-3.50mSv; each p<0.05). Effective organ doses at HP-CTCA tended to be lower than at CCA (0.37+/-0.40mSv), however this was not statistically significant (p=0.13). Effective doses calculated according to ICRP guidelines could be estimated using the DLP and a conversion coefficient of k=0.034mSv/[mGycm] (ICRP103) or k=0.028mSv/[mGycm] (ICRP60), respectively. HP-CTCA led to a dose reduction of 89% compared to RETRO-CTCA, regardless of the calculation method used. CONCLUSIONS: Radiation doses as determined by phantom measurements are significantly lower at HP-CTCA compared to SEQ-CTCA and RETRO-CTCA and comparable to uncomplicated diagnostic CCA. PMID- 21310566 TI - Central venous stenosis of left versus right arm: its prevalence and effects on image quality in CT of the neck. AB - OBJECTIVE: The purpose of this study was (1) to evaluate the prevalence of the left and right central venous stenosis by measuring the narrowest area and (2) to assess the effects of the central venous stenosis on perivenous artifacts and reflux of contrast material, in CT of the neck. MATERIALS AND METHODS: Images of a total of 443 CT of the neck with an injection of contrast material into the left (n = 249) or right (n = 194) arm were retrospectively reviewed. The maximum stenosis area in the central vein ipsilateral to the injection side was measured in each patient. We also graded the perivenous artifacts and reflux of contrast material with 4-point scale. These results were compared between patients with right arm injection and those with left arm injection. RESULTS: The maximum stenosis area in the left arm was significantly smaller than that in the right arm. The stenosis was most frequently identified at the medial clavicular region. The mean scores of the perivenous artifacts and the reflux of contrast material were significantly higher in patients with left arm injection than in those with right arm injection. The perivenous artifacts and reflux of contrast material were more prominent in patients with central venous stenosis (maximum stenosis area <50mm(2)) than those without stenosis. CONCLUSIONS: The image degradation in CT of the neck, due to perivenous artifacts and venous reflux, can be reduced with the right arm injection of contrast material when compared with the left arm injection. PMID- 21310567 TI - Prospective electrocardiography-triggered CT angiography of the great thoracic vessels in infants and toddlers with congenital heart disease: feasibility and image quality. AB - PURPOSE: To investigate feasibility and image quality and to calculate radiation dose estimates for computed tomography angiography (CTA) of the great thoracic vessels in infants and toddlers with congenital heart disease (CHD) using end systolic prospective electrocardiography-triggered sequential dual-source data acquisition. METHODS: This study was institutional review board approved; informed consent was obtained. Twenty children (age 1.2+/-1.1 years) underwent 22 prospective ECG-triggered sequential dual-source CTA examinations (Somatom Definition, Siemens) with tube current (250 mAs/rot) centered at 250 ms past the R-peak in the cardiac cycle (end-systole). Tube voltage was set to 80 kV. Image quality was evaluated by two readers independently using a four-point grading scale (4=excellent, 1=non-diagnostic). Radiation dose estimates were calculated from the dose-length-product (DLP). RESULTS: All CT images showed diagnostic image quality (mean score 3.67+/-0.67, kappa=0.85). Stair-step artifacts were present in one and breathing artifacts in 4 patients, with neither impairing diagnostic image quality. Mean heart rate (bpm) was 107.6+/-12.1 (76-130), mean heart rate variability (bpm) was 2.5+/-2.0 (1-9). Mean scan length (mm) was 90.7+/-22.7 (50-134). Mean estimated effective dose was 0.32+/-0.11 mSv. CONCLUSION: Prospective ECG-triggered sequential dual source CTA is feasible in infants and toddlers with CHD, thereby allowing almost motion-free imaging of the great thoracic vessels with the benefit of a low radiation dose. PMID- 21310568 TI - Accuracy of thoracic aortic measurements assessed by contrast enhanced and unenhanced magnetic resonance imaging. AB - AIM: To assess, whether unenhanced balanced steady-state-free precession sequences provide axial thoracic aortic measurements comparable to contrast enhanced magnetic resonance angiography with good intra- and interobserver agreement. MATERIALS AND METHODS: Enhanced and unenhanced sequences of the thoracic aorta in 23 consecutive patients were evaluated. Axial thoracic aortic diameters were measured at predefined levels by two independent readers. Pearson's correlation coefficient and Bland-Altman analysis were used to compare enhanced and unenhanced sequences. t-Test was used to determine possible significant differences between the measurements obtained by enhanced and unenhanced sequences. A p-value of less than .05 indicated statistical significance. Intraclass correlation coefficient and Bland-Altman were used for inter- and intraobserver correlation and agreement. RESULTS: There was no significant difference in diameter measurements between enhanced and unenhanced sequences (ascending aorta, p=0.98; descending aorta, p=0.52). Bland-Altman revealed good agreement between enhanced and unenhanced sequences for ascending (mean bias, -0.01cm; with 95% limits of agreement, +/-0.30cm) and descending aortic diameters (mean bias, 0.05cm; with 95% limits of agreement, +/-0.30cm). Inter- and intraobserver agreement (mean bias, less than +/-0.15; with 95% limits of agreement, less than +/-0.42cm for all measurements) as well as correlation (r>0.8 for all measurements) were excellent. CONCLUSION: Unenhanced balanced steady-state-free precession sequences enable rapid and accurate determination of axial thoracic aortic diameters with excellent inter- and intraobserver agreement, but without the risk of contrast media associated side-effects. PMID- 21310569 TI - The evaluation of anti-angiogenic treatment effects for implanted rabbit VX2 breast tumors using functional multi-slice spiral computed tomography (f-MSCT). AB - OBJECTIVE: Investigate the benefit of functional multi-slice spiral computed tomography (f-MSCT) perfusion imaging in the non-invasive assessment of targeted anti-angiogenesis therapy on an implanted rabbit VX2 breast tumor model. METHOD: 69 female pure New Zealand white rabbits were randomly assigned to one of the 4 groups and received treatment accordingly: control (saline), Endostar, neoadjuvant chemotherapy (Cyclophosphamide, Epirubicin and 5-Fluorouracil, CEF), combination therapy (Endostar and CEF). After 2 weeks of treatment, f-MSCT perfusion scannings were performed for all rabbits and information about blood flow (BF), blood volume (BV), mean transit time (MTT) and surface permeability (SP) was collected. After perfusion imaging, tumor tissues were sampled for immunohistochemistry and the Western blot test of VEGF protein expression. RESULTS: (1) The VEGF expression level, measured by immunohistochemistry and Western blot, decreased by treatment group (control > Endostar > CEF > combination therapy). The same was true for the mean BF, BV, MTT and PS, which decreased from the control group to the combination therapy group gradually. The mean MTT level increased in reverse order from the control to the combination therapy group. The difference between any 2 groups on these measures was statistically significant (P < 0.05). (2) There was moderate positive correlation between VEGF expression and BE, BV, or PS level (P < 0.05) and a negative correlation between VEGF expression and MTT level for all 4 groups (P < 0.05). CONCLUSION: Therefore, f-MSCT can be used as a non-invasive approach to evaluate the effect of anti-angiogenic therapy for implanted rabbit VX2 breast tumors. PMID- 21310570 TI - Predictive factors for complete excision and underestimation of one-pass en bloc excision of non-palpable breast lesions with the Intact((r)) breast lesion excision system. AB - OBJECTIVE: Image-guided percutaneous biopsy is the recommended initial diagnostic procedure for suspicious mammographic lesions. This study was conducted to determine the accuracy of the Intact((r)) breast lesion excision system (BLES) and to identify predictive factors for complete excision and underestimation. MATERIAL AND METHODS: A prospective study was conducted between January 28, 2008 and April 30, 2009 on 166 biopsy procedures using Intact((r)) biopsy device. Diagnoses obtained from biopsy specimen were compared with to final diagnosis on surgical excision specimen. RESULTS: Of the 166 patients, 15 (9%) displayed lesions with cell atypia, 28 (17%) had an intra ductal carcinoma (IDC) and 9 (5%) had an invasive carcinoma. Eight of 15 patients with cell atypia had open surgical excision, and none showed underestimation. All patients with IDC underwent surgical excision: we found an invasive carcinoma in 6 cases (21.4% underestimation) and a complete removal of the lesion by the Intact((r)) BLES in 11 cases (39%). All 9 patients with invasive carcinoma had a surgical excision, with 1 complete removal of the lesion by Intact((r)) BLES. Multivariate analyses did not identify predictive factors for underestimation; clear margins >=1mm on biopsy specimen was the only independent predictive factor of complete excision (OR=8.51, p=0.02). CONCLUSIONS: Intact((r)) BLES provides a safe alternative to vacuum assisted core needle biopsy (VACNB) with an underestimation rate comparable to those previously reported for VACNB. The high rate of complete removal of the lesions, particularly ISC, offers an interesting perspective of avoiding subsequent excisional surgery for small lesions and thus requires further confirmational study. PMID- 21310571 TI - Endovascular treatment paradigm of carotid blowout syndrome: review of 8-years experience. AB - OBJECTIVES: Endovascular treatment is effective in treating carotid blowout syndrome (CBS). We reviewed our experience in addressing CBS over eight years and presented an account of the treatment paradigm and management algorithm. METHOD: All cases of CBS from 2003 to 2010 with endovascular treatment performed in our center were reviewed. 15 CBS in 14 patients were recruited. Based on our management algorithm, treatment regimen was stratified into deconstructive or constructive methods. Their clinical presentations, angiographic features, angiographic and clinical outcomes were reviewed. RESULTS: 10 patients were treated with deconstructive method by means of permanent vessel occlusion (PVO) and 4 patients were treated with constructive method by means of placement of covered stent (n=3) or flow diverting device (n=1). Immediate hemostasis was achieved in all cases. 7 (50%) patients, in whom 5 treated with PVO and 2 with covered stent, had favorable outcomes and survived at a median follow-up period of 4 months (range: 1-84 months). CONCLUSION: Permanent vessel occlusion remains the gold standard of treatment and tends to show a favorable long-term outcome. Off-label use of covered stent and flow-diverting device can produce satisfactory results should balloon occlusion test fail, but long-term follow up would be required for definitive assessment. PMID- 21310572 TI - Genomospecies identification and phylogenomic relevance of AFLP analysis of isolated and non-isolated strains of Frankia spp. AB - Amplified fragment length polymorphism (AFLP) was tested as an alternative to the DNA-DNA hybridization technique (DDH) to delineate genomospecies and the phylogenetic structure within the genus Frankia. Forty Frankia strains, including representatives of seven DDH genomospecies, were typed in order to infer current genome mispairing (CGM) and evolutionary genomic distance (EGD). The constructed phylogeny revealed the presence of three main clusters corresponding to the previously identified host-infecting groups. In all instances, strains previously assigned to the same genomospecies were grouped in coherent clusters. A highly significant correlation was found between DDH values and CGM computed from AFLP data. The species definition threshold was found to range from 0.071 to 0.098 mismatches per site, according to host-infecting groups, presumably as a result of large genome size differences. Genomic distances allowed new Frankia strains to be assigned to nine genomospecies previously determined by DDH. The applicability of AFLP for the characterization of uncultured endophytic strains was tested on experimentally inoculated plants and then applied to Alnus incana and A. viridis field nodules hosting culture refractory spore-positive (Sp+, that sporulate in planta) strains. Only 1.3% of all AFLP fragments were shown to be generated by the contaminant plant DNA and did not interfere with accurate genomospecies identification of strains. When applied to field nodules, the procedure revealed that Alnus Sp+ strains were bona fide members of the Alnus Myrica host infecting group. They displayed significant genomic divergence from genomospecies G1 of Alnus infecting strains (i.e. Frankia alni) and thus may belong to another subspecies or genomospecies. PMID- 21310573 TI - A new arginase enzymatic reactor: development and application for the research of plant-derived inhibitors. AB - This work was dedicated to the development of a new micro immobilized enzyme reactor (IMER) by using an in situ procedure. Arginase was covalently immobilized on an ethylenediamine (EDA) monolithic convective interaction media (CIM) disk (12mm * 3mm i.d.) previously derivatized with glutaraldehyde. The activity of this IMER was investigated by inserting this micro-IMER in a HPLC system. The effect of the arginase inhibitors was evaluated by the simultaneous injection of each inhibitor with the nitro guanidino benzene (NGB) substrate. The relative IC50 values were found in agreement with those derived by the conventional spectrometric method. This arginase micro-IMER system was also used to study the effects of plant-derived products on the arginase activity. The pet ether extract from the stem bark of the plant Ficus glomerata Roxob. and the procyanidin oligomers of cocoa and chocolate inhibit the arginase activity. Our results confirmed the direct effect of some plant extracts on the arginase activity and their interest in therapies for treating several NO-dependent smooth disorders. PMID- 21310574 TI - Fluorous derivatization and fluorous-phase separation for fluorometric determination of naproxen and felbinac in human plasma. AB - Fluorous derivatization followed by fluorous-phase liquid chromatographic (LC) separation exploits the affinity between perfluoroalkyl compounds for highly selective and quantitative isolation of various analytes. However, the applicability of this technique as a simple pretreatment for fluorometric determination in clinical settings has not been fully explored. Here we show the applicability of this technique to the clinical determination of non-steroidal anti-inflammatory drugs (NSAIDs) in human plasma. Naproxen and felbinac, widely used native-fluorescent NSAIDs with a carboxyl group, can have toxic effects at acute doses, and were therefore chosen as representative NSAIDs. Samples were precolumn derivatized with a non-fluorescent fluorous amine, which allowed highly selective retention of only derivatized substances in the fluorous LC column. Thus, subsequently, only the retained fluorous-labeled and fluorescent analytes were detected fluorometrically at appropriate retention times. The detection limits for these two drugs were less than 11fmol on column. Correlation curves were liner over the range of 0.04-10 and 5-250nmol/mL plasma for both two drugs (r>0.999) with good repeatability. Thus, this method offers a simple, sensitive, and selective solution for determination of NSAIDs in clinical settings. PMID- 21310575 TI - Unifying the mathematical modeling of in vivo and in vitro microdialysis. AB - A unifying approach is presented for developing mathematical models of microdialysis that are applicable to both in vitro and in vivo situations. Previous models for cylindrical probes have been limited by accommodating analyte diffusion through the surrounding medium in the radial direction only, i.e., perpendicular to the probe axis, or by incomplete incorporation of diffusion in the axial direction. Both radial and axial diffusion are included in the present work by employing two-dimensional finite element analysis. As in previous models, the nondimensional clearance modulus (Theta) represents the degree to which analyte clearance from the external medium influences diffusion through the medium for systems exhibiting analyte concentration linearity. Incorporating axial diffusion introduces a second dimensionless group, which is the length-to radius aspect ratio of the membrane. These two parameter groups uniquely determine the external medium permeability, which is time dependent under transient conditions. At steady-state, the dependence of this permeability on the two groups can be approximated by an algebraic formula for much of the parameter ranges. Explicit steady-state expressions derived for the membrane and fluid permeabilities provide good approximations under transient conditions (quasi steady-state assumption). The predictive ability of the unifying approach is illustrated for microdialysis of sucrose in vivo (brain) and inert media in vitro, under both well-stirred and quiescent conditions. PMID- 21310576 TI - Application of a liquid chromatographic/tandem mass spectrometric method to a kinetic study of derivative glucosamine in healthy human urine. AB - A sensitive, selective and efficient liquid chromatographic/tandem mass spectrometric (LC/MS/MS) method was developed and validated for the determination of glucosamine in healthy human urine. Urine samples were extracted by acetonitrile and derivatized with o-phthalaldehyde/3-mercaptopropionic acid. Analysis was then carried out using ESI source and methanol/0.2% ammonium acetate 0.1% formic acid mobile phase gradient elution, with tolterodine tartrate as the internal standard. The linear calibration curve ranged from 0.41MUg/ml to 82.7MUg/ml. The intra-day and inter-day precisions were less than 3.93% and 10.0%, respectively. The extraction recoveries determined at three concentration levels were higher than 88.6%. The method was successfully applied for determining the urine concentration of glucosamine up to 24h after oral administration of 1g glucosamine sulfate dispersible table (containing 785.08mg glucosamine) from a clinical pharmacokinetic study in healthy volunteers. PMID- 21310577 TI - LC-MS/MS method for the simultaneous determination of clarithromycin, rifampicin and their main metabolites in horse plasma, epithelial lining fluid and broncho alveolar cells. AB - Clarithromycin (CLA) is a well established macrolide antibiotic which is frequently used in therapy of airway diseases in foals. It is extensively metabolized by CYP3A4 resulting in the antimicrobial active metabolite 14 hydroxyclarithromycin (OH-CLA). Rifampicin (RIF) is often comedicated to prevent resistance and augment therapy. RIF is a known inducer for metabolizing enzymes and transporter proteins. Therefore, comedication might bare the risks of pharmacokinetic drug interactions which were investigated in a clinical trial. As no adequate method to determine CLA, RIF and their main metabolites OH-CLA and 25 O-desacetylrifampicin (DAc-RIF) were described so far, we developed a selective and sensitive assay to measure concentrations of all four substances simultaneously in plasma, epithelial lining fluid (ELF) and broncho-alveolar cells (BAC) of foals. Drugs were measured after extraction with methyl tert-butyl ether using roxithromycin as internal standard and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) for detection. The chromatography was done isocratically using 25mM ammonium acetate buffer (pH 4)/acetonitrile (45%/55%, flow rate 200MUl/min). The MS/MS analysis was performed in the positive ion mode (m/z transitions: CLA, 748.5-590.1; OH-CLA, 764.1-606.1; RIF, 823.1 791.2; DAc-RIF, 781.1-749.1 and 837.3-679.2 for the internal standard). The method was validated according to selectivity, linearity, accuracy, precision, recovery, matrix effects and stability. The validation ranges for all substances were 2.5-25 for the low and 25-250ng/ml for the high validation range. The described assay was shown to be valid and successfully applied to measure disposition of CLA, OH-CLA, RIF and DAc-RIF in plasma, ELF and BAC of foals in a clinical trial. PMID- 21310578 TI - A case of an extensive dentigerous cyst in the maxillary sinus leading to epiphora and nasal obstruction. AB - BACKGROUND: The dentigerous cyst is defined as a cyst that originates by the separation of the follicle from around the crown of an unerupted tooth. The clinical examination reveals a missing tooth or teeth and possibly a hard swelling, sometimes resulting in facial asymmetry and possible pathologic fracture. A large maxillary cyst involves the whole sinus and can transmit pressure to the walls of the sinus and, consequently, cause ophthalmologic and nasal symptoms to develop. OBJECTIVES: To report the case of an extensive dentigerous cyst with swelling of the right cheek, accompanied by unilateral nasal obstruction and epiphora. CASE REPORT: A 21-year-old man presented with swelling of the right cheek, right-sided nasal obstruction, and watering of the right eye. Panoramic radiography revealed a relatively large and well-defined radiolucency enveloping an unerupted maxillary canine tooth. Computed tomography scan showed a cystic lesion measuring 5.2 cm horizontally, 4.3 cm vertically, and 4 cm sagittally, with expansion and erosion of the anterosinus cortical bone. The mass was seen to extend into the right half of the nasal cavity up to the right ethmoid air cells, and was in contact with the base of the skull. The bony margins of the right maxillary antrum were thinned out, the osteomeatal complex was pushed medially-superiorly, and the pterygoid plates were intact. Excision of the dentigerous cyst of the right maxilla was performed using the Caldwell-Luc approach under general anesthesia. CONCLUSION: A dentigerous cyst arising from an unerupted tooth should be considered in the differential diagnosis of nasal obstruction, watering or epiphora of the eye, and fistula of the gingivobuccal sulcus. PMID- 21310579 TI - Life-threatening rupture of a renal angiomyolipoma in a patient taking over-the counter horse chestnut seed extract. AB - BACKGROUND: Alternative medical therapies are increasingly being prescribed due to their good safety profile and perceived limited side effects. They are often unregulated and prescribed over the counter. One such medication is horse chestnut seed extract (HCSE), which is used for the treatment of chronic venous insufficiency and is known to affect blood coagulation. Angiomyolipoma (AML) is a benign fat-containing mesenchymal tumor of the kidney. It is often found incidentally and in most cases can be managed conservatively. Rupture of the kidney with hemorrhage is a well-known complication that may be serious and life threatening. Known risk factors for hemorrhage include anticoagulation as well as pregnancy, increased size of the lesion, high lesion vascularity, and aneurysm formation within the tumor. OBJECTIVES: The aim is to raise awareness of potential HCSE-induced anticoagulation, including, as in the case presented, acute renal AML hemorrhage. CASE REPORT: The case of a patient taking HCSE for venous insufficiency is presented. The patient suffered a life-threatening rupture of the kidney in the presence of known renal AML. She underwent emergency embolization with a successful outcome. Because HCSE-containing products are thought to be generally safe in the treatment of chronic venous insufficiency, it is important to be mindful of their potential anticoagulant properties and, therefore, their relative contraindication both in patients taking other anticoagulants and those with known renal AML. CONCLUSION: We demonstrate a potentially life-threatening association between HSCE-containing products and renal AML, highlighting the risk associated with HSCE-induced anticoagulation. PMID- 21310580 TI - Examining risk perception among men with a family history of prostate cancer. AB - OBJECTIVE: This paper explores factors that influence the formulation of risk perception among men with a family history of prostate cancer who are currently attending a prostate cancer screening clinic. METHODS: Semi-structured interviews were conducted with fifteen participants. Interview transcripts were analyzed using interpretative phenomenological analysis. RESULTS: The following themes were identified: Risk Information Pathways, Experience with Other Prostate Disease, Exposure to Prostate Cancer Screening, Exposure to Affected Relatives, Lifestyle Factors, Illness Beliefs, and Health-Based Risk Comparisons. CONCLUSION: Understanding the contributors to risk perception and applying this knowledge during screening visits and genetic counselling may help to reduce risk distortion and result in increased adherence to screening programs and reduced psychological distress. PRACTICE IMPLICATIONS: Prostate cancer screening should incorporate counselling to address patient-specific risk concepts in order to increase the accuracy and maintain the stability of risk perceptions. PMID- 21310581 TI - The role of cultural distance between patient and provider in explaining racial/ethnic disparities in HIV care. AB - OBJECTIVE: We sought to evaluate whether cultural distance between patients and providers was associated with quality of care for people living with HIV/AIDS, and whether cultural distance helped explain racial/ethnic disparities in HIV care. METHODS: We surveyed 437 patients and 45 providers at 4 HIV clinics in the U.S. We examined the association of patients' perceived cultural distance from their providers with patient ratings of healthcare quality, trust in provider, receipt of antiretroviral therapy, medication adherence, and viral suppression. We also examined whether racial/ethnic disparities in these aspects of HIV care were mediated by cultural distance. RESULTS: Greater cultural distance was associated with lower patient ratings of healthcare quality and less trust in providers. Compared to white patients, nonwhites had significantly lower levels of trust, adherence, and viral suppression. Adjusting for patient-provider cultural distance did not significantly affect any of these disparities (p-values for mediation >.10). CONCLUSION: Patient-provider cultural distance was negatively associated with perceived quality of care and trust but did not explain racial/ethnic disparities in HIV care. PRACTICE IMPLICATIONS: Bridging cultural differences may improve patient-provider relationships but may have limited impact in reducing racial/ethnic disparities, unless coupled with efforts to address other sources of unequal care. PMID- 21310582 TI - Perceptions of cause of illness in acute myocardial infarction patients: a longitudinal study. AB - OBJECTIVE: To assess change in patient's attributions of illness over the long term in patients with acute myocardial infarction (AMI). METHODS: 178 patients were asked during the index hospitalization and 2-2.5 years after discharge whether they thought each of 13 possible factors may have contributed to their illness. Two dichotomous variables, conventional attribution (attribution to traditional risk factors, CA) and psychosocial attribution (PA), were defined and assessed for each patient. RESULTS: General stress, cigarette smoking, and heredity were the most commonly mentioned attribution for the AMI. The proportion of individuals with positive CA increased at follow up. There was little congruence between patients' attributions and actual self-reported risk factors, either at baseline or at follow up. Age, education, country of birth, and anxiety were found as independent predictors of illness attribution. The participation in a cardiac prevention and rehabilitation program (CPRP) did not contribute to a significant change in CA attributions. CONCLUSION: Substantial proportions of patients have a poor understanding of the causes of their AMI both at onset of the illness and 2-2.5 years later, notwithstanding CPRP. PRACTICE IMPLICATIONS: The health care system can ill afford complacency with regards patient education and understanding. PMID- 21310583 TI - A comparison of buprenorphine induction strategies: patient-centered home-based inductions versus standard-of-care office-based inductions. AB - Although novel buprenorphine induction strategies are emerging, they have been inadequately studied. To examine our newly developed patient-centered home-based inductions, we conducted a subgroup analysis of 79 opioid-dependent individuals who had buprenorphine inductions at an urban community health center. Participants chose their induction strategy. Standard-of-care office-based inductions were physician driven, with multiple assessments, and observed, and the patient-centered home-based inductions emphasized patient self-management and included a "kit" for induction at home. We conducted interviews and extracted medical records. Using mixed nonlinear models, we examined associations between induction strategy and opioid use and any drug use. Compared with those with standard-of-care office-based inductions, participants with patient-centered home based inductions had no significant differences in opioid use (adjusted odds ratio [AOR] = 0.63, 95% confidence interval [CI] = 0.13-2.97) but greater reductions in any drug use (AOR = 0.05, 95% CI = 0.01-0.37). Taking into account the limitations of our observational cohort study design, we conclude that participants with patient-centered home-based inductions had similar reductions in opioid use and greater reductions in any drug use than those with standard-of care office-based inductions. It is essential that new induction strategies be based on existing models or theories and be well studied. PMID- 21310585 TI - Identifying psychological distress at key stages of the cancer illness trajectory: a systematic review of validated self-report measures. AB - CONTEXT: To enable study of psychological distress along the cancer journey, we need to be able to select and map validated measures through the cancer trajectory. OBJECTIVES: To examine the performance of self-report measures for identifying clinically significant levels of psychological distress across the cancer patient trajectory. METHODS: Electronic searches of Medline, PsychInfo, CINAHL, EmBase, The Cochrane Library, AMED, BNI, ASSIA, and Web of Science were undertaken. Only studies of self-report measures that used validated diagnostic tools for psychiatric diagnosis as the criterion measure were included. We then further limited our focus to those papers that specified a trajectory stage. RESULTS: Forty-eight different self-report measures were reported in the 85 papers identified. The Hospital Anxiety and Depression Scale (HADS) was the most frequently reported measure (23 times). Several other measures were reported between two and four times, but most (37) measures were reported only once. Twenty-two of the 85 included papers reported measure performance by trajectory stage. Best performing measures based on validation data available could be identified for each trajectory stage: for pretreatment, the HADS for identifying depression; during treatment, the HADS and Mental Health Inventory-5 (MHI-5) together for identifying clinically significant distress; post-treatment, the HADS for identifying depression; and at recurrence and during the palliative phase, the Brief Edinburgh Depression Scale (BEDS) for identifying depression. CONCLUSION: No single measure had evidence to support use throughout the illness trajectory in a longitudinal study, but the HADS, in combination with the MHI-5, was supported during the cancer treatment phase, and BEDS in the palliative care phase. PMID- 21310584 TI - [Epilepsy surgery: when thinking about? Who are the good candidates?]. AB - Epilepsy surgery concerns any patient with pharmacoresistant partial epilepsy, responsible for disability. Children and adult patients can be candidates for epilepsy surgery. A presurgical evaluation, adapted to each patient, must identify the most precisely the cortical area, where the seizures originate, using converging data: the clinical and electroencephalographic semiology of the seizures, the structural and sometimes functional brain imagings, and evaluate if the removal of the epileptogenic focus may induce a neurological or cognitive deficit, using neuropsychological tests and sometimes functional brain imagings. Such therapeutical strategy should be evoked as soon as possible in patients for whom the epilepsy becomes pharmacoresistant, and these patients should be oriented in specialized centres. The results of epilepsy surgery vary according to the lobar origin of the epileptogenic focus and to the existence of a visible lesion on brain MRI. A multidisciplinary evaluation of the benefits and risks should be presented to the patient. Results of the surgery are usually excellent when a focus is clearly identified and the neuropsychological tests did not predict a deficit. PMID- 21310586 TI - Attention deficit hyperactivity disorder (ADHD) in childhood epilepsy. AB - ADHD and epilepsy common are both common childhood disorders and both can have significant negative consequences on a child's behavioural, learning, and social development. Both conditions can co-occur and population studies suggest that the prevalence of ADHD in childhood epilepsy is between 12 and 17%. The prevalence of epilepsy in ADHD is lower but it is not clear if the rate of epilepsy is higher in ADHD populations than in the general population. There is a higher occurrence of ADHD--Primarily Inattentive subtype in children with epilepsy and the reasons for this are not altogether clear but attention difficulties are very prevalent in childhood epilepsy. Seizure/epilepsy variables do not appear to be important correlates in most cases of ADHD in epilepsy although they may play a role in some cases. Individuals with both epilepsy and intellectual disability may be at higher risk for significant ADHD symptoms although screening and assessment in children with intellectual disability and epilepsy may be challenging. Children with epilepsy and ADHD are likely to be at higher risk for more negative outcomes in school and in terms of quality of life compared with children with epilepsy alone. Published studies on the treatment of ADHD in childhood epilepsy have focussed exclusively on the use of psychopharmacology and particularly methylphenidate. Although methylphenidate appears to be effective for some children with epilepsy the issue of whether it may lower seizure threshold continues to be debated. Children with epilepsy are at significant risk for ADHD and there is a need for more studies focussing on safe and efficacious interventions for symptoms of ADHD in this population. PMID- 21310587 TI - Are gross motor skills and sports participation related in children with intellectual disabilities? AB - This study compared the specific gross motor skills of 156 children with intellectual disabilities (ID) (50 <= IQ >= 79) with that of 255 typically developing children, aged 7-12 years. Additionally, the relationship between the specific gross motor skills and organized sports participation was examined in both groups. The Test of Gross Motor Development-2 and a self-report measure were used to assess children's gross motor skills and sports participation, respectively. The children with ID scored significantly lower on almost all specific motor skill items than the typically developing children. Children with mild ID scored lower on the locomotor skills than children with borderline ID. Furthermore, we found in all groups that children with higher object-control scores participated more in organized sports than children with lower object control scores. Our results support the importance of attention for well developed gross motor skills in children with borderline and mild ID, especially to object-control skills, which might contribute positively to their sports participation. PMID- 21310588 TI - Physical activity and fitness in children with developmental coordination disorder: a systematic review. AB - Developmental coordination disorder (DCD) is a neurodevelopmental condition characterized by poor motor proficiency that interferes with a child's activities of daily living. Activities that most young children engage in such as running, walking, and jumping are important for the proper development of fitness and overall health. However, children with DCD usually find these activities challenging. A systematic review of the literature was conducted to synthesize the recent available data on fitness and physical activity in children with DCD, and to understand the extent of the differences between children with DCD and their typically developing peers. Systematic searches of electronic databases and reference lists identified 40 peer-reviewed studies meeting the inclusion criteria. These studies were reviewed in terms of: (a) study design, (b) population, (c) assessment tools, (d) measures, and (e) fitness and physical activity outcomes. It has been demonstrated that body composition, cardiorespiratory fitness, muscle strength and endurance, anaerobic capacity, power, and physical activity have all been negatively associated, to various degrees, with poor motor proficiency. However, differences in flexibility were not conclusive as the results on this parameter are mixed. Studies' limitations and the impact of results on future work are discussed. PMID- 21310589 TI - A model study on the circuit mechanism underlying decision-making in Drosophila. AB - Previous elegant experiments in a flight simulator showed that conditioned Drosophila is able to make a clear-cut decision to avoid potential danger. When confronted with conflicting visual cues, the relative saliency of two competing cues is found to be a sensory ruler for flies to judge which cue should be used for decision-making. Further genetic manipulations and immunohistological analysis revealed that the dopamine system and mushroom bodies are indispensable for such a clear-cut or nonlinear decision. The neural circuit mechanism, however, is far from being clear. In this paper, we adopt a computational modeling approach to investigate how different brain areas and the dopamine system work together to drive a fly to make a decision. By developing a systems level neural network, a two-pathway circuit is proposed. Besides a direct pathway from a feature binding area to the motor center, another connects two areas via the mushroom body, a target of dopamine release. A raised dopamine level is hypothesized to be induced by complex choice tasks and to enhance lateral inhibition and steepen the units' response gain in the mushroom body. Simulations show that training helps to assign values to formerly neutral features. For a circuit model with a blocked mushroom body, the direct pathway passes all alternatives to the motor center without changing original values, giving rise to a simple choice characterized by a linear choice curve. With respect to an intact circuit, enhanced lateral inhibition dependent on dopamine critically promotes competition between alternatives, turning the linear- into nonlinear choice behavior. Results account well for experimental data, supporting the reasonableness of model working hypotheses. Several testable predictions are made for future studies. PMID- 21310590 TI - Multivariate sigmoidal neural network approximation. AB - Here we study the multivariate quantitative constructive approximation of real and complex valued continuous multivariate functions on a box or RN, N?N, by the multivariate quasi-interpolation sigmoidal neural network operators. The "right" operators for our goal are fully and precisely described. This approximation is derived by establishing multidimensional Jackson type inequalities involving the multivariate modulus of continuity of the engaged function or its high order partial derivatives. Our multivariate operators are defined by using a multidimensional density function induced by the logarithmic sigmoidal function. The approximations are pointwise and uniform. The related feed-forward neural network is with one hidden layer. PMID- 21310591 TI - Interaction between COMT haplotypes and cannabis in schizophrenia: a case-only study in two samples from Spain. AB - Cannabis use is one of the environmental factors with more solid evidence contributing to schizophrenia risk, especially in genetically susceptible individuals. One of the genes that may interact with cannabis is COMT, although available data are scarce. Here, we present a case-only study of the putative COMT-cannabis interaction in schizophrenia. Two Spanish samples from Santiago de Compostela and Valencia were screened for cannabis use. One hundred and fifty five individuals from a total of 748 patients were identified as cannabis users. Five SNPs in COMT, defining three common functional haplotypes with different enzymatic activities, were genotyped and analyzed for association at the SNP, haplotype and genotype levels. An association was detected between cannabis use and low activity variants (P<0.01) in the joint analysis and results were consistent between the two samples. Schizophrenic subjects homozygous for the Met allele at rs4680 doubled the probability of lifetime prevalence of cannabis use in comparison to Val homozygous (Mantel-Haenszel OR=2.07, 95% CI: 1.27-3.26, P=0.0031, in the combined sample). These data are in contrast to those from Caspi et al. (Biol. Psychiatry 57 (2005)1117-1127) who found association between schizophrenia/schizophreniform disorder and homozygosity at the high activity Val variant of rs4680. The results of our study are discussed in the context of previous findings, suggesting the involvement of COMT polymorphisms in the association between cannabis use and schizophrenia as well as the existence of additional factors mediating this association. However, further research is needed to confirm the COMT-cannabis interaction. PMID- 21310592 TI - Victims of bullying in childhood and suicide attempts in adulthood. AB - PURPOSE: To examine whether self-reported exposure to bullying during childhood is associated with suicide attempts over the life course, and if so, what mechanisms could account for this relationship. SUBJECTS AND METHODS: A random probability sample comprising 7461 respondents was interviewed for the 2007 survey of psychiatric morbidity of adults in Great Britain. Survey respondents were asked about suicidal attempts and whether they were bullied in childhood. RESULTS: Recall of being bullied in childhood decreased with age from 25% of 16 24-year-olds to 4% among those 75 or over with few differences in the proportions between men and women. Bullying co-occurred with several victimisation experiences including sexual abuse and severe beatings and with running away from home. Even after controlling for lifetime factors known to increase the risk of suicidal behaviour, adults who reported bullying in childhood were still more than twice as likely as other adults to attempt suicide later in life. DISCUSSION: Being the victim of bullying involves the experience of suffering a defeat and humiliation that in turn could lead to entrapment, hopelessness, depression and suicidal behaviour. CONCLUSIONS: Bullying is already known to be associated with substantial distress and other negative consequences and this further evidence of a strong correlation with the risk of suicide in later life should increase further the motivation of society, services and citizens to act decisively to reduce bullying in childhood. PMID- 21310593 TI - Effects of the BDNF Val66Met polymorphism on neural responses to facial emotion. AB - The brain derived neurotrophic factor (BDNF) Val66Met polymorphism has been associated with affective disorders, but its role in emotion processing has not been fully established. Due to the clinically heterogeneous nature of these disorders, studying the effect of genetic variation in the BDNF gene on a common attribute such as fear processing may elucidate how the BDNF Val66Met polymorphism impacts brain function. Here we use functional magnetic resonance imaging examine the effect of the BDNF Val66Met genotype on neural activity for fear processing. Forty healthy participants performed an implicit fear task during scanning, where subjects made gender judgments from facial images with neutral or fearful emotion. Subjects were tested for facial emotion recognition post-scan. Functional connectivity was investigated using psycho-physiological interactions. Subjects were genotyped for the BDNF Val66Met polymorphism and the measures compared between genotype groups. Met carriers showed overactivation in the anterior cingulate cortex (ACC), brainstem and insula bilaterally for fear processing, along with reduced functional connectivity from the ACC to the left hippocampus, and impaired fear recognition ability. The results show that during fear processing, Met allele carriers show an increased neural response in regions previously implicated in mediating autonomic arousal. Further, the Met carriers show decreased functional connectivity with the hippocampus, which may reflect differential retrieval of emotional associations. Together, these effects show significant differences in the neural substrate for fear processing with genetic variation in BDNF. PMID- 21310595 TI - Magnetic resonance spectroscopy of the anterior cingulate cortex in eating disorders. AB - The anterior cingulate cortex plays a key role in eating disorders (ED), but it remains an open question whether there are deviations of the neurochemistry of this region in patients with ED. Seventeen adult female patients with ED (10 with bulimia nervosa, 7 with anorexia nervosa) were compared to 14 matched female healthy controls using single voxel magnetic resonance spectroscopy of the anterior cingulate cortex. Group comparisons did not reveal any differences between patients and controls, but a positive correlation between glutamate and myo-inositol signals with "drive for thinness" in patients with bulimia nervosa was found in exploratory correlation analyses. PMID- 21310594 TI - Brain morphometry changes and depressive symptoms after traumatic brain injury. AB - Traumatic brain injury (TBI) is associated with an increased risk of depressive symptoms. Recent imaging studies on spontaneous depression have implicated several brain structures; however, few studies have done the same for post-TBI depression. We report on a pilot observational study correlating atrophy of brain regions of interest in subjects after TBI with depressive symptoms measured by the Beck Depression Inventory-II. Regional brain volumes were calculated on both acute and 6-month MRI using an automated segmentation algorithm (FreeSurfer). Percent volume changes in brain regions were correlated with BDI-II scores using Spearman's rank order correlation coefficient. Correction for multiple comparisons was performed using the false discovery rate (FDR). Three regions of interest (left rostral anterior cingulate and bilateral orbitofrontal cortex) were found to be significantly correlated with depressive symptoms (FDR 0.05). With FDR 0.1, six regions were significantly correlated. The use of volumetric analysis of brain regions of interest to study post-TBI depression is worthy of further study. Regions associated with depressive symptoms in this pilot study were similar to those implicated in study of spontaneous depression. PMID- 21310596 TI - Controllable synthesis and characterization of porous polyvinyl alcohol/hydroxyapatite nanocomposite scaffolds via an in situ colloidal technique. AB - During the last decades, there have been several attempts to combine bioactive materials with biocompatible and biodegradable polymers to create nanocomposite scaffolds with excellent biocompatibility, bioactivity, biodegradability and mechanical properties. In this research, the nanocomposite scaffolds with compositions based on PVA and HAp nanoparticles were successfully prepared using colloidal HAp nanoparticles combined with freeze-drying technique for tissue engineering applications. In addition, the effect of the pH value of the reactive solution and different percentages of PVA and HAp on the synthesis of PVA/HAp nanocomposites were investigated. The SEM observations revealed that the prepared scaffolds were porous with three dimensional microstructures, and in vitro experiments with osteoblast cells indicated an appropriate penetration of the cells into the scaffold's pores, and also the continuous increase in cell aggregation on the scaffolds with increase in the incubation time demonstrated the ability of the scaffolds to support cell growth. According to the obtained results, the nanocomposite scaffolds could be considered as highly bioactive and potential bone tissue engineering implants. PMID- 21310597 TI - Optimized grafting of antimicrobial peptides on stainless steel surface and biofilm resistance tests. AB - Antibacterial peptides, magainin I and nisin were covalently bound to stainless steel surfaces. Several procedures of surface functionalisation processes have been investigated and optimized, each step being characterized by polarization modulation reflection absorption infrared spectroscopy (PM-RAIRS) and X-ray photoemission spectroscopy (XPS). Grafting of antibacterial peptides was successfully achieved by a 3 steps functionalisation process on a chitosan polymeric layer. The antibacterial activity of the anchored magainin and nisin was tested against a gram-positive bacteria, Listeria ivanovii, i.e., the possible survival and attachment of this bacteria, was characterized on modified stainless steel surfaces. The results revealed that the adsorbed peptides reduced the adhesion of bacteria on the functionalised stainless steel surface. PMID- 21310598 TI - Treatment of glioblastoma multiforme with radiotherapy and concomitant and adjuvant temozolomide: translation of randomised controlled trial evidence into routine clinical practice. PMID- 21310599 TI - Effect of soy isoflavones on blood pressure: a meta-analysis of randomized controlled trials. AB - BACKGROUND AND AIM: The effect of soy isoflavones on blood pressure is controversial. The objective of this study was to evaluate the effect of dietary soy isoflavones on blood pressure. METHODS AND RESULTS: Trials were searched in PubMed, the Cochrane Library, Embase and references cited in related reviews and studies. A total of eleven trials were reviewed. Meta-analysis results showed a mean decrease of 2.5 mm Hg (95% CIs, - 5.35 to 0.34 mm Hg; P = 0.08) for systolic blood pressure and 1.5 mm Hg (95% CIs, - 3.09 to 0.17 mm Hg; P = 0.08) for diastolic blood pressure in the soy isoflavones-treated group compared to placebo. Meta-regression and subgroup analyses indicated that blood pressure status was a significant predictor of heterogeneity for the effect of soy isoflavones on blood pressure. Subgroup analysis of hypertensive subjects revealed that a greater blood pressure reduction was identified in the soy isoflavone-treated group compared to placebo (5 trials; SBP: - 5.94, 95% CIs [- 10.55, - 1.34] mm Hg, P = 0.01; DBP: - 3.35, 95% CIs [- 6.52, - 0.19] mm Hg, P = 0.04). In contrast, treatment with soy isoflavones did not lead to a significant reduction in blood pressure in normotensive subjects (6 trials; SBP: 0.29, 95% CIs [- 2.39, 2.97] mm Hg, P = 0.83; DBP: - 0.43, 95% CIs [- 1.66, 0.81] mm Hg, P = 0.50). CONCLUSION: Soy isoflavones had an effect of lowering blood pressure in hypertensive subjects, but not in normotensive subjects. Larger trials need to be carried out to confirm the present findings. PMID- 21310600 TI - Role of dehydroepiandrosterone in management of glucocorticoid-induced secondary osteoporosis in female rats. AB - The current study aimed to evaluate the potential role of dehydroepiandrosterone (DHEA) in the protection and intervention of glucocorticoid-induced secondary osteoporosis in female rats. For this purpose this study was conducted on five groups of female Sprague Dawley rats which were classified into: (1) negative control group received saline as vehicle, (2) osteoporotic group orally administered with prednisolone (5 mg/kg b.wt.) daily for six months, (3) positive control group orally administered with DHEA (250 mg/kg b.wt.) three times weekly for six months, (4) protective group orally administered with prednisolone daily with simultaneous oral administration of DHEA three times weekly for six months and (5) therapeutic group orally administered with prednisolone daily for six months then orally administered with DHEA three times weekly for other six months. The obtained data revealed that prednisolone administration resulted in significant decrease in serum osteocalcin (OC), 1,25-dihydroxyvitamin D(3) (1,25 (OH)(2) D(3)) and osteoprotegerin (OPG) levels accompanied with significant increase in serum parathyroid hormone (PTH) and receptor activator nuclear factor kappa B ligand (RANKL) levels. Histopathological investigation of left femur bone showed that prednisolone administration produced compression of the reduced articular surface and atrophy of the epiphyseal bone. On the other hand, DHEA supplementation to osteoporotic rats increased serum OC, 1,25-(OH)(2) D(3) and OPG levels while decreased serum PTH and RANKL levels. Moreover, DHEA administration resulted in restoration of intact epiphyseal bony structure and articular surface. In conclusion, DHEA via its control on glucocorticoid activity and androgenic action provided potent effect on bone. PMID- 21310601 TI - gamma-Oryzanol recovers mouse hypoadiponectinemia induced by animal fat ingestion. AB - Adiponectin is an insulin-sensitizing adipocyte-derived adipokine. The decrease in plasma adiponectin level (hypoadiponectinemia) is involved in the development of insulin resistance and the resulting type 2 diabetes. Our previous studies have demonstrated that gamma-oryzanol (ORZ) from rice bran suppressed NF-kappaB activation and increased adiponectin secretion from adipocyte. In this study, we have evaluated effects of oral administration of animal fat (beef tallow) and palmitate on mouse serum adiponectin level. Oral administrations of beef tallow and palmitate significantly suppressed serum adiponectin levels into around half of the initial level from 48 to 96 h after administration compared with the case of corn oil (P<0.05). Coadministration of ORZ successfully remedied mouse hypoadiponectinemia induced by ingestion of beef tallow and the relative adiponectin levels attained to 1.66+/-0.23 at 96 h after administration (mean value+/-s.e., P<0.05). Diverse physiological functions of ORZ in crop bran might be promising us to prevent chronic inflammations in the pathogeneses of the metabolic or insulin resistance syndromes. PMID- 21310602 TI - Pathway engineering for functional isoprenoids. AB - Pathway engineering is to engineer biosynthetic pathways for compounds of interests in heterologous organisms such as microbes and higher plants, which has also been one of the most important fields in metabolic engineering and synthetic biology. This review focuses on pathway engineering researches for the production of functional isoprenoids containing monoterpenes, sesquiterpenes, diterpenes, and triterpenes as well as carotenoids and for the elucidation of relevant biosynthesis genes and enzymes, which have been performed in the last two years. As microbial hosts, Escherichia coli and Saccharomyces cerevisiae have often been employed, since they, specifically the former, are fully amenable to genetic manipulations with extensive molecular resources. Various crops have also been used as the hosts for engineering pathways of functional isoprenoids of the plant origin, particularly carotenoids. PMID- 21310603 TI - What's new in obstetric anesthesia? AB - The current article covers some of the major themes that emerged in 2009 in the fields of obstetric anesthesiology, obstetrics, and perinatology, with a special emphasis on the implications for the obstetric anesthesiologist. PMID- 21310604 TI - Transcutaneous carbon dioxide measurements and maternal pain scores in laboring parturients. PMID- 21310605 TI - Prenatal diagnosis of morbidly adherent placenta. PMID- 21310606 TI - Effect of thermal pretreatment on equilibrium moisture content of lignocellulosic biomass. AB - The equilibrium moisture content (EMC) of raw lignocellulosic biomass, along with four samples subjected to thermal pretreatment, was measured at relative humidities ranging from 11% to 97% at a constant temperature of 30 degrees C. Three samples were prepared by treatment in hot compressed water by a process known as wet torrefaction, at temperatures of 200, 230, and 260 degrees C. An additional sample was prepared by dry torrefaction at 300 degrees C. Pretreated biomass shows EMC below that of raw biomass. This indicates that pretreated biomass, both dry and wet torrefied, is more hydrophobic than raw biomass. The EMC results were correlated with a recent model that takes into account additional non-adsorption interactions of water, such as mixing and swelling. The model offers physical insight into the water activity in lignocellulosic biomass. PMID- 21310607 TI - Analysis of microbial communities developed on the fouling layers of a membrane coupled anaerobic bioreactor applied to wastewater treatment. AB - The structure of the biofouling layers formed on a pilot-scale membrane-coupled upflow anaerobic sludge blanket bioreactor (UASB) used to treat urban wastewater was analyzed by scanning electron microscopy and electron-dispersive X-ray microanalysis. For comparison, control samples of the membranes were fed either UASB effluent or raw wastewater in a laboratory-scale experiment. Microbial diversity in the fouling materials was analyzed by temperature gradient gel electrophoresis (TGGE) combined with sequence analysis of partial 16S rRNA. Significant differences in structure of the Bacteria communities were observed amongst the different fouling layers analyzed in the UASB membranes, particularly following a chemical cleaning step (NaClO), while the Archaea communities retained more similarity in all samples. The main Bacteria populations identified were evolutively close to Firmicutes (42.3%) and Alphaproteobacteria (30.8%), while Archaea were mostly affiliated to the Methanosarcinales and Methanospirillaceae. Sphingomonadaceae-related bacteria and methanogenic Archaea were persistently found as components of biofouling, regardless of chemical cleaning. PMID- 21310608 TI - A novel class of dual mPGES-1/5-LO inhibitors based on the alpha-naphthyl pirinixic acid scaffold. AB - Dual inhibition of microsomal prostaglandin E(2) synthase-1 (mPGES-1) and 5 lipoxygenase (5-LO) represents a promising strategy in the development of novel anti-inflammatory drugs targeting the arachidonic acid cascade. Herein, a class of alpha-naphthyl pirinixic acids is characterized as dual mPGES-1/5-LO inhibitors. Systematic structural variation was focused on the lipophilic backbone of the scaffold and yielded detailed structure-activity relationships (SAR) with compound 16 (IC(50) mPGES-1=0.94 MUM; IC(50) 5-LO=0.1 MUM) showing the most favorable in vitro pharmacological profile. PMID- 21310609 TI - Discovery of N-methyl-1-(1-phenylcyclohexyl)methanamine, a novel triple serotonin, norepinephrine, and dopamine reuptake inhibitor. AB - The current work discloses a novel cyclohexylarylamine chemotype with potent inhibition of the serotonin, norepinephrine, and dopamine transporters and potential for treatment of major depressive disorder. Optimized compounds 1 (SERT, NET, DAT, IC(50)=169, 85, 21 nM) and 42 (SERT, NET, DAT IC(50)=34, 295, 90 nM) were highly brain penetrant, active in vivo in the mouse tail suspension test at 30 mpk po and were not general motor stimulants. PMID- 21310610 TI - Discovery of muscarinic acetylcholine receptor antagonist and beta 2 adrenoceptor agonist (MABA) dual pharmacology molecules. AB - We sought to design dual pharmacology bronchodilators targeting both the M(3) muscarinic acetylcholine and beta-2 adrenergic (beta(2)) receptors by applying our multivalent approach to drug discovery. Herein, we describe our initial discovery and the SAR of the first such compounds with matched potencies at both receptors. PMID- 21310611 TI - Design and evaluation of a 2-(2,3,6-trifluorophenyl)acetamide derivative as an agonist of the GPR119 receptor. AB - The design and synthesis of a GPR119 agonist bearing a 2-(2,3,6 trifluorophenyl)acetamide group is described. The design capitalized on the conformational restriction found in N-beta-fluoroethylamide derivatives to help maintain good levels of potency while driving down both lipophilicity and oxidative metabolism in human liver microsomes. The chemical stability and bioactivation potential are discussed. PMID- 21310612 TI - Discovery of N-methyl-1-(1-phenylcyclohexyl)ethanamine, a novel triple serotonin, norepinephrine and dopamine reuptake inhibitor. AB - Novel chiral cyclohexylaryl amines were developed with potent reuptake inhibition against the serotonin, norepinephrine and dopamine transporters and activity at 10 and 30 mpk PO in the mouse tail suspension test. Prototype compound 31 (SERT, NET, DAT IC(50) <= 1, 21, 28 nM) was highly brain penetrant, had minimal CYP and hERG inhibition, and represents a previously undisclosed architecture with potential for treatment of major depressive disorder. PMID- 21310613 TI - Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer. AB - A novel 5-phenylamino-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione series of MEK inhibitors has been developed using structure-based drug design. Lead optimization of this series led to the discovery of TAK-733. This was advanced to Phase I clinical studies for cancer treatment. PMID- 21310614 TI - Muscle cramps and coffee. PMID- 21310615 TI - Four and a half LIM protein 1 gene mutations cause four distinct human myopathies: a comprehensive review of the clinical, histological and pathological features. AB - Mutations in the four and a half LIM protein 1 (FHL1) gene were recently identified as the cause of four distinct skeletal muscle diseases. Since the initial report outlining the first fhl1 mutation in 2008, over 25 different mutations have been identified in patients with reducing body myopathy, X-linked myopathy characterized by postural muscle atrophy, scapuloperoneal myopathy and Emery-Dreifuss muscular dystrophy. Reducing body myopathy was first described four decades ago, its underlying genetic cause was unknown until the discovery of fhl1 mutations. X-linked myopathy characterized by postural muscle atrophy is a novel disease where fhl1 mutations are the only cause. This review will profile each of the FHL1, with a comprehensive analysis of mutations, a comparison of the clinical and histopathological features and will present several hypotheses for the possible disease mechanism(s). PMID- 21310616 TI - Internal mammary lymph node metastasis in breast cancer: predictive models to assist with prognostic influence. AB - BACKGROUND: Metastatic breast cancer in the internal mammary nodes (IMN) indicates a poor prognosis. Several recent epidemiological surveys have determined a reduction in survival for patients with medial compared to lateral sector tumors attributing this to a higher rate of unrecognized IMN metastasis and hence these patients are undertreated with adjuvant therapy.(1-6) AIM: Through mathematical modeling based on large datasets we aim to quantify the impact on survival of IMN metastases at different tumor and axillary stages. METHODS: Mathematical models were created to estimate the survival of patients with and without IMN metastasis. It was assumed that the different rate of survival between medial and lateral sector breast cancers was a result of the differential rate of unrecognized IMN metastases with resultant under-staging and under treatment. We applied these models on a retrospective database analysis from the Surveillance, Epidemiology and End-Results (SEER) registries from 1994 to 2003. RESULTS: The 10-year odds of death (OOD) from breast cancer for patients with medial compared with lateral sector tumors ranged from 1.2 to 1.5 depending on stage. The predicted odds of breast cancer death for patients with unrecognized IMN metastases ranged from 2.4 to 20, with the highest OOD in the groups with small tumors and no axillary node metastasis. CONCLUSIONS: Through modeling we have been able to predict and quantify the significantly worse survival outcomes for patients with undiagnosed IMN metastasis. PMID- 21310617 TI - Mechanisms of GII.4 norovirus evolution. AB - Since the late 1990s norovirus (NoV) strains belonging to a single genotype (GII.4) have caused at least four global epidemics. To date, the higher epidemiological fitness of the GII.4 strains has been attributed to a faster rate of evolution within the virus capsid, resulting in the ability to escape herd immunity. Four key factors have been proposed to influence the rate of evolution in NoV. These include host receptor recognition, sequence space, duration of herd immunity, and replication kinetics. In this review we discuss recent advancements in our understanding of these four mechanisms in relation to GII.4 evolution. PMID- 21310618 TI - Outcome of medulloblastoma in children treated with reduced-dose radiation therapy plus adjuvant chemotherapy. AB - Medulloblastoma is the most common malignant brain tumor in children. Post surgical craniospinal irradiation (CSI; 30-36 Gy) plus local boost radiation therapy (RT; 54-56 Gy) is a standard treatment for children with medulloblastoma who are over 3 years old, resulting in a 5-year overall survival (OS) rate of 46% to 65% in average-risk patients and 50% in high-risk patients. The addition of chemotherapy has the benefit of reducing complications from radiation and improving the OS rate. Using this approach, the estimated 5-year OS rates for patients with average- and high-risk medulloblastomas treated with different protocols are 65% to 85% and 16% to 70%, respectively. In this study, we determined the outcome of patients with average- and high-risk medulloblastomas treated with reduced dosage CSI and chemotherapy with an oral etoposide-based regimen. The study included 49 patients, with a mean age of 7.7 +/- 3.4 years. Twenty-six patients (53%) were classified as average-risk and 23 patients (47%) as high-risk. In the average-risk group, the 5-year progression free survival (PFS) rate was 62.9% +/- 10% and the 5-year OS rate was 70.4% +/- 9.5%. In the high-risk group the 5-year PFS rate was 48.9% +/- 13% and the 5-year OS rate was 49.7% +/- 13%. In the average-risk group, patients who received CSI of either 24 Gy (n=20) or 36 Gy (n=9) showed no difference in their 5-year PFS and OS rates. We found that patients who were <= 10 years old and patients who were female had a significantly better 5-year PFS rate. PMID- 21310619 TI - Synthesis and biological activity of amino acid conjugates of abscisic acid. AB - We prepared 19 amino acid conjugates of the plant hormone abscisic acid (ABA) and investigated their biological activity, enzymatic hydrolysis by a recombinant Arabidopsis amidohydrolases GST-ILR1 and GST-IAR3, and metabolic fate in rice seedlings. Different sets of ABA-amino acids induced ABA-like responses in different plants. Some ABA-amino acids, including some that were active in bioassays, were hydrolyzed by recombinant Arabidopsis GST-IAR3, although GST-ILR1 did not show hydrolysis activity for any of the ABA-amino acids. ABA-L-Ala, which was active in all the bioassays, an Arabidopsis seed germination, spinach seed germination, and rice seedling elongation assays, except in a lettuce seed germination assay and was hydrolyzed by GST-IAR3, was hydrolyzed to free ABA in rice seedlings. These findings suggest that some plant amidohydrolases hydrolyze some ABA-amino acid conjugates. Because our study indicates the possibility that different plants have hydrolyzing activity toward different ABA-amino acids, an ABA-amino acid may function as a species-selective pro-hormone of ABA. PMID- 21310620 TI - Identification of new GATA4-small molecule inhibitors by structure-based virtual screening. AB - Members of the GATA family of transcription factors are zinc finger proteins that were shown to play evolutionary conserved roles in cell differentiation and proliferation in different organisms. We hypothesized that by finding new molecules that inhibit their function to be crucial in future therapeutical interventions for various diseases. By virtual high throughput screening using a version of glide (Schrodinger(r)) program with both crystal and NMR structure of GATA C-terminal zinc finger, we identified new small molecular weight chemicals with lead-like properties. We used in vitro cell-based assays to show that these molecules selectively and efficiently inhibit GATA4 activity by inhibiting its interaction with the DNA. In addition we showed that these molecules can block the activation of downstream target genes by GATA4. Moreover these compounds can moderately enhanced a mouse model of myoblast differentiation into myotubes. This might be partially due to decreased GATA4/DNA interaction as shown by gel retardation assays. Further investigation is needed to reach selectivity and efficacy. Our study however do show that in silico screening combined with in vitro studies are efficient tools to unravel new molecules that interact with zinc finger proteins such as GATA4. PMID- 21310621 TI - Radiosynthesis, biodistribution and micro-SPECT imaging study of dendrimer-avidin conjugate. AB - Partially acetylated generation five polyamidoamine (PAMAM) dendrimer (G5-Ac) was reacted with biotin and 2-(p-isothiocyanatobenzyl)-6-methyl-diethylenetria minepentaacetic acid (1B4M-DTPA), respectively to form the complex Bt-G5-Ac-1B4M which was further conjugated with avidin to give the conjugate Av-G5-Ac-1B4M. Then both of the conjugates were radiolabeled with technetium-99m ((99m)Tc), respectively. Their in vitro cellular uptake study shows that the conjugate of Av G5-Ac-1B4M-(99m)Tc exhibits much higher cellular uptake in HeLa cells than that of Bt-G5-Ac-1B4M-(99m)Tc. Accordingly the following evaluation such as in vitro/in vivo stability, biodistribution and micro-SPECT imaging was observed only for the conjugate of Av-G5-Ac-1B4M-(99m)Tc. PMID- 21310622 TI - Sensilla on the antennal funiculus of the blow fly, Protophormia terraenovae (Diptera: Calliphoridae). AB - The morphology of the antennal funiculus and the external morphological characteristics and distribution of sensilla of blow fly, Protophormia terraenovae, have been studied using light and scanning electron microscopy. Cross section of the funiculus is roughly triangular in shape, with an anterior medial, anterior-lateral, and posterior surface. The latter presents some large size pits on restricted lateral and median areas of the proximal funiculus, and several smaller-size ones close to the pedicel-funiculus joint. The entire surface of the antennal sub-segment appears densely populated by microtrichia and is inhabited by seven types of sensilla: one trichoid, two basiconic, one auriculate, one coeloconic, and two basiconic-like pit sensilla. Trichoid, basiconic, auriculate and basiconic-like types display a multiporous wall, a feature characteristic of insect olfactory sensilla. It remains to be verified whether or not the coeloconic structure type has wall pores. The most abundant sensilla are the trichoid ones, which are followed by the basiconic, coeloconic and auriculate types in a decreasing density order. The basiconic-like pit sensilla are present only on the posterior funicular surface, unlike the remaining ones which populate the entire sub-segment. The blow fly' funiculus displays a significant, even though moderate sexual dimorphism, the female sub segment being bigger and presenting a higher number of trichoid and auriculate sensilla. The presence of multiple wall pores in most of sensilla types implies an olfactory modality for sensory neurons they accomodate, thus indicating that the blow fly' funiculus is a plain olfactory organ. PMID- 21310623 TI - Development of in-situ measurement for 90 Sr specific activity by beta-ray survey meter combined with sensitivity correction by Monte Carlo calculation. AB - The objective of this study was to develop an in-situ measurement technique for the instant detection of the (90)Sr contamination. A numerical method to correct the detection efficiency of the beta survey meter was applied for an elk antler sample from the vicinity of the Mayak facility. The estimated (90)Sr specific activity of 0.21+/-0.04 Bq/g agrees within the factor of two to the value 0.11+/ 0.06 Bq/g evaluated with the imaging plate, which was previously validated. Also, the dependence of the detection efficiency was shown to be an exponential function of the sample thickness and nearly proportional to the area of the sample. PMID- 21310624 TI - Simulation of a method for determining one-dimensional 137 Cs distribution using multiple gamma spectroscopic measurements with an adjustable cylindrical collimator and center shield. AB - With multiple in situ gamma spectroscopic measurements obtained with an adjustable cylindrical collimator and a circular shield, the arbitrary one dimensional distribution of radioactive material can be determined. The detector responses are theoretically calculated, field measurements obtained, and a system of equations relating detector response to measurement geometry and activity distribution solved to estimate the distribution. This paper demonstrates the method by simulating multiple scenarios and providing analysis of the system conditioning. PMID- 21310625 TI - Clinical and pathological features of three-year survivors of malignant pleural mesothelioma following extrapleural pneumonectomy. AB - OBJECTIVE: Surgery-based multimodality therapy is associated with long-term survival in a significant number of pleural mesothelioma patients. We explored factors associated with 3-year survival in patients with malignant pleural mesothelioma, who underwent extrapleural pneumonectomy, to help refine patient selection criteria for surgery and other therapies. METHODS: With Institutional Review Board approval, we reviewed records in the International Mesothelioma Program Patient Data Registry to identify all patients, who underwent extrapleural pneumonectomy for malignant pleural mesothelioma between 1 January 1988 and 31 May 2007. Vital status as of 31 May 2010 was confirmed. Fisher's exact test was used to compare dichotomous variables for patients who survived at least 3 years with those who did not. Kaplan-Meier analysis was used to estimate the cumulative survival probability for all 3-year survivors. RESULTS: Among 636 patients who underwent extrapleural pneumonectomy, 117 (18%) survived at least 3 years following surgery, including 26 remaining alive and four lost to follow-up. Of the 3-year survivors, 39 (33%) were female, 61 (52%) had left-sided disease, and the median age was 56 years (range 27-77). Relatively more 3-year survivors were younger than, or at the median age (p=0.0005), or female (p=0.0007), had epithelial tumor histology (p<0.0001) and/or had normal white blood cell count (p=0.0001), hemoglobin (p<0.0001), or platelet count (p<0.0001) preoperatively. The median survival of the 117 patients who survived 3-years was 59 months. Among these patients, a significant association between age and survival was found only for women. CONCLUSIONS: A significant proportion of patients undergoing extrapleural pneumonectomy for pleural mesothelioma experienced extended survival. Although favorable prognostic features were more common, the cohort of 3-year survivors included a substantial number of patients with late-stage disease. The longest survival (median greater than 7 years) was experienced by women under the median age of 56 years. These data support the role of macroscopic cytoreduction through extrapleural pneumonectomy in the context of multimodality therapy to extend survival for malignant pleural mesothelioma. Further efforts to treat micrometastatic disease and improve patient selection are warranted. PMID- 21310626 TI - Synthesis, crystal structure, antimicrobial activity and DNA-binding of hydrogen bonded proton-transfer complex of 2,6-diaminopyridine with picric acid. AB - A proton-transfer (charge transfer) complex formed on the reaction between 2,6 diaminopyridine (donor) and picric acid (acceptor) was synthesized and characterized by FTIR, (1)H NMR, thermal and elemental analysis. The crystal structure determined by single-crystal X-ray diffraction indicates that cation and anion are joined together by strong N(+)-H- -O(-) type hydrogen bonds. The hydrogen-bonded charge transfer (HBCT) complex was screened for its pharmacology such as antimicrobial activity against various fungal and bacterial strains and Calf thymus DNA-binding. The results showed that HBCT complex (100MUg/ml) exhibited good antibacterial antifungal activity as that of standard antibiotics Tetracycline and Nystatin. A molecular frame work through H-bonding interactions between neighboring moieties is found to be responsible for high melting point of resulting complex. This has been attributed to the formation of 1:1 HBCT complex. PMID- 21310627 TI - Photo-activated 5-hydroxyindole-3-acetic acid induces apoptosis of prostate and bladder cancer cells. AB - 5-Hydroxyindole-3-acetic acid (5-HIAA), an indole derivative, is the main metabolite of serotonin in the human body. We determined whether or not ultraviolet B (UVB)-activated 5-HIAA (5-HIAA(UVB)) affects the viability of human prostate (LnCaP and PC-3) and bladder cancer cells (TCCSUP). While 5-HIAA alone had no cytotoxic effect at <1mM, 5-HIAA(UVB) induced LnCaP, PC-3, and TCCSUP cell death in a time- and dose-dependent manner. Cell cycle analysis showed that 5 HIAA(UVB) markedly increased the sub-G(0)/G(1) phase and resulted in cell cycle disruption. To elucidate the death mechanism by 5-HIAA(UVB), we examined the signal transduction pathways related to apoptosis using Western blot analysis. 5 HIAA(UVB) led to phosphorylation of stress-activated signaling proteins, such as c-Jun N-terminal kinase (JNK) and/or p38 mitogen-activated protein kinase (MAPK). Furthermore, 5-HIAA(UVB) activated caspase-8, -9, and -3 and cleaved poly(ADP ribose) polymerase (PARP), which are indicators of apoptosis. From these findings, the present study demonstrated that 5-HIAA(UVB) induces apoptotic cell death of prostate and bladder cancer cells via stress-mediated signaling and apoptotic pathways. Therefore, we suggest that 5-HIAA might be used as a new photosensitizer for photodynamic cancer therapy. PMID- 21310628 TI - A comparison of polycystic ovary syndrome and related factors between lesbian and heterosexual women. AB - OBJECTIVES: Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder associated with infertility, cardiovascular disease and type 2 diabetes. Despite anecdotal evidence that lesbians may have higher PCOS rates than heterosexuals, little empirically based evidence supports this theory. To address this gap, we examined PCOS prevalence and associated factors among a community sample of lesbian and heterosexual women. METHODS: Lesbian (n = 114) and heterosexual (n = 97) women aged 35 to 45 who participated in The Epidemiologic STudy of HEalth Risk (ESTHER) Project (Pittsburgh, PA) were recruited into our PCOS exploratory study between April and October 2008. A reproductive endocrinologist, "blinded" to participant sexual orientation, identified women with PCOS using a modified version of the 2003 Rotterdam Diagnostic Criteria for PCOS. Sexual orientation was defined by self-reported sexual identity, behavior, and attraction. Fisher's exact, chi-square, and Wilcoxon rank-sum tests were used for analysis. RESULTS: Approximately 6.2% (n = 13) of the total sample (n = 211) had PCOS. PCOS rates did not significantly differ between lesbian and heterosexual women ([7.9%, n = 9] vs. [4.1%, n = 4]; p = .256). No significant differences in PCOS-related factors were found between lesbian and heterosexual women: polycystic ovaries ([10.5%, n = 12] vs. [6.2%, n = 6]; p = 0.261), hirsutism ([24.6%, n = 28] vs. [15.5%, n = 15]; p = 0.102), oligomenorrhea ([3.6%, n = 4] vs. [5.4%, n = 5]; p = 0.735), adult acne ([21.1%, n = 24] vs. [24.7%, n = 24], p = 0.524), and median testosterone ([1.69 ng/mL, n = 114] vs. [1.52 ng/mL, n = 97]; p = 0.069) and androstenedione ([1.63 ng/mL, n = 114] vs. [1.51 ng/mL, n = 97]; p = 0.079) concentrations, respectively. CONCLUSION: PCOS and related factors did not differ by sexual orientation. Despite this, our observed rates warrant the need for additional studies to examine the relationship between PCOS diagnoses, PCOS-related factors, and sexual orientation. PMID- 21310629 TI - Dry mouth as an initial sign of food-borne botulism: a case report and review of the literature. AB - Botulism is a rare neuroparalytic disease caused by a potent neurotoxin produced by Clostridium botulinum. There are different clinical types of botulism. Early diagnosis of the condition is essential for effective treatment. We report a case of food-borne botulism in identical twins characterized by severe initial oral involvement and a review of the literature about the condition. PMID- 21310630 TI - Alveolar crest regeneration using curvilinear dentoalveolar distraction osteogenesis: a preliminary study. AB - OBJECTIVE: The objective of this study was to reconstruct alveolar crest at home position using distraction osteogenesis (DO) with a personalized curvilinear distractor designed through computer-aided technology. STUDY DESIGN: Five adult dogs were recruited and the maxillary alveolar bone from the first incisor to the first premolar was excised. The dentoalveolar segment adjacent to the defect was osteotomized as a bone transport disk. After 8 weeks of consolidation, the dogs were humanely killed, and the regenerated bone was analyzed. RESULTS: The DO was successful in the experimental group. The radiographs and histology both verified new bone bridging distraction gap. However, the newly formed bone was located more internally and was not in original position. CONCLUSIONS: The proposed method to reconstruct alveolar crest at home position is improper. The key point was how to maintain the distraction space and hold it at the home position. The barrier membrane technique may be used together with DO to resolve the problem. PMID- 21310631 TI - The effect of varying healing times on orthodontic mini-implant stability: a microscopic computerized tomographic and biomechanical analysis. AB - OBJECTIVE: The aim of this study was to evaluate the effect of different healing times on the stability of titanium mini-implants used for orthodontic anchorage. STUDY DESIGN: Eight male beagles were used and randomized into 4 groups according to different healing times (1, 3, 5, and 7 weeks); each group had 2 beagles. Sixty-four mini-implants were inserted bilaterally in the maxilla and mandible of the beagles. Microscopic computerized tomography (MUCT) and pull-out test were used for morphometric and biomechanical analysis, respectively. RESULTS: All MUCT parameters and F(max) (maximum pull-out force) increased with the prolongation of healing time. One week after insertion, all 4 measurements, namely osseointegration, trabecular bone volume density, intersection surface, and F(max), were lower in the maxilla group than in the mandible group (P < .05). Between the span of 1 and 3 weeks after insertion, a more obvious rising tendency of the 4 values was observed in the maxilla group than in the mandible group. Five and 7 weeks after insertion, the maxilla group expressed higher values of the 4 measurements than the mandible group (P < .05). CONCLUSIONS: Although insertion in the mandible could provide higher primary stability for mini implants, with the prolongation of healing time, insertion in the maxilla achieves higher osseointegration. The results indicated that insertion in maxilla has a more positive effect on the stability of mini-implants than insertion in the mandible. PMID- 21310632 TI - Curved versus straight root canals: the benefit of activated irrigation techniques on dentin debris removal. AB - OBJECTIVE: The aim of this study was to compare the efficacy of hydrodynamic and ultrasonic-activated irrigation to conventional syringe irrigation in removing dentin debris in straight and curved root canals. STUDY DESIGN: Twelve human teeth were selected for study. The root canals of 6 single-rooted premolars with straight canals and 6 molar roots with curved canals were prepared to a size of 45 and split longitudinally. To simulate canal irregularities, 3 standardized holes were cut in 1 canal wall. The canals and holes were then covered with debris. After reassembly, 3 irrigation techniques were compared: syringe irrigation, hydrodynamic irrigation, and ultrasonic irrigation. The amount of debris that remained was evaluated microscopically and graded with a 4-score system. RESULTS: The hydrodynamic and ultrasonic irrigation techniques were significantly (P < .001) more efficient as compared with syringe irrigation in both the straight and curved root canals. Ultrasonic irrigation demonstrated a higher efficiency in the straight root canals (P < .01), whereas hydrodynamic irrigation was more efficient in the curved canals (P < .01). CONCLUSIONS: In the straight canals, ultrasonic irrigation was the most effective, but in the curved root canals, hydrodynamic irrigation was superior. PMID- 21310633 TI - Commercial mouthwashes are more effective than azole antifungals against Candida albicans biofilms in vitro. AB - OBJECTIVE: The aim of this study was to evaluate and compare the activity of prescription and over-the-counter antimicrobial compounds against planktonic and biofilm forms of Candida albicans isolated from cases of oral candidiasis in vitro. STUDY DESIGN: The efficacy of azoles, polyenes, an echinocandin, and 4 over-the-counter mouthwashes were tested against C. albicans-derived planktonic and biofilm cells. RESULTS: Planktonic cells were shown to be highly sensitive to all of the antifungal agents tested. Sessile cells were highly resistant to azoles (>=128 mg/L) but equally sensitive to caspofungin and short treatments with Corsodyl, Listerine, and Oraldene. CONCLUSIONS: Although C. albicans is sensitive to azole antifungal agents in planktonic form, it is highly resistant within the biofilm. The good efficacy of the over-the-counter mouthwashes against candidal biofilms in vitro suggests that clinical trials should now be designed to establish their role in the clinical management of oral candidal infections. PMID- 21310634 TI - Racing towards the genes for speed. PMID- 21310635 TI - Long-term effects of intermittent equine parathyroid hormone fragment (ePTH-1-37) administration on bone metabolism in healthy horses. AB - Intermittent administration of parathyroid hormone (PTH) is an anabolic therapy for osteoporotic conditions in humans. This study evaluated the effects of equine PTH fragment (ePTH-1-37) administration on bone metabolism in 12 healthy horses. Six horses each were treated once daily for 120days with subcutaneous injections of 0.5MUg/kg ePTH-1-37 or placebo. Blood was collected to determine ionized calcium (Ca(++)), total Ca (Ca(T)), inorganic phosphorus, serum equine osteocalcin (eOC), carboxy-terminal telopeptide of type I collagen (ICTP), bone specific alkaline phosphatase, and carboxy-terminal cross-linked telopeptide of type I collagen. Bone mineral density (BMD) was determined with dual X-ray absorptiometry of the metacarpus and calcaneus. Significantly higher blood Ca(++) and plasma Ca(T) concentrations were measured 5h after ePTH-1-37 administration compared to placebo. Higher serum eOC concentrations were found for ePTH-1-37 treatment at days 90 (P<0.05) and 120 (P=0.05). Significantly higher serum ICTP levels were observed with ePTH-1-37 treatment at days 60 and 90. For both study groups, BMD increased significantly in the calcaneus. Long-term use of ePTH-1-37 seemed to have no negative effects on bone metabolism in healthy horses. The absence of undesirable side effects is the premise to ensure safety for further clinical investigations in horses with increased bone resorption processes. PMID- 21310636 TI - The canine elbow: a joint in the focus of research. PMID- 21310638 TI - Metastatic gastric adenocarcinoma primarily presenting in the fallopian tube. AB - We report a 48-year-old woman presenting with gastric adenocarcinoma metastatic only to the left fallopian tube. In addition to invasive, poorly differentiated adenocarcinoma, there were areas simulating intraepithelial carcinoma, suggesting a primary fallopian tube lesion. The differential diagnosis included a metastatic process, based on unusual morphologic patterns with occasional signet-ring cells, single-cell linear pattern of infiltration, and abundant lymphvascular space invasion. Metastasis from an upper gastrointestinal primary was confirmed by immunostains (cytokeratin 7, CDX-2, and p53 positive in the tumor cells and cytokeratin 20, WT-1, estrogen, and progesterone receptors negative). Imaging studies and a posterior biopsy demonstrated primary gastric adenocarcinoma with similar histology and immunoprofile. We report an unusual case of primary gastric adenocarcinoma presenting only in the fallopian tube and discuss its mimics and differential diagnosis. PMID- 21310637 TI - Dynamic temporal and spatial regulation of mu opioid receptor expression in primary afferent neurons following spinal nerve injury. AB - Despite using prescribed pain medications, patients with neuropathic pain continue to experience moderate to severe pain. There is a growing recognition of a potent peripheral opioid analgesia in models of inflammatory and neuropathic pain. The goal of this study was to characterize the temporal and spatial expression of mu opioid receptor (mOR) mRNA and protein in primary afferent neurons in a rat L5 spinal nerve ligation model of persistent neuropathic pain. Bilateral L4 and L5 dorsal root ganglia (DRGs), L4 and L5 spinal cord segments, and hind paw plantar skins were collected on days 0 (naive), 3, 7, 14, and 35 post-spinal nerve ligation or post-sham surgery. We found that expression of mOR mRNA and protein in primary afferent neurons changed dynamically and site specifically following L5 spinal nerve ligation. Real-time RT-PCR, immunohistochemistry, and Western blot analysis demonstrated a down-regulation of mOR mRNA and protein in the injured L5 DRG. In contrast, in the uninjured L4 DRG, mOR mRNA transiently decreased on day 7 and then increased significantly on day 14. Western blot analysis revealed a persistent increase in mOR protein expression, although immunohistochemistry showed no change in number of mOR positive neurons in the uninjured L4 DRG. Interestingly, mOR protein expression was reduced in the skin on days 14 and 35 post-nerve injury and in the L4 and L5 spinal cord on day 35 post-nerve injury. These temporal and anatomically specific changes in mOR expression following nerve injury are likely to have functional consequences on pain-associated behaviors and opioid analgesia. PMID- 21310639 TI - Mucin poor mucinous tubular and spindle cell carcinoma of the kidney, with nonclassic morphologic variant of spindle cell predominance and psammomatous calcification. AB - Mucinous tubular and spindle cell carcinoma (MTSCC) is a rare type of kidney tumor that has only been recently described. The classic MTSCCs are polymorphic renal neoplasms characterized by small, elongated tubules lined by cuboidal cells and/or cords of spindled cells separated by pale mucinous stroma. Nonclassic morphologic variants and features of MTSC have not been well studied and rarely been reported. We report a challenging case of mucin-poor MTSCC with marked spindle cell predominance and focal psammomatous calcification in a 39-year-old man and describe its histologic and immunohistochemical features. Pathologists must be aware of the histologic spectrum of MTSCCs to ensure their accurate diagnosis. PMID- 21310640 TI - BINANA: a novel algorithm for ligand-binding characterization. AB - Computational chemists and structural biologists are often interested in characterizing ligand-receptor complexes for hydrogen-bond, hydrophobic, salt bridge, van der Waals, and other interactions in order to assess ligand binding. When done by hand, this characterization can become tedious, especially when many complexes need be analyzed. In order to facilitate the characterization of ligand binding, we here present a novel Python-implemented computer algorithm called BINANA (BINding ANAlyzer), which is freely available for download at http://www.nbcr.net/binana/. To demonstrate the utility of the new algorithm, we use BINANA to confirm that the number of hydrophobic contacts between a ligand and its protein receptor is positively correlated with ligand potency. Additionally, we show how BINANA can be used to search through a large ligand receptor database to identify those complexes that are remarkable for selected binding features, and to identify lead candidates from a virtual screen with specific, desirable binding characteristics. We are hopeful that BINANA will be useful to computational chemists and structural biologists who wish to automatically characterize many ligand-receptor complexes for key binding characteristics. PMID- 21310641 TI - Determination of half value layers of X-ray equipment using computed radiography imaging plates. AB - A method for determining half value layers (HVLs) of inverter-type X-ray equipment using a computed radiography (CR) systems was developed. This method is similar to the traditional method, where the air kerma (K) is measured using an ionization based dosimeter and increasing aluminum (Al) absorber thickness, but utilized an imaging plate (IP) and the sensitivity index (S number) of the CR system as the dosimeter and the dosimeter reading, respectively. The IP and the S number were calibrated using an ionization chamber having traceability to the National Standard Ionization Chamber. A modified version of the S number definition equation K=a * S(-b) was used to translate the S number to K values for X-ray beams produced using tube voltages ranging from 50 to 120 kV and additional Al filtration up to 2.5mm. The coefficient 'a' varied depending on the beam quality, while the coefficient 'b' showed a constant value of 0.991. The HVLs in the range from 1.8 to 5.5mm Al that were obtained with this method were in good agreement with those obtained with the traditional method, as uncertainties were between -7 and 4%. This method can be used to determine the HVLs of inverter-type X-ray equipment within an acceptable accuracy. PMID- 21310642 TI - [Quality of initial prescription of home oxygen therapy in a healthcare area of the Murcia Region (Spain)]. AB - OBJECTIVE: To analyse the quality of the prescription of home oxygen therapy (OT) in a health area of Murcia. METHODS: A prospective study of 125 patients in a respiratory therapy clinic, evaluated with a questionnaire and blood-gas analysis while breathing ambient air. Related respiratory therapy was also assessedin COPD and asthma patients. RESULTS: We studied 125 cases in the 3 months following the prescription of home oxygen therapy in 72 men (58%) and 53 women (42%) with a mean age of 77.2 +/- 11.6. The most common type of home OT prescribed was for palliative cases in 45 patients (36%), followed by COPD in 42 (33.6%). In 88 (92%) of the 96 medical reports that we evaluated, insufficient data as to how to administer oxygen were available. Twenty-five percent of home OT prescriptions were given without blood-gas analyses, and in the 65 cases with a blood-gas analysis only 11 (17%) met oxygen value criteria for home OT as per regulations. Oxygen desaturation was not present in 31% of the palliative care home OT cases. The analysis of blood-gases during the clinic visit in non-palliative care cases demonstrated that 61% did not meet the blood-gas criteria to continue on home OT. Eighty percent of COPD and asthma patients on home OT did not receive the correct respiratory therapy. CONCLUSIONS: Quality problems in the prescription of home OT exist in our area. Palliative care is the principal reason for home OT prescriptions. In COPD and asthma patients who receive home OT, related respiratory therapy is not ideal. PMID- 21310643 TI - [Transfusion transmitted bacterial infectious (TTBI) with blood component accountability score 2: Retrospective analysis of the French e-fit database 2000 2007. Groupe de travail-validation des IBTT (Working group for validation of transfusion-transmitted bacterial infections)]. AB - PURPOSE OF THE STUDY: Transfusion transmitted bacterial infection is an adverse reaction occurring in a patient during blood transfusion and due to the presence of bacteria in the blood component. For each transfusion transmitted bacterial infection suspicion, clinical and biological investigations should allow to either affirm the accountability of the transfused product in the occurrence of the infection (accountability score 4) or exclude it (accountability score 0). However, among 60,175 adverse reaction sheets extracted from the French e-FIT database (AFSSAPS), 143 are classified as transfusion transmitted bacterial infection diagnosis and 97 of them show a score of accountability 2 (possible). This study aims to analyze these 97 adverse reaction sheets and search for the reasons that led the haemovigilance network actors not to refine the degree of accountability in line with an exclusion or a confirmation of transfusion origin. METHOD: During collective reading sessions, each adverse reaction sheet among the 97 extracted was re-analyzed with an accountability criteria grid, built beforehand, and proposed in the technical guide sheet for transfusion transmitted bacterial infection (e-Fit AFSSAPS). RESULTS: Among the 97 analyzed adverse reaction sheets with a score accountability of 2: 12.4 % were considered as "non analysable"; 54% were reclassified in another diagnosis category: non haemolytic febrile reaction (n=12), unknown diagnosis (n=17); patient infection before transfusion (n=23); blood component's "smear" (n=9); retrograde contamination of blood component (n=5). Finally, only 18.5% adverse reaction sheets (n=18) were maintained with a true diagnosis of transfusion transmitted bacterial infection an accountability score of 2. These cases were in agreement with those described in number 2, 3 or 4 in the annex sheet "Fiche Technique TTBI". 70% of adverse reaction sheets reclassified under another diagnosis as transfusion transmitted bacterial infection had been declared between 2000 and 2004. In order to improve transfusion transmitted bacterial infection suspicions diagnosis approach and to guide the French haemovigilance network in the investigations following a transfusion transmitted bacterial infection suspicion, the group propose recommendations after each adverse reaction sheets category analysis. CONCLUSION: The improvement measures taken as part of the French haemovigilance declaration framework allowed to perfect the data quality of transfusion transmitted bacterial infection. Progresses are still to be made to improve clinical and biological declaration, in order to precise the accountability of a blood component in the occurrence of an adverse transfusion transmitted bacterial infection effect. Tracking transfusion transmitted bacterial infection notifications by a group of experts at the national level is still recommended. PMID- 21310644 TI - An in-shoe device to measure plantar pressure during daily human activity. AB - In this work, we report the development of a novel device, integrated into a shoe, to monitor plantar pressure under real-life conditions by reducing the spatial and temporal resolution. The device consists of a shoe insole with seven pressure-sensitive conductive rubber sensors and a wireless data transmission unit incorporated into a smaller measurement unit. One advantage of this approach is that the mass and volume of the measurement unit are less than 1/10th and 1/50th, respectively, of that reported for other devices. A comparison experiment was conducted for validation of the device using the F-scan system, and the initial test of the device was conducted by recording unobstructed gaits of one young adult subject and two elderly subjects. Each subject performed a straight, level walking trial at a comfortable speed for 7 m without any assistive device while wearing the in-shoe device. Changes in the plantar pressure during gait were recorded. Compared with the young subject, the pressure under the heel of the elderly subject was found to be smaller and less steep. This in-shoe device can be used to monitor plantar pressure during daily living and is expected to be useful in various clinical applications. PMID- 21310645 TI - Knee acoustic emission: a potential biomarker for quantitative assessment of joint ageing and degeneration. AB - Based on a single time-point study of 34 healthy and 19 osteoarthritic knees in three different age groups (early, middle and late adulthood), this paper reports the potential of knee acoustic emission as a biomarker to monitor joint ageing and degeneration. Measurements were made of short transient high frequency acoustic emission signals generated by knee joints under stress during repeated sit-stand-sit movements along with joint angle. A statistically significant feature profile was established using a four-phase model of sit-stand-sit movements and two waveform features. The four-phase movement model is derived from joint angle measurement during repeated sit-stand-sit movements, and it consists of the ascending-acceleration and ascending-deceleration phases in the sit-to-stand movement, followed by the descending-acceleration and descending deceleration phases in the stand-to-sit movement. The two statistically significant waveform features are extracted from AE measurement during repeated sit-stand-sit movements, and they consist of the peak magnitude value and average signal level of each AE burst. In addition to the use of bilateral plots, statistical distributions and 2D colour histograms to visualise the differences and similarities among participants, use of principal component analysis showed not only distinct data clusters corresponding to participating groups, but also an age- and disease-related trajectory progressing from the early adulthood healthy group to the late adulthood healthy group followed by the middle adulthood osteoarthritic group to the late adulthood osteoarthritic group. Furthermore, this trajectory shows increasing areas for each data cluster, with a highly compact cluster for the early adulthood healthy group at one end and a widely spread cluster for the late adulthood osteoarthritic group at the other end. From these results, a strong basis is formed for further development of knee acoustic emission as a convenient and non-invasive biomarker for quantitative assessment of joint ageing and degeneration. PMID- 21310646 TI - Dopamine agonist-triggered pathological behaviors: surveillance in the PD clinic reveals high frequencies. AB - BACKGROUND: Compulsive behaviors provoked by dopamine agonists often go undetected in clinical series, especially if not specifically inquired about. AIM: To determine the frequency of compulsive behaviors in a Parkinson's disease (PD) clinic where agonist-treated patients were routinely asked about such aberrant behaviors. METHODS: We utilized the Mayo Health Science Research database to ascertain all PD patients taking a dopamine agonist over a two year period (2007-2009). All were seen by a Mayo-Rochester Movement Disorders Staff specialist who routinely inquired about behavior compulsions. RESULTS: Of 321 PD patients taking an agonist, 69 (22%) experienced compulsive behaviors, and 50/321 (16%) were pathologic. However, when the analysis was restricted to patients taking agonist doses that were at least minimally therapeutic, pathological behaviors were documented in 24%. The subtypes were: gambling (25; 36%), hypersexuality (24; 35%), compulsive spending/shopping (18; 26%), binge eating (12; 17%), compulsive hobbying (8; 12%) and compulsive computer use (6; 9%). The vast majority of affected cases (94%) were concurrently taking carbidopa/levodopa. Among those with adequate followup, behaviors completely or partly resolved when the dopamine agonist dose was reduced or ceased. CONCLUSIONS: Dopamine agonist treatment of PD carries a substantial risk of pathological behaviors. These occurred in 16% of agonist-treated patients; however, when assessing patients whose dose was at least minimally in the therapeutic range, the frequency jumped to 24%. Pathological gambling and hypersexuality were most common. Carbidopa/levodopa therapy taken concurrently with a dopamine agonist appeared to be an important risk factor. PMID- 21310647 TI - Health-related quality of life and its determinants in Parkinson's disease: results of an Italian cohort study. AB - Parkinson's disease (PD) is a common neurodegenerative disorder with a progressive disabling course. Health-related quality of life (HrQoL) in Italian patients with PD has not been evaluated. The objective of this study was to evaluate HrQol of an Italian cohort of PD patients and to provide a comprehensive analysis of HrQoL determinants. We performed a cross-sectional survey of 70 outpatients with idiopathic PD recruited in the department of Neurology, Napoli University, Italy. Clinical data included the Unified PD Rating Scale (UPDRS), motor and non-motor symptoms. The generic instrument EuroQol (EQ-5D and EQ-VAS) was used to evaluate HrQol. Factors influencing HrQol were assessed by multivariate regression analysis. Severe problems in at least one dimension of the EQ-5D were experienced by 60% of PD patients versus 4.7% in general Italian population. The dimensions most affected were mobility, pain/discomfort and anxiety/depression with only 17.4%, 18.8% and 17.4% of patients, respectively, reporting no problems in these dimensions. The mean EQ-VAS score was 54.20 +/- 18.38. Independent determinants of reduced HrQoL were increased UPDRS scores, motor fluctuations, dyskinesias, depression and dementia. PD strongly affects HrQol in Italian patients. The results of this study should be considered in the development of national healthcare programmes aimed at improvement of the HrQoL in Italian patients with PD. In particular, these programmes should concentrate not only on motor but also on non-motor manifestations of PD. PMID- 21310648 TI - Downregulation and translocation of nuclear ING4 is correlated with tumorigenesis and progression of head and neck squamous cell carcinoma. AB - ING4 (inhibitor of growth gene 4) is a new member of the ING gene family and is implicated in chromatin remodeling and repression of cell growth. In order to explore the roles of ING4 in head and neck squamous cell carcinoma (HNSCC), ING4 expression was assessed in 214 cases of HNSCC by immunohistochemistry using tissue microarray, and in three oral SCC cell lines by immunohistochemistry and Western blotting. Expression of ING4 was also compared to clinicopathological variables, TUNEL assay staining, and the expression of several tumorigenic markers. We found nuclear expression of ING4 was gradually decreased from non cancerous epithelium and dysplasia to HNSCC and was negatively correlated with a poorly-differentiated status, T staging, and TNM staging in HNSCC. In contrast, cytoplasmic expression of ING4 was significantly increased in HNSCC and was significantly associated with lymph node metastasis and 14-3-3eta expression. In addition, nuclear expression of ING4 was positively correlated with p21 and p300 expression and with the apoptotic index. These results suggest that the decreases in nuclear ING4 may play important roles in tumorigenesis, progression and tumor differentiation in HNSCC. Increases in cytoplasmic ING4 may be due to 14-3-3eta binding and may also be involved in malignant progression. Nuclear ING4 may modulate the transactivation of target genes, promoting apoptosis and cell cycle arrest through interactions with p300 and p21. PMID- 21310649 TI - The frequent co-expression of the oncogenes PIK3CA and PAK1 in oral carcinomas. AB - PIK3CA and PAK1 are critical genes in the PI3K/AKT/PAK pathway. Amplification and strong expression of PIK3CA and PAK1 were identified in around 50% and 88% oral carcinomas, respectively, while co-expression of PIK3CA and PAK1 together was found to be present in 80% of oral carcinomas. PIK3CA and PAK1 amplification was more obvious in recurrent tumors than their primary counterparts. Low grade amplification of PAK1 was prevalent in tumor risk individuals. Knockdown of expression of PIK3CA and PAK1 reduced the oncogenic potential of tumor cells. This study is the first to demonstrate the concordant PIK3CA and PAK1 alterations in oral carcinoma. PMID- 21310650 TI - Efficacy and safety of medical ozone (O(3)) delivered in oil suspension applications for the treatment of osteonecrosis of the jaw in patients with bone metastases treated with bisphosphonates: Preliminary results of a phase I-II study. AB - Osteonecrosis of the jaw (ONJ) is an adverse event that has been reported in patients receiving cancer treatment regimens, including bevacizumab, bisphosphonates, and denosumab. We performed a preliminary open label, prospective phase I-II study in patients treated with bisphosphonate to evaluate the treatment effect and tolerability of medical ozone (O(3)) delivered in an oil suspension on BONJ lesions <=2.5cm. Ten consecutive patients with BONJ lesions not responsive to conservative treatment were pre-treated with 10days of antibiotics to reduce purulent secretions on the gum. The exposed bone lesion and osteomucosal edge was cleaned with an ultrasonic scaler. The BONJ lesion was treated with 10 local applications of medical O(3) delivered in an oil suspension for 10min. In all patients, mucosal lesions resolved with complete reconstitution of oral and jaw tissue, with 3-10 applications. No toxicity was reported. Unexpectedly, total sequestration of the necrotic bone, with spontaneous expulsion in eight patients and new bone formation around the necrotic area in two patients was observed. No patient required surgical intervention. In two patients with pre-and post-treatment X-rays, no residual bone lesions were observed after treatment. These preliminary results show the efficacy and tolerability of O(3) delivered in an oil suspension applied directly to BONJ lesions <=2.5cm, thus indicating that BONJ can be a manageable and potentially curable condition. PMID- 21310651 TI - Slow eye movements distribution during nocturnal sleep. AB - OBJECTIVE: To assess the distribution across nocturnal sleep of slow eye movements (SEMs). METHODS: We evaluated SEMs distribution in the different sleep stages, and across sleep cycles in nocturnal recordings of 10 healthy women. Sleep was scored according to standard criteria, and the percentage of time occupied by the SEMs was automatically detected. RESULTS: SEMs were differently represented during sleep stages with the following order: wakefulness after sleep onset (WASO): 61%, NREM sleep stage 1: 54%, REM sleep: 43%, NREM sleep stage 2: 21%, NREM sleep stage 3: 7%, and NREM sleep stage 4: 3% (p<0.0001). There was no difference between phasic and tonic REM sleep. SEMs progressively decreased across the NREM sleep cycles (38%, 15%, 13% during NREM sleep stage 2 in the first three sleep cycles, p=0.006), whereas no significant difference was found for REM, NREM sleep stage 1, slow-wave sleep and WASO. CONCLUSIONS: Our findings confirm that SEMs are a phenomenon typical of the sleep onset period, but are also found in REM sleep. The nocturnal evolution of SEMs during NREM sleep stage 2 parallels the homeostatic process underlying slow-wave sleep. SIGNIFICANCE: SEMs are a marker of sleepiness and, potentially, of sleep homeostasis. PMID- 21310652 TI - EEG coherence and symptom profiles of children with Attention Deficit/Hyperactivity Disorder. AB - OBJECTIVE: We compared EEG coherence in children with and without AD/HD, and sought to relate observed anomalies to AD/HD symptoms. METHODS: Forty children with AD/HD and 40 age- and sex-matched controls had eyes-closed resting EEG coherence calculated for eight interhemispheric electrode pairs and eight intrahemispheric pairs (four within each hemisphere) in the delta, theta, alpha, beta and "40 Hz" gamma bands. RESULTS: At short-medium inter-electrode distances, the AD/HD group had increased intrahemispheric coherence in delta and theta, and reduced (L>R) laterality in delta, alpha, beta and gamma. Over longer inter electrode distances, the AD/HD group had reduced intrahemispheric coherence in alpha. In interhemispheric comparisons, the AD/HD group had reduced frontal coherence in delta, alpha and gamma, increased temporal theta and reduced temporal alpha coherences, and increased central/parietal/occipital coherence in theta. Smaller left-lateralized coherences in AD/HD correlated negatively with DSM Inattentive and DSM Total scores, and smaller frontal interhemispheric coherence in alpha correlated negatively with DSM Hyperactive/Impulsive score. CONCLUSIONS: The negative correlations between AD/HD coherence anomalies and symptoms suggest that several anomalies reflect compensatory brain function. SIGNIFICANCE: Coherence differences in AD/HD may reflect anomalous frontal right hemisphere linkages that help compensate functional brain anomalies in the left frontal regions in this disorder. PMID- 21310653 TI - Functional imaging of sleep vertex sharp transients. AB - OBJECTIVE: The vertex sharp transient (VST) is an electroencephalographic (EEG) discharge that is an early marker of non-REM sleep. It has been recognized since the beginning of sleep physiology research, but its source and function remain mostly unexplained. We investigated VST generation using functional MRI (fMRI). METHODS: Simultaneous EEG and fMRI were recorded from seven individuals in drowsiness and light sleep. VST occurrences on EEG were modeled with fMRI using an impulse function convolved with a hemodynamic response function to identify cerebral regions correlating to the VSTs. A resulting statistical image was thresholded at Z>2.3. RESULTS: Two hundred VSTs were identified. Significantly increased signal was present bilaterally in medial central, lateral precentral, posterior superior temporal, and medial occipital cortex. No regions of decreased signal were present. CONCLUSION: The regions are consistent with electrophysiologic evidence from animal models and functional imaging of human sleep, but the results are specific to VSTs. The regions principally encompass the primary sensorimotor cortical regions for vision, hearing, and touch. SIGNIFICANCE: The results depict a network comprising the presumed VST generator and its associated regions. The associated regions functional similarity for primary sensation suggests a role for VSTs in sensory experience during sleep. PMID- 21310654 TI - Development of a strain for efficient degradation of polychlorinated biphenyls by patchwork assembly of degradation pathways. AB - Rhodococcus jostii RHA1 accumulates chlorobenzoates (CBA) during the degradation of polychlorinated biphenyls (PCBs). CBA degradation is considered one of the rate-limiting steps in the complete degradation of PCBs. To reduce the accumulation of CBAs, the upper pathway enzyme genes for PCB degradation of RHA1 were introduced into a CBA-degrading bacterium, Burkholderia sp. NK8. The resulting recombinant strain exhibited no biphenyl 2,3-dioxygenase (BphA) activity encoded by bphAaAbAcAd genes, which encode the large and small subunits of the terminal oxygenase component and the ferredoxin and reductase subunits responsible for electron transfer from NADH to the large subunit. The remaining enzyme genes involved in the transformation of biphenyl to benzoate, bphB2C1D1, which encode dehydrogenase, ring-cleavage dioxygenase and hydrolase, conferred activities to NK8. To obtain the BphA activity of RHA1 in NK8, sets of BphA genes were constructed by combining the bphAaAbAcAd genes of RHA1 and bphA3A4 of Pseudomonas pseudoalcaligenes KF707, encoding the ferredoxin and reductase subunits. Hybrid derivatives of BphA containing the KF707 bphA3 conferred BphA activity to NK8, and a derivative containing the RHA1 bphAaAb and KF707 bphA3A4 genes exhibited the highest BphA activity. A plasmid containing the RHA1 bphAaAb and KF707 bphA3A4 genes plus the RHA1 bphB2C1D1 genes was constructed and introduced into NK8. The resulting recombinant strain efficiently degraded 2-, 3- and 4-chlorobiphenyls with an apparent reduction in CBA accumulation in comparison to the recombinant mutant strain, which had an insertion in the cbeA gene to inactivate CBA dioxygenase. PMID- 21310655 TI - Profound oxygen desaturation due to central apneas associated with interictal generalized spike-wave discharges. PMID- 21310656 TI - The risk factors for oral mucositis and the effect of cryotherapy in patients after the BEAM and HD-l-PAM 200 mg/m(2) autologous hematopoietic stem cell transplantation. AB - PURPOSE: Oral mucositis (OM) still represents a significant complication of hematopoietic stem cell transplantations (HSCT). Observational studies focusing on risk factor definitions are still warranted. METHOD: A total of 126 patients participated in this observational study after autologous HSCT with the BEAM and HD-l-PAM 200mg/m(2) conditioning regimens. Basic clinical and laboratory variables and their impact on OM were assessed. RESULTS: Age, gender, body mass index, and baseline absolute neutrophil counts were not shown to have any negative impact on OM development. The multivariate analysis revealed oral cryotherapy non-provision as being the most significant predictor for OM incidence (p < 0.0001), followed by BEAM conditioning regimen (p = 0.007), OM in a patient's history (p = 0.002) and lower number of days since the last chemotherapy (p = 0.025). The cryotherapy was remarkably effective both in the single high-dose melphalan 200mg/m(2) conditioning regimen (18% OM in cryotherapy vs. 68% without it, p<0.0001) and in the multidrug BEAM (melphalan 140mg/m(2)) regimen (38% vs. 86%, p=0.006). CONCLUSION: Oral cryotherapy should be implemented into supportive care management in patients treated with high-dose melphalan short-infusion chemotherapy. Large and well-designed randomized trials are necessary to obtain more significant and reliable results and understanding regarding OM risk factors. PMID- 21310657 TI - Show us a sign: the search for "game changing" prostate cancer biomarkers. PMID- 21310658 TI - Prognostic value of an RNA expression signature derived from cell cycle proliferation genes in patients with prostate cancer: a retrospective study. AB - BACKGROUND: Optimum management of clinically localised prostate cancer presents unique challenges because of the highly variable and often indolent natural history of the disease. To predict disease aggressiveness, clinicians combine clinical variables to create prognostic models, but the models have limited accuracy. We assessed the prognostic value of a predefined cell cycle progression (CCP) score in two cohorts of patients with prostate cancer. METHODS: We measured the expression of 31 genes involved in CCP with quantitative RT-PCR on RNA extracted from formalin-fixed paraffin-embedded tumour samples, and created a predefined score and assessed its usefulness in the prediction of disease outcome. The signature was assessed retrospectively in a cohort of patients from the USA who had undergone radical prostatectomy, and in a cohort of randomly selected men with clinically localised prostate cancer diagnosed by use of a transurethral resection of the prostate (TURP) in the UK who were managed conservatively. The primary endpoint was time to biochemical recurrence for the cohort of patients who had radical prostatectomy, and time to death from prostate cancer for the TURP cohort. FINDINGS: After prostatectomy, the CCP score was useful for predicting biochemical recurrence in the univariate analysis (hazard ratio for a 1-unit change [doubling] in CCP 1.89; 95% CI 1.54-2.31; p=5.6*10(-9)) and the best multivariate analysis (1.77, 1.40-2.22; p=4.3*10(-6)). In the best predictive model (final multivariate analysis), the CCP score and prostate specific antigen (PSA) concentration were the most important variables and were more significant than any other clinical variable. In the TURP cohort, the CCP score was the most important variable for prediction of time to death from prostate cancer in both univariate analysis (2.92, 2.38-3.57, p=6.1*10(-22)) and the final multivariate analysis (2.57, 1.93-3.43; p=8.2*10(-11)), and was stronger than all other prognostic factors, although PSA concentration also added useful information. Heterogeneity in the hazard ratio for the CCP score was not noted in any case for any clinical variables. INTERPRETATION: The results of this study provide strong evidence that the CCP score is a robust prognostic marker, which, after additional validation, could have an essential role in determining the appropriate treatment for patients with prostate cancer. FUNDING: Cancer Research UK, Queen Mary University of London, Orchid Appeal, US National Institutes of Health, and Koch Foundation. PMID- 21310659 TI - Stroke intervention pathways: NMDA receptors and beyond. AB - Despite abundant evidence from basic/preclinical research that excessive NMDAR (N methyl-d-aspartate receptor) stimulation is a crucial step required for brain damage following a stroke, clinical trials for NMDAR blockers have all ended with disappointments. The past decade of stroke research has revealed distinct NMDAR subpopulations and many specific effectors downstream of these receptors that are differentially responsible for neuronal survival and death. These new advancements provide promising targets for the development of novel NMDAR-based neuroprotective stroke therapies that could have greater therapeutic windows and reduced side effects. In this review, we discuss these advancements with a particular emphasis on the identification of novel signaling effectors downstream of proneuronal death NMDARs and the potential implications of these findings for the development of stroke therapeutics. PMID- 21310660 TI - Interaction of zervamicin IIB with lipid bilayers. Molecular dynamics study. AB - In this work we have studied the interaction of zervamicin IIB (ZrvIIB) with the model membranes of eukaryotes and prokaryotes using all-atom molecular dynamics. In all our simulations zervamicin molecule interacted only with lipid headgroups but did not penetrate the hydrophobic core of the bilayers. During the interaction with the prokaryotic membrane zervamicin placed by its N-termini towards the lipids and rotated at an angle of 40 degrees relatively to the bilayer surface. In the case of eukaryotic membrane zervamicin stayed in the water and located parallel to the membrane surface. We compared hydrogen bonds between peptide and lipids and concluded that interactions of ZrvIIB with prokaryotic membrane are stronger than those with eukaryotic one. Also it was shown that two zervamicin molecules formed dimer and penetrated deeper in the area of lipid headgroups. PMID- 21310662 TI - Cured of fear of flying. AB - A woman is described who developed fear of flying because she took mefloquine as malaria prophylaxis prior to the flight. Mefloquine, because of its potential neurotoxicity, should not be used for persons with fear of flying. PMID- 21310661 TI - The first 5-year follow up of distal antegrade continence enema stomas. AB - AIM: We investigated 5-year results of distal sites for antegrade continence enemas (DACE). METHODS: Patients with DACE sites placed more than 5 years previously were identified. Details of procedures were obtained. Parents, and patients over 18, were telephoned and asked to answer a standardised questionnaire. RESULTS: 31 patients were identified. Median age at DACE placement was 7 years (range 3-20). Median follow up was 92 months (range 66-145). 22 tubes were placed endoscopically, 7 were placed at open surgery and 2 at laparoscopic surgery. 28 responses to the telephone questionnaire were obtained. Of these, 15 were still using their DACE and 13 had stopped. Of those who had ceased washouts: 7 reported resolution of symptoms, 4 had a colostomy, 1 an ileostomy and 1 patient had abandoned their DACE. In patients using their stoma, washouts took a median of 5 min, with a median time to result of 25 min. 10 patients reported no soiling, 4 monthly and 1 daily soiling. Median satisfaction score was 8/10 (range 1-10/10). 24 (85%) said that they would recommend a DACE. CONCLUSIONS: This is the first report of 5-year follow up of a series of patients performing DACE washouts. The results are encouraging. PMID- 21310663 TI - Regulation of acute graft-versus-host disease by human umbilical cord blood derived stromal cells in haploidentical stem cell transplantation in mice through very late activation antigen-4. AB - Human umbilical cord blood derived stromal cells (hUCBDSCs), a novel resource isolated by our laboratory, have been shown to exert an immunologic regulation. Very late activation antigen-4 (VLA-4) has been associated with graft-versus-host disease (GVHD). This study aimed to investigate the possible mechanism by in vitro co-cultured splenocytes of donor mice with hUCBDSCs and in haploidentical stem cell transplantation in mice with acute GVHD. Both hUCBDSCs and human bone marrow stromal cells (hBMSCs) elicited decreased lymphocyte expression of VLA-4, but this decrease was stronger with hUCBDSCs than with hBMSCs (p<0.05). Cotransplantation of bone marrow with hUCBDSCs significantly decreased the expression of VLA-4 compared with control mice (p<0.05). A significant reduction of VLA-4 labeling in the target organs of GVHD was evident in haploidentical mice cotransplanted with hUCBDSCs. Our study shows that hUCBDSCs may protect mouse recipients of haploidentical stem cell transplantation from aGVHD via downregulating the expression of VLA-4. PMID- 21310664 TI - Primed status of transitional B cells associated with their presence in the cerebrospinal fluid in early phases of multiple sclerosis. AB - In the present study we showed that transitional B cells of patients with clinically isolated syndrome (CIS) and relapsing-remitting multiple sclerosis (RR MS) are reduced in the peripheral blood (PB) (5.5- and 3.7-fold, respectively). In addition, these cells appeared to up-regulate different integrins (alpha4 and beta1). These observations were associated with a primed cellular status, confirmed by an increased proportion of circulating CD80(+) transitional B cells. Interestingly, these results correlate with presence of transitional B cells in the CSF. Furthermore, these cells were absent in the CSF of individuals with other inflammatory neurological disease, and their levels in paired PB and CD80 expression were normal. Altogether, our data revealed that a differential primed status of transitional B cells is a characteristic feature of early phases of MS disease, and this functional status is associated with the ability of these cells to cross the blood-CSF barrier. PMID- 21310665 TI - Multicultural challenges in epilepsy. AB - Epilepsy is a common neurological condition throughout the world. Its care involves medical expertise, but may also bring different cultural challenges. We discuss clinical, social and psychological outcomes in different cultural settings. We point out differences and similarities in epilepsy epidemiology (etiology and risk factors, prognosis, and natural history), disparities in care and health services, and cultural influences and traditional beliefs, with special respect to practical issues and possible transcultural misunderstandings. We also discuss the relevance of multicultural issues to clinicians working in developed countries. PMID- 21310666 TI - Epilepsy and stigma: an approach to understanding through the life and works of the Brazilian writer Machado de Assis (1839-1908). AB - Machado de Assis (1839-1908)-novelist, short story writer, essayist, and poet-is a fascinating personality. Had he written in French, English, German, or Italian, he would have achieved universal fame and would be in the same company as Balzac, Tolstoy, Dickens, and Dostoevsky. This article discusses stigma in epilepsy through Machado de Assis' life, literary work, and letters to other Brazilian writers. Founder of the Brazilian Academy of Letters, Machado offers an insoluble enigma to psychologists and essayists. Born in stark poverty, feeble, and ugly, he had to fight the taint of epilepsy. The documentation of epilepsy in Machado de Assis' texts and letters and the testimony of his contemporaries is unique, allowing the comprehension of scientific concepts and stigma related to epilepsy in the 19th century, when the positivist ideas of the Italian neuropsychiatrist Cesare Lombroso (1835-1909) permeated nascent Brazilian neuropsychiatry. Much of the stigma associated with epilepsy we witness today emerged from these concepts. Even today in Brazil, when barbaric crimes are committed, headlines in newspapers produced by forensic psychiatrists often attribute the conduct of the criminal to epileptic behavior. PMID- 21310667 TI - Characterization of childhood-onset complex partial seizures associated with autism spectrum disorder. AB - Autism spectrum disorder (ASD) has a close relationship with epilepsy. A previous study showed complex partial seizures (CPS) to be the most frequent type of epileptic seizures in cases of ASD. Patients with childhood-onset CPS were retrospectively studied to investigate the prevalence of ASD and to characterize the association between CPS and ASD. The study cohort comprised 86 patients with CPS manifesting at 1 to 9 years of age. Symptomatic CPS and Panayiotopoulos syndrome were excluded. Patients with ASD (ASD group) were compared with those without ASD (non-ASD group). Of the 86 patients with childhood-onset CPS, 36 (42%) also had ASD. This ASD group was predominantly male (68.6%), with higher rates of intellectual disability (69%), and reported frequent seizures (60% had monthly or more frequent seizures). CPS without secondary generalization were more common in the ASD group (69%) than in the non-ASD group (36%), as were frontal paroxysms on EEG (54.5% vs 30%, respectively). In the non-ASD group, 82% of cases had been seizure free for 2 or more years, in comparison to 50% in the ASD group. ASD is frequently associated with childhood-onset CPS. Male gender, cognitive deficits, frequent seizures, and frontal paroxysms are risk factors for the association of ASD with CPS. PMID- 21310668 TI - A role for sleep disruption in cognitive impairment in children with epilepsy. AB - Early-onset epilepsy is associated with a poor cognitive outcome, with the cumulative burden of both ictal and interictal epileptiform discharges likely to contribute significantly. Memory consolidation has been shown to occur during sleep in healthy children, with an associated electroencephalographic signature. This may be disrupted in children with epilepsy, who exhibit a high incidence of sleep disorders, whether directly related to their seizures or as a comorbidity. Conversely, seizure semiology may be influenced by sleep. In this review we present clinical and experimental evidence that suggests that the disruption of sleep architecture by epileptiform discharges may be an important factor contributing to cognitive impairment in children with epilepsy. PMID- 21310669 TI - Trajectories of pain and analgesics in oncology outpatients with metastatic bone pain. AB - A large proportion of oncology outpatients with bone metastasis report unrelieved pain that significantly interferes with daily functioning and quality of life. However, little is known about the longitudinal pattern of pain intensity and analgesic prescriptions or use. Moreover, despite considerable advantages, the use of sophisticated statistical techniques, such as hierarchical linear modeling (HLM) has not been applied to the study of pain and analgesic outcomes. In a prospective longitudinal study, HLM was used to explore predictors of pain intensity and analgesic prescription and intake at the time of enrollment into the study (intercept) and over the course of 6 weeks (trajectory) in a sample of oncology outpatients with bone metastasis who received standard care for pain. In addition to corroborating known predictors of pain intensity, previously unrecognized variables were found that appear to affect both pain and analgesic outcomes. Importantly, some of the predictors of the trajectories of pain intensity and analgesic use (ie, pain-related distress and Pain Management Index (PMI) scores) are particularly amenable to interventions. Findings from this study suggest that sophisticated statistical modeling can be used in pain research to identify individual risk factors and propose novel targets that can be used to improve pain management in oncology outpatients with bone metastasis. PERSPECTIVE: Findings from this study suggest that a large amount of inter individual variability exists in patients' experiences with cancer pain and analgesic use. Future studies need to elucidate the mechanisms that underlie these differences. PMID- 21310670 TI - Pain-related attentional biases: the importance of the personal relevance and ecological validity of stimuli. AB - The literature regarding pain-related attentional biases is currently marked by considerable inconsistency. The primary aim of the present study was to examine whether 2 stimulus-related factors may be important to the detection of pain related attentional biases: 1) the personal relevance of stimuli; and 2) their ecological validity. To do this, the present research compared the ability of a word-based dot-probe task (ie, lower ecological validity) and picture-based dot probe task (ie, higher ecological validity) to detect attentional biases using generally selected (ie, lower personal relevance) and idiosyncratically selected stimuli (ie, higher personal relevance). To do this, the present study used a large sample of chronic pain patients and matched pain-free individuals. Attentional biases were found among both chronic pain patients and pain-free individuals for idiosyncratically selected pictorial stimuli (ie, highest ecological validity and personal relevance) but not for generally selected pictorial stimuli or for pain-related word stimuli, irrespective of whether they were idiosyncratically or generally selected. These biases were found to stem from vigilance for pain-related stimuli. Overall, the findings of the present study suggest that similar pain-related attentional biases can be found among both pain-free individuals and chronic pain patients and that stimulus-related factors may be important to the detection of those biases. PERSPECTIVE: To date, research examining pain-related attentional biases has yielded inconsistent results. The present study sought to examine 2 stimulus-related factors often identified for their potential to influence the consistency of findings. The findings of this study highlight the importance of considering stimulus-related factors when designing and interpreting pain-related dot-probe research. PMID- 21310671 TI - Economic effects of an eradication protocol for first appearance of Pseudomonas aeruginosa in cystic fibrosis patients: 1995 vs. 2009. AB - BACKGROUND: Acquisition of Pseudomonas aeruginosa (Psa) and infection with mucoid strains is associated with repeated pulmonary exacerbations which often require intravenous and long-term nebulised antibiotic treatments, repeated hospitalizations and leads to a more precipitous decline in lung function. Anti Psa antibiotic therapy early in the course of Psa infection in patients with cystic fibrosis (CF) may result in eradication of Psa and prevention or delay of colonization with the organism. From January 1995 to December 2009 our paediatric CF clinic has followed an early eradication protocol for the first appearance of Psa. In this paper we report on the economic effects after 15 years as reflected in hospitalization and antibiotic usage and cost. METHODS: The Psa-eradication protocol includes 2 weeks of IV piperacillin and tobramycin, followed by oral ciprofloxacin for 3 weeks, and nebulised colistimethate for 6 months. The same protocol is used for newly diagnosed CF patients who grow Psa on their first visit or who grow a mucoid strain, multiresistant strain of Psa or whose Psa co cultured with Burkholderia cepacia complex, and for patients in whom Psa recurs after initial clearance. RESULTS: 195 Psa eradication courses were completed from 1995 to 2009 with an overall Psa clearance rate of 90%. Patients that only cultured a Psa classic (non-mucoid) strain had a clearance rate was 96.5%. The percentage of children chronically infected with Psa has declined from 44% in 1994 to 15% in 2009.Total days spent in hospital for all reasons declined by 43%; chronic Psa hospital days declined by 75%; IV and nebulised anti-Psa antibiotic costs reduced by 44%. CONCLUSIONS: Results indicate that application of a Pseudomonas eradication protocol as described in this report has economic and resource utilization benefits in addition to clinical benefits. PMID- 21310672 TI - Coeliac disease in Libyan children: a screening study based on the rapid determination of anti-transglutaminase antibodies. AB - BACKGROUND: Coeliac disease is a common disorder in North Africa; however, there are no data on coeliac disease prevalence in Libya. AIM: (1) To determine coeliac disease prevalence in Libyan schoolchildren by screening with a rapid test for IgA anti-transglutaminase determination on a blood drop; (2) to evaluate the accuracy of the rapid anti-transglutaminase test. PATIENTS AND METHODS: We screened 2920 students (1452 females and 1468 males) attending school in El Beida (Libya) by the rapid anti-transglutaminase test. Conventional ELISA anti transglutaminase in rapid test positives and small intestinal biopsy in ELISA positives were performed for coeliac disease diagnosis. Conventional IgA anti transglutaminase was performed also in 800 rapid test negative subjects. RESULTS: The rapid anti-transglutaminase test was positive in 50/2920 (1.7%) subjects but only 20/50 were confirmed by the ELISA determination. The diagnosis of coeliac disease was biopsy-confirmed in 19 out of these 20. The serum ELISA IgA anti transglutaminase was positive in 4 out of 800 rapid test negative children. Coeliac disease prevalence was 0.79-1.13%. CONCLUSIONS: Coeliac disease in Libyan children is as common as in Europe, affecting around 1% of the general population. The rapid test for IgA anti-transglutaminase determination on a blood drop was not an efficient screening test. PMID- 21310673 TI - Safety and efficacy of peginterferon alpha plus ribavirin in patients with chronic hepatitis C and coexisting heart disease. AB - BACKGROUND: Chronic hepatitis C patients with coexisting heart disease are often denied antiviral treatment due to safety concerns. However, this is not evidence based. AIMS: To evaluate safety and efficacy of pegylated interferon and ribavirin in chronic hepatitis C patients with heart disease. METHODS: Patients with overt heart disease (ischaemic heart disease, prior mechanical heart valve replacement, chronic arrhythmias and cardiomyopathy) and chronic hepatitis C were treated with standard pegylated interferon/ribavirin doses for standard duration. Cardiovascular safety was monitored by electrocardiography, echocardiography and measurement of troponin and B-type natriuretic peptide. RESULTS: Twenty-three patients (65.2% male, median age 57 years, 47.8% genotype 1) were treated. Three patients (13%) suspended treatment prematurely; 52% obtained sustained virological response, 39% relapsed, 9% were non-responders. No serious adverse event was observed. Post-treatment clinical examination, electrocardiography and echocardiography did not show any sign of progression of the pre-existing heart disease. CONCLUSIONS: Treatment with pegylated interferon/ribavirin may be safely offered to carefully selected chronic hepatitis C patients with coexisting, clinically significant heart disease. In these patients, the outcome of antiviral treatment overlaps that observed in other patient subgroups. PMID- 21310674 TI - Clinical experience with hyaluronic acid-filler complications. AB - Hyaluronic acid (HA) fillers have become the material of choice for soft-tissue augmentation. HA fillers are longer lasting, less immunogenic and can be broken down by hyaluronidase. These advantages make HA fillers the most common of the temporary fillers on the market. However, early and delayed complications, ranging from minor to severe, can occur following HA-filler injection. We evaluated and treated 28 cases of HA-filler-related complications that were referred to our hospital over a period of 5 years from July 2004 to October 2009. Twenty-eight patients were included in our study; 82.1% of the patients were female and 17.9% were male. Complications were roughly classified as nodular masses, inflammation, tissue necrosis and dyspigmentation. Affected locations, in descending order of frequency, were the perioral area, forehead, including glabella, nose, nasolabial fold, mentum, including marionette wrinkles, cheek area and periocular wrinkles. The most disastrous complication was alar rim necrosis following injection of the nasolabial fold. We propose two 'danger zones' that are particularly vulnerable to tissue necrosis following filler injection: the glabella and nasal ala. Although there is no definite treatment modality for the correction of HA-filler complications, we have managed them with various available treatment modalities aimed at minimising patient morbidity. PMID- 21310675 TI - [Outcome and outlook of living donor kidney transplantation activity in France]. AB - INTRODUCTION: In France, the bioethic law of 2004 authorized the extension of the living donor (LD) pool to members of the extended family and any person justifying of a 2 year-long relationship. The number of living donor kidney transplantation (LDKT) increased until reaching a maximum of 246 grafts in 2006 (9% of total activity). Two years later, in 2008, LKG activity slowed down to 7.6% of the total activity (222 grafts). METHODS: We analyzed all LDKT carried out in France since 2000 according to various indicators. In addition, a questionnaire was sent to renal transplant teams in order to identify potential causes for the decrease in LKG observed in France. RESULTS: From 2000 to 2006, over 1400 LDKT were performed in France. However, donor to recipient relations show that the large increase observed in 2006 was not linked to the extension of the LD pool. LDKT activity then started decreasing as soon as 2007. The questionnaire was sent back by 40/44 (91%) renal transplant teams. Their answers led to the identification of potential constrain impacting LDKT activity in France. Among these obstacles: workload and time-consuming to prepare the transplantation and the donor, ethical constrains and lack of appropriate communication and information delivered to the professionals. DISCUSSION: The important increase in LKG activity in 2006 is not clearly understood. However, several approaches to develop the activity in the next years have been identified. PMID- 21310676 TI - [Calcimimetics: physiology, results of preclinical and clinical studies, and perspectives]. AB - Secondary hyperparathyroidism is associated with an increased risk of skeletal fractures and mortality in dialysis patients. Classical treatments such as active vitamin D derivatives and surgical parathyroidectomy are efficient but have some limitations. Second generation calcimimetics allow to control serum PTH levels without increasing serum calcium phosphorus product. This article reviews the physiological bases of PTH regulation, the mode of action of calcimimetics and the results of preclinical and clinical studies evaluating the effect of calcimimetics on different biochemical, clinical and histological parameters. PMID- 21310677 TI - The story behind the name: from the Mayor's scarf to the "Mayo Clinic" or the strange semantic journey of a flexible immobilization device. PMID- 21310678 TI - Primary aneurysmal bone cyst of the patella: a case report. AB - An aneurysmal bone cyst is rare in the patella. We report the case of a 28-year old woman who presented with chronic pain and no previous trauma history. Treatment included curettage of the cyst and filling with a corticocancellous graft. Thirty-one months after surgery, the knee was mobile and painless and graft incorporation was good. PMID- 21310679 TI - Indications for ambulatory gastrointestinal and endocrine surgery in adults. PMID- 21310680 TI - Isolated gastric outlet obstruction due to corrosive ingestion. AB - OBJECTIVES: To analyze the diagnostic and therapeutic aspects of isolated gastric outlet obstruction secondary to corrosive ingestion. PATIENTS AND METHODS: Retrospective chart review of eight patients who developed gastric stricture following corrosive ingestion and were treated in the Digestive and General Surgery Service of Yopougon Teaching Hospital in Abidjan from 1991 to 2009. RESULTS: Six men and two women (mean age of 34.3 [range 21 to 48 years]) had isolated gastric outlet obstruction following accidental (n=2) or suicidal (n=6) acid ingestion. Two patients sought hospital medical attention two days after ingestion, whereas six patients came to hospital with a mean delay of 60.8 days (range 12 and 96 days). Patients sought medical attention for poor general status (n=6), postprandial vomiting (n=4), early satiety (n=2) and retrosternal pain (n=2). Two patients, who presented early to hospital, underwent upper gastrointestinal tract endoscopy the day after admission and then received a feeding jejunostomy whereas the esogastroduodenal barium swallow and feeding jejunostomy were performed after a mean delay of 2 days (range 1 and 3 days) and 3 days (range 1 and 5 days), respectively. The findings at upper endoscopy and barium swallow were: microgastria (n=2), midgastric stricture (n=1), antropyloric stricture (n=4) and gastric body stricture (n=1). One patient died preoperatively as the result of severe nutritional depletion. A follow-up endoscopy and barium swallow were performed respectively 21 and 35 days later. Definitive surgery was performed after a mean delay of 85 days (range 74 to 123 days) in the remaining seven patients. Gastric lesions were managed by total gastrectomy with Roux-en-Y esophagojejunostomy (n=2), partial gastrectomy with gastrojejunostomy (n=2) or simple gastrojejunostomy (n=3). During the mean follow-up period of 4 years (range 1 to 7 years), all patients were free of symptoms. CONCLUSION: Isolated corrosive gastric stricture is relatively rare. Surgery tailored according to the extent of gastric stricture provides excellent results. PMID- 21310681 TI - The role of surgery in the management of Barrett's esophagus (from dysplasia to cancer). AB - The goal of this review is to evaluate, through a review of the surgical literature, the role of esophagectomy in the management of Barrett's esophagus as it evolves histologically from intestinal metaplasia through increasing grades of dysplasia to adenocarcinoma. We precisely define the indications and therapeutic modalities of esophagectomy for high-grade dysplasia, superficial adenocarcinoma, and invasive adenocarcinoma. PMID- 21310682 TI - Honey in otorhinolaryngology: when, why and how? AB - In this review of the literature devoted to the use of honey, the authors analyse the composition, indications, benefits and adverse effects of this product in otorhinolaryngology and head and neck surgery. Published data indicate that honey applied topically to skin and mucosal wounds and/or burns and administered orally as antitussive medication (after the first year of life) is highly effective with no adverse effects. The physiological action of honey is the result of various mechanisms (osmotic, detersion, bactericidal action). Various medicinal honeys are available worldwide, but only one has Food and Drug Administration approval for the treatment of wounds. After the first year of life, the use of food honey appears to be as effective as medicinal honey, while decreasing the overall cost of treatment. PMID- 21310683 TI - Liver diseases unique to pregnancy: a 2010 update. AB - Liver disorders occurring during pregnancy may be specifically pregnancy-related, or may be due to an intercurrent or chronic liver disease, which may present in anyone, pregnant or not. This review focuses on the liver diseases unique to pregnancy. Hyperemesis gravidarum, which occurs during early pregnancy, may be associated with liver dysfunction. Intrahepatic cholestasis of pregnancy typically occurs during the second or third trimester. Pruritus and the associated biological signs of cholestasis improve rapidly after delivery. Mutations in gene encoding biliary transporters, especially ABCB4 encoding the multidrug resistance 3 protein, have been found to be associated with this complex disease. Ursodeoxycholic acid is currently the most effective medical treatment in improving pruritus and liver tests. Pre-eclampsia, which presents in late pregnancy frequently involves the liver, and HELLP syndrome (Hemolysis Elevated Liver enzymes-Low Platelets) is a life-threatening complication. Prognosis of acute fatty liver of pregnancy has been radically transformed by early delivery, and clinicians must have a high index of suspicion for this condition when a woman presents nausea or vomiting, epigastric pain, jaundice, or polyuria-polydipsia during the third trimester. Acute fatty liver of pregnancy has been found to be associated with a defect of long-chain 3-hydroxyacyl coenzyme A dehydrogenase in the fetus, and mothers and their offspring should undergo DNA testing at least for the main associated genetic mutation (c.1528G>C). PMID- 21310684 TI - Proximally migrated pancreatic stent successfully removed using needle-knife and forceps: complication after precut papillotomy assisted by pancreatic stenting. AB - Pancreatic stent-assisted ampullary precut papillotomy is a rescue method for cases with difficult bile duct cannulation during endoscopic retrograde cholangiopancreatography (ERCP). We describe a case in which post-ERCP pancreatitis (PEP) developed due to the proximal migration of pancreatic stent, after precut papillotomy. Removal of the migrated pancreatic stent was achieved after needle-knife incision of the pancreatic duct's orifice followed by retrieval of the stent using rat-tooth forceps, which resulted in rapid resolution of the PEP. Caution is needed when pancreatic stent is placed after papillary incision. Needle-knife incision of the pancreatic duct orifice followed by forceps removal is an effective technique for rescuing pancreatic stent migration. PMID- 21310685 TI - The status of humoral immunity in occult HBV infection in south-eastern Iranian patients. AB - BACKGROUND: Occult hepatitis B infection (OBI) is characterized as a form of hepatitis in which, despite of absence of detectable HBsAg, HBV-DNA is present in patient's peripheral blood. The aim of this study was to investigate components of humoral immunity during OBI as a possible measure of how patients respond to Hepatitis B viral infections. MATERIAL AND METHODS: In this study, HBsAg-/anti HBc+/HBV-DNA+ samples were assigned as OBI cases and SRID techniques were performed to measure levels of circulating antibodies (IgG, IgM and IgA) as well as C3, C4. In addition, complement system function was assessed by CH50. RESULTS: Our results showed that the serum levels of IgG and C4 were significantly lower in OBI patients, while IgM and C3 were higher in patients when compared to healthy controls. Serum levels of IgA and CH50 were not significantly different between OBI patients and controls. DISCUSSION: Based on these results, it could be concluded that although OBI patients produced elevated levels of IgM there may be a problem converting and progressing this response to generate enough IgG to overcome HBV infection. PMID- 21310686 TI - Widely used pesticides with previously unknown endocrine activity revealed as in vitro antiandrogens. AB - BACKGROUND: Evidence suggests that there is widespread decline in male reproductive health and that antiandrogenic pollutants may play a significant role. There is also a clear disparity between pesticide exposure and data on endocrine disruption, with most of the published literature focused on pesticides that are no longer registered for use in developed countries. OBJECTIVE: We used estimated human exposure data to select pesticides to test for antiandrogenic activity, focusing on highest use pesticides. METHODS: We used European databases to select 134 candidate pesticides based on highest exposure, followed by a filtering step according to known or predicted receptor-mediated antiandrogenic potency, based on a previously published quantitative structure-activity relationship (QSAR) model. In total, 37 pesticides were tested for in vitro androgen receptor (AR) antagonism. Of these, 14 were previously reported to be AR antagonists ("active"), 4 were predicted AR antagonists using the QSAR, 6 were predicted to not be AR antagonists ("inactive"), and 13 had unknown activity, which were "out of domain" and therefore could not be classified with the QSAR ("unknown"). RESULTS: All 14 pesticides with previous evidence of AR antagonism were confirmed as antiandrogenic in our assay, and 9 previously untested pesticides were identified as antiandrogenic (dimethomorph, fenhexamid, quinoxyfen, cyprodinil, lambda-cyhalothrin, pyrimethanil, fludioxonil, azinphos methyl, pirimiphos-methyl). In addition, we classified 7 compounds as androgenic. CONCLUSIONS: Due to estimated antiandrogenic potency, current use, estimated exposure, and lack of previous data, we strongly recommend that dimethomorph, fludioxonil, fenhexamid, imazalil, ortho-phenylphenol, and pirimiphos-methyl be tested for antiandrogenic effects in vivo. The lack of human biomonitoring data for environmentally relevant pesticides presents a barrier to current risk assessment of pesticides on humans. PMID- 21310687 TI - Finger-number interaction: an ideomotor account. AB - Recent findings have shown that processing numerical magnitude may interact with finger movements through goal-directed movements. Here we tested these number finger interactions in a response-effect (R-E) paradigm. During a learning phase, participants read meaningless consonant-vowel (CV) syllables immediately followed by unrelated opening or closing finger movements; during a transfer test, they again named these CV syllables in response to processing a small or a large number. The results showed that responding to a large magnitude number during the transfer phase was slower in an incompatible situation, that is, when the answer was the CV syllable that had been associated to a grip closure during the learning phase. This interference effect demonstrates that ideomotor principles can account for the link between the meaning of numbers and the perception of actions through an anticipated-magnitude code. PMID- 21310688 TI - Signal detection and threshold models of source memory. AB - Recently, several authors claimed that the curvilinear shape of rating-based source memory receiver operating characteristics (ROCs) refutes threshold models. However, rating-based ROCs are not diagnostic to disprove threshold models. Furthermore, source memory ROC-analyses ignore influences of other processes like old-new-detection and old-new-response-tendencies, so direct estimation of parameters is preferable. Five source monitoring experiments with different response bias manipulations and materials were conducted. We fitted the Two High Threshold Multinomial Model of Source Monitoring by Bayen, Murnane, and Erdfelder (1996) and the Multivariate Signal Detection Model for Selection DeCarlo (2003). We also included rating-based ROCs. The results suggest that both models are at least equally valid as measurement tools which capture bias processes in the corresponding parameters, and they can perhaps be integrated theoretically. PMID- 21310689 TI - Beyond procedure's content: the role of accessibility experiences and personal uncertainty in procedural justice judgements. AB - Procedural justice concerns play a critical role in economic settings, politics, and other domains of human life. Despite the vast evidence corroborating their relevance, considerably less is known about how procedural justice judgments are formed. Whereas earlier theorizing focused on the systematic integration of content information, the present contribution provides a new perspective on the formation of justice judgments by examining the influence of accessibility experiences. Specifically, we hypothesize that procedural justice judgments may be formed based on the ease or difficulty with which justice-relevant information comes to mind. Three experiments corroborate this prediction in that procedures were evaluated less positively when the retrieval of associated unfair aspects was easy compared to difficult. Presumably this is because when it feels easy (difficult) to retrieve unfair aspects, these are perceived as frequent (infrequent), and hence the procedure as unjust (just). In addition to demonstrating that ease-of-retrieval may influence justice judgments, the studies further revealed that reliance on accessibility experiences is high in conditions of personal certainty. We suggest that this is because personal uncertainty fosters systematic processing of content information, whereas personal certainty may invite less taxing judgmental strategies such as reliance on ease-of retrieval. PMID- 21310690 TI - The representation of multiplication and division facts in memory. AB - Recently, using a training paradigm, Campbell and Agnew (2009) observed cross operation response time savings with nonidentical elements (e.g., practice 3 + 2, test 5 - 2) for addition and subtraction, showing that a single memory representation underlies addition and subtraction performance. Evidence for cross operation savings between multiplication and division have been described frequently (e.g., Campbell, Fuchs-Lacelle, & Phenix, 2006) but they have always been attributed to a mediation strategy (reformulating a division problem as a multiplication problem, e.g., Campbell et al., 2006). Campbell and Agnew (2009) therefore concluded that there exists a fundamental difference between addition and subtraction on the one hand and multiplication and division on the other hand. However, our results suggest that retrieval savings between inverse multiplication and division problems can be observed. Even for small problems (solved by direct retrieval) practicing a division problem facilitated the corresponding multiplication problem and vice versa. These findings indicate that shared memory representations underlie multiplication and division retrieval. Hence, memory and learning processes do not seem to differ fundamentally between addition-subtraction and multiplication-division. PMID- 21310691 TI - Retrieval-induced forgetting of performed and observed bizarre and familiar actions. AB - To investigate whether people show retrieval-induced forgetting (RIF) for bizarre and familiar actions that they performed or observed, three experiments were conducted. In Experiment 1, participants performed bizarre and familiar actions with different objects during learning (e.g., pencil: balance the pencil across the cup, sharpen the pencil). They repeatedly performed a set of the bizarre or familiar actions during retrieval practice. After a distracter task, participants' cued recall was tested. Participants showed RIF for both bizarre and familiar actions. In Experiment 2, half of the participants performed the bizarre and familiar actions themselves; the other half observed the experimenter performing the actions. Replicating the results of Experiment 1, participants who performed the actions showed RIF for bizarre and familiar actions. In contrast, participants who observed the actions did not show RIF for either action type. Experiment 3 examined whether this lack of RIF for observed actions occurred due to a lack of active recall during retrieval practice; it did. Overall, the three experiments demonstrated RIF for both bizarre and familiar performed and observed actions. A distinctiveness account of the results is provided. PMID- 21310692 TI - Causal beliefs and empirical evidence. AB - Causal beliefs often facilitate decision making. However, strong causal beliefs can also lead to neglect of relevant empirical evidence causing errors in risky decision making (e.g., medical, financial). We investigated the impact of pre training and post-experience on the evaluation of empirical evidence in a two alternative medical diagnostic task. Participants actively searched for information about two patients on the basis of four available cues. The first experiment indicated that pre-training can weaken the strong influence of causal beliefs reducing neglect of empirical evidence. The second experiment demonstrated that increasing amounts of empirical evidence can improve people's ability to decide in favor of a correct diagnosis. The current research converges with other recent work to clarify key mechanisms and boundary conditions shaping the influence of causal beliefs and empirical evidence in decisions and causal judgments. PMID- 21310693 TI - Dissociations between ABA-, ABC-, and AAB-renewal of Pavlovian modulation in human sequential feature positive discrimination learning. AB - Using a conditioned suppression preparation, we investigated extinction and aba-, abc-, and aab-renewal of Pavlovian modulation in human sequential Feature Positive (FP) discrimination learning, X -> A+/A-. Extinction treatment was administered in the acquisition context a (aaa- and aab-groups) or in a new context b (aba- and abc-groups) and comprised X -> A- extinction trials. Discriminative X -> A/A responding was lost in all groups when tested in the extinction context. In the aba-group, the discriminative X -> A/A responding totally recovered when retested in the acquisition context a. For the aaa-, the aab-, and the abc-group, discriminative X -> A/A responding did not reappear when tested for renewal in, respectively, contexts a, b, and c. The demonstration of aba-renewal of extinguished modulation, but not abc- and aab-renewal, suggests that extinction in a context different from the acquisition context and a return to the original acquisition context might both be critical for renewal of Pavlovian modulation in human FP-discrimination learning. PMID- 21310694 TI - Evidence of vocal and manual event files in auditory negative priming. AB - Negative priming with auditory as well as with visual stimuli has been shown to involve the retrieval of prime response information as evidenced by an increase of prime response errors to the probes of ignored repetition trials compared to control trials. We investigated whether prime response retrieval processes were also present for response modalities other than manual responding. In an auditory four alternative forced choice task participants either vocally or manually identified a target sound while ignoring a distractor sound. Negative priming was of equal size in both response modalities. What is more, for both response modalities, there was evidence of increased prime response errors in ignored repetition trials compared to control trials. The findings suggest that retrieval of event files of the prime episode including prime response information is a general mechanism underlying the negative priming phenomenon irrespective of stimulus or response modality. PMID- 21310695 TI - Women's own-gender bias in face recognition memory. AB - Women remember more female than male faces, whereas men do not seem to display an own-gender bias in face recognition memory. Why women remember female faces to a greater extent than male faces is unclear; one proposition is that women attend more to and thereby process female faces more effortfully than male faces during encoding. A manipulation that distracts attention and reduces effortful processing may therefore decrease women's own-gender bias by reducing memory for female faces relative to male faces. In three separate experiments, women and men encoded female and male faces for later recognition in full attention and divided attention conditions. Results consistently showed that women, in contrast to men, displayed a reliable own-gender bias. Importantly, the magnitude of women's own gender bias was not reduced in divided attention conditions, indicating that it is not a result of effortful processing of female faces. We suggest these results reflect that women have greater perceptual expertise for female faces, facilitating recognition memory. PMID- 21310696 TI - Conscious and unconscious reward cues can affect a critical component of executive control. AB - The present study investigates whether updating an important function of executive control can be driven by unconscious reward cues. Participants had to memorize several numbers and update those numbers independently according to a sequence of arithmetic operations. At the beginning of each trial, a reward (1 euro or 5 cents) was presented, either subliminally or supraliminally. Participants could earn the reward if they found the correct response on the updating task. Results showed better performance when a high (conscious or unconscious) reward was at stake compared to a low reward. This suggests that subliminal information can influence a component process of executive control traditionally thought to require consciousness. PMID- 21310697 TI - [Dobutamine stress cardiovascular magnetic resonance imaging in patients with peripheral artery disease]. AB - Patients with peripheral arterial disease often have coronary heart disease, as well. However, their assessment with classical noninvasive cardiology methods is often non-diagnostic or limited. The aim of this study was to analyze the feasibility and the risks of dobutamine stress cardiovascular MRI for cardiac evaluation of patients with peripheral arterial disease. 21 patients with peripheral artery disease (mean+/-SD age 64.3+/-7.7 years) were studied prospectively with dobutamine stress cardiovascular MRI. The protocol was completed by all of 21 patients. The target heart rate was attained in 95.2% of the studies. No serious adverse event occurred. The image quality scores (1-4) for all ventricular wall segments were high (median, interquartile range) (4 [4 4]). Five patients (23.8%) have inducible wall motion abnormality. Interobserver agreement was almost perfect for wall motion scores (kappa = 0.87, p<0.0001). Dobutamine stress cardiovascular MRI is feasible with low risk for the cardiological assessment of patients with peripheral arterial disease. PMID- 21310698 TI - [The "gray zone" in organized mammography screening: histocytological correlations]. AB - The National Public Health Program has established the organized mammography screening in Hungary. The aim of this study was to conduct an audit of "gray zone" smears of the organized mammography screening in comparison with histopathological diagnoses. METHODS: Cytology results were rated to C3 atypia probably benign and C4 suspicious of malignancy. RESULTS: 1361 women had aspiration cytology performed from a total of 47,718 mammography non-negative lesions. 105 (7.8%) were diagnosed as C3, whereas 78 (5.7) as C4. Of the 105 patients with C3 diagnosis 61 (58%) patients underwent surgical biopsy. Histology proved malignancy in 20 (32.8%) cases, and benign lesion in 41 (67.2%) cases. All (100%) of the 78 patients with C4 diagnosis had open biopsies; 69 (88.4%) cases were histologically malignant and 9 (11.6%) cases were benign lesions. CONCLUSION: The auditing results of fine needle aspiration cytology of "gray zone" in organized mammography screening meet the proposed threshold values. Authors conclude that the "gray zone" category in breast cytology is useful and of value if used judiciously. PMID- 21310699 TI - [Results of complex lipid-lowering therapy in patients with a history of acute coronary syndrome]. AB - Authors aimed to assess how target values in serum lipid concentrations (LDL- and HDL-cholesterol, triglyceride) can be achieved in patients with a history of acute coronary syndrome during follow up in an outpatient cardiology clinic. METHODS: 201 patients with a history of acute coronary syndrome were included and were followed up between January 1 and May 31, 2007.Authors analyzed serum lipid parameters of the patients and the lipid-lowering medications at the time of the first meeting and during follow up lasting two years. RESULTS: During the enrollment visit only 26.4% of the patients had serum LDL cholesterol at target level, whereas high triglycerides and low HDL cholesterol levels were observed in 40.3% and 33.3% of the patients, respectively. Only 22 patients (10.9%) achieved the target levels in all three lipid parameters. Of the 201 patients, 179 patients participated in the follow up, and data obtained from these patients were analyzed. There was a positive trend toward better lipid parameters; 42.5% of the patients reached the desired LDL-cholesterol target value and 17.3% of the patients had HDL-cholesterol and triglycerides target values. CONCLUSIONS: These findings are consistent with those published in the literature. Beside the currently used therapeutic options for achieving optimal LDL-cholesterol, efforts should be made to reduce the so-called "residual cardiovascular risk" with the use of a widespread application of combination therapy. PMID- 21310700 TI - [Phyllodes tumours of the breast]. PMID- 21310701 TI - [Traces of the activity of Medical Society of Eperjes (Saros County) published in Orvosi Tar (1842-1848)]. PMID- 21310702 TI - [Gustav Mahler's death centenary (1860-1911)]. PMID- 21310703 TI - [The memory of a medieval caesarean section on a numizmatics curio]. PMID- 21310705 TI - Telomeres: unlocking the mystery of cell division and aging. AB - Telomeres are DNA sequences that cap the ends of chromosomes, protecting them from fraying and fusing together during replication. During replication, telomeres lose some of their genetic material but are repaired by the ribonucleoprotein telomerase. Both telomeres and telomerase are linked to cell senescence and apoptosis, and research suggests they play key roles in aging, cancer, hereditary syndromes, and chronic diseases. Several theories of aging are reviewed along with the potential impact of telomerase in developing new treatments. PMID- 21310706 TI - There's no place like home: a pharmacist fills the need. AB - As both the number and complexity of patients receiving health care at home continues to increase, there is also a growing need for pharmacists to oversee these patients' medication regimens. This article describes the practice of one pharmacist whose skills in medication therapy management and patient counseling have carved out a unique niche caring for home health patients. PMID- 21310707 TI - Evaluation of the effectiveness of cholecalciferol in long-term care elderly patients with hypovitaminosis D. AB - OBJECTIVE: To study the efficacy and safety of cholecalciferol (vitamin D3) 2,000 units daily for 12 weeks in elderly patients with hypovitaminosis D. Secondarily, to postulate causes for those patients who did not return to normal 25-hydroxy vitamin D (25-OHD) levels. DESIGN: One-group, pretest post-test. Retrospective chart review. Data collected from Computerized Patient Record System. SETTING: Long-term care facility at Central Arkansas Veterans Healthcare System. PATIENTS, PARTICIPANTS: Potential study subjects were elderly patients (>= 65 years of age) treated with total daily dose of cholecalciferol 2,000 units daily by mouth, for at least 12 weeks' duration period between July 1, 2007, and July 31, 2009, with documented 25-OHD levels before and after treatment. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Efficacy of cholecalciferol was assessed by categorizing patients as responders (25-OHD levels >= 30 ng/mL) and nonresponders (25-OHD levels < 30 ng/mL). Safety of vitamin D3 was determined by measuring prevalence of hypercalcemia. Patient demographics, disease states, and medications that can affect 25-OHD levels between responders and nonresponders of vitamin D treatment were assessed. RESULTS: 24 patients were included in analysis. 58.3% (14) of patients responded to cholecalciferol treatment and 41.7% (10) of patients did not. The mean 25-OHD level after treatment was 38.7 ng/mL in responders and 26.4 ng/mL in non responders. Twelve patients (50%) developed hypercalcemia. CONCLUSION: The present study has shown that some long-term care elderly patients respond to three months of vitamin D supplementation. The reason why some patients did not respond cannot be determined from this study. PMID- 21310708 TI - Safety and tolerability of galantamine SA in dementia patients transitioned from donepezil. AB - OBJECTIVE: To demonstrate the safety and tolerability of galantamine SA in dementia patients transitioned from donepezil. DESIGN: One group, pretest posttest SETTING: Veterans Affairs (VA) hospital serving U.S. veterans. PATIENTS, PARTICIPANTS: Charts of 193 patients changed from donepezil to galantamine SA were reviewed. INTERVENTION: In an effort to limit the cost of medications being used for Alzheimer's disease, the Bedford VA Hospital began an initiative to transition patients to the generic sustained-release galantamine SA. A chart review was performed using the VA computerized patient record for all patients transitioned from either donepezil or rivastigmine to galantamine. Progress notes were reviewed for the first three months following initial medication exchange to determine galantamine tolerability and reasons for discontinuation. MAIN OUTCOME MEASURE: Galantamine SA tolerability at three months. RESULTS: Of the 193 patients transitioned to galantamine SA, 94.3% remained on the drug at three months. The most common reason for medication withdrawal was mental status change (n = 5). CONCLUSION: Transition to galantamine SA in a real world clinical setting was well-tolerated among patients with dementia. PMID- 21310709 TI - The consultant pharmacist provides consultation and recommendations for a medical patient. AB - This case focuses on a general medical patient who resides in a local senior community-housing center and who has multiple comorbid diseases that are commonly seen in practice. The patient's past medical history includes coronary artery disease, peptic ulcer disease, hypertension, and type 2 diabetes mellitus. The patient was recently hospitalized and treated with an intravenous antibiotic for an influenza-related pneumonia infection, then discharged with a prescription for a course of oral fluoroquinolone antibiotics. This case discusses and addresses each of the patient's conditions, various drug interactions, and issues pertaining to the patient. An interdisciplinary-team approach is important for the medical management of a patient with multiple comorbid diseases along with the contribution of a consultant pharmacist as pharmacotherapy expert. PMID- 21310710 TI - The BCL2 gene is regulated by a special AT-rich sequence binding protein 1 mediated long range chromosomal interaction between the promoter and the distal element located within the 3'-UTR. AB - The 279-bp major breakpoint region (mbr) within the 3'-untranslated region (3' UTR) of the BCL2 gene is a binding site of special AT-rich sequence binding protein 1 (SATB1) that is well known to participate in the long-range regulation of gene transcription. Our previous studies have revealed that the mbr could regulate BCL2 transcription over a 200-kb distance and this regulatory function was closely related to SATB1. This study is to explore the underlying mechanism and its relevance to cellular apoptosis. With chromosome conformation capture (3C) and chromatin immunoprecipitation (ChIP) assays we demonstrated that the mbr could physically interact with BCL2 promoter through SATB1-mediated chromatin looping, which was required for epigenetic modifications of the promoter, CREB accessibility and high expression of the BCL2 gene. During early apoptosis, SATB1 was a key regulator of BCL2 expression. Inhibition of SATB1 cleavage by treatment of cells with a caspase-6 inhibitor or overexpression of mutant SATB1 that was resistant to caspase-6, inhibited disassembly of the SATB1-mediated chromatin loop and restored the BCL2 mRNA level in Jurkat cells. These data revealed a novel mechanism of BCL2 regulation and mechanistically link SATB1-mediated long range interaction with the regulation of a gene controlling apoptosis pathway for the first time. PMID- 21310711 TI - Genome-wide chromatin occupancy analysis reveals a role for ASH2 in transcriptional pausing. AB - An important mechanism for gene regulation involves chromatin changes via histone modification. One such modification is histone H3 lysine 4 trimethylation (H3K4me3), which requires histone methyltranferase complexes (HMT) containing the trithorax-group (trxG) protein ASH2. Mutations in ash2 cause a variety of pattern formation defects in the Drosophila wing. We have identified genome-wide binding of ASH2 in wing imaginal discs using chromatin immunoprecipitation combined with sequencing (ChIP-Seq). Our results show that genes with functions in development and transcriptional regulation are activated by ASH2 via H3K4 trimethylation in nearby nucleosomes. We have characterized the occupancy of phosphorylated forms of RNA Polymerase II and histone marks associated with activation and repression of transcription. ASH2 occupancy correlates with phosphorylated forms of RNA Polymerase II and histone activating marks in expressed genes. Additionally, RNA Polymerase II phosphorylation on serine 5 and H3K4me3 are reduced in ash2 mutants in comparison to wild-type flies. Finally, we have identified specific motifs associated with ASH2 binding in genes that are differentially expressed in ash2 mutants. Our data suggest that recruitment of the ASH2-containing HMT complexes is context specific and points to a function of ASH2 and H3K4me3 in transcriptional pausing control. PMID- 21310712 TI - Regulation of gene expression in restriction-modification system Eco29kI. AB - The Eco29kI restriction-modification (R-M) system consists of two partially overlapping genes, eco29kIR, encoding a restriction endonuclease and eco29kIM, encoding methyltransferase. The two genes are thought to form an operon with the eco29kIR gene preceding the eco29kIM gene. Such an organization is expected to complicate establishment of plasmids containing this R-M system in naive hosts, since common logic dictates that methyltransferase should be synthesized first to protect the DNA from cleavage by the endonuclease. Here, we characterize the Eco29kI gene transcription. We show that a separate promoter located within the eco29kIR gene is sufficient to synthesize enough methyltransferase to completely modify host DNA. We further show that transcription from two intragenic antisense promoters strongly decreases the levels of eco29kIR gene transcripts. The antisense transcripts act by preventing translation initiation from the bicistronic eco29kIR-eco29kIM mRNA and causing its degradation. Both eco29kIM and antisense promoters are necessary for Eco29kI genes establishment and/or stable maintenance, indicating that they jointly contribute to coordinated expression of Eco29kI genes. PMID- 21310713 TI - Monitoring DNA replication in fission yeast by incorporation of 5-ethynyl-2' deoxyuridine. AB - We report procedures to allow incorporation and detection of 5-ethynyl-2' deoxyuridine (EdU) in fission yeast, a thymidine analogue which has some technical advantages over use of bromodeoxyuridine. Low concentrations of EdU (1 uM) are sufficient to allow detection of incorporation in cells expressing thymidine kinase and human equilibrative nucleoside transporter 1 (hENT1). However EdU is toxic and activates the rad3-dependent checkpoint, resulting in cell cycle arrest, potentially limiting its applications for procedures which require labelling over more than one cell cycle. Limited DNA synthesis, when elongation is largely blocked by hydroxyurea, can be readily detected by EdU incorporation using fluorescence microscopy. Thus EdU should be useful for detecting early stages of S phase, or DNA synthesis associated with DNA repair and recombination. PMID- 21310714 TI - Optimization of turn-back primers in isothermal amplification. AB - The application of isothermal amplification technologies is rapidly expanding and currently covers different areas such as infectious disease, genetic disorder and drug dosage adjustment. Meanwhile, many of such technologies have complex reaction processes and often require a fine-tuned primer set where existing primer design tools are not sufficient. We have developed a primer selection system for one important primer, the turn-back primer (TP), which is commonly used in loop-mediated amplification (LAMP) and smart amplification process (SmartAmp). We chose 78 parameters related to the primer and target sequence, and explored their relationship to amplification speed using experimental data for 1344 primer combinations. We employed the least absolute shrinkage and selection operator (LASSO) method for parameter selection and estimation of their numerical coefficients. We subsequently evaluated our prediction model using additional independent experiments and compared to the LAMP primer design tool, Primer Explorer version4 (PE4). The evaluation showed that our approach yields a superior primer design in isothermal amplification and is robust against variations in the experimental setup. Our LASSO regression analysis revealed that availability of the 3'- and 5'-end of the primer are particularly important factors for efficient isothermal amplification. Our computer script is freely available at: http://gerg.gsc.riken.jp/TP_optimization/. PMID- 21310715 TI - 2'-O-ribose methylation of cap2 in human: function and evolution in a horizontally mobile family. AB - The 5' cap of human messenger RNA consists of an inverted 7-methylguanosine linked to the first transcribed nucleotide by a unique 5'-5' triphosphate bond followed by 2'-O-ribose methylation of the first and often the second transcribed nucleotides, likely serving to modify efficiency of transcript processing, translation and stability. We report the validation of a human enzyme that methylates the ribose of the second transcribed nucleotide encoded by FTSJD1, henceforth renamed HMTR2 to reflect function. Purified recombinant hMTr2 protein transfers a methyl group from S-adenosylmethionine to the 2'-O-ribose of the second nucleotide of messenger RNA and small nuclear RNA. Neither N(7) methylation of the guanosine cap nor 2'-O-ribose methylation of the first transcribed nucleotide are required for hMTr2, but the presence of cap1 methylation increases hMTr2 activity. The hMTr2 protein is distributed throughout the nucleus and cytosol, in contrast to the nuclear hMTr1. The details of how and why specific transcripts undergo modification with these ribose methylations remains to be elucidated. The 2'-O-ribose RNA cap methyltransferases are present in varying combinations in most eukaryotic and many viral genomes. With the capping enzymes in hand their biological purpose can be ascertained. PMID- 21310716 TI - DNA translocation by type III restriction enzymes: a comparison of current models of their operation derived from ensemble and single-molecule measurements. AB - Much insight into the interactions of DNA and enzymes has been obtained using a number of single-molecule techniques. However, recent results generated using two of these techniques-atomic force microscopy (AFM) and magnetic tweezers (MT)-have produced apparently contradictory results when applied to the action of the ATP dependent type III restriction endonucleases on DNA. The AFM images show extensive looping of the DNA brought about by the existence of multiple DNA binding sites on each enzyme and enzyme dimerisation. The MT experiments show no evidence for looping being a requirement for DNA cleavage, but instead support a diffusive sliding of the enzyme on the DNA until an enzyme-enzyme collision occurs, leading to cleavage. Not only do these two methods appear to disagree, but also the models derived from them have difficulty explaining some ensemble biochemical results on DNA cleavage. In this 'Survey and Summary', we describe several different models put forward for the action of type III restriction enzymes and their inadequacies. We also attempt to reconcile the different models and indicate areas for further experimentation to elucidate the mechanism of these enzymes. PMID- 21310717 TI - GPU-powered tools boost molecular visualization. AB - Recent advances in experimental structure determination provide a wealth of structural data on huge macromolecular assemblies such as the ribosome or viral capsids, available in public databases. Further structural models arise from reconstructions using symmetry orders or fitting crystal structures into low resolution maps obtained by electron-microscopy or small angle X-ray scattering experiments. Visual inspection of these huge structures remains an important way of unravelling some of their secrets. However, such visualization cannot conveniently be carried out using conventional rendering approaches, either due to performance limitations or due to lack of realism. Recent developments, in particular drawing benefit from the capabilities of Graphics Processing Units (GPUs), herald the next generation of molecular visualization solutions addressing these issues. In this article, we present advances in computer science and visualization that help biologists visualize, understand and manipulate large and complex molecular systems, introducing concepts that remain little-known in the bioinformatics field. Furthermore, we compile currently available software and methods enhancing the shape perception of such macromolecular assemblies, for example based on surface simplification or lighting ameliorations. PMID- 21310718 TI - Childhood deaths from injuries: trends and inequalities in Europe. AB - BACKGROUND: In 1998, a UNICEF report quantified the large East-West gap in Europe in child mortality from external causes (injuries and violence). In the past decade, much has changed in central and eastern Europe, economically, politically and socially. This study updates the earlier analysis, tracking changes in deaths from external causes in the different parts of Europe. METHODS: The WHO mortality database was used to examine mortality from external causes for children aged 1 14 years between 1993 and 2008, by country, European subregion and cause. RESULTS: Deaths from external causes have fallen in all of Europe since 1993. However, a clear east-west divide persists, with higher death rates in the former Soviet countries, especially the Commonwealth of Independent States (CIS). Trends in specific causes also vary geographically; the greatest overall declines have been in transport-related deaths, drowning, poisoning and 'other' external causes. Transport, drowning and 'other' remain the commonest external causes of death in childhood. CONCLUSION: Child injury mortality rates have fallen across Europe. In the former Soviet countries, this is likely to reflect improvements in living conditions since transition. Yet, large geographical inequalities remain, highlighting the need for enhanced measures to prevent injuries, particularly in the CIS countries and the Baltic states. However, except in a few countries, there is still little research on the nature of the problem or the effectiveness of potential interventions. Child deaths from injuries are avoidable and measures to reduce them would have a significant impact upon the overall burden of child mortality in Europe. PMID- 21310719 TI - Commentary: Can 'many weak' instruments ever be 'strong'? PMID- 21310720 TI - Anaphylactic reaction after methylene blue-treated plasma transfusion. AB - Methylene blue-treated fresh-frozen plasma (MB-FFP) is mainly used in Europe. The advantage of the methylene blue system is that units can be treated individually. The combined action of methylene blue and illumination is a photodynamic process preventing viral RNA and DNA replication. We report the first immediate allergic hypersensitivity reaction to methylene blue-treated plasma transfusion. The clinical course and subsequent assessment of the allergic reaction, including skin tests and basophil activation test, confirmed methylene blue-induced IgE mediated anaphylaxis. All immediate reactions after MB-FFP transfusion should be investigated to document the underlying mechanism. PMID- 21310721 TI - Relative concentrations of haemostatic factors and cytokines in solvent/detergent treated and fresh-frozen plasma. AB - BACKGROUND: Indications, efficacy, and safety of plasma products are highly debated. We compared the concentrations of haemostatic proteins and cytokines in solvent/detergent-treated plasma (SDP) and fresh-frozen plasma (FFP). METHODS: Concentrations of the following parameters were measured in 25 SDP and FFP samples: fibrinogen (FBG), factor (F) II, F V, F VII, F VIII, F IX, F X, F XIII, von Willebrand factor (vWF), D-Dimers, ADAMTS-13 protease, tumour necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, IL-8, and IL-10. RESULTS: Mean FBG concentrations in SDP and FFP were similar, but in FFP, the range was larger than in SDP (P<0.01). Mean F II, F VII, F VIII, F IX, and F XIII levels did not differ significantly. Higher concentrations of F V (P<0.01), F X (P<0.05), vWF (P<0.01), and ADAMTS-13 (P<0.01) were found in FFP. With the exception of F VIII and F IX, the range of concentrations for all of these factors was smaller (P<0.05) in SDP than in FFP. Concentrations of TNF-alpha, IL-8, and IL-10 (all P<0.01) were higher in FFP than in SDP, again with a higher variability and thus larger ranges (P<0.01). CONCLUSIONS: Coagulation factor content is similar for SDP and FFP, with notable exceptions of less F V, vWF, and ADAMTS-13 in SDP. Cytokine concentrations (TNFalpha, IL-8, and IL-10) were significantly higher in FFP. The clinical relevance of these findings needs to be established in outcome studies. PMID- 21310722 TI - Population pharmacokinetics of nalbuphine after surgery in children. AB - BACKGROUND: Nalbuphine is an opioid analgesic agent widely used for control of mild-to-severe pain. However, limited data are available on the pharmacokinetics of this drug in children. The aim of this study was to characterize the population pharmacokinetics of nalbuphine in patients with ages ranging from 1 to 11 yr and to identify patient characteristics partially explaining inter individual variability in nalbuphine pharmacokinetic parameters. METHODS: Twenty two children were included in this study. They received nalbuphine after surgery by continuous infusion (loading dose, 0.2 mg kg(-1) over 10 min followed by continuous infusion of 0.8 mg kg(-1) over 24 h). If pain relief was not adequate, 0.1 mg kg(-1) bolus doses were allowed in 10 min. Eleven blood samples were collected per patient. The data were analysed by non-linear mixed-effect modelling with the use of a two-compartment structural model. RESULTS: Twenty patients completed the study. In the final model, the parameter values were standardized for a body weight of 70 kg using an allometric model. Population parameter estimates were: clearance 130 litre h(-1) 70 kg(-1), inter-compartment clearance 75.6 litre h(-1) 70 kg(-1), central volume of distribution 210 litre 70 kg(-1), and peripheral volume of distribution 151 litre 70 kg(-1). In the children of this study, total clearance expressed in litre h(-1) kg(-1) decreased significantly with increasing age and the elimination half-life significantly increased. CONCLUSIONS: The allometric power model developed in this study best reflected the data and may be useful for dose adjustment. PMID- 21310723 TI - Longitudinal associations of maternal depressive symptoms, maternal involvement, and diabetes management across adolescence. AB - OBJECTIVE: To examine whether maternal depressive symptoms: (a) predicted the level of maternal involvement in diabetes management tasks across adolescence; and (b) moderated associations of involvement with adolescent adherence, metabolic control, and depression. METHODS: Eighty-two youth aged 10-15 years with type 1 diabetes and their mothers completed measures at baseline and 16 months later. Participants rated maternal involvement in diabetes tasks, adherence, and depressive symptoms; metabolic control was indexed from medical records. RESULTS: Maternal depressive symptoms were associated with higher involvement at baseline, and slower declines in involvement across time. At baseline, involvement was associated with lower adolescent depression and better metabolic control, but this association was stronger when mothers reported fewer depressive symptoms. Interactions of maternal depression with involvement across time suggested maternal involvement was associated with better subsequent adherence primarily when mothers reported fewer depressive symptoms. CONCLUSIONS: Mothers' depressive symptoms may undermine her care-giving effectiveness during adolescence. PMID- 21310724 TI - The major histocompatibility complex and multiple sclerosis: a smoking gun? PMID- 21310725 TI - Independent contribution of temporal beta-amyloid deposition to memory decline in the pre-dementia phase of Alzheimer's disease. AB - The relationship between beta-amyloid deposition and memory deficits in early Alzheimer's disease is unresolved, as past studies show conflicting findings. The present study aims to determine the relative contribution of regional beta amyloid deposition, hippocampal atrophy and white matter integrity to episodic memory deficits in non-demented older individuals harbouring one of the characteristic hallmarks of Alzheimer's disease, i.e. with beta-amyloid pathology. Understanding these relationships is critical for effective therapeutic development. Brain magnetic resonance imaging and [(11)C]Pittsburgh Compound B-positron emission tomography scans were obtained in 136 non-demented individuals aged over 60 years, including 93 healthy elderly and 43 patients with mild cognitive impairment. Voxel-based correlations were computed between a memory composite score and grey matter volume, white matter volume and beta amyloid deposition imaging datasets. Hierarchical linear regression analyses were then performed using values extracted in regions of most significant correlations to determine the relative contribution of each modality to memory deficits. All analyses were conducted pooling all groups together as well as within separate subgroups of cognitively normal elderly, patients with mild cognitive impairment and individuals with high versus low neocortical beta-amyloid. Brain areas of highest correlation with episodic memory deficits were the hippocampi for grey matter volume, the perforant path for white matter volume and the temporal neocortex for beta-amyloid deposition. When considering these three variables together, only hippocampal volume and temporal beta-amyloid deposition provided independent contributions to memory deficits. In contrast to global beta-amyloid deposition, temporal beta-amyloid deposition was still related to memory independently from hippocampal atrophy within subgroups of cognitively normal elderly, patients with mild cognitive impairment or cases with high neocortical beta-amyloid. In the pre-dementia stage of Alzheimer's disease, subtle episodic memory impairment is related to beta-amyloid deposition, especially in the temporal neocortex, and independently from hippocampal atrophy, suggesting that both factors should be independently targeted in therapeutic trials aimed at reducing cognitive decline. PMID- 21310726 TI - Arterial spin labelling reveals an abnormal cerebral perfusion pattern in Parkinson's disease. AB - There is a need for objective imaging markers of Parkinson's disease status and progression. Positron emission tomography and single photon emission computed tomography studies have suggested patterns of abnormal cerebral perfusion in Parkinson's disease as potential functional biomarkers. This study aimed to identify an arterial spin labelling magnetic resonance-derived perfusion network as an accessible, non-invasive alternative. We used pseudo-continuous arterial spin labelling to measure cerebral grey matter perfusion in 61 subjects with Parkinson's disease with a range of motor and cognitive impairment, including patients with dementia and 29 age- and sex-matched controls. Principal component analysis was used to derive a Parkinson's disease-related perfusion network via logistic regression. Region of interest analysis of absolute perfusion values revealed that the Parkinson's disease pattern was characterized by decreased perfusion in posterior parieto-occipital cortex, precuneus and cuneus, and middle frontal gyri compared with healthy controls. Perfusion was preserved in globus pallidus, putamen, anterior cingulate and post- and pre-central gyri. Both motor and cognitive statuses were significant factors related to network score. A network approach, supported by arterial spin labelling-derived absolute perfusion values may provide a readily accessible neuroimaging method to characterize and track progression of both motor and cognitive status in Parkinson's disease. PMID- 21310727 TI - Parcellating the neuroanatomical basis of impaired decision-making in traumatic brain injury. AB - Cognitive dysfunction is a devastating consequence of traumatic brain injury that affects the majority of those who survive with moderate-to-severe injury, and many patients with mild head injury. Disruption of key monoaminergic neurotransmitter systems, such as the dopaminergic system, may play a key role in the widespread cognitive dysfunction seen after traumatic axonal injury. Manifestations of injury to this system may include impaired decision-making and impulsivity. We used the Cambridge Gambling Task to characterize decision-making and risk-taking behaviour, outside of a learning context, in a cohort of 44 patients at least six months post-traumatic brain injury. These patients were found to have broadly intact processing of risk adjustment and probability judgement, and to bet similar amounts to controls. However, a patient preference for consistently early bets indicated a higher level of impulsiveness. These behavioural measures were compared with imaging findings on diffusion tensor magnetic resonance imaging. Performance in specific domains of the Cambridge Gambling Task correlated inversely and specifically with the severity of diffusion tensor imaging abnormalities in regions that have been implicated in these cognitive processes. Thus, impulsivity was associated with increased apparent diffusion coefficient bilaterally in the orbitofrontal gyrus, insula and caudate; abnormal risk adjustment with increased apparent diffusion coefficient in the right thalamus and dorsal striatum and left caudate; and impaired performance on rational choice with increased apparent diffusion coefficient in the bilateral dorsolateral prefrontal cortices, and the superior frontal gyri, right ventrolateral prefrontal cortex, the dorsal and ventral striatum, and left hippocampus. Importantly, performance in specific cognitive domains of the task did not correlate with diffusion tensor imaging abnormalities in areas not implicated in their performance. The ability to dissociate the location and extent of damage with performance on the various task components using diffusion tensor imaging allows important insights into the neuroanatomical basis of impulsivity following traumatic brain injury. The ability to detect such damage in vivo may have important implications for patient management, patient selection for trials, and to help understand complex neurocognitive pathways. PMID- 21310728 TI - IkappaB kinase 2 determines oligodendrocyte loss by non-cell-autonomous activation of NF-kappaB in the central nervous system. AB - The IkappaB kinase complex induces nuclear factor kappa B activation and has recently been recognized as a key player of autoimmunity in the central nervous system. Notably, IkappaB kinase/nuclear factor kappa B signalling regulates peripheral myelin formation by Schwann cells, however, its role in myelin formation in the central nervous system during health and disease is largely unknown. Surprisingly, we found that brain-specific IkappaB kinase 2 expression is dispensable for proper myelin assembly and repair in the central nervous system, but instead plays a fundamental role for the loss of myelin in the cuprizone model. During toxic demyelination, inhibition of nuclear factor kappa B activation by conditional ablation of IkappaB kinase 2 resulted in strong preservation of central nervous system myelin, reduced expression of proinflammatory mediators and a significantly attenuated glial response. Importantly, IkappaB kinase 2 depletion in astrocytes, but not in oligodendrocytes, was sufficient to protect mice from myelin loss. Our results reveal a crucial role of glial cell-specific IkappaB kinase 2/nuclear factor kappa B signalling for oligodendrocyte damage during toxic demyelination. Thus, therapies targeting IkappaB kinase 2 function in non-neuronal cells may represent a promising strategy for the treatment of distinct demyelinating central nervous system diseases. PMID- 21310729 TI - The improvement of movement and speech during rapid eye movement sleep behaviour disorder in multiple system atrophy. AB - Multiple system atrophy is an atypical parkinsonism characterized by severe motor disabilities that are poorly levodopa responsive. Most patients develop rapid eye movement sleep behaviour disorder. Because parkinsonism is absent during rapid eye movement sleep behaviour disorder in patients with Parkinson's disease, we studied the movements of patients with multiple system atrophy during rapid eye movement sleep. Forty-nine non-demented patients with multiple system atrophy and 49 patients with idiopathic Parkinson's disease were interviewed along with their 98 bed partners using a structured questionnaire. They rated the quality of movements, vocal and facial expressions during rapid eye movement sleep behaviour disorder as better than, equal to or worse than the same activities in an awake state. Sleep and movements were monitored using video-polysomnography in 22/49 patients with multiple system atrophy and in 19/49 patients with Parkinson's disease. These recordings were analysed for the presence of parkinsonism and cerebellar syndrome during rapid eye movement sleep movements. Clinical rapid eye movement sleep behaviour disorder was observed in 43/49 (88%) patients with multiple system atrophy. Reports from the 31/43 bed partners who were able to evaluate movements during sleep indicate that 81% of the patients showed some form of improvement during rapid eye movement sleep behaviour disorder. These included improved movement (73% of patients: faster, 67%; stronger, 52%; and smoother, 26%), improved speech (59% of patients: louder, 55%; more intelligible, 17%; and better articulated, 36%) and normalized facial expression (50% of patients). The rate of improvement was higher in Parkinson's disease than in multiple system atrophy, but no further difference was observed between the two forms of multiple system atrophy (predominant parkinsonism versus cerebellar syndrome). Video-monitored movements during rapid eye movement sleep in patients with multiple system atrophy revealed more expressive faces, and movements that were faster and more ample in comparison with facial expression and movements during wakefulness. These movements were still somewhat jerky but lacked any visible parkinsonism. Cerebellar signs were not assessable. We conclude that parkinsonism also disappears during rapid eye movement sleep behaviour disorder in patients with multiple system atrophy, but this improvement is not due to enhanced dopamine transmission because these patients are not levodopa-sensitive. These data suggest that these movements are not influenced by extrapyramidal regions; however, the influence of abnormal cerebellar control remains unclear. The transient disappearance of parkinsonism here is all the more surprising since no treatment (even dopaminergic) provides a real benefit in this disabling disease. PMID- 21310730 TI - Regimen selection for first-line FOLFIRI and FOLFOX based on UGT1A1 genotype and physical background is feasible in Japanese patients with advanced colorectal cancer. AB - OBJECTIVE: We examined the feasibility of regimen selection for first-line irinotecan, 5-fluorouracil and leucovorin or oxaliplatin, 5-fluorouracil and leucovorin in Japanese patients with advanced colorectal cancer based on UDP glucuronosyltransferase 1A1 genotype as well as physical status of patients related to diarrhea. METHODS: As first-line irinotecan, 5-fluorouracil and leucovorin is a little bit superior to oxaliplatin, 5-fluorouracil and leucovorin with respect to efficacy and toxicity, patients without risk factors of irinotecan-induced toxicity were first assigned to irinotecan, 5-fluorouracil and leucovorin. Patients with UDP-glucuronosyltransferase 1A1 28/ 28, 6/ 6, 28/ 6 or 28/ 27 and those with ascites, peritoneal dissemination or diarrhea first received oxaliplatin, 5-fluorouracil and leucovorin to avoid the irinotecan induced neutropenia and diarrhea, respectively. We retrospectively evaluated the feasibility of this strategy by assessing toxicity and total progression-free survival in first- and subsequent second-line therapies in all patients studied. RESULTS: In the first-line irinotecan, 5-fluorouracil and leucovorin (n = 61), Grade 4 neutropenia, febrile neutropenia and Grade 3 diarrhea occurred in 8.2, 3.3 and 3.3% of patients, respectively. In the first-line oxaliplatin, 5 fluorouracil and leucovorin (n = 26), Grade 4 neutropenia, febrile neutropenia, Grade 3 thrombocytopenia and Grade 3 neuropathy were observed in 11.5, 3.8, 3.8 and 7.7% of patients, respectively. In the second-line oxaliplatin, 5 fluorouracil and leucovorin (n = 38), Grade 3 diarrhea occurred in 2.6% of patients. In the second-line irinotecan monotherapy (n = 11), Grade 4 or febrile neutropenia occurred in 18% of patients and Grade 3 diarrhea in 9.1% of patients. In second-line S-1 (n = 9), Grade 3 anemia occurred in 2 patients. Median total progression-free survival in all 87 patients was 11.5 months. CONCLUSIONS: Present regimen selection strategy would be feasible, since it causes less toxicity and similar efficacy comparing to previous studies. Determination of appropriate reduced dose in the second-line irinotecan monotherapy or other standard second-line therapy for patients with high-risk to irinotecan-induced toxicity might make this strategy more effective. PMID- 21310731 TI - Depth and origin of prostatic involvement by urothelial carcinoma: prognostic significance and staging interpretation. AB - OBJECTIVE: To investigate the prognostic significance of prostatic involvement by bladder urothelial carcinoma using the new 2009 TNM staging system. METHODS: From 1993 to 2008, 77 consecutive men who were clinically and/or pathologically diagnosed with bladder cancer underwent radical cystectomy. Patients were classified into several groups, according to the presence, extent and invading pathway of prostatic involvement by urothelial carcinoma, whether there was stromal or non-stromal involvement, and whether there was contiguous or non contiguous involvement. Cause-specific survivals were calculated in each group and they were compared. RESULTS: Prostatic involvement was observed in 23 (30%) patients: 10 had non-contiguous non-stromal involvement, 5 had non-contiguous stromal involvement and 8 had contiguous stromal involvement. Patients with stromal involvement (both contiguous and non-contiguous) showed significantly shorter cause-specific survival compared with those without prostatic stromal involvement (P= 0.002). The survival of patients with contiguous prostatic stromal involvement was similar to that of patients with non-contiguous prostatic stromal involvement (P= 0.79). Multivariate analysis showed that prostatic stromal involvement (both contiguous and non-contiguous) (hazard ratio, 8.4; P< 0.001), lymph node involvement (hazard ratio, 4.4; P= 0.016) and perivesical fat involvement (hazard ratio, 3.8; P= 0.029) were predictive of cause-specific survival. CONCLUSIONS: The depth of prostatic involvement has a significant impact on survival for patients with bladder urothelial carcinoma; however, whether its origin is contiguous or non-contiguous does not appear to be important. PMID- 21310732 TI - Three-dimensional coronary sinus reconstruction-guided left ventricular lead implantation based on intraprocedural rotational angiography: a novel imaging modality in cardiac resynchronization device implantation. AB - AIMS: Rotational angiography (RA) of the coronary sinus (CS) provides more anatomical insights compared with static angiographies. We evaluated intraprocedural three-dimensional (3D) CS reconstruction (RC) based on RA, using syngo((r)) DynaCT Cardiac to guide CS lead implantation. METHODS AND RESULTS: In 24 patients with indication for cardiac resynchronization therapy, intraprocedural RA and 3D RC of the CS was performed. Lead placement was guided by 3D image integration into real-time fluoroscopy. Rotational angiography and 3D RCs were evaluated regarding visibility of the CS and tributaries, CS-to-target vein angles, and vessel diameters. The target vein for CS lead implantation, identified by RA, was successfully displayed by 3D RC in 20 (91%) of 22 patients with adequate RA. All lead implantations were guided successfully by 3D image integration into real-time fluoroscopy. Cranial or caudal angulations were used in 95% of the procedures without further angiographies. Rotational angiography displayed a mean of 2.9 +/- 1.0 second-order side branches compared with 1.8 +/- 1.1 in 3D RCs (P< 0.05). The CS-to-target vein angle estimated from static projections (right anterior oblique 20 degrees , left anterior oblique 40 degrees , and even optimal RA view) differed substantially from 3D RCs. Main vessel diameters did not differ significantly between both techniques. CONCLUSION: Intraprocedural 3D RC of the CS and 3D image integration-guided lead placement is feasible. Coronary sinus-to-target vein angles seemed to be misestimated even by RA views compared with 3D RC. Thus RA and 3D CS RC should be applied routinely for CS lead implantation. PMID- 21310733 TI - Can non-invasive parameters of sympatho-vagal modulation derived from Holter monitoring contribute to risk stratification for primary implantable cardiac defibrillator implantation? PMID- 21310734 TI - Clinical trial end points for high-grade glioma: the evolving landscape. AB - To review the strengths and weaknesses of primary and auxiliary end points for clinical trials among patients with high-grade glioma (HGG). Recent advances in outcome for patients with newly diagnosed and recurrent HGG, coupled with the development of multiple promising therapeutics with myriad antitumor actions, have led to significant growth in the number of clinical trials for patients with HGG. Appropriate clinical trial design and the incorporation of optimal end points are imperative to efficiently and effectively evaluate such agents and continue to advance outcome. Growing recognition of limitations weakening the reliability of traditional clinical trial primary end points has generated increasing uncertainty of how best to evaluate promising therapeutics for patients with HGG. The phenomena of pseudoprogression and pseudoresponse have made imaging-based end points, including overall radiographic response and progression-free survival, problematic. Although overall survival is considered the "gold-standard" end point, recently identified active salvage therapies such as bevacizumab may diminish the association between presalvage therapy and overall survival. Finally, advances in imaging as well as the assessment of patient function and well being have strengthened interest in auxiliary end points assessing these aspects of patient care and outcome. Better appreciation of the strengths and limitations of primary end points will lead to more effective clinical trial strategies. Technical advances in imaging as well as improved survival for patients with HGG support the further development of auxiliary end points evaluating novel imaging approaches as well as measures of patient function and well being. PMID- 21310735 TI - UV-induced bleaching of deep traps in Harshaw TLD LiF:Mg,Cu,P and LiF:Mg,Ti. AB - The effects of UV-induced bleaching of deep traps on Harshaw thermoluminescent (TL) LiF:Mg,Cu,P and LiF:Mg,Ti materials were investigated. During a normal heating cycle, LiF:Mg,Cu,P is limited to a maximum temperature of 240 degrees C. LiF:Mg,Ti can be read to higher temperatures; however, encapsulation in polytetrafluoroethylene limits the maximum readout temperature to 300 degrees C. Generally, for both materials, these respective temperatures are sufficient for emptying traps corresponding to the main dosemetric peaks. However, when the dosemeters are subjected to a high dose level, such as 1 Gy (much higher than individual monitoring dose levels), higher temperature traps are filled that cannot be emptied without exceeding the above-mentioned maximum temperatures. These high temperature traps tend to be unstable during normal readout and can significantly increase the residual TL signal. The purpose of this study was to investigate the applicability of a UV-induced bleaching technique for emptying higher temperature traps following high-dose applications. In addition, in the case of LiF:Mg,Cu,P, where the maximum readout temperature is significantly lower, we investigated the possibility of reducing the residual signal using the application of repeated readout cycles. The optical bleaching approach was found to be effective in the case of LiF:Mg,Ti; however, for LiF:Mg,Cu,P, no reduction in the residual signal was observed. For this latter material, the application of repeatable readout cycles is very effective and residual signals equivalent to dose levels as low as 0.01 mGy were observed following an initial dose of 5 Gy. To the best of our knowledge, this work is the first attempt to apply an 'optical annealing' technique to the Harshaw thermoluminescent dosemeter (TLD) materials. PMID- 21310736 TI - Neutrophil gelatinase-associated lipocalin as a biomarker of acute kidney injury- where do we stand today? PMID- 21310737 TI - An extreme and life-threatening case of recurrent D-lactate encephalopathy. AB - D-lactic acidosis has been reported in patients after a variety of gastrointestinal surgeries, particularly jejunoileal bypass. An insufficient length of small intestine to metabolize ingested carbohydrates leads to an abnormal carbohydrate load in the colon. These carbohydrates are metabolized by colonic anaerobes (especially Lactobacillus species) into the dextrorotary isomer of lactate. Unlike its levorotary counterpart, D-lactate has neurotoxic effects and patients suffering from a significant D-lactate burden may suffer encephalopathic symptoms. These symptoms are usually mild and self-limiting in patients with normal renal function. We present here a case of D-lactic acidosis in a patient with end-stage renal disease who developed recurrent and life threatening respiratory failure due to severe D-lactic acid encephalopathy. To our knowledge, no previously reported case has been sufficiently severe to necessitate endotracheal intubation and mechanical ventilation. An array of treatments including hemodialysis effected a prompt reversal of sensorium to baseline. We describe the potential treatments for D-lactic acidosis, which can be viewed as a paradigm of substrate, catalyst and pathologic product and review reports of their relative efficacy. PMID- 21310738 TI - Device for continuous extracorporeal blood purification using target-specific metal nanomagnets. AB - BACKGROUND: The present work illustrates how magnetic separation-based blood purification using ultra-strong iron nanomagnets can be implemented into an extracorporeal blood purification circuit. By this promising technique, today's blood purification may be extended to specifically filter high-molecular compounds without being limited by filter cut-offs or column surface saturation. METHODS: Blood spiked with digoxin (small molecule drug) and interleukin-1beta (inflammatory protein) was circulated ex vivo through a device composed of approved blood transfusion lines. Target-specific nanomagnets were continuously injected and subsequently recovered with the aid of a magnetic separator before recirculating the blood. RESULTS: Magnetic blood purification was successfully carried out under flow conditions: already in single-pass experiments, removal efficiencies reached values of 75 and 40% for digoxin and interleukin-1beta, respectively. Circulating 0.5 L of digoxin-intoxicated blood in a closed loop, digoxin concentration was decreased from initially toxic to therapeutic concentrations within 30 min and purification extents of 90% were achieved after 1.5 h. CONCLUSIONS: Magnetic separation can be successfully implemented into an extracorporeal blood purification device. Simultaneous and specific filtering of high-molecular compounds may offer promising new therapeutic tools for the future treatment of complex diseases, such as sepsis and autoimmune disorders. PMID- 21310739 TI - Combination of everolimus with calcineurin inhibitor medication resulted in post transplant haemolytic uraemic syndrome in lung transplant recipients--a case series. AB - BACKGROUND: Post-transplant haemolytic uraemic syndrome (HUS) is a rare but serious disease with a high mortality rate, when left untreated. Immunosuppressive drugs like calcineurin inhibitors as well as mammalian target of rapamycin inhibitors have been reported as causative agents for post transplant HUS. METHODS: A retrospective observational study was performed in lung transplant recipients, who took part in an interventional study, in two centres. Haemoglobin, platelets, creatinine and lactate dehydrogenase levels were monitored during routine follow-up and patients with deteriorating kidney function were screened for post-transplant HUS. All cases of post-transplant HUS were identified by clinical and laboratory findings. Outcome was recorded until 6 months after diagnosis. RESULTS: A total of 2188 visits in 512 lung transplant recipients (outpatients) were analysed. Out of those, 126 patients took part in an interventional study. In this study, 67 were switched to everolimus in combination with calcineurin inhibitors 4 weeks after transplantation, 59 patients remained on standard immunosuppression (calcineurin inhibitors, mycophenolate mofetil and prednisolone). Five cases of post-transplant HUS were identified in the everolimus group. None of the patients had evidence of gastrointestinal infection or preexisting renal disease. Post-transplant HUS was treated with therapeutic plasma exchange and methylprednisolone pulse therapy. Everolimus was discontinued in all five patients. This treatment regimen led to normalization of haemoglobin, platelets and improved renal function. Two patients developed end-stage renal failure and were maintained on haemodialysis. One patient died due to multiorgan failure. Improvement of renal function was seen in two patients. No further cases were recorded in patients without everolimus during the study period. CONCLUSIONS: Our data should raise the awareness of post transplant HUS in lung transplant recipients. Post-transplant HUS is a rare disease, but it is a serious cause of acute renal failure in lung transplant recipients treated with a combination of everolimus and calcineurin inhibitors. PMID- 21310740 TI - Cost-effectiveness analysis of renal replacement therapy in Austria. AB - BACKGROUND: Providing renal replacement therapy (RRT) for end-stage renal disease patients is resource intensive. Despite growing financial pressure in health care systems worldwide, cost-effectiveness studies of RRT modalities are scarce. METHODS: We developed a Markov model of costs, quality of life and survival to compare three different assignment strategies to chronic RRT in Europe. RESULTS: Mean annual treatment costs for haemodialysis were ?43,600 during the first 12 months, ?40,000 between 13 and 24 months and ?40,600 beyond 25 months after initiation of treatment. Mean annual treatment costs for peritoneal dialysis were ?25,900 during the first 12 months, ?15,300 between 13 and 24 months and ?20,500 beyond 25 months. Mean annual therapy costs for a kidney transplantation during the first 12 months were ?50,900 from a living donor, ?51,000 from a deceased donor, ?17,200 between 13 and 24 months and ?12,900 beyond 25 months after engraftment. Over the next 10 years in Austria with a population of 8 million people, increased assignment to peritoneal dialysis of 20% incident patients saved ?26 million with a discount rate of 3% and gained 839 quality-adjusted life years (QALYs); additionally, increasing renal transplants to 10% from live donations saved ?38 million discounted and gained 2242 QALYs. CONCLUSIONS: Live donor renal transplantation is cost effective and associated with increase in QALYs. Therefore, preemptive live kidney transplantation should be promoted from a fiscal as well as medical point of view. PMID- 21310741 TI - Comparison of removal capacity of two consecutive generations of high-flux dialysers during different treatment modalities. AB - BACKGROUND: Innovative modifications have been introduced in several types of dialyser membranes to improve adequacy and permselectivity. Which aspects of removal are modified and how this relates to different diffusive or convective strategies has, however, been insufficiently investigated. METHODS: In a prospective cross-over study, 14 chronic kidney disease (Stage 5D) patients were dialysed with a second-generation high-flux dialyser (Polynephron) in comparison to a first-generation type (DIAPES-HF800). Both dialysers were assessed in haemodialysis, in online pre-dilution and in post-dilution haemodiafiltration. Reduction ratio (RR, %) of small water-soluble compounds (urea and uric acid), low-molecular weight proteins (LMWPs) (beta(2)-microglobulin, cystatin C, myoglobin and retinol-binding protein) and protein-bound solutes (hippuric acid, indole acetic acid, indoxylsulphate and p-cresylsulphate) was assessed, together with albumin losses into the dialysate. RESULTS: Comparing the two types of membranes, the second-generation dialyser demonstrated a higher RR for LMWPs, whilst at the same time exhibiting lower albumin losses but only during post dilution haemodiafiltration. No differences in RR were detected for both the small water-soluble and the protein-bound compounds. Comparing dialysis strategies, convection removed the same amount of solute or more as compared to diffusion. CONCLUSIONS: The second-generation membrane resulted in a higher removal of LMWPs compared to the first-generation membrane, but for the other solutes, differences were less prominent. Convection was superior in removal of a broad range of uraemic retention solutes especially with the first-generation membrane. PMID- 21310742 TI - Deceased donor transplantation in the elderly--are we creating false hope? AB - BACKGROUND: Increasing numbers of older patients are developing established renal failure and considering kidney transplant as a renal replacement therapy (RRT) option. The probability of older patients actually receiving a deceased donor kidney transplant is unclear, preventing informed choice about pursuing the option of transplantation. We sought to analyse our RRT population to determine the probability of receiving a deceased donor kidney transplant in patients commencing RRT categorized by age and for whom there was no suitable living kidney donor. METHODS: Patients commencing dialysis in our centre between 1992 and 2009 were identified. Time to listing on the deceased donor transplant waiting list and time to first deceased donor transplant were determined by Kaplan-Meier analysis for patients, categorized by age, with censoring at the date of first living donor kidney transplant, death or last dialysis. RESULTS: One-thousand-five-hundred-and-thirteen patients were categorized into groups by age in years [1: <35 (n = 134), 2: 35-49.9 (n = 207), 3: 50-64.9 (n = 415), 4: >65-74.9 (n = 438) and 5: >= 75 (n = 319)]. The probability of being listed for deceased donor transplant within 1 year of commencing RRT was 75, 54, 27, 4 and 0.8% in Groups 1-5, respectively. If listed, the probability of receiving a deceased donor transplant within 5 years of starting RRT was 81, 48, 26, 8 and 0% in Groups 1-5, respectively. In Groups 1-4, 93% (n = 63), 87% (n = 65), 76% (n = 45) and 100% (n = 7) of the patients, respectively, who received a deceased donor transplant were alive and off dialysis 1 year after transplant. The reason patients who were listed did not receive a transplant was usually death on the waiting list. CONCLUSIONS: The likelihood of being listed for transplant falls with increasing age at the time of starting RRT. Even for patients listed for transplant, the probability of older patients actually receiving a transplant is much lower than for younger patients, with only 8% of listed patients aged 65 74.9 years being transplanted within 5 years. This is partly the result of death on the waiting list but may also be related to organ allocation policies. Assessment for possible deceased donor transplantation involves a considerable investment in time and effort for the patient, as well as in health care resources, and a patient's decision whether to proceed with assessment should be informed by the kind of information we have produced. As there may be regional and national variations in practice, each centre should generate such data for use locally. PMID- 21310743 TI - Normative data for Rey's Auditory Verbal Learning Test in individuals with schizophrenia. AB - Deficits in episodic memory, related to medial temporal lobe dysfunction, are a core component of schizophrenia. Rey's Auditory Verbal Learning Test (RAVLT) is one of the most widely used neuropsychological memory tasks in clinical practice but normative data are limited. Over the last 15 years, the RAVLT has been used to assess verbal episodic memory performance as part of the Western Australian Family Study of Schizophrenia (WAFSS). This study aims to provide RAVLT norms, derived from the WAFSS, for individuals meeting DSM-IV and ICD-10 diagnostic criteria for schizophrenia or schizophrenia-spectrum disorder, for use in clinical settings. Performance on three immediate and one delayed recall trials, and additional measures of encoding and forgetting, is presented for 492 patients and 260 healthy community controls. Results indicated that age and sex (both groups) and IQ (schizophrenia group only) significantly influenced performance. Norms are presented, as means and standard deviations, stratified accordingly. Additional between-groups analysis clearly shows a significant memory deficit in schizophrenia even when patients are matched on IQ, age, and sex with healthy controls. PMID- 21310744 TI - Assessing the dimensionality of lifetime DSM-IV alcohol use disorders and a quantity-frequency alcohol use criterion in the Australian population: a factor mixture modelling approach. AB - AIMS: With the revision of the DSM-IV underway, two important research issues currently dominate the addiction literature: (a) how can the dimensionality of DSM-IV alcohol use disorders (AUD) diagnostic criteria best be described? and (ii) should a quantity-frequency alcohol use (QF) criterion be added to the existing diagnostic criteria set in the DSM-V? The current study addressed these aims by analysing lifetime data from a recent Australian population survey. METHODS: Data from adults screened for lifetime DSM-IV AUD in the 2007 National Survey on Mental Health and Wellbeing (NSMHWB) were analysed (n = 5409). A series of alternative factor analytic, latent class and factor mixture or 'hybrid' models were used to assess the dimensionality of lifetime DSM-IV AUD diagnostic criteria and a lifetime QF criterion. RESULTS: Examination of the goodness-of-fit indices revealed that a one-factor or a two-factor model, a three-class latent class model or a two-factor zero-class hybrid model, were all acceptable models for the data. A simple structure one-factor model was considered to be the most parsimonious and theoretically meaningful model, given the high correlation between the abuse and dependence factors (0.874) in the two-factor model. The inclusion of the QF criterion did not enhance the fit of the one-factor model. CONCLUSIONS: Incorporating both dimensional and categorical conceptions of lifetime AUD did not provide substantial gains over a simple structure unidimensional model of AUD severity. The utility of a QF use criterion in helping to diagnose AUD is questionable. These findings should be of relevance to the DSM-5 substance use disorder workgroup. PMID- 21310745 TI - GeneReporter--sequence-based document retrieval and annotation. AB - GeneReporter is a web tool that reports functional information and relevant literature on a protein-coding sequence of interest. Its purpose is to support both manual genome annotation and document retrieval. PubMed references corresponding to a sequence are detected by the extraction of query words from UniProt entries of homologous sequences. Data on protein families, domains, potential cofactors, structure, function, cellular localization, metabolic contribution and corresponding DNA binding sites complement the information on a given gene product of interest. AVAILABILITY AND IMPLEMENTATION: GeneReporter is available at http://www.genereporter.tu-bs.de. The web site integrates databases and analysis tools as SOAP-based web services from the EBI (European Bioinformatics Institute) and NCBI (National Center for Biotechnology Information). PMID- 21310746 TI - FISH Finder: a high-throughput tool for analyzing FISH images. AB - MOTIVATION: Fluorescence in situ hybridization (FISH) is used to study the organization and the positioning of specific DNA sequences within the cell nucleus. Analyzing the data from FISH images is a tedious process that invokes an element of subjectivity. Automated FISH image analysis offers savings in time as well as gaining the benefit of objective data analysis. While several FISH image analysis software tools have been developed, they often use a threshold-based segmentation algorithm for nucleus segmentation. As fluorescence signal intensities can vary significantly from experiment to experiment, from cell to cell, and within a cell, threshold-based segmentation is inflexible and often insufficient for automatic image analysis, leading to additional manual segmentation and potential subjective bias. To overcome these problems, we developed a graphical software tool called FISH Finder to automatically analyze FISH images that vary significantly. By posing the nucleus segmentation as a classification problem, compound Bayesian classifier is employed so that contextual information is utilized, resulting in reliable classification and boundary extraction. This makes it possible to analyze FISH images efficiently and objectively without adjustment of input parameters. Additionally, FISH Finder was designed to analyze the distances between differentially stained FISH probes. AVAILABILITY: FISH Finder is a standalone MATLAB application and platform independent software. The program is freely available from: http://code.google.com/p/fishfinder/downloads/list. PMID- 21310747 TI - Entropy-accelerated exact clustering of protein decoys. AB - MOTIVATION: Clustering is commonly used to identify the best decoy among many generated in protein structure prediction when using energy alone is insufficient. Calculation of the pairwise distance matrix for a large decoy set is computationally expensive. Typically, only a reduced set of decoys using energy filtering is subjected to clustering analysis. A fast clustering method for a large decoy set would be beneficial to protein structure prediction and this still poses a challenge. RESULTS: We propose a method using propagation of geometric constraints to accelerate exact clustering, without compromising the distance measure. Our method can be used with any metric distance. Metrics that are expensive to compute and have known cheap lower and upper bounds will benefit most from the method. We compared our method's accuracy against published results from the SPICKER clustering software on 40 large decoy sets from the I-TASSER protein folding engine. We also performed some additional speed comparisons on six targets from the 'semfold' decoy set. In our tests, our method chose a better decoy than the energy criterion in 25 out of 40 cases versus 20 for SPICKER. Our method also was shown to be consistently faster than another fast software performing exact clustering named Calibur. In some cases, our approach can even outperform the speed of an approximate method. AVAILABILITY: Our C++ software is released under the GNU General Public License. It can be downloaded from http://www.riken.jp/zhangiru/software/durandal_released.tgz. PMID- 21310748 TI - Treating women under 36 years old without top-quality embryos on day 2: a prospective study comparing double embryo transfer with single blastocyst transfer. AB - BACKGROUND Embryologists currently face a challenge when counselling patients regarding the stage and the number of embryos to transfer when no top-quality embryos (TQE) are available. METHODS The aim of this study was to evaluate the efficacy of single blastocyst transfer (SBT) in comparison with the transfer of two cleavage-stage embryos in women under 36 years old. A total of 450 women under 36 years undergoing their first or second IVF treatment who had no TQE on Day 2 were included in this prospective study. Couples were assigned to either a SBT or a double cleavage-stage embryo transfer (DET). The clinical end-points monitored were rates of implantation, delivery and multiple deliveries. RESULTS The rate of transfer was significantly lower for couples assigned to the SBT group compared with the DET group (88 versus 100%, respectively, P < 0.001) while the delivery rate per oocyte retrieval was similar in both groups (26.7%). By contrast, the rate of multiple deliveries was significantly lower in the SBT group compared with the DET group (3.3 versus 23.3%, respectively, P < 0.01). Blastocyst cryopreservation was twice as high in the SBT group compared with the DET group (39 versus 18%, respectively, P < 0.001). CONCLUSIONS These findings show the value of extended embryo culture for couples without TQE. In such situations, delaying embryo transfer in order to select a single blastocyst with the highest potential for implantation can reduce the number of multiple pregnancies. Furthermore, our results demonstrate that extended culture allows blastocyst cryopreservation from embryos not available for Day 2 cryopreservation. PMID- 21310753 TI - The inhibition of anaplastic lymphoma kinase in non-small cell lung tumours with the ALK rearrangement may result in tumour shrinkage. PMID- 21310749 TI - Observer agreement in the evaluation of the uterine cavity by hysteroscopy prior to in vitro fertilization. AB - BACKGROUND Hysteroscopy is known as the most accurate test for diagnosing intrauterine pathology. To optimize fertility treatment, it is increasingly common to perform hysteroscopy as a routine procedure prior to IVF. However, literature on the reproducibility of screening hysteroscopy is lacking. Therefore, the aim of the study was to assess the intra- and inter-observer agreement in the individual evaluation of the uterine cavity using video recordings of hysteroscopy procedures in asymptomatic patients prior to IVF. METHODS Screening hysteroscopies of 123 unselected, asymptomatic, infertile women with an indication for IVF/ICSI treatment were recorded on DVD. After editing, the hysteroscopy performer and three other experienced gynecologists independently assessed all recordings, focusing on the appearance of predefined intrauterine abnormalities (i.e. endometrial polyps, myomas, adhesions or septa). The intra- and inter-observer agreement was calculated and expressed as perfect agreement and kappa coefficient or intraclass correlation coefficient. RESULTS In total, 123 hysteroscopy procedures were recorded. After editing and selection, based on the record quality, 107 remained for assessment and analysis. The intraobserver agreement on the appearance of any of the predefined intrauterine abnormalities was substantial (kappa = 0.707), whereas the interobserver agreement was moderate (kappa = 0.491). Perfect agreement occurred only in 77.6% of the cases. CONCLUSIONS Interobserver agreement among experienced gynecologists appeared to be rather disappointing. The latter may have implications for the diagnostic accuracy of screening hysteroscopy prior to IVF, as well as for its clinical significance in IVF programs. PMID- 21310754 TI - Hydatid disease versus textiloma: a diagnostic challenge. PMID- 21310757 TI - MRI in assessment of lung cancer. PMID- 21310755 TI - Paracetamol reduces influenza-induced immunopathology in a mouse model of infection without compromising virus clearance or the generation of protective immunity. AB - BACKGROUND: Seasonal influenza A infection affects a significant cohort of the global population annually, resulting in considerable morbidity and mortality. Therapeutic strategies are of limited efficacy, and during a pandemic outbreak would only be available to a minority of the global population. Over-the-counter medicines are routinely taken by individuals suffering from influenza, but few studies have been conducted to determine their effectiveness in reducing pulmonary immunopathology or the influence they exert upon the generation of protective immunity. METHODS: A mouse model of influenza infection was utilised to assess the efficacy of paracetamol (acetaminophen) in reducing influenza induced pathology and to examine whether paracetamol affects generation of protective immunity. RESULTS: Administration (intraperitoneal) of paracetamol significantly decreased the infiltration of inflammatory cells into the airway spaces, reduced pulmonary immunopathology associated with acute infection and improved the overall lung function of mice, without adversely affecting the induction of virus-specific adaptive responses. Mice treated with paracetamol exhibited an ability to resist a second infection with heterologous virus comparable with that of untreated mice. CONCLUSIONS: Our results demonstrate that paracetamol dramatically reduces the morbidity associated with influenza but does not compromise the development of adaptive immune responses. Overall, these data support the utility of paracetamol for reducing the clinical symptoms associated with influenza virus infection. PMID- 21310758 TI - Risk for second malignancies in non-Hodgkin's lymphoma survivors: a meta analysis. AB - BACKGROUND: Late side-effects are becoming an important issue in non-Hodgkin's lymphoma (NHL) survivors. We intended to estimate pooled relative risk (RR) of secondary malignant neoplasms (SMNs), to evaluate site-associated RR and the impact of different treatments. DESIGN: We carried out an electronic search of Medline and EMBASE seeking articles investigating the risk of SMNs and reporting RR measures. The studies were evaluated for heterogeneity before meta-analysis and for publication bias. Pooled RRs were estimated using fixed- and random effects models. RESULTS: A total of 23 studies met the inclusion criteria. Pooled RRs of SMNs overall and for solid tumors were 1.88 and 1.32, respectively. We found an excess of risk for several specific cancer sites. Radiotherapy alone did not increase the risk for SMNs, while chemotherapy and combined treatments augmented the RR. Regression analyses revealed a positive significant association for all SMNs with total body irradiation, and for solid SMNs with younger age. No publication bias was observed. CONCLUSIONS: Our results indicate that NHL patients experience a higher risk for SMNs than the general population and that various treatments have different impact on RR. More information will be necessary to evaluate possible interactions with genetic susceptibility and environmental exposure. PMID- 21310759 TI - Tumor-ratio-metastasis staging system as an alternative to the 7th edition UICC TNM system in gastric cancer after D2 resection--results of a single-institution study of 1343 Chinese patients. AB - BACKGROUND: In this study, we assessed the prognostic value of the lymph node ratio (LNR), established a hypothetical tumor-ratio-metastasis (TRM) staging system and compared it with the 7th edition International Union Against Cancer pathological N (pN) and tumor-node-metastasis (TNM) system. PATIENTS AND METHODS: A total of 1343 gastric cancer patients undergoing D2 resection were staged using the TRM staging system and the 7th edition TNM system. Optimal cut points of LNR were calculated using X-tile software and validated by bootstrapping. Homogeneity, discriminatory ability, and monotonicity of gradients of the TRM and TNM systems were compared using linear trend chi(2), likelihood ratio chi(2) statistics, and Akaike information criterion (AIC) calculations. RESULTS: Optimal cut points classified patients into LNR0 (0%), LNR1 (1%-30%), LNR2 (31%-60%), and LNR3 (61%-100%) groups. In univariate, multivariate and stratified analyses, the LNR staging showed superiority to the 7th edition pN staging. The TRM staging system had higher linear trend and likelihood ratio chi(2) scores and smaller AIC values compared with those for the TNM system, which represented the optimum prognostic stratification. CONCLUSIONS: The novel TRM staging system predicts survival of gastric cancer more accurately than the 7th edition TNM system. It may be considered as an alternative to TNM system. PMID- 21310760 TI - Imatinib treatment duration is related to decreased estimated glomerular filtration rate in chronic myeloid leukemia patients. AB - BACKGROUND: We analyzed the incidence of acute kidney injury and chronic renal failure in chronic myeloid leukemia (CML) patients using imatinib and investigated whether there is a relation between duration of imatinib therapy and decrease in estimated glomerular filtration rate (GFR). PATIENTS AND METHODS: One hundred five CML patients on imatinib therapy were enrolled. Creatinine, urea, uric acid, and potassium measurements from imatinib treatment onset until the end of follow-up (median 4.5 years) were included in the analysis. GFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation. RESULTS: During follow-up, 7% of patients developed acute kidney injury; creatinine levels returned to baseline in only one of them. According to the regression equation, the mean baseline value of the estimated GFR was 88.9 ml/min/1.73 m(2). Estimated GFR decreased significantly with imatinib treatment duration; the mean decrease per year was 2.77 ml/min/1.73 m(2) (P < 0.001); 12% of patients developed chronic renal failure. Age, hypertension, and a history of chronic renal failure or interferon usage were not significantly related to the mean decrease in the estimated GFR over time. CONCLUSION: The introduction of imatinib therapy in nonclinical trial CML patients is associated with potentially irreversible acute renal injury, and the long-term treatment may cause a clinically relevant decrease in the estimated GFR. PMID- 21310761 TI - Androgen receptor expression is significantly associated with better outcomes in estrogen receptor-positive breast cancers. AB - BACKGROUND: The objective of the study was to evaluate the implications of androgen receptor (AR) in breast cancers. PATIENTS AND METHODS: We investigated immunohistochemical AR expression from the tissue microarrays of 931 patients between 1999 and 2005, and analyzed demographics and outcomes using uni /multivariate analyses. Tumors with >=10% nuclear-stained cells were considered positive for AR. RESULTS: AR was expressed in 58.1% of patients. AR was significantly related to older age at diagnosis, smaller size, well differentiated tumors, higher positivity of hormone receptors, non-triple negative breast cancers (non-TNBCs), and lower proliferative index. In estrogen receptor (ER)-negative tumors, AR was distinctively associated with human epidermal growth factor receptor type 2 (HER2) overexpression. With a mean follow up of 72.7 months, AR was positively related to survival in ER-positive but not in ER-negative tumors. In Cox's models, AR was an independent prognostic factor for disease-free survival in ER-positive cancers. Interestingly, molecular apocrine tumors (ER negative and AR positive) with HER2 positive status showed trends of poorer outcome, but AR had no impact on survival in patients with TNBC. CONCLUSIONS: AR is significantly associated with favorable features in breast cancers and related to better outcomes in ER-positive not in ER-negative tumors. These results suggest that AR could be an additional marker for endocrine responsiveness in ER-positive cancers and a candidate for therapeutic targeting of ER-negative tumors. PMID- 21310762 TI - A sugar for congestive heart failure patients. PMID- 21310763 TI - The oligopeptide transporters: a small gene family with a diverse group of substrates and functions? AB - Genes in the Oligopeptide Transport family encode integral membrane proteins that are believed to translocate their substrates from either the extracellular environment or an organelle into the cytosol. Phylogenetic analyses of plant transporters have revealed two distant clades: the Yellow Stripe-Like (YSL) proteins and the so-called Oligopeptide Transporters (OPTs), for which the family was named. Three categories of substrates have been identified for this family: small peptides, secondary amino acids bound to metals, and glutathione. Notably, the YSL transporters are involved in metal homeostasis through the translocation of metal-chelates, indicating a level of conservation both in biological function as well as substrates. In contrast, the functions of OPT proteins seem to be less defined and, in this review, I will examine the supporting and contradictory evidence for the proposed roles of OPTs in such diverse functions as long distance sulfur distribution, nitrogen mobilization, metal homeostasis, and heavy metal sequestration through the transport of glutathione, metal-chelates, and peptides. PMID- 21310764 TI - Intranasal localizability of odorants: influence of stimulus volume. AB - When an odorant is presented to one side of the nose and air to the other, the ability to localize which side received the odorant depends upon trigeminal nerve stimulation. It has been shown that performance on this lateralization task increases as stimulus concentration increases. In this study, we determined the influences of stimulus volume and sex on the ability to localize each of 8 odorants presented at neat concentrations: anethole, geraniol, limonene, linalool, menthol, methyl salicylate, phenyl ethanol, and vanillin. At a low stimulus volume (11 mL), only menthol was localized at an above-chance level. At a high stimulus volume (21 mL), above-chance localization occurred for all odorants except vanillin. Women were significantly better than men in localizing menthol. Stimuli rated as most intense were those that were most readily localized. The detection performance measures, as well as rated intensity values, significantly correlated with earlier findings of the trigeminal detectability of odorants presented to anosmic and normosmic subjects. This study suggests that differences in stimulus volume may explain some discrepant findings within the trigeminal chemosensory literature and supports the concept that vanillin may be a "relatively pure" olfactory stimulus. PMID- 21310765 TI - Hand-arm vibration syndrome: a common occupational hazard in industrialized countries. AB - Regular exposure to hand-transmitted vibration can result in symptoms and signs of peripheral vascular, neurological and other disorders collectively known as the hand-arm vibration syndrome (HAVS). A significant proportion of workers can suffer from HAVS after using vibrating power tools. HAVS is a chronic and progressive disorder. Early recognition and prevention is the key to managing vibrating tool exposures and health effects. This article gives a broad overview of the condition with a detailed account of its pathogenesis, identification and management. PMID- 21310766 TI - Fracture resistance of orthodontic mini-implants: a biomechanical in vitro study. AB - Sufficient primary stability is of importance for the survival of orthodontic mini-implants. This means that adequate torque has to be achieved during insertion. However, as moments exceeding the fracture resistance of a mini implant may result in their fracture, the maximum torque load capacity should be known. In this study, the threshold torque values resulting in the fracture of various mini-implant types and diameters were evaluated. Forty-one different mini implants with diameters ranging from 1.3 to 2.0 mm (Aarhus screw, Abso Anchor, Ancora, Bone screw, Dual Top, Lomas, MAS, O.S.A.S, Ortho Easy, Spider Screw, and Tomas pin) were inserted in acrylic glass by a robot system. Ten specimens of each mini-implant type were tested. The insertion torque was measured and the maximum torque at the time of mini-implant fracture was evaluated. Significance of the mean value differences was evaluated by Kruskal-Wallis tests. Fracture moments varied depending on the diameter of the mini-implants. The measured values ranged from 108.9 Nmm (MAS 1.3*11 mm) to 640.9 Nmm (Lomas 2.0*11 mm). The differences were highly statistically significant (P<0.001). The risk of mini implant fracture should be borne in mind at the time of insertion, especially if mini-implants with a small diameter are employed. To minimize the risk of fracture, pre-drilling should be carried out if the mini-implants are to be inserted at a site with a high bone density. PMID- 21310767 TI - Three-dimensional evaluation of early crossbite correction: a longitudinal study. AB - The aim of this longitudinal study was to assess whether correction of unilateral posterior crossbite in the primary dentition results in improvement of facial symmetry and increase of palatal surface area and palatal volume. A group of 60 Caucasian children in the primary dentition, aged 5.3 +/- 0.7 years, were collected at baseline. The group consisted of 30 children with a unilateral posterior crossbite with midline deviation of at least 2 mm (CB) and 30 without malocclusion (NCB). The CB group was treated using an acrylic plate expander. The children's faces and dental casts were scanned using a three-dimensional laser scanning device. Non-parametric tests were used for data analysis to assess differences over the 30 months period of follow-up. The CB children had statistically significantly greater facial asymmetry in the lower part of the face (P < 0.05) and a significantly smaller palatal volume (P < 0.05) than the NCB children at baseline. There were no statistically significant differences between the two groups at 6, 12, 18, and 30 months follow-ups. Treatment of unilateral posterior crossbite in the primary dentition period resulted in an improvement of facial symmetry in the lower part of the face (P < 0.05) and increase of the palatal surface area and palatal volume (P < 0.001). At 30 months, relapse was observed in eight children (26.7 per cent). Treatment of unilateral posterior crossbite in the primary dentition improves facial symmetry and increases the palatal surface area and the palatal volume, though it creates normal conditions for normal occlusal development and skeletal growth. PMID- 21310768 TI - Older men's explanatory model for osteoporosis. AB - PURPOSE: To explore the nature of men's experiences of osteoporosis by developing an understanding of men's explanatory models. DESIGN AND METHODS: This descriptive study invited community-residing male osteoporosis patients aged 50+ to participate in interviews about osteoporosis. Participants were recruited from a hospital-affiliated bone clinic. Men completed a questionnaire on demographic, medication, and fracture-related information, and descriptive statistics were calculated using Statistical Package for the Social Sciences. Interviews elicited the 5 domains of men's explanatory model (Kleinman, 1987) and open-ended information regarding men's experiences living with this disorder. Narrative data were analyzed both for content and inductively. RESULTS: Men's narratives demonstrate that an osteoporosis diagnosis is accompanied by negative psychosocial sequelae in this population. Men defined it as a disease of the bone that may increase the likelihood of fracture and that may cause pain. Participants reported that osteoporosis is diagnosed by bone mineral density (BMD) score and that disease progression is measured by a decrease in BMD and an increase in pain or new fractures. Men described a reluctance to take medications, dissatisfaction with side effects, and a perception that osteoporosis treatment in men had little basis in long-term medication efficacy or safety data. They viewed osteoporosis as a degenerative chronic disease with an overall stable course. IMPLICATIONS: Participants' explanatory models for osteoporosis are substantively different than clinical models. These differences provide a foundation for exploring the importance of gender to osteoporosis outcomes, a context for making sense of men's bone health behavior, and a clear case for an increase in advocacy and educational efforts for men who have or are at risk for osteoporosis. PMID- 21310770 TI - Acidic buffer or plus cyclosporine a postconditioning protects isolated rat hearts against ischemia-reperfusion injury. AB - BACKGROUND: It is well documented that transient acidosis during reperfusion is protective. The aim of this study was to evaluate the cardioprotection of acidic buffer or plus cyclosporine A in isolated rat hearts after cardioplegic arrest. METHODS: Langendorff-perfused Sprague-Dawley rat hearts were perfused for 20 min with Krebs-Henseleit (K-H) buffer followed by 30 min of crystalloid cardioplegia and 60 min of reperfusion. Control hearts were perfused with Krebs-Henseleit buffer. Acidic buffer post-conditioning hearts were perfused with acidic K-H buffer (pH 6.8) for the first 3 min of reperfusion. Acidic buffer plus cyclosporine A hearts were perfused with K-H acidic buffer (pH 6.8) containing cyclosporine A (0.2 MUmol/L) for the first 3 min of reperfusion. RESULTS: Compared with the control group, acidic buffer or plus cyclosporine A post conditioning significantly improved myocardial performance, decreased cytochrome C release into the cytosol, increased Bcl-2 expression and decreased Bax expression, decreased sensitivity of mPTP-opening to [Ca2+] and the rate of apoptosis after reperfusion. CONCLUSION: These findings suggested that acidic buffer or plus cyclosporine A post-conditioning prevented apoptosis-related mitochondrial permeabilization and provided the myocardial protection after cardioplegic arrest. PMID- 21310769 TI - Emerging diagnostic and therapeutic molecular imaging applications in vascular disease. AB - Assessment of vascular disease has evolved from mere indirect and direct measurements of luminal stenosis to sophisticated imaging methods to depict millimeter structural changes of the vasculature. In the near future, the emergence of multimodal molecular imaging strategies may enable robust therapeutic and diagnostic ('theragnostic') approaches to vascular diseases that comprehensively consider structural, functional, biological and genomic characteristics of the disease in individualized risk assessment, early diagnosis and delivery of targeted interventions.This review presents a summary of recent preclinical and clinical developments in molecular imaging and theragnostic applications covering diverse atherosclerosis events such as endothelial activation, macrophage inflammatory activity, plaque neovascularization and arterial thrombosis. The main focus is on molecular targets designed for imaging platforms commonly used in clinical medicine including magnetic resonance, computed tomography and positron emission tomography. A special emphasis is given to vascular ultrasound applications, considering the important role this imaging platform plays in the clinical and research practice of the vascular medicine specialty. PMID- 21310771 TI - Transitions in marital status and functional health and patterns of intergenerational coresidence among China's elderly population. AB - OBJECTIVES: Transitions from marriage to widowhood are consequential and fraught with risk in developing country contexts. We investigate whether transitions to widowhood, as well as transitions to worsened functional health, predict transition into coresidential living arrangements with children in a rapidly aging China. We also inquire whether coresidence transitions vary by older adults' gender and the presence of grandchildren in skip generation households. METHODS: Longitudinal prospective analyses of the Chinese Longitudinal Healthy Longevity Surveys (1998-2005) assess whether transition to widowhood and transition to relatively poor functional health influence elderly coresidence with children. Several logistic regression models are estimated using robust standard error estimation to address data clustering at the person level. RESULTS: When coresidence shifts occur, they are shaped by the needs of older adults. Specifically, a significant rise in coresidential living follows widowhood as well as deterioration in functional health. Among older adults coresiding with grandchildren, shifts to coresidence with own children following widowhood and worsened functional health are attenuated, suggesting that skip generation households may be supportive arrangements for older adults. DISCUSSION: Results are interpreted in light of the adaptability of living arrangements, novel forms such as skip generation households, and intergenerational support for China's elderly population. PMID- 21310772 TI - Precarious employment, bad jobs, labor unions, and early retirement. AB - OBJECTIVES: We examined the extent to which involuntary job loss, exposure to "bad jobs," and labor union membership across the life course are associated with the risk of early retirement. METHODS: Using data from the Wisconsin Longitudinal Study, a large (N=8,609) sample of men and women who graduated from high school in 1957, we estimated discrete-time event history models for the transition to first retirement through age 65. We estimated models separately for men and women. RESULTS: We found that experience of involuntary job loss and exposure to bad jobs are associated with a lower risk of retiring before age 65, whereas labor union membership is associated with a higher likelihood of early retirement. These relationships are stronger for men than for women and are mediated to some extent by pre-retirement differences in pension eligibility, wealth, job characteristics, and health. DISCUSSION: Results provide some support for hypotheses derived from theories of cumulative stratification, suggesting that earlier employment experiences should influence retirement outcomes indirectly through later-life characteristics. However, midlife employment experiences remain associated with earlier retirement, net of more temporally proximate correlates, highlighting the need for further theorization and empirical evaluation of the mechanisms through which increasingly common employment experiences influence the age at which older Americans retire. PMID- 21310773 TI - Primary thromboprophylaxis for hospice inpatients: who needs it? AB - Primary thromboprophylaxis (PTP) is a Department of Health priority in England. The NICE guidelines agree that PTP is inappropriate in the dying patient, but should be considered for those with reversible pathology. In the light of continued variation and uncertainty in UK hospice practice, we assessed PTP prescribing in three hospices. Case notes were reviewed from consecutive patients admitted before (300 patients) and after (350 patients) implementation of the Pan Birmingham Cancer Network (PBCN) venous thromboembolism prophylaxis (VTE) prevention guidelines. Just under half (43%; 40%) of patients had a contraindication to anticoagulation and PTP. Whilst just under a tenth (8.6%; 8.7%) in each group had a temporary increased risk of VTE, considerably fewer (3.6%; 6.3%) had a temporary increased risk of VTE without contraindication to PTP. Patients receiving PTP increased slightly from 1% to 3.6% and documentation of PTP decisions increased from 5% to 81%. Whilst the PBCN VTE tool is a useful tool to tailor an approach for this complex patient group, many questions remain. Clinical trials that include patients with advanced disease with relevant outcome measures are needed to help inform the clinicians who care for them. PMID- 21310774 TI - Effect of exposure to high temperatures during early pregnancy on hippocampal dependent learning and memory integrity in neonatal rats. AB - To explore the influence of short-term (0, 30 and 60 min) exposure to high temperatures on the integrity of hippocampal-dependent learning and memory in neonatal rats. Confocal laser scanning microscopy (CLSM) was used to observe neuronal apoptosis in the hippocampi of neonatal rats. In situ hybridization was conducted for the detection of hippocampal c-fos messenger RNA (mRNA) expression, and reverse transcription-polymerase chain reaction was performed to test the expression of NR1 (an N-methyl-D-aspartate receptor [NR] subunit) gene in the hippocampus. Finally, the Morris water maze (MWM) was used to evaluate hippocampal-dependent learning and memory. The number of c-fos mRNA-positive cells in the hippocampus was positively correlated with increasing heat exposure times. NR1 mRNA expression in the hippocampal CA1 area was positively correlated with the proportion of dead and apoptotic cells. In addition, neonatal rats exposed to high temperatures had significantly reduced platform crossings in the MWM compared to controls. The duration of heat exposure during early pregnancy was correlated with severe deficits in hippocampal-dependent learning and memory in neonatal rats. PMID- 21310775 TI - Toxicity of tetramethylammonium hydroxide: review of two fatal cases of dermal exposure and development of an animal model. AB - To document two cases of patients who were fatally exposed to tetramethylammonium hydroxide (TMAH) on the skin and to establish a rat model to investigate the effects of dermal exposure to TMAH. The charts of two workers who died from occupational accidental exposure to TMAH were reviewed. The 4-hour lethal dose (LD50) of TMAH was determined by applying solutions mimicking the two most common industrially used concentrations (2.38% and 25%) of TMAH to the skin of Sprague Dawley rats. Exposure of the rat's skin to 2.38% or 25% TMAH generated LD50 values of 85.9 mg/kg and 28.7 mg/kg, respectively. Application of either concentration of TMAH to the skin produced a rapid, significant increase in the rate of respiration. The serum concentrations of tetramethylammonium (TMA) also changed significantly with time of exposure to both concentrations of TMAH. The level of blood urea nitrogen decreased significantly in rats exposed to the 2.38% TMAH, and rats exposed to the 25% solution had a significant decrease in the serum concentration of sodium. Injection of atropine after 5 minutes of exposure did not significantly overcome any of the toxic effects observed with either solution of TMAH. The preliminary results in the rat model indicated that the lethality of TMAH cannot be fully explained by the severity of the patients' chemical burns, and the physiologic effects on respiratory and kidney functions were probably involved. PMID- 21310776 TI - Testicular apoptosis and histopathological changes induced by a 2.45 GHz electromagnetic field. AB - There is a growing public concern about the potential human health hazard caused by exposure to electromagnetic radiation (EMR). The objective of this study is to investigate the effects of 2450 mhz electromagnetic field on apoptosis and histopathological changes on rat testis tissue. Twelve-week-old male Wistar Albino rats were used in this study. Eighteen rats equally divided into three different groups which were named group I, II and III. Cage control (group I), sham control (group II) and 2.45 GHz EMR (group III) groups were formed. Group III were exposed to 2.45 GHz EMR, at 3.21 W/kg specific absorption rate for 60 minutes/ day for 28 days. There was no difference among the groups for the diameter of the seminiferous tubules, pyknotic, karyolectic and karyotic cells. However, the number of Leydig cells of testis tissue of the rats in group III was significantly reduced comparing with the group I (p < 0.05). Estimation of spermatogenesis using the Johnsen testicular biopsy score revealed that the difference between groups is statistically significant. The level of TNF-alpha, Caspase-3 and Bcl-2 were compared, and no significant difference was found between the groups. When Bax apoptosis genes and Caspase-8 apoptosis enzyme were compared, there were significant differences between the groups (p < 0.05). Electromagnetic field affects spermatogenesis and causes to apoptosis due to the heat and other stress-related events in testis tissue. PMID- 21310777 TI - Benefit of nanocarrier of magnetic magnesium in rat malathion-induced toxicity and cardiac failure using non-invasive monitoring of electrocardiogram and blood pressure. AB - Medical management in acute organophosphate (OP) poisoning is not always successful because of tissue hypoxia which results in a reduction of heart contractility and cell damage. This study reports improvement of malathion (MAL) induced cardiac failure by a nanocarrier of magnetic isotope of Mg (PMC16). A rat model of acute MAL poisoning was set up. PMC16 nanoparticle at doses of 0.05, 0.1, 0.2 LD50 = 896 mg/kg) were administered intravenously (iv) 30 minutes after a single intraperitoneal (ip) injection of MAL (0.25 LD50= 207 mg/kg). Atropine (AT; 40 mg/kg, ip) plus pralidoxime (PAM; 40 mg/kg, ip) and magnesium sulfate (MgSO4; 600 mg/kg, iv) were used as standard therapy or controls. Anesthetized animals were monitored for heart rate, electrocardiogram, blood pressure, and blood oxidative stress biomarkers like cellular lipid peroxidation, total thiol molecules, antioxidant power, gamma glutamil transpeptidase, and acetylcholinesterase (AChE) as a marker of OP toxicity. Results indicated that after MAL administration, heart rate and BP decreased and R-R duration increased. PMC16 markedly restored BP at all doses as compared with MgSO4. PMC16 at the dose of 0.05 LD50 significantly increased BP in comparison to AT + PAM. PMC16 restored heart rate at dose of 0.2 LD50 and reduced lipid peroxidation at dose of 0.05 LD50 as compared to MgSO4. PMC16 also improved total antioxidant power at all doses when compared to AT + PAM and reduced GGT activity at dose of 0.2 LD50 but did not affect total thiol molecules. MgSO4 could improve MAL-induced reduction of total antioxidant power. After 24 h, PMC16 significantly improved MAL suppressed AChE activity at doses of 0.05 and 0.1 LD50. PMC16 at all doses significantly recovered MAL-induced arrhythmia when compared to standard therapies. It is concluded that PMC16 is able to control OP-induced cardiac failure and toxicity. PMID- 21310778 TI - Prenatal and perinatal acrylamide disrupts the development of cerebellum in rat: Biochemical and morphological studies. AB - Acrylamide is known to cause neurotoxicity in the experimental animals and humans. The literature on its neurotoxic effect in the adult animals is huge, but the effect of acrylamide on the embryonic and postnatal development is relatively less understood. The present study examined its effects on the development of external features and cerebellum in albino rats. Acrylamide was orally administered to non-anesthetized pregnant females by gastric intubation 10 mg/kg/day. The animals were divided into three groups as follows. (1) Group A, newborn from control animals; (2) Group B; newborns from mothers treated with acrylamide from day 7 (D7) of gestation till birth (prenatal intoxicated group); (3) Group C; newborns from mothers treated with acrylamide from D7 of gestation till D28 after birth (perinatally intoxicated group). Acrylamide administered either prenatally or perinatally has been shown to induce significant retardation in the newborns' body weights development, increase of thiobarbituric acid reactive substances (TBARS) and oxidative stress (significant reductions in glutathione reduced [GSH], total thiols, superoxide dismutase [SOD] and peroxidase activities) in the developing cerebellum. Acrylamide treatment delayed the proliferation in the granular layer and delayed both cell migration and differentiation. Purkinje cell loss was also seen in acrylamide-treated animals. Ultrastructural studies of Purkinje cells in the perinatal group showed microvacuolations and cell loss. The results of this study show that prenatal and perinatal acrylamide or its metabolites disrupts the biochemical machinery, cause oxidative stress and induce structural changes in the developing rat cerebellum. PMID- 21310779 TI - Assessment of some renal indices in people occupationally exposed to lead. AB - Exposure to lead has been reported to have adverse health implications. An assessment of renal function in people occupationally exposed to lead was carried out using the following biochemical markers urea, creatinine, sodium, potassium, chloride and bicarbonate. A total of 53 test subjects (mean age 30.9 +/- 7.7) were randomly selected among some workers occupationally exposed to lead in Osogbo city and 42 apparently healthy subjects (mean age 30.1 +/- 1.2) were used as controls. The plasma urea, creatinine, chloride and bicarbonate concentration were determined using modified Berthelot method, Jaffe's reaction, Schales and Schales method and back titration methods, respectively. The plasma sodium and potassium concentrations were determined using flame emission spectrophotometry while blood lead level was also determined using atomic absorption spectrophotometry. The result showed significant increases in mean plasma concentration of creatinine (84.9 +/- 13.6-97.4 +/- 28.7 MUmol/L), sodium (131.9 +/- 3.9-134.8 +/- 3.7 mmol/L) and chloride (98.2 +/- 4.0-100.4 +/- 3.9 mmol/L) in test subjects when compared with controls (p < 0.05). Furthermore, significant increases (p < 0.01) were observed in mean plasma concentration of urea (4.7 +/- 1.2-5.7 +/- 1.3 mmol/L) and blood lead levels (18.5 +/- 3.5-69.7 +/- 13.2 mg/L) in test subjects in comparison with controls. In contrast, there were no significant differences observed when mean plasma potassium and bicarbonate levels in test subjects were compared with controls (p > 0.05). These results indicate that occupational exposure to lead may compromise renal function. PMID- 21310780 TI - Evidence for cross-modal plasticity in adult mouse visual cortex following monocular enucleation. AB - The goal of this study was to assess cortical reorganization in the visual system of adult mice in detail. A combination of deprivation of one eye and stimulation of the remaining eye previously led to the identification of input-specific subdivisions in mouse visual cortex. Using this information as a reference map, we established to what extent each of these functional subdivisions take part in cortical reactivation and reorganization upon unilateral enucleation. A recovery experiment revealed a differential laminar and temporal reactivation profile. Initiation of infragranular recovery of molecular activity near the border with nonvisual cortex and simultaneous hyperactivation of this adjacent cortex implied a partial nonvisual contribution to this plasticity. The strong effect of somatosensory deprivation as well as stimulation on infragranular visual cortex activation in long-term enucleated animals support this view. Furthermore, targeted tracer injections in visual cortex of control and enucleated animals revealed preexisting connections between the visual and somatosensory cortices of adult mice as possible mediators. In conclusion, this study supports an important cross-modal component in reorganization of adult mouse visual cortex upon monocular enucleation. PMID- 21310781 TI - Basic visual function and cortical thickness patterns in posterior cortical atrophy. AB - Posterior cortical atrophy (PCA) is characterized by a progressive decline in higher-visual object and space processing, but the extent to which these deficits are underpinned by basic visual impairments is unknown. This study aimed to assess basic and higher-order visual deficits in 21 PCA patients. Basic visual skills including form detection and discrimination, color discrimination, motion coherence, and point localization were measured, and associations and dissociations between specific basic visual functions and measures of higher order object and space perception were identified. All participants showed impairment in at least one aspect of basic visual processing. However, a number of dissociations between basic visual skills indicated a heterogeneous pattern of visual impairment among the PCA patients. Furthermore, basic visual impairments were associated with particular higher-order object and space perception deficits, but not with nonvisual parietal tasks, suggesting the specific involvement of visual networks in PCA. Cortical thickness analysis revealed trends toward lower cortical thickness in occipitotemporal (ventral) and occipitoparietal (dorsal) regions in patients with visuoperceptual and visuospatial deficits, respectively. However, there was also a lot of overlap in their patterns of cortical thinning. These findings suggest that different presentations of PCA represent points in a continuum of phenotypical variation. PMID- 21310782 TI - Do the congenitally blind have a stria of Gennari? First intracortical insights in vivo. AB - The primary visual cortex V1, when dissected, is characterized by an easily identifiable anatomical landmark: the stria of Gennari or Gennari stripe. However, the origin and function of the Gennari stripe is so far unknown. In order to shed some light on this question, we acquired 7-T magnetic resonance imaging (MRI) brain scans of congenitally blind (CB) people, who have never had visual experience. If the stria of Gennari requires visual input to develop or to maintain its homeostasis, such subjects should lack this structure. If it is reliably detectable in the CB, it must form and persist independently of visual sensation. This question has never previously been explored in living subjects. For the first time, the use of 7-T high-resolution MRI enables such investigations because of the excellent signal-to-noise ratio at this magnetic field strength. For comparison, we scanned sighted subjects using the same experimental parameters. We detected the stria of Gennari reliably in both sighted and blind subjects, showing that this anatomical feature is not a developmental result of visual input, and it does not degenerate in the absence of visual input. PMID- 21310783 TI - The changing face of commissioning in England. PMID- 21310784 TI - Influence of the combination and phase variation status of the haemoglobin receptors HmbR and HpuAB on meningococcal virulence. AB - Neisseria meningitidis can utilize haem, haemoglobin and haemoglobin-haptoglobin complexes as sources of iron via two TonB-dependent phase variable haemoglobin receptors, HmbR and HpuAB. HmbR is over-represented in disease isolates, suggesting a link between haemoglobin acquisition and meningococcal disease. This study compared the distribution of HpuAB and phase variation (PV) status of both receptors in disease and carriage isolates. Meningococcal disease (n = 214) and carriage (n = 305) isolates representative of multiple clonal complexes (CCs) were investigated for the distribution, polyG tract lengths and ON/OFF status of both haemoglobin receptors, and for the deletion mechanism for HpuAB. Strains with both receptors or only hmbR were present at similar frequencies among meningococcal disease isolates as compared with carriage isolates. However, >90 % of isolates from the three CCs CC5, CC8 and CC11 with the highest disease to carriage ratios contained both receptors. Strains with an hpuAB-only phenotype were under-represented among disease isolates, suggesting selection against this receptor during systemic disease, possibly due to the receptor having a high level of immunogenicity or being inefficient in acquisition of iron during systemic spread. Absence of hpuAB resulted from either complete deletion or replacement by an insertion element. In an examination of PV status, one or both receptors were found in an ON state in 91 % of disease and 71 % of carriage isolates. We suggest that expression of a haemoglobin receptor, either HmbR or HpuAB, is of major importance for systemic spread of meningococci, and that the presence of both receptors contributes to virulence in some strains. PMID- 21310785 TI - KlHsl1 is a component of glycerol response pathways in the milk yeast Kluyveromyces lactis. AB - In Saccharomyces cerevisiae, HSL1 (NIK1) encodes a serine-threonine protein kinase involved in cell cycle control and morphogenesis. Deletion of its putative orthologue in Kluyveromyces lactis, KlHSL1, gives rise to sensitivity to the respiratory inhibitor antimycin A (AA). Resistance to AA on glucose (Rag+ phenotype) is associated with genes (RAG) required for glucose metabolism/glycolysis. To understand the relationship between RAG and KlHSL1, rag and Klhsl1Delta mutant strains were investigated. The analysis showed that all the mutants contained a phosphorylated form of Hog1 and displayed an inability to synthesize/accumulate glycerol as a compatible solute. In addition, rag mutants also showed alterations in both cell wall and membrane fatty acids. The pleiotropic defects of these strains indicate that a common pathway regulates glucose utilization and stress response mechanisms, suggesting impaired adaptation of the plasma membrane/cell wall during the respiratory-fermentative transition. KlHsl1 could be the link between these adaptive pathways and the morphogenetic checkpoint. PMID- 21310786 TI - GapA+ Mycoplasma gallisepticum ts-11 has improved vaccine characteristics. AB - Mycoplasma gallisepticum (MG) is an important poultry pathogen that causes respiratory disease and loss of production worldwide, and is currently controlled with live attenuated vaccines. These vaccines have limitations as they vary in their pathogenicity, the protection afforded and their transmissibility, but have been shown to effectively reduce losses associated with challenge in the field. A live attenuated vaccine, ts-11, has been used for the control of M. gallisepticum in several countries. This vaccine is highly dose-dependent and the flock antibody response is weak. GapA is the primary cytadherence molecule in M. gallisepticum, and the absence of GapA expression has been observed in the vast majority of cells in the ts-11 vaccine strain. In this study the immunogenicity of a GapA(+) M. gallisepticum ts-11 vaccine was investigated in specific-pathogen free chickens. Birds vaccinated with GapA(+) M. gallisepticum ts-11 were protected against clinical signs of disease following challenge with virulent M. gallisepticum, and GapA(+) M. gallisepticum ts-11 was shown to be non-pathogenic and more immunogenic at a lower dose than the currently available M. gallisepticum ts-11 vaccine. Thus, GapA(+) M. gallisepticum ts-11 appears to have improved potential as a vaccine candidate. PMID- 21310787 TI - Salivaricin 9, a new lantibiotic produced by Streptococcus salivarius. AB - Salivaricin 9 (Sal9) is a 2560 Da lantibiotic having just 46 % amino acid identity with its closest known homologue, the Streptococcus pyogenes lantibiotic SA-FF22. The Sal9 locus (designated siv) in Streptococcus salivarius strain 9 was partially sequenced and localized to an approximately 170 kb megaplasmid, which also harbours the locus for the lantibiotic salivaricin A4. The entire locus was fully characterized in the draft genome sequence of S. salivarius strain JIM8780 and shown to consist of eight genes, having the following putative functions: sivK, sensor kinase; sivR, response regulator; sivA, Sal9 precursor peptide; sivM, lantibiotic modification enzyme; sivT, ABC transporter involved in the export of Sal9 and concomitant cleavage of its leader peptide; and sivFEG, encoding lantibiotic self-immunity. Intriguingly, in contrast to strain 9, the siv locus was chromosomally located in strain JIM8780--the first lantibiotic locus shown not to be exclusively plasmid-associated in S. salivarius. Sal9 containing extracts specifically induced lantibiotic production in both strain 9 and strain JIM8780, indicating that Sal9 functions as a signal peptide for upregulation of its own biosynthesis. Screening representative strains of three streptococcal species (S. salivarius, S. pyogenes and S. mitis) for sivA indicated that it was present only in S. salivarius, with 12 of 28 tested S. salivarius positive. Since Sal9 was inhibitory to all tested S. pyogenes strains it appears to have potential as an important component of the bacteriocin armoury of S. salivarius probiotics intended to control S. pyogenes infections of the human oral cavity. PMID- 21310788 TI - Increased level of intragenomic 16S rRNA gene heterogeneity in commensal strains closely related to Haemophilus influenzae. AB - The 16S rRNA gene sequence of strains closely related to, but excluded from, Haemophilus influenzae was investigated and a conspicuously high number of polymorphic nucleotide positions due to intragenomic 16S rRNA gene heterogeneity was observed. The average frequency of 16S rRNA gene polymorphic nucleotide positions in 31 variant strains was 7.0*10(-3), which is approximately ten times the level observed in validated strains of H. influenzae. Sixty-seven polymorphic nucleotide positions in seven strains most likely originated from the simultaneous presence of two distinct types of helix 18 as a consequence of prior recombinatorial events. The increased level of 16S rRNA gene polymorphism in commensal taxa excluded from the pathogenic species H. influenzae is unexplained. The heterogeneity imposes difficulties on rRNA gene-based classification and systematics. PMID- 21310789 TI - A comparative genome analysis of the RpoS sigmulon shows a high diversity of responses and origins. AB - The stationary-phase response mediated by the RpoS sigma factor (sigma(S), sigma38) has been widely studied as a general mechanism of activation of highly diverse genes that maintain cell viability. In bacteria, genes for diverse functions have been associated with this response, showing that bacteria use a large number of functions to contend with adverse conditions in their environment. However, little is known about how the genes have been functionally recruited in diverse organisms. In this work, we address the analysis of genes regulated by sigma(S), based on a comparative genomic-scale analysis considering four versatile bacterial species that represent different lifestyles and taxonomic groups, Escherichia coli K-12, Geobacter sulfurreducens, Borrelia burgdorferi and Bacillus subtilis, as well as the extent of conservation in bacterial genomes, as a means of assessing the evolution of this sigmulon across all organisms completely sequenced. The analysis presented here shows that genes associated with the sigma(S) response have been recruited from diverse regulons to achieve a global response. In addition, and based on the distribution of orthologues, we show a group of genes that is highly conserved among all organisms, mainly associated with glycerol metabolism, as well as diverse functional genes recruited in a lineage-specific manner. PMID- 21310790 TI - Mutational analysis of human NOD1 and NOD2 NACHT domains reveals different modes of activation. AB - Nucleotide-binding oligomerization domain-containing protein (NOD)1 and NOD2 are intracellular pattern recognition receptors (PRRs) of the nucleotide-binding domain and leucine-rich repeat containing (NLR) gene family involved in innate immune responses. Their centrally located NACHT domain displays ATPase activity and is necessary for activation and oligomerization leading to inflammatory signaling responses. Mutations affecting key residues of the ATPase domain of NOD2 are linked to severe auto-inflammatory diseases, such as Blau syndrome and early-onset sarcoidosis. By mutational dissection of the ATPase domain function, we show that the NLR-specific extended Walker B box (DGhDE) can functionally replace the canonical Walker B sequence (DDhWD) found in other ATPases. A requirement for an intact Walker A box and the magnesium-co-ordinating aspartate of the classical Walker B box suggest that an initial ATP hydrolysis step is necessary for activation of both NOD1 and NOD2. In contrast, a Blau-syndrome associated mutation located in the extended Walker B box of NOD2 that results in higher autoactivation and ligand-induced signaling does not affect NOD1 function. Moreover, mutation of a conserved histidine in the NACHT domain also has contrasting effects on NOD1 and NOD2 mediated NF-kappaB activation. We conclude that these two NLRs employ different modes of activation and propose distinct models for activation of NOD1 and NOD2. PMID- 21310792 TI - The protective effects of helmets in skiers and snowboarders. PMID- 21310791 TI - Early life exposure to diagnostic radiation and ultrasound scans and risk of childhood cancer: case-control study. AB - OBJECTIVE: To examine childhood cancer risks associated with exposure to diagnostic radiation and ultrasound scans in utero and in early infancy (age 0 100 days). DESIGN: Case-control study. SETTING: England and Wales. PARTICIPANTS: 2690 childhood cancer cases and 4858 age, sex, and region matched controls from the United Kingdom Childhood Cancer Study (UKCCS), born 1976-96. MAIN OUTCOME MEASURES: Risk of all childhood cancer, leukaemia, lymphoma, and central nervous system tumours, measured by odds ratios. RESULTS: Logistic regression models conditioned on matching factors, with adjustment for maternal age and child's birth weight, showed no evidence of increased risk of childhood cancer with in utero exposure to ultrasound scans. Some indication existed of a slight increase in risk after in utero exposure to x rays for all cancers (odds ratio 1.l4, 95% confidence interval 0.90 to 1.45) and leukaemia (1.36, 0.91 to 2.02), but this was not statistically significant. Exposure to diagnostic x rays in early infancy (0-100 days) was associated with small, non-significant excess risks for all cancers and leukaemia, as well as increased risk of lymphoma (odds ratio 5.14, 1.27 to 20.78) on the basis of small numbers. CONCLUSIONS: Although the results for lymphoma need to be replicated, all of the findings indicate possible risks of cancer from radiation at doses lower than those associated with commonly used procedures such as computed tomography scans, suggesting the need for cautious use of diagnostic radiation imaging procedures to the abdomen/pelvis of the mother during pregnancy and in children at very young ages. PMID- 21310793 TI - Reduction of childhood mortality through millennium development goal 4. PMID- 21310794 TI - Interpretation of random effects meta-analyses. PMID- 21310798 TI - Microinvasive neuroendocrine carcinoma arising from a central papilloma of the breast. PMID- 21310799 TI - Extralevator abdominoperineal resections and the need for pathological assessment of fresh tissue specimens. PMID- 21310800 TI - Community optometrist referral of those aged 65 and over for raised IOP post NICE: AOP guidance versus joint college guidance--an epidemiological model using BEAP. AB - BACKGROUND/AIMS: To identify the percentage of those aged 65 and over who might be referred by community optometrists as ocular hypertensive suspects in the post NICE era when differing guidance is followed by community optometrists. METHOD: The authors constructed an epidemiologically based model utilising Bridlington Eye Assessment Project (BEAP) data. Ocular hypertensive suspects' data were subjected to two algorithms (Association of Optometrists (AOP) and Joint College) to determine referral of suspects if community optometrists followed either algorithm. RESULTS: 85 of 1643 people (5.2%) tested by BEAP, with normal acuity and visual fields, recorded Goldmann IOPs of >21 mm Hg in either or both eyes. Without pachymetric information, all 85 would be referred under the AOP algorithm, decreasing to 31 (1.9%) under the joint College algorithm (63% reduction). If central corneal thickness readings influenced referral, 39 (2.4%) would be referred under the AOP algorithm and 13 (0.8%) under the joint College algorithm. CONCLUSION: If community optometrists use Goldmann tonometry and pachymetry, following the joint College guidelines, referrals of OHT suspects could be reduced to a fifth of those under the original AOP guidance. Community optometrists should be encouraged to use GAT and pachymetry in order to refine referrals when another examination is normal. Potential savings to the NHS are considerable. PMID- 21310801 TI - The incidence of visual impairment due to retinopathy of prematurity (ROP) and concomitant disabilities in the Netherlands: a 30 year overview. AB - AIM: To determine the incidence of visual impairment (VI) caused by retinopathy of prematurity (ROP) and concomitant disabilities in preterm neonates born between 2000 and 2009 in the Netherlands. METHODS: Data were retrieved from the Dutch institutes for the visually impaired. They were compared with similar Dutch studies conducted in 1975-1987, 1986-1994 and 1994-2000. RESULTS: Records of 42 infants with VI due to ROP were included. A gradual decrease of gestational age and birthweight but an increase of duration of artificial ventilation, supplemental oxygen administration, bronchopulmonary dysplasia, developmental delay and behavioural abnormalities was found. Compared with the previous study (1994-2000), significantly fewer children were visually impaired due to ROP (1.84 per 100,000 live births/year vs 3.93 per 100,000 live births/year, p=0.000), the incidence of complete blindness decreased from 27.5% to 7.1% (p < 0.05) and more children were treated (66.7% vs 56.9%, NS). The incidence of concomitant disabilities was high and did not differ greatly from the previous study. CONCLUSION: This was a retrospective study showing a significant decrease in VI due to ROP in the Netherlands. Changes in neonatal care practices did not result in a decrease in the incidence of concomitant disabilities. More children were treated for ROP, but 33% were not treated. PMID- 21310802 TI - Air-pulse corneal applanation signal curve parameters for the characterisation of keratoconus. AB - AIMS: To test the use of parameters obtained from the ocular response analyser (ORA) to distinguish between normal and keratoconic eyes, to determine the severity of keratoconus (KC), and to evaluate changes after treatment with cross linking (CXL) and intrastromal corneal ring (ICR) implantation. METHODS: In total, 42 parameters were derived from the ORA's applanation response curve. Data on 119 subjects were included in the study. We determined the power of discrimination between control subjects (n=48) and KC patients (stages I and II, n=54) using receiver operating characteristic (ROC) curves. We then tested the correlation between all KC stages (n=71) and the ORA parameters. Finally, we evaluated the changes at 4 months after CXL (n=22) and ICR (n=39). RESULTS: The ROC curves for 12 parameters showed excellent results; 24 parameters generated moderate results and six parameters generated poor results. The correlations between the KC stages and 14 parameters were significant, with good to moderate results. The corneal resistance factor and the area under the second peak of the signal curve produced the best results in distinguishing between normal and KC eyes. Two parameters after CXL (p2area and time1) and six parameters after ICR implantation (aplhf, uslope11, w11, path11, time1 and deltatime) showed significant differences with respect to the preoperative conditions. CONCLUSION: Most of the new waveform parameters demonstrated good ability to distinguish between KC and normal eyes. The changes in the parameter values after CXL and ICR treatments were smaller than expected. PMID- 21310803 TI - Whole orbital tissue culture identifies imatinib mesylate and adalimumab as potential therapeutics for Graves' ophthalmopathy. AB - BACKGROUND AND AIMS: Biologicals and small inhibitory molecules are used to treat inflammatory diseases, but their efficacy varies upon clinical application. Using a whole orbital tissue culture system, we tested the potential efficacy of imatinib mesylate (a tyrosine kinase inhibitor that blocks platelet-derived growth factor (PDGF)-receptor, c-Abl and c-Kit activity) and adalimumab (an anti TNF-alpha antibody) for the treatment of Graves' ophthalmopathy (GO). METHODS: Orbital fat tissue from GO patients (n=10) was cultured with or without imatinib mesylate or adalimumab. PDGF-B and tumour necrosis factor (TNF)-alpha mRNA expression levels were determined in the primary orbital tissue, and interleukin (IL)-6 and hyaluronan were measured in tissue-culture supernatants. RESULTS: Imatinib mesylate significantly (p=0.005) reduced IL-6 and hyaluronan production. The inhibition of hyaluronan production correlated positively and significantly (p<0.05) with the PDGF-B mRNA level in the primary tissue. Adalimumab also significantly (p=0.005) reduced IL-6 production. The amount of IL-6 inhibition correlated positively with the TNF-alpha mRNA level in the primary tissue, but this was not significant. CONCLUSIONS: Imatinib mesylate can be expected to reduce inflammation and tissue remodelling in GO, while adalimumab can be mainly expected to reduce inflammation. This in vitro tissue-culture model may, in future, prove valuable to test novel therapeutics for their presumed effect in GO as well as in other inflammatory diseases. PMID- 21310804 TI - Trends in mortality from appendicitis and from gallstone disease in English populations, 1979-2006: study of multiple-cause coding of deaths. AB - OBJECTIVE: To report on trends in mortality from appendicitis and from gallstone disease. DESIGN AND SETTING: Analysis of data from death certificates including all certified causes of death, termed 'mentions', not just the underlying cause, using data from Oxford ('mentions' available from 1979 to 2006) and all England ('mentions' available from 1995 to 2006). OUTCOME MEASURES: Mortality rates across all years studied, and in periods defined by changes to national rules in selecting the underlying cause of death. RESULTS: In the Oxford region, mortality rates for appendicitis based on underlying cause fluctuated between periods defined by coding rule changes. Those based on mentions were more stable: they were 3.3 per million population in 1979-83 and 3.5 in 2001-6. Nationally, mentions-based rates fell from 3.4 per million in 1995-2000 to 3.1 in 2001-2006, a small but statistically significant decline. For gallstone disease in Oxford, rates fell in the early years but then levelled off. Mortality rates for gallstones in England actually rose slightly between 1995-2000 (15.0 deaths per million) and 2001-6 (15.6 per million). The majority of deaths from appendicitis and gallstone disease were in the elderly. CONCLUSIONS: Appendicitis and gallstones are considered to be avoidable causes of death. Mortality rates for each cause have not shown any substantial falls in the recent periods covered by this study. It is possible that deaths were not, in fact, avoidable, but audits into the circumstances of deaths from these diseases may be warranted. Mortality data based on underlying cause alone substantially underestimate deaths from these two conditions. PMID- 21310805 TI - Using the ISBAR handover tool in junior medical officer handover: a study in an Australian tertiary hospital. AB - BACKGROUND: Despite being essential to patient care, current clinical handover practices are inconsistent and error prone. Efforts to improve handover have attracted attention recently, with the ISBAR tool increasingly utilised as a format for structured handover communication. However, ISBAR has not been validated in a junior medical officer setting. OBJECTIVE: To assess the effect of the ISBAR handover tool on junior medical officer (JMO) handover communication in an Australian hospital. METHODS: JMOs who participated in after-hours handover during an 11 week clinical term from June to August 2009 were recruited. After hours handover was audiotaped, and JMOs completed a survey to assess current handover perception and practice. JMOs then participated in a 1 h education session on handover and use of the ISBAR handover tool, and were encouraged to handover using this method. Following the education session, participants were surveyed to measure perceived changes in handover with use of ISBAR, and handover was again audiotaped to assess differences in information transfer and duration. RESULTS: Following the introduction of ISBAR, 25/36 (71%) of JMOs felt there was an overall improvement in handover communication. Specifically, they perceived improvement in the structure and consistency of handover, they felt more confident receiving handover, and they believed patient care and safety were improved. Audio-tape data demonstrated increased transfer of key clinical information during handover with no significant effect on handover duration. CONCLUSIONS: Use of the ISBAR tool improves JMO perception of handover communication in a time neutral fashion. Consideration should be given to the introduction of ISBAR in all JMO handover settings. PMID- 21310806 TI - Cancer care in the UK: updating the professional culture. PMID- 21310808 TI - Association between obesity history and hand grip strength in older adults- exploring the roles of inflammation and insulin resistance as mediating factors. AB - BACKGROUND: To examine the association between obesity history and hand grip strength, and whether the association is partly explained by subclinical inflammation and insulin resistance. METHODS: Data are from 2,021 men and women aged 55 years and older participating in the representative population-based Health 2000 Survey in Finland. Body mass and body height, maximal hand grip strength, C-reactive protein, and insulin resistance based on homeostasis model assessment (HOMA-IR) were measured in a health examination. Recalled weight at 20, 30, 40, and 50 years of age were recorded to obtain a hierarchical classification of obesity history. Obesity was defined as body mass index >= 30 kg/m2. RESULTS: Earlier onset of obesity was associated with lower hand grip strength (p < .001) after controlling for age, sex, education, smoking, alcohol use, physical activity, several chronic diseases, and current body weight. Based on adjusted logistic regression models, the odds (95% confidence interval) for very low relative hand grip strength were 2.76 (1.78-4.28) for currently obese, 5.57 (3.02-10.28) for obese since age of 50 years, 6.53 (2.98-14.30) for obese since age of 40 years, and 10.36 (3.55-30.24) for obese since age of 30 years compared with never obese participants. The associations remained highly significant even after adjusting for current C-reactive protein and HOMA-IR, but these variables had only minor role in explaining the association between obesity history and hand grip strength. CONCLUSIONS: Long-term exposure to obesity is associated with poor hand grip strength later in life. Maintaining healthy body weight throughout the life span may help to maintain adequate muscle strength in old age. Prospective studies with information on prior muscle strength are needed to examine in detail the causal association between obesity history and muscle strength. PMID- 21310809 TI - Observational study of 1-year mortality rates before and after a major earthquake among Chinese nonagenarians. AB - BACKGROUND: Little is known about mortality among nonagenarians after an earthquake. METHODS: Using secondary data analyses from the 2005 study called the Project of Longevity and Aging in Dujiangyan(n = 870), 1-year mortality rates were compared among a pre-earthquake group and a post-earthquake group of nonagenarians. All participants were from Dujiangyan, 50 km from the epicenter of the May 12, 2008 earthquake, in China. The pre-earthquake group was a subset of the 870 Project of Longevity and Aging in Dujiangyan participants, ages 93-95 years at the beginning of "Time Frame 1" (July 2005 through June 2006; n = 228). The post-earthquake group was a different subset of the 870 Project of Longevity and Aging in Dujiangyan participants, ages 93-95 years and alive at the beginning of Time Frame 2 (July 2008 through June 2009; n = 235). Time Frame 2 excluded a 7 week period following the earthquake in order to account for deaths due to trauma. Pre-earthquake health assessment data from the 2005 Project of Longevity and Aging in Dujiangyan study were used to calculate unadjusted/adjusted hazard ratios (HRs) for mortality. RESULTS: One-year mortality rates were 8.3% (19/228) and 16.2% (38/235) in the pre-earthquake group and the post-earthquake group, respectively (p =.01). In unadjusted analyses, only "being in the post-earthquake group" was associated with death (HR = 2.04; 95% confidence interval [CI], 1.17 3.53; p = .011). In the multivariable Cox regression model, being in the post earthquake group continued to be the strongest risk factor associated with mortality (HR = 2.47; 95% CI, 1.39-4.40; p = .002). Other significant risk factors included impaired cognition (HR = 1.97; 95% CI, 1.10-3.53; p = .024), serum albumin (HR = 0.90; 95% CI, 0.82-0.98; p < .015), and serum triglycerides (HR = 1.51; 95% CI, 1.15-1.99; p = .003). CONCLUSION: The May 12, 2008 earthquake in Wenchuan, China, was associated with a twofold increase in the 1-year mortality among a group of nonagenarians who lived nearby. PMID- 21310811 TI - Longitudinal versus cross-sectional evaluations of leukocyte telomere length dynamics: age-dependent telomere shortening is the rule. AB - BACKGROUND: Leukocyte telomere length (LTL) is considered a biomarker of human aging and based on cross-sectional studies it shortens with age. However, longitudinal studies reported that many adults display LTL lengthening. METHODS: Using Southern blots, we compared cross-sectional rates of age-related LTL change across a ~20 year age range with those based on longitudinal evaluations in three surveys (S1, S2, and S3) with three time intervals: S1-S2 (5.8 years), S2-S3 (6.6 years), and S1-S3 (12.4 years). Hierarchical linear modeling was used to explore LTL dynamics using LTL data from S1, S2, and S3. RESULTS: Cross-sectionally, mean LTL shortenings were 24.6, 25.4, and 23.6 bp/y at S1, S2, and S3, respectively. Longitudinally, more variation was observed in the rate of LTL change during the shorter than longer follow-up periods. Furthermore, using simple differences in LTL, 14.4% and 10.7% of individuals displayed LTL lengthening during S1-S2 and S2 S3, respectively, but only 1.5% during S1-S3 (p < 0.001). The estimated mean rate of LTL shortening based on averaging empirical Bayes' estimates of LTL from a parsimonious hierarchical linear modeling model was 31 bp/y with a range from 23 to 47 bp/y with none of the participants showing LTL lengthening over the average 12.4 years of follow-up. CONCLUSIONS: As aging displays a unidirectional progression, it is unlikely that LTL elongates with age. LTL elongation in longitudinal studies primarily reflects measurement errors of LTL in relation to the duration of follow-up periods. PMID- 21310810 TI - Age-related skeletal muscle decline is similar in HIV-infected and uninfected individuals. AB - BACKGROUND: Skeletal muscle (SM) mass decreases with advanced age and with disease in HIV infection. It is unknown whether age-related muscle loss is accelerated in the current era of antiretroviral therapy and which factors might contribute to muscle loss among HIV-infected adults. We hypothesized that muscle mass would be lower and decline faster in HIV-infected adults than in similar aged controls. METHODS: Whole-body (1)H-magnetic resonance imaging was used to quantify regional and total SM in 399 HIV-infected and 204 control men and women at baseline and 5 years later. Multivariable regression identified associated factors. RESULTS: At baseline and Year 5, total SM was lower in HIV-infected than control men. HIV-infected women were similar to control women at both time points. After adjusting for demographics, lifestyle factors, and total adipose tissue, HIV infection was associated with lower Year 5 SM in men and higher SM in women compared with controls. Average overall 5-year change in total SM was small and age related, but rate of change was similar in HIV-infected and control men and women. CD4 count and efavirenz use in HIV-infected participants were associated with increasing SM, whereas age and stavudine use were associated with decreasing SM. CONCLUSIONS: Muscle mass was lower in HIV-infected men compared with controls, whereas HIV-infected women had slightly higher SM than control women after multivariable adjustment. We found evidence against substantially faster SM decline in HIV infected versus similar-aged controls. SM gain was associated with increasing CD4 count, whereas stavudine use may contribute to SM loss. PMID- 21310812 TI - Genome-wide association studies in multiple sclerosis: lessons and future prospects. AB - Multiple sclerosis (MS) is an inflammatory neurodegenerative disease with complex aetiology. A haplotype within the major histocompatibility region is the major risk factor for MS, but despite clear evidence for a genetic component additional risk variants were not identified until the recent advent of genome-wide association studies (GWAS). At present, 10 GWAS have been conducted in MS, and together with follow-up studies these have confirmed 16 loci with genome-wide significance. Many of these common risk variants are located at or near genes with central immunological functions and the majority are associated with other autoimmune diseases. However, evidence from pathway analyses on more modestly associated variants also supports the involvement of neurological genes. Although the mechanisms by which the associated variants exert their effects are still poorly understood, some have been shown to correlate with expression of nearby genes. Further studies are required to define the functionally relevant variants in the identified regions and to investigate their effects at the molecular and cellular level. Finally, many genetic risk variants for MS remain to be identified. In order to expose some of the loci with more modest effects, a GWAS in nearly 10,000 MS patients has recently been completed. PMID- 21310813 TI - Embryonic genotype and inbreeding affect preimplantation development in cattle. AB - Infertility in cattle herds is a growing problem with multifactorial causes. Embryonic genotype and level of inbreeding are among the many factors that can play a role on reproductive efficiency. To investigate this issue, we produced purebred and crossbred bovine embryos by in vitro techniques from Holstein oocytes and Holstein or Brown Swiss semen and analyzed several cellular and molecular features. In the first experiment, purebred and crossbred embryos, obtained from abattoir oocytes, were analyzed for cleavage, development to morula/blastocyst stages, amino acid metabolism and gene expression of developmentally important genes. The results indicated significant differences in the percentage of compacted morulae, in the expression of three genes at the blastocyst stage (MNSOD, GP130 and FGF4) and in the utilization of serine, asparagine, methionine and tryptophan in day 6 embryos. In the second experiment, bovine oocytes were collected by ovum pick up from ten Holstein donors and fertilized with the semen of the respective Holstein sires or with Brown Swiss semen. The derived embryos were grown in vitro up to day 7, and were then transferred to synchronized recipients and recovered on day 12. We found that purebred/inbred embryos had lower blastocyst rate on days 7-8, were smaller on day 12 and had lower expression of the trophoblast gene PLAC8. Overall, these results indicate reduced and delayed development of purebred embryos compared with crossbred embryos. In conclusion, this study provides evidence that embryo genotype and high inbreeding can affect amino acid metabolism, gene expression, preimplantation development and therefore fertility in cattle. PMID- 21310814 TI - Heifer nutrient intake during early- and mid-gestation programs adult offspring adiposity and mRNA expression of growth-related genes in adipose depots. AB - Changes in maternal nutrient intake during gestation alter IGF receptor abundance and leptin (LEP) mRNA expression in fetal adipose tissue. It is not known whether such changes persist into adult life and whether they are associated with an effect on phenotype. We investigated the effect of high (240%) and low (70%) levels of recommended daily crude protein intake for beef heifers during the first and second trimesters of gestation on singleton progeny (n=68): subcutaneous (SC) adipose tissue depth at rump (P8) and rib (RF) sites from 65 until 657 days of age; plasma leptin concentrations from birth until 657 days and expression of IGF1 and IGF2, their receptors (IGF1R and IGF2R) and LEP mRNA in perirenal (PR), omental (OM) and SC adipose tissue at 680 days of age. High protein diets during the first trimester increased LEP and IGF1 mRNA in PR of males and females, respectively, compared with low-protein diets, and decreased IGF1R mRNA in SC of all progeny but increased RF depth of males between 552 and 657 days. High-protein diets compared with low-protein diets during the second trimester increased IGF1R mRNA in PR and OM of all progeny; LEP mRNA in PR of males; and IGF2 and IGF2R mRNA in OM of all progeny. Conversely, LEP mRNA in OM and IGF2 mRNA in PR of all progeny were decreased following exposure to high- compared with low-protein diets during the second trimester. Heifer diet during gestation has permanent sex- and depot-specific effects on the expression of adipogenic and adipocytokine genes and offspring adiposity. PMID- 21310815 TI - Fibroblast growth factors activate mitogen-activated protein kinase pathways to promote migration in ovine trophoblast cells. AB - Fibroblast growth factors (FGFs) 2 and FGF10 are uterine- and conceptus-derived factors that mediate trophoblast activities in cattle and sheep. To extend our understanding of how FGFs may control peri-implantation development in ruminants, we determined whether FGF2 and FGF10 impact trophoblast cell migration. Transwell inserts containing 8 MUm pores were used to examine whether FGF2 or FGF10 supplementation increased oTr1 cell migration. Supplementation with 0.5 ng/ml FGF2 or FGF10 did not affect oTr1 cell migration number, but exposure to 5 or 50 ng/ml FGF2 or FGF10 increased (P<0.05) oTr1 cell migration when compared with controls. The involvement of specific MAP kinase (MAPK) cascades in mediating this FGF response was examined by using pharmacological inhibitors of specific MAPKs. Western blot analysis indicated that FGF2 and FGF10 increased phosphorylation status of MAPKs 1, 3, 8, 9, and 14. Exposure to specific inhibitors blocked FGF induction of each MAPK. Exposure to inhibitors before supplementation with FGF2 or FGF10 prevented FGF induction of cell migration, indicating that each of these signaling molecules was required for FGF effects. A final series of studies examined whether FGF2 and FGF10 also mediated the migration of a bovine trophoblast line (CT1 cell). Increases in migration were detected in each cell line by supplementing 5 or 50 ng/ml FGF2 or FGF10 (P<0.05). In summary, FGF2 and FGF10 regulate migratory activity of ovine trophoblast cells through MAPK-dependent pathways. These outcomes provide further evidence that FGFs function as mediators of peri-implantation conceptus development in cattle and sheep. PMID- 21310816 TI - A dense network of dendritic cells populates the murine epididymis. AB - One of the most intriguing aspects of male reproductive physiology is the ability to generate spermatogenic cells - which are 'foreign' to the host - without triggering immune activation. After leaving the testis, spermatozoa enter the epididymis where they mature and are stored. In this study, we report a previously unrecognized dense network of dendritic cells (DCs) located at the base of the epididymal epithelium. This network was detected in transgenic mice expressing CD11c-EYFP and CX3CR1-GFP reporters. Epididymal DCs (eDCs) establish intimate interactions with the epithelium and project long dendrites between epithelial cells toward the lumen. We show that isolated eDCs express numerous leukocyte markers described previously in other organs that are in contact with the external environment, and present and cross-present ovalbumin to T cells in vitro. eDCs are, therefore, strategically positioned to regulate the complex interplay between immune tolerance and activation, a balance that is fundamental to male fertility. PMID- 21310817 TI - Beneficial effect of glatiramer acetate treatment on syndecan-1 expression in dextran sodium sulfate colitis. AB - Syndecan-1, the most abundant heparan sulfate proteoglycan in the gastrointestinal tract, is reduced in the regenerative epithelium in inflammatory bowel disease (IBD). This study explored the effects of the immunomodulator glatiramer acetate (GA; Copaxone) treatment on syndecan-1 expression in dextran sodium sulfate (DSS)-induced colitis. Acute and chronic colitis was induced in C57BL/6 mice by 2 and 1.5% DSS in tap water, respectively. GA was applied subcutaneously, 2 mg per mouse per day, starting on the day of DSS induction until the mice were sacrificed. Syndecan-1 expression was assessed by immunohistochemistry. The effect of adoptive transfer of GA-specific T cells as an organ-specific therapy also was evaluated. Syndecan-1 expression was significantly lower in both colitis groups compared with that in naive mice (p < 0.0001). GA attenuated clinical scores and pathological manifestations of colitis and led to the reinstatement of normal levels of syndecan-1. After adoptive transfer, GA-specific cells homed to the surface epithelium of the distal colon, accompanied by the augmentation of syndecan-1 staining in their vicinity. We concluded that syndecan-1 expression is reduced in DSS-induced colitis and could be a potential prognostic factor in IBD. Treatment with GA exerts not only an anti-inflammatory effect but also a possible beneficial effect in stabilizing the intestinal epithelium barrier and tissue repair in DSS colitis. GA may be applied as a novel drug for IBD, shifting treatment from immunosuppression toward immunomodulation. PMID- 21310818 TI - Renal dysfunction associated with intra-abdominal hypertension and the abdominal compartment syndrome. AB - Once considered mostly a postsurgical condition, intra-abdominal hypertension (IAH) and the abdominal compartment syndrome (ACS) are now thought to increase morbidity and mortality in many patients receiving medical or surgical intensive care. Animal data and human observational studies indicate that oliguria and acute kidney injury are early and frequent consequences of IAH/ACS and can be present at relatively low levels of intra-abdominal pressure (IAP). Among medical patients at particular risk are those with septic shock and severe acute pancreatitis, but the adverse effects of IAH may also be seen in cardiorenal and hepatorenal syndromes. Factors predisposing to IAH/ACS include sepsis, large volume fluid resuscitation, polytransfusion, mechanical ventilation with high intrathoracic pressure, and acidosis, among others. Transduction of bladder pressure is the gold standard for measuring intra-abdominal pressure, and several nonsurgical methods can help reduce IAP. The role of renal replacement therapy for volume management is not well defined but may be beneficial in some cases. IAH/ACS is an important possible cause of acute renal failure in critically ill patients and screening may benefit those at increased risk. PMID- 21310819 TI - IL-1beta receptor antagonist reduces inflammation in hemodialysis patients. AB - Chronic inflammation is highly prevalent in maintenance hemodialysis (MHD) patients and associates with increased mortality. IL-1beta, a pro-inflammatory cytokine, is elevated in MHD patients. A balance between IL-1beta and its naturally occurring antagonist may determine the inflammatory response and its consequences in this population. We performed a pilot randomized placebo controlled trial to evaluate the efficacy of the administration of recombinant human IL-1 receptor antagonist (IL-1ra) on biomarkers of inflammation and nutrition in MHD patients with three consecutive high sensitivity C-reactive protein (hsCRP) measurements >5 mg/L. We randomly assigned 22 patients to placebo or IL-1ra (1:1) for 4 weeks; 14 completed the trial. Patients in the IL-1ra arm had a 53% reduction in mean hsCRP compared with 1% in the placebo arm (P = 0.008), a 40% reduction in mean IL-6 levels compared with a 20% increase in the placebo arm (P = 0.03), and a 23% increase in mean prealbumin compared with 6% in the placebo arm (P = NS). In conclusion, the administration of IL-1ra in MHD patients can lower biomarkers of inflammation. Whether IL-1ra administration improves survival in this population requires additional long-term studies. PMID- 21310820 TI - Altered dynamics and differential infection profiles of lymphoid and myeloid cell subsets during acute and chronic HIV-1 infection. AB - The dynamics of immune cell populations during acute HIV-1 infection are not fully deciphered, especially for non-T cells. In this study, we tested whether specific cellular subsets of the innate arm of the immune response are affected early after HIV-1 infection. Using a cohort of HIV-1-infected individuals, we have monitored the relative frequency of blood T lymphocytes, monocytes, and DCs at various infection stages and measured their respective intracellular HIV-1 DNA loads. The HIV-1 DNA load in naive CD4(+) T lymphocytes, which are lost very early during acute infection, was ten- to 100-fold lower than in CD57(-) and CD57(+) memory CD4(+) T lymphocytes. We observed that despite rapid, persistent loss after HIV-1 infection, pDCs represented a non-negligible HIV-1 DNA reservoir. CD16(+) proinflammatory cDCs and monocytes accumulated gradually, and HIV-infected CD16(+) monocytes contained higher HIV-1 DNA loads than their CD16( ) counterpart during acute infection. During chronic infection, CD16(+) cDCs exhibited higher HIV-1 DNA loads than the CD16(-) population. Overall, our results demonstrate that non-T cell compartments are a major HIV-1 DNA reservoir, and CD16(+) monocytes and CD16(+) cDCs potentially play an important role in HIV 1 dissemination. PMID- 21310821 TI - Donor phosphorus levels and recipient outcomes in living-donor kidney transplantation. AB - BACKGROUND AND OBJECTIVES: In living-donor kidney transplantation, various donor factors, including gender, age, and baseline kidney function, predict allograft function and recipient outcomes after transplantation. Because higher phosphorus is predictive of vascular injury in healthy adults, the effect of donor phosphorus levels on recipient renal function after transplantation was investigated. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Phosphorus levels in 241 living donors were analyzed from a 7-year period, and recipient renal function and acute rejection at 1 year posttransplantation were examined controlling for other influencing factors, including multiple donor variables, HLA matching, and acute rejection. RESULTS: Female and African-American donors had significantly higher phosphorus levels predonation. By multivariable analysis, higher donor phosphorus correlated with higher recipient serum creatinine (slope=0.087, 95% confidence interval [CI]: 0.004 to 0.169, P=0.041) and lower recipient estimated GFR (slope=-4.321, 95% CI: -8.165 to -0.476, P=0.028) at 12 months. Higher donor phosphorus also displayed an independent correlation with biopsy-proven acute rejection and delayed or slow graft function after transplantation. CONCLUSIONS: In a cohort of living kidney donors, higher donor phosphorus correlated with female gender and African-American ethnicity and was an independent risk factor for early allograft dysfunction after living-donor kidney transplantation. PMID- 21310822 TI - Association of decreased glomerular filtration rate with racial differences in survival after acute myocardial infarction. AB - BACKGROUND AND OBJECTIVES: African-American race and decreased kidney function have been associated with higher mortality after acute myocardial infarction (AMI). However, whether there are racial differences in the prevalence or prognostic importance of renal insufficiency in AMI is unknown. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: Among 1847 AMI patients enrolled in the multicenter Prospective Registry Evaluating Myocardial Infarction Event and Recovery (PREMIER) study, estimated glomerular filtration rate (eGFR) was used to stratify prognosis and to examine potential interactions among eGFR, race, and mortality. Multivariable proportional hazards regression was used to examine the effect of race and eGFR on 3.5-year all-cause mortality. RESULTS: Race and eGFR were significantly associated with mortality. After adjustment for eGFR alone, differences in mortality by race were substantially attenuated (unadjusted hazard ratio [HR] for African Americans=1.56 [95% confidence interval {CI}=1.2 to 2.1]; eGFR-adjusted HR=1.32 [95% CI=0.99 to 1.75]). A similar magnitude of attenuation in racial differences in survival was observed after adjustment for all covariates except eGFR (HR=1.29 [95% CI=0.96 to 1.72]). A final model adjusting for all covariates only slightly attenuated the association further. No interaction between race and eGFR was detected. CONCLUSIONS: Renal insufficiency, which may represent chronic kidney disease, is a prognostically important comorbidity in African Americans after AMI. However, the effect of decreased eGFR on mortality is comparable between races, suggesting that preventing renal insufficiency in African Americans could be an important target to reduce racial disparities in post-AMI survival. PMID- 21310823 TI - Absence of class II-associated invariant chain peptide on leukemic blasts of patients promotes activation of autologous leukemia-reactive CD4+ T cells. AB - Immune escape in cancer poses a substantial obstacle to successful cancer immunotherapy. Multiple defects in HLA class I antigen presentation exist in cancer that may contribute to immune escape, but less is known about roles for HLA class II antigen presentation. On class II(+) leukemic blasts, the presence of class II-associated invariant chain peptide (CLIP) is known to be correlated with poor survival in acute myeloid leukemia (AML). In this study, we evaluated the functional significance of CLIP expression on leukemic blasts of AML patients. CD4(+) T cells from patients were cocultured with autologous CLIP(-) and CLIP(+) primary leukemic blasts and analyzed for several functional parameters by flow cytometry. Increased HLA-DR and IFN-gamma expression was observed for CD4(+) T cells stimulated with CLIP(-) leukemic blasts, in contrast to CLIP(+) leukemic blasts, which indicated an activation and polarization of the CD4(+) T cells toward T-helper 1 cells. In addition, CLIP(-) leukemic blasts induced greater outgrowth of effector memory CD4(+) T cells (with HLA-DR restricted T-cell receptor Vbeta repertoires) that were associated with better leukemia-specific reactivity than with CLIP(+) leukemic blasts. Our findings offer a clinical rationale to downmodulate CLIP on leukemic blasts as a strategy to degrade immune escape and improve leukemia-specific T-cell immunity in AML patients. PMID- 21310824 TI - Light at night activates IGF-1R/PDK1 signaling and accelerates tumor growth in human breast cancer xenografts. AB - Regulation of diurnal and circadian rhythms and cell proliferation are coupled in all mammals, including humans. However, the molecular mechanisms by which diurnal and circadian rhythms regulate cell proliferation are relatively poorly understood. In this study, we report that tumor growth in nude rats bearing human steroid receptor-negative MCF-7 breast tumors can be significantly accelerated by exposing the rats to light at night (LAN). Under normal conditions of an alternating light/dark cycle, proliferating cell nuclear antigen (PCNA) levels in tumors were maximal in the early light phase but remained at very low levels throughout the daily 24-hour cycle period monitored. Surprisingly, PCNA was expressed in tumors continually at a high level throughout the entire 24-hour period in LAN-exposed nude rats. Daily fluctuations of Akt and mitogen activated protein kinase activation in tumors were also disrupted by LAN. These fluctuations did not track with PCNA changes, but we found that activation of the Akt stimulatory kinase phosphoinositide-dependent protein kinase 1 (PDK1) directly correlated with PCNA levels. Expression of insulin-like growth factor 1 receptor (IGF-1R), an upstream signaling molecule for PDK1, also correlated with fluctuations of PDK1/PCNA in the LAN group. In addition, circulating IGF-1 concentrations were elevated in LAN-exposed tumor-bearing nude rats. Finally, RNAi-mediated knockdown of PDK1 led to a reduction in PCNA expression and cell proliferation in vitro and tumor growth in vivo, indicating that PDK1 regulates breast cancer growth in a manner correlated with PCNA expression. Taken together, our findings demonstrate that LAN exposure can accelerate tumor growth in vivo, in part through continuous activation of IGF-1R/PDK1 signaling. PMID- 21310825 TI - The androgen receptor induces integrin alpha6beta1 to promote prostate tumor cell survival via NF-kappaB and Bcl-xL Independently of PI3K signaling. AB - Recent studies indicate that androgen receptor (AR) signaling is critical for prostate cancer cell survival, even in castration-resistant disease wherein AR continues to function independently of exogenous androgens. Integrin-mediated adhesion to the extracellular matrix is also important for prostate cell survival. AR-positive prostate cancer cells express primarily integrin alpha6beta1 and adhere to a laminin-rich matrix. In this study, we show that active nuclear-localized AR protects prostate cancer cells from death induced by phosphoinositide 3-kinase (PI3K) inhibition when cells adhere to laminin. Resistance to PI3K inhibition is mediated directly by an AR-dependent increase in integrin alpha6beta1 mRNA transcription and protein expression. Subsequent signaling by integrin alpha6beta1 in AR-expressing cells increased NF-kappaB activation and Bcl-xL expression. Blocking AR, integrin alpha6, NF-kappaB, or Bcl xL concurrent with inhibition of PI3K was sufficient and necessary to trigger death of laminin-adherent AR-expressing cells. Taken together, these results define a novel integrin-dependent survival pathway in prostate cancer cells that is regulated by AR, independent of and parallel to the PI3K pathway. Our findings suggest that combined targeting of both the AR/alpha6beta1 and PI3K pathways may effectively trigger prostate cancer cell death, enhancing the potential therapeutic value of PI3K inhibitors being evaluated in this setting. PMID- 21310826 TI - STAT3 expression, molecular features, inflammation patterns, and prognosis in a database of 724 colorectal cancers. AB - PURPOSE: STAT3 is a transcription factor that is constitutively activated in some cancers. It seems to play crucial roles in cell proliferation and survival, angiogenesis, tumor-promoting inflammation, and suppression of antitumor host immune response in the tumor microenvironment. Although the STAT3 signaling pathway is a potential drug target, clinical, pathologic, molecular, or prognostic features of STAT3-activated colorectal cancer remain uncertain. EXPERIMENTAL DESIGN: Utilizing a database of 724 colon and rectal cancer cases, we evaluated phosphorylated STAT3 (p-STAT3) expression by immunohistochemistry. The Cox proportional hazards model was used to compute mortality HR, adjusting for clinical, pathologic, and molecular features, including microsatellite instability (MSI), the CpG island methylator phenotype (CIMP), LINE-1 methylation, 18q LOH, TP53 (p53), CTNNB1 (beta-catenin), JC virus T-antigen, and KRAS, BRAF, and PIK3CA mutations. RESULTS: Among the 724 tumors, 131 (18%) showed high-level p-STAT3 expression (p-STAT3-high), 244 (34%) showed low-level expression (p-STAT3-low), and the remaining 349 (48%) were negative for p-STAT3. p-STAT3 overexpression was associated with significantly higher colorectal cancer specific mortality [log-rank P = 0.0020; univariate HR (p-STAT3-high vs. p-STAT3 negative): 1.85, 95% CI: 1.30-2.63, P(trend) = 0.0005; multivariate HR: 1.61, 95% CI: 1.11-2.34, P(trend) = 0.015]. p-STAT3 expression was positively associated with peritumoral lymphocytic reaction (multivariate OR: 3.23; 95% CI: 1.89-5.53, P < 0.0001). p-STAT3 expression was not associated with MSI, CIMP, or LINE-1 hypomethylation. CONCLUSIONS: STAT3 activation in colorectal cancer is associated with adverse clinical outcome, supporting its potential roles as a prognostic biomarker and a chemoprevention and/or therapeutic target. PMID- 21310827 TI - Atypical protein kinase Ciota (PKCiota) promotes metastasis of esophageal squamous cell carcinoma by enhancing resistance to Anoikis via PKCiota-SKP2-AKT pathway. AB - Protein kinase Ciota (PKCiota) is an atypical PKC isoform and participates in multiple aspects of the transformed phenotype in human cancer cells. We previously reported that frequent amplification and overexpression of PKCiota were correlated with lymph node metastasis in primary esophageal squamous cell carcinomas (ESCC). In the present study, short interfering RNA-mediated silencing of PKCiota revealed that this enzyme was required for cell migration, invasion, and resistance to anoikis. In vivo experiments showed that PKCiota suppression decreased tumor growth in esophageal cancer xenografts and lung metastases in nude mice. At the molecular level, knockdown of PKCiota in suspended ESCC cells caused a decrease in S-phase kinase-associated protein 2 (SKP2) that had been reported to promote resistance to anoikis via the PI3K/AKT pathway. AKT phosphorylation was abolished after PKCiota suppression, but AKT activation could be refreshed by PKCiota upregulation, suggesting that PKCiota enhanced cell resistance to anoikis via the PKCiota-SKP2-PI3K/AKT pathway. Addition of the proteasome inhibitor MG132 prevented the decrease of SKP2 in PKCiota silenced cells, and polyubiquitin-SKP2 was elevated after PKCiota depletion, showing that PKCiota might regulate the expression of SKP2 through the ubiquitin-proteasome pathway in suspended cells. Furthermore, overexpression of SKP2 in PKCiota downregulated cells restored cell resistance to anoikis. Most importantly, PKCiota expression significantly correlated with SKP2 in 133 ESCC tissues (P = 0.031). Taken together, our data show that PKCiota promotes tumorigenicity and metastasis of human esophageal cancer and that SKP2 is a candidate downstream effector of PKCiota signaling in ESCC. PMID- 21310828 TI - Low-carbohydrate diet scores and risk of type 2 diabetes in men. AB - BACKGROUND: Fat and protein sources may influence whether low-carbohydrate diets are associated with type 2 diabetes (T2D). OBJECTIVE: The objective was to compare the associations of 3 low-carbohydrate diet scores with incident T2D. DESIGN: A prospective cohort study was conducted in participants from the Health Professionals Follow-Up Study who were free of T2D, cardiovascular disease, or cancer at baseline (n = 40,475) for up to 20 y. Cumulative averages of 3 low carbohydrate diet scores (high total protein and fat, high animal protein and fat, and high vegetable protein and fat) were calculated every 4 y from food frequency questionnaires and were associated with incident T2D by using Cox models. RESULTS: We documented 2689 cases of T2D during follow-up. After adjustments for age, smoking, physical activity, coffee intake, alcohol intake, family history of T2D, total energy intake, and body mass index, the score for high animal protein and fat was associated with an increased risk of T2D [top compared with bottom quintile; hazard ratio (HR): 1.37; 95% CI: 1.20, 1.58; P for trend < 0.01]. Adjustment for red and processed meat attenuated this association (HR: 1.11; 95% CI: 0.95, 1.30; P for trend = 0.20). A high score for vegetable protein and fat was not significantly associated with the risk of T2D overall but was inversely associated with T2D in men aged <65 y (HR: 0.78; 95% CI: 0.66, 0.92; P for trend = 0.01, P for interaction = 0.01). CONCLUSIONS: A score representing a low-carbohydrate diet high in animal protein and fat was positively associated with the risk of T2D in men. Low-carbohydrate diets should obtain protein and fat from foods other than red and processed meat. PMID- 21310829 TI - The timing and duration of a sensitive period in human flavor learning: a randomized trial. AB - BACKGROUND: By using the response to protein hydrolysate formula (PHF) as a model system, we discovered the existence of a sensitive period, before 4 mo, when exposure determines the hedonic tone to flavors. OBJECTIVE: We aimed to characterize the timing and duration of this sensitive period. DESIGN: Healthy infants, whose parents had chosen formula feeding, were randomly assigned into 1 of 6 groups at age 0.5 mo: 2 control groups, one fed cow milk-based formula (CMF) and the other fed PHF for 7 mo; 2 groups fed PHF for either 1 or 3 mo beginning at 1.5 mo and CMF otherwise; and 2 groups fed PHF for 1 mo beginning at either 2.5 or 3.5 mo and CMF otherwise. Brief access taste tests were conducted monthly, and complete "meals" of both formulas occurred at the end of the study. RESULTS: Three months of PHF exposure led to acceptance similar to that at 1 mo of exposure. Although these infants were more accepting than were infants with no exposure, they were less accepting than were infants with 7 mo of exposure, which suggests a dosing effect. The time when flavor experiences began was also significant. Among infants exposed to PHF for 1 mo, those who were first fed PHF at 3.5 mo rejected PHF relative to CMF more than did infants exposed at younger ages. CONCLUSION: The general principles observed are likely of broader significance, indicating a fundamental feature of mammalian development and reflecting the importance of familiarizing infants with flavors that their mothers consume and transmit to breast milk. This trial was registered at clinicaltrials.gov as NCT00994747. PMID- 21310830 TI - Trends in carbohydrate, fat, and protein intakes and association with energy intake in normal-weight, overweight, and obese individuals: 1971-2006. AB - BACKGROUND: The prevalence of obesity in the United States has increased dramatically. OBJECTIVE: The aim of this study was to determine trends in carbohydrate, fat, and protein intakes in adults and their association with energy intake by using data from the National Health and Nutrition Examination Survey (NHANES)-a representative sample of the US population. DESIGN: Data on adults aged 20-74 y from the first NHANES (NHANES I, 1971-1975; n = 13,106) were compared with data from NHANES 2005-2006 (n = 4381). Normal weight was defined as a body mass index (BMI; in kg/m(2)) of 19 to <25, overweight as a BMI of 25 to <30, and obese as a BMI of >=30. Carbohydrate, fat, and protein intakes were obtained by dietary recall. Regression analyses were adjusted for potential confounders. RESULTS: The prevalence of obesity increased from 11.9% to 33.4% in men and from 16.6% to 36.5% in women. The percentage of energy from carbohydrates increased from 44.0% to 48.7%, the percentage of energy from fat decreased from 36.6% to 33.7%, and the percentage of energy from protein decreased from 16.5% to 15.7%. Trends were identical across normal-weight, overweight, and obese groups. Energy intake increased substantially in all 3 BMI groups. In NHANES 2005-2006, a 1% increase in the percentage of energy from protein was associated with a decrease in energy intake of 32 kcal (substituted for carbohydrates) or 51 kcal (substituted for fat). Similar findings were seen across all BMI categories, in men and women, and in NHANES I. CONCLUSIONS: Energy intake and the prevalence of obesity have increased dramatically. Dietary interventions should focus on decreasing energy intake and potentially by substituting protein for fat or carbohydrates. PMID- 21310831 TI - Marked differences in gustatory and gastrointestinal sensitivity to oleic acid between lean and obese men. AB - BACKGROUND: Both orosensory stimulation and feedback from the gastrointestinal tract contribute to energy intake regulation. OBJECTIVE: We evaluated the hypothesis that overweight or obese subjects would be less sensitive to both oral and intraduodenal oleic acid exposure than would lean subjects. DESIGN: Eleven overweight or obese and 8 lean men were studied on 2 occasions, during which antropyloroduodenal pressures, plasma cholecystokinin and peptide YY, and appetite were measured during 90-min intraduodenal infusions of saline or oleic acid (18:1 load: 0.78 kcal/min); energy intake (buffet lunch) was determined immediately afterward. Oral detection thresholds for 18:1 and recent dietary intake (2-d recall) were also quantified. RESULTS: In lean subjects, the number of isolated pyloric pressure waves (IPPWs) was greater during 18:1 infusion than during saline infusion (P < 0.05); no significant differences were observed between the 18:1 and saline infusions in the overweight or obese subjects. In both groups, 18:1 stimulated plasma cholecystokinin and peptide YY and suppressed energy intake compared with saline (P < 0.05), with trends for reduced cholecystokinin and energy intake responses in the overweight or obese subjects. Detection thresholds for 18:1 were greater in overweight or obese (7.9 +/- 0.1 mmol/L) than in lean (4.1 +/- 0.4 mmol/L) subjects (P < 0.05). Overweight or obese subjects had greater recent energy (P < 0.05) and fat (P = 0.07) intakes than did lean subjects. There was a direct relation (r = 0.669) of body mass index with 18:1 detection thresholds and inverse relations (r < -0.51) of IPPWs with body mass index and 18:1 detection thresholds (P < 0.05). CONCLUSIONS: The ability to detect oleic acid both orally and within the gastrointestinal tract is compromised in obese men, and oral and gastrointestinal responses to oleic acid are related. This trial was registered at www.actr.org.au (Australian New Zealand Clinical Trials Registry) as 12609000557235. PMID- 21310832 TI - Is there really a negative association between waist circumference and height in adults? PMID- 21310833 TI - Oral acetyl-L-carnitine therapy reduces fatigue in overt hepatic encephalopathy: a randomized, double-blind, placebo-controlled study. AB - BACKGROUND: Fatigue is frequently reported in hepatic encephalopathy (HE) and may be related to hyperammonemia. Acetyl-L-carnitine (ALC) offers neuroprotective benefits and improves mitochondrial energetics and function. OBJECTIVE: This study evaluated the effect of exogenous ALC on physical and mental fatigue, fatigue severity, and physical activity in patients with mild and moderate hepatoencephalopathy (HE1 and HE2, respectively). DESIGN: A total of 121 patients with overt HE were recruited to the study and were subdivided into 2 groups according to their initial HE grade [HE1 (n = 61) or HE2 (n = 60)]. Thirty-one patients with HE1 and 30 with HE2 received 2 g ALC, and 30 patients with HE1 and 30 patients with HE2 received placebo twice a day for 90 d. All patients underwent clinical and laboratory assessments and automated electroencephalogram analysis. RESULTS: At the end of the study period, the ALC-treated patients in the HE1 group showed significantly better improvement than did the placebo group in mental fatigue score (-1.7 compared with -0.3; P < 0.05), the fatigue severity scale (-6.4 compared with 2.3; P < 0.001), 7-d Physical Activity Recall questionnaire score (17.1 compared with -2.5; P < 0.001), and Short Physical Performance Battery (2.1 compared with 0.2; P < 0.001); the HE2 group showed significantly better improvement in the fatigue severity scale (-8.1 compared with -5.1; P < 0.001) and 6-min walk test (19.9 compared with 2.3; P < 0.05). Significant decreases in NH(4)(+) were observed in both groups (P < 0.001). CONCLUSION: Patients with HE treated with ALC showed a decrease in the severity of both mental and physical fatigue and an increase in physical activity. This trial was registered at clinicaltrials.gov as NCT01223742. PMID- 21310834 TI - Prenatal fatty acid status and child adiposity at age 3 y: results from a US pregnancy cohort. AB - BACKGROUND: Exposure to polyunsaturated fatty acids (PUFAs) in early life may influence adiposity development. OBJECTIVE: We examined the extent to which prenatal n-3 (omega-3) and n-6 (omega-6) PUFA concentrations were associated with childhood adiposity. DESIGN: In mother-child pairs in the Project Viva cohort, we assessed midpregnancy fatty acid intakes (n = 1120), maternal plasma PUFA concentrations (n = 227), and umbilical cord plasma PUFA concentrations (n = 302). We performed multivariable regression analyses to examine independent associations of n-3 PUFAs, including docosahexaenoic and eicosapentaenoic acids (DHA + EPA), n-6 PUFAs, and the ratio of n-6:n-3 PUFAs, with child adiposity at age 3 y measured by the sum of subscapular and triceps skinfold thicknesses (SS + TR) and risk of obesity (body mass index >=95th percentile for age and sex). RESULTS: Mean (+/-SD) DHA + EPA intake was 0.15 +/- 0.14 g DHA + EPA/d, maternal plasma concentration was 1.9 +/- 0.6%, and umbilical plasma concentration was 4.6 +/- 1.2%. In children, SS + TR was 16.7 +/- 4.3 mm, and 9.4% of children were obese. In the adjusted analysis, there was an association between each SD increase in DHA + EPA and lower child SS + TR [-0.31 mm (95% CI: -0.58, -0.04 mm) for maternal diet and -0.91 mm (95% CI: -1.63, -0.20 mm) for cord plasma] and lower odds of obesity [odds ratio (95% CI): 0.68 (0.50, 0.92) for maternal diet and 0.09 (0.02, 0.52) for cord plasma]. Maternal plasma DHA + EPA concentration was not significantly associated with child adiposity. A higher ratio of cord plasma n-6:n-3 PUFAs was associated with higher SS + TR and odds of obesity. CONCLUSION: An enhanced maternal-fetal n-3 PUFA status was associated with lower childhood adiposity. PMID- 21310835 TI - The association between breastfeeding and the cardiovascular system in early childhood. AB - BACKGROUND: Breastfeeding is suggested to have beneficial effects on children's health and future health status. However, its cardiovascular effects in childhood and possibly later in life remain largely unclear. OBJECTIVE: The aim of the present study was to determine the cardiovascular effects of exclusive breastfeeding in early childhood. DESIGN: We used the ongoing WHeezing Illnesses STudy LEidsche Rijn (WHISTLER) birth cohort to obtain data on infant feeding. In the first 306 children who were 5 y of age, ultrasonographic measurements of the carotid artery were performed to obtain carotid intima-media thickness (CIMT), distensibility, and elastic modulus. RESULTS: At 5 y of age, children who had been exclusively breastfed in infancy for 3 to 6 mo had a CIMT that was 21.1 MUm greater than that of exclusively formula-fed children (95% CI: 5.0, 37.2 MUm; P = 0.01, adjusted for confounders). CIMT was not significantly different between children exclusively breastfed for either <3 or >6 mo and formula-fed children. In addition, no significant differences in carotid stiffness were observed between groups. CONCLUSIONS: The duration of exclusive breastfeeding in infancy is related to properties of the carotid arterial wall at the age of 5 y, as shown by the greater CIMT in children who were exclusively breastfed for 3 to 6 mo. This relation was independent of early growth in infancy and current cardiovascular disease risk factors. The choice of infant feeding appears to have an effect on the vascular system already in early childhood. PMID- 21310836 TI - Randomized trial of a behavioral intervention to prevent excessive gestational weight gain: the Fit for Delivery Study. AB - BACKGROUND: Excessive weight gain during pregnancy is a major risk factor for postpartum weight retention and future weight gain and obesity in women, but few adequately powered randomized controlled trials have examined the efficacy of a behavioral weight-control intervention during pregnancy. OBJECTIVE: This study examined whether a behavioral intervention during pregnancy could decrease the proportion of women who exceeded the 1990 Institute of Medicine (IOM) recommendations for gestational weight gains and increase the proportion of women who returned to pregravid weights by 6 mo postpartum. DESIGN: This study was a randomized, assessor-blind, controlled trial. Participants were pregnant (13.5 wk gestation), normal-weight (NW; n = 201) and overweight or obese (OW/OB; n = 200) women whose average age was 28.8 y. Participants were randomly assigned within the 1990 IOM weight category (NW compared with OW/OB) to standard care (n = 200) or to a behavioral intervention to prevent excessive gestational weight gain (n = 201). The intervention included one face-to-face visit; weekly mailed materials that promoted an appropriate weight gain, healthy eating, and exercise; individual graphs of weight gain; and telephone-based feedback. The retention at the 6-mo postpartum assessment was 82%. RESULTS: Intent-to-treat analyses showed that the intervention, compared with standard care, decreased the percentage of NW women who exceeded IOM recommendations (40.2% compared with 52.1%; P = 0.003) and increased the percentages of NW and OW/OB women who returned to their pregravid weights or below by 6 mo postpartum (30.7% compared with 18.7%; P = 0.005). CONCLUSION: A low-intensity behavioral intervention during pregnancy reduced excessive gestational weight gains in NW women and prevented postpartum weight retention in NW and OW/OB women. This trial was registered at clinicaltrials.gov as NCT01117961. PMID- 21310837 TI - Reexamining the recommended follow-up interval after obtaining an in-range international normalized ratio value: results from the Veterans Affairs study to improve anticoagulation. AB - BACKGROUND: Patients receiving oral anticoagulation therapy should be tested often enough to optimize control, but excessive testing increases burden and cost. We examined the relationship between follow-up intervals after obtaining an in-range (2.0-3.0) international normalized ratio (INR) and anticoagulation control. METHODS: We studied 104,451 patients who were receiving anticoagulation therapy from 100 anticoagulation clinics in the US Veterans Health Administration. Most patients (98,877) had at least one in-range INR followed by another INR within 56 days. For each such patient, we selected the last in-range INR and characterized the interval between this index value and the next INR. The independent variable was the site mean follow-up interval after obtaining an in range INR. The dependent variable was the site mean risk-adjusted percentage of time in the therapeutic range (TTR). RESULTS: The site mean follow-up interval varied from 25 to 38 days. As the site mean follow-up interval became longer, the risk-adjusted TTR was worse (-0.51% per day, P = .004). This relationship persisted when the index value was the first consecutive in-range INR (-0.63%, P < .001) or the second (-0.58%, P < .001), but not the third or greater (-0.12%, P = .46). CONCLUSIONS: Sites varied widely regarding follow-up intervals after obtaining an in-range INR (25-38 days). Shorter intervals were generally associated with better anticoagulation control, but after obtaining a third consecutive in-range value, this relationship was greatly attenuated and no longer statistically significant. Our results suggest that a maximum interval of 28 days after obtaining the first or second in-range value and consideration of a longer interval after obtaining the third or greater consecutive in-range value may be appropriate. PMID- 21310838 TI - Effects of BMI on static lung volumes in patients with airway obstruction. AB - BACKGROUND: Both chronic airway obstruction and obesity are increasing in prevalence but the effect of their combination on pulmonary function parameters across the range of airway obstruction is unknown. METHODS: We studied the impact of increasing BMI on static lung volumes and airway function in a cohort of 2,265 subjects from a large pulmonary function laboratory database who were 40 to 80 years of age and met GOLD (Global Initiative for Chronic Obstructive Lung Disease) spirometric criteria for COPD (postbronchodilator FEV1/FVC < 0.7). We also evaluated the influence of severity of airway obstruction (by GOLD criteria) on these relationships. RESULTS: With increasing BMI in the group as a whole, functional residual capacity, residual volume, expiratory reserve volume, and specific airway resistance (sRaw) decreased exponentially (all P < .001); total lung capacity (TLC) decreased linearly (P < .001); and inspiratory capacity (IC) and IC/TLC increased linearly (P < .001). However, vital capacity was not influenced significantly. The effects of increasing BMI on FEV1/FVC and sRaw were greatest in GOLD stage III/IV (P < .05), whereas increasing BMI had greater effects on IC in GOLD stage I (P < .001). CONCLUSIONS: With increasing BMI, subjects with airway obstruction had consistent reductions in lung hyperinflation, with significant improvements in IC and the FEV1/FVC ratio; this effect was greatest in patients with the most severe airway obstruction. These results have important implications for the clinical assessment of patients with combined obesity and airway obstruction. PMID- 21310841 TI - NCCN Guidelines and the International Community. PMID- 21310839 TI - Family history is a risk factor for COPD. AB - BACKGROUND: Studies have shown that family history is a risk factor for COPD, but have not accounted for family history of smoking. Therefore, we sought to identify the effects of family history of smoking and family history of COPD on COPD susceptibility. METHODS: We compared 821 patients with COPD to 776 control smokers from the Genetic Epidemiology of COPD (COPDGene) Study. Questionnaires captured parental histories of smoking and COPD, as well as childhood environmental tobacco smoke (ETS) exposure. Socioeconomic status was defined by educational achievement. RESULTS: Parental history of smoking (85.5% case patients, 82.9% control subjects) was more common than parental history of COPD (43.0% case patients, 30.8% control subjects). In a logistic regression model, parental history of COPD (OR, 1.73; P < .0001) and educational level (OR, 0.48 for some college vs no college; P < .0001) were significant predictors of COPD, but parental history of smoking and childhood ETS exposure were not significant. The population-attributable risk from COPD family history was 18.6%. Patients with COPD with a parental history had more severe disease, with lower lung function, worse quality of life, and more frequent exacerbations. There were nonsignificant trends for more severe emphysema and airway disease on quantitative chest CT scans. CONCLUSIONS: Family history of COPD is a strong risk factor for COPD, independent of family history of smoking, personal lifetime smoking, or childhood ETS exposure. Although further studies are required to identify genetic variants that influence COPD susceptibility, clinicians should question all smokers, especially those with known or suspected COPD, regarding COPD family history. PMID- 21310842 TI - Invasive breast cancer. PMID- 21310843 TI - Is there a need for axillary dissection in breast cancer? AB - The involvement of axillary nodes remains a significant prognostic factor in breast cancer. However, management has changed from complete surgical staging to sentinel lymph node biopsies. Although little controversy exists regarding patients with negative sentinel lymph node biopsies, some remains regarding what to do with patients with small volume of axillary disease. This article focuses on the examination of recent evidence in management of the axilla. It focuses on both the prognostic and therapeutic information gleaned from isolated tumor cells and micrometastatic disease and on the use of completion axillary lymph node dissections or axillary radiation in preventing regional recurrence. PMID- 21310844 TI - Inflammatory breast cancer. AB - Inflammatory breast cancer (IBC) represents the most virulent form of breast cancer, characterized by involvement of the skin and rapid progression of the disease. Management involves careful coordination of multidisciplinary modalities, including imaging, systemic chemotherapy, surgery, and radiation therapy. The use of neoadjuvant chemotherapy has contributed significantly to improvement in overall survival since the first descriptions of this entity, and has made the role of locoregional therapy, including surgery and radiation, critical to continued improvements in this disease. This article examines the unique epidemiology and pathology of IBC, and reviews the various treatment modalities, noting the significance of a multimodality approach and delineating each of the specific components. Moreover, the current research in IBC is briefly described, which experts hope will further improve systemic therapies. PMID- 21310845 TI - Trastuzumab-related cardiac dysfunction. AB - The use of trastuzumab in the adjuvant and metastatic treatment of breast cancer is associated with both symptomatic and asymptomatic cardiotoxicity. The long term significance of these events, isolating known cardiotoxic effects of anthracyclines from those of trastuzumab, and the appropriateness of referring to trastuzumab-related cardiotoxicity as reversible rather than responsive to trastuzumab withdrawal and heart failure medical therapy, are issues that continue to be debated. This article provides an overview of the available cardiac safety data from the major trastuzumab clinical trials in breast cancer, highlighting areas of ongoing controversy. Important recent data documenting the occurrence and prognostic use of cardiac troponin I elevations among patients treated with trastuzumab are placed into context with the mechanistic insight these data provide and the implications for clinical practice today. PMID- 21310846 TI - Role of adjuvant and posttreatment exercise programs in breast health. AB - Growing evidence suggests that physical activity may be an important part of survivorship care for women with a history of breast cancer. Observational evidence suggests that women who are physically active after breast cancer diagnosis have a 30% to 50% lower risk of breast cancer recurrence, breast cancer death, and overall death compared with sedentary individuals. Although randomized controlled trials have not been performed to test the ability of exercise to improve outcomes in women with early-stage breast cancer, many small intervention studies have shown the safety and potential benefits of exercise in the adjuvant and posttreatment settings. These studies have shown that physical activity can be performed safely both during and after adjuvant treatment for breast cancer, and that women who increase physical activity in these settings experience improvements in fitness, strength, quality of life, and other end points. Although more research is needed to fully define the role of exercise in breast cancer survivors, the many proven benefits of physical activity have led the American Cancer Society and American College of Sports Medicine to encourage regular participation in moderate-intensity recreational activity for most breast cancer survivors. This article reviews the growing evidence that exercise could be an important part of breast cancer survivorship, and describes current exercise guidelines for breast cancer survivors. PMID- 21310847 TI - The first Databases special issue: the new category opens a new portal to Plant and Cell Physiology. PMID- 21310849 TI - A simplified and high-throughput chromogenic assay for testing tissue factor dependent procoagulant activity. AB - Tissue factor (TF), the primary initiator of the coagulation cascade, plays a critical role in hemostasis and thrombosis, and inhibition of TF activity appears to be an attractive target for the treatment of cardiovascular diseases. However, few selective small-molecule inhibitors of TF are available, and the present assays for measuring TF activity are relatively expensive and complex. The authors present a simple and high-throughput chromogenic assay for screening TF inhibitors based on using commercial human prothrombin complex instead of purified coagulation factors, reducing the dosage, and performing with a one stage procedure. In the optimized assay, <45 uL cell lysates was incubated with Tris-CaCl(2) buffer (pH 7.3) containing human prothrombin complex at 37 degrees C for 15 min in 96-well or 384-well plates. Tris-EDTA buffer (pH 8.4) containing chromogenic substrate Xa was then added and the absorbance measured at 405 nm. This simplified assay was more sensitive or precise than some reported methods for TF procoagulant activities. Two known active compounds (curcumin and simvastatin) inhibiting TF activity were tested by the simplified assay to validate the screening method. Furthermore, berberine and cryptotanshinone suppressed TF activity induced by lipopolysaccharides in human monocytes by this assay and might be promising new TF inhibitors. PMID- 21310850 TI - Rapid and quantitative assessment of cell quality, identity, and functionality for cell-based assays using real-time cellular analysis. AB - Strict quality control of cells is required for the standardization and interpretation of results in all areas of cell-based research, especially in drug discovery. Real-time cellular analysis using electrical impedance as a readout offers a rapid and highly reproducible method for quality control as it provides a quantitative measure of overall cell morphology and growth. In a case study, the authors demonstrate that samples of a single cell line obtained from several different labs show clear differences in their impedance profiles when compared with the corresponding standard cell line. A number of kinetic parameters were derived from the impedance profiles and used to quantify the differences among these cell lines. Our findings indicate that this methodology can detect cell line differences including mix-ups or contaminations, genetic alterations, and potential epigenetic changes occurring during passaging, all of which can occur in the time scale of a screening campaign. Finally, we provide evidence that these impedance profile differences can be predictive of different outcomes in cell-based functional assays for the effects of small molecules on otherwise seemingly identical cell lines. PMID- 21310851 TI - MicroRNA hsa-miR-613 targets the human LXRalpha gene and mediates a feedback loop of LXRalpha autoregulation. AB - The nuclear receptor liver X receptor (LXR) is a ligand-dependent transcription factor that plays an important role in the metabolism and homeostasis of cholesterol, lipids, bile acids, and steroid hormones. MicroRNAs (miRNAs) are recently recognized important negative regulators of gene expression. In this report, we showed that miRNA hsa-miR-613 played an important role in the autoregulation of the human LXRalpha gene. hsa-miR-613 targeted the endogenous LXRalpha through its specific miRNA response element (613MRE) within the LXRalpha 3'-untranslated region. Interestingly and paradoxically, the expression of hsa miR-613 itself was induced upon the activation of LXR. However, hsa-miR-613 did not appear to be a direct LXR target gene. Instead, the positive regulation of hsa-miR-613 by LXR was mediated by the sterol regulatory element binding protein (SREBP)-1c, a known LXR target gene. Promoter analysis revealed an SREBP response element in the hsa-miR-613 gene promoter. Treatment with insulin also induced the expression of hsa-miR-613 in an SREBP-1c-dependent manner, further supporting the role of SREBP-1c in the positive regulation of this miRNA species. Finally, the autoinduction of LXRalpha by a LXR agonist was enhanced when hsa-miR-613 was inhibited or SREBP-1c was down-regulated. hsa-miR-613 appeared to specifically target the human LXRalpha. We propose that the negative regulation mediated by hsa-miR-613 and SREBP-1c and the previously reported positive regulation mediated by an LXR response element in the LXRalpha gene promoter constitute a ying-yang mechanism to ensure a tight regulation of this nuclear receptor of many metabolic functions. PMID- 21310848 TI - Analysis of leaf and root transcriptomes of soil-grown Avena barbata plants. AB - Slender wild oat (Avena barbata) is an annual grass dominant in many grassland ecosystems in Mediterranean climate. This species has been the subject of ecological studies aimed at understanding the effect of global climate change on grassland ecosystems and the genetic basis for adaptation under varying environmental conditions. We present the sequencing and analysis of cDNA libraries constructed from leaf and root samples collected from A. barbata grown on natural soil and under varying rainfall patterns. More than 1 million expressed sequence tags (ESTs) were generated using both GS 454-FLX pyrosequencing and Sanger sequencing, and these tags were assembled into consensus sequences. We identified numerous candidate polymorphic markers in the data set, providing possibilities for linking the genomic and the existing genetic information for A. barbata. Using the digital Northern method, we showed that genes involved in photosynthesis were down-regulated under high rainfall while stress-related genes were up-regulated. We also identified a number of genes unique to the root library with unknown function. Real-time reverse transcription-PCR was used to confirm the root specificity of some of these transcripts such as two genes encoding O-methyl transferase. Also we showed differential expression of five root-specific genes under three water levels and two developmental stages. Through a combination of Sanger and 454-based sequencing technologies, we were able to generate a large set of transcribed sequences for A. barbata. This data set provides a platform for further studies of this important wild grass species. PMID- 21310852 TI - Growth hormone signaling in human T47D breast cancer cells: potential role for a growth hormone receptor-prolactin receptor complex. AB - GH receptor (GHR) and prolactin (PRL) receptor (PRLR) are structurally similar cytokine receptor superfamily members that are highly conserved among species. GH has growth-promoting and metabolic effects in various tissues in vertebrates, including humans. PRL is essential for regulation of lactation in mammals. Recent studies indicate that breast tissue bears GHR and PRLR and that both GH and PRL may impact development or behavior of breast cancer cells. An important facet of human GH (hGH) and human PRL (hPRL) biology is that although hPRL interacts only with hPRLR, hGH binds well to both hGHR and hPRLR. Presently, we investigated potential signaling effects of both hormones in the estrogen receptor- and progesterone receptor-positive human T47D breast cancer cell line. We found that this cell type expresses ample GHR and PRLR and responds well to both hGH and hPRL, as evidenced by activation of the Janus kinase 2/signal transducer and activator of transcription 5 pathway. Immunoprecipitation studies revealed specific GHR-PRLR association in these cells that was acutely enhanced by GH treatment. Although GH caused formation of disulfide-linked and chemically cross linked GHR dimers in T47D cells, GH preferentially induced tyrosine phosphorylation of PRLR rather than GHR. Notably, both a GHR-specific ligand antagonist (B2036) and a GHR-specific antagonist monoclonal antibody (anti GHR(ext-mAb)) failed to inhibit GH-induced signal transducer and activator of transcription 5 activation. In contrast, although the non-GHR-specific GH antagonist (G120R) and the PRL antagonist (G129R) individually only partially inhibited GH-induced activation, combined treatment with these two antagonists conferred greater inhibition than either alone. These data indicate that endogenous GHR and PRLR associate (possibly as a GHR-PRLR heterodimer) in human breast cancer cells and that GH signaling in these cells is largely mediated by the PRLR in the context of both PRLR-PRLR homodimers and GHR-PRLR heterodimers, broadening our understanding of how these related hormones and their related receptors may function in physiology and pathophysiology. PMID- 21310853 TI - Exploring and comparing the characteristics of nonlatent and latent composite scores: implications for pay-for-performance incentive design. AB - A concise and reliable composite quality score would be helpful in judging the quality of a hospital's services, especially for pay-for-performance (P4P) initiatives. This study compared several nonlatent and latent composite quality scores to evaluate the quality of care using diabetes mellitus (DM) P4P data and discusses their characteristics and implications for P4P policy. The authors describe a cross-sectional study of the DM P4P data collected from the claims data of the Bureau of National Health Insurance (NHI) in Taiwan from January 2007 to December 2007. The DM patient outcome data, such as hemoglobin A1C values, were retrieved from the P4P database sponsored by the Bureau of NHI in Taiwan. The composite scores were derived from the following methods: 1) nonlatent scores methods (e.g., the raw sum score and the all-or-none score methods)and 2) latent scores methods (e.g., item-response theory-based Models I and II and the PRIDIT model). These scores are compared in terms of 2 aspects-agreement of hospital rankings (using Spearman's rank correlation) and reliability (using bootstrap methods). The latent methods were superior to the nonlatent methods because they were more reliable and had specific weighting themes. The correlations among the 3 latent methods were moderately high. The use of the PRIDIT approach, which is moderately difficult compared with item response theory-based model, is recommended if the insurer wants to balance convenience and precision. PMID- 21310854 TI - Eliciting benefit-risk preferences and probability-weighted utility using choice format conjoint analysis. AB - This study applies conjoint analysis to estimate health-related benefit-risk tradeoffs in a non-expected-utility framework. We demonstrate how this method can be used to test for and estimate nonlinear weighting of adverse-event probabilities and we explore the implications of nonlinear weighting on maximum acceptable risk (MAR) measures of risk tolerance. We obtained preference data from 570 Crohn's disease patients using a web-enabled conjoint survey. Respondents were presented with choice tasks involving treatment options that involve different efficacy benefits and different mortality risks for 3 possible side effects. Using conditional logit maximum likelihood estimation, we estimate preference parameters using 3 models that allow for nonlinear preference weighting of risks--a categorical model, a simple-weighting model, and a rank dependent utility (RDU) model. For the second 2 models we specify and jointly estimate 1- and 2-parameter probability weighting functions. Although the 2 parameter functions are more flexible, estimation of the 1-parameter functions generally performed better. Despite well-known conceptual limitations, the simple weighting model allows us to estimate weighting function parameters that vary across 3 risk types, and we find some evidence of statistically significant differences across risks. The parameter estimates from RDU model with the single parameter weighting function provide the most robust estimates of MAR. For an improvement in Crohn's symptom severity from moderate and mild, we estimate maximum 10-year mortality risk tolerances ranging from 2.6% to 7.1%. Our results provide further the evidence that quantitative benefit-risk analysis used to evaluate medical interventions should account explicitly for the nonlinear probability weighting of preferences. PMID- 21310855 TI - Can life expectancy and QALYs be improved by a framework for deciding whether to apply clinical guidelines to patients with severe comorbid disease? AB - BACKGROUND: Guidelines with short-term harms and long-term benefits are often applied to chronically ill patients who may not benefit. The payoff time framework has been proposed (i.e., do not apply a guideline if a patient's life expectancy (LE) is shorter than when a guideline's cumulative incremental benefits first exceed its cumulative incremental harms), but its health impact is unclear. OBJECTIVE: To investigate whether the payoff time framework improves LE and/or quality-adjusted life-years (QALY) for chronically ill patients. METHODS: I evaluate impact of the payoff time framework on LE and QALYs, assuming (1) high and constant background mortality rate from chronic illness (>= 10% per year), (2) immediate guideline-related harm with probability < 1, and (3) constant guideline-related benefit that occurs over an extended time. I apply the framework to questions of whether to screen chronically ill 50-year-old women for colorectal cancer using colonoscopy, and whether to advocate intensive glucose control for chronically ill diabetics. RESULTS: If a guideline's payoff time is greater than a patient's LE, then withholding that guideline will increase LE and QALYs for that patient. For a 50-year-old chronically ill woman with background mortality > 0.15 per year (corresponding to LE < 6.5 years), withholding CR screening will increase LE. For a diabetic with background mortality > 0.11 per year (corresponding to LE < 9.4 years), withholding CR screening will increase QALYs. CONCLUSION: The payoff time framework may indicate when withholding a guideline with short-term harms and long-term benefits may increase LE and/or QALY. PMID- 21310856 TI - Searching the journal for evidence-based radiology. PMID- 21310857 TI - Identification and clinical impact of multiple sclerosis cortical lesions as assessed by routine 3T MR imaging. AB - BACKGROUND AND PURPOSE: Histopathologic studies have reported widespread cortical lesions in MS; however, in vivo detection by using routinely available pulse sequences is challenging. We investigated the relative frequency and subtypes of cortical lesions and their relationships to white matter lesions and cognitive and physical disability. MATERIALS AND METHODS: Cortical lesions were identified and classified on the basis of concurrent review of 3D FLAIR and 3D T1-weighted IR-SPGR 3T MR images in 26 patients with MS. Twenty-five patients completed the MACFIMS battery. White matter lesion volume, cortical lesion number, and cortical lesion volume were assessed. RESULTS: Overall, 249 cortical lesions were detected. Cortical lesions were present in 24/26 patients (92.3%) (range per patient, 0-30; mean, 9.6 +/- 8.8). Most (94.4%, n = 235) cortical lesions were classified as mixed cortical-subcortical (type I); the remaining 5.6% (n = 14) were classified as purely intracortical (type II). Subpial cortical lesions (type III) were not detected. White matter lesion volume correlated with cortical lesion number and cortical lesion volume (r(S) = 0.652, r(S) = 0.705, respectively; both P < .001). After controlling for age, depression, and premorbid intelligence, we found that all MR imaging variables (cortical lesion number, cortical lesion volume, white matter lesion volume) correlated with the SDMT score (R(2) = 0.513, R(2) = 0.449, R(2) = 0.418, respectively; P < .014); cortical lesion number also correlated with the CVLT-II scores (R(2) = 0.542 0.461, P < .043). The EDSS scores correlated with cortical lesion number and cortical lesion volume (r(S) = 0.472, r(S) = 0.404, respectively; P < .05), but not with white matter lesion volume. CONCLUSIONS: Our routinely available imaging method detected many cortical lesions in patients with MS and was useful in their precise topographic characterization in the context of the gray matter-white matter junction. Routinely detectable cortical lesions were related to physical disability and cognitive impairment. PMID- 21310858 TI - Complex bilobular, bisaccular, and broad-neck microsurgical aneurysm formation in the rabbit bifurcation model for the study of upcoming endovascular techniques. AB - BACKGROUND AND PURPOSE: Despite rapid advances in the development of materials and techniques for endovascular intracranial aneurysm treatment, occlusion of large broad-neck aneurysms remains a challenge. Animal models featuring complex aneurysm architecture are needed to test endovascular innovations and train interventionalists. MATERIALS AND METHODS: Eleven adult female New Zealand rabbits were assigned to 3 experimental groups. Complex bilobular, bisaccular, and broad-neck venous pouch aneurysms were surgically formed at an artificially created bifurcation of both CCAs. Three and 5 weeks postoperatively, the rabbits underwent 2D-DSA and CE-3D-MRA, respectively. RESULTS: Mortality was 0%. We observed no neurologic, respiratory, or gastrointestinal complications. The aneurysm patency rate was 91% (1 aneurysm thrombosis). There was 1 postoperative aneurysm hemorrhage (9% morbidity). The mean aneurysm volumes were 176.9 +/- 63.6 mm(3), 298.6 +/- 75.2 mm(3), and 183.4 +/- 72.4 mm(3) in bilobular, bisaccular, and broad-neck aneurysms, respectively. The mean operation time was 245 minutes (range, 175-290 minutes). An average of 27 +/- 4 interrupted sutures (range, 21 32) were needed to create the aneurysms. CONCLUSIONS: This study demonstrates the feasibility of creating complex venous pouch bifurcation aneurysms in the rabbit with low morbidity, mortality, and high short-term aneurysm patency. The necks, domes, and volumes of the bilobular, bisaccular, and broad-neck aneurysms created are larger than those previously described. These new complex aneurysm formations are a promising tool for in vivo animal testing of new endovascular devices. PMID- 21310859 TI - Multimodal imaging does not delay intravenous thrombolytic therapy in acute stroke. AB - BACKGROUND AND PURPOSE: Patients with acute ischemic stroke require immediate medical treatment, and a CT to rule out hemorrhage is required before tPA. We adapted our protocol to include multimodal CT: unenhanced CT, CTA, and PCT. The purpose of this study was to determine whether multimodal CT imaging delays initiation of IV tPA beyond 60 minutes from hospital arrival. MATERIALS AND METHODS: All patients admitted during 3 years through the ED with a stroke alert and time from symptom onset to hospital arrival <2.5 hours were included. We examined 2 subgroups (multimodal CT versus unenhanced CT) to determine whether multimodal CT delayed tPA administration. Logistic regression was used to identify variables that predicted tPA within 60 minutes. RESULTS: There were 123 patients in the analysis, including 108 patients who were examined with multimodal CT. The median time from arrival to tPA was 56 minutes and was shorter for patients examined with multimodal CT (55 versus 78 minutes, P = .02). After adjustment, variables that were associated with tPA administration within 60 minutes included prehospital stroke alert (OR = 3.47, P = .03), time to CT (OR = 0.94, P = .01), and onset-to-arrival time (OR = 1.02, P = .04). There was no statistically significant difference in the odds of receiving timely tPA for multimodal versus unenhanced CT (OR = 3.99, P = .07). CONCLUSIONS: In our single center experience, the use of multimodal imaging in patients with acute stroke did not delay IV tPA beyond 60 minutes. Further study is needed to assess the feasibility of the routine use of multimodal imaging in the acute stroke setting. PMID- 21310860 TI - Hemodynamics of cerebral aneurysm initiation: the role of wall shear stress and spatial wall shear stress gradient. AB - BACKGROUND AND PURPOSE: Cerebral aneurysms are preferentially located at arterial curvatures and bifurcations that are exposed to major hemodynamic forces, increasingly implicated in the life cycle of aneurysms. By observing the natural history of aneurysm formation from its preaneurysm state, we aimed to examine the hemodynamic microenvironment related to aneurysm initiation at certain arterial segments later developing an aneurysm. MATERIALS AND METHODS: The 3 patients included in the study underwent cerebral angiography with 3D reconstruction before a true aneurysm developed. The arterial geometries obtained from the 3D DSA models were used for flow simulation by using finite-volume modeling. The WSS and SWSSG at the site of the future aneurysm and the flow characteristics of the developed aneurysms were analyzed. RESULTS: The analyzed regions of interest demonstrated significantly increased WSS, accompanied by an increased positive SWSSG in the adjacent proximal region. The WSS reached values of >5 times the temporal average values of the parent vessel, whereas the SWSSG approximated or exceeded peaks of 40 Pa/mm in all 3 cases. All patients developed an aneurysm within 2 years, 1 of which ruptured. CONCLUSIONS: The results of this hemodynamic study, in accordance with the clinical follow-up, suggest that the combination of high WSS and high positive SWSSG focused on a small segment of the arterial wall may have a role in the initiation process of aneurysm formation. PMID- 21310861 TI - Complex spinal-paraspinal fast-flow lesions in CLOVES syndrome: analysis of clinical and imaging findings in 6 patients. AB - CLOVES syndrome is a complex disorder of congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal/scoliosis/spinal anomalies. We report the occurrence of spinal-paraspinal fast-flow lesions within or adjacent to the truncal overgrowth or a cutaneous birthmark in 6 patients with CLOVES syndrome. PMID- 21310862 TI - Electron microscopy characterization of airborne micro- and nanoparticulate matter. AB - The aim of this work was to offer a state-of-the-art critical survey for characterizing airborne nano- and microparticles by means of electron microscopy (EM) techniques and to highlight advantages and limits of different possible operation modes. Procedures of collection and sample preparation are revisited and improved to analyse airborne particles deposited on filtering membranes by using various sampling methods. Three kinds of electron microscopes are used to this end: scanning electron microscope (SEM), field emission scanning electron microscope (FE-SEM) and transmission electron microscope (TEM). Following and extending previous studies, we optimized procedures by varying both the sample collection/preparation and the operational parameters of the microscopes. In particular, we diversified the sampling methods applied, using ad hoc filters as well as common filters for standard gravimetric measures. This approach enabled us to achieve a simple and clean procedure allowing direct SEM or TEM observation of the collected particulate matter. PMID- 21310863 TI - 3, 4-Didehydroretinol kinetics differ during lactation in sows on a retinol depletion regimen and the serum:milk 3, 4-didehydroretinol:retinol ratios are correlated. AB - 3, 4-Didehydroretinol (DR) metabolism was previously followed in vitamin A (VA) replete lactating sows. This study followed DR appearance and clearance after dosage in serum and milk during 2 lactation cycles in sows (n = 8) fed VA-free feed for 3 gestation-lactation cycles. During lactations 2 and 3, 35 MUmol 3, 4 didehydroretinyl acetate was given orally after overnight food deprivation. Blood and milk were collected at 0, 1.5, 3, 5, 7, 9, 16, 24, 36, 48, 60, and 72 h; livers were obtained at kill. Samples were analyzed for DR, retinol (R), and 3, 4 didehydroretinyl esters. During lactations 2 and 3, the 5-h serum DR:R ratios were 0.028 +/- 0.017 and 0.069 +/- 0.042, respectively, and serum R concentrations were 0.75 +/- 0.23 and 0.86 +/- 0.37 MUmol/L, respectively. The DR:R ratio and serum R were 0.018 +/- 0.013 and 0.94 +/- 0.12 MUmol/L, respectively, in VA-replete sows from the same herd. After lactation 3, liver VA was 0.23 +/- 0.05 MUmol/g, indicating low-normal VA status. Serum DR area-under the curve from 0 to 48 h increased as liver stores decreased. Thirteen to 23% of DR dose was secreted into milk, consistent with VA-replete sows. Milk DR concentrations were greater during lactation 3 than 2. Peak concentration occurred earlier and the half-life was shorter for milk DR in the more VA depleted sows. The milk and serum DR:R were correlated from 3 to 9 h (r = 0.70; P < 0.0001) and increased as VA stores decreased regardless of serum R concentration. Milk DR:R may replace serum measurements during lactation. PMID- 21310864 TI - Dietary whey protein lowers the risk for metabolic disease in mice fed a high-fat diet. AB - Consuming a high-fat (HF) diet produces excessive weight gain, adiposity, and metabolic complications associated with risk for developing type 2 diabetes and fatty liver disease. This study evaluated the influence of whey protein isolate (WPI) on systemic energy balance and metabolic changes in mice fed a HF diet. Female C57BL/6J mice received for 11 wk a HF diet, with or without 100 g WPI/L drinking water. Energy consumption and glucose and lipid metabolism were examined. WPI mice had lower rates of body weight gain and percent body fat and greater lean body mass, although energy consumption was unchanged. These results were consistent with WPI mice having higher basal metabolic rates, respiratory quotients, and hepatic mitochondrial respiration. Health implications for WPI were reflected in early biomarkers for fatty liver disease and type 2 diabetes. Livers from WPI mice had significantly fewer hepatic lipid droplet numbers and less deposition of nonpolar lipids. Furthermore, WPI improved glucose tolerance and insulin sensitivity. We conclude that in mice receiving a HF diet, consumption of WPI results in higher basal metabolic rates and altered metabolism of dietary lipids. Because WPI mice had less hepatosteatosis and insulin resistance, WPI dietary supplements may be effective in slowing the development of fatty liver disease and type 2 diabetes. PMID- 21310865 TI - Feeding oscillating dietary crude protein concentrations increases nitrogen utilization in growing lambs and this response is partly attributable to increased urea transfer to the rumen. AB - Our objective was to determine the effects of feeding oscillating compared with static dietary crude protein (CP) concentrations on nitrogen (N) retention and urea flux across ruminal epithelia. Twenty-seven Suffolk wether lambs (n = 9) were assigned to a medium-CP diet [MEDIUM; 127 g CP?kg dry matter (DM)(-1)] or to diets with oscillating CP content (OSC) fed in 2 different sequences, i.e. 2 d of low CP (103 g CP?kg DM(-1)) followed by 2 d of high CP (161 g CP?kg DM(-1); OSC HIGH) or vice versa (OSC-LOW). Diet adaptation was for 24 d, followed by 8 d of total urine and feces collection. On d 33, lambs were slaughtered 4 h after the morning feeding, such that those receiving OSC-LOW and OSC-HIGH diets were slaughtered on d 3 of receiving the low- or high-CP diets, respectively. Ruminal epithelia were collected and mounted in Ussing chambers and the serosal-to mucosal urea flux (J(sm-urea)) was measured using (14)C-urea. Ruminal NH(3)-N concentration was lower (P = 0.001) in lambs fed OSC-LOW compared with those fed OSC-HIGH. Although N intake was similar, retained N (P = 0.001) and microbial N supply (P = 0.001) were greater in lambs fed OSC compared with those fed MEDIUM. The total J(sm-urea) was higher (P = 0.001) in lambs fed OSC-LOW compared with those fed OSC-HIGH. Across diets, the addition of phloretin [a known specific inhibitor of facilitative urea transporter (UT)-B] reduced J(sm-urea) by 19.5 22.3% (P = 0.001); however, phloretin-insensitive J(sm-urea) was the predominant route for transepithelial urea transfer. Taken together, these data indicate that feeding oscillating dietary CP concentrations improves N retention partly by increasing urea recycling to the rumen when animals are fed low-CP diets, but the greater rates of urea transfer cannot be attributable to upregulation of UT-B. PMID- 21310866 TI - Low plasma vitamin B-6 status affects metabolism through the kynurenine pathway in cardiovascular patients with systemic inflammation. AB - It is unclear whether reduced plasma pyridoxal 5'-phosphate (PLP) during inflammation reflects an altered distribution or increased requirement of vitamin B-6 that may impair overall vitamin B-6 status in tissues. In plasma from 3035 patients undergoing coronary angiography for suspected coronary heart disease, we investigated if plasma concentrations of any metabolites in the kynurenine pathway, which depend on PLP as cofactor, may serve as metabolic marker(s) of vitamin B-6 status. We also examined the association of vitamin B-6 status with serum or plasma concentrations of several inflammatory markers. Among the kynurenines, only 3-hydroxykynurenine (HK) was inversely related to PLP and showed a positive relation to 4 investigated inflammatory markers. A segmented relationship was observed between PLP and HK, with a steep slope at PLP concentrations < 18.4 nmol/L, corresponding to the 5th percentile, and an almost zero slope at higher PLP concentrations. Low PLP and the steep PLP-HK slope were essentially confined to participants with 1 or more inflammatory markers in the upper tertile. Oral supplementation with pyridoxine hydrochloride (40 mg/d) for 1 mo increased plasma PLP 8-fold, reduced the geometric mean (95% CI) of HK from 29.5 to 20.2 nmol/L (P < 0.001), and abolished the steep segment of the PLP-HK curve. The steep inverse relationship of plasma PLP with HK at low plasma PLP and the lowering of HK by pyridoxine suggest plasma HK as a metabolic marker of vitamin B-6 status. Thus, low plasma PLP during inflammation may reflect impaired cellular vitamin B-6 status, as indicated by the concurrent increase in plasma HK. PMID- 21310867 TI - Cortical and trabecular bone, bone mineral density, and resistance to ex vivo fracture are not altered in response to life-long vitamin A supplementation in aging rats. AB - High vitamin A (VA) intakes have been correlated with increased risk of bone fracture. Over 50% of the U.S. adult population reports use of dietary supplements, which can result in VA intakes > 200% of the RDA. In this study, 2 experiments were designed to determine the effect of dietary VA on cortical and trabecular bone properties and resistance to ex vivo fracture. In Expt. 1, we investigated whether orally administered VA accumulates in bone. Seven-week-old rats were treated daily with VA (6 mg/d for 14 d). Total retinol increased in both the tibia and femur (P < 0.01). In Expt. 2, we conducted a longitudinal study in which rats were fed 1 of 3 levels of dietary VA (marginal, adequate, and supplemented, equal to 0.35, 4, and 50 MUg retinol/g diet, respectively) from weaning until the ages of 2-3 mo (young), 8-10 mo (middle-age), and 18-20 mo (old). Tibial trabecular and cortical bone structure, bone mineral density, and resistance to fracture were measured using micro-computed tomography and material testing system analysis, respectively. The VA-marginal diet affected measures of cortical bone dimension, suggesting bone remodeling was altered. VA supplementation increased medullary area and decreased cortical thickness in young rats (P < 0.05), but these changes were not present during aging. VA supplementation did not affect resistance to fracture or bone mineral content in old rats. From these results, we conclude that VA-marginal status affects trabecular bone more than cortical bone, and VA supplementation at a moderate level over the lifetime is unlikely to increase the risk of age-related bone fracture in rats. PMID- 21310868 TI - Dietary arachidonate differentially alters desaturase-elongase pathway flux and gene expression in liver and intestine of suckling pigs. AB - Because dietary arachidonate (ARA) and its eicosanoid derivatives are major regulators of intestinal homeostasis and repair following injury, we evaluated the effects of dietary ARA on desaturation and elongation of (13)C-18:2(n-6) and mRNA abundance of Delta-6-desaturase (FADS2), elongase (ELOVL5), and Delta-5 desaturase (FADS1) in liver and intestine. Day-old pigs (n = 96) were fed milk based formula containing 0, 0.5, 2.5, or 5% ARA or 5% eicosapentaenoic acid of total fatty acids for 4, 8, and 16 d. In liver, the desaturation rate [nmol/(g tissue?h)] of (13)C-18:2(n-6) to (13)C-18:3(n-6) decreased 56% between 4 and 16 d but was not affected by diet. Whereas accumulation in (13)C-20:3(n-6) also decreased with age by 67%, it increased linearly with increasing dietary ARA (P < 0.06). In comparison, intestinal flux was ~50% less than liver flux and was unaffected by age, but desaturation to (13)C-18:3(n-6) increased linearly (by 57%) in pigs fed ARA diets (P < 0.001), equaling the rate observed in sow-fed controls. In both liver and intestine, alternate elongation to (13)C-20:2(n-6) (via Delta-8-desaturase) was markedly elevated in pigs fed the 0% ARA diet compared with all other dietary treatments (P < 0.01). Transcript abundance of FADS2, ELOVL5, and FADS1 was not affected in liver by diet (P > 0.05) but decreased precipitously between birth and d 4 (~70%; P < 0.05). In contrast, intestinal abundance of FADS2 and FADS1 increased 60% from d 4 to 16. In conclusion, dietary ARA regulated the desaturase-elongase pathway in a tissue specific manner. In liver, ARA had modest effects on (n-6) fatty acid flux, and intestinal FADS2 activity and mRNA increased. Additionally, hepatic flux decreased with postnatal age, whereas intestinal flux did not change. PMID- 21310869 TI - Comparison of cardiovascular prognosis by 3 serum cystatin C methods in the Heart and Soul Study. AB - BACKGROUND: Cystatin C is a promising new biomarker to determine the estimated glomerular filtration. However, the Siemens' cystatin C assay (Siemens), used in many longitudinal studies, has had limited clinical applicability because it requires a specific, dedicated instrument. Other companies, including Gentian and Roche, have developed cystatin C assays that can be used with most routine clinical chemistry analyzers. METHODS: We compared the agreement of Gentian and Roche with Siemens assays in 948 participants at the baseline visit of the Heart and Soul Study, a cohort of participants with established coronary artery disease who were followed for an average of 8 years. We then compared associations of all 3 cystatin C measures and eGFR-Modification of Diet in Renal Disease (MDRD) with clinical outcomes. RESULTS: The Gentian assay had higher correlation with Siemens (r = 0.96) than did Roche (r = 0.93, P < 0.001). After cross-tabulating quartiles of each cystatin C measure, agreements (kappa statistic) were higher for Siemens and Gentian (0.73, 95% CI 0.72-0.75) than for Roche and Siemens (0.64, 0.63-0.66) or for Roche and Gentian (0.69, 0.65-0.71). These differences in agreement had minimal impact on associations with clinical outcomes; the hazard ratios (HRs) for mortality comparing the high vs low quartiles were 3.2 (95% CI 2.1-4.8) for Siemens, 3.1 (CI 2.1-4.7) for Gentian, 3.1 (CI 2.1-4.7) for Roche, and 1.6 (CI 1.1-2.3) for eGFR-MDRD, after multivariate adjustment. CONCLUSIONS: In summary, agreement with the Siemens' assay was modestly higher for the Gentian compared with the Roche assay, although all 3 methods for cystatin C measurement had similar utility as predictors of clinical outcomes. PMID- 21310870 TI - Alzheimer disease: advances in pathogenesis, diagnosis, and therapy. PMID- 21310871 TI - High-sensitivity cardiac troponin for screening large populations of healthy people: is there risk? PMID- 21310872 TI - Comparisons in the epidemiology, diagnostic features and cure rate by transsphenoidal surgery between paediatric and adult-onset Cushing's disease. AB - OBJECTIVE: There are few published comparisons between paediatric and adult-onset Cushing's disease (CD). We compare the epidemiology, diagnostic features and cure rate by transsphenoidal surgery (TSS) in these groups. DESIGN: Retrospective review of patient databases in a single university hospital centre. PATIENTS: Totally, 41 paediatric (mean age 12.3 +/- 3.5 years; range 5.7-17.8) and 183 adult (mean age 40 +/- 13 years; range 18.0-95.0) patients with CD were investigated. RESULTS: Paediatric CD was characterised by male (63%) and adult CD by a female predominance (79%, P<0.0001). There were small but significant differences in clinical presentation. Biochemical features of CD were comparable except the serum cortisol increase during a CRH test: mean change (105%, n=39) in paediatric and (54%, n=123) in adult subjects (P<0.0001). Macroadenomas were more common in adult (15%, 28/183) than in paediatric (2%, 1/41, P=0.04) CD. Corticotroph microadenomas were more easily visualised by pituitary magnetic resonance imaging (MRI) in adult (76%, 50/66) compared with paediatric (55%, 21/38, P=0.045) CD with poorer concordance of imaging with surgical findings in children (P=0.058). The incidence of ACTH lateralisation by bilateral simultaneous inferior petrosal sinus sampling was comparable in paediatric (76%, 25/33) and adult (79%, 46/58; P=0.95) patients with good surgical concordance in both (82% paediatric and 79% adult). Cure rates by TSS were comparable, with a paediatric cure rate of 69%. CONCLUSION: Several features of paediatric CD are distinct: increased frequency of prepubertal CD in males, the different clinical presentation, the decreased presence of macroadenomas and the frequent absence of radiological evidence of an adenoma on MRI. PMID- 21310873 TI - Different vitamin D substrate-product relationship after oral vitamin D supplementation in familial benign hypercalcemia, primary hyperparathyroidism, and healthy controls. AB - CONTEXT: In healthy subjects and in patients with primary hyperparathyroidism (PH), the administration of a low dose of 25(OH)D (25 MUg/day) increases the serum levels of both 25(OH)D and 1,25(OH)(2)D. It is unknown whether this relationship is present in patients affected by familial benign hypocalciuric hypercalcemia (FBH). OBJECTIVE: To evaluate the different vitamin D substrate product relationship after oral vitamin D supplementation in familial benign hypercalcemia, PH, and healthy controls. DESIGN: We evaluated the main physiological regulators of 1alpha-hydroxylase and the substrate-product relationship of 25(OH)D and 1,25(OH)(2)D in 20 patients with PH, 25 with FBH, and 122 healthy sex- and age-matched controls before and after administration of 25(OH)D for 2 weeks. RESULTS: 25(OH)D increased significantly in all subjects, whereas 1,25(OH)(2)D serum levels increased significantly in PH patients and healthy controls but not in patients with FBH. Therefore, a significant positive substrate-product relationship of 25(OH)D-1,25(OH)(2)D was found in PH and healthy controls, but not in FBH. Monomeric calcitonin (hCT-M) was significantly lower at baseline and after 25(OH)D supplementation in the FBH group compared with the other two groups. CONCLUSIONS: The lack of 1,25(OH)(2)D increase in FBH may be due to a direct inhibitory effect on 1alpha-hydroxylase of hypercalcemia per se, increased metabolic clearance of 1,25(OH)(2)D, or a decreased stimulus of 1alpha-hydroxylase related to persistently low levels of hCT. PMID- 21310874 TI - Effects of cigarette smoke and hypoxia on pulmonary circulation in the guinea pig. AB - Cigarette smoke (CS) and chronic hypoxia (CH) can produce pulmonary hypertension. Similarities and differences between both exposures and their interaction have not been explored. The aim of the present study was to investigate the effects of CS and CH, as single factors or in combination, on the pulmonary circulation in the guinea pig. 51 guinea pigs were exposed to CS for 12 weeks and 32 were sham exposed. 50% of the animals in each group were additionally exposed to CH for the final 2 weeks. We measured pulmonary artery pressure (P(pa)), and the weight ratio between the right ventricle (RV) and left ventricle plus the septum. Pulmonary artery contractility in response to noradrenaline (NA), endothelium dependent vasodilatation and distensibility were evaluated in organ bath chambers. The number of small intrapulmonary vessels showing immunoreactivity to smooth muscle (SM) alpha-actin and double elastic laminas was assessed microscopically. CS and CH induced similar increases of P(pa) and RV hypertrophy (p<0.05 for both), effects that were further enhanced when both factors were combined. CH increased the contractility to NA (p<0.01) and reduced the distensibility (p<0.05) of pulmonary arteries. Animals exposed to CS showed an increased number of small vessels with positive immunoreactivity to SM alpha actin (p<0.01) and those exposed to CH a greater proportion of vessels with double elastic laminas (p<0.05). We conclude that CH amplifies the detrimental effects of CS on the pulmonary circulation by altering the mechanical properties of pulmonary arteries and enhancing the remodelling of pulmonary arterioles. PMID- 21310875 TI - Propofol versus propofol plus hydrocodone for flexible bronchoscopy: a randomised study. AB - Propofol and the combination of a benzodiazepine and an opiate have been established for sedation in flexible bronchoscopy. It is as yet unknown whether propofol in combination with an opiate is superior to propofol alone to suppress cough during the procedure. 300 consecutive patients undergoing flexible bronchoscopy at a tertiary care university hospital were randomly allocated to receive either the combination propofol and hydrocodone or propofol alone in a double-blind fashion. The primary end-point was the cough score during the procedure as estimated by the physician using a visual analogue scale. Demographics were similar in both groups. Compared with propofol alone, median (interquartile range) cough scores assessed by physicians, nurses and patients were significantly lower in the group randomised to the combination propofol and hydrocodone (2.5 (1.5-4.0) versus 2.0 (1.0-3.0), respectively, p=0.011). Additionally, patients receiving the combination required significantly lower doses of propofol than those receiving propofol alone (200 mg (140-280) versus 260 mg (180-350), p<0.0001). Complex examinations, including bronchoalveolar lavage or transbronchial biopsy, benefited more from additional opiate. The duration of the procedure, time to discharge and complication rate were similar in both groups. The combination of propofol and hydrocodone is safe and superior to propofol alone for cough suppression in flexible bronchoscopy. PMID- 21310876 TI - Airway inflammation is augmented by obesity and fatty acids in asthma. AB - Obesity and asthma are associated, but the mechanism(s) of the association have yet to be elucidated. The aim of this study was to assess airway inflammation in relation to obesity and plasma fatty acids in males and females with and without asthma. Obese (n=68) and nonobese (n=47) adults with asthma, and obese (n=16) and nonobese (n=63) healthy controls had induced sputum and venous blood samples analysed for inflammatory markers. There was a positive interaction between obesity and asthma on sputum neutrophil percentage (p=0.012) and C-reactive protein level (p=0.003). Although sputum eosinophil percentage was elevated in asthma (p=0.001), there was no effect of obesity (p=0.16). Sputum neutrophil percentage was positively associated with body mass index in females with asthma (beta=1.015, 95% CI 0.258-1.772; p=0.009) and neutrophilic asthma was present in a greater proportion of obese compared with non-obese females (42.9% versus 16.2%; p=0.017). In males with asthma, sputum neutrophil percentage was positively associated with total plasma saturated fatty acids (beta=0.108, 95% CI 0.036-0.180; p=0.004) and negatively with monounsaturated fatty acids (beta= 0.068, 95% CI -0.131- -0.005; p=0.035). This was the first study to demonstrate an increase in neutrophilic airway inflammation in obese asthma. This relationship was significant only in females with asthma. In males, saturated and monounsaturated fatty acids were important predictors of neutrophilic airway inflammation in asthma. PMID- 21310877 TI - Elemental carbon exposure and lung function in school children from Mexico City. AB - Though exposure to air pollution has a detrimental effect on respiratory health, few studies have examined the association between elemental carbon exposure and lung function among schoolchildren. The aim of the present study was to present the association between short-term elemental carbon exposure and lung function in schoolchildren from Mexico City. 55 asthmatic and 40 non-asthmatic children were followed for an average of 22 weeks. A spirometry test was performed every 15 days during follow-up. Portable air samplers collected particulate matter onto Teflon filters. Gravimetric analysis was conducted and elemental carbon was quantified using transmission densitometry. The association between the main variables was analysed using linear mixed effects models. The mean +/- sd of elemental carbon light absorption was 92.7 +/- 54.7 Mm(-1). An increase of one interquartile range in the 24-h average of elemental carbon (100.93 Mm(-1)) was associated with a significant negative impact on forced expiratory volume in 1 s (FEV(1)) (-62.0 (95% CI -123.3- -1.2) mL) and forced expiratory flow at 25-75% of forced vital capacity (FVC) (FEF(25-75%)) (-111 (95% CI -228.3- -4.1) mL) among asthmatic children, equal to 3.3% and 5.5%, respectively; and on FEV(1) (-95.0 (95% CI -182.3- -8.5) mL) and FVC (-105.0 (95% CI -197.0- -13.7) mL) among non asthmatic children. Exposure to elemental carbon resulted in an important negative effect on lung function in atopic schoolchildren, regardless of asthma status. PMID- 21310878 TI - What the pulmonary specialist should know about the new inhalation therapies. AB - A collaboration of multidisciplinary experts on the delivery of pharmaceutical aerosols was facilitated by the European Respiratory Society (ERS) and the International Society for Aerosols in Medicine (ISAM), in order to draw up a consensus statement with clear, up-to-date recommendations that enable the pulmonary physician to choose the type of aerosol delivery device that is most suitable for their patient. The focus of the consensus statement is the patient use aspect of the aerosol delivery devices that are currently available. The subject was divided into different topics, which were in turn assigned to at least two experts. The authors searched the literature according to their own strategies, with no central literature review being performed. To achieve consensus, draft reports and recommendations were reviewed and voted on by the entire panel. Specific recommendations for use of the devices can be found throughout the statement. Healthcare providers should ensure that their patients can and will use these devices correctly. This requires that the clinician: is aware of the devices that are currently available to deliver the prescribed drugs; knows the various techniques that are appropriate for each device; is able to evaluate the patient's inhalation technique to be sure they are using the devices properly; and ensures that the inhalation method is appropriate for each patient. PMID- 21310879 TI - Noneosinophilic asthma in children: relation with airway remodelling. AB - Noneosinophilic asthma is increasingly recognised as an important clinical pathological phenotype in adults. However, this entity has scarcely been investigated in children. In particular, it is unknown whether airway remodelling would develop in children with non-eosinophilic asthma to the same degree as in children with eosinophilic disease. We analysed bronchial biopsies from 80 children undergoing bronchoscopy for appropriate clinical indications: 21 with noneosinophilic asthma, 34 with eosinophilic asthma and 25 control children. Features of airway remodelling - basement membrane thickening, epithelial loss and angiogenesis - and immune activation - inflammatory infiltrate, interleukin (IL)-4, IL-5, transforming growth factor (TGF)-beta, TGF-beta receptor type II - were quantified by histology and immunohistochemistry. The main components of airway remodelling were present in children with noneosinophilic asthma just as in those with eosinophilic disease. Indeed, compared with control children, both noneosinophilic and eosinophilic asthmatic children had thickened basement membrane, increased epithelial loss and higher number of vessels. Moreover, in both groups of asthmatics, expression of IL-4 and IL-5 was increased, while that of TGF-beta receptor type II was reduced, compared with controls. This study demonstrates that structural changes typical of asthma develop in asthmatic children even in the absence of a prominent eosinophilic infiltrate, indicating that other mechanisms, besides eosinophilic inflammation, may promote airway remodelling early in life. PMID- 21310880 TI - In utero cigarette smoke exposure impairs somatic and lung growth in BALB/c mice. AB - The aim of this study was to assess whether in utero tobacco smoke exposure alone affects early-life lung growth and development. Pregnant BALB/c mice were exposed to cigarette smoke from six cigarettes per day, or air, from day 8 to 20 of gestation. At 2 weeks of age, pups were weighed and had their lung volumes and lung mechanics measured. Pups born from mothers exposed to cigarette smoke (CS pups; n=17) were significantly lighter (6.76 +/- 0.76 versus 7.72 +/- 0.68 g) and had lower lung volumes (0.123 +/- 0.02 versus 0.149 +/- 0.02 mL) than control pups (n=20). Respiratory mechanics were adversely impacted by cigarette smoke exposure. CS pups had higher baseline airway resistance, tissue damping and tissue elastance. These differences were largely due to lower lung volumes. Both tissue damping and elastance were increased excessively in CS pups at high transrespiratory pressures, while other parameters were not affected. There were no histological differences between groups. In utero tobacco smoke exposure significantly affects growth and development in BALB/c mice. These impacts may partially explain the susceptibility of infants born to smoking mothers to early respiratory disease and chronic respiratory disease as adults. PMID- 21310881 TI - Evaluation of moxifloxacin for the treatment of tuberculosis: 3 years of experience. AB - Moxifloxacin (MFX) is a powerful second-line anti-tuberculosis (TB) agent, but the optimal dose has not yet been established and long-term safety data are scarce. We retrospectively reviewed the medical charts of TB patients treated at the Tuberculosis Centre Beatrixoord, University Medical Centre Groningen (Haren, the Netherlands) receiving MFX 400 mg once daily as part of their TB treatment between January 1 2006 and January 1 2009. Safety data and drug-drug interactions were evaluated. Efficacy was predicted based on the area under the concentration time curve up to 24 h post-dosage (AUC(0-24h))/minimal inhibitory concentration (MIC) ratio. 89 patients were treated with a median dose of 6.9 mg . kg(-1) MFX once daily for a median period of 74 days. Discontinuation of therapy occurred in only three patients due to gastrointestinal side-effects and hypersensitivity. Pharmacokinetic analysis showed an AUC(0-24h)/MIC ratio <100 in eight out of 16 patients. A large variation in protein binding affected the unbound AUC(0-24h) considerably. These data show that MFX treatment was well tolerated in 89 patients receiving a dose of 400 mg once daily for a prolonged period. Considering the variability in (un)bound AUC(0-24h)/MIC ratio, therapeutic drug monitoring is recommended in selected patients (i.e. rifampicin co-medication; MIC >= 0.25 mg . L(-1)) to assess optimal therapy. PMID- 21310882 TI - Multi-symptom asthma as an indication of disease severity in epidemiology. AB - Epidemiological questionnaires have failed to identify individuals with severe asthma. The extent of symptoms of asthma can, however, be easily established in epidemiology, by identification of multiple symptoms. We hypothesise that reporting of multiple symptoms of asthma reflects uncontrolled disease and is a sign of more severe asthma. The aims of the current study were, therefore, to determine the prevalence and determinants of multi-symptom asthma. A postal questionnaire was sent to 30,000 randomly selected individuals aged 16-75 yrs. A subgroup underwent clinical examinations. Multi-symptom asthma was defined as reported physician-diagnosed asthma, use of asthma medication, recurrent wheeze, attacks of shortness of breath and at least one additional respiratory symptom. The prevalence of multi-symptom asthma was 2.0%, and it was more common among females (2.4 versus 1.5%; p<0.001) and those with a body mass index >30 kg . m( 2). Multi-symptom asthmatics had lower forced expiratory volume in 1 s, higher exhaled nitric oxide fraction and more pronounced hyperresponsiveness. Family history of both asthma and allergy (OR 7.3), and occupational exposure to gas dust or fumes (OR 2.0) were also significant risk factors. Multi-symptom asthmatics comprise 2% of the general population; multi-symptom asthma is related to signs of more severe disease and could be used as an epidemiological marker of disease severity. PMID- 21310883 TI - Increased arginase activity contributes to airway remodelling in chronic allergic asthma. AB - Airway remodelling, characterised by increased airway smooth muscle (ASM) mass, subepithelial fibrosis, goblet cell hyperplasia and mucus gland hypertrophy, is a feature of chronic asthma. Increased arginase activity could contribute to these features via increased formation of polyamines and l-proline downstream of the arginase product l-ornithine, and via reduced nitric oxide synthesis. Using the specific arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH), we studied the role of arginase in airway remodelling using a guinea pig model of chronic asthma. Ovalbumin-sensitised guinea pigs were treated with ABH or PBS via inhalation before each of 12 weekly allergen or saline challenges, and indices of arginase activity, and airway remodelling, inflammation and responsiveness were studied 24 h after the final challenge. Pulmonary arginase activity of repeatedly allergen-challenged guinea pigs was increased. Allergen challenge also increased ASM mass and maximal contraction of denuded tracheal rings, which were prevented by ABH. ABH also attenuated allergen-induced pulmonary hydroxyproline (fibrosis) and putrescine, mucus gland hypertrophy, goblet cell hyperplasia, airway eosinophilia and interleukin-13, whereas an increased l-ornithine/l-citrulline ratio in the lung was normalised. Moreover, allergen-induced hyperresponsiveness of perfused tracheae was fully abrogated by ABH. These findings demonstrate that arginase is prominently involved in allergen-induced airway remodelling, inflammation and hyperresponsiveness in chronic asthma. PMID- 21310884 TI - Outcomes of hospitalisation for right heart failure in pulmonary arterial hypertension. AB - The aim of this study was to examine the causes and outcomes of hospitalisation in patients with pulmonary arterial hypertension (PAH). 205 consecutive hospitalisations occurring between 2000 and 2009 in 90 PAH patients were studied. The leading causes for hospitalisation were right heart failure (RHF; 56%), infection (16%) and bleeding disorders (8%). For patients with RHF, in-hospital mortality was 14% overall, 46% for patients receiving inotropes and 48% for those admitted to the intensive care unit. The predictors for in-hospital mortality were the presence of connective tissue disease (CTD) (OR 4.92), systolic blood pressure <100 mmHg (OR 4.32) and Na <= 136 mEq . L(-1) (OR 4.29). Mortality after discharge was 13, 26 and 35% at 3, 6 and 12 months, respectively. World Health Organization functional class prior to admission, renal dysfunction, Charlson comorbidity index, and the presence of CTD were all predictors of mortality after discharge. Hyponatraemia and low systolic blood pressure upon admission and underlying CTD are the main prognostic factors for in-hospital mortality in patients with PAH admitted for RHF. The short-term outcomes after discharge are poor and remarkably worse in patients with underlying CTD or renal impairment. Early recognition of these factors may guide decisions regarding more aggressive therapy, including consideration for lung transplantation. PMID- 21310885 TI - Flexibility of foveal attention during ocular pursuit. AB - Smooth pursuit of natural objects requires flexible allocation of attention to inspect features. However, it has been reported that attention is focused at the fovea during pursuit. We ask here if foveal attention is obligatory during pursuit, or if it can be disengaged. Observers tracked a stimulus composed of a central dot surrounded by four others and identified one of the dots when it dimmed. Extinguishing the center dot before the dimming improved task performance, suggesting that attention was released from it. To determine if the center dot automatically usurped attention, we provided the pursuit system with an alternative sensory signal by adding peripheral motion that moved with the stimulus. This also improved identification performance, evidence that a central target does not necessarily require attention during pursuit. Identification performance at the central dot also improved, suggesting that the spatial extent of the background did not attract attention to the periphery; instead, peripheral motion freed pursuit attention from the central dot, affording better identification performance. The results show that attention can be flexibly allocated during pursuit and imply that attention resources for pursuit of small and large objects come from different sources. PMID- 21310886 TI - Exposure to the chinese famine in early life and the risk of metabolic syndrome in adulthood. AB - OBJECTIVE: To examine whether exposure to the Chinese famine during fetal life and early childhood is associated with the risks of metabolic syndrome and whether this association is modified by later life environment. RESEARCH DESIGN AND METHODS: We used data of 7,874 adults born between 1954 and 1964 from the 2002 China National Nutrition and Health Survey. Famine exposure groups were defined as nonexposed; fetal exposed; and early childhood, midchildhood, or late childhood exposed. Excess death rate was used to determine the severity of the famine. The ATP III criteria were used for the definition of metabolic syndrome (three or more of the following variables: elevated fasting triglyceride levels, lower HDL cholesterol levels, elevated fasting glucose levels, higher waist circumference, high blood pressure). RESULTS: In severely affected famine areas, adults who were exposed to the famine during fetal life had a higher risk of metabolic syndrome, as compared with nonexposed subjects (odds ratio 3.13 [95% CI 1.24-7.89, P = 0.016]). Similar associations were observed among adults who were exposed to the famine during early childhood, but not for adults exposed to the famine during mid- or late childhood. Participants who were born in severely affected famine areas and had Western dietary habits in adulthood or were overweight in adulthood had a particularly high risk of metabolic syndrome in later life. CONCLUSIONS: Exposure to the Chinese famine during fetal life or infancy is associated with an increased risk of metabolic syndrome in adulthood. These associations are stronger among subjects with a Western dietary pattern or who were overweight in adulthood. PMID- 21310887 TI - Emergent behavior in lung structure and function. PMID- 21310888 TI - Application of carbon monoxide diffusing capacity in the mouse lung. AB - In the past decade the mouse has become the primary animal model of a variety of lung diseases. To assess various mechanisms underlying such pathologies, it is essential to make functional measurements that can reflect the developing pathology. In this regard, the diffusing capacity for carbon monoxide is a variable that directly reflects structural changes in the lung. Although measurement of single-breath diffusing capacity of the lung for carbon monoxide (DL(CO)) has also been previously reported in mice by a number of investigators, a number of technical issues have precluded routine and widespread use of this metric in mouse models. In the present report, we describe a means to quickly and simply measure a dimensionless variable closely related to the DL(CO) in mice, termed a diffusion factor for carbon monoxide (DF(CO)). The DF(CO) procedure involves a 9-s lung inflation with tracer gases in an anesthetized mouse, followed by a 1-min gas analysis time. We have tested the approach with two common models of lung pathology, elastase-induced emphysema and bleomycin-induced fibrosis. Results show a significant 15% reduction in DF(CO) in emphysema, and a 41% reduction in the fibrosis model. Repeat measurements within a mouse were found to be highly reproducible. This pulmonary function test can thus be used to detect structural changes with these pathological models. The method can also be used to measure changes in pulmonary blood volume, since the uptake of CO is highly dependent on this variable in addition to the gas exchange surface area. PMID- 21310889 TI - Exercise protects against doxorubicin-induced oxidative stress and proteolysis in skeletal muscle. AB - Doxorubicin (Dox) is a potent antitumor agent used in cancer treatment. Unfortunately, Dox is myotoxic and results in significant reductions in skeletal muscle mass and function. Complete knowledge of the mechanism(s) by which Dox induces toxicity in skeletal muscle is incomplete, but it is established that Dox induced toxicity is associated with increased generation of reactive oxygen species and oxidative damage within muscle fibers. Since muscular exercise promotes the expression of numerous cytoprotective proteins (e.g., antioxidant enzymes, heat shock protein 72), we hypothesized that muscular exercise will attenuate Dox-induced damage in exercise-trained muscle fibers. To test this postulate, Sprague-Dawley rats were randomly assigned to the following groups: sedentary, exercise, sedentary with Dox, or exercise with Dox. Our results show increased oxidative stress and activation of cellular proteases (calpain and caspase-3) in skeletal muscle of animals treated with Dox. Importantly, our findings reveal that exercise can prevent the Dox-induced oxidative damage and protease activation in the trained muscle. This exercise-induced protection against Dox-induced toxicity may be due, at least in part, to an exercise-induced increase in muscle levels of antioxidant enzymes and heat shock protein 72. Together, these novel results demonstrate that muscular exercise is a useful countermeasure that can protect skeletal muscle against Dox treatment-induced oxidative stress and protease activation in skeletal muscles. PMID- 21310890 TI - Congestive heart failure with preserved ejection fraction is associated with severely impaired dynamic Starling mechanism. AB - Sedentary aging leads to increased cardiovascular stiffening, which can be ameliorated by sufficient amounts of lifelong exercise training. An even more extreme form of cardiovascular stiffening can be seen in heart failure with preserved ejection fraction (HFpEF), which comprises ~40~50% of elderly patients diagnosed with congestive heart failure. There are two major interrelated hypotheses proposed to explain heart failure in these patients: 1) increased left ventricular (LV) diastolic stiffness and 2) increased arterial stiffening. The beat-to-beat dynamic Starling mechanism, which is impaired with healthy human aging, reflects the interaction between ventricular and arterial stiffness and thus may provide a link between these two mechanisms underlying HFpEF. Spectral transfer function analysis was applied between beat-to-beat changes in LV end diastolic pressure (LVEDP; estimated from pulmonary artery diastolic pressure with a right heart catheter) and stroke volume (SV) index. The dynamic Starling mechanism (transfer function gain between LVEDP and the SV index) was impaired in HFpEF patients (n = 10) compared with healthy age-matched controls (n = 12) (HFpEF: 0.23 +/- 0.10 ml.m-2.mmHg-1 and control: 0.37 +/- 0.11 ml.m-2.mmHg-1, means +/- SD, P = 0.008). There was also a markedly increased (3-fold) fluctuation of LV filling pressures (power spectral density of LVEDP) in HFpEF patients, which may predispose to pulmonary edema due to intermittent exposure to higher pulmonary capillary pressure (HFpEF: 12.2 +/- 10.4 mmHg2 and control: 3.8 +/- 2.9 mmHg2, P = 0.014). An impaired dynamic Starling mechanism, even more extreme than that observed with healthy aging, is associated with marked breath by-breath LVEDP variability and may reflect advanced ventricular and arterial stiffness in HFpEF, possibly contributing to reduced forward output and pulmonary congestion. PMID- 21310891 TI - Effects of hypohydration on thermoregulation during exercise before and after 5 day aerobic training in a warm environment in young men. AB - We examined whether enhanced cardiovascular and thermoregulatory responses during exercise after short-term aerobic training in a warm environment were reversed when plasma volume (PV) expansion was reversed by acute isotonic hypohydration. Seven young men performed aerobic training at the 70% peak oxygen consumption rate (Vo(2peak)) at 30 degrees C atmospheric temperature and 50% relative humidity, 30 min/day for 5 days. Before and after training, we performed the thermoregulatory response test while measuring esophageal temperature (T(es)), forearm skin vascular conductance, sweat rate (SR), and PV during 30 min exercise at the metabolic rate equivalent to pretraining 65% Vo(2peak) in euhydration under the same environment as during training in four trials (euhydration and hypohydration, respectively). Hypohydration targeting 3% body mass was attained by combined treatment with low-salt meals to subjects from ~48 h before the test and administration of a diuretic ~4 h before the test. After training, the T(es) thresholds for cutaneous vasodilation and sweating decreased by 0.3 and 0.2 degrees C (P = 0.008 and 0.012, respectively) when PV increased by ~10%. When PV before and after training was reduced to a similar level, ~10% reduction from that in euhydration before training, the training-induced reduction in the threshold for cutaneous vasodilation increased to a level similar to hypohydration before training (P = 0.093) while that for sweating remained significantly lower than that before training (P = 0.004). Thus the enhanced cutaneous vasodilation response after aerobic training in a warm environment was reversed when PV expansion was reversed while the enhanced SR response remained partially. PMID- 21310892 TI - Responsiveness of the human airway in vitro during deep inspiration and tidal oscillation. AB - In healthy individuals, deep inspiration produces bronchodilation and reduced airway responsiveness, which may be a response of the airway wall to mechanical stretch. The aim of this study was to examine the in vitro response of isolated human airways to the dynamic mechanical stretch associated with normal breathing. Human bronchial segments (n = 6) were acquired from patients without airflow obstruction undergoing lung resection for pulmonary neoplasms. The side branches were ligated and the airways were mounted in an organ bath chamber. Airway narrowing to cumulative concentrations of acetylcholine (3 * 10(-6) M to 3 * 10( 3) M) was measured under static conditions and in the presence of "tidal" oscillations with intermittent "deep inspiration." Respiratory maneuvers were simulated by varying transmural pressure using a motor-controlled syringe pump (tidal 5 to 10 cmH(2)O at 0.25 Hz, deep inspiration 5 to 30 cmH(2)O). Airway narrowing was determined from decreases in lumen volume. Tidal oscillation had no effect on airway responses to acetylcholine which was similar to those under static conditions. Deep inspiration in tidally oscillating, acetylcholine contracted airways produced potent, transient (<1 min) bronchodilation, ranging from full reversal in airway narrowing at low acetylcholine concentrations to ~50% reversal at the highest concentration. This resulted in a temporary reduction in maximal airway response (P < 0.001), without a change in sensitivity to acetylcholine. Our findings are that the mechanical stretch of human airways produced by physiological transmural pressures generated during deep inspiration produces bronchodilation and a transient reduction in airway responsiveness, which can explain the beneficial effects of deep inspiration in bronchial provocation testing in vivo. PMID- 21310893 TI - Retinoic acid inhibits endometrial cancer cell growth via multiple genomic mechanisms. AB - Previous studies have indicated that retinoic acid (RA) may be therapeutic for endometrial cancer. However, the downstream target genes and pathways triggered by ligand-activated RA receptor alpha (RARalpha) in endometrial cancer cells are largely unknown. In this study, 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide, flow cytometry, and immunoblotting assays were used to assess the roles of RA and the RA agonist (AM580) in the growth of endometrial cancer cells. Illumina-based microarray expression profiling of endometrial Ishikawa cells incubated with and without AM580 for 1, 3, and 6 h was performed. We found that both RA and AM580 markedly inhibited endometrial cancer cell proliferation, while knockdown of RARalpha could block AM580 inhibition. Knockdown of RARalpha significantly increased proliferating cell nuclear antigen and BCL2 protein levels. Incubation of Ishikawa cells with or without AM580 followed by microarray expression profiling showed that 12 768 genes out of 47 296 gene probes were differentially expressed with significant P values. We found that 90 genes were the most regulated genes with the most significant P value (P<0.0001) using F-test. We selected four highly regulated genes with diverse functions, namely G0S2, TNFAIP2, SMAD3, and NRIP1. Real-time PCR verified that AM580 highly regulated these genes, whereas chromatin immunoprecipitation-PCR assay demonstrated that ligand-activated RARalpha interacted with the promoter of these genes in intact endometrial cancer cells. AM580 also significantly altered 18 pathways including those related to cell growth, differentiation, and apoptosis. In conclusion, AM580 treatment of Ishikawa cells causes the differential expression of a number of RARalpha target genes and activation of signaling pathways. These pathways could, therefore, mediate the carcinogenesis of human endometrial cancer. PMID- 21310894 TI - Clinical decision rules for children with minor head injury: a systematic review. AB - INTRODUCTION: Clinical decision rules aid clinicians with the management of head injured patients. This study aimed to identify clinical decision rules for children with minor head injury and compare their diagnostic accuracy for detection of intracranial injury (ICI) and injury requiring neurosurgical intervention (NSI). METHODS: Relevant studies were identified by an electronic search of key databases. Papers in English were included with a cohort of at least 20 children suffering minor head injury (GCS 13-15). Studies of a decision rule derived to identify patients at risk of ICI or NSI had to include a proportion of the cohort undergoing imaging. Study quality was assessed using the QUADAS checklist. RESULTS: 16 publications, representing 14 cohorts, with 79 740 patients were included. Only four rules were tested in more than one cohort. Of the validated rules the paediatric emergency care applied research network (PECARN) rule was most consistent (sensitivity 98%; specificity 58%). For neurosurgical injury all had high sensitivity (98-100%) but the children's head injury algorithm for the prediction of important clinical events (CHALICE) rule had the highest specificity (86%) in its derivation cohort. CONCLUSION: Of the current decision rules for minor head injury the PECARN rule appears the best for children and infants, with the largest cohort, highest sensitivity and acceptable specificity for clinically significant ICI. Application of this rule in the UK would probably result in an unacceptably high rate of CT scans per injury, and continued use of the CHALICE-based NICE guidelines represents an appropriate alternative. PMID- 21310895 TI - Clinical outcomes of severe malnutrition in a high tuberculosis and HIV setting. AB - OBJECTIVE: Case death rates for severe childhood malnutrition remain stubbornly elevated in high HIV prevalence settings, despite the implementation of WHO guidelines. This study examined case death and other clinical outcomes in malnourished children with and without HIV infection. METHODS: A prospective, observational study was undertaken at three tertiary hospitals in Johannesburg, South Africa. All severely malnourished children had their HIV status established, and anthropometric, clinical and diagnostic findings and admission outcomes were analysed. FINDINGS: Just over half (51%) of the 113 severely malnourished children were HIV infected, but 31/58 (54%) of these children had their positive status diagnosed only after admission. Marasmic children were significantly more likely to be HIV infected (OR 9.7, 95% CI 3.5 to 29.1). Tuberculosis (TB) was strongly suspected and treated in 27 children (24%) although confirmed in only five (4%). The overall case death rate was 11.5%. HIV infection, pallor and shock were significant predictors of death. HIV-infected children were six times more likely to die compared with HIV-negative children (19% vs 3.6%, OR 6.2, 95% CI 1.2 to 59). HIV-'affected' children (HIV negative but exposed) and HIV-negative children had similar outcomes. CONCLUSION: HIV infection significantly increases severe malnutrition case death. WHO guidelines for the management of severe malnutrition in high HIV prevalence settings need to be modified to include routine HIV and TB testing and offer guidance on the criteria and timing of TB treatment and highly active antiretroviral therapy initiation. PMID- 21310896 TI - Reliability of outcome measures for people with lower-limb amputations: distinguishing true change from statistical error. AB - BACKGROUND: Use of outcome measures to examine outcomes of amputation is complicated by a number of factors, including ease of administration and lack of scientific evidence to guide selection and interpretation. OBJECTIVE: The purposes of this study were: (1) to estimate test-retest reliability of a modified version of the Prosthetic Evaluation Questionnaire (PEQ), scales of a version of the 36-Item Short-Form Health Survey questionnaire adapted for the veteran population (SF-36V), the Orthotics and Prosthetics Users' Survey (OPUS), the Patient-Specific Functional Scale (PSFS), the Two-Minute Walk Test, the Six Minute Walk Test, the Timed "Up & Go" Test, and the Amputee Mobility Predictor; (2) to calculate minimal detectable change (MDC) of each measure; and (3) to conduct item analysis of the modified PEQ. DESIGN: This was a multi-site study with repeated measurements. METHODS: Forty-four patients with unilateral lower limb amputation participated. Participants were tested twice within 1 week. We calculated test-retest reliability of each measure using intraclass correlation coefficient (ICC [2,1]), estimated standard error of the measurement and MDC, and assessed scale score distribution. RESULTS: The study demonstrated strong test retest reliability scores of performance measures (ICC=.83-.97) suggesting that these measures are good choices for evaluation of people with lower-limb amputation. Reliability of PEQ subscales (ICC=.41-.93) was comparable to that reported in the literature (ICC=.56-.90). LIMITATIONS: This study examined only statistically measurable differences and did not evaluate whether changes in scores were clinically important. CONCLUSIONS: Minimal detectable change scores can be used to determine whether change in test scores exceeds measurement error associated with day-to-day variation. This is the first study to present test retest reliability data on the self-reported OPUS scales, the PSFS in people with lower-limb amputations, and a new, easier-to-use scoring mechanism for the PEQ. PMID- 21310897 TI - Validation of the treadmill Six-Minute Walk Test in people following cardiac surgery. AB - BACKGROUND: The Six-Minute Walk Test (6MWT) often is used to measure exercise capacity in people with cardiopulmonary diseases but has some disadvantages. The 6MWT administered on a treadmill (Tr6MWT) requires less physical space and allows for easier monitoring of vital parameters than the traditional 6MWT. OBJECTIVE: The objectives of this study were: (1) to analyze the validity of the Tr6MWT in people who underwent cardiac surgery; (2) to compare the reliability, responsiveness, and people's tolerance of the Tr6MWT with those of the 6MWT; and (3) to evaluate the agreement between the 2 tests. DESIGN: This study was designed to assess reliability and validity. METHODS: Twenty-six participants who were inpatients were assessed before a 2-week rehabilitation program. Twenty of them also were assessed after rehabilitation. All participants performed 3 Tr6MWT trials and 3 6MWT trials that were randomly assigned on 2 consecutive days. RESULTS: The Pearson r correlation coefficient between the Tr6MWT and the 6MWT was .72, indicating satisfactory concurrent validity. The Tr6MWT was as well tolerated as the 6MWT. The Tr6MWT produced reproducible results after 2 practice tests, whereas the 6MWT did so after only 1 practice test. Both tests showed high test-retest reliability (intraclass correlation coefficient of >.94; standard errors of measurement of 23 m for the Tr6MWT and 18.5 m for the 6MWT). The Tr6MWT showed better responsiveness than the 6MWT (effect sizes of 0.9 for the Tr6MWT and 0.6 for the 6MWT). The distance covered during the Tr6MWT was significantly shorter (X=62 m, SD=91) before rehabilitation but not after rehabilitation. LIMITATIONS: A crossover randomized procedure could have improved the reliability of the Tr6MWT in people who performed the 6MWT first. CONCLUSIONS: The Tr6MWT appears to be an instrument with adequate concurrent validity and to be tolerable, reliable, and responsive for the evaluation of exercise capacity in people after cardiac surgery even though it is not interchangeable with the 6MWT. PMID- 21310898 TI - Predictors of response to physical therapy intervention in patients with primary hip osteoarthritis. AB - BACKGROUND: Few studies have investigated or identified common clinical tests and measures as being associated with progression of hip osteoarthritis (OA); fewer still are longitudinal studies exploring prognostic variables associated with long-term outcome following physical therapy treatment. OBJECTIVE: The purpose of this study was to determine a set of prognostic factors that maximize the accuracy of identifying patients with hip osteoarthritis (OA) likely to demonstrate a favorable response to physical therapy intervention. DESIGN: This was a prognostic study. METHODS: Ninety-one patients with a clinical diagnosis of hip OA were analyzed to determine which clinical measures, when clustered together, were most predictive of a favorable response to physical therapy intervention. Responders were determined based on OMERACT-OARSI response criteria, which included percent and absolute changes in pain, function, and global rating of change over 1 year. These data served as the reference standard for determining the predictive validity of baseline clinical examination variables. Using multivariate regression analyses and calculations for sensitivity, specificity, and positive and negative likelihood ratios, a cluster was identified. RESULTS: Five baseline variables (unilateral hip pain, age of <=58 years, pain of >=6/10 on a numeric pain rating scale, 40-m self-paced walk test time of <=25.9 seconds, and duration of symptoms of <=1 year) were retained in the final model. Failure to exhibit a condition of 1 of the 5 predictor variables decreased the posttest probability of responding favorably to physical therapy intervention from 32% to <1% (negative likelihood ratio=0.00, 95% confidence interval=0.00-0.70). Having at least 2 out of 5 predictor variables at baseline increased the posttest probability of success with physical therapy intervention from 32% to 65% (positive likelihood ratio=3.99, 95% confidence interval=2.66-4.48), and having 3 or more of 5 predictor variables increased the posttest probability of success to 99% or higher. A comparison with a control group that did not receive physical therapy further substantiated the cluster. LIMITATIONS: The small sample size and the number of variables entered into the logistic regression model may have resulted in spurious findings. This study must be validated in replication studies before it can be considered for use in clinical practice. CONCLUSIONS: This study completed the first step in the development of a preliminary cluster of baseline variables that identify patients with hip OA as positive responders to physical therapy intervention. PMID- 21310899 TI - Upregulation of antibody response to heat shock proteins and tissue antigens in an ocular ischemia model. AB - PURPOSE: The aim of this study was to characterize the serum antibody reactivities occurring after ocular ischemia reperfusion. The time course of serum antibody responses was examined. METHODS: Wistar rats were exposed to transient ocular ischemia by elevating intraocular pressure to 130 mm Hg for 60 minutes. Axonal damage was evaluated on optic-nerve sections 2 and 4 weeks later. Blood samples collected before and several times after ischemia were used for antibody detection via customized protein microarrays. Different tissue antigens, including heat shock proteins (HSPs) and crystallins, were selected based on previous identification of antibody reactivities in studies on ischemic events or ophthalmic diseases associated with ischemia. Antibody reactivity was compared using multivariate statistical techniques. RESULTS: Significant axonal damage was observed 2 and 4 weeks after ocular ischemia (P < 0.05). Animals showed certain immunoreactivities against antigens even before ischemia, whereas many reactivities increased afterward. Significantly different responses were detected 2, 3, and 4 weeks after ischemia (P < 0.05). Antibody reactivity against actin, glial fibrillary acidic protein, HSP 27, vimentin, or spectrin continually increased. CONCLUSIONS: Ischemia induced by acute intraocular pressure elevation led to complex changes in antibody reactivities in sera of treated animals. Upregulation of serum autoantibodies, especially against heat shock and structural proteins, progressively increased throughout the 4-week follow-up period, whereas others such as ubiquitin decreased. The upregulation of anti-HSP 27 antibodies might be an attempt to protect the tissue from ischemic damage. PMID- 21310901 TI - Response of retinal Connexin43 to optic nerve injury. AB - PURPOSE: To characterize the spatial and temporal expression of Connexin43 (Cx43) after partial optic nerve transection and evaluate its relationship to retinal ganglion cell (RGC) loss and retinal glial response. METHODS: Partial, unilateral, superior optic nerve transection was performed in 150 Wistar rats. The retinas were evaluated at 8 and 24 hours and 3, 7, 14, 28, and 56 days after injury. Immunohistochemical analysis identified changes in several markers including Cx43 immunoreactivity (ir), RGC counts (Brn3a), and retinal astrocytes (GFAP). RESULTS: After injury, superior retinal Cx43-ir peaked at 3 days (192.1% of control; P = 0.0002) and 28 days (212.1% of control; P < 0.0001) and troughed at 14 days (73.8% of control; P = 0.0028) and 56 days (72.5% of control; P = 0.0232). Inferior retinal Cx43-ir was elevated at only 28 days (127.4% increase; P = 0.0481). Superior RGC loss began at 3 days (84.0% of control; P = 0.0454) and continued to decline by 56 days (18.8% of control; P < 0.0001). Inferior RGC loss began at 28 days (73.4% of control; P = 0.0021). An increase in GFAP-ir occurred in the superior retina from day 3 (153.7% of control; P = 0.0017) and from day 28 (186.7% of control; P = 0.0013) in the inferior retina, persisting in both the superior and inferior retina to 56 days (P = 0.0027). CONCLUSIONS: A biphasic upregulation of retinal Cx43 protein occurs in the superior retina with peaks at 3 and 28 days after injury, but at only 28 days in the inferior retina. There is an associated loss of RGCs and a retinal astrocytic inflammatory response. PMID- 21310902 TI - Interactive expressions of HtrA1 and VEGF in human vitreous humors and fetal RPE cells. AB - PURPOSE: High-temperature requirement factor A1 (HtrA1) is associated with exudative age-related macular degeneration, an angiogenic retinal disease related to vascular endothelial growth factor (VEGF). This study investigates the interactive relationship between the expressions of HtrA1 and VEGF. METHODS; The vitreous humor levels of HtrA1, VEGF, and pigment epithelium-derived factor were determined in 55 unrelated Han Chinese patients who underwent ocular surgeries. Expressions of HTRA1 and VEGFA were studied interactively and under stress conditions in primary human fetal retinal pigment epithelial (RPE) cells to evaluate their regulations. RESULTS: Vitreous levels of HtrA1 were significantly associated with that of VEGF in vitreous samples from all patients (Pearson's correlation coefficient test, r = 0.650, P = 7.91 * 10(-8)) and from patients with retinal detachment (r = 0.835, P = 2.14 * 10(-7)). On stress induction, HTRA1 and VEGFA were upregulated in human fetal RPE cells treated by tunicamycin and dithiothreitol, but reduced after treatment by MG132. However, HtrA1 and VEGF did not regulate each other in their expressions. CONCLUSIONS: This study revealed an association between HtrA1 and VEGF in human vitreous humors and RPE cells. They are both related to stress and inflammatory conditions. PMID- 21310900 TI - Activation of unfolded protein response in transgenic mouse lenses. AB - PURPOSE: Overloading of unfolded or misfolded proteins in the endoplasmic reticulum (ER) can cause ER stress and activate the unfolded protein response (UPR) in the cell. The authors tested whether transgene overexpression in the mouse lens would activate the UPR. METHODS: Transgenic mice expressing proteins that either enter the ER secretory pathway or are synthesized in cytosol were selected. Activation of the UPR was assessed by determining the expression levels of the ER chaperone protein BiP, the spliced form of X-box binding protein-1 (Xbp 1) mRNA, and the transcription factor CHOP. Changes in the ubiquitin-proteasome system in the mouse lens were detected by ubiquitin immunofluorescence. RESULTS: BiP expression was upregulated in the fiber cells of transgenic mouse lenses expressing platelet-derived growth factor-A (PDGF-A), dominant-negative fibroblast growth factor receptor (DN-FGFR), or DN-Sprouty2 (DN-Spy2). BiP upregulation occurred around embryonic day 16.5, primarily in the fiber cells adjacent to the organelle free zone. Fiber cell differentiation was disrupted in the PDGF-A and DN-Spry2 lenses, whereas the fiber cells were degenerating in the DN-FGFR lens. High levels of UPR activation and ubiquitin-labeled protein aggregates were found in the DN-FGFR lens, indicating inefficient disposal of unfolded/misfolded proteins in the fiber cells. CONCLUSIONS: This study implies that overexpression of some transgenes in the lens can induce ER or overall cell stress in fiber cells, resulting in the activation of UPR signaling pathways. Therefore, investigators should assess the levels of UPR activation when they analyze the downstream effects of transgene expression in the lens. PMID- 21310903 TI - Inhibition of TGFBIp expression by lithium: implications for TGFBI-linked corneal dystrophy therapy. AB - PURPOSE. The purpose of this study was to investigate the effects and molecular mechanisms of lithium on inhibition of TGFBIp expression as a potential therapy for TGFBI-linked corneal dystrophy. METHODS. Primary culture corneal fibroblasts were isolated from the corneas of healthy subjects and patients with granular corneal dystrophy type 2 (GCD2) with a homozygous mutation in TGFBI R124H. Levels of TGFBIp and its mRNA in corneal fibroblasts treated with various lithium (LiCl) concentrations were analyzed by Western blot, RT-PCR, and quantitative real-time PCR. RESULTS. LiCl treatment reduced the expression levels of normal and mutant TGFBIp in a dose- and a time-dependent manner. Furthermore, TGF-beta1-induced TGFBIp expression decreased by 35% and 67% after treatment with 5 mM and 10 mM LiCl, respectively. LiCl decreased the level of pSmad3 (S423/425) in a dose dependent manner. Furthermore, LiCl increased the level of pGSK-3alpha/beta (S21/9) in a dose-dependent manner. Also observed was the interaction between GSK 3beta and Smad3, which was enhanced by lithium. In addition, Western blot analysis showed that the ratio of LC3-II/LC3-I in corneal fibroblasts increased after LiCl treatment. Cell viability at different doses was greater than 98%, indicating that LiCl did not induce significant corneal fibroblast death. Finally, the observed attenuating effects of LiCl on TGFBIp expression were not the results of cell death. CONCLUSIONS. The accumulation of mutant TGFBIp ultimately leads to the histopathologic and clinical manifestations associated with TGFBI-linked corneal dystrophy. These data strongly suggest that lithium may be used for the prevention or treatment of this disease. PMID- 21310904 TI - Intraocular fluid dynamics and retinal shear stress after vitrectomy and gas tamponade. AB - PURPOSE: To evaluate fluid dynamics and fluid shear stress on the retinal wall in a model eye after vitrectomy and gas tamponade in relation to saccadic eye movements and sudden head movements and to correlate the results with gas fill fraction (GF). Methods. Analyses was undertaken using high-resolution computational fluid dynamic software. The fluid volume within the eye was discretized using 6 * 10(5) elements and solved with a volume-of-fluid METHOD: The eye was abstracted to a sphere. Vertical and horizontal saccades and sudden rectilinear displacement of the head were examined. GF was varied from 20% to 80% of the eye height filled with gas. RESULTS: Maximum shear stress during horizontal and vertical saccades was 1.0 Pa (Pascal) and 2.5 Pa, respectively, and was dependent on GF. Rapid rectilinear acceleration of the head caused a maximum shear stress of 16 Pa, largely independent of GF. Fluid sloshing within the eye decayed within 0.1 second. Stresses were maximum at the contact line and equator of the eye and were parallel to the direction of motion. CONCLUSIONS: This study predicts that saccadic eye movements and normal head movements after vitrectomy and gas tamponade generate only small fluid shear stresses on the retina that are below published norms for retinal adhesion strength. Sudden, jerking head movements generate fluid shear forces similar to retinal adhesion strength that localize to the area of gas-fluid interface. Fluid sloshing occurs after movement, but rapidly decays on cessation of movement. These results suggest that restrictive posturing after vitrectomy and gas tamponade may be unnecessary. Patients should avoid sudden head movements. PMID- 21310905 TI - Dynamic imaging of axonal transport in living retinal ganglion cells in vitro. AB - PURPOSE: Disruption of the axonal transport of neurotrophic factors plays a critical role in the apoptosis of retinal ganglion cells (RGCs) in glaucomatous optic neuropathy. Live-cell imaging in vitro was used in this study, to visualize and evaluate the axonal transport of brain-derived neurotrophic factor (BDNF) in both living and axon-damaged RGCs. METHODS: Rat RGCs were purified by a two-step immunopanning method. Cultivated RGCs were transfected with a plasmid encoding BDNF tagged with green fluorescent protein (GFP), and the dynamics of BDNF-GFP in the axons and dendrites were analyzed by time-lapse imaging. Changes in the axonal transport of BDNF-GFP were examined after treatment with 1 mM colchicine, and RGC death after treatment was evaluated with ethidium homodimer-1. RESULTS: The expression of BDNF-GFP showed a vesicular pattern in the axons and dendrites of cultivated RGCs. Time-lapse imaging revealed that the mean velocity of BDNF GFP in the axons (0.86 +/- 0.37 MUm/s; maximum = 2.03 MUm/s) was significantly greater (P < 0.0001) than that in the dendrites (mean = 0.49 +/- 0.19 MUm/s). Colchicine significantly inhibited the axonal transport of BDNF-GFP at 2 and 3 hours after treatment (P = 0.003 and 0.0002, respectively) without affecting cell viability; however, RGC death was detected 24 hours after treatment. CONCLUSIONS: Live-cell imaging revealed the dynamics of the axonal transport of BDNF in living RGCs, which clearly differed from the movements in dendrites. Furthermore, it was possible to confirm the disruption of axonal transport in colchicine-treated RGCs before cell death. PMID- 21310906 TI - Ocular surface health during 30-day continuous wear: rigid gas-permeable versus silicone hydrogel hyper-O2 transmitted contact lenses. AB - PURPOSE: To determine the effects on corneal epithelial permeability and ocular response of 30 nights of continuous wear (CW) of gas permeable (GP) and silicone hydrogel (SiH) contact lenses. METHODS: Ninety-one subjects successfully completed 30 days of CW of either GP (n = 42) or SiH (n = 49) contact lenses. Epithelial permeability (P(dc)) was measured by scanning fluorometer at an afternoon (PM) baseline session and again the next morning (AM). One randomly selected eye of each subject was patched overnight and the patch removed immediately before the AM visit. P(dc) measurements and ocular examinations were conducted at baseline and after 30 days of CW. RESULTS: Epithelial permeability increased significantly after 30 days of CW in the patched eyes of the GP group (P = 0.022) and in the unpatched eyes of the SiH group (P = 0.004). The increase was driven primarily by the Asian subjects in each group (GP, P = 0.015; SiH, P = 0.001). There was no significant increase in either lens group in the non-Asian subjects. Multivariate models suggest that the change in AM P(dc) from baseline to 30 days of CW was also related to lens type (P = 0.035), time awake before measurement (P = 0.001), palpebral aperture size (P = 0.003), lens deposits (P = 0.020), and horizontal lens bearing (P = 0.003). CONCLUSIONS: Subclinical increases in epithelial permeability can be caused by contact lens CW, despite the elimination of hypoxia. GP lenses permit recovery of the epithelium more quickly than do SiH lenses. Asians appear to be more susceptible to contact lens induced epithelial changes than do non-Asians. PMID- 21310907 TI - Characterization of ocular tissues using microindentation and hertzian viscoelastic models. AB - PURPOSE: The authors applied a novel microindentation technique to characterize biomechanical properties of small ocular and orbital tissue specimens using the hertzian viscoelastic formulation, which defines material viscoelasticity in terms of the contact pressure required to maintain deformation by a harder body. METHODS: They used a hard spherical indenter having 100 nm displacement and 100 MUg force precision to impose small deformations on fresh bovine sclera, iris, crystalline lens, kidney fat, orbital pulley tissue, and orbital fatty tissue; normal human orbital fat, eyelid fat, and dermal fat; and orbital fat associated with thyroid eye disease. For each tissue, stress relaxation testing was performed using a range of ramp displacements. Results for single displacements were used to build quantitative hertzian models that were, in turn, compared with behavior for other displacements. Findings in orbital tissues were correlated with quantitative histology. RESULTS: Viscoelastic properties of small specimens of orbital and ocular tissues were reliably characterized over a wide range of rates and displacements by microindentation using the hertzian formulation. Bovine and human orbital fatty tissues exhibited highly similar elastic and viscous behaviors, but all other orbital tissues exhibited a wide range of biomechanical properties. Stiffness of fatty tissues tissue depended strongly on the connective tissue content. CONCLUSIONS: Relaxation testing by microindentation is a powerful method for characterization of time-dependent behaviors of a wide range of ocular and orbital tissues using small specimens, and provides data suitable to define finite element models of a wide range of tissue interactions. PMID- 21310908 TI - Computational quantification of complex fundus phenotypes in age-related macular degeneration and Stargardt disease. AB - PURPOSE: To describe an automated method of quantification of specific fundus phenotypes and evaluate its performance in differentiating drusen, the hallmark lesions of age-related macular degeneration (AMD), from similar-looking bright lesions, the pisciform deposits or flecks typical of Stargardt disease (SD). METHODS: Fundus macular images of 30 eyes of 30 subjects were studied. Fifteen subjects had a clinical diagnosis of AMD with at least 10 intermediate and/or 1 large drusen, and the other 15 had SD. As a test of bright-lesion separation, AMD and SD subjects were chosen from the heterogeneous phenotypes of each disorder, to be as visually similar as possible. Drusen and fleck properties were quantified from the color images by using an automated method, and a shape classifier was used to divide the images as characteristic of either AMD or SD. Image identification performance was quantified by using the area under the receiver operating characteristic curve (AUC). RESULTS: All SD subjects demonstrated at least one disease-associated variant of the ABCA4 gene. The method achieved an AUC of 0.936 for differentiating AMD from SD. CONCLUSIONS: Automated quantification of fundus phenotypes was achieved, and the results show that the method can differentiate AMD from SD, two distinctly different genetically associated disorders, by quantifying the properties of the bright lesions (drusen and flecks) in their fundus images, even when the images were visually selected to be similar. Quantification of fundus phenotypes may allow recognition of new phenotypes, correlation with new genotypes and may measure disease-specific biomarkers to improve management of patients with AMD or SD. PMID- 21310909 TI - Edaravone, an ROS scavenger, ameliorates photoreceptor cell death after experimental retinal detachment. AB - PURPOSE: To investigate whether edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger, would be neuroprotective against photoreceptor cell death in a rat model of retinal detachment (RD). METHODS: RD was induced in adult Brown Norway rats by subretinal injection of sodium hyaluronate. Edaravone (3, 5, or 10 mg/kg) or physiologic saline was administered intraperitoneally once a day until death on day 3 or 5. Oxidative stress in the retina was assessed by 4 hydroxynonenal staining or ELISA for protein carbonyl content. Photoreceptor death was assessed by TUNEL and measurement of the outer nuclear layer thickness. Western blot analysis and caspase activity assays were performed. Inflammatory cytokine secretion and inflammatory cell infiltration were evaluated by ELISA and immunostaining, respectively. RESULTS: RD resulted in increased generation of ROS. Treatment with 5 mg/kg edaravone significantly reduced the ROS level, along with a decrease in TUNEL-positive cells in the photoreceptor layer. A caspase assay also confirmed decreased activation of caspase-3, -8, and -9 in RD treated with edaravone. The level of the antiapoptotic Bcl-2 was increased in detached retinas after edaravone treatment, whereas the levels of the stress-activated p ERK1/2 were decreased. In addition, edaravone treatment resulted in a significant decrease in the levels of TNF-alpha, MCP-1, and macrophage infiltration. CONCLUSIONS: Oxidative stress plays an important role in photoreceptor cell death after RD. Edaravone treatment may aid in preventing photoreceptor cell death after RD by suppressing ROS-induced photoreceptor damage. PMID- 21310910 TI - Contrast sensitivity outcomes in the ABC Trial: a randomized trial of bevacizumab for neovascular age-related macular degeneration. AB - PURPOSE: To report the impact of intravitreous bevacizumab therapy on contrast sensitivity in patients with neovascular age-related macular degeneration (nAMD). METHODS: This was a prospective, multicenter, double-masked, randomized, controlled trial of 131 patients with nAMD. The patients with nAMD had received intravitreal bevacizumab (n = 65) or standard therapy (n = 66) in the study eye with a 6-week cycle of assessment. The bevacizumab treatment was 1.25 mg/0.05 mL, given as three initial treatments with further retreatment as needed according to standard retreatment criteria and a 1-year (54-week) follow-up. Contrast sensitivity was determined during the study using a Pelli-Robson chart. RESULTS: At the week-54 examination, bevacizumab-treated patients were more likely to gain at least 6 letters or more of contrast sensitivity than the patients receiving standard care (23 [35.4%] versus 10 [15.2%], P = 0.009). In addition the bevacizumab-treated patients were less likely to lose 6 or more letters with a better mean letter change at week 54 than the patients receiving standard care (3 [4.6%] versus 14 [21.2%], and +4.0 versus -0.7 letters; P < 0.05 for both comparisons). CONCLUSIONS: Consistent with the visual acuity outcomes, bevacizumab improved the chances of a clinically relevant gain in contrast sensitivity in the study population. Given the association between contrast sensitivity and visual disability, the beneficial effects of bevacizumab therapy on contrast sensitivity outcomes are expected to have a favorable impact on patients' daily activities. (www.controlled-trials.com number, ISRCTN83325075.). PMID- 21310911 TI - Lack of TNF-alpha promotes caspase-3-independent apoptosis during murine cytomegalovirus retinitis. AB - PURPOSE: Both caspase-dependent and caspase-independent apoptosis contribute to retinal damage during murine cytomegalovirus (MCMV) retinitis, and TNF-alpha is among the inducers of apoptosis. The aim of this study was to determine the contribution of TNF-alpha by studying virus replication and apoptosis in immunosuppressed (IS) TNF-alpha(-/-) mice. METHODS: IS TNF-alpha(-/-) mice or wild-type mice were inoculated with MCMV by the supraciliary route. Injected eyes were examined by plaque assay, electron microscopy, Western blot analysis (caspase-3, caspase-8, caspase-12, Bid, NF-kappaB, cFlip, XIAP), staining for MCMV early antigen, and TUNEL assay. RESULTS: Although the titer of MCMV was similar in both groups, significantly more apoptotic cells were observed in the retinas of IS TNF-alpha(-/-) mice than in those of wild-type mice. The level of active caspase-3 was similar in both groups; however, more activated proteins for genes involved in the mitochondrial pathway (cleaved caspase-8, tBid) and endoplasmic reticulum (ER) stress (cleaved caspase-12) and, though less active, NF-kappaB subunits and antiapoptotic proteins (XIAP and cFlip) were detected in the TNF-alpha(-/-) eyes compared with wild-type mice. CONCLUSIONS: Although TNF alpha is an inducer of apoptosis, the results of this study suggest that TNF alpha is also antiapoptotic by the following mechanism: TNF-alpha activation of NF-kappaB promotes the production of the antiapoptosis genes, c-flip or XIAP, which, in turn, inhibit the activation of caspase-8 and the mitochondrial pathway or the activation of caspase-12 and ER stress. PMID- 21310912 TI - Fundus autofluorescence and spectral-domain optical coherence tomography characteristics in a rapidly progressing form of geographic atrophy. AB - PURPOSE: To further characterize a previously described phenotypic variant of geographic atrophy (GA) associated with rapid progression and a diffuse-trickling appearance on fundus autofluorescence (FAF). METHODS: Thirty-six patients (60 eyes; 72.2% women; mean age, 69.4 +/- 10.7 years) with this distinct phenotype were examined by simultaneous confocal scanning laser ophthalmoscopy (cSLO) and spectral-domain optical coherence tomography (SD-OCT) imaging. Images were qualitatively and quantitatively analyzed and compared with 60 eyes (38 patients) with non diffuse-trickling GA. RESULTS: The atrophic area in the diffuse trickling phenotype showed a grayish FAF signal and characteristic coalescent lobular configuration at the lesion boundaries. SD-OCT revealed a marked splitting of band 4 (the presumptive retinal pigment epithelium (RPE)/Bruch's membrane (BM) complex) in all 240 analyzed border sections of diffuse-trickling GA eyes (four borders/eye) with a mean distance between the inner and outer parts of band 4 of 23.2 +/- 7.5 MUm. This finding was present in only 13.8% (33/240) of analyzed border sections in non diffuse-trickling GA. CONCLUSIONS: Patients with the rapidly progressing diffuse-trickling GA phenotype exhibited a characteristic marked separation within the RPE/BM complex on SD-OCT-imaging. The presumed histopathologic correlates are basal laminar deposits. Such deposits may promote RPE cell death and, thus, contribute to rapid GA progression. The persistence of these deposits within the atrophic lesion may account for the distinct grayish FAF appearance, which differs from the markedly reduced signal in other forms of GA. Identification of such alterations based on FAF and SD-OCT imaging may be helpful in future interventional trials directed toward slowing GA progression. (ClinicalTrials.gov number, NCT00393692.). PMID- 21310913 TI - Topical flagellin-mediated innate defense against Candida albicans keratitis. AB - PURPOSE: This study was conducted to investigate whether flagellin, the sole ligand of Toll-like receptor-5 (TLR5), induces an innate defense that is sufficient to protect injured corneas from Candida albicans. METHODS: Scarified corneas of adult B6, TLR5(-/-), Camp(-/-) (cathelicidin-related antimicrobial peptide), or PMN-depleted mice were pretreated with Pseudomonas aeruginosa flagellin or a mutant and then were inoculated with C. albicans. The corneas were compared for disease progression, cytokine and Camp expression, and PMN infiltration before and after C. albicans infection. Disease progress was recorded by digital photography and clinical scoring, cytokine levels were determined by ELISA, the levels of Camp gene product were assessed by Western blot, and PMN infiltration was measured by MPO determination and immunohistochemistry. RESULTS: Topical application of flagellin induced profound protection against Candida keratitis in a TLR5-dependent manner. The improved disease outcome including reduced tissue inflammation and rapid functional recovery can be attributed to a marked decrease in fungal burden at the early stage of C. albicans infection in flagellin-exposed B6 mouse corneas. Although both PMN infiltration and Camp upregulation contributed to corneal innate defense against fungal infection, Camp ablation totally, and PMN depletion partially, abrogated flagellin-induced fungal clearance in B6 mouse corneas. CONCLUSIONS: Flagellin induces a strong innate defense and promotes robust resistance to C. albicans infection in the cornea. Topical flagellin or its mimetic may become a new prophylactic agent for preventing contact lens or trauma/injury-associated microbial keratitis. PMID- 21310914 TI - Histamine elevates free intracellular calcium in mouse retinal dopaminergic cells via H1-receptors. AB - PURPOSE: Previously, retinopetal axons containing histamine and dopaminergic neurons expressing histamine H(1)-receptor had been localized in mouse retinas using anatomic techniques. The goal of these experiments was to demonstrate that these receptors are functional. METHODS: Dopaminergic cells were acutely isolated from retinas of transgenic mice expressing red fluorescent protein under control of the tyrosine hydroxylase promoter and loaded with the calcium indicator Fura 2. RESULTS: Under control conditions, there were spontaneous oscillations in the levels of free intracellular calcium in dopaminergic cells. These oscillations were abolished in nominally calcium-free extracellular medium and in 1 MUM tetrodotoxin, findings suggesting that the oscillations were mediated by calcium entry across the plasma membrane in response to sodium-dependent action potentials. Histamine increased the mean free intracellular calcium in the dopaminergic cells by increasing the frequency and/or amplitude of the calcium oscillations. The effects of histamine were dose-dependent and reached maximum at 5 MUM. With this dose, there was a 65% increase in the mean free intracellular calcium concentration. The histamine H(1)-receptor antagonist, pyrilamine, blocked the effects of 5 MUM histamine when applied at 50 MUM. The selective histamine H(1)-receptor agonists, 2-(3-trifluoromethylphenyl) histamine and methylhistaprodifen significantly increased mean free intracellular calcium when applied at 5 MUM. CONCLUSIONS: Histamine released from retinopetal axons in the mouse retina can elevate intracellular calcium levels in the perikarya of dopaminergic cells via the activation of histamine H(1)-receptors. PMID- 21310915 TI - Screening of SPATA7 in patients with Leber congenital amaurosis and severe childhood-onset retinal dystrophy reveals disease-causing mutations. AB - PURPOSE: To investigate the prevalence of sequence variants in the gene SPATA7 in patients with Leber congenital amaurosis (LCA) and autosomal recessive, severe, early-onset retinal dystrophy (EORD) and to delineate the ocular phenotype associated with SPATA7 mutations. METHODS: Patients underwent standard ophthalmic evaluation after providing informed consent. One hundred forty-one DNA samples from patients with LCA and EORD had been analyzed for mutations by using a microarray, with negative results. One additional patient underwent SPATA7 screening due to a region of autozygosity surrounding this gene. A further patient was screened who had a compatible ocular phenotype. The entire SPATA7 coding sequence was assayed, including the intron-exon junctions, by using a combination of direct DNA sequencing and high-resolution melting screening. RESULTS: Screening of SPATA7 identified several known and novel single-nucleotide polymorphisms (SNPs). Affected individuals from five unrelated families were identified to have coding changes. Clinical features demonstrated a severe infantile onset retinal dystrophy, similar to Leber congenital amaurosis. The retina had widespread retinal pigment epithelial atrophy, with minimal pigment migration into the neurosensory retina. Fundus autofluorescence imaging showed a parafoveal annulus of increased autofluorescence. High-definition optical coherence tomography showed preservation of the inner segment/outer segment junction at the fovea. CONCLUSIONS: Mutations in SPATA7 are a rare cause of childhood retinal dystrophy accounting for 1.7% of disease in this cohort. Affected patients present in infancy with severe visual loss, but may have some preservation of the photoreceptor structure in the central retina. PMID- 21310916 TI - Characteristics of straylight in normal young myopic eyes and changes before and after LASIK. AB - PURPOSE: To investigate the characteristics of straylight and relevant factors in normal young myopic eyes and to assess changes in straylight and possible influencing factors before and after laser in situ keratomileusis (LASIK). METHODS: In this prospective nonrandomized study, 105 eyes of 105 patients were included. The level of straylight was measured with a straylight meter, and relationships with some optic parameters were analyzed in normal young myopic eyes. The difference between postoperative and preoperative straylight and the relationship with ablation were studied before and 1, 4, and 10 months after LASIK surgery. RESULTS: For normal eyes, sphere, astigmatism, keratometric (K) value, corneal central thickness (CCT), and anterior chamber depth (ACD) showed no significant correlation with straylight. However, straylight values showed a statistically significant increase 1 and 4 months after surgery (P < 0.05) but returned to preoperative levels at 10 months after surgery (P > 0.05) in LASIK eyes. No statistically significant relationship was found between straylight values and ablation depth, ablation ratio, residual bed thickness (RBT), or RBT/CCT (P > 0.05) after surgery. CONCLUSIONS: Specific optic parameters (refractive power, K value, CCT, and ACD) have no significant correlation with straylight. Although straylight increased during the early postoperative period, the parameter returned to preoperative levels over time. PMID- 21310917 TI - Copy number variations and primary open-angle glaucoma. AB - PURPOSE: This study sought to investigate the role of rare copy number variation (CNV) in age-related disorders of blindness, with a focus on primary open-angle glaucoma (POAG). Data are reported from a whole-genome copy number screen in a large cohort of 400 individuals with POAG and 500 age-matched glaucoma-free subjects. METHODS: DNA samples from patients and controls were tested for CNVs using a combination of two microarray platforms. The signal intensity data generated from these arrays were then analyzed with multiple CNV detection programs including CNAG version 2.0, PennCNV, and dChip. RESULTS: A total of 11 validated CNVs were identified as recurrent in the POAG set and absent in the age matched control set. This set included CNVs on 5q23.1 (DMXL1, DTWD2), 20p12 (PAK7), 12q14 (C12orf56, XPOT, TBK1, and RASSF3), 12p13.33 (TULP3), and 10q34.21 (PAX2), among others. The CNVs presented here are exceedingly rare and are not found in the Database of Genomic Variants. Moreover, expression data from ocular tissue support the role of these CNV-implicated genes in vision-related processes. In addition, CNV locations of DMXL1 and PAK7 overlap previously identified linkage signals for glaucoma on 5p23.1 and 20p12, respectively. CONCLUSIONS: The data are consistent with the hypothesis that rare CNV plays a role in the development of POAG. PMID- 21310918 TI - A potential role for angiopoietin 2 in the regulation of the blood-retinal barrier in diabetic retinopathy. AB - PURPOSE: Although VEGF has been identified as an important mediator of the blood retinal barrier alteration in diabetic retinopathy, the hypothesis for this study was that that other molecules, including the angiopoietins (Ang-1 and -2), may play a role. The expression of angiopoietins was analyzed in an animal model of diabetic retinopathy, and the role of Ang-2 in the regulation of diabetes-induced alterations of vascular permeability was characterized. METHODS: Diabetes was induced in rats, and human retinal endothelial cells (HRECs) were grown in media with 5.5 or 30.5 mM glucose. Levels of Ang-1 and -2 mRNA and protein were analyzed. Fluorescence-based assays were used to assess the effect of Ang-2 on vascular permeability in vivo and in vitro. The effect of Ang-2 on VE-cadherin function was assessed by measuring the extent of tyrosine phosphorylation. RESULTS: Ang-2 mRNA and protein increased in the retinal tissues after 8 weeks of diabetes and in high-glucose-treated cells. Intravitreal injection of Ang-2 in rats produced a significant increase in retinal vascular permeability. Ang-2 increased HREC monolayer permeability that was associated with a decrease in VE cadherin and a change in monolayer morphology. High glucose and Ang-2 produced a significant increase in VE-cadherin phosphorylation. CONCLUSIONS; Ang-2 is upregulated in the retina in an animal model of diabetes, and hyperglycemia induces the expression of Ang-2 in isolated retinal endothelial cells. Increased Ang-2 alters VE-cadherin function, leading to increased vascular permeability. Thus, Ang-2 may play an important role in increased vasopermeability in diabetic retinopathy. PMID- 21310919 TI - VEGF-induced retinal angiogenic signaling is critically dependent on Ca2+ signaling by Ca2+/calmodulin-dependent protein kinase II. AB - PURPOSE: The authors conducted an in vitro investigation of the role of Ca(2+) dependent signaling in vascular endothelial growth factor (VEGF)-induced angiogenesis in the retina. METHODS: Bovine retinal endothelial cells (BRECs) were stimulated with VEGF in the presence or absence of 1,2-bis(2 aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA-AM; intracellular Ca(2+) chelator), U73122 (phospholipase C (PLC) inhibitor), xestospongin C (Xe-C), and 2-aminoethoxydiphenyl borate (2APB) (inhibitors of inositol-1,4,5 triphosphate (IP(3)) signaling). Intracellular Ca(2+) concentration ([Ca(2+)](i)) was estimated using fura-2 Ca(2+) microfluorometry, Akt phosphorylation quantified by Western blot analysis, and angiogenic responses assessed using cell migration, proliferation, tubulogenesis, and sprout formation assays. The effects of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN93 were also evaluated on VEGF-induced Akt signaling and angiogenic activity. RESULTS: Stimulation of BRECs with 25 ng/mL VEGF induced a biphasic increase in [Ca(2+)](i), with an initial transient peak followed by a sustained plateau phase. VEGF-induced [Ca(2+)](i) increases were almost completely abolished by pretreating the cells with BAPTA-AM, U73122, Xe-C, or 2APB. These agents also inhibited VEGF-induced phosphorylation of Akt, cell migration, proliferation, tubulogenesis, and sprouting angiogenesis. KN93 was similarly effective at blocking the VEGF-induced activation of Akt and angiogenic responses. CONCLUSIONS: VEGF increases [Ca(2+)](i) in BRECs through activation of the PLC-IP(3) signal transduction pathway. VEGF-induced phosphorylation of the proangiogenic protein Akt is critically dependent on this increase in [Ca(2+)](i) and the subsequent activation of CaMKII. Pharmacologic inhibition of Ca(2+) mediated signaling in retinal endothelial cells blocks VEGF-induced angiogenic responses. These results suggest that the PLC/IP(3)/Ca(2+)/CaMKII signaling pathway may be a rational target for the treatment of angiogenesis-related disorders of the eye. PMID- 21310920 TI - Intravitreal injection of AAV2 transduces macaque inner retina. AB - PURPOSE: Adeno-associated virus serotype 2 (AAV2) has been shown to be effective in transducing inner retinal neurons after intravitreal injection in several species. However, results in nonprimates may not be predictive of transduction in the human inner retina, because of differences in eye size and the specialized morphology of the high-acuity human fovea. This was a study of inner retina transduction in the macaque, a primate with ocular characteristics most similar to that of humans. METHODS: In vivo imaging and histology were used to examine GFP expression in the macaque inner retina after intravitreal injection of AAV vectors containing five distinct promoters. RESULTS: AAV2 produced pronounced GFP expression in inner retinal cells of the fovea, no expression in the central retina beyond the fovea, and variable expression in the peripheral retina. AAV2 vector incorporating the neuronal promoter human connexin 36 (hCx36) transduced ganglion cells within a dense annulus around the fovea center, whereas AAV2 containing the ubiquitous promoter hybrid cytomegalovirus (CMV) enhancer/chicken beta-actin (CBA) transduced both Muller and ganglion cells in a dense circular disc centered on the fovea. With three shorter promoters--human synapsin (hSYN) and the shortened CBA and hCx36 promoters (smCBA and hCx36sh)--AAV2 produced visible transduction, as seen in fundus images, only when the retina was altered by ganglion cell loss or enzymatic vitreolysis. CONCLUSIONS: The results in the macaque suggest that intravitreal injection of AAV2 would produce high levels of gene expression at the human fovea, important in retinal gene therapy, but not in the central retina beyond the fovea. PMID- 21310921 TI - Development of IL-22-producing NK lineage cells from umbilical cord blood hematopoietic stem cells in the absence of secondary lymphoid tissue. AB - Human secondary lymphoid tissues (SLTs) contain interleukin-22 (IL-22)-producing cells with an immature NK phenotype. Given their location, these cells are difficult to study. We have generated large numbers of NK22 cells from hematopoietic stem cells. HSC-derived NK22 cells show a CD56(+)CD117(high)CD94(-) phenotype, consistent with stage III NK progenitors. Like freshly isolated SLT stage III cells, HSC-derived NK22 cells express NKp44, CD161, CCR6, IL1 receptor, AHR, and ROR-gammatau. IL-1beta and IL-23 stimulation results in significant IL 22 but not interferon-gamma production. Supernatant from these cells increases CD54 expression on mesenchymal stem cells. Thus, IL-22-producing NK cells can be generated in the absence of SLT. HSC-derived NK22 cells will be valuable in understanding this rare NK subset and create the opportunity for human translational clinical trials. PMID- 21310922 TI - Regulation of S100A10 by the PML-RAR-alpha oncoprotein. AB - Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia that results from the expression of the promyelocytic leukemia-retinoic acid receptor alpha (PML-RAR-alpha) oncoprotein. It is characterized by severe hemorrhagic complications due in part to excessive fibrinolysis, resulting from the excessive generation of the fibrinolytic enzyme, plasmin, at the cell surface of the PML cells. The treatment of patients with all-trans retinoic acid (ATRA) effectively ameliorates the disease by promoting the destruction of the PML-RAR alpha oncoprotein. In the present study we show for the first time that the plasminogen receptor, S100A10, is present on the extracellular surface of APL cells and is rapidly down-regulated in response to all-trans retinoic acid. The loss of S100A10 is concomitant with a loss in fibrinolytic activity. Furthermore, the induced expression of the PML-RAR-alpha oncoprotein increased the expression of cell surface S100A10 and also caused a dramatic increase in fibrinolytic activity. Depletion of S100A10 by RNA interference effectively blocked the enhanced fibrinolytic activity observed after induction of the PML-RAR-alpha oncoprotein. These experiments show that S100A10 plays a crucial role in the generation of plasmin leading to fibrinolysis, thus providing a link to the clinical hemorrhagic phenotype of APL. PMID- 21310923 TI - Hyperdiploidy is less frequent in AL amyloidosis compared with monoclonal gammopathy of undetermined significance and inversely associated with translocation t(11;14). AB - In multiple myeloma (MM) pathogenesis, hyperdiploidy and nonhyperdiploidy are recognized as 2 major cytogenetic pathways. Here, we assessed the role of hyperdiploidy in 426 patients with monoclonal plasma cell disorders, among them 246 patients with AL amyloidosis (AL), by interphase fluorescence in situ hybridization. Hyperdiploidy was defined by a well-established score requiring trisomies for at least 2 of the 3 chromosomes 5, 9, and 15. The hyperdiploidy frequency in AL was a mere 11% compared with 30% in monoclonal gammopathy of undetermined significance (P < .001) and 46% in AL with concomitant MM I (P < .001). Overall, hyperdiploidy was associated with an intact immunoglobulin, kappa light chain restriction, higher age, and bone marrow plasmacytosis, but was unrelated to the organ involvement pattern in AL. Clustering of 6 major cytogenetic aberrations in AL by an oncogenetic tree model showed that hyperdiploidy and t(11;14) were almost mutually exclusive, whereas gain of 1q21 favored hyperdiploidy. Deletion 13q14 and secondary IgH translocations were equally distributed between ploidy groups. We conclude that the interphase fluorescence in situ hybridization-based hyperdiploidy score is also a feasible tool to delineate hyperdiploid patients in early-stage monoclonal gammopathies and that the cytogenetic pathogenetic concepts developed in MM are transferable to AL. PMID- 21310924 TI - LDOC1 mRNA is differentially expressed in chronic lymphocytic leukemia and predicts overall survival in untreated patients. AB - We previously identified LDOC1 as one of the most significantly differentially expressed genes in untreated chronic lymphocytic leukemia (CLL) patients with respect to the somatic mutation status of the immunoglobulin heavy-chain variable region genes. However, little is known about the normal function of LDOC1, its contribution to the pathophysiology of CLL, or its prognostic significance. In this study, we have investigated LDOC1 mRNA expression in a large cohort of untreated CLL patients, as well as in normal peripheral blood B-cell (NBC) subsets and primary B-cell lymphoma samples. We have confirmed that LDOC1 is dramatically down-regulated in mutated CLL cases compared with unmutated cases, and have identified a new splice variant, LDOC1S. We show that LDOC1 is expressed in NBC subsets (naive > memory), suggesting that it may play a role in normal B cell development. It is also expressed in primary B-cell lymphoma samples, in which its expression is associated with somatic mutation status. In CLL, we show that high levels of LDOC1 correlate with biomarkers of poor prognosis, including cytogenetic markers, unmutated somatic mutation status, and ZAP70 expression. Finally, we demonstrate that LDOC1 mRNA expression is an excellent predictor of overall survival in untreated CLL patients. PMID- 21310925 TI - Negative regulation of mTOR activation by diacylglycerol kinases. AB - The engagement of TCR induces T-cell activation, which initiates multiple characteristic changes such as increase in cell size, cell division, and the production of cytokines and other effector molecules. The mammalian target of rapamycin (mTOR) regulates protein synthesis, transcription, cell survival, and autophagy. Critical roles of mTOR in T-cell activation and effector/memory differentiation have been revealed using chemical inhibitors or by genetic ablation of mTOR in T cells. However, the connection between mTOR signaling and other signaling cascades downstream of TCR is unclear. We demonstrate that diacylglycerol (DAG) and TCR engagement activate signaling in both mTOR complexes 1 and 2 through the activation of the Ras-mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (Mek1/2)-extracellular signal regulated kinase 1/2 (Erk1/2)-activator protein 1 (AP-1), known collectively as the Ras-Mek1/2-Erk1/2-AP-1 pathway. Deficiency of RasGRP1 or inhibition of Mek1/2 activity drastically decreases TCR-induced mTOR activation, whereas constitutively active Ras or Mek1 promotes mTOR activation. Although constitutively active Akt promotes TCR-induced mTOR activation, such activation is attenuated by Mek1/2 inhibition. We demonstrated further that DAG kinases (DGKs) alpha and zeta, which terminate DAG-mediated signaling, synergistically inhibit TCR-induced mTOR activation by inhibiting the Ras-Mek1/2-Erk/12 pathway. These observations provide novel insights into the regulation of mTOR activation. PMID- 21310926 TI - KDM2b/JHDM1b, an H3K36me2-specific demethylase, is required for initiation and maintenance of acute myeloid leukemia. AB - The histone H3 lysine 36 dimethyl-specific demethylase KDM2b/JHDM1b, which is highly expressed in various human leukemias, was previously found to be important in regulating cell proliferation and cellular senescence. However, its functions in leukemia development and maintenance are unclear. Here, we demonstrate that ectopic expression of Kdm2b/Jhdm1b is sufficient to transform hematopoietic progenitors. Conversely, depletion of Kdm2b/Jhdm1b in hematopoietic progenitors significantly impairs Hoxa9/Meis1-induced leukemic transformation. In leukemic stem cells, knockdown of Kdm2b/Jhdm1b impairs their self-renewing capability in vitro and in vivo. The functions of Kdm2b/Jhdm1b are mediated by its silencing of p15(Ink4b) expression through active demethylation of histone H3 lysine 36 dimethyl. Thus, our study suggests that Kdm2b/Jhdm1b functions as an oncogene and plays a critical role in leukemia development and maintenance. PMID- 21310927 TI - Targeted deletion of the mouse Mitoferrin1 gene: from anemia to protoporphyria. AB - Mitoferrin1 is 1 of 2 homologous mitochondrial iron transporters and is required for mitochondrial iron delivery in developing erythroid cells. We show that total deletion of Mfrn1 in embryos leads to embryonic lethality. Selective deletion of Mfrn1 in adult hematopoietic tissues leads to severe anemia because of a deficit in erythroblast formation. Deletion of Mfrn1 in hepatocytes has no phenotype or biochemical effect under normal conditions. In the presence of increased porphyrin synthesis, however, deletion of Mfrn1 in hepatocytes results in a decreased ability to convert protoporphyrin IX into heme, leading to protoporphyria, cholestasis, and bridging cirrhosis. Our results show that the activity of mitoferrin1 is required to manage an increase in heme synthesis. The data also show that alterations in heme synthesis within hepatocytes can lead to protoporphyria and hepatotoxicity. PMID- 21310928 TI - JAK blockade and HTLV. PMID- 21310929 TI - Sobering realities of surviving Hodgkin lymphoma. PMID- 21310930 TI - Predicting response in CML. PMID- 21310931 TI - The times they are a-changin'. PMID- 21310932 TI - CD9 phones home with a TEM of its own. PMID- 21310933 TI - Fitness without exhaustion. PMID- 21310934 TI - What keeps the power on in lymphomas? PMID- 21310935 TI - Who controls the controllers? PMID- 21310936 TI - Interleukin-7 induces HIV type 1 R5-to-X4 switch. PMID- 21310937 TI - Transition to homozygosity does not appear to provide a clonal advantage to hematopoietic progenitors carrying mutations in TET2. PMID- 21310938 TI - Immunosuppressor FK506 increases endoglin and activin receptor-like kinase 1 expression and modulates transforming growth factor-beta1 signaling in endothelial cells. AB - Hereditary hemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, is an autosomal-dominant vascular disease. The clinical manifestations are epistaxis, mucocutaneous and gastrointestinal telangiectases, and arteriovenous malformations in internal organs. Patients show severe epistaxis, and/or gastrointestinal bleeding, both of which notably interfere with their quality of life. There are two predominant types of HHT caused by mutations in endoglin (ENG) and ACVRL1/activin receptor-like kinase 1 (ALK1) genes, named HHT1 and HHT2, respectively. ENG and ALK1 code for proteins involved in the transforming growth factor (TGF)-beta1 signaling pathway, and it is widely accepted that HHT pathogenicity results from haploinsufficiency. No cure for HHT has been found, so identification of drugs able to increase the expression of these genes is essential when proposing new therapies. We report the efficacy of tacrolimus (FK506) in increasing ENG and ALK1 expression. The rationale comes from a case report of a patient with HHT who received a liver transplantation after hepatic failure due to a liver arteriovenous malformation. The liver was transplanted, and the immunosuppressor FK506 was used to prevent the rejection. After the first month of FK506 treatment, the internal and external telangiectases, epistaxes, and anemia disappeared. Here, we find that the immunosuppressor FK506 increases the protein and mRNA expression of ENG and ALK1 in cultured endothelial cells and enhances the TGF-beta1/ALK1 signaling pathway and endothelial cell functions like tubulogenesis and migration. These results suggest that the mechanism of action of FK506 involves a partial correction of endoglin and ALK1 haploinsufficiency and may therefore be an interesting drug for use in patients with HHT who undergo transplantation. PMID- 21310939 TI - Novel nano-composite multilayered biomaterial for osteochondral regeneration: a pilot clinical trial. AB - BACKGROUND: In recent years, there has been an increasing interest in and awareness of the importance of subchondral bone, for its role in the pathogenesis of articular surface damage and for the care that should be taken when treating such damage. PURPOSE: The objective of this pilot clinical study was to test the safety and performance of a newly developed type I collagen-hydroxyapatite nanostructured biomimetic osteochondral scaffold that aims to regenerate cartilage and subchondral bone. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A multilayer gradient nano-composite scaffold was obtained by nucleating collagen type I fibrils with hydroxyapatite nanoparticles. Thirty patients (9 female, 21 male; mean age, 29.3 years) with knee chondral or osteochondral lesions were treated with scaffold implantation. Lesion size varied from 1.5 cm(2) to 6.0 cm(2). Twenty-eight patients were followed for 2 years and were clinically evaluated using the International Knee Documentation Committee and Tegner scores. At final follow-up, magnetic resonance imaging evaluation was performed in 24 patients, and they were evaluated with the MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue) score. RESULTS: The Tegner and International Knee Documentation Committee objective and subjective scores improved significantly from the baseline evaluation to the 6-, 12-, and 24-month follow-ups. Further analysis showed a slower recovery but the same results for patients who presented with adverse events, for older patients, for patients who underwent previous surgery, and for those with patellar lesions. In contrast, a faster recovery was observed in active patients. At magnetic resonance imaging evaluation, complete filling of the cartilage and complete integration of the graft was shown in 70% of the lesions. However, the subchondral lamina and bone were considered intact in a minority of cases (7% and 47%, respectively). CONCLUSION: This open 1-step procedure was used for the treatment of chondral and osteochondral knee defects. The present pilot study highlighted the safety and potential clinical benefit of the graded biomimetic osteochondral scaffold in promoting bone and cartilage tissue restoration by itself and with good clinical and magnetic resonance imaging results at the 2-year follow-up. PMID- 21310940 TI - Natural history of nonoperatively treated symptomatic rotator cuff tears in patients 60 years old or younger. AB - BACKGROUND: Rotator cuff tears are the most frequent tendon injury in the adult population. However, the natural history of nonoperatively treated full-thickness tears is poorly defined. Knowledge of the expected evolution in tear size is important when considering nonoperative versus surgical care, especially in relatively young, active patients. PURPOSE: To evaluate the size change of nonoperatively treated full-thickness rotator cuff tears over 2 to 3 years' follow-up. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The authors prospectively followed patients 60 years old or younger who had a full-thickness rotator cuff tear equal to or larger than 5 mm, as diagnosed by bilateral shoulder ultrasound, and who were treated nonoperatively. At 2 to 3 years after the index ultrasound examination, a repeat ultrasound examination was performed by the same ultrasonographer. Results of the follow-up ultrasound examinations of both shoulders were compared with those of the index ultrasound examinations for change in rotator cuff tear size. The correlations were examined between these changes and age, sex, history of initial trauma, size of tear on the index ultrasound, and current shoulder symptoms. RESULTS: Fifty-one patients with 61 rotator cuff tears were evaluated. At a follow-up of 25 to 39 months (mean, 29), 49% of the tears (30 tears) increased in size, 43% (26 tears) had not changed, and 8% (5 tears) decreased in size. For 25% (10 shoulders ) of initially intact shoulders (41 shoulders), a new full-thickness rotator cuff tear was diagnosed. No correlation was found between the change in tear size and age of the patient (P = .85), sex (P = .93), existence of a prior trauma (P = .63), size of tear at index ultrasound (P = .62), and bilateral tears (P = 1.00). There was a correlation between the existence of considerable pain at the time of the follow up ultrasound and a clinically significant increase in tear size (P = .002). CONCLUSION: Full-thickness rotator cuff tears tend to increase in size in about half of patients aged 60 years or younger. Surgery should be initially considered in these patients to prevent a probable increase in size tear. Patients treated nonoperatively should be routinely monitored for tear size increase, especially if they remain symptomatic. PMID- 21310941 TI - Breast cancer stem cells: treatment resistance and therapeutic opportunities. AB - The clinical and pathologic heterogeneity of human breast cancer has long been recognized. Now, molecular profiling has enriched our understanding of breast cancer heterogeneity and yielded new prognostic and predictive information. Despite recent therapeutic advances, including the HER2-specific agent, trastuzumab, locoregional and systemic disease recurrence remain an ever-present threat to the health and well being of breast cancer survivors. By definition, disease recurrence originates from residual treatment-resistant cells, which regenerate at least the initial breast cancer phenotype. The discovery of the normal breast stem cell has re-ignited interest in the identity and properties of breast cancer stem-like cells and the relationship of these cells to the repopulating ability of treatment-resistant cells. The cancer stem cell model of breast cancer development contrasts with the clonal evolution model, whereas the mixed model draws on features of both. Although the origin and identity of breast cancer stem-like cells is contentious, treatment-resistant cells survive and propagate only because aberrant and potentially druggable signaling pathways are recruited. As a means to increase the rates of breast cancer cure, several approaches to specific targeting of the treatment-resistant cell population exist and include methods for addressing the problem of radioresistance in particular. PMID- 21310942 TI - Capsaicin promotes a more aggressive gene expression phenotype and invasiveness in null-TRPV1 urothelial cancer cells. AB - Capsaicin (CPS) has been found to exhibit either tumor promoting or suppressing effects, many of which are mediated by the specific transient receptor potential vanilloid type-1 (TRPV1). Herein, we provide evidence that CPS treatment induced a more aggressive gene phenotype and invasiveness in 5637 cells-lacking TRPV1 receptor. CPS treatment of 5637 cells induced upregulation of pro-angiogenetic (angiopoietin 1, angiopoietin 2 and vascular endothelial growth factor), pro invasive and pro-metastatic genes (MMP1, MMP9, TIMP1, TIMP3, granzyme A (GZMA), NM23A and S100A) with a downregulation of apoptotic genes (Fas/CD95 and tumor necrosis factor receptor superfamily member 1A). CPS increased the invasiveness of 5637 cells by triggering IGF (insulin-like growth factor)-1 release, GZMA and MMP9 activation, alpha-tubulin disassembly and cytoskeleton degradation. Finally, in order to evaluate the relationship between the lack of TRPV1 expression and increased CPS-induced invasiveness, we transfected 5637 cells with the TRPV1 complementary DNA (cDNA) sequence. We found that TRPV1-expressing cells show CPS mediated calcium level increase, growth inhibition and apoptosis. Moreover, CPS induced migration and MMP9 activation were reverted, suggesting an inhibitory role played by TRPV1 in urothelial cancer cell invasion and metastasis. PMID- 21310943 TI - High-constitutive HuR phosphorylation at Ser 318 by PKC{delta} propagates tumor relevant functions in colon carcinoma cells. AB - Overexpression of the messenger RNA (mRNA)-binding protein HuR is an important feature of many tumors and in most cases correlates with a high-grade malignancy. Since phosphorylation of HuR by protein kinase C delta (PKCdelta) at serine (Ser) 318 implies an important mode in HuR regulation, we studied its functional role in dysregulated HuR and related functions in colon carcinoma cells. Coimmunoprecipitation experiments revealed a high-constitutive association of nuclear PKCdelta with HuR. Using a phospho-Ser 318-specific HuR antibody, we found a strong increase in nuclear HuR phosphorylation in DLD-1 cells when compared with nontransformed CCD 841 colon epithelial cells. Importantly, a strong increase in HuR phosphorylation at Ser 318 was also found in tissue specimen from human colon carcinomas. Employing ribonucleoprotein immunoprecipitation, we show that DLD-1 cells displayed a strong and constitutive RNA binding of HuR to cyclooxygenase-2 (COX-2) and cyclin A encoding mRNAs that was strongly impaired by rottlerin, an inhibitor of novel PKCs. Accordingly, rottlerin accelerated the decay of COX-2 and cyclin A encoding mRNAs concomitant with a reduced expression of both genes. Functionally, migration and invasion is similarly impaired in PKCdelta- or HuR-small interfering RNA-depleted cells and in tumor cells transfected with a nonphosphorylatable serine-to-alanine 318 HuR construct. Conversely, expression of a phosphomimetic Ser 318 aspartic acid (D) HuR caused a significant increase in migration and proliferation of CCD 841 cells. Our data suggest that the increased HuR phosphorylation at Ser 318 by PKCdelta reflects an important regulatory paradigm for aberrant HuR functions and emphasize the antitumorigenic potential of PKCdelta inhibitory strategies. PMID- 21310944 TI - Macrophages induce COX-2 expression in breast cancer cells: role of IL-1beta autoamplification. AB - Tumor-associated macrophages and high levels of cyclooxygenase-2 (COX-2) are associated with poor prognosis in breast cancer patients, but their potential interdependence has not been evaluated. The objective of this study was to determine whether macrophages regulate COX-2 expression in breast cancer cells. For this purpose, THP-1 cells were cocultured with HCC1954 breast cancer cells. Coculture led to increased COX-2 expression in the HCC1954 cells and elevated prostaglandin E(2) levels in conditioned media. Similar results were observed when THP-1 cells were incubated with HCC1937 breast cancer cells or when human monocyte-derived macrophages were cocultured with HCC1954 cells. Coculture triggered production of reactive oxygen species (ROS) in HCC1954 cells. COX-2 induction was blocked in cells preincubated with an reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor or by silencing p67PHOX, a subunit of NADPH oxidase. ROS production triggered activation of Src and mitogen activated protein kinases (MAPKs). Blocking Src or MAPK activities or antagonizing the activator protein-1 (AP-1) transcription factor attenuated COX-2 induction in HCC1954 cells. Coculture caused rapid induction of interleukin-1beta (IL-1beta) in both breast cancer cells and macrophages. Increased IL-1beta expression was blocked by an interleukin-1 receptor antagonist (IL-1Ra), suggesting autocrine and paracrine effects. Importantly, macrophage-induced COX-2 expression was blocked in HCC1954 cells preincubated with IL-1Ra or anti-IL-1beta IgG. Together, these results indicate that macrophage-mediated induction of COX-2 in breast cancer cells is a consequence of IL-1beta-mediated stimulation of ROS >Src->MAPK->AP-1 signaling. IL-1beta-dependent induction of COX-2 in breast cancer cells provides a mechanism whereby macrophages contribute to tumor progression and potential therapeutic targets in breast cancer. PMID- 21310945 TI - Individual differences in recovery time from attentional capture. AB - Working memory capacity reflects a core ability of the individual that affects performance on many cognitive tasks. Recent work has suggested that an important covariate of memory capacity is attentional control, and specifically that low capacity individuals are more susceptible to attentional capture by distractors than high-capacity individuals are, with the latter being able to resist capture. Here, we tested an alternative account according to which all individuals are equally susceptible to attentional capture, but high-capacity individuals recover more quickly than low-capacity individuals. Using psychophysical and electrophysiological methods, we measured recovery time from attentional capture. In two experiments, we found that high- and low-capacity individuals showed equivalent attentional capture effects in the initial moments following capture, but that low-capacity individuals took much longer to recover than high-capacity individuals did. These results suggest that the poor attentional control associated with low capacity is due to slow disengagement from distractors. PMID- 21310946 TI - Approximate likelihood calculation on a phylogeny for Bayesian estimation of divergence times. AB - The molecular clock provides a powerful way to estimate species divergence times. If information on some species divergence times is available from the fossil or geological record, it can be used to calibrate a phylogeny and estimate divergence times for all nodes in the tree. The Bayesian method provides a natural framework to incorporate different sources of information concerning divergence times, such as information in the fossil and molecular data. Current models of sequence evolution are intractable in a Bayesian setting, and Markov chain Monte Carlo (MCMC) is used to generate the posterior distribution of divergence times and evolutionary rates. This method is computationally expensive, as it involves the repeated calculation of the likelihood function. Here, we explore the use of Taylor expansion to approximate the likelihood during MCMC iteration. The approximation is much faster than conventional likelihood calculation. However, the approximation is expected to be poor when the proposed parameters are far from the likelihood peak. We explore the use of parameter transforms (square root, logarithm, and arcsine) to improve the approximation to the likelihood curve. We found that the new methods, particularly the arcsine based transform, provided very good approximations under relaxed clock models and also under the global clock model when the global clock is not seriously violated. The approximation is poorer for analysis under the global clock when the global clock is seriously wrong and should thus not be used. The results suggest that the approximate method may be useful for Bayesian dating analysis using large data sets. PMID- 21310947 TI - Dysphagia management: a survey of school-based speech-language pathologists in Vermont. AB - PURPOSE: This study (a) gathered information about the kinds of dysphagia management services school-based speech-language pathologists (SLPs) provide, (b) examined the attitudes of SLPs related to dysphagia management, (c) compared the responses of SLPs on the basis of their experience working in a medical setting, and (d) investigated the relationship between SLPs' training and their confidence to provide dysphagia services. METHOD: Fifty-two school-based SLPs practicing in Vermont responded to a survey designed to gather information on the variables of interest. RESULTS: Respondents reported a low incidence of students requiring dysphagia services and SLPs providing a wide range of dysphagia services. Results indicated variability in attitudes related to dysphagia management, but trends were also evident. Chief among them were SLPs' low levels of confidence to provide dysphagia services and the need for additional training in dysphagia management. SLPs who had experience in a medical setting reported greater confidence to evaluate and treat students with dysphagia compared to those without experience in a medical setting. Relationships between a variety of previous training experiences and confidence to treat dysphagia were also revealed. CONCLUSION: This study expanded previous research in this area. Factors accounting for our results, limitations, directions for future research, and implications for practice are discussed. PMID- 21310948 TI - Survey of K-3rd-grade teachers' knowledge of ear infections and willingness to participate in prevention programs. AB - PURPOSE: Ear infections are prevalent in kindergarten through 3rd-grade (K-3rd) children and can affect their performance at school. Chewing gum, when administered by parents and teachers, can help prevent ear infections in children. This pilot study surveyed K-3rd-grade teachers in the Santa Barbara School Districts to assess their knowledge about ear infections and their willingness to participate in ear infection prevention programs. METHOD: A 37 item questionnaire was developed and was e-mailed to a convenience sample of 112 teachers in February 2010. RESULTS: Response rate was 26%; 29 teachers responded. Most respondents were experienced females >= 36 years of age who said that their education provided no information about ear infections. Less than half said that they knew signs of ear infections or that ear infections could be prevented, but more than half believed that ear infections could hinder children's development and quality of life. All of the schools and almost all of the teachers did not permit chewing gum on campus or in their classrooms, but most teachers said they would participate in ear infection prevention programs, let students chew xylitol gum if it prevented ear infections, and wanted more information on this topic. CONCLUSION: Although teachers said they would participate in ear infection prevention programs, obstacles were identified that could preclude the use of xylitol chewing gum. Prevention programs should be developed, but xylitol gum prophylaxis regimens may be better directed at in-home use. PMID- 21310949 TI - Perturbation of the quinone-binding site of complex II alters the electronic properties of the proximal [3Fe-4S] iron-sulfur cluster. AB - Succinate-ubiquinone oxidoreductase (SQR) and menaquinol-fumarate oxidoreductase (QFR) from Escherichia coli are members of the complex II family of enzymes. SQR and QFR catalyze similar reactions with quinones; however, SQR preferentially reacts with higher potential ubiquinones, and QFR preferentially reacts with lower potential naphthoquinones. Both enzymes have a single functional quinone binding site proximal to a [3Fe-4S] iron-sulfur cluster. A difference between SQR and QFR is that the redox potential of the [3Fe-4S] cluster in SQR is 140 mV higher than that found in QFR. This may reflect the character of the different quinones with which the two enzymes preferentially react. To investigate how the environment around the [3Fe-4S] cluster affects its redox properties and catalysis with quinones, a conserved amino acid proximal to the cluster was mutated in both enzymes. It was found that substitution of SdhB His-207 by threonine (as found in QFR) resulted in a 70-mV lowering of the redox potential of the cluster as measured by EPR. The converse substitution in QFR raised the redox potential of the cluster. X-ray structural analysis suggests that placing a charged residue near the [3Fe-4S] cluster is a primary reason for the alteration in redox potential with the hydrogen bonding environment having a lesser effect. Steady state enzyme kinetic characterization of the mutant enzymes shows that the redox properties of the [3Fe-4S] cluster have only a minor effect on catalysis. PMID- 21310950 TI - Genome-wide analysis of transcription factor E2F1 mutant proteins reveals that N- and C-terminal protein interaction domains do not participate in targeting E2F1 to the human genome. AB - Previous studies of E2F family members have suggested that protein-protein interactions may be the mechanism by which E2F proteins are recruited to specific genomic regions. We have addressed this hypothesis on a genome-wide scale using ChIP-seq analysis of MCF7 cell lines that express tagged wild type and mutant E2F1 proteins. First, we performed ChIP-seq for tagged WT E2F1. Then, we analyzed E2F1 proteins that lacked the N-terminal SP1 and cyclin A binding domains, the C terminal transactivation and pocket protein binding domains, and the internal marked box domain. Surprisingly, we found that the ChIP-seq patterns of the mutant proteins were identical to that of WT E2F1. However, mutation of the DNA binding domain abrogated all E2F1 binding to the genome. These results suggested that the interaction between the E2F1 DNA binding domain and a consensus motif may be the primary determinant of E2F1 recruitment. To address this possibility, we analyzed the in vivo binding sites for the in vitro-derived consensus E2F1 motif (TTTSSCGC) and also performed de novo motif analysis. We found that only 12% of the ChIP-seq peaks contained the TTTSSCGC motif. De novo motif analysis indicated that most of the in vivo sites lacked the 5' half of the in vitro derived consensus, having instead the in vivo consensus of CGCGC. In summary, our findings do not provide support for the model that protein-protein interactions are involved in recruiting E2F1 to the genome, but rather suggest that recognition of a motif found at most human promoters is the critical determinant. PMID- 21310951 TI - Cysteine proteases bleomycin hydrolase and cathepsin Z mediate N-terminal proteolysis and toxicity of mutant huntingtin. AB - N-terminal proteolysis of huntingtin is thought to be an important mediator of HD pathogenesis. The formation of short N-terminal fragments of huntingtin (cp-1/cp 2, cp-A/cp-B) has been demonstrated in cells and in vivo. We previously mapped the cp-2 cleavage site by mass spectrometry to position Arg167 of huntingtin. The proteolytic enzymes generating short N-terminal fragments of huntingtin remain unknown. To search for such proteases, we conducted a genome-wide screen using an RNA-silencing approach and an assay for huntingtin proteolysis based on the detection of cp-1 and cp-2 fragments by Western blotting. The primary screen was carried out in HEK293 cells, and the secondary screen was carried out in neuronal HT22 cells, transfected in both cases with a construct encoding the N-terminal 511 amino acids of mutant huntingtin. For additional validation of the hits, we employed a complementary assay for proteolysis of huntingtin involving overexpression of individual proteases with huntingtin in two cell lines. The screen identified 11 enzymes, with two major candidates to carry out the cp-2 cleavage, bleomycin hydrolase (BLMH) and cathepsin Z, which are both cysteine proteases of a papain-like structure. Knockdown of either protease reduced cp-2 cleavage, and ameliorated mutant huntingtin induced toxicity, whereas their overexpression increased the cp-2 cleavage. Both proteases partially co-localized with Htt in the cytoplasm and within or in association with early and late endosomes, with some nuclear co-localization observed for cathepsin Z. BLMH and cathepsin Z are expressed in the brain and have been associated previously with neurodegeneration. Our findings further validate the cysteine protease family, and BLMH and cathepsin Z in particular, as potential novel targets for HD therapeutics. PMID- 21310952 TI - A third metal is required for catalytic activity of the signal-transducing protein phosphatase M tPphA. AB - Protein phosphatase M (PPM) regulates key signaling pathways in prokaryotes and eukaryotes. Novel structures of bacterial PPM members revealed three divalent metal ions in their catalytic centers. The function of metal 3 (M3) remained unclear. To reveal its function, we created variants of tPphA from Thermosynechococcus elongatus in all metal-coordinating residues, and multiple variants were created for the M3 coordinating Asp-119 residue. The structures of variants D119A and D193A were resolved, showing loss of M3 binding but unaffected binding of M1 and M2 in the catalytic center of D119A, with the nucleophilic water molecule in the correct place. The catalytic activity of this variant was highly impaired. This and further structure-function analyses showed that M3 is required for catalysis by providing a water molecule as a proton donor during catalysis. Mutation of the homologue Asp residue in human PP2Calpha also caused loss of function, suggesting a general requirement of M3 in PPM-catalyzed reactions. PMID- 21310953 TI - Regulation of the incorporation of tissue factor into microparticles by serine phosphorylation of the cytoplasmic domain of tissue factor. AB - The mechanisms that regulate the incorporation and release of tissue factors (TFs) into cell-derived microparticles are as yet unidentified. In this study, we have explored the regulation of TF release into microparticles by the phosphorylation of serine residues within the cytoplasmic domain of TF. Wild-type and mutant forms of TF, containing alanine and aspartate substitutions at Ser253 and Ser258, were overexpressed in coronary artery and dermal microvascular endothelial cells and microparticle release stimulated with PAR2 agonist peptide (PAR2-AP). The release of TF antigen and activity was then monitored. In addition, the phosphorylation state of the two serine residues within the released microparticles and the cells was monitored for 150 min. The release of wild-type TF as procoagulant microparticles peaked at 90 min and declined thereafter in both cell types. The TF within these microparticles was phosphorylated at Ser253 but not at Ser258. Aspartate substitution of Ser253 resulted in rapid release of TF antigen but not activity, whereas TF release was reduced and delayed by alanine substitution of Ser253 or aspartate substitution of Ser258. Alanine substitution of Ser258 prolonged the release of TF following PAR2-AP activation. The release of TF was concurrent with phosphorylation of Ser253 and was followed by dephosphorylation at 120 min and phosphorylation of Ser258. We propose a sequential mechanism in which the phosphorylation of Ser253 through PAR2 activation results in the incorporation of TF into microparticles, simultaneously inducing Ser258 phosphorylation. Phosphorylation of Ser258 in turn promotes the dephosphorylation of Ser253 and suppresses the release of TF. PMID- 21310954 TI - Structure-function analysis of grass clip serine protease involved in Drosophila Toll pathway activation. AB - Grass is a clip domain serine protease (SP) involved in a proteolytic cascade triggering the Toll pathway activation of Drosophila during an immune response. Epistasic studies position it downstream of the apical protease ModSP and upstream of the terminal protease Spaetzle-processing enzyme. Here, we report the crystal structure of Grass zymogen. We found that Grass displays a rather deep active site cleft comparable with that of proteases of coagulation and complement cascades. A key distinctive feature is the presence of an additional loop (75 loop) in the proximity of the activation site localized on a protruding loop. All biochemical attempts to hydrolyze the activation site of Grass failed, strongly suggesting restricted access to this region. The 75-loop is thus proposed to constitute an original mechanism to prevent spontaneous activation. A comparison of Grass with clip serine proteases of known function involved in analogous proteolytic cascades allowed us to define two groups, according to the presence of the 75-loop and the conformation of the clip domain. One group (devoid of the 75-loop) contains penultimate proteases whereas the other contains terminal proteases. Using this classification, Grass appears to be a terminal protease. This result is evaluated according to the genetic data documenting Grass function. PMID- 21310955 TI - Dissociating quaternary structure regulates cell-signaling functions of a secreted human tRNA synthetase. AB - Many tRNA synthetases are homodimers that are catalytically inactive as monomers. An example is the 528-amino acid human tyrosyl-tRNA synthetase, which is made up of an N-terminal catalytic unit (TyrRS(Mini)) and a 164-amino acid C-domain. Although native TyrRS has no known cytokine functions, natural proteolysis of secreted TyrRS releases TyrRS(Mini), which not only has the same aminoacylation activity as native TyrRS but also has strong activity for stimulating migration of polymorphonuclear leukocytes. The migration-stimulating activity is dependent on an ELR tripeptide motif, similar to that in CXC cytokines like IL-8, and also has the familiar bell-shaped concentration dependence seen for CXC cytokines. Here we show that in contrast to IL-8, where the bell-shaped dependence arises from the effects of CXCR1/2 receptor internalization, TyrRS(Mini) does not induce internalization of CXCR1/2. A rationally designed non-associating monomer and a non-dissociating dimer were constructed. With these constructs, the bell-shaped concentration dependence of leukocyte migration was shown to arise from the agonist (for migration) activity of the catalytically inactive monomer and the antagonist activity of the catalytically active dimer. Thus, the dissociating quaternary structure of TyrRS(Mini) regulates two opposing cytokine activities and suggests the possibility of dissociating quaternary structures regulating novel functions of other tRNA synthetases. PMID- 21310956 TI - Amino acid signaling in yeast: activation of Ssy5 protease is associated with its phosphorylation-induced ubiquitylation. AB - The yeast Ssy5 protein is a serine-type endoprotease autoprocessed into a catalytic domain and a large inhibitory prodomain. When external amino acids are detected by the plasma membrane Ssy1 sensor, Ssy5 is activated and catalyzes endoproteolytic processing of the Stp1 and Stp2 transcription factors. These Stp proteins then migrate into the nucleus and activate transcription of several amino acid permease genes. Previous studies showed that Ssy5 activation involves the SCFGrr1 ubiquitin ligase complex, but the molecular mechanisms of this activation remain unclear. We here report that the prodomain of Ssy5 is phosphorylated in a casein kinase I-dependent manner in response to amino acid detection. We describe a mutant form of Ssy5 whose prodomain is not phosphorylated and show that it is nonfunctional. Amino acid detection also induces ubiquitylation of the Ssy5 prodomain. This prodomain ubiquitylation requires its prior phosphorylation and the SCFGrr1 complex. When this ubiquitylation is defective, Ssy5 accumulates as a phosphorylated form but remains inactive. A constitutive Ssy5 form in which the prodomain fails to inhibit the catalytic domain does not need to be phosphorylated or ubiquitylated to be active. Finally, we provide evidence that ubiquitylation of the inhibitory prodomain rather than its subsequent degradation is the key step in the Ssy5 activation mechanism. We propose that the Ssy5 protease is activated by phosphorylation-induced ubiquitylation, the effect of which is relief from inhibition by its prodomain. PMID- 21310957 TI - Solution structure of the PilZ domain protein PA4608 complex with cyclic di-GMP identifies charge clustering as molecular readout. AB - Cyclic diguanosine monophosphate (c-di-GMP) is a ubiquitous bacterial second messenger that controls the switch from a single-cell lifestyle to surface attached, multicellular communities called biofilms. PilZ domain proteins are a family of bacterial c-di-GMP receptors, which control various cellular processes. We have solved the solution structure of the Pseudomonas aeruginosa single-domain PilZ protein PA4608 in complex with c-di-GMP by NMR spectroscopy. Isotope labeling by (13)C and (15)N of both the ligand and the protein made it possible to define the structure of c-di-GMP in the complex at high precision by a large number of intermolecular and intraligand NOEs and by two intermolecular hydrogen bond scalar couplings. Complex formation induces significant rearrangements of the C- and N-terminal parts of PA4608. c-di-GMP binds as an intercalated, symmetric dimer to one side of the beta-barrel, thereby displacing the C-terminal helix of the apo state. The N-terminal RXXXR PilZ domain motif, which is flexible in the apo state, wraps around the ligand and in turn ties the displaced C terminus in a loose manner by a number of hydrophobic contacts. The recognition of the dimeric ligand is achieved by numerous H-bonds and stacking interactions involving residues Arg(8), Arg(9), Arg(10), and Arg(13) of the PilZ motif, as well as beta-barrel residues Asp(35) and Trp(77). As a result of the rearrangement of the N and C termini, a highly negative surface is created on one side of the protein complex. We propose that the movement of the termini and the resulting negative surface form the basis for downstream signaling. PMID- 21310958 TI - MicroRNA-29c is a signature microRNA under high glucose conditions that targets Sprouty homolog 1, and its in vivo knockdown prevents progression of diabetic nephropathy. AB - Although several recent publications have suggested that microRNAs contribute to the pathogenesis of diabetic nephropathy, the role of miRNAs in vivo still remains poorly understood. Using an integrated in vitro and in vivo comparative miRNA expression array, we identified miR-29c as a signature miRNA in the diabetic environment. We validated our profiling array data by examining miR-29c expression in the kidney glomeruli obtained from db/db mice in vivo and in kidney microvascular endothelial cells and podocytes treated with high glucose in vitro. Functionally, we found that miR-29c induces cell apoptosis and increases extracellular matrix protein accumulation. Indeed, forced expression of miR-29c strongly induced podocyte apoptosis. Conversely, knockdown of miR-29c prevented high glucose-induced cell apoptosis. We also identified Sprouty homolog 1 (Spry1) as a direct target of miR-29c with a nearly perfect complementarity between miR 29c and the 3'-untranslated region (UTR) of mouse Spry1. Expression of miR-29c decreased the luciferase activity of Spry1 when co-transfected with the mouse Spry1 3'-UTR reporter construct. Overexpression of miR-29c decreased the levels of Spry1 protein and promoted activation of Rho kinase. Importantly, knockdown of miR-29c by a specific antisense oligonucleotide significantly reduced albuminuria and kidney mesangial matrix accumulation in the db/db mice model in vivo. These findings identify miR-29c as a novel target in diabetic nephropathy and provide new insights into the role of miR-29c in a previously unrecognized signaling cascade involving Spry1 and Rho kinase activation. PMID- 21310959 TI - Membrane anchoring and interaction between transmembrane domains are crucial for K+ channel function. AB - The small viral channel Kcv is a Kir-like K(+) channel of only 94 amino acids. With this simple structure, the tetramer of Kcv represents the pore module of all complex K(+) channels. To examine the structural contribution of the transmembrane domains (TMDs) to channel function, we performed Ala scanning mutagenesis of the two domains and tested the functionality of the mutants in a yeast complementation assay. The data reveal, in combination with computational models, that the upper halves of both TMDs, which face toward the external medium, are rather rigid, whereas the inner parts are more flexible. The rigidity of the outer TMD is conferred by a number of essential aromatic amino acids that face the membrane and probably anchor this domain in the bilayer. The inner TMD is intimately connected with the rigid part of the outer TMD via pi...pi interactions between a pair of aromatic amino acids. This structural principle is conserved within the viral K(+) channels and also present in Kir2.2, implying a general importance of this architecture for K(+) channel function. PMID- 21310960 TI - RPB5-mediating protein is required for the proliferation of hepatocellular carcinoma cells. AB - RPB5-mediating protein (RMP) is associated with the RNA polymerase II subunit RPB5. RMP functionally counteracts the transcriptional activation of hepatitis B virus X protein that has been shown to play a role in the development of hepatocellular carcinoma (HCC). However, the effect of RMP on the growth of HCC remains unclear. In this study, we characterized the potential role of RMP in the proliferation of human HCC cells using two cell lines, SMMC-7721 and HepG2. We found that RMP expression increased when HCC cells were treated with (60)Co gamma irradiation. Cell growth and colony formation assays suggest that RMP plays an antiapoptotic role in the proliferation and growth of HCC cells. We also show that RMP depletion induced the G(2) arrest of HCC cells characterized by the decreased expression of Cdk1 and Cyclin B. Tumor formation assays further confirmed the in vivo requirement of RMP during HCC growth. In conclusion, our results demonstrate that RMP is a radiation-sensitive factor, and it may play essential roles in HCC growth by affecting the proliferation and apoptosis of HCC cells. PMID- 21310961 TI - Evidence for direct activation of mTORC2 kinase activity by phosphatidylinositol 3,4,5-trisphosphate. AB - mTORC2 (mammalian target of rapamycin complex 2) plays important roles in signal transduction by regulating an array of downstream effectors, including protein kinase AKT. However, its regulation by upstream regulators remains poorly characterized. Although phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P(3)) is known to regulate the phosphorylation of AKT Ser(473), the hydrophobic motif (HM) site, by mTORC2, it is not clear whether PtdIns(3,4,5)P(3) can directly regulate mTORC2 kinase activity. Here, we used two membrane-docked AKT mutant proteins, one with and the other without the pleckstrin homology (PH) domain, as substrates for mTORC2 to dissect the roles of PtdIns(3,4,5)P(3) in AKT HM phosphorylation in cultured cells and in vitro kinase assays. In HEK293T cells, insulin and constitutively active mutants of small GTPase H-Ras and PI3K could induce HM phosphorylation of both AKT mutants, which was blocked by the PI3K inhibitor LY294002. Importantly, PtdIns(3,4,5)P(3) was able to stimulate the phosphorylation of both AKT mutants by immunoprecipitated mTOR2 complexes in an in vitro kinase assay. In both in vivo and in vitro assays, the AKT mutant containing the PH domain appeared to be a better substrate than the one without the PH domain. Therefore, these results suggest that PtdIns(3,4,5)P(3) can regulate HM phosphorylation by mTORC2 via multiple mechanisms. One of the mechanisms is to directly stimulate the kinase activity of mTORC2. PMID- 21310963 TI - Tomography of reaction-diffusion microemulsions reveals three-dimensional Turing patterns. AB - Spatially periodic, temporally stationary patterns that emerge from instability of a homogeneous steady state were proposed by Alan Turing in 1952 as a mechanism for morphogenesis in living systems and have attracted increasing attention in biology, chemistry, and physics. Patterns found to date have been confined to one or two spatial dimensions. We used tomography to study the Belousov-Zhabotinsky reaction in a microemulsion in which the polar reactants are confined to aqueous nanodroplets much smaller than the scale of the stationary patterns. We demonstrate the existence of Turing patterns that can exist only in three dimensions, including curved surfaces, hexagonally packed cylinders, spots, and labyrinthine and lamellar patterns. PMID- 21310962 TI - The proximal hydrogen bond network modulates Bacillus subtilis nitric-oxide synthase electronic and structural properties. AB - Bacterial nitric-oxide synthase (NOS)-like proteins are believed to be genuine NOSs. As for cytochromes P450 (CYPs), NOS-proximal ligand is a thiolate that exerts a push effect crucial for the process of dioxygen activation. Unlike CYPs, this catalytic electron donation seems controlled by a hydrogen bond (H-bond) interaction between the thiolate ligand and a vicinal tryptophan. Variations of the strength of this H-bond could provide a direct way to tune the stability along with the electronic and structural properties of NOS. We generated five different mutations of bsNOS Trp66, which can modulate this proximal H-bond. We investigated the effects of these mutations on different NOS complexes (FeIII, FeIICO, and FeIINO), using a combination of UV-visible absorption, EPR, FTIR, and resonance Raman spectroscopies. Our results indicate that (i) the proximal H-bond modulation can selectively decrease or increase the electron donating properties of the proximal thiolate, (ii) this modulation controls the sigma-competition between distal and proximal ligands, (iii) this H-bond controls the stability of various NOS intermediates, and (iv) a fine tuning of the electron donation by the proximal ligand is required to allow at the same time oxygen activation and to prevent uncoupling reactions. PMID- 21310964 TI - Dynamic control of chiral space in a catalytic asymmetric reaction using a molecular motor. AB - Enzymes and synthetic chiral catalysts have found widespread application to produce single enantiomers, but in situ switching of the chiral preference of a catalytic system is very difficult to achieve. Here, we report on a light-driven molecular motor with integrated catalytic functions in which the stepwise change in configuration during a 360 degrees unidirectional rotary cycle governs the catalyst performance both with respect to activity and absolute stereocontrol in an asymmetric transformation. During one full rotary cycle, catalysts are formed that provide either racemic (R,S) or preferentially the R or the S enantiomer of the chiral product of a conjugate addition reaction. This catalytic system demonstrates how different molecular tasks can be performed in a sequential manner, with the sequence controlled by the directionality of a rotary cycle. PMID- 21310965 TI - Different B cell populations mediate early and late memory during an endogenous immune response. AB - Memory B cells formed in response to microbial antigens provide immunity to later infections; however, the inability to detect rare endogenous antigen-specific cells limits current understanding of this process. Using an antigen-based technique to enrich these cells, we found that immunization with a model protein generated B memory cells that expressed isotype-switched immunoglobulins (swIg) or retained IgM. The more numerous IgM(+) cells were longer lived than the swIg(+) cells. However, swIg(+) memory cells dominated the secondary response because of the capacity to become activated in the presence of neutralizing serum immunoglobulin. Thus, we propose that memory relies on swIg(+) cells until they disappear and serum immunoglobulin falls to a low level, in which case memory resides with durable IgM(+) reserves. PMID- 21310966 TI - Cortical constriction during abscission involves helices of ESCRT-III-dependent filaments. AB - After partitioning of cytoplasmic contents by cleavage furrow ingression, animal cells remain connected by an intercellular bridge, which subsequently splits by abscission. Here, we examined intermediate stages of abscission in human cells by using live imaging, three-dimensional structured illumination microscopy, and electron tomography. We identified helices of 17-nanometer-diameter filaments, which narrowed the cortex of the intercellular bridge to a single stalk. The endosomal sorting complex required for transport (ESCRT)-III co-localized with constriction zones and was required for assembly of 17-nanometer-diameter filaments. Simultaneous spastin-mediated removal of underlying microtubules enabled full constriction at the abscission site. The identification of contractile filament helices at the intercellular bridge has broad implications for the understanding of cell division and of ESCRT-III-mediated fission of large membrane structures. PMID- 21310967 TI - The world's technological capacity to store, communicate, and compute information. AB - We estimated the world's technological capacity to store, communicate, and compute information, tracking 60 analog and digital technologies during the period from 1986 to 2007. In 2007, humankind was able to store 2.9 * 10(20) optimally compressed bytes, communicate almost 2 * 10(21) bytes, and carry out 6.4 * 10(18) instructions per second on general-purpose computers. General purpose computing capacity grew at an annual rate of 58%. The world's capacity for bidirectional telecommunication grew at 28% per year, closely followed by the increase in globally stored information (23%). Humankind's capacity for unidirectional information diffusion through broadcasting channels has experienced comparatively modest annual growth (6%). Telecommunication has been dominated by digital technologies since 1990 (99.9% in digital format in 2007), and the majority of our technological memory has been in digital format since the early 2000s (94% digital in 2007). PMID- 21310968 TI - Ghost prey and missing conflicts: reinterpreting the implications of bald eagle diet composition on the California Channel Islands. PMID- 21310969 TI - In vivo lipidomics using single-cell Raman spectroscopy. AB - We describe a method for direct, quantitative, in vivo lipid profiling of oil producing microalgae using single-cell laser-trapping Raman spectroscopy. This approach is demonstrated in the quantitative determination of the degree of unsaturation and transition temperatures of constituent lipids within microalgae. These properties are important markers for determining engine compatibility and performance metrics of algal biodiesel. We show that these factors can be directly measured from a single living microalgal cell held in place with an optical trap while simultaneously collecting Raman data. Cellular response to different growth conditions is monitored in real time. Our approach circumvents the need for lipid extraction and analysis that is both slow and invasive. Furthermore, this technique yields real-time chemical information in a label-free manner, thus eliminating the limitations of impermeability, toxicity, and specificity of the fluorescent probes common in currently used protocols. Although the single-cell Raman spectroscopy demonstrated here is focused on the study of the microalgal lipids with biofuel applications, the analytical capability and quantitation algorithms demonstrated are applicable to many different organisms and should prove useful for a diverse range of applications in lipidomics. PMID- 21310970 TI - The amino acid dipeptide: small but still influential after 50 years. PMID- 21310971 TI - Making data maximally available. PMID- 21310977 TI - Profile: Mohamed ElBaradei. From nuclear watchdog to the maelstrom of Cairo. PMID- 21310976 TI - Pharmaceuticals. Pfizer's shakeup means less money for research. PMID- 21310978 TI - Biomedical research. The genome project: what will it do as a teenager? Interview by Jocelyn Kaiser. PMID- 21310979 TI - U.S. science policy. Ending earmarks also means the end of many research projects. PMID- 21310980 TI - Human genome 10th anniversary. What would you do? PMID- 21310981 TI - Human genome 10th anniversary. Will computers crash genomics? PMID- 21310982 TI - Computer models. Coming soon to a lab near you: drag-and-drop virtual worlds. PMID- 21310983 TI - Assessing performance through understanding. PMID- 21310984 TI - Undercutting the grant process. PMID- 21310985 TI - No mystery about the polio outbreak. PMID- 21310986 TI - Leading the charge to virtual meetings. PMID- 21310987 TI - Research funding. Measuring the results of science investments. PMID- 21310988 TI - Molecular biology. The eukaryotic ribosome. PMID- 21310989 TI - Computer science. Learning from nature. PMID- 21310990 TI - Cell biology. The lives of proteins. PMID- 21310991 TI - Medicine. The genetics of primary aldosteronism. PMID- 21310992 TI - Materials science. Unusual thermoelastic properties of methanol monohydrate. PMID- 21310993 TI - Genome-sequencing anniversary. Genome literacy. PMID- 21310994 TI - Genome-sequencing anniversary. My genome. PMID- 21310996 TI - Genome-sequencing anniversary. My genome, my identity, my health. PMID- 21310997 TI - Genome-sequencing anniversary. The landscape of human evolution. PMID- 21310998 TI - Genome-sequencing anniversary. Personal genomes: for one and for all. PMID- 21310999 TI - Genome-sequencing anniversary. First steps on a long road. PMID- 21311000 TI - Genome-sequencing anniversary. An anniversary party. PMID- 21311001 TI - Genome-sequencing anniversary. What will drive genomics over the next 10 years? PMID- 21311002 TI - Dealing with data. Challenges and opportunities. Introduction. PMID- 21311003 TI - Rescue of old data offers lesson for particle physicists. PMID- 21311004 TI - Is there an astronomer in the house? PMID- 21311005 TI - May the best analyst win. PMID- 21311006 TI - Climate data challenges in the 21st century. AB - Climate data are dramatically increasing in volume and complexity, just as the users of these data in the scientific community and the public are rapidly increasing in number. A new paradigm of more open, user-friendly data access is needed to ensure that society can reduce vulnerability to climate variability and change, while at the same time exploiting opportunities that will occur. PMID- 21311007 TI - Challenges and opportunities of open data in ecology. AB - Ecology is a synthetic discipline benefiting from open access to data from the earth, life, and social sciences. Technological challenges exist, however, due to the dispersed and heterogeneous nature of these data. Standardization of methods and development of robust metadata can increase data access but are not sufficient. Reproducibility of analyses is also important, and executable workflows are addressing this issue by capturing data provenance. Sociological challenges, including inadequate rewards for sharing data, must also be resolved. The establishment of well-curated, federated data repositories will provide a means to preserve data while promoting attribution and acknowledgement of its use. PMID- 21311008 TI - Changing the equation on scientific data visualization. AB - An essential facet of the data deluge is the need for different types of users to apply visualizations to understand how data analyses and queries relate to each other. Unfortunately, visualization too often becomes an end product of scientific analysis, rather than an exploration tool that scientists can use throughout the research life cycle. However, new database technologies, coupled with emerging Web-based technologies, may hold the key to lowering the cost of visualization generation and allow it to become a more integral part of the scientific process. PMID- 21311009 TI - Challenges and opportunities in mining neuroscience data. AB - Understanding the brain requires a broad range of approaches and methods from the domains of biology, psychology, chemistry, physics, and mathematics. The fundamental challenge is to decipher the "neural choreography" associated with complex behaviors and functions, including thoughts, memories, actions, and emotions. This demands the acquisition and integration of vast amounts of data of many types, at multiple scales in time and in space. Here we discuss the need for neuroinformatics approaches to accelerate progress, using several illustrative examples. The nascent field of "connectomics" aims to comprehensively describe neuronal connectivity at either a macroscopic level (in long-distance pathways for the entire brain) or a microscopic level (among axons, dendrites, and synapses in a small brain region). The Neuroscience Information Framework (NIF) encompasses all of neuroscience and facilitates the integration of existing knowledge and databases of many types. These examples illustrate the opportunities and challenges of data mining across multiple tiers of neuroscience information and underscore the need for cultural and infrastructure changes if neuroinformatics is to fulfill its potential to advance our understanding of the brain. PMID- 21311010 TI - The disappearing third dimension. AB - Three-dimensional computing is driving what many would call a revolution in scientific visualization. However, its power and advancement are held back by the absence of sustainable archives for raw data and derivative visualizations. Funding agencies, professional societies, and publishers each have unfulfilled roles in archive design and data management policy. PMID- 21311011 TI - Advancing global health research through digital technology and sharing data. AB - The imperative for improving health in the world's poorest regions lies in research, yet there is no question that low participation, a lack of trained staff, and limited opportunities for data sharing in developing countries impede advances in medical practice and public health knowledge. Extensive studies are essential to develop new treatments and to identify better ways to manage healthcare issues. Recent rapid advances in availability and uptake of digital technologies, especially of mobile networks, have the potential to overcome several barriers to collaborative research in remote places with limited access to resources. Many research groups are already taking advantage of these technologies for data sharing and capture, and these initiatives indicate that increasing acceptance and use of digital technology could promote rapid improvements in global medical science. PMID- 21311012 TI - More is less: signal processing and the data deluge. AB - The data deluge is changing the operating environment of many sensing systems from data-poor to data-rich--so data-rich that we are in jeopardy of being overwhelmed. Managing and exploiting the data deluge require a reinvention of sensor system design and signal processing theory. The potential pay-offs are huge, as the resulting sensor systems will enable radically new information technologies and powerful new tools for scientific discovery. PMID- 21311013 TI - Ensuring the data-rich future of the social sciences. AB - Massive increases in the availability of informative social science data are making dramatic progress possible in analyzing, understanding, and addressing many major societal problems. Yet the same forces pose severe challenges to the scientific infrastructure supporting data sharing, data management, informatics, statistical methodology, and research ethics and policy, and these are collectively holding back progress. I address these changes and challenges and suggest what can be done. PMID- 21311014 TI - Metaknowledge. AB - The growth of electronic publication and informatics archives makes it possible to harvest vast quantities of knowledge about knowledge, or "metaknowledge." We review the expanding scope of metaknowledge research, which uncovers regularities in scientific claims and infers the beliefs, preferences, research tools, and strategies behind those regularities. Metaknowledge research also investigates the effect of knowledge context on content. Teams and collaboration networks, institutional prestige, and new technologies all shape the substance and direction of research. We argue that as metaknowledge grows in breadth and quality, it will enable researchers to reshape science-to identify areas in need of reexamination, reweight former certainties, and point out new paths that cut across revealed assumptions, heuristics, and disciplinary boundaries. PMID- 21311015 TI - Access to stem cells and data: persons, property rights, and scientific progress. AB - Many fields have struggled to develop strategies, policies, or structures to optimally manage data, materials, and intellectual property rights (IPRs). There is growing recognition that the field of stem cell science, in part because of its complex IPRs landscape and the importance of cell line collections, may require collective action to facilitate basic and translational research. Access to pluripotent stem cell lines and the information associated with them is critical to the progress of stem cell science, but simple notions of access are substantially complicated by shifting boundaries between what is considered information versus material, person versus artifact, and private property versus the public domain. PMID- 21311016 TI - On the future of genomic data. AB - Many of the challenges in genomics derive from the informatics needed to store and analyze the raw sequencing data that is available from highly multiplexed sequencing technologies. Because single week-long sequencing runs today can produce as much data as did entire genome centers a few years ago, the need to process terabytes of information has become de rigueur for many labs engaged in genomic research. The availability of deep (and large) genomic data sets raises concerns over information access, data security, and subject/patient privacy that must be addressed for the field to continue its rapid advances. PMID- 21311017 TI - Negative linear compressibility and massive anisotropic thermal expansion in methanol monohydrate. AB - The vast majority of materials shrink in all directions when hydrostatically compressed; exceptions include certain metallic or polymer foam structures, which may exhibit negative linear compressibility (NLC) (that is, they expand in one or more directions under hydrostatic compression). Materials that exhibit this property at the molecular level--crystalline solids with intrinsic NLC--are extremely uncommon. With the use of neutron powder diffraction, we have discovered and characterized both NLC and extremely anisotropic thermal expansion, including negative thermal expansion (NTE) along the NLC axis, in a simple molecular crystal (the deuterated 1:1 compound of methanol and water). Apically linked rhombuses, which are formed by the bridging of hydroxyl-water chains with methyl groups, extend along the axis of NLC/NTE and lead to the observed behavior. PMID- 21311018 TI - Complete fourth metatarsal and arches in the foot of Australopithecus afarensis. AB - The transition to full-time terrestrial bipedality is a hallmark of human evolution. A key correlate of human bipedalism is the development of longitudinal and transverse arches of the foot that provide a rigid propulsive lever and critical shock absorption during striding bipedal gait. Evidence for arches in the earliest well-known Australopithecus species, A. afarensis, has long been debated. A complete fourth metatarsal of A. afarensis was recently discovered at Hadar, Ethiopia. It exhibits torsion of the head relative to the base, a direct correlate of a transverse arch in humans. The orientation of the proximal and distal ends of the bone reflects a longitudinal arch. Further, the deep, flat base and tarsal facets imply that its midfoot had no ape-like midtarsal break. These features show that the A. afarensis foot was functionally like that of modern humans and support the hypothesis that this species was a committed terrestrial biped. PMID- 21311019 TI - Embryological evidence identifies wing digits in birds as digits 1, 2, and 3. AB - The identities of the digits of the avian forelimb are disputed. Whereas paleontological findings support the position that the digits correspond to digits one, two, and three, embryological evidence points to digit two, three, and four identities. By using transplantation and cell-labeling experiments, we found that the posteriormost digit in the wing does not correspond to digit four in the hindlimb; its progenitor segregates early from the zone of polarizing activity, placing it in the domain of digit three specification. We suggest that an avian-specific shift uncouples the digit anlagen from the molecular mechanisms that pattern them, resulting in the imposition of digit one, two, and three identities on the second, third, and fourth anlagens. PMID- 21311020 TI - Structure of MyTH4-FERM domains in myosin VIIa tail bound to cargo. AB - The unconventional myosin VIIa (MYO7A) is one of the five proteins that form a network of complexes involved in formation of stereocilia. Defects in these proteins cause syndromic deaf-blindness in humans [Usher syndrome I (USH1)]. Many disease-causing mutations occur in myosin tail homology 4-protein 4.1, ezrin, radixin, moesin (MyTH4-FERM) domains in the myosin tail that binds to another USH1 protein, Sans. We report the crystal structure of MYO7A MyTH4-FERM domains in complex with the central domain (CEN) of Sans at 2.8 angstrom resolution. The MyTH4 and FERM domains form an integral structural and functional supramodule binding to two highly conserved segments (CEN1 and 2) of Sans. The MyTH4-FERM/CEN complex structure provides mechanistic explanations for known deafness-causing mutations in MYO7A MyTH4-FERM. The structure will also facilitate mechanistic and functional studies of MyTH4-FERM domains in other myosins. PMID- 21311021 TI - HSPC117 is the essential subunit of a human tRNA splicing ligase complex. AB - Splicing of mammalian precursor transfer RNA (tRNA) molecules involves two enzymatic steps. First, intron removal by the tRNA splicing endonuclease generates separate 5' and 3' exons. In animals, the second step predominantly entails direct exon ligation by an elusive RNA ligase. Using activity-guided purification of tRNA ligase from HeLa cell extracts, we identified HSPC117, a member of the UPF0027 (RtcB) family, as the essential subunit of a tRNA ligase complex. RNA interference-mediated depletion of HSPC117 inhibited maturation of intron-containing pre-tRNA both in vitro and in living cells. The high sequence conservation of HSPC117/RtcB proteins is suggestive of RNA ligase roles of this protein family in various organisms. PMID- 21311022 TI - K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. AB - Endocrine tumors such as aldosterone-producing adrenal adenomas (APAs), a cause of severe hypertension, feature constitutive hormone production and unrestrained cell proliferation; the mechanisms linking these events are unknown. We identify two recurrent somatic mutations in and near the selectivity filter of the potassium (K(+)) channel KCNJ5 that are present in 8 of 22 human APAs studied. Both produce increased sodium (Na(+)) conductance and cell depolarization, which in adrenal glomerulosa cells produces calcium (Ca(2+)) entry, the signal for aldosterone production and cell proliferation. Similarly, we identify an inherited KCNJ5 mutation that produces increased Na(+) conductance in a Mendelian form of severe aldosteronism and massive bilateral adrenal hyperplasia. These findings explain pathogenesis in a subset of patients with severe hypertension and implicate loss of K(+) channel selectivity in constitutive cell proliferation and hormone production. PMID- 21311023 TI - Leishmania RNA virus controls the severity of mucocutaneous leishmaniasis. AB - Mucocutaneous leishmaniasis is caused by infections with intracellular parasites of the Leishmania Viannia subgenus, including Leishmania guyanensis. The pathology develops after parasite dissemination to nasopharyngeal tissues, where destructive metastatic lesions form with chronic inflammation. Currently, the mechanisms involved in lesion development are poorly understood. Here we show that metastasizing parasites have a high Leishmania RNA virus-1 (LRV1) burden that is recognized by the host Toll-like receptor 3 (TLR3) to induce proinflammatory cytokines and chemokines. Paradoxically, these TLR3-mediated immune responses rendered mice more susceptible to infection, and the animals developed an increased footpad swelling and parasitemia. Thus, LRV1 in the metastasizing parasites subverted the host immune response to Leishmania and promoted parasite persistence. PMID- 21311024 TI - Posttranslational modification of pili upon cell contact triggers N. meningitidis dissemination. AB - The Gram-negative bacterium Neisseria meningitidis asymptomatically colonizes the throat of 10 to 30% of the human population, but throat colonization can also act as the port of entry to the blood (septicemia) and then the brain (meningitis). Colonization is mediated by filamentous organelles referred to as type IV pili, which allow the formation of bacterial aggregates associated with host cells. We found that proliferation of N. meningitidis in contact with host cells increased the transcription of a bacterial gene encoding a transferase that adds phosphoglycerol onto type IV pili. This unusual posttranslational modification specifically released type IV pili-dependent contacts between bacteria. In turn, this regulated detachment process allowed propagation of the bacterium to new colonization sites and also migration across the epithelium, a prerequisite for dissemination and invasive disease. PMID- 21311025 TI - A new role for the extracellular calcium-sensing receptor demonstrated by using CCK-eGFP BAC mice. PMID- 21311026 TI - Protein hydrolysate-induced cholecystokinin secretion from enteroendocrine cells is indirectly mediated by the intestinal oligopeptide transporter PepT1. AB - Dietary protein is a major stimulant for cholecystokinin (CCK) secretion by the intestinal I cell, however, the mechanism by which protein is detected is unknown. Indirect functional evidence suggests that PepT1 may play a role in CCK mediated changes in gastric motor function. However, it is unclear whether this oligopeptide transporter directly or indirectly activates the I cell. Using both the CCK-expressing enteroendocrine STC-1 cell and acutely isolated native I cells from CCK-enhanced green fluorescent protein (eGFP) mice, we aimed to determine whether PepT1 directly activates the enteroendocrine cell to elicit CCK secretion in response to oligopeptides. Both STC-1 cells and isolated CCK-eGFP cells expressed PepT1 transcripts. STC-1 cells were activated, as measured by ERK(1/2) phosphorylation, by both peptone and the PepT1 substrate Cefaclor; however, the PepT1 inhibitor 4-aminomethyl benzoic acid (AMBA) had no effect on STC-1 cell activity. The PepT1-transportable substrate glycyl-sarcosine dose-dependently decreased gastric motility in anesthetized rats but had no affect on activation of STC-1 cells or on CCK secretion by CCK-eGFP cells. CCK secretion was significantly increased in response to peptone but not to Cefaclor, cephalexin, or Phe-Ala in CCK-eGFP cells. Taken together, the data suggest that PepT1 does not directly mediate CCK secretion in response to PepT1 specific substrates. PepT1, instead, may have an indirect role in protein sensing in the intestine. PMID- 21311027 TI - Proliferation modulates intestinal smooth muscle phenotype in vitro and in colitis in vivo. AB - Intestinal inflammation causes an increased intestinal wall thickness, in part, due to the proliferation of smooth muscle cells, which impairs the contractile phenotype elsewhere. To study this, cells from the circular muscle layer of the rat colon (CSMC) were isolated and studied, both in primary culture and after extended passage, using quantitative PCR, Western blot analysis, and immunocytochemistry. By 4 days in vitro, both mRNA and protein for the smooth muscle marker proteins alpha-smooth muscle actin, desmin, and SM22-alpha were reduced by >50%, and mRNA for cyclin D1 was increased threefold, evidence for modulation to a proliferative phenotype. Continued growth caused significant further decrease in expression, evidence that phenotypic loss in CSMC was proportional to the extent of proliferation. In CSMC isolated at day 2 of trinitrobenzene sulfonic acid-induced colitis, flow cytometry and Western blotting showed that these differentiated markers were reduced in mitotic CSMC, while similar to control in nonmitotic CSMC. By day 35 post-trinitrobenzene sulfonic acid, when inflammation has resolved, CSMC were hypertrophic, but, nonetheless, showed markedly decreased expression of smooth muscle protein markers per cell. In vitro, day 35 CSMC displayed an accelerated loss of phenotype and increased thymidine uptake in response to serum or PDGF-BB. Furthermore, carbachol-induced expression of phospho-AKT (a marker of cholinergic response) was lost from day 35 CSMC in vitro, while retained in control cells. Therefore, proliferation reduces the expression of smooth-muscle-specific markers in CSMC, possibly leading to altered contractility. However, inflammation-induced proliferation in vivo also causes lasting changes that include unexpected priming for an exaggerated response to proliferative stimuli. Identification of the molecular mechanisms of intestinal smooth muscle cell phenotypic modulation will be helpful in reducing the detrimental effects of inflammation. PMID- 21311028 TI - The functional -374T/A polymorphism of the receptor for advanced glycation end products may modulate Crohn's disease. AB - The receptor for advanced glycation end products (RAGE) is involved in innate immune mechanisms. Polymorphisms of the RAGE gene have been described as a factor amplifying inflammation in susceptible patients, but the association with Crohn's disease (CD) is not known. The coding RAGE polymorphism G82S (rs2070600) and two promoter polymorphisms, -374T/A (rs1800624) and -429T/C (rs1800625), were studied in two samples from Germany and the United States consisting of 421 and 317 CD patients and 549 and 218 controls, respectively. To test the functional relevance, additional data on serum soluble RAGE (sRAGE), tissue RNA, and protein levels were collected and immunohistochemical stainings of bowel tissue of CD patients and healthy controls as well as models of experimental (dextran sodium sulfate-induced) colitis in RAGE knockout and wild-type mice were performed. The 374T/A RAGE promotor single nucleotide polymorphism (SNP) was negatively associated with CD (odds ratio = 0.708, 95% confidence interval = 0.535-0.938, P = 0.016) and with stenosis (OR = 0.627, P = 0.04) in the German sample. Transmission disequilibrium testing confirmed an undertransmission of the -374A allele. Serum sRAGE levels were higher in patients in complete remission of the 374AA/TA group (1,975 +/- 299 pg/ml; -374TT group: 1,310 +/- 153 pg/ml SE, P < 0.05) and showed a trend toward decreased levels in CD patients with active disease compared with CD patients in remission. Further in vitro and in vivo studies indicated that an increase of sRAGE ameliorates inflammation. The -429T/C and the G82S polymorphism were not associated with CD. The -374T/A RAGE polymorphism leading to facilitated RAGE gene transcription may to some degree protect from developing a stricturing subphenotype of CD, most likely by increasing levels of sRAGE, which neutralizes proinflammatory mediators. PMID- 21311029 TI - SPARC downregulation attenuates the profibrogenic response of hepatic stellate cells induced by TGF-beta1 and PDGF. AB - Liver fibrosis is an active process that involves changes in cell-cell and cell extracellular matrix (ECM) interaction. Secreted protein, acidic and rich in cysteine (SPARC) is an ECM protein with many biological functions that is overexpressed in cirrhotic livers and upregulated in activated hepatic stellate cells (aHSCs). We have recently shown that SPARC downregulation ameliorates liver fibrosis in vivo. To uncover the cellular mechanisms involved, we have specifically knocked down SPARC in two aHSC lines [the CFSC-2G (rat) and the LX-2 (human)] and in primary cultured rat aHSCs. Transient downregulation of SPARC in hepatic stellate cells (HSCs) did not affect their proliferation and had only minor effects on apoptosis. However, SPARC knockdown increased HSC adhesion to fibronectin and significantly decreased their migration toward PDFG-BB and TGF beta(1). Interestingly, TGF-beta(1) secretion by HSCs was reduced following SPARC small interfering RNA (siRNA) treatment, and preincubation with TGF-beta(1) restored the migratory capacity of SPARC siRNA-treated cells through mechanisms partially independent from TGF-beta(1)-mediated induction of SPARC expression; thus SPARC knockdown seems to exert its effects on HSCs partially through modulation of TGF-beta(1) expression levels. Importantly, collagen-I mRNA expression was reduced in SPARC siRNA-transfected HSCs. Consistent with previous results, SPARC knockdown in aHSCs was associated with altered F-actin expression patterns and deregulation of key ECM and cell adhesion molecules, i.e., downregulation of N-cadherin and upregulation of E-cadherin. Our data together suggest that the upregulation of SPARC previously reported for aHSCs partially mediates profibrogenic activities of TGF-beta(1) and PDGF-BB and identify SPARC as a potential therapeutic target for liver fibrosis. PMID- 21311030 TI - Lysine acetylation is a widespread protein modification for diverse proteins in Arabidopsis. AB - Lysine acetylation (LysAc), a form of reversible protein posttranslational modification previously known only for histone regulation in plants, is shown to be widespread in Arabidopsis (Arabidopsis thaliana). Sixty-four Lys modification sites were identified on 57 proteins, which operate in a wide variety of pathways/processes and are located in various cellular compartments. A number of photosynthesis-related proteins are among this group of LysAc proteins, including photosystem II (PSII) subunits, light-harvesting chlorophyll a/b-binding proteins (LHCb), Rubisco large and small subunits, and chloroplastic ATP synthase (beta subunit). Using two-dimensional native green/sodium dodecyl sulfate gels, the loosely PSII-bound LHCb was separated from the LHCb that is tightly bound to PSII and shown to have substantially higher level of LysAc, implying that LysAc may play a role in distributing the LHCb complexes. Several potential LysAc sites were identified on eukaryotic elongation factor-1A (eEF-1A) by liquid chromatography/mass spectrometry and using sequence- and modification-specific antibodies the acetylation of Lys-227 and Lys-306 was established. Lys-306 is contained within a predicted calmodulin-binding sequence and acetylation of Lys 306 strongly inhibited the interactions of eEF-1A synthetic peptides with calmodulin recombinant proteins in vitro. These results suggest that LysAc of eEF 1A may directly affect regulatory properties and localization of the protein within the cell. Overall, these findings reveal the possibility that reversible LysAc may be an important and previously unknown regulatory mechanism of a large number of nonhistone proteins affecting a wide range of pathways and processes in Arabidopsis and likely in all plants. PMID- 21311031 TI - Proteins of diverse function and subcellular location are lysine acetylated in Arabidopsis. AB - Acetylation of the epsilon-amino group of lysine (Lys) is a reversible posttranslational modification recently discovered to be widespread, occurring on proteins outside the nucleus, in most subcellular locations in mammalian cells. Almost nothing is known about this modification in plants beyond the well-studied acetylation of histone proteins in the nucleus. Here, we report that Lys acetylation in plants also occurs on organellar and cytosolic proteins. We identified 91 Lys-acetylated sites on 74 proteins of diverse functional classes. Furthermore, our study suggests that Lys acetylation may be an important posttranslational modification in the chloroplast, since four Calvin cycle enzymes were acetylated. The plastid-encoded large subunit of Rubisco stands out because of the large number of acetylated sites occurring at important Lys residues that are involved in Rubisco tertiary structure formation and catalytic function. Using the human recombinant deacetylase sirtuin 3, it was demonstrated that Lys deacetylation significantly affects Rubisco activity as well as the activities of other central metabolic enzymes, such as the Calvin cycle enzyme phosphoglycerate kinase, the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase, and the tricarboxylic acid cycle enzyme malate dehydrogenase. Our results demonstrate that Lys acetylation also occurs on proteins outside the nucleus in Arabidopsis (Arabidopsis thaliana) and that Lys acetylation could be important in the regulation of key metabolic enzymes. PMID- 21311032 TI - Mechanism of plastid division: from a bacterium to an organelle. PMID- 21311033 TI - Detailed quantitative analysis of architectural traits of basal roots of young seedlings of bean in response to auxin and ethylene. AB - Vertical placement of roots within the soil determines their efficiency of acquisition of heterogeneous belowground resources. This study quantifies the architectural traits of seedling basal roots of bean (Phaseolus vulgaris), and shows that the distribution of root tips at different depths results from a combined effect of both basal root growth angle (BRGA) and root length. Based on emergence locations, the basal roots are classified in three zones, upper, middle, and lower, with each zone having distinct architectural traits. The genotypes characterized as shallow on BRGA alone produced basal roots with higher BRGA, greater length, and more vertically distributed roots than deep genotypes, thereby establishing root depth as a robust measure of root architecture. Although endogenous indole-3-acetic acid (IAA) levels were similar in all genotypes, IAA and 1-N-naphthylphthalamic acid treatments showed different root growth responses to auxin because shallow and deep genotypes tended to have optimal and supraoptimal auxin levels, respectively, for root growth in controls. While IAA increased ethylene production, ethylene also increased IAA content. Although differences in acropetal IAA transport to roots of different zones can account for some of the differences in auxin responsiveness among roots of different emergence positions, this study shows that mutually dependent ethylene auxin interplay regulates BRGA and root growth differently in different genotypes. Root length inhibition by auxin was reversed by an ethylene synthesis inhibitor. However, IAA caused smaller BRGA in deep genotypes, but not in shallow genotypes, which only responded to IAA in the presence of an ethylene inhibitor. PMID- 21311035 TI - Interconnection between methyl salicylate and lipid-based long-distance signaling during the development of systemic acquired resistance in Arabidopsis and tobacco. PMID- 21311034 TI - Proline dehydrogenase contributes to pathogen defense in Arabidopsis. AB - L-proline (Pro) catabolism is activated in plants recovering from abiotic stresses associated with water deprivation. In this catabolic pathway, Pro is converted to glutamate by two reactions catalyzed by proline dehydrogenase (ProDH) and Delta(1)-pyrroline-5-carboxylate dehydrogenase (P5CDH), with Delta(1) pyrroline-5-carboxylate (P5C) as the intermediate. Alternatively, under certain conditions, the P5C derived from Pro is converted back to Pro by P5C reductase, thus stimulating the Pro-P5C cycle, which may generate reactive oxygen species (ROS) as a consequence of the ProDH activity. We previously observed that Pro biosynthesis is altered in Arabidopsis (Arabidopsis thaliana) tissues that induce the hypersensitive response (HR) in response to Pseudomonas syringae. In this work, we characterized the Pro catabolic pathway and ProDH activity in this model. Induction of ProDH expression was found to be dependent on salicylic acid, and an increase in ProDH activity was detected in cells destined to die. To evaluate the role of ProDH in the HR, ProDH-silenced plants were generated. These plants displayed reduced ROS and cell death levels as well as enhanced susceptibility in response to avirulent pathogens. Interestingly, the early activation of ProDH was accompanied by an increase in P5C reductase but not in P5CDH transcripts, with few changes occurring in the Pro and P5C levels. Therefore, our results suggest that in wild-type plants, ProDH is a defense component contributing to HR and disease resistance, which apparently potentiates the accumulation of ROS. The participation of the Pro-P5C cycle in the latter response is discussed. PMID- 21311036 TI - Oleic acid prevents detrimental effects of saturated fatty acids on bovine oocyte developmental competence. AB - Mobilization of fatty acids from adipose tissue during metabolic stress will increase the amount of free fatty acids in blood and follicular fluid and, thus, may affect oocyte quality. In this in vitro study, the three predominant fatty acids in follicular fluid (saturated palmitic and stearic acid and unsaturated oleic acid) were presented to maturing oocytes to test whether fatty acids can affect lipid storage of the oocyte and developmental competence postfertilization. Palmitic and stearic acid had a dose-dependent inhibitory effect on the amount of fat stored in lipid droplets and a concomitant detrimental effect on oocyte developmental competence. Oleic acid, in contrast, had the opposite effect, causing an increase of lipid storage in lipid droplets and an improvement of oocyte developmental competence. Remarkably, the adverse effects of palmitic and stearic acid could be counteracted by oleic acid. These results suggest that the ratio and amount of saturated and unsaturated fatty acid is relevant for lipid storage in the maturing oocyte and that this relates to the developmental competence of maturing oocytes. PMID- 21311037 TI - Testicular lumicrine factors regulate ERK, STAT, and NFKB pathways in the initial segment of the rat epididymis to prevent apoptosis. AB - The initial segment of the epididymis is vital for male fertility; therefore, it is important to understand the mechanisms that regulate this important region. Deprival of testicular luminal fluid factors/lumicrine factors from the epididymis results in a wave of apoptosis in the initial segment. In this study, a combination of protein array and microarray analyses was used to examine the early changes in downstream signal transduction pathways following loss of lumicrine factors. We discovered the following cascade of events leading to the loss of protection and eventual apoptosis: in the first 6 h after loss of lumicrine factors, down-regulation of the ERK pathway components was observed at the mRNA expression and protein activity levels. Microarray analysis revealed that mRNA levels of several key components of the ERK pathway, Dusp6, Dusp5, and Etv5, decreased sharply, while the analysis from the protein array revealed a decline in the activities of MAP2K1/2 and MAPK1. Immunostaining of phospho MAPK3/1 indicated that down-regulation of the ERK pathway was specific to the epithelial cells of the initial segment. Subsequently, after 12 h of loss of lumicrine factors, levels of mRNA expression of STAT and NFKB pathway components increased, mRNA levels of several genes encoding cell cycle inhibitors increased, and levels of protein expression of several proapoptotic phosphatases increased. Finally, after 18 h of loss of protection from lumicrine factors, apoptosis was observed. In conclusion, testicular lumicrine factors protect the cells of the initial segment by activating the ERK pathway, repressing STAT and NFKB pathways, and thereby preventing apoptosis. PMID- 21311038 TI - Complex networks govern coiled-coil oligomerization--predicting and profiling by means of a machine learning approach. AB - Understanding the relationship between protein sequence and structure is one of the great challenges in biology. In the case of the ubiquitous coiled-coil motif, structure and occurrence have been described in extensive detail, but there is a lack of insight into the rules that govern oligomerization, i.e. how many alpha helices form a given coiled coil. To shed new light on the formation of two- and three-stranded coiled coils, we developed a machine learning approach to identify rules in the form of weighted amino acid patterns. These rules form the basis of our classification tool, PrOCoil, which also visualizes the contribution of each individual amino acid to the overall oligomeric tendency of a given coiled-coil sequence. We discovered that sequence positions previously thought irrelevant to direct coiled-coil interaction have an undeniable impact on stoichiometry. Our rules also demystify the oligomerization behavior of the yeast transcription factor GCN4, which can now be described as a hybrid--part dimer and part trimer- with both theoretical and experimental justification. PMID- 21311039 TI - Evidence that chromium modulates cellular cholesterol homeostasis and ABCA1 functionality impaired by hyperinsulinemia--brief report. AB - OBJECTIVE: Trivalent chromium (Cr3+) is an essential micronutrient. Findings since the 1950s suggest that Cr3+ might benefit cholesterol homeostasis. Here we present mechanistic evidence in support of this role of Cr3+. METHODS AND RESULTS: High-density lipoprotein cholesterol generation in 3T3-L1 adipocytes, which are rendered ineffective by the hyperinsulinemia that is known to accompany disorders of lipid metabolism, was corrected by Cr3+. Mechanistically, Cr3+ reversed hyperinsulinemia-induced cellular cholesterol accrual and associated defects in cholesterol transporter ATP-binding cassette transporter-A1 trafficking and apolipoprotein A1-mediated cholesterol efflux. Moreover, direct activation of AMP-activated protein kinase, which is known to be activated by Cr3+, or inhibition of hexosamine biosynthesis pathway activity, which is known to be elevated by hyperinsulinemia, mimics Cr3+ action. CONCLUSIONS: These findings suggest a mechanism of Cr3+ action that fits with long-standing claims of its role in cholesterol homeostasis. Furthermore, these data imply a mechanistic basis for the coexistence of dyslipidemia with hyperinsulinemia. PMID- 21311040 TI - Roles of prostaglandin E2-EP3/EP4 receptor signaling in the enhancement of lymphangiogenesis during fibroblast growth factor-2-induced granulation formation. AB - OBJECTIVE: One of the hallmarks of inflammation is lymphangiogesis that drains the interstitial fluids. During chronic inflammation, angiogenesis is induced by a variety of inflammatory mediators, such as prostaglandins (PGs). However, it remains unknown whether they enhance lymphangiogenesis. We examined the roles of cyclooxygenase-2 (COX-2) and PGE2 receptor signaling in enhancement of lymphangiogenesis during proliferative inflammation. METHODS AND RESULTS: Lymphangiogenesis estimated by podoplanin/vascular endothelial growth factor (VEGF) receptor-3/LYVE-1 expression was upregulated during proliferative inflammation seen around and into subcutaneous Matrigel plugs containing fibroblast growth factor-2 (125 ng/site). A COX-2 inhibitor (celecoxib) significantly reduced lymphangiogenesis in a dose-dependent manner, whereas topical PGE2 enhanced lymphangiogenesis. Topical injection of fluorescein isothiocyanate-dextran into the Matrigel revealed that lymphatic flow from the Matrigels was COX-2 dependent. Lymphangiogenesis was suppressed in the granulation tissues of mice lacking either EP3 or EP4, suggesting that these molecules are receptors in response to endogenous PGE2. An EP3-selective agonist (ONO-AE-248) increased the expression of VEGF-C and VEGF-D in cultured macrophages, whereas an EP4-selective agonist (ONO-AE1-329) increased VEGF-C expression in cultured macrophages and increased VEGF-D expression in cultured fibroblasts. CONCLUSIONS: Our findings suggest that COX-2 and EP3/EP4 signaling contributes to lymphangiogenesis in proliferative inflammation, possibly via induction of VEGF-C and VEGF-D, and may become a therapeutic target for controlling lymphangiogenesis. PMID- 21311041 TI - Insulin resistance and the relationship of a dyslipidemia to coronary heart disease: the Framingham Heart Study. AB - OBJECTIVE: The goal of this study was to examine the effect of insulin resistance (IR) in subjects without diabetes on the relationship of a dyslipidemia with high triglycerides and low high-density lipoprotein cholesterol (HDL-C) to the development of coronary heart disease (CHD). METHODS AND RESULTS: Lower and higher fasting plasma HDL-C and triglyceride concentrations (defined at the study population median) and presence or absence of IR (defined by upper quartile Homeostatic Model Assessment values) were related to the development of myocardial infarction or CHD death in Framingham Heart Study participants without diabetes or a history of CHD (n=2910) attending the 1991 to 1995 examination. During follow-up (mean, 14 years), 128 participants experienced an incident CHD event. With Kaplan-Meier plots, the incidence of CHD was significantly greater with than without IR at either the lowest HDL-C or the highest triglycerides (P<0.001). In multivariable Cox models adjusted for major CHD risk factors, including waist circumference, only subgroups with IR had a significantly higher incidence of CHD. Compared with a reference group without IR and with higher-than median HDL-C or lower-than-median triglycerides, the hazard ratio (HR) for incident events was significant with only IR and a lower HDL-C (HR 2.83, P<0.001) or higher triglycerides (HR 2.50, P<0.001). These findings were similar in men and women. CONCLUSIONS: In this community-based sample exclusive of diabetes, incident CHD risk associated with plasma HDL-C or triglycerides was significantly increased only in the presence of IR. PMID- 21311042 TI - Pivotal role of protein kinase Cdelta in angiotensin II-induced endothelial cyclooxygenase-2 expression: a link to vascular inflammation. AB - OBJECTIVE: The purpose of this study was to examine the hypothesis that angiotensin II (Ang II) induced endothelial cyclooxygenase-2 (COX-2) expression, which in turn mediated the generation of proinflammatory cytokines. METHODS AND RESULTS: Western blot analysis on primary rat endothelial cells showed Ang II induced COX-2 expression, which was abolished by cotreatment of p38 mitogen activated protein kinase (SB 202190) and extracellular signal-regulated kinase 1/2 (PD 98059) inhibitors. Protein kinase Cdelta (PKCdelta) inhibitor (rottlerin) prevented extracellular signal-regulated kinase 1/2 phosphorylation and COX-2 expression. The pivotal role of PKCdelta was further supported by a similar stimulatory effect of the PKC activator on COX-2 expression, signified by Ang II stimulated translocation of PKCdelta to the plasma membrane, and confirmed by PKCdelta phosphorylation at Tyr311. Small interfering RNA targeting PKCdelta diminished COX-2 expression, which was further abrogated by SB 202190. Human mesenteric arteries incubated with Ang II showed increased levels of endothelial COX-2 and monocyte chemoattractant protein-1; the former was inhibited by SB 202190 plus rottlerin, whereas the latter was prevented by COX-2 inhibitor. CONCLUSIONS: The present study pinpoints a novel role of PKCdelta in Ang II induced endothelial COX-2 upregulation and identifies a COX-2-dependent proatherosclerotic cytokine monocyte chemoattractant protein-1. The findings raise the possibility of curtailing endothelial COX-2 expression as a means of limiting or preventing vascular inflammation. PMID- 21311043 TI - Ablation of the leptin receptor in the hypothalamic arcuate nucleus abrogates leptin-induced sympathetic activation. AB - RATIONALE: The hypothalamic arcuate nucleus (ARC) is considered a major site for leptin signaling that regulates several physiological processes. OBJECTIVE: To test the hypothesis that leptin receptor in the ARC is required to mediate leptin induced sympathetic activation. METHODS AND RESULTS: First, we used the ROSA Cre reporter mice to establish the feasibility of driving Cre expression in the ARC in a controlled manner with bilateral microinjection of adenovirus-expressing Cre recombinase (Ad-Cre). Ad-Cre microinjection into the ARC of ObR(flox/flox) mice robustly reduced ObR expression and leptin-induced Stat3 activation in the ARC but not in the adjacent nuclei, confirming the efficacy and selectivity of the ARC deletion of ObR. Critically, deletion of ObR in the ARC attenuated brown adipose tissue and renal sympathetic nerve responses to leptin. We also examined whether ObR in the ARC is required for the preserved leptin-induced increase in renal sympathetic activity in dietary obesity. We found that deletion of ARC ObR abrogated leptin-induced increases in renal sympathetic discharge and resolved arterial pressure elevation in diet-induced obese ObR(flox/flox) mice. CONCLUSIONS: These data demonstrate a critical role for ObR in the ARC in mediating the sympathetic nerve responses to leptin and in the adverse sympathoexcitatory effects of leptin in obesity. PMID- 21311044 TI - Dynamic calcium movement inside cardiac sarcoplasmic reticulum during release. AB - RATIONALE: Intra-sarcoplasmic reticulum (SR) free [Ca] ([Ca](SR)) provides the driving force for SR Ca release and is a key regulator of SR Ca release channel gating during normal SR Ca release or arrhythmogenic spontaneous Ca release events. However, little is known about [Ca](SR) spatiotemporal dynamics. OBJECTIVE: To directly measure local [Ca](SR) with subsarcomeric spatiotemporal resolution during both normal global SR Ca release and spontaneous Ca sparks and to evaluate the quantitative implications of spatial [Ca](SR) gradients. METHODS AND RESULTS: Intact and permeabilized rabbit ventricular myocytes were subjected to direct simultaneous measurement of cytosolic [Ca] and [Ca](SR) and FRAP (fluorescence recovery after photobleach). We found no detectable [Ca](SR) gradients between SR release sites (junctional SR) and Ca uptake sites (free SR) during normal global Ca release, clear spatiotemporal [Ca](SR) gradients during isolated Ca blinks, faster intra-SR diffusion in the longitudinal versus transverse direction, 3- to 4-fold slower diffusion of fluorophores in the SR than in cytosol, and that intra-SR Ca diffusion varies locally, dependent on local SR connectivity. A computational model clarified why spatiotemporal gradients are more detectable in isolated local releases versus global releases and provides a quantitative framework for understanding intra-SR Ca diffusion. CONCLUSIONS: Intra-SR Ca diffusion is rapid, limiting spatial [Ca](SR) gradients during excitation-contraction coupling. Spatiotemporal [Ca](SR) gradients are apparent during Ca sparks, and these observations constrain models of dynamic Ca movement inside the SR. This has important implications for myocyte SR Ca handling, synchrony, and potentially arrhythmogenic spontaneous contraction. PMID- 21311046 TI - Differential Notch signaling in the epicardium is required for cardiac inflow development and coronary vessel morphogenesis. AB - RATIONALE: The proepicardium is a transient structure comprising epicardial progenitor cells located at the posterior limit of the embryonic cardiac inflow. A network of signals regulates proepicardial cell fate and defines myocardial and nonmyocardial domains at the venous pole of the heart. During cardiac development, epicardial-derived cells also contribute to coronary vessel morphogenesis. OBJECTIVE: To study Notch function during proepicardium development and coronary vessel formation in the mouse. METHODS AND RESULTS: Using in situ hybridization, RT-PCR, and immunohistochemistry, we find that Notch pathway elements are differentially activated throughout the proepicardial epicardial-coronary transition. Analysis of RBPJk-targeted embryos indicates that Notch ablation causes ectopic procardiogenic signaling in the proepicardium that in turn promotes myocardial differentiation in adjacent mesodermal progenitors, resulting in a premature muscularization of the sinus venosus horns. Epicardium specific Notch1 ablation using a Wt1-Cre driver line disrupts coronary artery differentiation, reduces myocardium wall thickness and myocyte proliferation, and reduces Raldh2 expression. Ectopic Notch1 activation disrupts epicardium development and causes thinning of ventricular walls. CONCLUSIONS: Epicardial Notch modulates cell differentiation in the proepicardium and adjacent pericardial mesoderm. Notch1 is later required for arterial endothelium commitment and differentiation and for vessel wall maturation during coronary vessel development and myocardium growth. PMID- 21311045 TI - Mitochondrial oxidative stress mediates angiotensin II-induced cardiac hypertrophy and Galphaq overexpression-induced heart failure. AB - RATIONALE: Mitochondrial dysfunction has been implicated in several cardiovascular diseases; however, the roles of mitochondrial oxidative stress and DNA damage in hypertensive cardiomyopathy are not well understood. OBJECTIVE: We evaluated the contribution of mitochondrial reactive oxygen species (ROS) to cardiac hypertrophy and failure by using genetic mouse models overexpressing catalase targeted to mitochondria and to peroxisomes. METHODS AND RESULTS: Angiotensin II increases mitochondrial ROS in cardiomyocytes, concomitant with increased mitochondrial protein carbonyls, mitochondrial DNA deletions, increased autophagy and signaling for mitochondrial biogenesis in hearts of angiotensin II treated mice. The causal role of mitochondrial ROS in angiotensin II-induced cardiomyopathy is shown by the observation that mice that overexpress catalase targeted to mitochondria, but not mice that overexpress wild-type peroxisomal catalase, are resistant to cardiac hypertrophy, fibrosis and mitochondrial damage induced by angiotensin II, as well as heart failure induced by overexpression of Galphaq. Furthermore, primary damage to mitochondrial DNA, induced by zidovudine administration or homozygous mutation of mitochondrial polymerase gamma, is also shown to contribute directly to the development of cardiac hypertrophy, fibrosis and failure. CONCLUSIONS: These data indicate the critical role of mitochondrial ROS in cardiac hypertrophy and failure and support the potential use of mitochondrial-targeted antioxidants for prevention and treatment of hypertensive cardiomyopathy. PMID- 21311047 TI - Body mass index and the impact of a health promotion intervention on health services use and expenditures. AB - OBJECTIVE: To examine the effect of body mass index (BMI) on the impact of a health promotion intervention on health services use and expenditures among Medicare beneficiaries with disabilities. METHOD: We analyzed data from 452 Medicare beneficiaries who participated in a Medicare demonstration. The intervention included the following components: patient education, health promotion coaching, medication management, and physician care management. We performed the analysis by using generalized linear models (GLM) to examine the impact of BMI and the intervention on total health care expenditures. RESULTS: The intervention was cost neutral over the 2-year study period. Participants in the intervention group used less home health aide services (p = .03) and had fewer nursing home days (p = .05). The intervention appeared to have smaller effects on expenditures as BMI level increased. DISCUSSION: The findings suggest that a health promotion intervention may achieve better beneficiary outcomes without an increase in resource use in this Medicare population. PMID- 21311048 TI - Calling the doctor: a qualitative study of patient-initiated physician consultation among rural older adults. AB - OBJECTIVE: Guided by Leventhal's self-regulatory model and Cockerham's theory of health lifestyles, we explore two questions regarding physician consultation among elderly rural adults: What symptom characteristics prompt patient-initiated physician consultation? Do participants' accounts of responses to symptoms, including the decision to consult a physician, incorporate descriptions of change over time? METHOD: We analyze data from semistructured in-depth interviews with 62 older rural adults. RESULTS: Accounts of decisions to initiate contact with physicians support prior research. Some symptoms encouraged immediate consultation; others prompted periods of monitoring and lay management. Physicians were most often contacted if changes were new, unusually severe, persisted or worsened, or failed to respond to lay treatment. DISCUSSION: We characterize participants' responses to symptoms as bricolages to highlight their construction from available materials. Incorporating the integrating concept of bricolage and Cockerham's emphasis on both general dispositions and symptom specific responses represents an important extension of Leventhal's conceptualization of illness behavior, including patient-initiated physician consultation. PMID- 21311049 TI - Drinking patterns and the development of functional limitations in older adults: longitudinal analyses of the health and retirement survey. AB - OBJECTIVE: To examine whether consistent low-risk drinking is associated with lower risk of developing functional limitations among older adults. METHOD: Data were obtained from five waves of the Health and Retirement Study. Function was assessed by questions measuring four physical abilities and five instrumental activities of daily living. Five different drinking patterns were determined using data over two consecutive survey periods. RESULTS: Over the follow-up periods, 38.6% of older adults developed functional limitations. Consistent low risk drinkers had lower odds of developing functional limitations compared with consistent abstainers, and the effect of consistent low-risk drinking was greater among those aged 50 to 64 years compared with those aged >=65 years. Other drinking patterns were not associated with lower odds of incident functional limitation. DISCUSSION: Consistent low-risk drinking was associated with lower odds of developing functional limitations, and this association was greater among older middle-aged adults aged 50 to 64 years. PMID- 21311050 TI - Combined strategy of mesenchymal stem cell injection with vascular endothelial growth factor gene therapy for the treatment of diabetes-associated erectile dysfunction. AB - This study was designed to investigate the effect of vascular endothelial growth factor 164 adenovirus (Ad-VEGF(164))-transfected mesenchymal stem cells (MSC) on improving erectile function in diabetic rats. Forty-five male Sprague-Dawley rats were injected with streptozotocin to develop type 1 diabetes, whereas 10 served as normal controls. Diabetic rats were randomly divided into 3 groups: rats that underwent intracavernous injection with phosphate-buffered saline (DM+PBS), unmodified MSCs (DM+MSC), and Ad-VEGF(164)-transfected MSCs (DM+VMSC). Normal controls received intracavernous injection of PBS. Four weeks after injection, erectile function was measured by cavernous nerve electrostimulation. Penile tissue was harvested for histology and enzyme-linked immunoassay. Prior to injection, high expression of VEGF was confirmed in Ad-VEGF(164)-transfected MSCs by enzyme-linked immunoassay. Four weeks after injection, the erectile function, as well as the content of smooth muscle and endothelium in corpus cavernosum increased significantly in the MSC-injected groups compared with the DM+PBS group. There was a significant improvement of erectile function, the content of smooth muscle and endothelium, and the VEGF concentration in the corpus cavernosum in the DM+VMSC group compared with the DM+MSC group. Our study validates the effect of intracavernous injection of MSCs for diabetes-associated erectile dysfunction in an animal model. The combined strategy of MSC injection with VEGF gene therapy-enhanced therapy of MSCs for the treatment of diabetes associated erectile dysfunction. PMID- 21311051 TI - Sellami H, Gdoura R, Mabrouk I, Frikha-Gargouri O, Keskes L, Mallek Z, Aouni M, Hammami A. A proposed mouse model to study male infertility provoked by genital serovar E, Chlamydia trachomatis. J Androl. 2011;32:86-94. PMID- 21311052 TI - Simultaneous accumulation of hyaluronan binding protein 1 (HABP1/p32/gC1qR) and apoptotic induction of germ cells in cryptorchid testis. AB - In the experimentally cryptorchid rat, spermatogenic arrest is associated with the formation of multinuclear giant cells, leading to large-scale apoptosis and elimination of germ cells from the seminiferous epithelium. Using this model, the role of Hyaluronan Binding Protein 1 (HABP1), which expresses a stage specifically in post-meiotic cells during spermatogenesis, was examined. Cryptorchidism induced complete arrest of spermatogenesis by 2 days, and by 3-5 days many large and small multinucleated giant cells populated the affected tubules. Ultrastructure of the giant cells revealed both single and multiple chromatin aggregation, with some less compact and distorted, and others broken down into tiny fragments. These cells along with other germ cells were stained terminal deoxynucleotidyl transferase dUTP nick-end labeling positive, demonstrating strong expression of Bax and Heat Shock Protein 70. Simultaneously, there was an up-regulation of the proprotein form of HABP1 in these cells and a decrease in the mature form of protein. The above findings indicate a possible role for HABP1 proprotein in apoptosis induction of germ cells in the cryptorchid testes. PMID- 21311054 TI - Transcranial magnetic stimulation at the interface with other techniques: a powerful tool for studying the human cortex. AB - Transcranial magnetic stimulation (TMS) has developed into a very powerful tool in the hands of basic and clinical neuroscientists alike to study function and dysfunction of the human brain noninvasively and painlessly. However, as a stand alone technique, the potential of TMS to gain knowledge is relatively limited. This potential can be strongly enhanced by combining TMS with simultaneous measurements in other electrophysiological (EEG) or imaging modalities (PET, fMRI, NIRS, MRS) or by combining TMS with exposure to neuroactive drugs (pharmaco TMS). This review provides an up-to-date synopsis of these combined approaches and highlights important examples that have advanced our understanding of how TMS interacts with neuronal networks in the human brain. PMID- 21311055 TI - Emergency department crowding and time to care in patients with acute stroke. AB - BACKGROUND AND PURPOSE: Emergency department (ED) crowding occurs when demands for ED care exceed the supply of available resources. Prior studies have shown that ED crowding is associated with a delay in provision of critical ED services, but the impact of ED crowding on acute stroke care has not been extensively studied. METHODS: We conducted a retrospective study of patients who presented to the ED with acute stroke symptoms (ischemic stroke, transient ischemic attack, intracerebral hemorrhage) at 2 hospitals. All patients with active stroke symptoms who presented within 3 hours were included and a random sample of patients with symptoms >3 hours was used for comparison. The association between ED crowding measures (waiting room number, ED occupancy, number of admitted patients, and total patient hours) and time to head CT order, completion, and interpretation, and time to administration of thrombolysis was determined. RESULTS: Of 253 patients presenting with acute stroke symptoms <=3 hours from symptom onset, 52 (21%) received thrombolysis. A random comparison group of 253 patients with symptoms >3 hours was identified. There was no significant association between ED crowding and delays in CT timing or thrombolysis in patients with symptoms <=3 hours. Several measures of ED crowding were associated with prolonged times to CT order and completion in patients with symptoms >3 hours. CONCLUSIONS: ED crowding was not associated with care delays in thrombolysis-eligible patients with stroke. However, those with symptoms >3 hours do experience CT delays at higher levels of ED crowding. PMID- 21311053 TI - Small changes, big impact: posttranslational modifications and function of huntingtin in Huntington disease. AB - Huntington disease (HD) is a neurodegenerative disorder caused by an elongated polyglutamine tract in huntingtin (htt). htt normally undergoes different posttranslational modifications (PTMs), including phosphorylation, SUMOylation, ubiquitination, acetylation, proteolytic cleavage, and palmitoylation. In the presence of the HD mutation, some PTMs are significantly altered and can result in changes in the clinical phenotype. A rate-limiting PTM is defined as one that can result in significant effects on the phenotype in animal models. For example, the prevention of proteolysis at D586 as well as constitutive phosphorylation at S13 and S16 can obviate the expression of phenotypic features of HD. The enzymes involved in these modifications such as caspase-6, the IkappaB kinase (IKK) complex, and still to be characterized phosphatases therefore represent promising therapeutic targets for HD. Identifying and testing specific modulators of PTMs now constitute the next big challenges in order to further validate these targets and proceed towards the goal of a mechanism-based treatment for HD. PMID- 21311056 TI - Cognitive context determines dorsal premotor cortical activity during hand movement in patients after stroke. AB - BACKGROUND AND PURPOSE: Stroke patients often have difficulties in simultaneously performing a motor and cognitive task. Functional imaging studies have shown that movement of an affected hand after stroke is associated with increased activity in multiple cortical areas, particularly in the contralesional hemisphere. We hypothesized patients for whom executing simple movements demands greater selective attention will show greater brain activity during movement. METHODS: Eight chronic stroke patients performed a behavioral interference test using a visuo-motor tracking with and without a simultaneous cognitive task. The magnitude of behavioral task decrement under cognitive motor interference (CMI) conditions was calculated for each subject. Functional MRI was used to assess brain activity in the same patients during performance of a visuo-motor tracking task alone; correlations between CMI score and movement-related brain activation were then explored. RESULTS: Movement-related activation in the dorsal precentral gyrus of the contralesional hemisphere correlated strongly and positively with CMI score (r(2) at peak voxel=0.92; P<0.05). Similar but weaker relationships were observed in the ventral precentral and middle frontal gyrus. There was no independent relationship between hand motor impairment and CMI. CONCLUSIONS: Results suggest that variations in the degree to which a cognitive task interferes with performance of a concurrent motor task explains a substantial proportion of the variations in movement-related brain activity in patients after stroke. The results emphasize the importance of considering cognitive context when interpreting brain activity patterns and provide a rationale for further evaluation of integrated cognitive and movement interventions for rehabilitation in stroke. PMID- 21311057 TI - Visual perfusion-diffusion mismatch is equivalent to quantitative mismatch. AB - BACKGROUND AND PURPOSE: The concept of stroke MRI mismatch based on qualitative evaluation of diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) has been applied in clinical practice for several years. The benefit of MRI in providing pathological evidence of ischemia before thrombolytic treatment has been demonstrated. The purpose of this study is to determine the reliability of the qualitative method and compare it with quantitative mismatch measurement in thrombolytic-treated patients. METHODS: Patients (n=70) were selected from the Lesion Evolution of Stroke and Ischemic On Neuroimaging (LESION) database if they: (1) were treated with intravenous recombinant tissue plasminogen activator; (2) had a pretreatment MRI with evaluable DWI and PWI; and (3) had acute ischemic lesion volume >10 mL on DWI as determined by core imaging laboratory measurements. Quantitative mismatch was defined as a difference of >50 mL between abnormal mean transit time and DWI volumes. Sample characteristics and postdischarge modified Rankin Scale for the positive mismatch patients were compared between the subgroups identified by qualitative versus quantitative methods. RESULTS: Patient characteristics and thrombolytic outcomes (sex, age, National Institutes of Health Stroke Scale, mismatch volume, and modified Rankin Scale) did not differ for mismatch patients identified by qualitative versus quantitative methods. Qualitative mismatch selection among neurologists had a high sensitivity (0.82), specificity (0.80), accuracy (0.81), and positive predictive value (0.88) compared with quantitative measurements. CONCLUSIONS: We observed that qualitative evaluation of mismatch identified the same thrombolytic treated patients compared with retrospective quantitative mismatch measurements. PMID- 21311058 TI - Age-dependent susceptibility to infarct growth in women. AB - BACKGROUND AND PURPOSE: It is not known if there is a relationship between gender and tissue outcome in human ischemic stroke. We sought to identify whether the proportion of initially ischemic to eventually infarcted tissue was different between men and women with ischemic stroke. METHODS: We studied 141 consecutive patients with acute ischemic stroke who had a baseline MRI obtained within 12 hours of symptom onset, a follow-up imaging on Day 4 or later, and diffusion weighted imaging/mean transmit time mismatch on initial MRI. Lesion growth was calculated as percentage of mismatch tissue that underwent infarction on follow up (percentage mismatch lost). Multivariable analyses explored the effect of gender and other predictors of tissue outcome on percentage mismatch lost. RESULTS: There was no difference in median percentage mismatch lost between men (19%) and women (11%; P=0.720). There was, however, an interaction between gender and age; median percentage mismatch lost was 7% (0% to 12%) in women and 18% (1% to 35%) in men younger than the population median (71 years, P=0.061). The percentage mismatch lost was not different between men and women >=71 years old (25% in both groups). The linear regression model revealed gender (P=0.027) and the interaction between age and gender (P=0.023) as independent predictors of percentage mismatch lost. CONCLUSIONS: There is an age-by-gender interaction in tissue outcome after ischemic stroke; brain infarcts in women <70 years grow approximately 50% less than infarcts in their male counterparts. These findings extend the well-known concept that there is a differential age-by-gender effect on stroke incidence, mortality, and functional outcome to the tissue level. PMID- 21311059 TI - Carotid plaque area and intima-media thickness in prediction of first-ever ischemic stroke: a 10-year follow-up of 6584 men and women: the Tromso Study. AB - BACKGROUND AND PURPOSE: Carotid plaque and intima-media thickness (IMT) are recognized as risk factors for ischemic stroke, but their predictive value has been debated and varies between studies. The purpose of this longitudinal population-based study was to assess the risk of ischemic stroke associated with plaque area and IMT in the carotid artery. METHODS: IMT and total plaque area in the right carotid artery were measured with ultrasound in 3240 men and 3344 women aged 25 to 84 years who participated in a population health study in 1994 to 1995. First-ever ischemic strokes were identified through linkage to hospital and national diagnosis registries, with follow-up until December 31, 2005. RESULTS: Incident ischemic strokes occurred in 7.3% (n=235) of men and 4.8% (n=162) of women. The hazard ratio for 1 SD increase in square-root-transformed plaque area was 1.23 (95% CI, 1.09-1.38; P=0.0009) in men and 1.19 (95% CI, 1.01-1.41; P=0.04) in women when adjusted for other cardiovascular risk factors. The multivariable-adjusted hazard ratio in the highest quartile of plaque area versus no plaque was 1.73 (95% CI, 1.19-2.52; P=0.004) in men and 1.62 (95% CI, 1.04 2.53; P=0.03) in women. The multivariable-adjusted hazard ratio for 1 SD increase in IMT was 1.08 (95% CI, 0.95-1.22; P=0.2) in men and 1.24 (95% CI, 1.05-1.48; P=0.01) in women. There were no differences in stroke risk across quartiles of IMT in multivariable analysis. CONCLUSIONS: In the present study, total plaque area appears to be a stronger predictor than IMT for first-ever ischemic stroke. PMID- 21311060 TI - Altered expression of PIWI RNA in the rat brain after transient focal ischemia. AB - BACKGROUND AND PURPOSE: The PIWI-interacting RNA (piRNA) is the most predominant RNA species in eukaryotes. The piRNA are a class of noncoding RNAs that bind and degrade the RNA formed by the transposons to control the transposon-induced gene mutations. The role of piRNA after focal ischemia is not yet evaluated. METHODS: We profiled 39 727 piRNAs in the cerebral cortex of adult rats subjected to transient focal ischemia using microarrays. The RT targets of stroke-responsive piRNAs were identified with bioinformatics. To understand how piRNAs are controlled, we analyzed the transcription factor binding sites in the putative promoters of 10 representative stroke-responsive piRNAs. RESULTS: In the ipsilateral cortex of ischemic rats, 105 piRNAs showed altered expression (54 up- and 51 downregulated; >2.5-fold) compared with shams. Twenty-five of those showed a >5-fold change. A bioinformatics search showed that the transposon targets of the highly stroke-responsive piRNAs are distributed among the 20 autosomal chromosomes and there is a redundancy in the targets between the piRNAs. Furthermore, the transposon targets were observed to be highly repetitious for each piRNA across the chromosome length. Of the 159 transcription factors observed to have binding sites in the piRNA gene promoters, 59% belonged to 20 major families indicating that transcription factors control stroke-responsive piRNAs in a redundant manner. CONCLUSIONS: The present study is the first to show that many piRNAs are expressed in adult rodent brain and several of them respond to focal ischemia. PMID- 21311061 TI - Ethnicity and functional outcome after stroke. AB - BACKGROUND AND PURPOSE: There is limited information on the influence of ethnicity on functional outcome after stroke. We examined functional outcomes among European New Zealanders, Maori, Pacific, and Asian people 6 months after stroke in a population-based context. METHODS: This was a prospective incidence and 6-month outcomes study of all new stroke patients (excluding subarachnoid hemorrhage) that occurred over 1 year in a defined geographical area in Auckland, New Zealand, during 2002 to 2003. Ethnicity was self-defined. Outcome measures included the Frenchay Activities Index, 36-item Short Form questionnaire, independence, death, composite of death and dependence, and living situation. RESULTS: Functional measures were available in 1127 patients 6 months after stroke. Frenchay Activities Index scores were associated with ethnicity on both univariable and multivariable analysis, with Asian and Pacific people having worse scores. Physical Component Summary score of the 36-item Short Form was associated with ethnicity on univariable (scores for Pacific, Maori, and Asian people were higher than those for Europeans) but not multivariable analysis. Asian people were less likely to be dead compared to Europeans, and Pacific people were more likely to be dependent on others for help than Europeans. Pacific people were more likely to be dead or dependent than Europeans. Asian and Pacific people were more likely to be living at home than Europeans. CONCLUSIONS: Ethnicity was associated independently with functional outcomes. The association was attenuated when adjusted for stroke severity and other covariates. The direction of the relationship was not consistent between measures for individual ethnic groups. PMID- 21311062 TI - Cerebral infarction after subarachnoid hemorrhage contributes to poor outcome by vasospasm-dependent and -independent effects. AB - BACKGROUND AND PURPOSE: The pathogenesis of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage remains incompletely understood. It is generally assumed that it is caused by angiographic vasospasm. Our aim was to clarify the relationship among angiographic vasospasm, neurological worsening, cerebral infarction, and poor outcome and to investigate whether cerebral infarction also contributes to poor outcome by vasospasm-independent effects. METHODS: This exploratory analysis used data from 413 patients included in the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS-1) trial. We studied the incidence of neurological worsening, cerebral infarction, and poor outcome in patients with and without angiographic vasospasm. Path analysis implemented by structural equation modeling was performed to determine direct and indirect path coefficients. RESULTS: Of the 194 patients with moderate to severe vasospasm, 43% had neurological worsening of any cause, 20% had cerebral infarction, and 46% poor outcome. Path coefficients for direct effects on poor outcome were 0.20 for World Federation of Neurological Surgeons Grade 4 to 5, 0.13 for history of hypertension, 0.19 for angiographic vasospasm, 0.16 for neurological worsening, and 0.11 for new cerebral infarction. Cerebral infarction contributed to poor outcome by vasospasm-dependent and -independent effects. CONCLUSIONS: Our data show that the majority of patients with moderate to severe angiographic vasospasm did not have neurological worsening of any cause or cerebral infarction. Besides, cerebral infarction also has a direct effect on outcome independent of angiographic vasospasm. This suggests that other coexisting factors might be involved in the pathogenesis of delayed cerebral ischemia, which should also be an important research target to improve outcome after subarachnoid hemorrhage. PMID- 21311063 TI - Traditional risk factors for incident cardiovascular events have limited importance in later life compared with the health in men study cardiovascular risk score. AB - BACKGROUND AND PURPOSE: This study aimed to determine, among older men, the risk and independent significant baseline prognostic factors for first-ever stroke and MI. METHODS: We performed a prospective cohort study of 4382 community-dwelling older men (mean age, 75.4+/-4.2 years) with no history of stroke or MI. Baseline data comprised questionnaire responses, clinical measurements, and comorbidity. RESULTS: After a median of 6 years (interquartile range, 5.2-7.2) of follow-up, the overall rate of stroke/MI was 2.61 (95% CI, 2.42-2.81) per 100 person-years. Among major traditional risk prediction variables, only age and smoking were significantly associated with stroke/MI. In our final multivariate model, the independent significant predictors of stroke/MI were age (HR for age older than 85, 3.18; 95% CI, 2.05-4.93), diastolic blood pressure <70 mm Hg (Hazard ratio [HR], 1.45; 95% CI, 1.18-1.78), high-sensitivity C-reactive protein >3 mg/L (HR, 1.29; 95% CI, 1.05-1.59), homocysteine >15 umol/L (HR, 1.35; 95% CI, 1.09-1.67), waist-to-hip ratio >1 (HR, 1.47; 95% CI, 1.20-1.18), and fair or poor self reported health (HR, 1.52; 95% CI, 1.19-1.94). A new risk model incorporating these variables performed well compared with the Framingham risk equation (Harrell C of 0.660 versus C of 0.620; integrated discrimination improvement of 1.85%; z=4.95; P<0.001; net reclassification index of 0.08; z=2.0; P=0.023). The model was used to develop an 8- point clinical risk score comprising the independent predictors of stroke/MI among this population. CONCLUSIONS: Traditional vascular risk factors did not optimally predict stroke/MI among this cohort of community-dwelling older men. We have constructed a new risk score that requires validation in other data sets. PMID- 21311065 TI - Restenosis is more frequent after carotid stenting than after endarterectomy: the EVA-3S study. AB - BACKGROUND AND PURPOSE: Carotid angioplasty and stenting (CAS) may be more often associated with residual or recurrent stenosis than carotid endarterectomy (CEA). We compared the rates of restenosis in patients treated with CAS or CEA in the EVA-3S trial. METHODS: Five hundred seven patients (242 treated by CAS and 265 by CEA) had carotid ultrasound follow-up (mean carotid ultrasound follow-up, 2.1 years) according to a predefined protocol. Carotid restenosis of 50% to 69% was diagnosed on planimetry, whereas carotid restenosis of >=70% or occlusion was diagnosed using either planimetry or velocity criteria. RESULTS: The rate of carotid restenosis of >=50% or occlusion was significantly higher after CAS (12.5%) than after CEA (5.0%; time ratio, 0.16; 95% CI, 0.03-0.76; P=0.02). The rates of severe restenosis of >=70% or occlusion were low and did not differ significantly between the 2 groups (3-year rates are 3.3% in the CAS group and 2.8% in the CEA group). Age at baseline was the only vascular risk factor significantly associated with carotid restenosis. Our study could not detect any effect of carotid restenosis on ipsilateral stroke. CONCLUSIONS: The short-term rate of carotid restenosis of >=50% or occlusion is ~2.5-times more common after CAS than after CEA, a difference accounted for by an excess risk in moderate restenosis. More data with longer follow-up are needed to assess the rates of late severe restenosis and to determine the relation between restenosis and recurrent stroke over time. PMID- 21311064 TI - Sex differences in the response to poly(ADP-ribose) polymerase-1 deletion and caspase inhibition after stroke. AB - BACKGROUND AND PURPOSE: Emerging data suggest that the molecular cell death pathways triggered by ischemic insults differ in the male and female brain. Cell death in males is initiated by poly(ADP-ribose) polymerase-1 (PARP-1) activation; however, manipulation of this pathway paradoxically increases ischemic damage in females. In contrast, females are exquisitely sensitive to caspase-mediated cell death. The effect of caspase inhibition in PARP-1 knockout mice was evaluated to determine if the detrimental effects of PARP deletion in females were secondary to increased caspase activation. METHODS: Focal stroke was induced by transient or permanent middle cerebral artery occlusion (MCAO) in wild-type (WT) and PARP 1(-/-) mice of both sexes. The pan-caspase inhibitor, quinoline-Val-Asp(Ome)-CH2 O-phenoxy (Q-VD-OPh), was administered 90 minutes after middle cerebral artery occlusion. Infarct size and neurological sores were assessed. Separate cohorts were used for protein analysis for PAR, Apoptosis inducing factor (AIF), caspase 9, and caspase-3. RESULTS: WT mice of both sexes had increased nuclear AIF after stroke compared to PARP-1(-/-) mice. PARP-1(-/-) females had higher mitochondrial cytochrome C and activated caspase-9 and -3 levels than WT female mice. PARP-1(-/ ) females also had an increase in stroke-induced cytosolic cytochrome C release compared with WT females, which was not seen in males. Q-VD-OPh decreased caspase 9 in both males and females but only led to reduction of infarct in females. PARP 1(-/-) males had smaller infarcts, whereas PARP-1(-/-) females had larger strokes compared with WT. Q-VD-OPh significantly decreased infarct in both WT and PARP-1( /-) females in both transient and permanent MCAO models, but had no effect in males. CONCLUSIONS: Deletion of PARP-1 reduces infarct in males but exacerbates injury in females. PARP-1(-/-) females have enhanced caspase activation. The detrimental effects of PARP loss in females can be reversed with caspase inhibition. PMID- 21311066 TI - An analysis of inflation times during balloon-assisted aneurysm coil embolization and ischemic complications. AB - BACKGROUND AND PURPOSE: The introduction of balloon remodeling has revolutionized the approach to coiling of wide-neck aneurysms. We studied the effects of balloon inflation during coil embolization on ischemic complications. METHODS: A retrospective review was undertaken of the most recent 147 patients undergoing balloon remodeling for unruptured intracranial aneurysm coil embolization at a single institution (81 balloon, 66 unassisted). All underwent postprocedural MRI. RESULTS: Among patients in the "balloon" group, the mean total inflation time was 18 minutes (range, 1-43), a mean number of inflations of 4 (range, 1-9), a mean maximum single inflation time of 7 minutes (range, 1-19), a mean reperfusion time of 2.2 minutes between inflations, and an average procedure time of 2 hours and 10 minutes. Asymptomatic diffusion-weighted imaging abnormalities were detected on postprocedural MRI in 21.5% of patients and symptomatic lesions were identified in 3.8%. Both silent and symptomatic ischemic rates were similar in the internal control group. Patients with ischemic findings were older and more likely have diabetes; no differences were found with respect to total balloon inflation time, number of inflations, maximum inflation time, or reperfusion times. CONCLUSIONS: We found no significant relationship between balloon inflation practices and ischemic events. Older and diabetic patients were more likely to have ischemic events develop. PMID- 21311067 TI - Low serum homoarginine is a novel risk factor for fatal strokes in patients undergoing coronary angiography. AB - BACKGROUND AND PURPOSE: Low serum concentrations of the amino acid homoarginine have been associated with endothelial dysfunction and an increased risk of all cause and cardiovascular mortality. We aimed to investigate whether homoarginine levels are also associated with fatal strokes and a history of nonfatal cerebrovascular disease. METHODS: Serum homoarginine was measured in 3305 participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study who were referred to coronary angiography at baseline (1997 to 2000) and were followed up with respect to mortality. RESULTS: During a median follow-up time of 9.9 years, 991 patients died including 61 fatal (ischemic and hemorrhagic) strokes. In a binary logistic regression analysis, the odds ratio (with 95% CI) for fatal stroke per SD of homoarginine was 0.52 (0.37 to 0.73; P<0.001) and remained significant after multivariable adjustments (0.62 [0.42 to 0.91]; P=0.014). For previous cerebrovascular disease events, the multivariable adjusted OR per SD of homoarginine was 0.82 (0.70 to 0.96; P=0.014). CONCLUSIONS: Low homoarginine levels are a novel risk factor for fatal strokes and are reduced in patients with a history of cerebrovascular disease. Further studies are needed to explore the significance of homoarginine to risk stratification and therapeutic approaches in the prevention of strokes. PMID- 21311068 TI - Hemophagocytic syndrome in a pancytopenic simian retrovirus-infected male rhesus macaque (Macaca mulatta). AB - Hemophagocytic syndrome (HPS) is a macrophage hyperactivation disorder triggered by disrupted T-cell macrophage cytokine interaction. HPS has been reported in humans, dogs, cats, and cattle, and it is infrequent and poorly characterized in animals. A 16-year-old male rhesus macaque was euthanized because of severe pancytopenia, including nonregenerative anemia (hematocrit = 5.5%), neutropenia (0.29 K/MUl), and thrombocytopenia (21 K/MUl). Bone marrow was hypocellular with normal maturation, myeloid hypoplasia, and few megakaryocytes. There were numerous morphologically normal macrophages (12% of nucleated cells), with 6% of nucleated cells being hemophagocytic macrophages in the bone marrow. Serology was negative, but polymerase chain reaction and immunohistochemistry were positive for simian retrovirus type 2. Blood and bone marrow findings were consistent with HPS. Cytopenias are common in simian retrovirus-infected macaques, but HPS has not been reported. An association between simian retrovirus infection and HPS is undetermined, but retrovirus-associated HPS has been observed in humans. PMID- 21311069 TI - Characterization of the host response in systemic isosporosis (atoxoplasmosis) in a colony of captive American goldfinches (Spinus tristis) and house sparrows (Passer domesticus). AB - Systemic isosporosis, also known as atoxoplasmosis, is a common parasitic disease of passerines. Infection is thought to be endemic in wild birds with fulminant, fatal disease occurring under the influence of stress, concurrent infections, or immunosuppression. Here, we describe the histologic and immunohistochemical characteristics of the cellular infiltrate occurring in captive colonies of American goldfinches and house sparrows. Necropsies were performed on 9 birds, and histologic examination was performed on the intestines of 7 additional birds. Lesions were most severe in the proximal small intestines. Histologically, the changes ranged from variably intense infiltrates of lymphocytes that filled the lamina propria to sheets of large, atypical cells that expanded and obliterated normal mucosal epithelium and invaded through the wall of the intestine and into the ceolomic cavity. Both the smaller lymphocytes and large atypical cells were immunoreactive for CD3. Intracellular parasites consistent with Isospora were detected in the large atypical cells, but they were more easily detectable in the more differentiated lymphocytes. Polymerase chain reaction and virus isolation performed on tissues from 7 birds were negative for retroviruses and herpesvirus. The immunohistochemical results of this study and the destructive nature of the cellular infiltrate suggest that the lesion represents T-cell lymphoma. In birds, lymphomas are most often associated with herpes and retroviruses; the absence of these viruses suggests that the parasite initiated neoplastic transformation. Though much work needs to be done to prove the transformative nature of the lesions, these preliminary results suggest that passerine birds may be susceptible to parasite-associated lymphomas. PMID- 21311070 TI - Extraskeletal osteosarcoma of the heart presenting as infective endocarditis. AB - A 7 yr old castrated male Labrador retriever (35.6 kg) was evaluated for an acute onset of vomiting of 24 hr duration. On initial examination, the patient was febrile (103.8 degrees F) and tachycardic (150 beats/min). Thoracic radiographs revealed left atrial enlargement with mild pulmonary infiltrates. The dog's condition worsened and repeat radiographs revealed worsening pulmonary infiltrates and pleural effusion. Treatment for heart failure was initiated. An echocardiogram showed a large 3 cm * 4 cm vegetation on the atrial surface of the posterior mitral valve. The patient was euthanized due to poor clinical appearance and infective endocarditis was suspected. Necropsy revealed an osteosarcoma of the posterior mitral valve, which cultured negative. PMID- 21311071 TI - Hereditary phosphofructokinase deficiency in wachtelhunds. AB - Hereditary phosphofructokinase (PFK) deficiency was diagnosed in two Wachtelhund dogs and suspected in three related Wachtelhund dogs with exercise intolerance, hemolytic anemia, and pigmenturia. Severe, persistent reticulocytosis in light of only mild anemia together with hemoglobinuria after strenuous exercise suggested PFK deficiency. Low erythrocyte PFK activity together with low 2,3 diphosphoglycerate concentrations and a high hemoglobin-oxygen affinity confirmed the diagnosis. The PFK deficiency is due to a single missense mutation in the muscle-type PFK M-PFK gene in English springer and American cocker spaniels, whippets, and mixed-breed dogs; however, these PFK-deficient Wachtelhunds do not have the same PFK mutation. PMID- 21311072 TI - Polycythemia and inappropriate erythropoietin concentrations in two dogs with renal T-cell lymphoma. AB - Two dogs presented with suspected renal disease and polycythemia. Abdominal ultrasound examinations performed on both dogs revealed coalescing masses causing bilateral renomegaly. Serum erythropoietin (EPO) concentrations were physiologically inappropriate. Postmortem examinations revealed renal T-cell lymphoma in both dogs. One of the two dogs also had involvement of the liver and mesentery. EPO-immunohistochemistry on tissue samples demonstrated positive staining in tumor cells and occasional normal renal cells. This report illustrates that paraneoplastic EPO production may induce polycythemia. The pattern of EPO-immunohistochemistry staining suggested that the mechanism of production was due to tumor production of EPO and local hypoxia-induced EPO production from compression of normal renal cells and vasculature. PMID- 21311073 TI - Acute necrotizing myopathy in a dog. AB - A 9 yr old spayed female cocker spaniel presented for an acute onset of weakness. Rhabdomyolysis and myoglobinuria were found 36 hr after presentation. The dog was managed for several electrolyte and mineral abnormalities and rhabdomyolysis induced acute renal failure. The diagnosis of idiopathic necrotizing myopathy was determined by histopathology and by the exclusion of underlying infectious agents and metabolic defects. The dog recovered completely from the acute crisis and acute renal failure. PMID- 21311074 TI - Feline cerebrovascular disease: clinical and histopathologic findings in 16 cats. AB - Sixteen cats with cerebrovascular disease confirmed via histology to be of nontraumatic and nonneoplastic origins are described. In addition, the anatomy of the arterial supply of the cat's brain is reviewed. It is suggested that this unique arterial design may influence the incidence of cerebrovascular accidents in this species. Of the 16 cats reviewed, seven cats had ischemic infarctions, five had hemorrhagic infarctions, and four were diagnosed with intracranial hemorrhage. The median age was 8 yr and 9.5 yr in cats with infarctions and intracranial hemorrhages, respectively. Clinical signs were severe, acute, consistent with the localization of the cerebrovascular lesion, and influenced by underlying pathology. Four cats with infarction showed lateralized neurologic signs. Four cats with infarctions were diagnosed with pulmonary disease antemortem and three cats had hyperthyroidism. Cerebrospinal fluid analysis and computed tomography scans were available in two cats. None of the infarctions were grossly visible. All cats with hemorrhagic infarcts had severe liver pathology and nephritis was identified in four cats. Hypoxia was a feature in four cats and one cat suffered cardiac failure. In conclusion, the clinical picture is influenced by the type of cerebrovascular disease, the localization of the intracranial lesions, and any underlying pathology. PMID- 21311075 TI - Unusual systemic signs in a dog with sterile neutrophilic-macrophagic lymphadenitis and nodular panniculitis. AB - A 7 mo old female English springer spaniel was presented with diarrhea, vomiting, apathy, and hyperthermia. Further examinations revealed generalized lymphadenomegaly consistent with sterile neutrophilic-macrophagic lymphadenitis and pulmonary involvement. Subcutaneous nodules developed one day after presentation. Histology was consistent with sterile idiopathic nodular panniculitis and vasculitis. No infectious organism was isolated. The dog responded to prednisolone, but relapsed during medication tapering. Cyclosporine had to be added to control the disease. No further relapse had occurred 98 wk after the first presentation. This is an unusual presentation of a systemic sterile neutrophilic-macrophagic lymphadenitis with nodular panniculitis and vasculitis associated with gastrointestinal and pulmonary signs. PMID- 21311077 TI - Primary uterine inertia in four labrador bitches. AB - Uterine inertia is a common cause of dystocia in the bitch and is designated as primary (i.e., uterine contractions fail to ever be initiated) or secondary (i.e., uterine contractions cease after a period of time but before labor is completed). The etiology of primary uterine inertia is not well understood. The accurate diagnosis of primary uterine inertia requires the use of tocodynamometry (uterine monitoring). Primary uterine inertia has been postulated to result from a failure of luteolysis resulting in persistently elevated progesterone concentrations. In this study, primary uterine inertia was diagnosed in a series of four bitches in which luteolysis was documented suggesting some other etiopathogenesis for primary uterine inertia. PMID- 21311076 TI - Fatal aortic endocarditis associated with community-acquired Serratia marcescens infection in a dog. AB - A 12 yr old Dalmatian was referred for evaluation of acute lethargy, fever, neurologic signs, and a recently ausculted heart murmur. Echocardiography in combination with blood cultures resulted in a diagnosis of nonhospital-acquired Serratia marcescens bacteremia and aortic valve endocarditis. Despite early diagnosis and aggressive therapy, the dog failed to respond to antimicrobials and died within 6 hr after admission. Necropsy findings included aortic valve endocarditis, septicemia, and diffuse thromboembolic disease. There was no history of pre-existing underlying disease or immunosuppressive therapy, and the dog had not been hospitalized before referral. PMID- 21311078 TI - Diagnosis and management of ureteroceles in two female dogs. AB - Two intact female dogs were examined for refractory pollakiuria and stranguria. One of these two dogs also exhibited urinary incontinence. Ectopic ureteroceles were diagnosed via ultrasonography and cystoscopy in both dogs. Both dogs were taken to surgery for ureterocele resection and neoureterostomy, resulting in complete resolution of clinical signs. Although uncommonly reported in the veterinary literature, ectopic ureteroceles can be associated with recurrent lower urinary tract infection with and without urinary incontinence. With a correct diagnosis and appropriate treatment, prognosis for ectopic ureteroceles can be good provided there is not a concurrent significant loss of renal function. PMID- 21311079 TI - A review of neuroendoscopy and potential applications in veterinary medicine. AB - The endoscope was first developed over 200 yr ago. Endoscopy has since been applied to many disciplines of medicine. Its application to the nervous system was initially slow and not widely accepted and mainly involved the biopsy of tumors and the treatment of hydrocephalus. Several reasons for neuroendoscopy's limited use include inadequate endoscope technology, high skill level required, the advent of the surgical microscope, and the development of other treatments such as ventricular shunting. Over the past 50 yr, improvements in optical glass lenses, fiber optics, and electrical circuitry has led to better equipment and a revival of neuroendoscopy. Neuroendoscopy is now used in many diseases in human medicine including hydrocephalus, neoplasia, and intracranial cysts. This review presents the history of neuroendoscopy, the equipment and technology used, and the possible translation of techniques currently used in human medicine to veterinary medicine. PMID- 21311080 TI - Vascularized ulnar bone grafts for limb-sparing surgery for the treatment of distal radial osteosarcoma. AB - The objective of this retrospective study was to compare vascularized free or roll-in ulnar bone grafts for limb-sparing surgery in dogs with radial osteosarcoma with the cortical allograft, metal endoprosthesis, or distraction osteogenesis techniques. Overall, the ulnar graft techniques used in this study demonstrated excellent healing properties. Complications included recurrence of the tumor in 25% (2/8) of the dogs, metastasis in 50% (4/8) of the dogs, implant loosening in 37.5% (3/8) of the dogs, implant failure in 12.5% (1/8) of the dogs, and infection in 62.5% (5/8) of the dogs. Mean survival time was 29.3 mo (range, 9 to 61 mo). The mean metastasis-free interval was 33.67 mo (range, 8 to 54 mo). Tumors recurred locally in two dogs at 10 mo and 20 mo postoperatively. This study yielded similar long-term complications as other limb-sparing options (such as cortical allografts and metal endoprostheses) and allowed dogs to bear weight on the operated limb with acceptable limb function. More research is needed regarding specific healing times for ulnar vascularized grafts, time until implant removal, and the extent of radial bone that could ultimately be replaced by the ulna. PMID- 21311081 TI - Cerebellar hemorrhage in extremely low birth weight siblings: is there a familial disposition? AB - Cerebellar hemorrhage is an underrecognized complication in the preterm neonate. It is multifactorial including combined maternal, intrapartum, and early postnatal factors. We present the case of 2 preterm brothers, 24 + 1 and 24 + 3 weeks of gestation, who both died because of cerebellar hemorrhage. We sought familial pathogenic factors predisposing to cerebellar hemorrhage. Cerebral imaging performed by ultrasonography through the anterior fontanel was normal and showed no signs of bleeding or brain edema. Postmortem neuropathologic findings confirmed cerebellar hemorrhagic lesions in both infants. Cerebellar vessels showed no signs of morphologic disorders or malformations. There might be a hint to a familial disposition. Neonatal cranial ultrasound protocols should include brainstem and posterior fossa examination with specific scans through the mastoid fontanel. PMID- 21311082 TI - A methodology for assessing treatment response in Hashimoto's encephalopathy: a case study demonstrating repeated computerized neuropsychological testing. AB - Hashimoto's encephalopathy, a steroid-responsive encephalopathy, presents with cognitive deterioration, psychiatric symptoms, and seizures and is often associated with elevation of anti-thyroid peroxidase antibodies or thyroid dysfunction. Because of the absence of a gold-standard diagnostic test and serological marker of disease, improvement in cognitive impairment is an important sign when assessing response to corticosteroid treatment. The purpose of this case study is to present a methodology for tracking neurocognitive functioning using computerized testing (CNS Vital Signs) in a 14-year-old girl with Hashimoto's encephalopathy. Computerized neuropsychological testing was done prior to commencing corticosteroid treatment, as well as at 7 follow-up assessments over 1 year. Improvement in cognitive, psychological, and behavioral functioning heralded a response to treatment, which was sustained during tapering of medication. Computerized neuropsychological testing seems to be a viable tool for tracking cognitive functioning (when rapid assessments are desired) and assessing response to corticosteroid treatment in Hashimoto's encephalopathy. PMID- 21311083 TI - Timeliness of tissue-type plasminogen activator therapy in acute ischemic stroke: patient characteristics, hospital factors, and outcomes associated with door-to needle times within 60 minutes. AB - BACKGROUND: The benefits of intravenous tissue-type plasminogen activator (tPA) in acute ischemic stroke are time dependent, and guidelines recommend an arrival to treatment initiation (door-to-needle) time of <=60 minutes. METHODS AND RESULTS: Data from acute ischemic stroke patients treated with tPA within 3 hours of symptom onset in 1082 hospitals participating in the Get With the Guidelines Stroke Program from April 1, 2003, to September 30, 2009 were studied to determine frequency, patient and hospital characteristics, and temporal trends in patients treated with door-to-needle times <=60 minutes. Among 25 504 ischemic stroke patients treated with tPA, door-to-needle time was <=60 minutes in only 6790 (26.6%). Patient factors most strongly associated with door-to-needle time <=60 minutes were younger age, male gender, white race, or no prior stroke. Hospital factors associated with <=60 minute door-to-needle time included greater annual volumes of tPA-treated stroke patients. The proportion of patients with door-to-needle times <=60 minutes varied widely by hospital (0% to 79.2%) and increased from 19.5% in 2003 to 29.1% in 2009 (P<0.0001). Despite similar stroke severity, in-hospital mortality was lower (adjusted odds ratio, 0.78; 95% confidence interval, 0.69 to 0.90; P<0.0003) and symptomatic intracranial hemorrhage was less frequent (4.7% versus 5.6%; P<0.0017) for patients with door to-needle times <=60 minutes compared with patients with door-to-needle times >60 minutes. CONCLUSIONS: Fewer than one-third of patients treated with intravenous tPA had door-to-needle times <=60 minutes, with only modest improvement over the past 6.5 years. These findings support the need for a targeted initiative to improve the timeliness of reperfusion in acute ischemic stroke. PMID- 21311084 TI - Working with translators and interpreters in research: lessons learned. AB - The purpose of this special section is to describe culturally competent approaches for working with translators or interpreters who participate in transcultural studies. This article provides background for three exemplars of lessons learned in working with translators in transcultural studies: (a) the resettlement transition experiences of women from the Dinka tribe of Southern Sudan (Baird), (b) Samoans' risk for heart disease (Siaki), and (c) culturally Deaf adults' perceptions about depression (Sheppard).Capitalizing the word "Deaf" has gained wide acceptance to indicate a linguistic minority of people who have a hearing loss and use American Sign Language, a hallmark of Deaf culture. In each case, the individual researcher made adaptations to the usual processes of translation/back-translation when appropriate to the cultural context and the specific situations of the translators. Although these lessons were learned during research-related activities, they may apply to other circumstances when nurses work with bilingual/bicultural translators (e.g., translating consent forms or communicating with persons who have limited literacy in their native language). PMID- 21311085 TI - Physical violence in the workplace among Jordanian hospital nurses. AB - PURPOSE: Lack of policies and assertive legislation on workplace violence has placed Jordanian nurses at frequent risk for workplace violence. The purposes of this research were to (a) investigate the level of physical violence and the complaints and responses of Jordanian hospital nurses to such violence and (b) describe workplace policies that deal with violence and recommend policy directions. DESIGN: A descriptive exploratory survey was used to investigate physical workplace violence among a convenience sample of 420 Jordanian nurses. Data were collected by a self-administered questionnaire that was developed in 2003 by the International Labour Organization, International Council of Nurses, World Health Organization, and Public Services International. RESULTS: The findings indicated that 22.5% of the participants were exposed to physical workplace violence. The contributing factors as indicated by the participants were related to the administration, staff, security, patients and families, and the public. DISCUSSION: Participants who had experienced workplace violence were very dissatisfied with the manner in which the incidents were handled. IMPLICATIONS: It is important to investigate consequences of workplace violence on the satisfaction of employees and the quality of heath care service. Instituting appropriate policies and legislation would minimize workplace violence. PMID- 21311086 TI - The cultural context of smoking among immigrants from the former Soviet Union. AB - The purpose of this descriptive, qualitative study was to gain understanding of the cultural context of smoking among immigrants from former Soviet Union countries now living in the Midwest United States. Semistructured interviews were conducted in focus group or individual settings (N = 14), including smokers and former smokers recruited from community settings. Social factors and stress management strongly motivated smoking behavior. Personal willpower was the most helpful cessation strategy, with firm lack of openness to pharmacologic approaches. Top past stressors included food insecurity and societal unrest, with the top current stressors being acculturative issues. The importance of social connectedness and the relatively low priority of prevention were also themes. Based on these interviews, interventions should include acculturative stress management and maintaining social connectedness, while addressing life experiences in the insecurity of basic needs. Smoking cessation interventions that are tailored beyond just language use and address these specific issues are suggested. PMID- 21311087 TI - Translating questions for use with Samoan adults: lessons learned. AB - The purpose of this article was to present the process of translating questions about perceived risk for diabetes into Samoan and describe important cultural adaptations to the modified Brislin's translation model for cross-cultural research. With the assistance of a culture broker and several Samoan translators, 14 questions were translated into the Samoan language. Cultural adaptations included using a group approach, working with a matai, and following protocols such as fa'alavelave. Questions were back-translated and then pilot tested. Results from the pilot testing supported the use of these cultural modifications in the translation model. PMID- 21311088 TI - What can we learn from the national heart failure audit? PMID- 21311089 TI - Radiation protection in occupational and environmental settings. PMID- 21311090 TI - Preventing falls in restaurants: where the sole meets the floor. PMID- 21311091 TI - Toward high-quality gradient estimation on regular lattices. AB - In this paper, we present two methods for accurate gradient estimation from scalar field data sampled on regular lattices. The first method is based on the multidimensional Taylor series expansion of the convolution sum and allows us to specify design criteria such as compactness and approximation power. The second method is based on a Hilbert space framework and provides a minimum error solution in the form of an orthogonal projection operating between two approximation spaces. Both methods lead to discrete filters, which can be combined with continuous reconstruction kernels to yield highly accurate estimators as compared to the current state of the art. We demonstrate the advantages of our methods in the context of volume rendering of data sampled on Cartesian and Body-Centered Cubic lattices. Our results show significant qualitative and quantitative improvements for both synthetic and real data, while incurring a moderate preprocessing and storage overhead. PMID- 21311092 TI - Compressive rendering: a rendering application of compressed sensing. AB - Recently, there has been growing interest in compressed sensing (CS), the new theory that shows how a small set of linear measurements can be used to reconstruct a signal if it is sparse in a transform domain. Although CS has been applied to many problems in other fields, in computer graphics, it has only been used so far to accelerate the acquisition of light transport. In this paper, we propose a novel application of compressed sensing by using it to accelerate ray traced rendering in a manner that exploits the sparsity of the final image in the wavelet basis. To do this, we raytrace only a subset of the pixel samples in the spatial domain and use a simple, greedy CS-based algorithm to estimate the wavelet transform of the image during rendering. Since the energy of the image is concentrated more compactly in the wavelet domain, less samples are required for a result of given quality than with conventional spatial-domain rendering. By taking the inverse wavelet transform of the result, we compute an accurate reconstruction of the desired final image. Our results show that our framework can achieve high-quality images with approximately 75 percent of the pixel samples using a nonadaptive sampling scheme. In addition, we also perform better than other algorithms that might be used to fill in the missing pixel data, such as interpolation or inpainting. Furthermore, since the algorithm works in image space, it is completely independent of scene complexity. PMID- 21311093 TI - Real-time resolution of self-intersection in dynamic cylindrical free-form deformation. AB - This paper presents a method of self-intersection detection and resolution for dynamic cylindrical-lattice-based free-form deformation (FFD). The lattice-based approach allows efficient computation of deformation of complex geometries. But excessive deformation can cause visual anomalies such as surface infiltration and distortion. This paper derives a geometrically intuitive sufficient condition to guarantee that the FFD function is a homeomorphism and there is no self intersection. The FFD function is defined by linear and quadratic B-Spline functions with the control points of the cylindrical lattice cell. The sufficient condition is satisfied if each trilinear function of the nine prism-shaped pentahedrons derived from the cell has a positive Jacobian determinant. The positivity is satisfied if the 12 tetrahedrons derived from the pentahedron have positive volumes. Based on the sufficient condition, the proposed method converts the self-intersection problem into a point-face collision detection and response problem suitable for dynamic simulation. The efficiency and accuracy of the self intersection detection algorithm is analyzed and compared with a previous method. The results show that the proposed technique allows simulation of excessive deformation of tubular objects in an efficient and realistic manner. PMID- 21311094 TI - Could NSP5a3a be a target for head and neck cancer? PMID- 21311095 TI - Molecular identification and targeting of colorectal cancer stem cells. AB - Tumor initiating or cancer stem cells (CSCs) are suggested to be responsible for tumor initiation and growth. Moreover, therapy resistance and minimal residual disease are thought to result from selective resistance of CSCs. Isolation of CSCs from colon carcinomas can be accomplished by selection of a subpopulation of tumor cells based on expression of one or multiple cell surface markers associated with cancer stemness, like CD133, CD44, CD24, CD29, CD166 and Lgr5. Identification of colon CSCs will lead to a better rational for new therapies that aim to target this fraction specifically. In this review, we analyze known markers used for selection of colon CSCs and their potential function in CSC biology. Moreover, we discuss potential targeting strategies for eradicating CSCs specifically in order to develop more effective therapeutic strategies as well as to address more fundamental questions like the actual role of CSCs in tumor growth. PMID- 21311096 TI - Direct interaction between p53 and Tid1 proteins affects p53 mitochondrial localization and apoptosis. AB - The p53 tumor suppressor induces apoptosis in response to genotoxic and environmental stresses. Separately from its functions as a transcription factor, it is also capable to be translocated to the mitochondria and plays a critical role in transcription-independent mitochondrial apoptosis. We previously demonstrated that Tid1 interacts with p53, resulting in mitochondrial translocation of the complex and induction of intrinsic apoptosis [1]; however, the mechanism how they interact has been unknown. In this study, far western analyses demonstrated that Tid1 directly interacted with p53. Using domain deletion mutant constructs, we determined that DnaJ domain of Tid1 was necessary for the interaction, while either N- or C-terminal domains of p53 were sufficient for the interaction. In breast cancer cells, depletion of Tid1 by short hairpin RNA (shRNA) led to absence of p53 accumulation at mitochondria and resistance to apoptosis under hypoxic or genotoxic stresses. Our studies imply that Tid1 could be important in the potential combination chemotherapies of p53-related cancers. PMID- 21311097 TI - A molecular signature of normal breast epithelial and stromal cells from Li Fraumeni syndrome mutation carriers. AB - Specific changes in gene expression during cancer initiation should enable discovery of biomarkers for risk assessment, early detection and targets for chemoprevention. It has been previously demonstrated that altered mRNA and proteome signatures of morphologically normal cells bearing a single inherited "hit" in a tumor suppressor gene parallel many changes observed in the corresponding sporadic cancer. Here, we report on the global gene expression profile of morphologically normal, cultured primary breast epithelial and stromal cells from Li-Fraumeni syndrome (LFS) TP53 mutation carriers. Our analyses identified multiple changes in gene expression in both morphologically normal breast epithelial and stromal cells associated with TP53 haploinsufficiency, as well as interlocking pathways. Notably, a dysregulated p53 signaling pathway was readily detectable. Pharmacological intervention with the p53 rescue compounds CP 31398 and PRIMA-1 provided further evidence in support of the central role of p53 in affecting these changes in LFS cells and treatment for this cancer. Because loss of signaling mediated by TP53 is associated with the development and survival of many human tumors, identification of gene expression profiles in morphologically normal cells that carry "one-hit" p53 mutations may reveal novel biomarkers, enabling the discovery of potential targets for chemoprevention of sporadic tumors as well. PMID- 21311098 TI - NSP 5a3a: a potential novel cancer target in head and neck carcinoma. AB - NSP 5a3a along with three other distinct though similar splice variants were initially identified corresponding to locus HCMOGT-1 on chromosome 17p11.2 [1]. Secondary structure analysis of the novel structural protein (NSP) isoforms revealed similarity to Spectrin like proteins containing coiled coil domains [1]. The NSP 5a3a isoform had been found to be highly expressed in-vitro in particular cancer cell lines while very low to un-detectable levels in normal body tissues [1]. Subsequent investigation of this isoform revealed its novel interaction with B23 [2], a multifunctional nucleolar protein involved in ribosome biogenesis, rRNA transcription, mitosis, cell growth control, and apoptosis [3]. Subsequent investigation, elucidated NSP 5a3a's potential involvement in cellular processes such as ribosome biogenesis and rRNA processing by validating NSP 5a3a's novel interaction with B23 and ribonuclear protein hnRNP-L possibly implicating NSP 5a3a's involvement in cellular activities such as RNA metabolism and processing [4]. In this preliminary investigation, we wanted to observe the effect that over expressing NSP 5a3a may have on cell cycle and its potential application in cancer treatment in aggressive cancers such as head and neck carcinomas. Over expressed NSP 5a3a in HN30 cells induced a significant degree of apoptosis, an average of a 10.85 fold increase compared to controls 3 days post-transfection. This effect was more significant then the apoptosis observed between Fadu cells over-expressing NSP 5a3a and its controls. Though, the apoptosis induced in the WI38 control cell line showed an average of a 13.2 fold increase between treated and controls comparable to the HN30 cell line 3 days post-transfection. Molecular analysis indentified a novel p73 dependent mechanism independent of p53 and caspase 3 activity through which NSP 5a3a is inducing apoptosis. We propose NSP 5a3a as a potential therapeutic target for site directed cancer treatment in perhaps certain head and neck carcinomas by induction of apoptosis. PMID- 21311099 TI - A two-locus system controls susceptibility to colitis-associated colon cancer in mice. AB - We have previously shown that the differential susceptibility of A/J (susceptible) and C57BL/6J (B6, resistant) mouse strains to azoxymethane (AOM) induced colorectal cancer (CRC) is controlled by the chromosome 3 locus, Ccs3. We report that A/J and B6 mice also show differential susceptibility to colitis associated colorectal cancer (CA-CRC) induced by combined administration of AOM and dextran sulfate. This differential susceptibility is not controlled by Ccs3, but is under distinct genetic control. Linkage analyses in (A/J x B6)F2 mice detected a major CA-CRC susceptibility locus on chromosome 9 (Ccs4) which controls tumor multiplicity and tumor surface area. Susceptibility alleles at Ccs4 are inherited in a recessive fashion, with A/J alleles being associated with susceptibility. We also detected a second locus on chromosome 14 that acts in an additive fashion with Ccs4. Strikingly, F2 mice homozygous for A/J alleles at both loci (Ccs4 and chromosome 14) are as susceptible to CA-CRC as the A/J controls while mice homozygous for B6 alleles are as resistant as the B6 controls, thus supporting the role of two interacting loci in this CA-CRC model. This indicates that susceptibility to chemically-induced CRC and susceptibility to CA-CRC are under distinct genetic control in mice, and probably involve distinct cellular pathways. PMID- 21311100 TI - Natural antisense transcript: a concomitant engagement with protein-coding transcript. AB - The vertebrate genome contains large spans of non-coding RNA, which for the most part were considered of little functional value to the organism. Recent studies have indicated that vertebrate genomes may have stored hidden secrets in this large span of non-coding RNA, which we refer to here as "Natural Antisense Transcripts (NATs)." NATs can be found in introns, exons, promoters, enhancers, intergenic sequences, and untranslated regions of the genome. They can be located in either the plus or minus DNA strand. NATs utilize several mechanisms that include DNA replication interference, chromatin remodeling, transcriptional interference, RNA masking, double-stranded RNA (dsRNA)-dependent mechanisms and translation interference to mechanistically regulate gene expression. Recently, NAT levels have been identified as dysregulated in various disease states. This review presents an overview of the current state of NAT biology and highlights the main points with specific examples. PMID- 21311101 TI - Human T cell leukemia virus type 1 (HTLV-1) and oncogene or oncomiR addiction? AB - The mechanism of HTLV-1 transformation of cells to Adult T cell leukemia (ATL) remains not fully understood. Currently, the viral Tax oncoprotein is known to be required to initiate transformation. Emerging evidence suggests that Tax is not needed to maintain the transformed ATL phenotype. Recent studies have shown that HTLV-1 transformed cells show deregulated expression of cellular microRNAs (miRNAs). Here we discuss the possibility that early ATL cells are Tax-oncogene addicted while late ATL cells are oncogenic microRNA (oncomiR) - addicted. The potential utility of interrupting oncomiR addiction as a cancer treatment is broached. PMID- 21311102 TI - An activating transcription factor 5-mediated survival pathway as a target for cancer therapy? AB - Genes that are highly expressed in cancer cells and are essential for their viability are attractive targets for the development of novel cancer therapeutics. Activating transcription factor 5 (ATF5) is an anti-apoptotic protein that is highly expressed in malignant glioma but not normal brain tissues, and is essential for glioma cell survival. Recent work has revealed an essential survival pathway mediated by ATF5 in malignant glioma; pharmacological inhibition of this pathway leads to tumor regression in mice. ATF5 is also highly expressed in a variety of other cancers, and preliminary studies have shown that the ATF5-mediated survival pathway is active in diverse human cancer cell lines. Targeting this pathway may therefore have therapeutic implications for the treatment of a wide range of cancers. In this perspective, we summarize recent advances in ATF5 research, focusing on its role in promoting cancer and its potential as a target for cancer therapy. PMID- 21311103 TI - Framingham risk score and early markers of atherosclerosis in a cohort of adults infected with HIV. AB - BACKGROUND: The utility of the Framingham risk score among individuals infected with HIV is poorly understood. We examined the association of Framingham risk scores with surrogate markers of atherosclerosis in a carefully characterized cohort of adults infected with HIV. METHODS: We calculated Framingham risk scores and measured carotid intima-media thickness (c-IMT) and coronary artery calcium (CAC) scores in 334 participants from the Nutrition for Healthy Living study. Cardiovascular risk factors, c-IMT and CAC scores were assessed for each Framingham risk subgroup (low versus intermediate/high risk). We used adjusted and unadjusted linear and logistic regression to examine the association between clinical factors and Framingham risk group with c-IMT and CAC scores. RESULTS: Patients with intermediate/high Framingham risk scores were more likely to have internal c-IMT >= 1.0 mm (26% versus 12%; P=0.003) and common c-IMT >= 0.8 mm (22% versus 5%; P < 0.001). These patients were also more likely to have detectable CAC (78% versus 48%; P < 0.001). Intermediate/high Framingham risk scores were significantly associated with internal c-IMT >= 1.0 mm (odds ratio 2.65 [95% confidence interval 1.37-5.13]) and common c-IMT >= 0.8 mm (odds ratio 5.24 [95% confidence interval 2.39-11.50]). Intermediate/high Framingham risk scores were also significantly associated with detectable CAC (odds ratio 3.84 [95% confidence interval 2.05-7.16]). The addition of HIV-related variables did not improve the accuracy of the Framingham risk score. CONCLUSIONS: Our study shows that increased Framingham risk scores are associated with abnormal early and late surrogate markers of atherosclerosis in adults infected with HIV, and might predict the risk of cardiovascular complications in this population. PMID- 21311104 TI - HIV type-1 drug resistance in treatment-naive patients monitored using minority species assays: a systematic review and meta-analysis. AB - BACKGROUND: The detection of mutations associated with drug resistance in HIV type-1 might be increased by applying minority species assays capable of identifying low frequency mutations in comparison with the use of population sequencing alone. Because minority species assays are mutation-specific, the benefit of this approach differs depending on the mutation being detected. METHODS: We performed a systematic review of published data reporting detection of genotypic drug resistance using allele-specific (AS)-PCR minority assays and by standard DNA sequencing in drug-naive populations. We calculated the fold increase of mutation detection for each study and pooled these via meta-analysis, displaying results using Forest plots. RESULTS: Our studies revealed an increase in detection of 1.9-fold (95% confidence interval [CI] 1.3-2.7; P < 0.0005) for K103N, 4.4-fold (95% CI 1.2-16.6; P = 0.026) for Y181C, 4.8-fold (95% CI 1.5 15.1; P = 0.008) for L90M and 8.7-fold (95% CI 4.0-18.6; P < 0.0005) for M184V. We found no relationship between AS-PCR assay sensitivity and frequency of additional mutation detection. CONCLUSIONS: Additional detection of drug resistance mutations using AS-PCR minority mutation assays vary significantly depending on the mutation examined; however, the most marked increase in detection of resistance mutations was observed for M184V, a mutation seldom detected by standard techniques in drug-naive patients. We suggest that the presence of drug resistance mutations can be more accurately estimated using a combination of AS-PCR and standard genotyping. PMID- 21311105 TI - Inhibition of lytic reactivation of Kaposi's sarcoma-associated herpesvirus by alloferon. AB - BACKGROUND: Alloferon, an immunomodulatory peptide, has antiviral capability against herpesvirus. In this research, we aimed to investigate the effect of alloferon on the regulation of the life cycle of Kaposi's sarcoma-associated herpesvirus (KSHV), and its mechanisms. We also assessed the antiviral activity of alloferon on natural killer (NK) cells as an early antiviral immune responder. METHODS: We first examined the change in cell proliferation and the expression of the viral genes in a KSHV-infected cell line, body-cavity-based B lymphoma (BCBL) 1, under the lytic cycle by 12-O-tetradecanoyl-phorbol-13-acetate (TPA) treatment. To elucidate the antiviral mechanism of alloferon, we tested calcium influx and the activation of the extracellular signal-regulated kinase (ERK) pathway. Furthermore, we evaluated the cytotoxicity of NK cells against BCBL-1 by alloferon. RESULTS: Alloferon effectively recovered the suppressed proliferation of BCBL-1 by TPA, which was achieved by the down-regulation of lytic-cycle related viral genes, RTA, K8 and vIRF2. To clarify the signal transduction pathways related to the regulation of the viral genes by alloferon, we confirmed that the calcium influx into BCBL-1 was apparently inhibited by alloferon, which preceded the suppression of the phosphorylation of ERK and the activation of AP-1 by TPA. Moreover, when NK cells were exposed to alloferon, their cytolytic activity was improved, and this was mediated by the enhancement of perforin/granzyme secretion. CONCLUSIONS: The results of this study suggest that alloferon can be used as an effective antiviral agent for the regulation of the KSHV life cycle by the down-regulation of AP-1 activity and for the the enhancement of antiviral immunity by up-regulation of NK cell cytotoxicity. PMID- 21311106 TI - Factors associated with liver fibrosis in intravenous drug users coinfected with HIV and HCV. AB - BACKGROUND: Reliable non-invasive methods for the evaluation of liver fibrosis are desirable, and the risk factors associated with fibrosis are not fully identified. METHODS: A cross-sectional study of a cohort of 805 HIV-HCV coinfected patients with active HCV replication, most (95.2%) of whom were intravenous drug users, was conducted. Liver fibrosis was measured by transient elastometry with cutoff values of 7.2 kPa (significant fibrosis), 9.4 kPa (advanced fibrosis) and 14.0 kPa (cirrhosis), and by liver fibrosis indexes (LFI; APRI, Forns and FIB-4). Available liver biopsies were also evaluated. RESULTS: The prevalences of significant fibrosis, advanced fibrosis and cirrhosis were 55.8%, 38.4% and 23.5%, respectively. A number of parameters were associated both in the univariate and multivariate analyses with each of the diverse fibrosis groups; however, only six of them were predictive of all stages of fibrosis: heavy alcohol intake (odds ratio [OR] 3.37, 95% confidence interval [CI] 2.02 5.59; P < 0.001), duration of HCV infection (OR 1.13, 95% CI 1.07-1.19; P < 0.001), CDC category C3 (OR 1.80, 95% CI 1.07-3.02; P=0.026), anti-HCV treatment failure (OR 4.37, 95% CI 2.24-8.55; P < 0.001), thrombocytopaenia (OR 1.015, 95% CI 1.011-1.019; P < 0.001) and increased aspartate aminotransferase (1.006, 95% CI 1.0021-1.010; P = 0.004). Furthermore, 53%, 68% and 80% of patients with significant fibrosis, advanced fibrosis and cirrhosis, respectively, had increased measures on at least one of the LFI, with the Forns index being the most sensitive. Area under the receiver operating characteristic curves of elastometry to predict histological fibrosis was 0.83 (95% CI 0.76-0.90), 0.89 (95% CI 0.83-0.95) and 0.87 (95% CI 0.80-0.94) for Metavir score >= F2, >= F3 and F4, respectively. CONCLUSIONS: Elastometry constitutes a useful tool in the diagnosis and follow-up of HIV-HCV-coinfected patients. Fibrosis is associated with diverse factors, some of them treatable or preventable, which need to be addressed considering the high prevalence and course of fibrosis in these patients. PMID- 21311107 TI - HBV core region variability: effect of antiviral treatments on main epitopic regions. AB - BACKGROUND: Amino acid (AA) changes in specific hepatitis B core antigen (HBcAg) regions were assessed in patients infected with chronic hepatitis B (CHB) after a 12-month untreated period and after receiving antiviral therapy (interferon, lamivudine or adefovir dipivoxil), and in inactive hepatitis B surface antigen positive carriers. METHODS: Samples corresponding to different time points in 76 CHB cases (64 on-treatment) and 4 inactive carriers were included. The main precore mutation, T-helper immunodominant epitope at AA 50-69 (Th50-69), minor T helper epitope (Th28-47), B-cell immunodominant epitope (B74-84) and a conserved region of HBcAg at AA 1-11 (AA1-11) were directly sequenced. For comparisons, the average number of AA changes in each region was standardized to 12 months (Av12). RESULTS: AA changes clustered mainly in immunodominant regions (69%). The highest percentage of cases (%n) with changes and highest Av12 changes were detected after interferon treatment (%n=73%, Av12=3.1 in Th50-69 and %n=86%, Av12=2.7 in B74-84). At baseline, immunodominant regions had higher Av12 changes in hepatitis B e antigen-negative patients and those with main precore mutations. Changes in the Th28-47 region were more frequent after nucleoside/nucleotide analogue treatment (40%) than before treatment (9%). Codons 74 and 77 were the most polymorphic, and the double change E64D-N67T was significantly observed. Codon 84 substitutions were mainly associated with interferon treatment (P=0.05). CONCLUSIONS: Natural and treatment-induced substitutions in HBV core protein, occurring especially with interferon treatment, were characterized. Some immune stimulating activity related to the minor Th28-47 epitope might be associated with nucleoside/nucleotide analogues; this activity was also seen in inactive carriers. PMID- 21311108 TI - Potent inhibition of human enterovirus 71 replication by type I interferon subtypes. AB - BACKGROUND: Enterovirus 71 (EV71) infection can induce a series of syndromes including herpangina, viraemia, hand-foot-and-mouth disease and even death. Outbreaks of EV71 infection have been reported periodically over the world and have caused a great number of casualties and a high medical expenditure. Some interferons (IFNs) have been used for the treatment of viral infections for decades; however, conventional IFNs only display mild anti-EV71 activities. No effective drug is currently available for the treatment of EV71 infection. Here, we aimed to investigate whether some IFN subtypes display potent anti-EV71 activities. METHODS: The antiviral activities of 17 type I IFNs were assayed in Vero cells using the cytopathic effect method. Cells were incubated with different concentrations of type I IFNs before or after virus infection. Viral replication was determined by quantitative real-time PCR (qRT-PCR). The expression levels of IFN downstream antiviral genes were also measured by qRT PCR. RESULTS: Out of 17 type I IFNs, 4 IFNs (IFN-alpha4, IFN-alpha6, IFN-alpha14 and IFN-alpha16) displayed potent antiviral activity. Compared with conventional IFN-alpha2a, IFN-alpha14 displayed approximately 20* higher antiviral activity. The superior antiviral effect of IFN-alpha14 was caused by a strong induction of the downstream antiviral effectors. CONCLUSIONS: IFN-alpha14 and three other IFNs could be considered for the treatment of EV71 infection. PMID- 21311109 TI - Analysis of drug resistance during HIV RNA viraemia in the MONET trial of darunavir/ritonavir monotherapy. AB - BACKGROUND: When patients have HIV RNA suppressed to <50 copies/ml on current treatment, switching to darunavir (DRV)/ritonavir (DRV/r) monotherapy could prevent the development of resistance to other drug classes. METHODS: In the MONET trial, 256 patients with HIV RNA<50 copies/ml on current highly active antiretroviral therapy (57% with protease inhibitors [PIs] and 43% with non nucleoside reverse transcriptase inhibitors) and no history of virological failure were randomized to DRV/r 800/100 mg once daily, either as monotherapy (monotherapy arm) or with two nucleoside reverse transcriptase inhibitors (NRTIs; triple therapy arm). All samples with HIV RNA >= 50 copies/ml were genotyped, and a virtual phenotype was calculated (VircoType HIV-1 assays; Virco BVBA, Mechelen, Belgium). RESULTS: A total of 63 patients had >= 1 HIV RNA result >= 50 copies/ml, of whom 38 were successfully genotyped. Most HIV RNA increases were transient and in the range of 50-200 copies/ml. Overall, 36 of the 38 (95%) successfully genotyped patients showed no International AIDS Society-USA major PI mutations, DRV mutations or NRTI mutations. Two patients showed some evidence of PI resistance during transient HIV RNA elevations: one patient in the monotherapy arm had a single DRV mutation (L33F) when HIV RNA was 63 copies/ml (the virus was phenotypically sensitive to DRV [fold change 0.8]) and one PI pretreated patient taking tenofovir disoproxil fumarate/emtricitabine/DRV/r had re-emergence of pre existing NRTI (M184V) and PI (V82I and L90M) mutations after a short treatment interruption (this virus remained phenotypically sensitive to DRV/r). Both patients showed sustained HIV RNA suppression to week 48 remaining with the same treatment. CONCLUSIONS: Emergence of drug resistance after changing a suppressive triple antiretroviral therapy to DRV/r with or without nucleoside analogues is uncommon. PMID- 21311110 TI - Protective murine and human monoclonal antibodies against eczema vaccinatum. AB - BACKGROUND: Eczema vaccinatum is the most common severe pathology associated with smallpox vaccination (vaccinia virus), occurring at high rates among individuals with a previous history of atopic dermatitis (atopic eczema). METHODS: Monoclonal antibodies capable of neutralizing vaccinia virus, anti-H3 and anti-B5, were developed as a potential therapy for treatment of human eczema vaccinatum. RESULTS: Using a small animal model of eczema vaccinatum, we demonstrated that both murine and fully human monoclonal antibodies effectively limited eczema vaccinatum disease, foreshortening both the disease kinetics and the severity of the erosive viral skin lesions. CONCLUSIONS: These neutralizing antibodies would likely be effective at reducing or eliminating clinical disease in people with eczema vaccinatum or other severe side effects of the smallpox vaccine. PMID- 21311111 TI - Comparison of multiplex restriction fragment mass polymorphism and sequencing analyses for detecting entecavir resistance in chronic hepatitis B. AB - BACKGROUND: Drug resistance is a major limitation to the long-term efficacy of controlling chronic hepatitis B (CHB). There is a growing need to analyse multiple mutations associated with drug resistance because sequential or combinational use of antivirals is increasingly being used in treatment. In this study, we introduced a multiplex restriction fragment mass polymorphism (RFMP) assay for detecting mutations conferring entecavir and lamivudine resistance, and compared its performance with direct or clonal sequencing assays. METHODS: Multiplex PCR was performed with mixed primers designed to interrogate rt184, rt202, rt204 and rt250. The PCR products were digested with restriction enzymes and the resulting fragments were analysed by mass spectrometry. A total of 251 serum samples, taken serially from 45 patients who received entecavir treatment after confirmed diagnosis of lamivudine resistance and inadequate adefovir dipivoxil response, were analysed by the multiplex RFMP assay. RESULTS: The multiplex RFMP assay correctly identified known viral sequences with sufficient analytical sensitivity to detect as few as 100 IU/ml of HBV and with superior ability to determine haplotypes composed of neighbouring variations. Complex mutational patterns and relative abundances determined by multiplex RFMP assay were in good concordance with results obtained by direct or clonal sequencing analyses. Defined mixtures were successfully and consistently identified at 2% relative concentration of mutant versus wild-type virus by the assay. CONCLUSIONS: The multiplex RFMP assay is an accurate and sensitive means to detect entecavir and lamivudine resistance mutations, simultaneously. The method is expected to enable early and efficient diagnosis of multiple drug resistance mutations for optimal management of CHB. PMID- 21311112 TI - Fucoidan therapy decreases the proviral load in patients with human T lymphotropic virus type-1-associated neurological disease. AB - BACKGROUND: Human T-lymphotropic virus type-1 (HTLV-1) is a human retrovirus that causes HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukaemia (ATL). A higher viral load in individuals with HTLV-1 infection increases their risk of developing HAM/TSP and ATL. Moreover, the high proviral load is associated with the clinical progression of HAM/TSP. Reduction of the number of HTLV-1-infected cells is therefore crucial for preventing and treating HTLV-1-associated diseases. Recently, fucoidan, a complex sulphated polysaccharide derived from marine seaweed, has been demonstrated to exert inhibitory effects on HTLV-1 infection in vitro. In this study, we examined the in vivo effects of fucoidan on HTLV-1 infection. METHODS: In this single-centre open-label trial, 13 patients with HAM/TSP were treated with 6 g fucoidan daily for 6-13 months. The HTLV-1 proviral DNA load and frequencies of HTLV-1-specific CD8(+) T-cells, natural killer cells, invariant natural killer T-cells and dendritic cells in the peripheral blood were analysed. Furthermore, the in vitro inhibitory effect of fucoidan on cell-to-cell HTLV-1 infection was examined by using luciferase reporter cell assays. RESULTS: Fucoidan inhibited the cell-to cell transmission of HTLV-1 in vitro. Furthermore, fucoidan therapy resulted in a 42.4% decrease in the HTLV-1 proviral load without affecting the host immune cells. During the treatment, no exacerbation was observed. Four patients with HAM/TSP developed diarrhoea, which improved immediately after stopping fucoidan administration. CONCLUSIONS: Fucoidan is a new potential therapeutic agent for the prevention and treatment of HTLV-1-associated diseases. PMID- 21311114 TI - Minor drug-resistant HIV type-1 variants in breast milk and plasma of HIV type-1 infected Ugandan women after nevirapine single-dose prophylaxis. AB - BACKGROUND: Nevirapine single-dose (NVP-SD) reduces mother-to-child transmission of HIV type-1 (HIV-1), but frequently induces resistance mutations in the HIV-1 genome. Little is known about drug-resistant HIV-1 variants in the breast milk of women who have taken NVP-SD. METHODS: Blood and breast milk samples of 39 HIV-1 infected Ugandan women were taken 6-12 weeks after NVP-SD intake. Samples were analysed by population sequencing and allele-specific real-time PCR (AS-PCR) with detection limits for NVP-resistant HIV-1 variants (K103N and Y181C) of < 1% of the total viral population. RESULTS: AS-PCR results for both plasma and breast milk were obtained for 19 women who constituted the final study group (HIV-1 subtype frequencies were A1 n = 11, D n = 5, G n = 2 and C n = 1). A total of 7 (37%) and 10 (53%) women carried NVP-resistant virus in breast milk and plasma, respectively. Overall, 71% (5/7) women with NVP-resistant HIV-1 in breast milk displayed >1 drug-resistant variant. Resistance in breast milk was higher at week 6 (6/13 samples [46%]) compared with week 12 (1/6 samples [17%]). In total, 10 drug-resistant populations harbouring the K103N and/or Y181C mutation were detected in the 19 breast milk samples; 7 (70%) were caused by resistant minorities (< 5% of the total HIV-1 population). In the four women with drug resistant virus in both plasma and breast milk, the mutation patterns differed between the two compartments. CONCLUSIONS: Minor populations of drug-resistant HIV-1 were frequently found in breast milk of Ugandan women after exposure to NVP SD. Further studies need to explore the role of minor drug-resistant variants in the postnatal transmission of (resistant) HIV-1. PMID- 21311113 TI - Virological characterization of patients failing darunavir/ritonavir or lopinavir/ritonavir treatment in the ARTEMIS study: 96-week analysis. AB - BACKGROUND: In the Phase III ARTEMIS Trial, treatment-naive patients received once-daily darunavir/ritonavir (DRV/r) 800/100 mg (n = 343) or lopinavir/ritonavir (LPV/r) 800/200 mg (total daily dose; n = 346) plus fixed dose tenofovir disoproxil fumarate/emtricitabine. The primary outcome measure was non-inferiority of DRV/r versus LPV/r (HIV type-1 [HIV-1] RNA<50 copies/ml). Here, a detailed 96-week resistance analysis is presented. METHODS: Virological failures (VFs) were defined as patients who had lost (rebounders) or who had never achieved (never suppressed) HIV-1 RNA < 50 copies/ml after week 12. Genotypic and phenotypic determinations were performed on plasma samples with HIV 1 RNA >= 50 copies/ml. The end point was defined as the last on-treatment visit with available genotype and/or phenotype. RESULTS: The VF rate was significantly lower in DRV/r (12%, n = 40) versus LPV/r patients (17%, n = 59; P = 0.0437). Among DRV/r patients, 24 rebounded and 16 were never suppressed, whereas among LPV/r patients, 33 rebounded and 26 were never suppressed. Transient HIV-1 RNA increases (>= 50 copies/ml) occurred in 50% (n = 12) DRV/r and 48% (n = 16) LPV/r rebounders; these viral levels returned to undetectable by end point without any changes to the study regimen. No major (primary) protease inhibitor (PI) resistance-associated mutations (RAMs) developed in VFs with an available genotype at baseline and end point, and almost all developing minor PI RAMs were polymorphic. At end point, all VFs with available phenotypes at baseline and end point remained susceptible to all PIs, including study PIs. CONCLUSIONS: The VF rate was lower with DRV/r than LPV/r. The findings of this resistance analysis confirmed the lack of development of major PI RAMs and the preservation of phenotypic susceptibility to all PIs in patients with VF. PMID- 21311115 TI - Multi-nucleoside reverse transcriptase inhibitor resistant HIV type-1 in a patient from Sierra Leone failing stavudine, lamivudine and nevirapine. AB - We report a 33-year-old HIV type-1 (HIV-1)-infected male from Sierra Leone who harboured extensive drug resistance mutations to all nucleoside reverse transcriptase inhibitors (NRTIs) and non-NRTIs, including the multi-NRTI resistance Q151M complex, K65R, M184I and Y181I, after using standard first-line generic fixed-dose stavudine, lamivudine and nevirapine (TriomuneTM) for 36 months. In the context of non-B subtypes in resource-limited countries, first line stavudine-containing regimens have been associated with more extensive and complex mutation patterns, compared with subtype B viruses. Whether the extensive and complex NRTI resistance patterns found among African patients failing first line antiretroviral therapy is explained by viral genetic diversity or by different patient monitoring strategies remains to be elucidated. Emerging multi NRTI resistance in sub-Saharan Africa would not only compromise second-line treatment options and the success of antiretroviral rollout, but could also contribute to the spread of drug-resistant variants worldwide. PMID- 21311116 TI - Chronic interstitial nephritis in an HIV type-1-infected patient receiving ritonavir-boosted atazanavir. AB - Here, we report a case of chronic granulomatous tubulo-interstitial nephritis related to atazanavir crystals in a HIV type-1-infected patient. Renal function in this patient was partially recovered after atazanavir withdrawal and steroid therapy. Many reports have described atazanavir-associated urolithiasis, but this is the first case that describes chronic granulomatous nephropathy. PMID- 21311117 TI - Imaging soft x-rays using a microchannel plate. AB - The GOLDHELOX Project is a student run project to construct a robotic solar telescope that will be used to take images of the sun in the soft X-ray region (171?181A) of the spectrum. The optical system uses a microchannel plate (MCP) detector. We tested the MCP to familiarize ourselves with and verify that MCP's can be used to image soft X-rays. Soft X-rays were created by a Manson source attached to a proportional counter to determine the amount of emitted X-rays detected by the MCP. The voltages on the MCP were varied to observe responses of varying voltage differences. Most of the observations were visible observations along with images made by a 35 mm camera with a telephoto lens. We found the 1000 V difference to produce the strongest and clearest images. PMID- 21311118 TI - NASA G-133 "GoldHelox": A Project Update. AB - NASA G-133, also known as the "GoldHelox Project", is a fully autonomous, soft X ray, solar telescope designed for use on board the space shuttle. Conceived, designed and built by students at Brigham Young University, it will image the sun with a spatial resolution of 2.5 arc-seconds with a temporal resolution of one second. The instrument will image X-rays with wavelengths between 171A and 181A coming from highly ionized Fe lines in the sun's corona. Data will consist of several hundred high resolution photographs that will help in understanding the initial phases of solar flares, and the relationship between solar flares and the physics of the coronal-chromospheric transition region. This paper briefly outlines the project's goals, gives a brief overview of the construction and operation of the instrument and addresses the unique aspects of running a predominantly undergraduate research project. It summarizes the lessons learned to date, and the current project status. PMID- 21311119 TI - Soft x-ray performance of high-resolution superconducting spectrometers. AB - We are developing high-resolution, broad-band, superconducting X-ray spectrometers for applications in materials science, astrophysics and biophysics. These spectrometers are superconducting microcalorimeters based on superconducting tunnel junction sensors made from thin films of niobium and aluminum. The energy resolution of these spectrometers can be more than an order of magnitude better than that of the best Si(Li) or Ge(Li) detectors. We present results of recent measurements characterizing the performance of these detectors for X-ray energies from 70 eV to 500 eV, where the energy resolution ranged from 4 eV FWHM (at 70 eV) to 12 eV FWHM (at 500 eV). PMID- 21311120 TI - Grazing Incidence XUV Spectroheliograph RES-C for the CORONAS-I Mission. AB - The RES-C grazing incidence XUV spectroheliograph has been developed in the P. N. Lebedev Physical Institute (FIAN) as a part of the CORONAS-I project. Its objective is to obtain images of the full Sun in monochromatic lines over the spectral range of 180?210A, which includes prominent emission from ions of Fe VIII?Fe~XIII, O VI, and Fe XXIV. Here, we describe the optical scheme of the spectroheliograph, and show results of XUV testing of its individual component elements as well as of the complete assembled instrument. XUV measurements were made of the absolute diffraction efficiency and stray-light level for both holographic and mechanically ruled gratings, the spectral reflectivity of the multilayer-coated mirrors, the transmittance of the thin aluminum blocking filters, and the combined spectral efficiency of the whole instrument. The spectral and spatial resolutions of the spectroheliograph were measured by recording spectrally dispersed images of a laser plasma source in monochromatic lines of fluorine ions between 185?200A. For comparison, we also present spectral images of the Sun obtained with the spectroheliograph as flown on the CORONAS-I satellite mission. PMID- 21311121 TI - Observations of the Solar Atmosphere from the Solar and Heliospheric Observatory (SOHO). AB - The Solar and Heliospheric Observatory (SOHO) spacecraft was launched on December 2, 1995, into a halo orbit around the first Lagrangian Point L1 between Sun and Earth, carrying into space a payload of twelve Sun observing instruments. Among them is a set of four complementary telescope/spectrometers to study phenomena and dynamics of the Sun's atmosphere in the far or extreme ultraviolet: The Extreme-Ultraviolet Imaging Telescope (EIT), the Coronal Diagnostic Spectrometer (CDS), the Solar Ultraviolet Measurements of Emitted Radiation (SUMER), and the Ultraviolet Coronagraph Spectrometer (UVCS). The spectral coverage of these instruments, which extents from 151 to 1610A, allows remote sensing investigations of the solar atmosphere by means of spectroscopic and imaging techniques with a spatial resolution down to 1~arcsec. Each one of these instruments by itself is a technological achievement making use of normal incidence, grazing incidence, or multilayer optical techniques to cover the appropriate spectral ranges for each scientific objective. Many of the plasma diagnostic studies have been carried out during the first months of the mission, and this contribution will give an overview of the capabilities of each instrument and the types of observations being made by individual and joint operations. PMID- 21311122 TI - X-ray diffraction comparator - new possibilities. AB - We have studied the possibilities to determine precisely the lattice constants of quartz using an X-ray diffractometer-comparator. This device has double-crystal optical scheme, continuously swinging crystal-monochromator and an original angular reference system. The measurement strategy uses the difference in angular positions of two different Bragg planes relative the third one. On assumption that the wavelength of the used radiation is known with accuracy of +/- 1.2,ppm, the accuracy of determined lattice constants is estimated in +/- 5*10-5A. The described measurement strategy proves to be efficient in measuring the changes of the lattice constants with temperature and in precision testing of a quartz single-crystal homogeneity. We discuss also the features of other instruments for the automatic sorting of quartz blanks in groups by the cut angle, which use the same monochromator pendulum system. PMID- 21311123 TI - Materials for refractive x-ray optics. AB - An X-ray lens using refraction has been proposed by Tomie, and demonstrated for 14 keV X-rays by Snigirev et al. This type of lens is made from a series of very weak lens elements. I calculate the properties of such lenses constructed of various chemical elements and compounds over the range of 1 to 30 keV. In general, I find that X-ray optics made from low density, low Z materials have the widest useful apertures, but require more lens elements than denser and higher Z materials. PMID- 21311124 TI - Experimental study and simulation of the damage induced to various multilayer interferential mirrors by soft x-ray plasma-laser sources. AB - The damage induced to various multilayer interferential mirrors (MIMs) by intense soft X-ray plasma-laser sources are studied both experimentally and theoretically. The mirrors consist of periodic bilayers made up with C/W, Si/Mo, Si/W?. One set of Si/W MIMs is coated with a 100 nm Si film devised to protect the multilayer structure. In the experiment, one resolves in time the evolution of the diffraction pattern of a MIM illuminated by the radiation of a NaCl probing laser-plasma and exposed to the heating radiation emitted by a gold laser plasma. One measures the damage threshold time and the damage threshold fluence. Simulations are performed by combining an optical code with a Lagrangian thermomechanical code giving at each time the density and the thickness of each layer in the MIM. PMID- 21311125 TI - Monochromatic imaging of x-ray source by many-beam dynamical diffraction. AB - We tested the X-ray monochromatic single crystal imaging method proposed by Fraenkel and Kalman (B. S. Fraenkel and Z. H. Kalman, Physica Scripta 41, 400 (1990)) on the basis of combined polarization factors. We performed dynamical calculation of the angular distribution of intensity of the imaging reflection. It was verified that the polarization of the incident wave has really a decisive role for an applicability of the method. An integrated intensity procedure was developed for simulating the conditions during practical imaging. Its applicability is examined in detail for three cases of multiple diffraction with the primary reflection 420 in Ge crystal. Only two cases of the three mentioned showed to be adjustable, producing sufficiently sharp image. A contrast of the image of the adjusted crystal on background level was calculated for those two cases. PMID- 21311126 TI - Signal Dependence on Irradiation Geometry of Cd1-xZnxTe Detectors for Digital X Ray Imaging. AB - CdZnTe is one of the most promising semiconductor material in the field of digital X-ray imaging, and may be operated at room temperature. To improve the detector characteristics, ternary systems such as Cd1-xZnxTe were grown by the high pressure Bridgman (HPG) technique. The signal performance characteristics of quasi-resistive Cd1-xZnxTe semiconductor detectors, was studied at different directions of irradiation, within the X-ray diagnostic energy range. The experimental results suggest that the total efficiency of these semiconductor detectors depends upon the energy absorption efficiency as well as the charge collection efficiency. This imaging detector allows one to investigate methods to improve the detection and imaging performance parameters as part of the development of an X-ray imaging system. PMID- 21311127 TI - Cd1-xZnx Te Detectors for Digital X-Ray Chest Imaging. AB - Radiographic studies with the aim of optimizing the imaging potential of Cd1 xZnxTe detectors for digital chest radiography have been performed. A geometrical chest phantom has been designed, and the dependence of both the signal-to-noise ratio and contrast resolution of a planar Cd1-xZnxTe detector on the phantom thickness has been experimentally determined. Specifically, the detected signal and noise contributions were measured and related to phantom thickness. The results of this study indicate that Cd1-xZnxTe detectors exhibit both high signal to-noise ratio and contrast resolution. At present time, several studies are in process to experimentally identify and quantify the imaging potential of Cd1 xZnxTe detectors for digital radiographic applications. PMID- 21311128 TI - Contrast Study of CdZnTe Detectors for Digital Mammography. AB - Experiments have been performed with the aim of optimizing the image quality parameters of CdZnTe detectors for digital mammography. A geometrical breast phantom has been designed, and the dependence of the contrast resolution of a planar CdZnTe detector on the phantom thickness has been experimentally determined. Specifically, the detected signal and noise contributions were measured and related to phantom thickness. The results of this study indicate that the CdZnTe detectors exhibit a high contrast resolution. On the other hand, the dynamic range of this detector can be improved significantly by further implementation of the data acquisition electronics. PMID- 21311129 TI - Confirmation of action constant for bremsstrahlung. AB - A new action constant for bremsstrahlung has been derived and published by the author. This paper provides experimental confirmation of that action constant by measurements of the intensity of bremsstrahlung from pure metal elements. Such measurements must be taken under the condition that essentially all of the kinetic energy of an incident electron is converted into the energy of an emergent photon. The dependence of the intensity on the exponent of the atomic number, Z, of the target element (measured to be 4/3) shows that the new constant is valid. PMID- 21311130 TI - Absolute Doubly Differential Cross Section for Bremsstrahlung Spectra Produced in 7.0 keV e^---Ag and Au Collisions. AB - The first experimental data are presented for the absolute doubly differential cross section (DDCS) for non-characteristics (bremsstrahlung) X-ray spectra produced by 7.0 keV electron bombardment of (semi-thick) targets of silver and gold at a photon detection angle of 90 degree. The bremsstrahlung spectra are corrected for detector's efficiency as well as for target effects; namely, electron energy loss, backscattering and photon-attenuation in the target. The DDCS values so obtained are compared with the predictions of a thin target bremsstrahlung theory. The agreement between experiment and theory for DDCS both in magnitude and shape is found to be satisfactory within the systematic experimental uncertainty of about 27%. penetrating electrons into the thick targets and the depth distribution of photons generated inside the targets are expected to be also present in the interaction. However, the contributions of these effects to the DDCS have not been taken into consideration. Various possible reasons for the existing discrepancy between experiment and theory are pointed out. PMID- 21311131 TI - Prediction of a Large ASE Effect in Silver Plasmas Produced by a Short-Pulse Drive Laser. AB - A Ne-like laser scheme is considered for a pure silver plasma. Level populations and gain coefficients are calculated with an atomic-kinetics model. It is shown that large gain values (GL>100) are achievable in a hot dense quasi-steady-state silver plasma at lambda=10.038 nm (2-1 transition) and lambda=12.298 nm (0-1 transition). Lasing is also possible at lambda=2.75 nm (2s-2p transition). The plasma conditions needed are: electron temperature 3?5& keV and density 5 * 1022 < ne < 1023;cm-3;. These plasma conditions can be created with a high-contrast, high-intensity short-pulse visible light laser driver. PMID- 21311132 TI - Artificial preparation, indoor passage, and nature breed of Oncomelania hupensis infected with Schistosoma Japonicum. AB - OBJECTIVE: To prepare the infected Oncomelania hupensis by artificial method for the research on the activity, vaccine, and genetic variation of Schistosoma Japonicum (S. Japonicum). METHODS: The mature eggs of S. Japonicum were collected by Nylon silk method and the miracidia were incubated under appropriate conditions. Negative snails were infected with miracidia in different proportion by means of individual or collective infection to seek the best method and proportion of infection between miracidia and snails. Infected snails were divided into 12 groups in total. I-VI groups were for individual infection and VII-XII groups were for collective infection. There were 200 snails in each group. The infection ratios between snails and miracidia in Group I-VI or VII-XII were 1:0,1:5,1:10,1:15,1:20,1:25, respectively. The infected snails were screened, numbered, and reared singly. The amount of cercariae was calculated once every 10 days until the infected snails died. Then cercariae shedding quantity, infection quantity, and mortality of infected snails in every group were compared to find the best infection method and the best infection proportion between miracidia and snails. The cercariae were collected from the first generation of infected snails and were used to infect experimental animals. The mature eggs of S. Japonicum were saved from the infected experimental animals and incubated to get miracidia. The snails were artificially infected by miracidium to get the second generation of infected snails. The developmental rates of adult worms, the egg density in fecal and liver were compared between artificially and naturally infected snails. Results In individual infection Group I-VI,the average infection value of snails were 0 +/- 0,22.7 +/- 4.2,31.7 +/- 4.5,53.0 +/- 5.3,39.3 +/- 5.9,32.7 +/- 4.7,the average fatality of snails were 21.7 +/- 3.1,25.0 +/- 3.6,31.3 +/- 4.9,44.7 +/- 6.5,78.3 +/- 9.5,89.7 +/- 13.6, and the average value of cercariae shedding from infected snails were 0.0 +/- 0.0,308.0 +/- 96.6,428.1 +/- 146.2,527.0 +/- 171.1,571.4 +/- 148.9,602.9 +/- 356.3, respectively. In collective infection Group VII-XII,the average infection value of snails were 0 +/- 0,12.3 +/- 2.5,18.7 +/- 4.7,28.3 +/- 4.2,33.3 +/- 4.7,29.3 +/- 5.5,and the average fatality of snails were 22.7 +/- 3.8,23.7 +/- 4.5,28.3 +/ 5.5,47.0 +/- 9.5,75.7 +/- 8.5,86.3 +/- 12.2, and the average value of cercariae shedding from infected snails were 0 +/- 0,244.5 +/- 57.3,292.3 +/- 74.8,347.1 +/ 100.8,477.2 +/- 142.1,447.3 +/- 161.4, respectively. The second generation of artificially infected snails was obtained successfully. The average infection rate and fatality rate for the second generation of artificially infected snails were 24.65% and 24.50%, both of which were not obviously different from that of the first generation of artificially infected snails (P>0.05). In the animal experiment, the worm growth rate for the naturally infected snails, the first or second generation of artificially infected snails were 68.50%,73.50% or 71.00%. There was no obvious difference among them (P>0.05). The fecal (or liver) eggs per gram for the naturally infected snails, the first or the second generation of artificially infected snails were 1 503 +/- 269,1 683 +/- 233, or 1 541 +/- 117 (or 6 641 +/- 1 819,6 272 +/- 1 419, or 7 263 +/- 1 643). There was no significant difference among the 3 groups (P>0.05). CONCLUSION: Infected snails can be obtained through the artificial method by using S. Japonicum miracidia to infect snails. Individual infection has the advantage over collective infection. The optimal proportion of infection between snails and miracidia is 1:15. There was no significant difference between the first and the second generation of artificially infected snails in the average of cercariae shedding, infection, and fatality average of snails. There was no significant difference between artificially and naturally infected snails in the developmental rate of adult worms, fecal and liver eggs per gram. PMID- 21311133 TI - Dysfunctional beliefs and attitudes on sleep and sleep disturbances pre- and post antidepressant treatments in patients with major depression. AB - OBJECTIVE: To explore the relationship between dysfunctional beliefs and attitudes on sleep and sleep disturbances before and after a short-term pharmacotherapy in patients with major depression. METHODS: Sixty-six (29 male, 37 female, 34.0 +/- 9.5 years old) patients with major depression were recruited before the treatment. Dysfunctional Beliefs and Attitudes about Sleep (DBAS) questionnaire, Pittsburgh Sleep Quality Index (PSQI), Hamilton Depression Rating Scale (HDRS), and Hamilton Anxiety Scale (HAMA) were assessed before and after a 4-week antidepressant treatment. RESULTS: After the 4-week antidepressant treatment, depressive and anxiety symptoms were alleviated significantly, whereas sleep disturbance still persisted. And sleep quality was closely related with problematic sleep beliefs after the treatment. CONCLUSION: Some evidences are provided for cognitive behavioral therapy during antidepressant therapy, and the therapy should be matched with problematic beliefs and attitudes. PMID- 21311134 TI - Effects of total flavonoids of Epimedium sagittatum on the mRNA expression of the estrogen receptor alpha and beta in hypothalamus and hippocampus in ovariectomized rats. AB - OBJECTIVE: To explore the effect of total flavonoids of Epimedium sagittatum (TFE) on the mRNA expressions of the estrogen receptor alpha (ERalpha) and estrogen receptor beta(ERbeta) in hippocampus and hypothalamus in ovariectomized (OVX) Sprague-Dawley(SD) rats, and the mechanism of TFE against postmenopausal osteoporosis. METHODS: Forty-eight female SD rats,aged 10-11 months old, were randomly divided into 4 groups: a sham group, an ovariectomy group (rats were bilaterally ovariectomized), a TFE group, and a 17beta-estradiol group (rats were fed with TFE and 17beta-estradiol for 4 months, respectively). The RT-PCR was performed to determine the mRNA expression of ERalpha and ERbeta in hypothalamus and hippocampus. RESULTS: Serum estradiol level, bone mineral density (BMD) of vertebra,wet weight of uterus, and the mRNA expressions of ERalpha and ERbeta in hypothalamus and hippocampus were markedly decreased in OVX rats, all of which were reversed by 17beta-estradiol treatment except the mRNA expression of ERbeta. Similar results were achieved by TFE treatment except the wet weight of uterus. CONCLUSION: TFE can improve BMD of vertebra in the OVX rats without side effects on the uterus. The mechanism may be related to increasing the mRNA expressions of ERalpha and ERbeta in hypothalamus and hippocampus. PMID- 21311135 TI - Protective effects of IGF-1 on neurons under condition of hypoxia and the role of PI3K signal pathway. AB - OBJECTIVE: To investigate the protective effects of insulin like growth factor 1(IGF-1) on cortical neurons under condition of hypoxia and the possible mechanism. METHODS: Cerebral cortical neurons from newborn rats were cultured under the condition of oxygen and glucose deprivation (OGD) . On day 7, neurons were treated with IGF-1 or IGF-1 plus LY294002 or PD98059 under condition of OGD or normal condition. MTT assay was used to analyze the viability of neurons in each group. The expression of total Akt and p-Akt were analyzed by Western blot. RESULTS: Compared with the control, the neuron viability was significantly higher in IGF-1 treated group under normal or OGD condition (P<0.05). The protective effects of IGF-1 were attenuated in the presence of LY294002 but not PD98059. The result of Western blot showed IGF-1 upregulated the expression of p-Akt, which was inhibited by LY294002. CONCLUSION: PI3K pathway may play an important role in neuroprotection afforded by IGF-1. PMID- 21311136 TI - Effects of fosinopril and losartan on renal Klotho expression and oxidative stress in spontaneously hypertensive rats. AB - OBJECTIVE: To explore effects of fosinopril and losartan on renal Klotho expression and oxidative stress in spontaneously hypertensive rats (SHR) and the mechanisms underlying the protection against renal damage. METHODS: Fifteen male SHRs (22 weeks old) were randomly divided into 3 groups (n=5 in each group): a SHR group, a fosinopril group [10 mg/(kg.d)], and a losartan group [50 mg/(kg.d)]. Age-matched Wistar-Kyoto (WKY) rats were chosen for a control group. Eight weeks later, tail arterial pressure, 24 hours urinary protein (Upro),urinary N-acetyl-beta-D-glucosaminidase (NAGase) were measured. Renal pathological changes were examined under light microscopy by HE staining. The renal mRNA and protein expression of Klotho were determined by RT-PCR, immunohistochemical staining or Western blot. The levels of total antioxidant capacity (TAOC), malondialdehyde (MDA), Cu/Zn superoxide dismutase (Cu/Zn-SOD), Mn superoxide dismutase (Mn-SOD), catalase (CAT), and glutathione peroxidase (GSH Px) were determined. RESULTS: The typical pathological characteristics of hypertensive renal damage were observed in the kidney of the SHR group.Compared with the SHR group, the systolic pressure, Upro, and urinary NAGase, the content of MDA and renal pathological damage was reduced while the renal Klotho expression and activities of TAOC, Cu/Zn-SOD, CAT, and GSH-Px were increased (P<0.05 or P<0.01) in the fosinopril or losartan group. There was no significant difference in renal Mn-SOD level among the 4 groups (P>0.05). CONCLUSION: Fosinopril and losartan can exert protection against hypertensive renal damage through upregulating Klotho expression as well as reducing oxidative stress. PMID- 21311137 TI - Epithelial-to-mesenchymal transdifferentiation of peritoneal mesothelial cells mediated by oxidative stress in peritoneal fibrosis rats. AB - OBJECTIVE: To investigate the role of oxidative stress in the epithelial-to mesenchymal transdifferentiation (EMT) of peritoneal mesothelial cells in rat model of peritoneal fibrosis and the effect of probucol on peritoneal fibrosis. METHODS: The rat model of peritoneal fibrosis was induced by 4.25% high glucose peritoneal dialysis fluid (PDF). The rats were randomly divided into 4 groups:the control group, the saline group, the peritoneal fibrosis group, and the probucol group. A 4 hour peritoneal equilibration test (PET) was performed 4 weeks later. The peritoneal function and net ultrafiltration (UF) volume were determined. The level of malondialdehyde (MDA) and glutathione peroxidase (GSH-Px) in peritoneal tissue were examined. The histology of peritoneal membrane was evaluated by light microscopy. E-cadherin and alpha-smooth muscle actin (alpha-SMA) protein expression was evaluated by immunohistochemical method and Western blot. RESULTS: The mesothelial cells were detached from peritoneal membrane in peritoneal firbosis rats. Comparing with the control rats, the thickness of visceral peritoneum, the level of MDA, and the-SMA protein expression were increased while the net ultrafiltration volume, the level of GSH-Px and E-cadherin protein expression were decreased in peritoneal firbosis rats. All these changes were reversed in the rats treated with probucol. CONCLUSION: Oxidative stress plays an important role in transdifferentiation of peritoneal mesothelial cell in the peritoneal fibrosis rats. Probucol can improve structure and function of peritoneum, and partially reverse the EMT by reducing the oxidative stress. PMID- 21311138 TI - [Effect of Danshensu on fibronectin and collagen-1 secretion induced by high glucose in human peritoneal mesothelial cells]. AB - OBJECTIVE: To investigate the possible role of Danshensu on fibronectin (FN) and collagen-I (Col-I) secretion induced by high glucose in human peritoneal mesothelial cells (HPMCs). METHODS: HPMCs were treated with high glucose and Danshensu at different concentrations. The mRNA expression of FN, Col-I, endothelin-1 (ET-1), and heme oxygenase-1 (HO-1) were examined by reverse transcription-polymerase chain reaction (RT-PCR). The protein expression of FN, Col-I HO-1 and ET-1 were analyzed by enzyme-linked immunosorbent assay or immunofluorescence method. RESULTS: The expression of protein and mRNA of FN and Col-I were attenuated by Danshensu in both dose-dependent and time-dependent manner. The mRNA and protein levels of ET-1 were decreased, and the mRNA and protein levels of HO-1 increased in the Danshensu groups in a dose-dependent manner compared with the high glucose group. The expression of ET-1 and HO-1 showed little difference in a time gradient of danshensu(P>0.05). CONCLUSION: Danshensu can protect HPMCs through inhibiting the expression of FN and Col-I induced by high glucose, which is related to the suppression of oxidative stress. PMID- 21311139 TI - [Effect of apolipoprotein A-I mimetic peptides on cholesterol efflux in RAW264.7 cells]. AB - OBJECTIVE: To determine the effect and possible mechanism of an apolipoprotein (apo) A-I mimetic peptide, D-4F, on cholesterol efflux in RAW264.7 macrophages. METHODS: RAW264.7 macrophages were incubated in the medium containing 8-bromo cAMP (8-Br-cAMP, 0.5 mmol/L) and ox-LDL (50 MUg/mL) for 24 h. Then various concentrations of D-4F (0-100 MUg/mL) or H89 (20 MUmol/L, a protein kinase A inhibitor) were added for the purpose of interference. The intracellular cyclic AMP (cAMP) level was determined by enzyme-linked immunoabsobant assay (ELISA). ATP binding cassette transporter A1 (ABCA1) expression in the macrophages was quantitated by real-time PCR and Western blot. RESULTS: D-4F significantly increased the cholesterol efflux in both concentration and time-dependent manner accompanied by the increase in the intracellular cAMP level, ABCA1 mRNA and protein expression. The effect of D-4F on cholesterol efflux ABCA1 expression was enhanced by 8-Br-cAMP. Although H89 did not affect the basal cholesterol efflux and ABCA1 expression, it could attenuate the effect of 8-Br cAMP. CONCLUSION: D 4F affects cholesterol efflux, cAMP level, and ABCA1 expression in macrophages, which is likely involved in the pathway of cAMP/PKA/ABCA1. PMID- 21311140 TI - [Atorvastatin attenuates hypoxic pulmonary hypertension in rats by inhibiting RhoA/Rho kinase pathway]. AB - OBJECTIVE: To investigate whether atorvastatin treatment can improve the symptoms of hypoxia-induced pulmonary hypertension in rats by inhibiting RhoA/Rho kinase pathway. METHODS: A total of 32 Westar rats was divided into 4 groups: normoxic controls (Group A), hypoxic controls (Group B), hypoxia plus atorvastatin [10 mg/(kg.d)] group(Group C), and hypoxia plus the vehicle of atorvastatin (Group D). Rats for hypoxia treatment were maintained under the condition of 10% FiO2 6 h/d for 4 weeks. At the end of 4 weeks, rats were anesthetized and the mean pulmonary arterial pressure (mPAP) was measured by right heart catheterization. The ratios of arteriole wall thickness to vascular external diameter (WT%), and vascular area to total vascular area (WA%) were measured by a computerized image analyzer. RhoA and phos-MYPT-1 expression in the pulmonary artery were determined by Western blot. RESULTS: Comparing with Group A, the mPAP [(29.6 +/- 1.1)mmHg vs (16.8 +/- 0.7)mmHg], RV/(LV+S) [(39.0 +/- 0.7)%vs (29.4 +/- 0.5)%], WT% [(35.6 +/ 2.4)% vs (22.3 +/- 1.2)%] and WA% [(56.5 +/- 5.1)% vs (36.6 +/- 2.3)%] in Group B were all significantly increased (P<0.05). Comparing with Group B, the mPAP [(25.3 +/- 3.2)mmHg], RV/(LV+S) [(36.3 +/- 2.1)%], WT%[(29.2 +/- 3.2)%] and WA% [(48.1 +/- 2.7)%] in Group C were significantly decreased. The vehicle of atorvastatin had no such effect. The expression of RhoA and phos-MYPT-1 in the pulmonary artery was increased in Group B, but it was decreased in Group C. CONCLUSION: RhoA/Rho kinase pathway plays an important role in the development of hypoxic pulmonary hypertension. Atorvastatin can improve the symptoms of hypoxic pulmonary hypertension by inhibiting RhoA/Rho kinase activity. PMID- 21311141 TI - [Clinical features and prognosis analysis of small-cell lung cancer complicated with hyponatremia]. AB - OBJECTIVE: To evaluate the clinical features and prognosis of small-cell lung cancer (SCLC) complicated with hyponatremia. METHODS: The clinical data of 158 patients with SCLC of the Second Xiangya Hospital from January 2000 to December 2007 were studied retrospectively. RESULTS: The incidence rate of hyponatremia in SCLC was 42.4%(67/158). The median survival time was 7.6 months in patients with subnormal serum sodium, and 14.1 months in patients with normal values. There was significantly different between 2 groups (P<0.001). The patients who did not fully regain normal values of serum sodium, had poorer survival (6.2 months) compared with the patients with normal serum sodium (10.3 months, P=0.044). CONCLUSION: The incidence rate of hyponatremia in SCLC is high. The prognosis of SCLC with hyponatremia is very poor, especially in those who can not regain normal values of serum sodium after the treatment. So diagnosis and treatment at early stage are very important. PMID- 21311142 TI - [Relationship of hyperhomocysteinemia in pregnant rats and congenital heart defects in the newborn rats]. AB - OBJECTIVE: To investigate the relationship between homocysteine (HCY) and congenital heart defects, and to observe the toxic effect of different doses of HCY on embryonic heart development in mammalian. METHODS: A total of 30 SD pregnant rats were randomly divided into 3 groups: a high dose group [200 mg/(kg.d)], a low dose group [(100 mg/(kg.d)] and a control group (equal volume of physiologic saline, n=10 in each group). The HCY or vehicle was given intraperitoneally from 7 to 20 days after uterineincision delivery. The contents of HCY in serum were analyzed by high performance liquid chromatogram electrochem before the pregnancy and 20 days after the pregnancy. The structure changes of the newborn rats heart were observed by stereoscope. The ultrastructure changes of cadiomyocyte were observed through transmission electron microscope. RESULTS: Comparing with the control, serum HCY in rats 20 days after pregnancy was significantly increased in the high or low dose group [(30.47 +/- 1.12), (20.90 +/- 1.08)vs(10.98 +/- 0.77)MUmol/L, P<0.01)], indicating that the hyperhomocysteinemia animal model was successfully established. The incidence rate of congenital heart defects in neonatal was significantly increased in the high or low dose group(14.13%, 9.57% vs 0.76%, P<0.01). The number of apoptotic cells were significantly increased in the high dose group. CONCLUSION: Hyperhomocysteinemia may exert toxic effect on embryonic heart development in pregnancy rats, which led to congenital heart defects in the newborn rats. Hyperhomocysteinemia induced cardiomyocyte apoptosis may, at least partially, contribute to the heart defects. PMID- 21311143 TI - [Cardiac perforation and tamponade in percutaneous cardiac intervention]. AB - OBJECTIVE: To explore the cause of cardiac perforation and tamponade during cardiac catheterization and intervention and to evaluate the effectiveness of the emergency treatment for tamponade in our hospital. METHODS: The clinical data from 23, 319 patients who received diagnostic catheterization or therapeutic procedures were analyzed retrospectively. RESULTS: Cardiac perforation and cardiac tamponade were observed in 22 of the 23, 319 patients during catheter procedures. It includes 1 in coronary artery angiography, 9 in percutaneous balloon mitral valvuloplasty, 3 in diagnosis, 2 in congenital heart disease intervention, 2 in pacemaker implantation, 2 in atrial fibrillation ablation and the other 3 in coronary revascularization. The occurrence of cardiac perforation in 11 patients was related to puncture of the interatrial septum and/or the procedure in the left atrial procedure and 2 were related to high pressure injection. Seventeen patients were found cardiac tamponade in the process of catheterization, and 5 were found at 2-14 h after operation. Pericardiocentesis and pericardial catheter drainage were performed in 20 patients and 11 of them succeeded. Among the other 11 patients, 7 were successfully saved by thoracotomy and 4 died. CONCLUSION: Cardiac tamponade is a severe and fatal complication that may occur in different catheter procedures. Early prevention and diagnosis and performingperi cardiocentesis and drainage timely are critical to reduce the mortality. PMID- 21311144 TI - [Clinical application of completed video-assisted thoracic surgery lobectomy (with 186 cases report)]. AB - OBJECTIVE: To evaluate the postsurgery effects of completed video-assisted thoracic surgery (VATS) lobectomy and the indication for non-small cell lung cancer cases (NSCLC). METHODS: Retrospective analysis of 186 patients received completed VATS technique surgery for lobectomy from October 2007 to July 2010. RESULTS: All surgeries (186 cases) were performed successfully, and there was no death and severe postsurgery complications. Among the 186 patients, 1.6%(3/186) were switched to open thoracic operation. Up to now, all patients was alive, and the longest time for return was 31 months. Compared with regular lobectomy, bleeding, time for postoperative drainage and hospital stay were all decreased in completed VAST (P<0.05). In NSCLC cases, the average number of dissected lymph node was 14.5(4-22). CONCLUSION: VATS lobectomy is safe and feasible. It is particularly useful for early stage NSCLC (esp.I-IIb) with proper indication. PMID- 21311145 TI - [Measurement of intracranial hematoma volume by personal computer]. AB - OBJECTIVE: To explore the method for intracranial hematoma volume measurement by the personal computer. METHODS: Forty cases of various intracranial hematomas were measured by the computer tomography with quantitative software and personal computer with Photoshop CS3 software, respectively. the data from the 2 methods were analyzed and compared. RESULTS: There was no difference between the data from the computer tomography and the personal computer (P>0.05). CONCLUSION: The personal computer with Photoshop CS3 software can measure the volume of various intracranial hematomas precisely, rapidly and simply. It should be recommended in the clinical medicolegal identification. PMID- 21311146 TI - [Relationship between the chronic periodontitis and the depression anxiety psychological factor]. AB - OBJECTIVE: To explore the relationship between the chronic periodontitis (CP) and the depression-anxiety psychological factors. METHODS: Thirty-one patients and 29 age, gender-matched volunteers were enrolled for this study. In order to assess the depression-anxiety psychological index, the subjects filled the questionnaire regarding the demographic and socioeconomic information, the oral hygiene habit, the Center for Epidemiologic Studies Depression Scale (CES-D) and the Self Rating Anxiety Scale(ASA). Calculus index (CI), bleeding on probing (BOP), probing depth (PD), clinical attachment loss (CAL), furcation involvement (FI) and tooth mobility were assessed at 6 sites per tooth of all erupted teeth by a manual periodontal probe. The data were analyzed by the analysis of variance, chi(2) test, and multivariable logistic step wise analysis via the software of SPSS 15.0. RESULTS: The mean CAL of the control group was 0.46 +/- 0.16,the mean CAL of the moderate, high, and severe CP group was 2.84 +/- 0.12, 3.51 +/- 0.34, and 4.71 +/- 0.51, respectively, which is significant difference between each other (P<0.01). The depression index of the volunteers, the moderate CP, the high CP, and the severe CP was 30.52 +/- 3.73, 35.83 +/- 7.76, 37.25 +/- 6.16, 37.82 +/- 5.94, respectively. The anxiety index among the 4 groups was 26.69 +/- 3.55, 37.67 +/- 6.31, 32.87 +/- 5.54, and 35.94 +/- 6.30, respectively. The depression and anxiety indexes of the periodontitis groups were higher than those of the control (P<0.01) while there was no significant difference among the 3 CP groups (P>0.05). The multivariate logistic analysis of the relationship between CP and the depression-anxiety psychological factors showed that the depression psychological factor was B=2.301,OR=9.988 while the optimistic coping style was B=-5.174,OR=0.006 in the equation of the regression. CONCLUSION: The depression psychological factor was related to the progression of CP. In addition, the optimistic coping style could prevent the progression of the CP. PMID- 21311147 TI - The doctrine of informed consent in surgical practice. AB - Physicians and other professionals in the field of medicine have to perform invasive and non-invasive procedures on patients as part of their duties. There is a legal basis upon which these procedures are done; this is called 'informed consent.' Sociocultural factors have strong influence on the sick role. These factors influence the application of informed consent in Nigeria. PMID- 21311148 TI - Evaluation of the effectiveness of deworming and participatory hygiene education strategy in controlling anemia among children aged 6-15 years in Gadagau community, Giwa LGA, Kaduna, Nigeria. AB - BACKGROUND: Anemia is one of the most common and most serious health disorders worldwide. The World Health Organization (WHO) estimated that about 40% of the total world's population (more than 2 billion individuals) suffer from anemia. In developing countries, the prevalence rate of anemia is about 20% in school-aged children. More than 10 million African children are thought to be anemic (Hb < 11 g/dl). Also, in Africa, it is estimated that more than half of all children over 5 years and pregnant women are anemic. Community-based estimates of anemia prevalence in settings where malaria is endemic range between 49% and 76%. In Nigeria, the prevalence rate for anemia among children was 29.4%. It was highest in the South-East (49.7%) and lowest in the North-East (11.1%). OBJECTIVE: The study aimed at evaluating the effectiveness of deworming and participatory hygiene education strategy in controlling anemia among children aged 6-15 years in the Gadagau community, north-western Nigeria. MATERIALS AND METHODS: A cross sectional descriptive study of 306 children aged 6-15 years selected from two rural communities (Gadagau, which was the study group and Karau-Karau, which was the control group) in the Giwa Local Government Area of Kaduna State Nigeria using a multistage sampling technique. The studies involved parasitological examination and anemia evaluation before and at 3 months after the children were dewormed. RESULTS: Only 301 children (150 children in study group and 151 children in control group) were studied. The results showed that those who were dewormed and had participatory hygiene education lectures (study group) had significantly higher mean hemoglobin, from an initial 10.4 g/dl to a post intervention of 12.4 g/dl (paired t-test = 13.96; P = 0.00). Also, there was a rise in the mean hemoglobin of the control group, but not as much as in the study group, from an initial mean hemoglobin of 10.5 g/dl to a post-intervention of 11.2 g/dl (paired t-test = 2.89; P = 0.004). Comparing the study and the control groups, those who were dewormed and also had participatory hygiene education lectures (study group) had a significantly higher reduction in the level of children who had ova of intestinal helminthes present in their stool than those in the control group (Chi 2 = 31.61; df = 1, P = 0.00). CONCLUSION: This study therefore concludes that including participatory hygiene education to deworming programmes will greatly improve the hemoglobin level of children in areas where there is a high prevalence of hookworm infections, especially as a short-term preventive measure for anemia in children. PMID- 21311149 TI - Knowledge and attitudes of physicians relating to reporting of adverse drug reactions in Sokoto, north-western Nigeria. AB - BACKGROUND/OBJECTIVES: Adverse drug reactions (ADRs) are important causes of morbidities. Voluntary reporting of ADR is important in safety surveillance of medicines already in the market. This study was, therefore, conducted to appraise the current documentation of ADR in Sokoto, to analyze the extent to which clinicians appreciate factors that could affect reporting ADRs. MATERIALS AND METHODS: Four hospitals within Sokoto metropolis were selected by convenient sampling. Pre-validated questionnaires containing questions on demographic and professional characteristics, and questions that evaluate attitudes as listed in the so-called "deadly sins" of Inman were self-administered by physicians. Data from respondents were analyzed by logistic regression. RESULTS: Of 61 physicians interviewed, 43 (70.5%) had encountered potential ADRs in the 12 months before the study but only 3 (7.0%) of these were reported. Fifty eight (95.1%) of the respondents were not aware that an ADR reporting system was available in Sokoto but all the 3 respondents who were aware of the existence of a reporting system had reported an ADR. Generally, there was no significant relationship between demographic and professional attributes and scores obtained on each of the Inman's attitude measured except that more experienced physicians tend to believe that ADRs are not impossible to identify and female physicians were more reluctant to engage representatives of pharmaceutical companies on ADRs related to their drugs. Additional attitudes that may influence ADRs reporting were identified. CONCLUSION: Adverse drug reactions are under-reported in Sokoto. Lack of physicians' awareness of channels for reporting appears to be the major cause. PMID- 21311150 TI - Psychosocial characteristics of female infertility in a tertiary health institution in Nigeria. AB - OBJECTIVES: Women with infertility experience higher rates of psychological distress compared with their fertile counterparts. In developing countries, socio cultural factors may aggravate this distress. We aimed to determine the prevalence of psychological distress as well as its associated socio-cultural characteristics among women attending the infertility clinic of a tertiary hospital in Nigeria. MATERIALS AND METHODS: Women (n=100) attending an infertility clinic were consecutively recruited over a two-month period and compared with a similar number of pregnant women attending the antenatal clinic at the same hospital. A semi-structured questionnaire was designed to record socio-demographic and clinical variables. The 30-item General Health Questionnaire was used to screen for psychological distress. RESULTS: The prevalence of probable psychological distress was significantly higher among the infertile group compared with their fertile counterparts (P<0.001). There were significant differences between the groups in terms of their mean age (P<0.01), employment status (P<0.02), educational status (P<0.01), and duration of marriage (P<0.001). Infertile women who had previously sought help from a traditional or faith-based healer for infertility were more likely to experience probable psychological distress (P<0.017). CONCLUSION: Infertile women are more vulnerable to psychological distress and require psychological support. There is a need to incorporate mental health screening and treatment in the routine care of infertile women in Nigeria. PMID- 21311151 TI - Use of non-vascularized autologous fibula strut graft in the treatment of segmental bone loss. AB - BACKGROUND: Fractures resulting in segmental bone loss challenge the orthopedic surgeon. Orthopedic surgeons in developed countries have the option of choosing vascularized bone transfers, bone transport, allogenic bone grafts, bone graft substitutes and several other means to treat such conditions. In developing countries where such facilities or expertise may not be readily available, the surgeon has to rely on other techniques of treatment. Non-vascularized fibula strut graft and cancellous bone grafting provides a reliable means of treating such conditions in developing countries. MATERIALS AND METHODS: Over a period of six years all patients with segmental bone loss either from trauma or oncologic resection were included in the study. Data concerning the type of wound, size of gap and skin loss at tumor or fracture were obtained from clinical examination and radiographs. RESULT: Ten patients satisfied the inclusion criteria for the study. The average length of the fibula strut is 7 cm, the longest being 15 cm and the shortest 3 cm long. The average defect length was 6.5 cm. Five patients had Gustillo III B open tibial fractures. One patient had recurrent giant cell tumor of the distal radius and another had a polyostotic bone cyst of the femur, which was later confirmed to be osteosarcoma. Another had non-union of distal tibial fracture with shortening. One other patient had gunshot injury to the femur and was initially managed by skeletal traction. The tenth patient had a comminuted femoral fracture. All trauma patients had measurement of missing segment, tissue envelope assessment, neurological examination, and debridement under general anesthesia with fracture stabilization with external fixators or casts. Graft incorporation was 80% in all treated patients. CONCLUSION: Autologous free, non-vascularized fibula and cancellous graft is a useful addition to the armamentarium of orthopedic surgeon in developing countries attempting to manage segmental bone loss, whether created by trauma or excision of tumors. PMID- 21311152 TI - Ophthalmologic abnormalities among deaf students in Kaduna, Northern Nigeria. AB - BACKGROUND: The association between deafness and ocular problems is well established; however the nature and prevalence of these problems are diverse across the globe. OBJECTIVE: The aim of this study is to determine the nature and prevalence of ophthalmologic abnormalities in deaf students and offer treatment to those with remediable conditions. METHOD: Six hundred and twenty deaf students aged between 5 and 38 years were examined in a school for the deaf. RESULTS: One hundred and thirty (20.9%) had some form of ophthalmologic abnormality. Some had anterior segment abnormalities such as corneal opacities (0.5%) and allergic conjunctivitis (3.4%) while others had posterior segment abnormalities like optic atrophy (0.3%), Waardenburg syndrome (0.6%) and Ushers syndrome (0.6%). Refractive error was the most common (7.9%). CONCLUSION: Since these deaf students use their sight to compensate for the deafness, routine ophthalmologic examination should be carried out on them so that ophthalmologic abnormalities are detected early and treatment offered for remediable diseases. PMID- 21311153 TI - Proteinuria among adult sickle cell anemia patients in Nigeria. AB - BACKGROUND/OBJECTIVE: The life expectancy of patients with sickle cell anemia (SCA) has improved with modern medical care, and this has led to frequent observation of various chronic complications of the disease including abnormalities in renal function. Proteinuria is not only a marker of renal disease but is also a predictor of disease progression. This screening study was aimed at evaluating the prevalence of proteinuria among adult SCA patients in Kano, Nigeria, which has not been reported previously. MATERIAL AND METHODS: A total of 200 adult SCA patients were studied. They consisted of 100 men and 100 women. Blood was collected for the assay of serum urea, sodium, potassium, chloride, bicarbonate, and creatinine and estimated glomerular filtration rate (eGFR) was determined using the Cockcroft-Gault formula. Urine dipstick test for the presence of proteinuria and other abnormalities was done, and 24-hour urine protein was measured in those with significant proteinuria. RESULTS: Mean age of the male patients was 25.1 +/- 1.0 years, whereas the mean age of the female patients was 22.8 +/- 4.2 years. Twenty eight percent (32 males, 24 females) of the subjects were observed to have significant proteinuria. The mean estimated eGFR of the males was 88 +/- 19.6 ml/min while that of the females was 92 +/- 10.2 ml/min. The male SCA patients with proteinuria had a mean eGFR of 70 +/- 6.9 ml/min, whereas the female SCA patients with proteinuria had mean eGFR of 101 +/- 2.5 ml/min. Among the male patients with proteinuria, 50% had chronic kidney disease (CKD). CONCLUSION: Proteinuria which is a marker of renal insufficiency is common among adult SCA patients, and routine screening for proteinuria may help detect those at increased risk of renal disease. CKD prevalence is high among SCA patients with significant proteinuria. PMID- 21311154 TI - Using methylene blue for perioperative localization of the hydrocele sac in boys. AB - BACKGROUND: Ligation of a patent processus vaginalis via the inguinal approach is the standard operative technique for the treatment of hydroceles in infants and children. Although a simple technique, identification of the processus vaginalis can be difficult even for the experienced surgeon. AIMS: To investigate the use of methylene blue in the perioperative identification of the patent processus vaginalis in a group of children presenting with hydrocele. MATERIALS AND METHODS: Twenty consecutive patients with hydrocele between the ages of 1 and 9 years were recruited for the study. Methylene blue 0.3-0.5 ml was injected slowly into the hydrocele fluid through the scrotal wall after aspiration, followed by routine ligation of the hydrocele track. RESULTS: The track of the processus vaginalis was clearly visualized in 17 (85%) of the patients, while in 3 (15%) patients no track could be seen, the hydrocele being localized to the tunica vaginalis. There were no cases of inadvertent testicular injury and there was no intraoperative complication. No patient reacted in any abnormal way to the methylene blue. CONCLUSION: The technique helps in the identification of a patent processus vaginalis when it is present. It may be useful in cases where difficulty in identification of the hydrocele tract is anticipated in a child. PMID- 21311155 TI - Detection of Salmonella typhi agglutinins in sera of patients with other febrile illnesses and healthy individuals. AB - BACKGROUND AND PURPOSE: Widal test is frequently applied for the detection of Salmonella agglutinins to diagnose Salmonella enterica serotype Typhi infection. There are however a number of controversies challenging the diagnostic utility of this test. This study was performed to determine the prevalence of Salmonella agglutinins in patients with other febrile illnesses and healthy blood donors. MATERIALS AND METHODS: Sera from 50 healthy blood donors were compared for the presence of Salmonella agglutinins in various groups of patients with other febrile illnesses using Widal test in the division of Serology and Immunology at King Khalid University Hospital, Riyadh. The patient groups of other febrile illnesses included infections with Beta-hemolytic streptococcus (n = 50), Brucella (n = 46), Helicobacter pylori (n = 24), Treponema pallidum (n = 30), Toxoplasma (n = 44), and other parasites (n = 20). RESULTS: Majority of the patients and normal individuals were tested positive for Widal test at dilution of less than 1 : 40 both for the O (62.5%) and H (64.6%) antigen. A decreasing trend in Widal reactivity was observed with increasing dilutions of the serum samples. At 1 : 160 titer, which is generally considered as a cut off point for positive Widal test, 6.4 and 11% individuals had positive Widal test for O and H Salmonella antigens, respectively. CONCLUSION: Detection of a significant number of positive Widal tests in conditions where it is expected to be nonreactive appears to be a serious problem in making a correct diagnosis of typhoid fever, thus challenging the diagnostic utility of the Widal test. PMID- 21311156 TI - Adult large bowel obstruction: a review of clinical experience. AB - BACKGROUND: Adult large bowel obstruction is an infrequent cause of acute obstruction in Africa and India. The cause of obstruction varies between regions of the world. Current controversy concerns the surgical management of the acutely obstructed left colon. MATERIALS AND METHODS: This is a prospective study of adult patients with acute large bowel obstruction over a 6-year period. The diagnosis of adult obstruction was made from a history of constipation, abdominal distension, abdominal pain, nausea, and radiographic features of large bowel obstruction. Laparotomy was performed on all patients after resuscitation. If the obstruction involved the right colon resection and primary ileo-colic anastomosis was performed, while for a lesion in the left colon a resection and primary colocolic anastomosis was performed after intraoperative antegrade colonic irrigation. If the obstructing lesions were thought to be malignant and too advanced to merit any excisional or the patient's general condition was too poor to withstand resection, a biopsy was taken and a decompressive bypass procedure given pending the confirmation of the diagnosis. The clinical course and postoperative outcome were carefully documented. RESULTS: A total of 50 patients aged 20-80 years, with a median age of 49 years, presented with features consistent with large bowel obstruction. Of these, 32 had simple sigmoid volvulus and were offered sigmoid colectomy and primary colorectal anastomosis, while 3 further patients with compound sigmoid volvulus had double resection with primary ileo-ileal and colorectal anastomosis. A patient with sigmoid volvulus had a Hartmann's procedure. Twelve patients had colon cancer, four had left hemicolectomy and primary colocolic anastomosis; three, sigmoid colectomy and primary colorectal anastomosis; three, low anterior resection and primary colorectal anastomosis; one decompressive colostomy and one, a right hemicolectomy and primary ileocolic anastomosis. The two patients with functional obstruction (Ogilvie syndrome) had tube caecostomy. All resections and primary anastomosis involving the right colon were preceded by antegrade on-table colonic lavage. One clinical anastomotic leak occurred in a low rectal anastomosis and minor wound infection in 10 patients. Operative mortality occurred in three patients with sigmoid volvulus. CONCLUSION: Adult large bowel obstruction is infrequent in our community and is caused commonly by sigmoid volvulus. Resection and primary anastomosis of the acute left-sided large bowel obstruction seems safe after antegrade on-table colonic lavage, provided bowel gangrene with peritonitis or any additional risk factor for anastomotic breakdown is not present. PMID- 21311157 TI - Aero-disaster in Port Harcourt, Nigeria: a case study. AB - BACKGROUND: Aero-disaster in Nigeria is posing a serious problem to government, the public and relatives of victims, as many lives are lost in a single event. MATERIALS AND METHODS: A case study based on an incident at an international airport in Nigeria on December 10, 2005. Detailed autopsy was performed on 97 fully identified bodies out of the 106 victims. Variables considered include ages, sex, pattern of injuries and death as well as problems associated with identification of bodies. RESULTS: A total of 97 (91.5%) out of the 106 deaths recorded were autopsied. Nine (8.5%) bodies were beyond identification, and hence autopsy could not be properly done on them. Fifty-nine (60.8%) were males and 38 (39.2%) were females, giving a ratio of 1.4:1. Sixty-one (62.9%) were children and adolescents below the age of 20 years. Severe burns 27 (27.8%), multiple injuries with burns 21 (21.6%), inhalation of fumes 20 (20.6%), multiple injuries only 16 (16.5%), severe head injury alone 11 (11.3%) and ruptured viscous 2 (2.1%) were the causes of death at autopsy in that order of frequency. CONCLUSION: Aero-disaster, though rare in Port Harcourt, is posing a serious problem in Nigeria in recent times. Various agencies should be established to adequately control mass disasters in Nigeria. Adequate maintenance of aircraft and strict observation and enforcement of aviation laws may drastically reduce the frequency of accidents and subsequent deaths. PMID- 21311158 TI - Efficacy of a clinical stroke score in monitoring complications in acute ischaemic stroke patients could be used as an independent prognostic factor. AB - BACKGROUND: Presence of medical complications in stroke patients has been established. The efficacy of a stroke score in intensive monitoring of these complications in acute ischaemic stroke patients has not been studied. METHODS: Eighty-seven patients with acute ischaemic stroke were assessed with National Institute of Health Stroke Scale (NIHSS) by the examiner within days of admission; (1, 7, 30, and 90 days). Onset and types of complications were documented within the duration of the study period, using a questionnaire and laboratory investigations. RESULTS: Fifty-nine [67.8%] patients in the study population had complications, with mean initial NIHSS score 17.1 +/- 7.9; mortality was 39%, and 27.8% of survivors had good recovery. In patients without complications, the mean initial NIHSS score was 11.4 +/- 6.0; mortality was not observed, and 50% of survivors had good recovery. CONCLUSION: All patients without complications survived. High NIHSS scores, (with minimal changes below baseline) were related to high mortality and morbidity in the complications group. PMID- 21311159 TI - Severe pentasomide Armillifer armillatus infestation complicated by hepatic encephalopathy. AB - BACKGROUND: Diagnosis of Armillifer armillatus infestation is usually incidental, commonly via autopsy or radiography. Affected individual are usually asymptomatic. The case presented here, however, had severe thoracic and abdominal involvement with clinical manifestations. AIM: To report a case of heavy A. armillatus infestation in an adult female Nigerian rural dweller complicated by hepatic parenchyma damage. SETTING: Case report from semi-urban southern Nigeria, using clinical records and imaging findings. MATERIALS AND METHODS: Clinical case records, including laboratory results and radiographic /computed tomography images. CONCLUSION: Parenchymal damage with organ dysfunction can be seen with severe A. armillatus infestation. Thus, there is a need for regular health education regarding the risk of A. armillatus infestation for individuals who consume snake meat. PMID- 21311160 TI - Bilateral osteonecrosis of the femoral heads in a patient with systemic lupus erythematosus. PMID- 21311161 TI - Association between head circumference and body size. AB - BACKGROUND/AIMS: Studies on the association between head circumference (HC) and height or weight have shown variable results. METHODS: Using data from the Dutch nationwide survey performed in 1997 (n = 14,500), we calculated correlations for different ages, and fitted a regression model for the estimation of HC. HC versus height charts were created for different age groups. Data from children from other ethnic groups and children with various growth disorders were plotted on the charts and compared with reference data. RESULTS: Correlations between HC and height or weight showed similar patterns: highest at birth, followed by a rapid decline to a stable level and a peak in adolescence. On charts containing the regression line +/-2 standard deviations for subjects aged 0-2 months and 2 months to 21 years, Turkish and Moroccan children, as well as children with idiopathic short stature and small for gestational age, had a normal HC for height, whereas children with an insulin-like growth factor 1 receptor defect or Sotos syndrome showed trends towards a smaller or larger HC for height, respectively. CONCLUSION: HC correlates strongly with height and weight. The charts of HC for height may serve as an additional tool to interpret HC in short or tall children. PMID- 21311162 TI - Effect of exercise and respiratory training on clinical progression and survival in patients with severe chronic pulmonary hypertension. AB - BACKGROUND: Even though specific agents for the treatment of patients with pulmonary hypertension (PH) are available, in PH patients, physical capacity and quality of life (QoL) are often restricted and survival is reduced. OBJECTIVES: This study prospectively investigated the long-term effects of respiratory and exercise training in patients with severe chronic PH regarding safety, time to clinical worsening and survival. METHODS: Fifty-eight consecutive patients with severe PH on stable disease-targeted medication received exercise and respiratory training in hospital for 3 weeks and continued at home. They were prospectively followed for 24 +/- 12 months. Primary endpoints were time to clinical worsening and survival. Adverse events and changes in the 6-min walking test, QoL, WHO functional class and gas exchange were secondary endpoints and were evaluated at baseline and at weeks 3 and 15. RESULTS: All patients tolerated the exercise training well without severe adverse events. In week 15, 6-min walking test results were significantly improved compared to baseline (by 84 +/- 49 m, p < 0.001), as well as QoL scores, WHO functional class (from 2.9 +/- 0.5 to 2.6 +/- 0.6, p < 0.01), peak oxygen consumption (from 12.5 +/- 3.0 to 14.6 +/- 3.9 ml/min/kg, p < 0.001), heart rate at rest (from 75 +/- 12 to 61 +/- 18 beats/min, p < 0.001) and maximal workload (from 65 +/- 21 to 80 +/- 25 W, p < 0.001). Survival at 1 and 2 years was 100 and 95%, respectively. Fifteen events occurred during the follow-up. CONCLUSION: This study indicates that exercise and respiratory training as add-on to medical treatment may improve exercise capacity and QoL, and that they have a good long-term safety in the described setting. PMID- 21311163 TI - Genetic background predicts poor prognosis in frontotemporal lobar degeneration. AB - BACKGROUND: Ruling out predictors of survival in frontotemporal lobar degeneration (FTLD) is a clinical challenge for defining disease outcomes and monitoring therapeutic interventions. Little is known about determinants of survival in FTLD. OBJECTIVE: The aim of the present study was to identify whether genetic determinants are key, not only as risk factors but as predictors of survival in FTLD. METHODS: Ninety-seven FTLD patients were considered in the present study. A clinical evaluation and a standardized assessment were carried out. Each patient underwent blood sampling for genetic testing, and mutations within the progranulin (PGRN) gene, microtubule-associated protein tau (MAPT) haplotype, apolipoprotein E (APOE) genotype and 4 vascular endothelial growth factor (VEGF) polymorphisms were evaluated. Discrete-time survival models were applied. RESULTS: Monogenic FTLD due to PGRN mutations [odds ratio (OR) = 3.62, 95% confidence interval (CI) = 1.12-11.7; p = 0.032], and MAPT *H2 haplotype (OR = 3.23, 95% CI = 1.08-9.69; p = 0.036) were associated with an increased hazard risk of poor outcome. Conversely, APOE genotype, and VEGF polymorphisms were not associated with survival risk in the FTLD sample. CONCLUSIONS: Genetic background is not only crucial in disease pathogenesis, but it also modulates disease course. Genetic factors influencing prognosis should be taken into account to include homogeneous groups in future clinical trials and to monitor efficacy of future interventions. PMID- 21311164 TI - Stage-by-stage effects of surgical margin status on biochemical failure after radical prostatectomy in patients with clinically localized prostate cancer. AB - PURPOSE: To evaluate the effects of pathological stage and surgical margin status on biochemical failure rates after radical prostatectomy (RP). MATERIALS AND METHODS: The records of 205 patients who underwent RP for clinically localized prostate cancer (CaP) were evaluated. Known risk factors for biochemical failure (BF) were analyzed using univariate and multivariate logistic regression analysis. The effects of surgical margin status together with pathological stage on BF were evaluated. p values lower than 0.05 were accepted to be statistically significant. RESULTS: Pathological stage, positive surgical margin (PSM), seminal vesicle invasion, lymph node involvement, biopsy Gleason score and postoperative Gleason score were the factors associated with BF in univariate analysis. Logistic regression analysis revealed that pT3a patients with PSM had a significant BF rate when compared to pT2 patients with a negative surgical margin (NSM) (OR 7.46, p = 0.002). pT3a patients with a NSM had a similar BF rate to that of pT2 patients with PSM. CONCLUSIONS: pT2 patients with PSM had a similar biochemical prognosis to that of pT3a patients without PSM, implicating that a PSM may have a negative effect on prognosis similar to that of extracapsular invasion. PMID- 21311165 TI - FOXE1 polyalanine tract length polymorphism in patients with thyroid hemiagenesis and subjects with normal thyroid. AB - BACKGROUND/AIMS: Recent studies have pointed to the correlation between FOXE1 polyalanine tract (FOXE1-polyAla) length polymorphism and genetic susceptibility to thyroid dysgenesis causing congenital hypothyroidism. The objective of this study was a first assessment of the role of FOXE1-polyAla expansion in the genetic background of thyroid hemiagenesis (TH). METHODS: The group studied consisted of 40 patients with TH, including 6 familial cases and a control group of 89 subjects with a normal thyroid. The polyAla tract and flanking sequence of FOXE1 was amplified using conventional PCR. Subsequently, capillary electrophoresis was performed to estimate the length of products. RESULTS: A short variant of FOXE1-polyAla, containing 12 alanines, was present in 5 control subjects (5.6%), but was not found in TH. The incidence of longer variants (>=16 codons) of FOXE1-polyAla was significantly higher in patients with the familial form of TH in comparison to those with sporadic TH (p = 0.003) and controls (p = 0.005). CONCLUSIONS: There is high polymorphic variability of FOXE1-polyAla in both groups. Shorter variants of FOXE1-polyAla are underrepresented in subjects with familial TH. Therefore, FOXE1-polyAla tract expansion may contribute to the molecular background of familial but not sporadic forms of TH. Further studies are still required to confirm such findings. PMID- 21311166 TI - Further evidence on mitochondrial targeting of beta-amyloid and specificity of beta-amyloid-induced mitotoxicity in neurons. AB - BACKGROUND/AIMS: Impaired mitochondrial function has been described in Alzheimer's disease. We previously reported that, in neuronal cells, beta-amyloid 1-42 (Abeta(1-42)) is targeted to mitochondria. We have also reported that, when incubated with isolated rat brain mitochondria, Abeta(1-42) inhibits complex IV, uncouples the mitochondrial respiratory chain, and promotes opening of the membrane permeability transition pore. Here, we further analyzed the targeting and mitotoxicity of Abeta(1-42). METHODS AND RESULTS: Immunoelectron microscopy revealed that the mitochondrial targeting of Abeta(1-42) was concentration- and time-dependent. Incubation of human neuroblastoma cells with Abeta(1-42) increased the release of adenylate kinase, a mitochondrial enzyme released after membrane permeability transition pore opening. However, it failed to trigger DNA fragmentation and apoptosis, suggesting that the ability of this peptide to uncouple the respiratory chain underlies its mitotoxicity and cytotoxicity. Abeta(1-42) targeting to mitochondria was blocked by caprospinol, a steroid derivative shown to protect neuronal cells against Abeta(1-42)-induced neurotoxicity. Further experiments revealed that the mitotoxic effect of Abeta(1 42) is specific to its primary amino acid sequence and suggested that it may be also related to its tertiary structure. Importantly, the mitotoxic effect of Abeta(1-42) was not restricted to brain cells, indicating that it is not cell- or tissue-specific. CONCLUSION: Taken together, these results suggest that extracellular Abeta(1-42) targets neuronal mitochondria to exert its toxic effects. PMID- 21311167 TI - Microvascular endothelial dysfunction in obstructive sleep apnea is caused by oxidative stress and improved by continuous positive airway pressure therapy. AB - BACKGROUND: Endothelial dysfunction has recently been demonstrated in obstructive sleep apnea (OSA), but the underlying mechanisms are not entirely understood. Oxidative stress is a typical feature of OSA. OBJECTIVES: We investigated the influence of oxidative stress and continuous positive airway pressure (CPAP) on microvascular endothelial function in OSA. METHODS: Endothelial function of forearm resistance vessels was assessed by strain gauge venous occlusion plethysmography after intra-arterial infusion of the endothelium-independent vasodilator sodium nitroprusside (1.6, 3.2, and 4.0 MUg/min) and the endothelium dependent vasodilator acetylcholine (Ach, 15, 30 and 40 MUg/min) in patients with (n = 11) and without (n = 8) OSA (apnea-hypopnea index >=15/h). These measurements have been repeated after local intra-arterial infusion of the antioxidant vitamin C (25 MUg/min). Furthermore, 6 patients have been reevaluated after 6 months of OSA treatment. RESULTS: Patients with OSA demonstrated impaired endothelial function compared to those without OSA. Thus, related to baseline flow, the increase in forearm blood flow induced by Ach was blunted in patients with OSA (148.7 +/- 29.7% in OSA vs. 233.6 +/- 45.7% in controls, p = 0.001). This difference, however, was abolished by co-infusion of vitamin C. Endothelial function markedly improved following treatment in 5 of 6 OSA patients. CONCLUSIONS: This study strongly suggests that microvascular endothelial function is affected by OSA predominantly through increased oxidative stress, and treatment of OSA may improve endothelial function mainly by reducing oxidative stress. The role of oxidative stress-induced endothelial dysfunction as a potential promoter of atherosclerosis and an increased cardiovascular risk in patients with OSA should be investigated in further controlled studies. PMID- 21311168 TI - Different molecular and structural adaptations with eccentric and conventional strength training in elderly men and women. AB - Reprogramming of gene expression contributes to structural and functional adaptation of muscle tissue in response to altered use. The aim of this study was to investigate mechanisms for observed improvements in leg extension strength, gain in relative thigh muscle mass and loss of body and thigh fat content in response to eccentric and conventional strength training in elderly men (n = 14) and women (n = 14; average age of the men and women: 80.1 +/- 3.7 years) by means of structural and molecular analyses. Biopsies were collected from m. vastus lateralis in the resting state before and after 12 weeks of training with two weekly resistance exercise sessions (RET) or eccentric ergometer sessions (EET). Gene expression was analyzed using custom-designed low-density PCR arrays. Muscle ultrastructure was evaluated using EM morphometry. Gain in thigh muscle mass was paralleled by an increase in muscle fiber cross-sectional area (hypertrophy) with RET but not with EET, where muscle growth is likely occurring by the addition of sarcomeres in series or by hyperplasia. The expression of transcripts encoding factors involved in muscle growth, repair and remodeling (e.g., IGF-1, HGF, MYOG, MYH3) was increased to a larger extent after EET than RET. MicroRNA 1 expression was decreased independent of the training modality, and was paralleled by an increased expression of IGF-1 representing a potential target. IGF-1 is a potent promoter of muscle growth, and its regulation by microRNA 1 may have contributed to the gain of muscle mass observed in our subjects. EET depressed genes encoding mitochondrial and metabolic transcripts. The changes of several metabolic and mitochondrial transcripts correlated significantly with changes in mitochondrial volume density. Intramyocellular lipid content was decreased after EET concomitantly with total body fat. Changes in intramyocellular lipid content correlated with changes in body fat content with both RET and EET. In the elderly, RET and EET lead to distinct molecular and structural adaptations which might contribute to the observed small quantitative differences in functional tests and body composition parameters. EET seems to be particularly convenient for the elderly with regard to improvements in body composition and strength but at the expense of reducing muscular oxidative capacity. PMID- 21311169 TI - Dermoscopy of pigmented lesions of the vulva: a retrospective morphological study. AB - BACKGROUND: The dermoscopic patterns of pigmented skin tumors are influenced by the body site. OBJECTIVE: To evaluate the clinical and dermoscopic features associated with pigmented vulvar lesions. METHODS: Retrospective analysis of clinical and dermoscopic images of vulvar lesions. The chi2 test was used to test the association between clinical data and histopathological diagnosis. RESULTS: A total of 42 (32.8%) melanocytic and 86 (67.2%) nonmelanocytic vulvar lesions were analyzed. Nevi significantly prevailed in younger women compared with melanomas and melanosis and exhibited most commonly a globular/cobblestone (51.3%) and a mixed (21.6%) pattern. Dermoscopically all melanomas showed a multicomponent pattern. Melanotic macules showed clinical overlapping features with melanoma, but their dermoscopic patterns differed significantly from those observed in melanomas. CONCLUSION: The diagnosis and management of pigmented vulvar lesions should be based on a good clinicodermoscopic correlation. Dermoscopy may be helpful in the differentiation of solitary melanotic macules from early melanoma. PMID- 21311170 TI - Neurogenesis, cellular plasticity and cognition: the impact of stem cells in the adult and aging brain--a mini-review. AB - The hippocampus is a structure equipped with a high degree of flexibility and adaptation. In contrast to most structures of the adult central nervous system, the hippocampus can rely on a form of plasticity known as neurogenesis. The continuous provision of new neurons derived from resident adult neural stem cells appears to facilitate the execution of hippocampal-dependent tasks since reduction or blockage of neurogenesis is associated with cognitive impairments. Importantly, however, although hippocampal neurogenesis is maintained all throughout life, its levels decrease steadily along with aging. Notwithstanding some evidence that in age-matched animals neurogenesis levels and learning performance are tightly associated, these two parameters do not appear to be directly coupled when comparing individuals of various age groups. Additional components, and in particular experience, appear to play a fundamental roles in hippocampal functions. In this review, we speculate on the impact of neurogenesis level modulation on cognitive performances, putting in perspective recent studies made in the aging human population and in rodent models of aging. PMID- 21311171 TI - Validation of an endobronchial ultrasound simulator: differentiating operator skill level. AB - BACKGROUND: Endobronchial ultrasound (EBUS) is a revolutionary diagnostic procedure. There is currently no accepted method of assessing EBUS technical skill or competency. OBJECTIVES: This study aimed to validate a computer EBUS simulator in differentiating between operators of varying clinical EBUS experience. METHODS: A convenience sample (n = 22) of bronchoscopists was separated into four cohorts based on previous bronchoscopy experience: group A = novice bronchoscopists, no EBUS experience (n = 4), group B = expert bronchoscopists, no EBUS experience (n = 5), group C = basic clinical EBUS training (n = 9), group D = EBUS experts (n = 4). After a standardized introduction session on the EBUS simulator, participants performed 2 simulated cases on an EBUS simulator with performance metrics measured by the simulator. RESULTS: Significant differences between groups were noted for total procedure time, percentage of lymph nodes identified and percentage of successful biopsies (p < 0.05, ANOVA). Group D performed significantly better than all other groups for total procedure time and percentage of lymph nodes identified (p < 0.05). Group C performed significantly better than groups A and B for total procedure time, percentage of lymph nodes identified and percentage of successful biopsies (p < 0.05, ANOVA). CONCLUSIONS: An EBUS simulator can accurately discriminate between operators with different levels of clinical EBUS experience. EBUS simulators show promise as a tool for assessing training and evaluating competency. PMID- 21311172 TI - Antiviral resistance mutations and genotype-associated amino acid substitutions in treatment-naive hepatitis B virus-infected individuals from the Indian subcontinent. AB - BACKGROUND/AIMS: Antiviral resistance is a major challenge to the treatment currently available for hepatitis B virus (HBV). In this study, mutations that may affect the antiviral efficacy in treatment-naive HBV-infected individuals were analyzed. METHODS: Ninety-seven treatment-naive HBV-infected individuals were included in this study. HBV reverse transcriptase (rt) domains were sequenced and nucleotide differences were compared to GenBank wild-type sequences. Furthermore, HBV genotypes, subgenotypes and subtypes were determined by analyzing surface gene sequences. RESULTS: An adefovir-related rtI233V mutation was identified in 4 subjects. The rtS213T lamivudine and entecavir refractory mutant was presented in 3 individuals. Altogether, drug-related, atypical and novel HBVrt amino acid substitutions were seen in 73 positions. The HBV genotypes A, C, D and G were depicted in 15, 21, 60 and 1 individuals, respectively. There were 17 HBVrt amino acid substitutions that are associated with certain genotypes of HBV. Mutations in HBVrt corresponded to established surface gene mutations in 9 patients. CONCLUSION: This data shows that antiviral resistant HBV strains do exist in treatment-naive individuals in this region. Further studies are essential to characterize the role of HBVrt amino acid substitutions in response to anti-HBV therapy. PMID- 21311173 TI - Lung sequestration: a rare cause for pulmonary symptoms in adulthood. AB - BACKGROUND: Lung sequestration is a rare congenital pulmonary disorder and is usually diagnosed in children with recurrent pulmonary infections. Lung sequestrations are not commonly found to be a cause of respiratory symptoms in adults. OBJECTIVES: It was the aim of this study to show that pulmonary sequestration is rare in advanced age and can be accompanied by severe pulmonary symptoms. METHODS: We conducted a case series analysis of patient characteristics, symptoms, diagnosis and treatment of 11 adults with a lung sequestration at the Thoraxklinik Heidelberg between 2001 and 2009. RESULTS: From 2001 to 2009, intralobar lung sequestration was diagnosed and treated in 11 adults aged 19 to 58 years with an average age of 39.9 +/- 11.3 years and a male:female distribution of 5:6. In 3 patients (27.3%), the predominant symptom was hemoptysis. Recurrent pulmonary infections occurred in 1 patient (9.1%); pneumonia and lung abscess were detected in 2 patients (18.2%). In 3 cases (27.3%), dry cough was the predominant symptom, and in only 2 cases (18.2%), lung sequestration was asymptomatic. Eight patients (72.7%) were diagnosed by imaging techniques prior to surgery. In 3 cases (27.3%), diagnosis was made intraoperatively and by pathological examination. Surgical intervention included 7 lobectomies (63.6%), 3 wedge resections (27.3%) and 1 (9.1%) segmentectomy. CONCLUSION: Lung sequestration in adults is rare, but it can cause severe pulmonary symptoms. In cases of recurrent pulmonary infections of identical localization or recurrent hemoptysis, lung sequestration should be considered in order for the diagnosis to be made rapidly. Surgical resection is the treatment of choice. PMID- 21311174 TI - Prediction of birth weight discordance in twin pregnancies by second- and third- trimester ultrasound. AB - INTRODUCTION: Our purpose was to examine whether the prenatal prediction of a critical birth weight discordance (BWD) in twin pregnancies can be improved by using either different formulae for prenatal fetal weight estimation or single biometric measurements or by assessing the intertwin discordance in the second trimester rather than shortly before birth. MATERIAL AND METHODS: We conducted a retrospective study involving 196 twin pregnancies with an ultrasound examination between 18 and 25 weeks of gestation and one within 14 days prior to delivery. The accuracy was assessed by comparing the prenatal intertwin discordance (PID) with the BWD. PID was estimated by 5 common fetal weight estimation formulae and by single biometric measurements prior to delivery and in the second trimester. RESULTS: The fetal weight estimation accuracy was similar in mono- and dichorionic pregnancies and the smaller and the larger twin. PID was most accurate with the fetal weight estimation formulae prior to delivery. The second trimester measurements resulted in an underestimation of the BWD. Detection and false-positive rates for a BWD >=20% were about 65 and 15%. DISCUSSION: About two thirds of the twin pregnancies with a relevant BWD can be detected prior to delivery. An optimal detection rate requires fetal weight estimation close to delivery. PMID- 21311175 TI - The effect of tidal volume on systemic inflammation in Acid-induced lung injury. AB - BACKGROUND: Overwhelming systemic inflammation has been implicated in the progression of acute lung injury (ALI) leading to multiple organ failure (MOF) and death. Previous studies suggest that mechanical ventilation (MV) may be a key mediator of MOF through an upregulation of the systemic inflammatory response. OBJECTIVES: It was the aim of this study to investigate mechanisms whereby mechanical stress induced by different tidal volumes may contribute to the development of systemic inflammation and maladaptive peripheral organ responses in the setting of ALI. METHODS: An acid aspiration model of ALI was employed in 129X1/SVJ mice through an intratracheal administration of hydrochloric acid followed by MV employing either a low (5 ml/kg) or high (12.5 ml/kg) tidal volume ventilation for 120 min. The isolated perfused mouse lung setup was used to assess the specific contribution of the lung to systemic inflammation during MV. Furthermore, lung perfusate collected over the course of MV was used to assess the effects of lung-derived mediators on activation (expression of a proadhesive phenotype) of liver endothelial cells. RESULTS: High tidal volume MV of acid injured lungs resulted in greater physiologic and histological indices of lung injury compared to control groups. Additionally, there was an immediate and significant release of multiple inflammatory mediators from the lung into the systemic circulation which resulted in greater levels of mRNA adhesion molecule expression in liver endothelial cells in vitro. CONCLUSIONS: This study suggests that MV, specifically tidal volume strategy, influences the development of MOF through an upregulation of lung-derived systemic inflammation resulting in maladaptive cellular changes in peripheral organs. PMID- 21311176 TI - Eosinophilic pleural effusion complicating allergic bronchopulmonary aspergillosis. AB - Allergic bronchopulmonary aspergillosis (ABPA) is primarily a disease of patients with cystic fibrosis or asthma, who typically present with bronchial obstruction, fever, malaise, and expectoration of mucus plugs. We report a case of a young man with a history of asthma who presented with cough, left-sided pleuritic chest pain and was found to have lobar atelectasis and an eosinophilic, empyematous pleural effusion. Bronchoscopy and sputum cultures grew Aspergillus fumigatus, and testing confirmed strong allergic response to this mold, all consistent with a diagnosis of ABPA. This novel and unique presentation of ABPA expands on the differential diagnosis of eosinophilic pleural effusions. PMID- 21311178 TI - Androgen receptor mutations are associated with altered epigenomic programming as evidenced by HOXA5 methylation. AB - Male external genital differentiation is accompanied by implementation of a long term, male-specific gene expression pattern indicating androgen programming in cultured genital fibroblasts. We hypothesized the existence of an epigenetic background contributing to this phenomenon. DNA methylation levels in 2 normal scrotal fibroblast strains from 46,XY males compared to 2 labia majora fibroblast strains from 46,XY females with complete androgen insensitivity syndrome (AIS) due to androgen receptor (AR) mutations were analyzed by Illumina GoldenGate methylation arrays(r). Results were validated with pyrosequencing in labia majora fibroblast strains from fifteen 46,XY patients and compared to nine normal male scrotal fibroblast strains. HOXA5 showed a significantly higher methylation level in complete AIS. This finding was confirmed by bisulfite pyrosequencing of 14 CpG positions within the HOXA5 promoter in the same strains. Extension of the 2 groups revealed a constant low HOXA5 methylation pattern in the controls in contrast to a highly variable methylation pattern in the AIS patients. HOXA5 represents a candidate gene of androgen-mediated promoter methylation. The constantly low HOXA5 DNA methylation level of normal male scrotal fibroblast strains and the frequently high methylation levels in labia majora fibroblast strains in AIS indicate for the first time that androgen programming in sexual differentiation is not restricted to global gene transcription but also occurs at the epigenetic level. PMID- 21311177 TI - Nuclear receptor coactivators are coexpressed with steroid receptors and regulated by estradiol in mouse brain. AB - BACKGROUND/AIMS: The steroid hormones, including estradiol (E) and progesterone, act in the brain to regulate female reproductive behavior and physiology. These hormones mediate many of their biological effects by binding to their respective intracellular receptors. The receptors for estrogens (ER) and progestins (PR) interact with nuclear receptor coactivators to initiate transcription of steroid responsive genes. Work from our laboratory and others reveals that nuclear receptor coactivators, including steroid receptor coactivator-1 (SRC-1) and SRC 2, function in brain to modulate ER-mediated induction of the PR gene and hormone dependent behaviors. In order for steroid receptors and coactivators to function together, both must be expressed in the same cells. METHODS: Triple-label immunofluorescence was used to determine if E-induced PR cells also express SRC-1 or SRC-2 in reproductively relevant brain regions of the female mouse. RESULTS: The majority of E-induced PR cells in the medial preoptic area (61%), ventromedial nucleus of the hypothalamus (63%) and arcuate nucleus (76%) coexpressed both SRC-1 and SRC-2. A smaller proportion of PR cells expressed either SRC-1 or SRC-2, while a few PR cells expressed neither coactivator. In addition, compared to control animals, 17beta-estradiol benzoate (EB) treatment increased SRC-1 levels in the arcuate nucleus, but not the medial preoptic area or the ventromedial nucleus of the hypothalamus. EB did not alter SRC-2 expression in any of the three brain regions analyzed. CONCLUSIONS: Taken together, the present findings identify a population of cells in which steroid receptors and nuclear receptor coactivators may interact to modulate steroid sensitivity in brain and regulate hormone-dependent behaviors in female mice. Given that cell culture studies reveal that SRC-1 and SRC-2 can mediate distinct steroid-signaling pathways, the present findings suggest that steroids can produce a variety of complex responses in these specialized brain cells. PMID- 21311179 TI - Genomic mapping of human chromosome paints on the threatened masked Titi monkey (Callicebus personatus). AB - Callicebus is a complex genus of neotropical primates thought to include 29 or more species. Currently, the genus is divided into 5 species groups: donacophilus, cupreus, moloch, torquatus and personatus. However, the phylogenetic relationships among the species are still poorly understood. This genus is karyotypically diverse and shows extensive variation in diploid number (2n = 16 to 50). To foster a better understanding of the chromosomal diversities and phylogenetic relationships among the species of Callicebus, we performed a chromosome-painting analysis on the Callicebus personatus genome using human probes, and compared the resulting hybridization map to those of previously mapped titi species. We detected 38 hybridization signals per haploid autosomal set of C. personatus. Few ancestral syntenies were conserved without rearrangement, but 4 human associations (HSA20/13, 3c/8b, 1b/1c and 21/3a/15a/14) were demonstrated to be apomorphic traits for C. persona tus. G-banding suggested that these associations are shared with C. nigrifrons and C. coimbrai (personatus group), while C. personatus is linked with C. pallescens (donacophilus group) by 2 synapomorphies: HSA10b/11 (submetacentric) and an inversion of HSA1a. PMID- 21311180 TI - Aneuploidy and DNA fragmentation in sperm of carriers of a constitutional chromosomal abnormality. AB - Among various causes responsible for infertility, it has been admitted for a long time that male infertility can be due to impaired spermatogenesis and/or balanced structural chromosomal abnormalities. Sperm DNA fragmentation is also considered as another cause of infertility. Most of the studies on male infertility have concerned either aneuploidy in the sperm of carriers of constitutional chromosomal abnormalities or sperm DNA fragmentation. This review is aimed at analyzing these 2 parameters in the same patients. Furthermore, we present work on the study of these 2 parameters in the same gametes of 4 carriers of a balanced chromosomal abnormality. Meiotic segregation was analyzed by fluorescent in situ hybridization and DNA fragmentation was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. It was shown that aneuploidy and DNA fragmentation were increased in the sperm of carriers of a balanced chromosomal abnormality. For all 4 carriers of a balanced structural abnormality, there was a 2-5 times higher proportion of spermatozoa with unbalanced chromosomal content and fragmented DNA than among those with normal/balanced content. Moreover, we found a non-random distribution with more gametes with DNA fragmentation when these arose from a particular segregation mode. The mechanism which would tend to explain our results is abortive apoptosis. In conclusion, both meiotic segregation and DNA fragmentation studies should be integrated in the genetic exploration of male carriers of a chromosomal structural abnormality. PMID- 21311181 TI - Mosaic aneuploidy in early fetal losses. AB - Chromosomal mosaicism is the presence of 2 or more cell lines with different karyotypes in the same individual. Mosaic karyotypes are a remarkable feature of early stages of human embryo development. They result from mitotic errors in chromosome segregation and demonstrate the clearest example of somatic mutagenesis in human beings. This review is devoted to the classification of chromosomal mosaicism and the analysis of its underlying mechanisms, incidence and phenotypic effects during embryo development. A model for tissue-specific aneuploid cell line compartmentalization in spontaneous abortions is introduced. PMID- 21311182 TI - The human cleavage stage embryo is a cradle of chromosomal rearrangements. AB - The first cell cycles following in vitro fertilization (IVF) of human gametes are prone to chromosome instability. Many, but often not all, blastomeres of an embryo acquire a genetic makeup during cleavage that is not representative of the original zygotic genome. Whole chromosomes are missegregated, but also structural rearrangements of chromosomes do occur in human cleavage stage embryogenesis following IVF. Analysis of pre- and postnatal DNA samples indicates that the in vivo human conceptions also endure instability of chromosome number and structure during cleavage of the fertilized oocyte. This embryonic chromosome instability not necessarily undermines normal human development, but may lead to a spectrum of conditions, including loss of conception, genetic disease and genetic variation development. In this review, the structural instability of chromosomes during human cleavage stage embryogenesis is catalogued, channeled into etiologic models and linked to genomic profiles of healthy and diseased newborns. PMID- 21311183 TI - Assessment of kidney volume in polycystic kidney disease using magnetic resonance imaging without contrast medium. AB - BACKGROUND/AIMS: Total renal volume (TRV) is an important index to evaluate the progression of autosomal-dominant polycystic kidney disease (ADPKD). TRV has been assessed by manually tracing renal contours from CT or MR scans, often employing contrast medium (CM). We developed a fast and nearly automated technique based on the analysis of MR images acquired without CM injection for TRV quantification. METHODS: 30 ADPKD patients underwent MRI. After the selection of one point inside each kidney for the entire volume, the automatic extraction of kidney contours was performed on each acquired slice; the segmentation procedure was based on region growing and on the application of morphological operators and curvature based motion. The area inside each contour was calculated and TRV was derived. Volume measurements were validated by comparison with measurements obtained by stereology. RESULTS: TRV estimated in patients was 768 +/- 545 ml (range 161 3,111 ml). The automatic measurements were in excellent correlation with the manual ones (r = 0.99, y = x - 0.7), with a small bias and narrow limits of agreement in both absolute (-5 +/- 37 ml) and percentage (-0.6 +/- 9.6%) terms. CONCLUSION: This preliminary study showed the feasibility of a fast and nearly automated method for determining TRV; importantly it does not require the use of potentially nephrotoxic CM. PMID- 21311184 TI - Effects of mycophenolate mofetil combined with corticosteroids for induction therapy of microscopic polyangiitis. AB - AIMS: We prospectively compared the effects of oral mycophenolate mofetil (MMF) or intravenous cyclophosphamide (IVC) combined with corticosteroids for induction therapy of microscopic polyangiitis (MPA) with renal involvement over a follow-up period of 6 months. METHODS: 41 MPA patients were randomly assigned to either the open-label MMF group or the IVC group. Patients in the MMF group (n = 19) received oral MMF 1.0 g/day (1.5 g/day for patients with a body weight >70 kg) and patients in the IVC group (n = 22) received IVC in monthly pulses of 1.0 g per pulse (0.8 g per pulse for patients with a body weight <50 kg). Both groups received intravenous methylprednisolone 360-500 mg/day for 3 days, followed by oral prednisone 0.6-0.8 mg/kg/day and gradual tapering. RESULTS: There was no significant difference of estimated glomerular filtration rate (eGFR) level between the IVC and MMF groups at baseline. At 6 months, the eGFR level increased significantly in both groups, but there was no significant difference between the two. Three patients in the IVC group and 1 in the MMF group received maintenance dialysis within 6 months (p = 0.36). The remission rate was 63.6% in the IVC group and 78.9% in the MMF group (p = 0.23). CONCLUSION: MMF is effective for inducing remission in Chinese MPA patients and may represent an alternative therapy to monthly impulses of IVC. PMID- 21311185 TI - Serum selenium levels in hemodialysis patients are significantly lower than those in healthy controls. AB - Serum selenium levels have been thought to be decreased in hemodialysis patients; however, results of previous studies have been inconsistent. Population-based hemodialysis patients (n = 1,041) and randomly recruited healthy controls (n = 384) were enrolled. Serum selenium levels were determined by inductively coupled plasma mass spectrometry and compared in hemodialysis patients and controls using analysis of covariance after adjustment for confounding factors with p < 0.1 as the result of the multiple regression analysis. Age, serum albumin levels, hsCRP levels, LDLC levels, HDLC levels, regular drinking habit and hemodialysis treatment were significantly associated with serum selenium levels in multiple regression analysis. Multivariate-adjusted means (95% CIs) of serum selenium levels were 103 MUg/l (101-105) in hemodialysis patients and 117 MUg/l (114-121) in controls. Selenium levels in hemodialysis patients were decreased. Whether decreased serum selenium levels contribute to increased risks for morbidity and mortality in hemodialysis patients should be examined. PMID- 21311186 TI - Validation of the measurement of haemodialysis access flow using a haemoglobin dilution test. AB - Monitoring of blood flows in arteriovenous fistulae and arteriovenous grafts is recommended to predict access thrombosis. The ultrasound dilution technique (UDT) is the gold standard. We compare a recently described haemoglobin dilution technique (HDT) with the UDT in measurement of vascular access flow. Access blood flow was measured in 67 stable dialysis patients using HDT by bedside Hemocue (Hemocue AB, Angelholm, Sweden) and laboratory measurement. Access blood flow was then measured by UDT in the same dialysis session. Median flow rate by UDT was 950 ml/min (IQR 490-1,440 ml/min), by Hemocue HDT 935 ml/min (IQR 475-1,395 ml/min, p = 0.534), and by laboratory haemoglobin HDT 920 ml/min (IQR 463-1,378 ml/min). Bland-Altman plots demonstrated poor agreement between UDT and HDT (limits of agreement for Hemocue HDT -22.7 to 20.1%, for laboratory HDT -21.2 to 20.4%). HDT can be used to measure vascular access flow but requires validation against clinical outcomes before being recommended as an alternative to UDT. PMID- 21311187 TI - Inhibitory effects of Oenothera biennis (evening primrose) seed extract on Streptococcus mutans and S. mutans-induced dental caries in rats. AB - BACKGROUND: Oenothera biennis (evening primrose) seed extract (OBSE) is known to contain polyphenols, which may possess antioxidant activities. Polyphenols extracted from several plants are reported to exhibit cariostatic activities by inhibiting mutans streptococcus growth and glucosyltransferase activities. The purpose of the present study was to examine the inhibitory effects of OBSE on the development of dental caries, both in vitro and in vivo. METHODS: OBSE was investigated for its inhibitory effects on cellular aggregation, hydrophobicity, sucrose-dependent adherence and insoluble glucan synthesis. Furthermore, biofilm formation was examined in the presence of OBSE, using confocal microscopic imaging. An animal experiment was also performed to examine the in vivo effects. RESULTS: OBSE induced a strong aggregation of Streptococcus mutans MT8148 cells, while cell surface hydrophobicity was decreased by approximately 90% at a concentration of 0.25 mg/ml. The sucrose-dependent adherence of the MT8148 cells was also reduced by addition of OBSE, with a reduction rate of 73% seen at a concentration of 1.00 mg/ml. Additionally, confocal microscopic observations revealed the biofilm development phase to be remarkably changed in the presence of OBSE. Furthermore, insoluble glucan synthesis was significantly reduced when OBSE was present at concentrations greater than 0.03 mg/ml. In an animal experiment, the caries scores in rats given OBSE (0.05 mg/ml in drinking water) were significantly lower than those in rats given water without OBSE. CONCLUSION: Our results indicate that OBSE has inhibitory activity on dental caries. PMID- 21311188 TI - The morphology of the rat vibrissal follicle-sinus complex revealed by three dimensional computer-aided reconstruction. AB - The vibrissal follicle-sinus complex (FSC) is a sensory receptor of the mammalian integumentary system that is located around the mouth. The purpose of the present study was to identify the actual 3-dimensional structure of the rat vibrissal FSC. Rat skin tissue was serially sectioned at a thickness of 10 MUm and then stained with Masson's trichrome. The serial sections were reconstructed 3 dimensionally using Reconstruct software. The rat vibrissal follicle is a spindle shaped structure that is embedded within a blood sinus and enveloped within a thick collagenous capsule. The vibrissal FSC is innervated by the deep vibrissal and superficial vibrissal nerves. The deep vibrissal nerve, travelling in the basal-to-apical direction, penetrates the thick collagenous capsule of the vibrissal FSC. The sinus system can be divided into a superior portion, known as the ring sinus, and an inferior portion, known as the cavernous sinus. The ring sinus contains a C-shaped structure, the ringwulst, which is suspended from the mesenchymal sheath of the follicle. Collagenous trabeculae can be seen in the cavernous sinus but not in the ring sinus. The ring sinus encircles the follicle obliquely and asymmetrically. The ringwulst encircles the follicle incompletely, in a C-shaped fashion. This study has demonstrated the previously underappreciated 3-dimensional structure of the vibrissal FSC, which differs from previously reported descriptions, and provides data that will enhance the understanding of vibrissal function. PMID- 21311189 TI - Granulocyte-monocyte apheresis - not the end of the road yet! PMID- 21311190 TI - Effect and safety of granulocyte-monocyte adsorption apheresis for patients with ulcerative colitis positive for cytomegalovirus in comparison with immunosuppressants. AB - BACKGROUND: Cytomegalovirus (CMV) infection exacerbates ulcerative colitis (UC) refractory to immunosuppressive therapies (IMT). However, the underlying UC remained active in some UC patients, despite the fact that CMV-DNA in colonic mucosa became negative after antiviral therapy. Therefore, new therapeutic strategies for UC patients concomitant with CMV infection in mucosa are required. AIMS: The aim of this study was to evaluate the effect and safety of granulocyte monocyte adsorption apheresis (GMA) in UC patients positive for CMV infection after antiviral therapy. METHODS: From October 2003 to December 2008, 64 patients with UC refractory to IMT, including steroids and immunomodulators, were enrolled in this retrospective, observational, multicenter study, which was reviewed and approved by the Institutional Review Board of Kyoto University. CMV infection was investigated by 3 methods (histologic examination, CMV antigenemia, and polymerase chain reaction). We investigated the clinical outcomes of GMA and IMT after 2 weeks of treatment with ganciclovir. RESULTS: Thirty-one (48.4%) of 64 patients with UC refractory to IMT were positive for CMV. Of the 31 patients, 4 (12.9%) underwent colectomy. Twenty-seven patients (87.1%) underwent antiviral therapy. Of those 27 patients, 7 achieved remission following antiviral therapy alone. Of the remaining 20 patients who did not achieve remission despite the disappearance of CMV-DNA, 11 and 9 patients were treated with additional GMA (GMA group) and IMT (IMT group), respectively. Of 11 patients (GMA group), 9 achieved remission and 2 underwent colectomy. Out of the remaining 9 patients (IMT group), 4 achieved remission and 5 underwent colectomy. CMV-DNA was not detected in 11 patients after GMA, but it was detected again in all 5 patients of the IMT group who underwent colectomy. The total colectomy rate in UC patients positive for CMV was 35.5% (11/31). In addition, colectomy-free survival in the CMV relapse (+) group was estimated to be 12.9% at 65 months, while that in the CMV relapse (-) group was estimated to be 100% at 60 months. CONCLUSION: The colectomy ratio tends to be high in refractory UC patients with recurrent CMV reactivation or infection. Therefore, GMA might be a safe and effective treatment for UC patients positive for CMV because it does not induce CMV reactivation. PMID- 21311191 TI - Pathogenesis of strictures in ulcerative colitis: a field to explore. PMID- 21311192 TI - Factors attributing hypoxemic events during upper-gastrointestinal endoscopy. PMID- 21311193 TI - Selective pelvic autonomic nerve stimulation with simultaneous intraoperative monitoring of internal anal sphincter and bladder innervation. AB - BACKGROUND: Pelvic autonomic nerve preservation avoids postoperative functional disturbances. The aim of this feasibility study was to develop a neuromonitoring system with simultaneous intraoperative verification of internal anal sphincter (IAS) activity and intravesical pressure. METHODS: 14 pigs underwent low anterior rectal resection. During intermittent bipolar electric stimulation of the inferior hypogastric plexus (IHP) and the pelvic splanchnic nerves (PSN), electromyographic signals of the IAS and manometry of the urinary bladder were observed simultaneously. RESULTS: Stimulation of IHP and PSN as well as simultaneous intraoperative monitoring could be realized with an adapted neuromonitoring device. Neurostimulation resulted in either bladder or IAS activation or concerted activation of both. Intravesical pressure increase as well as amplitude increase of the IAS neuromonitoring signal did not differ significantly between stimulation of IHP and PSN [6.0 cm H(2)O (interquartile range [IQR] 3.5-9.0) vs. 6.0 cm H(2)O (IQR 3.0-10.0) and 12.1 MUV (IQR 3.0-36.7) vs. 40.1 MUV (IQR 9.0-64.3)] (p > 0.05). CONCLUSIONS: Pelvic autonomic nerve stimulation with simultaneous intraoperative monitoring of IAS and bladder innervation is feasible. The method may enable neuromonitoring with increasing selectivity for pelvic autonomic nerve preservation. PMID- 21311194 TI - Arytenoid asymmetry in relation to posture, neck tension and glottal attack in singers. AB - OBJECTIVES: To look at the incidence of arytenoid asymmetry in a group of healthy singers and to investigate whether the asymmetry correlates with posture, neck tension and glottal attack. MATERIALS AND METHOD: The medical records and video recordings of 42 singers were reviewed retrospectively. Posture, neck tension and glottal attack were evaluated in relation to arytenoid asymmetry during adduction. RESULTS: The number of singers was 42, with a male-to-female ratio of 2:1. The age range was 16-38 years, with a mean of 24+/-4.13 years. The total prevalence of arytenoid asymmetry was 50%, with a predominance in males and on the right side. The most common asymmetry was that of the cuneiform cartilages, accounting for 40.5% of the total sample and 81% of the total asymmetries. There was no correlation between arytenoid asymmetry and either posture, neck tension or glottal attack (p=0.343, 0.489 and 0.945, respectively). CONCLUSION: One out of 2 singers is likely to have arytenoid asymmetry during adduction. The presence of asymmetry does not correlate with posture, neck tension or glottal attack. PMID- 21311195 TI - Neutrophil gelatinase-associated lipocalin as a predictor of complications and mortality in patients undergoing non-cardiac major surgery. AB - INTRODUCTION: We tested the hypothesis that urinary and serum neutrophil gelatinase-associated lipocalins (NGAL) early after non-cardiac major surgery predict postoperative acute kidney injury (AKI), complications and mortality. METHODS: We studied 74 patients undergoing orthopedic, vascular and abdominal surgery lasting >=2 h. NGAL was measured in preoperative, as well as 2- and 6 hour postoperative samples. The primary outcome was AKI. Secondary outcome was postoperative infection and death. RESULTS: 10 patients (13.5%) developed AKI, 19 (26%) reached secondary outcomes, of whom 5 (7%) died. Serum NGAL was significantly higher in patients with diabetes and chronic kidney disease (CKD). No significant correlation was detected between serum or urine NGAL and subsequent development of AKI. Urine NGAL at 6 h and serum NGAL at 2 and 6 h were strongly correlated with postoperative infection and death (p = 0.004, p = 0.013 and p = 0.001, respectively). CONCLUSIONS: Our data suggest that in the general surgical population, NGAL could serve as a potent early biomarker for postoperative infection, and that the presence of CKD and diabetes mellitus is associated with higher levels of NGAL and may influence its predictive value. PMID- 21311196 TI - Computer-based, personalized cognitive training versus classical computer games: a randomized double-blind prospective trial of cognitive stimulation. AB - BACKGROUND: Many studies have suggested that cognitive training can result in cognitive gains in healthy older adults. We investigated whether personalized computerized cognitive training provides greater benefits than those obtained by playing conventional computer games. METHODS: This was a randomized double-blind interventional study. Self-referred healthy older adults (n = 155, 68 +/- 7 years old) were assigned to either a personalized, computerized cognitive training or to a computer games group. Cognitive performance was assessed at baseline and after 3 months by a neuropsychological assessment battery. Differences in cognitive performance scores between and within groups were evaluated using mixed effects models in 2 approaches: adherence only (AO; n = 121) and intention to treat (ITT; n = 155). RESULTS: Both groups improved in cognitive performance. The improvement in the personalized cognitive training group was significant (p < 0.03, AO and ITT approaches) in all 8 cognitive domains. However, in the computer games group it was significant (p < 0.05) in only 4 (AO) or 6 domains (ITT). In the AO analysis, personalized cognitive training was significantly more effective than playing games in improving visuospatial working memory (p = 0.0001), visuospatial learning (p = 0.0012) and focused attention (p = 0.0019). CONCLUSIONS: Personalized, computerized cognitive training appears to be more effective than computer games in improving cognitive performance in healthy older adults. Further studies are needed to evaluate the ecological validity of these findings. PMID- 21311197 TI - Sensitivity and specificity of stroke symptom questions to detect stroke or transient ischemic attack. AB - BACKGROUND/AIMS: Undiagnosed stroke is a major public health problem. The Questionnaire for Verifying Stroke-Free Status (QVSS) includes eight items and was originally designed to detect stroke-free individuals. Its six symptom related questions could potentially be used to screen for undiagnosed stroke or transient ischemic attack (TIA), but the sensitivity and specificity of just the six symptom-related questions are unknown. METHODS: A research assistant administered the QVSS to outpatients from Veterans Administration stroke and general medicine clinics. Neurologists, blinded to QVSS scores, interviewed and examined all subjects to determine stroke status. Responses to the six symptom questions of the QVSS were compared against the neurologist-determined stroke/TIA status. RESULTS: The sensitivity of the individual symptom questions ranged from 0.22 to 0.60, and the specificity ranged from 0.79 to 0.95. The sensitivity of any of the six symptom questions was 0.82, and the specificity was 0.62. CONCLUSION: The six symptom-related questions of the QVSS demonstrate a high sensitivity and moderate specificity for the diagnosis of stroke or TIA compared with neurological exam. Though these findings should be validated in a more representative general population, these questions have potential for meeting the public health objective of detecting clinically unrecognized but symptomatic stroke. PMID- 21311198 TI - rho-Kinase inhibition reduces early microvascular leukocyte accumulation in the rat kidney following ischemia-reperfusion injury: roles of nitric oxide and blood flow. AB - AIM: To study whether microvascular leukocyte accumulation after rat renal ischemia and reperfusion (IR) is decreased by Rho kinase inhibition, independently of effects upon nitric oxide (NO) and renal blood flow. METHODS: Male Wistar rats were subjected to 60 min of ischemia by bilateral clamping and 60 min of reperfusion of the renal arteries, or a sham procedure. Haemodynamics were monitored and microsphere blood flow to the kidneys was measured. The infusion of the Rho kinase inhibitor (Y27632) was commenced before clamping and IR. The NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), was administered after the start of reperfusion whilst the dopamine-1 receptor agonist fenoldopam, a renal vasodilator, was infused during the reperfusion period. Digital imaging microscopy analysis of cryosections was done to determine leukocyte accumulation and vasodilator-stimulated phosphoprotein serine 239 phosphorylation (p-VASP ser 239), a marker of endothelial NO. RESULTS: Leukocytes (60-70% neutrophils) accumulated within blood vessels in the corticomedullary junction and medulla of the kidney. Leukocyte accumulation was markedly reduced by the Rho kinase inhibitor but not by fenoldopam. However, both drugs improved renal blood flow and microvascular expression of p-VASP ser 239 in the corticomedullary junction and medulla, which were decreased following IR. L-NAME treatment of IR animals pretreated with the Rho kinase inhibitor reduced blood flow and p-VASP ser 239 expression and increased leukocyte accumulation. CONCLUSION: Early microvascular leukocyte accumulation in the corticomedullary junction and medulla of the rat kidney after IR is ameliorated by Rho kinase inhibition. This effect is partly independent upon attenuation of decreased NO and renal blood flow. PMID- 21311199 TI - Transfused macrophages ameliorate pancreatic and renal injury in murine diabetes mellitus. AB - BACKGROUND: Alternatively activated macrophages (M2 macrophages) are able to reduce renal injury in murine adriamycin nephropathy. However, the effect of M2 macrophages in other renal diseases such as diabetic nephropathy remains unknown. METHODS: Macrophages were separated from splenocytes and polarized with IL-4 and IL-13 into a protective phenotype. Mice underwent adoptive transfer with M2 macrophages, and then diabetes was induced by tail vein injection with streptozotocin (STZ). Blood glucose levels were monitored daily. Mice were sacrificed at week 10 after STZ. Renal function and histopathological injury were assessed quantitatively. RESULTS: Transfused M2 macrophages accumulated progressively in kidneys for up to 10 weeks after STZ. Kidneys from diabetic mice transfused with M2 macrophages had less tubular atrophy, glomerular hypertrophy and interstitial expansion than did control diabetic mice. M2 macrophages suppressed the development of interstitial fibrosis. In addition, the degree of pancreatic islet injury, as assessed by insulin staining, haemoglobin A1c and blood glucose was reduced after transfusion of M2 macrophages. In vivo, activation of kidney endogenous macrophage cytokine expression was inhibited by M2 macrophages. CONCLUSION: Our findings show that M2 macrophages can protect against islet and renal injury in streptozotocin-induced diabetes, providing a potential therapeutic strategy for diabetes and diabetic nephropathy. PMID- 21311200 TI - Variability in the assessment of 'adequate' chest excursion during simulated neonatal resuscitation. AB - BACKGROUND: International neonatal resuscitation guidelines recommend assessing chest excursion when the heart rate is not improving. However, the accuracy in assessing 'adequate' chest excursion lacks objectivity. AIM: It was the aim of this study to test the accuracy in the assessment of 'adequate' chest excursion by measuring intra- and inter-observer variability of participants during simulated neonatal resuscitation. METHODS: Thirty-seven staff members (8 neonatologists, 8 registrars, 21 nurses) of the Neonatal Intensive Care Unit, Leiden University Medical Center, Leiden, The Netherlands, ventilated 2 different intubated, leak-free manikins at 2 attempts, each with a different compliance. Blinded to the manometer, participants could change the peak inflation pressure until chest movement was adequate according to their perception. Inflating pressures were recorded. RESULTS: According to the participants, a median (interquartile range) pressure of 18 cm H2O (16-22) at the first and 18 cm H2O (16-25) at the second attempt were needed to reach adequate chest excursion in the Laerdal manikin. The HAL manikin needed 26 cm H2O (19-31) and 24 cm H2O (22 33), respectively. The inter-observer coefficient of variance was 30% with the Laerdal manikin at both attempts, and 35 and 40% with the HAL manikin, respectively. The intra-observer coefficient of variance was 15% (8-23) with the Laerdal and 13% (9-20) with the HAL manikin. In both manikins and attempts, no significant differences in pressures and variances of pressures between the 3 groups were found. CONCLUSION: 'Adequate' chest excursion is a subjective parameter for guidance of appropriate ventilation during neonatal resuscitation. PMID- 21311201 TI - Dexamethasone and betamethasone for prenatal lung maturation: differences in vascular endothelial growth factor expression and alveolarization in rats. AB - BACKGROUND: Fetal and postnatal lung development is regulated by glucocorticoids. The use of antenatal corticosteroids is reported to produce effects on vascular endothelial growth factor (VEGF), which plays a crucial role in pulmonary development. OBJECTIVES: The purpose of this study was to compare pulmonary VEGF expression in newborn rats that were exposed to antenatal betamethasone versus dexamethasone and to evaluate its impact on the alveolarization period of rats (0 14 days of life). METHODS: Betamethasone, dexamethasone or equivalent saline solution (control group) was administered to pregnant rats on 20th and 21st days of gestation. Pulmonary VEGF mRNA, VEGF protein expression, and alveolarization changes were evaluated at birth and at 14 days of life. RESULTS: Betamethasone and dexamethasone were observed to have different actions on VEGF expression with a correlation with alveolarization on both days of study. Antenatal dexamethasone decreased VEGF expression, betamethasone tended to produce the induction of the expression of VEGF, and moreover, betamethasone did not produce a decrease in alveolarization as seen in the animals that received dexamethasone. CONCLUSIONS: Our results support the notion that betamethasone could be a better choice than dexamethasone for antenatal lung maturation. PMID- 21311202 TI - Long-term resistance training is associated with reduced circulating levels of IL 6, IFN-gamma and TNF-alpha in elderly women. AB - OBJECTIVE: The increase in inflammatory activity associated with aging is a characteristic of chronic disease processes that accounts for most of the mortality in the elderly. Resistance training (RT) has been shown to promote metabolic and functional benefits in this population. The objective of this study was to investigate the association between long-term RT and circulating levels of the proinflammatory mediators IL-6, TNF-alpha and IFN-gamma in elderly women. METHODS: This cross-sectional study included 54 older outpatients divided into a group that underwent RT (n = 28) for an average of 8.6 +/- 0.3 months and a sedentary group (n = 26). Measurements were taken only at the end of the intervention, and cytokine values were log-transformed. Dietary intake was controlled as a confounding factor. RESULTS: The RT group presented reduced levels of log10IFN-gamma (approx. 45%; p = 0.003), log10IL-6 (approx. 30%; p = 0.002) and log10TNF-alpha (approx. 22%; p = 0.036). Total caloric intake and systolic arterial blood pressure were significantly lower in the RT group (p = 0.001 and p = 0.022, respectively). Pearson's product moment correlation test revealed a negative association between the fat-free mass (FFM) index and log transformed IL-6 levels (p = 0.03; n = 54) and a trend towards significance for the correlation between the FFM index and log10IFN-gamma (p = 0.05; n = 54). CONCLUSION: Long-term, moderate-intensity RT in elderly women is associated with lower circulating levels of cytokines that are potentially implicated in disorders associated with physical inactivity and aging. PMID- 21311203 TI - Psychological stress and psychosomatic treatment: major impact on serious blood disorders? AB - OBJECTIVE: To demonstrate evidence of possible major impacts of psychological stress and psychosomatic interventions on myeloproliferative blood disorders and develop new approaches for the unification and quantified analysis of stress and psychosomatic treatments. METHODS: This 3.5- year longitudinal study was based upon the regular blood tests of a person with myelofibrosis who experienced severe and repeated work-related psychological stress and was subjected to psychosomatic treatment in the form of regular (approximately 4 h per day) self hypnosis sessions. Statistical data analysis was conducted on the basis of an introduced concept of generalized stress that mathematically unifies psychological stress and psychosomatic treatment. RESULTS: Severe stress and psychosomatic treatment were statistically shown to have a major (dominant) impact on blood platelet counts well described by an exponential dependence on cumulative levels of generalized stress. The typical relaxation time for the impacts of both stress and treatment was shown to be approximately 2 months. Only approximately 12% of the total variation in platelet counts could be attributed to factors other than psychological stress and psychosomatic treatment. The psychosomatic intervention resulted in a consistent reduction of high platelet counts from approximately 1,400 x 109 l-1 to approximately the middle of the normal range, with other blood parameters being either approximately stable or showing indications of a strengthening immune system. CONCLUSIONS: Our findings give hope for a possible development of psychosomatic treatments of at least some blood disorders. They also indicate a highly instrumental role of platelets in the quantified analysis of stress, psychosomatic interventions, and their neuroimmunological pathways. PMID- 21311204 TI - Long-term maternal separation differentially alters serum corticosterone levels and blood neutrophil activity in A/J and C57BL/6 mouse offspring. AB - OBJECTIVES: In this work, we searched for maternal separation effects on serum corticosterone levels and blood neutrophil activity in adult male A/J and C57BL/6 mouse offspring. METHODS: 40 male A/J mice and 40 male C57BL/6 mice were divided within each strain into two groups. Mice in the maternal separation group were separated from their mothers (1 h/day) on postnatal days 0-13. Mice in the control group were left undisturbed. On postnatal day 45, blood was drawn from all mice and used to assess neutrophil activity by flow cytometry and serum corticosterone levels by radioimmunoassay. RESULTS: The results showed that each mouse strain responded differently to maternal separation, but in both cases, serum corticosterone levels were affected. In both strains, adult mice that experienced maternal separation showed lower serum corticosterone levels than control mice. In relation to control mice kept together with their mothers, the levels of serum corticosterone were 72.7 and 36.36% lower in A/J and C57BL/6 mice submitted to maternal separation, respectively. The current findings showed that maternal separation increased neutrophil activity in mice after reaching adulthood. The observed effects, although in the same direction, differed between A/J and C57BL/6 mice. Maternal separation increased both the percentage and intensity of phagocytosis in C57BL/6 mice, but had no effects on A/J mice. Furthermore, maternal separation increased basal and propidium iodide-labeled Staphylococcus aureus-induced oxidative burst in A/J mice but did not affect oxidative burst in C57BL/6 mice. Finally, phorbol myristate acetate-induced oxidative burst increased in both strains. CONCLUSION: These results indicate that early maternal separation increases innate immunity, most likely by modifying hypothalamus-pituitary-adrenal axis activity. This suggests that maternal separation is a good model for stress which produces long-term neuroimmune changes whatever the animal species and strain used. PMID- 21311205 TI - Surface quality of porcine corneal lenticules after Femtosecond Lenticule Extraction. AB - PURPOSE: To determine the surface characteristics of porcine corneal lenticules after Femtosecond Lenticule Extraction. METHODS: The Carl Zeiss Meditec AG VisuMax(r) femtosecond laser system was used to create refractive corneal lenticules on 10 freshly isolated porcine eyes. The surface regularity on the corneal lenticules recovered was evaluated by assessing scanning electron microscopy images using an established scoring system. RESULTS: All specimens yielded comparable score results of 5-7 points (SD = 0.59) per lenticule (score range minimum 4 to maximum 11 points). Surface irregularities were caused by tissue bridges, cavitation bubbles or scratches. CONCLUSION: The Femtosecond Lenticule Extraction procedure is capable of creating corneal lenticules of predictable surface quality. However, future studies should focus on the optimization of laser parameters as well as surgical technique to improve the regularity of the corneal stromal bed. PMID- 21311206 TI - Expression of tumor necrosis factor-alpha, interleukin-1alpha, interleukin-6 and interleukin-10 in chronic otitis media with bone osteolysis. AB - The purpose of this study was to evaluate the expression of proinflammatory and immunoregulatory cytokines in chronic otitis media. The expression levels of TNF alpha, IL-1alpha, IL-6 and IL-10 were determined by Western blot analysis of tissue samples obtained during ear surgery. The expression levels of TNF-alpha, IL-1alpha and IL-6 in cholesteatoma tissues were substantially higher compared to those determined in the granulation tissue. The highest levels of TNF-alpha, IL-1 and IL-6 proteins were observed in patients with bone destruction. There were no significant differences in the expression of IL-10 levels in cholesteatoma and normal skin, but in the granulation tissue its level was substantially higher. The level of IL-10 in cholesteatoma tissues inversely correlated with the expression of proinflammatory cytokines, the degree of bone destruction and cholesteatoma invasion. Increased expressions of TNF-alpha, IL-1alpha and IL-6 in chronic otitis media and a strong positive correlation between these cytokine levels and the degree of bone destruction indicate the destructive behavior of cholesteatoma or granulation tissue. PMID- 21311207 TI - alpha-Tocopherol treatment ameliorates chronic pancreatitis in an experimental rat model induced by trinitrobenzene sulfonic acid. AB - OBJECTIVE: To investigate the effects of alpha-tocopherol on pancreatic fibrosis and survival in rats with experimental chronic pancreatitis induced by trinitrobenzene sulfonic acid (TNBS). METHODS: Chronic pancreatitis was induced in male Sprague-Dawley rats by infusion of TNBS into the pancreatic duct. alpha Tocopherol (300, 600 or 900 mg/kg) was orally administered to rats with experimental pancreatitis (treatment group) daily for 4 weeks. The relative pancreatic weight, pancreatic pseudocyst and death rate were observed. Paraffin embedded tissue samples were sliced, stained by hematoxylin-eosin and histopathologically examined. RESULTS: alpha-Tocopherol administration significantly ameliorated the pancreatic weight loss induced by TNBS in chronic pancreatitis rats compared to the control group. There were pancreatic pseudocysts in 69% of the alpha-tocopherol group, and in 100% of the control group. alpha-Tocopherol administration led to a significant increase of the survival rate. The histopathologic scores were higher in the control group than in the alpha-tocopherol group. Subgroup analysis of histopathologic scores revealed that a high dose of alpha-tocopherol results in less pancreatic injuries. CONCLUSION: alpha-Tocopherol treatment elevates survival rate, extenuates fibrosis and increases relative pancreatic weight in the chronic pancreatitis model. alpha-Tocopherol therapy in chronic pancreatitis is now required to confirm these findings and establish the role of this treatment in the management of this disabling condition. and IAP. PMID- 21311208 TI - Recurrent acute pancreatitis and persistent hyperamylasemia as a presentation of pancreatic osteoclastic giant cell tumor: an unusual presentation of a rare tumor. AB - Giant cell tumors of the pancreas are rare neoplasms divided into three forms: osteoclastic, pleomorphic, and mixed. We report an unusual case of a 62-year-old male presenting with recurrent acute pancreatitis and found to have a mass in the head of the pancreas on routine imaging. Endoscopic retrograde cholangiopancreatography showed a main pancreatic duct stricture, with brush cytology revealing the diagnosis of osteoclastic giant cell tumor of the pancreas. Whipple's procedure was successfully performed for resection of this tumor. and IAP. PMID- 21311209 TI - Incidence of pancreatic cancer in chinese patients with chronic pancreatitis. AB - BACKGROUND AND AIM: It is suggested that patients with chronic pancreatitis (CP) have a markedly increased risk of pancreatic cancer compared with the general population. This study was designed to determine the rate of pancreatic cancer in CP patients in China. METHODS: This was a semiprospective, single-center study including 420 consecutive CP patients (285 males and 135 females, median age at onset 39.5 years), with the median follow-up time being 102.3 months (range 24 419 months). We calculated the standardized incidence ratio (SIR) based on the pancreatic cancer incidence in the general population of China. RESULTS: Four cases of pancreatic cancer (0.9% of patients) were observed in 3,591 patient years (expected number of cases 0.15; SIR 27.2, 95% CI 7.4-69.6). Similar results were seen in alcoholics and non-alcoholics, and in smokers and non-smokers. When patients lost to follow-up were considered to be followed up until the end point without having developed pancreatic cancer (4,280 patient-years), SIR was 22.8 (CI 6.2-58.4). Based on the Cox model, with inserting factors being sex, age at the time of CP clinical onset, type of pancreatitis, and presence or absence of diabetes, calcification, alcohol use and smoking status, only age was found to correlate positively with the occurrence of pancreatic cancer (>50 years, hazard ratio, 1.8 +/- 0.5; p = 0.044). CONCLUSION: The risk of pancreatic cancer is markedly increased in CP patients in China compared with the general population, especially in older patients. and IAP. PMID- 21311210 TI - The epithelial cell and lung cancer: the link between chronic obstructive pulmonary disease and lung cancer. AB - Chronic obstructive pulmonary disease (COPD) and lung cancer currently form the basis for an enormous disease burden in the developed world. As a result of changing smoking trends and tobacco use, regrettably, a similar picture is arising rapidly within the developing world. COPD is a recognised risk factor for lung cancer, and a significant proportion of patients diagnosed with lung cancer have COPD. An association between both conditions has long been suspected but has proven difficult to demonstrate thus far. However, the common factors between both conditions are now becoming apparent thanks to recent clinical and molecular advances. Abnormal regulation of the immune system and the establishment of chronic inflammation appear to be key events in this process. In addition, the complex interplay between genes and environment and the possibility of a genetic basis to lung cancer susceptibility in the context of COPD are becoming clearer concepts. As we begin to unravel the common pathways and molecules in the pathogenesis of both conditions, we may be able to not only identify novel strategies to prevent and treat COPD and lung cancer, but also recognise molecular markers to identify patients at high risk of developing lung cancer. PMID- 21311211 TI - Functional level, physical activity and wellbeing in nursing home residents in three Nordic countries. AB - BACKGROUND AND AIMS: The main aim of this study was to describe physical and cognitive function and wellbeing among nursing home residents in three Nordic countries. A second aim was to compare groups of differing ages, levels of dependency in daily life activities (ADL), degree of fall-related self-efficacy, wellbeing and cognitive function. METHODS: 322 residents from nursing homes in Sweden, Norway and Denmark were included. Physical and cognitive function, level of physical activity and wellbeing were assessed by means of reliable and valid instruments. RESULTS: The mean age of participants was 85 years. Sixty percent could rise from a chair and 64% could walk independently. Men were younger and more physically active than women. Participants with a high level of dependency in ADL had lower physical and cognitive functions, were less physically active, and had lower fall-related self-efficacy than participants less dependent in ADL. Participants with low cognitive function had high fall-related self-efficacy. CONCLUSIONS: These data demonstrate that elderly residents in nursing homes in Sweden, Norway and Denmark are frail but heterogeneous. Significant differences in physical activity, physical function and dependency in ADL were seen in relation to age, fall-related self-efficacy, wellbeing and cognitive function. PMID- 21311212 TI - Targeting the insulin-like growth factor network in cancer therapy. AB - During the last decades, changes in the insulin-like growth factor (IGF) signaling have been related to the pathogenesis of cancer. Therefore, IGFs became highly attractive therapeutic cancer targets. Several drugs including monoclonal antibodies (mAB), small molecule tyrosine kinase inhibitors (RTKIs), anti-sense oligonucleotids (ASOs) and IGF-binding proteins (IGFBPs) targeting the IGF axis were developed. With over 60 ongoing clinical trials, the IGF1 receptor (IGF1R) is currently one of the most studied molecular targets in the field of oncology. In this review, we provide an overview on the IGF axis, its signaling pathways and its significance in neoplasia. We critically review the preclinical and clinical studies investigating the role of IGF1R as a cancer target and discuss preliminary results and possible limitations. PMID- 21311213 TI - Proanthocyanidins produce significant attenuation of doxorubicin-induced mutagenicity via suppression of oxidative stress. AB - This study has been initiated to determine whether proanthocyanidins can protect against doxorubicin-induced mutagenicity in mice and to elucidate the potential mechanism of this protection. Pretreatment of mice with proanthocyanidins (100 mg/kg/day, orally) for 7 days and simultaneously with doxorubicin (12 mg/kg, i.p.) for another day, significantly reduced the frequency of bone marrow DNA strand breaks and micronucleated polychromatic erythrocytes compared to doxorubicin-treated mice alone. Furthermore, proanthocyanidins caused a reduction in bone marrow suppression induced by doxorubicin treatment. In male germline, orally administration of proanthocyanidins (100 mg/kg/day, orally) for 7 consecutive days before and 7 consecutive days after treatment with doxorubicin (12 mg/kg, i.p.), significantly elevated the levels of sperm count and motility reduced by doxorubicin treatment. Furthermore, proanthocyanidins significantly decreased the elevated levels of spermatogonial and spermatocyte chromosomal aberrations and sperm head abnormality induced by doxorubicin. Prior administration of proanthocyanidins ahead of doxorubicin reduced the doxorubicin induced testicular lipid peroxidation and prevented the reduction in testicular non-protein sulfhydryl significantly. Conclusively, this study provides for the first time that proanthocyanidins have a protective role in the abatement of doxorubicin-induced mutagenesis and cell proliferation changes in germinal cells of mice that reside, at least in part, in their radical scavenger activity. Therefore, proanthocyanidins can be a promising chemopreventive agent to avert secondary malignancy and abnormal reproductive outcomes risks in cancer patients receiving doxorubicin-involved treatment. PMID- 21311215 TI - An assessment of thermal stability of Clostridium difficile toxoid formulations. AB - Strains of Clostridium difficile produce toxins A and B that can cause diarrhoea and pseudomembranous colitis. Currently, there is no preventative therapy for this infection but antibodies to the toxins provide protection, therefore a toxoid-based vaccine is needed. To evaluate thermal stability, a lyophilized and liquid formulation of toxoids A and B were stored at a range of temperatures for 5 weeks. Changes in toxoid structures and immune responses in an animal model before and after the incubation period were assessed. The structural integrity and the immune responses to liquid formulations were affected when stored at 56 degrees C but the lyophilized formulation was thermally stable and same treatment did not result in significant loss of immunological responses when immunized in an animal model. PMID- 21311216 TI - The immunogenicity and safety of vaccination with purified Vero cell rabies vaccine (PVRV) in China under a 2-1-1 regimen. AB - BACKGROUND: In China, rabies vaccine is only permitted to use under the Essen 5 dose regimen for the rabies post-exposure prophylaxis (PEP). However, Purified chick embryo cell vaccine made in India (Rabipur) has been approved in use under 2-1-1 immune program in 2010. Our objective is to confirm the immunogenicity and safety of PVRV manufactured in China (SPEEDA) under 2-1-1 program, compared with Rabipur and with the Essen 5-dose regimen. METHODS: A total of 112 subjects were divided into three groups: 50 subjects in test group A, 32 subjects in control group B and 30 subjects in control group C. "Zagreb" 2-1-1 program was chosen for group A and B using SPEEDA and Rabipur, "Essen" 5-dose regimen was adopted for group C using SPEEDA, thus to observe the general and local reactions within 72 h post vaccination. Serum samples were also collected at D0, D7, D14 and D45 to determine the rabies serum neutralizing antibody by rapid fluorescent focus inhibition test (RFFIT). RESULTS: All groups showed similar immunogenicity. The neutralizing antibody titers at D14 and D45 of all subjects showed more than 0.5 IU/ml. No moderate and severe adverse effects were observed, though mild adverse reactions may occur. CONCLUSIONS: PVRV (SPEEDA), under 2-1-1 regimen, is equally safe and immunogenic as the PCECV (Rabipur) for post-exposure prophylaxis vaccination. PMID- 21311214 TI - Signaling of reactive oxygen and nitrogen species in Diabetes mellitus. AB - Disorder of physiological signaling functions of reactive oxygen species (ROS) superoxide and hydrogen peroxide and reactive nitrogen species (RNS) nitric oxide and peroxynitrite is an important feature of diabetes mellitus type 1 and type 2. It is now known that hyperglycemic conditions of cells are associated with the enhanced levels of ROS mainly generated by mitochondria and NADPH oxidase. It has been established that ROS stimulate many enzymatic cascades under normal physiological conditions, but hyperglycemia causes ROS overproduction and the deregulation of ROS signaling pathways initiating the development of diabetes mellitus. On the other hand the deregulation of RNS signaling leads basically to a decrease in NO formation with subsequent damaging disorders. In the present work we will consider the pathological changes of ROS and RNS signaling in enzyme/gene regulated processes catalyzed by protein kinases C and B (Akt/B), phosphatidylinositol 3'-kinase (PI3-kinase), extracellular signal-regulated kinase 1/2 (ERK1/2), and some others. Furthermore we will discuss a particularly important role of several ROS-regulated genes and adapter proteins such as the p66shc, FOXO3a, and Sirt2. The effects of low and high ROS levels in diabetes will be also considered. Thus the regulation of damaging ROS levels in diabetes by antioxidants and free radical scavengers must be one of promising treatment of this disease, however, because of the inability of traditional antioxidative vitamin E and C to interact with superoxide and hydrogen peroxide, new free radical scavengers such as flavonoids, quinones and synthetic mimetics of superoxide dismutase (SOD) should be intensively studied. PMID- 21311217 TI - Current experience with school-located influenza vaccination programs in the United States: a review of the medical literature. AB - In the United States, all children 6 months through 18 years of age are recommended to be vaccinated against influenza annually. However, the existing pediatric immunization infrastructure does not have the capacity to vaccinate a high proportion of children each year. School-located influenza vaccination (SLIV) programs provide an opportunity to immunize large numbers of school-age children. We reviewed the medical literature in order to document the current U.S. experience to benefit future SLIV programs. Published reports or abstracts for 36 SLIV programs were identified, some of which spanned multiple years. The programs immunized between 70-128,228 students. While most programs vaccinated 40 50% of students, coverage ranged from 7-73%. Higher percentages of elementary students were vaccinated compared with middle and high school students. While many programs offered only intranasal vaccine, several programs have successfully used both the intranasal and injectable vaccines. Faculty and staff were immunized in some programs and uptake in this group varied considerably. Students were vaccinated quickly during school hours. Costs, where reported, ranged from approximately $20-$27 per dose delivered, including both vaccine and administration costs. The greatest need for future U.S. SLIV program implementation is the development of a financially sustainable model that can be replicated annually on a national scale. PMID- 21311218 TI - Increasing uptake of Gardasil among American adolescents: comparisons with the history of Hepatitis B vaccination. AB - OBJECTIVES: This paper identifies differences in the uptake rate of Gardasil and contrasts Gardasil uptake rate with the history of Hepatitis B vaccination. METHODS: A targeted review of peer-reviewed journals and industry commentary was conducted. New trends were calculated and figures created based on secondary data. RESULTS: The distribution of HPV vaccine does not conform to the geographic incidence rate of cervical cancer. Contrary to contemporary belief, school immunization mandates for Hepatitis B vaccines were not the impetus for their acceptance. Familial beliefs about HPV vaccines appear to be the most significant challenge to Gardasil uptake rate. CONCLUSIONS: Gardasil is at a critical juncture for increased uptake. Evidence-based educational interventions are needed. PMID- 21311219 TI - The flip side of the coin: role of ZRF1 and histone H2A ubiquitination in transcriptional activation. AB - We have recently reported that the protein ZRF1 specifically binds to monoubiquitinated histone H2A and derepresses Polycomb target genes at the onset of cellular differentiation. Our results suggest that ZRF1 exerts its function in a two-step mechanism, by initially displacing the Polycomb-repressive complex 1 (PRC1) from chromatin and subsequently acting together with histone H2A-specific deubiquitinases to facilitate transcriptional activation of its target genes. These findings demonstrate an ambiguity of the epigenetic monoubiquitin mark at histone H2A. Once considered to be a hallmark of gene silencing, it is now clear that this mark can also be utilized as a recruitment platform for proteins engaged in gene activation. Genome-wide analyses demonstrate that ZRF1 is recruited to typical Polycomb target genes, thereby putting it in a position to have an impact on differentiation and animal development. This molecular mechanism for ZRF1 may represent one of the first steps in switching silenced genes to a transcriptionally active state. We discuss here our recent findings in the light of progress made in understanding Polycomb-mediated silencing. PMID- 21311220 TI - Paradoxical microRNAs: individual gene repressors, global translation enhancers. AB - In mammalian cells, microRNAs regulate the expression of target mRNAs generally by reducing their stability and/or translation, and thereby control diverse cellular processes such as senescence. We recently reported the differential abundance of microRNAs in young (early-passage, proliferating) relative to senescent (late-passage, non-proliferating) WI-38 human diploid fibroblasts. Here we report that the levels of the vast majority of mRNAs were unaltered in senescent compared to young WI-38 cells, while overall mRNA translation was potently reduced in senescent cells. Downregulation of Dicer or Drosha, two major enzymes in microRNA biogenesis, lowered microRNA levels, but, unexpectedly, it also reduced global translation. While a reduction in Dicer levels markedly enhanced cellular senescence, reduction of Drosha levels did not, suggesting that the Drosha/Dicer effects on translation may be independent of senescence, and further suggesting that microRNAs may directly or indirectly enhance mRNA translation in WI-38 cells. We discuss possible scenarios through which Dicer/Drosha/microRNAs could enhance translation. PMID- 21311221 TI - The transcription factor FOXM1c binds to and transactivates the promoter of the tumor suppressor gene E-cadherin. AB - This study demonstrates for the first time that FOXM1c transactivates the murine E-cadherin promoter. It shows also that the purified DNA-binding domain of FOXM1c binds to the murine and human E-cadherin promoters in vitro, namely to a perfectly conserved FOXM1 site. Thus, this study identifies E-cadherin as a new direct FOXM1c target gene. This finding is surprising because E-cadherin is a tumor suppressor gene whereas FOXM1 is a proliferation-associated and tumorigenesis-promoting transcription factor. The transmembrane glycoprotein E cadherin mediates cell-cell adhesion in adherens junctions. Its expression is frequently lost or reduced in human tumors, which correlates with poor prognosis. Downregulation of E-cadherin represents a central event in epithelial-to mesenchymal transition. In contrast, FOXM1 contributes to oncogenic transformation and participates in tumor initiation and progression. It is overexpressed in many human cancers and a high FOXM1 level correlates with poor prognosis. FOXM1 stimulates cell proliferation and promotes cell cycle progression at the G1/S- and G2/M-transitions. The surprising finding that FOXM1c transactivates the promoter of the tumor suppressor gene E-cadherin points to a tumor-suppressive property of FOXM1. This view is supported by FOXM1's new tumor suppressor role as others reported that urethane-induced lung tumorigenesis is increased in mice with an endothelial cell-specific foxm1 deletion. PMID- 21311222 TI - Kelch repeat proteins control yeast PKA activity in response to nutrient availability. AB - Regulation of protein kinase A (PKA) by binding of cAMP to the regulatory subunit and the resulting release of the active catalytic subunit is a very well established mechanism of kinase activation. We have shown recently that PKA in budding yeast is also subject to an additional level of regulation that that modulates its activity in response to nutrient availability. Nutrient regulation of PKA activity requires a pair of proteins, Gpb1 and Gpb2, that contain several kelch repeats, a sequence motif that predicts that they fold into a beta propeller structure. The regulatory process mediated by Gpb1 and Gpb2 causes an increase in the stability and phosphorylation of the PKA regulatory subunit Bcy1 in response to low extracellular glucose concentrations. Phosphorylation of serine-145 of Bcy1 controls its stability, and other phosphorylation events at the cluster of serines at positions 74-84 correlate with changes in nutrient availability. Here we present data consistent with a model in which the effects of Gpb1 and Gpb2 on Bcy1 are an indirect consequence of their primary effects on the PKA catalytic subunits. PMID- 21311223 TI - Understanding PLZF: two transcriptional targets, REDD1 and smooth muscle alpha actin, define new questions in growth control, senescence, self-renewal and tumor suppression. AB - PLZF can function as a transcriptional activator or as a transcriptional repressor. Recent studies have identified two direct transcriptional targets of PLZF, REDD1 and smooth muscle alpha-actin. REDD1 is activated by PLZF. It mediates the PLZF-dependent downregulation of TORC1 and is responsible for the maintenance of pluripotency in cultures of spermatogonial progenitor cells. This activity may extend to other stem-like cell types. The effect of REDD1 on TORC1 also raises the possibility that REDD1 controls cell growth, tumorigenicity and senescence. The regulatory loop extending from PLZF via REDD1 to TORC1 identifies REDD1 as a critical determinant of TOR activity. The transcription of smooth muscle alpha-actin is repressed by PLZF. In fibroblasts, this downregulation is accompanied by a change of cell shape and a dramatic reorganization of the cytoskeleton. It is also correlated with the acquisition of cellular resistance to oncogenic transformation. The resistance is selective, it works against some oncoproteins but not against others. The molecular mechanisms underlying the changes in the cytoskeleton and in the susceptibility to oncogenic transformation are unknown. However these changes are dependent on the activity of RAS and thus probably involve the RAC/RHO family of proteins. PMID- 21311225 TI - Drosophila melanogaster Cyclin G coordinates cell growth and cell proliferation. AB - Mammalian Cyclins G1 and G2 are unconventional cyclins whose role in regulating the cell cycle is ambiguous. Cyclin G1 promotes G2/M cell cycle arrest in response to DNA damage whereas ectopic expression of CCNG2, that encodes Cyclin G2, induces G1/S cell cycle arrest. The only Drosophila Cyclin G was previously shown to be a transcriptional regulator that interacts with the chromatin factor Corto and controls expression of the homeotic gene Abdominal B. It is very close to mammalian Cyclin G1 and G2 except in its N-terminal region, that interacts with Corto, and that seems to have been acquired in dipterans. Ubiquitous misregulation of Cyclin G (CycG) using transgenic lines lengthens development and induces phenotypes suggesting growth or proliferation defects. Using tissue specific misregulation of CycG and FACS, we show that overproduction of Cyclin G produces small cells whereas shortage produces large cells, suggesting that Cyclin G negatively regulates cell growth. Furthermore, overexpression of CycG lengthens the cell cycle, with a prominent effect on G1 and S phases. Genetic interactions with Cyclin E suggest that Cyclin G prevents G1 to S transition and delays S phase progression. Control of cell growth and cell cycle by Cyclin G might be achieved via interaction with a network of partners, notably the cyclin dependent kinases CDK4 and CDK2. PMID- 21311224 TI - Stat1 is a suppressor of ErbB2/Neu-mediated cellular transformation and mouse mammary gland tumor formation. AB - The anti-tumor function of Stat1 as a regulator of innate immunity and tumor immune surveillance has been long studied and is well understood; however, less clear is its tumor-site specific role. Although Stat1 phosphorylated at tyrosine (Y) 701 and serine (S) 727 is essential for interferon (IFN) signalling, its function in signalling induced in breast cancer cells is not understood. Herein, we show that Stat1 Y701 phosphorylation is increased in human breast tumor cells with elevated levels of ErbB2/HER-2 and in cells transfected with ErbB2/Neu. However, pharmacological inhibition of ErbB2/HER-2 results in the inhibition of Stat1 Y701 phosphorylation indicating an atypical role of phosphorylated Stat1 in the inhibition of ErbB2/HER-2 signalling. Consistent with this notion, we found that Stat1 suppresses tumor development by an activated form of ErbB2/Neu in mouse embryonic fibroblasts in xenograft tumor assays; however, this anti-tumor function of Stat1 does not rely on Y701 and S727 phosphorylation. Experiments with transgenic mice demonstrated that Stat1 acts to suppress Neu-mediated breast tumorigenesis through immune regulatory and tumor-site specific mechanisms. Our data reveal a previous uncharacterized anti-tumor activity of Stat1 in ErbB2/Neu mediated cell transformation and breast oncogenesis with possible implications in the diagnosis and treatment of ErbB2-positive breast cancers. PMID- 21311226 TI - BAG3 protein is induced during cardiomyoblast differentiation and modulates myogenin expression. PMID- 21311227 TI - Messengers made for micro-destruction. PMID- 21311228 TI - Role for histone deacetylase 3 in maintenance of genome stability. PMID- 21311229 TI - Slowly cycling versus rapidly cycling intestinal stem cells: distinct roles or redundancy. PMID- 21311230 TI - The PKA paradox: is Bim the answer? PMID- 21311231 TI - Plugging PKA into ERK scaffolds. AB - Cancers often arise in part through derangements in protein kinase signaling. A striking example of this is the finding that approximately 30% of human tumors have mutations in Ras or B-Raf, leading to aberrant ERK kinase activation. Kinase signaling networks are often organized by scaffolding and anchoring proteins that help shape the dynamics of signal processing. AKAP-Lbc associates with the ERK scaffold protein KSR-1 to organize a growth factor and cAMP responsive signaling network. AKAP-Lbc also directs PKA phosphorylation of KSR-1 on a critical residue to ensure maximal signaling efficiency. PMID- 21311232 TI - Unleash the wild type: restoration of p53 suppressive activity in skin cancer. PMID- 21311233 TI - Cell cycle control by a methylation-phosphorylation switch. PMID- 21311234 TI - SAHF, to senesce or not to senesce? PMID- 21311235 TI - MiRegulators in cancer stem cells of solid tumors. PMID- 21311236 TI - A kinase's work is never done: Rad53 monitors chromatin near replication origins. PMID- 21311237 TI - Life and death responses to trophinin-mediated adhesion during blastocyst implantation. PMID- 21311238 TI - Beyond nutrients and bonding: p63-positive progenitors in breast milk. PMID- 21311239 TI - KAP1: a new link between the DNA damage response and PML nuclear bodies. PMID- 21311240 TI - Large at birth lifespan dearth? PMID- 21311241 TI - Daring to venture beyond the bench. AB - Few people are exactly where they thought they would be 20 years into their careers. Careers, like life, are full of twists and turns. Brains and an inviolable work ethic are table stakes in virtually every profession involving science. Beyond these basics, however, each of us brings our personal blend of talents and skills to creating a career. Some of us know exactly what we want and chart a direct course. Others are masters at seizing opportunities. Still others go with the natural flow of events. Since success and security can only come with time, begin by choosing your adventure. Follow your interests and passions. Radically rewrite your resume, network, take people to coffee, get out of your comfort zone. Sticking to the same things you've already tried simply means you travel the same path over and over. Stepping out into the unknown can be scary, but it can also lead to unexpected places. Take a look. PMID- 21311244 TI - Withdrawal of propoxyphene from the US market: implications for the clinical nurse specialist. PMID- 21311245 TI - The clinical nurse specialist in an Irish hospital. AB - PURPOSE: This study was set in an acute Irish health care setting and aimed to explore the activity of the clinical nurse specialist (CNS) in this setting. DESIGN: Quantitative methodology, using a valid and reliable questionnaire, provided descriptive statistics that gave accurate data on the total population of CNSs in the health care setting. SETTING: The study was set in an acute-care 750-bed hospital that had 25 CNSs in practice. SAMPLE: The sample consisted of all 25 CNSs who are the total population of CNSs working in the acute health care institution. FINDINGS: The findings show the CNS to be active in the roles of researcher, educator, communicator, change agent, leader, and clinical specialist, but the level of activity varies between different roles. CONCLUSION: There is variety in the activity of CNSs in the various roles and to what extent they enact the role. IMPLICATIONS FOR PRACTICE: The findings merit further study on CNS role activity and possible variables that influence role activity. PMID- 21311246 TI - Implementation of customized health information technology in diabetes self management programs. AB - PURPOSE: The project was a nurse-led implementation of a software application, designed to combine clinical and demographic records for a diabetes education program, which would result in secure, long-term record storage. BACKGROUND/RATIONALE: Clinical information systems may be prohibitively expensive for small practices and require extensive training for implementation. A review of the literature suggests that the use of simple, practice-based registries offer an economical method of monitoring the outcomes of diabetic patients. PROJECT DESCRIPTION: The database was designed using a common software application, Microsoft Access. The theory used to guide implementation and staff training was Rogers' Diffusion of Innovations theory (1995). OUTCOMES: Outcomes after a 3-month period included incorporation of 100% of new clinical and demographic patient records into the database and positive changes in staff attitudes regarding software applications used in diabetes self-management training. These objectives were met while keeping project costs under budgeted amounts. CONCLUSIONS: As a function of the clinical nurse specialist (CNS) researcher role, there is a need for CNSs to identify innovative and economical methods of data collection. The success of this nurse-led project reinforces suggestions in the literature for less costly methods of data maintenance in small practice settings. Ongoing utilization and enhancement have resulted in the creation of a robust database that could aid in the research of multiple clinical issues. IMPLICATIONS: Clinical nurse specialists can use existing evidence to guide and improve both their own practice and outcomes for patients and organizations. Further research regarding specific factors that predict efficient transition of informatics applications, how these factors vary according to practice settings, and the role of the CNS in implementation of such applications is needed. PMID- 21311247 TI - Comparison of oxygen saturation values obtained from fingers on physically restrained or unrestrained sides of the body. AB - OBJECTIVE: The aim of this study was to compare semiexperimentally the pulse oximetry values obtained from a finger on restrained or unrestrained sides of the body. BACKGROUND: The pulse oximeter provides a noninvasive measurement of the oxygen saturation of hemoglobin in arterial blood. One of the procedures most frequently applied to patients in intensive care units is the application of physical restraint. Circulation problems are the most important complication in patients who are physically restrained. Evaluation of oxygen saturation from body parts in which circulation is impeded or has deteriorated can cause false results. METHODS: The research sample consisted of 30 hospitalized patients who participated in the study voluntarily and who were concordant with the inclusion criteria of the study. Patient information and patient follow-up forms were used for data collection. Pulse oximetry values were measured simultaneously using OxiMax Nellcor finger sensors from fingers on the restrained and unrestrained sides of the body. Numeric and percentile distributions were used in evaluating the sociodemographic properties of patients. RESULTS: A significant difference was found between the oxygen saturation values obtained from a finger of an arm that had been physically restrained and a finger of an arm that had not been physically restrained. The mean oxygen saturation value measured from a finger of an arm that had been physically restrained was found to be 93.40 (SD, 2.97), and the mean oxygen saturation value measured from a finger of an arm that had not been physically restrained was found to be 95.53 (SD, 2.38). CONCLUSIONS: The results of this study indicate that nurses should use a finger of an arm that is not physically restrained when evaluating oxygen saturation values to evaluate them correctly. PMID- 21311248 TI - Profile. PMID- 21311249 TI - The art and science of conversation: implications for long-term care. PMID- 21311251 TI - Harmful, harmless or helpful? The n-6 fatty acid debate goes on. PMID- 21311252 TI - Have the metabolic support pendulums in the intensive care unit stopped swinging? PMID- 21311253 TI - Bibliography. Current world literature. Lipid metabolism and therapy. PMID- 21311255 TI - Accountable care and cardiovascular nursing. PMID- 21311256 TI - Summaries of nursing care-related systematic reviews from the Cochrane library: homocysteine-lowering interventions for preventing cardiovascular events. PMID- 21311257 TI - Council on Cardiovascular Nursing. PMID- 21311258 TI - The evolving science of care in perinatal loss. PMID- 21311259 TI - Special editorial. Cesarean birth. PMID- 21311260 TI - A note from the publisher. Why perinatal and neonatal nursing in one journal? PMID- 21311261 TI - Determining the value of nursing care. PMID- 21311262 TI - Neonatal nurses: what about their grief and loss? PMID- 21311263 TI - Apology, disclosure, and unanticipated outcomes. PMID- 21311265 TI - Truth telling and severe fetal diagnosis: a virtue ethics perspective. AB - PURPOSE: Increased use of prenatal technologies has increased the numbers of women and partners whose fetus is diagnosed with a severe impairment. Virtue ethics provides a useful perspective to consider truth telling in this context, specifically how couples and providers interpret the diagnosis and prognosis to create truth. Virtue ethics is person-centered rather than act-centered, with moral actions guided by how a virtuous person would act in the same circumstance. Phronesis (practical wisdom) guides these actions. SUBJECTS AND METHODS: Fifteen women and 10 male partners with a severe fetal diagnosis participated in this longitudinal ethnography examining their experiences across 3 available care options: termination, routine obstetric care, and perinatal end-of-life care. Data from 39 interviews were analyzed to determine how they created meaning and truth in context of the diagnosis. RESULTS AND CONCLUSIONS: Providers' interactions were usually, but not always, characterized by the practice of phronesis. Couples were in a more complex moral situation than were providers. Those who terminated created a socially acceptable truth within a negative social environment related to abortion. Those seeking routine care had uncertain fetal prognoses and struggled with the meanings of "odds" of survival. One couple with end-of-life care experienced a close alignment of the facts and the truth they made public. PMID- 21311266 TI - Continuity and change in mothers' narratives of perinatal hospice. AB - OBJECTIVES: (1) To broadly explore the experiences of women who chose to continue pregnancies affected by lethal fetal diagnoses and (2) to develop knowledge useful to nurses and other healthcare professionals who provide perinatal hospice (PH) care. DESIGN: Qualitative descriptive study using narrative analysis. PARTICIPANTS: Fifteen women who learned during their pregnancies of a lethal fetal diagnosis and chose to continue the affected pregnancies. METHOD: Participants' stories of their PH experiences were recorded in face-to-face interviews. A qualitative approach using narrative analysis was used to identify themes and develop suggestions for care. RESULTS: The element of time was prevalent in mothers' stories. Some aspects of mothers' experiences continued, particularly feelings of love and connection to their babies. Mothers also reported evolving changes in their thoughts and feelings. Personal changes such as increased compassion, faith, and strength were frequently mentioned. Mothers described transient phases of highs and lows. Drawing personal meanings or life lessons was the main way mothers connected their experiences to their present lives. CONCLUSIONS: Mothers' descriptions of their experiences can enhance nurses' understanding of perinatal loss. Established care practices, such as birth planning and creating mementoes, were supported. Nurses can help mothers experiencing loss by elucidating and reflecting their personal meanings. PMID- 21311267 TI - Making a case: creating a perinatal palliative care service using a perinatal bereavement program model. AB - This article explores the innovative approach of creating a perinatal palliative care service in an institution that already has a perinatal bereavement program. The proposed model focuses on the importance of establishing and maintaining relationship among and between nurses, other clinicians, and parents. The authors examine theoretical and clinical perspectives, recognizing the presence of both grief and hope from the moment of a life-threatening fetal diagnosis. The article identifies key program development processes, potential barriers, and practical implementation strategies as methods to ensure the delivery of seamless perinatal palliative care from diagnosis, through pregnancy, delivery, and the baby's living and dying. PMID- 21311269 TI - Interconception care for couples after perinatal loss: a comprehensive review of the literature. AB - Perinatal loss can be emotionally devastating for couples who experience miscarriage, fetal or neonatal death. Nurses in a variety of settings can assist couples through their grief by providing emotional support, giving information about the grief process, and in planning for a future pregnancy or deciding to forego future childbearing. This article explicates the relationship between grief and perinatal loss and its effects on couples, specifically in the interconception period, when the initial grief and distress have begun to subside. Interconception care focuses on bridging the couple from the end of the postpartum period to the subsequent pregnancy or decision not to conceive again. Nurses assist couples in distinguishing between uncomplicated grief, complicated grief, and depression, and make appropriate referrals. Openness to expressions of grief, helping couples mobilize support, considering readiness for another pregnancy, and directing couples to useful Internet sites are essential nursing interventions. PMID- 21311271 TI - Neonatal end-of-life spiritual support care. AB - The death of an infant is a profound loss that may complicate, disrupt, or end relationships between parents; and lead to maladaptive grieving, long-term decreased quality of life, and symptoms related to psychological morbidity. Facing neonatal loss is frequently experienced as traumatic assault on parents' spiritual and existential world of meaning. This article highlights the importance of supporting parents through loss by providing comprehensive care that focuses not only on the neonate's physical needs, but also addresses parents' and families' spiritual, religious, and existential needs. Our objective is to increase practitioners' awareness of spiritual and existential distress and to provide strategies to address such needs, particularly at the end of life. PMID- 21311270 TI - Parent decision making for life support for extremely premature infants: from the prenatal through end-of-life period. AB - Most deaths of extremely premature infants occur in the perinatal period. Yet, little is known about how parents make life support decisions in such a short period of time. In the paper, how parents make life support decisions for extremely premature infants from the prenatal period through death from the perspectives of parents, nurses, and physicians is described. Five cases, comprised of five mothers, four neonatologists, three nurses, and one neonatal nurse practitioner, are drawn from a larger collective case study. Prenatal, postnatal and end-of-life interviews were conducted, and medical record data were obtained. In an analysis by two research team members, mothers were found to exhibit these characteristics: desire for and actual involvement in life support decisions, weighing pain, suffering and hope in decision making, and wanting everything done for their infants. All mothers received decision making help and support from partners and family, but relationships with providers were also important. Finally, external resources impacted parental decision making in several of the cases. By understanding what factors contribute to parents' decision making, providers may be better equipped to prepare and assist parents when making life support decisions for their extremely premature infants. PMID- 21311273 TI - Embrace: addressing anticipatory grief and bereavement in the perinatal population: a palliative care case study. AB - Anticipatory grief is experienced by families who are informed that their unborn child may not survive in utero or during or after delivery. The child who survives delivery, but is critically ill, brings a combination of emotions to the family: joy in welcoming a new life and fear for the future. The healthcare team members caring for the patient and family often witness this grief and are impacted. In the perinatal setting, the care continuum for these patients begins at diagnosis, typically in the prenatal setting, and continued support extends beyond the presumed life expectancy of the child. This case study is provided to demonstrate the utilization of a palliative care interdisciplinary approach to meeting the complex bereavement needs of a family who was expecting a child with a life-impacting congenital condition. PMID- 21311274 TI - Perinatal grief and support spans the generations: parents' and grandparents' evaluations of an intergenerational perinatal bereavement program. AB - PURPOSE: As perinatal loss, miscarriage, still birth, or neonatal death may result in signs and symptoms of grief in the entire family, perinatal bereavement programs (PBPs) should consider offering intergenerational services. The purpose of this program evaluation was to identify and evaluate siblings' and grandparents' utilization of a hospital-based PBP's intergenerational support services and education offerings with regard to the entire family's coping with the loss. METHODS: Written program evaluation surveys of parents and grandparents, with an opportunity for free response, along with parent phone follow-up, were utilized to evaluate whether a variety of inpatient/outpatient services for parents, siblings, and grandparents were useful to the entire family. RESULTS: Parents indicated that when siblings and grandparents were included in the PBP's services and education offerings, utilization of the services was useful to the entire family. Furthermore, grandparents also found the utilization of the PBP's intergenerational services to be useful in their own and their child's coping with the loss. CONCLUSION: This program evaluation affirms the usefulness of the offering of intergenerational inpatient and outpatient services by PBPs for entire families. PMID- 21311275 TI - When it simply won't go away.... PMID- 21311277 TI - Extramedullary ependymoma near the conus medullaris with lumbar nerve root attachment: case report. AB - BACKGROUND AND IMPORTANCE: Ependymomas are the most common primary spinal cord tumor, most frequently located near the cauda equina and conus medullaris. We believe that this is the first reported case of a low-grade, nonmyxopapillary (World Health Organization grade 2), intradural, extramedullary ependymoma involving a spinal nerve root. CLINICAL PRESENTATION: An 87-year-old woman presented with a chief complaint of acute onset of severe right hip and lateral thigh pain without midline back pain. She had baseline chronic bladder dysfunction, which remained unchanged. Her physical examination was significant for 4/5 strength in her right hip flexion (possibly related to pain), and 5 beats of clonus bilaterally. She had no point tenderness at the level of her compression fracture. Computed tomography of the patient's lumbar spine revealed a well-corticated, chronic compression fracture of the L3 vertebral body. Magnetic resonance images demonstrated an ovoid-shaped, 1.5*1-cm, well circumscribed, intradural, extramedullary lesion at the conus medullaris. The patient underwent an L1-3 laminectomy with intradural resection of the mass, which was found to be intricately involved with a single nerve root. The nerve root was coagulated and sectioned, and a gross total resection of the tumor was achieved. CONCLUSION: The patient tolerated the procedure well, with no complications or any postoperative neurological deficit. Her right-sided pain immediately resolved after surgery. Her strength and ambulation were normal after surgery. No adjuvant radiotherapy was offered to the patient. This case illustrates a unique tumor presentation and the successful surgical treatment of the condition. PMID- 21311278 TI - Lumbar subdural hematoma from intracranial subarachnoid hemorrhage presenting with bilateral foot drop: case report. AB - BACKGROUND AND IMPORTANCE: We report a patient with lumbar subdural hematoma secondary to intracranial subarachnoid hemorrhage (SAH) presenting with bilateral foot drop and describe our management. CLINICAL PRESENTATION: A 37-year-old woman presented with grade 4 SAH and hydrocephalus requiring emergent external ventricular drainage. Angiography demonstrated a left vertebral artery dissection and pseudoaneurysm that was treated with embolization of the vertebral artery. Six days after admission, her neurologic examination significantly improved. She was awake, alert, following commands, and moving all her extremities normally except for bilateral foot drop. An MRI scan revealed a lumbar subdural hematoma with severe thecal sac compression at L4-S1. The patient was initially treated with expectant management followed by surgery after she demonstrated only modest improvement. Evacuation of the hematoma was undertaken by an L5-S1 laminectomy and drainage of the liquefied clot in the subdural, extra-arachnoid space. Postoperatively, the patient demonstrated improved strength in all muscle groups except for left lower extremity eversion. CONCLUSION: We present a case of subdural hematoma that caused bilateral foot drop. Neurologic improvement occurred after evacuation of the hematoma. PMID- 21311279 TI - Diagnosis of Eagle syndrome with 3-dimensional angiography and near-infrared spectroscopy: case report. AB - BACKGROUND AND IMPORTANCE: Elongated styloid processes sometimes compress the cervical carotid artery, causing transient ischemic attacks. Most patients with Eagle syndrome who experience transient ischemic attacks have bilateral elongated styloid processes; therefore, it is necessary to determine which side is causing the Eagle syndrome to treat it. This is the first report of the usefulness of 3 dimensional angiography and near-infrared spectroscopy (NIRS) for the diagnosis of Eagle syndrome. CLINICAL PRESENTATION: A 40-year-old man experienced transient loss of consciousness when flexing his neck. On 3-dimensional computed tomography, bilateral elongated styloid processes were revealed. We were able to determine the side of concern using 3-dimensional angiography and NIRS. Three dimensional angiography with his neck flexed showed a compressive dent in the cervical portion of the left internal carotid artery. On NIRS, during neck flexion, the concentrations of oxygenated hemoglobin and total hemoglobin decreased in his left motor area, which was resolved immediately when he returned his neck to its natural position. This led to decreased cerebral blood flow in the left hemisphere of his brain. After partial removal of left styloid process, he was symptom free, even when keeping his neck flexed. NIRS showed that the concentrations of oxygenated hemoglobin increased in the left motor area during neck flexion. CONCLUSION: We report the usefulness of 3-dimensional angiography and NIRS for diagnosing Eagle syndrome. Three-dimensional angiography and NIRS can visualize anatomic structures and provide hemodynamic information for an appropriate surgical strategy. PMID- 21311280 TI - A case of a spinal epidural capillary hemangioma: case report. AB - BACKGROUND AND IMPORTANCE: Spinal hemangiomas usually arise from the vertebral body. Epidural hemangiomas are rare lesions, and most reported cases are cavernous. We report a case of a capillary hemangioma in the thoracic epidural space. CLINICAL PRESENTATION: The 57-year-old male patient initially presented with low thoracic spine pain. A magnetic resonance image of the thoracolumbar spine demonstrated an avidly enhancing epidural mass lesion in the lower thoracic spine with extension into the adjacent foramina at 2 levels on the right side. The patient developed progressive myelopathy over the course of 2.5 years despite minimal radiological changes. Surgical treatment resulted in good recovery. Histopathologically, the lesion corresponded to a vascular tumor composed of vessels of various calibers with fibrous septa between them. CONCLUSION: Early treatment of this type of lesion should be advocated to prevent deterioration and permanent neurological deficits. Appropriate treatment appears to be gross total resection. PMID- 21311281 TI - Endovascular treatment of an aneurysm of a persistent primitive hypoglossal artery with complete resolution of brainstem compressive symptoms: case report. AB - BACKGROUND AND IMPORTANCE: Aneurysms of the posterior circulation may manifest with neurological deficits related to mass effect on the brainstem. We present an unusual case of an aneurysm resulting in selective lower-extremity weakness and gait instability. CLINICAL PRESENTATION: A 61-year-old man presents with progressively worsening gait instability over the course of several months. A magnetic resonance image and computed tomographic angiogram demonstrate a persistent hypoglossal artery associated with an aneurysm invaginating into the pontomedullary junction. The patient manifested only lower-extremity symptoms. An endovascular approach through the right internal carotid artery and persistent primitive hypoglossal artery was assayed, coiling off the aneurysm with complete angiographic occlusion. One month after the procedure, the patient reported marked improvement in symptoms with residual difficulty walking. At the 1-year postprocedure interval, he reported nearly complete resolution of symptoms. CONCLUSION: Endovascular therapy of an aneurysm invaginating into the brainstem is safe and efficacious. PMID- 21311282 TI - Hemorrhagic synovial cyst: the possible role of initial trauma and subsequent microtrauma in its pathogenesis: case report. AB - BACKGROUND AND IMPORTANCE: Intraspinal synovial cysts are uncommon causes of back and radicular leg pain. Usually associated with degenerative spinal disease, these juxtafacet cysts are usually located in the lumbar spine and may rarely undergo intracystic hemorrhage. The pathogenesis of these cysts are unclear, and risk factors that may contribute to hemorrhagic complications are largely unknown. CLINICAL PRESENTATION: A 68-year-old man presented to the clinic 4 months after a fall on ice with persistent back pain and lumbar radiculopathy. A week after the initial clinic consultation, the patient presented to the emergency room with increased pain and worsening weakness in the left foot. An emergent magnetic resonance image showed thecal sac compression secondary to a large, juxtafacet cyst that was hyperintense on T1-weighted and hypointense on T2 weighted images. Lumbar decompressive laminectomies were performed at L3 and L4 with cyst removal and stabilization. CONCLUSION: We present the eighth reported case of a hemorrhagic juxtafacet cyst secondary to physical trauma, the second in which the patient's symptoms acutely worsened several months after the initial insult without new trauma. We also present summary statistics of the 31 cases of hemorrhagic juxtafacet cysts reported in the literature and propose a putative mechanism that may account for the development and progression of symptoms in some patients. PMID- 21311283 TI - Clinical problem-solving: aneurysm or spinal arteriovenous fistula-bait and switch. AB - OBJECTIVE: The authors use an instructive case to review the challenges of diagnosis in subarachnoid hemorrhage (SAH) and to reinforce the nuances of clinical management. IMPORTANCE: The presented case highlights critical issues in patient selection and challenges in the diagnosis of SAH and the management of both aneurysmal and arteriovenous fistula-related SAH. The critical points in decision making and diagnosis are discussed, and the case is accompanied by a brief review of the literature on the issues being faced. CLINICAL PRESENTATION: The present case is a patient presenting with SAH who was found to have an anterior communicating artery aneurysm. However, clues in the presentation and workup point to another etiology. CONCLUSION: A strong history of sudden neck pain before headache and abundance of SAH along the brainstem mandates a need to thoroughly evaluate the source of hemorrhage from cervical vessels through an angiogram. PMID- 21311284 TI - Clinical problem solving: monster on the hook--case problems in neurosurgery. AB - BACKGROUND AND OBJECTIVE: Nonfunctioning and functioning pituitary tumors can present in numerous ways. They may be difficult to diagnose correctly and, even with proper treatment, may lead to complications. METHODS: We present the case of a patient who presented with a large, invasive sellar mass and underwent both medical and surgical treatment for this lesion. The patient's course did not progress as was expected from his initial workup. RESULTS: The patient's history, physical examination, laboratory values, pathologic specimens, and radiologic findings are discussed. His management before, during, and after medical therapy and surgery is reviewed by pituitary experts from 2 different institutions. Aspects of diagnosis and management of sellar lesions are presented and reviewed in the literature. CONCLUSION: Neurosurgeons frequently treat patients with sellar lesions and should remember that despite modern laboratory, pathologic, and radiologic techniques, the diagnosis and treatment of these lesions is not always clear. PMID- 21311285 TI - The role of neuroanatomic dissection in modern stereotactic neurosurgery. PMID- 21311287 TI - Regarding efficacy of neurosurgery resident education. PMID- 21311292 TI - Venous thromboembolism prophylaxis in patients undergoing cranial neurosurgery: a systematic review and meta-analysis. AB - BACKGROUND: Randomized clinical trials (RCTs) have usually supported using heparin prophylaxis against venous thromboembolism (VTE) in patients undergoing cranial neurosurgery. The tradeoff between benefit and bleeding risk, however, has not been adequately characterized. OBJECTIVE: To conduct a systematic review and meta-analysis assessing the extent to which low-dose unfractionated heparin (LDUH) or low-molecular-weight heparin (LMWH) prophylaxis reduces the rate of VTE and increases the rate of intracerebral hemorrhage (ICH) and other bleeding in patients undergoing elective cranial neurosurgery. METHODS: We selected RCTs that evaluated LDUH or LMWH prophylaxis of VTE in patients undergoing elective cranial neurosurgery. A meta-analysis assessing heparins vs no heparin (either with or without mechanical methods) was performed. RESULTS: Eight RCTs were identified. Six RCTs involving 1170 patients evaluated LDUH or LMWH vs a control group. Five of 6 trials found a significant reduction in the risk of symptomatic and asymptomatic VTE with heparin prophylaxis. The pooled risk ratio was 0.58 (95% confidence interval, 0.45-0.75). ICH was more common in those receiving heparin, but not statistically significantly. For every 1000 patients who receive heparin prophylaxis, 91 VTE events will be prevented (approximately 35 of which are proximal deep vein thrombosis or pulmonary embolism and 9 to 18 of which are symptomatic), whereas 7 ICHs and 28 more minor bleeds will occur. CONCLUSION: Heparin prophylaxis for patients undergoing elective cranial neurosurgery reduces the risk of VTE but may also increase bleeding risks with a ratio of serious or symptomatic VTE relative to serious bleeding that is only slightly favorable. PMID- 21311293 TI - Large between-center differences in outcome after moderate and severe traumatic brain injury in the international mission on prognosis and clinical trial design in traumatic brain injury (IMPACT) study. AB - BACKGROUND: Differences between centers in patient outcome after traumatic brain injury are of importance for multicenter studies and have seldom been studied. OBJECTIVE: To quantify the differences in centers enrolling patients in randomized clinical trials (RCTs) and surveys. METHODS: We analyzed individual patient data from 9578 patients with moderate and severe traumatic brain injury enrolled in 10 RCTs and 3 observational studies. We used random-effects logistic regression models to estimate the between-center differences in unfavorable outcome (dead, vegetative state, or severe disability measured with the Glasgow Outcome Scale) at 6 months adjusted for differences in patient characteristics. We calculated the difference in odds of unfavorable outcome between the centers at the higher end vs those at the lower end of the outcome distribution. We analyzed the total database, Europe and the United States separately, and 4 larger RCTs. RESULTS: The 9578 patients were enrolled at 265 centers, and 4629 (48%) had an unfavorable outcome. After adjustment for patient characteristics, there was a 3.3-fold difference in the odds of unfavorable outcome between the centers at the lower end of the outcome distribution (2.5th percentile) vs those at the higher end of the outcome distribution (97.5th percentile; P<.001). In the 4 larger RCTs, the differences between centers were similar. However, differences were smaller between centers in the United States (2.4-fold) than between centers in Europe (3.8-fold). CONCLUSION: Outcome after traumatic brain injury differs substantially between centers, particularly in Europe. Further research is needed to study explanations for these differences to suggest where quality of care might be improved. PMID- 21311294 TI - Predictors of hyperperfusion syndrome before and immediately after carotid artery stenting in single-photon emission computed tomography and transcranial color coded real-time sonography studies. AB - BACKGROUND: Hyperperfusion syndrome (HPS) is a critical complication after carotid artery stenting (CAS) and carotid endarterectomy (CEA). OBJECTIVE: To identify predictors of HPS before and immediately after CAS. METHODS: We analyzed patients who underwent elective CAS from 2005 to 2008, and underwent single photon emission computed tomography (SPECT) and transcranial color-coded real time sonography before and immediately after CAS. HPS was defined as post-CAS deteriorating neurological conditions with headache not secondary to cerebral ischemia. We assessed the measures of blood flow between the two cortical hemispheres by taking the ratio of cerebral blood flow (CBF) of the affected to unaffected hemisphere excluding any ischemic/infarcted areas (asymmetry index); the measures of blood flow within each cortical hemisphere by comparing the CBF in the affected cortical hemispheric area to the CBF in the ipsilateral cerebellar hemisphere (middle cerebral artery [MCA]-to-cerebellar activity ratio); cerebral vasoreactivity (CVR); MCA mean blood flow velocity in the affected hemisphere; and MCA mean blood flow velocity ratio (preoperative to postoperative). RESULTS: Sixty-four patients were analyzed retrospectively. Nine patients presented with HPS. Logistic regression analysis showed that CVR (P<.01) and MCA mean blood flow velocity (P<.05) were the significant predictors among the pre-CAS variables, and that MCA mean blood flow velocity ratio (P<.05) and MCA-to-cerebellar activity ratio change (P<.05) were significant predictors among the post-CAS variables. CONCLUSION: SPECT and transcranial color-coded real-time sonography studies are useful in predicting HPS. PMID- 21311295 TI - Predictors of survival after surgical treatment of spinal metastasis. AB - BACKGROUND: Surgery for spinal metastasis is a palliative treatment aimed at improving patient quality of life by alleviating pain and reversing or delaying neurologic dysfunction, but with a mean survival time of less than 1 year and significant complication rates, appropriate patient selection is crucial. OBJECTIVE: To identify the most significant prognostic variables of survival after surgery for spinal metastasis. METHODS: Chart review was performed on 200 surgically treated spinal metastasis patients at Stanford Hospital between 1999 and 2009. Survival analysis was performed and variables entered into a Cox proportional hazards model to determine their significance. RESULTS: Median overall survival was 8.0 months, with a 30-day mortality rate of 3.0% and a 30 day complication rate of 34.0%. A Cox proportional hazards model showed radiosensitivity of the tumor (hazard ratio: 2.557, P<.001), preoperative ambulatory status (hazard ratio: 2.355, P=.0001), and Charlson Comorbidity Index (hazard ratio: 2.955, P<.01) to be significant predictors of survival. Breast cancer had the best prognosis (median survival, 27.1 months), whereas gastrointestinal tumors had the worst (median survival, 2.66 months). CONCLUSION: We identified the Charlson Comorbidity Index score as one of the strongest predictors of survival after surgery for spinal metastasis. We confirmed previous findings that radiosensitivity of the tumor and ambulatory status are significant predictors of survival. PMID- 21311296 TI - What factors predict the response of larger brain metastases to radiosurgery? AB - BACKGROUND: Approximately 20 to 40% of patients with systemic malignancies develop brain metastases. OBJECTIVE: To assess the potential role of stereotactic radiosurgery (SRS) for larger metastatic brain tumors, we reviewed our recent experience. METHODS: Between 2004 and 2008, 70 patients with a metastatic brain tumor larger than 3 cm in maximum diameter underwent Gamma knife SRS. Thirty three patients had received previous whole brain radiation therapy (WBRT) and 37 received only SRS. RESULTS: The overall median follow-up was 8.1 months. At the first planned imaging follow-up at 2 months, 29 (41%) tumors had >50% volume reduction, 22 (31%) had 10 to 50% volume reduction, and 19 (28%) were stable or larger. We also evaluated brain edema using MRI T2 images. In 11 patients (16%) the peritumoral edema volume was reduced by more than 50%, in 25 (36%) it was reduced by 10 to 50%, in 21 (30%) it was stable, and in 13 (19%) it was increased. Twenty (36%) discontinued corticosteroids by the time of first imaging follow-up. Because of persistent symptoms, 7 patients (10%) required a craniotomy to remove the tumor. Tumor volume reduction (>50%) was associated with a single metastasis (P=.012), no previous WBRT (P=.002), and a tumor volume<16 cm3 (P=.002). The better peritumoral edema volume reduction (>50%) was associated with a single metastasis (P=.024), no previous WBRT (P=.05), and breast cancer histology (P=.044). CONCLUSION: Surgical resection remains the primary approach for larger brain metastases if feasible. Tumor volume is a better indicator than maximum diameter. Tumor volume and edema responded better in patients who underwent SRS alone. PMID- 21311297 TI - Neuroprotective effects of bone marrow stem cells overexpressing glial cell line derived neurotrophic factor on rats with intracerebral hemorrhage and neurons exposed to hypoxia/reoxygenation. AB - BACKGROUND: Intracerebral hemorrhage (ICH) represents at least 15% of all strokes in the Western population and a considerably higher proportion at 50% to 60% in the Oriental population. OBJECTIVE: To investigate whether administration of bone marrow stem cells (BMSCs) overexpressing glial cell line-derived neurotrophic factor (GDNF) provides more efficient neuroprotection for rats with ICH and neurons exposed to hypoxia/reoxygenation. METHODS: Primary rat BMSCs were transfected with rat GDNF gene using virus vector (GDNF/BMSCs) and blank virus plasmid (BVP/BMSCs). Primary rat cortical neurons of rats were exposed to hypoxia and then reoxygenated with GDNF/BMSCs (GDNF/BMSCs group) or BVP/BMSCs (BMSCs group) treatment for 12 hours and 1, 2, 3, and 5 days. Hoechst 33258 staining was used to evaluate apoptosis. GDNF/BMSCs, BVP/BMSCs, and saline (GDNF/BMSCs, BMSCs, and control groups) were injected into the right striatum 3 days after rat ICH induced by injecting collagenase. Modified neurological severity scores and hematoxylin and eosin staining were performed to evaluate neurological function and lesion volume at 1 and 2 weeks after transplantation. Immunostaining was used to observe differentiation of grafted cells (neurofilament-200 for neurons, glial fibrillary acidic protein for astrocytes). The GDNF level and apoptosis were evaluated by Western blotting and terminal deoxynucleotidyl transferase dUTP nick end labeling, respectively. RESULTS: The GDNF/BMSCs group had significantly lowered apoptosis compared with the BMSCs group at the given time. The GDNF/BMSCs group had significantly improved functional deficits and reduced lesion volume compared with the BMSCs group. Stable GDNF expression in the GDNF/BMSCs group was detected at the given time in the host brain. The neurofilament-positive grafted cells in the GDNF/BMSCs group were more numerous than in the BMSCs group. The GDNF/BMSCs group had significantly decreased apoptotic cells compared with the BMSCs group. CONCLUSION: These results suggest that GDNF/BMSCs provide better neuroprotection for rats with ICH and neurons exposed to hypoxia/reoxygenation. PMID- 21311298 TI - Favorable outcome in traumatic brain injury patients with impaired cerebral pressure autoregulation when treated at low cerebral perfusion pressure levels. AB - BACKGROUND: Cerebral pressure autoregulation (CPA) is defined as the ability of the brain vasculature to maintain a constant blood flow over a range of different systemic blood pressures by means of contraction and dilatation. OBJECTIVE: To study CPA in relation to physiological parameters, treatment, and outcome in a series of traumatic brain injury patients. METHODS: In this prospective observational study, 44 male and 14 female patients (age, 15-72 years; mean, 38.7 years; Glasgow Coma Scale score, 4-13; median, 7) were analyzed. Patients were divided into groups on the basis of status of CPA (more pressure active vs more pressure passive) and level of cerebral perfusion pressure (CPP; low vs high CPP). The proportions of favorable outcome in the groups were assessed. Differences in physiological variables in the different groups were analyzed. RESULTS: Patients with more impaired CPA treated at CPP levels below median had a significantly higher proportion of favorable outcome compared with patients with more impaired CPA treated at CPP levels above median. No significant difference in outcome was seen between patients with more intact CPA when divided by level of CPP. In patients with more impaired CPA, CPP<50 mm Hg and CPP<60 mm Hg were associated with favorable outcome, whereas CPP>70 mm Hg and CPP>80 mm Hg were associated with unfavorable outcome. In patients with more intact CPA, no difference in physiological variables was seen between patients with favorable and unfavorable outcomes. CONCLUSION: Our results support that in traumatic brain injury patients with impaired CPA, CPP should not be elevated. PMID- 21311299 TI - Superficial temporal artery to middle cerebral artery bypass in acute ischemic stroke and stroke in progress. AB - BACKGROUND: Surgical reperfusion may be beneficial in patients with acute ischemic stroke who are ineligible for thrombolysis. OBJECTIVE: To evaluate the outcome of superficial temporal artery to middle cerebral artery (STA-MCA) bypass in acute stroke and stroke in progress. METHODS: The clinical and radiological data of 9 patients treated by STA-MCA bypass requiring urgent reperfusion but ineligible for intra-arterial thrombolysis (IAT) were reviewed. Pooled analysis was performed of published literature concerning STA-MCA bypass in acute stroke (21 cases in 2 articles). RESULTS: Of the 9 patients enrolled, symptom aggravation occurred during medical treatment in 4 patients and after IAT in 2. Three patients were ineligible for IAT despite being within 8 hours of symptom onset. Bypass significantly improved National Institutes of Health Stroke Scale scores (preoperatively, 12.4+/-4.88; 3 days postoperatively, 8.6+/-6.39, P=.046; discharge, 5.4+/-5.15, P=.008; 3 mo postoperatively 3.7+/-4.82, P=.008) without significant infarction growth by diffusion weighted imaging (preoperatively, 15.0+/-8.87 mL; 7 days postoperatively, 15.2+/-8.28 mL; P=.110). Abnormal perfusion regions (mean transit time>145% of contralateral side value) were reduced in all cases (2.63+/-0.93 mL). Good outcomes (modified Rankin scale<=2) were achieved by 6 patients. Pooled analysis with our patients showed a significant neurological improvement (P<.001) and a good outcome in 25 (83.3%) patients without hemorrhage or complication. CONCLUSION: STA-MCA bypass may be beneficial to patients with acute stroke or stroke in progress who are ineligible for IAT. Furthermore, it appears safe when the infarction is small. These findings indicate that STA-MCA bypass could be considered as a treatment option in selected patients with acute stroke or stroke in progress. PMID- 21311300 TI - Language and motor mapping during resection of brain arteriovenous malformations: indications, feasibility, and utility. AB - BACKGROUND: Microsurgical resection of arteriovenous malformations (AVMs) located in the language and motor cortex is associated with the risk of neurological deterioration, yet electrocortical stimulation mapping has not been widely used. OBJECTIVE: To demonstrate the usefulness of intraoperative mapping with language/motor AVMs. METHODS: During an 11-year period, mapping was used in 12 of 431 patients (2.8%) undergoing AVM resection (5 patients with language and 7 patients with motor AVMs). Language mapping was performed under awake anesthesia and motor mapping under general anesthesia. RESULTS: Identification of a functional cortex enabled its preservation in 11 patients (92%), guided dissection through overlying sulci down to the nidus in 3 patients (25%), and influenced the extent of resection in 4 patients (33%). Eight patients (67%) had complete resections. Four patients (33%) had incomplete resections, with circumferentially dissected and subtotally disconnected AVMs left in situ, attached to areas of eloquence and with preserved venous drainage. All were subsequently treated with radiosurgery. At follow-up, 6 patients recovered completely, 3 patients were neurologically improved, and 3 patients had new neurological deficits. CONCLUSION: Indications for intraoperative mapping include preoperative functional imaging that identifies the language/motor cortex adjacent to the AVM; larger AVMs with higher Spetzler-Martin grades; and patients presenting with unruptured AVMs without deficits. Mapping identified the functional cortex, promoted careful tissue handling, and preserved function. Mapping may guide dissection to AVMs beneath the cortical surface, and it may impact the decision to resect the AVM completely. More conservative, subtotal circumdissections followed by radiosurgery may be an alternative to observation or radiosurgery alone in patients with larger language/motor cortex AVMs. PMID- 21311301 TI - Treatment outcome of aneurysmal subarachnoid hemorrhage in patients aged 70 years and older. AB - BACKGROUND: The incidence of subarachnoid hemorrhage is increasing, especially in the elderly as life expectancy increases. Aggressive treatment of aneurysms in the elderly is usually avoided because of a presumed poor prognosis. OBJECTIVE: The aim of this study was to assess the outcome of treatment in patients older than 70 years old. METHODS: We performed a retrospective chart review of 150 patients aged 70 years and older who were treated at Jefferson Hospital from 2004 to 2009. Data including World Federation of Neurological Surgeons grade and Hunt and Hess classification, specific management components, and treatment outcome on discharge were analyzed. RESULTS: One hundred ten patients had aneurysms coiled, 9 patients had aneurysms clipped, 11 patients had aneurysms that were not treated, and 20 patients had no visible aneurysms. Overall, increased World Federation of Neurological Surgeons grades correlated strongly with poor clinical outcome. Statistical tests indicate that patients who died (mean, 78.8, n=35) or who went into rehabilitation (mean, 76.5, n=81) were significantly older than patients who were discharged home (mean, 73.1, n=20). However, day of presentation after initial symptom(s) of subarachnoid hemorrhage and placement of ventriculoperitoneal shunt also influenced clinical outcome. Patients who had a ventriculoperitoneal shunt were more likely to go into rehabilitation than patients who did not, and patients without a ventriculoperitoneal shunt were more likely to die. CONCLUSION: Older age should not preclude a patient from aneurysm treatment. Factors such as low Hunt and Hess or World Federation of Neurological Surgeons grades, earlier presentation to the hospital after initial symptoms, early shunting, prompt interventions, and tailored postoperative management can result in favorable clinical outcomes. PMID- 21311302 TI - Fundamental skills for entering neurosurgery residents: report of a Pacific region "boot camp" pilot course, 2009. AB - BACKGROUND: Incorporation of the first postgraduate year of training into neurological surgery residencies in 2009 posed new challenges to neurosurgical educators. A "boot camp" course was held in August 2009 to introduce first year neurosurgical trainees to various fundamental cognitive and practical skills. OBJECTIVE: The effectiveness of this course was evaluated by electronic survey of all trainees and faculty members. METHODS: Eighteen trainees entering 5 western neurosurgical residencies (in either the first or second postgraduate year) participated in a course taught by 10 faculty members at a single host institution (Oregon Health & Science University) for 2 days. All trainees completed an online survey evaluating the relevance and quality of each didactic and hands-on course component and answered additional questions about the goals and design of the course. Faculty members were also surveyed. RESULTS: All trainees thought the course met its goals, provided relevant and useful information and experience, and was likely to improve patient care. In particular, hands-on procedural and operative course components were highly valued. CONCLUSION: A fundamental skills boot camp course for first year neurosurgical trainees seems valuable. PMID- 21311303 TI - Harvey Cushing's innovative attempt at xenotransplanting a rabbit spinal cord in a patient after resection of a peripheral nerve tumor in 1902. AB - OBJECTIVE: A review of Harvey Cushing's surgical cases at Johns Hopkins Hospital revealed new information about his early work using nerve xenografts to repair peripheral nerve injuries. METHODS: The Johns Hopkins Hospital surgical records from 1896 to 1912 were reviewed. A single case in which Cushing used a xenograft to repair a peripheral nerve defect was selected for further study. RESULTS: In August 1902, a 23-year-old woman presented with tingling and numbness in her left foot and focal tenderness in the popliteal region. Cushing performed an exploratory operation, revealing an encapsulated tumor originating from the internal popliteal nerve. After resecting the segment of involved nerve, Cushing harvested the spinal cord from a rabbit and used it to span the 18-cm defect. At a 5-month postoperative follow-up, according to Cushing's clinical notes, the patient had partially regained some sensation in her leg and foot. Seven months later, the patient presented with a local tumor recurrence, and her leg was amputated. An examination of the amputated specimen demonstrated that the xenograft was still intact without gross evidence of xenograft rejection. CONCLUSION: Despite its questionable functional success, we report a previously unpublished operative case by Harvey Cushing in which a rabbit spinal cord was transplanted into a human to bridge a sciatic nerve gap. This sheds light on the potential for animal tissue as a source for the treatment of neurological disease in humans. PMID- 21311304 TI - Evaluation of angiographically occult spinal dural arteriovenous fistulae with surgical microscope-integrated intraoperative near-infrared indocyanine green angiography: report of 3 cases. AB - BACKGROUND: Spinal dural arteriovenous fistulae (dAVFs), are lesions involving an aberrant connection between a radicular feeding artery and the venous system of the spinal cord at the dural sleeve of the nerve root. When rare dAVFs are occult on digitally subtracted catheter-based angiography, they present a diagnostic and therapeutic challenge. OBJECTIVE: We report 3 cases of angiographically occult spinal dAVFs that were evaluated during surgery with indocyanine green (ICG) fluorescent microscope-integrated angiography. METHODS: Three patients with clinical and magnetic resonance imaging features suggestive of a spinal dAVF but no abnormality on digital subtraction angiography underwent surgical exploration with the aid of microscope-integrated ICG videoangiography. RESULTS: In all 3 cases, ICG identified the intradural vein draining the fistula, clearly distinguishing it from an artery or uninvolved medullary vein. CONCLUSION: ICG angiography can rapidly identify a draining vein as it enters the spinal canal even in dAVFs not identifiable on catheter-based digital subtraction angiography. PMID- 21311305 TI - Intracranial cysts containing cerebrospinal fluid-like fluid: results of endoscopic neurosurgery in a series of 64 consecutive cases. AB - BACKGROUND: Intracranial cysts containing cerebrospinal fluid (CSF) may be developmental or acquired. OBJECTIVE: To analyze the results of endoscopic neurosurgery in the management of intracranial CSF cysts. METHODS: In a 7-year period, 64 consecutive patients underwent endoscopic neurosurgery for CSF cysts. Group 1 consisted of 13 patients with acquired cysts; group 2 included 51 patients with developmental cysts. In all cases, the cyst walls were fenestrated through small burr holes with frameless guided operative endoscopes. Follow-up ranged from 1 to 6 years (mean, 3.4 years). RESULTS: There were no mortality and no permanent morbidity, apart from a patient (1.6%) who remained neurologically intact but required ventriculoperitoneal shunting because of intraoperative hemorrhage. The planned fenestrations could be performed in all patients except 2, owing to thick, opaque cyst walls. In group 1, 6 patients fully recovered and remained intact throughout the follow-up, whereas 7 improved but had various degrees of neurological disabilities that were related to their initial diseases. Radiological results were excellent in all cases. In group 2, there were 7 asymptomatic patients who remained unchanged and 44 "symptomatic" patients: 40 (91%) clinically improved, 4 (9%) remained unchanged, and none worsened. Cyst size decreased in 37 patients (74%) and remained unchanged in 13 (26%). CONCLUSION: In this series, patients of different ages, harboring cysts of various sizes and locations, could be satisfactorily treated with endoscopic neurosurgery. PMID- 21311306 TI - Stackable carbon fiber cages for thoracolumbar interbody fusion after corpectomy: long-term outcome analysis. AB - BACKGROUND: Reconstruction of the thoracolumbar spine after corpectomy is a challenge for fractures, infections, and tumors. OBJECTIVE: To analyze fusion rates, clinical outcomes, and the percent of vertebral body coverage achieved by using stackable carbon fiber-reinforced polyetheretherketone cages in thoracolumbar corpectomies, and to measure the actual size of the cages and compare this measurement with the size of the vertebra(e) replaced by the cage. METHODS: A retrospective study of 40 patients who underwent thoracolumbar corpectomies was performed. Preoperative imaging included plain films, computed tomography scans, and magnetic resonance imaging. Postoperatively, plain films and computed tomography scans were obtained, and the width of decompression and cross-sectional area of the cage were measured. The ratio of the area of the cage to the calculated area of the replaced vertebral body was used to determine the percent of vertebral body coverage. RESULTS: The mean follow-up period was 43 months. Successful fusion was observed in 39 patients. One patient experienced cage subsidence with kyphosis. One additional patient incurred a neurological complication that was corrected without long-term consequence. The mean correction of sagittal alignment was 10 degrees , and the mean width of bony decompression was 20 mm. The mean ratio of the area of the carbon fiber cage to the area of the resected vertebral body was 60%. CONCLUSION: Stackable carbon fiber cages are effective devices for achieving thoracolumbar fusions. No failures of the cages occurred over long-term follow-up. Excellent clinical and radiographic results were achieved by covering a mean of 60% of the vertebral body with the cage. PMID- 21311308 TI - Which indexes are appropriate among those derived from selective arterial calcium stimulation and venous sampling (ASVS) for diagnosing pancreatic insulinomas? Evaluation using receiver operating characteristic analyses. PMID- 21311307 TI - Proteinase-activated receptor 2 mediates thermal hyperalgesia and is upregulated in a rat model of chronic pancreatitis. AB - OBJECTIVES: The mechanism of pain in chronic pancreatitis (CP) has yet to be explored. Proteinase-activated receptor 2 (PAR2) plays a pronociceptive role in visceral pain. The study aimed to assess the expression of PAR2 in dorsal root ganglia (DRGs) and validate its role of thermal hyperalgesia in CP. METHODS: Chronic pancreatitis model was induced by trinitrobenzene sulfonic acid infusion into rat pancreatic ducts. Abdominal hyperalgesia was measured by thermal withdrawal latencies. The expression of PAR2 and transient receptor potential vanilloid 1 (TRPV1) were analyzed by immunofluorescence and Western blot. The messenger RNA encoding PAR2 was quantitated by real-time polymerase chain reaction. The effects of short-term and long-term ulinastatin treatment on abdominal thermal hyperalgesia of rats with CP were measured. RESULTS: Rats with CP showed a decreased thermal withdrawal latency. Proteinase-activated receptor 2 and TRPV1 were significantly upregulated in DRGs. The increased PAR2 protein expression was tightly correlated with thermal withdrawal latencies and TRPV1 expression. Short-term ulinastatin treatment inhibited the development of thermal hyperalgesia of rats with CP in a dose-dependent manner. CONCLUSIONS: The thermal hyperalgesia in CP is associated with an up-regulation of the PAR2 in DRGs. Proteinase-activated receptor 2 was involved in the pain generation in rats with CP. PMID- 21311309 TI - Optimal size range for enteric-coated pancreatin preparations. PMID- 21311310 TI - Early experience with robotic total pancreatectomy. PMID- 21311311 TI - Unprecedented case of desmoplastic fibroblastoma in the pancreas. PMID- 21311312 TI - Acute pancreatitis associated with Henoch-Schonlein purpura. PMID- 21311313 TI - An unusual case of rectal bleeding: colosplenic fistula complicating pancreatitis. PMID- 21311314 TI - Hemosuccus pancreaticus: a new mechanism. PMID- 21311315 TI - How fast can pancreatic cancer grow? A case of pancreatic carcinoma developed within 5 months after a negative examination to the advanced stage with multiple liver and bone metastases. PMID- 21311316 TI - Mixed ductal-endocrine carcinoma of the pancreas metastatic to the liver. PMID- 21311317 TI - Recurrent pleural effusion as an unusual presentation of acute pancreatitis in children. PMID- 21311318 TI - Targeting STAT3 signaling in pancreatic cancer promotes antiapoptotic gene expression. PMID- 21311319 TI - Estimation of the rate of pelvic inflammatory disease diagnoses: trends in England, 2000-2008. AB - BACKGROUND: Pelvic inflammatory disease (PID) is difficult to define and diagnose; therefore, a standardized methodology for identifying and monitoring PID diagnoses is required. We estimated the rate of PID in general practice in England, and investigated variations by definition of PID, time, age, and geographical area. METHODS: We analyzed the United Kingdom General Practice Research Database between 2000 and 2008. Definitions of "definite," "probable," and "possible" PID among female patients (aged 16 to 44 years) were determined according to medical codes that denoted diagnoses or symptoms indicative of PID. Diagnoses rates were calculated per 100,000 person-years (py). Trends were assessed using Poisson regression. RESULTS: The rate of clinical PID diagnoses was 281/100,000 py (95% confidence interval [95% CI]: 277-286) for definite cases; 326/100,000 py (95% CI: 321-331) for definite and probable cases; and 1117/100,000 py (95% CI: 1107-1126) for definite, probable, and possible cases. During 2000 to 2008, the rate of definite/probable PID decreased by 10.4% per year (95% CI: 9.7-11.1; P<0.001). Rates declined in all areas and among all age groups with greatest decline in women aged 16 to 19 years. Meanwhile, the rate of possible PID increased. CONCLUSIONS: The definition of PID used has a major effect on the rate and trends over time. There was heterogeneity in rates of definite/probable PID by age and region, but homogeneity with regard to a trend of declining rates. Ongoing monitoring of PID diagnoses, with standard case definitions, will contribute to the evaluation of chlamydia screening in England. PMID- 21311320 TI - An uncommon cause of postoperative bleeding. AB - The postoperative phase can be associated with an increased risk of thrombosis and abnormal bleeding. We report the case of a patient admitted to our intensive care unit for postoperative monitoring who developed two episodes of hemorrhagic shock. A thromboelastogram performed with heparinase I digestion demonstrated the action of endogenous heparin-like substances whose presence was subsequently confirmed at the histological examination of the tumor. Heparinase-modified thromboelastography has proven to be an effective and rapid point-of-care coagulation test and in our case allowed early detection of circulating heparinoids. PMID- 21311321 TI - Antiplatelet, anticoagulant, and fibrinolytic activity in vitro of extracts from selected fruits and vegetables. AB - A diet rich in fruits and vegetables is known to decrease the risk of cardiovascular disease. However, the information regarding the antithrombotic activity (antiplatelet, anticoagulant, and fibrinolytic) of fruits and vegetables is scarce. The aim of this study was to assess the antithrombotic activity of extracts from fruits and vegetables widely consumed in central Chile. The study included samples of 19 fruits and 26 vegetables, representative of the local diet. The extracts prepared from each sample included an aqueous (juice or pressed solubles) and/or methanol-soluble fraction. The extracts were evaluated for antiplatelet, anticoagulant, and fibrinolytic activity in vitro at a final concentration of 1 mg/ml. The antiplatelet activity was assessed by platelet aggregation inhibition; anticoagulant activity was measured by the prothrombin time (PT), diluted prothrombin time (dPT), activated partial thromboplastin time (APTT), kaolin clotting time (KCT), and thrombin time. The fibrinolytic effect was determined with the euglobin clot lysis time and fibrin plate methods. Extracts of green beans and tomatoes inhibited platelet aggregation induced by ADP and arachidonic acid, in a concentration-dependent manner. The methanolic extracts of grapes prolonged the PT and dPT. Finally, extracts of raspberry prolonged the APTT and also presented fibrinolytic activity. In conclusion, from a screening that included a variety of fruits and vegetables, we found antiplatelet activity in green beans and tomatoes, anticoagulant activities in grapes and raspberries, whereas fibrinolytic activity was observed only in raspberries. Further investigations are necessary to advance in knowledge of the active compounds of these fruits and vegetables and their mechanisms of action. PMID- 21311322 TI - Acute-on-chronic liver failure: the kidneys. AB - PURPOSE OF REVIEW: Acute-on-chronic liver failure (ACLF) is defined as an abrupt deterioration of liver function in patients with established liver disease. Kidney function is almost universally altered in patients with ACLF due to underlying circulatory abnormalities. We review current advances during the past year in the diagnosis and management of renal failure in ACLF. RECENT FINDINGS: The adequate measurement of renal function by means of clearance methods remains the gold standard for estimation of the glomerular filtration rate in patients with cirrhosis. The new definition of acute kidney injury needs to be specifically studied in patients with cirrhosis. Alternative kidney biomarkers of renal function in cirrhosis are promising and need further investigation. The most common cause of renal failure in cirrhosis is that associated with infections followed by hypovolemia-induced renal failure, intrinsic renal diseases, hepatorenal syndrome, and drug-induced renal failure. Adrenal insufficiency commonly occurs in patients with cirrhosis and hemodynamic instability. The proper diagnosis relies on corticotropin stimulation testing and the role of hydrocortisone therapy in these patients merits further investigation. Hyponatremia in cirrhosis is a major risk factor for the development of hepatic encephalopathy and is associated with a poor outcome in patients with ACLF and also after deceased donor and living-related liver transplantation. Vasoconstrictor drugs, particularly terlipressin, are effective for the management of hepatorenal syndrome. Predictive factors of response to terlipressin include serum bilirubin levels and the presence of an early increase in mean arterial pressure. SUMMARY: The ongoing advances in the diagnosis and management of patients with ACLF and renal failure will improve the diagnosis, therapy and outcome of these patients. PMID- 21311323 TI - The role of the endocannabinoid system in islet biology. AB - PURPOSE OF REVIEW: The endogenous cannabinoids (endocannabinoids) are long-chain polyunsaturated fatty acids synthesized on demand in situ by catabolism of phospholipid precursors in the cell membrane. Here we discuss the emerging role of the endocannabinoids in the function of the pancreatic islet of Langerhans in particular on the secretion of insulin from the islet beta cell. RECENT FINDINGS: It is now established that there is a functional endocannabinoid system in the pancreatic islet of Langerhans and that endocannabinoids are released concurrently with glucose-induced insulin secretion. The majority of the published papers show evidence of negative effects of the endocannabinoids on insulin secretion with antagonism of the cannabinoid 1 receptor improving beta cell function. This indicates that there is a tonic inhibition of insulin secretion by endocannabinoids. Here we examine these reports and recent papers showing that endocannabinoids increase insulin secretion and discuss the discrepancies in these observations. SUMMARY: Conclusions on the exact nature of the effects of endocannabinoids on insulin secretion require rigorous study examining both acute and long-term effects at physiologically relevant doses employing both whole animal and clinically relevant models such as human islets in vitro and explanted in vivo, in rodent models of diabetes. PMID- 21311324 TI - Macrophage polarization and bacterial infections. AB - PURPOSE OF REVIEW: Macrophages are the first line of defense against pathogens, and the mode of their activation will determine the success or failure of the host response to pathogen aggression. Based on limited numbers of markers, activated macrophages can be classified as classically activated (M1) macrophages that support microbicidal activity or alternatively activated (M2) macrophages that are not competent to eliminate pathogens. The development of high-throughput gene expression methods affords a reappraisal of the concept of macrophage activation in human infectious diseases. RECENT FINDINGS: By combining microarray data and conventional approaches, it is becoming clear that the M1 polarization program is associated with gastrointestinal infections (e.g. typhoid fever and Helicobacter pylori gastritis) and active tuberculosis. An M2 signature is observed in lepromatous leprosy, Whipple's disease, and localized infections (keratitis, chronic rhinosinusitis). However, these findings could not be predicted from the analysis of the M1/M2 programs of macrophages stimulated in vitro. SUMMARY: The reappraisal of macrophage polarization by high-throughput methods is critical to understanding the role of macrophage polarization in infectious diseases. Only the identification of individual profiles will support promising therapeutic approaches based on target determination. PMID- 21311325 TI - True impact of antibiotic resistance on treatment outcomes and the cost of healthcare delivery. Editorial. PMID- 21311326 TI - Gene-gene and gene-environment interactions defining lipid-related traits. AB - PURPOSE OF REVIEW: Steps towards reducing chronic disease progression are continuously being taken through the form of genomic research. Studies over the last year have highlighted more and more polymorphisms, pathways and interactions responsible for metabolic disorders such as cardiovascular disease, obesity and dyslipidemia. RECENT FINDINGS: Many of these chronic illnesses can be partially blamed by altered lipid metabolism, combined with individual genetic components. Critical evaluation and comparison of these recent studies is essential in order to comprehend the results, conclusions and future prospects in the field of genomics as a whole. Recent literature elucidates significant gene--diet and gene -environment interactions resulting in altered lipid metabolism, inflammation and other metabolic imbalances leading to cardiovascular disease and obesity. SUMMARY: Epigenetic and epistatic interactions are now becoming more significantly associated with such disorders, as genomic research digs deeper into the complex nature of genetic individuality and heritability. The vast array of data collected from genome-wide association studies must now be empowered and explored through more complex interaction studies, using standardized methods and larger sample sizes. In doing so the etiology of chronic disease progression will be further understood. PMID- 21311327 TI - Functional validation of new pathways in lipoprotein metabolism identified by human genetics. AB - PURPOSE OF REVIEW: Recent genome-wide association studies (GWAS) have identified approximately 100 genomic loci that are associated with plasma lipid traits, two thirds of which had never been previously associated with lipoprotein metabolism. Identification of the causal genes and variants, functional validation of these genes and biological pathways, and elucidation of molecular mechanisms is required and poses a daunting task. RECENT FINDINGS: Human genetics have been used to recently 'validate' genes, such as LIPG, SCARB1 and ANGPTL3, which were previously implicated in lipoprotein metabolism through classical wet bench approaches. Additionally, many novel genes have been identified as associated with plasma lipid traits by GWAS, though only relatively few have been functionally validated through targeted sequencing and genetic manipulation in cells and animals. These types of studies have defined new roles in lipid metabolism for the novel lipid genes SORT1 and TRIB1. These examples demonstrate the ways in which human genetics can validate candidate genes, as well as provide a novel discovery that requires functional validation at the bench, and point towards a more complete understanding of the molecular physiology of lipoprotein metabolism. SUMMARY: This review summarizes recent developments in the use of human genetics to validate candidate genes in lipoprotein metabolism as well as in the functional validation of novel GWAS loci associated with plasma lipid traits. PMID- 21311328 TI - Novel agents and new therapeutics in castration-resistant prostate cancer. AB - PURPOSE OF REVIEW: This review highlights recent therapeutic advances in systemic therapies for prostate cancer (PCa). RECENT FINDINGS: Progress in PCa therapeutics has been made during the past year with the approval of a vaccine therapy, second-line chemotherapy, and reported survival advantage for a CYP (17,20) lyase inhibitor in castration-resistant prostate cancer (CRPC). This report will summarize the recently reported and expected data for PCa trials including an evaluation of intermittent vs. continuous androgen deprivation therapy. Denosumab is shown to support bone mineral density in hormonal sensitive PCa patients. Targeting of androgen-dependent pathways in CRPC postchemotherapy has been shown to improve survival with the lyase inhibitor abiraterone, and lead to prostate-specific antigen and objective responses with an androgen receptor antagonist (MDV3100). However, the addition of bevacizumab to docetaxel/prednisone in treating metastatic CRPC failed to provide a survival benefit. Cabazitaxel in metastatic CRPC postdocetaxel did demonstrate a survival benefit. Provenge, an autologous dendritic cell-based vaccine, demonstrated a reduction in the risk of death in metastatic CRPC. Other immunotherapy agents, including Prostvac and ipilimumab are under investigation. We also discuss the receptor tyrosine kinase inhibitor XL184 and poly (ADP-ribose) polymerase inhibitors which are in early clinical trials. SUMMARY: Recent advances in androgen targeting, chemotherapy, immunotherapy, and other targeted therapies have led to significant improvements in the care of CRPC patients. PMID- 21311329 TI - Bladder cancer. AB - PURPOSE OF REVIEW: To review the epidemiology, diagnosis, and management of all stages of bladder cancer with an emphasis on studies published within the last year. RECENT FINDINGS: Smoking continues to be the most important risk factor for the development of bladder cancer, and this risk has increased over time. Although a number of urinary markers for bladder cancer are now approved by the Food and Drug Administration, there is not enough evidence that any marker can replace surveillance cystoscopy. Management of high-risk patients with nonmuscle invasive cancer remains a challenge, with continued controversy over which patients may safely be treated with bladder-sparing regimens. Efforts toward developing agents for bacillus Calmette-Guerin-refractory superficial bladder cancer continue, however, none to date have shown high rates of long-term success. In patients undergoing cystectomy, reports using more standardized measures of complications have demonstrated high rates of postoperative morbidity and mortality, particularly in elderly individuals. Robot-assisted radical cystectomy is being more widely studied as a potential approach to decrease operative blood loss and shorten recovery. Although more expensive, increasing evidence suggests that it is well tolerated, does not increase the risk of positive surgical margins, and can achieve similar lymph node counts as open cystectomy in experienced hands and with careful patient selection. Despite level I evidence supporting the use of neoadjuvant chemotherapy, there remains disagreement regarding its use vs. selective adjuvant therapy, given the modest benefits seen with current regimens. SUMMARY: Progress continues in bladder cancer diagnosis and management, and we anticipate that future work will further advance the care of patients with this disease. PMID- 21311330 TI - Coping with sexual concerns after cancer. AB - PURPOSE OF REVIEW: This review presents an overview of recent developments in research examining coping with the effects of cancer treatment on sexuality. RECENT FINDINGS: A search was conducted using PubMed and Web of Knowledge to find papers published or in press in 2010. Papers examining coping efforts, effects of cancer treatment in special populations (e.g., advanced cancer, non-western populations), or on broad dimensions of sexuality, and psychosocial and physiological intervention studies addressing sexual issues in cancer were included. Findings underscore the complex effects of treatments (e.g., hormonal therapy for prostate cancer) on patients' sexuality. Studies suggest that successful coping efforts often occur within the context of the relationship and frequently include a process of adjusting one's concept of sexual function and activity through shifting to thoughts and behaviors that center on intimacy and sexual activities other than intercourse (e.g., 'flexible coping'). SUMMARY: Results confirm the importance of sexual issues to individuals with cancer and argue for more research on sexual effects of cancer treatment in understudied populations and further empirical studies examining coping with sexual concerns after cancer. Clinical implications include the need for providers to address the broader range of sexual effects of treatments beyond sexual performance. PMID- 21311331 TI - Antigen detection in bronchoalveolar lavage fluid for diagnosis of fungal pneumonia. AB - PURPOSE OF REVIEW: The purpose of this review is to describe important findings published during the past 18 months using bronchoalveolar lavage (BAL) for diagnosis of pulmonary mycoses. RECENT FINDINGS: Clinical studies and meta analysis have established a high sensitivity and specificity for Aspergillus galactomannan testing of BAL specimens for diagnosis of invasive aspergillosis, superior to that observed with other diagnostic methods. Similar findings have been reported in histoplasmosis and blastomycosis. SUMMARY: Fungal antigen testing of BAL specimens is recommended if bronchoscopy is performed for diagnosis of pulmonary infiltrates in patient groups at risk for aspergillosis or the endemic mycoses if the diagnosis cannot be established by evaluation of sputum specimens or detection of antigen in the urine or serum. PMID- 21311332 TI - Pulmonary aspiration syndromes. AB - PURPOSE OF REVIEW: Pulmonary aspiration syndromes are a common cause of morbidity and mortality. These syndromes are often misdiagnosed and their management is frequently suboptimal. This paper reviews the clinical features and management of the most common aspiration syndromes. RECENT FINDINGS: Pulmonary aspiration syndromes refer to a group of pulmonary diseases resulting from aspiration of foreign material into the lung. The type of syndrome depends on the quantity and nature of the aspirated material as well as its chronicity. The most common syndromes include aspiration pneumonia, diffuse aspiration bronchiolitis, and aspiration pneumonitis. Aspiration pneumonia and diffuse aspiration bronchiolitis generally occur in elderly, debilitated patients with dysphagia and usually present as 'community acquired pneumonia', which tends to be recurrent in patients with diffuse aspiration bronchiolitis. Treatment consists of broad spectrum antibiotics and management of the underlying dysphagia. Aspiration pneumonitis follows the aspiration of gastric contents, usually in patients with a marked decreased level of consciousness. Treatment of aspiration pneumonitis is essentially supportive; however, corticosteroids and other immunomodulating agents may have a role in these patients. SUMMARY: Aspiration syndromes are common with their management dictated by the type of aspiration syndrome. PMID- 21311333 TI - Contemporary role of radiation therapy in the adjuvant or salvage setting following radical prostatectomy. AB - PURPOSE OF REVIEW: Adjuvant and salvage radiotherapy after radical prostatectomy have an established role in the management of high-risk patients. We discuss contemporary data on optimal timing and doses of radiotherapy, role of hormonal therapy and pelvis irradiation, and toxicity. RECENT FINDINGS: Positive surgical margins are not predictive of reduced overall survival, even in patients treated with adjuvant radiotherapy. Salvage irradiation fails to decrease the risk of death. In both adjuvant and salvage settings, radiation doses more than 66-70 Gy result in a significant improvement of biochemical relapse-free survival, whereas hormonal therapy is still of unproven effect. Early referral for salvage radiotherapy might be as effective as adjuvant irradiation, although only less than 50% of patients whose prostate-specific antigen is more than 0.5 ng/ml at referral benefit from salvage radiotherapy. The prophylactic irradiation of pelvic nodal area may have a role in postprostatectomy irradiation owing to the risk of occult lymph-nodal metastases. New radiotherapy techniques lead to a significant reduction in rectal, but not urinary, toxicity. SUMMARY: Ongoing Phase III trials will address the role of hormonal therapy and pelvic irradiation in combination with standard dose adjuvant and salvage radiotherapy. In the case of positive results, these findings should be confirmed also in combination with high radiation doses. PMID- 21311334 TI - Surgical anatomy of the prostate in the era of radical robotic prostatectomy. AB - PURPOSE OF REVIEW: New insights in the anatomy of the prostate and the surrounding tissue evolve the technique of radical prostatectomy for the treatment of prostate cancer. RECENT FINDINGS: Regarding the course of the erectile nerves along the prostate, recent studies confirmed the presence of parasympathetic pro-erectile nerve fibers at the anterolateral aspect of the prostate. Another study of intraoperative electrostimulation of those nerves confirmed an increase in intracavernosal pressure by stimulations between the 1 and 3 o'clock position. Therefore, it is very likely that these anterior nerve fibers have an effect on erectile function. Regarding the urethral sphincter in the male, a study showed no attachment of the external sphincter to the levator ani muscle, probably resulting in an absence of a levator ani support to the continence mechanism. The male urinary sphincter seems to be in isolation responsible for urinary continence. SUMMARY: The nerve fibers at the anterolateral aspect of the prostate seem to participate in erectile function, which renders the concept of a high anterior release during nerve sparing beneficial. The isolated urinary sphincter mechanism results in the need to conserve as much urethral length as possible during radical prostatectomy to avoid urinary incontinence. PMID- 21311335 TI - A critical analysis of the long-term impact of brachytherapy for prostate cancer: a review of the recent literature. AB - PURPOSE OF REVIEW: A number of articles have been published in the past several months providing long-term follow-up data on large brachytherapy series from centers of excellence or highly experienced individual practitioners. Our purpose is to review this recent literature and place it in context, especially as compared with notable articles in the recent past that have described less favorable outcomes. RECENT FINDINGS: A total of 3773 patients were included in three large permanent seed implant studies, the first with almost exclusively low dose rate permanent seed brachytherapy monotherapy, the second including a large proportion of patients receiving 6 months of androgen suppression, and the third including both supplemental external beam radiotherapy (EBRT) and hormonal therapy. The 7-10 year biochemical no evidence of disease rates ranged from 94 to 95.6%, with the vast majority of patients achieving prostate specific antigen nadirs less than 0.4 ng/ml. Eight to 10 year follow-up on high-dose rate brachytherapy patients treated with combined EBRT and an high-dose rate boost are equally impressive, especially considering that these series contain a large proportion of men with unfavorable disease. SUMMARY: Both low-dose rate and high dose rate prostate brachytherapy, either alone or given as a boost combined with moderate-dose EBRT, provide impressive long-term disease control and may be the optimal form of intraprostatic dose escalation. PMID- 21311336 TI - Contemporary imaging analyses of pelvic lymph nodes in the prostate cancer patient. AB - PURPOSE OF REVIEW: To review contemporary imaging of pelvic lymph nodes in patients with prostate cancer as well as to analyze its significance and usefulness in clinical practice. RECENT FINDINGS: Because of poor sensitivity and specificity of computed tomography (CT) and MRI, new imaging modalities of lymph nodes in prostate cancer patients would be desirable. Three-dimensional reconstruction by fusion imaging between single-photon emission computed tomography after injection of Tc-99m colloid particles into the prostate and CT or MRI, has permitted a precise mapping of the primary lymphatic landing sites, or sentinel lymph nodes of the prostate. Intraoperative search for sentinel lymph nodes by gamma-probe in open and laparoscopic surgery is possible. Routine use of choline PET/CT for initial staging of prostate cancer is not yet recommended. MRI combined with ultrasmall particles of iron oxide (USPIO) permits differentiation with a very high sensitivity between benign and malignant lymph nodes, independently of their size. Diffusion-weighted MRI combined with USPIO is a promising method for detecting lymph nodes metastases even in normal sized nodes. Both improved MRI methods are not yet introduced in routine clinical practice. SUMMARY: USPIO-MRI or/with diffusion-weighted MRI seems to be a promising noninvasive imaging modality for accurate imaging of lymph nodes in patients with prostate cancer. PMID- 21311337 TI - Quality improvement of newborn screening in real time. PMID- 21311338 TI - Public health genomics: the end of the beginning. PMID- 21311339 TI - The American College of Medical Genetics, the first 20 years. AB - The American College of Medical Genetics (ACMG) celebrates its 20th anniversary this month, having been founded in March of 1991. The ACMG has firmly established itself as a major medical association representing the needs of the many patients with genetic disorders and the expanding number of genetic clinical and laboratory professionals that strive to diagnose, treat and prevent these disorders. Over the last two decades they have had major accomplishments related to their original mission: They have become members of the American Medical Association House of Delegates and the American Board of Medical Specialists, pushed through laboratory Current Procedural Terminology codes, developed a manual for billing and reimbursement, have been active in a number of national arenas including Health and Human Services, Food and Drug Administration, Center for Disease Control, National Institutes of Health and with other professional organizations (College of American Pathologists, American College of Obstetricians and Gynecologists, American Society of Clinical Oncology). They have secured grant funding, developed major educational programs (Board courses, MOC modules, CD-ROMS), a well respected medical journal, a successful and well attended annual meeting, major relationships with industry, and have been leaders in the legal arena, challenging patents for genetic testing, etc. In the future, the tools and knowledge of medical genetics will permeate all of medicine and the ACMG should embrace, encourage and assist all of those varying medical specialists, counselors, nurses and scientists who are involved in providing genetic services. PMID- 21311340 TI - Downsizing genomic medicine: approaching the ethical complexity of whole-genome sequencing by starting small. AB - As we look to a time when whole-genome sequencing is integrated into patient care, it is possible to anticipate a number of ethical challenges that will need to be addressed. The most intractable of these concern informed consent and the responsible management of very large amounts of genetic information. Given the range of possible findings, it remains unclear to what extent it will be possible to obtain meaningful patient consent to genomic testing. Equally unclear is how clinicians will disseminate the enormous volume of genetic information produced by whole-genome sequencing. Toward developing practical strategies for managing these ethical challenges, we propose a research agenda that approaches multiplexed forms of clinical genetic testing as natural laboratories in which to develop best practices for managing the ethical complexities of genomic medicine. PMID- 21311341 TI - The advent of personal genome sequencing. AB - Rapid technological advances are decreasing DNA sequencing costs and making it practical to undertake complete human genome sequencing on a large scale for the first time. Disease studies that involve sequencing hundreds of patient genomes are underway. The all-inclusive sequencing price per genome is expected to reach $1000 over the next few years and will likely decline further in the following years. This dramatic price decline will herald widespread personal genome sequencing and lead to significant improvements in human health and reduced health care costs. Key to realizing these benefits will be medical genomics' and systems biology's success in providing increasing contextual interpretation of biological and medical effects of the detected sequence variants in a genome. Given the substantial potential benefits and the manageability of the health and discrimination risks involved with the possible misuse of this information, we propose that governments and insurance companies support or even require personal genome sequencing. Critical to the widespread acceptance of personal genome sequencing, however, will be the need to educate physicians and the public about the realistic benefits and risks of such an analysis to prevent overinterpretation and misuse of this valuable information. PMID- 21311342 TI - Unifying cancer genetics. PMID- 21311343 TI - Chronic blood pressure and appetite responses to central leptin infusion in rats fed a high fat diet. AB - OBJECTIVE: Obesity has been suggested to induce selective leptin resistance whereby leptin's anorexic effects are attenuated, whereas the effects to increase sympathetic nervous system activity and blood pressure remain intact. Most studies, however, have tested only the acute responses to leptin administration. This study tested whether feeding a high-fat diet causes resistance to the appetite and cardiovascular responses to chronic central leptin infusion. METHODS: Sprague-Dawley rats were fed high-fat diet (40% kcal from fat, n=5) or normal-fat diet (13% kcal from fat, n=5) for a year. Radiotelemeters were implanted for continuous monitoring of mean arterial pressure (MAP) and heart rate (HR). A 21G steel cannula was implanted in the lateral cerebral ventricle [intracerebroventricular (ICV)]. After recovery, leptin was infused ICV at 0.02 MUg/kg per min for 10 days. RESULTS: High-fat rats were heavier than normal-fat rats (582+/-12 vs. 511+/-19 g) and exhibited significantly higher MAP (114+/-3 vs. 96+/-7 mmHg). Although the acute (24 h) effects of leptin were attenuated in high-fat rats, chronic ICV leptin infusion decreased caloric intake in both groups similarly (50+/-8 vs. 40+/-10%) by day 5. Despite decreased food intake and weight loss, leptin infusion significantly increased MAP and HR in both high fat and normal-fat rats (7+/-2 and 5+/-1 mmHg; 18+/-11 and 21+/-10 b.p.m., respectively). CONCLUSION: These results suggest that obesity induced by feeding a high-fat diet blunts the acute anorexic effects of leptin but does not cause significant resistance to the chronic central nervous system effects of leptin on appetite, MAP, or HR. PMID- 21311344 TI - Effect of three different between-inning recovery methods on baseball pitching performance. AB - A decrease in blood hydrogen ions (H) may allow for the recovery of a muscle, which should allow for greater performance in subsequent activity. The purpose of this study was to determine which of 3 forms of recovery were the most effective after an inning of pitching in baseball. Three different measurements were used to determine which recovery method was most effective; the difference in blood lactate (BLa) levels was used as a biological measurement, average pitching speed was the physiological measurement, and the psychological measurement was done on how the pitchers perceived their pitching and recovery. The recovery methods that were used were passive recovery (PR), active recovery (AR), and electromuscular stimulation (EMS). Seven college men aged 21 (+/-2 years) who were National Collegiate Athletic Association Division II college baseball pitchers were assessed during game play simulations. Blood lactate levels decreased significantly from the premeasurement to the postmeasurement with the EMS recovery method (p < 0.0005); however, BLa did not change for PR (p = 0.017) or AR (p = 0.134). Perceived recovery was also found to be best in the EMS and PR conditions. These findings suggest that EMS is an effective recovery method between innings of pitching. PMID- 21311345 TI - Effects of strength, endurance, and concurrent training on aerobic power and dynamic neuromuscular economy in elderly men. AB - The aim of this study was to investigate the effects of concurrent training on endurance capacity and dynamic neuromuscular economy in elderly men. Twenty-three healthy men (65 +/- 4 years) were divided into 3 groups: concurrent (CG, n = 8), strength (SG, n = 8), and aerobic training group (EG, n = 7). Each group trained 3 times a week for 12 weeks, strength training, aerobic training, or both types of training in the same session. The maximum aerobic workload (Wmax) and peak oxygen uptake (VO2peak) of the subjects were evaluated on a cycle ergometer before and after the training period. Moreover, during the maximal test, muscle activation was measured at each intensity by means of electromyographic signals from the vastus lateralis (VL), rectus femoris (RF), biceps femoris long head, and gastrocnemius lateralis to determine the dynamic neuromuscular economy. After training, significant increases in VO2peak and Wmax were only found in the CG and EG (p < 0.05), with no difference between groups. Moreover, there was a significant decrease in myoelectric activity of the RF muscle at 50 (EG), 75 and 100 W (EG and CG) and in the VL for the 3 groups at 100 W (p < 0.05). No change was seen in the electrical signal from the lateral gastrocnemius muscle and biceps femoris. The results suggest specificity in adaptations investigated in elderly subjects, because the most marked changes in the neuromuscular economy occurred in the aerobically trained groups. PMID- 21311346 TI - Translation of exercise testing to exercise prescription using the talk test. AB - Traditionally defined in terms of %maximal heart rate (%HRmax) or %maximal metabolic equivalents, the process of exercise prescription is still difficult and individually imprecise. An alternative, and simpler, method is to define exercise intensity in terms of the Talk Test, which may be a surrogate for ventilatory threshold and more consistent with contemporary recommendations for index training intensity in well-trained and athletic individuals. This study was designed to determine how much of a reduction in the absolute exercise intensity from those observed during incremental exercise testing was necessary to allow for comfortable speech during exercise training. Fourteen well-trained (5-7 h.wk( 1)) individuals performed 2 incremental exercise tests (to evaluate reproducibility) and 3 steady-state training bouts (40 minutes), based on the stage before the last positive (LP) stage of the Talk Test (LP-1), the LP stage, and the equivocal (EQ) stage. The LP-1 and LP runs resulted in %HRmax and rating of perceived exertion (RPE) values within the recommended range for exercise training, the EQ run in an unacceptably high %HRmax and RPE. Most subjects could still speak comfortably during the LP-1 and LP stages, and no subject could speak comfortably during the EQ stage. The HR (r = 0.84), RPE (r = 0.81), and Talk Test (r = 0.71) responses during paired incremental tests were well correlated. The results of this test suggest that the absolute exercise intensity during the LP-1 and LP stages of incremental exercise tests with the Talk Test may produce steady state exercise responses appropriate for training in well-trained and athletic individuals and that the reproducibility of the Talk Test is satisfactory. PMID- 21311347 TI - Effect of different rest intervals after whole-body vibration on vertical jump performance. AB - Whole-body vibration (WBV) may potentiate vertical jump (VJ) performance via augmented muscular strength and motor function. The purpose of this study was to evaluate the effect of different rest intervals after WBV on VJ performance. Thirty recreationally trained subjects (15 men and 15 women) volunteered to participate in 4 testing visits separated by 24 hours. Visit 1 acted as a familiarization visit where subjects were introduced to the VJ and WBV protocols. Visits 2-4 contained 2 randomized conditions per visit with a 10-minute rest period between conditions. The WBV was administered on a pivotal platform with a frequency of 30 Hz and an amplitude of 6.5 mm in 4 bouts of 30 seconds for a total of 2 minutes with 30 seconds of rest between bouts. During WBV, subjects performed a quarter squat every 5 seconds, simulating a countermovement jump (CMJ). Whole-body vibration was followed by 3 CMJs with 5 different rest intervals: immediate, 30 seconds, 1 minute, 2 minutes, or 4 minutes. For a control condition, subjects performed squats with no WBV. There were no significant (p > 0.05) differences in peak velocity or relative ground reaction force after WBV rest intervals. However, results of VJ height revealed that maximum values, regardless of rest interval (56.93 +/- 13.98 cm), were significantly (p < 0.05) greater than the control condition (54.44 +/- 13.74 cm). Therefore, subjects' VJ height potentiated at different times after WBV suggesting strong individual differences in optimal rest interval. Coaches may use WBV to enhance acute VJ performance but should first identify each individual's optimal rest time to maximize the potentiating effects. PMID- 21311348 TI - Metabolic responses to Wii FitTM video games at different game levels. AB - The Wii FitTM is a form of interactive gaming designed to elicit health and fitness benefits to replace sedentary gaming. This study was designed to determine the effectiveness of Wii FitTM fitness games. The purpose of the study was to determine the %VO2max and energy expenditure from different Wii FitTM games at different levels including the step and hula games. Eight healthy young women completed a preliminary trial to determine VO2max and later played the Wii FitTM during 2 separate counterbalanced trials. During each session, subjects played levels of Wii FitTM games for 10 minutes each level. One session involved beginning and intermediate hula, and the other session involved beginning and intermediate steps. The VO2 was measured continuously via metabolic cart, and rating of perceived exertion (RPE) was assessed at the end of each game level. The lowest %VO2max, kcal.min, and RPE occurred during the beginning step game and the highest values occurred during the intermediate hula game. Respiratory exchange ratio was significantly higher in the intermediate hula than beginning hula game but was not significantly different between step game levels. The intermediate hula and step games produced the greatest energy expenditure with an equivalent effect of a walking speed of >5.63 km.h (>3.5 miles.h). This is the first study to determine the percentage of VO2max and caloric expenditure elicited by different Wii FitTM video games at different game levels in adults. Findings suggest that the Wii FitTM can be used as an effective activity for promoting physical health in this population. PMID- 21311349 TI - Recovery after heavy resistance exercise and skeletal muscle androgen receptor and insulin-like growth factor-I isoform expression in strength trained men. AB - The effects of heavy resistance exercise on skeletal muscle androgen receptor (AR) protein concentration and mRNAs of AR, insulin-like growth factor-I (IGF) IEa, and mechano growth factor (MGF) expression were examined from biopsies of vastus lateralis (VL) muscle before and 48 hours after heavy resistance exercise (5 * 10 repetition maximum [RM] leg press and 4 * 10RM squats) in 8 adult strength trained men. The present exercise induced an acute decrease in maximal isometric force and increased serum total testosterone (T) and free testosterone (FT) concentrations. During 2 recovery days, maximal isometric force and subjective perception of physical fitness remained significantly lowered, whereas serum creatine kinase activity, subjective muscle soreness, and muscle swelling (i.e., thickness of VL by ultrasound) were significantly increased compared to pre-exercise values. Subjective perception of physical fitness was followed up to 7 days, and by 6 days postexercise, it was elevated above the pre-exercise level. Basal T and FT concentrations remained unaltered after the exercise. No statistically significant changes were observed in AR protein or mRNA expression, but IGF-IEa (p < 0.05) and MGF (p < 0.05) mRNA expression were increased compared to pre-exercise levels. These findings indicate that IGF-IEa and MGF responses may be related to acute regenerative processes in muscle because of exercise and may contribute to muscular adaptation to resistance exercise. Subjective perception of physical fitness suggests that recovery over a pre-exercise level of the present type of heavy resistance exercise can take approximately 6 days. PMID- 21311350 TI - Neuromuscular training improves knee kinematics, in particular in valgus aligned adolescent team handball players of both sexes. AB - The purpose of this study was to investigate the effects of added neuromuscular training (NMT), as compared to just regular training (RT), on lower extremity kinematics and single leg stability in adolescent team handball players of both sexes and to investigate whether these effects are more evident in valgus aligned athletes. Eighty adolescent team handball players (NMT: n = 49, RT: n = 31) were tested on knee kinematics in a drop jump and single leg stability in a 1-leg hop test. Based on the initial results in the drop jump test, both groups were subdivided into an above-average valgus aligned (AAVA; NMT: n = 27, RT: n = 22) and a below average valgus aligned (NMT: n = 22, RT: n = 9) group. All groups received 10 weeks of handball training either without (RT) or with in-season NMT. A significant interaction of training and valgus group was found for all absolute and for 2 out of 4 normalized knee distances in the drop jump test (p < 0.024) and for contact time after the first landing (p = 0.029). The AAVA-NMT group showed the largest relative progression (18-37%) for all these parameters. In the 1-leg hop test, a significant effect of NMT compared to RT was found for both legs (p < 0.042). Compared to RT alone, added in-season NMT has the greatest benefits on knee kinematics and single leg stability, in particular in AAVA adolescent team handball players of both sexes. The results of this study suggest that adolescent team handball players of both sexes should be given NMT, 20 minutes twice a week for 10 weeks to improve landing kinematics and single leg stability. "At risk" players with higher initial valgus angles will benefit most from this NMT. PMID- 21311351 TI - Strength and conditioning practices in rowing. AB - There is limited published research on the practices of strength and conditioning (S &C) coaches in Great Britain. Information about training program design would be useful in developing models of good practice and ecologically valid intervention studies. The aim of this research was to quantify the training practices of coaches responsible for the S&C of rowing athletes. A questionnaire was developed that consisted of 6 sections: (a) personal details, (b) physical testing, (c) strength and power development, (d) flexibility development, (e) unique aspects of the program, and (f) any further relevant comments regarding the athletes prescribed training program. Twenty-two rowing and 10 S&C coaches with an average of 10.5 +/- 7.2 years' experience agreed to complete the questionnaire. Approximately, 34% coached rowers of Olympic standard, 34% coached national standard, 3% coached regional standard, 19% coached club standard, and 10% coached university standard rowers. All coaches agreed that strength training enhanced rowing performance and the majority (74%) indicated that athletes' strength trained 2-3 times a week. Almost all coaches (94%) reported their rowers performed strength training, with 81% using Olympic lifting, and 91% employing a periodized training model. The clean (63%) and squat (27%) were rated the most important prescribed exercises. Approximately 50% of coaches used plyometrics such as depth jumps, box drills, and standing jumps. Ninety-four percent indicated they conducted physical testing on their rowers, typically assessing cardiovascular endurance (80%), muscular power (70%), muscular strength (70%), and anaerobic capacity (57%). This research represents the only published survey to date on the S&C practices in rowing within Great Britain. PMID- 21311352 TI - Velocity loss as an indicator of neuromuscular fatigue during resistance training. AB - PURPOSE: This study aimed to analyze the acute mechanical and metabolic response to resistance exercise protocols (REP) differing in the number of repetitions (R) performed in each set (S) with respect to the maximum predicted number (P). METHODS: Over 21 exercise sessions separated by 48-72 h, 18 strength-trained males (10 in bench press (BP) and 8 in squat (SQ)) performed 1) a progressive test for one-repetition maximum (1RM) and load-velocity profile determination, 2) tests of maximal number of repetitions to failure (12RM, 10RM, 8RM, 6RM, and 4RM), and 3) 15 REP (S * R[P]: 3 * 6[12], 3 * 8[12], 3 * 10[12], 3 * 12[12], 3 * 6[10], 3 * 8[10], 3 * 10[10], 3 * 4[8], 3 * 6[8], 3 * 8[8], 3 * 3[6], 3 * 4[6], 3 * 6[6], 3 * 2[4], 3 * 4[4]), with 5-min interset rests. Kinematic data were registered by a linear velocity transducer. Blood lactate and ammonia were measured before and after exercise. RESULTS: Mean repetition velocity loss after three sets, loss of velocity pre-post exercise against the 1-m.s load, and countermovement jump height loss (SQ group) were significant for all REP and were highly correlated to each other (r = 0.91-0.97). Velocity loss was significantly greater for BP compared with SQ and strongly correlated to peak postexercise lactate (r = 0.93-0.97) for both SQ and BP. Unlike lactate, ammonia showed a curvilinear response to loss of velocity, only increasing above resting levels when R was at least two repetitions higher than 50% of P. CONCLUSIONS: Velocity loss and metabolic stress clearly differs when manipulating the number of repetitions actually performed in each training set. The high correlations found between mechanical (velocity and countermovement jump height losses) and metabolic (lactate, ammonia) measures of fatigue support the validity of using velocity loss to objectively quantify neuromuscular fatigue during resistance training. PMID- 21311355 TI - Effect of l-arginine infusion on glucose disposal during exercise in humans. AB - PURPOSE: We have previously shown that local infusion of a nitric oxide synthase (NOS) inhibitor attenuates increases in leg glucose uptake during exercise in humans. We have also shown that infusion of the NOS substrate, l-arginine (l Arg), increases glucose clearance, although the mechanisms involved were not determined. A potential mechanism for NO-mediated glucose disposal is via interactions with NOS and the energy sensor AMP-activated protein kinase (AMPK). The aim of this study was to determine the mechanism(s) by which l-Arg infusion increases glucose disposal during exercise in humans by examining total NOS activity and AMPK signaling. METHODS: Seven males cycled for 120 min at 64% +/- 1% VO(2)peak, during which the [6,6-H]glucose tracer was infused. During the final 60 min of exercise, either saline alone (Control, CON), or saline containing l-Arg HCl (l-Arg, 30 g at 0.5 g.min(-1)) was coinfused in a double blind, randomized, counterbalanced order. RESULTS: l-Arg increased the glucose rate of disappearance and glucose clearance rate during exercise; however, this was accompanied by a 150% increase in plasma insulin concentration from 65 to 75 min (P < 0.05) that remained significantly elevated until 90 min of exercise. Skeletal muscle AMPK signaling, nNOSMU phosphorylation by AMPK, and total NOS activity increased to a similar extent in the two trials. CONCLUSIONS: The increase in glucose disposal after l-Arg infusion during exercise is likely due to the significantly higher plasma insulin concentration. PMID- 21311354 TI - Midhumerus adaptation in fast-pitch softballers and the effect of throwing mechanics. AB - PURPOSE: Throwing is a vigorous activity that generates large internal loads. There is limited evidence of the effect of these loads on bone adaptation. The aim of this study was to investigate the 1) magnitude of bone adaptation within the midshaft humerus of female fast-pitch softball players and 2) influence of throwing mechanics (windmill vs overhand throwing) on the magnitude of adaptation. METHODS: Midshaft humeral bone mass, structure, and estimated strength were assessed via peripheral quantitative computed tomography in fast pitch softball players (throwers; n = 15) and matched controls (controls; n = 15). The effect of throwing was examined by comparing dominant-to-nondominant differences in throwers to controls, whereas the influence of mechanics was determined by comparing dominant-to-nondominant differences in throwers who primarily play as pitcher (windmill thrower), catcher (overhand thrower), or fielder (overhand thrower). RESULTS: Throwers had greater dominant-to-nondominant difference in midshaft humeral bone mass, structure, and estimated strength relative to controls (all P < 0.05). The largest effect was for estimated torsional strength with throwers having a mean dominant-to-nondominant difference of 22.5% (range = 6.7%-43.9%) compared with 4.4% (range = -8.3% to 17.5%) in controls (P < 0.001). Throwing mechanics seemed to influence the magnitude of skeletal adaptation, with overhand throwers having more than double dominant-to nondominant difference in midshaft humeral bone mass, structure, and estimated strength than windmill throwers (all P < 0.05). CONCLUSIONS: Throwing induces substantial skeletal adaptation at the midshaft humerus of the dominant upper extremity. Throwing mechanics seems to influence the magnitude of adaptation, as catchers and fielders (overhand throwers) had twice as much adaptation as pitchers (windmill throwers). The latter finding may have implications for skeletal injury risk at the midshaft humerus in throwing athletes. PMID- 21311356 TI - Evaluation of the Omron HJ-720ITC pedometer under free-living conditions. AB - INTRODUCTION: The primary purpose of this study was to examine the accuracy of the Omron HJ-720ITC piezoelectric pedometer in a free-living environment during a 24-h period. A secondary purpose was to compare the accuracy the Omron to that of a spring-levered pedometer. METHODS: A total of 62 adult volunteers were classified according to body mass index (BMI) category: normal weight (n = 19), overweight (n = 23), and obese (n = 20). Subjects wore five devices during a 24-h period except when bathing or sleeping. The criterion pedometer (StepWatch-3) was worn on the lateral side of the right ankle. Omron HJ-720ITC pedometers were worn in three locations: (a) on the belt, (b) in the pants pocket, and (c) on a lanyard around the neck. A comparison pedometer (Yamax SW-200) was worn on the belt. RESULTS: The Omron HJ-720ITC underestimated the steps per day in all three BMI categories compared with the criterion measure (P < 0.05). The Omron was most accurate in the pocket location, recording 68%, 70%, and 65% of steps in the normal, overweight, and obese BMI categories, respectively. In the obese group, the Omron was more accurate than the Yamax pedometer, but in the normal and overweight groups, it was less accurate than the Yamax. CONCLUSIONS: Results from our study show that the Omron significantly underestimates steps per day under free-living conditions. This is due, in part, to the presence of a 4-s step filter that contributes to an underestimation of steps accumulated during intermittent activities. In the pocket, the Omron accuracy was similar for lean, overweight, and obese individuals. In contrast, the accuracy of the Yamax pedometer declined with increasing BMI categories. PMID- 21311357 TI - Effect of crank length on joint-specific power during maximal cycling. AB - Previous investigators have suggested that crank length has little effect on overall short-term maximal cycling power once the effects of pedal speed and pedaling rate are accounted for. Although overall maximal power may be unaffected by crank length, it is possible that similar overall power might be produced with different combinations of joint-specific powers. Knowing the effects of crank length on joint-specific power production during maximal cycling may have practical implications with respect to avoiding or delaying fatigue during high intensity exercise. PURPOSE: The purpose of this study was to determine the effect of changes in crank length on joint-specific powers during short-term maximal cycling. METHODS: Fifteen trained cyclists performed maximal isokinetic cycling trials using crank lengths of 150, 165, 170, 175, and 190 mm. At each crank length, participants performed maximal trials at pedaling rates optimized for maximum power and at a constant pedaling rate of 120 rpm. Using pedal forces and limb kinematics, joint-specific powers were calculated via inverse dynamics and normalized to overall pedal power. RESULTS: ANOVAs revealed that crank length had no significant effect on relative joint-specific powers at the hip, knee, or ankle joints (P > 0.05) when pedaling rate was optimized. When pedaling rate was constant, crank length had a small but significant effect on hip and knee joint power (150 vs 190 mm only) (P < 0.05). CONCLUSIONS: These data demonstrate that crank length does not affect relative joint-specific power once the effects of pedaling rate and pedal speed are accounted for. Our results thereby substantiate previous findings that crank length per se is not an important determinant of maximum cycling power production. PMID- 21311359 TI - Clinical predictors of foot orthoses efficacy in individuals with patellofemoral pain. AB - PURPOSE: There is emerging evidence that foot orthoses are effective in the management of patellofemoral pain syndrome (PFPS). However, the identification of those most likely to benefit from foot orthoses has not been adequately explored. The aim of this study was to develop a preliminary clinical prediction rule to help identify individuals with PFPS who are most likely to benefit from foot orthoses. METHODS: A total of 60 individuals with PFPS were issued with noncustomized prefabricated foot orthoses containing built-in arch supports and 4 degrees rear foot varus wedging. Patient-reported level of improvement was documented at 12 wk. Potential baseline predictor variables of interest included patient demographics, pain characteristics, footwear motion control properties, foot and ankle characteristics, and functional performance measures. RESULTS: Fourteen (25%) participants reported marked improvement at 12 wk. The number of participants with marked improvement increased to 78% if three of the following four criteria were met: footwear motion control properties score of <5.0 (indicative of less supportive footwear), usual pain <22.0 mm, ankle dorsiflexion range of motion (knee flexed) <41 degrees , and reduced single-leg squat pain when wearing the orthoses. CONCLUSIONS: Individuals with PFPS who wear less supportive footwear, report lower levels of pain, exhibit less ankle dorsiflexion range of motion, and report an immediate reduction in pain with foot orthoses when performing a single-leg squat are more likely to benefit from foot orthoses. PMID- 21311360 TI - VO2 kinetics and performance in soccer players after intense training and inactivity. AB - PURPOSE: The study's purpose was to examine the effects of a short-term period with intensified training or training cessation of trained soccer players on VO(2) kinetics at 75% maximal aerobic speed, oxidative enzymes, and performance in repeated high-intensity exercise. METHODS: After the last match of the season, 18 elite soccer players were, for a 2-wk period, assigned to a high-intensity training group (n = 7) performing 10 training sessions mainly consisting of aerobic high-intensity training (8 * 2 min) and speed endurance training (10-12 * 30-s sprints) or a training cessation group (n = 11) that refrained from training. RESULTS: For the training cessation group, VO(2) kinetics became slower (P < 0.05) with a larger time constant (tau = 21.5 +/- 2.9 vs 23.8 +/- 3.2 s (mean +/- SD, before vs after)) and a larger mean response time (time delay + tau = 45.0 +/- 1.8 vs 46.8 +/- 2.2 s). The amount of muscle pyruvate dehydrogenase (17%, P < 0.01) and maximal activity of citrate synthase (12%) and 3-hydroxyacyl CoA (18%, P < 0.05) were lowered. In addition, the fraction of slow twitch fibers (56% +/- 18% vs 47% +/- 15%, P < 0.05), Yo-Yo intermittent recovery level 2 test (845 +/- 160 vs 654 +/- 99 m), and the repeated sprint performance (33.41 +/- 0.96 vs 34.11 +/- 0.92 s, P < 0.01) were reduced. For the high-intensity training group, running economy was improved (P < 0.05), and the amount of pyruvate dehydrogenase (17%) and repeated sprint performance (33.44 +/- 1.17 vs 32.81 +/- 1.01 s) were enhanced (P < 0.05). CONCLUSIONS: Inactivity slows VO(2) kinetics in association with a reduction of muscle oxidative capacity and repeated high intensity running performance. In addition, intensified training of already well trained athletes can improve mechanical efficiency and repeated sprint performance. PMID- 21311361 TI - Impairment of 3000-m run time at altitude is influenced by arterial oxyhemoglobin saturation. AB - The decline in maximal oxygen uptake (DeltaVO(2)max) with acute exposure to moderate altitude is dependent on the ability to maintain arterial oxyhemoglobin saturation (SaO2). PURPOSE: This study examined if factors related to DeltaVO(2)max at altitude are also related to the decline in race performance of elite athletes at altitude. METHODS: Twenty-seven elite distance runners (18 men and 9 women, VO(2)max = 71.8 +/- 7.2 mL.kg(-1).min(-1)) performed a treadmill exercise at a constant speed that simulated their 3000-m race pace, both in normoxia and in 16.3% O2 (~2100 m). Separate 3000-m time trials were completed at sea level (18 h before altitude exposure) and at 2100 m (48 h after arrival at altitude). Statistical significance was set at P <= 0.05. RESULTS: Group 3000-m performance was significantly slower at altitude versus sea level (48.5 +/- 12.7 s), and the declines were significant in men (48.4 +/- 14.6 s) and women (48.6 +/ 8.9 s). Athletes grouped by low SaO2 during race pace in normoxia (SaO2 < 91%, n = 7) had a significantly larger DeltaVO(2) in hypoxia (-9.2 +/- 2.1 mL.kg( 1).min(-1)) and Delta3000-m time at altitude (54.0 +/- 13.7 s) compared with athletes with high SaO2 in normoxia (SaO2 > 93%, n = 7, DeltaVO(2) = -3.5 +/- 2.0 mL.kg(-1).min(-1), Delta3000-m time = 38.9 +/- 9.7 s). For all athletes, SaO2 during normoxic race pace running was significantly correlated with both DeltaVO(2) (r = -0.68) and Delta3000-m time (r = -0.38). CONCLUSIONS: These results indicate that the degree of arterial oxyhemoglobin desaturation, already known to influence DeltaVO(2)max at altitude, also contributes to the magnitude of decline in race performance at altitude. PMID- 21311362 TI - Volume-dependent response of precooling for intermittent-sprint exercise in the heat. AB - PURPOSE: This study aimed to assess the effects of precooling volume on neuromuscular function and performance in free-paced intermittent-sprint exercise in the heat. METHODS: Ten male, team-sport athletes completed four randomized trials involving an 85-min free-paced intermittent-sprint exercise protocol in 33 degrees C +/- 33% relative humidity. Precooling sessions included whole body (WB), head + hand (HH), head (H), and no cooling (CONT) applied for 20 min before exercise and 5 min during exercise. Maximal voluntary contractions were assessed before and after intervention and during and after exercise. Exercise performance was assessed with sprint times, percent decline and distances covered during free paced bouts. Measures of core (Tc) and skin (Tsk) temperatures, HR, perceptual exertion, and thermal stress were monitored throughout. Venous and capillary blood samples were analyzed for metabolite, muscle damage, and inflammatory markers. RESULTS: WB precooling facilitated the maintenance of sprint times during the exercise protocol with reduced percent decline (P = 0.04). Mean and total hard running distances increased with precooling 12% compared with CONT (P < 0.05); specifically, WB was 6%-7% greater than HH (P = 0.02) and H (P = 0.001), respectively. No change was evident in mean voluntary or evoked force before to after exercise with WB and HH cooling (P > 0.05). WB and HH cooling reduced Tc by 0.1 degrees C-0.3 degrees C compared with other conditions (P < 0.05). WB Tsk was suppressed for the entire session (P = 0.001). HR responses after WB cooling were reduced (P = 0.05; d = 1.07) compared with CONT conditions during exercise. CONCLUSIONS: A relationship between precooling volume and exercise performance seems apparent, as larger surface area coverage augmented subsequent free-paced exercise capacity, in conjunction with greater suppression of physiological load. Maintenance of maximal voluntary contraction with precooling despite increased work output suggests the role of centrally mediated mechanisms in exercise pacing regulation and subsequent performance. PMID- 21311363 TI - A 45-minute vigorous exercise bout increases metabolic rate for 14 hours. AB - INTRODUCTION: The magnitude and duration of the elevation in resting energy expenditure after vigorous exercise have not been measured in a metabolic chamber. This study investigated the effects of inserting a 45-min vigorous cycling bout into the daily schedule versus a controlled resting day on 24-h energy expenditure in a metabolic chamber. METHODS: Ten male subjects (age = 22 33 yr) completed two separate 24-h chamber visits (one rest and one exercise day), and energy balance was maintained for each visit condition. On the exercise day, subjects completed 45 min of cycling at 57% Wmax (mean +/- SD = 72.8% +/- 5.8% VO(2)max) starting at 11:00 a.m. Activities of daily living were tightly controlled to ensure uniformity on both rest and exercise days. The area under the energy expenditure curve for exercise and rest days was calculated using the trapezoid rule in the EXPAND procedure in the SAS and then contrasted. RESULTS: The 45-min exercise bout resulted in a net energy expenditure of 519 +/- 60.9 kcal (P < 0.001). For 14 h after exercise, energy expenditure was increased 190 +/- 71.4 kcal compared with the rest day (P < 0.001). CONCLUSIONS: In young male subjects, vigorous exercise for 45 min resulted in a significant elevation in postexercise energy expenditure that persisted for 14 h. The 190 kcal expended after exercise above resting levels represented an additional 37% to the net energy expended during the 45-min cycling bout. The magnitude and duration of increased energy expenditure after a 45-min bout of vigorous exercise may have implications for weight loss and management. PMID- 21311364 TI - Does hemoglobin mass increase from age 16 to 21 and 28 in elite endurance athletes? AB - PURPOSE: It is unclear if hemoglobin mass (Hbmass) and red cell volume (RCV) increase in endurance athletes with several years of endurance training from adolescence to adulthood. The aim of this study, therefore, was to determine with a controlled cross-sectional approach whether endurance athletes at the ages of 16, 21, and 28 yr are characterized by different Hbmass, RCV, plasma volume (PV), and blood volume (BV). METHODS: BV parameters (CO rebreathing), VO(2max) and other blood, iron, training, and anthropometric parameters were measured in three endurance athlete groups AG16 (n = 14), AG21 (n = 14), and AG28 (n = 16) as well as in three age-matched control groups (<2 h endurance training per week): CG16 (n = 16), CG21 (n = 15), and CG28 (n = 16). RESULTS: In AG16, body weight-related Hbmass (12.4 +/- 0.7 g.kg(-1)), RCV, BV, and VO(2max) (66.1 +/- 3.8 mL.kg.( 1)min(-1)) were lower (P < 0.001) than those in AG21 (14.2 +/- 1.1 g.kg(-1), 72.9 +/- 3.6 mL.kg.(-1)min(-1)) and AG28 (14.6 +/- 1.1 g.kg(-1), 73.4 +/- 6.0 mL.kg.( 1)min(-1)). Results for these parameters did not differ between AG21 and AG28 and among the control groups. VO(2max), PV, and BV were higher for AG16 than for CG16 (12.0 +/- 1.0 g.kg(-1), 58.9 +/- 5.0 mL.kg.(-1)min(-1)) but not Hbmass and RCV. CONCLUSIONS: Our results suggest that endurance training has major effects on Hbmass and RCV from ages 16 to 21 yr, although there is no further increase from ages 21 to 28 yr in top endurance athletes. On the basis of our findings, an early detection of the aptitude for endurance sports at age 16 yr, solely based on levels of Hbmass, does not seem to be possible. PMID- 21311365 TI - Beneficial effect of creatine supplementation in knee osteoarthritis. AB - INTRODUCTION: The aim of this study was to investigate the efficacy of creatine (CR) supplementation combined with strengthening exercises in knee osteoarthritis (OA). METHODS: A randomized, double-blind, placebo-controlled trial was performed. Postmenopausal women with knee OA were allocated to receive either CR (20 g.d(-1) for 1 wk and 5 g.d(-1) thereafter) or placebo (PL) and were enrolled in a lower limb resistance training program. They were assessed at baseline (PRE) and after 12 wk (POST). The primary outcome was the physical function as measured by the timed-stands test. Secondary outcomes included lean mass, quality of life, pain, stiffness, and muscle strength. RESULTS: Physical function was significantly improved only in the CR group (P = 0.006). In addition, a significant between-group difference was observed (CR: PRE = 15.7 +/- 1.4, POST = 18.1 +/- 1.8; PL: PRE = 15.0 +/- 1.8, POST = 15.2 +/- 1.2; P = 0.004). The CR group also presented improvements in physical function and stiffness subscales as evaluated by the Western Ontario and McMaster Universities Osteoarthritis Index (P = 0.005 and P = 0.024, respectively), whereas the PL group did not show any significant changes in these parameters (P > 0.05). In addition, only the CR group presented a significant improvement in lower limb lean mass (P = 0.04) as well as in quality of life (P = 0.01). Both CR and PL groups demonstrated significant reductions in pain (P < 0.05). Similarly, a main effect for time revealed an increase in leg-press one-repetition maximum (P = 0.005) with no significant differences between groups (P = 0.81). CONCLUSIONS: CR supplementation improves physical function, lower limb lean mass, and quality of life in postmenopausal women with knee OA undergoing strengthening exercises. PMID- 21311369 TI - Application of two different hemostatic procedures during microsurgical median nerve reconstruction in the rat does not hinder axonal regeneration. AB - BACKGROUND: Hemostatic procedures by means of electrical coagulation or application of topical agents are widely used to avoid postoperative bleeding during microsurgical reconstruction of peripheral nerves. It is speculated, however, that extensive hemostasis could provoke significant nerve damage. OBJECTIVE: To examine the effects of 2 intraoperative hemostatic procedures on peripheral nerve regeneration. METHODS: In 36 adult rats divided into 3 groups, the median nerve was transected and repaired by end-to-end neurorrhaphy. During surgery, bleeding was treated in groups 2 and 3 by application of either the topical hemostatic agent Floseal or routine bipolar coagulation. The degree of nerve regeneration was assessed in terms of motor function recovery using weekly grasping test evaluation for 3 months, muscle mass recovery of flexor digitorum sublimis, and stereological assessment of myelinated axon regeneration. RESULTS: Neither of the 2 applied hemostatic methods induced any negative effects on nerve regeneration as defined by grip strength, muscle mass recovery, and morphology of myelinated nerve fibers. In contrast, Floseal-treated animals showed a faster progression of motor function recovery, and animals subjected to bipolar coagulation revealed a higher muscle mass recovery compared with the control group. CONCLUSION: Controlled application of bipolar coagulation or Floseal does not exert a negative effect on the nerve regeneration outcome in rats. We propose that these methods can be applied safely to patients. PMID- 21311370 TI - Magnetic microparticles for endovascular aneurysm treatment: in vitro and in vivo experimental results. AB - OBJECTIVE: Endovascular treatment of intracranial aneurysms employing endosaccular coiling can be associated with aneurysm perforation, coil herniation or incomplete obliteration fueling the interest to investigate novel endovascular techniques. We aimed to test a novel embolization material in experimental aneurysms in vitro and in vivo whereby intra-arterially administered magnetic microparticles (MMPs) are navigated into the lumen of vascular aneurysms with assistance from an external magnetic field. METHODS: MMPs are core-shell particles suspended in saline that have a shell made of a polymeric material and a core made of magnetite (Fe3O4). They have a diameter of 1.4 MUm. During MMP administration via a microcatheter, a magnetic field was applied externally to direct the particles with the use of a solid-state neodymium magnet. Experiments were performed in a perfused silicone vessel and aneurysm model to evaluate application techniques and fluid dynamics and in the elastase aneurysm model in rabbits to evaluate in vivo compatibility, including multiorgan histological examinations and long-term stability of aneurysm embolization. RESULTS: It was possible to steer and hold the MMPs within the aneurismal cavity where they occluded the lumen progressively. After removal of the external magnetic field, the results remained stable in vivo for the remainder of the observational period (30 minutes); after a 12-week observational period, recanalization of the aneurysm occurred. CONCLUSION: MMPs can be magnetically directed into aneurysms, allowing short-term obliteration. Although the method has yet to show reliable long-term stability, these experiments provide proof of concept, encouraging further investigation of intravascular magnetic compounds. PMID- 21311371 TI - Ventral intermediate thalamic stimulation for monoclonal gammopathy-associated tremor: case report. AB - BACKGROUND AND IMPORTANCE: Peripheral and central sensory loss are often associated with significant tremor or sensory ataxia, which can be highly refractory to medical therapy. CLINICAL PRESENTATION: We present the case of a 67 year-old man with progressive and debilitating intention tremor from monoclonal gammopathy-associated peripheral neuropathy. The patient was implanted with bilateral thalamic deep brain stimulator electrodes under microelectrode guidance. Following optimization of stimulation parameters, the patient's appendicular tremor and gait improved, as did his general activities of daily living. CONCLUSION: These initial findings suggest that deep brain stimulation may benefit not only tremor presumed to originate from central nervous system dysfunction, but also tremor originating peripherally from neuropathy-related sensory loss. PMID- 21311372 TI - Relationship between decompressive craniectomy and hydrocephalus. PMID- 21311373 TI - Surgical approaches to tumors of the gyrus cinguli. PMID- 21311374 TI - "Double-barrel" stent reconstruction of a symptomatic fusiform basilar artery aneurysm: case report. AB - BACKGROUND AND IMPORTANCE: Giant fusiform aneurysms of the basilar artery are associated with a high rate of morbidity and mortality. Treatment of these lesions can be difficult, especially when there are poor anatomic collaterals such as posterior communicating arteries. These lesions often have no acceptable treatment. The authors present a case of a patient with a symptomatic, fusiform basilar artery aneurysm successfully treated with a side-by-side (double-barrel), telescoping stent construct. CLINICAL PRESENTATION: A 56-year-old man presented with chief concerns of dysarthria and left-sided hemiparesis. MRI and conventional catheter-based angiography revealed a dolichoectatic basilar artery with 3 large fusiform aneurysms throughout its length. Flow through the patient's aneurysm was successfully reduced with a side-by-side stent construct and coiling of the proximal aneurysm dilation. The patient experienced stabilization of his ischemic events and neurologic recovery. A total of 6 Neurform-2 4.5 * 30-mm stents were navigated and positioned from the proximal posterior cerebral arteries to the distal vertebral arteries in a side-by-side (double-barrel), telescoping manner. These were deployed simultaneously by 2 operators to oppose the stent struts as well as the arterial wall. Next, the proximal aneurysmal dilation was coiled to near occlusion. Successful flow redirection and aneurysm thrombosis was observed. CONCLUSION: A novel, endovascular stenting technique for successfully treating symptomatic, giant basilar artery aneurysms is presented. This patient at 4 months was living independently with no further neurologic events or decline. PMID- 21311375 TI - The versatile distal access catheter: the Cleveland Clinic experience. AB - BACKGROUND: Vascular access is fundamental to any endovascular intervention. Concentric Medical has developed the Outreach Distal Access Catheter (DAC), which affords stable access at the target vessel modulating the forces at play within the thrombectomy device complex. The DAC is a device with novel access characteristics useful in a host of other types of clinical scenarios. OBJECTIVE: To review our experience with the DAC family of devices, the theory, and method of use. METHODS: A retrospective review of all cases in which the DAC was used during the period 2008 to 2010 was conducted and the cases classified by indication. Catheter-related complications were recorded. The use of the DAC in a variety of settings including intracranial stenting, aneurysm coil embolization, and arteriovenous malformation embolization is described. RESULTS: The DAC was used in 103 procedures performed in 93 patients between August 2008 and February 2010. Indications included acute stroke, treatment of intracranial atherosclerosis, vasospasm therapy, arteriovenous malformation embolization, and aneurysm embolization. In those procedures, 113 catheters were used. No complications directly attributable to DAC use were identified. CONCLUSION: The DAC is useful for gaining access to the cerebral vasculature, especially in patients with significant tortuosity or when re-access of distal vasculature is required multiple times. PMID- 21311376 TI - Posterior communicating artery aneurysm-related oculomotor nerve palsy: influence of surgical and endovascular treatment on recovery: single-center series and systematic review. AB - BACKGROUND: Compression of the third nerve resulting in oculomotor nerve palsy (ONP) is a common initial symptom and in some cases the only neurological deficit in patients with posterior communicating artery (PcomA) aneurysms. OBJECTIVE: To analyze the resolution of ONP after surgical or endovascular treatment in comparison with its spontaneous course. METHODS: Between June 1999 and April 2008, 5 of 914 consecutive patients with ruptured and 10 of 344 with unruptured intracranial aneurysms causing ONP were treated at our institution. ONP was recorded at admission and at follow-up. The electronic database MEDLINE was searched for published studies of PcomA aneurysm-caused ONP. Two reviewers independently extracted data. RESULTS: Overall, 26 studies and 15 patients of the current series totaling 201 PComA aneurysms met the inclusion criteria. A total of 132 patients underwent surgical clipping, 54 patients were treated endovascularly, and 15 patients remained untreated. Surgical treatment was associated with a significantly higher rate of complete ONP resolution (55% vs 32%; P=.006; odds ratio [OR], 2.6; 95% confidence interval [CI], 1.3-5.1) and ONP resolution of any degree (92% vs 74%; P=.001; OR, 4.3; 95% CI, 1.8-10.4) compared with endovascularly treated patients. In the multivariate analyses, surgical clipping was significantly associated with ONP resolution of any degree (P<.0001; OR, 12.2; 95% CI, 3-49) and of complete resolution (P=.006; OR, 7.1; 95% CI, 1.8 28). CONCLUSION: The present data indicate that ONP caused by PComA aneurysms resolves in a significantly higher portion of patients after surgical treatment compared with endovascular coiling and the spontaneous course. PMID- 21311377 TI - Therapeutic impact of human bone marrow stromal cells expanded by animal serum free medium for cerebral infarct in rats. AB - BACKGROUND: The donor cell culture in animal serum-free medium is important for the clinical application of cell transplantation therapy. Recently, human-derived platelet lysate (PL) gained interest as a substitute for fetal calf serum (FCS), but there are no studies that evaluate the validity of human bone marrow stromal cells (hBMSCs) expanded with PL-containing medium for central nervous system disorders. OBJECTIVE: To test the hypothesis that hBMSCs expanded with FCS-free, PL-containing medium can promote functional recovery after cerebral infarct. METHODS: hBMSCs were cultured in the FCS- or PL-containing medium. Cell-growth kinetics were analyzed. The vehicle or hBMSCs was stereotactically transplanted into the ipsilateral striatum of the rats subjected to permanent middle cerebral artery occlusion 7 days after the insult. Motor function was assessed for 8 weeks, and the fate of transplanted hBMSCs was examined using immunohistochemistry. RESULTS: There was no significant difference in hBMSC expansion between the 2 groups. Transplantation of hBMSCs expanded with the FCS- or PL-containing medium equally promoted functional recovery compared with the vehicle group. Histological analysis revealed that there were no significant differences in their migration, survival, and neural differentiation in the infarct brain between the 2 groups. CONCLUSION: hBMSCs expanded with PL containing medium retained their capacity of migration, survival, and differentiation and significantly promoted functional recovery when stereotactically transplanted into the infarct brain. The PL may be a clinically valuable and safe substitute for FCS in expanding hBMSCs to regenerate the infarct brain. PMID- 21311378 TI - Continuous local intra-arterial nimodipine administration in severe symptomatic vasospasm after subarachnoid hemorrhage. AB - BACKGROUND: Cerebral vasospasm (CV) is a potentially disastrous consequence of subarachnoid hemorrhage despite medical treatment. Nimodipine is a potent drug for vessel relaxation, but side effects may preclude a sufficient dose. OBJECTIVE: To explore whether continuous local intra-arterial nimodipine administration (CLINA) can reverse vasospasm and prevent delayed ischemic neurological deficit. METHODS: Six consecutive subarachnoid hemorrhage patients (5 women; mean age, 47.2 years) with severe CV despite maximum medical therapy underwent CLINA within 2 hours after the onset of clinical symptoms. After anticoagulation, microcatheters were inserted distally in the concerning supra aortic vessels. Glyceryl trinitrate injection (2 mg) was followed by CLINA (nimodipine 0.4 mg/h for 70-147 hours). Duration of CLINA was determined by neurological status, transcranial Doppler sonography, and partial tissue oxygen pressure values. RESULTS: In all patients, neurological deficits improved or partial tissue oxygen pressure values returned to normal and transcranial Doppler sonography confirmed a reduced blood flow velocity within 12 hours. Magnetic resonance imaging showed no ischemic lesion caused by CV. Neurological outcome was good (modified Rankin Scale score, 0-2) in 3 patients, whereas 1 patient had a moderate clinical outcome (modified Rankin Scale score, 3-4) and 2 patients had a poor outcome (modified Rankin Scale score, 5) because of the SAH. CONCLUSION: Preliminary data show that CLINA is a straightforward, effective, and safe option for patients with severe CV refractory to medical therapy. Dilation of spastic arteries starts within a few hours and is lasting. Indication for CLINA is peripheral and diffuse CV at any location. PMID- 21311379 TI - Neuroform stent-assisted embolization of incidental anterior communicating artery aneurysms: long-term clinical and angiographic follow-up. AB - BACKGROUND: Anterior communicating artery (A-comm) aneurysm is one of the most common intracranial aneurysms. Treatments include neurosurgical clipping or endovascular embolization. OBJECTIVE: To retrospectively examine the long-term results of Neuroform stent-assisted coil embolization of incidental A-comms, with a focus on stent-associated stenosis, long-term angiographic aneurysm occlusion outcome, delayed stent-related thromboembolus, subsequent subarachnoid hemorrhage from the treated aneurysm, and procedural complications. METHODS: Between January 7, 2003 and June 16, 2009, 44 Neuroform stents were placed as an adjunct to embolization of A-comms. Patient charts were reviewed retrospectively. Angiographic follow-up of at least 3 months (up to 6.5 years, mean 65 weeks) was available for 33 patients. Aneurysm occlusion success was determined using the Raymond classification for aneurysm remnants. RESULTS: Referencing the last angiogram in the follow-up course, complete occlusion, dog-ear residual, residual neck, and residual aneurysm were found in 24, 2, 3, and 4 patients, respectively. Stenosis (45% and asymptomatic) of the artery where the stent had been placed was found in 1 patient. One patient had delayed transient ischemic attack after dual antiplatelet therapy was stopped prematurely. Retreatment based on the presence of residual aneurysm was performed or recommended in 2 patients. In 2 patients with residual or recurrent aneurysm filling, their age or clinical condition did not warrant retreatment. CONCLUSION: Neuroform stent-assisted embolization provides long-term control of A-comms with a low incidence of aneurysm growth after treatment. The need for retreatment is uncommon, and retreatment is safe if performed. Subsequent bleeding from treated aneurysms was not observed in this study. PMID- 21311380 TI - A comparative effectiveness analysis of alternative strategies to assess hypothalamic-pituitary-adrenal axis function after microsurgical resection of pituitary tumors. AB - BACKGROUND: Observational methods can be used in conjunction with the comparative effectiveness research (CER) paradigm to inform decisions between alternative patient management strategies in real-world clinical settings. OBJECTIVE: To present a brief review of current observational research regarding 3 strategies for predicting normal hypothalamic-pituitary-adrenal (HPA) axis function after surgical resection of pituitary tumors and to apply the CER model to compare these management alternatives. METHODS: We designed and conducted 2 prospective observational studies involving 183 patients undergoing microsurgical resection for pituitary tumors. These investigations yielded a comprehensive database comprising longitudinal data from multiple clinical domains. We investigated 3 potential strategies to predict normal postoperative HPA axis function in this cohort, including preoperative adrenocorticotrophic hormone stimulation testing and measurement of serum cortisol levels immediately after surgery or on the first postoperative day. We performed a focused comparative effectiveness review to help inform the decision between the 3 potential clinical management strategies. RESULTS: This investigation illustrates the use of observational research methods in conjunction with CER methodology as one means of informing clinical management decisions. Of the 3 strategies for assessing postoperative HPA axis function studied, preoperative and immediate postoperative adrenocorticotrophic hormone stimulation testing had the highest sensitivity, accuracy, and positive predictive value for normal HPA axis function postoperatively. The preoperative strategy was also the most cost-effective approach (12% reduction vs benchmark). CONCLUSION: The decision to use any of the 3 strategies outlined requires attention to a specific patient's clinical situation, but this decision may be aided by the results of this CER analysis. PMID- 21311381 TI - Transcranial Doppler to screen on admission patients with mild to moderate traumatic brain injury. AB - BACKGROUND: Detecting patients at risk for secondary neurological deterioration (SND) after mild to moderate traumatic brain injury is challenging. OBJECTIVE: To assess the diagnostic accuracy of transcranial Doppler (TCD) on admission in screening these patients. METHODS: This prospective, observational cohort study enrolled 98 traumatic brain injury patients with an initial Glasgow Coma Scale score of 9 to 15 whose initial computed tomography (CT) scan showed either absent or mild lesions according to the Trauma Coma Data Bank (TCDB) classification, ie, TCDB I and TCDB II, respectively. TCD measurements of the 2 middle cerebral arteries were obtained on admission under stable conditions in all patients. Neurological outcome was reassessed on day 7. RESULTS: Of the 98 patients, 21 showed SND, ie, a decrease of >= 2 points from the initial Glasgow Coma Scale or requiring any treatment for neurological deterioration. Diastolic cerebral blood flow velocities and pulsatility index measurements were different between patients with SND and patients with no SND. Using receiver-operating characteristic analysis, we found the best threshold limits to be 25 cm/s (sensitivity, 92%; specificity, 76%; area under curve, 0.93) for diastolic cerebral blood flow velocity and 1.25 (sensitivity, 90%; specificity, 91%; area under curve, 0.95) for pulsatility index. According to a recursive-partitioning analysis, TCDB classification and TCD measurements were the most discriminative among variables to detect patients at risk for SND. CONCLUSION: In patients with no severe brain lesions on CT after mild to moderate traumatic brain injury, TCD on admission, in complement with brain CT scan, could accurately screen patients at risk for SND. PMID- 21311382 TI - Is cauda equina syndrome being treated within the recommended time frame? AB - BACKGROUND: Cauda equina syndrome (CES) is a rare but devastating medical condition requiring urgent surgery to halt or reverse neurological compromise. Controversy exists as to how soon surgery must be performed after diagnosis, and clinical and medicolegal factors make this question highly relevant to the spine surgeon. It is unclear from the literature how often CES patients are treated within the recommended time frame. OBJECTIVE: To determine whether CES patients are being treated in compliance with the current guideline of surgery within 48 hours and to assess incidence, demography, comorbidities, and outcome measures of CES patients. METHODS: We searched the 2003 to 2006 California State Inpatient Databases to identify degenerative lumbar disk disorder patients surgically treated for CES. An International Classification of Disease, ninth revision, clinical modification, diagnosis code was used to identify CES patients with advanced disease. RESULTS: The majority (88.74%) of California's CES patients received surgery within the recommended 48-hour window after diagnosis. The incidence of CES in surgically treated degenerative lumbar disk patients was 1.51% with an average of 397 cases per year in California. CES patients had worse outcomes and used more healthcare resources than other surgically treated degenerative lumbar disk patients; this disparity was more pronounced for patients with advanced CES. CES patients treated after 48 hours had 3 times the odds of a nonroutine discharge as patients treated within 48 hours (odds ratio = 3.082; P < .001). CONCLUSION: In California, patients are being treated within the recommended 48-hour time frame. PMID- 21311383 TI - Health-related quality of life after aneurysmal subarachnoid hemorrhage: profile and clinical factors. AB - BACKGROUND: Health-related quality of life has recently been suggested as a supplement to the traditional neurological outcome measures from the patient's perspective according to the World Health Organization model and may capture the effects of other factors such as posttraumatic stress disorder and neuroendocrine dysfunction. OBJECTIVE: To explore the profile and clinical factors of quality of life after aneurysmal subarachnoid hemorrhage using the data we obtained from the recently completed Intravenous Magnesium Sulphate After Aneurysmal Subarachnoid Hemorrhage (IMASH) trial. METHODS: This study was registered at www.strokecenter.org/trials and www.ClinicalTrials.gov (NCT00124150). Data from a patient cohort obtained with the Short Form-36 questionnaire completed at 6 months were used for analysis. RESULTS: Patients with aneurysmal subarachnoid hemorrhage demonstrated a decrease in quality of life according to the Short Form 36 at 6 months. The physical and mental health scores correlated with the Extended Glasgow Outcome Scale and had the potential to avoid the ceiling effect. Multiple regression analyses showed that the physical component scores were related to age, World Federation of Neurological Surgeons grade, and chronic hydrocephalus and that the mental component scores were not related to the traditional prognostic factors. CONCLUSION: Subarachnoid hemorrhage caused a decrease in quality of life. Chronic hydrocephalus is related to a decrease in physical health quality of life. PMID- 21311384 TI - Long-term outcome after microendoscopic diskectomy for lumbar disk herniation: a prospective clinical study with a 5-year follow-up. AB - BACKGROUND: Several authors have reported results obtained with the microendoscopic diskectomy (MED) technique, but the long-term outcome has not been described. This report summarizes our clinical experience with the lumbar MED technique with a long-term follow-up period. OBJECTIVE: To evaluate the efficacy of the MED for lumbar disk herniation and to report long-term outcome and complications (5-year follow-up). METHODS: One hundred twenty consecutive patients with lumbar disk herniation were treated with the METRx system.We included all types of lumbar herniated disks: contained, not contained, foraminal, and migrated disk herniations. The results were evaluated with the Visual Analog Scale (VAS) pain score, Oswestry Disability Index score, patient satisfaction questionnaire, and modified Macnab criteria. RESULTS: The average age of patients was 41 years; 65 were men and 55 were women. The most commonly affected level was L5-S1 (54.2%). The follow-up time after surgery was 5 years in all cases. We obtained good or excellent results in 75% of patients and regular results in 18%. Good subjective satisfaction was observed with surgery in 92% of patients. The mean decrease in the Oswestry Disability Index score was 52.8 +/- 21.6; the mean decrease in leg VAS score was 6.1 +/- 2.3; and the mean decrease in lumbar VAS score was 1.9 +/- 3.3. Adjusted mean differences were statistically significant in all cases (P < .05). CONCLUSION: MED not only reduces the incision, tissue damage, and postoperative period of incapacity but also offers long-term results comparable to those of conventional techniques. PMID- 21311385 TI - Long-term outcomes of primary craniofacial reconstruction for craniosynostosis: a 12-year experience. AB - BACKGROUND: The purpose of this study was to critically assess long-term outcomes after open reconstruction of craniosynostosis within the recent decade. METHODS: The authors performed a retrospective, institutional review board-approved review of open repair for craniosynostosis between 1997 and 2009. Surgical factors, complications, and long-term outcomes were assessed. Pearson chi-square, Fisher's exact, and Kaplan-Meier analyses were performed. RESULTS: Of 212 patients, 72 underwent primary extended synostectomy and 140 had traditional open craniofacial repair. Mean follow-up was 36.3 months (range, 0.5 to 138 months). Indications included sagittal (n = 96), metopic (n = 40), unicoronal (n = 33), bicoronal (n = 24), multisutural (n = 15), bilambdoidal (n = 3), and unilambdoidal (n = 1) synostoses; 8.5 percent of patients were syndromic. Surgical reconstruction was performed at a mean age of 11.3 months (range, 0.2 to 117.8 months), including nonsyndromic patients at an average age of 10.6 months and syndromic patients at age 19.3 months. There were no deaths. A 3.3 percent complication rate included two cerebral contusions, two hematomas, one cerebrospinal fluid leak, one infection, and one wound breakdown. Patients were categorized as 89.2 percent Whitaker class I/II and 10.8 percent Whitaker class III/IV. Major and total reoperation rates were 9.0 percent and 10.8 percent, respectively. Higher total reoperation rate and Whitaker class III/IV distribution significantly correlated with syndromic diagnosis, bicoronal synostosis, and surgical age younger than 6 months. CONCLUSIONS: In this experience of contemporary open craniosynostosis surgery, rates of morbidity, mortality, and reoperation were low. These results support the merits of surgical delay, targeting an age of 6 months or older, and may serve as a more accurate metric of comparison to current minimally invasive techniques for craniosynostosis repair. PMID- 21311386 TI - Free tissue transfer with distraction osteogenesis is effective for limb salvage of the infected traumatized lower extremity. AB - BACKGROUND: Salvage of acute and chronic tibial osseocutaneous defects in the lower extremity poses a formidable problem. Although local, distant, and free tissue transfer or bone grafting alone may be adequate for repair of small wounds or osseous defects, large or complicated defects necessitate a different approach. The authors describe their experience with free tissue transfer in combination with distraction osteogenesis for complex composite osteocutaneous defects. METHODS: The authors reviewed a consecutive series of 28 patients who underwent treatment over an 8-year period, with follow-up ranging from 1 to 8.5 years. Mean time to flap after injury was 1082 days (range, 6 days to 30 years). Indications for treatment included infected nonunion of the tibia (n = 18), acute traumatic bone loss (n = 5), skin and soft-tissue breakdown that occurred during distraction osteogenesis (n = 4), and exposed bone following previous failed free flap (n = 1). RESULTS: Free flaps used included the rectus abdominis (n = 17), latissimus dorsi (n = 5), gracilis (n = 5), and radial forearm (n = 1). Mean length of bone gap was 63 mm (range, 30 to 140 mm), and mean area of wound requiring flap coverage was 219 cm (range, 35 to 400 cm). Twenty-five patients (89.3 percent) had successful flap coverage and went on to ambulate independently and return to work. The minor complication rate was 42.9 percent. CONCLUSIONS: Distraction osteogenesis in combination with free tissue transfer is a powerful technique that allows limb salvage, particularly when local and regional flaps are unavailable or inadequate. For infected nonunion of the tibia, it permits a staged approach that allows underlying osteomyelitis to declare itself and provides vascularized healthy soft-tissue coverage that facilitates repeated operations for the purpose of distraction. PMID- 21311387 TI - Reconstruction of post-radical parotidectomy defects. AB - BACKGROUND: Radical parotidectomy presents a unique combination of reconstructive challenges. The high visibility of the region and the specialized structures involved create an interdependence between aesthetics and function. This article describes the authors' surgical concepts and experience in post-radical parotidectomy reconstruction. METHODS: The various components of reconstruction following radical parotidectomy, including contour restoration, skin coverage, mandible reconstruction, and facial reanimation, are reviewed. The authors discuss their methods of choice and specific technical refinements. Twenty-one post-radical parotidectomy reconstruction patients (male:female, 17:4; median age, 75 years) treated from July of 2006 through May of 2010 were identified. Information on patient demographics, etiology, reconstruction technique, surgical complications, postoperative adjuvant radiotherapy, and survival was obtained. RESULTS: The most common indication for radical parotidectomy was metastatic cutaneous squamous cell carcinoma, followed by carcinoma ex pleomorphic adenoma and direct extension from primary cutaneous malignancy. The authors' standard approach in reconstruction was a combination of anterolateral thigh free flap and cervicofacial rotation advancement flap, repair of the facial nerve with the nerve to the vastus lateralis segmental interpositional graft, gold weight loading of the upper eyelid, lateral canthopexy, temporalis and digastric muscle transfers, and a delayed brow lift. Surgical complications include undercorrection of facial reanimation, gold weight extrusion, wound breakdown, and infections. Seventeen patients (81 percent) received adjuvant radiotherapy (range, 50 to 66 Gy to the primary site, 40 to 60 Gy to the neck). CONCLUSIONS: Radical parotidectomy is a morbid procedure that is sometimes necessary for oncologic control. With sound principles and attention to detail in reconstruction, however, quality of life can be greatly improved. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 21311388 TI - Labia minora reconstruction using clitoral hood flaps, wedge excisions, and YV advancement flaps. AB - BACKGROUND: Labia minora reduction (labioplasty, labiaplasty) is the most common female genital aesthetic procedure. The majority of labia reductions are performed by trimming the labial edges. Many of these women present with (1) asymmetry; (2) scalloping of the labial edges with wide, occasionally painful scars; and (3) abrupt termination and distortion of the clitoral hood at its normal junctions with the clitoral frenula and the upper labium. Reconstruction can usually be performed with wedge excisions, labial YV advancement, and touch up trimming. Reconstruction of a labial amputation, however, required the development of a new clitoral hood flap. METHODS: Twenty-four clitoral hood flaps were performed on 17 patients from June of 2006 through May of 2010. An island clitoral hood flap randomly based on the dartos fascia of the lower clitoral hood and medial labium majus is transposed to the ipsilateral labial defect to reconstruct a labium. Of the 10 patients with unilateral flaps, nine of the patients had previous bilateral labial reductions. Reconstruction of the opposite side in these nine women was performed using one or a combination of the following: wedge excisions, YV advancement flaps, or controlled touch-up trimming. RESULTS: All 24 flaps survived, with four minor complications. Five patients underwent revision of a total of seven flaps, but only two were for complications. As experience increased, revisions for aesthetic improvement became less common. CONCLUSION: Reconstruction of labia minora defects secondary to trimming labia reductions is very successful using a combination of clitoral hood flaps, wedge excisions, and YV advancements. PMID- 21311389 TI - Volunteers in plastic surgery guidelines for providing surgical care for children in the less developed world. AB - BACKGROUND: A significant need is met by volunteer groups who provide free reconstructive plastic surgery for underserved children in developing countries. However, at present there are no consistent guidelines for volunteer groups in plastic surgery seeking to provide high-quality and safe care. METHODS: With these quality and safety standards in mind, in 2006, the Volunteers in Plastic Surgery Committee of the American Society of Plastic Surgeons/Plastic Surgery Educational Foundation undertook a project to develop a detailed set of guidelines for volunteer groups from developed countries seeking to provide plastic surgery services to children in developing countries. To make the guidelines include both surgical and anesthetic needs, they were developed in conjunction with the Society for Pediatric Anesthesia. RESULTS: Guidelines for the delivery of plastic surgery care by volunteer groups to developing countries have been reviewed and approved by the boards of both organizations (the American Society of Plastic Surgeons/Plastic Surgery Educational Foundation and the Society for Pediatric Anesthesia). These include guidelines for the initial site visit, site and patient selection, staff and equipment that should be available, and procedures that can be safely performed based on the site and available facilities. Guidelines for assessment of outcomes, dealing with adverse outcomes, and quality improvement are also provided. CONCLUSIONS: Any plastic surgery group undertaking an international mission trip should be able to go to one source to find a detailed discussion of the perceived needs in providing high-quality, safe care for children. The present document was created to satisfy this need. PMID- 21311390 TI - A systematic review on the use of fibrin glue for peripheral nerve repair. AB - BACKGROUND: Although Tisseel (Baxter, Deerfield, Ill.) was introduced over 30 years ago, the literature remains scant regarding its use and efficacy in peripheral nerve repairs. The goal of this systematic review was to summarize current literature on this topic and discuss differences in clinical outcome between the use of fibrin glue and conventional suturing methods for the repair of peripheral nerves. METHODS: A comprehensive electronic literature search was run in the following databases: Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, MEDLINE, CINAHL, and EMBASE. Articles were classified into three categories: animal, human, and cadaveric studies. RESULTS: Sixteen articles were included in the final analysis (kappa = 0.78). The most consistent outcome measure of the studies assessed was histopathology, which was evaluated in nine of 16 studies. This was followed closely by biomechanics, which were evaluated in eight of 16 studies. Histopathological studies demonstrated less significant granulomatous inflammation in the fibrin groups as well as better overall axonal regeneration, fiber alignment, and recovery of nerve conduction velocities. Animal and cadaveric studies demonstrated no significant differences in stiffness and peak load at failure between microsuture and fibrin groups. CONCLUSIONS: Although the majority of the reviewed studies employed animal models, most indicated that the performance of fibrin glue was equal, if not superior, to that of microsuturing when repairing peripheral nerves. Overall, many authors reported that fibrin glue was a quicker and easier modality to use than microsuture repair. There is, however, not a single well-controlled human trial assessing the efficacy of fibrin glue in relation to that of suturing techniques. PMID- 21311391 TI - Pulsed radiofrequency energy accelerates wound healing in diabetic mice. AB - BACKGROUND: Impaired healing is a problematic and common complication of chronic wounds. Although pulsed radiofrequency energy has been used in the treatment of chronic wounds with promising efficacy, its mechanism is still poorly characterized. In this study, the authors used a diabetic mouse model to illustrate the action of pulsed radiofrequency energy on cutaneous wounds and set the stage to begin to understand its mechanism. METHODS: Full-thickness cutaneous wounds were created in diabetic mice (n = 26). The experimental group (n = 13) was subject to pulsed radiofrequency energy treatment two times per day, whereas the sham group (n = 13) was subjected to sham devices. The rate of wound closure was evaluated by digital analysis of surface area of the wound bed, zone of reepithelialization, and rate of contraction. Mice were euthanized on days 7, 10, 22, and 42 and wounds were evaluated qualitatively and quantitatively by hematoxylin and eosin, Masson's trichrome, and Ki-67 assay for cell proliferation. RESULTS: In the experimental group, the rate of wound closure was significantly accelerated, particularly beyond day 17. Contraction contributed to the wound healing process rather than reepithelialization. This was also associated with increased granulation tissue that was most prominent by day 22 and with enhanced dermal cell proliferation, with 25 percent and 45 percent Ki-67 positive nuclei on days 10 and 22, respectively, as compared with control animals. CONCLUSION: These results indicate that pulsed radiofrequency energy accelerates impaired wound healing mainly through wound contraction by means of stimulating cell proliferation, granulation tissue formation, and collagen deposition. PMID- 21311392 TI - A multidisciplinary protocol for planned skin-preserving delayed breast reconstruction for patients with locally advanced breast cancer requiring postmastectomy radiation therapy: 3-year follow-up. AB - BACKGROUND: The authors examined the safety of a protocol for planned skin preserving delayed breast reconstruction after postmastectomy radiotherapy with placement of a tissue expander for patients with locally advanced breast cancer (stages IIB and III). METHODS: The authors compared 47 patients treated according to the protocol between December 2003 and May 2008 with 47 disease-stage-matched control patients who underwent standard delayed reconstruction after postmastectomy radiotherapy (no skin preservation or tissue expander) during the same period. RESULTS: Protocol-group complication rates were 21 percent for skin preserving mastectomy and placement of the expander (stage 1), 5 percent for postmastectomy radiotherapy, 25 percent for expander reinflation after radiotherapy, and 24 percent for skin-preserving delayed reconstruction. The complication rate for standard delayed reconstruction was 38 percent. Tissue expander loss rates were 32 percent overall, 9 percent for stage 1, 5 percent for postmastectomy radiotherapy, and 22 percent for reinflation. Wound-healing complications after reconstruction occurred in 3 percent of protocol-group and 10 percent of control-group patients. The median follow-up time for patients still alive at last follow-up was 40 months (range, 8.5 to 85.3 months). Three-year recurrence-free survival rates were 92 percent (95 percent CI, 83 to 100 percent) and 86 percent (95 percent CI, 76 to 98 percent) for the protocol and control groups, respectively (p = 0.87). CONCLUSION: In patients with locally advanced breast cancer, skin-preserving mastectomy with a deflated tissue expander on the chest wall during postmastectomy radiotherapy does not increase locoregional recurrence risk and is associated with lower complication rates of definitive reconstruction. PMID- 21311394 TI - Surgery versus conservative treatment for symptomatic lumbar spinal stenosis: a systematic review of randomized controlled trials. AB - STUDY DESIGN: Systematic review. OBJECTIVE: To compare the effectiveness of surgery versus conservative treatment on pain, disability, and loss of quality of life caused by symptomatic lumbar spinal stenosis (LSS). SUMMARY OF BACKGROUND DATA: LSS is the most common reason for spine surgery in persons older than 65 years in the United States. METHODS: Randomized controlled trials (RCTs) comparing any form of conservative and surgical treatment were searched in CENTRAL, MEDLINE, EMBASE, and TripDatabase databases until July 2009, with no language restrictions. Additional data were requested from the authors of the original studies. The methodological quality of each study was assessed independently by two reviewers, following the criteria recommended by the Cochrane Back Review Group. Only data from randomized cohorts were extracted. RESULTS: A total of 739 citations were reviewed. Eleven publications corresponding to five RCTs were included. All five scored as high quality despite concerns deriving from heterogeneity of treatment, lack of blinding, and potential differences in the size of the placebo effect across groups. They included a total of 918 patients in whom conservative treatments had failed for 3 to 6 months, and included orthosis, rehabilitation, physical therapy, exercise, heat and cold, transcutaneous electrical nerve stimulation, ultrasounds, analgesics, nonsteroidal anti-inflammatory drugs, and epidural steroids. Surgical treatments included the implantation of a specific type of interspinous device and decompressive surgery (with and without fusion, instrumented or not). In all the studies, surgery showed better results for pain, disability, and quality of life, although not for walking ability. Results of surgery were similar among patients with and without spondylolisthesis, and slightly better among those with neurogenic claudication than among those without it. The advantage of surgery was noticeable at 3 to 6 months and remained for up to 2 to 4 years, although at the end of that period differences tended to be smaller. CONCLUSION: In patients with symptomatic LSS, the implantation of a specific type of device or decompressive surgery, with or without fusion, is more effective than continued conservative treatment when the latter has failed for 3 to 6 months. PMID- 21311396 TI - Value of preoperative pulmonary function test in flaccid neuromuscular scoliosis surgery. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: To evaluate the prognostic value of preoperative pulmonary function test (PFT) for postoperative pulmonary complications and to identify the operability associated with severely decreased forced vital capacity (FVC) (<30%) status in flaccid neuromuscular scoliosis. SUMMARY OF BACKGROUND DATA: The preoperative PFT, especially more than 30% FVC, is known as a critical factor for the operability of flaccid neuromuscular scoliosis. But only one study reported that patients with pre-existing respiratory failure on nocturnal noninvasive ventilation can undergo an operation for deformity correction without mortality and severe complications. METHODS: A total of 74 patients (45 male and 29 female) presented with flaccid neuromuscular scoliosis. For all patients, preoperative PFTs were evaluated and subdivided into three groups (<30% FVC, 30%-50% FVC, and >50% FVC). Then postoperative pulmonary complications, pneumothorax, pneumonia, atelectasis, prolonged ventilator care in the intensive care unit (more than 72 hours), and postoperative tracheostomy were evaluated. RESULTS: Among these patients, 59 had muscular dystrophy; 5, spinal muscular atrophy; 2, cerebral palsy; and 8, others. The mean age at surgery was 16.8 years (range, 5-32 years). The mean preoperative Cobb angle was 54.6 degrees (16 degrees -135 degrees ). The overall postoperative pulmonary complication rate was 31% (23 complications in 74 patients). The less than 30% FVC group had 6 complications among 18 patients; the 30% to 50% FVC group had 7 complications among 18 patients; and the more than 50% FVC group had 10 complications among 38 patients. There were no deaths during the perioperative period. There is no statistical difference between the three groups (P = 0.6195). CONCLUSION: Patients with flaccid neuromuscular scoliosis can undergo an operation for deformity correction regardless of the severely decreased pulmonary function. PMID- 21311397 TI - Modeling nucleus pulposus regeneration in vitro: mesenchymal stem cells, alginate beads, hypoxia, bone morphogenetic protein-2, and synthetic peptide B2A. AB - STUDY DESIGN: Using a low cell density, hypoxic, alginate-bead culture system, the effects of bone morphogenetic protein-2 (BMP-2) and synthetic peptide B2A on cell proliferation and extracellular matrix (ECM) synthesis were assessed at days 0, 3, 5, and 7, using nucleus pulposus (NP)-like differentiated mesenchymal stem cells (MSCs). OBJECTIVE: This is a preliminary investigation into B2A's potential adjunctive role with MSCs and BMP-2, in NP regeneration. SUMMARY OF BACKGROUND DATA: B2A analogs, alone and in combination with BMP-2, have been shown to promote proliferation and ECM production in chondrocytes and MSCs. Articular chondrocytes and NP cells often respond in a similar manner to growth factor treatments, thus suggesting a potential role for B2A in treating disc degeneration by NP regeneration. METHODS: Using the NP regeneration in vitro model (low cell density, hypoxic, alginate bead culture), B2A and BMP-2 were evaluated alone and in combination, to determine effects on proliferation and ECM synthesis in the presence of transforming growth factor-beta 3 on NP-like differentiated MSCs. RESULTS: B2A administration induced mild proliferation of NP like differentiated MSCs and diminished an initial wave of low-dose BMP-2 prompted apoptosis. Individually and in combination, B2A and BMP-2 were found to inhibit transforming growth factor-beta 3-permitted collagen accumulation; levels remained similar in their presence. Both collagen I (Col I) and collagen II (Col II) were found in almost all specimens, but increased B2A levels favored Col II unlike BMP-2, which favored Col I. BMP-2 resulted in a minor reduction in aggrecan synthesis, which was unchanged by B2A. CONCLUSION: Using this in vitro model, B2A induced proliferation, continuous aggrecan synthesis, and stabilized collagen accumulation favoring Col II. These characteristics are consistent with cells of the young, healthy NP, indicating potential use of the peptide early in an MSC-based NP-regeneration therapy; whereas, BMP-2 induced apoptosis, Col I accumulation, and aggrecan production hindrance, and was found untherapeutic. PMID- 21311398 TI - Upregulated expression of connexin43 in spinal ligament fibroblasts derived from patients presenting ossification of the posterior longitudinal ligament. AB - STUDY DESIGN: A case-control study was conducted. OBJECTIVE: To investigate different expressions of connexin43 (Cx43) between spinal ligament fibroblasts from patients with ossification of the posterior longitudinal ligament (OPLL) and non-OPLL patients and demonstrate knockdown of Cx43 protein expression by RNA interference inhibiting expression of osteoblast-specific genes in OPLL cells. SUMMARY OF BACKGROUND DATA: The OPLL is characterized by ectopic bone formation in spinal ligaments. Some evidence indicates that ligament fibroblasts from OPLL patients have osteogenic characteristics. However, the relevant cellular signaling pathways remain unclear. METHODS: Twenty patients presenting with OPLL and 18 non-OPLL patients underwent anterior decompression between January 2008 and June 2009. Specimens of the posterior longitudinal ligament were collected intraoperatively. Tissue fragment cell culture was performed. Inverted phase contrast microscopy and hematoxylin-eosin staining were used to observe cell morphology. The mouse antivimentin antibody was used to identify the cultured cells via immunocytochemistry and immunofluorescence. The messenger RNA expression of osteoblast-specific genes of osteocalcin (OCN), alkaline phosphatase (ALP), and type I collagen (COL I) were detected in OPLL and non-OPLL cells by semiquantitative reverse transcription-polymerase chain reaction. The protein expression of Cx43 was detected via Western blotting. And then, after 72 hours, when RNA interference against Cx43 was performed in OPLL cells, expression of the indexes mentioned earlier was compared again between the transfection group and the nontransfection group. RESULTS: Cultivated cells were observed 7 to 10 days after cell culture. Hematoxylin-eosin staining showed fusiform and multiangular star morphologies, large and elliptical cell nuclei, and ill-defined cell appearances. Immunocytochemistry and immunofluorescence exhibited positive results of vimentin staining. The messenger RNA expressions of OCN, ALP, and COL I and protein expressions of Cx43 from OPLL fibroblasts were greater than those from non-OPLL cells, and the difference was significant. Furthermore, knockdown of Cx43 protein expression inhibited the messenger RNA expressions of OCN, ALP, and COL I remarkably in the transfection group compared with the nontransfection group, 72 hours after RNA interference targeting Cx43 was performed in OPLL cells. CONCLUSION: Tissue fragment culture of the cervical posterior longitudinal ligament provided a successful fibroblast culture, showing good adherence and subculture. The cultured fibroblasts from OPLL patients exhibited osteogenic characteristics, in which Cx43 played an important role. PMID- 21311399 TI - Spinal fusion in the United States: analysis of trends from 1998 to 2008. AB - STUDY DESIGN: Epidemiological study using national administrative data. OBJECTIVE: To provide a complete analysis of national trends in spinal fusion from 1998 to 2008 and compare with trends in laminectomy, hip replacement, knee arthroplasty, percutaneous transluminal coronary angioplasty, and coronary artery bypass graft. SUMMARY OF BACKGROUND DATA: Previous studies have reported a rapid increase in volume of spinal fusions in the United States prior to 2001, but limited reports exist beyond this point, analyzing all spinal fusion procedures collectively. METHODS: Data were obtained from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample for the years 1998 to 2008. Discharges were identified using International Classification of Diseases, Ninth Revision, Clinical Modification procedure codes for the following procedures: spinal fusion, laminectomy, hip replacement, knee arthroplasty, percutaneous transluminal coronary angioplasty, and coronary artery bypass graft. Population based utilization rates were calculated from the US census data. RESULTS: Between 1998 and 2008, the annual number of spinal fusion discharges increased 2.4-fold (137%) from 174,223 to 413,171 (P < 0.001). In contrast, during the same time period, laminectomy, hip replacement, knee arthroplasty, and percutaneous coronary angioplasty yielded relative increases of only 11.3%, 49.1%, 126.8%, and 38.8% in discharges, while coronary artery bypass graft experienced a decrease of 40.1%. Between 1998 and 2008, mean age for spinal fusion increased from 48.8 to 54.2 years (P < 0.001), in-hospital mortality rate decreased from 0.29% to 0.25% (P < 0.01), and mean total hospital charges associated with spinal fusion increased 3.3-fold (P < 0.001). The national bill for spinal fusion increased 7.9 fold (P < 0.001). CONCLUSION: Frequency, utilization, and hospital charges of spinal fusion have increased at a higher rate than other notable inpatient procedures, as seen in this study from 1998 to 2008. In addition, patient demographics and hospital characteristics changed significantly; in particular, whereas the average age for spinal fusion increased, the in-hospital mortality rate decreased. PMID- 21311400 TI - Acute low back pain and primary care: how to define recovery and chronification? AB - STUDY DESIGN: A prospective cohort study. OBJECTIVE: To establish outcome measures for recovery and chronic pain for studies with patients who present with recent-onset acute low back pain (LBP) in primary care. SUMMARY OF BACKGROUND DATA: Among back pain researchers, no consensus exists about outcome definitions or how to identify primary-care patients as not-recovered from an episode of LBP. Cut points for outcome scales have mostly been arbitrarily chosen. Theoretical models for establishing minimal important change values in studies of patients with LBP have been proposed and need to be applied to real data. METHODS: A sample of 521 patients who presented with acute LBP (<4 weeks) in primary care clinics were observed for 6 months and scores for pain and disability were compared with ratings on a Global Perceived Effect Scale. Using multiple potential "gold standards" as anchors (reference standards), the receiver operating characteristic method was used to determine optimal cut points for different ways of defining nonrecovery from acute LBP. RESULTS: Minimal important change values and upper limits for pain and disability scores as well as minimal important percentage changes are presented for five different definitions of recovery. A previously suggested 30% change from baseline scores does not accurately discriminate between recovered patients and nonrecovered patients in patients presenting with acute LBP in primary care. CONCLUSION: Outcome definitions that combine ratings from perceived recovery scales with pain and disability measures provide the highest accuracy in discriminating recovered patients from nonrecovered patients. PMID- 21311401 TI - A new bone surrogate model for testing interbody device subsidence. AB - STUDY DESIGN: An in vitro biomechanical study investigating interbody device subsidence measures in synthetic vertebrae, polyurethane foam blocks, and human cadaveric vertebrae. OBJECTIVE: To compare subsidence measures of bone surrogates with human vertebrae for interbody devices varying in size/placement. SUMMARY OF BACKGROUND DATA: Bone surrogates are alternatives when human cadaveric vertebrae are unavailable. Synthetic vertebrae modeling cortices, endplates, and cancellous bone have been developed as an alternative to polyurethane foam blocks for testing interbody device subsidence. METHODS: Indentors placed on the endplates of synthetic vertebrae, foam blocks, and human vertebrae were subjected to uniaxial compression. Subsidence, measured with custom-made extensometers, was evaluated for an indentor seated either centrally or peripherally on the endplate. Failure force and indentation stiffness were determined from force displacement curves. RESULTS: Subsidence measures in human vertebrae varied with indentor placement: failure forces were higher and indentors subsided less with peripheral placement. Subsidence measures in foam blocks were insensitive to indentor size/placement; they were similar to human vertebrae for centrally placed but not for peripherally placed indentors. Although subsidence measures in synthetic vertebrae were sensitive to indentor size/placement, failure force and indentation stiffness were overestimated, and subsidence underestimated, for both centrally placed and peripherally placed indentors. CONCLUSION: The synthetic endplate correctly represented the human endplate geometry, and thus, failure force, stiffness, and subsidence in synthetic vertebrae were sensitive to indentor size/placement. However, the endplate was overly strong and thus synthetic vertebrae did not accurately model indentor subsidence in human cadaveric vertebrae. Foam blocks captured subsidence measures more accurately than synthetic vertebrae for centrally placed indentors, but because of their uniform density were not sufficiently robust to capture changes generated from different indentor sizes/placements. The current bone surrogates are not accurate enough in terms of material property distribution to completely model subsidence in human cadaveric vertebrae. PMID- 21311402 TI - Lumbar disc herniation in the Spine Patient Outcomes Research Trial: does educational attainment impact outcome? AB - STUDY DESIGN: Randomized trial with concurrent observational cohort. A total of 1171 patients were divided into subgroups by educational attainment: high school or less, some college, and college degree or above. OBJECTIVE: To assess the influence of education level on outcomes for treatment of lumbar disc herniation. SUMMARY OF BACKGROUND DATA: Educational attainment has been demonstrated to have an inverse relationship with pain perception, comorbidities, and mortality. METHODS: The Spine Patient Outcomes Research Trial enrolled surgical candidates (imaging-confirmed disc herniation with at least 6 weeks of persistent signs and symptoms of radiculopathy) from 13 multidisciplinary spine clinics in 11 US states. Treatments were standard open discectomy versus nonoperative treatment. Outcomes were changes from baseline for 36-Item Short Form Health Survey (SF-36), bodily pain (BP), and physical function (PF) scales and the modified Oswestry Disability Index (ODI) at 6 weeks, 3 months, 6 months, and yearly through 4 years. RESULTS: Substantial improvement was seen in all patient cohorts. Surgical outcomes did not differ by level of education. For nonoperative outcomes, however, higher levels of education were associated with significantly greater overall improvement over 4 years in BP (P = 0.007), PF (P = 0.001), and ODI (P = 0.003). At 4 years a "dose-response" type relationship was shown for BP (high school or less = 25.5, some college = 31, and college graduate or above = 36.3, P = 0.004) and results were similar for PF and ODI. The success of nonoperative treatment in the more educated cohort resulted in an attenuation of the relative benefit of surgery. CONCLUSION: Patients with higher educational attainment demonstrated significantly greater improvement with nonoperative treatment while educational attainment was not associated with surgical outcomes. PMID- 21311403 TI - Distribution of three antituberculous drugs and their metabolites in different parts of pathological vertebrae with spinal tuberculosis. AB - STUDY DESIGN: To detect drug concentration levels and metabolite using high performance liquid chromatography. OBJECTIVE: To map concentration levels of three antituberculous drugs and two metabolites in the abnormal osseous tissues around the foci of patients with spinal tuberculosis. SUMMARY OF BACKGROUND DATA: Concentration levels of antituberculous drugs in the focus of spinal tuberculosis has been reported. However, the mapping of drugs distribution in different regions surrounding the foci of tuberculosis vertebrae remains unexplored, as well as the metabolite of the drugs. METHODS: Thirty-eight patients with spinal tuberculosis were assigned into sclerotic group (n = 13) and nonsclerotic group (n = 25) based on computed tomographic (CT) images. All patients received a chemotherapy 10 months with 2HRZE/8H(2)R(2)E(2). All patients received surgery after 4 weeks of chemotherapy. Samples of serum, ilium, and pathologic vertebral tissues, including the foci, sclerotic wall (if applicable), region I of abnormal osseous tissues (within 4 mm), and region II of abnormal osseous tissues (more than 4 mm) from the foci were collected during operation. Concentration levels and metabolite of three drugs were measured using high-performance liquid method for all samples. Differences of means within groups were evaluated by ANOVA and Dunnett post hoc. A significant levels was set at P < 0.05. RESULTS: Concentration levels of drugs varied greatly in different regions of spinal tuberculosis vertebrae. Concentration levels of isoniazid and rifampin were higher than the effective bactericidal concentration (EBC) level and that of pyrazinamide was five times of the minimal inhibitory concentration in the region II of abnormal osseous tissues and the ilium of nonsclerotic group. Three drugs achieved EBC in the region I of abnormal osseous tissues in the nonsclerotic group but not in the sclerotic group. Except pyrazinamide no drugs and their metabolite were identified in the foci of the sclerotic group, whereas there is trace of drugs and their metabolite in the foci of the nonsclerotic group. CONCLUSION: Three drugs resulted in an effective bactericidal concentration level in osseous tissues around the foci of spinal tuberculosis except the osseous tissues 4 mm surrounding the sclerotic wall. The results suggested that osseous tissues within 4 mm surrounding the sclerotic wall should be excised during the surgery. PMID- 21311405 TI - A finite element analysis of sacroiliac joint ligaments in response to different loading conditions. AB - STUDY DESIGN: A finite element analysis of the sacroiliac joint (SIJ) and its associated ligaments utilizing a three-dimensional model constructed from computed tomography scans. OBJECTIVE: To characterize the sacroiliac ligament strains in response to flexion, extension, and axial rotation loads and quantify the changes in SIJ stress and angular displacement in response to changes in ligament stiffness. SUMMARY OF BACKGROUND DATA: The SIJ may be a major contributor to low back pain in up to 13% to 30% of patients. States of ligament laxity are often associated with hypermobility and possibly pain of SIJ origin. The mechanism by which the SIJ generates pain is both controversial and poorly understood. METHODS: A finite element model of the human pelvis, SIJs, and sacroiliac ligaments was constructed from computed tomography scans. Ligament stiffnesses were altered and the SIJ stresses were compared with the original case. For simulated flexion, extension, and axial rotation scenarios, sacroiliac ligament strains were characterized and compared. RESULTS: Sacroiliac joint stress and angular motion increases as ligament stiffness decreases. Periarticular intraligamentous strains vary depending on the magnitude and direction of the applied loads. Maximum ligamentous strains occur at the interosseous sacroiliac ligament. CONCLUSION: The sacroiliac ligaments function to constrain the SIJ and decrease stress across the SIJ for different load scenarios. Decreasing sacroiliac ligament stiffness leads to both increased joint motion and stress. PMID- 21311404 TI - Outcomes for single-level lumbar fusion: the role of bone morphogenetic protein. AB - STUDY DESIGN: Retrospective analysis of a population-based insurance claims data set. OBJECTIVE: To determine the risk of repeat fusion and total costs associated with bone morphogenetic protein (BMP) use in single-level lumbar fusion for degenerative spinal disease. SUMMARY OF BACKGROUND DATA: The use of BMP has been proposed to reduce overall costs of spinal fusion through prevention of repeat fusion procedures. Although radiographic fusion rates associated with BMP use have been examined in clinical trials, few data exist regarding outcomes associated with BMP use in the general population. METHODS: Using the MarketScan claims data set, 15,862 patients that underwent single-level lumbar fusion from 2003 to 2007 for degenerative disease were identified. Propensity scores were used to match 2372 patients who underwent fusion with BMP to patients who underwent fusion without BMP. Logistic regression models, Kaplan-Meier estimates, and Cox proportional hazards models were used to examine risk of repeat fusion, length of stay, and 30-day readmission by BMP use. Cost comparisons were evaluated with linear regression models using logarithmic transformed data. RESULTS: At 1 year from surgery, BMP was associated with a 1.1% absolute decrease in the risk of repeat fusion (2.3% with BMP vs. 3.4% without BMP, P = 0.03) and an odds ratio for repeat fusion of 0.66 (95% confidence interval [CI] = 0.47 0.94) after multivariate adjustment. BMP was also associated with a decreased hazard ratio for long-term repeat fusion (adjusted hazards ratio = 0.74, 95% CI = 0.58-0.93). Cost analysis indicated that BMP was associated with initial increased costs for the surgical procedure (13.9% adjusted increase, 95% CI = 9.9%-17.9%) as well as total 1-year costs (10.1% adjusted increase, 95% CI = 6.2% 14.0%). CONCLUSION: At 1 year, BMP use was associated with a decreased risk of repeat fusion but also increased health care costs. PMID- 21311406 TI - Implant survival analysis and failure modes of the X-Stop interspinous distraction device. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To review the clinical outcome, implant survivorship and reasons for failure after X-Stop implantation. SUMMARY OF BACKGROUND DATA: Conflicting data exist concerning clinical outcome of the X-Stop interspinous spacer and little information is being published about implant survivorship and the need for revision surgery. METHODS: This retrospective review evaluated 46 patients who underwent implantation of the X Stop interspinous spacer for the treatment of neurogenic claudication. After a mean follow-up of 40 months, pain levels, 36-Item Short Form Health Survey (SF 36), Oswestry Disability Index (ODI), and the need for subsequent surgery were assessed and a Kaplan-Meier survivorship analysis was performed. RESULTS: Within the follow-up period, the revision rate was found to be 30.4%. Lack of improvement at 6-week follow-up correlated well with subsequent revision surgery, which predominantly took place within 12 months after the index surgery. In patients who did not need to undergo revision surgery, clinical outcome parameters improved significantly. Kaplan-Meier survivorship analysis predicted an implant survival probability of 0.68 at 48 months postoperatively. CONCLUSION: Clinical outcome after X-Stop implantation might be considerably less favorable than when it was being published previously. Patient selection might be a reason for early revision surgery. More criteria for better X-Stop indications might be needed. PMID- 21311407 TI - Pattern of 18F-FDG uptake in the spinal cord in patients with non-central nervous system malignancy. AB - STUDY DESIGN: Retrospective review. OBJECTIVE: To (1) propose a standard method to quantitate 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG) uptake in the spinal cord and (2) use this methodology to retrospectively characterize the pattern of uptake within the entire spinal cord using whole-body positron emission tomography/computed tomography (PET/CT) imaging. SUMMARY OF BACKGROUND DATA: A physiologic understanding of glucose metabolism within the spinal cord may provide insight regarding infectious, inflammatory, vascular, and neoplastic spinal cord diseases. METHODS: Institutional review board approval was obtained. A total of 131 consecutive whole-body PET/CT studies from July to August 2004 were reviewed, and using exclusionary criteria of: (1) severe spinal arthropathy or curvature, (2) motion artifact, (3) canal hardware, (4) spinal tumor, and (5) marrow hyperplasia, 92 studies of neurologically intact patients (49 men and 43 women) were selected for a retrospective review of spinal cord 18F-FDG activity. The transaxial CT was used to define the canal and circular regions of interests were placed within the canal at the level of the vertebral body midpoint from C1 to L3. Region of interest total count, area, and maximum standardized uptake value (SUVmax) were recorded. Measurements at L5 served as an internal control. For comparative analysis, the cord-to-background (CTB) ratio was defined as spinal cord SUVmax to L5 SUVmax. RESULTS: Mean CTB decreased along each spinal level from cranial to caudal (P < 0.001). Significant relative increases were observed at the T11-T12 vertebral body levels (P < 0.001). Although insignificant, a relative increase was observed at C4. No significant interactions of age or sex on CTB were observed. CONCLUSION: The pattern of 18F FDG uptake within the spinal cord, observed in patients with non-central nervous system malignancy, may be helpful in understanding glucose physiology of spinal cord diseases and warrants further research. PMID- 21311408 TI - Partial spondylectomy for primary leiomyosarcoma of C2 vertebra. AB - STUDY DESIGN: A primary leiomyosarcoma located on the left side of the C2 is reported. Left-sided partial spondylectomy and anterior reconstruction with posterior stabilization was performed by a two-staged operation. OBJECTIVE: To emphasize the occurrence of primary leiomyosarcoma and the importance of proper stabilization in the upper cervical spine. SUMMARY OF BACKGROUND DATA: Leiomyosarcoma is a rare malignant neoplasm of the bone and the primary leiomyosarcoma of the spine is extremely rare. Radical tumor excision is the goal in case of vertebral leiomyosarcoma, but to both gain surgical access to the upper cervical spine and obtain anterior reconstruction is challenging. METHODS: Leiomyosarcoma of the C2 in a 25-year-old woman with mild neurologic deficits is reported. A left-sided partial spondylectomy of C2 was performed. The defect of the vertebral body was reconstructed by expandable titanium prosthesis, and posterior craniocervical fixation was performed by the polyaxial screws in the lateral masses and rod/plates. RESULTS: The surgical margin was very small. The pathology of the tumor was reported as leiomyosarcoma. No sign of local recurrence or metastasis was evident 1 year after surgery. CONCLUSION: Leiomyosarcoma, although rare, should be kept in mind as one of the possible diagnoses when a patient with an upper cervical tumor is presented and complete tumor removal must be the goal. PMID- 21311409 TI - Type IX collagen neo-deposition in degenerative discs of surgical patients whether genotyped plus or minus for COL9 risk alleles. AB - STUDY DESIGN: Immunohistochemical analysis of type IX collagen in disc tissue from spinal fusion patients. OBJECTIVE: To determine if collagen IX can be detected in adult disc tissue removed at spinal fusion surgery from patients either with or without degeneration-associated tryptophan single nucleotide polymorphisms (SNPs) and whether the distribution is associated either with severity of degeneration or incidence of a collagen IX SNP genotype. SUMMARY OF BACKGROUND DATA: Genetic factors are strongly associated with risk of development and/or progression of disc degeneration. Two SNPs that introduce tryptophan polymorphisms in COL9A2 and COL9A3 are independently linked to an increased risk of lumbar disc disease. Although tryptophan variants are associated with accelerated degeneration, it is not known if collagen IX can be detected in adult disc tissue. METHODS: We selected age-matched disc samples from five clinical groups: fracture with Trp(-) (six cases), herniation (six cases), degeneration (five cases), spondylolisthesis with Trp(-) (eight cases), and spondylolisthesis/herniation/fracture with Trp(+) (six cases of Trp3 allele and one case of Trp2 allele). Using hematoxylin and eosin staining and immunohistochemical staining (collagens IX and IIA), 78 sections from 32 patients were analyzed. Selected disc tissues were assayed biochemically for collagen IX. RESULTS: Focal deposition of collagen IX was observed in regions of adult human disc tissue from spines showing degenerative changes in patients whether or not they were positive for a tryptophan SNP. However, in nondegenerative control disc tissue from fracture cases, little or no collagen IX was detected. The latter finding was confirmed by direct biochemical analyses for collagen IX in pooled samples of normal adult human annulus fibrosus or nucleus pulposus. CONCLUSION: During growth and maturation of the disc, collagen IX is presumably removed completely during matrix remodeling so that the protein is absent from normal adult annulus and nucleus but can reappear at sites of degeneration presumably as part of a repair response to mechanical injury. PMID- 21311410 TI - Association of genetic polymorphisms in the influx transporter SLCO1B3 and the efflux transporter ABCB1 with imatinib pharmacokinetics in patients with chronic myeloid leukemia. AB - This study explored the association of 14 single nucleotide polymorphisms in three genes coding for influx transporters (SLC22A1, SLCO1B1, and SLCO1B3), two genes coding for efflux transporters (ABCB1 and ABCG2), and four genes coding for enzymes (CYP2C9, CYP2C19, CYP2D6, and CYP3A5) with the pharmacokinetics of imatinib in Japanese patients with chronic myeloid leukemia. Pharmacokinetic parameters were estimated by a population pharmacokinetic analysis based on 622 plasma samples from 34 patients at steady state. Approximately 4.6-fold variability in individual clearance was observed (range, 3.4-15.5 L/hr). The individual estimated clearance was significantly increased in patients with the SLCO1B3 334GG genotype (median value +/- standard deviation, 9.5 +/- 3.1 L/hr; n = 19) compared with SLCO1B3 334TT and TG genotypes (7.0 +/- 3.1 L/hr; n = 15) (P = 0.019). Patients with the ABCB1 3435CC genotype had significantly higher imatinib clearance (12.7 +/- 3.0 L/hr; n = 7) compared with patients with ABCB1 3435CT and TT genotypes (7.9 +/- 2.7 L/hr; n = 27) (P = 0.035). In conclusion, the present study suggests that single nucleotide polymorphisms of the influx transporter SLCO1B3 and the efflux transporter ABCB1 were functionally associated with individual variability of imatinib pharmacokinetics in Japanese patients with chronic myeloid leukemia. PMID- 21311411 TI - The role of inosine-5'-monophosphate dehydrogenase in thiopurine metabolism in patients with inflammatory bowel disease. AB - BACKGROUND: There is a large interindividual variability in thiopurine metabolism. High concentrations of methylthioinosine-5'-monophosphate (meTIMP) and low concentrations of 6-thioguanine nucleotides (6-TGNs) have been associated with a lower response rate and an increased risk of adverse events. In this study, the role of inosine-5'-monophosphate dehydrogenase (IMPDH) for differences in metabolite patterns of thiopurines was investigated. METHODS: IMPDH activity and thiopurine metabolite concentrations were determined in patients with inflammatory bowel disease and a normal thiopurine methyltransferase (TPMT) phenotype and meTIMP/6-TGN concentration ratio > 20 (n = 26), in patients with a metabolite ratio <= 20 (n = 21), in a subgroup with a metabolite ratio <4 (n = 6), and in 10 patients with reduced TPMT activity. In vitro studies were conducted on human embryonic kidney cells (HEK293) with genetically engineered IMPDH and TPMT activities. RESULTS: Patients with metabolite ratios >20 had lower IMPDH activity than those with ratios <= 20 (P < 0.001). Metabolite ratios >20 were only observed in patients with normal TPMT activity. Downregulation of IMPDH activity in HEK293 cells was associated with an increase in the concentration of meTIMP (fold change: 17 up to 93, P < 0.001) but, unexpectedly, also of 6 thioguanosine monophosphate (fold change: 2.6 up to 5.0, P < 0.001). CONCLUSIONS: These data question the general view of IMPDH as the rate-limiting enzyme in the phosphorylation of thiopurines. Investigations of other mechanisms are needed to more fully explain the various metabolite patterns and outcomes in patients under treatment. PMID- 21311412 TI - Interleukin-13 protects mouse intestine from ischemia and reperfusion injury through regulation of innate and adaptive immunity. AB - BACKGROUND: Ischemia-reperfusion (I/R) injury is a major factor leading to intestinal dysfunction or graft loss after intestinal surgery or transplantation. This study investigated the cytoprotective effects and putative mechanisms of interleukin (IL)-13 after intestinal I/R injury in the mouse. METHODS: Mouse warm intestinal I/R injury induced by clamping the superior mesenteric artery for 100 min with tissue analysis at 4 and 24 hr after reperfusion. Treated animals received intravenous recombinant murine IL-13 (rIL-13) and anti-IL-13 antibody, whereas controls received saline. RESULTS: rIL-13 administration markedly prolonged animal survival (100% vs. 50% in saline controls) and resulted in near normal histopathological architecture. rIL-13 treatment also significantly decreased myeloperoxidase activity. Mice conditioned with rIL-13 had a markedly depressed Toll-like receptor-4 expression and increased the expression of Stat6, antioxidant hemeoxygenase-1, and antiapoptotic A20, Bcl-2/Bcl-xl, compared with that of controls. Unlike in controls, the expression of mRNA coding for IL 2/interferon-gamma, and interferon-gamma-inducible protein (IP)-10/monocyte chemotactic protein-1 remained depressed, whereas that of IL-13/IL-4 reciprocally increased in the mice treated with rIL-13. Administration of anti-IL13 antibody alone or in combination with rIL-13 resulted in outcomes similar to that seen in controls. CONCLUSIONS: This study demonstrates for the first time that IL-13 plays a protective role in intestinal warm I/R injury and a critical role in the regulation of Stat6 and Toll-like receptor-4 signaling. The administration of IL 13 exerts cytoprotective effects in this model by regulating innate and adaptive immunity while the removal of IL-13 using antibody therapy abrogates this effect. PMID- 21311413 TI - Antioxidant activities and polyphenolic contents of three selected Micromeria species from Croatia. AB - Antioxidant activities of three selected Micromeria species growing in Croatia (M. croatica, M. juliana and M. thymifolia) were evaluated using five different antioxidant assays, in comparison with plant polyphenolic constituents and reference antioxidants. All studied ethanolic extracts exhibited considerable activity to scavenge DPPH and hydroxyl free radicals, reducing power, iron chelating ability and total antioxidant capacity in the order: M. croatica > M. juliana > M. thymifolia. Total polyphenol (9.69-13.66%), phenolic acid (5.26 6.84%), flavonoid (0.01-0.09%) and tannin (3.07-6.48%) contents in dried plant samples were determined spectrophotometrically. A strong positive correlation between antioxidant activities and contents of phenolic acids and tannins was found, indicating their responsibility for effectiveness of tested plants. Our findings established Micromeria species as a rich source of antioxidant polyphenols, especially the endemic M. croatica. PMID- 21311414 TI - Flavonoids and the CNS. AB - Flavonoids are present in almost all terrestrial plants, where they provide UV protection and colour. Flavonoids have a fused ring system consisting of an aromatic ring and a benzopyran ring with a phenyl substituent. The flavonoids can be divided into several classes depending on their structure. Flavonoids are present in food and medicinal plants and are thus consumed by humans. They are found in plants as glycosides. Before oral absorption, flavonoids undergo deglycosylation either by lactase phloridzin hydrolase or cytosolic beta glucosidase. The absorbed aglycone is then conjugated by methylation, sulphatation or glucuronidation. Both the aglycones and the conjugates can pass the blood-brain barrier. In the CNS several flavones bind to the benzodiazepine site on the GABA(A)-receptor resulting in sedation, anxiolytic or anti-convulsive effects. Flavonoids of several classes are inhibitors of monoamine oxidase A or B, thereby working as anti-depressants or to improve the conditions of Parkinson's patients. Flavanols, flavanones and anthocyanidins have protective effects preventing inflammatory processes leading to nerve injury. Flavonoids seem capable of influencing health and mood. PMID- 21311415 TI - [Role of a mini-invasive approach in the diagnosis and treatment of tubo peritoneal infertility as an altenative to IVF]. AB - AIM: Tubal factor infertility accounts for approximately 25-35% of cases of female infertility. Identifiable causes of tubal infertility are postinfectious tubal damage, postsurgical adhesion formation, and endometriosis-related adhesions. Aim of this study was to evaluate the results of a diagnostic/therapeutic minimally invasive approach in patients with suspect or ascertained mechanical infertility in terms of obtained pregnancies. METHODS: The study enrolled 143 patients who underwent diagnostic or operative laparoscopy, with chromopertubation, peritoneal or endometrial culture, salpingoscopy when indicated and diagnostic or operative hysteroscopy. Nine patients with submucous intramural or multiple intramural fibroids underwent miomectomy by minilaparotomy following hysteroscopy and chromopertubation. Patients were contacted periodically by telephone to monitor the onset and outcome of pregnancy. The mean length of follow- up was 49 months (range: 11 to 118 months). RESULTS: Of the 152 patients considered in the study, 61 became pregnant (40%). Twenty-three pregnancies resulted in miscarriage, two in tubal pregnancy and one patient aborted after a diagnosis of Down syndrome. In total, 32% of the patients achieved a term pregnancy. CONCLUSION: The diagnostic/therapeutic mini-invasive approach allows women to become pregnant naturally and it is, therefore, an option for couples with ethical and religious concerns. The percentage of pregnancies is higher than after in-vitro fertilization. When efficacious, this approach allows additional spontaneous conceptions without renewed therapy and the course of pregnancy and the type of delivery will not differ from those in a normal population. PMID- 21311416 TI - Randomized controlled study on clinical efficacy of isoflavones plus Lactobacillus sporogenes, associated or not with a natural anxiolytic agent in menopause. AB - AIM: The aim of this paper was to evaluate the activity of magnolia bark extract added to isoflavones and lactobacilli in menopausal women with typical menopausal symptoms and concomitant borderline psychoaffective and/or sleep alterations, of severity not requiring a psychopharmacological therapy. METHODS: Menopausal women were enrolled in a multicenter, controlled, parallel-group study and randomized to E (isoflavones 60 mg + Lactobacillus sporogenes + calcium and vitamin D3 - Estromineral, Rottapharm Madaus) versus ES (magnolia bark extract + E - Estromineral serena) 1 tablet/night for 12 weeks. RESULTS: In 91 gynecological centers, 634 women were treated (300 with E and 334 with ES), mean age 53.1 years and Body Mass Index (BMI) 25.2 kg/m2; 28% were past hormone replacement therapy HRT users and 3.3% had had a previous breast cancer. Both treatments significantly reduced versus baseline the symptoms tested at 0, 4, 8 and 12 weeks. E and ES showed a similar efficacy on hot flushing, nocturnal sweating with awakenings, palpitations and vaginal dryness. ES was more active on insomnia, irritability, anxiety, depressed mood, asthenia and loss of libido. Woman's well-being and physician's final judgment were positive in >70% in both groups. The rate of adverse events was 1% with E (metrorrhagia, cramps and constipation) and 1.2% with ES (gastralgia, blood loss, constipation and breast tension). CONCLUSION: Isoflavones are effective in improving the classical menopause symptoms. The clinical activity of magnolia bark extract on the relevant psycho-affective symptoms, particularly anxiety, irritability and insomnia, was evident. ES in the mild psychical alterations that can occur in climacterium avoids to run the known dependence risks linked to psychopharmacological agents withdrawals. PMID- 21311417 TI - Recurrence of ovarian cyst after sclerotherapy. AB - AIM: The aim of this paper was to evaluate correlation between cyst recurrence and some cyst characteristics after sclerotherapy of non-neoplastic ovarian cyst with alcohol-erythromycin combination. METHODS: Fifty two cases of simple ovarian cysts were subjected to sclerotherapy with alcohol and erythromycin. Two patients were excluded due to suspicious cytologic result. All patients were followed-up monthly with color Doppler ultrasonography for over 12 months. Failure of procedure was considered if recurrent cyst diameter exceeds 5 centimeters detected by ultrasound. Cyst size, volume and color of aspirate, steroid hormone, and tumor marker levels of the cyst fluid were correlated to the recurrence rate. RESULTS: The fluid of cyst was serous in 32 cases and dark chocolate-colored in twenty cases. Cytological analyses of thirty cysts were acellular sediment, twenty were suitable with endometrioma and two were reported as suspicious. At 12 month follow-up, 12 cyst recurrences was detected. There was no difference in aspirated cyst volume, cyst size and FSH and LH content of recurrent and resolved cyst. The cyst wall thickness of recurrent cyst was higher than that of resolved cyst (P<0.001). The mean estradiol and progesterone concentrations of resolved cysts were significantly higher than that of recurrent cysts on the other hand, the mean CA125 levels in recurrent cysts (347.9+/-204.4) was significantly higher as compared to the mean CA125 concentrations of resolved cyst (16.75+/-22.45). CONCLUSION: Aspiration and sclerotherapy with alcohol and erythromycin yielded a relatively high recurrence rate in cyst with a bloody aspirate and high CA125 levels in cyst fluid. PMID- 21311418 TI - Transvaginal hydrolaparoscopy. AB - In 1998, Gordts et al. introduced the concept of transvaginal hydrolaparoscopy (THL) to explore the pelvic cavity through a vaginal incision using a saline solution medium. Several reviews have validated the concept of THL in comparison to the gold standard, i.e. laparosco-py. In a literature review of 187 patients from six studies including one prospective double blind trial, a high concordance was found between THL and laparoscopy ranging from 77.8% to 100%. In a review of 1516 THL, the rate of failure was 5.4% and linked to a retroverted uterus and the presence of adhesions. Another review of 1205 THL, revealed that complete exploration of the pelvis including analysis of both sides with visualization of ovaries and tubes was achieved in 88.3%. In a review of 4232 procedures from 10 studies, bowel injuries occurred in 0.61%. In a multicenter study, the incidence of bowel perforation was 0.65% and decreased to 0.25% after an initial learning experience of 50 THL: 92% of these bowel injuries were managed expectantly without consequences. In addition to diagnostic THL, the relevance of operative THL has been validated mainly for ovarian drilling for polycystic ovary syndrome. Despite the advantages of THL in terms of cost, reliability as compared to laparoscopy in detecting pelvic abnormalities and its superiority in detecting subtle lesions, as well as the feasibility of performing it under local anesthesia thereby contributing to the couple's participation, uptake of THL remains relatively low underlining the need to promote this minimally invasive procedure. PMID- 21311419 TI - [Proteomic applications in gynecology-obstetrics]. AB - Proteomics has recently emerged as a powerful approach both for discovering biomarkers as well as for understanding the physiopathology of unclear gynecological-obstetrical disorders. Currently, several biological fluids and fetal tissues were successfully tested, including maternal plasma, amniotic fluid, cervical-vaginal fluid, urine, saliva, placental trophoblast, amnio chorionic membranes and cord blood. The potential of proteomics on the polycystic ovary syndrome (PCOS) involves biomarkers discovery for a more accurate diagnosis of the syndrome and identification, within the patients with PCOS, those who respond more easily to treatment and those who will be at increased risk for future metabolic complications. The proteomic approach applied to patients with endometriosis would allow not only a non-invasive early diagnosis, but also a staging of the disease and a prediction of infertility risk. Proteomics also involves oncological field, in order to discover biomarkers that allow early diagnosis and prognosis of female genital malignancies. In addition to this, proteomics could be used to understand and predict obstetrical complications such as recurrent spontaneous abortion, preterm birth and preeclampsia. However, further studies are needed on a larger cohort of patients to introduce these biomarkers in clinical practice. PMID- 21311420 TI - [Prevention of postoperative abdominal adhesions in gynecological surgery. Consensus paper of an Italian gynecologists' task force on adhesions]. AB - Adhesions are the most frequent complication of abdominopelvic surgery, causing important short- and long-term problems, including infertility, chronic pelvic pain and a lifetime risk of small bowel obstruction. They also complicate future surgery with considerable morbidity and expense, and an important mortality risk. They pose serious quality of life issues for many patients with associated social and healthcare costs. Despite advances in surgical techniques, the healthcare burden of adhesion-related complications has not changed in recent years. Adhesiolysis remains the main treatment although adhesions reform in most patients. There is rising evidence, however, that surgeons can take important steps to reduce the impact of adhesions. A task force of Italian gynecologists with a specialist interest in adhesions having reviewed the current evidence on adhesions and considered the opportunities to reduce adhesions in Italy, have approved a collective consensus position. This consensus paper provides a comprehensive overview of adhesions and their consequences and practical proposals for actions that gynecological surgeons in Italy should take. As well as improvements in surgical technique, developments in adhesion-reduction strategies and new agents offer a realistic possibility of reducing adhesion formation and improving outcomes for patients. They should be adopted particularly in high risk surgery and in patients with adhesiogenic conditions. Patients also need to be better informed of the risks of adhesions. PMID- 21311421 TI - Social and ethical determinants of sexuality: gender and health. AB - The aim of this paper is to expand concepts of gender and explore how behaviours associated with sexual identity affect health risks, as well as the right to sexual expression for sexual minorities and persons with disabilities, to promote safe sexual behaviour and reduce the incidence of sexually transmitted diseases, through the internationally sanctioned Sexual and Reproductive Health concept. During the XX century the multiple meanings of sexuality have been progressively recognized and its physical and psychological health dimension have become a reality, enshrined in United Nations (UN) documents. Countries have begun to adapt their legislations to this new reality and Conventions today guarantee equal sexual and reproductive rights to persons with disabilities, while the nature of variant sexual behaviours is being debated. Sexual and reproductive health is today an acknowledged goal for every individual and the right to equality for persons with variant behaviours and disabilities, as well as the coexistence of diverse meanings of sexuality an established fact. Healthy and safe sexual behaviour should become an important goal for all societies and cultures. PMID- 21311422 TI - [Ischemic necrosis caused by sigmoid colon perforation in a patient with total vasculitis resulting from systemic lupus erythematosus: a case report]. PMID- 21311423 TI - [Parvovirus B19: unexpected epidemiology]. PMID- 21311424 TI - Neuropsychological assessment in prepubertal patients with congenital adrenal hyperplasia: preliminary study. AB - AIM: Individuals with congenital adrenal hyperplasia (CAH) provide a test population for the theory that elevated testosterone levels alter pre-/perinatal brain development. METHODS: Seven prepuberal girls with CAH and seven matched controls has been submitted to a neuropsychological evaluation. We measured abilities where gender differences repeatedly has been observed or that had earlier shown differences between CAH subjects and controls. The following cognitive functions were tested: general intelligence, attention, verbal and non verbal abilities, cerebral dominance for verbal and non-verbal material, frontal functions, peripheral dominance and motor fluency. Since several animal studies shown hippocampal morphological changes induced by prolonged hydrocortisone exposure, we also investigated memory functions. RESULTS: No differences were recorded between two groups on those abilities that are not sexually dimorphic. The mean general intelligence level of the patients was significantly lower than the controls', in agreement with previous studies. The verbal and non-verbal tasks revealed an age-related male-like pattern (i.e., verbal disadvantage) and an inversion of the hemispheric dominances. The latter observation was supported by a right-to-left shift of the peripheral dominances. The patients memory performances were all inferior to the controls'. The results are discussed in the light of possible hormonal influences. CONCLUSION: Our main findings support the hypothesis that elevated pre-/perinatal androgen exposure can influence some cognitive pattern of specific sexual dimorphic abilities in prepubertal subjects. PMID- 21311425 TI - Vitamin D status in a group of Spanish schoolchildren. AB - AIM: The aim was to determine the vitamin D status of a group of Spanish schoolchildren in order to help in the design of campaigns to prevent vitamin D deficiency in this subpopulation. METHODS: This was a cross-sectional observational study, carried out in schools in Madrid (Spain), during 2007-2008. The study enrolled 102 schoolchildren (aged 9-13 years). Vitamin D intake was monitored using a three-day food record. All foods consumed were converted into energy and nutrients and the vitamin D intake compared to that recommended. The children's serum 25-OH-cholecalciferol (25[OH]D) concentrations were also recorded. RESULTS: Vitamin D intake (2.83+/-3.27 mg/day) was below that recommended in 86.9% of the children, and the serum 25(OH)D concentration (49.6+/ 15.9 nmol/L) below 50 nmol/L (moderate deficit) in 51% of the children; in 8% it was below 30 nmol/L (severe deficit). The children who showed a coverage of at least 67% of the recommended intake of vitamin D (Group HD) consumed more dairy products, fish, fruit and vegetables than those whose intakes covered <67% of the recommended intake (Group LD). The HD children had higher serum 25(OH)D concentrations than the LD children; in addition, fewer cases of deficit were seen among them. CONCLUSION: The vitamin D status of the studied children was likely to improve, and could be ameliorated via a relatively increased consumption of dairy products, fish, cereals, fruits and vegetables, by including foods fortified in vitamin D if necessary, and by increased - but safe - exposure to the sun. PMID- 21311426 TI - Environmental exposure to endotoxin in rural and urban Egyptian school children and its relation to asthma and atopy. AB - AIM: The environmental exposure of farm children to micro-organisms in dust has been related to a reduced prevalence of asthma and atopy. The aim of this study was to evaluate the relation between settled dust endotoxin and development of asthma and/or atopy in rural and urban school children. METHODS: A comparative study was conducted on 40 rural and 40 urban school children (6-12 years). Parental self-reported allergic symptoms questionnaires were distributed. Forced expiratory volume in the first second (FEV1), forced vital capacity (FVC) were measured using MIR spirobank and FVE1% was calculated. Skin prick testing with the most common aeroallergens was performed. Limulus amebocyte lysate endotoxin content was measured in settled dust samples. RESULTS: The rural group which has higher exposure to farm animals and feeding on farm milk has less allergic symptoms. Rural students showed highly significant FEV1, FEV1% and significant FVC versus urban students (110.9+/-19.7, 103.8+/-12.2, 105.8+/-24.3 vs. 92.3+/ 24.2, 98.4+/-18.9, 92.7+/-23.2, respectively). Rural school dust contains significantly higher level of endotoxin (2-3 EU/mg) than urban school (0-0.1 EU/mg). Urban residence was associated with increase risk of asthma after age and sex adjustments ([ORadj], 5.16; 95% [CI], 0.95-28). CONCLUSION: Our results support the hygiene theory, i.e., endotoxin exposure could be protective to asthma and atopy in school children. PMID- 21311427 TI - Lipid profile, thyroid function, and serum magnesium level in type I diabetic children. AB - AIM: This study aim was to investigate the changes of lipid profile, thyroid function and Magnesium (Mg) level in type I diabetic children. METHODS: This descriptive cross-sectional stu-dy was done on fifty type 1 diabetes mellitus (T1DM) patients and fifty age-matched healthy children from Rafsanjan city, Iran. After completing questionnaire for demographic information, blood glucose, lipid profile, Mg, thyroid hormones, height, weight and waist circumference were measured. RESULTS: No significant differences between the groups in body mass index (BMI), waist circumference, lipid profile, and T4 level were found. The mean T3 and serum TSH levels in cases were significantly different from the control group (P=0.046 and P=0.039, respectively). The most of patients in both groups had serum Mg level more than 2 mg/dl with no significant difference. CONCLUSION: According to the results, there was a significant association between type I diabetes and serum TSH and T3 levels. Considering this finding, assessment of thyroid hormones in diabetic children is recommended. PMID- 21311428 TI - New adolescent polycystic ovary syndrome perspectives. AB - Polycystic ovary syndrome (PCOS) is a common but heterogeneous disorder that usually arises during puberty. This endocrine disorder is associated with chronic anovulation and hyperandrogenemia with clinical manifestation of oligomenorrhea, hirsutism and acne. While the underlying etiology of PCOS remains unknown, it is commonly associated with obesity and insulin resistance leading to increased risk of cardiovascular disease, dyslipidemia and type 2 diabetes mellitus in hyperandrogenemic phenotypes. Menstrual irregularities and insulin resistance in obese adolescents are usually indistinguishable from the clinical manifestations of PCOS and pose a diagnostic dilemma due to higher circulating androgens during puberty. Consequently, a universal consensus on the definition of hyperandrogenemia in adolescents has been elusive. Nevertheless, hyperandrogenemia, independent of obesity, in postmenarchal adolescents is associated with increased risk of cardiometabolic syndrome. Therefore, treatment strategies including lifestyle changes and/or use of insulin-sensitizers, hormone replacement and antiandrogens should be utilized in order to delay long-term cardiovascular and metabolic complications of this endocrinopathy. PMID- 21311429 TI - Fertility preservation in children and adolescents with cancer. AB - With excellent survival rates for individuals diagnosed with cancer during childhood or adolescence an awareness of quality of life, including fertility preservation is essential. Chemotherapeutic regimens that include alkylating agents and radiation treatments directed at the gonads or pituitary, including total body irradiation are particularly gonadotoxic. Assessment of potential for gonadotoxicity and appropriateness of fertility preservation techniques prior to the start of cancer directed therapies in every individual pediatric patient is crucial for limiting this late effect of therapy. Sperm banking for postpubertal males prior to the initiation of gonadotoxic therapy should be considered standard of care. Postpubertal females receiving highly gonadotoxic therapy that places them at risk of acute ovarian failure should consider embryo or oocyte cryopreservation prior to the initiation of therapy. Oocyte cryopreservation, as well as cryopreservation of gonadal tissue, whether ovarian or testicular, remain experimental and as such should be offered as part of a research protocol. Females who receive treatment that deplete their ovarian reserve should be evaluated for the development of premature menopause following their treatment. Embryo or oocyte cryopreservation post therapy may offer females at risk of premature menopause the opportunity to preserve their reproductive window. Further research clarifying gonadotoxicity of contemporary treatment regimens and improving interventions to preserve fertility are necessary to prevent infertility as a long term adverse effect of cancer treatment. The establishment of programs that streamline access to current fertility preservation techniques will assist in ensuring that all eligible patients can avail themselves of current options. PMID- 21311430 TI - Complete clinical recovery of a central pontine and extrapontine myelinolysis delayed onset in a child with acute myeloblastic leukemia. AB - Central pontine myelinolysis (CPM) is a demyelinating disease of the pons often associated with the demyelination of extrapontine areas of the central nervous system. It typically occurs 0.5-7 days after a rapid increment in serum Na level in hyponatremic patients and may lead to death. A 2.5-year-old child with a diagnosis of acute myeloblastic leukemia developed febril neutropenia, diarrhea, gastrointestinal hemorrhage followed by pulmonary aspergillosis. He could not tolerate enteral nutrition. He was given broad spectrum antibiotics and antifungal treatment. Laboratory tests showed electrolyte abnormalities including hyponatremia, hypokalemia and hypophosphatemia in a chronic course. Twenty three days after a rapid correction of hyponatremia (16 mEq/L/24 h) he revealed flask quadriparesis, disphagia, mutism, irregular respiratory pattern and loss of cough and gag reflex. Cranial magnetic resonance showed central pontine and extrapontine myelinolysis. He required mechanical ventilation and then he regained his neurologic functions. He completed chemotherapy protocol and underwent hematopoietic stem cell transplantation. After 2.5 years of the occurrence of CPM he is in completely normal physical and neurological status. CPM is a very severe but rare disorder in children with underlying disease. In the presence of multiple etiologic factors it may reveal a delayed onset and optimum outcome can be seen even in the severe clinical presentation with adequate intensive support. PMID- 21311431 TI - Dumping syndrome: an unusual cause of severe hyperinsulinemic hypoglycemia in neurologically impaired children with gastrostomy. AB - This paper describes severe hyperinsulinemic hypoglycemia during bolus enteral feeding in two neurologically impaired children. Both children were affected by dysphagia with swallowing difficulties; caloric intake was inadequate. For these reasons, percutaneous endoscopic gastrostomy had been positioned during the first months of life. In one patient due to persisting vomiting, after a few months, a gastrojejunal tube (PEG-J) was inserted. Hypoglycemia was revealed by routine blood tests, without evidence of specific symptoms. Continuous subcutaneous glucose monitoring showed wide glucose excursions, ranging from hypoglycemia to hyperglycemia. Extremely high levels of insulin were detected at the time of hypoglycemia. A diagnosis of dumping syndrome (DS) was suspected in both children. In the child with PEG, the tip of the gastrostomy catheter was found to be lying in the bulbus duodeni. Once this had been pulled back, hypoglycemic episodes disappeared. The child with PEG-J needed continuous enteral feeding to reach a normal glucose balance. DS is a relatively common complication in children with gastrostomy, but extremely irregular glucose levels, ranging from hypoglycemia to hyperglycemia, and increased insulin secretion had not been previously demonstrated. The incidence of DS is probably underestimated in children receiving enteral feeding for neurological impairment. In these patients intensive monitoring of blood glucose levels should be performed to calibrate meals. Repeated underestimated hypoglycemic episodes could worsen neurological damage and cause a deterioration in clinical conditions. PMID- 21311432 TI - Subacute sclerosing panencephalitis: a case report. AB - Subacute sclerosing panencephalitis (SSPE) is a progressive neurological disorder of childhood and early adolescence caused by persistent defective measles virus. Clinical manifestations appear many years after the acute measles infection. The incidence of SSPE has substantially declined after the introduction of an effective vaccine. We report a case of a child with SSPE that began with atonia, dysarthria, and intellectual deterioration without the presence of any particular EEG anomalies. We have reported this girl who was affected by this severe affliction in the hope that, because of the rarity of SSPE, it would not go undiagnosed. PMID- 21311433 TI - [Libero Martoni: The paediatrician who brought "Nelson" to Italy]. AB - Libero Martoni, director of the paediatric clinic in Bologna, brought the study of paediatrics to Italy and through an accurate and precise translation, introduced him to Italian paediatricians. Since 1955, the year of the first Italian translation, it has remained to today the fundamental text of paediatrics. It brought a remarkable contribution to the field of puericulture, hepatology and oncohematolgy, both in research and in manuals. PMID- 21311434 TI - [Peculiarities of protein Ki-67 expression in cases of leukoplakia and epidermoid cancer of oral mucous membrane]. AB - There were presented results of the study directed to disclosure of malignant cell changes criterion in cases of oral mucous membrane leukoplakia with different degrees of neoplastic transformation according to WHO-2005 classification of squamous intraepithelial neoplasia (SIN). With the help of immunohistochemical method proliferation in different layers of oral mucous membrane epithelium was evaluated. It was established that most important for diagnostics was the correspondence of proliferating cells in parabasal and basal epithelium layers. Figure less than 1 was corresponding to normal epithelium and SIN1, between 1 and 2 was corresponding to SIN2, 2 and more was characteristic itoSIN3. PMID- 21311435 TI - [Regulatory peptides influence on hypoxia induced tooth germ pathology of new born albino rats]. AB - Intrauterine hypoxia decreased the nucleolar organizator quantity in enameloblasts of newborn albino rats tooth germ. Influence the leu-encepgalin synthetic analog dalargin and non-opiate synthetic leu-encephalin on newborn rats from 2 to 6 day abolished the intrauterine hypoxia affect. The main mechanism of peptide antioxidant effect may be NO system stimulation. PMID- 21311436 TI - [Laser doppler estimation of the influence of tobacco-smoking on the blood microcirculation in the periodont at the patients with the different stages of periodontal diseases]. AB - Smoking appears to be one of the most significant risk factors in the development and progression of periodontal disease. Smoking is also a risk factor in the development of peripheral vascular diseases. Blood vessels in smokers are fewer and are subjected to stenosis. Clinically, it is well known that bleeding on probing, gingival exudates and redness and swelling in gingival sites of smokers are less than in non-smokers. According to previous studies, there is a relative increase in gingival blood flow immediately after smoking, while gingival blood flow itself is considerably decreased in healthy smokers in comparison with non smokers. In this investigation, we used laser Doppler flowmetry to study gingival microcirculation in smokers with light, moderate and heavy periodontitis in comparison with non-smokers with the same diseases. Our results show, that smoking decreases gingival blood flow in smokers with periodontitis comparing to non-smokers with periodontitis. Immediately after smoking there is an increase in gingival microcirculation. In 30 minutes we observed a marked decrease in gingival blood flow in all groups, followed by gradual restoration of blood flow rate, registered before smoking. This restoration took 1.5-2 hrs in group with light periodontitis, 2 hrs in group with moderate periodontitis and more than 2 hrs in group with heavy periodontitis. We suppose, that constant changes in blood supply of periodontal tissue caused by smoking may contribute to higher prevalence and faster progression of inflammatory periodontal diseases in smokers. PMID- 21311437 TI - [Development of new approaches for objective dental tissue characteristiss reproduction for preparation of highly aesthetical restoration]. AB - A new method of color quality control based on spectrophotometry has been developed for dental restoration. A comparative analysis of quality of subjective color control by trained and non-trained observers has been made. Based on comparative analysis of the results of subjective color-control and spectrophotometry the maximum amount of allowed color difference has been set (dE=2.8). PMID- 21311438 TI - [Polymorphism of IL1alpha and IL1beta genes and bacterial invasion in patients with chronic generalized periodontitis]. AB - Researchers studied polymorphism of IL-1alpha and IL-1beta genes among patients of different ages with severe chronic generalized periodontitis and people with healthy periodontium. The study demonstrated a correlation between high frequency of genetic polymorphism in IL-1alpha -899 and IL-1beta +3953 loci and development of severe periodontitis among patients less than 35 years of age, as well as markers of P. intermedia, T. denticola, HSV1 and EBV in periodontal pocket. PMID- 21311439 TI - [Comparative analysis of "lipid peroxidation-antioxidant protection" system status in saliva of patients with slight and moderate stages of chronic parodontitis]. AB - The comparative analysis of "lipid peroxidation-antioxidant protection" system status (LP-AOP) in mixed saliva of patients with chronic periodontitis (CP) of a mild (n=90) and moderate (n=42) stages was performed. It was established that CP in a moderate stage of severity was characterized by the content decrease of isopropanol dissolved products of LP in saliva with simultaneous worsening of periodontal and affected status in comparison with CP of a slight stage. Correlation analysis of integral cohort of patients (n=132) demonstrated the AOP enhancement due to the increase of ceruloplasmin concentration in the saliva as periodontal disorders was aggravated. It appeared that adaptive enhancement of AOP in progressing CP caused the limitation of LP and restrains the escalation of CP-associated affective disorders. PMID- 21311440 TI - [Clinical laboratory approaches to parodontitis treatment optimization]. AB - In order to determine cycloferon liniment clinical-pathogenetic efficacy in comprehensive parodontitis therapy examination and treatment of 80 patients was done. It was determined that the cycloferon liniment use in comprehensive treatment of patients with parodontitis let to reduce infectious load in parodontal pockets and local inflammation intensity, to normalize the secretory immunoglobulin level and immune status indices that provided speed up of healing process and reduction relapse frequency. PMID- 21311441 TI - [Endodontic treatment quality analysis according to the computer tomography data]. AB - Endodontic treatment quality of different teeth groups was analysed according to computer tomography data. 1000 dental root canals of 521 teeth of 115 patients of different age groups were studied. The study results testified to low level of endodontic treatment quality. In 71.7% of cases instrumental processing and obturation of dental root canals were fulfilled inadequately. The most often mistake of endodontic treatment was insufficient root canals instrumental processing (62.8%). PMID- 21311442 TI - [Influence of thyroid gland function status upon reaction of hard dental and periodontal tissues on chronic stress]. AB - In experiments on 190 adult male Wistar rats it was established that at chronic stress (the congested housing of animals during 3 months) the status of marginal periodontal tissues and hard dental tissues (degree of gum recession, atrophy of alveolar bone, teeth mobility; enamel acid resistance) depended upon the organism thyroid status: hypothyroidism (intragastric introduction of mercazolil in the of 12 mg/kg body weight during 14 days, then in half dose up to the end of the experiment) increased intensity of stress disturbances whereas small L-thyroxin doses (5-8 MUg/kg body weight intragastrally during 28 days after that in half dose) essentially limited them. PMID- 21311443 TI - [Use of KollapAn L in cases of maxilla alveolar ridge trauma]. AB - Results of research have shown, that application KollapAn L at the fracture site of an alveolar ridge of upper jaw raises efficiency of treatment and reduces complications up to 20%. PMID- 21311444 TI - [Use of fiber laser scalpel with wave length 1.9 um in outpatient surgical stomatology]. AB - Fiber laser is used successfully in surgical stomatology in treatment of oral soft tissues diseases due to its merits: coagulation effect, painless postoperative period, etc. PMID- 21311445 TI - [Comprehensive approach to treatment of patients with teeth-jaws anomalies accompanied by nose functional disturbances and esthetic deformations]. AB - Problem of medical rehabilitation of patients with teeth-jaws anomalies accompanied by nose functional disturbances and esthetic deformations was viewed. Method of comprehensive reconstructive intervention on facial cranium was presented allowing to restore correct jaws relationship to cranium base. Correction of nasal and endonasal structures was performed, functions of nasal breathing and esthetic face parameters as a whole were restored. Comprehensive approach to planning and carrying out surgical treatment let to receive high esthetic and functional results. PMID- 21311446 TI - [Quality of life in patients with total and subtotal auricle defects after burns]. AB - Auricle defects elimination is an actual problem of maxillofacial surgery because an auricle has complex 3-dimensional anatomic structure and its loss (partial or full) produces psychological discomfort in any patient and can even led to social disadaptation. The most complicated problems were the patients with spacious after burn neck and face deformations who demonstrated the lowest results during talks and when different methods were used. Besides the psychological techniques we used test questionnaire SF36. The results of the checkup testified to difficulties of social and personal adaptation in such patients and need in additional methods of their life quality increase and advisability of bringing in their adaptation specialists of adjacent medical areas, psychotherapist and clinical psychologists. PMID- 21311447 TI - [Prevalence of secondary deformities of dentition and diseases of temporomandibular joint in the population of Far East]. AB - Epidemiological survey of 1161 indigenous people (I group) and 1000 people came (II group) of the population of Far East in the age over than 20 years was conducted. Established that the deformation of dentitions at diagnosis was found in 22.13% I group, 20.1% II group, reduced occlusion in 15.84% (I group) and 11.0% (II group). Pathology of the TMJ was defined at 8.68% of men and 26.15% of women in group I, 8.24% men and 30.04% of women in group II. PMID- 21311448 TI - [Comparative analysis of soft tissue of the face in men and women]. AB - Comprehensive cephalometric analysis of "normal" adults was accomplished by examining 67 adults with normal bite. The purpose of this study was to compare the sexual distinctions of soft profile of the face. PMID- 21311449 TI - [Comparative characteristic of sociologic study results in the field of orthodotia during the period from 2004 to 2009 (monitoring study)]. AB - Monitoring of the results was carried out including own sociologic study in the field of orthodotia during the last 6 years. The investigation was done with the help of standardized specially developed questionnaire form reflecting the questions connected with orthodontic help appealability and population motivation to receive it. The received data let to evaluate in dynamics the orthodontic service status and prospects of its development. PMID- 21311450 TI - [On the expert assessment of undesirable outcomes of rhinoplasty]. AB - The Expert Commission of the Institute of Plastic Surgery and Cosmetology has undertaken comparative analysis of complaints over poor quality of the surgical treatment for the correction of nasal deformities from the patients operated during the periods of 2001-2003 and 2004-2006. The analysis has demonstrated that the frequency of undesirable outcomes of rhinoplastic interventions remains rather high. The majority of the aesthetically unacceptable postoperative deformations are usually due to technical errors during surgery. It is concluded that systematic analysis of the causes leading to professional mistakes and unfavourable outcomes of the surgical treatment is needed to collect data necessary for the development of measures for their prevention. PMID- 21311451 TI - [Endonasal surgery of choanal atresia]. AB - This paper was designed to study clinical manifestations of choanal atresia (CA) in 11 patients with a view to optimizing methods for medical and diagnostic management of this severe pathology using endonasal surgical techniques. Detailed analysis of possible causes of congenital CA and mechanisms of acquired CA was performed using computed tomography (CT) and retrograde endoscopy with the help of rigid optics. Potential of certain instruments designed and manufactured in Russia for the management of CA is demonstrated, such as retrograde 110o Sekunda endoscope and silicone horseshoe-shaped protectors. An original diagnostic algorithm is proposed allowing for the development of indications for surgical intervention, determination of its extent, and the choice of the post-operative treatment. Improved surgical instruments have been designed for the purpose. A case of hereditary CA in a child and his mother are presented along with results of treatment of nasopharyngeal scleroma in two patients. Clinical manifestations of CA concomitant with scleroma, diphtheria, and chemical chaonal burns are considered. PMID- 21311452 TI - [Vegetative adaptation in children presenting with chronic adenoiditis]. AB - Publications reporting the comprehensive analysis of the psychovegetative status in children with chronic adenoiditis are practically lacking in the literature. The objective of the present work was to study the functional state of the vegetative nervous system (vegetative nerve tone, vegetative reactivity, and vegetative regulation of vital activity) and manifestations of vegetative disorders in the clinical picture of chronic adenoiditis in preschool children. PMID- 21311453 TI - [The level of endothelin-1 in blood serum and nasal secretion of patients presenting with chronic rhinitis]. AB - The level of endothelin-1 (ET-1) in blood serum and nasal secretion was simultaneously determine by the relevant immunoenzyme assay in 23 of patients presenting with chronic rhinitis and in12 healthy subjects. It was shown that both vasomotor and chronic hypertrophic rhinitides are characterized by a similar (two-fold) rise in the serum ET-1 concentration. The six-fold increase of the ET 1 level in nasal secretion in chronic hypertrophic rhinitis compared with the respective normal parameter exceeds that in the vasomotor form of this pathology. PMID- 21311454 TI - [Spontaneous and provoked nystagmus in healthy subjects: on the so-called "vestibular" form]. AB - A total of 25 healthy subjects were available for the study of provoked nystagmus using a series of vestibulometric functional tests affecting different component of the vestibular system. The study has demonstrates the high diagnostic value of provoked nystagmus and the importance of a series of vestibulometric functional tests as a tool for the evaluation of vestibular reactivity. Provoked nystagmus was documented in 3 cases using the full series of functional tests and was absent in 9 cases under the same conditions. It is concluded that observation of provoked nystagmus in individual tests reflects its etiology whereas its occurrence in the entire series of these tests suggests diagnosis of latent vestubular dysfunction. PMID- 21311455 TI - [Oropharyngeal candidiasis in the practical work of the otorhinolaryngologist]. AB - Mycotic diseases are ubiquitous pathologies. Candidiasis frequently affects oral and pharyngeal mucosa (oropharyngeal candidiasis). The immunodeficiency conditions are the key factors responsible for the development of mycoses. Colonization of pharyngeal mucosa by yeast-like fungi is a frequent consequence of local and systemic antibacterial therapy. Clinical manifestations of ENT diseases caused by microscopic fungi depend on the localization of the pathological process. Mycotic lesions in the pharynx are especially often caused by fungi of the genus Candida. Mild cases are possible to manage by the local treatment. Severe infection refractory to local therapy and characterized by regular relapses require systemic antimycotic agents to be applied. The application of fluconazole is generally accepted to be the method of choice for the elimination of different strains of Candida. PMID- 21311456 TI - [The incidence of chronic purulent otitis media and the treatment of this pathology in Moscow]. AB - Analysis of medical appealability of adult subjects in outpatient clinics of Moscow during the last 5 years (2003-2008) has demonstrated a tendency toward the increased incidence of ear diseases and mastoid process lesions as well as the concomitant decrease of the incidence and prevalence of chronic purulent otitis media (CPOM). Accordingly, the surgical activity in specialized otorhinolaryngological facilities has grown up to 8.9%. Treatment of chronic purulent otitis media accounts for 47.5% of this value. 26.4% of the patients presenting with CPOM undergo hearing-saving operation on the middle ear and sometimes classical radical surgery. Patients with CPOM account for 41.1% of their total number in surdological departments. Treatment by hearing-preserving surgery on the middle ear is given in surdological departments to only 13% of the patients presenting with CPOM. In the departments for urgent otorhinolaryngological aid, patients with chronic purulent otitis media constitute 4.4% of the total and 45% of them undergo sanitizing hearing preserving surgery on the middle ear (including extensive interventions in the cases developing complications). PMID- 21311457 TI - [On certain aspects of the problem of chronic tonsillitis]. AB - Based on the current literature data and the results of original studies on the role of non-infectious (atopic) allergy in pathogenesis of chronic tonsillitis (CT), the author considers it unjustified under the current state of the art to characterize CT as an infectious allergic disease. He maintains that the classification of chronic tonsillitis proposed by Preobrazhensky and Pal'chun remains the most acceptable one for the practical purposes. PMID- 21311458 TI - [The speaking fundamental frequency and the singing voice type]. AB - The objective of this study was to determine the speaking fundamental frequency (SFO) in professional opera singers and its dependence on their voice type, if any. A total of 75 persons were available for observation using a special computer clinical program. Male voices were categorized into three groups (viz, tenor, baritone, and bass), female ones into 2 groups (soprano and mezzo soprano). It was shown that borderlines between SFO types varied within a wide range in all study groups. Significant differences in SFO were documented between tenors, baritones, and basses and between sopranos and mezzo-sopranos; the differences were insignificant between baritones and basses. It is concluded that the speaking fundamental frequency depends on the type of the singing voice; however this characteristic may serve only as an auxiliary tool but can not be used for the classification of singing voices. PMID- 21311459 TI - [Computer-aided techniques for the treatment and rehabilitation of patients suffering vertigo and balance disorders]. AB - A new computerized method is proposed for the correction and elimination of undesirable illusory sensations (dizziness), vestibulo-oculomotor (nystagmus), and vestibulo-postural (imbalance) reactions. The method allows to teach the subject about how to avoid generalization of afferent signals over the effector mechanisms in the central nervous system by developing a fixational reflex employing delayed biological feedback for the assessment of efforts being exerted (self-control of training results). Three variants of application of this technique were evaluated depending on the type of stimulation software intended to induce illusory and oculomotor reactions of a defined sensory modality (visual, vestibular or combined). The study involved 30 subjects divided into three groups. They had been taught using the visual (group 1), vestibular (group 2) or combined (group 3) methods. Each group was comprised of an approximately equal number of subjects with vestibulopathies of either peripheral or central origin. The study demonstrated that the proposed approach allows to invoke, with the use of a computer stimulation software, abnormal illusory and vestibulo oculomotor responses and inhibit them by developing the adequate fixational reflex. Comparative analysis of the results obtained by teaching the patients with the help of the three different methods revealed the dependence of their effectiveness on the level of disturbances in the vestibular system. The visual method of correction proved to be especially efficacious for the patients with peripheral vestibulopathy, and the vestibular methods for the patients with central vestibulopathy. Patients with combined peripheral and central vestibulopathy required the choice of training modalities (either visual or vestibular) on an individual basis. PMID- 21311460 TI - [Advantages and disadvantages of the application of endoscopic techniques at different stages of tympanoplasty]. AB - The objective of this work was to evaluate advantages and disadvantages of selected tympanoplastic stages under the endoscopic control during the surgical treatment of 93 patients presenting with chronic otitis media. The endoscopic techniques has indisputable advantages over traditional surgical microscopy when applied to elucidate the character and extent of the pathological process in the middle ear. This method allows to reveal granulation and cholesteatoma in difficult of access pockets and folds of the middle ear without enlargement of the extent of surgical intervention, to evaluate the "continuity" of the chain of auditory ossicles, etc. At the same time the use of an endoscope during performance of the majority of tympanoplastic procedures creates some difficulties related to the necessity of regular cleaning of the instrument and the impossibility of application of the bimanual technique. PMID- 21311461 TI - [Certain peculiarities of rhinoseptoplasty in children]. AB - This paper reports the results of examination and treatment of children presenting with deviation of the nasal septum. All of them underwent septoplasty simultaneous with rhinoplasty, vasotomy of inferior nasal concha, and correction of bullous middle nasal concha (if indicated). It is recommended that the data obtained be taken into consideration during rhinoseptoplastic surgey in children. PMID- 21311462 TI - [Application of a hemostatic glue for the prevention of intra- and postoperative complications of septoplasty]. AB - The authors describe the application of a hemostatic glue between the mucoperichondrial layers for the prevention of development of nasal septum hematoma and other possible complications of septoplasty. Analysis of the efficiency of the treatment of 30 patients by septoplasty with intraoperative application of the hemostatic glue has demonstrated the possibility of its use during surgery on the nasal septum. PMID- 21311463 TI - [The role of X-ray computed tomography in the detection of metastatic lesions in the regional lymphatic nodes in patients presenting with primary diagnosis of laryngeal and laryngo-pharyngeal cancer]. AB - The objective of this study was to evaluate the clinical significance of X-ray multispiral computed tomography with the use of internal contrast for the clinical diagnostics of metastatic lesions in the regional lymphatic nodes of patients presenting with primary diagnosis of squamous cell cancer of the larynx and laryngopharynx. A total of 78 patients with laryngeal cancer and 22 with the primary diagnosis of laryngo-pharyngeal cancer were examined by X-ray computed tomography that revealed metastatic lesions in the regional lymphatic nodes. A detailed description of the most characteristic metastatic lesions is presented, viz. (1) active accumulation of the contrast agent in the peripheral parts of the lymph nodes, (2) the presence of a central necrotic zone, (3) the indistinct outer contour of the affected lymphatic nodes, and (4) compaction of the fatty tissue surrounding them. The use of computed tomography allowed localization of the affected nodes to be correctly determine in all the examined cases. Moreover, the method made it possible to evaluate the extent of the carcinogenic process and its clinical stage. PMID- 21311464 TI - [Transnasal wounds of the base of the skull encountered in the practical work of the otorhinolaryngologist]. AB - The authors describe rare clinical observations of patients suffering transnasal injuries to the base of the skull. Based on their own experience, they propose practical recommendations for the management of such cases. PMID- 21311465 TI - [Treatment and prevention of thromboembolism in patients with intracranial hemorrhage]. AB - Frequency of venous thromboses and thromboembolic complications was retrospectively analyzed in 95 patients with intracranial hemorrhage of various etiology. Thrombosis of inferior caval vessels was registered in 19 (20%) patients; of them 3 patients had thromboembolism of a pulmonary artery, lethal in one case. The high frequency of venous thromboses indicates the necessity of early use of anticoagulants in treatment dosages and importance of the prophylaxis measures. Cava-filter implantation for pulmonary artery thromboembolism prevention should be considered only in patients with strong contraindications for anticoagulant therapy. PMID- 21311466 TI - [Diagnostics and treatment of posttraumatic septic costal osteomyelitis]. AB - Results of treatment and diagnostics of 47 patients with posttraumatic septic costal osteomyelitis were analyzed. 26 patients had open and 21 - closed thoracic injuries. Major reasons of osteomyelitis tended to be the initial infection of the bony injury, pleural surgical revision through the initial wound and late medical help by the closed thoracic injuries. Osteomyelitis was diagnosed with the help of and X-ray examination in 14,9%, multispiral computed tomography was informative in 48,4% and scintigraphy demonstrated bone destruction and inflammation in 96,8% of cases. With no depandance from the type of an injury, the most frequent infectious agents were the Staphylococcus aureus (51,2%) and Pseudomonas aeruginosa (32,5%). Conservative treatment was successful in 26,9% after open injuries and in 42,9% of the blunt thoracic trauma. Wide costal resections were conducted in 73,1% and 52,4% of patients with open and closed injuries, respectively. PMID- 21311467 TI - [Laser photodynamic therapy of septic wounds]. AB - Two comparable groups, 60 patients in each, were included in the study. Localization and area of the wounds, as well as basic treatment were equal in these groups. Patients of the main group received the additional photodynamic therapy with chlorine photosensibilizing agent. It led to the shortening of the wound clearing time and stimulation of the epithelisation together with fast decrease of bacterial load. Morphologic analysis showed faster inflammation decrease and granulation as well as lesser microcirculatory disorders in wounds treated with photodynamic therapy. Moreover, cicatrixes were more elastic and gentle in these patients. PMID- 21311468 TI - [Simultaneous laparoscopic cholecystectomy and gynecologic operative procedures]. AB - Treatment results of 64 patients who had simultaneous laparoscopic cholecystectomy and gynecologic surgery were compared with treatment results of 66 patients after simultaneous laparoscopic cholecystectomy and gynecologic surgery, performed through laparotomy. The influence of carboxyperitoneum on central hemodynamics and terms of its normalization, time of patients' recovery and number of complications were thoroughly studied. Simultaneous laparoscopic surgery proved to be more preferable, allowing manipulations on different levels of the abdominal cavity, lower operative stress, earlier patient activization, better esthetic effect and economic profit. PMID- 21311469 TI - [The immune system disorders by the adhesive abdominal disease]. AB - State of the immune system was analyzed in 30 patients with the adhesive abdominal disease in long postoperative terms out of the attack of the disease. Survey had demonstrated certain disorders in both cell and humoral immune systems. Strong decrease of immunoglobulins G and A, T-lymphocytes and neutrophilic phagocytic activity were registered. Thus, the use of agents, activising T- and B-cell immunity should be considered in patients with the adhesive abdominal disease. PMID- 21311470 TI - [Minimally invasive surgical accesses for the treatment of the acute cholecystitis]. AB - The 3-year experience minimally invasive surgery for the treatment of the acute cholecystitis was summarized. Criteria of the access choice and terms of surgery were substantiated. Treatment tactics of the acute cholecystits with the use of minimally invasive surgery were outlined, which allowed to decrease the rate of unreasonable "open" operations. PMID- 21311471 TI - [Prognostic value of peroxidase and antioxidant systems in patients with sterile pancreonecrosis]. AB - The submitted survey is based on the analysis of results of conservative and surgical treatment of 123 patients with sterile pancreonecrosis in the view of a complex estimation of intensity of infringement of peroxidation and antioxidation. The research specifies the role of independent predictors of inflammation in a complex estimation of the disease severity and complications possibility after surgery. PMID- 21311472 TI - [Prognostic factors in the treatment of the bile duct injuries and strictures]. AB - To describe the prognostic factors after surgical reconstruction data. were collected prospectively on 60 patients treated at the Scientific Center of Surgery named after M.Topchubashov and N5 City Hospital with major bile duct injuries and postoperative bile duct strictures between 2000 and 2009. Of the 60 patients 21 had bile duct injuries, other 39 had postoperative strictures. In 15 of 53 patients with iatrogenic injury of bile ducts trauma was recognized and repaired intraoperatively. In 22 patients was early, in 16 patients delayed recognition of bile duct injury. Most of patients had undergone a choledocho (8) or hepaticojejunostomy (33) by Roux. External drainage of bile ducts was performed in 24 patients. Of the 60 patients undergoing surgical reconstruction, 47 hud completed treatment. Of patients who had completed treatment, 82,9% were considered to have a successful outcome (24 patients excellent, 15 patients - good results) without the need for follow-up invasive, diagnostic, or therapeutic interventional procedures. Patients with reconstruction after injury or stricture without external drainage had a better overall outcome (92,9% successful outcome) than patients with drainage of bile ducts (68,4% successful outcome). Number of stents and length of postoperative stenting also were significant predictors of outcome. Type of operation (laparoscopic or open cholecystectomy) had nd significant influence on outcome. At the same time a successful outcome, without the need for biliary stents, was obtained in 87,5% of patients after laparoscopic cholecystectomy versus 71,8% after open cholecystectomy. PMID- 21311473 TI - [The new method of the acute appendicitis diagnostics]. AB - The original method of the acute appendicitis diagnostics (the "throw" symptom) has been worked out and checked up on 61 patients. The informativity of the symptom is up to 94-100%. Depending on the localization of the appendix and severity of the disease. Statistical analysis proves that the "throw" symptom is a new independent symptom of the acute appendicitis. PMID- 21311474 TI - [Surgical hemostasis by liver and spleen traumas]. AB - Various methods of surgical hemostasis by liver and spleen traumas were described. Liver and spleen ruptures were modeled in vivo using 135 experimental animals (dogs). Definitive hemostasis was achieved by spleen resection in 69 (78,4%) and liver resection in 22 (71,0%) animals. The suggested suturing technique and surgical algorithm was successfully clinically applied. PMID- 21311475 TI - [Treatment of esophageal varices bleeding with the use of transformable probes]. AB - Construction of the original transformable esophageal probe is thoroughly described. The innovated construction suggests lesser traumatisation by insertion and spiral expansion, together with secure compression hemostasis. Unlike the traditionally used obturating Blackmore probe, the spiral transformable original construction leaves the esophageal lumen open for further endoscopic hemostatic procedures. The feature provides exclusive advantages of the original construction. PMID- 21311476 TI - [New techniques of abdominoplasty]. AB - Treatment results of 34 patients with deformations of the anterior abdominal wall were prospectively analyzed. Liposuction above the umbilical level was applied as the first stage of the operation, which was the key feature of the new method. It permitted the increased mobility of the abdominal flap and allowed avoiding the flap dissection. The preliminary liposuction led to less intraoperative trauma and, as a result, decreased the number of complications and easened postoperative rehabilitation of the patients. PMID- 21311477 TI - [The role of ischemic-reperfusion syndrome in critical state pathology]. AB - Pathogenetic parameters of abdominal and mesenchymal sepsis, traumatic and burn shock, acute pancreatits, ischemic-reperfusion syndrome by renal transplantation, blood flow restoration by reconstructive cardiac surgery, critical limb ischemia in patients with obstructive vessel diseases etc., such as endotoxicosis, cytokinemia, biochemic changes, laser Doppler flowmetry indexes and morphologic signs of tissue necrosis were analyzed. The study proved the pathophisiological universatility of ischemic-reperfusion syndrome as a generated evolutionally and genetically encoded response to superagression, such as iatrogenic blood flow restoration. PMID- 21311478 TI - [New methods of surgical correction of the puerperal anal sphincter insufficiency]. AB - Treatment results of 612 patients aged from 17 to 71 years, with benign perineal diseases were analyzed. The rectovaginal fistula was diagnosed in 84 (13,7%), puerperal anal sphincter insufficiency - in 88 (14,4%) and rectocele was diagnosed in 139 (22,7%) of patients. 237 (38,7%) cases of perineal ruptures were analyzed retrospectively and 64 (10,5%) acute ruptures were analyzed prospectively. The suggested modified levatoroplasty includes the dissection of the proper fascia of the puborectal muscle, followed by the placation of the anterior muscle wall of the rectum and the posterior fascial sheet. After secure fixation of the first suture line, the second line sutures are applied on muscle tissue using monofilament resorbable material. The third line of the sutures connects anterior sheets of the proper fascia of the levators. Long-term follow up results were obtained in 80 (95,2%) of the operated patients. 63 patients reported excellent results, sphincter function had improved in 15 patients and operation had no effect in 2 cases. PMID- 21311479 TI - [Levels of S100beta protein in patients with mild traumamic brain injury]. AB - The prospective study of plasma S100beta protein levels in 19 patients with mild traumamic brain injury treated with conservative methods was carried out. The S100beta protein levels were measured on the admission of the patient and after 24 and 48 h. The level of S100beta increased above normal values (>0,105 mkg/l) in 11 patients (58%) in the first 6 h after the trauma. The CT analysis revealed brain matter lesions in 8 patients (42%), MRI - in 11 (58%) cases. The increase of baseline S100beta levels above normal values was found in all patients with brain matter lesions seen in CT and in 27% of patients with the normal CT. CT revealed brain lesions in 73% and MRI in 100% of patients with mild traumamic brain injury and increased plasma S100beta levels. There was no correlation between the S100beta level and the type of brain lesion, its localization or volume and the fracture of cranial bones. Also, no correlation was found between S100beta levels and EEG changes (p>0,05). PMID- 21311480 TI - [Psychophysiological disturbances in attention-deficit hyperactivity disorder in adolescents]. AB - We have studied 128 adolescents, aged 15-16 years, with attention-deficit hyperactivity disorder (ADHD) using clinico-psychopathological, psychometric and electroencephalographic methods. Taking into account the age dynamics, the following components of ADHD have been singled out: motor (impulsivity hyperactivity), subjective-cognitive (attention deficit) and somato-autonomic. The significance of subjective-cognitive disturbances, along with neurophysiological dysfunction, in the ADHD pathogenesis has been proved. Quantitative (productivity deficit) and qualitative (concentration deficit) disorders have been assessed. Author substantiated the deficit of emotional motivational self-regulation measured by the M. Luscher test and the Self assessment scale. The specific for ADHD pattern of alpha-rhythm reactivity has been found in EEG. PMID- 21311481 TI - [Autonomous component in cervicocranial pains and grounds for its pathogenetic treatment]. AB - An analysis of an autonomous component of the pain syndrome has been performed in 484 patients with neck and head pain syndromes. The frequency of autonomous disorders in this cohort reaches 84,7%. Autonomous dysregulation in different nosological groups as assessed with the A.M. Vein questionnaire was seen in all types of pain syndromes but was most distinct in cases of migraine, cervicogenic headache, headache of tension and trigeminal neuropathy. The data obtained suggest the deficiency of brain regulatory mechanism functions responsible for adaptation of the organism to external and internal changes and explain, in large, signs of maladaptation in patients with cervicocranial pain syndromes. The use of vegetotropic drugs in the complex therapy of neck and head pain is pathogenetically substantiated. PMID- 21311482 TI - [Long-term dyskinetic remissions in shift-like schizophrenia]. AB - The study sample included 32 patients with long-term remissions (from 5 to 33 years) developed after episodes of shift-like schizophrenia with catatonic disorders. All patients showed a good social and professional adjustment. This type of remissions was designated as "dyskinetic" due to the predomination of motor disturbances, microcatatonic symptoms of stupor and excitement. The diskinetic remission was characterized by stereotype urge to act, psychomotor passivity and decompensation "catatonic reactions". Two types of dyskinetic remission were singled out: hyper- and hypokinetic. Their psychopathological structure was defined by the hypersthenic defect including "the monotonous activity and the rigidity of the affect" in the first type and "irritable asthenia" in the second one. The hypothesis was developed: catatonic symptoms included to the structure of mentioned types of defect. PMID- 21311483 TI - [Efficacy of pantogam in the treatment of hyperkinetic disorders in children]. AB - We have analyzed the efficacy of nootropic drug pantogam in the treatment of hyperkinetic disorders in children aged 6-12 years. The results of the randomized placebo-controlled trial demonstrated the decrease of major symptoms of hyperkinetic disorders (inattention, hyperactivity, impulsivity), comorbid mental and behavior disorders, the improvement of cognitive functions in the group of children treated with pantogam during 6 weeks and the absence of significant changes in the placebo group. It has been concluded that pantogam is effective in the treatment of hyperkinetic disorders in children. PMID- 21311484 TI - [Efficacy of cytoflavin in patients in the acute ischemic stroke]. AB - We present the results of a multicenter study on efficacy of cytoflavin in the treatment of patients with acute ischemic stroke. Seventy patients (41 of the main group and 29 of the control group) were enrolled in the study. All patients received basic therapy aimed at improving systemic hemodynamics, rheological blood properties and at the prevention of stroke complications. Patients of the main group were treated with cytoflavin as follows: days 1-10 - 20 ml (in 400 ml of the 0,9% NaCl solution) twice a day intravenously in drops; days 11-35 - 850 mg twice a day. We assessed the dynamics of restoration of lost functions (NIHSS, the Rankin scale, the Barthel index) and volumes of ischemic lesion (MRI T1-, T2 , diffusion-weighted images). Results of the study on patients of the control group were supplemented with literature data about 306 patients studied using clinical scales and 40 patients studied with MRI. We revealed a trend towards an effect of cytoflavin on the preservation of brain matter in the acute phase of stroke. Cytoflavin reduced the neurological deficit and improved activities of daily living in patients that may be explained by the less brain damage. PMID- 21311485 TI - [Akatinol memantine in patients with vascular cognitive disorders]. AB - Treatment of cognitive disorders developed in cerebrovascular pathology is an actual medical problem. Of great importance is the timed diagnosis of these changes in the earlier phases of the development of cognitive deficit as well as adequate therapy that can delay and prevent the development of such complication as dementia. Pathogenetic mechanisms of cognitive disorders are associated with brain vascular and neurodegenerative changes that determine using drugs with vasoactive, metabolic and/or neuromediator effects. Memantine (the active component of akatinol memantine) is a drug that exerts an effect on the glutamatergic system, a non competitive antagonist of NMDA-receptors. The results of studies on the efficacy of this drug in moderate cognitive disorders are inconsistent and the amount of research is small. The present study aimed at the evaluation of changes of neuropsychological parameters in patients with moderate cognitive impairment caused by cerebrovascular pathology who were treated with memantine compared to the control group. Results of randomized open study suggested a significant clinical efficacy of akatinol memantine in the treatment of patients with vascular cognitive disorders. The treatment with akatinol memantine in dose 20 mg/day (10 mg twice a day) during six months significantly reduced cognitive deficit. The most distinct dynamics was related with ideation praxis, visual-spatial and speech functions, word selection, storage of instructions, increasing of volume of audio-speech and visual memory. PMID- 21311486 TI - [Effect of glatiramer acetate (copaxone) on the structure and functions of the thyroid gland in patients with multiple sclerosis]. AB - A study included 158 patients stratified into 3 groups: 57 patients with multiple sclerosis (MS) of the main group who were treated with copaxone in dosage 20 mg/d during 4,3+/-2,6 years, 49 patients without MS with different neurological diseases of the control group and 52 patients diagnosed with "confirmed MS" in the remission stage who were not treated with disease-modifying drugs. Demographic data, severity of MS patient's state, ultra-sound and hormonal data assessing the thyroid gland function were analyzed. The results obtained in the study demonstrated the relative safety of copaxone in respect to changes in thyroid gland function, the low risk for the elevation of blood antibodies to thyreoperoxidase, changes of hormonal indices and the development of thyroid dysfunction. PMID- 21311487 TI - [Modern aspects of treatment of chronic brain ischemia in atherosclerotic lesions of precerebral arteries]. AB - Epidemiologic, etiologic and pathogenetic aspects of chronic brain ischemia are reviewed. Based on the modern conception of neuroplasticity, neuroprotection and neurogenesis, the authors substantiate the lines of pharmacotherapy. The results of the clinical study of photochromotherapy in the restorative treatment of chronic brain ischemia are presented. PMID- 21311488 TI - [Efficacy of cavinton in the treatment of patients with chronic blood flow insufficiency. Russian multicenter clinical-epidemiological program "CALIPSO"]. AB - The multicenter clinical-epidemioilogical program "CALIPSO" included 4865 patients with chronic cerebrovascular insufficiency associated with arterial hypertension. Patients received cavinton in intravenous infusions in drops during one week in dosage (25 mg in the 1-4 days, 50 mg in the 5-7 days) and then perorally in dose 30 mg/day during 90 days. The data analysis of the first 1011 individual medical records revealed the significant decrease of patient's complaints (p<0,001) and severity of neurological symptoms (p<0,05) as well as the improvement in scores on the Tinnetti scale (p<0,001) and the MMSE (p<0,001). The safety profile of the drug was confirmed. PMID- 21311489 TI - [Lyrica (pregabalin) in the treatment of focal refractory epilepsy in adults]. AB - Efficacy and tolerability of a new antiepileptic drug pregabalin (lyrica) as an add-on drug in patients with focal refractory epilepsy was analyzed. The most commonly used dosage was 450 mg/d. For the 6-month treatment of 19 patients, aged 18-30 years, a positive effect of the combined therapy was observed in 68,4%, the remission was achieved in 31,6% and the significant improvement in 36,8%. Drug was discontinued due to the lack of efficacy and intolerance in 31,6%. Drowsiness was the most frequent adverse event and hemorrhagic vasculitis was registered in one patient. Two cases of effective use of the drug during pregnancy with the birth of healthy children are reported. A case of the high efficacy of pregabalin in migraine-epilepsy is described. High efficacy and good tolerability as well as favorable pharmacokinetic characteristics and distinct anxyolytic effect give indications for use of pregabalin in clinical practice. PMID- 21311490 TI - [Clinical features of the formation and possibilities of treatment of posttraumatic cognitive disturbances]. AB - We studied the efficacy of akatinol memantine compared to that of piracetam in the treatment of 41 patients with posttraumatic cognitive disturbances (20 patients were treated with akatinol memannine and 21 patients with piracetam) during 24 weeks. Ten patients had a severe traumatic brain injury (TBI) and 11 patients had mild TBI. Treatment efficacy was assessed during 6 months using the data of clinical examination, neuropsychological testing, CT and MRI. Akatinol exerted a distinct positive, stable and continuously effect on a broad spectrum of cognitive disturbances while the effect of piracetam was observed only for some cognitive functions and was short-term (during 1 month). Both drugs were well-tolerated by patients. PMID- 21311491 TI - [Diagnosis of attention-deficit hyperactivity disorder with a conditioned reflexes approach]. AB - A new conditioned reflexes approach for assessment of attention deficit hyperactivity disorder (ADHD) symptoms in children has been used. Successful solving of behavioral task was related with the ability of children to shift their attention on spatially located sensory signals in radial labyrinth with asymmetric schedule of rewards. The innovative method developed gives a good possibility to increase the accuracy of ADHD evaluation in children of different age as well as to reduce the time for their behavioral testing. PMID- 21311492 TI - [Clinical features of myasthenia related with autoantibodies to muscle specific tyrosine kinase (MuSK)]. AB - Anti-acetylcholine receptor antibodies are detected in 80 to 90% of patients with generalized myasthenia gravis - seropositive myasthenia gravis (SPMG). Approximately 10% to 20% of patients with autoimmune MG do not have antibodies to acetylcholine receptor (AChR) - seronegative MG (SNMG). An immunological study of the blood serum of patients with SNMG revealed patients with or without antibodies to muscle specific tyrosine kinase (MuSK+ and MuSK-, respectively). A clinical study of 13 MuSK+ patients with myasthenia showed that this group was characterized by predominant affect of mimic and bulbar muscles with the rare involvement of eye movement and body muscles. In Musk+ patients with myasthenia, the clinical efficacy of antitoxin esterase drugs was minimal or absent. No unequivocal conclusion on the clinical pattern of this form of myasthenia has been made. PMID- 21311493 TI - [Clinical features of migraine and parameters of trigeminal somatosensory evoked potentials in patients with different levels of thyroid-stimulating hormone]. AB - Levels of thyroid-stimulating hormone (TSH), trigeminal somatosensory evoked potentials (TSEPs) and quality of life (QoL) were studied in 50 migraine patients and 10 healthy subjects. The latency of P1 as well as the asymmetry of P1 latency and N1P1 amplitude were enlarged in migraine patients. Lower levels of TSH were correlated with more pronounced asymmetries in TSEPs. QoL in migraine was inversely correlated with TSH levels, pain intensity, MIDAS score, passive strategies preference, levels of anxiety and depression. IN CONCLUSION: TSH levels may modulate the function of trigeminal system in migraine. PMID- 21311494 TI - Echocardiographic measures of ventricular function and pulmonary artery size: prognostic markers of congenital diaphragmatic hernia? AB - OBJECTIVE: To compare echocardiographic measures of biventricular function and pulmonary artery size in infants with congenital diaphragmatic hernia (CDH) and normal controls, and examine their correlation, if any, with outcomes in CDH. STUDY DESIGN: We included consecutive neonates (<1 month old) with CDH and term controls without structural heart defects. Clinical and outcomes data were recorded and echocardiograms evaluated for right ventricular (RV) and left ventricular (LV) myocardial performance index (MPI), cardiac output index (CI) and McGoon index, among others. Statistical analyses (SPSS version 17, SPSS, Chicago, IL, USA) included between-group comparisons, using analysis of variance and chi(2)-test and binary regression, with significance set at P<0.05. RESULT: Infants with CDH (n=34) were comparable with controls (n=35) in their age, weight, gestational age and gender. CDH was left sided in 24 (70%) neonates. Extracorporeal membrane oxygenation (ECMO) was required in 15 (45%) neonates; 18 (53%) infants survived. MPIs, CI and eccentricity index in systole were significantly worse in the CDH group, compared with controls and among CDH infants who died, compared with survivors. Infants with CDH who died or needed ECMO had significantly impaired MPIs and CI than survivors. On regression analyses, LV CI and MPIs were independently associated with mortality. CONCLUSION: Infants with CDH had significantly impaired ventricular function and pulmonary hypertension, compared with controls. In the CDH group, LV dysfunction was associated with death and adverse outcomes. Further studies incorporating echocardiographic indices as prognostic markers of CDH are warranted. PMID- 21311495 TI - Ultrasound-guided umbilical catheter insertion in neonates. AB - OBJECTIVE: Umbilical catheter placement is a routine neonatal emergency procedure that has large variability in technical methods. Commonly used methods are unable to accurately estimate insertion lengths, and X-rays cannot always identify malpositioned catheters. In clinical practice, the placement of umbilical lines takes time away from nursing during a critical transition period. Ultrasound is a safe and commonly used tool in the nursery for clinical management of sick neonates and has been shown to readily identify central catheter tip position. In this study, we sought to determine a more time-efficient and accurate means of umbilical catheter placement using bedside ultrasound. STUDY DESIGN: This is a prospective, randomized, pilot trial of infants of any age or weight admitted to the neonatal intensive care unit who required umbilical catheter placement. Infants were excluded if they had congenital heart disease, abdominal wall defects or had a single umbilical artery. Catheters were placed using either the conventional method, with blinded evaluation of the catheters using ultrasound, or with ultrasound guidance, with input pertaining to catheter tip location. The number of X-rays required to confirm proper positioning, completion time points throughout the procedure and manipulations of the lines were recorded for both groups. RESULT: Ultrasound use decreased the time of line placement with an average saving of 64 min, as well as decreased the number of manipulations required and X-rays taken to place the catheters. The average X-ray time from request to viewing per X-ray was 40 min for all subjects. CONCLUSION: Ultrasound guided umbilical catheter placement is a faster method to place catheters requiring fewer manipulations and X-rays when compared with conventional catheter placement. PMID- 21311496 TI - Hospital readmission among infants with gastroschisis. AB - OBJECTIVE: Infants with gastroschisis have significant perinatal morbidity including long hospitalizations and feeding intolerance. Two thirds are premature and 20% are growth restricted. Despite these known risk factors for post-natal complications, little is known about readmission for infants with gastroschisis. Our objective was to determine the frequency and indication for hospital readmission after initial discharge among infants with gastroschisis. STUDY DESIGN: Retrospective cohort study. All surviving infants treated for gastroschisis at Cincinnati Children's Hospital Medical Center, born between January 2006 and December 2008 were included. Main outcome measures included the frequency and indication for readmission. Associated neonatal risk factors also were assessed. RESULT: Fifty-eight patients were analyzed. Twenty-three (40%) subjects were readmitted (five with multiple readmissions); 65% of readmissions occurred in the first year and 70% involved complications directly related to gastroschisis. The most common reasons for readmission were bowel obstruction and abdominal distention/pain. Median time to readmission directly related to gastroschisis was 23 weeks (range 5 to 92). All three infants with home parenteral nutrition were readmitted. Readmission was not associated with gestational age, birth weight or length of initial hospitalization. CONCLUSION: Readmission after initial hospitalization is common in gastroschisis patients. Parental counseling should include education regarding the possibility of complications requiring readmission. Determinants of readmission require further study. PMID- 21311497 TI - Long-term outcome following selective serotonin reuptake inhibitor induced neonatal abstinence syndrome. AB - OBJECTIVE: To assess the long-term neurodevelopment of children exposed in utero to selective serotonin reuptake inhibitors (SSRIs) that developed a neonatal abstinence syndrome (NAS). STUDY DESIGN: Neurodevelopmental evaluation was performed at the age of 2 to 6 years. Children who developed NAS were compared with those who did not using univariate and logistic regression analyses. RESULT: Thirty children with NAS and 52 without NAS participated in the study. Both groups were similar in mean cognitive ability (106.9+/-14.0 vs 100.5+/-14.6, P=0.12) and developmental scores (98.9+/-11.4 vs 95.7+/-9.9, P=0.21). However, there was a trend towards small head circumference in the NAS group (20 vs 6%, P=0.068). NAS was associated with an increased risk of social-behavior abnormalities (odds ratio (OR) 3.03, 95% confidence interval (CI) 1.07 to 8.60, P=0.04) and advanced maternal age (OR 1.12, 95% CI 1.00 to 1.25, P=0.04). CONCLUSION: Infants who developed NAS had normal cognitive ability, but were at an increased risk for social-behavioral abnormalities. Follow-up evaluation of symptomatic neonates should be considered. PMID- 21311498 TI - Use of the Ages and Stages Questionnaire and Bayley Scales of Infant Development II in neurodevelopmental follow-up of extremely low birth weight infants. AB - OBJECTIVE: For infants born with extremely low birth weight (ELBW), we examined the (1) correlation between results on the Ages and Stages Questionnaire (ASQ) and the Bayley Scales of Infant Development-II (BSID-II) at 18 to 22 months corrected age; (2) degree to which earlier ASQ assessments predict later BSID-II results; (3) impact of ASQ use on follow-up study return rates. STUDY DESIGN: ASQ data were collected at 4, 8, 12 and 18 to 22 months corrected age. The BSID-II was completed at 18 to 22 months corrected age. ASQ and BSID-II 18 to 22 month sensitivity and specificity were examined. Ability of earlier ASQs to predict later BSID-II scores was examined through linear regression analyses. RESULT: ASQ sensitivity and specificity at 18 to 22 months were 73 and 65%, respectively. Moderate correlation existed between earlier ASQ and later BSID-II results. CONCLUSION: For extremely low birth weight infant assessment, the ASQ cannot substitute for the BSID-II, but seems to improve tracking success. PMID- 21311499 TI - Blood urea nitrogen and serum bicarbonate in extremely low birth weight infants receiving higher protein intake in the first week after birth. AB - OBJECTIVE: To determine correlation between early protein administration and serum blood urea nitrogen (BUN) or bicarbonate (HCO(3)(-)) in extremely low birth weight (ELBW) infants during the first week of life. STUDY DESIGN: A retrospective review of 154 ELBWs was conducted. Laboratory and nutritional data from postnatal days 1, 4 and 7 were collected. Repeated measures models estimated the relationship of protein intake with BUN and HCO(3)(-) in the first week of life. RESULT: In total, 359 separate BUN and HCO(3)(-) values were analyzed. Each gram per kilogram of protein administered was associated with an increase in mean BUN of 3.3 mg/dl. This effect decreased daily by 2.1 mg/dl. Each gram per kilogram of protein administered was associated with a decrease in mean HCO(3)(-) by 0.9 mmol/l. CONCLUSION: The association between protein load and BUN is positive but decreasing over time. Protein is associated with a clinically insignificant decrease in HCO(3)(-). Concerns regarding metabolic derangement from early protein administration in ELBWs are unwarranted. PMID- 21311500 TI - Pilot trial of late booster doses of surfactant for ventilated premature infants. AB - OBJECTIVE: Many premature infants at risk for bronchopulmonary dysplasia experience episodes of surfactant dysfunction with reduced surfactant protein B (SP-B). In this study, we investigated the safety and responses to booster doses of surfactant. STUDY DESIGN: A total of 87 infants, 500 to 1250 g birth weight, who were ventilated at 7 to 10 days received 2 or 3 doses of Infasurf (Calfactant, Forest Pharmaceuticals, St Louis, MO, USA) within a 1-week period. RESULT: For 184 doses, occurrence rates of transient bradycardia (13) and plugged endotracheal tube (5) were low, and no other adverse effects were noted. Treatment transiently improved the respiratory severity score (FiO(2) * mean airway pressure), SP-B content (+75%) and surface properties of isolated surfactant. Levels of eight proinflammatory cytokines in tracheal aspirate were interrelated and unchanged from baseline after surfactant treatment. CONCLUSION: Booster doses of surfactant for premature infants with lung disease are safe and transiently improve respiratory status as well as composition and function of endogenous surfactant. PMID- 21311502 TI - Community Kangaroo Mother Care: implementation and potential for neonatal survival and health in very low-income settings. AB - OBJECTIVE: Immediate Kangaroo Mother Care (KMC), an intervention following childbirth whereby the newborn is placed skin-to-skin (STS) on mother's chest to promote thermal regulation, breastfeeding and maternal-newborn bonding, is being taught in very low-income countries to improve newborn health and survival. Existing data are reviewed to document the association between community-based KMC (CKMC) implementation and its potential benefits. STUDY DESIGN: New analyses of the sole randomized controlled study of CKMC in Bangladesh and others' experiences with immediate KMC are presented. RESULT: Newborns held STS less than 7 h per day in the first 2 days of life do not experience substantially better health or survival than babies without being held STS. CONCLUSION: Most women who were taught CKMC hold their newborns STS, but do so in a token manner unlikely to improve health or survival. Serious challenges exist to provide effective training and postpartum support to achieve adequate STS practices. These challenges must be overcome before scaling up. PMID- 21311501 TI - A review of alternatives to di (2-ethylhexyl) phthalate-containing medical devices in the neonatal intensive care unit. AB - OBJECTIVE: To conduct an extensive literature and toxicological database review on substitute compounds and available alternative medical products to replace polyvinyl chloride (PVC) and/or di(2-ethylhexyl) phthalate (DEHP), and conduct a DEHP-medical inventory analysis at a large metropolitan neonatal intensive care unit (NICU). STUDY DESIGN: A systematic search for DEHP-free alternative products was performed using online databases. An informal audit of a large metropolitan NICU was undertaken in 2005 and 2006; 21 products were identified that could potentially contain DEHP. Availability of DEHP-free alternatives was determined through company websites and phone interviews. RESULT: Two alternative approaches are available for replacing DEHP in NICU medical products: (1) replacement by DEHP-free plasticizers; and (2) replacement of PVC entirely through the use of other polymers. Both approaches seem to provide less harmful substitutes to DEHP, but support PVC-free polymers as the preferred alternative. However, significant data gaps exist, particularly for the alternative polymers. In all, 10 out of 21 (48%) products in the NICU audit were DEHP-free; six consisted of alternative polymers and four of alternative plasticizers. Of the remaining 11 products, only three were available without DEHP at the time of the audit. CONCLUSION: Because of significant data gaps, systematic toxicological testing of DEHP-free alternatives is imperative. Continued development of alternative products is also needed. PMID- 21311503 TI - Echocardiographic detection of pulmonary hypertension in extremely low birth weight infants with bronchopulmonary dysplasia requiring prolonged positive pressure ventilation. AB - OBJECTIVE: The goal of this study was to delineate the epidemiology of echocardiographically diagnosed pulmonary hypertension (PH) in extremely low birth weight (ELBW) infants with bronchopulmonary dysplasia (BPD) requiring prolonged positive pressure ventilation (PPV), and to determine the independent relationship between PH and mortality in these patients. STUDY DESIGN: Our retrospective cohort included ELBW infants, with BPD requiring prolonged PPV, hospitalized in Cincinnati, Ohio during 2003-2009, as recorded in the National Institute of Child Health and Human Development Neonatal Research Network Database. Following chart review, a logistic regression model was constructed to understand the contribution of PH to mortality in infants with BPD requiring prolonged PPV. RESULT: We identified 216 patients (19%) with BPD requiring prolonged PPV among 1156 ELBW infants. Of these patients, 41% received echocardiography after 4 weeks of life, with 37% showing evidence of PH. Logistic regression analysis demonstrated that infants with BPD requiring prolonged PPV, with PH detectable by echocardiogram, were four times more likely to die (adjusted odds ratio): 4.6, 95% confidence interval: 1.3-16.5) when compared with infants with BPD requiring prolonged PPV without echocardiographic evidence of PH. CONCLUSION: Pulmonary hypertension appears to be an important, independent determinant of death in infants with BPD requiring prolonged PPV. PMID- 21311504 TI - Vitamin D3 supplementation for 16 weeks improves flow-mediated dilation in overweight African-American adults. AB - BACKGROUND: A growing body of evidence has linked vitamin D deficiency to increased risk of cardiovascular disease. Vitamin D deficiency is also more common in African Americans for whom an increased cardiovascular disease risk exists. This study sought to test the hypothesis that 16 weeks of 60,000 IU monthly supplementation of oral vitamin D(3) would improve flow-mediated dilation (FMD) in African Americans, whereas no change would be observed in the placebo group. METHODS: A randomized, double-blind, placebo-controlled clinical trial was conducted. Fifty-seven African-American adults were randomly assigned to either the placebo group or vitamin D group. RESULTS: Following 16 weeks of placebo (n = 23; mean age 31 +/- 2 years) or 60,000 IU monthly oral vitamin D(3) (n = 22; mean age 29 +/- 2 years), serum concentrations of 25-hydroxyvitamin D (25(OH)D) increased from 38.2 +/- 3.0 to 48.7 +/- 3.2 nmol/l and 34.3 +/- 2.2 to 100.9 +/- 6.6 nmol/l, respectively. No changes in serum parathyroid hormone (PTH), serum calcium, or urine calcium/creatinine were observed following either treatment. Following 16 weeks of treatment, significant improvements in FMD were only observed in the vitamin D group (1.8 +/- 1.3%), whereas the placebo group had no change (-1.3 +/- 0.6%). Similarly, the vitamin D group exhibited an increase in absolute change in diameter (0.005 +/- 0.004 cm) and FMD/shear (0.08 +/- 0.04 %/s(-1), area under the curve (AUC) * 10(3)) following treatment, whereas no change (-0.005 +/- 0.002 cm and -0.02 +/- 0.02 %/s(-1), AUC, respectively) was observed following placebo. CONCLUSION: Supplementation of 60,000 IU monthly oral vitamin D(3) (~2,000 IU/day) for 16 weeks is effective at improving vascular endothelial function in African-American adults. PMID- 21311505 TI - Regional differences in hypertensive cardiovascular remodeling between fishing and farming communities in Japan. AB - BACKGROUND: Effects of dietary n-3 polyunsaturated fatty acids (n-3 PUFA) intake on the cardiovascular system have been reported, and thus we hypothesized that the prevalence of hypertensive cardiovascular remodeling would be lower in a fishing than a farming community. METHODS: We recruited 263 essential hypertensives from a fishing and 333 from a farming village; all subjects were >=40 years (mean 73 years; 42% men). They were cross-sectionally examined for serum eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), asymmetric dimethylarginine (ADMA) levels, left ventricular mass index (LVMI), and common carotid artery (CCA) and internal-carotid artery (ICA) intima-media thickness (IMT). RESULTS: Compared to the patients in the farming village, those in the fishing village had higher serum EPA and DHA levels (63.3 vs.70.9 ug/ml, 137.2 vs.157.8 ug/ml) and lower ADMA levels (0.49 vs.0.47 nmol/ml; all P < 0.05). LVMI and both CCA-IMT and ICA-IMT levels were lower in the fishing than the farming village (113.2 vs.121.6 g/m(2), 0.88 vs.0.94 mm, 1.10 vs.1.17 mm: all P < 0.01) even after adjustment for age, sex, body mass index (BMI), duration of hypertensive medication, number of antihypertensive medications, and 24-h systolic blood pressure (SBP) level. The differences in LVMI and IMT levels between these communities also remained unchanged (all P < 0.01) after additional adjustment for the regional differences in EPA, DHA, and ADMA levels. A multivariable linear regression analysis showed that the difference in place of residence was independently associated with LVMI as well as with both CCA-IMT and ICA-IMT levels (all P < 0.01). CONCLUSION: The prevalence of cardiovascular remodeling was significantly lower in patients in the fishing community than in those in the farming community. Further investigations are required to explain the mechanisms underlying this association. PMID- 21311506 TI - The comparison of a technology-based system and an in-person behavioral weight loss intervention. AB - The purpose of this study was to compare a technology-based system, an in-person behavioral weight loss intervention, and a combination of both over a 6-month period in overweight adults. Fifty-one subjects (age: 44.2 +/- 8.7 years, BMI: 33.7 +/- 3.6 kg/m(2)) participated in a 6-month behavioral weight loss program and were randomized to one of three groups: standard behavioral weight loss (SBWL), SBWL plus technology-based system (SBWL+TECH), or technology-based system only (TECH). All groups reduced caloric intake and progressively increased moderate intensity physical activity. SBWL and SBWL+TECH attended weekly meetings. SBWL+TECH also received a TECH that included an energy monitoring armband and website to monitor energy intake and expenditure. TECH used the technology system and received monthly telephone calls. Body weight and physical activity were assessed at 0 and 6 months. Retention at 6 months was significantly different (P = 0.005) between groups (SBWL: 53%, SBWL+TECH: 100%, and TECH: 77%). Intent-to-treat (ITT) analysis revealed significant weight losses at 6 months in SBWL+TECH (-8.8 +/- 5.0 kg, -8.7 +/- 4.7%), SBWL (-3.7 +/- 5.7 kg, -4.1 +/- 6.3%), and TECH (-5.8 +/- 6.6 kg, -6.3 +/- 7.1%) (P < 0.001). Self-report physical activity increased significantly in SBWL (473.9 +/- 800.7 kcal/week), SBWL+TECH (713.9 +/- 1,278.8 kcal/week), and TECH (1,066.2 +/- 1,371 kcal/week) (P < 0.001), with no differences between groups (P = 0.25). The TECH used in conjunction with monthly telephone calls, produced similar, if not greater weight losses and changes in physical activity than the standard in-person behavioral program at 6 months. The use of this technology may provide an effective short term clinical alternative to standard in-person behavioral weight loss interventions, with the longer term effects warranting investigation. PMID- 21311507 TI - Elevated BMI is associated with decreased blood flow in the prefrontal cortex using SPECT imaging in healthy adults. AB - Obesity is a risk factor for stroke and neurodegenerative disease. Excess body fat has been linked to impaired glucose metabolism, insulin resistance, and impulsivity and may be a precursor to decline in attention and executive cognitive function. Here, we investigated the effects of high BMI on regional cerebral blood flow (rCBF) using single photon emission computed tomography (SPECT) imaging in healthy subjects. A total of 16 adult men and 20 adult women were recruited from the community between January 2003 and July 2009 as part of a healthy brain study (HBS) conducted at the Amen Clinics, a private medical facility. Participants in the study were screened to exclude medical, neurological, and psychiatric conditions, including substance abuse. Subjects were categorized as normal or overweight according to BMI. Using a two sample t test, we determined the effects of BMI on rCBF in normal vs. overweight subjects. Subjects were matched for age and gender. Statistical parametric mapping (SPM) revealed a higher BMI in healthy individuals that is associated with decreased rCBF in Broadmann areas 8, 9, 10, 11, 32, and 44, brain regions involved in attention, reasoning, and executive function (P < 0.05, corrected for multiple comparisons). We found that an elevated BMI is associated with decreased rCBF in the prefrontal cortex of a healthy cohort. These results indicate that elevated BMI may be a risk factor for decreased prefrontal cortex function and potentially impaired executive function. PMID- 21311508 TI - Obesity duration is associated to pulmonary function impairment in obese subjects. AB - Obesity is associated with pulmonary function disturbances. We hypothesized that lung function decreases with increasing duration of obesity. We evaluated pulmonary function tests (PFTs) in 188 nonsmoking subjects with primary obesity (aged 8-76 years; 36% with systemic hypertension). Duration of obesity was assessed by questionnaire in adults, and by height and weight growth patterns in children. Asthma and/or other allergic diseases were investigated by standardized questionnaires. BMI and BMI-standard deviation scores (SDS) were 38.7 and 2.4 kg/m(2), respectively. Forty-six percent of patients were atopic. Among subjects with ever asthma (33%), 20 had current asthma (11% of the total). Forced vital capacity (FVC), forced expiratory volume in 1 s, total lung capacity (TLC), and functional residual capacity (FRC) were 103, 104, 95, and 76% predicted, respectively. Mean duration of obesity was 8.3 years. Compared with subjects who had been obese for <=5 years, patients who had been obese for >15 years had significantly lower values on PFTs (P < 0.05). In subjects with systemic hypertension, PFTs were lower than in patients without hypertension (P < 0.01). Duration of obesity was significantly related to all PFTs (P <= 0.001). In a multiple regression analysis where duration and severity of obesity, hypertension, atopy, asthma, and family history of atopic diseases were independent variables, duration of obesity was a predictor of lower PFTs (P < 0.01). Of the remaining variables, only hypertension contributed to lower lung volumes. In obese individuals, lung function was significantly lower in subjects with greater years of obesity. Fat loss programs should be encouraged to prevent late pulmonary function impairment. PMID- 21311509 TI - Longitudinal body composition data in exclusively breast-fed infants: a multicenter study. AB - Reference %fat and total fat-free mass data is necessary for evaluating growth in infants. We aimed to develop longitudinal %fat and total fat-free mass data in infants from birth to 6 months of age. An observational, multicenter, prospective cohort study was conducted with assessments at birth, 1 week, 2 weeks, 1, 2, 3, 4, 5, and 6 months of age. Subjects were exclusively breast-fed and were enrolled at three centers. Whole-body composition (i.e., % fat and total fat-free mass) were assessed using air-displacement plethysmography (ADP) (PEA POD; Life Measurement, Concord, CA). Maternal prepregnancy BMI, gestational weight gain, and infant anthropometric data were collected. A total of 160 infants (boys = 84) were assessed from birth to 4 months of age. Mean birth weight was 3.46 +/- 0.39 kg % fat and fat-free mass significantly increased from birth to 4 months of age (P < 0.0001). Gender-specific %fat and total fat-free mass curves for infants from birth to 4 months of age were created. This study will be beneficial to health-care professionals in evaluating normal growth and nutritional patterns in the first months of life. PMID- 21311510 TI - Hemojuvelin: a new link between obesity and iron homeostasis. AB - The adipose tissue may play an active role in systemic iron regulation and this role may be determinant in obese patients. Indeed, we reported previously that hepcidin, the iron-regulatory hormone, is expressed in adipose tissue and its messenger RNA (mRNA) expression is increased in adipose tissue of morbidly obese patients. The objectives of this study were to characterize the status of hemojuvelin (HJV), another iron-regulatory protein, within the adipose tissue of morbidly obese patients. Since cell-associated HJV acts as a coreceptor of bone morphogenetic protein (BMP) to enhance hepcidin expression in liver cells, we investigated the possible involvement of this pathway in adipose tissue in regulating hepcidin expression. HJV expression was studied in adipose tissue of morbidly obese patients. Soluble HJV blood concentrations were assessed. Hepcidin regulation through BMP pathway was investigated in cultured adipocytes. HJV was expressed both at mRNA and protein levels in adipose tissue. Moreover, its mRNA expression was highly increased in adipose tissue of obese patients and correlated with mRNA hepcidin expression levels. Interestingly, HJV expressed by adipose tissue may be effective since cultured adipocytes increased their hepcidin expression when challenged with BMP2 through Smad effectors. In addition, blood concentrations of soluble HJV were significantly increased. In conclusion, adipose tissue may influence iron homeostasis in obese patients by expressing major iron-regulatory proteins and the BMP signaling pathway could be involved in regulating hepcidin expression in this tissue. PMID- 21311511 TI - High allelic burden of four obesity SNPs is associated with poorer weight loss outcomes following gastric bypass surgery. AB - Genome-wide association and linkage studies have identified multiple susceptibility loci for obesity. We hypothesized that such loci may affect weight loss outcomes following dietary or surgical weight loss interventions. A total of 1,001 white individuals with extreme obesity (BMI >35 kg/m(2)) who underwent a preoperative diet/behavioral weight loss intervention and Roux-en-Y gastric bypass surgery were genotyped for single-nucleotide polymorphisms (SNPs) in or near the fat mass and obesity-associated (FTO), insulin induced gene 2 (INSIG2), melanocortin 4 receptor (MC4R), and proprotein convertase subtilisin/kexin type 1 (PCSK1) obesity genes. Association analysis was performed using recessive and additive models with pre- and postoperative weight loss data. An increasing number of obesity SNP alleles or homozygous SNP genotypes was associated with increased BMI (P < 0.0006) and excess body weight (P < 0.0004). No association between the amounts of weight lost from a short-term dietary intervention and any individual obesity SNP or cumulative number of obesity SNP alleles or homozygous SNP genotypes was observed. Linear mixed regression analysis revealed significant differences in postoperative weight loss trajectories across groups with low, intermediate, and high numbers of obesity SNP alleles or numbers of homozygous SNP genotypes (P < 0.0001). Initial BMI interacted with genotype to influence weight loss with initial BMI <50 kg/m(2), with evidence of a dosage effect, which was not present in individuals with initial BMI >=50 kg/m(2). Differences in metabolic rate, binge eating behavior, and other clinical parameters were not associated with genotype. These data suggest that response to a surgical weight loss intervention is influenced by genetic susceptibility and BMI. PMID- 21311512 TI - Bone age advancement in prepubertal children with obesity and premature adrenarche: possible potentiating factors. AB - Obesity and premature adrenarche (PA) are both associated with bone age (BA) advancement of unclear etiology, which may lead to earlier puberty, suboptimal final height and obesity in adulthood. Our objective was to understand the hormonal and anthropometric characteristics of BA advancement in a spectrum of prepubertal children with and without obesity and PA. In this cross-sectional study of 66 prepubertal children (35 PA, 31 control, 5-9 years), BMI z-score, hormonal values and response to an oral glucose tolerance test were the main outcome measures. Subjects were divided into tertiles by BA divided by chronological age (BA/CA), an index of BA advancement. Subjects in the top tertile for BA/CA had the highest dehydroepiandrosterone sulfate (DHEAS), free testosterone (%), hemoglobin A(1C), BMI z-score, and weight (P < 0.05). BMI z score (r = 0.47), weight (r = 0.40), free testosterone (%) (r = 0.34), and DHEAS (r = 0.30) correlated with BA/CA (P < 0.02). Regression analysis showed greater BA/CA in PA compared to controls after controlling for weight (0.21 +/- 0.56, P < 0.004). An exploratory stepwise regression model showed that weight, estradiol, and DHEAS were the strongest predictors of BA/CA accounting for 24% of its variance. Obesity was highly associated with BA advancement in this study of prepubertal children. In addition, children with PA had greater BA/CA at any given weight when compared to controls. These findings suggest a possible hormonal factor, which potentiates the effect of obesity on BA advancement in children with obesity and/or PA. PMID- 21311513 TI - The erosive effects of saliva following chewing gum on enamel and dentine: an ex vivo study. AB - OBJECTIVES: The primary objective was to determine the erosive effect of expectorated saliva, following chewing acidic gum, on enamel and dentine samples, using a non-acidic gum as a negative control. Secondary objectives were to determine the effect of brushing enamel and dentine samples and the effect of individual saliva pH and buffering. DESIGN: A single-centre, single-blind, placebo-controlled, two-way crossover study. SETTING: A clinical trial, involving healthy participants, undertaken at Bristol Dental School and Hospital. METHODS: Eight healthy participants expectorated saliva onto prepared enamel and dentine samples while chewing gum (strawberry flavoured acidic gum [active] or peppermint flavoured non-acidic gum [control]). Half of the enamel and dentine samples were brushed before measurement by contact profilometry. MAIN OUTCOME MEASURES: Mean enamel and dentine erosion, with and without brushing and the relationship to salivary buffering.Results At 10 days, mean depth of surface loss from dentine samples (95% CI), following chewing of acid-containing gum and subsequent brushing, was -11.34 MUm (2.22 MUm) and from un-brushed dentine samples was 11.02 MUm (1.71 MUm). No significant erosion was noted for other groups. CONCLUSIONS: Frequent chewers of acid-containing gums are susceptible to dentine erosion even in the presence of good salivary buffering. Enamel erosion was insignificant within the time constraints of the present study but warrants further investigation. PMID- 21311514 TI - Oral surgery services and training. PMID- 21311515 TI - Beggaring belief. PMID- 21311518 TI - Stress modified swallowing. PMID- 21311519 TI - Cornered. PMID- 21311520 TI - Childhood caries a matter of national shame. PMID- 21311521 TI - Putting Wales at the forefront of dental training. PMID- 21311522 TI - Henry Schein supports King's training programmes. PMID- 21311523 TI - BDA makes proactive start to 2011. PMID- 21311525 TI - Help Haiti's oral health. PMID- 21311528 TI - Dental drill to be drowned out. PMID- 21311529 TI - Leadership theory: implications for developing dental surgeons in primary care? AB - The development of leadership in healthcare has been seen as important in recent years, particularly at the clinical level. There have been various specific initiatives focusing on the development of leadership for doctors, nurses and other health care professions: for example, a leadership competency framework for doctors, the LEO programme and the RCN clinical leadership programme for nurses. The NHS has set up a Leadership Council to coordinate further developments. However, there has not been the same focus in dentistry, although the recent review of NHS dental services (Steele review) has proposed a need for leadership initiatives in NHS dentistry as a medium-term action. Central to this will be a need to focus on the leadership role for dental surgeons. Leadership is all the more important in dentistry, given the change of government and the policy of retrenchment, major public sector reform, the emergence of new organisations such as new commissioning consortia, possible changes to the dental contract, new ways of working, and changes to the profession such as the requirements for the revalidation of dental surgeons. The question is: which leadership theory or approach is best for dental surgeons working in primary care? This paper builds on earlier work exploring this question in relation to doctors generally, and GPs, in particular, and planned work on nurses. It will seek to address this question in relation to dental surgeons working in primary care. PMID- 21311530 TI - Dental appliances with inadequate occlusal coverage: a case report. AB - A case is presented which illustrates the occlusal problems that can develop when a dental appliance such as a temporomandibular splint with incomplete occlusal cover is worn for a reasonable length of time. As in this case, the selective over-eruption of posterior teeth not incorporated in the appliance can lead to the development of an anterior open bite and an increased overjet. A simple orthodontic method to correct the iatrogenic malocclusion through the re intrusion of the over-erupted teeth is shown and the importance of providing long term dental appliances with full occlusal contact is discussed. PMID- 21311531 TI - Maxillary sinus disease: diagnosis and treatment. AB - The maxillary sinus is the paranasal sinus that impacts most on the work of the dentist as they will often be required to make a diagnosis in relation to orofacial pain that may be sinogenic in origin. Maxillary sinus disease is often coincidentally observed on radiographs, and dentists often have to make a diagnosis and plan treatment based on the interpretation of the image. This paper aims to guide the dental professional through some of the disease processes involving the paranasal sinuses and in particular the maxillary sinus. The outcome is to encourage comprehensive history taking and examination of the patient to facilitate an accurate diagnosis that will enable successful treatment. PMID- 21311536 TI - Summary of: Thirty-five year review of a mercury monitoring service for Scottish dental practices. PMID- 21311537 TI - Summary of: The erosive effects of saliva following chewing gum on enamel and dentine: an ex vivo study. PMID- 21311538 TI - Dental practitioners with a special interest in periodontics: the West Sussex experience. AB - The experience of a pilot service involving practitioners with a special interest in periodontics is described. The service functioned as a clinical network between the primary and secondary sector and featured consultant outreach. Between June 2006 and May 2007 it experienced 441 referrals. It improved patient access to periodontal care and was successful in targeting specific disease categories and in meeting key performance indicators. The service was non surgical and emphasised patient self-efficacy. It produced highly effective clinical outcomes. It was well accepted by both patients and referring practitioners. It did not replace the need for a consultant-led service in the eyes of the referring practitioners. The BPE was used to identify suitable patients; audit indicated that there was a tendency for practitioners to underscore the level of periodontal disease. PMID- 21311556 TI - Haploidentical bone marrow transplantation with post-grafting cyclophosphamide: multicenter experience with an alternative salvage strategy. PMID- 21311557 TI - Activated K-Ras protein accelerates human MLL/AF4-induced leukemo lymphomogenicity in a transgenic mouse model. PMID- 21311558 TI - Determinants of laminin polymerization revealed by the structure of the alpha5 chain amino-terminal region. AB - The polymerization of laminin into a cell-associated network--a key step in basement membrane assembly--is mediated by the laminin amino-terminal (LN) domains at the tips of the three short arms of the laminin alphabetagamma heterotrimer. The crystal structure of a laminin alpha5LN-LE1-2 fragment shows that the LN domain is a beta-jelly roll with several elaborate insertions that is attached like a flower head to the stalk-like laminin-type epidermal growth factor-like tandem. A surface loop that is strictly conserved in the LN domains of all alpha-short arms is required for stable ternary association with the beta- and gamma-short arms in the laminin network. PMID- 21311559 TI - Regenerating the epigenome. AB - The ability of some organisms to regenerate parts of their body has fascinated scientists for decades. The process of regeneration depends on the potential of certain cells to proliferate and contribute to the formation of new tissue. Organisms have evolved two strategies by which to achieve this: the maintenance of adult stem cells and the induction of stem-cell properties in differentiated cells. In both cases, cells must undergo extensive epigenetic reprogramming to attain the specialized functions of the new tissue. Ultimately, the regenerative capacity of a tissue might depend on the plasticity of the cellular epigenome, which determines the ability of the cell to respond to injury-related signals. Understanding this epigenetic plasticity will allow the development of strategies to stimulate the regeneration of damaged tissues and organs in humans. PMID- 21311560 TI - Academic doping or Viagra for the brain? The history of recreational drug use and pharmacological enhancement can provide insight into these uses of neuropharmaceuticals. PMID- 21311561 TI - Quantitative proteomics of the integrin adhesome show a myosin II-dependent recruitment of LIM domain proteins. AB - A characteristic of integrins is their ability to transfer chemical and mechanical signals across the plasma membrane. Force generated by myosin II makes cells able to sense substrate stiffness and induce maturation of nascent adhesions into focal adhesions. In this paper, we present a comprehensive proteomic analysis of nascent and mature adhesions. The purification of integrin adhesion complexes combined with quantitative mass spectrometry enabled the identification and quantification of known and new adhesion-associated proteins. Furthermore, blocking adhesion maturation with the myosin II inhibitor blebbistatin markedly impaired the recruitment of LIM domain proteins to integrin adhesion sites. This suggests a common recruitment mechanism for a whole class of adhesion-associated proteins, involving myosin II and the zinc-finger-type LIM domain. PMID- 21311562 TI - Cohesin subunit Rad21L, the new kid on the block has new ideas. PMID- 21311563 TI - The Beclin 1 network regulates autophagy and apoptosis. AB - Beclin 1, the mammalian orthologue of yeast Atg6, has a central role in autophagy, a process of programmed cell survival, which is increased during periods of cell stress and extinguished during the cell cycle. It interacts with several cofactors (Atg14L, UVRAG, Bif-1, Rubicon, Ambra1, HMGB1, nPIST, VMP1, SLAM, IP(3)R, PINK and survivin) to regulate the lipid kinase Vps-34 protein and promote formation of Beclin 1-Vps34-Vps15 core complexes, thereby inducing autophagy. In contrast, the BH3 domain of Beclin 1 is bound to, and inhibited by Bcl-2 or Bcl-XL. This interaction can be disrupted by phosphorylation of Bcl-2 and Beclin 1, or ubiquitination of Beclin 1. Interestingly, caspase-mediated cleavage of Beclin 1 promotes crosstalk between apoptosis and autophagy. Beclin 1 dysfunction has been implicated in many disorders, including cancer and neurodegeneration. Here, we summarize new findings regarding the organization and function of the Beclin 1 network in cellular homeostasis, focusing on the cross regulation between apoptosis and autophagy. PMID- 21311564 TI - Genomic instability in induced stem cells. AB - The ability to reprogram adult cells into stem cells has raised hopes for novel therapies for many human diseases. Typical stem cell reprogramming protocols involve expression of a small number of genes in differentiated somatic cells with the c-Myc and Klf4 proto-oncogenes typically included in this mix. We have previously shown that expression of oncogenes leads to DNA replication stress and genomic instability, explaining the high frequency of p53 mutations in human cancers. Consequently, we wondered whether stem cell reprogramming also leads to genomic instability. To test this hypothesis, we examined stem cells induced by a variety of protocols. The first protocol, developed specifically for this study, reprogrammed primary mouse mammary cells into mammary stem cells by expressing c Myc. Two other previously established protocols reprogrammed mouse embryo fibroblasts into induced pluripotent stem cells by expressing either three genes, Oct4, Sox2 and Klf4, or four genes, OSK plus c-Myc. Comparative genomic hybridization analysis of stem cells derived by these protocols revealed the presence of genomic deletions and amplifications, whose signature was suggestive of oncogene-induced DNA replication stress. The genomic aberrations were to a significant degree dependent on c-Myc expression and their presence could explain why p53 inactivation facilitates stem cell reprogramming. PMID- 21311565 TI - Mouse granzyme K has pro-inflammatory potential. AB - Granzymes (gzms) are key components of T-killer (Tc) cells believed to mediate pro-apoptotic activities. Recent evidence suggests that gzms also possess non cytotoxic activities that contribute to host defense. In this study, we show that Tc cells from lymphocytic choriomeningitis virus (LCMV)-infected wild-type (wt) and gzm A/B-deficient mice express similar levels of gzmK protein, with both mouse strains efficiently controlling infection. GzmK, in recombinant form or secreted by ex vivo-derived LCMV-immune gzmAxB(-/-) Tc cells, lacks pro-apoptotic activity. Instead, gzmK induces primary mouse macrophages to process and secrete interleukin-1beta, independent of the ATP receptor P2X(7). Together with the finding that IL-1Ra (Anakinra) treatment inhibits virus elimination but not generation of cytotoxic Tc cells in wt mice, the data suggest that Tc cells control LCMV through non-cytotoxic processes that involve gzmK. PMID- 21311566 TI - TLR-2 and TLR-9 are sensors of apoptosis in a mouse model of doxorubicin-induced acute inflammation. AB - Anthracycline antibiotics are inducers of an immunogenic form of apoptosis that has immunostimulatory properties because of the release of damage-associated molecular patterns. To study the mechanisms used by the innate immune system to sense this immunogenic form of cell death, we established an in vivo model of cell death induced by intraperitoneal injection of doxorubicin, a prototype of anthracyclines. The acute sterile inflammation in this model is characterized by rapid influx of neutrophils and increased levels of IL-6 and monocyte chemotactic protein-1. We demonstrate that acute inflammation induced by doxorubicin is associated with apoptosis of monocytes/macrophages and that it is specific for doxorubicin, an immunogenic chemotherapeutic. Further, the inflammatory response is significantly reduced in mice deficient in myeloid differentiation primary response gene 88 (MyD88), TLR-2 or TLR-9. Importantly, a TLR-9 antagonist reduces the recruitment of neutrophils induced by doxorubicin. By contrast, the acute inflammatory response is not affected in TRIF(Lps2) mutant mice and in TLR-3, TLR 4 and caspase-1 knockout mice, which shows that the inflammasome does not have a major role in doxorubicin-induced acute inflammation. Our findings provide important new insights into how the innate immune system senses immunogenic apoptotic cells and clearly demonstrate that the TLR-2/TLR-9-MyD88 signaling pathways have a central role in initiating the acute inflammatory response to this immunogenic form of apoptosis. PMID- 21311567 TI - DAPK activates MARK1/2 to regulate microtubule assembly, neuronal differentiation, and tau toxicity. AB - Death-associated protein kinase (DAPK) is a key player in several modes of neuronal death/injury and has been implicated in the late-onset Alzheimer's disease (AD). DAPK promotes cell death partly through its effect on regulating actin cytoskeletons. In this study, we report that DAPK inhibits microtubule (MT) assembly by activating MARK/PAR-1 family kinases MARK1/2, which destabilize MT by phosphorylating tau and related MAP2/4. DAPK death domain, but not catalytic activity, is responsible for this activation by binding to MARK1/2 spacer region, thereby disrupting an intramolecular interaction that inhibits MARK1/2. Accordingly, DAPK(-/-) mice brain displays a reduction of tau phosphorylation and DAPK enhances the effect of MARK2 on regulating polarized neurite outgrowth. Using a well-characterized Drosophila model of tauopathy, we show that DAPK exerts an effect in part through MARK Drosophila ortholog PAR-1 to induce rough eye and loss of photoreceptor neurons. Furthermore, DAPK enhances tau toxicity through a PAR-1 phosphorylation-dependent mechanism. Together, our study reveals a novel mechanism of MARK activation, uncovers DAPK functions in modulating MT assembly and neuronal differentiation, and provides a molecular link of DAPK to tau phosphorylation, an event associated with AD pathology. PMID- 21311568 TI - Prelamin A-mediated recruitment of SUN1 to the nuclear envelope directs nuclear positioning in human muscle. AB - Lamin A is a nuclear lamina constituent expressed in differentiated cells. Mutations in the LMNA gene cause several diseases, including muscular dystrophy and cardiomyopathy. Among the nuclear envelope partners of lamin A are Sad1 and UNC84 domain-containing protein 1 (SUN1) and Sad1 and UNC84 domain-containing protein 2 (SUN2), which mediate nucleo-cytoskeleton interactions critical to the anchorage of nuclei. In this study, we show that differentiating human myoblasts accumulate farnesylated prelamin A, which elicits upregulation and recruitment of SUN1 to the nuclear envelope and favors SUN2 enrichment at the nuclear poles. Indeed, impairment of prelamin A farnesylation alters SUN1 recruitment and SUN2 localization. Moreover, nuclear positioning in myotubes is severely affected in the absence of farnesylated prelamin A. Importantly, reduced prelamin A and SUN1 levels are observed in Emery-Dreifuss muscular dystrophy (EDMD) myoblasts, concomitant with altered myonuclear positioning. These results demonstrate that the interplay between SUN1 and farnesylated prelamin A contributes to nuclear positioning in human myofibers and may be implicated in pathogenetic mechanisms. PMID- 21311569 TI - Wbp2 cooperates with Yorkie to drive tissue growth downstream of the Salvador Warts-Hippo pathway. AB - The Salvador-Warts-Hippo (SWH) pathway is a key controller of tissue growth in both flies and mammals, and deregulation of pathway activity contributes to tumour formation. The SWH pathway regulates cell growth, proliferation and apoptosis by restricting activity of the Yorkie transcriptional co-activator protein. The proteins that function together with Yorkie to drive transcription and tissue growth are beginning to be revealed and include the Scalloped (Sd), Teashirt (Tsh) and Homothorax (Hth) transcription factors. In this study, we define Wbp2 as a promoter of Yorkie-dependent growth of Drosophila melanogaster tissues. Mammalian WBP2 was previously identified as a protein that interacts with the mammalian Yorkie homologue, Yes-associated protein. WBP2 has been shown to enhance steroid hormone-dependent transcription in cultured cells but its in vivo function has remained obscure. We show that D. melanogaster Wbp2 interacts with Yorkie in a WW domain- and PY motif-dependent manner and that Wbp2 can enhance Yorkie's transcriptional co-activator properties. In vivo, Wbp2 is required for growth of the D. melanogaster wing, and reduction of Wbp2 expression suppresses overgrowth of tissues that lack the warts growth-suppressive gene. Collectively, these studies define an important role for Wbp2 as a downstream component of the SWH tissue growth-control pathway. PMID- 21311570 TI - Brow suspension using 3-0 Prolene. PMID- 21311571 TI - Prognostic factors for recurrence with unilateral recess-resect procedure in patients with intermittent exotropia. AB - PURPOSE: To evaluate the prognostic factors, particularly age at the time of surgery, for recurrence after unilateral medial rectus resection and lateral rectus recession (R&R) procedures in patients with intermittent exotropia, or X(T). METHODS: Medical records of 489 subjects who received unilateral R&R procedures with more than 12 months of follow-up were reviewed. The patients' surgical outcomes with a deviation of less than 10 prism diopters (PD) of exotropia and less than 5 PD of esotropia were defined as a success. Outcomes with more than 11 PD of exotropia were designated as recurrences, and those with esotropia of more than 5 PD after 3 months of operation were noted as overcorrection. The prognostic factors for recurrence were analyzed by the multivariate logistic regression test. RESULTS: Of the 489 subjects, 209 had successful surgical outcomes and 280 had recurrences, whereas overcorrection was not found. Mean age at operation was 8.9 +/- 6.5 years, mean preoperative distant X(T) size was 32.9 +/- 6.0 PD, and mean follow-up period was 27.5 +/- 17.9 months. On the basis of the survival analysis in which survival represented time of recurrence, the mean duration was 31.2 +/- 1.7 months. Age at onset, age at surgery, and immediate postoperative alignment proved to be significant factors influencing a favorable outcome by multivariate logistic regression analysis (P<0.05). However, gender, family history, and preoperative deviation size were not significantly predictive of success (P>0.05). CONCLUSION: In unilateral R&R procedures, increasing patient age at the time of surgery was associated with lower recurrence rates. Recurrence rates also increased with the immediate postoperative angle and with the postoperative angle of deviation at 1, 3, 6, and 12 months. PMID- 21311572 TI - Calcium overload is associated with lipofuscin formation in human retinal pigment epithelial cells fed with photoreceptor outer segments. AB - PURPOSE: To investigate the role of Ca2(+) in lipofuscin formation in human retinal pigment epithelial (RPE) cells that phagocytize bovine photoreceptor outer segments (POSs). METHODS: Cultured human RPE cells fed with 2 * 107per l bovine POS were treated with flunarizine, an antagonist of Ca2(+) channel, or/and centrophenoxine, a lipofuscin scavenger. The Ca2(+) changes and lipofuscin formation were measured with fluoresence dye Fluo-3/AM ester, laser scanning confocal microscopy (LSCM) and flow cytometry (FCM). The activity of RPE cells was measured by methyl thiazolyl tetrazolium (MTT) assay and argyrophilic nucleolar organizer regions (AgNORs) assay. RESULTS: The Ca2(+) fluorescence intensity (CFI) of RPE cells fed with POS was significantly increased compared with the controls (165.36 +/- 29.92 U). It reached a peak with 777.33 +/- 63.86 U (P<0.01) at 12 h, and then decreased but still maintained a high level of 316.90 +/- 36.07 U (P<0.01) for 4 days. Flunarizine and centrophenoxine significantly decreased the Ca2(+) overload to 227.18 +/- 14.00 U at 12 h and 211.06 +/- 20.45 U at 4 days. FCM confirmed these changes. The drugs also showed an inhibitory effect on the lipofuscin formation. The proliferation rate of the cells fed with POS increased significantly. Both drugs had inhibitory effects on the activity of the cultured cells. This tendency was confirmed by AgNORs assay. CONCLUSIONS: The Ca2(+) inflow initiated lipofuscin accumulation in RPE cells fed with POS. Flunarizine and centrophenoxine can decrease Ca2(+) overload and lipofuscin formation in RPE cells, accompanied by maintaining cellular vitality. PMID- 21311573 TI - Reply: the report 'Spontaneous dislocation of an Artisan phakic IOL causing corneal decompensation requiring an endothelial graft' by Harsum et al. PMID- 21311574 TI - In vivo confocal microscopy of ocular surface squamous neoplasia. AB - PURPOSE: To analyse in vivo structural and cellular features of ocular surface squamous neoplasia using clinical confocal microscopy. METHODS: Ten consecutive cases of untreated ocular surface squamous neoplasia were in vivo investigated using clinical confocal microscopy (ConfoScan4, Nidek Co. Ltd, Gamagori, Japan) with a * 40 surface non-contact objective lens. Confocal microscopy images were compared with cytologic samples obtained by scraping technique. RESULTS: Confocal microscopy examination revealed large areas of superficial cells debris and/or keratin debris accompanied by syncytial-like groupings, loss of the normal structure of the conjunctival epithelium and or of the corneal basal epithelium layer, papillomatous organization, large fibrovascular structures, and fine vessels perpendicular to the tumour surface. Sub-epithelial (pre-Bowman) space involvement was documented in four cases (50%). Irregular healthy tissue infiltration at the lateral edge of the lesion was documented in two cases (20%) whereas abrupt demarcation between neoplastic cells and normal epithelium was documented in eight cases (80%). In vivo cyto-morphologic study using clinical confocal microscopy showed cellular anisocytosis, pleocytosis, and anisonucleosis, enlarged nuclei with high nuclear to cytoplasmic ratio, high reflective cytoplasm and indistinct cytoplasmic borders in all cases (100%) . CONCLUSION: CCM appears to be a promising and non-invasive method for in vivo structural and cellular analysis of OSSN. PMID- 21311575 TI - Factors associated with acquisition of human infective and animal infective trypanosome infections in domestic livestock in Western Kenya. AB - BACKGROUND: Trypanosomiasis is regarded as a constraint on livestock production in Western Kenya where the responsibility for tsetse and trypanosomiasis control has increasingly shifted from the state to the individual livestock owner. To assess the sustainability of these localised control efforts, this study investigates biological and management risk factors associated with trypanosome infections detected by polymerase chain reaction (PCR), in a range of domestic livestock at the local scale in Busia, Kenya. Busia District also remains endemic for human sleeping sickness with sporadic cases of sleeping sickness reported. RESULTS: In total, trypanosome infections were detected in 11.9% (329) out of the 2773 livestock sampled in Busia District. Multivariable logistic regression revealed that host species and cattle age affected overall trypanosome infection, with significantly increased odds of infection for cattle older than 18 months, and significantly lower odds of infection in pigs and small ruminants. Different grazing and watering management practices did not affect the odds of trypanosome infection, adjusted by host species. Neither anaemia nor condition score significantly affected the odds of trypanosome infection in cattle. Human infective Trypanosoma brucei rhodesiense were detected in 21.5% of animals infected with T. brucei s.l. (29/135) amounting to 1% (29/2773) of all sampled livestock, with significantly higher odds of T. brucei rhodesiense infections in T. brucei s.l. infected pigs (OR = 4.3, 95%CI 1.5-12.0) than in T. brucei s.l. infected cattle or small ruminants. CONCLUSIONS: Although cattle are the dominant reservoir of trypanosome infection it is unlikely that targeted treatment of only visibly diseased cattle will achieve sustainable interruption of transmission for either animal infective or zoonotic human infective trypanosomiasis, since most infections were detected in cattle that did not exhibit classical clinical signs of trypanosomiasis. Pigs were also found to be reservoirs of infection for T. b. rhodesiense and present a risk to local communities. PMID- 21311576 TI - CAG repeats determine brain atrophy in spinocerebellar ataxia 17: a VBM study. AB - BACKGROUND: Abnormal repeat length has been associated with an earlier age of onset and more severe disease progression in the rare neurodegenerative disorder spinocerebellar ataxia 17 (SCA17). METHODOLOGY/PRINCIPAL FINDINGS: To determine whether specific structural brain degeneration and rate of disease progression in SCA17 might be associated with the CAG repeat size, observer-independent voxel based morphometry was applied to high-resolution magnetic resonance images of 16 patients with SCA17 and 16 age-matched healthy controls. The main finding contrasting SCA17 patients with healthy controls demonstrated atrophy in the cerebellum bilaterally. Multiple regression analyses with available genetic data and also post-hoc correlations revealed an inverse relationship again with cerebellar atrophy. Moreover, we found an inverse relationship between the CAG repeat length and rate of disease progression. CONCLUSIONS: Our results highlight the fundamental role of the cerebellum in this neurodegenerative disease and support the genotype-phenotype relationship in SCA17 patients. Genetic factors may determine individual susceptibility to neurodegeneration and rate of disease progression. PMID- 21311577 TI - Methylation at global LINE-1 repeats in human blood are affected by gender but not by age or natural hormone cycles. AB - Previously, we reported on inter-individual and gender specific variations of LINE-1 methylation in healthy individuals. In this study, we investigated whether this variability could be influenced by age or sex hormones in humans. To this end, we studied LINE-1 methylation in vivo in blood-derived DNA from individuals aged 18 to 64 years and from young healthy females at various hormone levels during the menstrual cycle. Our results show that no significant association with age was observed. However, the previously reported increase of LINE-1 methylation in males was reconfirmed. In females, although no correlation between LINE-1 or Alu methylation and hormone levels was observed, a significant stable individual specific level of methylation was noted. In vitro results largely confirmed these findings, as neither estrogen nor dihydrotestosterone affected LINE-1 or Alu methylation in Hek293T, HUVEC, or MDA-kb2 cell lines. In contrast, a decrease in methylation was observed in estrogen-treated T47-Kbluc cell lines strongly expressing estrogen receptor. The very low expression of estrogen receptor in blood cells could explain the observed insensitivity of methylation at LINE-1 to natural hormonal variations in females. In conclusion, neither natural cycle of hormones nor age has a detectable effect on the LINE-1 methylation in peripheral blood cells, while gender remains an important factor. PMID- 21311578 TI - A phase I randomized placebo controlled trial of the safety of 3% SPL7013 Gel (VivaGel(r)) in healthy young women administered twice daily for 14 days. AB - OBJECTIVE: To assess the safety of VivaGel(r) used vaginally twice daily for 14 days among healthy, sexually-abstinent women, aged 18-24 years in the USA and Kenya. DESIGN: Randomized placebo controlled trial. METHODS: Participants were randomized 2?1, VivaGel to placebo. Safety was assessed by comparing genitourinary (GU) adverse events (AEs), colposcopy findings, vaginal lactobacilli and laboratory abnormalities by arm. RESULTS: Fifty-four women were enrolled; 35 in the VivaGel arm and 19 in the placebo arm. Twenty-six (74%) and 10 (53%) women reported taking all doses of VivaGel and placebo, respectively. No grade 3 or 4 AEs, or serious AEs occurred. Twenty-five (71%) participants in the VivaGel arm compared to 10 (53%) participants in the placebo arm had at least one grade 1 or 2 GU AE associated with product use (RR = 1.4, 95% CI 0.8-2.2). All seven grade 2 GU AEs associated with product use occurred among four women in the VivaGel arm. Vulvar and cervical erythema, cervical lesions, symptomatic BV, urinary frequency and metrorrhagia were more common in the VivaGel arm than the placebo arm. Twenty-nine (83%) participants in the VivaGel arm had a colposcopic finding compared to 10 (53%) participants in the placebo arm (RR = 1.6, 95%CI = 1.0-2.5). Two women in the VivaGel arm prematurely discontinued product use themselves due to a reported GU AE. Persistence of H2O2-producing and non producing lactobacilli did not differ by study arm. CONCLUSIONS: GU AEs and colposcopic findings consistent with mild epithelial irritation and inflammation occurred more commonly among women in the VivaGel arm. TRIAL REGISTRATION: ClinicalTrials.gov NCT003311032. PMID- 21311579 TI - A research agenda to underpin malaria eradication. AB - The interruption of malaria transmission worldwide is one of the greatest challenges for international health and development communities. The current expert view suggests that, by aggressively scaling up control with currently available tools and strategies, much greater gains could be achieved against malaria, including elimination from a number of countries and regions; however, even with maximal effort we will fall short of global eradication. The Malaria Eradication Research Agenda (malERA) complements the current research agenda- primarily directed towards reducing morbidity and mortality--with one that aims to identify key knowledge gaps and define the strategies and tools that will result in reducing the basic reproduction rate to less than 1, with the ultimate aim of eradication of the parasite from the human population. Sustained commitment from local communities, civil society, policy leaders, and the scientific community, together with a massive effort to build a strong base of researchers from the endemic areas will be critical factors in the success of this new agenda. PMID- 21311580 TI - A research agenda for malaria eradication: drugs. AB - Antimalarial drugs will be essential tools at all stages of malaria elimination along the path towards eradication, including the early control or "attack" phase to drive down transmission and the later stages of maintaining interruption of transmission, preventing reintroduction of malaria, and eliminating the last residual foci of infection. Drugs will continue to be used to treat acute malaria illness and prevent complications in vulnerable groups, but better drugs are needed for elimination-specific indications such as mass treatment, curing asymptomatic infections, curing relapsing liver stages, and preventing transmission. The ideal malaria eradication drug is a coformulated drug combination suitable for mass administration that can be administered in a single encounter at infrequent intervals and that results in radical cure of all life cycle stages of all five malaria species infecting humans. Short of this optimal goal, highly desirable drugs might have limitations such as targeting only one or two parasite species, the priorities being Plasmodium falciparum and Plasmodium vivax. The malaria research agenda for eradication should include research aimed at developing such drugs and research to develop situation-specific strategies for using both current and future drugs to interrupt malaria transmission. PMID- 21311581 TI - A research agenda for malaria eradication: monitoring, evaluation, and surveillance. AB - Monitoring, evaluation, and surveillance measure how well public health programs operate over time and achieve their goals. As countries approach malaria elimination, these activities will need to shift from measuring reductions in morbidity and mortality, to detecting infections (with or without symptoms) and measuring transmission. Thus, the monitoring and evaluation and surveillance research and development agenda needs to develop the tools and strategies that will replace passive surveillance of morbidity with active and prompt detection of infection, including confirmation of interruption of transmission by detecting present and past infections, particularly in mobile populations. The capacity to assess trends and respond without delay will need to be developed, so that surveillance itself becomes an intervention. Research is also needed to develop sensitive field tests that can detect low levels of parasitaemia, together with strategies for their implementation. Other areas to explore include the rigorous evaluation of the utility of more detailed maps of disease and infection incidence and prevalence, the development of new maps to inform programmatic responses and the use of surveillance technologies based on cell phone or real time internet Web-based reporting. Because any new strategies for monitoring and evaluation and surveillance for eradication have major implications for program implementation, research is also needed to test systems of delivery for acceptability, feasibility, efficiency, cost-effectiveness, and community engagement. Finally, there is a clear need to systematically review the information from past elimination efforts for malaria and other infectious diseases. PMID- 21311582 TI - The role of research in viral disease eradication and elimination programs: lessons for malaria eradication. AB - By examining the role research has played in eradication or regional elimination initiatives for three viral diseases--smallpox, poliomyelitis, and measles--we derive nine cross-cutting lessons applicable to malaria eradication. In these initiatives, some types of research commenced as the programs began and proceeded in parallel. Basic laboratory, clinical, and field research all contributed notably to progress made in the viral programs. For each program, vaccine was the lynchpin intervention, but as the programs progressed, research was required to improve vaccine formulations, delivery methods, and immunization schedules. Surveillance was fundamental to all three programs, whilst polio eradication also required improved diagnostic methods to identify asymptomatic infections. Molecular characterization of pathogen isolates strengthened surveillance and allowed insights into the geographic source of infections and their spread. Anthropologic, sociologic, and behavioural research were needed to address cultural and religious beliefs to expand community acceptance. The last phases of elimination and eradication became increasingly difficult, as a nil incidence was approached. Any eradication initiative for malaria must incorporate flexible research agendas that can adapt to changing epidemiologic contingencies and allow planning for posteradication scenarios. PMID- 21311583 TI - A research agenda for malaria eradication: diagnoses and diagnostics. AB - Many of malaria's signs and symptoms are indistinguishable from those of other febrile diseases. Detection of the presence of Plasmodium parasites is essential, therefore, to guide case management. Improved diagnostic tools are required to enable targeted treatment of infected individuals. In addition, field-ready diagnostic tools for mass screening and surveillance that can detect asymptomatic infections of very low parasite densities are needed to monitor transmission reduction and ensure elimination. Antibody-based tests for infection and novel methods based on biomarkers need further development and validation, as do methods for the detection and treatment of Plasmodium vivax. Current rapid diagnostic tests targeting P. vivax are generally less effective than those targeting Plasmodium falciparum. Moreover, because current drugs for radical cure may cause serious side effects in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, more information is needed on the distribution of G6PD deficiency variants as well as tests to identify at-risk individuals. Finally, in an environment of very low or absent malaria transmission, sustaining interest in elimination and maintaining resources will become increasingly important. Thus, research is required into the context in which malaria diagnostic tests are used, into diagnostics for other febrile diseases, and into the integration of these tests into health systems. PMID- 21311584 TI - A research agenda for malaria eradication: basic science and enabling technologies. AB - Today's malaria control efforts are limited by our incomplete understanding of the biology of Plasmodium and of the complex relationships between human populations and the multiple species of mosquito and parasite. Research priorities include the development of in vitro culture systems for the complete life cycle of P. falciparum and P. vivax and the development of an appropriate liver culture system to study hepatic stages. In addition, genetic technologies for the manipulation of Plasmodium need to be improved, the entire parasite metabolome needs to be characterized to identify new druggable targets, and improved information systems for monitoring the changes in epidemiology, pathology, and host-parasite-vector interactions as a result of intensified control need to be established to bridge the gap between bench, preclinical, clinical, and population-based sciences. PMID- 21311585 TI - Some lessons for the future from the Global Malaria Eradication Programme (1955 1969). AB - Encouraged by the early success of using dichloro-diphenyl-trichloroethane (DDT) against malaria, the World Health Organization (WHO) embarked on the Global Malaria Eradication Program (GMEP) in 1955. Fourteen years later, the campaign was discontinued when it was recognised that eradication was not achievable with the available means in many areas, although the long-term goal remained unchanged. During the GMEP, malaria was permanently eliminated from many regions. In other areas, however, substantial gains were lost in resurgences, sometimes of epidemic proportions. During the 1970s and 1980s, because of economic and financial crises, international support for malaria control declined rapidly, but in the past decade, following increasing demands from endemic countries and promising results from scaling up of control activities, interest in malaria elimination and the long-term goal of eradication has received international political and financial support. In 2007, there was a renewed call for malaria eradication and a consultative process to define a research and development agenda for malaria eradication (malERA) was established. Lessons learned from the GMEP (1955-1969) highlight the fact that no single strategy can be applicable everywhere and that a long-term commitment with a flexible strategy that includes community involvement, integration with health systems, and the development of agile surveillance systems is needed. PMID- 21311586 TI - A research agenda for malaria eradication: vaccines. AB - Vaccines could be a crucial component of efforts to eradicate malaria. Current attempts to develop malaria vaccines are primarily focused on Plasmodium falciparum and are directed towards reducing morbidity and mortality. Continued support for these efforts is essential, but if malaria vaccines are to be used as part of a repertoire of tools for elimination or eradication of malaria, they will need to have an impact on malaria transmission. We introduce the concept of "vaccines that interrupt malaria transmission" (VIMT), which includes not only "classical" transmission-blocking vaccines that target the sexual and mosquito stages but also pre-erythrocytic and asexual stage vaccines that have an effect on transmission. VIMT may also include vaccines that target the vector to disrupt parasite development in the mosquito. Importantly, if eradication is to be achieved, malaria vaccine development efforts will need to target other malaria parasite species, especially Plasmodium vivax, where novel therapeutic vaccines against hypnozoites or preventive vaccines with effect against multiple stages could have enormous impact. A target product profile (TPP) for VIMT is proposed and a research agenda to address current knowledge gaps and develop tools necessary for design and development of VIMT is presented. PMID- 21311587 TI - A research agenda for malaria eradication: vector control. AB - Different challenges are presented by the variety of malaria transmission environments present in the world today. In each setting, improved control for reduction of morbidity is a necessary first step towards the long-range goal of malaria eradication and a priority for regions where the disease burden is high. For many geographic areas where transmission rates are low to moderate, sustained and well-managed application of currently available tools may be sufficient to achieve local elimination. The research needs for these areas will be to sustain and perhaps improve the effectiveness of currently available tools. For other low to-moderate transmission regions, notably areas where the vectors exhibit behaviours such as outdoor feeding and resting that are not well targeted by current strategies, new interventions that target predictable features of the biology/ecologies of the local vectors will be required. To achieve elimination in areas where high levels of transmission are sustained by very efficient vector species, radically new interventions that significantly reduce the vectorial capacity of wild populations will be needed. Ideally, such interventions should be implemented with a one-time application with a long-lasting impact, such as genetic modification of the vectorial capacity of the wild vector population. PMID- 21311588 TI - A research agenda for malaria eradication: health systems and operational research. AB - Health systems research and development is needed to support the global malaria eradication agenda. In this paper, we (the malERA Consultative Group on Health Systems and Operational Research) focus on the health systems needs of the elimination phase of malaria eradication and consider groupings of countries at different stages along the pathway to elimination. We examine the difference between the last attempt at eradication of malaria and more recent initiatives, and consider the changing health system challenges as countries make progress towards elimination. We review recent technological and theoretical developments related to health systems and the renewed commitment to strengthening health systems for universal access and greater equity. Finally, we identify a number of needs for research and development, including tools for analyzing and improving effective coverage and strengthening decision making and discuss the relevance of these needs at all levels of the health system from the community to the international level. PMID- 21311589 TI - Species delimitation in taxonomically difficult fungi: the case of Hymenogaster. AB - BACKGROUND: False truffles are ecologically important as mycorrhizal partners of trees and evolutionarily highly interesting as the result of a shift from epigeous mushroom-like to underground fruiting bodies. Since its first description by Vittadini in 1831, inappropriate species concepts in the highly diverse false truffle genus Hymenogaster has led to continued confusion, caused by a large variety of prevailing taxonomical opinions. METHODOLOGY: In this study, we reconsidered the species delimitations in Hymenogaster based on a comprehensive collection of Central European taxa comprising more than 140 fruiting bodies from 20 years of field work. The ITS rDNA sequence dataset was subjected to phylogenetic analysis as well as clustering optimization using OPTSIL software. CONCLUSIONS: Among distinct species concepts from the literature used to create reference partitions for clustering optimization, the broadest concept resulted in the highest agreement with the ITS data. Our results indicate a highly variable morphology of H. citrinus and H. griseus, most likely linked to environmental influences on the phenology (maturity, habitat, soil type and growing season). In particular, taxa described in the 19(th) century frequently appear as conspecific. Conversely, H. niveus appears as species complex comprising seven cryptic species with almost identical macro- and micromorphology. H. intermedius and H. huthii are described as novel species, each of which with a distinct morphology intermediate between two species complexes. A revised taxonomy for one of the most taxonomically difficult genera of Basidiomycetes is proposed, including an updated identification key. The (semi )automated selection among species concepts used here is of importance for the revision of taxonomically problematic organism groups in general. PMID- 21311590 TI - Glucose depletion in the airway surface liquid is essential for sterility of the airways. AB - Diabetes mellitus predisposes the host to bacterial infections. Moreover, hyperglycemia has been shown to be an independent risk factor for respiratory infections. The luminal surface of airway epithelia is covered by a thin layer of airway surface liquid (ASL) and is normally sterile despite constant exposure to bacteria. The balance between bacterial growth and killing in the airway determines the outcome of exposure to inhaled or aspirated bacteria: infection or sterility. We hypothesized that restriction of carbon sources--including glucose- in the ASL is required for sterility of the lungs. We found that airway epithelia deplete glucose from the ASL via a novel mechanism involving polarized expression of GLUT-1 and GLUT-10, intracellular glucose phosphorylation, and low relative paracellular glucose permeability in well-differentiated cultures of human airway epithelia and in segments of airway epithelia excised from human tracheas. Moreover, we found that increased glucose concentration in the ASL augments growth of P. aeruginosa in vitro and in the lungs of hyperglycemic ob/ob and db/db mice in vivo. In contrast, hyperglycemia had no effect on intrapulmonary bacterial growth of a P. aeruginosa mutant that is unable to utilize glucose as a carbon source. Our data suggest that depletion of glucose in the airway epithelial surface is a novel mechanism for innate immunity. This mechanism is important for sterility of the airways and has implications in hyperglycemia and conditions that result in disruption of the epithelial barrier in the lung. PMID- 21311591 TI - Meaningful gesture in monkeys? Investigating whether mandrills create social culture. AB - BACKGROUND: Human societies exhibit a rich array of gestures with cultural origins. Often these gestures are found exclusively in local populations, where their meaning has been crafted by a community into a shared convention. In nonhuman primates like African monkeys, little evidence exists for such culturally-conventionalized gestures. METHODOLOGY/PRINCIPAL FINDINGS: Here I report a striking gesture unique to a single community of mandrills (Mandrillus sphinx) among nineteen studied across North America, Africa, and Europe. The gesture was found within a community of 23 mandrills where individuals old and young, female and male covered their eyes with their hands for periods which could exceed 30 min, often while simultaneously raising their elbow prominently into the air. This 'Eye covering' gesture has been performed within the community for a decade, enduring deaths, removals, and births, and it persists into the present. Differential responses to Eye covering versus controls suggested that the gesture might have a locally-respected meaning, potentially functioning over a distance to inhibit interruptions as a 'do not disturb' sign operates. CONCLUSIONS/SIGNIFICANCE: The creation of this gesture by monkeys suggests that the ability to cultivate shared meanings using novel manual acts may be distributed more broadly beyond the human species. Although logistically difficult with primates, the translocation of gesturers between communities remains critical to experimentally establishing the possible cultural origin and transmission of nonhuman gestures. PMID- 21311593 TI - Neuronal genes for subcutaneous fat thickness in human and pig are identified by local genomic sequencing and combined SNP association study. AB - Obesity represents a major global public health problem that increases the risk for cardiovascular or metabolic disease. The pigs represent an exceptional biomedical model related to energy metabolism and obesity in humans. To pinpoint causal genetic factors for a common form of obesity, we conducted local genomic de novo sequencing, 18.2 Mb, of a porcine QTL region affecting fatness traits, and carried out SNP association studies for backfat thickness and intramuscular fat content in pigs. In order to relate the association studies in pigs to human obesity, we performed a targeted genome wide association study for subcutaneous fat thickness in a cohort population of 8,842 Korean individuals. These combined association studies in human and pig revealed a significant SNP located in a gene family with sequence similarity 73, member A (FAM73A) associated with subscapular skin-fold thickness in humans (rs4121165, GC-corrected p-value = 0.0000175) and with backfat thickness in pigs (ASGA0029495, p-value = 0.000031). Our combined association studies also suggest that eight neuronal genes are responsible for subcutaneous fat thickness: NEGR1, SLC44A5, PDE4B, LPHN2, ELTD1, ST6GALNAC3, ST6GALNAC5, and TTLL7. These results provide strong support for a major involvement of the CNS in the genetic predisposition to a common form of obesity. PMID- 21311592 TI - Genetic and evolutionary analyses of the human bone morphogenetic protein receptor 2 (BMPR2) in the pathophysiology of obesity. AB - OBJECTIVE: Human bone morphogenetic protein receptor 2 (BMPR2) is essential for BMP signalling and may be involved in the regulation of adipogenesis. The BMPR2 locus has been suggested as target of recent selection in human populations. We hypothesized that BMPR2 might have a role in the pathophysiology of obesity. RESEARCH DESIGN AND METHODS: Evolutionary analyses (dN/dS, Fst, iHS) were conducted in vertebrates and human populations. BMPR2 mRNA expression was measured in 190 paired samples of visceral and subcutaneous adipose tissue. The gene was sequenced in 48 DNA samples. Nine representative single nucleotide polymorphisms (SNPs) were genotyped for subsequent association studies on quantitative traits related to obesity in 1830 German Caucasians. An independent cohort of 925 Sorbs was used for replication. Finally, relation of genotypes to mRNA in fat was examined. RESULTS: The evolutionary analyses indicated signatures of selection on the BMPR2 locus. BMPR2 mRNA expression was significantly increased both in visceral and subcutaneous adipose tissue of 37 overweight (BMI>25 and <30 kg/m2) and 80 obese (BMI>30 kg/m2) compared with 44 lean subjects (BMI< 25 kg/m2) (P<0.001). In a case-control study including lean and obese subjects, two intronic SNPs (rs6717924, rs13426118) were associated with obesity (adjusted P<0.05). Combined analyses including the initial cohort and the Sorbs confirmed a consistent effect for rs6717924 (combined P = 0.01) on obesity. Moreover, rs6717924 was associated with higher BMPR2 mRNA expression in visceral adipose tissue. CONCLUSION: Combined BMPR2 genotype-phenotype-mRNA expression data as well as evolutionary aspects suggest a role of BMPR2 in the pathophysiology of obesity. PMID- 21311594 TI - Inexplicable inefficiency of avian molt? Insights from an opportunistically breeding arid-zone species, Lichenostomus penicillatus. AB - The majority of bird species studied to date have molt schedules that are not concurrent with other energy demanding life history stages, an outcome assumed to arise from energetic trade-offs. Empirical studies reveal that molt is one of the most energetically demanding and perplexingly inefficient growth processes measured. Furthermore, small birds, which have the highest mass-specific basal metabolic rates (BMR(m)), have the highest costs of molt per gram of feathers produced. However, many small passerines, including white-plumed honeyeaters (WPHE; Lichenostomus penicillatus), breed in response to resource availability at any time of year, and do so without interrupting their annual molt. We examined the energetic cost of molt in WPHE by quantifying weekly changes in minimum resting metabolic rate (RMR(min)) during a natural-molt period in 7 wild-caught birds. We also measured the energetic cost of feather replacement in a second group of WPHEs that we forced to replace an additional 25% of their plumage at the start of their natural molt period. Energy expenditure during natural molt revealed an energy conversion efficiency of just 6.9% (+/-0.57) close to values reported for similar-sized birds from more predictable north-temperate environments. Maximum increases in RMR(min) during the molt of WPHE, at 82% (+/ 5.59) above individual pre-molt levels, were some of the highest yet reported. Yet RMR(min) maxima during molt were not coincident with the peak period of feather replacement in naturally molting or plucked birds. Given the tight relationship between molt efficiency and mass-specific metabolic rate in all species studied to date, regardless of life-history pattern (Efficiency (%) = 35.720 x 10(-0.494BMRm); r2 = 0.944; p = or < 0.0001), there appears to be concomitant physiological costs entrained in the molt period that is not directly due to feather replacement. Despite these high total expenditures, the protracted molt period of WPHE significantly reduces these added costs on a daily basis. PMID- 21311595 TI - Wide-Field Multi-Parameter FLIM: long-term minimal invasive observation of proteins in living cells. AB - Time-domain Fluorescence Lifetime Imaging Microscopy (FLIM) is a remarkable tool to monitor the dynamics of fluorophore-tagged protein domains inside living cells. We propose a Wide-Field Multi-Parameter FLIM method (WFMP-FLIM) aimed to monitor continuously living cells under minimum light intensity at a given illumination energy dose. A powerful data analysis technique applied to the WFMP FLIM data sets allows to optimize the estimation accuracy of physical parameters at very low fluorescence signal levels approaching the lower bound theoretical limit. We demonstrate the efficiency of WFMP-FLIM by presenting two independent and relevant long-term experiments in cell biology: 1) FRET analysis of simultaneously recorded donor and acceptor fluorescence in living HeLa cells and 2) tracking of mitochondrial transport combined with fluorescence lifetime analysis in neuronal processes. PMID- 21311596 TI - Saccharomyces cerevisiae as a model organism: a comparative study. AB - BACKGROUND: Model organisms are used for research because they provide a framework on which to develop and optimize methods that facilitate and standardize analysis. Such organisms should be representative of the living beings for which they are to serve as proxy. However, in practice, a model organism is often selected ad hoc, and without considering its representativeness, because a systematic and rational method to include this consideration in the selection process is still lacking. METHODOLOGY/PRINCIPAL FINDINGS: In this work we propose such a method and apply it in a pilot study of strengths and limitations of Saccharomyces cerevisiae as a model organism. The method relies on the functional classification of proteins into different biological pathways and processes and on full proteome comparisons between the putative model organism and other organisms for which we would like to extrapolate results. Here we compare S. cerevisiae to 704 other organisms from various phyla. For each organism, our results identify the pathways and processes for which S. cerevisiae is predicted to be a good model to extrapolate from. We find that animals in general and Homo sapiens in particular are some of the non fungal organisms for which S. cerevisiae is likely to be a good model in which to study a significant fraction of common biological processes. We validate our approach by correctly predicting which organisms are phenotypically more distant from S. cerevisiae with respect to several different biological processes. CONCLUSIONS/SIGNIFICANCE: The method we propose could be used to choose appropriate substitute model organisms for the study of biological processes in other species that are harder to study. For example, one could identify appropriate models to study either pathologies in humans or specific biological processes in species with a long development time, such as plants. PMID- 21311598 TI - Added value measures in education show genetic as well as environmental influence. AB - Does achievement independent of ability or previous attainment provide a purer measure of the added value of school? In a study of 4000 pairs of 12-year-old twins in the UK, we measured achievement with year-long teacher assessments as well as tests. Raw achievement shows moderate heritability (about 50%) and modest shared environmental influences (25%). Unexpectedly, we show that for indices of the added value of school, genetic influences remain moderate (around 50%), and the shared (school) environment is less important (about 12%). The pervasiveness of genetic influence in how and how much children learn is compatible with an active view of learning in which children create their own educational experiences in part on the basis of their genetic propensities. PMID- 21311597 TI - Potency, efficacy and durability of DNA/DNA, DNA/protein and protein/protein based vaccination using gp63 against Leishmania donovani in BALB/c mice. AB - BACKGROUND: Visceral leishmaniasis (VL) caused by an intracellular protozoan parasite Leishmania, is fatal in the absence of treatment. At present there are no effective vaccines against any form of leishmaniasis. Here, we evaluate the potency, efficacy and durability of DNA/DNA, DNA-prime/Protein-boost, and Protein/Protein based vaccination against VL in a susceptible murine model. METHODS AND FINDINGS: To compare the potency, efficacy, and durability of DNA, protein and heterologous prime-boost (HPB) vaccination against Leishmania donovani, major surface glycoprotein gp63 was cloned into mammalian expression vector pcDNA3.1 for DNA based vaccines. We demonstrated that gp63 DNA based vaccination induced immune responses and conferred protection against challenge infection. However, vaccination with HPB approach showed comparatively enhanced cellular and humoral responses than other regimens and elicited early mixed Th1/Th2 responses before infection. Moreover, challenge with parasites induced polarized Th1 responses with enhanced IFN-gamma, IL-12, nitric oxide, IgG2a/IgG1 ratio and reduced IL-4 and IL-10 responses compared to other vaccination strategies. Although, vaccination with gp63 DNA either alone or mixed with CpG- ODN or heterologously prime-boosting with CpG- ODN showed comparable levels of protection at short-term protection study, DNA-prime/Protein-boost in presence of CpG significantly reduced hepatic and splenic parasite load by 107 fold and 1010 fold respectively, in long-term study. The extent of protection, obtained in this study has till now not been achieved in long-term protection through HPB approach in susceptible BALB/c model against VL. Interestingly, the HPB regimen also showed marked reduction in the footpad swelling of BALB/c mice against Leishmania major infection. CONCLUSION/SIGNIFICANCE: HPB approach based on gp63 in association with CpG, resulted in robust cellular and humoral responses correlating with durable protection against L. donovani challenge till twelve weeks post-vaccination. These results emphasize the potential of DNA prime/Protein-boost vaccination over DNA/DNA and Protein/Protein based vaccination in maintaining long-term immunity against intracellular pathogen like Leishmania. PMID- 21311599 TI - Overexpression of BMI-1 promotes cell growth and resistance to cisplatin treatment in osteosarcoma. AB - BACKGROUND: BMI-1 is a member of the polycomb group of genes (PcGs), and it has been implicated in the development and progression of several malignancies, but its role in osteosarcoma remains to be elucidated. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we found that BMI-1 was overexpressed in different types of osteosarcomas. Downregulation of BMI-1 by lentivirus mediated RNA interference (RNAi) significantly impaired cell viability and colony formation in vitro and tumorigenesis in vivo of osteosarcoma cells. BMI-1 knockdown sensitized cells to cisplatin-induced apoptosis through inhibition of PI3K/AKT pathway. Moreover, BMI-1-depletion-induced phenotype could be rescued by forced expression of BMI-1 wobble mutant which is resistant to inhibition by the small interfering RNA (siRNA). CONCLUSIONS/SIGNIFICANCE: These findings suggest a crucial role for BMI-1 in osteosarcoma pathogenesis. PMID- 21311600 TI - The phagocytosis and toxicity of amorphous silica. AB - BACKGROUND: Inhalation of crystalline silica is known to cause an inflammatory reaction and chronic exposure leads to lung fibrosis and can progress into the disease, silicosis. Cultured macrophages bind crystalline silica particles, phagocytose them, and rapidly undergo apoptotic and necrotic death. The mechanism by which particles are bound and internalized and the reason particles are toxic is unclear. Amorphous silica has been considered to be a less toxic form, but this view is controversial. We compared the uptake and toxicity of amorphous silica to crystalline silica. METHODOLOGY/PRINCIPAL FINDINGS: Amorphous silica particles are phagocytosed by macrophage cells and a single internalized particle is capable of killing a cell. Fluorescent dextran is released from endo-lysosomes within two hours after silica treatment and Caspase-3 activation occurs within 4 hours. Interestingly, toxicity is specific to macrophage cell lines. Other cell types are resistant to silica particle toxicity even though they internalize the particles. The large and uniform size of the spherical, amorphous silica particles allowed us to monitor them during the uptake process. In mCherry-actin transfected macrophages, actin rings began to form 1-3 minutes after silica binding and the actin coat disassembled rapidly following particle internalization. Pre-loading cells with fluorescent dextran allowed us to visualize the fusion of phagosomes with endosomes during internalization. These markers provided two new ways to visualize and quantify particle internalization. At 37 degrees C the rate of amorphous silica internalization was very rapid regardless of particle coating. However, at room temperature, opsonized silica is internalized much faster than non-opsonized silica. CONCLUSIONS/SIGNIFICANCE: Our results indicate that amorphous and crystalline silica are both phagocytosed and both toxic to mouse alveolar macrophage (MH-S) cells. The pathway leading to apoptosis appears to be similar in both cases. However, the result suggests a mechanistic difference between FcgammaRIIA receptor-mediated and non-opsonized silica particle phagocytosis. PMID- 21311601 TI - Stereoselective VO(acac)(2) Catalyzed Epoxidation of Acyclic Homoallylic Diols. Complementary Preparation of C2-syn-3,4-Epoxy Alcohols. AB - A substrate-controlled stereoselective epoxidation of free and monoprotected homoallylic diols was developed. This second-generation approach is based on the incorporation of a primary hydroxy directing group at the C2 methyl carbon, which changes the nature of the vanadium ester intermediate providing a new diastereoselectivity manifold for the preparation of 3,4-epoxy alcohols. This modification favored the formation of the challenging C2-syn epoxy alcohol product not previously available using the standard homoallylic alcohol substrates. These new epoxy alcohol diastereomers expand the scope and generality for the utilization of 3,4-epoxy alcohols as precursors for stereoselective polypropionate synthesis. PMID- 21311602 TI - Sleep and Infant Learning. AB - Human neonates spend the majority of their time sleeping. Despite the limited waking hours available for environmental exploration, the first few months of life are a time of rapid learning about the environment. The organization of neonate sleep differs qualitatively from adult sleep, and the unique characteristics of neonatal sleep may promote learning. Sleep contributes to infant learning in multiple ways. First, sleep facilitates neural maturation, thereby preparing infants to process and explore the environment in increasingly sophisticated ways. Second, sleep plays a role in memory consolidation of material presented while the infant was awake. Finally, emerging evidence indicates that infants process sensory stimuli and learn about contingencies in their environment even while asleep. As infants make the transition from reflexive to cortically mediated control, learned responses to physiological challenges during sleep may be critical adaptations to promote infant survival. PMID- 21311603 TI - Are statin medications associated with lower urinary tract symptoms in men and women? Results from the Boston Area Community Health (BACH) Survey. AB - PURPOSE: Statins may ameliorate lower urinary tract symptoms (LUTS) through anti inflammatory or other pathways. We investigated the association between statin use and storage, voiding, and overall LUTS symptoms. METHODS: The Boston Area Community Health Survey is an epidemiologic study of Boston, MA residents (2301 men; 3202 women) 30-79 years of age. LUTS, voiding, and storage symptoms were ascertained through an interviewer-administered questionnaire and defined as scores of greater than or equal to 8, greater than or equal to 5, and greater than or equal to 4, respectively, on relevant components of the American Urologic Association Symptom Index. Participants were included if they had a history of provider-diagnosed high cholesterol or recently used statin medications (n = 1346). Associations were estimated using odds ratios (ORs) and 95% confidence intervals (CI) from multivariate logistic regression. RESULTS: In multivariate models, statin use had no association with LUTS (OR= 1.03, 95% CI: 0.70, 1.51) among women. No associations were observed for any LUTS among younger (<60) men, but among older (60+) men, we observed significant inverse associations for voiding (OR= 0.23, 95% CI: 0.08, 0.66), storage (OR = 0.24, 95% CI: 0.11, 0.56), and overall LUTS (OR = 0.15, 95% CI: 0.05, 0.44). CONCLUSIONS: Our results suggest that use of statins is associated with a lower prevalence of urologic symptoms among older men but not among women or younger men. PMID- 21311604 TI - Effects of amniotic membrane suspension in the rat alkali burn model. AB - PURPOSE: The main objective of this study is to determine the anti-inflammatory effect of topical amniotic membrane (AM) suspension on corneal alkali burn compared to topical serum eyedrops. METHODS: Thirty eyes from 30 Sprague-Dawley male rats were used. After alkali injuries using 1 N NaOH, the control group (n = 10) received topical PBS four times a day for 2 days. The first study group received topical 30% AM suspension, and the second study group (n = 10) received topical 30% rat serum. Using slit lamp biomicroscopy, injured corneas were evaluated and scored in terms of re-epithelialization, corneal opacity, and neovascularization (NV). Tissue sections were analyzed histologically for cellular infiltration, and immunohistochemical staining was conducted using rat anti-mouse F4/80 antibody for the detection of macrophages. RESULTS: In the inflammatory wound healing model, the epithelial healing ratios of the control group, the AM suspension group, and the serum eyedrop group were 1.8 +/- 15.1%, 34.1 +/- 17.7%, and 41.5 +/- 16.1%, respectively (p < 0.0001). The opacity scores for the control group, the AM suspension group, and the serum eyedrop group 48 h after the insult were 4.8 +/- 0.5, 3.4 +/- 0.5, and 3.0 +/- 0.8, respectively, showing a significant difference (p < 0.0001). Moreover, the NV scores for the control group, AM suspension group, and serum eyedrop group 48 h after the insult were 5.8 +/- 0.9, 4.0 +/- 1.3, and 4.3 +/- 0.9 (p = 0.006). Upon immunohistochemical evaluation using F4/80, significantly fewer F4/80+ cells were recruited in the AM suspension and serum eyedrop groups than the control group (p = 0.027). CONCLUSIONS: The suspension form of the amniotic membrane promoted epithelial healing and reduced corneal opacity and NV in alkali burn. It also suppressed F4/80 expression in the corneal stroma, indicating that the AM suspension maintains its beneficial biochemical effect on inflammatory corneal wound healing in vivo. PMID- 21311606 TI - Embracing complexity: towards more nuanced understandings of social capital and health. PMID- 21311605 TI - Exploring the retinal connectome. AB - PURPOSE: A connectome is a comprehensive description of synaptic connectivity for a neural domain. Our goal was to produce a connectome data set for the inner plexiform layer of the mammalian retina. This paper describes our first retinal connectome, validates the method, and provides key initial findings. METHODS: We acquired and assembled a 16.5 terabyte connectome data set RC1 for the rabbit retina at ~ 2 nm resolution using automated transmission electron microscope imaging, automated mosaicking, and automated volume registration. RC1 represents a column of tissue 0.25 mm in diameter, spanning the inner nuclear, inner plexiform, and ganglion cell layers. To enhance ultrastructural tracing, we included molecular markers for 4-aminobutyrate (GABA), glutamate, glycine, taurine, glutamine, and the in vivo activity marker, 1-amino-4-guanidobutane. This enabled us to distinguish GABAergic and glycinergic amacrine cells; to identify ON bipolar cells coupled to glycinergic cells; and to discriminate different kinds of bipolar, amacrine, and ganglion cells based on their molecular signatures and activity. The data set was explored and annotated with Viking, our multiuser navigation tool. Annotations were exported to additional applications to render cells, visualize network graphs, and query the database. RESULTS: Exploration of RC1 showed that the 2 nm resolution readily recapitulated well known connections and revealed several new features of retinal organization: (1) The well known AII amacrine cell pathway displayed more complexity than previously reported, with no less than 17 distinct signaling modes, including ribbon synapse inputs from OFF bipolar cells, wide-field ON cone bipolar cells and rod bipolar cells, and extensive input from cone-pathway amacrine cells. (2) The axons of most cone bipolar cells formed a distinct signal integration compartment, with ON cone bipolar cell axonal synapses targeting diverse cell types. Both ON and OFF bipolar cells receive axonal veto synapses. (3) Chains of conventional synapses were very common, with intercalated glycinergic-GABAergic chains and very long chains associated with starburst amacrine cells. Glycinergic amacrine cells clearly play a major role in ON-OFF crossover inhibition. (4) Molecular and excitation mapping clearly segregates ultrastructurally defined bipolar cell groups into different response clusters. (5) Finally, low-resolution electron or optical imaging cannot reliably map synaptic connections by process geometry, as adjacency without synaptic contact is abundant in the retina. Only direct visualization of synapses and gap junctions suffices. CONCLUSIONS: Connectome assembly and analysis using conventional transmission electron microscopy is now practical for network discovery. Our surveys of volume RC1 demonstrate that previously studied systems such as the AII amacrine cell network involve more network motifs than previously known. The AII network, primarily considered a scotopic pathway, clearly derives ribbon synapse input from photopic ON and OFF cone bipolar cell networks and extensive photopic GABAergic amacrine cell inputs. Further, bipolar cells show extensive inputs and outputs along their axons, similar to multistratified nonmammalian bipolar cells. Physiologic evidence of significant ON-OFF channel crossover is strongly supported by our anatomic data, showing alternating glycine-to-GABA paths. Long chains of amacrine cell networks likely arise from homocellular GABAergic synapses between starburst amacrine cells. Deeper analysis of RC1 offers the opportunity for more complete descriptions of specific networks. PMID- 21311607 TI - Social capital and health--implications for health promotion. AB - This article is a review of the PhD Thesis of Malin Eriksson, entitled 'Social capital, health and community action - implications for health promotion.' The article presents a theoretical overview of social capital and its relation to health, reviews empirical findings of the links between social capital and (self rated) health, and discusses the usefulness of social capital in health promotion interventions at individual and community levels. Social capital, conceptualized as an individual characteristic, can contribute to the field of health promotion by adding new knowledge on how social network interventions may best be designed to meet the needs of the target group. The distinction of different forms of social capital, i.e. bonding, bridging, and linking, can be useful in mapping the kinds of networks that are available and health-enhancing (or damaging) and for whom. Further, social capital can advance social network interventions by acknowledging the risk for unequal distribution of investments and returns from social network involvement. Social capital, conceptualized as characterizing whole communities, provides a useful framework for what constitutes health supporting environments and guidance on how to achieve them. Mapping and mobilization of social capital in local communities may be one way of achieving community action for health promotion. Social capital is context-bound by necessity. Thus, from a global perspective, it cannot be used as a 'cookbook' on how to achieve supportive environments and community action smoothly. However, social capital can provide new ideas on the processes that influence human interactions, cooperation, and community action for health promotion in various contexts. PMID- 21311608 TI - Effect of naturally acidic agents on microhardness and surface micromorphology of restorative materials. AB - OBJECTIVES: This study investigated the titratable acidity and erosive potential of acidic agents on the microhardness and surface micromorphology of four restorative materials. METHODS: Forty-seven discs of each restorative material; metal-reinforced glass ionomer cement (Ketac-S), resin-modified glass ionomer cement (Fuji II LC), resin composite (Filtek Z250) and amalgam (Valiant-Ph.D.), 12 mm in diameter and 2.5 mm in thickness, were divided into four groups (5 discs/group). Specimens were then immersed for 7 days into four storage media; deionized water (control), citrate buffer solution, green mango juice and pineapple juice. Microhardness testing before and after immersions was performed. Micromorphological changes were evaluated under a scanning electron microscope (SEM). Statistical significance among each group was analyzed using two-way repeated ANOVA and Tukey's tests. RESULTS: The Fuji II LC and the Ketac-S showed the highest reduction in microhardness (P<.05). The Valiant-Ph.D. and the Filtek Z250 showed some minor changes over the period of 7 days. The mango juice produced the greatest degradation effect (P<.05). CONCLUSIONS: This study suggested that for restorations in patients who have tooth surface loss, materials selected should be considered. In terms of materials evaluated, amalgam and resin composite are the most suitable for restorations. PMID- 21311609 TI - Does dental insurance make a difference in type of service received by Iranian dentate adults? AB - OBJECTIVES: To assess the relationship between insurance status and type of service received among dentate adults in a developing oral health care system. METHODS: A cross-sectional survey based on phone interviews in Tehran, Iran. Four trained interviewers collected data using a structured questionnaire. Of 1,531 subjects answering the phone call, 224 were <18 years; of the remaining 1,307, 221 (17%) refused to participate, and 85 (6%) were excluded as edentate or reporting no dental visit, leaving 1,001 eligible subjects in the sample. The questionnaire covered insurance status, socio-demographics, frequency of tooth brushing, dental attendance as reasons for, and time since last dental visit, and dental service received then. Data analysis included the chi-square test and logistic regression. RESULTS: Of the subjects, 71% had a dental insurance. Those with no insurance were more likely to report tooth extractions (OR=1.5) than those with an insurance coverage; for all other treatments no differences according to the insurance status appeared. Among the insured subjects, extractions were more likely for those reporting a problem-based dental visit (OR=6.0) or having a low level of education (OR=2.3). CONCLUSIONS: In Iran, with its developing oral health care system, dental insurance had only a minor impact on dental services reported. PMID- 21311610 TI - The effect of xylitol on the composition of the oral flora: a pilot study. AB - OBJECTIVES: Our aim was to investigate the effect of short-term xylitol consumption on the microbial composition of plaque and saliva. METHODS: Twelve volunteers (22-38 yrs) harboring mutans streptococci (MS) participated in the randomized, double-blind, cross-over study. The experimental chewing gum contained 65% xylitol while the control gum contained 63% sorbitol and 2% maltitol w/w. The polyol dose was approximately 6 g/day. Stimulated saliva and plaque samples were collected before and after the two four-week test periods. The samples were cultured for MS, total streptococci, lactobacilli, and total facultatives. A part of the samples were subjected to DNA-DNA hybridizations of 14 microbial plaque species: Actinomyces naeslundii, A. viscosus, Fusobacterium nucleatum, Lactobacillus acidophilus, L. fermentum, L. paracasei, L. rhamnose, L. plantarum, Streptococcus gordonii, S. oralis, S. parasanguis, S. salivarius, S. sanguinis, Veillonella parvula. RESULTS: The MS counts of the plaque samples collected from "caries-prone" tooth sites decreased significantly (P<.01) in the xylitol gum group but not in the sorbitol gum group. Also the plaque MS percentage decreased significantly in the xylitol gum group (P<.01). The salivary MS counts did not decrease either in the xylitol or in the sorbitol gum groups. Nor were changes detected in the salivary levels of total streptococci or lactobacilli. The DNA-DNA hybridization assay revealed no study-induced changes in the microbial composition of the dental plaque. CONCLUSIONS: Within the limitations of this pilot study, xylitol consumption reduced MS counts in plaque but appeared not to affect the microbial composition of plaque or saliva in general. PMID- 21311611 TI - Assessment of the antibacterial activity of calcium hydroxide combined with chlorhexidine paste and other intracanal medications against bacterial pathogens. AB - OBJECTIVES: The purpose of this study was to assess the in vitro antibacterial activity of four formulations of calcium hydroxide [Ca(OH)(2)] pastes against Enterococcus faecalis, Staphylococcus aureus, Pseudomonas aeruginosa and Streptococcus mutans. METHODS: A broth dilution test was performed, and the lengths of time for different pastes to kill the microbial cells were recorded and statistically analyzed. The following medications were assessed: Group I - Ca(OH)(2) + 2.0% chlorhexidine (CHX) gel; Group II - Ca(OH)(2) + camphorated paramonochlorophenol (CMCP) and propylene glycol; Group III - Ca(OH)(2) + propylene glycol; Group IV - Ca(OH)(2) + saline. RESULTS: The results showed that E. faecalis was the most resistant microorganism. Groups II and III eliminated all the microbial cells in 15 seconds. Group I took 45 seconds to eliminate E. faecalis. CONCLUSIONS: Under the conditions of this study, it was concluded that all the intracanal medications tested showed antibacterial activity. However, the association of Ca(OH)(2) and PMCC or Ca(OH)(2) and propylene glycol showed a better performance, since Groups II and III took a shorter length of time than the other groups to eliminate S. aureus and E. faecalis. PMID- 21311612 TI - Cephalometric comparison of pharyngeal airway in snoring and non-snoring patients. AB - OBJECTIVES: To compare the skeletal and the airway structures of the non-snoring individuals with simple snoring and patients with obstructive sleep apnea (OSA). METHODS: The first group consisted of 20 simple snoring cases (mean age: 37.5+/ 8.05 years; max: 50 years, min: 21 years), the second group consisted of 20 OSA cases (mean age: 40.0+/-8.28 years; max: 54 years, min: 27 years) and the third group consisted of 20 individuals without any respiration problems (mean age: 29.6+/-3.20 years; max: 35 years, min: 24 years). In the cephalometric films, 4 skeletal and 14 airway space measurements were done. The control group and the study groups were compared using the Dunnett t test, and the groups with snoring problems were compared using the Bonferroni test. RESULTS: No statistically significant differences were found between the three groups in skeletal measurements. The OSA and simple snoring groups showed no significant differences in airway measurements. The OSA group showed significantly increased soft palate angulation when compared with the control group (P<.05). Soft palate length, soft palate thickness and soft palate height were significantly higher in the OSA samples than in the control group (P<.001). Pharyngeal spaces in the soft palate area had the significantly lowest values in the OSA group. Inferior pharyngeal space distances in the control group were greater than in both study groups. The OSA group showed the most inferiorly positioned hyoid bone and the difference between OSA and control groups was significant (P<.01). CONCLUSIONS: The decreased airway dimension in the soft palate area due to increased soft palate volume must be taken into consideration in treatment planning of OSA patients. PMID- 21311613 TI - Can rye intake decrease risk of human breast cancer? AB - BACKGROUND: Rye contains more fibre and bioactive compounds than other cereals used for bread production. The fibre and compounds of the fibre complex could provide protection against breast cancer (BC). OBJECTIVE: To review the evidence and theoretical background for a role of rye and some of its components in the prevention of BC. DESIGN: A short review based to a great extent on the work by scientists in the Nordic countries. RESULTS: Some of the possible mechanisms by which the fibre complex could reduce BC risk are presented. The fibre through its effect on fermentation increases esterification of bile acids reducing toxicity of the free bile acids and is involved in the production of butyrate with potential anticancer effects including BC. The fibre reduces the enterohepatic circulation of the oestrogens leading to lower plasma oestrogen concentrations. The fibre complex contains bioactive compounds such as lignans and alkylresorcinols that are antioxidative and potentially anticarcinogenic. In addition, vitamins, minerals, and phytic acid in rye may provide protection against BC. CONCLUSION: Rye products made from wholegrain rye flour are likely to contribute to reduced BC risk. PMID- 21311614 TI - Utility of a three-dimensional endoscopic system in skull base surgery. AB - We evaluated the utility of a three-dimensional (3-D) endoscopic system for skull base surgery. We performed a retrospective case series in a tertiary care medical center. Thirty-six patients underwent skull base (nonpituitary) resections via 3 D endoscopic system. Fifteen patients (42%) were operated for excision of malignant tumors, 19 (53%) for excision of benign lesions, and 3 (8.3%) for skull base reconstruction. The tumors involved the cribriform plate (n = 13), sphenoid sinus and planum (n = 17), clivus (n = 7), and sella (n = 7). Complete tumor resection was achieved in 31 patients and subtotal resection in two. Five patients (14%) had postoperative complications. There was one case of meningitis, and there were no cases of cerebrospinal fluid leak. The surgeon's ability to recognize anatomic structures at the skull base was evaluated using the 3-D and two-dimensional systems. The 3-D technique was superior to the conventional technique for identification of the sella, carotid prominence, optic prominence, cribriform plate, sphenoid, and fovea ethmoidalis. The two systems were equal for detection of the turbinates, clivus, maxillary, ethmoids, and frontal sinuses. Endoscopic skull base surgery with stereoscopic viewing is feasible and safe. Further studies are required to evaluate the advantage of binocular vision in skull base surgery. PMID- 21311615 TI - Surgical Simulation of Extradural Anterior Clinoidectomy through the Trans superior Orbital Fissure Approach Using a Dissectable Three-dimensional Skull Base Model with Artificial Cavernous Sinus. AB - Extradural anterior clinoidectomy via the trans-superior orbital fissure (SOF) approach can provide extensive exposure of the anterior clinoid process and safe drilling under direct view. This technique requires peeling of the dura propria of the temporal lobe from the lateral wall of the SOF. Therefore, cadaveric dissection is mandatory to acquire surgical technique. However, chances for cadaveric dissection are limited. We propose modification of our three dimensional (3-D) skull base model made from surgically dissectable artificial bone with artificial cavernous sinus including multiple membranous layers and neurovascular structures to simulate extradural anterior clinoidectomy via the trans-SOF approach. The 3-D skull base model precisely reproduced the dura propria of the temporal lobe, periosteal bridge, and inner reticular layer in the cavernous sinus and SOF using silicone and varnish. The cranial nerves and blood vessels were made from rubber fibers and vinyl tube. Simulation of extradural anterior clinoidectomy via the trans-SOF approach could be performed on the model using a high-speed drill under the operating microscope. The steps of reconstruction of the skull base model and dissection promote clear understanding of the 3-D anatomy and techniques of extradural anterior clinoidectomy via the trans-SOF approach. PMID- 21311616 TI - Transpalpebral orbitofrontal craniotomy: a minimally invasive approach to anterior cranial vault lesions. AB - To describe a minimally invasive approach to anterior cranial vault pathology using a transpalpebral exposure with a miniorbitofrontal craniotomy. DESIGN: Case series. SETTING: Tertiary referral hospital with multidisciplinary skull base program. Participants include patients with intra-axial and extra-axial anterior skull base lesions who underwent the transpalpebral minicraniotomy approach. MAIN OUTCOME MEASURES: Feasibility of the approach to permit adequate exposure of targeted lesion. We applied this approach in seven patients for the repair of persistent cerebrospinal fluid leaks, pneumocephalus, and the biopsy or resection of midline brain tumors along the anterior cranial base. The approach allowed bimanual instrumentation working with either endoscopic or microscopic visualization for tumor resection and repair of dural and cranial base defects. We measured an average working distance of 4 cm to the sella. The transpalpebral miniorbitofrontal craniotomy approach to the anterior cranial base is quick, adequate, and safe and should be considered as an alternative to extended bifrontal approaches and/or pterional craniotomies for select anterior cranial vault pathology. PMID- 21311617 TI - Evolution of sinonasal symptoms following endoscopic anterior skull base surgery. AB - To assess the severity and evolution of sinonasal symptoms in patients following endoscopic anterior skull base surgery to define the typical postoperative course. DESIGN: Cross sectional study. Participants include 69 patients who underwent endoscopic skull base surgery by a dual surgeon team (otolaryngologist and neurosurgeon) from January 2008 to August 2009. MAIN OUTCOME MEASURES: Sinonasal Outcomes Test (SNOT)-20 survey scores at preoperative and at three postoperative time points. An ordinal logistic regression model was used to analyze the data, summarizing the relationship between the outcome (SNOT score) and the predictor (time point) using an odds ratio. Scores for the symptoms of need to blow nose, sneezing, runny nose, postnasal discharge, thick nasal discharge, ear fullness, and facial pain showed significant worsening at the early postoperative time point. These symptoms showed significant improvement over time; however, scores for post nasal discharge remained high at the late time period compared with baseline. All patients will experience considerable sinonasal symptoms following transnasal endoscopic skull base surgery. Postnasal discharge and thick nasal discharge improve significantly over time. Symptoms approach baseline by 6 to 9 months following surgery. PMID- 21311618 TI - Cerebrospinal fluid leaks of temporal bone origin: selection of surgical approach. AB - Cerebrospinal fluid leaks of the temporal bone are rare, often occult, and sometimes challenging to localize and repair. This is a retrospective study of eight patients with spontaneous cerebrospinal fluid leak and six patients with cerebrospinal fluid leak or encephalocele discovered during chronic ear surgery who were treated in a tertiary medical center over a 5-year period. All received preoperative temporal bone computed tomography, and six also underwent magnetic resonance imaging, one computed tomography cisternography, and one radionuclide cisternography. All patients initially underwent a transmastoid surgical approach. Additional exposure was necessary in three patients; two underwent middle fossa craniotomy and another required minicraniotomy. Primary surgical repair was successful in six of the eight patients with spontaneous leaks and in all six chronic ear patients. Both recurrences required intradural middle fossa repair. An individualized approach should be taken for repair of temporal bone cerebrospinal fluid leaks. In this series, most were successfully repaired in a single stage using a transmastoid or combined approach. The transmastoid approach provides information about the precise size and location of the dural defect. A primary transcranial approach is needed for defects that are multiple, located in the petrous apex, and in revision cases. PMID- 21311619 TI - The orbitopterional approach for large and giant middle cerebral artery aneurysms: a report of two cases and literature review. AB - We report two cases of complex middle cerebral artery aneurysms that were surgically treated using the orbitopterional approach in a two-piece method. The objective of this work is to discuss the usefulness of the orbitopterional approach in the surgical management of large and giant middle cerebral artery aneurysms. A 32-year-old man with a giant aneurysm and a 50-year-old woman with a large and complex aneurysm presented with subarachnoid hemorrhages. Both aneurysms were successfully clipped through an orbitopterional approach. This approach permits a more basal view of the vascular structures with only a minor retraction of frontal lobe. It also increases the view angle and amount of working space available. This approach should be considered as an alternative to the classic pterional craniotomy for the surgical management of such complex lesions. PMID- 21311620 TI - Computed tomography and magnetic resonance imaging of a basilar artery herniation into the sphenoid sinus. AB - We report a rare case of herniation of a basilar artery into the sphenoid sinus after a traumatic skull base fracture. Computed tomographic angiography, magnetic resonance imaging, and cerebral angiogram demonstrated patency of the basilar artery through the fractured clivus at the time of injury, a very rare occurrence. The following day, the patient developed pontine and cerebellar infarcts. In a patient with clival fracture, we advocate fast assessment of vertebrobasilar system with CTA and early anticoagulation treatment in those with vascular entrapment. PMID- 21311621 TI - Dermoid cyst of the orbit and frontal sinus: a case report. AB - We describe a case of a dermoid cyst involving the orbit and frontal sinus of an adult treated at our tertiary referral center, and we review the literature on dermoid cysts of the orbit and frontal sinus. A 28-year-old Caucasian man presented with right-sided supraorbital swelling resulting in diplopia and reduced visual acuity. Computed tomography and magnetic resonance imaging scans were preformed. Although a definitive diagnosis was unclear, the imaging findings were consistent with a dermoid cyst. The lesion was excised through an upper-lid incision. Postoperatively, the patient had a patent frontal sinus and his visual symptoms resolved. Dermoid cysts of the orbit are uncommon lesions that occur primarily in the pediatric population. Lesions extending into the frontal sinus have not been reported before in the literature. In adults, orbital dermoids are more likely to present with bone erosion, and therefore they should be considered in the differential diagnosis for orbital and frontal bone lesions extending into the frontal sinus. PMID- 21311622 TI - Concurrent Cochlear Implantation with Resection of Skull Base Hemangiopericytoma following Sudden Deafness in an Only Hearing Ear. AB - A 72-year-old man with a known left acoustic neuroma, left-sided deafness, and a recently diagnosed right infratemporal fossa (ITF) hemangiopericytoma, presented with sudden deafness in his right ear. Imaging revealed right-sided skull base extension and a large intracranial tumor component. The patient underwent a frontotemporal crainiotomy with concomitant ITF approach. Complete tumor resection was possible, though invasion of the otic capsule was present. Immediately postresection, a cochlear implant (CI) was performed via a transmastoid approach. Full electrode insertion was achieved and confirmed by visualization through the dehiscent middle fossa floor. Mastoid obliteration was then performed with a free fat graft. Postoperative imaging confirmed complete tumor resection (Simpson grade I) and adequate CI placement. Follow-up magnetic resonance imaging was performed at 6 and 12 months, and no tumor recurrence was seen. Prior to CI activation, the patient was completely deaf bilaterally. At 18 month follow-up, however, excellent hearing was achieved with the right CI (16 of 22 electrodes active), and the patient is now conversational with no obvious deficit. His cognitive function is excellent, corresponding to preoperative status, and he is independent in his activities of daily living. Following adjuvant radiation, our patient remains disease free at 18 months. PMID- 21311623 TI - Fatal Bilateral ACA Territory Infarcts after Pituitary Apoplexy: A Case Report and Literature Review. AB - Apoplexy of pituitary tumors is a common occurrence. In addition to commonly known presentations, cerebral infarcts and consequent focal neurologic deficits are a rare presentation. A rare case of pituitary apoplexy with associated subarachnoid bleed and bilateral anterior cerebral artery infarcts is described. Vasospasm leading to cerebral infarcts and consequent focal neurologic deficits as a presentation of pituitary apoplexy needs to be better appreciated. PMID- 21311624 TI - Reconstruction of a nasopharyngeal defect from cervical spine osteoradionecrosis. AB - Osteoradionecrosis of the cervical spine is a rare complication of radiation treatment of head and neck tumors that requires a multidisciplinary approach to management and reconstruction. The case of a 57-year-old man with osteoradionecrosis of the cervical spine secondary to radiation for metastatic hepatocellular carcinoma is presented. Operative debridement of the necrotic bone was performed and the nasopharyngeal soft tissue defect was reconstructed with a radial forearm free flap. The management and reconstruction options for osteoradionecrosis of the cervical spine are discussed. PMID- 21311625 TI - Lipomatosis of the trigeminal nerve causing trigeminal neuralgia: case report and literature review. AB - Cerebellopontine angle lipomas are rare and attempts at surgical excision are associated with significant morbidity. Lipomatosis of nerve, the fatty infiltration of nerves, is a distinct entity. We present a case of intractible trigeminal neuralgia caused by lipomatosis of the trigeminal nerve. CLINICAL CASE: A 25-year-old male presented with severe right-sided trigeminal neuralgia. Imaging showed a lesion involving the trigeminal nerve with signal characteristics of fat. At surgery the lesion was found to be a fatty infiltration of the nerve itself. Surgery was therefore limited to arachnoid adhesiolysis. The patient remains symptom-free and neurologically intact to date. Correctly identifying these lesions as lipomatosis of nerve rather than lipoma of the cerebellopontine angle make it clear that even partial surgical excision will inevitably result in neurological deficit and should not be attempted. However, in the case of intractable trigeminal neuralgia we demonstrate that surgery can still play a role. PMID- 21311626 TI - Tenth and twelfth nerve palsies in a patient with internal carotid artery dissection mistaken for cervical mass lesion. AB - Among the multiple causes for cranial nerve palsies, internal carotid artery dissection is rather uncommon. Patients usually present with unilateral head pain, Horner's syndrome, and signs of cerebral ischemia. We present the case of a 52-year-old male patient, who showed isolated palsies of the tenth and twelfth nerve without any other symptoms. Magnetic resonance imaging (T1) depicted a hyperintense lesion surrounding the internal carotid artery, which was mistaken for a cervical mass, and the patient underwent unnecessary surgical exploration of the neck. Angiography performed afterward could reveal the dissection of the internal carotid artery. This case shows that even in cases with mild and atypic symptoms, internal carotid artery dissection has always to be ruled out in lower cranial nerve palsies. PMID- 21311627 TI - Endoscopic transsphenoidal approach to petrous apex cholesteatoma. AB - The purpose of this report is to present indications and risks of endoscopic transsphenoidal approach to treat petrous apex cholesteatoma. This is a retrospective analysis of two cases of petrous apex cholesteatoma presenting with double vision who underwent an endoscopic transsphenoidal approach at Lariboisiere Hospital, Paris, France. Control of the lesion was satisfactory in both cases. However, a minor pontic stroke resulted in transient hemiparesis in the case with dehiscent dura around the petrous apex cholesteatoma. To our knowledge, there are the first cases of petrous apex cholesteatoma reported to be removed by an endoscopic transsphenoidal approach, using image guidance system, with minimal morbidity. PMID- 21311628 TI - beta-Blockers in coronary artery disease management. AB - Beta-blockers are a multiform group of drugs with multiple applications in the treatment of patients with cardiovascular disease. Their adverse actions are multiple and relate mainly to the beta-adrenergic receptor blockade.They are used to treat all forms of coronary disease, but especially in acute myocardial infarction and acute coronary syndromes. The administration to patients with coronary artery disease resulted in increased survival and improved QoL of these patients and therefore they are a key group of drugs for their management. However, because of side effects, they should be used with caution, especially in hemodynamically unstable patients. Therefore, the choice of the appropriate beta blocker for each patient will result in the best possible results with fewer side effects. PMID- 21311629 TI - microRNAs: a newly described class of encoded molecules that play a role in health and disease. AB - Micro RNAs are evolutionarily conserved, single stranded molecules of about 22 nucleotides in length and function post-transcriptionally by partial binding (partial complementarity) to the mRNA of genes. Binding of a specific miRNA to its target on an mRNA can inhibit its expression by a variety of mechanisms. Although the most common mechanism is translational repression as a result of miRNA binding to the 3'UTR of an mRNA, mechanisms involving mRNA degradation and destabilization have also been described. Micro RNAs are currently considered as "master regulators" of gene expression. Since a single miRNA can bind and consequently regulate the expression of more than 100 different transcripts it has been estimated that miRNAs may be able to regulate up to 30% of the protein coding genes in the human genome. As a result, miRNAs receive widespread attention on their potential role in complicated biological processes and multifactorial diseases. In this review we are discussing the biogenesis of miRNAs, their mode of action as well as their role in human diseases through genetic variations on their target sites. PMID- 21311630 TI - The introduction of medical humanities in the undergraduate curriculum of Greek medical schools: challenge and necessity. AB - BACKGROUND AND AIM: Medical humanities is a multidisciplinary field, consisting of humanities (theory of literature and arts, philosophy, ethics, history and theology), social sciences (anthropology, psychology and sociology) and arts (literature, theater, cinema, music and visual arts), integrated in the undergraduate curriculum of Medical schools. The aim of the present study is to discuss medical humanities and support the necessity of introduction of a medical humanities course in the curriculum of Greek medical schools. MATERIALS, METHODS AND RESULTS: Through the relevant Pub-Med search as well as taking into account various curricula of medical schools, it is evident that medical education today is characterized by acquisition of knowledge and skills and development of medical values and attitudes. Clinical observation with the recognition of key data and patterns in the collected information, is crucial in the final medical decision, i.e. in the complex process, through which doctors accumulate data, reach conclusions and decide on therapy. All sciences included in medical humanities are important for the high quality education of future doctors. The practice of Medicine is in large an image-related science. The history of anatomy and art are closely related, already from the Renaissance time. Studies have shown that attendance of courses on art critics improves the observational skills of medical students. Literature is the source of information about the nature and source of human emotions and behavior and of narratives of illness, and increases imagination. Philosophy aids in the development of analytical and synthetical thinking. Teaching of history of medicine develops humility and aids in avoiding the repetition of mistakes of the past, and quite often raises research and therapeutic skepticism. The comprehension of medical ethics and professional deontology guides the patient-doctor relationship, as well as the relations between physicians and their colleagues. The Medical Humanities course, which is already integrated in the undergraduate curriculum of many medical schools of Europe, USA and Australia, includes lectures by experts and students presentations on the above-mentioned areas and could be offered, for a semester, during the first years. CONCLUSION: The aim of Medical Humanities course is the development of imagination and interpretation of data through analytical complex procedures, the development of skills of close observation and careful interpretation of the patient "language" and the enhancement of empathy for the patients, as well as the development of the physician-patient relationship and finally the conceptualization/construction of personal and professional values. PMID- 21311631 TI - Physiology of bone turnover and its application in contemporary maxillofacial surgery. A review. AB - Backround: Bone formation and remodelling appear as normal developmental or healing processes being inducted by several factors as BMPs, biophysical forces and IGF. A local environment consisted of those factors is created and it is responsible for the changes in the direction bone formation-bone resorption. This exact dynamic property of the bone is evaluated and utilized in the reconstructive surgical treatment of craniofacial deformities. METHODS: Data with regard to the physiology of the biological process of bone turn over are initially analysed, followed by the applications of these mechanisms in orthognathic surgery, cleft lip and palate surgery and reconstructive surgery of midfacial deformities, including experimental data after a review of the contemporary international bibliography.Results-Conclusion: The growing knowledge of bone physiology will influence future surgery techniques and that is going to lead to greater therapeutic capabilities for our patients. PMID- 21311632 TI - Brain visual impairment in childhood: mini review. AB - Cerebral visual impairment (CVI) is one of the leading causes of severe visual impairment in childhood. This article was written to highlight any new knowledge related to cerebral visual impairment in childhood.The international literature was searched to describe the type of visual, oculomotor and / or visuo-perceptual disturbances and to discuss the prognosis. CVI children show a wide range of visual disturbances. These could be either visual, oculomotor, perceptual or a combination of all. The severity of CVI depends on the time, location and extend of the brain damage.The visual function seems to improve in CVI children, especially in the cortically damaged, mainly due to brain plasticity. The increased survival rate of very premature infants during the last decades has increased the incidence of CVI in childhood. Better understanding of the pathophysiological mechanisms of CVI, early diagnosis and early intervention could lead to a better quality of life of these children. PMID- 21311633 TI - Risk factors associated with anemia among Serbian school-age children 7-14 years old: results of the first national health survey. AB - BACKGROUND: Anemia in school-age children is an important public health problem and available data of its prevalence and existing risk factors are essential for planning preventive strategies. The purpose of the current study was to assess the prevalence of and the risk factors associated with anemia among the school age children 7-14 years years old in Serbia. METHODS: In the 2000 National Health Survey, a cross-sectional, multistage cluster survey, performed in 1688 private and refugee campuses households across the territory of Serbia a total of 525 cases were recruited. Socioeconomic, nutritional, physical activities and lifestyle data have been collected and hemoglobin levels were determined. RESULTS: The overall prevalence of anemia was 18% (94/525) [95% CI 15-21]. Age of 12-14 yrs (odds ratio 3.56 [95% CI 2.17-5.85], p=0.000), male gender (3.22 [1.92 5.42], p=0.000), refugee campuses residence (1.98 [1.22- 3.23], p=0.000), lunch skipping (3.43 [1.40-8.33], p=0.007), defective poultry intake (1.65 [1.01-2.62], p=0.047), lack of fish consumption (1.84 [1.07-3.18], p=0.028), disagreement that sport contributes protecting health (3.80 [2.02-6.95], p=0.000), absence of learning (1.80 [1.12-2.90], p=0.016) and defective book reading in free time (2.18 [1.03-4.61], p=0.04), were independent risk factors of anemia. The frequency of anemia was highest in schoolaged of male gender adolescent males 12 14 years old (46/105, 44%); in 12-14 years aged participants living in refugee campuses' households (22/63, 35%); in refugees of 7-14 yrs old male gender (32/101, 32%); in subjects with defective fish and poultry intake (35/118, 30%) and in participants who escaped reading and learning as lifestyle practices in free time (53/204, 26%). CONCLUSIONS: Socioeconomic, nutritional, physical and lifestyle risk factors could be considered by introducing preventive strategies of anemia in school-age children in Serbia. PMID- 21311634 TI - Poor endoscopic findings in children with non variceal upper gastrointestinal bleeding: is biopsy necessary? AB - BACKGROUND: Gastrointestinal bleeding in infants and children is a potentially serious condition in the practice of general pediatrics that requires investigation. The objective of this study is to describe the endoscopic and histopathological findings in children with upper gastrointestinal (UGI) bleeding of non variceal origin. PATIENTS AND METHODS: We performed a retrospective study of the medical records of 181 children, aged 1 month to 15.2 years, with non variceal UGI bleeding, who were admitted in our department over the period 1988 2008 and underwent upper GI endoscopy accompanied by histology. Patients were divided in 4 groups according to their age (=0-1 years, = 1-6 years, C=6-12 years, D= 12-16 years). RESULTS: An endoscopically evident bleeding source was detected in only 5% of all patients. Histological examination revealed increased incidence of eosinophilic infiltration in infants, in contrast to all other age groups, where non-specific or H. pylori related inflammation predominated. Peptic ulcer was found in 4.4% of all patients. CONCLUSION: Although an evident bleeding source was detected in only a small percentage of patients, the accompanying histological examination provided additional information regarding possible underlying diseases and contributed to the subsequent therapeutic management. PMID- 21311635 TI - Percutaneous Kirschner Wire fixation in distal radius metaphyseal fractures in children: does it change the overall outcome? AB - BACKGROUND AND OBJECTIVES: The aim of this study was to determine the effect of Kirschner wire fixation after closed reduction of radial metaphyseal fractures with high risk of redisplacement. PATIENTS AND METHODS: In this retrospective study 40 cases were studied in two groups. In group 1 (n=20, average age 11.2 years), K-wire fixation was performed after closed reduction. In group 2 (n=20 average age 10.1 years), only plaster immobilization was applied following closed reduction. The compared clinical and radiological parameters were, pain, limb deformitiy, range of motion of the wrist, angulation of the fracture site, radial distal epipihyseal angle and severity of translation. RESULTS: Redisplacement rate was 10% in group 1 and 50% in group 2. This shows, Kirschner wire fixation has a positive effect in the maintanence of the initial reduction (p<0.05). Age, gender, reduction quality had no effect on redisplacement (p>0.05). Concerning the severity of translation, the risk of redisplacement increases in stage 3 (50% 100%) and stage 4 (>100%) fractures (p<0,05). Concomitant complete ulnar fracture has also redisplacement risk (p<0.05). Redisplacement risk increases when the distance of fracture line to epiphyseal line was between 11-20 mm (p<0.05). There was no significiant difference between two groups after last evaluation based on radiological parameters and clinical results (p>0.05). CONCLUSIONS: This study shows that Kirschner wire fixation prevents redisplacement in early follow-up of first three weeks but there is no superiority after 20 months follow-up in distal metaphyseal fractures of children. PMID- 21311636 TI - Diagnostic yield and clinical management after capsule endoscopy in daily clinical practice: A single-center experience. AB - BACKGROUND: Capsule endoscopy is an effective method of examining the small bowel in patients with obscure gastrointestinal bleeding, suspected inflammatory mucosal diseases and neoplasms. We herein evaluate the diagnostic yield of capsule endoscopy and its effect on clinical management in daily clinical practice. PATIENTS AND METHODS: One hundred and one capsule endoscopies performed at the Department of Endoscopy and Motility Unit of G. Gennimatas General Hospital of Thessaloniki from May 2007 to February 2009 were retrospectively reviewed. Clinical management following capsule endoscopy findings was evaluated. The most frequent indication was obscure gastrointestinal bleeding (n=56, overt=20). RESULTS: The overall diagnostic yield was 47.5%. The diagnostic yield was 88.9% in patients with overt bleeding who underwent early capsule endoscopy (within 5 days), versus 36.4% in patients who underwent late capsule endoscopy (p=0.028). Moreover, it reached 81.8% in patients with abdominal pain, with/without diarrhea and abnormal biological markers, versus 8.3% in patients with normal biological markers (p<0.0001). Capsule endoscopy was diagnostic in all patients with symptomatic celiac disease. Adenomas were found in 9 of 14 familial adenomatous polyposis patients. Capsule retention (>72 hours) occurred in two patients. Forty-three of 48 (89.6%) patients with positive capsule endoscopy findings that received intervention or medical treatment had positive clinical outcomes. CONCLUSIONS: Capsule endoscopy has an important diagnostic role and contribution in the clinical management during routine clinical practice; however, it remains to be determined which patients are more likely to benefit from this expensive examination. PMID- 21311637 TI - Focal 6-o'-clock Nd: YAG-capsulotomy for the treatment of early onset incomplete capsular block syndrome. AB - We report on a patient who developed capsular block syndrome (CBS) in the early postoperative period with marked myopic shift in absence of anterior dislocation of the posterior-chamber intraocular lens (PC/IOL) and iris diaphragm. Treatment with focal 6-o'-clock Nd: YAG-capsulotomy resulted in complete visual acuity restoration. To the best of our knowledge this is the fist case of early onset CBS with significant myopic shift in absence of anterior PC/IOL dislocation, which was successfully treated with focal 6-o'-clock Nd: YAG-capsulotomy. The possible underlying pathophysiological mechanism is discussed. PMID- 21311638 TI - Exercise-induced rhabdomyolysis from stationary biking: a case report. AB - There are several reports concerning exercise and rabdomyolysis. There has been no report in the English literature of exercise induced rabdomyolisis from a stationary bike.A 63-year-old female recreational athlete presented to our hospital seeking treatment for lower back, leg pain and stiffness after exercising on a stationary bicycle one day prior. Blood work showed a raised CK of 38,120 U/L, a myoglobin of 5330 and an AST 495 U/L with normal urea and electrolytes. Urinalysis remained negative. She was admitted for oral and intravenous hydration and fluid balance monitoringThis is a very rare case of rhabdomyolysis due to exercise. This study highlights the difficulties faced by accident and emergency teams in distinguishing delayed onset muscle soreness (DOMS) from exercise-induced rhabdomyolysis, and reinforces the concept that rhabdomyolysis can occur at any level of exercise intensity. PMID- 21311639 TI - Acute renal dysfunction in a patient presenting with rhabdomyolysis due to Hypothyroidism attributed to Hashimoto's Disease. AB - We describe a patient with rhabdomyolysis and acute renal dysfunction due to hypothyroidism, attributed to Hashimoto's disease. Though rhabdomyolysis could be life-threatening, it is a rare complication of hypothyroidism, especially when other precipitating factors, such as exercise, alcohol, medications or renal failure, are absent. Nevertheless, hypothyroidism can be an authentic cause of rhabdomyolysis and should always be considered when elevated creatine kinase (CK) and other muscle enzymes concentrations cannot be attributed to any major factor. PMID- 21311640 TI - Pyeloureteritis cystica. AB - Pyeloureteritis cystica is a rare situation of the renal pelvis and ureters, characterized by cystical formations of the epithelium. The etiology is unknown and there is no specific treatment. It is usually diagnosed accidently during imaging of the upper urinary tract for different reasons. We present a case of pyeloureteritis cystica. PMID- 21311641 TI - Primary atypical teratoid/rhabdoid tumor of the spine in an infant. AB - Atypical teratoid/rhabdoid tumor of the spine is a rare pediatric neoplasm with poor prognosis. We report a case of an atypical teratoid/rhabdoid tumor of the cervical spine in a 2-months-old infant. The patient presented with rapidly progressing tetraparesis and respiratory failure. Magnetic resonance imaging of the spinal cord revealed an intradural, extramedullary mass occupying the spinal canal on the right at the level of C1-C5. Tumor cells were immunohistochemically positive for epithelial membrane antigen, vimentin, cytokeratins, S-100 protein, and CD57/Leu-7 antigen. Despite chemotherapy, the infant presented with progressive neurological deterioration and died 6 months after initial diagnosis. We review the literature on spinal malignant rhabdoid tumor and discuss the pathology, treatment, and outcome of these rare neoplasms. PMID- 21311642 TI - Successful treatment of a spontaneous haemothorax with recombinant factor VIIa in a haemophilic child with inhibitors. AB - Haemophilia A is an X-linked disorder caused by a deficiency of factor VIII. Haemorrhage in various sites may occur spontaneously or secondary to trauma depending on the severity of the deficiency. Common manifestations include haemarthrosis, epistaxis, gastrointestinal haemorrhage and haematuria. Spontaneous haemothorax has rarely been reported both in children and adults1,2. We report the case of a haemophiliac child presenting with spontaneous haemothorax due to the rarity of this clinical presentation in order to raise the awareness among clinicians. PMID- 21311643 TI - Synchronous oesophagectomy and hepatic resection for metastatic oesophageal cancer: report of a case. AB - BACKGROUND: Oesophageal cancer with liver metastasis is rare and when diagnosed is usually advanced and surgical management is contraindicated.Method-Results: We report the case of a patient who presented with oesophageal cancer and liver metastasis. The patient received chemotherapy combined with RFA to liver tumour. Subsequently she was subjected to oesophagectomy and liver resection of segment 5 extended into segment 8. Patient underwent adjuvant chemotherapy post-operatively and remains disease-free until now, 29 months after operation. CONCLUSION: Oesophageal cancer with concomitant liver metastasis is a rare and lethal disease. Multimodal management including surgery may offer prolonged survival in highly selected patients. PMID- 21311644 TI - Management and visualization of a kinked epidural catheter. AB - A lumbar epidural catheter inserted in a 29-year-old woman for labor analgesia. The catheter failed to provide adequate analgesia. Moreover, after labor, it proved difficult to be removed. After computer tomography (CT) and magnetic resonance impedance (MRI) examination the course of the catheter was visible, the entrapped catheter was dislodged intact, revealing a kinking near its distal tip. Kinking of an epidural catheter leading to entrapment is an unusual complication of epidural catheterization. PMID- 21311645 TI - Tuberculous orchitis US and MRI findings. Correlation with histopathological findings. AB - Tuberculosis of the testis is a rare disease. Although Ultrasound (US) findings of tuberculous epididymo-orchitis have been well described, there are only few reported cases describing the Magnetic Resonance Imaging (MR) findings of this disease. Herein, we describe the US and MR findings in a patient with tuberculous orchitis of the left testis and correlate them with the histopathological findings. In our case, the MR findings differ from previous studies because granulomatous areas in the testis had intermediate to high signal intensity on T2WI, while in all studies granulomatous areas in tuberculous epididymo-orchitis demonstrated invariably low signal intensity. PMID- 21311646 TI - Paraganglioma in a young patient with asymptomatic severe hypertension: a case report and review of the literature. AB - We present a case of a 19-year old woman who was admitted to our department with a recently, and incidentally, diagnosed severe hypertension [220/140 mmHg systolic/diastolic blood pressure (BP)]. The patient was asymptomatic. The laboratory investigation demonstrated both elevated plasma norepinephrine (1807 pg/ml, normal range 120-350 pg/ml) and 24h urinary free catecholamines (483 ug/24h, normal range <150 ug/24h), making the diagnosis of a catecholamineproducing tumor highly probable. Although magnetic resonance imaging of the abdomen showed normal adrenal glands, it revealed a mass (4x4 cm) anterior to the inferior vena cava. The diagnosis of paraganglioma was confirmed by the (131)Imeta- iodobenzylguanidine scintigraphy. Preoperatively, alpha- and beta adrenergic receptor blockers were administered. After successful resection of the tumor, the patient's BP was restored to normal and remained stable during the 3 month follow up. Plasma and 24h urinary catecholamine levels were also normalized. In conclusion, it is important to consider paragangliomas as a possible cause of secondary hypertension and proceed to diagnosis and treatment as described above, since surgical removal of the tumor, especially in sporadic cases, may cure the patient. PMID- 21311647 TI - Pasteurella multocida bacteremia, spontaneous bacterial peritonitis and septic arthritis in a cirrhotic patient. PMID- 21311648 TI - Spontaneous intraorbital hematoma: case report. AB - Spontaneous intraorbital hematoma is an uncommon clinical entity seen in ophthalmology practice. It is poorly represented in the literature. Current evidence attributes it to orbital trauma, neoplasm, vascular malformations, acute sinusitis, and systemic abnormalities. A 65-year-old female presented with spontaneous intraorbital hematoma manifesting as severe ocular pains, eyelid edema, proptosis, and diplopia, without a history of trauma. Computer tomography demonstrated a fairly well defined extraconal lesion with opacification of the paranasal sinuses. The principal differential based on all findings was that of a spreading sinus infection and an extraconal tumor. An unprecedented finding of a spontaneous orbital hematoma was discovered when the patient was taken to theater. We discuss the rarity of this condition and its management. PMID- 21311649 TI - Acquired unilateral rubella retinopathy in adult. AB - The authors report an uncommon case of unilateral rubella retinopathy in an adult patient, described for the first time in medical literature. A 28-year-old healthy white man acquired a case of vasculitis and retinitis on his right eye with sudden vision loss, preceded by an acute viral disease (best correct visual acuity was 20/200). Serology examinations on several viral diseases reveled positive signs to rubella. The treatment was based on corticoids therapy due to macular commitment with final visual acuity of 20/60. Serology concluded rubella etiology, with positive levels in the acute initial stage of viral infection, even during viral retinopathy. PMID- 21311650 TI - Long-term safety and efficacy of selective laser trabeculoplasty as primary therapy for the treatment of pseudoexfoliation glaucoma compared with primary open-angle glaucoma. AB - PURPOSE: To investigate the safety and efficacy of selective laser trabeculoplasty (SLT) to reduce intraocular pressure (IOP) in patients with pseudoexfoliation glaucoma (PXFG) compared with primary open-angle glaucoma (POAG). DESIGN: Non-randomized, prospective, clinical trial. METHODS: Nineteen eyes of 13 patients with POAG and 18 eyes of 13 patients with PXFG were treated with SLT. Patients were followed without antiglaucoma medications until additional medical, laser, or surgical intervention was initiated, at which time they were considered failures, had withdrawn from the study, or underwent a second SLT. RESULTS: The POAG and PXFG eyes showed similar reductions of IOP over the 49 months of follow-up. At 30 months of follow-up the POAG group showed a mean IOP of 17.6 +/- 2.8 mmHg and a mean IOP reduction of 5.7 +/- 2.1 mmHg; the PXFG group showed a mean IOP of 18.3 +/- 4.7 and a mean IOP reduction of 5.3 +/- 3.0 mmHg. Four eyes in the PXFG group and three eyes in the POAG group failed by 30 months. The cumulative probability of success was 74% for the PXFG group and 77% for the POAG group. Four PXFG eyes underwent a second SLT after 30 months of follow-up with a final IOP of 17.6 +/- 2.8 mmHg. There were no serious adverse events. CONCLUSION: SLT is a safe and effective method to lower IOP in patients with PXFG as initial glaucoma therapy. Both groups showed similar IOP reductions and failure rates. PMID- 21311651 TI - Divergence insufficiency associated with high myopia. AB - PURPOSE: Divergence insufficiency is generally regarded as a neurological event. While high myopia is not a well-known cause of divergence insufficiency, we frequently encounter divergence insufficiency in high-myopia patients. Thus, the purpose of this study was to report detailed information on such cases and examine mechanisms that might potentially be responsible for this disorder. METHODS: We investigated 20 cases of high myopia (>-6 D) with divergence insufficiency, 20 cases of high myopia without double vision, and 10 normal cases as controls. Using magnetic resonance imaging (MRI), a coronal image 6 mm anterior to the eyeball-optic nerve junction was measured and used to examine the extraocular muscle (EOM) path shift and angle of the eye. Higher angles in each patient were used for statistical comparison. RESULTS: In high-myopia patients with divergence insufficiency, ocular axis measurements ranged from 24.8 to 31.0 (mean +/- SD: 27.6 +/- 1.6) mm. In high-myopia patients without double vision, the ocular axis length was 27.6 +/- 1.3 mm. In normal cases, the ocular axis length was 23.5 +/- 1.0 mm. The EOM angles in these patients ranged from 100 to 140 (112.9 +/- 9.7) degrees, which was significantly higher (P < 0.05) than that seen in the high-myopia patients without double vision (average EOM angle, 99.2 +/- 2.8 degrees) and normal cases (average EOM angle, 97.9 +/- 3.8 degrees). However, orbital lengths in the patients were 41.0 to 48.9 (44.6 +/- 2.3) mm, which also differed from the high-myopia patients without double vision (average orbital length, 49.9 +/- 2.0 mm) significantly (P < 0.05). In normal cases, average orbital length was 45.5 +/- 1.6 mm. CONCLUSION: In high-myopia patients with divergence insufficiency, nasal shift of the superior rectus and an inferior shift of the lateral rectus were observed, but the orbital lengths were normal. Divergence insufficiency may be caused mechanically by shifts of the EOM due to the presence of a long axis. Therefore, high myopia with a long axis can be considered to be a risk factor for the occurrence of divergence insufficiency. PMID- 21311652 TI - Scleral fixation of foldable acrylic intraocular lenses in aphakic post vitrectomy eyes. AB - PURPOSE: To evaluate the outcome for scleral fixation of a foldable acrylic intraocular lens (IOL) in aphakic post-pars plana vitrectomy eyes for vitreoretinal disease. METHODS: The medical records of 15 patients were reviewed. We evaluated such factors as the underlying vitreoretinal disease, preoperative expected refraction and postoperative actual refraction, best corrected visual acuity (BCVA), corneal endothelial cell density, and intraoperative and postoperative complications. RESULTS: The most common cause of underlying vitreoretinal disease was retinal detachment, which was found in 8 cases. The mean refractive error was -0.10 diopters (D). The mean minimum angle of resolution (logMAR) values of BCVA were 0.27 preoperatively and 0.14 postoperatively. The mean corneal endothelial cell density was 2400 cells/mm(2) preoperatively and 2187 cells/mm(2) postoperatively. No significant differences were observed in either the logMAR values of BCVA or the corneal endothelial cell density before and after surgery. No intraoperative complications occurred in any of the patients. Postoperative complications occurred in a total of 7 eyes, and the most severe complications comprised 4 cases of transient ocular hypertension. CONCLUSION: The results for the scleral fixation of foldable acrylic IOLs were good in aphakic post-vitrectomy eyes. PMID- 21311653 TI - Relationship between chronic sclerosing dacryoadenitis with high level of IgG4 and Castleman disease. AB - The purpose of this study is to present a case of chronic sclerosing dacryoadenitis with high level of IgG4 in a patient diagnosed earlier with Castleman disease. A 79-year-old man noticed a swelling of his lower left jaw that was first seen 8 years earlier. He was diagnosed with Castleman disease from the histopathological examination of a biopsy of the submandibular gland. Since then, the size of the gland had not changed, and he had no systemic inflammatory signs or symptoms. He developed diplopia a year earlier, and CT scans showed bilateral swelling of the lacrimal glands. He was referred to our hospital for further examinations. The patient underwent partial dacryoadenectomy. From the histopathological examinations, he was diagnosed with chronic sclerosing dacryoadenitis with high level of the serum IgG4. He underwent oral steroid therapy and the swollen lacrimal glands were significantly improved. The results suggest that there may be pathological links between IgG4-related dacryoadenitis and Castleman disease. PMID- 21311654 TI - Optical coherence tomography guided peeling of macular epiretinal membrane. AB - Optical coherence tomography (OCT) has emerged as a powerful diagnostic aid in disorders of the vitreoretinal juncture. The purpose of this study is to determine whether OCT can be used as an additional tool for evaluating an architecture including the thickened area, and the identifiable edge of a macular epiretinal membrane (ERM), and helping us to dissect the ERM from the retinal surface more easily and safely. In two cases with ERM, the edges of the membranes were detected by OCT, and the peeling of the membrane was started at the area easily. OCT guided ERM peeling might be useful for dissecting ERM membranes without any hesitation. PMID- 21311655 TI - In vivo characterization of ischemic retina in diabetic retinopathy. AB - OBJECTIVE: The aim of this article is to characterize pathomorphologic changes within particular layers of fluorescein angiographically 'ischemic' compared to 'nonischemic' retina in patients with diabetic retinopathy. METHODS: Cross sectional images of ischemic retinal areas were obtained using Heidelberg Spectralis optical coherence tomography (OCT). Presumed retinal ischemia was defined as focal hypofluorescence in early or early and late phase fluorescein angiography. Pathomorphologic changes on OCT were evaluated and the thickness of retinal layers measured and compared with nonischemic retina at corresponding topographic locations in a matched-pairs design based on 22 eyes (mean age 64 +/- 14). RESULTS: In all eyes, based on spectral domain-OCT cross-section images, the retina layers in ischemic retinal areas could be segmented. Total retinal thickness was significantly increased in ischemic compared to nonischemic areas (381 +/- 94 MUm versus 323 +/- 89 MUm, P = 0.005). Middle retinal layers (inner nuclear layer, outer plexiform layer, and outer nuclear layer) were significantly thickened in retinal ischemic areas (215 +/- 82 MUm versus 168 +/- 62 MUm, P = 0.002). The inner retinal layers (retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer) showed a nonsignificant change (117 +/- 53 MUm versus 98 +/- 30 MUm), while the outer layers were slightly thinned (photoreceptors plus retinal pigment epithelium layer; 51 +/- 9 MUm versus 57 +/- 8 MUm, P = 0.02) in ischemic versus nonischemic retina. CONCLUSIONS: Ischemic diabetic retina seems to be thickened due to thickening of, in particular, middle retinal layers, which can be measured with high-resolution OCT. PMID- 21311656 TI - Comparison of outcomes with multifocal intraocular lenses: a meta-analysis. AB - PURPOSE: To compare the clinical outcome of different multifocal intraocular lenses (IOLs) based on information reported in the international literature. METHODS: All comparative clinical trials that involved implanting at least one multifocal IOL in patients with cataract or presbyopia were extracted from the literature. Clinical outcomes included uncorrected near visual acuity, uncorrected distance visual acuity, visual acuity, spectacle independence, and halos. Random effects meta-analyses were conducted to compare outcomes for the different IOL types. RESULTS: Twenty papers were identified describing 11 monofocal IOLs and 35 multifocal IOLs (19 diffractive, including 12 ReSTOR((r)), 14 refractive, and two accommodative) patient cohorts. Multifocal and monofocal uncorrected distance visual acuity was 0.165 (0.090-0.240) and 0.093 (0.088 0.098), respectively. Compared with monofocal IOLs, multifocal IOLs produced better uncorrected near visual acuity (0.470 [0.322-0.618] versus 0.141 [0.131 0.152]; P < 0.0001), resulting in higher spectacle independence (incidence rate ratio [IRR] 3.62 [2.90-4.52]; P < 0.0001). Compared with refractive multifocal IOLs, diffractive multifocal IOLs produced a similar uncorrected distance visual acuity (0.105 [0.098-0.111] versus 0.085 [0.029-0.140]; P <= 0.78, not significant) and better uncorrected near visual acuity (0.217 [0.118-0.317] versus 0.082 [0.067-0.098]; P < 0.0001) resulting in higher spectacle independence (IRR 1.75 [1.24-2.48]; P < 0.001). Compared with other multifocal IOLs, ReSTOR produced a better uncorrected distance visual acuity (0.067 [0.059 0.076] versus 0.093 [0.088-0.098]; P < 0.0001) and better uncorrected near visual acuity (0.064 [0.046-0.082] versus 0.141 [0.131-0.152]; P < 0.006), resulting in higher spectacle independence (IRR 2.06 [1.26-1.36]; P < 0.004). Halo incidence rates with different types of multifocal implants did not differ significantly. CONCLUSION: Multifocal IOLs provide better uncorrected near visual acuity than monofocal IOLs, leading to less need for spectacles. Multifocal IOL design might play a role in postsurgical outcome, because better results were obtained with diffractive lenses. ReSTOR showed better uncorrected near visual acuity, uncorrected distance visual acuity, and higher spectacle independence rates compared with other multifocal IOLs. PMID- 21311657 TI - Radiation therapy for neovascular age-related macular degeneration. AB - Antivascular endothelial growth factor (anti-VEGF) therapies represent the standard of care for most patients presenting with neovascular (wet) age-related macular degeneration (neovascular AMD). Anti-VEGF drugs require repeated injections and impose a considerable burden of care, and not all patients respond. Radiation targets the proliferating cells that cause neovascular AMD, including fibroblastic, inflammatory, and endothelial cells. Two new neovascular AMD radiation treatments are being investigated: epimacular brachytherapy and stereotactic radiosurgery. Epimacular brachytherapy uses beta radiation, delivered to the lesion via a pars plana vitrectomy. Stereotactic radiosurgery uses low voltage X-rays in overlapping beams, directed onto the lesion. Feasibility data for epimacular brachytherapy show a greatly reduced need for anti-VEGF therapy, with a mean vision gain of 8.9 ETDRS letters at 12 months. Pivotal trials are underway (MERLOT, CABERNET). Preliminary stereotactic radiosurgery data suggest a mean vision gain of 8 to 10 ETDRS letters at 12 months. A large randomized sham controlled stereotactic radiosurgery feasibility study is underway (CLH002), with pivotal trials to follow. While it is too early to conclude on the safety and efficacy of epimacular brachytherapy and stereotactic radiosurgery, preliminary results are positive, and these suggest that radiation offers a more durable therapeutic effect than intraocular injections. PMID- 21311658 TI - Softec HD hydrophilic acrylic intraocular lens: biocompatibility and precision. AB - Intraocular lens development is driven by higher patient expectations for ideal visual outcomes. The recently US Food and Drug Administration-approved Softec HD(TM) lens is an aspheric, hydrophilic acrylic intraocular lens (IOL). The hydrophilic design of the lens is optimized to address dysphotopsia while maintaining biocompatibility, optical clarity, resistance to damage, and resistance to biocontamination. Aspheric lenses decrease postoperative spherical aberration. The addition of the Softec lens provides clinicians with another option for IOL placement; however, randomized comparative studies of this lens to others already on the market remain to be completed. PMID- 21311659 TI - Fulminant bilateral Haemophilus influenzae keratitis in a patient with hypovitaminosis A treated with contaminated autologous serum. AB - We report on a patient with hypovitaminosis A treated with autologous serum (AS) who had bilateral infectious ulcers positive for Haemophilus influenzae. The patient suffered a perforation of his right eye and total healing of his left eye with a residual leukoma. In cases of severe malnutrition, serum levels of vitamins and bacteriostatic and growth factors are reduced, so AS would not only be ineffective but also increase the risk of secondary corneal infection. The prophylactic use of a topical antibiotic would be useful in treatment with AS, especially in patients who do not use and adequately store the eye drops, as in our patient. PMID- 21311660 TI - Freezing adversely affects measurement of vascular endothelial growth factor levels in human aqueous samples. AB - PURPOSE: Aqueous levels of vascular endothelial growth factor (VEGF) can be a surrogate marker of intraocular VEGF activity and a measure of efficacy of anti VEGF treatment in a variety of vasoproliferative retinal disorders, including diabetic retinopathy, age-related macular degeneration, and central retinal vein occlusion. Measurement of the VEGF level may be adversely affected by premeasurement variables, such as freezing and delay, in sample analysis. We aim to evaluate the effect of storage and delayed measurement of human aqueous VEGF levels in these conditions. METHODS: Aqueous samples collected from patients receiving intravitreal injection of bevacizumab for various retinal diseases were divided into two groups. In Group 1, the VEGF levels were analyzed on the same day; in Group 2, the VEGF levels were analyzed after 21 days of freezer storage ( 80 degrees C) using immunobead assay. Statistical comparison using a paired t test was performed between the two groups. RESULTS: Thirty-one aqueous humor samples were collected, and the VEGF concentration for fresh samples was 7.8 +/- 5.9 pg/mL (mean +/- SD) compared to 6.5 +/- 6.0 pg/mL in frozen samples, resulting in a statistically significant difference (P = 0.03). CONCLUSIONS: Accurate measurement of the VEGF level is a vital component of clinical decision making. Delayed analysis of VEGF levels in aqueous samples may result in significant sample degradation and lower levels of measured VEGF. PMID- 21311661 TI - Ten years to VISION 2020: why information matters. PMID- 21311662 TI - Research for VISION 2020. PMID- 21311663 TI - Keeping good nursing records: a guide. PMID- 21311664 TI - Managing patient records in the eye unit. PMID- 21311665 TI - Clinical auditing to improve patient outcomes. PMID- 21311666 TI - Managing information in eye care programmes: the health systems perspective. PMID- 21311667 TI - Information for onchocerciasis control. PMID- 21311668 TI - Ten years to VISION 2020: how are we doing? PMID- 21311669 TI - How to apply an eye pad, shield, and bandage. PMID- 21311670 TI - How to care for and clean optical surfaces. PMID- 21311672 TI - CPD: Test yourself. PMID- 21311671 TI - Trichiasis surgery: a patient-based approach. PMID- 21311674 TI - Magnolol Inhibits LPS-induced NF-kappaB/Rel Activation by Blocking p38 Kinase in Murine Macrophages. AB - This study demonstrates the ability of magnolol, a hydroxylated biphenyl compound isolated from Magnolia officinalis, to inhibit LPS-induced expression of iNOS gene and activation of NF-kappaB/Rel in RAW 264.7 cells. Immunohisto-chemical staining of iNOS and Western blot analysis showed magnolol to inhibit iNOS gene expression. Reporter gene assay and electrophoretic mobility shift assay showed that magnolol inhibited NF-kappaB/Rel transcriptional activation and DNA binding, respectively. Since p38 is important in the regulation of iNOS gene expression, we investigated the possibility that magnolol to target p38 for its anti inflammatory effects. A molecular modeling study proposed a binding position for magnolol that targets the ATP binding site of p38 kinase (3GC7). Direct interaction of magnolol and p38 was further confirmed by pull down assay using magnolol conjugated to Sepharose 4B beads. The specific p38 inhibitor SB203580 abrogated the LPS-induced NF-kappaB/Rel activation, whereas the selective MEK-1 inhibitor PD98059 did not affect the NF-kappaB/Rel. Collectively, the results of the series of experiments indicate that magnolol inhibits iNOS gene expression by blocking NF-kappaB/Rel and p38 kinase signaling. PMID- 21311675 TI - Sigma-1 Receptor Antagonist BD1047 Reduces Allodynia and Spinal ERK Phosphorylation Following Chronic Compression of Dorsal Root Ganglion in Rats. AB - Many therapeutic roles have been proposed for sigma-1 receptor (Sig-1R), but the involvement of Sig-1R in neuropathic pain has currently not been well explored. The present study aimed to evaluate the anti-nociceptive effect of Sig-1R antagonist (BD1047) in a rat model of chronic compression of the dorsal root ganglion (CCD), which is a model of human foraminal stenosis and radicular pain. When stainless steel rods were inserted into the intervertebral foramen of lumbar vertebrae 4 and 5, the CCD developed reliable mechanical (from 3 day) and cold allodynia (from 1 day) as compared with the sham operation group. The spinal expressions of Sig-1R and phosphorylation of extracellular signal-regulated kinase (pERK) were significantly increased from day 3 to day 14 after CCD surgery, as is consistent with the manifestation of allodynia. The BD 1047 (10, 30, 100 mg/kg) administered on postoperative days 0~5 dose-dependently suppressed both the induction of allodynia and the elevation of the spinal pERK expression in a manner comparable with that of gabapentin (100 mg/kg). At 7 days post-CCD surgery, BD1047 (10, 30, 100 mg/kg) administration also produced anti-nociceptive effects on the mechanical and cold allodynia similar with those of gabapentin (100 mg/kg). Therefore, this data suggested that Sig-1R may play an important role in both the development and maintenance of CCD-induced neuropathy. PMID- 21311676 TI - Melatonin Induces Apoptotic Cell Death via p53 in LNCaP Cells. AB - In this study, we examined whether melatonin promotes apoptotic cell death via p53 in prostate LNCaP cells. Melatonin treatment significantly curtailed the growth of LNCaP cells in a dose- and time-dependent manner. Melatonin treatment (0 to 3 mM) induced the fragmentation of poly(ADP-ribose) polymerase (PARP) and activation of caspase-3, caspase-8, and caspase-9. Moreover, melatonin markedly activated Bax expression and decreased Bcl-2 expression in dose increments. To investigate p53 and p21 expression, LNCaP cells were treated with 0 to 3 mM melatonin. Melatonin increased the expressions of p53, p21, and p27. Treatment with mitogen-activated protein kinase (MAPK) inhibitors, PD98059 (ERK inhibitor), SP600125 (JNK inhibitor) and SB202190 (p38 inhibitor), confirmed that the melatonin-induced apoptosis was p21-dependent, but ERK-independent. With the co treatment of PD98059 and melatonin, the expression of p-p53, p21, and MDM2 did not decrease. These effects were opposite to the expression of p-p53, p21, and MDM2 observed with SP600125 and SB202190 treatments. Together, these results suggest that p53-dependent induction of JNK/p38 MAPK directly participates in apoptosis induced by melatonin. PMID- 21311677 TI - Effects of Glycyrrhizae Radix on Repeated Restraint Stress-induced Neurochemical and Behavioral Responses. AB - Glycyrrhizae radix (GR) is an herbal medicine that is commonly used in the East Asia for treating a variety of diseases, including stomach disorders. The objective of the present study was to examine the anti-stress effects of GR on repeated stress-induced alterations of anxiety, learning and memory in rats. Restraint stress was administered for 14 days (2 h/day) to the rats in the Control and GR groups (400 mg/kg/day, PO). Starting on the eighth day, the rats were tested for spatial memory on the Morris water maze test (MW) and for anxiety on the elevated plus maze (EPM). We studied the changes of the expressions of cholineacetyl transferase (ChAT) and tyrosine hydroxylase (TH) in the locus coerleus (LC) using immunohistochemistry. The results showed that the rats treated with GR had significantly reduced stress-induced deficits on their learning and memory on the spatial memory tasks. In addition, the ChAT immunoreactivities were increased. Gor the EPM, treatment with GR increased the time spent in the open arms (p<0.001) as compared to that of the control group. Moreover, GR treatment also normalized the increases of the TH expression in the LC (p<0.001). In conclusion, administration of GR improved spatial learning and memory and reduced stress-induced anxiety. Thus, the present results suggest that GR has the potential to attenuate the behavioral and neurochemical impairments caused by stress. PMID- 21311678 TI - Metformin Inhibits Isoproterenol-induced Cardiac Hypertrophy in Mice. AB - The present study examined whether metformin treatment prevents isoporterenol induced cardiac hypertrophy in mice. Chronic subcutaneous infusion of isoproterenol (15 mg/kg/24 h) for 1 week using an osmotic minipump induced cardiac hypertrophy measured by the heart-to-body weight ratio and left ventricular posterior wall thickness. Cardiac hypertrophy was accompanied with increased interleukin-6 (IL-6), transforming growth factor (TGF)-beta, atrial natriuretic peptide (ANP), collagen I and III, and matrix metallopeptidase 2 (MMP 2). Coinfusion of metformin (150 mg/kg/24 h) with isoproterenol partially inhibited cardiac hypertrophy that was followed by reduced IL-6, TGF-beta, ANP, collagen I and III, and MMP-2. Chronic subcutaneous infusion of metformin did not increase AMP-activated protein kinase (AMPK) activity in heart, although acute intraperitoneal injection of metformin (10 mg/kg) increased AMPK activity. Isoproterenol increased nitrotyrosine levels and mRNA expression of antioxidant enzyme glutathione peroxidase and metformin treatment normalized these changes. These results suggest that metformin inhibits cardiac hypertrophy through attenuating oxidative stress. PMID- 21311679 TI - Plasminogen activator inhibitor-1 antisense oligodeoxynucleotides abrogate mesangial fibronectin accumulation. AB - Excessive extracellular matrix (ECM) accumulation is the main feature of chronic renal disease including diabetic nephropathy. Plasminogen activator inhibitor (PAI)-1 is known to play an important role in renal ECM accumulation in part through suppression of plasmin generation and matrix metalloproteinase (MMP) activation. The present study examined the effect of PAI-1 antisense oligodeoxynucleotide (ODN) on fibronectin upregulation and plasmin/MMP suppression in primary mesangial cells cultured under high glucose (HG) or transforming growth factor (TGF)-beta1, major mediators of diabetic renal ECM accumulation. Growth arrested and synchronized rat primary mesangial cells were transfected with 1 uM phosphorothioate-modified antisense or control mis-match ODN for 24 hours with cationic liposome and then stimulated with 30 mM D-glucose or 2 ng/ml TGF-beta1. PAI-1 or fibronectin protein was measured by Western blot analysis. Plasmin activity was determined using a synthetic fluorometric plasmin substrate and MMP-2 activity analyzed using zymography. HG and TGF-beta1 significantly increased PAI-1 and fibronectin protein expression as well as decreased plasmin and MMP-2 activity. Transient transfection of mesangial cells with PAI-1 antisense ODN, but not mis-match ODN, effectively reversed basal as well as HG- and TGF-beta1-induced suppression of plasmin and MMP-2 activity. Both basal and upregulated fibronectin secretion were also inhibited by PAI-1 antisense ODN. These data confirm that PAI-1 plays an important role in ECM accumulation in diabetic mesangium through suppression of protease activity and suggest that PAI-1 antisense ODN would be an effective therapeutic strategy for prevention of renal fibrosis including diabetic nephropathy. PMID- 21311680 TI - Curcumin Induces Downregulation of E2F4 Expression and Apoptotic Cell Death in HCT116 Human Colon Cancer Cells; Involvement of Reactive Oxygen Species. AB - E2F transcription factors and their target genes have been known to play an important role in cell growth control. We found that curcumin, a polyphenolic phytochemical isolated from the plant Curcuma longa, markedly suppressed E2F4 expression in HCT116 colon cancer cells. Hydrogen peroxide was also found to decrease E2F4 protein level, indicating the involvement of reactive oxygen species (ROS) in curucmin-induced downregulation of E2F4 expression. Involvement of ROS in E2F4 downregulation in response to curcumin was confirmed by the result that pretreatment of cells with N-acetylcystein (NAC) before exposure of curcumin almost completely blocked the reduction of E2F4 expression at the protein as well as mRNA level. Anti-proliferative effect of curcumin was also suppressed by NAC which is consistent to previous reports showing curcumin-superoxide production and induction of poly (ADP-ribose) polymerase (PARP) cleavage as well as apoptosis. Expression of several genes, cyclin A, p21, and p27, which has been shown to be regulated in E2F4-dependent manner and involved in the cell cycle progression was also affected by curcumin. Moreover, decreased (cyclin A) and increased (p21 and p27) expression of these E2F4 downstream genes by curcumin was restored by pretreatment of cells with NAC and E2F4 overexpression which is induced by doxycycline. In addition, E2F4 overexpression was observed to partially ameliorate curcumin-induced growth inhibition by cell viability assay. Taken together, we found curcumin-induced ROS down-regulation of E2F4 expression and modulation of E2F4 target genes which finally lead to the apoptotic cell death in HCT116 colon cancer cells, suggesting that E2F4 appears to be a novel determinant of curcumin-induced cytotoxicity. PMID- 21311681 TI - The development of phasic and tonic inhibition in the rat visual cortex. AB - Gamma-aminobutyric acid (GABA)-ergic inhibition is important in the function of the visual cortex. In a previous study, we reported a developmental increase in GABA(A) receptor-mediated inhibition in the rat visual cortex from 3 to 5 weeks of age. Because this developmental increase is crucial to the regulation of the induction of long-term synaptic plasticity, in the present study we investigated in detail the postnatal development of phasic and tonic inhibition. The amplitude of phasic inhibition evoked by electrical stimulation increased during development from 3 to 8 weeks of age, and the peak time and decay kinetics of inhibitory postsynaptic potential (IPSP) and current (IPSC) slowed progressively. Since the membrane time constant decreased during this period, passive membrane properties might not be involved in the kinetic changes of IPSP and IPSC. Tonic inhibition, another mode of GABA(A) receptor-mediated inhibition, also increased developmentally and reached a plateau at 5 weeks of age. These results indicate that the time course of the postnatal development of GABAergic inhibition matched well that of the functional maturation of the visual cortex. Thus, the present study provides significant insight into the roles of inhibitory development in the functional maturation of the visual cortical circuits. PMID- 21311682 TI - Induction of the Intrinsic Apoptotic Pathway by 3-Deazaadenosine Is Mediated by BAX Activation in HL-60 Cells. AB - 3-Deazaadenosine (DZA), a potent inhibitor of S-adenosylhomocysteine hydrolase, was previously proposed to induce intrinsic apoptosis in human leukemic cells. In the present study, we analyzed the mechanism underlying the DZA-induced intrinsic apoptotic pathway. DZA activated typical caspase-dependent apoptosis in HL-60 cells, as demonstrated by an accumulation of hypo-diploidic cells, the processing of multiple procaspases and an inhibitory effect of z-VAD-Fmk on this cell death. During DZA-induced apoptosis, cytochrome c (cyt c) was released into the cytosol. This was neither prevented by z-VAD-Fmk and nor was it associated with the dissipation of mitochondrial membrane potential (DeltaPsi(m)). Prior to the release of cyt c, BAX was translocated from the cytosol to mitochondria and underwent oligomerization. Finally, the overexpression of BCL-XL protected HL-60 cells from apoptosis by blocking both the cyt c release and BAX oligomerization. Collectively, these findings suggest that DZA may activate intrinsic apoptosis by stimulating BAX activation and thereby the release of cyt c. PMID- 21311683 TI - The role of the pattern edge in goldfish visual motion detection. AB - To understand the function of edges in perception of moving objects, we defined four questions to answer. Is the focus point in visual motion detection of a moving object: (1) the body or the edge of the object, (2) the leading edge or trailing edge of the object, (3) different in scotopic, mesopic and photopic luminance levels, or (4) different for colored objects? We measured the Optomotor Response (OMR) and Edge Triggering Response (ETR) of goldfish. We used a square and sine wave patterns with black and red stripes and a square wave pattern with black and grey stripes to generate OMR's and ETR's in the goldfish. When we used black and red stripes, the black leading edges stimulated an ETR under scotopic conditions, red leading edges stimulated an ETR under photopic conditions, and both black and red leading edges stimulated an ETR under mesopic luminance levels. For black and gray stripes, only black leading edges stimulated an ETR in all three light illumination levels. We observed less OMR and ETR results using the sine wave pattern compared to using the square wave pattern. From these results, we deduced that the goldfish tend to prefer tracking the leading edge of the pattern. The goldfish can also detect the color of the moving pattern under photopic luminance conditions. We decided that ETR is an intriguing factor in OMR, and is suitable as a method of behavioral measurement in visual system research. PMID- 21311684 TI - Functional Expression of TRPV4 Cation Channels in Human Mast Cell Line (HMC-1). AB - Mast cells are activated by specific allergens and also by various nonspecific stimuli, which might induce physical urticaria. This study investigated the functional expression of temperature sensitive transient receptor potential vanilloid (TRPV) subfamily in the human mast cell line (HMC-1) using whole-cell patch clamp techniques. The temperature of perfusate was raised from room temperature (RT, 23~25C to a moderately high temperature (MHT, 37~39C to activate TRPV3/4, a high temperature (HT, 44~46C to activate TRPV1, or a very high temperature (VHT, 53~55C to activate TRPV2. The membrane conductance of HMC-1 was increased by MHT and HT in about 50% (21 of 40) of the tested cells, and the I/V curves showed weak outward rectification. VHT-induced current was 10-fold larger than those induced by MHT and HT. The application of the TRPV4 activator 4alpha phorbol 12,13-didecanoate (4alphaPDD, 1uM) induced weakly outward rectifying currents similar to those induced by MHT. However, the TRPV3 agonist camphor or TRPV1 agonist capsaicin had no effect. RT-PCR analysis of HMC-1 demonstrated the expression of TRPV4 as well as potent expression of TRPV2. The [Ca(2+)](c) of HMC 1 cells was also increased by MHT or by 4alphaPDD. In summary, our present study indicates that HMC-1 cells express Ca(2+)-permeable TRPV4 channels in addition to the previously reported expression of TRPV2 with a higher threshold of activating temperature. PMID- 21311685 TI - Effect of Extremely Low Frequency Electromagnetic Fields (EMF) on Phospholipase Activity in the Cultured Cells. AB - This study was conducted to investigate the effects of extremely low frequency electromagnetic fields (EMF) on signal pathway in plasma membrane of cultured cells (RAW 264.7 cells and RBL 2H3 cells), by measuring the activity of phospholipase A(2) (PLA(2)), phospholipase C (PLC) and phospholipase D (PLD). The cells were exposed to the EMF (60 Hz, 0.1 or 1 mT) for 4 or 16 h. The basal and 0.5 uM melittin-induced arachidonic acid release was not affected by EMF in both cells. In cell-free PLA(2) assay, we failed to observe the change of cPLA(2) and sPLA(2) activity. Also both PLC and PLD activities did not show any change in the two cell lines exposed to EMF. This study suggests that the exposure condition of EMF (60 Hz, 0.1 or 1 mT) which is 2.4 fold higher than the limit of occupational exposure does not induce phospholipases-associated signal pathway in RAW 264.7 cells and RBL 2H3 cells. PMID- 21311686 TI - Neuroprotection by valproic Acid in mouse models of permanent and transient focal cerebral ischemia. AB - Valproic acid (VPA) is a well-known anti-epileptic and mood stabilizing drug. A growing number of reports demonstrate that VPA is neuroprotective against various insults. Despite intensive efforts to develop new therapeutics for stroke over the past two decades, all treatments have thus far failed to show clinical effect because of treatment-limiting side effects of the drugs. Therefore, a safety validated drug like VPA would be an attractive candidate if it has neuroprotective effects against ischemic insults. The present study was undertaken to examine whether pre- and post-insult treatments with VPA protect against brain infarct and neurological deficits in mouse transient (tMCAO) and permanent middle cerebral artery occlusion (pMCAO) models. In the tMCAO (2 hr MCAO and 22 hr reperfusion) model, intraperitoneal injection of VPA (300 mg/kg, i.p.) 30 min prior to MCAO significantly reduced the infarct size and the neurological deficit. VPA treatment immediately after reperfusion significantly reduced the infarct size. The administration of VPA at 4 hr after reperfusion failed to reduce the infarct size and the neurological deficit. In the pMCAO model, treatment with VPA (300 mg/kg, i.p.) 30 min prior to MCAO significantly attenuated the infarct size, but did not affect the neurological deficit. Western blot analysis of acetylated H3 and H4 protein levels in extracts from the ischemic cortical area showed that treatment with VPA increased the expression of acetylated H3 and H4 at 2 hrs after MCAO. These results demonstrated that treatment with VPA prior to ischemia attenuated ischemic brain damage in both mice tMCAO and pMCAO models and treatment with VPA immediately after reperfusion reduced the infarct area in the tMCAO model. VPA could therefore be evaluated for clinical use in stroke patients. PMID- 21311687 TI - Cytotoxic Activity and Structure Activity Relationship of Ceramide Analogues in Caki-2 and HL-60 Cells. AB - B13, a ceramide analogue, is a ceramidase inhibitor and induces apoptosis to give potent anticancer activity. A series of thiourea B13 analogues was evaluated for their in vitro cytotoxic activities against human renal cancer Caki-2 and leukemic cancer HL-60 in the MTT assay. Some compounds (12, 15, and 16) showed stronger cytotoxicity than B13 and C6-ceramide against both tumor cell lines, and compound (12) gave the most potent activity with IC(50) values of 36 and 9 uM, respectively. Molecular modeling of thiourea B13 analogues was carried out by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). We obtained highly reliable and predictive CoMSIA models with cross-validated q(2) values of 0.707 and 0.753 and CoMSIA contour maps to show the structural requirements for potent activity. These data suggest that the amide group of B13 could be replaced by thiourea, that the stereochemistry of 1,3-propandiol may not be essential for activity and that long alkyl chains increase cytotoxicity. PMID- 21311688 TI - Sleep quality predicts quality of life in chronic obstructive pulmonary disease. AB - PURPOSE: Chronic obstructive pulmonary disease (COPD) patients may suffer from poor sleep and health-related quality of life. We hypothesized that disturbed sleep in COPD is correlated with quality of life. METHODS: In 180 patients with COPD (forced expired volume in 1 second [FEV(1)] 47.6 +/- 15.2% predicted, 77.8% male, aged 65.9 +/- 11.7 years), we administered general (Health Utilities Index 3) and disease-specific (St George's Respiratory) questionnaires and an index of disturbed sleep (Pittsburgh Sleep Quality Index). RESULTS: Overall scores indicated poor general (Health Utilities Index 3: 0.52 +/- 0.38), disease- specific (St George's: 57.0 +/- 21.3) quality of life and poor sleep quality (Pittsburgh 11.0 +/- 5.4). Sleep time correlated with the number of respiratory and anxiety symptoms reported at night. Seventy-seven percent of the patients had Pittsburg scores >5, and the median Pittsburgh score was 12. On multivariate regression, the Pittsburgh Sleep Quality Index was an independent predictor of both the Health Utilities Index 3 and the St George's scores, accounting for 3% and 5%, respectively, of the scores. Only approximately 25% of the patients demonstrated excessive sleepiness (Epworth Sleepiness Scale >9). CONCLUSIONS: Most patients with COPD suffer disturbed sleep. Sleep quality was correlated with general and disease-specific quality of life. Only a minority of COPD patients complain of being sleepy. PMID- 21311689 TI - Comparative cost-effectiveness of a fluticasone-propionate/salmeterol combination versus anticholinergics as initial maintenance therapy for chronic obstructive pulmonary disease. AB - PURPOSE: Relative costs and utilization-related outcomes of a fluticasone propionate 250 MUg + salmeterol 50 MUg combination (FSC), tiotropium bromide, and ipratropium as initial maintenance therapy in COPD have not been compared in a commercially-insured population. METHODS: This retrospective, observational cohort study used health care claims data from January 2004 to June 2009 from a large administrative database for patients aged >=40 years with COPD. Time-to first COPD-related health care event beginning 30 days following therapy initiation with FSC (n = 16,684), ipratropium alone or in fixed dose combination with albuterol (n = 14,449), or tiotropium (n = 12,659) was estimated using Cox proportional hazard models that controlled for differences in patient demographic characteristics, health care utilization, and comorbidities at baseline. Mean adjusted costs and numbers of COPD-related health care encounters and prescription medication fills were compared among patients with 12 months of follow-up (FSC, n = 12,595; ipratropium, n = 10,617; tiotropium, n = 9126). RESULTS: With FSC as the reference, risk for a COPD-related hospitalization and/or emergency department visit was significantly higher for ipratropium (hazard ratio [HR] 1.64, 95% confidence interval [CI] 1.50-1.79) and tiotropium (HR 1.29, CI 1.17-1.41). Mean adjusted 12-month COPD-related total health care costs were lower for FSC ($2068, standard deviation [SD] $1190) than for ipratropium ($2841, SD $1858) and tiotropium ($2408, SD $1511, both P <0.05). Mean number of COPD-related hospitalizations, emergency department visits, and outpatient visits associated with an oral corticosteroid or antibiotic were also lower for FSC than for ipratropium and tiotropium (all P <0.05). CONCLUSIONS: In this retrospective "real-world" observational sample of COPD patients, initiating treatment with FSC was associated with significantly better clinical and economic outcomes compared with short- and long-acting anticholinergic therapy. Consistent with the goal of preventing and reducing exacerbations advocated by global guidelines, the findings suggest that initiation of maintenance treatment with FSC may afford clinical benefits at a lower cost than anticholinergic treatment. PMID- 21311690 TI - Fractal correlation property of heart rate variability in chronic obstructive pulmonary disease. AB - BACKGROUND: It was reported that autonomic nervous system function is altered in subjects with chronic obstructive pulmonary disease (COPD). We evaluated short- and long-term fractal exponents of heart rate variability (HRV) in COPD subjects. PATIENTS AND METHODS: We analyzed data from 30 volunteers, who were divided into two groups according to spirometric values: COPD (n = 15) and control (n = 15). For analysis of HRV indices, HRV was recorded beat by beat with the volunteers in the supine position for 30 minutes. We analyzed the linear indices in the time (SDNN [standard deviation of normal to normal] and RMSSD [root-mean square of differences]) and frequency domains (low frequency [LF], high frequency [HF], and LF/HF), and the short- and long-term fractal exponents were obtained by detrended fluctuation analysis. We considered P < 0.05 to be a significant difference. RESULTS: COPD patients presented reduced levels of all linear exponents and decreased short-term fractal exponent (alpha-1: 0.899 +/- 0.18 versus 1.025 +/- 0.09, P = 0.026). There was no significant difference between COPD and control groups in alpha-2 and alpha-1/alpha-2 ratio. CONCLUSION: COPD subjects present reduced short-term fractal correlation properties of HRV, which indicates that this index can be used for risk stratification, assessment of systemic disease manifestations, and therapeutic procedures to monitor those patients. PMID- 21311691 TI - Vitamin D and responses to inhaled fluticasone in severe chronic obstructive pulmonary disease. AB - BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) demonstrate variable responses to inhaled corticosteroids (ICS). The factors contributing to this variability are not well understood. Data from patients with asthma have suggested that low 25-hydroxyvitamin D [25(OH)D] levels contribute to a lack of ICS response in asthma. The objective of this study was to determine whether serum levels of 25(OH)D were related to ICS responses in patients with COPD. METHODS: A total of 60 exsmokers with severe COPD (mean forced expiratory volume in one second [FEV(1)] 1.07 L, 36% of predicted) spent 4 weeks free of any ICS, followed by 4 weeks of ICS use (fluticasone propionate 500 MUg twice daily). Spirometry was performed prior to and after 4 weeks of ICS use. Blood 25(OH)D levels were measured prior to ICS use and examined for relationships to changes in FEV(1) following the 4 weeks of ICS use. RESULTS: The mean 25(OH)D level was 23.3 +/- 9.3 ng/mL. There was a high prevalence of vitamin D insufficiency (35%) and deficiency (40%). There was no relationship between baseline 25(OH)D and changes in FEV(1) following 4 weeks of ICS. CONCLUSION: Baseline 25(OH)D does not contribute to the variation in short-term FEV(1) responses to ICS in patients with severe COPD. PMID- 21311692 TI - Changing patterns in long-acting bronchodilator trials in chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. Developments in the understanding of COPD have led to standard guidelines for diagnosis, treatment, and spirometry assessments, which have in turn influenced trial designs and inclusion criteria. Substantial clinical evidence has been gained from clinical trials and supports a positive approach to COPD management. However, there appear to be changing trends in recent trials. Large bronchodilator studies have reported lower improvements in trough forced expiratory volume in 1 second (FEV(1)) values versus placebo than were observed in earlier studies, while the rate of FEV(1) decline seems to be lower in more recent trials. In addition, recent evidence has called into question the usefulness of bronchodilator reversibility testing as a trial inclusion criterion. Baseline patient populations and use of concomitant medications have also changed over recent years due to increased treatment options. The impact of these many variables on clinical trial results is explored, with a particular focus on changes in inclusion criteria and patient baseline demographics. PMID- 21311693 TI - Optimizing management of chronic obstructive pulmonary disease in the upcoming decade. AB - Chronic obstructive pulmonary disease (COPD) is a leading cause of disability and mortality. Caring for patients with COPD, particularly those with advanced disease who experience frequent exacerbations, places a significant burden on health care budgets, and there is a global need to reduce the financial and personal burden of COPD. Evolving scientific evidence on the natural history and clinical course of COPD has fuelled a fundamental shift in our approach to the disease. The emergence of data highlighting the heterogeneity in rate of lung function decline has altered our perception of disease progression in COPD and our understanding of appropriate strategies for the management of stable disease. These data have demonstrated that early, effective, and prolonged bronchodilation has the potential to slow the rate of decline in lung function and to reduce the frequency of exacerbations that contribute to functional decline. The goals of therapy for COPD are no longer confined to controlling symptoms, reducing exacerbations, and maintaining quality of life, and slowing disease progression is now becoming an achievable aim. A challenge for the future will be to capitalize on these observations by improving the identification and diagnosis of patients with COPD early in the course of their disease, so that effective interventions can be introduced before the more advanced, disabling, and costly stages of the disease. Here we critically review emerging data that underpin the advances in our understanding of the clinical course and management of COPD, and evaluate both current and emerging pharmacologic options for effective maintenance treatment. PMID- 21311694 TI - Unicentric study of cell therapy in chronic obstructive pulmonary disease/pulmonary emphysema. AB - Within the chronic obstructive pulmonary disease (COPD) spectrum, lung emphysema presents, as a primarily histopathologic feature, the destruction of pulmonary parenchyma and, accordingly, an increase in the airflow obstruction distal to the terminal bronchiole. Notwithstanding the significant advances in prevention and treatment of symptoms, no effective or curative therapy has been accomplished. In this context, cellular therapy with stem cells (SCs) arises as a new therapeutic approach, with a wide application potential. The purpose of this study is to evaluate the safety of SCs infusion procedure in patients with advanced COPD (stage IV dyspnea). After selection, patients underwent clinical examination and received granulocyte colony-stimulating factor, immediately prior to the bone marrow harvest. The bone marrow mononuclear cells (BMMC) were isolated and infused into a peripheral vein. The 12-month follow-up showed a significant improvement in the quality of life, as well as a clinical stable condition, which suggest a change in the natural process of the disease. Therefore, the proposed methodology in this study for BMMC cell therapy in sufferers of advanced COPD was demonstrated to be free of significant adverse effects. Although a larger sample and a greater follow-up period are needed, it is possible to infer that BMMC cell therapy introduces an unprecedented change in the course or in the natural history of emphysema, inhibiting or slowing the progression of disease. This clinical trial was registered with ClinicalTrials.gov (NCT01110252) and was approved by the Brazilian National Committee of Ethics in Research (registration no. 14764, CONEP report 233/2009). PMID- 21311695 TI - Economic burden of chronic bronchitis in the United States: a retrospective case control study. AB - BACKGROUND: Chronic bronchitis (CB) is often misdiagnosed or diagnosed at a later stage of chronic obstructive pulmonary disease (COPD). We examined how this later diagnosis may impact health care costs and utilization during the 12 months prior to and 24 months post initial CB diagnosis. METHODS: This retrospective case control analysis used claims data from a large US database from July 1, 2003 through June 30, 2007. Patients with CB aged 40 years and older were propensity matched (N = 11,674) to patients without evidence of COPD or asthma by demographics, CB diagnosis quarter/year, and comorbidities. Group differences were assessed using Student's t-test and Pearson chi-square test statistics. RESULTS: Six months prediagnosis, CB patients had higher frequencies of any hospitalization (9.6%, 6.7%; P < 0.05), emergency department/urgent care visits (13.3%, 6.7%; P < 0.05), and prescriptions (97.3%, 94.1%; P < 0.05). Six months postdiagnosis, CB patients had 5.6 times more hospitalizations (P < 0.05) and 3.1 times more emergency department/urgent care visits (P < 0.05) compared with controls. Mean total costs (US$) for CB patients 12 months prediagnosis were significantly higher than controls (months 12-7: $4212, $3826; P < 0.05; months 6 1: $5289, $4285; P < 0.05). CB patients had higher mean total costs ($8919; P < 0.05) 6 months postdiagnosis. Costs remained $2429 higher for CB patients 19-24 months postdiagnosis (P < 0.05). CONCLUSION: Health care costs and utilization among CB patients are increased both prior to diagnosis and during the 2 years postdiagnosis. This study suggests that not accurately diagnosing CB early has a substantial impact on health care costs, and that the economic burden for CB patients remains elevated even after adjustment for comorbidities associated with COPD. PMID- 21311696 TI - Quality of life in ostomy patients: a qualitative study. AB - PURPOSE: Therapeutic procedures may not only treat disease but also affect patient quality of life. Therefore, quality of life should be measured in order to assess the impact of disease and therapeutic procedures. To identify clients' problems, it is necessary to assess several dimensions of quality of life, including physical, spiritual, economic, and social aspects. In this regard, we conducted a qualitative study to explore quality of life and its dimensions in ostomy patients referred to the Iranian Ostomy Association. METHODS: Fourteen patients were interviewed about their quality of life dimensions by purposeful sampling. Data were gathered by semistructured interviews and analyzed using the content analysis method. RESULTS: Nine main themes emerged using this approach, including physical problems related to colostomy, impact of colostomy on psychological functioning, social and family relationships, travel, nutrition, physical activity, and sexual function, as well as religious and economic issues. CONCLUSION: The findings of the study identified a number of challenges in quality of life for patients with ostomy. The results can be used by health care providers to create a supportive environment that promotes better quality of life for their ostomy patients. PMID- 21311697 TI - Impact of intensive nutritional education with carbohydrate counting on diabetes control in type 2 diabetic patients. AB - This pilot study assessed the impact of an intensive carbohydrate counting educational intervention on diabetes control in type 2 diabetic patients. An experimental, prospective study design was used to assess the effect of nutritional education on diabetes control. The impact and efficacy of the education were measured over a 1-year period through changes in diabetes clinical markers, including hemoglobin A(1c), lipid profiles, glucose levels, patients' energy levels, and sense of well-being. Six patients were initially enrolled in the pilot study, with only three patients completing the intervention phase and the 3-month follow-up. Two patients were followed-up at the 1-year mark for their diabetes, although neither continued participation in the study beyond the 3 month mark. Marginal improvements in clinical markers at 3 months were found. However, due to the small sample size, changes in the clinical profiles may have occurred because of variables unrelated to the nutritional intervention. Further research is indicated for the control of these variables. PMID- 21311698 TI - Results from a systematic writing program in grief process: part 2. AB - OBJECTIVE: This paper, the second of two, reports the results of a systematic writing program used as a tool in the grief process. The study was based on a specifically developed program, which has been described and discussed previously in Part 1. METHODS: The study had a qualitative research design, with a hermeneutic phenomenological approach. The research tool of the study, a writing program, was developed and implemented. A purposive sample was used, consisting of 13 bereaved adults. RESULTS: From an analysis of all of the texts written during the program, we drew four conclusions. Writing yields new thoughts and increases knowledge. Writing is stressful as well as a relief. Writing awakens and preserves memories. The value of writing is related to the forms, ways, and situations of writing. CONCLUSION: We have discussed handling grief with a unique process. Our findings reveal a great breadth and variation in the experiences associated with different writing forms, ways of writing, and writing situations. This implies that flexibility and individualization are important when implementing grief management programs like this. We believe that a structured writing program can be helpful in promoting thought activity and as a tool to gain increased coherence and understanding of the grief process. This writing program may be a valuable guide for program development and future research. PMID- 21311699 TI - Tendency to adhere to provider-recommended treatments and subsequent pain severity among individuals with cancer. AB - BACKGROUND: Patients' general tendency to adhere to health care provider recommended treatments is associated with a number of health outcomes, but whether it influences pain severity over time among individuals with cancer is unclear. We explored the relationship between adherence tendency and subsequent pain severity among cancer patients participating in a randomized controlled trial of coaching to enhance communication with physicians and reduce pain severity. METHODS: Associations between baseline Medical Outcomes Study general adherence measure score and pain severity over 12 weeks were examined with repeated-measures regression models. Model 1 included sociodemographics, study group and site, follow-up point, and baseline pain; Model 2 included these variables plus partner status, physical and mental health status (12-item Short Form Health Survey [SF-12((r))]), and pain control self-efficacy. RESULTS: Of 307 patients randomized, 224 (73%) had at least one follow-up pain severity assessment plus complete data for other model variables and were included in the analyses. In Model 1, adherence tendency was associated with less subsequent pain severity: a one standard deviation increase in adherence tendency was associated with a 0.22-point adjusted mean decrease in pain severity on a 0-10 scale (95% confidence interval 0.40, 0.03). The association was diminished and not statistically significant in Model 2, primarily due to adjustment for the SF-12. CONCLUSION: Tendency to adhere to provider-recommended treatments was associated with subsequent pain severity among individuals with cancer, suggesting a potential way of predicting and intervening to improve cancer pain control. However, the association was attenuated after adjusting for health status, suggesting mediation or confounding of the relationship by health status. PMID- 21311700 TI - Preferences related to attention-deficit/hyperactivity disorder and its treatment. AB - OBJECTIVES: A growing body of literature has highlighted the importance of considering patient preferences as part of the medical decision-making process. The purpose of the current review was to identify and summarize published research on preferences related to attention-deficit/hyperactivity disorder (ADHD) and its treatment, while suggesting directions for future research. METHODS: A literature search identified 15 articles that included a choice-based assessment of preferences related to ADHD. RESULTS: The 15 studies were grouped into four categories based on preference content: preference for a treatment directly experienced by the respondent or the respondent's child; preference for general treatment approaches; preference for a specific treatment attribute or outcome; and preference for aspects of ADHD-related treatment. Preference assessment methods ranged from global single items to detailed choice-based procedures, with few studies using rigorously developed assessment methods. Respondents included patients with ADHD, clinicians, parents, teachers, and survey respondents from the general population. Factors influencing preference include treatment characteristics, effectiveness for specific symptoms, side effects, and respondent demographics. Minimal research has examined treatment preferences of adults with ADHD. DISCUSSION: Because there is no dominant treatment known to be the first choice for all patients, ADHD is a condition for which individual preferences can play an important role when making treatment decisions for individual patients. Given the potential role of preferences in clinical decision-making, more research is needed to better understand the preferences of patients with ADHD and other individuals who are directly affected by the disorder, such as parents and teachers. PMID- 21311701 TI - Treatment planning for children with attention-deficit/hyperactivity disorder: treatment utilization and family preferences. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common condition that often results in child and family functional impairments. Although there are evidence-based treatment modalities available, implementation of and persistence with treatment plans vary with patients. Family preferences also vary and may contribute to variability in treatment utilization. OBJECTIVE: The objective of this study is to describe the evidence-based treatments available for ADHD, identify patterns of use for each modality, and examine patient and parent treatment preferences. METHOD: Literature review. RESULTS: Treatment options differ on benefits and risks/costs. Therefore, treatment decisions are preference sensitive and depend on how an informed patient/parent values the tradeoffs between options. Literature on patient and parent ADHD treatment preferences is based on quantitative research assessing the construct of treatment acceptability and qualitative and quantitative research that assesses preferences from a broader perspective. After a child is diagnosed with ADHD, a variety of factors influence the initial selection of treatment modalities that are utilized. Initial parent and child preferences are shaped by their beliefs about the nature of the child's problems and by information (and misinformation) received from a variety of sources, including social networks, the media, and health care providers. Subsequently, preferences become further informed by personal experience with various treatment modalities. Over time, treatment plans are revisited and revised as families work with their health care team to establish a treatment plan that helps their child achieve goals while minimizing harms and costs. CONCLUSIONS: Studies have not been able to determine the extent to which utilization rates are consistent with the underlying distribution of informed patient/parent treatment preferences. There are challenges to ensure that patient/parent preferences are consistently well informed, elicited, and discussed in the treatment planning process. Interventions are needed to promote such interactions. PMID- 21311702 TI - Getting a Knack for NAC: N-Acetyl-Cysteine. AB - N-acetyl-cysteine, N-acetylcysteine, N-acetyl cysteine, and N-acetyl-L-cysteine are all designations for the same compound, which is abbreviated as NAC. NAC is a precursor to the amino acid cysteine, which ultimately plays two key metabolic roles. Through its metabolic contribution to glutathione production, cysteine participates in the general antioxidant activities of the body. Through its role as a modulator of the glutamatergic system, cysteine influences the reward reinforcement pathway. Because of these functions, NAC may exert a therapeutic effect on psychiatric disorders allegedly related to oxidative stress (e.g., schizophrenia, bipolar disorder) as well as psychiatric syndromes characterized by impulsive/compulsive symptoms (e.g., trichotillomania, pathological nail biting, gambling, substance misuse). While the dosages, pharmacological strategies (monotherapy versus augmentation), and long-term risks are not fully evident, NAC appears to be a promising, relatively low-risk intervention. If so, NAC might be an ideal treatment strategy for a variety of psychiatric conditions in both psychiatric and primary care settings. PMID- 21311703 TI - International assessment of functional skills in people with schizophrenia. AB - Disability is very common in schizophrenia and is related to cognitive impairments, some illness symptoms, and deficits in skills needed to function in the everyday environment (i.g., functional capacity). Research on measurement of the ability to perform the skilled acts required for successful everyday functioning has advanced considerably in the past five years. However, different environmental situations require different skill sets, and one of the major challenges in research on functional capacity is identification of the differences in skills that are required across environments. This article reviews the challenges associated with international measurement of functional capacity. The authors present their perspectives on what can be done with existing measures and what needs to be done in the future. As America becomes more multicultural, these challenges will also occur close to home as well. PMID- 21311704 TI - L-methylfolate Plus SSRI or SNRI from Treatment Initiation Compared to SSRI or SNRI Monotherapy in a Major Depressive Episode. AB - OBJECTIVE: Evaluate the efficacy of L-methylfolate in combination with SSRI or SNRI compared to SSRI or SNRI monotherapy in a major depressive episode. DESIGN: A retrospective analysis of L-methylfolate plus SSRI/SNRI at treatment initiation (n=95) and SSRI/SNRI monotherapy (n=147) from patient charts. SETTING: Outpatient, private psychiatric clinic/practice. PARTICIPANTS: Adults 18 to 70 with major depressive episode (single or recurrent). MEASUREMENTS: Clinical Global Impressions-Severity (CGI-S) and safety/tolerability measures. RESULTS: Major improvement (CGI-S reduced by >=2 points) was experienced by 18.5 percent of L-methylfolate plus SSRI/SNRI patients (CGI-S=4-5) compared to 7.04 percent of SSRI/SNRI monotherapy (p=0.01) patients at 60 days. Forty percent of L methylfolate plus SSRI/SNRI patients with greater functional impairment (CGI-S=5) experienced major improvement compared to 16.3 percent of SSRI/SNRI monotherapy patients (p=0.02). Median times to major improvement were 177 days for L methylfolate plus SSRI/SNRI patients and 231 days for SSRI/SNRI monotherapy patients (p=0.03). Median time to major improvement for L-methylfolate plus SSRI/SNRI patients with greater functional impairment (CGI-S=5) was 85 days and 150 days for SSRI/SNRI monotherapy patients (p=0.018). There were no significant differences between groups in adverse events. Discontinuation due to adverse events was 17.9 percent in L-methylfolate plus SSRI/SNRI patients compared to 34 percent in the SSRI/SNRI monotherapy patients over duration of the study (p=0.0078). CONCLUSION: L-methylfolate plus antidepressant at treatment onset was more effective in improving depressive symptoms and function measured by CGI-S scores within 60 days than antidepressant monotherapy, led to major symptomatic improvement more rapidly than SSRI/SNRI monotherapy, and was better tolerated. PMID- 21311705 TI - A Naturalistic, Single-blind Comparison of Rapid Dose Administration of Divalproex ER Versus Quetiapine in Patients with Acute Bipolar Mania. AB - OBJECTIVE: When treating acute bipolar mania, the speed of onset of anti-manic effects is crucial. Quetiapine and divalproex ER are widely used agents to treat acute mania. Rapid dose administration regimens for divalproex ER and for quetiapine have been described. We conducted a naturalistic, head-to-head, pilot study comparing the efficacy and safety of rapidly titrated divalproex ER and quetiapine in acutely manic inpatients, with the primary outcome being improvement within the first seven days. METHOD: Thirty consenting bipolar patients with acute mania (Young Mania Rating Scale >17 ) needing hospitalization due to acute mania were randomized to receive rapidly loaded divalproex ER (30mg/kg/day) or rapidly titrated quetiapine (200mg Day 1, raised by 200mg/day up to 800mg as tolerated). Assessments were made on Day 1 (baseline), Day 3, Day 7, Day 14, and Day 21 and included Young Mania Rating Scale, Clinical Global Impressions-Severity, Clinical Global Impressions-Improvement, and Montgomery Asberg Depression Rating Scale. Raters but not patients or treating physicians were blinded (single-blinded study). RESULTS: Subjects in both treatment groups exhibited significant and rapid improvement in their mania starting at Day 3 with few significant adverse effects; however, there were no significant differences in the degree or rate of improvement between the two treatment groups in any of the efficacy or adverse effects scales. CONCLUSION: RESULTS of this small study indicate that rapid-dose administration of both quetiapine and divalproex ER produce rapid improvement in acute mania within the first seven days and both seem to be well tolerated. PMID- 21311706 TI - How to Use Your Clinical Judgment to Screen for and Diagnose Psychogenic Nonepileptic Seizures without Video Electroencephalogram. AB - In this article, the authors emphasize the value of proper understanding of the nature of psychogenic nonepileptic seizures in order to reach the right diagnosis based on clinical symptoms and signs. The authors review the literature and provide information regarding epidemiology, etiology and pathogenesis, diagnosis, and features of psychogenic nonepileptic seizures as they compare to epileptic seizures. The authors make suggestions for treatment and provide a clinical diagnostic tool that can aid clinicians in identifying a psychogenic nonepileptic seizure episode. PMID- 21311707 TI - Higher cortical functions: attention and vigilance. AB - The ability to sustain attention over time (vigilance) is a cognitive function that often is impaired in patients with psychiatric disorders. Attention has been found to be disordered in a number of psychiatric conditions, including attention deficit disorder, schizophrenia, antisocial personality disorder, and the impulse control disorders. Less widely known is the finding that attention also is affected in patients suffering from anxiety disorders, posttraumatic stress disorder, mood disorders, and borderline personality disorder.In this article, the significance of attention deficits with regard to the mood disorders, anxiety disorders, posttraumatic stress disorder, and borderline personality disorder, is described. PMID- 21311708 TI - The Dopamine Dilemma-Part II: Could Stimulants Cause Tolerance, Dependence, and Paradoxical Decompensation? AB - In this commentary, the author calls to attention that stimulants are commonly prescribed to children for years without seeming regard to the lack of studies on efficacy and safety during long-term use. The author examines evidence for stimulants losing efficacy over time and provides multiple possible mechanisms. The potential for paradoxical decompensation, an iatrogenic worsening of symptoms over time, is considered and discussed. Recommendations for detecting and responding to possible stimulant tolerance and dependence are provided. PMID- 21311710 TI - Cardiovascular guidelines in German health care: confusion in implementation. PMID- 21311711 TI - Physicians' knowledge of and compliance with guidelines: an exploratory study in cardiovascular diseases. AB - BACKGROUND: Guidelines are one of the means by which health care organizations try to improve health care and lower its cost. Studies have shown, however, that guidelines are still not being adequately implemented. In this exploratory study, we examine the link between physicians' knowledge of and compliance with guidelines: specifically, guidelines for the treatment of three cardiovascular diseases (arterial hypertension, heart failure and chronic coronary heart disease [CHD]) in primary care. METHODS: We assessed primary care physicians' knowledge of the guidelines with a representative postal survey, using a questionnaire about the treatment of cardiovascular diseases (2500 questionnaires sent). We assessed the responding physicians' compliance with the guidelines by analyzing patient data from a sample of 30 of them for various indicators of compliance. Of these 30 physicians, 15 met our operational criteria for adequate knowledge of the guidelines, and 15 did not. RESULTS: 437 (40%) of the physicians knew the guidelines adequately. Physicians answered questions about chronic CHD in accordance with the guidelines more often than they did questions about arterial hypertension (74% versus 11%). Our exploratory analysis of guideline compliance revealed that physicians who knew the guidelines adequately performed no differently than physicians who did not with respect to 12 of the 16 compliance indicators. As for the remaining 4 compliance indicators, it turned out, surprisingly, that physicians who did not know the guidelines adequately performed significantly better than those who did. CONCLUSION: These preliminary findings imply that physicians' knowledge of guidelines does not in itself lead to better guideline implementation. Further studies are needed to address this important issue. PMID- 21311712 TI - Step down treatment with antiepileptic drugs. PMID- 21311714 TI - The treatment of spinal metastases. AB - BACKGROUND: The rising life expectancy of cancer patients has led to a greater need for treatment of spinal metastases. Interdisciplinary collaboration is important so that each patient's treatment can be properly tailored to the overall prognosis. The main factors to be considered are the histology of the primary tumor, potential spinal instability, and compression of neural structures. METHODS: We discuss the treatment options for spinal metastases on the basis of a selective literature review and our own extensive experience in an interdisciplinary tumor center. RESULTS: For spinal canal compression or impending spinal instability, the treatment of choice is decompression and stabilization, by either a dorsal approach (lumbar and thoracic spine) or a ventral approach (cervical spine). Radical ventral tumor resection is indicated only for solitary metastases in patients with a favorable long-range prognosis. If the tumor is radiosensitive, radiotherapy is given either as adjuvant treatment after surgery or as the primary treatment for multiple spinal metastases in the absence of an acute neurological deficit. Various fractionation schemes with different total radiation doses are used. Bisphosphonate treatment is an integral component of the overall treatment strategy. CONCLUSION: The treatment of spinal metastases requires interdisciplinary collaboration and must be tailored to each patient's overall prognosis. PMID- 21311716 TI - Pharmacokinetic profile of an intradeltoid diclofenac injection in obese Indian volunteers. AB - BACKGROUND: A new propylene glycol-free and reduced-volume formulation of diclofenac sodium 75 mg/mL designed for intradeltoid administration has been found to be bioequivalent to a reference formulation of diclofenac sodium 75 mg/3 mL given via the intragluteal route in normal healthy volunteers. Standard needles may not reach the gluteus maximus muscle in many cases, especially in the obese. The objective of this study was to determine the pharmacokinetic parameters of the new formulation and compare the bioavailability of intradeltoid diclofenac sodium 75 mg/mL with that of the intragluteal 75 mg/3 mL reference formulation in obese volunteers. METHODS: A comparative, two-way, single-dose, bioavailability study was carried out in 10 obese (body mass index > 25) male Indian volunteers after a washout period of seven days. Blood samples were collected until six hours following drug administration and analyzed using a prevalidated high-pressure liquid chromatography method. RESULTS: The mean maximum plasma concentration and time to reach maximum plasma concentration for the test formulation were 1.30 MUg/mL and 0.50 hours, respectively, versus 0.93 MUg/ mL and 1.08 hours for the reference formulation. The mean areas under the curve from 0 to last measurable time point (AUC(0-t)) for the test and reference formulations were 2.71 MUg.h/mL and 2.73 MUg.h/mL, respectively. The mean AUCs from 0 to infinity (AUC(0-infinity)) for the test and reference formulations were 3.71 MUg.h/mL and 3.75 MUg.h/mL, respectively. CONCLUSION: The results suggest that the test formulation of diclofenac sodium 75 mg/mL has an AUC(0-t) and AUC(0 infinity) comparable with the reference intragluteal formulation of diclofenac sodium 75 mg/3 mL, but with an earlier time to reach maximum plasma concentration and a trend towards a higher maximum plasma concentration. This could be attributed to faster absorption from the deltoid region than from the gluteal region. The test formulation could be helpful in the management of pain in obese or overweight patients and those with dense subcutaneous fat in the gluteal area. PMID- 21311715 TI - Megalin/LRP2 expression is induced by peroxisome proliferator-activated receptor alpha and -gamma: implications for PPARs' roles in renal function. AB - BACKGROUND: Megalin is a large endocytic receptor with relevant functions during development and adult life. It is expressed at the apical surface of several epithelial cell types, including proximal tubule cells (PTCs) in the kidney, where it internalizes apolipoproteins, vitamins and hormones with their corresponding carrier proteins and signaling molecules. Despite the important physiological roles of megalin little is known about the regulation of its expression. By analyzing the human megalin promoter, we found three response elements for the peroxisomal proliferator-activated receptor (PPAR). The objective of this study was to test whether megalin expression is regulated by the PPARs. METHODOLOGY/PRINCIPAL FINDINGS: Treatment of epithelial cell lines with PPARalpha or PPARgamma ligands increased megalin mRNA and protein expression. The stimulation of megalin mRNA expression was blocked by the addition of specific PPARalpha or PPARgamma antagonists. Furthermore, PPAR bound to three PPAR response elements located in the megalin promoter, as shown by EMSA, and PPARalpha and its agonist activated a luciferase construct containing a portion of the megalin promoter and the first response element. Accordingly, the activation of PPARalpha and PPARgamma enhanced megalin expression in mouse kidney. As previously observed, high concentrations of bovine serum albumin (BSA) decreased megalin in PTCs in vitro; however, PTCs pretreated with PPARalpha and PPARgamma agonists avoided this BSA-mediated reduction of megalin expression. Finally, we found that megalin expression was significantly inhibited in the PTCs of rats that were injected with BSA to induce tubulointerstitial damage and proteinuria. Treatment of these rats with PPARgamma agonists counteracted the reduction in megalin expression and the proteinuria induced by BSA. CONCLUSIONS: PPARalpha/gamma and their agonists positively control megalin expression. This regulation could have an important impact on several megalin-mediated physiological processes and on pathophysiologies such as chronic kidney disease associated with diabetes and hypertension, in which megalin expression is impaired. PMID- 21311717 TI - Virtual human technology: patient demographics and healthcare training factors in pain observation and treatment recommendations. AB - BACKGROUND: Patients' sex, race, and age have been found to affect others' perception of their pain. However, the influence of these characteristics on treatment recommendations from laypersons and healthcare providers is understudied. DESIGN: To address this issue, 75 undergraduates and 107 healthcare trainees (HTs) used a web-based delivery system to view video clips of virtual human (VH) patients presenting with different standardized levels of pain. Subjects then rated the VHs' pain intensity and recommended the amount of medical treatment the VHs should receive. RESULTS: Results indicated that, compared with undergraduates, HTs perceived African Americans and older adults as having less pain but were more willing to recommend medical treatment for these patients than were undergraduate participants. HTs and undergraduates rated female, African American, older, and high-pain-expressing adults as having greater pain intensity than male, Caucasian, younger, and lower-pain-expressing adults. Moreover, they also recommended that female, older, and high-pain-expressing adults receive more medical treatment than male, younger, and lower-pain-expressing adults. CONCLUSIONS: This study found that the characteristics of the VHs and whether the participants were undergraduates or HTs influenced the ratings of pain assessment and treatment recommendations. The findings are consistent with the previous VH literature showing that VH characteristics are important cues in the perception and treatment of pain. However, this is the first study to identify differences in pain-related decisions between individuals who are pursuing healthcare careers and those who are not. Finally, not only does this study serve as further evidence for the validity and potential of VH technology but also it confirms prior research that has shown that biases regarding patient sex, race, and age can affect pain assessment and treatment. PMID- 21311718 TI - Treatment of trigeminal neuralgia: role of radiofrequency ablation. AB - Trigeminal neuralgia (TN) is a neuropathic pain condition affecting the face. It has a significant impact on the quality of life and physical function of patients. Evidence suggests that the likely etiology is vascular compression of the trigeminal nerve leading to focal demyelination and aberrant neural discharge. Secondary causes such as multiple sclerosis or brain tumors can also produce symptomatic TN. Treatment must be individualized to each patient. Carbamazepine remains the drug of choice in the first-line treatment of TN. Minimally invasive interventional pain therapies and surgery are possible options when drug therapy fails. Younger patients may benefit from microvascular decompression. Elderly patients with poor surgical risk may be more suitable for percutaneous trigeminal nerve rhizolysis. The technique of radiofrequency rhizolysis of the trigeminal nerve is described in detail in this review. PMID- 21311719 TI - Agrammatic aphasic production and comprehension of unaccusative verbs in sentence contexts. AB - This study examined the Argument Structure Complexity Hypothesis (ASCH, [J. Neuroling. 16 (2003) 151]), by investigating agrammatic aphasic comprehension and elicited production of two types of intransitive verbs (i.e. unergatives and unaccusatives) in sentence contexts. The ASCH attributes production difficulty frequently observed in agrammatic aphasia to the argument structure entries of verbs, stating that verbs with a more complex argument structure (in terms of the number and type of arguments) are more difficult for agrammatic aphasic patients to produce than those with a less complex argument structure. Results showed that eight agrammatic aphasic subjects had production difficulty with unaccusative verb sentences, as compared to unergatives, in the face of near-normal comprehension of both sentence types. These findings support the ASCH that predicts production difficulty with sentences involving unaccusatives with more complex argument structures. Error patterns observed also indicated successful lemma access in that the full array of verb argument structures were produced during sentence attempts, suggesting that complex argument structures hinder appropriate processing after the lemma level. PMID- 21311720 TI - Verb production in agrammatic aphasia: The influence of semantic class and argument structure properties on generalisation. AB - BACKGROUND: Some individuals with agrammatic aphasia have difficulty producing verbs when naming and generating sentences (Miceli, Silveri, Villa, & Caramazza, 1984; Saffran, Schwartz, & Marin, 1980; Zingeser & Berndt, 1990). And when verbs are produced there is an over-reliance on verbs requiring simple argument structure arrangements (Thompson, Lange, Schneider, & Shapiro, 1997; Thompson, Shapiro, Schneider, & Tait, 1994). Verbs, as argument-taking elements, show especially complex semantic and argument structure properties. This study investigated the role these properties have on verb production in individuals with agrammatic aphasia. AIM: This treatment study examined the extent to which semantic class and argument structure properties of verbs influenced the ability of seven individuals with agrammatic Broca's aphasia to retrieve verbs and then use them in correct sentence production. Verbs from two semantic classes and two argument structure categories were trained using either a semantic or an argument structure verb retrieval treatment. Specifically, acquisition and generalisation to trained and untrained verbs within and across semantic and argument structure categories was examined. In addition, the influence of verb production on each participant's sentence production was also examined. METHODS #ENTITYSTARTX00026; PROCEDURES: Utilising a single-subject crossover design in combination with a multiple baseline design across subjects and behaviours, seven individuals with agrammatic aphasia were trained to retrieve verbs with specific argument structures from two semantic classes under two treatment conditions-semantic verb retrieval treatment and verb argument structure retrieval treatment. Treatment was provided on two-place and three-place motion or change of state verbs, counterbalanced across subjects and behaviours. A total of 102 verbs, depicted in black and white drawings, were utilised in the study, divided equally into motion and change of state verbs (semantic classes) and one-place, two-place, and three place verbs (argument structure arrangements). Verbs were controlled for syllable length, picturability, phonological complexity, and frequency. These same stimulus items were used to elicit the sentence production probe. OUTCOMES #ENTITYSTARTX00026; RESULTS: Both treatments revealed significant effects in facilitating acquisition of verb retrieval in all participants. Minimal within and across verb category generalisation occurred. However, it was found that as retrieval of verbs improved, grammatical sentence production improved. This occurred without direct treatment on sentence production. CONCLUSIONS: The results of this study lend support for treatment focused on verb production with individuals with agrammatic aphasia and support the use of linguistic-based treatment strategies. PMID- 21311722 TI - LSPR Imaging: Simultaneous Single Nanoparticle Spectroscopy and Diffusional Dynamics. AB - A wide-field localized surface plasmon resonance (LSPR) imaging method using a liquid crystal tunable filter (LCTF) is used to measure the scattering spectra of multiple Ag nanoparticles in parallel. This method provides the ability to characterize moving Ag nanoparticles by measuring the scattering spectra of the particles while simultaneously tracking their motion. Consequently, single particle diffusion coefficients can be determined. As an example, several single Ag nanoprisms are tracked, the LSPR scattering spectrum of each moving particle is obtained, and the single particle diffusion coefficient is determined from its trajectory. Coupling diffusion information with spectral information in real time is a significant advance and addresses many scientific problems, both fundamental and biological, such as cell membrane protein diffusion, functional plasmonic distributions, and nanoparticle growth mechanisms. PMID- 21311721 TI - Prevalence and risk factors for gastroesophageal reflux disease in an impoverished minority population. AB - BACKGROUND AND AIMS: An epidemiological link between an increased body mass index and complaints of typical heartburn symptoms has been identified. It appears that increasing waist circumference, rather than overall weight is most important. Studies to date have not included minority, impoverished communities. Our aim was to determine the impact of obesity on the prevalence of reflux disease in an impoverished community while controlling for known confounders. METHODS: DESIGN Cross-sectional survey delivered by in-home interviews, convenience sampling, and targeted mailing. Data queried include demographics, medical history, lifestyle habits, and symptoms of reflux disease. Height, weight, hip and waist circumference measured in participating subjects. PARTICIPANTS: 503 subjects living in the zip code immediately surrounding Temple University Hospital. Included only adults living in the hospital's zip code for at least 3 years. RESULTS: The highest quartile of waist circumference (>=42 in.) demonstrated a strong association with GERD (AOR = 2.15; 95% CI 1.18-3.90). Smoking increased the odds by 1.72 (95% CI 1.13-2.62). There was no relationship between body mass index, waist-hip ratio, or diet and reflux classification. CONCLUSIONS: Increasing waist circumference, but not overall body mass index or waist-hip ratio, and smoking are risk factors for prevalent GERD. No association between reflux disease and lifestyle choices such as coffee drinking and fast food dining were found. LIMITATIONS: Potential for recall bias and disease misclassification. Possible methodological errors in self-measurement of waist and hip circumference. PMID- 21311723 TI - e-Science, caGrid, and Translational Biomedical Research. AB - Translational research projects target a wide variety of diseases, test many different kinds of biomedical hypotheses, and employ a large assortment of experimental methodologies. Diverse data, complex execution environments, and demanding security and reliability requirements make the implementation of these projects extremely challenging and require novel e-Science technologies. PMID- 21311724 TI - Genetic polymorphisms of ATP-binding cassette (ABC) proteins, overall survival and drug toxicity in patients with Acute Myeloid Leukemia. AB - The overall survival of patients with acute myeloid leukemia (AML) remains poor due to both intrinsic and acquired chemotherapy resistance. Over expression of ATP binding cassette (ABC) proteins in AML cells has been suggested as a putative mechanism of drug resistance. Genetic variation among individuals affecting the expression or function of these proteins may contribute to inter-individual variation in treatment outcomes. DNA from pre-treatment bone marrow or blood samples from 261 patients age 20-85 years, who received cytarabine and anthracycline-based therapy at Roswell Park Cancer Institute between 1994 and 2006, was genotyped for eight non-synonymous single nucleotide polymorphisms in the ABCB1, ABCC1 and ABCG2 drug transporter genes. Heterozygous (AG) or homozygous (AA) variant genotypes for rs2231137 (G34A) in the ABCG2 (BRCP) gene, compared to the wild type (GG) genotype were associated with both significantly improved survival (HR=0.44, 95%CI=0.25-0.79), and increased odds for toxicity (OR=8.41, 95%CI= 1.10-64.28). Thus genetic polymorphisms in the ABCG2 (BRCP) gene may contribute to differential survival outcomes and toxicities in AML patients via a mechanism of decreased drug efflux in both, AML cells and normal progenitors. PMID- 21311725 TI - PUTATIVE CSF PROTEIN BIOMARKER CANDIDATES FOR AMNESTIC MILD COGNITIVE IMPAIRMENT. AB - The identification of individuals at risk for Alzheimer's disease (AD) is essential for the timely administration of treatment approaches aimed at slowing the onset or progression of the disease. As amnestic forms of mild cognitive impairment (aMCI) may represent preclinical AD, the search for specific diagnostic biomarkers that characterize those with aMCI is a key research objective. Using surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDITOF-MS), we screened the cerebrospinal fluid (CSF) of Religious Orders Study participants with a clinical diagnosis of no cognitive impairment (NCI), aMCI, or mild/moderate AD for potential biomarkers. CSF was fractionated on immobilized metal affinity chromatography (IMAC) protein arrays preloaded with either gallium (IMAC-Ga), which binds phosphoproteins, or copper (IMAC-Cu) to isolate copper-binding proteins. SELDI TOF-MS analysis of the IMAC Ga arrays revealed a phosphopeptide of 2490 Da that was selectively increased ~2 fold in aMCI and AD CSF compared to NCI. SELDI TOF-MS analysis of the IMAC-Cu arrays identified 2 proteins of 11.7 and 13.3 kDa that were both selectively increased ~1.5-1.6-fold in aMCI and AD CSF. Increasing levels of each protein were associated with poorer performance on the Mini Mental State Exam and higher Braak stage. Hence, increased CSF levels of these proteins may be potential biomarkers for preclinical AD and aid in the development of a CSF biomarker panel with high predictive value for identifying people who would most benefit from early therapeutic interventions to modify disease progression. PMID- 21311726 TI - Generalized Performance Evaluation of X-ray Image Intensifier compared with a Microangiographic System. AB - Standard objective parameters such as MTF, NPS, NEQ and DQE do not reflect complete system performance, because they do not account for geometric unsharpness due to finite focal spot size and scatter due to the patient. The inclusion of these factors led to the generalization of the objective quantities, termed GMTF, GNNPS, GNEQ and GDQE defined at the object plane. In this study, a commercial x-ray image intensifier (II) is evaluated under this generalized approach and compared with a high-resolution, ROI microangiographic system previously developed and evaluated by our group. The study was performed using clinically relevant spectra and simulated conditions for neurovascular angiography specific for each system. A head-equivalent phantom was used, and images were acquired from 60 to 100 kVp. A source to image distance of 100 cm (75 cm for the microangiographic system) and a focal spot of 0.6 mm were used. Effects of varying the irradiation field-size, the air-gaps, and the magnifications (1.1 to 1.3) were compared. A detailed comparison of all of the generalized parameters is presented for the two systems. The detector MTF for the microangiographic system is in general better than that for the II system. For the total x-ray imaging system, the GMTF and GDQE for the II are better at low spatial frequencies, whereas the microangiographic system performs substantially better at higher spatial frequencies. This generalized approach can be used to more realistically evaluate and compare total system performance leading to improved system designs tailored to the imaging task. PMID- 21311727 TI - A Prototype Micro-Angiographic Fluoroscope and Its Application in Animal Studies. AB - In order to satisfy the high resolution (3 to 10 cycles/mm) imaging requirements in neurovascular image-guided interventional (IGI) procedures, a micro angiographic fluoroscope (MAF) is being developed to enable both rapid sequence angiography (15 fps) at high exposure levels (hundreds of MUR/frame) as well as fluoroscopy at high frame rates (30 fps) and low exposure levels (5 to 20 MUR/frame). The prototype MAF consists of a 350-MUm-thick CsI(Tl) scintillator coupled by a 2:1 fiber-optical taper to an 18 mm diameter variable-gain light image intensifier with two-stage microchannel plate (MCP) viewed by a 12-bit, 1024x1024, 30 fps CCD camera with digital interface board. The optical set-up enables variation of effective pixel-size from 31 to 50 micron. The first frame lag of the MAF in fluoroscopic 30 fps mode (2:1 binning) was less than 0.8% at exposures of 5-23 MUR/frame. MTF, NPS, and DQE in angiographic mode were measured for IEC standard spectrum RQA 5. At spatial frequencies of 4 and 10 cycles/mm the MTF was 14% and 1.5%, and the DQE was 12% and 1.2%, respectively, while the DQE(0) was 60%. Acquisition software was developed to acquire 15 fps angiography and 30 fps fluoroscopy for real-time dark field and flat field correction or real time roadmapping. Images obtained with the MAF in small animal IGI procedures are demonstrated. The linearity versus x-ray intensity and MCP working range effects has been studied. We plan to expand the current 3.6 cm diameter field of view to 6 cm in the next model of the MAF. PMID- 21311728 TI - Region of interest (ROI) computed tomography (CT): Comparison with full field of view (FFOV) and truncated CT for a human head phantom. AB - Cone-beam CT reconstruction can be performed at lower integral dose, by using a non-uniform beam filter between the x-ray source and the patient to obtain good image quality within an ROI with minimal artifacts. To evaluate the method, a human head phantom was placed on a rotary stage. Cone-beam projection images of the phantom were obtained with and without an ROI filter (dose reduction factor ~7). A mapping function was established to equalize the intensity outside the ROI (to compensate for the attenuation by the filter) to the intensity inside by assuming that those features lying both inside and outside very close to the edge of the ROI are the same. Reconstructed images were obtained using equalized projection images for 2 cases: one in which the outside region was smoothed using an averaging filter and the other with no smoothing outside. In addition, a third case was simulated by calculating the average pixel value inside the ROI for each image and assigning this value to all pixels outside the ROI for that image. The images were then back projected using a Feldkamp algorithm. We found that the three cases yield results inside the ROI comparable to those obtained using FFOV projections. In addition, the ROI filter reconstruction with smoothing provides image information outside the ROI comparable to the FFOV reconstruction. CT using an ROI filter provides a means to reconstruct reliable 3D for a volume of interest with greatly reduced integral dose compared to FFOV projections and with minimal artifacts. PMID- 21311729 TI - A Novel Representation for Riemannian Analysis of Elastic Curves in R AB - We propose a novel representation of continuous, closed curves in R(n) that is quite efficient for analyzing their shapes. We combine the strengths of two important ideas - elastic shape metric and path-straightening methods -in shape analysis and present a fast algorithm for finding geodesics in shape spaces. The elastic metric allows for optimal matching of features while path-straightening provides geodesics between curves. Efficiency results from the fact that the elastic metric becomes the simple (2) metric in the proposed representation. We present step-by-step algorithms for computing geodesics in this framework, and demonstrate them with 2-D as well as 3-D examples. PMID- 21311730 TI - An ion-channel-containing model membrane: structural determination by magnetic contrast neutron reflectometry. AB - To many biophysical characterisation techniques, biological membranes appear as two-dimensional structures with details of their third dimension hidden within a 5 nm profile. Probing this structure requires methods able to discriminate multiple layers a few Angstroms thick. Given sufficient resolution, neutron methods can provide the required discrimination between different biochemical components, especially when selective deuteration is employed. We have used state of-the-art neutron reflection methods, with resolution enhancement via magnetic contrast variation to study an oriented model membrane system. The model is based on the Escherichia coli outer membrane protein OmpF fixed to a gold surface via an engineered cysteine residue. Below the gold is buried a magnetic metal layer which, in a magnetic field, displays different scattering strengths to spin-up and spin-down neutrons. This provides two independent datasets from a single biological sample. Simultaneous fitting of the two datasets significantly refines the resulting model. A beta-mercaptoethanol (betaME) passivating surface, applied to the gold to prevent protein denaturation, is resolved for the first time as an 8.2 +/- 0.6 A thick layer, demonstrating the improved resolution and confirming that this layer remains after OmpF assembly. The thiolipid monolayer (35.3 +/- 0.5 A), assembled around the OmpF is determined and finally a fluid DMPC layer is added (total lipid thickness 58.7 +/- 0.9 A). The dimensions of trimeric OmpF in isolation (53.6 +/- 2.5 A), after assembly of lipid monolayer (57.5 +/- 0.9 A) and lipid bilayer (58.7 +/- 0.9 A), are precisely determined and show little variation. PMID- 21311731 TI - New microangiography system development providing improved small vessel imaging, increased contrast to noise ratios, and multi-view 3D reconstructions. AB - A new microangiographic system (MA) integrated into a c-arm gantry has been developed allowing precise placement of a MA at the exact same angle as the standard x-ray image intensifier (II) with unchanged source and object position. The MA can also be arbitrarily moved about the object and easily moved into the field of view (FOV) in front of the lower resolution II when higher resolution angiographic sequences are needed. The benefits of this new system are illustrated in a neurovascular study, where a rabbit is injected with contrast media for varying oblique angles. Digital subtraction angiographic (DSA) images were obtained and compared using both the MA and II detectors for the same projection view. Vessels imaged with the MA appear sharper with smaller vessels visualized. Visualization of ~100 MUm vessels was possible with the MA whereas not with the II. Further, the MA could better resolve vessel overlap. Contrast to noise ratios (CNR) were calculated for vessels of varying sizes for the MA versus the II and were found to be similar for large vessels, approximately double for medium vessels, and infinitely better for the smallest vessels. In addition, a 3D reconstruction of selected vessel segments was performed, using multiple (three) projections at oblique angles, for each detector. This new MA/II integrated system should lead to improved diagnosis and image guidance of neurovascular interventions by enabling initial guidance with the low resolution large FOV II combined with use of the high resolution MA during critical parts of diagnostic and interventional procedures. PMID- 21311732 TI - Evaluation of an asymmetric stent patch design for a patient specific intracranial aneurysm using Computational Fluid Dynamic (CFD) calculations in the Computed Tomography (CT) derived lumen. AB - Stenting may provide a new, less invasive therapeutic option for cerebral aneurysms. However, a conventional porous stent may be insufficient in modifying the blood flow for clinical aneurysms. We designed an asymmetric stent consisting of a low porosity patch welded onto a porous stent for an anterior cerebral artery aneurysm of a specific patient geometry to block the strong inflow jet. To evaluate the effect of the patch on aneurysmal flow dynamics, we "virtually" implanted it into the patient's aneurysm geometry and performed Computational Fluid Dynamics (CFD) analysis. The patch was computationally deformed to fit into the vessel lumen segmented from the patient CT reconstructions. After the flow calculations, a patch with the same design was fabricated using laser cutting techniques and welded onto a commercial porous stent, creating a patient-specific asymmetric stent. This stent was implanted into a phantom, which was imaged with X-ray angiography. The hemodynamics of untreated and stented aneurysms were compared both computationally and experimentally. It was found from CFD of the patient aneurysm that the asymmetric stent effectively blocked the strong inflow jet into the aneurysm and eliminated the flow impingement on the aneurysm wall at the dome. The impact zone with elevated wall shear stress was eliminated, the aneurysmal flow activity was substantially reduced, and the flow was considerably reduced. Experimental observations corresponded well qualitatively with the CFD results. The demonstrated asymmetric stent could lead to a new minimally invasive image guided intervention to reduce aneurysm growth and rupture. PMID- 21311733 TI - Microangiographic Image Guided Localization of a New Asymmetric Stent for Treatment of Cerebral Aneurysms. AB - For treatment of cerebral aneurysms, the low porosity patch-like region of a new asymmetric stent must be accurately aligned both longitudinally and rotationally to cover the aneurysm orifice. Image guided interventions (IGI) for this task using either a high spatial resolution microangiographic detector (MA) or a standard x-ray image intensifier (XII) are compared. MA is a custom built phosphor-fiberoptic-CCD x-ray detector; the MA array is 1024X1024 with 43 microns pixels. We designed an experimental simulation of the IGI which involved localization using a combination of a computer-controlled rotational stage supported on a linear traverse. A catheter containing the asymmetric stent with special gold markers was positioned near the aneurysm of a vessel phantom which is contained in a flow loop to enable contrast injection for creation of roadmap images. We used four different configurations for the markers consisting of dots and lines. The true stent alignment, obtained by direct visual viewing, was determined to better than one degree rotational accuracy. The resultant IGI localization accuracy under radiographic control with the microangiographic detector was 4 degrees compared to 12 degrees for the XII. In general the line markers performed better than the dot markers. Experimental data show that high resolution detectors such as MA can vastly improve the accuracy of localization and tracking of devices such as asymmetric stents. This should enable development of more effective treatment devices and interventions. (Partial support from NIH grants NS38746, NS43294, and EB002873; UB STOR, Toshiba MSC, and Guidant Corp.). PMID- 21311734 TI - Density Estimation with Replicate Heteroscedastic Measurements. AB - We present a deconvolution estimator for the density function of a random variable from a set of independent replicate measurements. We assume that measurements are made with normally distributed errors having unknown and possibly heterogeneous variances. The estimator generalizes the deconvoluting kernel density estimator of Stefanski and Carroll (1990), with error variances estimated from the replicate observations. We derive expressions for the integrated mean squared error and examine its rate of convergence as n -> infinity and the number of replicates is fixed. We investigate the finite-sample performance of the estimator through a simulation study and an application to real data. PMID- 21311735 TI - Efficiency of the Human Observer Compared to an Ideal Observer Based on a Generalized NEQ Which Incorporates Scatter and Geometric Unsharpness: Evaluation with a 2AFC Experiment. AB - Under certain assumptions the detectability of the ideal observer can be defined as the integral of the system Noise Equivalent Quanta multiplied by the squared object spatial frequency distribution. Using the detector Noise-Equivalent-Quanta (NEQ(D)) for the calculation of detectability inadequately describes the performance of an x-ray imaging system because it does not take into account the effects of patient scatter and geometric unsharpness. As a result, the ideal detectability index is overestimated, and hence the efficiency of the human observer in detecting objects is underestimated. We define a Generalized-NEQ (GNEQ) for an x-ray system referenced at the object plane that incorporates the scatter fraction, the spatial distributions of scatter and focal spot, the detector MTF(D), and the detector Normalized-Noise-Power-Spectrum (NNPS(D)). This GNEQ was used in the definition of the ideal detectability for the evaluation of the human observer efficiency during a two Alternative Forced Choice (2-AFC) experiment, and was compared with the case where only the NEQ(D) was used in the detectability calculations. The 2-AFC experiment involved the detection of images of polyethylene tubes (diameters between 100-300 MUm) filled with iodine contrast (concentrations between 0-120 mg/cm(3)) placed onto a uniform head equivalent phantom placed near the surface of a microangiographic detector (43 MUm pixel size). The resulting efficiency of the human observer without regarding the effects of scatter and geometric unsharpness was 30%. When these effects were considered the efficiency was increased to 70%. The ideal observer with the GNEQ can be a simple optimization method of a complete imaging system. PMID- 21311736 TI - Experimental comparison of cone beam CT (CBCT) reconstruction and multi-view reconstruction (MVR) for microangiography (MA) detector system. AB - The new Multi-View Reconstruction (MVR) method for generating 3D vascular images was evaluated experimentally. The MVR method requires only a few digital subtraction angiographic (DSA) projections to reconstruct the 3D model of the vessel object compared to 180 or more projections for standard CBCT. Full micro CBCT datasets of a contrast filled carotid vessel phantom were obtained using a Microangiography (MA) detector. From these datasets, a few projections were selected for use in the MVR technique. Similar projection views were also obtained using a standard x-ray image intensifier (II) system. A comparison of the 2D views of the MVRs (MA and II derived) with reference micro-CBCT data, demonstrated best agreement with the MA MVRs, especially at the curved part of the phantom. Additionally, the full 3D MVRs were compared with the full micro CBCT 3D reconstruction resulting for the phantom with the smallest diameter (0.75 mm) vessel, in a mean centerline deviation from the micro-CBCT derived reconstructions of 29 MUm for the MA MVR and 48 MUm for the II MVR. The comparison implies that an MVR may be substituted for a full micro-CBCT scan for evaluating vessel segments with consequent substantial savings in patient exposure and contrast media injection yet without substantial loss in 3D image content. If a high resolution system with MA detector is used, the improved resolution could be well suited for endovascular image guided interventions where visualization of only a small field of view (FOV) is required. PMID- 21311737 TI - Synthesis of Berberine-Efflux Pump Inhibitor Hybrid Antibacterials. AB - This paper reports the compact synthesis of two isomeric dual-action hybrid antimicrobials where the 13-position of the antibacterial berberine has been linked via 3'- and 4'-methylene bridges to INF55 (5-nitro-2-phenylindole), an inhibitor of the bacterial NorA multidrug-resistance pump. PMID- 21311738 TI - Get The FACS Fast: Automated FACS face analysis benefits from the addition of velocity. AB - Much progress has been made in automated facial image analysis, yet current approaches still lag behind what is possible using manual labeling of facial actions. While many factors may contribute, a key one may be the limited attention to dynamics of facial action. Most approaches classify frames in terms of either displacement from a neutral, mean face or, less frequently, displacement between successive frames (i.e. velocity). In the current paper, we evaluated the hypothesis that attention to dynamics can boost recognition rates. Using the well-known Cohn-Kanade database and support vector machines, adding velocity and acceleration decreased the number of incorrectly classified results by 14.2% and 11.2%, respectively. Average classification accuracy for the displacement and velocity classifier system across all classifiers was 90.2%. Findings were replicated using linear discriminant analysis, and found a mean decrease of 16.4% in incorrect classifications across classifiers. These findings suggest that information about the dynamics of a movement, that is, the velocity and to a lesser extent the acceleration of a change, can helpfully inform classification of facial expressions. PMID- 21311739 TI - The Influence of Dating Relationships on Friendship Networks, Identity Development, and Delinquency. AB - Prior research has documented general associations between dating and delinquency, but little is known about the specific ways in which heterosexual experiences influence levels of delinquency involvement and substance use. In the current study, we hypothesize that an adolescent's level of effort and involvement in heterosexual relationships play a significant role in forming the types of friendship networks and views of self that influence the likelihood of delinquency involvement and substance use. Analyses based on a longitudinal sample of adolescent youth (n=1,090) show that high levels of dating effort and involvement with multiple partners significantly increases unstructured and delinquent peer contacts, and influences self-views as troublemaker. These broader peer contexts and related self-views, in turn, mediate the path between dating relationships, self-reported delinquency, and substance use. Findings also document moderation effects: among those youths who have developed a troublemaker identity and who associate with delinquent peers, dating heightens the risk for delinquent involvement. In contrast, among those individuals who have largely rejected the troublemaker identity and who do not associate with delinquent friends, dating relationships may confer a neutral or even protective benefit. The analyses further explore the role of gender and the delinquency of the romantic partner. PMID- 21311740 TI - Translational Research Design Templates, Grid Computing, and HPC. AB - Design templates that involve discovery, analysis, and integration of information resources commonly occur in many scientific research projects. In this paper we present examples of design templates from the biomedical translational research domain and discuss the requirements imposed on Grid middleware infrastructures by them. Using caGrid, which is a Grid middleware system based on the model driven architecture (MDA) and the service oriented architecture (SOA) paradigms, as a starting point, we discuss architecture directions for MDA and SOA based systems like caGrid to support common design templates. PMID- 21311741 TI - Histone deacetylase inhibitors sodium butyrate and valproic acid delay spontaneous cell death in purified rat retinal ganglion cells. AB - PURPOSE: Histone deacetylase inhibitors (HDACi) have neuroprotective effects under various neurodegenerative conditions, e.g., after optic nerve crush (ONC). HDACi-mediated protection of central neurons by increased histone acetylation has not previously been demonstrated in rat retinal ganglion cells (RGCs), although epigenetic changes were shown to be associated with cell death after ONC. We investigated whether HDACi can delay spontaneous cell death in purified rat RGCs and analyzed concomitant histone acetylation levels. METHODS: RGCs were purified from newborn (postnatal day [P] 0-P2) rat retinas by immunopanning with antibodies against Thy-1.1 and culturing in serum-free medium for 2 days. RGCs were treated with HDACi, each at several different concentrations: 0.1-10 mM sodium butyrate (SB), 0.1-2 mM valproic acid (VPA), or 0.5-10 nM trichostatin A (TSA). Negative controls were incubated in media alone, while positive controls were incubated in 0.05-0.4 IU/ul erythropoietin. Survival was quantified by counting viable cells using phase-contrast microscopy. The expression of acetylated histone proteins (AcH) 3 and 4 was analyzed in RGCs by immunohistochemistry. RESULTS: SB and VPA enhanced RGC survival in culture, with both showing a maximum effect at 0.1 mM (increase in survival to 188% and 163%, respectively). Their neuroprotective effect was comparable to that of erythropoietin at 0.05 IU/ul. TSA 0.5-1.0 nM showed no effect on RGC survival, and concentrations >= 5 nM increased RGC death. AcH3 and AcH4 levels were only significantly increased in RGCs treated with 0.1 mM SB. VPA 0.1 mM produced only a slight effect on histone acetylation. CONCLUSIONS: Millimolar concentrations of SB and VPA delayed spontaneous cell death in purified RGCs; however, significantly increased histone acetylation levels were only detectable in RGCs after SB treatment. As the potent HDACi TSA was not neuroprotective, mechanisms other than histone acetylation may be the basis on which SB and VPA are acting in this model. Additional studies are necessary to identify HDACi-targeted genes and pathways involved in RGC protection. PMID- 21311742 TI - Molecular genetics of Chinese families with TGFBI corneal dystrophies. AB - PURPOSE: To identify clinical features and mutations within the transforming growth factor-beta-induced (TGFBI) gene in three Chinese families with Granular corneal dystrophy, type 1 (GCD1) and Granular corneal dystrophy, type 2 (GCD2). METHODS: Clinical features of GCD1 and GCD2 in three Chinese families were studied with slit-lamp and in vivo laser scanning confocal microscopy (LSCM). Molecular genetic analysis was performed on nine patients and fifteen unaffected individuals from these families. All exons of TGFBI were amplified by polymerase chain reaction (PCR) and sequenced. RESULTS: Morphological changes in the cornea among affected individuals from three Chinese families examined by in vivo LSCM were almost the same. A heterozygous mutation C>T (R555W) was identified in exon 12 of TGFBI in patients of family A with GCD1. Another heterozygous mutation G>A (R124H) was found in exon 4 of TGFBI in affected members of family B and C with GCD2. CONCLUSIONS: Mutations R555W and R124H in TGFBI were identified in three Chinese families with GCD. Even though there are a variety of mutations in TGFBI of GCD, the different subtypes of GCD (GCD1, GCD2, and GCD3) are in fact the same disorder. Our work supports the hypothesis that corneal dystrophies with the common genetic basis in TGFBI should be grouped together as TGFBI corneal dystrophies. PMID- 21311743 TI - Vesicular glutamate transporter 3 in age-dependent optic neuropathy. AB - PURPOSE: To determine retinal vesicular glutamate transporter 3 (VGLUT3) expression alterations in a mouse model of progressive optic neuropathy (glaucoma). METHODS: Tissue specimens were obtained from age-matched DBA/2J and control C57BL/6J mice for western blot analysis. Enucleated globes from DBA/2J, C57BL/6J, and BALB/cJ mice were fixed in formalin, paraffin-embedded, and sectioned for VGLUT3 protein localization. RESULTS: western blot analysis of the control retinas revealed the expression of a ~55 kDa immunoreactive VGLUT3 protein that is to be expected in tissues such as retina, brain, liver, heart, and kidney tissue, but not in intestinal or lung tissue. Furthermore, a strong ~130 kDa immunoreactive VGLUT3 isoform that is restricted to the central nervous system (the brain and retinas) was also identified in the controls, but was not detected in the DBA/2J retinas. Immunofluorescence microscopy showed a lack of VGLUT3 expression in the synapses between amacrine and retinal ganglion cells in DBA/2J retinas, in contrast to its strong expression in the C57BL/6J and BALB/cJ controls. CONCLUSIONS: Our results implicate the dysregulated expression of a central nervous system-specific VGLUT3 isoform as a predisposing factor in the development of optic neuropathy in DBA/2J mice, a spontaneous mouse model of glaucoma. In striking parallel to the visual system defects of glaucomatous DBA/2J mice, the inner ear of VGLUT3 knockout mice displays a progressive loss of inner hair cell to spiral-ganglion neuron synapses. A significant reduction in the number of spiral-ganglion neurons leads to age-associated deafness. Thus, we propose that the absence of this biochemically uncharacterized 130 kDa VGLUT3 isoform in the DBA/2J retina is a predisposing factor in synaptic instability, and a contributing factor in the age-dependent and progressive loss of ganglion cells projecting to the brain. PMID- 21311744 TI - Effect of curcumin on the modulation of alphaA- and alphaB-crystallin and heat shock protein 70 in selenium-induced cataractogenesis in Wistar rat pups. AB - PURPOSE: To investigate the expression of alphaA- and alphaB-crystallin and heat shock protein 70 (Hsp 70) during curcumin treatment of selenium-induced cataractogenesis in Wistar rat pups. METHODS: Group I Wistar rat pups received only saline and served as the control. Group II Wistar rat pups were intraperitoneally injected with selenium (15 uM/kg bodyweight) to induce cataract. Group III Wistar rat pups also underwent selenium-induced cataract but were cotreated with 75 mg/kg body weight of curcumin (single oral dose). Group IV Wistar rat pups with selenium-induced cataract were post-treated with curcumin at the group III dosage 24 h after selenium administration. Group V Wistar rat pups with selenium-induced cataract were pretreated with curcumin at the group III dosage 24 h before selenium administration. RESULTS: This study found higher levels of alphaA- and alphaB-crystallin and Hsp 70 in lenses injected with selenium alone (group II) than in control lenses (group I). Similar results were observed in the group III and IV lenses. In contrast, in group V, the presence of curcumin 24 h before selenium injection decreased the alphaA- and alphaB crystallin and Hsp 70 levels to almost the same as those found in group I lenses. CONCLUSIONS: Curcumin suppressed the expression of selenite-induced alphaA- and alphaB-crystallin and Hsp 70, and may therefore suppress cataract formation in rat pups. PMID- 21311745 TI - Travel patterns in China. AB - The spread of infectious disease epidemics is mediated by human travel. Yet human mobility patterns vary substantially between countries and regions. Quantifying the frequency of travel and length of journeys in well-defined population is therefore critical for predicting the likely speed and pattern of spread of emerging infectious diseases, such as a new influenza pandemic. Here we present the results of a large population survey undertaken in 2007 in two areas of China: Shenzhen city in Guangdong province, and Huangshan city in Anhui province. In each area, 10,000 randomly selected individuals were interviewed, and data on regular and occasional journeys collected. Travel behaviour was examined as a function of age, sex, economic status and home location. Women and children were generally found to travel shorter distances than men. Travel patterns in the economically developed Shenzhen region are shown to resemble those in developed and economically advanced middle income countries with a significant fraction of the population commuting over distances in excess of 50 km. Conversely, in the less developed rural region of Anhui, travel was much more local, with very few journeys over 30 km. Travel patterns in both populations were well-fitted by a gravity model with a lognormal kernel function. The results provide the first quantitative information on human travel patterns in modern China, and suggest that a pandemic emerging in a less developed area of rural China might spread geographically sufficiently slowly for containment to be feasible, while spatial spread in the more economically developed areas might be expected to be much more rapid, making containment more difficult. PMID- 21311746 TI - Facilitate insight by non-invasive brain stimulation. AB - Our experiences can blind us. Once we have learned to solve problems by one method, we often have difficulties in generating solutions involving a different kind of insight. Yet there is evidence that people with brain lesions are sometimes more resistant to this so-called mental set effect. This inspired us to investigate whether the mental set effect can be reduced by non-invasive brain stimulation. 60 healthy right-handed participants were asked to take an insight problem solving task while receiving transcranial direct current stimulation (tDCS) to the anterior temporal lobes (ATL). Only 20% of participants solved an insight problem with sham stimulation (control), whereas 3 times as many participants did so (p = 0.011) with cathodal stimulation (decreased excitability) of the left ATL together with anodal stimulation (increased excitability) of the right ATL. We found hemispheric differences in that a stimulation montage involving the opposite polarities did not facilitate performance. Our findings are consistent with the theory that inhibition to the left ATL can lead to a cognitive style that is less influenced by mental templates and that the right ATL may be associated with insight or novel meaning. Further studies including neurophysiological imaging are needed to elucidate the specific mechanisms leading to the enhancement. PMID- 21311747 TI - Renal function is related to severity of coronary artery calcification in elderly persons: the Rotterdam study. AB - BACKGROUND: Coronary artery calcification (CAC) has been proposed to be the underlying mechanism of the increased risk of coronary heart disease with reductions in glomerular filtration rate (GFR). Since renal function diminishes with aging we examined the association between GFR and CAC in the Rotterdam Study, a population-based study of elderly individuals. METHODS: The study was performed in 1703 subjects without a history of coronary heart disease. GFR was estimated using the modification of diet in renal disease equation. We used analysis of covariance to test for mean differences in CAC between GFR tertiles. RESULTS: The mean CAC scores in the middle and lowest GFR tertile did not significantly differ from the mean CAC score in the highest GFR tertile (geometric mean CAC score 4.1 and 4.3 vs 4.2). In a multivariable model the mean CAC score did also not differ between the GFR tertiles. As the interaction term between age and GFR was significant (P = 0.037), we divided the population in two age categories based on median age of 70 years. Below 70 years, the mean CAC scores did not differ between the GFR tertiles. Above median age, mean CAC score in the lowest GFR tertile was significantly higher than the mean CAC score in the highest tertile in a multivariable model (CAC 4.9 vs 4.5, p = 0.010). CONCLUSION: In this population-based study we observed that the association between CAC and GFR is modified by age. In participants at least 70 years of age, a decrease in GFR was associated with increased CAC. PMID- 21311748 TI - Histone deacetylase activity modulates alternative splicing. AB - There is increasing evidence to suggest that splicing decisions are largely made when the nascent RNA is still associated with chromatin. Here we demonstrate that activity of histone deacetylases (HDACs) influences splice site selection. Using splicing-sensitive microarrays, we identified ~700 genes whose splicing was altered after HDAC inhibition. We provided evidence that HDAC inhibition induced histone H4 acetylation and increased RNA Polymerase II (Pol II) processivity along an alternatively spliced element. In addition, HDAC inhibition reduced co transcriptional association of the splicing regulator SRp40 with the target fibronectin exon. We further showed that the depletion of HDAC1 had similar effect on fibronectin alternative splicing as global HDAC inhibition. Importantly, this effect was reversed upon expression of mouse HDAC1 but not a catalytically inactive mutant. These results provide a molecular insight into a complex modulation of splicing by HDACs and chromatin modifications. PMID- 21311749 TI - Brain perihematoma genomic profile following spontaneous human intracerebral hemorrhage. AB - BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) represents about 15% of all strokes and is associated with high mortality rates. Our aim was to identify the gene expression changes and biological pathways altered in the brain following ICH. METHODOLOGY/PRINCIPAL FINDINGS: Twelve brain samples were obtained from four deceased patients who suffered an ICH including perihematomal tissue (PH) and the corresponding contralateral white (CW) and grey (CG) matter. Affymetrix GeneChip platform for analysis of over 47,000 transcripts was conducted. Microarray Analysis Suite 5.0 was used to process array images and the Ingenuity Pathway Analysis System was used to analyze biological mechanisms and functions of the genes. We identified 468 genes in the PH areas displaying a different expression pattern with a fold change between -3.74 and +5.16 when compared to the contralateral areas (291 overexpressed and 177 underexpressed). The top genes which appeared most significantly overexpressed in the PH areas codify for cytokines, chemokines, coagulation factors, cell growth and proliferation factors while the underexpressed codify for proteins involved in cell cycle or neurotrophins. Validation and replication studies at gene and protein level in brain samples confirmed microarray results. CONCLUSIONS: The genomic responses identified in this study provide valuable information about potential biomarkers and target molecules altered in the perihematomal regions. PMID- 21311750 TI - A PXR-mediated negative feedback loop attenuates the expression of CYP3A in response to the PXR agonist pregnenalone-16alpha-carbonitrile. AB - The nuclear receptor superfamily of ligand-activated transcription factors plays a central role in the regulation of cellular responses to chemical challenge. Nuclear receptors are activated by a wide range of both endogenous and exogenous chemicals, and their target genes include those involved in the metabolism and transport of the activating chemical. Such target gene activation, thus, acts to remove the stimulating xenobiotic or to maintain homeostatic levels of endogenous chemicals. Given the dual nature of this system it is important to understand how these two roles are balanced, such that xenobiotics are efficiently removed while not impacting negatively on homeostasis of endogenous chemicals. Using DNA microarray technology we have examined the transcriptome response of primary rat hepatocytes to two nuclear receptor ligands: Pregnenalone-16alpha-carbonitrile (PCN), a xenobiotic PXR agonist, and lithocholic acid, an endogenous mixed PXR/VDR/FXR agonist. We demonstrate that despite differences in the profile of activated nuclear receptors, transcriptome responses for these two ligands are broadly similar at lower concentrations, indicating a conserved general response. However, as concentrations of stimulating ligand rises, the transcriptome responses diverge, reflecting a need for specific responses to the two stimulating chemicals. Finally, we demonstrate a novel feed-back loop for PXR, whereby ligand-activation of PXR suppresses transcription of the PXR gene, acting to attenuate PXR protein expression levels at higher ligand concentrations. Through in silico simulation we demonstrate that this feed-back loop is an important factor to prevent hyperexpression of PXR target genes such as CYP3A and confirm these findings in vitro. This novel insight into the regulation of the PXR-mediated regulatory signal networks provides a potential mechanistic rationale for the robustness in steroid homeostasis within the cell. PMID- 21311751 TI - Towards electrosynthesis in shewanella: energetics of reversing the mtr pathway for reductive metabolism. AB - Bioelectrochemical systems rely on microorganisms to link complex oxidation/reduction reactions to electrodes. For example, in Shewanella oneidensis strain MR-1, an electron transfer conduit consisting of cytochromes and structural proteins, known as the Mtr respiratory pathway, catalyzes electron flow from cytoplasmic oxidative reactions to electrodes. Reversing this electron flow to drive microbial reductive metabolism offers a possible route for electrosynthesis of high value fuels and chemicals. We examined electron flow from electrodes into Shewanella to determine the feasibility of this process, the molecular components of reductive electron flow, and what driving forces were required. Addition of fumarate to a film of S. oneidensis adhering to a graphite electrode poised at -0.36 V versus standard hydrogen electrode (SHE) immediately led to electron uptake, while a mutant lacking the periplasmic fumarate reductase FccA was unable to utilize electrodes for fumarate reduction. Deletion of the gene encoding the outer membrane cytochrome-anchoring protein MtrB eliminated 88% of fumarate reduction. A mutant lacking the periplasmic cytochrome MtrA demonstrated more severe defects. Surprisingly, disruption of menC, which prevents menaquinone biosynthesis, eliminated 85% of electron flux. Deletion of the gene encoding the quinone-linked cytochrome CymA had a similar negative effect, which showed that electrons primarily flowed from outer membrane cytochromes into the quinone pool, and back to periplasmic FccA. Soluble redox mediators only partially restored electron transfer in mutants, suggesting that soluble shuttles could not replace periplasmic protein-protein interactions. This work demonstrates that the Mtr pathway can power reductive reactions, shows this conduit is functionally reversible, and provides new evidence for distinct CymA:MtrA and CymA:FccA respiratory units. PMID- 21311752 TI - Mitochondrial genome sequence and expression profiling for the legume pod borer Maruca vitrata (Lepidoptera: Crambidae). AB - We report the assembly of the 14,054 bp near complete sequencing of the mitochondrial genome of the legume pod borer (LPB), Maruca vitrata (Lepidoptera: Crambidae), which we subsequently used to estimate divergence and relationships within the lepidopteran lineage. The arrangement and orientation of the 13 protein-coding, 2 rRNA, and 19 tRNA genes sequenced was typical of insect mitochondrial DNA sequences described to date. The sequence contained a high A+T content of 80.1% and a bias for the use of codons with A or T nucleotides in the 3rd position. Transcript mapping with midgut and salivary gland ESTs for mitochondrial genome annotation showed that translation from protein-coding genes initiates and terminates at standard mitochondrial codons, except for the coxI gene, which may start from an arginine CGA codon. The genomic copy of coxII terminates at a T nucleotide, and a proposed polyadenylation mechanism for completion of the TAA stop codon was confirmed by comparisons to EST data. EST contig data further showed that mature M. vitrata mitochondrial transcripts are monocistronic, except for bicistronic transcripts for overlapping genes nd4/nd4L and nd6/cytb, and a tricistronic transcript for atp8/atp6/coxIII. This processing of polycistronic mitochondrial transcripts adheres to the tRNA punctuated cleavage mechanism, whereby mature transcripts are cleaved only at intervening tRNA gene sequences. In contrast, the tricistronic atp8/atp6/coxIII in Drosophila is present as separate atp8/atp6 and coxIII transcripts despite the lack of an intervening tRNA. Our results indicate that mitochondrial processing mechanisms vary between arthropod species, and that it is crucial to use transcriptional information to obtain full annotation of mitochondrial genomes. PMID- 21311753 TI - Content-specific working memory modulation of the attentional blink. AB - Three experiments were conducted to investigate the effects of working memory content on temporal attention in a rapid serial visual presentation attentional blink paradigm. It was shown that categorical similarity between working memory content and the target stimuli pertaining to the attentional task (both digits) increased attentional blink magnitude compared to a condition in which this similarity was absent (colors and digits, respectively). This effect was only observed when the items in working memory were not presented as conjunctions of the involved categories (i.e., colored digits). This suggested that storage and retrieval from working memory was at least preferentially conjunctive in this case. It was furthermore shown that the content of working memory enhanced the identification rate of the second target, by means of repetition priming, when inter-target lag was short and the attentional blink was in effect. The results are incompatible with theories of temporal attention that assume working memory has no causal role in the attentional blink and support theories that do. PMID- 21311754 TI - Rho GTPase Cdc42 is a direct interacting partner of Adenomatous Polyposis Coli protein and can alter its cellular localization. AB - Adenomatous Polyposis Coli (APC) is a tumor suppressor gene product involved in colon cancer. APC is a large multidomain molecule of 2843 amino acid residues and connects cell-cell adhesion, the F-actin/microtubule cytoskeleton and the nucleus. Here we show that Cdc42 interacts directly with the first three armadillo repeats of APC by yeast two-hybrid screens. We confirm the Cdc42-APC interaction using pulldown assays in vitro and FRET assays in vivo. Interestingly, Cdc42 interacts with APC at leading edge sites where F-actin is enriched. In contrast, Cdc42 interacts with the truncated mutant APC1-1638 in cellular puncta associated with the golgi-lysozome pathway in transfected CHO cells. In HCT116 and SW480 cells, Cdc42 induces the relocalization of endogenous APC and the mutant APC1-1338 to the plasma membrane and cellular puncta, respectively. Taken together, these data indicate that the Cdc42-APC interaction induces localization of both APC and mutant APC and may thus play a direct role in the functions of these proteins. PMID- 21311755 TI - Solid tumor-targeted infiltrating cytotoxic T lymphocytes retained by a superantigen fusion protein. AB - Successful immune-mediated regression of solid tumors is difficult because of the small number of cytotoxic T lymphocytes (CTLs) that were traffic to the tumor site. Here, the targeting of tumor-specific infiltrating CTLs was dependent on a fusion protein consisting of human epidermal growth factor (EGF) and staphylococcal enterotoxin A (SEA) with the D227A mutation. EGF-SEA strongly restrained the growth of murine solid sarcoma 180 (S180) tumors (control versus EGF-SEA, mean tumor weight: 1.013 versus 0.197 g, difference = 0.816 g). In mice treated with EGF-SEA, CD4+, CD8+ and SEA-reactive T lymphocytes were enriched around the EGFR expressing tumor cells. The EGF receptors were potentially phosphorylated by EGF-SEA stimulation and the fusion protein promoted T cells to release the tumoricidal cytokines interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). Intratumoral CTLs secreted cytolytic pore-forming perforins and granzyme B proteins near the surface of carcinomas, causing the death of many tumor cells. We additionally show that labeled EGF-SEA was directly targeted to the tumor tissue after intravenous (i.v.) injection. The findings demonstrate that antibody-like EGF-SEA plays an important role in arresting CTLs in the solid tumor site and has therapeutic potential as a tumor-targeting agent. PMID- 21311756 TI - Isotopic investigation of contemporary and historic changes in penguin trophic niches and carrying capacity of the southern Indian ocean. AB - A temperature-defined regime shift occurred in the 1970s in the southern Indian Ocean, with simultaneous severe decreases in many predator populations. We tested a possible biological link between the regime shift and predator declines by measuring historic and contemporary feather isotopic signatures of seven penguin species with contrasted foraging strategies and inhabiting a large latitudinal range. We first showed that contemporary penguin isotopic variations and chlorophyll a concentration were positively correlated, suggesting the usefulness of predator delta13C values to track temporal changes in the ecosystem carrying capacity and its associated coupling to consumers. Having controlled for the Suess effect and for increase CO2 in seawater, delta13C values of Antarctic penguins and of king penguins did not change over time, while delta13C of other subantarctic and subtropical species were lower in the 1970s. The data therefore suggest a decrease in ecosystem carrying capacity of the southern Indian Ocean during the temperature regime-shift in subtropical and subantarctic waters but not in the vicinity of the Polar Front and in southward high-Antarctic waters. The resulting lower secondary productivity could be the main driving force explaining the decline of subtropical and subantarctic (but not Antarctic) penguins that occurred in the 1970s. Feather delta15N values did not show a consistent temporal trend among species, suggesting no major change in penguins' diet. This study highlights the usefulness of developing long-term tissue sampling and data bases on isotopic signature of key marine organisms to track potential changes in their isotopic niches and in the carrying capacity of the environment. PMID- 21311757 TI - Accommodating dynamic oceanographic processes and pelagic biodiversity in marine conservation planning. AB - Pelagic ecosystems support a significant and vital component of the ocean's productivity and biodiversity. They are also heavily exploited and, as a result, are the focus of numerous spatial planning initiatives. Over the past decade, there has been increasing enthusiasm for protected areas as a tool for pelagic conservation, however, few have been implemented. Here we demonstrate an approach to plan protected areas that address the physical and biological dynamics typical of the pelagic realm. Specifically, we provide an example of an approach to planning protected areas that integrates pelagic and benthic conservation in the southern Benguela and Agulhas Bank ecosystems off South Africa. Our aim was to represent species of importance to fisheries and species of conservation concern within protected areas. In addition to representation, we ensured that protected areas were designed to consider pelagic dynamics, characterized from time-series data on key oceanographic processes, together with data on the abundance of small pelagic fishes. We found that, to have the highest likelihood of reaching conservation targets, protected area selection should be based on time-specific data rather than data averaged across time. More generally, we argue that innovative methods are needed to conserve ephemeral and dynamic pelagic biodiversity. PMID- 21311758 TI - Structural and functional similarities between osmotin from Nicotiana tabacum seeds and human adiponectin. AB - Osmotin, a plant protein, specifically binds a seven transmembrane domain receptor-like protein to exert its biological activity via a RAS2/cAMP signaling pathway. The receptor protein is encoded in the gene ORE20/PHO36 and the mammalian homolog of PHO36 is a receptor for the human hormone adiponectin (ADIPOR1). Moreover it is known that the osmotin domain I can be overlapped to the beta-barrel domain of adiponectin. Therefore, these observations and some already existing structural and biological data open a window on a possible use of the osmotin or of its derivative as adiponectin agonist. We have modelled the three-dimensional structure of the adiponectin trimer (ADIPOQ), and two ADIPOR1 and PHO36 receptors. Moreover, we have also modelled the following complexes: ADIPOQ/ADIPOR1, osmotin/PHO36 and osmotin/ADIPOR1. We have then shown the structural determinants of these interactions and their physico-chemical features and analyzed the related interaction residues involved in the formation of the complexes. The stability of the modelled structures and their complexes was always evaluated and controlled by molecular dynamics. On the basis of these results a 9 residues osmotin peptide was selected and its interaction with ADIPOR1 and PHO36 was modelled and analysed in term of energetic stability by molecular dynamics. To confirm in vivo the molecular modelling data, osmotin has been purified from nicotiana tabacum seeds and its nine residues peptide synthesized. We have used cultured human synovial fibroblasts that respond to adiponectin by increasing the expression of IL-6, TNF-alpha and IL-1beta via ADIPOR1. The biological effect on fibroblasts of osmotin and its peptide derivative has been found similar to that of adiponectin confirming the results found in silico. PMID- 21311759 TI - Automatic stimulus-induced medial premotor cortex activation without perception or action. AB - Who has ever been surprised to return to the bowl of salted peanuts without realizing it, even after having eating a moderate number and deciding to stop? Using rapid event-related functional magnetic resonance imaging (fMRI) in healthy volunteers, we investigated the neural correlates of automatic processes induced by subliminal stimuli. We demonstrated that the automatic activation of motor programs elicited unconsciously in the medial premotor cortex was normally restricted to specific contexts set by the environment, but can occur below the threshold of awareness even when no movement was executed. This novel finding expands our view on brain mechanisms underlying unconscious motor control and provides new evidence that activation of the motor preparation system and consciousness are not obligatory linked. PMID- 21311760 TI - Zebrafish as a model system to study the physiological function of telomeric protein TPP1. AB - Telomeres are specialized chromatin structures at the end of chromosomes. Telomere dysfunction can lead to chromosomal abnormalities, DNA damage responses, and even cancer. In mammalian cells, a six-protein complex (telosome/shelterin) is assembled on the telomeres through the interactions between various domain structures of the six telomere proteins (POT1, TPP1, TIN2, TRF1, TRF2 and RAP1), and functions in telomere maintenance and protection. Within the telosome, TPP1 interacts directly with POT1 and TIN2 and help to mediate telosome assembly. Mechanisms of telomere regulation have been extensively studied in a variety of model organisms. For example, the physiological roles of telomere-targeted proteins have been assessed in mice through homozygous inactivation. In these cases, early embryonic lethality has prevented further studies of these proteins in embryogenesis and development. As a model system, zebrafish offers unique advantages such as genetic similarities with human, rapid developmental cycles, and ease of manipulation of its embryos. In this report, we detailed the identification of zebrafish homologues of TPP1, POT1, and TIN2, and showed that the domain structures and interactions of these telosome components appeared intact in zebrafish. Importantly, knocking down TPP1 led to multiple abnormalities in zebrafish embryogenesis, including neural death, heart malformation, and caudal defect. And these embryos displayed extensive apoptosis. These results underline the importance of TPP1 in zebrafish embryogenesis, and highlight the feasibility and advantages of investigating the signaling pathways and physiological function of telomere proteins in zebrafish. PMID- 21311761 TI - The etiology of multiple sclerosis: genetic evidence for the involvement of the human endogenous retrovirus HERV-Fc1. AB - We have investigated the role of human endogenous retroviruses in multiple sclerosis by analyzing the DNA of patients and controls in 4 cohorts for associations between multiple sclerosis and polymorphisms near viral restriction genes or near endogenous retroviral loci with one or more intact or almost-intact genes. We found that SNPs in the gene TRIM5 were inversely correlated with disease. Conversely, SNPs around one retroviral locus, HERV-Fc1, showed a highly significant association with disease. The latter association was limited to a narrow region that contains no other known genes. We conclude that HERV-Fc1 and TRIM5 play a role in the etiology of multiple sclerosis. If these results are confirmed, they point to new modes of treatment for multiple sclerosis. PMID- 21311762 TI - Sense and antisense transcripts of convergent gene pairs in Arabidopsis thaliana can share a common polyadenylation region. AB - The Arabidopsis genome contains a large number of gene pairs that encode sense and antisense transcripts with overlapping 3' regions, indicative for a potential role of natural antisense transcription in regulating sense gene expression or transcript processing. When we mapped poly(A) transcripts of three plant gene pairs with long overlapping antisense transcripts, we identified an unusual transcript composition for two of the three gene pairs. Both genes pairs encoded a class of long sense transcripts and a class of short sense transcripts that terminate within the same polyadenylation region as the antisense transcripts encoded by the opposite strand. We find that the presence of the short sense transcript was not dependent on the expression of an antisense transcript. This argues against the assumption that the common termination region for sense and antisense poly(A) transcripts is the result of antisense-specific regulation. We speculate that for some genes evolution may have especially favoured alternative polyadenylation events that shorten transcript length for gene pairs with overlapping sense/antisense transcription, if this reduces the likelihood for dsRNA formation and transcript degradation. PMID- 21311763 TI - DNA polymerase beta as a novel target for chemotherapeutic intervention of colorectal cancer. AB - Chemoprevention presents a major strategy for the medical management of colorectal cancer. Most drugs used for colorectal cancer therapy induce DNA alkylation damage, which is primarily repaired by the base excision repair (BER) pathway. Thus, blockade of BER pathway is an attractive option to inhibit the spread of colorectal cancer. Using an in silico approach, we performed a structure-based screen by docking small-molecules onto DNA polymerase beta (Pol beta) and identified a potent anti-Pol-beta compound, NSC-124854. Our goal was to examine whether NSC-124854 could enhance the therapeutic efficacy of DNA alkylating agent, Temozolomide (TMZ), by blocking BER. First, we determined the specificity of NSC-124854 for Pol-beta by examining in vitro activities of APE1, Fen1, DNA ligase I, and Pol-beta-directed single nucleotide (SN)- and long-patch (LP)-BER. Second, we investigated the effect of NSC-124854 on the efficacy of TMZ to inhibit the growth of mismatch repair (MMR)-deficient and MMR-proficient colon cancer cell lines using in vitro clonogenic assays. Third, we explored the effect of NSC-124854 on TMZ-induced in vivo tumor growth inhibition of MMR-deficient and MMR-proficient colonic xenografts implanted in female homozygous SCID mice. Our data showed that NSC-124854 has high specificity to Pol-beta and blocked Pol-beta directed SN- and LP-BER activities in in vitro reconstituted system. Furthermore, NSC-124854 effectively induced the sensitivity of TMZ to MMR-deficient and MMR proficient colon cancer cells both in vitro cell culture and in vivo xenograft models. Our findings suggest a potential novel strategy for the development of highly specific structure-based inhibitor for the prevention of colonic tumor progression. PMID- 21311764 TI - Diversity in viral anti-PKR mechanisms: a remarkable case of evolutionary convergence. AB - Most viruses express during infection products that prevent or neutralize the effect of the host dsRNA activated protein kinase (PKR). Translation of Sindbis virus (SINV) mRNA escapes to PKR activation and eIF2 phosphorylation in infected cells by a mechanism that requires a stem loop structure in viral 26S mRNA termed DLP to initiate translation in the absence of functional eIF2. Unlike the rest of viruses tested, we found that Alphavirus infection allowed a strong PKR activation and eIF2alpha phosphorylation in vitro and in infected animals so that the presence of DLP structure in mRNA was critical for translation and replication of SINV. Interestingly, infection of MEFs with some viruses that express PKR inhibitors prevented eIF2alpha phosphorylation after superinfection with SINV, suggesting that viral anti-PKR mechanisms could be exchangeable. Thus, translation of SINV mutant lacking the DLP structure (DeltaDLP) in 26S mRNA was partially rescued in cells expressing vaccinia virus (VV) E3 protein, a known inhibitor of PKR. This case of heterotypic complementation among evolutionary distant viruses confirmed experimentally a remarkable case of convergent evolution in viral anti-PKR mechanisms. Our data reinforce the critical role of PKR in regulating virus-host interaction and reveal the versatility of viruses to find different solutions to solve the same conflict. PMID- 21311765 TI - Reconciling the evidence on serum homocysteine and ischaemic heart disease: a meta-analysis. AB - BACKGROUND: Results from genetic epidemiological studies suggest that raised serum homocysteine is a cause of ischaemic heart disease, but the results of randomised trials suggest otherwise. We aimed to update meta-analyses on each type of study using the latest published data and test a hypothesis based on antiplatelet therapy use in the trials to explain the discrepancy. METHODS AND FINDINGS: Meta-analyses of ischaemic heart disease using (i) 75 studies in which the prevalence of a mutation (CT) in the MTHFR gene (which increases homocysteine) was determined in cases (22,068) and controls (23,618), and (ii) 14 randomised trials (39,597 participants) of homocysteine lowering and ischaemic heart disease events. The summary estimates from the two analyses were compared. Meta-analysis of the MTHFR studies showed a statistically significantly increased risk of ischaemic heart disease in TT compared with CC homozygotes; odds ratio 1.16 (1.04 to 1.29) for a 1.9 umol/L homocysteine difference (TT minus CC). Meta analysis of randomised trials showed no significant reduction in IHD risk from folic acid; relative risk 1.00 (0.93 to 1.08), despite a reduction in homocysteine of 3.3 umol/L. There was a statistically significant difference in risk reduction between the 5 trials with the lowest prevalence of antiplatelet therapy (60% on average, usually aspirin), RR 0.93 (0.84 to 1.05) and the 5 trials with the highest prevalence (91% on average), RR 1.09 (1.00 to 1.19), p = 0.037 for the difference. CONCLUSION: Discordant results from MTHFR studies and randomised trials could be explained by aspirin reducing or negating the anti platelet effect of lowering homocysteine. On this basis, folic acid would have a role in the primary prevention of ischaemic heart disease, when aspirin is not taken routinely, but not in secondary prevention, when it is routine. PMID- 21311766 TI - Different binding properties and function of CXXC zinc finger domains in Dnmt1 and Tet1. AB - Several mammalian proteins involved in chromatin and DNA modification contain CXXC zinc finger domains. We compared the structure and function of the CXXC domains in the DNA methyltransferase Dnmt1 and the methylcytosine dioxygenase Tet1. Sequence alignment showed that both CXXC domains have a very similar framework but differ in the central tip region. Based on the known structure of a similar MLL1 domain we developed homology models and designed expression constructs for the isolated CXXC domains of Dnmt1 and Tet1 accordingly. We show that the CXXC domain of Tet1 has no DNA binding activity and is dispensable for catalytic activity in vivo. In contrast, the CXXC domain of Dnmt1 selectively binds DNA substrates containing unmethylated CpG sites. Surprisingly, a Dnmt1 mutant construct lacking the CXXC domain formed covalent complexes with cytosine bases both in vitro and in vivo and rescued DNA methylation patterns in dnmt1-/- embryonic stem cells (ESCs) just as efficiently as wild type Dnmt1. Interestingly, neither wild type nor DeltaCXXC Dnmt1 re-methylated imprinted CpG sites of the H19a promoter in dnmt1-/- ESCs, arguing against a role of the CXXC domain in restraining Dnmt1 methyltransferase activity on unmethylated CpG sites. PMID- 21311767 TI - Single honeybee silk protein mimics properties of multi-protein silk. AB - Honeybee silk is composed of four fibrous proteins that, unlike other silks, are readily synthesized at full-length and high yield. The four silk genes have been conserved for over 150 million years in all investigated bee, ant and hornet species, implying a distinct functional role for each protein. However, the amino acid composition and molecular architecture of the proteins are similar, suggesting functional redundancy. In this study we compare materials generated from a single honeybee silk protein to materials containing all four recombinant proteins or to natural honeybee silk. We analyse solution conformation by dynamic light scattering and circular dichroism, solid state structure by Fourier Transform Infrared spectroscopy and Raman spectroscopy, and fiber tensile properties by stress-strain analysis. The results demonstrate that fibers artificially generated from a single recombinant silk protein can reproduce the structural and mechanical properties of the natural silk. The importance of the four protein complex found in natural silk may lie in biological silk storage or hierarchical self-assembly. The finding that the functional properties of the mature material can be achieved with a single protein greatly simplifies the route to production for artificial honeybee silk. PMID- 21311768 TI - Environmental conditions influence the plant functional diversity effect on potential denitrification. AB - Global biodiversity loss has prompted research on the relationship between species diversity and ecosystem functioning. Few studies have examined how plant diversity impacts belowground processes; even fewer have examined how varying resource levels can influence the effect of plant diversity on microbial activity. In a field experiment in a restored wetland, we examined the role of plant trait diversity (or functional diversity, (FD)) and its interactions with natural levels of variability of soil properties, on a microbial process, denitrification potential (DNP). We demonstrated that FD significantly affected microbial DNP through its interactions with soil conditions; increasing FD led to increased DNP but mainly at higher levels of soil resources. Our results suggest that the effect of species diversity on ecosystem functioning may depend on environmental factors such as resource availability. Future biodiversity experiments should examine how natural levels of environmental variability impact the importance of biodiversity to ecosystem functioning. PMID- 21311769 TI - Plasmin plays an essential role in amplification of psoriasiform skin inflammation in mice. AB - BACKGROUND: Although increased levels of plasminogen activators have been found in psoriatic lesions, the role of plasmin converted from plasminogen by plasminogen activators in pathogenesis of psoriasis has not been investigated. METHODOLOGY/PRINCIPAL FINDINGS: Here we examined the contribution of plasmin to amplification of inflammation in patients with psoriasis. We found that plasminogen was diminished, but that the amount and activity of its converted product plasmin were markedly increased in psoriasis. Moreover, annexin II, a receptor for plasmin was dramatically increased in both dermis and epidermis in psoriasis. Plasmin at sites of inflammation was pro-inflammatory, eliciting production of inflammatory factors, including CC chemokine ligand 20 (CCL20) and interleukin-23 (IL-23), that was mediated by the nuclear factor-kappaB (NF kappaB) signaling pathway and that had an essential role in the recruitment and activation of pathogenic C-C chemokine receptor type 6 (CCR6)+ T cells. Moreover, intradermal injection of plasmin or plasmin together with recombinant monocyte/macrophage chemotactic protein-1 (MCP-1) resulted in induction of psoriasiform skin inflammation around the injection sites with several aspects of human psoriasis in mice. CONCLUSIONS/SIGNIFICANCE: Plasmin converted from plasminogen by plasminogen activators plays an essential role in amplification of psoriasiform skin inflammation in mice, and targeting plasmin receptor--annexin II--may harbor therapeutic potential for the treatment of human psoriasis. PMID- 21311770 TI - Metabolic robustness and network modularity: a model study. AB - BACKGROUND: Several studies have mentioned network modularity-that a network can easily be decomposed into subgraphs that are densely connected within and weakly connected between each other-as a factor affecting metabolic robustness. In this paper we measure the relation between network modularity and several aspects of robustness directly in a model system of metabolism. METHODOLOGY/PRINCIPAL FINDINGS: By using a model for generating chemical reaction systems where one can tune the network modularity, we find that robustness increases with modularity for changes in the concentrations of metabolites, whereas it decreases with changes in the expression of enzymes. The same modularity scaling is true for the speed of relaxation after the perturbations. CONCLUSIONS/SIGNIFICANCE: Modularity is not a general principle for making metabolism either more or less robust; this question needs to be addressed specifically for different types of perturbations of the system. PMID- 21311771 TI - Effects of an infectious fungus, Batrachochytrium dendrobatidis, on amphibian predator-prey interactions. AB - The effects of parasites and pathogens on host behaviors may be particularly important in predator-prey contexts, since few animal behaviors are more crucial for ensuring immediate survival than the avoidance of lethal predators in nature. We examined the effects of an emerging fungal pathogen of amphibians, Batrachochytrium dendrobatidis, on anti-predator behaviors of tadpoles of four frog species. We also investigated whether amphibian predators consumed infected prey, and whether B. dendrobatidis caused differences in predation rates among prey in laboratory feeding trials. We found differences in anti-predator behaviors among larvae of four amphibian species, and show that infected tadpoles of one species (Anaxyrus boreas) were more active and sought refuge more frequently when exposed to predator chemical cues. Salamander predators consumed infected and uninfected tadpoles of three other prey species at similar rates in feeding trials, and predation risk among prey was unaffected by B. dendrobatidis. Collectively, our results show that even sub-lethal exposure to B. dendrobatidis can alter fundamental anti-predator behaviors in some amphibian prey species, and suggest the unexplored possibility that indiscriminate predation between infected and uninfected prey (i.e., non-selective predation) could increase the prevalence of this widely distributed pathogen in amphibian populations. Because one of the most prominent types of predators in many amphibian systems is salamanders, and because salamanders are susceptible to B. dendrobatidis, our work suggests the importance of considering host susceptibility and behavioral changes that could arise from infection in both predators and prey. PMID- 21311772 TI - A large change in temperature between neighbouring days increases the risk of mortality. AB - BACKGROUND: Previous studies have found high temperatures increase the risk of mortality in summer. However, little is known about whether a sharp decrease or increase in temperature between neighbouring days has any effect on mortality. METHOD: Poisson regression models were used to estimate the association between temperature change and mortality in summer in Brisbane, Australia during 1996 2004 and Los Angeles, United States during 1987-2000. The temperature change was calculated as the current day's mean temperature minus the previous day's mean. RESULTS: In Brisbane, a drop of more than 3 degrees C in temperature between days was associated with relative risks (RRs) of 1.157 (95% confidence interval (CI): 1.024, 1.307) for total non-external mortality (NEM), 1.186 (95%CI: 1.002, 1.405) for NEM in females, and 1.442 (95%CI: 1.099, 1.892) for people aged 65-74 years. An increase of more than 3 degrees C was associated with RRs of 1.353 (95%CI: 1.033, 1.772) for cardiovascular mortality and 1.667 (95%CI: 1.146, 2.425) for people aged <65 years. In Los Angeles, only a drop of more than 3 degrees C was significantly associated with RRs of 1.133 (95%CI: 1.053, 1.219) for total NEM, 1.252 (95%CI: 1.131, 1.386) for cardiovascular mortality, and 1.254 (95%CI: 1.135, 1.385) for people aged >= 75 years. In both cities, there were joint effects of temperature change and mean temperature on NEM. CONCLUSION: A significant change in temperature of more than 3 degrees C, whether positive or negative, has an adverse impact on mortality even after controlling for the current temperature. PMID- 21311775 TI - Collision-induced gas-phase reactions of perhalogenated closo-dodecaborate clusters--a comparative study. AB - The gas phase reactivity of perhalogenated closo-dodecaborate clusters [B(12)X(12)](2-) (X = F, Cl, Br, I) with N-tetraalkylated ammonium counter ions was investigated by electrospray ionization ion trap mass spectrometry (ESI-IT MS). Collisions with the background gases introduced a broad variety of gas phase reactions. This study represents the first experimental approach to a new class of boron-rich boron clusters that are not accessible in the condensed phase. The anionic ion pair [B(12)X(12) + N(C(n)H(2n+1))(4)](-) is generally found as the ion of highest mass. Its reaction sequence starts with an alkyl transfer from the ammonium ion to the dodecaborate cluster. Subsequently, the alkylated intermediate [B(12)X(12) + C(n)H(2n+1)](-) decomposes to give very reactive ions of the general formula [B(12)X(11)](-). These ions possess a free boron vertex and immediately bind to the residual gases N(2) and H(2)O in the ion trap by formation of the corresponding adducts [B(12)X(11) + N(2)](-) and [B(12)X(11) + H(2)O](-). Subsequent fragmentations of the water adduct repetitively substitute halogen atoms by hydroxyl groups. The fragmentation process of the free anion [B(12)X(12)](2-) depends on the applied excitation energy and on the halogen substituent X. A radical dehalogenation of the B(12) unit is observed for X = I, whereas for X = Cl or F the loss of small molecules (mainly BX(3)) dominates. The different reaction behavior is explained by the different electron affinity of the halogens and the strength of the boron-halogen-bonds. Surprisingly, isolation of the fragment ion [B(12)I(9)](-) in the ion trap yields the highly stable [B(24)I(18)](2-) dianion. This observation suggests a reaction between two negative ions in the gas phase. PMID- 21311773 TI - Cathepsin-D, a key protease in breast cancer, is up-regulated in obese mouse and human adipose tissue, and controls adipogenesis. AB - The aspartic protease cathepsin-D (cath-D) is overexpressed by human epithelial breast cancer cells and is closely correlated with poor prognosis in breast cancer. The adipocyte is one of the most prominent cell types in the tumor microenvironment of breast cancer, and clinical studies have shown that obesity increases the incidence of breast cancer. Here, we provide the first evidence that cath-D expression is up-regulated in adipose tissue from obese human beings, as well as in adipocytes from the obese C57BI6/J mouse. Cath-D expression is also increased during human and mouse adipocyte differentiation. We show that cath-D silencing in 3T3-F442A murine preadipocytes leads to lipid-depleted cells after adipogenesis induction, and inhibits of the expression of PPARgamma, HSL and aP2 adipocyte differentiation markers. Altogether, our findings demonstrate the key role of cath-D in the control of adipogenesis, and suggest that cath-D may be a novel target in obesity. PMID- 21311774 TI - Epithelial tissues have varying degrees of susceptibility to Kras(G12D)-initiated tumorigenesis in a mouse model. AB - Activating mutations in the Kras gene are commonly found in some but not all epithelial cancers. In order to understand the susceptibility of different epithelial tissues to Kras-induced tumorigenesis, we introduced one of the most common Kras mutations, Kras(G12D), broadly in epithelial tissues. We used a mouse model in which the G12D mutation is placed in the endogenous Kras locus controlled by inducible, Cre-mediated recombination in tissues expressing cytokeratin 19 including the oral cavity, GI tract, lungs, and ducts of the liver, kidney, and the pancreas. Introduction of the Kras(G12D) mutation in adult mouse tissues led to neoplastic changes in some but not all of these tissues. Notably, many hyperplasias, metaplasias and adenomas were observed in the oral cavity, stomach, colon and lungs, suggesting that exposure to products of the outside environment promotes Kras(G12D)-initiated tumorigenesis. However, environmental exposure did not consistently correlate with tumor formation, such as in the small intestine, suggesting that there are also intrinsic differences in susceptibility to Kras activation. The pancreas developed small numbers of mucinous metaplasias with characteristics of early stage pancreatic intraepithelial neoplasms (PanINs), supporting the hypothesis that pancreatic ducts have the potential to give rise pancreatic cancer. PMID- 21311776 TI - Varying spin state composition by the choice of capping ligand in a family of molecular chains: detailed analysis of magnetic properties of chromium(III) horseshoes. AB - We report a detailed physical analysis on a family of isolated, antiferro magnetically (AF) coupled, chromium(III) finite chains, of general formula (Cr(RCO(2))(2)F)(n) where the chain length n = 6 or 7. Additionally, the chains are capped with a selection of possible terminating ligands, including hfac (= l,l,l,5,5,5-hexafluoropentane-2,4-dionate(l-)), acac (= pentane-2,4-dionate(l-)) or (F)(3). Measurements by inelastic neutron scattering (INS), magnetometery and electron paramagnetic resonance (EPR) spectroscopy have been used to study how the electronic properties are affected by n and capping ligand type. These comparisons allowed the subtle electronic effects the choice of capping ligand makes for odd member spin 3/2 ground state and even membered spin 0 ground state chains to be investigated. For this investigation full characterisation of physical properties have been performed with spin Hamiltonian parameterisation, including the determination of Heisenberg exchange coupling constants and single ion axial and rhombic anisotropy. We reveal how the quantum spin energy levels of odd or even membered chains can be modified by the type of capping ligand terminating the chain. Choice of capping ligands enables Cr-Cr exchange coupling to be adjusted by 0, 4 or 24%, relative to Cr-Cr exchange coupling within the body of the chain, by the substitution of hfac, acac or (F)(3) capping ligands to the ends of the chain, respectively. The manipulation of quantum spin levels via ligands which play no role in super-exchange, is of general interest to the practise of spin Hamilton modelling, where such second order effects are generally not considered of relevance to magnetic properties. PMID- 21311777 TI - Redistribution of meta-tetra(hydroxyphenyl)chlorin (m-THPC) from conventional and PEGylated liposomes to biological substrates. AB - We used the phenomenon of previously described photoinduced fluorescence quenching and fluorescence polarization to evaluate the transfer of meta tetra(hydroxyphenyl)chlorin (m-THPC) from commercial high-drug load liposomes to plasma proteins and model membranes. Fluorescence quenching of m-THPC in liposomes by iodide indicates that part of m-THPC in PEGylated liposomes is localized in the PEG shell, while the rest is bound to the lipid bilayer. It was shown that the two molecule pools in the commercial PEGylated liposomal formulation Fospeg(r) condition the characteristics of the m-THPC release kinetics. A substantial percentage of m-THPC from Fospeg(r) is released much faster than from the conventional liposomal formulation Foslip(r). Using the technique of resonance light scattering, it was shown that partial m-THPC aggregation is present in liposomes with very high drug loads, higher in PEGylated liposomes compared to conventional ones. PMID- 21311778 TI - Interlayer interaction and relative vibrations of bilayer graphene. AB - The van der Waals corrected first-principles approach (DFT-D) is for the first time applied for investigation of interlayer interaction and relative motion of graphene layers. A methodological study of the influence of parameters of calculations with the dispersion corrected and original PBE functionals on characteristics of the potential relief of the interlayer interaction energy is performed. Based on the DFT-D calculations, a new classical potential for interaction between graphene layers is developed. Molecular dynamics simulations of relative translational vibrations of graphene layers demonstrate that the choice of the classical potential considerably affects dynamic characteristics of graphene-based systems. The calculated low values of the Q-factor for these vibrations Q~ 10-100 show that graphene should be perfect for the use in fast responding nanorelays and nanoelectromechanical memory cells. PMID- 21311779 TI - Protein-inspired modified DNAzymes: dramatic effects of shortening side-chain length of 8-imidazolyl modified deoxyadenosines in selecting RNaseA mimicking DNAzymes. AB - The discovery of imidazole/amine-functionalized DNAzymes that efficiently cleave RNA independently of divalent metal cations (M(2+)) and cofactors underscores the importance of expanding the catalytic repertoire with modified nucleosides. Considerable effort has gone into defining polymerase tolerances of various modified dNTPs for synthesizing and amplifying modified DNA. While long linkers are generally found to enhance incorporation and therefore increase sequence space, shorter linkers may reduce the entropic penalty paid for orienting catalytic functionality. Catalytic enhancement ultimately depends on both the functional group and appropriate linkage to the nucleobase. Whether a shorter linker provides enough catalytic enhancement to outweigh the cost of reduced polymerizability can only be determined by the outcome of the selection. Herein, we report the selection of DNAzyme 20-49 (Dz20-49), which depends on amine, guanidine, and imidazole-modified dNTPs. In contrast to previous selections where we used dA(ime)TP (8-(4-imidazolyl)ethylamino-2'-dATP), here we used dA(imm)TP (8 (4-imidazolyl)methylamino-2'-dATP), in which the linker arm is shortened by one methylene group. Although the most active clone, Dz20-49, was absolutely dependent on the incorporation of either dA(imm)p or dA(ime)p, it catalyzed cofactor independent self-cleavage with a rate constant of 3.1 +/- 0.3 * 10(-3) min(-1), a value not dissimilar from unmodified catalysts and strikingly inferior to modified catalysts selected with dA(ime)TP. These results demonstrate that very subtle differences in modified nucleotide composition may dramatically effect DNAzyme selection. PMID- 21311780 TI - Growth limits in platinum oxides formed on Pt-skin layers on Pt-Co bimetallic nanoparticles. AB - The dynamical oxidation processes of Pt-skin layers on Pt(3)Co were investigated in situ and in real-time by time-resolved X-ray absorption spectroscopy combined with electrochemical measurements. Growth limit behaviors and the suppression of higher-order formation of surface oxides were observed, and these might explain the highly durable nature of Pt-skin layers. PMID- 21311781 TI - White light-emitting devices based on carbon dots' electroluminescence. AB - We demonstrate the first white light-emitting device originating from single carbon dot components. A maximum external quantum efficiency of 0.083% at a current density of 5 mA cm(-2) with a color-rendering index of 82 is realized, indicating that carbon dots have great potential to be an alternative phosphor for fabricating white light electroluminescent devices. PMID- 21311782 TI - Photocatalytic CdSe QDs-decorated ZnO nanotubes: an effective photoelectrode for splitting water. AB - Arrays of ZnO nanorods (NRs) were successfully converted into nanotubes (NTs), used as photoelectrodes in photoelectrochemical (PEC) cells after their sensitization with CdSe quantum dots (QDs) and a strong correlation between the PEC performance and geometrical structure of ZnO NTs@CdSe(QDs) and ZnO NRs@CdSe(QDs) was established under the same conditions. PMID- 21311783 TI - Modulating DNA-templated silver nanoclusters for fluorescence turn-on detection of thiol compounds. AB - Based on the fact that the fluorescence response pattern of a silver nanocluster to a specific analyte is highly dependent on the nature of the DNA template, we develop a novel fluorescence turn-on assay for thiol compounds with high specificity and sensitivity by modulating DNA-templated silver nanoclusters. PMID- 21311784 TI - Guilty as charged: non-innocent behavior by a pincer ligand featuring a central cationic phosphenium donor. AB - The synthesis of a new pincer ligand containing a central cationic N-heterocyclic phosphenium donor is described. The electrophilic nature of this cationic ligand renders it non-innocent, and coordination of this ligand to a PtCl(2) fragment leads to chloride migration from Pt to the cationic phosphorus center. PMID- 21311785 TI - Calibration and applications of the DeltaMP2 method for calculating core electron binding energies. AB - We calibrated a method for the evaluation of core electron binding energies, based on the energy differences between the cation and neutral molecule evaluated at the level of Moller-Plesset perturbation theory. The central feature of the method is the use of a mixed basis set: a large all-electron basis set is used for the atom whose core electron is removed, while the model core potential basis set is employed for all remaining atoms. Calibration was carried out for 55 molecules and 114 binding energies of 1s core electrons for the atoms C, N, O, and F. The average absolute deviation for all the core electron binding energies is 0.163 eV. The method was applied to the calculation of the core electron binding energies of five nucleic acid bases (uracil, adenine, cytosine, guanine, and thymine) and several of their low-energy tautomers. PMID- 21311786 TI - Rovibrational state specific scattering distributions of the O((1)D) + CD(4)-> OD + CD3 (v1, v2, N) reaction. AB - The rovibrational state distributions and state-resolved scattering distributions of CD(3) radicals produced by the reaction O((1)D) + CD(4) were investigated by crossed molecular beam ion imaging. The rotational structure of the resonance enhanced multiphoton ionization spectrum of CD(3) in the ground vibrational state indicates that the low K rotational states of CD(3) radicals are preferentially populated. The state-resolved scattering distributions of CD(3) (v = 0) and those of the excited states of the out-of-plane bending (v(2)) mode exhibit a structureless forward-scattering component due to an insertion pathway and a structured backward-scattering component due to an abstraction path. The scattering distributions of CD(3) in the excited state of the C-D symmetric stretch (v(1)) do not exhibit the abstraction component. The scattering distribution of the abstraction component gradually extends in the forward direction with increasing intensity as the v(2) vibration becomes more strongly excited. This suggests that abstraction with a larger impact parameter results in stronger excitation of v(2). PMID- 21311787 TI - A computational study on the structures of methylamine-carbon dioxide-water clusters: evidence for the barrier free formation of the methylcarbamic acid zwitterion (CH3NH2+COO-) in interstellar water ices. AB - We investigated theoretically the interaction between methylamine (CH(3)NH(2)) and carbon dioxide (CO(2)) in the presence of water (H(2)O) molecules thus simulating the geometries of various methylamine-carbon dioxide complexes (CH(3)NH(2)/CO(2)) relevant to the chemical processing of icy grains in the interstellar medium (ISM). Two approaches were followed. In the amorphous water phase approach, structures of methylamine-carbon dioxide-water [CH(3)NH(2)/CO(2)/(H(2)O)(n)] clusters (n = 0-20) were studied using density functional theory (DFT). In the crystalline water approach, we simulated methylamine and carbon dioxide interactions on a fragment of the crystalline water ice surface in the presence of additional water molecules in the CH(3)NH(2)/CO(2) environment using DFT and effective fragment potentials (EFP). Both the geometry optimization and vibrational frequency analysis results obtained from these two approaches suggested that the surrounding water molecules which form hydrogen bonds with the CH(3)NH(2)/CO(2) complex draw the carbon dioxide closer to the methylamine. This enables, when two or more water molecules are present, an electron transfer from methylamine to carbon dioxide to form the methylcarbamic acid zwitterion, CH(3)NH(2)(+)CO(2)(-), in which the carbon dioxide is bent. Our calculations show that the zwitterion is formed without involving any electronic excitation on the ground state surface; this structure is only stable in the presence of water, i.e. in a methyl amine-carbon dioxide water ice. Notably, in the vibrational frequency calculations on the methylcarbamic acid zwitterion and two water molecules we find the carbon dioxide asymmetric stretch is drastically red shifted by 435 cm(-1) to 1989 cm(-1) and the carbon dioxide symmetric stretch becomes strongly infrared active. We discuss how the methylcarbamic acid zwitterion CH(3)NH(2)(+)CO(2)(-) might be experimentally and astronomically identified by its asymmetric CO(2) stretching mode using infrared spectroscopy. PMID- 21311788 TI - Interactions of Schiff-base ligands with gold nanoparticles: structural, optical and electrocatalytic studies. AB - A study on optical and electrochemical properties resulting upon interaction of Schiff base ligands with gold nanoparticles is presented. The measurements of the optical absorption and fluorescence properties have provided important information about structure-properties dependence. We show that in function of the isomer structure and its attachment orientation with respect to the metal nanoparticle, their optical properties can be modulated. Nanoparticle assemblies mediated by 3,4-DHS were also obtained based on a control of the interparticle interactions and their electrocatalytic activity toward NADH oxidation was investigated. PMID- 21311789 TI - Ion transfer through solvent polymeric membranes driven by an exponential current flux. AB - General analytical equations which govern ion transfer through liquid membranes with one and two polarized interfaces driven by an exponential current flux are derived. Expressions for the transient and stationary E-t, dt/dE-E and dI/dE-E curves are obtained, and the evolution from transient to steady behaviour has been analyzed in depth. We have also shown mathematically that the voltammetric and stationary chronopotentiometric I(N)-E curves are identical (with E being the applied potential for voltammetric techniques and the measured potential for chronopotentiometric techniques), and hence, their derivatives provide identical information. PMID- 21311790 TI - Effective solvent mediated potentials of Na+ and Cl- ions in aqueous solution: temperature dependence. AB - The effective solvent-mediated potentials for Na(+) and Cl(-) ions in aqueous solution were calculated in a wide range of temperatures from 0 to 100 degrees C. The potentials have been determined using the inverse Monte Carlo approach, from the ion-ion radial distribution functions computed in 50 ns molecular dynamics simulations of ions and explicit water molecules. We further separated the effective potentials into a short-range part and an electrostatic long-range part represented by a coulombic potential with some dielectric permittivity. We adjusted the value of the dielectric permittivity to provide the fastest possible decay of the short-range potentials at larger distances. The obtained temperature dependence of the dielectric permittivity follows well the experimental data. We show also that the largest part of the temperature dependence of the effective potentials can be attributed to the temperature-dependent dielectric permittivity. PMID- 21311791 TI - Iodobismuthates with N-alkyl- or N,N'-dialkyl-4,4'-bipyridinium: syntheses, structures and dielectric properties. AB - The solvothermal reactions of BiI(3), KI, I(2), 4,4'-bipyridine (4,4'-bipy), and a small amount of water in alcohol and acetonitrile produced four bipyridinium iodobismuthates {[MQ](3)[Bi(2)I(6)(MU-I)(3)][Bi(2)I(6)(MU-I)(2)(MQ)(2)](3)} (1, MQ(+) = N-methyl-4,4'-bipyridinium), {[EQ](3)[Bi(2)I(6)(MU-I)(3)][Bi(2)I(6)(MU I)(2)(EQ)(2)](3)} (2, EQ(+) = N-ethyl-4,4'-bipyridinium), [MV][BiI(5)] (Eur. J. Inorg. Chem., 2010, 5326) (3, MV(2+) = N,N'-dimethyl-4,4'-bipyridinium), and [EV](2)[Bi(4)I(10)(MU-I)(4)(MU(3)-I)(2)] (4, EV(2+) = N,N'-diethyl-4,4' bipyridinium). In these reactions, 4,4'-bipy was partly or completely alkylated by alkyl groups generated from the cleavage of C-O bond of alcohols, forming the N-alkyl-4,4'-bipyridinium cation (Q(+)) and the N,N'-dialkyl-4,4'-bipyridinium dication (V(2+)), respectively. Compounds 1-4 were characterized by elemental analysis, IR, (1)H NMR and single-crystal X-ray diffraction analysis. The optical, electrical conductive and dielectric properties of these compounds were investigated. The dielectric constants of the Q(+)-based compounds were larger than the values of the V(2+)-based ones, which showed that the weak electrostatic interactions in the structures may benefit the polarizability of molecules, thereby resulting in a larger dielectric response of the structures under an external electric field, while the strong electrostatic interactions between the positive and negative charge units would lead to a low dielectric constant (low k) behavior of these compounds. PMID- 21311792 TI - Theoretical studies of 31P NMR spectral properties of phosphanes and related compounds in solution. AB - Selected theoretical methods, basis sets and solvation models have been tested in their ability to predict (31)P NMR chemical shifts of large phosphorous containing molecular systems in solution. The most efficient strategy was found to involve NMR shift calculations at the GIAO-MPW1K/6-311++G(2d,2p)//MPW1K/6 31G(d) level in combination with a dual solvation model including the explicit consideration of single solvent molecules and a continuum (PCM) solvation model. For larger systems it has also been established that reliable (31)P shift predictions require Boltzmann averaging over all accessible conformations in solution. PMID- 21311793 TI - Organometallic dithiolene complexes of the group 8-10 metals: reactivities, structures and electrochemical behavior. AB - Research progress in the organometallic dithiolene complexes such as [Cp(or Cp*)M(dithiolene)] (M = Co, Rh, Ir, Ni), [(C(6)R(6))Ru(dithiolene)] and [(C(4)R(4))Pt(dithiolene)] complexes during the past decade is described and the reactivities, structures and electrochemical behavior are summarized in this paper. The five-membered metalladithiolene ring (MS(2)C(2)) undergoes addition reactions to the M[double bond, length as m-dash]S bond to form 18-electron adducts by an imido, alkylidene, alkene or norbornene group and also undergoes dimerizations on the basis of the unsaturation in the ring. The aromaticity of the ring causes substitution reactions on the dithiolene carbon by a C-centered radical, S-centered radical or succinimide group when the ring has a C-H bond. Furthermore a dithiolene-dithiolene homo-coupling reaction by an acid or dithiolene-aryl cross-coupling occurs based on the aromaticity in the ring. Dissociations of the 18-electron adducts are observed by those thermolyses, photolyses, electrochemical redox reactions and other chemical reactions with tertiary phosphorus compounds. One representative example of them is the imido adduct dissociation with PR(3) under heating toward the intramolecular imido migration to a Cp ligand. Since all products are rearomatized by those adduct dissociations, it is concluded that the 'coexistence of aromaticity and unsaturation' in the metallacycle mediates the diverse chemical reactions. PMID- 21311795 TI - Fluorescent labeling of membrane proteins on the surface of living cells by a self-catalytic glutathione S-transferase omega 1 tag. AB - Imaging a specific protein of interest in live cell has versatile applications in biological research. Recently, diverse chemical tags have been developed to overcome the limits of autofluorescence protein (FP) tags. However, current chemical methods still need to be progressed to compete with FPs in the scope of specificity and convenience in staining procedure. We report a novel protein tagging method that provides a convenient and specific fluorescent labeling of membrane proteins. Omega tag is developed by employing a mammalian enzyme glutathione sulfur-transferase omega 1 (GSTO1) and its partner dye, 5-bromomethyl fluorescein (BMF). Omega-tagged membrane proteins were labeled by BMF efficiently for live cell imaging and in-gel analysis. Endocytosis of epidermal growth factor receptor (EGFR) was successfully visualized by using this Omega tagging system. Omega tag will provide a convenient tool for the physiological study of membrane proteins in live cells. PMID- 21311796 TI - Facile preparation of water-soluble fluorescent gold nanoclusters for cellular imaging applications. AB - We report a facile strategy to synthesize water-soluble, fluorescent gold nanoclusters (AuNCs) in one step by using a mild reductant, tetrakis(hydroxymethyl)phosphonium chloride (THPC). A zwitterionic functional ligand, D-penicillamine (DPA), as a capping agent endowed the AuNCs with excellent stability in aqueous solvent over the physiologically relevant pH range. The DPA-capped AuNCs displayed excitation and emission bands at 400 and 610 nm, respectively; the fluorescence quantum yield was 1.3%. The effect of borohydride reduction on the optical spectra and X-ray photoelectron spectroscopy (XPS) results indicated that the AuNC luminescence is closely related to the presence of Au(I) on their surfaces. In a first optical imaging application, we studied internalization of the AuNCs by live HeLa cells using confocal microscopy with two-photon excitation. A cell viability assay revealed good biocompatibility of these AuNCs. Our studies demonstrate a great potential of DPA-stabilized AuNCs as fluorescent nanoprobes in bioimaging and related applications. PMID- 21311797 TI - An 2-(2'-aminophenyl)benzoxazole-based OFF-ON fluorescent chemosensor for Zn2+ in aqueous solution. AB - A water-soluble fluorescent sensor, 1, based on the "receptor-spacer-fluorophore" [2-(2'-aminophenyl)benzoxazole-amide-2-picolylamine] sensor platform, demonstrates the high sensitivity for Zn(2+) with a 25-fold fluorescence enhancement upon chelation to Zn(2+) and also exhibits high selectivity to Zn(2+) over other metal ions. X-ray crystal structure of Zn(2+) complex reveals that the amide oxygen (O2) cooperates with 2-picolylamine unit (N3, N4) as a receptor bind Zn(2+). PMID- 21311794 TI - Infection with the carcinogenic human liver fluke, Opisthorchis viverrini. AB - Throughout Southeast Asia there is a strikingly high incidence of cholangiocarcinoma (CCA--hepatic cancer of the bile duct epithelium), particularly in people from rural settings in Laos and Northeast Thailand who are infected with the liver fluke, Opisthorchis viverrini, one of only three carcinogenic eukaryotic pathogens. More ubiquitous carcinogenic microbes, such as Helicobacter pylori, induce cancer in less than 1% of infected people, while as many as one-sixth of people with opisthorchiasis will develop CCA. The mechanisms by which O. viverrini causes cancer are multi-factorial, involving mechanical irritation from the activities and movements of the flukes, immunopathology, dietary nitrosamines and the secretion of parasite proteins that promote a tumourigenic environment. Genomic and proteomic studies of the liver fluke secretome have accelerated the discovery of parasite proteins with known/potential roles in pathogenesis and tumourigenesis, establishing a framework towards understanding, and ultimately preventing, the morbidity and mortality attributed to this highly carcinogenic parasite. PMID- 21311798 TI - Photodecaging from 9-substituted 2,7-dihydroxy and dimethoxyfluorenes: competition between heterolytic and homolytic pathways. AB - 2,7-Dihydroxy-9-fluorenol (9), 2,7-dimethoxy-9-fluorenol (10), and 2,7-dimethoxy 9-acetoxyfluorene (11) were prepared and their photochemistry was studied in methanol and aqueous methanol solution in the hopes of observing efficient expulsion of the substituents positioned at the 9-position. For all three compounds, the primary photoproducts were 2,7-disubstituted-9-fluorenes and 2,7 disubstituted-9-methoxyfluorenes. A mechanism of reaction is proposed for production of these products, and involves competing homolytic and heterolytic pathways that produce radical and carbocation intermediates. Reaction quantum yields (for substrate disappearance) ranged between 0.21 and 0.31. PMID- 21311799 TI - Chiral single-molecule magnets: a partial Mn(III) supertetrahedron from achiral components. AB - A [Mn(III)(9)] partial supertetrahedron is a Single-Molecule Magnet (SMM) with an energy barrier to magnetisation reversal of ~30 K and represents the first chiral SMM obtained from achiral starting materials. PMID- 21311800 TI - Solvent response of polymers for micromachine manipulation. AB - A novel solvent responsive polymer micromachine has been successfully fabricated by two-photon photopolymerization (TPP) of methacrylate-based photoresists. The moving part of the micromachine could be easily driven by interfacial solvent polarity induced swelling and shrinking of the photopolymer networks. Furthermore, the driving performance of the micromachine could be precisely modulated by varying the laser scanning step length during fabrication. PMID- 21311801 TI - Pt-Ag clusters and their neutral mononuclear Pt(II) starting complexes: structural and luminescence studies. AB - The mononuclear complexes [Pt(bzq)(S^S)] [S^S = pyrrolidinedithiocarbamate (pdtc 1), dimethyldithiocarbamate (dmdtc 2)] were prepared by reaction of [Pt(bzq)(NCMe)(2)]ClO(4) with an equimolecular amount of [NH(4)(pdtc)] and [Na(dmdtc).2H(2)O] respectively in MeOH. Reactions of 1 and 2 with AgClO(4) in 1 : 1 and 2 : 1 molar ratios rendered the heteropolinuclear compounds [{Pt(bzq)(S^S)Ag}(2)](ClO(4))(2) (S^S = pdtc 3, dmdtc 4) and [{Pt(bzq)(S^S)}(2)Ag](ClO(4)) (S^S = pdtc 5, dmdtc 6) respectively. The X-ray studies on single crystals of 3 and 4 showed that both consist of tetranuclear [Pt(2)Ag(2)] clusters with the Pt-Ag and the Ag-Ag distances in the range of those corresponding to Pt-Ag dative bonds and argentophilic interactions. In 3 the tetranuclear [Pt(2)Ag(2)] clusters are connected into infinite polymeric chains by Pt...Pt metallophilic interactions (Pt...Pt = 3.1890(7) A). The X-ray study on a single crystal of 5 showed that it is a polymer based on trinuclear [Pt(2)Ag] clusters containing two unsupported Pt-Ag dative bonds and connected by Ag-S bonds in such a way that the "Pt-Ag-S-Pt-Ag-S" atoms draw a zigzag polymeric chain. TD-DFT calculations carried out for 1 indicate that the lowest energy absorption band in CH(2)Cl(2) can be described as a mixture of (1)MLCT, (1)IL and (1)L'LCT transitions. Powdered samples of 1 at 298 K and 77 K show a green-yellow emission band coming mainly from a (3)LC excited state. However complex 2 shows "luminescence thermochromism": the colour of its luminescence changes from green yellow at 77 K to orange-red at 298 K. The emission of the Pt-Ag clusters, 3-6, in the solid state, are due to excimeric (3)pipi and/or (3)MMLCT (dsigma* ->pi*) low-lying excited states, indicating that the presence of silver in the clusters makes the "Pt(bzq)(S^S)" fragments interact to a large extent through Pt...Pt and/or pi-pi interactions. Solid 3 is a highly selective vapochromic compound towards acetonitrile although this behaviour is not fully reversible. PMID- 21311802 TI - Nanoporous bimetallic Pt-Au alloy nanocomposites with superior catalytic activity towards electro-oxidation of methanol and formic acid. AB - We present a facile route to fabricate novel nanoporous bimetallic Pt-Au alloy nanocomposites by dealloying a rapidly solidified Al(75)Pt(15)Au(10) precursor under free corrosion conditions. The microstructure of the precursor and the as dealloyed sample was characterized using X-ray diffraction, scanning electron microscopy, transmission electron microscopy, high-resolution transmission electron microscopy, and energy dispersive X-ray (EDX) analysis. The Al(75)Pt(15)Au(10) precursor is composed of a single-phase Al(2)(Au,Pt) intermetallic compound, and can be fully dealloyed in a 20 wt.% NaOH or 5 wt.% HCl aqueous solution. The dealloying leads to the formation of the nanoporous Pt(60)Au(40) nanocomposites (np-Pt(60)Au(40) NCs) with an fcc structure. The morphology, size and crystal orientation of grains in the precursor can be conserved in the resultant nanoporous alloy. The np-Pt(60)Au(40) NCs consist of two zones with distinct ligament/channel sizes and compositions. The formation mechanism of these np-Pt(60)Au(40) NCs can be rationalized based upon surface diffusion of more noble elements and spinodal decomposition during dealloying. Electrochemical measurements demonstrate that the np-Pt(60)Au(40) NCs show superior catalytic activity towards the electro-oxidation of methanol and formic acid in the acid media compared to the commercial JM-Pt/C catalyst. This material can find potential applications in catalysis related areas, such as direct methanol or formic acid fuel cells. Our findings demonstrate that dealloying is an effective and simple strategy to realize the alloying of immiscible systems under mild conditions, and to fabricate novel nanostructures with superior performance. PMID- 21311803 TI - An expeditious asymmetric synthesis of the pentacyclic core of the cortistatins by an intramolecular (4+3) cycloaddition. AB - A concise, asymmetric synthesis of the pentacyclic framework of the cortistatins has been accomplished in 12 steps from commercially available starting materials, employing a highly diastereoselective intramolecular (4+3) cycloaddition of epoxy enolsilanes as the key step. PMID- 21311804 TI - Enzymatic biosensors based on SWCNT-conducting polymer electrodes. AB - This short review is focused on recent advances in the combination of conducting polymers and SWCNTs for the fabrication of electrochemical biosensors. The different properties of conducting polymers and SWCNTs are discussed in respect of their use in immobilizing and wiring biomolecules on electrode surfaces. We further describe the functionalization techniques used in the fabrication of these devices and their associated biosensing performances. PMID- 21311805 TI - Synthesis of hierarchical TS-1 by caramel templating. AB - Hierarchical TS-1 with a well connected network of meso/macropores inside the zeolite crystal was directly synthesized by using caramel as the template. PMID- 21311806 TI - An inorganic-organic diblock copolymer photoresist for direct mesoporous SiCN ceramic patterns via photolithography. AB - A high resolution negative-tone-type of inorganic-organic diblock copolymer photoresist was synthesized as a novel precursor for simple and direct fabrication of SiCN ceramic mesoporous patterns with ordered nanoscale pores by using a "top-down" photolithographic technique and the subsequent sacrificial processes of a "bottom-up" self-assembled nanostructure. PMID- 21311807 TI - Mechanisms and advancement of antifading agents for fluorescence microscopy and single-molecule spectroscopy. AB - Modern fluorescence microscopy applications go along with increasing demands for the employed fluorescent dyes. In this work, we compared antifading formulae utilizing a recently developed reducing and oxidizing system (ROXS) with commercial antifading agents. To systematically test fluorophore performance in fluorescence imaging of biological samples, we carried out photobleaching experiments using fixed cells labeled with various commonly used organic dyes, such as Alexa 488, Alexa 594, Alexa 647, Cy3B, ATTO 550, and ATTO 647N. Quantitative evaluation of (i) photostability, (ii) brightness, and (iii) storage stability of fluorophores in samples mounted in different antifades (AFs) reveal optimal combinations of dyes and AFs. Based on these results we provide guidance on which AF should preferably be used with a specific dye. Finally, we studied the antifading mechanisms of the commercial AFs using single-molecule spectroscopy and reveal that these empirically selected AFs exhibit similar properties to ROXS AFs. PMID- 21311808 TI - A MUL-scale micromachined microbial fuel cell having high power density. AB - We report a MEMS (Micro-Electro-Mechanical Systems)-based microbial fuel cell (MFC) that produces a high power density. The MFC features 4.5-MUL anode/cathode chambers defined by 20-MUm-thick photo-definable polydimethylsiloxane (PDMS) films. The MFC uses a Geobacter-enriched mixed bacterial culture, anode-respiring bacteria (ARB) that produces a conductive biofilm matrix. The MEMS MFC generated a maximum current density of 16,000 MUA cm(-3) (33 MUA cm(-2)) and power density of 2300 MUW cm(-3) (4.7 MUW cm(-2)), both of which are substantially greater than achieved by previous MEMS MFCs. The coulombic efficiency of the MEMS MFC was at least 31%, by far the highest value among reported MEMS MFCs. The performance improvements came from using highly efficient ARB, minimizing the impact of oxygen intrusion to the anode chamber, having a large specific surface area that led to low internal resistance. PMID- 21311809 TI - High-fidelity determination of security threats via a Boolean biocatalytic cascade. AB - The ability to assess diverse security threats using a biochemical logic network system is demonstrated. The new biocatalytic cascade, emulating a NOR logic gate, is able to identify the presence of explosive compounds and nerve agents by providing a simple and rapid 'YES'/'NO' alert. PMID- 21311810 TI - An ab initio spin-orbit-corrected potential energy surface and dynamics for the F + CH4 and F + CHD3 reactions. AB - We report an analytical ab initio three degrees of freedom (3D) spin-orbit correction surface for the entrance channel of the F + methane reaction obtained by fitting the differences between the spin-orbit (SO) and non-relativistic electronic ground state energies computed at the MRCI+Q/aug-cc-pVTZ level of theory. The 3D model surface is given in terms of the distance, R(C-F), and relative orientation, Euler angles phi and theta, of the reactants treating CH(4) as a rigid rotor. The full-dimensional (12D) "hybrid" SO-corrected potential energy surface (PES) is obtained from the 3D SO-correction surface and a 12D non SO PES. The SO interaction has a significant effect in the entrance-channel van der Waals region, whereas the effect on the energy at the early saddle point is only ~5% of that at the reactant asymptote; thus, the SO correction increases the barrier height by ~122 cm(-1). The 12D quasiclassical trajectory calculations for the F + CH(4) and F + CHD(3) reactions show that the SO effects decrease the cross sections by a factor of 2-4 at low collision energies and the effects are less significant as the collision energy increases. The inclusion of the SO correction in the PES does not change the product state distributions. PMID- 21311811 TI - A 'Sleeping Trojan Horse' which transports metal ions into cells, localises in nucleoli, and has potential for bimodal fluorescence/PET imaging. AB - A rhenium polypyridine-based molecular vessel is membrane impermeant when empty, but, upon loading with metal ions, the cationic form is taken up by MCF-7 cells, localising in nucleoli. The luminescence of the vessel and its copper binding ability suggest potential as a bimodal fluorescence/PET imaging agent. PMID- 21311812 TI - Dynamics of H and D abstraction in the reaction of Cl atom with butane 1,1,1,4,4,4-d6. AB - We report the primary (D-atom) and secondary (H-atom) abstraction dynamics of chlorine atom reaction with butane-1,1,1,4,4,4-d(6). The H- and D-atom abstraction channels were studied over a range of collision energies: 10.4 kcal mol(-1) and 12.9 kcal mol(-1); 5.2 kcal mol(-1) to 12.8 kcal mol(-1), respectively, using crossed molecular beam dc slice ion imaging techniques. Single photon ionization at 157 nm was used to probe the butyl radical products resulting from the H- and D-atom abstraction reactions. These two channels manifest distinct dynamics principally in the translational energy distributions, while the angular distributions are remarkably similar. The reduced translational energy distribution for the primary abstraction showed marked variation with collision energy in the backward direction, while the secondary abstraction showed this variation in the forward direction. PMID- 21311813 TI - Point-of-care testing system enabling 30 min detection of influenza genes. AB - We developed a portable and easy-to-use nucleic acid amplification test (NAT) system for use in point-of-care testing (POCT). The system shows sensitivity that is sufficiently higher than that of the currently available rapid diagnostic kit and is comparable to that of real-time reverse transcription polymerase chain reaction (RT-PCR) for influenza testing. PMID- 21311817 TI - A unified platform for optoelectrowetting and optoelectronic tweezers. AB - A platform capable of seamlessly unifying both optoelectrowetting and optoelectronic tweezers is presented. This enables the user to manipulate aqueous droplets (with electrowetting) as well as individual particles within those droplets (with dielectrophoresis). The device requires no photolithography and droplet/particle manipulation can occur continuously over the entire surface of the device. Droplet and 10 um polystyrene particle speeds of up to 8 mm s(-1) and 60 um s(-1), respectively, are demonstrated. Particle concentration within, and subsequent splitting of, a droplet is performed resulting in average concentration efficiencies of 93%. Serial concentration is also demonstrated resulting in exponentially increasing particle concentrations and a 10* concentration increase. Finally, the platform is used to select a single cell out of a cohort and subsequently encapsulate it in its own aqueous droplet. PMID- 21311818 TI - A methionine-based turn-on chemical sensor for selectively monitoring Hg2+ ions in 100% aqueous solution. AB - Dansyl-labeled methionine is synthesized by solid-phase synthesis, and found to be a highly sensitive and selective sensor for Hg(2+). The sensor sensitively detects Hg(2+) ions in aqueous solution by a turn-on response; however, the sensor detects Hg(2+) ions by a turn-off response in organic and mixed aqueous organic solutions. We investigated the binding stoichiometry, binding constant, and binding mode of the sensor under various solvent conditions. In 100% aqueous solution, 2 : 1 complexation of the sensor with Hg(2+) ions is more favorable than 1 : 1 complexation, whereas the sensor preferentially forms a 1 : 1 complex in 100% CH(3)CN or in 50% CH(3)CN-aqueous solutions. Results reveal that the stoichiometry of the sensor-Hg(2+) complex plays an important role in the type of response to Hg(2+) ions, and that 2 : 1 complexation is required for a turn-on response to Hg(2+) ions in aqueous solution. PMID- 21311819 TI - Haemostasis management of massive bleeding. AB - Trauma-induced coagulopathy (TIC) is a frequent complication of severely injured patients. The etiology of TIC is complex. Contributing factors include overwhelming generation of thrombin and activated protein C, consumption of coagulation factors and platelets, hyperfibrinolysis, and dilution of clotting factors through administration of fluids. In addition, hypothermia and shock associated metabolic acidosis augment the clotting dysfunctions. The occurrence of TIC has been shown to be an independent risk factor for death after trauma warranting aggressive treatment. On admission to the emergency room patients with massive blood loss should be employed on basis of clinical and diagnostic variables to identify patients at high risk of coagulopathy. Patients at high risk should be treated with tranexamic acid (1 g bolus followed by 1 g/8 h), and critical factor and platelet deficiencies should be corrected by transfusion of factor concentrates and platelet concentrates. In addition, plasma should be administered in a 1:1 ratio with red cells. The use of recombinant factor VIIa should be considered if major bleeding persists despite best-practive use of blood products. PMID- 21311820 TI - Old and new anticoagulants. AB - Vitamin-K-antagonists (VKA) and heparins have been complementary anticoagulants for prevention and treatment of thrombosis for almost 70 years. In contrast to heparins, VKA have not been modified pharmacologically, however treatment surveillance has improved by introducing INR and self-monitoring/management. Disclosure of the molecular basis of interaction with VKORC1, the target enzyme of VKA, has helped to better understand coumarin sensitivity and resistance. New oral anticoagulants have now been approved and stimulated expectations in patients and physicians to get rid of the burdening frequent controls of VKA without loss of efficacy and safety. This review will summarize the development and profile of the new substances. Main difference compared to VKA is their direct mode of action against one clotting factor which is factor IIa in dabigatran and factor Xa in rivaroxaban and other "xabanes" currently under intensive investigation. Half lifes of the new anticoagulants are much shorter than that of the mainly used coumarins (phenprocoumon, warfarin), making "anticoagulation bridging" unnecessary before surgery. Therapeutic width of direct thrombin inhibitors and factor Xa inhibitors is broader and they are given at fixed doses. Clinical studies in thromboprophylaxis, thromboembolism and atrial fibrillation indicate at least non-inferiority or even superior efficacy compared with enoxaparin and VKA at comparable safety outcomes. Limitations of the new substances may arise from gastrointestinal side effects, mode of metabolism and route of elimination. Specific antidots are not available for none of them. Undoubtedly, the new oral anticoagulants are very promising. But, although thousands of study patients already have been treated, there are questions to be answered such as treatment adherence in absence of monitoring, safety and efficacy in risk patients, dosage adjustment and interactions with other drugs, before conclusions can be drawn towards their potential to replace VKA. PMID- 21311821 TI - The impact and management of acquired platelet dysfunction. AB - Platelet function can be abnormally increased, as in association with acute vascular events, or defective, as in a variety of clinical settings. Acquired platelet dysfunction may occur at any age and range in severity from mild to life threatening haemorrhages. Diagnostic work-up of platelet disorders requires meticulous evaluation of medical history, specifically of any drugs interfering with platelet function, careful clinical examination and a staged laboratory protocol to assess the underlying platelet defect(s). To identify hyperactive platelets ex vivo, costly procedures may be required using flow cytometry and distict epitope-specific monoclonal antibodies. Currently, this approach can be recommended for research purposes only. Drugs represent the most common cause of platelet dysfunction in our overmedicated society. While aspirin, clopigogrel (more recently also prasugrel) and integrin alphaIIbbeta3 (GPIIb-IIIa) receptor antagonists (abciximab, eptifibatide and tirofiban) are well-known prototypes of antiplatelet drugs, other widely used agents (e.g. nonsteroidal anti-inflammatory drugs, antibiotics, serotonin reuptake inhibitors and volume expanders) can also impair platelet function and thus cause or aggravate hemorrhages. Identification of individual patients with pre-existing hemostatic defects remains crucial (i) to prevent bleeding complications, (ii) to manage symptoms adequately, (iii) to minimize the risk from invasive procedures, and (iv) to avoid unnecassary exposure to blood products. Screening for platelet dysfunction can be performed by point-of-care testing followed by platelet aggregometry in response to various agonists. While mild bleeding episodes due to antiplatelet therapy can be managed by withdrawal of the drug(s), severe hemorrhages may require immediate platelet transfusions. Apart from that, the prohemostatic armamentarium is limited to desmopressin, antifibrinolytic agents, and recombinant factor VIIa. PMID- 21311822 TI - Monitoring of antiplatelet therapy. Current limitations, challenges, and perspectives. AB - Screening of platelet function can be performed by point-of-care testing followed by platelet aggregometry in response to agonists such as collagen, adenosine diphosphate, epinephrine, and arachidonic acid. Despite in use for decades, this technique is not well standardized. Monitoring of antiplatelet therapy is increasingly applied in patients at high risk for re-thrombosis or bleeding. To assess pharmacological inhibition of platelet function, agonist-induced platelet aggregation, thromboxane B2 (TxB2) and vasodilator-stimulated protein phosphorylation (VASP) are being measured. While serum TxB2 levels of < 2 ng/ml reflect aspirin-induced inhibition of cyclo-oxygenase-1 activity with high sensitivity, VASP exhibits a wide variability upon treatment with clopidogrel or prasugrel. Multiple studies reveal an association between high residual platelet reactivity and adverse cardiovascular events in patients on antiplatelet therapy. However, despite the plethora of platelet function assays currently under investigation, their use in daily practice cannot be recommended. This is due to several reasons: (i) there is no consensus on the method and a respective cut-off value associated with clinical adverse outcome, and (ii) data demonstrating any benefit of tailored antiplatelet therapy and its monitoring (based on assessment of platelet functions) are still limited. Thus, appropriate identification of 'resistant' or 'poor responders' to antiplatelet agents remains challenging in clinical practice. PMID- 21311823 TI - [General practitioners and patients' social representations of the doctor-patient relationship in Bogota, Colombia]. AB - OBJECTIVE: The present study intended to examine the social representation of the doctor-patient relationship in a sample of patients and doctors in Bogota. METHODS: The sample consisted of 34 subjects: 17 patients (9 male and 8 female) and 17 general practitioners (10 male and 7 female) who were attended or worked, respectively, under the state's obligatory health plan. The techniques used for collecting information were in-depth interview and association web; these were applied to all subjects in the study. RESULTS: The results showed that the doctors' social representation was centred on offering a professional and human service which is in constant danger due to patient-imposed barriers and health system capacity. Patients' centred their social representation on the doctors' ability to offer a professional and human service allowing them to improve their quality of life. Patients perceived that doctors who were negligent or dehumanised presented the greatest barrier to them obtaining the necessary implements to manage and improve their quality of life. CONCLUSIONS: Doctors and patients' social representation were similar regarding what they wanted to give and obtain; however, they conflicted regarding whom they perceived as being responsible for not being able to succeed in accomplishing their objectives. PMID- 21311824 TI - Domestic maternal experience with preterm newborn children. AB - OBJECTIVE: Exploring maternal experience with premature newborn children in a domestic environment. METHODS: The study was qualitative and used focus group interviews with 24 women who had had preterm deliveries in a public maternity hospital located in Northeast Brazil during June and October 2005. The mothers returned to the hospital facility at least 30 days after the newborn were discharged to share their experiences in caring for a premature infant at home. RESULTS: Interview data was analysed for content, four thematic nuclei being identified: hospital discharge, preparing the family for discharge, caring for a premature baby at home and life changes arising from the premature birth. The greatest difficulties reported by the mothers in caring for their premature children at home were related to feeding and feelings of insecurity and fear were expressed which showed the need for a support network for the families following discharge. CONCLUSIONS: The mothers care of premature infants at home represented changes for parents in everyday family life, work and social life, thus showing the need for a support network for them during the transition from hospital to home when considering premature children. PMID- 21311825 TI - [The epidemiology of canine rabies in Colombia]. AB - OBJECTIVE: An epidemiological-ecological study was carried out on canine rabies in Colombia to describe its tendency and explore the factors associated with its incidence. METHODS: Socio-economic variable data was collected by questionnaire applied to the rabies control programme's regional epidemiology coordinators in each Colombian department. Statistical association analysis was carried out on the 2001-2006 historical epidemiologic data on canine rabies incidence and sources of official national survey figures. Incidence rate ratios and Spearman correlation tests were calculated. RESULTS: Canine rabies incidence rate was 0.4 cases x 100,000 dogs/year (without adjustment for 2001-2006). Average immunisation coverage from 1994 to 2005 was 45 % to 63 %; only 25 % of Colombian departments had higher than 60 % immunisation coverage. The following variables were associated with the presence of canine rabies: an urban population, immunisation coverage, a lack of a cold chain for vaccines, a lack of participation in surveillance committees, the lack of an epidemiological map, the unavailability of a rabies' diagnosis laboratory, the absence of trained human resources, the absence of a zoonosis centre for observing dogs, comparative analysis between monthly and semester basis data and the percentage of people displaced by internal violence. CONCLUSIONS: The analysis suggested the need for active surveillance and rapid response. Canine rabies is associated with the weaknesses of regional control programmes. Internal human migration could influence human-dog-selvatic reservoir ratios and rabies frequency. PMID- 21311826 TI - [Evaluating an Information, Education and Communication (IEC) strategy which was adopted for Aedes aegypti control in La Dorada, Colombia]. AB - OBJECTIVE: Estimating the impact of the Information, Education and Communication strategy on Aedes aegypti infestation in homes in La Dorada, Colombia. METHODS: A cross-sectional study was carried out during June and July 2008 in La Dorada; 228 houses were chosen and vector presence was measured in two ways: immature forms were captured by the rapid sweeping method in water tanks and adults were captured by active collection. A survey simultaneously measured exposure to the strategy. EPI Info 2000 was used for analysing the database so created. Prevalence ratios and 95 % confidence intervals were calculated. RESULTS: A relationship was found between being a housewife and not having larvae present in the home. No immature forms were found in houses where somebody washed the water tank at least once a week. There were also no larvae in homes where people had knowledge about larvae and dengue transmission. The presence of adult forms was found in houses having more than one water tank. Almost 80 % of the interviewees acquired knowledge about dengue transmission through the strategy. CONCLUSIONS: Although all strategy components had not been implemented, several factors were found which might have a protective effect (i.e. being related to vector absence). The study showed that the strategy achieved only partial success in La Dorada. PMID- 21311827 TI - Women's quality of life: University of the Third Age, Goias, Brazil. AB - OBJECTIVES: Assessing the quality of life (QOL) of elderly women attending the University of the Third Age (UNATI) at the Federal University of Goias in Brazil. METHODS: This was a descriptive, observational study of 38 elderly women aged 60 or older. A socio-demographic information form and the WHOQOL-BREF and WHOQOLOLD questionnaires were applied for QOL assessment. RESULTS: Most women were aged 60 69 (58.8 %). The WHOQOL-BREF QOL scores in the physical, psychological, social relationships and environmental domains bore no statistical relevance; however, the general QOL before (67.86+/-2.91) and after (60.71+/-8.71) attending UNATI had p=0.049 significance. As for the WHOQOL-OLD, only the sensorial functioning domain (before: 61.84+/-20.74; after: 71.38+/-17.66; p=0.014) and the death and dying domain were significant (before: 56.36+/-25.48; after: 67.27+/-25.35; p=0.001). CONCLUSIONS: The elderly women demonstrated typical socio-demographic characteristics and their concerns to stay healthy within possible income, socialisation and health delivery service patterns were considered good. The WHOQOL-BREF revealed that the general domain played a major role compared to other domains. The sensorial functioning and the death and dying domains on the WHOQOL-OLD characterised this particular population's anxieties, wishes and gender needs. PMID- 21311828 TI - [Basic health unit embracement: focusing on user satisfaction]. AB - OBJECTIVE: Health service care quality is directly linked to user embracement and satisfaction, these being essential to any change made in working practice in providing health services. This study was aimed at evaluating users' perception of a basic health unit (BHU), analysing their satisfaction and participation in social control. METHOD: This was an exploratory study; the data was collected by using a structured interview on BHU users in a medium-sized Brazilian city. RESULTS: Most users were pleased with the service being provided and highlighted its strengths such as resolution, humanisation and solidarity. The weaknesses revealed by the interviews were related to accumulated demand, poor physical area and non participation. CONCLUSIONS: A relationship involving respect and professionals really listening to their clients makes the difference in health provision; however, the complaints made must also be considered for effective embracement of the service being provided in the BHU. Investment must be made in BHU physical infrastructure allowing professionals to work better and making the BHU more comfortable for their users. PMID- 21311829 TI - [Dignified social support for elderly institutionalised adults in Medellin, 2008]. AB - OBJECTIVE: Analysing the social support provided for elderly institutionalised adults being cared for in Elderly Welfare Centres (Centros de Bienestar del Anciano de Medellin) in Medellin during 2008. MATERIALS: This was a cross sectional descriptive study (primary information source) which addressed some characteristics related to the social support being received by 273 elderly people institutionalised in 37 social welfare centres. Univariate and bivariate analysis was applied to the data. RESULTS: The institutionalised people were mostly single or widowed women aged between 65 and 84 who had received primary and secondary education; most were affiliated to the contributory health regimen. Loneliness, health problems and family decision were the main causes for them having become institutionalised. They were visited by their children and other relatives and such support was rated as being satisfactory; however, more than half of them had feelings of loneliness and one sixth claimed to be humiliated and insulted by their loved ones. It should be noted that a few of them reported being mistreated by their caregivers. Institutionalised elderly adults performed recreational activities, were satisfied with the support received from friends, with cohabitation and the pertinent institution. CONCLUSIONS: Social support networks were strong within the institution (i.e. Elderly Welfare Centres); the elderly seemed to receive greater abuse from family members and cohabitants than institutional caregivers. Loneliness generally leads elderly adults to become institutionalised; however, once having entered an institution (being partly motivated by little family contact and average satisfaction with friends and the institution itself) their neglect and social vulnerability becomes evident. PMID- 21311830 TI - [The effects of pedagogical training on university teaching in the field of health]. AB - OBJECTIVE: Evaluating changes in teaching adopted by teachers after participating in the Pedagogical Health Science Formation extension course taught by the National University of Colombia's Pedagogical Support and Teaching Formation Group from the Medicine Faculty. This was a part-time course; it dealt with topics such as didactics, curriculum, evaluation and the teacher's role. METHODS: A qualitative, exploratory study was carried out, involving a personal interview formulated by the investigators; this was held in each participant's place of work. Fifty teachers who had taken the course between 2003 and 2004 were interviewed. The questionnaire consisted of ten semi-structured questions. RESULTS: After taking the course, 82 % of the participants considered that the quality of their communication with students was one of their most valued qualities, having understood that learning is a process which must be shared by both teachers and students. 64 % of the participants stated that they had acquired new concepts about evaluation and had increased their use of more participative pedagogical strategies. CONCLUSION: Teaching training courses had a positive effect on teaching, reflected in the quality of communication, teacher student relationships and the pedagogic strategies used, all being very important elements in constructivist-orientated pedagogical models. The study's results agreed with other investigators' prior experience. The university must encourage this kind of intervention which will promote its own academic development by improving its teachers' performance. PMID- 21311831 TI - [Cigarette smoking and the risk of high-school students becoming dependent on nicotine]. AB - OBJECTIVE: Establishing cigarette smoking prevalence, the factors associated with it and the risk of nicotine dependence in adolescents attending school in Cartagena, Colombia. METHOD: This was a cross-sectional study of a probability sample of 1,152 adolescent students from public and private schools in Cartagena. Students anonymously and individually completed a questionnaire containing sociodemographic and psychosocial characteristics. A descriptive analysis was then made of the variables investigated. All qualitative and quantitative variables were then dichotomised and odds ratios (OR) were estimated with 95 % confidence intervals. RESULTS: 1,014 students successfully completed the survey. Mean age was 15.1 years. 355 (35.0 %) students had experimented with cigarettes, 70 (6.9 %) reported smoking regularly and 18/70 (257 %) presented a high risk of nicotine dependence. The following variables were associated with smoking: being an elementary school student (4.08 OR; 2.27 to 7.35 95 %CI), being over 15 (3.71 OR; 2.85-7.44 95 %CI), having parents who smoked (2.47 OR; 1.42 to 4.31 95 %CI), being male (2.37 OR; 1.40 to 4.00 95 %CI) and having a brother or sister who smoked (2.21 OR; 1.16 to 4.21 95 %CI). CONCLUSIONS: The prevalence of smoking was low in high-school students from Cartagena. The frequency of smokers was higher amongst basic secondary education students, males older than fifteen and in whom the parents or brothers or sisters were smokers. PMID- 21311832 TI - [Comparing two diagnostic methods used for breast neoplasm in a cancer centre in Colima, Mexico]. AB - OBJECTIVE: Determining the relationship between mammography neoplasm reports and histopathological diagnosis of neoplasms. METHODS: A descriptive cross-sectional study was carried out. Patients were included who were attending the state cancerology centre (Centro Estatal de Cancerologia) in Colima, Mexico. Inclusion parameters were: females having mammography and BIRADS score of 1 or over; females having biopsy and histopathology diagnosis; females of all ages, all clinic stages having a complete clinic record. Frequency, percentages, means and standard deviations were applied for descriptive statistics. Student's t-test, the Chi square test, OR and 95 %CI were applied for inferential statistics. Differences were considered to be significant when p<0.05. RESULTS: No relationship between a BIRADS score classified as being benign (BIRADS I-II-III) or malign (BIRADS IV-V) was found with histopathological results (benign or malign) (p=0.0666). Significant relationships by category were found in a separate analysis: category IV (OR=0.024, 95 %CI=0.005-0.11, p=0.0007) and category V (OR=40.5, 95 %CI=9.03-181.3, p=0.0002). CONCLUSIONS: I, III and V BIRADS scores had a relationship with histopathological diagnosis, while category II and IV BIRADS scores had no relationship. However, only categories 4 and5 were statistically significant. PMID- 21311833 TI - [Methicillin-resistant Staphylococcus aureus in children attending school in Cartagena, Colombia]. AB - OBJECTIVE: Determining nasal carriers of methicillin-resistant Staphylococcus aureus (MRSA) and associated risk factors for nasal colonisation in a school-aged population in the seaside city of Cartagena, Colombia. METHODS: A cross sectional, analytical study was carried out on 100 healthy schoolchildren to determine MRSA nasal carriage and its association with risk factors. Bacteria were identified using conventional methods. Antibiotic sensitivity was determined by the Kirby Bauer method. RESULTS: A total of 36 isolates of S. aureus were identified in the school children. 25 % of the strains were oxacillin-resistant, 66.7 % oxacillin-sensitive and 8.3 % had intermediate susceptibility. 67 % of the MRSA strains isolated were sensitive to all antibiotics tested. One strain (MRSA Ant4) showed resistance to antibiotics having different mechanisms of action. CONCLUSIONS: This is the first study in Cartagena which determined the frequency of S. aureus and MRSA strains nasal carriers in a school population (33 % and 9 %, respectively). All S. aureus oxacillin-resistant strains were cephoxitin resistant, thereby leading to the presence of the mecA gene being suspected. Having used beta-lactam antibiotics during the last three months increased the likelihood of being an MRSA nasal carrier by around five times (OR=4.72; 0.96 23.98 95 %CL; p<0.05). The antibiotypes (Ant) found suggested the presence of community-acquired (multisensitive CA-MRSA,) and hospital-acquired-MRSA (multidrug resistant HA-MRSA,). PMID- 21311834 TI - [Applying the clustering technique for characterising maintenance outsourcing]. AB - OBJECTIVE: Using clustering techniques for characterising companies providing health institutions with maintenance services. METHODS: The study analysed seven pilot areas' equipment inventory (264 medical devices). Clustering techniques were applied using 26 variables. Response time (RT), operation duration (OD), availability and turnaround time (TAT) were amongst the most significant ones. RESULTS: Average biomedical equipment obsolescence value was 0.78. Four service provider clusters were identified: clusters 1 and 3 had better performance, lower TAT, RT and DR values (56 % of the providers coded O, L, C, B, I, S, H, F and G, had 1 to 4 day TAT values: = 50 years of age after fragility fracture. METHODS: Six to eight months after fracture, women were randomized into three groups: (1) control, (2) written materials, or (3) videocassette and written materials. Written materials for both the patient and physician detailed osteoporosis, fragility fracture, and available treatments; written materials for physicians were provided through patients. The educational videocassette presented similar information as the written material, but in greater depth. Rates of osteoporosis diagnosis and treatment following intervention were compared among groups using survival analysis methods. Statistical significance was set at p < 0.0167. RESULTS: At randomization, 1,174 women were without osteoporosis diagnosis and treatment, and after follow-up, 12% of the control group, 15% of the written materials group (p = 0.073), and 16% (p = 0.036) of the videocassette and written materials group were diagnosed with osteoporosis (statistical comparisons to control). Treatment rates were 8% for the control group, 12% for the written materials group (p = 0.052), and 11% for the videocassette and written materials group (p = 0.157). At randomization, 1,314 women were without treatment and after follow-up therapy was initiated in 10% of the control group, 13% of the written materials group (p = 0.107), and 13% of the videocassette and written materials group (p = 0.238). CONCLUSIONS: The educational interventions assessed in this trial were not satisfactory to increase osteoporosis diagnosis or treatment in recently fractured women to a clinically meaningful degree. PMID- 21311872 TI - Fast capillary electrophoresis-time-of-flight mass spectrometry using capillaries with inner diameters ranging from 75 to 5 MUm. AB - Fast electrophoretic separations in fused silica capillaries (CE) coupled to time of-flight mass spectrometry (TOF-MS) are presented. CE separations of the model analytes (epinephrine, norepinephrine, dopamine, histidine, and isoproterenol) under conditions of high electric field strengths of up to 1.25 kV cm(-1) are completed in 20 s. Coupling of CE with TOF-MS is accomplished using a coaxial sheath liquid electrospray ionization interface. The influence of parameters inherent to the interface and their effects, including suction pressure and dilution, are discussed. In addition to standard capillaries of 75 and 50 MUm inner diameter (ID), separations in capillaries with IDs of 25, 15, and 5 MUm have been successfully applied to this setup. The analytical performance is compared over this range of capillary dimensions, and both advantages and disadvantages are discussed. PMID- 21311873 TI - Combined non-destructive XRF and SR-XAS study of archaeological artefacts. AB - We report on a non-destructive study of Sicilian ceramic fragments of cultural heritage interest, classified as "proto-majolica" pottery and dating back to the twelfth to thirteen centuries AD. The analytical approach used is based on the employment of two totally non-invasive spectroscopic techniques: X-ray fluorescence (XRF), using a portable energy-dispersive XRF analyser, and X-ray absorption spectroscopy, using synchrotron radiation as a probe (SR-XAS). XRF measurements allowed us to collect elemental and spatially resolved information on major and minor constituents of the decorated coating of archaeological pottery fragments, so providing preliminary results on the main components characterizing the surface. In particular, we assigned to Fe and Mn the role of key elements of the colouring agent. With the aim of obtaining more detailed information, we performed SR-XAS measurements at the Fe and Mn K-edges at the Italian BM08 beamline at the European Synchrotron Radiation Facility (Grenoble, France). The experimental data were analysed by applying principal component analysis and least-squares fitting to the near-edge part of the spectra (X-ray absorption near-edge structure) to determine the samples' speciation. From the overall results, umber, a class of brownish pigments characterized by a mixture of hydrated iron and manganese oxides, has been ascribed as a pigmenting agent. PMID- 21311874 TI - Culturing and investigation of stress-induced lipid accumulation in microalgae using a microfluidic device. AB - There is increasing interest in using microalgae as a lipid feedstock for the production of biofuels. Lipids used for these purposes are triacylglycerols that can be converted to fatty acid methyl esters (biodiesel) or decarboxylated to "green diesel." Lipid accumulation in most microalgal species is dependent on environmental stress and culturing conditions, and these conditions are currently optimized using slow, labor-intensive screening processes. Increasing the screening throughput would help reduce the development cost and time to commercial production. Here, we demonstrated an initial step towards this goal in the development of a glass/poly(dimethylsiloxane) (PDMS) microfluidic device capable of screening microalgal culturing and stress conditions. The device contained power-free valves to isolate microalgae in a microfluidic growth chamber for culturing and stress experiments. Initial experiments involved determining the biocompatibility and culturing capability of the device using the microalga Tetraselmis chuii. With this device, T. chuii could be successfully cultured for up to 3 weeks on-chip. Following these experiments, the device was used to investigate lipid accumulation in the microalga Neochloris oleabundans. It was shown that this microalga could be stressed to accumulate cytosolic lipids in a microfluidic environment, as evidenced with fluorescence lipid staining. This work represents the first example of microalgal culturing in a microfluidic device and signifies an important expansion of microfluidics into the biofuels research arena. PMID- 21311875 TI - On-line SPE LC-MS/MS for the quantification of Delta9-tetrahydrocannabinol (THC) and its two major metabolites in human peripheral blood by liquid chromatography tandem mass spectrometry. AB - A universal and robust analytical method for the determination of Delta9 tetrahydrocannabinol (THC) and two of its metabolites Delta9-(11-OH) tetrahydrocannabinol (11-OH-THC) and 11-nor-Delta9-carboxy-tetrahydrocannabinol (THC-COOH) in human whole blood was developed and validated for use in forensic toxicology. Protein precipitation, integrated solid phase extraction and on-line enrichment followed by high-performance liquid chromatography separation and detection with a triple quadrupole mass spectrometer were combined. The linear ranges used for the three cannabinoids were from 0.5 to 20 ng/mL for THC and 11 OH-THC and from 2.5 to 100 ng/mL for THC-COOH, therefore covering the requirements for forensic use. Correlation coefficients of 0.9980 or better were achieved for all three analytes. No relevant hydrolysis was observed for THC-COOH glucuronide with this procedure--in contrast to our previous GC-MS procedure, which obviously lead to an artificial increase of the THC-COOH concentration due to the hydrolysis of the glucuronide-conjugate occurring at high pH during the phase-transfer catalyzed methylation step. PMID- 21311876 TI - Chiral analyses of dextromethorphan/levomethorphan and their metabolites in rat and human samples using LC-MS/MS. AB - In order to develop an analytical method for the discrimination of dextromethorphan (an antitussive medicine) from its enantiomer, levomethorphan (a narcotic) in biological samples, chiral analyses of these drugs and their O demethyl and/or N-demethyl metabolites in rat plasma, urine, and hair were carried out using LC-MS/MS. After the i.p. administration of dextromethorphan or levomethorphan to pigmented hairy male DA rats (5 mg/kg/day, 10 days), the parent compounds and their three metabolites in plasma, urine and hair were determined using LC-MS/MS. Complete chiral separation was achieved in 12 min on a Chiral CD Ph column in 0.1% formic acid-acetonitrile by a linear gradient program. Most of the metabolites were detected as being the corresponding O-demethyl and N, O didemethyl metabolites in the rat plasma and urine after the hydrolysis of O glucuronides, although obvious differences in the amounts of these metabolites were found between the dextro and levo forms. No racemation was observed through O- and/or N-demethylation. In the rat hair samples collected 4 weeks after the first administration, those differences were more clearly detected and the concentrations of the parent compounds, their O-demethyl, N-demethyl, and N, O didemethyl metabolites were 63.4, 2.7, 25.1, and 0.7 ng/mg for the dextro forms and 24.5, 24.6, 2.6, and 0.5 ng/mg for the levo forms, respectively. In order to fully investigate the differences of their metabolic properties between dextromethorphan and levomethorphan, DA rat and human liver microsomes were studied. The results suggested that there might be an enantioselective metabolism of levomethorphan, especially with regard to the O-demethylation, not only in DA rat but human liver microsomes as well. The proposed chiral analyses might be applied to human samples and could be useful for discriminating dextromethorphan use from levomethorphan use in the field of forensic toxicology, although further studies should be carried out using authentic human samples. PMID- 21311877 TI - Characterization of the interface interaction of cobalt on top of copper- and iron-phthalocyanine. AB - The electronic structure of the interface between ferromagnetic cobalt and the organic semiconductors copper- (CuPc) and iron-phthalocyanine (FePc) was investigated by means of photoemission spectroscopy (UPS, IPES, and XPS). These metal-phthalocyanine (MePc) molecules have an open shell structure and are known to show promising properties for their use in organic spintronics. In spintronic devices, the interface between ferromagnetic electrode and the organic layer determines the spin injection properties and is hence important for the quality of, e.g., a possible spin-valve device. For this purpose, cobalt was deposited onto the MePcs, such as in devices with ferromagnetic top contacts. The reported investigations reveal a diffusion of cobalt into the organic layers and chemical reactions at the interface. PMID- 21311878 TI - Basal ganglia-dependent processes in recalling learned visual-motor adaptations. AB - Humans learn and remember motor skills to permit adaptation to a changing environment. During adaptation, the brain develops new sensory-motor relationships that become stored in an internal model (IM) that may be retained for extended periods. How the brain learns new IMs and transforms them into long term memory remains incompletely understood since prior work has mostly focused on the learning process. A current model suggests that basal ganglia, cerebellum, and their neocortical targets actively participate in forming new IMs but that a cerebellar cortical network would mediate automatization. However, a recent study (Marinelli et al. 2009) reported that patients with Parkinson's disease (PD), who have basal ganglia dysfunction, had similar adaptation rates as controls but demonstrated no savings at recall tests (24 and 48 h). Here, we assessed whether a longer training session, a feature known to increase long-term retention of IM in healthy individuals, could allow PD patients to demonstrate savings. We recruited PD patients and age-matched healthy adults and used a visual-motor adaptation paradigm similar to the study by Marinelli et al. (2009), doubling the number of training trials and assessed recall after a short and a 24-h delay. We hypothesized that a longer training session would allow PD patients to develop an enhanced representation of the IM as demonstrated by savings at the recall tests. Our results showed that PD patients had similar adaptation rates as controls but did not demonstrate savings at both recall tests. We interpret these results as evidence that fronto-striatal networks have involvement in the early to late phase of motor memory formation, but not during initial learning. PMID- 21311879 TI - Characterisation of HFBII biosurfactant production and foam fractionation with and without antifoaming agents. AB - The effects of foaming on the production of the hydrophobin protein HFBII by fermentation have been investigated at two different scales. The foaming behaviour was characterised in standard terms of the product enrichment and recovery achieved. Additional specific attention was given to the rate at which foam, product and biomass overflowed from the fermentation system in order to assess the utility of foam fractionation for HFBII recovery. HFBII was expressed as an extracellular product during fed-batch fermentations with a genetically modified strain of Saccharomyces cerevisiae, which were carried out with and without the antifoam Struktol J647. In the presence of antifoam, HFBII production is shown to be largely unaffected by process scale, with similar yields of HFBII on dry matter obtained. More variation in HFBII yield was observed between fermentations without antifoam. In fermentations without antifoam, a maximum HFBII enrichment in the foam phase of 94.7 was measured with an overall enrichment, averaged over all overflowed material throughout the whole fermentation, of 54.6 at a recovery of 98.1%, leaving a residual HFBII concentration of 5.3 mg L(-1) in the fermenter. It is also shown that uncontrolled foaming resulted in reduced concentration of biomass in the fermenter vessel, affecting total production. This study illustrates the potential of foam fractionation for efficient recovery of HFBII through simultaneous high enrichment and recovery which are greater than those reported for similar systems. PMID- 21311881 TI - A celluloytic complex from Clostridium cellulovorans consisting of mannanase B and endoglucanase E has synergistic effects on galactomannan degradation. AB - In our previous study using a fluorescently labeled cohesin biomarker, we detected and identified a putative cellulosomal mannanase belonging to the glycosyl hydrolase family 26 from Clostridium cellulovorans in xylan-containing cultures. In this study, a mannanase gene, manB from C. cellulovorans, was expressed in Escherichia coli. The optimal pH of a purified enzyme was around pH 7.0 and the optimal temperature was 40 degrees C. The purified mannanase B (ManB) showed high hydrolytic activity toward galactomannan. An assembly of ManB with mini-CbpA, which contains a carbohydrate-binding module that provides proximity to insoluble substrates, increased the activity toward galactomannan [locust bean gum (LBG) and guar gum] 1.7- and 2.0-fold over those without mini CbpA. We tested the synergistic effects on galactomannan (LBG and guar gum) degradation using cellulosomal mannanase ManB with cellulosomal endoglucanase E, which was predicted to have mannanase activity in C. cellulovorans as a cellulolytic complex. When assembled with the mini-CbpA, the mixture of endoglucanase E (EngE) and ManB at a molar ratio of 1:2 showed the highest synergistic effect (2.4-fold) on LBG. The mixture at a ratio of 1:3 showed the highest synergistic effect (2.8-fold) on guar gum. These synergistic actions indicated that ManB assembled with mini-CbpA hydrolyzed insoluble galactomannan, which in turn promoted soluble galactomannan degradation by EngE. PMID- 21311882 TI - CT-guided percutaneous cryoablation of osteoid osteoma in children: an initial study. AB - OBJECTIVE: The purpose of this study was to evaluate the safety and efficacy of CT-guided percutaneous cryoablation for osteoid osteoma in children. MATERIALS AND METHODS: This study was approved by the institutional ethics committee. From January 2007 to July 2008, six children (four boys, two girls, mean age 12.6 years old) with osteoid osteoma were treated with CT-guided percutaneous cryoablation. The procedures were carried out under conscious sedation and local anesthesia. CT guidance was used for procedural planning, instrument guidance, and monitoring. An argon-based cryoablation system was used. Each cryoablation included two freezing-thawing cycles. Follow-up was performed to assess technical and clinical outcome for a minimum of 12 months. A visual analog scale (VAS) was used to assess severity of pain pre- and post-procedure, and mean VAS for the group was compared pre- and post-procedure with a t-test. The mean clinical follow-up period was 28.7 months (ranging from 18 to 36 months). RESULTS: Cryoablation was technically and clinically successful for all patients. No major immediate or delayed complications were observed. Significant pain relief (P <0.05) was observed in all patients after operation. Mean VAS were 6.57 +/- 0.55 pre-procedure and 0.57 +/- 0.10 1 month post-procedure. Patients were allowed to fully bear their weight and function without limitation within 3 days after the procedure. Pain recurrence was not observed in any patient. CONCLUSION: Percutaneous cryoablation is safe and effective for the treatment of osteoid osteomas in children. Notably, this procedure can be accomplished without general anesthesia. PMID- 21311883 TI - Automatic radiographic quantification of hand osteoarthritis; accuracy and sensitivity to change in joint space width in a phantom and cadaver study. AB - OBJECTIVE: To validate a newly developed quantification method that automatically detects and quantifies the joint space width (JSW) in hand radiographs. Repeatability, accuracy and sensitivity to changes in JSW were determined. The influence of joint location and joint shape on the measurements was tested. METHODS: A mechanical micrometer set-up was developed to define and adjust the true JSW in an acrylic phantom joint and in human cadaver-derived phalangeal joints. Radiographic measurements of the JSW were compared to the true JSW. Repeatability, systematic error (accuracy) and sensitivity (defined as the smallest detectable difference (SDD)) were determined. The influence of joint position on the JSW measurement was assessed by varying the location of the acrylic phantom on the X-ray detector with respect to the X-ray beam and the influence of joint shape was determined by using morphologically different human cadaver joints. RESULTS: The mean systematic error was 0.052 mm in the phantom joint and 0.210 mm in the cadaver experiment. In the phantom experiments, the repeatability was high (SDD = 0.028 mm), but differed slightly between joint locations (p = 0.046), and a change in JSW of 0.037 mm could be detected. Dependent of the joint shape in the cadaver hand, a change in JSW between 0.018 and 0.047 mm could be detected. CONCLUSIONS: The automatic quantification method is sensitive to small changes in JSW. Considering the published data of JSW decline in the normal and osteoarthritic population, the first signs of OA progression with this method can be detected within 1 or 2 years. PMID- 21311884 TI - Diffusion-weighted imaging (DWI) in musculoskeletal MRI: a critical review. AB - Magnetic resonance imaging (MRI) is the mainstay of diagnosis, staging and follow up of much musculoskeletal pathology. Diffusion-weighted magnetic resonance imaging (DWI) is a recent addition to the MR sequences conventionally employed. DWI provides qualitative and quantitative functional information concerning the microscopic movements of water at the cellular level. A number of musculoskeletal disorders have been evaluated by DWI, including vertebral fractures, bone marrow infection, bone marrow malignancy, primary bone and soft tissue tumours; post treatment follow-up has also been assessed. Differentiation between benign and malignant vertebral fractures by DWI and monitoring of therapy response have shown excellent results. However, in other pathologies, such as primary soft tissue tumours, DWI data have been inconclusive in some cases, contributing little additional information beyond that gained from conventional MR sequences. The aim of this article is to critically review the current literature on the contribution of DWI to musculoskeletal MRI. PMID- 21311885 TI - Precise delineation of ureterocele anatomy: virtual magnetic resonance cystoscopy. AB - PURPOSE: To evaluate the application of virtual magnetic resonance cystoscopy (VMRC) in precise detection of ureterocele extension compared with conventional cystoscopy (as the gold standard) and other imaging modalities. MATERIALS AND METHODS: Medical records of 55 patients, with confirmed diagnosis of ureterocele during endoscopic surgery, were reviewed retrospectively. Thirty-two of them (14 girls and 18 boys, age range: 4-22 months) whom underwent investigation with magnetic resonance urography, voiding cystourethrography, and ultrasonography were included. Images were obtained using T1-scanner with pulse sequences (TR = 30-50 ms, TE = 2-8 ms, echo train length = 8 moderate, filip angel = 40 degrees ). Using multiplanar reformation from source images, the bladder was evaluated to determine ureterocele anatomy. Virtual findings were compared with other imaging studies. RESULTS: Cystoscopy confirmed 3(9%) bilateral and 9(28%) unilateral intravesical ureteroceles, and 20(63%) ectopic type. VMRC was the most sensitive method in detection of ureterocele anatomy and its extension (detection rate: 94%) It detected one case of bilateral intravesical and three ectopic types, which were not detected in other imaging modalities. CONCLUSION: VMRC is a promising non-invasive technique in exact detection of ureterocele extension prior to endoscopic operation. It permits evaluation of concurrent genitourinary abnormalities and facilitates preoperative planning especially in complex ectopic ureteroceles. It may be indicated as a clinical routine, when conventional cystoscopy is contraindicated. PMID- 21311886 TI - Environmental Burkholderia cepacia strain Cs5 acting by two analogous alkyl quinolones and a didecyl-phthalate against a broad spectrum of phytopathogens fungi. AB - An environmental Burkholderia cepacia strain named Cs5 was isolated and identified first using API biochemical identification system and then with 16S rDNA and recA sequence homology search. This bacterium exhibited a broad spectrum of fungicidal activities against Alternaria alternata, Aspergillus niger, Fusarium culmorum, F. graminearum, F. oxysporum and Rhizoctonia solani. In the liquid conditions, the MIC of A. niger and R. solani were reached with, respectively, 1.25-2% of the Cs5 liquid culture supernatant. However, in the solid conditions, the same inhibition was caused in the presence of 3% of the Cs5 supernatant. The exhibition of these two fungi at low concentrations of supernatant Cs5 caused various morphological changes of their mycelia which were observed by confocal microscopy. Three antifungal compounds, named Cs5-255, Cs5 257 and Cs5-446, were purified from the Cs5 culture. The structural analysis of these molecules showed that Cs5-255 and Cs5-257 are analogous and belonged to the alkyl-quinolone family, while Cs5-446 was a didecyl-phthalate, isolated for the first time from a bacterium. PMID- 21311887 TI - Coregulation of gene expression by sigma factors RpoE and RpoS in Salmonella enterica serovar Typhi during hyperosmotic stress. AB - Salmonella enterica serovar Typhi (S. Typhi) is the cause of typhoid fever, a food-borne disease that is prevalent worldwide, most particularly in developing countries. RNA polymerase sigma factors RpoE (sigma(E)) and RpoS (sigma(S)) govern transcription initiation of two sets of genes in Escherichia and Salmonella. It was previously suggested that some genes might be coregulated by RpoE and RpoS in Salmonella under conditions of environmental stress, but experimental evidence has been lacking. We therefore constructed rpoS deletion (DeltarpoS) and double rpoE/rpoS deletion (DeltarpoE/DeltarpoS) mutants of S. Typhi and compared their growth properties with an rpoE mutant (DeltarpoE) and wild-type strains under conditions of hyperosmotic stress. We report that the DeltarpoE, DeltarpoS, and DeltarpoE/DeltarpoS strains grew more slowly under hyperosmotic stress conditions than the wild-type strain, and the DeltarpoE/DeltarpoS strain grew most slowly. The global transcriptional profiles of DeltarpoE, DeltarpoS, DeltarpoE/DeltarpoS after 30 min of hyperosmotic stress were investigated using a Salmonella genomic DNA microarray. The results of microarray indicated that the expression levels of 38 genes were markedly reduced during hyperosmotic stress in the double mutant DeltarpoE/DeltarpoS strain, but expression levels were not significantly affected by single DeltarpoE or DeltarpoS mutations. This was confirmed for several key genes by qRT-PCR. This study therefore indicated crosstalk between sigma factors RpoE and RpoS in S. Typhi under hyperosmotic conditions and provides new insights into the regulatory networks of S. Typhi. PMID- 21311888 TI - Pulmonary Langerhans cell histiocytosis in adults: high-resolution CT-pathology comparisons and evolutional changes at CT. AB - OBJECTIVE: To compare high-resolution (HR) CT and histopathological findings and to evaluate serial CT findings in pulmonary Langerhans cell histiocytosis (PLCH). METHODS: We reviewed CT of lung lesions in 27 adults (M:F = 20:7, mean age, 41 +/ 12.3 years) with PLCH. After evaluating lung abnormalities including nodules, micronodules, thick-walled, thin-walled, and bizarre-shaped cysts and reticulation, observers compared CT findings obtained at lung biopsy sites with histopathological findings. The final CT was compared with the initial CT to determine disease extent changes. RESULTS: The most frequently observed patterns of lung abnormalities were micronodules (n = 24, 89%), thick-walled (n = 22, 82%), and thin-walled (n = 22, 82%) cysts. Even thin-walled and bizarre cysts harboured active inflammatory Langerhans cell sheets and eosinophils in their walls. In thin-walled cysts, we noted pericystic inflammatory cell infiltrations along the alveolar walls, as well as pericystic emphysema. Thin-walled or bizarre cysts demonstrated a tendency to coalesce with surrounding cysts via their cystic wall destruction. Fourteen (52%) patients showed improvement and nine (33%) showed progressing disease. CONCLUSION: More than half of patients with pulmonary PLCH show improvement at follow-up CT. Even thin-walled cysts harbour active inflammatory cells on histopathology and exhibit improvement at follow-up CT. PMID- 21311889 TI - Nitric oxide effects depend on different mechanisms in different regions of the rat heart. AB - The important role of nitric oxide (NO) in regulating cardiac functions has been investigated in prior research. However, NO-induced signaling mechanisms in the different regions of the heart have not been explored until now. In this study, the mechanism of NO effects on the spontaneously beating right atrium and left papillary muscle isolated from the rat heart was examined. The NO donor diethylamine NONOate (DEA/NO) (0.1-100 MUM) depressed the resting and developed tensions, as well as the sinus rate, of the right atrium. The effect of DEA/NO on contractions of the right atrium was blocked by the soluble guanylate cyclase (sGC) inhibitor, ODQ (1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one) (10 MUM). The ATP-sensitive potassium channel (K(ATP)) blocker glyburide (3 MUM) reversed DEA/NO-induced decreases in the resting tension. The suppressor effect of DEA/NO on the sinus rate was inhibited only by the superoxide radical scavenger superoxide dismutase (25 U/ml). Neither the cGMP-dependent protein kinase (PKG) inhibitor KT5823 (0.1 MUM) nor the cAMP-dependent protein kinase (PKA) inhibitor KT5720 (1 MUM) changed DEA/NO responses in the right atrium. While the resting tension of the right atrium was decreased by the NO precursor L-arginine (1-100 MUM), it was increased by the nitric oxide synthase inhibitor L-NMMA (0.1-100 MUM). The sinus rate was not affected by L-arginine or L-NMMA. The left papillary muscle contraction was not influenced by any of these NO-related agents. These results show that high concentration NO-induced depression of the contraction of the right atrium is due to sGC and K(ATP) channel activation, but suppression of the sinus rate depends on redox regulation. Our results may have important implications for the region-dependent functional disability of cardiac myocytes, as well as the regulation of heart performance in high NO-induced pathological conditions. PMID- 21311890 TI - RET-protooncogene variants in patients with sporadic neoplasms of the digestive tract and the central nervous system. AB - PURPOSE: The RET protooncogene plays a crucial role in neural crest development; accordingly, mutations of RET cause MEN2A and familial medullary thyroid carcinoma, while the expression deregulation of RET is involved in the pathophysiology of glioblastoma multiforme (GBM) and pancreatic cancer (PDAC). The aim of this study was to evaluate if germline variants of the RET protooncogene are associated with GBM, pancreatic cancer and gastric cancer (GC). METHODS: Genomic DNA from peripheral blood was isolated from 100 patients with GBM, 65 patients with GC and 54 patients with PDAC. The coding sequence of RET promoter, exon 2 and exon 13 was amplified. Sequence variations at -5 and -1 in the promotor and in exon 2 were determined through a LightCycler assay, and analysis of exon 13 was carried out by genomic sequencing. RESULTS: There was no significant association of the RET-promoter or exon 2 genotypes with the phenotype in the different populations, although there was an increase of the GG genotype of the -5G>A variant in all cancers compared to controls. Sequencing of exon 13 identified mutation c.2372A>T in codon 791 (Y791F) in heterozygous state in one of 100 GBM patients, in two of 65 patients with gastric cancer, in two of 54 PDAC patients and in none of the controls. CONCLUSIONS: Although our data did not reach significance in our small cohorts, we cannot rule out the involvement of the -5G promoter allele and the c.2372A>T mutation in the development of the aforementioned tumours. PMID- 21311891 TI - Clinical outcomes of stapled transanal rectal resection (STARR) for obstructed defecation syndrome (ODS): a single institution experience in South Korea. AB - PURPOSE: The purpose of this study was to assess both the short- and long-term functional outcomes of stapled transanal rectal resection (STARR) in ODS patients. PATIENTS AND METHODS: We performed a retrospective review of data that were collected from January 2005 to October 2008. Between January 2005 to June 2006, 58 patients who underwent STARR were enrolled in this study. Follow-up was scheduled for 3 months and 1 year after surgery with the Cleveland Clinic Florida (CCF) constipation score and satisfaction grade. To evaluate the long-term functional outcome, we interviewed the patients by telephone using questionnaires for the CCF score and satisfaction grade on October 2008. RESULTS: The median follow-up period was 34 months (range, 27-46 months). The mean age and sex ratio were 54 years (range, 19-85 years) and 8:50 (M/F). The mean CCF constipation scores were 17.6 before the surgery, 9.5 at 3 months, 9.6 at 12 months, and 10.3 at the time of the latest interview. The satisfaction grade, which was rated as excellent and good by 63.4% of the patients at the time of the latest interview, was worse than that at 3 months (37.8%). Among the cases of the excellent group (19 cases) at postoperative 3 months, 13 cases (68.4%) were classified as excellent or good at the time of the latest interview. CONCLUSION: The STARR is a safe and effective surgical procedure for restoring the anatomy and function in ODS patients. Strict selection of patients is needed in enhancing and maintaining the patients' satisfaction after the procedure. PMID- 21311892 TI - A meta-analysis and systematic review of prophylactic endoscopic treatments for postpolypectomy bleeding. AB - PURPOSE: The aim of this meta-analysis and systematic review was to determine whether bleeding prophylaxis benefits patients after colonoscopic polypectomy. METHODS: A systematic review of the literature was performed to find prospective randomized controlled trials of postpolypectomy hemorrhage prophylaxis. Studies were selected according to specific criteria and analyzed to generate pooled data. RESULTS: Eight studies encompassing 2,595 polyps met the criteria for the meta-analysis. The rate of early bleeding was significantly decreased relative to the control when a single prophylactic technique was used [2.58% vs. 8.15%, OR = 0.34 (95% CI, 0.20-0.58), P < 0.0001]. The use of multiple prophylactic techniques resulted in a lower early postpolypectomy hemorrhage rate compared with the use of a single prophylactic technique [0% vs. 8.41%, OR = 0.12 (95% CI, 0.03-0.47), P = 0.002]. The late bleeding rate did not differ significantly between the monotherapy and control groups [0.61% vs. 1.39%, OR = 0.37 (95% CI, 0.11-1.28), P = 0.12], and the use of combined preventative techniques did not significantly decrease the late postpolypectomy bleeding (PPB) rate compared with use of a single prophylactic method [1.43% vs. 2.05%, OR = 0.70 (95% CI, 0.32 1.55), P = 0.38]. CONCLUSION: Prophylactic endoscopic treatments are effective at reducing early PPB after colonoscopic polypectomy. However, patients with late PPB may not benefit from bleeding prophylaxis. PMID- 21311894 TI - Lynch syndrome in Tunisia: first description of clinical features and germline mutations. AB - PURPOSE: High rates of early colorectal cancers (CRC) are observed in Tunisia suggesting genetic susceptibility. Nevertheless, up to now, no molecular study has been performed in the Tunisian population. In our research, we evaluated the clinical characteristics of Tunisian families suspected of Lynch syndrome and the contribution of DNA mismatch repair (MMR) genes. METHODS: Thirty-one unrelated families suspected of Lynch syndrome were studied. Probands were tested for the presence of germline mutations in the MMR genes MLH1, MSH2, MSH6 and in MUTYH. Available tumours were analysed for microsatellite instability and expression of MMR proteins. Detailed family and medical histories were collected. RESULTS: A total of 134 cancers were noted in the 31 families, the most frequent type of cancer corresponding to CRC (69%), followed by uterine cancer (7.5%). Germline mutations were identified in 11 (35.5%) families (six MSH2, five MLH1, including seven novel mutations), seven of which fulfilled the Amsterdam criteria (sensitivity, 63.6%; positive predictive value, 58.3%). Noteworthy, germline mutations were detected in 52.6% of male patients tested, but in only 8.3% of females (p = 0.02). Moreover, CRC were essentially left sided in families without detected mutation (p = 0.017). Ages of onset of cancers and tumour spectrum were very similar in families with or without MMR germline mutation, contrasting with previous studies performed in other populations. CONCLUSIONS: MMR genes contribute significantly to CRC susceptibility in the Tunisian population. However, the cause of early CRC susceptibility remains unknown in most cases, especially in women and in patients with early left colon or rectal cancer. PMID- 21311895 TI - Occurrence of acute myocardial infarction in winter tourists: data from a retrospective questionnaire. AB - BACKGROUND: Every year millions of tourists spend their vacation in Tyrol, Austria during the winter season. They often perform sports at high altitudes and at low temperatures, factors that might cause acute myocardial infarction (AMI). This study aimed to evaluate the relationship of first physical activity and the onset of AMI in winter tourists. METHODS: We carried out a retrospective analysis of consecutive patients admitted to the Department of Internal Medicine III at the Medical University of Innsbruck with the diagnosis of an AMI between 2006 and 2010. We identified 172 patients as potential candidates for the questionnaire. We successfully contacted 110 patients (mean age: 60 +/- 10 years). The location of visit, duration of stay, time of arrival, first sportive activity and onset of symptoms were assessed. RESULTS: During the first 2 days of physical activity , 56% of AMIs occurred. In tourists who suffered AMI during, or within 1 h after cessation of activity (52%), the mean time from the start of the activity to the onset of symptoms was 2.0 +/- 1.7 h. 56% of patients performed less than 2.5 h of sport per week before their vacation and 70% had >=2 cardiovascular risk factors. Although the mean planned vacation time was 8.3 +/- 3.7 days, 39% of the patients suffered from AMI on the day of arrival or the day after. CONCLUSION: The majority of AMIs in winter tourists happens within the first 2 days after arrival and within the first 2 days of physical activity. PMID- 21311893 TI - Inflammatory bowel disease-associated colorectal cancer: proctocolectomy and mucosectomy do not necessarily eliminate pouch-related cancer incidences. AB - BACKGROUND: Colorectal cancer (CRC), the most lethal long-term complication of inflammatory bowel disease (IBD), is the culmination of a complex sequence of molecular and histologic derangements of the colon epithelium that are initiated and at least partially sustained by prolonged chronic inflammation. Dysplasia, the earliest histologic manifestation of this process, plays an important role in cancer prevention by providing the first clinical alert that this sequence is under way and by serving as an endpoint in colonoscopic surveillance of patients at high risk for CRC. Restorative proctocolectomy (RPC) is indicated for patients with IBD, specifically for ulcerative colitis that is refractory to medical treatment, emergency conditions, and/or in case of neoplastic transformation. Even after RPC with mucosectomy, pouch-related carcinomas have recently been reported with increasing frequency since the first report in 1984. We review IBD associated CRC and pouch-related neoplasia prevalence, adverse events, risk factors, and surveillances. METHODS: Literature of IBD-associated CRC patients and those undergoing RPC surgeries through 2010 were prospectively reviewed. RESULTS: We found 12 studies from retrospective series and 15 case reports. To date, there are 43 reported cases of pouch-related cancers. Thirty-two patients had cancer in the anal transit zone (ATZ); of these, 28 patients had mucosectomy. Eleven patients had cancer found in the pouch body. CONCLUSION: RPC with mucosectomy does not necessarily eliminate risks. There is little evidence to support routine surveillance of pouch mucosa and the ATZ except for patients associated with histological type C changes, sclerosing cholangitis, and unremitting pouchitis. PMID- 21311896 TI - The proteoglycan-dystrophin complex in genetic cardiomyopathies--lessons from three siblings with limb-girdle muscular dystrophy-2I (LGMD-2I). PMID- 21311897 TI - The Arg389Gly beta1-adrenoceptor gene polymorphism influences the acute effects of beta-adrenoceptor blockade on contractility in the human heart. AB - BACKGROUND: The beta(1)-adrenoceptor (beta(1)AR) mediates cardiostimulatory effects of catecholamines in the heart. The Arg389Gly polymorphism of the beta(1)AR gene has recently been shown to determine the responsiveness to catecholamines in vitro, and we previously reported that dobutamine induced an augmented contractile response in humans homozygous for the Arg389 allele. The aim of the present study was to evaluate whether the Arg389Gly beta(1)AR gene polymorphism influences the responsiveness to beta-blocker treatment on cardiac contractility. METHODS: We investigated 30 healthy male volunteers who were genotyped for the Arg389Gly polymorphism and subjected to modified dobutamine stress-echocardiography (DSE) with and without pretreatment with metoprolol controlled release/extended release (CR/XL). Fractional shortening (FS) as a parameter for left-ventricular contractility and heart rate were measured. To control for pre- and afterload effects, rate corrected velocity of circumferential fiber shortening (Vcfc) was calculated. RESULTS: Homozygous Arg389 carriers had a significantly higher increase in contractility upon dobutamine stimulation than individuals carrying the Gly389 allele. Pretreatment with metoprolol CR/XL prior to DSE blunted the dobutamine-induced increase of FS and Vcfc in homozygous Arg389 carriers to the level of subjects carrying the Gly389 allele. In the latter group, metoprolol had a modest effect on the dobutamine-induced increase in FS at low concentrations of dobutamine, and no significant effect at peak stress (40 MUg/kg/min of dobutamine). CONCLUSION: The responsiveness to beta-blockers with respect to cardiac contractility is determined by the Arg389Gly beta(1)AR gene polymorphism. These findings offer a molecular explanation for interindividual differences in the responsiveness to beta-blocker treatment in humans. PMID- 21311898 TI - Serum soluble E-selectin and NT-proBNP levels additively predict mortality in diabetic patients with chronic heart failure. AB - BACKGROUND: Neuroendocrine activation with endothelial dysfunction is a key pathophysiological process in chronic heart failure (CHF). Although increased soluble E-selectin (sE-selectin) levels predict adverse events in several forms of cardiovascular disease, there are only scarce data on its predictive value in CHF. The aim of our study was to investigate whether sE-selectin is a useful predictor of mortality in CHF patients and whether its predictive power is additive to that of NT-proBNP. METHODS: Plasma levels of sE-selectin were measured by ELISA in 192 CHF patients with clinical systolic heart failure. The study population was followed up for 14.9 months on average; 46 patients died during this period. RESULTS: Levels of sE-selectin were significantly higher in non-surviving patients than in survivors (p = 0.005) and significantly correlated with the following inflammatory markers: CRP (r = 0.242, p = 0.001), TNF-alpha (r = 0.201, p = 0.005), TNF-RII (r = 0.207, p = 0.004), and IL-6 (r = 0.339, p < 0.0001). According to Cox regression analysis of the prediction power of sE selectin for all-cause mortality, high sE-selectin levels independently and significantly predicted short-term mortality in CHF (HR 1.47, 95% CI 1.103 1.956). Furthermore, sE-selectin predicted mortality in CHF patients with concomitant diabetes mellitus, as well as simultaneously elevated sE-selectin and NT-proBNP levels additively predicted mortality. CONCLUSIONS: This study demonstrated a weak correlation of sE-selectin level with inflammatory markers and prediction of short-term mortality in diabetic CHF patients. Elevated serum sE-selectin levels and concomitantly increased NT-proBNP concentrations have additive predictive power in CHF. This suggests that parallel activation of various pathophysiological pathways confers increased risk of adverse outcome in CHF. PMID- 21311899 TI - Statin effect on thrombin inhibitor effectiveness during percutaneous coronary intervention: a post-hoc analysis from the ISAR-REACT 3 trial. AB - OBJECTIVE: To determine whether statin therapy influences the efficacy of thrombin inhibitor bivalirudin or unfractionated heparin (UFH) during PCI. SETTING AND PATIENTS: The post-hoc analysis of the ISAR-REACT 3 Trial included 4,570 patients: 3,106 patients were on statin therapy and 1,464 patients were not on statin therapy at the time of PCI procedure. MAIN OUTCOME MEASURES: The primary outcome of this analysis was the 30-day composite of death, myocardial infarction, target vessel revascularization (TVR) or major bleeding. RESULTS: The primary outcome occurred in 7.9% patients (n = 246) in the statin group versus 9.8% (n = 143) in the non-statin group (P = 0.036). There was an interaction in univariate (P = 0.028) and multivariable (P = 0.026) analysis between pre-PCI statin therapy and the type of antithrombotic therapy regarding myocardial infarction. In the statin group, bivalirudin significantly reduced the incidence of major bleeding (2.6 vs. 4.3%, P = 0.013) with no significant difference in the incidence of myocardial infarction (4.9 vs. 5.2%; P = 0.73) compared with UFH. In the non-statin group, bivalirudin was inferior to UFH regarding the incidence of myocardial infarction (7.1 vs. 4.1%, P = 0.013), yet major bleeding remained lower among bivalirudin-treated patients (4.0 vs. 5.2%, P = 0.25). CONCLUSION: This post-hoc analysis suggests the existence of an interaction between statin therapy before PCI and antithrombotic therapy during PCI. Patients receiving bivalirudin therapy at the time of PCI showed less periprocedural myocardial infarction when on pre-PCI statin therapy which has to be investigated in further studies. PMID- 21311900 TI - Qualification of the analytical and clinical performance of CSF biomarker analyses in ADNI. AB - The close correlation between abnormally low pre-mortem cerebrospinal fluid (CSF) concentrations of amyloid-beta1-42 (Abeta(1-42)) and plaque burden measured by amyloid imaging as well as between pathologically increased levels of CSF tau and the extent of neurodegeneration measured by MRI has led to growing interest in using these biomarkers to predict the presence of AD plaque and tangle pathology. A challenge for the widespread use of these CSF biomarkers is the high variability in the assays used to measure these analytes which has been ascribed to multiple pre-analytical and analytical test performance factors. To address this challenge, we conducted a seven-center inter-laboratory standardization study for CSF total tau (t-tau), phospho-tau (p-tau(181)) and Abeta(1-42) as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). Aliquots prepared from five CSF pools assembled from multiple elderly controls (n = 3) and AD patients (n = 2) were the primary test samples analyzed in each of three analytical runs by the participating laboratories using a common batch of research use only immunoassay reagents (INNO-BIA AlzBio3, xMAP technology, from Innogenetics) on the Luminex analytical platform. To account for the combined effects on overall precision of CSF samples (fixed effect), different laboratories and analytical runs (random effects), these data were analyzed by mixed-effects modeling with the following results: within center %CV 95% CI values (mean) of 4.0-6.0% (5.3%) for CSF Abeta(1-42); 6.4-6.8% (6.7%) for t-tau and 5.5-18.0% (10.8%) for p tau(181) and inter-center %CV 95% CI range of 15.9-19.8% (17.9%) for Abeta(1-42), 9.6-15.2% (13.1%) for t-tau and 11.3-18.2% (14.6%) for p-tau(181). Long-term experience by the ADNI biomarker core laboratory replicated this degree of within center precision. Diagnostic threshold CSF concentrations for Abeta(1-42) and for the ratio t-tau/Abeta(1-42) were determined in an ADNI independent, autopsy confirmed AD cohort from whom ante-mortem CSF was obtained, and a clinically defined group of cognitively normal controls (NCs) provides statistically significant separation of those who progressed from MCI to AD in the ADNI study. These data suggest that interrogation of ante-mortem CSF in cognitively impaired individuals to determine levels of t-tau, p-tau(181) and Abeta(1-42), together with MRI and amyloid imaging biomarkers, could replace autopsy confirmation of AD plaque and tangle pathology as the "gold standard" for the diagnosis of definite AD in the near future. PMID- 21311902 TI - New ependymal cells are born postnatally in two discrete regions of the mouse brain and support ventricular enlargement in hydrocephalus. AB - A heterogeneous population of ependymal cells lines the brain ventricles. The evidence about the origin and birth dates of these cell populations is scarce. Furthermore, the possibility that mature ependymal cells are born (ependymogenesis) or self-renewed (ependymal proliferation) postnatally is controversial. The present study was designed to investigate both phenomena in wild-type (wt) and hydrocephalic alpha-SNAP mutant (hyh) mice at different postnatal stages. In wt mice, proliferating cells in the ventricular zone (VZ) were only found in two distinct regions: the dorsal walls of the third ventricle and Sylvian aqueduct (SA). Most proliferating cells were monociliated and nestin+, likely corresponding to radial glial cells. Postnatal cumulative BrdU labeling showed that most daughter cells remained in the VZ of both regions and they lost nestin-immunoreactivity. Furthermore, some labeled cells became multiciliated and GLUT-1+, indicating they were ependymal cells born postnatally. Postnatal pulse BrdU-labeling and Ki-67 immunostaining further demonstrated the presence of cycling multiciliated ependymal cells. In hydrocephalic mutants, the dorsal walls of the third ventricle and SA expanded enormously and showed neither ependymal disruption nor ventriculostomies. This phenomenon was sustained by an increased ependymogenesis. Consequently, in addition to the physical and geometrical mechanisms traditionally explaining ventricular enlargement in fetal onset hydrocephalus, we propose that postnatal ependymogenesis could also play a role. Furthermore, as generation of new ependymal cells during postnatal stages was observed in distinct regions of the ventricular walls, such as the roof of the third ventricle, it may be a key mechanism involved in the development of human type 1 interhemispheric cysts. PMID- 21311901 TI - The optic nerve head is the site of axonal transport disruption, axonal cytoskeleton damage and putative axonal regeneration failure in a rat model of glaucoma. AB - The neurodegenerative disease glaucoma is characterised by the progressive death of retinal ganglion cells (RGCs) and structural damage to the optic nerve (ON). New insights have been gained into the pathogenesis of glaucoma through the use of rodent models; however, a coherent picture of the early pathology remains elusive. Here, we use a validated, experimentally induced rat glaucoma model to address fundamental issues relating to the spatio-temporal pattern of RGC injury. The earliest indication of RGC damage was accumulation of proteins, transported by orthograde fast axonal transport within axons in the optic nerve head (ONH), which occurred as soon as 8 h after induction of glaucoma and was maximal by 24 h. Axonal cytoskeletal abnormalities were first observed in the ONH at 24 h. In contrast to the ONH, no axonal cytoskeletal damage was detected in the entire myelinated ON and tract until 3 days, with progressively greater damage at later time points. Likewise, down-regulation of RGC-specific mRNAs, which are sensitive indicators of RGC viability, occurred subsequent to axonal changes at the ONH and later than in retinas subjected to NMDA-induced somatic excitotoxicity. After 1 week, surviving, but injured, RGCs had initiated a regenerative-like response, as delineated by Gap43 immunolabelling, in a response similar to that seen after ON crush. The data presented here provide robust support for the hypothesis that the ONH is the pivotal site of RGC injury following moderate elevation of IOP, with the resulting anterograde degeneration of axons and retrograde injury and death of somas. PMID- 21311903 TI - Metastatic neoplasms of the ovaries: a clinicopathological study of 97 cases. AB - OBJECTIVE: To present the clinicopathological features of metastatic ovarian neoplasms with emphasis in the diagnostic challenge. METHODS: This is a retrospective study including 97 patients with pathological diagnosis of metastatic ovarian neoplasms, examined during the decade 2000-2009. The gross, microscopical and immunohistochemical characteristics as well as the clinical data (age of the patients, origin of the neoplasm, symptoms, treatment options) and 5-year survival rates were examined. RESULTS: The mean age of the patients is 55 years (range 26-78 years). 62.89% of the tumors were metastatic from extragenital organs (from stomach 21.65%, breast 15.46%, colon 15.46%, appendix 3.09%, pancreas 2.06%, lung 1.03% and kidney 1.03%, sarcoma 1.03% melanoma 1.03%) and 37.11% tumors originated from the genital tract. The 3-year survival rates ranged from 25.39% for metastatic ovarian neoplasms originating outside the genital tract up to 29.41% for those originating from the genital tract. Tumor immunohistochemistry is a helpful aid in the differential diagnosis mainly between primary mucinous ovarian tumors and metastatic colon cancers and in the recognition of metastatic breast cancers and other neoplasms of the GI tract. CONCLUSION: The management of metastatic ovarian neoplasms should include specific immunohistochemical methods in order to identify the primary neoplasm site. The differential diagnosis of a pelvic mass should always include metastatic neoplasms of the ovaries. PMID- 21311904 TI - Post-mortem ABCB1 genotyping reveals an elevated toxicity for female digoxin users. AB - BACKGROUND: P-glycoprotein, a common transporter molecule, is known to affect metabolic functions in humans. Polymorphisms of the multidrug resistance gene (ABCB1/MDR1) coding for P-glycoprotein have been linked to changes in the processing of several commonly used medications in patients. Here, we have evaluated the impact of ABCB1 single nucleotide polymorphisms on digoxin fatality, through investigation of the relationship between post-mortem digoxin concentration and ABCB1 genotype. METHODS: The effect of three ABCB1 single nucleotide polymorphisms (SNPs) (3435C>T, 1236C>T, and 2677G>T) on digoxin concentration was examined in 112 deceased Finnish subjects through RT-PCR genotyping of post-mortem blood samples. These subjects were selected on the basis of digoxin findings during the post-mortem toxicology screen, and categorized by digoxin concentration into three distinct groups. The distributions of mutant alleles and haplotypes in the deceased were compared to a random sample of 143 Finns. RESULTS: Mutant genotype frequencies showed a positive relationship with post-mortem digoxin concentration for all SNPs. Female subjects showed a more emphatic pattern, suggesting a higher risk of digoxin intoxication. CONCLUSIONS: These findings demonstrate a link between ABCB1 polymorphisms and increased mortality, and suggest that individualized genotyping should be considered prior to digoxin treatment. This research also exemplifies the value of gender-segregated genotyping studies in helping establish drug safety parameters, while allowing more decisive determination of cause and manner of death in a medico-legal context. PMID- 21311905 TI - Genetic variation in caspase-1 as predictor of accelerated progression from mild cognitive impairment to Alzheimer's disease. PMID- 21311906 TI - Teleneurology: is it really at a distance? AB - Telemedicine refers to the transfer of medical information from one site to another using distance communications technology. This approach has benefitted many medical specialties, with telestroke being a prelude to its applications in neurology. Our review will focus on the use of telemedicine in neurological practice (teleneurology) following a brief discussion of telestroke. Given the emerging nature of trial evidence in teleneurology, our aim is to provide a narrative review and highlight areas that merit further investigation. PMID- 21311907 TI - Analytical and numerical analysis of inverse optimization problems: conditions of uniqueness and computational methods. AB - One of the key problems of motor control is the redundancy problem, in particular how the central nervous system (CNS) chooses an action out of infinitely many possible. A promising way to address this question is to assume that the choice is made based on optimization of a certain cost function. A number of cost functions have been proposed in the literature to explain performance in different motor tasks: from force sharing in grasping to path planning in walking. However, the problem of uniqueness of the cost function(s) was not addressed until recently. In this article, we analyze two methods of finding additive cost functions in inverse optimization problems with linear constraints, so-called linear-additive inverse optimization problems. These methods are based on the Uniqueness Theorem for inverse optimization problems that we proved recently (Terekhov et al., J Math Biol 61(3):423-453, 2010). Using synthetic data, we show that both methods allow for determining the cost function. We analyze the influence of noise on the both methods. Finally, we show how a violation of the conditions of the Uniqueness Theorem may lead to incorrect solutions of the inverse optimization problem. PMID- 21311908 TI - Significant increase in travel-associated dengue fever in Germany. AB - Increasing numbers of dengue fever (DF) cases reflect the increasing travel mobility together with the expanding geographical distribution of the vector Aedes aegypti. Compared with earlier surveys in Germany, higher incidences occur and correlate well with ongoing outbreaks. Therefore, we investigated 767 serum samples from 594 returning travellers with suspected DF between 2005 and 2010, which where sent from different hospitals in the drainage area Frankfurt/Main. Established diagnostic assays were ELISA, immunofluorescence and chromatographic tests. We obtained 112 dengue-seropositive serum samples from totally 60 patients: the detection rate was 10.1% (60 out of 594). A significant increase was found in 2010. Most patients were aged between 40 and 49, and indirect immunofluorescence technique indicated mainly DF serotype 2. Actual data reveal a significant rise in imported DF cases in 2010 according to an increasing risk to acquire DF virus infection. Nevertheless, dengue haemorrhagic fever and dengue shock syndrome are still rare in travellers, but those with a history of dengue should be tested for DF serotypes and advised to protect themselves well from mosquitoes when travelling to endemic areas. PMID- 21311910 TI - Bioactivity of essential oils of Zingiber officinalis and Achyranthes aspera against mosquitoes. AB - Due to the global health problems associated with mosquito-borne diseases, over two million people primarily in the tropical countries are at risk. The widely and commonly used chemical method though effective, has some major disadvantages making insect control practically difficult. In view of the above, it is unavoidable to search for new molecules, which are eco-friendly, cheaper, and safer. The present study deals with evaluation of bioactive potential of two commonly occurring plants against mosquitoes presenting an alternative to the conventional chemical methods. Essential oils extracted by steam distillation from rhizome of Zingiber officinalis and leaf and stem of Achyranthes aspera were evaluated for larvicidal, attractant/repellent, and oviposition attractant/deterrent activity against two mosquito species viz. Aedes aegypti and Culex quinquefasciatus. The highest larvicidal activity, i.e., LC(50) = 154 ppm and LC(50) = 197 ppm for A. aegypti and C. quinquefasciatus, respectively was shown by Z. officinalis. This oil also offers 5-h protection at the concentration of 0.5 mg/cm2 from both mosquito species. The highest oviposition deterrence activity was exhibited by A. aspera stem oil, i.e., 100% and 85.71%, in case of A. aegypti and C. quinquefasciatus, respectively, at the concentration of 0.1%. These results reveal that both these oils have control potential against A. aegypti and C. quinquefasciatus. PMID- 21311911 TI - Non-host volatiles mediate associational resistance to the pine processionary moth. AB - An increasing body of evidence indicates that the association between different plant species may lead to a reduction in insect herbivory, i.e. associational resistance. This might be due to a top-down regulation of herbivores by increased numbers of natural enemies or to a disruptive bottom-up influence of lower host plant accessibility. In particular, the richer plant communities release more diverse plant odours that may disturb olfactory-guided host choice and mating behaviour of insect herbivores, i.e. the "semiochemical diversity hypothesis". However, this hypothesis has been rarely tested experimentally in natural habitats, notably forest ecosystems. We tested the effects of non-host volatiles (NHV) on mate and host location by the pine processionary moth (PPM) at the scale of individual pine trees with branches of non-host tree (birch) at their base. Pheromone trap catches and the numbers of larval nests were both reduced by non host presence under treated pine trees, confirming an associational resistance mediated by NHV. In both males and females, the antenna could detect several birch volatiles, including methyl salicylate (MeSa). MeSa inhibited the attraction of the PPM male to pheromone traps, as did bark and leaf chips from birch trees. Our test of three doses of MeSa at the habitat scale (50 m forest edges) showed that the reduction in the numbers of male PPM captured in traps and in larval nests was MeSa dose-dependent. These results show that odours released by deciduous non-host trees can reduce herbivory by a forest defoliator in conifers, providing support to the "semiochemical diversity hypothesis" as a mechanism of associational resistance. PMID- 21311912 TI - The origin of interstitial myofibroblasts in chronic kidney disease. AB - Chronic kidney diseases (CKD), independent of their primary cause, lead to progressive, irreversible loss of functional renal parenchyma. Renal pathology in CKD is characterized by tubulointerstitial fibrosis with excessive matrix deposition produced by myofibroblasts. Because blocking the formation of these scar-forming cells represents a logical therapeutic target for patients with progressive fibrotic kidney disease, the origin of renal myofibroblasts is a subject of intense investigation. Although the traditional view holds that resident fibroblasts are the myofibroblast precursor, for the last 10 years, injured epithelial cells have been thought to directly contribute to the myofibroblast pool by the process of epithelial-to-mesenchymal transition (EMT). The recent application of genetic fate mapping techniques in mouse fibrosis models has provided new insights into the cell hierarchies in fibrotic kidney disease and results cast doubt on the concept that EMT is a source of myofibroblast recruitment in vivo, but rather point to the resident pericyte/perivascular fibroblast as the myofibroblast progenitor pool. This review will highlight recent findings arguing against EMT as a direct contributor to the kidney myofibroblast population and review the use of genetic fate mapping to elucidate the cellular mechanisms of kidney homeostasis and disease. PMID- 21311913 TI - Characteristics and correlates of sleep disturbances in cancer patients. AB - PURPOSE: Few studies of sleep disturbances in cancer patients have focused on the period before chemotherapy starts. Understanding sleep disturbances in this period is important since early intervention has the potential to reduce the severity or chronicity of these problems. The present study sought to characterize sleep disturbances in this period, examine if they could be predicted by demographic, clinical, or lifestyle factors, and identify their relationship to fatigue, depression, and physical and mental well-being. METHODS: Patients (N = 288) with breast cancer (32%), lung cancer (32%), or other cancers (36%) about to begin chemotherapy completed self-report measures assessing demographic and lifestyle characteristics, sleep, fatigue, depression, and quality of life. RESULTS: Twenty-six percent of patients rated their sleep quality as fairly or very bad. Poorer overall sleep was significantly predicted by less education, more medical comorbidities, previous radiotherapy, less physical activity, and current tobacco use, but these variables accounted for only 7% of the variability in sleep disturbances. After controlling for significant relationships with depression and fatigue, sleep disturbances explained significant variability in physical well-being but not mental well being. CONCLUSIONS: Sleep disturbances are common before the start of chemotherapy and contribute to poorer physical well-being independent of fatigue and depression. Demographic, clinical, and lifestyle variables had limited value in predicting sleep disturbances. However, depression and fatigue were highly correlated with sleep. Future research should seek to identify common etiological factors (e.g., cytokine production) and implement longitudinal designs to examine temporal relationships among these three symptoms in cancer patients. PMID- 21311914 TI - Music's relevance for adolescents and young adults with cancer: a constructivist research approach. AB - PURPOSE: Music is one of the most widely used activities amongst young people, significant in personal and group identity, motivation, physical release, and emotional support. Adolescents and young adults with cancer (AYA) require specialized care because of intensified challenges related to developmental vulnerability, treatment toxicity effects, and slower improvements in survival rates compared to other age groups. To advance effective supportive care for AYA, understanding their thoughts about music is necessary. This study examines AYAs' perspectives about music's role in their lives. METHODS: A constructivist research approach with grounded theory design was applied. Twelve people, 15 to 25 years old, known to onTrac@PeterMac Victorian Adolescent & Young Adult Cancer Service, participated. Respondents completed a brief music demographic questionnaire and participated in a semi-structured interview. Qualitative inter rater reliability was integrated. RESULTS: Participants mostly reported music's calming, supportive, and relaxing effects, which alleviated hardship associated with their cancer diagnoses. Themes encompassed: music backgrounds, changed "musicking", endurance and adjustment, time with music therapists, and wisdom. Music provided supportive messages, enabled personal and shared understandings about cancer's effects, and elicited helpful physical, emotional, and imagery states. Music therapy could also promote normalized and supportive connections with others. A musician, however, struggled to get music "back" post-treatment. Supportive music-based strategies were recommended for other AYA and their health care providers. CONCLUSIONS: Music can signify and creatively enable AYAs' hope, endurance, identity development, and adjustment through cancer treatment and post treatment phases. Health professionals are encouraged to support AYAs' music based self-care and "normalized" activities. PMID- 21311915 TI - The relationship between unmet needs and distress amongst young people with cancer. AB - PURPOSE: Most psychosocial research in cancer has been restricted to paediatric or older adult populations. This study aimed to explore psychological distress and unmet needs in adolescents and young adults (AYA) with cancer and identify predictors of distress among demographic and illness characteristics and supportive care needs. METHODS: Fifty-three patients between 16 and 30 years completed a cross-sectional survey, administered shortly after presentation to an AYA oncology service and within 4 months of diagnosis. Measures included the Beck Depression Inventory-Fast Screen (BDI-FS), State-Trait Anxiety Inventory-State Form (STAI-S) and the Supportive Care Needs Survey. Level of distress-related sypmtomatology in this population was based on previous work, whereby a cut-off score of 4 or greater was used for the BDI-FS, and one standard deviation above the sample population mean was used for the STAI-S. RESULTS: Prevalence of distress (25%) was lower than that found previously in AYA with cancer. Physical and daily living needs were the most frequently unmet needs overall, followed by psychological needs, health system and information needs and care and support needs. Lastly, being pre-treatment predicted increased depression and state anxiety, while having treatment post-surgery predicted reduced state anxiety. After controlling for treatment status, however, the main predictors of depression and state anxiety were physical and daily living needs and health system and information needs, respectively. CONCLUSIONS: Lower levels of distress and unmet psychological needs were related to the few participants (17%) in this study who were pre-treatment, when distress was most likely. However, physical needs and information needs, which are almost inevitable throughout treatment and beyond, were more important predictors of distress. Further exploration must consider the psychosocial difficulties underlying this association and the needs of AYA at transitions between critical periods in their cancer journey (i.e., upon diagnosis, during treatment, etc.). PMID- 21311916 TI - Leg pain and psychological variables predict outcome 2-3 years after lumbar fusion surgery. AB - Prediction studies testing a thorough range of psychological variables in addition to demographic, work-related and clinical variables are lacking in lumbar fusion surgery research. This prospective cohort study aimed at examining predictions of functional disability, back pain and health-related quality of life (HRQOL) 2-3 years after lumbar fusion by regressing nonlinear relations in a multivariate predictive model of pre-surgical variables. Before and 2-3 years after lumbar fusion surgery, patients completed measures investigating demographics, work-related variables, clinical variables, functional self efficacy, outcome expectancy, fear of movement/(re)injury, mental health and pain coping. Categorical regression with optimal scaling transformation, elastic net regularization and bootstrapping were used to investigate predictor variables and address predictive model validity. The most parsimonious and stable subset of pre surgical predictor variables explained 41.6, 36.0 and 25.6% of the variance in functional disability, back pain intensity and HRQOL 2-3 years after lumbar fusion. Pre-surgical control over pain significantly predicted functional disability and HRQOL. Pre-surgical catastrophizing and leg pain intensity significantly predicted functional disability and back pain while the pre surgical straight leg raise significantly predicted back pain. Post-operative psychomotor therapy also significantly predicted functional disability while pre surgical outcome expectations significantly predicted HRQOL. For the median dichotomised classification of functional disability, back pain intensity and HRQOL levels 2-3 years post-surgery, the discriminative ability of the prediction models was of good quality. The results demonstrate the importance of pre surgical psychological factors, leg pain intensity, straight leg raise and post operative psychomotor therapy in the predictions of functional disability, back pain and HRQOL-related outcomes. PMID- 21311918 TI - Bilateral subthalamic deep brain stimulation using single track microelectrode recording. AB - BACKGROUND: Microelectrode recording (MER) is widely used during deep brain stimulation (DBS) procedures because MER can identify structural borders and eloquent structures, localize somatotopic arrangements, and provide an outline of the three-dimensional shapes of target nuclei. However, MER may cause intracranial hemorrhage. We preformed single track MER during DBS procedures, analyzed the accuracy of electrode positioning with MRI, and compared the amount of air and the potential risk of intracranial hemorrhage. METHOD: A total of 46 electrodes were placed in 23 patients who suffered from advanced Parkinson's disease and who underwent bilateral subthalamic nucleus DBS using single track MER. Each patient's Unified Parkinson's Disease Rating Scale (UPDRS) score and levo-dopa equivalent dosage (LED) were estimated pre- and postoperatively. The accuracy of electrode positioning and fontal air thickness was measured by a pre- or postoperative magnetic resonance imaging (MRI) merging technique. FINDINGS: The mean electrode positioning error was 0.92 mm (0.3-2.94 mm). The mean frontal air thickness on postoperative MRI was 3.85 mm (0-10.3 mm), which did not affect the electrode accuracy statistically (p = 0.730). A total of nine electrodes required repositioning after single-track MER because they affected microstimulation or because an abnormally short STN length was observed during MER. In this series, one patient suffered from an intracranial hemorrhage after surgery that appeared to be due to venous infarction rather than related to MER. CONCLUSIONS: Although MER can facilitate accurate positioning of electrodes, multi-track MER may increase the risk of intracranial hemorrhage. The accuracy of electrode positioning appears to be acceptable under single track MER during STN DBS with careful electrophysiological and neurological monitoring. The risk of intracranial hemorrhage appears to be minimal, especially in elderly patients with atrophic brains. PMID- 21311917 TI - Effect of recombinant streptokinase on the development of chronic cerebral vasospasm after subarachnoid hemorrhage in a swine model. AB - BACKGROUND: After subarachnoid hemorrhage (SAH), the formation of subarachnoid clots and their associated resolution may be involved in the development of chronic cerebral vasospasm. To dissolve and wash out the subarachnoid clot is one of the therapeutic strategies for prevention of cerebral vasospasm. OBJECTIVE: We investigated the effect of recombinant streptokinase (r-SK), a synthetic plasminogen activator, which is added to degenerate oxyhemoglobin, one of the strongest spasmogenic substances. The efficacy and safety of this therapy concerning the development of chronic cerebral vasospasm were evaluated in a swine model. METHODS: Eighteen healthy porcine subjects were used. Each was randomly assigned to one of three groups: saline control (A), SAH treated with saline (B), and r-SK injection into the cisterna magna (C). SAH was produced by introduction of blood clots into the cisterna magna on each of 2 days in all subjects in groups B and C. At 24-h post-SAH, a one-time dosage of 15 mg of r-SK was administered to those subjects randomized to group C. Continuous drainage was applied in all three groups. Vessel diameter was evaluated by angiography before the induction of SAH and at day 7 following SAH. RESULTS: The pre- and post-SAH angiographs of subjects in group A determined no significant difference in mean vessel caliber. In group B, pre- and post-SAH angiography indicated significant (p < 0.05) reductions of the mean vessel caliber of the right internal carotid artery (ICA) and basilar artery (BA) compared with the baseline values before SAH. In the r-SK treated group, the mean percent reduction in vessel caliber of the right ICA and BA on day 7 angiograms showed no significant difference compared with the baseline value before SAH. CONCLUSIONS: Chronic cerebral vasospasm was inhibited in the animals to whom r-SK was administered for 1 day after double administration of blood clots to the cisterna magna to induce SAH. The results suggest that the post-SAH presence of subarachnoid clots that contain oxyhemoglobin might be involved in the pathogenesis of vasospasm. Further degeneration of these clots by r-SK may have a promising effect for prevention of vasospasm. PMID- 21311919 TI - Methyl-beta cyclodextrin alters the production and infectivity of Sendai virus. AB - Cellular membrane cholesterol has been shown to support various membrane proteins. However, the role and function of membrane cholesterol in viral production are still unclear. Here, we investigated the effects of cholesterol depletion from the cell membrane on the production of hemagglutinating virus of Japan (HVJ; Sendai virus). Cholesterol depletion from LLC-MK2 cells by methyl beta cyclodextrin treatment resulted in a marked increase in the production of both HVJ from the infected cells and virus-like particles from M-gene-transfected cells. The HVJ produced from cholesterol-depleted cells possessed a reduced amount of envelope cholesterol and showed a rather wide range of particle sizes and amount of envelope protein compared to HVJ produced from untreated cells. Direct depletion of envelope cholesterol from HVJ significantly impaired its infectivity, even without a change in envelope protein composition. These results suggest that membrane cholesterol plays important roles in regulating the production of infectious HVJ. PMID- 21311920 TI - The human cytomegalovirus TRL11/IRL11-encoded FcgammaR binds differentially to allelic variants of immunoglobulin G1. AB - Human cytomegalovirus (HCMV) has evolved several immune-evasion strategies. One strategy involves encoding Fcgamma receptor (FcgammaR)-like proteins that thwart the Fcgamma-mediated effector functions. Our aim was to determine whether GM allotypes-immunoglobulin gamma chain determinants expressed primarily on the Fc segment-modulate this viral strategy through differential binding to the viral FcgammaR. Results of our ELISA binding studies show that the mean absorbance values for binding to the HCMV TRL11/IRL11-encoded FcgammaR were higher for IgG1 expressing the GM 3 allotype than for those expressing the allelic GM 1,2,17 determinants (p = 0.0005), a finding with potential implications for genetic etiology of HCMV-associated diseases. PMID- 21311921 TI - Complete genomic sequence of virulent Cronobacter sakazakii phage ESSI-2 isolated from swine feces. AB - A newly identified virulent Cronobacter sakazakii phage, ESSI-2, was isolated from fecal samples from swine. The morphological characteristics evident under a transmission electron microscope indicated that phage ESSI-2 belonged to the family Myoviridae. The genome of phage ESSI-2 comprised a double-stranded DNA of 28,765 bp with a G+C content of 55.17%. Bioinformatic analysis of the phage genome identified 36 putative open reading frames (ORFs). The genome of phage ESSI-2 was not significantly similar to that of a previously reported bacteriophage of the members of Enterobacteriaceae. A lysogeny module was found within the genome of this virulent phage. PMID- 21311922 TI - A novel recombinant tomato-infecting begomovirus capable of transcomplementing heterologous DNA-B components. AB - The genome of a tomato-infecting begomovirus from Ranchi, India, was cloned, sequenced and analysed. The viral genome shared 88.3% sequence identity with an isolate belonging to the species Tobacco curly shoot virus (TbCSV), and this virus should therefore be considered a member of a new species, tentatively named Tomato leaf curl Ranchi virus (ToLCRnV). The DNA-beta molecule, which had 74.5% sequence identity with tomato leaf curl Bangladesh betasatellite (ToLCBDB), is named tomato leaf curl Ranchi betasatellite (ToLCRnB). Phylogenetic analysis revealed that ToLCRnV is related to tomato leaf curl Bangladesh virus (ToLCBDV), tobacco curly shoot virus (TbCSV) and tomato leaf curl Gujarat virus (ToLCGV). An infectivity study with ToLCRnV established the monopartite nature of the viral genome, whereas inoculation with ToLCRnB resulted in increased symptom severity. ToLCRnV could transreplicate DNA-B of tomato leaf curl Gujarat virus (ToLCGV) and tomato leaf curl New Delhi virus (ToLCNDV), both in N. benthamiana and tomato, although DNA-B accumulation of was less than with the wild-type combinations. ToLCRnB could be efficiently replicated by DNA-A of both ToLCNDV and ToLCGV. A leaf disk assay suggests that DNA-A could transreplicate the homologous DNA-B and DNA-beta more efficiently than the heterologous one. PMID- 21311923 TI - Rays, intrusive growth, and storied cambium in the inflorescence stems of Arabidopsis thaliana (L.) Heynh. AB - Arabidopsis thaliana is a model plant used in analysis of different aspects of plant growth and development. Under suitable conditions, secondary growth takes place in the hypocotyl of Arabidopsis plants, a finding which helps in understanding many aspects of xylogenesis. However, not all developmental processes of secondary tissue can be studied here, as no secondary rays and intrusive growth have been detected in hypocotyl. However, results presented here concerning the secondary growth in inflorescence stems of Arabidopsis shows that both secondary rays and intrusive growth of cambial cells can be detected, and that, in the interfascicular regions, a storied cambium can be developed. PMID- 21311924 TI - Newborn gender as a predictor of postpartum mood disturbances in a sample of Swedish women. AB - Postpartum depression (PPD) is a condition that affects about 10% of newly delivered women. The aim of this study was to examine the possible association between offspring gender and risk for development of PPD in Sweden. The study was undertaken as part of the UPPSAT project, a population-based longitudinal study in Uppsala, Sweden. From May 2006 to June 2007, women who gave birth at Uppsala University Hospital and fulfilled the inclusion criteria were asked to participate. The participating women filled out, at three points during the first 6 months after delivery, questionnaires containing the Edinburgh Postnatal Depression Scale as well as questions concerning various lifestyle factors, medical history, breast feeding habits, social support parameters, and diet factors. No significant difference in risk of PPD in relation to baby gender could be shown 6 weeks and 6 months after delivery. However, women who gave birth to a male offspring had a significantly higher risk of self-reported depressive symptomatology 5 days after delivery. The association remained statistically significant after adjustment for possible confounders in a logistic regression model. This longitudinal study demonstrates that, in Sweden, the gender of the offspring is not associated with a higher risk for self-reported postpartum depression in the mother 6 weeks or 6 months after delivery. The birth of a baby boy, however, gives the mother a higher risk of postpartum blues 5 days after delivery. PMID- 21311925 TI - Depressive symptoms as a determinant of breast and cervical cancer screening in women: a population-based study in Ontario, Canada. AB - The objective of this study was to investigate the relationship between depression and screening for breast and cervical cancer. The study sample included Ontario female respondents to the Canadian Community Health Survey Cycle 1.2, Mental Health and Well Being component (2002). Women with Major Depressive Disorder (MDD) were identified based on the World Mental Health Composite International Diagnostic Interview and women with clinically significant depressive symptoms were identified using the Kessler 6-item Distress Scale (K6 >= 8). Respondents eligible for screening (N = 4,042 for cervical cancer and N = 1,403 for breast cancer) were linked to Ontario administrative data to prospectively ascertain screening outcomes. Both women with MDD and K6 >= 8 were less likely to receive breast cancer screening than their non-depressed counterparts (46.1% vs. 61.5% for MDD, Chi(2) = 5.47, p = 0.02; 49.9% vs. 61.9% for K6, Chi(2) = 6.61, p = 0.01). Adjusted analyses revealed persistence of the association between K6 >= 8 and breast cancer screening (adjusted odds ratio (AOR) 0.63, 95% CI 0.40-0.97). Neither MDD nor K6 >= 8 were found to be associated with cervical cancer screening in the full sample. A sub-group analysis by age revealed that women over age 40 years with K6 >= 8 were less likely to receive cervical cancer screening than their non-depressed counterparts (49.9% vs. 64.5%, X(2) = 6.47, p = 0.01). This association approached statistical significance in adjusted analysis (AOR = 0.65, 95% CI 0.41-1.04). This study's findings suggest that attention to the uptake of preventive services in women with depressive symptoms is warranted. PMID- 21311926 TI - Rural residence and risk for perinatal depression: a Canadian pilot study. AB - Few studies have examined whether rural residence is associated with increased or decreased risk for postpartum depression (PPD). To address this research gap, this pilot study examined rates of depressive symptoms and perceived social support among women living in rural (population <10,000), semi-rural (population 10,000-20,000), and urban (downtown Toronto, population approximately 2.5 million) areas. Women were consecutively recruited at 25-35 weeks gestation from midwifery clinics and hospital-based prenatal care practices in two catchment areas and asked to complete a demographic questionnaire including postal code. On the basis of their responses, rural, semi-rural, and urban mothers were contacted by telephone at 36 weeks gestation (baseline) and 6-8 weeks postpartum (primary outcome). During each assessment, participants completed standardized measures of social connectedness, mental health, and health service utilization, including the Edinburgh Postnatal Depression Scale (EPDS) and the Medical Outcome Study Social Support Scale. A total of 87 participants [N = 23 rural (R), N = 23 semi rural (SR), N = 41 urban (U)] were recruited into the study. There were no statistically significant differences between groups in mean EPDS scores during pregnancy (U = 7.1, SR = 5.3, R = 5.3, p = 0.15) or at 6 weeks postpartum (U = 5.3, SR = 4.4, R = 4.2, p = 0.43). The proportion of women with EPDS scores >12 similarly did not differ between groups. There were few statistically significant differences between groups on indicators of social connectedness; however, urban women reported significantly lower scores on measures of social network diversity and social capital than either the semi-rural or rural groups. This pilot study is limited by its small sample size; however, our data do not support the hypothesis that there are clinically important differences in risk for PPD associated with rural residence. Further studies examining potential relationships between indicators of social connectedness and perinatal mental health may be warranted. PMID- 21311927 TI - Case series of perimenopausal women with insomnia treated with mirtazapine followed by prolonged-release melatonin add-on and monotherapy. AB - OBJECTIVES: The sedating antidepressant mirtazapine is used off label for insomnia in perimenopausal women. Despite its apparent efficacy, mirtazapine causes significant increases in appetite and weight gain. Prolonged-release melatonin (PRM) is approved for primary insomnia in patients aged 55 years and older. A clinical experience with PRM add-on to mirtazapine in facilitating mirtazapine withdrawal while maintaining improved sleep quality and abrogating weight gain in perimenopausal women with insomnia is described. METHODS: Eleven perimenopausal women (ages 45-52; FSH = 53 +/- 8; normal BMI, 22.9 +/- 0.6) with insomnia, who do not suffer from depression as assessed by the Hamilton scale, were treated with 15 mg mirtazapine (Remeron(r)) for 2-4 weeks. PRM, 2 mg (Circadin(r)), was then added on, and mirtazapine was tapered off for another 1-3 months. Prospective data on body weight and subjectively assessed sleep quality and well-being (assessed by the Pittsburgh Sleep Quality Index, PSQI, and Well Being Index, WHO-5, respectively) were collected before, during, and at the end of the treatment. RESULTS: Sleep quality ratings improved significantly (by 103% on average) during combined mirtazapine and PRM intake and 180% during subsequent intake of PRM alone or together with very low doses of mirtazapine (P < 0.05 for all). Well-being significantly improved by 83% during the treatment. Seven of 11 women demonstrated weight gain following mirtazapine intake, five of whom have started to reduce weight following mirtazapine withdrawal and PRM intake. No adverse events were reported. CONCLUSION: Application of mirtazapine followed by PRM add-on and monotherapy improves sleep in perimenopausal women while evading mirtazapine-induced weight gain. These results warrant further investigation of a larger population in controlled clinical trials. PMID- 21311928 TI - Does anterior lumbar interbody fusion promote adjacent degeneration in degenerative disc disease? A finite element study. AB - BACKGROUND: The increase in the number of anterior lumbar interbody fusions being performed carries with it the potential for the long-term complication of adjacent segmental degeneration. While its exact mechanism remains uncertain, adjacent segment degeneration has become much more widespread. Using a nonlinear, three-dimensional finite element model to analyze and compare the biomechanical influence of anterior lumbar interbody fusion and lumbar disc degeneration on the superior adjacent intervertebral disc, we attempt to determine if anterior lumbar interbody fusion aggravates adjacent segment degeneration. METHODS: A normal three-dimensional non-linear finite element model of L3-5 has been developed. Three different grades of disc degeneration models (mild, moderate, severe) and one anterior lumbar interbody fusion model were developed by changing either the geometry or associated material properties of the L4-5 segment. The 800 N pre compressive loading plus 10 Nm moments simulating flexion, extension, lateral bending and axial rotation in five steps was imposed on the L3 superior endplate of all models. The intradiscal pressure, intersegmental rotation range and Tresca stress of the annulus fibrosus in the L3-4 segment were investigated. RESULTS: The intradiscal pressure, intersegmental rotation range and Tresca stress of the L3-4 segment in the fusion model are higher than in the normal model and different degeneration models under all motion directions. The intradiscal pressures in the three degenerative models are higher than in the normal model in flexion, extension and lateral bending, whereas in axial rotation, the value of the mild degeneration model is lower. The intersegmental rotation ranges in the three degenerative models are higher than in the normal model in flexion and extension. The values for the mild degeneration model in lateral bending and all the degeneration models in axial rotation are lower than in the normal model. The Tresca stresses are higher in the three degenerative models than in the normal model. CONCLUSION: Anterior lumbar interbody fusion has more adverse biomechanical influence than disc degeneration on the adjacent upper disc and may aggravate the adjacent upper segmental degeneration. PMID- 21311930 TI - Preoperative predictors of postoperative pulmonary complications in neuromuscular scoliosis. AB - BACKGROUND: Neuromuscular scoliosis (NMS) is associated with progressive restrictive lung disease and an increased risk of prolonged ventilation following surgery. This study reports the experiences of a single institution and evaluates whether preoperative pulmonary function tests (PFT) can predict the development of postoperative pulmonary complications. METHODS: Correlations between preoperative PFT (forced expired volume in 1 s, FEV(1); forced vital capacity, FVC) findings and postoperative pulmonary complications were searched for among 74 NMS patients who underwent surgical correction at our medical center from 2002 to 2008. RESULTS: Thirty-seven patients (50%) developed a pulmonary complication. The independent factors found to contribute to the development of a pulmonary complication were: FEV(1) <40% of the predicted value (P = 0.007), FVC <39.5% of the predicted value (P = 0.005), a larger Cobb angle (>69 degrees ) (P = 0.002), and older age (>16.5 years) (P = 0.027). Of these 37 patients, 6 needed postoperative ventilation. PFT findings found to be independently associated with the need for postoperative ventilation were: FEV(1) <40% of the predicted value (P = 0.017) and FVC <39.5% of the predicted value (P = 0.015). CONCLUSIONS: NMS patients with a preoperative FVC of <39.5% of the predicted value, an FEV(1) <40% of the predicted value, a Cobb angle of >69 degrees , or age >16.5 years were found to be more likely to develop a postoperative pulmonary complication. PMID- 21311929 TI - Assessment of pure single nerve root resection in the treatment of spinal schwannoma: focus on solitary spinal schwannomas located below the thoracolumbar junction. AB - BACKGROUND: The incidence of neurological deficits is reportedly low after sacrificing the affected nerve root during spinal schwannoma treatment. Although the incidence has been widely reported, the operative method for nerve root resection has been not clarified. To evaluate the safety of pure nerve root resection, we focused on solitary spinal schwannomas below the thoracolumbar level and investigated the effect of affected nerve resection. METHODS: Twenty three spinal schwannoma patients were retrospectively examined. The mean age at surgery was 53 years. We investigated preoperative symptoms, duration of the disorder, postoperative neurological deficits, and clinical outcomes. In addition, we measured tumor size on computed tomography after myelography or on magnetic resonance images using image-analysis software. We retrospectively assessed correlations among duration of symptoms, tumor size, and postoperative neurological deficits. RESULTS: The tumors comprised 19 intradural schwannomas and 4 dumbbell-shaped schwannomas. No postoperative neurological deficits were observed in the intradural schwannoma patients. In contrast, three of the four dumbbell-shaped schwannoma patients experienced postoperative neurological deficits. Among these three patients, two recovered quickly whereas one never recovered. The mean duration of the disorder was 29 months. The postoperative modified JOA score (13.0) was significantly improved compared with the preoperative score (8.9). The mean maximum tumor sizes were 97.2 mm(2) for the intradural schwannomas and 884.0 mm(2) for the dumbbell-shaped schwannomas. There were no correlations among tumor size, duration of the disorder, and postoperative neurological deficits. CONCLUSIONS: On the basis of this study, we recommend pure single nerve resection for treatment of intradural spinal schwannomas before such tumors progress and involve other normal roots, because postoperative neurological deficits did not occur in our intradural schwannoma patients, irrespective of tumor size, when this procedure was used. However, dumbbell-shaped schwannoma patients should be carefully treated operatively, because high incidence of postoperative neurological deficits can be expected. PMID- 21311931 TI - Acidiferrobacter thiooxydans, gen. nov. sp. nov.; an acidophilic, thermo tolerant, facultatively anaerobic iron- and sulfur-oxidizer of the family Ectothiorhodospiraceae. AB - A comprehensive physiological and phylogenetic characterisation was carried out of "Thiobacillus ferrooxidans" m-1, an acidophilic iron-oxidizing bacterium first described over 25 years ago. Phylogenetically, strain m-1 is a gammaproteobacterium, most closely related to alkaliphilic Ectothiorhodospira spp. and only distantly to iron-oxidizing acidithiobacilli. Physiological examination confirmed that strain m-1 can grow autotrophically not only by ferrous iron oxidation but also, in contrast to previous reports, by oxidation of elemental sulfur, sulfide and tetrathionate, using either oxygen or ferric iron as terminal electron acceptor. The bacterium was also found to be thermo tolerant, growing optimally at 38 degrees C and up to a maximum of 47 degrees C. Growth in liquid media required an external osmotic potential of >2 bar, and was optimal at ~5 bar, though no growth occurred where the medium osmotic potential was close to that of sea water (~26 bar). From this, it was concluded that strain m-1 is a moderate osmophile. Strain m-1 was also shown to be diazotrophic and tolerant of elevated concentrations of many metals typically found in mine impacted environments. On the basis of these data, m-1 is proposed as the type strain of a new genus and species of bacteria, Acidiferrobacter thiooxydans (DSM 2392, JCM 17358). PMID- 21311932 TI - A computerized protein-protein interaction modeling study of ampicillin antibody specificity in relation to biosensor development. AB - Nonspecific interactions between immobilized biomolecules and interfering proteins significantly impede biosensor development and commercialization. Advances in bioinformatics and computer technology have facilitated a greater understanding of biological interactions. We employed two different protein protein docking programs to simulate the nonspecific interaction between ampicillin antibody and potential interfering proteins (human serum albumin and ovalbumin). To evaluate the contact and probability of association with the active site of the antibody, different amino acid chains from human serum albumin (HSA) and ovalbumin (OVA) were modeled in the simulation. In addition, a well known specific immune complex, lysozyme and lysozyme antibody, was simulated for comparison. The results demonstrated that the cluster density of nonspecific interactions was smaller than the specific interaction between lysozyme and antibody, and that the dock scores were scattered. However, the active site of ampicillin antibody was prone to nonspecific protein interactions. The strength of interaction was different for specific binding and nonspecific binding. These results provide a platform for detecting the probability of nonspecific interactions and for improving methods of biosensor detection construction with reduced nonspecific adsorption. PMID- 21311934 TI - Transabdominal pre-peritoneal inguinal hernia repair with external fixation. AB - PURPOSE: To find a method that has all the advantages of laparoscopic transabdominal preperitoneal (TAPP) inguinal hernia repair but with considerably reduced costs. BACKGROUND: Controversy exits regarding whether it is necessary to secure the mesh prosthesis during laparoscopic TAPP inguinal hernia repair. It is unknown whether stapling the mesh affects recurrence rate or the incidence of neuralgia in a port-site hernia. We choose to fix the mesh to the exterior, thus reducing port size, cost and pain. METHODS: We conducted a prospective trial for laparoscopic TAPP inguinal hernia repair in which we fixed the mesh to the anterior abdominal wall using two prolene threads that passed to the exterior and were tied in place. The study was conducted at Al Hayat Hospital Jeddah, Saudi Arabia, between September 2008 and April 2009. Included in the study were 42 patients with unilateral inguinal hernia. RESULTS: The operative time ranged from 35 to 85 min and follow up was for 9-16 months, during which time there was no recurrence, no post TAPP pain. The procedure reduces the port size required and was also associated with reduced cost. CONCLUSION: It is not necessary to secure the mesh during laparoscopic TAPP inguinal hernia repair from the interior. External fixation allows a reduction in size of the ports needed, and leads to a considerable reduction in cost. PMID- 21311933 TI - Effect of atom- and group-based truncations on biomolecules simulated with reaction-field electrostatics. AB - The performance of the reaction-field method of electrostatics is tested in molecular dynamics simulations of protein human interleukin-4 and a short DNA fragment in explicit solvent. Two truncation schemes are considered: one based on the position of atomic charges in water molecules and the other on the position of groups of charges. The group-based truncation leads to the melting of the DNA double helix. In contrast, the atom-based truncation maintains the helical structure intact. Similarly for the protein, the group-based truncation leads to an unfolding at pH 2 while the atom-based truncation produces stable trajectories at low and normal pH, in agreement with experiment. Artificial repulsion between charged residues associated with the group-based truncation is identified as the microscopic reason behind unfolding of the protein. Implications of different truncation schemes in reaction-field simulations of biomolecules are discussed. PMID- 21311935 TI - The effectiveness of methicillin-resistant Staphylococcus aureus colonisation screening in asymptomatic healthcare workers in an Irish orthopaedic unit. AB - Methicillin-resistant Staphylococcus aureus (MRSA) infections are associated with increased mortality, costs and length of stay compared to non-MRSA infections. This observational 4-year study analyses the impact of screening and treating orthopaedic healthcare workers for MRSA colonisation. A total of 1,011 swabs were taken from 566 healthcare workers. Positive healthcare workers were treated with topical mupirocin to both anterior nares. The prevalence of MRSA colonisation on initial testing was 4.77%. The rate of positive MRSA colonisation of those tested on more than one occasion fell from 5.88% to 2.71% (p = 0.055) on subsequent screening. All healthcare workers receiving treatment were successfully cleared of colonisation; however, some required more than one course of treatment. These results show that there could be a role for screening and treating orthopaedic staff for MRSA colonisation as part of a strategy to reduce the prevalence of MRSA infections in orthopaedic units. PMID- 21311936 TI - Comparison of three rapid and easy bacterial DNA extraction methods for use with quantitative real-time PCR. AB - The development of fast and easy on-site molecular detection and quantification methods for hazardous microbes on solid surfaces is desirable for several applications where specialised laboratory facilities are absent. The quantification of bacterial contamination necessitates the assessment of the efficiency of the used methodology as a whole, including the preceding steps of sampling and sample processing. We used quantitative real-time polymerase chain reaction (qrtPCR) for Escherichia coli and Staphylococcus aureus to measure the recovery of DNA from defined numbers of bacterial cells that were subjected to three different DNA extraction methods: the QIAamp DNA Mini Kit, Reischl et al.'s method and FTA Elute. FTA Elute significantly showed the highest median DNA extraction efficiency of 76.9% for E. coli and 108.9% for S. aureus. The Reischl et al. method and QIAamp DNA Mini Kit inhibited the E. coli qrtPCR assay with a 10-fold decrease of detectable DNA. None of the methods inhibited the S. aureus qrtPCR assay. The FTA Elute applicability was demonstrated with swab samples taken from the International Space Station (ISS) interior. Overall, the FTA Elute method was found to be the most suitable to selected criteria in terms of rapidity, easiness of use, DNA extraction efficiency, toxicity, and transport and storage conditions. PMID- 21311937 TI - Resurgence of measles in the French military forces in 2010. AB - Since the start of 2010 there has been a flare-up of measles in France, following on the resurgence observed in 2008. The aim of this study was to present results of the epidemiological surveillance of measles in the French armed forces and to describe the increase in incidence. Measles was surveyed from 1992 to 2010. Criteria for report were those used for French national compulsory notification. The data, concerning active military personnel, were provided by the physicians in the armed forces using anonymous data collection forms. Between 1992 and July 2010, 689 cases of measles were notified. Since 2002, the mean incidence rate was 1 case per 100,000. A significant increase has been observed for 2010 (13.9 cases per 100,000 in 2010 versus 1.8 in 2009). The 28 cases reported in 2010 involved five clusters and three isolated cases. The mean age of affected subjects was 27 years. Only 30% of cases had been vaccinated. The epidemic resurgence of measles observed in 2010 in the French armed forces follows the same pattern as that observed nationally and at European level, and can be seen as the likely consequence of inadequate vaccination cover. PMID- 21311938 TI - Bactericidal synergy of lysostaphin in combination with antimicrobial peptides. AB - Drug-resistant staphylococci constitute a serious problem that urgently requires the discovery of new therapeutic agents. There has been a resurgence in interest in using lysostaphin (a specific anti-staphylococcal enzyme) as a treatment for infections caused by these important pathogens. However, bacterial resistance to lysostaphin is a problem, but the use of a combination treatment may surmount this issue. In this present study, using viable counts from suspension incubations, lysostaphin is shown to be synergistically bactericidal in combination with various conventional antimicrobial peptides, the antimicrobial protein bovine lactoferrin, a lantibiotic (nisin), and certain lipopeptides used clinically (colistin, daptomycin and polymyxin B). Combinations that act in synergy are of clinical importance as these reduce the doses of the compounds needed for effective treatments and decrease the chances of resistance being selected. The use of lysostaphin in combination with a peptide may represent a new avenue in tackling drug-resistant staphylococci. PMID- 21311939 TI - Umbilical cord blood procalcitonin level in early neonatal infections: a 4-year university hospital cohort study. AB - This article describes a study of procalcitonin (PCT) measured in cord blood as a discriminating marker of early-onset neonatal infection. This was a monocenter retrospective study with prospective collection of data including all babies born during the study period. Those presenting infection risk factors had PCT measurement. Three groups were defined: certainly infected, probably infected, and non-infected. A total of 12,485 newborns were included, 2151 had PCT measurement, and 26 were infected. Receiver operating curves of PCT determined 0.6 ng/ml as the best cut-off, with an area under the curve of 0.96 (CI 95% 0.95 0.98). Sensitivity, specificity, positive and negative predictive value and positive and negative likelihood ratios were 0.92 (range, 0.75-0.98), 0.97 (0.96 0.98), 0.28 (0.20-0.36), 0.99 (0.99-0.99), 32 (24-41) and 0.08 (0.02-0.3), respectively. Post-test probabilities were 28% (23-33) if the test was positive, and less than 0.001% (0-1.10(-5)) if the test was negative. Gestational age between 28 and 32 weeks (OR 4.4; range, 1.2-16.2) and pH at birth < 7.10 (OR 2.9; 1.1-7.4) were other independent factors of increasing PCT (p < 0.05). PCT measured in umbilical cord blood is reliable to detect early infected and non infected newborns. PMID- 21311940 TI - High prevalence of edin-C encoding RhoA-targeting toxin in clinical isolates of Staphylococcus aureus. AB - Staphylococcus aureus, a major causative agent of human infection, produces a large array of virulence factors, including various toxins. Among them, the host RhoA GTPase ADP-ribosylating EDIN toxins are considered as potential virulence factors. Using the polymerase chain reaction (PCR) assay, we analyzed the virulence profile of 256 S. aureus isolates from various clinical sites of infections. We developed specific primers to detect the three isoforms of edin encoding genes. We found a prevalence of 14% (36 bacteria) of edin-encoding genes among these clinical isolates. Strikingly, we found that 90% of all edin-bearing S. aureus isolates carried the type-C allele. Both the spa types and the profile of virulence factors of these edin-positive isolates are highly variable. Notably, we show for the first time that edin-C-positive isolates were more frequently recovered from deep-seated infections than other types of infections. Our present work, thus, strongly suggests that the presence of edin-C is a risk factor of S. aureus dissemination in tissues and, thus, represents a predictive marker for a pejorative evolution of staphylococcal infections. PMID- 21311941 TI - Mycoplasma pneumoniae infection in primary care investigated by real-time PCR in England and Wales. AB - Real-time PCR was employed to detect a conserved region of the P1 cytadhesin gene of Mycoplasma pneumoniae in combined nose and throat swabs collected from patients attending GP surgeries during 2005-2009 with symptoms of respiratory tract infection (RTI). Samples were collected as part of an annual winter epidemiological and virological linked study in England and Wales. A total of 3,987 samples were tested, 65 (1.7%, 95%CI 1.3-2.1) had detectable M. pneumoniae DNA. Positive patients were detected of both gender, aged from 9 months to 78 years, who had clinical signs of upper RTI, fever and/or myalgia, an influenza like illness to lower RTI. Mixed infections were identified in four cases, two with influenza A H1, one with H3 and one with influenza B. Children aged 5-14 years were more likely to have detectable M. pneumoniae in samples than all other age groups (Fishers p = 0.03), attributed to the 2005-2006 season in which 6.0% (12/200, 95%CI 3.4-10.3) of 5-14 year olds had detectable M. pneumoniae in comparison to 2.2% in 2006-2007 (3/141 95%CI 0.5-6.4), 2.2% in 2007-2008 (2/89 95%CI 0.1-8.3) and 0% in 2008-2009 (0/151 95%CI 0-2.9). PMID- 21311942 TI - Compliance with recommendations and clinical outcomes for formal and informal infectious disease specialist consultations. AB - The purpose of this study was to compare compliance with recommendations and clinical outcomes between formal and informal infectious disease specialist consultations. Six hundred twenty-seven consecutive adult inpatients who received an infectious disease consultation in a university-affiliated hospital were included. After adjusting for quintile of propensity score, we compared compliance with the consultant's recommendations and clinical outcomes for 443 (70.7%) and 184 (29.3%) formal and informal consultations. Informal and formal consultations were associated with comparable levels of compliance with recommendations for antimicrobial treatment (86.5% vs 88.9%; adjusted odds ratio [aOR], 0.63; 95% confidence interval, 0.34-1.14; P = 0.13) and diagnostic or monitoring tests (72.6% vs 72.0%; aOR, 0.91 [0.53-1.57]; P = 0.73). The rates of early clinical improvement (58.2% vs 58.6%; aOR, 1.11 [0.70-1.74]; P = 0.66), subsequent consultation (34.2% vs 36.3%; aOR, 0.80 [0.53-1.21]; P = 0.29), in hospital mortality (4.9% vs 8.4%; aOR, 0.55 [0.24-1.24]; P = 0.15), and the median length of stay (23 vs 20 days; aOR of discharge, 0.90 [0.74-1.10]; P = 0.30) did not differ depending on the type of consultation. This study provides observational evidence that informal consultations result in levels of compliance with recommendations comparable to formal consultations, without compromising patient safety. Further study is needed to refine the criteria for requesting or providing informal rather than formal consultations. PMID- 21311943 TI - The PCR-invader method (structure-specific 5' nuclease-based method), a sensitive method for detecting EGFR gene mutations in lung cancer specimens; comparison with direct sequencing. AB - BACKGROUND: Several sensitive assays, including the PCR-invader method (structure specific 5' nuclease-based method), have been used to detect EGFR mutations in non-small-cell lung cancer (NSCLC). However, validation has not been reported. We assessed the detection rate of EGFR mutation by the PCR-invader method and direct sequencing using same clinical specimens. PATIENTS AND METHODS: EGFR mutations were analyzed with the PCR-invader method and compared with direct sequencing using paraffin tissues and pleural and pericardial effusions from NSCLC patients. The relationships between the treatment responses and mutations were evaluated retrospectively. RESULTS: Fifty-four samples from 42 NSCLC patients were studied. EGFR mutations were identified in 52% of the patients and 52% of the samples with the PCR-invader method, but only in 43% of the patients and in 35% of the samples by direct sequencing. In the samples obtained from the same patients at different sites and different times, EGFR mutations were coincident in nine out of ten patients by the PCR-invader method but in six out of ten patients by direct sequencing. Seventeen patients with EGFR mutations were treated with gefitinib; the response rate (RR) and disease control rate (DCR) were 41 and 94%, and median treatment duration was more than 6 months. Seven EGFR mutation-negative patients were treated with gefitinib; the RR and DCR were 0 and 14%, and median treatment duration was 1 month. CONCLUSION: The PCR-invader method was useful for detecting EGFR mutations in clinical lung cancer specimens and is more sensitive than direct sequencing. PMID- 21311944 TI - Regional context-sensitive support vector machine classifier to improve automated identification of regional patterns of diffuse interstitial lung disease. AB - We propose the use of a context-sensitive support vector machine (csSVM) to enhance the performance of a conventional support vector machine (SVM) for identifying diffuse interstitial lung disease (DILD) in high-resolution computerized tomography (HRCT) images. Nine hundred rectangular regions of interest (ROIs), each 20 * 20 pixels in size and consisting of 150 ROIs representing six regional disease patterns (normal, ground-glass opacity, reticular opacity, honeycombing, emphysema, and consolidation), were marked by two experienced radiologists using consensus HRCT images of various DILD. Twenty one textual and shape features were evaluated to characterize the ROIs. The csSVM classified an ROI by simultaneously using the decision value of each class and information from the neighboring ROIs, such as neighboring region feature distances and class differences. Sequential forward-selection was used to select the relevant features. To validate our results, we used 900 ROIs with fivefold cross-validation and 84 whole lung images categorized by a radiologist. The accuracy of the proposed method for ROI and whole lung classification (89.88 +/- 0.02%, and 60.30 +/- 13.95%, respectively) was significantly higher than that provided by the conventional SVM classifier (87.39 +/- 0.02%, and 57.69 +/- 13.31%, respectively; paired t test, p < 0.01, and p < 0.01, respectively). We conclude that our csSVM provides better overall quantification of DILD. PMID- 21311945 TI - Borrelia burgdorferi bacteremia. PMID- 21311946 TI - Rothia dentocariosa endocarditis with mitral valve prolapse: case report and brief review. PMID- 21311947 TI - Alternate schedules of hepatitis B vaccination: which one is better? PMID- 21311948 TI - Role of p21 in SP600125-induced cell cycle arrest, endoreduplication, and apoptosis. AB - The anti-cancer effect of the c-Jun N-terminal kinase (JNK) inhibitor SP600125 has been well evaluated in human cancer cells. However the role of p21 in SP600125-mediated G(2)/M distribution is not fully understood. Our results showed that the transcriptional activation of p21 by SP600125 is mediated through the proximal regions of multiple Sp1 sites in the p21 promoter following ERK dependent phosphorylation of Sp1. In this process, p21 induces endoreduplication through the inhibition of cyclin E/Cdk2 activity at 24 h but does not directly regulate cyclin B1/Cdc2 activity. Furthermore, SP600125 induces the phosphorylation of p21 at Thr 145 through the PI3K/Akt pathway. Akt-mediated phosphorylation of p21 and protection of apoptosis are completely abolished by inhibitors of PI3K and Akt. In summary using time points, we identified the dual functions of p21 as an inhibitor of cell-cycle progression at 24 h and as an anti apoptotic factor at 48 h. PMID- 21311949 TI - Use of sleeping sites by a titi group (Callicebus coimbrai) in the Brazilian Atlantic Forest. AB - Predation pressure affects most aspects of primate behaviour, and is especially pronounced in the context of the use of sleeping sites, given the vulnerability of the animal at this time. Most small-bodied platyrrhines have highly systematic patterns of sleeping site choice and use. This study analyses the use of sleeping sites by a free-ranging group of titis (Callicebus coimbrai) monitored at a site in Sergipe, Brazil, between July, 2009 and June, 2010. When the subjects approached a sleeping tree their behaviour was typically cautious, including slow and silent movement, early retirement (20-162 min before sunset on 52 dry afternoons), and sleeping in a tight huddle with their tails entwined. Despite this behaviour, which has an obvious anti-predator function, the group slept in only three different trees during the course of the study, and returned to the same tree used on the previous night on a quarter of evenings (n = 56). This was despite the availability within the group's home range of a large number of trees with similar structural characteristics (i.e. tall, open crown in the upper canopy). Surprisingly, the three trees were all members of the same species, Licania littoralis (Chrysobalanaceae). The choice of this species, which was not an important source of dietary resources, and the repeated use of a small number of sites, did not seem to be related to factors such as ranging or foraging patterns, but may have a been a response to the specific threat from capuchins, Cebus xanthosternos. PMID- 21311950 TI - Identifying the needs of brain tumor patients and their caregivers. AB - The purpose of this study is to identify the needs of brain tumor patients and their caregivers to provide improved health services to these populations. Two different questionnaires were designed for patients and caregivers. Both questionnaires contained questions pertaining to three realms: disease symptoms/treatment, health care provider, daily living/finances. The caregivers' questionnaires contained an additional domain on emotional needs. Each question was evaluated for the degree of importance and satisfaction. Exploratory analyses determined whether baseline characteristics affect responder importance or satisfaction. Also, areas of high agreement/disagreement in satisfaction between the participating patient-caregiver pairs were identified. Questions for which >50% of the patients and caregivers thought were "very important" but >30% were dissatisfied include: understanding the cause of brain tumors, dealing with patients' lower energy, identifying healthful foods and activities for patients, telephone access to health care providers, information on medical insurance coverage, and support from their employer. In the emotional realm, caregivers identified 9 out of 10 items as important but need further improvement. Areas of high disagreement in satisfaction between participating patient-caregiver pairs include: getting help with household chores (P value = 0.006) and finding time for personal needs (P value < 0.001). This study provides insights into areas to improve services for brain tumor patients and their caregivers. The caregivers' highest amount of burden is placed on their emotional needs, emphasizing the importance of providing appropriate medical and psychosocial support for caregivers to cope with emotional difficulties they face during the patients' treatment process. PMID- 21311951 TI - MGMT promoter methylation and immunoexpression in aggressive pituitary adenomas and carcinomas. AB - MGMT promoter hypermethylation of aggressive pituitary adenomas and pituitary carcinomas and low protein expression are implicated in improved response to treatment with temozolomide (TMZ). The aim of the present study was to investigate MGMT promoter methylation and immunoexpression in an aggressive subset of pituitary adenomas and carcinomas. Our material consisted of 12 silent subtype 3 (SS3) adenomas, 10 primary carcinomas, and 4 disseminated metastases. Two different tissue samples of 7 of the 12 SS3 adenomas and all carcinomas were analyzed for MGMT promoter methylation and immunohistochemical expression of MGMT. Immunoexpression was assessed semi-quantitatively as a percentage of immunoreactive nuclei. Overall 33% of carcinomas exhibited homogenous MGMT methylation in tumor and metastatic specimens. Low immunohistochemical MGMT expression was noted in 50% of carcinomas. Overall, 42% of the SS3 adenomas exhibited MGMT promoter methylation. MGMT immunostaining was predominantly negative (92%), with homogenous immunostaining results across different samples. Whereas all the methylated SS3 adenomas had low MGMT immunoreactivity, five unmethylated adenomas exhibited absent/low MGMT expression. There was no relationship between methylation status and MGMT immunoexpression was not apparent. MGMT methylation and low immunohistochemical expression seen in a subset of carcinomas and SS3 adenomas, suggesting that a subset of tumors may respond to treatment with TMZ. Heterogeneous MGMT methylation status in SS3 adenomas and the lack of concordance between methylation and immunohistochemical expression of MGMT suggest complex regulatory mechanisms, highlighting the need for improved methods in the research on a correlation between MGMT changes and response to TMZ. PMID- 21311952 TI - Enhanced functional stability of plasminogen activator inhibitor-1 in patients with livedoid vasculopathy. AB - Livedoid vasculopathy (LV) is a chronic, recurrent, painful cutaneous disease with distinctive clinical features and an uncertain etiology. The skin lesions are recognizable by focal purpura, depigmentation and shallow ulcers. Thrombophilic conditions occur frequently in patients with LV. While no definitive treatment exists for LV, smoking cessation, antiplatelet therapy, immunosuppressive treatment, and anabolic steroids are often included in the therapeutic ladder. Recently, a possible link between LV and impaired fibrinolysis was established as cutaneous LV lesions responded to tissue plasminogen activator (t-PA) infusion suggesting that inhibition of the fibrinolysis through plasminogen activator inhibitor-1 (PAI-1) activity may determine the disease course in patients with LV. In this study, we investigated PAI-1 antigen (Ag) and activity levels in 20 patients with biopsy proven LV (mean age 26 +/- 11, M/F = 7/13, median disease duration 3.5 years). All patients received antiplatelet treatment with aspirin and/or dipyrimadole and 14 patients received anabolic steroids or immunosuppressive treatment. Fasting PAI-1 Ag and activity levels were measured at 9 AM in all patients. Both Ag (34 (26) ng/ml) (median (interquartile range)) and specific activity (17 (23) IU/fmole) levels of PAI-1 were moderately elevated in LV patients compared to the controls, however, PAI-1 kinetic studies demonstrated markedly enhanced stability of PAI-1 activity in plasma from patients with LV. Specific activity at 16 h was significantly higher than expected specific activity levels (7 (11) vs. 0.07 (0.09) IU/fmole, P < 0.01). While the exact mechanism of increased stability of PAI-1 activity is not known, it may be due to post-translational modifications or increased binding affinity for a stabilizing cofactor. In conclusion, enhanced stability of PAI-1 may contribute to the pathophysiology of LV, and systemic or local treatment with PAI-1 inhibitors may offer a potential treatment alternative in patients with LV. PMID- 21311954 TI - Current knowledge on diagnosis and staging of neuroendocrine tumors. AB - Neuroendocrine tumors (NETs) consist of a heterogeneous group of malignancies with various clinical presentations and growth rates. The incidence has been estimated to 2.5-5 per 100,000 people per year and prevalence of 35 per 100,000. The largest group is the gastroenteropancreatic NETs. Small intestinal NETs are the most common followed by pancreatic NETs in the gastrointestinal tract. A classification system (World Health Organization) was established in year 2000 and recently updated in 2010, taking into consideration the histopathology and tumor biology of the tumors. To further refine the classification a "tumor node metastasis" staging has been suggested by the European Neuroendocrine Tumor Society. The same organization has also proposed a grading system (G1, G2, and G3). The diagnosis of a NET is based on histopathology on tumor specimens, circulating biomarkers as well as imaging. Traditional radiology, such as computerized tomography and magnetic resonance imaging, is still the basis but is complemented with somatostatin receptor scintigraphy and positron emission tomography with specific isotopes such (68)Ga-DOTA-octreotate, F18-dopamine, or C11-5 hydroxytryptamine. Molecular imaging will increase in importance in the near future. There is still an unmet need for more sensitive biomarkers for diagnosis and follow-up. PMID- 21311953 TI - AXR1-ECR1 and AXL1-ECR1 heterodimeric RUB-activating enzymes diverge in function in Arabidopsis thaliana. AB - RELATED TO UBIQUITIN (RUB) modification of CULLIN (CUL) subunits of the CUL-RING ubiquitin E3 ligase (CRL) superfamily regulates CRL ubiquitylation activity. RUB modification requires E1 and E2 enzymes that are analogous to, but distinct from, those activities required for UBIQUITIN (UBQ) attachment. Gene duplications are widespread in angiosperms, and in line with this observation, components of the RUB conjugation pathway are found in multiples in Arabidopsis. To further examine the extent of redundancy within the RUB pathway, we undertook biochemical and genetic characterizations of one such duplication event- the duplication of the genes encoding a subunit of the RUB E1 into AUXIN RESISTANT1 (AXR1) and AXR1 LIKE1 (AXL1). In vitro, the two proteins have similar abilities to function with E1 C-TERMINAL-RELATED1 (ECR1) in catalyzing RUB1 activation and RUB1-ECR1 thioester formation. Using mass spectrometry, endogenous AXR1 and AXL1 proteins were found in complex with 3HA-RUB1, suggesting that AXR1 and AXL1 exist in parallel RUB E1 complexes in Arabidopsis. In contrast, AXR1 and AXL1 differ in ability to correct phenotypic defects in axr1-30, a severe loss-of-function AXR1 mutant, when the respective coding sequences are expressed from the same promoter, suggesting differential in vivo functions. These results suggest that while both proteins function in the RUB pathway and are biochemically similar in RUB-ECR1 thioester formation, they are not functionally equivalent. PMID- 21311955 TI - Innovations therapy: mammalian target of rapamycin (mTOR) inhibitors for the treatment of neuroendocrine tumors. AB - Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare neoplasms that require a multidisciplinary approach for an optimal management. The lack of effectiveness of traditional DNA-damaging agents has led to the exploration of new targeted drugs in order to exploit phenotypical features of GEP-NET therapy. However, due to the orphan setting of these tumors, deeper characterization of molecular features and pathways that characterize cell growth, apoptosis, angiogenesis, and invasion are lacking, particularly genetic mutations or epigenetic alterations that generate oncogenic dependency or even addiction. The PI3K-AKT-mTOR pathway has been implicated as having a crucial role in GEP-NETs not only due to the overexpression of several growth factors and their receptors that finally activate this axis but also hereditary syndromes with constitutive activation of the mTOR pathway with high incidence of GEP-NETs. In this article, we aim to review the recent development of the main molecules that target mTOR complex and have showed promising activity in the treatment of GEPNETs. PMID- 21311956 TI - Genetic factors in metastatic progression of cutaneous melanoma: the future role of circulating melanoma cells in prognosis and management. AB - The greatest potential for improvement of outcome for patients with Cutaneous Malignant Melanoma lies in the prevention of systemic metastasis. Despite extensive investigation, current prognostic indicators either alone or in combination, although related to melanoma progression, are not sufficient to accurately predict the pattern of progression and outcome for any individual patient. Metastasis related death has been recorded in patients initially diagnosed with early stage tumour as well as in patients many years after initial tumour removal. The trouble finding a predictable pattern in the puzzle of melanoma progression may be linked to the fact that most of the material studied for prognosis is either, cutaneous primaries or metastatic deposits, rather than the melanoma cells in the circulatory system which are responsible for disease progression. In this review article we discuss the potential use of circulating tumour cell (CTC) detection and quantification for identifying patients at risk of metastatic deposits. We also discuss current therapies for the treatment of metastatic melanoma and analyse how CTCs may be used to evaluate the effectiveness of current therapies and to pinpoint patients who require further treatment. PMID- 21311957 TI - Interdisciplinary science and the design of a single-dose antibiotic therapy. AB - Azithromycin is a unique antibiotic due to its serum half-life of 69 h. This half life is long enough to permit administration of an entire course of therapy in a single dose, if the gastrointestinal (GI) side effects of such a high dose can be minimized. A series of exploratory clinical pharmacology studies were carried out to understand the site-specific absorption and toleration constraints involved in delivering a 2 g oral single-dose regimen. These studies demonstrated that (a) GI side effects were locally mediated in the GI tract, (b) the duodenum was more sensitive than the ileocecal region, and (c) colonic absorption was limited. A novel controlled release suspension dosage form was designed to meet these constraints, and was shown to deliver the desired systemic dose with acceptable toleration. This dosage form, Zmax(r), is an oral powder-for-constitution which possesses two major features: (a) 200 MUm controlled release microspheres which release the drug as they transit down the small intestine, and (b) alkalizing agents which raise the pH of the gastric milieu for ~20 min to minimize gastric release of the drug (which has high solubility at low pH), in order to minimize exposure of the drug to the sensitive duodenal region. The ability to provide a high single dose of azithromycin results in "front-loading" the mononuclear and polymorphonuclear leukocytes which concentrate the drug and carry it to sites of infection. This provides high drug concentrations early on at infection sites, when the bacterial burden is greatest, potentially improving efficacy and potentially overcoming resistant bacterial strains. Finally, this revolutionary single dose formulation gives 100% compliance, which maximizes the likelihood of therapeutic success. PMID- 21311958 TI - Development and in vitro-in vivo evaluation of polymeric implants for continuous systemic delivery of curcumin. AB - PURPOSE: The introduction of curcumin into clinics is hindered by its low water solubility and poor bioavailability. To overcome these limitations, we developed curcumin implants using poly (epsilon-caprolactone) as the polymeric matrix. METHODS: Implants were prepared by melt-extrusion method; in vitro drug release was optimized for effects of polymer composition, drug load, surface area and water-soluble additives. Implants were also tested under in vivo conditions for cumulative curcumin release, and liver concentration was correlated with its efficacy to modulate selected xenobiotic-metabolizing enzymes (CYP1A1 and GSTM). RESULTS: Drug release from implants followed biphasic release pattern with Higuchi kinetics and was proportional to the surface area of implants. Drug release increased proportionately from 2 to 10% (w/w) drug load, and incorporation of 10% (w/w) of water-soluble additives (F-68, PEG 8000 and cyclodextrin) did not significantly alter the drug release. In vivo drug release was found to be ~1.8 times higher than in vitro release. Curcumin was detected at 60 +/- 20 ng/g in the liver after four days of implantation and was almost constant (8-15 ng/g) for up to 35 days. This time-dependent drop in curcumin level was found to be due to induction of CYP1A1 and GSTM (MU) enzymes which led to increased metabolism of curcumin. CONCLUSION: Our data showed that these implants were able to release curcumin for long duration and to modulate liver phase I and phase II enzymes, demonstrating curcumin's biological efficacy delivered via this delivery system. PMID- 21311959 TI - Are cancer survivors willing to participate in research? AB - Little is known about the late and long term effects of having survived cancer and its treatments. A cancer survivor registry with a representative longitudinal cohort of survivors from all types of cancers would facilitate the study of these effects. A group of researchers, cancer survivors and cancer registrars used hospital cancer registries to identify cancer survivors diagnosed from 1990 through 2006. All eligible cancer survivors were invited to participate in a cancer survivor registry. We describe our methods for engaging the community, who responded to the invitation and who agreed to participate. We used Chi square tests with a significance level of .05 to assess associations with response and participation rates. We used logistic regression to examine associations with participation after adjustment for the effect of age. Logistic regression was also used to assess the independent effects of those variables that were significantly associated with participation after adjustment for age. Of the 6031 eligible survivors, 55% responded to the invitation. Of those who responded 61% agreed to participate in the cancer survivor registry for an overall participation rate of 33%. Rural residence, less education, full time employment, and lower income were independently related to not participating, but marital status was not associated with participation after adjustment for these variables. It is very difficult to recruit a representative sample of cancer survivors to participate in a cancer survivor registry. More research on how to engage the underserved population (rural residents, less education and lower income) is warranted. PMID- 21311960 TI - Evaluating a community based participatory approach to research with disadvantaged women in the southern suburbs of Beirut. AB - This manuscript presents the evaluation of a 3 year community-based participatory research (CBPR) approach involving the testing of a psychosocial intervention to improve reproductive and mental health of married women in a disadvantaged community in Beirut, Lebanon. The community-based participatory approach involved a community advisory committee (CAC), a local women committee (LWC), and university researchers. The evaluation of the CBPR approach followed qualitative assessment which included: analysis of compiled field notes and minutes of meetings of CAC and LWC throughout the 3 years of the intervention, and focus group discussions and individual interviews conducted with the CAC and the LWC members following completion of the trial. The CBPR approach confirmed feasibility, cultural adequacy, as well as representation of community needs. Five main emerging themes came out of the FGD and interviews with CAC and LWC. The community and women involved viewed that the CBPR approach allowed for a good understanding of the community, they felt ownership of the study, acknowledged that participation gave the women voices, and established trust, and acknowledged the challenges faced. This manuscript describes how the community was involved, reports on their evaluation of the CBPR process, and discusses challenges to CBPR in this particular context. PMID- 21311961 TI - Influence of aging on membrane permeability transition in brain mitochondria. AB - The mitochondrial inner membrane permeability transition (MPT) plays an important role in the pathophysiology of acute disorders of the central nervous systems, including ischemic and traumatic brain injury, and possibly in neurodegenerative diseases. Opening of the permeability transition pore (PTP) by a combination of abnormally elevated intramitochondrial Ca2+ and oxidative stress induces the collapse of transmembrane ion gradients, resulting in membrane depolarization and uncoupling of oxidative phosphorylation. This loss of ATP synthesis eventually results in cellular metabolic failure and necrotic cell death. Drugs, e.g., cyclosporin A, can inhibit the permeability transition through their interaction with the mitochondria-specific protein, cyclophilin D, and demonstrate neuroprotection in several animal models. These characteristics of the MPT were developed almost exclusively from experiments performed with young, mature rodents whereas the neuropathologies associated with the MPT are most prevalent in the elderly population. Some evidence indicates that the sensitivity of mitochondria to Ca2+-induced PTP opening is greater in the aged compared to the young mature brain; however, the basis for this difference is unknown. Based on knowledge of factors that regulate the MPT and on other comparisons between cells and mitochondria from young and old animals, several features may be important. These aging-related features include impaired neuronal Ca2+ homeostasis, increased oxidative stress, increased cyclophilin D protein levels, oxidative modification of the adenine nucleotide translocase and of cardiolipin, and changes in the levels of anti-death mitochondrial proteins, e.g., Bcl-2. The influence of aging on both the contribution of the MPT to neuropathology and the neuroprotective efficacy of MPT inhibitors is a substantial knowledge gap that requires extensive research at the subcellular, cellular, and animal model levels. PMID- 21311963 TI - A comparison of autism prevalence trends in Denmark and Western Australia. AB - Prevalence statistics for autism spectrum disorders (ASD) vary widely across geographical boundaries. Some variation can be explained by diagnostic methods, case ascertainment and age at diagnosis. This study compared prevalence statistics for two distinct geographical regions, Denmark and Western Australia, both of which have had population-based registers and consistent classification systems operating over the past decade. Overall ASD prevalence rates were higher in Denmark (68.5 per 10,000 children) compared with Western Australia (51.0 per 10,000 children), while the diagnosis of childhood autism was more prevalent in Western Australia (39.3 per 10,000 children) compared with Denmark (21.8 per 10,000 children). These differences are probably caused by local phenomena affecting case ascertainment but influence from biological or geographical factors may exist. PMID- 21311964 TI - Interactive voice response self-monitoring to assess risk behaviors in rural substance users living with HIV/AIDS. AB - Community-dwelling HIV/AIDS patients in rural Alabama self-monitored (SM) daily HIV risk behaviors using an Interactive Voice Response (IVR) system, which may enhance reporting, reduce monitored behaviors, and extend the reach of care. Sexually active substance users (35 men, 19 women) engaged in IVR SM of sex, substance use, and surrounding contexts for 4-10 weeks. Baseline predictors of IVR utilization were assessed, and longitudinal IVR SM effects on risk behaviors were examined. Frequent (n = 22), infrequent (n = 22), and non-caller (n = 10) groups were analyzed. Non-callers had shorter durations of HIV medical care and lower safer sex self-efficacy and tended to be older heterosexuals. Among callers, frequent callers had lost less social support. Longitudinal logistic regression models indicated reductions in risky sex and drug use with IVR SM over time. IVR systems appear to have utility for risk assessment and reduction for rural populations living with HIV disease. PMID- 21311965 TI - The Ndc80 complex: integrating the kinetochore's many movements. AB - The Ndc80 complex lies at the heart of the kinetochore, a large protein machine that accurately segregates chromosomes during cell division. The Ndc80 complex has structural roles in assembling the kinetochore, but also functions to congress chromosomes and to signal the spindle checkpoint. It directly binds to microtubules and is currently the best candidate for the long-sought protein that couples microtubule depolymerization to chromosome movement. A combination of structural and genetic data has recently converged to generate the first models for this fascinating motor activity. Additionally, recent data point to an increasingly dynamic role for Ndc80 in the kinetochore-one which involves not only simple binding to microtubules but also shifts in complex shape and its location within the overall kinetochore structure. In this review, we discuss recent advances in our understanding of the Ndc80 complex and address future areas of research. PMID- 21311966 TI - Effects of estradiol and IGF-1 on the sodium calcium exchanger in rat cultured cortical neurons. AB - The Na(+)/Ca(2+) exchanger (NCX) is an important bidirectional transporter of calcium in neurons and has been shown to be involved in neuroprotection. Calcium can activate a number of cascades that can result in apoptosis and cell death, and NCX is a key factor in regulating the cytoplasmic concentration of this ion. 17-beta-estradiol and insulin-like growth factor 1 (IGF-1) are known neuroprotective hormones with interacting mechanisms and effects on intracellular calcium; however, their relationship with the NCX has not been explored. In this article, the effects of these two hormones on neuronal NCX were tested using the whole-cell patch clamp technique on rat primary culture neurons. Both 17-beta estradiol and IGF-1 produced an increase in the NCX-mediated inward current and a decrease in the NCX-mediated outward current. However, the IGF-1 effect was lower than that of 17-beta-estradiol, and the effect of both agents together was greater than the sum of each agent alone. Neither of the agents affected the pattern of regulation by extracellular or intrapipette calcium. Inhibitors of the IGF-1 and 17-beta-estradiol receptors and inhibitors of the main signaling pathways failed to change the observed effects, indicating that these actions were not mediated by the classical receptors of these hormones. These effects on the NCX could be a mechanism explaining the neuroprotective actions of 17-beta estradiol and IGF-1, and these findings could help researchers to understand the role of the NCX in neuroprotection. PMID- 21311967 TI - The prognostic role of circulating tumor cells (CTCs) detected by RT-PCR in breast cancer: a meta-analysis of published literature. AB - The prognostic significance of circulating tumor cells (CTCs) in patients with breast cancer is controversial. We performed a meta-analysis of published literature to assess whether the detection of CTCs in patients diagnosed with primary breast cancer can be used as a prognostic factor. We searched Medline, Science Citation Index, and Embase databases as well as reference lists of relevant articles (including review articles) for studies that assessed the prognostic relevance of tumor cell detection in the peripheral blood (PB). A total of 24 eligible studies with 4,013 cases and 1,333 controls were included. Meta-analyses were performed using a random-effects model, using the hazard ratio (HR) and 95% confidence intervals (95% CIs) as effect measures. The positive detection of CTCs in patients was significantly associated with poor overall survival (OS) (HR = 3.00 [95% CI 2.29-3.94], n = 17, P < 0.0001) and recurrence free survival (RFS) (HR = 2.67 [95% CI 2.09-3.42], n = 22, P < 0.0001). CTC positive breast cancers were significantly associated with high histological grade (HR = 1.21 [95% CI 1.09-1.35], n = 34, P < 0.0001), tumor size (>2 cm) (HR = 1.12 [95% CI 1.02-1.22], n = 31, P = 0.01). and nodal status (>=1) (HR = 1.10 [95% CI 1.00-1.21], n = 32, P = 0.037), but cytokeratin-19 (CK-19) mRNA-positive CTCs were not associated with these clinicopathological parameters of breast cancer. Furthermore, the presence of CTCs was not associated with estrogen receptor (ER) negativity, progesterone receptor (PR) negativity, or human epidermal growth factor receptor type 2 (HER2) positivity. Detection of CTCs in the PB indicates poor prognosis in patients with primary breast cancer. Larger clinical studies are required to further evaluate the role of these markers in clinical practice. PMID- 21311968 TI - Is the toxicity of adjuvant aromatase inhibitor therapy underestimated? Complementary information from patient-reported outcomes (PROs). AB - Adjuvant endocrine treatment-related adverse effects have a strong impact on patients' quality of life and thereby limit therapy's risk benefit ratio resulting in morbidity and treatment discontinuation. Still, many AI adverse effects remain untreated given that they are unrecognized by conservative methods (e.g., proxy ratings). The ability of complementary patient-reported outcomes (PROs) to provide a more comprehensive assessment of side-effects is to be explored. A cross-sectional study sample of 280 postmenopausal, early stage breast cancer patients was subjected to a comprehensive PRO assessment (FACT B/+ES) at their after-care appointment. Prevalence and severity of patient reported physical side-effects and psychosocial burden related to adjuvant AI therapy were compared with prevalences derived from pivotal phase IV trials (ATAC 2005, BIG1-98 2005). Across all symptom categories, highest prevalence rates were found for joint pain (59.6%), hot flushes (52%), lost interest in sexual intercourse (51.4%), and lack of energy (40.3%). Overall, PROs resulted in significantly higher prevalence rates as compared to physician ratings for all symptoms published in pivotal clinical trials except vaginal bleeding and nausea. The treatment duration exerted no significant impact on symptom frequency (P > 0.05). Established prevalence rates of endocrine treatment-related toxicity seem to be underestimated. The incorporation of PRO data should be mandatory or at least highly recommended in clinical treatment planning to arrive at a more accurate assessment of a patient's actual symptom burden enabling improved individualized management of side-effects and mediating the preservation of treatment adherence. PMID- 21311969 TI - Unfavourable pattern of metastases in M0 breast cancer patients during 1978-2008: a population-based analysis of the Munich Cancer Registry. AB - Little is known about time trends in metastases in the patients treated in routine health care facilities without metastases at diagnosis (M0) and about survival after these metastases. Data on 33,771 M0 patients with primary breast cancer diagnosed between 1978 and 2003 were obtained from the Munich Cancer Registry. Survival analyses were restricted to the patients with metastases within 5 years of the initial diagnosis. The incident number of the patients approximately doubled each period and 5-year overall survival increased from 77% in the first to 82% percent in the last period. 5490 (16%) M0 patients developed metastases within 5 years after the initial diagnosis. The hazard of developing metastases was lowest in the most recent period compared to the first period (HR = 0.50, P < 0.001). The hazard of dying after metastases was equal for patients diagnosed between 1978-1984 and 1995-2003 (HR 1.08, P = 0.3). The percentage of the patients that developed bone metastases decreased each time period, but the percentage primary liver and CNS metastases increased. Exclusion of site of metastases in the multivariate analysis led to a 20% (P = 0.02) higher hazard of dying following metastases in the last versus the first period. In the period 1978-2008, unfavourable changes in the pattern of metastases were exhibited and no improvement was observed in survival of the patients after occurrence of metastases. An explanation might be the increased use of adjuvant systemic treatment, which has less effect on the highly lethal liver and CNS metastases than on bone metastases. The increased use also appeared to contribute to the overall prevention of metastases in breast cancer and therefore to improve overall survival. PMID- 21311970 TI - Lysozyme transgenic goats' milk positively impacts intestinal cytokine expression and morphology. AB - In addition to its well-recognized antimicrobial properties, lysozyme can also modulate the inflammatory response. This ability may be particularly important in the gastrointestinal tract where inappropriate inflammatory reactions can damage the intestinal epithelium, leading to significant health problems. The consumption of milk from transgenic goats producing human lysozyme (hLZ) in their milk therefore has the potential to positively impact intestinal health. In order to investigate the effect of hLZ-containing milk on the inflammatory response, young pigs were fed pasteurized milk from hLZ or non-transgenic control goats and quantitative real-time PCR was performed to assess local expression of TNF-alpha, IL-8, and TGF-beta1 in the small intestine. Histological changes were also investigated, specifically looking at villi width, length, crypt depth, and lamina propria thickness along with cell counts for intraepithelial lymphocytes and goblet cells. Significantly higher expression of anti-inflammatory cytokine TGF-beta1 was seen in the ileum of pigs fed pasteurized milk containing hLZ (P = 0.0478), along with an increase in intraepithelial lymphocytes (P = 0.0255), and decrease in lamina propria thickness in the duodenum (P = 0.0001). Based on these results we conclude that consuming pasteurized milk containing hLZ does not induce an inflammatory response and improves the health of the small intestine in pigs. PMID- 21311971 TI - Candida uthaithanina sp. nov., an anamorphic yeast species in Nakaseomyces clade isolated in Thailand. AB - Three yeast stains were isolated from two unknown fruits (strains DD2-22-1(T) and SK44) and moss (strain ST-449) in Thailand. Analysis of the D1/D2 domain of the large subunit (LSU) rRNA gene sequences of the three strains revealed that they belonged to the same species. In terms of pairwise sequence similarity, Candida cf. glabrata UWO(PS) 98-110.4 and Candida nivariensis were the closest undescribed and recognized taxa, but the levels of nucleotide substitutions were 1.7-1.9% and 2.0-2.2%, respectively. The levels of nucleotide substitutions were sufficient to justify the description of a separate species of Candida. In the phylogenetic tree based on the D1/D2 domain of the LSU rRNA gene the three strains were placed in a separate branch in the Nakaseomyces clade with C. cf. glabrata UWO(PS)98-110.4, C. nivariensis, Candida glabrata, Candida bracarensis, Candida kungkrabaensis and Nakaseomyces delphensis. Phenotypic characteristics of the three strains were similar which included proliferation by multilateral budding, absence of ascospores, arthrospores or ballistospores; negative for Diazonium blue B and urease tests. The major ubiquinone was Q-6. On the basis of the above findings, the three strains were assigned to a single novel species of Candida, for which the name Candida uthaithanina sp. nov is proposed. The type strain is DD2-22-1(T) (= BCC 29899(T) = NBRC 104876(T) = CBS 10932(T)). PMID- 21311972 TI - Religion and mental health during incarceration: a systematic literature review. AB - Religion and spirituality (RS) as a coping resource for facing stressful life events is encountered with increasing frequency in the medical literature. RS is associated with more favourable outcomes among people suffering from mental disorders. Detention is a stressful situation and the prevalence of mental disorders in places of detention is increased compared with the community. This literature review examined the association between RS and the mental health of detainees. PubMed, PsycINFO, Web of Science and the Internet were systematically searched from inception of each data base to August 1st 2010. Peer reviewed articles that reported primary empirical data about the impact of spirituality on the mental health and behaviour of detained persons were selected. Qualitative studies are also discussed. Twelve empirical studies including a total of 4,823 individuals met our inclusion criteria. RS is associated with lower frequency and severity of depressive episodes. The strongest reported effect of RS on prison life is a reduction of incidents and disciplinary sanctions. Prospective targeted studies are needed in order verify the hypothesis that RS reduces suicide among detainees. PMID- 21311973 TI - Stability of intimate partner violence by men across 12 years in young adulthood: effects of relationship transitions. AB - The present study examined the stability of young men's intimate partner violence (IPV) over a 12-year period as a function of relationship continuity or discontinuity. Multiwave measures of IPV (physical and psychological aggression) were obtained from 184 men at risk for delinquency and their women partners. The effects of relationship continuity versus transitions on change in IPV were examined using multilevel analyses. In general, men's IPV decreased over time. Men's physical aggression in their early 20s predicted levels of physical aggression about 7 years later, and men's psychological aggression in their early 20s predicted levels of psychological aggression about 10-12 years later. As hypothesized, higher stability in IPV was found for men who stayed with the same partners, whereas men experiencing relationship transitions showed greater change. The IPV of new partners was linked to the changes in men's IPV that occurred with repartnering. There was less change in men's IPV over time as men changed partners less frequently. PMID- 21311974 TI - Inhibition of photosynthetic oxygen evolution and electron transfer from the quinone acceptor QA- to QB by iron deficiency. AB - The effect of iron deficiency on photosynthetic electron transport in Photosystem II (PS II) was studied in leaves and thylakoid membranes of lettuce (Lactuca sativa, Romaine variety) plants. PS II electron transport was characterized by oxygen evolution and chlorophyll fluorescence parameters. Iron deficiency in the culture medium was shown to affect water oxidation and the advancement of the S states. A decrease of maximal quantum yield of PS II and an increase of fluorescence intensity at step J and I of OJIP kinetics were also observed. Thermoluminescence measurements revealed that charge recombination between the quinone acceptor of PS II, Q(B), and the S(2) state of the Mn-cluster was strongly perturbed. Also the dark decay of Chl fluorescence after a single turnover white flash was greatly retarded indicating a slower rate of Q(A)(-) reoxidation. PMID- 21311975 TI - XZH-5 inhibits STAT3 phosphorylation and causes apoptosis in human hepatocellular carcinoma cells. AB - Growing evidence has demonstrated that signal transducer and activator of transcription 3 (STAT3), which is constitutively activated in patients with hepatocellular carcinoma (HCC), plays an important role in HCC development, progression, and prognosis. Interleukin-6 (IL-6) is a multifunctional inflammatory cytokine, which may induce STAT3 activation in a variety of human cancers. In this study, we demonstrated that blocking STAT3 phosphorylation with STAT3 small molecule inhibitors SD-1029 and Stattic caused apoptosis in HCC cells. Then we characterized the inhibitory effects of a novel small molecule XZH 5 on STAT3 phosphorylation in HCC cell lines. XZH-5 reduced constitutive STAT3 phosphorylation at Tyr705 and the expression of STAT3 downstream genes. The inhibition of STAT3 in HCC cells resulted in the induction of apoptosis and reduction of colony forming ability. In addition, XZH-5 also inhibited IL-6 induced STAT3 phosphorylation, nuclear translocation and STAT3 DNA binding activity. In contrast, it had no effect on IFN-gamma-induced STAT1 phosphorylation, indicating the more selective effects on STAT3. These results suggested that XZH-5 may serve as a lead compound for further development of STAT3 specific small molecule inhibitors for HCC therapy. PMID- 21311976 TI - Apoptotic microtubule network organization and maintenance depend on high cellular ATP levels and energized mitochondria. AB - Microtubule cytoskeleton is reformed during apoptosis, forming a cortical structure beneath plasma membrane, which plays an important role in preserving cell morphology and plasma membrane integrity. However, the maintenance of the apoptotic microtubule network (AMN) during apoptosis is not understood. In the present study, we examined apoptosis induced by camptothecin (CPT), a topoisomerase I inhibitor, in human H460 and porcine LLCPK-1alpha cells. We demonstrate that AMN was organized in apoptotic cells with high ATP levels and hyperpolarized mitochondria and, on the contrary, was dismantled in apoptotic cells with low ATP levels and mitochondrial depolarization. AMN disorganization after mitochondrial depolarization was associated with increased plasma membrane permeability assessed by enhancing LDH release and increased intracellular calcium levels. Living cell imaging monitoring of both, microtubule dynamics and mitochondrial membrane potential, showed that AMN persists during apoptosis coinciding with cycles of mitochondrial hyperpolarization. Eventually, AMN was disorganized when mitochondria suffered a large depolarization and cell underwent secondary necrosis. AMN stabilization by taxol prevented LDH release and calcium influx even though mitochondria were depolarized, suggesting that AMN is essential for plasma membrane integrity. Furthermore, high ATP levels and mitochondria polarization collapse after oligomycin treatment in apoptotic cells suggest that ATP synthase works in "reverse" mode during apoptosis. These data provide new explanations for the role of AMN and mitochondria during apoptosis. PMID- 21311977 TI - Identification of alkaptonuria in the general population: a United Kingdom experience describing the challenges, possible solutions and persistent barriers. AB - Progress in research into rare diseases is challenging. This paper discusses strategies to identify individuals with the rare genetic disease alkaptonuria (AKU) within the general population. Strategies used included a questionnaire survey of general practitioners, a dedicated website and patient network contact, targeted family screening and medical conference targeting. Primary care physicians of the UK were targeted by a postal survey that involved mailing 11,151 UK GPs; the response rate was 18.2%. We have identified 75 patients in the UK with AKU by the following means: postal survey (23), targeted family screening (11), patient networks and the website (41). Targeting medical conferences (AKU, rare diseases, rheumatology, clinical biochemistry, orthopaedics, general practitioners) did not lead to new identification in the UK but helped identify overseas cases. We are now aware of 626 patients worldwide including newly identified non-UK people with AKU in the following areas: Slovakia (208), the rest of Europe (including Turkey) (79), North America (including USA and Canada) (110), and the rest of the world (154). A mechanism for identifying individuals with AKU in the general population-not just in the UK but worldwide-has been established. Knowledge of patients with AKU, both in the UK and outside, is often confined to establishing their location in a particular GP practice or association with a particular medical professional. Mere identification, however, does not always lead to full engagement for epidemiological research purposes or targeting treatment since further barriers exist. PMID- 21311979 TI - Autism as a natural human variation: reflections on the claims of the neurodiversity movement. AB - Neurodiversity has remained a controversial concept over the last decade. In its broadest sense the concept of neurodiversity regards atypical neurological development as a normal human difference. The neurodiversity claim contains at least two different aspects. The first aspect is that autism, among other neurological conditions, is first and foremost a natural variation. The other aspect is about conferring rights and in particular value to the neurodiversity condition, demanding recognition and acceptance. Autism can be seen as a natural variation on par with for example homosexuality. The broad version of the neurodiversity claim, covering low-functioning as well as high-functioning autism, is problematic. Only a narrow conception of neurodiversity, referring exclusively to high-functioning autists, is reasonable. We will discuss the effects of DSM categorization and the medical model for high functioning autists. After a discussion of autism as a culture we will analyze various possible strategies for the neurodiversity movement to claim extra resources for autists as members of an underprivileged culture without being labelled disabled or as having a disorder. We will discuss their vulnerable status as a group and what obligation that confers on the majority of neurotypicals. PMID- 21311980 TI - Primary aldosteronism: A contrarian view. AB - This paper provides evidence that primary aldosteronism is likely much less common than is believed by the other authors of this collection. The basis for this contrarian view is simple: there is no way to know the true prevalence of PA because of the uncertain validity of all of the diagnostic procedures used to find and characterize this disease. Moreover, even if these uncertainties are overcome, the eventual treatment of most who have PA can be provided without the need for extensive testing and expensive treatment. PMID- 21311981 TI - Childbearing after hyperthermic intraperitoneal chemotherapy: results from an international survey. AB - BACKGROUND: Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) can improve survival in selected patients with primary or secondary peritoneal malignancies. With the opportunity for long-term survival, questions about the impact of those procedures in fertility in women of childbearing age can be raised. MATERIALS AND METHODS: An international survey was performed among all teams participating in the International Peritoneal Surface Malignancy Group in order to collect data about pregnancies and their outcome in women having undergone previous CRS with adjuvant HIPEC. RESULTS: There were 7 pregnancies reported after CRS and HIPEC in women treated for peritoneal malignancies. All these women conceived spontaneously, most of them within 2 years after the procedure. They delivered most often by vaginal way after an uneventful pregnancy. Their newborns were healthy, except 1 case of congenital diaphragmatic hernia requiring emergent surgery. There were 2 additional uneventful pregnancies reported after the diagnosis of pseudomyxoma peritonei and before CRS and HIPEC, with the support of the medical team. Another woman having undergone oocytes retrieval and embryo cryopreservation prior to the surgery was mother of twins after the procedure via a surrogate mother. CONCLUSION: Childbearing after cytoreductive surgery and heated intraperitoneal chemotherapy is possible in women conserving their genital organs after the procedure. The question of fertility should be considered and discussed in women in reproductive age prior to cytoreductive surgery and heated intraperitoneal chemotherapy. Different options could be offered in this setting. Multidisciplinary decision making involving surgical oncologists and fertility specialists is important. PMID- 21311982 TI - Success and failure of primary medical, nonoperative management in breast cancer. AB - BACKGROUND: Nonoperative but systemic therapy as first-line management is offered to some patients with breast cancer (BC) who have assumed limited life expectancy, such as older women or those who have distant metastases at initial presentation. We evaluated rates of and predicting factors for success and failure of this therapy approach. METHODS: Seventy-five patients who were initially treated only systemically, and cases in which local control while avoiding surgery was the intended long-term therapy goal were analyzed. Additionally, two stage-dependent subgroups were distinguished (A: stage I-III, n = 31; B: stage IV, n = 44). Failure of therapy was defined as when secondary surgery had to be performed due to locoregional progression or in case of no surgery when severe locoregional clinical signs/symptoms were observed during the further course. RESULTS: Patients in group A were older than those in group B (81 vs. 67.5 years; P < 0.001) and showed an increased survival (5-year rates: 40.2% vs. 24.3%). In 24 patients of the entire cohort (32%), secondary surgery had to be performed; surgery was performed more often in group A (58.1% vs. 13.6%). In the cases in which no surgery was performed (n = 51), 11 women (21.6%) suffered from severe locoregional symptoms in the palliative situation (A: n = 1; B: n = 10). Although the presence of stage IV was a significant factor for therapy success (odds ratio (OR), 2.59; 95% confidence interval (CI), 0.95-7.05; P = 0.039), skin involvement was associated with failure of therapy (OR, 3.57; 95% CI, 1.16-11.11; P = 0.031). CONCLUSIONS: Nonoperative treatment may be offered to selected patients with BC who have assumed limited life expectancy. These women must be openly informed that this approach is not successful in nearly half of the cases. PMID- 21311983 TI - Microsurgical reconstruction of the oral cavity with free flaps from the anterolateral thigh and the radial forearm: a comparison of perioperative data from 161 cases. AB - BACKGROUND: Free flaps are commonly used for reconstruction of extensive tumor resection defects in the oral cavity. The radial forearm free flap (RFFF) is the most frequent choice. However, a major problem of RFFF is a limitation in its size. The anterolateral thigh free flap (ALTFF) has become popular as an alternative donor site in maxillofacial surgery. We have compared patient data after reconstructions of the oral cavity using the RFFF or ALTFF. MATERIALS AND METHODS: Perioperative data of 161 oral cancer patients with ALTFF (45) or RFFF (116) reconstructions were reviewed and statistically analyzed for the following characteristics: sex, histology, primary tumor localization, defect type, American Society of Anesthesiology score, success rates, revisions, wound healing disorders, fistula rates, type of reconstruction, prolonged stay in an intensive care unit (ICU) and in hospital, donor site, flap size, length of operation, and number of follow-up visits. RESULTS: Flap success was 97.8% (44 of 45) in the ALTFF group and 97.4% (113 of 116) for RFFF. The mean size was higher in ALTFF than in RFFF (110 vs. 29 cm(2); P < 0.001). ALTFF needed less postoperative care and developed fewer wound healing disorders (P = 0.005 and P = 0.035). Operative time was significantly shorter in RFFF reconstructions (P = 0.020). Intraoperative arterial spasm was the most significant complication in ALTF and postoperative venous thrombosis in RFFF. CONCLUSIONS: ALTFF has distinct advantages over RFFF with respect to intraoral reconstruction. However, the RFFF remains as a very reliable flap because of the minimal variability in its anatomy. PMID- 21311984 TI - A review of the oncologic and surgical management of breast cancer in the augmented breast: diagnostic, surgical and surveillance challenges. AB - BACKGROUND: The challenges of managing breast cancer in women with augmented breasts include screening, diagnosis, oncologic and revisional surgery, and surveillance. In addition, women with augmented breasts frequently have greater expectations of cosmetic outcomes. More breast clinicians will be affected by these challenges as augmentation grows in popularity and women with implants reach the age range in which they are at higher risk of developing breast cancer. In the United States, more than 2 million women have undergone augmentation, making this the second most commonly performed cosmetic procedure. With a lifetime risk of developing breast cancer of 1 in 8, it is projected that more than 50,000 women who undergo augmentation each year in the United States will develop breast cancer at some point in their lives. METHODS: This is a review of current practice based on an exhaustive literature search of PubMed, Google Scholar, and conference proceedings. A series of case studies is presented to illustrate mammographic changes and cosmetic outcomes in augmented breasts that have required treatment for breast cancer. RESULTS: An evidence-based summary of recommendations has been produced to guide breast surgeons in managing this particular group of patients. CONCLUSIONS: Management of breast cancer in previously augmented breasts presents a unique range of challenges. Patients can be reassured that the presence of an implant does not increase the risk of breast cancer developing or affect the prognosis if breast cancer does develop. Clinical judgement is made balancing surgical and oncologic principles to provide the best cosmetic outcome. PMID- 21311985 TI - The impact of pretreatment assessment of oropharynx on interstitial soft palate radiofrequency surgery outcome--a multi-center study in patients with habitual snoring. AB - PURPOSE: Interstitial radiofrequency (RF) surgery of the soft palate (SP) is an established option in the treatment of habitual snoring. The decision-making process in the management of habitual snoring would benefit from diagnostic guidelines for oropharyngeal findings. Our aim was to investigate the correlation of systematic clinical pretreatment oropharyngeal examination scores with the efficacy of interstitial RF surgery of SP in a multi-center study. METHODS: Seventy-four patients (58 (78%) males and 16 (22%) females) with the median age of 42 years (range, 23-64), pre-treatment BMI of 25.6 kg/m(2) (range, 20.0-28.0), and preoperative AHI of three events/h (range, 0-10), received a single session of RF surgery. Thirty-two, five, 16, and 21 patients, respectively, were treated at the participating centers with a follow-up time of 13 weeks (range 12-16). The primary outcome measure was the efficacy of the treatment on snoring assessed by the patient and the bed partner with visual analog scale (VAS). RESULTS: The snoring showed a significant change demonstrating decreased snoring (VASpatpre 7 (range, 5-10) >=VASpatpost 4.25 (range, 1-8), P < 0.001, VASbedppre 8 (range, 4 10) >=VASbedppost 5 (range, 1-10), P < 0.001). Twenty-one patients (28.4%) experienced a successful treatment outcome. The increased grade of the uvula had a negative impact on the snoring results. CONCLUSION: Systematic clinical pretreatment oropharyngeal examination scores showed that the increasing grade of the uvula correlated significantly with the short-term post-treatment change in snoring. We suggest that patients with habitual snoring and uvula grade III should be initially treated with SP interstitial RF surgery and concomitant uvular surgery. A grading tool is proposed for oropharyngeal examination to help in the most appropriate treatment decision for each individual snoring patient. PMID- 21311987 TI - Male perpetration of teen dating violence: associations with neighborhood violence involvement, gender attitudes, and perceived peer and neighborhood norms. AB - This study aims to examine the link between male perpetration of teen dating violence (TDV) and neighborhood violence, as well as associations with gender attitudes and perceived peer and neighborhood norms related to violence among a sample of urban adolescent boys. Participants of this cross-sectional study (N = 275) were between the ages of 14 and 20 years and recruited from urban community health centers. Crude and adjusted logistic and linear regression models were used to examine TDV perpetration in relation to (a) neighborhood violence involvement, (b) perceptions of peer violence, (c) perceptions of neighborhood violence, and (d) gender attitudes. Slightly more than one in four (28%) boys reported at least one form of TDV perpetration; among boys who have ever had sex, almost half (45%) reported at least one form of TDV perpetration. In logistic and linear regression models adjusted for demographics, boys who reported TDV perpetration were more likely to report involvement in neighborhood violence (odds ratio (OR) = 3.1; 95% confidence interval (CI) = 1.7-5.5), beliefs that their friends have perpetrated TDV (OR = 2.7; 95%CI = 1.4-5.1), perceptions of violent activity within their neighborhood (OR = 3.0; 95%CI = 1.4-6.3), and greater support of traditional gender norms (beta = 3.2, p = 0.002). The findings suggest that efforts are needed to address boys' behaviors related to the perpetration of multiple forms of violence and require explicit efforts to reduce perceived norms of violence perpetration as well as problematic gender attitudes (e.g., increasing support for gender equity) across boys' life contexts. PMID- 21311988 TI - The cystic fibrosis neutrophil: a specialized yet potentially defective cell. AB - Cystic fibrosis (CF) is one of the commonest genetically inherited diseases in the world. It is characterized by recurrent respiratory tract infections eventually leading to respiratory failure. One of the hallmarks of this disease is a persistent and predominantly neutrophil driven inflammation. Neutrophils provide the first line of defence by killing and digesting phagocytosed bacteria and fungi, yet despite advances in our understanding of the molecular and cellular basis of CF, there remains a paradox of why recruited CF neutrophils fail to eradicate bacterial infections in the lung. This review describes mechanisms involved in neutrophil migration, microbial killing and apoptosis leading to inflammatory resolution. We discuss dysregulated neutrophil activity and consider genetic versus inflammatory neutrophil reprogramming in CF and ultimately pharmacological modulation of the CF neutrophil for therapeutic intervention. PMID- 21311990 TI - Chest multidetector computed tomography (MDCT) in patients with suspected acute pulmonary embolism: diagnostic yield and proportion of other clinically relevant findings. AB - PURPOSE: The authors evaluated the diagnostic yield of chest multidetector computed tomography (MDCT) in acute pulmonary embolism (PE) and the proportion of other clinically relevant findings in a large cohort of consecutive inpatients and patients referred from the emergency department (outpatients). MATERIALS AND METHODS: A total of 327 radiological reports of chest MDCT scans performed for suspected acute PE in 327 patients (158 men, 169 women; mean age 69 years, standard deviation 17.33 years; 233 inpatients, 94 outpatients) were retrospectively evaluated and classified into four categories: 1, positive for PE; 2, negative for PE but positive for other findings requiring specific and immediate intervention; 3, completely negative or positive for findings with a potential for significant morbidity requiring specific action on follow-up; 4, indeterminate. The distribution of findings by categories among the entire population and inpatients and outpatients separately was calculated (chi-square test, alpha=0.05). RESULTS: In the entire population, the diagnostic yield (i.e. proportion of cases classified as category 1) was 20.2% (66/327). Proportions of cases classified as categories 2, 3 and 4 were 27.5% (90/327), 44.3% (145/327) and 7.9% (26/327), respectively. No statistically significant difference was found between inpatients and outpatients (p=0.193). CONCLUSIONS: In patients with suspected acute PE, chest MDCT provides evidence of conditions requiring immediate and specific intervention (i.e. categories 1 and 2) in nearly 50% of cases, without differences between inpatients and outpatients. PMID- 21311989 TI - Application of a new pulmonary artery obstruction score in the prognostic evaluation of acute pulmonary embolism: comparison with clinical and haemodynamic parameters. AB - PURPOSE: Evaluation of computed tomography (CT) pulmonary angiography parameters revealing pulmonary embolism (PE) severity with particular attention to pulmonary obstruction indexes. Comparison with clinical and hemodynamic data and determination of predictive role in the development of chronic pulmonary heart disease. MATERIALS AND METHODS: This retrospective study analyzes 45 not consecutive patients from November 2007 to December 2008 with CT angiography diagnosis of acute PE. Included in the study are patients at the first documented episode of acute PE, with 6 month follow-up. Patients with severe pre-existent cardiopulmonary pathology or neoplastic diseases were excluded from the study. CT angiography evaluated right ventricular (RV)/left ventricular (LV) ratio, obstruction index according to Qanadli and Total Clot Burden (Ghanima score). PE indexes were compared with Troponin I measurement and echocardiography result; at last hospitalization and intensive care time were reported. RESULTS: A significant association was found between Ghanima and Qanadli score: the two indexes are equivalent in quantification of pulmonary arterial obstruction (p<0.001). Among others CT parameters, the new Ghanima score evidenced the best accuracy to detect patients evolving to chronic pulmonary heart disease (76%). This value is higher than that of echocardiography (71%). Troponins showed highest accuracy (82%). CONCLUSIONS: Ghanima score can be used in emergency CT angiography diagnosis as prognostic marker for a quickly risk stratification of pulmonary heart disease or death in patients with acute PE. This approach allows to obtain, with just one test, both the diagnosis and a rather accurate acute PE risk stratification. PMID- 21311991 TI - Recanalisation of thrombotic arterial occlusions with rotational thrombectomy. AB - PURPOSE: This study sought to assess the effectiveness of rotational thrombectomy (RT) with the Rotarex device in the treatment of thrombotic occlusions in native arteries, by-pass grafts, stents and stent-grafts. MATERIALS AND METHODS: Over the last 4 years, 22 patients (14 men and 8 women; mean age 62.6 years) affected by 5 acute (<14 days) thrombotic occlusions of the native arteries (4 plaque thromboses in the common iliac artery and one on a dissection intimal flap of the external iliac artery), 17 subacute and chronic thromboses affecting 4 femoro popliteal by-pass grafts, 10 stents (7 in the common iliac artery and 3 in the superficial femoral artery) and 3 stents-grafts were studied. Acute thromboses of native arteries were follow-up with colour-Doppler ultrasound (US) examination at 1 and 3 months. Subacute and chronic thrombotic occlusions were follow-up with colour-Doppler US examination at 1, 3, 6 and 12 months and yearly thereafter. RESULTS: Immediate technical success was achieved without any need for additional procedures in all acute occlusions of native arteries (4/22 cases). In the subacute and chronic occlusions, the procedure was completed with percutaneous transluminal angioplasty (PTA) (8/22), cutting balloon (6/22) and stenting (5/22). The complication rate was 4.8% (1 rupture of the external iliac artery repaired with a stent-graft). CONCLUSIONS: Arterial recanalisation with RT is the treatment of choice for acute thrombosis of healthy native arteries (4-7 mm); the treatment of thrombosis complicating calcified plaques or dissection intimal flaps may cause rupture of the arterial wall. In subacute and chronic occlusions of by-pass grafts, stents and stent grafts, additional procedures are necessary to achieve complete recanalisation. PMID- 21311992 TI - Misty mesentery: a pictorial review of multidetector-row CT findings. AB - The term "misty mesentery" indicates a pathological increase in mesenteric fat attenuation at computed tomography (CT). It is frequently observed on multidetector CT (MDCT) scans performed during daily clinical practice and may be caused by various pathological conditions, including oedema, inflammation, haemorrhage, neoplastic infiltration or sclerosing mesenteritis. In patients suffering from acute abdominal disease, misty mesentery may be considered a feature of the underlying disease. Otherwise, it may represent an incidental finding on MDCT performed for other reasons. This article describes the MDCT features of misty mesentery in different diseases in order to provide a rational approach to the differential diagnosis. PMID- 21311993 TI - Anatomical and functional evaluation of the myocardium in patients with acute coronary syndrome (NSTEMI) using MR imaging. AB - PURPOSE: The aim of our study was to evaluate the role of magnetic resonance (MR) imaging in identifying the location and extent of acute ischaemic injury to predict reversibility and distinguish areas of acute from chronic ischaemia in patients with acute coronary syndrome non- ST-elevation myocardial infarction (NSTEMI). MATERIALS AND METHODS: We evaluated 22 patients with NSTEMI acute coronary syndrome confirmed by coronary angiography (CA). We studied ventricular function indices and segmental changes in wall thickness and kinetics by cine-MR imaging sequences. Subsequently, we evaluated myocardial wall oedema with T2 weighted black-blood short-tau inversion recovery turbo spin echo (T2 BB-STIRTSE) sequences and identified areas of myocardial necrosis using T1-weighted turbo field-echo inversion recovery (T1 TFE-IR) sequences after contrast material administration. RESULTS: The results obtained with the single sequences were as follows: T2 BB-STIR-TSE: 96.8% sensitivity, 100% specificity, 99.7% negative predictive value, 99.7% positive predictive value; T1 TFE-IR: 45.8% sensitivity, 96.9% specificity, 92.3% negative predictive value, 90.3% positive predictive value; systolic wall thickening: 87.5% sensitivity, 91.8% specificity, 98.7% negative predictive value, 50% positive predictive value, 91.4% accuracy. CONCLUSIONS: Our study suggests that the sequences used for evaluating oedema and assessing viability allow for precise localisation and differentiation of areas of acute and chronic ischaemia by quantifying the possible mismatch between ischaemia and necrosis. PMID- 21311994 TI - Prospective evaluation of drug-induced lung toxicity with high-resolution CT and transbronchial biopsy. AB - PURPOSE: This study compared the results of high-resolution computed tomography (HRCT) and cytohistology after transbronchial biopsy in the evaluation of drug related interstitial lung disease (DR-ILD). MATERIALS AND METHODS: Patients with a clinical and imaging diagnosis of DR-ILD were prospectively included in a study protocol lasting 5 years. All patients were evaluated by bronchoscopy with transbronchial biopsy or bronchoalveolar lavage (BAL) following an HRCT examination that raised a suspicion of DR-ILD. Two radiologists (one senior and one junior), unaware of the diagnosis, reported the single HRCT findings, their distribution and predominant pattern. In the event of disagreement, the diagnosis was subsequently reached by consensus. Cytohistological examination was considered the gold standard in the diagnosis of DR-ILD. Patients who were unable to undergo the endoscopic procedure were excluded from the study. RESULTS: The study included 42 patients (25 men, 17 women; age range 20-84 years). Transbronchial biopsy was performed in all but four patients (one case of alveolar haemorrhage and three cases of lipoid pneumonia) in whom the diagnosis was established with BAL. Assessment of the HRCT images revealed the following patterns: noncardiogenic pulmonary oedema (n=13); organising pneumonia (OP) (n=9); hypersensitivity pneumonitis (HP) (n=2); alveolar haemorrhage (AH) (n=2); nonspecific interstitial pneumonia (NSIP) (n=5); lipoid pneumonia (LP) (n=1); sarcoid-like pattern (n=1). Cytohistological diagnosis revealed diffuse alveolar damage (DAD) in 11 patients, OP in seven, HP in three, AH in three, chronic interstitial pneumonia (CIP) in eight, LP in three and pseudosarcoidosis in one. Subdivision of the drugs into antineoplastic and nonantineoplastic agents showed that the most common patterns were CIP (n=6), DAD (n=2) and OP (n=2) in the antineoplastic group and DAD (n=9) and OP (n=5) in the nonantineoplastic group. Sensitivity and specificity of the radiological analysis was excellent, especially for patterns such as OP and DAD (sensitivity 0.86 and specificity 0.88 for OP; sensitivity 1 and specificity 0.93 for DAD). CONCLUSIONS: HRCT demonstrated excellent sensitivity and specificity. In cases in which its specificity was low, HRCT was nonetheless useful for biopsy planning and clinical radiological monitoring after discontinuation of the drug treatment. PMID- 21311995 TI - Imaging findings of sacroiliac joints in spondyloarthropathies and other rheumatic conditions. AB - PURPOSE: The authors sought to evaluate the role of the different imaging techniques in the study of sacroiliac joints in patients with spondyloarthropathies (SpA) and other rheumatic conditions and to assess potential pitfalls in the radiological diagnosis. MATERIALS AND METHODS: Forty three consecutive patients with sacroiliitis as the predominant symptom of a rheumatic disorder were retrospectively studied. Radiography, computed tomography (CT) and magnetic resonance (MR) imaging were performed. The following imaging findings were evaluated: bone marrow oedema, intra-articular effusion, synovial reaction, joint-space widening, bone sclerosis or hyperostosis, subchondral erosions and, in final stages, joint-space narrowing and ankylosis. All images were independently reviewed by two musculoskeletal radiologists. RESULTS: Radiography demonstrated bone sclerosis in 10 patients (23%), subchondral erosions in 15 (34%), jointspace widening in 8 (18%), joint-space narrowing in 17 (39%) and ankylosis in 3 (6%). CT examination showed sclerosis of the sacroiliac joint in 17 patients (41%), subchondral erosions in 21 (53%), joint-space widening in 22 (53%), joint-space narrowing in 18 (43%) and ankylosis in 7 (17%). At MR, we found bone marrow oedema in 25 patients (92%), intra-articular effusion in 26 (96%), synovial reaction in 21 (77%) and joint-space widening in 5 (18%). CONCLUSIONS: Radiological study of the sacroiliac joints in patients with different rheumatic disorders represents a problem of difficult diagnostic evaluation due to the complexity of the anatomical region and the variability of radiographic findings. The integrated use of conventional radiography, CT and MR imaging is suggested to avoid misdiagnosis. PMID- 21311996 TI - Benefits of 3D technique in guiding percutaneous retroperitoneal biopsies. AB - PURPOSE: This study aimed to assess the usefulness and advantages of multiplanar reformations (MPR) during multidetector-row computed tomography (MDCT)-guided percutaneous fine-needle aspiration biopsy (FNAB) and core biopsy of retroperitoneal lesions that are difficult to access with the guidance of ultrasound and axial CT alone owing to overlying bony structures, large vessels or abdominal organs. MATERIALS AND METHODS: MDCT-guided retroperitoneal FNAB and core biopsy was performed on 14 patients with suspected retroperitoneal neoplasm. We used MPR images (sagittal and coronal) obtained with a six-detector-row MDCT scanner and 20-22 gauge Chiba needles. RESULTS: Using MDCT with 3D MPR allowed biological samples to be obtained in all cases (ten cytological and four histological) and diagnostic samples in 11/14 cases (78.5%). Histological samples were deemed adequate for diagnostic assessment in all cases and cytological samples in 7/10 cases (70%). CONCLUSIONS: MPR images allowed sampling of retroperitoneal lesions until now considered unreachable with the guidance of axial MDCT alone. Compared with the conventional procedure, the use of MPR images does not increase the procedure time. PMID- 21311997 TI - Structuring survivorship care: discipline-specific clinician perspectives. AB - INTRODUCTION: Several models for survivorship care are prominent within the cancer literature; however, there is little empirical research that examines what oncology clinicians perceive to be the best approach to caring for cancer survivors, what services survivorship programs should include, and how prepared they feel to care for cancer survivors. METHODS: An IRB approved web-based survey of all clinical staff was conducted at a NCI designated comprehensive cancer center with a 49.8% response rate (N = 377). Data were summarized using frequencies and relative frequencies, and pairwise tests of statistical significance were utilized to evaluate differences between clinician type groups. RESULTS: Overall, the largest proportion of respondents preferred a disease specific survivorship model (37.6%). This preference was specifically observed in oncology physicians and nurses. When asked where specific survivorship services should be provided, respondents indicated a preference for services directly related to survivors' medical treatment (i.e. information about late effects) to be delivered in a disease-specific survivorship clinic, and ancillary services (i.e. nutrition and fertility counseling) to be housed in a centralized comprehensive survivorship clinic. Physicians felt that they have significantly more information, training, and resources to care for cancer survivors than did oncology nurses. DISCUSSION/CONCLUSION: These results indicate that oncology clinicians prefer a combination of survivorship care delivery models where continuing medical needs are met in disease-specific clinics, and comprehensive wellness services are offered in a centralized comprehensive survivorship clinic. Results also suggest that planning for survivorship initiatives should include additional resources, education, and training for clinical staff. IMPLICATIONS FOR CANCER SURVIVORS: These findings underscore the need for a universally accepted definition of cancer survivorship, and support a model for delivering care to cancer survivors that is a blend of the disease-specific and comprehensive survivorship programs. PMID- 21311998 TI - Genomic risk profiling: attitudes and use in personal and clinical care of primary care physicians who offer risk profiling. AB - BACKGROUND: Genomic risk profiling involves the analysis of genetic variations linked through statistical associations to a range of disease states. There is considerable controversy as to how, and even whether, to incorporate these tests into routine medical care. OBJECTIVE: To assess physician attitudes and uptake of genomic risk profiling among an 'early adopter' practice group. DESIGN: We surveyed members of MDVIP, a national group of primary care physicians (PCPs), currently offering genomic risk profiling as part of their practice. POPULATION: All physicians in the MDVIP network (N = 356) RESULTS: We obtained a 44% response rate. One third of respondents had ordered a test for themselves and 42% for a patient. The odds of having ordered personal testing were 10.51-fold higher for those who felt well-informed about genomic risk testing (p < 0.0001). Of those who had not ordered a test for themselves, 60% expressed concerns for patients regarding discrimination by life and long-term/disability insurers, 61% about test cost, and 62% about clinical utility. The odds of ordering testing for their patients was 8.29-fold higher among respondents who had ordered testing for themselves (p < 0.0001). Of those who had ordered testing for patients, concerns about insurance coverage (p = 0.014) and uncertain clinical utility (p = 0.034) were associated with a lower relative frequency of intention to order testing again in the future. CONCLUSIONS: Our findings demonstrate that respondent familiarity was a key predictor of physician ordering behavior and clinical utility was a primary concern for genomic risk profiling. Educational and interpretive support may enhance uptake of genomic risk profiling. PMID- 21311999 TI - Understanding social capital and HIV risk in rural African American communities. AB - BACKGROUND: African Americans (AA) and rural communities often suffer disproportionately from poorer health. Theory-guided research examining how individual- and community-level factors influence health behaviors and contribute to disparities is needed. OBJECTIVE: To understand how a social network model that captures the interplay between individual and community factors might inform community-based interventions to reduce HIV risk in rural AA communities. DESIGN: Qualitative study. SETTING AND PARTICIPANTS: Eleven focus groups with 38 AA 16-24 year olds, 42 adults over age 25, and 13 formerly incarcerated individuals held in community settings in two rural, predominantly AA counties in North Carolina. Thirty-seven semi-structured interviews with multiethnic key informants. APPROACH: Semi-structured interviews and focus groups with open-ended questions assessed a) perceptions of multi-level HIV risk determinants from a social network model (individual, interpersonal, social, economic, political and structural) identified through literature review and b) community needs and assets affecting local HIV rates. Qualitative data was analyzed using directive content analysis guided by a social network model. RESULTS: We identified four themes regarding the interaction between individuals and their communities that mediate HIV risk: interpersonal processes, community structural environment, social disorder, and civic engagement. Communities were characterized as having a high degree of cohesiveness, tension, and HIV-related stigma. The community structural environment-characterized by neighborhood poverty, lack of skilled jobs, segregation, political disenfranchisement and institutional racism-was felt to reduce the availability and accessibility of resources to combat HIV. Adults noted an inability to combat social problems due to social disorder, which fuels HIV risk behaviors. Civic engagement as a means of identifying community concerns and developing solutions is limited by churches' reluctance to address HIV related issues. CONCLUSION: To combat HIV-related stigma, physicians should follow recommendations for universal HIV testing. Besides asking about individual health behaviors, physicians should ask about the availability of support and local community resources. Physicians might consider tailoring their treatment recommendations based on available community resources. This strategy may potentially improve patient adherence and clinical outcomes. PMID- 21312000 TI - Authorship and responsibility in health sciences research: a review of procedures for fairly allocating authorship in multi-author studies. AB - While there has been significant discussion in the health sciences and ethics literatures about problems associated with publication practices (e.g., ghost- and gift-authorship, conflicts of interest), there has been relatively little practical guidance developed to help researchers determine how they should fairly allocate credit for multi-authored publications. Fair allocation of credit requires that participating authors be acknowledged for their contribution and responsibilities, but it is not obvious what contributions should warrant authorship, nor who should be responsible for the quality and content of the scientific research findings presented in a publication. In this paper, we review arguments presented in the ethics and health science literatures, and the policies or guidelines proposed by learned societies and journals, in order to explore the link between author contribution and responsibility in multi-author multidisciplinary health science publications. We then critically examine the various procedures used in the field to help researchers fairly allocate authorship. PMID- 21312001 TI - Pregnancy in women with Type 1 and Type 2 diabetes in Dublin. AB - INTRODUCTION: The Confidential Enquiry into Maternal and Child Health (CEMACH) reported outcomes of pregnancies in women with pre-gestational diabetes (PGDM) in the UK (n = 3,733). This study aimed to compare CEMACH outcomes with PGDM pregnancies in Dublin. METHODS: Retrospective chart review of all PGDM pregnancies. Comparison to CEMACH are shown in brackets. RESULTS: One hundred and ten PGDM women delivered in Dublin. Thirty (27%) had T2 diabetes (vs. 27%). Fifty nine (53%) women had a booking HbA1c less than 7% (vs. 66%). Nineteen women (17.3%) had a first trimester miscarriage (vs. 8.5%). Of the 91 remaining women, 71 (78%) women underwent induction of labour (vs. 38.9%). Fifty-four women (59.3%) were delivered by caesarean section (vs. 67.4%). Two infants (2.1%) were macrosomic (vs. 5.7%). There was one intrauterine death (0.1 vs. 0.6%) and no maternal deaths (vs. five). CONCLUSION: These results serve to underline the continued importance of multidisciplinary care for pregnant women with diabetes. PMID- 21312003 TI - Oxidative stress parameters of L929 cells cultured on plasma-modified PDLLA scaffolds. AB - Oxidative stress may produce high level of reactive oxygen species (ROS) following cell exposure to endogenous and exogenous factors. Recent experiments implicate oxidative stress as playing an essential role in cytotoxicity of many materials. The aim of this study was to measure intracellular malondialdehyde (MDA), advanced oxidation protein product (AOPP) levels, and superoxide dismutase (SOD) activities of L929 fibroblasts cultured on PDLLA, polyethylene glycol (PEG), or ethylenediamine (EDA) grafted PDLLA by plasma polymerization method. Cell proliferation on these scaffolds was studied by 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl tetrazolium bromide assay. The study showed that MDA, AOPP levels, and SOD activities in L929 fibroblast cells cultured on all scaffolds were significantly different compared to the control group and each other. The highest MDA (0.42 +/- 0.76 nmol/mg protein), AOPP (14.99 +/- 4.67 nmol/mg protein) levels, and SOD activities (7.49 +/- 3.74 U/mg protein) were observed in cells cultured on non-modified scaffolds; meanwhile, the most cell proliferation was obtained in EDA-modified scaffolds (MDA 0.15 +/- 0.14 nmol/mg protein, AOPP 13.12 +/- 3.86 nmol/mg protein, SOD 4.82 +/- 2.64 U/mg protein). According to our finding, EDA- or PEG-modified scaffolds are potentially useful as suitable biomaterials in tissue engineering. PMID- 21312002 TI - Prevalence, management and outcomes of traumatic brain injury patients admitted to an Irish intensive care unit. AB - BACKGROUND: Traumatic brain injury is one of the leading causes of death and disability among young people. However outcomes from traumatic brain injury can be improved by use of parameters such as intracranial pressure monitoring (ICP) to guide treatment, early surgical intervention and management of these patients in a neurosurgical centre. AIMS: To examine the incidence of traumatic brain injury, compliance with best practice guidelines and outcomes in patients admitted to an intensive care unit in a major teaching hospital in Ireland. METHODS: Retrospective chart review. RESULTS: Forty-six patients were admitted over a 3-year period, half of whom had GCS <8. Medical management was appropriate but only two patients were transferred to a neurosurgical centre and none received ICP monitoring. Overall mortality of 37% was higher than international norms. CONCLUSIONS: Irish patients with severe head injury do not currently receive care in accordance with international evidence-based guidelines. PMID- 21312004 TI - Economic evaluation of human papilloma virus vaccination in the European Union: a critical review. AB - The human papilloma virus (HPV) vaccine is a new and expensive vaccine potentially effective in the prevention of a cancer. We reviewed the economic evaluations (EEs) on the vaccine in the EU to assess their potential contribution to public decision-making in a fairly homogeneous setting where HPV vaccination has been widely adopted. A literature search on PubMed selected EEs on HPV vaccines in the EU for the period 2007-2010 using the terms "HPV vaccines" and "Costs and cost analysis." Fifteen articles were eventually selected. All studies were based on modelling techniques, either "cohort" or "dynamic transmission": three were cost utility, three cost-effectiveness, and the remainder included both. The ten studies explicitly assessing one of the two vaccines were all sponsored by their manufacturer, while the five studies unrelated to the vaccine type were funded by public agencies. Apart from two studies, utility estimates were always obtained from three US sources. Direct costs were always vaccination, diagnosis and treatment of related pathologies. Incremental cost-effectiveness ratio (ICER) results were less favourable when life years gained were valued rather than quality-adjusted life years, genital warts were excluded, and booster doses and extension of vaccination to men were included in the base-case analysis. All but one of the sponsored EEs recommend in favour of the vaccination strategy, which is dominant in one English study. The ICER results were very sensitive to discount rates, followed by duration of protection and vaccine price. At such an early stage, when the vaccines' efficacy have been demonstrated by well-designed studies, it is not possible (and not even reasonable) to wait for several years to measure their effectiveness; public decision-makers might benefit more from EEs designed to indicate sustainable prices using realistic estimates of crucial variables like coverage rates, rather than referring to a large number of assumptions in order to show acceptable cost-effectiveness. PMID- 21312005 TI - Molecular cloning and characterization of a membrane associated NAC family gene, SiNAC from foxtail millet [Setaria italica (L.) P. Beauv]. AB - The plant-specific NAC (NAM, ATAF, and CUC) transcription factors have diverse role in development and stress regulation. A transcript encoding NAC protein, termed SiNAC was identified from a salt stress subtractive cDNA library of S. italica seedling (Puranik et al., J Plant Physiol 168:280-287, 2011). This single/low copy gene containing four exons and four introns within the genomic sequence encoded a protein of 462 amino acids. Structural analysis revealed that highly divergent C terminus contains a transmembrane domain. The NAC domain consisted of a twisted antiparallel beta-sheet packing against N terminal alpha helix on one side and a shorter helix on the other side. The domain was predicted to homodimerize and control DNA-binding specificity. The physicochemical features of the SiNAC homodimer interface justified the dimeric form of the predicted model. A 1539 bp fragment upstream to the start codon of SiNAC gene was cloned and in silico analysis revealed several putative cis-acting regulatory elements within the promoter sequence. Transactivation analysis indicated that SiNAC activated expression of reporter gene and the activation domain lied at the C terminal. The SiNAC:GFP was detected in the nucleus and cytoplasm while SiNAC DeltaC(1-158):GFP was nuclear localized in onion epidermal cells. SiNAC transcripts mostly accumulated in young spikes and were strongly induced by dehydration, salinity, ethephon, and methyl jasmonate. These results suggest that SiNAC encodes a membrane associated NAC-domain protein that may function as a transcriptional activator in response to stress and developmental regulation in plants. PMID- 21312006 TI - A comparison of the two evidence-based drug therapies for chronic migraine. PMID- 21312007 TI - The Use of Interferon-gamma Release Assays for Tuberculosis Screening in International Travelers. AB - Tuberculosis (TB) infection is relatively frequent among travellers to high incidence-countries, especially in long-term travellers and those involved in health work. It is important to diagnose recent infection, both for the affected individual and to prevent further transmission. Based on published literature, we assess the value of interferon-gamma release assays (IGRAs) as a complement to or replacement of the tuberculin skin test (TST) for the diagnosis of latent TB infection in the setting of a travel clinic. A comparison of available IGRAs with the TST in terms of operating characteristics and practical considerations is presented. We conclude that IGRAs offer some practical advantages that may benefit certain well-defined patient groups of a travel clinic, but that current evidence is incomplete. We identify research questions to better define the role of IGRAs in these populations. PMID- 21312008 TI - A review of the psychobiology of dementia caregiving: a focus on resilience factors. AB - The recent aging trend in the United States has resulted in exponential growth in the number of informal dementia caregivers. Caring for a family member with dementia has been associated with negative health outcomes that are likely related to physiologic changes resulting from stress. However, caregiving is not always associated with health morbidity. In this review, we highlight resilience factors that appear to have a beneficial relationship with health outcomes. Specifically, we highlight 11 studies that examined the relationship of one of three broad resilience domains (personal mastery, self-efficacy, and coping style) to caregiver health outcomes. Our main findings were that higher levels of personal mastery and self-efficacy, and increased use of positive coping strategies appear to have a protective effect on various health outcomes in dementia caregivers. Continued research is warranted to help guide prospective directions for caregiver interventions focusing on increasing caregiver resilience and the corresponding impact on caregiver health. PMID- 21312009 TI - Power and pitfalls of the genome-wide association study approach to identify genes for Alzheimer's disease. AB - Until recently, the search for genes contributing to Alzheimer's disease (AD) had been slow and disappointing, with the notable exception of the APOE epsilon4 allele, which increases risk and reduces the age at onset of AD in a dose dependent fashion. Findings from genome-wide association studies (GWAS) made up of fewer than several thousand cases and controls each have not been replicated. Efforts of several consortia--each assembling much larger datasets with sufficient power to detect loci conferring small changes in AD risk--have resulted in robust associations with many novel genes involved in multiple biological pathways. Complex data mining strategies are being used to identify additional members of these pathways and gene-gene interactions contributing to AD risk. Guided by GWAS results, next-generation sequencing and functional studies are under way with the hope of helping us better understand AD pathology and providing new drug targets. PMID- 21312010 TI - Psychiatric diagnosis in adolescents with sickle cell disease: a preliminary report. AB - Sickle cell disease (SCD), the most common genetic hemoglobin disorder, affects more than 70,000 Americans, primarily those of African and Mediterranean descent. SCD, characterized by chronic hemolytic anemia; recurrent, episodic painful episodes; vaso-occlusive complications affecting multiple organ systems; and increased risk of infections, is associated with a shortened life span for affected individuals. However, recent medical advances have significantly increased survivability and quality of life for individuals with SCD. Despite these advances, adolescents with SCD continue to face many challenges of living with a chronic condition that requires lifelong medical management that may place them at risk of psychiatric symptoms and disorders. Studies focusing on children and adolescents with SCD suggest greater risks for psychosocial difficulties and depressive and anxiety symptoms. This article describes findings from a structured psychiatric interview administered to 40 adolescents and their parents. The rates of reported psychiatric diagnosis were significantly higher than those reported for the general population. Awareness of risks for psychiatric disorders in SCD could lead to increased identification and interventions that may improve medical and psychiatric outcomes. PMID- 21312011 TI - A patient presenting nasal septum perforation during bevacizumab-containing chemotherapy for advanced breast cancer. AB - Nasal septum perforation is a rare but described complication of the anti angiogenetic agent bevacizumab. This is the case of a 48-year-old female breast cancer patient, who developed a nasal septum perforation during treatment with paclitaxel and bevacizumab for advanced disease. After 2 cycles the patient developed nasal irritation and occasional epistaxis; after the 4th cycle with bevacizumab the symptoms worsened to include nasal congestion, major epistaxis and rhinorrhoea. Anterior rhinoscopy revealed a large perforation involving the antero-inferior portion of the cartilaginous nasal septum surrounded by necrotic mucosa. The upper septum and the columellar strut were intact. The patient denied use of cocaine or other intranasal irritants. Bevacizumab was discontinued and with only a topical intranasal vitamin application the symptoms improved. One month later anterior rhinoscopy showed that the lesion healed and normal mucosa surrounded the previous site of perforation. The patient continued successfully with other chemotherapy regimens (gemcitabine and then vinorelbine) until irreversible progressive disease led to her death in February 2010. Thus far 8 other cases of bevacizumab-related nasal septum perforation have been published: 5 patients with colorectal cancer, 2 patients with breast cancer and 1 with ovarian cancer. Nasal septum perforation is an emerging challenge with targeted therapies and in particular with antiangiogenetic or antivascular agents. A rapid diagnosis is important and hence we recommend that patients undergoing treatment with bevacizumab and presenting with nasal symptoms (epistaxis, crusting, rhinorrhoea, nasal congestion and local pain or irritation) should undergo anterior rhinoscopy immediately. PMID- 21312012 TI - Solution formulation development of a VEGF inhibitor for intravitreal injection. AB - PF-00337210 is a potent, selective small molecule inhibitor of VEGFRs and has been under consideration for the treatment of age-related macular degeneration. An ophthalmic solution formulation intended for intravitreal injection was developed. This formulation was designed to maximize drug properties such that the formulation would precipitate upon injection into the vitreous for sustained delivery. As a parenteral formulation with additional constraints dictated by this specialized delivery route, multiple features were balanced in order to develop a successful formulation. Some of these considerations included low dosing volumes (<=0.1 mL), a limited repertoire of safe excipients for intravitreal injection, and the unique physical chemical properties of the drug. The aqueous solubility as a function of pH was characterized, buffer stressing studies to select the minimal amount of buffer were conducted, and both chemical and physical stability studies were executed. The selected formulation consisted of an isotonic solution comprised of PF-00337210 free base in a citrate-buffered vehicle containing NaCl for tonicity. The highest strength for regulatory toxicology studies was 60 mg/mL. The selected formulation exhibited sufficient chemical stability upon storage with no precipitation, and acceptable potency and recovery through an intravitreal dosing syringe. Formulation performance was simulated by precipitation experiments using extracted vitreous humor. In simulated injection experiments, PF-00337210 solutions reproducibly precipitated upon introduction to the vitreous so that a depot was formed. To our knowledge, this is the first time that a nonpolymeric in situ-forming depot formulation has been developed for intravitreal delivery, with the active ingredient as the precipitating agent. PMID- 21312013 TI - Optimal techniques with the Diamondback 360 degrees System achieve effective results for the treatment of peripheral arterial disease. AB - The Diamondback 360(r) Orbital PAD System (DB360) is a novel orbital atherectomy system for the treatment of calcified lower extremity lesions associated with peripheral arterial disease (PAD). This percutaneous, endovascular system incorporates the use of centrifugal force and differential sanding to modify plaque morphologies. The mechanism of differential sanding discriminates between compliant arterial tissue and diseased fibro-calcific or calcific plaque. An eccentrically mounted diamond-coated crown orbits at high speeds and removes a thin layer of calcific plaque with each pass of the crown. The crown creates a more concentric, smooth vessel lumen with increased diameter, increased lesion compliance and improved blood flow while protecting the vessel media. As a result, the risk for post-procedure thrombus formation and potential for restenosis may be reduced. The risk of intra-procedural events (slow flow, hemolysis, spasm and pain) may be reduced due to the design of this orbital sanding system along with proper technique. Extensive benchtop, in vivo, and clinical testing has confirmed these results and is presented within this paper. In addition, guidelines for selecting the most appropriate crown size and type (solid versus classic) and step-by-step procedural technique and pharmacology information are presented. The DB360 System provides a safe, efficacious, and cost-effective endovascular method for PAD treatment. Careful understanding of procedural methods, use of pharmacological drugs, and understanding of device operation contributes to improved treatment success. PMID- 21312014 TI - Progressive arteriolar vasoconstriction and fatigue during tetanic contractions of rat skeletal muscle are inhibited by alpha-receptor blockade. AB - Voluntary muscle contractions activate sympathetic efferent pathways. Using a fatiguing electrical stimulation protocol designed specifically to enhance sympathetically-mediated vasoconstrictor tone, we explored the temporal profile and mechanistic bases of the evoked vasoconstrictor response and its role in muscle fatigue. Spinotrapezius muscles of Wistar rats were exteriorized and stimulated tetanically (100 Hz, 6-8 V, stimulus duration 700 ms) every 3 s for 2.5 min. The extent and time course of diameter changes in arterioles (1A and 2A) and venules (1V and 2V) were determined after each of 10 discrete sets of muscle stimulation at 5-min intervals. At first, to compare the effect of stimulation parameters in this preparation, stimulations were performed with rectangular pulses of either 0.2- or 4-ms pulse duration. As expected the 0.2-ms pulse stimulation did not affect arteriolar diameter or muscle fatigability. In contrast, during and following 4-ms pulse stimulations, there was a surprising arteriolar vasoconstriction rather than the expected vasodilation. Arteriolar (but not venular) vasoconstriction (reduced arteriolar diameter by 38.6 +/- 2.6% in the 10th set) increased progressively with muscle fatigue (to 29 +/- 12% of initial tension in the 10th set) for the 4-ms pulse condition. Superfusion with the selective alpha1-adrenergic receptor antagonist prazosin (1 MUM) and/or alpha2-adrenergic receptor antagonist rauwolscine (10 MUM) abolished both the arteriolar vasoconstriction and significantly reduced fatigue (i.e., % initial tension, alpha1: 46.8 +/- 10.3%; alpha2: 39.0 +/- 5.8%; alpha1 + alpha2: 48.7 +/- 16.3% in the 10th set; all P < 0.05 vs. control). We conclude that sequential bouts of contractions induce a progressively greater degree of alpha-adrenergic receptor-induced arteriolar (but not venular) vasoconstriction which contributes significantly to fatigue in this model. PMID- 21312015 TI - Laparoscopic adrenal-sparing surgery: personal experience, review on technical aspects. AB - Partial adrenalectomy is usually performed for the treatment of bilateral pheochromocytomas and in case of sporadic, monolateral tumors, to minimize the risk of adrenal failure, especially in younger patients. Due to the lack of consistent series, many issues such as correct surgical indications and technical aspects still need to be debated. From 2007 to 2010 we performed four unilateral partial adrenalectomies (3 aldosterone-producing adenomas and 1 cortisol producing adenoma), and three bilateral subtotal adrenalectomies, consisting in total adrenalectomy on one side and partial adrenalectomy on the contralateral gland (3 bilateral pheochromocytomas in MEN IIa). In case of single tumor, partial adrenalectomy was carried out without adrenal vein ligation and the results were similar to total adrenalectomy both in terms of surgical and functional outcome, with normalization of hormone levels and control of hypertension. Operating time and postoperative stay were not significantly different from unilateral total adrenalectomy. In case of bilateral subtotal adrenalectomy our results demonstrate effectiveness in terms of surgical outcome and control of hypertension, but one patient needed steroid replacement therapy due to post-operative adrenocortical failure. Care must be taken when giving indication to adrenal sparing surgery, because this procedure can be technically difficult, and due to the risk of recurrence, especially in case of bilateral tumors, it can affect both surgical and functional outcomes. PMID- 21312016 TI - Imagining the near and far future: the role of location familiarity. AB - Plausible personal events envisioned as occurring in the near future tend to be reported as more vivid than those set in the far future. Why is this? The present set of three experiments identified one's familiarity with the location in which the event is placed as critical in this regard. Specifically, Experiment 1 demonstrated that amongst a wide range of phenomenological characteristics, clarity of location appears to drive the overall difference in vividness between events imagined to take place in the near and the far future. Experiments 2 and 3 were designed to further elucidate this finding. Experiment 2 demonstrated that near future events are more likely than far future events to be imagined in familiar locations. Experiment 3 showed that future events set in familiar locations tend to be imagined with greater clarity than those set in unfamiliar locations. The results of all three experiments converge on the conclusion that the difference in vividness of events imagined as occurring in the near and far future is mediated by one's familiarity with the location in which the event is imagined to occur. PMID- 21312017 TI - Transitional probabilities and positional frequency phonotactics in a hierarchical model of speech segmentation. AB - The present study explored the influence of a new metrics of phonotactics on adults' use of transitional probabilities to segment artificial languages. We exposed French native adults to continuous streams of trisyllabic nonsense words. High-frequency words had either high or low congruence with French phonotactics, in the sense that their syllables had either high or low positional frequency in French trisyllabic words. At test, participants heard low-frequency words and part-words, which differed in their transitional probabilities (high for words, low for part-words) but were matched for frequency and phonotactic congruency. Participants' preference for words over part-words was found only in the high congruence languages. These results establish that subtle phonotactic manipulations can influence adults' use of transitional probabilities to segment speech and unambiguously demonstrate that this prior knowledge interferes directly with segmentation processes, in addition to affecting subsequent lexical decisions. Implications for a hierarchical theory of segmentation cues are discussed. PMID- 21312019 TI - [Genodermatoses]. PMID- 21312020 TI - [Multiple dark nodules on the trunk]. AB - A 61-year-old man with dark nodules on his trunk was referred by his internist because of concern about a malignant melanoma. Clinically the nodules were blue purple and had a maximum diameter of 5mm. The main dermoscopic features were red to blue lacunae, which were variously sized and smooth bordered. These typical findings led to certain diagnosis of multiple venous hemangiomas. No further investigation or treatment was required. PMID- 21312021 TI - Ia-like alloantigens in the chicken: Serologic characterization an ontogeny of cellular expression. AB - Alloantisera raised in highly inbred lines of chickens, 7(2) and 15I(5) , by reciprocal immunization with lymphocytes were shown by immunofluorescence to react with B cells, cells of the monocyte-macrophage series, and an unidentified population of mononuclear cells prevalent in the spleen and bone marrow. Variable immunogenicity of the 'Ia'(2) and 'Ia'(15) alloantigens was observed. The alloantigens detected by these sara could be redistributed on the B-cell surface independently of immunoglobulin determinants or previously recognized antigens encoded by the major histocompatibility complex (B locus), and were more resistant to proteolysis than slgM. Analysis of several inbred lines of chickens revealed an association between expression of these antigens and the B haplotype. Strains of the B(2) haplotype expressed the antigen detected by anti-7 2 and vice versa. These data suggest that the B-cell alloantigens detected are encoded by genes linked to the MHC and may be analogous to la antigens of mice and DR antigens of man. 'Ia' alleles were co dominantly expressed on lymphocytes of F(1) hybrids. During ontogeny 'a'(+) cells were first detected in the bursa at 10 days of incubation , 3 days before 'Ia'(+). IgM(+) cells could be detected. Both 'Ia'(+).IgM(+) and 'Ia'(+).IgM(-) populations of bursal cells increased in parallel until day 18, when plateau levels were reached. Development of 'Ia'(+).IgM(-) cells throughout the body was unaffected by bursectomy at hatching. Cell surface expression of 'Ia' antigens was apparently increased with B-Iymphocyte maturation and was detectable on most, but not all, mature plasma cells. PMID- 21312022 TI - [Current status of methotrexate]. PMID- 21312023 TI - [Radiological diagnosis of osteoporosis]. AB - Having at their disposal a wide range of imaging techniques, radiologists play a crucial role in the diagnostic evaluation of patients with osteoporosis. The radiological tests range from dual energy X-ray absorptiometry (DXA), which is the only reference method accepted by the WHO, to conventional radiographs for fracture characterization, to more recent techniques for analyzing trabecular structure, and the findings are decisive in initiating correct management of osteoporosis patients. This review provides an overview of established radiological techniques and an outline of new diagnostic approaches. PMID- 21312024 TI - [Facial edema as an earlier presenting sign of giant cell arteritis. Possible relationship with angioedema]. AB - Giant cell arteritis (GCA) is a chronic granulomatous vasculitis of unknown etiology occurring in the elderly. New-onset headache, scalp tenderness, jaw claudication, temporal artery abnormalities on physical examination, visual symptoms and associated polymyalgia rheumatica represent the most typical and frequent features of the disease. However, facial edema is being more commonly recognized as a presenting symptom that may herald the disease. We present a case with facial edema as initial symptom and discuss if this rare symptom of GCA is due to hereditary or acquired angioedema. PMID- 21312027 TI - Evolutionary toxicology: contaminant-induced genetic mutations in mosquitofish from Sumgayit, Azerbaijan. AB - This study builds on a long-term program that has shown Sumgayit, Azerbaijan to contain wetlands with high levels of a diversity of chemical contaminants. Previous contaminant and biomarker studies of turtles and frogs showed a correlation between somatic chromosomal damage and chemical contaminants at Sumgayit. The objective of this study was to determine if a recently arrived species (mosquitofish) has genetic impacts similar to native species (marsh frogs) thus confirming the pattern is not the result of historical events such as glacial cycles, but is associated with recent chemical contamination. Nucleotide sequences of the mtDNA control region of invasive mosquitofish (Gambusia holbrooki) from Sumgayit were compared to mosquitofish from pristine sites in Europe and Azerbaijan and to native North American populations. Persistent heteroplasmy for a hyper-mutable simple sequence repeat and low haplotype and nucleotide diversities were observed in all invasive populations. However, Sumgayit possessed four de novo haplotypes and heteroplasmic conditions. All of the observed variable nucleotide positions were within or adjacent to a cytosine mononucleotide repeat. This repeat was within a conserved secondary structure; the region likely undergoes expansion and contraction at a rate sufficient to prevent fixation of the common 1/3 heteroplasmy. Whereas the 1/3 heteroplasmy appeared coincident with the establishment of mosquitofish in Europe, other forms of heteroplasmy resulted from contaminant-induced de novo mutations in Sumgayit. We conclude that Sumgayit is a mutational hotspot caused by legacy contaminants from chemical factories from the era of the Soviet Union. PMID- 21312028 TI - Using chemical fractionation to evaluate the phytoextraction of cadmium by switchgrass from Cd-contaminated soils. AB - The purpose of this study is to evaluate the phytoextraction of cadmium (Cd) from contaminated soils by switchgrass (Panicum virgatum L.), which is a promising energy crop with high biomass. Two ecotypes of switchgrass cultivars, Alamo and Blackwell, were investigated in a pot experiment. Dry weight and plant Cd concentration of the switchgrass plants growing on Cd-spiked soils (0, 20, and 60 mg Cd kg(-1) soil) with chelating agent amendments (1 g kg(-1) citric acid [CA] and 0.1 g kg(-1) ethylene diaminetetraacetic acid [EDTA]) were measured to examine the phytotoxicity and accumulation of Cd in the switchgrass. Fractions of Cd (F1, exchangeable; F2, carbonate; F3, Fe-Mn oxide; F4, organic matter; F5, residual) for the soils sampled at the time of harvesting were also determined using chemically sequential extractions. In the results, the dry weight of the switchgrass decreased with increasing Cd, with a significant dry weight reduction when Cd exceeded 20 mg kg(-1). However, the high Cd spike of 60 mg kg(-1) was not lethal to Alamo and Blackwell, which suggests that switchgrass plants can tolerate Cd and grow in contaminated soils. Compared with the control, the CA and EDTA amendments had no adverse effect on the growth of switchgrass plants. With regard to Cd accumulation, higher plant Cd concentrations were frequently found after CA amendment in Alamo; however, the Cd concentrations of Blackwell plants may increase when amended with EDTA. On the basis of the fractionation of soil Cd, dry weight and plant Cd concentration could be expressed as a function of Cd fractionation to predict the phytoextraction of Cd. Thus, the fractionation of Cd is a useful approach for evaluating the phytoextraction of Cd by switchgrass in contaminated soils. According to the comparison of phytoextractions of Cd between Alamo and Blackwell, Alamo plants removed substantially more Cd from Cd-spiked soils than Blackwell. Therefore, Alamo is better suited for the phytoextraction of Cd from contaminated soils. PMID- 21312029 TI - Assessment of synthetic musk fragrances in seven wastewater treatment plants of Beijing, China. AB - Seven typical synthetic musks were measured in influents, effluents and sewage sludge from seven wastewater treatment plants of Beijing in three seasons. Galaxolide and tonalide were the dominant musks, and the levels were medium compared with those from other regions. Musk concentrations and galaxolide/tonalide ratios were low in warm seasons relative to cold seasons in both water and sludge samples. The removal efficiencies of galaxolide and tonalide ranged in <14.3%-98.0% and <18.5%-98.7%, respectively. The discharge of galaxolide and tonalide through effluents into environment were 1.8-685.6 g/d (mean: 70.1 g/d) and 1.6-195.3 g/d (mean: 22.9 g/d), respectively. PMID- 21312030 TI - The use of passerine feathers to evaluate heavy metal pollution in Central Portugal. AB - In 2003, two sampling strategies were applied in order to evaluate metal contamination in passerine bird feathers. One strategy included the use of nest boxes and nestling great tits in a forest habitat (MU). The other strategy focused on the use of mist nets to capture adult blackbirds, robins and blackcaps in a fragmented non-forested habitat (EST). There was a significantly higher concentration of mercury in great tits (1.09 +/- 0.40) sampled in MU and also in robins (3.44 +/- 0.91) and blackcaps (1.62 +/- 1.99) sampled in EST, in comparison to the reference site (0.66 +/- 0.68; 2.04 +/- 1.12; 0.32 +/- 0.43; respectively). Concerning interspecific differences, robins accumulated significantly more metals than blackbirds or blackcaps. PMID- 21312031 TI - The MEK inhibitor SL327 blocks acquisition but not expression of lithium-induced conditioned place aversion: a behavioral and immunohistochemical study. AB - RATIONALE: Recent evidence involves extracellular signal-regulated kinase (ERK) in positive motivational properties of drugs as determined by conditioned place preference but, to date, its role in conditioned place aversion (CPA) still awaits to be fully characterized. OBJECTIVES: The aim of this study was to assess whether activated ERK (pERK) plays a role in the acquisition and/or expression of lithium-induced CPA. METHODS: C57BL/6J mice were subjected to lithium (150 mg/kg) induced CPA. The role of pERK was determined by administering the mitogen activating extracellular kinase inhibitor, SL327, (a) 25 and 50 mg/kg, before each exposure to the lithium-associated compartment (acquisition), and (b) 25, 50, and 100 mg/kg, before post-conditioning test (expression). To assess whether ERK is activated by acute lithium and, in distinct experiments, during CPA expression, mice were sacrificed, 30 min after lithium, and immediately after post-conditioning test, respectively, for pERK immunohistochemistry. RESULTS: Lithium increased pERK-positive neurons in bed nucleus of stria termialis, in central and basolateral amygdala and elicited significant CPA. SL327 (50 mg/kg) significantly prevented its acquisition. In addition, the post-conditioning test of lithium-conditioned mice determined a significant increase of pERK-positive neurons in the dorsal striatum and SL327 (50 mg/kg), administered before post conditioning test, while failing at the doses of 25, 50, and 100 mg/kg, to affect lithium-induced CPA expression, completely prevented it. CONCLUSIONS: These results indicate that pERK is critical for acquisition, but not expression, of lithium-induced CPA and that its activation in the dorsal striatum, during expression, is not critical for retrieval of the aversive memory. PMID- 21312032 TI - The role of setting in the oral self-administration of alcohol in the rat. AB - RATIONALE: We have previously found that rats that were kept at all times in the self-administration (SA) chambers (resident group) self-administered more heroin than rats that were transferred to the SA chambers immediately before testing (Non-Resident group). Alcohol resembles heroin in its ability to produce, at recreational doses, mood elevation, euphoria, drowsiness, and sedation. Furthermore, alcohol presents some similarities with the mechanisms of action of heroin at the levels of the mesostriatal circuitry. Therefore, we predicted that, as for heroin, alcohol intake would be greater in the Resident than in the Non Resident group. MATERIALS AND METHODS: In Experiment 1, oral self-administration of ethanol and wine solutions (2.5%, 5%, and 10%, v/v) was assessed in Resident and Non-Resident rats using both one-bottle (three sessions) and two-bottle (seven sessions) tests. In addition, we also assessed the intake of water (Experiment 2) and of 0.04% saccharin-0.003% quinine solution (Experiment 3). RESULTS: During the one-bottle sessions, alcohol intake of Resident rats was up to two times that of Non-Resident rats. During the two-bottle sessions, Resident rats drank two times more 5% alcohol than water, whereas Non-Resident rats took equal amount of the two fluids. The average daily intake of pure ethanol for Resident rats given access to 5% solutions was 0.71 +/- 0.076 vs. 0.46 +/- 0.078 g/kg for Non-Resident rats. No group differences in the intake of water and of saccharin-quinine solution were found. CONCLUSION: The present report demonstrates at a preclinical level the importance of setting for alcohol self administration. PMID- 21312033 TI - Synthesis, conformational analysis and biological properties of a dicarba derivative of the antimicrobial peptide, brevinin-1BYa. AB - Brevinin-1BYa (FLPILASLAAKFGPKLFCLVTKKC), first isolated from skin secretions of the frog Rana boylii, displays broad-spectrum antimicrobial activity and potent haemolytic activity. This study investigates the effects on conformation and biological activity of replacement of the intramolecular disulphide bridge in the peptide by a non-reducible dicarba bond. Dicarba-brevinin-1BYa was prepared by microwave irradiation of [Agl(18),Agl(24)]-brevinin-1BYa (Agl = allylglycine) in the presence of a second generation Grubbs' catalyst. Circular dichroism spectroscopy in 50% trifluoroethanol-water indicated that the degree of alpha helicity of the dicarba derivative (22%) was less than that of brevinin-1BYa (27%) but comparable to that of the acyclic derivative [Ser(18),Ser(24)]-brevinin 1BYa (23%). Dicarba-brevinin-1BYa showed a two-fold increase in potency against reference strains of Escherichia coli, Staphylococcus aureus, and Candida albicans compared with the native peptide and displayed potent bactericidal activity against clinical isolates of methicillin-resistant S. aureus (MRSA) and multidrug-resistant Acinetobacter baumannii (MIC in the range 1-8 MUM). Compared with brevinin-1BYa and [Ser(18),Ser(24)]-brevinin-1BYa, the dicarba derivative was associated with increased cytotoxicity against human erythrocytes (2.5-fold), MDA-MB-231 breast carcinoma cells (1.3-fold) and HepG2 hepatoma-derived cells (1.5-fold). PMID- 21312034 TI - A kinked antimicrobial peptide from Bombina maxima. II. Behavior in phospholipid bilayers. AB - The preceding contribution by Toke et al. has studied the structure of the cationic antimicrobial peptide maximin-4 in detergent micelles and in organic solvent, revealing a different kink angle and side-chain interactions in the two different environments. Here, we have examined the same peptide in lipid bilayers using oriented circular dichroism (OCD) and solid-state (15)N nuclear magnetic resonance (NMR) in aligned samples. OCD showed that maximin-4 is helical and adopts an oblique alignment in the membrane, and lacks the characteristic realignment response that is often observed for amphipathic alpha-helical peptides at a peptide:lipid ratio between 1:100 and 1:20. Solid-state (15)N-NMR experiments suggest that maximin-4 also remains unaffected by lipid charge and temperature. Analyzing (15)N labels in positions Ala12, Ala13, and Leu14, an oblique tilt angle of the N-terminal helix of ~130 degrees relative to the membrane normal was found, in good agreement with the amphiphilic profile of this segment. An additional constraint at Ala22 in the C-terminal segment is found to be compatible with a continuous alpha-helix, but unfavorable side-chain interactions make this solution unlikely. Instead, a kink at Gly16 seems fully compatible with all known constraints and with the biophysical expectations in the membrane-bound state, given the liquid-state NMR structures. It thus seems that the flexible kink in maximin-4 allows the two helical segments to adjust to the local environment. The irregular amphiphilic profile and the resulting versatility in shape might explain why maximin-4 lacks the realignment response that has been characteristically observed for many related frog peptides forming straight amphipathic alpha-helices. PMID- 21312035 TI - Preoperative neutrophil-to-lymphocyte ratio (NLR) is associated with reduced disease-free survival following curative resection of pancreatic adenocarcinoma. AB - BACKGROUND: Serological proinflammatory markers such as C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) have been associated with reduced survival for many different types of cancer. This study determined the prognostic value of the preoperative value of these markers in patients with resectable pancreatic adenocarcinoma. METHODS: Consecutive patients who underwent pancreaticoduodenectomy for pancreatic ductal adenocarcinoma were entered into our database from 2001 to the present day. CRP, NLR, and PLR at the time of presentation were recorded as well as overall and disease-free survival. RESULTS: Seventy-four patients were identified. Overall median survival was 35.0 months and median disease-free survival was 27.0 months. Follow-up ranged from 1 to 125.8 months. Preoperative NLR was significantly greater in those patients who developed recurrence in the follow-up period (4.5 vs. 3.1). CRP and PLR were not found to differ significantly between the two groups. Kaplan-Meier survival analysis of patients with NLR > 5 demonstrated a disease-free survival of 12 months compared with 52 months for those patients with NLR < 5 (p < 0.001). CONCLUSION: Preoperative NLR offers important prognostic information regarding disease-free survival following curative resection of pancreatic ductal adenocarcinoma. PMID- 21312036 TI - Defining surgical role models and their influence on career choice. AB - BACKGROUND: Positive encounters with surgeons have previously been shown to influence perceptions of surgical careers. Despite this, negative perceptions persist. We investigated whether identifying role models in surgery influences career choice and defined the ideal qualities of a surgical role model as perceived by newly qualified doctors. METHODS: A 36-item questionnaire was distributed to newly qualified graduates from a large UK medical school. Results were analysed using GraphPad Prism 5.00. RESULTS: Questionnaires were returned by 208 of 320 graduates (65%). Median age was 24 years (range = 23-51); 63% female, 37% male; 71% standard undergraduate course, 28% graduate-entry course. Overall, 131 respondents (63%) felt they were able to identify a surgical role model; there were no statistically significant differences between gender or course type. There was a significant difference between identification of a surgical role model and interest in pursuing surgical careers (P = 0.0006), with 41% of those who identified a role model interested compared with 17% of those who did not. Overall, 564 key qualities for a surgical role model were suggested by respondents. These were grouped by theme, with common attributes including good teacher, enthusiastic, and approachable. CONCLUSIONS: Junior doctors were twice as likely to express interest in pursuing a surgical career if they identified a positive surgical role model. Changes in medical school demographics are occurring, with increasing proportions of female and graduate-entry doctors. These groups are less likely to choose a surgical career, so promoting interest in surgery will become increasingly important to maintain high-quality applicants. Defining and promoting perceptions of surgical role models to the wider surgical community may be one way of addressing this. PMID- 21312037 TI - Treatment outcome and prognosis of patients with lymph node recurrence of thoracic esophageal squamous cell carcinoma after curative resection. AB - BACKGROUND: This study aimed to assess treatment outcome and factors influencing survival after lymph node recurrence of thoracic esophageal squamous cell carcinoma (SCC) after curative resection. METHODS: A total of 207 patients who underwent curative resection of thoracic esophageal SCC between March 1999 and March 2009 were retrospectively analyzed. Of these, lymph node recurrence was observed in 45 (21.7%) patients. Twenty-nine patients received intensive treatment (radiation therapy, chemoradiotherapy, or lymphadenectomy) directed at recurrent nodes, 9 patients received chemotherapy, and 7 patients received best supportive care (BSC). Treatment outcome and prognostic factors of these patients were investigated. RESULTS: Patients who received intensive treatment had significantly higher survival rates after recurrence than those who received chemotherapy or BSC (P = 0.0049 and 0.0004, respectively). In univariate analysis of survival after recurrence, the number of recurrent nodes (a single node or multiple nodes), the region of recurrent nodes (limited to a single region or extended to multiple regions), and the presence of simultaneous organ recurrence (present or absent) were prognostic factors (P = 0.0004, 0.0017, and <0.0001, respectively). Multivariate analysis demonstrated that the region of recurrent nodes and simultaneous organ recurrence were independent prognostic factors (P = 0.0396 and 0.0006, respectively). CONCLUSIONS: Our findings suggest that the region of recurrent nodes (limited to a single region or extended to multiple regions) and simultaneous organ recurrence are factors influencing survival after lymph node recurrence of thoracic esophageal SCC after curative resection. PMID- 21312039 TI - Cardiac-specific overexpression of E3 ligase Nrdp1 increases ischemia and reperfusion-induced cardiac injury. AB - Cardiomyocyte death is a major event of myocardial infarction. Previously, we and others have shown that E3 ligase-mediated protein turnover plays a critical role in cardiac injury. In this study, we sought to determine the role of a newly identified E3 ligase, neuregulin receptor degradation protein-1 (Nrdp1), on cardiac ischemia/reperfusion (I/R) injury. I/R injury markedly upregulated Nrdp1 expression in heart tissue. To elucidate the role of Nrdp1 in I/R-induced cardiac injury, neonatal cardiomyocytes were infected with adenoviral constructs expressing wild-type, dominant-negative Nrdp1 genes. Increased Nrdp1 expression enhanced I/R-induced cardiomyocyte apoptosis and inflammation as compared with the green fluorescent protein (GFP) control; these effects were attenuated by overexpression of a dominant-negative Nrdp1 (C34S/H36Q). Furthermore, cardiac specific Nrdp1 overexpression in vivo in mouse significantly increased infarct size, the number of TUNEL-positive nuclei and inflammatory cells, as well as mortality, as compared with wild-type mice after I/R injury. The mechanisms underlying these effects were associated with the downregulation of an Nrdp1 substrate, ErbB3, accompanied by suppression of its downstream targets AKT, ERK1/2, and activation of p38 and JNK1/2. Together, these results provide evidence for an important role for Nrdp1 in regulating I/R-induced cardiac injury. Nrdp1 may constitute a new therapeutic target for ameliorating the I/R induced cardiac injury. PMID- 21312038 TI - Time domains of the hypoxic ventilatory response in ectothermic vertebrates. AB - Over a decade has passed since Powell et al. (Respir Physiol 112:123-134, 1998) described and defined the time domains of the hypoxic ventilatory response (HVR) in adult mammals. These time domains, however, have yet to receive much attention in other vertebrate groups. The initial, acute HVR of fish, amphibians and reptiles serves to minimize the imbalance between oxygen supply and demand. If the hypoxia is sustained, a suite of secondary adjustments occur giving rise to a more long-term balance (acclimatization) that allows the behaviors of normal life. These secondary responses can change over time as a function of the nature of the stimulus (the pattern and intensity of the hypoxic exposure). To add to the complexity of this process, hypoxia can also lead to metabolic suppression (the hypoxic metabolic response) and the magnitude of this is also time dependent. Unlike the original review of Powell et al. (Respir Physiol 112:123 134, 1998) that only considered the HVR in adult animals, we also consider relevant developmental time points where information is available. Finally, in amphibians and reptiles with incompletely divided hearts the magnitude of the ventilatory response will be modulated by hypoxia-induced changes in intra cardiac shunting that also improve the match between O(2) supply and demand, and these too change in a time-dependent fashion. While the current literature on this topic is reviewed here, it is noted that this area has received little attention. We attempt to redefine time domains in a more 'holistic' fashion that better accommodates research on ectotherms. If we are to distinguish between the genetic, developmental and environmental influences underlying the various ventilatory responses to hypoxia, however, we must design future experiments with time domains in mind. PMID- 21312040 TI - Sleep homeostasis in alcohol-dependent, depressed and healthy control men. AB - Visually scored and power spectral analyses (PSA) of polysomnography (PSG) recordings reveal abnormalities in alcohol dependence (AD) and major depressive disorder (MDD), including deficiencies in slow wave activity (SWA) during non rapid eye movement (NREM) sleep. SWA parameters reflect the integrity of the homeostatic sleep drive, which have not been compared in those with AD or MDD. Ten men with AD were compared with 10 men with MDD and 10 healthy controls (HCs), all aged 20-40 years. They maintained an 11 pm to 6 am sleep schedule for 5-7 days, followed by 3 consecutive nights of PSG in the laboratory: night 1 for adaptation/screening; night 2 for baseline recordings; and night 3 as the challenge night, delaying sleep until 2 am. SWA was quantified with PSA across 4 NREM periods. Men with AD generated the least SWA at baseline. In response to sleep delay, HC men showed the expected SWA enhancement and a sharper exponential decline across NREM periods. Both the MDD and the AD groups showed a significantly blunted SWA response to sleep delay. Men with MDD had the least SWA in the first NREM period (impaired accumulation of sleep drive), whereas men with AD had the slowest SWA decay rate (impaired dissipation of sleep drive). These results suggest that both SWA generation and its homeostatic regulation are impaired in men with either AD or MDD. Finding interventions that selectively improve these different components of sleep homeostasis should be a goal of treatment for AD and MDD. PMID- 21312041 TI - Overexpression of transcription factor ZmPTF1 improves low phosphate tolerance of maize by regulating carbon metabolism and root growth. AB - A bHLH (basic helix-loop-helix domain) transcription factor involved in tolerance to Pi starvation was cloned from Zea mays with an RT-PCR coupled RACE approach and named ZmPTF1. ZmPTF1 encoded a putative protein of 481 amino acids that had identity with OsPTF1 in basic region. Real-time RT-PCR revealed that ZmPTF1 was quickly and significantly up-regulated in the root under phosphate starvation conditions. Overexpression of ZmPTF1 in maize improved root development, enhanced biomass both in hydroponic cultures and sand pots, and the plants developed more tassel branches and larger kernels when they were grown in low phosphate soil. Compared with wild type, overexpressing ZmPTF1 altered the concentrations of soluble sugars in transgenic plants, in which soluble sugars levels were lower in the leaves and higher in the roots. Overexpression of ZmPTF1 enhanced the expression of fructose-1,6-bisphosphatase and sucrose phosphate synthase1 participated in sucrose synthesis in the leaves but decreased them in the root, and reduced the expression of genes involved in sucrose catabolism in the roots. The modifications on the physiology and root morphology of the plants enhanced low phosphate tolerance and increased the yield under low phosphate conditions. This research provides a useful gene for transgenic breeding of maize that is tolerant to phosphate deficiency and is helpful for exploring the relationship between sugar signaling and phosphate concentrations in cells. PMID- 21312042 TI - Plant response to stress meets dedifferentiation. AB - Plant response to various stress conditions often results in expression of common genes, known as stress-responsive/inducible genes. Accumulating data point to a common, yet elusive process underlying the response of plant cells to stress. Evidence derived from transcriptome profiling of shoot apical meristem stem cells, dedifferentiating protoplast cells as well as from senescing cells lends support to a model in which a common response of cells to certain biotic and abiotic stresses converges on cellular dedifferentiation whereby cells first acquire a stem cell-like state before assuming a new fate. PMID- 21312043 TI - Intense cold and mortality in Castile-La Mancha (Spain): study of mortality trigger thresholds from 1975 to 2003. AB - Studies on temperature-mortality time trends especially address heat, so that any contribution on the subject of cold is necessarily of interest. This study describes the modification of the lagged effects of cold on mortality in Castile La Mancha from 1975 to 2003, with the novelty of also approaching this aspect in terms of mortality trigger thresholds. Cross-correlation functions (CCFs) were thus established with 15 lags, after application of ARIMA models to the mortality data and minimum daily temperatures (from November to March), and the results for the periods 1975-1984, 1985-1994 and 1995-2003 were then compared. In addition, daily mortality residuals for the periods 1975-1989 and 1990-2003 were related to minimum temperatures grouped in 2 degrees C intervals, with a cold threshold temperature being obtained in cases where such residuals increased significantly (p < 0.05) with respect to the mean for the study period. A cold-related mortality trigger threshold of -3 degrees C was obtained for Ciudad Real for the period 1990-2003. The significant number of lags (p < 0.05) in the CCFs declined every 10 years in Toledo (5-2-0), Cuenca (4-2-0), Albacete (4-3-0) and Ciudad Real (3-2-1). This meant that, while the trend in cold-related mortality trigger thresholds in the region could not be ascertained, it was possible to establish a reduction in the lagged effects of cold on mortality, attributable to the improvement in socio-economic conditions over the study period. Evidence was shown of the effects of cold on mortality, a finding that renders the adoption of preventive measures advisable in any case where intense cold is forecast. PMID- 21312044 TI - Implementation of multivariate linear mixed-effects models in the analysis of indoor climate performance experiments. AB - The aim of the current study was to apply multivariate mixed-effects modeling to analyze experimental data on the relation between air quality and the performance of office work. The method estimates in one step the effect of the exposure on a multi-dimensional response variable, and yields important information on the correlation between the different dimensions of the response variable, which in this study was composed of both subjective perceptions and a two-dimensional performance task outcome. Such correlation is typically not included in the output from univariate analysis methods. Data originated from three different series of experiments investigating the effects of air quality on performance. The example analyses resulted in a significant and positive correlation between two performance tasks, indicating that the two tasks to some extent measured the same dimension of mental performance. The analysis seems superior to conventional univariate statistics and the information provided may be important for the design of performance experiments in general and for the conclusions that can be based on such studies. PMID- 21312045 TI - Effect of pioglitazone on cardiac sympathovagal modulation in patients with type 2 diabetes. AB - This study aims to examine the effect of pioglitazone on potential progression of autonomic damage in addition to changes in control of cardiovascular function in patients with type 2 diabetes (T2DM). Thirty patients with T2DM and 32 healthy subjects participated in the study. Sympathovagal activity, assessed by power spectral analysis (PSA) of R-R intervals variability, and blood pressure (BP) were studied during clinostatism and orthostatism in controls and patients. We have assessed blood pressure control by 24-hour monitoring of ambulatory blood pressure. Patients were treated with pioglitazone (30 mg/day) for 6 months, and then re-evaluated by PSA for heart rate variability (HRV). Reduced levels of HbA1c (P < 0.0001) and urinary albumin (P = 0.008) were observed in pioglitazone treated patients compared to untreated baseline levels. Arterial BP remained unchanged following pioglitazone treatment. T2DM patients had reduced HRV (low frequency power; LF; P < 0.0001 and LF/HF; LF/HF; P < 0.0001) at baseline (clinostatism) compared to controls. Baseline clinostatic differences between groups persisted after pioglitazone treatment and no effect of treatment on basal HRV variables was observed. In controls, HF decreased and LF and LF/HF ratio increased in the orthostatic position. A similar effect for HF was observed in patients, but LF and LF/HF did not increase. The normal difference between HF power in clinostatism versus orthostatism observed for controls (P < 0.0001) was restored in patients following pioglitazone treatment (P = 0.028). A significant decrease from lying to standing position in orthostatic LF-power (P < 0.0001) and LF/HF (P < 0.0001) was also observed between patients and controls. Although no differences in autonomic control of HRV were observed between controls and patients with T2DM, significant differences were observed in sympathovagal balance following either clinostatic or orthostatic challenge. These findings provide initial evidence of a potential additional benefit afforded by pioglitazone for the improvement of cardiac sympathovagal balance in T2DM. PMID- 21312046 TI - Application of artificial gel antibodies for investigating molecular polymorphisms of human pituitary growth hormone. AB - Artificial gel antibodies were used to investigate human growth hormone (GH) activity in preparations purified from human pituitary glands. A partially purified fraction containing differently sized structural variants of GH was processed to yield monomeric and dimeric forms suitable for synthesizing artificial polyacrylamide gel antibodies. These two types of GH antibodies were used for investigating GH activity in experiments using HPLC gel-permeation and ion-exchange chromatography. In the size-exclusion experiments, both hormone fractions eluted as homogeneous peaks, whereas the ion exchanger resolved the hormones into several active components. The GH monomer antibodies exhibited a much higher affinity for monomeric GH than for dimeric GH, and the GH dimer antibodies exhibited a much higher affinity for dimeric GH than for monomeric GH. It was concluded that these two sets of antibodies might be useful for discriminating between dimeric and monomeric GH in clinical samples. PMID- 21312047 TI - Changes in brain protein expression are linked to magnesium restriction-induced depression-like behavior. AB - There is evidence to suggest that low levels of magnesium (Mg) are associated with affective disorders, however, causality and central neurobiological mechanisms of this link are largely unproven. We have recently shown that mice fed a low Mg-containing diet (10% of daily requirement) display enhanced depression-like behavior sensitive to chronic antidepressant treatment. The aim of the present study was to utilize this model to gain insight into underlying mechanisms by quantifying amygdala/hypothalamus protein expression using gel based proteomics and correlating changes in protein expression with changes in depression-like behavior. Mice fed Mg-restricted diet displayed reduced brain Mg tissue levels and altered expression of four proteins, N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (DDAH1), manganese-superoxide dismutase (MnSOD), glutamate dehydrogenase 1 (GDH1) and voltage-dependent anion channel 1. The observed alterations in protein expression may indicate increased nitric oxide production, increased anti-oxidant response to increased oxidative stress and potential alteration in energy metabolism. Aberrant expressions of DDAH1, MnSOD and GDH1 were normalized by chronic paroxetine treatment which also normalized the enhanced depression-like behavior, strengthening the link between the changes in these proteins and depression-like behavior. Collectively, these findings provide first evidence of low magnesium-induced alteration in brain protein levels and biochemical pathways, contributing to central dysregulation in affective disorders. PMID- 21312048 TI - X-Linked adrenoleukodystrophy in a 7-year-old boy presenting with psychiatric symptoms. PMID- 21312049 TI - Strategies in landmark use by orangutans and human children. AB - Landmark use has been demonstrated in a variety of organisms, yet the manner in which landmarks are encoded and subsequently used appears to vary between and sometimes within species, even when faced with identical landmark arrays. In the present experiments, orangutans and human children were shown a square array of identical landmarks and were trained to locate a hidden goal in the centre of the array. In Experiments 1 and 2, the search space appeared to be discrete, with white gridlines dividing up the space, and in Experiments 3a and 3b, the search space was uniformly coloured, making it appear continuous. In all experiments, following training, subjects were given a single expansion test, to determine their landmark strategy use, based on peak search activity. The orangutans appeared to use absolute directional vectors from individual landmarks, with peak search activities on the inner corners of the square array, and they used this strategy persistently. In contrast, human children showed two landmark-based strategies, absolute directional vectors and a relational or "middle" strategy, with the majority of children starting their search in the middle region. Although some children, especially young children, persistently used one strategy like the orangutans, many changed strategies when the original one failed to yield the hidden goal. PMID- 21312050 TI - The REAL database reveals no significant risk of serious infection during treatment with a methotrexate dose of more than 8 mg/week in patients with rheumatoid arthritis. PMID- 21312051 TI - Vasopressin analogues and V1a receptor agonists in septic shock. AB - This article reviews the role of arginine-vasopressin and the vasopressin analogue terlipressin as potent alternative vasoconstrictors in the treatment of fluid and catecholamine-refractory septic shock. Terlipressin is the most selective, clinically available V1 receptor agonist, and may be more potent than arginine-vasopressin in restoring catecholamine refractory septic shock. Recent experimental and clinical studies on terlipressin, as well as the possible benefit of selective V1a receptor agonists, are discussed. PMID- 21312052 TI - Concepts of animal welfare in relation to positions in animal ethics. AB - When animal ethicists deal with welfare they seem to face a dilemma: On the one hand, they recognize the necessity of welfare concepts for their ethical approaches. On the other hand, many animal ethicists do not want to be considered reformist welfarists. Moreover, animal welfare scientists may feel pressed by moral demands for a fundamental change in our attitude towards animals. The analysis of this conflict from the perspective of animal ethics shows that animal welfare science and animal ethics highly depend on each other. Welfare concepts are indispensable in the whole field of animal ethics. Evidence for this can be found by analyzing the structure of theories of animal ethics and the different ways in which these theories employ welfare concepts. Furthermore, the background of values underneath every welfare theory is essential to pursue animal welfare science. Animal ethics can make important contributions to the clarification of underlying normative assumptions with regard to the value of the animal, with regard to ideas about what is valuable for the animal, and with regard to the actions that should follow from the results of animal welfare science. PMID- 21312053 TI - Oxidized phosphatidylcholine induces migration of bone marrow-derived mesenchymal stem cells through Kruppel-like factor 4-dependent mechanism. AB - Platelet-activating factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3 phosphorylcholine) and PAF-like oxidized phospholipids including 1-palmitoyl-2 oxovaleroyl-sn-glycero-3-phosphorylcholine (POVPC) are generated upon LDL oxidation. The aim of this study was to evaluate the question of whether POVPC can regulate migration of human bone marrow-derived stem cells (hBMSCs) and to characterize signaling mechanisms involved in the POVPC-induced cell migration. POVPC treatment resulted in dose- and time-dependent increase of hBMSCs migration. Treatment of cells with BN52021, a specific antagonist of PAF receptor, completely blocked cell migration induced by not only PAF but also POVPC. Silencing of endogenous PAF receptor expression using PAF receptor specific small interfering RNA resulted in significant attenuation of cell migration induced by PAF or POVPC. Both PAF and POVPC induced expression of Kruppel-like factor 4 (KLF4) in hBMSCs. POVPC- or PAF-induced cell migration was abrogated by small interfering RNA-mediated depletion of endogenous KLF4. These results suggest that PAF receptor plays a pivotal role in POVPC-induced migration of human BMSCs through PAF receptor-mediated expression of KLF4. PMID- 21312054 TI - A Drosophila model for the screening of bioavailable NADPH oxidase inhibitors and antioxidants. AB - NADPH oxidase is the major source of non-mitochondrial cellular reactive oxygen species (ROS), and also is reported to be a major cause of various diseases including atherosclerosis and hypertension. In order to screen a new curative reagent that can suppress NADPH oxidase activity, we developed a Drosophila melanogaster fly that would overexpress human Dual oxidase 2 (hDuox2), a member of the NADPH oxidase family, as a screening model. These flies (GMR-GAL4/UAS hDuox2) had a high generation of ROS in the posterior region of the eye discs along with an easily recognizable rough-eye phenotype, which is an ideal and convenient marker for further screening steps. Moreover, the hDuox2-induced rough eye phenotype can be rescued by feeding with a culture medium containing mulberry leaves (MLs), which reportedly have an antimetabolic effect. Some commercially available antioxidants such as quercetin-3-O-D-glucoside or quercetin-3-O-glucose 6''-acetate, or the naringin contained in MLs and other herbs, also have shown a similar suppressing effect on the rough-eye phenotype. Our results suggest that flavonoid glycoside is absorbed from the intestine and functions in the body of D. melanogaster as it does in mammalian models such as rats. Thus, the GMR GAL4/UAS-hDuox2 fly line is a promising model for the screening of novel drugs such as NADPH oxidase inhibitors and/or antioxidants. PMID- 21312055 TI - Characterization of apoptosis and proliferation in esophageal carcinoma EC109 cells following siRNA-induced down-regulation of TRAF6. AB - Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an activator of the NF-kappaB transcription factor. NF-kappaB is involved in a variety of inflammatory, anti-apoptotic, and gene regulatory pathways and was recently found to be over-expressed in esophageal cancer cells. Here we investigated the function of TRAF6 in the esophageal cancer cell line EC109. siRNA targeting TRAF6 was introduced into EC109 cells and TRAF6 mRNA and protein levels were subsequently examined via RT-PCR and western blotting. Rates of apoptosis and cell proliferation were also measured using flow cytometry, ethynyl deoxyuridine (EdU), and CCK-8 (Cell Counting Kit-8) assays. The real-time PCR array was applied to profile the expression of TRAF6 related genes. TRAF6-siRNA reduced TRAF6 mRNA and protein expressions. NF-kappaB p65 protein expression was decreased in TRAF6-targeting siRNA-transfected cells compared to cells of the negative control. TRAF6-siRNA also significantly inhibited proliferation and enhanced apoptosis of EC109 cells. These studies suggested that TRAF6 was required for NF-kappaB activation in EC109 cells and it may be a good molecular target for suppressing the survival and proliferation of esophageal cancer cells. PMID- 21312056 TI - Metabolism of 4-pyridone-3-carboxamide-1-beta-D-ribonucleoside (4PYR) in rodent tissues and in vivo. AB - Our previous studies identified 4-pyridone-3-carboxamide-1-beta-D-ribonucleoside (4PYR) phosphates in human erythrocytes. We demonstrated formation of these nucleotides by phosphorylation of 4PYR and potential toxicity due to disruption of erythrocyte energy balance. This study aimed to evaluate the ability of the other cell types to phosphorylate 4PYR to characterize function and toxicity of these compounds. Homogenates of rat heart, kidneys, and liver were used to study the rate of 4PYR phosphorylation in the presence of ATP. In another experiment, 4PYR was administered into mouse as repeated subcutaneous injections and into rats as intraperitoneal infusion. After 7 days, heart, liver, kidney, lungs, and skeletal muscle were collected, and the concentration of 4PYR nucleotides was evaluated. HPLC was used to measure 4PYR and 4PYR nucleotides in homogenate and specimens from in vivo experiments. 4PYR was rapidly phosphorylated by the liver homogenate (390 +/- 27 nmol/min/g wet wt). Significant rates were reported in the heart and kidneys' homogenates: 34.3 +/- 4.3 nmol/min/g and 33.2 +/- 9.2 nmol/min/g, respectively. Phosphorylation of 4PYR was almost completely inhibited by adenosine kinase inhibitor 5'-iodotubercidin. Administration of 4PYR in vivo resulted in accumulation of 4PYR monophosphate in the liver, heart, skeletal muscle, and lung (20-220 nmol/g dry wt) except kidney (<1 nmol/g). In contrast to erythrocytes, no 4PYR triphosphate formation (<1 nmol/g) was observed in any of the organs studied. We conclude that not only the erythrocytes but also other cell types are capable of phosphorylating 4PYR to form 4PYR monophosphate. Potential toxicity or physiological role of 4PYR in peripheral organs could be considered, but mechanisms will be different from that in erythrocytes. PMID- 21312057 TI - Biomechanics of the sarcolemma and costameres in single skeletal muscle fibers from normal and dystrophin-null mice. AB - We studied the biomechanical properties of the sarcolemma and its links through costameres to the contractile apparatus in single mammalian myofibers of Extensor digitorum longus muscles isolated from wild (WT) and dystrophin-null (mdx) mice. Suction pressures (P) applied through a pipette to the sarcolemma generated a bleb, the height of which increased with increasing P. Larger increases in P broke the connections between the sarcolemma and myofibrils and eventually caused the sarcolemma to burst. We used the values of P at which these changes occurred to estimate the tensions and stiffness of the system and its individual elements. Tensions of the whole system and the sarcolemma, as well as the maximal tension sustained by the costameres, were all significantly lower (1.8-3.3 fold) in muscles of mdx mice compared to WT. Values of P at which separation and bursting occurred, as well as the stiffness of the whole system and of the isolated sarcolemma, were ~2-fold lower in mdx than in WT. Our results indicate that the absence of dystrophin reduces muscle stiffness, increases sarcolemmal deformability, and compromises the mechanical stability of costameres and their connections to nearby myofibrils. PMID- 21312059 TI - Association between the M268T polymorphism in the angiotensinogen gene and essential hypertension in a South Indian population. AB - Essential hypertension is a complex multifactorial disease caused by interactions between genetic and environmental factors. It is an independent determinant of cardiovascular risk. The main aim of this study was to investigate the possible influence of angiotensinogen M268T polymorphisms on hypertension in two endogamous caste populations of South India. Systolic and diastolic blood pressure, anthropometric variables, and lipid profiles were assessed. Direct sequencing of PCR products was adopted for genotyping. This polymorphism was found to be in Hardy-Weinberg equilibrium in the patients and controls of both populations. Binary odds ratios showed significant association between the M268T polymorphism and hypertension in both populations. Multivariate analysis revealed significant differences in body mass index, chest girth, calf circumference, skinfold measurements, total cholesterol, and triglyceride levels between these genotypes in the Gavara and Vaishya populations. These data further support the hypothesis that hypertension is influenced by the AGT M268T polymorphism. PMID- 21312060 TI - The analysis of groEL gene in Salmonella enterica subspecies enterica serovar Typhimurium isolated from avians by PCR-Restriction Fragment Length Polymorphism method. AB - Salmonella enterica subspecies enterica serovar Typhimurium causes food-borne outbreaks and systemic diseases in humans and animals. groEL gene (also known as mopA gene in S. Typhimurium), possessing conserved sequence, plays an important role in invasion of bacteria. The purpose of present study was to identify the polymorphism of groEL gene among different avians in different regions by PCR RFLP method. Fifty two S. Typhimurium isolates (Broiler (n = 13), Layer (n = 12), Duck (n = 5), Goose (n = 5), Sparrow (n = 8), Canary (n = 3), Pigeon (n = 5) and Casco parrot (n = 1). were identified using serotyping as well as multiplex-PCR. Then, amplification of groEL gene performed and amplified products subjected to restriction digestion with BsuRI enzyme. Three RFLP profiles, A, B and C, generated DNA fragments between approximately 100-1,000 bp in size, were observed. The RFLP profile A was observed in 35 (67.3%), profile B in 14 (26.9%) and profile C in 3 (5.77%) of isolates. S. Typhimurium isolates recovered from 13 broilers (two of which profile A, 9 profile B and 2 profile C) and from 8 sparrows (two of which profile A, 5 profile B and 1 profile C) showed all three profiles, but 12 layers and other avians (including Canary (n = 3), Goose (n = 5), Duck (n = 5), Pigeon (n = 5) and Casco parrot (n = 1)) showed profile A. None of these profiles was allotted for a special region. The result of present study showed that S. Typhimurium undergoes genetic mutations in groEL gene under unpleasant milieu in different regions and in different avians. Thus, genetic diversity, despite conserved nature of groEL gene in S. Typhimurium, may exist but it depends on the condition where bacteria have settled. To our knowledge, three RFLP profiles of groEL gene generated by BsuRI restriction enzyme were not reported previously. PMID- 21312062 TI - High fluid shear stress and spatial shear stress gradients affect endothelial proliferation, survival, and alignment. AB - Cerebral aneurysms develop near bifurcation apices, where complex hemodynamics occur: Flow impinges on the apex, accelerates into branches, then slows again distally, creating high wall shear stress (WSS) and positive and negative spatial gradients in WSS (WSSG). Endothelial responses to these kinds of high WSS hemodynamic environments are not well characterized. We examined endothelial cells (ECs) under elevated WSS and positive and negative WSSG using a flow chamber with constant-height channels to create regions of uniform WSS and converging and diverging channels to create positive and negative WSSG, respectively. Cultured bovine aortic ECs were subjected to 3.5 and 28.4 Pa with and without WSSG for 24 and 36 h. High WSS inhibited EC alignment to flow, increased EC proliferation assessed by bromodeoxyuridine incorporation, and increased apoptosis determined by terminal deoxynucleotidyl transferase dUTP mediated nick-end labeling. These responses to high WSS were either accentuated or ameliorated by WSSG: Positive WSSG (+980 Pa/m) inhibited alignment and stimulated proliferation and apoptosis, whereas negative WSSG (-1120 Pa/m) promoted alignment and suppressed proliferation and apoptosis. These results demonstrate that ECs discriminate between positive and negative WSSG under high WSS conditions. EC responses to positive WSSG may contribute to pathogenic remodeling that occurs at bifurcations preceding aneurysm formation. PMID- 21312063 TI - Study of the association between growth differentiation factor 15 gene polymorphism and coronary artery disease in a Chinese population. AB - Growth differentiation factor (GDF)-15 belongs to a member of the transforming growth factor-beta cytokine superfamily, and elevated GDF-15 concentrations are linked to increased risk of cardiovascular diseases and future adverse cardiac events in apparently healthy elderly women, acute coronary syndrome, and chronic heart failure. However, its genetic mechanisms are still unknown. We investigated whether GDF-15 -3148C>G variant (SNP, rs4808793) is associated with a predisposition to coronary artery disease (CAD) and its severity in a Chinese population. We studied 418 consecutive patients, including 192 with coronary stenosis >=50% or previous myocardial infarction and 226 controls without documented CAD. Coronary artery disease cases and controls were genotyped for SNP rs4808793 by using the ligase detection reaction method. The three genotypes CC, CG, and GG were present in rs4808793. No differences were found in genotype distribution and allele frequencies of rs4808793 between subjects with and without CAD, or when grouped according to sex. Logistic regression did not reveal any increased risk of CAD in subjects carrying the CG, GG genotype, or G allele at rs4808793 compared with individuals carrying the CC genotype or C allele; this finding was the same when subjects were grouped by sex (all P > 0.05). Rs4808793 does not affect main anthropometric and metabolic characteristics, nor did there exists any association between rs4808793 and the severity of coronary lesions (all P > 0.05). Our data do not support an association of rs4808793 with CAD or its severity in a Chinese population. PMID- 21312065 TI - Development and validation of the living with chronic obstructive pulmonary disease questionnaire. AB - PURPOSE: Available patient-reported outcome (PRO) measures for chronic obstructive pulmonary disease (COPD) focus primarily on impairment (symptoms) and activities (functioning). The purpose of the study was to develop a patient-based PRO measure for COPD that captures the overall everyday impact of living with COPD from the patient's perspective. METHODS: LCOPD items (Living with COPD Questionnaire) were generated from qualitative interviews in the U.K. and focus groups in the U.S.A. The draft measure was tested for face and content validity in both countries. Item reduction and testing for reproducibility and construct validity was conducted via Rasch and traditional psychometric analyses. RESULTS: The draft LCOPD was found to be relevant and acceptable to patients in the U.K. (N = 19) and U.S. (N = 16). Application of Rasch analysis to data collected in validation studies (n = 162 in the U.K. and 145 in U.S.) identified a 22-item scale that measured a single construct in both countries. Psychometric analyses indicated that this version was internally consistent and reproducible. Scores on the measure were related as expected to clinician ratings of disease severity and patient ratings of COPD severity and general health. CONCLUSIONS: The LCOPD is a new measure examining the everyday impact of living with COPD. It demonstrates good scaling properties and may prove valuable in understanding treatment benefits. PMID- 21312064 TI - Quality of life: a key variable to consider in the evaluation of adjustment in parents of children with autism spectrum disorders and in the development of relevant support and assistance programmes. AB - PURPOSE: Our primary objective was to identify cognitive and behavioural profiles that affect adjustment, in order to make relevant recommendations about support and assistance for parents of autistic children. METHOD: One hundred and sixty French parents completed a battery of questionnaires and self-report measures developed or adapted to assess (1) the child and family situations; (2) perceived stress; (3) perceived social support; (4) perceived control; (5) coping strategies; and (6) quality of life. RESULTS: The psychometric properties of the instruments we used proved to be adequate. Our results support the pre-existing data and our findings may prove to be of interest to clinicians. Our primary finding was that emotion-focused coping strategies seem to be less effective. Parents who employed emotion-focused strategies were more stressed and more disturbed in most parts of their life. They also experienced more guilt and reported more false beliefs about PDD. CONCLUSIONS: Our data underscore the need for psychoeducation programmes for parents, focused on handling stress and emotions, modifying false beliefs and solving the daily problems that arise from PDD. We propose a 5-axis intervention model for parents of children with PDD, based on cognitive-behavioural therapies and on a stress management programme. PMID- 21312066 TI - Olig2 is useful in the differential diagnosis of oligodendrogliomas and extraventricular neurocytomas. AB - A 42-year-old woman had suffered from headaches since April 2009. Computed tomography revealed a tumor with marked calcification in the left frontal lobe adjacent to the left anterior horn of the lateral ventricle. T1-weighted gadolinium-enhanced magnetic resonance imaging showed a well-enhanced tumor at the lesion. Dynamic methionine positron emission tomography showed no delayed methionine attenuation. Initial preoperative diagnosis was extraventricular neurocytoma (EVN). However, oligodendroglioma was determined upon a second diagnosis. The patient underwent total tumor removal. Hematoxylin and eosin staining showed the characteristic fried egg-like cells, round nuclei, and immunohistochemically, the tumor cells were positive for glial fibrillary acidic protein, synaptophysin, neuronal nuclear antigen, microtubule-associated protein 2 and Olig2. The MIB-1 labeling index was 20%, which suggested malignancy. Although these findings demonstrated that the tumor had glioneuronal character, it was difficult to differentiate between EVN and oligodendroglioma. There have been reports that Olig2 immunohistochemistry is generally positive in cases of oligodendroglioma, but not in cases of neurocytoma. We completed the diagnosis as oligodendroglioma. Subsequent electron microscopy results presented oligodendroglial but not neuronal characteristics. We concluded that Olig2 is useful in the differential diagnosis of oligodendrogliomas and EVNs. PMID- 21312067 TI - The acyl coenzymeA:monoacylglycerol acyltransferase 3 (MGAT3) gene is a pseudogene in mice but encodes a functional enzyme in rats. AB - Triglyceride (TAG) absorption involves its initial hydrolysis to fatty acids and monoacylglycerol (MAG), which are resynthesized back to diacylglycerol (DAG) and TAG within enterocytes. The resynthesis of DAG is facilitated by fatty acyl-CoA dependent monoacylglycerol acyltransferases (MGATs). Three MGAT enzymes have been isolated in humans and the expression of MGAT2 and MGAT3 in the intestines suggests their functional role in the TAG absorption. In this paper, we report that the Mogat3 gene appears to be a pseudogene in mice while it is a functional gene in rats. Examination of the mouse genomic Mogat3 sequence revealed multiple changes that would result in a translational stop codon or frameshifts. The rat Mogat3 gene, however, is predicted to encode a functional enzyme of 362 amino acids. Expression of rat MGAT3 in human embryonic kidney 293 (HEK293) cells led to the formation of a 36-kDa protein that displayed significant MGAT but not DGAT activity. Tissue expression analysis of rat MGAT3 by real-time PCR analysis indicated that rat MGAT3 has a high level of expression in intestines and pancreas. Our results thus provide the molecular basis to understand the relative functional role of MGAT2 and MGAT3 and also for future exploration of MGAT3 function in animal models. PMID- 21312068 TI - Pancreatoduodenal junction: review of anatomy and pathologic conditions. AB - INTRODUCTION: The pancreatoduodenal junction is a small anatomic area where pathologic processes involving the distal bile duct, duodenum, pancreatic head, ampulla de Vater, and retroperitoneum converge. Differential diagnosis includes a spectrum of entities that ranges from anatomical variants to malignancies. PURPOSE: The aim of this paper was to review the anatomy and different pathologic conditions, whether tumoral, inflammatory, or congenital in origin, in this specific area that involves the pancreatic head, duodenum, duodenal ampulla, distal pancreatobiliary tract junction, and retroperitoneum. METHODS: Computed tomography (CT) and magnetic resonance (MR) help us to identify specific radiologic signs that allow to divide the pancreatic-duodenal junction abnormalities into three cathegories: (1) normal variants and congenital anomalies (pancreas divisum, santorinicele, annular pancreas,duodenal duplication cyst, choledocal cyst,...); (2) acquired non-tumoral: traumatic, iatrogenic, inflammatory (duodenal hematoma, duodenal iatrogenic perforation, groove pancreatitis, gastroduodenal artery pseudoaneurysm,...); (3) tumoral (pancreatic head adenocarcinoma, periampullary tumors, neuroendocrine pancreatic tumors, duodenal adenocarcinoma,...). The images illustrate morphologic aspects of these entities. RESULTS AND CONCLUSIONS: CT and MR are the most appropiate imaging modalities to evaluate pancreatoduodenal junction. Knowing the imaging features is crucial to reach the right diagnosis and treatment of the different entities that involve this anatomic area. PMID- 21312069 TI - Ischemic preconditioning attenuates lactate release by the liver during hepatectomies under vascular control: a case-control study. AB - BACKGROUND: We have previously demonstrated lactate release by the liver itself in hepatectomies performed under selective hepatic vascular exclusion. We hypothesized that ischemic preconditioning applied in this setting might lead to a reduction of hepatic lactate production. METHODS: Twenty-one patients underwent hepatectomy under inflow and outflow occlusion combined with ischemic preconditioning (IP group, n = 21). These patients were matched 1:1 with patients subjected to the same technique of hepatectomy under vascular occlusion without ischemic preconditioning (control group, n = 21). The transhepatic lactate gradient (hepatic vein-portal vein) was calculated before liver dissection and 60 min post-reperfusion. RESULTS: In the control group, the transhepatic lactate gradient before liver resection was negative indicating consumption by the liver. After 60 min post-reperfusion, this gradient became positive, indicating net lactate production by the liver (0.2 +/- 0.3 vs. -0.3 +/- 0.2 mmol/L, P < 0.001). In the IP group, the liver consumed lactate both before resection and 60 min post reperfusion (gradients -0.2 +/- 1.1 and -0.1 +/- 0.6 mmol/L, respectively). The magnitude of lactate release by the liver correlated with systemic hyperlactatemia post-reperfusion and 24 h postoperatively (r(2) = 0.54, P < 0.001 and r(2) = 0.67, P < 0.001, respectively). Significant correlations between the transhepatic lactate gradient post-reperfusion and peak postoperative AST as well as the apoptotic response of the liver remnant were also demonstrated (r(2) = 0.72, P < 0.001 and r(2) = 0.66, P < 0.001, respectively). CONCLUSION: The microcirculatory derangement and cellular aerobic metabolism breakdown elicited by ischemia-reperfusion insults can be prevented with hepatoprotective measures such as ischemic preconditioning. The transhepatic lactate gradient could act as a monitoring and prognostic tool of the efficacy of ischemic preconditioning. PMID- 21312070 TI - High-dose testosterone propionate treatment reverses the effects of endurance training on myocardial antioxidant defenses in adolescent male rats. AB - This study was aimed at evaluation of changes in activities of selected antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase) and contents of key nonenzymatic antioxidants (glutathione, protein thiol groups, and alpha- and gamma-tocopherols) in the left heart ventricle of young male Wistar rats subjected to endurance training (treadmill running, 1 h daily, 5 days a week, for 6 weeks) or/and testosterone propionate treatment (8 or 80 mg/kg body weight, intramuscularly, once a week, for 6 weeks) during adolescence. The training alone increased the activities of key antioxidant enzymes, but lowered the pool of nonenzymatic antioxidants and enhanced myocardial oxidative stress as evidenced by elevation of the lipid peroxidation biomarker malondialdehyde. The lower-dose testosterone treatment showed mixed effects on the individual components of the antioxidant defense system, but markedly enhanced lipid peroxidation. The higher-dose testosterone treatment decreased the activities of the antioxidant enzymes, lowered the contents of the nonenzymatic antioxidants, except for that of gamma-tocopherol, reversed the effect of endurance training on the antioxidant enzymes activities, and enhanced lipid peroxidation more than the lower-dose treatment. These data demonstrate the potential risk to cardiac health from exogenous androgen use, either alone or in combination with endurance training, in adolescents. PMID- 21312071 TI - Type 1 receptor parathyroid hormone (PTH1R) influences breast cancer cell proliferation and apoptosis induced by high levels of glucose. AB - Increased breast cancer incidence parallels the increase in cases of type 2 diabetes. We investigated the effect of type 1 receptor parathyroid hormone (PTH1R) expression on viability and apoptosis of breast cancer cells exposed to high levels of glucose. Upregulation of PTH1R was detected in patients with invasive ductal carcinoma of the breast and diabetes. In vitro, PTH1R silencing suppressed cell proliferation and apoptosis induced by high levels of glucose by regulating Bax/Bcl-2 expression. These results suggest PTH1R silencing may represent a novel treatment approach for patients diagnosed with invasive ductal carcinoma of the breast who are also managing diabetes. PMID- 21312072 TI - The influence of intraoperative pleural perfusion with matrine-cisplatin or cisplatin on stromal cell-derived factor-1 in non-small cell lung cancer patients with subclinical pleural metastasis. AB - The early diagnosis and treatment of non-small cell lung cancer (NSCLC) in patients with subclinical pleural metastasis is currently a challenge. In an effort to establish a method for the diagnosis and treatment of these patients, we conducted a single-blind study during which intraoperative pleural lavage cytology (PLC) was performed in 164 patients with NSCLC without obvious pleural effusion. Stromal cell-derived factor-1 (SDF-1) serum concentrations were analyzed using enzyme-linked immunoassay on day 1 prior to tumor resection and on day 7 postoperatively. Western blot analysis was used for the detection of CXCR4 protein expression in resected tumors. Intraoperative pleural perfusion chemotherapy, with either cisplatin or cisplatin plus matrine, was given to patients with positive PLC. A group of 30 patients with NSCLC that did not undergo intraoperative PLC were used as a control group. Of the 164 study patients, 41 (25%) patients had positive PLC. Serum SDF-1 concentrations were higher in PLC-positive patients compared with patients negative for PLC and control patients. Serum SDF-1 concentrations were also lower at postoperative day 7 in patients treated with cisplatin plus matrine compared with control patients and those perfused with cisplatin alone. A lower incidence of chemotherapy related adverse events was observed in patients treated with cisplatin plus matrine versus those treated with cisplatin alone during the first postoperative month. Patients with positive PLC showed a higher CXCR4 protein expression than patients with negative PLC. Based on the results of this study, PLC combined with serum SDF-1 concentration measurements may be considered as an effective index to determine the risk of subclinical pleural metastasis in patients with lung cancer. In addition, cisplatin plus matrine was confirmed as an initial approach for pleural perfusion and was superior to cisplatin alone. PMID- 21312073 TI - Potential and pitfalls of using large administrative claims data to study the safety of osteoporosis therapies. AB - Long-term bisphosphonate use may be associated with several rare adverse events. Such associations are not optimally evaluated in conventional randomized controlled trials due to the requirements of large numbers of patients and long term follow-up. Alternatively, administrative claims data from various sources such as Medicare have been used. Because claims data are collected for billing and reimbursement purposes, they have limitations, including uncertain diagnostic validity and lack of detailed clinical information. Using such data for pharmacoepidemiologic research requires complex methodologies that may be less familiar to many researchers and clinicians. In this review, we discuss the strengths and limitations of using claims data for osteoporosis drug safety research, summarize recent advancements in methodologies that may be used to address the limitations, and present directions for future research using claims data. PMID- 21312074 TI - Juvenile dermatomyositis. AB - Juvenile dermatomyositis (JDM) is a rare, often chronic autoimmune disease with onset during childhood. It is characterized by weakness in proximal muscles and pathognomonic skin rashes. Although the etiology remains unclear, it has been proposed that JDM is caused by a vasculopathy within the muscle tissue and multiple other organ systems of genetically susceptible individuals, possibly in response to environmental triggers. The goals of treatment include control of the underlying inflammatory myositis and prevention and/or treatment of complications (eg, contractures and calcinosis). Delayed treatment may lead to poorer outcome in terms of disease course and calcinosis. The course in JDM is variable. Monocyclic disease occurs in about one third of patients. These patients have a good response to standard therapy. Early recognition and aggressive immunosuppressive treatment result in improved prognosis. PMID- 21312075 TI - The presence of an ossific nucleus does not protect against osteonecrosis after treatment of developmental dysplasia of the hip. AB - BACKGROUND: Osteonecrosis (ON) is a major complication after treatment of developmental dysplasia of the hip (DDH). Several studies have explored the absence of the femoral head ossific nucleus at the time of hip reduction as a risk factor for the development of ON, but findings have been inconsistent. QUESTIONS/PURPOSES: We therefore determined the incidence of ON in children who underwent reduction of a dislocated hip in the presence or absence of the ossific nucleus. PATIENTS AND METHODS: We retrospectively reviewed the radiographs of 105 hips in 89 patients treated for DDH at the age of 18 months or younger. Radiographs were graded for the presence of the ossific nucleus at the time of hip reduction and for the presence of ON, as graded by the Bucholz and Ogden classification, for patients at a mean age of 10 years. We used log-binomial regression to estimate if the presence of the ossific nucleus was associated with a lower incidence of ON. RESULTS: We identified ON in 37 of the 105 hips (35%). The incidence of ON at 10 years was 40% in the absence of the ossific nucleus and 32% in the presence of the ossific nucleus (adjusted relative risk, 0.86; 95% confidence interval, 0.36-1.81). When only radiographic changes of Grade II and greater were considered ON, the risk was still not increased (relative risk, 1.26; 95% confidence interval, 0.62-2.56). CONCLUSION: Patients with an ossific nucleus at the time of hip reduction showed a slight tendency toward better outcomes. The ossific nucleus did not protect for ON. LEVEL OF EVIDENCE: Level III, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 21312076 TI - Reduced wear of cross-linked UHMWPE using magnesia-stabilized zirconia femoral heads in a hip simulator. AB - BACKGROUND: To reduce wear, the ideal bearing surface in joint arthroplasty should be smooth and hydrophilic. Ceramics generally offer better wettability than metals and can be polished to a smoother finish. However, clinical studies have found no reduction in liner wear when using yttria-stabilized zirconia (Y TZP) instead of cobalt chromium alloy (CoCr) femoral heads. QUESTION/PURPOSES: We (1) determined whether a hard, diamond-like carbon (DLC) coating would enhance the wettability of CoCr and magnesia-stabilized zirconia (Mg-PSZ) femoral heads without increasing roughness, and (2) compared their wear performance. METHODS: In an observational study limited to CoCr and Mg-PSZ heads, we measured roughness and contact angle on as-received and DLC-coated heads. Eight heads then were subjected to 11 million cycles of wear in a hip simulator against cross-linked ultrahigh molecular weight polyethylene (XLPE) liners. RESULTS: Mg-PSZ femoral heads were smoother and more hydrophilic than CoCr heads. Although DLC coatings did not reduce roughness, they reduced the contact angle of CoCr and Mg-PSZ substrates, which may provide enhanced lubrication in vivo. In hip simulator tests, liners bearing against CoCr heads wore at a greater rate compared with Mg PSZ heads. The DLC coating on Mg-PSZ heads did not reduce wear further. CONCLUSIONS: The wear rate of XLPE versus Mg-PSZ was seven times less than CoCr heads, probably owing to lower roughness and greater wettability of Mg-PSZ heads. CLINICAL RELEVANCE: The use of Mg-PSZ femoral heads should lead to reduced wear in vivo compared with CoCr heads, but the clinical benefit of DLC-coated Mg-PSZ is unclear. PMID- 21312077 TI - Alloprosthetic composite is a suitable reconstruction after periacetabular tumor resection. AB - BACKGROUND: Resection of a tumor of the pelvis is most disabling when the acetabulum is excised and a durable reconstruction of the defect is hard to achieve. All available methods are associated with frequent complications. Few large series have been published, and fewer have focused entirely on complete resections of the acetabulum. The use of an allograft-prosthetic composite allows customization on the operating table. However, while such composites restore anatomy and function of the pelvis the use of pelvic allografts is controversial and the durability is unknown. QUESTIONS/PURPOSES: We therefore examined (1) the frequency of allograft and prosthetic failure, (2) positive and negative factors influencing the survival of the allograft prosthetic composite, and (3) function of patients with this reconstruction. PATIENTS AND METHODS: We retrospectively evaluated 35 patients who had resection of the entire acetabulum and reconstruction with an allograft-prosthetic composite. Function was scored by the Musculoskeletal Tumor Society system. Followup in 24 survivors averaged 120 months (range, 61-188 months). RESULTS: Greater than 75% of the allografts were still in place at last followup, and the original prosthetic reconstruction was still in place in 56%. Infection was an important negative factor for allograft survival. The average functional score was 72%, with better mean scores for patients who had reconstruction with a stemmed cup and an artificial ligament (average 89%). CONCLUSIONS: An allograft-prosthetic composite provides a versatile substitution of the pelvis and hip, with functional scores approximately 75% of normal. PMID- 21312079 TI - Detection of asymptomatic malaria infection among the Afghani immigrant population in Iranshahr district of southeastern Iran. AB - Asymptomatic malaria infection is often associated with subpatent level of parasitaemia and normal clinical examination. Such infection becomes a greater cause for concern when involved in blood transfusion and vector transmission. This study was performed to monitor the situation of asymptomatic malaria among the Afghani immigrants and native residents in Iranshahr district, a malaria endemic area in southeastern Iran, by performing conventional light microscopy. Out of 446 samples collected from Afghani immigrant participants, seven (1.6%) thick blood smears were diagnosed as Plasmodium vivax. None of the individuals who tested positive had malaria symptoms and they did not remember having had any malaria signs during the past two years. Out of 496 samples collected from native resident participants, three (0.6%) thick blood smears were detected as P. vivax and Plasmodium falciparum with mild malaria symptoms. An asymptomatic Plasmodium infected individual can be a source of malaria parasites for transmission of the agents. PMID- 21312078 TI - Does norepinephrine influence pain behavior mediated by dorsal root ganglia?: a pilot study. AB - BACKGROUND: Postganglionic neurons in the sympathetic nervous system reportedly are involved in lumbar radicular pain and release norepinephrine (NE), a neurotransmitter. Increased numbers of sympathetic nerve fibers have been found in dorsal root ganglion (DRG) neurons in a root constriction model. Whether this is a reasonable model for pain, however, is unclear QUESTIONS/PURPOSES: We asked whether: (1) painful behaviors occurred in the root constriction model; (2) NE enhanced the excitability of DRG neurons in the root constriction model; and (3) which adrenoceptors were related to the mediation of the NE effects. METHODS: The L5 root was sutured proximal to the DRG as the root constriction model. Behavioral tests were performed until 28 days after surgery. At 10 to 14 days after the root constriction, DRG neurons were quickly excised and digested with collagenase for electrophysiologic studies. Action potentials were recorded from single DRG neurons using a whole-cell patch clamp technique. NE (10 MUmol/L) was directly applied to the DRG neurons. The adrenergic sensitivity was examined in combination with antagonists. RESULTS: The rats with root constriction exhibited painful behavior. NE increased the excitability of DRG neurons in the root constriction model. The effects of NE were inhibited by pretreatment with an alpha-antagonist and alpha(2)-antagonist but not an alpha(1)-antagonist. CONCLUSIONS: Our observations suggest NE plays an important role in generating lumbar radicular pain mainly via alpha(2)-adrenoceptors. CLINICAL RELEVANCE: An alpha(2)-antagonist may be an appropriate agent for trials to treat lumbar radicular pain. PMID- 21312081 TI - [Preliminary evaluation of the insecticide susceptibility in Anopheles gambiae and Culex quinquefasciatus from Lobito (Angola), using WHO standard assay]. AB - Field collections of the most common urban mosquito vectors Anopheles gambiae and Culex quinquefasciatus were carried out in June 2003, March 2004 and November 2005 to gather preliminary data on the insecticide susceptibility in mosquitoes from Lobito (Angola) using the WHO standard bioassays. Bioassays were performed on F0 adults emerging from the field larval collections and on unfed adults from landing catches on volunteers. Batches of mosquitoes from three selected locations (Alto Liro, San Jao and Bela Vista) were exposed for 1 hour to several insecticides such as DDT 4%, carbosulfan 0.4%, permethrin 1%, deltamethrin 0.05% and cyfluthrin 0.15%, in order to estimate the immediate knockdown times (kdT50 and kdT95) and the mortality rate after exposure. The results revealed that mosquito susceptibility to insecticides varied depending on the insecticide, the site and the period of collection. The main local malaria vector A. gambiae (both M and S forms) was basically resistant to DDT and susceptible to all pyrethoids, regardless of the period and the site of collections. The overall mortality rate due to DDT was 73% in Alto Liro, 89% in San Jao and varied depending on the period in Bela Vista between 95% in March 2004 and 100% in November 2005. The mortality due to pyrethoids was 100% at all locations, with the kdT50 and KdT95 times ranging between 9 and 16 minutes and between 18 and 29 minutes, respectively. Concerning the C. quinquefasciatus, populations from Yard and Caponte were resistant to all insecticides tested; the mortality rate was 40% with deltamethrin and 70% with permethrin, while no lethal effect was observed with DDT or carbosulfan. In conclusion, despite its probable high resistance to DDT, the main local malaria vector A. gambiae remained fully susceptible to pyrethroids. This could forecast a good biological efficacy of the scheduled vector control interventions in Angola, based on a large-scale distribution of long-lasting, insecticide-treated nets and on the implementation of indoor residual spraying. The local vector control programme must include well-adapted IEC campaigns and full participation of the community for better management of the insecticide resistance in targeted mosquitoes and for better control of malaria vector populations. PMID- 21312082 TI - [New S3 guidelines "uncomplicated urinary tract infections"]. PMID- 21312083 TI - [National S3 guideline on uncomplicated urinary tract infection: recommendations for treatment and management of uncomplicated community-acquired bacterial urinary tract infections in adult patients]. AB - BACKGROUND: Urinary tract infections (UTI) belong to the most frequent bacterial infections in outpatients. Increasing antibiotic resistance rates and a new appreciation of the epidemiological side effects of antibiotics ("collateral damage") have warranted an update of the guidelines on uncomplicated UTI as an S3 clinical guideline. METHODS: The guideline was developed by the Deutsche Gesellschaft fur Urologie (DGU) in collaboration with the Deutsche Gesellschaft fur Allgemein- und Familienmedizin (DEGAM), Deutsche Gesellschaft fur Gynakologie und Geburtshilfe (DGGG), Deutsche Gesellschaft fur Hygiene und Mikrobiologie (DGHM), Deutsche Gesellschaft fur Infektiologie (DGI), Deutsche Gesellschaft fur Nephrologie (DGfN), Paul-Ehrlich-Gesellschaft fur Chemotherapie (PEG) and a patient representative. The systematic review of the literature on the topics of the guideline was performed for the time period of 1 January 1998 to 30 April 2008 in the databases of the Cochrane Library and MEDLINE. International guidelines of the years 1999-2007 were included. RESULTS: Uncomplicated UTI comprise uncomplicated cystitis and uncomplicated pyelonephritis. The leading uropathogen is Escherichia coli. The choice of the antibiotic substance follows the five primary aspects: (1) individual patient risk and antibiotic pretreatment; (2) bacterial spectrum and antibiotic susceptibility; (3) effectivity of the antimicrobial substance demonstrated in clinical studies; (4) epidemiological effects ("collateral damage"); and (5) adverse effects. If antibiotics such as trimethoprim/sulfamethoxazole or fluoroquinolones have previously been given, the risk for pathogens to become resistant against these substances is increased. Because of increasing resistance rates of E. coli against trimethoprim/sulfamethoxazole also in uncomplicated UTI, trimethoprim alone or in combination with sulfamethoxazole is no longer regarded as the first line agent in the empiric treatment of uncomplicated cystitis, unless the regional resistance rate is below 20%. The antibiotic resistance rates of fluoroquinolones in uncomplicated UTI are still below 10% in Germany, but there is a significant emergence of resistance compared to earlier years. Moreover, fluoroquinolones and group 3 cephalosporins exhibit negative epidemiological effects resulting in selection of multi-resistant pathogens. Because these antibiotic classes are needed in therapy of life-threatening infections, such effects should be taken seriously. For substances like fosfomycin, nitrofurantoin or mecillinam"collateral damage" has not been documented or only to a lesser degree. Therefore, for empiric therapy of frequent uncomplicated cystitis fosfomycin-trometamol, nitrofurantoin or pivmecillinam (not listed in Germany) are recommended as first-line antibiotics. For oral first-line treatment of uncomplicated pyelonephritis, fluoroquinolones are still recommended in sufficiently high dosage due to the resistance rates of E. coli still being below 10% and the superior effectivity compared to other antibiotics. Asymptomatic bacteriuria (ASB) should only be treated in exceptional cases such as pregnant women or prior to expected mucocutaneous traumatising interventions of the urinary tract. CONCLUSION: The S3 guideline on uncomplicated urinary tract infections is a comprehensive set of evidence- and consensus-based recommendations dealing with epidemiology, diagnosis, therapy and management of uncomplicated bacterial UTI of adult outpatients. A broad implementation in all disciplines taking care of patients with UTI is necessary in order to ensure a prudent antibiotic policy in these frequent infections and thus improve patient care. PMID- 21312084 TI - [Ewing's sarcoma of the kidneys with simultaneous seminoma]. AB - Extraosseous Ewing's sarcoma (EOE) is rarely observed in the urinogenital tract, which results in only sporadic descriptions of primary EOE of the kidneys in the literature with cytologic analyses. A timely diagnosis and differentiated therapy of this aggressive disease are compromised by its infrequent appearance and scarce available data. With a simultaneously diagnosed seminoma our case report supports and extends further the data collected so far. PMID- 21312085 TI - [GeSRU Jahresplan 2011/2012]. PMID- 21312086 TI - [AUO-study AB34/09: an open-label, randomised, multicentre, phase II study to evaluate the efficacy of chemotherapy with gemcitabine and cisplatin in combination with the EGF receptor antibody panitumumab (GemCisP) versus GemCis in the first-line therapy of locally advanced/metastatic urothelial carcinoma in patients with wild-type HRAS - PURO]. PMID- 21312087 TI - [The ABC's of medical statistics. Reading and understanding clinical trials]. AB - Clinical trials test hypotheses that are accepted or rejected according to a predetermined probability of error (level of significance). Significance does not however mean relevance. Good parameters of relevance are absolute risk reduction and based on this the calculation of the number of patients who need to be treated for one additional patient to benefit. The randomized controlled trial is the gold standard for comparative evaluation of effects. In the ideal scenario it is designed so that a difference established by statistical methods becomes probable. In non-inferiority studies care should be taken that no equivalence is shown but rather that the difference is not greater than a predefined margin of error for differences. Meta-analyses of studies with similar endpoints have the potential to improve the level of evidence. Since the findings of meta-analyses depend on the studies included, critical assessment of the results is essential. PMID- 21312091 TI - [Treatment of glioblastoma recurrences]. PMID- 21312092 TI - [Beneficial outcomes of an interdisciplinary psychoeducative group intervention for patients with malignant gliomas and their relatives]. AB - BACKGROUND: To assess the impact of psychoeducative group interventions on patients with high-grade glioma (glioblastoma, mixed glioma, and astrocytoma) and their relatives. METHODS: A total of one hundred and four patients and relatives underwent group interventions between September 2007 and May 2010 and were coached by a psychologist and a physician in the context of an interdisciplinary meeting. Questionnaires were distributed after every meeting. RESULTS: In general, group interventions were experienced as helpful to discuss psychic aspects, new life circumstances, and medical questions. CONCLUSIONS: Psychoeducative group interventions represent an important support for brain tumor patients and their relatives for discussing anxiety, concerns, and needs and thus improve their quality of life. PMID- 21312093 TI - [Patient reported outcome monitoring using a tablet PC is suitable for measuring quality of life in patients with gliomas]. AB - A computer-based tool for the monitoring of patient-related outcomes, the "Computer-based Health Evaluation System" (CHES) was developed at the medical university of Innsbruck. The software-generated graphic QOL profiles were found to be an important tool for screening patients for clinically relevant problems and were successfully used in oncology, geriatrics, psychiatry, and psychosomatics. The authors report their experience with CHES in 34 patients with recurrent gliomas. The computer-based QoL monitoring was repeated in median 5.4 times per patients and found feasible and well accepted by patients and personnel. PMID- 21312094 TI - [Pseudoprogression or pseudoresponse: a challenge for the diagnostic imaging in Glioblastoma multiforme]. AB - This methodological paper on magnetic resonance tomography imaging recalls the assessment criteria on therapy response of Glioblastoma multiforme as defined by David Macdonald in 1990 that have remained State of the Art since their first publication. It defines the terms "pseudoprogression", "radiation induced necrosis" and "pseudoresponse". These phenomena are seen increasingly since the introduction of radiochemotherapy with Temozolomide as treatment standard in glioblastoma and since the use of antiangiogenetic therapy in malignant gliomas. Therefore, the assessment criteria have been recently updated with the newly proposed "RANO criteria (Response assessment in Neuro-Oncology)". Furthermore, the potential of additional information to conventional MR by MR perfusion, MR diffusion and MR spectroscopy is briefly discussed. PMID- 21312095 TI - Management of recurrent malignant glioma--neurosurgical strategies. AB - There is currently no standard for neurosurgical interventions in patients with recurrent high grade gliomas. An individualized approach is recommended as well for decision-making as for planning an intervention with resection of the outmost possible amount of tumor tissue while preserving neurological function and thus quality of life. Recent technical developments of imaging and of neuronavigation and visualization of tumor tissue with in vivo fluorescence with 5-Ala have proved helpful in improving symptoms and prolonging survival times also for patients with recurrent malignant gliomas. PMID- 21312096 TI - [Reirradiation of recurrent glioblastoma]. AB - Patients with glioblastoma are treated by radiotherapy in combination with temozolamid. Recurrent and progressive disease can be managed by several treatment options. Some series reported about reirradiation of brain tumors, but there are no randomised studies. Modern high precise radiation techniques can be an option for a save and effective treatment without systemic side effects. The published series show median survival rates from 6 to 12 months. Concomitant systemic therapies are evaluated in phase I/II studies. Indication for irradiation and decision of the technique and fractionation scheme have to be chosen individually. There is no curative intent for reirradiation, possible serious side effects and negative influence on life quality have to be omitted. PMID- 21312097 TI - [Direct costs of osteoarthritis]. AB - The aim of this study was to calculate the direct costs of illness in patients with advanced osteoarthritis of the hip and knee. Costs were reported retrospectively by a self-administered questionnaire, covering the period of 12 months prior to joint replacement. Total direct costs amounted to 2747.- euros, medical costs were 1148.- euros, and non-medical costs were 1599.- euros. Late stage osteoarthritis is expensive because of high costs mainly from personal care and household assistance caused by severe loss of function. PMID- 21312099 TI - Priming effects with ambiguous figures. AB - We varied the format and semantic content of primes to determine the degree to which they would influence the interpretation of ambiguous figures. The primes were objects or object names that were related in some way to one of the two organizations of the ambiguous figures. In Experiment 1, we provided some normative data regarding the stimulus materials, whereas in Experiment 2, an orienting question was used to focus attention on the semantic relationship between the prime and the figure. In Experiment 3, we used the orienting question to divert attention away from the relationship by asking about physical features of the figures. Recognition responses to biased versions of the figures and to new figures were measured. Primes that were loosely and indirectly associated with one of the two interpretations of an ambiguous figure were found to be effective at biasing the interpretation of an ambiguous figure in the direction of the primed alternative but only if attention was focused on the semantic relationship between the two stimuli. Attention to the physical characteristics of the stimuli during encoding eliminated the prime's influence on complex object perception. These findings are consistent with the conceptual priming literature and extend those of some recent studies (Balcetis & Dale, 2007; Feist & Gentner, 2007), which show that the interpretation of complex figures can be biased by the advanced presentation of related verbal information. PMID- 21312101 TI - Cytogenetics analysis. AB - The establishment of reliable and meaningful chromosomal (cytogenetic, karyotypic) changes in hematological disorders, primarily the leukemias and lymphomas, must be based on the examination of the involved cells or tissues. Thus, in the case of the leukemias bone marrow (BM) aspirations yield optimal results in the preponderant number of patients, whereas in the lymphomas affected tissues, usually lymph nodes, are the best source of cells carrying cytogenetic anomalies. Generally, BM is not a good source of cells for cytogenetic analysis in lymphoma. Not only is the marrow often not affected by the lymphoma, but also when it is, the number of abnormal cells is relatively small and/or the abnormal cells are not in division and, hence, do not yield a sufficient number of metaphases for cytogenetic analysis. In some situations, blood cells can be utilized as a source of metaphases affected by karyotypic changes, e.g., in cases with about 10% immature cells in the peripheral blood (PB), in chronic lymphocytic leukemia (CLL), in cases where the marrow is fibrotic or extremely hypocellular, or in determining the presence of Ph+cells in established cases of chronic myelocytic leukemia (CML) (1,2). PMID- 21312102 TI - FISH Analysis. AB - In situ hybridization of specific DNA or RNA sequences to cellular targets was developed over 20 yr ago (1,2). The early techniques employed isotopically labeled probes and subsequent autoradiographic detection using a photographic emulsion overlying the metaphase chromosomes, nuclei, or whole cells. However, autoradiography requires long exposure periods, and is not practical for clinical application. In the late 1970s, nonisotopic methods of nucleic acid labeling were developed. The subsequent improvements in the detection of reporter molecules using immunocytochemistry and immunofluorescence, in conjunction with advances in fluorescence microscopy and image analysis, have made the technique safer, faster and reliable. PMID- 21312103 TI - Comparative genomic hybridization for the analysis of leukemias and lymphomas. AB - Cytogenetic methods have become increasingly important tools for both research in hematological malignancies and for the diagnostic workup of leukemias and lymphomas. The knowledge about specific chromosomal aberrations has been an essential prerequisite for the identification of pathogenetically relevant genes. Important examples are molecular genetic analyses of the breakpoint regions in chromosomal translocations, which resulted in the detection of protooncogenes such as ABL in chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) [t(9,22)(q34;q11)], or MYC in Burkitt's lymphoma [t(8;14)(q24;q32); for a review see refs. 1 and 2]. PMID- 21312104 TI - Spectral Karyotyping (SKY) of Hematologic Malignancies. AB - The discovery of the Philadelphia chromosome in chronic myeloid leukemia (CML) by Novell and Hungerford in 1960 (1), the subsequent clarification of this chromosomal abnormality as areciprocal translocation t(9;22)(q34;q1 1) by Rowley in 1973 (2), the identification of the genes involved at the translocation breakpoints (3,4), and ultimately the demonstration of the leukemogenic activity of the resulting fusion product (5), represent hallmarks for our understanding of malignant diseases as genetic disorders. The elucidation of the Philadelphia translocation emphasizes the importance of cytogenetic analysis of hematologic malignancies. Clarification of this chromosomal aberration as a reciprocal translocation became only possible after the development of cytogenetic banding techniques by Caspersson et al. in 1970 (6). Chromosome banding analysis revealed numerous nonrandom chromosomal aberrations, particularly balanced translocations in leukemias and lymphomas, e.g., the translocation t(8;21)(q22;q22) in acute myeloid leukemia (AML) first described by Rowley et al. in 1973 (7). These balanced translocations were shown to be of etiologic as well as diagnostic, prognostic, and therapeutic importance. They result in an altered gene function by two main mechanisms: (1) sequences of, in most instances, a transcription factor or receptor tyrosine kinase gene are fused to a normally unrelated gene, creating specific fusion proteins with oncogenic properties, and (2) protooncogenes are repositioned to the vicinity of promoter/enhancer elements of the immunoglobulin- or T-cell receptor genes, thereby initiating their activation (8). PMID- 21312105 TI - Molecular genetic methods in diagnosis and treatment. AB - During the past 20 yr, molecular biology and molecular genetics have provided techniques and procedures that allow the precise diagnoses of leukemias and lymphomas (for a review, see ref. 1). These methodologies have provided powerful, robust, and precise characterizations of genetic mutations and gene rearrangements (both normal and abnormal) that have been applied to the diagnosis and treatment of these malignancies. In this chapter we discuss methodologies currently utilized within the molecular diagnostic laboratory of cancer centers and major academic hospitals. We introduce these methodologies in both general terms and within the context of a differential diagnosis of leukemia/lymphoma. The long-term goal of the molecular hematologist/oncologist is to describe all mutations that occur within a given type or subtype of leukemia/lymphoma. This involves the discovery of new somatic and possibly hereditary mutations that contribute to the genesis of these hematologic malignancies. However, for this information to be useful in treatment regimens, therapies that target or affect these growth-dysregulating mutations must be found. Because diagnosis of mutation and gene rearrangement in the hematologic malignancies is far ahead of therapeutic modalities, we also discuss new research tools that will have impact on the experimental hematologist. PMID- 21312106 TI - Detecting Monoclonal Immunoglobulin andT-Cell Receptor Gene Rearrangements in B- andT-Cell Malignancies by Polymerase Chain Reaction. AB - B cells undergo gene rearrangement of one of their immunoglobulin heavychain genes at an early stage in B-cell development. During rearrangement of the immunoglobulin heavy-chain gene (IgH), a variable gene segment (V) is joined to a diversity gene segment (D), and then subsequently this complex is recombined to a joining gene segment (J). Nucleotides are added and removed at random at the V-D and D-J junctions (1). Similarly, early in development of T cells, the T-cell receptor (TCR) genes rearrange. In the case of the T-cell receptor gamma (TCRgamma) gene, the V-gene segment is brought into juxtaposition of a J-gene segment. Nucleotides are then added and deleted at random at the V-J junction (2). It is these gene rearrangements that are responsible for the immune repertoire. Usually only one of the chromosomes will rearrange and the other remains in the germ-line configuration. Although, if the first rearrangement is ineffective then the other chromosome may rearrange. The IgH and TCRgamma rearrangements will vary in DNA sequence and usually in size between lymphocyte clones and a normal individual will have a very large number of different IgH or TCRgamma rearrangements. PMID- 21312107 TI - Quantifying residual leukemia by "clone-specific" polymerase chain reaction. AB - Molecular biology tests can quantify extremely low levels of cancer cells, provided that a genetic marker for the cancer is known. Acute lymphoblastic leukemia (ALL) exhibits many genetic abnormalities, but most are uncommon or technically difficult to use as markers for sensitive quantification. We therefore use the leukemia clone's rearranged immunoglobulin heavy-chain (IgH) gene as a clonal marker (1,2). A very sensitive, quantitative polymerase chain reaction (PCR) test with "clone-specific" primers can be developed for 60-70% of B-lineage ALLs (see Fig. 1 ). Fig. 1. Strategy for quantifying residual disease. PMID- 21312108 TI - NPM-ALK Reverse Transcriptase-Polymerase Chain Reaction for Detecting the t(2;5) of Non-Hodgkin's Lymphoma. AB - The development of modern molecular biology techniques and their use in characterizing the genetic abnormalities that are of pathogenic significance in non-Hodgkin's lymphoma (NHL) now provides a means to diagnose and rationally subcategorize these neoplasms in addition to the more traditional use of morphologic and immunophenotypic criteria. The shortcomings of traditional methods of NHL diagnosis and classification have been especially evident within the morphological subset commonly referred to as the large-cell lymphomas, which comprise approx 25% and 40% of NHL in children and adults, respectively (1). The marked cytological, immunological, and clinical heterogeneity of this group of tumors suggests that it is comprised of several biologically different neoplasms, but morphological and immunophenotypic subclassification schema have failed to identify meaningful subsets within the large-cell lymphomas. Recently, however, two recurrent genetic abnormalities in large-cell NHL-activation of the BCL6/LAZ3 zinc finger gene located at 3q27 (altered in approx 30% of large-cell lymphomas [2-4]) and the NPM-ALK fusion gene (5-7) produced by the t(2;5)-have been analyzed to now permit the identification of patient subsets that have reproducibly different therapeutic responses and survival rates in most studies, both of these molecular genetic subtypes appearing to have a superior prognosis compared to those cases lacking these gene abnormalities. PMID- 21312109 TI - Diagnostic flow cytometry in hematologic malignancies. AB - During the past 30 years, we have seen flow cytometry (FCM) emerge from being a research tool requiring a group of engineers, an optical bench, and a darkened room to a benchtop flow cytometer that is used routinely in a clinical setting. The flow cytometer is to cell biology what the UV-visible spectrophotometer is to solution spectroscopy. Several events have contributed to the development of this technology to where it is now an indispensable tool in the diagnosis and clinical monitoring of disease. Many cell types are now under intense investigation. The clinical application of FCM to lymphocyte subset immunophenotyping in the leukemias and lymphomas was responsible for the early development of clinical FCM. PMID- 21312110 TI - Flow cytometric analysis of hematologic neoplasia. AB - Flow cytometry (FCM) is a powerful technology that allows the rapid analysis of cellular components such as surface and intracellular antigens, or DNA content. The measurements are fast and are based on optical signals emitted by cells labeled with fluorochromes as they flow suspended in a liquid medium through an intense laser beam. The signals include scattered light, which provides information on cell size and granularity, and fluorescence derived from dyes or fluorochrome-labeled antibodies bound to specific cell components. PMID- 21312111 TI - In situ hybridization in flow cytometry. AB - Molecular approaches to diagnostic questions in clinical medicine are greatly impacting the way researchers and clinicians investigate and treat disease. By combining molecular techniques with classical immunologic tools such as flow cytometry (FCM; 1-3), one can begin to more fully understand and appreciate the role of cellular heterogeneity in disease processes. The marriage of these two powerful techniques, termed molecular cytometry, will, in one instance, allow investigators to explore expression of nucleic acid sequences in subpopulations of cells defined by immunologic phenotype while, conversely, making it possible to examine the heterogeneity of cellular characteristics within populations identified by the presence of specific nucleic acid sequences or gene expression. Future developments may result in several advantages for the patient that may include, but are not limited to, earlier detection of viral infection, earlier and more sensitive detection of malignancy, and higher sensitivity and resolution of small populations of infected or aberrant cells. These developments may also assist in the identification of therapeutically resistant populations within a neoplasia, more effective and specific monitoring of therapy, and possibly the identification of new and disease-specific targeted therapies based on genetic information. The characterization and assessment of cellular heterogeneity is clearly key to understanding disease onset, progression, and therapeutic response in both infectious disease and in human malignancies. PMID- 21312112 TI - Quantitative fluorescence cytometry. AB - The phenotypes useful in distinguishing normal and neoplastic leukocytes are often identified by fluorescence staining reactions detected on flow cytometers. These reactions were originally observed by fluorescence microscopy, and cells were classified by human observers as simply negative or positive, with the positive cells sometimes distinguished as dim or bright. These terms are still used in analyzing flow cytometry (FCM) results. However, recent advances in our understanding of fluorescence signals from stained cells (1) now permit the translation of terms like "dim" and "bright" into real mass units of fluorescence intensity, a process that we call quantitative fluorescence cytometry (QFCM). Although the translation is not yet exact and certain technical details remain to be resolved, a general understanding of QFCM is now accessible and helpful in interpreting staining patterns. PMID- 21312113 TI - Methods in leukocyte cytochemistry. AB - During the development and maturation of hematopoetic precursors, certain enzymes and associated substances, such as glycogen, are produced in the developing cells (1,2), which, if detected, can provide important clues to the lineage and classification of leukemias. Although the evaluation of abnormal populations of white blood cells has been greatly refined by the use of immunohistochemistry, flow-cytometric analysis (3), and molecular studies, cytochemistry still plays an important role in the assessment of the abnormal marrow and peripheral blood smear. Cytochemical studies, therefore, still have a role to play in the evaluation of leukemias and other hematological diseases see Fig. 1 ). Fig. 1. Uses of cytochemical studies in the evaluation of blood and bone marrow smears. PMID- 21312114 TI - Immunohistochemistry in leukemias and lymphomas. AB - The characterization of the antigenic and immunologic properties of lymphoid and hematologic neoplasms has dramatically increased our understanding of the biology of these diseases and at the same time greatly enhanced our diagnostic abilities. Immunophenotyping has helped delineate specific lineage aberrancies indicative of malignant transformation, such as monoclonality, in the form of light- and/or heavy-chain immunoglobulin restriction, or loss of pan-B or pan-T cell antigens, or aberrant crosslineage coexpression of antigens. Unique immunophenotypic profiles have now been described for most forms of lymphoma and leukemia. Classic Hodgkin's disease, for example, has the singular combination of CD15 and CD30 positivity, in the absence of CD45 (see Fig. 1 ). Additional examples are mantle cell lymphoma with its unique nuclear expression of cyclin D1, and hairy cell leukemia, characterized by coexpression of CD22 and CD1 1c, a monocytoid marker. Beyond its diagnostic utility, immunohistochemistry (IHC) may have prognostic significance reflecting the biologic behavior of these diseases; a case in point is CD 10 in large B-cell lymphomas, whose absence conveys a worse prognosis. Fig. 1. Classic Hodgkin's disease phenotype. Reed-Sternberg cell (upper left) coexpressing CD 15 (upper right) and CD30 (lower right), in the absence of CD45 (lower left). PMID- 21312115 TI - Apoptosis : molecular regulation of cell death and hematologic malignancies. AB - Apoptosis, or programmed cell death, represents in cell biology a functional program as important as cell growth or differentiation. Programmed cell death is of basic importance for the development of multicellular organisms and its basic mechanisms are conserved during the evolution of metazoa. Mammalian cells exhibit several different apoptotic pathways that converge to a common endpoint. Each pathway is triggered by a different stimulus: growth factor default, irradiation, induction of the p53 oncosuppressor protein, glucocorticoid hormones (in lymphocytes), ligand binding to Fas/APO (CD95), or tumor necrosis factor receptor (TNF-R), perforin secreted by cytotoxic T cells (reviewed by Hale et al. [1]). As opposed to necrosis, apoptosis is a "clean" process: as the cell shrinks, the cell membrane turns into the "apoptotic shell," the nucleus is condensed and reduced in volume, and eventually the cell disappears from the tissue, due to phagocytosis by neighboring cells or professional phagocytes, such as macrophages. PMID- 21312116 TI - Cytokine receptors : qualitative and quantitative analysis. AB - Much has been written on the possible role of cytokines in hematopoietic malignancies. In some instances, such as interleukin-6 (IL-6) in multiple myeloma, there is evidence for a central role in maintaining malignant growth (1). The relationship between IL-6 and multiple myeloma is probably more complex, involving other cytokines that signal through receptors, which share the gp130 chain with the IL-6 receptor. Another strong association is that of IL-2 with acute T-cell lymphoma/leukemia, which express and release large amounts of the IL 2 receptor-alpha chain (CD25, Tac) (2). In other hematopoietic malignancies there is no strong evidence for the involvement of cytokines in the malignant process. Nevertheless, if a malignant clone expresses receptors for a cytokine and that cytokine is available, the end result may be accelerated proliferation or enhanced survival of the malignant cells. Conversely, expression of receptor for cytokines such as transforming growth factor-beta (TGF-beta), which tend to inhibit proliferation, or molecules like Fas, which induce apoptosis, may control the malignant clone. Thus cytokine receptor expression may provide valuable information on the behavior of the malignant clone (3). These considerations make a case for screening of cytokine receptor expression as a part of routine diagnostic evaluation of patients with hematopoietic malignancy. It is emphasized, however, that at present cytokine receptor expression is a research tool, with the possible exception of the determination of soluble IL-2 receptor alpha chain (Tac, CD25). Measurement of soluble Tac has been widely reviewed (4) and will not be described here. PMID- 21312117 TI - Asthma: application of cell and molecular biology techniques to unravel causes and pathophysiological mechanisms. AB - The condition termed "asthma" has been difficult to define satisfactorily. Much of this problem arises from poor understanding of its causes, natural history, and pathophysiology, and also from a lack of a specific marker(s) of the disease. To the clinician, the diagnosis of asthma is not difficult in most cases, particularly if patients present early with symptoms of intermittent wheeze and chest tightness, and if their symptoms respond to particular treatments, such as beta-adrenergic agonists. Early definitions of asthma included the presence of airway obstruction that could spontaneously reverse with treatment, and also the increased narrowing of the airways to non-specific bronchoconstrictor stimuli, i.e., bronchial hyperresponsiveness (BHR). The essential elements of this definition were useful in separating asthma from other conditions, such as chronic bronchitis, chronic obstructive pulmonary disease, and emphysema, which could sometimes be diagnostically confused with asthma. More recently, the definition of asthma has been enhanced by the recognition that the airway submucosa of patients with asthma are chronically inflamed with a typical inflammatory infiltrate, and that inflammatory processes are important causes of the chief characteristics of asthma: airway obstruction and BHR. In addition, the loss of reversibility of airway obstruction as a long-term effect of the chronic inflammatory process is recognized: PMID- 21312118 TI - Culture of normal human airway epithelial cells and measurement of mucin synthesis and secretion. AB - The plasticity of conducting airway epithelia is well recognized (1-3). Under normal conditions, the epithelia express mucociliary function, which is the first pulmonary defense mechanism against inhaled air pollutants. Aberrance in this function is either the cause or one of the major contributors to the pathogenesis of various pulmonary diseases, such as asthma and bronchitis. To exert this vital defense function, mucus-secreting cell types of surface epithelium and sub- mucosal gland synthesize and secrete a high-mol-wt mucous glycoprotein, mucin, which is responsible for the viscoelastic property of the surface mucus layer. Secreted mucus, which is able to trap air pollutants and microorganisms, is steadily removed from the airway surface by ciliary escalation. Overall, the coordinated mucociliary function helps to maintain homeostasis in airway lumen. PMID- 21312119 TI - Brush Biopsy and Culture of Airway Epithelial Cells: beta-Adrenergic Receptor System Function. AB - Stimulation by catecholamine agonists of the beta-adrenergic coupled adenylyl cyclase (betaAR-AC) system, expressed on human tracheobronchial epithelial cells (ECs), elicits a variety of cellular responses that favorably affect airway function, the intensity of the inflammatory reaction, and even the integrity of the epithelial lining (1-6). For example, beta-agonist-stimulated production of second messenger, cyclic adenosine monophosphate (cAMP), enhances salt and water exchange (2), ciliary beating (3), mucus secretion by goblet cells (1,4), proliferation of airway ECs (5), and protection against free radical induced injury (6). PMID- 21312120 TI - Isolation and characterization of human airway fibroblasts in culture. AB - Asthma is considered an airway inflammatory disorder characterized by variable airflow obstruction and airway hyperresponsiveness (1). The inflammatory component of asthma has been studied extensively over the past few years, but, more recently, the potential contribution of airway wall remodeling to functional and clinical changes has been emphasized (2,3). Although the methods of sampling of bronchial tissue were previously limited, being obtained mostly from autopsic or surgical specimens, they have improved recently. PMID- 21312121 TI - Flow cytometric analysis of blood monocytes and alveolar macrophages. AB - Pulmonary monocytes and macrophages are believed to function in a wide range of biological roles, including host defense against foreign organisms, maintenance of immunological homeostasis in the lung, presentation of antigen to lymphocytes, and migration to sites of tissue injury and inflammation (1). There is also mounting evidence that recruited blood monocytes and resident alveolar macrophages (AM) in lung disease express an activated phenotype, suggesting that they may play important roles in chronic respiratory diseases, including asthma and interstitial lung diseases (2-6). PMID- 21312122 TI - Expression of IL-10 and GM-CSF in Blood Monocytes and Alveolar Macrophages. AB - Peripheral blood monocytes (PBMs) and alveolar macrophages (AMs) are widely recognized as cells that play a central role in the regulation of immune and inflammatory activities, as well as in tissue remodeling. The fulfillment of these activities is mediated by complex and multifactorial processes involving products derived from macrophages and monocytes (1). Monocytes are an important source of cytokines that are released in asthma and are likely precursor cells to AMs. Macrophages usually elaborate powerful suppressive signals to limit the proliferative potential of T-cells, thus maintaining local immunologic homeostasis (2). In asthma, macrophages and monocytes may be stimulated by specific allergens to augment T-cell proliferation (3), which may result from a different profile of cytokines released from these cells. For example, increased release of granulocyte-macrophage colony-stimulating factor (GM-CSF) may inhibit the immunosuppressive effect of macrophages (4). Indeed, macrophages and monocytes from asthmatic subjects release increased amounts of proinflammatory cytokines, such as interleukin-1beta (IL-1), tumor necrosis factor-alpha, Interferon-gamma (IFN-gamma), IL-6, and GM-CSF (5-8). Inhaled steroids used for the treatment of asthma reduce the number of infiltrating eosinophils, T-cells, macrophages, and mast cells in the airway submucosa (9). Suppression of proinflammatory cytokine release, such as GM-CSF, IL-4, IL-5, and regulated upon activation, normal T-cell expressed and secreted (RANTES), from many inflammatory and resident airway cells, is a likely mechanism of steroid action (10-12). Proinflammatory cytokine expression. PMID- 21312123 TI - MAP Kinase Expression in Eosinophils. AB - The mitogen-activated protein kinases (MAPK) are an expanding family of proline directed serine/threonine kinases that are activated, following their dual phosphorylation at conserved threonine and tyrosine residues, by a family of MAPK kinases (MEK). Presently, the MAPK family can be divided into three groups: the extracellular signal-regulated kinases (ERK), composed of ERK-1/2/3/4/5, the c jun N-terminal kinases (JNK)-46/54; and the p38 MAP kinase (p38 MAPK) composed of p38/p38beta/p38gamma/p38delta (1). Of these enzymes, the authors have detected ERK-1/2/3/5, JNK-46/54, and p38 in guinea pig peritoneal eosinophils by Western analysis: ERK-4 and p38beta were apparently absent. PMID- 21312124 TI - Human eosinophil isolation and the measurement of apoptosis. AB - Eosinophils have been implicated in allergic diseases, such as bronchial asthma, which is characterized by elevated eosinophil numbers in the bronchoalveolar lavage fluid and peripheral blood. Their accumulation and activation within the airway mucosa is thought to cause tissue injury, contraction of airway smooth muscle, and increased bronchial responsiveness (1-3). The balance between cell maturation and death is of great importance in determining the number of eosinophils in the blood and tissues (4-6). Following in vitro culture in the absence of cytokines, eosinophils undergo apoptosis, or programmed cell death (7,8), a process that can be inhibited by cytokines such as interleukin-3 and -5 and granulocyte-macrophage colony-stimulating factor (GM-CSF), and accelerated by such factors as corticosteroids and Fas (7-11). PMID- 21312125 TI - Adhesion of T-cells to airway smooth muscle cells. AB - Cell adhesion molecules (CAMs) have been implicated in many cellular functions, including development, tumor metastasis, leukocyte activation, homing, and transendothelial migration, and can also serve as viral receptors. The role of CAMs on leukocytes and endothelial cells, and the interactions between these cell types, have been extensively characterized. The current model of leukocyte recruitment and homing involves the expression and activation of a cascade of CAMs, as well as the local production of chemoattractants, leading to leukocyte adhesion and transmigration into lymph nodes and sites of inflammation (1). Most studies have focused on the mechanisms that control leukocyte adhesion and transendothelial migration, yet the subsequent interactions of infiltrating leukocytes with other cell types in the submucosa, and with the extracellular matrix, may also be important for sustaining the inflammatory response. PMID- 21312126 TI - Proliferation of circulating T-cells. AB - Together with B-lymphocytes, T-lymphocytes (or T-cells) comprise the antigen (Ag) specific arm of the immune response. The Ag receptors of both cell types are generated by recombination of multiple gene segments (1), giving rise to a large repertoire of receptors of differing specificity. When a lymphocyte encounters Ag, cellular activation occurs via aggregation of cell surface Ag receptors (2). The consequences of activation are numerous, but, in the case of the T-cell, include clonal expansion, via proliferation, and also secretion of soluble mediators and growth factors, such as interleukin-2 (for a review of the role of the T-lymphocyte in allergic disease, see ref. 3). PMID- 21312127 TI - Differential display analysis of inflammatory genes in airway epithelium. AB - Airway epithelial cells (ECs) form a continuous pseudostratified layer in the lung, creating a tight barrier that protects underlying tissue from the external environment. As such, airway ECs have been described classically as barrier cells that are involved in homeostasis; these cells respond to a variety of environmental stimuli, resulting in the alteration of their cellular functions, such as ion transport and movement of airway secretions. Recent evidence, however, suggests that airway ECs may also act as immune-effector cells, in response to noxious endogenous or exogenous stimuli. Several studies have shown that airway ECs express and secrete various immune molecules, such as lipid mediators, oxygen radicals, adhesion molecules, and a wide variety of cytokines, including chemokines (1). Through the expression and production of these immune molecules, the epithelium is now thought to be important in the initiation and exacerbation of inflammatory diseases of the lung, such as asthma. PMID- 21312128 TI - Analysis of Transcription Factor Activation: NFkappaB as a Regulator of Inflammatory Genes in Epithelial Cells. AB - In addition to being essential for differentiation and maturation, regulated gene expression governs many cellular responses to their local environment. For example, cytokines, viral infection, and numerous other inflammatory stimuli elicit the expression of specific response genes. Such signals are generally. PMID- 21312129 TI - Transient Transgenic Approaches for Investigating the Role of GM-CSF in Pulmonary Inflammation and Immune Diseases. AB - Granulocyte-macrophage colony-stimulating factor (GM-CSF), a 23-kDa polypeptide, was originally identified as a hematopoietic growth factor, but has recently been found to be a multifunctional cytokine with many proinflammatory activities (1,2). GM-CSF can be produced by, and act upon, a broad range of cell types, including both immature and mature granulocyte and monocyte lineage cells, dendritic cells, and tissue structural cells. Abundant in vitro observations have suggested that GM-CSF is able to induce both differentiation and activation of these cells (1). PMID- 21312130 TI - Quantitative Analysis of RANTES mRNA in Endobronchial Biopsies Using Polymerase Chain Reaction. AB - Inflammation of the airways is considered to be the key pathogenetic factor in asthma, airway hyperreactivity and clinical symptoms are considered secondary. PMID- 21312131 TI - Intracellular cytokine staining for analysis by flow cytometry. AB - To determine the function of a particular cell type, it is necessary either to have a large number of similar (ideally identical) cells or to use extremely sensitive methods to detect the activity of a single cell. Lymphocytes present special difficulties, because they have very precise antigen (Ag) recognition requirements, and, under physiological conditions, they will only be activated if they are exposed to their particular Ag. Polyclonal mitogens, such as phytohemagglutinin (PHA) or anti-CD3, will activate most T-cells, but may not elicit a truly physiological response in terms of cytokine production, and so on. Moreover, the biological readout (release of cytokines into culture supernatant) will represent the net balance of the integrated response of all the activated cells, minus any consumption of cytokines by the cultured cells. PMID- 21312132 TI - Localization of IL-4 and IL-5 mRNA in Bronchial Biopsies. AB - Cytokines are important biochemical mediators essential in initiating and maintaining inflammatory reactions associated with allergic disease in man. Although cytokines can be secreted from a variety of different cell types, considerable attention has been focused on T-lymphocyte-derived cytokines, which have been clearly implicated in the modulation of the immune system. Bronchial asthma is associated with persistent infiltration of the airways with activated CD4(+)T-lymphocytes, as well as other inflammatory cells exhibiting a T-helper type-2 (Th2)-like cytokine profile (1-3). PMID- 21312133 TI - Immunohistochemical analysis of adhesion molecules in airway biopsies. AB - Adhesion molecules are receptors found on the surface of leukocytes and endothelial cells, which bind to their ligands, either on other cells or on the extracellular matrix. The function of adhesion molecules is to allow leukocytes to interact with other hemopoetic cells or with foreign antigens (Ags) in the blood, to transiently adhere to the vascular endothelium, to migrate between endothelial cells and through the basement membrane into the surrounding tissue, and to adhere to the epithelium. There are three main groups of adhesion molecules: the integrins, immunoglobulin (Ig) supergene family, and the selectins: These are summarized in Table 1 (1-7). Table 1 Summary of Adhesion Molecules Group CD number Name Expressed on Ligand Integrins CD 49a VLA-1 T lymphocytes, fibroblasts, basement membrane Laminin, collagen B1 very late antigens CD 49b VLA-2 Activated T lymphocytes, platelets, fibroblasts, endothelium, epithelium Collagen, laminin CD 49c VLA-3 Epithelium, fibroblasts Laminin, collagen, fibronectin CD 49d VLA-4 Leukocytes, fibroblasts VCAM-1, fibronectin CD 49e VLA-5 Leukocytes, platelets, epithelium Fibronectin CD 49f VLA 6 T lymphocytes, platelets Laminin B2 leukocyte integrins CD 11a LFA-1 Leukocytes ICAM-1, ICAM-2, ICAM-3 CD 11b Mac-1 Macrophages, monocytes, granulocytes ICAM-1, fibrinogen, C3bi CD 11c p150.95 Macrophages, monocytes, granulocytes Fibrinogen, C3bi IG Supergene family CD 54 ICAM-1 Endothelium, leukocytes, epithelium LFA-1 Mac-1 CD 102 ICAM-2 Endothelium, leukocytes LFA-1 CD 106 VCAM-1 Endothelium, dendritic cells, tissue macrophages VLA-4 Selectins CD 62E E selectin Endothelium Sialyl Lewis x CD 62P P selectin Platelets, endothelium Sialyl Lewis x CD 62L L selectin Leukocytes Mannose-6-P, fructose-6-P. PMID- 21312134 TI - Site-Directed Mutagenesis in the Investigation of beta-Adrenoreceptor Exosite. AB - beta(2)-adrenergic receptor agonists (beta-agonists) are first-line agents for the treatment of acute bronchospasm. These drugs achieve bronchodilation primarily via activation of beta(2)-adrenergic receptors (beta(2)AR) located on airway smooth muscle cells. In addition, beta-agonists may alleviate bronchospasm, and protect against airway hyperresponsiveness, by interacting with beta(2)AR expressed on other lung cells, resulting in such diverse actions as alterations in ion permeability, changes in mucocilliary beat frequency, and so on (1). Most beta-agonists in clinical use are structural derivatives of the endogenous beta(2)AR agonist, adrenaline, including substituted catecholamines, such as isoprenaline and isoetharine; resourcinols, such as metaproterenol, fenoterol, and terbutaline; and saligenins, such as salbutamol and salmeterol. Of these, salmeterol, a highly lipophilic derivative of the partial agonist, salbutamol, represents the latest long-acting generation of beta-agonists, with a duration of activity in excess of 24 h (2). PMID- 21312135 TI - Methods for Determining beta(2)-Adrenoreceptor Genotype. AB - Polymorphisms of the beta(2)-adrenoceptor (beta(2)AR) have been the focus of much interest as part of the search to elucidate the genetic basis of asthma and allergic disease. More recently, these polymorphisms have also been implicated in the genetic etiology of essential hypertension (1,2) and obesity (3,4). This chapter describes in detail the method of allele-specific-oligonucleotide hybridization (ASO), a technique that has been used extensively by the authors' group to determine beta(2)AR genotype. This method should prove useful not only to those intending to analyze beta(2)AR polymorphisms, but also for the analysis of other candidate genes, given that this technique can be adapted and applied to any known single-base mutation. PMID- 21312136 TI - Modulation of beta-Adrenoreceptor Expression in the Airways. AB - beta-Adrenoceptors (betaAR) are members of the G-protein-coupled receptor superfamily, consisting of three subtypes: beta(1), beta(2), and beta(3) (1). cDNAs and genes encoding three subtypes have been cloned from several species, including human. There are only beta(1)- and beta(2)ARs to be found in lung (2), which regulate many aspects of lung function. In addition to desensitization and downregulation at the cell surface membrane, the number of betaARs expressed is modulated by regulation of steady-state levels of mRNA and the rate of gene transcription (3). Regulation of beta- and beta(2)AR mRNAs and gene transcription in lung may occur after exposure to receptor agonists or drug treatments (4-6). Thus, this could represent a mechanism for long-term modulation of betaAR expression. PMID- 21312137 TI - Chemical mutational analysis of glucocorticoid receptor. AB - This chapter describes a chemical method for mutational analysis of the human glucocorticoid receptor (hGR) cDNA. Corticosteroid-resistant (CR) asthma is associated with in vitro and in vivo defects in mononuclear cell function (1). In addition, molecular studies using these cells have revealed that there is reduced binding of the hGR to its DNA recognition site, the glucocorticoid response element, compared to corticosteroid-sensitive (CS) controls (2). The authors therefore postulated that a point mutation of the primary structure of the GR was responsible for this functional defect, necessitating a method that would be sensitive enough to detect single-base-pair (bp) mismatches. PMID- 21312138 TI - Histone acetylation and deacetylation. AB - In the resting cell, DNA is tightly compacted to prevent transcription factor accessibility. During activation of the cell, this compact inaccessible DNA is made available to DNA-binding proteins, thus allowing the induction of gene transcription (1 ,2). DNA is packaged into chromatin, a highly organized and dynamic protein-DNA complex. The fundamental subunit of chromatin, the nucleosome, is composed of an octomer of four core histones, an H3/H4 tetramer and two H2A/H2B dimers, surrounded by 146 bp DNA (2,3). The packaging of DNA into nucleosomes acts as a barrier to the initiation of transcription by preventing the access of transcriptional factors, and RNA polymerase II, to their cognate recognition sequences (4). Specific lysine residues in the N-terminal tails of the core histone can be post-translationally modified by acetylation of the epsilon-amino group. The dynamic equilibrium of core histone acetylation is established and maintained by histone acetyltransferase (HAT) and histone deacetylase (HDAC). Several transcriptional regulators possess intrinsic HAT and HDAC activities, strongly suggesting that histone acetylation and deacetylation play a causal role in regulating transcription (5-8). There is compelling evidence that increased gene transcription is associated with an increase in histone acetylation; hypoacetylation of histone is correlated with reduced transcription or gene silencing (2 ,7,8; Fig 1). PMID- 21312139 TI - Genome-wide search for asthma genes. AB - In addition to important environmental factors, it is now well established that genetic factors contribute significantly to the development of asthma and atopy, accounting for between 30 and 60% of the predisposition (1-3). This genetic predisposition is likely to result from the inheritance of a multiple number of polymorphic or mutant genes (4). Over the past decade, numerous researchers have conducted genetic linkage and/or association studies that aimed to identify such genes. These two types of studies are fundamentally different. A linkage study compares the inheritance pattern of the disease phe-notype to the inheritance pattern of a particular genetic marker in pedigrees, looking for coinheritance, and thus linking that particular marker locus to the disease. The association study, on the other hand, identifies candidate genes by comparing particular gene variant (allele) frequency in cases and controls, and therefore implicating that particular allele in the predisposition to the disease. Detecting genetic linkage usually indicates the presence of a gene within a genetic distance of approx 10 centimorgans (cM) around the linked locus. Genetic association tends to operate within a much shorter genetic distance (1 cM), but this distance varies, depending on the structure of the study population (relating to the ancestor founder effect). PMID- 21312140 TI - [High volume local infiltration analgesia (LIA) for total hip and knee arthroplasty: a brief review of the current status]. AB - Local infiltration analgesia (LIA) is usually performed intraoperatively by the surgeon who injects 150 mL (300 mg Ropivacain, 30 mg Ketorolac and 0.5 mg adrenalin) into the bone, cartilage, ligament, musculature, or hyperdermis. A tight bandage and ice cooling for 4 - 6 hours lengthen the duration of analgesia, mobilisation can be undertaken about 5 hours after the operation. Besides large observation-in-use studies, there are 11 randomised studies in the fields of total hip and knee arthroplasty that report comparisons with systemic analgesia as well as with epidural or peripheral anaesthesia, all of which showed positive results for LIA. In addition LIA is safe, has favourable costs and does not require any special technical abilities in contrast to epidural and peripheral regional anaesthesia. PMID- 21312141 TI - [Pitfalls of anesthesiologic management in paediatric strabismus surgery]. AB - Strabismus surgery is one of the most common paediatric operation procedures. As associated with congenital syndrome, congenital heart disease and neuromuscular disorder, the anesthesiologic management has to be planned carefully. Considering high incidences of oculocardiac reflex (OCR) and postoperative nausea and vomiting (PONV) anesthesia can be performed to decrease both. Induction of anesthesia with ketamine or midzolam reduces risk of oculocardiac reflex, whereas propofol or remifentanil lead to higher incidences of OCR. A combination anti emetic therapy from different drug classes is recommend to patients at high risk for nausea and vomiting like patients undergoing strabismus surgery. A combination therapy of ondansetron and dexamethasone lead to a risk reduction of PONV to at least 10 %. Further, the incidence of OCR and PONV is significantly reduced in children receiving peribulbar block on top of general anaesthesia. PMID- 21312142 TI - [Intra-arterial ECG leads of a positive P-wave potential during central venous catheterization]. AB - The application of a central venous catheter (CVC) is a routine procedure in anaesthesia and intensive care medicine. Although the procedure is generally carried out without complications, nevertheless numerous and, in part acute life threatening and lethal complications have been described. The complication rate during placement of a CVC is up to 12%. To ensure the correct position of the catheter, different methods may be used: for example the intravascular feeder of a positive P-wave of the ECG. In the case of a position check via the ECG (alpha Card), the catheter's point serves as a unipolar electrode. The intraatrial ECG lead is used as a raised and heightened P-wave potential for the correct catheter position. In this case, we present a 65 year-old critically ill patient with an occlusion of the right superficial femoral artery and acute respiratory distress syndrome (ARDS) in whom a puncture trial of the right internal jugular vein was carried out. This was followed by the placement of the CVC intended for the right internal jugular vein which, however, turned out to be a direct puncture of the right carotid artery. Despite the inaccurate intra-arterial position, forwarding of the catheter showed a typical raised and heightened P-wave potential. The artery puncture was checked via a blood gas analysis and the artery blood pressure diagram tracing. The removal and correct placement of the CVC were achieved without any problems. These findings emphasize the P-wave potential in the ECG feeder does not correlate with the transition from the superior vena cava to the right atrium. Consequently, this does not preclude an intra-arterial malposition. PMID- 21312143 TI - [Hospital hygiene. Norovirus infections]. AB - Outbreaks of gastroenteritis caused by noroviruses have become an increasing problem for institutions in the health-care system over the past years. Staff members are also afflicted by the outbreaks of infection due to the highly contagious nature of noroviruses and this can lead to bottlenecks in health-care management and to economic losses. An acute gastroenteritis due to norovirus usually begins with severe nausea, heavy often projectile vomiting and a pronounced feeling of unwellness. In addition, there can be diarrhoea and abdominal cramps. The incubation time amounts to around one day. As a rule the disease is self-limiting and clears up after 2 to 3 days. However, the clinical pictures for one and the same type of pathogen can vary markedly from mild to severe illness. Since there is no way to treat the cause of a noroviral infection, prophylactic hygiene measures, especially of standard hygiene, are of particular importance. The necessary hygiene measures (especially hand hygiene) are aimed at interrupting the faecal-oral transmission pathway. PMID- 21312144 TI - [The chronic pain patient as an emergency. (Acute=) pain therapy outside of the routine]. PMID- 21312145 TI - [Breakthrough pain in cancer patients]. AB - The treatment of cancer pain shows a special challenge in the ambulatory and stationary treatment of various medical departments. A multifactorial design has to be established for the treatment of breakthrough pain episodes. The development of fast acting lipophilic opioids has improved the therapy of breakthrough pain. Combining these opioids with non-opioid analgetics, adjuvant drugs, interventional procedures, radiotherapy, orthotic devices and surgical /orthopedic interventions delivers a multimodal approach to manage breakthrough cancer pain. PMID- 21312146 TI - [Acute pain therapy for non opioid-naive patients]. AB - Patients used to opioids belong to 2 groups: patients under opioid therapy due to tumor pain or chronic non malignant pain and, second, opioid addicts with current uncontrolled abuse, under substitution therapy or former opioid addicts ("clean"). Perioperatively these patients are difficult to manage because of the complex medical as well as psychosocial factors. Despite these problems, these patients have a right to receive sufficient perioperative pain therapy and this should not be withheld. Due to the lack of controlled studies this review summarizes standardized examples and alternatives in the acute pain treatment of patients using opioids. Early interdisciplinary cooperation, prevention of withdrawal through substitution of opioids and alternative treatment strategies like regional analgesia or ketamine as well as carefully titration of opioids are the essential components of the treatment of these patients. Furthermore, these patients require a clear and empathic guidance by medical and nursing staff. PMID- 21312147 TI - [Acute exacerbation of chronic non-malignant pain]. AB - Common recommendations for the treatment of acute exacerbations of non-malignant chronic pain (e.g. migraine, trigeminal neuralgia, cluster headache or chronic pancreatitis) are often not adequate to provide sufficient analgesia. Specific recommendations based on the underlying disease mechanisms are usually more likely to offer efficacious treatment algorithms. In the case of migraine, triptanes represent an option to improve analgesia if NSARs fail, and in cluster headache triptanes and especially inhalation of oxygen have been proven to be the most effective measures. German guidelines recommend intravenous procaine, besides pethidine and buprenorphine, for the management of acute exacerbations of chronic pancreatitis. The objective of this survey is to provide recommendations for the treatment of acutely exacerbated pain states on the basis of international guidelines. The authors place particular emphasis on parenteral drug administration to achieve a rapid onset of action. PMID- 21312148 TI - [Non-algesic acute conditions: constipation, nausea and sickness in tumor and other patients]. AB - Constipation, nausea and sickness are frequent accessory symptoms in patients suffering from chronic pain. Typical causes are the underlying disease and the medical treatment against chronic pain. Most often opioid treatment induces an enteric dysfunction syndrome with constipation as a leading symptom and, especially in the initial phase, nausea due to direct stimulation of central structures. Therefore prophylactic and therapeutic strategies should be determined routinely and additionally, in special cases, different reserve measures might be applied. PMID- 21312149 TI - [Anesthetic assistance in West Africa. Objectives, difficulties and opportunities for development.]. PMID- 21312150 TI - [Acute renal failure in intensive care - 8. Critical Care Symposium of the Department of Anesthesiology and Intensive Care.]. PMID- 21312152 TI - [Guidelines for research reports: an application of CONSORT 2010 statements]. AB - INTRODUCTION: Reporting guidelines are not only useful for authors in compiling complete and transparent reports but they can use also be used by readers for the critical appraisal of the study. In this study, we apply the CONSORT 2010 reporting guideline to illustrate its value as the first step in the critical appraisal. PATIENTS AND METHODS: We have applied the checklist of the CONSORT 201 statement to the publication of Richter et al. [7]. This has been done by both authors independently. We report for each item of the 25 item checklist whether it was adequately reported, and we comment on each item. RESULTS: The paper of Richter et al. does not comply with the CONSORT 2010 checklist and the CONSORT extension for summaries in all items. CONCLUSION: The most important reporting guidelines are now available in German (https://www.thieme connect.de/ejournals/toc/dmw/104011). They are useful for authors of research articles to compile complete and transparent reports. Readers can use items of these reporting guidelines for judging the quality of a published study. To this end, there is a need to distinguish between reporting quality and the quality of a specific study. PMID- 21312155 TI - [Diagnostic accuracy of language tests and parent rating for identifying language disorders]. AB - BACKGROUND: Until now German language tests have been rarely evaluated for their diagnostic accuracy. The goal of the study was to determine whether frequently used German language instruments are valid measures for identifying developmental language disorders in 3-year-old children. MATERIAL AND METHODS: The language test SETK 3-5 (including the short version SSV) and the parent questionnaire SBE 3-KT were administered to 88 children with and without language impairment. The procedure of the selection of children enabled an extrapolation to general population. A language sample rating was used as a gold standard. RESULTS: Depending on case definition 6-22% of children were classified as language impaired by SETK 3-5, 9% by SSV and 15% by SBE-3-KT. Sensitivity, specificity and positive predictive values of SETK 3-5 for specified cut-offs were 35-93%, 86-97% and 41-58%, respectively. The corresponding values of SSV were 49%, 96%, 56% and of SBE-3-KT 92%, 93%, 59%. CONCLUSIONS: 3-year-old children with developmental language disorders can been identified with sufficient accuracy by means of SETK 3-5, an individual language test, as well as by SBE-3-KT, a parent questionnaire. However, the number of false positive classifications is relatively high. The hit rate of SSV, an individual short test, was too low for clinical use. PMID- 21312156 TI - [Stroboscopy findings: a comparison of flexible CCD-videostroboscopy and rigid stroboscopy]. AB - OBJECTIVE: After exclusion of morphologic laryngeal alterations by laryngoscopy the prospective study compared stroboscopy findings using a flexible distal charge-coupled device chip-optic (CCD-optic) and a rigid 70 degrees - or 90 degrees -laryngoscope. MATERIAL AND METHODS: 52 patients with functional dysphonia and 47 candidates for speech therapy education were checked with both examination methods. The stroboscopy results were rated randomized and pseudonymized by 3 experts assessed by a study protocol according to the European laryngological society basic protocol 2001. RESULTS: The interrater-reliability was moderate to good. Using the flexible videolaryngoscopy less gaging, less supraglottic contraction during phonation, more often a complete glottal closure and more often a normal mucosal wave movement were found. CONCLUSION: To get an optimal endoscopy result the combination of rigid laryngoscopy and flexible videolaryngoscopy and -stroboscopy will be recommended. Because of the variety of stroboscopic findings for the diagnosis of functional dysphonia additional the case history and functional voice examinations are necessary. PMID- 21312157 TI - [Respiratory therapy (bagging, air stacking) for patients in early neurorehabilitation]. AB - In a pilot project we examined whether an improvement of oxygen saturation (SPO (2)) can be established by applying a modified respiratory intervention technique (bagging) for patients in early neurorehabilitation. The "bagging" method involves adding air into the lungs during the inspiration phase by using a resuscitation bag. Subsequently, the patient is requested to cough, and is given manual support on the chest by the therapist. We examined a group of 11 patients who received 1 - 2 bagging interventions per day over a period of 12 days. By applying the bagging method, a continuous and stable improvement of oxygen saturation could be accomplished for all patients. A single case analysis confirmed this effect for each patient. Furthermore, we observed an improvement of the patients' vigilance, improved quality of bronchial secretion and marked improvements in swallowing and phonation. The bagging method is an easy-to-learn and inexpensive method that leads to a stable and sustained increase in oxygen saturation and to improvement of other clinical parameters. PMID- 21312158 TI - [Student grants in Saxony--a successful story?]. AB - BACKGROUND: The lack of general practitioners in rural areas is a problem for many industrialised countries. There seems to be a promising solution among medical students. This was recognised in Saxony in 2009 and an appropriate sponsoring programme was set up. In this study we have examined the utility, the factors influencing the interest in this sponsorship and its acceptance. METHODS: Answers to a written questionnaire sent to medical students in Saxony were evaluated with the help of descriptive statistics. RESULTS: 25 of the total of 1 055 students who received the questionnaire stated that they used the sponsorship programme. Positive influencing factors for interest were above all a higher state of knowledge, the students' background, stage of studies and type of financial support. The primary reasons for rejecting the program were, besides fear of being bound by it (74%), the wish for advanced training in a different specialty (54%) and the wish to work in a hospital (33%). DISCUSSION: By adapting the conditions of the sponsorship programme and by targetted communications, it should be possible to increase its acceptance. Thus, financial compensation for not used sponsoring could induce more advanced students to accept aid. Students from rural districts should be specifically approached since they exhibit a higher affinity for choosing to practice in rural areas. It would also be helpful to focus more on students who finance their studies themselves. In general, it can be assumed that a higher density of information would also lead to a greater interest. PMID- 21312159 TI - [Hereditary vascular malformations: classification, symptoms, diagnostics and prognosis]. AB - The understanding of hereditary vascular anomalies was hampered for a long time by unclear und unspecific terminology. Today, the classification of the International Society for the Study of Vascular Anomalies (ISSVA) differentiates between vascular tumours (mostly infantile haemangioma) with active endothelial proliferation and regression and vascular malformations (VM), which are defects of the vascular morphogenesis and are distinguished in predominantly venous, arterial, capillary, lymphatic, arteriovenous or combined VM. Symptoms are pain, swelling and restricted movement, accompanied by skin signs like dys-plastic veins and capillary VM (naevus flammeus). Thrombophlebitis and chronic venous insufficiency are related to venous VM. Arteriovenous VM are progressive and can cause ischaemic necroses, in rare cases even a high-output cardiac fail-ure. Lymphatic VM lead to localised swelling, in the long run often to recurrent erysipelas and lymphorroea. Primary imaging is provided by -ul-trasound including flow measurements. Mor-phol-ogy and organ involvement is best delineated by magnetic resonance imaging. Phlebography is used to image deep venous system anomalies and is always accompanied by varicography of the dysplastic parts of the venous VM. Digital subtraction angiography is performed to demon-strate the flow pattern in feeding arteries, the nidus and the drainage veins of arteriovenous VM. Besides size and localisation the prognosis of the patients is determined by the pressure (the high-er the pressure, the poorer the prognosis) and the flow rate (the higher the flow rate, the poorer the prognosis) in the VM. Diagnosis and treatment of these rare diseases are best performed in special ised, interdisciplinary centres. PMID- 21312160 TI - [The embolisation of venous malformations]. AB - BACKGROUND: The treatment of congenital, vascular malformations is a challenge for physicians and patients. Although different therapeutic options have been described to date, their individual relevance has still to be defined. A METHODS: We performed a retrospective study of 61 patients with a venous malformation (VM, mean age 22 years), who were referred to our depart-ment during the last 5 years. The size of the VM was larger than 5 cm in 41 patients (66 %). The lower extremities were involved in 45 cases (73 %). The most frequent clinical manifestations were recurrent swelling (80 %), pain (63 %), varicosis (60 %) and thrombophlebitis (39 %). MR angiography with venous sequences was always performed before treatment. Depending on the localisation and the extension of the VM, different techniques of embolisation were selected: foam sclerotherapy or application of synthetic glue by direct punction, coiling of pelvic veins or arterial embolisation with glue. RESULTS: 42 patients (69 %) underwent a procedure because of the complaints or the extension of the VM. An embolisation was performed in 25 patients with 65 interventional sessions. The most frequent technique was foam sclerotherapy (45 *), followed by glue injection (13 *), pelvic -venous coiling (6 *) and arterial embolisation with glue (1 *). Fifteen patients (60 %) reported a very good and 8 patients a marked improvement (32 %). In two cases there was no change of the complaints. The postinterventional complications were severe pain (n = 3) and skin/fat necrosis at the toe of one patient. CONCLUSIONS: The embolisation of venous malformations is an effective therapeutic tool. Different techniques can be used to address specific localisations and morphological patterns. The com-plication rate is very low when a step-by-step -approach is used, so that a repeat intervention is feasible. However, a more specific documentation of the post-interventional changes of the VM is needed before a general recommendation can be given. PMID- 21312161 TI - [Medical health care in Germany - large regional differences]. PMID- 21312162 TI - Current concepts and new developments for autologous in vivo endothelialisation of biomaterials for intravascular applications. AB - Circulating endothelial progenitor cells (EPCs) in the peripheral blood of adults represent an auspicious cell source for tissue engineering of an autologous endothelium on blood-contacting implants. Novel materials biofunctionalised with EPC-specific capture molecules represent an intriguing strategy for induction of selective homing of progenitor cells. The trapped EPCs can differentiate into endothelial cells and generate a non-thrombogenic surface on artificial materials. However, the success of this process mainly depends on the use of optimised capture molecules with a high selectivity and affinity. In recent years, various biomedical engineering strategies have emerged for in situ immobilisation of patient's own stem cells on blood contacting materials. The realisation of this in vivo tissue engineering concept and generation of an endothelium on artificial surfaces could exceedingly enhance the performance of not only small calibre vascular grafts and stents, but also, in general all blood contacting medical devices, such as heart valves, artificial lungs, hearts, kidneys, and ventricular assist devices. PMID- 21312163 TI - Time kinetics of bone defect healing in response to BMP-2 and GDF-5 characterised by in vivo biomechanics. AB - This study reports that treatment of osseous defects with different growth factors initiates distinct rates of repair. We developed a new method for monitoring the progression of repair, based upon measuring the in vivo mechanical properties of healing bone. Two different members of the bone morphogenetic protein (BMP) family were chosen to initiate defect healing: BMP-2 to induce osteogenesis, and growth-and-differentiation factor (GDF)-5 to induce chondrogenesis. To evaluate bone healing, BMPs were implanted into stabilised 5 mm bone defects in rat femurs and compared to controls. During the first two weeks, in vivo biomechanical measurements showed similar values regardless of the treatment used. However, 2 weeks after surgery, the rhBMP-2 group had a substantial increase in stiffness, which was supported by the imaging modalities. Although the rhGDF-5 group showed comparable mechanical properties at 6 weeks as the rhBMP-2 group, the temporal development of regenerating tissues appeared different with rhGDF-5, resulting in a smaller callus and delayed tissue mineralisation. Moreover, histology showed the presence of cartilage in the rhGDF 5 group whereas the rhBMP-2 group had no cartilaginous tissue. Therefore, this study shows that rhBMP-2 and rhGDF-5 treated defects, under the same conditions, use distinct rates of bone healing as shown by the tissue mechanical properties. Furthermore, results showed that in vivo biomechanical method is capable of detecting differences in healing rate by means of change in callus stiffness due to tissue mineralisation. PMID- 21312164 TI - [The role played by Toll-like receptors in cerebral infarction processes]. PMID- 21312165 TI - [Cognitive reserve questionnaire. Scores obtained in a healthy elderly population and in one with Alzheimer's disease]. AB - INTRODUCTION: The term cognitive reserve describes the capacity of the adult brain to minimise the clinical manifestation of a neurodegenerative process. The acquisition of cognitive reserve has been linked to the performance of certain intellectual and cognitive activities throughout the whole of the individual's life. AIMS: To create a new cognitive reserve questionnaire (CRQ), to establish its relation with the cognitive functions and to obtain the standard values in the cognitively healthy elderly Spanish population. SUBJECTS AND METHODS: The sample consisted of 55 cognitively healthy controls and 53 patients with Alzheimer's disease. All the subjects were asked to complete the CRQ, which consists of eight items with several different possible answers, together with a brief neuropsychological battery. RESULTS: Age had no significant influence on the score obtained on the CRQ in either of the groups, yet the number of years of schooling did exert a significant effect. In both groups significant correlations were found between the score on the CRQ and performance in neuropsychological tests that measure executive functioning. CONCLUSIONS: The CRQ is a useful questionnaire for assessing the degree of cognitive reserve in healthy controls and in patients in the early stages of Alzheimer's disease. The CRQ is associated with the cognitive performance of executive functioning. PMID- 21312166 TI - [CADASIL: a case series of 11 patients]. AB - INTRODUCTION: The term CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) refers to a hereditary systemic microangiopathy caused by mutations of the NOTCH3 gene located on chromosome 19. It typically presents in young people with migraine attacks and recurrent ischemic strokes, leading to a progressive subcortical cognitive decline over several years. AIM: To describe the symptoms of onset and clinical manifestations in 11 CADASIL patients diagnosed by genetic testing or skin biopsy. PATIENTS AND METHODS: Detailed physical and neurological examinations, vital signs, electrocardiogram, laboratory investigations (including glucose levels, lipid profile, coagulation studies and homocysteine levels, among others), brain MRI, Mini-Mental Test and Trail Making Test A and B were done. In addition, some patients with complaints related to depressive symptoms or impaired cognition received the Montgomery and Asberg Depression Rating Scale and a battery of neuropsychological examinations (the Stroop Color and Word Test and the V-ADAS cog that includes the Maze Test). RESULTS AND CONCLUSIONS: Our patients presented with a clinical course and a radiological pattern similar to those described previously in the literature. We found a delay in the detection of this pathology and previous diagnostic errors in some patients and their relatives. Multiple sclerosis was the most frequent misdiagnosis. The course of the disease was barely modified by therapeutic interventions introduced to control the progression of the symptoms. Cognitive complaints in patients with advanced stages were common and the executive abilities were found to be impaired in many cases. PMID- 21312167 TI - [Brixton Spatial Anticipation Test, executive function development and the relationship with the Tower of London]. AB - INTRODUCTION: Rule induction and shifting abilities are among executive functions. The Brixton Spatial Anticipation Test (BSAT) was designed for the evaluation of this dimension in adult populations. There are no papers that explore its implementation during development, or its relations to other executive tasks and fluid intelligence. AIM: To study the behavior in the BSAT of a primary school population (6 to 11 years), comparing it with the performance on a well-known executive task and a fluid intelligence test level. SUBJECTS AND METHODS: Trough a descriptive-correlational, transversal design, the Tower of London (TOL), the BSAT and the Progressive Matrix Raven's Test (PMRT) were applied in 44 children of both sexes, from 1st to 6th grade (primary school), medium to high socio-economical stratum, from Montevideo. The BSAT is applied for the first time in normal children, so it's relevant for its knowledge. RESULTS: A similar progressive and ascending performance was observed for both BSAT and TOL. Positive and significative correlations were found between BSAT and PMRT, specially with AB and B series. Positive but non significative correlations were observed between BSAT and TOL. CONCLUSIONS: Executive functions follow a progressive and ascending pattern trough development in children, with light differences in relation to the executive component evaluated by each task. The factor 'g' of fluid intelligence, could be an important predictor of executive components taped by BSAT but not TOL. PMID- 21312168 TI - [Abnormal movements of peripheral origin: seven case reports]. AB - INTRODUCTION: Movement disorders induced by central nervous system trauma are well recognized. The relation between peripheral injury and the subsequent development of movement disorders has been documented in many reports, specially dystonia and tremor. Pathophysiological mechanisms underlying these movement disorders are not well understood. CASE REPORTS: We report a group of seven patients with movement disorders induced by peripheral trauma. The inclusion criteria used for the patients were: the trauma was well documented for the patient and the medical history, and the onset of the movement disorder was anatomically and temporally related to the injury. We describe seven patients presenting respectively oromandibular dystonia, radicular myoclonus, tremor, segmental dystonia, lower limbs dystonia, segmental myoclonus and tremor, of the body parts previously exposed to traumatic injuries. CONCLUSIONS: Individual predisposition and central changes with pathological reorganization in response to peripheral injury have been considered in the pathogenesis of peripherally induced movements disorders. PMID- 21312169 TI - [Review of the novelties presented at the 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) (I)]. AB - The new insights presented at European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held in the city of Gothenburg, Sweden, in October 2010, have been summarized at the third edition of Post-ECTRIMS meeting held in Madrid in November 2010. The age is an important factor related to the course and prognosis of multiple sclerosis (MS). The evolution to progressive disease persists more than 50 years after diagnosis of MS and a reduction in the delay of diagnosis has been detected. Several strategies have been proposed in order to improve the efficacy of magnetic resonance regarding prognosis and course of disease. The studies presented at the Congress reflect the influence of gender on course and severity of disease symptoms, showing an increase of worldwide prevalence of MS in women. Neuroprotective action of estrogen receptor beta has been reported. The genome wide association studies have allowed investigators to identify numerous susceptible alleles. In this regard, HLA class II genes, seems to contribute to genetic risk for developing neutralizing antibodies against beta interferon. Vitamin D deficiency and Epstein-Barr virus have been highlighted as risk factors for MS in the reported findings. On the subject of the ongoing controversy regarding the role of inflammation and degeneration in MS, several arguments have been found to support the role of CNS autoimmunity to explain the presence of inflammatory phenomenon. The available data hold the potential therapeutic role of mesenchymal cells given the involvement of these stem cells in CNS repair. PMID- 21312170 TI - [Improvements in the diagnosis of dystrophinopathies: what have we learnt in these last 20 years?]. AB - INTRODUCTION. Dystrophinopathies are X-linked genetic disorders caused by mutations in the DMD gene. Genetic tests are of utmost importance for management and genetic counseling of these diseases. However, the complexity of the DMD gene is a challenge for diagnosis. AIM. To describe recent advances in the diagnosis of dystrophinopathies, after 20 years since the firsts molecular assays for genetic screening for these diseases. DEVELOPMENT. Currently, a variety of strategies such as automated mutation detection, cell-based methods and high throughput haplotyping have been developed to facilitate diagnosis of dystrophinopathies, carrier detection, prenatal and preimplantation diagnosis. CONCLUSION. New technologies have improved early detection and optimal management of dystrophinopathies and have established the basis for future molecular medicine. The most significant advances in dystrophinopathy diagnosis are reviewed herein. PMID- 21312171 TI - [A novel case of anti-NMDA receptor encephalitis with no associated tumour]. PMID- 21312172 TI - [Spontaneous tumour regression in neurofibromatosis type 1 and macrophage inhibitory factor]. PMID- 21312173 TI - [Cerebral venous thrombosis as a complication following a diagnostic lumbar puncture]. PMID- 21312174 TI - [Altered consciousness states associated with spirituality]. PMID- 21312176 TI - [Bacterial meningitis due to gram-negative bacilli in immunosuppressed adults who have not undergone neurosurgery]. PMID- 21312177 TI - Morphological characterization of a brown lemur hybrid zone (Eulemur rufifrons * E. cinereiceps). AB - Hybridization has recently been identified as a pervasive force in the evolution of primates. In this study, we characterized a hybrid zone between two species of brown lemur (Eulemur rufifrons and E. cinereiceps) in the Andringitra region of southeastern Madagascar using morphological traits. We immobilized animals along a north-south transect (~80 km), scored them for their degree of hybridity using pelage traits and measured standard morphometric variables. Results from our study suggest that hybridization between E. rufifrons and E. cinereiceps is extensive, with the hybrid zone extending over 42.6 km and being composed mostly of later generation hybrids. We also identified significant variation between ancestral groups in our study: hybrid males exhibited longer tails than both parental species and sexual dimorphism in upper canine height favoring males was documented in E. rufifrons. These patterns could suggest that gene flow between parental and hybrid populations is relatively limited. Finally, significant differences between ancestral groups in relative body mass and skin-fold thickness were absent in our study, indicating that, as measured by these proxies, hybrids are equally as fit as parental forms. Based on these preliminary findings, the Andringitra hybrid zone could conform to the bounded superiority model of hybrid zone stability (i.e., it could be being maintained by selection favoring hybrids within transitional habitats). Accordingly, hybrids in Andringitra may be an unusual case among primates, representing a stable recombinant but distinct lineage. This conclusion has important implications for evolutionary processes within the brown lemur species complex. PMID- 21312178 TI - What lies beneath? An evaluation of lower molar trigonid crest patterns based on both dentine and enamel expression. AB - The nearly ubiquitous presence of a continuous crest connecting the protoconid and metaconid of the lower molars (often referred to as the middle trigonid crest), is one of several dental traits that distinguish Homo neanderthalensis from Homo sapiens. This study examined variation in trigonid crest patterns on the enamel and dentine surfaces to (1) evaluate the concordance between the morphology of trigonid crests at the inner dentine and the outer enamel surfaces; (2) examine their developmental origin(s); and (3) examine trait polarity through comparison with Australopithecus africanus and Pan. The sample included 73 H. neanderthalensis, 67 contemporary H. sapiens, 5 A. africanus, and 24 Pan lower molars. Results indicate general agreement in the morphology observed on the dentine and enamel surfaces. All but one H. neanderthalensis molar shows some trigonid crest development, whereas trigonid crests occur in low frequency in contemporary humans. Pan and A. africanus both also show high frequencies of a continuous trigonid crest. However, the origin of the trigonid crest differs among groups. H. neanderthalensis uniquely possesses a 'middle' trigonid crest that originates from the mesial accessory ridge of one or both cusps. Based on our results we suggest that presence of a continuous middle trigonid crest at the dentine surface is primitive and the lack of any trigonid crest is derived. Genetic drift may explain the high frequency of trigonid crests in H.neanderthalensis. However, H. neanderthalensis still appears to be derived relative to Pan and A. africanus in its high frequency of the mesial-mesial trigonid crestconfiguration. PMID- 21312179 TI - Odontometric sex discrimination in the Herculaneum sample (79 AD, Naples, Italy), with application to juveniles. AB - Sex determination of subadult skeletal remains with satisfactory accuracy represents one of the most important limitations of archaeological research and forensic practice. Teeth are one of the most durable physical elements of an individual that remain after death, and constitute a potential source of information about the biological sex of that individual. This study was based on the skeletal remains of 117 individuals from the ancient city of Herculaneum (Naples, Italy), victims of the eruption of the nearby volcano Vesuvius on 24/25 August, 79 AD. It has been possible to develop discriminant function formulae based on dental dimensions of adult individuals whose sex had previously been determined based on descriptive osteologic criteria. These formulae were subsequently applied to the permanent dentitions of immature individuals of the same population in order to estimate their sex. The results show that the canine is the tooth with the greatest sex dimorphism in adults, providing percentages of correct assignment of sex between 76.5% and 100% depending on the dimension used. Of the 30 subadult individuals in the target sample, estimation of sex was possible for 22 individuals. Sex assignments matched those determined from descriptive characteristics of the ilia and mandible in 73.33% of the cases. The results provide some optimism that this method may be applicable to juvenile archaeological samples. PMID- 21312180 TI - Mitochondrial DNA structure in North Africa reveals a genetic discontinuity in the Nile Valley. AB - Human population movements in North Africa have been mostly restricted to an east west direction due to the geographical barriers imposed by the Sahara Desert and the Mediterranean Sea. Although these barriers have not completely impeded human migrations, genetic studies have shown that an east-west genetic gradient exists. However, the lack of genetic information of certain geographical areas and the focus of some studies in parts of the North African landscape have limited the global view of the genetic pool of North African populations. To provide a global view of the North African genetic landscape and population structure, we have analyzed ~2,300 North African mitochondrial DNA lineages (including 269 new sequences from Libya, in the first mtDNA study of the general Libyan population). Our results show a clinal distribution of certain haplogroups, some of them more frequent in Western (H, HV0, L1b, L3b, U6) or Eastern populations (L0a, R0a, N1b, I, J) that might be the result of human migrations from the Middle East, sub Saharan Africa, and Europe. Despite this clinal pattern, a genetic discontinuity is found in the Libyan/Egyptian border, suggesting a differential gene flow in the Nile River Valley. Finally, frequency of the post-LGM subclades H1 and H3 is predominant in Libya within the H sequences, highlighting the magnitude of the LGM expansion in North Africa. PMID- 21312181 TI - Deep into the roots of the Libyan Tuareg: a genetic survey of their paternal heritage. AB - Recent genetic studies of the Tuareg have begun to uncover the origin of this semi-nomadic northwest African people and their relationship with African populations. For centuries they were caravan traders plying the trade routes between the Mediterranean coast and south-Saharan Africa. Their origin most likely coincides with the fall of the Garamantes who inhabited the Fezzan (Libya) between the 1st millennium BC and the 5th century AD. In this study we report novel data on the Y-chromosome variation in the Libyan Tuareg from Al Awaynat and Tahala, two villages in Fezzan, whose maternal genetic pool was previously characterized. High-resolution investigation of 37 Y-chromosome STR loci and analysis of 35 bi-allelic markers in 47 individuals revealed a predominant northwest African component (E-M81, haplogroup E1b1b1b) which likely originated in the second half of the Holocene in the same ancestral population that contributed to the maternal pool of the Libyan Tuareg. A significant paternal contribution from south-Saharan Africa (E-U175, haplogroup E1b1a8) was also detected, which may likely be due to recent secondary introduction, possibly through slavery practices or fusion between different tribal groups. The difference in haplogroup composition between the villages of Al Awaynat and Tahala suggests that founder effects and drift played a significant role in shaping the genetic pool of the Libyan Tuareg. PMID- 21312182 TI - Gender and population history: sex bias revealed by studying genetic admixture of Ngazidja population (Comoro Archipelago). AB - The peopling of Comoro Archipelago is defined by successive waves of migration from three main areas: the East African Coast (Bantu-speaking populations), the Persia and Arabian Peninsula, and Southeast Asia (especially Indonesia). It follows an apparent classic trihybrid admixture model. To better understand the Comorian population admixture dynamics, we analyzed the contributions of these three historical parental components to its genetic pool. To enhance accuracy and reliability, we used both classical and molecular markers. Samples consist of published data: blood group frequencies, 14 KIR genes, 19 mitochondrial DNA SNPs (to highlight female migrations), 14 Y chromosome SNPs (male migrations). We revealed distinct admixture patterns for autosomal and uniparental markers. KIR gene frequencies had never been used to estimate admixture rates, this being a first assessment of their informative power in admixture studies. To avoid major methodological and statistical bias, we determined admixture coefficients through nine well-tried estimators and their associated software programs (ADMIX95, ADMIX, admix 2.0, LEA, LEADMIX, and Mistura). Results from mtDNA and Y chromosome markers point to an important sex-bias in the admixture event. The original Bantu gene pool received a predominant male-mediated contribution from the Arabian Peninsula and Persia, and a female-mediated contribution from Southeast Asia. Admixture rates estimated from autosomal KIR gene markers point also to an unexpected elevated Austronesian contribution. PMID- 21312183 TI - Energetics during reproduction: a doubly labeled water study of lactating baboons. AB - Understanding the costs and regulation of reproduction in primates requires understanding the separate but linked effects of energy availability and total energy expenditure (TEE). We compared variation in TEE and energy intake (EI) between two periods, early lactation and after the resumption of sexual cycling, for eight females from two groups of normally reproducing colony-living baboons (Papio h. anubis). Total energy expenditure was assessed using the doubly labeled water method. TEE was correlated with maternal mass both during early lactation and after the resumption of cycling. TEE after the resumption of cycling was positively related to infant growth rates; mothers with rapidly growing infants had higher energy expenditure. TEE was however unrelated to maternal rank and only weakly associated with reproductive parameters such as delay to conception. EI in early lactation was related to infant mass and interbirth intervals, but unrelated to infant growth or reproductive parameters once cycling had resumed. Energy availability (EA; the difference between intake and expenditure) differed significantly between subordinate and dominant females during early lactation, was highly variable among individuals as a function of body composition, and is suggested to follow a nonlinear relationship as a complex function of social status, lactation stage, infant growth, and female fertility. Thus, as a consequence of reduced energy availability, subordinate females in this captive context may experience reproductive delays even though the total energy expenditure after the return of cycling was similar between high and low ranking females. PMID- 21312184 TI - Improving stable isotopic interpretations made from human hair through reduction of growth cycle error. AB - A recent trend in stable isotopic analysis involves the reconstruction of short term variations in diet using hair segments. However, bulk hair samples typically contain a growth cycle error, which may conceal or confound the most recently incorporated isotopic information. It is assumed that, at any given time, ~85-90% of scalp hairs are actively growing, while the remaining 10-15% have transitioned into a resting or inactive phase, which lasts up to 4 months before hairs are shed. This study uses growth phase to determine the effects of age, sex, and health status on carbon and nitrogen isotopic ratios of hair analyzed in sequential segments. For this study, we selected archaeological hair samples from 10 individuals from Dakhleh Oasis, Egypt. Isotopic analyses of actively growing hair segments were compared to those for mixed growth phase segments from each individual. These data demonstrate the presence of growth cycle error and show that an understanding of structural-functional relationships is essential for interpreting normal versus pathological changes in hair follicle and fiber production. In situations where diet change and mobility produce variations in an individual's isotopic composition, elimination of positional-temporal error in sequential segment hair analyses can facilitate greater understanding of intraindividual metabolic reactions and changes in hair growth cycles. Phase identification may aid in determining the presence of pathological conditions in individuals, especially in those lacking skeletal indications, and provide a more precise estimation of seasonal dietary patterns, access to changing food resources, and metabolic equilibration to a new locality. PMID- 21312185 TI - Intrapopulation variation in stature and body proportions: social status and sex differences in an Italian medieval population (Trino Vercellese, VC). AB - The phenotypic expression of adult body size and shape results from synergistic interactions between hereditary factors and environmental conditions experienced during growth. Variation in body size and shape occurs even in genetically relatively homogeneous groups, due to different occurrence, duration, and timing of growth insults. Understanding the causes and patterns of intrapopulation variation can foster meaningful information on early life conditions in living and past populations. This study assesses the pattern of biological variation in body size and shape attributable to sex and social status in a medieval Italian population. The sample includes 52 (20 female, 32 male) adult individuals from the medieval population of Trino Vercellese, Italy. Differences in element size and overall body size (skeletal height and body mass) were assessed through Monte Carlo methods, while univariate non-parametric tests and Principal Component Analysis (PCA) were employed to examine segmental and overall body proportions. Discriminant Analysis was employed to determine the predictive value of individual skeletal elements for social status in the population. Our results highlight a distinct pattern in body size and shape variation in relation to status and sex. Male subsamples exhibit significant postcranial variation in body size, while female subsamples express smaller, nonsignificant differences. The analysis of segmental proportions highlighted differences in trunk/lower limb proportions between different status samples, and PCA indicated that in terms of purely morphological variation high status males were distinct from all other groups. The pattern observed likely resulted from a combination of biological factors and cultural practices. PMID- 21312186 TI - Inhibition of Notch signaling prevents experimental fibrosis and induces regression of established fibrosis. AB - OBJECTIVE: Tissue fibrosis caused by pathologic activation of fibroblasts with increased synthesis of extracellular matrix components is a major hallmark of systemic sclerosis (SSc). Notch signaling regulates tissue differentiation, and abnormal activation of Notch signaling has been implicated in the pathogenesis of various malignancies. The present study was undertaken to investigate the role of Notch signaling in SSc and to evaluate the therapeutic potential of Notch inhibition for the treatment of fibrosis. METHODS: Activation of the Notch pathways was analyzed by staining for the Notch intracellular domain (NICD) and quantification of levels of HES-1 messenger RNA. In the mouse model of bleomycin induced dermal fibrosis and in tight skin 1 mice, Notch signaling was inhibited by the gamma-secretase inhibitor DAPT and by overexpression of a Notch-1 antisense construct. RESULTS: Notch signaling was activated in SSc in vivo, with accumulation of the NICD and increased transcription of the target gene HES-1. Overexpression of a Notch antisense construct prevented bleomycin-induced fibrosis and hypodermal thickening in tight skin 1 mice. Potent antifibrotic effects were also obtained with DAPT treatment. In addition to prevention of fibrosis, targeting of Notch signaling resulted in almost complete regression of established experimental fibrosis. CONCLUSION: The present results demonstrate that pharmacologic as well as genetic inhibition of Notch signaling exerts potent antifibrotic effects in different murine models of SSc. These findings might have direct translational implications because different inhibitors of the gamma secretase complex are available and have yielded promising results in cancer trials. PMID- 21312187 TI - Antiinflammatory and antifibrotic effects of the oral direct thrombin inhibitor dabigatran etexilate in a murine model of interstitial lung disease. AB - OBJECTIVE: Activation of the coagulation cascade leading to generation of thrombin has been documented extensively in various forms of lung injury, including that associated with systemic sclerosis. We previously demonstrated that the direct thrombin inhibitor dabigatran inhibits thrombin-induced profibrotic signaling in lung fibroblasts. This study was undertaken to test whether dabigatran etexilate attenuates lung injury in a murine model of interstitial lung disease. METHODS: Lung injury was induced in female C57BL/6 mice by a single intratracheal instillation of bleomycin. Dabigatran etexilate was given as supplemented chow beginning on day 1 of bleomycin instillation (early treatment, study of antiinflammatory effect) or on day 8 following bleomycin instillation (late treatment, study of antifibrotic effect). Mice were killed 2 weeks or 3 weeks after bleomycin instillation, and lung tissue, bronchoalveolar lavage (BAL) fluid, and plasma were investigated. RESULTS: Both early treatment and late treatment with dabigatran etexilate attenuated the development of bleomycin-induced pulmonary fibrosis. Dabigatran etexilate significantly reduced thrombin activity and levels of transforming growth factor beta1 in BAL fluid, while simultaneously reducing the number of inflammatory cells and protein concentrations. Histologically evident lung inflammation and fibrosis were significantly decreased in dabigatran etexilate-treated mice. Additionally, dabigatran etexilate reduced collagen, connective tissue growth factor, and alpha-smooth muscle actin expression in mice with bleomycin-induced lung fibrosis, whereas it had no effect on basal levels of these proteins. CONCLUSION: Inhibition of thrombin using the oral direct thrombin inhibitor dabigatran etexilate has marked antiinflammatory and antifibrotic effects in a bleomycin model of pulmonary fibrosis. Our data provide preclinical information about the feasibility and efficacy of dabigatran etexilate as a new therapeutic approach for the treatment of interstitial lung disease. PMID- 21312188 TI - The effectiveness of pulsed electrical stimulation in the management of osteoarthritis of the knee: results of a double-blind, randomized, placebo controlled, repeated-measures trial. AB - OBJECTIVE: To determine the effectiveness of subsensory, pulsed electrical stimulation (PES) in the symptomatic management of osteoarthritis (OA) of the knee. METHODS: This was a double-blind, randomized, placebo-controlled, repeated measures trial in 70 participants with clinical and radiographically diagnosed OA of the knee who were randomized to either PES or placebo. The primary outcome was change in pain score over 26 weeks measured on a 100-mm visual analog scale (VAS). Other measures included pain on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), function on the WOMAC, patient's global assessment of disease activity (on a 100-mm VAS), joint stiffness on the WOMAC, quality of life on the Medical Outcomes Study Short-Form 36 (SF-36) health survey, physical activity (using the Human Activity Profile and an accelerometer), and global perceived effect (on an 11-point scale). RESULTS: Thirty-four participants were randomized to PES and 36 to placebo. Intent-to treat analysis showed a statistically significant improvement in VAS pain score over 26 weeks in both groups, but no difference between groups (mean change difference 0.9 mm [95% confidence interval -11.7, 13.4]). Similarly, there were no differences between groups for changes in WOMAC pain, function, and stiffness scores (-5.6 [95% confidence interval -14.9, 3.6], -1.9 [95% confidence interval 9.7, 5.9], and 3.7 [95% confidence interval -6.0, 13.5], respectively), SF-36 physical and mental component summary scores (1.7 [95% confidence interval -1.5, 4.8] and 1.2 [95% confidence interval -2.9, 5.4], respectively), patient's global assessment of disease activity (-2.8 [95% confidence interval -13.9, 8.4]), or activity measures. Fifty-six percent of the PES-treated group achieved a clinically relevant 20-mm improvement in VAS pain score at 26 weeks compared with 44% of controls (12% [95% confidence interval -11%, 33%]). CONCLUSION: In this sample of subjects with mild-to-moderate symptoms and moderate-to-severe radiographic OA of the knee, 26 weeks of PES was no more effective than placebo. PMID- 21312189 TI - Antibodies interfering with the type 3 muscarinic receptor pathway inhibit gastrointestinal motility and cholinergic neurotransmission in Sjogren's syndrome. AB - OBJECTIVE: In primary Sjogren's syndrome (SS), impairment of the gastrointestinal (GI) tract is common, and includes reduced esophageal motor function, delayed gastric emptying, and abnormalities in colonic motility; the pathogenesis is as yet unknown. We undertook this study to investigate the role of functional antibodies to the type 3 muscarinic receptor (M3R) in GI dysfunction associated with primary SS. METHODS: Muscle strip and whole-organ functional assays were used to determine whether IgG with anti-M3R activity from patients with primary SS disrupted neurotransmission in tissue from throughout the mouse GI tract. Specificity of the autoantibody for the M3R was determined using knockout mice that were deficient in the expression of muscarinic receptor subtypes. RESULTS: Functional antibodies to the M3R inhibited neuronally mediated contraction of smooth muscle from throughout the GI tract and disrupted complex contractile motility patterns in the colon. The autoantibodies were not active on tissue from mice that lacked the M3R, providing compelling evidence of the direct interaction of patient autoantibodies with the M3R. CONCLUSION: Our results indicate that anti-M3R autoantibodies have the potential to mediate multiple dysfunctions of the GI tract in primary SS, ranging from reduced esophageal motor activity to altered colonic motility. We hypothesize that altered GI motility forms part of a broader autonomic dysfunction mediated by pathogenic anti-M3R autoantibodies in primary SS. PMID- 21312190 TI - Risk of recurrence following delayed large flap reconstruction after mastectomy for breast cancer. AB - BACKGROUND: The aim of this retrospective matched cohort study was to evaluate the rate of recurrence among women with delayed large flap breast reconstruction after mastectomy for breast cancer. The recurrence rate among women treated at a single hospital was compared with that in an individually matched control group of women with breast cancer who did not have reconstruction after mastectomy. METHODS: Between 1982 and 2001, 125 women with previous invasive breast carcinoma underwent delayed large flap breast reconstruction with pedicled musculocutaneous or microvascular flaps (a median of 32 months after mastectomy). They were matched individually with 182 women with breast cancer who had a mastectomy but did not undergo breast reconstruction. Matching criteria were year of diagnosis, age at diagnosis and treating hospital. Medical records were evaluated until October 2007. Histopathological specimens for all included women were re evaluated. The endpoint was locoregional or distant breast cancer recurrence. The risk of recurrent disease was calculated using a Cox proportional hazards analysis, adjusted for established prognostic factors. RESULTS: Median follow-up for the entire cohort was 146 months. The reconstruction group had a 2.08 (95 per cent confidence interval 1.07 to 4.06) times higher risk of recurrent disease than the mastectomy only group. CONCLUSION: Women with breast cancer who had delayed reconstruction with a large flap in this study had a higher risk of recurrent disease than those with mastectomy alone. PMID- 21312191 TI - Interferon-alpha induces unabated production of short-lived plasma cells in pre autoimmune lupus-prone (NZB*NZW)F1 mice but not in BALB/c mice. AB - IFN-alpha is known to play a critical role in the pathogenesis of systemic lupus erythematosus (SLE), but the mechanisms remain unclear. We previously showed that within weeks, exposure to IFN-alpha in vivo induces lupus in pre-autoimmune lupus prone NZB*NZW F1 (NZB/W) but not in BALB/c mice. In the current study, we show that in vivo expression of IFN-alpha induces sustained B-cell proliferation in both BALB/c and NZB/W mice. In NZB/W but not BALB/c mice, B-cell proliferation was accompanied by a rapid and unabated production of autoantibody-secreting cells (ASCs) in secondary lymphoid organs, suggesting that a B-cell checkpoint is altered in the autoimmune background. The majority (>95%) of ASCs elicited in IFN alpha-treated NZB/W mice were short-lived and occurred without the induction of long-lived plasma cells. A short course of cyclophosphamide caused a sharp drop in IFN-alpha-elicited short-lived plasma cells, but the levels recovered within days following termination of treatment. Thus, our work provides new insights into effectiveness and limitations of the current SLE therapies. PMID- 21312192 TI - CD8+ Foxp3+ T cells share developmental and phenotypic features with classical CD4+ Foxp3+ regulatory T cells but lack potent suppressive activity. AB - "Suppressor T cells" were historically defined within the CD8(+) T-cell compartment and recent studies have highlighted several naturally occurring CD8(+) Foxp3(-) Treg populations. However, the relevance of CD8(+) Foxp3(+) T cells, which represent a minor population in both thymi and secondary lymphoid organs of nonmanipulated mice, remains unclear. We here demonstrate that de novo Foxp3 induction in peripheral CD8(+) Foxp3(-) T cells is counter-regulated by DC mediated co-stimulation via CD80/CD86. CD8(+) Foxp3(+) T cells fail to develop in TCR-transgenic mice with Rag1(-/-) background, similar to classical CD4(+) Foxp3(+) Tregs. Notably, both naturally occurring and induced CD8(+) Foxp3(+) T cells express bona fide Treg markers including CD25, GITR, CTLA4 and CD103, and show defective IFN-gamma production upon restimulation when compared with their CD8(+) Foxp3(-) counterparts. However, utilizing DEREG transgenic mice for the isolation of Foxp3(+) cells by eGFP reporter expression, we demonstrate that induced CD8(+) Foxp3(+) T cells similar to activated CD8(+) Foxp3(-) T cells only mildly suppress T-cell proliferation and IFN-gamma production. We therefore categorize CD8(+) Foxp3(+) T cells as a tightly controlled population sharing certain developmental and phenotypic properties with classical CD4(+) Foxp3(+) Tregs, but lacking potent suppressive activity. PMID- 21312193 TI - Immune inhibitory receptors: essential regulators of phagocyte function. AB - Phagocytes, including neutrophils, monocytes, and macrophages, play a crucial role in host defense by recognition and elimination of invading pathogens. Phagocytic cells produce reactive oxygen species (ROS), inflammatory cytokines, and chemokines, leading to bacterial killing and to recruitment and activation of additional immune cells. However, inflammatory mediators are potentially harmful for the host and their production is therefore tightly controlled by multiple regulatory mechanisms. One such mechanism is immune suppression by immune inhibitory receptors, which are increasingly acknowledged as potent regulators of the immune response. So far, research has focused on the role of these receptors in the regulation of NK cells, B cells, and T cells. Importantly, an accumulating number of inhibitory receptors have been identified on phagocytes. Here, we review the role of inhibitory receptors in the regulation of phagocyte cytokine production, migration, apoptosis, ROS production, and phagocytosis. Furthermore, we discuss the intracellular mechanisms utilized by distinct inhibitory receptors to regulate specific phagocyte functions. We demonstrate that inhibitory receptors are important regulators of the immune response, which bacteria can use to their advantage. PMID- 21312194 TI - Bisphenol A promotes testicular seminoma cell proliferation through GPER/GPR30. PMID- 21312196 TI - A novel solubility-enhanced curcumin formulation showing stability and maintenance of anticancer activity. AB - Curcumin (CUR) is an active food compound, but its insolubility and instability in water contributes to low bioavailability. In this study, the solubility of CUR was enhanced by utilizing the solubilizing properties of rubusoside (RUB). The solubility of CUR in water increased linearly from 61 MUg/mL to 2.318 mg/mL in the presence of RUB ranging from 1% to 10% (w/v). Dynamic light scattering and transmission electron microscopy studies found that CUR and RUB formed CUR-RUB nanoparticle (~8 nm) complexes. The RUB-solubilized CUR was stable in physiological conditions and did not precipitate when diluted or degrade when spray-dried to a completely reconstitutable powder. Furthermore, cell viability assays demonstrated the efficacy of RUB-solubilized CUR against human colon, breast, and pancreatic cancer cell lines. The development of this new solubilized, stable, and biologically active CUR formulation lays the foundation for future bioavailability improvement. PMID- 21312195 TI - Preclinical therapeutic response of residual metastatic disease is distinct from its primary tumor of origin. AB - Cancer-related deaths are caused principally by recurrence and metastasis arising from residual disease, whose therapeutic responses has been suggested to be substantially different from primary tumors. However, experimental animal models designed for evaluating the therapeutic responses of residual disease are mostly lacking. To overcome this deficiency, we have developed a preclinical model that recapitulates the progression for advanced nonsmall cell lung cancer (NSCLC). An archived Lewis lung carcinoma mouse tumor, propagated only through serial in vivo transplantation and never adapted to cell culture, was stably labeled using lentivirus-encoded biomarkers, consistently expressed through an RNA polymerase II promoter. Labeled tumors were inoculated into syngeneic immunocompetent mice to ensure superior tumor-host interactions. Primary tumors were resected on reaching a predetermined size, followed by treatment in a setting akin to postsurgical first-line adjuvant chemotherapy and routine imaging to monitor the progression of pulmonary metastasis. We discovered that efficacious treatment, instead of reducing disease growth rates, significantly prolonged disease-free survival and overall survival. As in the clinic, cisplatin-based regimes were more effective in this model. However, the response of metastases to specific agents could not be predicted from, and often opposed, their effects on subcutaneous "primary" tumors, possibly due to their distinct growth kinetics and host interactions. We here introduce a clinically relevant model of residual metastatic disease that may more accurately predict the therapeutic response of recurrent, metastatic disease. PMID- 21312197 TI - Maternal serum hCG, PAPP-A and AFP as predictors of hemoglobin Bart disease at mid-pregnancy. AB - OBJECTIVE: To evaluate the ability of maternal serum-free beta-human chorionic gonadotrophin (beta-hCG), pregnancy-associated plasma protein-A (PAPP-A), and alpha fetoprotein (AFP) levels in the screening of fetuses with hemoglobin (Hb) Bart's disease among pregnancies at risk. MATERIALS AND METHODS: Pregnancies at risk for fetal Hb Bart's disease scheduled for cordocentesis at 18 to 22 weeks were recruited into the study. Maternal serum-free beta-hCG, PAPP-A, and AFP concentrations were measured before cordocentesis, and the final fetal diagnosis of Hb Bart disease was based on fetal Hb typing using high-performance liquid chromatography. RESULTS: Of 57 recruited pregnancies, 11 had fetal Hb Bart's disease and 46 were unaffected. Maternal serum alpha-fetoprotein (MSAFP) concentrations were significantly higher in women with fetal Hb Bart's disease than those with unaffected fetuses (median 99.53 vs 50.83, P < 0.001), whereas the concentrations of free beta-hCG and PAPP-A were not significantly different between the two groups (P = 0.543 and 0.777, respectively). CONCLUSION: Second trimester MSAFP may be clinically a useful screening test for fetal Hb Bart's disease among pregnancies at risk. PMID- 21312198 TI - Reference ranges of fetal aortic and pulmonary valve diameter derived by STIC from 14 to 40 weeks of gestation. AB - OBJECTIVE: To develop reference ranges of fetal aortic and pulmonary valve diameter derived from volume datasets of spatio-temporal image correlation (STIC). METHODS: A cross-sectional study was undertaken on low-risk pregnancies with well-established data from 14 to 40 weeks. Volume datasets of STIC were acquired for subsequent off-line analysis. Aortic and pulmonary valve diameters were measured in STIC multiplanar view using 4D-View version 9. Normal Z scores and centile reference ranges were constructed from these measurements against gestational age (GA) and biparietal diameter (BPD) as independent variables, using regression models for both mean and SD. RESULTS: A total of 606 volume datasets were successfully measured. Normal reference ranges for predicting mean values and SD of aortic and pulmonary valve diameter were constructed based on best-fit equations (linear function) as follows: mean aortic diameter (mm) was modeled as a function of GA (weeks) and BPD (mm) as - 2.4838 + 0.2702 * GA, (SD = 0.1482 + 0.0156 * GA) and - 1.5952 + 0.0989 * BPD (SD = 0.1672 + 0.00572 * BPD). Mean pulmonary diameter was modeled as - 2.5924 + 0.2935 * GA (SD = 0.2317 + 0.01524 * GA) and - 1.6830 + 0.1083 * BPD (SD = 0.1971 + 0.0059 * BPD). CONCLUSION: We have provided nomograms and Z scores of fetal aortic and pulmonary valve diameters. These reference ranges may be a useful tool in the assessment of fetal cardiac abnormalities. PMID- 21312199 TI - Differential proteomics analysis of amniotic fluid in pregnancies of increased nuchal translucency with normal karyotype. AB - OBJECTIVES: To investigate the functional roles of differentially expressed proteins in amniotic fluid supernatant (AFS) from normal karyotype pregnancies with increased nuchal translucency (NT). METHODS: AFS from fetuses with increased NT (>3.4 mm, N = 14) and control (<0.7 mm, N = 14) were analyzed by two dimensional electrophoresis and in-gel digestion to identify the difference of expressed proteins between both groups. Targeted proteins were confirmed by western blot and ELISA. The roles of biological networks in pathophysiology of NT were determined using MetaCore mapping. RESULTS: Levels of apolipoprotein-A1 (Entrez Gene ID 335), alpha-1 antitrypsin (SERPINA1, ID 5265) and prolactin (ID 5617) were significantly decreased in AFS of fetuses with increased NT compared with those in controls. According to Gene Ontology terms, biological processes of functional networks were mainly involved in steroid metabolism. On the basis of the database of MetaCore, these proteins are considered as the potential biomarkers of cardiovascular disorders. The prediction of tissue distribution from this network in fetal organs such as liver, skin, and kidney supported that these three proteins may play different roles between two groups. CONCLUSION: The combination of using quantitative proteomics and functional network analysis could integrally analyze the pathophysiology of fetuses with increased NT. PMID- 21312200 TI - Basic Molecular Evolution Workshop--A trans-African virtual training course: "Virtual Workshops": Is Africa ready to embrace the concept? PMID- 21312201 TI - Medical complications of bulimia nervosa and their treatments. AB - OBJECTIVE: To present a cogent and practical review of the medical complications and their treatment in patients with bulimia nervosa. METHOD: Thorough review of the medical literature from 1990 to current in regards to the medical complications of bulimia nervosa and the therapeutic intervention that are effective to treat them. RESULTS: Extensive and detailed review of the medical complications of bulimia nervosa. PMID- 21312204 TI - Purging disorder: psychopathology and treatment outcomes. AB - OBJECTIVE: To characterize a tertiary care treatment-seeking sample and assess post-treatment remission and completion rates for purging disorder (PD). METHOD: Consecutively admitted women with PD (n = 122), anorexia nervosa (AN) restricting subtype (AN-R; n = 146), AN binge-purge subtype (AN-B; n = 154), and bulimia nervosa-purging subtype (BN-P; n = 415) were compared on general and eating disorder specific psychopathology. A subsample (n = 256) attended a day treatment program and were assessed for post-treatment remission and completion rates. RESULTS: PD occurred in 17.3% of eating disorders not otherwise specified and 6.7% of total eating disorder referrals. PD patients were similar to AN-B and BN P, but had higher levels than AN-R, on general and eating disorder psychopathology. PD individuals did not have different post-treatment remission or completion rates compared to other eating disorders. DISCUSSION: The results add to a growing literature on the utility of PD as a diagnosis. PMID- 21312202 TI - Parental divorce and disordered eating: an investigation of a gene-environment interaction. AB - OBJECTIVE: We investigated gene-environment interactions (GxE) for associations between parental divorce and disordered eating (DE). METHOD: Participants were 1,810 female twins from the Michigan State University Twin Registry and the Minnesota Twin Family Study. The Minnesota Eating Behaviors Survey was used to assess DE. We tested for GxE by comparing the heritability of DE in twins from divorced versus intact families. It was hypothesized that divorce would moderate the heritability of DE, in that heritability would be higher in twins from divorced than twins from intact families. RESULTS: As expected, the heritability of body dissatisfaction was significantly higher in twins from divorced than intact families. However, genetic influences were equal in twins from divorced and intact families for all other forms of DE. DISCUSSION: Although divorce did not moderate heritability of most DE symptoms, future research should replicate GxEs for body dissatisfaction and identify factors underlying this unique relationship. PMID- 21312205 TI - Disordered eating and religious observance: a focus on ultra-Orthodox Jews in an adult community study. AB - OBJECTIVE: To broaden the socio-cultural context of eating disturbances by exploring religious observance and its presumed protective role for ultra Orthodox women. METHOD: Detailed telephone interviews with community sample of adult Jewish women in Israel, including 261 ultra-Orthodox. Frequency of 14 symptoms of disordered eating (DEB) assessed. Hierarchical regressions examine predictors of DEB severity within observance categories (ultra-Orthodox, Orthodox, Traditional, and Secular). RESULTS: Contrary to expectations, no significant differences were found in the frequency of serious DEB between the most and least religiously observant, ultra-Orthodox, and Secular women. Regressions reveal similar predictors of DEB severity (obesity followed by self criticism) as well as substantial variations in amount of variance explained. DISCUSSION: Apparently, rigorous religious adherence does not protect ultra Orthodox women from serious eating problems. Additional analyses can inform socio cultural perspectives by examining the connection between body dissatisfaction and disordered eating in this insular and isolated religious community, whose exposure to secular media is prohibited. PMID- 21312206 TI - An fMRI investigation of emotional processing of body shape in bulimia nervosa. AB - OBJECTIVE: Cognitive-behavioral theories of eating disorder etiology emphasize the role of body-oriented self-schemas. Examination of brain regions associated with self-referencing, such as medial prefrontal cortex (mPFC), during processing of body-related stimuli can thus be utilized to evaluate such theories. METHOD: Twelve women with bulima nervosa (BN) and 12 comparison women underwent functional brain imaging while viewing images of women with either thin or overweight bodies in a self-referencing context. RESULTS: For thin bodies, there was no significant mPFC activation for either group. For overweight bodies, mPFC activation was significantly greater for BN patients, with a focus in subregions associated with emotional processing. DISCUSSION: These findings are consistent with cognitive models of eating disorders which posit that negative body-related stimuli are more central to self-schemas and more emotionally provocative in persons with eating disorders, lending support to treatment and prevention interventions that emphasize body overvaluation as a primary target of change. PMID- 21312207 TI - Preface. PMID- 21312208 TI - Some methodological issues in biosurveillance. AB - This paper briefly summarizes a short course I gave at the 12th Biennial Centers for Disease Control and Prevention (CDC) and Agency for Toxic Substances and Disease Registry (ATSDR) Symposium held in Decatur, Georgia on April 6, 2009. The goal of this short course was to discuss various methodological issues of biosurveillance detection algorithms, with a focus on the issues related to developing, evaluating, and implementing such algorithms. PMID- 21312209 TI - Comments on 'some methodological issues in biosurveillance'. PMID- 21312210 TI - Comments on 'some methodological issues in biosurveillance'. PMID- 21312211 TI - Comments on 'some methodological issues in biosurveillance'. PMID- 21312212 TI - Comments on 'some methodological issues in biosurveillance'. PMID- 21312213 TI - Comments on 'some methodological issues in biosurveillance'. PMID- 21312215 TI - Fast Bayesian scan statistics for multivariate event detection and visualization. AB - The multivariate Bayesian scan statistic (MBSS) is a recently proposed, general framework for event detection and characterization in multivariate space-time data. MBSS integrates prior information and observations from multiple data streams in a Bayesian framework, computing the posterior probability of each type of event in each space-time region. MBSS has been shown to have many advantages over previous event detection approaches, including improved timeliness and accuracy of detection, easy interpretation and visualization of results, and the ability to model and accurately differentiate between multiple event types. This work extends the MBSS framework to enable detection and visualization of irregularly shaped clusters in multivariate data, by defining a hierarchical prior over all subsets of locations. While a naive search over the exponentially many subsets would be computationally infeasible, we demonstrate that the total posterior probability that each location has been affected can be efficiently computed, enabling rapid detection and visualization of irregular clusters. We compare the run time and detection power of this 'Fast Subset Sums' method to our original MBSS approach (assuming a uniform prior over circular regions) on semi synthetic outbreaks injected into real-world Emergency Department data from Allegheny County, Pennsylvania. We demonstrate substantial improvements in spatial accuracy and timeliness of detection, while maintaining the scalability and fast run time of the original MBSS method. PMID- 21312216 TI - Comparison of the early aberration reporting system (EARS) W2 methods to an adaptive threshold method. AB - In this paper we examine some of the methodologies implemented by the Centers for Disease Control and Prevention's (CDC) BioSense program. The program uses data from hospitals and public health departments to detect outbreaks using the Early Aberration Reporting System (EARS). The EARS method W2 allows one to monitor syndrome counts (W2count) from each source and the proportion of counts of a particular syndrome relative to the total number of visits (W2rate). We investigate the performance of these methods, which are designed using an empiric recurrence interval (RI), with simulated parametric data. Counts from the Poisson and negative binomial distributions are generated, and used to examine W2 properties. An adaptive threshold monitoring method is introduced based on fitting sample data to the above distributions, then converting the current value to a Z-score through a p-value. We compare the thresholds required to obtain given values of the RI for different sets of parameter values. We then simulate 1 week outbreaks in our data and calculate the proportion of times these methods correctly signal an outbreak using Shewhart and exponentially weighted moving average (EWMA) charts. Our results indicate that the adaptive threshold method gives more consistent statistical performance across different parameter sets and amounts of baseline historical data used for computing the statistics. For the sensitivity analysis, the EWMA chart is superior to its Shewhart counterpart in nearly all cases and the adaptive threshold methods tend to outperform the W2 methods. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 21312217 TI - Important issues related to using pooled samples for environmental chemical biomonitoring. AB - Pooling samples for analysis was first proposed in the 1940s to reduce analytical measurement costs associated with screening World War II recruits for syphilis. Later, it progressed to more complex screening strategies, to population prevalence estimation for discrete quantities, and to population mean estimation for continuous quantities. Recently, pooled samples have also been used to provide efficient alternatives for gene microarray analyses, epidemiologic studies of biomarkers of exposure, and characterization of populations regarding environmental chemical exposures. In this study, we address estimation and bias issues related to using pooled-sample variance information from an auxiliary source to augment pooled-sample variance estimates from the study of interest. The findings are illustrated by using pooled samples from the National Health and Nutrition Examination Survey 2001-2002 to assess exposures to perfluorooctanesulfonate and other polyfluoroalkyl compounds in the U.S. population. PMID- 21312218 TI - Ecological-type inference in matched-pair studies with fixed marginal totals. AB - This paper applies a Bayesian approach to ecological-type inference in matched pair studies because traditional methods that assume parallel tables are not directly applicable. The proposed procedure is based on a hierarchical Bayes structure which models information about the within-pair association. The proposed algorithm relies on Markov chain Monte Carlo simulation, recovers the full table, and reports its accuracy in terms of credible sets for the cell counts. This methodology is motivated and illustrated with examples from split mouth designs assessing the effectiveness of dental sealant materials and cross over trials comparing two forms of insulin. PMID- 21312220 TI - Spatiotemporal surveillance methods in the presence of spatial correlation. AB - Health surveillance involves collecting public health data on chronic and infectious diseases to detect changes in disease incidence rates in order to improve public health. Timely detection of disease clusters is essential in prospective public health surveillance. Most existing health surveillance research is based on the assumption that observations from different regions are independent. This paper proposes a set of multivariate surveillance schemes generalized from well-known detection methods in multivariate statistical process control based on likelihood ratio tests. We use Monte Carlo simulations to compare these methods for health surveillance in the presence of spatial correlations. By taking advantage of correlations among regions,the proposed schemes are able to perform better than existing surveillance methods and provide faster and more accurate detection of outbreaks. An example of breast cancer in New Hampshire is presented to demonstrate the application of these methods when observations are spatially correlated counts. PMID- 21312219 TI - Timely detection of localized excess influenza activity in Northern California across patient care, prescription, and laboratory data. AB - Timely detection of clusters of localized influenza activity in excess of background seasonal levels could improve situational awareness for public health officials and health systems. However, no single data type may capture influenza activity with optimal sensitivity, specificity, and timeliness, and it is unknown which data types could be most useful for surveillance. We compared the performance of 10 types of electronic clinical data for timely detection of influenza clusters throughout the 2007/08 influenza season in northern California. Kaiser Permanente Northern California generated zip code-specific daily episode counts for: influenza-like illness (ILI) diagnoses in ambulatory care (AC) and emergency departments (ED), both with and without regard to fever; hospital admissions and discharges for pneumonia and influenza; antiviral drugs dispensed (Rx); influenza laboratory tests ordered (Tests); and tests positive for influenza type A (FluA) and type B (FluB). Four credible events of localized excess illness were identified. Prospective surveillance was mimicked within each data stream using a space-time permutation scan statistic, analyzing only data available as of each day, to evaluate the ability and timeliness to detect the credible events. AC without fever and Tests signaled during all four events and, along with Rx, had the most timely signals. FluA had less timely signals. ED, hospitalizations, and FluB did not signal reliably. When fever was included in the ILI definition, signals were either delayed or missed. Although limited to one health plan, location, and year, these results can inform the choice of data streams for public health surveillance of influenza. PMID- 21312221 TI - Clinical epidemiology and individualized medicine. PMID- 21312222 TI - Classical 18.5-and 21.5-kDa isoforms of myelin basic protein inhibit calcium influx into oligodendroglial cells, in contrast to golli isoforms. AB - The myelin basic protein (MBP) family arises from different transcription start sites of the golli (gene of oligodendrocyte lineage) complex, with further variety generated by differential splicing. The "classical" MBP isoforms are peripheral membrane proteins that facilitate compaction of the mature myelin sheath but also have multiple protein interactions. The early developmental golli isoforms have previously been shown to promote process extension and enhance Ca(2+) influx into primary and immortalized oligodendrocyte cell lines. Here, we have performed similar studies with the classical 18.5- and 21.5-kDa isoforms of MBP. In contrast to golli proteins, overexpression of classical MBP isoforms significantly reduces Ca(2+) influx in the oligodendrocyte cell line N19 as well as in primary cultures of oligodendroglial progenitor cells. Pharmacological experiments demonstrate that this effect is mediated by voltage-operated Ca(2+) channels (VOCCs) and not by ligand-gated Ca(2+) channels or Ca(2+) release from intracellular stores. The pseudo-deiminated 18.5-kDa and the full-length 21.5-kDa isoforms do not reduce Ca(2+) influx as much as the unmodified 18.5-kDa isoform. However, more efficient membrane localization (of overexpressed, pseudo deiminated 18.5-kDa and 21.5-kDa isoforms of classical MBP containing the 21-nt 3'-untranslated region transit signal) further reduces the Ca(2+) response after plasma membrane depolarization, suggesting that binding of classical MBP isoforms to the plasma membrane is important for modulation of Ca(2+) homeostasis. Furthermore, we have found that the mature 18.5-kDa isoform expressed in oligodendrocytes colocalizes with VOCCs, particularly at the leading edge of extending membrane processes. In summary, our findings suggest a key role for classical MBP proteins in regulating voltage-gated Ca(2+) channels at the plasma membrane of oligodendroglial cells and thus also in regulation of multiple developmental stages in this cell lineage. PMID- 21312223 TI - Novel GLP-1 mimetics developed to treat type 2 diabetes promote progenitor cell proliferation in the brain. AB - One of the symptoms of diabetes is the progressive development of neuropathies. One mechanism to replace neurons in the CNS is through the activation of stem cells and neuronal progenitor cells. We have tested the effects of the novel GLP 1 mimetics exenatide (exendin-4; Byetta) and liraglutide (NN2211; Victoza), which are already on the market as treatments for type 2 diabetes, on the proliferation rate of progenitor cells and differentiation into neurons in the dentate gyrus of brains of mouse models of diabetes. GLP-1 analogues were injected subcutaneously for 4, 6, or 10 weeks once daily in three mouse models of diabetes: ob/ob mice, db/db mice, or high-fat-diet-fed mice. Twenty-four hours before perfusion, animals were injected with 5'-bromo-2'-deoxyuridine (BrdU) to mark dividing progenitor cells. By using immunohistochemistry and stereological methods, the number of progenitor cells or doublecortin-positive young neurons in the dentate gyrus was estimated. We found that, in all three mouse models, progenitor cell division was enhanced compared with nondiabetic controls after chronic i.p. injection of either liraglutide or exendin-4 by 100-150% (P < 0.001). We also found an increase in young neurons in the DG of high-fat-diet-fed mice after drug treatment (P < 0.001). The GLP-1 receptor antagonist exendin(9-36) reduced progenitor cell proliferation in these mice. The results demonstrate that GLP-1 mimetics show promise as a treatment for neurodegenerative diseases such as Alzheimer's disease, because these novel drugs cross the blood-brain barrier and increase neuroneogenesis. PMID- 21312224 TI - Factors responsible for neurofibrillary tangles and neuronal cell losses in tauopathy. AB - TgTauP301L mice that overexpress the mutant human tauP301L present in FTDP-17 reproduce neurofibrillary tangles (NFTs), neuronal cell losses, memory disturbance, and substantial phenotypic variation. To demonstrate factors responsible for NFT formation and neuronal cell losses, sets of TgTauP301L for comparison with or without NFTs and neuronal cell losses were studied with oligonucleotide microarrays. Gene expressions were altered in biological pathways, including oxidative stress, apoptosis, mitochondrial fatty acid betaoxidation, inflammatory response pathway, and complement and coagulation cascade pathways. Among 24 altered genes, increased levels of apolipoprotein D (ApoD) and neuronal PAS domain protein 4 (Npas4) and decreased levels of doublecortin (DCX) and potassium channel, voltage-gated, shaker-related subfamily, beta member 1 (Kcnab1) were found in the TgTauP301L with NFTs and neuronal cell losses, Alzheimer's brains, and tauopathy brains. Thus, many biological pathways and novel molecules are associated with NFT formation and neuronal cell losses in tauopathy brains. PMID- 21312225 TI - Effects of metal ions on fibroblasts and spiral ganglion cells. AB - Degeneration of spiral ganglion cells (SGC) after deafness and fibrous tissue growth around the electrode carrier after cochlear implantation are two of the major challenges in current cochlear implant research. Metal ions are known to possess antimicrobial and antiproliferative potential. The use of metal ions could therefore provide a way to reduce tissue growth around the electrode array after cochlear implantation. Here, we report on in vitro experiments with different concentrations of metal salts with antiproliferative and toxic effects on fibroblasts, PC-12 cells, and freshly isolated spiral ganglion cells, the target cells for electrical stimulation by a cochlear implant. Standard cell lines (NIH/3T3 and L-929 fibroblasts and PC-12 cells) and freshly isolated SGC were incubated with concentrations of metal ions between 0.3 MUmol/liter and 10 mmol/liter for 48 hr. Cell survival was investigated by neutral red uptake, CellQuantiBlue assay, or counting of stained surviving neurons. Silver ions exhibited distinct thresholds for proliferating and confluent cells. For zinc ions, the effective concentration was lower for fibroblasts than for PC-12 cells. SGC showed comparable thresholds for reduced cell survival not only for silver and zinc ions but also for copper(II) ions, indicating that these ions might be promising for reducing tissue growth on the surface of CI electrode arrays. These effects were also observed when combinations of two of these ions were investigated. PMID- 21312226 TI - Interactive 3D anatomy and affinities of Bathysciadiidae (Gastropoda, Cocculinoidea): Deep-sea limpets feeding on decaying cephalopod beaks. AB - The anatomy of five bathysciadiid limpets, the type species Bathysciadium costulatum (Locard, 1898), Bathysciadium sp. B (off New Zealand), Bathypelta pacifica (Dall, 1908), Bathypelta sp. A (off New Zealand), and Bathyaltum wareni n.g., n.sp. (deep East Atlantic Ocean Basins), which all feed on decaying cephalopod beaks, has been investigated by means of semithin serial sectioning and interactive, computer-aided 3D reconstructions. Bathyaltum wareni is described as a species new to science based on additional SEM photos of shell and radula. Differences between species are found in conditions of shell, protoconch, mantle papilla, copulatory organ, receptaculum openings, oral lappets, and rectal histology. The Bathysciadiidae share several synapomorphies with the Cocculinidae (s. str.), namely the pseudoplicatid gill, a single, left kidney, the hermaphroditic gonad with the single, glandular gonoduct, and the statocysts with single statoliths. Therefore, these families are united in a clade Cocculinoidea, which is considered to be highly modified offshoot of early gastropods independent of the likewise "cocculiniform" Lepetelloidea, which should be classified among the Vetigastropoda. PMID- 21312227 TI - A morphological study of the vertebral venous plexus and its connections in the Cape dune mole-rat, Bathyergus suillus (Bathyergidae). AB - Bathyergus suillus are subterranean rodents found in the Western Cape of South Africa, where they inhabit sandy, humid burrows. Vertebral venous plexuses around the vertebral column have been implicated in aiding the maintenance of a constant central nervous system temperature via its connections with muscles and interscapular brown adipose tissue. The morphology of the vertebral venous plexuses and its connections in B.suillus were investigated. Frozen (n = 10) animals were defrosted; the venous system injected with latex and the vertebral venous plexuses, azygos- and intercostal veins dissected along the dorsal and ventral aspects of the vertebral column. Specimens (n = 4) were used for histological serial cross sections of the thoracic vertebrae. Veins drained from the interscapular brown adipose tissue to the external vertebral venous plexus, via a dorsal vein at the spinous process of T2 which might represent the "vein of Sulzer" described in rats. The intercostal veins cranial to the level of T8 drained directly into the ventral external vertebral venous plexus instead of into the azygos vein as seen in rats. The azygos vein was situated ventrally on the thoracic vertebral bodies in the median plane as opposed to most rodents that have a left sided azygos vein. The internal vertebral venous plexus consisted of two ventrolateraly placed longitudinal veins in the spinal epidural space. Veins from the forelimbs entered the internal vertebral venous plexus directly at the levels of C7 and T1 and have not been described in other rodents. Serial histological sections, revealed no regulatory valves in vessels leading toward the internal vertebral venous plexus, allowing blood to presumably move in both directions within the vertebral venous plexus. The vertebral venous plexus of B. suillus shows similarities to that of the rat but the vessels from the forelimbs draining directly into to the internal vertebral venous plexus and the position of the azygos vein and the intercostal veins draining into the external vertebral venous plexus are notable exceptions. PMID- 21312228 TI - Four-dimensional analysis of early pelvic girdle development in Rana temporaria. AB - A key event in vertebrate evolution is the linkage of the appendicular to the axial skeleton. The present study investigates the developmental dynamics of pelvic girdle morphogenesis in Rana temporaria up until metamorphosis, with respect to its functional and spatio-temporal organization. The main questions to be addressed are: initial location and the number of elements contributing to pelvic girdle formation, mechanism of bridging between the pelvic anlage and the sacrum and arthrogenesis. Serial histological sections of specimens from Gosner Stages 30 to 41 were bright-field microscopically examined and 3D-reconstructed. 3D-models were merged to 4D-animations illustrating the complex developmental dynamics through time. The results reveal the initial formation of a single mesenchymal condensation located close to the appendicular skeleton, but far from the axial skeleton. In addition, our analysis detects a thin connective tissue strand in R. temporaria guiding the elongation of the ilium towards the sacrum. The 4D-visualization allows novel insight into the ilio-sacral bridging process and the reorientation of the pelvis. PMID- 21312229 TI - Comparative internal structure of dorsal lips and radiolar appendages in Sabellidae (Polychaeta) and phylogenetic implications. AB - Fan worms (Sabellidae) possess paired modified prostomial structures at the base of the radiolar crown, dorso-lateral to the mouth, called dorsal lips. The dorsal lips are involved in the sorting of particles collected by the radiolar crown. The range of variation in the morphology of dorsal lips is extensive, and probably this is not only due to adaptations to different environments and feeding preferences but also due to phylogenetic constraints. In this study, we describe and compare the morphology of dorsal lips in a range of sabellid taxa based on histological cross-sections of these structures, and compare our data and terminology with those of previous studies. Dorsal lips are maintained erect in most taxa by a modified radiole fused to them known as dorsal radiolar appendage. We suggest that dorsal radiolar appendages with an internal supporting axis (cellular or acellular) and probably also the ventral lips are synapomorphies of the family. PMID- 21312230 TI - Organogenesis in the budding process of the freshwater bryozoan Cristatella mucedo Cuvier, 1798 (Bryozoa, Phylactolaemata). AB - The phylogenetic position of bryozoans has been disputed for decades, and molecular phylogenetic analyzes have not unequivocally clarified their position within the Bilateria. As probably the most basal bryozoans, Phylactolaemata is the most promising taxon for large-scale phylogenetic comparisons. These comparisons require extending the morphological and developmental data by investigating different phylactolaemate species to identify basal characters and resolve in-group phylogeny. Accordingly, we analyzed the bud development and the organogenesis of the freshwater bryozoan Cristatella mucedo, with special focus on the formation of the digestive tract and differentiation of the coelomic compartments. Most parts of the digestive tract are formed as an outpocketing at the future anal side growing towards the mouth area. The ganglion is formed by an invagination between the anlagen of the mouth and anus. The lophophoral arms develop as paired lateral protrusions into the lumen of the bud and are temporarily connected by a median, thin bridge. All coelomic compartments are confluent during their development and also in the adult. The epistome coelom develops by fusion of two peritoneal infolds between the gut loop and overgrows the ganglion medially. The coelomic ring canal on the oral side develops by two lateral ingrowths and supplies the oral tentacles. On the forked canal, supplying the innermost row of tentacles above the epistome, a bladder-shaped swelling, probably with excretory function, is present in some adults. It remains difficult to draw comparisons to other phyla because only few studies have dealt with budding of potentially related taxa in more detail. Nonetheless, our results show that comparative organogenesis can contribute to phylactolaemate systematics and, when more data are available, possibly to that of other bryozoan classes and bilaterian phyla. PMID- 21312231 TI - Microvascularization of the interhyoid muscle in larval Xenopus laevis (Daudin): Scanning electron microscopy of vascular corrosion casts and correlative light microscopy. AB - The interhyoid muscle in tadpoles of Xenopus laevis (Daudin) is an important part of the buccal pump, a functional unit that provides unidirectional flow of water through mouth and pharynx. In anuran tadpoles, this flow is crucial in both respiration (gas exchange) and food intake (ingestion). The microvascular anatomy of the interhyoid muscles of 43 tadpoles of X. laevis from developmental stages 49-60 was examined by scanning electron microscopy of vascular corrosion casts and correlative light microscopy of paraplast embedded Goldner stained serial tissue sections. Analysis of vascular corrosion casts of the interhyoid muscle showed that several descending branches of external carotid arteries supplied the interhyoid muscle. Arteries splitted into many arterioles at the dorsal surface of the interhyoid muscle and formed sheaths of longitudinally orientated capillaries around muscle fibers. Postcapillary vessels formed perpendicularly orientated arrays of collecting venules (mean diameter: 15.6 MUm), which drained the interhyoid muscle from the ventral surface into external jugular veins. Cast analyses revealed sprouting angiogenesis at the capillary level and nonsprouting angiogenesis at distal domains of the venous system. Both means of angiogenesis that persisted throughout the developmental periods examined are thought to represent a superposition of concurrent developmental and physiological processes. The dense microvascular bed of the interhyoid muscle reflects its high demand for supply with oxygen and nutrients. PMID- 21312232 TI - Ultrastructural localization of hair keratin homologs in the claw of the lizard Anolis carolinensis. AB - The claw of lizards is largely composed of beta-keratins, also referred to as keratin-associated beta-proteins. Recently, we have reported that the genome of the lizard Anolis carolinensis contains alpha keratin genes homologous to hair keratins typical of hairs and claws of mammals. Molecular and immunohistochemical studies demonstrated that two hair keratin homologs named hard acid keratin 1 (HA1) and hard basic keratin 1 (HB1) are expressed in keratinocytes forming the claws of A. carolinensis. Here, we extended the immunocytochemical localization of the novel reptilian keratins to the ultrastructural level. After sectioning, claws were subjected to immunogold labeling using antibodies against HA1, HB1, and, for comparison, beta-keratins. Electron microscopy showed that the randomly organized network of tonofilaments in basal and suprabasal keratinocytes becomes organized in long and parallel bundles of keratin in precorneous layers, resembling cortical cells of hairs. Entering the cornified part of the claw, the elongated corneous cells fuse and accumulate corneous material. HA1 and HB1 are absent in the basal layer and lower spinosus layers of the claw and are expressed in the upper and precorneous layers, including the elongating corneocytes. The labeling for alpha-keratin was loosely associated with filament structures forming the fibrous framework of the claws. The ultrastructural distribution pattern of hard alpha-keratins resembled that of beta-keratins, which is compatible with the hypothesis of an interaction during claw morphogenesis. The data on the ultrastructural localization of hair keratin homologs facilitate a comparison of lizard claws and mammalian hard epidermal appendages containing hair keratins. PMID- 21312233 TI - Design, synthesis and cytotoxicity of a new series of isoxazolidine based nucleoside analogues. AB - 5-Arylisoxazolidin-3-yl-3-diethoxyphosphonates have been synthesized from N methyl-C-diethoxyphosphorylnitrone and vinyl aryls in good yields and their transformation into the respective phosphonic acids has been accomplished via dealkylation procedure using trimethylsilyl bromide. Phosphonates having 1- and 2 naphthyl substituents at C5 in the isoxazolidine ring as well as the respective phosphonic acids have been found cytotoxic to HeLa and K562 cells with IC(50) in the 0.1-0.3 mM range. Preliminary studies on mechanism of action imply that intercalation to DNA is not responsible for their cytotoxic properties. PMID- 21312234 TI - Survivin (BIRC5) cell cycle computational network in human no-tumor hepatitis/cirrhosis and hepatocellular carcinoma transformation. AB - Survivin (BIRC5) relationship with tumor is presented in several papers. However, how the molecular network and interpretation concerning BIRC5 cell cycle between no-tumor hepatitis/cirrhosis and hepatocellular carcinoma (HCC) remains to be elucidated. Here, we constructed and analyzed significant higher expression gene BIRC5 activated and inhibited cell cycle network from HCC versus no-tumor hepatitis/cirrhosis patients (viral infection HCV or HBV) in GEO Dataset by combination of gene regulatory network inference method based on linear programming and decomposition procedure with the CapitalBio MAS 3.0 software based on the integration of public databases including Gene Ontology, KEGG, BioCarta, GenMapp, Intact, UniGene, OMIM, etc. Compared the same and different activated and inhibited BIRC5 network with GO analysis between no-tumor hepatitis/cirrhosis and HCC, our result showed BIRC5 cell cycle network weaker transcription factor activity in both no-tumor hepatitis/cirrhosis and HCC (1); stronger nucleus protein binding but weaker cytoplasm protein binding in no-tumor hepatitis/cirrhosis (2); stronger cytoplasm protein phosphatase binding but weaker ubiquitin-protein ligase activity in HCC (3). Therefore, we inferred BIRC5 cell cycle module less transcription from RNA polymerase II promoter in both no tumor hepatitis/cirrhosis and HCC (4). We deduced BIRC5 cell cycle module different from more mitosis but less complex-dependent proteasomal ubiquitin dependent protein catabolism as a result increasing cell division and cell numbers in no-tumor hepatitis/cirrhosis to more protein amino acid autophosphorylation but less negative regulation of ubiquitin ligase activity during mitotic cell cycle as a result increasing growth and cell volume in HCC (5). PMID- 21312235 TI - Two nucleus-localized CDK-like kinases with crucial roles for malaria parasite erythrocytic replication are involved in phosphorylation of splicing factor. AB - The kinome of the human malaria parasite Plasmodium falciparum comprises representatives of most eukaryotic protein kinase groups, including kinases which regulate proliferation and differentiation processes. Despite extensive research on most plasmodial enzymes, little information is available regarding the four identified members of the cyclin-dependent kinase-like kinase (CLK) family. In other eukaryotes, CLKs regulate mRNA splicing through phosphorylation of Serine/Arginine-rich proteins. Here, we investigate two of the PfCLKs, the Lammer kinase homolog PfCLK-1, and PfCLK-2. Both PfCLKs show homology with the yeast Serine/Arginine protein kinase Sky1p and are transcribed throughout the asexual blood stages and in gametocytes. PfCLK-1/Lammer possesses two nuclear localization signal sites and PfCLK-2 possesses one of these signal sites upstream of the C-terminal catalytic domains. Indirect immunofluorescence, Western blot, and electron microscopy data confirm that the kinases are primarily localized in the parasite nucleus, and PfCLK-2 is further present in the cytoplasm. The two kinases are important for completion of the asexual replication cycle of P. falciparum, as demonstrated by reverse genetics approaches. In vitro kinase assays show substrate phosphorylation by the PfCLKs, including the Sky1p substrate, splicing factor Npl3p, and the plasmodial alternative splicing factor PfASF-1. Mass spectrometric analysis of co immunoprecipitated proteins indicates assembly of the two PfCLKs with proteins with predicted nuclease, phosphatase, or helicase functions. Our data indicate a crucial role of PfCLKs for malaria blood stage parasites, presumably by participating in gene regulation through the post-transcriptional modification of mRNA. PMID- 21312236 TI - Leukocyte-mediated cell dissemination and metastasis: findings from multiple types of human tumors. AB - Our previous studies revealed that leukocyte infiltration could trigger human breast and prostate tumor invasion through focal disruptions of the tumor capsule, which selectively favors monoclonal proliferation of tumor progenitors or a biologically more aggressive cell clone overlying the focal disruptions. Our current study, involving multiple types of human tumors, further shows that leukocyte infiltration could also trigger tumor metastasis through the following pathways: [1] more leukocytes migrate to focally disrupted tumor capsules, which forms leukocyte aggregates surrounding newly formed tumor cell clusters, [2] the physical movement of leukocytes into proliferating tumor cells disrupts the intercellular junctions and cell-surface adhesion molecules, causing the disassociation of tumor cells from the tumor core, [3] leukocytes are conjoined with some of these tumor cells through plasma membrane fusion, creating tumor cell-leukocyte chimeras (TLCs), and [4] the leukocyte of TLCs impart migratory capacity to associated tumor cell partners, physically dragging them to different tissue sites. Our findings suggest a novel pathway for tumor cell dissemination from the primary sites and the subsequent journey to new sites. Our findings also provide a unique explanation for the cellular mechanism of leukocytes on tumor invasion and metastasis. If confirmed, our hypothesis and technical approach may significantly facilitate early detection and intervention of tumor invasion and metastasis. PMID- 21312237 TI - Antiproliferative mechanism of a cannabinoid agonist by cell cycle arrest in human gastric cancer cells. AB - For gastric cancers, the antineoplastic activity of cannabinoids has been investigated in only a few reports and knowledge regarding the mechanisms involved is limited. We have reported previously that treatment of gastric cancer cells with a cannabinoid agonist significantly decreased cell proliferation and induced apoptosis. Here, we evaluated the effects of cannabinoids on various cellular mediators involved in cell cycle arrest in gastric cancer cells. AGS and MKN-1 cell lines were used as human gastric cancer cells and WIN 55,212-2 as a cannabinoid agonist. Cell cycles were analyzed by flow cytometry and western blotting. Treatment with WIN 55,212-2 arrested the cell cycle in the G0/G1 phase. WIN 55,212-2 also upregulated phospho-ERK1/2, induced Kip1/p27 and Cip1/WAF1/p21 expression, decreased cyclin D1 and cyclin E expression, decreased Cdk 2, Cdk 4, and Cdk 6 expression levels, and decreased phospho-Rb and E2F-1 expression. ERK inhibitor decreased the proportion of G0/G1 phase which was induced by WIN 55,212 2. Inhibition of pAKT led to cell cycle arrest in gastric cancer cells. Cell cycle arrest preceded apoptotic response. Thus, this cannabinoid agonist can reduce gastric cancer cell proliferation via G1 phase cell cycle arrest, which is mediated via activation of the MAPK pathway and inhibition of pAKT. PMID- 21312238 TI - Isolation and characterization of mesenchymal stem cells from human umbilical cord blood: reevaluation of critical factors for successful isolation and high ability to proliferate and differentiate to chondrocytes as compared to mesenchymal stem cells from bone marrow and adipose tissue. AB - Human umbilical cord blood (CB) is a potential source for mesenchymal stem cells (MSC) capable of forming specific tissues, for example, bone, cartilage, or muscle. However, difficulty isolating MSC from CB (CB-MSC) has impeded their clinical application. Using more than 450 CB units donated to two public CB banks, we found that successful cell recovery fits a hyper-exponential function of time since birth with very high fidelity. Additionally, significant improvement in the isolation of CB-MSC was achieved by selecting cord blood units having a volume >=90 ml and time <=2 h after donor's birth. This resulted in 90% success in isolation of CB-MSC by density gradient purification and without a requirement for immunoaffinity methods as previously reported. Using MSC isolated from bone marrow (BM-MSC) and adipose tissue (AT-MSC) as reference controls, we observed that CB-MSC exhibited a higher proliferation rate and expanded to the order of the 1 * 10(9) cells required for cell therapies. CB-MSC showed karyotype stability after prolonged expansion. Functionally, CB-MSC could be more readily induced to differentiate into chondrocytes than could BM-MSC and AT-MSC. CB-MSC showed immunosuppressive activity equal to that of BM-MSC and AT-MSC. Collectively, our data indicate that viable CB-MSC could be obtained consistently and that CB should be reconsidered as a practical source of MSC for cell therapy and regenerative medicine using the well established CB banking system. PMID- 21312239 TI - Stromal cell-derived factor-1/CXCR4 promotes IL-6 production in human synovial fibroblasts. AB - The production of chemokine stromal cell-derived factor (SDF)-1 is significantly higher in synovial fluid of patients with osteoarthritis (OA). IL-6 is a multifunctional cytokine that plays a central role in both OA and rheumatoid arthritis. However, the effects of SDF-1alpha on human synovial fibroblasts are largely unknown. In this study, we investigated the intracellular signaling pathway involved in SDF-1alpha-induced IL-6 production in human synovial fibroblast cells. SDF-1alpha caused concentration- and time-dependent increases in IL-6 production. SDF-1alpha also increased the mRNA and surface expression of CXCR4 receptor in human synovial fibroblasts. CXCR4-neutralizing antibody, CXCR4 specific inhibitor (AMD3100), or small interfering RNA against CXCR4 inhibited the SDF-1alpha-induced increase of IL-6 expression. The transcriptional regulation of IL-6 by SDF-1alpha was mediated by phosphorylation of phosphatidylinositol 3-kinase (PI3K)/Akt and activation of the activator protein (AP)-1 component of c-Jun. The binding of c-Jun to the AP-1 element on the IL-6 promoter and the increase in AP-1 luciferase activity was enhanced by SDF-1alpha. Co-transfection with CXCR4, PI3K, Akt, and c-Jun mutants or siRNA inhibited the potentiating action of SDF-1alpha on AP-1 promoter activity. Taken together, our results suggest that SDF-1alpha-increased IL-6 production in human synovial fibroblasts via the CXCR4 receptor, PI3K, Akt, c-Jun, and AP-1 signaling pathways. PMID- 21312240 TI - Effects of phenytoin and Echinacea purpurea extract on proliferation and apoptosis of mouse embryonic palatal mesenchymal cells. AB - Cleft palate is one of the most common birth defects. Several environment factors are involved in the disorder, such as smoking, vitamin deficiency and teratogens. We investigated the teratogenic agent phenytoin and extract of the immunostimulant Echinacea purpurea in the etiology of cleft palate associated with the proliferation and apoptosis of mouse embryonic palatal mesenchymal (MEPM) cells. We measured the effects of phenytoin, E. purpurea extract, and the mixture of phenytoin and E. purpurea extract on the cell viability of MEPM cells by CCK-8 assay and on the proliferation and apoptosis of MEPM cells by BrdU labeling assay, flow cytometry, and TUNEL assay. Exposure to phenytoin for 24 h inhibited cell proliferation and increased cell apoptosis of MEPM cells, and E. purpurea extract had the reverse effect. Importantly, treatment with the mixture of phenytoin and E. purpurea extract increased the proliferation and decreased the apoptosis of MEPM cells as compared with treatment with phenytoin alone. The teratogenic effect of phenytoin on cleft palate is associated with the proliferation and apoptosis of MEPM cells, and E. purpurea extract may have a protective effect. PMID- 21312241 TI - MicroRNA identity and abundance in developing swine adipose tissue as determined by Solexa sequencing. AB - MicroRNAs (miRNAs) are small ~22-nt regulatory RNAs that regulate the stability and translation of cognate mRNAs. MiRNAs participate in the regulation of adipogenesis, and identification of the full repertoire of miRNAs expressed in adipose tissue is likely to significantly increase our understanding of adipose tissue growth and development. Here, we adopted a deep sequencing approach to determine the identity and abundance of miRNAs in developing swine adipose tissue. Via this approach, we identified the sequences and relative expression levels of 227 conserved miRNAs (of which 59 were novel) and 66 potential porcine miRNAs. The expression levels displayed a large range, as reflected by the number of sequence reads, which varied from several counts for rare miRNAs to several million reads for the most abundant miRNAs. The abundant miRNAs principally belonged to 32 miRNA gene families, including miR-143, miR-103, let-7, and miR 148. Of the conserved miRNAs, 93 miRNAs were up-regulated and 33 miRNAs were down regulated in the adult pig adipose tissue. Moreover, we observed sequence variants and seed edits of the miRNAs. KEGG pathway analysis and GO term enrichment suggested that highly expressed miRNAs are involved in adipose tissue development, signal transduction, cell-cell and cell-extracellular matrix communication, neural development and function, and lipid metabolism including carboxylic acid, oxoacid, fatty acid, steroid, glycerolipid, alcohol and phospholipid metabolism. Our results expand the number of known porcine miRNAs and provide a thorough account of the miRNA transcriptome in porcine adipose tissue. PMID- 21312242 TI - Further evaluation of a novel nano-scale gene vector for in vivo transfection of siRNA. AB - In this research, a lipid-cationic polymer (LCP) containing the side-chain branching of brassidic acid was synthesized using chemical methods. As a gene vector for small interfering ribonucleic acid (siRNA) transfection, the efficiency and biosafety of LCP were preliminarily evaluated to investigate its possible application on tumor gene therapy. The toxicity, side-effects, and biosafety of LCP were investigated in animals based on the results of in vitro experiments. The siRNA against cyclooxygenase-2 (COX-2) was transfected by LCP to interfere with the COX-2 expression in nude-transplanted tumors. Hematoxylin and eosin stains, immunohistochemistry, reverse transcription-polymerase chain reaction, and Western blot were performed to evaluate the efficiency of LCP for siRNA transfection. The animal toxicity experiment showed that a high concentration of LCP had a low toxic effect on animals and did not induce allergic or pyrogenic reactions. The results from the in vivo transfection indicated that LCP could efficiently transfect siRNA and silence the target gene expression. The LCP gene vector for siRNA transfection is highly efficient during in vivo transfection and had low toxicity. From all aspects of tumor gene therapy and basic research, LCP is valuable for scientific research and medical applications. PMID- 21312243 TI - Regulation of AMP-activated protein kinase by LKB1 and CaMKK in adipocytes. AB - AMP-activated protein kinase (AMPK) is a serine/threonine kinase that regulates cellular and whole body energy homeostasis. In adipose tissue, activation of AMPK has been demonstrated in response to a variety of extracellular stimuli. However, the upstream kinase that activates AMPK in adipocytes remains elusive. Previous studies have identified LKB1 as a major AMPK kinase in muscle, liver, and other tissues. In certain cell types, Ca(2+) /calmodulin-dependent protein kinase kinase beta (CaMKKbeta) has been shown to activate AMPK in response to increases of intracellular Ca(2+) levels. Our aim was to investigate if LKB1 and/or CaMKK function as AMPK kinases in adipocytes. We used adipose tissue and isolated adipocytes from mice in which the expression of LKB1 was reduced to 10-20% of that of wild-type (LKB1 hypomorphic mice). We show that adipocytes from LKB1 hypomorphic mice display a 40% decrease in basal AMPK activity and a decrease of AMPK activity in the presence of the AMPK activator phenformin. We also demonstrate that stimulation of 3T3L1 adipocytes with intracellular [Ca(2+) ] raising agents results in an activation of the AMPK pathway. The inhibition of CaMKK isoforms, particularly CaMKKbeta, by the inhibitor STO-609 or by siRNAs, blocked Ca(2+) -, but not phenformin-, AICAR-, or forskolin-induced activation of AMPK, indicating that CaMKK activated AMPK in response to Ca(2+) . Collectively, we show that LKB1 is required to maintain normal AMPK-signaling in non-stimulated adipocytes and in the presence of phenformin. In addition, we demonstrate the existence of a Ca(2+) /CaMKK signaling pathway that can also regulate the activity of AMPK in adipocytes. PMID- 21312244 TI - A dynamic multimedia environmental and bioaccumulation model for brominated flame retardants in Lake Huron and Lake Erie, USA. AB - Polybrominated biphenyls (PBBs) and polybrominated diphenyl ethers (PBDEs) may pose a worldwide pollution problem because of their persistence, long-range transport capability, and predisposition to bioaccumulate. The ubiquitous presence of PBBs and PBDEs has heightened interest in determination of their fate. We report results for a fugacity-based dynamic environmental and bioaccumulation model of the fate of hexabromobiphenyl (hexaBB) discharged into the Saginaw Bay region of Lake Huron, USA. We calculated transient fugacity profiles of hexaBB in Lake Huron and Lake Erie water and sediment during the 1970s, 1980s, and 1990s. The hexaBB concentrations in the environmental compartments were used as inputs for a dynamic bioaccumulation model of Lake Huron and Lake Erie aquatic biota. The model results indicate that the sediment compartments of Lakes Huron and Erie serve as reservoirs for the accumulation and slow transfer of hexaBB to the food web constituents of these lakes. We present bioaccumulation factors (BAFs) and compare the predicted hexaBB concentrations in lake trout from the bioaccumulation model with measurements during the period 1980 to 2000. An uncertainty analysis for this model suggests that errors associated with input parameter uncertainty can be reduced by refining estimates of the sediment degradation half-life of hexaBB. The corroborated PBB model has carryover application for modeling the fate of polybrominated diphenyl ether (PBDE) contaminants in the Great Lakes. By fitting model outputs to field measurement data using the transformed least square fit method, we report estimations of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) emission rates into the Lake Huron and Lake Erie watershed areas. PMID- 21312246 TI - Nickel toxicity in embryos and larvae of the South American toad: effects on cell differentiation, morphogenesis, and oxygen consumption. AB - Nickel, a widely distributed heavy metal in the biosphere, produces systemic, carcinogenic, and teratogenic effects. The objectives of the present study are to report the acute, short-term chronic, and chronic toxicity of Ni in Rhinella arenarum embryos as well as the stage-dependent susceptibility to this heavy metal, including oxygen consumption, teratogenesis, and adverse effects on cell differentiation processes. The stages evaluated were blastula (S.7), gastrula (S.11), tail bud (S.17), fin circulation (S.22), and complete operculum (S.25), in this last case by means of toxicity profile curves. Nickel increases its adverse effects gradually, with a maximum value after 96 h. The 50% lethal concentrations (LC50s) for 96, 168, and 240 h at S.25 were 1.14, 0.60, and 0.48 mg Ni2(+) /L, respectively; S.11 and S.22 were the least and most susceptible to Ni with, LC50s 96 h of 6.12 and 0.19 mg Ni2(+) /L, respectively. A reduction of approximately 25% in oxygen consumption anticipates lethal effects from S.17 onward. The main teratogenic effects were retarded growth and development, extremely severe axis incurvations, persistent yolk plug, asymmetry, microcephaly and mouth and gill agenesia, and limited neuromuscular activity. Ciliated cells were not functional. The possibility of associating the remarkable stage dependent susceptibility to Ni with environmental changes during the evolutionary process is also considered. PMID- 21312245 TI - Relationships between benthic macroinvertebrate community structure and geospatial habitat, in-stream water chemistry, and surfactants in the effluent dominated Trinity River, Texas, USA. AB - Over the past 20 years, benthic macroinvertebrate community structure studies have been conducted on the upper Trinity River, Texas, USA, which is dominated by municipal wastewater treatment plant (WWTP) and industrial effluents. The Trinity River is located in the Dallas-Fort Worth metropolitan area, and is the most highly populated and industrialized watershed in Texas. As such, the Trinity River represents a near-worst-case scenario to examine the environmental effects of domestic-municipal and industrial effluents on aquatic life. A 1987 to 1988 study concluded that many stretches of the river supported a diverse benthic community structure; however, a decline in taxa richness occurred immediately downstream of WWTPs. A 2005 study designed to parallel the 1987 to 1988 efforts evaluated how changes in water quality, habitat, and increased urbanization impacted benthic community structure. Physicochemical measurements, habitat quality, geospatial variables, and benthic macroinvertebrates were collected from 10 sites. Surfactants were measured and toxic units (TUs) were calculated for surface water and pore water as indicators of domestic/household use of cleaning products. Total TUs indicated a low potential for biological impacts. Toxic unit distribution was not dependent on WWTP location and did not correlate with any benthic variable. Eight environmental parameters were determined to be useful for predicting changes in benthic macroinvertebrate community structure: surfactant surface water TUs (SWTU), in-stream habitat cover, and surface water total organic carbon were the top three parameters. Abundance, taxa richness, and taxa similarity in 2005 had increased since the earlier study throughout the immediate vicinity of the metropolitan area. PMID- 21312247 TI - Inhibition of pyrene biotransformation by piperonyl butoxide and identification of two pyrene derivatives in Lumbriculus variegatus (Oligochaeta). AB - Using the freshwater annelid Lumbriculus variegatus (Oligochaeta), the presence of cytochrome P450 (CYP) isozymes was investigated by analyzing metabolites of the polycyclic aromatic hydrocarbon (PAH) pyrene in treatments with and without the CYP inhibitor piperonyl butoxide (PBO). The results show a low biotransformation capability of L. variegatus (7% of total pyrene body burden as metabolites at 168 h). Addition of PBO resulted in a significant reduction of metabolites, suggesting the presence of a CYP in L. variegatus. Besides 1 hydroxypyrene, three peaks representing unknown metabolites were detected in LC FLD (liquid chromatography with fluorescence detection) chromatograms of L. variegatus. Deconjugations showed that sulfonation and glucosidation are involved in the formation of these unknowns. Further studies with the time of flight mass analyzer provided the identification of the glucose-sulfate conjugate of 1 hydroxypyrene. The same metabolites were detected in the solvent-nonextractable fraction by incubation of the tissue residues with proteinase K, suggesting that part of these metabolites are bound to proteins. Overall, the slow biotransformation of pyrene by L. variegatus (involving CYP) supports the use of this species in standard bioaccumulation tests; however, the tissue-bound metabolite fraction described in the current study deserves further investigation for its toxicity and availability to upper trophic levels through diet. PMID- 21312248 TI - Complex evaluation of ecotoxicity and genotoxicity of antimicrobials oxytetracycline and flumequine used in aquaculture. AB - Ecotoxicity and genotoxicity of widely used veterinary antimicrobials oxytetracycline and flumequine was studied with six model organisms (Vibrio fischeri, Pseudomonas putida, Pseudokirchneriella subcapitata, Lemna minor, Daphnia magna, Escherichia coli). Overall median effective concentration (EC50) values ranged from 0.22 mg/L to 86 mg/L. Pseudomonas putida was the most sensitive organism (EC50 values for 16-h growth inhibition were 0.22 and 0.82 mg/L for oxytetracycline and flumequine, respectively), followed by duckweed Lemna minor (7-d growth inhibition, EC50 2.1 and 3.0 mg/L) and green alga Pseudokirchneriella subcapitata (4-d growth inhibition, EC50 3.1 and 2.6 mg/L). The least sensitive organism was Daphnia magna (48-h immobilization, lowest observed-effect concentration [LOEC] of oxytetracycline of 400 mg/L). Oxytetracycline showed limited genotoxicity (SOS-chromotest with Escherichia coli, minimal genotoxic concentration of 500 mg/L), and flumequine was genotoxic at 0.25 mg/L. Based on the reported measured concentrations (MECs) and predicted no-effect concentrations (PNECs), oxytetracycline may be concluded to be of ecotoxicological concern (calculated risk quotient = 8), whereas flumequine seems to represent lower risk. PMID- 21312249 TI - Influence of sewage and pharmaceuticals on soil microbial function. AB - Although sewage effluent application to land is a common approach to recycle water and provide nutrients to plants, bioactive pharmaceuticals contained in sewage may change soil quality by affecting soil microbial communities. Establishing causal effects, however, is difficult, because trace levels of pharmaceuticals are confounded with other effluent constituents. Therefore, two originally similar soil microbial communities, one irrigated in situ with sewage effluent for 12 years and another nonirrigated, were exposed to high levels of acetaminophen, aspirin, carbamazepine, chlorpromazine, and tetracycline. The objectives of the current study were to determine the influence of high levels of pharmaceuticals on several soil microbial properties, the effect that prolonged effluent irrigation with ambient levels of pharmaceuticals had on soil microbial function, and how this effect would change in response to pharmaceutical exposure. Several pharmaceuticals, at high exposure levels, imposed stress on the soil microbial community as judged by increased CO(2) respiration, decreased biomass carbon, and altered substrate utilization affinities. Prolonged effluent irrigation, which altered the genetic fingerprint of the microbial community, also mitigated the response that exposure to pharmaceuticals had on the microbial community and enabled degradation of the antimicrobial salicylic acid after aspirin exposure. In conclusion, prolonged irrigation with sewage effluent containing pharmaceuticals at ambient levels influenced the microbial community so that they were able to better cope with sudden exposure to high levels of pharmaceuticals. PMID- 21312250 TI - Seasonality in contaminant accumulation in Arctic marine pelagic food webs using trophic magnification factor as a measure of bioaccumulation. AB - Seasonality in biomagnification of persistent organic pollutants (POPs; polychlorinated biphenyls, chlorinated pesticides, and brominated flame retardants) in Arctic marine pelagic food webs was investigated in Kongsfjorden, Svalbard, Norway. Trophic magnification factors (TMFs; average factor change in concentration between two trophic levels) were used to measure food web biomagnification in biota in May, July, and October 2007. Pelagic zooplankton (seven species), fish (five species), and seabirds (two species) were included in the study. For most POP compounds, highest TMFs were found in July and lowest were in May. Seasonally changing TMFs were a result of seasonally changing POP concentrations and the delta15N-derived trophic positions of the species included in the food web. These seasonal differences in TMFs were independent of inclusion/exclusion of organisms based on physiology (i.e., warm- versus cold blooded organisms) in the food web. The higher TMFs in July, when the food web consisted of a higher degree of boreal species, suggest that future warming of the Arctic and increased invasion by boreal species can result in increased food web magnification. Knowledge of the seasonal variation in POP biomagnification is a prerequisite for understanding changes in POP biomagnification caused by climate change. PMID- 21312251 TI - Metals and polycyclic aromatic hydrocarbons in colonial waterbird eggs from Lake Athabasca and the Peace-Athabasca Delta, Canada. AB - In 2009, aquatic bird eggs from a variety of species were collected from three sites in northern Alberta, Canada. Two sites were located in receiving waters of the Athabasca River, which drains the oil sands industrial region north of Fort McMurray, Alberta. The third site, located on the Peace River, was remote from the influence of the Athabasca River. Levels of mercury, arsenic, and polycyclic aromatic hydrocarbons (PAHs) were measured in the eggs along with nitrogen stable isotopes (delta15N) as an indicator of bird trophic position. Levels of As and PAHs in eggs were low, whereas Hg was measureable in all samples. Egg Hg levels increased with delta15N values (a proxy of food web trophic position); however, some eggs exhibited Hg levels greater than expected based on trophic position. These eggs were from sites in receiving waters of the Athabasca River, namely, Mamawi Lake and Egg Island. Levels of Hg in egg pools were correlated with naphthalene levels, perhaps indicating a common source of contamination. Temporal comparison of Hg levels in California gull (Larus californicus) eggs from the Lake Athabasca colony indicated that egg Hg burdens increased 40% from 1977 to 2009. More research is required to evaluate temporal trends in levels of environmental contaminants and to identify sources. PMID- 21312252 TI - Chesapeake Bay watershed pesticide use declines but toxicity increases. AB - Large areas of the Chesapeake Bay, USA, watershed are in agricultural land use, but there is no baywide program to track application rates of current-use pesticides in any of the watershed jurisdictions. Watershed studies demonstrate that several pesticides are present in surface and groundwater throughout the region. Between 1985 and 2004, the Maryland Department of Agriculture conducted surveys to estimate pesticide application within the state. Application rates of the dominant insecticides and herbicides were compiled over the survey period. Toxicity of the pesticides was tabulated, and the toxic units (TU) of applied active ingredients were calculated for several animal and plant species. The total mass of pesticides being applied to the watershed declined during the survey period. Due to increasing potency of the chemicals, however, total TUs applied have remained static or have significantly increased depending on the species of bioassay test organism used to assess toxicity. Applying estimates of pesticide transport into rivers in the Mississippi River basin show that significant quantities of pesticides may be entering Chesapeake Bay. PMID- 21312253 TI - Specific immunoadsorption therapy using a tryptophan column in patients with refractory heart failure due to dilated cardiomyopathy. AB - BACKGROUND: Certain cardiac-specific autoantibodies found in patients with dilated cardiomyopathy (DCM) play a role in mediating myocardial damage and fatal ventricular arrhythmias resulting in sudden cardiac death. Immunoadsorption therapy (IA) is one of the therapeutic tools to remove such autoantibodies. Clinical studies from Germany have shown that nonspecific IA using columns loaded by sheep antihuman IgG or protein A improved hemodynamic data and affected favorably cardiac function and survival in patients with heart failure (HF) due to DCM. The goal of this study is to determine if IA therapy using the high profile tryptophan column, which has high affinity for IgG3 subclass, affects favorably cardiac function in patients with severe HF who are refractory to conventional therapy. METHODS AND RESULTS: IA therapy was conducted in 16 patients with DCM (age 53 +/- 4, male 8, New York Heart Association functional class III/IV, mean ejection fraction 18 +/- 2%). Study subjects had autoantibodies directed against either beta1-adrenergic or M2-muscarinic receptors. Plasma brain natriuretic peptide levels were significantly decreased after IA (P = 0.016). Plasma inflammatory cytokines including interleukin-6 and tumor necrosis factor-alpha did not change after each session of IA. Six-minute walk distance was significantly increased after IA (P = 0.01). Left ventricular ejection fraction increased by 3% 3 months after IA (P = 0.039). CONCLUSIONS: Our initial experience demonstrated safety and short-term efficacy of IA using a new IgG3-specific tryptophan column for patients with advanced HF due to DCM. Long term follow-up is needed to confirm the effects on cardiac function and morbidity/mortality in such patients. PMID- 21312254 TI - Efficacy and safety of peripheral blood stem cell collection in elderly donors; does age interfere? AB - Elderly patients with hematological malignancies are often reliant on allogeneic transplantations. Older family relatives are increasingly involved in utilization as PBSC donors. We analyzed the mobilization results from 103 donors of age >=55 years in comparison with 121 younger donors of age <55 years. The median CD34+ count in peripheral blood on day +5 of the mobilization was higher in younger than in older donor group (72.0 vs. 37.0 cells/MUL, P < 0.0001). Linear regression showed a negative correlation between the age and CD34+ count in peripheral blood (P < 0.0001) and apheresis product (P < 0.0001). Based on multivariate analysis, the amount of circulating CD34+ cells appeared to be negatively influenced by age (P < 0.001) and positively by the preapheresis WBC count (P < 0.001). The precollection CD34+ (P < 0.0001), PLT (P = 0.0144) counts, and age (P = 0.0392) were confirmed as independent factors determining the collection yield. The side effects of G-CSF administration were similar in both the groups. Apheresis complications were more frequently recorded in elderly donors (29 vs. 15%, P = 0.0096). Higher age represents a risk factor for poorer mobilization results. A requirement for more than one apheresis in older donors occurs more frequently to obtain the adequate amount of CD34+ cells. Mobilization and collection procedures are associated with acceptable risks and complication rates in elderly donors. PMID- 21312255 TI - Plasma extraction rate and collection efficiency during therapeutic plasma exchange with Spectra Optia in comparison with Haemonetics MCS+. AB - For therapeutic plasma exchange (TPE), continuous and intermittent flow separators are known to be efficient. This study was undertaken to compare the performances of the Spectra Optia, a continuous flow centrifugal apheresis system recently developed by CaridianBCT, with the Haemonetics Multicomponents System (MCS)+ apheresis system based on intermittent flow centrifugation. The primary objective of the study was to compare the time required to exchange one total plasma volume with both separators. The secondary objectives were to determine the plasma exchange efficiency, the plasma extraction rate, the percentage of target exchange volume achieved, and the loss of cellular components. The study involved prospectively paired comparison of 16 TPE on each device performed in patients with chronic diseases treated with TPE. The time required to exchange 1 total plasma volume was 182 +/- 36 minutes for MCS+ procedures and 100 +/- 20 minutes for the Spectra Optia procedures (P < 0.05, all results presented as mean +/- standard deviation). A significantly higher plasma extraction rate was achieved (30.2 +/- 4.3 vs 16.8 +/- 3.4 mL/min, respectively, P < 0.05), and the plasma exchange efficiency was slightly better with the Spectra Optia compared with the MCS+ procedures (83.4 +/- 7.0 vs 80.0 +/- 8.5%, P < 0.05). The platelet loss was significantly lower with the Spectra Optia compared with the MCS+ procedures (1.6 +/- 2.3 vs 7.5 +/- 4.2%, respectively, P < 0.05), whereas the red blood cells loss was comparable. In conclusion, the Spectra Optia has significantly higher extraction rate and exchange efficiency than the MCS+ allowing to remove the same amount of plasma in less time, by processing less blood. It also removes significantly less platelets than the MCS+ separator. PMID- 21312256 TI - Flow cytometric platelet cross-matching to predict platelet transfusion in acute leukemia. AB - A great variety of patient- and product-related factors influence the outcome of platelet transfusions. Our study assessed the predictive value of a flow cytometric platelet cross match test for the outcome of HLA matched and unmatched platelet transfusions in patients with acute leukemia. Thirty nine patients (26 adults and 13 children) received 60 ABO compatible apheresis platelet unites ranging from 1 to 4 per patient (mean = 1.54; median = 2). We performed flowcytometric platelet cross-matching, HLA Class I typing by sequence-specific primer (SSP) for patients and complement-dependent cytotoxicity (CDC) for donors and screening of HLA Class I antibodies by ELISA. Effectiveness of platelet transfusion was evaluated using the corrected count increment which was calculated at 60 min and 18- to 24-h posttransfusion. Multivariate analysis was performed to detect which variable can predict transfusion response more than others. Cross-matched platelet transfusions associated with good response in 51.4% of transfusion events in adults and 73.3% in children. The noncrossmatched platelet transfusions associated with poor response in 83.3% in adults and 100% in children (P-values 0.143, 0.041, respectively). In the presence of clinical factors or HLA alloimmunization in adults, cross-matched platelets were associated with good response in 29.6 and 22.2% respectively. In children this occurred in 81.8 and 66.7%, respectively. In presence or absence of HLA matching, flow cytometry platelet cross-matching was the most predictor for transfusion response (P = 0.05). Because of the difficulties to find frequent HLA matched donors for acute leukemia patients; flow cytometric platelet cross-matching may provide the most useful way for selecting donors. It is useful even in the presence of alloimunization in children. PMID- 21312257 TI - The nuts and bolts of curriculum and assessment. AB - A curriculum is a planned educational experience. This broad definition includes everything from a single didactic lecture to a rotation or clerkship to an entire training program such as an internship, residency or fellowship. This guide is a six-step approach for creating any of these curricula. Steps 1 through 6 include: (1) identify the problem, (2) perform a needs assessment, (3) create goals and objectives, (4) develop the program, (5) implement the program, and (6) evaluate participants and the program. Use of these steps may at first seem laborious, yet results are user friendly and simplify subsequent curricula updating. Education accrediting agencies are increasing their expectations for detailed curricula and evaluations. This approach helps meet these standards. PMID- 21312258 TI - Therapeutic cytapheresis: too many platelets, too many white blood cells. AB - Myeloproliferative disorders may present with thrombocytosis and/or leukocytosis with symptoms ranging from minor to life-threatening. Therapeutic cytapheresis (TC), the removal of excess and/or abnormal cells such as platelets and white blood cells, can be used to rapidly reduce cells in the symptomatic patient. The patient's clinical status determines the need for TC as symptoms may not correlate to laboratory values. TC does not alter the underlying disease process but serves as a bridge until drug therapy is initiated. Because of low frequency of procedures performed and the often urgent need for treatment, clinical data for the use of TC are difficult to collect and analyze. American Society for Apheresis Clinical Applications Committee has described indications for TC for treatment of disease entities. These publications provide guidelines for these less commonly performed procedures. Maintaining staff education, competency, and proficiency for these urgent procedures is an ongoing challenge for the majority of therapeutic apheresis programs. PMID- 21312259 TI - The post-platelet 100,000 count: effects of platelet collection and future. AB - Currently, the majority of platelets transfused in the United States are collected by apheresis. The recent Food and Drug Administration guidance document published maintains that a postdonation platelet count for a donor remain >100,000/MUL. During apheresis procedures, platelets are released from the splenic pool into circulation. This allows for higher postdonation platelet counts than anticipated. Some current plateletpheresis instruments take this into account when determining a safe product to be collected. On other instruments, the software does not allow for this correction. This may impact collections, but is expected to be resolved with a software update. PMID- 21312260 TI - Effect of heparin-induced extracorporeal lipoprotein apheresis on renal function. AB - During the course of heparin-induced extracorporeal lipoprotein apheresis, a patient with no prior known renal impairment or proteinuria demonstrated sustained improvement in estimated glomerular filtration rate, commensurate with reduction in serum lipids and creatine phosphokinase levels. Causes and implications of this observation, which was not a priori, are discussed. PMID- 21312261 TI - Theoretical efficacy of using albumin/plasma versus full plasma replacement in TTP. PMID- 21312262 TI - LOHAS: loss-of-heterozygosity analysis suite. AB - Detection of loss of heterozygosity (LOH) plays an important role in genetic, genomic and cancer research. We develop computational methods to estimate the proportion of homozygous SNP calls, identify samples with structural alterations and/or unusual genotypic patterns, cluster samples with close LOH structures and map the genomic segments bearing LOH by analyzing data of genome-wide SNP arrays or customized SNP arrays. In addition to cancer genetics/genomics, we also apply the methods to study long contiguous stretches of homozygosity (LCSH) in general populations. The LCSH analysis aids in the identification of samples with complex LCSH patterns indicative of nonrandom mating and/or meiotic recombination cold spots, separation of samples with different genetic backgrounds and sex, and mapping of regions of LCSH. Affymetrix Human Mapping 500K Set SNP data from an acute lymphoblastic leukemia study containing 304 cancer patients and 50 normal controls and from the HapMap Project containing 30 African trios, 30 Caucasian trios and 90 independent Asian samples were analyzed. We identified common gene regions of LOH, e.g., ETV6 and CDKN1B, and identified frequent regions of LCSH, e.g., the region that encompasses the centromeric gene desert region of chromosome 16. Unsupervised analysis separated cancer subtypes and ethnic subpopulations by patterns of LOH/LCSH. Simulation studies considering LOH width, effect size and heterozygous interference fraction were performed, and the results show that the proposed LOH association test has good test power and controls type 1 error well. The developed algorithms are packaged into LOHAS written in R and R GUI. PMID- 21312263 TI - Dual-colour fluorescence microscopy using yEmCherry-/GFP-tagging of eisosome components Pil1 and Lsp1 in Candida albicans. AB - PCR-based gene targeting technologies have previously been developed for Candida albicans molecular genetic manipulation. Modular marker plasmids for the functional analysis of C. albicans genes have been generated to delete genes, exchange promoters and tag genes with GFP. Here, we have embedded two fluorescent proteins encoded by Venus and yEmCherry into the pFA-plasmid series and demonstrate their usefulness in dual colour microscopy. To this end we analysed the localization of C. albicans homologues of Pil1 and Lsp1, which in S. cerevisiae are components of eisosomes. We find that Pil1/Lsp1-containing eisosomes are cortical protein complexes in C. albicans.Pil1 and Lsp1, tagged with either GFP or yEmCherry, strictly co-localized during all growth stages. Eisosomes, however, localized at distinct positions not overlapping with either cortical actin patches or the endocytosis marker protein Abp1 in yeast or the Spitzenkorper in hyphal cells. To demonstrate the use of Venus yellow fluorescent protein we performed time lapse microscopy of yeast and hyphal stages using a histone H4-Venus tag. As demonstrated, these additions to the toolbox enable a wide range of in vivo applications in C. albicans. PMID- 21312264 TI - Safety and efficacy of the cathepsin K inhibitor ONO-5334 in postmenopausal osteoporosis: the OCEAN study. AB - Osteoporosis occurs when there is an imbalance between resorption and formation of bone, with resorption predominating. Inhibitors of cathepsin K may rebalance this condition. This is the first efficacy study of a new cathepsin K inhibitor, ONO-5334. The objective of the study was to investigate the efficacy and safety of ONO-5334 in postmenopausal osteoporosis. This was a 12-month, randomized, double-blind, placebo- and active-controlled parallel-group study conducted in 13 centers in 6 European countries. Subjects included 285 postmenopausal women aged 55 to 75 years with osteoporosis. Subjects were randomized into one of five treatment arms: placebo; 50 mg twice daily, 100 mg once daily, or 300 mg once daily of ONO-5334; or alendronate 70 mg once weekly. Lumbar spine, total hip, and femoral neck BMD values were obtained along with biochemical markers of bone turnover and standard safety assessments. All ONO-5334 doses and alendronate showed a significant increase in BMD for lumbar spine, total hip (except 100 mg once daily), and femoral neck BMD. There was little or no suppression of ONO-5334 on bone-formation markers compared with alendronate, although the suppressive effects on bone-resorption markers were similar. There were no clinically relevant safety concerns. With a significant increase in BMD, ONO-5334 also demonstrated a new mode of action as a potential agent for treating osteoporosis. Further clinical studies are warranted to investigate long-term efficacy as well as safety of ONO-5334. PMID- 21312265 TI - Bone turnover markers and bone mineral density response with risedronate therapy: relationship with fracture risk and patient adherence. AB - Surrogate markers of fracture risk--bone turnover markers (BTMs) and bone mineral density (BMD)--can be used to monitor treatment response. We assessed whether changes in these markers greater than the least significant change (LSC) were associated with fracture risk reduction and greater adherence. This secondary analysis of the Improving Measurements of Persistence on ACtonel Treatment (IMPACT) study--a multinational prospective, open-label, cluster-randomized study of postmenopausal women on oral risedronate 5 mg/d for 52 weeks-assessed adherence by electronic monitors. Urinary N-terminal cross-linked telopeptide of type 1 collagen (uNTX) and serum C-terminal cross-linked telopeptide of type 1 collagen (sCTX) levels were assessed at baseline and weeks 10 and 22, and BMD at baseline and week 52. Fractures were recorded as adverse events. In 2302 women, responses beyond LSC in BTMs (uNTX and sCTX) and BMD (spine only) were associated with a reduced risk of nonvertebral fractures (NVFs) and all fractures. NVF incidence was about 50% lower in patients with 30% or more of uNTX reduction at week 22 (1.6%) than in those with less than 30% reduction (3.2%, p = .015). NVFs also were reduced in patients with more than 3% spine BMD increase at 52 weeks than those with 3% or less. Responses greater than LSC in BTMs and BMD were associated with greater adherence, but there was no association between adherence and fracture outcomes at 52 weeks. Changes greater than the LSC in BTMs and BMD reflect better treatment adherence, were associated with fracture risk reduction, and identify differences in individual responsiveness to risedronate. PMID- 21312266 TI - CYR61 downregulation reduces osteosarcoma cell invasion, migration, and metastasis. AB - Osteosarcoma is the most common primary tumor of bone. The rapid development of metastatic lesions and resistance to chemotherapy remain major mechanisms responsible for the failure of treatments and the poor survival rate for patients. We showed previously that the HMGCoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitor statin exhibits antitumoral effects on osteosarcoma cells. Here, using microarray analysis, we identify Cyr61 as a new target of statins. Transcriptome and molecular analyses revealed that statins downregulate Cyr61 expression in human and murine osteosarcoma cells. Cyr61 silencing in osteosarcoma cell lines enhanced cell death and reduced cell migration and cell invasion compared with parental cells, whereas Cyr61 overexpression had opposite effects. Cyr61 expression was evaluated in 231 tissue cores from osteosarcoma patients. Tissue microarray analysis revealed that Cyr61 protein expression was higher in human osteosarcoma than in normal bone tissue and was further increased in metastatic tissues. Finally, tumor behavior and metastasis occurrence were analyzed by intramuscular injection of modified osteosarcoma cells into BALB/c mice. Cyr61 overexpression enhanced lung metastasis development, whereas cyr61 silencing strongly reduced lung metastases in mice. The results reveal that cyr61 expression increases with tumor grade in human osteosarcoma and demonstrate that cyr61 silencing inhibits in vitro osteosarcoma cell invasion and migration as well as in vivo lung metastases in mice. These data provide a novel molecular target for therapeutic intervention in metastatic osteosarcoma. PMID- 21312268 TI - Risk of fractures in older adults using antihypertensive medications. AB - Many medications used to control blood pressure have been associated with bone metabolism. In addition, hypertension itself may be associated with reduced bone mineral density. We examined the relative risk of fracture among subjects with hypertension initiating single-drug therapy for antihypertension treatment. We assembled a large cohort of Medicare beneficiaries with a diagnosis of hypertension who had not filled a prescription for an antihypertensive medication in the prior 365 days. All subsequently began treatment with a single antihypertensive drug. These subjects were followed forward using health care utilization data to determine the risk of a typical osteoporotic fracture. Adjusted Cox proportional hazards regression models were constructed to assess the relative risk of fracture across types of antihypertensive medications. We identified 376,061 eligible subjects. Fracture rate in the total cohort was 35.2 per 1000 person-years [95% confidence interval (CI) 34.4-36.1]. Rates varied significantly across type of antihypertensive, with thiazide diuretics having the lowest rate (28.5, 95% CI 25.4-31.9) and loop diuretics the highest rate (49.0, 95% CI 46.1-52.1). In models adjusting for relevant comorbidities and comedications accessible in health care utilization data, the risk of fracture was reduced in users of angiotensin receptor blockers [hazard ratio (HR) = 0.76, 95% CI 0.68-0.86) and thiazide diuretics (HR = 0.85, 95% CI 0.76-0.97) compared with calcium channel blockers. The adjusted fracture risk was not significantly different from the reference for loop diuretics, beta blockers, and angiotensin converting enzyme (ACE) inhibitors. It is concluded that the risk of fracture differs across users of different antihypertensive medications. PMID- 21312267 TI - Sclerostin is a locally acting regulator of late-osteoblast/preosteocyte differentiation and regulates mineralization through a MEPE-ASARM-dependent mechanism. AB - The identity of the cell type responsive to sclerostin, a negative regulator of bone mass, is unknown. Since sclerostin is expressed in vivo by mineral-embedded osteocytes, we tested the hypothesis that sclerostin would regulate the behavior of cells actively involved in mineralization in adult bone, the preosteocyte. Differentiating cultures of human primary osteoblasts exposed to recombinant human sclerostin (rhSCL) for 35 days displayed dose- and time-dependent inhibition of in vitro mineralization, with late cultures being most responsive in terms of mineralization and gene expression. Treatment of advanced (day 35) cultures with rhSCL markedly increased the expression of the preosteocyte marker E11 and decreased the expression of mature markers DMP1 and SOST. Concomitantly, matrix extracellular phosphoglycoprotein (MEPE) expression was increased by rhSCL at both the mRNA and protein levels, whereas PHEX was decreased, implying regulation through the MEPE-ASARM axis. We confirmed that mineralization by human osteoblasts is exquisitely sensitive to the triphosphorylated ASARM-PO4 peptide. Immunostaining revealed that rhSCL increased the endogenous levels of MEPE-ASARM. Importantly, antibody-mediated neutralization of endogenous MEPE-ASARM antagonized the effect of rhSCL on mineralization, as did the PHEX synthetic peptide SPR4. Finally, we found elevated Sost mRNA expression in the long bones of HYP mice, suggesting that sclerostin may drive the increased MEPE-ASARM levels and mineralization defect in this genotype. Our results suggest that sclerostin acts through regulation of the PHEX/MEPE axis at the preosteocyte stage and serves as a master regulator of physiologic bone mineralization, consistent with its localization in vivo and its established role in the inhibition of bone formation. PMID- 21312269 TI - Elevated Dickkopf-2 levels contribute to the abnormal phenotype of human osteoarthritic osteoblasts. AB - The Wnt signaling pathway is crucial for osteogenesis and regulates terminal osteoblast differentiation. Although osteoarthritic (OA) osteoblasts show an abnormal phenotype and poor in vitro mineralization, the mechanism leading to this situation still remains unknow. Recent evidence indicates that Wnt signaling may be altered in OA osteoblasts. In this study we determined whether an alteration of the Wnt/beta-catenin signaling pathway is responsible for the abnormal phenotype of OA osteoblasts. Expression of the Wnt signaling antagonist Dickkopf-1 (DKK1) was similar in normal and OA osteoblasts, whereas DKK2 expression was higher in OA osteoblasts than in normal osteoblasts. OA osteoblasts showed a decrease of Wnt3a-dependent Wnt/beta-catenin signaling, measured by the TOPflash reporter assay and by Western blot analysis, compared with normal osteoblasts. Correcting DKK2 levels in OA osteoblasts by siRNA techniques enhanced Wnt/beta-catenin signaling. Elevated DKK2 levels could be explained by elevated transforming growth factor beta1 (TGF-beta1) in OA osteoblasts, and exogenous TGF-beta1 increased DKK2 expression in normal osteoblasts, whereas ablating TGF-beta1 expression in OA osteoblasts reduced DKK2 expression. Inhibiting TGF-beta1 or DKK2 expression corrected the abnormal phenotype of OA osteoblasts. In vitro mineralization of OA osteoblasts also was increased by DKK2 siRNA. We conclude that elevated TGF-beta1 levels in OA osteoblasts can stimulate DKK2 expression, which, in turn, is responsible, at least in part, for their abnormal phenotype. PMID- 21312270 TI - IGF-1R signaling in chondrocytes modulates growth plate development by interacting with the PTHrP/Ihh pathway. AB - Systemic derangements and perinatal death of generalized insulin-like growth factor 1 (IGF-1) and IGF-1 receptor (IGF-1R) knockout mice preclude definitive assessment of IGF-1R actions in growth-plate (GP) chondrocytes. We generated cartilage-specific Igf1r knockout ((Cart) Igf1r(-/-)) mice to investigate local control of chondrocyte differentiation in the GP by this receptor. These mice died shortly after birth and showed disorganized chondrocyte columns, delayed ossification and vascular invasion, decreased cell proliferation, increased apoptosis, and increased expression of parathyroid hormone-related protein (Pthrp) RNA and protein in their GPs. The increased Pthrp expression in the knockout GPs likely was due to an increase in gene transcription, as determined by the increased activity of a LacZ reporter that was inserted downstream of the endogenous PTHrP promoter and bred into the knockout mice. To circumvent the early death of (Cart) Igf1r(-/-) mice and investigate the role of IGF-1R during postnatal growth, we made tamoxifen (Tam)-inducible, cartilage-specific Igf1r knockout ((TamCart) Igf1r(-/-)) mice. At 2 weeks of age and 7 to 8 days after Tam injection, the (TamCart) Igf1r(-/-) mice showed growth retardation with a disorganized GP, reduced chondrocyte proliferation, decreased type 2 collagen and Indian Hedgehog (Ihh) expression, but increased expression of PTHrP. Consistent with in vivo observations, in vitro knockout of the Igf1r gene by adenoviral expression of Cre recombinase suppressed cell proliferation, promoted apoptosis, and increased Pthrp expression. Our data indicate that the IGF-1R in chondrocytes controls cell growth, survival, and differentiation in embryonic and postnatal GPs in part by suppression of Pthrp expression. PMID- 21312271 TI - Trabecular bone of growth plate origin influences both trabecular and cortical morphology in adulthood. AB - Skeletal fragility is common at metaphyseal regions of long bones. The cortices of this region are derived by coalescence of trabeculae around the periphery of the growth plate, not by periosteal apposition, as occurs in the diaphyses. We therefore hypothesized that trabecular bone in childhood predicted both cortical and trabecular morphology in adulthood. To test this hypothesis, we measured distal radial and tibial structure using high-resolution peripheral quantitative computed tomography in 61 daughter-mother pairs, mean age 12.5 years (range 7 to 19 years) and 44.1 years (range 32 to 50 years), respectively. The daughters' trabecular bone volume (BV/TV), thickness, number, and separation predicted the corresponding traits in their mothers. Their trabecular BV/TV also predicted their mothers' cortical thickness (r = 0.32, p = .02). By contrast, the daughters' cortical thickness did not predict their mothers' cortical thickness. The daughters had higher trabecular BV/TV than their mothers (mean +/- SD, radius 0.134 +/- 0.024 versus 0.124 +/- 0.033, p = .03; tibia 0.145 +/- 0.021 versus 0.135 +/- 0.032, p < .01) owing to greater trabecular number, not thickness, and less trabecular separation. Abnormalities in the development of metaphyseal trabecular bone are likely to influence fragility in both trabecular and cortical bone of this region in adulthood. PMID- 21312273 TI - Progression and prognostic factors of motor impairment, disability and quality of life in newly diagnosed Parkinson's disease. AB - OBJECTIVE: To determine progression and prognostic factors of progression rate of motor impairment, disability, and quality of life (QoL) in patients with newly diagnosed Parkinson's disease. METHODS: A group of 126 patients with newly diagnosed PD recruited from outpatient clinics participated in this 3-year prospective cohort study. Motor impairment was rated with the Unified Parkinson Disease Rating Scale Motor-Examination. Disability was rated using the Schwab and England Activities of Daily Living Scale, the AMC Linear Disability Score. QoL was assessed with the Parkinson's Disease Quality of Life questionnaire. Linear mixed model analyses were conducted to identify determinants of progression rate of motor impairment, disability, and poor QoL. RESULTS: Motor impairment progressed with 3 points per year. There was a slight progression of disability and QoL during 3 years of follow-up. Female sex was a prognostic factor for slower progression of motor impairment and QoL. Older age at onset showed to prognosticate faster progression of disability and impaired QoL. Furthermore, independent of follow-up time, older age at onset was associated with worse motor impairment; nondopaminergic reactive symptoms (Axial impairment) were associated with more disability and poorer QoL; comorbidity showed relation with disability and QoL but to a lesser extent; self-reported mood symptoms were associated with poorer QoL; and disease duration correlated with motor impairment. CONCLUSIONS: Motor impairment, disability, and QoL of newly diagnosed Parkinson patients show progression in the first 3 years. Older age at onset predicts worse progression rate of disability and impaired QoL over time. Female sex predicts slower progression of motor impairment and less decline of QoL. PMID- 21312272 TI - Adipokines and the risk of fracture in older adults. AB - Adiponectin and leptin are adipokines that influence bone metabolism in vitro and in animal models. However, less is known about the longitudinal association of leptin and adiponectin with fracture. We tested the hypothesis that low leptin and high adiponectin levels are each individually associated with fracture risk in a prospective cohort study in Memphis and Pittsburgh among 3075 women and men aged 70 to 79 years from the Health Aging and Body Composition (Health ABC) study. There were 406 incident fractures (334 nonvertebral and 72 vertebral) over a mean of 6.5 +/- 1.9 years. Cox regression was used to estimate the hazard ratios for fracture. Sex modified the association between adiponectin and fracture (p = .025 for interaction). Men with the highest adiponectin level (tertile 3) had a 94% higher risk of fracture [hazard ratio (HR) = 1.94; 95% confidence interval (CI) 1.20-3.16] compared with the lowest tertile (tertile 1; p = .007 for trend) after adjusting age, race, body mass index (BMI), education, diabetes, weight change, and hip bone mineral density (BMD). Among women, after adjusting for age and race, this association was no longer significant (p = .369 for trend). Leptin did not predict fracture risk in women (p = .544 for trend) or men (p = .118 for trend) in the multivariate models. Our results suggest that adiponectin, but not leptin, may be a novel risk factor for increased fracture risk independent of body composition and BMD and that these relationships may be influenced by sex. More research is needed to understand the physiologic basis underlying these sex differences. PMID- 21312274 TI - Mutation and copy number analysis in paroxysmal kinesigenic dyskinesia families. PMID- 21312275 TI - Parkinson's disease sleep scale--validation of the revised version PDSS-2. AB - BACKGROUND: The previous Parkinson's disease sleep scale (PDSS) is a 15-item visual analogue scale that assesses the profile of nocturnal disturbances in Parkinson's disease (PD) patients. OBJECTIVE: To extend the scale so that it becomes a frequency measure scale with five categories and encompasses unmet needs such as restless legs syndrome, akinesia, pain, and sleep apnea. METHODS: For validation of the PDSS-2, PD patients' ratings and investigators' interviews were compared to ratings from a semistructured interview with a caregiver/partner, and to related scales. PDSS-2 was repeated for test-retest reliability after 1-3 days. RESULTS: A total of 113 PD patients showed a mean (SD) total score of 16.5 (+/-8.9) (range: 2-40) indicating mild to moderate sleep disturbances. PDSS-2 item-total correlation for proving internal consistency was satisfactory (correlations >0.30). From a factor analysis, three subscales were derived: (1) "motor problems at night," (2) "PD symptoms at night" and (3) "disturbed sleep." The alpha coefficient for the total score was 0.73, for subscales 0.47 to 0.66. The test-retest-reliability intra-class-coefficient for the total score was 0.80, with 0.69 and 0.77 within the subscales. For discriminative validity, significant differences were found in the PDSS-2 total score depending on CGI and Hoehn and Yahr severity levels. A comparison between caregivers' and patients' ratings was carried out. CONCLUSION: The PDSS-2, with an extended spectrum of nocturnal disabilities and easier use for patients, is a reliable, valid, precise, and potentially treatment-responsive tool for measuring sleep disorders in PD. PMID- 21312276 TI - Imaging evidence of nigral damage in dystonia secondary to disulfiram intoxication. PMID- 21312277 TI - Myoclonus and angiokeratomas in adult galactosialidosis. PMID- 21312278 TI - Impulsivity and compulsivity in drug-naive patients with Parkinson's disease. AB - BACKGROUND: Abnormal repetitive behaviors have been reported in Parkinson's disease (PD) during dopamine replacement therapy (DRT) and associated with individual predisposing features, including impulsivity. However, impulsivity and compulsive symptoms have never been explored in PD patients before initiation of DRT. We previously reported a 20% of impulse control disorders (ICD) in an Italian cohort. METHODS: 103 consecutive newly diagnosed drug-naive PD patients (means: age = 60.5 +/- 9.2 years; duration = 15.4 +/- 15.3 months) were screened for compulsive sexual behavior, compulsive buying, intermittent explosive disorder (Minnesota Impulsive Disorders Interview, MIDI), and pathological gambling (South Oaks Gambling Screen, SOGS). Barratt Impulsiveness Scale (BIS-11) and Maudsley Obsessional-Compulsive Questionnaire (MOCQ/R) assessed impulsivity, obsessive-compulsive symptoms, respectively. Depression (GDS-15) and general cognitive status were additionally assessed. We also compared ICDs frequency with our healthy controls. RESULTS: 17.5% of PD patients screened positive for at least one ICD at MIDI (17/103) and SOGS (1/103), though none had a disorder based on DSM-IV criteria. These frequencies were similar to healthy controls. There was a trend toward higher scores in BIS-11 attentive-impulsivity subscale (15.2 +/- 4.8 vs. 18.7 +/- 4.9; P = 0.007) and in MOCQ/R-Doubting subscale (0.67 +/- 1.1 vs. 1.5 +/- 1.2; P = 0.007) in PD with ICD. We also observed a positive correlation between GDS-15 and BIS-11. CONCLUSIONS: Similar to our healthy control population, we found a significant proportion of early PD patients positive for ICDs before starting treatment. We also found a relationship between impulsivity and depression. A detailed behavioral assessment before starting dopaminergic therapy is recommended. PMID- 21312279 TI - Cortically evoked responses of human pallidal neurons recorded during stereotactic neurosurgery. AB - Responses of neurons in the globus pallidus (GP) to cortical stimulation were recorded for the first time in humans. We performed microelectrode recordings of GP neurons in 10 Parkinson's disease (PD) patients and 1 cervical dystonia (CD) patient during surgeries to implant bilateral deep brain stimulation electrodes in the GP. To identify the motor territories in the external (GPe) and internal (GPi) segments of the GP, unitary responses evoked by stimulation of the primary motor cortex were observed by constructing peristimulus time histograms. Neurons in the motor territories of the GPe and GPi responded to cortical stimulation. Response patterns observed in the PD patients were combinations of an early excitation, an inhibition, and a late excitation. In addition, in the CD patient, a long-lasting inhibition was prominent, suggesting increased activity along the cortico-striato-GPe/GPi pathways. The firing rates of GPe and GPi neurons in the CD patient were lower than those in the PD patients. Many GPe and GPi neurons of the PD and CD patients showed burst or oscillatory burst activity. Effective cathodal contacts tended to be located close to the responding neurons. Such unitary responses induced by cortical stimulation may be of use to target motor territories of the GP for stereotactic functional neurosurgery. Future findings utilizing this method may give us new insights into understanding the pathophysiology of movement disorders. PMID- 21312280 TI - Cervical dystonia associated with facioscapulohumeral dystrophy: expanding the clinical spectrum? PMID- 21312281 TI - Symptomatology and markers of anxiety disorders in Parkinson's disease: a cross sectional study. AB - Anxiety is understudied in Parkinson's disease (PD), which is not justified by the prevalence and impact of anxiety disorders on quality of life in PD patients. In this cross-sectional study, 342 patients suffering from idiopathic PD underwent a research-based assessment including DSM IV criteria for anxiety disorders, the Hamilton anxiety rating scale (HARS) and the beck anxiety inventory (BAI). Thirty-four percent (34%) of subjects met the DSM IV criteria for at least one anxiety disorder; 11.8% met criteria for multiple anxiety disorders; and 11.4% had clinically relevant anxiety symptoms without meeting the criteria for any specific anxiety disorder. Score profiles on the HARS and BAI differed significantly between the disorders, but these differences were associated with different scores on a limited number of items, and the respective symptom profiles were not readily interpretable. Female sex, the presence of motor fluctuations, as well as a previous history of an anxiety disorder were markers for anxiety disorders. The use of a mono-amino oxidase (MAO)-B inhibitor was associated with a reduced prevalence of anxiety disorders. Research into anxiety in PD is hampered by the questionable validity of DSM IV defined anxiety disorders in this population. A first focus for research should therefore be the identification of clinically useful anxiety presentations and their validation in PD. PMID- 21312282 TI - On doing nothing: descriptions of sleep, fatigue, and motivation in encephalitis lethargica. AB - Epidemics of encephalitis lethargica (EL), from 1917 to the 1930s, are an important milestone in the history of movement disorders. Today, the two best known features of EL are somnolence and parkinsonism but the full clinical picture was variable and complex. States of wakeful inactivity--as opposed to drowsiness--were often described both in the acute and postacute stages and were referred to in the EL literature as "lethargy" or "torpor." The study described here is based on a survey of clinical descriptions published in English, French, and German from 1917 to 1942. Its focus is on the history of clinical ideas, rather than applying modern pathophysiological concepts retrospectively. Descriptions of lethargy are explored as a way of elucidating concepts of sleep, fatigue, and motivation during the study period. The literature described many patients who had (1) lethargy without interruption in consciousness; (2) slowness of movement and catalepsy without other prominent parkinsonian features; and (3) apathy and lack of initiative without severe disorders of mood or thought content. Hence observers distinguished a state of wakeful inactivity from primary disorders of sleep, movement and behavior. Contemporaneous accounts suggest that writers had difficulty in reconciling their observations with preexisting concepts; there still may be limitations in our ability to describe and classify the clinical states connected during the epidemic era with the term "lethargy." PMID- 21312283 TI - Postural sway approaches center of mass stability limits in Parkinson's disease. AB - BACKGROUND: Although Parkinson's disease (PD) is a well recognised risk factor for falls, how this disease and its therapy affect postural stability and leaning balance remains unclear. The aim of this study was to examine the effects of PD and levodopa on postural sway and leaning balance. METHODS: Performances of 28 PD participants {median [inter-quartile range (IQR)] duration of PD: 10 (6-13) years, median (IQR) UPDRS motor score "off": 22 (14-31) "on" and "off" levodopa were compared with 28 age- and gender-matched healthy controls on two measures of controlled leaning balance [ratio of anterior-posterior (AP) sway to maximal balance range (MBR) and coordinated stability]. RESULTS: PD participants had greater ratio of AP sway to MBR than controls (P < 0.001), indicating that they swayed more as a proportion of their limits of stability, both "off" and "on" levodopa (P < 0.001). They also performed poorer in the coordinated stability test both "off" and "on" levodopa compared to controls (P < 0.001, for both), suggesting greater difficulty in controlling the center of mass at or near the limits of stability. Levodopa improved PD "participants" leaning balance (P < 0.001) and reduced the AP sway to MBR ratio (P < 0.001), although not to the level of controls. CONCLUSIONS: PD participants perform poorer than controls in leaning balance tests but significantly improve when "on" levodopa. Regardless of medication state, PD participants sway markedly more as a percentage of their limits of stability than controls suggesting a higher risk of falling. PMID- 21312284 TI - Long-term clinical outcome in meige syndrome treated with internal pallidum deep brain stimulation. AB - Deep brain stimulation of the globus pallidus internus (GPi DBS) is effective in the treatment of primary segmental and generalized dystonia. Although limb, neck, or truncal dystonia are markedly improved, orofacial dystonia is ameliorated to a lesser extent. Nevertheless, several case reports and small cohort studies have described favorable short-term results of GPi DBS in patients with severe Meige syndrome. Here, we extend this preliminary experience by reporting long-term outcome in a multicenter case series, following 12 patients (6 women, 6 men) with Meige syndrome for up to 78 months after bilateral GPi DBS. We retrospectively assessed dystonia severity based on preoperative and postoperative video documentation. Mean age of patients at surgery was 64.5 +/- 4.4 years, and mean disease duration 8.3 +/- 4.4 years. Dystonia severity as assessed by the Burke Fahn-Marsden Dystonia Rating Scale showed a mean improvement of 45% at short-term follow-up (4.4 +/- 1.5 months; P < 0.001) and of 53% at long-term follow-up (38.8 +/- 21.7 months; P < 0.001). Subscores for eyes were improved by 38% (P = 0.004) and 47% (P < 0.001), for mouth by 50% (P < 0.001) and 56% (P < 0.001), and for speech/swallowing by 44% (P = 0.058) and 64% (P = 0.004). Mean improvements were 25% (P = 0.006) and 38% (P < 0.001) on the Blepharospasm Movement Scale and 44% (P < 0.001) and 49% (P < 0.001) on the Abnormal Involuntary Movement Scale. This series, which is the first to demonstrate a long-term follow-up in a large number of patients, shows that GPi DBS is a safe and highly effective therapy for Meige syndrome. The benefit is preserved for up to 6 years. PMID- 21312285 TI - Substantia nigra hyperechogenicity with LRRK2 G2019S mutations. AB - BACKGROUND: Transcranial sonography (TCS) area of hyperechogenicity in the substantia nigra (aSN) is increased in idiopathic and genetic Parkinson's disease (PD). METHODS: We performed TCS in 34 LRRK2 G2019S mutation carriers manifesting PD, 24 non-manifesting mutation carriers, and 28 idiopathic PD patients and compared them with 40 healthy controls (total, n = 126). RESULTS: Compared with the controls (mean 0.15 cm(2) ), the aSN values in all other groups were increased. The mean aSN was 0.23 cm(2) in nonmanifesting mutation carriers (P = .015), 0.34 cm(2) in idiopathic PD patients (P < .0001), 0.32 cm(2) in LRRK2 associated PD patients (P < .0001), and 0.33 cm(2) in the overall PD group (P < .0001). LRRK2-associated PD patients had a higher aSN than did nonmanifesting carriers (P = .011), but there was no significant difference in aSN between patients with idiopathic and LRRK2-associated PD (P = .439). CONCLUSIONS: Our results suggest that SN pathoanatomical alterations may not be substantially different between idiopathic and LRRK2-associated PD. The findings in the nonmanifesting mutation carriers suggest the presence of intermediate nigrostriatal pathology consistent with the age-dependent reduced penetrance of this mutation. PMID- 21312286 TI - Attentional biases in clinical populations with alcohol use disorders: is co morbidity ignored? AB - OBJECTIVE: To identify how psychiatric co-morbidity was identified and assessed, in studies of attentional bias in clinical samples of patients with alcohol use disorders (AUDs). DESIGN: Systematic review methodology was used to identify studies and abstract data on alcohol-related attentional biases and measurement of psychiatric co-morbidity. RESULTS: Seventeen papers were identified that met the criteria for inclusion. All but one study were in patients meeting criteria for alcohol dependence. In 10 of the 17 studies, either no mention or minimal statements were made pertaining to possible co-morbid conditions (including other substance use): five excluded patients with psychiatric diagnoses, (variously defined), and two excluded patients on 'psychotropic medication'. Slow response latencies to all word types were found in studies where co-morbid conditions were not considered. CONCLUSIONS: Despite the high prevalence of psychiatric pathology in patients with AUDs (particularly depression), and the acknowledged impact that this has on aetiology, presentation and outcome, psychiatric co-morbidity has not been consistently measured or described in experimental studies on alcohol related attentional biases in clinical samples. In order to have an accurate appreciation of the role of attentional biases in patients with AUDs, there needs to be a consistent approach to measuring the co-occurrence of other psychopathology. Further research is needed to assess the impact of co morbidities on attentional biases in AUDs, to enable the development of more targeted psychological and pharmacological treatments. PMID- 21312287 TI - Why do young women smoke? VII COMT as a risk modifying gene for Nicotine dependence - role of gene-gene interaction, personality, and environmental factors. AB - OBJECTIVES: Catechol-O-methyltransferase (COMT) may be a risk modifying gene for Nicotine dependence (ND) rather than a direct susceptibility gene for this phenotype. Brain nicotinic cholinergic receptors modulate dopaminergic transmission, and several variants within the neighboring CHRNA5-CHRNA3 genes have been associated with ND. Therefore, it is biologically reasonable to study the interactive contribution of COMT and the CHRNA5 and CHRNA3 genes to ND. METHODS: Using a case-control sample of 90 young, Israeli, Jewish female smokers (FTND >= 4) and 108 controls (FTND = 0 during heaviest period of smoking), we studied association with ND of 8 COMT tagging SNPs, their interaction with tagging CHRNA5-A3 SNPs and the role of background, personality, and environmental factors. RESULTS: None of the COMT SNPs were associated directly with ND. In pairwise interaction analysis of SNPs from the two loci (COMT SNP-CHRNA5-CHRNA3 SNP), the interaction of intronic COMT SNP, rs9332377, with CHRNA3 3'UTR SNP rs660652 was significantly associated with ND (p = 0.0005), withstanding correction for multiple testing. CONCLUSION: Addition of the genetic interaction variable into a model of non-genetic ND predictors [parental smoking, novelty seeking (NS), and lifetime history of trauma], substantially increases the percentage of ND variance explained by the model, as well as the percentage of cases correctly identified by it. PMID- 21312288 TI - Glucose and caffeine effects on sustained attention: an exploratory fMRI study. AB - OBJECTIVE: Caffeine and glucose can have beneficial effects on cognitive performance. However, neural basis of these effects remain unknown. Our objective was to evaluate the effects of caffeine and glucose on sustained attention, using functional magnetic resonance imaging (fMRI). METHODS: Forty young right-handed, healthy, low caffeine-consuming subjects participated in the study. In a double blind, randomised design, subjects received one of the following beverages: vehicle (water, 150 ml); vehicle plus 75 g of glucose; vehicle plus 75 mg of caffeine; vehicle plus 75 g of glucose and 75 mg of caffeine. Participants underwent two scanning fMRI sessions (before and 30 min after of the administration of the beverage). A continuous performance test was used to assess sustained attention. RESULTS: Participants who received combined caffeine and glucose had similar performance to the others but had a decrease in activation in the bilateral parietal and left prefrontal cortex. CONCLUSIONS: Since these areas have been related to the sustained attention and working memory processes, results would suggest that combined caffeine and glucose could increase the efficiency of the attentional system. However, more studies using larger samples and different levels of caffeine and glucose are necessary to better understand the combined effects of both substances. PMID- 21312289 TI - In vitro and in vivo evaluation of the effects of duloxetine on P-gp function. AB - OBJECTIVE: To evaluate the effect of duloxetine (DLX) on the P-glycoprotein (P gp) function in vitro and in vivo. METHOD: In vitro experiment was conducted using the Caco-2 cell, a human colon cancer cell line that naturally expresses the P-gp and P-gp function was evaluated by monitoring whether DLX affect the accumulation of Rhd123. In vivo study was conducted by quantitating the effect of orally administered DLX on the bioavailability of talinolol. RESULTS: In the in vitro study, incubation of Caco-2 cell with DLX caused a concentration-dependent increase in the accumulation of Rhd123. In the in vivo study, co-administration of DLX increased the bioavailability of talinolol. The ratio (90% confidence intervals) of AUC(0-60), AUC(0-infinity), and C(max) (talinolol alone versus talinolol plus DLX) were 0.87(0.77-1.06), 0.85(0.74-1.01), 0.87 (0.68-1.12). CONCLUSION: Our results suggest that DLX could inhibit the function of P-gp in vitro and in vivo, and caution should be exercised when DLX is to be co administered with drugs that are P-gp substrate. PMID- 21312290 TI - Amantadine versus methylphenidate in children and adolescents with attention deficit/hyperactivity disorder: a randomized, double-blind trial. AB - OBJECTIVE: The aim of the present study was to further evaluate, under double blind and controlled conditions, the efficacy of amantadine for attention deficit/hyperactivity disorder (ADHD) in children and adolescents as compared to methylphenidate. METHODS: This was a 6-week randomized clinical trial. Forty patients (28 boys and 12 girls) with a DSM-IV-TR diagnosis of ADHD were the study population of this trial. All study subjects were randomly assigned to receive the treatment using capsule of amantadine at a dose of 100-150 mg/day depending on weight (100 mg/day for <30 kg and 150 mg/day for >30 kg) or methylphenidate at a dose of 20-30 mg/day for a 6-week double blind, randomized clinical trial. The principal measure of outcome was the Teacher and Parent Attention deficit/hyperactivity disorder Rating Scale-IV. RESULTS: No significant differences were observed between the two groups on the Parent and Teacher Rating Scale scores (df = 1; F = 0.02; p = 0.86 and df = 1; F = 0.01; p = 0.89, respectively). Side effects of decreased appetite and restlessness were observed more frequently in the methylphenidate group. CONCLUSION: The results of this study indicate that amantadine significantly improved symptoms of ADHD and was well tolerated and it may be beneficial in the treatment of children with ADHD. Nevertheless, the present results do not constitute proof of efficacy. PMID- 21312291 TI - Plasma levels of brain-derived neurotrophic factor and interleukin-6 in patients with dysthymic disorder: comparison with age- and sex-matched major depressed patients and healthy controls. AB - In the present study, we investigated the serum BDNF levels and plasma IL-6 levels in patients with dysthymic disorder, major depressive disorder and control subjects. Eighteen patients who met the DSM-IV criteria (American Psychiatric Association, 1994) for dysthymic disorder (male/female: 5/13; age: 36 +/- 9 year) and 20 patients (male/female: 7/13; age: 38 +/- 10 year) who met the criteria for major depressive disorder were enrolled. The serum BDNF levels in patients with dysthymic and major depressive disorder were significantly lower than those in the control subjects. However, no difference was found between the dysthymic group and major depression group. The plasma IL-6 levels in the dysthymic group and major depression group were significantly higher than those in the control group. No difference was observed in the plasma IL-6 levels between the dysthymic group and major depression group. These results suggest that the pathophysiology of dysthymic disorder and major depression might be similar in terms of the blood levels of BDNF and IL-6. PMID- 21312292 TI - Efficacy of reboxetine in adults with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled clinical trial. AB - OBJECTIVE: The main aim of this study is to evaluate the efficacy of reboxetine, a specific noradrenergic reuptake inhibitor, in adults with attention deficit/hyperactivity disorder (ADHD). METHODS: In a double blind placebo controlled clinical trial, the efficacy of 8 mg/day of reboxetine (twice daily) was compared with placebo in 40 adults diagnosed with ADHD during 6 weeks. The measures were Conners' Adult ADHD Rating Scale-Self-Report, Screening Version (CAARS-S, SV), Hamilton Anxiety and Depression Rating Scales, Clinical Global Impression - Severity Scale (CGI-S), and Global Assessment of Functioning Scale (GAF). RESULTS: There was a main effect of time and significant time X treatment (reboxetine vs. placebo) interaction on CAARS subscales and CGI scores which decreased along the study (p < 0.01). There was also a main effect of time and time X treatment interaction on GAF score which increased at the end point of the study (p < 0.01). In terms of Hamilton Anxiety and Depression Rating Scales there was just a main effect of time on Hamilton Depression Scale (p < 0.01). Irritability, anxiety, sleep disturbance, and dry mouth were the common side effects of reboxetine. CONCLUSION: Reboxetine could be used and tolerated as an effective treatment for adults with ADHD. PMID- 21312294 TI - Lithium clearly and directly affects the activity of the thyroid gland in human. PMID- 21312293 TI - The role of nicotine content information in smokers' subjective responses to nicotine and placebo inhalers. AB - OBJECTIVE: A growing body of evidence suggests that non-pharmacological factors may play an important role in smoking cessation outcomes using nicotine replacement therapies. This study examined the role of information about nicotine content in smokers' subjective responses to nicotine and placebo inhalers, using the four conditions of the balanced-placebo design in a mixed within/between subjects design. METHODS: Twenty-four adult smokers (12 male) completed two laboratory sessions following overnight abstinence from smoking. Participants were randomly assigned to receive either nicotine inhalers or placebo inhalers in both sessions but were told that they received a nicotine-containing inhaler in one session and a nicotine-free inhaler in the other. In each session participants completed subjective assessments before and after inhaler administration using visual analogue scales and the Brief Questionnaire of Smoking Urges. RESULTS: While neither nicotine content nor information about it significantly affected cigarette craving associated with withdrawal relief, participants reported a greater reduction in craving associated with intention to smoke when told the inhalers contained nicotine than when told the inhalers were nicotine-free, regardless of actual nicotine content. CONCLUSIONS: Findings suggest that psychological factors play an important role in smokers' subjective responses to nicotine inhalers, the effects of which cannot be solely attributed to the direct pharmacological effects of nicotine. PMID- 21312297 TI - Efficacy of rivastigmine transdermal patch on activities of daily living: item responder analyses. AB - OBJECTIVE: In Alzheimer's disease (AD), rivastigmine has demonstrated statistically significant efficacy versus placebo on cognition and activities of daily living (ADL). The aim of this retrospective analysis was to further evaluate the treatment effects of rivastigmine on individual ADL items. METHODS: This exploratory analysis focused on the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) outcome from a large, international, 24 week, controlled trial of rivastigmine once-daily transdermal patch and twice daily capsules in AD (CENA713D2320, NCT00099242). Percentages of patients "improving" or "not worsening" on individual ADL items were calculated and changes from baseline with rivastigmine versus placebo were evaluated. RESULTS: Patients received rivastigmine patch (9.5 mg/24 h; n = 247), capsule (12 mg/day; n = 254), and placebo (n = 281). Statistically significant changes from baseline in composite ADCS-ADL scores in both rivastigmine treatment groups versus placebo (p < 0.05) had previously been reported. In this responder analysis of the subset of patients who showed baseline functional impairments on each item, statistically significant differences favoring rivastigmine were seen on the following functions: bathing, clearing dishes, obtaining a beverage, garbage disposal, traveling, shopping, writing, using household appliances, and talking about current events. A responder analysis of emergence of ADL impairment was not as sensitive to treatment effects. CONCLUSIONS: These findings suggest that rivastigmine may benefit specific ADL, particularly in patients who are already exhibiting functional impairment. Further research is required to improve understanding of how drugs such as rivastigmine exert their clinical effects. PMID- 21312298 TI - Poly(triazine imide) with intercalation of lithium and chloride ions [(C3N3)2(NH(x)Li(1-x))3?LiCl]: a crystalline 2D carbon nitride network. AB - Poly(triazine imide) with intercalation of lithium and chloride ions (PTI/Li(+)Cl(-)) was synthesized by temperature-induced condensation of dicyandiamide in a eutectic mixture of lithium chloride and potassium chloride as solvent. By using this ionothermal approach the well-known problem of insufficient crystallinity of carbon nitride (CN) condensation products could be overcome. The structural characterization of PTI/Li(+)Cl(-) resulted from a complementary approach using spectroscopic methods as well as different diffraction techniques. Due to the high crystallinity of PTI/Li(+)Cl(-) a structure solution from both powder X-ray and electron diffraction patterns using direct methods was possible; this yielded a triazine-based structure model, in contrast to the proposed fully condensed heptazine-based structure that has been reported recently. Further information from solid-state NMR and FTIR spectroscopy as well as high-resolution TEM investigations was used for Rietveld refinement with a goodness-of-fit (chi(2)) of 5.035 and wRp=0.05937. PTI/Li(+)Cl(-) (P6(3)cm (no. 185); a=846.82(10), c=675.02(9) pm) is a 2D network composed of essentially planar layers made up from imide-bridged triazine units. Voids in these layers are stacked upon each other forming channels running parallel to [001], filled with Li(+) and Cl(-) ions. The presence of salt ions in the nanocrystallites as well as the existence of sp(2)-hybridized carbon and nitrogen atoms typical of graphitic structures was confirmed by electron energy-loss spectroscopy (EELS) measurements. Solid-state NMR spectroscopy investigations using (15)N-labeled PTI/Li(+)Cl(-) proved the absence of heptazine building blocks and NH(2) groups and corroborated the highly condensed, triazine-based structure model. PMID- 21312299 TI - Convenient and efficient FRET platform featuring a rigid biphenyl spacer between rhodamine and BODIPY: transformation of 'turn-on' sensors into ratiometric ones with dual emission. AB - We have connected a borondipyrromethene (BODIPY) donor to the 5' position of a tetramethylrhodamine (TMR) acceptor to form a high efficiency (over 99%) intramolecular fluorescence resonance energy transfer (FRET) cassette, BODIPY rhodamine platform (BRP). While the good spectral overlap between the emission of BODIPY and the absorption of TMR was one favorable factor, another feature of this FRET system was the rigid and short biphenyl spacer that favored efficient through-bond energy transfer. More importantly, in this system, the 2'-carboxyl group of the rhodamine unit was preserved for the further modifications, which was as convenient as those carbonyl groups on the original rhodamines without connection to donors. For this reason, BRP is clearly differentiated from the previous ratiometric sensors based on donor rhodamine systems. To illustrate its value as a versatile platform, we introduced typical Hg(2+) receptors into BRP, through convenient one-pot reactions on the 2'-carboxyl group, and successfully developed two ratiometric sensors, BRP-1 and BRP-2, with different spirocyclic receptors that recognized Hg(2+) on different reaction mechanisms. Upon excitation at a single wavelength (488 nm), at which only BODIPY absorbed, both of the FRET sensors exhibited clear Hg(2+)-induced changes in the intensity ratio of the two strong emission bands of BODIPY and rhodamine. It should be noted that these ratiometric Hg(2+) sensors exhibited excellent sensitivity and selectivity Hg(2+), as well as pH insensitivity, which was similar to the corresponding 'turn on' rhodamine sensors. While both ratiometric probes were applicable for Hg(2+) imaging in living cells, BRP-1 exhibited higher sensitivity and faster responses than BRP-2. Our investigation indicated that on a versatile platform, such as BRP, a large number of highly efficient ratiometric sensors for transition-metal ions could be conveniently developed. PMID- 21312300 TI - A tetragonal 2D array of single-molecule magnets with modulated collective behavior. PMID- 21312301 TI - Chiral Lewis base catalyzed highly enantioselective reduction of N-alkyl beta enamino esters with trichlorosilane and water. PMID- 21312302 TI - Silicon-based chemistry: an original and efficient one-step approach to [18F] nucleosides and [18F]-oligonucleotides for PET imaging. AB - Take it eaSi! Nucleosides, dinucleotides, and one oligonucleotide, all modified by click chemistry, have for the first time been directly and very efficiently labeled with (18)F by using a silicon-based, one-step approach that opens the way for the development of a new class of positron emission tomography (PET) tracers (see graphic). PMID- 21312303 TI - A chromo-fluorogenic tetrazole-based CoBr2 coordination polymer gel as a highly sensitive and selective chemosensor for volatile gases containing chloride. PMID- 21312304 TI - Physiological aspects of male libido enhanced by standardized Trigonella foenum graecum extract and mineral formulation. AB - The aim of the clinical study was to evaluate the effect of Testofen, a standardized Trigonella foenum-graecum (Fenugreek) extract and mineral formulation, on male libido (sexual drive, urge or desire) in a double blind randomized placebo controlled study. The study recruited 60 healthy males aged between 25 and 52, without erectile dysfunction and randomized to an oral dose (two tablets per day) of the active treatment (600 mg Testofen per day) or placebo for 6 weeks. The primary outcome measure was the DISF-SR (male) self administered QOL total score and the four domain scores. The secondary outcome was specific quality of life parameters. Testofen had an overall positive effect on physiological aspects of libido. In particular, there was a significant increase in the subdomains of sexual arousal and orgasm. Testofen had a positive effect on QOL in self-reported satisfaction with muscle strength, energy and well being but did not have an effect on mood or sleep. Serum prolactin and testosterone levels remained within the reference range. It was concluded that Testofen demonstrated a significant positive effect on physiological aspects of libido and may assist to maintain normal healthy testosterone levels. PMID- 21312305 TI - Inhibition of inducible nitric oxide synthase and cyclooxygenase-2 expression by phenolic compounds from roots of Rhododendron mucronulatum. AB - The roots of Rhododendron mucronulatum Turzaninov have been used in Oriental traditional medicine for the treatment of dysuria, fever, increase of digestive activity and tonics in China and Korea. Activity guided isolation of the roots of Rhododendron mucronulatum Turzaninov has led to the isolation of three flavonoids, one flavan 3-ol and one proanthocyanidin. Chemical investigation of the 80% Me2 CO extract from the roots of Rhododendron mucronulatum led to the isolation and identification of five compounds: taxifolin (1), taxifolin 3-O-beta D-glucopyranoside (2), quercetin 3-O-alpha-L-arabinofuranoside (3), (-) epicatechin (4), procyanidin B-3 (5). To investigate the antioxidative and antiinflammatory effects of these compounds, their 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activities and the protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-stimulated HaCaT cells were also quantified by western blotting and their end products, nitric oxide (NO) and prostaglandin E2 (PGE2 ), respectively. Compounds (1-5) showed potent DPPH radical scavenging compared with positive controls (L-ascorbic acid). Also, compounds 1 and 2 dose-dependently inhibited the expressions of inflammatory mediators, NO and PGE2 , suggesting they are promising candidates as antiinflammatory agents. PMID- 21312306 TI - Improvement of insulin resistance by Chlorella in fructose-rich chow-fed rats. AB - Chlorella is a type of unicellular fresh water algae. In an attempt to develop new agents for handling insulin resistance, Chlorella was employed to screen the effect on insulin resistance in rats induced by fructose-rich chow. A single oral administration of Chlorella for 90 min decreased the plasma glucose in a dose dependent manner in rats receiving 4-week fructose-rich chow. In addition, chronic treatment with Chlorella for 15 days also lowered plasma glucose in the same manner. Then, the insulin action on glucose disposal rate was measured using the glucose-insulin index, values of the areas under the curves of glucose and insulin during the intraperitoneal glucose tolerance test (IPGTT). Oral administration (three times daily for 5 days) of Chlorella to rats receiving 4 weeks of fructose-rich chow abolished the elevated value of the glucose-insulin index, indicating that Chlorella has an ability to improve insulin resistance. An increase of insulin sensitivity by Chlorella was further evaluated using the plasma glucose lowering action of exogenous insulin in streptozotocin-induced diabetic rats (STZ-diabetic rats). Oral administration of Chlorella three times daily to STZ-diabetic rats increased the response to exogenous insulin 15 days later. The obtained results suggest that oral administration of Chlorella has the ability to improve insulin sensitivity, which may be used as an adjuvant therapy for patients with insulin resistance. PMID- 21312307 TI - Antiinflammatory constituents from Eclipta prostrata using RAW264.7 macrophage cells. AB - The whole plant extract of Eclipta prostrata and its isolated compounds were tested for their antiinflammatory effects against lipopolysaccharide (LPS) induced nitric oxide (NO), prostaglandin E2 (PGE2 ) and tumor necrosis factor alpha (TNF-alpha) release in RAW264.7 cells, as well as for the antiinflammatory mechanism of the active compound on mRNA expression. Among the isolated compounds, orobol (5) exhibited the highest activity against NO release with an IC50 value of 4.6 MUm, followed by compounds 1, 2 and 4 with IC50 values of 12.7, 14.9 and 19.1 MUm, respectively. The IC50 value of compound 5 against PGE2 release was found to be 49.6 MUm, whereas it was inactive towards TNF-alpha (IC50 > 100 MUm). The mechanism of orobol (5) was found to down-regulate iNOS and COX 2 mRNA expression in a concentration-dependent manner. The present study may support the traditional use of Eclipta prostrata for the treatment of inflammatory-related diseases. PMID- 21312308 TI - In vivo detection of intermediate metabolic products of [1-(13) C]ethanol in the brain using (13) C MRS. AB - In this study, in vivo (13) C MRS was used to investigate the labeling of brain metabolites after intravenous administration of [1-(13) C]ethanol. After [1-(13) C]ethanol had been administered systemically to rats, (13) C labels were detected in glutamate, glutamine and aspartate in the carboxylic and amide carbon spectral region. (13) C-labeled bicarbonate HCO 3- (161.0 ppm) was also detected. Saturating acetaldehyde C1 at 207.0 ppm was found to have no effect on the ethanol C1 (57.7 ppm) signal intensity after extensive signal averaging, providing direct in vivo evidence that direct metabolism of alcohol by brain tissue is minimal. To compare the labeling of brain metabolites by ethanol with labeling by glucose, in vivo time course data were acquired during intravenous co infusion of [1-(13) C]ethanol and [(13) C(6) ]-D-glucose. In contrast with labeling by [(13) C(6) ]-D-glucose, which produced doublets of carboxylic/amide carbons with a J coupling constant of 51 Hz, the simultaneously detected glutamate and glutamine singlets were labeled by [1-(13) C]ethanol. As (13) C labels originating from ethanol enter the brain after being converted into [1 (13) C]acetate in the liver, and the direct metabolism of ethanol by brain tissue is negligible, it is suggested that orally or intragastrically administered (13) C-labeled ethanol may be used to study brain metabolism and glutamatergic neurotransmission in investigations involving alcohol administration. In vivo (13) C MRS of rat brain following intragastric administration of (13) C-labeled ethanol is demonstrated. PMID- 21312309 TI - Laser desorption ionisation-time of flight mass spectrometry of the tolyporphins, bioactive metabolites from the cyanobacterium Tolypothrix nodosa. AB - INTRODUCTION: The tolyporphins are metabolites isolated from the cyanobacterium Tolypothrix nodosa, comprising a porphyrin-like macrocycle with C-glycoside, hydroxide or acetate substituents. Previous studies of porphyrins by MALDI/LDI TOF MS indicate that strong radical cations and anions are usually observed in the parent spectra with little fragmentation of the macrocycle. The spectra of the tolyporphins were obtained and trends in the series utilised to partially characterise two new analogues. OBJECTIVE: To examine tolyporphins by LDI-TOF MS and utilise trends observed to partially characterise two new analogues. METHODOLOGY: The tolyporphins were analysed by LDI-TOF MS in positive and negative ion mode and by a post source decay method (LIFT) in positive ion mode. Tolyporphin A was also analysed by MALDI-TOF MS for comparison. Results were analysed and used to obtain structural information on two new analogues. RESULTS AND DISCUSSION: The resulting spectra generally contained intense radical cations or anions, with little fragmentation of the macrocyclic core or the C-glycosides observed. These results are consistent with previous studies of porphyrins. Major fragment ions observed in LIFT spectra yielded key structural information. An inseparable mixture of two tolyporphins was also examined. Analysis of the LIFT spectrum of the parent ion resulted in the postulation of structures of these two new analogues. CONCLUSIONS: Tolyporphins yield LDI-TOF mass spectra somewhat analogous to those of porphyrins; furthermore, the substituents fragment in a characteristic manner permitting partial characterisation of the new analogues tolyporphins L and M by comparison of their LDI-TOF mass spectra with those of the known analogues. PMID- 21312310 TI - Solution structure and fluctuation of the Mg(2+)-bound form of calmodulin C terminal domain. AB - Calmodulin (CaM) is a Ca(2+)-binding protein that functions as a ubiquitous Ca(2+)-signaling molecule, through conformational changes from the "closed" apo conformation to the "open" Ca(2+)-bound conformation. Mg(2+) also binds to CaM and stabilizes its folded structure, but the NMR signals are broadened by slow conformational fluctuations. Using the E104D/E140D mutant, designed to decrease the signal broadening in the presence of Mg(2+) with minimal perturbations of the overall structure, the solution structure of the Mg(2+)-bound form of the CaM C terminal domain was determined by multidimensional NMR spectroscopy. The Mg(2+) induced conformational change mainly occurred in EF hand IV, while EF-hand III retained the apo structure. The helix G and helix H sides of the binding sequence undergo conformational changes needed for the Mg(2+) coordination, and thus the helices tilt slightly. The aromatic rings on helix H move to form a new cluster of aromatic rings in the hydrophobic core. Although helix G tilts slightly to the open orientation, the closed conformation is maintained. The fact that the Mg(2+) induced conformational changes in EF-hand IV and the hydrophobic core are also seen upon Ca(2+) binding suggests that the Ca(2+)-induced conformational changes can be divided into two categories, those specific to Ca(2+) and those common to Ca(2+) and Mg(2+). PMID- 21312311 TI - Antiviral responses induced by the TLR3 pathway. AB - Antiviral responses are successively induced in virus-infected animals, and include primary innate immune responses such as type I interferon (IFN) and cytokine production, secondary natural killer (NK) cell responses, and final cytotoxic T lymphocyte (CTL) responses and antibody production. The endosomal Toll-like receptors (TLRs) and cytoplasmic RIG-I-like receptors (RLRs), which recognize viral nucleic acids, are responsible for virus-induced type I IFN production. RLRs are expressed in most tissues and cells and are primarily implicated in innate immune responses against various viruses through type I IFN production, whereas nucleic acid-sensing TLRs, TLRs 3, 7, 8 and 9, are expressed on the endosomal membrane of dendritic cells (DCs) and play distinct roles in antiviral immunity. TLR3 recognizes viral double-stranded RNA taken up into the endosome and serves to protect the host against viral infection by the induction of a range of responses including type I IFN production and DC-mediated activation of NK cells and CTLs, although the deteriorative role of TLR3 has also been reported in some virus infections. Here, we review the current knowledge on the role of TLR3 during viral infection, and the current understanding of the TLR3-signalling cascade that operates via the adaptor protein TICAM-1 (also called TRIF). PMID- 21312312 TI - Breast cancer recurrence risk reduction beliefs in breast cancer survivors: prevalence and relation to behavior. AB - OBJECTIVE: There is a growing body of evidence suggesting breast cancer (BC) recurrence risk might be linked to behavioral factors. However, little is known about BC survivors' beliefs regarding the link between their behavior and recurrence risk. The objective of this study was to describe BC survivors' beliefs regarding performance of behaviors potentially associated with BC recurrence risk reduction, and to examine the link between these behaviors and BC recurrence risk reduction beliefs, worry, and risk perception. METHODS: 200 female BC survivors (age, years: mean=57.7, standard deviation=9.2) completed a questionnaire assessing beliefs about the effectiveness of 14 potential BC recurrence risk reduction behaviors, their performance of these potential risk reduction behaviors, recurrence worry, and perception of personal lifetime BC recurrence risk. RESULTS: The behaviors most frequently endorsed as potentially reducing BC recurrence risk included avoiding tobacco use (84%), exercising at least three times per week (74%), eating an average of five servings a day of fruits and vegetables (72%), and limiting food intake to maintain current weight or lose weight (70%). Multivariate logistic regression analyses predicting behavioral performance showed that beliefs were consistently associated with behavior while worry and risk perception were largely unrelated to behavior. CONCLUSIONS: BC survivors' beliefs about the effectiveness of potential BC recurrence risk reduction behaviors are largely consistent with empirical findings and relate strongly to actual behavioral performance. Misconceptions about the effects of behavior to reduce BC recurrence risk are important targets for clinical and public health efforts. PMID- 21312313 TI - Facultative stem cells in liver and pancreas: fact and fancy. AB - Tissue turnover is a regular feature of higher eukaryotes, either as part of normal wear and tear (homeostasis) or in response to injury (regeneration). Cell replacement is achieved either through replication of existing cells or differentiation from a self-renewing pool of stem cells. The major distinction regards cellular potential, because stem cells by definition have a capacity to differentiate, while replication implies that cells adopt a single fate under physiologic conditions. A hybrid model, the facultative stem cell (FSC) model, posits that tissues contain cells that normally exhibit unipotency but have the capacity to function as stem cells upon injury. The FSC paradigm is well established in urodele amphibians, but the nature and role of FSCs in mammals is less defined. Here, we review the evidence for FSCs in two mammalian organs, the liver and the pancreas, and discuss alternative models that could account for regeneration in these organs. PMID- 21312314 TI - Patterns of human genetic variation inferred from comparative analysis of allelic mutations in blood group antigen genes. AB - Comparative analysis of allelic variation of a gene sheds light on the pattern and process of its diversification at the population level. Gene families for which a large number of allelic forms have been verified by sequencing provide a useful resource for such studies. In this regard, human blood group-encoding genes are unique in that differences of cell surface traits among individuals and populations can be readily detected by serological screening, and correlation between the variant cell surface phenotype and the genotype is, in most cases, unequivocal. Here, we perform a comprehensive analysis of allelic forms, compiled in the Blood Group Antigen Gene Mutation database, of ABO, RHD/CE, GYPA/B/E and FUT1/2 gene families that encode the ABO, RH, MNS, and H/h blood group system antigens, respectively. These genes are excellent illustrative examples showing distinct mutational patterns among the alleles, and leading to speculation on how their origin may have been driven by recurrent but different molecular mechanisms. We illustrate how alignment of alleles of a gene may provide an additional insight into the DNA variation process and its pathways, and how this approach may serve to catalog alleles of a gene, simplifying the task and content of mutation databases. PMID- 21312315 TI - Treatment of chronic anorexia nervosa: a 4-year follow-up of adult patients treated in an acute inpatient setting. AB - Despite evidence from a number of long-term follow-up studies of anorexia nervosa that nearly 50% of patients eventually make a full recovery, controlled trials of psychotherapy for anorexia nervosa are lacking. Those with severe and enduring problems represent a considerable therapeutic challenge. Thirty-four consecutive adult referrals to the inpatient treatment unit who fulfilled Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnostic criteria for anorexia nervosa were examined pre-admission, post-discharge and 4 years after admission. Characteristics of remitted and non-remitted patients were examined. Secondary analyses considered the differences between patients with anorexia nervosa, restricting type and anorexia nervosa binging/purging type. The findings highlight a number of differences between patients with anorexia nervosa (restricting type) versus anorexia nervosa (binging/purging type) as well as remitted versus non-remitted patients. The use of a comprehensive battery of assessments found that resolution of eating disorder symptomatology was paralleled by improvements in emotional and psychological distress and improvement in body image perception and coping skills. Better results were obtained for those who had continuity of care on an outpatient basis. This pattern is particularly significant given the more 'chronic' nature of the sample that were older, with a higher incidence of binge-eating and purging than previous samples. Results provide some encouragement for the treatment of those adults with anorexia nervosa who typically have less favourable outcomes. PMID- 21312316 TI - The pathology of bleomycin-induced fibrosis is associated with loss of resident lung mesenchymal stem cells that regulate effector T-cell proliferation. AB - Tissue-resident mesenchymal stem cells (MSCs) are important regulators of tissue repair or regeneration, fibrosis, inflammation, angiogenesis, and tumor formation. Here, we define a population of resident lung MSCs (luMSCs) that function to regulate the severity of bleomycin injury via modulation of the T cell response. Bleomycin-induced loss of these endogenous luMSCs and elicited fibrosis (pulmonary fibrosis), inflammation, and pulmonary arterial hypertension (PAH). Replacement of resident stem cells by administration of isolated luMSCs attenuated the bleomycin-associated pathology and mitigated the development of PAH. In addition, luMSC modulated a decrease in numbers of lymphocytes and granulocytes in bronchoalveolar fluid and demonstrated an inhibition of effector T-cell proliferation in vitro. Global gene expression analysis indicated that the luMSCs are a unique stromal population differing from lung fibroblasts in terms of proinflammatory mediators and profibrotic pathways. Our results demonstrate that luMSCs function to protect lung integrity after injury; however, when endogenous MSCs are lost, this function is compromised illustrating the importance of this novel population during lung injury. The definition of this population in vivo in both murine and human pulmonary tissue facilitates the development of a therapeutic strategy directed at the rescue of endogenous cells to facilitate lung repair during injury. PMID- 21312317 TI - Functional effects of adult human olfactory stem cells on early-onset sensorineural hearing loss. AB - Transplantation of exogenous stem cells has been proposed as a treatment to prevent or reverse sensorineural hearing loss. Here, we investigate the effects of transplantation of adult human olfactory mucosa-derived stem cells on auditory function in A/J mice, a strain exhibiting early-onset progressive sensorineural hearing loss. Recent evidence indicates that these stem cells exhibit multipotency in transplantation settings and may represent a subtype of mesenchymal stem cell. Olfactory stem cells were injected into the cochleae of A/J mice via a lateral wall cochleostomy during the time period in which hearing loss first becomes apparent. Changes in auditory function were assessed 1 month after transplantation and compared against animals that received sham injections. Hearing threshold levels in stem cell-transplanted mice were found to be significantly lower than those of sham-injected mice (p < .05) for both click and pure tone stimuli. Transplanted cells survived within the perilymphatic compartments but did not integrate into cochlear tissues. These results indicate that transplantation of adult human olfactory mucosa-derived stem cells can help preserve auditory function during early-onset progressive sensorineural hearing loss. PMID- 21312318 TI - Pharmacological intervention studies using mouse models of the inflammatory bowel diseases: translating preclinical data into new drug therapies. AB - Most therapeutic agents used in clinical practice today were originally developed and tested in animal models so that drug toxicity and safety, dose-responses, and efficacy could be determined. Retrospective analyses of preclinical intervention studies using animal models of different diseases demonstrate that only a small percentage of the interventions reporting promising effects translate to clinical efficacy. The failure to translate therapeutic efficacy from bench to bedside may be due, in part, to shortcomings in the design of the clinical studies; however, it is becoming clear that much of the problem resides within the preclinical studies. One potential strategy for improving our ability to identify new therapeutics that may have a reasonable chance of success in clinical trials is to identify the most immunologically-relevant mouse models of IBD and pharmacologic strategies that most closely mimic the clinical situation. This review presents a critical evaluation of the different mouse models and pharmacological approaches that may be used in intervention studies as well as discuss emerging issues related to study design and data interpretation of preclinical studies. PMID- 21312319 TI - Reproductive toxicity in male mice caused by organic extracts in tap water from the Jialing River in Chongqing, China. AB - BACKGROUND: Recently, male reproductive disturbances caused by organic pollutants have aroused particular public concern about the safety of drinking water. The aim of this study was to investigate the toxicity of organic extracts (OE) in tap water from the source of the Jialing River in China on the reproductive system of male mice. METHODS: Kunming male mice were randomly divided into four groups, which included a solvent control (dimethylsulfoxide), a low-, mid-, and high-dose of OE (12.5, 25, and 50 l/kg bw/day, respectively) treated groups. Mice were administered intraperitoneal injections of OE at different doses for five consecutive days. On the 15th day, after treatments, the mice were sacrificed. RESULTS: The results showed that the number of epididymal sperm in the high OE group was decreased significantly (p<0.05); however, the frequency of sperm abnormalities in all treated groups were increased significantly (p<0.05). In addition, serum testosterone and follicle-stimulating hormone levels in the treated groups were also decreased significantly (p<0.05), and mid- and high doses of OE resulted in a significant decrease in the activity of acid phosphatase and increased activity of gamma-glutamyl transpeptidase (p<0.05). Histological changes were observed in the mid- and high-dose OE-treated groups. CONCLUSIONS: The findings of this study suggest that mid and high doses of OE could disturb the male reproductive system in mice. The potential adverse effects of these compounds on the male reproductive system are worthy of further study. PMID- 21312320 TI - Developmental defects of coronary vasculature in rat embryos administered bis diamine. AB - BACKGROUND: Conotruncal anomalies are often associated with abnormal coronary arteries. Although bis-diamine is known to induce conotruncal defects, its pathological effects on coronary vascular development have not been demonstrated. This study sought to assess the teratogenic effects of bis-diamine on coronary vascular development and the pathogenesis of this anomalous association. METHODS AND RESULTS: A single 200 mg dose of bis-diamine was administered to pregnant Wistar rats at 10.5 days of gestation. Fifty-two embryos from 10 mother rats underwent morphological analysis of the coronary arteries. Three embryos each were removed from four mothers on embryonic days (ED) 14.5, 15.5, 16.5, and 17.5 and used for immunohistochemical studies using the anti-vascular cell adhesion molecule (VCAM)-1 antibody. Conotruncal anomalies were detected in 48 of 52 embryos, and an aplastic or hypoplastic left coronary artery was found in all of them. In control embryos at ED 16.5, VCAM-1-positive epicardial cells were transformed into mesenchymal cells in vascular plexus, which appeared to differentiate into the endothelial cells of coronary vasculature. In the heart at ED 17.5, coronary vasculature was well developed and connected with coronary ostia near the aorta. However, poor epicardial-mesenchymal transformation and subsequent differentiation was revealed in bis-diamine-treated embryos at EDs 16.5 and 17.5, causing abnormal development of the coronary vasculature and incomplete connections with coronary ostia of the aorta. CONCLUSIONS: Anomalous coronary arteries in the bis-diamine-treated embryos are induced by the disruption of epicardial-mesenchymal transformation and subsequent poor development of coronary vasculature. Incomplete hatching of the coronary ostium is associated with abnormal truncal division. PMID- 21312321 TI - ILSI/HESI maternal toxicity workshop summary: maternal toxicity and its impact on study design and data interpretation. AB - Workshops on maternal toxicity were held at the annual Society of Toxicology, Teratology Society, and European Teratology Society meetings in 2009. Speakers presented background information prior to a general discussion on this topic. The following recommendations/options are based on the outcome of the discussions at the workshops: 1. A comprehensive evaluation of all available data from general toxicity studies, range-finding Developmental and Reproductive Toxicology (DART) studies, class effects, structure-activity relationships, exposure studies, etc. is essential for appropriate dose selection for definitive DART studies. The intent is to avoid marked maternal toxicity leading to mortality or decreased body weight gains of greater than 20% for prolonged periods. (a) Evaluate alternative endpoints for dose selection and data interpretation (e.g., target tissue effects and pharmacology) for biotherapeutics. (B) Evaluate additional maternal parameters based on effects and/or target organs observed in short-term (e.g., 2- or 4-week) general toxicity studies. 2. Evaluate all available data to determine a cause-effect relationship for developmental toxicity. (a) Conduct a pair-feeding/pair-watering study as a follow-up. (b) Evaluate individual data demonstrating maternal toxicity in the mother with adverse embryo-fetal outcomes in the litter associated with the affected mother. (c) Conduct single-dose studies at increasing doses as a complement to conventional embryo-fetal toxicity studies for certain classes of compounds that affect the hERG channel. 3. Support statements that embryo-fetal effects are caused by maternal toxicity and/or exaggerated pharmacology, especially for malformations. (a) Provide mechanistic or other supporting data. (b) Establish the relevance of the DART findings in animals for human exposures. Birth Defects Res (Part B) 92:36-51, 2010. (c) 2011 Wiley-Liss, Inc. PMID- 21312322 TI - Artesunate and artelinic acid: association of embryotoxicity, reticulocytopenia, and delayed stimulation of hematopoiesis in pregnant rats. AB - The artemisinin antimalarials cause embryo death and malformations in animals by killing embryonic erythroblasts. Groups of pregnant rats (N = 4) were administered 35 and 48 umol/kg artesunate and 17.2, 28.7, 48, 96, and 191 umol/kg artelinic acid as a single oral dose on gestational day (GD) 12. Litters were examined on GD21. The ED(50) for embryo death with artelinic acid (23.4 umol/kg) was just slightly lower than that for decreased reticulocyte count at 24 hr postdose (33.5 umol/kg) and both had similarly steep dose responses (maximal effects of total litter loss and ~60% decreases in reticulocyte count at 48 umol/kg). Results with artesunate were similar. The correlation coefficient between embryo death and decreased reticulocyte count was 0.82 (p<0.01). The close relationship between embryotoxicity and reticulocytopenia is suggestive of a common mechanism-artemisinin-induced mitochondrial damage leading to cell death. At 9 days postdose, treatment with artesunate and artelinic acid also caused increases in counts of reticulocytes, lymphocytes, basophils, and monocytes (up to 3.7 *, 1.7 *, 4.7 *, and 1.7 * control, respectively). This stimulation of hematopoiesis may have been mediated by the direct oxidative conversion of artesunate or artelinic acid to the artemisininyl hydroperoxide within the bone marrow cells or by an indirect increase in reactive oxygen species. The high correlation between embryotoxicity and reticulocytopenia further supports the assertion that therapeutic dosage regimens of artemisinins that cause decreases in reticulocyte count in pregnant women during the putative critical period (approximately postconception wk 3 to 9) are at risk of also causing adverse effects on the embryo. PMID- 21312323 TI - Prenatal TCDD causes persistent modulation of the postnatal immune response, and exacerbates inflammatory disease, in 36-week-old lupus-like autoimmune SNF1 mice. AB - BACKGROUND: Prenatal exposure to the persistent environmental pollutant and model Ah receptor agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), has been shown to permanently suppress postnatal cell-mediated immunity. More recently, skewing of select adult T and B cell responses toward enhanced inflammation has also been described in C57BL/6 mice after prenatal TCDD. This raises questions about adverse postnatal immune consequences of prenatal TCDD in animals genetically predisposed to inappropriate inflammatory responses. METHODS: Lupus-prone SNF(1) mice were exposed to 0, 40, or 80 ug/kg TCDD on gestation day (gd) 12 and examined at 36 weeks-of-age for immunomodulatory effects that correlated with worsened lupus pathology. RESULTS: Bone marrow pro- and large pre-B cells were decreased by prenatal TCDD, in both adult male and female mice, as were pre- and immature B cells. Splenic CD23(-) CD1(hi) and CD19(+) CD5(+) B cells were increased in males, as were B220(hi) B cells in females, further suggesting persistent disruption of B cell lymphopoiesis by prenatal TCDD. Female mice displayed decreased IL-10 production by ConA-activated splenocytes, while males underproduced IL-4. Autoreactive CD4(+) Vbeta17a(+) spleen T cells were increased in both sexes by 80 ug/kg TCDD. Male mice but not females showed increased anti ds DNA and cardiolipin autoantibody levels. CONCLUSIONS: Prenatal TCDD augmented the hallmark indicators of SLE progression in the lupus-prone SNF(1) mice, including renal immune complex deposition, glomerulonephritis, and mesangial proliferation. Prenatal TCDD therefore caused persistent modulation of the postnatal immune response, and exacerbated inflammatory disease, in lupus-like autoimmune SNF(1) mice. PMID- 21312324 TI - Treatment of primary CNS lymphoma with high-dose methotrexate in immunocompetent patients. PMID- 21312325 TI - Inborn errors of cobalamin absorption and metabolism. AB - Derivatives of cobalamin (vitamin B(12)) are required for activity of two enzymes in humans. Adenosylcobalamin is required for activity of mitochondrial methylmalonylCoA mutase and methylcobalamin is required for activity of cytoplasmic methionine synthase. Deficiency in cobalamin, or inability to absorb cobalamin normally, can result in accumulation of methylmalonic acid and homocysteine in blood and urine. Methylmalonic acidemia can result in metabolic acidosis which in severe cases may be fatal. Hyperhomocysteinemia along with hypomethioninemia can result in hematologic (megaloblastic anemia, neutropenia, thrombocytopenia) and neurologic (subacute combined degeneration of the cord, dementia, psychosis) defects. Inborn errors affecting cobalamin absorption (inherited intrinsic factor deficiency, Imerslund-Gra sbeck syndrome) and transport (transcobalamin deficiency) have been described. A series of inborn errors of intracellular cobalamin metabolism, designated cblA-cblG, have been differentiated by complementation analysis. These can give rise to isolated methylmalonic acidemia (cblA, cblB, cblD variant 2), isolated hyperhomocysteinemia (cblD variant 1, cblE, cblG) or combined methylmalonic acidemia and hyperhomocysteinemia (cblC, classic cblD, cblF). All these disorders are inherited as autosomal recessive traits. The genes underlying each of these disorders have been identified. Two other disorders, haptocorrin deficiency and transcobalamin receptor deficiency, have been described, but it is not clear that they have any consistent clinical phenotype. PMID- 21312327 TI - Newborn screening for lysosomal storage disorders. AB - Lysosomes are intracellular organelles containing acid hydrolases that degrade biological macromolecules. Lysosomal storage disorders (LSDs) are caused by absent activity of one or more of these enzymes due to mutations of genes encoding lysosomal hydrolases or enzymes that process, target, and transport these enzymes. The specific signs and symptoms of each LSD derive from the type of material accumulated within the lysosome, the site (organ) of accumulation and the response of the body (sometimes in the form of an inflammatory or immune response) to the accumulated material. Interest for inclusion of these disorders in newborn screening programs derives from the availability of effective therapy in the form of enzyme replacement or substrate reduction therapy and bone marrow transplant that may improve long-term outcome especially if started prior to irreversible organ damage. Based on the availability of therapy and suitable screening methods, Gaucher disease, Fabry disease, Pompe disease, mucopolysaccharidosis I and II, Niemann-Pick disease, and Krabbe disease are candidates for newborn screening. Pilot newborn screening projects have been performed for some of these conditions that indicate the feasibility of this approach. This review will provide insight into these screening strategies and discuss their advantages and limitations. (c) 2011 Wiley-Liss, Inc. PMID- 21312326 TI - Argininosuccinate lyase deficiency-argininosuccinic aciduria and beyond. AB - The urea cycle consists of six consecutive enzymatic reactions that convert waste nitrogen into urea. Deficiencies of any of these enzymes of the cycle result in urea cycle disorders (UCD), a group of inborn errors of hepatic metabolism that often result in life threatening hyperammonemia. Argininosuccinate lyase (ASL) is a cytosolic enzyme which catalyzes the fourth reaction in the cycle and the first degradative step, that is, the breakdown of argininosuccinic acid to arginine and fumarate. Deficiency of ASL results in an accumulation of argininosuccinic acid in tissues, and excretion of argininosuccinic acid in urine leading to the condition argininosuccinic aciduria (ASA). ASA is an autosomal recessive disorder and is the second most common UCD. In addition to the accumulation of argininosuccinic acid, ASL deficiency results in decreased synthesis of arginine, a feature common to all UCDs except argininemia. Arginine is not only the precursor for the synthesis of urea and ornithine as part of the urea cycle but it is also the substrate for the synthesis of nitric oxide, polyamines, proline, glutamate, creatine, and agmatine. Hence, while ASL is the only enzyme in the body able to generate arginine, at least four enzymes use arginine as substrate: arginine decarboxylase, arginase, nitric oxide synthetase (NOS) and arginine/glycine aminotransferase. In the liver, the main function of ASL is ureagenesis, and hence, there is no net synthesis of arginine. In contrast, in most other tissues, its role is to generate arginine that is designated for the specific cell's needs. While patients with ASA share the acute clinical phenotype of hyperammonemia, encephalopathy, and respiratory alkalosis common to other UCD, they also present with unique chronic complications most probably caused by a combination of tissue specific deficiency of arginine and/or elevation of argininosuccinic acid. This review article summarizes the clinical characterization, biochemical, enzymatic, and molecular features of this disorder. Current treatment, prenatal diagnosis, diagnosis through the newborn screening as well as hypothesis driven future treatment modalities are discussed. PMID- 21312328 TI - Newly cleaned physician uniforms and infrequently washed white coats have similar rates of bacterial contamination after an 8-hour workday: a randomized controlled trial. AB - BACKGROUND: Governmental agencies in the United Kingdom and Scotland have recently instituted guidelines banning physicians' white coats and the wearing of long-sleeved garments to decrease nosocomial transmission of bacteria. OBJECTIVE: Our aim was to compare the degree of bacterial and methicillin-resistant Staphylococcus aureus contamination of physicians' white coats with that of newly laundered, standardized short-sleeved uniforms after an 8-hour workday and to determine the rate at which bacterial contamination of the uniform ensued. DESIGN: The design was a prospective, randomized controlled trial. SETTING: The setting was a university-affiliated public safety-net hospital. PARTICIPANTS: One hundred residents and hospitalists on an internal medicine service participated. INTERVENTION: Subjects wore either a physician's white coat or a newly laundered short-sleeved uniform. MEASUREMENTS: Bacterial colony count and the frequency with which methicillin-resistant Staphylococcus aureus was cultured from both garments over time were measured. RESULTS: No statistically significant differences were found in bacterial or methicillin-resistant Staphylococcus aureus contamination of physicians' white coats compared with newly laundered short-sleeved uniforms or in contamination of the skin at the wrists of physicians wearing either garment. Colony counts of newly laundered uniforms were essentially zero, but after 3 hours of wear they were nearly 50% of those counted at 8 hours. CONCLUSIONS: Bacterial contamination occurs within hours after donning newly laundered short-sleeved uniforms. After 8 hours of wear, no difference was observed in the degree of contamination of uniforms versus infrequently laundered white coats. Our data do not support discarding long sleeved white coats for short-sleeved uniforms that are changed on a daily basis. PMID- 21312329 TI - Quality improvement projects targeting health care-associated infections: comparing Virtual Collaborative and Toolkit approaches. AB - BACKGROUND: Collaborative and toolkit approaches have gained traction for improving quality in health care. OBJECTIVE: To determine if a quality improvement virtual collaborative intervention would perform better than a toolkit-only approach at preventing central line-associated bloodstream infections (CLABSIs) and ventilator-associated pneumonias (VAPs). DESIGN AND SETTING: Cluster randomized trial with the Intensive Care Units (ICUs) of 60 hospitals assigned to the Toolkit (n=29) or Virtual Collaborative (n=31) group from January 2006 through September 2007. MEASUREMENT: CLABSI and VAP rates. Follow-up survey on improvement interventions, toolkit utilization, and strategies for implementing improvement. RESULTS: A total of 83% of the Collaborative ICUs implemented all CLABSI interventions compared to 64% of those in the Toolkit group (P = 0.13), implemented daily catheter reviews more often (P = 0.04), and began this intervention sooner (P < 0.01). Eighty-six percent of the Collaborative group implemented the VAP bundle compared to 64% of the Toolkit group (P = 0.06). The CLABSI rate was 2.42 infections per 1000 catheter days at baseline and 2.73 at 18 months (P = 0.59). The VAP rate was 3.97 per 1000 ventilator days at baseline and 4.61 at 18 months (P = 0.50). Neither group improved outcomes over time; there was no differential performance between the 2 groups for either CLABSI rates (P = 0.71) or VAP rates (P = 0.80). CONCLUSION: The intensive collaborative approach outpaced the simpler toolkit approach in changing processes of care, but neither approach improved outcomes. Incorporating quality improvement methods, such as ICU checklists, into routine care processes is complex, highly context-dependent, and may take longer than 18 months to achieve. PMID- 21312330 TI - Simultaneous determination of 13 phytohormones in oilseed rape tissues by liquid chromatography-electrospray tandem mass spectrometry and the evaluation of the matrix effect. AB - In the experiment, a high-performance liquid chromatography and electrospray ionization-tandem mass spectrometry with selected reaction monitoring was used to simultaneously determine various classes of phytohormones, including indole-3 acetic acid, alpha-naphthaleneacetic acid, 2-chlorobenzoic acid, 4-chlorobenzoic acid, indole-3-butyric acid, gibberellic acid, 2,4-dichlorophenoxyacetic acid, 2 naphthoxyacetic acid, abscisic acid, 2,3,5-triiodobenzoic acid, uniconazole, paclobutrazol and 2,4-epibassinolide in rape tissues. The analyses were separated by an HPLC equipped with a reversed-phase column using a binary solvent system composed of methanol and water, both containing 0.1% of formic acid. The matrix effect was also considered and determined. The technology was applied to analyze rape tissues, including roots, stems, leaves, flowers, immature pods and rape seeds. The rape tissues were subjected to ultrasound-assisted extraction and purified by dispersive solid-phase extraction, and then transferred into the liquid chromatography system. The detection limit for each plant hormone was defined by the ratio of signal/background noise (S/N) of 3. The results showed perfect linearity (R(2) values of 0.9987-1.0000) and reproducibility of elution times (relative standard deviations, RSDs,<1%) and peak areas (RSDs,<7%) for all target compounds. PMID- 21312331 TI - Analysis of saikosaponins in Bupleuri Radix and Caihu-shugan-san using reversed phase HPLC with pulsed amperometric detection. AB - A simple and sensitive reversed-phase (RP) HPLC coupled with pulsed amperometric detection (PAD) method was developed to determine the saikosaponin content in Bupleuri Radix or Caihu-shugan-san. Four saikosaponins in Bupleuri Radix and Caihu-shugan-san were extracted with a 6:4 solution of 10 mM sodium phosphate buffer (pH 8)/100% ethanol. Pulsed amperometric detection of carbohydrates in four major saikosaponins was highly sensitive when used with a water-acetonitrile gradient on an alkaline RP column with a post-column delivery system. The limits of detection (S/N=3) and of quantification (S/N=10) of saikosaponins were 0.01 0.02 and 0.03-0.05 MUg/mL, respectively. The intra- and inter-day precision (RSDs) were each <9.7% and the average recoveries were 95.0-97.6% in Bupleuri Radix. This method can be used to analyze saikosaponins in Bupleuri Radix and Caihu-shugan-san. PMID- 21312332 TI - Evaluation of a novel microextraction technique for aqueous samples: porous membrane envelope filled with multiwalled carbon nanotubes coated with molecularly imprinted polymer. AB - A novel microextraction technique based on membrane-protected multiwalled carbon nanotubes coated with molecularly imprinted polymer (MWCNTs-MIP) was developed. In this technique, MWCNTs-MIP were packed inside a polypropylene membrane envelope, which was then clamped onto a paper clip. For extraction, the packed membrane envelope was first impregnated with toluene and then placed in sample solutions. Target analytes in the solutions were first extracted into toluene in the membrane envelope, and were then extracted specifically onto the MWCNTs-MIP. After the extraction, target analytes were desorbed in methanol for liquid chromatography analysis. MWCNTs-MIP of prometryn were used as a model to demonstrate the feasibility of this novel microextraction technique. Factors affecting the extraction including organic solvent, stirring rate, extraction time, salt concentration, and pH were investigated. Under the optimized conditions, the limits of detection (a signal-to-noise ratio of 3) for the selected triazine herbicides were 0.08-0.38 MUg/L. The prepared membrane envelope could be used at least 50 times. The developed method was used for the analysis of the triazines spiked in river water, wastewater, and liquid milk, with recoveries ranging from 79.3-97.4, 58.9-110.3 and 76.2-104.9%, respectively. PMID- 21312333 TI - Polymer/hemoglobin assemblies: biodegradable oxygen carriers for artificial red blood cells. AB - In routine clinical procedures, blood transfusion is now suffering from the defects of the blood products, like cross-matching, short storage time and virus infection. Various blood substitutes have been designed by researchers through continual efforts. With recent progress in nanotechnology, new types of artificial red blood cells with cellular structure are available. This article aims to describe some artificial red blood cells which encapsulate or conjugate hemoglobin molecules through various approaches, especially the nanoscale self assembly technique, to mitigate the adverse effects of free hemoglobin molecules. These types of artificial red blood cell systems, which make use of biodegradable polymers as matrix materials, show advantages over the traditional types. PMID- 21312334 TI - Azamacrocyclic metal complexes as CXCR4 antagonists. AB - The chemokine receptor CXCR4 is a member of the seven transmembrane GPCR family, which is implicated in multiple diseases, including HIV infection, cancers, and rheumatoid arthritis. Low-molecular-weight nonpeptidic compounds, including AMD3100 and various pyridyl macrocyclic zinc(II) complexes, have been identified as selective antagonists of CXCR4. In the present study, structure-activity relationship studies were performed by combining the common structural features of alkylamino and pyridiyl macrocyclic antagonists. Several new zinc(II) or copper(II) complexes demonstrated potent anti-HIV activity, strong CXCR4-binding activity, and significant inhibitory activity against Ca(2+) mobilization induced by CXCL12 stimulation. These results may prove useful in the design of novel CXCR4 antagonists, and the compounds described could potentially be developed as therapeutics against CXCR4-relevant diseases or chemical probes to study the biological activity of CXCR4. PMID- 21312335 TI - Fabrication and characterization of poly(lactic-co-glycolic acid) microsphere/amorphous calcium phosphate scaffolds. AB - Although hydroxyapatite (HAP) and beta-tricalcium phosphate have been used extensively as osteoconductive minerals in biomaterial scaffolds for bone regeneration, they lack the capacity to stimulate osteoblastic differentiation of progenitor cells. In contrast, amorphous calcium phosphates (ACPs), which convert to HAP under aqueous conditions, have the potential to facilitate osteoblastic differentiation through the transient local release of calcium and phosphate ions. Therefore, in this study ACPs were synthesized using zinc and zirconia divalent cations as stabilizers (denoted ZnACP and ZrACP, respectively) and compared to HAP. Analysis of ion release into serum-containing cell culture medium revealed transiently elevated levels of calcium and phosphorous, consistent with the enhanced solubility of ZrACP and ZnACP relative to HAP. In addition, X-ray diffraction analysis revealed partial conversion of ZrACP to HAP but no conversion of ZnACP after 96 h. Next, scaffolds were fabricated by sintering mixtures of 300-500 um poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres and 0.5 wt% calcium phosphate mineral (HAP, ZrACP or ZnACP) at 70 degrees C for 24 h. Scanning electron microscopy revealed a porous microsphere matrix with calcium phosphate particulates clinging to the microsphere surfaces both prior to and after 14 days in culture medium. Finally, the incorporation of calcium phosphate resulted in a lower compressive modulus in the range 127 to 74 89 MPa. Taken together, these results indicate that ZrACP, ZnACP and HAP minerals exhibit very different properties, and therefore may elicit different osteoblastic responses in vitro. PMID- 21312336 TI - Chitosan-poly(butylene succinate) scaffolds and human bone marrow stromal cells induce bone repair in a mouse calvaria model. AB - Tissue engineering sustains the need of a three-dimensional (3D) scaffold to promote the regeneration of tissues in volume. Usually, scaffolds are seeded with an adequate cell population, allowing their growth and maturation upon implantation in vivo. Previous studies obtained by our group evidenced significant growth patterns and osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs) when seeded and cultured on melt-based porous chitosan fibre mesh scaffolds (cell constructs). Therefore, it is crucial to test the in vivo performance of these in vitro 3D cell constructs. In this study, chitosan-based scaffolds were seeded and cultured in vitro with hBMSCs for 3 weeks under osteogenic stimulation conditions and analysed for cell adhesion, proliferation and differentiation. Implantation of 2 weeks precultured cell constructs in osteogenic culture conditions was performed into critical cranial size defects in nude mice. The objective of this study was to verify the scaffold integration and new bone formation. At 8 weeks of implantation, scaffolds were harvested and prepared for micro-computed tomography (uCT) analysis. Retrieved implants showed good integration with the surrounding tissue and significant bone formation, more evident for the scaffolds cultured and implanted with human cells. The results of this work demonstrated that chitosan-based scaffolds, besides supporting in vitro proliferation and osteogenic differentiation of hBMSCs, induced bone formation in vivo. Thus, their osteogenic potential in orthotopic location in immunodeficient mice was validated, evidencing good prospects for their use in bone tissue-engineering therapies. PMID- 21312337 TI - Ovine cortical osteoblasts outperform bone marrow cells in an ectopic bone assay. AB - Reviewing the available literature, one could conclude that marrow-derived mesenchymal stem cells (BMSCs) are the 'gold standard' source for bone tissue engineering applications, due to their multilineage differentiation potential and easy accessibility. However, comprehensive studies comparing their osteogenic potential with bone-derived osteoblasts (OBs) to justify the preferred application of BMSCs based on performance are few. To address these shortfalls, in the present study, ovine BMSCs and OBs seeded onto scaffolds were characterized in vitro and transplanted subcutaneously into NOD/SCID mice in combination with and without recombinant human bone morphogenetic protein 7 (rhBMP-7). It was hypothesized that cell origin, ossification type and degree of vascularization and ossification depends on the nature and commitment of transplanted cells and stimulating growth factors, such as rhBMP-7. After retrieval, specimens were analysed by biomechanical testing, uCT analysis, scanning electron microscopy/energy-dispersive X-ray spectroscopy and histo- and immunohistochemistry for osteocalcin, type II collagen and BrdU. The results showed a high degree of cell survival and proliferation ectopically, resulting in active contribution to endochondral osteogenesis. When compared to BMSCs, OBs showed a higher degree of bone deposition while OB-derived bone was of higher maturation. Stimulation with rhBMP-7 increased the rate of bone synthesis for both BMSCs and OBs, additionally promoting neovascularization and osteoclast activity. These results suggest that the origin and commitment of transplanted cells highly influence the type and degree of ossification, that rhBMP-7 represents a powerful adjuvant for bone tissue-engineering applications, and that mature bone is an adequate alternative cell source for bone tissue-engineering applications. PMID- 21312338 TI - Development of an osteoconductive PCL-PDIPF-hydroxyapatite composite scaffold for bone tissue engineering. AB - Hydroxyapatite (HAP)-containing poly-epsilon-caprolactone (PCL)-polydiisopropyl fumarate (PDIPF) composite (Blend) was developed as an alternative for bone tissue engineering. The physicochemical, mechanical and biocompatibility properties of these composites were evaluated using two osteoblast-like cell lines (UMR106 and MC3T3E1) and compared with the blend without HAP and PCL/HAP films. The increment in the elastic modulus and the decrease in the elongation-at break of Blend-HAP suggest that the mechanical properties of the HAP scaffolds have improved significantly. The addition of HAP to both PCL and Blend significantly improves the cell biocompatibility and osteogenicity of the scaffolds. Evidence for this notion is based in several observations: (a) HAP polymer increases proliferation of osteoblastic cells; (b) HAP included in the blend increases the ALP expression in UMR106 cells; (c) HAP-Blend increases the type-I collagen production in both cell lines, and d) higher levels of the osteogenic transcription factor Runx-2 were detected when MC3T3E1 osteoblasts were induced to differentiate and mineralize on HAP-polymer scaffolds. In conclusion, a novel biocompatible HAP-Blend composite with uniform dispersion of semi-nano HAP particles and good interphase compatibility has been prepared successfully. The development of HAP-Blend composite, with improved physical, mechanical and osteoinductive properties, may potentially be used in bone tissue engineering applications. PMID- 21312339 TI - The small molecule PKA-specific cyclic AMP analogue as an inducer of osteoblast like cells differentiation and mineralization. AB - Osteoblastic differentiation is an important landmark for bone formation, bone repair and regeneration; however, it is a very complex process controlled by different signalling mechanisms. Several groups have reported that the cyclic adenosine monophosphate (cAMP) signalling system is responsible for regulating osteoblast cell differentiation. Nonetheless, to date, the principle role of the cAMP molecules related to this process remains controversial. Moreover, the underlying cAMP-dependent signalling cascade governing the osteoblastic differentiation has not been clarified. In this study we investigated the roles of the cAMP-dependent protein kinase A (PKA) signalling in proliferation, differentiation and mineralization of osteoblast-like MC3T3-E1 cells, using the PKA-specific small molecule cAMP analogue, 6-Bnz-cAMP, at 100 uM. Alkaline phosphatase (ALP) activity, runt transcription factor 2 (Runx2), osteopontin (OPN) and osteocalcin (OCN) protein expressions were used as osteoblast-specific markers to demonstrate osteoblastic differentiation. Further, calcium measurement of the extracellular matrix was employed as the hallmark of matrix mineralization or calcification. We report here that activation of PKA by the small molecule 6 Bnz-cAMP induces osteoblastic differentiation and matrix mineralization of osteoblast-like MC3T3-E1 cells. Moreover, 6-Bnz-cAMP does not induce cytotoxicity to the cells, as revealed by our cell proliferation studies. Therefore, based on these findings, we propose that the PKA-specific small molecule 6-Bnz-cAMP may serve as a novel bone-inducing growth factor for repairing and regenerating bone tissues during bone-regenerative engineering. PMID- 21312340 TI - Oxygen diffusion through collagen scaffolds at defined densities: implications for cell survival in tissue models. AB - For the success of any biomaterial for tissue engineering, its mechanical properties and ability to support nutrient diffusion will be critical. Collagen scaffolds are ideal candidates, due to their ability to immerse cells in a biomimetic nanofibrous matrix. We have established O(2) diffusion coefficients through native, dense collagen scaffolds at two tissue-like densities, with and without photo-chemical crosslinking, by adapting an optical fibre-based system for real-time core O(2) monitoring deep within collagen constructs. Using a Fick's law model, we then derived O(2) diffusion coefficients; 4.5 * 10(-6) cm(2) /s for 11% density collagen scaffolds; 1.7 * 10(-6) cm(2) /s for 34% collagen scaffolds; 3.4 * 10(-6) cm(2) /s for photochemically crosslinked collagen scaffolds at 11%. Both O(2) diffusion coefficients of the 11% collagen fall within the range of native intestinal submucosa. The high diffusion coefficients of these collagen scaffolds, as well as their material properties, render them viable tissue-engineering matrices for tissue replacement. PMID- 21312341 TI - Akt1 interacts with epidermal growth factor receptors and hedgehog signaling to increase stem/transit amplifying cells in the embryonic mouse cortex. AB - A subset of precursors in the embryonic mouse cortex and in neurospheres expresses a higher level of the serine/threonine kinase Akt1 than neighboring precursors. We reported previously that the functional significance of high Akt1 expression was enhanced Akt1 activity, resulting in an increase in survival, proliferation, and self-renewal of multipotent stem/transit amplifying cells. Akt1 can interact with a number of signaling pathways, but the extrinsic factors that are required for specific effects of elevated Akt1 expression have not been identified. In this study we addressed the contributions of signaling via epidermal growth factor (EGF) and hedgehog (Hh) receptors. In EGF receptor-null precursors or following transient inhibition of EGF receptor tyrosine kinase activity, elevating Akt1 by retroviral transduction could still increase survival and proliferation but could not increase self-renewal. We also found that elevated Akt1 expression induced the expression of EGF receptors (EGFRs) in wild type precursors. Several extrinsic factors, including Shh, can induce EGFR expression by cortical precursors, and we found that elevating Akt1 allowed them to respond to a subthreshold concentration of Shh to induce EGFRs. In precursors that lack the Hh receptor smoothened, however, elevating Akt1 did not increase EGFR expression or self-renewal, though it could still stimulate proliferation. These findings suggest that a subset of precursors in the embryonic cortex that express an elevated level of Akt1 can respond to lower concentrations of Shh than neighboring precursors, resulting in an increase in their expression of EGFRs. Signaling via EGFRs is required for their self-renewal. PMID- 21312342 TI - Facilitated intracellular transport of TrkA by an interaction with nerve growth factor. AB - Intracellular transport of neurotrophin receptors together with neurotrophins is one of the key events of neurotrophin signaling for the growth and the survival of neurons. However, the involvement of neurotrophin signaling in the regulation of intracellular transport of neurotrophin receptors has been remained unclear. We visualized the behavior of TrkA, a receptor of nerve growth factor (NGF), by labeling with GFP in PC12 cells. We found remarkable changes of the behavior of TrkA-GFP upon the application of NGF. Before the application, only ~37% of the fluorescent dots of TrkA showed translocations along neurites of PC12 cells. After the application, number of the dots showing the directional movement increased to ~65%. The averaged velocities of the directional movement of TrkA GFP dots became higher after the application of NGF. We tested the idea whether NGF binding accelerated the translocations of TrkA by simultaneously observing TrkA-GFP and fluorescently labeled NGF, Cy3.5-NGF. The velocity of TrkA-GFP dots associated with Cy3.5-NGF was remarkably higher than that of TrkA-GFP dots without Cy3.5-NGF. On the basis of these observations, we hypothesize that there is a signaling mechanism within a single vesicle that facilitates the intracellular transport of each vesicle containing the activated TrkA. PMID- 21312343 TI - Vision drives correlated activity without patterned spontaneous activity in developing Xenopus retina. AB - Developing amphibians need vision to avoid predators and locate food before visual system circuits fully mature. Xenopus tadpoles can respond to visual stimuli as soon as retinal ganglion cells (RGCs) innervate the brain, however, in mammals, chicks and turtles, RGCs reach their central targets many days, or even weeks, before their retinas are capable of vision. In the absence of vision, activity-dependent refinement in these amniote species is mediated by waves of spontaneous activity that periodically spread across the retina, correlating the firing of action potentials in neighboring RGCs. Theory suggests that retinorecipient neurons in the brain use patterned RGC activity to sharpen the retinotopy first established by genetic cues. We find that in both wild type and albino Xenopus tadpoles, RGCs are spontaneously active at all stages of tadpole development studied, but their population activity never coalesces into waves. Even at the earliest stages recorded, visual stimulation dominates over spontaneous activity and can generate patterns of RGC activity similar to the locally correlated spontaneous activity observed in amniotes. In addition, we show that blocking AMPA and NMDA type glutamate receptors significantly decreases spontaneous activity in young Xenopus retina, but that blocking GABA(A) receptor blockers does not. Our findings indicate that vision drives correlated activity required for topographic map formation. They further suggest that developing retinal circuits in the two major subdivisions of tetrapods, amphibians and amniotes, evolved different strategies to supply appropriately patterned RGC activity to drive visual circuit refinement. PMID- 21312344 TI - Ultrasonography for detecting enthesitis in juvenile idiopathic arthritis. AB - OBJECTIVE: Enthesitis is a major feature of juvenile idiopathic arthritis (JIA) but is difficult to diagnose clinically. Our objective was to compare the accuracy of ultrasonography with power Doppler (US-PD) versus clinical examination for diagnosing enthesitis in patients with JIA and healthy controls. METHODS: Twenty-six consecutive patients with JIA and 41 healthy volunteers underwent standardized clinical and US-PD examinations of 5 entheseal sites (proximal and distal quadricepital tendon insertions, Achilles tendon, and plantar fascia). US-PD reproducibility was evaluated. US-PD enthesitis was defined as a PD signal at the enthesis insertion. Bursitis, erosions, and cartilage vascularization were recorded. RESULTS: In the JIA group, 27 (12.5%) of the entheseal sites exhibited clinical enthesitis (distal patellar ligament in 45% of cases) and 20 (9.4%) exhibited US-PD enthesitis (distal patellar tendon in 30%), including 10 clinically normal sites (50%). US-PD enthesitis was found in several patients with oligoarthritis or polyarthritis. Clinical enthesitis (P < 0.0001) and HLA-B27-positive (P = 0.05) status were significantly associated with US-PD enthesitis. Erosion and bursitis, but not tendon thickening, were associated with US-PD enthesitis. US-PD enthesitis was not found at any of the 410 entheseal sites in controls; grade 1 cartilage vascularization was noted at 6% of the control sites. CONCLUSION: Enthesitis is a rare phenomenon in JIA. Clinically silent enthesitis is detected by US-PD and can be found in JIA categories other than enthesitis-related arthritis. Tendon thickening and cartilage vascularization can be detected in healthy controls. These findings may have implications for patient classification of the use of US-PD. PMID- 21312345 TI - Cognitive-behavioral mechanisms in a pain-avoidance and a pain-persistence treatment for high-risk fibromyalgia patients. AB - OBJECTIVE: The heterogeneity of cognitive-behavioral patterns in patients with fibromyalgia (FM) has been proposed to underlie the variability in treatment outcomes. It has previously been shown that pain-avoidance and pain-persistence treatments tailored to the patient's pattern are effective in improving physical and psychological functioning and overall impact in high-risk patients with heightened psychological distress. In the present study, the cognitive-behavioral effects of these treatments were evaluated to provide insight into the main proposed mechanisms, specifically pain-avoidance behaviors and activity pacing in the pain-avoidance and pain-persistence treatments, respectively. METHODS: High risk FM patients were classified into 2 groups, pain avoidance and pain persistence, and randomized in groups to the relevant treatment or waiting-list control condition. The pain-avoidance and pain-persistence treatments both comprised 16 twice-weekly sessions of cognitive-behavioral therapy and exercise training. Cognitive--behavioral factors assessed at pre- and posttreatment and 6 months of followup were evaluated using linear mixed models. RESULTS: A significant treatment effect was found for pain-avoidance behavior in the pain avoidance treatment and for activity pacing in the pain-persistence treatment, showing improvements in the treatment condition relative to the controls. Furthermore, the effect on functioning was mediated by changes in pain-avoidance behavior in the pain-avoidance treatment and by changes in activity pacing in the pain-persistence treatment. Both treatments also showed significant improvements in other relevant cognitive-behavioral factors. CONCLUSION: Both the pain avoidance and pain-persistence treatments are effective in improving cognitive behavioral factors in high-risk FM patients. Pain-avoidance behavior and activity pacing might be important mediating mechanisms for beneficial outcomes in pain avoidance and pain-persistence treatments, respectively. PMID- 21312346 TI - Serum free light chains as biomarkers for systemic lupus erythematosus disease activity. AB - OBJECTIVE: To evaluate serum free light chains (FLC) as a putative biomarker of systemic lupus erythematosus (SLE) activity. METHODS: Seventy-five SLE patients and 41 age- and sex-matched rheumatoid arthritis (RA) controls were enrolled. Disease activity was assessed using the Safety of Estrogens in Lupus Erythematosus: National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) definition and physician global assessments for SLE and the Disease Activity Score in 28 joints for RA. Serum FLC levels were compared against other biomarkers (IgG, C3, C4, double-stranded DNA [dsDNA] antibody). Nonparametric tests were used to compare 1) FLC and IgG in SLE versus RA and healthy controls, 2) FLC and IgG among different levels of activity in SLE, and 3) FLC in active versus nonactive RA. Correlation of FLC, C3, C4, dsDNA antibody, and IgG with the SLEDAI and modified SLEDAI (M-SLEDAI) were obtained. RESULTS: FLC was higher in SLE than in RA; both were higher than referent healthy controls. Total FLC was significantly higher in subjects with greater SLE disease activity than lower/no activity. There were no significant differences in IgG, C4, or dsDNA antibody stratified by disease activity. Total FLC and C3 showed moderate to strong correlation with the SLEDAI and M-SLEDAI. In RA, no differences were seen in FLC levels for different levels of disease activity. Similar results were seen after controlling for renal function, age, and sex. In multiple linear regression, FLC significantly explained 50% variance of the SLEDAI after adjusting for renal function, age, and sex. CONCLUSION: Serum FLC levels correlate strongly with disease activity in SLE, but not in RA. Serum FLC may be used as a biomarker of SLE disease activity. PMID- 21312347 TI - Using the Center for Epidemiologic Studies Depression Scale to screen for depression in systemic lupus erythematosus. AB - OBJECTIVE: Identifying persons with systemic lupus erythematosus (SLE) at risk for depression would facilitate the identification and treatment of an important comorbidity conferring additional risk for poor outcomes. The purpose of this study was to determine the utility of a brief screening measure, the Center for Epidemiologic Studies Depression Scale (CES-D), in detecting mood disorders in persons with SLE. METHODS: This cross-sectional study examined 150 persons with SLE. Screening cut points were empirically derived using threshold selection methods, and receiver operating characteristic curves were estimated. The empirically derived cut points of the CES-D were used as the screening measures and were compared to other commonly used CES-D cut points in addition to other commonly used methods to screen for depression. Diagnoses of major depressive disorder or other mood disorders were determined using a "gold standard" structured clinical interview. RESULTS: Of the 150 persons with SLE, 26% of subjects met criteria for any mood disorder and 17% met criteria for major depressive disorder. Optimal threshold estimations suggested a CES-D cut score of 24 and above, which yielded adequate sensitivity and specificity in detecting major depressive disorder (88% and 93%, respectively) and correctly classified 92% of participants. To detect the presence of any mood disorder, a cut score of 20 and above was suggested, yielding sensitivity and specificity of 87% and correctly classifying 87%. CONCLUSION: These results suggest the CES-D may be a useful screening measure to identify patients at risk for depression. PMID- 21312348 TI - Randomized comparison of a multidisciplinary team care program with usual care in patients with systemic sclerosis. AB - OBJECTIVE: To compare the effectiveness of a multidisciplinary team care program with usual outpatient care in patients with systemic sclerosis (SSc; scleroderma). METHODS: We performed a randomized controlled trial comparing a 12 week multidisciplinary team care program (1 day per week; individual treatments, group exercises, and group education) with outpatient clinic care. Outcome measures included the Hand Mobility in Scleroderma (HAMIS) test, grip strength, maximal mouth opening (MMO), 6-minute walk distance (6MWD), maximum aerobic capacity (VO(2max) ), Checklist Individual Strength 20 (CIS-20), SSc Health Assessment Questionnaire (HAQ), and Short Form 36 (SF-36), assessed at 0, 12, and 24 weeks. Statistical comparisons of change scores were done by analysis of covariance. RESULTS: Twenty-eight patients were assigned to the intervention group (mean age 53.9 years, 15 of 28 with diffuse SSc) and 25 were assigned to the control group (mean age 51.7 years, 15 of 25 with diffuse SSc). Twenty-five patients (89%) in the intervention group completed the treatment program. At 12 weeks, there was a significantly greater improvement in grip strength (2.2 versus -1.8 kg; P = 0.001), MMO (1.4 versus -0.9 mm; P = 0.011), 6MWD (42.8 versus 3.9 meters; P = 0.021), and HAQ score (-0.18 versus 0.13; P = 0.025) in the intervention group, whereas differences for the other outcome measures did not reach significance. At 24 weeks, the effect on grip strength persisted. CONCLUSION: In patients with SSc, a 12-week multidisciplinary day patient treatment program was more effective than regular outpatient care with respect to 6MWD, grip strength, MMO, and HAQ score, but not for VO(2max) , HAMIS test, CIS 20, SF-36, and visual analog scale for pain. This study provides a first step in quantifying the effect of a multidisciplinary team care program and warrants the conduct of further intervention studies. PMID- 21312349 TI - Estimation of minimum clinically important difference for pain in fibromyalgia. AB - OBJECTIVE: To estimate the minimum clinically important difference (MCID) for several pain measures obtained from the Brief Pain Inventory (BPI) for patients with fibromyalgia. METHODS: Data were pooled across 12-week treatment periods from 4 randomized, double-blind, placebo-controlled studies designed to evaluate the safety and efficacy of duloxetine for the treatment of fibromyalgia. Each study enrolled subjects with American College of Rheumatology--defined fibromyalgia who presented with moderate to severe pain. The MCIDs for the BPI average pain item score and the BPI severity score (the mean of the BPI pain scale values: right now, average, least, and worst) were estimated by anchoring against the Patient's Global Impressions of Improvement scale. RESULTS: The anchor-based MCIDs for the BPI average pain item and severity scores were 2.1 and 2.2 points, respectively. These MCIDs correspond to 32.3% and 34.2% reductions from baseline in scores. CONCLUSION: In these analyses, the MCIDs for several pain measures obtained from the BPI were similar (~2 points) and corresponded to a 30-35% improvement from baseline to end point. These findings may be beneficial for use in designing clinical trials in which the BPI is used to evaluate improvements in pain severity. PMID- 21312350 TI - A review of advanced small-scale parallel bioreactor technology for accelerated process development: current state and future need. AB - The pharmaceutical and biotech industries face continued pressure to reduce development costs and accelerate process development. This challenge occurs alongside the need for increased upstream experimentation to support quality by design initiatives and the pursuit of predictive models from systems biology. A small scale system enabling multiple reactions in parallel (n >= 20), with automated sampling and integrated to purification, would provide significant improvement (four to fivefold) to development timelines. State of the art attempts to pursue high throughput process development include shake flasks, microfluidic reactors, microtiter plates and small-scale stirred reactors. The limitations of these systems are compared to desired criteria to mimic large scale commercial processes. The comparison shows that significant technological improvement is still required to provide automated solutions that can speed upstream process development. PMID- 21312351 TI - Effects of phenolic monomers on growth of Acidothermus cellulolyticus. AB - Previous studies on biological pretreatment of switchgrass by solid-state fermentation with Acidothermus cellulolyticus 11B have shown that inhibitory compounds prevent growth on untreated switchgrass. A. cellulolyticus was grown in liquid medium containing cellobiose with phenolic monomers added to determine if the phenolic compounds are one possible source of inhibition. Cinnamic acid derivatives (trans-p-coumaric, trans-ferulic, and hydrocinnamic acids), hydroxybenzoic acids (p-hydroxybenzoic, syringic, and vanillic acids), benzaldehydes (vanillin and p-hydroxybenzaldehyde), and condensed tannin monomers (catechin and epicatechin) were tested at levels up to 20 mM. All compounds exhibited a dose-response relationship and strongly inhibited growth at 20 mM. trans-p-Coumaric acid was found to be the strongest inhibitor of A. cellulolyticus growth, with a specific growth rate of 0.004 h(-1) at 1 mM (0.18 h(-1) without phenolic monomer). GC-MS and HPLC methods were used to confirm the presence of these phenolic compounds in switchgrass and measure the amounts extracted using different conditions. The amounts of phenolic compounds measured were found to be higher than the threshold for growth inhibition. Leaching with water at 55 degrees C was inefficient at removing bound phenolics, whereas NaOH treatment improved efficiency. Phenolic compounds spiked into alkaline pretreated switchgrass were also found to inhibit growth of A. cellulolyticus in solid-state fermentation. However, addition of insoluble polyvinylpolypyrrolidone (PVPP) to switchgrass improved growth of A. cellulolyticus in liquid cultures, providing a possible approach for alleviating microbial inhibition due to phenolic compounds in lignocellulose. PMID- 21312352 TI - Efficient production of D-glucosaminic acid from D-glucosamine by Pseudomonas putida GNA5. AB - D-glucosaminic acid was produced efficiently from glucosamine by oxidative fermentation using a newly isolated strain, Pseudomonas putida GNA5. After optimization of the fermentation process, 51.5 g L(-1) D-glucosaminic acid was produced from an initial concentration of 60 g L(-1) D-glucosamine-HCl after 72 h of oxidative fermentation, which corresponded to a molar yield of 95.4%. This production process is potentially of considerable economic significance because very few by-products were detected. Furthermore, D-glucosaminic acid was accumulated stably during the oxidative fermentation process without the addition of an inhibitor of D-glucosaminic acid breakdown, even though D-glucosamine was exhausted. These results suggest that the mechanisms of D-glucosaminic acid related metabolism differ between Pseudomonas putida GNA5 and the strain Pseudomonas genera, which was previously reported to produce D-glucosaminic acid. PMID- 21312353 TI - Influence of growth temperature on the production of antibody Fab fragments in different microbes: a host comparative analysis. AB - Microorganisms encounter diverse stress conditions in their native habitats but also during fermentation processes, which have an impact on industrial process performance. These environmental stresses and the physiological reactions they trigger, including changes in the protein folding/secretion machinery, are highly interrelated. Thus, the investigation of environmental factors, which influence protein expression and secretion is still of great importance. Among all the possible stresses, temperature appears particularly important for bioreactor cultivation of recombinant hosts, as reductions of growth temperature have been reported to increase recombinant protein production in various host organisms. Therefore, the impact of temperature on the secretion of proteins with therapeutic interest, exemplified by a model antibody Fab fragment, was analyzed in five different microbial protein production hosts growing under steady-state conditions in carbon-limited chemostat cultivations. Secretory expression of the heterodimeric antibody Fab fragment was successful in all five microbial host systems, namely Saccharomyces cerevisiae, Pichia pastoris, Trichoderma reesei, Escherichia coli and Pseudoalteromonas haloplanktis. In this comparative analysis we show that a reduction of cultivation temperature during growth at constant growth rate had a positive effect on Fab 3H6 production in three of four analyzed microorganisms, indicating common physiological responses, which favor recombinant protein production in prokaryotic as well as eukaryotic microbes. PMID- 21312354 TI - Cell-free synthesis and multifold screening of Candida antarctica lipase B (CalB) variants after combinatorial mutagenesis of hot spots. AB - We have developed a strategy for rapid and combinatorial optimization of the hot spot residues of enzymes. After combinatorial randomization of target locations in the Candida antarctica lipase B (CalB) gene, the individual variant genes isolated in the E.coli cells were expressed in the cell-free protein synthesis system to analyze different parameters of the resulting CalB variants. The enzymatic assays for the hydrolysis of para-nitrophenyl-ester (pNP-ester) and triglyceride, synthesis of wax ester, and thermal stability of the variant enzymes were carried out simultaneously in 96-well microtiter plates. From the 1,000 variant genes tested in each assay, we were able to identify a series of the variant enzymes having markedly improved hydrolytic, synthetic activity, or thermal stability. The improved traits of the cell-free selected CalB variants were well reproduced when the corresponding genes were expressed in Pichia pastoris. Therefore, we expect that the proposed strategy of cell-free expression screening can serve as a viable option for rapid and precise tuning of enzyme molecules, not only for analytical purposes but also for industrial applications through large scale production using microbial cells transformed with variant genes selected from the cell-free expression screening. PMID- 21312355 TI - Overexpression of an exogenous phytoene synthase gene in the unicellular alga Chlamydomonas reinhardtii leads to an increase in the content of carotenoids. AB - Phytoene synthase (PSY) catalyses the first step in the production of carotenoids, which has been described as a key regulatory step in the carotenoids biosynthetic pathway. PSY gene from Dunaliella salina was constitutively expressed in Chlamydomonas reinhardtii under the control of the RBCS2 and HSP70A promoters and targeted to the chloroplast by the RBCS2 transit peptide. DsPSY overexpression resulted in a stable increase in the corresponding PSY transcript level and in the content of carotenoids such as violaxanthin, lutein, and beta carotene, reaching between 125 and 260% the levels in control untransformed cells. PMID- 21312356 TI - Chemo-enzymatic epoxidation-process options for improving biocatalytic productivity. AB - The reactor choice is crucial when designing a process where inactivation of the biocatalyst is a problem. The main bottleneck for the chemo-enzymatic epoxidation has been found to be enzyme inactivation by the hydrogen peroxide, H(2) O(2) , substrate. In the work reported here, the effect of reaction parameters on the reaction performance have been investigated and used to establish suitable operating strategies to minimize the inactivation of the enzyme, using rapeseed methyl ester (RME) as a substrate in a solvent-free system. The use of a controlled fed-batch reactor for maintaining H(2) O(2) concentration at 1.5 M resulted in increased productivity, up to 76 grams of product per gram of biocatalyst with higher retention of enzyme activity. Further investigation included a multistage design that separated the enzymatic reaction and the saturation of the RME substrate with H(2) O(2) into different vessels. This setup showed that the reaction rate as well as enzyme inactivation is strongly dependent on the H(2) O(2) concentration. A 20-fold improvement in enzymatic efficiency is required for reaching an economically feasible process. This will require a combination of enzyme modification and careful process design. PMID- 21312357 TI - The influence of pretreatment and enzyme loading on the effectiveness of batch and fed-batch hydrolysis of corn stover. AB - To try to improve hydrolysis yields at elevated solids loadings, a comparison was made between batch and fed-batch addition of fresh substrate at the initial and later phases of hydrolysis. Both ethanol (EPCS) and steam-pretreated corn stover (SPCS) substrates were tested at low (5 FPU) and high (60 FPU) loadings of cellulase per gram of cellulose. The fed-batch addition of fresh substrate resulted in a slight decrease in hydrolysis yields when compared with the corresponding batch reactions. A 72-h hydrolysis of the SPCS substrate resulted in a hydrolysis yield of 66% compared with 51% for the EPCS substrate. When the enzyme adsorption and substrate characteristics were assessed during batch and fed-batch hydrolysis, it appeared that the irreversible binding of cellulases to the more recalcitrant original substrate limited their access to the freshly added substrate. After 72-h hydrolysis of the SPCS substrate at low enzyme loadings, ~40-50% of the added cellulases were desorbed into solution, whereas only 20% of the added enzyme was released from the EPCS substrate. Both simultaneous and sequential treatments with xylanases and cellulases resulted in an up to a 20% increase in hydrolysis yields for both substrates at low enzyme loading. Simons' stain measurements indicated that xylanase treatment increased cellulose access, thus facilitating cellulose hydrolysis. PMID- 21312358 TI - Design and characterization of a new bioreactor for continuous ultra-slow uniaxial distraction of a three-dimensional scaffold-free stem cell culture. AB - A computer controlled dynamic bioreactor for continuous ultra-slow uniaxial distraction of a scaffold-free three-dimensional (3D) mesenchymal stem cell pellet culture was designed to investigate the influence of stepless tensile strain on behavior of distinct primary cells like osteoblasts, chondroblasts, or stem cells without the influence of an artificial culture matrix. The main advantages of this device include the following capabilities: (1) Application of uniaxial ultra-slow stepless distraction within a range of 0.5-250 MUm/h and real time control of the distraction distance with high accuracy (mean error -3.4%); (2) tension strain can be applied on a 3D cell culture within a standard CO(2) incubator without use of an artificial culture matrix; (3) possibility of histological investigation without loss of distraction; (4) feasibility of molecular analysis on RNA and protein level. This is the first report on a distraction device capable of applying continuous tensile strain to a scaffold free 3D cell culture within physiological ranges of motion comparable to distraction ostegenesis in vivo. We expect the newly designed microdistraction device to increase our understanding on the regulatory mechanisms of mechanical strains on the metabolism of stem cells. PMID- 21312359 TI - Extractive fermentation of clavulanic acid by Streptomyces DAUFPE 3060 using aqueous two-phase system. AB - The influence of four variables, specifically PEG molar mass (400, 1,000, and 8,000 g/mol), concentrations of PEG and phosphate salts (15, 20, and 25% for both), and agitation intensity (110, 150, and 200 rpm), on clavulanic acid (CA) extraction by extractive fermentation with PEG/phosphate salts aqueous two-phase system was investigated in shaken flasks using a 2(4-1) -fractional factorial design. After selection of the two most significant variables (agitation intensity and PEG molar mass), an optimization study conducted according to a 2(2) -central composite design revealed that 25% PEG 8,000 g/mol and phosphate salts at 240 rpm (run 6) were the best conditions for the extractive fermentation, leading to the best results in terms of partition coefficient (k = 8.2), yield of CA in the PEG-rich phase (eta(T) = 93%) and productivity (P = 5.3 mg/Lh). As a first attempt to make a scale-up of these results, the effectiveness of the extractive fermentation was then checked in a bench-scale bioreactor under conditions as close as possible to the optimum ones determined in flasks. The highest CA concentration obtained in the PEG-rich phase (691 mg/L) was 30% higher than in flasks, thus demonstrating the potential of such a new process, integrating the production and extraction steps, as a promising, low-cost tool to obtain high yields of this and similar products. PMID- 21312360 TI - Efficient production of cellulase in the culture of Acremonium cellulolyticus using untreated waste paper sludge. AB - Cellulase was produced by Acremonium cellulolyticus using untreated waste paper sludge (PS) as the carbon source. The clay present in PS did not show any inhibitory effect on cellulase production but did alter the pH during fermentation. On the flask scale, the maleate buffer concentration and pH were key factors that affected the efficiency of cellulase production from PS cellulose. Optimum cellulase production in a 3-L fermentor of working volume 1.5 L was achieved by controlling the pH value at 6.0 using 2 M NaOH and 2 M maleic acid, and the productivity reached 8.18 FPU/mL. When 40.89 g/L PS cellulose, 2.2 g/L (NH(4) )(2) SO(4) , and 4.4 g/L urea were added to a 48-h culture, the cellulase activity was 9.31 FPU/mL at the flask scale and 10.96 FPU/mL in the 3-L fermentor. These values are ~80% of those obtained when pure cellulose is used as the carbon source. The method developed here presents a new route for the utilization of PS. PMID- 21312361 TI - Study of in situ 1-butanol pervaporation from A-B-E fermentation using a PDMS composite membrane: validity of solution-diffusion model for pervaporative A-B-E fermentation. AB - In this study, the application of a new polydimethylsiloxane (PDMS)/dual support composite membrane was investigated by incorporating the pervaporation process into the A-B-E (acetone-butanol-ethanol) fermentation. The performance of the A-B E fermentation using the integrated pervaporation/fermentation process showed higher biomass concentrations and higher glucose consumption rates than those of the A-B-E fermentation without pervaporation. The performance of the membrane separation was studied during the separation of 1-butanol from three different 1 butanol solutions: binary, model, and fermentation culture solutions. The solution-diffusion model, specifically the mass transfer equation based on Fick's First Law, was shown to be applicable to the undefined A-B-E fermentation culture solutions. A quantitative comparison of 1-butanol separation from the three different solutions was made by calculating overall mass transfer coefficients of 1-butanol. It was found that the overall mass transfer coefficients during the separation of binary, model, and fermentation culture solutions were 1.50, 1.26, and 1.08 mm/h, respectively. PMID- 21312362 TI - Effect of protein and solution properties on the Donnan effect during the ultrafiltration of proteins. AB - Formulation of protein biopharmaceuticals as highly concentrated liquids can improve the drug substance storage and supply chain, improve the target product profile, and allow greater flexibility in dosing methods. The Donnan effect can cause a large offset in pH from the target value established with the diafiltration buffer during the concentration and diafiltration of charged proteins with ultrafiltration membranes. For neutral formulations, the pH will typically increase above the diafiltration buffer pH for basic monoclonal antibodies and decline below the diafiltration buffer pH for acidic Fc-fusion proteins. In this study, new equations for the Donnan effect during the diafiltration and concentration of proteins in solutions containing monovalent and divalent ions were derived. The new Donnan models obey mass conservation laws, account for the buffering capacity of proteins, and account for protein-ion binding. Data for the pH offsets of an Fc-fusion protein and a monoclonal antibody were predicted in both monovalent and divalent buffers using these equations. To compensate for the pH offset caused by the Donnan effect, diafiltration buffers with pH and excipient values offset from the ultrafiltrate pool specifications can be used. The Donnan offset observed during the concentration of an acidic Fc-fusion protein was mitigated by operating at low temperature. It is important to account for the Donnan effect during preformulation studies. The excipients levels in an ultrafiltration pool may differ from the levels in a protein solution obtained by adding buffers into concentrated protein solutions due to the Donnan effect. PMID- 21312363 TI - Facilitative production of an antimicrobial peptide royalisin and its antibody via an artificial oil-body system. AB - Royalisin found in the royal jelly of Apis mellifera is an antimicrobial peptide (AMP). It has a molecular weight of 5.5 kDa, which contains six cysteine residues. In this study, royalisin was overexpressed in Escherichia coli AD494 (DE3) as two oleosin-fusion proteins for preparation of its antibodies and functional purification. The recombinant royalisin, fused with oleosin central hydrophobic domain in both N- and C-termini, was reconstituted with triacylglycerol and phospholipids to form artificial oil bodies (AOBs). The AOBs were then purified to raise the antibodies. These antibodies could recognize both the native and recombinant royalisins, but not oleosin. Another oleosin-intein S fusion protein was purified by AOBs system, and royalisin was subsequently released from the AOBs through self-splicing of the intein. The recombinant royalisin exhibited high antibacterial activity, which suggested that it was refolded to its functional structure. These results demonstrated that AOBs system is an efficient method to functionally express and purify small AMPs. In addition, it also provides a facile platform for the production of antibodies against small peptides. PMID- 21312364 TI - Effects of varying virus-spiking conditions on a virus-removal filter PlanovaTM 20N in a virus validation study of antibody solutions. AB - We aimed to investigate the effect of virus-spiking conditions on the filter performance (flux, flux decay, and parvovirus reduction) of the small virus filter PlanovaTM 20N. We used three kinds of porcine parvovirus (PPV) stocks: serum, serum-free, and purified. The flux profile with PPV spiking was similar to that without spiking for normal load filtration of about 250-300 L/m(2) . High volume (3 vol %) of serum-free PPV and 1 vol % serum PPV reduced the flux to some extent for high-load filtration (over 10 h, ca., 500 L/m(2) , 5 mg/mL IgG solution). Log reduction value (LRV) of PPV was maintained at a high level (>5) over the filtration volume. Flux for PlanovaTM 20N was only minimally affected by the use of different virus stocks for spiking. Transmission electron microphotography showed that the distribution of PPV particles captured inside the membrane wall was reached until the -60% thickness of the membrane, showing that the membrane of PlanovaTM 20N has a thick effective layer for virus removal. These results provided evidence for the robustness of the filter performance of PlanovaTM 20N, showing that it was not easily affected by virus spiking conditions and that it has a large capacity for high-load conditions. PMID- 21312365 TI - Effect of surfactant pluronic F-68 on CHO cell growth, metabolism, production, and glycosylation of human recombinant IFN-gamma in mild operating conditions. AB - The control of glycosylation to satisfy regulatory requirements and quality consistency of recombinant proteins produced by different processes has become an important issue. With two N-glycosylation sites, gamma-interferon (IFN-gamma) can be seen as a prototype of a recombinant therapeutic glycoprotein for this purpose. The effect of the nonionic surfactant Pluronic F-68 (PF-68) on cell growth and death was investigated, as well as production and glycosylation of recombinant IFN-gamma produced by a CHO cell line that was maintained in a rich protein-free medium in the absence or presence of low agitation. Under these conditions, a dose-dependent effect of PF-68 (0-0.1%) was shown not only to significantly enhance growth but also to reduce cell lysis. Interestingly, supplementing the culture medium with PF-68 led to increased IFN-gamma production as a result of both higher cell densities and a higher specific production rate of IFN-gamma. If cells were grown with agitation, lack of PF-68 in the culture medium decreased the fraction of the fully glycosylated IFN-gamma glycoform (2N) from 80% to 65-70% during the initial period. This effect appeared to be due to a lag phase in cell growth observed during this period. Finally, a global kinetic study of CHO cell metabolism indicated higher efficiency in the utilization of the two major carbon substrates when cultures were supplemented with PF-68. Therefore, these results highlight the importance of understanding how media surfactant can affect cell growth as well as cell death and the product quality of a recombinant glycoprotein expressed in CHO cell cultures. PMID- 21312366 TI - Improved seeding of chondrocytes into polyglycolic acid scaffolds using semi static and alginate loading methods. AB - Cell seeding and attachment in three-dimensional scaffolds is a key step in tissue engineering with implications for cell differentiation and tissue development. In this work, two new seeding methods were investigated using human chondrocytes and polyglycolic acid (PGA) fibrous mesh scaffolds. A simple semi static seeding method using culture plates and tissue flasks was developed as an easy-to-perform modification of static seeding. An alginate-loading method was also studied, using alginate hydrogel as an adjuvant for entrapping cells within PGA scaffolds. Both the semi-static and PGA-alginate methods produced more homogeneous cell distributions than conventional static and dynamic seeding. Using 20 * 10(6) cells, whereas the seeding efficiency for static seeding was only 52%, all other techniques produced seeding efficiencies of >= 90%. With 40 * 10(6) cells, the efficiency of semi-static seeding declined to 74% while the dynamic and PGA-alginate methods retained their ability to accommodate high cell numbers. The seeded scaffolds were cultured in recirculation bioreactors to determine the effect of seeding method on cartilage production. Statically seeded scaffolds did not survive the 5-week cultivation period. Deposition of extracellular matrix in scaffolds seeded using the semi-static and PGA-alginate methods was more uniform compared with scaffolds seeded using the dynamic method. The new semi-static and PGA-alginate seeding methods developed in this work are recommended for tissue engineering because they provide substantial benefits compared with static seeding in terms of seeding efficiency, cell distribution, and cartilage deposition while remaining simple and easy to execute. PMID- 21312367 TI - Fed-batch bioreactor performance and cell line stability evaluation of the artificial chromosome expression technology expressing an IgG1 in Chinese hamster ovary cells. AB - The artificial chromosome expression (ACE) technology system uses an engineered artificial chromosome containing multiple site-specific recombination acceptor sites for the rapid and efficient construction of stable cell lines. The construction of Chinese hamster ovary(CHO) cell lines expressing an IgG1 monoclonal antibody (MAb) using the ACE system has been previously described (Kennard et al., Biotechnol Bioeng. 2009;104:540-553). To further demonstrate the manufacturing feasibility of the ACE system, four CHO cell lines expressing the human IgG1 MAb 4A1 were evaluated in batch and fed-batch shake flasks and in a 2 L fed-batch bioreactor. The batch shake flasks achieved titers between 0.7 and 1.1 g/L, whereas the fed-batch shake flask process improved titers to 2.5-3.0 g/L. The lead 4A1 ACE cell line achieved titers of 4.0 g/L with an average specific productivity of 40 pg/(cell day) when cultured in a non optimized 2-L fed-batch bioreactor using a completely chemically defined process. Generational stability characterization of the lead 4A1-expressing cell line demonstrated that the cell line was stable for up to 75 days in culture. Product quality attributes of the 4A1 MAb produced by the ACE system during the stability evaluation period were unchanged and also comparable to existing expression technologies such as the CHO-dhfr system. The results of this evaluation demonstrate that a clonal, stable MAb-expressing CHO cell line can be produced using ACE technology that performs competitively using a chemically defined fed-batch bioreactor process with comparable product quality attributes to cell lines generated by existing technologies. PMID- 21312368 TI - Role of iron and sodium citrate in animal protein-free CHO cell culture medium on cell growth and monoclonal antibody production. AB - Chemically defined iron compounds were investigated for the development of animal protein-free cell culture media to support growth of CHO cells and production of monoclonal antibodies (mAb). Using a multivessel approach of 96-well plates, shake flasks, and bioreactors, we identified iron and its chemical partner citrate as critical components for maintenance of continuous cell growth and mAb production. The optimized iron concentration range was determined to be 0.1-0.5 mM and that for citrate 0.125-1 mM. This complete formulation is able to maintain cell growth to similar levels as those supplemented with iron compounds alone; however, mAb productivity was enhanced by 30-40% when citrate was present. The addition of sodium citrate (SC) did not affect product quality as determined by size exclusion chromatography, ion exchange chromatography, reversed phase and normal phase-HPLC. No significant changes in glucose and lactate profiles, amino acid utilization, or mAb heavy and light chain expression ratios were observed. Cellular ATP level was ~30% higher when SC was included suggesting that SC may have a role in enhancing cellular energy content. When cell lysates were analyzed by LC-MS to assess the overall cellular protein profile, we identified that in the SC-containing sample, proteins involved in ribosome formation and protein folding were upregulated, and those functions in protein degradation were downregulated. Taken together, this data demonstrated that iron and citrate combination significantly enhanced mAb production without altering product quality and suggested these compounds had a role in upregulating the protein synthetic machinery to promote protein production. PMID- 21312369 TI - Characterization of the proteases involved in the N-terminal clipping of glucagon like-peptide-1-antibody fusion proteins. AB - In an attempt to develop high producing mammalian cell lines expressing glucagon like-peptide-1-antibody fusion proteins (GLP-1), we have noted that the N terminal GLP-1 portion of the fusion protein was susceptible to proteolytic degradation during cell culture, which resulted in an inactive product. The majority of the N-terminal clipped product appeared to be due to the removal of the entire biologically active peptide (30 amino acids) from the intact molecule. A number of parameters that influenced the degradative process were investigated. Additionally, protease inhibitors specific for each class of protease were tested. Results suggested that one or more serine-threonine class of protease(s) were involved in this process and inhibitors that are specific for this class of protease, including benzamidine hydrochloride could significantly inhibit the proteolytic degradation of the fusion proteins. Identification of the specific proteases involved in this process by shotgun proteomics methodology will pave the way for engineering the CHOK1SV cell line which will serve as a superior host for the production of future fusion protein products. PMID- 21312370 TI - Activity of maize transglutaminase overexpressed in Escherichia coli inclusion bodies: an alternative to protein refolding. AB - Transglutaminases (TGases) catalyze protein post-translational modification by epsilon-(gamma-glutamyl) links and covalent polyamine conjugation. In plants, this enzyme is poorly characterized and only the maize plastidial TGase gene (tgz) has been cloned. The tgz gene (Patent WWO03102128) had been subcloned and overexpressed in Escherichia coli cells, and the recombinant protein (TGZp) was present mainly in inclusion bodies (IB) fraction. In this work, after overexpression of TGZ15p and SDS-PAGE IB fraction analysis, bands about 65 and 56 kDa were obtained. Western blot, alkylation and MALDI-TOF/TOF analyses indicated that the 56 kDa band corresponded to a truncated sequence from the native TGZ15p (expected MW 65 kDa), by elimination of a chloroplast signal peptide fragment during expression processing. So that large-scale protein production and protein crystallization can be applied, we characterized the TGZ15p enzyme activity in the IB protein fraction, with and without refolding. Results indicate that it presented the biochemical characteristics of other described TGases, showing a certain plant-substrate preference. Solubilization of the IB fraction with Triton X-100 as nondenaturing detergent yielded active TGZ without the need for refolding, giving activity values comparable to those of the refolded protein, indicating that this is a valuable, faster way to obtain TGZ active protein. PMID- 21312371 TI - High-density microcarrier cell cultures for influenza virus production. AB - Influenza virus A/PR/8/34 virus propagation in adherent Madin-Darby canine kidney cells in high-density microcarrier cultures is described. To improve virus yields, perfusion and repeated fed-batch modes were applied using cell-specific feed rates. Cell densities up to 1.1 * 10(7) cells/mL were achieved. Cell specific virus yields in high-density cultures were at similar levels compared with standard, low-density cultivations. In the average 2,400 and 3,300 virions per cell were obtained for two variants of the virus strain A/PR/8/34, PR8 National Institute for Biological Standards and Control (NIBSC) and PR8-Robert Koch Institute, respectively. Maximum virus titer (HA activity = 1,778 HAU/100 MUL) for virus variant PR8-NIBSC was obtained for a cultivation infected before maximum cell concentration was reached. PMID- 21312372 TI - Diffusion of biologically relevant molecules through gel-like tissue scaffolds. AB - Encapsulation of living cells into gel-like matrices that are capable of maintaining their viability over an extended time period is starting to play a major role in medicine in applications such as, cell-based sensors, cellular therapy, and tissue engineering. The permeability of nutrients and waste products through these matrices is critical to their performance. In this article, we report a methodology for selecting scaffolds with different permeabilities and surface area/volume ratios that can be used to house a 3D cell aggregate. Such a system can be modeled if the consumption or production rates for metabolites and waste products, respectively and the diffusion coefficients of these solutes in culture medium and the encapsulating gel matrix are known. A transient finite volume mass diffusion model, based on Fick's law, is derived where the consumption of a solute by the cells is modeled through a source term. The results show that the "performance" of cell-doped gel is critically dependent on the rate at which cells consume key molecules e.g., glucose. Pragmatically, the model also provides insight as to how many cells a given gel geometry and structure can support. The approach used applies to any porous structure where mass transport occurs through diffusion. PMID- 21312373 TI - Respiration rate in human primary renal proximal and early distal tubular cells in vitro: considerations for biohybrid renal devices. AB - BACKGROUND: For biotechnological use of cells in tissue engineered applications, such as biohybrid renal devices, optimal culture conditions are required. Oxygen delivery is one of the most important cell determined system criterion for ex vivo applications. It is involved in the maintenance of highly oxygen-dependent renal tubular epithelial cells, affecting metabolic state, differentiation, and desired transport functions. The purpose of this study was to examine respiratory patterns such as basal oxygen consumption, solute transport-related oxygen demand, and oxygen concentration-dependent oxygen uptake of renal tubular epithelial cells in vitro. METHODS: Respiratory patterns of highly purified human primary renal proximal (hPTC) and early distal tubular cells (hTALDC) were analyzed by perfusion respirometry. Spontaneous oxygen consumptions and maximum respirations after carbonyl cyanide m-chlorophenyl hydrazone (CCCP) uncoupling were measured. Respiration fractions contributing to basolateral Na(+) /K(+) ATPase transport activities were assessed via ouabain inhibition and Na(+) -free medium. Furthermore, we determined oxygen uptake in dependency of oxygen concentration and morphology in various culture conditions (shaken, static). RESULTS: Respiration of solely hPTC strongly depended on oxygen concentration in a Michaelis-Menten pattern at noncritical oxygen concentrations. Respiration of both cell types was significantly increased by CCCP, whereas average Na(+) /K(+) ATPase-based oxygen uptake fractions differ significantly between the two cell types. Nevertheless, no significant differences were found in spontaneous respiration between hPTC and hTALDC. CONCLUSIONS: Our results clearly indicate that cell-specific oxygen consumption parameters have to be considered in the design of biotechnological devices intended to support kidney function by cell supported renal replacement therapy. PMID- 21312374 TI - Crystallization of silver through reduction process using Elaeis guineensis biosolid extract. AB - This study presents a special, economically valuable, unprecedented eco-friendly green process for the synthesis of silver nanoparticles. The silver nanoparticles were obtained from a waste material with oil palm biosolid extract as the reducing agent. The use of the oil palm biosolid extract for the nanoparticle synthesis offers the benefit of amenability for large-scale production. An aqueous solution of silver (Ag(+) ) ions was treated with the oil palm biosolid extract for the formation of Ag nanoparticles. The nanometallic dispersion was characterized by surface plasmon absorbance measuring 428 nm. Transmission electron microscopy showed the formation of silver nanoparticles in the range of 5-50 nm. Scanning electron microscopy-energy dispersive spectroscopy (SEM-EDS) and X-ray diffraction analysis of the freeze-dried powder confirmed the formation of metallic silver nanoparticles. Moreover, Fourier Transform Infrared Spectroscopy provided evidence of phenolics or proteins as the biomolecules that were likely responsible for the reduction and capping agent, which helps to increase the stability of the synthesized silver nanoparticles. In addition, we have optimized the production with various parameters. PMID- 21312375 TI - Interactions and phase behavior of a monoclonal antibody. AB - Protein phase behavior is implicated in numerous aspects of downstream processing either by design, as in crystallization or precipitation processes, or as an undesired effect, such as aggregation. An improved understanding of protein phase behavior is, therefore, important for developing rational design strategies for important process steps. This work explores the phase behavior of a monoclonal antibody (mAb), IDEC-152, which exhibits liquid-liquid separation, aggregation, gelation, and crystallization. A systematic study of numerous factors, including the effects of solution composition and pH, has been conducted to explore the phase behavior of this antibody. Phenomena observed include a significant dependence of the cloud point on the cation in sulfate salts and nonmonotonic trends in pH dependence. Additionally, conditions for crystallization of this mAb are reported for the first time. Protein-protein interactions, as determined from the osmotic second virial coefficient, are used to interpret the phase behavior. PMID- 21312377 TI - Comments on point: Counterpoint: Left ventricular volume during diastasis is/is not the physiological in vivo equilibrium volume and is/is not related to diastolic suction. PMID- 21312376 TI - Synthesis and biophysical properties of polymerized human serum albumin. AB - The use of many plasma expanders (PEs) is often limited by undesirable side effects, such as red blood cell (RBC) aggregation (hydroxyethyl starch), nephrotoxicity (dextran), and extravasation (albumin). Despite its natural prevalence in the bloodstream, human serum albumin (HSA) can increase the risk of mortality when administered to patients with increased vascular permeability (i.e., patients suffering from burns, septic shock, and endothelial dysfunction). The harmful extravasation of HSA can be limited by polymerizing HSA to increase its molecular size. In this study, HSA was nonspecifically cross-linked with glutaraldehyde at different cross-link densities by varying the molar ratio of glutaraldehyde to HSA. The results of this study show that the weight-averaged molecular weight (MW), viscosity, and extent of RBC aggregation of polymerized HSA increases with increasing cross-link density, whereas the colloid osmotic pressure (COP) decreases with increasing cross-link density. Interestingly, circular dichroism measurements indicate that the secondary structure of HSA is unaffected by polymerization. Altogether, these results show that glutaraldehyde can effectively cross-link HSA to produce high MW polymers, yielding a novel series of potential PEs that exhibit low COP and high viscosity. PMID- 21312378 TI - Last word on point: Counterpoint: Left ventricular volume during diastasis is not the physiological in vivo equilibrium volume and is not related to diastolic suction. PMID- 21312379 TI - [Medico-Prophylactic Faculty of I. M. Sechenov Moscow Medical Academy and its achievements]. AB - Major achievements of Medico-Prophylactic Faculty, I.M. Sechenov Moscow Medical Academy, for the period of 2000-2010 are reported. PMID- 21312380 TI - [Infectious diseases in the age of globalization]. AB - The study was aimed to analyse effect of major globalization-related factors on clinical and epidemiological manifestations of infectious diseases. It is shown that they modify the nature of epidemic process influencing its constituent components and significantly accelerate development of infections. All the four major components of globalization, viz. economic, environmental, political, and demographic, are interrelated and influence not only the prevalence of diseases but also the possibility of their prevention. The global character of the threat dictates the necessity of combined approach to its management based on the norms and principles of international law regulating provision of medical services, human rights, environmental protection, trade, and other human activities. Epidemiological safety depends on political will of individual states, financial support of global and national infrastructures for monitoring all factors of the epidemiological process. PMID- 21312381 TI - [Implementation of F. F. Erisman's scientific ideas at the general hygiene department]. AB - F.F. Erisman, a prominent scientist, gifted tutor, and outstanding public figure is ranked among the founders of hygienic science in this country. He created a university course of hygiene and founded a large scientific school. His scientific and public work was continued by many disciples, such as G.V. Khlopin, C.F. Bubnov, N.K. Ignatov, S.S. Orlov, A.N. Sysin, N.V. Krasnovskaya, etc. To day, personnel of the Department develop universal approaches to rate setting as regards environmental factors harmful for human health. PMID- 21312382 TI - [Infectious intestinal morbidity in Russia]. AB - Retrospective epidemiological analysis of the incidence of viral hepatitis A, Sonne and Flexner (bacillary) dysenteries, and rotavirus infection in different regions of Russia for the period of 2003-2008 revealed common and distinct features in the epidemic process of these conditions. All of them proved more widespread among children than in adults. Their distribution over the country's territory is highly nonuniform. The incidence among population at large and children under 14 is proportional to the fraction of such children. Correlation analysis confirmed significant dependence of morbidity level on the fraction of children under 14 years in the general population structure (r = 0.3-0.8). The strongest dependence was documented for viral hepatitis A (r = 0.5-0.7, p < 0.05) and rotavirus infection (r = 0.5-0.8, p < 0.05). It is concluded that the incidence of various intestinal infections is influenced not only by sanitary and hygienic conditions at a given territory but also by demographic structure of its population. PMID- 21312383 TI - [Immunobiological properties of bacteria]. AB - Opsonins found on the surface of microbial cells in vivo and ex vivo are characterized. The possibility of their visualization by immune electron and fluorescent microscopy has been demonstrated. Opsonins are shown to play a role in immune-mediated adhesion of bacteria to phagocytes and erythrocytes and formation of virus-bacterium associations. Staphylococci, Streptococci, and Propionibacteria appear to actively adsorb blood proteins on their cell surface giving rise to well-apparent capsular structures tentatively called immunoglobulin coatings. Pathogen (microorganism)-associated molecular patterns of gram-positive and gram-negative bacteria show different degree of interaction with soluble proteins that in turn promote their adhesion to blood corpuscles. The role of erythrocytes in transportation and elimination of immune complexes bound to their membrane receptors is discussed. PMID- 21312384 TI - Funding: Researching outside the box. PMID- 21312385 TI - Equality: The fight for access. PMID- 21312387 TI - Proceedings of the Third International Congress on Physical Activity and Public Health. Toronto, Canada. May 5-8, 2010. PMID- 21312386 TI - Driving change. Proceedings of the General Practice and Primary Health Care Research Conference. July 2009. Melbourne, Australia. PMID- 21312388 TI - Proceedings of the National Institutes of Health State-of-the-Science Conference, Diagnosis and Management of Ductal Carcinoma In Situ. September 2009. PMID- 21312390 TI - Retraction. ACOG Committee Opinion No. 402: Antenatal corticosteroid therapy for fetal maturation. PMID- 21312391 TI - The UK's fix for fixated threats. PMID- 21312392 TI - Russia's drug-supply system leaves HIV patients wanting. PMID- 21312389 TI - Gene expression alterations by conditional knockout of androgen receptor in adult Sertoli cells of Utp14b jsd/jsd (jsd) mice. AB - Spermatogenesis is dependent primarily on testosterone action on the Sertoli cells, but the molecular mechanisms have not been identified. Attempts to identify testosterone-regulated target genes in Sertoli cells have used microarray analysis of gene expression in mice lacking the androgen receptor (AR) in Sertoli cells (SCARKO) and wild-type mice, but the analyses have been complicated both by alteration of germ cell composition of the testis when pubertal or adult mice were used and by differences in Sertoli-cell gene expression from the expression in adults when prepubertal mice were used. To overcome these limitations and identify AR-regulated genes in adult Sertoli cells, we compared gene expression in adult jsd (Utp14b jsd/jsd, juvenile spermatogonial depletion) mouse testes and with that in SCARKO-jsd mouse testes, since their cellular compositions are essentially identical, consisting of only type A spermatogonia and somatic cells. Microarray analysis identified 157 genes as downregulated and 197 genes as upregulated in the SCARKO-jsd mice compared to jsd mice. Some of the AR-regulated genes identified in the previous studies, including Rhox5, Drd4, and Fhod3, were also AR regulated in the jsd testes, but others, such as proteases and components of junctional complexes, were not AR regulated in our model. Surprisingly, a set of germ cell-specific genes preferentially expressed in differentiated spermatogonia and meiotic cells, including Meig1, Sycp3, and Ddx4, were all upregulated about 2-fold in SCARKO-jsd testes. AR-regulated genes in Sertoli cells must therefore be involved in the regulation of spermatogonial differentiation, although there was no significant differentiation to spermatocytes in SCARKO-jsd mice. Further gene ontogeny analysis revealed sets of genes whose changes in expression may be involved in the dislocation of Sertoli cell nuclei in SCARKO-jsd testes. PMID- 21312393 TI - Dying in isolation. PMID- 21312394 TI - Behavioral neurobiology of schizophrenia and its treatment. Preface. PMID- 21312395 TI - Assessing function and functional outcome in schizophrenia. AB - The diagnosis of schizophrenia can only be made in the presence of a loss of functioning in domains such as employment, independent living, and social functioning. Accurately measuring functioning is central to research on the course of the disorder, treatment and rehabilitation outcomes, and biosocial factors in schizophrenia. Assessments of functional disability have described three dimensions of functioning: functional capacity, functional performance, and functional outcome. The "competence/performance" distinction refers to the observation that an individual may demonstrate an ability to perform a functional task (capacity) but may not do so in her own community environment (performance). Functional outcomes are the result of both capacity and performance. Several recent reviews have compared the characteristics, reliability, and validity of various functional assessment instruments. Two major initiatives are underway to gather additional comparative data about functional assessment strategies. Recently, both the recovery movement and the recognition of the role of environmental factors in functioning have raised questions about the conceptual content of the functioning construct (construct validity). For instance, several studies have demonstrated that features of functioning need not track together over the course of the illness. In addition, the notion of recovery emphasizes processes like community integration and subjective well-being that are not static outcomes but are continually evolving features of the life course in chronic illness. Findings on the dynamic role of environmental moderators such as support and opportunity also present challenges to scientific constructs. For these reasons and others, the ecological validity of functional assessments has become a central concern. Both the verisimilitude and veridicality of functional assessments can be empirically assessed, but to date very few studies have measured the extent to which functional measures accurately predict individuals' behavior in their usual environments. Observational studies in naturalistic environments are one important area for future research. PMID- 21312396 TI - Antipsychotics and metabolics in the post-CATIE era. AB - Schizophrenia patients have high prevalence of cardiovascular (CV) disease risk factors and high CV mortality, with increasing concern over the contribution of antipsychotic medications to cardiometabolic risk. The design of the NIMH sponsored Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial was driven by a need to understand the efficacy and safety differences between atypical antipsychotics, and between atypical and typical antipsychotics. The CATIE data indicated differences between olanzapine and other antipsychotics in phase 1 on the primary outcome measure, time to drug discontinuation, yet olanzapine was not superior to risperidone in the phase 2 tolerability arm, and was inferior to clozapine in the phase 2 efficacy arm. However, CATIE provided clear confirmation of the metabolic liability for olanzapine and also quetiapine, particularly on measures associated with insulin resistance: fasting triglycerides and central adiposity. Current research is focused on analyzing the adiposity-independent impact of certain antipsychotics on glucose-insulin homeostasis, and the disease-specific biological factors that predispose schizophrenia patients to metabolic dysfunction. The CATIE data also highlighte the high prevalence of metabolic disorders in chronic schizophrenia patients, and the moderating role of gender and race or ethnicity in antipsychotic-associate metabolic adverse effects. In the post-CATIE era, safety concerns remain the primary driver of antipsychotic prescribing habits. Absent compelling efficacy data that differentiates between antipsychotics for nonrefractory schizophrenia, the CATIE results reinforce the need for additional metabolically neutral antipsy chotic treatment options, and the importance of ongoing physical health monitorin for schizophrenia patients. PMID- 21312397 TI - Pharmacological strategies for enhancing cognition in schizophrenia. AB - Researchers have long recognized that individuals with schizophrenia experience challenges in a wide range of cognitive domains, and research on cognitive impairment in schizophrenia is not a recent phenomena. However, the past 10-20 years have seen an increasing recognition of the central importance of cognition to understanding function and outcome in this illness (Green et al. in Schizophr Bull 26:119-136, 2000), an awareness that has shifted the emphasis of at least some work on schizophrenia. More specifically, there has been a rapidly growing body of work on methods of enhancing cognition in schizophrenia, as a means to potentially facilitate improved outcome and quality of life for individuals with this debilitating illness. The current chapter reviews the results of a range of studies examining adjunctive pharmacological treatments to enhance cognition in schizophrenia using a range of designs, including single-dose studies, open-label repeated dosing studies, and double-blind parallel group and crossover designs with repeated dosing. Although many of the single-dose and open-label studies have suggested positive cognitive effects from a range of agents, few of the larger-scale double-blind studies have generated positive results. The current state of results may reflect the need to identify alternative molecular mechanisms for enhancing cognition in schizophrenia or the need to reconceptualize the ways in which pharmacological agents may improve cognition in this illness, with a concomitant change in the traditional clinical trial study design used in prior studies of cognitive enhancement in schizophrenia. PMID- 21312399 TI - Antipsychotic drug development. AB - Schizophrenia typically manifests itself with a wide array of symptoms--positive, negative, cognitive, and affective--and may also involve neurodevelopmental and neurodegenerative aspects. Each of these symptom dimensions may be derived from pathology at one or more receptor types, localized in different regions of the brain. The absence of a single therapeutic target for schizophrenia has therefore prompted the de-emphasis of selective "magic bullets" and a critical re examination of the intramolecular polypharmacy afforded by antipsychotics. In this chapter, we present a review of some of the receptor targets that are currently thought to mediate symptoms of schizophrenia, and discuss their possible implications for future antipsychotic drug development. Therapeutic strategies for schizophrenia that successfully exploit the multifunctionality of antipsychotics will take into account the entire receptor activity "portfolio" of the agent and provide a total therapeutic response that, like the elephant of the Buddhist parable, is greater than the sum of its parts. PMID- 21312398 TI - Treatment implications of the schizophrenia prodrome. AB - Schizophrenia is a debilitating neurodevelopmental disorder that strikes at a critical period of a young person's life. Early identification of individuals in the prodromal phase of a psychotic illness can lead to earlier treatment and perhaps prevention of many of the devastating effects of a first psychotic episode. International research efforts have demonstrated the success of community outreach and education regarding the schizophrenia prodrome and it is now possible to use empirically defined clinical and demographic criteria to identify individuals at a substantially increased risk for a psychotic illness. The development of clinical staging criteria for psychosis that incorporates type and severity of clinical symptoms, level of global and social functioning, family history, substance use, neurocognitive functioning, and perhaps neurobiological information, could help to specify appropriate treatment for vulnerable individuals at different phases of the prodrome. Preliminary psychosocial and pharmacologic treatment studies report initial success in reducing severity of prodromal symptoms in "at-risk" samples, but further work is needed to refine the prodromal criteria and perform well controlled treatment studies in adequately powered samples. Treatment algorithms can then be tailored to presenting symptoms, number of risk factors present, and evidence of progression of the illness, to assure appropriate, safe and effective interventions in the early stages of psychosis. PMID- 21312400 TI - Antipsychotic dosing and drug delivery. AB - This chapter addresses the current state of affairs regarding proposed mechanism of action for antipsychotic medications and how this mechanism relates to dosing and delivery strategies. The initial portion describes the history of antipsychotic medication, including key discoveries that contribute to the dopamine hypothesis of schizophrenia and provide evidence that dopamine D2 receptor antagonism remains the most copasetic explanation for both determination of dose and degree of efficacy for current antipsychotic medications. Early observations regarding the unique properties of clozapine and how those observations led to the misconception and misnomer of atypicality are also discussed. Subsequent sections relate the dosing of available medications using chlorpromazine equivalents, with a discussion of non-D2-related mechanisms to antipsychotic effects. The balance of the chapter explores the temporal pattern of receptor occupancy as a key determinant of antipsychotic effectiveness, noting that continuous infusion would present the optimal method of treatment. In addition to the pharmacodynamic benefits of continuous long-term delivery systems, the incidence, causes, and clinical consequences of poor adherence are addressed. These observations are then discussed in the context of clinical studies and meta-analyses, demonstrating superiority of long-term depot preparations over oral administration. However, despite overwhelming evidence in favor of long-term delivery systems, few options are available to provide such ideal medication delivery profiles. Barriers to creating traditional depot preparations for a large number of antipsychotic agents, as well as efforts to address these limitations with polymer-based microspheres are described. The potential extension of current formulations to very long-term delivery implants using biodegradable and nonbiodegradable platforms is then described. Benefits as well as limitations of such systems are discussed with respect to clinical and ethical issues as well as a brief description of potential regulatory and logistic barriers to developing better delivery options. In summary, this chapter describes the basis for relating the dose of all existing antipsychotic medications to dopamine D2 receptor affinity and the potential contribution of continuous occupancy to enhanced efficacy through superior biological effects and improved adherence. PMID- 21312401 TI - Functional brain imaging in schizophrenia: selected results and methods. AB - Functional brain imaging studies of patients with schizophrenia may be grouped into those that assume that the signs and symptoms of schizophrenia are due to disordered circuitry within a critical brain region and studies that assume that the signs and symptoms are due to disordered connections among brain regions. Studies have investigated the disordered functional brain anatomy of both the positive and negative symptoms of schizophrenia. Studies of spontaneous hallucinations find that although hallucinations are associated with abnormal brain activity in primary and secondary sensory areas, disordered brain activation associated with hallucinations is not limited to sensory systems. Disordered activation in non-sensory regions appear to contribute to the emotional strength and valence of hallucinations, to be a factor underlying an inability to distinguish ongoing mental processing from memories, and to reflect the brain's attempt to modulate the intensity of hallucinations and resolve conflicts with other processing demands. Brain activation studies support the view that auditory/verbal hallucinations are associated with an impaired ability of internal speech plans to modulate neural activation in sensory language areas. In early studies, negative symptoms of schizophrenia were hypothesized to be associated with impaired function in frontal brain areas. In support of this hypothesis meta-analytical studies have found that resting blood flow or metabolism in frontal cortex is reduced in schizophrenia, though the magnitude of the effect is only small to moderate. Brain activation studies of working memory (WM) functioning are typically associated with large effect sizes in the frontal cortex, whereas studies of functions other than WM generally reveal smaller effects. Findings from some functional connectivity studies have supported the hypothesis that schizophrenia patients experience impaired functional connections between frontal and temporal cortex, although the nature of the disordered connectivity is complex. More recent studies have used functional brain imaging to study neural compensation in schizophrenia, to serve as endophenotypes in genetic studies and to provide biomarkers in drug development studies. These emerging trends in functional brain imaging research are likely to help stimulate the development of a general neurobiological theory of the complex symptoms of schizophrenia. PMID- 21312402 TI - Neurochemical imaging in schizophrenia. AB - Recent advances in the development and applications of neurochemical brain imaging methods have improved the ability to study the neurochemistry of the living brain in normal processes as well as psychiatric disorders. In particular, positron emission tomography (PET) and single photon emission computed tomography (SPECT) have been used to determine neurochemical substrates of schizophrenia and to uncover the mechanism of action of antipsychotic medications. The growing availability of radiotracers for monoaminergic neurotransmitter synthesis, transporters and receptors, has enabled the evaluation of hypotheses regarding neurotransmitter function in schizophrenia derived from preclinical and clinical observations. This chapter reviews the studies using neurochemical brain imaging methods for (1) detection of abnormalities in indices of dopamine and serotonin transmission in patients with schizophrenia compared to controls, (2) development of new tools to study other neurotransmitters systems, such as gamma-aminobutyric acid (GABA) and glutamate, and (3) characterization of target occupancy by antipsychotic drugs, as well as its relationship to efficacy and side effects. As more imaging tools become available, this knowledge will expand and will lead to better detection of disease, as well as better therapeutic approaches. PMID- 21312403 TI - A selective review of volumetric and morphometric imaging in schizophrenia. AB - Brain imaging studies have long supported that schizophrenia is a disorder of the brain, involving many discrete and widely spread regions. Generally, studies have shown decreases in cortical gray matter (GM) volume. Here, we selectively review recent papers studying GM volume changes in schizophrenia subjects, both first episode (FE) and chronic, in an attempt to quantify and better understand differences between healthy and patient groups. We focused on the cortical GM of the prefrontal cortex, limbic and paralimbic structures, temporal lobe, and one subcortical structure (the caudate nucleus). We performed a search of the electronic journal database PsycINFO using the keywords "schizophrenia" and "MRI," and selected for papers published between 2001 and 2008. We then screened for only those studies utilizing manual or manually edited tracing methodologies for determining regions of interest (ROIs). Each region of interest was indexed independently; thus, one paper might yield results for numerous brain regions. Our review found that in almost all ROIs, cortical GM volume was decreased in the patient populations. The only exception was the caudate nucleus - most studies reviewed showed no change, while one study showed an increase in volume; this region, however, is particularly sensitive to medication effects. The reductions were seen in both FE and chronic schizophrenia. These results clearly support that schizophrenia is an anatomical disorder of the brain, and specifically that schizophrenia patients tend to have decreased cortical GM in regions involved in higher cognition and emotional processing. That these reductions were found in both FE and chronic subjects supports that brain abnormalities are present at the onset of illness, and are not simply a consequence of chronicity. Additional studies assessing morphometry at different phases of the illness, including prodromal stages, together with longitudinal studies will elucidate further the role of progression in this disorder. PMID- 21312404 TI - Neurophysiological measures of sensory registration, stimulus discrimination, and selection in schizophrenia patients. AB - Cortical Neurophysiological event related potentials (ERPs) are multidimensional measures of information processing that are well suited to efficiently parse automatic and controlled components of cognition that span the range of deficits exhibited in schizophrenia patients. Components following a stimulus reflect the sequence of neural processes triggered by the stimulus, beginning with early automatic sensory processes and proceeding through controlled decision and response related processes. Previous studies employing ERP paradigms have reported deficits of information processing in schizophrenia across automatic through attention dependent processes including sensory registration (N1), automatic change detection (MMN), the orienting or covert shift of attention towards novel or infrequent stimuli (P3a), and attentional allocation following successful target detection processes (P3b). These automatic and attention dependent information components are beginning to be recognized as valid targets for intervention in the context of novel treatment development for schizophrenia and related neuropsychiatric disorders. In this review, we describe three extensively studied ERP components (N1, mismatch negativity, P300) that are consistently deficient in schizophrenia patients and may serve as genetic endophenotypes and as quantitative biological markers of response outcome. PMID- 21312406 TI - Prepulse inhibition of the startle reflex: a window on the brain in schizophrenia. AB - Prepulse inhibition (PPI) of the startle response is an important measure of information processing deficits and inhibitory failure in schizophrenia patients. PPI is especially useful because it occurs in the same lawful manner in all mammals, from humans to rodents, making it an ideal candidate for cross-species translational research. PPI deficits occur across the "schizophrenia spectrum" from schizophrenia patients to their clinically unaffected relatives. Parallel animal model and human brain imaging studies have demonstrated that PPI is modulated by cortico-striato-pallido-thalamic (and pontine) circuitry. This circuitry is also implicated in schizophrenia neuropathology and neurophysiology. The finding of PPI deficits in schizophrenia patients has been replicated by many groups, and these deficits correlate with measures of thought disorder and appear to be "normalized" by second generation antipsychotic (SGA) medications. Consistent pharmacological effects on PPI have been demonstrated; among these, dopamine agonists induce PPI deficits and (in animal models) these are reversed by first and SGA medications. PPI is also significantly heritable in humans and animals and can be used as a powerful endophenotype in studies of families of schizophrenia patients. Genomic regions, including the NRGL-ERBB4 complex with its glutamatergic influences, are strongly implicated in PPI deficits in schizophrenia. PPI continues to hold promise as an exciting translational cross species measure that can be used to understand the pathophysiology and treatment of the schizophrenias via pharmacological, anatomic, and genetic studies. PMID- 21312407 TI - Neurocognition in schizophrenia. AB - Neuropsychological deficits among schizophrenia patients have been consistently documented in research over the past 20 years and are reviewed in this chapter. Discussion of general abilities is presented as a background and is followed by analysis of functioning in specific cognitive domains. Overall intellectual deficits are indicated by results from both general intelligence tests and composite test battery scores. Within specific cognitive domains, effect size differences are noted in numerous areas, including attention, with indications that working memory is affected more severely than simple attention, likely due to inclusion of an executive component in such tasks. There is also evidence of slowed processing speed among schizophrenia patients, likely contributing to deficits in other domains which rely on rapid and efficient assimilation of information. Executive impairments have been found on tests assessing set shifting abilities, selective attention, and inhibition of inappropriate responses. Learning and memory deficits have been demonstrated extensively, with some evidence that recall of verbal material is more affected than recall of visual information, and that recognition abilities are comparatively less impaired than recall for both modalities. Receptive and expressive language abilities are compromised in schizophrenia patients, as well as visual perceptual, constructional, and fine motor skills. Social cognition is an area of particular importance due to its relevance to functional outcome. Deficits in expression and recognition of facial and prosodic affect have been demonstrated, although subjective experience of emotion appears to be relatively well preserved. Neuropsychological deficits described in this review appear to generally remain stable throughout adulthood, supporting neurodevelopmental, rather than neurodegenerative, models of the illness. Finally, cognitive deficits are increasingly used as endophenotypes, which is likely an important direction of future research. PMID- 21312405 TI - Eye tracking dysfunction in schizophrenia: characterization and pathophysiology. AB - Eye tracking dysfunction (ETD) is one of the most widely replicated behavioral deficits in schizophrenia and is over-represented in clinically unaffected first degree relatives of schizophrenia patients. Here, we provide an overview of research relevant to the characterization and pathophysiology of this impairment. Deficits are most robust in the maintenance phase of pursuit, particularly during the tracking of predictable target movement. Impairments are also found in pursuit initiation and correlate with performance on tests of motion processing, implicating early sensory processing of motion signals. Taken together, the evidence suggests that ETD involves higher-order structures, including the frontal eye fields, which adjust the gain of the pursuit response to visual and anticipated target movement, as well as early parts of the pursuit pathway, including motion areas (the middle temporal area and the adjacent medial superior temporal area). Broader application of localizing behavioral paradigms in patient and family studies would be advantageous for refining the eye tracking phenotype for genetic studies. PMID- 21312408 TI - Animal models of schizophrenia. AB - Schizophrenia may well represent one of the most heterogenous mental disorders in human history. This heterogeneity encompasses (1) etiology; where numerous putative genetic and environmental factors may contribute to disease manifestation, (2) symptomatology; with symptoms characterized by group; positive -behaviors not normally present in healthy subjects (e.g. hallucinations), negative--reduced expression of normal behaviors (e.g. reduced joy), and cognitive--reduced cognitive capabilities separable from negative symptoms (e.g. impaired attention), and (3) individual response variation to treatment. The complexity of this uniquely human disorder has complicated the development of suitable animal models with which to assay putative therapeutics. Moreover, the development of animal models is further limited by a lack of positive controls because currently approved therapeutics only addresses psychotic symptoms, with minor negative symptom treatment. Despite these complexities however, many animal models of schizophrenia have been developed mainly focusing on modeling individual symptoms. Validation criteria have been established to assay the utility of these models, determining the (1) face, (2) predictive, (3) construct, and (4) etiological validities, as well as (5) reproducibility of each model. Many of these models have been created following the development of major hypotheses of schizophrenia, including the dopaminergic, glutamatergic, and neurodevelopmental hypotheses. The former two models have largely consisted of manipulating these neurotransmitter systems to produce behavioral abnormalities with some relevance to symptoms or putative etiology of schizophrenia. Given the serotonergic link to hallucinations and cholinergic link to attention, other models have manipulated these systems also. Finally, there has also been a drive toward creating mouse models of schizophrenia utilizing transgenic technology. Thus, there are opportunities to combine both environmental and genetic factors to create more suitable models of schizophrenia. More sophisticated animal tasks are also being created with which to ascertain whether these models produce behavioral abnormalities consistent with patients with schizophrenia. While animal models of schizophrenia continue to be developed, we must be cognizant that (1) validating these models are limited to the degree by which Clinicians can provide relevant information on the behavior of these patients, and (2) any putative treatments that are developed are also likely to be given with concurrent antipsychotic treatment. While our knowledge of this devastating disorder increases and our animal models and tasks with which to measure their behaviors become more sophisticated, caution must still be taken when validating these models to limit complications when introducing putative therapeutics to human trials. PMID- 21312410 TI - Prefrontal cortical circuits in schizophrenia. AB - Impaired cognitive functioning, including deficits in working memory, is considered to be a core and disabling feature of schizophrenia that is difficult to treat. Deficits in working memory in schizophrenia are attributable, at least in part, to specific pathological alterations in the neuronal circuitry of the dorsolateral prefrontal cortex that involve, but are not restricted to, disturbances in glutamate, GABA, and dopamine neurotransmission. Cannabis use provides an example of an environmental exposure that may have a deleterious impact on these neurotransmitter systems and thereby contribute to worsening of cognitive functioning in schizophrenia. Increasing knowledge of the nature of the molecular alterations in these cortical circuits may lead to the development of new pathophysiologically informed treatment options for cognitive deficits in schizophrenia. PMID- 21312411 TI - Thalamic pathology in schizophrenia. AB - The thalamus plays a critical role in the coordination of information as it passes from region to region within the brain. A disruption of that information flow may give rise to some of the cardinal symptoms of schizophrenia. In support of this hypothesis, schizophrenia-like syndromes emerge when illnesses, such as stroke, selectively damage the thalamus while sparing the rest of the brain. Evidence from many sources has implicated thalamic dysfunction in schizophrenia. In postmortem studies, several subregions of the thalamus, including the mediodorsal nucleus and the pulvinar, have been shown to have fewer neurons in schizophrenia. Neurochemical disturbances are also seen, with changes in both the glutamate and dopamine systems; thalamic glutamate receptor expression is altered in schizophrenia, and dopamine appears to be elevated in thalamic subregions, while evidence exists of an imbalance between dopamine and other neurotransmitters. In vivo studies using magnetic resonance imaging have demonstrated smaller thalamic volumes in schizophrenia, as well as shape deformations suggesting changes in those thalamic regions that are most densely connected to the portions of the brain responsible for executive function and sensory integration. These changes seem to be correlated with clinical symptoms. The thalamus is a starting point for several parallel, overlapping networks that extend from thalamic nuclei to the cortex. Evidence is emerging that changes in the thalamic nodes of these networks are echoed by changes at other points along the chain; this suggests that schizophrenia might be a disease of disrupted thalamocortical neural networks. This model distributes the pathology throughout the network, but also concentrates attention on the thalamus as a critical structure, especially because of its role in coordinating the flow of information within and between neural networks. PMID- 21312412 TI - Hippocampal pathology in schizophrenia. AB - The hippocampus is abnormal in schizophrenia. Smaller hippocampal volume is the most consistent finding and is present already in the early stages of the illness. The underlying cellular substrate is a subtle, yet functionally significant reduction of hippocampal interneurons. Neuroimaging studies have revealed a pattern of increased hippocampal activity at baseline and decreased recruitment during the performance of memory tasks. Hippocampal lesion models in rodents have replicated some of the pharmacological, anatomical and behavioral phenotype of schizophrenia. Taken together, this pattern of findings points to a disinhibition of hippocampal pyramidal cells and abnormal cortico-hippocampal interactions in schizophrenia. PMID- 21312413 TI - Integrative circuit models and their implications for the pathophysiologies and treatments of the schizophrenias. AB - A preponderance of evidence indicates that the heterogeneous group of schizophrenias is accompanied by disturbances in neural elements distributed throughout multiple levels of interconnected cortico-striato-pallido-thalamic circuitry. These disturbances include a substantial loss of, or failure to develop, both cells and/or appropriate cellular connections in regions that include at least portions of the hippocampus, parahippocampal gyrus, entorhinal cortex, amygdala, prefrontal and anterior cingulate cortex, superior and transverse temporal gyri, and mediodorsal, anterior, and pulvinar nuclei of the thalamus; they appear to reflect failures of early brain maturation, that become codified into dysfunctional circuit properties, that in the opinion of this author cannot be "undone" or even predictably remediated in any physiological manner by existing pharmacotherapies. These circuit disturbances are variable across individuals with schizophrenia, perhaps reflecting the interaction of multiple different risk genes and multiple different epigenetic events. Evidence for these complex circuit disturbances has significant implications for many areas of schizophrenia research, and for future efforts toward developing more effective therapeutic approaches for this group of disorders. The conclusion of this chapter is that such future efforts should focus on further developing and refining medications that target nodal or convergent circuit points within the limbic-motor interface, with the goal of constraining the scope and severity of psychotic exacerbations, to be used in concert with systematic rehabilitative psychotherapies designed to engage healthy neural systems to compensate for and replace dysfunctional higher circuit elements. This strategy should be applied in both preventative and treatment settings, and disseminated for community delivery via an evidence-based manualized format. In contrast to alternative treatment strategies that range from complex polypharmacy to gene therapies to psychosurgical interventions, the use of combined medication plus targeted cognitive and behavioral psychotherapy has both common sense and time-tested documented efficacy with numerous other neuropsychiatric disorders. PMID- 21312414 TI - Experimental approaches for identifying schizophrenia risk genes. AB - Schizophrenia is a severe, debilitating and common psychiatric disorder, which directly affects approximately 1% of the population worldwide. Although previous studies have unequivocally shown that schizophrenia has a strong genetic component, our understanding of its pathophysiology remains limited. The precise genetic architecture of schizophrenia remains elusive and is likely to be complex. It is believed that multiple genetic variants, with each contributing a modest effect on disease risk, interact with environmental factors resulting in the phenotype. In this chapter, we summarise the main molecular genetic approaches that have been utilised in identifying susceptibility genes for schizophrenia and discuss the advantages and disadvantages of each approach. First, we detail the findings of linkage mapping in pedigrees (affected families), which analyse the co-segregation of polymorphic genetic markers with disease phenotype. Second, the contribution of targeted and genome-wide association studies, which compare differential allelic frequencies in schizophrenia cases and matched controls, is presented. Third, we discuss about the identification of susceptibility genes through analysis of chromosomal structural variation (gains and losses of genetic material). Lastly, we introduce the concept of re-sequencing, where the entire genome/exome is sequenced both in affected and unaffected individuals. This approach has the potential to provide a clarified picture of the majority of the genetic variation underlying disease pathogenesis. PMID- 21312415 TI - Epigenetics of schizophrenia. AB - Epigenetic regulators of gene expression including DNA cytosine methylation and posttranslational histone modifications could play a role for some of the molecular alterations associated with schizophrenia. For example, in prefrontal cortex of subjects with schizophrenia, abnormal DNA or histone methylation at sites of specific genes and promoters is associated with changes in RNA expression. These findings are of interest from a neurodevelopmental perspective because there is increasing evidence that epigenetic markings for a substantial portion of genes and loci are highly regulated during the first years of life. Furthermore, there is circumstantial evidence that a subset of antipsychotic drugs, including the atypical, Clozapine, interfere with chromatin remodeling mechanisms. Challenges for the field include (1) no clear consensus yet regarding disease-associated changes, (2) the lack of cell-specific chromatin assays which makes it difficult to ascribe epigenetic alterations to specific cell populations, and (3) lack of knowledge about the stability or turnover of epigenetic markings at specific loci in (brain) chromatin. Despite these shortcomings, the study of DNA and histone modifications in chromatin extracted from diseased and control brain tissue is likely to provide valuable insight into the genomic risk architecture of schizophrenia, particularly in the large majority of cases for which a straightforward genetic cause still remains elusive, PMID- 21312416 TI - Molecules, signaling, and schizophrenia. AB - Schizophrenia is one of the most common psychiatric disorders, but despite some progress in identifying the genetic factors implicated in its development, the molecular mechanisms underlying its etiology and pathogenesis remain poorly understood. However, accumulating evidence suggests that regardless of the underlying genetic complexity, the mechanisms of the disease may impact a small number of common signaling pathways. In this review, we discuss the evidence for a role of schizophrenia susceptibility genes in intracellular signaling cascades by focusing on three prominent candidate genes: AKT, PPP3CC (calcineurin), and DISC1. We describe the regulation of a number of signaling cascades by AKT and calcineurin through protein phosphorylation and dephosphorylation, and the recently uncovered functions of DISC1 in cAMP and GSK3beta signaling. In addition, we present independent evidence for the involvement of their downstream signaling pathways in schizophrenia. Finally, we discuss evidence supporting an impact of these susceptibility genes on common intracellular signaling pathways and the convergence of their effects on neuronal processes implicated in schizophrenia. PMID- 21312417 TI - Comments on point: Counterpoint: Left ventricular volume during diastasis is/is not the physiological in vivo equilibrium volume and is/is not related to diastolic suction. PMID- 21312409 TI - Models of neurodevelopmental abnormalities in schizophrenia. AB - The neurodevelopmental hypothesis of schizophrenia asserts that the underlying pathology of schizophrenia has its roots in brain development and that these brain abnormalities do not manifest themselves until adolescence or early adulthood. Animal models based on developmental manipulations have provided insight into the vulnerability of the developing fetus and the importance of the early environment for normal maturation. These models have provided a wide range of validated approaches to answer questions regarding environmental influences on both neural and behavioral development. In an effort to better understand the developmental hypothesis of schizophrenia, animal models have been developed, which seek to model the etiology and/or the pathophysiology of schizophrenia or specific behaviors associated with the disease. Developmental models specific to schizophrenia have focused on epidemiological risk factors (e.g., prenatal viral insult, birth complications) or more heuristic models aimed at understanding the developmental neuropathology of the disease (e.g., ventral hippocampal lesions). The combined approach of behavioral and neuroanatomical evaluation of these models strengthens their utility in improving our understanding of the pathophysiology of schizophrenia and developing new treatment strategies. PMID- 21312418 TI - Comments on point: Counterpoint: Left ventricular volume during diastasis is/is not the physiological in vivo equilibrium volume and is/is not related to diastolic suction. PMID- 21312419 TI - Last word on point: Counterpoint: Left ventricular volume during diastasis is not the physiological in vivo equilibrium volume and is not related to diastolic suction. PMID- 21312421 TI - Foreword. PMID- 21312420 TI - [Second combined meeting of the SPE (Exotic Pathology Society) and the Italian Society for Tropical Medicine (SIMET): vector transmitted disease and public health, Venice, 14th and 15th June 2010]. PMID- 21312422 TI - Medical Aspects of Gall-Stones. PMID- 21312423 TI - The Prevention of Puerperal Sepsis. PMID- 21312424 TI - Some Cases of Pyrexia without Physical Signs. PMID- 21312425 TI - Internal Piles: Diagnosis and Treatment. PMID- 21312427 TI - Pulmonary Tuberculosis from the Physician's Viewpoint. PMID- 21312426 TI - The Diagnosis and Treatment of Empyema. PMID- 21312428 TI - Cases Seen in the Wards. PMID- 21312429 TI - Surgical Out-Patients at Prince of Wales's General Hospital. PMID- 21312432 TI - Post-Graduate Courses: A Suggested Improvement. PMID- 21312430 TI - Post-Graduate Teaching in London. PMID- 21312433 TI - Chronic Urinary Infection: With B. Coli Communis. PMID- 21312435 TI - Post-Graduate Instruction outside London. PMID- 21312434 TI - The Role of Light: In the Prevention and Cure of Disease. PMID- 21312437 TI - Tuberculous Laryngitis. PMID- 21312436 TI - Needs of the General Practitioner. PMID- 21312438 TI - Adaptation: Successful and Unsuccessful. PMID- 21312440 TI - Post-Graduate Teaching in London: Comments of an Overseas Doctor. PMID- 21312439 TI - Vertigo. PMID- 21312441 TI - Post-Graduate Instruction: An Appreciation. PMID- 21312442 TI - Some Observations on Diabetes and Insulin in General Practice. PMID- 21312443 TI - Chronic Lesions of the Stomach. PMID- 21312445 TI - Catarrhal Infection and the Catarrhal Child. PMID- 21312444 TI - In the Medical Wards of the Prince of Wales's General Hospital. PMID- 21312446 TI - Renal Disease: Some Points in Treatment. PMID- 21312448 TI - Round the Wards at the Bolingbroke Hospital. PMID- 21312447 TI - The Role of Vaccine Therapy: In Coliform Infections of the Urinary Tract. PMID- 21312449 TI - Dyspepsia. PMID- 21312450 TI - Remarks on Manipulative Surgery or Bonesetting. PMID- 21312451 TI - The Economics of Public Health. PMID- 21312452 TI - Technique in Thecal Puncture: The Perfect Operation. PMID- 21312453 TI - Marasmus. PMID- 21312454 TI - Vomiting. PMID- 21312455 TI - Pyogenic Infections of the Skin in Children. PMID- 21312456 TI - Bromide Eruptions. PMID- 21312458 TI - Diagnosis of Cancer of the Stomach. PMID- 21312457 TI - Drug Eruptions. PMID- 21312459 TI - Auricular Flutter and Fibrillation. PMID- 21312461 TI - "Prostatic" Neurasthenia. PMID- 21312460 TI - Radiograms as an Aid to Diagnosis in Lung Diseases. PMID- 21312462 TI - Disabilities of the Hip-joint in Children. PMID- 21312463 TI - Cases from Wards and Out-Patients. PMID- 21312464 TI - Breathlessness and Dyspnoea in Childhood. PMID- 21312465 TI - Diagnosis of Urinary Diseases in Children. PMID- 21312466 TI - Pathology of Bronchiectasis. PMID- 21312467 TI - Post-Graduate Clinical Demonstration. PMID- 21312468 TI - Importance of Post-Graduate Training. PMID- 21312469 TI - Demonstration of Cases and Specimens: In the Throat Department of Brompton Hospital for Consumption and Diseases of the Chest. PMID- 21312470 TI - The Theoretical Aspects of Acidosis. PMID- 21312471 TI - The Silhouette Radiogram in the Interpretation of Clinical Signs. PMID- 21312472 TI - Post-Graduate Hostel. PMID- 21312473 TI - Treatment of Diseases of the Skin by Ultra-violet Rays. PMID- 21312474 TI - Some Neurological Case Notes. PMID- 21312475 TI - X Rays in the Diagnosis of Gall-Bladder Lesions: With Special Reference to the Newer Technique. PMID- 21312476 TI - Acute OEdema of the Lungs. PMID- 21312477 TI - Abdominal Tuberculosis in Children. PMID- 21312479 TI - Clinical Cases: At the Central London Ophthalmic Hospital. PMID- 21312478 TI - Errors of Refraction: With Special Reference to Squint. PMID- 21312481 TI - Antenatal Care as it Affects the Child in Utero. PMID- 21312480 TI - Lecture-Demonstrations in Provincial Towns. PMID- 21312482 TI - The Conversion Neurosis. PMID- 21312484 TI - Provincial Post-Graduate Work and Publicity. PMID- 21312483 TI - Notes on Post-Graduate Work in Vienna. PMID- 21312485 TI - The Treatment of Uterine Fibroids. PMID- 21312486 TI - Infective Osteomyelitis in Childhood. PMID- 21312487 TI - Antenatal Care as it Affects the Child in Utero. PMID- 21312489 TI - Intestinal Obstruction from Gall-stone: "Gall-stone Ileus.". PMID- 21312488 TI - Notes on Post-Graduate Work in Vienna and Berlin. PMID- 21312490 TI - Minor Degrees of Spinal Curvature. PMID- 21312491 TI - Our Duty to Colonial Visitors. PMID- 21312492 TI - Compression of the Spinal Cord. PMID- 21312493 TI - Intestinal Obstruction from Gall-Stone: "Gall-Stone Ileus.". PMID- 21312494 TI - Ultra-Violet Light: Its Properties and Therapeutic Uses. PMID- 21312495 TI - Some Apparently Trivial Ophthalmic Symptoms which may be of Importance. PMID- 21312496 TI - Compression of the Spinal Cord. PMID- 21312497 TI - Some Cases of Difficulty in Diagnosis which a Clinical Pathologist may Encounter. PMID- 21312498 TI - Post-Graduate Clinical Demonstration. PMID- 21312500 TI - Head Injuries. PMID- 21312499 TI - Acute Appendicitis. PMID- 21312501 TI - Spectral "Heart Disease" and Respiratory Arrhythmia. PMID- 21312502 TI - Surgical Tuberculosis. PMID- 21312503 TI - Diagnosis of Holes in Prehistoric Skulls: A Differential Diagnosis of the Various Kinds of Holes Discovered in the Skulls of Prehistoric Man. PMID- 21312504 TI - Extra-Mural Post-Graduate Work: Conducted by the Canadian Medical Association. PMID- 21312505 TI - Desiderata of New Zealand Post-Graduates. PMID- 21312506 TI - Suppression and Retention of Urine. PMID- 21312507 TI - Haemoptysis. PMID- 21312508 TI - Functional Nervous Disorders of the Heart. PMID- 21312509 TI - The Care and Feeding of the Premature Infant. PMID- 21312510 TI - The Diagnosis of Some Acute Eruptions. PMID- 21312512 TI - Poliomyelitis and Polio-Encephalitis. PMID- 21312511 TI - The Prophylaxis of Scarlet Fever and Diphtheria. PMID- 21312513 TI - Functional Nervous Disorders of the Heart. PMID- 21312514 TI - Post-Graduate Clinical Demonstration at the Hampstead General Hospital. PMID- 21312515 TI - Common Mistakes in the Diagnosis and Treatment of Acute Abscess. PMID- 21312516 TI - The Diagnosis of Some Acute Eruptions. PMID- 21312517 TI - Streptococci: Their Toxins and Antitoxins. PMID- 21312518 TI - Rheumatism. PMID- 21312519 TI - The Treatment of Diabetes. PMID- 21312520 TI - Abdominal Pain in Pregnancy. PMID- 21312521 TI - The Enlarged Prostate: Its Diagnosis and Treatment. PMID- 21312523 TI - Post-Graduate Teaching and the Neville Chamberlain Committee. PMID- 21312522 TI - Clinical Demonstration at the Maudsley Hospital. PMID- 21312524 TI - The Intensive Alkaline Treatment of Gastric Ulcer. PMID- 21312525 TI - Special Diplomas. PMID- 21312526 TI - Gastro-Jejunostomy versus Partial Gastrectomy in the Treatment of Gastric Ulcer. PMID- 21312528 TI - The Use and Abuse of Antiseptics. PMID- 21312527 TI - A Clinical Lecture on Some Points on the Diagnosis and Treatment of Infectious Diseases. PMID- 21312529 TI - Medicine and the State: Summary of a Lecture Delivered. PMID- 21312530 TI - Treatment of Endocrine Disorders. PMID- 21312531 TI - Etiology and Treatment of Eczema. PMID- 21312533 TI - Surgical Hints. PMID- 21312532 TI - Bronchiectasis. PMID- 21312534 TI - The Uses and Limitations of Light Treatment. PMID- 21312535 TI - The General Principles of Nutrition. PMID- 21312536 TI - Bleeding from the Nose and Throat. PMID- 21312537 TI - Treatment of Uterine Prolapse. PMID- 21312538 TI - The General Principles of Nutrition. PMID- 21312539 TI - Remarks on Cases Seen at the East Sussex Hospital, Hastings, and A Lecture on Splenomegaly. PMID- 21312541 TI - The Correction of Errors of Accommodation and of Refraction of the Eyes. PMID- 21312540 TI - Clinical Cases from Wards and Out-patients'. PMID- 21312542 TI - Diagnosis of Diseases of the Rectum and Colon. PMID- 21312543 TI - Mental Defect and its Importance to the Community. PMID- 21312544 TI - The Nature of Mental Deficiency. PMID- 21312546 TI - The Nature of Mental Deficiency. PMID- 21312545 TI - Clinical Tours for Medical Practitioners. PMID- 21312547 TI - The "Hysterical" Breast. PMID- 21312549 TI - Practical Hints in Medicine (Psychological). PMID- 21312548 TI - Practical Hints in Medicine (Psychological). PMID- 21312550 TI - The High-Grade Mental Defect in Relation to General Practice. PMID- 21312551 TI - X-rays as an Aid in the Diagnosis of Diseases of the Alimentary Tract. PMID- 21312552 TI - A Museum for Post-Graduate Study. PMID- 21312553 TI - The High-Grade Mental Defect in Relation to General Practice. PMID- 21312554 TI - Toxicology in its Application to Medical Practice. PMID- 21312555 TI - Round the Wards. PMID- 21312556 TI - The Role of the Sanatorium in the Treatment of Pulmonary Tuberculosis. PMID- 21312557 TI - Deformed and Painful Feet. PMID- 21312559 TI - A Visit to Papworth Village Settlement. PMID- 21312558 TI - The Cinematograph in Medical Education. PMID- 21312560 TI - Round the Wards. PMID- 21312561 TI - Correspondence. PMID- 21312562 TI - Dull and Backward Children. PMID- 21312563 TI - Hypertrophic Stenosis of the Pylorus. PMID- 21312564 TI - Hiccup. PMID- 21312566 TI - The Canary Islands as a Health Resort. PMID- 21312565 TI - Asthma. PMID- 21312567 TI - Amentia in Relation to Cerebral Disease and Abnormality. PMID- 21312568 TI - Albuminuria and Glycosuria. PMID- 21312569 TI - A Post-Graduate Clinical and Pathological Demonstration. PMID- 21312570 TI - Amentia in Relation to Cerebral Disease and Abnormality. PMID- 21312571 TI - Correspondence. PMID- 21312572 TI - The Secondary Forms of Mental Deficiency. PMID- 21312574 TI - Intestinal Obstruction. PMID- 21312573 TI - Post-Graduate Lecture on Fractures, With Explanatory X-Ray Photographs, Illustrations and Apparatus. PMID- 21312575 TI - Some Basic Remedies in the Treatment of Diseases of the Skin. PMID- 21312577 TI - London School of Hygiene and Tropical Medicine: University of London. PMID- 21312576 TI - Some Haematological Notes. PMID- 21312578 TI - The Induction of Abortion. PMID- 21312579 TI - The Value of Radiology in Some Intrathoracic Diseases. PMID- 21312580 TI - Surgical Resurrections-I. PMID- 21312581 TI - Angina Pectoris. PMID- 21312582 TI - Surgical Resurrections-II. PMID- 21312583 TI - Some Apparent Difficulties of General Practitioners in Ophthalmic Work. PMID- 21312584 TI - Empyaema in Children. PMID- 21312586 TI - Ridding the Empire of Leprosy: A Far-Spread Campaign. PMID- 21312585 TI - Fractures at the Wrist-Joint. PMID- 21312587 TI - Surgical Resurrections-III. PMID- 21312588 TI - Pitfalls in Dermatology. PMID- 21312589 TI - Pyelo-Nephritis in Children. PMID- 21312590 TI - Fibrosis of Lung in Children. PMID- 21312591 TI - Surgical Resurrections-IV. PMID- 21312592 TI - The Diagnosis of Chorea. PMID- 21312594 TI - Surgical Resurrections-V. PMID- 21312593 TI - Some Recent Work on Acute Infectious Diseases. PMID- 21312595 TI - Diagnosis of Malignant Disease in the Chest. PMID- 21312596 TI - Ideals in Medical Education. PMID- 21312597 TI - Calcium Metabolism and Treatment. PMID- 21312598 TI - Surgical Resurrections-VI. PMID- 21312599 TI - The Clinical Significance of the Blood-Film. PMID- 21312600 TI - A Lecture on Crime and Insanity. PMID- 21312601 TI - A Lecture on Crime and Insanity (Lecture II). PMID- 21312602 TI - A Consideration of the Various Methods of Drug Administration. PMID- 21312603 TI - Tuberculosis: The Subject for Teaching Medicine. PMID- 21312604 TI - Some Clinical Aspects of Arterial Pressure. PMID- 21312605 TI - A Lecture on Crime and Insanity. PMID- 21312607 TI - Surgical Resurrections-VII. PMID- 21312606 TI - After-Results of Gassing and Gunshot-wound Chest, especially in Relation to Tuberculosis. PMID- 21312608 TI - Correspondence. PMID- 21312609 TI - Caesarian Section. PMID- 21312610 TI - A Plea for the Study of Meteorological Conditions in Relation to Open-Air Treatment and Tuberculosis. PMID- 21312611 TI - A Lecture on Crime and Insanity. PMID- 21312612 TI - Royal Medical Benevolent Fund Christmas Gifts. PMID- 21312613 TI - A Lecture on Crime and Insanity. Lecture IV. PMID- 21312614 TI - The Technique of Treatment of Varicose Veins, of Haemorrhoids, and of Blood Transfusion. PMID- 21312615 TI - The Treatment of the Common Cold. PMID- 21312616 TI - The Stools in Infancy. PMID- 21312618 TI - Some Electrocardiographic Problems. PMID- 21312617 TI - The Relationship Between Certain Diseases of the Kidney. PMID- 21312620 TI - Varieties of Simple and Thyrotoxic Goitre and Their Differentiation. PMID- 21312619 TI - Analgesia and Anaesthesia in Labour. PMID- 21312621 TI - Uses and Abuses of Digitalis. PMID- 21312622 TI - The Role of Hydrology in Medical Practice. PMID- 21312623 TI - The Treatment of General Paralysis by Malaria. PMID- 21312624 TI - The Role of Hydrology in Medical Practice. PMID- 21312625 TI - Intrathoracic Tumours. PMID- 21312626 TI - Crime and Insanity. PMID- 21312627 TI - The Question of Vaccination against Smallpox. PMID- 21312628 TI - Local Anaesthesia in Rectal Surgery. PMID- 21312629 TI - Crime and Insanity. PMID- 21312631 TI - The Canadian Visit. PMID- 21312630 TI - Post-Graduate Medical Study. PMID- 21312632 TI - The Fellowship of Medicine and Post-Graduate Medical Association. PMID- 21312633 TI - Post-Graduate Teaching in Special Subjects. PMID- 21312634 TI - The Future of Post-Graduate Teaching in London. PMID- 21312635 TI - Post-Graduate Facilities in Canada. PMID- 21312636 TI - The British Medical Association at Winnipeg. PMID- 21312637 TI - Remarks upon the Pathology of Acute Abdominal Disease. PMID- 21312638 TI - X-ray Examination of the Urinary Tract. PMID- 21312639 TI - The Complications of Prostatectomy. PMID- 21312640 TI - Lecture on Gastric Surgery. PMID- 21312641 TI - Some Points in Connection with the Toxic Effects of Lead, Arsenic, Morphine, Cocaine, etc. PMID- 21312642 TI - The Treatment of Chronic Nasal Discharge. PMID- 21312643 TI - Malignant Disease of the Prostate and Bladder. PMID- 21312644 TI - Malignant Disease of the Prostate and Bladder. PMID- 21312645 TI - Obstruction of the Colon. PMID- 21312646 TI - Hypertension and Renal Disease. PMID- 21312647 TI - Common Practices in Infant Feeding. PMID- 21312649 TI - The Treatment of Toxic Goitre. PMID- 21312648 TI - The Heart in Pulmonary Disease. PMID- 21312651 TI - Asthma and Allied Conditions. PMID- 21312650 TI - Enlargement of the Mediastinal Glands in Children. PMID- 21312652 TI - Fever of Obscure Origin in Childhood. PMID- 21312654 TI - The Surgical Clinics of Vienna. PMID- 21312653 TI - The Early Diagnosis of Gastric Cancer. PMID- 21312655 TI - The Early Diagnosis of Pulmonary Tuberculosis. PMID- 21312657 TI - Facio-Cervical Actinomycosis. PMID- 21312656 TI - Tinnitus. PMID- 21312658 TI - Hammer Toe. PMID- 21312659 TI - Division of the Vas Deferens in Prostatectomy. PMID- 21312660 TI - Correspondence. PMID- 21312661 TI - The Principles and Practice of Medicine. PMID- 21312662 TI - Some Common Causes of Sterility and their Treatment. PMID- 21312663 TI - Diabetes and Pregnancy with the Record of Seven Cases. PMID- 21312664 TI - The Treatment of Pneumonia. PMID- 21312665 TI - The Diagnosis and Treatment of Urinary Diseases in Children. PMID- 21312666 TI - Puerperal Infection. PMID- 21312668 TI - London's Milk Supply. PMID- 21312667 TI - Lateral Curvature of the Spine (Scoliosis). PMID- 21312670 TI - "Some Important Points on Infant Feeding.": Abridged. PMID- 21312669 TI - The Royal Society of Medicine. PMID- 21312671 TI - The Management of Abdominal Operations in Infants. PMID- 21312672 TI - Collapse Therapy in the Treatment of Pulmonary Tuberculosis. PMID- 21312673 TI - The Antagonism of Hyperthyroidism and Pulmonary Tuberculosis. PMID- 21312675 TI - Practical Notes on Lymphadenoma. PMID- 21312674 TI - Some Aspects of the Diagnosis and Treatment of Diverticulitis. PMID- 21312676 TI - A Common Painful Affection of the Feet: The Ingrowing Toe Nail. PMID- 21312678 TI - Round the Hospitals: The London Temperance Hospital. PMID- 21312677 TI - Clinical Notes on Three Cases of Purpura Haemorrhagica. PMID- 21312679 TI - Venesection. PMID- 21312680 TI - The Use and Abuse of Plaster of Paris. PMID- 21312681 TI - Relief of Pain in Cystitis of Old Age. PMID- 21312683 TI - In the Operating Theatre. PMID- 21312682 TI - Three Important Points in the Post-Operative Treatment of Haemorrhoids. PMID- 21312684 TI - The Septic Uterus: The Treatment by Glycerine Irrigation. PMID- 21312685 TI - Some Impressions. PMID- 21312686 TI - Post-Graduate Training. PMID- 21312688 TI - A Lecture on Diabetes. PMID- 21312687 TI - Final Fellowship Classes. PMID- 21312689 TI - The Clinical Importance of Blood-sugars. PMID- 21312690 TI - Technique for the Induction of Artificial Pneumothorax. PMID- 21312691 TI - The Serum Treatment of Pneumonia. PMID- 21312692 TI - Abdomino-Pelvic Pain in Women. PMID- 21312693 TI - Indications for Treatment by Glycerine Irrigation. PMID- 21312694 TI - Some Surgical Hints. PMID- 21312696 TI - Foreign Bodies. PMID- 21312695 TI - The Use of Catheters. PMID- 21312698 TI - Correspondence. PMID- 21312697 TI - Some Impressions. PMID- 21312699 TI - The Pathology of Malignant Disease of the Lung and Pleura. PMID- 21312700 TI - Alopecia and its Treatment. PMID- 21312701 TI - Intestinal Indigestion of Children. PMID- 21312702 TI - The Use and Abuse of Pessaries. PMID- 21312703 TI - Everyday Eye Injuries. PMID- 21312704 TI - Abdominal Drainage Tubes. PMID- 21312706 TI - Correspondence. PMID- 21312705 TI - Some Impressions of the Mayo Clinic. PMID- 21312708 TI - Chest Radiograms. PMID- 21312707 TI - Chorea. PMID- 21312709 TI - Some Emergencies in Medical Practice. PMID- 21312710 TI - Tonsillectomy. PMID- 21312711 TI - Some Practical Points in the Technique of Cystoscopy. PMID- 21312712 TI - Abdominal Incisions. PMID- 21312713 TI - Treatment of Gleet. PMID- 21312714 TI - Some Impressions. the Spas of Czecho-Slovakia. PMID- 21312715 TI - Correspondence. PMID- 21312716 TI - Some Meditations on Medication. PMID- 21312718 TI - Treatment of Fibroids. PMID- 21312717 TI - Biochemistry in Relation to Modern Medicine. PMID- 21312719 TI - The AEtiology and Treatment of Leucorrhoea. PMID- 21312720 TI - Comments on a Case of Duodenal Ulcer. PMID- 21312721 TI - Hysterical Hip. PMID- 21312722 TI - Some Remarks on the Routine of Examination of a Patient. PMID- 21312723 TI - Swelling in Right Forearm. PMID- 21312724 TI - A Case of Gumma of Cheek and "Dental" Ulcer of Tongue. PMID- 21312725 TI - A Case of Cystic Swelling in the Groin. PMID- 21312726 TI - A Tumour of Voluntary Muscle. PMID- 21312727 TI - A Case of Gonococcic Synovitis. PMID- 21312729 TI - The Indications for Treatment by X-rays. PMID- 21312728 TI - A Case of Erb's Paralysis and Ruptured Biceps Tendon Secondary to Osteo-Arthritis of Shoulder. PMID- 21312730 TI - Medical Treatment of Graves' Disease. PMID- 21312731 TI - Two Cardiac Cases Shown to the M.R.C.P. Class. PMID- 21312732 TI - A Case of Diabetes with Chronic Pulmonary Tuberculosis and Syphilitic Aortitis. PMID- 21312733 TI - Intrathoracic Goitre. PMID- 21312734 TI - The Technique of Operations on the Thyroid Gland. PMID- 21312735 TI - The Indications for Surgical Treatment in Goitre. PMID- 21312736 TI - Apropos to Fractures. PMID- 21312737 TI - The Use of Muscle Grafts in Mastoid Operations. PMID- 21312739 TI - Case of Hydrocele of Femoral Hernial Sac. PMID- 21312738 TI - Comments on a Case of Multiple Chronic Inflammatory Tumours. PMID- 21312740 TI - The Clinic Control of Diabetes Mellitus. PMID- 21312742 TI - A Case of Acute Combined Degeneration of the Spinal Cord Occurring in a Patient with Addisonian Anaemia who was being Treated with Liver Extract. PMID- 21312741 TI - Abdominal Tumour. PMID- 21312743 TI - Streptococcal Infection of the Skin in Childhood. PMID- 21312744 TI - Comments on a Case of Renal Failure. PMID- 21312745 TI - A Case for Diagnosis. PMID- 21312747 TI - Treatment of Fractures of the Upper Limb. PMID- 21312746 TI - The Technique of Operations on the Thyroid Gland. PMID- 21312748 TI - The Technique of the Injection Treatment of Hydrocele. PMID- 21312749 TI - Indications for Caesarean Section. PMID- 21312750 TI - Migraine. PMID- 21312751 TI - The Bronchoscope in the Diagnosis and Treatment of Pulmonary Diseases. PMID- 21312752 TI - Psycho-Therapy in General Practice. PMID- 21312753 TI - The Treatment of Thoracic Empyema. PMID- 21312754 TI - A Case of OEsophageal Diverticulum of the "Pressure" Type. Operations. Cure. PMID- 21312755 TI - A Short Note on Endoscopic Resection of the Prostate. PMID- 21312756 TI - Migraine. PMID- 21312757 TI - A Case of Liver Abscess (Entamoeba histolytica) Treated by Open Operation and Emetine. PMID- 21312758 TI - Stiff Knee following Fractures of the Thigh. PMID- 21312760 TI - Sex Determination. PMID- 21312759 TI - Excretion Urography. PMID- 21312761 TI - A Case of Intestinal Obstruction with Comments. PMID- 21312762 TI - Brachial Plexus Anaesthesia for Operations on the Upper Limb: An Extract from a Letter from an American Post-Graduate. PMID- 21312763 TI - Congenital Syphilis. PMID- 21312764 TI - Sterility in Women: Some Clinical Observations. PMID- 21312765 TI - The Medical Aspect of Haematuria. PMID- 21312766 TI - A Case of Silicosis. PMID- 21312768 TI - Calcium Metabolism and the Parathyroids. PMID- 21312767 TI - Cases Demonstrated at the F.R.C.S. Class. PMID- 21312769 TI - London Clinic and Nursing Home. PMID- 21312770 TI - Correspondence. PMID- 21312771 TI - Extracts from Letters from Post-Graduates. PMID- 21312773 TI - Migraine and Mysticism. PMID- 21312772 TI - The Different Types of Prostatic Disease: With Special Reference to Diagnosis and Treatment and an Analysis of 227 Cases of Enlargement submitted to Surgical Treatment. PMID- 21312774 TI - Use and Abuse of Toes. PMID- 21312776 TI - Cases Demonstrated at the F.R.C.S. Class. PMID- 21312775 TI - Notes on So-called Congenital Hypertrophic Pyloric Stenosis in Infants. PMID- 21312777 TI - Cases Demonstrated at the M.R.C.P. Class. PMID- 21312778 TI - Correspondence. PMID- 21312779 TI - Acute Thyreoiditis. PMID- 21312780 TI - Diuretics. PMID- 21312781 TI - Anaemia. PMID- 21312783 TI - Cases Demonstrated at the M.R.C.P. Class. PMID- 21312782 TI - An Abdominal Tumour. PMID- 21312784 TI - Loss of Power in the Hand. PMID- 21312785 TI - Correspondence. PMID- 21312786 TI - Electrical Treatment in Rheumatic Conditions. PMID- 21312788 TI - Round the Wards with Mr. Lockhart-Mummery at St. Mark's Hospital. PMID- 21312787 TI - Some Observations on Leprosy in Great Britain at the Present Time. PMID- 21312789 TI - Intra-Uterine Glycerine in the Treatment of Gonorrhoea. PMID- 21312790 TI - The Recognition of Common Organic Nervous Disorders. PMID- 21312791 TI - Deformities of the Foot in Children: The Treatment of those Types due to Affections of the Nervous System. PMID- 21312792 TI - A Case of Low Blood-Pressure treated with Pituitary Whole Gland by the Mouth. PMID- 21312793 TI - Cases Demonstrated at the M.R.C.P. Class. PMID- 21312794 TI - Interesting Cases. PMID- 21312795 TI - Cases for Diagnosis. PMID- 21312796 TI - Report of Affiliated Societies. PMID- 21312797 TI - Further Remarks on Cases for Discussion: Published in the "Post-Graduate Medical Journal" for February, 1933, p. 69. PMID- 21312798 TI - Sinusitis as a Cause of Tonsillitis. PMID- 21312799 TI - The Significance of Bleeding as a Symptom in Gynaecology. PMID- 21312800 TI - Some Affections of the Skin in Childhood. PMID- 21312801 TI - The Treatment of Chronic B. coli Infections of the Urinary Tract by a Ketogenic Diet. PMID- 21312802 TI - The Uses and Indications for Intravenous and Rectal Anaesthetics. PMID- 21312803 TI - The Treatment of Pneumonia. PMID- 21312804 TI - Arsenical Jaundice. PMID- 21312805 TI - Appendicostomy. PMID- 21312806 TI - The Choice of Anaesthetic in Rectal Surgery. PMID- 21312807 TI - Some Painful Conditions about the Anus. PMID- 21312808 TI - A Case of Spontaneous Pneumothorax. PMID- 21312809 TI - Acute Thoracic Empyema. PMID- 21312810 TI - Painful Backs. PMID- 21312811 TI - The Effects on the Heart of Disease of other Systems, and Indications in Treatment. PMID- 21312812 TI - The Value of Radium in Non-Malignant Gynaecological Conditions. A Lecture Delivered at Chelsea Hospital for Women. PMID- 21312813 TI - Cases Demonstrated at the F.R.C.S. Class. PMID- 21312814 TI - Correspondence. PMID- 21312815 TI - Personal Experiences in the Diagnosis and Treatment of Conditions Apparently of Tubercular Origin. PMID- 21312816 TI - Allergic Skin Affections Related to Fungus Infection. PMID- 21312817 TI - Case of Primary Carcinoma of the Lung. PMID- 21312818 TI - A Post-Graduate Lecture on "Frequency of Micturition.". PMID- 21312819 TI - A Case of Chronic Rheumatic Disease. PMID- 21312820 TI - Cases Demonstrated at the F.R.C.S. Class. PMID- 21312821 TI - The Legal Pitfalls of the Surgeon. PMID- 21312823 TI - Prevention of Tuberculosis at the Pre-School Age-Period. PMID- 21312822 TI - Psychiatric Problems in General Practice. PMID- 21312824 TI - Mal-Descent of the Testis, and some of its Problems. PMID- 21312826 TI - The Treatment of Obesity. PMID- 21312825 TI - The Technique of Alkali Therapy in Cases of B. C. C. Pyelitis. PMID- 21312828 TI - Report of Affiliated Societies. PMID- 21312827 TI - A Case of Embolism of the Popliteal Artery Associated with Bacterial Endocarditis. PMID- 21312829 TI - Report of Affiliated Societies. PMID- 21312831 TI - Albuminuria and Eclampsia. PMID- 21312830 TI - Pre-Natal Care. PMID- 21312832 TI - The Treatment of Ante-Partum Haemorrhage. PMID- 21312833 TI - Breech Presentations in General Practice. PMID- 21312834 TI - Caesarean Section. PMID- 21312836 TI - The Uses of Dried Milks in Infant Feeding. PMID- 21312835 TI - The Repair of Injuries to the Perineum and Vaginal Walls. PMID- 21312838 TI - A New Portable Irrigator. PMID- 21312837 TI - Modern Improvements in Obstetrics. PMID- 21312839 TI - Cataract Extraction: From the point of view of the General Practitioner. PMID- 21312840 TI - Some Notes on Prognosis in Cases of Pain over the Heart. PMID- 21312841 TI - Some Common Aural and Nasal Conditions. Their Diagnosis and Treatment. PMID- 21312842 TI - The Clinical Picture Gallery in Medical Education. PMID- 21312843 TI - Cases Demonstrated at the M.R.C.P. Class. PMID- 21312844 TI - A Case for Diagnosis. PMID- 21312845 TI - A Case of Complete Heart Block. PMID- 21312846 TI - Case Demonstrated at the F.R.C.S. Class. PMID- 21312847 TI - Cataract Extraction: From the point of view of the General Practitioner. PMID- 21312848 TI - What do we mean by Rheumatism? PMID- 21312849 TI - Pulmonary Tuberculosis in Childhood. PMID- 21312850 TI - A case of "Complicated" Abortive Tabes Dorsalis with Commentary. PMID- 21312851 TI - Lumbago. PMID- 21312853 TI - The Treatment of Inguinal Hernia in Male Infants. PMID- 21312852 TI - Stenosis of the OEsophagus. PMID- 21312854 TI - Colles's Fracture. PMID- 21312855 TI - The Diagnosis of Diseases of the Urinary Tract in General Practice. PMID- 21312856 TI - Cases Demonstrated at the F.R.C.S. Class. PMID- 21312857 TI - An Appreciation. PMID- 21312858 TI - Local and Spinal Anaesthesia. PMID- 21312859 TI - The Treatment of Bladder Growths. PMID- 21312860 TI - Hallux Valgus. PMID- 21312862 TI - Chronic Constipation in Infancy and Childhood. PMID- 21312861 TI - On Fits and Faints. PMID- 21312863 TI - Chronic Empyemata. PMID- 21312865 TI - The Treatment of Speech Disorders. PMID- 21312864 TI - Report of Affiliated Society. PMID- 21312866 TI - Surgery of the Lung. PMID- 21312867 TI - The Epilepsies in Childhood. PMID- 21312868 TI - The Hippocratic Tradition. PMID- 21312869 TI - Cases Demonstrated at M.R.C.P. Class. PMID- 21312870 TI - Cases Demonstrated at the F.R.C.S. (Final) Class. PMID- 21312872 TI - The Hippocratic Tradition. PMID- 21312871 TI - Glycosuria in Childhood. PMID- 21312873 TI - Report of Affiliated Society. PMID- 21312875 TI - The Clinical Varieties of Disorder of Function. PMID- 21312874 TI - The Toxaemias of Pregnancy: I.-Early. PMID- 21312876 TI - The Toxaemias of Pregnancy: II.-Late. PMID- 21312877 TI - Stammering. PMID- 21312878 TI - The Treatment of Compound Fractures. PMID- 21312879 TI - Cases Demonstrated at the M.R.C.P. Class. PMID- 21312880 TI - Case Shown at the F.R.C.S. Class. PMID- 21312881 TI - Report of Affiliated Society. PMID- 21312882 TI - The Treatment of Pneumonia. PMID- 21312883 TI - The Thiersch Graft. Its Preparation and Uses. PMID- 21312884 TI - Some Principles in the Treatment of Diseases of the Stomach. PMID- 21312885 TI - The Causes and Diagnostic Importance of Haematuria in Surgical Conditions. PMID- 21312886 TI - Report of Affiliated Society. PMID- 21312887 TI - Verbatim Report of Debate. PMID- 21312888 TI - Report of Affiliated Society. PMID- 21312890 TI - Some Points on the Nervous and Psychological AEtiology of Skin Disorder. PMID- 21312889 TI - A Review of Anaemia. PMID- 21312891 TI - The Prevention and Treatment of Infections by Specific Immune Therapy. PMID- 21312892 TI - Stone in the Upper Urinary Tract. PMID- 21312893 TI - Case Shown at the M.R.C.P. Course. PMID- 21312894 TI - Report of Affiliated Society. PMID- 21312895 TI - On Medical Ophthalmology. PMID- 21312896 TI - Ocular Injuries and Emergencies. PMID- 21312897 TI - Errors of Refraction and Their Sequelae. PMID- 21312898 TI - Squint. PMID- 21312899 TI - Failing Sight after Middle Age. PMID- 21312900 TI - Ocular Palsies. PMID- 21312901 TI - Correspondence. PMID- 21312902 TI - The Diagnosis and Treatment of Early Poliomyelitis. PMID- 21312903 TI - The Application of the Thiersch Graft to Special Areas. PMID- 21312904 TI - Glaucoma. PMID- 21312905 TI - A Neurological Problem by an Anonymous Member. PMID- 21312906 TI - Vision and Colour Vision. PMID- 21312907 TI - Diseases and Injuries of the Lower Spine with Special Reference to Compensation Cases. PMID- 21312908 TI - Renal Efficiency Tests. PMID- 21312909 TI - Intracranial Aneurism. PMID- 21312910 TI - An Alternative Diagnosis for Case of "Anonymous Member.". PMID- 21312911 TI - Vesical Papilloma. PMID- 21312912 TI - The Diagnosis and Treatment of the Fractured Spine in the Lumbodorsal Region. PMID- 21312913 TI - Notes on a Case of Acute Infective Endocarditis Terminating in Complete Recovery. PMID- 21312915 TI - Obstructive Emphysema Due to Bronchial Carcinoma. PMID- 21312914 TI - Case of Acholuric Jaundice. PMID- 21312916 TI - Report of Affiliated Society. PMID- 21312917 TI - The Principles of Dietetics. PMID- 21312918 TI - Diet of the Infant. PMID- 21312920 TI - Preventive Measures in Nasal Sinus Therapy. PMID- 21312919 TI - The Causes and Treatment of Pruritus Ani. PMID- 21312922 TI - Report of Affiliated Society. PMID- 21312921 TI - Case of Primary Thrombosis of Brachial Atrery. PMID- 21312923 TI - The Hippocratic Tradition. PMID- 21312924 TI - The Common Anaemias: (With special reference to certain modern conceptions). PMID- 21312925 TI - Report of Affiliated Society. PMID- 21312926 TI - Verbatim Report of Debate. PMID- 21312927 TI - Anaesthesia in Thoracic Surgery. PMID- 21312928 TI - The Surgery of Pulmonary Tuberculosis. PMID- 21312930 TI - Lung Abscess. PMID- 21312929 TI - Intrathoracic Neoplasms. PMID- 21312931 TI - Bronchiectasis. PMID- 21312933 TI - Report of Affiliated Society. PMID- 21312932 TI - The Treatment of Empyema. PMID- 21312935 TI - Some Observations on the Operation of Radical Cure of an Inguinal Hernia. PMID- 21312934 TI - Thoracic Surgery: An Introductory Chapter. PMID- 21312936 TI - Radium Treatment in Cancer. PMID- 21312937 TI - Diet for the Convalescent and the Aged. PMID- 21312938 TI - The Diet of the Nephritic. PMID- 21312939 TI - Diet in Gastric Diseases. PMID- 21312940 TI - Crural Monoplegia. PMID- 21312941 TI - Pott's Puffy Tumour: With Description of a Case. PMID- 21312943 TI - Report of Affiliated Society. PMID- 21312942 TI - Rupture of a Graafian Follicle: "The Dissension Cyst" Diagnosis. PMID- 21312944 TI - John Hughlings Jackson, 1835-1911. PMID- 21312946 TI - Psychology and Aphasia. PMID- 21312945 TI - Dr. Hughlings Jackson's Principles of Cerebral Pathology. PMID- 21312947 TI - Epilepsy. PMID- 21312948 TI - Jacksonian Epilepsy: A background and a post-script. PMID- 21312949 TI - Hughlings Jackson and the Ophthalmoscope. PMID- 21312950 TI - Vaginal Prolapse. PMID- 21312951 TI - The Nature of Mental Deficiency. PMID- 21312952 TI - A Case of Sub-Phrenic Abscess and Empyema. PMID- 21312953 TI - A Case of Auricular Flutter. PMID- 21312954 TI - The Fracture Problem. PMID- 21312955 TI - Report of Affiliated Society. PMID- 21312956 TI - Haematuria. PMID- 21312957 TI - Carcinoma of Stomach: Problems in Differential Diagnosis. PMID- 21312958 TI - Treatment of Vascular Naevi with Injection of 2% Sodium Morrhuate Froth. PMID- 21312959 TI - Report of Affiliated Society. PMID- 21312961 TI - An Ascaris Infection: A Case in which the diagnosis and cure were effected by mistake. PMID- 21312960 TI - Chorea Complicated by Septicaemia, Meningitis and Cerebral Symptoms following Serotherapy, with Recovery. PMID- 21312962 TI - Carcinoma of the Stomach: Another Contribution to the Difficulties of Diagnosis. PMID- 21312963 TI - Lead Poisoning in the Infant and Young Child. PMID- 21312964 TI - Case Shown at the F.R.C.S. Class. PMID- 21312965 TI - Report of Affiliated Society. PMID- 21312966 TI - Sinusitis and Mental Disorder. PMID- 21312967 TI - Some Points in the Differential Diagnosis of Chronic Indigestion. PMID- 21312968 TI - The Full-Thickness Skin Graft. PMID- 21312969 TI - Causes of Still Birth: An Analysis of a hundred consecutive Hospital Cases. PMID- 21312970 TI - Rheumatism in School Children: A Report on the L.C.C. Rheumatism Supervisory Clinic, Stoke-Newington. PMID- 21312971 TI - Dissociation in the Ponderal and Statural Growth of the Atrophic Infant. PMID- 21312972 TI - Migraine: A Close Analysis of a Further Series of One Hundred Cases. PMID- 21312973 TI - Tuberculous Perifocal Infiltrations (Including Epituberculosis). PMID- 21312974 TI - The Treatment of Asthma. PMID- 21312975 TI - Glandular Fever. PMID- 21312976 TI - Congenital Hypertrophic Pyloric Stenosis. PMID- 21312977 TI - A Case of "Silent Bronchiectasis". PMID- 21312978 TI - A Case of Old Hip Disease. PMID- 21312979 TI - The Progress of Urology during the Last 75 Years. PMID- 21312980 TI - Congenital Anomalies and Abnormalities of the Urinary Tract. PMID- 21312981 TI - Laboratory Investigations in Urology. PMID- 21312982 TI - Pyuria. PMID- 21312983 TI - Renal Tuberculosis. PMID- 21312985 TI - Renal Tumours. PMID- 21312984 TI - The Diagnosis of Urinary Calculi. PMID- 21312986 TI - Tumours of the Bladder. PMID- 21312987 TI - The Present Day Treatment of Tumours of the Prostate. PMID- 21312988 TI - Debate on Maternal Mortality. PMID- 21312989 TI - Report of Affiliated Society. PMID- 21312990 TI - The Treatment of Acute Lobar Pneumonia. PMID- 21312991 TI - The Pituitary Gland. PMID- 21312992 TI - Cases Demonstrated at M.R.C.P. Class. PMID- 21312993 TI - Tetany. PMID- 21312995 TI - Haemoptysis. PMID- 21312994 TI - The Acute Abdomen. PMID- 21312996 TI - Neuro-Surgery in the relief of Gynaecological Pain. PMID- 21312998 TI - Report of Affiliated Society. PMID- 21312997 TI - Adrenal Gland. PMID- 21312999 TI - Sir Michael Foster. PMID- 21313001 TI - Deafness-Its Prevention and Relief. PMID- 21313000 TI - Hypertension in Women:-A Clinical Study. PMID- 21313002 TI - Non-Operative Gynaecological Treatment. PMID- 21313003 TI - Carditis-Its Nature and Cause. PMID- 21313004 TI - The Value of Electrocardiography in Diagnosis. PMID- 21313005 TI - The Diagnosis and Treatment of Cardiac Pain. PMID- 21313006 TI - Endocarditis Lenta. PMID- 21313007 TI - The Disabled Heart and Pregnancy. PMID- 21313008 TI - Syphilis of the Cardio-Vascular System. PMID- 21313009 TI - The Dosage of Digitalis. PMID- 21313010 TI - Cysts of the Epididymis. PMID- 21313011 TI - Congenital Duodenal Atresia. PMID- 21313012 TI - A Case of Substernal Goitre. PMID- 21313014 TI - Report of Affiliated Society. PMID- 21313013 TI - Cases Demonstrated at M.R.C.P. Class. PMID- 21313016 TI - Modern Anaesthesia. PMID- 21313015 TI - Chronic Rheumatic Joint Disease in General Practice. PMID- 21313017 TI - Extra-Renal Azotaemia. PMID- 21313018 TI - The Present Day Treatment of Gastric and Duodenal Ulcers in the United States. PMID- 21313019 TI - The Pharmacology and Therapeutics of Radiation. PMID- 21313020 TI - The Thyroid Gland. PMID- 21313022 TI - Examination of the Rectum. PMID- 21313021 TI - The Surgical Anatomy of the Anal Canal and Rectum. PMID- 21313023 TI - Pain in the Rectum and Anus. PMID- 21313024 TI - Benign Tumours of the Rectum. PMID- 21313025 TI - The Treatment of Internal Piles. PMID- 21313026 TI - Ano-Rectal Fistulae. PMID- 21313027 TI - Cancer of the Rectum. PMID- 21313028 TI - Anaesthesia in Rectal Surgery. PMID- 21313029 TI - The Role of Surgery in the Treatment of Chronic Peptic Ulcer. PMID- 21313030 TI - Sciatica and Cervical Rib. PMID- 21313031 TI - Recent Advances in Hormone Therapy. PMID- 21313033 TI - Bladder Neck Obstruction in General Practice. PMID- 21313032 TI - Gastroscopy. PMID- 21313034 TI - A Note on the Treatment of Hypertrophic Pyloric Stenosis. PMID- 21313035 TI - Anatomy of Approach to the Abdomen. PMID- 21313036 TI - Post-Operative Chest Conditions. PMID- 21313037 TI - The Treatment of Pulmonary Suppuration: Including its Surgical Relief. PMID- 21313039 TI - The Need of an Anaesthetic Chart. PMID- 21313038 TI - The Significance of Small Traces of Blood in the Urine. PMID- 21313040 TI - Report of Affiliated Society. PMID- 21313041 TI - Earache. PMID- 21313042 TI - Cardiospasm: AEtiology and Treatment. PMID- 21313044 TI - Two Cases of Cardiovascular Syphilis: (With Special reference to treatment and to certain physical signs). PMID- 21313043 TI - Perforated Peptic Ulcer. PMID- 21313045 TI - Report of Affiliated Societies. PMID- 21313046 TI - Causes of Sudden Death. PMID- 21313047 TI - A Case of Chronic Atrophy of the Liver. PMID- 21313049 TI - Classification of Nephritis. PMID- 21313048 TI - The Present Position of Endocrinology. PMID- 21313050 TI - Acute and Sub-Acute Nephritis. PMID- 21313051 TI - Chronic Nephritis. PMID- 21313052 TI - Nephrosis. PMID- 21313053 TI - Essential Hypertension. PMID- 21313054 TI - Renal Function Tests in Nephritis and Allied Conditions. PMID- 21313055 TI - Testes. PMID- 21313056 TI - Renal Sympathetico-Tonus. PMID- 21313057 TI - Recent Advances in the Treatment of Addison's Disease. PMID- 21313058 TI - The Pituitary-Adrenal-Gonadal Complex. PMID- 21313059 TI - Mock Trial: Held in the Barnes Hall, Royal Society of Medicine, Wimpole Street, London, W.1. on Thursday, March 11th, 1937. PMID- 21313061 TI - The Treatment of Glycosuria. PMID- 21313060 TI - Some Observations on Acute Appendicitis. PMID- 21313062 TI - Thymus. PMID- 21313063 TI - Some Practical Points in the Diagnosis and Treatment of Anaemia. PMID- 21313064 TI - Physiotherapy in Diseases of the Skin. PMID- 21313065 TI - The Future of Speech Therapy. PMID- 21313066 TI - A Note on two unusual cases of Thrombopenic Purpura. PMID- 21313067 TI - The Use of Hormones in Obstetrics and Gynaecology. PMID- 21313068 TI - The Differential Diagnosis in Splenomegaly. PMID- 21313069 TI - Trichomoniasis. PMID- 21313070 TI - Cancer of the Stomach. PMID- 21313071 TI - The Radiology of Duodenal Ulcer. PMID- 21313072 TI - A Plea for Cholecystectomy combined with Choledochostomy in cases of Chronic Cholecystitis associated with Gall-Stones. PMID- 21313074 TI - Familial Spontaneous Pneumothorax. PMID- 21313073 TI - The Treatment of Carbuncles. PMID- 21313075 TI - The Problem of Chronic Rheumatism. PMID- 21313076 TI - Rheumatoid Arthritis. PMID- 21313077 TI - Osteoarthritis. PMID- 21313078 TI - Gout. PMID- 21313080 TI - Report of Affiliated Society: Forfarshire Medical Association. PMID- 21313079 TI - Fibrositis. PMID- 21313081 TI - Some Recent Advances in the Treatment of Fractures. PMID- 21313082 TI - Manipulative Surgery. PMID- 21313083 TI - Talipes Equino Varus. PMID- 21313085 TI - Low Back Pain of Obscure Origin. PMID- 21313084 TI - "Flat Feet". PMID- 21313086 TI - The Surgery of Muscle and Tendon in Relation to Paralysis and Injury. PMID- 21313088 TI - Injuries and Displacements of the Semilunar Cartilages. PMID- 21313087 TI - Tuberculous Disease of Joints. PMID- 21313089 TI - Osteitis. PMID- 21313090 TI - Some Indications for Hormone Therapy, and its Rationale. PMID- 21313091 TI - The Diagnosis and Treatment of Ureteric Calculi. PMID- 21313092 TI - The Principles of Treatment of Post-Partum Haemorrhage. PMID- 21313093 TI - Comfort after Laparotomy. PMID- 21313094 TI - The Arthropathies. PMID- 21313095 TI - Cardio-Vascular Syphilis. PMID- 21313097 TI - Correspondence. PMID- 21313096 TI - Acute Intestinal Obstruction. PMID- 21313098 TI - Affiliated Society: Sutton & District Medical Society (Season 1937-1938). PMID- 21313099 TI - General Considerations Concerning the Management and Treatment of Patients Suffering from Bright's Disease. PMID- 21313100 TI - The Treatment of Haematemesis. PMID- 21313102 TI - Mucous Colitis. PMID- 21313101 TI - The Technique of Blood Grouping and The Indications for Blood Transfusion. PMID- 21313103 TI - The Surgical Treatment of Pulmonary Tuberculosis. PMID- 21313105 TI - The Differential Diagnosis of Haemoptysis. PMID- 21313104 TI - Some Points in the Modern Technique of Cataract Extraction. PMID- 21313106 TI - Debate on Abortion. PMID- 21313107 TI - Left Ventricular Failure. PMID- 21313108 TI - Hay-Fever and Hay-Asthma. PMID- 21313109 TI - The Diagnosis of Epilepsy Beginning in Adult Life. PMID- 21313110 TI - The Male Climacteric. PMID- 21313111 TI - Cardiac Emergencies (Part I.). PMID- 21313112 TI - The Value of Testosterone Propionate in Hyperthyroidism. PMID- 21313113 TI - Factors in Painless Tonsillectomy. PMID- 21313114 TI - The Diagnosis of Appendicitis. PMID- 21313116 TI - Body Weight in Health and Disease. PMID- 21313115 TI - The Organisation of Fracture Clinics in Europe and America. PMID- 21313118 TI - Acute Otitis Media. PMID- 21313117 TI - Cardiac Emergencies (Part II). PMID- 21313119 TI - Non-Surgical Drainage of the Gall-Bladder. PMID- 21313120 TI - Artificial Anterior Pneumomediastinum. PMID- 21313121 TI - Surgery of the Pancreas. PMID- 21313122 TI - Physical Medicine in Diseases of the Cardio-Vascular System. PMID- 21313124 TI - The Diagnosis and Treatment of Empyema. PMID- 21313123 TI - Some Remarks on Differential Diagnosis of Blood Diseases. PMID- 21313126 TI - Ruptured Spleen. PMID- 21313125 TI - Important Symptoms in Relation to Diagnosis and Treatment of Mental Disorder. PMID- 21313127 TI - Gold Therapy in Rheumatoid Arthritis. PMID- 21313128 TI - The Mercurial Diuretics. PMID- 21313129 TI - Report of Cases Demonstrated at the F.R.C.S. Class. PMID- 21313130 TI - Thrombosis of the Inferior Vena Cava. PMID- 21313131 TI - The X-Ray Examination of the Heart. PMID- 21313132 TI - Prognosis in Pulmonary Tuberculosis. PMID- 21313133 TI - Air Raid Precautions in Relationship to the General Practitioner. PMID- 21313134 TI - The Jubilee of Sir Patrick Manson (1878-1938): A Tribute to his Work on the Malaria Problem. PMID- 21313135 TI - Trypanosomiasis. PMID- 21313137 TI - Modern Tropical Hygiene. PMID- 21313136 TI - The Plague: A Brief Review of the History and Development of our Knowledge of the AEtiology of the Disease. PMID- 21313138 TI - Syphilis of the Central Nervous System. PMID- 21313140 TI - Simple Spontaneous Pneumothorax. PMID- 21313139 TI - Glaucoma. PMID- 21313141 TI - Gaucher's Disease: From the Clinical Point of View. PMID- 21313142 TI - Treatment of Chronic Fibrositis by Manipulation. PMID- 21313143 TI - Prevention and Treatment of Neuro-Syphilis. PMID- 21313144 TI - Mendelism and Medicine. PMID- 21313145 TI - Radiology in the Diagnosis of Duodenal Ulcer. PMID- 21313146 TI - Vinyl Ether for Minor Surgery and Dentistry. PMID- 21313147 TI - Some Conditions with which Hypertension is Associated: (Based on a Post-Graduate Lecture given at the Royal Free Hospital on September 23rd, 1938.). PMID- 21313148 TI - Cancer of the Breast. PMID- 21313149 TI - Bronchiectasis. PMID- 21313151 TI - Debate on a State Medical Service. PMID- 21313150 TI - Case of Dermoid Sarcoma of Rectus Abdominalis. PMID- 21313152 TI - The Investigation of a Suspected Case of Brain Tumour. PMID- 21313153 TI - The Pathology of Intracranial Tumours. PMID- 21313154 TI - Tumours of the Temporal Lobe of the Brain and their Treatment. PMID- 21313155 TI - Tumours of the Frontal Lobe. PMID- 21313157 TI - Meningeal Tumours. PMID- 21313156 TI - Subtentorial Tumours. PMID- 21313158 TI - Tumours of the Parietal and Occipital Lobes. PMID- 21313159 TI - Hypothalamic and Pituitary Tumours. PMID- 21313160 TI - Pre- and Post-Operative Management of Surgical Cases. PMID- 21313162 TI - Some Problems of the Rheumatic Child. PMID- 21313161 TI - Recent Advances in the Biochemistry of the Vitamin B Complex and their Clinical Importance. PMID- 21313164 TI - The Occipito-Posterior Case. PMID- 21313163 TI - Observations on Persistent and Recurrent Headache with special reference to Migraine. PMID- 21313165 TI - Pre- and Post-Operative Management of Surgical Cases. Lecture II. PMID- 21313166 TI - The Immediate Treatment of Head Injuries. PMID- 21313167 TI - Cutaneous Lesions of Acquired Syphilis. PMID- 21313168 TI - The Value of Manipulation in the Treatment of Rheumatic Diseases. PMID- 21313169 TI - Observations on Persistent and Recurrent Headache with Special Reference to Migraine. PMID- 21313170 TI - Low Arterial Pressure. PMID- 21313171 TI - Acute Mastoiditis. PMID- 21313172 TI - The Treatment of Epilepsy by Sodium-Di-Phenyl Hydantionate (Epanutin). PMID- 21313173 TI - Myasthenia Gravis. PMID- 21313174 TI - Chyluria. PMID- 21313175 TI - The Treatment of Carcinoma of the Lip. PMID- 21313176 TI - Cases shown at F.R.C.S. Demonstration. PMID- 21313177 TI - Blood Transfusion by the Continuous Drip Method. PMID- 21313179 TI - The Classification of Jaundice: With details of some of the causes of this condition. PMID- 21313178 TI - Pleural Effusions in Tuberculosis. PMID- 21313180 TI - Septic Infections of the Neck: With special reference to Surgical Anatomy. PMID- 21313181 TI - Foreword: To the Symposium on Focal Sepsis. PMID- 21313183 TI - The Faucial Tonsils and Accessory Sinuses of the Nose in relation to Focal Sepsis. PMID- 21313182 TI - The Teeth as a Source of Focal Sepsis. PMID- 21313184 TI - The Gall-Bladder as a Site of Focal Sepsis. PMID- 21313185 TI - The Bowel as a Focus of Sepsis in Chronic Rheumatic Disease. PMID- 21313186 TI - Focal Sepsis in the Male Uro-Genital Tract. PMID- 21313188 TI - War Injuries of the Chest: General Considerations. PMID- 21313187 TI - The Gynaecological Aspect of Focal Sepsis. PMID- 21313189 TI - Haemothorax. PMID- 21313190 TI - Penetrating Wounds of the Chest. PMID- 21313191 TI - Late Effects of Penetrating Wounds of the Chest. PMID- 21313192 TI - The Syndrome of Traumatic Shock. PMID- 21313193 TI - War Injuries of the Kidney, Ureter, and Urinary Bladder. PMID- 21313194 TI - War Wounds of the Intestines and their Treatment. PMID- 21313195 TI - Gas Gangrene. PMID- 21313196 TI - The Treatment of Wounds of Blood Vessels. PMID- 21313197 TI - Amputations of the Extremities in Cases of War Wounds. PMID- 21313198 TI - Surgery of Deformities Resulting from War Injuries of the Extremities. PMID- 21313199 TI - Non-Perforating Injuries of the Eyeball. PMID- 21313200 TI - Perforating Wounds of the Eyeball with and without a Retained Foreign Body. PMID- 21313201 TI - Injuries of the Orbit. PMID- 21313202 TI - Disturbances of Sight Resulting from Injuries which do not involve the Eyes. PMID- 21313203 TI - Head Injuries in War. PMID- 21313204 TI - War Injuries of Jaws and Face. PMID- 21313206 TI - War Injuries of Peripheral Nerves. PMID- 21313205 TI - War Injuries of the Spine and Spinal Cord. PMID- 21313207 TI - Tetanus. PMID- 21313208 TI - The Mayo Brothers. PMID- 21313209 TI - Observations on Sahli's Haemoglobinometer. PMID- 21313210 TI - The Treatment of Muscular Rheumatism by Injection. PMID- 21313211 TI - Chaulmoogra Oil in the Treatment of Chronic Arthritis. PMID- 21313212 TI - Radium Therapy. PMID- 21313213 TI - The Uses of Lipiodol in Gynaecological Practice. PMID- 21313215 TI - The Irrigation Treatment for Painful Shoulders. PMID- 21313214 TI - Some Dangers in the First Month of Life. PMID- 21313216 TI - Excision of the Breast through Transverse Incisions. PMID- 21313217 TI - Vitamin C. PMID- 21313218 TI - The Vitamin B Complex. PMID- 21313219 TI - Vitamin D. PMID- 21313220 TI - The "Newer" Vitamins. PMID- 21313221 TI - Vitamin A. PMID- 21313222 TI - Summary of the series of Articles on the Vitamins. PMID- 21313223 TI - History of Intravenous Anaesthesia with Six Years' Experience in the use of Pentothal Sodium. PMID- 21313224 TI - The Use of Hypertonic Saline in Surgical Practice. PMID- 21313225 TI - Cancer of the Mouth. PMID- 21313226 TI - Cancer of the Penis. PMID- 21313227 TI - Cancer of the Skin. PMID- 21313228 TI - Repair of the Perineum under Local Anaesthesia. PMID- 21313229 TI - Carcinoma of the Prostate. PMID- 21313231 TI - Carcinoma of the Uterus. PMID- 21313230 TI - Malignant Tumours of the Kidneys. PMID- 21313232 TI - Pneumothorax Mistaken for Heart Disease. PMID- 21313233 TI - Cancer of the Lung. PMID- 21313234 TI - Cancer of Bones. PMID- 21313236 TI - Organisation and Treatment of Air-Raid Casualties. PMID- 21313235 TI - Malignant Disease of the Thyroid Gland. PMID- 21313237 TI - The Use of Specific Prophylactic Measures in the Control of Acute Infectious Diseases. PMID- 21313239 TI - Heart Failure in the Aged: A clinical study. PMID- 21313238 TI - Recent Therapeutic Advances in Surgery. PMID- 21313240 TI - The Progress of Helminthology in the U.S.S.R. PMID- 21313241 TI - Organisation of the Medical Services in the U.S.S.R. PMID- 21313242 TI - Public Health. PMID- 21313243 TI - Doctor and Patient in the Soviet Union. PMID- 21313244 TI - Tuberculosis in the U.S.S.R. PMID- 21313245 TI - Gynaecology and Obstetrics in the U.S.S.R. PMID- 21313247 TI - The Formation of the Anglo-Soviet Medical Committee. PMID- 21313246 TI - Foreword. PMID- 21313248 TI - Soviet Surgery. PMID- 21313249 TI - Cancer of the Oesophagus. PMID- 21313250 TI - Induction of Labour and Trial Labour. PMID- 21313252 TI - Classification of Rheumatism. PMID- 21313251 TI - Notes of Three Cases: Demonstrated at Special M.R.C.P. Classes at the Brompton Hospital. PMID- 21313253 TI - The Virtues and Vices of Sulphapyridine: A Critical Survey. PMID- 21313255 TI - Cardiac Problems in Recruits: An address given to the Norwood Medical Society, October 17, 1941. PMID- 21313254 TI - Some Aspects of Heart Disease in Relation to Rheumatism. PMID- 21313256 TI - Notes on four Surgical Cases. PMID- 21313257 TI - Alteration in Respiratory Rhythm in Surgical Anaesthesia. PMID- 21313258 TI - Medical Cases Demonstrated during a Recent M.R.C.P. Course. PMID- 21313259 TI - The Management of Patients with Chronic Gastric Ulcer. PMID- 21313260 TI - The Allergic Aspects of Urticaria and Angioneurotic Oedema. PMID- 21313261 TI - Practicalities: Anaesthesia in General Practice. PMID- 21313262 TI - Rare Appearance of Clonorchis Sinensis in England. PMID- 21313263 TI - Clinical Page: Reports on Two Cases Seen in General Practice. PMID- 21313264 TI - The Medical Aspects of Injuries of the Chest: (Being a Lecture delivered to the members of Sector 3 of the E.M.S.). PMID- 21313265 TI - Primary Tuberculosis of the Lung and some of its Consequences. PMID- 21313267 TI - Clinical Page. PMID- 21313266 TI - Physiology in Relation to Medical Practice and Therapeutics, Part I. PMID- 21313268 TI - Incontinence of Urine in Women. PMID- 21313269 TI - Treatment of Imperfect Descent of the Testis. PMID- 21313270 TI - The Clinical Study of the Cardio-Vascular System. PMID- 21313272 TI - The Sociopathic Offender. PMID- 21313271 TI - A Case of Infective Poly-Arthritis associated with Chronic Bilateral Bronchiectasis. PMID- 21313273 TI - Simultaneous Occurrence of Herpes Zoster and Varicella: With a Report of Three Cases. PMID- 21313274 TI - The Clinical Study of the Cardio-Vascular System. PMID- 21313275 TI - A Case of Polyradiculoneuritis. A note on the Treatment of Nephrotic Oedema. PMID- 21313276 TI - Backache. PMID- 21313277 TI - Backache from Pelvic Causes. PMID- 21313278 TI - Vitamins and the Milk Standards. PMID- 21313279 TI - The Clinical Study of the Cardio-Vascular System. Part III. PMID- 21313280 TI - Three Cases Illustrating Rare Diseases of the Ileo-caecal Region. PMID- 21313281 TI - Leucorrhoea. PMID- 21313282 TI - Some Recent Advances in the Application of Ante-Natal Care. PMID- 21313283 TI - The Electrocardiograph in the Diagnosis of Cardio-Vascular Diseases. PMID- 21313284 TI - A Case of Endocarditis Lenta with Inconspicuous Symptoms. A Case of Benign Lymphocytic Chorio-meningitis. PMID- 21313285 TI - Tuberculosis of the Knee-Joint. PMID- 21313286 TI - The Technique of Excision of the Internal Semilunar Cartilage. PMID- 21313287 TI - Rehabilitation. PMID- 21313288 TI - Principles of Occupational Therapy in the Treatment of the Injured. PMID- 21313290 TI - Treatment of Minor Injuries of the Ankle. PMID- 21313289 TI - The Treatment of Some of the Cardiac Diseases. PMID- 21313291 TI - Introductory. PMID- 21313292 TI - Statistical Survey. PMID- 21313293 TI - Pathology. PMID- 21313294 TI - Diagnosis and Surgical Treatment. PMID- 21313295 TI - Radiological Investigation. PMID- 21313296 TI - Treatment by the Insertion of Radon Seeds. PMID- 21313298 TI - Symptomatic Treatment. PMID- 21313297 TI - Deep X-ray Treatment. PMID- 21313299 TI - Medical Planning. Part I. PMID- 21313301 TI - Intra-thoracic Tuberculosis in Childhood. PMID- 21313300 TI - Survey of Alimentary Symptoms and Signs in Young Children. PMID- 21313303 TI - Treatment of some of the Cardio-Vascular Diseases. Part II. PMID- 21313302 TI - Neonatal Mortality: British Paediatric Association Report. PMID- 21313304 TI - Surgical Causes of Constipation. PMID- 21313306 TI - Another Rare Tumour of Ileocaecal Origin. PMID- 21313305 TI - Diarrhoea in Adults-Some Causes and their Treatment. PMID- 21313308 TI - Petrol. PMID- 21313307 TI - Treatment of some of the Cardio-Vascular Diseases: Part III. PMID- 21313309 TI - Vomiting. PMID- 21313310 TI - Medical Planning II: "Co-Operation". PMID- 21313311 TI - Electricity and Radiations in Rehabilitation from War Injuries. PMID- 21313313 TI - Surgery in Old Age. PMID- 21313312 TI - The Rehabilitation of Non-Tuberculous Disease and Injury of the Chest. PMID- 21313314 TI - Approach to Old Age. PMID- 21313315 TI - Medical Planning. PMID- 21313316 TI - Medical Planning. PMID- 21313318 TI - Introducing Obstetrics and Gynaecology. PMID- 21313317 TI - Medical Planning III: The Patient. PMID- 21313320 TI - Ante-Partum Haemorrhage. PMID- 21313319 TI - The Difficulties and Dangers of the Multipara. PMID- 21313321 TI - Prolapse. PMID- 21313322 TI - Medical Planning IV: Enterprise. PMID- 21313323 TI - Rehabilitation in a Maxillo Facial and Plastic Centre. PMID- 21313324 TI - Anaesthesia for Abdominal Surgery in Adults. PMID- 21313326 TI - Some Aspects of Local Anaesthesia. PMID- 21313325 TI - Gravity Control in Spinal Anaesthesia. PMID- 21313327 TI - Medical Planning Evolution or Revolution? PMID- 21313328 TI - Medical Planning V. PMID- 21313329 TI - Treatment of Open Fractures. PMID- 21313330 TI - The Treatment of Osteoarthritis by Intra-Articular Injection of Lipiodol and Gomenol. PMID- 21313331 TI - Glandular Fever. PMID- 21313332 TI - Wellcome Museum of Medical Science Wellcome Historical Medical Museum. PMID- 21313333 TI - Medical Planning. PMID- 21313334 TI - Post-Partum Haemorrhage. PMID- 21313335 TI - Ovarian Dysfunction. PMID- 21313336 TI - The Difficulties and Dangers of the Primiparous Woman. PMID- 21313337 TI - The Anatomy and Physiology of the Foot. PMID- 21313338 TI - The Diagnosis and Treatment of the Common Causes of Pain in the Foot. PMID- 21313339 TI - Painful Feet from the Physician's Point of View. PMID- 21313340 TI - Medical Planning. Part VIII. The Post-Graduate. PMID- 21313341 TI - The Use of the Ophthalmoscope in Practice. PMID- 21313342 TI - Ophthalmic Emergencies in General Practice. PMID- 21313344 TI - Disease and Prognosis in Old Age. PMID- 21313343 TI - The Place of Orthoptics in Modern Ophthalmological Practice. PMID- 21313345 TI - The Pathology of Renal Tuberculosis. PMID- 21313346 TI - Healed Microscopic Foci of Tuberculosis in the Kidney. PMID- 21313347 TI - The Tuberculous Kidney; Diagnosis and Prognosis. PMID- 21313348 TI - Correspondence. PMID- 21313349 TI - An Appreciation. PMID- 21313350 TI - Blood Agglutinins in Relation to Blood Transfusion. PMID- 21313351 TI - The Application of Present Knowledge about the Rh Factor. PMID- 21313352 TI - The Medico-Legal Importance of the Blood Groups. PMID- 21313353 TI - Tuberculosis and the Rheumatic Diseases: Some Analogous Medical, Social and Economic Aspects. PMID- 21313354 TI - The Clinical Pathology of Gall-Bladder Disease. PMID- 21313355 TI - Some Aspects of the Clinical Diagnosis of Acute Affection of the Gall-Bladder and Bile Ducts. PMID- 21313357 TI - The Surgery of Gall-Bladder Disease. PMID- 21313356 TI - The Clinical Diagnosis of Chronic Gall-Bladder Disease. PMID- 21313358 TI - Anaesthesia in Gall-Bladder Surgery. PMID- 21313359 TI - Meningoencephalitis; A Diagnostic Survey. PMID- 21313360 TI - The Cerebro-Spinal Fluid in Meningitis. PMID- 21313362 TI - Suppurative Meningitis. PMID- 21313361 TI - The Anatomy of the Meninges. PMID- 21313363 TI - Encephalitis. PMID- 21313364 TI - Acute Aseptic Meningitis. PMID- 21313365 TI - Various Manifestations of Non-specific Arachnoiditis of indefinite aetiology. PMID- 21313366 TI - Cysticercosis. PMID- 21313367 TI - Surgery in Relation to Meningitis. PMID- 21313368 TI - The Care of the Dying. PMID- 21313369 TI - A Plea for the extended use of Unna's Paste Bandages. PMID- 21313370 TI - Medical Sickness Annuity and Life Assurance Society, Ltd. PMID- 21313371 TI - The Diagnosis of Cerebrospinal Fever: (Meningococcal Meningitis) Incorporating the Differential Diagnosis of Meningitis. PMID- 21313372 TI - Introductory. PMID- 21313373 TI - Mass Radiography: A new Weapon against Tuberculosis. PMID- 21313374 TI - Mass Radiography. PMID- 21313375 TI - The Problem of Early Diagnosis in Pulmonary Tuberculosis. PMID- 21313377 TI - The Future of Post-Graduate Education. PMID- 21313376 TI - Selective Mass Radiography: A Review of the Southwark Scheme. PMID- 21313378 TI - Neurological Disorders in relation to Pregnancy. PMID- 21313379 TI - Disorders of the Endocrine Glands in Relation to Pregnancy. PMID- 21313381 TI - Heart Disease in Pregnancy. PMID- 21313380 TI - Blood Disorders in Relation to Pregnancy. PMID- 21313383 TI - The White Paper. PMID- 21313382 TI - Correspondence. PMID- 21313384 TI - Post-Graduate Education. PMID- 21313385 TI - Venereal Disease in Relation to Pregnancy. PMID- 21313386 TI - Pulmonary Tuberculosis and Pregnancy. PMID- 21313387 TI - Carcinoma in Relation to Pregnancy. PMID- 21313388 TI - Vomiting in the New-Born. PMID- 21313389 TI - Some Recent Advances in Chemotherapeutic Drugs. PMID- 21313391 TI - The Endocrine Treatment of Sterility. PMID- 21313390 TI - The White Paper. PMID- 21313392 TI - Uterotubal Insufflation and Hysterosalpinography. PMID- 21313394 TI - A Note on the Problem of Subfertility. PMID- 21313395 TI - The Organisation of a Sterility Service within a Family Planning Association Clinic. PMID- 21313393 TI - Investigation and Treatment of Sterility in the Male. PMID- 21313397 TI - The Clinical Pathology of Pancreatic Disease (excluding Diabetes). PMID- 21313396 TI - The Diagnosis of Chronic Pancreatitis. PMID- 21313398 TI - Diagnosis and Treatment of Tumours of the Pancreas. PMID- 21313399 TI - Acute Pancreatitis. PMID- 21313400 TI - Oil Acne. PMID- 21313401 TI - The Anatomy, Physiology and Surgical Consideration of the Oesophagus. PMID- 21313403 TI - Radiology in Diseases of the Oesophagus. PMID- 21313402 TI - Extramucous Oesophagocardiomyotomy in Cardiospasm. PMID- 21313404 TI - The Surgical Treatment of Carcinoma of the Oesophagus. PMID- 21313405 TI - Carcinoma in the Upper Third of the Oesophagus. PMID- 21313406 TI - Life Assurance-Some Medical Aspects. PMID- 21313407 TI - The Examination for Life Assurance. PMID- 21313408 TI - Life Assurance-Some Underwriting Aspects. PMID- 21313409 TI - On Blood Pressure. PMID- 21313410 TI - Developmental Abnormalities of Cervical Vertebrae in a Case of Generalised Neurofibromatosis. PMID- 21313411 TI - The Anatomy and Physiology of Micturition and the Effect of various Neurological Disorders upon this Function. PMID- 21313412 TI - Acute and Chronic Retention. PMID- 21313414 TI - Disorders of Micturition in Childhood. PMID- 21313413 TI - Incontinence of Urine in Women. PMID- 21313415 TI - The Use of Stilboestrol in the Treatment of Carcinoma of the Prostate. PMID- 21313416 TI - Chronic Rheumatic Diseases: With Special Reference to Chronic Arthritis a Survey Based on 1,000 Cases. PMID- 21313417 TI - Management of the Pneumonias in Adults. PMID- 21313418 TI - Diagnosis and Treatment of Pneumonia in Infancy and Childhood. PMID- 21313420 TI - Sulphonamide Chemotherapy. PMID- 21313421 TI - The Art of Orthopaedics. PMID- 21313419 TI - Pneumonia in Old Age. PMID- 21313423 TI - Surgery in Thyrotoxicosis. PMID- 21313422 TI - Sclerotic Therapy in Practice. PMID- 21313424 TI - The Heart in Thyroid Dysfunction. PMID- 21313426 TI - Chronic Rheumatic Diseases. (Part II). PMID- 21313425 TI - The Thyroid in Relation to Other Endocrine Glands. PMID- 21313427 TI - Sclerotic Therapy in Practice. (Part II): Varicose Veins. PMID- 21313428 TI - The Art of Orthopaedics. (Part II). PMID- 21313429 TI - Sclerotic Therapy in Practice. Part III: Haemorrhoids... Their Treatment by Injection. PMID- 21313430 TI - The Art of the Orthopaedics. Part III. PMID- 21313431 TI - Diagnosis of Acute Intestinal Obstruction. PMID- 21313432 TI - Diagnosis and Surgery of Chronic Intestinal Obstruction: Including Acute on Chronic Obstruction. PMID- 21313433 TI - Intestinal Obstruction in Childhood. PMID- 21313434 TI - Radiological Investigation of Intestinal Obstruction. PMID- 21313435 TI - Physiological Mechanisms in Intestinal Obstruction and its Treatment. PMID- 21313436 TI - The Therapy of Shock: Some Lessons from Military Surgery. PMID- 21313437 TI - First Aid Treatment of Burns. PMID- 21313438 TI - Notes on the Burn Creams. PMID- 21313439 TI - The Care of the Burned Patient. PMID- 21313440 TI - Fractures-Part I Principles of Diagnosis and Treatment. PMID- 21313442 TI - A Statistical Study of 1,000 Cases of Chronic Rheumatism-Part III. PMID- 21313441 TI - Sclerotic Therapy in Practice-Part IV: The Injection Treatment of Hydrocele and Some Other Conditions. PMID- 21313443 TI - A Review on Pruritus Ani. PMID- 21313444 TI - Surgical Closure of the Patent Ductus Arteriosus. PMID- 21313445 TI - Fractures-Part II. The Upper Limb-Diagnosis and Treatment. PMID- 21313446 TI - The Art of Orthopaedics. Part IV: Injuries and Diseases of the Shoulder and Elbow Joints. PMID- 21313447 TI - Chronic Rheumatic Diseases-Part IV: A Statistical Study of 1,000 Cases of Chronic Rheumatism. PMID- 21313448 TI - Medical Aspects of Chronic Peptic Ulcer. PMID- 21313449 TI - X-Ray Appearances of Gastric, Duodenal and Jejunal Ulcer. PMID- 21313450 TI - Anaesthesia for Gastric Operations. PMID- 21313451 TI - Surgical Treatment of Chronic Gastric and Duodenal Ulcer. PMID- 21313453 TI - The Technique of Thyroidectomy: Recent Advances in the Management of Cases. PMID- 21313452 TI - The Complications of Gastric and Duodenal Ulcer. PMID- 21313454 TI - Clinical Observations on Malaria. PMID- 21313456 TI - Congenital Heart Disease. PMID- 21313455 TI - The Art of Orthopaedics. Part V. Diagnosis of Diseases of the Knee Joint. PMID- 21313458 TI - Sterility in Practice: An Editorial Commentary. PMID- 21313457 TI - Fractures, Part III Fractures of the Lower Limb. PMID- 21313459 TI - Rontgen's Jubilee. PMID- 21313461 TI - Correspondence. PMID- 21313460 TI - Two Truants from Medicine. PMID- 21313463 TI - Hysteria. PMID- 21313462 TI - The Library in a Research Organisation. PMID- 21313465 TI - To Clot or Not to Clot. PMID- 21313464 TI - The Limbless. PMID- 21313466 TI - The Doctor and the Nurse. PMID- 21313467 TI - The Young and the Old Patient. PMID- 21313468 TI - The Doctor and the Nurse. PMID- 21313469 TI - The Nurse and the Doctor. PMID- 21313470 TI - Off with her head. PMID- 21313471 TI - Secret Remedies. PMID- 21313472 TI - The Doctor and the Nurse. PMID- 21313473 TI - Internationalism. PMID- 21313474 TI - Portal Hypertension. PMID- 21313476 TI - Annual Stock Taking. PMID- 21313475 TI - Coarctation of the Aorta. PMID- 21313477 TI - Bronchogenic Carcinoma. PMID- 21313478 TI - The Pathology of Tumours. PMID- 21313479 TI - Peptic Ulceration. PMID- 21313481 TI - The New Alchemy. PMID- 21313480 TI - Peripatetics. PMID- 21313482 TI - Round Trip. PMID- 21313483 TI - Ophthalmological Society of the United Kingdom. PMID- 21313484 TI - Training the Doctor. PMID- 21313485 TI - A Visit to Holland. PMID- 21313486 TI - Aid for the Deaf. PMID- 21313487 TI - Delay in the Sun. PMID- 21313488 TI - Artificial Limbs. PMID- 21313489 TI - Anaesthesia. PMID- 21313490 TI - Rheumatoid Arthritis. PMID- 21313491 TI - Behind the Nylon Curtain. PMID- 21313492 TI - Georgia Warm Springs Foundation. PMID- 21313493 TI - Radioactive Dye in Localization of Brain Tumours. PMID- 21313494 TI - Sir William Hale-White, K.B.E. PMID- 21313495 TI - Sir William Osler: A Retrospect. PMID- 21313496 TI - Sir William Broadbent, Bart. PMID- 21313497 TI - 'Compound E'. PMID- 21313499 TI - Robert Lawson Tait. PMID- 21313498 TI - William Smellie. PMID- 21313500 TI - Foreword. PMID- 21313502 TI - Sir Gordon Gordon-Taylor, K.B.E., C.B., F.R.C.S. PMID- 21313501 TI - The Bladder in Paraplegia. PMID- 21313504 TI - A Plea for Barabbas. PMID- 21313503 TI - William Cayley, M.D., F.R.C.P. PMID- 21313505 TI - The Specific Treatment of Typhoid Fever. PMID- 21313507 TI - The Aetiology of Disseminated Sclerosis. PMID- 21313506 TI - Cardiospasm. PMID- 21313508 TI - An Important Physical Sign. PMID- 21313510 TI - Neurological Number. PMID- 21313509 TI - Radiology. PMID- 21313511 TI - The Pathology of Intracranial Tumours. PMID- 21313512 TI - Viral Infections of the Human Nervous System: Classification and General Considerations. PMID- 21313513 TI - Tumours of the Frontal Lobe. PMID- 21313514 TI - Pituitary, Pineal and Third Ventricle Tumours. PMID- 21313515 TI - Cerebral Angiography. PMID- 21313516 TI - The Orthopaedic Rehabilitation of a Patient after Excision of a Cerebral Tumour. PMID- 21313517 TI - Spastic Paraplegia in Middle Age. PMID- 21313518 TI - Sir Victor Horsley. PMID- 21313519 TI - Physical Medicine. PMID- 21313520 TI - Virus Pneumonia. PMID- 21313521 TI - Acromegaly and Gigantism: Including a New Syndrome in Childhood. PMID- 21313522 TI - Diabetes Insipidus. PMID- 21313523 TI - The Modern Concept of Muscle Testing. PMID- 21313524 TI - Electromyography as an Aid to Diagnosis. PMID- 21313525 TI - Case Report: Facial Nerve Palsy. PMID- 21313526 TI - A Recurring Mass in the Right Iliac Fossa. PMID- 21313527 TI - Revolver Bullet in the Cauda Equina: With a Note on the Ballistics. PMID- 21313528 TI - Weighing the Odds. PMID- 21313530 TI - Cholera in Egypt. PMID- 21313529 TI - Due Skill and Care. PMID- 21313531 TI - The Nursing Situation. PMID- 21313532 TI - The Electron Microscope. PMID- 21313533 TI - Protection of Surgeons. PMID- 21313534 TI - The First International Exhibition of Medical Photography. PMID- 21313535 TI - Controlled Hypertension. PMID- 21313537 TI - Widening Horizons. PMID- 21313536 TI - Radioactive Isotopes in Medicine. PMID- 21313538 TI - A World Health Service? PMID- 21313540 TI - Peptic Ulcer. PMID- 21313539 TI - Tuberculosis (Attested Herds) Scheme, 1950. PMID- 21313541 TI - English Domestic Medicine in the Eighteenth Century-III: From the Letters of Josiah Wedgwood. PMID- 21313542 TI - Film on Oxygen Therapy. PMID- 21313544 TI - The Care of the Aged. PMID- 21313543 TI - Telling the Relatives. PMID- 21313545 TI - Correspondence. PMID- 21313547 TI - Correspondence. PMID- 21313546 TI - Correspondence. PMID- 21313548 TI - The Effect of Potassium and Calcium on the Electrocardiogram. PMID- 21313549 TI - Festival Year. PMID- 21313550 TI - The Present Status of Chemotherapeutic and Antibiotic Drugs. PMID- 21313551 TI - Correspondence. PMID- 21313552 TI - The Treatment of Acute Leukaemia. PMID- 21313554 TI - Deep Pelvic Retractor. PMID- 21313553 TI - Dissecting Aneurysms of the Aorta. PMID- 21313555 TI - C.S.F. Pressure during Compression of the Jugular Veins. PMID- 21313556 TI - Aspiration of Stomach Contents during Anaesthesia. PMID- 21313557 TI - Mepacrine and Lupus Erythematosus. PMID- 21313558 TI - Treatment of Abscesses. PMID- 21313560 TI - Ruptured Bladder in a Child. PMID- 21313559 TI - The Treatment of Hyperthyroidism. PMID- 21313562 TI - The Nation Mourns. PMID- 21313561 TI - The Specialist. PMID- 21313563 TI - Letters to the Editor. PMID- 21313564 TI - Letters to the Editor. PMID- 21313565 TI - The Bone Bank. PMID- 21313566 TI - Ingenuity. PMID- 21313567 TI - The British Orthopaedic Scene. PMID- 21313568 TI - Medical Olympians. PMID- 21313569 TI - Travel. PMID- 21313571 TI - Pre-Registration House Officers. PMID- 21313570 TI - A College of General Practice. PMID- 21313572 TI - 'Plastics'. PMID- 21313573 TI - Electrolytes. PMID- 21313575 TI - The Changing Face of Medicine. PMID- 21313574 TI - A College of General Practice. PMID- 21313576 TI - A Preliminary Report. PMID- 21313578 TI - The Adrenal Gland. PMID- 21313577 TI - The Effect of Liver Supplement on the Growth of Children. PMID- 21313580 TI - The Cost of the Health Service. PMID- 21313579 TI - Request for Reprints concerning Stress and the Adaptive Hormones. PMID- 21313581 TI - Correspondence. PMID- 21313582 TI - The Coronation. PMID- 21313584 TI - The Radical Surgery of Cancer. PMID- 21313583 TI - The Postgraduate Student from the Dominions or Colonies. PMID- 21313585 TI - Chemotherapy of Virus Infections. PMID- 21313586 TI - Diseases of the Blood. PMID- 21313587 TI - Peptic Ulcer. PMID- 21313588 TI - The New Mimics. PMID- 21313589 TI - Follow-up Clinics. PMID- 21313590 TI - Clinico-Pathological Conference-No. 22: The borderline of lupus erythematosus disseminatus. PMID- 21313591 TI - Introductory. PMID- 21313592 TI - Hypothermia. PMID- 21313594 TI - The Importance of Sleep. PMID- 21313593 TI - Specialization. PMID- 21313595 TI - A Doctor's Leisure. PMID- 21313596 TI - An Open Mind. PMID- 21313597 TI - Fibrocystic Disease of the Pancreas in Adolescence. PMID- 21313598 TI - The College of General Practitioners. PMID- 21313599 TI - Applying for Any Appointment. PMID- 21313600 TI - Obliterative Arterial Disease. PMID- 21313601 TI - The Acute Abdomen. PMID- 21313602 TI - The Lay Press and Medical Matters. PMID- 21313603 TI - The Early Diagnosis of Carcinoma. PMID- 21313604 TI - Panel Discussions. PMID- 21313605 TI - Foreign Bodies in Surgery. PMID- 21313606 TI - Volunteers. PMID- 21313607 TI - Registrars in Teaching and Non-Teaching Hospitals. PMID- 21313608 TI - The Letters after a Doctor's Name. PMID- 21313609 TI - The Exchange Fellowship. PMID- 21313610 TI - Carcinoid Tumours. PMID- 21313611 TI - The New Pharmacy. PMID- 21313612 TI - A Symptom or a Diagnosis. PMID- 21313613 TI - Antibiotic Resistant Organisms. PMID- 21313614 TI - Diseases of the Liver. PMID- 21313615 TI - Arteriography. PMID- 21313616 TI - The Retirement of Miss Worth. PMID- 21313618 TI - The Aetiology of Atherosclerosis. PMID- 21313617 TI - The Medical Congress. PMID- 21313619 TI - The Use of Hospital Beds. PMID- 21313620 TI - The Thyroid. PMID- 21313622 TI - Fragmentation in Medical Education. PMID- 21313623 TI - Open Heart Surgery. PMID- 21313624 TI - Hypothermia. PMID- 21313625 TI - Tobacco Smoking. PMID- 21313626 TI - Genito-Urinary Surgery. PMID- 21313628 TI - Doctor or Mister. PMID- 21313627 TI - Adrenalectomy or Hypophysectomy for Advanced Carcinoma of the Breast. PMID- 21313630 TI - The First Years of the National Health Service. PMID- 21313629 TI - The Surgery of Duodenal Ulceration. PMID- 21313632 TI - Cerebral Vascular Disease. PMID- 21313631 TI - Medical Libraries. PMID- 21313633 TI - Man-made Environmental Hazards. PMID- 21313634 TI - The Antibiotic Resistant Staphylococcus. PMID- 21313635 TI - Diseases of the Rectum and colon. PMID- 21313636 TI - The Languages of Science. PMID- 21313637 TI - Radiation Hazards. PMID- 21313638 TI - Pulmonary Function in Bronchial Asthma. PMID- 21313640 TI - The Use and Misuse of Drugs in Symptomatic Treatment of the Allergic Nose. PMID- 21313639 TI - The Place of Allergy in Asthma. PMID- 21313641 TI - Cell Counts. PMID- 21313642 TI - The Diagnosis and Management of Haemophilia and Christmas Disease. PMID- 21313643 TI - Stenosis of the Superior Mesenteric Artery. PMID- 21313645 TI - The Kidney. PMID- 21313644 TI - Thrombosis of the Inferior Vena Cava: Case Report. PMID- 21313646 TI - Torsion of the Appendix. PMID- 21313647 TI - Bilateral Polycystic Ovaries. PMID- 21313648 TI - Chronic Otitis Media. PMID- 21313649 TI - The Birth of a Medical Journal. PMID- 21313650 TI - The Surgery of the Thyroid Gland. PMID- 21313651 TI - 3. The Treatment of Amoebic Dysentery. PMID- 21313652 TI - Agadir. PMID- 21313653 TI - The Vascular Pattern of the Anterior Muscles of the Forearm in Adults in Relation to Volkmann's Ischaemic Contracture. PMID- 21313654 TI - Respiratory Capacity following Tubal Insufflation. PMID- 21313655 TI - A Case of Renal Asthma. PMID- 21313656 TI - A Case of Crush Injury of the Chest: Department of Surgery, Western Infirmary, Glasgow. PMID- 21313657 TI - Artificial Emphysema in the Diagnosis of Surgical Conditions of the Trunk. PMID- 21313658 TI - Two Cases of Tuberose Sclerosis: Royal Alexandra Hospital for Sick Children, Brighton. PMID- 21313659 TI - A Study of Liver Disorder in Ulcerative Colitis. PMID- 21313660 TI - Alimentary Granulomata and the Immune Response. PMID- 21313661 TI - Neurological Disorders Associated with Malignant Disease. PMID- 21313663 TI - Cancer Research in the Far East. PMID- 21313662 TI - Chemotherapy in Malignant Disease: The Present Position. PMID- 21313664 TI - The Diagnosis and Treatment of Cerebrovascular Disease. PMID- 21313665 TI - Portable Equipment for Intensive Therapy. PMID- 21313666 TI - Sudden Death in Infancy: Royal Alexandra Hospital for Sick Children, Brighton. PMID- 21313667 TI - The Operative Closure of Ventricular Septal Defects in Childhood. PMID- 21313668 TI - Surgery of the Aortic Valve. PMID- 21313669 TI - The Motility of the Small Intestine. PMID- 21313670 TI - Protein-Losing Gastroenteropathy. PMID- 21313671 TI - Steatorrhoea: Held at the Western Infirmary, Glasgow. PMID- 21313672 TI - The Prognosis of Crohn's Disease of the Small Intestine. PMID- 21313673 TI - A Case of Werner's Syndrome. PMID- 21313674 TI - Postgraduate Medical Education in New England. PMID- 21313676 TI - Some Aspects of Radiological Investigation of the Heart and Great Vessels. PMID- 21313675 TI - Splitting of the Glomerular Basement Membrane. PMID- 21313677 TI - Congenital Absence of Pain. PMID- 21313679 TI - Traumatic Ischaemia: Held at the Western Infirmary, Glasgow. PMID- 21313678 TI - Liver Disease in Infancy: Held at the Royal Alexandra Hospital for Sick Children, Brighton. PMID- 21313680 TI - Ruptured Adrenal Cyst. PMID- 21313681 TI - Bronchial Carcinoma Presenting as Cardiac Tamponade. PMID- 21313682 TI - Subphrenic Suppuration and its Complications. PMID- 21313683 TI - Carcinoma of the Male Breast: A Case Report and Review of the Literature. PMID- 21313684 TI - Bilirubin Metabolism. PMID- 21313685 TI - Some Endocrine Changes in Liver Disease. PMID- 21313686 TI - The Activity of Malignant Tumours and Response to Therapeutic Agents, Studied by Continuous Records of Radioactive Phosphorus Uptake. PMID- 21313687 TI - The Diagnosis and Treatment of Malignant Melanoma of the Skin. PMID- 21313688 TI - Life from a Couvelaire Uterus. PMID- 21313690 TI - Benign Ulcer of the Greater Gastric Curvature Complicating Steroid Therapy. PMID- 21313689 TI - Infectious Diseases: Annual Review of Significant Publications. PMID- 21313691 TI - The Management of Head Injuries. PMID- 21313692 TI - Cardiac Arrest. PMID- 21313693 TI - Cardiac Arrhythmias. PMID- 21313694 TI - Myocardial Infarction. PMID- 21313695 TI - Pulmonary OEdema. PMID- 21313696 TI - The Diagnosis and Management of Pulmonary Embolism. PMID- 21313697 TI - The Management of Peripheral Arterial Emboli. PMID- 21313698 TI - The Treatment of Cardiac Emergencies in Infancy. PMID- 21313699 TI - Observations on Digitalis Intoxication-A Plea. PMID- 21313700 TI - The Glasgow Postgraduate Medical Television Programme. PMID- 21313701 TI - Primary Chronic Inflammation of the Cystic Duct. PMID- 21313702 TI - Primary Amyloidosis. PMID- 21313703 TI - Acute Thyro-Parathyrotoxicosis. PMID- 21313704 TI - Hepatic Clearance and Lm of Galactose in Normal and Cirrhotic Subjects. PMID- 21313705 TI - Ivory Exostosis of the Skull. PMID- 21313706 TI - Hypoplastic Anaemia-An Unusual Complication of Chlordiazepoxide Hydrochloride Therapy. PMID- 21313707 TI - A Metastatic Deposit in the Patella from a Carcinoma of the Breast. PMID- 21313708 TI - Hyperthyroidism Complicated by Periodic Paralysis. PMID- 21313709 TI - Histopathology of Voluntary Muscle. PMID- 21313710 TI - Some Biochemical Aspects of the Myopathies. PMID- 21313711 TI - Muscular Dystrophy and Related Disorders. PMID- 21313712 TI - The Non-Dystrophic Myopathies. PMID- 21313713 TI - Myasthenia Gravis. PMID- 21313714 TI - Dermatomyositis following Treatment of Cancer. PMID- 21313717 TI - Splenic Mechanisms in the Pathogenesis of Anaemia. PMID- 21313716 TI - The Sideroblastic Anaemias. PMID- 21313715 TI - Thalassaemia. PMID- 21313718 TI - The Diagnostic Value of Leukocyte Stains in Leukaemias. PMID- 21313719 TI - The Treatment of Acute Leukaemia in Adults with Cyclophosphamide. PMID- 21313720 TI - Haemolysis in Malignant Blood Diseases. PMID- 21313721 TI - Spontaneous Rupture of a Normal Spleen in a Haemophiliac. PMID- 21313722 TI - Spontaneous Rupture of the Spleen in Infectious Mononucleosis Presenting in the Casualty Department. PMID- 21313723 TI - Adolescent Coxa Vara. PMID- 21313724 TI - Achalasia of the Cardia. PMID- 21313725 TI - A Trial of Clorindione-A Long Acting Oral Anticoagulant. PMID- 21313726 TI - Unrepaired meniscal tears associated with knee osteoarthritis. Study is part of an ongoing effort to prevent and treat OA, which has become a global burden, according to the World Health Organization. PMID- 21313727 TI - Increased statin dose could mean a 22% decrease in vascular events. Even patients with low baseline LDL can benefit from increased doses. PMID- 21313728 TI - Update: non-invasive screening test for colon cancer; colonoscopy refined. These new findings may improve accuracy and subsequent treatment for colon cancer; some experts disagree. PMID- 21313729 TI - Extroverted personality can mask signs of depression. Research shows that friends and relatives of outgoing and agreeable people often miss symptoms of mood disorders. PMID- 21313730 TI - Rate of decline in kidney function affects risk of death. It's important to monitor trends in your kidney function over time, not just view a snapshot of your kidneys' status today. PMID- 21313731 TI - What can you tell me about red yeast rice? I've heard a lot about its cholesterol-lowering benefits in the media, but I'm reluctant to take it because I think it falls into the supplement category and thus is unregulated. PMID- 21313732 TI - [The use of the stereomicroscopy in the forensic medicine practice]. AB - INTRO: In everyday medico-legal practice the situations occur when it is necessary to magnify something and bring it up to the level of magnifying glass and closer to the eye of the examiner, and this way to determine the character of wounds, the way and angle of the attack, vicinity of the instrument of assault and where necessary also to determine the option of other person being present and causing the injury mentioned above. One of the options which enables the forensic pathologist to evaluate the case is the stereomicroscopic examination. It can be done at the place of the autopsy being performed (in vivo) and also in a laboratory (in vitro) after taking samples. OBJECTIVE: The objective of the work is to present methodically quite simple, for time, space and finances not too demanding a method, the results of which is possible to apply in medico-legal practice. METHODS: The work provides the inside of the cases selected by the author in which the stereomicroscopy has been used as one of the examination methods. The clothing of the victim was examined where the victim suffered thoracic injury caused by gunshot in one case, and the skin and parietal bone in the second case of gunshot injury of the head. Furthermore the appearance of stabbing wounds to the skin was investigated with the identification of angles, of the residue of the paint of a motor vehicle on the clothing of a female pedestrian; and the plant seeds obtained from the crime scene which were found on the body of the victim namely in the head wounds. RESULTS: By further investigations into these cases other options were discovered as to the next more detailed examinations of the cases and the confirmation of the diagnosis. There is a certain value in the photo documentation which was made with every case. CONCLUSION: Stereomicroscopic examination is a suitable method by means of which it is possible to follow all the morphological findings which the forensic pathologist has to deal with in his work. It significantly broadens the knowledge spectre and the substance and the meaning of the autopsy as such, i. e. it supports the process of determination of the cause of death and the circumstances of the death. It is a simple method which has a great potential to become one of the major investigation methods. The author is the first to present the results of using of the stereomicroscopy in our conditions. This method is not even often used abroad. PMID- 21313733 TI - [Another mechanism of decollement]. AB - The cause of decollement is usually considered to be tangential brute blunt force impacting the body surface especially in case of hitting or running-over injury of the pedestrian's body by a car. The term rolling effect or rolling mechanism is used as well. The dissociation of tissue layers with other epiphenomenon occurs. The presented group of 152 decollement determined in 103 autopsy cases during the 4 years period comprises the observation of decollement of different etiology of the injuries (traffic accidents, falls from the high, compression of the torso); in the traffic accidents the occurrence in various participants of the traffic, not only in the case of the collision of the pedestrians with various traffic vehicles, but also in drivers of various traffic vehicles, and fellow-travelers as well. The topic, the localization, the content, the extent, and vital reaction and combination injuries were followed-up. According to the variability of the injury etiology, not restricted to the traditional conception of the decollement mechanism, it is obvious that the passed on rule by far is not covering the whole content of this concept. We didn't find any alternative interpretation of until now presented mechanism in the literature. The medical literature focuses mostly on the clinical aspect of this injury. In this paper, the biomechanics of the decollement origin also in case of the tissue compression by the pressure applied perpendicularly to the body surface, the dependences on physical properties of the actively or passively affecting object, the relevance of the ratio of the tissue structures compression in one direction and transversal dilation in other two directions according to the Poisson's constant, the question of tangential factor of the force in case of vertical falling on the horizontal plane, and biomechanical relations in case of body landing on an oblique surface are discussed. The mechanism of decollement is more complex as presented until now. The forensic interpretation of findings should reflex the above-mentioned facts. PMID- 21313734 TI - [IgG4-related systemic sclerosing disease: a review]. AB - IgG4-related systemic sclerosing disease (SSD) is a multisystemic condition characterized by an increased number of IgG4-producing plasma cells which occurs mainly in older men. SSD involves particularly pancreas, hepatobiliary system, salivary glands and retroperitoneum. Microscopically, the findings include lymphoplasmacytic inflammation, fibrosis and vascular changes in the form of obliterative phlebitis. Using immunohistochemistry, an increased number of IgG4 positive plasma cells might be detected in affected tissues. Since SSD frequently mimicks a malignancy both clinically and radiologically, this inflammatory sclerosing condition should be considered in the differential diagnosis of neoplastic and/or pseudoneoplastic lesions. PMID- 21313735 TI - [Muir-Torre syndrome--a phenotypic variant of Lynch syndrome]. AB - Muir-Torre syndrome (MTS) represents an autosomal dominantly inherited condition and is considered a phenotypic variant of the more common hereditary nonpolyposis colorectal cancer syndrome (HNPCC), or Lynch syndrome. MTS combines at least one cutaneous neoplasm with sebaceous differentiation (e.g. sebaceoma, sebaceous adenoma, and sebaceous carcinoma), and at least one visceral malignancy. MTS is a genetic disorder caused by a germline mutation in one of the DNA mismatch repair (MMR) genes. Tumors in MTS patients are characteristically associated with the loss of MMR protein expression and/or microsatellite instability (70%). Patients who are suspected to have MTS/Lynch syndrome are often identified by dermatologists, dermatopathologists/pathologists, gastroenterologists and gynecologists. If MTS is suspected on a clinicopathological ground, necessary additional laboratory investigations should be performed only in specialized pathological departments providing immunohistochemistry and molecular biologic analysis service. PMID- 21313736 TI - [Lymphatic system: morphology and pathology update]. AB - The lymphatic system is crucial for the maintenance of tissue fluid balance, immune surveillance, and fatty acids absorption in the intestine. The lymphatic vessels are also involved in the pathogenesis of tumor metastasis, lymphedema, and various inflammatory processes. Recently, several markers specific for lymphatic endothelium were found. Progress in the field of lymphatic growth factors and their receptors, and molecular lymphatic biology has helped to understand better the lymphatic vasculature. This review summarizes the updates on lymphatic system research and possible applications in routine pathological diagnostics. PMID- 21313737 TI - [What is your diagnosis? Multilocular mesothelial inclusion cyst (MMIC) of the aorta]. PMID- 21313738 TI - [The pathologist should not be forced to work as a forensic physician]. PMID- 21313739 TI - [Development of the control unit and power source for an implantable assisted circulation pump]. PMID- 21313740 TI - [An indirect measurement system for controlling rotor blood pumps]. PMID- 21313741 TI - [Bearing units of an axial blood pump: design and triboengineering features]. PMID- 21313742 TI - [Bench tests of an implantable axial blood pump]. PMID- 21313743 TI - [Experimental determination of conditions for the existence of a bimodal temporal distribution of the laser pulse passing through the homogeneous layer of a high scattering biological medium]. PMID- 21313744 TI - [A programmable teaching unit for Renart-200 hemodialysis apparatus]. PMID- 21313745 TI - [Possibilities of medical application of the laser nanoengineering method]. PMID- 21313746 TI - [Rotor pumps for artificial and assisted circulation]. PMID- 21313747 TI - [Age-related changes in the level of serum bone markers in healthy children]. AB - Age-related changes in the blood level of bone metabolic markers were compared in healthy children living in different geographical regions. The absolute value of carboxy-terminal telopeptide of type 1 collagen type 1 (beta-CrossLaps) and that of total procollagen type 1 amino-terminal propeptide (PINP) were found to depend on living conditions and the nature of changes in the serum markers of bone metabolism was related to the processes of natural growth and development in children. A child's individual growth curve can be used to identify target groups for the prevention of osteopenia. PMID- 21313748 TI - [Content of epidermal growth factor in biosubstrates and macrophage count in defect healing in children and adolescents with duodenal ulcer disease]. AB - The concentrations of epidermal growth factor (EGF) in saliva, gastric juice, and blood and those of macrophages in mucosal biopsy specimens were determined in children with duodenal ulcer disease. The maximum level of EGF was noted in the saliva. There were unidirectional positive changes in the levels of EGF and macrophages during ulcerative defect healing. PMID- 21313749 TI - [Clinical and laboratory criteria for diagnosis in antiphospholipid syndrome: what is it important for a practitioner to know (a lecture)]. AB - The antiphospholipid syndrome (APS) is antibody-induced thrombosis, whose diagnostic basis is the obligatory presence of serological markers along with clinical manifestations. Its laboratory markers are antiphospholipid antibodies (aPAs), the highest informative value has been proven for lupus anticoagulant (LA), cardiolipin antibodies, fl-glycoprotein 1. LA should be determined at a laboratory in accordance with the recommendations of the International Society on Thrombosis and Hemostasis. Obstetric abnormality in APS should be regarded as a thrombotic complication and its management in this case does not differ from that and prevention of thrombosis, aPAs may be detectable in various illnesses, but their blood presence is not an indication for immunosuppressive therapy. The paper describes a case of primary APS in a female patient. PMID- 21313750 TI - [Platelet structure and functions (a review of literature). Part 1]. AB - The paper reviews literature updates on the organization and specific features of megakaryocytopoiesis, the mechanisms of its regulation, possible ways for platelets to occur from megakaryocytes. It characterizes thrombocytopoiesis, by describing the detailed structural organization of platelets and gives data on the relationship of the morphofunctional features of platelets to the ploidy of megakaryocytes that give rise to the latter. The structure and clinical value of a number of platelet activation markers, such as CD41/CD61, CD42, CD62p, platelet leukocyte aggregates, microvesicles, are described. PMID- 21313751 TI - [Interactive information program in the cytological diagnosis of colonic and rectal diseases]. AB - An interactive information program has been elaborated for the cytological diagnosis of colonic and rectal diseases. Images of cytological specimens obtained at colonoscopy in patients with various colonic and rectal diseases are entered into the database of the interactive program. The information program has been tested by medical cytologists and clinical diagnostic laboratory physicians. PMID- 21313752 TI - [Chromosome nucleolus-forming regions in assessment of neoadjuvant radiation and combined therapy for glandular breast carcinoma]. AB - The findings of a change in the content of the main types of nucleoli and argentophilic granules involved in the structural organization, formation of active forms allow evaluation of the efficiency of radiation exposure and its combined modes during neoadjuvant therapy for glandular breast carcinoma by cytogenetic studies. A comparative study of chromosome nucleolus-forming regions before and after neoadjuvant radiotherapy and its combined modes with polychemo- and hormone therapy makes it possible to detect such aspects of therapeutic pathomorphism as the signs of tumor cell destruction and death, which appear after radiotherapy in combination with polychemotherapy. PMID- 21313753 TI - [Proposals for standardization of clinical laboratory studies: technology "cytological study of lymph node specimens"]. AB - This proposal contains unique requirements for a cytological study of lymph node specimens at the cytological and clinical diagnostic laboratories of health care facilities certified for this kind of work. The paper gives requirements for the performance of technologies, for specialists and auxiliary personnel, specialists' knowledge and skills, medical staff safeguarding. The conditions for rendering a service, necessary equipment, ware, and reagents are described in details. The specific features of a pre-analytical stage, methods for the fixation and staining of smears, the interpretation and recording of findings, and the control of the quality of a performed study, as well as the cost characteristics in conventional units of man-hours. The developed technology may be of great importance to the health care facilities certified for rendering this service. PMID- 21313754 TI - [PCR technique for prenatal diagnosis of fetal rhesus factor from peripheral maternal blood]. AB - A procedure is proposed for the noninvasive determination of fetal rhesus factor in rhesus-negative pregnant women, which is based on the detection of the RHD gene in peripheral maternal blood by a PCR technique. The studies have shown the high sensitivity and specificity of determination of rhesus factor in a fetus at more than 15 weeks gestation. The technique does not require the use of such invasive and pregnancy-threatening procedures, as amniocentesis, cordocentesis or chorion biopsy. Furthermore, determination of fetal blood rhesus factor in rhesus negative patients makes it possible to reduce expenses on the management of pregnancy, to avoid multiple determination of antibody rhesus and prevention of rhesus immunization, and to timely initiate therapeutic and preventive measures. PMID- 21313755 TI - [Genetic identification of antagonistically active lactobacillus strains isolated from the oral cavity of healthy individuals]. AB - Examination of dental deposits from 45 healthy individuals detected 3 lactobacillus strains showing a high antagonism toward test cultures. The api 50 CH "bio Merieux" test systems were employed to identify strains as Lactobacillus fermentum 39, Lactobacillus rhamnosus 24 and Lactobacillus paracasei 50. The results of analyzing the sequences of the 16S rRNA genes of the test strains confirmed this identification, except for the latter strain. The taxonomic status of the third strain L. rhamnosus 50 was determined by the bioinformative analysis of the nucleotide sequence of the 16S rRNA genes. PMID- 21313756 TI - [Identification of Vibrio cholerae serogroups O1 and O139 by monoclonal antibodies in the slide agglutination test]. AB - The agglutinating properties of MCA-O1 of the IgG class and MCA-O139 of the IgM class towards epitopes of O-antigen of Vibrio cholerae O1 and accordingly Vibrio cholerae O139 were studied. The ascitic and cultural fluids by hybridomas F8G12 and D11 deposited in the specialized Collection of Cell Cultures of Vertebrates (Saint Petersburg) under RKKK (II) 386 D and RKKK (II) 674 D were the sources of monoclonal immunoglobulins. The advantage of diagnostic monoclonal immunoglobulins is that they are distinguished for strict specificity and their use in practical health care contributes to the higher specificity of a laboratory test for cholera and to its shorter performance. PMID- 21313757 TI - [Immunohistochemical study of epidermal growth factor receptor expression in esophageal squamous cell carcinoma]. AB - Primary tumors from 31 patients with esophageal squamous cell carcinoma (ESCC) were immunohistochemically studied for the expression of markers of ESCC in order to define the clinical value of the levels of EGFR and HER-2 in the tumors. EGFR and HER-2 hyperexpression in the tumors of patients with ESCC was ascertained to be an important marker for the analysis of the clinical features of ESCC. There was an association of the elevated levels of EGFR and HER-2 in the tumors of ESCC patients with the presence of vascular tumor invasion (p = 0.006) and that with the poor outcome of the disease (p = 0.004). The findings suggest that estimation of changes found in EGRF and HER-2 expression in the tumors of patient with ESCC is of great interest for the individual prediction of the disease course and for the development of new approaches to treating these tumors, including targeted therapy against these tyrosine kinase receptors. PMID- 21313759 TI - [Brain infarction in the internal carotid artery bed in atherosclerosis]. AB - Gross and microscopic studies of the brain and its vascular system were conducted in 139 autopsy brain infarction specimens in atherosclerosis. Of them, 102 specimens displayed 193 infarctions of various extent and duration in the bed of the internal carotid artery (ICA) and its branches. The infarctions were solitary and multiple in 56 and 46 cases, respectively. The revealed infarctions were extensive (n = 22), large (n = 26), medium-sized (n = 86), small in-depth (n = 38), and small superficial (n = 21). The occurrence of great (extensive, large, and medium-sized) infarctions was found to be pathogenetically associated with atherothrombosis obliterans, cardiogenic or less frequently arterioarterial thromboembolism of ICA and its main branches. Atherosclerotic small in-depth and small superficial infarctions, as well as a number of median-sized infarctions occurred mainly via mechanism of cerebrovascular insufficiency in carotid tandem atherostenosis. The extent and location of brain infarction are greatly influenced by the site of hemodynamic carotid artery atherostenosis or thrombosis, the state of collateral circulation, the structure of the arterial circle of Willis, the state of the heart, etc. PMID- 21313758 TI - [Molecular biological features of ectopic and eutopic endometrium in genital endometriosis]. AB - The molecular biological features of the eutopic and ectopic endometrium were studied in 46 patients with adenomyosis, 44 with endometrioid cysts in the ovaries, and 34 with disseminated mixed forms of genital endometriosis. Reproductive-aged patients with the eutopic endometrium in a proliferation phase with hyperplastic or inflammatory changes were selected. Ten samples of the endometrium in a phase proliferation, which had been obtained at medicolegal autopsy of women without reproductive disorders, were studied as a control group. Both the glandular and stromal components of the ectopic and eutopic endometrium in different forms of endometriosis were shown to differ from the intact endometrium in their molecular biological features (the expression of Ki-67, Bcl 2, Bax, vascular endothelial growth factor, transforming growth factor-beta1, matrix metalloproteinases 2 and 10, matrix metalloproteinase-2 inhibitor, the enzyme cytochrome P450 aromatase. PMID- 21313760 TI - [Pathomorphological characteristics of various portions of the aorta and pulmonary artery in coarctation in babies of the first month of life]. AB - A total of 554 case and autopsy records were clinically and morphologically analyzed. There was aortic coarctation (AC) in 47 cases, including 32 cases in babies aged less than 1 month. Pathomorphologic changes in the aorta and pulmonary artery in AC are a dynamic process and reflect the signs of increased vascular permeability, damaged muscle elements, and formed minor vessels. It may be suggested that such changes reflect impaired vascular blood flow at the sites of AC, which should be kept in mind in the early diagnosis and prediction of complications. PMID- 21313761 TI - [PTEN gene in triple-negative breast cancer]. AB - The paper gives the results of studying the expression of the PTEN gene product by an immunohistochemical method, as well as deletion of the gene by fluorescence in situ hybridization in the tumor cells of 80 patients with triple-negative breast cancer (TNBC). The gene product was absent in the tumor cell nuclei in 56 products. The bulk of the remaining patients who showed a positive response had lobular carcinomas or tumors with an unidentified microscopic variant due to secondary posttherapeutic changes. Lobular carcinomas in a control group presented by patients without TNBC also contained the PTEN gene product. Therefore, all positively responding tumor cells failed to express basaloid markers and androgen receptors. The immunohistochemically detectable absence of the PTEN gene product is usually coupled with deletion at locus 10q23; however, in several cases the negative immunohistochemical reaction is associated with no deletion at the above locus, which suggests that there are mechanisms for PTEN gene dysregulation other than deletion in TNBC. The presence of the PTEN gene product in the tumor cells is associated with good prognosis in patients with TNBC. PMID- 21313762 TI - [Impact of technical characteristics of histological equipment on the research costs]. AB - The paper provides a comparative technical-and-economical assessment of manual and hardware-based methods for histological tissue processing in terms of cost optimization. The presented data may be useful to experts to make decisions on the logistical support of pathology laboratories. PMID- 21313763 TI - [Logistic support and ways for reducing costs in a pathological laboratory]. AB - The paper provides a comparative technical-and-economical assessment of the basic reagents that are most commonly used for histological processing of tissue specimens in terms of cost optimization. The presented data may be useful to experts to make decisions on the current logistical support of pathology laboratories. PMID- 21313764 TI - [The clinical and morphological characteristics of mucinous cystic tumors of the pancreas]. AB - The authors present the data available in the literature and the results of their studies of intraoperative specimens from 24 patients with mucinous cystic tumors of the pancreas. The latter are a special group of neoplasms that are unrelated to the gland's ducts and consist of the mucin-producing epithelium with underlying ovarian-like stroma. Mucinous cystadenocarcinoma are detectable in older women (mean age 54.8 years), they are large and multicompartmental in nature. Microscopic study has indicated that all types of mucinous cystic tumors are characterized by ovarian-like stroma, the cells of which show a positive reaction to progesterone receptor antibodies. More significant ovarian-like stroma is typical of mucinous cystadenoma. The high (more than 30%) proliferative activity of epithelial lining cells is suggestive of the malignant nature of the process. PMID- 21313765 TI - [Sweat gland polyneoplasia with extensive metastases]. AB - The paper describes a case of sweat gland polyneoplasia with extensive metastases in a 47-year-old woman, which is indicative of extreme malignancy of this tumor. PMID- 21313766 TI - [The diffuse type of giant cell tumors of the tendon sheaths]. AB - The authors give a morphological and immunohistochemical description of diffuse giant cell tumors of the tendon sheath, which differ in the composition of neoplastic cells. Immunohistological detection of CD68, HAM56, CD45, and lysozyme is of crucial importance in the differential diagnosis with malignant soft tissue tumors. Attention is drawn to the high proliferative activity of tumor cells; the Ki-67 index is as high as 40% in occasional portions, which may give a misimpression of malignancy. PMID- 21313767 TI - [Ectopic hormone production of beta-subunit of human chorionic gonadotropin by cells of signet ring cell carcinoma of the stomach]. AB - The ectopic hormone production by tumor cells that have a light optical structure of typical non-endocrine cancers has long attracted the attention of investigation all over the world. Specifically, this concerns the phenomenon of the ectopic production of the beta-subunit of human chorionic gonadotropin (beta hCG) by non-germinogenic tumors, which is, according to R.K. Iles's data, encountered in 20-40% of malignant epithelial tumors. Despite the fact that beta hCG synthesis is traditionally regarded as the prerogative of germinogenic tumors, the world's literature contains strong evidence for latent beta-hCG gene expression and many cases of clinically evident manifestation of the effects of chorionic gonadotropin. The latter fact, if a clinician and a pathologist are unaware of the behavior of a tumor, may give rise to a diagnostic error and incorrect treatment policy. PMID- 21313768 TI - [Morphological changes in thyroid tissue after preoperative fine-needle nodule biopsy]. AB - The paper considers morphological changes in thyroid tissue after preoperative fine-needle biopsy of benign and malignant tumors at the above site in 5 patients. The found changes made the postoperative histological diagnosis of a tumor process difficult as; (a) there was total necrosis (2 cases of follicular tumor and papillary cancer from oxyphilic cells according to the data of a preoperative cytological study); (b) there were signs that mimicked those of invasive tumor growth in the proper fibrous capsules (2 cases of follicular adenomas); (c) there was abundant formation of fibrous tissue in the center of follicular adenoma. The paper discusses the rate and nature of the most common morphological changes induced by preoperative puncture biopsy. PMID- 21313769 TI - [Arteriovenous malformation as a source of recurrent gastrointestinal hemorrhages]. AB - The paper describes a case of arteriovenous malformation (AVM) in a 64-year-old patient with recurrent gastric hemorrhage and posthemorrhagic iron-deficiency anemia. The source of hemorrhage was detected by esophagogastroduodenoscopy. AMV should be treated surgically, by excising the portion of antral mucosal portion of the stomach (mucosectomy). PMID- 21313771 TI - [Morphogenesis of Far Eastern tick-borne encephalitis]. AB - Based on their findings and the data available in the literature, the authors provide the current interpretation of tickborne encephalitis (TBE) in terms of the immunopathological essence of inflammation. The pathomorphological pattern of the central nervous system is shown to reflect the hyperergic nature of inflammation in TBE. The progressive development of the immediate hypersensitivity reactions initiated by the damaging action of the virus on brain tissue and the delayed hypersensitivity ones that provide the formation of local (tissue) immunity. Integrated assessment of human and experimental TBE-induced pathology has established the variability in its manifestations, which depends on the properties of an initiating virus strain, the type of the body's virus induced immune response, and the stage of morphogenesis of the disease. On this basis, the authors identified 3 clinical and morphological variants of manifestation of an infectious process in TBE. PMID- 21313770 TI - [A method for assessing bacterial microflora by fluorescence in situ hybridization]. AB - The use of current diagnostic methods in a pathologist's practice, including the assessment of the bacterial microflora by the molecular microbiological technique fluorescence in situ hybridization is important and promising. The detection of bacteria and changes in the microbial flora makes it possible to clarify the nature of found morphological changes and to expand the diagnostic value of a postmortem study. PMID- 21313772 TI - [Pigmented villonodular synovitis]. AB - Pigmented villonodular synovitis (PVNS) is a destructive proliferative tumoroid disease of the synovial sheath of the joints, bursae, and tendon. The microscopic pattern of PVNS is characterized by mosaicism: compact cell zones alternate with loose few-celled fields. The synovial sheath is hyperplastic; its stroma exhibits hemosiderin and siderophages, as well as histiocytes, lymphocytes, multinucleated giant osteoclasts, foamy and synoviocyte-like cells. Proliferation with destructive growth was noted in PVNS. A distinction is made between focal and diffuse, intraarticular and extraarticular forms of the disease. Early diagnosis of the disease favors effective treatment and prevention of soft tissue and bone destruction and reduces the risk of recurrences. PMID- 21313773 TI - [Acute erosive gastropathies]. AB - There is a rise in the rates of acute erosive gastropathies in patients with cardiovascular and other somatic diseases. The role of acute erosive gastropathy induced hemorrhages in the tanatogenesis of these diseases is underestimated; the problems of their prevention, diagnosis, and treatment remained unsolved. Many factors, mainly acute or chronic ischemia of the gastroduodenal mucosa, as well as its age-related involution, Helicobacter pylori infection, reflux gastritis, multiple organ dysfunction, drug-induced damage, etc., which are implicated in the pathogenesis of acute erosive gastropathies in patients with cardiovascular and other somatic diseases, are summarized. PMID- 21313774 TI - [Keep moving]. PMID- 21313775 TI - [Rotavirus infections]. AB - Rotaviruses are genetically highly variable, non-enveloped viruses with a double stranded, segmented ribonucleic acid genome. They are a major cause of gastroenteritis worldwide. In children aged less than 5 years, they are the most frequent agent of severe acute diarrheal illnesses. In less developed countries, rotavirus diseases are one of the most frequent causes of death in infants and little children. Typically, symptomatic rotavirus diseases in infants (<5 years) and the elderly (>70 years) arise with sudden onset of watery diarrhoea with high risk of dehydration, accompanied by vomiting and, in several cases, unspecific respiratory symptoms such as cold and sore throat. In adults aged less than 70 years, illnesses due to rotavirus appear generally mild or as travel diarrhoea. Although rotavirus infections are considered to by systemic, extraintestinal manifestations such as rotavirus central nervous system diseases are relatively rare. Rotaviruses are transmitted primarily from person-to-person by the faecal oral route. Treatment of rotavirus diarrhoea is usually symptomatic and comprises a sufficient fluid and electrolyte substitution. Although nitazoxanide and some other drugs show high efficacy against rotavirus in vitro and in vivo, there is currently no recommended specific antiviral therapy. For prophylaxis, special attention should be paid to adequate hygienic rules. Because of the high stability of rotaviruses to changing environmental conditions, disinfection should be performed applying disinfectants with proven activity against rotaviruses. In Germany, two efficient and secure live vaccines against rotaviruses have been approved. Their application, however, is not generally recommended. PMID- 21313776 TI - [Analgesia for pediatric patients. Standards and special aspects]. AB - In this paper we describe the assessment and medical treatment of pain in children according to the concept of the Centre of Pediatrics and Adolescent Medicine at the university of Freiburg, Germany. Opiate therapy in children as well as novel data about the association of paracetamol (acetaminophen) and wheezing/asthma bronchiale in children are discussed. Special aspects of analgesia for painful procedures and a nitrous oxide/oxygen mixture which has been recently introduced in Germany are described. The second part of the paper presents results of our prospective study about continuous infusion of fentanyl and midazolam in a fixed combination in 19 critically ill patients with a median age of 46 months, 40% of these patients had an ARDS. The mortality rate was 21%. A median dose of fentanyl of 3.9 microg/kg/h (midazolam 0.26 mg/kg/h) was infused. The fentanyl serum level (median 4.2 ng/ml, range 1.7-17.8 ng/ml) correlated significantly with the administered dose while the midazolam serum levels (median 911 ng/ml, range 234-4 651 ng/ml) correlated neither with the administered dose nor with any of the analysed parameters. CONCLUSION: A standard protocol for the assessment and treatment of pain should be established in every pediatric hospital. The data about the association of asthma bronchiale and paracetamol cannot be interpreted conclusively, but show that even for well known substances clinical trials may lead to new awareness. The study data about continuous infusion of fentanyl and midazolam show a good correlation of the fentanyl application to serum levels, while midazolam appears to be not the optimal substance for continuous sedation in this setting. PMID- 21313777 TI - [Tilt testing in the diagnosis and treatment of syncope]. AB - Neurocardiogenic syncope is an entity with significant prevalence and incidence. Although with low mortality, it has negative implications in the quality of life of these patients. Today, there are international guidelines for the diagnosis of syncope, and tilt testing has been accepted as a useful diagnostic test, particularly in recurrent syncope of unknown etiology. Several protocols have been described in the last years, first including a passive phase only and later with the introduction of provocative agents, from which sub-lingual nitrates are the most widely accepted due to the simplified protocol and good results. The use of tilt testing in the evaluation of the treatment results is limited due to problems related with it's reproducibility, that are however the base for a treatment option recently available--tilt training--however with variable success rates. In this review, we will talk about clinical practice aspects related with tilt testing. PMID- 21313778 TI - [Bicuspid aortic valve and aortic disease: past, present and future]. AB - Bicuspid Aortic Valve is the most common cardiac congenital abnormality occurring in 1% to 2% of the general population. The acquired bicuspid valve has been considered by some authors to be a rheumatic disease consequence. Meanwhile, some recent experimental studies where atrioventricular valves have been studied for the presence of rheumatic stigmata have excluded this hypothesis. There are some theories that can explain the genesis of this disease but actually Bicuspid Aortic Valve is often considered a benign lesion early in life, but its valvular and vascular complications result in considerable morbidity and mortality later in life. Beside beta-blockers, there are some drugs that are being study and may be used in a nearly future for slower disease progression, although the definitive treatment still is the cardiac valve replacement surgery. PMID- 21313779 TI - A sulphydryl reducing agent, dithiothreitol, modifies agonist-nicotinic receptor interaction in an identified insect neurone. PMID- 21313780 TI - Acetylcholine receptors of thoracic dorsal midline neurones in the cockroach, Periplaneta Americana. AB - The actions of acetylcholine and cholinergic ligands have been studied using dorsal midline neurones from the rnetathoracic ganglion of the cockroach Periplaneta americana.Both nicotine and oxotremorine depolarized dorsal midline neuronal cell bodies.Dose-response curves for nicotine and oxotremorine saturated at different levels. Nicotine-induced depolarizations were completely or partially blocked by mecamylamine, d-tubocurarine, strychnine, and bicuculline, but were insensitive to alpha-bungarotoxin(100 nM), atropine (100 micronM),Scopolamine (10 micronM), and pirenzepine (50 micronM). Following pretreatment with collagenase, the dorsal midline neurones were sensitive to high doses of alpha-bungarotoxin (3 micronM). Oxotremorine-induced depolarizations were blocked by scopolamine (10 micronM) atropine (100 micronM), and pirenzepine (50 micronM) and were insensitive to mecamylamine (10 micronM) and d-tubocurarine (100 micronM). The results indicate the coexistence of at least two distinct acetylcholine receptors on dorsal midline neuronal cell bodies in the cockroach metathoracic ganglion. PMID- 21313781 TI - Actions of a coral toxin analogue (bipinnatin-B) on an insect nicotinic acetylcholine receptor. AB - The lophotoxin analogue, bipinnatin-B, is a potent neurotoxin isolated from the gorgonian coral Pseudopterogorgia bipinnata. When tested on the cell body of an identified motor neurone, the fast coxal depressor motor neurone (Df) in the cockroach metathoracic ganglion, bipinnatin-B, at concentrations of 10 micronM,partially blocked nicotine-induced depolarization. Blockade of the response to nicotine was almost complete at 30 micronM bipinnatin-B, and was partially reversible on rebathing the preparation in normal saline. Responses of the same neurone to GABA were unaffected by 30 micronM bipinnatin-B. PMID- 21313783 TI - Reduction of disulphide bonds in human haptoglobin 2-1. AB - Gradual reduction of disulphide bonds in human haptoglobin, type 2-1, was carried out either by the use of sodium borohydride or 2-mercaptoethanol, newly exposed sulphydryl groups as determined by the Ellman's reagent and by the incorporation of [(14) C] acetamide, respectively. Cleavage of disulphide bonds resulted in the formation of a number of intermediates, separated in polyacrylamide gel electrophoresis, with sulphydryl groups blocked by the radioactive label. On the basis of molecular mass determinations, subunit composition of intermediates, was postulated. The ability of haptoglobin to form an active peroxidase-like complex with hemoglobin depended to a considerable extent on the presence of intact disulphide bonds. On the contrary,throughout the course of reduction of inter- and intrachain disulphides, antigenic reactivity was found to remain unchanged. PMID- 21313784 TI - Abner Doubleday, Marc Bloch, and the cultural significance of baseball in rural America. AB - In 1907 baseball's promoters decreed that Civil War hero Abner Doubleday created the game in the village of Cooperstown, New York, in 1839. Baseball thus acquired a distinctly rural American origin and a romantic pastoral appeal. Skeptics have since presented irrefutable evidence that America's pastime was neither born in the United States nor was a product of rural life. But in their zeal to debunk the myth of baseball's rural beginnings, historians have fallen prey to what Annales School founder Marc Bloch famously called the "idol of origins," and all but neglected the very real phenomenon of rural baseball itself. The claim that baseball has always been "a city game for city men" does not stand up to empirical scrutiny anymore than the Doubleday myth itself, as this address demonstrates with three case studies -- Cooperstown in the 1830s, Davisville, California, in the 1880s, and Milroy, Minnesota, in the 1950s. Baseball may have been a source of rural nostalgia for city people, but it was the sport of choice for farmers and a powerful cultural agent. PMID- 21313785 TI - "The herald of prosperity": tracing the boll weevil myth in Alabama. AB - As scholars and singers have pointed out in monographs and folk songs, the cotton boll weevil was a devastating force on southern farming and rural life. No symbol is more indicative of this destruction than Enterprise, Alabama's boll weevil monument. This essay examines not how the cotton pest destroyed the region's staple crop, but how women and men across race and class lines understood the beetle's threat and used it to their advantage. The statue, like the countless blues and folk songs about the pest, was a cultural statement that shaped the understanding of the bug itself and its supposed transformation of southern agriculture. By examining the local conditions that gave rise to dramatic, albeit short-lived, crop diversification, and in turn the monument's erection, this essay uncovers the ways in which the boll weevil myth was as important a force on southern life as the long-snouted beetle itself. PMID- 21313786 TI - [Ameliorative effect of n-3 fatty acid on insulin resistance through GPR120]. PMID- 21313787 TI - [Paradigm shift in regulation of bone metabolism--bone and nervous system]. PMID- 21313788 TI - United States life tables by Hispanic origin. AB - OBJECTIVES: This report presents complete period life tables by Hispanic origin, race for the non-Hispanic white and non-Hispanic black populations, and sex for the United States based on age-specific death rates in 2006. METHODS: The methods used to estimate the probability of death for ages 0-80 for the Hispanic population and 0-65 for the non-Hispanic white and non-Hispanic black populations are the same as those used in annual U.S. life tables since 1997, with an important modification. Age-specific death rates are first corrected for racial and ethnic misclassification on U.S. death certificates. To address the effects of age misstatement at the oldest ages, the methodology used to estimate mortality for ages 66 and over for the non-Hispanic white and non-Hispanic black populations is the same as that used to estimate the annual life tables since 2005. For the Hispanic population, the probability of death for ages over 80 is estimated as a function of non-Hispanic white mortality with the use of the Brass relational logit model. RESULTS: Life expectancy at birth for the total population in 2006 was 77.7 years; 80.6 years for the Hispanic population, 78.1 years for the non-Hispanic white population, and 72.9 years for the non-Hispanic black population. The Hispanic population has a life expectancy advantage at birth of 2.5 years over the non-Hispanic white population and 7.7 years over the non-Hispanic black population. Although seemingly paradoxical, these results are consistent with the findings of numerous studies which show a Hispanic mortality advantage despite this population's lower socioeconomic status. Nonetheless, the procedures used in this report to correct for racial and ethnic misclassification and age misstatement are not error free and therefore some of the observed advantage may still be a function of data artifact. This report does not address other factors that may explain the Hispanic mortality advantage. PMID- 21313789 TI - Electrical stimulation and electrode properties. Part 2: pure metal electrodes. AB - Electrical stimulation can cause significant damage to clinical electrodes as well as patient injury. In this study, the effects of stimulation on pure metal electrodes were investigated without the complexities introduced by the multiple elements that make up the clinical electrode. As with the clinical electrodes, there was significant decomposition of pure stainless steel anodes with no associated significant changes in the cathodes when stimulation employed long pulse durations. Effects of stimulation were greater when the anode and cathode were closer under constant voltage stimulation but were distance independent under constant current stimulation. High ionic content of the solution also increased the degree of damage to the anode as did the presence of chloride in the solution. Electrode composition also influenced the amount damage to the anode. Platinum and platinum-iridium electrodes showed no damage with any stimulus while stainless steel showed the lowest resistance to corrosion for direct current (DC) stimulation. Tungsten electrodes behaved very differently than stainless steel, decomposing with pulse stimulation and resisting decomposition during DC stimulation because of the formation of surface protective layers. Because platinum was able to maintain high levels of current over time, prolonged stimulation produced dramatic increases in the temperature of the solution; however, even short periods of stimulation were sufficient to produce dramatic changes in pH in the neighborhood of the electrode. PMID- 21313790 TI - Dravet syndrome: a technologist's perspective. AB - Dravet Syndrome (DS), also known as Severe Myoclonic Epilepsy in Infancy (SMEI) is a rare, primarily genetic disorder which develops in infancy. The characteristics of DS are frequent, prolonged, primarily generalized seizures which occur initially with fever and eventually evolve to multiple afebrile seizure types such as myoclonic, atypical absence, and complex partial seizures. Patients, who are initially developmentally normal, will experience concomitant developmental regression as the syndrome progresses. Because it is a childhood disorder, DS is not well known outside the realm of pediatrics. An astute EEG technologist should be able to recognize key factors both clinically and electrographically which point suspicion to the diagnosis of Dravet Syndrome. PMID- 21313791 TI - A report of two cases of lip and tongue bite injury associated with transcranial motor evoked potentials. AB - Transcranial electric motor evoked potentials (TCeMEPs) are routinely used intraoperatively to detect and prevent iatrogenic injury to the spinal cord, specifically the corticospinal tract. Complications related to TCeMEP testing include the potential for seizure induction, cardiac arrhythmia, scalp burns, infection, and tongue or lip laceration. Among this list of potential complications, tongue and lip lacerations are the most common and most directly attributable to transcranial stimulation. The technique of low voltage stimulation and the correct placement of oral bite blocks is successful in preventing patient bite injuries. We report two cases of patient bite injuries following TCeMEPs and discuss potential mechanisms of injury and prevention. PMID- 21313792 TI - Protecting the genitofemoral nerve during direct/extreme lateral interbody fusion (DLIF/XLIF) procedures. AB - A 77-year-old male presented with a history of severe lower back pain for 10 years with radiculopathy, positive claudication type symptoms in his calf with walking, and severe "burning" in his legs bilaterally with walking. Magnetic resonance imaging (MRI) revealed lumbar stenosis at the L3-L4 and L4-L5 levels. During the direct or extreme lateral interbody fusion (DLIF/XLIF) procedure, bilateral posterior tibial, femoral, and ulnar nerve somatosensory evoked potentials (SSEPs) were recorded with good morphology of waveforms observed. Spontaneous electromyography (S-EMG) and triggered electromyography (T-EMG) were recorded from cremaster and ipsilateral leg muscles. A left lateral retroperitoneal transpsoas approach was used to access the anterior disc space for complete discectomy, distraction, and interbody fusion. T-EMG ranging from 0.05 to 55.0 mA with duration of 200 microsec was used for identification of the genitofemoral nerve using a monopolar stimulator during the approach. The genitofemoral nerve (L1-L2) was identified, and the guidewire was redirected away from the nerve. Post-operatively, the patient reported complete pain relief and displayed no complications from the procedure. Intraoperative SSEPs, S-EMG, and T EMG were utilized effectively to guide the surgeon's approach in this DLIF thereby preventing any post-operative neurological deficits such as damage to the genitofemoral nerve that could lead to groin pain. PMID- 21313793 TI - Update of instruments for GC and GC/MS. PMID- 21313794 TI - Modern gas chromatography, column liquid chromatography, planar chromatography, and bioanalytical methods for the analysis of pesticides and study of quantitative structure-retention relationships. PMID- 21313795 TI - Bioanalytical methods for food contaminant analysis. AB - Foods are complex mixtures of lipids, carbohydrates, proteins, vitamins, organic compounds, and other naturally occurring substances. Sometimes added to this mixture are residues of pesticides, veterinary and human drugs, microbial toxins, preservatives, contaminants from food processing and packaging, and other residues. This milieu of compounds can pose difficulties in the analysis of food contaminants. There is an expanding need for rapid and cost-effective residue methods for difficult food matrixes to safeguard our food supply. Bioanalytical methods are established for many food contaminants such as mycotoxins and are the method of choice for many food allergens. Bioanalytical methods are often more cost-effective and sensitive than instrumental procedures. Recent developments in bioanalytical methods may provide more applications for their use in food analysis. PMID- 21313796 TI - Determination of pesticide residues in sewage sludge: a review. AB - Pesticides are widely applied to protect plants from diseases, weeds, and insect damage, and they usually come into contact with soil where they may undergo a variety of transformations and provide a complex pattern of metabolites. Spreading sewage sludge on agricultural lands has been actively promoted by national authorities as an economic way of recycling. However, as a byproduct of wastewater treatment, sewage sludge may contain pesticides and other toxic substances that could be incorporated into agricultural products or be distributed in the environment. This article reviews the determination of pesticides in sewage sludge samples. Sample preparation including pretreatment, extraction, and cleanup, as well as the subsequent instrumental determination of pesticide residues, are discussed. Extraction techniques such as Soxhlet extraction, ultrasound-assisted extraction, pressurized liquid extraction, supercritical fluid extraction, and matrix solid-phase dispersion and their most recent applications to the determination of pesticides in sewage sludge samples are reviewed. Determination of pesticides, generally carried out by GC and HPLC coupled with different detectors, especially MS for the identification and quantification of residues, is summarized and discussed. PMID- 21313797 TI - Quantitative structure-retention relationship studies as an analytical tool in the determination and modeling of pesticide residues in plant organisms. AB - Crop models use mathematical equations to simulate the physical and chemical processes that generally control the uptake, translocation, and sorption of pesticides in all parts of plants. Our interest is focused on method optimization to determine the new compounds using stationary and mobile phases with different physicochemical properties. The work deals with five fungicides composed of nitrogen-containing heterocycles, 1,2,4-triazoles. The sample preparation liquid extraction and solid-phase-based methods are used to determine and model the pesticide residues in plants organisms. Analysis of these compounds is generally carried out by GC or HPLC coupled to different detectors, especially to mass spectrometers, in hyphenated techniques that have been extremely developed in recent years. The relationships between the chromatographic retention factor (k) and those physicochemical properties that are relevant in quantitative structure retention relationship (QSRR) studies were investigated. The accuracy of the simple linear regressions between the chromatographic retention and the descriptors for all of the compounds was satisfactory (correlation coefficient 0.83 < or = R2 < or = 0.99). The QSRR models of these nitrogen-containing heterocyclic compounds could be predicted with a multiple linear regression equation having the statistical index R2 = 1.00. Evaluation of chromatographic properties of the new stationary phases and description of the molecular separation mechanism using the QSRR method, including molecular modeling, were performed. A universal model is presented that links the physicochemical parameters describing the fungicide compounds with the anatomical, physiological, and biochemical properties of the plant. PMID- 21313798 TI - Use of pressurized liquid extraction for the simultaneous analysis of 28 polar and 94 non-polar pesticides in agricultural soils by GC/QqQ-MS/MS and UPLC/QqQ MS/MS. AB - Due to the wide range of pesticides that can be used in agriculture, the development of fast multiresidue methods that simultaneously determine polar and non-polar pesticides is greatly demanded. This study shows the development and validation of a multiresidue method for the analysis of 98 non-polar pesticides and 28 polar pesticides in soil. A simultaneous extraction step by pressurized liquid extraction was utilized. The optimum results were obtained using ethyl acetate-methanol (3:1, v/v) with 2 min of preheat time and 85 degrees C as the extraction temperature. The final determination of non-polar pesticides was performed by GC, whereas polar pesticides were determined by ultra-performance liquid chromatography (UPLC). Both GC and UPLC were coupled to triple-quadrupole analyzers operating in tandem MS. The optimized extraction procedure was validated. The average extraction recoveries were in the range 72-108% (10 microg/kg) and 71-106% (50 microg/kg), with RSD values < or = 26%. The matrix effect was also evaluated, and matrix-matched standard calibration was finally applied for quantification. The suitability of the method was also checked by the analysis of a certified reference material. Furthermore, 26 real soil samples were analyzed by the proposed methods in order to assess their applicability. Several pesticides (e.g., bifenthrin, triadimefon, or endosulfan) were found in the samples. PMID- 21313799 TI - Multiresidue analysis of 95 pesticides at low nanogram/liter levels in surface waters using online preconcentration and high performance liquid chromatography/tandem mass spectrometry. AB - A new multiresidue method for the analysis of 95 pesticides and breakdown products with a wide range of physiochemical properties in surface and ground water using online solid-phase extraction coupled with HPLC/MS/MS is presented. Using an injection volume of only 500 microL filtered water, an LOD in the 1-10 ng/L range was achieved for all but one substance, and recoveries were, with a few exceptions, in the 70-120% range. Large differences were found in the adsorption of pesticides on nine filter materials tested for filtration of the water samples. Filters of regenerated cellulose were chosen due to good recoveries and easy handling. Results from the proposed method were compared with results from previously used methods for 31 pesticides in 99 surface water samples, collected in 2008, with good agreement. PMID- 21313800 TI - Application of HPLC and TLC with diode array detection after SPE to the determination of pesticides in water samples from the Zemborzycki Reservoir (Lublin, southeastern Poland). AB - The application of TLC with a diode array detector (TLC-DAD) and HPLC-DAD after SPE for identification and quantitative analysis of pesticides in water samples is demonstrated. The procedures described for the determination of compounds are inexpensive and can be applied to routine analysis of analytes in water samples after preliminary cleanup and concentration by SPE. Average recoveries for four different cartridges and three solvents by the proposed HPLC-DAD method after SPE also are presented. The efficiency of the SPE procedure was evaluated using real water samples from the Zemborzycki Reservoir, near Lublin, southeastern Poland. The method was validated for precision, repeatability, and accuracy. PMID- 21313801 TI - Separation of four mixtures of pesticides by pressurized planar electrochromatography (PPEC). AB - Examples of separations of four mixtures of pesticides by pressurized planar electrochromatography (PPEC) under different operating conditions are presented. The samples were separated on a prewetted RP-18W chromatographic plate in a system with acetonitrile-buffer as the mobile phase. A potential of 2.3 kV was applied to a 10 cm long plate to create the electric field. Reproducible retention of pesticides was obtained during PPEC in the closed system when the sorbent layer of the plate was prewetted and equilibrated with the mobile phase. The reported separations of pesticides by PPEC are over 10 times faster than the corresponding separations by TLC. PMID- 21313802 TI - Real-time polymerase chain reaction detection of fishmeal in feedstuffs. AB - A SYBR Green PCR system was developed for detection of fishmeal in feedstuffs. The real-time PCR method combines the use of fish-specific primers that amplify an 87 base pair (bp) fragment of the mitochondrial 12S ribosomal RNA gene from fish species, and a positive control primer pair that amplifies a 99 bp fragment of the nuclear 18S ribosomal RNA gene in all eukaryotic organisms. The specificity of the primers was tested against 52 animal species and six plant species. Reference feedstuff samples were successfully tested for the presence of fishmeal, demonstrating the applicability of the assay to feedstuffs. PMID- 21313803 TI - Quantitative determination of chemical constituents from seeds of Nigella sativa L. using HPLC-UV and identification by LC-ESI-TOF. AB - An HPLC method was developed for the simultaneous determination of nine compounds of Nigella sativa L. The separation was achieved within 23 min by using C18 column material, a water-acetonitrile mobile phase, both containing 0.1% acetic acid gradient system and a temperature of 35 degrees C. The method was validated for linearity, repeatability, LOD, and LOQ. The LOD and LOQ of nine compounds were in the range of 0.09-10 and 0.3-25 microg/mL, respectively. The wavelength used for quantification with the diode array detector was 205 and 260 nm. LC/MS coupled with electrospray ionization interface method is described for the identification of compounds in N. sativa L. samples. This method involved the use of [M+H]+ and [M+Na]+ ions in the positive ion mode with extracted ion chromatogram. PMID- 21313804 TI - Liquid chromatography-particle beam electron ionization mass spectrometry method for analysis of botanical extracts: evaluation of ephedrine alkaloids in standard reference materials. AB - The preliminary validation of a high-performance liquid chromatography particle beam mass spectrometry method (HPLC-PB/MS) with electron impact ionization source for analysis of botanical extracts is presented. The LC-PB/MS system was evaluated for the analysis of ephedrine alkaloids using ephedra-containing National Institute of Standards and Technology dietary supplement standard reference materials (SRMs) 3241 Ephedra Sinica Stapf Native Extract and 3242 Ephedra Sinica Stapf Commercial Extract. The ephedrine alkaloids were separated by reversed-phase chromatography using a phenyl column at room temperature. A linear gradient method with a mobile phase composition varying from 5:95 [MeOH:0.1% trifluoroacetic acid (TFA) in water] to 20:80 (MeOH:0.1% TFA in water) at a flow rate of 1.0 ml/min, with an analysis time of less than 20 min, was used. The source block temperature was evaluated to determine the optimal operating conditions by monitoring the intensities and fragmentation patterns of the ephedrine alkaloids. Ephedrine and N-methylephedrine were taken as a representative of the test alkaloids. The LODs on the sub-nanogram level were achieved, with ephedrine, pseudoephedrine, and methylephedrine in the SRMs quantified by a standard addition method with recoveries of > or = 86% and RSDs of < or = 14% (n = 3). PMID- 21313805 TI - Fingerprint analysis of Ginkgo biloba leaves and related health foods by high performance liquid chromatography/electrospray ionization-mass spectrometry. AB - A fingerprint analysis method was developed for Ginkgo biloba leaves and was successfully used for quality evaluation of related health foods by HPLC with electrospray ionization MS. Fifteen samples of G. biloba leaves, which were collected from 15 different locations in China, were analyzed and identified in this study. By both peak analysis and similarity analysis of the fingerprint chromatograms, variation of constituents was easily observed in the leaves from different sources. By comparison with batches of authentic leaves, the authenticity, and quality consistency of related health foods in different matrixes were effectively estimated. It is important to mention that studying a wide range of authentic leaves from various habitats made the quality evaluation of commercial products more convincing and reasonable. The fingerprint-based strategy of the developed method should provide improved QC of G. biloba leaves and products. PMID- 21313806 TI - Quantitative analysis of eugenol in clove extract by a validated HPLC method. AB - Clove (Eugenia caryophyllata) is a well-known medicinal plant used for diarrhea, digestive disorders, or in antiseptics in Korea. Eugenol is the main active ingredient of clove and has been chosen as a marker compound for the chemical evaluation or QC of clove. This paper reports the development and validation of an HPLC-diode array detection (DAD) method for the determination of eugenol in clove. HPLC separation was accomplished on an XTerra RP18 column (250 x 4.6 mm id, 5 microm) with an isocratic mobile phase of 60% methanol and DAD at 280 nm. Calibration graphs were linear with very good correlation coefficients (r2 > 0.9999) from 12.5 to 1000 ng/mL. The LOD was 0.81 and the LOQ was 2.47 ng/mL. The method showed good intraday precision (%RSD 0.08-0.27%) and interday precision (%RSD 0.32-1.19%). The method was applied to the analysis of eugenol from clove cultivated in various countries (Indonesia, Singapore, and China). Quantitative analysis of the 15 clove samples showed that the content of eugenol varied significantly, ranging from 163 to 1049 ppb. The method of determination of eugenol by HPLC is accurate to evaluate the quality and safety assurance of clove, based on the results of this study. PMID- 21313807 TI - Ultra-fast gradient LC method for omeprazole analysis using a monolithic column: assay development, validation, and application to the quality control of omeprazole enteric-coated pellets. AB - A method was optimized for the analysis of omeprazole (OMZ) by ultra-high speed LC with diode array detection using a monolithic Chromolith Fast Gradient RP 18 endcapped column (50 x 2.0 mm id). The analyses were performed at 30 degrees C using a mobile phase consisting of 0.15% (v/v) trifluoroacetic acid (TFA) in water (solvent A) and 0.15% (v/v) TFA in acetonitrile (solvent B) under a linear gradient of 5 to 90% B in 1 min at a flow rate of 1.0 mL/min and detection at 220 nm. Under these conditions, OMZ retention time was approximately 0.74 min. Validation parameters, such as selectivity, linearity, precision, accuracy, and robustness, showed results within the acceptable criteria. The method developed was successfully applied to OMZ enteric-coated pellets, showing that this assay can be used in the pharmaceutical industry for routine QC analysis. Moreover, the analytical conditions established allow for the simultaneous analysis of OMZ metabolites, 5-hydroxyomeprazole and omeprazole sulfone, in the same run, showing that this method can be extended to other matrixes with adequate procedures for sample preparation. PMID- 21313808 TI - Optimization and validation of an RP-HPLC method for direct determination of metformin hydrochloride in human urine and in a dosage form. AB - A simple, selective, sensitive, accurate, and precise method was developed for determination of metformin hydrochloride (MF) in human urine using RP-HPLC. The method depends upon using an octylsilyl (C8) 5 microm particle size column at ambient temperature with mobile phase consisting of 33 mM sodium dihydrogen phosphate containing 6.38 mM hexanesulfonic acid sodium salt and adjusted to apparent pH 3.0 with phosphoric acid-acetonitrile (93 + 7, v/v) at a flow rate of 1.5 mL/min. Quantitation was achieved with UV detection at 231 nm based on peak area with a linear calibration curve over the concentration range of 0.01-50 microg/mL. The proposed method was applied to the determination of the urinary excretion pattern of MF (the cumulative amounts excreted were calculated without pretreatment of the urine sample) and for determination of the dissolution pattern of MF tablets. The proposed method was completely validated according to the U.S. Food and Drug Administration guidelines. PMID- 21313809 TI - Stress degradation studies and kinetic determinations of duloxetine enteric coated pellets by HPLC. AB - A stability-indicating HPLC assay method was developed for the quantitative determination of duloxetine (DLX) in a pharmaceutical dosage form in the presence of its degradation products, and kinetic determinations were evaluated in acid conditions and UV-C radiation exposure. Chromatographic separation was achieved by use of an ACE C18 column (250 x 4.0 mm id, 5 microm particle size). The mobile phase was prepared by mixing aqueous 50 mM potassium phosphate buffer (pH 6.0 containing 0.3% triethylamine) and acetonitrile (60 + 40, v/v). DLX was rapidly degraded in an acid medium and in the presence of hydrogen peroxide and UV-C radiation; it was more stable in alkaline medium. The described method was linear over a range of 4.0-14.0 microg/mL for determination of DLX (r = 0.9998). The precision was demonstrated by the RSD of intraday (0.79-1.07%) and interday (0.85%) studies. The mean recovery was found to be 100.56%. The acid degradation of DLX in 0.1 M HCI solution showed an apparent zero-order kinetics (k = 0.177 microg/mL/min), and the photodegradation demonstrated an apparent first-order kinetics (k = 0.082 microg/mL/min). The developed method was found to be simple, specific, robust, linear, precise, and accurate for the determination of DLX in enteric-coated pellets. PMID- 21313810 TI - An interlaboratory investigation on the use of high-performance thin layer chromatography to perform assays of lamivudine-zidovudine, metronidazole, nevirapine, and quinine composite samples. AB - Two laboratories extensively investigated the use of HPTLC to perform assays on lamivudine-zidovudine, metronidazole, nevirapine, and quinine composite samples. To minimize the effects of differences in analysts' technique, the laboratories conducted the study with automatic sample application devices in conjunction with variable-wavelength scanning densitometers to evaluate the plates. The HPTLC procedures used relatively innocuous, inexpensive, and readily available chromatography solvents used in the Kenyon or the Global Pharma Health Fund Minilabs TLC methods. The use of automatic sample applications in conjunction with variable- wavelength scanning densitometry demonstrated an average repeatability or within-laboratory RSD of 1.90%, with 73% less than 2% and 97% at 2.60% or less, and an average reproducibility or among-laboratory RSD of 2.74%. PMID- 21313811 TI - Quantitative analysis of the cholesterol-lowering drugs ezetimibe and simvastatin in pure powder, binary mixtures, and a combined dosage form by spectrophotometry, chemometry, and high-performance column liquid chromatography. AB - Simple, accurate, sensitive, and precise UV spectrophotometric, chemometric, and HPLC methods were developed for simultaneous determination of a two-component drug mixture of ezetimibe (EZ) and simvastatin (SM) in laboratory-prepared mixtures and a combined tablet dosage form. Four spectrophotometric methods were developed, namely, ratio spectra derivative, ratio subtraction, isosbestic point, and mean centering of ratio spectra. The developed chemometric-assisted spectrophotometric method was the concentration residual augmented classical least-squares method; its prediction ability was assessed and compared to the conventional partial least-squares method. The developed HPLC method used an RP ZORBAX C18 column (5 microm particle size, 250 x 4.6 mm id) with isocratic elution. The mobile phase was acetonitrile-pH 3.5 phosphate buffer (40 + 60, v/v) at a flow rate of 1.0 mL/min, with UV detection at 230 nm. The accuracy, precision, and linearity ranges of the developed methods were determined. The developed methods were successfully applied for determination of EZ and SM in bulk powder, laboratory-prepared mixtures, and a combined dosage form. The results obtained were compared statistically with each other and to those of a reported HPLC method; there was no significant difference between the proposed methods and the reported method regarding both accuracy and precision. PMID- 21313812 TI - LC/MS/MS study for identification of entacapone degradation product obtained by photodegradation kinetics. AB - Entacapone is indicated for clinical use as an adjunct to levodopalcarbidopa to treat patients with idiopathic Parkinson's Disease who experience the signs and symptoms of end-of-dose wearing-off. The aim of this study was to determine the photodegradation kinetics and to elucidate the structure of the main degradation product. The stability of entacapone was studied in order to investigate the degradation kinetics of this drug using LC as a stability indicator. Entacapone was subjected to accelerated photodegradation. This study was carried out with methanolic solutions, prepared from coated tablets, in quartz cells under UV light at 254 nm. The degradation process of entacapone in solutions can be described by second-order kinetics under the experimental conditions used in this study. The LC/MS/MS determinations revealed that in the above conditions the photodegraded product formed the geometric isomer of entacapone (Z-entacapone). The obtained results show the importance of appropriate light protection during the drug development process, storage, and handling. PMID- 21313813 TI - Development and validation of a high-performance liquid chromatographic method for determination of eprosartan in bulk drug and tablets. AB - A simple, precise, and accurate isocratic RP-HPLC method was developed and validated for determination of eprosartan in bulk drug and tablets. Isocratic RP HPLC separation was achieved on a Phenomenex C18 column (250 x 4.6 mm id, 5 microm particle size) using the mobile phase 0.5% formic acid-methanol acetonitrile (80 + 25 + 20, v/v/v, pH 2.80) at a flow rate of 1.0 mL/min. The retention time of eprosartan was 7.64 +/- 0.05 min. The detection was performed at 232 nm. The method was validated for linearity, precision, accuracy, robustness, solution stability, and specificity. The method was linear in the concentration range of 10-400 microg/mL with a correlation coefficient of 0.9999. The repeatability for six samples was 0.253% RSD; the intraday and interday precision were 0.21-0.57 and 0.33-0.71% RSD, respectively. The accuracy (recovery) was found to be in the range of 99.86-100.92%. The drug was subjected to the stress conditions hydrolysis, oxidation, photolysis, and heat. Degradation products produced as a result of the stress conditions did not interfere with detection of eprosartan; therefore, the proposed method can be considered stability-indicating. PMID- 21313814 TI - Development and validation of a new HPLC-UV method for the simultaneous determination of triclabendazole and ivermectin B1a in a pharmaceutical formulation. AB - A rapid, simple, and sensitive RP-HPLC analytical method was developed for the simultaneous determination of triclabendazole and ivermectin in combination using a C18 RP column. The mobile phase was acetonitrile-methanol-water-acetic acid (56 + 36 + 7.5 + 0.5, v/v/v/v) at a pH of 4.35 and flow rate of 1.0 mL/min. A 245 nm UV detection wavelength was used. Complete validation, including linearity, accuracy, recovery, LOD, LOQ, precision, robustness, stability, and peak purity, was performed. The calibration curve was linear over the range 50.09-150.26 microg/mL for triclabendazole with r = 0.9999 and 27.01-81.02 microg/mL for ivermectin with r = 0.9999. Calculated LOD and LOQ for triclabendazole were 0.03 and 0.08 microg/mL, respectively, and for ivermectin 0.07 and 0.20 microg/mL, respectively. The intraday precision obtained was 98.71% with RSD of 0.87% for triclabendazole and 100.79% with RSD 0.73% for ivermectin. The interday precision obtained was 99.51% with RSD of 0.35% for triclabendazole and 100.55% with RSD of 0.59% for ivermectin. Robustness was also studied, and there was no significant variation of the system suitability of the analytical method with small changes in experimental parameters. PMID- 21313815 TI - Effect of gamma irradiation on caprolactam migration from multilayer polyamide 6 films into food simulants: development and validation of a gas chromatographic method. AB - A GC method to determine caprolactam in water, 15% ethanol, and olive oil food simulants was developed and validated. Linear ranges varied from 0.96 to 642.82 microg/mL for water, 0.64 to 800.32 microg/mL for 15% ethanol, and 1.06 to 1062.34 microg/g for olive oil, with correlation coefficients higher than 0.999. Method precision studies showed RSD values lower than 5.45%, while method accuracy studies showed recovery from 72 to 111% for all simulants. The effect of gamma irradiation on caprolactam migration from multilayer polyamide 6 (PA-6) films intended for cheese into water, 15% ethanol, olive oil, and 3% acetic acid simulants was also studied. For migration assay, non-irradiated and irradiated (12 kGy) films were placed in contact with the simulant and exposed at 40 degrees C for 10 days. The validated method was used to quantify caprolactam migration from multilayer PA-6 films into the simulants, which ranged from 1.03 to 7.59 mg/kg for non-irradiated films, and from 4.82 to 11.32 mg/kg for irradiated films. Irradiation caused almost no changes in caprolactam levels, with the exception of olive oil, which showed an increase in the caprolactam level. All multilayer PA-6 films were in accordance with the requirements of the legislation for caprolactam migration. PMID- 21313816 TI - Determination of aflatoxin in processed dried cassava root: validation of a new analytical method for cassava flour. AB - A new method that uses HPLC with a photochemical reactor for enhanced detection was developed and validated for the determination of aflatoxins in cassava flour. Samples were spiked with a mixture of four aflatoxins at 5, 10, and 20 microg/kg mixed with either 1 or 5 g NaCI and extracted with methanol-water (80 + 20, v/v) by shaking for 10 or 30 min. An immunoaffinity column was used for cleanup. HPLC with postcolumn derivatization, for enhancement of aflatoxin fluorescence, and fluorescence determination were used for quantitation of the toxin concentration. The method was validated for recovery, linearity, and precision at the three concentrations tested. Recovery ranges were 52-70, 69-85, and 80-89% for the spiking levels of 5.0, 10.0, and 20.0 microg/kg, respectively. It appears that the amount of salt (NaCl) and the shaking time are critical factors in this method; optimal performance was obtained when 1 g salt was used and the shaking time was 10 min. The good linearity and precision of the method allowed baseline separation from interferences, e.g., coumarins. PMID- 21313817 TI - Determination of calcium, magnesium, sodium, and potassium in foodstuffs by using a microsampling flame atomic absorption spectrometric method after closed-vessel microwave digestion: method validation. AB - This paper describes a validation process in compliance with the NFIEN ISO/IEC 17025 standard for the determination of the macrominerals calcium, magnesium, sodium, and potassium in foodstuffs by microsampling with flame atomic absorption spectrometry after closed-vessel microwave digestion. The French Standards Commission (Agence Francaise de Normalisation) standards NF V03-110, NF EN V03 115, and XP T-90-210 were used to evaluate this method. The method was validated in the context of an analysis of the 1322 food samples of the second French Total Diet Study (TDS). Several performance criteria (linearity, LOQ, specificity, trueness, precision under repeatability conditions, and intermediate precision reproducibility) were evaluated. Furthermore, the method was monitored by several internal quality controls. The LOQ values obtained (25, 5, 8.3, and 8.3 mg/kg for Ca, Mg, Na, and K, respectively) were in compliance with the needs of the TDS. The method provided accurate results as demonstrated by a repeatability CV (CVr) of < 7% and a reproducibility CV (CVR) of < 12% for all the elements. Therefore, the results indicated that this method could be used in the laboratory for the routine determination of these four elements in foodstuffs with acceptable analytical performance. PMID- 21313818 TI - Method for the direct determination of available carbohydrates in low carbohydrate products using high-performance anion exchange chromatography. AB - An improved method for direct determination of available carbohydrates in low level products has been developed and validated for a low-carbohydrate soy infant formula. The method involves modification of an existing direct determination method to improve specificity, accuracy, detection levels, and run times through a more extensive enzymatic digestion to capture all available (or potentially available) carbohydrates. The digestion hydrolyzes all common sugars, starch, and starch derivatives down to their monosaccharide components, glucose, fructose, and galactose, which are then quantitated by high-performance anion-exchange chromatography with photodiode array detection. Method validation consisted of specificity testing and 10 days of analyzing various spike levels of mixed sugars, maltodextrin, and corn starch. The overall RSD was 4.0% across all sample types, which contained within-day and day-to-day components of 3.6 and 3.4%, respectively. Overall average recovery was 99.4% (n = 10). Average recovery for individual spiked samples ranged from 94.1 to 106% (n = 10). It is expected that the method could be applied to a variety of low-carbohydrate foods and beverages. PMID- 21313819 TI - Rapid method for the determination of capsaicin and dihydrocapsaicin in Gochujang using ultra-high-performance liquid chromatography. AB - A sensitive and specific heating block method coupled with ultra-HPLC (u-HPLC) was developed for the analysis of capsaicin in Gochujang and validated by comparing with a conventional HPLC (AOAC Method 995.03). The method validation parameters yielded good results, including linearity, precision, accuracy, and recovery. The u-HPLC separation was performed on a reversed C18 column (50 x 2 mm id, particle size 2 microm), followed by fluorescence detection (excitation 280 nm, emission 325 nm). Methanol was used as the extracting solvent, and the amount of sample taken was approximately 0.2 g; the optimum amount of extraction solvent and extraction time were 15 mL and 1 h, respectively. The recovery of capsaicin in Gochujang was more than 93%, and the LOD and LOQ of the u-HPLC analysis were 0.05 and 0.16 microg/g for capsaicin and 0.05 and 0.16 microg/g for dihydrocapsaicin. The calibration graphs for capsaicin and dihydrocapsaicin were linear from 0.2 to 10.0 microg/mL for u-HPLC. The interday and intraday precisions (RSD values) were < 6.27%. PMID- 21313821 TI - Classification of wines from five Spanish origin denominations by aromatic compound analysis. AB - Wine is a complex matrix in which aroma compounds play an important role in the characterization of the flavor pattern of a given wine. Twelve volatile compounds were determined in 244 samples of Spanish red wines from different denominations of origin: Rioja, Navarra, Valdepenas, La Mancha, and Carinena. The samples were analyzed by GC using headspace solid-phase microextraction. The concentration (mg/mL) intervals obtained were 3-methyl-butyl acetate (3.9 to 116), 3-methyl-1 butanol (93 to 724), ethyl hexanoate (0.8 to 39), 1-hexanol (0.3 to 6.7), ethyl octanoate (1.4 to 41), diethyl succinate (0.2 to 13), 2-phenyl ethyl acetate (0 to 5.3), hexanoic acid (0 to 8.3), geraniol (0 to 3.0), 2-phenylethanol (1.5 to 56), octanoic acid (0 to 20), and decanoic acid (0 to 3.3). Wines were classified by multivariate statistical methods: principal component analysis, and lineal discriminant analysis. A correct differentiation among wines according to their origin was obtained by lineal discriminant analysis. PMID- 21313820 TI - Optical determination of L-tyrosine based on eggshell membrane immobilized tyrosinase. AB - An optical biosensor based on the eggshell membrane immobilized tyrosinase is described for the detection of L-tyrosine (L-Tyr). The detection scheme was based on the measurement of absorption value of color adduct resulting from the reaction of 3-methyl-2-benzothiazolinone hydrazone and dopa-quinone produced from the enzymatic oxidation of L-Tyr. The prepared biosensor demonstrated optimum activity at pH 7, optimum temperature range of 20-40 degrees C and a linear response for the L-Tyr concentration in range of 5-200 microM. It also showed good operation stability for repeated measurements (over 300 times) and storage stability after it had been kept at 4 degrees C for 3 months. PMID- 21313822 TI - ELISA kit for determination of egg white proteins: interlaboratory study. AB - An interlaboratory study was conducted in 11 laboratories to validate an ELISA method developed for the quantitative determination of egg white proteins (EWPs) in foods. The ELISA kit used for this study is based on sheep polyclonal antibody. It does not produce any false-positive results or cross-reactivity in a broad food matrix range with zero EWP content. All participants obtained the Egg ELISA Kit-native with standard operational procedure and the list of samples, as well as the samples and a protocol for recording test results. The study included 10 food samples. Four samples of food matrix with zero EWP content showed EWP content lower than the first standard (EWP content 0.5 mg/kg). One sample of food matrix with zero EWP content revealed EWP content higher than standard 3 (1.5 mg EWP/kg). Five food samples containing EWP as an ingredient tested positive and one negative. The statistical tests (Cochran, Dixon, and Mandel) and analysis of variance were used to evaluate the interlaboratory study results. Repeatability and reproducibility limits, as well as LOQ (1.4 mg EWP/kg) and LOD (0.43 mg EWP/kg), were calculated for the kit. PMID- 21313823 TI - Genotyping of Francisella tularensis, the causative agent of tularemia. AB - Francisella tularensis is a facultative, intracellular, zoonotic pathogen and the causative agent of tularemia. Historically, F. tularensis has been subdivided into subspecies on the basis of phenotypic traits, including biochemical reactivity and virulence. More recently, a number of genotypic methods, ranging from relatively insensitive methods to full genome sequencing, have been used to investigate genetic diversity within F. tularensis. These analyses indicate that F. tularensis is a pathogen of low sequence diversity with pair-wise average nucleotide identities > 99.2% across subspecies. Nonetheless, genomic rearrangements and sequence deletions exist between and within F. tularensis subspecies, creating polymorphisms detectable by genotyping methods. Genetic subpopulations intermediate to the subspecies and strain level have been identified within F. tularensis subsp. tularensis and F. tularensis subsp. holarctica by several different typing methods. These genetic subpopulations have been associated with differences in disease severity, geographic distribution, and transmission patterns. For example, one F. tularensis subsp. tularensis subpopulation has been found to be significantly associated with mortality in humans. Additionally, genotypic analyses of Francisella spp. have provided information for use in the rational design of strain panels for validation of F. tularensis diagnostic tests. This review provides a guide to the various F. tularensis genotyping methods. PMID- 21313824 TI - Theoretical and experimental aspects of microbicidal activities of hard surface disinfectants: are their label claims based on testing under field conditions? AB - High-touch environmental surfaces are important in the spread of many nosocomial pathogens. Although such surfaces are routinely disinfected, the testing and label claims of many common disinfectants do not reflect the realities of field use. A study was conducted to determine the influence of several crucial factors on the action of disinfectants in general, and to assess the killing efficiency of selected chemistries against Staphylococcus aureus and Pseudomonas aeruginosa, related to their drying times (i.e., after one application) and label-specified contact times using a quantitative carrier test. The products were also tested for their ability to wet a hydrophobic (epoxy resin) surface. The hard-surface disinfectants (in-use concentration in ppm) tested were: (a) chlorine bleach (500); (b) quaternary ammonium compounds (quat; 600) alone; (c) quat (3000) with 17% isopropanol (v/v); (d) quat (3000) with 60% ethanol (v/v); (e) phenolic (800) alone; (f) quat (2000), phenolic (3000) with 70% ethanol (v/v); and (g) accelerated hydrogen peroxide (AHP; 5000 of H2O2). The arbitrarily set criterion of bactericidal activity was > or = 6 log10 reduction in the viability of both species tested. All surfaces tested with all products dried in < 5 min, with alcohol-based surfaces drying significantly faster. Even though the alcohol-free quat and phenolic claim a contact time of 10 min, they dried in < 4 min after a single application and failed to meet the performance criterion. Bleach (500 ppm) dried in about 3 min and was effective. AHP also dried in about 3 min and met its label claim even at 1 min of contact. Quat (3000) with 17% isopropanol dried at 1 min and was effective. Quat (3000) with 60% ethanol and quat (2000), phenolic (3000) with 70% ethanol dried in < 1 min, and were ineffective. AHP, alcohol containing quats, and quat-phenolic-alcohol gave acceptable wettability, while quat and phenolic alone, as well as bleach, covered the treated surface unevenly. The findings show that label claims, especially those for contact times, fail to reflect the way many hard-surface disinfectants are used in the field. PMID- 21313825 TI - Determination of trace amounts of Pd(II) ions in water and road dust samples by flame atomic absorption spectrometry after preconcentration on modified organo nanoclay. AB - This paper describes the application of organo nanoclay, an easily prepared and stable solid sorbent, to the preconcentration of trace amounts of palladium ions in aqueous solution. The organo nanoclay was prepared by adding tetradecyldimethylbenzylamonium chloride onto montmorillonite, which was then modified with 1-(2-pyridylazo)-2-naphthol. The modified nanoclay was used as a solid sorbent for separation and preconcentration of trace amounts of Pd(II) ions, and a simple, sensitive, and economical method was developed for determination of trace amounts of palladium by flame atomic absorption spectrometry. The sorption of Pd(II) ions was quantitative in the pH range of 1.5 5.0, whereas quantitative desorption occurred with 5.0 mL of a mixture containing 1.0 M thiourea and 1.0 M HCl. The RSD of the method was +/- 2.1% (n = 10; concn = 0.5 microg/mL), and the LOD (3sigma(bl); sigma = SD and bl = blank) was 0.1 ng/mL. The calibration curve was linear for concentrations of 0.5-8.0 microg/mL in the initial solution, and the preconcentration factor was 140. The maximum capacity of the sorbent was 2.4 mg Pd(II)/g modified organo nanoclay. The influences of the experimental parameters, including sample pH, eluant volume, eluant type, sample volume, and interfering ions, on the recoveries of the palladium ion were investigated. The proposed method was applied to the preconcentration and determination of palladium in different samples. PMID- 21313826 TI - A fast, inexpensive, and safe method for residue analysis of meptyldinocap in different fruits by liquid chromatography/tandem mass spectrometry. AB - An analytical method is reported for residue analysis of the fungicide meptyldinocap in different fruit matrixes that involves extraction with ethyl acetate, hydrolysis of the residues with ethanolamine, and determination by LC/MS/MS. The method involves extraction of 10 g sample with 10 mL ethyl acetate; evaporation of the ethyl acetate phase to dryness, and subsequent hydrolysis of the residues to 4,6-dinitro-2-(1-methylheptyl) phenol on reaction with 1% ethanolamine. The pH of this hydrolyzed product was neutralized with formic acid and analyzed by LC/MS/MS. The hydrolysis reaction followed pseudo-first-order kinetics, and the reaction product was spectroscopically confirmed as 2-(1 methylheptyl)-4,6-dinitrophenol. The method offered > 80% recoveries at an LOQ of 10 ng/g for grape and mango, 25 ng/g for pomegranate with intralaboratory Horwitz ratio < 0.5, and measurement uncertainties < 10% at LOQ levels. Considering first order rate kinetics, activation energy, enthalpy of activation, and entropy of activation varied as solvent > mango > grape > pomegranate. Free energy of activation at 298 K was higher than at 280 K and was similar for solvent and three matrixes at both temperatures. PMID- 21313827 TI - Analysis of acrylonitrile, 1,3-butadiene, and related compounds in acrylonitrile butadiene-styrene copolymers for kitchen utensils and children's toys by headspace gas chromatography/mass spectrometry. AB - A headspace gas chromatography/mass spectrometry method was developed for the simultaneous determination of the residual levels of acrylonitrile (AN), 1,3 butadiene (1,3-BD), and their related compounds containing propionitrile (PN) and 4-vinyl-1-cyclohexene (4-VC) in acrylonitrile-butadiene-styrene (ABS) copolymers for kitchen utensils and children's toys. A sample was cut into small pieces, then N,N-dimethylacetamide and an internal standard were added in a sealed headspace vial. The vial was incubated for 1 h at 90 degrees C and the headspace gas was analyzed by gas chromatography/mass spectrometry. The recovery rates of the analytes were 93.3-101.8% and the coefficients of variation were 0.3-6.5%. In ABS copolymers, the levels were 0.3-50.4 microg/g for AN, ND-4.5 microg/g for PN, 0.06-1.58 microg/g for 1,3-BD, and 1.1-295 microg/g for 4-VC. The highest level was found for 4-VC, which is a dimer of 1,3-BD, and the next highest was for AN, which is one of the monomers of the ABS copolymer. Furthermore, the method was also applied to acrylonitrile-styrene (AS) copolymers and polystyrenes (PS) for kitchen utensils, and nitrile-butadiene rubber (NBR) gloves. In AS copolymers, AN and PN were detected at 16.8-54.5 and 0.8-6.9 microg/g, respectively. On the other hand, the levels in PS and NBR samples were all low. PMID- 21313828 TI - Simultaneous analysis of 70 pesticides using HPlc/MS/MS: a comparison of the multiresidue method of Klein and Alder and the QuEChERS method. AB - Since 2003, two new multipesticide residue methods for screening crops for a large number of pesticides, developed by Klein and Alder and Anastassiades et al. (Quick, Easy, Cheap, Effective, Rugged, and Safe; QuEChERS), have been published. Our intention was to compare these two important methods on the basis of their extraction efficiency, reproducibility, ruggedness, ease of use, and speed. In total, 70 pesticides belonging to numerous different substance classes were analyzed at two concentration levels by applying both methods, using five different representative matrixes. In the case of the QuEChERS method, the results of the three sample preparation steps (crude extract, extract after SPE, and extract after SPE and acidification) were compared with each other and with the results obtained with the Klein and Alder method. The extraction efficiencies of the QuEChERS method were far higher, and the sample preparation was much quicker when the last two steps were omitted. In most cases, the extraction efficiencies after the first step were approximately 100%. With extraction efficiencies of mostly less than 70%, the Klein and Alder method did not compare favorably. Some analytes caused problems during evaluation, mostly due to matrix influences. PMID- 21313829 TI - Rapid method for the determination of organochlorine pesticides and PCBs in fish muscle samples by microwave-assisted extraction and analysis of extracts by GC ECD. AB - A procedure for the multiresidue determination of organochlorine pesticides and polychlorinated biphenyls in fish muscle samples has been developed. The method is based on the microwave-assisted extraction (MAE) of food samples from an acetonitrile-water (95 + 5, v/v) mixture followed by SPE cleanup of the extracts and analysis by GC with an electron capture detector. MAE operational parameters, such as the extraction solvent, temperature, and time, were optimized with respect to the extraction efficiency of the target compounds from food samples with 10-13% fat content. The chosen extraction technique allows reduction of the solvent consumption and extraction time when compared with methods already used. Acetonitrile is a good extraction solvent for low-fat matrixes (2-20% fat content), such as fish samples, because it does not significantly dissolve the highly polar proteins, salts, and sugars commonly found in food and gives high recoveries of a wide polarity range of analytes. For purification, SPE using LC Florisil was shown to be sufficient for the removal of coextracted substances. Recoveries > 78% with RSD values < 15% were obtained for all compounds under the selected conditions. Method quantification limits were in the 5-10 microg/kg range. The method was applied to the analysis of samples of herring (Clupea harengus) purchased at the local fish market. The method is rapid and reliable for the determination of organochlorine analytes in fish muscle. PMID- 21313830 TI - Simultaneous determination of antazoline and naphazoline by the net analyte signal standard addition method and spectrophotometric technique. AB - A novel net analyte signal standard addition method (NASSAM) was used for simultaneous determination of the drugs anthazoline and naphazoline. The NASSAM can be applied for determination of analytes in the presence of known interferents. The proposed method is used to eliminate the calibration and prediction steps of multivariate calibration methods; the determination is carried out in a single step for each analyte. The accuracy of the predictions against the H-point standard addition method is independent of the shape of the analyte and interferent spectra. The net analyte signal concept was also used to calculate multivariate analytical figures of merit, such as LOD, selectivity, and sensitivity. The method was successfully applied to the simultaneous determination of anthazoline and naphazoline in a commercial eye drop sample. PMID- 21313831 TI - Early history of regulatory requirements for poultry biologics in the United States. AB - Congress passed the Virus-Serum-Toxin Act in 1913, giving the U.S. Department of Agriculture (USDA) authority to prevent the importation or interstate shipment of worthless, contaminated, dangerous, or harmful veterinary biological products. The passage of this act marked the beginning of regulatory requirements for veterinary biological products in the United States. In 1913, only a few biologics establishments produced products for the poultry industry. The first license issued by the USDA for a poultry product was in 1918 to the University of California, Berkeley, for fowlpox vaccine. The list of biological products for poultry grew slowly in the 1920s. However, this began to change with the licensing of laryngotracheitis vaccine in 1933; pigeonpox vaccine in 1939; several Newcastle disease vaccines (inactivated in 1946, Roakin strain in 1948, B1 strain in 1950, and La Sota strain in 1952); and the first bronchitis vaccine in 1953. With the development of these and other new products, the biologics industry began to move its emphasis on hog cholera serum and virus to one based on the production of numerous new vaccines and bacterial products. The USDA's approach to the regulation of biologics in the early 1950s was still geared to the production of hog cholera products; however, as a result of the intervention of a group of dedicated poultry scientists, who were concerned about the poor performance of Newcastle disease vaccines, this soon changed. This presentation describes the initiation and development of modern standards for poultry biologics that occurred as a result of this intervention. The development and improvement of standards and regulatory requirements to address mycoplasma, leukosis, and other extraneous virus contaminations in chicken embryo origin products are reviewed. The licensing of products to meet new and emerging disease problems in the poultry industry and the close interaction among research scientists, poultry industry, biologics manufacturers, and government regulatory officials that has been needed to ensure the availability of products that meet appropriate standards of purity, safety, potency, and efficacy are also addressed. PMID- 21313832 TI - Genotyping of newly isolated infectious bronchitis virus isolates from northeastern Georgia. AB - Sixteen infectious bronchitis virus (IBV) field isolates obtained from vaccinated commercial broiler chickens showing clinical respiratory disease were characterized by reverse transcriptase-polymerase chain reaction and sequence analysis of the hypervariable region of the S1 spike glycoprotein gene. The genetic relationship among these variants and reference strains was determined by phylogenetic analysis and use of the basic local alignment search tool. All the isolates formed a distinct phylogenetic group with very short branched distances, suggesting that isolates had a similar origin. All the isolates showed 85% amino acid identity with recently described Australian isolates, particularly N1-62. Given that little was known about this new emergent IBV we have characterized five field isolates by sequencing the entire S1 gene. Multiple sequence alignment of deduced amino acid sequences with commonly used vaccine strains revealed that most substitutions occurred in the 53-148 amino acid region. A possible recombination site with N1-62 isolate was identified between amino acid residues 115-121. All the field isolates shared four or five out of seven amino acid residues with N1-62 in this region as opposed to Ark-DPI and Mass 41 reference strains, which shared only two residues. Results indicate that IBV isolates reported here can be considered as new IBV genotype. PMID- 21313833 TI - Polymerase chain reaction-based identity assay for pathogenic turkey Eimeria. AB - Diagnosis of turkey Eimeria infection by conventional parasitologic methods is challenging and, until now, no molecular tools existed that clearly distinguished the four widely recognized pathogenic species: Eimeria adenoeides, E. meleagrimitis, E. gallopavonis, and E. dispersa. In this study, the internal transcribed spacer region one (ITS-1) was amplified and sequenced from 23 conventionally characterized reference samples. Phylogenic analysis segregated samples into five distinct cluster groups. The ITS-1 region(s) within each cluster were of a particular length and shared from 96% to 100% identity, while amplified ITS-1 region(s) between clusters differed in length and shared only 10.6% to 49.7% sequence identity. In addition, we developed PCR primer sets as diagnostic tools capable of specifically identifying members of each of the five clusters. PMID- 21313834 TI - Characterization of recombinant raccoonpox vaccine vectors in chickens. AB - Raccoonpox virus (RCN) has been used as a recombinant vector against several mammalian pathogens but has not been tested in birds. The replication of RCN in chick embryo fibroblasts (CEFs) and chickens was studied with the use of highly pathogenic avian influenza virus H5N1 hemagglutinin (HA) as a model antigen and luciferase (luc) as a reporter gene. Although RCN replicated to low levels in CEFs, it efficiently expressed recombinant proteins and, in vivo, elicited anti HA immunoglobulin yolk (IgY) antibody responses comparable to inactivated influenza virus. Biophotonic in vivo imaging of 1-wk-old chicks with RCN-luc showed strong expression of the luc reporter gene lasting up to 3 days postinfection. These studies demonstrate the potential of RCN as a vaccine vector for avian influenza and other poultry pathogens. PMID- 21313835 TI - Tibial dyschondroplasia-associated proteomic changes in chicken growth plate cartilage. AB - Tibial dyschondroplasia (TD) is a poultry leg problem that affects the proximal growth plate of the tibia, preventing its transition to bone. To understand the disease-induced proteomic changes, we compared the protein extracts of cartilage from normal and TD-affected growth plates. TD was induced by feeding thiram to chickens 2 wk before tissue harvest. Proteins were extracted from whole tissues and from conditioned media (CM) prepared by incubating appropriate growth plate tissues in serum-free culture medium for 48 hr. The extracts were prefractionated to contain proteins ranging between 10 and 100 kD. Equal amounts of proteins were subjected to 2D gel electrophoresis with three individual samples per group. The gels were silver stained, and digital images were compared and analyzed with Melanie software to determine differentially expressed protein spots. On comparison of two sets of gels, 47 matching spots were detected in tissue extracts and 27 in CM extracts. Among the matching spots, 12 were determined to be down-regulated in tissue extracts (P < or = 0.05) and two in CM extracts (P < or = 0.05) of TD-affected growth plates. Altogether, 32 protein spots could be identified in both tissue and CM extracts by in-gel trypsin digestion, followed by peptide mass fingerprinting and mass spectrometry (MS)/MS fragmentation. The down-regulated proteins included alpha-enolase, G protein, origin recognition complex, peptidyl prolyl isomerase, calumenin, type II collagen precursor, and the expressed sequence tag pgm2n.pk014.f20, a protein with homology to human reticulocalbin-3 (RCN3). Most of the downregulated proteins are associated with signal transduction, energy metabolism, and secretory functions that are integral to cell viability. Consistent with our earlier findings that the TD chondrocytes are nonviable, the current results suggest that thiram very likely interferes with basic metabolic functions of chondrocytes, leading to their death and, consequently, to the pathogenesis of TD. PMID- 21313836 TI - Epidemic of infectious laryngotracheitis in Italy: characterization of virus isolates by PCR-restriction fragment length polymorphism and sequence analysis. AB - Between May 2007 and October 2008, 34 outbreaks of mild to moderate forms of infectious laryngotracheitis (ILT) occurred in commercial broiler flocks in Italy. Affected birds showed watery eyes, conjunctivitis, nasal discharge, reduction of feed and water consumption, and gasping with expectoration of blood stained mucus. The mortality rate was < 10%. Gross lesions consisted of conjunctivitis, excess of mucus, blood, or presence of diphtheritic membranes in trachea. A real-time PCR assay was performed to confirm the presence of ILT virus (ILTV) DNA in tracheal tissue homogenates. Twenty-three ILTV isolates were propagated on the chorion-allantoic membrane of embryonated chicken eggs showing typical plaques. PCR combined with restriction fragment length polymorphism and gene sequencing of isolates showed a high genetic correlation between field strains and chicken embryo origin vaccines. PMID- 21313837 TI - Presence of arsenic resistance in Salmonella enterica serovar Kentucky and other serovars isolated from poultry. AB - A collection of 125 Salmonella enterica poultry isolates (71 serovar Kentucky isolates, and the remainder belonging to serovars Alachua, Enteritidis, Hadar, Heidelberg, Montevideo, Mbandaka, Senftenberg, Typhimurium, and Worthington) were tested for the ability to grow on tryptic soy agar containing sodium arsenite [As(III)] or arsenate [As(V)]. All serovar Kentucky isolates and 18 of the non Kentucky isolates were able to grow in the presence of 0.1 mM As(III), and 69 grew in the presence of 1 mM As(V). Thirty of the non-Kentucky isolates did not grow at these As(III) and As(V) concentrations, but seven grew at 1 mM As(III) and 10 mM As(V). PCR-based analysis demonstrated the presence of arsB and arsD sequences in all Kentucky isolates, whereas one or both of these sequences were present in only 30 of the other isolates. It remains to be determined if these arsenic-resistance determinants benefit Salmonella exposed to man-made arsenic containing compounds in poultry environments. PMID- 21313838 TI - Accumulation of a low pathogenic avian influenza virus in zebra mussels (Dreissena polymorpha). AB - In order to investigate the potential role of mussels as a vector of influenza A viruses, we exposed zebra mussels (Dreissena polymorpha) to natural lake water containing a low pathogenic H5N1 avian influenza virus. Mussels were kept in water containing virus for 48 hr, then transferred into fresh water for another 14 days. Virus detection in mussels and water samples was performed by quantitative real-time reverse transcriptase-PCR (qRRT-PCR) and egg culture methods. Virus uptake was detected in all of the mussel groups that were exposed to virus. Even after 14 days in fresh water, virus could still be detected in shellfish material by both qRRT-PCR and egg culture methods. The present study demonstrates that zebra mussels are capable of accumulating influenza A viruses from the surrounding water and that these viruses remain in the mussels over an extended period of time. PMID- 21313839 TI - Genetic diversity of avian infectious bronchitis virus isolated from domestic chicken flocks and coronaviruses from feral pigeons in Brazil between 2003 and 2009. AB - To detect the presence of infectious bronchitis virus or avian coronavirus, a nested reverse transcriptase PCR (RT-PCR) method was developed with the aim of amplifying a fragment of 530 bases, comprising the gene coding S1 protein. In the first step, all samples were submitted to RNA extraction, RT-PCR, and nested PCR. Next, only the positive nested-PCR samples were propagated in specific-pathogen free (SPF) embryonated chicken eggs for virus isolation. Positive samples were then sequenced and analyzed using a molecular phylogeny approach. Tracheal swab samples were collected from 23 different domestic chickens distributed in three regions of Brazil, in the period between 2003 and 2009. Also analyzed were six swab samples (tracheal and cloacal) from asymptomatic pigeons (Columba livia), caught in an urbanized region in southeastern Brazil. The study revealed two major phylogenetic groups: one clustered with the Massachusetts vaccine serotype and another joined with the D207 strain. Interestingly, samples grouped with the Connecticut and Arkansas serotypes were also found. Pigeon isolates clustered with the Massachusetts serotype showed significant similarity (close to 100%) to those obtained from chickens. Only one pigeon isolate was seen to be grouped with the Connecticut serotype, and no correlation was observed between sample grouping and region origin. Understanding the diversity of genotypes and eco-epizootiology of the disease in different environments is expected to be helpful for vaccine production aimed at the main circulating variants. In this respect, one could also expect benefits in the management of other bird species that may act as avian coronavirus reservoirs. PMID- 21313840 TI - Efficacy of avian influenza vaccine in poultry: a meta-analysis. AB - Vaccination is an effective method for controlling avian influenza (AI), especially in countries with endemic infection. This study conducted a Bayesian meta-analysis to evaluate the efficacy of AI vaccines in chickens. We included both inactivated and recombinant fowlpox virus expressing H5 (rFPV-H5) vaccine studies that used specific-pathogen-free chickens where outcomes against the H5N1 or H5N2 AI viruses were measured. Vaccine efficacy was evaluated by protection from mortality, protection from morbidity, reductions in virus isolation from the respiratory tract, and reductions in virus isolation from the cloaca. The efficacies for homologous inactivated vaccines by those four outcomes were 92% (95% confidence interval 90%-95%), 94% (91%-96%), 54% (50%-58%), and 88% (84% 91%), respectively. Corresponding figures for heterologous inactivated vaccines were 68% (63%-73%), 78% (74%-81%), 24% (16%-31%), and 71% (64%-77%); and efficacies for rFPV-H5 vaccine were 97% (94%-99%), 93% (90%-94%), 21% (14%-27%), and 78% (72%-84%), respectively. Although those vaccines protect chickens from morbidity and mortality, virus shedding would be an important biosecurity issue for further AI endemic control. PMID- 21313841 TI - Protection induced by infectious laryngotracheitis virus vaccines alone and combined with Newcastle disease virus and/or infectious bronchitis virus vaccines. AB - Two types of live attenuated vaccines have been used worldwide for the control of infectious laryngotracheitis virus (ILTV): 1) chicken embryo origin (CEO) vaccines; and 2) tissue culture origin vaccines (TCO). However, the disease persists in spite of extensive use of vaccination, particularly in areas of intense broiler production. Among the factors that may influence the efficiency of ILTV live attenuated vaccines is a possible interference of Newcastle Disease virus (NDV) and infectious bronchitis virus (IBV) vaccines with the protection induced by ILTV vaccines. The protection induced by CEO and TCO vaccines was evaluated when administered at 14 days of age alone or in combination with the B1 type strain of NDV (B1) and/or the Arkansas (ARK) and Massachusetts (MASS) serotypes of IBV vaccines. Two weeks after vaccination (28 days of age), the chickens were challenged with a virulent ILTV field strain (63140 isolate, group V genotype). Protection was evaluated at 5 and 7 days postchallenge by scoring clinical signs and quantifying the challenge virus load in the trachea using real time PCR (qPCR). In addition, the viral load of the vaccine viruses (ILTV, NDV, and IBV) was quantified 3 and 5 days postvaccination also using qPCR. The results of this study indicate that the NDV (B1) and IBV (ARK) vaccines and a multivalent vaccine constituted by NDV (B1) and IBV (ARK and MASS) did not interfere with the protection induced by the CEO ILTV vaccine. However, the NDV (BI) and the multivalent (B1/MASS/ARK) vaccines interfered with the protection induced by the TCO vaccine (P < 0.05). Either in combination or by themselves, the NDV and IBV vaccines decreased the tracheal replication of the TCO vaccine and the protection induced by this vaccine, since the ILTV-vaccinated and -challenged chickens displayed significantly more severe clinical signs and ILTV load (P < 0.05) than chickens vaccinated with the TCO vaccine alone. Although NDV and IBV challenges were not performed, the antibody responses elicited by NDV and/or the IBV vaccinations were significantly reduced (P < 0.05) when applied in combination with the CEO vaccine. PMID- 21313842 TI - Low-dose immunization of northern bobwhites (Colinus virginianus) with Eimeria lettyae provides protection against a high-dose challenge. AB - To determine whether northern bobwhite quail (Colinus virginianus) could be immunized against Eimeria lettyae by a low-dose inoculation of oocysts, we inoculated 30 birds each with either 100 or 1000 oocysts at 2 days of age (given orally by pipette). Four weeks after immunization, the immunized birds and unimmunized controls were challenged with 1 x 10(6) E. lettyae oocysts. Eight days after challenge, birds were killed and weighed, and their intestines examined for gross lesions. Effectiveness of the immunization was measured by analyzing weight gain, intestinal lesions, severity of diarrhea, feed conversion ratio, and oocyst production. After challenge, birds immunized with 100 or 1000 oocysts gained an average of 33.3 g and 28.9 g, respectively, whereas unimmunized challenged birds gained an average of 11.5 g. Immunized quail produced approximately 99.7% fewer oocysts, had minimal gross intestinal and cecal lesions, had minimal diarrhea, and had a 50% lower feed conversion ratio compared to unimmunized challenged controls. These findings indicate that vaccination is a viable option for controlling coccidiosis in quail and that further research into vaccination is warranted. PMID- 21313843 TI - Single vaccination provides limited protection to ducks and geese against H5N1 high pathogenicity avian influenza virus. AB - Since 2002, high pathogenicity avian influenza (HPAI) has spread from Asia to Europe and into Africa, causing the largest epizootic of HPAI of the last 50 yr, including infecting domestic and wild waterfowl. Our study was conducted to investigate whether a single vaccination of 7-day-old domestic ducks and geese with inactivated oil emulsion vaccines resulted in protection against HPAI virus challenge at 30 days of age. In ducks, some but not all vaccines decreased oropharyngeal and cloacal viral shedding for different periods postchallenge when compared with the sham group. In geese, decreased morbidity signs and mortality were noted but limited to some vaccines. Best protection was seen with a vaccine homologous to HPAI challenge virus. Limited decreases in oropharyngeal and cloacal viral shedding and mixed results were attained when looking at seroconversion. Our results indicate a single dose of oil-emulsified vaccine optimized for chickens did not provide adequate protection for ducks and geese against HPAI virus, and, at a minimum, additional research is needed to formulate waterfowl-specific vaccines. PMID- 21313844 TI - Diagnostic utility of egg yolk for the detection of avian metapneumovirus antibodies in laying hens. AB - Surveillance and diagnosis of avian metapneumovirus (AMPV) infection typically involve measurement of serum antibodies. In the current study, eggs instead of serum samples were used for the detection of AMPV antibodies in egg-laying chicken hens by enzyme-linked immunosorbent assay (ELISA). AMPV-free commercial layer hens were experimentally challenged with AMPV strain SC1509 through intravenous or oculonasal administration. Antibody levels were determined by ELISA. AMPV antibodies were detected in egg yolks from challenged hens by 7 days postinoculation (dpi), with the peak titer at 16 dpi. Antibody levels in eggs laid at 28 dpi correlated well (r = 0.93) with sera taken 28 dpi from the same hens. In a field trial of the yolk ELISA, six broiler breeder farms were surveyed, and all tested positive for AMPV antibodies in hen eggs, although positivity varied from farm to farm. Abnormal discolored eggs collected from outbreak farms had significantly higher titers of AMPV yolk antibodies than normal eggs from the same farm, unlike clinically healthy farms, where normal and abnormal eggs had similar antibody titers. These results indicate that diagnosis of AMPV infection by yolk ELISA to detect anti-AMPV antibodies may be a suitable alternative to serologic testing. PMID- 21313845 TI - An economic analysis of the impact of subclinical (mild) necrotic enteritis in broiler chickens. AB - Costs to broiler producers associated with subclinical (mild) necrotic enteritis (SNE) were estimated using published information on impacts on body weight and feed conversion rate (FCR) associated with SNE and costs and revenues associated with broiler production. Estimates were expressed in U.S. dollars from the perspective of poultry producers. SNE was estimated to result in a 12% reduction in body weight and a 10.9% increase in FCR compared with healthy birds. For the purposes of this analysis, we considered scenarios involving hypothetical flocks of 20,000 birds raised to final body weights ranging from 4.63 to 7.94 lb. The incidence of SNE was assumed to occur at 20% based on the literature. For flocks raised for the length of time required to reach these target weights, SNE resulted in a loss to producers ranging from US$878.19 to US$1480.52 per flock. When feed costs required to obtain SNE flocks having a total live body weight equal to equivalent healthy flocks at market age were calculated, the increased cost to producers ranged from US$370.49 to US$739.38 per flock. SNE has the potential to cause a significant negative economic impact in broiler flocks. Strategies to reduce the incidence of SNE may help to increase the profitability of broiler production. PMID- 21313846 TI - Causes of mortality in commercial organic layers in Denmark. AB - A longitudinal study investigated the courses of mortality in commercial free range organic layer flocks in Denmark. In total, 15 organic egg-producing flocks from 11 farms were randomly selected among 80 farms registered in Denmark. Four farms with confined egg production on deep litter were included for comparison. Flock sizes ranged from 2260 to 5940 layers. The flocks were monitored from introduction to the layer farm until slaughter. Flock mortalities ranged from approximately 2% to 91%, with a mean of 20.8% for organic flocks compared with 7% for confined flocks on deep litter. In total, 4608 layers were submitted for postmortem examination, representing > 40% of all the dead layers in the investigated flocks. Outbreaks of erysipelas (Erysipelothrix rhusiopathiae) and fowl cholera (Pasteurella multocida) were observed in two and three organic flocks, respectively. The mortality rate reached 91% in one organic flock dually affected by erysipelas and fowl cholera. In six organic flocks, outbreaks of blackhead were diagnosed. Concurrent infections of erysipelas and blackhead were diagnosed in one organic flock. Escherichia coli infections in the form of septicemia were identified in all organic flocks. In addition, cannibalism and constipation contributed significantly to the mortality in some organic flocks. In the confined deep litter flocks, E. coli infection, constipation, and cannibalism represented the most common causes of mortality. PMID- 21313847 TI - Protection against infectious laryngotracheitis by in ovo vaccination with commercially available viral vector recombinant vaccines. AB - Infectious laryngotracheitis (ILT) is a highly contagious respiratory disease of chickens caused by infectious laryngotracheitis virus (ILTV). The disease is mainly controlled through biosecurity and by vaccination with live-attenuated vaccines. The chicken embryo origin (CEO) vaccines, although proven to be effective in experimental settings, have limited efficacy in controlling the disease in dense broiler production sites due to unrestricted use and poor mass vaccination coverage. These factors allowed CEO vaccines to regain virulence, causing long lasting and, consequently, severe outbreaks of the disease. A new generation of viral vector fowl poxvirus (FPV) and herpesvirus of turkey (HVT) vaccines carrying ILTV genes has been developed and such vaccines are commercially available. These vaccines are characterized by their lack of transmission, lack of ILTV-associated latent infections, and no reversion to virulence. HVT-vectored ILTV recombinant vaccines were originally approved for subcutaneous HVT or transcutaneous (pox) delivery. The increased incidence of ILTV outbreaks in broiler production sites encouraged the broiler industry to deliver the FPV-LT and HVT-LT recombinant vaccines in ovo. The objective of this study was to evaluate the protection induced by ILTV viral vector recombinant vaccines after in ovo application in 18-day-old commercial broiler embryos. The protection induced by recombinant ILTV vaccines was assessed by their ability to prevent clinical signs and mortality; to reduce challenge virus replication in the trachea; to prevent an increase in body temperature; and to prevent a decrease in body weight gain after challenge. In this study, both recombinant vectored ILTV vaccines provided partial protection, thereby mitigating the disease, but did not reduce challenge virus loads in the trachea. PMID- 21313848 TI - Different routes of inoculation impact infectivity and pathogenesis of H5N1 high pathogenicity avian influenza virus infection in chickens and domestic ducks. AB - The H5N1 type A influenza viruses classified as Qinghai-like virus (clade 2.2) are a unique lineage of type A influenza viruses with the capacity to produce significant disease and mortality in gallinaceous and anseriform birds, including domestic and wild ducks. The objective of this study was to determine the susceptibility and pathogenesis of chickens and domestic ducks to A/Whooper Swan/Mongolia/224/05 (H5N1) high pathogenicity avian influenza (HPAI) virus when administered through respiratory or alimentary routes of exposure. The chickens and ducks were more susceptible to the H5N1 HPAI virus, as evidenced by low infectious and lethal viral doses, when exposed by intranasal as compared to alimentary routes of inoculation (intragastric or oral-fed infected chicken meat). In the alimentary exposure pathogenesis study, pathologic changes included hemorrhage, necrosis, and inflammation in association with virus detection. These changes were generally observed in most of the visceral organs of chickens, between 2 and 4 days postinoculation (DPI), and are similar to lesions and virus localization seen in birds in natural cases or in experimental studies using the intranasal route. Alimentary exposure to the virus caused systemic infection in the ducks, characterized by moderate lymphocytic encephalitis, necrotized hepatitis, and pancreatitis with a corresponding demonstration of virus within the lesions. In both chickens and ducks with alimentary exposure, lesions, virus, or both were first demonstrated in the upper alimentary tract on 1 DPI, suggesting that the alimentary tract was the initial site affected upon consumption of infected meat or on gavage of virus in liquid medium. However, as demonstrated in the infectivity study in chickens, alimentary infection required higher exposure doses to produce infection as compared to intranasal exposure in chickens. These data suggest that upper respiratory exposure to H5N1 HPAI virus in birds is more likely to result in virus infection and transmission than will consumption of infected meat, unless the latter contains high doses of virus, as found in cannibalized infected carcasses. PMID- 21313849 TI - Development and validation of an indirect enzyme-linked immunosorbent assay for the detection of antibodies against duck swollen head hemorrhagic disease virus. AB - An indirect enzyme-linked immunosorbent assay (iELISA) was developed for detecting antibody to duck swollen head hemorrhagic disease virus (DSHDV) using purified whole virus by sucrose density gradient ultracentrifugation as a coating antigen. Antiserum against DSHDV strains HY-99 (hyperimmume serum) was prepared in 30-day-old ducks by vaccination with inactivated DSHDV and used as positive sera. The iELISA test was optimized with different reagents or dilutions. The validation results showed that this assay was only specific for antibodies against duck viral swollen head hemorrhagic disease. The OD450 value for positive serum diluted 1:800 was also determined to be greater than the positive threshold. The highest coefficient of variation value was 3.66% for the intra assay and 5.79% for the interassay, which were all less than 10%. This assay has been successfully applied to the examination of the duck sera clinically. These results in this study indicate that the newly-developed iELISA offers a precise, specific, sensitive, and reproducible means of measuring DSHDV antibodies in duck sera. PMID- 21313850 TI - Molecular characterization of pandemic H1N1 influenza viruses isolated from turkeys and pathogenicity of a human pH1N1 isolate in turkeys. AB - Suspected human-to-animal transmission of the 2009 pandemic H1N1 (pH1N1) virus has been reported in several animal species, including pigs, dogs, cats, ferrets, and turkeys. In this study we describe the genetic characterization of pH1N1 viruses isolated from breeder turkeys that was associated with a progressive drop in egg production. Sequence analysis of all eight gene segments from three viruses isolated from this outbreak demonstrated homology with other human and swine pH1N1 isolates. The susceptibility of turkeys to a human pH1N1 isolate was further evaluated experimentally. The 50% turkey infectious dose (TID50) for the human isolate A/Mexico/LnDRE/4487/2009 was determined by inoculating groups of 8 10-week-old turkeys with serial 10-fold dilutions of virus by oronasal and cloacal routes. We estimated the TID50 to be between 1 x 10(5) and 1 x 10(6) TCID50. The pathogenesis of pH1N1 in oronasally or cloacally inoculated juvenile turkeys was also examined. None of the turkeys exhibited clinical signs, and no significant difference in virus shedding or seroconversion was observed between the two inoculation groups. More than 50% of the turkeys in both oronasal and cloacal groups shed virus beginning at 2 days postinoculation (dpi). All birds that actively shed virus seroconverted by 14 dpi. Virus antigen was demonstrated by immunohistochemistry in the cecal tonsils and bursa of Fabricius in two of the birds that were infected by the cloacal route. Virus transmission to naive contact turkeys was at best doubtful. This report provides additional evidence that pH1N1 can cross the species barrier and cause disease outbreaks in domestic turkeys. However, it appears that the reproductive status of the host as well as environmental factors such as concurrent infections, stress, the presence or absence of litter, and stocking density may also contribute to efficient infection and transmission of this agent. PMID- 21313851 TI - Effect of a prior exposure to a low pathogenic avian influenza virus in the outcome of a heterosubtypic low pathogenic avian influenza infection in mallards (Anas platyrhynchos). AB - Wild birds, particularly Anseriformes and Charadriiformes, are considered the natural reservoir of low pathogenic avian influenza (LPAI) viruses. The high prevalence and subtype diversity of avian influenza viruses at premigrational staging areas provide the perfect opportunity for multiple exposures to different LPAI virus subtypes. Natural consecutive and concurrent infections of sentinel ducks with different LPAI virus subtypes have been reported. The protective immune response from different LPAI virus infections is not understood nor is the effect of such repeated exposures. This study experimentally evaluated the effect of a prior exposure to a LPAI virus on the outcome of a heterosubtypic LPAI virus infection in mallards (Anas platyrhynchos). The results of this investigation suggest that recent prior exposure to a LPAI virus may affect the outcome of a subsequent heterosubtypic LPAI infection in mallards by reducing the duration of cloacal and oropharyngeal viral shedding as well as the viral load excreted via the cloaca. Wild mallards are likely exposed to multiple subtypes of LPAI virus during the periods of peak viral circulation, and the results of this study suggest that the duration of viral shedding in subsequent exposures might be reduced. PMID- 21313852 TI - Revised Mycoplasma synoviae vlhA PCRs. AB - Mycoplasma synoviae (MS) is an important pathogen of chickens and turkeys. In recent years sequence analysis of the partial MS variable lipoprotein and hemagglutinin A (vlhA) gene PCR product has been utilized routinely for MS strain genotyping. Several PCR assays have been proposed for the amplification of the conserved upstream region of the MS vlhA gene; however, in several clinical instances the published assays failed to generate vlhA PCR products from confirmed MS-positive cases. These occurrences hindered our capability to genotype those cases. In silico analysis of the published MS vlhA PCRs raised concerns, which were addressed by the design of revised MS vlhA PCRs. The published and revised assays were tested for their relative sensitivity and specificity with laboratory and clinical MS-positive samples. One of the revised MS vlhA PCRs (revised Hong) was demonstrated to be more sensitive and specific, and amplified all clinical samples analyzed in this study. PMID- 21313853 TI - Effect of a radiant energy-treated lysozyme antimicrobial blend on the control of clostridial necrotic enteritis in broiler chickens. AB - A cage study was conducted to demonstrate the effect of Entegard REV, a lysozyme based antimicrobial blend, on the performance of broiler chickens and necrotic enteritis (NE) disease reduction of birds that were challenged with Eimeria maxima and Clostridium perfringens. In the experiment, challenge by the infectious agents without medication resulted in impaired feed consumption, weight gain, and feed conversions and caused high incidence of gross NE lesions and NE mortality rate. Entegard REV included in feed at 200 g/metric ton (MT) was very effective in reducing negative health effects in the birds after NE challenge, and its ability to control the disease was not statistically different from a commonly used antibiotic growth promotant, bacitracin methylene disalicilate, at 55 g/MT. PMID- 21313854 TI - Modified H5 real-time reverse transcriptase-PCR oligonucleotides for detection of divergent avian influenza H5N1 viruses in Egypt. AB - The efforts exerted to prevent circulation of highly pathogenic avian influenza (HPAI) H5N1 virus in birds are the best way to prevent the emergence of a new virus subtype with pandemic potential. Despite the blanket vaccination strategy against HPAI H5N1 in Egypt, continuous circulation of the virus in poultry has increased since late 2007 as a result of the presence of genetic and antigenic distinct variant strains that have escaped during the immune response of vaccinated birds. Although the suspected poultry flocks have had signs and lesions commonly seen in HPAI H5N1-infected birds, escape of variant strains from detection by real-time reverse transcriptase-PCR (RRT-PCR) was observed. Sequence analysis of these variants revealed multiple single nucleotide substitutions in the primers and probe target sequences of the H5 gene by real-time RT-PCR. This study describes the results of RRT-PCR, modified from an existing protocol with regard to the detection of the partial H5 gene segment of the Egyptian H5N1 divergent viruses and applied to nationwide surveillance. The modified RRT-PCR assay was more sensitive than the original one in the detection of Egyptian isolates, with 104% amplification efficiency. Sixty-one field samples were found to be positive in our assay, but only 51 samples tested positive by the original protocol and were more sensitive than matrix gene RRT-PCR detection assay. A detection limit of 10 mean embryo infective dose (EID50) with the updated oligonucleotides primers and probe set was found. For the foreseeable future, mutation of H5N1 viruses and the endemic situation in developing countries require continuous improvement of current diagnostics to aid in the containment of the H5N1 virus in poultry sectors and to lower the threat of influenza virus spread. PMID- 21313855 TI - Histopathologic findings in chickens experimentally infected with Gallibacterium anatis by nasal instillation. AB - Histologic findings in chickens experimentally infected by nasal instillation with reference strains of Gallibacterium anatis are described. No clinical signs were observed in experimentally infected birds; however, sequential histologic examinations of trachea, lung, air sacs, and liver revealed lesions in all infected chickens. Our observations suggest that the reference strains of G. anatis used in this experiment are capable of causing primary infection in chickens. Despite that the experimental birds were inoculated by intranasal route, lesions were detected in the liver, suggesting a probable bacteremia. Because several degrees of severity were established in histopathologic lesions, probable variations in virulence, among the experimental strains, also are discussed. PMID- 21313856 TI - Eye surface area and dosage rates for spray vaccination. AB - Spray application of Mycoplasma gallisepticum (MG) vaccines is a labor- and time saving means of mass vaccination of layer chickens. Recent assessment of spray characteristics of nozzles commonly used to apply MG vaccine in layer chicken operations has shown that the amount of respirable droplets (< 5 microm) is negligible. Topical application of vaccine onto the eye surface has been suggested as a route of vaccination, but no estimates of vaccine load delivered via spray application were found in the literature. Estimates of eye surface area were developed using digital imaging; 24 layer pullets were used for analysis, and the mean eye surface area, corrected for corneal curvature, was found to be 0.609 cm2. This surface area was then used to estimate vaccine load for commercially available live MG vaccine sprayed through popular nozzles. Less than 3000 colony-forming units can be expected for direct deposition onto the surface of an eye. PMID- 21313857 TI - Atypical distribution of fowl pox lesions in broilers. AB - An unusual cutaneous fowl pox outbreak occurred in 8-wk-old broilers in California. Rounded and longitudinal, proliferative scratch-associated lesions were found only in feathered areas of the body. Both sides of the hip, the lower abdomen, pericloacal area, and lateral lower neck area were involved. The head, legs, feet, and toes did not have lesions. Birds in only one section of one of five houses were affected. Fifteen percent condemnations occurred in birds from the affected house due to the skin lesions. A diagnosis of fowl pox was achieved by histopathology, viral isolation, and direct electron microscopy. The unusual distribution of pox lesions was assumed to be associated with skin scratches. There was no evidence that mosquitoes or other types of insects were involved in this outbreak. To the knowledge of the authors, this is the first report of this kind of unusual fowl pox in the United States. PMID- 21313858 TI - Myxosarcomas associated with avian leukosis virus subgroup A infection in fancy breed chickens. AB - Formalin-fixed suspect tumors were submitted to the Poultry Diagnostic and Research Center at the University of Georgia (Athens, GA) for diagnosis. Samples were from fancy breed chickens with a history of increased tumor prevalence in both hens and roosters. Microscopically, in all the samples, there were neoplastic proliferations of spindle-shaped cells. The matrix surrounding tumor cells stained positively with Alcian blue at pH 2.5, but neoplastic cells did not stain with periodic acid-Schiff. Immunohistochemistry stains were positive for vimentin and neuron-specific enolase and negative for desmin, smooth muscle actin, and S-100 protein. Tumors were determined to be myxosarcomas. All samples were positive for PCR targeting the gp85 avian leukosis virus (ALV) envelope protein. However, analysis of the predicted amino acid sequences in the envelope gene from three separate samples showed high similarity between them and to ALV subgroup A. PMID- 21313859 TI - Hepatic hemosiderosis in red-spectacled Amazons (Amazona pretrei) and correlation with nutritional aspects. AB - Alimentary habits of free-living Psittaciformes vary significantly among different species. Amazona pretrei is under risk of extinction and has very specific free-living dietary habits, which are based on Parana pine seeds. Hemosiderosis is a pathologic process characterized by intracellular accumulation of iron without other evident lesions. It is associated with increased prevalence of infections, neoplasms, and hepatopathies. The purpose of this study was to quantify hepatic hemosiderin deposits in captive A. pretrei and verify their association with nutritional parameters. Liver samples were processed for histopathology and stained with Prussian blue. The sections were analyzed by computerized morphometry to quantify the hepatic hemosiderin deposits. The hepatic hemosiderosis rates showed positive correlation with age and time in captivity. These results suggest that the menus and commercial rations for Psittacidae must be carefully revised. PMID- 21313860 TI - A possible application of care-based ethics to people with disabilities during a pandemic. AB - Should people with exceptionally profound disabilities be given an equal chance of surviving a pandemic, even when their care might require a greater use of limited medical resources? How might an ethics of care be used to shape a policy regarding these patients? PMID- 21313861 TI - Bedside ethics and health system catastrophe: imagine if you will... AB - Preparations for large-scale disasters have tended to focus on triage schema, stockpiling of materials, and other logistical concerns. Less attention has been given to the myriad of distressing and almost unthinkable ethically charged dilemmas that will emerge at the bedside during a catastrophe, and how they may be best managed. Yet, it is these bedside issues that may limit or thwart the effectiveness of disaster planning, and, therefore, they ought to be carefully considered. PMID- 21313862 TI - Family participation in the care of patients in public health disasters. AB - The ethical implications of disaster planning garner increasing scrutiny. The role of families in disaster efforts is a topic that requires additional ethical examination. This article reviews the potential roles for families before and during disasters, with particular attention to the impact on children and vulnerable elderly patients. The potential positive and negative impact of family participation in different aspects of healthcare and disaster efforts is assessed. PMID- 21313863 TI - Sufficiency of care in disasters: ventilation, ventilator triage, and the misconception of guideline-driven treatment. AB - This essay examines the management of ventilatory failure in disaster settings where clinical needs overwhelm available resources. An ethically defensible approach in such settings will adopt a "sufficiency of care" perspective that is: (1) adaptive, (2) resource-driven, and (3) responsive to the values of populations being served. Detailed, generic, antecedently written guidelines for "ventilator triage" or other management issues typically are of limited value, and may even impede ethical disaster response if they result in rescuers' clumsily interpreting events through the lens of the guideline, rather than customizing tactics to the actual context. Especially concerning is the tendency of some expert planners to mistakenly assume that medical treatment of respiratory failure: (1) always requires full-feature mechanical ventilators, (2) will always occur in hospitals, and (3) can be planned in advance without sophisticated public consultation about likely ethical dilemmas. PMID- 21313864 TI - Pandemic preparedness planning: will provisions for involuntary termination of life support invite active euthanasia? AB - A number of influential reports on influenza pandemic preparedness include recommendations for extra-autonomous decisions to withdraw mechanical ventilation from some patients, who might still benefit from this technology, when demand for ventilators exceeds supply. An unintended implication of recommendations for nonvoluntary and involuntary termination of life support is that it make pandemic preparedness plans vulnerable to patients' claims for assisted suicide and active euthanasia. Supporters of nonvoluntary passive euthanasia need to articulate why it is both morally different and morally superior to voluntary active euthanasia if they do not wish to invite expansion of end-of-life options during health system catastrophe. PMID- 21313865 TI - Should palliative care be a necessity or a luxury during an overwhelming health catastrophe? AB - In the event of a widespread health catastrophe in which either or both human and material resources were in critically short supply, rationing must take place, especially if the scarcity will last for some time. There are several tested allocation methods that are routinely used during emergencies. These include triage procedures employed by emergency departments and the military on the battlefield. The goal is to save the lives of as many as possible. When it is not possible to save all, or even most, who come for care, what should be done, if anything, with those whose fate is death? The central tenet and goal of medicine is the relief of suffering. If we take this seriously as an axiom of practice, then healthcare providers and the institutions in which they work are duty-bound to provide comfort and relief to all, especially the dying. There are several ways this can be done. One is to prepare by training sufficient individuals to provide what might be called emergency palliative care. These people do not all have to be doctors but could (and should) include people from a range of backgrounds including nursing, allied health, pastoral care, and social work. For them to be able to do their jobs effectively, some basic supplies should be stockpiled so the pain and suffering associated with untreated illness and injury can be relieved. However, what happens when there is a shortage of, say, opiates, so that relief of air hunger and pain cannot be eased? Then critical decisions must be made. Alternative sources of symptom relief not considered under ordinary circumstances might be used. However, it is possible to imagine a situation when all resources are in critically short supply. Those remaining resources, logically and morally, should be allocated to persons who can survive. In this scenario, what can be offered to the suffering dying? This might depend on the attitude of personnel caring for patients. In desperate circumstances, it is possible the proscription against active euthanasia could be justifiably overridden by concern for ongoing, relentless, and unmitigated suffering. Any justification that could be made for such action would be undermined by arbitrary or capricious administration. Thus, preparation for a catastrophic healthcare emergency should take into account all conceivable outcomes. PMID- 21313866 TI - Taking seriously the "what then?" question: an ethical framework for the responsible management of medical disasters. AB - When healthcare resources become overwhelmed in medical disasters, as they inevitably will, we have to ask, in an unflinching fashion, the question: "What then?" or more precisely, "What should we do when we run out of resources?" In a mass casualty event worthy of the designation, we will indeed run out of resources, perhaps quite quickly. This article provides an ethical framework for the responsible management of medical disasters in which the "What then?" question must be asked. The framework begins with a critique of existing guidance from professional associations of physicians and then argues for an alternative approach that qualifies the obligation to preserve life, takes seriously the ethical challenges of overwhelmed healthcare resources, and countenances physician-assisted suicide as a last resort. PMID- 21313867 TI - The elephant in the room: collaboration and competition among relief organizations during high-profile disasters. AB - The non-governmental organizations (NGOs) that assume the bulk of emergency care during large-scale disasters in the developing world must expend considerable time and resources to ensure donations to sustain their field operations. This long-standing dilemma for the humanitarian community can create a competitive environment that: Compromises the delivery and quality of services, Allows the effectiveness of operations to be compromised by a lack of cooperation and collaboration, Disrupts the timely and accurate coordination and analysis of outcome measures that are crucial to successful response in the future, and Undermines the long-term capacity of indigenous aid organizations. This article addresses problems and potential solutions for improved coordination and long term capacity-building of humanitarian aid. PMID- 21313868 TI - Medical school oath-taking: the moral controversy. AB - Professions typically formulate codes of ethics. Medical students are exposed to various codes and often are expected to recite some code or oath at their graduation. This article reports the findings of a study of one large medical class, asked upon entry to medical school and again at the beginning of their fourth term, which of 13 specified professional, religious, and secular codes of ethics they would turn to for moral guidance in their practice of medicine. The study finds great diversity in the students' choices and no clear pattern of change by their fourth term. Very few students chose the oath they would be asked to recite at their graduation. The article probes the problems this creates for school administrators and professors as well as students. It asks the implications for professional oath-taking at graduation and in the practice of the profession. PMID- 21313869 TI - Allocating scarce medical resources to the overweight. AB - BACKGROUND: A programmatic research effort investigated how lay people weigh information on hypothetical patients when making decisions regarding the allocation of scarce medical resources. This study is partly replicative and partly innovative, and looks particularly at whether overweight patients would be discriminated against in allocating resources. AIMS: This study aims to determine the importance given to specific patient characteristics when lay participants are asked to allocate scarce medical resources. SAMPLE: In all, 156 British adults (82 males, 73 females), aged 19 to 84 years, took part. There were few students. METHOD: Participants completed a questionnaire requiring them to rank 16 hypothetical patients for access to a kidney dialysis machine.The demographic information presented regarding each hypothetical patient differed on four dimensions: gender, weight, mental health, and religiousness. RESULTS: There were significant main effects for gender, weight, and mental health; females, patients of normal weight, and the mentally well were ranked the highest priority for access to a kidney dialysis machine. Participants discriminated most regarding the weight of hypothetical patients. CONCLUSION: Different patient characteristics, unrelated to medical prognoses, particularly being overweight, may have an impact on decisions regarding the use of scarce medical resources. PMID- 21313870 TI - Legal briefing: Crisis standards of care and legal protections during disasters and emergencies. AB - This article outlines current safe harbors in the law for healthcare practitioners who work in a disaster setting. It reviews available legal protection in crisis situations with respect to the Emergency Medical Treatment and Labor Act (EMTALA), criminal liability, and licensure. PMID- 21313871 TI - Stem cells therapy for retinal degeneration. AB - Stem cell therapy is widely considered as a therapeutic approach for retinal degeneration. Retinal injury results in permanent visual disturbance or blindness. Repair of such damage by stem cells is one of the most feasible types of central nervous system repair. In this review, we consider how stem cells might be optimized for use as donor cells. We discuss the benefits of stem cells for transplantation in retinal degenerative disease. A wide range of stem cells from different sources is being investigated for the treatment of retinal degeneration. This study reviews the recent and old achievements about stem cells for retinal repair. PMID- 21313872 TI - Antifungal activity of some plant extracts on Alternaria alternata, the causal agent of alternaria leaf spot of potato. AB - Pure methanol (m) and methanol water (mw) extracts of 5 plants namely: peppermint, eucalyptus, lavandula, Russian knapweed and datura were screened for their antifungal ability against Alternaria alternata, the causal agent of Alternaria leaf spot of potato at 5, 10 and 15% concentrations in vitro. Fungicide mancozeb 0.2% was also used for better comparison. Poisoned food technique and spore germination assay method were used to evaluate the antifungal efficacy of plant extracts. Present findings showed that methanol extracts of eucalyptus, peppermint and lavandula had impressive antifungal effects in inhibiting the mycelial growth as well as spore germination of the pathogen. It was also found that methanol extracts were quite more effective than methanol water extracts in this regard. Methanol extracts of peppermint (15%), lavandula (15%), peppermint (10%) and eucalyptus (15%) demonstrated promising ability in inhibiting the mycelial growth of A. alternata by 0.13, 0.40, 0.43 and 0.50 cm, mycelial growth respectively, while majority of methanol water extracts had either less or no effects in this connection. Spore germination of A. alternata was prominently reduced by methanol extracts, while those of methanol water extracts had very less effects in this regard. Mancozeb (0.2%), methanol extracts of eucalyptus (15%) and peppermint (10%) by 2, 6 and 7% spore germination were best, while methanol water extracts of datura 10, 15 and 5%, lavandula 15 and 10% and also Russian knapweed 5% represented no effect and by 91, 89, 87, 87, 85 and 85% spore germination were at par with control. Findings from this study confirmed that plant extracts can be used as less hazardous natural fungicides in controlling plant pathogenic fungi, thus reducing the dependence on the synthetic fungicides. Methanol extracts of peppermint, eucalyptus and lavandula might be promising materials for natural formulations in controlling Alternaria leaf spot of potato in the field. PMID- 21313873 TI - Preliminary studies on allelopatic effect of some woody plants on seed germination of rye-grass and tall fescue. AB - In order to investigation of allelopathic effects of some ornamental trees on seed germination of rye-grass (Lolium prenne) and tall fescue (Festuca arundinaceae), this experiment was conducted in a randomized complete block design with 3 replicates at the laboratory of Horticultural Sciences Department of Ferdowsi University of Mashhad, during 2008. In this research, we studied the effect of aqueous and hydro-alcoholic extracts of Afghanistan pine (Pinus eldarica), arizona cypress (Cupressus arizonica), black locust (Robinia psedue acacia) and box elder (Acer negundo) leaves that prepared in 1:5 ratio on seed germination percent and rate for two grasses. The results showed that all extracts decreased statistically seed germination in compared to control treatment. The highest germination percentage and germination rate of tested grass detected in control treatment. Hydro-alcoholic extracts of all woody plants (15, 30%) were completely inhibited seed germination of rye-grass and tall fescue. Also aqueous extract of arizona cypress was completely inhibited seed germination of tall fescue and had more inhibitory activity than other aqueous extracts on rye-grass. Between aqueous extracts, the highest and lowest seed germination of rye-grass was found in Afghanistan pine and arizona cypress, respectively. PMID- 21313874 TI - Interferon-gamma low producer genotype +5644 over presented in patients with focal brucellosis. AB - Genetic polymorphisms that affect production levels of certain cytokines may determine the risk, severity or protection in some infectious diseases like brucellosis. IFN-gamma plays a key role in the defense mechanism against brucella infection. This study aimed to determine the influence of the polymorphism within the +5644 position of IFN-gamma gene on the susceptibility to brucellosis. We investigated the allelic and genotypes distribution of A5644G polymorphism in IFN gamma gene in an Iranian population comprising 259 patients with brucellosis and 238 healthy controls. The single nucleotide polymorphism was determined using the polymerase chain reaction in association with sequence-specific primers (PCR-SSP) incorporating mismatches at the 3'-end. Allelic and genotype frequencies of G5644A polymorphism of IFN-gamma gene were not significantly differed between patients with brucellosis and controls (p > 0.05). Stratification of patients to focal and non focal diseases revealed a significant increased of 5644A allele in patients with focal brucellosis (79.31% vs. 61.94%, p = 0.0005). Moreover, multivariate logistic regression models showed patients harboring the INF-y G5644A genotype were significantly more likely to develop focal infectious complications (OR = 3.45, p = 0.0004, 95% CI = 1.26-7.94). The present study suggests that the variant genotypes of G6544A of IFN-gamma might be associated with focal form of brucellosis and play as a genetic risk factor in brucellosis. PMID- 21313875 TI - Effect of diltiazem on retention and retrieval of memory in young and aged mice. AB - Diltiazem (DTZ) is widely used in the prophylaxis of hypertension and treatment of angina. The effects of DTZ and other calcium channel blockers on memory have been discussed with several procedures and different theories have been suggested. In the present study, the effect of DTZ on retention and retrieval of memory in young and aged mice was investigated by using the passive avoidance apparatus. For this purpose, after weighting, coding and classifying the mice, they were grouped as follow: test group received electric shock plus DTZ (10 and 30 mg kg(-1), i.p.), blank group received electric shock plus normal saline and control group received only electric shock. In all three groups delay time of leaving the platform for both retention and retrieval test of memory was measured. DTZ was administered immediately after receiving electric shock in the retention test, but in retrieval test DTZ was administered 24 h after receiving electric shock. The results indicated that 30 mg kg(-1) of DTZ impaired retention and retrieval of young mice memory. The 30 mg kg(-1) of DTZ enhanced retention while 10 and 30 mg kg(-1) of it improved retrieval of aged mice memory. PMID- 21313876 TI - Safety of human therapeutic morphine vaccine employing Lohmann specific pathogen free eggs. AB - One of the sensitive and standard tests to control the safety of a vaccine is the inoculation of such vaccine to the air pocket of Lohmann specific pathogen free eggs. The aim of this study is to control the safety of morphine vaccine. This study reveals the safety of morphine vaccine by employing Lohmann specific pathogen free embryo eggs. The changeable parameters in this test were: weight of eggs, safety of eggs embryo, vaccine concentration, normal saline and temperature of the incubator. To study, the safety of morphine vaccine, we used 30 eggs (after controlling the safety of eggs and their embryos) which were divided into two groups of control (15 eggs) and test (15 eggs). After weighing the eggs, the eggs under experiment were inoculated with morphine vaccine and the control group was inoculated with physiological solution. Both groups were incubated and weight of the eggs and chickens were determined accordingly. The eggs of each group were controlled by their weights showing healthy, normal growth and evolution. The comparison between the weights of control and experimental groups did not show any significant changes. Exactly growth and evolution of each group were found equally to be balancing for three weeks after injection. Finally all eggs were observed to be safe, alive and in evolutionary form. By comparing the growth and evolution amongst each egg in the group under experiment, after injection, the eggs did not show any adverse reaction after inoculation with therapeutic human morphine vaccine. PMID- 21313877 TI - Beauveria bassiana characterization and efficacy vs. Sunn pest, Eurygaster integriceps Puton (Hemiptera:Scutelleridae). AB - The objectives of this study were to evaluate the efficacy of Sunn pest entomopathogenic fungi collected from wheat fields and overwintering sites in Syria and characterize them under different temperature regimes. Eleven isolates of Beauveria bassiana (Bals.) Vuil. were included in this study: five were isolated from overwintered adults of Sunn Pest, Eurygaster integriceps Puton and six from nymphs and new adults in wheat fields. Growth rate and conidial production were tested at 15, 20, 25, 30 and 35 degrees C. Results showed that highest growth rate of tested fungal isolates was at 25 degrees C, except for the two isolates SPDR-1 and SPDR-2 which exhibited highest growth rate at 20 degrees C. The highest production of conidia of tested fungal isolates was at 20 degrees C, except for isolates SPSR-1, SPSQ and SPSS which exhibited higher production at 25 degrees C. Virulence test of the tested fungal isolates on overwintered adults Sunn Pest showed that percent mortality after 14 days ranged between 86-100%. PMID- 21313878 TI - Comparative efficacy sensitivity and specificity of the tests used for the Diagnosis of Helicobacter pylori. AB - Abstract: A total number of 157 samples were examined by 4 different tests-In house rapid urease (iRUT), Culture, Histopathology and Immunochromatography (Immuno CardSTAT) for the detection of Helicobacter pylori from the patients reported to Hospital Kuala Lumpur, Malaysia during 2007 to 2008. Out of the samples examined 47 (29.9%) were positive for H. pylori by the tests used in the laboratory. Efficacy of detection of the bacteria by the tests- In-house rapid urease, Culture, Histopathology and Immuno CardSTAT were 31.8, 13.9, 30.3 and 32.8%, respectively. However, sensitivity and specificity of the iRUT were 91.5 and 93.6%, respectively and the Positive Predictive Value (PPV) was 86% and the Negative Predictive Value (NPV) was 96.3%. The sensitivity for Immuno CardSTAT rapid test was 100% and the specificity was 79.3%. The PPV was 50% and the NPV was 100%. Convenient methods to the authors were 'In house rapid urease test and Immunochromatography though variability of specificities were observed. PMID- 21313879 TI - The research of mandibular foramen in panorex X-ray. AB - In the present investigation position of mandibular foramen of the mandible in relation to other landmarks were studied. Panoramic x-ray of 103 females and 94 males who come to above mentioned clinic selected by available sampling. All samples were Iranian with the age above 18 years old. X-ray machine and method were same for all samples. Special landmarks in right side of mandible were identified and their distance from mandibular foramen were recorded by millimetric ruler. The measured landmarks were as follow: Mandibular angle, Coronoid process, Mandibular notch, Head of mandible, Posterior border of ramus of mandible, Anterior border of the ramus, External oblique line, Mylohyoid line, Occlusal plane: mandibular angle were measured by protractor. Results between male and female were compared by Mann Whitney U test. The average of both sexes ages were 34.7 years. Difference between distance of mandibular foramen from following landmarks between male and females were significant: (1) Mandibular angle, (2) Head of mandible, (3) Posterior border of ramus, (4) Mylohyoid and (5) Occlusal plane. Present investigation revealed position variation of M.F. in relation to other landmarks and differences between male and female, we suggest kind of investigation individual under 18 years old. PMID- 21313880 TI - A review on hyperthyroidism: thyrotoxicosis under surveillance. AB - Thyrotoxicosis exhibit collective clinical manifestation, caused by excessive serum thyroid hormones particularity thyroxin. The clinical signs and symptoms included general alteration of metabolic process leading to weight loss fatigue and weakness and some specific disorders such as cardiovascular, neuromuscular reproductive gastrointestinal dermatological and bone disorders. The diagnosis of thyrotoxicosis relay on the thyroid function test carried out by the laboratory serum measurement of thyroxin, triiodothyronine and thyroid stimulating hormones accompanied by other para-medical examinations suggested by clinicians and endociologicst. In thyrotoxicosis serum level of thyroid hormones and thyroxin in particular elevated accompanied by pituitary thyroid stimulating hormone suppression reaching to undetectable level in sever thyrotoxicosis. Among the most common cause of thyrotoxicosis are, thyroid autoimmunity diseases thyroid toxic, adenoma toxic nodular and multinodular hyperthyroidism. The main aim behind this review is to explore the clinical manifestation, the causative factors, diagnosis, metabolic disorder occur due to thyrotoxicosis. PMID- 21313881 TI - An overview of German cockroach, Blattella germanica, studies conducted in Iran. AB - The control and elimination of German cockroach, the most important worldwide pest species, has been an economic and public health success. Too many studies have been conducted in Iran, whereas these researches was scattered in form of national and international articles that has needed to add up of them in an overview article. With doing of this work the way is smooth to future studies and the strategies of these studies will be distinguished. This article is outlook in direction of above aims. The susceptibility level and insecticide resistance mechanisms of German cockroach to organochlorated, organophosphate, carbamate and pyrethroid insecticide groups have been studied. The new insecticidal compounds include fipronil and avermectins acting at GABA and glutamate receptors in proximity to chloride channels, diacylhydrazines mimicking the action of ecdysone, indoxacarb acting at a novel site in sodium channels and imidacloprid, thiamethoxam and spinosad acting at novel sites on the nicotinic acetylcholine receptor, several promising products acting at new target sites, which are currently not affected by resistance that will be used for pest control specially Blattella germanica. Attentive to resistance of B. germanica to current consuming insecticides and ever-increasing add to intensity of it, the researchers have been considering the susceptibility level of B. germanica and efficiency estimation of them to above-mentioned insecticides for control of this pest. The strategies of future researches are study of the susceptibility level of B. germanica and efficiency estimation of them to above-mentioned insecticides for control of this pest in Iran. PMID- 21313882 TI - Application of biotic indices in assessing the ecological quality status of Bahrekan estuary (Persian Gulf). AB - The aim of present study was to examine the macro invertebrates as an assessment tool for characterization of the state of Bahrekan estuary in Persian Gulf, by using different biotic indices. An investigation on benthos was carried out during autumn 2008 to summer 2009 in the Bahrekan estuary (Persian Gulf). In order to identify and assess the benthic community structure, seasonal sampling was done from 21 stations with three replicates using van veen grab (./285 m2). The ecological indices, such as (AMBI, BI and Bentix), Shannon-Wiener index (H'), species richness (S) were applied to the available benthic species data, and evaluated comparatively. The grain size of sediments and total organic matter as essential factors in distribution and population diversity of macrobenthos communities were also analysed. According to the results, 17 groups of macrobenthos were identified. Out of 111 genus/species identified in this study, Gastropoda was the dominate group (79.8%), followed by Bivalvia (5.5%). Pyrgohydrobia sp. belonged to gastropoda was dominant in all of seasons. The results showed that all of the stations are characterized as muddy bottom and Bahrekan estuary are classified in slightly to moderate pollution status. PMID- 21313883 TI - In vitro antioxidant, lipoxygenase and xanthine oxidase inhibitory activities of fractions from Cienfuegosia digitata Cav., Sida alba L. and Sida acuta Burn f. (Malvaceae). AB - In this study polyphenol content, antioxidant activity, lipoxygenase (LOX) and Xanthine Oxidase (XO) inhibitory effects of n-hexane, dichloromethane, ethyl acetate and n-butanol fractions of aqueous acetone extracts from S. alba L., S. acuta Burn f and Cienfuegosia digitata Cav. were investigated. The total phenolics, flavonoids, flavonols and total tannins were determined by spectrophotometric methods using Folin-ciocalteu, AlCl3 reagents and tannic acid, respectively. The antioxidant potential was evaluated using three methods: inhibition of free radical 2,2-diphenyl-1-picrylhydramzyl (DPPH), ABTS radical cation decolorization assay and Iron (III) to iron (II) reduction activity (FRAP). For enzymatic activity, lipoxygenase and xanthine oxidase inhibitory activities were used. This study shows a relationship between polyphenol contents, antioxidant and enzymatic activities. Present results showed that ethyl acetate and dichloromethane fractions elicit the highest polyphenol content, antioxidant and enzymatic activities. PMID- 21313884 TI - Rice yield modeling under salinity and water stress conditions using an appropriate macroscopic root water uptake equation. AB - The objectives of this study were to evaluate the application of different macroscopic root water extraction models for prediction of rice grain yield based on data obtained in a greenhouse experiment. In this experiment, the irrigation treatments were continuous flooding (control), intermittent flooding (1- and 2 day intervals) and the salinity levels of irrigation water were 0.6 (control), 1.5, 3, 4.5 and 6 dS m(-1) in the year of 2005 and 0.6 (control), 1.5, 2.5, 3.5 and 4.5 dS m(-1) in the year of 2006. A local cultivar (Ghasrodashty/Komphiroozy) was planted in pots under greenhouse condition during years 2005 and 2006. Grain yield and evapotranspiration at different treatments were determined. The effect of salinity and water stress on root-water uptake coefficient was determined by FAO and Homaee and Feddes methods and grain yield was predicted by production functions. The FAO method did not predict the interaction effects of salinity and water stress on reduction of water uptake coefficient especially at high salinity levels, while the Homaee and Feddes method predicted properly the effects of salinity and water stress on root-water uptake coefficient. Further, yield was predicted by using the root-water uptake coefficient suggested by FAO and Homaee and Feddes methods. The results indicated that the FAO method did not predict the yield properly especially in continuous flooding and salinity level of more than threshold values, but the Homaee and Feddes method predicted the grain yield with minimum error. PMID- 21313885 TI - Characteristics of adult outpatients with erythema multiforme. AB - Erythema Multiforme (EM) is a type of allergic reaction that occurs in response to medications, infections, or different illnesses. In many cases, a definite underlying cause may not be identified. This study aimed to evaluate adult EM outpatients with regard to patients' characteristics, the disease and the underlying contributors. In this cross-sectional study, 61 adult EA outpatients referred to the Dermatology Clinic of Tabriz Sina Hospital were recruited during a 12-month period (January 2009-January 2010). The diagnosis was made based on clinical and morphologic grounds. Age, sex, types of EA, location and type of the lesions and the underlying causes were documents. An infectious etiology was suspected when a preceding illness was noticed without drug ingestion within 1 week prior to the onset of the rash. A drug related to the condition was defined as every drug that has been taken during 21 days prior to the onset of any symptoms. There were 34 males and 27 females with a mean age of 26.8 +/- 15.3 (18 57) years enrolled. The EM was minor in 62.3% and major in 37.7% of patients. The upper limb was involved in all patients. The lesions were maculo-papular, vesiculobullous and bullous in 83.6, 13.1 and 3.3% cases, respectively. Drugs and herpes simplex were the main causes in 49.2 and 16.4% of patients, respectively. The disease was idiopathic in 34.4%. The underlying drugs were sulfonamides in 12 cases (19.7%), penicillin in 5 cases (8.2%), salicylic acid, aspirin, cimetidine and amoxicillin each one in 3 cases (4.9%) and barbiturate in 1 case (1.6%). Five cases (8.2%) were recurrent EM including 4 males and 1 female, 3 idiopathic and 2 cases due to sulfonamides. PMID- 21313886 TI - Mixed infections of Vibrio cholerae O1 Ogawa EL Tor with Shigella dysenteriae. AB - Mixed infections caused by enteric pathogens such as bacteria, virus, protozoa and helminthes were reported in different literatures. This report also describes the co-infections caused by Vibrio cholerae O1 Ogawa EL Tor with Shigella dysenteriae in a patient. A 36-year-old man was admitted in Fatemeh Zahra Hospital of Bushehr Iran with fever, vomiting and dysentery. His stool sample was cultured, for identification purposes TCBS, XLD and other media were used. V. cholerae and S. dysenteriae were identified. Both species were resistant to ampicillin and sensitive to nalidixic acid and trimethoprim-sulfamethoxazol. Shigella was resistant to tetracycline. The results of the study showed that places where diarrheal diseases especially cholera are endemic, it is better to examine for those patients with dysentery for the presence of the V. cholerae O1. That will prevent the spread of pathogenic organism in the community. PMID- 21313887 TI - Role of Clostridium perfringens in causing abomasal ulcers in buffalo. AB - In this study, the correlation between abomasal ulcers and presence of Clostridium perfringens (C. perfringens) was evaluated in 80 (50 affected and 30 non affected) randomly slaughtered buffaloes in Ahvaz slaughterhouse. Immediately after the slaughter, the abomasums was isolated and an incision was made on the wall of it. Then the abomasums were emptied and its interior was washed with water. The inner surface was examined for presence of abnormal lesion. Ulcers from affected and piece of abomasa from non affected buffaloes were cultured. Cultures were also made from contents of all samples and smears were also prepared from affected and non affected tissues. Cultures from content samples (12%) of 50 ulcerated abomasa were positive for C. perfringens while the agents were isolated from 1 content (3.3%) of non ulcerated abomasa. There was no statistical difference between presence of C. perfringens in contents and abomasal ulcers. Totally C. perfringens were isolated from ulcers of 6 (12%) ulcerated and tissues of 3 (10%) non ulcerated cases. Statistical analysis showed no correlation between presences of C. perfringens and abomasal ulcers. There was no statistical difference between sex and age of the affected animals. In conclusion C. perfringens seems not to be solely, a cause ofabomasal ulcers in buffaloes. PMID- 21313888 TI - Remote sensing and GIS application for assessment of land suitability potential for agriculture in the IBB governorate, the Republic of Yemen. AB - In the present study, an assessment of land suitability potential for agriculture in the study area of IBB governorate, Republic of Yemen has been conducted through close examination of the indicators of land characteristics and qualities. The objective of this study is to evaluate the available land resource and produce the potential map of the study area. Remote sensing data help in mapping land resources, especially in mountainous areas where accessibility is limited. Satellite imagery data used for this study includes data from multi temporal Landsat TM which dated June 2001. The parameters taken into consideration were 16 thematic maps i.e., slope, DEM, rainfall, soil, land use, land degradation as well as land characteristics maps. Satellite image of the study area has been classified for land use, land degradation and soil maps preparation, while topo sheet and ancillary data have been used for slope and DEM maps and soil properties determination. The land potential of the study area was categorized as very high, high, moderate, low and very low by adopting the logical criteria. These categories were arrived at by integrating the various layers with corresponding weights in a Geographical Information System (GIS). The study demonstrates that the study area can be categorized into spatially distributed agriculture potential zones based on the soil properties, terrain characteristics and analyzing present land use. This approach has the potential as a useful tool for guiding policy decision on sustainable land resource management. PMID- 21313889 TI - Non-obstructive lower urinary tract symptoms versus prostate volume in benign prostatic hyperplasia. AB - This study was aimed to determine the relation between sonographically measured prostate volume and the severity of non-obstructive Lower Urinary Tract Symptoms (LUTS) in Benign Prostatic Hyperplasia (BPH). This was an analytic-descriptive, cross-sectional and prospective study which was carried out on a sequential sample of 60 male patients since 2006 to 2008. The patients were divided to three groups (prostate volume < 40 cc; 40 cc < or = prostate volume < or = 59 cc; prostate volume > or = 60 cc) based on the ultrasonographic volume of the prostate. The American Urological Association scores of frequency, urgency, nocturia and dysuria were compared between three groups. The mean age and the mean total score of non-obstructive symptoms of BPH of the patients were 71.18 +/ 8.74 and 13.38 +/- 2.96, respectively. According to our findings there was no statistical significant difference between three groups in the scores of frequency (p = 0.369), dysuria (p = 0.85) and nocturia (p = 0.861). A statistically significant difference between three groups was found in urgency score (p = 0.037). Only a significant correlation between urgency and the prostate volume was found (p = 0.024, r = 0.291). According to our findings in this work on relation between the non-obstructive symptoms and prostate volume in BPH patients we found that urgency was the only non-obstructive symptom that may be associated with prostate volume. Prospective studies are required in this regard to elucidate the symptom-related causes of LUTS in the patients with BPH. PMID- 21313890 TI - Pancreatic islet beta cell protective effect of oral vanadyl sulphate in streptozotocin-induced diabetic rats, an ultrastructure study. AB - We sought to determine the ultrastructure of pancreatic islet beta cells of streptozotocin-induced diabetic rats treated with oral vanadyl sulphate. Diabetes was induced in male Wistar rats by intravenous injection of 40 mg kg(-1) streptozotocin. The same volume of normal saline was injected in sham animals. Animals were divided into treated and control groups. Vanadyl sulphate was added to the drinking water of the treated animals at a concentration of 1 mg mL(-1) up to three months. Two months after vanadyl sulphate withdrawal animals were killed. Ultrastructure of islet beta cells were studied by transmission electron microscope. In diabetic treated rats plasma glucose and fluid intake returned to normal levels within three months while control animals remained diabetic. Well granulated cytoplasm, well developed endoplasmic reticulum, increase in the number of immature granules in the cytoplasm with no clear signs of cell injury were found in the islet beta cells of diabetic treated rats. Lymphocyte filteration, nuclear picnosis, cytoplasmic vacuolization were found frequently in the islet beta cells of untreated diabetic rats. In conclusion as was evident in thin sections of panceatic islet beta cells of treated diabetic rats in this study, vanadyl sulphate through preserving islet beta cells structure and ultrastructure contributes in reversing diabetic signs and symptoms in streptozotocin induced diabetic rats. PMID- 21313891 TI - Effect of flax seeds and date palm leaves extracts on serum concentrations of glucose and lipids in alloxan diabetic rats. AB - The aim of the present investigation was to examine the effect of Flax Seeds (FS) and Date Palm Leaves (DPL) extracts on the concentration of serum glucose and lipids in alloxan diabetic rats. Rats were divided into six groups, normal control rats (without treatment with either FS or DPL), normal control rats treated with either FS or DPL extract for four weeks, diabetic control rats and diabetic rats treated with either FS or DPL extract for four weeks. The concentration of glucose in diabetic rats treated with FS (D+FS) for four weeks was significantly decreased from 17.20 +/- 2.33 to 8.14 +/- 0.54 mmol L(-1) (p < 0.001). Serum total cholesterol concentration (TC) of diabetic rats treated with either FS or DPL extract showed significant decrease by 40 and 31% respectively in the fourth week. Also, serum low density lipoprotein cholesterol (LDL-C) concentration was significantly decreased after two weeks of treatment (p < 0.001 and p < 0.01, respectively). However, no significant changes were obtained in serum high density lipoprotein cholesterol (HDL-C) concentration. Results of the present study showed that FS extract has a hypoglycaemic effect against alloxan diabetic rats. Present findings also showed that treatment of alloxan diabetic rats with either FS or DPL extract significantly decreased serum concentration of TC and LDL-C. Present findings suggest that both of FS and DPL extracts could have a protective effect against diabetes complications as well as against hyperlipidemia through improvement of lipid profile. PMID- 21313892 TI - Effects of oral clonidine premedication on haemodynamic response to laryngoscopy and tracheal intubation: a clinical trial. AB - The objective of this study was to evaluate the efficacy of pre-anesthetic orally administration of clonidine on pulse rate and blood stress response to laryngoscopy and tracheal intubation. In a double-blinded, randomized study, 274 ASA I and II subjects with age of 18 to 45 years scheduled for elective surgery under general anesthesia were enrolled. They were randomly allocated to receive oral clonidine (0.2 mg) or placebo as premedication 90-120 min before surgery. All the patients received Succinylcholine (1.5 mg kg(-1)) after induction of anesthesia with Fentanyl (50 microg) and Thiopentone (5 mg kg(-1)). The anesthesia was maintained with halothane (1.5 Mac) in 50% mixture of N2O/O2. Heart rate and systolic blood pressure were recorded before, immediately after and then every 5 min after intubation until 20 min. The Clonidine group showed a significant superiority over placebo in the prevention of increase in systolic blood pressure as well as heart rate over the intubation. A significant difference was observed in both heart rate and systolic blood pressures were significantly higher in Control group at three subsequent measurements following intubation. The results of this study suggest that orally administered clonidine in preanesthetic period, provides more haemodynamic stability and attenuates the stress response to laryngoscopy and intubation. PMID- 21313893 TI - Production of desferrioxamine B (Desferal) using corn steep liquor in Streptomyces pilosus. AB - The aim of this study was evaluation of corn steep liquor as an alternative or substitution medium for production of desferrioxamine B in streptomyces pilosus. Desferrioxamine B is the major siderophore of Streptomyces pilosus. The genus Streptomyces are Gram positive and GC (Guanine/Cytosine) rich bacteria that are important for production of many antibiotics and secondary metabolites. These metabolites get more attention in industrial and medical fields. Desferrioxamine B is used clinically to treat disorders related to iron overload and pathological iron deposition in human. Corn Steep Liquor (CSL) is a by-product of corn wet milling. It is an excellent source of organic nitrogen and important constituent of some culture media. Nowadays CSL was mainly used for feeding of livestock. In this study we substitute the conventional media with CSL and surveyed its effect on production of desferrioxamine B. The CSL is cheaper than other media and its availability is so easy. In this research, for the first time we used a cheap material for production of a valuable product. Our results showed that the use of CSL solely, increased the production of Desferal more than three times in comparison with conventional media such as soybean. PMID- 21313894 TI - Effects of combination of intrathecal lidocaine and two doses of intrathecal midazolam on post-operative pain in patients undergoing herniorrhaphy: a randomized controlled trial. AB - Assessment of the effect of combination of intrathecal midazolam and lidocaine on postoperative pain was the aim of this study. This randomized controlled trial was performed during 2007 in a teaching hospital of Arak University of Medical Sciences. Forty five male patients who were candidates for elective inguinal herniorrhaphy entered the study and randomly divided into three groups of control (lidocaine 5% plus normal saline), M 0.5 (lidocaine 5% and midazolam 0.5 mg) and M 1.0 (lidocaine 5% and midazolam 1 mg) according intrathecal solution injected for spinal anesthesia. Mean arterial blood pressure, heart rate, post-operative pain, narcotic requirements and complications (nausea, vomiting, pruritic, headache, hypotension and bradycardia) were recorded. The severity of post operative pain was lowest in M 1.0 group in all postoperative measurements except at 2 h after operation. With regard of complications, only there was significant difference in vomiting between three groups which had the highest frequency in M 0.5 group. No severe hypotension was seen; though, bradycardia occurred in one patient in M 0.5 group which needed treatment. Present findings suggest that administration of intrathecal midazolam (especially 1 mg) together with lidocaine is effective in reducing post-operative pain in patients undergoing open inguinal herniorrhaphy and is not associated with adverse effect. PMID- 21313895 TI - Ventricular tachycardia due to flumazenil administration. AB - Flumazenil is one of imidazo-benzodiazepine (Anexate) which has been generally used as benzodiazepine competitive antagonist for the treatment of benzodiazepine intoxication during recent decades. Some has recommended diagnostic usage in ICU as well, for suspected benzodiazepine intoxicated cases. In this study we present a patient intoxicated with lorazepam who developed a ventricular tachycardia after receiving flumazenil as therapeutic mean, though the attack was appropriately terminated by administration of a bolus dose of Amiodarone. We believe that the ventricular tachycardia onset in above mentioned case is secondary to Flumazenil administration in susceptible patient with previous history of ischemic heart disease. Ventricular tachycardia has rarely reported as flumazenil side effects. PMID- 21313896 TI - Improvement of decerebrate status in a hanged child following emergent tracheostomy. AB - This study is a clinical description of one child with decerebrated status due to hanging that made excellent recovery. There are limited reports have explained decerebrated status improvement among children in the literature. The case presented, is an eleven year-old boy brought by Emergency Medical Services into the Emergency Department with decerebrated status due to hanging during swinging. Concerning severe hypoxemia and suspected, emergent tracheostomy was carried out to ensure a proper reliable airway. Patient was put under mechanical ventilation and decerebrated status was surprisingly resolved completely during one hour. We believe that reversible cerebral status has been due to brain stem decreased function without any previous or permanent pathologic neurological disorder. PMID- 21313897 TI - Obstetrical brachial plexus palsy: electrodiagnostical study and functional outcome. AB - Obstetrical Brachial Plexus Palsy (OBPP) is a complication of difficult delivery and resulted from excessive traction on the brachial plexus during delivery. Erb palsy, klumpke paralysis and panplexus palsy reported in 46, 0.6 and 20% of patients, respectively. Unilateral injury is more common than bilateral injury. Risk factors include macrosomia, multiparity, prior delivery of a child with OBPP, breech delivery shoulder dystocia, vacium and forceps assisted delivery and excessive maternal weight gain. The recovery rate is usually reported to be between 80 and 90%. We evaluated 42 children with OBPP. Out of them, we could follow only 28 cases during two years. Poor to moderate recovery occurred in 13 cases. Good to complete (expected) recovery occurred in 15 cases. Most of the patients were females. Right side palsy was more prevalent than left side palsy. Vaginal delivery without forceps was the most mode of delivery. Vertex was the most common presentation. Most of the patients were term. The mean weight of the birth was 3.8 kg. Erb palsy and pan-plexus palsy consisted of 71.4 and 28.6% of lesions. In patients with Erb palsy, there were preganglionic palsy in 3 (15.8%) and postganglionic palsy in 16 (84.2%) cases, while all the patients with panplexus palsy had postganglionic palsy. All patients with complete recovery (9 of 15) had Erb palsy and postganglionic lesion. Erb palsy was present in 71.4% and panplexus palsy was present in 28.6% of cases. Also, 23.8% of cases had preganglionic and 76.2% of cases had postganglionic injures. PMID- 21313898 TI - Occurrence, pathogenicity and distribution of Fusarium spp. in stored wheat seeds Kermanshah Province, Iran. AB - Fusarium is one of the most important pathogenic and toxigenic fungi widely distributed all over the world, including Iran. Fusarium species are found frequently in stored agriculture products especially wheat. The objective of this study was to identify Fusarium species associated with stored wheat seeds and their pathogenicity on root and head of wheat in Kermanshah, the leading province in wheat production in Iran. In this survey 75 seed samples of stored wheat were collected from 10 different regions during 2006-2008 and tested for the presence of Fusarium. Fusarium spp. were found in 51 (68%) of 75 samples. A total of 580 Fusarium strains were isolated, identified and preserved. All these strains belong to 20 Fusarium spp. according to morphological characters. Each conidial suspension of selected strains representing all species was evaluated for their pathogenicity on roots and spikes of healthy wheat var. Fallat in the greenhouse. F. graminearum, F. crookwellense, F. trichothecioides, F. culmorum and F. verticillioides were the most pathogenic to wheat's head. Foot rot assessment revealed that F. pseudograminearum and F. culmorum were the most damaging species. Of the Fusarium isolates, F. graminearum was the most prevalent followed by F. verticillioides and F. proliferatum. This is the first comprehensive report on identity and distribution of Fusarium spp. from stored wheat seeds in Iran while F. nelsonii was reported for the first time from wheat seeds in Iran. PMID- 21313899 TI - Assessment of short-term memory in Arabic speaking children with specific language impairment. AB - Children with Specific Language Impairment (SLI) may have some kind of memory disorder that could increase their linguistic impairment. This study assessed the short-term memory skills in Arabic speaking children with either Expressive Language Impairment (ELI) or Receptive/Expressive Language Impairment (R/ELI) in comparison to controls in order to estimate the nature and extent of any specific deficits in these children that could explain the different prognostic results of language intervention. Eighteen children were included in each group. Receptive, expressive and total language quotients were calculated using the Arabic language test. Assessment of auditory and visual short-term memory was done using the Arabic version of the Illinois Test of Psycholinguistic Abilities. Both groups of SLI performed significantly lower linguistic abilities and poorer auditory and visual short-term memory in comparison to normal children. The R/ELI group presented an inferior performance than the ELI group in all measured parameters. Strong association was found between most tasks of auditory and visual short-term memory and linguistic abilities. The results of this study highlighted a specific degree of deficit of auditory and visual short-term memories in both groups of SLI. These deficits were more prominent in R/ELI group. Moreover, the strong association between the different auditory and visual short-term memories and language abilities in children with SLI must be taken into account when planning an intervention program for these children. PMID- 21313900 TI - Anatomical distribution of central nervous system plaques in multiple sclerosis: an Iranian experience. AB - Multiple Sclerosis (MS) begins most commonly in young adults and is characterized by multiple areas of Central Nervous System (CNS) white matter inflammation, demyelination and glial scarring. The most valuable laboratory aid for diagnosing MS is Magnetic Resonance Imaging (MRI). An advanced type of MRI that exploits molecular diffusion can detect acute and active lesions. Early diagnosis and onset of treatment help to hinder disease progression. The aim of this study was to compare the findings of conventional and Diffusion-Weighted (DW) MRI in assessing the cerebral lesions of MS patients. Thirty patients with clinically definite MS (mean age 32.76 +/- 8.79 years) and an age- and sex-matched control group of 30 healthy volunteers (mean age 32.75 +/- 9.23 years) were enrolled in this 12 month descriptive-prospective survey. Both groups were subjected to conventional and DW MRI and were compared in respect of the total number, morphology, location and the mean size of the intra-cerebral MS plaques. The sensitivities and specificities of both imaging methods in detecting these plaques were determined. The conventional method revealed significantly more plaques within the brain (p < 0.05) and showed more ovoid lesions. More lesions were detected by the conventional method in the periventricular area, centrum semiovale and corpus callosum. The minimum plaque size was significantly lower in the conventional method group. The sensitivity of both methods was 100%. The specificities of conventional and DW MRI were 86.6 and 96.6%, respectively, so DW MRI may detect lesions that are not obvious by routine methods. PMID- 21313901 TI - The hypolipidemic effect of Citrullus colocynthis on patients with hyperlipidemia. AB - Citrullus colocynthis is one of the medical herbs that traditionally have been used as an antidiabetic medication in tropical and subtropical countries. The aim of this study was to investigate the hypolipidemic effect of Citrullus colocynthis beyond the hypoglycemic impact on human. One hundred dislipidemic patients were randomly divided into two groups namely treated (n = 50) group and placebo (n = 50) group. The subjects were treated daily by powdered seeds of Citrullus colocynthis (300 mg) and placebo for 6 weeks. The serums, TG, Chol, LDL C, HDL-C, SGOT and SGPT were measured with enzymatic methods at the beginning and the end of the project. The significance of differences within these groups was calculated by Paired T-test and by analysis of covariance between them. There were significant differences within and between treated and placebo groups during our treatment in TG and in Cholesterol after intervention (p < 0.05). A daily intake of 300 mg day(-1) of powdered seeds of Citrullus colocynthis can lower the triglyceride and cholesterol concentration significantly in nondiabetic hyperlipidemic patients. PMID- 21313902 TI - Determination of some heavy metal concentrations in razor clam (Solen brevis) from Tanjung Lumpur coastal waters, Pahang, Malaysia. AB - An effort to analyze selected heavy metal accumulation by the razor clam (Solen brevis) from Tanjung Lumpur was conducted on January to April 2010. A total of fifty individuals of Razor clam Solen brevis were sampled and metals such as Iron (Fe), Zinc (Zn), Copper (Cu), Manganese (Mn), Lead (Pb) and Cadmium (Cd) Concentrations were determined using Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Among the metals Fe occurred in elevated concentration in the soft tissue of razor clam followed by Zn. Cd was found to be in least concentration in the sample. Mean concentration of Fe, Zn, Mn, Cu, Cd and Pb in the soft tissue were 415.2 +/- 56.52, 87.74 +/- 11.85, 18.71 +/- 2.10, 8.64 +/- 1.75, 0.67 +/- 0.29 and 1.61 +/- 0.45 microg g(-1) dw, respectively indicating that the bioaccumulation of essential metals in the soft tissue was greater than the non essential heavy metals. Metal accumulation in the soft tissue of razor clam followed Fe > Zn > Mn > Cu > Pb > Cd order in present study. The observed concentration of acute toxicity of metals in Solen brevis (Family: Solenidae) from Tanjung Lumpur Coastal waters was lower than the permissible limit recommended by National and international standards proved that this species could be utilized for human consumption. PMID- 21313903 TI - Effect of adding ketamine to pethidine on postoperative pain in patients undergoing major abdominal operations: a double blind randomized controlled trial. AB - To determine the effect of adding ketamine to pethidine in reducing post operative pain in patients undergoing major abdominal operations, in a double blind randomized controlled trial, 100 patients aged 15-60 years who were candidate for elective major abdominal surgery allocated into two groups of pethidine + ketamine group (5 mg pethidine and 0.25 mg kg(-1) ketamine) or pethidine and placebo group (10 mg pethidine and NS) according to the regimen prescribed in postanesthesia care unit. Severity of pain (using visual analogue scale), prescribed dose of pethidine and side effects were recorded until 24 h after operation. Regarding post-operative pain, pethidine + ketamine group showed significant lower scores in all the times except 0 min, 2, 6 and 16 h. Nausea was significantly less frequent amongst pethidine + placebo group at times of 0, 15, 30 and 45 min (p < 0.05). Comparison of two groups did not show significant differences in prescribed pethedine dose in 0, 9, 12, 16, 20 and 24 h (p > 0.05). Yet, the mean dose of administered pethidine as rescue analgesic was significant lower in pethidine + ketamine group compared to pethidine + placebo group (112 +/ 31.5 mg vs. 133.5 +/- 24.5 mg, p < 0.001). In conclusion, our results showed that co-administration of ketamine and pethidine in postanesthesia care unit will improve postoperative pain and reduce narcotic consumption. It may, however, increase rate of postoperative nausea in the first hour after operation. PMID- 21313904 TI - Comparison the effects of metoclopramide and dropridol associated with dexamethasone on post operative nausea and vomiting. AB - The aim of study was, comparison of effects of Metoclopramide and Dropridol associated with Dexamethasone on prevalence of nausea and vomiting after operation was considered. In this study 160 patients ASA physical status I were divided into two groups. In both groups, premedication and induction of anesthesia were given equally according to weight. To the first group, Metoclopramide associated with Dexamethasone and to the second group, Dropridol associated with Dexamethasone was ordered. At the end of the operation, after removing tracheal tube, prevalence of nausea and vomiting in both groups was considered after 2 h and results were analyzed with t-test and Chi-square. Ratio of nausea and vomiting after operation in the first group was 24% and in the second 8%. So results show that prevalence of nausea and vomiting in the second group was considerably lower than the first group (p < 0.004). According to the results of this study our conclusion, Dropridol with dexamethasone given at the before of general anesthesia was more effective in decreasing the prevalence of nausea and vomiting in patients compared with metoclopramide with dexamethasone. PMID- 21313905 TI - The effect of seed extraction methods on seed quality of two cultivar's tomato (Solanum lycopersicum L.). AB - In order to compare of different methods and identify the optimum condition for tomato seed extraction, factorial experiments with 3 replications was conducted. In the first experiment, pulp of two tomato cultivars (Faraon, Dominator) were fermented at two temperatures (25, 35 degrees C) and six periods (24, 48, 72, 96, 120, 144 h). The germination of seeds in laboratory as well as seedling emergence and preliminary growth in greenhouse were studied and measured. The results showed that effect of cultivar on traits (except of seedling emergence) was significant. Also the effect of temperature of fermentation, duration of fermentation and also interaction effects of them on seed germination were significant. Totally seed quality decreased with increasing temperature and duration of fermentation and the fermentation duration from 24 to 48 h at temperature 25 degrees C, is recommended. In the second experiment, tomato seeds were extracted by HCL (pH was arranged to 1, 2, 3 for 10, 20, 30 min), H2SO4 (pH was arranged to 1, 2, for 15, 30 min), Sodium carbonate (5, 10% for 24 and 48 h) and fermentation. Percentage germination, germination rate, length of radicle and length of plumule were used for seed quality assessment. The results showed that interaction effect between pH and duration of HCL treatments was significant for seed germination (percentage and rate) and there was an interaction effect between concentration and duration for germination rate in alkali treatments. Different extraction methods had not detrimental effect on percentage germination, but acid treatments produce very bright clean seeds in compare to other treatments. PMID- 21313906 TI - Influence of humic acid derived from composted wastes of Nigeria origin on oxidative and antioxidant status of African mud catfish (Clarias gariepinus). AB - The utilization of organic fertilizer, a product of composted organic wastes, is being advocated in Nigeria as a solid waste management alternative. The application of such products near surface water could increase organic matter load of the aquatic environment, thus increasing the humic substance concentration that influence metal speciation and bioavailability in water. In this study, Humic Acid (HA), a major humic substance fraction, derived from composted organic wastes of Nigeria origin was evaluated for effects on the oxidative and antioxidant status of African Mud Catfish (Clarias gariepinus) exposed to different HA (100, 250, 500 and 1000 mg L(-1)) concentrations in static water culture. Lipid peroxidation was estimated via malondialdehyde (MDA) using thiobarbituric acid assay while oxidative stress was assessed spectrophotometrically, via superoxide dismutase (SOD), glutathione (GSH) and catalase (CAT) using standard enzymatic assay techniques. Results showed that treatments increased MDA by 20 to 70% but decreased SOD, CAT and GSH by 10 to 42.56%, 43.62 to 64.09% and 9.84 to 67.68%, respectively. Negative coefficient (r) was obtained for CAT (r = - 0.491; p > 0.10), GSH (r = - 0.551; p > 0.10) versus HA concentration but correlation was positive for MDA (r = 0.998; p = 0.012) and the latter. Study revealed humic acid-mediated oxidative stress and lipid oxidation in the fish. The adverse impact was a function of humic acid concentration and an assessment of heavy metal-humic acid mixture effect on the oxidative and antioxidant status of fresh water fish is recommended. PMID- 21313907 TI - Ultrastructural study of muscles fibers in tick Hyalomma (Hyalomma) anatolicum anatolicum (Ixodoidea: Ixodidae). AB - In the present study, ticks were obtained from a colony maintained at 28 degrees C and 75% relative humidity in at the Department of Biology, University College Umm Al-Qura University, Saudi Arabia and the Transmission Electron Microscope technique (TEM) was used to describes the ultrastructure and description of muscle of the of ixodid tick Hyalomma (Hyalomma) anatolicum anatolicum. The results showed that muscles of the unfed ticks Hyalomma (Hyalomma) anatolicum anatolicum in longitudinal sections are spindle-shaped to cylindrical muscle fibers. In the unfed nymph Hyalomma (Hyalomma) anatolicum anatolicum skeletal and visceral muscles are distinguished according to structure, function and position. These muscles include the capitulum, dorsoventral and leg oblique muscles. All muscle fibers are ensheathed (covered by sheath) in a sarcolemma. Their muscle fibers have striated pattern of successive sarcomeres whose thick myosin filaments are surrounded by orbitals of up to 12 thin actin filaments. The cytoplasm of the epidermal cell appears largely devoted with complicated microtubules present in parallel with long axis of adjacent muscle fibers. The cell membrane invaginates into tubular system extending deeply into the sarcoplasm and closely associated to cisternae of sarcoplasmic reticulum. The tubular system and sarcoplasmic reticulum forming two-membered (dyads) are considered to be the main route of calcium ions whose movement are synchronized with the motor impulse to control muscles contraction. In the sarcoplasm two types of muscle fibers are recognized according to thickness and density and mitochondrial size, distribution and population. Both skeletal and visceral muscles are invaginated by tracheoles and innervated by nerve axons containing synaptic vesicles. The actin and myosin filaments are slightly interrupted and the tubular system sarcoplasmic reticulum is well demonstrated. PMID- 21313908 TI - Potential nephrotoxicity in African mud catfish (Clarias gariepinus) following exposure to compost derived humic acid. AB - Influence of compost-derived Humic Acid (HA) on nephrotoxicity in juvenile African mud catfish (Clarias gariepinus) was evaluated in static water culture. Fish samples were exposed to different HA concentrations (0, 100, 250, 500 and 1000 mg L(-1)) for 45 days at 5 samples per aquarium. Renal function was assessed spectrophotometrically via levels of serum albumin, measured using bromocresol green, creatinine by Jaffe method and urea by Nesslerization method. Results revealed that the mean value of albumin or urea in the exposed group (1), at each HA concentration, was lower than the value found in the control group (II). Creatinine was relatively higher in I relative to II. Significant (p < 0.05) variations for I and II were obtained at 250 to 1000 mgHA L(-1) for the three biomarkers. Relative to increasing HA concentration, decreasing albumin (0.84 to 0.43 g dL(-1): r = -0.114; p > 0.10), urea (5.21 to 1.95 mg dL(-1); r = -0.586; p > 0.10) and increasing creatinine (0.20 to 1.53 mg dL(-1): r = +0.704; p > 0.10) were recorded; r is correlation coefficient. Changes in urea were not predictive of nephrotic syndrome but alterations in albumin and creatinine revealed induced nephrotoxicity, especially at elevated HA concentrations (above 100 mg L(-1)). Overall, the effect of humic acid was dose-dependent. Further studies at various humic acid concentrations, especially below 100 mg L(-1), are required to establish the actual nephrotoxic dose. PMID- 21313909 TI - Prediction of latency interval in preterm premature rupture of membranes using sonographic myometrial thickness. AB - Despite recent advances in perinatal care, Preterm Premature Rupture of Membranes (PPROM) continues to lead to important obstetric complications. This study was aimed to evaluate the role of sonographic measurement of myometrial thickness in prediction of latency interval in women with PPROM. This analytic- descriptive and case- control study was performed on pregnant women with PPROM presenting to Tabriz Al-Zahra Hospital since 2006 to 2008. Thirty pregnant women with PPROM and 30 pregnant women with normal pregnancy were enrolled. Mean gestational age was 30.60 +/- 1.99 week and in case and 31.13 +/- 20.01 week in control group (p = 0.307). Mean gravidity was 1.63 +/- 0.49 in case and 1.47 +/- 0.50 in control group (p = 0.210). Mean parity was 0.53 +/- 0.62 in case and 0.57 0.50 in control group (p = 0.819). Mean anterior myometrial thickness was 8.23 +/- 2.59 mm in case and 7.71 +/- 1.45 mm in control group (p = 0.344). Mean posterior myometrial thickness was 8.90 +/- 2.86 mm in case and 8.12 +/- 1.54 mm in control group (p = 0.197). Mean fundus myometrial thickness was 9.10 +/- 3.54 mm in case and 8.77 +/ 1.77 mm in control group (p = 0.648). Mean latency interval of women with PPROM was 18.70 +/- 20.68 day and mean sonography to labor interval was 57.30 +/- 16.14 day (p < 0.01). Mean latency interval of women with PPROM was significantly shorter than mean sonography to labor interval in control group patients (p < 0.05). In our study, 50% of women in 10 first days after PPRM labored and only 43.3% of women labored in 7 first days after PPROM. In this study, significant correlation was not found between myocardial sickness in anterior, posterior and fundus with latency interval. PMID- 21313910 TI - Isolation of beta-(1-3) glucan compound from the water extract of indonesian jamur tanduk (Termitomyces eurirrhizus Berk). AB - Jamur Tanduk (Termitomyces eurirrhizus Berk) is one of uncultivated edible mushrooms from genus Termitomyces found in various regions in Indonesia. The purpose of this study is to analyze the chemical structure of its beta-glucan compound that possesses bioactivity as lowering cholesterol levels. Isolation and identification of beta-glucan compound from water extract of Jamur tanduk (local name), Termitomyces eurirrhizus Berk collected in Sumedang has been done. beta glucan was isolated with Wasterlund methods and obtained as white powder. Isolated compound was identified based on interpretation of spectroscopies data such as Ultra-Violet (UV), Infra-Red (IR) and nuclear magnetic resonance one dimensional such as 1Hidrogen-Nuclear Magnetic Resonance (1H-NMR), 13Carbon- 13C NMR) and Distortionless Enhancement by Polarization Transfer (DEPT) and two dimensional such as Correlation spectroscopy (COSY), Hetero Multiple Quantum Connectivity (HMQC) and Hetero Multiple Bond Connectivity (HMBC). The determination of molecule weight of sample based on viscosity measurements and obtained that beta-glucan has 322 molecules of glucose. PMID- 21313911 TI - The effect of manipulations of incubation temperature on embryonic and post hatching growth of native Saudi chickens. AB - Embryonated egg is an ideal, environment in which to investigate the effects of incubation temperature on the development of the chick embryo. The objective of the current study were to investigate the effect of increasing the incubation temperature of chick embryo by 1.2 degrees C for 7 days (ED4 to ED11) on the body movement and mass of native saudi chick embryo. This objective was extended to examine the influence of pre-hatching temperature on post-hatching growth. Therefore, a total of 180 hatching egg of native Saudi chicken divided into two equal groups incubated at temperature 37.5 degrees C. The incubation temperature was raised to 38.7 degrees C from ED4 to ED11 in treated group before being returned to the control group incubation temperature (37.5 degrees C). The study revealed that elevating the incubation temperature of the eggs of native Saudi chicken by just 1.2 degrees C, from 37.5 to 38.7 degrees C, during embryonic days (ED) 4-11 causes significant increase in embryonic movement as demonstrated in day 8 in the chicks incubated at 38.7 degrees C together with an increase in embryonic development, the embryos incubated at higher temperature were heavier in weights and exhibit significantly longer legs than the controls in ED12 and 15. The increase in pre-hatching incubation temperature (38.7 degrees C) did not reveal any significant effects on post-hatching growth or of feed conversion efficiency. PMID- 21313912 TI - Internalisation of microbes in vegetables: microbial load of Ghanaian vegetables and the relationship with different water sources of irrigation. AB - The occurrence of pathogens in the internal parts of vegetables is usually associated with irrigation water or contaminated soil and could pose risk to consumers as the internalised pathogens are unaffected by external washing. This study was carried out to assess the rate of internalisation of microbes in common Ghanaian vegetables. Standard microbiological methods were employed in microbial enumeration of vegetables collected at the market and farm levels, as well as irrigation water and soil samples. The overall mean counts of vegetables were 4.0 x 10(3) cfu g(-1); 8.1 x 10(2) cfu g(-1); 2.0 x 10(2) cfu g(-1); 3.5 x 10(2) cfu g(-1) for total bacteria, coliform counts, faecal coliform counts and yeast counts, respectively. The rate of internalisation of coliforms in vegetables irrigated with stream/well water was 2.7 times higher than those irrigated with pipe water. The mean coliform counts (4.7 x 10(7) cfu g(-1)) and faecal coliform counts (1.8 x 10(6) cfu g(-1)) of soil samples were similar to those of stream water suggesting both sources exerted similar contamination rates on the vegetables. Generally, there were no significant variations between the rates of internalisation of microbes at the market and farm levels at p < 05, indicating that internalisation of microbes in the vegetables mainly occurred at the farm level. The study has shown that microbial contamination of vegetables in Ghana is not limited to the external surface, but internal vegetable parts could harbour high microbial loads and pose risk to consumers. Safety practices associated with the commodity should therefore not be limited to external washing only. There is the additional need of heating vegetables to eliminate microbes both externally and internally before consumption. PMID- 21313913 TI - The children reference range of thyroid hormones in Northern Iran. AB - Hypothyroidism is associated with mental and growth abnormality in children. The aim of this study was to determine the reference range of thyroid stimulating hormone (TSH). Thyroxin (T4) and triodothyronine (T3) of children in Northern Iran. The sample population for this study consists of subjects of 4 age groups up to 21 years. The subjects were selected randomly from people referred to Danesh Medical Diagnostic Laboratory in Gorgan Northern Iran. Thyroid hormone level were investigated with Radio immunoassay. The mean concentration for T4, T3, TSH for the sample population of 4 groups were as follow (113.5, 107.4, 102.9, 99.2 nmol L(-1)), (1.9, 1.7, 1.9, 1.6 nmol L(-1)) and (2.1,3.5, 2.9, 2.7 mIu L(-1)). The mean value of T3, TSH were higher for females but the mean value of T4 was slightly higher in males. The findings of this investigation indicated that there is an inverse age correlation in particular for T4 in all age groups. On the bases of the results from this study, we conclude that reference range, in all age groups and lower, upper limits of our reference range are not universally similar; therefore determination of reference range in each region is a critical need for clinical practice. PMID- 21313914 TI - Lifestyle related causes of cancer and chemoprevention through phytonutrients. AB - Cancer is a leading cause of death worldwide. There are a lot of cancer causing agents which are divided as physical carcinogens, chemical carcinogens and biological carcinogens. But most of the carcinogens or causes of cancer are related to our lifestyle like diet, habit, occupation, radiation and some infection, etc. Chemoprevention is highly necessary to prevent cancer related preterm death. For this besides avoiding the causes of cancer we should concentrate ourselves on our diet. Because, numerous phytochemicals derived from edible plants have been reported to interfere with a specific stage of the carcinogenic process. Many mechanisms have been shown to account for the anticarcinogenic actions of dietary constituents and recently attention has been focused on intracellular-signalling cascades as common molecular targets for various chemopreventive phytochemicals. In this study, we tried to describe lifestyle related causes of cancer and the molecular basis of cancer prevention through the phytochemicals. PMID- 21313915 TI - The histopathalogical effects of retinoic acid on the tissues. AB - The aim of this study is to sum up the important information that has emerged from the last 10 years of experimental investigations over the effects of retinoic acid (RA) on embryonic structure and adult tissues. Administration of exogenous RA can affect the connective tissues including enhancement of myeloid compartment and suppression of erythroid cells and conversion of hematopoietic stem cells to erythroid progenitors. Also, it is able to induce osteogenic differentiation of stem cells derived from adipose tissues and etc. Examining the neural tissue highlighted that disruption of RA signaling in the adult leads to degeneration of motor neurons and development of some diseases. In vitro administration of All-Trans Retinoic Acid (ATRA) increased dendritic growth and synaptophysin puncta intensity and increased expressions of neuronal nuclei, neuron specific enolase, synaptophysin. RA also promotes expression of a marker of mature astrocytes. On muscular tissue, it can inhibit proliferation of smooth muscle cells (SMC) while promoting differentiation of SMC in vitro instead. The ATRA stimulates skeletal myogenesis while inhibiting cardiomyogenesis and hypertrophy and proliferation of cultured neonatal cardiomyocytes and cardiofibroblasts. In addition, differences in levels of embryonic RA may contribute to variability in great artery anomalies. In epithelial tissue, the squamous epithelium exposed to ATRA showed the columnar differentiation independent to proliferation. Also RA seems able to rescue the regeneration process of injured gut and revealing a better wound healing of the intestine undergone intra-operative radiotherapy. It can interrupt the process of progressive fibrosis, enhancements of the langerhans islets, exocrine pancreas, modulate the health of the mammary glands and repairs the lung cell. Thus, differences in levels of endogenous RA in embryonic and adult tissues may contribute to anomalies and pathogenesis of disease, furthermore RA has paradoxical effects on the parts forming the connective and muscles tissue in equal conditions. PMID- 21313916 TI - Virulence of environmental Stenotrophomonas maltophilia serologically cross reacting with Shigella-specific antisera. AB - This research involved an environmental strain of Stenotrophomonas maltophilia which has been reported to produce serological cross-reactivity with Shigella dysenteriae type 8 specific antisera. Since clinical diagnosis of shigellosis is largely based on culture and serology, the investigation was aimed at in vivo and in vitro virulence comparison between the culturally similar environmental S. maltophilia isolate and the reference S. dysenteriae strains. The findings of this study revealed the absence of virulent genes of Shigella sp. like ipaH, virA and stx1 and characteristic invasive large plasmid in the test isolate. The Western blot analysis revealed that serological cross-reactivity of Stenotrophomonas maltophilia was due to certain protein component(s) in its outer membrane. The isolate was capable of producing extracellular protease, exhibited alpha hemolysis and was negative for hemagglutinating assay. The isolate gave negative reaction with rabbit ileal loop and Sereny tests. The S. maltophilia isolate did not possess any enterotoxic or invasive property as that of virulent S. dysenteriae strains. Further characterizations and adequate genetic manipulations of this environmental isolate may contribute to the development of a potential vaccine candidate for shigellosis. PMID- 21313917 TI - Low dose vaginal misoprostol versus prostaglandin E2 suppository for early uterine evacuation: a randomized clinical trial. AB - Misoprostol is a cheap product of prostaglandin E1 which has gained interest in pregnancy termination. The aim of this study was to compare the effect of vaginal misoprostol and prostaglandin E2 suppository in pregnancy termination before 20 weeks of gestational age. In this clinical trial, 111 participants under 20 weeks of gestational age who needed pregnancy termination were enrolled. They were divided into two groups misoprostol and prostaglandine E2 treatment. Fifty four people received vaginal misoprostol as 25 microg per 4 h up to 3 days and 57 participants received prostaglandine E2 vaginal suppositories. Data were analyzed using SPSS software. Mean age of participants was 27.5 years and its standard deviation was 6.1 years. Mean gestational age was 13.1 weeks based on sonographic measurement and it was 14.5 weeks by LMP estimation. Mean induction to evacuation time was 3.1 days and in misoprostol group was 2.4 +/- 0.88 days. Half of the patients in control group and 70% of them in misoprostol group succeeded pregnancy termination in 48 h. Vaginal misoprostol compared to prostaglandine E2 vaginal suppository has higher efficacy in shorter time. PMID- 21313918 TI - Human papillomaviruses prevalence and genital co-infections in HIV-seropositive women in Ouagadougou (Burkina Faso). AB - The vaginal swabs among HIV-positive women in Africa often revealed opportunistic infections such as human Papillomavirus (HPV) and Mycoplasma that induce respectively cervix cancer and diseases such as vaginosis, abortions, infertility in through salpingitis. The purposes of this study were to: (1) seek for, the prevalence of pathogens such as HPV and Mycoplasma; (2) characterize the strains of HPV and estimate their prevalence; (3) identify among these women, those who were co-infected by these pathogens in order to cure them. From February 2009 to January 2010, 156 HIV-positive women attending our medical centers and aged from 19-45 years (mean age 33.65 +/- 5.75 years) had voluntarily accepted vaginal specimen's tests. PCR, ELISA and molecular hybridization were used for the identification and characterization of these pathogens. The results revealed the presence of Mycoplasma and HPV in 25.64 and 58.33% cases, respectively. The following HPV genotypes and the following prevalence were recorded: HPV-50'S (24.11%), HPV-18 (21.28%), HPV-30'S (18.44%) and HPV-16 (5.67%). The study also enable the identification of co-infections such as HPV-18 strains with HPV-30'S (5.67%) and HPV-30'S with HPV-50'S (3.55%). Other germs infecting the female genital tract including Candida albicans (20.51%), Escherichia coli (12.18%), Treponema pallidum (3.85%), Streptococcus agalactiae (3.21%) and Staphylococcus aureus (1.92%) were isolated. This preliminary research work showed the incidence of several genital pathogens, this could be a springboard for nationwide epidemiological study on HPV strains circulating in Burkina Faso. PMID- 21313919 TI - Effects of electromagnetic fields on mental health of the staff employed in gas power plants, Shiraz, 2009. AB - The aims of this study are to assess, in a power station in Shiraz, the effects of noise and electromagnetic field on psychological mood. By the great industrial and technological improvements human beings have been exposed to different types of physical and chemical factors. Some of these factors such as electromagnetism are known as the constant components of the environment. According to the studies carried out in one of the power stations in Shiraz, psychological disorders caused by jobs are among the most important problems of the workers. This study is performed to determine the presence or absence of these psychological disorders. This cross-sectional study is performed on these groups : (1) The gas power plant staff who were in contact with electromagnetic field and nose, (2) employees who were only exposed to noise and (3) a group of staff employed in the administrative parts of the Telecommunication companies who did not have any history of being exposed to electromagnetic field and sounds. The General Health Questionnaire (GHQ) is used in this study to recognize psychosomatic disorders. Measurements indicate that range of electromagnetic field varies from 0.087 micro Tesla in the phone homes to 30 micro Tesla in power stations. The results of this study has shown that a significant number of staff which were exposed to electromagnetic fields and noise (78.2%) were suspected to have a kind of mental disorders. The results obtained from this study which shows the prevalence of mental disorders among the suspected case is higher than the results of Noorbala and colleagues study in 2006. PMID- 21313920 TI - Pattern of laminin expression during kidney morphogenesis in Balb/c mice. AB - Basement membrane of glomerular mesangium (BMG) is one of important components which play a key role to support of the capillary loops in a renal glomerulus and completeness of BMG due to interaction of ureteric bud and metanephric mesenchyme during glomerulogenesis. As laminin contribute in extra cellular matrix and especially in basement membrane, the aim of the present study was to demonstrate the distribution of this molecule so, in this investigation specific antibody against laminin have been used in light microscopy to study development of BMG of fetal and postnatal mouse glomerular mesangium. Female inbred Balb/c mice were selected and were kept under normal condition and finding vaginal plug was assumed as day zero of pregnancy. Two pregnant mice were sacrificed by cervical dislocation in one of gestational days 13-18, respectively and their fetuses were fixed, serially sectioned and by using antibody against laminin in BMG were carried out. The same process was used for kidneys preparation at 15 postnatal days. Present data revealed that laminin showed weak reaction on day 14 of gestation. The amount of laminin increased continuously until next days of fetal life and primary of 10 days postnatal in BMG. After this period, laminin reaction did not show significant change in newborns. These data indicate that laminin appears just during the glomerulogenesis and because of continuity with vasculature which is required for Extra Cellular Matrix (ECM) and glomerular endothelial cell differentiation, laminin, is the one of major structural proteins in BMG. PMID- 21313921 TI - The prize. PMID- 21313922 TI - 2010 John H. Gibbon Lecture. Just say yes! AB - Advancing anything requires change and a new method. It can be a challenge to bring about the change that you believe in. This change however requires you to plan and say no to the old way of doing things. Fortunately there is a positive way to say no whereby important needs are met. As Ury suggests, we need to focus on how the two opposing forces need to be addressed. There is your internal focus of what's important to you and the opposing external focus of others--what's important to them. We can't lose sight of this because when we do, we risk disrespecting others. As technicians we are in a unique position as perfusionists whereby we work closely with physicians and on occasion will direct them to perform tasks. Additionally, many other non-physicians are not familiar with our responsibilities. We need to make others knowledgeable of the education, skill, and passion we possess. I really enjoy what I do as a perfusionist and I am proud to be recognized for my team's contribution and of having received the Gibbon award. Bob Parsons, the CEO and founder of The Go Daddy Group, Inc., said "We're not here for a long time, we're here for a good time!" This all has been a real good time. Thank you. My Perfusion Team is currently: Barbara Elmer, Marie Kilcullen, Jim McVey, Marie Zanichelli, Junli Liu, Anthony Lamonica, Karen Hussey, Lilia Voevidko, Haleh Ebrahimi, Sergey Savy, Akilah Richards, Diana Froehlich. PMID- 21313923 TI - Back to the stacks--looking at classic papers related to the current practice of cardiopulmonary bypass. PMID- 21313924 TI - Extracorporeal life support for pandemic influenza: the role of extracorporeal membrane oxygenation in pandemic management. AB - The recent global threat of a severe pandemic influenza outbreak has suggested that extracorporeal life support will begin to play an evolving role in the care of critically ill influenza stricken patients. The highly communicable attributes of influenza could result in widespread infection and an associated increased need for advanced life support. Supply and demand equilibrium may be abruptly disrupted, and ethical decisions regarding the allocation of life saving resources will inevitably need to be made. Protocol oriented planning, research analysis, and advanced technologies are critical factors in averting catastrophe. This review article details the epidemiology, diagnostic techniques, and interventions for the influenza A virus, including H1N1. PMID- 21313925 TI - Is there an association between hyperglycemia and clinical outcome in adult patients receiving extracorporeal membrane oxygenation. AB - Perioperative hyperglycemia frequently develops in critically ill patients and has been associated with adverse outcome. In this study, we tried to identify whether hyperglycemia was associated with adverse outcome in adult patients receiving extracorporeal membrane oxygenation. From 2004 through 2008, 44 adult patients received extracorporeal membrane oxygenation. Clinical records of these 44 consecutive patients were retrospectively analyzed. Glucose levels were monitored and recorded every 3 hours during the support period. The mean glucose level was computed for all patients for whom data were available within the first 48 hours after extracorporeal membrane oxygenation setup. More than 15% of blood glucose levels above 180 mg/dL were defined as hyperglycemia. Clinical outcomes were compared between patients with and without hyperglycemia. The primary outcome was death from any cause in hospital. A p value < .05 was accepted as significant. The overall survival was 68%. Twenty-eight patients were allocated to group 1 with a mean glucose of 179 +/- 40 mg per deciliter. The other 16 patients allocated to group 2 with a mean glucose of 140 +/- 16 mg per deciliter. There is no significant difference in the mortality of the two groups. Perioperative complications were also similar between the two groups. Glucose levels were not associated with mortality and complications in adult patients receiving extracorporeal membrane oxygenation. PMID- 21313926 TI - Hyaluronan based heparin free coated open and closed extracorporeal circuits for high risk coronary revascularization. AB - This prospective randomized study compares the inflammatory response and fibrinolytic activation of fully coated/uncoated and open/closed extracorporeal circuits (ECC) in high risk patients. Over a 2-month period, 48 patients with EuroSCOREs 6 or greater undergoing coronary revascularization were prospectively randomized to one of the four perfusion protocols: Group 1: Closed and totally hyaluronan based heparin free coated (Vision HFO-GBS-HF, Gish Biomedical, Rancho Santa Margarita, CA) ECC with a soft-shell coated venous reservoir (SVR11S2-HFC, Gish Biomedical) and a hard-shell cardiotomy (CAPVRF44, Gish Biomedical) (n = 12); Group 2: Closed and totally uncoated identical ECC with soft-shell uncoated venous reservoir and a hard-shell cardiotomy (n = 12); Group 3: Open, totally hyaluronan based heparin free coated ECC (n = 12); and Group 4: Control-open, uncoated ECC (n = 12). Blood samples were collected at T1: Baseline; T2: 15 minutes after cardiopulmonary bypass (CPB) initiation; T3: before cessation of CPB; T4: 15 minutes after protamine reversal, and T5: in the intensive care unit. Serum IL-6 levels were significantly lower at T2 in all study groups, at T3 for coated groups, and T4 for closed+coated group (p < .05 versus control). Creatine kinase M-band (MB) levels in coronary sinus blood demonstrated well preserved myocardium after CPB in both coated groups versus Control (p < .05). Neutrophil CD11b/CD18 levels were significantly lower for all study groups versus control at T2, for both coated groups at T3 and only for closed + coated group at T4 (p < .05). Postoperative hemorrhage (mL) was 510 +/- 40 in closed + coated and 536 +/- 40 in open + coated groups (control: 784 +/- 48, p < .05). No significant differences in thrombin-antithrombin complex and free plasma hemoglobin were observed. Desorbed protein amount on ECC (mg/dL) was 1.7 +/- .01 in closed+coated, 2.01 +/- .01 in open+coated, and 3.3 +/- .015 in control groups (p < or = .05). Use of a closed and completely heparin free coated ECC may reduce neutrophil degradation, cytokine release characterized by improved clinical outcomes including reduced blood loss, reduced requirement for inotropes, and reduced atrial fibrillation. PMID- 21313927 TI - Using biomarkers to improve the preoperative prediction of death in coronary artery bypass graft patients. AB - The current risk prediction models for mortality following coronary artery bypass graft (CABG) surgery have been developed on patient and disease characteristics alone. Improvements to these models potentially may be made through the analysis of biomarkers of unmeasured risk. We hypothesize that preoperative biomarkers reflecting myocardial damage, inflammation, and metabolic dysfunction are associated with an increased risk of mortality following CABG surgery and the use of biomarkers associated with these injuries will improve the Northern New England (NNE) CABG mortality risk prediction model. We prospectively followed 1731 isolated CABG patients with preoperative blood collection at eight medical centers in Northern New England for a nested case-control study from 2003-2007. Preoperative blood samples were drawn at the center and then stored at a central facility. Frozen serum was analyzed at a central laboratory on an Elecsys 2010, at the same time for Cardiac Troponin T, N-Terminal pro-Brain Natriuretic Peptide, high sensitivity C-Reactive Protein, and blood glucose. We compared the strength of the prediction model for mortality using multivariable logistic regression, goodness of fit and tested the equality of the receiving operating characteristic curve (ROC) area. There were 33 cases (dead at discharge) and 66 randomly matched controls (alive at discharge).The ROC for the preoperative mortality model was improved from .83 (95% confidence interval: .74-.92) to .87 (95% confidence interval: .80-.94) with biomarkers (p-value for equality of ROC areas .09). The addition of biomarkers to the NNE preoperative risk prediction model did not significantly improve the prediction of mortality over patient and disease characteristics alone. The added measurement of multiple biomarkers outside of preoperative risk factors may be an unnecessary use of health care resources with little added benefit for predicting in-hospital mortality. PMID- 21313928 TI - Patient directed bypass: cooling for aortic surgery--a preliminary concept. AB - No consensus exists as to the temperature to cool to on bypass for surgery involving the aortic arch. Excluding normothermic surgery, which is rarely performed for arch work, circulatory arrest, anterograde, and retrograde cerebral perfusion either in isolation or in combination remain the techniques of "cerebral protection." To date, no account of individual patient body or cerebral function variation is involved. Utilizing an electronic perfusion database we retrospectively analyzed 10 patients undergoing aortic arch work with regard to mixed venous saturations during cooling. Perfusion related variables were registered and uploaded to www.perfsort.net. We regarded a saturation of 100% as being indicative of no oxygen extraction, implying no metabolic activity--the theoretical goal prior to a circulatory arrest period. There is enormous variation in the temperature at which metabolic activity of the body stops. We had a range from 17-25 degrees. Patients were cooled for an average of 6 (SD 3.4) degrees below which oxygen extraction had ceased to occur. Potentially we are adding 111 minutes (SD 62) of unnecessary bypass time. This may imply that excessive cooling is occurring in some individuals undergoing arch surgery. Patient directed cooling for aortic arch surgery may help to reduce the morbidity/physical insult associated with severe hypothermia. This work is very preliminary but may help us to depart from the one size fits all paradigm that exists in current clinical practice. Correlation with bispectral index, electroencephalogram monitoring and neurological outcomes is needed. PMID- 21313929 TI - Vicarious audiovisual learning in perfusion education. AB - Perfusion technology is a mechanical and visual science traditionally taught with didactic instruction combined with clinical experience. It is difficult to provide perfusion students the opportunity to experience difficult clinical situations, set up complex perfusion equipment, or observe corrective measures taken during catastrophic events because of patient safety concerns. Although high fidelity simulators offer exciting opportunities for future perfusion training, we explore the use of a less costly low fidelity form of simulation instruction, vicarious audiovisual learning. Two low fidelity modes of instruction; description with text and a vicarious, first person audiovisual production depicting the same content were compared. Students (n = 37) sampled from five North American perfusion schools were prospectively randomized to one of two online learning modules, text or video.These modules described the setup and operation of the MAQUET ROTAFLOW stand-alone centrifugal console and pump. Using a 10 question multiple-choice test, students were assessed immediately after viewing the module (test #1) and then again 2 weeks later (test #2) to determine cognition and recall of the module content. In addition, students completed a questionnaire assessing the learning preferences of today's perfusion student. Mean test scores from test #1 for video learners (n = 18) were significantly higher (88.89%) than for text learners (n = 19) (74.74%), (p < .05). The same was true for test #2 where video learners (n = 10) had an average score of 77% while text learners (n = 9) scored 60% (p < .05). Survey results indicated video learners were more satisfied with their learning module than text learners. Vicarious audiovisual learning modules may be an efficacious, low cost means of delivering perfusion training on subjects such as equipment setup and operation. Video learning appears to improve cognition and retention of learned content and may play an important role in how we teach perfusion in the future, as simulation technology becomes more prevalent. PMID- 21313930 TI - Center for Transforming Healthcare releases first targeted solutions. PMID- 21313931 TI - Top standards compliance issues for the first half of 2010. PMID- 21313932 TI - Flu vaccination challenge enters third season with room for more participants and better rates. PMID- 21313933 TI - "Living healthily doesn't just mean going to the gym". PMID- 21313935 TI - "It's not cheesy or crackers to celebrate public services.". PMID- 21313934 TI - "You have to invest in yourself. You cannot expect it to be handed to you." Interview by Charlotte Santry. PMID- 21313936 TI - "A commissioning role would release nurses' creativity.". PMID- 21313937 TI - Ensuring patients stay safe. PMID- 21313938 TI - Caring for critically injured soldiers. AB - This article highlights the specific challenges faced by clinical staff caring for military casualties and identifies why routine clinical practice needs to be adapted to provide effective care. The types of injury are discussed as well as pain management regimens, which have to be tailored to accommodate particular patterns of injuries. Flashbacks and hallucinations are common problems following traumatic injury and affect each soldier differently. The need for psychological support is explored because this is one of the most challenging aspects of caring for military casualties and their families. PMID- 21313939 TI - Dealing with phantom limb pain after amputation. AB - Patients usually experience phantom limb pain after amputation but it may also occur following resection of other parts of the body, such as the breast and internal organs like the rectum. The causes are complex and patients require careful assessment to ensure they receive appropriate care. This article describes the causes of phantom limb pain and discusses assessment strategies. PMID- 21313940 TI - What prevents one to one care? AB - BACKGROUND: In 2007, West London Mental Health Trust was visited by the Healthcare Commission (now the Care Quality Commission), which identified several issues needing attention. One major concern was the lack of effective interaction between nurses and service users in acute care. AIM: To determine why mental health nurses on acute admissions wards struggle to spend one to one time with service users, and how to address the problem. METHOD: Interviews with four senior nurses were conducted to identify initial concerns and problems. This data formed a basis for semi-structured interviews with all 11 acute admissions ward managers at the trust. RESULTS: Five common themes were identified as the major barriers to one to one care: administrative duties; understanding one to one sessions; control over workload; staff needs; and ward culture. CONCLUSION: Staff training and education have been improved, and policies implemented. As the study is small, replicating it nationally would give a better overall picture of this issue in mental health services. PMID- 21313941 TI - From the top: a guide to being an effective leader. PMID- 21313942 TI - The lifespan of time intervals in reference memory. AB - To further explore how memory influences time judgments, we conducted two experiments on the lifespan of temporal representations in memory. Penney et al (2000, Journal of Experimental Psychology Human Perception and Performance 26 1770-1787) reported that the perceived duration of auditorily and visually marked intervals differs only when both marker-type intervals are compared directly. This finding can be explained by a 'memory-mixing' process, whereby the memory trace of previous intervals influences the perception of upcoming ones, which are then added to the memory content. In the experiments discussed here, we manipulated the mixing mode of auditory/visual signal presentations. In experiment 1, signals from the same modality were either grouped by blocks or randomised within blocks. The results showed that the auditory/visual difference decreased but remained present when modalities were grouped by blocks. In experiment 2, we used a line-segmentation task. The results showed that, after a training block was performed in one modality, the perceived duration of signals from the other modality was distorted for at least 30 trials and that the magnitude of the difference decreased as the block went on. The results of both experiments highlight the influence of memory on time judgments, providing empirical support to, and quantitative portrayal of, the memory-mixing process. PMID- 21313943 TI - Differential effect of luminance contrast reduction and noise on motion induction. AB - Motion perception in a region is affected by motion in the surround regions. When a physically static or flickering stimulus surrounded by moving stimuli appears to move in the direction opposite to that of the surround motion, it is referred to as motion contrast. When the centre appears to move in the same direction, it is referred to as motion assimilation. We investigated how noise and luminance contrast affect motion induction by employing static and dynamic counterphase flickering targets. The tendency of motion assimilation was found to be stronger at a high noise level than at a low noise level for both static and dynamic targets. On the other hand, a decrease of luminance contrast tended to strengthen the tendency of motion contrast. However, the addition of noise and the decrease of luminance contrast decreased the visibility of motion comparably. These results suggest that the visual system changes the mode of motion induction according to the noise level, but not the visibility. PMID- 21313944 TI - Properties of long-range illusory contours produced by offset-arcs. AB - Researchers have used several different types of illusory contours to investigate properties of human perception. One rarely used illusory contour is a combination of the abutting grating and Kanizsa illusions. We call this the offset-arcs illusion and provide an empirical investigation of the illusion. Through a series of four experiments, using different methods of measurement, we show that changes to the phase of the abutting-grating part of the inducing stimulus can dramatically change the perceived strength and clarity of the long-range illusory contour. The easy manipulation of illusion strength should make the offset-arcs illusion applicable to a wide range of studies that utilize long-range illusory contours. The lack of a brightness component to the illusion should allow the offset-arcs illusion to help separate perceptual grouping from surface brightness effects that are often confounded in other illusory contours. PMID- 21313945 TI - The relative contribution of relative height, linear perspective, and texture gradients to pictorial depth perception in 7-month-old infants. AB - In the current preferential-reaching experiments, 7-month-olds were tested for their ability to respond to a combination of relative height and texture gradients. The infants were presented with a display in which these pictorial depth cues specified that two toys were at different distances. The experimental displays differed from the textured surfaces employed in earlier studies in that linear perspective of the contours of the texture elements was omitted. Experiment A shows that the infants still preferred to reach for the apparently nearer toy under monocular, but not binocular, viewing conditions, indicating that they responded to the pictorial depth cues. In experiment B, relative height and texture provided the infants with conflicting information for depth. Here, relative height outperformed texture information. A statistical comparison between the experiments as well as systematic comparisons with experimental conditions from an earlier study (Hemker et al, 2010 Infancy 15 6-27) revealed that texture gradients, unlike linear perspective, neither enhanced nor weakened the effect exerted by relative height. In sum, 7-month-old infants are obviously more sensitive to relative height and to the linear perspective of the surface contours than to the texture gradients of compression, perspective, and density. PMID- 21313946 TI - Inverting faces does not abolish cultural diversity in eye movements. AB - Face processing is widely understood to be a basic, universal visual function effortlessly achieved by people from all cultures and races. The remarkable recognition performance for faces is markedly and specifically affected by picture-plane inversion: the so-called face-inversion effect (FIE), a finding often used as evidence for face-specific mechanisms. However, it has recently been shown that culture shapes the way people deploy eye movements to extract information from faces. Interestingly, the comparable lack of experience with inverted faces across cultures offers a unique opportunity to establish the extent to which such cultural perceptual biases in eye movements are robust, but also to assess whether face-specific mechanisms are universally tuned. Here we monitored the eye movements of Western Caucasian (WC) and East Asian (EA) observers while they learned and recognised WC and EA inverted faces. Both groups of observers showed a comparable impairment in recognising inverted faces of both races. WC observers deployed a scattered inverted triangular scanpath with a bias towards the mouth, whereas EA observers uniformly extended the focus of their fixations from the centre towards the eyes. Overall, our data show that cultural perceptual differences in eye movements persist during the FIE, questioning the universality of face-processing mechanisms. PMID- 21313947 TI - Brightness enhancement seen through a tube. AB - We report a fascinating phenomenon that emerges when a surface is viewed through a tube held close to one eye, with the other eye open. The disk-shaped area seen through the tube looks strikingly brighter and, when viewed on a textured background, also of higher spatial contrast than the same surface area viewed without a tube. The effect is reminiscent of a spotlight illuminating the area under consideration. We call this the 'tube effect'. The tube effect is one of the strongest contrast illusions known to us. It requires a matching luminance that is twice as high as the reference luminance seen through the tube. Brightness ratings increase linearly with the log of the background luminance. The effect (i) produces a dark afterimage, (ii) reverses in polarity with low ambient illumination, (iii) assumes the complementary colour of the illuminant, and (iv) persists with fully dilated pupils. Potential explanations include simultaneous contrast (due to the penumbra and dark inner walls of the tube) and veiling of the surround (due to local adaptation and a lower gain factor). PMID- 21313948 TI - Mapping emotion category boundaries using a visual expectation paradigm. AB - Past research showing categorical perception of emotional facial expressions has relied on identification and discrimination tasks that require an explicit response via keypress. Here we report a new paradigm for investigating the category boundary of emotional facial expressions that, instead, relies on an implicit response--eye direction. Participants were trained to expect a target stimulus on a particular side of the monitor, predicted by an emotional expression on a face image. An eye-tracker then recorded eye movements of participants as they viewed novel intermediate facial-expression stimuli. Anticipatory eye movement was taken as evidence of categorisation. Results from two experiments suggest that this implicit method can be used to determine category boundaries, and that the boundaries found with this method are similar to those found with the keypress response. PMID- 21313949 TI - The perseverance of numerical distance effect in attentional blink. AB - In a number comparison task, it is easier to respond faster when the two numbers are further apart than when they are close. This inverse relationship between the size difference and the time to judge such difference is called the numerical distance effect (NDE). In this study we investigated whether attention plays a critical role in the surfacing of NDE and the way we process Arabic numbers. In experiments 1 and 2, with an attentional blink paradigm that was designed to modulate attention, we tested whether a limited or unlimited pool of attentional resources would have an impact on the performance and trend of NDE. The results showed a dissociable effect of attention that changed the overall accuracy but not the trend of NDE. In experiment 3 we examined whether the number priming effect, another phenomenon associated with the distance-related effect, would be affected during the attentional blink period. We found the pattern of number priming effect was not affected by attentional blink. An explanation of the role of attention in number distance processing, as well as how it interacts with Arabic number representation, is discussed. PMID- 21313950 TI - The nose tells it to the eyes: crossmodal associations between olfaction and vision. AB - Crossmodal linkage between the olfactory and visual senses is still largely underexplored. In this study, we investigated crossmodal olfactory-visual associations by testing whether and how visual processing of objects is affected by the presence of olfactory cues. To this end, we explored the influence of prior learned associations between an odour (eg odour of orange) and a visual stimulus naturally associated with that odour (picture of orange) on the movements of the eyes over a complex scene. Participants were asked to freely explore a photograph containing an odour-related visual cue embedded among other objects while being exposed to the corresponding odour (subjects were unaware of the presence of the odour). Eye movements were recorded to analyse the order and distribution of fixations on each object of the scene. Our data show that the odour-related visual cue was explored faster and for a shorter time in the presence of the congruent odour. These findings suggest that odours can affect visual processing by attracting attention to the possible odour source and by facilitating its identification. PMID- 21313951 TI - Motion impressions enhanced by converging motion lines. AB - We investigated how motion lines drawn in the background of a running human silhouette affect motion impressions of a runner in a static image. Observers evaluated the strength and direction of motion impression. The results show that parallel lines do not enhance frontoparallel motion impressions, while converging lines do so in an in-depth direction. This is a counter-example to the hypothesis that motion lines in the background represent motion streaks of the background when one visually tracks a moving object. PMID- 21313952 TI - The importance of social factors is a matter of perception. AB - Caucasian female faces were randomly assigned to participants' in- or out-group following false feedback on a personality inventory. Participants recognised in group faces better than out-group faces, but they showed no evidence of category contingent opposing aftereffects. We conclude that the explanatory power of social-cognitive models will be enhanced when they are integrated with models of perceptual expertise. PMID- 21313953 TI - Healthcare community bands together to face tough issues. PMID- 21313954 TI - "Nothing was disposable & we only had ether". A historic journey. PMID- 21313955 TI - The microvascular network of the pituitary gland: a model for the application of fractal geometry to the analysis of angioarchitecture and angiogenesis of brain tumors. AB - In geometrical terms, tumor vascularity is an exemplary anatomical system that irregularly fills a three-dimensional Euclidean space. This physical characteristic, together with the highly variable vessel shapes and surfaces, leads to considerable spatial and temporal heterogeneity in the delivery of oxygen, nutrients and drugs, and the removal of metabolites. Although these biological features have now been well established, quantitative analyses of neovascularity in two-dimensional histological sections still fail to view tumor architecture in non-Euclidean terms, and this leads to errors in visually interpreting the same tumor, and discordant results from different laboratories. A review of the literature concerning the application of microvessel density (MVD) estimates, an Euclidean-based approach used to quantify vascularity in normal and neoplastic pituitary tissues, revealed some disagreements in the results and led us to discuss the limitations of the Euclidean quantification of vascularity. Consequently, we introduced fractal geometry as a better means of quantifying the microvasculature of normal pituitary glands and pituitary adenomas, and found that the use of the surface fractal dimension is more appropriate than MVD for analysing the vascular network of both. We propose extending the application of this model to the analysis of the angiogenesis and angioarchitecture of brain tumors. PMID- 21313956 TI - Microsurgical endoscopic-assisted retrosigmoid intradural suprameatal approach: anatomical considerations. AB - AIM: The aim of this study was to evaluate the feasibility of microscopic endoscopic assisted suprameatal tubercle drilling with a retrosigmoid approach and it focuses on the anatomic structures identified with the endoscope. The advantages of the 30 degrees optic view are also described. METHODS: Fifty dry temporal bones were studied in order to estimate the variability of the prominence of the suprameatal tubercle. Eight fresh cadaveric specimens were prepared for a retrosigmoid approach to allow for microscopic endoscopic assisted suprameatal tubercle drilling. The increase in trigeminal exposure and neurovascular structures visualization with the endoscope, using 0 degrees and 30 degrees optics were then evaluated. RESULTS: Three major types of the suprameatal tubercle were found: 1) a large size tubercle (> 6 mm, 9/50 cases); 2) a medium size tubercle (3-6 mm, 37/50 cases); and 3) an almost absent suprameatal tubercle (< 3 mm, 4/50 cases). Microscopic endoscopic assisted suprameatal tubercle drilling with opening of the Meckel's Cave was found to be technically feasible in all cases. The increase in trigeminal nerve exposition was of 9 mm on average. Endoscopic exploration with 0 degrees and 30 degrees optics made possible the identification of all neurovascular structures in the area. CONCLUSION: Microscopic endoscopic assisted suprameatal tubercle drilling is a feasible procedure that allows the identification of all neurovascular structures in the cerebellopontine angle and petrous apex region. The opening of Meckel's Cave may be particularly useful for lesions located in the cerebellopontine angle having a minor component that extends anteriorly and laterally in the middle cranial fossa. PMID- 21313957 TI - Lateral lumbar interbody fusion via a unilateral true percutaneous approach associated with minimally invasive pedicle screw fixation for degenerative disc disease and lumbar instability. A technical note. AB - In recent years, minimally invasive surgical techniques for lumbar fusion and fixation procedures gained worldwide popularity. Herein we describe a personal technique for percutaneous lumbar interbody fusion associated with minimally invasive posterior fixation for patients affected by degenerative disc disease and lumbar instability. The procedure is described in a step-by-step way and early results are presented. Although the present data reflect only an early experience, we believe that this is a straightforward procedure which may be more advantageous in terms of surgical invasiveness, potentially saving operative and recovery time and reducing risks compared to posterior or anterior approaches for lumbar interbody fusion. PMID- 21313958 TI - Posterior epidural disc herniation at L3-L4 mimicking a spinal tumor: a case report. AB - Posterior epidural disc migration is a rare event. Many differential diagnoses are possible in the posterior epidural space other than disc disease. This is a case report of L3-L4 posterior epidural disc herniation that was misdiagnosed as a tumor depending on the preoperative magnetic resonance imaging study with a peripheral ring enhancement around the mass lesion after IV gadolinium. Decompressive L4 laminectomy was performed and a free disc fragment was observed beneath the lamina. There wasneither dural tearnor attachment to it. The patient was free of pain postoperatively. After 3 months, the patient applied to the outpatient clinic for a regular control T he patient was neurologically intact and free of pain. Diagnosis of posterior migrated disc fragment with subtle clinical findings, even though the free fragment has to pass through many anatomical barriers including the nevre roots, is a clinical challenge. Many differential diagnoses should be kept in mind. MRI findings (especially with contrast material use) are useful which should be imprinted with clinical knowledge. PMID- 21313959 TI - A case of very long-term appearing drug tolerance to intrathecal baclofen. AB - A 66-year-old man affected by familial spastic paraplegia since he was 22 developed drug tolerance to intrathecal baclofen after 16 years of treatment A stable dosage of 850 microg/day, achieved after the first two years, appeared to be progressively inadeguate to relief his spasticity. No other evidence of additional diseases or progression of his neurological disease were recognized. The daily dosage was then increased to 1200 microg/day without any decrease in spasticity or improvement in the patient's motor performance. Thus a slow and progressive decrease of the daily dosage was performer by 10% each 15 days while the patient's clinical condition was monitored. The patient reached a complete withdrawal of the baclofen administration experiencing the same spasticity and motor performance he experienced at the beginning of his therapy with intrathecal baclofen in 1991. The patient was then kept on drug holiday for three months without any variation in his clinical picture. A stabilized daily baclofen dosage of 250 microg was then reached to maintain the same improvement of motor performance that the patient had experienced before the onset of drug-tolerance signs. Some cases of drug tolerance to intrathecal baclofen were previously reported but this is an original case of very long-term onset of this phenomenon. PMID- 21313960 TI - A medically treated multiple cerebral hydatid cyst disease. AB - Echinococcosis is a potentially fatal parasitic disease that can affect many animals and humans. The disease results from infection by tapeworm larvae of the genus Echinococcus--notably, E. granulosus, E. multilocularis, E. vogeli andE. oligarthrus. Cyst hydatid disease is usually seen in adults, and mainly affects liver and/or lungs (90%). Cerebral involvement is very rare (1-3%), and more common in children. Therapy consists of medical treatment and surgical intervention if it is possible. The authors report the case of a 55-year-old male patient with multiple intracranial hydatid cysts, who was successfully treated with albendazole (10 mg/kg/day) alone without any surgical intervention. PMID- 21313961 TI - Nubac disc arthroplasty via the posterior approach. Technical note. AB - The author describes the details of Nubac disc arthroplasty via the posterior approach and discusses indications, limitations and benefits of this procedure. This surgical technique provides the following main steps: 1) patient positioning in a prone-kneeling position; 2) subperiosteal exposure of the index interlaminar space; 3) limited laminotomy (involving both the inferior edge of the hemilamina above and the superior edge of the hemilamina below), resection up to the medial one third of the facet joint, and partial flavectomy; 4) minimum nerve root retraction; 5) removal of eventual free disc fragments and annular cutting to obtain a small window (4 mm x 6 mm) through the annulus; 6) total nucleus pulposus evacuation; 7) annular window dilatation; 8) trial spacer implant sizing; 9) implant insertion into the disc cavity. Nubac disc arthroplasty via the posterior approach can be recommended for patients suffering from degenerative disc disease with disc herniation at L4-L5 and/or L5-S1 in order to relieve the back pain and to delay or to prevent disc degeneration progression status postdiscectomy. A middle height of the index disc of at least 5 mm is prerequisite for performing nucleus replacement. PMID- 21313962 TI - Reflections and forward thinking. PMID- 21313963 TI - Live and love. PMID- 21313964 TI - Restricting preoperative diagnosis to two-dimensional images in oral implantology can potentially cause implant failures. PMID- 21313965 TI - Limited field cone beam computed tomography: evaluation of endodontic healing in three cases. PMID- 21313966 TI - Occult pathology detected in cone beam data volumes. PMID- 21313967 TI - Lumps and bumps--what is that stone? PMID- 21313968 TI - Veteran's shrapnel in the maxillofacial region. PMID- 21313969 TI - Global oral health of older people--call for public health action. AB - BACKGROUND: The aim of this report is (1) to provide a global overview of oral health conditions in older people, use of oral health services, and self care practices; (2) to explore what types of oral health services are available to older people, and (3) to identify some major barriers to and opportunities for the establishment of oral health services and health promotion programmes. METHODS: A postal questionnaire designed by the World Health Organization (WHO) was distributed worldwide to the Chief Dental Officers or country oral health focal points at ministries of health. WHO received 46 questionnaires from countries (39% response rate). In addition, systematic data were collected from the WHO Global Oral Health Data Bank and the World Health Survey in order to include oral health information on the remaining countries. In total, the data base covers 136 out 193 countries, i.e., 71% of all WHO Member States. RESULTS: Dental caries and periodontal disease comprise a considerable public health problem in the majority of countries. Significant disparities within and between regions are observed in epidemiologic indicators of oral disease. The prevalence rates of tooth loss and experience of oral problems vary substantially by WHO Region and national income. Experience of oral problems among older people is high in low income countries; meanwhile, access to health care is poor, in particular in rural areas. Although tooth brushing is the most popular oral hygiene practice across the world, regular tooth brushing appears less common among older people than the population at large. In particular, this practice is less frequent in low income countries; in contrast, traditional oral self-care is prevalent in several countries of Africa and Asia. While fluoridated toothpaste is widely used in developed countries, it is extremely infrequent in most developing countries. Oral health services are available in developed countries; however, the use of such services is low among the older people. Lack of financial support from government and/or lack of third party payment systems render oral health services unaffordable to them. According to the country reports, health promotion programmes targeting older people are rare and this reflects the lack of oral health policies. Although some countries have introduced oral health promotion initiatives, worldwide there are few population oriented preventive or curative activities currently implemented that focus specifically on the elderly. Barriers to the organization of such programmes relate to weak national health policy, lack of economic resources, the impact of poor oral health, and lack of tradition in oral health. Opportunities for oral health programmes for old-age people are related to updated information on the burden of oral disease and need for care, fair financing of age-friendly primary health care, integration of oral health into national health programmes, availability of oral health services, and ancillary personnel. CONCLUSION: It is highly recommended that countries establish oral health programmes to meet the needs of the elderly. Relevant and measurable goals must be defined to direct the selection of suitable interventions to improve their oral health. The common risk factors approach must be applied in public health interventions for disease prevention. The integration of oral health into national general health programmes may be effective to improve the oral health status and quality of life of this population group. PMID- 21313970 TI - Sustaining anti-leprosy activities requires radical changes. PMID- 21313971 TI - Sustainability in fighting leprosy--revitalising high ambitions. PMID- 21313972 TI - Leprosy and the millennium development goals. PMID- 21313973 TI - Sustainability of leprosy control: the role of the International Federation of Anti-Leprosy Associations (ILEP). PMID- 21313974 TI - Referral system: a vital link in the sustainability of leprosy services. PMID- 21313975 TI - Health care utilisation in Indian leprosy patients in the era of elimination. AB - OBJECTIVE: The health care utilisation pattern among Indian leprosy patients accessing a tertiary care centre over an 18 month period was studied. DESIGN: A study was conducted at the Dermatology Outpatient Clinic at the Christian Medical College, Vellore, from January 2005 to June 2006. The profile of patients was assessed and a subgroup was interviewed on their healthcare use, including any delays and costs incurred. RESULTS: 198 patients presented of which 115 patients (58.1%) were on treatment for leprosy or a leprosy reaction (active) including 35 new patients (17.7%), and 83 (41.9%) patients were not on active treatment (inactive). 81 patients were interviewed in depth, 14 (17.3%) were new patients included among 54 (66.7%) patients with active disease, and 27 (33.3%) with inactive disease. The average delay from the onset of symptoms to starting treatment in those interviewed was 13.4 months, 7.9 months of which was a patient related delay and 5.4 months of which was the health care system-related delay. In patients who had been released from treatment, 78.6% (22/28) required care after cure. CONCLUSIONS: Improved awareness is required to reduce patient-related delays and systems for sustained training need to be in place to tackle the problem of health care system-related delays. Care after cure is a felt need for many patients released from treatment. PMID- 21313976 TI - Integration of leprosy into GHS in India: a follow up study (2006-2007). AB - In India leprosy services, were integrated into the General Health Services (GHS), in a phased manner, in different provinces, from 2001 to 2004. This study reports the findings from a follow-up operational research undertaken in 2006 2007, to assess the level of integration, on predetermined indicators related to: referral services, training of health functionaries, availability of diagnosis, treatment, MDT dispersal and counselling guidelines in health facilities, recording and reporting by GHS staff, MDT stock management and involvement of health sub-centres in different Indian provinces. Nine provinces, 18 districts, 88 health facilities and 108 sub-centres were selected, by using multistage stratified random sampling techniques. Reverse integration, as reflected by the training and deployment of vertical staff in GHS, was also assessed. Data was collected by medical officers experienced in leprosy, with the assistance of state health functionaries, and recorded on separate schedules for health facility and sub-centre levels. The study also touched on the issue of client perception towards MDT services by interviewing 149 under treatment/cured leprosy cases (who had completed treatment within the last year), in the community with the help of local interpreters. Results showed wide variations across the selected provinces in various parameters. District leprosy nuclei were understaffed in 12(66.7%) districts, and district hospitals were not working as referral institutions anywhere. The training status of medical officers and multi purpose workers in leprosy was low in Andhra Pradesh (6.9 and 22.4%), Madhya Pradesh (26.3 and 14.5%), Rajasthan (19.7 and 40.9%) and Kerala (25.5 and 65.7%). MDT stock availability as per the National Leprosy Eradication Programme (NLEP) guidelines was not adequate in all provinces. Availability of patient counseling guidelines was nil/low in Kerala, Karnataka, West Bengal, Orissa, Rajasthan and Andhra Pradesh. The involvement of sub-centres, in case referral, recording and dispensing MDT was nil Kerala and Rajasthan and poor in Andhra Pradesh. Ninety percent of clients in Kerala and 38.0% in Andhra Pradesh and Madhya Pradesh did not get MDT in the nearest health facilities or sub-centres. PMID- 21313977 TI - Lessons from the evolution of a CBR programme for people affected by leprosy in Northern Nigeria. AB - OBJECTIVE: This paper reviews the 13-year evolution of the social economic activities in Northern Nigeria from a welfare-oriented to a community-centred programme for people affected by leprosy. DESIGN: The review relied on the analysis of policy and strategy documents, programme guidelines and statistical and evaluation reports. RESULTS: Findings revealed that the transformation among other things, demanded formulation of new programme policies and guidelines; and staff training in CBR principles and practice. Findings also showed that adopting CBR principles and community development projects can stimulate improvements in living conditions, self-esteem and acceptance of people affected by leprosy into the community. Regardless of becoming a more inclusive and participatory programme wherein people affected by leprosy contribute to programme implementation and evaluation; groups affected by leprosy remain economically dependent on the programme and partnership mobilisation is weak. This explains why the priorities for sustaining the processes and impacts generated through CBR in northern Nigeria include: i) empowering groups to access mainline services; ii) working through partners to implement CBR and attract extra funding/ownership of interventions, and iii) promoting human rights of people affected by leprosy and working for a barrier free environment. CONCLUSIONS: In the absence of an agreeable understanding and method of assessing sustainability in CBR, we recommend the field-testing of a proposal for evaluating sustainability, to determine its utility in different contexts. Such field-tests have the potential of influencing policy and practice in the future. PMID- 21313978 TI - Sustainability of leprosy services in South Pacific Islands: the Kiribati experience. PMID- 21313979 TI - Prospects for sustaining leprosy control in Uganda. PMID- 21313980 TI - An example of political decision to control leprosy in a small municipality in Brazil. PMID- 21313981 TI - Commitment to reducing disability: the Brazilian experience. PMID- 21313982 TI - Role of community youth volunteers in rehabilitation of people affected by leprosy: a case study from China. PMID- 21313983 TI - A concise history of school-based smoking prevention research: a pendulum effect case study. AB - School-based cigarette smoking prevention was initiated shortly after the first Surgeon General's Report in 1964. This article highlights a sequence of events by which school-based tobacco use prevention research developed as a science, and illustrates a pendulum effect, with confidence in tobacco use prevention increasing and decreasing at/different points in time. Suggestions are offered to advance school-based smoking prevention research. PMID- 21313984 TI - Adolescents' attention to traditional and graphic tobacco warning labels: an eye tracking approach. AB - The objective of this study was determine if the inclusion of Canadian-style graphic images would improve the degree to which adolescents attend to, and subsequently are able to recall, novel warning messages in tobacco magazine advertising. Specifically, our goal was to determine if the inclusion of graphic images would (1) increase visual attention, as measured by eye movement patterns and fixation density, and (2) improve memory for tobacco advertisements among a group of 12 to 14 year olds in the western United States. Data were collected from 32 middle school students using a head-mounted eye-tracking device that recorded viewing time, scan path patterns, fixation locations, and dwell time. Participants viewed a series of 20 magazine advertisements that included five U.S. tobacco ads with traditional Surgeon General warning messages and five U.S. tobacco ads that had been modified to include non-traditional messages and Canadian-style graphic images. Following eye tracking, participants completed unaided- and aided-recall exercises. Overall, the participants spent equal amounts of time viewing the advertisements regardless of the type of warning message. However, the warning messages that included the graphic images generated higher levels of visual attention directed specifically toward the message, based on average dwell time and fixation frequency, and were more likely to be accurately recalled than the traditional warning messages. PMID- 21313985 TI - Risky alcohol use, peer and family relationships and legal involvement in adolescents with antisocial problems. AB - The aim of the study was to examine risk and vulnerability factors contributing to problems with alcohol use in adolescence. Data relating to seven life areas (medical status, school status, social relationships, family background and relationships, psychological functioning, legal involvement, and alcohol use) was gathered using the ADAD (Adolescent Drug Abuse Diagnosis) interview. A total of 1163 Swedish adolescents (809 boys and 354 girls) between the ages of 12 and 20 years old were interviewed. All had antisocial problems and were detained at special youth homes. It was found that for those aged between 12 and 18 years, the general risk factors for alcohol use were leisure and peer problems, problems associated with family background and relationships, and criminal behavior. These results suggest that drug abuse treatment planning should focus on altering the predisposing factors that exist in these domains. It was also found that the ADAD problem areas seem to be most useful as prognostic indicators of treatment outcome for adolescents with antisocial problems who are under 18 years of age. PMID- 21313986 TI - Effects of beverage-specific alcohol consumption on drinking behaviors among urban youth. AB - Alcoholic beverage consumption among high school students has shifted from beer to liquor. The current longitudinal study examined the effects of beverage specific alcohol use on drinking behaviors among urban youth. Data included 731 adolescents who participated in Project Northland Chicago and reported consuming alcohol in 7th grade. Logistic regression tested the effects of beverage-specific use on consequences (e.g., alcohol use in the past month, week, heavy drinking, and ever drunkenness). Compared to wine users, adolescents who reported drinking hard liquor during their last drinking occasion had increased odds of alcohol use during the past month (OR = 1.44; 95% CI = 1.01-2.05), past week (OR = 3.37; 95% CI = 1.39-8.18), and ever drunkenness (OR = 1.56; 95% CI = 1.07-2.29). Use of hard liquor was associated with increased risk of alcohol-related consequences. Early selection of certain alcoholic beverages (e.g., hard liquor) may result in negative health outcomes and problematic alcohol use over time. PMID- 21313987 TI - Attitudes about addiction: a national study of addiction educators. AB - The following study, funded by the National Institute of Drug Abuse (NIDA), utilized the Addiction Belief Inventory (ABI; Luke, Ribisl, Walton, & Davidson, 2002) to examine addiction attitudes in a national sample of U.S. college/university faculty teaching addiction-specific courses (n=215). Results suggest that addiction educators view substance abuse as a coping mechanism rather than a moral failure, and are ambivalent about calling substance abuse or addiction a disease. Most do not support individual efficacy toward recovery, the ability to control use, or social use after treatment. Modifiers of addiction educator attitudes include level of college education; teaching experience; licensure/certification, and whether the educator is an addiction researcher. Study implications, limitations, and directions for future research are discussed. PMID- 21313988 TI - Substance abuse and dependency risk: the role of peer perceptions, marijuana involvement, and attitudes toward substance use among college students. AB - Many college students are using substances at levels consistent with Substance Abuse or Dependence, yet little explanation for this phenomenon exits. The aim of this study was to explore a risk factor profile that best separates those with low and high potential for having a substance use disorder (SUD). A discriminant function analysis revealed that participants with a high probability of having a SUD misperceive others' alcohol and marijuana use to a greater extent than those with a low probability of having a SUD. Implications for educators and counselors on college campuses are discussed. PMID- 21313989 TI - Short-term exposure to one dialect affects processing of another. AB - It is well established that speakers accommodate in speech production. Recent work has shown a similar effect in perception-speech perception is affected by a listener's beliefs about the speaker. In this paper, we explore the consequences of such perceptual accommodation for experiments in speech perception and lexical access. Our interest is whether perceptual accommodation to one speaker-the experimenter who meets participants, for example--might have carry-over effects on participants' behavior in subsequent tasks that do not directly involve the experimenter's voice. We explore this possibility by exposing groups of participants to different varieties of English before they participate in experiments involving speech perception and/or lexical access. Our results reveal that the nature of this prior exposure considerably influences participants' behavior in the tasks. This suggests that the phonetic detail of encountered speech is stored in the lexicon, together with information about the speaker's regional origin. Subparts of phonetically detailed lexical distributions can then be effectively'primed' by exposure to speakers or lexical items associated with particular dialects.We argue for an exemplar model of lexical representation with both word-level and phoneme-level representations.The consequences of cross dialectal priming vary, depending on whether tasks involve primarily word-level or phoneme-level access. PMID- 21313990 TI - Syntactic structure guides prosody in temporarily ambiguous sentences. AB - A pair of speaking and listening studies investigated the prosody of sentences with temporary Object/Clause and Late/Early Closure ambiguities. Speakers reliably produced prosodic cues that allowed listeners to disambiguate Late/Early Closure sentences, but only infrequently produced prosody that disambiguated Object/Clause sentences, as shown by the results of listening studies.The two continuations for Object/Clause sentences were not pronounced with identical prosody, but the differences in their productions were not helpful to listeners. Speakers' different performance on the two sentence types is traced to their different syntactic structures. These results illustrate the importance of the syntax-prosody mapping in production and test the prosodic predictions of syntax prosody models like that ofWatson and Gibson (2004). PMID- 21313991 TI - Processing coordination ambiguity. AB - We examined temporarily ambiguous coordination structures such as put the butter in the bowl and the pan on the towel. Minimal Attachment predicts that the ambiguous noun phrase the pan will be interpreted as a noun-phrase coordination structure because it is syntactically simpler than clausal coordination. Constraint-based theories assume that interpretations are the result of a constraint-satisfaction process, which predicts that frequency or context can bias the parser to initially pursue a more complex interpretation.The results showed an initial preference for noun-phrase coordination, despite the fact that sentential coordination is more frequent in imperative structures. These data suggest that the parser uses a syntactic simplicity heuristic for building initial structural analyses. PMID- 21313992 TI - The Wildcat Corpus of native- and foreign-accented English: communicative efficiency across conversational dyads with varying language alignment profiles. AB - This paper describes the development of the Wildcat Corpus of native- and foreign accented English,a corpus containing scripted and spontaneous speech recordings from 24 native speakers of American English and 52 non-native speakers of English.The core element of this corpus is a set of spontaneous speech recordings, for which a new method of eliciting dialogue-based, laboratory quality speech recordings was developed (the Diapix task). Dialogues between two native speakers of English, between two non-native speakers of English (with either shared or different LIs), and between one native and one non-native speaker of English are included and analyzed in terms of general measures of communicative efficiency.The overall finding was that pairs of native talkers were most efficient, followed by mixed native/non-native pairs and non-native pairs with shared LI. Non-native pairs with different LIs were least efficient.These results support the hypothesis that successful speech communication depends both on the alignment of talkers to the target language and on the alignment of talkers to one another in terms of native language background. PMID- 21313993 TI - Cleaning agents and asthma. AB - Although cleaners represent a significant part of the working population worldwide, they remain a relatively understudied occupational group. Epidemiological studies have shown an association between cleaning work and asthma, but the risk factors are uncertain. Cleaning workers are exposed to a large variety of cleaning products containing both irritants and sensitizers, as well as to common indoor allergens and pollutants. Thus, the onset or aggravation of asthma in this group could be related to an irritant-induced mechanism or to specific sensitization. The main sensitizers contained in cleaning products are disinfectants, quaternary ammonium compounds (such as benzalkonium chloride), amine compounds, and fragrances.The strongest airway irritants in cleaning products are bleach (sodium hypochlorite), hydrochloric acid, and alkaline agents (ammonia and sodium hydroxide), which are commonly mixed together. Exposure to the ingredients of cleaning products may give rise to both new-onset asthma, with or without a latency period, and work-exacerbated asthma. High-level exposure to irritants may induce reactive airways dysfunction syndrome. Cleaning workers may also have a greater relative risk of developing asthma due to prolonged low-to moderate exposure to respiratory irritants. In addition, asthma-like symptoms without confirmed asthma are also common after exposure to cleaning agents. In many cleaners, airway symptoms induced by chemicals and odors cannot be explained by allergic or asthmatic reactions. These patients may have increased sensitivity to inhaled capsaicin, which is known to reflect sensory reactivity, and this condition is termed airway sensory hyperreactivity. PMID- 21313994 TI - Increased body mass index does not lead to a worsening of asthma control in a large adult asthmatic population in Spain. AB - BACKGROUND: Data on the association between obesity and asthma control are conflicting. We performed an analysis to elucidate the association between body mass index (BMI) and asthma control in a large sample of asthmatics. MATERIALS AND METHODS: Data were obtained from a previous study in which the Asthma Control Questionnaire (ACQ) and Asthma Control Test (ACT) were validated for a Spanish population. The study sample comprised 607 adult (> or = 18 years) asthmatic patients (61% female), of whom 235 (39%) had mild-persistent asthma, 246 (41%) had moderate-persistent asthma, and 126 (21%) had severe-persistent asthma. RESULTS: The analysis showed a significant but very low correlation between BMI and ACQ-forced expiratory volume in the first second of expiration (FEV1) (r=0.1, P=.007) and ACQ-peak expiratory flow (PEF) (r=0.1, P=.010), but not ACQ-without lung function (wLF) (r=0.06, P=.116) or ACT. No significant association was found between BMI and asthma control as defined by physicians or according to ACT or ACQ (ACQ-FEV1, ACQ-PEF and ACQ-wLF) scores. We found no significant associations between ACT, ACQs (ACQ-FEV1, ACQ-PEF and ACQ-wLF), and BMI when BMI was classified as low (BMI, <18.5 kg/m2), normal (18.5-24.9 kg/m2), overweight (25 29.9 kg/m2), obesity (BMI, > or = 30 kg/m2), or morbid obesity (BMI, >34.9 kg/m2). However, the percentage of patients with poor control was slightly greater in patients with low BMI and obesity. CONCLUSIONS: Using specific and validated tools, and in the context of clinical practice, this study did not find a relevant association between BMI and asthma control. PMID- 21313995 TI - Clinical features of drug-induced hypersensitivity syndrome in 38 patients. AB - BACKGROUND: The clinical features of drug-induced hypersensitivity syndrome (DIHS) or drug rash with eosinophilia and systemic symptoms (DRESS) syndrome are complicated, and the incidence of this condition is very low. OBJECTIVE: To evaluate the clinical course of DIHS/DRESS and identify effective treatment options. METHODS: This study was a retrospective analysis of prospectively collected clinical data in 38 consecutive patients with DIHS/DRESS diagnosed between March 2004 and January 2009. We investigated the clinical features, response to treatment, and outcome of 38 patients. RESULTS: The study patients consisted of 18 men (47.4%) and 20 women (52.6%). The most common causative drugs were anticonvulsants (47.4%) and antibiotics (18.4%), followed by nonsteroidal anti-inflammatory drugs (NSAIDs) (13.2%), allopurinol (5.3%), and undetermined agents (15.8%). The latency period ranged from 3 to 105 days, with a mean (SD) of 25.2 (21.5) days. Systemic corticosteroids were administered to 16 patients (42.1%). Twenty-two (57.9%) patients were treated with topical corticosteroids and antihistamines (no systemic corticosteroids). Complete recovery was noted in 36 patients (94.8%). Two of the patients treated with systemic corticosteroids had a poor outcome: one died due to an opportunistic infection secondary to long term systemic corticosteroid treatment; the other showed progressive deterioration of liver damage, although the final outcome is not known. CONCLUSION: The drugs associated with DIHS/DRESS were variable and most frequently included anticonvulsants, beta-lactam antibiotics, and NSAIDs. The syndrome was more common than generally recognized. Additional studies are needed to evaluate the clinical indications for systemic corticosteroids in patients with DIHS/DRESS. PMID- 21313996 TI - Strong association between the -308 TNF promoter polymorphism and allergic rhinitis in Pakistani patients. AB - BACKGROUND: Allergic rhinitis (AR) is a common complex allergic inflammatory disorder. The tumor necrosis factor (TNF) alpha polymorphism G-308A is present in the promoter region of the gene and considered to be important due to its role in different allergic diseases. OBJECTIVES: We aimed to identify genetic associations between this polymorphism and AR in patients of Pakistani origin. METHODS: We analyzed the distribution of G-308A in 153 unrelated AR patients and 116 unrelated healthy controls. Samples were genotyped for G-308A using restriction fragment length polymorphism. RESULTS: The TNF -308A allele (TNF2) was significantly more frequent in patients with AR (37%) than in controls (16%, P<.001; chi2=32.15). Genotype distribution was also significantly different between patients and controls (P<.001; chi2=40.81). The TNF2 homozygous genotype and TNF1/2 heterozygous genotype were significantly more common in AR patients (TNF2, 12%; TNF1/2, 49%) than in controls (TNF2, 4%; TNF1/2, 23%), whereas the normal TNF1 homozygous genotype was more frequent in controls (73%) than in patients (39%). CONCLUSION: Our results suggest a strong association between the promoter polymorphism of TNF-alpha and AR in Pakistani cohorts. PMID- 21313997 TI - General trends in airborne pollen production and pollination periods at a Mediterranean site (Badajoz, southwest Spain). AB - BACKGROUND: The aim of this study was to determine trends in the airborne pollen concentration and pollination period for the principal sources of pollen in Badajoz (southwest Spain) over 15 years of monitoring (1994-2008). METHODS: Airborne pollen was monitored by continuous sampling with a Hirst volumetric sampler. Pollen trends were investigated by linear regression and correlation analysis using mean annual and monthly pollen concentrations. The aerobiological results were compared with meteorological data (temperature and rainfall). RESULTS: During the study period, the mean total annual rainfall was 66.2 mm lower than normal and the mean annual temperature 0.8 degrees C higher than normal. No temporal trend was found for total airborne pollen concentration, but differences were observed for monthly data, namely, an increase in January, February, and May and a decrease in March and June. For the different pollen types studied, there was a general trend toward increased values in the month with the highest values, and this trend seemed to be related to temperature.The beginning of the main pollen season occurred later, and the end occurred sooner; therefore, the main pollen season seems to be shorter. CONCLUSIONS: Our data reflect trends in the response of plants to changing rainfall stress patterns in Mediterranean countries, and these trends seem to be different from those of temperate countries. Nonetheless, a longer study period will be required to confirm these preliminary conclusions. PMID- 21313998 TI - Exercise-induced airway obstruction in young asthmatics measured by impulse oscillometry. AB - BACKGROUND: Impulse oscillometry (IOS) is a good method for measuring airway resistance. It does not require special breathing skills and it can reflect different aspects of airway obstruction to those revealed by spirometry, which is an effort-dependent maneuver. OBJECTIVE: To evaluate the characteristics of airway obstruction in young asthmatics after an exercise bronchial provocation test (EBPT) using IOS. METHODS: Forty-seven young adults were enrolled in the study. All the participants underwent a methacholine bronchial provocation test (MBPT) and an EBPT for the evaluation of their asthma. IOS and spirometric parameters were collected at baseline and at 0, 5, 10, 20, and 30 minutes post EBPT.The participants were divided into 2 groups according to MBPT positivity: an airway hyperresponsiveness (AHR) group and a no-AHR group. RESULTS: There were differences in the percent decrease in forced expiratory volume in the first second (FEV1) between the 2 groups at 5, 10, and 20 minutes after exercise. Resistance at 5 Hz (R5) increased in the AHR group but not in the no-AHR group at 5 and 10 minutes after exercise. Integration of reactance from 5 Hz to resonance frequency (area of reactance, AX) was also increased in the AHR group at only 5 and 10 minutes post-EBPT. Delta R5 and delta AX at 5 and 10 minutes post-exercise were well correlated with the percent decrease in FEV1. CONCLUSIONS: IOS parameters, especially delta R5 and delta AX, may be useful for performing objective evaluations and improving our understanding of exercise-induced airway obstruction in young asthmatics. PMID- 21313999 TI - Production and immunogenicity of hypoallergenic codon-optimized DNA vaccine encoding mature Der p 1 allergen. AB - BACKGROUND: Genetic vaccination with plasmid DNA encoding allergens is a promising potential approach for the treatment or prevention of allergy. Nonetheless, because the allergens expressed can display immunoglobulin (Ig) E reactivity, methods to deliver hypoallergenic variants can minimize the risk of type 2 helper (T(H)2) cell priming after DNA immunization. METHODS: A humanized synthetic gene encoding mature Dermatophagoides pteronyssinus group 1 (Der p 1) allergen was cloned into the pHIS expression vector carrying unmethylated CpG 2006 (CpG 2006) motif but devoid of signal sequence. The immunogenicity of this DNA construct was compared in naive mice with that of recombinant ProDer p 1 protein adjuvanted with alum. RESULTS: Codon optimization of the cDNA encoding mature Der p 1 markedly improved allergen expression. Mature Der p 1, expressed intracellularly in Human Embryonic Kidney 293 cells (HEK 293 cells) transfected with codon-optimized Der p 1 cDNA (pHIS-mHuDer p 1), was shown to be hypoallergenic as it displayed no IgE reactivity. Intradermal vaccinations of naive Balb/C mice with pHIS-mHuDer p 1 elicited an allergen-specific T(H)1 response characterized by the production of specific IgG2a, a very low amount of specific IgG1, and no specific IgE. Lipoplex formulation with cationic liposome composed of lecithin, N-[1-(2,3-Dioleoyloxy)propyl]-N,N,N-trimethylammonium methylsulfate (DOTAP) and cholesterol not only accelerated the induction of T(H)1 response but also increased its intensity. CONCLUSION: A codon-optimized DNA vaccine encoding mature Der p 1 in a lipoplex formulation could represent a promising hypoallergenic vaccine candidate for safer immunotherapy against house dust mite allergy. PMID- 21314000 TI - Sensitization to the pollen pan-allergen profilin. Is the detection of immunoglobulin E to multiple homologous proteins from different sources clinically useful? AB - BACKGROUND: Profilin is a highly conserved protein regarded as a pan-allergen in pollen and vegetable food. Homologous proteins from different sources are highly cross-reactive. OBJECTIVE: To assess whether detecting immunoglobulin (Ig) E to multiple profilins from different sources is clinically more useful than detecting IgE to a single representative profilin. METHODS: Sera from 43 subjects sensitized to profilin selected in 2 allergy centers in Northern Italy showing a different pollen exposure profile were studied for their IgE reactivity to 5 profilins (Bet v 2, Ole e 2, Hev b 8, Mer a 1, and Phl p 12) using a commercial allergen microarray immunoassay. RESULTS: All 43 patients (100%) scored positive to at least 1 profilin on ISAC, although reactivity to all 5 profilins was observed in only 37 cases (86%). In approximately half of the reactors, IgE reactivity to Ole e 2 was much weaker than that to other profilins irrespective of the primary sensitizing allergen source, suggesting a low sensitivity of this allergen. Much discrepancy in IgE to Bet v 2 measured by ISAC microarray and ImmunoCAP was observed. CONCLUSION: Detecting IgE reactivity to a single marker protein (eg, Bet v 2) is sufficient to diagnose or exclude sensitization to profilin. Detecting IgE to multiple homologous, cross-reacting allergen proteins is not clinically more informative and increases the risk of confusion and misinterpretation. PMID- 21314001 TI - The burden of unscheduled health care for asthma in Latin America. AB - OBJECTIVES: To determine the level and cost of unscheduled health care resource use in adults and children across all asthma symptom severities in Latin America. METHODS: The level and cost of health care resource use were analysed for 2074 patients with asthma included in the Asthma Insights and Reality in Latin America (AIRLA) survey from 10 Latin American countries. Health care resource use was multiplied by country-specific unit costs to estimate average per-patient annual costs. Patients were classified as adults (> or = 16 years) or children (<16 years), with disease severity categorized using a symptom severity index. RESULTS: Persistent asthma symptoms were experienced by 53.1% of patients (50.1% of children and 54.6% of adults). In the year preceding the survey, 57.1% of patients required unscheduled health care resource use and 45.1% reported at least 1 emergency hospital contact. The percentage of patients reporting unscheduled health care resource use was greatest amongst those with severe persistent symptoms (71.9%) but it was also high in those with mild intermittent symptoms (45.7%). An average of 73.2% of annual costs of asthma-related health care for the 10 countries was due to unscheduled health care. Expenditure on unscheduled care was greatest amongst both adults and children with severe persistent asthma symptoms (US $558 and US $769, respectively). Adults and children with mild intermittent symptoms also incurred considerable unscheduled costs (US $204 and US $215, respectively). CONCLUSIONS: Poorly controlled asthma imposes a considerable cost burden driven by unscheduled health care resource use in Latin America. Treatments to control asthma and reduce the need for unscheduled health care could reduce this cost in both adults and children. PMID- 21314002 TI - One-year follow-up of clinical and inflammatory parameters in children allergic to grass pollen receiving high-dose ultrarush sublingual immunotherapy. AB - BACKGROUND: In a previous double-blind placebo-controlled study, we analyzed a high-dose sublingual immunotherapy (SLIT) ultrarush protocol in asthmatic children monosensitized to grass pollen. In the present open-label study, we assessed the effect of SLIT on symptom score and nonspecific bronchial hyperreactivity in the same cohort followed for 1 subsequent year. METHODS: The study population comprised 35 children who were enrolled in our previous study. Placebo-treated patients were switched to active treatment; therefore, SLIT was administered for a further year to all patients. SLIT was considered effective if it reduced the severity of clinical symptoms and decreased the use of symptomatic medication. The effect of SLIT on nonspecific bronchial hyperreactivity (methacholine challenge test) was also measured. RESULTS: The symptom scores for asthma and rhinitis and medication score remained unchanged in the group who continued SLIT. We also observed further significant improvement in the results of the methacholine challenge test during the third year of treatment. CONCLUSIONS: High-dose ultrarush SLIT reduced the severity of allergic symptoms in the first 2 grass pollen seasons but continuously improved bronchial hyperreactivity in children with asthma, suggesting that SLIT should be continued despite the lack of further improvement in clinical symptoms. PMID- 21314003 TI - Allergy to quinolones: low cross-reactivity to levofloxacin. AB - BACKGROUND: Immediate-type hypersensitivity reactions to quinolones are rare. Some reports describe the presence of cross-reactivity among different members of the group, although no predictive pattern has been established. No previous studies confirm or rule out cross-reactivity between levofloxacin and other quinolones.Therefore, a joint study was designed between 2 allergy departments to assess cross-reactivity between levofloxacin and other quinolones. MATERIAL AND METHODS: We studied 12 patients who had experienced an immediate-type reaction (4 anaphylaxis and 8 urticaria/angioedema) after oral administration of quinolones. The culprit drugs were as follows: ciprofloxacin (5), levofloxacin (4), levofloxacin plus moxifloxacin (1), moxifloxacin (1), and norfloxacin (1). Allergy was confirmed by skin tests and controlled oral challenge tests with different quinolones. The basophil activation test (BAT) was applied in 6 patients. RESULTS: The skin tests were positive in 5 patients with levofloxacin (2), moxifloxacin (2), and ofloxacin (2). BAT was negative in all patients (6/6). Most of the ciprofloxacin-reactive patients (4/5) tolerated levofloxacin. Similarly, 3 of 4 levofloxacin-reactive patients tolerated ciprofloxacin. Patients who reacted to moxifloxacin and norfloxacin tolerated ciprofloxacin and levofloxacin. CONCLUSIONS: Our results suggest that skin testing and BAT do not help to identify the culprit drug or predict cross-reactivity. Oral challenge testing is the only way to confirm tolerance to a quinolone before prescribing it as a safe alternative. Levofloxacin could be a safer alternative in cases of reaction to first-, second-, or fourth-generation quinolones. PMID- 21314004 TI - A novel RAB27A mutation in a patient with Griscelli syndrome type 2. AB - Griscelli syndrome type 2 is a rare autosomal recessive primary immunodeficiency disease caused by a mutation in the RAB27A gene and characterized by oculocutaneous hypopigmentation and variable cellular immunodeficiency. We report the case of a 6-month-old infant with silvery hair, eyelashes, and eyebrows who was referred to our center because of fever and hepatosplenomegaly. Bone marrow studies indicated hemophagocytosis, whilst microscopic examination of the hair showed irregular agglomerations of pigment in hair shafts. Molecular analysis revealed a novel homozygous mutation in exon 5, namely, a single-base substitution (g.42996 A>G) leading to an amino acid change (S115G) and thus confirming the diagnosis of Griscelli syndrome type 2. Griscelli syndrome could be more common than thought, especially in regions with high rates of consanguinity. As the prognosis of disease is usually poor, prompt diagnosis and appropriate treatment are vital to avoid complications. PMID- 21314005 TI - Prothrombotic state in Churg-Strauss syndrome: a case report. AB - An increased risk of thrombosis has been described in patients with hypereosinophilic syndromes, including Churg-Strauss syndrome (CSS). We report the case of a 43-year-old man with CSS who presented with asthma, pansinusitis, blood eosinophilia (9650/microL), peripheral neuropathy, cutaneous eosinophilic vasculitis, and a positive result for antineutrophil cytoplasmic antibodies. An analysis of plasma during active disease revealed elevated levels of prothrombin fragment 1+2 (marker of thrombin generation) (832 pM; normal range, 68-229 pM) and D-dimer (marker of fibrin degradation) (2300 ng/mL; normal range, 130-250 ng/mL), which indicate an increased risk of thrombosis. Both parameters returned to normal values during remission after immunosuppressive treatment. Skin histology showed leukocytoclastic vasculitis with numerous eosinophils in the dermal infiltrate. Immunohistochemistry revealed expression of tissue factor by skin-infiltrating eosinophils, as confirmed by colocalization with eosinophil cationic protein, a classic marker of eosinophil granulocytes. In conclusion, we present a patient with active CSS and a prothrombotic state that reverted during remission achieved by immunosuppressive therapy. PMID- 21314006 TI - Topical drug-induced acute generalized exanthematous pustulosis misdiagnosed as an oral drug-related eruption. PMID- 21314007 TI - Risk factors for systemic reactions to allergen-specific subcutaneous immunotherapy. PMID- 21314008 TI - Etiology and clinical picture of anaphylaxis in ambulatory patients from Caracas, Venezuela. PMID- 21314009 TI - Aquagenic urticaria in 2 adolescents. PMID- 21314010 TI - A comparison between morphine and histamine as a positive control agent for intradermal skin testing: an evidence-based study. PMID- 21314011 TI - Rapid immunochromatography of total tear immunoglobulin E in allergic conjunctivitis with Allerwatch. PMID- 21314012 TI - Fixed drug eruption due to propofol after an intradermal test. PMID- 21314013 TI - Nonimmediate systemic hypersensitivity reaction to beta-lactam intradermal tests. PMID- 21314014 TI - Antituberculosis drug-induced drug rash with eosinophilia and systemic symptoms syndrome confirmed by patch testing. PMID- 21314016 TI - State of the art in muscle glycogenoses. AB - The recognition of a series of metabolic/enzymatic dysfunctions in glycogenoses has allowed new therapeutic advances for their treatment due to the development of recombinant enzyme. A recent advance appears enzymatic replacement therapy (ERT) in glycogenosis type II in both infantile, juvenile and adult form. Targeted manipulation of diet has been tried both in glycogenosis type II (Pompe disease) and type V (Mc Ardle disease). PMID- 21314015 TI - Pathogenesis and treatment of mitochondrial myopathies: recent advances. AB - In this brief review, I have highlighted recent advances in several areas of mitochondrial medicine, including mtDNA-related diseases, mendelian mitochondrial encephalomyopathies, and therapy. The pathogenic mechanisms of mtDNA mutations, especially those affecting mitochondrial protein synthesis, are still largely unknown. The pathogenicity of homoplasmic mtDNA mutations has become evident but has also called attention to modifying nuclear genes, yet another example of impaired intergenomic signaling. The functional significance of the homoplasmic changes associated with mitochondrial haplogroups has been confirmed. Among the mendelian disorders, a new form of "indirect hit" has been described, in which the ultimate pathogenesis is toxic damage to the respiratory chain. Three therapeutic strategies look promising: (i) allogeneic hematopoietic stem cell transplantation in MNGIE (mitochondrial neurogastrointestinal encephalomyopathy); (ii) bezafibrate, an activator of PGC-1alpha, has proven effective in animal models of mitochondrial myopathy; and (iii) pronucleus transfer into a normal oocyte is effective in eliminating maternal transmission of mtDNA, thus preventing the appearance of mtDNA-related disorders. PMID- 21314017 TI - State of the art in hereditary muscle channelopathies. AB - A combination of electrophysiological and genetic studies has resulted in the identification of several skeletal muscle disorders to be caused by pathologically functioning ion channels and has led to the term channelopathies. Typical hereditary muscle channelopa thies are congenital myasthenic syndromes, non-dystrophic myotonias, periodic paralyses, malignant hyperthermia, and central core disease. Most muscle channelopathies are commonly considered to be benign diseases. However, life-threatening weakness episodes or progressive permanent weakness may make these diseases severe, particularly the periodic paralyses (PP). Even in the typical PP forms characterized by episodic occurrence of weakness, up to 60% of the patients suffer from permanent weakness and myopathy with age. In addition, some PP patients present with a predominant progressive muscle weakness phenotype. The weakness can be explained by strongly depolarized fibers that take up sodium and water and that are electrically inexcitable. Drugs that repolarize the fiber membrane can restore muscle strength and may prevent progression. PMID- 21314019 TI - Brachial plexopathy complicating Epstein-Barr virus infection in an adult. AB - Acute Epstein-Barr virus (EBV) infection is associated with central and peripheral neurological complications such as meningitis, encephalitis, myelitis and radiculopathy in 0.5-7.5% of patients. The peripheral nervous system manifestations of acute EBV infection include mononeuropathy, mononeuritis multiplex, autonomic neuropathy, and polyradiculopathy. Brachial plexopathy in children and immunocompromised adults with acute EBV infection has been described, likely as a dysimmune neuropathy triggered by the EBV. We present a case of brachial plexopathy complicating prior EBV infection in a healthy adult. PMID- 21314018 TI - State of the art in muscle lipid diseases. AB - Fatty acid oxidation in mitochondrial matrix is a major source of energy in muscle, especially when physiological energy demand is increased and exceeds what can be provided through glycolysis. Not surprisingly, a group of muscle disorders due to defects in this system usually leads to the development of acute rhabdomyolysis in conditions such as infection, fasting and prolonged exercise. This group includes beta-oxidation cycle defects and deficiencies of carnitine palmitoyltransferase II (CPTH) and very-long-chain acyl-CoA dehydrogenase (VLCAD). Muscle pathology is usually not very helpful for the diagnosis but immunohistochemistry may be useful for screening VLCAD deficiency. Another group of lipid dysmetablolism is lipid storage myopathy (LSM) that is pathologically characterized by increased lipid droplets both in number and size in muscle fibers. So far, causative genes have been identified in four different LSMs, comprising primary carnitine deficiency, multiple acyl-CoA dehydrogenase deficiency or glutaric aciduria type II, neutral lipid storage disease with ichthyosis, and neutral lipid storage disease with myopathy. Clinically, the LSM patients show slowly progressive muscle weakness unlike the former group. Final diagnosis is usually made by specific biochemical assays with mutation analyses. As some effective drugs have been widely used and some promising therapies are under certified, comprehensive understanding of these diseases from clinical, pathological and molecular aspects would be of much help for the patients. PMID- 21314020 TI - Sophie takes into care a patient with breathlessness. PMID- 21314021 TI - Worth the wait. New, more effective therapies for hepatitis C are on the way. PMID- 21314022 TI - International workshop on adverse drug reactions and co-morbiditles in HIV and the Tenth International Congress on Drug Therapy in HIV Infection in Glasgow. PMID- 21314023 TI - Point of orgin: the discovery and spread of HIV. PMID- 21314024 TI - Bones of contention: premature aging and bone loss emerge as new concerns with HIV. PMID- 21314025 TI - Now is the future--and it's time for action. PMID- 21314026 TI - Attach and conquer. Four reasons why implementing a strategy for 275 compliance can drive cost savings this year. PMID- 21314027 TI - EHRs: Why one size doesn't fit all. HITECH Act regulations should not be adopted in isolation, but rather customized to organizations and their practitioners. PMID- 21314028 TI - APH gives self-insured healthcare employers data they can trust. In-house integration helps APH take control of data quality and accelerate revenue by 50 percent. PMID- 21314029 TI - Optimize your mobile assets. A hospital redesigns its distribution and management processes using a real-time location system. PMID- 21314030 TI - IICC aims to connect labs and clinicians. PMID- 21314031 TI - Making real-time data available to all. An anesthesia information-management system delivers tangible value in a large hospital surgery environment. PMID- 21314032 TI - Stretching dollars without compromising care. Two industry veterans lay out a pathway to physician-directed, best-practice improvements through comparative effectiveness research. PMID- 21314033 TI - Building a solid infrastructure for ACOs. Use an HIE to leverage existing information systems. PMID- 21314034 TI - Unrealistic optimism in early-phase oncology trials. PMID- 21314036 TI - Institutional not-for-cause compliance review programs. PMID- 21314035 TI - Consent for future genetic research: the NHANES experience in 2007-2008. PMID- 21314037 TI - Building our future. PMID- 21314038 TI - Diagnostic discussion. Calcifying epithelial odontogenic tumor or Pindborg tumor. PMID- 21314039 TI - Trauma to the primary dentition. AB - The guiding principle in managing trauma to the primary dentition is potential sequelae to the permanent tooth. If the risk to the permanent tooth is great, the primary tooth should be removed. If esthetics is a concern to the parent, a number of appliances can be fabricated to temporarily manage this issue. It is important that parents realize that the desire to maintain optimum esthetics by maintaining a significantly injured primary tooth can, in many cases, cause more damage to the permanent tooth. Where avulsions have occurred, the old adage "when in doubt, leave it out" is still perhaps the most reliable advice. PMID- 21314041 TI - The oral cancer screening examination: getting patients to say YES. PMID- 21314040 TI - Epinephrine. PMID- 21314042 TI - Suboptimization. PMID- 21314043 TI - The dental patient who is 'high'. PMID- 21314044 TI - The hidden curriculum and my three wishes. AB - Personal ideals often clash with the reward structure of dental education. The hidden curriculum sometimes teaches corner-cutting and worse while publically espousing high standards. Changing the professionals without changing the profession in which they work multiplies frustration and offers little hope of progress. Three wishes for changes to the system are identified: (a) fixed dates for National Board testing, (b) comprehensive admissions standards, and (c) no live-patient, one-shot initial licensure examinations. PMID- 21314045 TI - New leaders in dentistry: dental students. AB - Leadership opportunities for dental students have opened dramatically in recent decades because of the humanistic approach to education that shares responsibility for learning between students and faculty and that values mutual respect. Technology has also had an effect because it creates instant access and global communities. This new student leadership is most apparent in the American Student Dental Association (ASDA), which recently developed a White Paper on ethics, assisted in the establishment of Student Professionalism and Ethics Clubs at schools, and is developing a policy on unsupervised dental care. Students are also demonstrating leadership in research; in dual degrees that enhance teaching and policy; and in community service and outreach. PMID- 21314046 TI - Dental students--dental advocates. AB - Student advocacy and involvement in the political process is built into the structure of the American Student Dental Association (ASDA), especially in its Legislative Grassroots Network and an internal communication network among students to ensure political awareness. Students are concerned with such issues as a universally accepted, non-patient-based licensure process, mid-level providers, loan availability and tax deductibility, financial support for schools, and service early in one's professional career (giving forward rather than giving back). Through collaboration with the American Dental Education Association and with many state associations, students participate in lobbying, awareness campaigns, and behind the scenes as legislative aids. Although students share the same love for the profession that animates established practitioners, they are perceived by legislators as being different. Students are involved in the legislative process because it represents their future. PMID- 21314047 TI - Free lunches and student involvement. AB - Dental students have precious little free time, so the challenge of promoting involvement in discussion about issues that affect their future becomes one of many priorities. The staple in schools has been the free lunch with an invited speaker, and that has not worked well. At the University of Southern California (USC) dental school we experimented with making time and opportunity for students to engage multiple outside parties on a single topic, initial licensure. This case describes a much more engaged study response. PMID- 21314048 TI - Experiencing the "Michigan difference" in predental advising. AB - African-American dental students at the University of Michigan are engaged in identifying, guiding, and preparing promising predental students for a career in dentistry. Collaborating with the Student National Dental Association (SNDA), the Predental Association at the school, and with the help of faculty members and the administration, students have developed an Impressions Day and participate in a Research Day, a golf outing, an Elementary School Outreach program, a Dental Initiatives activity, the Scholars Program for Dental Leadership, and participation in the school's Mentor Program. All of these activities engage current students in helping those at various stages in the predental education pipeline learn about, evaluate their potential for, and prepare for careers in dentistry. PMID- 21314049 TI - The need for research in the predoctoral dental education. AB - Research exposure and experience in dental school is valuable to promote critical thinking, to make practitioners effective consumers of the literature, and to begin the preparation of future oral researchers. Some of the federally funded research training opportunities for students are mentioned. The Commission on Dental Accreditation standards relative to research are also described. PMID- 21314050 TI - Maximizing beneficence and autonomy. Ethical support for the use of nonpharmacological methods for managing dental anxiety. AB - This article examines advantages associated with nonpharmacological behavioral management techniques and suggests that there are benefits to their use (such as achieving a more lasting solution to the problem of dental anxiety) that are not realized with medication-based interventions. Analyses that use Kantian and existential viewpoints for exploring the use of medication versus behavioral interventions for managing life problems yield parallel conclusions: there are advantages gained by using behavioral interventions that are not always associated with medication-based interventions. These analyses, taken together with an understanding of the psychology of dental anxiety management, suggest that using nonpharmacological techniques for the management of dental anxiety can maximize adherence to the ethical principles of beneficence and patient autonomy. The authors discuss the barriers that make nonpharmacological interventions for anxiety management difficult for dentists to routinely use, and suggest that additional training in these methods and increased collaboration with mental health professionals are needed for dentists. PMID- 21314051 TI - Risk management. AB - Every plan contains risk. To proceed without planning some means of managing that risk is to court failure. The basic logic of risk is explained. It consists in identifying a threshold where some corrective action is necessary, the probability of exceeding that threshold, and the attendant cost should the undesired outcome occur. This is the probable cost of failure. Various risk categories in dentistry are identified, including lack of liquidity; poor quality; equipment or procedure failures; employee slips; competitive environments; new regulations; unreliable suppliers, partners, and patients; and threats to one's reputation. It is prudent to make investments in risk management to the extent that the cost of managing the risk is less than the probable loss due to risk failure and when risk management strategies can be matched to type of risk. Four risk management strategies are discussed: insurance, reducing the probability of failure, reducing the costs of failure, and learning. A risk management accounting of the financial meltdown of October 2008 is provided. PMID- 21314052 TI - Health insurance exchanges: benefits to be determined. PMID- 21314053 TI - Diagnosing the nation's condition: Plato was right. PMID- 21314054 TI - Reduction in reimbursement for part B imaging services in non-hospital facilities. PMID- 21314055 TI - Registry check required for all prospective employees? PMID- 21314056 TI - Medical marijuana: clinical considerations and concerns. PMID- 21314057 TI - Legislatiye agenda 2011: focusing on priorities. PMID- 21314058 TI - Deja vu all over again: the challenge of hospital readmissions. PMID- 21314059 TI - How sick is sick? PMID- 21314060 TI - Brentwood surgeon uses practice profits to help the hurting. PMID- 21314061 TI - Make more by spending less in 2011. PMID- 21314062 TI - Implementing EHR--it isn't easy. PMID- 21314063 TI - Prevalence of 25-hydroxyvitamin D deficiency in an urban general internal medicine academic practice. AB - Vitamin D deficiency has received increased academic interest because of its association with many common disease processes. The goal of our study was to document the prevalence of vitamin D deficiency. A retrospective chart review of 25-hydroxyvitamin D (ng/mL) levels at the University of Tennessee Health Science Center was conducted on general internal medicine patients over an 18-month period. The 25-hydroxyvitamin D deficient patients were divided into four groups: severe (<7 ng/mL), moderate (7.0-20.9 ng/mL), mild (21-31.9 ng/mL), and sufficient (>32 ng/mL). We found that an overwhelming majority of our patients were mildly to severely deficient (87 percent) with 17 percent severely deficient, 53 percent moderately deficient, 17 percent mildly deficient, and only 13 percent sufficient. The prevalence of 25-hydroxyvitamin D deficiency among this population was higher than expected based on the prevalence of 25 hydroxyvitamin D deficiency reported in literature. Based on this data, we believe a greater percentage of the general population needs to be studied in order to discover the true prevalence of vitamin D deficiency. PMID- 21314064 TI - A case report of vinorelbine monotherapy-related acute bronchospasm and non-ST elevation acute coronary syndrome. AB - Vinorelbine is a semi-synthetic vinca-alkaloid with a broad spectrum anti-tumor activity. The dose-limiting toxicity of vinorelbine is neutropenia and leucopenia which is seen in majority of the patients. The previous case reports on the cardiac toxicity occurred mainly in combination therapy of vinorelbine with cisplatin or carboplatin. We offer evidence that acute coronary syndrome and resultant diastolic heart failure developed as a result of acute bronchospasm due to intravenous vinorelbine monotherapy. PMID- 21314065 TI - Alliance: getting involved for medicine's sake. PMID- 21314066 TI - Translating research to practice. PMID- 21314067 TI - The promise and challenge of practice-research collaborations: Guiding principles and strategies for initiating, designing, and implementing program evaluation research. AB - The authors present a set of guiding principles and strategies to facilitate the collaborative efforts of social work researchers and practitioners as they initiate, design, and implement outcome evaluations of human service interventions and programs. Beginning with an exploration of the interpersonal barriers to practice-research collaborations, and building on their experiences in successfully completing a community-based research evaluation, the authors identify specific relationship-focused principles and strategies and illustrate how these approaches can guide practice-research teams through the various sequential activities of the evaluation research process. In particular, it is suggested that practice-research collaborations can be formed, strengthened, and sustained by emphasis on a spirit of discovery and shared leadership at the start of the relationship, use of a comprehensive evaluation model to clarify and frame the evaluation and program goals, beginning where the client is when selecting research methodology and measurement tools, commitment to keeping the program first and recording everything during the implementation and data-collection stages, discussion of emerging findings and presentation of findings in graphic format at the data-analysis stage, and a total team approach at the dissemination stage. PMID- 21314068 TI - Alcohol treatment and cognitive-behavioral therapy: enhancing effectiveness by incorporating spirituality and religion. AB - Cognitive-behavioral therapy (CBT) is an effective modality for the treatment of alcoholism. Given widespread interest in incorporating spirituality into professional treatment, this article orients practitioners to spiritually modified CBT, an approach that may enhance outcomes with some spiritually motivated clients. More specifically, by integrating clients' spiritual beliefs and practices into treatment, this modality may speed recovery, enhance treatment compliance, prevent relapse, and reduce treatment disparities by providing more culturally congruent services. The process of constructing spiritually modified CBT self-statements is described and illustrated, and suggestions are provided for working with client spirituality in an ethical manner. The article concludes by emphasizing the importance of this approach in light of the growing spiritual diversity that characterizes contemporary society. PMID- 21314069 TI - Reconciling paternalism and empowerment in clinical practice: an intersubjective perspective. AB - The focus of this article is on illustrating how the differences between the paternalistic and empowerment approaches embedded within social work have unnecessarily evolved into competing approaches to practice. Tracing the historical evolution of both paternalistic and empowerment approaches, the article posits that social work is more amenable to an integrated holistic approach to practice than to either a diagnostic or strengths-based approach. Building on G.WE Hegel's notion of recognition and feminist psychoanalystJessica Benjamin's theory of intersubjectivity, the article considers how a simultaneous focus on both strengths and vulnerabilities provides an integrated framework that embraces the joint social work values of personal caring and social justice. Clinical case vignettes are provided to illustrate the limitations of focusing too narrowly on either clients' pathology or clients' strengths. Social workers are encouraged to acknowledge their own vulnerabilities to better appreciate clients' vulnerabilities and strengths. PMID- 21314070 TI - Client participation in managing social work service--an unfinished quest. AB - "Client participation" is a popular ideal and object of rhetorical commitment in social work service. But the much-touted potential of this concept requires careful and critical scrutiny. This article reports on a study of client participation initiatives in the Hong Kong welfare sector. The study identified significant differences in the institutional structure ofclient-participation initiatives and their social dynamics between service units targeting elderly people or people with disabilities and those targeting a clientele with supposed moral or psychosocial failures. The findings suggest that client-participation mandates allowing sustained interaction with service users through regular membership in a structure for discussion are more effective than ad hoc measures with unstable participation, assuming that the goal is mutuality and trust in cooperative inquiry with service users. The findings also suggest that both a service provider's genuine belief in the primacy of the users' voice and a user's legitimate claim of experiential knowledge are imperative to realizing the potential of client participation. PMID- 21314072 TI - Stressful encounters with social work clients: a descriptive account based on critical incidents. AB - This article presents the findings of an analysis of 130 critical incidents reported by social workers in Israel. Almost all the incidents turned out to be upsetting events that caused the writers a great deal of pain, frustration, and self-doubt. Content analysis yielded four main categories of incidents or events: (1) client hostility and aggression toward the worker, (2) client behaviors that violated the unwritten rules of the profession or the workers' expectations, (3) inherent professional dilemmas, and (4) workers' personal issues. Although the events may not be typical of worker-client interactions, they tend to undermine the workers' professional confidence and color their entire work experience. Recommendations are made for training that better prepares social workers for the difficult situations they may encounter and for supervision that helps them to deal with such situations more effectively. PMID- 21314071 TI - Saving our criminal justice system: the efficacy of a collaborative social service. AB - On a typical day in 2008, 776,573 individuals were behind bars in nearly 3,500 U.S. jails. Yet the potential benefits of social services in achieving lower recidivism rates and successful reintegration are understudied in jail populations. This three-year study investigated the effects of collaboration based in-jail services and postrelease transitional services provided by the Allegheny County Jail Collaborative (ACJC). The results included a significantly lower recidivism rate among inmate participants, similar service benefits across racial groups, and successful reintegration into community life among a large majority of participants. At 12 months postrelease, participants had a 50 percent lower recidivism rate than members of the matched comparison group, who were unexposed to the intervention, and multiple indicators showed successful reintegration. This reduced rate would save the county an estimated $5.3 million annually, largely due to increased public safety and lower victimization costs. Data sources included the ACJ's historical inmate data sets from the pre-ACJC and post-ACJC intervention periods, three postrelease face-to-face survey interviews, and focus group sessions with former inmate participants and the study interviewers.The critical importance of social workers in rehabilitative efforts with jail inmates is discussed along with recommendations and implications for policy, practice, and research. PMID- 21314073 TI - Best practices in wraparound: a multidimensional view of the evidence. AB - This article presents a systematic review of the effectiveness of wraparound, a value-guided, widely used service planning process and philosophy of care originally developed for children with serious emotional disturbance and their families. In contrast to conventional systematic reviews, which concentrate on the empirical literature, this article uses the multidimensional evidence-based practice approach, which adds professional knowledge and consumer perspectives to a value-critical analysis. The findings contextualize the limited empirical support for wraparound within a social work value frame, suggesting areas of improvement for the implementation of the wraparound model. A broader ecological frame for wraparound highlights the need to include more natural supports on teams, to ensure backing from higher level administrators, and to emphasize client self-determination. Youths and families should be afforded leadership roles on teams and be supported by parent advocates. To extend the empowerment idea of wraparound beyond the individual case level, a clear commitment to social justice by working toward systems changes must be added. PMID- 21314074 TI - Crisis intervention by social workers in fire departments: an innovative role for social workers. AB - This article describes a unique use of social workers as crisis response team (CRT) members in a nontraditional host setting, municipal fire departments in Arizona. The role of modern-day firefighters has changed dramatically and now includes responding to a wide variety of crises and emergencies other than fires, such as motor vehicle accidents, family abuse, suicides, mental health incidents, accidents, and shootings. These traumatic events can lead to compassion fatigue in medically trained first responders who lack training to address the emotional needs of those involved in these crisis situations or to provide follow-up to ensure that their needs are met postemergency. Originally, CRTs were developed in these fire departments to address the needs of firefighters themselves. However, their functions have expanded to address the needs of customers served by the fire department, both at the scene and during the postintervention period. Using principles of crisis intervention and trauma theory, social workers and social work students placed in these agencies are benefiting both firefighters and community members served by the fire department. PMID- 21314075 TI - Felon disenfranchisement and the fight for universal suffrage. PMID- 21314076 TI - Mary Richmond and the image of social work. PMID- 21314077 TI - The UK Spending Review. PMID- 21314078 TI - IPPNW's 19th World Congress demands fulfillment of pledge for a nuclear-weapons free world. PMID- 21314079 TI - Reflections on the 2010 NPT review conference. PMID- 21314080 TI - The use of depleted uranium ammunition under contemporary international law: is there a need for a treaty-based ban on DU weapons? AB - This article examines whether the use of Depleted Uranium (DU) munitions can be considered illegal under current public international law. The analysis covers the law of arms control and focuses in particular on international humanitarian law. The article argues that DU ammunition cannot be addressed adequately under existing treaty based weapon bans, such as the Chemical Weapons Convention, due to the fact that DU does not meet the criteria required to trigger the applicability of those treaties. Furthermore, it is argued that continuing uncertainties regarding the effects of DU munitions impedes a reliable review of the legality of their use under various principles of international law, including the prohibition on employing indiscriminate weapons; the prohibition on weapons that are intended, or may be expected, to cause widespread, long-term and severe damage to the natural environment; and the prohibition on causing unnecessary suffering or superfluous injury. All of these principles require complete knowledge of the effects of the weapon in question. Nevertheless, the author argues that the same uncertainty places restrictions on the use of DU under the precautionary principle. The paper concludes with an examination of whether or not there is a need for--and if so whether there is a possibility of achieving--a Convention that comprehensively outlaws the use, transfer and stockpiling of DU weapons, as proposed by some non-governmental organisations (NGOs). PMID- 21314081 TI - Mortality, crime and access to basic needs before and after the Haiti earthquake: a random survey of Port-au-Prince households. AB - On 12 January 2010 an earthquake measuring 7.0 on the Richter Scale struck Haiti, causing unprecedented death, injury and destruction for an event of this magnitude. Our aim was to generate a rapid assessment of the primary consequences for the population of the metropolitan area of Port-au-Prince, the national capital. During the summer of 2009 we conducted a survey of 1,800 households in metropolitan Port-au-Prince. Six weeks after the earthquake, we attempted to trace these households in order to re-interview them. The questionnaire examined mortality and injuries generated by the natural disaster, as well as the character of victimization, food security and living arrangements following the quake. Data analysis incorporated sampling weights and adjusted for clustering within households. The original 2009 survey featured a 90 per cent response rate; in 2010 we re-interviewed 93 per cent of these households. We estimate that 158,679 people in Port-au-Prince (95 per cent CI 136,813-180,545) died during the quake or in the six-week period afterwards owing to injuries or illness. Children were at particular risk for death. In the six weeks after the earthquake, 10,813 people (95 per cent CI 6,726-14,900) were sexually assaulted, the vast majority of whom were female. In the same period 4,645 individuals (95 per cent CI 1,943 7,347) were physically assaulted. Of all households, 18.6 per cent (95 per cent CI 16.6-20.8) were experiencing severe food insecurity six weeks after the earthquake. 24.4 per cent (95 per cent CI 22.1-26.9) of respondents' homes were completely destroyed. Many residents of Port-au-Prince died during or as a result of the earthquake, albeit fewer than were widely reported. More than half of the capital's population experienced moderate to severe food insecurity, though remittances are a major protective factor in promoting food security. Survivors continue to experience high levels of sexual assault and limited access to durable shelter. PMID- 21314082 TI - Aspects of neutrality: two Dutch ambulances at the eastern front in the First World War. AB - The paper looks at two First World War ambulance teams which distinctly differed from each other, both in the way they perceived the war and the places at the front where they worked. The first was working on the Serbian side and the second on the Austrian-Hungarian. The questions raised are: how was medical neutrality defined (was it defined at all)? Was neutrality maintained, and if so how? The writings of several protagonists are closely examined, and placed in context, to show that total neutrality was not adhered to by the physicians and nurses of these ambulances. Apparently neutrality in wartime is difficult, even for men and women coming from a neutral country with an occupation seen as essentially neutral. PMID- 21314083 TI - The ban on GP orthodontics. PMID- 21314084 TI - Evaluating the effect of Sabbagh Universal Spring during treatment of growing class II malocclusions. AB - Angle Class II division 1 malocclusion has been one of the most encountered problems in the orthodontic practice. In growing patients, mandibular repositioning appliances are the method of choice to induce mandibular growth and are termed functional appliances. This study was carried out to investigate the possible effect of the Sabbagh Universal Spring2 (SUS2) on the dental and skeletal cephalometric measurements in the permanent dentition of ten growing patients with Class II division 1 malocclusion and to compare its effect with the similar available data of similar fixed functional appliances. It was concluded that the Sabbagh Universal Spring2 appliance works well with the treatment philosophy of Class II division 1 malocclusion with retruded mandible by advancing the mandible anteriorly. PMID- 21314085 TI - Class II skeletal treatment- orthopedic repositioning with the supermarionator. AB - Class II Skeletal deep bite cases may require orthopedic repositioning and/or bite opening procedure to facilitate correction; the appliance described in this article, The Supermarionator, is easily office-fabricated and can be an adjunct for the correction of these cases. PMID- 21314086 TI - Comparison of shear bond strength of orthodontic brackets bonded with light emitting diode (LED). AB - Light-emitting diode (LED) light curing units (LCU) have recently been used to polymerize resin-based orthodontic adhesives and preliminary studies indicate their use has been successful. The objectives of this study were to evaluate the shear bond strength (SBS) oforthodontic brackets bonded to enamel with a LED LCU (LEDMAX 4, Hilux, Kulzer comp.) at 10, 20 and 40 seconds and comparing them with that of 40 seconds light exposure from a conventional halogen-based LCU (Hilux unit, Heraeus Kulzer comp.). Also to assess the amount of adhesive remaining on the tooth after debonding using Adhesive Remnant Index (ARI). 120 extracted human premolars were divided into 4 groups of 30 each. After photo polymerization, all the samples were stored in distilled water at 37 degrees C for 24 hours and then subjected to a shear force with universal testing machine until bracket failure. All the recordings were evaluated statistically ANOVA and Turkey tests revealed that, no statistically significant differences were found among the shear bond strengths of 40 sec halogen (10.15 +/- 1.55), 20 sec LED (9.58 +/- 1.71) and 40 sec LED (10.34 +/- 1.83) cured groups; but the bond strength of 10 sec cure LED group (7.56 +/- 1.47) showed significantly lower than the other groups. Chi square comparisons indicated that there were no significant differences in the ARI scores between the 4 groups tested. The results of this study are promising for orthodontic application of LED curing units in clinics, but further in vivo trials should be performed before validation. PMID- 21314087 TI - Transposition of bilateral maxillary canine and first premolar. AB - The following case report describes the treatment of a 16-year-old female patient with complete transposition of maxillary first premolars and canines. Retained deciduous maxillary canines and buccal eruption of permanent maxillary canines led to non-consonant smile arc of the patient and obliteration of buccal corridors. Mechanics for correction were individualized based on factors such as facial pattern, age, malocclusion, tooth-size discrepancy, stage of eruption, and magnitude of the transposition. Thus an attempt was made to align transposition by maintaining order of transposed canine and first premolar and attain a consonant smile arc with a normal buccal corridor width. PMID- 21314088 TI - Incredible change. PMID- 21314089 TI - Easily upright a mesially displaced permanent low second molar. PMID- 21314090 TI - How to escape excessive talkers. PMID- 21314092 TI - Orbital interactions in selenomethyl-substituted pyridinium ions and carbenium ions with higher electron demand. AB - Computational, solution phase, and crystal structure analysis of 2- and 4 organoselenylmethyl-substituted pyridinium ions (10a-c and 11a-c) provides strong evidence for C-Se hyperconjugation (sigma(C-Se)-pi*) between the C-Se sigma-bond and the pi-deficient aromatic ring and a through-space interaction (n(Se)-pi*) between the selenium p-type lone pair and the pi-deficient aromatic ring. There is also a weak anomeric-type interaction (n(Se)-sigma*(CC)) involving the selenium p-type lone pair electrons and the polarized CH(2)-C(Ar) sigma-bond. NBO analysis of calculated cations with varying electron demand (B3LYP/6-311++G**) show that C-Se hyperconjugation (sigma(C-Se)-pi*) is the predominant mode of stabilization in the weakly electron-demanding pyridinium ions (10d, 11d, 14, and 15); however, the through-space (n(Se)-pi*) interaction becomes more important as the electron demand of the beta-Se-substituted carbocation increases. The anomeric interaction (n(Se)-sigma*(CC)) is relatively weak in all ions. PMID- 21314093 TI - A synthesis of acetamidines. AB - The condensation of primary amine with N,N-dimethylacetamide dimethyl acetal yields a mixture of acetamidine and imidate ester. The product distribution in this reaction depends on the temperature, solvent, and structure of the primary amine. It is possible to suppress the formation of imidate ester by performing the reaction in the presence of excess dimethyl amine, yielding acetamidine as the exclusive product. For acetamidines that cannot be purified either by crystallization or distillation, this new method is necessary for the generation of pure acetamidines in good yields. PMID- 21314091 TI - Relating form and function of EF-hand calcium binding proteins. AB - The EF hand, a helix-loop-helix structure, is one of the most common motifs found in animal genomes, and EF-hand Ca(2+)-binding proteins (EFCaBPs) are widely distributed throughout the cell. However, researchers remain confounded by a lack of understanding of how peptide sequences code for specific functions and by uncertainty about the molecular mechanisms that enable EFCaBPs to distinguish among many diverse cellular targets. Such knowledge could define the roles of EFCaBPs in health and disease and ultimately enable control or even design of Ca(2+)-dependent functions in medicine and biotechnology. In this Account, we describe our structural and biochemical research designed to understand the sequence-to-function relationship in EFCaBPs. The first structural goal was to define conformational changes induced by binding Ca(2+), and our group and others established that solution NMR spectroscopy is well suited for this task. We pinpointed residues critical to the differences in Ca(2+) response of calbindin D(9k) and calmodulin (CaM), homologous EFCaBPs from different functional classes, by using direct structure determination with site-directed mutagenesis and protein engineering. Structure combined with biochemistry provided the foundation for identifying the fundamental mechanism of cooperativity in the binding of Ca(2+) ions: this cooperativity provides EFCaBPs with the ability to detect the relatively small changes in concentration that constitute Ca(2+) signals. Using calbindin D(9k) as a model system, studies of the structure and fast time scale dynamics of each of the four ion binding states in a typical EF-hand domain provided direct evidence that site-site communication lowers the free energy cost of reorganization for binding the second ion. Our work has also extended models of how EFCaBPs interact with their cellular targets. We determined the unique dimeric architecture of S100 proteins, a specialized subfamily of EFCaBPs found exclusively in vertebrates. We described the implications for how these proteins transduce signals and went on to characterize interactions with peptide fragments of important cellular targets. Studies of the CaM homolog centrin revealed novel characteristics of its binding of Ca(2+) and its interaction with its cellular target Kar1. These results provided clear examples of how subtle differences in sequence fine-tune EFCaBPs to interact with their specific targets. The structural approach stands at a critical crossroad, shifting in emphasis from descriptive structural biochemistry to integrated biology and medicine. We present our dual-molecular-switch model for Ca(2+) regulation of gating functions of voltage-gated sodium channels in which both CaM and an intrinsic EF-hand domain serve as coupled Ca(2+) sensors. A second example involves novel EFCaBP extracellular function, that is, the role of S100A8/S100A9 heterodimer in the innate immune response to bacterial pathogens. A mechanism for the antimicrobial activity of S100A8/S100A9 was discovered. We describe interactions of S100A8/S100A9 and S100B with the cell surface receptor for advanced glycation end products. Biochemical and structural studies are now uncovering the mechanisms by which EFCaBPs work and are helping to define their biological activities, while simultaneously expanding knowledge of the roles of these proteins in normal cellular physiology and the pathology of disease. PMID- 21314094 TI - Recognition of polycyclic aromatic hydrocarbons and their derivatives by the 1,3 dinaphthalimide conjugate of calix[4]arene: emission, absorption, crystal structures, and computational studies. AB - Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants as well as well-known carcinogens. Therefore, it is important to develop an effective receptor for the detection and quantification of such molecules in solution. In view of this, a 1,3-dinaphthalimide derivative of calix[4]arene (L) has been synthesized and characterized, and the structure has been established by single crystal XRD. In the crystal lattice, intermolecular arm-to-arm pi...pi overlap dominates and thus L becomes a promising receptor for providing interactions with the aromatic species in solution, which can be monitored by following the changes that occur in its fluorescence and absorption spectra. On the basis of the solution studies carried out with about 17 derivatives of the aromatic guest molecular systems, it may be concluded that the changes that occur in the fluorescence intensity seem to be proportional to the number of aromatic rings present and thus proportional to the extent of pi...pi interaction present between the naphthalimide moieties and the aromatic portion of the guest molecule. Though the nonaromatic portion of the guest species affects the fluorescence quenching, the trend is still based on the number of rings present in these. Four guest aldehydes are bound to L with K(ass) of 2000-6000 M(-1) and their minimum detection limit is in the range of 8-35 MUM. The crystal structure of a naphthaldehyde complex, L.2b, exhibits intermolecular arm-to-arm as well as arm-to-naphthaldehyde pi...pi interactions. Molecular dynamics studies of L carried out in the presence of aromatic aldehydes under vacuum as well as in acetonitrile resulted in exhibiting interactions observed in the solid state and hence the changes observed in the fluorescence and absorption spectra are attributable for such interactions. Complex formation has also been delineated through ESI MS studies. Thus L is a promising receptor that can recognize PAHs by providing spectral changes proportional to the aromatic conjugation of the guest and the extent of aromatic pi...pi interactions present between L and the guest. PMID- 21314095 TI - Pd(0)-catalyzed [1,5]-sigmatropic hydrogen shift of propargylic esters toward substituent naphthylamines. AB - A novel and convenient carboannulation method for the synthesis of highly substituted naphthylamine derivatives has been developed though a Pd(0)-catalyzed [1,5]-sigmatropic hydrogen shift and cyclization reaction of propargyl esters. PMID- 21314097 TI - Pentanidium-catalyzed enantioselective phase-transfer conjugate addition reactions. AB - A new chiral entity, pentanidium, has been shown to be an excellent chiral phase transfer catalyst. The enantioselective Michael addition reactions of tert-butyl glycinate-benzophenone Schiff base with various alpha,beta-unsaturated acceptors provide adducts with high enantioselectivities. A successful gram-scale experiment at a low catalyst loading of 0.05 mol % indicates the potential for practical applications of this methodology. Phosphoglycine ester analogues can also be utilized as the Michael donor, affording enantioenriched alpha aminophosphonic acid derivatives and phosphonic analogues of (S)-proline. PMID- 21314096 TI - Evolution of fat crystal network microstructure followed by NMR. AB - Model systems composed of tristearin in solid state and tricaprin in liquid state with different solid-fat content (SFC) and storage time have been investigated by relaxation NMR and NMR diffusometry. The T(2) relaxation of the tricaprin in the melt exhibited a bimodal distribution as previously observed. The SFC had a major effect on the T(2) relaxation. This effect was explained according to the fast diffusive exchange model in porous media. According to this model the changes in T(2) relaxation as a function of the SFC and storage time were explained by the decrease of the surface-to-volume ratio of the crystal induced by Ostwald ripening. The diffusion coefficient D of the tricaprin in the melt decreased for higher SFC. Since no significant variation of D was observed for different diffusion time, D reflected the long-range connectivity and the tortuosity was calculated. During storage the diffusion coefficient remained constant. PMID- 21314098 TI - Synthesis of cyclophanes with planar and helical chirality. AB - Novel helical macrocyclic imines derived from planar chiral [2.2]paracyclophane were synthesized. The chiroptical properties of the enantiopure compounds were investigated and their absolute configurations were assigned. PMID- 21314099 TI - Cytotoxic oleanane-type saponins from Albizia inundata. AB - Bioassay-guided fractionation of a CH(2)Cl(2)-MeOH extract of the aerial parts of Albizia inundata resulted in the isolation of two new natural oleanane-type triterpene saponins {3-O-[alpha-L-arabinopyranosyl(1->6)]-2-acetamido-2-deoxy beta-D-glucopyranosyl oleanolic acid (1) and 3-O-[alpha-L-arabinopyranosyl(1->2) alpha-L-arabinopyranosyl(1->6)]-2-acetamido-2-deoxy-beta-D-glucopyranosyl acacic acid lactone (2)} along with seven known saponins {3-O-[alpha-L arabinopyranosyl(1->6)]-2-acetamido-2-deoxy-beta-D-glucopyranosyl echinocystic acid (3), 3-O-[beta-D-xylopyranosyl (l->2)-alpha-L-arabinopyranosyl(l->6)]-2 acetamido-2-deoxy-beta-D-glucopyranosyl acacic acid lactone (concinnoside D) (4), 3-O-[beta-D-glucopyranosyl(l->2)]-beta-D-glucopyranosyl oleanolic acid (5), 3-O [alpha-L-arabinopyranosyl(1->2)-alpha-L-arabinopyranosyl(l->6)]-beta-D glucopyranosyl oleanolic acid (6), 3-O-[beta-D-xylopyranosyl(1->2)-alpha-L arabinopyranosyl(l->6)]-beta-D-glucopyranosyl oleanolic acid (7), 3-O-[alpha-L arabinopyranosyl(l->2)-alpha-L-arabinopyranosyl(1->6)-[beta-D-glucopyranosyl(l >2)]-beta-D-glucopyranoside echinocystic acid (8), and 3-O-[beta-D xylopyranosyl(l->2)-alpha-L-arabinopyranosyl(1->6)-[beta-D-glucopyranosyl(l->2)] beta-D-glucopyranoside echinocystic acid (9)}. The structures of 1 and 2 were established on the basis of extensive 2D NMR ((1)H-(1)H COSY or DQF-COSY, HSQC, HMBC, TOCSY, and HSQC-TOCSY) spectroscopic, ESIMS, and chemical methods. Saponins 1, 3, 6, and 7 showed cytotoxicity against human head and neck squamous cells (JMAR, MDA1986) and melanoma cells (B16F10, SKMEL28) with IC(50) values in the range 1.8-12.4 MUM, using the MTS assay. PMID- 21314101 TI - Cation environment of BaCeO3-based protonic conductors II: new computational models. AB - Quantum chemical calculations have been carried out to simulate Y-doped BaCeO(3) derivatives. Hartree-Fock energy functional was used to study octahedral site environments embedded in a Pmcn orthorhombic framework, showing local arrangement characterized by Ce-O-Ce, Ce-O-Y, and Y-O-Y (Z-O-Xi) configurations and including or not hydrogen close to the moieties encompassing those configurations. The latter are, in fact, representative of - and, in our modeling approach, were treated as - local arrangements that could be found in Y:BaCeO(3)-doped materials. The geometrical optimizations performed on the structural models and a detailed orbital analysis of these systems allowed us to confirm and deepen new interpretations, concerning experimental findings already reported in the literature. In particular, the bimodal distribution characterizing the Y-O first coordination shell, found by EXAFS analysis, could be attributed to a local clustering of Y atoms showing characteristic Y-O-Y arrangements. Moreover, the local charge analysis, characterizing the models containing or not hydrogen atoms, showed that the moving protons are able to dynamically change the properties of their near environment, in any case, leaving unaltered the global protonic conduction features of the material, irrespective of the kind of cation in a given Z-O-Xi moiety. PMID- 21314100 TI - Probing human red cone opsin activity with retinal analogues. AB - Retinal analogues have been used to probe the chromophore binding pocket and function of the rod visual pigment rhodopsin. Despite the high homology between rod and cone visual pigment proteins, conclusions drawn from rhodopsin studies should not necessarily be extrapolated to cone visual pigment proteins. In this study, the effects of full-length and truncated retinal analogues on the human red cone opsin's ability to activate transducin, the G protein in visual transduction, were assessed. The result with beta-ionone (6) confirms that a covalent bond is not necessary to deactivate the red cone opsin. In addition, several small compounds were found able to deactivate this opsin. However, as the polyene chain is extended in a trans configuration beyond the 9-carbon position, the analogues became agonists up to all-trans-retinal (3). The 22-carbon analogue (2) appeared to be neither an agonist nor an inverse agonist. Although the all trans-C17 (5) analogue was an agonist, the 9-cis-C17 (11) compound was an inverse agonist, a result that differs from that with rhodopsin. These results suggest that the red cone opsin has a more open structure in the chromophore binding region than rhodopsin and its activation or deactivation as a G-protein receptor may be less selective than rhodopsin. PMID- 21314102 TI - Cascade cyclization, dipolar cycloaddition to bridged tricyclic amines related to the Daphniphyllum alkaloids. AB - A tandem one-pot reaction of an aldehyde with a primary amine involving condensation and then cyclization (N-alkylation), followed by intramolecular dipolar cycloaddition of the resulting nitrone or azomethine ylide, provides a synthesis of bridged tricyclic amines. The reaction was most successful using hydroxylamine, and when the dipolarophile was an unsaturated ester, subsequent reduction of the N-O bond and cyclization to the lactam provided the core ring system of the yuzurimine, daphnilactone B, and bukittinggine type Daphniphyllum alkaloids. PMID- 21314103 TI - Gold(I)-catalyzed intramolecular amination of allylic alcohols with alkylamines. AB - A 1:1 mixture of (1)AuCl [1 = P(t-Bu)(2)o-biphenyl] and AgSbF(6) catalyzes the intramolecular amination of allylic alcohols with alkylamines to form substituted pyrrolidine and piperidine derivatives. Gold(I)-catalyzed cyclization of (R,Z)-8 (N-benzylamino)-3-octen-2-ol (96% ee, 95% de) led to isolation of (R,E)-1-benzyl 2-(1-propenyl)piperidine in 99% yield with 96% ee, consistent with the net syn addition of the amine relative to the departing hydroxyl group. PMID- 21314104 TI - Bromination-mediated regioselective preparation of cyclopentadienyl-type [60]fullerene derivatives with alkoxy, peroxy, and bromo or hydro addends. AB - Bromine reacts with the 1,2-bisadduct C(60)(OOtBu)(2) efficiently to form the cyclopentadienyl-type compound 4 (C(60)(OOtBu)(2)Br(4)). In the presence of AgClO(4), the four bromine atoms can be replaced regioselectively by methoxyl groups in a stepwise fashion to form C(60)(OOtBu)(2)Br(4-x)(OMe)(x). A second alcohol may be introduced by treating partially methoxylated compound 6 (C(60)(OOtBu)(2)Br(2)(OMe)(2)) with ROH/AgClO(4). Other related reactions have been investigated to explore the reactivity patterns. The structure of compound 6 was confirmed by single crystal X-ray analysis. PMID- 21314105 TI - Atomic volume as a descriptor for carbon electronic structure and stability. AB - Electron density at the carbon atom is a significant factor determining the stability of molecules, but it is difficult to quantify. Using the Atoms in Molecules (AIM) quantum theory, we calculated the atomic charges and volumes of carbon atoms in highly oxidized compounds. The two parameters are shown to be good quantitative descriptors of electron depletion and can be used as an indicator for stability/reactivity of such compounds. PMID- 21314106 TI - Chirality transfer in Au-catalyzed cyclization reactions of monoallylic diols: selective access to specific enantiomers based on olefin geometry. AB - The gold(I)-catalyzed cyclization of monoallylic diols to form tetrahydropyrans is shown to be highly stereoselective when chiral allylic alcohols are employed. Substrates that differ only in olefin geometry provide enantiomeric products from formal S(N)2' reactions in high yields with excellent chirality transfer. The allylic alcohol stereochemistry also efficiently controls the facial selectivity when the substrates include additional stereocenters. PMID- 21314107 TI - Synthesis of alpha-carbolines via Pd-catalyzed amidation and Vilsmeier-Haack reaction of 3-acetyl-2-chloroindoles. AB - A new class of alpha-carboline derivatives has been synthesized by Pd(2)(dba)(3)/BINAP catalyzed amidation of 3-acetyl-2-chloroindoles followed by a Vilsmeier-Haack reaction and is reported. PMID- 21314108 TI - Silver-mediated palladium-catalyzed direct C-H arylation of 3-bromoisothiazole-4 carbonitrile. AB - Silver(I) fluoride-mediated Pd-catalyzed C-H direct arylation/heteroarylation of 3-bromoisothiazole-4-carbonitrile (1a) gives twenty-four 5-aryl/heteroaryl-3 bromoisothiazole-4-carbonitriles. The reaction was partially optimized with respect to catalyst, ligand, and base. During this study 3,3'-dibromo-5,5' biisothiazole-4,4'-dicarbonitrile (3a) was isolated as a byproduct and subsequently prepared via the silver-mediated Pd-catalyzed oxidative dimerization of 3-bromoisothiazole-4-carbonitrile in 67% yield. The analogous phenylation and oxidative dimerization of 3-chloroisothiazole-4-carbonitrile (1b) gave 3-chloro-5 phenylisothiazole-4-carbonitrile (4) and 3,3'-dichloro-5,5'-biisothiazole-4,4' dicarbonitrile (3b) in 96% and 69% yields, respectively. PMID- 21314109 TI - Bioinspired imprinted PHEMA-hydrogels for ocular delivery of carbonic anhydrase inhibitor drugs. AB - Hydrogels with high affinity for carbonic anhydrase (CA) inhibitor drugs have been designed trying to mimic the active site of the physiological metallo-enzyme receptor. Using hydroxyethyl methacrylate (HEMA) as the backbone component, zinc methacrylate, 1- or 4-vinylimidazole (1VI or 4VI), and N-hydroxyethyl acrylamide (HEAA) were combined at different ratios to reproduce in the hydrogels the cone shaped cavity of the CA, which contains a Zn(2+) ion coordinated to three histidine residues. 4VI resembles histidine functionality better than 1VI, and, consequently, pHEMA-ZnMA(2) hydrogels bearing 4VI moieties were those with the greatest ability to host acetazolamide or ethoxzolamide (2 to 3 times greater network/water partition coefficient) and to sustain the release of these antiglaucoma drugs (50% lower release rate estimated by fitting to the square root kinetics). The use of acetazolamide as template during polymerization did not enhance the affinity of the network for the drugs. In addition to the remarkable improvement in the performance as controlled release systems, the biomimetic hydrogels were highly cytocompatible and possessed adequate oxygen permeability to be used as medicated soft contact lenses or inserts. The results obtained highlight the benefits of mimicking the structure of the physiological receptors for the design of advanced drug delivery systems. PMID- 21314110 TI - Biotin-4-fluorescein based fluorescence quenching assay for determination of biotin binding capacity of streptavidin conjugated quantum dots. AB - The valency of quantum dot nanoparticles conjugated with biomolecules is closely related to their performance in cell tagging, tracking, and imaging experiments. Commercially available streptavidin conjugates (SAv QDs) are the most commonly used tool for preparing QD-biomolecule conjugates. The fluorescence quenching of biotin-4-fluorscein (B4F) provides a straightforward assay to quantify the number of biotin binding sites per SAv QD. The utility of this method was demonstrated by quantitatively characterizing the biotin binding capacity of commercially available amphiphilic poly(acrylic acid) Qdot ITK SAv conjugates and poly(ethylene glycol) modified Qdot PEG SAv conjugates with emission wavelengths of 525, 545, 565, 585, 605, 625, 655, 705, and 800 nm. Results showed that 5- to 30-fold more biotin binding sites are available on ITK SAv QDs compared to PEG SAv QDs of the same color with no systematic variation of biotin binding capacity with size. PMID- 21314111 TI - Diels-Alder Click cross-linked hyaluronic acid hydrogels for tissue engineering. AB - Hyaluronic acid (HA) is a naturally occurring polymer that holds considerable promise for tissue engineering applications. Current cross-linking chemistries often require a coupling agent, catalyst, or photoinitiator, which may be cytotoxic, or involve a multistep synthesis of functionalized-HA, increasing the complexity of the system. With the goal of designing a simpler one-step, aqueous based cross-linking system, we synthesized HA hydrogels via Diels-Alder "click" chemistry. Furan-modified HA derivatives were synthesized and cross-linked via dimaleimide poly(ethylene glycol). By controlling the furan to maleimide molar ratio, both the mechanical and degradation properties of the resulting Diels Alder cross-linked hydrogels can be tuned. Rheological and degradation studies demonstrate that the Diels-Alder click reaction is a suitable cross-linking method for HA. These HA cross-linked hydrogels were shown to be cytocompatible and may represent a promising material for soft tissue engineering. PMID- 21314112 TI - A step further in the analysis of human bile proteome. AB - Bile was shown to collect proteins known as potential cancer biomarkers. Thorough proteomic analysis of bile is of particular interest to search for new, more sensitive and more specific, biomarkers of cancers affecting the biliary tract and surrounding organs, such as the pancreas and the liver. Therefore, extending the knowledge of the bile proteome is highly relevant, but this has proved technically difficult. In this study, we describe a strategy that circumvents problems related to the biochemical complexity of this sample and the presence of high concentrations of interfering substances. Bile collected from a patient suffering from a biliary stenosis caused by a pancreatic adenocarcinoma was fractionated by a differential centrifugation scheme, involving a stepwise increase in centrifugation speeds. Pellets and the final supernatant were further fractionated by polyacrylamide gel electrophoresis and proteins were in-gel digested prior to LC-MS/MS analysis. This approach allowed the identification of 445 unique proteins with at least two peptides (812 proteins if single-hit proteins were included), which represents a 3-fold increase in the knowledge of bile proteome. The subsequent literature comparison revealed that numerous biliary proteins identified in this sample were related to pancreas cancer. Immunoblot analysis of some known tumor markers revealed that they were preferentially associated with the soluble fraction rather than with pellets containing cellular components. PMID- 21314113 TI - High-efficiency NO(x) absorption in water using equipment packed with a glass fiber filter. AB - NO(X) absorption in water is quite difficult by comparison with other exhausted gas, such as SO(2), CO(2), and NH(3) because of low solubility of NO(X) in water. We have been developed a NO(X) absorption equipment with a glass fiber filter having high porosity and surface area. When feed NO(X) gas concentration was high, high NO(X) removal efficiency was obtained. This was because the surface area per glass fiber filter volume was about 40 to 600 times higher than for common packing materials. For verification test and industrial application, a high concentration of NO(X) gas (206,000 ppm) produced by a metal dissolution process was treated with a series of two absorption experiments. We can attain 97.6% of NO(X) removal efficiency, and HNO(3) concentration in water was concentrated up to 56.3 wt %. Furthermore, ozone addition to gas and usage of ozone saturated water as an absorbent resulted in complete removal of NO(X) in the gas (up to 120 ppm). This result indicated the importance of aqueous phase oxidation of HNO(2), which produces NO in the gas phase. PMID- 21314114 TI - Acute toxicity of cadmium in Daphnia magna under different calcium and pH conditions: importance of influx rate. AB - Water chemistry is generally thought to influence metal toxicity via affecting metal bioavailability and bioaccumulation, but its effects on tissue residue based toxicity are poorly known. We conducted toxicity tests in parallel with uptake kinetics experiments of cadmium (Cd) in waters of different calcium (Ca) concentrations and pH levels using acclimated Daphnia magna as a model organism. Both the acute toxicity and uptake of Cd were reduced by higher Ca concentration and lower pH. Strikingly constant median effective influx rates (EJ(50), 1.3-1.6 MUg g(-1) h(-1)) of Cd were observed when the concentration of Ca varied from 0.5 to 200 mg L(-1), indicating that acclimation to different Ca levels did not affect the tissue residue-based toxicity. The EJ(50) values increased consistently with decreasing pH level, showing that acclimation to acidic water decreased the tissue residue-based toxicity. With the use of calcium uptake inhibitors, we demonstrated that both Ca channel and Ca(2+)/Na(+) exchanger were involved in Cd uptake in daphnids, but there were also other possible pathways with higher affinity. The relative importance of different pathways was clearly dependent on the ambient Ca availability. Our findings are helpful for the development of a more accurate biotic ligand model in predicting the acute toxicity of Cd to daphnids. PMID- 21314116 TI - Bactericidal paper impregnated with silver nanoparticles for point-of-use water treatment. AB - There is an urgent need for cheap point-of-use methods to purify drinking water. We describe a method to deactivate pathogenic bacteria by percolation through a paper sheet containing silver nanoparticles. The silver nanoparticles are deposited by the in situ reduction of silver nitrate on the cellulose fibers of an absorbent blotting paper sheet. The aim is to achieve inactivation of bacteria during percolation through the sheet, rather than removal of bacteria from the effluent by filtration. The silver-nanoparticle containing (AgNP) papers were tested for performance in the laboratory with respect to bacteria inactivation and silver leaching as suspensions of bacteria percolated through the paper. The AgNP sheets exhibited antibacterial properties toward suspensions of Escherichia coli and Enterococcus faecalis, with log reduction values in the effluent of over log 6 and log 3, respectively. The silver loss from the AgNP sheets was minimal, with values under 0.1 ppm (the current US EPA and WHO limit for silver in drinking water). These results show promise that percolation of bacterially contaminated water through paper embedded with silver nanoparticles could be an effective emergency water treatment. PMID- 21314117 TI - "Nanocellulose" as a single nanofiber prepared from pellicle secreted by Gluconacetobacter xylinus using aqueous counter collision. AB - This study attempted to prepare a single cellulose nanofiber, "nanocellulose", dispersed in water from 3D networks of nanofibers in microbial cellulose pellicle using aqueous counter collision (ACC), which allows biobased materials to be down sized into nano-objects only using water jets without chemical modification. The nanocellulose thus prepared exhibited unique morphological properties. In particular, the width of the nanocellulose, which could be controlled as desired on nanoscales, was smaller than that of just secreted cellulose nanofiber, resulting in larger specific surface areas. Moreover, ACC treatment transformed cellulose I(alpha) crystalline phase into cellulose I(beta) phase with the crystallinity kept >70%. In this way, ACC method depending on the treatment condition could provide the desired fiber width at the nanoscale and the different ratios of the two crystalline allomorphs between cellulose I(alpha) versus I(beta), which thus opens further pathways into versatile applications as biodegradable single nanofibers. PMID- 21314119 TI - Sensitive detection of protein-lipid interaction change on bacteriorhodopsin using dodecyl beta-D-maltoside. AB - A light-driven proton pump bacteriorhodopsin (bR) forms a two-dimensional hexagonal lattice with about 10 archaeal lipids per monomer bR on purple membrane (PM) of Halobacterium salinarum. In this study, we found that the weakening of the bR-lipid interaction on PM by addition of alcohol can be detected as the significant increase of protein solubility in a nonionic detergent, dodecyl beta D-maltoside (DDM). The protein solubility in DDM was also increased by bR-lipid interaction change accompanied by structural change of the apoprotein after retinal removal and was about 7 times higher in the case of completely bleached membrane than that of intact PM. Interestingly, the cyclic and milliseconds order of structural change of bR under light irradiation also led to increasing the protein solubility and had a characteristic light intensity dependence with a phase transition. These results indicate that there is a photointermediate in which bR-lipid interaction has been changed by its dynamic structural change. Because partial delipidation of PM by CHAPS gave minor influence for the change of the protein solubility compared to intact PM in both dark and light conditions, it is suggested that specific interactions of bR with some lipids which remain on PM even after delipidation treatment have a key role for the change of solubility in DDM induced by alcohol binding, ligand release, and photon absorption on bR. PMID- 21314118 TI - Mesoporous silica-coated hollow manganese oxide nanoparticles as positive T1 contrast agents for labeling and MRI tracking of adipose-derived mesenchymal stem cells. AB - Mesoporous silica-coated hollow manganese oxide (HMnO@mSiO(2)) nanoparticles were developed as a novel T(1) magnetic resonance imaging (MRI) contrast agent. We hypothesized that the mesoporous structure of the nanoparticle shell enables optimal access of water molecules to the magnetic core, and consequently, an effective longitudinal (R(1)) relaxation enhancement of water protons, which value was measured to be 0.99 (mM(-1)s(-1)) at 11.7 T. Adipose-derived mesenchymal stem cells (MSCs) were efficiently labeled using electroporation, with much shorter T(1) values as compared to direct incubation without electroporation, which was also evidenced by signal enhancement on T(1)-weighted MR images in vitro. Intracranial grafting of HMnO@mSiO(2)-labeled MSCs enabled serial MR monitoring of cell transplants over 14 days. These novel nanoparticles may extend the arsenal of currently available nanoparticle MR contrast agents by providing positive contrast on T(1)-weighted images at high magnetic field strengths. PMID- 21314120 TI - Synthesis of soybean oil-based polymeric surfactants in supercritical carbon dioxide and investigation of their surface properties. AB - This paper reports the preparation of polymeric surfactants (HPSO) via a two-step synthetic procedure: polymerization of soybean oil (PSO) in supercritical carbon dioxide followed by hydrolysis of PSO (HPSO) with a base. HPSO was characterized and identified by using a combination of FTIR, (1)H NMR, (13)C NMR, and GPC methods. The effects of HPSO polysoaps on the surface tension of water and interfacial tension of water-hexadecane were investigated as a function of concentration of HPSO and counterion chemistry. HPSO polysoaps were effective at lowering the surface tension of water and the interfacial tension of water hexadecane. They displayed minimum values of surface tension in the range of 20.5 39.6 dyn/cm at a concentration range of 3.2-32 MUM and minimum values of interfacial tension in the range of 15.6-31.44 dyn/cm. The minimum surface and interfacial tension values were highly dependent on the nature of the counterion and increased in the order K(+) < Na(+) < TEA(+). These results suggested that a very low concentration of surfactant can be used to reduce the surface tension of water and interfacial tension of water-hexadecane. Water-hexadecane interfacial energy was also calculated from measured surface tension data using Antonoff, harmonic mean (HM), and geometric mean (GM) methods. Measured values agreed well with those calculated using the HM and GM. The HM method predicted slightly higher values than the GM method, but the Antonoff method did not agree with measured values. PMID- 21314121 TI - Disease control effect of strevertenes produced by Streptomyces psammoticus against tomato fusarium wilt. AB - During screening of microorganisms producing antifungal metabolites, Streptomyces psammoticus strain KP1404 was isolated. The culture extract of this strain showed potent disease control efficacy against Fusarium wilt on tomato plants. The antifungal metabolites ST-1 and ST-2 were isolated from the culture extract using a variety of chromatographic procedures. On the basis of MS and NMR spectrometric analysis, the structures of the antifungal active compounds ST-1 and ST-2 were determined to be the polyene antibiotics strevertene A and strevertene B, respectively. In vitro, strevertenes A and B showed inhibitory effects against the mycelial growth of Alternaria mali , Aspergillus oryzae , Cylindrocarpon destructans , Colletotrichum orbiculare , Fusarium oxysporum f.sp. lycopersici, and Sclerotinia sclerotiorum , even at concentrations of 4-16 MUg/mL. Fusarium wilt development on tomato plants was strongly retarded by treatment with 1 MUg/mL of these strevertenes. The disease control efficacies of strevertenes on Fusarium wilt were as remarkable as that of benomyl. PMID- 21314122 TI - Influence of wine pH on changes in color and polyphenol composition induced by micro-oxygenation. AB - The presence of oxygen in red wine leads to the transformation of ethanol into ethanal, which after capturing a proton will react with flavanols to start the process of forming ethyl bridges between flavanols and between flavanols and anthocyanins. Wine pH also conditions the equilibrium between the different anthocyanin structures and may thus affect anthocyanin reactivity. Consequently, the aim of this paper was to study how the pH can affect the changes induced by micro-oxygenation in two wines with different phenolic composition. The differences between micro-oxygenated wines and their controls were, in general, greater when the pH was more acidic. Specifically, the differences between micro oxygenated wines and their corresponding controls in terms of color intensity, anthocyanin concentration, PVPP index, ethyl-linked pigments, B-type vitisins, polymeric pigments, and ethylidene-bridged flavanols were greater at lower pH. In contrast, the effects of micro-oxygenation when the pH was less acidic were much less evident and sometimes practically nonexistent. These results demonstrate for the first time that the pH of the wine has a great influence on oxygen-induced changes of color and phenolic compounds. PMID- 21314123 TI - alpha-Mangostin, a dietary xanthone, induces autophagic cell death by activating the AMP-activated protein kinase pathway in glioblastoma cells. AB - This study is the first to investigate the anticancer effects of alpha-mangostin in human glioblastoma cells. alpha-Mangostin decreases cell viability by inducing autophagic cell death but not apoptosis. Pretreatment of cells with the autophagy inhibitors 3-methyladenine (3-MA) and bafilomycin or knockdown beclin-1, resulted in the suppression of alpha-mangostin-mediated cell death. We also found that liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signaling is a critical mediator of alpha-mangostin-induced inhibition of cell growth. Activation of AMPK induces alpha-mangostin-mediated phosphorylation of raptor, which subsequently associates with 14-3-3gamma and results in the loss of mTORC1 activity. The phosphorylation of both downstream targets of mTORC1, p70 ribosomal protein S6 kinase (p70S6 kinase) and 4E-BP1, is also diminished by activation of AMPK. Furthermore, the inhibition of AMPK expression with shRNAs or an inhibitor of AMPK reduced alpha-mangostin-induced autophagy and raptor phosphorylation, supporting the theory that activation of AMPK is beneficial to autophagy. A further investigation revealed that alpha-mangostin also induced autophagic cell death in transplanted glioblastoma in nude mice. Together, these results suggest a critical role for AMPK activation in the alpha-mangostin-induced autophagy of human glioblastoma cells. PMID- 21314124 TI - Model aging and oxidation effects on varietal, fermentative, and sulfur compounds in a dry botrytized red wine. AB - From harvest until wine arrives to the consumer, oxygen plays a crucial role in the definition of the final aroma. In the present research, the effect of the model oxidative aging on a dry red Botrytis wine, such as Italian Amarone, was considered. Amarone wine was submitted to model oxidative aging and then analyzed with two different approaches (SPE-GC-MS and HS-SPME/GC-MS). The same sampling plan was adopted to study the model aging of the same Amarone wine in anaerobic conditions. The HS-SPME/GC-MS method was applied to investigate for the first time the effect of the oxidative aging on a vast number of fermentative sulfur compounds. This research highlighted peculiar evolutions for several volatile compounds. In particular, benzaldehyde showed a sensitive increment during the oxidative aging, with a rate much higher than that reported for non-Botrytis red wines. On the other hand, several sulfides (dimethyl sulfide, 3-(methylthio)-1 propanol, etc.) disappeared after just 15 days of oxidative aging. A wine oxidation marker such as 3-(methylthio)-propanal was not found in any of the oxidized wines; conversely methionol-S-oxide was tentatively identified. This evidence has not been mentioned in the literature. A possible involvement of grape withering process and Botrytis in these mechanisms was supposed: a dry red wine, produced from the same but without any grape withering process and Botrytis infection (e.g., Bardolino wine), was submitted to oxidative aging and analysis. This red wine showed an evolution similar to those reported in the literature for dry red wines but significantly different from the Amarone wine. PMID- 21314125 TI - Chemical and cellular antioxidant activity of phytochemicals purified from olive mill waste waters. AB - The isolation and identification of a phytocomplex from olive mill waste waters (OMWW) was achieved. The isolated phytocomplex is made up of the following three phenolic compounds: hydroxytyrosol (3,4-DHPEA), tyrosol (p-HPEA) and the dialdehydic form of decarboxymethyl elenolic acid, linked with (3,4 dihydroxyphenyl)ethanol (3,4-DHPEA-EDA). The purification of this phytocomplex was reached by partial dehydration of the OMWW, followed by liquid-liquid extraction with ethyl acetate and middle pressure liquid chromatography (MPLC) on a Sephadex LH-20 column. The phytocomplex accounted for 6% of the total phenolic content of the OMWW. The phytocomplex and individual compounds were tested for antioxidant capacity by the oxygen radical absorbance capacity (ORAC) method. The ORAC phytocomplex produced 10,000 ORAC units/g dry weight, whereas the cellular antioxidant activity, measured by the cellular antioxidant activity in red blood cell (CAA-RBC) method, demonstrated that the phytocomplex and all of the components are able to permeate the cell membrane thus exhibiting antioxidant activity inside the red blood cells. Our phytocomplex could be employed in the formulation of fortified foods and nutraceuticals, with the goal to obtain substantial health protective effects due to the suitable combination of the component molecules. PMID- 21314126 TI - Suppression of hepatitis B virus x protein-mediated tumorigenic effects by ursolic Acid. AB - This study investigated the potential effects of natural products ursolic acid (UA) and oleanolic acid (OA) against HBx-mediated tumorigenic activities in vitro and in vivo. HBx transactivated Sp-1 and Smad 3/4 in Huh7 and FL83B hepatocytes and induced cell migration of Huh7 and HepG2. HBx also induced MMP-3 secretion in Huh7 and acted against TGF-beta-induced apoptosis in Hep3B. UA almost completely blocked the HBx-mediated effects, while OA had a partial inhibitive effect. Utilization of specific MAPK inhibitors and immunoblotting demonstrated that UA selectively activated MAPK signaling in certain tested cells. Preintraperitoneal injection of UA fully prevented the tumor growth of HBV-containing 2.2.15 cells, while OA-treated mice had smaller tumors than the control group. Our results suggested that UA possesses a hepatoprotective ability and illustrated the evident effects against HBx-mediated tumorigenic activities without toxicity in a mouse model. PMID- 21314128 TI - Isoindolinone inhibitors of the murine double minute 2 (MDM2)-p53 protein-protein interaction: structure-activity studies leading to improved potency. AB - Inhibition of the MDM2-p53 interaction has been shown to produce an antitumor effect, especially in MDM2 amplified tumors. The isoindolinone scaffold has proved to be versatile for the discovery of MDM2-p53 antagonists. Optimization of previously reported inhibitors, for example, NU8231 (7) and NU8165 (49), was guided by MDM2 NMR titrations, which indicated key areas of the binding interaction to be explored. Variation of the 2-N-benzyl and 3-alkoxy substituents resulted in the identification of 3-(4-chlorophenyl)-3-((1 (hydroxymethyl)cyclopropyl)methoxy)-2-(4-nitrobenzyl)isoindolin-1-one (74) as a potent MDM2-p53 inhibitor (IC(50) = 0.23 +/- 0.01 MUM). Resolution of the enantiomers of 74 showed that potent MDM2-p53 activity primarily resided with the (+)-R-enantiomer (74a; IC(50) = 0.17 +/- 0.02 MUM). The cellular activity of key compounds has been examined in cell lines with defined p53 and MDM2 status. Compound 74a activates p53, MDM2, and p21 transcription in MDM2 amplified cells and shows moderate selectivity for wild-type p53 cell lines in growth inhibition assays. PMID- 21314127 TI - Biological activity of peanut (Arachis hypogaea) phytoalexins and selected natural and synthetic Stilbenoids. AB - The peanut plant (Arachis hypogaea L.), when infected by a microbial pathogen, is capable of producing stilbene-derived compounds that are considered antifungal phytoalexins. In addition, the potential health benefits of other stilbenoids from peanuts, including resveratrol and pterostilbene, have been acknowledged by several investigators. Despite considerable progress in peanut research, relatively little is known about the biological activity of the stilbenoid phytoalexins. This study investigated the activities of some of these compounds in a broad spectrum of biological assays. Since peanut stilbenoids appear to play roles in plant defense mechanisms, they were evaluated for their effects on economically important plant pathogenic fungi of the genera Colletotrichum, Botrytis, Fusarium, and Phomopsis. We further investigated these peanut phytoalexins, together with some related natural and synthetic stilbenoids (a total of 24 compounds) in a panel of bioassays to determine their anti inflammatory, cytotoxic, and antioxidant activities in mammalian cells. Several of these compounds were also evaluated as mammalian opioid receptor competitive antagonists. Assays for adult mosquito and larvae toxicity were also performed. The results of these studies reveal that peanut stilbenoids, as well as related natural and synthetic stilbene derivatives, display a diverse range of biological activities. PMID- 21314129 TI - Design, synthesis, and biological evaluation of novel carbohydrate-based sulfamates as carbonic anhydrase inhibitors. AB - Carbonic anhydrases (CAs) IX and XII are enzymes with newly validated potential for the development of personalized, first-in-class cancer chemotherapies. Here we present the design and synthesis of novel carbohydrate-based CA inhibitors, several of which were very efficient inhibitors (K(i)<10 nM) with good selectivity for cancer-associated CA isozymes over off-target CA isozymes. All inhibitors comprised a carbohydrate core with one hydroxyl group derivatized as a sulfamate. Five different carbohydrates were chosen to present a selection of molecular shapes with subtle stereochemical differences to the CA enzymes active site. Variable modifications of the remaining sugar hydroxyl groups were incorporated to provide an incremental coverage of chemical property parameters that are associated with biopharmaceutical performance. All sulfamate inhibitors displayed ligand efficiencies that are consistent with those reported for good drug lead candidates. PMID- 21314130 TI - Hierarchical alignment and full resolution pattern recognition of 2D NMR spectra: application to nematode chemical ecology. AB - Nuclear magnetic resonance (NMR) is the most widely used nondestructive technique in analytical chemistry. In recent years, it has been applied to metabolic profiling due to its high reproducibility, capacity for relative and absolute quantification, atomic resolution, and ability to detect a broad range of compounds in an untargeted manner. While one-dimensional (1D) (1)H NMR experiments are popular in metabolic profiling due to their simplicity and fast acquisition times, two-dimensional (2D) NMR spectra offer increased spectral resolution as well as atomic correlations, which aid in the assignment of known small molecules and the structural elucidation of novel compounds. Given the small number of statistical analysis methods for 2D NMR spectra, we developed a new approach for the analysis, information recovery, and display of 2D NMR spectral data. We present a native 2D peak alignment algorithm we term HATS, for hierarchical alignment of two-dimensional spectra, enabling pattern recognition (PR) using full-resolution spectra. Principle component analysis (PCA) and partial least squares (PLS) regression of full resolution total correlation spectroscopy (TOCSY) spectra greatly aid the assignment and interpretation of statistical pattern recognition results by producing back-scaled loading plots that look like traditional TOCSY spectra but incorporate qualitative and quantitative biological information of the resonances. The HATS-PR methodology is demonstrated here using multiple 2D TOCSY spectra of the exudates from two nematode species: Pristionchus pacificus and Panagrellus redivivus. We show the utility of this integrated approach with the rapid, semiautomated assignment of small molecules differentiating the two species and the identification of spectral regions suggesting the presence of species-specific compounds. These results demonstrate that the combination of 2D NMR spectra with full-resolution statistical analysis provides a platform for chemical and biological studies in cellular biochemistry, metabolomics, and chemical ecology. PMID- 21314131 TI - Proteome scale turnover analysis in live animals using stable isotope metabolic labeling. AB - At present most quantitative proteomics investigations are focused on the analysis of protein expression differences between two or more sample specimens. With each analysis a static snapshot of a cellular state is captured with regard to protein expression. However, any information on protein turnover cannot be obtained using classic methodologies. Protein turnover, the result of protein synthesis and degradation, represents a dynamic process, which is of equal importance to understanding physiological processes. Methods employing isotopic tracers have been developed to measure protein turnover. However, applying these methods to live animals is often complicated by the fact that an assessment of precursor pool relative isotope abundance is required. Also, data analysis becomes difficult in case of low label incorporation, which results in a complex convolution of labeled and unlabeled peptide mass spectrometry signals. Here we present a protein turnover analysis method that circumvents this problem using a (15)N-labeled diet as an isotopic tracer. Mice were fed with the labeled diet for limited time periods and the resulting partially labeled proteins digested and subjected to tandem mass spectrometry. For the interpretation of the mass spectrometry data, we have developed the ProTurnyzer software that allows the determination of protein fractional synthesis rates without the need of precursor relative isotope abundance information. We present results validating ProTurnyzer with Escherichia coli protein data and apply the method to mouse brain and plasma proteomes for automated turnover studies. PMID- 21314132 TI - Analysis of amyloid-beta peptides in cerebrospinal fluid samples by capillary electrophoresis coupled with LIF detection. AB - We report a CE-LIF method for the separation and detection of five synthetic amyloid-beta peptides corresponding to an important family of CSF-biomarkers in the context of Alzheimer disease (AD). The presumed most relevant peptides (Abeta1-42, Abeta1-40, and Abeta1-38) that may support the differentiation between AD and healthy patients or other dementias were successfully detected in CSF by incorporating an immunoconcentration step prior to CE analysis of derivatized peptides. We labeled the Abeta peptides with a fluoroprobe dye before CE-LIF analysis. This reagent reacts with the amino groups of lysine residues and produced mostly ditagged Abeta peptides under the proposed experimental conditions. The labeling reaction displayed similar efficiency with each one of the five different synthetic Abeta peptides that were tested. The limit of detection of the CE-LIF method approached 280 attomoles of injected synthetic labeled Abeta peptides. We obtained excellent correlation between peak areas and peptide concentrations from 35 nM to 750 nM. For the detection of Abeta peptides in human CSF samples, we enriched the peptides by immunoprecipitation prior to the CE-LIF analysis. The comparison of the CE-LIF profiles obtained from CSF samples from 3 AD patients and 4 non-demented control subjects indicated noticeable differences, suggesting that this method, which relies on a multibiomarker approach, may have potential as a clinical diagnostic test for AD. PMID- 21314133 TI - Nuclear quadrupole resonance: a technique to control hydration processes in the pharmaceutical industry. AB - Pharmaceuticals can exist in many solid forms, which can have different physical and chemical properties. These solid forms include polymorphs, solvates, amorphous, and hydrates. Particularly, hydration process can be quite common since pharmaceutical solids can be in contact with water during manufacturing process and can also be exposed to water during storage. In the present work, it is proved that NQR technique is capable of detecting different hydrated forms not only in the pure raw material but also in the final product (tablets), being in this way a useful technique for quality control. This technique was also used to study the dehydration process from pentahydrate to trihydrate. PMID- 21314134 TI - Comparative assessment of different histidine-tags for immobilization of protein onto surface plasmon resonance sensorchips. AB - Surface plasmon resonance (SPR) is widely used to assess the kinetics and thermodynamics of binding of two molecules. The major challenge is immobilization of one molecule onto the sensorchip for robust detection of binding of the other molecule. We have compared a number of immobilization strategies for noncovalent attachment of an example protein (the substrate binding protein SiaP) by hexa histidine (His), deca-His, and double-His tags to a nickel-nitrilotriacetic acid (NTA) surface. The stability of immobilization was assessed, and the binding of two low molecular weight ligands, Neu5Ac and 2-keto-3-deoxy-D-glycero-D-galacto nononic acid (KDN), at different temperatures studied. The hexa-His tagged SiaP washed off from the surface too rapidly for ligand binding to be measured reliably. Systematic variation of chip loading identified conditions under which the deca-His tagged SiaP could generate reliable results. The double-His tagged protein performed as well as covalently attached deca-His tagged protein at 15, 25, and 35 degrees C. The observed ligand binding kinetics were comparable for all immobilization strategies, and thermodynamic values calculated from SPR are in agreement with solution-based isothermal titration calorimetry measurements. Extended trials suggest that covalent attachment is preferable for screening campaigns, whereas the double-His-tag strategy allows rapid regeneration of the chip, for example, when tight binding compounds are assessed. PMID- 21314135 TI - Electrochemical monitoring of the fluorescence emission of tetrazine and bodipy dyes using total internal reflection fluorescence microscopy coupled to electrochemistry. AB - A very sensitive technique where an electrochemical cell is coupled to a total internal reflection fluorescence microscopy setup is described and applied for the first time to the electrochemical monitoring of the fluorescence of organic dyes in solution. It is shown that this setup basically allows both spatial and time resolution for the recorded fluorescence signal as a function of the electrode potential: indeed the variations of the emission intensity are recorded within the diffusion layer for a classical cyclic voltammetry or chronoamperometry experiment inducing the redox conversion of an emissive form into a non emissive one (and conversely). Simultaneously, the variations of the emissive state lifetime are measured to discriminate between a mechanism involving only the conversion into a non emissive form from one involving a quenching between the emitter and the electrogenerated species. The results concerning the investigation of the electrochemical monitoring of the fluorescence properties for two types of original dyes are presented, demonstrating the possibility to switch on and off the emission in a fully reversible way and to investigate in depth the mechanisms associated to this switch. PMID- 21314136 TI - Foam films as thin liquid gas separation membranes. AB - In this letter, we testify the feasibility of using freestanding foam films as a thin liquid gas separation membrane. Diminishing bubble method was used as a tool to measure the permeability of pure gases like argon, nitrogen, and oxygen in addition to atmospheric air. All components of the foam film including the nature of the tail (fluorocarbon vs hydrocarbon), charge on the headgroup (anionic, cationic, and nonionic) and the thickness of the water core (Newton black film vs Common black film) were systematically varied to understand the permeation phenomena of pure gases. Overall results indicate that the permeability values for different gases are in accordance with magnitude of their molecular diameter. A smaller gaseous molecule permeates faster than the larger ones, indicating a new realm of application for foam films as size selective separation membranes. PMID- 21314137 TI - Parallel detection of intrinsic fluorescence from peptides and proteins for quantification during mass spectrometric analysis. AB - Direct mass spectrometric quantification of peptides and proteins is compromised by the wide variabilities in ionization efficiency which are hallmarks of both the MALDI and ESI ionization techniques. We describe here the implementation of a fluorescence detection system for measurement of the UV-excited intrinsic fluorescence (UV-IF) from peptides and proteins just prior to their exit and electrospray ionization from an ESI capillary. The fluorescence signal provides a quantifiable measure of the amount of protein or peptide present, while direct or tandem mass spectrometric analysis (MS/MS) on the ESI-generated ions provides information on identity. We fabricated an inexpensive, modular fluorescence excitation and detection device utilizing an ultraviolet light-emitting diode for excitation in a ~300 nL fluorescence detection cell integrated into the fused silica separation column. The fluorescence signal is linear over 3 orders of magnitude with on-column limits of detection in the low femtomole range. Chromatographically separated intact proteins analyzed using UV-IF prior to top down mass spectrometry demonstrated sensitive detection of proteins as large as 77 kDa. PMID- 21314138 TI - Vapor-phase toxicity of Derris scandens Benth.-derived constituents against four stored-product pests. AB - The vapor-phase toxicity of Derris scandens Benth.-derived constituents was evaluated against four stored-product pests ( Callosobruchus chinensis L., Sitophilus oryzae L., Rhyzopertha dominica L., and Tribolium castaneum H.) using fumigation bioassays and compared to those of commonly used insecticides. The structures of all constituents of were characterized by spectroscopic analyses [nuclear magnetic resonance (NMR) and mass spectrometry]. The sensitivity of the test insect to compounds varied with exposure time, concentration, and insect species. Over 100% mortality after 24 h was achieved with the compounds osajin (2), scandinone (5), sphaerobioside (8), and genistein (9) against all of the test insects, while laxifolin (3) and lupalbigenin (4) showed 100% mortality after 72 h against T. csataneum and R. dominica . Scandenone (1), scandenin A (6), and scandenin (7) were less effective. Among the insects, C. chinensis , S. oryzae , and R. dominica were more susceptible to the treatments, whereas T. castaneum was less susceptible. The results of fumigation tests indicated that compounds from D. scandens whole plant extract are potential candidates to control stored-product pests. PMID- 21314139 TI - "Off-on" electrochemical hairpin-DNA-based genosensor for cancer diagnostics. AB - A simple and robust "off-on" signaling genosensor platform with improved selectivity for single-nucleotide polymorphism (SNP) detection based on the electronic DNA hairpin molecular beacons has been developed. The DNA beacons were immobilized onto gold electrodes in their folded states through the alkanethiol linker at the 3'-end, while the 5'-end was labeled with a methylene blue (MB) redox probe. A typical "on-off" change of the electrochemical signal was observed upon hybridization of the 27-33 nucleotide (nt) long hairpin DNA to the target DNA, in agreement with all the hitherto published data. Truncation of the DNA hairpin beacons down to 20 nts provided improved genosensor selectivity for SNP and allowed switching of the electrochemical genosensor response from the on-off to the off-on mode. Switching was consistent with the variation in the mechanism of the electron transfer reaction between the electrode and the MB redox label, for the folded beacon being characteristic of the electrochemistry of adsorbed species, while for the "open" duplex structure being formally controlled by the diffusion of the redox label within the adsorbate layer. The relative current intensities of both processes were governed by the length of the formed DNA duplex, potential scan rate, and apparent diffusion coefficient of the redox species. The off-on genosensor design used for detection of a cancer biomarker TP53 gene sequence favored discrimination between the healthy and SNP-containing DNA sequences, which was particularly pronounced at short hybridization times. PMID- 21314140 TI - Global sensitivity analysis of chemical-kinetic reaction mechanisms: construction and deconstruction of the probability density function. AB - This paper investigates global sensitivity analysis as applied to reaction mechanisms. It uses the HDMR (high-dimensional model representation) expansion and the features of the sensitivity indices to explore the probability density function (pdf) of predicted target outputs that results from the uncertainties in the rate coefficients. We study the autoignition of H(2)/O(2) mixtures, where the pdf describes the uncertainty in ignition delay times due to the uncertainties in the rate coefficients. The global sensitivity analysis in conjunction with the HDMR expansion allows for the deconstruction of the pdf in several different ways. These deconstructions allow the features of the pdf to be understood in terms of the constitute reactions in much finer detail than the study of a variance decomposition alone. PMID- 21314141 TI - CH2 b1B1-a1A1 band origin at 1.20 MUm. AB - The origin band in the b(1)B(1)-a(1)A(1) transition of CH(2) near 1.2 MUm has been recorded at Doppler-limited resolution using diode laser transient absorption spectroscopy. The assignments of rotational transitions terminating in upper state levels with K(a) = 0 and 1, were confirmed by ground state combination differences and extensive optical-optical double resonance experiments. The assigned lines are embedded in a surprisingly dense spectral region, which includes a strong hot band, b(0,1,0) K(a) = 0 - a(0,1,0) K(a) = 1 sub-band lines, with combination or overtone transitions in the a(1)A(1) state likely responsible for the majority of unassigned transitions in this region. From measured line intensities and an estimate of the concentration of CH(2) in the sample, we find the transition moment square for the 0(00) <- 1(10) transition in the b(1)B(1)(0,0,0)(0)-a(1)A(1)(0,0,0)(1) sub-band is 0.005(1) D(2). Prominent b(1)B(1)(0,1,0)(0)-a(1)A(1)(0,1,0)(1) hot band lines were observed in the same spectral region. Comparison of the intensities of corresponding rotational transitions in the two bands suggests the hot band has an intrinsic strength approximately 28 times larger than the origin band. Perturbations of the excited state K(a) = 0 and 1 levels are observed and discussed. The new measurements will lead to improved future theoretical modeling and calculations of the Renner-Teller effect between the a and b states in CH(2). PMID- 21314142 TI - Synthesis and antiproliferative activity of a C,N-cycloplatinated(II) complex with a potentially intercalative anthraquinone pendant. AB - The synthesis of the novel anthraquinone platinum derivate [Pt(ppy)Cl(1C3)] (2) [Hppy = N,C-chelating 2-phenylpyridine; 1C3 = 1-[(3-aminopropyl)amino]-anthracene 9,10-dione] and its values of IC(50) against a panel of human tumor cell lines representative of ovarian (A2780 and A2780cisR) and breast cancers (T47D) are reported. At 24 h incubation time, complex 2 was more active than cisplatin (about 9-fold) and the free ligand 1C3 (about 2-fold) in T47-D. The observation that the cisplatin IC(50) falls by about 10-fold from 24 to 72 h, whereas that for 2 changes little, suggests substantial differences in the mode of action. Complex 2 also showed high cytotoxicity against A2780 (about 3-fold greater than cisplatin at 24 h). On the other hand, very low resistance factors (RF) of 2 in A2780cisR at 24-72 h (RF = 1.3) were observed. The interaction of 2 with DNA was followed by electrophoretic mobility and UV-visible spectroscopy, and its reaction with the model nucleobase 9-EtG was studied by (1)H NMR and ESI-MS. Theoretical calculations at the B3LYP/def2-TZVPP//BP86/def2-TZVP level of theory on complex 2 show a labile Pt-Cl bond that allows easy replacement of Cl by N nucleophiles such as 9-EtG, which forms a stronger Pt-N bond. PMID- 21314143 TI - Multiple boron-boron bonds in neutral molecules: an insight from the extended transition state method and the natural orbitals for chemical valence scheme. AB - We have analyzed the character of B?B and B=B bonds in the neutral molecules of general form: LHB?BHL (2-L) and LB=BL (3-L), for various ancillary ligands L attached to the boron center, based on a recently developed method that combines the extended transition state scheme with the theory of natural orbitals for chemical valence (ETS-NOCV). In the case of molecules with the B?B bond, 2-L, we have included L = PMe(3), PF(3), PCl(3), PH(3), C(3)H(4)N(2)?C(NHCH)(2), whereas for molecules containing the B=B connection, 3-L, the following ligands were considered L = CO, PMe(3), PCl(3), (Me(2)NCH(2)CH(2)O)(2)Ge. The results led us to conclude that use of phosphorus ligands leads to strengthening of the B?B bond by 6.4 kcal/mol (for 2-PMe(3)), by 4.4 (for 2-PF(3)) and by 9.2 (for 2-PH(3)), when compared to a molecule developed on the experimental basis, 2-C(3)H(4)N(2) (DeltaE(total) = -118.3 kcal/mol). The ETS scheme has shown that all contributions, that is, (i) orbital interaction DeltaE(orb), (ii) Pauli repulsion DeltaE(Pauli), and (iii) electrostatic stabilization DeltaE(elstat), are important in determining the trend in the B?B bond energies, DeltaE(total). ETS NOCV results revealed that both sigma(B?B) and pi(B?B) contributions are responsible for the changes in DeltaE(orb) values. All considered molecules of the type LB=BL, 3-L, exhibit a stronger B=B bond when compared to a double B?B connection in 2-L (|DeltaE(total)| is lower by 11.8-42.5 kcal/mol, depending on the molecule). The main reason is a lower Pauli repulsion contribution noted for 3-CO, 3-PMe(3), and 3-PCl(3) molecules. In addition, in the case of 3-PMe(3) and 3-PCl(3), the orbital interaction term is more stabilizing; however, the effect is less pronounced compared to the drop in the Pauli repulsion term. In all of the systems with double and triple boron-boron bonds, the electronic factor (DeltaE(orb)) dominates over the electrostatic contribution (DeltaE(elstat)). Finally, the strongest B=B connection was found for 3-Ge [L = (Me(2)NCH(2)CH(2)O)(2)Ge], predominantly as a result of the strongest sigma- and pi-contributions, despite the highest destabilization originating from the sizable bulkiness of the germanium-containing ligand. The data on energetic stability of multiple boron-boron bonds (relatively high values of bond dissociation energies |DeltaE(total)|), suggest that it should be possible to isolate experimentally the novel proposed systems with double B?B bonds, 2 PMe(3), 2-PF(3), 2-PCl(3), and 2-PH(3), and those with triple B=B connections, 3 PMe(3), 3-Ge, and 3-PCl(3). PMID- 21314144 TI - Hydration structure of the Ti(III) cation as revealed by pulse EPR and DFT studies: new insights into a textbook case. AB - The (17)O and (1)H hyperfine interactions of water ligands in the Ti(III) aquo complex in a frozen solution were determined using Hyperfine Sublevel Correlation (HYSCORE) and Pulse Electron Nuclear Double Resonance (ENDOR) spectroscopies at 9.5 GHz. The isotropic hyperfine interaction (hfi) constant of the water ligand (17)O was found to be about 7.5 MHz. (1)H Single Matched Resonance Transfer (SMART) HYSCORE spectra allowed resolution of the hfi interactions of the two inequivalent water ligand protons and the relative orientations of their hfi tensors. The magnetic and geometrical parameters extracted from the experiments were compared with the results of DFT computations for different geometrical arrangements of the water ligands around the cation. The theoretical observable properties (g tensor (1)H and (17)O hfi tensors and their orientations) of the [Ti(H(2)O)(6)](3+) complex are in quantitative agreement with the experiments for two slightly different geometrical arrangements associated with D(3d) and C(i) symmetries. PMID- 21314145 TI - Synthesis, structure, and spectroscopic characterization of [H(8-n)Rh22(CO)35](n ) (n = 4, 5) and [H2Rh13(CO)24{Cu(MeCN)}2](-) clusters: assessment of CV and DPV as techniques to circumstantiate the presence of elusive hydride atoms. AB - The previously ill-characterized [H(x)Rh(22)(CO)(35)](4-/5-) carbonyl cluster has been obtained as a byproduct of the synthesis of [H(3)Rh(13)(CO)(24)](2-) and effectively separated by metathesis of their sodium salts with [NEt(4)]Cl. Although the yields are modest and never exceed 10-15% (based on Rh), this procedure affords spectroscopically pure [H(3)Rh(22)(CO)(35)](5-) anion. Formation of the latter in mixture with other Rh clusters was also observed by electrospray ionization-mass spectrometry (ESI-MS) in the oxidation of [H(2)Rh(13)(CO)(24)](3-) with Cu(2+) salts. The recovery of further amounts of [H(3)Rh(22)(CO)(35)](5-) was hampered by too similar solubility of the salts composing the mixture. Conversely, the reaction in CH(3)CN of [H(2)Rh(13)(CO)(24)](3-) with [Cu(MeCN)(4)](+)[BF(4)](-) leads to the [H(2)Rh(13)(CO)(24){Cu(MeCN)}(2)](-) bimetallic cluster. The X-ray crystal structures of [H(4)Rh(22)(CO)(35)](4-), [H(3)Rh(22)(CO)(35)](5-), and [H(2)Rh(13)(CO)(24){Cu(MeCN)}(2)](-) are reported. From a formal point of view, the metal frame of the former two species can be derived by interpenetration along two orthogonal axes of two moieties displaying the structure of the latter. The availability of [H(8-n)Rh(22)(CO)(35)](n-) salts prompted their detailed chemical, spectroscopic, and electrochemical characterization. The presence of hydride atoms has been directly proved both by ESI-MS and (1)H NMR. Moreover, both [H(4)Rh(22)(CO)(35)](4-) and [H(3)Rh(22)(CO)(35)](5-) undergo distinctive electrochemically reversible redox changes. This allows to assess electrochemical studies as indisputable though circumstantial evidence of the presence of (1)H NMR-silent hydride atoms in isostructural anions of different charge. PMID- 21314146 TI - Assessment of the intermediacy of arylpalladium carboxylate complexes in the direct arylation of benzene: evidence for C-H bond cleavage by "ligandless" species. AB - Palladium-catalyzed direct arylations of benzene have been proposed to occur by the generation of a phosphine-ligated arylpalladium pivalate complex LPd(Ar)(OPiv) and reaction of this complex with benzene. We have isolated an example of the proposed intermediate and evaluated whether this complex does react with benzene to form the biaryl products of direct arylation. In contrast to the proposed mechanism, no biaryl product was formed from cleavage of the benzene C-H bond by LPd(Ar)(OPiv). However, reactions of LPd(Ar)(OPiv) with benzene and additives that displace or consume the phosphine ligand formed the arylated products in good yield, suggesting that a "ligandless" arylpalladium(II) carboxylate complex undergoes the C-H cleavage step. Consistent with this conclusion, we found that reactions catalyzed by Pd(OAc)(2) without a ligand occur faster than, and with comparable selectivities to, reactions catalyzed by Pd(OAc)(2) and a phosphine ligand. PMID- 21314147 TI - Iron(II) cage complexes of N-heterocyclic amide and bis(trimethylsilyl)amide ligands: synthesis, structure, and magnetic properties. AB - Metallation of hexahydropyrimidopyrimidine (hppH) by [Fe{N(SiMe(3))(2)}(2)] (1) produces the trimetallic iron(II) amide cage complex [{(Me(3)Si)(2)NFe}(2)(hpp)(4)Fe] (2), which contains three iron(II) centers, each of which resides in a distorted tetrahedral environment. An alternative, one-pot route that avoids use of the highly air-sensitive complex 1 is described for the synthesis of the iron(II)-lithium complex [{(Me(3)Si)(2)N}(2)Fe{Li(bta)}](2) (3) (where btaH = benzotriazole), in which both iron(II) centers reside in 3 coordinated pyramidal environments. The structure of 3 is also interpreted in terms of the ring laddering principle developed for alkali metal amides. Magnetic susceptibility measurements reveal that both compounds display very weak antiferromagnetic exchange between the iron(II) centers, and that the iron(II) centers in 2 and 3 possess large negative axial zero-field splittings. PMID- 21314148 TI - Proton transfer in concentrated aqueous hydroxide visualized using ultrafast infrared spectroscopy. AB - While it is generally recognized that the hydroxide ion can rapidly diffuse through aqueous solution due to its ability to accept a proton from a neighboring water molecule, a description of the OH(-) solvation structure and mechanism of proton transfer to the ion remains controversial. In this report, we present the results of femtosecond infrared spectroscopy measurements of the O-H stretching transition of dilute HOD dissolved in NaOD/D(2)O. Pump-probe, photon echo peak shift, and two-dimensional infrared spectroscopy experiments performed as a function of deuteroxide concentration are used to assign spectral signatures that arise from the OH(-) ion and its solvation shell. A spectral feature that decays on a ~110 fs time scale is assigned to the relaxation of transiently formed configurations wherein a proton is equally shared between a HOD molecule and an OD(-) ion. Over picosecond waiting times, features appear in 2D IR spectra that are indicative of the exchange of population between OH(-) ions and HOD molecules due to deuteron transfer. The construction of a spectral model that includes spectral relaxation, chemical exchange, and thermalization processes, and self consistently treats all of our data, allows us to qualitatively explain the results of our experiments and gives a lower bound of 3 ps for the deuteron transfer kinetics. PMID- 21314149 TI - Theoretical investigations on removal reactions of ethenol by H atom. AB - Ethenol is a recently identified combustion intermediate. However, its chemistry remains unclear. In present work, the removal reactions of ethenol by H atom are investigated. The geometries of all species involved in the reaction are optimized at B3LYP/6-311++G(d,p), and their single point energies are extrapolated to the infinite-basis-set limit at the level CCSD(T). Energies are also calculated at G3B3, CBS-APNO, and CCSD(T)/6-311++G(3df, 2p) for comparison. A total of six elementary reactions, including four abstractions and two additions, with explicit transition states are investigated. The results show that the reactions are selective: for abstractions, the hydrogen atom, linked to the oxygen atom, is the most reactive; while for additions, the preferred carbon site is the head "CH(2)?". The rate constants are estimated in the temperature range 300-3000 K according to the conventional transition state theory with the Eckart tunneling model. The dominant channels are the two additions in the whole temperature range. The abstractions can be competitive at high temperature but still do not dominate. The calculated rate constants for the reverse reaction of (R6), syn-CH(2)?CHOH + H <-> CH(3).CHOH, are consistent with the available literature values. Finally, the Fukui functions are calculated to analyze the site reactivity. PMID- 21314150 TI - Effect of temperature on the surface tension of 1-hexanol aqueous solutions. AB - This paper describes the effect of temperature on the surface tension and adsorption kinetics of 1-hexanol aqueous solutions. The experiments were performed in a closed chamber where both liquid and vapor phases coexisted, and the surface tension was influenced by a combination of liquid and vapor phase adsorption. The surface tension of 1-hexanol aqueous solutions at steady-state was found to decrease upon an increase in temperature, and a linear relationship was observed between them. The modified Langmuir equation of state and the modified kinetic transfer equation were used to model the experimental data of the steady-state and dynamic (time-dependent) surface tension, respectively. The equilibrium constants and adsorption rate constants were evaluated through nonlinear regression for temperatures ranging from 10 to 35 degrees C. From the steady-state modeling, the equilibrium constants for adsorption from vapor phase and liquid phase were found to increase with temperature. From the dynamic modeling, the adsorption rate constants for adsorption from vapor phase and liquid phase were found to increase with temperature too. Small deviations from the experimental data have been observed in the dynamic modeling. These deviations may be due to the experimental errors or more likely the limitations of the model used. PMID- 21314151 TI - Photoacid generating ligands for development of positive-tone directly photopatternable metal complexes. AB - Photoacid generating ligands, 4-(2-nitrobenzy-loxycarbonyl)catechol and 4-(6 nitroveratryloxycarbonyl)catechol, and indium tin and titanium complexes thereof, were synthesized. These metal complexes perform as positive-tone, directly photopatternable indium tin oxide (ITO) or titanium oxide film precursors. After exposure, acid-bearing selectively soluble complexes could be removed to give patterned films upon developing in aqueous base, which were transformable to the corresponding pattern-preserving metal oxide film. Micropatterning of ITO and titanium oxide films was accomplished with the photoreactivity of the 2 nitrobenzyloxycarbonyl (NBOC) and 6-nitroveratryloxycarbonyl (NVOC) moiety bearing ligands. PMID- 21314152 TI - Surfactant concentration regime in miniemulsion polymerization for the formation of MMA nanodroplets by high-pressure homogenization. AB - This article focuses on the adequate surfactant concentration regime in which MMA droplets are stabilized sufficiently against coalescence during high-pressure homogenization but still no diffusion processes from droplets to micelles take place in the polymerization. Monomer miniemulsions with different surfactant concentrations were prepared with different energy inputs. Emulsions result that depend either on the surfactant concentration or on the energy input of the homogenization process. For both cases, the occupancy of the interface is compared as a function of the droplet size. It is shown that the surfactant concentration needed for the stabilization of a specified interface area decreases with increasing droplet size. For the dependence of droplet size on the energy input, it is shown that more surfactant can be applied before emulsion polymerization starts, but the applicable surfactant concentration is lower than the cmc and also depends on droplet size. PMID- 21314153 TI - Switching atomic friction by electrochemical oxidation. AB - Friction between the sliding tip of an atomic force microscope and a gold surface changes dramatically upon electrochemical oxidation of the gold surface. Atomic scale variations of the lateral force reveal details of the friction mechanisms. Stick-slip motion with atomic periodicity on perfect Au(111) terraces exhibits extremely low friction and almost no dependence on load. Significant friction is observed only above a load threshold at which wear of the surface is initiated. In contrast, irregular stick-slip motion and a linear increase of friction with load are observed on electrochemically oxidized surfaces. The observations are discussed with reference to the amorphous structure of the oxo-hydroxide surface and atomic place exchange mechanisms upon oxidation. Reversible, fast switching between the two states of friction has been achieved in both perchloric and sulfuric acid solutions. PMID- 21314154 TI - Controlling inplane orientation of a monolayer colloidal crystal by meniscus pinning. AB - We demonstrate the usage of meniscus pinning by surface relief boundaries to control in-plane orientation of monolayer colloidal crystals without the interruption of grain disorientation. By optimizing the pinning boundary and withdrawal speed, a well controlled linear meniscus contact line offers unidirectional growth of a colloidal crystal-densely packed crystal direction ?11? and ?10? parallel to linear edge-giving rise to a single domain crystal with only twins and vacancies present as residual defects. The pinning effect works by eliminating the wavy contact line induced by fingering instability which is commonly found in liquid wetting film. It is found that surfactants and colloidal particles play significant roles to enhance edge pinning, increasing the distance traveled by receding bulk meniscus (during substrate withdrawal) before liquid depinning or rupturing. PMID- 21314155 TI - Mulberry leaf polyphenols possess antiatherogenesis effect via inhibiting LDL oxidation and foam cell formation. AB - Oxidized low-density lipoprotein (ox-LDL) and its uptake by machrophage are the hallmark in atherogenesis. In the present study, we aimed to investigate the antiatherogenic effect of mulberry leaf extracts (MLE) and the polyphenolic extracts (MLPE), which contained polyphenols including quercetin (11.70%), naringenin (9.01%) and gallocatechin gallate (10.02%). Both MLE and MLPE inhibited the oxidation and lipid peroxidation of LDL, while MLPE was shown to be more potent. As 1.0 mg/mL MLE reduced 30% of ox-LDL-generated ROS, 0.5 mg/mL MLPE decreased 46% of the ROS and was shown to be more potent on elevating SOD-1 and GPx in macrophages. At the same dose of 0.5 mg/mL, MLPE exhibited 1.5-fold potency than MLE in decreasing the formation of foam cells. Both MLE and MLPE reduced the expression of PPARgamma, CD36 and SR-A, implicating the molecular regulation on ox-LDL uptake. These results suggested that MLPE potentially could be developed as an antiatherogenic agent and deserve further investigation. PMID- 21314156 TI - Monolayer collapse regulating process of adsorption-desorption of palladium nanoparticles at fatty acid monolayers at the air-water interface. AB - In this paper, we investigate the affinity of palladium nanoparticles, stabilized with glucose oxidase, for fatty acid monolayers at the air-water interface, exploiting the interaction between a planar system and spheroids coming from the aqueous subphase. A decrease of the monolayer collapse pressure in the second cycle of interface compression proved that the presence of the nanoparticles causes destabilization of the monolayer in a mechanism driven by the interpenetration of the enzyme into the bilayer/multilayer structure formed during collapse, which is not immediately reversible after monolayer expansion. Surface pressure and surface potential-area isotherms, as well as infrared spectroscopy [polarization modulation infrared reflection adsorption spectroscopy (PM-IRRAS)] and deposition onto solid plates as Langmuir-Blodgett (LB) films, were employed to construct a model in which the nanoparticle has a high affinity for the hydrophobic core of the structure formed after collapse, which provides a slow desorption rate from the interface after monolayer decompression. This may have important consequences on the interaction between the metallic particles and fatty acid monolayers, which implies the regulation of the multifunctional properties of the hybrid material. PMID- 21314157 TI - Dual fluorescence and ultrafast intramolecular charge transfer with 6-N,N dialkylaminopurines. A two-state model. AB - 6-N,N-Dimethyl-9-methyladenine (DMPURM) and 6-N,N-dimethyladenine (DMPURH) show dual fluorescence from a locally excited (LE) and an intramolecular charge transfer (ICT) state in solvents of different polarity over extended temperature ranges. The fluorescence quantum yields are very small, in particular those of LE. For DMPURM in acetonitrile (MeCN) at 25 degrees C, for example, Phi'(ICT) = 3.2 * 10(-3) and Phi(LE) = 1.6 * 10(-4). The large value of Phi'(ICT)/Phi(LE) indicates that the forward LE -> ICT reaction is much faster than the back reaction. The data obtained for the intersystem crossing yield Phi(ISC) show that internal conversion (IC) is the dominant deactivation channel from LE directly to the ground state S(0). For DMPURM in MeCN with Phi(ISC) = 0.22, Phi(IC) = 1 - Phi(ISC) - Phi'(ICT) - Phi(LE) = 0.78, whereas in cyclohexane an even larger Phi(IC) of 0.97 is found. The dipole moment gradually increases upon excitation, from 2.5 D (S(0)), via 6 D (LE) to 9 D (ICT) for DMPURM and from 2.3 D (S(0)), via 7 D (LE) to 8 D (ICT) for DMPURH. From the temperature dependence of Phi'(ICT)/Phi(LE), a reaction enthalpy -DeltaH of 11 kJ/mol is obtained for DMPURM in n-hexane (epsilon(25) = 1.88), increasing to 17 kJ/mol in the more polar solvent di-n-butyl ether (epsilon(25) = 3.05). With DMPURM in diethyl ether, an activation energy of 8.3 kJ/mol is determined for the LE -> ICT reaction (k(a)). The femtosecond excited state absorption spectra at 22 degrees C undergo an ultrafast decay: 1.0 ps in CHX and 0.63 ps in MeCN for DMPURM, still shorter (0.46 ps) for DMPURH in MeCN. With DMPURM in n-hexane, the LE fluorescence decay time tau(2) increases upon cooling from 2.6 ps at -45 degrees C to 6.9 ps at -95 degrees C. The decay involves ICT and IC as the two main pathways: 1/tau(2) ? k(a) + k(IC). As a model compound (no ICT) is not available, its lifetime tau(0)(LE) ~ 1/k(IC) is not known, which prevents a separate determination of k(a). The excited state reactions of DMPURM and DMPURH are treated with a two-state model: S(0) -> LE ? ICT. With 6-N-methyl-9-methyladenine (MPURM) and 9-methyladenine (PURM), the fluorescence quantum yield is very low (<5 * 10(-5)) and dominated by impurities, due to enhanced IC from LE to S(0). PMID- 21314158 TI - Influence of nanoreactor environment and substrate location on the activity of horseradish peroxidase in olive oil based water-in-oil microemulsions. AB - Oxidative enzymatic reactions using horseradish peroxidase (HRP) were carried out in water-in-oil (w/o) microemulsions composed of olive oil/lecithin/1 propanol/water, a model biomimetic system. The substrates used (gallic acid, octyl gallate and 2,2'-azino-bis[3-ethylbenzo-thiazoline-6-sulfonic acid] (ABTS)) have different hydrophobicities and possible locations in the microemulsion system. HRP reactivity with reference to substrate hydrophobicity and structural characteristics of the microemulsions is discussed. The nature of the enzyme microenvironments was examined using dynamic light scattering (DLS), differential scanning calorimetry (DSC) and diffusion NMR (DOSY) methodologies while the location of various enzymatic substrates in the microemulsion phase was assessed by solubility measurements and by taking pressure-area isotherms of mixed monolayers of the substrates with dipalmitoyl-phosphatidylcholine (DPPC), which is a major constituent of lecithin. In contrast to the bulk aqueous phase, in the severely restricted environment of the polar domains of the microemulsion HRP reacted faster with octyl gallate, a substrate that is solubilized at the lipid interfaces. HRP was deactivated in the olive oil microemulsions within a few hours, a phenomenon that has also been observed in other microemulsion systems. PMID- 21314159 TI - Nanomechanical membrane-type surface stress sensor. AB - Nanomechanical cantilever sensors have been emerging as a key device for real time and label-free detection of various analytes ranging from gaseous to biological molecules. The major sensing principle is based on the analyte-induced surface stress, which makes a cantilever bend. In this letter, we present a membrane-type surface stress sensor (MSS), which is based on the piezoresistive read-out integrated in the sensor chip. The MSS is not a simple "cantilever," rather it consists of an "adsorbate membrane" suspended by four piezoresistive "sensing beams," composing a full Wheatstone bridge. The whole analyte-induced isotropic surface stress on the membrane is efficiently transduced to the piezoresistive beams as an amplified uniaxial stress. Evaluation of a prototype MSS used in the present experiments demonstrates a high sensitivity which is comparable with that of optical methods and a factor of more than 20 higher than that obtained with a standard piezoresistive cantilever. The finite element analyses indicate that changing dimensions of the membrane and beams can substantially increase the sensitivity further. Given the various conveniences and advantages of the integrated piezoresistive read-out, this platform is expected to open a new era of surface stress-based sensing. PMID- 21314160 TI - Substituent effects on the properties related to detonation performance and sensitivity for 2,2',4,4',6,6'-hexanitroazobenzene derivatives. AB - To look for superior and safe high energy density compounds (HEDCs), 2,2',4,4',6,6'-hexanitroazobenzene (HNAB) and its -NO(2), -NH(2), -CN, -NC, ONO(2), -N(3), or -NF(2) derivatives were studied at the B3LYP/6-31G* level of density functional theory (DFT). The isodesmic reactions were applied to calculate the heats of formation (HOFs) for these compounds. The theoretical molecular density (rho), detonation energy (E(d)), detonation pressure (P), and detonation velocity (D), estimated using the Kamlet-Jacobs equations, showed that the detonation properties of these compounds were excellent. The effects of substituent groups on HOF, rho, E(d), P, and D were studied. The order of contribution of the substituent groups to P and D was -NF(2) > -ONO(2) > -NO(2) > -N(3) > -NH(2). Sensitivity was evaluated using the nitro group charges, frontier orbital energies, and bond dissociation enthalpies (BDEs). The trigger bonds in the pyrolysis process for all these HNAB derivatives may be Ring-NO(2), Ring-N?N, Ring-NF(2), or O-NO(2) varying with the attachment of different substituents. BDEs of trigger bonds except those of -ONO(2) derivatives are relatively large, which means these compounds suffice the stability request of explosives. Taking both detonation properties and sensitivities into consideration, some -NF(2) and NO(2) derivatives may be potential candidates for HEDCs. PMID- 21314161 TI - Synthesis of robust raspberry-like particles using polymer brushes. AB - Synthesis of chemically and mechanically robust raspberry-like particles as well as wetting properties of coatings based on them is reported. The raspberry-like particles were prepared by immobilization of silica nanoparticles on the surface of silica microparticles coated by poly(glycidyl methacrylate) brush layer. The raspberry-like particles retain their structure after ultrasonication and exposure to organic solvents that allows their use as substrates for immobilization on polymers. Fabrication ultrahydrophobic surfaces using raspberry like particles with immobilized poly(pentafluorostyrene) was also demonstrated. PMID- 21314162 TI - Optimization of band structure and quantum-size-effect tuning for two-photon absorption enhancement in quantum dots. AB - The two-photon absorption, 2PA, cross sections of PbS quantum dots, QDs, are theoretically and experimentally investigated and are shown to be enhanced with increasing quantum confinement. This is in contrast to our previous results for CdSe and CdTe QDs where the reduced density of states dominated and resulted in a decrease in 2PA with a decrease in QD size. Qualitatively this trend can be understood by the highly symmetric distribution of conduction and valence band states in PbS that results in an accumulation of allowed 2PA transitions in certain spectral regions. We also measure the frequency nondegenerate 2PA cross sections that are up to five times larger than for the degenerate case. We use a k.p four-band envelope function formalism to model the increasing trend of the two-photon cross sections due to quantum confinement and also due to resonance enhancement in the nondegenerate case. PMID- 21314163 TI - Responsive polymer-coated mesoporous silica as a pH-sensitive nanocarrier for controlled release. AB - pH-responsive polymer poly(4-vinyl pyridine) is coated on mesoporous silica through the facile "grafting to" method. The grafted polymer nanoshell can work as a pH-sensitive barrier to control the release of trapped molecules from mesoporous silica. PMID- 21314164 TI - Influence of polymeric residue on the thermal conductivity of suspended bilayer graphene. AB - The thermal conductivity (kappa) of two bilayer graphene samples each suspended between two microresistance thermometers was measured to be 620 +/- 80 and 560 +/ 70 W m(-1) K(-1) at room temperature and exhibits a kappa ? T(1.5) behavior at temperatures (T) between 50 and 125 K. The lower kappa than that calculated for suspended graphene along with the temperature dependence is attributed to scattering of phonons in the bilayer graphene by a residual polymeric layer that was clearly observed by transmission electron microscopy. PMID- 21314165 TI - Comprehensive study of alkaloids from Crinum asiaticum var. sinicum assisted by HPLC-DAD-SPE-NMR. AB - A comprehensive study of the alkaloids presentin the leaves of Crinum asiaticum var. sinicum, assisted by HPLC-SPE-NMR, led to the characterization of 21 compounds of similar polarity on an analytical scale. Thirteen of these were isolated for further structural confirmation. Seven are proved to be new, namely, (+)-siculine (4), 1-epijosephinine (11), 7-methoxycrinamabine (10), 2-O acetylcrinamabine (16), 3-O-acetyl-8-O-demethylmaritidine (17), 2-O acetylbulbisine (18), and 1-O-acetylbulbisine (19). In addition, dihydrovittatine (6) and 8-O-demethyloxomaritidine (21) were isolated for the first time from Nature, although they have been prepared previously as synthetic products. Their structures were established by spectroscopic analysis. PMID- 21314166 TI - A facile in situ hydrothermal method to SrTiO3/TiO2 nanofiber heterostructures with high photocatalytic activity. AB - Heterostructured SrTiO3/TiO2 nanofibers were fabricated by in situ hydrothermal method using TiO2 nanofibers as both template and reactant. The as-fabricated heterostructures composite included SrTiO3 nanocubes or nanoparticles assembled uniformly on the surface of TiO2 nanofibers. Compared with the pure TiO2 nanofibers, SrTiO3/TiO2 nanofibers exhibited enhanced photocatalytic activity in the decomposition of Rhodamine B (RB) under ultraviolet light. The enhanced photocatalytic activity of SrTiO3/TiO2 nanofibers could be attributed to the improvement of charge separation derived from the coupling effect of TiO2 and SrTiO3 nanocomposite. PMID- 21314167 TI - Hydroxyl-directed cyclizations of 1,6-enynes. AB - The palladium-catalyzed, hydroxyl-directed cyclization reactions of 1,6-enynes provide a highly diastereoselective process for the syntheses of stereochemically defined cyclopentanes. Consistently high levels of cis-selectivity are possible using homopropargyl alcohols in contrast to the corresponding propargyl alcohols. Hydroborylative enyne cyclizations coupled with this directing group effect provide a useful method for the syntheses of multifaceted compounds bearing all carbon quaternary centers. PMID- 21314168 TI - Adsorption of R-OH molecules on TiO2 surfaces at the solid-liquid interface. AB - The exploration of TiO2 surface reactivity from first-principles calculations has been almost always limited to the gas phase, even though most of the chemically relevant applications of this interface involve the solid-liquid boundary. The reason for this limitation is the complexity of the solid-liquid interface, which poses a serious challenge to standard ab initio methodologies as density functional theory (DFT). In this work we study the interaction of H2O, CH3OH, H2O2, and HCO2H with anatase (101) and rutile (110) surfaces in aqueous solution, employing a continuum solvation model in a DFT framework in periodic boundary conditions [ J. Chem. Phys. 2009 , 131 , 174108 ]. Different adsorption configurations were analyzed, examining the effect of the first water monolayer explicitly included in the simulation. For water and methanol, molecular adsorption was found to be the most stable in the presence of the solvent, while for hydrogen peroxide the preferred configuration depended on the surface. The explicit inclusion of the first water monolayer turns out to be important since it may play a role in the stabilization of the adsorbates at the interface. In general, the slightly positive adsorption energy values obtained (with respect to water) suggest that CH3OH and H2O2 will poorly adsorb from an aqueous solution at the titania surface. Among the three species investigated other than water, the formic acid was the only one to exhibit a higher affinity for the surface than H2O. PMID- 21314169 TI - Importance of the indium tin oxide substrate on the quality of self-assembled monolayers formed from organophosphonic acids. AB - The role of indium tin oxide (ITO) surface structure and chemistry on the formation of self-assembled monolayers (SAM) derived from organophosphonic acids has been investigated. The surface hydroxide content, crystal structure, and roughness of unmodified ITO surfaces were analyzed with X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), atomic force microscopy (AFM), and contact angle measurements. Organophosphonic acid monolayer modified ITO surfaces were then characterized using electrochemistry, contact angle measurements and impedance spectroscopy. To ascertain the extent of defects, Pb was underpotentially deposited (UPD) onto the monolayer modified ITO surfaces at defect sites and regions where the monolayer was weakly bound. The extent of defects, and the location of defects, in monolayers formed on different ITO surfaces were determined from the amount of charge passed during UPD of Pb at identical conditions, followed by XPS analysis of the Pb 4f peak and imaging with scanning tunnelling microscopy (STM). The results demonstrate that the crystal structure and hydroxide ion concentration of ITO surfaces significantly influence the quality of self-assembled monolayer formation as does the surface roughness. The most well-packed stable monolayers formed only on smooth amorphous ITO substrates with homogeneous grains and high hydroxide content. Lower quality SAMs with significant defects formed on polycrystalline surfaces and the higher the roughness the more the defects. STM defect mapping revealed that the location of defects in monolayers occurred at the boundaries between grain edges on the polycrystalline surfaces. This shows that the substrate characteristics have a strong influence on the quality of monolayers formed on ITO surfaces. PMID- 21314170 TI - Highly diastereo- and enantioselective aldol reaction of methyl alpha isocyanoacetate: a cooperative catalysis approach. AB - The cooperative catalyst activity between a chiral transition-metal catalyst and an achiral organocatalyst has been identified as one of the critical asymmetric reaction optimization components in the highly diastereo- and enantioselective aldol reaction of methyl alpha-isocyanoacetate. PMID- 21314171 TI - Chromonic liquid crystalline phases of pinacyanol acetate: characterization and use as templates for the preparation of mesoporous silica nanofibers. AB - We report on the self-aggregation of the cationic dye pinacyanol acetate and its use for the preparation of nanostructured silica via templated sol-gel reaction. The dye forms nematic and hexagonal chromonic liquid crystals at low concentrations in water (i.e., from 0.75 wt %); the type of counterion appears to play an important role in liquid crystal formation. From analysis of small X-ray scattering (SAXS) curves, it is inferred that dye aggregates have the morphology of hollow long tubes with one-molecule-thick walls; the diameter of the tubes does not to change much with concentration. The dye aggregates can be aligned by shear or by a magnetic field. The high-resolution (1)H NMR spectra show that aggregation takes place over a range of concentrations rather than having a sharp "critical" aggregation. Within the aggregates the conjugated moiety, including the three-carbon link, is in close proximity to the aromatic groups of stack neighbors. On the other hand, dye aggregates direct the formation of silica nanofibers synthesized via sol-gel reaction, mimicking the elongated structures found in aqueous media. The nanofibers show a hierarchical organization; i.e., they contain hexagonal arrays of 3 nm cylindrical mesopores left after calcination of the templating molecules, and the pore walls are 2.7 nm thick. As the nanofibers form entangled networks, the obtained materials also show interparticle porosity. The present findings open new possibilities for the use of commercial cationic dyes in the synthesis of nanostructured materials. PMID- 21314172 TI - Probing mesitylborane and mesitylborate ligation within the coordination sphere of Cp*Ru(P(i)Pr3)+: a combined synthetic, X-ray crystallographic, and computational study. AB - The reaction of Cp*Ru(P(i)Pr(3))Cl (1) with MesBH(2) (Mes = 2,4,6 trimethylphenyl) afforded the mesitylborate complex Cp*Ru(P(i)Pr(3))(BH(2)MesCl) (2, 66%). Exposure of 2 to the chloride abstracting agent LiB(C(6)F(5))(4).2.5OEt(2) provided [Cp*Ru(P(i)Pr(3))(BH(2)Mes)](+)B(C(6)F(5))(4)(-) (3, 54%), which features an unusual eta(2)-B-H monoborane ligand. The related borate complex Cp*Ru(P(i)Pr(3))(BH(3)Mes) (5, 65%) was prepared from 1 and LiH(3)BMes. Attempts to effect the insertion of unsaturated organic substrates into the B-H bonds of 3 were unsuccessful, and efforts to dehydrohalogenate 2 using KO(t)Bu instead afforded the mesitylborate complex Cp*(P(i)Pr(3))Ru(BH(2)MesOH) (6, 48%). Treatment of 1 with benzyl potassium generated an intermediate hydridoruthenium complex (7) resulting from dehydrogenation of a P(i)Pr fragment, which in turn was observed to react with MesBH(2) to afford the mesitylborate complex Cp*(P((i)Pr)(2)(CH(3)CCH(2)))Ru(BH(3)Mes) (8, 47%). Crystallographic characterization data are provided for 2, 3, 5, 6, and 8. A combined X-ray crystallographic and density functional theory (DFT) investigation of 3 and 5, using Natural Bond Orbital (NBO) and Atoms in Molecules (AIM) analysis, revealed that 3 and 5 are best described as donor-acceptor complexes between a Cp*(P(i)Pr(3))Ru(+) fragment and a bis(eta(2)-B-H) coordinating mesitylborane(borate) ligand. Significant sigma-donation from the B-H bonds into the Ru(II) center exists as evidenced by the NBO populations, bond orders, and AIM delocalization indices. In the case of 3, the vacant p orbital on boron is stabilized by Ru->B pi back-donation as well as by resonance with the mesityl group. PMID- 21314173 TI - Monolayer reactions of protected Au nanoclusters with monothiol tiopronin and 2,3 dithiol dimercaptopropanesulfonate. AB - The novel thiol bridging "staple motif RS-Au-SR" discovered at the Au-thiolate interface has tremendously advanced the structural understanding of monolayer protected Au clusters (AuMPCs). In this paper, multidentate dithiol ligands are introduced into the monolayer of the Au clusters. The impacts of dithiols on the Au-monothiolate interfacial bonding and related physical properties are explored. A correlation is established of the near-IR luminescence with Au-tiopronin monothiol interactions that are constrained by the dithiol molecule structures. Two types of monolayer reaction are studied: (1) monothiol tiopronin AuMPCs with dithiol molecule 2,3-dimercaptopropanesulfonate (DMPS) and (2) DMPS Au dithiol clusters (AuDTCs) with tiopronin monothiol ligands. Upon the addition of excess DMPS molecules into tiopronin MPC solution, tiopronin molecules are efficiently liberated from the original AuMPCs monitored by proton NMR. The process is accompanied by the decrease of near-infrared luminescence of the tiopronin AuMPCs. A slower enhancement of the 282 nm absorption band is observed, a signature of DMPS Au4DTCs characterized by mass spectrometry. The analysis of the reaction kinetics reveals a two-step mechanism: a facile ligand replacement followed by a sluggish core etching process. The reverse approach, tiopronin molecules reacting with DMPS DTCs, results in the addition of tiopronin into DMPS monolayer instead of ligand exchange. Near-IR luminescence intensifies with the monolayer addition of tiopronin. PMID- 21314174 TI - Processes controlling the diameter distribution of single-walled carbon nanotubes during catalytic chemical vapor deposition. AB - Single-walled carbon nanotubes are grown by catalytic chemical vapor deposition in various conditions of temperature and carbon precursor pressure. Systematic analyses of the Raman radial breathing modes at two laser wavelengths are used to monitor the evolution of the diameter distribution. Two distinct domains with opposite influences of the temperature and the precursor pressure on the diameter distribution are evidenced. Thanks to specially designed experiments made of two successive growths, three processes are identified to influence the diameter distribution during the nanotube growth: (i) at too low precursor pressure, nanotube nucleation cannot occur on the smallest catalyst particles; (ii) at low temperature and high precursor pressure, small catalyst particles are preferably encapsulated by disordered carbon structures; (iii) at high temperature, catalyst coarsening causes the disappearance of the smallest catalyst particles. PMID- 21314175 TI - 17-Hydroxycyclooctatin, a fused 5-8-5 ring diterpene, from Streptomyces sp. MTE4a. AB - A new diterpene with a fused 5-8-5 ring system was isolated from the fermentation broth of a soil actinomycete. The stereochemistry at C-15 was determined in an unusual manner using a decomposition product. PMID- 21314176 TI - Organization of inorganic nanomaterials via programmable DNA self-assembly and peptide molecular recognition. AB - An interesting alternative to top-down nanofabrication is to imitate biology, where nanoscale materials frequently integrate organic molecules for self assembly and molecular recognition with ordered, inorganic minerals to achieve mechanical, sensory, or other advantageous functions. Using biological systems as inspiration, researchers have sought to mimic the nanoscale composite materials produced in nature. Here, we describe a combination of self-assembly, molecular recognition, and templating, relying on an oligonucleotide covalently conjugated to a high-affinity gold-binding peptide. After integration of the peptide-coupled DNA into a self-assembling superstructure, the templated peptides recognize and bind gold nanoparticles. In addition to providing new ways of building functional multinanoparticle systems, this work provides experimental proof that a single peptide molecule is sufficient for immobilization of a nanoparticle. This molecular construction strategy, combining DNA assembly and peptide recognition, can be thought of as programmable, granular, artificial biomineralization. We also describe the important observation that the addition of 1-2% Tween 20 surfactant to the solution during gold particle binding allows the gold nanoparticles to remain soluble within the magnesium-containing DNA assembly buffer under conditions that usually lead to the aggregation and precipitation of the nanoparticles. PMID- 21314177 TI - DNA-gold nanoparticle reversible networks grown on cell surface marker sites: application in diagnostics. AB - Effective identification of breast cancer stem cells (CSC) benefits from a multiplexed approach to detect cell surface markers that can distinguish this subpopulation, which can invade and proliferate at sites of metastasis. We present a new approach for dual-mode sensing based on targeting using pointer and signal enhancement using enhancer particle networks for detection by surface plasmon resonance (SPR) and surface-enhanced Raman scattering (SERS). We demonstrate our concept to detect cell surface markers, CD44 and CD24, in three breast cancer cell lines to identify a CD44+/CD24- subpopulation of CSCs. The designed network structure can be well-controlled and has improved sensitivity compared to conventional approaches with ability to detect a single target on the membrane of a living cell. We have also developed a fractal approach to model the dimension of the network structure and developed an empirical relationship to estimate the number of particles in the network and its size. The empirical equation was validated with experiments and finite-difference time-domain simulations, and the cell phenotyping results were found to be in good agreement with published data from conventional sorting by flow cytometry. PMID- 21314178 TI - Efficient quantum dot-quantum dot and quantum dot-dye energy transfer in biotemplated assemblies. AB - CdSe semiconductor nanocrystal quantum dots are assembled into nanowire-like arrays employing microtubule fibers as nanoscale molecular "scaffolds." Spectrally and time-resolved energy-transfer analysis is used to assess the assembly of the nanoparticles into the hybrid inorganic biomolecular structure. Specifically, we demonstrate that a comprehensive study of energy transfer between quantum dot pairs on the biotemplate and, alternatively, between quantum dots and molecular dyes embedded in the microtubule scaffold comprises a powerful spectroscopic tool for evaluating the assembly process. In addition to revealing the extent to which assembly has occurred, the approach allows determination of particle-to-particle (and particle-to-dye) distances within the biomediated array. Significantly, the characterization is realized in situ, without need for further sample workup or risk of disturbing the solution-phase constructs. Furthermore, we find that the assemblies prepared in this way exhibit efficient quantum dot-quantum dot and quantum dot-dye energy transfer that affords faster energy-transfer rates compared to densely packed quantum dot arrays on planar substrates and to small-molecule-mediated quantum dot-dye couples, respectively. PMID- 21314179 TI - Internal and external validation strategies for the evaluation of long-term effects in NIR calibration models. AB - Some of the practical aspects of long-term calibration-set building are presented in this study. A calibration model able to predict the Kolbach index for brewing malt is defined, and four different validations and resampling schemes were applied to determine its real predictive power. The results obtained demonstrated that one single performance criterion might be not sufficient and can lead to over- or underestimation of the model quality. Comparing a simple leave-one sample-out cross-validation (CV) with two more challenging CVs with leave-N samples-out, where the resamplings were repeated 200 times, it is demonstrated that the error of prediction value has an uncertainty, and these values change according to the type and the number of validation samples. Then, two kinds of test-set validations were applied, using data blocks based on the sample collection's year, demonstrating that it is necessary to consider long-term effects on NIR calibrations and to be conservative in the number of factors selected. The conclusion is that one should be modest in reporting the prediction error because it changes according to the type of validation used to estimate it and it is necessary to consider the long-term effects. PMID- 21314181 TI - Ionothermal synthesis and magnetic studies of novel two-dimensional metal-formate frameworks. AB - Five novel two-dimensional frameworks containing formate-bridged metal-centered octahedra are synthesized ionothermally from two ionic liquids previously unused as solvents in hybrid synthesis, 2-hydroxyethylammonium (HEA) formate, and 1 hydroxy-3-proplyammonium (HPA) formate. Templating effects of the cation from each ionic liquid drive the formation of different structures. [NH(3)C(2)H(4)OH](2)[M(CHO(2))(4)] (1: M = Co, 2: M = Ni) exhibit the same stoichiometry and connectivity as their manganese analogue (3: M = Mn), but the manganese form exhibits a different topology from 1 and 2. [NH(3)C(3)H(6)OH][M(CHO(2))(3)(H(2)O)] (4: M = Co, 5: M = Mn) were synthesized using the HPA formate ionic liquid with a metal-formate connectivity related to those of 1-3. Canted antiferromagnetic ordering occurs at low temperatures (1: T(N) = 7.0 K, 2: T(N) = 4.6 K, 3: T(N) = 8.0 K, 4: T(N) = 7.0 K, 5: T(N) = 9.2 K), similar to the magnetic properties previously reported for other metal formate hybrid materials. PMID- 21314180 TI - Elucidation of the enantioselective enzymatic hydrolysis of chiral herbicide dichlorprop methyl by chemical modification. AB - Up to 25% of the current pesticides are chiral, the molecules have chiral centers, but most of them are used as racemates. In most cases, enantiomers of chiral pesticides have different fates in the environment. Knowledge of the function of amino acids of enzymes involved in enantioselective behaviors contributes to the understanding of the enantioselectivity of chiral pesticides. In this work, Aspergillus niger lipase (ANL, EC3.1.1.3) was chemically modified using bromoacetic acid (BrAc), 2,3-butanedione (BD), N-bromosuccinimide (NBS), and methanal. The enantioselectivity of the enzymatic hydrolysis of 2,4 dichlorprop-methyl (DCPPM) was investigated by chiral GC. The results have suggested that histidine, arginine, and tryptophan are essential for lipase activity and might be involved in the catalytic site of ANL. In addition, histidine and lysine play an important role in determining the observed enantioselective hydrolysis of chiral herbicide dichlorprop methyl. The molecular modeling study revealed that the essential hydrogen bonds formed between DCPPM and catalytic residues of ANL might be responsible for the enantioselectivity of DCPPM. The loss of enantioselectivity can also arise from the fact that the modification of the amino acids may cause changes in both the nature of the ANL enzyme conformation and the binding pattern of DCPPM. Our study provides basic information for the exploration of the enantioselective interaction mechanism of enzymes with chiral pesticides. PMID- 21314182 TI - Gold-catalyzed nucleophilic cyclization of functionalized allenes: a powerful access to carbo- and heterocycles. PMID- 21314183 TI - Controlling volume shrinkage in soft lithography through heat-induced cross linking of patterned nanofibers. AB - When poly(isopropylidene diallylmalonate) rich in threo-disyndiotactic sequences (st(rich)-2) was utilized as a cross-linkable ink for microcontact printing, the resultant submicrometer-scale patterns featuring 700 and 300 nm wide stripes were successfully insolubilized while maintaining their high dimensional integrity by heat-induced cross-linking with elimination of CO(2) and acetone. In sharp contrast, although the thermal properties and reactivities of a polymer rich in threo-diisotactic sequences (it(rich)-2) and a polymer having low stereoregularity (2(low)) are little different from those of st(rich)-2, the patterns printed with these reference polymers collapsed considerably upon heating as a result of a volume shrinkage effect. The striking difference between st(rich)-2 and the other two polymers most likely arises from the nanofiber forming character of st(rich)-2, where the printed stripes are porous and much less affected by the volume shrinkage of individual nanofibers. PMID- 21314184 TI - Protease-sensitive, polymer-caged liposomes: a method for making highly targeted liposomes using triggered release. AB - Liposomes have become useful and well-known drug delivery vehicles because of their ability to entrap drugs without chemically modifying them and to deliver them somewhat selectively to tumorous tissue via the enhanced permeation and retention (EPR) effect. Although useful, liposome preparations are still less than ideal because of imperfect specificity, slow release kinetics in the tumor, and leakiness prior to reaching the tumor site. Cancer-associated proteases (CAPs), which are differentially expressed in tumors, have also gained traction recently as a method for tumor targeting and drug delivery. By combining the EPR effect with CAPs sensitivity, a much more specific liposome can be produced. The method described here creates an improved liposome system that can target more specifically, with faster release kinetics and lower general leaking, by deliberately producing a very unstable liposome (loaded with hyperosmotic vehicle) that is subsequently stabilized by a cross-linked polymer shell containing consensus sequences for cancer-associated proteases (protease triggered, caged liposomes). A cholesterol-anchored, graft copolymer, composed of a short peptide sequence for urokinase plasminogen activator (uPA) and poly(acrylic acid), was synthesized and incorporated into liposomes prepared at high osmolarities. Upon cross-linking of the polymers, the protease-triggered, caged liposomes showed significant resistance to osmotic swelling and leaking of contents. Protease-triggered, caged liposomes also showed significant and substantial differential release of contents in the presence of uPA, while bare liposomes showed no differential effect in the presence of uPA. Thus a protease sensitive liposome system with fast release kinetics was developed that could be used for more specific targeting to tumors. PMID- 21314185 TI - Mimicking the role of the antenna in photosynthetic photoprotection. AB - One mechanism used by plants to protect against damage from excess sunlight is called nonphotochemical quenching (NPQ). Triggered by low pH in the thylakoid lumen, NPQ leads to conversion of excess excitation energy in the antenna system to heat before it can initiate production of harmful chemical species by photosynthetic reaction centers. Here we report a synthetic hexad molecule that functionally mimics the role of the antenna in NPQ. When the hexad is dissolved in an organic solvent, five zinc porphyrin antenna moieties absorb light, exchange excitation energy, and ultimately decay by normal photophysical processes. Their excited-state lifetimes are long enough to permit harvesting of the excitation energy for photoinduced charge separation or other work. However, when acid is added, a pH-sensitive dye moiety is converted to a form that rapidly quenches the first excited singlet states of all five porphyrins, converting the excitation energy to heat and rendering the porphyrins kinetically incompetent to readily perform useful photochemistry. PMID- 21314186 TI - Biomimetic total syntheses of flinderoles B and C. AB - A simple and efficient biomimetic synthesis of pyrrolo[1,2-a]indoles using a highly stereo- and regioselective [3 + 2] reaction cascade was developed and then further applied in the first total synthesis of flinderoles B and C, which proceeded in 17.2% yield over the longest linear sequence of 11 steps. PMID- 21314188 TI - CO dissociation mechanism in racemization of alcohols by a cyclopentadienyl ruthenium dicarbonyl catalyst. AB - (13)CO exchange studies of racemization catalyst (eta(5)-Ph(5)C(5))Ru(CO)(2)Cl and (eta(5)-Ph(5)C(5))Ru(CO)(2)(Ot-Bu) by (13)C NMR spectroscopy are reported. CO exchange for the active catalyst form, (eta(5)-Ph(5)C(5))Ru(CO)(2)(Ot-Bu) is approximately 20 times faster than that for the precatalyst (eta(5) Ph(5)C(5))Ru(CO)(2)Cl. An inhibition on the rate of racemization of (S)-1 phenylethanol was observed on addition of CO. These results support the hypothesis that CO dissociation is a key step in the racemization of sec-alcohols by (eta(5)-Ph(5)C(5))Ru(CO)(2)Cl, as also predicted by DFT calculations. PMID- 21314187 TI - Adduction of cholesterol 5,6-secosterol aldehyde to membrane-bound myelin basic protein exposes an immunodominant epitope. AB - Myelin degradation in the central nervous system (CNS) is a clinical hallmark of multiple sclerosis (MS). A reduction in the net positive charge of myelin basic protein (MBP) via deimination of arginine to citrulline has been shown to correlate strongly with disease severity and has been linked to myelin instability and a defect that precedes neurodegeneration and leads to autoimmune attack. Recently, we have shown that lipid-derived aldehydes, such as cholesterol 5,6-secosterols atheronal A (1a) and atheronal B (1b), modulate the misfolding of certain proteins such as apolipoprotein B(100), beta-amyloid, alpha-synuclein, and kappa- and lambda-antibody light chains in a process involving adduction of the hydrophobic aldehyde to lysine side chains, resulting in a decrease in the net positive charge of the protein. In this study, we show that the presence of either atheronal A (1a) or atheronal B (1b) in large unilamellar vesicles (cyt LUVs) with the lipid composition found in the cytosolic myelin sheath and bovine MBP (bMBP) leads to an atheronal concentration-dependent increase in the surface exposure of the immunodominant epitope (V86-T98) as determined by antibody binding. Other structural changes in bMBP were also observed; specifically, 1a and 1b induce a decrease in the surface exposure of L36-P50 relative to control cyt-LUVs as measured both by antibody binding and by a reduction in the level of cathepsin D proteolysis of F42 and F43. Structure-activity relationship studies with analogues of 1a and 1b point to the aldehyde moiety of both compounds being critical to their effects on bMBP structure. The atheronals also cause a reduction in the size of the bMBP-cyt-LUV aggregates, as determined by fluorescence microscopy and dynamic light scattering. These results suggest that formation of an imine between inflammatory-derived aldehydes, which effectively reduces the cationic nature of MBP, can lead to structural changes in MBP and a decrease in myelin stability akin to deimination and as such may make a hitherto unknown contribution to the onset and progression of MS. PMID- 21314189 TI - BMHP1-derived self-assembling peptides: hierarchically assembled structures with self-healing propensity and potential for tissue engineering applications. AB - Self-assembling peptides (SAPs) are rapidly gaining interest as bioinspired scaffolds for cell culture and regenerative medicine applications. Bone Marrow Homing Peptide 1 (BMHP1) functional motif (PFSSTKT) was previously demonstrated to stimulate neural stem cell (NSC) viability and differentiation when linked to SAPs. We here describe a novel ensemble of SAPs, developed from the BMHP1 (BMHP1 SAPs), that spontaneously assemble into tabular fibers, twisted ribbons, tubes and hierarchical self-assembled sheets: organized structures in the nano- and microscale. Thirty-two sequences were designed and evaluated, including biotinylated and unbiotinylated sequences, as well as a hybrid peptide-peptoid sequence. Via X-ray diffraction (XRD), CD, and FTIR experiments we demonstrated that all of the BMHP1-SAPs share similarly organized secondary structures, that is, beta-sheets and beta-turns, despite their heterogeneous nanostructure morphology, scaffold stiffness, and effect over NSC differentiation and survival. Notably, we demonstrated the self-healing propensity of most of the tested BMHP1 SAPs, enlarging the set of potential applications of these novel SAPs. In in vitro cell culture experiments, we showed that some of these 10-mer peptides foster adhesion, differentiation, and proliferation of human NSCs. RGD functionalized and hybrid peptide-peptoid self-assembling sequences also opened the door to BMHP1-SAP functionalization with further bioactive motifs, essential to tailor new scaffolds for specific applications. In in vivo experiments we verified a negligible reaction of the host nervous tissue to the injected and assembled BMHP1-SAP. This work will pave the way to the development of novel SAP sequences that may be useful for material science and regenerative medicine applications. PMID- 21314190 TI - Stille polycondensation for synthesis of functional materials. PMID- 21314191 TI - Pentasubstituted ferrocene and dirhodium(II) tetracarboxylate as building blocks for discrete fullerene-like and extended supramolecular structures. AB - The synthesis of a penta(1-methylpyrazole)ferrocenyl phosphine oxide ligand (1) [Fe(C(5)(C(3)H(2)N(2)CH(3))(5))(C(5)H(4)PO(t-C(4)H(9))(2))] is reported together with its X-ray crystal structure. Its self-assembly behavior with a dirhodium(II) tetraoctanoate linker (2) [Rh(2)(O(2)CC(7)H(15))(4)] was investigated for construction of fullerene-like assemblies of composition [(ligand)(12)(linker)(30)]. Reaction between 1 and 2 in acetonitrile resulted in the formation of a light purple precipitate (3). Evidence for the ligand-to linker ratio of 1:2.5 expected for a fullerene-like structure [Fe(C(5)(C(3)H(2)N(2)CH(3))(5))(C(5)H(4)PO(t C(4)H(9))(2))](12)[Rh(2)(O(2)CC(7)H(15))(4)](30) was obtained from (1)H NMR and elemental analysis. IR and Raman studies confirmed the diaxially bound coordination environment of the dirhodium linker by comparing the stretching frequencies of the carboxylate group and the rhodium-rhodium bond with those in model compound (5), [Rh(2)(O(2)CC(7)H(15))(4)](C(3)H(3)N(2)CH(3))(2), the bis adduct of linker 2 with 1-methylpyrazole. X-ray powder diffraction and molecular modeling studies provide additional support for the formation of a spherical molecule topologically identical to fullerene with a diameter of approximately 38 A and a molecular formula of [(1)(12)(2)(30)]. Dissolution of 3 in tetrahydrofuran (THF) followed by layering with acetonitrile afforded purple crystals of [(1)(2)(2)](infinity) (6) [Fe(C(5)(C(3)H(2)N(2)CH(3))(5))(C(5)H(4)PO(t C(4)H(9))(2))][Rh(2)(O(2)CC(7)H(15))(4)](2) with a two-dimensional polymeric structure determined by X-ray crystallography. The dirhodium linkers link ferrocenyl units by coordination to the pyrazoles but only four of the five pyrazole moieties of the pentapyrazole ligand are coordinated. The ligand-to linker ratio of 1:2 in 6 was confirmed by (1)H NMR spectroscopy and elemental analysis, while results from IR and Raman are in agreement with the diaxially coordinated environment of the linker observed in the solid state. PMID- 21314192 TI - Photoswitching magnetic crossover in organic molecular systems. AB - We have theoretically designed efficient photomagnetic diradicals using both substituted and unsubstituted cyclophanediene (CPD) and dihydropyrenes (DHP) as spacers. Nitronyl nitroxide (NN), oxoverdazyl (o-VER), and tetrathiafulvalene (TTF) are chosen as monoradical centers. Molecular geometries have been optimized by the density functional method UB3LYP using the 6-311G(d,p) basis set. Final single point calculations have been done with the 6-311++G(d,p) basis. Absorption wavelengths have been estimated from time-dependent density functional treatment using restricted spin-polarized density functionals (RB3LYP) and 6-31G basis. Both the substituted and unsubstituted CPD species with mixed monoradical centers are found to be antiferromagnetically coupled. Diradicals with the same centers but with DHP coupler exhibit strong ferromagnetic coupling. Also, photoexcitations of the diradicals are generally red-shifted by only a few nanometers from those of the 15,16-dimethyl pyrenes. This indicates that on photoexcitation a consistent magnetic crossover from an antiferromagnetic to a ferromagnetic regime is possible. The accompanying change in magnetic exchange coupling constant DeltaJ is very large, varying from 445 to 1003 cm(-1). As far as organic molecular magnetism is concerned, this observation is entirely new and likely to be of technological significance. PMID- 21314194 TI - Determination of organic acids in tissues and exudates of maize, lupin, and chickpea by high-performance liquid chromatography-tandem mass spectrometry. AB - This article describes a fast and simple methodology for the extraction and determination of organic acids in tissues and root exudates of maize, lupin, and chickpea by LC/MS/MS. Its main advantage is that it does not require sample prepurification before HPLC analysis or sample derivatization to improve sensibility. The results obtained showed good precision and accuracy, a recovery close to 100%, and no significant matrix effect. Moreover, the sensibility of the method is in general better than that of previously described methodologies, with detection limits between 15 and 900 pg injected. PMID- 21314193 TI - Sugar-based enantiomeric and conformationally constrained pyrrolo[2,1-c][1,4] benzodiazepines as potential GABAA ligands. AB - Synthesis of a library of pyrrolo[2,1-c][1,4]-benzodiazepines derived from spiro bicyclic D- or L-proline analogues containing a D- or L-fructose moiety was developed. The L-fructose moiety was obtained by using a new synthetic pathway starting from L-arabinose through a six steps synthesis in 18% overall yield. Molecular modeling calculations and DNMR studies showed that D- and L-fructose based pyrrolobenzodiazepines exhibit a rigid (P)- and (M)-helical conformation, respectively, in which the C-11a substituent was always pseudoequatorial. Additionally, pyrrolobenzodiazepines functionalized with a chloride, bromide, nitro, or amino group in the benzene ring, with or without N-methylation and with or without protection of sugar alcohol groups, allowed a relationship between the molecular structure and biological activity to be established. The conformation of the diazepam ring was not the sole key player influencing binding affinities, and the sugar moiety can in some cases increase the binding activity, possibly by participating in the binding event. Finally, these compounds have increased the understanding of the differential recognition of (M)-/(P)-helical benzodiazepines on GABA(A) receptor. PMID- 21314195 TI - Molecular classification of barley (Hordeum vulgare L.) mutants using derivative NIR spectroscopy. AB - Near-infrared reflectance (NIR) spectroscopy was used in the characterization of grain morphology mutants of barley ( Hordeum vulgare L.) in relation to grain nitrogen (N) content and protein composition. Derivative spectroscopy provided spectra with enhanced resolution, allowing wavelengths to be identified with clear differences in contribution from associated chemical bonds. Comparisons of fourth-derivative spectra of wholemeal flour from high-N grains with flour from low-N grains identified wavelengths at which there were statistically significant differences between the groups. Their importance was independently confirmed by step-up regression using these wavelengths to generate an equation predicting N content (R(2) = 0.98). Fourth-derivative spectral comparisons also allowed novel biochemical differences to be predicted. Visual assessment of the spectra of all mutants revealed a variable region (1470-1520 nm, corresponding to N-H stretch vibrations) that allowed two extreme sets to be defined. The protein extracted from these two sets differed markedly in hordein content. PMID- 21314196 TI - Quantitative 23Na magnetic resonance imaging of model foods. AB - Partial (23)Na MRI invisibility in muscle foods is often referred to as an inherent drawback of the MRI technique, impairing quantitative sodium analysis. Several model samples were designed to simulate muscle foods with a broad variation in protein, fat, moisture, and salt content. (23)Na spin-echo MRI and a recently developed (23)Na SPRITE MRI approach were compared for quantitative sodium imaging, demonstrating the possibility of accurate quantitative (23)Na MRI by the latter method. Good correlations with chemically determined standards were also obtained from bulk (23)Na free induction decay (FID) and CPMG relaxation experiments on the same sample set, indicating their potential use for rapid bulk NaCl measurements. Thus, the sodium MRI invisibility is a methodological problem that can easily be circumvented by using the SPRITE MRI technique. PMID- 21314197 TI - Enzyme production by wood-rot and soft-rot fungi cultivated on corn fiber followed by simultaneous saccharification and fermentation. AB - This research aims at developing a biorefinery platform to convert lignocellulosic corn fiber into fermentable sugars at a moderate temperature (37 degrees C) with minimal use of chemicals. White-rot (Phanerochaete chrysosporium), brown-rot (Gloeophyllum trabeum), and soft-rot (Trichoderma reesei) fungi were used for in situ enzyme production to hydrolyze cellulosic and hemicellulosic components of corn fiber into fermentable sugars. Solid-substrate fermentation of corn fiber by either white- or brown-rot fungi followed by simultaneous saccharification and fermentation (SSF) with coculture of Saccharomyces cerevisiae has shown a possibility of enhancing wood rot saccharification of corn fiber for ethanol fermentation. The laboratory-scale fungal saccharification and fermentation process incorporated in situ cellulolytic enzyme induction, which enhanced overall enzymatic hydrolysis of hemi/cellulose components of corn fiber into simple sugars (mono-, di-, and trisaccharides). The yeast fermentation of the hydrolyzate yielded 7.8, 8.6, and 4.9 g ethanol per 100 g corn fiber when saccharified with the white-, brown-, and soft-rot fungi, respectively. The highest ethanol yield (8.6 g ethanol per 100 g initial corn fiber) is equivalent to 35% of the theoretical ethanol yield from starch and cellulose in corn fiber. This research has significant commercial potential to increase net ethanol production per bushel of corn through the utilization of corn fiber. There is also a great research opportunity to evaluate the remaining biomass residue (enriched with fungal protein) as animal feed. PMID- 21314198 TI - Effect of heat on aspalathin, iso-orientin, and orientin contents and color of fermented rooibos (Aspalathus linearis) iced tea. AB - The phenolic quality of commercial South African fermented rooibos iced teas in terms of aspalathin, iso-orientin, and orientin contents in comparison to a "cup of tea" was shown to be inferior. The role of the different manufacturing stages of powdered extract used in iced tea formulation and, more specifically, the impact of pasteurization and sterilization on the color and phenolic content of the beverage, were assessed as potential causes of its inferior phenolic quality. Aspalathin and its corresponding flavones, iso-orientin and orientin, were found to be present at all stages of the powdered extract production process. Spray drying did not significantly (P >= 0.05) alter the aspalathin, iso-orientin, or orientin content of concentrates. Simulated normal-temperature sterilization (NTS at 121 degrees C/15 min) and high-temperature sterilization (HTS at 135 degrees C/4 min), but not necessarily pasteurization (93 degrees C/30 min), significantly (P < 0.05) reduced the aspalathin, iso-orientin, and orientin contents of different iced tea formulations. Heat-induced losses of iso-orientin and orientin were lower than those for aspalathin. Conversion of aspalathin to the flavones is implicated. The addition of ascorbic acid and/or citric acid to the base iced tea formulation containing only rooibos extract and sugar proved to be beneficial, especially for the retention of aspalathin. Browning, that is, absorbance at 420 nm, was significantly (P < 0.05) increased in the base formulation. In the case of the formulations also containing ascorbic acid and/or citric acid, absorbance remained unchanged or decreased when subjected to NTS and HTS treatments. This was attributed to removal of brown polymers from solution as the pH values of these formulations were lower than that of the base formulation. PMID- 21314200 TI - Retraction: Oxidative stability of unsaturated monoacyl trehalose in aqueous solution. PMID- 21314199 TI - Synthesis and biological activity evaluation of 1,2,3-thiadiazole derivatives as potential elicitors with highly systemic acquired resistance. AB - Elicitors provide a broad spectrum of systemic acquired resistance by altering the physical and physiological status of the host plants and, therefore, are among the most successful directions in modern pesticide development for plant protection. To develop a novel elicitor with highly systemic acquired resistance, two series of thiazole- and oxadiazole-containing thiadiazole derivatives were rationally designed and synthesized according to the principle of combination of bioactive substructures in this work. Their structures were characterized by (1)H nuclear magnetic resonance (NMR), infrared (IR), high-resolution mass spectrometry (HRMS), or elemental analysis. Their potential systemic acquired resistance as an elicitor was also evaluated; bioassay results indicated that, among the 23 compounds synthesized, three compounds, 10a, 10d, and 12b, displayed better systemic acquired resistance than the positive control, tiadinil, a commercialized 1,2,3-thiadiazole-based elicitor. In addition, three other compounds, 10f, 12c, and 12j, exhibited a certain degree of fungus growth inhibition in vitro or in vivo. Our results demonstrated that, in combination of bioactive substructures is an interesting exploration for novel pesticide development, thiazole- and oxadiazole-containing thiadiazole derivatives are potential elicitors with good systemic acquired resistance. PMID- 21314201 TI - Degradation process of lead chromate in paintings by Vincent van Gogh studied by means of synchrotron X-ray spectromicroscopy and related methods. 1. Artificially aged model samples. AB - On several paintings by artists of the end of the 19th century and the beginning of the 20th Century a darkening of the original yellow areas, painted with the chrome yellow pigment (PbCrO(4), PbCrO(4).xPbSO(4), or PbCrO(4).xPbO) is observed. The most famous of these are the various Sunflowers paintings Vincent van Gogh made during his career. In the first part of this work, we attempt to elucidate the degradation process of chrome yellow by studying artificially aged model samples. In view of the very thin (1-3 MUm) alteration layers that are formed, high lateral resolution spectroscopic methods such as microscopic X-ray absorption near edge (MU-XANES), X-ray fluorescence spectrometry (MU-XRF), and electron energy loss spectrometry (EELS) were employed. Some of these use synchrotron radiation (SR). Additionally, microscopic SR X-ray diffraction (SR MU XRD), MU-Raman, and mid-FTIR spectroscopy were employed to completely characterize the samples. The formation of Cr(III) compounds at the surface of the chrome yellow paint layers is particularly observed in one aged model sample taken from a historic paint tube (ca. 1914). About two-thirds of the chromium that is present at the surface has reduced from the hexavalent to the trivalent state. The EELS and MU-XANES spectra are consistent with the presence of Cr(2)O(3).2H(2)O (viridian). Moreover, as demonstrated by MU-XANES, the presence of another Cr(III) compound, such as either Cr(2)(SO(4))(3).H(2)O or (CH(3)CO(2))(7)Cr(3)(OH)(2) [chromium(III) acetate hydroxide], is likely. PMID- 21314202 TI - Degradation process of lead chromate in paintings by Vincent van Gogh studied by means of synchrotron X-ray spectromicroscopy and related methods. 2. Original paint layer samples. AB - The darkening of the original yellow areas painted with the chrome yellow pigment (PbCrO(4), PbCrO(4).xPbSO(4), or PbCrO(4).xPbO) is a phenomenon widely observed on several paintings by Vincent van Gogh, such as the famous different versions of Sunflowers. During our previous investigations on artificially aged model samples of lead chromate, we established for the first time that darkening of chrome yellow is caused by reduction of PbCrO(4) to Cr(2)O(3).2H(2)O (viridian green), likely accompanied by the presence of another Cr(III) compound, such as either Cr(2)(SO(4))(3).H(2)O or (CH(3)CO(2))(7)Cr(3)(OH)(2) [chromium(III) acetate hydroxide]. In the second part of this work, in order to demonstrate that this reduction phenomenon effectively takes place in real paintings, we study original paint samples from two paintings of V. van Gogh. As with the model samples, in view of the thin superficial alteration layers that are present, high lateral resolution spectroscopic methods that make use of synchrotron radiation (SR), such as microscopic X-ray absorption near edge (MU-XANES) and X-ray fluorescence spectrometry (MU-XRF) were employed. Additionally, MU-Raman and mid FTIR analyses were carried out to completely characterize the samples. On both paint microsamples, the local presence of reduced Cr was demonstrated by means of MU-XANES point measurements. The presence of Cr(III) was revealed in specific areas, in some cases correlated to the presence of Ba(sulfate) and/or to that of aluminum silicate compounds. PMID- 21314203 TI - Flow-based autocorrelation studies for the detection and investigation of single particle surface-enhanced resonance Raman spectroscopic events. AB - We report on the characterization and detection of single metallic nanoparticles using a combination of correlation spectroscopy and surface-enhanced resonance Raman spectroscopy (SERRS). Minimizing the number of independent characterization steps is critical to efficiently perform such an analysis. In this article, we improve upon conventional diffusion-limited approaches by implementing a flow based system with high temporal resolution detection. The benefits of flow over diffusion measurements allow for a higher throughput of detected events resulting in shorter analysis times. The nanoparticles are sized using their rotational diffusion time calculated with a modified autocorrelation function. Experiments are performed using Au nanoparticles labeled with the reporter molecule malachite green isothiocyanate on a custom-built Raman spectrometer. PMID- 21314204 TI - Involvement of caspase-9 but not caspase-8 in the anti-apoptotic effects of estradiol and 4-OH-Estradiol in MCF-7 human breast cancer cells. AB - OBJECTIVES: Evidence is accumulating that certain estradiol metabolites may play a more important role in enhancing breast cancer risk than their parent substance - 17 beta-estradiol (E2). Of special interest are the metabolites 2 hydroxyestradiol (2-OH-E2), which can show anticarcinogenic effect, while that of 4-hydroxyestradiol (4-OH-E2) may be rather procarcinogenic. We suggest that local activation of cytochrome P450 enzymes - CYP1A1 and/or CYP1B1 - by E2 could generate active metabolites that affect the apoptosis and thereby promote mammary carcinogenesis. Over the last several years, there has been accumulating evidence that, apart from the receptor-mediated (extrinsic) pathway, also the mitochondrial (intrinsic) pathway plays a role in E2-induced apoptosis. In the present study, we have compared the effect of these metabolites and their parent substance E2 on caspase-8 and caspase-9 activity as well as on the end step of apoptosis DNA fragmentation. METHODS: MCF-7 human breast cancer cells (ATCC) were routinely cultured in DMEM supplemented with 10 % heat-inactivated FBS. Forty eight hours before experiments, the medium was removed and replaced by DMEM without phenol red supplemented with 5 % heat-inactivated fetal bovine serum. For determination of caspase-8 and caspase-9 activities, MCF-7 cells were seeded in 48-well culture plates at a density of 15 x 104 cells/well and incubated with 1 nM E2 and its metabolites for 24 h. DNA fragmentation, caspase-8 and caspase-9 activities were determined in cell lysates by ELISAs. The CYP1A1 and CYP1B1 protein expression was evaluated by Western blotting. RESULTS: E2 had no effect on CYP1A1 protein levels. However an increase in CYP1B1 protein expression was observed within 48 hrs of exposure. None of the compounds tested changed caspase 8 activity as compared to the controls. Statistically significant decrease in caspase-9 activity and DNA fragmentation was observed in the presence of E2 and 4 OH-E2, but no significant effect was found for the metabolite 2-OH-E2. CONCLUSIONS: It was found that local activation of cytochrome P450 enzyme CYP1B1 by E2 may change the local metabolic activation pathway into 4-OH-E2 as well as the activation of caspase-9 (a part of the intrinsic mitochondrial apoptotic pathway) in the antiapoptotic effect of E2 and 4-OH-E2. PMID- 21314205 TI - Risk of malignancy in non-diagnostic thyroid fine-needle aspiration biopsy in multinodular goitre patients. AB - OBJECTIVE: Although the majority of biopsies is adequate for a cytological diagnosis, 5-20 % will be insufficient or nondiagnostic. Patients with nondiagnostic FNABs (ND-FNAB) may be further managed by continued observation, repeated FNAB, or thyroidectomy. The aim of this study was to determine the risk of malignancy in ND-FNAB, and to determine if there are any clinical factors that can be used to distinguish malignant versus benign disease in multinodular goitre patients with ND-FNAB. METHODS: A total of 411 multinodular goiter patients who underwent both a FNAB and thyroidectomy was the subject of study. Seventy nine of these patients with ND-FNAB were further reviewed retrospectively, and demographical and clinical factors were investigated to determine if there is any predictor of malignancy in this group of patients. Among these patients, FNAB has been repeated one more time in 5 (6.3 %) patients, and two more times in 9 (11.3 %) patients. RESULTS: Among 79 patients with ND-FNAB, 10 patients (12.6 %) had malignancy as found postoperatively. There were no differences in age, sex, functional status of the thyroid gland, and nodule size between patients with benign versus malignant disease. CONCLUSION: Nondiagnostic FNAB remains a significant problem in the evaluation of thyroid nodules. Despite ultrasound guidance, clinicians should inform patients that there is a 5-15 % malignancy risk of initial nondiagnostic specimens. PMID- 21314206 TI - Gender specific influence of endogenous glutamate release on stress-induced fear in rats. AB - OBJECTIVE: Stress, fear and anxiety are among major public health concerns. The role of glutamate in these processes is becoming more recognized with promising new drug targets. The aim of this study was to establish the gender specificity of a possible treatment of fear by glutamate antagonists in correspondence with changes in stress-hormone release. METHODS: Footshock-induced fear was used as an anxiogenic situation in rats. A combination of two ionotrop receptor antagonists such as MK-801 (dizocilpine; 0.2 mg/kg) for NMDA (N-methyl-D-aspartic acid) and GYKI 52466 (benzodiazepine derivative; 10 mg/kg) for AMPA/kainate receptors were used for 5 days following the hypothesis that they potentiate each other the main action, but at the same time the side effects may be minimized. RESULTS: Female rats tried to avoid the electrical stimulus more actively than males, as they spent more time with exploration and jumping and less time with freezing or rest. Ionotropic glutamate receptor antagonists have anxiolytic action. MK-801 was more effective in females, as it prevented the footshock-induced freezing per se, while in males it was effective only in combination with GyKI 52466. The locomotor side effect of MK-801 was not visible after repeated administration. The freezing behavior was positively correlated with the changes in prolactin but not with adrenocorticotropin levels. CONCLUSIONS: We proved the involvement of endogenous glutamate neurotransmission in stress-induced fear. Therapeutical usage may involve a combination of different receptor antagonists. Special attention should be paid to the gender, as females seem to be more sensitive, therefore they require smaller doses. During the treatment the prolactin levels should be monitored. PMID- 21314207 TI - Expression of NIS in the thyroid and pituitary of female rats after a single dose of potassium iodide. AB - OBJECTIVE: The aim of this work was to study the expression of NIS in the thyroid and anterior pituitary in rats after a single dose of iodide appropriate to the content of iodide in iodine-positive points in the thyroid and pituitary. METHODS: A total of 41 inbred rat females of local laboratory strain weighing 250 300 g at the stage of diestrus and/or metestrus were used. Pituitaries and thyroids were dissected from 15 control rats at the same time as these from four groups of 6-8 rats each which were given various doses of potassium iodide dissolved in 0.5 ml distilled water (6 rats - 1 MUg/100 g body weight; 8 rats - 4 MUg/100 g ; 6 rats - 8 MUg/100 g ; 6 rats - 25 MUg/100 g.) by gavage at 48 h before sacrifice. In 6 rats of control group the concentration of iodine in thyroids and pituitaries was estimated in terms of percent by weight in dry tissue (wt% I-2 dry tissue) using the wavelength dispersive spectrometry (WDS) quantitative analysis. The expression of NIS in thyroids and pituitaries in terms of the percentage of positive immunostained area (% PA) was measured by streptavidin-biotin method using specific polyclonal antibodies. RESULTS: In thyroids, the concentration of iodine in iodine-positive points ranged from 2.5 to 59.3 (mean of 16.7+/-3.0) in terms of wt% I-2 dry tissue (100 % iodine positive points), while in pituitaries it ranged from 0.17 to 6.3 (mean of 1.4+/ 0.3) in all points and 2.2+/-0.4 in iodine-positive points. Histochemical reaction for NIS in the pituitaries at 48 hours after iodide administration showed a dose related increase beginning from 4 MUg/100 g (from 1.8+/-0.7 to 12.9+/-1.0 % PA, respectively to the dose of iodide), while such increase in the thyroids started from 8 MUg/100g (from 3.7+/-1.2 to 9.1+/-2.0 % PA). It remained still increased in pituitaries after the dose of 8 MUg/100g (11.4+/-1.0 % PA) and 25 MUg/100g (13.9+/-1.5 % PA), while such increase in thyroids was found only after the dose of 25 MUg/100g (11.9+/-2.8 % PA). CONCLUSION: It was found that in the pituitaries of rat females the expression of NIS started after the dose of 4 MUg iodide/100g, while that in the thyroids started after 8 MUg iodide/100g. Thus, it may be suggested that the pituitary appears more susceptible to the level of iodide in blood. PMID- 21314209 TI - Role of catecholamine-induced activation of vagal afferent pathways in regulation of sympathoadrenal system activity: negative feedback loop of stress response. AB - Stress-induced activation of the hypothalamic-pituitary-adrenal axis and sympathoadrenal system is precisely regulated by well-documented negative feedback mechanisms. These include direct negative feedback effect of glucocorticoids on brain structures regulating the hypothalamic-pituitary-adrenal axis activity. However, since the blood-brain-barrier is impermeable to circulating catecholamines, the role of circulating epinephrine and norepinephrine in feedback regulation of the sympathoadrenal system activity is unclear. Here we show that vagal innervation of the adrenal medulla combined with the presence of beta-adrenergic receptors on vagal sensory neurons, the epinephrine-induced activation of vagal afferents, and increased plasma epinephrine levels following subdiaphragmatic vagotomy indicate that sensory fibers of the vagus nerve participate in the monitoring of plasma and tissue catecholamine concentrations. Furthermore, it shows that signaling transmitted by vagal afferents regulates sympathoadrenal system activity at the level of the brain. Therefore, we propose that vagal sensory fibers, directly activated by epinephrine and norepinephrine, represent the afferent limb of a negative feedback loop that adjusts the activity of the sympathoadrenal system according to actual plasma and tissue catecholamine levels. PMID- 21314208 TI - Prostatic assessment in rats after bilateral orchidectomy and calcitonin treatment. AB - OBJECTIVE: Bilateral orchidectomy is widely used as a treatment in patients with metastatic prostatic cancer, but post-orchidectomy osteoporosis is a common sequel which is commonly treated by postoperative calcitonin injection. Since the increase in the invasiveness of malignant prostatic cells has been attributed to the use of calcitonin, this study was aimed to elucidate the effect of calcitonin on the structure of the prostate after orchidectomy in rats used as mammalian model. METHODS: A total of 84 adult male albino rats were divided into three groups: Group 1 (12 control rats); Group 2 (36 rats subjected to bilateral orchidectomy); Group 3 (36 rats subjected to bilateral orchidectomy and injected subcutaneously with calcitonin (5 ug/kg) every other day. Six animals of Group 2 and 3 were sacrificed two, four, eight, sixteen and twenty four weeks after orchidectomy. The prostates were removed and processed for morphometric measurements by using the image analyzer computer system. RESULTS: The present study demonstrated a decrease in the height and apoptosis of the epithelial lining of the prostatic acini. There was also an increase in the interacinar fibromuscular stroma. However, calcitonin administration following orchidectomy limited these changes. CONCLUSION: Bilateral orchidectomy produced time related atrophic changes in the prostate, while a simultaneous administration of calcitonin inhibits the development of these atrophic changes. PMID- 21314210 TI - Pregnancy- and lactation-associated osteoporosis: a narrative mini-review. AB - Pregnancy and lactation represent stress states for maternal health and development. Pregnancy and lactation-associated osteoporosis (PLaOs) are uncommon and rare conditions characterized by the occurrence of fragility fracture(s), most commonly vertebral, in late pregnancy or during the postpartum period. The etiology and pathogenesis of these conditions is not clear and several theories are proposed. Due to the rarity of the disease, various isolated clinical cases are reported in the medical literature and only one case-control study thus far. In the current review we try to analyze the pathophysiologic pathways implicated in these conditions and provide possible explanations regarding etiology; we present data on the epidemiology, clinical course, diagnosis and current approved treatment modalities of PLaOs. PMID- 21314211 TI - Polymeric nanoparticles - targeted drug delivery systems for treatment of CNS disorders and their possible endocrine disrupting activities. AB - Drug delivery to the central nervous system (CNS) represents one of the most priority challenges in research and development of pharmaceutical nanotechnology products. Among the various non-invasive approaches for CNS delivery, nanoparticle carriers and particularly polymeric nanoparticles (PNs) seem to be one of the most interesting. This review deals with PNs as CNS drug delivery systems and their potential endocrine disrupting properties. Possible interference with the development of neuroendocrine-reproductive system is considered. Special regard is being paid to potential mechanisms of PNs toxicity. Necessity to investigate the toxicity of nanomaterials and their impact on human health are discussed. PMID- 21314212 TI - Insufficient primary care services to the rural population of Greece. PMID- 21314213 TI - Attraction and retention of qualified health workers to rural areas in Nigeria: a case study of four LGAs in Ogun State, Nigeria. AB - INTRTODUCTION: A shortage of health workers is a major problem for Nigeria, especially in rural areas where more than 70% of the population live. At the primary care level, trained community health officers provide services normally reserved for doctors or medical specialists. The community health officers must therefore be supported and motivated to provide effective quality healthcare services. This study aimed to determine factors that will attract and retain rural and urban health workers to rural Nigerian communities, and to examine differences between the two groups. METHODS: A cross-sectional survey measured health workers' work experience, satisfaction with, and reasons for undertaking their current work; as well as reasons for leaving a work location. Data were also gathered on factors that attract health workers to rural settings and also retain them. RESULTS; Rural health workers were generally more likely to work in rural settings (62.5%) than their urban counterparts (16.5%). Major rural motivators for both groups included: assurances of better working conditions; effective and efficient support systems; opportunities for career development; financial incentives; better living conditions and family support systems. The main de-motivator was poor job satisfaction resulting from inadequate infrastructure. Rural health workers were particularly dissatisfied with career advancement opportunities. More urban than rural health workers expressed a wish to leave their current job due to poor job satisfaction resulting from poor working and living conditions and the lack of career advancement opportunities. CONCLUSIONS: Motivational factors for attraction to and retention in rural employment were similar for both groups although there were subtle differences. Addressing rural health manpower shortages will require the development of a comprehensive, evidence-based rural health manpower improvement strategy that incorporates a coordinated intersectoral approach, involving partnership with a range of stakeholders in rural health development. PMID- 21314214 TI - Uniting the tribes of health system improvement. AB - Nested within a growing national consensus that the performance of the US healthcare system needs to be improved are largely distinct "tribes" of experts with varying interpretations of what would constitute improvement: the quality improvement tribe, the payment reform tribe, the consumer engagement tribe, and the HIT tribe. PMID- 21314215 TI - HITECH lays the foundation for more ambitious outcomes-based reimbursement. AB - Through the Health Information Technology for Economic and Clinical Health (HITECH) Act, the federal government is making up to $27 billion available in incentive payments, followed by penalties, over 10 years for eligible professionals and hospitals. HITECH is extended by the sections of the Patient Protection and Affordable Care Act (PPACA) that deal with payment reform. Of particular importance are those sections that discuss accountable care organizations and the different ways that Medicare will pay for care. These changes may be more significant to the industry and to healthcare information technology (HIT) than the "meaningful use" regulation itself. In some ways, meaningful use becomes the tactical plan for achieving the strategic plan outlined by PPACA. The HIT market will evolve to include exchanging data, orchestrating the coordination of care across settings, and finally guiding caregivers with contextual knowledge at the point of care. PMID- 21314216 TI - Congressional intent for the HITECH Act. AB - The Health Information Technology for Economic and Clinical Health (HITECH) Act, which was enacted as part of the American Recovery and Reinvestment Act of 2009, calls for an unprecedented federal investment in health information technology (IT). Incentive payments will be made available through the Medicare programs and Medicaid to doctors and hospitals that use health IT in a meaningful way (ie, to advance delivery of high-quality healthcare). These IT systems have to be certified as meeting certain technological standards. The Congressional Budget Office has projected that HITECH will reduce federal and private sector spending on health services during the next decade by tens of billions of dollars by increasing efficiency. PMID- 21314217 TI - A health plan prescription for health information technology. AB - The economic stimulus law of 2009 included incentive payments to encourage providers and hospitals to adopt and "meaningfully use" electronic health records. One resource was excluded from these regulations: patient data from the patient's health insurer, although health insurance companies tie together multiple sectors of the healthcare industry in a single patient-centered data form known as the claims history. They also have considerable experience with information technology (IT). As a result, they are uniquely positioned to move adoption of health IT systems forward. Health plan technologies should be included in the meaningful-use requirements. The result will be additional functionality, which in the end will improve quality, lower costs, and improve individual health. PMID- 21314218 TI - Smart health community: the hidden value of health information exchange. AB - Investments in health information technology are accelerating the digitization of medicine. The value from these investments, however, can grow beyond efficiencies by filling the information gaps between the various stakeholders. New work processes, governance structures, and relationships are needed for the coevolution of healthcare markets and business models. But coevolution is slow, hindered by the scarcity of incentives for legacy delivery systems and constrained by the prevailing patient-healthcare paradigm. The greater opportunity lies in wellness for individuals, families, communities, and society at large: a consumer-community paradigm. Capturing new value from this opportunity can start with investment in health information exchange and the creation of Smart Health Communities. By shifting the focus of exchange from public servant to value-added service provider, these communities can serve as a platform for a wider array of wellness services from consumer care, traditional healthcare, and research. PMID- 21314219 TI - Increasing consumerism in healthcare through intelligent information technology. AB - In healthcare, consumerism is not a product or program. Instead, it is an orientation to new care delivery models that encourage and enable greater patient responsibility through the intelligent use of information technology. Despite the promise of consumerism, current approaches have not fully realized the potential benefits of improved outcomes and lower cost. We recommend 4 guiding principles to ensure that next-generation innovation yields the returns that providers, patients, and other stakeholders expect: (1) keep the consumer at the center of innovation, (2) keep it simple, (3) link products and services to a broader "ecosystem" of care, and (4) encourage health in addition to treating illness. Now may be a particularly compelling time to invest in a consumerist approach. PMID- 21314220 TI - Optimizing health information technology's role in enabling comparative effectiveness research. AB - Health information technology (IT) is a key enabler of comparative effectiveness research (CER). Health IT standards for data sharing are essential to advancing the research data infrastructure, and health IT is critical to the next step of incorporating clinical data into data sources. Four key principles for advancement of CER are (1) utilization of data as a strategic asset, (2) leveraging public-private partnerships, (3) building robust, scalable technology platforms, and (4) coordination of activities across government agencies. To maximize the value of the resources, payers and providers must contribute data to initiatives, engage with government agencies on lessons learned, continue to develop new technologies that address key challenges, and utilize the data to improve patient outcomes and conduct research. PMID- 21314221 TI - Health information technology and health system redesign--the Quality Chasm revisited. AB - UnitedHealth Group constructed the Diabetes Prevention and Control Alliance (DPCA) in a manner consistent with the recommendations for health system redesign outlined in the Institute of Medicine's Crossing the Quality Chasm. This evidence based, multidisciplinary education and intervention program is enabled by a state of-the-art health information technology (HIT) infrastructure. DPCA coordinates and connects a variety of interventions through HIT, including community-based services offered by YMCAs and local pharmacists. Our initial experience in operating DPCA gives us confidence that large-scale prevention and disease control management programs make economic sense, are worthy of front-end investment, and can achieve cost-effective results. Others who want to use our model will benefit from policymakers' efforts to prioritize future versions of transaction and coding standards that meet the needs of preventive healthcare as much as they do acute and chronic care. PMID- 21314222 TI - Health information technology and the medical school curriculum. AB - Medical schools must teach core biomedical informatics competencies that address health information technology (HIT), including explaining electronic medical record systems and computerized provider order entry systems and their role in patient safety; describing the research uses and limitations of a clinical data warehouse; understanding the concepts and importance of information system interoperability; explaining the difference between biomedical informatics and HIT; and explaining the ways clinical information systems can fail. Barriers to including these topics in the curricula include lack of teachers; the perception that informatics competencies are not applicable during preclinical courses and there is no place in the clerkships to teach them; and the legal and policy issues that conflict with students' need to develop skills. However, curricular reform efforts are creating opportunities to teach these topics with new emphasis on patient safety, team-based medical practice, and evidence-based care. Overarching HIT competencies empower our students to be lifelong technology learners. PMID- 21314223 TI - Physician ePortfolio: the missing piece for linking performance with improvement. AB - The movement toward improvement in healthcare quality and patient safety has led to greater emphasis on practice performance measurement and physician accountability. Health information technology provides clinical data for quality measurement but hasn't provided the link to practice-based learning and improvement. An electronic portfolio for practice-based learning and improvement (ePortfolio) that combines practice data for identification of competency and performance gaps along with learning and process interventions offers true practice-based learning and performance improvement. Automated reporting can assist in the ever-increasing burden of documentation for maintenance of licensure, maintenance of specialty board certification, credentialing, payer recognition programs, and other physician accountability requirements. PMID- 21314224 TI - Electronic health records: potential to transform medical education. PMID- 21314225 TI - Electronic health record adoption and quality improvement in US hospitals. AB - OBJECTIVE: To estimate the relationship between quality improvement and electronic health record (EHR) adoption in US hospitals. STUDY DESIGN: National cohort study based on primary survey data about hospital EHR capability collected in 2003 and 2006 and on publicly reported hospital quality data for 2004 and 2007. METHODS: Difference-in-differences regression analysis to assess the relationship between EHR adoption and quality improvement for acute myocardial infarction, heart failure, and pneumonia care. RESULTS: Availability of a basic EHR was associated with a significant increase in quality improvement for heart failure (additional improvement, 2.6%; 95% confidence interval [CI], 1.0%-4.1%). However, adoption of advanced EHR capabilities was associated with significant decreases in quality improvement for acute myocardial infarction and heart failure. We observed 0.9% (95% CI, -1.7% to -0.1%) less improvement for acute myocardial infarction quality scores and 3.0% (95% CI, -5.2% to -0.8%) less improvement for heart failure quality scores among hospitals that newly adopted an advanced EHR, and 1.2% (95% CI, -2.0% to -0.3%) less improvement for acute myocardial infarction quality scores and 2.8% (95% CI, -5.4% to -0.3%) less improvement for heart failure quality scores among hospitals that upgraded their basic EHR. CONCLUSIONS: Mixed results suggest that current practices for implementation and use of EHRs have had a limited effect on quality improvement in US hospitals. However, potential "ceiling effects" limit the ability of existing measures to assess the effect that EHRs have had on hospital quality. In addition to the development of standard criteria for EHR functionality and use, standard measures of the effect of EHRs on quality are needed. PMID- 21314226 TI - Effects of documentation-based decision support on chronic disease management. AB - OBJECTIVE: To evaluate whether a new documentation-based clinical decision support system (CDSS) is effective in addressing deficiencies in the care of patients with coronary artery disease (CAD) and diabetes mellitus (DM). STUDY DESIGN: Controlled trial randomized by physician. METHODS: We assigned primary care physicians (PCPs) in 10 ambulatory practices to usual care or the CAD/DM Smart Form for 9 months. The primary outcome was the proportion of deficiencies in care that were addressed within 30 days after a patient visit. RESULTS: The Smart Form was used for 5.6% of eligible patients. In the intention-to-treat analysis, patients of intervention PCPs had a greater proportion of deficiencies addressed within 30 days of a visit compared with controls (11.4% vs 10.1%, adjusted and clustered odds ratio =1.14; 95% confidence interval, 1.02-1.28; P = .02). Differences were more pronounced in the "on-treatment" analysis: 17.0% of deficiencies were addressed after visits in which the Smart Form was used compared with 10.6% of deficiencies after visits in which it was not used (P <.001). Measures that improved included documentation of smoking status and prescription of antiplatelet agents when appropriate. CONCLUSIONS: Overall use of the CAD/DM Smart Form was low, and improvements in management were modest. When used, documentation-based decision support shows promise, and future studies should focus on refining such tools, integrating them into current electronic health record platforms, and promoting their use, perhaps through organizational changes to primary care practices. PMID- 21314227 TI - Health information technology is leading multisector health system transformation. PMID- 21314228 TI - Healthcare information technology interventions to improve cardiovascular and diabetes medication adherence. AB - OBJECTIVE: To determine the efficacy of healthcare information technology (HIT) interventions in improving adherence. STUDY DESIGN: Systematic search of randomized controlled trials of HIT interventions to improve medication adherence in cardiovascular disease or diabetes. METHODS: Interventions were classified as 1-way patient reminder systems, 2-way interactive systems, and systems to enhance patient-provider interaction. Studies were subclassified into those with and without real-time provider feedback. Cohen's d effect sizes were calculated to assess each intervention's magnitude of effectiveness. RESULTS: We identified 7190 articles, only 13 of which met inclusion criteria. The majority of included studies (54%, 7 studies) showed a very small ES. The effect size was small in 15%, large in 8%, and was not amenable to calculation in the remainder. Reminder systems were consistently effective, showing the largest effect sizes in this review. Education/counseling HIT systems were less successful, as was the addition of realtime adherence feedback to healthcare providers. Interactive systems were rudimentary and not integrated into electronic health records; they exhibited very small effect sizes. Studies aiming to improve patient-provider communication also had very small effect sizes. CONCLUSIONS: There is a paucity of data about HIT's efficacy in improving adherence to medications for cardiovascular disease and diabetes, although simple patient reminder systems appear effective. Future studies should focus on more sophisticated interactive interventions that expand the functionality and capabilities of HIT and better engage patients in care. PMID- 21314229 TI - Achieving meaningful use: a health system perspective. AB - In 2002, Partners HealthCare (Partners) launched a strategy to accelerate the use of ambulatory electronic medical records across its network of 6000 physicians. Through focus on quality software products, creation of a system of financial incentives, and active engagement of health system leadership, Partners reached high levels of physician adoption by late 2006. Partners eventually introduced a mandate that made ambulatory electronic medical record use a requirement for all of its physicians. During this multi-year initiative, Partners also focused on the effective use of electronic medical records and introduced a series of tactics designed to optimize the use of these systems. With introduction of the meaningful-use concepts in the Health Information Technology for Economic and Clinical Health (HITECH) Act, Partners will transition its efforts toward this important national priority. Partners' experience offers some unique insights into the process of electronic medical record adoption across a large, diverse health system. PMID- 21314230 TI - Strategies for tumor-directed delivery of siRNA. AB - INTRODUCTION: Current treatment of malignant tumors relies predominantly on chemotherapy delivering a single antineoplastic drug or a combination of two or more drugs intravenously. Problems with such treatments can include the killing of healthy cells, adverse side effects and chemoresistance. As cancer basically results from different types of mutation leading to the overexpression or suppression of the signaling cascades responsible for cancer cell survival and proliferation, tailor-made approaches capable of interfering precisely with those pathways are the potential revolutionary tools that could pave the way for highly effective cancer therapy. AREAS COVERED: This review summarizes recent progress in the identification and validation of the target genes for cancer gene therapy using small interfering RNA (siRNA) technology and, more importantly, the delivery strategies that have been designed and implemented for tumor-directed delivery of siRNAs. EXPERT OPINION: Cancer-targeted delivery of a gene in order to produce a particular protein (such as a tumor-suppressor or a nucleic acid sequence that can silence the expression of a specific gene, such as an oncogene or an antiapoptotic gene) is the most promising concept for cancer treatment in the future. siRNA has the ability to recognize and cleave a specific mRNA, thus inhibiting the expression of a particular protein. The success of targeted gene silencing as a potential cancer therapeutic demands the development of more effective delivery devices and the removal of siRNA off-target effects. PMID- 21314231 TI - Neurobiological aspects of Alzheimer's disease. AB - INTRODUCTION: The molecular pathogenesis of Alzheimer's disease (AD) includes a variety of risk factors, extracellular deposition of beta-amyloid, accumulation of intracellular neurofibrillary tangles, oxidative neuronal damage and inflammatory cascades. Although amyloid-beta-containing senile plaques and phospho-tau-containing neurofibrillary tangles are hallmark lesions of AD, neither is specific to nor even a marker of the disease. From a biochemical point of view the most consistent finding is a decreased level of choline acetyltransferase. In recent years, cumulative evidence has been gained on the involvement of neuronal lipoprotein activity, and on the role of cholesterol and other lipids in pathogenesis. Although basic research has made remarkable progress in the past two decades, currently available drugs are only able to improve cognitive symptoms temporarily and no treatment can reverse, stop or even slow this inexorable neurodegenerative process. AREAS COVERED: The various neurobiological events associated with development of AD and the multiple treatment approaches for combating this disorder. EXPERT OPINION: AD is a complex multifactorial disorder and thus a single target or pathogenic pathway is unlikely to be identified. Developing therapeutic interventions demands a greater understanding of the processes and the differential involvement of the various mediators. Effective therapeutics are urgently needed, and it is hoped that anti amyloid strategies will offer a significant step towards a causal therapy. PMID- 21314232 TI - The therapeutic potential of targeting the glucagon-like peptide-2 receptor in gastrointestinal disease. AB - INTRODUCTION: Glucagon-like peptide-2 (GLP-2) is a pleiotropic intestinotrophic hormone that enhances digestive and absorptive capacity by acting through a limited population of intestinal GLP-2 receptors. The development of protease resistant analogs or GLP-2/IgG fusion proteins confers a longer circulating half life than the native peptide. GLP-2 has garnered interest as a therapeutic most notably by reducing reliance on total parenteral nutrition in patients with short bowel syndrome. AREAS COVERED: The clinical evidence for benefit in conditions requiring longer term treatment with GLP-2 receptor agonists, for example short bowel syndrome and inflammatory bowel disease. Benefits of short-term GLP-2 treatment are emerging in pre-clinical models, such as post-operative ileus, GI mucositis and conditions of altered intestinal permeability. The therapeutic utility of GLP-2 receptor agonists is limited by concern that it predisposes patients to gastrointestinal cancers, or their re-occurrence in cancer patients. This affects the types of diseases treated and, possibly, the duration of dosing. EXPERT OPINION: GLP-2 is therapeutically attractive in diseases to enhance absorptive capacity, restore mucosal health and reduce inflammation. Long-term surveillance studies with a marketed therapeutic agent are needed to weigh the benefits of GLP-2 treatment against the potential effects on co-morbidities and increased risk of intestinal carcinogenesis. PMID- 21314233 TI - XL184 (cabozantinib) for medullary thyroid carcinoma. AB - INTRODUCTION: Intrathyroidal medullary thyroid carcinoma (MTC) can generally be cured by surgery, but distant metastases are often already present at diagnosis.Currently, there is no effective treatment for metastatic MTC. In these cases, consensus treatment guidelines explicitly recommend new experimental drugs. Several kinase inhibitors are now being tested for treatment of MTC in clinical trials and XL184, an oral, small-molecule multi-kinase inhibitor, seems to be one of the most promising of these compounds. AREAS COVERED: We review preliminary data on the safety and efficacy of XL184 in metastatic MTC based on an extensive search of the literature, which included published articles, abstracts and website information. In particular,the review focuses on the rationale for using XL184 in advanced MTC. The compound has been specifically designed to target multiple signaling pathways,and this is expected to produce synergistic antitumor effects superior to those achieved by single-kinase inhibition. Preliminary results from the Phase I study of XL184 seem to support this hypothesis. EXPERT OPINION: Multiple receptor tyrosine kinases (RTKs) are concomitantly activated in the same tumor. The blockade of a single RTK may engage compensatory signaling that maintains cell growth. Targeting multiple kinases might overcome both intrinsic and acquired resistance to antitumoral drugs. PMID- 21314234 TI - Novel IkB kinase inhibitors for treatment of nuclear factor-kB-related diseases. AB - INTRODUCTION: NF-kB is a key regulator of inflammation and immunity in cancer development. The IkB kinase (IKK) is a multisubunit complex containing catalytic subunits termed IKK-alpha, -beta and -gamma. It is well known that many pro inflammatory stimuli require the IKK-beta subunit for NF-kB activation. AREAS COVERED: NF-kB affects the progression of inflammation-related diseases,such as myocardial ischemia, bronchial asthma, arthritis, cancer and other diseases. We review the characteristics and effects of these inhibitors on inflammatory and other diseases. EXPERT OPINION: Various synthesized IKK inhibitors have been developed and they will be used clinically in the near future. PMID- 21314235 TI - SNAPPE-II application in newborns with very low birth weight: evaluation of adverse outcomes in severe placental dysfunction. AB - AIM: The aim of this study was to evaluate the ability of the admission Score for Neonatal Acute Physiology - Perinatal Extension-II (SNAPPE-II) to predict adverse outcome among premature very low birth weight (BW) infants with abnormal Doppler blood flow in the uterus secondary to severe placental insufficiency of early onset. METHODS: A total of 86 neonates, weighing between 360 and 1498 g, were studied. Descriptive statistics of the population were reported. The areas under the receiver operating characteristics curves for the SNAPPE-II were calculated. The calibration of the model was assessed using the technique of Hosmer-Lemeshow. Adverse outcome was defined as mortality or the development of the following diagnoses: (1) periventricular-intraventricular hemorrhage (PIH); (2) retinopathy of prematurity stage 3 or 4; (3) periventricular leukomalacia; (4) bronchopulmonary dysplasia; (5) necrotizing enterocolitis (NEC). RESULTS: The SNAPPE-II area under curve was 0.86 (95% CI: 0.78-0.94) for mortality and 0.76 (95% CI: 0.65-0.86) for the prediction of adverse outcomes. Analyzing each morbidity variable, the SNAPPE-II AUC varied between 0.51 for NEC and 0.72 for PIH. CONCLUSION: SNAPPE-II shows accuracy in the prediction of adverse outcome for this highly selective group of very low BW infants compromised by severe placental insufficiency. PMID- 21314236 TI - Amniotic lamellar body counts can predict the occurrence of respiratory distress syndrome as well as transient tachypnea of the newborn (TTN). AB - AIMS: The purpose of this study is to predict the occurrence of transient tachypnea of the newborn (TTN) using amniotic lamellar body count (LBC) and compare the LBCs in neonates with TTN with the LBCs in neonates with respiratory distress syndrome (RDS) and controls. METHODS: Three hundred and eighty-one amniotic fluid samples were obtained at cesarean section from 27 to 40 weeks of gestation. Samples were analyzed immediately without centrifugation and the number of lamellar bodies was counted. RESULTS: The LBC in amniotic fluid ranged from 1,000 to 577,000/MUL. An LBC cut-off value of 48,500/MUL resulted in 84.7% sensitivity, 76.2% specificity, and 98.1% negative predictive value for predicting TTN. The LBC in neonates with TTN was significantly lower than that in controls (50,000 vs. 122,000; P<0.001) and significantly higher than that in neonates with RDS (50,000 vs. 21,000; P=0.042). CONCLUSIONS: We established a cut off value of LBC for predicting the occurrence of TTN. The LBC in neonates with TTN was significantly lower than that in controls. Amniotic LBC can be a useful marker to predict if neonatal respiratory management is required. PMID- 21314237 TI - Developmental outcomes of children exposed to antidepressants in pregnancy. AB - OBJECTIVE: To examine the developmental outcomes in children exposed to antidepressants in utero and compare those to children not exposed to these medications METHOD: A prospective case-controlled study of children exposed to antidepressants in pregnancy assessed 22 exposed and 19 not exposed children using the Bayley Scales of Infant Development, third edition. The control group was measured at a mean age of 23.09 (SD 3.82) months and the medicated group at 28.53 months (SD 6.22). Maternal variables were assessed using a purpose-designed questionnaire and the Beck Depression Inventory (II) in pregnancy and at three assessments in the postpartum. RESULTS: Children exposed to antidepressant medication in pregnancy scored lower on motor subscales in particular on fine motor scores than non-exposed children with a moderate effect size of Cohen's d = 0.47 fine motor and Cohen's d = 0.43 for gross motor. Due to lack of power these findings did not reach conventional criteria for statistical significance. There was no association found between maternal depression and neurodevelopment. CONCLUSIONS: This finding of a possible effect from antidepressant exposure in pregnancy on children's motor development is similar to the findings from a previous study. Future research is needed which assesses children at an older age using specific assessments of motor development. PMID- 21314238 TI - Assessing the value of existing recovery measures for routine use in Australian mental health services. AB - OBJECT: The concept of recovery has been recognized as important in the treatment of mental illness. A number of specific instruments exist which are designed to: (i) measure recovery at an individual level; and (ii) assess the recovery orientation of services. The current review aimed to identify these and evaluate their potential for routine use in Australian public sector mental health services. METHOD: We identified potential instruments by drawing on existing reviews, searching MEDLINE and PsycINFO, and consulting with experts. We used a hierarchical criterion-based approach to assess whether given instruments might be candidates for measuring recovery in the Australian context. RESULTS: We identified 33 instruments: 22 designed to measure individuals' recovery and 11 designed to assess the recovery orientation of services (or providers). Four of the former (Recovery Assessment Scale; Illness Management and Recovery Scales; Stages of Recovery Instrument; Recovery Process Inventory) and four of the latter (Recovery Oriented Systems Indicators Measure; Recovery Self Assessment; Recovery Oriented Practices Index; Recovery Promotion Fidelity Scale) were identified as promising candidates for routine use in Australian public sector mental health services. CONCLUSIONS: Further work is required, however, to determine which, if any, might best be used for this purpose; the possibility that modifications to existing instruments or the development of new instruments might be required should not be ruled out. It might be desirable to invest in two instruments: one designed to measure individuals' recovery and one designed to measure the recovery orientation of services. If Australia were to go down this path, it would make sense to align indicators in each as far as possible, and to ensure that they were consistent with existing endeavours aimed at monitoring and improving recovery-focused aspects of service quality. PMID- 21314239 TI - Protecting our patients' rights. PMID- 21314240 TI - Eradication therapies for HIV Infection: time to begin again. AB - Despite the success of antiretroviral therapy (ART) in decreasing mortality for HIV-1-infected patients, ART has not cured the disease. A persistent viral reservoir in the T cells of HIV patients receiving potent ART is a significant barrier preventing eradication of HIV infection. We will briefly review what is known about the mechanisms that establish and maintain persistent HIV infection despite ART, to create a framework in which to consider approaches to the clearance or eradication of infection ("cure"), or to allow clinical stability in the absence of ART ("functional cure"). With regard to eradication therapies, it could be said that as a field our position is analogous to that of ART early in the HIV pandemic. As then we must now simultaneously develop and optimize platforms and paradigms for the discovery and testing of eradication therapies, and begin to advance candidate therapies toward human testing. PMID- 21314241 TI - Human Vdelta1 gammadelta T cells expanded from peripheral blood exhibit specific cytotoxicity against B-cell chronic lymphocytic leukemia-derived cells. AB - BACKGROUND AIMS: There is increasing interest in using gammadelta T cells (GDTC) for cancer immunotherapy. Most studies have been concerned with the Vdelta2 subset in blood, for which several expansion protocols exist. We have developed a protocol to expand Vdelta1 and Vdelta2 preferentially from human blood. We have characterized these subsets and their specificities for leukemic targets. METHODS: GDTC were isolated from the peripheral blood mononuclear cells (PBMC) of healthy donors via positive magnetic cell sorting; their proliferation in vitro was induced by exposure to the mitogen concanavalin A (Con A). CD107 and cytotoxicity (Cr(51)-release and flow cytometric) assays were performed. GDTC clones and target cells were immunophenotyped via flow cytometry. RESULTS: Longer initial exposure to Con A typically resulted in higher Vdelta1 prevalence. Vdelta1 were activated by and cytotoxic to B-cell chronic lymphocytic leukemia (B CLL)-derived MEC1 cells, whereas Vdelta2 also responded to MEC1 but more so to the Philadelphia chromosome-positive [Ph+] leukemia cell line EM-enhanced green fluorescent protein (2eGFPluc). Vdelta2 clone cytotoxicity against EM-2eGFPluc correlated with Vdelta2 T-cell antigen receptor (TCR) and receptor found on Natural Killer cells and many T-cells (NKG2D), whereas Vdelta1 clone cytotoxicity versus MEC1 correlated with Vdelta1 TCR, CD56 and CD95 expression. Vdelta1 also killed Epstein-Barr Virus (EBV)-negative B-CLL-derived TMD2 cells. Immunophenotyping revealed reduced HLA-ABC expression on EM-2eGFPluc, whereas MEC1 and TMD2 exhibited higher Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAILR1). CONCLUSIONS: Our ability to expand peripheral Vdelta1 cells and show their cytotoxicity to B-CLL-derived cell lines suggests that this novel approach to the cellular treatment of B-CLL may be feasible. PMID- 21314242 TI - Mitochondrial genome of the American shad Alosa sapidissima. AB - The complete mitochondrial genome of Alosa sapidissima has been determined. The total length of the mitogenome was 16,697 bp and had a gene content (13 protein coding, 22 tRNAs and 2 rRNAs. Except for the seven tRNA and Nd6 genes, all other mitochondrial genes are encoded on the heavy strand. The overall base composition of the heavy strand is 28.3% A, 24.8% T, 28.9% C, 17.9% G, with an AT content of 53.1%. The DNA sequence of Alosa. sapidissima shared 97.1, 93.9, 88.8 and 82.3% sequence identity with that of Alosa alosa, Alosa pseudoharengus. Molecular data here presented provide a useful toll for evolutionary as well as population genetic studied. PMID- 21314243 TI - Functional studies (NeuroSPECT) of the human auditory pathway after stimulating binaurally with pure tones. AB - CONCLUSIONS: Our observations support the concept of bilateral cortical activation with monaural and binaural auditory stimulation. The observation that most of the significantly activated areas were the same with monaural or binaural stimulation suggests that the differences in auditory perception with binaural stimulation are not due to the involvement of significantly different processing centers but, more likely, to the type of information that reaches these centers for processing. The observation that the degree of stimulation was less intense in binaural than in monaural stimulation supports the concept that a richer binaural auditory stimulation compared with monaural stimulation does not mean summation of stimuli but integration and better processing of the information. For normal bilateral hearing subjects, a monaural stimulus is an uncommon event and may thus explain the more intense response. The repeatability of the results for monaural and binaural stimulation with pure tones in the same subjects confirms the consistency of the testing method. OBJECTIVES: (1) To determine which areas of the cerebral cortex and basal ganglia are activated by binaural stimulation with pure tones (left and right ear simultaneously) and what type of response occurs (e.g. excitatory or inhibitory) in these different areas. (2) To determine the degree of ipsilateral and/or contralateral cortical activation and/or inhibition. (3) To compare the data with our previous reports of monaural stimulation using the same technique and the same subjects. (4) To evaluate the consistency of our testing method. METHODS: Brain perfusion single photon emission computed tomography (SPECT) evaluation was conducted using auditory binaural stimulation with pure tones in six normal volunteers. Both ears were stimulated simultaneously. Tc99m HMPAO was injected while pure tones were delivered and the SPECT imaging was done 1 h later. RESULTS: After delivering pure tones there was bilateral activation in Brodmann areas 7 (somatosensory association cortex), 9 and 10 (executive frontal areas), 17, 18, and 19 (associative visual cortex). There was also activation in temporal areas 21, 22 (auditory association areas), and parietal areas 39 and 40 (Wernicke). There was also marked activation in both thalami. These activated areas were the same as those in our previous reports with monaural stimulation in the same subjects. However, except for areas 17, 18, 23, 31, and 32 (which remained over 4 SD above the normal maximum), the degree of activation was less intense in binaural compared with monaural stimulation. Inhibition was also less intense in binaural stimulation. PMID- 21314244 TI - Transtemporal management of temporal bone encephaloceles and CSF leaks: review of 56 consecutive patients. AB - CONCLUSIONS: This report details our experience in the management of 56 consecutive patients with mastoid encephaloceles and cerebrospinal fluid (CSF) leaks. The majority were managed through the transmastoid route with temporalis fascia and calvarial bone graft. Among the patients operated on at least 18 months before analysis, there was a median follow-up of 54 months with no intracranial complications. The average body mass index (BMI) of patients with spontaneous CSF leaks was found to be statistically significantly greater than that of patients with CSF leaks with traumatic, infectious or iatrogenic etiologies. OBJECTIVES: To investigate the long-term follow-up of patients with spontaneous, iatrogenic, and traumatic temporal bone encephaloceles and CSF leaks to determine the effectiveness of the repair, late intracranial complications, and recurrent lesions. METHODS: This is a retrospective review from a tertiary care center of 56 consecutive patients managed with CSF otorrhea, encephaloceles, and spontaneous pneumocephalus. All patients were repaired through transtemporal, middle cranial fossa or combined approaches for extradural repair and bone grafting. RESULTS: Of the 56 consecutive cases, 12 had CSF otorrhea alone, 19 had encephaloceles, and 23 had both. Two patients presented with spontaneous pneumocephalus without CSF leak. Thirty-three patients had spontaneous onset of their lesion without any history of temporal bone surgery or trauma. The average BMI of patients with spontaneous CSF leaks was found to be greater than the average BMI of patients with CSF leaks due to traumatic, infectious or iatrogenic causes. This difference was found to be statistically significant. Six of these had either preceding or subsequent contralateral mastoid or anterior fossa (sphenoid, ethmoid) CSF leak. Intracranial pressure was evaluated in these cases and most underwent VP shunting to reduce their intracranial pressure. Sixteen cases followed previous mastoid surgery or chronic ear disease and seven were attributed to previous temporal bone trauma. Lesions were repaired with the transtemporal approach (42), middle fossa (4), and combined (5) approaches. Five cases required petrosectomy and fat obliteration. There was one recurrent CSF leak 4 years after initial repair; the leak was anterior to the previously placed bone graft. PMID- 21314245 TI - Meta-analysis of ACE gene I/D polymorphism and bipolar disorder susceptibility. AB - BACKGROUND: A number of studies have been conducted to explore the association between ACE gene insertion/deletion (I/D) polymorphism and bipolar disorder (BPD). However, the reported results were conflicting. AIMS: The aim of our study was to find evidence on whether ACE gene I/D polymorphism is associated with BPD using a meta-analysis. METHODS: Data were collected from the following electronic databases: Pubmed, Elsevier Science Direct, Cochrane Library, CBM, CNKI and Wanfang. Meta-analysis was performed for genotypes ID vs. II, DD vs. II, DD vs. ID + II, ID + DD vs. II, and D allele vs. I allele in a fixed/random effect model. RESULTS: Seven studies that included data from 605 cases and 1541 controls were identified. When all groups were pooled, we did not detect the association of ACE gene I/D polymorphism with BPD (P > 0.05). In the subgroup analysis, we did not detect the association of ACE gene I/D polymorphism with BPD in Caucasians (P > 0.05). An association of ACE gene I/D polymorphism with BPD was found in Asians for the contrast of DD vs. ID + II (OR = 2.01, 95% CI 1.08-3.74, P = 0.03), but not for other contrasts (P > 0.05). CONCLUSIONS: This meta analysis suggests that there may be an association of ACE gene I/D polymorphism with BPD in Asians. Further studies are still needed in Asians. PMID- 21314246 TI - Synthesis and biological evaluation of 2,5-disubstituted 1,3,4-oxadiazole derivatives with both COX and LOX inhibitory activity. AB - Dual cyclooxygenase/lipoxygenase (COX/LOX) inhibitors constitute a valuable alternative to classical nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors for the treatment of inflammatory diseases. A series of 3-(5-phenyl/phenylamino-[1,3,4]oxadiazol-2-yl)-chromen-2-one and N-[5-(2-oxo 2H-chromen-3-yl)-[1,3,4]oxadiazol-2-yl]-benzamide derivatives were synthesized and screened for anti-inflammatory, analgesic activity. All the derivatives prepared are active in inhibiting oedema induced by carrageenan. Compound 4e was found more potent with 89% of inhibition followed by compound 4b (86%). Compounds with >70% of anti-inflammatory activity were tested for analgesic, ulcerogenic, and lipid peroxidation profile. Selected compounds were also evaluated for inhibition of COXs (COX-1 and COX-2) and LOXs (LOX-5, LOX-12, and LOX-15). Compound 4e was comparatively selective for COX-2, LOX-5, and LOX-15. Study revealed that these derivatives were more effective than ibuprofen with reduced side effects. It can be suggested that these derivatives could be used to develop more potent and safer NSAIDs. PMID- 21314247 TI - Incidence of neutropenia, chemotherapy delivery, and use of colony-stimulating factor in patients with non-Hodgkin lymphoma of different age groups. PMID- 21314248 TI - Use of DOP-PCR for amplification and labeling of BAC DNA for FISH. AB - Fluorescence in situ hybridization (FISH) is a powerful molecular cytogenetic method that permits rapid detection of specific chromosomal rearrangements. It is based on the hybridization of fluorescent labeled probes to metaphase chromosomes or interphase nuclei. The DNA probes commonly are generated from cloned sources such as bacterial artificial chromosomes (BACs). The major disadvantage of this approach is that it requires laborious and time-consuming work. We used a degenerate oligonucleotide primed polymerase chain reaction (DOP-PCR) for both amplification and labeling of very small amounts of purified BAC DNA for FISH. The DOP-PCR reaction was processed in two steps: pre-amplification followed by simultaneous amplification and labeling of BAC DNA. The DOP-PCR probes obtained provided good hybridization signals and low background. Thus, DOP-PCR can be used to produce unlimited quantities of FISH probes with decreased cost and labor. PMID- 21314249 TI - Epidemiology of superficial fungal diseases in French Guiana: a three-year retrospective analysis. AB - A three-year retrospective analysis of fungi isolated from specimens of patients with superficial fungal infections in French Guiana is presented. Clinical samples from 726 patients with presumptive diagnoses of onychomycosis (28.2% of the patients), tinea capitis (27.8%), superficial cutaneous mycoses of the feet (22.0%), and of other areas of the body (21.9%), were assessed by microscopic examination and culture. Dermatophytes accounted for 59.2% of the isolates, followed by yeasts (27.5%) and non-dermatophytic molds (13.1%). Trichophyton rubrum was the most common dermatophyte recovered from cases of onychomycosis (67.4%), tinea pedis (70.6%) and tinea corporis (52.4%). In contrast, Trichophyton tonsurans was the predominant species associated with tinea capitis (73.9%). Yeasts were identified as the principal etiologic agents of onychomycosis of the fingernails (74.2%), whereas molds were found mainly in cases of onychomycosis of the toenails. In such instances, Neoscytalidium dimidiatum (70.8%) was the most common mold recovered in culture. In conclusion, the prevalence of T. rubrum and the occurrence of onychomycosis and fungal infections of the feet in French Guiana are similar to results reported from Europe, whereas the frequency of tinea capitis and the importance of T. tonsurans in such infections are similar to the situation in the Americas. PMID- 21314250 TI - Risk factors for invasive aspergillosis in acute myeloid leukemia patients prophylactically treated with posaconazole. AB - Invasive aspergillosis (IA) is an important cause of morbidity and mortality in neutropenic patients with hematological malignancies. To investigate the immediate and mid-term benefits of posaconazole prophylaxis in AML patients undergoing first induction chemotherapy and to study the infection risk factors, we prospectively studied the IA incidence in these patients at our hospital between years 2007 and 2008; then we compared them to a matched control group without prophylaxis. There were 55 and 66 patients in each group respectively. At day 32 post-induction, two probable cases (3.6%) were scored in the prophylaxis group compared to 8 cases (12.1%) in the control group (4 possible and 4 probable). At day 100, it reached 7.27% and 15.5% respectively. Kaplan-Meier analysis at day 100 showed lower mortality rate in the prophylaxis group compared to the control group [3.64% (n = 2, none due to IA) and 10.61% (n = 7, four due to IA) respectively, P = 0.002]. Multivariate analysis showed age and lack of response to induction as independent infection risk factors. Posaconazole prophylaxis resulted in lower incidence of IA and significantly improved survival. Patient's age and response to induction treatment are two independent infection risk factors, and need more attention during future clinical trials linked to antifungal prophylaxis. PMID- 21314251 TI - Toward a comprehensive developmental model for alcohol use disorders in men. AB - The multiple risk factors for alcohol use (AU) and alcohol use disorders (AUDs) are interrelated through poorly understood pathways, many of which begin in childhood. In this report, the authors seek to develop an empirical, broad-based developmental model for the etiology of AU and AUDs in men. We assessed 15 risk factors in four developmental tiers in 1,794 adult male twins from the Virginia population based twin registry. The best fitting model explained 39% of the variance in late adolescent AU, and 30% of the liability to lifetime symptoms of AUD. AU and AUDs can be best understood as arising from the action and interaction of two pathways reflecting externalizing genetic/temperamental and familial/social factors. Peer group deviance was important in each pathway. Internalizing symptoms played a more minor role. Familial/social factors were especially important influences on AU, while genetic/temperamental factors were more critical for AUDs. We conclude that AU and AUDs in men are complex traits influenced by genetic, family, temperamental, and social factors, acting and interacting over developmental time. PMID- 21314252 TI - Evidence of overlapping genetic diathesis of panic attacks and gastrointestinal disorders in a sample of male twin pairs. AB - We explored the comorbidity between panic attacks (PA), whose symptoms can include gastrointestinal discomfort, and gastrointestinal disorders (GD). Structural equation modeling was used to analyze data from 1,874 MZ and 1,498 DZ male-male twin pairs from the Vietnam Era Twin Registry. PA and GD were associated (relative risk for GD = 2). The percentage of liability due to genetic factors was estimated to be 37% for PA and 31% for GD. There was significant correlation between the genetic risk factors for PA and GD (estimated r = .55, 95% CI of 34% to 82%) and no evidence of correlation between the environmental causes of PA and GD. Therefore, PA and GD comorbidity can be explained by overlapping genetic factors and not overlapping environmental factors. Although these data cannot identify a biological pathway for such a shared liability, it suggests the presence of GD may be informative for genetic studies of panic. PMID- 21314253 TI - Variance components models for physical activity with age as modifier: a comparative twin study in seven countries. AB - Physical activity is influenced by genetic factors whose expression may change with age. We employed an extension to the classical twin model that allows a modifier variable, age, to interact with the effects of the latent genetic and environmental factors. The model was applied to self-reported data from twins aged 19 to 50 from seven countries that collaborated in the GenomEUtwin project: Australia, Denmark, Finland, Norway, Netherlands, Sweden and United Kingdom. Results confirmed the importance of genetic influences on physical activity in all countries and showed an age-related decrease in heritability for 4 countries. In the other three countries age did not interact with heritability but those samples were smaller or had a more restricted age range. Effects of shared environment were absent, except in older Swedish participants. The study confirms the importance of taking age effects into account when exploring the genetic and environmental contribution to physical activity. It also suggests that the power of genome-wide association studies to identify the genetic variants contributing to physical activity may be larger in young adult cohorts. PMID- 21314254 TI - Trait emotional intelligence and the dark triad traits of personality. AB - This study presents the first behavioral genetic investigation of the relationships between trait emotional intelligence (trait EI or trait emotional self-efficacy) and the Dark Triad traits of narcissism, Machiavellianism, and psychopathy. In line with trait EI theory, the construct correlated positively with narcissism, but negatively with the other two traits. Generally, the correlations were consistent across the 4 factors and 15 facets of the construct. Cholesky decomposition analysis revealed that the phenotypic associations were primarily due to correlated genetic factors and secondarily due to correlated nonshared environmental factors, with shared environmental factors being nonsignificant in all cases. Results are discussed from the perspective of trait EI theory with particular reference to the issue of adaptive value. PMID- 21314255 TI - The Norfolk Island Eye Study (NIES): rationale, methodology and distribution of ocular biometry (biometry of the bounty). AB - AIM: To describe the recruitment, ophthalmic examination methods and distribution of ocular biometry of participants in the Norfolk Island Eye Study, who were individuals descended from the English Bounty mutineers and their Polynesian wives. METHODS: All 1,275 permanent residents of Norfolk Island aged over 15 years were invited to participate, including 602 individuals involved in a 2001 cardiovascular disease study. Participants completed a detailed questionnaire and underwent a comprehensive eye assessment including stereo disc and retinal photography, ocular coherence topography and conjunctival autofluorescence assessment. Additionally, blood or saliva was taken for DNA testing. RESULTS: 781 participants aged over 15 years were seen (54% female), comprising 61% of the permanent Island population. 343 people (43.9%) could trace their family history to the Pitcairn Islanders (Norfolk Island Pitcairn Pedigree). Mean anterior chamber depth was 3.32mm, mean axial length (AL) was 23.5mm, and mean central corneal thickness was 546 microns. There were no statistically significant differences in these characteristics between persons with and without Pitcairn Island ancestry. Mean intra-ocular pressure was lower in people with Pitcairn Island ancestry: 15.89mmHg compared to those without Pitcairn Island ancestry 16.49mmHg (P = .007). The mean keratometry value was lower in people with Pitcairn Island ancestry (43.22 vs. 43.52, P = .007). The corneas were flatter in people of Pitcairn ancestry but there was no corresponding difference in AL or refraction. CONCLUSION: Our study population is highly representative of the permanent population of Norfolk Island. Ocular biometry was similar to that of other white populations. Heritability estimates, linkage analysis and genome-wide studies will further elucidate the genetic determinants of chronic ocular diseases in this genetic isolate. PMID- 21314256 TI - Genetic and environmental contributions to the overlap between psychological, fatigue and somatic symptoms: a twin study in Sri Lanka. AB - BACKGROUND: Somatic symptoms often co-occur with psychological symptoms but this overlap is poorly understood. Some aspects of this overlap differ in the South Asian context, but it is not clear whether this is a reporting effect or an underlying difference in experienced illness. METHODS: Home interviews were administered to 4,024 twins randomly selected from a population-based twin register in the Colombo district of Sri Lanka (the CoTASS study). These included assessments of psychological, somatic and fatigue symptoms. The data were analyzed using factor analytic and quantitative genetic approaches. RESULTS: Confirmatory factor analysis showed that the symptoms from the three scales represented three separate dimensions, rather than all tapping into a single dimension. However, familial correlations among the data were most consistent with a common pathway model. This implies that a portion of the underlying vulnerability is common across psychological, fatigue and somatic symptoms. There were sex differences in the etiology of this model, with shared environmental and genetic influences playing different roles in men and women. CONCLUSIONS: There is a complex etiological relationship between psychological, fatigue and somatic symptoms. This is similar in Sri Lanka to Western countries, but there may be a greater influence from the family environment, suggesting that care needs to be taken when generalizing research findings between countries. People who complain of certain fatigue or somatic symptoms may well also have psychological symptoms, or may have genetic or environmental vulnerabilities to such problems. PMID- 21314257 TI - Strong genetic correlation between interview-assessed internalizing disorders and a brief self-report symptom scale. AB - Self-report scales for symptoms of anxiety and depression are frequently used for screening and research purposes. A moderate phenotypic association between disorders measured by diagnostic interviews and symptoms of anxiety and depression measured by self-report scales has been shown, but little is known about the overlap in these phenotypes' genetic and environmental variance. In the present study, we used twin modeling to identify common genetic and environmental liabilities underlying the phenotypic association between the self-report Symptom Checklist-5 (SCL-5) and lifetime internalizing disorders derived from the Composite International Diagnostic Interview (CIDI). The sample consisted of 7,992 young adult twins from the Norwegian Institute of Public Health Twin Panel (NIPHT), who all responded to a questionnaire. A subset of 2,793 individuals later underwent structured interviews. The best fitting model showed a strong genetic correlation of 0.82 (95% confidence interval; 0.61-1.0) between current self-report symptoms of anxiety and depression, and lifetime internalizing disorders, which suggests an almost complete overlap in genetic liability. The correlation between environmental factors was much lower: 0.16 (0.00-0.34, 95% CI). This implies that brief self-report scales capture genetic variance that is highly overlapping with the genetic variance common to internalizing disorder diagnoses. It thus follows that SCL-5 and similar instruments may be used as screening instruments for genetic risk factors that influence liability to internalizing disorders. In addition, existing data on self-report symptoms of anxiety and depression can be used with increased confidence to specify models including effects from genes coding for internalizing disorders. PMID- 21314258 TI - Relationships between state and trait anxiety inventory and alcohol use disorder identification test scores among Korean twins and families: the healthy twin study. AB - We explored heritabilities of the State and Trait Anxiety Inventory (STAI) and the Alcohol Use Disorders Identification Test (AUDIT), and associations including genetic and environmental correlations between the phenotypes among Korean twins and their families. We analyzed the data of 1,748 participants (835 men, 913 women, 656 individuals of monozygotic twins, 173 individuals of same-sexed dizygotic twins, 919 non-twin family members, age 30-79 years) from the Healthy Twin study. Heritabilities and bivariate analyses were assessed using the SOLAR package software. In the methods of generalized estimation equations, women in the 4th quartile of state and trait scores were 17% and 15%, respectively more likely to be hazardous alcohol users compared to women in the lower three quartiles (P < .05). However, there were no significant associations between these phenotypes in men. After adjusting for age and squared age, the heritability estimates were 0.26 in men and 0.34 in women for the state score; for the trait score, 0.35 in men and 0.31 in women; for the AUDIT score, 0.32 in men and 0.37 in women (P < .001). After adjusting for age and squared age, there was a significant genetic correlation between the trait score and the AUDIT score, and a significant non-genetic correlation between the state score and the AUDIT score in women, while there were no significant genetic or non-genetic correlations between these phenotypes in men. The STAI and AUDIT scores are heritable in Koreans and the relationships between these phenotypes may be inconsistent by sex. PMID- 21314259 TI - Monozygotic twins concordant and discordant for DCD: two sides to the story. AB - Being an identical twin does not necessarily mean having identical perceptions of family functioning, nor of the twin relationship. Using the co-twin control design, the aim of this study was to explore perceptions of family dynamics and the twin relationship in monozygotic (MZ) twins discordant and concordant for Developmental Coordination Disorder (DCD). It was hypothesized that, as has been found in twins discordant for cerebral palsy, twins without DCD would perceive family functioning as less healthy than would their co-twins with DCD. It was also hypothesized that the twin relationship would be regarded generally as mutually supportive. Questionnaire data on 866 sets of MZ twins aged 6 to 17 years were used to identify seven sets discordant, and two sets concordant for DCD. Quantitative (General Functioning Scale of the Family Assessment Device - FAD), and qualitative (semi-structured interview) measures were used to assess family dynamics and the twin relationship. In discordant sets, six of seven twins without DCD rated family functioning at a less healthy level than did their co twins with DCD. All twins in the DCD concordant sets rated their family functioning at a healthy level. From the semi-structured interviews, emergent themes included friendship, support, minimal sibling rivalry, and minor difficulties. It was concluded that, overall, the twin relationship was regarded as close and mutually supportive, with an ambivalent polarity between the best and most difficult aspects of being an identical twin. Implications for research, policy and clinical practice are discussed. PMID- 21314260 TI - Perinatal outcome of twins compared to singletons of the same gestational age: a case-control study. AB - Our objective was to determine the perinatal outcome of first- and second-born twins compared to singletons, born at the same gestational age. To that end we conducted a case-control study in Flanders (Northern Belgium). During a 10-year period (01.01.1999-31.12.2008), the entire twin population - 11,154 first- and 11,118 second-born twins (cases) - was compared to 22,228 singletons (controls) with respect to fetal and neonatal (0-27 days) mortality. Only case and control infants of >= 500 grams were included, which explained the unequal number of first- and second-born twins. Mothers and their infants of cases and of controls were derived from the Flemish perinatal database and were matched for maternal age and parity, gestational age and gender of the offspring. The main outcome measures were fetal and neonatal mortality according to gestational age. The frequency of fetal death was statistically significantly less frequent in preterm born twins than in singletons, except at term where the reverse was seen in second-born twins compared to controls. After adjustment for congenital malformations, the results stayed unchanged. Below 28 weeks gestation, singletons had a significantly lower neonatal mortality rate than twins that persisted after adjustment for congenital malformations: the first-born twin versus singleton OR 1.71 (1.17-2.51) and second-born versus singleton OR 2.09 (1.43-3.05). Between 28 and 32 weeks, the second-born twin showed a survival advantage over the control singleton. Between 32 and 36 6/7 weeks both twins had a significantly higher survival rate than the corresponding singleton controls. However, after adjustment for congenital malformations, the aforementioned differences between 28 and 36 6/7 weeks disappeared. When at term, twins and singletons had a comparable, though very low, neonatal death rate. These results confirm previous published data. In conclusion, we demonstrated that the neonatal death rate was lower for twins between 32 and 36 weeks (from 28 weeks for the second born twin) when compared to a singleton of the same gestational age. After adjusting for congenital malformations, there was no statistical significant difference. PMID- 21314261 TI - Insulin-like growth factor-1 levels in twins and its correlation with discordance. AB - This study aims to determine whether fetal growth is related to insulin-like growth factor-1 in dichorionic and monochorionic twins and also aims to investigate the correlation of insulin-like growth factor-1 to birthweight discordance in twins. We studied 100 women with twin pregnancies. The correlation tests of 36 discordant twins (15 monochorionic, 21 dichorionic) showed correlation between insulin-like growth factor-1 difference and birthweight discordance (insulin-like growth factor-1 vs. birthweight of first twin, r = +0.915, at 0.01 level, IGF-1 vs birthweight of second twin r = +0.790, at 0.01 level). In 49 monochorionic twins, independent of discordance, there was a correlation between birthweight discordance and insulin-like growth factor-1 difference (r = .538, at the 0.01 level). This correlation was not significant in dichorionic twins, r = .144, p = .01. These data suggest that growth discordances of twins exposed to the same maternal environment may be due to variations in IGF 1, depending upon the genetic similarity. PMID- 21314262 TI - Obstetric and perinatal outcomes of dichorionic twin pregnancies according to methods of conception: spontaneous versus in-vitro fertilization. AB - We have observed the inconsistent findings from various studies on twin pregnancy outcomes obtained by assisted reproductive technology and spontaneous conception. In most studies, however, the concrete chorionicity, regarded as a confounding factor for predicting the perinatal outcomes of twin pregnancies, has not been determined. The purpose of this study was to compare obstetric and perinatal outcomes of only the dichorionic twin pregnancies according to the methods of conception: spontaneous and in-vitro fertilization (IVF). The twin pairs with dichorionicity reported from 1995 to 2008 were investigated and we divided them into two groups which consisted of 286 and 134 twins by spontaneous conception and IVF, respectively. Odds ratios for associations between IVF and pregnancy outcomes were analyzed after adjustment for maternal age and parity. There were no risk differences between the two groups regarding the obstetric complications, which include preterm delivery, preterm labor, preterm premature rupture of membranes, preeclampsia, placenta previa, and abruption. Any differences were not shown in the two groups for the risk estimates of perinatal outcomes, such as low birthweight, very low birthweight, small for gestational age, Apgar scores of < 7 at 5 minutes, discordance in birthweights, congenital anomalies and mortality. However, twins conceived after IVF were less likely to be admitted to the neonatal intensive care unit than those conceived spontaneously (adjusted OR 0.488; 95% confidence interval 0.261-0.910). In the cases of dichorionic twins, IVF may not be associated with adverse perinatal and obstetric outcomes compared with spontaneous conception. PMID- 21314263 TI - Zygosity assessment by self-report; research reports; human interest. AB - The research implications and personal perspectives associated with twins' and families' self-reports of zygosity are reviewed. This is followed by summaries of recent research reports including a possible first case of the freemartin effect in humans, twin-singleton comparisons of mental health in Japanese students and mechanisms associated with ART-induced monozygotic twinning. A look at twin stories in the media includes the extraordinary revival of an infant male twin, the career decision of a pair of MZ twin basketball players and the loss of a five-year-old triplet. PMID- 21314265 TI - An examination of somatosensory area SIII in ferret cortex. AB - A somatotopically organized region on the suprasylvian gyrus of the ferret was examined using multiunit recordings and anatomical tracer injections. This area, which contains a representation of the face, was bordered by the primary somatosensory area (SI), anteriorly, and by the visually responsive rostral posterior parietal cortex (PPr), posteriorly. Anatomical tracers revealed connections to this region from cortical areas MI, SI, MRSS, PPr, and the thalamic posterior nucleus. These results are consistent with previous work in ferrets as well as with the location, physiology, and connectivity of area SIII in cats. Given its associations, functional properties, location, and homology, it is proposed that this region represents the third cortical somatosensory area (SIII) in ferrets. PMID- 21314266 TI - Immunosuppressive activity of florfenicol on the immune responses in mice. AB - Florfenicol is a new type of broad-spectrum antibacterial that has been used in veterinary clinics. It shows immunosuppressive activity on the immune responses to ovalbumin (OVA) in mice. In the present study, florfenicol suppressed lipopolysaccharide (LPS)-stimulated splenocyte proliferation in a concentration dependent manner in vitro and in vivo. BALB/c mice were immunized subcutaneously with OVA on days 1 and 4. Following the second immunization, mice were treated with a single daily oral dose of florfenicol (50, 100, and 200 mg/kg) for 10 consecutive days. On day 14, blood samples were collected to analyze OVA-specific IgG, IgG1, and IgG2b antibodies, and splenocytes were harvested to assess lymphocyte proliferation, CD3(+) T and CD19(+) B lymphocyte subsets. The results presented here demonstrate that florfenicol not only significantly suppressed Con A-, LPS- and OVA-induced splenocyte proliferation but also decreased the percentage of CD19(+) B cells in a dose-dependent manner and suppressed CD3(+) T cell at high doses. Moreover, OVA-specific IgG, IgG1 and IgG2b titers in OVA immunized mice were reduced by florfenicol. These results suggest that florfenicol could suppress humoral and cellular immune responses in mice. PMID- 21314267 TI - Topographic relationship between the medial intermuscular septum and the ulnar nerve in the upper arm. AB - OBJECT: The authors have observed that the ulnar nerve (UN) passes through the medial intermuscular septum (MIMS) into the posterior compartment of the upper arm in more complicated patterns than those described in anatomy textbooks. Given that these unreported patterns might be related to the idiopathic UN entrapment at the midarm, this study focused on the relationship between the MIMS and the UN. METHODS: One hundred upper arms were dissected. The site at which the UN pierced the MIMS was analyzed and measured from the medial epicondyle. RESULTS: The relationship between the MIMS and the UN could be classified into 3 types according to whether the nerve pierced the MIMS and whether it ran through a fibrous tunnel within the septum. The UN pierced the MIMS in the middle third of the upper arm. CONCLUSIONS: The results of this study are expected to further understanding of the relationship between the MIMS and the UN. They could also be helpful for surgeons aiming to relieve UN entrapment at the midarm, especially in nerve lesions of idiopathic origin. PMID- 21314269 TI - Gamma Knife surgery for parasellar meningiomas: long-term results including complications, predictive factors, and progression-free survival. AB - OBJECT: Stereotactic radiosurgery serves as an important primary and adjuvant treatment option for patients with many types of intracranial meningiomas. This is particularly true for patients with parasellar meningiomas. In this study, the authors evaluated the outcomes of Gamma Knife surgery (GKS) used to treat parasellar meningiomas. METHODS: The study is a retrospective review of the outcomes in 138 patients with meningiomas treated at the University of Virginia from 1989 to 2006; all patients had a minimum follow-up of 24 months. There were 31 men and 107 women whose mean age was 54 years (range 19-85 years). Eighty-four patients had previously undergone resection. The mean pre-GKS tumor volume was 7.5 ml (range 0.2-54.8 ml). Clinical and radiographic evaluations were performed, and factors related to favorable outcomes in each case were assessed. RESULTS: The mean follow-up duration was 84 months (median 75.5 months, range 24-216 months). In 118 patients (86%), the tumor volume was unchanged or had decreased at last follow-up. Kaplan-Meier analysis demonstrated radiographic progression free survival at 5 and 10 years to be 95.4% and 69%, respectively. Fourteen patients (10%) developed new cranial nerve palsies following GKS. Factors associated with tumor control included younger age, a higher isodose, and smaller tumor volume. A longer follow-up duration was associated with either a decrease or increase in tumor volume. Fourteen patients (10%) experienced new or worsening cranial nerve deficits after treatment. Factors associated with this occurrence were larger pretreatment tumor volume, lower peripheral radiation dose, lower maximum dose, tumor progression, and longer follow-up. CONCLUSIONS: Gamma Knife surgery offers an acceptable rate of tumor control for parasellar meningiomas and accomplishes this with a low incidence of neurological deficits. Radiological control after radiosurgery is more likely in those patients with a smaller tumor volume and a higher prescription dose. PMID- 21314270 TI - Quality of life in patients with intracranial gliomas: the impact of modern image guided surgery. AB - OBJECT: Outcome following brain tumor operations is often assessed by health professionals using various gross function scales. However, surprisingly little is known about how modern glioma surgery affects quality of life (QOL) as reported by the patients themselves. In the present study the authors aimed to assess changes in QOL after glioma surgery, to explore the relationship between QOL and traditional outcome parameters, and to examine possible predictors of change in QOL. METHODS: Eighty-eight patients with glioma were recruited from among those 16 years or older who had been admitted to the authors' department for brain tumor surgery in the period between January 2007 and December 2009. A 3D ultrasonography-based navigation system was utilized in nearly all operations and functional MR imaging data on eloquent lesions were incorporated into the neuronavigation system. Preoperative scores for QOL (EuroQol 5D [EQ-5D]) and functional status (Karnofsky Performance Scale [KPS]) were obtained. The EQ-5D and KPS scores were subsequently recorded 6 weeks postoperatively, as were responses to a structured interview about new deficits and possible complications. RESULTS: There was no change in the median EQ-5D indexes following surgery, 0.76 versus 0.75 (p = 0.419). The EQ-5D index value was significantly correlated with the KPS score (p < 0.001; rho = 0.769). The EQ-5D index values and KPS scores improved in 35.2% and 24.1% of cases, were equal in 20.5% and 47.2% of cases, and deteriorated in 44.3% and 28.7%, respectively. Thus, both improvement and deterioration were underestimated by the KPS score as compared with the patient-reported QOL assessment. New motor deficits (p = 0.003), new language deficits (p = 0.035), new unsteadiness and/or ataxia (p = 0.001), occipital lesions (p = 0.019), and no use of ultrasonography for resection control (p = 0.021) were independent predictors of worsening QOL in a multivariate model. CONCLUSIONS: The surgical procedures per se may not significantly alter QOL in the average patient with glioma; however, new deficits have a major undesirable effect on QOL. It seems that the active use of intraoperative ultrasonography may be associated with a preservation of QOL. The EQ-5D seems like a good outcome measure with a strong correlation to traditional variables while offering a more detailed description of outcome. PMID- 21314271 TI - Gamma Knife and meningiomas. PMID- 21314272 TI - Laparoscopic versus open insertion of the peritoneal catheter in ventriculoperitoneal shunt placement: review of 810 consecutive cases. AB - OBJECT: Traditional ventriculoperitoneal (VP) shunt surgery involves insertion of the distal catheter by minilaparotomy. However, minilaparotomy may be a significant source of morbidity during shunt surgery. Laparoscopic insertion of the distal catheter is an alternative technique that may simplify and improve the safety of shunt surgery. METHODS: The authors performed a retrospective review of hospital records of all patients undergoing new VP shunt insertion at a tertiary care center between 2004 and 2009. Patient characteristics and outcomes were compared between patients undergoing open or laparoscopic insertion of the distal catheter. Independent variables in the analysis included age, sex, race, body mass index, surgical technique, previous VP shunt placement, previous abdominal procedures, American Society of Anesthesiology (ASA) score, and indication for shunt placement. Dependent variables included the occurrence of shunt failure, cause of shunt failure, complications, length of stay (LOS), LOS after shunt placement, estimated blood loss, and operative time. RESULTS: The authors identified 810 patients who met the inclusion criteria; open or laparoscopic distal catheter insertion was performed in 335 and 475 patients, respectively. There were no significant differences between the groups regarding age, race, ASA score, or indication for shunt placement. The most common indication was hydrocephalus due to subarachnoid hemorrhage, followed by tumor-associated hydrocephalus, normal pressure hydrocephalus (NPH), and hydrocephalus due to trauma. The incidence of shunt failure was not statistically different between cohorts, occurring in 20.0% of laparoscopic and 20.9% of open catheter placement cases (p = 0.791). With analysis of causes of shunt failure, shunt obstruction occurred significantly more often in the open surgery cohort (p = 0.012). In patients with a known cause shunt obstruction, distal obstruction occurred in 35.7% of the open cohort obstructions and 4.8% of the laparoscopic cohort obstructions (p = 0.014). The relative risk of distal obstruction in open cases compared with laparoscopic cases was 7.50. Infections occurred in 8.2% of laparoscopic cases compared with 6.6% of open cases (p = 0.419). Within the NPH subgroup, the laparoscopically treated patients had significantly more overdrainage (p = 0.040), whereas those in the open cohort experienced significantly more shunt obstructions (p = 0.034). Laparoscopically treated patients had shorter operative times (p < 0.0005), inpatient LOS (p < 0.001), and inpatient LOS after VP shunt placement (p = 0.01) as well as less blood loss (p = 0.058). CONCLUSIONS: To our knowledge this is the largest reported comparison of distal VP shunt catheter insertion techniques. Compared with minilaparotomy, the laparoscopic approach was associated with decreased time in the operating room and a decreased LOS. Moreover, laparoscopy was associated with fewer distal shunt obstructions. Laparoscopic shunt surgery is a viable alternative to traditional shunt surgery. PMID- 21314273 TI - Real-time control of a prosthetic hand using human electrocorticography signals. AB - OBJECT: A brain-machine interface (BMI) offers patients with severe motor disabilities greater independence by controlling external devices such as prosthetic arms. Among the available signal sources for the BMI, electrocorticography (ECoG) provides a clinically feasible signal with long-term stability and low clinical risk. Although ECoG signals have been used to infer arm movements, no study has examined its use to control a prosthetic arm in real time. The authors present an integrated BMI system for the control of a prosthetic hand using ECoG signals in a patient who had suffered a stroke. This system used the power modulations of the ECoG signal that are characteristic during movements of the patient's hand and enabled control of the prosthetic hand with movements that mimicked the patient's hand movements. METHODS: A poststroke patient with subdural electrodes placed over his sensorimotor cortex performed 3 types of simple hand movements following a sound cue (calibration period). Time frequency analysis was performed with the ECoG signals to select 3 frequency bands (1-8, 25-40, and 80-150 Hz) that revealed characteristic power modulation during the movements. Using these selected features, 2 classifiers (decoders) were trained to predict the movement state--that is, whether the patient was moving his hand or not--and the movement type based on a linear support vector machine. The decoding accuracy was compared among the 3 frequency bands to identify the most informative features. With the trained decoders, novel ECoG signals were decoded online while the patient performed the same task without cues (free-run period). According to the results of the real-time decoding, the prosthetic hand mimicked the patient's hand movements. RESULTS: Offline cross validation analysis of the ECoG data measured during the calibration period revealed that the state and movement type of the patient's hand were predicted with an accuracy of 79.6% (chance 50%) and 68.3% (chance 33.3%), respectively. Using the trained decoders, the onset of the hand movement was detected within 0.37 +/- 0.29 seconds of the actual movement. At the detected onset timing, the type of movement was inferred with an accuracy of 69.2%. In the free-run period, the patient's hand movements were faithfully mimicked by the prosthetic hand in real time. CONCLUSIONS: The present integrated BMI system successfully decoded the hand movements of a poststroke patient and controlled a prosthetic hand in real time. This success paves the way for the restoration of the patient's motor function using a prosthetic arm controlled by a BMI using ECoG signals. PMID- 21314274 TI - Geographic variation and regional trends in adoption of endovascular techniques for cerebral aneurysms. AB - OBJECT: Considerable evolution has occurred in treatment options for cerebral aneurysms. Development of endovascular techniques has produced a significant change in the treatment of ruptured and unruptured intracranial aneurysms. Adoption of endovascular techniques and increasing numbers of patients undergoing endovascular treatment may affect health care expenditures. Geographic assessment of growth in endovascular procedures has not been assessed. METHODS: The National Inpatient Sample (NIS) was queried for ICD-9 codes for clipping and coiling of ruptured and unruptured cerebral aneurysms from 2002 to 2008. Patients with ruptured and unruptured cerebral aneurysms were compared according to in-hospital deaths, hospital length of stay, total hospital cost, and selected procedure. Hospital costs were adjusted to bring all costs to 2008 equivalents. Regional variation over the course of the study was explored. RESULTS: The NIS recorded 12,588 ruptured cerebral aneurysm cases (7318 clipped and 5270 coiled aneurysms) compared with 11,606 unruptured aneurysm cases (5216 clipped and 6390 coiled aneurysms), representing approximately 121,000 aneurysms treated in the study period. Linear regression analysis found that the number of patients treated endovascularly increased over time, with the total number of endovascular patients increasing from 17.28% to 57.59% for ruptured aneurysms and from 29.70% to 62.73% for unruptured aneurysms (p < 0.00001). Patient age, elective status, and comorbidities increased the likelihood of endovascular treatment (p < 0.00001, p < 0.00004, and p < 0.02, respectively). In patients presenting with subarachnoid hemorrhage (SAH), endovascular treatments were more commonly chosen in urban and academic medical centers (p = 0.009 and p = 0.05, respectively). In hospital deaths decreased over the study period in patients with both ruptured and unruptured aneurysms (p < 0.00001); presentation with SAH remained the single greatest predictor of death (OR 38.09, p < 0.00001). Geographic analysis showed growth in endovascular techniques concentrated in eastern and western coastal states, with substantial variation in adoption of endovascular techniques (range of percentage of endovascular patients [2008] 0%-92%). There were higher costs in patients treated endovascularly, but these differences were likely secondary to presenting diagnosis and site-of-service variations. CONCLUSIONS: The NIS database reveals a significant increase in the use of endovascular techniques, with the majority of both ruptured and unruptured aneurysms treated endovascularly by 2008. Differences in hospital costs between open and endovascular techniques are likely secondary to patient and site-of-service factors. Presentation with SAH was the primary factor affecting hospital cost and a greater percentage of endovascular procedures completed at urban academic medical centers. There is substantial regional variation in the adoption of endovascular techniques. PMID- 21314275 TI - IL-6 polymorphism associated with fatal outcome in patients with severe traumatic brain injury. AB - OBJECTIVE: The aim of this study was to test whether a functional polymorphism ( 174C/G) located in the promoter region of the interleukin-6 (IL-6) gene is associated with primary short-term outcome (death or Intensive Care Unit discharge) in patients with severe traumatic brain injury (TBI). METHODS: The study group consisted of 77 male patients who suffered severe TBI. The -174C/G IL 6 polymorphism was analysed by polymerase chain reaction (PCR) followed by restriction digestion. RESULTS: Severe TBI was associated with a 44% mortality rate. The GG genotype was significantly more frequent in the survivor group than in non-surviving patients (67% vs 41%; p =?0.038); similarly, the IL-6 -174G allele was more frequent in the survivor group than in non-surviving patients (81% vs 65%; p =0.031). CONCLUSION: The findings indicate that genetic variation regarding inflammatory response has significant impact on the short-term outcome for patients after acute severe TBI. PMID- 21314276 TI - Brief aphasia evaluation (minimum verbal performance): concurrent and conceptual validity study in patients with unilateral cerebral lesions. AB - INTRODUCTION: Aphasia tests validated according to the brain injury side are necessary, especially for Spanish instruments. OBJECTIVES: To study the concurrent validity of this Brief Aphasia Evaluation (BAE) to differentiate patients with left cerebral lesions (LC) from patients with right cerebral lesions (RC) as well as LC from healthy participants (HP). To study, through an unrestricted-sub-test-factor analysis, the BAE conceptual and content validity to generate a verbal homogeneous construct. MATERIALS AND METHODS: Data were obtained from a sample of 109 right-handed volunteers: 37 LC, 34 RC and 38 HP. The three groups were matched according to gender, age and education. RESULTS: Both groups of patients were similar in type and site of lesion, time since onset of condition, risk factors, presence of hemianopsia and hemiparesis and number of hospital visits. The Cronbach's alpha coefficient indicated an internal consistency of 0.99 for the total score and 0.88 or above for any of the sub tests. All sub-tests (with loadings of 0.65 or above) grouped in one factor which explained 78% of the variance. The BAE showed a sensitivity and specificity of 0.84 or above to identify the LC (median as cut-off point). CONCLUSIONS: This test of free distribution demonstrated a satisfactory validity. PMID- 21314277 TI - Dispositional optimism and outcome following traumatic brain injury. AB - OBJECTIVE: Despite vast literature examining the predictors of patient outcome following traumatic brain injury (TBI), the complicated relationship between personality and psychological, cognitive and functional outcomes remains poorly understood. The present study examined the relationship between the personality trait of dispositional optimism (DO) and outcome after moderate and severe TBI in the context of a proposed theoretical model. METHODS: Forty-five individuals who had sustained moderate-to-severe TBI were recruited through mailings and completed the Symptom Checklist Questionnaire-90 Revised (SCL-90-R), the Telephone Interview for Cognitive Status (TICS), the Craig Handicap Assessment Reporting Technique (CHART) and the Life Orientation Test-Revised (LOT-R). Analyses were conducted to test a model predicting the relationship between personality and patient outcome after TBI. RESULTS: DO was significantly correlated with psychological distress, but did not predict functional outcome. In addition, two significant mediating relationships were demonstrated: (1) psychological distress was shown to mediate the relationship between dispositional optimism and cognitive ability and (2) cognitive ability mediated the relationship between psychological distress and functional outcome. CONCLUSION: These findings illustrate that higher levels of DO in individuals sustaining moderate-to-severe TBI are related to better psychological functioning which in turn predicts improved cognitive and functional outcomes. PMID- 21314278 TI - Incremental contribution of reported previous head injury to the prediction of diagnosis and cognitive functioning in older adults. AB - BACKGROUND: Severe brain injuries may be a risk factor for the development of dementia in later life. Less severe incidents with relatively short or even no loss of consciousness may not carry the same prognosis. OBJECTIVES: This study used data from the first two waves of the Canadian Study of Health and Ageing (CSHA-1 and CSHA-2) to investigate two questions. (1) Does a history of head injury improve the prediction of the diagnosis of dementia? This analysis was based on the 921 elderly individuals who underwent a clinical assessment in CSHA 2 and, 5 years earlier, had reported whether or not they had had a head injury. (2) Does adding information about a history of head injury improve the prediction of neuropsychological test scores? This second analysis included 585 elderly people who underwent neuropsychological assessment in both waves and who also reported whether or not they had had a history of mild or moderate-to-severe head injury. RESULTS: RESULTS showed that the inclusion of head injury information did not improve the prediction of diagnostic outcome of dementia. Age and overall cognitive status were associated with most neuropsychological test scores, more so than the more limited influence of chronic health problems, which was associated with about half of the neuropsychological measures. PMID- 21314279 TI - Pharmacological and electrical stimulation in chronic disorders of consciousness: new insights and future directions. AB - BACKGROUND: Chronic disorders of consciousness are costly and challenging conditions to treat. Although recent studies that have tested pharmacological and electrical stimulation for these conditions are promising, the optimal intervention, mechanisms of action and side effects of these experimental therapies are unclear. OBJECTIVE: To systematically review the clinical results of treatments for vegetative state (VS) and minimally conscious state (MCS) from the last 10 years. METHODS: MEDLINE, LILACS and SCOPUS were searched as data sources. Because the potential bias when search is limited to databases of peer reviewed journals, reference lists were examined and experts in the field were contacted for other relevant or unpublished articles (i.e. negative studies). No negative unpublished studies were found. Studies were included related to therapeutic interventions in adult MCS or VS patients at least 3 and 12 months after non-traumatic and traumatic injuries, respectively. Eight studies met the inclusion criteria. The following interventions were reviewed: levodopa, amantadine, zolpidem, baclofen, dorsal column stimulation and deep brain stimulation. CONCLUSIONS: The adverse effects that were associated with these treatments were typically mild. Most of the studies demonstrated considerable improvements with the interventions, but their low strength of evidence limit the generalizability of the findings. PMID- 21314280 TI - Posterior lumbar interbody fusion versus posterolateral fusion with instrumentation in the treatment of low-grade isthmic spondylolisthesis: midterm clinical outcomes. AB - OBJECT: The purpose of this study was to compare the methods of posterior lumbar interbody fusion (PLIF) and posterolateral fusion (PLF) in cases of isthmic Grades 1 and 2 lumbar spondylolisthesis, and to evaluate the clinical efficacy of the procedures. METHODS: Operations were performed in 50 patients with lumbar spondylolisthesis in the authors' clinics between 2001 and 2007. Indications for surgery were low-back pain with or without sciatica and neurogenic claudication that had not improved after at least 6 months of conservative treatment. The study included 33 female and 17 male patients, with mean ages of 50.6 years in the PLIF group and 47.3 years in the PLF group. These patients were randomly allocated into 2 groups: decompression, posterior transpedicular instrumentation, and PLF (Group 1; 25 patients) and decompression, posterior transpedicular instrumentation, and PLIF (Group 2; 25 patients). In the PLIF group, titanium cages were used, and autograft material was obtained from the decompression. In the PLF group, bone fragments collected from the iliac crest were used as autografts. A minimum 18-month follow-up was available in all patients. For clinical evaluation, a visual analog scale, Oswestry Disability Index, and the 36 Item Short Form Health Survey were used. Improvements in pre- and postoperative spondylolisthesis, segmental angles, fusion ratios, and postoperative complications were evaluated radiologically. RESULTS: The average follow-up period was 3.3 years. Based on the etiologies, isthmic spondylolisthesis was detected in all patients. The spondylolisthesis levels in the patients who underwent PLIF were located at L3-4 (5 patients, 20%); L4-5 (14, 56%); and L5-S1 (6, 24%), whereas the levels in the ones treated with PLF were located at L3-4 (4 patients, 16%); L4-5 (13, 52%); and L5-S1 (8, 32%). In the clinical evaluations, good or excellent results were obtained in 22 (88%) cases in the PLIF group and 19 (76%) cases in the PLF group. Fusion ratios were 100% in the PLIF group and 84% in the PLF group. Both lumbar lordosis and the segmental angle showed greater improvement in the PLIF group. There was no difference in the complication rates for each group. CONCLUSIONS: Based on early clinical outcomes and the fusion ratios of adult isthmic spondylolisthesis, the authors found PLIF to be superior to PLF. PMID- 21314281 TI - Thoracic disc herniation and acute myelopathy: clinical presentation, neuroimaging findings, surgical considerations, and outcome. AB - OBJECT: Thoracic disc herniations (TDHs) may occasionally present with an acute myelopathy, defined as a variable degree of motor, sensory, and sphincter disturbances developing in less than 24 hours, and resulting in a Frankel Grade C or worse. Confronted with such a patient, the surgeon has to decide whether to perform an emergency operation and whether to use an anterior or posterior approach. The authors analyze their own experience and the pertinent literature, focusing on clinical presentation, imaging findings, surgical timing, technique, and outcome. METHODS: Among 250 patients who underwent surgery for symptomatic TDH, 209 had at least 1 year of follow-up at the time of writing, including 8 patients who presented with an acute myelopathy. They were surgically treated using standard thoracoscopic microdiscectomy, careful blood pressure monitoring, and intravenous methylprednisolone. The authors analyzed pre- and postoperative neuroimaging, and Frankel scores preoperatively, at discharge, and 1 year postoperatively. RESULTS: Although 5 patients had multiple TDHs, the symptomatic TDH was invariably situated between T9-10 and T11-12. Seven TDHs were giant, 6 were calcified, 6 were accompanied by myelomalacia, and 4 were accompanied by segmental stenosis. Although sudden dorsalgia was the initial symptom in 6, a precipitating event was noted in only 1. All patients had severe neurological deficits by the time they underwent surgery. Frankel grades improved from B to D in 2 patients, from C to E in 4, and from C to D and B to E in 1 patient each. All patients regained continence and ambulation. Transient complications were CSF leak (in 2 patients), and intraoperative blood loss greater than 1000 ml, reversible ischemic neurological deficit, and subileus (in 1 patient each). CONCLUSIONS: Approximately 4% of TDHs present with an acute myelopathy. They are often situated between T9-10 and T11-12, large or giant, and even calcified. They almost invariably cause important cord compression (sometimes aggravated by an associated segmental stenosis) and myelomalacia. Their clinical presentation may be misleading, and diagnosis may be delayed until other causes (especially vascular) have been excluded and the clinical picture has become more complete. Interestingly, whereas a precipitating event or trauma is rarely present, dorsalgia frequently precedes profound myelopathy and may help to make an early diagnosis. Remarkable recovery is possible even with profound neurological deficit, a delay of several days, in the elderly, and in the presence of myelomalacia, provided the spinal cord is adequately decompressed and intraoperative hypotension is strictly avoided. Although alternative approaches more familiar to most neurosurgeons may be used, the anterior transthoracic approach has the advantage of reaching the TDH in front of the compromised spinal cord, avoiding any manipulation. In experienced hands, thoracoscopic microdiscectomy combines the advantage and versatility of an anterior approach with minimal postoperative discomfort. The authors conclude that TDH-related acute myelopathy may have a favorable outcome when managed correctly, and they strongly recommend that every single patient should undergo surgical treatment. PMID- 21314282 TI - A novel modification for removal of the polyethylene core in artificial disc retrieval using a transpsoas minimally invasive technique. AB - Total disc replacement (TDR) surgeries have significantly increased in number since US FDA approval. However, the associated complications such as implant malposition, loosening, subsidence, implant migration, fractures, and infection may necessitate retrieval of the artificial disc and proceeding with interbody fusion. Retrieval of artificial discs in proximity to important vascular, urological, and other vital anatomical structures (for example, L4-5) presents numerous difficulties to spine and approach surgeons. To avoid the impediments of an anterior revision approach, in 2006 Pimenta et al. described an effective transpsoas lateral minimally invasive approach to retrieve the TDR device. In this paper, the authors adopted this technique in their surgical practice; however, they realized that a complex step involved the removal of the polyethylene core. The polyethylene core is compressed between the device endplates and is difficult to remove with the aid of a Kocher clamp as advised by Pimenta et al. Moreover, distraction on the endplates or the vertebral bodies to decrease the compression across the core is laborious, time consuming, and often not possible due to the approach and location of the lumbar plexus. In the present paper, the authors propose a novel modification to the polyethylene core removal with the use of a screw to create a better lever arm, apply effective distraction, and secure a good grip to enable core retrieval. This modification significantly reduced the operating time. PMID- 21314283 TI - Cystic deterioration of the C1-2 articulation: clinical implications and treatment outcomes. AB - OBJECT: Synovial cysts of the cervical spine are rare. Further, synovial cysts of the C1-2 articulation, or retroodontoid cysts, are very rare, with fewer than 20 cases reported overall. The authors report on a single-institution series of 10 patients with C1-2 retroodontoid synovial cysts. METHODS: The charts of 10 patients with pathologically confirmed synovial cysts following resection between January 1998 and June 2009 were reviewed. The clinical presentation, radiographic findings, surgical management, and pre- and postoperative functional levels (reported as a modified Rankin outcome) are reported. RESULTS: All 10 patients underwent attempts at complete resection of the synovial cyst; none of the lesions were simply aspirated. All 4 patients with an initial recommendation of observation alone ultimately underwent surgery because of their swift neurological deterioration. The mean age at surgery was 75.4 +/- 4.6 years (range 54-81 years). The mean presenting cyst volume was 4.6 +/- 1.7 cm(3). Nine of 10 patients underwent transoral resection of the cyst with posterior fusion. Six of the 10 patients underwent additional posterior laminectomy for decompression. The hospital length of stay varied from 2 to 45 days, with a mean of 19 +/- 7 days. All patients undergoing transoral decompression had varying degrees of difficulty with postoperative dysphagia, diagnosed using videofluoroscopy. All patients improved in their modified Rankin Scale score after surgical intervention with a mean follow-up of 42 months (95% CI 12-72 months). CONCLUSIONS: Synovial cysts of the atlantoaxial joint are rare. They occur in older patients in whom clinical deterioration is likely to occur. In most cases, these cysts can be diagnosed preoperatively. Transoral decompression with posterior fusion is an effective treatment for C1-2 degenerative cysts and can be accomplished with few complications. However, the ideal treatment for these lesions remains unknown. PMID- 21314284 TI - Efficacy and cost-effectiveness analysis of external beam and stereotactic body radiation therapy in the treatment of spine metastases: a matched-pair analysis. AB - OBJECT: The objective of this study was to compare the palliative efficacy and cost effectiveness of external beam radiation therapy (EBRT) to stereotactic body radiation therapy (SBRT) as primary treatment for bone metastatic disease of the spinal column. METHODS: Forty-four patients were matched based on age, primary tumor site, year of treatment, and location of metastasis. Outcomes of interest were pain relief, cost-effectiveness, toxicities, and need for further intervention. Pain relief was rated as excellent, good, fair, or poor, using a radiosurgical pain scale to combine visual analog scale and verbal descriptor ordinal scale scores. Medicare fee schedules were used to compute the charges for both the technical and professional components of care. Patients in the EBRT group were treated using a linear accelerator while patients in the SBRT group were treated with the CyberKnife robotic radiosurgery system. Patients received regular follow-up evaluations by a radiation oncologist and neurosurgeon. RESULTS: Forty-four patients (22 pairs) were analyzed. At a follow-up of 1 month, there was no statistically significant difference in pain between the 2 groups (p = 0.11). Patients who underwent SBRT had the highest total gross charge; depending on technique, EBRT treatments ranged from 29% to 71% of the SBRT charge. Patients treated using EBRT had more acute toxicities, and more of these patients underwent further intervention at the treated spinal level. There were no late complications attributed to either treatment modality. CONCLUSIONS: External beam radiation therapy remains an efficacious and cost-effective method of palliation of spine metastases. In this study, patients treated with EBRT had more acute toxicities and were more likely to require additional interventions at the treated sites. Stereotactic body radiation therapy, although more costly, resulted in comparable rates of pain relief and late treatment-related toxicity, and continues to show promise as an emerging modality for selected patients with spine metastases. PMID- 21314285 TI - Cudrania tricupidata bureau (CTB) glycoprotein inhibits proliferation by Di(2 ethylhexyl) phthalate in primary splenocytes: responses in cell proliferation signaling. AB - The aim of the present study was to evaluate inhibitory effect of CTB glycoprotein isolated from Cudrania tricuspidata Bureau on DEHP-induced cell proliferation in lymphocytes. Our results revealed that DEHP increased lymphocyte proliferation as confirmed by increasing [(3)H]thymidine incorporation, and proliferating cell nuclear antigen (PCNA), cyclin D1, and cyclin-dependent kinase (CDK)-4 expression. This was accompanied by induced intracellular Ca(2+) level, protein kinase C (PKC) translocation from cytosol to membrane, ERK1/2 phosphorylation, and nuclear factor (NF)-kappaB transcriptional activation in DEHP-treated cells. However, CTB glycoprotein (100 MUg/ml) reduced labeled thymidine incorporation and PCNA expression in DEHP-treated cells. Additionally CTB glycoprotein reduced Ca(2+) level, PKC translocation, ERK1/2 phosphorylation, NF-kappaB transcriptional activation, cell cycle proteins (cyclin D1 and CDK4) expression in cells. The activation of NF-kappaB was collectively blocked by pretreatment with PKC inhibitor (staurosporine) and ERK1/2 inhibitor (PD98059), respectively. The results from these experiments indicate that CTB glycoprotein inhibits cell proliferation via down regulations of Ca(2+)/PKC, ERK1/2, and cell cycle proteins induced by DEHP. Therefore, we suggest that the CTB glycoprotein might be one component for prevention of cell proliferation-related immune diseases. PMID- 21314286 TI - Optimal dendritic cell differentiation in rpmi media requires the absence of HEPES buffer. AB - Monocyte-derived dendritic cells (DCs) are considered an indispensible and one of primary tools for in vitro DC-based studies. For majority of in vitro DC-based studies the medium of choice is supplemented RPMI, with certain variable ingredients such as HEPES buffer or Phenol Red (PHR). In effort to identify potential obstruction of DC differentiation process due to presence of mentioned additives, we differentiated DCs using RPMI either with or without HEPES or PHR. Although PHR caused a certain down-regulation of immature DCs (iDCs) differentiation markers and lower expression of co-stimulatory molecules on mature DCs, these changes were not significant. In contrast, use of RPMI also containing HEPES resulted in significantly lower CD1a and DC-SIGN expression on iDCs and extensively lowered co-stimulatory molecule expression after DC activation (HEPES-DCs). Furthermore, DCs differentiated in HEPES-free RPMI possessed more genuine immature/mature DC characteristics in context of Th1 polarization. Additionally, during classical differentiation procedure, fewer DCs remained adherent and possessed better overall morphology in HEPES-free medium. In summary our study clarifies a seemingly minor, but a very important issue, that will most likely facilitate lab work for many scientists dealing with monocyte-derived DCs. PMID- 21314287 TI - Localization of IL-17+Foxp3+ T cells in esophageal cancer. AB - The etiology of cancer is unclear. Recent studies indicate that some cytokines, such as interleukin (IL)-17, and regulatory T cells are involved in the development of cancer. This study aims to detect a subset of T cell, IL17+Foxp3+ T cell, in the pathogenesis of esophageal cancer (Eca). Twelve patients with squamous Eca were recruited in this study. The surgically removed Eca tissue was collected. Cells isolated from Eca tissue were analyzed by flow cytometry. The results showed that 2-10% Eca tissue-derived CD4(+) T cells expressed Foxp3; only 0.2-0.8% non-ca tissue-derived CD4(+) T cells expressed Foxp3. Further analysis showed that 3-15% Eca-isolated CD4(+) T cells were also IL-17 positive whereas only 0.4-1.5% non-ca tissue-isolated CD4(+) T cells were IL-17 positive. We also found that about 4.8-11.2% Foxp3(+) IL-17(+) T cells in isolated CD4(+) T cells from Eca tissue that were significantly less than in non-ca tissue derived CD4(+) T cells. Less than 1% Foxp3(+) IL-17(+) T cells in isolated CD4(+) T cells in both Eca patients and healthy controls. Treatment with hypoxia markedly increased the expression of IL-6 in peripheral CD68+ cells. Coculturing CD68+ cells and Foxp3+ T cells under hypoxic environment resulted in abundant expression of IL-17 in Foxp3+ T cells that could be blocked by pretreatment with either anti-IL-17 or anti-transforming growth factor beta antibodies. We conclude that IL-17+Foxp3+ T cells may contribute to the development of Eca. PMID- 21314288 TI - Cyclophosphamide potentiates the antitumor effect of immunization with injection of immature dendritic cells into irradiated tumor. AB - Growth of a tumor on the left flank was suppressed by direct injection of immature DCs (iDCs) into the irradiated tumor on the right thigh (IR/DC). This antitumor immune effect of IR/DC was enhanced by pretreatment with CTX (CTX+IR/DC) and this effect was related with increased number of tumor-specific IFN-gamma secreting T cells and decreased ratio of CD4(+)CD25(+)/CD4(+) T cells. The treatment with CTX+IR/DC increased or decreased the levels of IL-2 or IL-10, respectively. These results demonstrated that antitumor effect of IR/DC could be augmented by pretreatment with low-dose CTX, suggesting a new antitumor therapeutic modality of chemoradioimmunotherapy. PMID- 21314289 TI - Induction of NKG2D ligands and increased sensitivity of tumor cells to NK cell mediated cytotoxicity by hematoporphyrin-based photodynamic therapy. AB - Natural killer (NK) cells are important innate effector cells which can irradicate tumor cells through specific interactions between activating receptors on NK cells and their cognate ligands on cancer cells. Recently, it has been known that induction of activating NKG2D ligands including MHC class I chain related (MIC) and UL16-binding protein (ULBP) families on tumor cells by various stresses makes them more susceptible to NK cell-mediated cytotoxicity. Therefore, it was investigated whether sublethal dose of hematoporphyrin-based photodynamic therapy (PDT) could up-regulate NKG2D ligands on tumor cells and increase the susceptibility of cancer cells against NK cells. Treatment with sublethal dose of hematoporphyrin-based PDT increased mRNA transcription and surface expression of ULBP1 and ULBP2 genes in SNU-1 human gastric tumor cell line and MICA/B, ULBP1, ULBP2 and ULBP3 genes in SW-900 human lung cancer cell line. These results were followed by increased susceptibility of cancer cells to NK cell-mediated cytotoxicity after sublethal PDT, which was abolished by addition of a blocking NKG2D mAb. Therefore, it could be suggested that the effect of hematoporphyrin based PDT might be mediated in part by the increased susceptibility to NK cells via induction of NKG2D ligands on tumor cells, which survived after treatment with PDT. PMID- 21314290 TI - An investigation of family carers' needs following stroke survivors' discharge from acute hospital care in Australia. AB - PURPOSE: To expand understanding of informal stroke care-giving, validated tools previously used in Hong Kong and in the U.K. were used with Australian stroke carers to assess their stroke-related knowledge, perceived needs, satisfaction with services received and sense of burden after stroke patients' discharge home from acute hospital care. METHODS: Record audit and telephone interviews with two cohorts of 32 carers recruited in Sydney and Brisbane 1 and 3 months post hospital discharge, using validated scales and open questions in May-July 2006. RESULTS: Female carers, those with prior care-giving responsibility, and those interviewed at three compared to one month post-discharge reported greatest needs and burden from the care-giving role; needs alone significantly predicted burden. Getting information and being prepared for life after discharge were central concerns. Some felt this was accomplished, but inadequate information giving and communication mismatches were apparent. CONCLUSIONS: Service providers need to develop partnership working with stroke families and provide a network of services and inputs that cut across conventional boundaries between health and social care, public, private and voluntary organisations, with care plans that deliver what they delineate. Stroke care-givers have common issues across countries and healthcare systems; collaborative research-based service development is advocated. PMID- 21314291 TI - The origin of Fusobacterium nucleatum involved in intra-amniotic infection and preterm birth. AB - OBJECTIVE: To evaluate the potential oral origin of Fusobacterium nucleatum found in amniotic fluid of women at high risk of preterm birth. METHODS: A transversal study nested into a cohort study of women with preterm labor and/or preterm premature rupture of membranes was undergone. Women with the presence of F. nucleatum in the amniotic fluid and their respective partners were invited to be examined for their periodontal health after delivery, and samples of saliva and subgingival plaque were collected. For each couple, specific PCR detection of Fusobacterium species was performed on each oral sample, and the DNA sequences were compared with the one obtained from amniotic fluid. RESULTS: Three women, all in preterm labor with intact membranes, were included. Intra-amniotic sludge was observed in all of them. A strain of F. nucleatum with 100% sequence identity with the strain detected in the amniotic fluid was found in the oral samples of one of them and of two partners. CONCLUSION: This study suggests that intra amniotic F. nucleatum could originate from the patient's or the partner's oral microflora. PMID- 21314292 TI - Risk factors for intrauterine fetal death (1988-2009). AB - OBJECTIVE: To determine risk factors for intrauterine fetal death (IUFD). STUDY DESIGN: A retrospective population-based study, of all singleton deliveries between the years 1988-2009 was conducted. Intrapartum deaths, postpartum death, and multiple gestations were excluded. A multiple logistic regression model was used to determine independent risk factors. RESULTS: During the study period, out of 228,239 singleton births, 1694 IUFD cases were recorded (7.4 per 1000 births). The following independent risk factors were identified in the logistic regression executed: Oligohydramnios (OR 2.6, 95% CI 2.1-3.2, p-value < 0.001), polyhydramnios (OR 1.8, 95% CI 1.4-2.2, p-value < 0.001), previous adverse perinatal outcome (OR 1.7, 95% CI 1.5-2.1, p-value < 0.001), congenital malformations (OR 2.0, 95% CI 1.8-2.3, p-value < 0.001), true knot of cord (OR 3.7, 95% CI 2.8-4.9, p-value < 0.001), meconium stained amniotic fluid (OR 2.7, 95% CI 2.3-3.0, p-value<0.001), placental abruption (OR 2.9, 95% CI 2.4-3.5, p value < 0.001), advanced maternal age (OR 1.03, 95% CI 1.02-1.04, p-value < 0.001), and hypertensive disorders (OR 1.24, 95% CI 1.0-1.4, p-value = 0.026). Jewish ethnicity (versus Bedouin - OR 0.64, 95% CI 0.57-0.72, p-value < 0.001), gestational diabetes (OR 0.7, 95% CI 0.5-0.8, p-value = 0.001), previous cesarean section (OR 0.8, 95% CI 0.7-0.97, p-value = 0.019), and recurrent abortions (OR 0.8, 95% CI 0.6-0.9, p-value = 0.011) were negatively associated with IUFD. CONCLUSION: Several independent risk factors were identified, suggesting a possible cause of death. Other pathologic conditions that facilitate tighter pregnancy surveillance and active management were found protective, pointing the benefit of such management approaches in high-risk pregnancies. PMID- 21314293 TI - In vitro manipulation of endothelial progenitor cell adhesion to vascular endothelium and extracellular matrix by the phorbol ester PMA. AB - Injection of endothelial progenitor cells (EPCs) into arteries for cell therapy is a promising field in regenerative medicine. However, adhesion of EPCs during capillary passage is restricted, and non-adhering cells are lost into circulation. Here we demonstrate that it is possible to achieve a three- to sevenfold higher rate of EPC adhesion to endothelium and extracellular matrix molecules after short-term activation with phorbol myristate acetate (PMA). In addition, differentiation and toxicity analyses of PMA activated EPCs showed no impact on cell differentiation and negligible impact on cell survival. PMID- 21314294 TI - Predicting equipment needs of children with cerebral palsy using the Gross Motor Function Classification System: a cross-sectional study. AB - BACKGROUND: Children with cerebral palsy (CP) routinely use assistive equipment to improve their independence. Specialist equipment is expensive and therefore not always available to the child when needed. AIM: The aim of this study was to determine whether the assistive equipment needs of children with CP and the associated costs could be predicted. METHOD: A cross-sectional study using a chart audit was completed. Two hundred forty-two children met eligibility criteria and were included in the study. Data abstracted from files pertained to the child's CP, associated impairments and assistive equipment prescribed. The findings were generated using linear regression modelling. RESULTS: Gross Motor Function Classification System (GMFCS) level [B = 3.01 (95% CI, 2.36-3.57), p = 0.000] and the presence of epilepsy [B = 2.35 (95% CI, 0.64-4.06), p = 0.008] predicted the prescription of assistive equipment. The more severely affected the gross motor function impairment, the more equipment that was required and the more the equipment cost. INTERPRETATION: The equipment needs of children with CP can be predicted for the duration of childhood. This information may be useful for families and for budget and service planning. PMID- 21314295 TI - A review of the evidence underpinning the use of visual and auditory feedback for computer technology in post-stroke upper-limb rehabilitation. AB - PURPOSE: To identify and review the evidence to determine the current scientific basis underpinning the use of visual and/or auditory feedback for computer technology in home-based upper-limb stroke rehabilitation. METHOD: A systematic search was conducted using the following databases: CINAHL (EBSCO), MEDLINE (Ovid and CSA), PubMed, Science Direct (Elsevier) and Cochrane Library. Journals, book chapters and conference proceedings were also used in the systematic search. Relevant papers were critically appraised using the Critical Appraisal Skills Programme tool for randomised controlled trials/quantitative designs. RESULTS: Four controlled trials were identified as being relevant. Although the evidence is scarce, existing findings suggest that extrinsic visual and auditory feedback may improve motor and functional performance. In addition, concurrent feedback, knowledge of performance, knowledge of results and explicit feedback may be key components in the promotion of improved performance. CONCLUSIONS: There is a paucity of evidence to inform the development and the use of technological systems for home-based stroke rehabilitation and specifically how such systems might be developed to provide best forms of feedback in the absence of a therapist. Further work is required to first investigate the efficacy of visual and auditory feedback using technology systems and second to explore their utilisation with the end user. PMID- 21314296 TI - Anatomic thoracoscopic lung resection for non-small cell lung cancer in stage I is associated with less morbidity and shorter hospitalization than thoracotomy. AB - BACKGROUND: Patients undergoing surgery for non-small cell lung cancer (NSCLC) are often elderly with co-morbid conditions and decreased performance status. Thus, the morbidity of lung resection via thoracotomy may be unacceptable for some patients. This is the reason why video-assisted thoracoscopic surgery (VATS) instead of open thoracotomy has gained more use and acceptance, especially in patients with stage I disease. The aim of this study was to evaluate the difference between VATS and open thoracotomy in treatment outcomes of stage I NSCLC patients. METHODS: A total of 328 stage I NSCLC patients underwent lobectomy, bilobectomy or segmentectomy between January 2000 and February 2010. VATS was implemented in 116 patients, of which 16 were converted to thoracotomy. Muscle-sparing anterolateral thoracotomy was performed in 212. Propensity-matched groups were analyzed based on preoperative variables and stage. RESULTS: VATS was associated with lower postoperative morbidity in both overall (p = 0.020) and propensity-matched analysis (p = 0.026) and shorter hospitalization (both p < 0.001). Patients selected for VATS were older (p = 0.001) with a significantly higher Charlson comorbidity index (p = 0.007) and poorer diffusion capacity (p < 0.001). The conversion rate was 14%. Between the two groups, no significant difference was observable in two-year overall and progression-free survival. CONCLUSIONS: Despite the VATS lobectomy and segmentectomy patients' being older, with more comorbid condition and poorer pulmonary function, the incidence of major complications was lower and hospitalization shorter than for open thoracotomy patients. For stage I NSCLC, VATS should be considered the primary surgical approach. PMID- 21314297 TI - European guidelines for quality assurance in cervical histopathology. AB - The current paper presents Chapter 5 of the second edition of the European Guidelines for Quality Assurance in Cervical Cancer Screening, which deals with the histopathological diagnosis of lesions of the uterine cervix. It completes a series of publications in journals containing the contents of other parts of the European Guidelines. Histopathology provides the final diagnosis on the basis of which treatment is planned, and serves as the gold standard for quality control of cytology and colposcopy. It is also the source of the diagnostic data stored at the cancer registry and used for evaluation of screening programmes. It is therefore important that histopathology standards are monitored and based on agreed diagnostic criteria. Histology is required to diagnose the degree of abnormality in women with persistent low-grade abnormalities including HPV lesions, as well as high-grade lesions. Cytology may also suggest either glandular abnormalities or be suggestive of high-grade CIN, AIS or invasive cancer. Histopathologists should be aware of, and familiar with, the nature of cytological changes which may be relevant to their reports. The accuracy of the histopathological diagnosis of tissue specimens depends on adequate samples, obtained by colposcopically directed punch biopsies (with endocervical curettage if necessary) or excision of the transformation zone or conisation. An accurate histological diagnosis further depends on appropriate macroscopic description, technical processing, microscopic interpretation and quality management correlating cytological and histological diagnosis. This paper proposes guidelines for sampling and processing of cervical tissue specimens obtained by biopsy, excision and/or curettage. PMID- 21314298 TI - The high frequency of restless legs syndrome in patients with amyotrophic lateral sclerosis. AB - Restless legs syndrome (RLS) appears to be more frequent in certain neurodegenerative disorders. The aim of our study was to determine the frequency and the determinants of the association of RLS with amyotrophic lateral sclerosis (ALS) in a French cohort. Information on sex, age, age at onset, site of onset, body mass index, disease duration, ALS Functional Rating Scale-Revised and use of technical supports was obtained in a cohort of 69 ALS subjects (69.6 +/- 9.7 years). RLS was diagnosed using the International RLS Study Group criteria. We compared our frequency rates by age with frequency rates of RLS in the French general population from literature. RLS was observed in 13 patients (18.8%). Frequency of RLS was higher (p = 0.007) in ALS patients older than 64 years than in the French general population of the same age group. There were no further demographic, clinical or biological differences between the patients with RLS and those without RLS, with the exception of a higher frequency of difficulty turning in bed and adjusting bedclothes (p = 0.023). In conclusion, RLS occurs frequently in ALS, and those affected should be identified and appropriately treated. PMID- 21314326 TI - A clinical follow-up study of reserve forces personnel treated for mental health problems following demobilisation. AB - BACKGROUND: The Reserves Mental Health Programme (RMHP) provides a clinical service for members of the United Kingdom's Reserve Forces deployed to combat operations since 2003. AIM: To assess whether mental health and occupational functioning changed after treatment. METHODS: We examined a treatment group with operationally attributable mental health problems and a non-intervention group with non-operationally attributable problems. A self-report, repeat measures study design examined post traumatic stress disorder (PTSD), common mental disorders, alcohol use and occupational functioning at follow up delivered by either telephone or post. RESULTS: One hundred three reservists were offered an initial assessment. Adjusted response rates were 66.7% (n=16) for the no treatment group and 62.7% (n=37) for the treatment group. The treatment group were more likely to be cases at baseline on all mental health outcome measures other than PTSD, but at follow up, they were no more likely to be so. A one-way ANCOVA was conducted to evaluate treatment outcome. This was not significant for all measures except for PTSD. On completion of treatment, three quarters of serving personnel returned to full occupational fitness. CONCLUSION: The RMHP appears to offer a clinically and occupationally effective intervention to recently de-mobilised reservists with operationally attributable mental health problems. PMID- 21314327 TI - Platelet GSK3B activity in patients with late-life depression: marker of depressive episode severity and cognitive impairment? AB - OBJECTIVE: Increased GSK3B activity has been reported as a state marker of major affective episodes in patients with depression and bipolar disorder. No study so far has addressed GSK3B activity in late-life depression. The aims of the present study were to determine GSK3B activity in platelets of elderly patients with major depression, and the association between GSK3B activity and the severity of depressive symptoms and cognitive impairment. METHODS: Forty drug-free elderly patients with major depressive episode were compared to healthy older adults (n = 13). Severity of the depressive episode and current cognitive state were determined by the Hamilton Depression Scale (HAM-D) and the Cambridge Cognitive Test (CAMCOG), respectively. Total- and ser-9-phosphorylated GSK3B (tGSK3B and pGSK3B) were determined in platelets by enzyme immunometric assays (EIA). GSK3B activity was indirectly inferred by the GSK3B ratio (i.e. pGSK3B/tGSK3B). RESULTS: Elderly depressed patients had significantly lower pGSK3B levels (P = 0.03) and GSK3B ratio (P = 0.03), indicating higher GSK3B activity. Higher GSK3B activity were observed in patients with severe depressive episode (HAM-D scores >22, P = 0.03) and with cognitive impairment (CAMCOG scores <86, P = 0.01). CONCLUSION: The present findings provide additional evidence of the involvement of GSK3B in the pathophysiology of late-life major depression. Higher GSK3B activity may be more relevant in those patients with more severe depressive symptoms and cognitive impairment. PMID- 21314329 TI - Upregulation of p53 expression in patients with colorectal cancer by administration of curcumin. AB - Biological therapies can be beneficial in cancer patients. The present study aims to examine the inhibitory mechanism of curcumin on cancer cells in patients with colorectal cancer. The results showed that curcumin administration increased body weight, decreased serum TNF-alpha levels, increased apoptotic tumor cells, enhanced expression of p53 molecule in tumor tissue, and modulated tumor cell apoptotic pathway. We conclude that the curcumin treatment improves the general health of patients with colorectal cancer via the mechanism of increased p53 molecule expression in tumor cells and consequently speeds up tumor cell apoptosis. PMID- 21314328 TI - Visfatin stimulates a cellular renin-angiotensin system in cultured rat mesangial cells. AB - OBJECTIVE: Visfatin is a newly identified proinflammatory adipocytokine whose plasma levels have been reported to be higher in subjects with type 2 diabetes mellitus. Recent studies have shown that visfatin increases the synthesis of profibrotic molecules in mesangial cells (MCs) and thus plays an important role in the pathogenesis of diabetic nephropathy. However, the mechanism by which visfatin induces kidney injury is unknown. The renin-angiotensin system (RAS) plays pivotal roles in renal diseases. Therefore, in this study the effect of visfatin on the regulation of RAS in MCs was examined. METHODS: Cultured rat MCs were treated with different doses of visfatin. We used real-time polymerase chain reaction to detect mRNA expression of renin, angiotensinogen (AGT), angiotensin converting enzyme (ACE), angiotensin II (Ang II) type 1 receptor (AT1), and Ang II type 2 receptor (AT2); western blot analysis for expression of ANG and AT1; and radioimmunoassay to measure Ang II production from MCs in the supernatants of culture media. RESULTS: Visfatin treatments increased renin, angiotensinogen (AGT), AT1 mRNA, and AGT, AT1 protein expression, as well as Ang II levels in a dose-dependent manner but did not affect ACE and AT2 mRNA levels in cultured rat MCs. CONCLUSIONS: Our findings suggest that visfatin imparts a detrimental effect on diabetic nephropathy at least partly through the activation of intrarenal RAS. PMID- 21314330 TI - Infusional mitoxantrone plus bolus melphalan as a stem cell transplant conditioning regimen for multiple myeloma. AB - This study combined infusional mitoxantrone with bolus melphalan as a transplant preparative regimen for multiple myeloma. Mitoxantrone was infused over 6 hr on days 6 and 5. Melphalan was given as a 15 min bolus on day 1 followed by autologous transplant on day 0. Thirty-five patients were enrolled; 57% of enrollees had received >= 2 prior treatments. The median overall survival was 5 years and 8 months, with 37% of the subjects alive >7 years posttransplantation. Myelosuppression and mucositis were the most frequent adverse events. This regimen is well tolerated and the survival compares well to other transplant trials. PMID- 21314331 TI - Overweight and obesity in long-term breast cancer survivors: how does sexual orientation impact BMI? AB - In noncancer populations lesbians have greater odds of obesity compared with heterosexual women, suggesting a similar pattern among cancer survivors. Weight of cancer survivors is an important area of study because obesity is associated with an increased risk of recurrence and shorter survival. Sixty-nine lesbian and bisexual and 257 heterosexual survivors of breast cancer were recruited to participate in a one-time telephone survey. Multinomial logit models do not support disparities in obesity due to sexual orientation. Our findings in breast cancer survivors suggest that lesbians are more likely to improve their weight related behaviors after cancer than heterosexual women. PMID- 21314332 TI - EGFR gene overexpression retained in an invasive xenograft model by solid orthotopic transplantation of human glioblastoma multiforme into nude mice. AB - Orthotopic xenograft animal model from human glioblastoma multiforme (GBM) cell lines often do not recapitulate an extremely important aspect of invasive growth and epidermal growth factor receptor (EGFR) gene overexpression of human GBM. We developed an orthotopic xenograft model by solid transplantation of human GBM into the brain of nude mouse. The orthotopic xenografts sharing the same histopathological features with their original human GBMs were highly invasive and retained the overexpression of EGFR gene. The murine orthotopic GBM models constitute a valuable in vivo system for preclinical studies to test novel therapies for human GBM. PMID- 21314333 TI - Mice lacking MSK1 and MSK2 show reduced skin tumor development in a two-stage chemical carcinogenesis model. AB - Mitogen- and stress-activated protein kinase (MSK)1/2 are two kinases involved in inflammation as well as in cell transformation. PURPOSE: To examine the role of MSK1/2 in skin tumor development. RESULTS: MSK1/2 knockout mice developed significantly fewer skin tumors compared with wild-type mice. The myeloperoxidase activity in TPA-treated skin from MSK1/2 knockout mice was significantly elevated compared with wild-type mice. Furthermore, the mRNA and protein levels of IL 1beta as well as the mRNA expression of TNF-alpha were significantly increased in MSK1/2 knockout mice. CONCLUSION: These data provide in vivo evidence that MSK1/2 signaling represents a novel tumor-promoting axis in skin carcinogenesis. PMID- 21314335 TI - Microwave ablation assisted by a computerised tomography-ultrasonography fusion imaging system for liver lesions: an ex vivo experimental study. AB - PURPOSE: To investigate the feasibility and validity of real-time guidance using a fusion imaging system that combines ultrasonography (US) and computerised tomography (CT) information in the targeting and subsequent microwave ablation of a liver target inconspicuous on US. MATERIALS AND METHODS: The study was an experimental ex vivo study in calf livers with internal targets, simulating a focal liver lesion, focused on the accuracy of real-time US using a multimodality fusion imaging system in combination with 15 gauge (G) microwave antennae. US image and pre-procedural CT image were fused by the external markers registration procedure. Microwave antennae were inserted into the liver to ablate the target assisted by the CT-US fusion imaging system. Finally, a post-procedural CT with needles in situ and multiplanar reconstructions were performed to compare with pre-procedural CT information in order to calculate the accuracy of positioning (distance between the needle tip and the target). RESULTS: Eight insertions were planned and eight ablations were performed in four calf livers. The calf livers were undertaken successfully on external markers registration procedure. The mean registration error in the four livers was 2.1 +/- 0.1 mm, 2.8 +/- 0.1 mm, 3.4 +/- 0.1 mm and 2.3 +/- 0.1 mm, respectively. The accuracy of the matched US-CT images was very satisfactory in the fact that it was found there was a mean discrepancy of 1.63 +/- 1.06 mm. CONCLUSION: Real-time registration and fusion of pre procedural CT volume images with intraprocedural US is feasible and accurate for microwave (MW) ablation in experimental setting. Further studies are warranted to validate the system under clinical conditions. PMID- 21314334 TI - Formulation and characterisation of magnetic resonance imageable thermally sensitive liposomes for use with magnetic resonance-guided high intensity focused ultrasound. AB - PURPOSE: Objectives of this study were to: 1) develop iLTSL, a low temperature sensitive liposome co-loaded with an MRI contrast agent (ProHance(r) Gd-HP-DO3A) and doxorubicin, 2) characterise doxorubicin and Gd-HP-DO3A release from iLTSL and 3) investigate the ability of magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) to induce and monitor iLTSL content release in phantoms and in vivo. METHODS: iLTSL was passively loaded with Gd-HP-DO3A and actively loaded with doxorubicin. Doxorubicin and Gd-HP-DO3A release was quantified by fluorescence and spectroscopic techniques, respectively. Release with MR-HIFU was examined in tissue-mimicking phantoms containing iLTSL and in a VX2 rabbit tumour model. RESULTS: iLTSL demonstrated consistent size and doxorubicin release kinetics after storage at 4 degrees C for 7 days. Release of doxorubicin and Gd-HP-DO3A from iLTSL was minimal at 37 degrees C but fast when heated to 41.3 degrees C. The magnitude of release was not significantly different between doxorubicin and Gd-HP-DO3A over 10 min in HEPES buffer and plasma at 37 degrees , 40 degrees and 41.3 degrees C (p > 0.05). Relaxivity of iLTSL increased significantly (p < 0.0001) from 1.95 +/- 0.05 to 4.01 +/- 0.1 mMs 1 when heated above the transition temperature. Signal increase corresponded spatially and temporally to MR-HIFU-heated locations in phantoms. Signal increase was also observed in vivo after iLTSL injection and after each 10-min heating (41 degrees C), with greatest increase in the heated tumour region. CONCLUSION: An MR imageable liposome formulation co-loaded with doxorubicin and an MR contrast agent was developed. Stability, imageability, and MR-HIFU monitoring and control of content release suggest that MR-HIFU combined with iLTSL may enable real-time monitoring and spatial control of content release. PMID- 21314336 TI - Vergence adaptation in subjects with convergence excess. AB - The main purpose of this study was to evaluate the vergence adaptive ability in subjects diagnosed with convergence excess (CE) phoria (ie, subjects with an esophoric shift from distance to near but without an intermittent tropia at near). Vergence adaptation was measured at far and near with both base-in and base-out prisms using a "flashed" Maddox rod technique in 20 control subjects and 16 subjects with CE. In addition, accommodative adaptation and the stimulus AC/A and CA/C cross-links were measured. The AC/A and CA/C ratios were found to be high and low, respectively, and accommodative adaptation was found to be reduced in CE subjects as compared with the controls (P<0.005), all as predicted by the present theory. However, vergence adaptive ability was found to be reduced in the CE subjects at both distance and near and in response to both base-in and base out prisms (P=0.002). This finding is not in accordance with and is difficult to reconcile with the present theory of CE. PMID- 21314337 TI - Unilateral congenital fibrosis of the extraocular muscles with lid retraction: surgical treatment with a silicon plate on the orbital floor. AB - Fibrosis of the extraocular muscles can be an acquired or congenital disorder (CFEOM). The congenital disorder(1) is a complex strabismus with congenital restrictive ophthalmoplegia with or without ptosis. The surgery is challenging because the eye muscles are replaced by fibrous tissue or fibrous bands and in most cases the results are not satisfactory. We present the first case report of unilateral CFEOM with palpebral adherence and hypotropia, which was managed with our technique of a silicon plate implant on the orbital floor. The purpose of the implantation of the silicon plate in the orbital floor is to improve the hypotropia caused by CFEOM. PMID- 21314338 TI - Electronic baropodometry in patients affected by ocular torticollis. AB - AIMS: To evaluate, by means of electronic baropodometry (EB), the postural findings in patients affected by ocular torticollis. METHODS: Posturographic analysis (length of the sway path, sway area, and mean velocity) was made in 54 patients with IV palsy, Duane Syndrome, or rectus superior palsy (group A) and compared with a control group of 45 healthy subjects (group B). The test was performed with both eyes open, then both closed, then with the affected eye open, and finally with the healthy eye open. RESULTS: With both eyes open or closed, the length of the sway path, the sway area, and mean velocity were significantly increased in group A compared with group B (P<0.0001). When the open eye was the one with the muscular paresis, the length of the sway path was significantly increased as compared with the healthy eye (P<0.0001), and the sway area was increased too (P<0.029). No statistical differences were observed mean velocity according to which eye was open (P=NS). CONCLUSIONS: EB is a useful instrument for studying secondary postural anomalies in patients affected by OT. PMID- 21314339 TI - About natural double vision. 1826. PMID- 21314342 TI - Primary everolimus-eluting stenting versus balloon angioplasty with bailout bare metal stenting of long infrapopliteal lesions for treatment of critical limb ischemia. AB - PURPOSE: To report the long-term outcomes of a single-center prospective study investigating primary placement of everolimus-eluting metal stents for recanalization of long infrapopliteal lesions compared to a matched historical control group treated with plain balloon angioplasty and provisional placement of bare metal stents in a bailout manner. METHODS: The study included 81 patients (63 men; mean age 71 years, range 45-85) suffering from critical limb ischemia (CLI) and angiographically proven long-segment (at least 1 lesion >4.5 cm) de novo infrapopliteal artery disease who underwent below-the-knee revascularization with either primary placement of everolimus-eluting stents (n = 47, 51 limbs, 102 lesions) or angioplasty and bailout bare metal stenting (n = 34, 36 limbs, 72 lesions). Clinical and angiographic follow-up was collected at regular time intervals. Primary clinical and angiographic endpoints included patient survival, major amputation-free survival, angiographic primary patency, angiographic binary restenosis (>50%), and overall event-free survival. Results were stratified according to endovascular treatment received. Multivariable Cox proportional hazards regression analysis was applied to adjust for confounding factors of heterogeneity. RESULTS: Baseline demographics were well matched. No significant differences were identified between the 2 groups with regard to overall 3-year patient survival (82.2% versus 65.7%; p = 0.90) and amputation-free survival (77.1% versus 86.9%; p = 0.20). Up to 3 years, lesions fully covered with everolimus-eluting stents were associated with significantly higher primary patency [hazard ratio (HR) 7.98, 95% CI 3.69 to 17.25, p < 0.0001], reduced binary restenosis (HR 2.94, 95% CI 1.74 to 4.99, p < 0.0001), and improved overall event-free survival (HR 2.19, 95% CI 1.16 to 4.13, p = 0.015) versus the matched historical control group. CONCLUSION: Primary infrapopliteal everolimus eluting stenting for CLI treatment significantly inhibits restenosis and improves long-term angiographic patency and overall patient event-free survival compared to balloon angioplasty and bailout bare metal stenting. PMID- 21314343 TI - Outback catheter for femoropopliteal occlusions: immediate and long-term results. AB - PURPOSE: To report a retrospective, single-center study that evaluates technical and clinical outcomes from subintimal recanalization of femoropopliteal chronic total occlusions (CTO) facilitated by the Outback re-entry catheter. METHODS: The Outback catheter was required to complete recanalization of femoropopliteal CTOs (mean lesion length 195 +/- 91 mm) in 118 limbs of 113 patients (77 men; mean age 70 +/- 10 years). In 80/118 (67.8%) limbs, treatment was performed for claudication and in the remaining 38 (32.2%) for critical limb ischemia (CLI). Technical and procedural success, clinical outcome, and cumulative patency rates in follow-up were evaluated. RESULTS: Re-entry was accomplished in 108/118 limbs (91.5%) with recanalization completed in 107/118 (90.7%). Of these, only 61/107 (57%) arteries were left with a residual stenosis <30%. Complications included minor bleeding of the target vessel (5/118, 4.2%) and minor hematoma/pseudoaneurysm at the access site (6/118, 5.1%). Acute reocclusion developed in 2/118 cases (1.7%) without major complication. After 12 months, primary patency was 56.7%, assisted primary patency 83.1%, and secondary patency 89.1%. Primary patency was significantly reduced in limbs with residual stenosis. Over a median 15-month follow-up (range 2-32), 4 major and 2 minor amputations were performed in patients with CLI. CONCLUSION: The Outback catheter is a reliable tool to recanalize challenging chronic femoropopliteal occlusions after failed guidewire re-entry. Restenosis rates are high, which may be due to the severity and extent of disease in these patients, who are particularly challenging. PMID- 21314344 TI - Commentary: Outback catheter in femoropopliteal subintimal angioplasty: new horizons in treating chronic total occlusions. PMID- 21314345 TI - Endovascular reconstruction of the occluded aortoiliac segment using "double barrel" self-expanding stents and selective use of the Outback LTD catheter. AB - PURPOSE: To present the early and midterm results of endovascular stent reconstruction of the occluded aortoiliac segment with selective use of the Outback LTD re-entry catheter. METHODS: Between April 2004 and February 2010, 8 patients (5 women; mean age 58.4 years, range 47-68) with occlusion of the infrarenal aorta extending to the common or external iliac arteries underwent endovascular reconstruction with double-barrel self-expanding stents. Indications for treatment were severe claudication in 6 and ulceration in 2 patients. RESULTS: The technical success rate was 100%, facilitated by the use of the Outback LTD catheter for accurate wire re-entry in 3 cases. There was no in hospital mortality. One patient had a major complication (femoral artery dissection, brachial artery thrombosis, and retroperitoneal hematoma) unrelated to the re-entry device. Mean operating time was 137 minutes (range 70-253) and length of stay was 1.5 days (range 1-2). During a mean follow-up of 12.5 months (range 6-29), primary patency was 100% with no secondary interventions. CONCLUSION: Total endovascular reconstruction of the occluded infrarenal aorta that extends into the iliac arteries is durable at midterm follow-up. Adjunctive use of the Outback LTD re-entry catheter can facilitate technical success. PMID- 21314346 TI - Stent-assisted below-the-ankle angioplasty for limb salvage. AB - PURPOSE: To report the clinical outcome of stent-assisted below-the-ankle angioplasty for limb salvage in the setting of critical limb ischemia (CLI). METHODS: A retrospective single-center study was conducted of 40 critical ischemic limbs in 31 patients (mean age 67 +/- 8 years, range 46-94) undergoing below-the-ankle stent-assisted angioplasty between April 2006 and April 2009. Coronary bare metal stents were implanted in cases of failed balloon angioplasty due to significant recoil, flow-limiting dissection, abrupt closure, or repeat early reocclusion. RESULTS: Technical success was 93% (37 limbs), with 3 failures to cross the occlusive lesions. Acute or subacute occlusion was evident in 9 (23%) limbs. The number of runoff vessels increased significantly (p < 0.001) from 0.6 +/- 0.8 to 1.8 +/- 0.8. During a clinical follow-up of 19.3 +/- 11.4 months (range 1-48), the number of repeat interventions for limb salvage was 2.2 +/- 1.6 (range 1-9), and a total of 1.6 +/- 0.9 stents (range 1-3) were implanted in 8 dorsalis pedis arteries. Acute or subacute stent thrombosis after stenting was observed in 2 of these, and symptomatic in-stent restenosis was detected in 4, which were all treated by repeat intervention. At 6, 12, and 24 months, the freedom from repeat intervention was 39.6%, 39.6%, and 35.2%, respectively. Amputation-free survival was 80.0%, 69.7%, and 62.7%, and limb salvage was 94.7%, 91.4%, and 82.1% at the same time points. Patient survival rates were 77.4%, 71.0%, and 71.0%, respectively. During a mean follow-up of 13.4 +/- 12.7 months (range 1-31 months) in 7 of the 8 stented arteries, all examined stents were deformed: stent compression was evident in 5 and stent fracture in 5. However, 7 limbs undergoing dorsalis pedis artery stenting showed complete wound healing; 1 limb had a resistant wound in the heel. CONCLUSION: Stent-assisted below-the ankle angioplasty produced a satisfactory clinical outcome but with the need for repeat intervention. Thus, further refinement in endovascular technology is mandatory to reduce the need for repeat interventions and to resolve stent deformity issues. PMID- 21314347 TI - Commentary: Below-the-ankle angioplasty: to stent or not to stent. PMID- 21314348 TI - Cardiva Catalyst II vascular access management device in percutaneous diagnostic and interventional procedures with same-day discharge (Catalyst II trial). AB - PURPOSE: To present a prospective, single-center trial of the Cardiva Catalyst II, a vascular closure device that provides temporary hemostasis after the procedure and is removed under manual compression, leaving no material behind. METHODS: During a 16-month period between April 2008 and July 2009, 400 procedures (100 interventions, 300 diagnostic procedures) were performed on 351 nonconsecutive patients (185 men; mean age 60.2 +/- 12.0 years, range 27-93). All interventions were performed utilizing bivalirudin for anti-thrombin therapy. Initial follow-up was done at a mean 1.3 +/- 0.7 days after the index procedure in all patients. Final follow-up, for diagnostic procedures as well as interventions, was performed at a mean 15.4 +/- 7.1 days. The primary and secondary endpoints were the rate of major and minor vascular complications, respectively. RESULTS: Successful deployment of the device was reported in 397 (99.3%) procedures, which were primarily in retrograde fashion (97.0%) from the right groin (92.5%). In most cases (309, 77.2%), a 5-F sheath was used. A major vascular complication occurred after 1 intervention; none was noted after diagnostic procedures. Minor vascular complications were recorded after 2 interventions and 5 diagnostic procedures. Overall vascular complication rates were 0.25% for major sequelae and 1.75% for minor events. Mean time to discharge after diagnostic procedures was 145.0 +/- 21.2 minutes versus 295.1 +/- 44.1 minutes after interventional procedures (p < 0.05). There was no death, stroke, myocardial infarction, or urgent hospital transfer in the study cohort. CONCLUSION: Cardiva Catalyst is safe and effective device in achieving local hemostasis after percutaneous diagnostic procedures and interventions performed under bivalirudin anticoagulation. The use of this device with an appropriate protocol facilitates same-day discharge. PMID- 21314349 TI - Commentary: The Cardiva Catalyst II device: a catalyzer of patient safety or a boomerang for the endovascular specialist? PMID- 21314350 TI - Study to determine the clinical significance of HEmolysis During Orbital AtheRectomy (CLEAR study). AB - PURPOSE: To evaluate the incidence of clinically evident hemolysis associated with orbital atherectomy used to treat severe peripheral artery disease. METHODS: The observational CLEAR study enrolled 31 subjects (16 men; mean age 71 +/- 10 years, range 44-92) with claudication (58.1%) or critical limb ischemia (38.7%) who underwent orbital atherectomy with the Diamondback 360 system at 4 US centers. The 42 lesions in 31 limbs were located in the superficial femoral (n = 19, 45.2%), popliteal (n = 8, 19.0%), and tibial arteries (n = 15, 35.8%). The majority of lesions (34, 81.0%) were de novo; moderate or severe calcification was identified in 90.5% of cases. Lesion and procedural parameters were analyzed at a core laboratory. Blood samples were collected during and post procedure and analyzed for markers of hemolysis. The primary endpoint was the occurrence of clinically significant hemolysis. The secondary endpoints included the occurrence of any clinical symptoms/signs potentially related to hemolysis. Statistical analysis was performed to identify predictors for hemolysis. RESULTS: Laboratory evidence of hemolysis was seen in 11 (35.5%) subjects. No one met the clinical event criteria, and so the primary endpoint of the study was not reached. The secondary endpoints were hypertensive crisis (1, 3.2%) and transient hemoglobinuria (3, 9.7%). Lower glomerular filtration rates, calcified plaque, long atherectomy runs, and solid crown selection were independent predictors of hemolysis. CONCLUSION: There was no clinically significant hemolysis after orbital atherectomy. The results of this study will enable users to predict conditions that predispose to high levels of red cell hemolysis following orbital atherectomy and to take appropriate measures to limit its occurrence. PMID- 21314351 TI - Commentary: a small step toward clarity in the toolbox. PMID- 21314352 TI - Endovascular management of arterioenteric fistulas: a systemic review and meta analysis of the literature. AB - PURPOSE: To present a systemic review and meta-analysis investigating the outcomes of endovascular management of arterioenteric fistula (AEF). METHODS: Literature review on AEF management with endovascular surgery using MEDLINE search, including two cases managed by the authors. RESULTS: Fifty-nine patients (50 men; mean age 68 years, range 23-90) were identified. AEF was successfully managed in 55 (93%) patients and 30-day mortality was 8.5% (5/59). During follow up, 10 (19%) patients developed recurrent bleeding, which occurred more often in AEFs due to cancer. The freedom from recurrence rate at 12 and 24 months was 71.5%. Seventeen (32%) patients developed sepsis, which was managed conservatively in 8 (7 successful). Freedom from sepsis at 12 and 24 months was 64%, while the freedom from combined recurrence and sepsis at 12 and 24 months was 59%. Patients who did not have intestinal repair had a higher rate of combined recurrence and sepsis compared to patients who did; the freedom from combined recurrence and sepsis at 12 months was 52% for patients not having intestinal repair versus 100% in patients who did (p = 0.022). Total AEF-related mortality rates at 12 and 24 months were 15% and 19%, respectively, significantly worse when AEF recurred (p = 0.001). Overall survival rates at 12 and 24 months were 68% and 52%; prognosis was worse in patients with perioperative sepsis, large bowel fistulization, tube graft placement, no intestinal repair, and recurrent AEF. CONCLUSION: Endovascular management of AEF can achieve satisfactory short and midterm results, better than those historically reported for open surgery, despite the high rate of recurrent bleeding and sepsis. Further investigation of the role played by intestinal repair is warranted. PMID- 21314353 TI - Endovascular management of malperfusion in acute type B aortic dissections. AB - PURPOSE: To examine the feasibility, efficacy, and midterm results of endovascular stent-graft management of acute type B aortic dissection complicated by renal, visceral, or lower limb malperfusion. METHODS: A retrospective review was conducted to identify all patients with acute type B dissection treated endovascularly at a single center between 1998 and 2009. Of the 85 patients identified, 23 (27%) consecutive patients (20 men; mean age 60.9 +/- 11.6 years) presented with clinical and imaging evidence of end-organ malperfusion: 7 (30%) renal, 6 (26%) lower limb, 4 (17%) renal and lower limb, 3 (13%) visceral, and single cases of renal/visceral, renal/lower limb/spinal cord, and renal/visceral/spinal cord/lower limb. RESULTS: All patients had stent-graft coverage of the proximal entry tear; 5 (22%) patients required additional branch vessel stenting, and 2 (9%) had femorofemoral bypass graft. Successful correction of malperfusion was achieved in 21 (91%) patients. In 1 patient, ischemia in the lower limb was resolved but not in the left kidney; the other patient had an ischemic but viable lower limb and did not require any additional intervention. Thirty-day mortality was 9% (2/23 patients). The incidences of postoperative stroke and paraplegia were 17% (4/23) and 9% (2/23), respectively. The 21 survivors were followed for 17.2 +/- 15 months; during this period, 1 patient died, 1 was lost to follow-up, and 5 patients underwent additional open or endovascular procedures. CONCLUSION: Endovascular coverage of the proximal entry tear in acute type B dissections complicated by end-organ malperfusion resulted in correction of malperfusion in the majority of patients. It is a reasonable first line of treatment, but its superiority must be assessed in comparison with other techniques, such as fenestration. PMID- 21314354 TI - Commentary: Management of malperfusion in acute type B aortic dissection: every answer raises several more questions. PMID- 21314355 TI - Near-infrared spectroscopy for monitoring spinal cord ischemia during hybrid thoracoabdominal aortic aneurysm repair. AB - PURPOSE: To describe a simple, noninvasive technique to detect changes in oxygen saturation at the level of the spinal cord and to suggest its suitability for individualized blood pressure management during and after thoracoabdominal aneurysm repair. CASE REPORT: A 53-year-old man with a history of multiple arch and thoracic aortic procedures underwent staged hybrid treatment of a large TAAA due to chronic dissection from the distal aortic arch into the iliac arteries. During the procedures, near-infrared spectroscopy (NIRS) sensors were applied over the 10th thoracic vertebra for continuous monitoring of tissue oxygen saturation (S(s)O(2)) during endovascular repair. After stent-graft deployment, mean S(s)O(2) decreased significantly. Moreover, the relationship between S(s)O(2) and arterial blood pressure became linear, reflecting pressure dependency of spinal cord perfusion after stent deployment. CONCLUSION: These data show that NIRS monitors post-endograft changes in S(s)O(2) that were strongly related to arterial blood pressure. Regional NIRS monitoring at the vertebral level may function as a valuable noninvasive guide to the management of blood pressure during thoracoabdominal aneurysm repair, both intra- and postoperatively. PMID- 21314356 TI - Commentary: Advances in noninvasive perispinal oximetry. PMID- 21314357 TI - Early outcome following endovascular repair of pararenal aortic aneurysms: triple versus double- or single-fenestrated stent-grafts. AB - PURPOSE: To review the early outcome following endovascular repair of pararenal aortic aneurysm using fenestrated stent-grafts and to determine if the number of fenestrations required is predicative of outcome. METHODS: A retrospective analysis was conducted of 20 consecutive patients (18 men; mean age of 75 +/- 7 years) treated with stent-grafts containing either <= 2 fenestrations (n = 10, group 1) or 3 fenestrations (n = 10, group 2). Target vessels also included those accommodated by a scallop (renal artery or superior mesenteric artery in group 1 and the celiac artery in group 2). RESULTS: Comorbidities were similar in both groups. Aneurysm size [median 6.9 (IQR 6.7-8.3) versus 6.0 cm (IQR 5.8-6.6), p = 0.03], procedure time (mean 6.6 +/- 2.1 versus 4.6 +/- 1.7 hours, p = 0.04), and intensive care stay [median 4.5 (IQR 2-14) versus 2 (IQR 1-3) days, p = 0.07] were greater in group 2. There were 2 postoperative deaths, both in group 2. Morbidity was significant and similar in both groups (4 patients in group 1 and 3 patients in group 2), including 1 patient requiring long-term hemodialysis. Target vessel preservation was similar in both groups (96% overall). There were 2 type II endoleaks (one in each group) and no type I or III endoleak. CONCLUSION: Triple-fenestrated stent-grafts allow patients with extensive pararenal aneurysms and significant comorbidity to be treated by endovascular means. Although the number of patients treated was small, which limited the validity of the comparison, longer procedures and greater early morbidity and mortality were seen in the triple-fenestrated group. At present, the procedures are technically more demanding and associated with increased risk compared with double or single fenestrations, but the technology continues to evolve. PMID- 21314358 TI - Sandwich technique for aortoiliac aneurysms extending to the internal iliac artery or isolated common/internal iliac artery aneurysms: a new endovascular approach to preserve pelvic circulation. AB - PURPOSE: To describe a new endovascular approach to preserve internal iliac artery (IIA) flow in patients with abdominal aortic aneurysm (AAA) involving the common iliac artery(ies) (CIA) or in cases of isolated CIA/IIA aneurysm. TECHNIQUE: The sandwich technique for isolated CIA/IIA aneurysms or aortoiliac aneurysms extending to the IIA includes 5 steps: (1) bifurcated stent-graft main body insertion through an ipsilateral femoral approach and positioned such that the distal end of the iliac limb is 1 cm above the IIA origin; (2) catheterization of the ipsilateral IIA through a left brachial access with a long 5-F multipurpose catheter and a 0.035-inch extra stiff floppy tip guidewire; (3) placement of a covered self-expanding stent 2 cm inside the IIA with a 6-cm overlap into the iliac limb, followed by positioning of an iliac limb extension 1 cm below the covered stent's proximal end (the iliac limb extension is deployed first and then the covered stent); (4) modeling of the iliac limb stent-grafts using a latex balloon and dilation of the covered stent with an angioplasty balloon; and (5) deployment of the contralateral iliac limb. For bilateral CIA aneurysms extending to both IIAs, repeat steps 2-4. CONCLUSION: This technique was developed to overcome current anatomical and device constraints, expanding the limits of endovascular aneurysm repair (EVAR) in a safe, easy to perform, and cost-effective manner. The sandwich technique appears a promising tool in the EVAR armamentarium, but more experience with the method is warranted. PMID- 21314359 TI - Commentary: The sandwich technique to preserve the hypogastric artery during EVAR. PMID- 21314360 TI - Preliminary embolization of the hypogastric artery to expand the applicability of endovascular aneurysm repair. AB - PURPOSE: To evaluate the efficacy and safety of preliminary hypogastric artery (HA) embolization prior to endovascular aneurysm repair (EVAR). METHODS: A retrospective review was conducted of all 101 consecutive patients (91 men; mean age 73.4 +/- 8.7 years) who underwent preliminary embolization of 133 HAs ~4 to 6 weeks prior to EVAR from January 2005 to August 2009. Fourteen patients with 19 HAs were treated using coils, while 87 patients were treated with Amplatzer Vascular Plugs (AVP) in 114 HAs. All the patients were evaluated before discharge; at 1, 3, and 6 months; and annually thereafter to evaluate the clinical symptoms, potential endoleaks, and the aneurysm size. RESULTS: In the coil group, complete occlusion was achieved in 16 (84.2%) of 19 procedures. There were no acute pelvic ischemic symptoms after HA embolization or EVAR. Five (35.7%) patients had buttock claudication and 2 (16.7%) of 12 men experienced new erectile dysfunction after embolization. At a mean 42.2-month follow-up (range 14 58), 3 (21.4%) patients had a type II leak via retrograde flow in the HA without aneurysm growth and were under observation. In the AVP group, all 114 HAs in 87 patients were successfully occluded; there was no device dislodgment or acute pelvic or limb ischemia observed. Buttock claudication and new sexual dysfunction developed in 12 (13.8%) patients and 4 (5.1%) of 79 men after the procedure, respectively. During a mean 26.4-month follow-up (range 4-54), 2 (2.3%) patients developed distal type I endoleaks after EVAR, but angiography confirmed that neither of the endoleaks was related to the vessel embolized with the AVP. Comparing the outcomes of the treatment groups, the AVP was placed with fewer intraoperative complications (p = 0.013) and more complete occlusion (p = 0.01) than coil embolization. The rate of buttock claudication was lower in the AVP group (p = 0.042). CONCLUSION: Hypogastric artery embolization prior to EVAR is safe and effective. In our experience, the AVP affords easier and more precise placement and provides more complete occlusion, with fewer intraoperative and postoperative ischemic complications than coil embolization. PMID- 21314361 TI - Commentary: Hypogastric artery interruption prior to EVAR: new devices and techniques to preserve pelvic collateral circulation can reduce complications. PMID- 21314362 TI - Penetrating aortic ulcer in the infrarenal stent-graft landing zone: treatment with coils and the ethylene vinyl alcohol copolymer onyx. AB - PURPOSE: To describe a technique to enable endovascular aneurysm repair in patients with penetrating aortic ulcer (PAU) in the infrarenal neck of an abdominal aortic aneurysm (AAA). TECHNIQUE: The technique is illustrated in a 76 year-old man with a 5.7-cm infrarenal AAA and a 2.3 * 1.8-cm PAU situated immediately distal to the right renal artery and covering 20% of the 28-mm diameter proximal aortic neck. During the stent-graft repair, the PAU was successfully excluded by embolization with coils and the ethylene vinyl alcohol copolymer Onyx. The AAA and PAU were completely excluded without complications. At 6 months, there were no signs of endoleak, the AAA remained excluded, and there was no reperfusion of the Onyx cast in the PAU. CONCLUSION: This technique for treatment of a PAU in the proximal neck of an AAA is a reasonable alternative in cases involving severely diseased infrarenal necks that would otherwise require open surgery. The liquid embolic agent Onyx performed well, with fast embolization and excellent control of the growing cast maintained by the interventionist. PMID- 21314364 TI - Gastroprotective effect and antioxidant properties of different Laurus nobilis L. leaf extracts. AB - Laurus nobilis L. (Family Lauraceae) is an evergreen tree widely distributed in the Mediterranean area and Europe. It is used in folk medicine of different countries as a stomachic and carminative as well as in treatment of gastric diseases. Extracts obtained with different methods (methanol and chloroform) from laurel leaves were evaluated for their gastroprotective activities in the rat. The antioxidant capacity of the different extracts has been also measured in vitro. In order to confirm the activities investigated, histological observations were performed. The gastric damage was significantly reduced by all extracts administered. The more effective protection was produced by chloroformic and methanolic crude extracts. The results obtained after oral administration of L. nobilis leaf extracts are in good agreement with their antioxidant capacity, confirming the relationship between pharmacological efficacy and antiradical activity. Histological evidences confirm the results evaluated with the animal procedures. PMID- 21314363 TI - Effects of dietary soy intake on maternal thyroid functions and serum anti thyroperoxidase antibody level during early pregnancy. AB - Soy and its isoflavones have been suggested to suppress thyroperoxidase (TPO), induce goiter, inhibit deiodinase, and modulate immune functions. This study initially investigated the effects of dietary soy consumption on maternal thyroid functions and anti-TPO antibody (TPOAb) production during early pregnancy. Data were collected through questionnaire from 505 women enrolled during early pregnancy by random sampling in Shenyang, China. Based on soy intake frequency, the subjects were divided into three groups (frequent [three or more times per week], conventional [more than twice per month but less than three times per week], and occasional [two or fewer times per month]). Serum thyrotropin (TSH), free thyroxine (FT(4)), and TPOAb were measured by chemiluminescence immunoassay. Additionally, the concentrations of two primary isoflavones (daidzein and genistein) and creatinine were assessed in the spot urine samples from representative subjects (about 20%) randomly selected from the three groups. The percentages of frequent, conventional, and occasional consumers were 18.6%, 62.6%, and 18.8%, respectively. No difference was found in age, medical records, family history of thyroid diseases, serum FT(4), TSH, and TPOAb levels, TPOAb positive percentages, or prevalence of thyroid dysfunctions among the groups. Both urinary daidzein and genistein levels were significantly higher in the frequent consumers compared with the other two groups. No correlations were found between urinary isoflavone levels and serum FT(4) or TSH. Urinary isoflavone levels were not significantly different between TPOAb-positive and -negative women among the randomly selected representative subjects. On the whole, our findings suggest dietary soy consumption during early pregnancy is not associated with the development of thyroid dysfunction or autoimmunity. PMID- 21314365 TI - Comparison of antioxidant capacities of Ganoderma lucidum (Curtis) P. Karst and Funalia trogii (Berk.) Bondartsev & Singer by using different in vitro methods. AB - The aim of the study was to investigate antioxidant activities of Ganoderma lucidum and Funalia trogii. Ethanol and water crude extracts from G. lucidum and F. trogii were investigated for their antioxidant capacity in some different assays, namely, the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, metal chelating activity against ferrous ions, and plasma lipid peroxidation inhibitory. In addition, the amounts of total phenol, ascorbic acid, beta-carotene, and lycopene components in the extracts were determined. Among the four mushroom extracts, G. lucidum water extract and G. lucidum ethanol extract showed the highest scavenging activity against DPPH radicals (50% inhibitory concentration = 0.055 +/- 0.001 mg/mL). Total phenol was the major antioxidant component found in the mushroom extracts. These results showed that G. lucidum may be used in pharmaceutical applications because of its effective antioxidant properties. PMID- 21314366 TI - Antioxidant and antimicrobial activities of essential oils obtained from oregano (Origanum vulgare ssp. hirtum) by using different extraction methods. AB - In this study, antioxidant and antimicrobial activities of essential oils obtained from oregano (Origanum vulgare ssp. hirtum) were determined by using solvent-free microwave extraction (SFME), supercritical fluid extraction, and conventional hydrodistillation (CH) methods. The inhibitory effects on the 2,2' azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical of essential oils obtained from oregano by using SFME and CH were similar. However, essential oil extracted by CH showed greater (2.69 MUmol/MUL of oil) Trolox equivalent antioxidant capacity (TEAC) than oregano oils obtained by SFME (P < .05). The difference between percentage inhibition and TEAC values most probably is due to the fact that undiluted and diluted samples are used in the percentage inhibition assay and the TEAC assay, respectively. TEAC values of oregano essential oils obtained by SFME at different microwave power levels were found to be similar and ranged from 0.72 to 0.84 MUmol/MUL of oil. Essential oils obtained by CH and SFME at different microwave powers inhibited the survival of Listeria monocytogenes, Salmonella typhimurium, and Escherichia coli O157:H7, whereas survival of Staphylococcus aureus was not influenced. In addition, oregano oil obtained by SFME at 40% power level did not show any inhibitory effect on E. coli O157:H7. PMID- 21314367 TI - Alfred Bielschowsky (1871-1940) A life for strabismology. PMID- 21314368 TI - Comparison of latent nystagmus and nasotemporal asymmetries of optokinetic nystagmus in adult humans and macaque monkeys who have infantile strabismus. AB - To determine whether macaque monkeys with infantile strabismus have latent nystagmus and directional asymmetries of horizontal optokinetic nystagmus (OKN) similar to those of humans with infantile strabismus, the authors recorded eye movements under conditions of monocular viewing. The presence of latent fixation nystagmus was tested by requiring the subjects to steadily fixate a stationary target subtending less than I deg of visual arc. OKN was tested using high contrast, vertically-oriented moving stripes that filled 80 deg of the visual field. A macaque monkey who had infantile strabismus induced by alternating occlusion from birth showed latent nystagmus highly similar to that recorded in an adult human subject with infantile strabismus. The strabismic monkey also had asymmetric OKN similar to that of the strabismic human, favoring nasally-directed stimulus motion when viewing with either eye. Neither nystagmus nor an OKN asymmetry was observed in a normal macaque or in humans who had normal binocular vision. The findings of latent nystagmus and OKN asymmetries in the strabismic monkey support the notion that monkeys who have infantile-onset strabismus are an appropriate ocular motor model of human infantile strabismus. PMID- 21314370 TI - Feuilleton Alfred Bielschowsky (1871-1940)A life for strabismology. PMID- 21314369 TI - Macular dystrophy as a retinal model of fixation disparity. AB - In patients with obligate fixation disparity central objects may be seen double when peripheral fusion manifests. The diplopia cannot be treated with prisms because fusional power of the peripheral retina breaks down central fusion. A different cortical integration of the peripheral and central retina is supposed to be the underlying cause. The authors report on the clinical findings of a 45 year-old man with macular dystrophy who complained about binocularly perceived vertical diplopia up to Id'. Investigation with Aulhorn's phase difference haploscope revealed an inhomogeneous retinal correspondence in the vertical plane with a displacement of the visual field center relative to the periphery by 0.6 degrees. Paracentral scarring was associated with a displacement of central retinal receptors. The center of the visual field and the peripheral field could not be fused simultaneously. The case reported may represent a model for a retinal origin of fixation disparity. PMID- 21314371 TI - A comparison between different contrast sensitivity tests in the detection of amblyopia. AB - Twenty adult patients with strabismic amblyopia were examined with seven different contrast sensitivity tests in order to determine which of these tests is the most sensitive in the detection of amblyopia. Both grating tests (Vistech, Arden, Cadwell, and Cambridge) and optotype tests (LH, Regan, and Pelli-Robson) were used. The following parameters of the contrast sensitivity function (CSF) were measured: maximum contrast sensitivity, total area of CSF and the area of 8 different spatial frequency bands in the CSF. Based on non-parametric tests, it was found that separations of the normal from the amblyopic eye by means of CSF could be done with: - maximum contrast sensitivity using the Vistech test; - total CSF area using all tests except the Cadwell test; - area of frequency bands (within 1-16 cycles per degree) using Vistech, Pelli-Robson, and the Arden tests; - maximum spatial frequency for tests with a fixed contrast using the LH and Regan tests. PMID- 21314372 TI - Monocular acuity in preschool children: Assessment with the Teller and Keeler acuity cards in comparison to the C-test. AB - The development of monocular grating acuity was studied in 210 children between 1 and 6 years using Teller Acuity Cards (TAC). 95 of these children were also tested with the Keeler Acuity Cards (KAC). Monocular visual acuity measured with the TAC showed a gradual increase from 8.4 to 32.4 c/deg for 7 to 79 month-olds and with the KAC from 14.5 to 31.4 c/deg for 19 to 78 month-olds. Mean visual acuity at 6 years was still 0.5-1.0 octave lower than grating acuity in adults. The results of 95 children tested with TAC and KAC did not indicate any significant differences between the acuity scores obtained with the two tests. Stimulus configuration of the TAC did not result in overestimation of acuity in children 1-6 years of age. In 141 older children (39-79 months), the TAC test was compared with a recognition test (C-test). Children between 3 and 5 years of age reached significantly lower acuities with the C-test than with the TAC. The C test showed a higher sensitivity for unconnected refractive errors than the acuity card tests. PMID- 21314373 TI - Sixty strabismus cases operated with the Computerized Strabismus Model 1.0: When does it benefit, when not ? AB - While, in routine strabismus surgery, empirical guidelines and experience are the best in judging which eye muscles to operate, a complex case may need a unique surgical approach, the consequences of which cannot always be envisioned in detail. We sought to improve the results of surgery in these cases by preoperative simulation of each case with the Computerized Strabismus Model 1.0 (CSM). The basis of this model was laid by David A. Robinson. It has been improved by us over the past years to the point that it can be used clinically. Improvements concerned, for example, the mechanics of the eye muscles and the anatomy of insertions and origins. The ease of operation has been improved and the algorithms have been made so much faster that a full calculation for 9 positions of gaze now takes 10 seconds on a hand-held Hewlett Packard 200LX Palmtop. From 1994 onwards, all cases to be operated in our department which were more complex than straightforward horizontal rectus muscle surgery were simulated in the model preoperatively. The predictions of the model compared well with the actual result of surgery in most cases. The model was particularly good in handling complex and unique disorders of motility. However, the model could not reliably predict the effect of strabismus surgery in cases with mechanical restrictions of motility. PMID- 21314374 TI - Alfred Bielschowsky (1871-1940): A life for strabismology. PMID- 21314375 TI - Errata. PMID- 21314376 TI - Adjustable horizontal rectus recession surgery for disparate distance-near ocular deviations. AB - Strabismic deviations which display incomitance changing from distance fixation to near fixation are the result of many disturbances of both the supranuclear and infranuclear ocular motor system. This report details the surgical treatment and outcome of 6 patients with disparate distance-near deviations due to different etiologies. The surgical procedure involves recessing all four horizontal recti on both eyes using the adjustable suture technique. The approach to surgery consisted of operating on the vergence angle with the larger deviation with a bilateral lateral rectus recession (BLREC) or a bilateral medial rectus recession (BMREC) and simultaneously operating on the smaller vergence angle, treating the total induced deviation with the bilateral recession not used first (remaining BLREC or BMREC). All patients had a significant decrease in their distance-near disparity, increased horizontal comitance, normalization of their accommodative convergence to accommodation ratios, and resolution of diplopia. A four horizontal recti muscle, adjustable suture recession is another technique that can be added to the treatment regimens for distance-near disparity strabismic syndromes. PMID- 21314377 TI - Long-term results after bimedial posterior fixation sutures for infantile esotropia. AB - Between 1984 and 1989, 79 patients were reexamined an average of 8 years after bimedial rectus muscle posterior fixation sutures. Patients who had to be operated additionally for vertical or cyclovertical motility disorders were excluded from the study. Seventy-five percent of the patients showed a residual deviation in the alternating prism and cover test of up to 5 degrees . With Bagolini striated glasses 60 patients were found to have simultaneous perception at near and distance. The effects on convergence and lateral gaze were examined. After completed surgical therapy consecutive exotropia was found in 5% of all cases. In every 5th patient a reoperation was required. The study shows that bilateral posterior fixation suture of the medial rectus muscles leads to good long-term results in correcting infantile esotropia. Compared to other surgical techniques, significant advantage results from the low number of consecutive exotropias. PMID- 21314378 TI - Initial pursuit responses using a fixation-gapramp paradigm. AB - Pursuit eye movements keep the image of a small moving target near the fovea with an admixture of smooth pursuit and saccades. To probe the initiation of pursuit, four humans and one monkey attended a bright laser spot that was rear-projected on a diffusely illuminated (1 cd/m(2)) tangent screen. Movement of the viewing eye was recorded with a magnetic search coil. After presenting a stationary target for a random time (1-3 sec), the computer extinguished the target in separate trial blocks for 40, 100, 200, or 500 ms. At the end of this gap period, the target reappeared on the fovea, moving centrifugally at 10 degrees /sec in a random direction before decelerating to a stop. The predominate initial response (< 90%) to unpredictable changes in target motions had four sequential components: a latent period, a primary smooth movement, a small saccade, and then a secondary smooth movement. None of five measured variables depended systematically on the gap duration: the latency to primary smooth pursuit (range of means 144-217 ms), average eye velocity in the first 50 msec of primary smooth pursuit (0.7-3.6 degrees /s), latency to the first saccade (207-319 ms), amplitude of the first saccade (1.6-2.7 degrees ), or average eye velocity in the first 100 ms of the secondary smooth pursuit (7.4-11-4 degrees /s). Our data do not support the hypothesis that a separate fixation system has to be disengaged before smooth pursuit can begin, as has been suggested for the saccadic system. PMID- 21314379 TI - The Fourth Monitoring Report of the Early vs. Late Infantile Strabismus Surgery Study: The Early vs. Late Infantile Strabismus Surgery Study Group. AB - The Early vs. Late Infantile Strabismus Surgery Study Group is a group of strabismologists and orthoptists from 58 clinics in 11 European countries. They investigate whether early or late surgery is preferable in infantile strabismus, in a non-randomized, prospective, multi-center trial.(1) Infants between 6 and 18 months of age receive a standardized entry examination and are then operated either before their second anniversary in clinics A, or between their 32nd and 60th month of age in clinics B. The children are evaluated at age six. After completion of the study, the two groups can then be compared regarding degree of binocular vision, angle of strabismus and visual acuity of the worse eye relative to the better. The current status of the study is reported here. Up to December 13, 1996, 58 clinics have entered a total of 532 patients. Currently, 232 children have been entered in the early surgery group and 300 in the late surgery group. Completeness of data and forms are excellent. Thirty-eight patients have definitively dropped out. There is no evidence for inhomogeneities between the two therapy groups concerning the distribution of the four most important prognostic factors: spherical equivalents, horizontal angle of squint, degree of amblyopia and limitation of abduction. PMID- 21314381 TI - Selected abstracts. PMID- 21314380 TI - Alfred Bielschowsky (1871-1940): A life for strabismology. PMID- 21314382 TI - Measurement of subjective and objective cyclodeviation in oblique eye muscle disorders. AB - Surgically induced changes of eye torsion often show a subjective over-effect which resolves later on. Hence the authors initiated a prospective study with the purpose of analyzing motoric and sensoric elements in postoperative rotational changes by comparing subjective and objective cycloduction. Fundus cyclometry, a new method for measurement of objective cycloduction, is introduced. An image of the posterior pole is obtained by an infrared Scanning Laser Ophthalmoscope without pupil dilatation and is transferred to a computer system by which nature and amount of objective cycloduction is calculated. Four patients who underwent surgery for oblique eye muscle disorders are presented. Objective torsional changes were slightly higher than subjective changes. Postoperative reduction of torsional changes was noted subjectively and objectively in all cases. For statistical reasons further investigations on a great number of patients are needed to interpret the postoperative changes in terms of motoric and sensoric cyclofusion. PMID- 21314383 TI - Sporadic Duane's Retraction Syndrome Associated with Imperforate Anus: Case Report. AB - Duane's retraction syndrome is sometimes associated with developmental ocular and extraocular abnormalities. This disorder may also be present in association with specific malformative syndromes. The authors report the clinical features of a seven-year-old female affected by Duane's retraction syndrome (D.R.S.), rectoperineal fistula, imperforate anus and other congenital malformations. From two extensive reviews of 106 reports published before 1982 and from a search (using Medline 1981-1994) for reports of congenital malformations associated with this syndrome, no cases of sporadic D.R.S. associated with the perineal malformations mentioned were found, even though imperforate anus is considered the commoner of hindgut malformation. PMID- 21314384 TI - Surgical dampening of nystagmus in patients with achromatopsia. AB - Lack of cone function is one and nystagmus is the other cause of low vision in patients with rod monochromatism. The nystagmus has been assumed to be a consequence of the increased light sensitivity due to the predominance of rods. However, symptoms of patients with cone dystrophy are not very different from those observed in patients with congenital nystagmus. For example, they occasionally have a dampening of the nystagmus on fixation at near. Therefore, like in congenital nystagmus, we can elicit convergence innervation during fixation at distance with prisms base-out or with a surgically induced divergence ('artificial divergence'). This approach only works in patients with binocular function, necessary to keep the eyes aligned. The authors report on three patients with complete rod monochromatism in whom they performed an artificial divergence operation (OAD) by recessing the medial rectus muscle and resecting the lateral muscle of one eye. After surgery, the measured visual acuity was the same but the nystagmus of these patients had been considerably reduced. The patients themselves considered the effect of surgery a great improvement. PMID- 21314386 TI - Selected abstracts. PMID- 21314385 TI - The Early vs. Late Infantile Strabismus Surgery Study: Monitoring Report: The Early vs. Late Infantile Strabismus Surgery Study Group. AB - The Early vs. Late Infantile Strabismus Surgery Study Group is a group of strabismologists and orthoptists who investigate whether early or late surgery is preferable in infantile strabismus, in a non-randomized, prospective, multi center trial. Infants between six and 18 months of age will receive a standardized entry examination and then be operated either before their second anniversary, in clinics A, or between 32nd and 60th month of age in clinics B. The children will be evaluated at age six. After completion of the study, the two groups can then be compared regarding degree of binocular vision, angle of strabismus and visual acuity of the worse eye relative to the better one. This is the second monitoring report of the study. PMID- 21314387 TI - Ophthalmoplegia in an adult with chronic inflammatory demyelinating polyradiculoneuropathy. AB - The authors present a 75-year-old patient with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and ophthalmoplegia. The patient had recurrent exacerbations and remissions of her polyneuropathy over the course of one year. Antibodies to ganglioside GM-I were not detected. Ophthalmoplegia in CIDP is uncommon, but is reported to occur in 3-8% of patients. Ophthalmologists should be aware of the association of CIDP and ophthalmoplegia. PMID- 21314388 TI - The results of surgical treatment in Duane's retraction syndrome. AB - In an attempt to evaluate the response to surgical treatment, the surgical outcome of 16 patients with Duane's retraction syndrome (DRS) was investigated. Single horizontal rectus muscle recession, transposition of vertical recti and recession of both horizontal recti were carried out. In one of the four patients with significant globe retraction, Y splitting of the lateral rectus muscle was added to the procedure to overcome the cosmetically unacceptable upshoot. Single horizontal muscle recession surgery was effective in reducing the abnormal head posture and the deviation in primary position. The results of both horizontal recti recession were not so predictable in reducing globe retraction. Recession of both horizontal recti was ineffective in vertical DRS. It is suggested that the variability of surgical outcome in DRS may be related to the different innervational patterns and mechanical factors. PMID- 21314389 TI - Dissociated vertical deviation and eye torsion: Relation to disparity-induced vertical vergence. AB - We studied the relation between vertical eye movements and binocular torsion in five subjects with dissociated vertical deviation (DVD). During trials, subject viewed a well illuminated Snellen letter chart, with both eyes uncovered during 4 seconds, Subsequently, DVD was induced by covering one eye during 4 seconds. Finally, both eyes were uncovered during 4 seconds. Several trials were recorded for each subject and covered eye. Eye movements were measured with scleral coils. We found that in all subjects, the vertical divergence followed an exponential course with a time constant of 0.67 +/- 0.14 seconds on average. In three of the five subjects this vertical divergence was associated with binocular torsion (cycloversion), partly, in the form of a cycloversional nystagmus. The time course of the vertical divergence as well as the direction and nystagmic nature of the cycloversion was similar to the behaviour that was previously observed in disparity induced vertical vergence in normal subjects. In two of the subjects, the torsion that was associated with the vertical divergence was monocular. Our results indicate that DVD and disparity induced vertical vergence share the same characteristics. In addition, they demonstrate that extorsion associated with the elevation in DVD possibly but not necessarily points at a dissociated torsional deviation. PMID- 21314390 TI - Surgical results in highly asymmetric dissociated vertical deviations. AB - The effect of surgery in highly asymmetric dissociated vertical deviations (DVD) was evaluated in 13 patients. All the patients had a moderate or large DVD (more than 15 PD) in one eye with a latent or very small (less than 5 PD) DVD in the fellow eye. As there was no strong fixation preference in either of the two eyes of the patients before surgery, bilateral surgery was performed. Eleven patients underwent surgery which consisted of conventional (3-5 mm) superior rectus (SR) recession combined with posterior fixation sutures placed 13 mm from the original insertion in the eye with moderate or large DVD, with posterior fixation sutures alone in the eye with minimal or latent DVD. In the remaining two patients, bilateral conventional SR recessions were combined with posterior fixation sutures. The mean follow-up was eight months. A cure was defined as latency or elimination of the hyperdeviation and was noted in five patients, two of whom had undergone bilateral SR recessions with posterior fixation sutures. All the remaining eight patients developed a cosmetically unacceptable moderate or large DVD (more than 15 PD) in the eye that had a very small DVD prior to surgery, two of them having a manifest comitant hypertropia postoperatively in addition to the DVD, demonstrating overcorrections with the previously elevated eye now in a hypotropic position. Performing posterior fixation sutures alone to the eye with a very small DVD does not seem to be effective in the surgical treatment of DVD; combining posterior fixation sutures with a recession of the SR muscle seems to be a more reasonable approach. PMID- 21314391 TI - 1 Experiences with asymmetrical recessions of the four horizontal recti in variable esodeviations. PMID- 21314393 TI - Alfred Bielschowsky (1871-1940): A life for strabismology. PMID- 21314392 TI - Abstracts of papers presented at the: XXV Meeting of the F.C. Donders Society for: Strabismus, Rotterdam, November 1996 27. PMID- 21314394 TI - 1 Prominent proptosis in childhood thyroid eye disease. Abbreviated source. PMID- 21314395 TI - Original papers: Large bimedial rectus recession (6.5 mm or more) in the management of large-angle esotropia. AB - A total of 101 patients (total group) with primary large angle esotropia who had primary bimedial rectus recession (BMR) of 6.5 mm or more were reviewed in a retrospective study. The average pre-operative size of the deviation was 63.5 prism diopters (PD) for near and 58.2 PD for distance. Of these, 26 patients (group I) attended for one post-operative visit only. The remaining 75 patients (group II) were followed for an average period of 17.7 months. Among group II patients there was an average shift in the post-operative deviation towards divergence consisting of-6.4 PD for near and-5.5 PD for distance. The alignment (deviation of 10 PD or below) rate in the first postoperative visit was 31.7%; undercorrection was 60.4% and overcorrection was 7.9%. At the end of the period of follow-up the above rates were 40%, 42.7%, and 17.3% respectively without further surgery. This increase in the overcorrection rate was solely derived from the initially aligned patients. Amblyopia and/or poor fixation were found to be of significance in the production of overcorrection. There was no direct relationship between the age of surgery, duration of follow-up or the degree of the BMR and the rate of correction. Among group II patients, post-operative ocular movements analysis revealed limitation of adduction of-0.5 to-0.75 (out of scale 0 to-4.00) in 22.7% (17/75) and-1.00 to-1.50 in 6.7% (5/75). None had more than-1.5 limitation of adduction. Large BMR is an acceptable surgical modality for the management of large angle esotropia. It has approximately 50% alignment rate. Slight undercorrection is recommended especially in the presence of significant amblyopia and/or poor fixation. No significant limitation of adduction was encountered. PMID- 21314396 TI - Original papers: Complications in strabismus surgery. AB - Perforation of the globe is a rare but specific risk of strabismus surgery, as proven by a review of the literature and statistic analyses of the authors. While in the 1960s and 1970s perforations occurred in about 10% of the operations, improved operation techniques and better material have reduced the perforation rate to 1% degrees at present. This tendency is confirmed by the authors' studies of the periods 1966-1970 (eight clinics; 10,349 strabismus operations; 37 perforations = 3.6% degrees ) and 1989-1993 (23 clinics; 44,211 operations; 67 perforations = 1.5% degrees ). The personal perforation rate of the authors (1.2% degrees of operated eyes) is in good agreement with the results in other clinics with specialized orthoptic departments. Three case reports demonstrate inadvertent perforation of the globe. In one case, intrabulbar steroid injection caused visual loss due to central retinal artery occlusion. The authors therefore recommend postoperative ophthalmoscopy of the fundus periphery with dilated pupils. PMID- 21314397 TI - Original papers: Prevalence of amblyogenic diseases in a preschool population sample of Valladolid, Spain. AB - OBJECTIVES: Amblyopia is the leading cause of monocular vision loss in people under 40 years, and especially in children. The purpose of the present investigation is to determine the prevalence of amblyopia and ocular pathology, specially the most common causes of amblyopia, in a population of 3-to 6-year-old children. PATIENTS AND METHODS: From a total of 8167 children, a geographically defined population of 3-to 6-year-old children, 2000 were randomly selected, and 1179 (58.9%) examined. Ophthalmologic examination included: Personal and familial history, visual acuity, extraocular motility, cover test at near distance, cycloplegic refraction with autorefractometer and fundus eye examination. Amblyopia was considered when corrected visual acuity was < 0.5 with Marquez optotypes and difference in visual acuity of 0.2 or more between eyes. Pathology considered as amblyogenic were strabismus, visual acuity asymmetry and anisometropia. RESULTS: The family history showed amblyopia in 249 (21.1%), strabismus in 227 (19.2%), and refractive errors in 808 (65.5%). Cover test was positive in 78 children (6.7%). A visual acuity difference of 0.2 or more between eyes was present in 88 (7.5%) children, and anisometropia over 1.5 diopters (in spherical equivalent) was present in 17 (1.4%) subjects. One hundred and twenty two (10.35%) children did not achieve a normal visual acuity: visual acuity in the better eye was less than 0.5 in 55 children under 5 years and less than 0.6 in 67 children over 5 years. The prevalence of amblyopia was 7.5%. CONCLUSIONS: The data support the importance of early detection and treatment of amblyopia and the need for visual screening at an early age. PMID- 21314399 TI - Clinical conferences: Misdirection syndrome. PMID- 21314398 TI - Original papers: Does strabismus surgery induce significant changes of corneal topography? AB - To determine whether strabismus surgery significantly influences corneal curvature, corneal topography was measured in 68 patients before and both one day and three months after strabismus surgery. With few exceptions, early corneal topographic changes were moderate, statistically not significant and nearly disappeared after 3 months. Long term absolute astigmatism increased not significantly by 0.16 D. Our results demonstrate that strabismus surgery can induce transitory but usually no long term changes of corneal topography. Patients should be informed, however, that in rare cases an induced astigmatism may persist. PMID- 21314400 TI - Feuilleton: Alfred Bielschowsky (1871-1940): A life for strabismology. PMID- 21314401 TI - Selected abstract. PMID- 21314402 TI - Statistical validation of a strabismus index calculated from objective ocular alignment data. AB - PURPOSE: Statistical analysis of a strabismus index used for objective interpretation of eye alignment data and improvement of this strabismus index. MATERIALS AND METHODS: Primary position eye alignment data of 330 subjects aged from a few months to young adulthood were collected with Purkinje Reflection Pattern Evaluation. Among these there were 95 strabismic subjects with inapparent, very small ocular misalignments from o degrees to about +/-5 degrees . The subjects were split into four age groups: up to 12 months of age, between 12 and 24 months, between 24 and 48 months and above 48 months of age. The measured and calculated angular variables and the strabismus index were tested statistically for age dependence and differences between the three orthoptic groups 'strabismus', 'referral' and 'non-referral'. The level of significance chosen was $aL=0.05. RESULTS: There was a significant dependence of most of the angular variables on the orthoptic group. A dependence of the variables on age was not found except for a few angular variables which seemed to be related to the somewhat larger fluctuations of fixation in the two lower age groups. There was no age dependence of the strabismus index. With a strabismus index threshold of 0.7, the sensitivity was 85% for the detection of cases who needed referral according to the orthoptic examination. CONCLUSIONS: This study provides the statistical basis for the strabismus index procedure which was initially introduced as an empirical procedure. It indicates that the strabismus index does not depend on age, so that limited cooperation in toddlers and infants has no major influence on the result of the data classification with the strabismus index. The strabismus index is a suitable means for objective, examiner independent decision making in screening for very small ocular misalignment. PMID- 21314403 TI - Extraocular muscle imbalance after scleral buckling. AB - Postoperative muscle imbalance was prospectively evaluated in 44 patients who underwent conventional scleral buckling operations. Strabismus was present in 27 of 44 patients (61%). Heterotropia resolved spontaneously during the first six postoperative months in nine of 27 patients (33%). Diplopia persisted in six patients (13.6%) and limitation of ductions occurred in 22 of 44 patients (50%). The risk of developing postoperative strabismus was 2.5 times longer if an implant was placed under a rectus muscle. Otherwise, presence, degree, and direction of the duction deficits did not correlate with placement of a local implant under the corresponding rectus muscles or their antagonists. Reoperation, preoperative detachment of macula and size of the local implant were not statistically correlated with extraocular muscle imbalance. We believe that decrease in postoperative swelling and increase in visual acuity that allows phoria adaptation are the main causes of spontaneous resolution. PMID- 21314404 TI - The results of surgery in a series of partially accommodative esotropic patients. AB - Three different surgical procedures were performed in 32 partially accommodative esotropic patients with a high accommodative convergence/accommodation (AC/A) ratio. The patients were followed-up for an average period of 2.5 years (range: four months to seven years). Recession of the medial rectus and resection of the lateral rectus (group I), bimedial recession (group 2) or bimedial recession with bimedial Faden operation (group 3) were performed, guided by the preoperative AC/A ratio, the difference between the distance and near deviations, and the alternation pattern. At the end of the follow-up period, the average distance and near deviations were found to be less than 10$DL in all three groups. The AC/A ratio of all patients was normal or close to normal in the postoperative period. PMID- 21314406 TI - An acuity cards cookbook. AB - Acuity cards are being more commonly used in clinical and screening practice. The author describes his experience from over 6000 infants tested with the method, using two commercially available sets of cards to provide users with comprehensive guidelines to allow them to get the most out of this useful test. PMID- 21314405 TI - Aplasia of the superior oblique tendon. AB - The authors describe two cases with unilateral aplasia of the superior oblique tendon. The incomitance pattern could not be explained solely by the lacking torque of the superior oblique muscle. Rather, a considerable adaptation of the central nervous system had to be invoked resulting in compensatory innervation of the remaining seven vertical muscles of both eyes. PMID- 21314407 TI - The Third Monitoring Report of the Early vs. Late Infantile Strabismus Surgery Study. AB - The Early vs. Late Infantile Strabismus Surgery Study Group is a group of strabismologists and orthoptists from 58 clinics in II European countries. They investigate whether early or late surgery is preferable in infantile strabismus, in a non-randomised, prospective, multi-centre trial. Infants between 6 and 18 months of age receive a standardised entry examination and are then operated either before their second anniversary in clinics A, or between their 32nd and 60th month of age in clinics B. The children are evaluated at age six. After completion of the study, the two groups can then be compared regarding degree of binocular vision, angle of strabismus and visual acuity of the worse eye relative to the better. The current state of the study is reported here. Fifty-eight clinics have entered a total of 463 patients up to March 1996. Patient recruitment rates have been less than expected during the last months. Currently, 186 children have been entered in the early surgery group and 277 in the late surgery group Completeness of data and forms are excellent. Only 25 patients have definitively dropped out. There is no evidence for inhomogeneities between the two therapy groups concerning the distribution of the four most important prognostic factors: spherical equivalents, horizontal angle of squint, degree of amblyopia and limitation of abduction. PMID- 21314408 TI - Congenital mono-ophthalmia syndrome. AB - Three patients affected by the congenital mono-ophthalmia syndrome were submitted to horizontal eye movements recording. The aim was to study the nystagmus and its characteristics, in order to give information that could explain signs and symptoms of the syndrome. Eye movements recording and analysis displayed a jerk nystagmus with a decreasing-velocity exponential slow phase, characteristic of a latent/manifest-latent nystagmus. The intensity of nystagmus decreased in adduction of the viewing eye, and increased in abduction in accordance with Alexander's law. The fast phase was toward the viewing eye. There was no reversal of the fast phase, nor an instability of gaze in the blind eye. PMID- 21314409 TI - Cycloduction as a possible side-effect of vertical transposition of horizontal eye muscles in A- and V-pattern. AB - In general an A-or V-symptom is an additional sign of an oblique muscle dysfunction and is treated by surgery of oblique muscles. The vertical transposition of horizontal rectus muscles is a suitable treatment only in those cases with no coexistent vertical deviation. The mechanical particularities of this vertical displacement are summarized. Possible side effects of this surgical method, including cyclotropia are reported. PMID- 21314410 TI - Selected abstracts. PMID- 21314411 TI - Symposium Proceedings: Abstracts of papers presented at the V Meeting of the Child Vision Research Society Frankfurt, Germany, 23-25 June 1995. PMID- 21314412 TI - Mechanics and strabismus. PMID- 21314413 TI - Reversed Fixation Test as a Means to Differentiate between Dissociated and Non Dissociated Strabismus. AB - Dissociated vertical deviation (DVD) depends on the balance of visual inputs coming through the right and left eyes. In the classical Bielschowsky Filter Test the balance of visual inputs is altered by darkening the retinal image of the fixing eye with a filter. In the Reversed Fixation Test (RFT) the balance of visual inputs is altered by not only darkening the fixing eye (occlusion put on) but also by brightening the squinting eye (occlusion removed) and, at the same time, switching the fixation to the other eye. In a series of 30 patients the RFT revealed a DVD component of 16.3 +/- 4.9+/- while the Bielschowsky Filter Test revealed 3.4 +/- 3.2+/- only. In seven cases the value of the Bielschowsky Filter Test was even zero while the RFT revealed a DVD component between 8 and 20+/-. The RFT allows a quantitative differentiation between DVD and esotropia with elevation in adduction (= upshoot in adduction or strabismus sursoadductorius or overaction of the inferior oblique muscle), even if both types of vertical deviation occur in the same patient. PMID- 21314414 TI - Absence of subcortical pathway optokinetic eye movements in an infant with cortical blindness. AB - Tracking of large visual targets by normal neonates and by infants with visual cortex damage has led to the suggestion that infants use subcortical vision to guide visuomotor behaviors. To test this assertion, the author recorded eye movements in a five-month-old infant who became cor-tically-blind following an anoxic episode. Use of a full-field, high-contrast visual stimulus failed to elicit any evidence of optokinetic nystagmus. The findings in this infant lead to the conclusion that retinotectal visual inputs are incapable of driving eye movements in the young human in the absence of cortical vision. PMID- 21314415 TI - Two techniques to evaluate visual acuity from the age of 18 months. AB - Two methods to measure visual acuity in children aged 18 months and upwards are described, the Kolt-test and the O-test. The validity of the tests was evaluated. These new tests are based on the ability of small children to identify symbols of increasing complexity as they grow older. Thus, a circle is recognized at 12 months, and a cross at about 24 months, while recognition of a triangle and a square comes in between. Correct performance is rewarded. Simplified procedures permit testing children with visual acuity below 0.1 (6/60, 20/200). The tests may also be used in mentally retarded persons if conventional methods fail. PMID- 21314418 TI - Abstracts of papers presented at the v meeting of the child vision research society frankfurt, Germany, 23-25 june 1995. PMID- 21314416 TI - Robinson's Computerized Strabismus Model Comes of Age. AB - In this article we review our further development of D.A. Robinson's computerized strabismus model. First, an extensive literature study has been carried out to get more accurate data on the anatomy of the average eye and the eye muscles, and about how these vary with age and with refraction. Secondly, the force-length relations that represent the mechanical characteristics of the eye muscles in the model have been determined more accurately in vivo recently, and the model was changed accordingly. Thirdly, many parameters that were free in the original model and not derived from in vivo measurements were replaced by derivatives from in vivo measurements or made redundant. Fourthly, the ease of operation was improved greatly and the algorithms were made so much faster that a calculation for nine positions of gaze now takes ten seconds on a handheld HP 200LX Palmtop. The predictions of the model compared well with clinical results in horizontal muscle surgery, oblique muscle surgery, forced duction tests and abducens, oculomotor or trochlear palsies. Consequently, complex strabismus surgery in our clinic is now guided by the predictions of the computerized model. PMID- 21314419 TI - Selected abstracts. PMID- 21314420 TI - Erratum. PMID- 21314421 TI - Fourth nerve palsy in pseudotumor cerebri. AB - A 13-year-old white female with a past medical history of facial acne treated with minocycline presented with headaches, normal visual acuity, bilaterally enlarged blind spots on visual field testing due to bilateral disc edema, and a right fourth nerve palsy. Neuroimaging studies were normal and a lumbar puncture revealed an elevated opening pressure but normal cerebrospinal fluid contents. The diagnosis of pseudotumor cerebri was made and the patient was treated with acetazolamide. The papilledema improved over several weeks and the fourth nerve palsy resolved completely. Fourth nerve palsy is an uncommonly reported nonlocalizing sign in pseudotumor cerebri. PMID- 21314422 TI - Early versus late alignment of infantile esotropia. AB - Fifty-two children with infantile esotropia had surgery for their esotropia between two and seven years of age. Another 49 had similar surgery before the age of two years. Of these 101 operated children, the esotropia in 70 patients was aligned to within 10 prism diopters. The patients with successful alignment were reviewed to study the effect of early versus late surgical intervention of their deviation, i.e. before and after two years of age. The motor and sensory states of the selected patients were analysed before and after surgical correction. The choice and number of surgical procedures employed are discussed. It appears that patients two years and older when strabismus was surgically corrected have a good chance of alignment, but less chance of attaining binocularity. In many cases there was a V-pat-tern esotropia, requiring surgery on the overacting inferior oblique muscles. In comparison, the younger group with earlier surgery appeared to show a better chance of attaining binocularity and fewer patients had significant V-pattern requiring surgery on the inferior oblique muscles. PMID- 21314423 TI - Synoptophore versus prism and cover test measurements in strabismus.: A question of instrument convergence? AB - It has long been advocated that the accuracy of the synoptophore is affected by the artificial viewing conditions it provides and the patient's awareness of its proximity, which results in an increase in the angle in ET and a decrease in XT. The aim of this retrospective study was to investigate the agreement between distance horizontal strabismus measurements taken with the synoptophore and PCT. Fifty-four measurements (n = 42: 28 with ET, 14 with XT) were analysed. The PCT was repeated by a second examiner and the measurements (n = 17) were compared to those of the first examiner's prism measurements. The main finding was a high agreement between the measurements obtained by the two methods (ICC: R = 0.91). There was an eso-shift of the deviation at the synoptophore (compared with the PCT) in 26% and an exo-shift in 28%. Therefore, over-convergence was just as likely to occur as un-der-convergence. The findings cannot support the popular notion that the synoptophore exaggerates the angle in ET and understates it in XT. Furthermore, it was shown that the variability between the two measurement methods was similar to the inter-examiner variability for the PCT. It was concluded that the synoptophore measurements are valid and that the phenomenon of over-convergence with this device ('instrument convergence') is not a relevant clinical entity. PMID- 21314424 TI - Fusion loss as a result of long-standing unilateral traumatic cataract or uncorrected aphakia. AB - Eight patients with secondary strabismus as a result of longstanding unilateral traumatic cataract or uncorrected aphakia were seen in the Orthoptic Department between April 1993 and September 1994. At the initial orthoptic examination three patients did not have any binocular vision and five patients demonstrated some form of binocularity although the fusional amplitude was seriously reduced. Three of these five patients showed just a small heterophoria and a better fusional amplitude within six months after a good optical correction and/or prescription of prisms with or without strabismus surgery. Orthoptic examination and therapy is mandatory in these patients because binocular functions can be restored in some of them, in spite of the long interval between trauma and optical correction. PMID- 21314425 TI - Unilateral modified Harada-lto procedure for excyclotorsion secondary to unilateral superior oblique palsy. AB - BACKGROUND: The Fells modification of the Harada-lto procedure is usually performed bilaterally for the correction of excyclotorsion secondary to acquired bilateral superior oblique paresis. Excyclotorsion is not usually a major complaint in true unilateral superior oblique paresis. Occasional cases, however, may find this symptom bothersome and it may interfere with fusion. The purpose of the present study is to determine the effect of the unilateral modified Harada lto procedure on the correction of symptomatic excyclotorsion in unilateral superior oblique paresis. METHOD: A retrospective case-note review of patients with unilateral superior oblique paresis undergoing unilateral modified Harada lto procedures during the five-year period 1988-1993 was performed. RESULTS: Six patients fulfilled the inclusion criteria. Superior oblique paresis was congenital in one case, secondary to trauma in two cases and idiopathic acquired in three cases. There were four males and two females aged from 25 to 63 years and all but one had previous surgery. The mean pre-operative excyclotorsion was approximately 10 degrees (range 8-14 degrees). Mean post-operative excyclotorsion was 3 degrees (range 2 degrees incyclotorsion -10 degrees excyclotorsion). CONCLUSION: The unilateral modified Harada-lto procedure is an effective surgical treatment of excyclotorsion resulting from superior oblique paresis and may improve sensory and motor fusion. PMID- 21314426 TI - Abstracts of papers presented at the V Meeting of the Bielschowsky Society for the Study of Strabismus Hamburg, Germany, 18-19 March, 1995. PMID- 21314427 TI - Abstracts of Strabismological and Neuro-ophthalmological Case Presentations Kantonsspital, Sankt Gallen, Switzerland 4 April 1995. PMID- 21314428 TI - Follicular helper CD4 T cells (TFH). AB - T cell help to B cells is a fundamental aspect of adaptive immunity and the generation of immunological memory. Follicular helper CD4 T (T(FH)) cells are the specialized providers of B cell help. T(FH) cells depend on expression of the master regulator transcription factor Bcl6. Distinguishing features of T(FH) cells are the expression of CXCR5, PD-1, SAP (SH2D1A), IL-21, and ICOS, among other molecules, and the absence of Blimp-1 (prdm1). T(FH) cells are important for the formation of germinal centers. Once germinal centers are formed, T(FH) cells are needed to maintain them and to regulate germinal center B cell differentiation into plasma cells and memory B cells. This review covers T(FH) differentiation, T(FH) functions, and human T(FH) cells, discussing recent progress and areas of uncertainty or disagreement in the literature, and it debates the developmental relationship between T(FH) cells and other CD4 T cell subsets (Th1, Th2, Th17, iTreg). PMID- 21314429 TI - It is a long way to GM agriculture. AB - When we discovered that crown gall induction on plants by Agrobacterium tumefaciens is a natural event of genetic engineering, we were convinced that this was the dawn of a new era for plant science. Now, more than 30 years later, I remain overawed by how far and how rapidly we progressed with our knowledge of the molecular basis of plant growth, development, stress resistance, flowering, and ecological adaptation, thanks to the gene engineering technology. I am impressed, but also frustrated by the difficulties of applying this knowledge to improve crops and globally develop a sustainable and improved high-yielding agriculture. Now that gene engineering has become so efficient, I had hoped that thousands of teams, all over the world, would work on improving our major food crops, help domesticate new ones, and succeed in doubling or tripling biomass yields in industrial crops. We live in a world where more than a billion people are hungry or starving, while the last areas of tropical forest and wild nature are disappearing. We urgently need a better supply of raw material for our chemical industry because petroleum-based products pollute the environment and are limited in supply. Why could this new technology not bring the solutions to these challenges? Why has this not happened yet; what did we do wrong? PMID- 21314430 TI - Actin structure and function. AB - Actin is the most abundant protein in most eukaryotic cells. It is highly conserved and participates in more protein-protein interactions than any known protein. These properties, along with its ability to transition between monomeric (G-actin) and filamentous (F-actin) states under the control of nucleotide hydrolysis, ions, and a large number of actin-binding proteins, make actin a critical player in many cellular functions, ranging from cell motility and the maintenance of cell shape and polarity to the regulation of transcription. Moreover, the interaction of filamentous actin with myosin forms the basis of muscle contraction. Owing to its central role in the cell, the actin cytoskeleton is also disrupted or taken over by numerous pathogens. Here we review structures of G-actin and F-actin and discuss some of the interactions that control the polymerization and disassembly of actin. PMID- 21314432 TI - Ecological physiology of diet and digestive systems. AB - The morphological and functional design of gastrointestinal tracts of many vertebrates and invertebrates can be explained largely by the interaction between diet chemical constituents and principles of economic design, both of which are embodied in chemical reactor models of gut function. Natural selection seems to have led to the expression of digestive features that approximately match digestive capacities with dietary loads while exhibiting relatively modest excess. Mechanisms explaining differences in hydrolase activity between populations and species include gene copy number variations and single-nucleotide polymorphisms. In many animals, both transcriptional adjustment and posttranscriptional adjustment mediate phenotypic flexibility in the expression of intestinal hydrolases and transporters in response to dietary signals. Digestive performance of animals depends also on their gastrointestinal microbiome. The microbiome seems to be characterized by large beta diversity among hosts and by a common core metagenome and seems to differ flexibly among animals with different diets. PMID- 21314433 TI - Zebrafish in endocrine systems: recent advances and implications for human disease. AB - Since its introduction as a genetic vertebrate model system approximately 30 years ago, the focus of zebrafish research has increasingly shifted to questions that are also relevant for human development and disease. Here, we review the potential of the zebrafish as a model for human endocrine systems. A recent review compared the functions of the different endocrine systems and glands in zebrafish with those in other vertebrates, including humans, coming to the conclusion that major aspects are conserved. Here, we present an updated overview of this rapidly growing field of zebrafish research, focusing on the hypothalamo pituitary axis, which links the central nervous system with the endocrine systems, and on major processes that are under (neuro)endocrine control and are the subject of intensive current research in other endocrine model organisms, such as feeding circuits and energy homeostasis, sleep, stress, reproduction, osmoregulation, and calcium homeostasis. Finally, we summarize the strengths and weaknesses of zebrafish as a model for studying endocrine systems. PMID- 21314431 TI - Myocardial remodeling: cellular and extracellular events and targets. AB - The focus of this review is on translational studies utilizing large-animal models and clinical studies that provide fundamental insight into cellular and extracellular pathways contributing to post-myocardial infarction (MI) left ventricle (LV) remodeling. Specifically, both large-animal and clinical studies have examined the potential role of endogenous and exogenous stem cells to alter the course of LV remodeling. Interestingly, there have been alterations in LV remodeling with stem cell treatment despite a lack of long-term cell engraftment. The translation of the full potential of stem cell treatments to clinical studies has yet to be realized. The modulation of proteolytic pathways that contribute to the post-MI remodeling process has also been examined. On the basis of recent large-animal studies, there appears to be a relationship between stem cell treatment post-MI and the modification of proteolytic pathways, generating the hypothesis that stem cells leave an echo effect that moderates LV remodeling. PMID- 21314434 TI - Cryptosporidiosis in rhesus macaques challenged during acute and chronic phases of SIV infection. AB - The intestinal immune dysfunction due to loss of mucosal and peripheral CD4(+) T cells in individuals with HIV/AIDS is presumably responsible for the establishment of persistent cryptosporidiosis. Simian immunodeficiency virus (SIV)-infected macaques were used to investigate the phase/timing in SIV infection, which permits a self-limiting Cryptosporidium parvum infection to become persistent in immunodeficient hosts because of significant mucosal immune defects. Two groups of SIV-infected macaques were challenged with C. parvum; one was challenged during the acute SIV infection phase (2 weeks post-SIV infection) and the second was challenged during the chronic SIV phase (CD4 counts 200-500 cells/MUl of blood). Samples (fecal, blood, biopsy, and necropsy) were collected at different time points after infection to correlate the progression of disease with the immune status of the animals. All seven SIV-infected macaques challenged during the acute phase of SIV infection became persistently infected and excreted oocysts for 1-4 months. However, four of the six in the chronic SIV phase became infected with cryptosporidiosis, of which one survived 2 weeks and one became naturally infected. Sequential analysis of CD4(+) in blood and intestines of coinfected macaques exhibited pronounced losses of CD4 T cells during the first 2 weeks after SIV infection, followed by transient rebound of CD4 T cells in the gut after C. parvum infection, and then a gradual loss over subsequent months. Persistent cryptosporidiosis was more consistently induced during the acute SIV phase indicating that profound viral damage to gut lymphoid tissue during the acute phase was more conducive, compared with the chronic phase, to establishing persistent cryptosporidiosis than low circulating CD4 T cells. PMID- 21314436 TI - Redox control of the ubiquitin-proteasome system: from molecular mechanisms to functional significance. AB - In their natural environments, cells are regularly exposed to oxidizing conditions that may lead to protein misfolding. If such misfolded proteins are allowed to linger, they may form insoluble aggregates and pose a serious threat to the cell. Accumulation of misfolded, oxidatively damaged proteins is characteristic of many diseases and during aging. To counter the adverse effects of oxidative stress, cells can initiate an antioxidative response in an attempt to repair the damage, or rapidly channel the damaged proteins for degradation by the ubiquitin-proteasome system (UPS). Recent studies have shown that elements of the oxidative stress response and the UPS are linked on many levels. To manage the extra burden of misfolded proteins, the UPS is induced by oxidative stress, and special proteasome subtypes protect cells against oxidative damage. In addition, the proteasome is directly associated with a thioredoxin and other cofactors that may adjust the particle's response during an oxidative challenge. Here, we give an overview of the UPS and a detailed description of the degradation of oxidized proteins and of the crosstalk between oxidative stress and protein degradation in health and disease. PMID- 21314435 TI - What we should know before using tissue engineering techniques to repair injured tendons: a developmental biology perspective. AB - Tendons connect muscles to bones, and serve as the transmitters of force that allow all the movements of the body. Tenocytes are the basic cellular units of tendons, and produce the collagens that form the hierarchical fiber system of the tendon. Tendon injuries are common, and difficult to repair, particularly in the case of the insertion of tendon into bone. Successful attempts at cell-based repair therapies will require an understanding of the normal development of tendon tissues, including their differentiated regions such as the fibrous mid section and fibrocartilaginous insertion site. Many genes are known to be involved in the formation of tendon. However, their functional roles in tendon development have not been fully characterized. Tissue engineers have attempted to generate functional tendon tissue in vitro. However, a lack of knowledge of normal tendon development has hampered these efforts. Here we review studies focusing on the developmental mechanisms of tendon development, and discuss the potential applications of a molecular understanding of tendon development to the treatment of tendon injuries. PMID- 21314437 TI - Clinical pharmacology of alcaftadine, a novel antihistamine for the prevention of allergic conjunctivitis. AB - PURPOSE: In this report, we characterize the in vitro pharmacokinetic properties of a new antihistamine, alcaftadine. In addition, we report results from phase 1 studies of several ophthalmic formulations of alcaftadine and examine the pharmacokinetic properties of one formulation in detail. METHODS: In vitro pharmacology employed a human liver microsome assay combined with index substrates or inhibitors for specific cytochromes. Metabolic fate of (14)C alcaftadine was determined by high-performance liquid chromatography-based separation of parent compound from metabolites. Plasma protein binding was determined by equilibrium dialysis using (3)H-labeled alcaftadine and (3)H labeled alcaftadine carboxylic acid metabolite. Relative tolerability (comfort) of 4 concentrations and 3 formulations of alcaftadine ophthalmic solution was assessed in 2 double-masked, randomized, placebo-controlled, contralateral studies in which formulations were compared to Tears Naturale II (placebo) in normal adult subjects. Data analysis focused on the mean differences in subject reported drop comfort scores (within each dose level, at each time point) and compared the study-treatment eye with the placebo eye. Pharmacokinetics of alcaftadine 0.25% ophthalmic solution were determined in an open-label, single center study after a single bilateral dose and after 7 days of once-a-day bilateral doses in healthy subjects 18-55 years old. RESULTS: Alcaftadine is not significantly metabolized by microsomal cytochromes, but it is rapidly converted to the carboxylic acid metabolite by one or more cytosolic enzymes. Neither the parent compound nor its carboxylic acid metabolite displayed significant plasma protein binding. Over a range of formulations and concentrations (0.05%-0.5%), alcaftadine was well tolerated and subjects reported little or no discomfort or taste perversion in any treatment group. Pharmacokinetic studies showed that both the parent compound and the carboxylic acid metabolite reach peak serum levels within minutes of administration and fall below detectable levels within 3 h of dosing. CONCLUSIONS: Based upon pharmacokinetic and phase 1 studies, the novel antihistamine alcaftadine is an appropriate drug for use as an ophthalmic formulation for prevention and treatment of ocular allergic conditions such as allergic conjunctivitis (alcaftadine ophthalmic solution 0.25% was recently approved for use by the FDA). Topical administration of alcaftadine 0.25% ophthalmic solution was well tolerated and had an acceptable safety profile. PMID- 21314438 TI - Curcumin prevents experimental diabetic retinopathy in rats through its hypoglycemic, antioxidant, and anti-inflammatory mechanisms. AB - PURPOSE: The purpose of this study was to evaluate the therapeutic potential of oral curcumin (1 g/kg body weight of rat) in the prevention and treatment of streptozotocin-induced diabetic retinopathy in Wistar albino rats. METHODS: The treatment was carried out for a period of 16 weeks in diabetic rats and evaluated for hyperglycemic, antioxidant (superoxide dismutase, catalase, and glutathione), and inflammatory parameters (tumor necrosis factor-alpha, vascular endothelial growth factor). Rat fundus was observed weekly to see any visible changes in the retina, such as tortuosity and dilation of retinal vessels. Histological changes were evaluated by transmission electron microscopy. RESULTS: Treatment with curcumin showed significant hypoglycemic activity compared with the diabetic group. Retinal glutathione levels were decreased by 1.5-fold, and antioxidant enzymes, superoxide dismutase and catalase, showed >2-fold decrease in activity in the diabetic group; on the other hand, curcumin positively modulated the antioxidant system. Proinflammatory cytokines, tumor necrosis factor-alpha and vascular endothelial growth factor, were elevated >2-fold in the diabetic retinae, but prevented by curcumin. Transmission electron microscopy showed degeneration of endothelial cell organelles and increase in capillary basement membrane thickness in diabetic retina, but curcumin prevented the structural degeneration and increase in capillary basement membrane thickness in the diabetic rat retinae. CONCLUSION: Based on the above results, it may be concluded that curcumin may have potential benefits in the prevention of retinopathy in diabetic patients. PMID- 21314439 TI - Time course of changes in ocular aberrations after instillation of carteolol long acting solution and timolol gel-forming solution. AB - PURPOSE: To investigate the influence of 2% carteolol long-acting solution (long acting carteolol) and 0.5% timolol gel-forming solution (timolol gel) on ocular wavefront aberrations. METHODS: Ocular aberrations were assessed in the right eye of 24 healthy volunteers at baseline and at 2, 5, 10, and 15 min after instillation of long-acting carteolol, timolol gel or physiological saline using the Hartmann-Shack aberrometer. Ten serial measurements were taken over 10 s at each time point, and the root mean square (RMS) of second-, third-, fourth-, and total higher-order aberrations were calculated. The stability index and fluctuation index were also determined. RESULTS: Second-order aberrations did not change significantly after instillation of study eye-drops. Higher-order aberrations increased significantly after instillation of long-acting carteolol and timolol gel. Timolol gel induced significantly larger changes than long acting carteolol in third-order RMS at 2 min (P = 0.001), fourth-order RMS at 2 (P < 0.001) and 5 (P = 0.013) min, and total higher-order RMS at 2 (P < 0.001) and 5 (P = 0.016) min after instillation, but not at 10 and 15 min after administration. Fluctuation index increased significantly after instillation of each eye-drop (P < 0.001), with significantly larger increases after timolol gel than long-acting carteolol at 2 min (P = 0.005) and 5 min (P = 0.011). No significant changes were observed in stability index. CONCLUSIONS: Both topical beta blockers with a once-daily dosing regimen temporarily deteriorate optical quality of the eye by increasing higher-order aberrations, and the increases are much larger after instillation of timolol gel than long-acting carteolol. PMID- 21314440 TI - Combination of flavonoids with Centella asiatica and Melilotus for diabetic cystoid macular edema without macular thickening. AB - PURPOSE: The purpose of this study was to evaluate the orally administered combination of flavonoids desmin and troxerutin with Centella asiatica and Melilotus for the treatment of diabetic cystoid macular edema (CME) without macular thickening. METHODS: In this prospective, interventional, controlled study, 40 consecutive patients with type 2 diabetes and CME without macular thickening at optical coherence tomography were randomized into 2 groups of 20 subjects each (treatment and control groups). The treatment group received an oral combination of desmin (300 mg/day) and troxerutin (300 mg/day) with C. asiatica (30 mg/die) and Melilotus (160 mg/die) for 14 months. Best collected visual acuity, central retinal thickness at optical coherence tomography, retinal sensitivity (RS), and stability of fixation at microperimetry were measured at baseline and monthly for 14 months. RESULTS: In both groups, mean best collected visual acuity, central retinal thickness, and stability of fixation did not show differences during follow-up (P > 0.05). At month 14, the RS was greater in the treated group (P = 0.01) and was significantly reduced in the control group only (P < 0.001). Five eyes in the study group showed disappearance of the intraretinal cysts after a mean time of 3.5 +/- 0.3 months, which persisted in the following months. These 5 eyes presented a greater RS at each follow-up visit when compared with the control group (P < 0.05). Anatomic improvement was never reported in the control group. CONCLUSIONS: The orally administered combination of flavonoids, C. asiatica, and Melilotus could be beneficial in preserving RS in diabetic CME without macular thickening. PMID- 21314441 TI - beta2-microglobulin, a novel biomarker of peripheral arterial disease, independently predicts aortic stiffness in these patients. AB - Arterial stiffness is a prominent feature of vascular ageing and strongly predicts cardiovascular and total mortality. The beta2-microglobulin, (beta2M) a newly identified biomarker of peripheral arterial disease (PAD), is related to renal insufficiency, inflammatory and neoplastic diseases, but may also play a role in vascular dysfunction. However, the relationship between arterial stiffness and beta2M has not been previously studied in patients with atherosclerosis. In the present study we examined a possible association between beta2M and arterial stiffness in patients with PAD and in healthy subjects. Plasma beta2M levels and parameters of arterial stiffness such as aortic pulse wave velocity (aPWV) and augmentation index (AIx) were measured in 66 patients with PAD and in 66 apparently healthy subjects. Plasma levels of beta2M, aPWV and AIx were significantly increased in patients with PAD compared with controls (1858.1 +/- 472.8 vs 1554.5 +/- 277.9 MUg/L, p < 0.001; 9.9 +/- 2.2 m/s vs 7.6 +/ 1.6 m/s, p < 0.001; 28 +/- 8 vs 14 +/- 11%, p < 0.001; respectively). There existed significant correlation between aPWV and beta2M for the patient group (R = 0.47; p < 0.001), but not for the controls (R = 0.14; p = 0.26). In multivariate analysis, beta2M remained independently associated with aPWV, fetuin A, age and glomerular filtration rate in patients (R(2) = 0.5, p < 0.001). We found no relationship between beta2M and AIx in either group. We demonstrated that among patients with PAD elevated plasma beta2M levels were associated with higher aortic stiffness irrespective of cardiovascular disease risk factors. These data suggest that beta2M may influence the pathogenesis of aortic stiffness in atherosclerosis. PMID- 21314442 TI - 10th annual meeting of the Safety Pharmacology Society: an overview. AB - The 10th annual meeting of the Safety Pharmacology (SP) Society covered numerous topics of educational and practical research interest. Biopolymers - the theme of the keynote address - were presented as essential components of medical devices, diagnostic tools, biosensors, human tissue engineering and pharmaceutical formulations for optimized drug delivery. Toxicology and SP investigators - the topic of the Distinguished Service Award Lecture - were encouraged to collaborate in the development of SP technologies and protocols applicable to toxicology studies. Pharmaceutical companies, originally organizations bearing all risks for developing their portfolios, are increasingly moving towards fully integrated networks which outsource core activities (including SP studies) to large contract research organizations. Future nonclinical data are now expected to be of such high quality and predictability power that they may obviate the need for certain expensive and time-consuming clinical investigations. In this context, SP is called upon to extend its risk assessment purview to areas which currently are not systematically covered, such as drug-induced QRS interval prolongation, negative emotions and feelings (e.g., depression), and minor chronic cardiovascular and metabolic changes (e.g., as produced by drugs for type 2 diabetes) which can be responsible for delayed morbidity and mortality. The recently approved ICH S9 guidance relaxes the traditional regulatory SP package in order to accelerate the clinical access to anticancer drugs for patients with advanced malignancies. The novel FDA 'Animal Rule' guidance proposes that for clinical candidates with well-understood toxicities, marketing approval may be granted exclusively on efficacy data generated in animal studies as human clinical investigations for these types of drugs are either unfeasible or unethical. In conclusion, the core messages of this meeting are that SP should consistently operate according to the 'fit-for-purpose' principle and gradually integrate new mechanism-oriented safety paradigms into the traditional ones for ensuring more effectively the safety of drugs for any population of patients in need. PMID- 21314444 TI - Sex differences in perceived life satisfaction and functional status one year after severe traumatic brain injury. AB - AIMS: The primary aim of this study was to describe and compare perceived life satisfaction and perceived functional motor and cognitive status 1 year after severe traumatic brain injury (TBI) in males and females, adjusting for demographics and severity of injury. METHODS: Data of 297 participants were abstracted from the National Institute on Disability Rehabilitation and Research (NIDRR)-funded Traumatic Brain Injury Model Systems (TBIMS). Participants were aged 16-50, enrolled in the TBIMS study between the years 1998 and 2008, diagnosed with severe TBI (defined as having an initial Glasgow Coma Scale [GCS] score between 3 and 8), and with perceived life satisfaction and functional status data available at 1 year postinjury. Multiple linear regression models were used to estimate the association between sex, demographic variables, severity of injury, and the outcome variables. RESULTS: Our findings indicate that sex did not significantly influence perceived satisfaction with life or motor function 1 year after severe TBI. However, females had significantly better (p = 0.031) cognitive outcomes compared to males 1 year after severe TBI, after controlling for demographics and severity of injury. CONCLUSIONS: Findings suggest that females may have better perceived cognitive functional outcomes than males 1 year after severe TBI. Further longitudinal research, including measurement of hormonal levels, is needed to determine if hormones influence outcomes of severe TBI as well as the trajectory of these outcomes. A better understanding of sex differences in outcomes after TBI will help clinicians improve strategies for rehabilitation. PMID- 21314445 TI - Effect of treatment assignment on intravaginal cleansing in a randomized study of the diaphragm with candidate microbicide. AB - BACKGROUND: Intravaginal cleansing may predispose women to adverse health outcomes and may interfere with the effectiveness and safety of female-initiated methods for preventing sexually transmitted infections (STIs). In a 4-week randomized study of 192 Malagasy sex workers, we evaluated associations between self-reported intravaginal cleansing and randomization assignment: diaphragm with viscous candidate microbicide gel (AcidformTM, TOPCAD, Chicago, IL, licensed to Instead, Coppell, TX), diaphragm with placebo hydroxyethylcellulose gel (HEC, ReProtect LLC, Baltimore, MD), Acidform alone, or HEC alone. METHODS: Women were counseled to avoid intravaginal cleansing and were blinded to gel assignment. We evaluated changes in self-reported intravaginal cleansing across the study and assessed the effects of treatment assignment and covariates on frequent (more than once daily) intravaginal cleansing. Significant predictors in domain specific models were evaluated in an all-domain multiple regression model. RESULTS: The proportion of women reporting intravaginal cleansing decreased from baseline (97%) to week 1 (82%) (p < 0.001). Self-reported frequent intravaginal cleansing decreased from baseline (87% to 56%) during the same time period (p < 0.001). In adjusted analyses, the Acidform-diaphragm group had 60% lower odds of frequent intravaginal cleansing during the study (odds ratio [OR] 0.4, 95% confidence interval [CI] 0.2-0.8) compared to the control group (HEC only). HEC diaphragm and Acidform only users did not differ from controls. Living on the coast of Madagascar, not cohabiting, frequent intravaginal cleansing at enrollment, and high coital frequency predicted frequent intravaginal cleansing during follow-up. CONCLUSIONS: Gel characteristics and the diaphragm's presence likely influenced women's cleansing. Viscous gel delivered by a cervical barrier (such as a diaphragm) may minimize the likelihood of frequent intravaginal cleansing. PMID- 21314447 TI - Early menarche and psychopathological symptoms in young Chinese women. AB - OBJECTIVE: To evaluate the psychopathological symptoms, suicide, and self-harming behaviors among students with early, on-time, and late menarche in high school and college and the association of early menarche with these disorders. METHODS: The design consisted of a cross-sectional study of 5597 high school students and 2768 college students. Menarche age, suboptimal mental health status, anxiety, depression, suicide, and self-harming behaviors were obtained by self-report questionnaire. RESULTS: In high school students, all the disorders occurred at significantly higher frequency in those with early menarche than in those with on time and late menarche. In college students, only suboptimal mental health status, depression, and suicidal ideation happened at significantly higher frequency in the early menarche group than in the other two groups. The college group had a lower frequency of all the disorders than the high school group for all three groups of girls, that is, with early, on-time, or late menarche. In a multivariate logistic regression model, early menarche persisted as a risk factor for all the disorders after other factors were controlled. CONCLUSIONS: Psychopathological symptoms, suicide, and self-harming behaviors are more common in early menarche students than in on-time and late menarche students. The effects of early menarche on the disorders might dissipate over time. Early menarche might serve as a predictor for the disorders in Chinese girls. PMID- 21314446 TI - Examining racial/ethnic disparities in sexually transmitted diseases among recent heroin-using and cocaine-using women. AB - BACKGROUND: This study examined racial differences in the prevalence of sexual risk behaviors and their associations with sexually transmitted diseases (STDs) among recent heroin-using and cocaine-using women. METHODS: Participants were 214 women (59% black, 41% white) who were recruited during 2002-2010 using targeted sampling to participate in a study in Baltimore, Maryland, and reported using heroin, cocaine, or crack during the previous 6 months. Participants completed self-report questionnaires about their drug use, sexual risk behaviors, and lifetime history of one of six STDs, including gonorrhea, syphilis, chlamydia, genital herpes, genital warts, or trichomoniasis. RESULTS: More black women (50%) than white women (28%) reported a lifetime STD. Although there were no racial differences in the lifetime prevalence of sexual risk behaviors assessed, there were racial differences in the sexual behaviors associated with ever having a lifetime STD. Simple logistic regressions revealed that ever having a casual sex partner or anal sex were correlates of having a lifetime STD among black women but not among white women. Multiple logistic regression analyses revealed that ever having a casual sex partner was significantly associated with having a lifetime STD among black women, and ever trading sex for money was significantly associated with having a lifetime STD among white women. CONCLUSIONS: Findings are consistent with national studies and elucidate racial disparities in STDs and associated sexual behaviors among recent heroin-using and cocaine-using women. Findings underscore the need to tailor STD prevention interventions differently for black and white recent heroin-using and cocaine-using women. PMID- 21314448 TI - The cross-cultural variation of predictors of human papillomavirus vaccination intentions. AB - BACKGROUND: The influence of health beliefs on human papillomavirus (HPV) vaccine acceptability have been extensively documented in past research. However, studies documenting the generalizability of prior findings to culturally diverse participants are lacking. The importance of generalizability studies is underscored by the immense disparities in cervical cancer rates across ethnicities. Moreover, theory in cultural psychology suggests that beliefs derived from personal expectations may not be the strongest predictors of intentions in individuals socialized in collectivist cultures. The purpose of this research was to investigate the strongest predictors of mothers' intentions to vaccinate their daughters across three cultural groups: Hispanic, non-Hispanic white, and African American. METHODS: One hundred fifty mothers were recruited from Public Health Department clinics in Milwaukee, Wisconsin. Mothers were asked to answer measures that assessed personal and normative predictors of intentions. RESULTS: Results indicated that predictors of vaccination intentions varied cross culturally. Specifically, culture moderated the influence of norms on intentions. CONCLUSIONS: Interventions designed for Hispanics may be more effective if norms, rather than attitudes, are targeted. PMID- 21314449 TI - Effectiveness of long and short bout walking on increasing physical activity in women. AB - BACKGROUND: The accumulation of physical activity (PA) throughout the day has been suggested as a means to increase PA behavior. It is not known, however, if accumulated PA results in equivalent increases in PA behavior compared with one continuous session. The purpose of this investigation was to compare changes in PA between participants assigned to walk daily in accumulated shorter bouts vs. one continuous session. METHODS: In this 8-week randomized controlled trial, 60 inactive women were randomly assigned to one of the following: (1) control group, (2) 30 minutes a day of walking 5 days a week in one continuous long bout (LB), or (3) three short 10-minute bouts (SB) of walking a day, all at a prescribed heart rate intensity. Walking was assessed by pedometer and self-reported walking log. Before and after measures were taken of average steps/day, resting systolic and diastolic blood pressure (SBP, DBP), resting heart rate (RHR), six-minute walk test (6MWT) distance, height, weight, body mass index (BMI), and hip and waist circumference. RESULTS: Both walking groups significantly increased PA measured as steps/day compared to controls (p < 0.001), and no significant differences were found between LB and SB groups. The LB group demonstrated significant decreases in hip circumference and significant increases in 6MWT distance compared to the control group. CONCLUSIONS: Both walking groups significantly increased PA participation. LB group participants completed more walking at a higher intensity than the SB and control groups, which resulted in significant increases in health benefits. PMID- 21314450 TI - An open label pilot study of transcranial magnetic stimulation for pregnant women with major depressive disorder. AB - OBJECTIVE: Despite the data that major depressive disorder (MDD) is common during pregnancy and that pregnant women prefer nonmedication treatment options, there is a paucity of research examining alternative treatments for this special population. We present the results of an open label pilot study examining treatment with transcranial magnetic stimulation (TMS) in pregnant women with MDD. METHODS: Ten women with MDD in the second or third trimester of pregnancy were treated with 20 sessions of 1-Hz TMS at 100% of motor threshold (MT) to the right dorsolateral prefrontal cortex. The total study dose was 6000 pulses. Antenatal monitoring was performed during treatment sessions 1, 10, and 20. RESULTS: Seven of ten (70%) subjects responded (decrease >=50% in Hamilton Depression Rating Scale [HDRS-17] scores). No adverse pregnancy or fetal outcomes were observed. All infants were admitted to the well baby nursery and were discharged with the mother. Mild headache was the only common adverse event and was reported by 4 of 10 (40%) subjects. CONCLUSIONS: TMS appears to be a promising treatment option for pregnant women who do not wish to take antidepressant medications. PMID- 21314451 TI - Comment and reply on: Are we not over-estimating the prevalence of celiac disease in the general population? PMID- 21314452 TI - Preface: RECOMB Conference on Systems Biology, Regulatory Genomics, and DREAM Challenges 2010 special issue. PMID- 21314453 TI - Combining drug and gene similarity measures for drug-target elucidation. AB - Understanding drugs and their modes of action is a fundamental challenge in systems medicine. Key to addressing this challenge is the elucidation of drug targets, an important step in the search for new drugs or novel targets for existing drugs. Incorporating multiple biological information sources is of essence for improving the accuracy of drug target prediction. In this article, we introduce a novel framework--Similarity-based Inference of drug-TARgets (SITAR)- for incorporating multiple drug-drug and gene-gene similarity measures for drug target prediction. The framework consists of a new scoring scheme for drug-gene associations based on a given pair of drug-drug and gene-gene similarity measures, combined with a logistic regression component that integrates the scores of multiple measures to yield the final association score. We apply our framework to predict targets for hundreds of drugs using both commonly used and novel drug-drug and gene-gene similarity measures and compare our results to existing state of the art methods, markedly outperforming them. We then employ our framework to make novel target predictions for hundreds of drugs; we validate these predictions via curated databases that were not used in the learning stage. Our framework provides an extensible platform for incorporating additional emerging similarity measures among drugs and genes. Supplementary Material is available at www.liebertonline.com/cmb. PMID- 21314454 TI - Mass conservation and inference of metabolic networks from high-throughput mass spectrometry data. AB - We present a step towards the metabolome-wide computational inference of cellular metabolic reaction networks from metabolic profiling data, such as mass spectrometry. The reconstruction is based on identification of irreducible statistical interactions among the metabolite activities using the ARACNE reverse engineering algorithm and on constraining possible metabolic transformations to satisfy the conservation of mass. The resulting algorithms are validated on synthetic data from an abridged computational model of Escherichia coli metabolism. Precision rates upwards of 50% are routinely observed for identification of full metabolic reactions, and recalls upwards of 20% are also seen. PMID- 21314455 TI - Alignment constrained sampling. AB - We present ALICO (ALIgnment COnstrainted) null set generator: a framework to generate randomized versions of an input multiple sequence alignment that preserve some of its crucial features including its dependence structure. In particular, we show that, on average, ALICO samples approximately preserve the PIDs (percent identities) between every pair of input sequences. At the same time our examples demonstrate that the average k-mer composition of each of the sampled sequences show great resemblance to the k-mer composition of our genomic training data. Of note is that ALICO requires only pairwise alignment training data rather than multiple alignment training data. We demonstrate the utility of ALICO in predicting the correct results returned by the "homology-aware" finders PhyloCon, MEME with conservation prior and PRIORITY-C, as well as by our "naive" finder GibbsMarkov, applied to the MacIsaac orthologous yeast data. Finally, we show that using ALICO sampling derived p-values to combine results from multiple finders often outperforms its best individual component. Supplementary Material is available at www.liebertonline.com/cmb . PMID- 21314456 TI - Adaptive control model reveals systematic feedback and key molecules in metabolic pathway regulation. AB - Robust behavior in metabolic pathways resembles stabilized performance in systems under autonomous control. This suggests we can apply control theory to study existing regulation in these cellular networks. Here, we use model-reference adaptive control (MRAC) to investigate the dynamics of de novo sphingolipid synthesis regulation in a combined theoretical and experimental case study. The effects of serine palmitoyltransferase over-expression on this pathway are studied in vitro using human embryonic kidney cells. We report two key results from comparing numerical simulations with observed data. First, MRAC simulations of pathway dynamics are comparable to simulations from a standard model using mass action kinetics. The root-sum-square (RSS) between data and simulations in both cases differ by less than 5%. Second, MRAC simulations suggest systematic pathway regulation in terms of adaptive feedback from individual molecules. In response to increased metabolite levels available for de novo sphingolipid synthesis, feedback from molecules along the main artery of the pathway is regulated more frequently and with greater amplitude than from other molecules along the branches. These biological insights are consistent with current knowledge while being new that they may guide future research in sphingolipid biology. In summary, we report a novel approach to study regulation in cellular networks by applying control theory in the context of robust metabolic pathways. We do this to uncover potential insight into the dynamics of regulation and the reverse engineering of cellular networks for systems biology. This new modeling approach and the implementation routines designed for this case study may be extended to other systems. Supplementary Material is available at www.liebertonline.com/cmb . PMID- 21314457 TI - Sensitivity analysis of retrovirus HTLV-1 transactivation. AB - Human T-cell leukemia virus type 1 is a human retrovirus endemic in many areas of the world. Although many studies indicated a key role of the viral protein Tax in the control of viral transcription, the mechanisms controlling HTLV-1 expression and its persistence in vivo are still poorly understood. To assess Tax effects on viral kinetics, we developed a HTLV-1 model. Two parameters that capture both its deterministic and stochastic behavior were quantified: Tax signal-to-noise ratio (SNR), which measures the effect of stochastic phenomena on Tax expression as the ratio between the protein steady-state level and the variance of the noise causing fluctuations around this value; t(1/2), a parameter representative of the duration of Tax transient expression pulses, that is, of Tax bursts due to stochastic phenomena. Sensitivity analysis indicates that the major determinant of Tax SNR is the transactivation constant, the system parameter weighting the enhancement of retrovirus transcription due to transactivation. In contrast, t(1/2) is strongly influenced by the degradation rate of the mRNA. In addition to shedding light into the mechanism of Tax transactivation, the obtained results are of potential interest for novel drug development strategies since the two parameters most affecting Tax transactivation can be experimentally tuned, e.g. by perturbing protein phosphorylation and by RNA interference. PMID- 21314458 TI - Design and construction of a versatile synthetic network for bistable gene expression in mammalian systems. AB - We constructed and modeled a novel synthetic network which may be able to exhibit bistable expression of a reporter gene in mammalian cells. This network is based on an aptamer-fused short-hairpin RNA (shRNA) directed against a single mRNA encoding both a EGFP reporter gene and the repressor tTR-KRAB, which, in turn, represses transcription of the shRNA. The activity of the shRNA can be controlled by an inducer molecule (theophylline) which prevents the aptamer-fused shRNA to be properly processed. Repression of the tTR-KRAB can be relieved by treatment with doxycyline. This reciprocal negative feed-back loop can exhibit a bistable response, as shown through the mathematical analysis performed here. Specifically, the network can be controlled to induce sustained expression of a shRNA, or the reporter gene, with a transient input of two different inducer molecules. PMID- 21314459 TI - Effect of licorice extract on the complications of diabetes nephropathy in rats. AB - The aim of this study was to investigate the protective action of licorice in diabetic nephropathy in male rats. Diabetes was induced in male Wistar rats by using streptozotocin (60 mg/kg body weight). Daily oral ingestion (1 g/kg body weight) of licorice extract for 60 days after the onset of diabetes reversed the adverse effect of diabetes on rats. Licorice extract alleviated blood glucose levels, restored renal function, and attenuated body-weight loss. In addition, licorice extract modulated the adverse effect of diabetes on renal malondialdehyde, glutathione, superoxide dismutase, and catalase activity. Further, licorice extract restored the total antioxidant capacity of diabetic rat kidneys. The biochemical analyses were reinforced by histologic investigations, where focal segmental glomerulosclerosis, tubular damage, and hyperemic kidney were the histologic changes seen in diabetic, but not in treated, rats. In conclusion, the biochemical analysis and the histologic investigations of diabetic rat kidneys treated with licorice extract revealed that licorice may have a potential therapeutic effect for diabetes due to its antioxidant and hyperglycemic properties. PMID- 21314460 TI - Antioxidant and drug detoxification potentials of Hibiscus sabdariffa anthocyanin extract. AB - The antioxidant and drug metabolizing potentials of Hibiscus anthocyanin extract in CCl(4)- induced oxidative damage of rat liver was investigated. Hibiscus anthocyanin extract effectively scavenge alpha-diphenyl-beta-picrylhydrazyl (DPPH) radical, superoxide ion, and hydrogen peroxide. It produced a 92% scavenging effect of DPPH radical at a concentration of 2.0 mg/mL. Hibiscus anthocyanin extract produced a 69 and 90% scavenging effect on superoxide ion and hydrogen peroxide, respectively, at 1.0 mg/mL, which compared favorably with the synthetic antioxidant (butylated hydroanisole and alpha-tocopherol). A reducing power of this anthocyanin was examined using K(3)Fe(CN)(6). Hibiscus anthocyanin extract has reducing power that is approximately 2-fold that of the synthetic antioxidant, butylated hydroanisole. Hibiscus anthocyanin extract produced a significantly increase and completely attenuated the CCl(4)-mediated decrease in antioxidant enzymes (e.g., catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase). However, the level of nonenzymic antioxidant molecules (i.e., vitamins C and E) were significant preserved by Hibiscus anthocyanin extract. There was an induction of phase II drug-detoxifying enzymes: glutathione S-transferase, NAD(H):quinone oxidoreductase, and uridyl diphosphoglucuronosyl transferase by 65, 45, and 57%, respectively. In view of these properties, Hibiscus sabdariffa anthocyanin extract can act as a prophylactic by intervening as a free radical scavenger both in vitro and in vivo as well as inducing the phase II drug detoxification enzymes. PMID- 21314461 TI - Protective effects of sesame oil on 4-NQO-induced oxidative DNA damage and lipid peroxidation in rats. AB - Sesame oil could be considered as a potent antioxidant and dietary supplement. It possesses antimutagenic, anti-inflammatory and anti-cardiac toxicity. In the view of available findings, the current study focused on determining the protective effects of sesame oil on 4-Nitroquinoline-1-oxide (4-NQO) -induced oxidative DNA damage and lipid peroxidation (LPO) in rats. Seven groups of Wistar albino rats each with 6 either sex were used. Groups were given vehicle control and sesame oil alone orally and 4-NQO (30 mg/kg) by intraperitoneal injection. Following the four dose levels (1, 2, 4, and 8 ml/kg orally), sesame oil plus 4-NQO were also tested. After 24 hours of 4-NQO injection, blood samples were drawn by venipuncture. DNA damage (8-hydroxy-2-deoxy guanosine; 8-OHdG) and LPO were estimated. LPO from the 4-NQO-treated group was 2.5-fold higher than that of the control LPO. Pretreatment with sesame oil reduced this by 16-61%. 8-OHdG DNA damage from 4-NQO was found to be 3-fold higher than that of controls. Pretreatment with sesame oil effectively protected against DNA damage in a dose dependent fashion. This study indicates that the antioxidant, sesame oil, effectively protected DNA damage and LPO induced by 4-NQO. PMID- 21314462 TI - Effects of maneb on testosterone release in male rats. AB - Maneb (Manganese ethylene-bis-dithiocarbamate) is a widely used fungicide in agriculture. In order to investigate its effect on male reproductive function, rats were intraperitonealy injected with maneb (1 and 4 mg/kg) for 9 or 18 days. After 6 and 14 days of treatment, the animals received human chorionic gonadotropin (hCG) via a jugular catheter and blood samples were collected at several intervals subsequent to the challenge. They were thereafter decapitated after 9 or 18 days, and organs (i.e., liver, seminal vesicles, and kidneys) were weighed. Leydig cells prepared from rats after 18 days of treatment were incubated with or without different stimulators or precursors [hCG, A23187, 25-OH cholesterol (25-OH-C), or androstenedione] for 1 hour, and the media were analyzed for testosterone or pregnenolone. Liver glutathione and thiobarbituric acid reactive substances (TBARS) as well as serum alanine aminotransferase (ALT) activity were also measured. Further, Leydig cells and testicular interstitial cells (TICs) prepared from normal rats were incubated with maneb (3-100 uM) for 1 or 2 hours, and testosterone release was assessed. The results showed that administration of maneb (4 mg/kg) for 9 and 18 days did not alter liver function, but resulted in a decrease of basal level of plasma testosterone (P < 0.01). In addition, basal testosterone and pregnenolone release by Leydig cells prepared from maneb 18-day treated animals were significantly reduced (P < 0.05). However, acute in vitro exposure of TIC or Leydig cells to maneb did not alter their testosterone release. These results suggested that maneb alters testosterone production, at least in part, through inhibition of CYP11A1 activitiy. PMID- 21314463 TI - D-serine treatment induces oxidative stress in rat brain. AB - D-serine plays a significant role in neuronal activity, including learning, memory, neuronal migration at developmental stages, and cell-death signaling. It has been also suggested that D-serine can potantiate the neurotoxicity induced by N-methyl-D-aspartate (NMDA) receptor activation due to its coagonist function. However, little is known about the role of D-serine in oxidative stress mechanisms. The aim of this study was to determine the possible neurotoxic or oxidative effects of the dose- (50-200 mg/kg) and time-dependent (2 or 6 hours) D serine administration on lipid, protein, DNA, mitochondrial integrity (i.e., function), levels of antioxidant enzyme activities (e.g., catalase, glutathione peroxidase, and superoxide dismutase), and glutathione (GSH) in the rat brain. Our results showed that D-serine significantly increases the levels of lipid peroxidation, protein carbonyls, and DNA damage. In addition, D-serine treatment changes cellular antioxidant status due to the decreased levels of antioxidant enzymes, GSH, and mitochondrial function. Therefore, it is concluded that the regulation of D-serine levels in the brain may be an important target for the development of neuroprotective strategies against neurodegenerative processes where excitotoxicity is involved. PMID- 21314464 TI - Cardioprotective effect of resveratrol on lipopolysaccharide-induced oxidative stress in rat. AB - Lipopolysaccharide (LPS) is a glycolipid component of the cell wall of Gram negative bacteria, which induces a deleterious effect on several organs, including the heart, eventually leading to septic shock and death. Endotoxemia induced cardiotoxicity is characterized by disturbed intracellular redox balance, excessive reactive oxygen species (ROS) accumulation, inducing DNA, protein, and membrane lipid damage. Resveratrol (trans-3,5,4' trihydroxystilbene; RVT) is a phytoalexin polyphenol that exhibits antioxidant and -inflammatory properties. We investigated the putative effect of a subacute treatment with this natural compound on LPS-induced cardiotoxicity in the rat. We found that resveratrol counteracted LPS-induced lipoperoxidation and decreased superoxide dismutase (SOD) activity, but had no effect on the LPS-induced decrease in catalase (CAT) nor on the increase in peroxidase (POD) activity. Resveratrol also reversed LPS induced myocardial nitric oxide (NO) elevation. More important, LPS-induced iron depletion from plasma to the myocardial compartment was abolished upon resveratrol treatment. All these data suggest that resveratrol is capable of alleviating LPS-induced cardiotoxicity, and that its mode of action may involve iron-shuttling proteins. PMID- 21314465 TI - The evaluation of genotoxic potential of ornidazole, nitroimidazole, in lymphocyte culture of patients with amebiasis. AB - The genotoxicity study of ornidazole (ONZ) was carried out on human lymphocyte chromosomes, using sister chromatid exchange (SCE) and micronucleus (MN). Thirty two patients with Entemoeba histolitica infection who received 1000 mg/day for 10 days were included in this study. SCE and MN were measured before and after therapy. A statistically significant increase was observed in the SCE (P < 0.001) and MN frequencies (P < 0.001) after ornidazole therapy. It was concluded that ONZ has a potential geno- and cytotoxic effect in human peripheral lymphocyte cultures. For this reason, further, detailed studies are needed to elucidate the ONZ mechanism of genotoxicity and its carcinogenic potential. PMID- 21314466 TI - Antimicrobial, antioxidant, and antimutagenic activities of selected marine natural products and tobacco cembranoids. AB - Multidrug resistance (MDR) in microorganisms is a cause of major concern for clinicians and pharmaceutical industries. Continuous development of new antimicrobial drugs with multiple targets and potentials is expected to efficiently combat MDR in these microorganisms. In a continued exploration of new antimicrobial drug leads, 11 marine natural products, semisynthetic, or related synthetic analogs (1-11) and two tobacco cembranoids (12 and 13) were screened for their antimicrobial, antioxidant, and antimutagenic activities. Eight compounds showed varying levels of both antibacterial and antifungal activities. Compounds such as 17-O-methyllatrunculin-A, verongiaquinol, (1S,2E,4R,6R,7E,11E) 2,7,11-cembratriene-4,6-diol), and manzamine-A showed a broad spectrum of activity, inhibiting six of seven tested bacteria with zone of inhibition diameter from 9 to 30 mm. Four of these active compounds also showed antifungal activity. The findings of the in vitro time-kill assay of the most active compound, verongiaquinol, against Staphylococcus aureus indicated its subinhibitory effect at the level lower than the minimal inhibitory concentration (MIC) values (i.e., 2 and 4 ug/mL). At the MIC (8 ug/mL), bacterial cells were completely killed within 18 hours of incubation. DPPH free radical scavenging activity was demonstrated by five compounds in the range of 89.65-36.19% decolorization. Further, four compounds evaluated for their antimutagenic activity against the directly acting mutagens, methyl methanesulfonate and sodium azide, in Salmonella typhimurium strains, interestingly, showed no sign of mutagenicity. Verongiaquinol and manzamine A, in fact, reduced the mutagenicity by 50-75% at a dose of 5 ug/plate in different test strains. Our study seems to provide some novel antimicrobial leads with strong antioxidant potential and the associated ability of antimutagenicity. PMID- 21314467 TI - An increase of oxidative stress markers and the alteration of the antioxidant enzymatic system are associated with spleen damage caused by methimazole-induced hypothyroidism. AB - Methimazole is the most widely used antithyroid drug in Europe and North America, but it causes several undesirable side effects, such as hematological dysfunctions and immunosuppression. Our aim in this work was to compare, over a time course, markers of oxidative stress, the redox environment, the antioxidant enzymatic system, and the glutathione cycle in the spleen of rats with methimazole- or thyroidectomy-caused hypothyroidism. We used 70-male Wistar rats divided into four groups: 1) euthyroid; 2) sham thyroidectomy; 3) thyroidectomy caused hypothyroidism, with parathyroid reimplant; and 4) methimazole-caused hypothyroidism. Five rats of the euthyroid- and methimazole-caused hypothyroidism groups were killed at the end of weeks 1, 2, 3, and 4 after treatment, and 5 rats of the sham thyroidectomy and thyroidectomy-caused hypothyroidism groups were killed at the end of weeks 2, 4, and 8 after the surgical procedure. Each spleen was excised and stored at -70 degrees C until oxidative stress, REDOX environment, and the antioxidant enzymatic-system markers were tested. The histological study showed that only methimazole-induced hypothyroidism caused cell damage. This damage was associated with an increase of oxidative-stress markers that were not compensated for by the antioxidant system. The increase of the glutathione-cycle enzymes was insufficient to prevent oxidative-stress markers. Methimazole causes oxidative stress and cell damage in the spleen, whereas hypothyroidism per se does not cause cell damage in this organ. Therefore, it is necessary to develop new antithyroid drugs without causing oxidative stress and cellular damage. PMID- 21314468 TI - Unexpected severe hepatotoxicity of ciprofloxacine: two case reports. AB - Ciprofloxacin is a fluoroquinolone antibiotic that has a relatively low rate of occurence of adverse side effects. However, increasing evidences suggest that ciprofloxacin may cause unexpected severe liver damage. Especially, the risk of hepatotoxicity is significantly higher in elderly men receiving drug for a long time. In this article, 2 cases of unexpected severe hepatoxicity of ciprofloxacin are presented. PMID- 21314469 TI - Study on toxicological aspects of crystal-mediated nephrotoxicity induced by FYX 051, a xanthine oxidoreductase inhibitor, in rats. AB - To clarify the toxicological aspects of crystal-mediated nephrotoxicity, we performed analysis concerning the correlation between representative kidney related parameters and renal histopathology, using the individual data obtained from the 4-week toxicity studies of FYX-051, a xanthine oxidoreductase inhibitor, by oral administration at 1 and 3 mg/kg to Sprague-Dawley (SD) rats and at 3 and 10 mg/kg to F344 rats. In SD rats, the correlation coefficient on histopathology between the right and left kidneys was 0.7826 and remained within a lower range of strong correlation (range: +/-0.7 ~ +/-0.9). The correlation coefficient between body-weight gains, urinary volume, osmolarity, serum blood urea nitrogen (BUN), creatinine, and relative kidney weights and renal histopathology was 0.6648, 0.7896, -0.7751, 0.8195, 0.8479, and 0.8969, respectively, showing a strong correlation, except a moderate correlation in body-weight gains (range: +/ 0.4 ~ +/-0.7). In F344 rats, the correlation coefficient on histopathology between the right and left kidneys was 0.8637, remaining within an upper range of strong correlation. The correlation coefficient between the above parameters and renal histopathology was -0.8175, 0.8616, -0.9045, 0.9010, 0.8991, and 0.9524, respectively, showing an extremely strong correlation in urinary osmolarity, serum BUN, and relative kidney weights (range: +/-0.9 ~ +/-1.0). Therefore, the present study suggests that FYX-051-induced nephrotoxicity may occur with more inconsistency in the degree of nephropathy between the right and left kidneys in SD rats than in F344 rats, which would explain the above outcomes. PMID- 21314470 TI - Selenium-mediated cardioprotection against adriamycin-induced mitochondrial damage. AB - Adriamycin (ADR) causes morphological and functional alterations in mitochondrial structure in the heart. The study's aim was to determine whether there is a protective effect of selenium (Se) on ADR-induced cardiac damage. Rats were divided into four groups: The first group was injected saline intraperitoneally (i.p.) for 21 days; the second group received 4 mg/kg i.p. ADR every alternate day for 8 days; the third group received 50 ug/kg i.p. Se for 21 days; and the fourth received the Se (for 21 days) and ADR (for 8 days) coadministration i.p. Left ventricular functions, electrocardiography parameters, and blood pressures were assessed. Mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) level, and thioredoxin reductase (TrxR) activity were determined. Total antioxidant (TAS) and oxidant status (TOS) in cytosol, mitochondria of myocytes, and plasma were measured. Left ventricular data demonstrated left ventricular systolic pressure (LVSP) decreased, left ventricular developed pressure (LVDP) decreased, and left ventricular end-diastolic pressure (LVEDP) increased in ADR treated animals, compared to the control and Se groups. ADR decreased the membrane potential and ATP level in myocyte mitochondria. TrxR activity decreased in the ADR group, compared to the Se group. Cytosolic and mitochondrial TAS decreased and mitochondrial and plasma TOS increased in the ADR group, compared to the control. The coadministration of Se with ADR attenuated left ventricular dysfunction, improved MMP and ATP levels, and prevented oxidative stress by increasing antioxidants (especially TrxR) and decreasing oxidants. We concluded that Se is effective against ADR-induced cardiac damage via the restoration of TAS and TOS, which prevented mitochondrial damage. PMID- 21314471 TI - Systemic toxicity and toxicokinetics of a high dose of polyethylene glycol 400 in dogs following intravenous injection. AB - Polyethylene glycol 400 (PEG-400) has been used in injections. However, limited data are available concerning the toxicity of a high dose of PEG-400 following intravenous (i.v.) injection. The aim of the present study was to estimate the systemic toxicity and toxicokinetics of a high dose of PEG-400 in dogs following i.v. injection. Twenty-four dogs were divided into four groups: a control group receiving normal saline and three test groups receiving 4.23, 6.34, and 8.45 g/kg of PEG-400, respectively, by i.v. injection once a day for 30 days. The repeated dose toxicity of PEG-400 was assessed. Toxicokinetic parameters of PEG-400 in dogs were estimated on days 1 and 30. Dry mouth and dry nasal mucus membrane were observed in dogs treated with 6.34 and 8.45 g/kg of PEG-400. Cloudy swelling of kidney cell and increased glomerular volume were observed in dogs treated with 8.45 g/kg of PEG-400 when the animals were sacrificed 24 hours after the last injection. No significant histological changes were found 21 days later. Repeated dosing did not affect the toxicokinetic profile of PEG-400 in dogs. This study has shown that the toxicity of a high dose of PEG-400 following repeated intravenous injections is low, and alterations produced are reversible. PMID- 21314472 TI - Neurochemical changes following a single dose of polybrominated diphenyl ether 47 in mice. AB - Polybrominated diphenyl ethers (PBDEs) are commonly used as commercial flame retardants in a variety of products, including plastics and textiles. Previous studies in our laboratory, and in the literature, showed that exposure to a specific PBDE congener (PBDE 47) during a critical period of brain development may lead to developmental delays and hyperactivity in adulthood. To date, the underlying causes of these behavioral alterations are unknown, although in vitro studies linked PBDEs with potential alterations in neurotransmitter levels, particularly acetylcholine (ACh) and dopamine (DA). Alterations in DA function have also been noted in cases of hyperactivity in rodents and humans. The current study examined monoamine levels in male mice acutely exposed to corn oil vehicle or PBDE 47 (1, 10, or 30 mg/kg) on postnatal day (PND) 10. Animals were sacrificed on PND 15, PND 20, and in adulthood (131-159 days old). The cortex, striatum, and cerebellum were isolated and analyzed by high-performance liquid chromatography to determine the concentration of monoamines within each brain region. A statistically significant increase in DA levels was seen within the cortex, regardless of age, but only in the 10-mg/kg PBDE treatment group. While these effects did not show a monotonic dose response, we previously reported hyperactivity in littermates in the same dose group, but not at the lower or higher dose. Thus, early developmental exposure to PBDE 47 alters the levels of cortical DA in male mice, which may correlate with behavioral observations in littermates. PMID- 21314473 TI - Short communication: decrease in mitochondrial transmembrane potential in peripheral blood mononuclear cells of HIV-uninfected subjects undergoing HIV postexposure prophylaxis. AB - To monitor the mitochondrial transmembrane potential (DeltaPsim), peripheral blood mononuclear cells (PBMCs) from 18 HIV-uninfected individuals completing a 4 week course of HIV postexposure prophylaxis (PEP) with emtricitabine/tenofovir and lopinavir/ritonavir were analyzed. DeltaPsim was assessed by FACS analysis after staining with JC-1 using a mixed effects regression analysis. Apoptosis was determined by Annexin-V-FITC and propidium iodide staining. DeltaPsim decreased significantly during HIV-PEP (p=0.0015 for the linear term, p=0.0039 for the quadratic term of days on PEP) and normalized several weeks after stopping antiretrovirals. The apoptosis rates did not change significantly (p=0.42). Even newer drugs such as tenofovir and emtricitabine may cause side effects due to mitochondrial dysfunction. PMID- 21314474 TI - Anders Fredrik Regnell--an early and generous sponsor of our society. PMID- 21314476 TI - Effect of CD4+ T cell count and antiretroviral treatment on two serological HIV incidence assays. AB - Serological assays are increasingly being used to measure HIV incidence in cross sectional studies, but their specificity to determine incident infections remains problematic. We estimated the specificity of the BED assay in a cohort of long term HIV-infected adults before and during antiretroviral treatment (ART) and evaluated an HIV avidity assay to detect BED-based false-recent results. We used the BED assay to test stored specimens from known long-term HIV-1-infected adult Ugandans before and at 3, 12, and 24 months after ART initiation. We evaluated the frequency of false-recent classifications by ART status and CD4(+) T(+) cell count. Specimens classified as BED false-recent were further tested with an avidity assay. In all, 950 blood specimens from 253 adults were tested with the BED assay. Of these, 149 (15.7%) specimens tested false-recent and 64 (24.9%) individuals tested false-recent at least once. Among all specimens tested, the proportion of false-recent rose with increasing CD4(+) cell count (<250 cells/MUl: 11.3%, 250-499: 17.8%, >=500: 21.4%; p for trend=0.002). Of 197 persons with all four BED results available, 75.6% were classified as long-term infected throughout and 8.1% as false-recent throughout; the remainder changed classification once (12.2%) or twice (4.1%). Of 105 false-recent specimens retested with the avidity assay, 101 (96.2%) were correctly classified as "long term." The BED assay's specificity varied with CD4(+) cell count and use of ART. Knowledge of these parameters for blood samples could improve incidence estimates using the BED assay. The additional use of an avidity assay may help to minimize the proportion of BED false-recent specimens. PMID- 21314477 TI - Channel properties of the translocator domain of the autotransporter Hbp of Escherichia coli. AB - Autotransporters produced by Gram-negative bacteria consist of an N-terminal signal sequence, a C-terminal translocator domain (TD), and a passenger domain in between. The TD facilitates the secretion of the passenger across the outer membrane. It generally consists of a channel-forming beta-barrel that can be plugged by an alpha-helix that is formed by a polypeptide fragment immediately N terminal to the barrel domain in the sequence. In this work, we characterized the TD of the hemoglobin protease Hbp of Escherichia coli by comparing its properties with the TDs of NalP of Neisseria meningitidis and IgA protease of Neisseria gonorrhoeae. All TDs were produced in inclusion bodies and folded in vitro. In the case of the TD of Hbp, this procedure resulted in autocatalytic intramolecular processing, which mimicked the in vivo processing. Liposome swelling assays and planar lipid bilayer experiments revealed that the pore of the Hbp TD was largely obstructed. In contrast, an Hbp TD variant that lacked only one amino-acid residue from the N terminus showed the opening and closing of a channel comparable to what was reported for the TD of NalP. Additionally, the naturally processed helix contributed to the stability of the TD, as shown by chemical denaturation monitored by tryptophan fluorescence. Overall these results show that Hbp is processed by an autocatalytic intramolecular mechanism resulting in the stable docking of the alpha-helix in the barrel. In addition, we could show that the alpha-helix contributes to the stability of TDs. PMID- 21314480 TI - The serotonin transporter expression in Drosophila melanogaster. AB - The serotonin transporter is an important regulator of serotonergic signaling. In order to analyze where the Drosophila melanogaster ortholog of the mammalian serotonin transporter (dSERT) is expressed in the nervous system, a dSERT antibody serum was used. Ectopic expression studies and loss of function analysis revealed that the dSERT antibody serum specifically recognizes dSERT. It was shown that in the embryonic nervous system dSERT is expressed in a subset of Engrailed-positive neurons. In the larval brain, dSERT is exclusively expressed in serotonergic neurons, all of which express dSERT. dSERT-positive neurons surround almost all brain neuropiles. In the mushroom body of the adult brain, extrinsic serotonergic neurons expressing dSERT engulf the mushroom body lobes. These neurons show regional differences in dSERT and serotonin expression. At the presynaptic terminals, serotonin release is sterically linked to serotonin reuptake. In contrast to this, there are other areas in serotonergic neurons where dSERT expression and/or function are uncoupled from synaptic neurotransmitter recycling and serotonin release. The localization pattern of dSERT can be employed to further understanding and analysis of serotonergic networks. PMID- 21314479 TI - A class of mild surfactants that keep integral membrane proteins water-soluble for functional studies and crystallization. AB - Mixed protein-surfactant micelles are used for in vitro studies and 3D crystallization when solutions of pure, monodisperse integral membrane proteins are required. However, many membrane proteins undergo inactivation when transferred from the biomembrane into micelles of conventional surfactants with alkyl chains as hydrophobic moieties. Here we describe the development of surfactants with rigid, saturated or aromatic hydrocarbon groups as hydrophobic parts. Their stabilizing properties are demonstrated with three different integral membrane proteins. The temperature at which 50% of the binding sites for specific ligands are lost is used as a measure of stability and dodecyl-beta-D maltoside ('C12-b-M') as a reference for conventional surfactants. One surfactant increased the stability of two different G protein-coupled receptors and the human Patched protein receptor by approximately 10 degrees C compared to C12-b-M. Another surfactant yielded the highest stabilization of the human Patched protein receptor compared to C12-b-M (13 degrees C) but was inferior for the G protein coupled receptors. In addition, one of the surfactants was successfully used to stabilize and crystallize the cytochrome b(6 )f complex from Chlamydomonas reinhardtii. The structure was solved to the same resolution as previously reported in C12-b-M. PMID- 21314481 TI - Short communication: severe immune suppression in patients infected with R5 tropic HIV-1 strains is associated with increased gp120 net charge at variable regions. AB - CXCR4-tropic viruses have been associated with advanced immune suppression. However, 50% of patients with AIDS exclusively harbor CCR5-tropic viruses. The net charge at HIV-1 envelope gp120 variable regions was examined in 66 HIV-1 infected individuals with CCR5-tropic viruses, of whom 30 had less than 200 cells/mm(3). A positive net charge at gp120 variable regions was significantly associated with lower CD4 counts. Thus, the net charge at gp120 variable regions could influence HIV-1 disease progression in subjects with CCR5-tropic viruses. PMID- 21314482 TI - A new approach to Parkinson's disease: inhibition of leucine-rich repeat kinase 2. AB - BACKGROUND: Genetic studies have shown that mutations in several genes may be linked to Parkinson's disease including leucine-rich repeat kinase-2 (LRRK2). The most common of the LRRK2 mutants is the Gly2019Ser mutant. OBJECTIVE/METHODS: A paper suggesting that inhibitors of Gly2019Ser mutant may be useful in the treatment of Parkinson's disease associated with this mutant is evaluated. RESULTS: Overexpression of the wild-type LRRK2 or the Gly2019Ser LRRK2 mutant type produced cortical neuron injury in cell culture, and the mutant also caused cell death; this was reduced by GW5074. Administered intraperitoneally to mice, GW5074 prevented the loss of neurons induced by the Gly2019Ser LRRK2 mutant. CONCLUSIONS: Selective Gly2019Ser LRRK2 mutant inhibitors may have potential in the treatment of Parkinsonism associated with mutations of this gene and GW5074 is a lead compound for this. PMID- 21314483 TI - Role of hTERT and WT1 gene expression in disease progression and imatinib responsiveness of patients with BCR-ABL positive chronic myeloid leukemia. AB - Most cases of leukemia show hTERT and WT1 gene overexpression. However, the role of these genes in the progression and monitoring of chronic myeloid leukemia (CML) has not been very well explored. Two hundred and eight patients diagnosed as having CML in chronic phase (CP), accelerated phase (AP), and blast crisis (BC) were studied. Real-time polymerase chain reaction (PCR) was performed for comparative quantification of BCR-ABL, hTERT, and WT1 gene expression. The expression levels of the three genes were compared among the three phases and seven imatinib-naive and -treated subgroups. Among the three major groups, the gene expression levels of hTERT (p < 0.01) and WT1 (p < 0.01) were significantly different. Freshly diagnosed, imatinib-responsive, and -unresponsive patients among these revealed interesting changes in hTERT and WT1 gene expression profiles, especially in 25 patients with CML in whom sequential samples were analyzed. Our results showed that hTERT and WT1 gene expression analyses provided relevant information for the understanding of disease progression and indicate their possible usefulness as surrogate markers for treatment monitoring. PMID- 21314484 TI - Treatment with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone combined with cytarabine and methotrexate results in poor mobilization of peripheral blood stem cells in patients with mantle cell lymphoma. AB - Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone combined with cytarabine and methotrexate) is an intense chemotherapy regimen frequently used for hematologic malignancies including mantle cell lymphoma. To address whether treatment with hyper-CVAD impairs mobilization of peripheral blood stem cells, we retrospectively analyzed mobilization data from 77 consecutive adult patients with mantle cell lymphoma who underwent peripheral blood stem cell (PBSC) mobilization for planned autologous stem cell transplant (ASCT). Compared to patients treated with alternative regimens, patients treated with hyper-CVAD collected fewer CD34+ cells, required more total days of pheresis, and more frequently required a second mobilization attempt, despite being more likely to have undergone mobilization with a VP16-containing regimen. In multivariable linear regression analysis, treatment with hyper-CVAD was associated with a significant reduction in total CD34+ cells mobilized (p < 0.001). These findings suggest that alternative mobilizing strategies prior to ASCT are needed for patients with mantle cell lymphoma who have received hyper-CVAD. PMID- 21314485 TI - Binucleated lymphocytes in patients with multiple sclerosis treated with natalizumab. PMID- 21314486 TI - c-myc rearrangement in B-cell lymphoblastic lymphoma with the involvement of multiple extranodal lesions. PMID- 21314487 TI - Hematogones are markedly decreased in chronic myeloid leukemia: multiparametric flow cytometric analysis. AB - Past studies have shown decreased hematogones in the bone marrow of patients with myelodysplastic syndromes and acquired aplastic anemia. In this study, we examined the bone marrow of patients with chronic myeloid leukemia (n = 33, mean age 49 years, age range 2-83 years) for the presence of hematogones and compared their frequency with that of age-matched controls (n = 50). We found that the percentages of total and stage I hematogones were decreased in chronic myeloid leukemia at diagnosis (n = 25) and at follow-up post therapy (n = 8) when compared to age-matched controls (diagnosis, total: 0.29% vs. 0.87%, p = 0.001; diagnosis, stage I: 0.06% vs. 0.20%, p = 0.008; follow-up, total: 0.17% vs. 0.87%, p < 0.001; follow-up, stage I: 0.04 vs. 0.20, p = 0.003). We also found a significant decrease in the number of natural killer cells in patients with chronic myeloid leukemia at diagnosis. Further studies are warranted to elucidate the mechanism of hematogone decrease in chronic myeloid leukemia and whether this finding also applies to other myeloproliferative neoplasms. PMID- 21314488 TI - Efficacy of routine surveillance with positron emission tomography/computed tomography in aggressive non-Hodgkin lymphoma in complete remission: status in a single center. AB - Post-therapy surveillance imaging in patients with lymphoma remains controversial. We report our experience with positron emission tomography/computed tomography (PET/CT) surveillance in patients with aggressive non-Hodgkin lymphoma in first complete remission (CR). The 138 PET/CTs performed in 52 patients revealed four unsuspected relapses. In one patient, relapse was visualized by fluorodeoxyglucose (FDG) accumulation without any significant CT pathology. The specificity and sensitivity of surveillance PET/CT were 89% and 100%, respectively. The predictive values of positive and negative PET/CTs were 21% and 100%, respectively. The cost of half-yearly routine PET/CT surveillance during the first 2 years in CR was $US8552 per patient and accounted for 81% of the total follow-up costs. PET/CT was effective in detecting unexpected relapse and normal PET/CT supported continuous CR. However, the impact of PET/CT was limited by the high number of false-positive results and PET/CT surveillance was costly compared to CT surveillance. PMID- 21314489 TI - Expanding the use of thrombopoietin mimetic drugs: what about chronic lymphocytic leukemia? PMID- 21314490 TI - Risk and response adapted therapy for early stage Hodgkin lymphoma: a prospective multicenter study of the Australasian Leukaemia and Lymphoma Group/Trans-Tasman Radiation Oncology Group. AB - In this prospective, multicenter, non-randomized study for patients with stage I II Hodgkin lymphoma, group 1 (without risk-factors [RF]) had three cycles of ABVD chemotherapy (adriamycin, bleomycin, vinblastine, and dacarbazine) and group 2 (any of bulk, extranodal site, >3 regions, raised erythrocyte sedimentation rate [ESR]) and group 3 (B-symptoms) received four cycles. Involved field radiotherapy (IFRT) 30 Gy was given after adequate chemotherapy response. Five-year overall survival and freedom from progression (FFP) were 96% (95% confidence interval [CI] 91-98%) and 90% (84-94%), respectively. Five-year FFP was 97% (90-99%), 89% (75-95%), and 73% (52-86%) for groups 1, 2, and 3, respectively. In patients with RF, chemotherapy responses of complete response unconfirmed (CRu), partial response (PR), and stable disease (SD) were associated with FFP of 90%, 86%, and 62% (p=0.17), and CR/no CR on functional imaging with FFP of 90%/67%, respectively (p=0.05). The 97% FFP in group 1 compares favorably with previously reported results from cooperative trial groups. Intensification of therapy warrants study in patients with RF and a poor chemotherapy response. PMID- 21314491 TI - Targeting aneuploid cancer cells. AB - INTRODUCTION: Most cancers are characterized by some degree of aneuploidy, although its relevance for tumor initiation or progression and the nature of the initial trigger are still not well understood. It was Theodor Boveri who first suggested a link between aneuploidy and cancer at the beginning of the last century, but it is only recently that the molecular mechanisms involved have started to be uncovered. AREAS COVERED: The molecular mechanisms that are at the origin of aneuploidy and their cellular consequences. Based on these new findings molecular targets have emerged which could lead to a specific treatment of at least some types of aneuploid tumors. EXPERT OPINION: Therapeutic intervention specifically for aneuploid cells is a very promising approach, however, although new promising targets have been spotted they still need to be tested for proof of concept. Targeting the spindle checkpoint could be an interesting approach for cancer therapy, however, as for other mitotic targets, the open question of the therapeutic window and sensitivity of normal hemopoietic cells has to be considered carefully. Future challenges will not only include identifying and validating druggable targets related to the relevant pathways, but also finding predictive biomarkers to define the responding patient population(s). PMID- 21314492 TI - New non-oral drug delivery systems for Parkinson's disease treatment. AB - INTRODUCTION: Parkinson's disease (PD) remains the only neurodegenerative disorder for which there are highly effective symptomatic therapies, but still unmet needs regarding its long-term management. Levodopa (LD) remains the most effective treatment; however, chronic use is associated with potentially disabling motor complications. AREAS COVERED: This review highlights a variety of new non-oral drug delivery strategies for non-invasive and invasive routes of drug administration for the treatment of PD. It also includes current and future trends of liposomes, solid lipid nanoparticles and biocompatible microparticles as new non-oral drug delivery systems. EXPERT OPINION: The long-term complications and limitations of LD treatment might be improved by changing therapy from the present pulsatile stimulation to a more constant stimulation of central dopamine receptors. Stimulation of these receptors may be possible with a new non-oral drug delivery system, with the aim of achieving long-lasting and less fluctuating drug levels, minimization of peak levels and thereby reduction of side effects. PMID- 21314493 TI - Delivery of biologics to select organelles--the role of biologically active polymers. AB - Biologics (i.e., nucleic acid and protein-based drugs) suffer from poor bioavailability, as membrane partitioning and intracellular targeting are a significant problem. Various strategies have been developed in an attempt to modulate biologics bioavailability by means of manipulating whole body pharmacokinetics and subcellular trafficking. Limited direct success has been observed. This review focuses on the components of nanomedicine systems rather than the whole, facilitating an overview of materials that may be of clinical relevance in the future. Some of the advantages and disadvantages associated with the use of soluble drug delivery systems are considered. Although the focus is on linear poly(amidoamine) polymers, emerging technologies capable of the delivery of large molecules to other specific intracellular compartments are also examined. The focus is maintained on cytosolic access for two reasons, initially because this intracellular compartment may be viewed as a 'gateway' to other intracellular organelles and also because this is where the greatest therapeutic benefit is likely to be found. It is likely that in the coming years and in combination with other existing, well-characterized drug delivery platform technologies, such as liposomal formulation or polymer conjugation, that the targeting of specific organelles will become more accessible. PMID- 21314494 TI - New approaches for the generation of induced pluripotent stem cells. AB - INTRODUCTION: The advent of induced pluripotent stem cell (iPSC) technology has opened up new vistas to generate patient-specific pluripotent stem cells from somatic cells. During the last 5 years, the iPSCs produced from a variety of somatic cell sources are found to be very similar, if not identical to embryonic stem cells. Invariably these cells are produced by viral transduction of four transcriptional factors that renders these cells unfit for therapeutic purposes. AREAS COVERED: This review discusses current developments emphasising on new and improved methods of generating iPSCs, including minimal or no genetic modifications via excisable lentiviral and transposon vectors or through repeated application of transient plasmid, episomal and adenovirus vectors. Recent use of small molecules, synthetic mRNA and microRNAs is also reviewed. EXPERT OPINION: iPSC technology is emerging as an unprecedented opportunity in biomedical research, disease modeling, drug discovery and regenerative medicine. However, to harness the full potential of this technology, a number of issues that need to be resolved pertaining to iPSC safety, stability, culture variability, their comparison with ES cells, the reprogramming mechanisms and better ways to direct a specific reprogramming process including lineage specifications. PMID- 21314495 TI - The spatial extent of binocular suppression in normal and strabismic subjects. AB - The authors investigated and specified the spatial extent of binocular suppression for normal and strabismic subjects at differing retinal eccentricities. Increment luminance thresholds for detecting a probe line which was presented to one eye were measured under the influence of a contralateral suppressing line. Probe sensitivities were obtained as a function of positional disparity of the contralateral suppressing line. Two normals and two strabismics served as subjects. The suppression patterns for the normal and strabismic subjects were similar except for the width of the suppression area. The interocular suppression functions were U-shaped, and there were significant effects of eccentricity. The spatial extent of suppression for normal subjects was between 2 and 20 min arc at the fovea or between 5 and 40 min arc at an eccentricity of 2 degrees. The maximum disparity which produced suppression effects in the strabismics was about half of that obtained for the normals, in either the foveal or near peripheral conditions. The psychophysically obtained U shaped functions appear to be similar to the neuro-physiological data from cat striate cortex by Kato, Bishop & Orban (1981). Therefore, the authors believe that these results may reflect the operation of an interocular version of the Westheimer function. PMID- 21314496 TI - The value of the occlusion test in decompensating exophorias and intermittent exotropias. AB - The importance of the occlusion test is analysed in patients who were operated for a decompensating exophoria or an intermittent exotropia. Of particular interest before and after the occlusion test was the number of the following variables: the distant angle, the near angle, the difference between these two (the so-called distant angle-near angle difference), and the angle at right respective left gaze. All patients included in this study had been examined at least three times preoperatively. The occlusion test was performed in all patients by occluding one eye on three consecutive days. A total of 36 patients with decompensating exophoria and 33 patients with intermittent exotropia were included in this retrospective clinical trial. Only the near angles of the patients with the decompensating exophorias demonstrated a statistically significant increase. All the other angles did not show a significant change. In contrast to what might have been expected, the difference between the distant angle and the near angle increased in the exophoria group. This was not the case in patients with intermittent exotropia. Thus the occlusion test cannot generally be recommended as an obligatory part of the preoperative diagnostics in patients with exophoria or intermittent exotropia. In selected cases it may however be worthwhile to decide on the exact extent of the operation planned. PMID- 21314498 TI - Selected abstracts. PMID- 21314497 TI - Force-length recording of eye muscles during local-anesthesia surgery in 32 strabismus patients. AB - Force-length recordings were made from isolated human eye muscles during strabismus surgery in local, eye-drop anesthesia in 32 adult patients. From each muscle three recordings were made: (I) while the patient looked with the other eye into the field of action of the recorded muscle, (2) looked ahead, and (3) looked out of the field of action of the recorded muscle. Non-innervated eye muscles (state 3) had an approximately exponential relation between force and length. During contraction evoked by letting the patient look ahead or into the field of action of the muscle (states 1 or 2), the relation between force and length was grossly linear. The approximate spring constants of horizontal rectus muscles that had not been operated on before ranged from 2 to 4 g/mm. In palsies, the degree of muscle paresis could be quantified accurately using this method and, accordingly, cases of true superior oblique palsy could be well differentiated from strabismus sursoadductorius (= upshoot in adduction) that may mimic a superior oblique palsy. In seven patients with Graves' disease of recent onset, affected muscles were found to be very stiff when the other eye looked ahead. It was expected that these stiff muscles would be able to shorten to some extent but would not be able to lengthen, due to fibrosis of the muscle. We found, however, that the affected muscles lengthened considerably when the other eye looked out of the field of action of the muscle. This implies that, in these cases of Graves' disease of recent onset, the raised muscle tension and reduced elasticity of the affected muscles and, hence, the strabismus were primarily caused by active muscle contraction, not by fibrosis. PMID- 21314499 TI - Foreword. PMID- 21314500 TI - Ametropic amblyopia. AB - Hypermetropia of more than 5 diopters or an astigmatism of 2 diopters or more is often the cause of amblyopia in the master eye, independent of the presence of a simultaneous strabismus or anisometropia. This amblyopia can be prevented with early spectacle correction. In the authors' study of 218 patients with high ametropia a correlation was not always present between visual acuity and the age of the first spectacle correction or the degree of ametropia. In some patients even correction of ametropia as late as seven to ten years of age led to spontaneous functional improvement of single optotypes acuity. The treatment of choice is to give the full ametropic correction at an early age. PMID- 21314501 TI - Examinations on the new lang test. AB - The New Lang-II stereopsis test employs, as compared to the Lang-I test, smaller disparities and a less dense arrangement of random dots. In 162 subjects the authors comparatively evaluated the results of the Lang-I and Lang-II tests. Ninety percent of subjects with normal binocular vision passed both tests without making any mistake (n = 127). However, about 70% of patients with microstrabismus failed both tests (n = 35). Little difference was found between the results of both tests. PMID- 21314502 TI - How Accurate is Orthoptic Examination at Age One?: The Early vs. Late Strabismus Surgery Study Group. AB - The Early vs. Late Strabismus Surgery Study Group is a group of strabismologists and orthoptists who wish to investigate whether early or late surgery is better in cases of infantile strabismus, in a controlled, multicentre, matched-pair trial: All infants will receive a standardized entry examination at age one and then be operated either before their second birthday in clinics A, or between the 32nd and 60th month of age in clinics B. The children will be evaluated at age six. After completion of the study, one child will be selected from each group, to form a pair of children with the same entry examination, who were operated early or late. Successive pairs will be generated so that finally two smaller groups with the same entry examinations are formed. These two groups can then be compared regarding degree of binocular vision, angle of squint and visual acuity of the worse eye. It was decided to perform first a pilot-study of the examination of infants age nine to 15 months, because we wanted to know to what degree of accuracy infants age one can be examined and what parts of the examination can be carried out most reliably and can therefore be used as parameters to match the pairs in the main study. 190 Children were each examined by three examiners on one day, according to a standardized examination sheet, and differences were quantified. We found that the angle of squint could be measured with reasonable precision: The largest difference between any two of the three measured angles averaged at 6.5". The angle did not increase when the infant was examined a second or third time. Variability of the angle, vertical divergence and up-/downshoot-in-adduction could not be assessed reliably. On the other hand, restriction of abduction (in a 4-class scale) could be measured with adequate precision: in 58% there were no differences at all between the three examinations. The degree of amblyopia could be well assessed by observing the fixation pattern by means of direct fundoscopy with a fixation mark or by comparing corneal reflexes during monocular fixation. Using a 3-class scale, there were no differences at all between the three examinations of the three orthoptists in 94% of the cases. In addition, amblyopia could be accurately assessed by observing the fixation behaviour of the child with either eye, in a 5 class scale. PMID- 21314503 TI - Abstracts of Papers Presented at the XVIIth Meeting of the F.C. Donders Society for Strabismology Leiden, The Netherlands, November 1992. PMID- 21314504 TI - Abstracts of papers presented at the meeting of the 'arbeitskreis schielen' at the annual meeting of the berufsverband der augenarzte deutschlands. PMID- 21314505 TI - Selected abstracts. PMID- 21314506 TI - Neuronal basis of optokinetic reflex pathology in naturally strabismic monkeys. AB - The optokinetic reflex and neuronal response properties in the central visual pathway were studied in three macaque monkeys (Macaca nemestrina) with early childhood strabismus of various origin. Binocularity in the primary visual cortex (VI) measured electrophysiologically was reduced both in a monkey with resolved strabismus and in a monkey with accommodative strabismus when compared to normal controls. By contrast, binocularity in the nucleus of the optic tract and dorsal terminal nucleus of the accessory optic system (NOT-DTN) was only reduced in the monkey with resolved strabismus ('resolved'), but appeared normal in animals with accommodative strabismus ('accom. 1 'and 'accom. 2'). Sub-threshold binocular interactions were normal in all animals. The velocity tuning curves of retinal slip neurons in the NOT-DTN of all strabismic monkeys were not different from normal controls. Horizontal optokinetic nystagmus was asymmetric in monkey 'accom. 2', and for the non-fixating eye in monkey 'resolved'. In monkey 'accom. 1' OKN was normal. Open loop eye velocity was lower in the monkey with resolved strabismus than in monkeys with accommodative strabismus. These data suggest that different causes of strabismus may affect neuronal response properties and behavior to different degrees. The effects on the optokinetic reflex of resolved, but early onset strabismus were more severe than those of accommodative strabismus. This corresponds to the wide variability of defects in the optokinetic system of strabismic humans. PMID- 21314507 TI - New data base program for quality control of strabismus surgery. AB - The authors report on a newly developed data base program for strabismus patients. All relevant preoperative and postoperative information regarding visual sensory data, motility, squinting angle in nine fields of gaze and head position are easily entered into the data base. The program flows easily through data collection. Its use does not require special computer skills. Depending on monitor size, data for each patient is compressed into three or four screens totaling 120 entry fields, 67 of which refer to preoperative and postoperative squint angle. Entry fields flow in a logical manner. Storing capacity is increased by a factor of up to 40 with 28 drop down fields, totaling 271 available entry fields per patient. To enhance easy access of data, no abbreviations have been used. PMID- 21314508 TI - Estimation of accommodation in early childhood: Targets and preliminary results. AB - Accommodative disorders can be found in a variety of patients of the pediatric ophthalmology age group. Detection and measurement of (insufficient) accommodation is necessary for adequate management of these patients. Dynamic retinoscopy reversal was used to estimate the accommodative amplitude. Subjective point of blur was compared in two groups of healthy and ophthalmologically normal preschool children: (1) six weeks to one year, (2) one year to six years, in comparison to a group of (3) five years to 12 years, who underwent two different tests. Four targets, mounted on a hand-held occluder, are introduced and tested, 1-3 showing different, more or less detailed and fine drawings of faces, 4 showing a grating of lower spatial frequency with a center of high spatial frequency. The subjective near point for the targets was also tested and compared in 12 young adults (16 to 31 years). The finest drawing appeared to be most adequate for reproducing the closest near point in young adults. This also applies for children above 2% years, while younger children showed better performance and more constant fixation with roughly outlined, schematic drawings of a smiling face. The grating was met with no (babies below two months) or little interest (older infants). The amplitude of accommodation seemed less good with the grating in preschool children. Thus, dynamic retinoscopy is an adequate method to estimate the amplitude of accommodation in early childhood, and the drawing of a smiling face on a 5 cm target is an adequate stimulus attracting attention and accommodation of preverbal children and even babies. PMID- 21314509 TI - Brown's syndrome associated with Smith-Magenis syndrome: Case report. AB - Brown's syndrome is generally an isolated clinical condition. The authors observed a girl with a right Brown's syndrome and a rare condition due to an interstitial deletion of chromosome 17, known as Smith-Magenis syndrome. A wide spectrum of congenital disorders have been reported in Smith-Magenis syndrome, but never Brown's syndrome. PMID- 21314510 TI - Myopia evolution in pre-school children after full optical correction. AB - The optical correction of myopia is a controversial procedure in immature human eyes due to the limited knowledge of the mechanisms regulating emmetropization and to the lack of controlled clinical trials. The authors reviewed retrospectively the records of 42 myopic children (16 males and 26 females, mean age 34 months, range 17-54) for whom full optical correction was prescribed and refraction evaluated with cycloplegic autorefractometry. The mean Spherical Equivalent (SphEq) at the diagnosis (To) was 6.062+/-3.67 diopters. Eighteen patients had isomyopic (+/-1D difference SphEq), 15 anisomyopic and 9 antimetropic eyes. No differences were found at To in the mean sphere, cylinder, SphEq and age of first correction between males and females. Follow-up was 42+/ 17 and 47+/-23 months respectively for each sex (T1). Compliance with spectacles was generally good. At T1, the mean SphEq was significantly reduced in the whole group (-5.32+/-3.39, P<0.001). However, analyzing the sexes separately, it was found that only spherical progression was halted in males, whereas females showed a significant reduction both in sphere (p<0.001) and in cylinder (p<0.001). Final visual acuity was 0.86+/-0.18 and 0.86+/-0.26 (p: n.s.). The authors conclude that full optical correction did not exacerbate myopia progression in infants. Females showed a higher plasticity to the emmetropization process. Myopia increased mostly in undercorrected patients, and decreased with spectacles in 61% of isomyopic, 73% of anisomyopic and 77% of antimetropic patients. These observations support the hypothesis that visual input can modulate eye growth, calling for an early correction strategy for controlling myopia in infants. PMID- 21314511 TI - Abstract of paper presented at the Wiesbadener Tagung des BVA. PMID- 21314512 TI - An international journal on strabismus. PMID- 21314513 TI - Detecting amblyogenic diseases with the photographic Bruckner test. AB - The authors evaluated the photographic Bruckner test for its ability to detect the main causes of amblyopia. One hundred four patients divided into four groups underwent this test: Group I, small deviation esotropia; Group II, large deviation esotropia; Group III, anisometropia; and Group IV, healthy controls. The results show high sensitivity (82%), specificity (91%), and accuracy (84%), indicating that this test could be a potential way to mass-screen pre-verbal and pre-school children to facilitate early detection of the main causes of amblyopia, when treatment is still possible. PMID- 21314514 TI - Spontaneous consecutive Brown syndrome following superior oblique palsy. AB - A 28-year-old female presented with a left trochlear nerve palsy, after indirect head trauma, with no fracture or orbital lesion. She had diplopia, a hypertropia and excyclotropia on right downgaze. Three months later the trochlear palsy had been replaced by Brown's syndrome: a deficit of elevation in adduction, with diplopia, incyclotropia and hypertropia in up-gaze. The Brown syndrome remained the same over a period of 18 months. A 31-year-old male suffered from severe brain contusion with intracerebral haemorrhage and bilateral trochlear nerve palsy. Three years later, he had a bilateral trochlear palsy with bilateral severe Brown's syndrome, with a right hypertropia and 10 degrees to 25 degrees incyclotropia in upgaze and 5 degrees to 10 degrees excyclotropia in downgaze. The field of binocular vision was shifted to left gaze. Orbital CT scan was normal. At surgery, the forced duction test was positive for Brown's syndrome on both sides and the tendon of the superior oblique muscle of the right eye was thickened. The field of binocular vision was centralized after surgery but torsional diplopia in upgaze and downgaze was present as before. Secondary Brown's syndrome after (persisting or vanishing) trochlear nerve palsy without any direct trauma to the superior oblique muscles or the orbit could be caused by a fibrotic reaction of the superior oblique tendon or adjacent structures. This could be due to inactivity or to indirect trauma. PMID- 21314515 TI - Cycloplegic refraction using atropine minidrops. AB - Topical application of atropine for cycloplegic refraction may be associated with alarming systemic reactions in infants and children. Cycloplegic refraction and pulse rate were compared after short-term minidrop application of atropine with a calibrated pipette (3 * 5 MUl) and standard atropine application from commercial bottles (twice daily 30-36 MU1 for three days) in 30 hypermetropic eyes of children between 1 and 7 years of age. The mean spherical equivalents of cycloplegic refraction achieved after minidrop application was 0.23 D lower than that following standard application. In many cases, there was a substantial increase in pulse rate 90 minutes after atropine instillation, both from minidrops and from commercial bottles. Short-term minidrop application of atropine with a calibrated pipette may be used for cycloplegic refraction in infants and children if one wishes to reduce the total atropine dose. PMID- 21314516 TI - Up- and downshoot in adduction after monocular patching in normal volunteers. AB - Upshoot-in-adduction and downshoot-in-adduction are non-paretic motility disorders that usually accompany a horizontal squint in children, together with V or A-pattern motility. Upshoot-in-adduction may sometime mimic a superior oblique palsy. The authors have found that even in healthy volunteers these motility disorders can be found and made manifest by patching. One eye of complaint-free volunteers with full stereopsis was patched for three days. Then the eye movements of the patched eye were recorded with the search coil technique, first before taking the patch off and secondly after putting the patch on the other eye. The latter registration served as reference for the first registration. It was found that 11 out of 18 volunteers had developed an upshoot in-adduction of the patched eye. In five cases no directional change was found whereas two cases had developed a downshoot-in-adduction. It seems that up- and downshoot-in-adduction are latent motility disorders that become manifest after disruption of fusion. In addition, the authors found undershooting saccades and postsaccadic drift of the patched eyes. PMID- 21314517 TI - Abstracts of papers presented at the IV Symposium of the Bielschowsky Society for the Study of Strabismus. PMID- 21314518 TI - Selected abstracts. PMID- 21314519 TI - Small and large field grating acuity versus recognition acuity in different groups of amblyopic patients. AB - Grating acuity was tested in 74 subjects with different amblyopia and five patients with pathological morphological findings, reducing visual acuity. Recognition acuity was tested with Landolt C single symbol and close inter-space 2.6 min. of arc. Grating acuity was tested with the Teller Acuity Cards with large (12.5 cm * 12.5 cm) and small (6.25 cm * 6.25 cm) test fields. Reduction of field size did not cause any significant difference. Patients with strabismic or strabismic and anisometropic amblyopia did not show a close correlation of recognition acuity with grating acuity. Stimulus deprivation amblyopia showed a good correlation between grating acuity (large and small field) and Landolt single optotype acuity. In children at risk for amblyopia, a difference in favour of large field gratings was found for both eyes (risk and non-risk eye) in the lower visual acuity group (identical with the lower age group). Better grating acuity for large fields seems to reflect an early stage of the visual development rather than that it is indicative for amblyopia. PMID- 21314520 TI - Effects of diagnostic occlusion on ocular alignment in normal subjects. AB - Diagnostic occlusion is used in strabismus to examine the changes in the angle of squint after a period of disrupted fusion. The aim of the present study was to investigate the effect of diagnostic occlusion on ocular alignment in normal subjects without strabismus and other ocular motility related symptoms. Diagnostic occlusion of the non-dominant eye was applied to ten subjects for three days. In all cases a small horizontal deviation was seen in the primary position and in three cases also a small vertical deviation was noted. Diagnostic occlusion for seven days was applied in nine persons. Changes in alignment of approximately the same size as after three days of occlusion were seen. In both groups incomitances of ocular alignment were noted that indicate small muscle imbalances particularly in the oblique muscles of normal subjects that are easily compensated by normal motor fusion. PMID- 21314521 TI - Effect of bimedial rectus recession with a loop on the deviation in essential infantile esotropia. AB - Thirty-two patients with essential infantile esotropia were treated by using a 2.5 millimeter loop, added to a 4 millimeter medial recti recession bilaterally. Objective deviation was more than 45 prism diopters (PD) in all of the patients preoperatively. After surgery the deviation ranged between -10 PD and +IO PD in 26 (81.2%) patients, and limitation of abduction disappeared in all of the cases. A slight limitation of adduction was encountered in two (6.2%) patients. The authors concluded that bimedial rectus recession with a loop is an effective method as an early surgical procedure in patients with infantile esotropia with a large deviation. PMID- 21314523 TI - 1 Optical correction of hypermetropia in early childhood results in better visual acuity in children of 8 to 12 years. PMID- 21314522 TI - The Early vs. Late Infantile Strabismus Surgery Study: First Monitoring Report. AB - The Early vs. Late Infantile Strabismus Surgery Study Group is a group of strabismologists and orthoptists who investigate whether early or late surgery is preferable in infantile strabismus, in a non-randomized, prospective, multi centre trial. Infants between six and 18 months of age will receive a standardized entry examination and then be operated either before their second anniversary in clinics A, or between their 32nd and 60th month of age in clinics B. The children will be evaluated at age six. After completion of the study, the two groups can then be compared regarding degree of binocular vision, angle of strabismus and visual acuity of the worse eye relative to the better one. This is the first monitoring report of the study. PMID- 21314524 TI - 2 Quantitative visual field assessment of squinting eye under binocular conditions in ten patients with microstrabismus. Preliminary report. PMID- 21314525 TI - 3 Objective assessment of Vernier acuity. a useful method to detect strabismic amblyopia? PMID- 21314526 TI - 4 Erstbrillen-Verordnung. First spectacle prescription. PMID- 21314527 TI - 5 a longitudinal study of a population based sample of astigmatic children. 1. Refraction and amblyopia. PMID- 21314528 TI - 1 the long-term results of surgical correction of childhood esotropia. PMID- 21314529 TI - 3 Stereoscopic cooperation between the fovea of one eye and the periphery of the other eye at large disparities. Implications for anomalous retinal correspondence in strabismus. PMID- 21314530 TI - 2 Characteristics of early onset esotropia. PMID- 21314531 TI - Original papers: Effects of diagnostic occlusion of the deviated and the dominant eye in intermittent exotropia. AB - A previous study of intermittent exotropia has shown that diagnostic occlusion of the deviating eye often could reveal a vertical deviation that had not been recorded initially. The aim of the present study was to investigate if diagnostic occlusion of the dominant eye was still more effective in this respect. In 19 patients diagnostic occlusion was performed on the deviating eye as well as on the dominant eye. In 13 patients a vertical deviation could be elicited. The size of the vertical deviation was almost the same irrespective of which eye was occluded. The horizontal deviation both for distance and near was slightly larger after occlusion of the dominant than of the non-dominant eye. The fusion capacity was increased after occlusion more often after occluding the non-dominant than the dominant eye. Anomalies such as dissociated vertical deviations and A- and V pattern were equally well diagnosed by occlusion of either eye. For a full diagnostic setup of patients with intermittent exotropia, occlusion of each eye separately is recommended in order to elicit maximal horizontal and vertical deviation. PMID- 21314532 TI - Original papers: Ocular motility disorders after surgery for retinitis pigmentosa 'Cuba-therapy'. AB - Since 1988 Cuban ophthalmologists use a combined 'therapy' for retinitis pigmentosa. The treatment, comprising ozonization, electrostimulation, vasodilators, and an unknown surgical procedure after O. Pelaez, is said to stop the progression of the disease. While the nature of the operation remains unclear and scientific proof of its efficacy is still absent, reports about persisting active and passive impairments of ocular motility are becoming more frequent. The authors present the pre-, intra- and postoperative findings in two patients who developed persisting diplopia after Pelaez's operation. In both cases, one with +14 degrees esotropia, the other with up to 25 degrees incyclotropia and bilateral Brown's syndrome, binocular single vision was restored by recession of the medial rectus and superior oblique muscles. Comparing the functional findings before and one year after 'Cuba-therapy', the treatment fails to prevent progressive loss of visual acuity and visual field. Therefore, the Cuban treatment trial should not be recommended in retinitis pigmentosa. PMID- 21314533 TI - Original papers: Electrocautery paraplical incision for Faden operation. AB - In case of Faden operation (Cuppers' operation) without recession of the muscle, the authors looked for a direct approach to the site where the posterior fixation sutures should be placed. They chose a paraplical incision. To prevent bleeding they used electrocautery following a surgical technique previously described. The authors performed electrocautery paraplical incision in 270 eyes of 238 patients (age ranged between 3 y and 55 y). Follow-up time was 2.4 y + 1.3. After electrocautery, preparation of the medial rectus muscle and Faden procedure (without disinsertion of the muscle) were carried out. Finally the conjunctiva was closed with single sutures. In no patient did long-term complications occur and only the following minor complications were observed intra- or perioperatively: in one patient orbital fat protruded during surgery. Postoperatively one eye had a corneal erosion and another severe eyelid edema. In another patient a swollen plica with consecutive putrid secretion was observed. In all three cases symptoms disappeared after therapy. Paraplical incision was even possible after previous strabismus surgery with limbal incision. In Faden operation without recession of the medial rectus muscle, electrocautery paraplical incision is an alternative method with minimal postoperative inflammation and minimal scarring. It allows good approach to the medial rectus muscle, with minimal intraoperative bleeding. Postoperative healing and cosmesis are good. PMID- 21314534 TI - Original papers: A combination horizontal/vertical prism bar A precisely calibrated tool for use in front of one eye. AB - The authors used an optical bench to investigate calibration and errors from improper positioning of prism bars manufactured by R.O. Gulden and Luneau. They urged Gulden to redesign its prism bars to be used back-to-back in front of one eye. The horizontal bar is held with its flat face posteriorly within a channel on the flat face of the vertical bar; the interface is positioned perpendicular to the direction of the fixation object, which demands that the horizontal prism bar be calibrated in the frontal plane position and the vertical bar in the Prentice position. Analysis of calibration demonstrated that Gulden's new combination horizontal/vertical prism bar can be used without significant error (within + 0.5delta of labelled values). Gulden's old vertical prism bar is also calibrated in the Prentice position. Luneau's horizontal and vertical prism bars are calibrated close to the frontal plane position (within +1.0delta and +0.4delta respectively). Improper positioning demonstrated an increasing error with larger prisms. Luneau's 25delta segment measured 27.8delta in the Prentice position, the 40delta segment 67.5delta. The 25delta segment of Gulden's new and old vertical prism bars measured 23.25delta in the frontal plane position. Gulden's vertical prism bars should always be held with the flat surface toward the examiner. Luneau's horizontal and vertical prism bars should be held one in front of each eye when used simultaneously; thus, neither eye is looking directly at the fixation object and defining primary and secondary deviations is not possible. The combination horizontal/vertical prism bar is manufactured by Gulden Ophthalmics, 225 Cadwalader Avenue, Elkins Park, PA 19117-2097. The Luneau prism bars are manufactured by Luneau Ophtalmologie, B.P. 252, 28005 Chartres Cedex, France. The authors have no proprietary or financial interest in these products or in the companies involved. PMID- 21314535 TI - Original papers: A ladder of Ryser filters in the diagnosis of strabismus. AB - The authors report a preliminary study on the usefulness of Ryser filters fixed on a pole to evaluate the degree of penalization needed to induce the imbalance of visual inputs coming through the right and the left eye. The method was tested on 87 patients, suffering from pure DVD (22 cases), esotropia associated with dvd (54 cases) and esotropia associated with dvd and dtd (II cases). The ladder, built of stratified polycarbonate, contains eight filters according to the scale 0-1.0-0.8-0.6-0.4-0.3-0.2-0.1-<0.1, and, despite the high penalizing capacity of the last filters, allows a good observation of the examined eye through the pole. PMID- 21314536 TI - Symposium Proceedings: Abstracts of papers presented at the XXI Meeting of the F.C. Donders Society for Strabismus October 1994, Utrecht, The Netherlands. PMID- 21314537 TI - Symposium Proceedings: Abstract of paper presented at the 32. Wiesbadener Tagung des BVA Wiesbaden, 18-22 November 1992. PMID- 21314538 TI - Selected abstracts. PMID- 21314539 TI - Examination, registration and analysis of clinical expressions of DVD. AB - The clinical appearance of dissociated vertical deviation (DVD) can be modified by the presence of other vertical deviations. This may be one of the reasons of relatively late diagnosis (sometimes even only after a first strabismus operation). If the DVD is not recognized preoperatively, this can lead to unexpected failure of the strabismus operation, with cosmetically unacceptable vertical deviations. The key to early diagnosis is a meticulous observation with special attention to differences in vertical deviations on right and left eye fixation in primary position and in levo- and dextroversion, using the alternating cover test. This is relatively easy and non-invasive. The authors propose a method for registration and analysis of the results. This method leads in most cases to a reliable diagnosis of the different components of the vertical deviation. The authors illustrate this method in 82 patients. In the large majority, the method presented allowed them to evaluate the respective importance of each component. Their sample illustrates convincingly the wide variety of clinical expressions of DVD. Only six patients presented a DVD without associated vertical deviations. In many cases the DVD was less important than the associated vertical deviations. This explains the difficulty of diagnosis of DVD in many cases. PMID- 21314540 TI - Original papers Binocular vision in children with unilateral traumatic aphakia. AB - Twelve consecutive children under the age of ten years who were referred to the authors' hospital between 1990 and 1993 with a combined perforating injury of the cornea and the lens were treated as follows: lensectomy, corneal suture (in 11 of them) and, shortly after surgery, correction of the refractive error with a contact lens and a bifocal glass. The other eye was occluded only if there was a manifest strabismus and if binocular single vision appeared unattainable. In nine children visual acuity was >= 20/ 40, eight children had orthotropia with binocular single vision. Compared with other reports in the literature the percentage of children with orthotropia and binocular single vision was high. The authors suggest that two factors explain the favourable results: (I) early correction of the refractive error for far and near vision and (2) restriction of occlusion therapy to cases with a manifest strabismus. PMID- 21314541 TI - The pathogenesis of Duane's syndrome A nuclear dysgenesis hypothesis. AB - The authors propose a model that provides an explanation for the ocular motility, anatomical and electromyographic features of Duane's syndrome. It is proposed that, in the human embryo, the abducens nucleus is derived from the same stem cells as the oculomotor nucleus. Duane's syndrome represents a failure of differentiation and displacement of the abducens nucleus from the oculomotor nucleus in the 21- to 26-day-old human embryo. PMID- 21314542 TI - Facilitation of vertical vergence by horizontal saccades, found in a patient with dissociated vertical deviation. AB - The authors examined vertical vergence in a 15-year-old girl with dissociated vertical deviation, a 6d' convergent strabismus, no binocular vision, latent nystagmus, and a minimal left amblyopia. Eye movements were recorded during 4s periods of (1) both eyes open, alternated with 4s-periods of (2a) right eye covered, (2b) left eye covered or (2c) both eyes closed. The patient preferred fixation with the right eye; when this eye was covered, the left eye took over fixation with an almost completely monocular, downward saccade (a horizontal saccade occurred at the same time). The right eye only made a very small saccade, and then started to drift upward with an exponentially decreasing velocity. Enright has shown that fast convergence or divergence may occur when a horizontal saccade is performed at the same time. Similarly, the authors suspected that, in their patient, vertical vergence was facilitated by the horizontal saccade that resulted, in this case of horizontal strabismus, from alternation of fixation. To examine whether this was the case, they compensated for the horizontal strabismus by placing a 30 prism-dioptre base-out prism in front of the left eye (the patient had no binocular vision). With the prism in place, the horizontal saccade that occurred when the right eye was covered was smaller, and only little vertical vergence occurred together with the horizontal saccade. It seems possible that vertical vergence is also facilitated by horizontal saccades. PMID- 21314543 TI - Symposium Proceedings Abstracts of papers presented at the Symposium (to honor Prof. Dr. Wolfgang Haase on his 60th birthday) on Visual Development and 'Update' in Strabismus. AB - Photorefractors are objective refraction devices that determine the refractive state from the size and shape of a static light reflex in the pupil of the eye. The technique may be of interest for pediatric ophthalmology, because it can be used with small children. The refraction technique requires only little cooperation. It is able to operate from an arbitrary working distance. Both eyes are measured at the same time. The following short communication describes basic working principles and the current state of development. PMID- 21314544 TI - Selected abstracts. PMID- 21314545 TI - Dissociated vertical deviation (DVD): The saccadic and slow eye movements. AB - Dissociated vertical deviation (DVD), a vertical strabismus, is often associated with infantile esotropia, latent nystagmus and excyclo-torsion. DVD usually becomes apparent at about three years of age. The authors wished to determine whether DVD is a manifestation of an abnormal motor vergence system or is part of a visual system disorder. Vertical eye movements of six subjects with DVD, on cover-uncover and alternate cover tests, were studied using the magnetic search eye coil system. Asymmetry between the eyes' saccades were quantified during the DVD upward movement and during a trial of pure vertical saccades. In three subjects the vertical deviation increased to its full amount through a smooth vertical divergence movement, and in the other three patients through a combination of smooth and asymmetrical saccade-like movements. The latencies of the DVD, the peak velocity of the deviation movements, its time constant and the asymmetries in the saccades suggest that DVD represents an abnormal vertical vergence system. PMID- 21314546 TI - Horizontal and vertical deviations after prism neutralization and diagnostic occlusion in intermittent exotropia. AB - The long-term result of surgery in intermittent exotropia is often an undercorrection and relapse into tropia. This may be due to an underestimation of the horizontal angle and/or an undetected vertical component. The aim of the present study was to test which method, prism neutralization or diagnostic occlusion was best suited to attain the maximal angle of horizontal and vertical deviation. Twenty-two patients with intermittent exotropia but without initial vertical or incomitant components participated in the study. The horizontal deviation was neutralized with prisms for periods of 14 days on four different occasions with diagnostic occlusion three times for periods of one, three or ten days in between. Measurements of sensory functions and the amount of deviations were performed before and after the procedures. It was shown that the largest horizontal deviation was elicited by prism neutralization without previous occlusion and the largest vertical deviation by diagnostic occlusion for ten days. Conditions of initial divergence excess and lateral incomitances usually were restored by both procedures. PMID- 21314547 TI - Effects of intraocular lens malposition on binocular single vision in bilaterally pseudophakic patients. AB - PURPOSE: To investigate the relationship between intraocular lens (IOL) malposition and quality of binocular single vision following uncomplicated extracapsular cataract extraction and posterior chamber IOL implantation. METHODS: Fifty-two bilaterally pseudophakic patients were included. The main outcome measures were visual acuity, stereoscopic acuity, horizontal and vertical amplitudes of fusion and heterophoria, tilting angle and decentration amount of the pseudophacos and summation of these values in somewhat vectorial manner to define the total decentration and tilt of IOLS. RESULTS: The mean total horizontal decentration was 0.19 mm and vertical decentration was 0.90 mm, mean total horizontal tilt being 1.55 degrees and vertical tilt 7.52 degrees. The mean stereoscopic acuity was found to be 1020 seconds of arc. Although the stereoscopic acuity threshold increased as decentration and tilt of IOLS increased, only the horizontal tilt was found to be statistically significantly correlated with stereoscopic acuity (pc0.01). CONCLUSION: The quality of binocular single vision may be affected by IOL malposition in pseudophakic patients. Therefore, when an IOL implantation is planned, the most appropriate IOL design and surgical technique causing least decentration and tilt should be preferred. PMID- 21314549 TI - Infant Vision Abstracts of posters presented at the 4th Meeting of the Child Vision Research Society EBBS Workshop Lyon, 11-13 July 1993. PMID- 21314548 TI - Lengthening extraocular muscle with autologous muscle transplants. AB - Increasing extraocular muscle length by regenerative growth has been proposed as a potentially useful means of treating patients with paralytic or multiple re operation strabismus. This study evaluates the viability and pattern of regeneration of fresh, autologous extraocular muscle and temporalis muscle transplants in the canine orbit. Bilateral grafts of either inferior oblique or temporalis muscle were sewn between host lateral rectus muscles and the globe. Grafts were biopsied and examined by light and electron microscopy at survival times to 56 days. Functional responses to abducens nucleus stimulation were examined in one extraocular muscle and one temporalis muscle graft at 15 weeks post-operatively. During the first week, both graft types were characterized by loss of pre-terminal nerve from neuromuscular junctions, muscle fiber necrosis that spared the central fibers, and inflammatory cell infiltrate. Myoblasts migrated into and fused within the existing basal laminae of degenerating fibers. By 14 days, grafts were populated by immature myofibers. Neuromuscular junctions were seen by 56 days, coinciding with muscle fiber differentiation as seen by enzyme histochemistry. Only two grafts failed to show regeneration. At 15 weeks survival, both types of grafts contracted in response to abducens nucleus stimulation. Free skeletal muscle grafts to extraocular muscle survive and mature with clear evidence of contractility by 15 weeks. These data suggest that muscle graft procedures could be useful in the management of certain types of strabismus where greater muscle length is needed. PMID- 21314550 TI - Diagnosis of isolated cyclovertical muscle overaction using a modification of the Parks' Three-Step Test. AB - PURPOSE: The purpose of this study is to develop and test criteria for diagnosis of an 'overacting' cyclovertical muscle using a modification of Parks' Three-Step Test. BACKGROUND: The Parks' Three-Step Test has become invaluable for isolation of a weak muscle in those strabismus cases in which there is a known paralysis. This test can yield confusing results in cases of non-paralytic vertical strabismus. The utricular induced ocular counter-rolling response combined with the premise that vertical strabismus is, in part, secondary to imbalances in vertical forces, are the physiologic bases for this test and the described modification. METHODS: A modification of the first step of the Parks' Three-Step Test was designed which isolates an 'overacting' cyclovertical muscle in the same manner as a 'paretic' muscle. Possible 'overacting' muscles are isolated in primary position, lateral gaze and right and left head tilt. Fifty patients from the author's practice with non-paralytic vertical strabismus examined from July, 1990 through June, 1991 who had complete ocular motility evaluations were included in this analysis. The modified test was used during patient evaluations to corroborate the clinical impression of a predominantly overacting cyclovertical muscle. RESULTS: The Three-Step Test modification correctly identifies a cyclovertical muscle as 'overacting' when the vertical deviation is asymmetric in horizontal gaze (step 2) and when the Bielschowsky head tilt (step 3) is asymmetric. CONCLUSIONS: This modification of the Parks' Three-Step Test assists with vertical strabismus diagnosis and can be an adjunct to surgical planning by isolating a cyclovertical muscle to weaken in order to balance vertical forces. PMID- 21314551 TI - Screening of pre-school children An epidemiological study. AB - 2482 children aged three to five years were examined by orthoptists in a screening procedure in Halle (former GDR). These screenings focused on monocular visual acuity tests with Pfluger's optotypes. 304 children were selected, apart from 100 already under ophthalmological treatment. All were invited for an examination at the University Clinic. Of 185 patients who came for an examination, 115 had findings calling for treatment. The prevalence of newly revealed squinters amounted to approximately 1 %, while the number of children with ametropias without squint was about five times higher. Administrative or legal regulations for ophthalmological preventive screening in early childhood are advocated. PMID- 21314552 TI - Surgical therapy for extreme upshoot in Duane's retraction syndrome A case presentation. AB - Up to 25% of the eyes affected with Duane's syndrome show upshoot and/or downshoot in attempted adduction. This is thought to be caused by the tight horizontal muscles both contracting in attempted adduction (leash or bridle effect) due to abnormal firing of the lateral rectus muscle through which the globe slips beneath the muscle. Surgical procedures successful in correcting the very disturbing cosmesis of gaze are posterior fixation, recession of the horizontal rectus muscles or splitting of lateral recti muscles insertion. The authors report on a 27-year-old male with Duane's syndrome type III with extreme upshoot in adduction. After recession of both horizontal muscles the upshoot on attempted adduction was no longer present postoperatively. At one year follow-up a very discrete upshoot in attempted adduction could be documented. The resolving of the upshoot postoperatively could be explained by the bridle mechanism alone. The low grade upshoot in attempted adduction at one year follow-up could have been caused by new adhesions of the check ligaments and Tenon's capsule at the level of the lateral rectus muscle resulting from surgery itself. The possibility of an anomalous cyclovertical innervation playing a role in the vertical anomalous movements as Duane originally hypothetized cannot be excluded. PMID- 21314553 TI - A case of monocular nystagmus blockage syndrome and manifest-latent nystagmus. AB - A 24-year-old man, left eye enucleated at the age of ten months, had jerk-right nystagmus with increasing amplitude in abduction and null position in near extreme adduction. Under occlusion or in darkness, the nystagmus changed to jerk left, the amplitude increased in adduction and null position was in abduction; as if his left eye had nystagmus blockage syndrome and he was seeing with this absent left eye! The difference between nystagmus blockage syndrome and latent nystagmus is discussed: nystagmus blockage syndrome is manifested by 'motor' maneuver of adduction and abduction, whereas latent nystagmus is induced with 'sensory' maneuver of occlusion. It suggests that nystagmus blockage syndrome and latent nystagmus may arise from different mechanisms despite their frequent concurrence. PMID- 21314554 TI - The Protocol for the Early vs. Late Infantile Strabismus Surgery Study. AB - The Early vs. Late Infantile Strabismus Surgery Study Group is a group of strabismologists and orthoptists who investigate whether early or late surgery is preferable in infantile strabismus, in a non-randomized, prospective, multi centre trial. Infants between 6 and 18 months of age will receive a standardized entry examination and then be operated either before their second anniversary in clinics A, or between their 32nd and 60th month of age in clinics B. The children will be evaluated at age six. After completion of the study, the two groups can then be compared regarding degree of binocular vision, angle of strabismus and visual acuity of the worse eye relative to the better. Zentrum zur methodischen Betreuung von Therapiestudien, Mrs H. Dinkel, Universitat Heidelberg, Im Neuenheimer Feld 305, W-69120 Heidelberg. 49.6221.565500. fax: 564195 Germany PD Dr. H.J. Simonsz, Orthoptics & Neuroophthalmology, Afdeling Oogheelkunde, University Hospital Dijkzigt, Dr. Molewaterplein 40, NL 3015 GD Rotterdam. 3 i. 10.4639222, ask for beeper 3394 fax: 4635105 The Netherlands PD Dr. med. G.H. Rolling, Schule fur Orthoptik, Universitats-Augenklinik, Im Neuenheimer Feld 400, W-69047 Heidelberg. 49.6221.566627/34/39 fax: 565422 Germany Dipl.-Inform. Med. U. Haag, Universitat Heidelberg, Zentrum zur methodischen Betreuung von Therapiestudien, Im Neuenheimer Feld 305, W-69120 Heidelberg. 49.6221.564192 fax: 564195 Germany Dr. A. Deak, Augenklinik, Koranyi Fasor, U-6720 Szeged. 36.62.12321/10822 fax: 22826 Hungary Mr P. Fells, F.R.C.S., F.C. Ophth., Lower Corridor Suite, Moorfields Eye Hospital, City Road, ECIV 2PD London. 44.71.2533411 fax: 2534696 (lower corridor suite) England Prof. R. Frosini, Istituto di Clinica Oculista dell' Universita di Firenze, Insegnamento di Ottica Fisiopatologica, Viale Morgagni 85,1-50134 Florence. Dr. R. Gomez de Liano, Nunez de Balboa 81, E-28006 Madrid. 34.1.5763229/72318 Spain Dr. O. Haugen, Orthoptic Department, Department of Ophthalmology, University of Bergen, N-3021 Bergen. Norway Dr. med. G. Klainguti, Clinique Ophtalmique, 15 Av. de France, CH-1004 Lausanne. 41.21.9637696/250211 Switzerland Prof.Dr. K. Krzystkowa, Ophthal. Clinic Medical Acad., 38 Copernika Str, P-31501 Krakow. 4812.223272/215210/210460/214577/220411 Poland M.C.M.E. van Lammeren, Afdeling Orthoptie, Dienst Oogziekten, U.Z. St. Rafael, Kapucijnenvoer 33, B-3000 Leuven. Prof. G. Lennerstrand, Institutionen for Oftalmiatrik, Huddinge sjukhus, S-14186 Huddinge. 46.8.7461000/3854/3418 Sweden Dr. med. H. Luka, Abt. f. Schielen, Schwachsichtigkeit und Bewegungsstorungen des Auges, Allgem. offentl. Krankenhaus der Landeshauptstadt St. Polten, A-3100 St. Polten. 43.512.85597/5040 43.2742.62521 (Klappe 2869) Dr. V. Paris, Rue de Luxembourg, 48, B-6900 Marche-en Famenne. 32.84314749 Belgium Dr. L.J.J.M. Prick-Wenniger, Afdeling Oogheelkunde, A.M.C., Meibergdreef 9, NL 1105 AZ Amsterdam. 31.20.5663881/6715637 The Netherlands Prof. M.A. Quere, 19, Rue Voltaire, F-44000 Nantes. 33.40.738370/083406 fax: 084649 France Dr. F. Reich-d'Almeida, Rua Castilho, No 65.z:Dto, P-1200 Lissabon. 351.1520619 Dr. med. R. Weidlich, Universitats Augenklinik, Leninallee 8, O-4020 Halle. 37.4684.9878/81 Germany. PMID- 21314555 TI - Abstracts of papers presented at the XVIIIth Meeting of the F.C. Donders Society for Strabismus at The Netherlands Ophthalmic Research Institute, Amsterdam, on April 1st, 1993. PMID- 21314556 TI - Selected abstracts. PMID- 21314557 TI - Squint operation under topical anesthesia in endocrine orbitopathy A 15 years' experience. AB - In the past 15 years all of our strabismus procedures in patients suffering from endocrine orbitopathy were carried out under topical anesthesia with full retention of all active motility of the globe. A total of 74 patients were operated on under such conditions with a total of 111 ocular muscles. In all instances the most affected muscle was the first to be operated on. In 52% of the patients this involved the inferior rectus muscle. Forty-five of the described patients required one operation, 21 needed two ocular muscle operations and four of the described patients needed a surgical procedure three times. In 91 % of the cases the ocular muscle surgery alone or the post-operative addition of prismatic correction led to a useful field of binocular single vision and stereopsis. A clear amount-to-effect correlation resulting from such surgery could not be established. The mechanical nature of the motility disturbance in these patients did not allow such a conclusion. PMID- 21314558 TI - Developmental adaptations in the extraocular muscles of Macaca nemestrina may reflect a predisposition to strabismus. AB - Extraoclar muscle development has been studied in two species of monkeys (Macaca nemestrina and Macaca fascicularis). In these studies, the authors have demonstrated a distinctive developmental difference between the two macaques. Specifically, tubular aggregates (ordered aggregations of sarcoplasmic reticulum) occur transiently in the orbital singly innervated muscle fiber type in nemestrina extraocular muscles only. Tubular aggregates are typically seen in skeletal muscle fast-twitch fibers during neuromuscular disease or experimental denervation. The alterations in developing extraocular muscle either may be indicative of a primary muscle disorder or may be secondary to neurologic maldevelopment. The authors suggest that the presence of tubular aggregates in the extraocular muscles of nemestrina monkeys may be indicative of aberrant innervation levels during early postnatal development. PMID- 21314559 TI - Botulinum toxin as a tool for testing the risk of postoperative diplopia. AB - If preoperative examinations indicate postoperative diplopia, we generally would dissuade a patient from a squint operation. In this situation, a reliable test for diplopia can be done by injection of Botulinum toxin into an eye-muscle. Thus a predominantly transient paresis is produced during which there is parallelism for a sufficient period of time, so that the patient has time enough to experience disturbing double vision or its absence. In all 31 patients of this study a clear decision for or against an operation was possible, only in three cases was an operation contraindicated. PMID- 21314560 TI - Endoscopically controlled surgical decompression of the orbit in malignant ophthalmopathy. AB - From May 1988, an endoscopically controlled endonasal orbital decompression was performed in 17 patients with malignant ophthalmopathy. Indications were exclusively acute loss of visual acuity or visual field defects, when medical and radiation therapy had failed. The new minimal invasive technique proceeds in three steps. First, an endonasal, endoscopically controlled ethmoidectomy with resection of the middle turbinate is done and the medial wall of the maxillary sinus is widely opened. Second, the medial and inferior orbital walls are removed, preserving the infraorbital nerve. In the last step, the periorbita is incised and the orbital fat herniates. The advantages of this procedure consist of the absence of exterior scars, the avoidance of lacrimal duct stenosis and bony defects in the maxilla and the prevention of the known morbidity of a Caldwell-Luc antrotomy with hypesthesia, dysesthesia and oro-antral fistula. The results were documented by computerized tomographic scans (CT), magnetic resonance imaging (MRI), Hertel measurements, evaluation of ocular motility and ophthalmoscopy. All patients had a postoperative improvement of visual acuity. An average of 3-4 mm improvement in Hertel measurements was reached. Four patients who had a diplopia before the interventions developed a more significant diplopia postoperatively, whereas in all other patients ocular motility either improved (five patients) or remained the same. In conclusion, the endoscopically controlled endonasal procedure enables greater preservation of normal structures and provides results comparable with the common extranasal and transantral procedures without the disadvantages of the latter. PMID- 21314561 TI - Muscle belting An alternative operative procedure for posterior fixation suture. AB - In posterior rectus belting, a modification of Cuppers' Fadenoperation (posterior fixation suture), a piece of silicone rubber is placed across the medial recti muscles and fixed to the sclera 12 mm behind the insertion. Performed as the only procedure, posterior belting was shown to be effective in 43 patients with excess esotropia at near fixation when bifocals were insufficient. Subsequent reoperations (should they become necessary) are both easier and quicker to perform than when following the standard posterior fixation suture. Secondary recess or resect surgery can be done while leaving the belts in place. B-mode ultrasonographic examination was used to demonstrate differences in anatomical outcome between the two techniques. PMID- 21314562 TI - Infant Vision Abstracts of papers presented at the 4th Meeting of the Child Vision Research Society EBBS Workshop Lyon, 11-13 July 1993. PMID- 21314563 TI - Selected abstracts. PMID- 21314565 TI - The right lateral position for laparoscopic diaphragmatic hernia repair in pregnancy: technique and review of the literature. AB - Maternal diaphragmatic hernia is a rare disorder of pregnancy. Laparoscopic repair of diaphragmatic hernias is gaining more and more consideration among the surgical community. To date, only a few centers have reported using the laparoscopic approach for diaphragmatic hernias occurring in pregnancy. As congenital diaphragmatic hernias occur mostly on the left side, a right lateral position would theoretically facilitate the surgery and would render an eventual simultaneous left thoracoscopy feasible without repositioning the patient. However, such a position in a pregnant woman has serious implications because of possible inferior vena cava compression by the gravid uterus. We performed a laparoscopic reduction and repair of a left foramen of Bochdalek hernia in a 26 week-pregnant patient, using a right lateral position. The right lateral position facilitated the procedure, without any adverse outcome for the fetus or the mother. This approach should be considered for any left diaphragmatic hernia repair occurring in pregnancy. PMID- 21314566 TI - Early and late outcomes of primary laparoscopic endorectal colon pull-through leaving a short rectal seromuscular sleeve for Hirschsprung disease. AB - AIM: The aim of this study was to report early and late outcomes of primary laparoscopic-assisted endorectal colon pull-through leaving a short seromuscular sleeve for Hirschsprung disease (HD) in the newborn. METHODS: Laparoscopic endorectal colon pull-through was performed by using four ports. CO(2) insuffaltion pressure was around 8-10 mm Hg. The ganglionic and aganglionic segments were initially identified by seromuscular biopsies obtained laparoscopically. The rest of the procedure was carried out according to Georgeson's technique. However, we left a short rectal seromuscular sleeve of 1.5 2 cm above the dentate line. RESULTS: From January 2003 to August 2009, 47 patients were operated upon by the same surgeon. Ages ranged from 3 to 30 days. The aganglionic segment was located in the rectum in 31 patients, in the sigmoid colon in 15 children, and in the left colon in 1 patient. The median operating time was 124 minutes. There were no perioperative deaths. There was no conversion to open surgery. There was minimal blood loss during surgery. Oral intakes of clear fluid were started 12 hours after surgery and advanced to formula on the second day. The mean hospital stay was 5.1 days (range, 4-8). Follow-up, ranging from 4 to 72 months, was obtained in 42 patients. Thirty patients (71.4%) had 1-2 defecations/day, 10 (23.8%) had 3-4 defecations/day, and 1 (2.4%) had more than 4 defecations/day. Constipation occurred in 1 patient (2.4%) and enterocolitis in 1 patient (2.4%). No patient had anastomotic fistula. Intermittent urinary did not occur in any patient. Erectile function, evaluated by infant's parents, was presented in all 34 males who were followed up. CONCLUSIONS: Primary laparoscopic assisted endorectal colon pull-through leaving a short rectal seromuscular sleeve is a safe, effective procedure for HD in the newborn. PMID- 21314567 TI - The transaxillary, totally endoscopic approach for head and neck endocrine surgery in children. AB - PURPOSE: The purpose of this study was to assess the safety, efficacy, and learning curve for transaxillary, totally endoscopic (TATE) head and neck endocrine surgery in children. MATERIALS AND METHODS: Between June 2005 and October 2009, 31 children with head and neck endocrine problems were subjected to the TATE approach. Safety, efficacy, complications, and time of operation were assessed. DATA: Thirty-one children (mean age, 12.7 years; F:M, 5:1) underwent a TATE approach. Glands ranged in size from 10 g (in a small 5-year-old) to 63 g (in one 16-year-old). No cervical incisions were required and there were no conversions to open surgery. Three patients in our early experience underwent a robot-assisted procedure. Two patients suffered from hyperparathyroidism and had adenomas removed, using rapid PTH in the operating room to confirm immediate success. Of the remaining 29 children, 2 girls had an adenoma of the right thyroid lobe removed uneventfully, and the reminder all had Graves disease, which was treated successfully. Complications included transient hypocalcemia in 3 patients who were also on steroids for unrelated medical problems; transient neuropraxia in 3 patients with very large glands; 1 postoperative, lateral, subcutaneous hematoma that resolved uneventfully; and 1 asthmatic with a spontaneous apical pneumothorax that presented as subcutaneous gas in the neck, 6 hours after the surgery and which resolved with chest tube placement. Average operative time for the first 10 patients was 288 minutes and for the subsequent patients was 155 minutes (range, 92-210 minutes). CONCLUSIONS: The TATE approach appears to be as safe and effective as open surgery for cervical endocrinopathies in children. Only transient, minor complications were observed. Operative time significantly decreases with experience, making the length of surgery comparable to its open counterpart. PMID- 21314569 TI - Hospice care, medical torture, and Blockbuster video. PMID- 21314570 TI - Managing hemorrhages in patients with head and neck carcinomas: a descriptive study of six years of admissions to an internal medicine/palliative care unit. PMID- 21314571 TI - Analysis of the nurses' and physicians' opinion regarding their end-of-life education. PMID- 21314572 TI - Words matter: the importance of the language we use. PMID- 21314573 TI - What Africa has to teach the United States about hospice and palliative care. PMID- 21314574 TI - Variation between end-of-life health care costs in Los Angeles and San Diego: why are they so different? AB - CONTEXT: Small area differences in health care use between Boston, Massachusetts, and New Haven, Connecticut, are well known. However, we do not know whether factors believed to account for these variations explain differences between other geographic areas. OBJECTIVE: To explore differences in health care use between the California counties of Los Angeles (LA) and San Diego. METHOD: Medicare data were obtained form the Dartmouth interactive website. In addition, hospital-level data were obtained for the California Office of Statewide Health Planning and Development (OSPHD). Health outcomes and self-reported disease prevalence were estimated from the California Health Interview Survey (CHIS). RESULTS: Physician supply was comparable between LA and San Diego. Fees per unit service were also equivalent. Hospital beds beds per 10,000 population were 35% higher in LA. Intensity of service use, particularly during the last 2 years of life, was significantly higher in LA, and costs were dramatically higher. Most of the differences were explained by discretionary hospital admissions, end-of-life care, and lower use of hospice care. Quality indicators favor San Diego. CONCLUSIONS: Medical care, particularly at the end of life, is significantly more expensive in LA than in San Diego, yet quality measures tend to favor in San Diego. Non-emergent hospital admissions and inpatient care at the end of life are important contributors to the cost differences. There is little reason to believe that the greater spending for health care in LA results in better patient outcomes. PMID- 21314575 TI - "Knowing" your learners and providing feedback. PMID- 21314576 TI - Giving feedback. AB - BACKGROUND: Giving feedback is a core element of medical education, one that is gaining attention but with a thin evidence base to guide medical educators. This review provides a definition of feedback and its purpose, selectively reviews the literature regarding educators' and learners' attitudes toward feedback, and provides an algorithm for giving feedback. DISCUSSION: The authors discuss the parallels between giving feedback and breaking bad news, emphasizing the importance of titrating the amount of information given, attending to affect, and making a plan for next steps. Special considerations for giving feedback in palliative care are highlighted, including the effect of heightened emotion in the clinical encounter and the difficulties of giving feedback about communication skills. PMID- 21314577 TI - The National POLST Paradigm Initiative, 2nd Edition #178. PMID- 21314578 TI - Prognosis of anoxic-ischemic encephalopathy #234. PMID- 21314579 TI - How palliative care transformed my perspective of medicine. PMID- 21314580 TI - An open casket. PMID- 21314581 TI - Bearing the unbearable. PMID- 21314583 TI - Intractable malignant ascites: an alternative management option. AB - BACKGROUND: Recurrent malignant ascites is a common management problem in oncology and palliative care. DISCUSSION: Here, we describe a case of malignant ascites managed by insertion of a Tenckhoff Catheter (TC), which resulted in successful symptomatic control and improvement in quality of life. PMID- 21314588 TI - Effect of needle type and injection technique on pain level and vitreal reflux in intravitreal injection. AB - PURPOSE: To evaluate the amount of reflux and degree of pain with intravitreal injection (IVT) using 6 different types of syringes/needles and 5 techniques of scleral incision, including 3 modifications of a beveled scleral incision. METHODS: This was a study conducted in 205 eyes of 205 patients. IVT of bevacizumab for retinal pharmacotherapy with 6 types of needles and 5 techniques of scleral incision. The severity of subjectively evaluated pain (0-10) and the width of the subconjunctival bleb arising from the vitreal reflux. Secondary outcomes were increase in intraocular pressure and complication rate. RESULTS: The straight technique caused greater vitreal reflux than the beveled approaches, when compared individually or as a group (P < 0.01). No difference in the severity of pain was found among all 5 types of incisions (P > 0.05). There was greater reflux with 26- and 27-gauge needles in comparison to 29- and 30-gauge needles (P < 0.001); however, the width of the needle significantly affected the degree of reflux only when using the nonbeveled incision (P < 0.001). The patients injected with the 26- or 27-gauge needle experienced more pain matched to the 29- and 30-gauge needles (P < 0.001). No difference was found between the incision technique or width of subconjunctival reflux and the increase in intraocular pressure (P > 0.05). Postinjection events included transient mild uveitis, disease-related vitreous hemorrhage, foreign body sensation, conjunctival hemorrhage, and mild punctuate keratitis. CONCLUSIONS: The beveled scleral incision showed benefit in performing IVTs. The 29- and 30-gauge needles caused less pain. PMID- 21314589 TI - Surgeon opinion on new technologies in orthopaedic surgery. AB - Technological advances such as computer navigation systems and robotics, including support systems for minimally invasive surgery, have the potential to revolutionise how orthopaedic surgery is carried out. However uptake has so far been limited. Increased awareness of user requirements in adoption decision making will be useful. In this regard, the opinion of the individual surgeon regarding his or her willingness to engage in a novel technology has rarely been garnished. This paper analyses the opinions of orthopaedic consultants from the UK and USA about technological advances in hip and knee arthroplasty, factors contributing to successful short-term and long-term surgical outcome, and patient preferences. The survey, using a web-based questionnaire, was carried out in 2006 2007 and followed up in 2010. The results of this research give a greater insight into why surgical technologies that have the potential to improve patient outcome are not more speedily adopted in the health service. PMID- 21314591 TI - Implementation of systematic instruction to increase client engagement in a day habilitation program. AB - BACKGROUND: Individuals with severe disability exiting school are likely to be enrolled in day activity and sheltered workshops at least as often as in supported employment. Such facilities are often staffed by paraprofessionals who may not have the skills to engage clients in meaningful activities. This article describes a 3-phase staff training project designed to increase client engagement in an adult habilitation centre. METHOD: The first phase of the project was to develop curriculum guidelines. The second phase was conducting a series of training for paraprofessional staff. And the third was the implementation of the clinical experience. The first author conducted a graduate level methods class on site at the adult habilitation centre. Staff participants (paraprofessional staff, supervisors, and graduate students) learned the components of systematic instruction and developed and implemented activities for clients. Engagement was measured before and after the 5-week clinical experience. RESULTS AND CONCLUSIONS: The engagement of clients increased with the implementation of systematic instruction following staff training. The implications are discussed. PMID- 21314592 TI - Inclusion in political and public life: the experiences of people with intellectual disability on government disability advisory bodies in Australia. AB - BACKGROUND: Civil and political participation lies at the core of citizenship. Increasingly, people with intellectual disability are members of disability advisory bodies. This study investigated the political orientations of advisory body members with intellectual disability, their participatory experiences, and the types of support they received. METHOD: The 9 people with intellectual disability who in 2005 were members of disability advisory bodies at a state, national, and Victorian local government level were interviewed, together with 12 other members or secretariat staff of these bodies. Observations were also conducted of advisory body meetings. RESULTS: The political perspective of members with intellectual disability varied, but all had a background in self advocacy. They found the work hard but rewarding and encountered both practical and intangible obstacles to participation. Members received varying types of practical support, but a supportive collegial milieu was characteristic among members who felt most confident about their participation. CONCLUSIONS: The milieu, structures, and processes of advisory bodies must all be adjusted to accommodate people with intellectual disability if they are to participate meaningfully. PMID- 21314593 TI - Ageing and health status in adults with intellectual disabilities: results of the European POMONA II study. AB - BACKGROUND: POMONA II was a European Commission public health-funded project. The research questions in this article focus on age-specific differences relating to environmental and lifestyle factors, and the 17 medical conditions measured by the POMONA Checklist of Health Indicators (P15). METHOD: The P15 was completed in a cross-sectional design for a stratified sample of 1,253 adults with ID across 14 European member states. RESULTS: Older people (55+) were more likely to live in larger residential homes. Rates of smoking and use of alcohol were lower than in the general population but were higher with older age. More than 60% of older adults had a sedentary lifestyle. Cataract, hearing disorder, diabetes, hypertension, osteoarthritis/arthrosis, and osteoporosis were positively associated with advancing age; allergies and epilepsy, negatively associated. CONCLUSIONS: Some evidence of health disparities was found for older people with ID, particularly in terms of underdiagnosed or inadequately managed preventable health conditions. PMID- 21314594 TI - Meta-analysis of deinstitutionalization adaptive behaviour outcomes: research and clinical implications. AB - BACKGROUND: A meta-analysis examined the effects of deinstitutionalisation on adaptive behaviour outcomes in persons with intellectual disability. The need for an updated review in this area is reflected by recent policy shifts in community care practices and the international status of deinstitutionalisation efforts. METHOD: Twenty-three studies were compared using standardised mean effect sizes across 5 demographic, 4 methodological, and 1 outcome variable. RESULTS: Moderate habilitative gains were found in 75% of adaptive behaviour domains. A weighted linear multiple regression revealed that larger effect sizes were significantly predicted by sample size and research design. Disability level also moderated the extent to which sample size affected the magnitude of effect sizes. CONCLUSIONS: These results are discussed in relation to the implications they have for community services for persons with intellectual disability. The difficulties in accurately comparing studies with dissimilar procedures and contexts are also outlined. PMID- 21314595 TI - Health status, social support, and quality of life among family carers of adults with profound intellectual and multiple disabilities (PIMD) in Taiwan. AB - BACKGROUND: Primary family carers of adults with profound intellectual and multiple disabilities (PIMD) experience a range of considerable demands. METHOD: A census survey was conducted in a city of Taiwan; 796 family carers of adults (aged 18 or older) diagnosed with intellectual disability and/or with multiple disabilities living with the family completed interviews. RESULTS: Adults with PIMD made up 9.5% of this group (n = 76). Nonparametric analyses showed that health status, formal social support, and quality of life (QoL; physical domain score) of carers of adults with PIMD were significantly lower than their counterparts (i.e., carers of adults with less severe disability), and that these variables were significantly associated with carer educational level, employment status, family income, and social networks. CONCLUSIONS: Interventions need to include the creation of a supportive environment for adults with PIMD and their lifelong family carers, particularly those who are more socially disadvantaged. PMID- 21314597 TI - Transcription factories and spatial organization of eukaryotic genomes. AB - The phenomenon of association of transcribed genes into so-called transcription factories and also the role of these associations in spatial organization of the eukaryotic genome are actively discussed in the modern literature. Some authors think that the association of transcribed genes into transcription factories constitutes a major factor supporting the function-dependent three-dimensional organization of the interphase genome. In spite of the obvious interest in the problem of spatial organization of transcription in the eukaryotic cell nucleus, the number of experimental studies of transcriptional factories remains rather limited and the results of these studies are often contradictory. In the current review we have tried to critically re-evaluate the published experimental results that constitute the basis for current models and also the models themselves. We have especially analyzed the existing contradictions and attempted to explain them whenever possible. We also discuss new models that can explain the biological significance of clustering of transcribed genes and show possible mechanisms of the origin of transcription factories in the course of evolution. PMID- 21314598 TI - A-to-I RNA editing: a contribution to diversity of the transcriptome and an organism's development. AB - The complexity of multicellular organisms requires both an increase in genetic information and fine tuning in regulation of gene expression. One of the mechanisms responsible for these functions is RNA editing. RNA editing is a complex process affecting the mechanism of changes in transcriptome sequences. The best studied example of this process is A-to-I RNA editing. On the organism's level, RNA editing plays a key role during ontogenesis and in the defense against pathogens. Disorders in A-to-I RNA editing lead to serious abnormalities. The importance of RNA editing increases with an increase in the organism's complexity. Correct RNA editing is an indispensable factor of an organism's development and probably determines the lifespan of higher eukaryotes. PMID- 21314599 TI - Study of alpha-crystallin structure by small angle neutron scattering with contrast variation. AB - The structure of the oligomeric protein alpha-crystallin from bovine eye lens was investigated by small-angle neutron scattering (SANS) with contrast variation. Based on the SANS curves, the match point for alpha-crystallin (43% D2O) and its average scattering length density at this point (2.4.10(10) cm(-2)) were evaluated. The radius of gyration and the distance distribution functions for alpha-crystallin were calculated. On the basis of these calculations, it was concluded that alpha-crystallin is characterized by homogeneous distribution of scattering density in the domains inaccessible for water penetration, and all polypeptide subunits in alpha-crystallin oligomers undergo equal deuteration. The latter indicates that all alpha-crystallin subunits are equally accessible for water and presumably for some other low molecular weight substances. These conclusions on the alpha-crystallin structure (homogeneous distribution of scattering density and equal accessibility of all subunits for low molecular weight substances) should be taken into account when elaborating alpha-crystallin quaternary structure models. PMID- 21314600 TI - Influence of distamycin, chromomycin, and UV-irradiation on extraction of histone H1 from rat liver nuclei by polyglutamic acid. AB - Rat liver nucleus histone H1 was fractionated by polyglutamic acid (PG) in the presence of distamycin A (DM) or chromomycin A(3) (CM). In the absence of the antibiotics, PG extracts from the nuclei about half of the nuclear H1. DM or CM added to the nuclei in saturating concentrations weakens the binding potential of most of H1. Titration of nuclei with DM shows that the number of binding sites for DM in the nuclei is less than in isolated DNA by only 20-25%, and this difference disappears after treatment of nuclei with PG. The lower CD value of DM complexes with nuclei compared to that of DM complexes with free DNA is evidence of a change in the DM-DNA binding mode in nuclear chromatin. About 25% of total histone H1 is sensitive only to DM and ~5% is sensitive only to CM. Half of the DM-sensitive H1 fraction seems to have a different binding mode in condensed compared relaxed chromatin. A small part of H1 (~3%) remains tightly bound to the nuclear chromatin independent of the presence of the antibiotics. Subfraction H1A is more DM-sensitive and H1B is more CM-sensitive. UV irradiation of nuclei results in dose-dependent cross-linking of up to 50% of total H1, which is neither acid-extractable nor recovered during SDS electrophoresis. PG with DM extracts only about 3% of H1 from UV-stabilized chromatin. DM treatment of the nuclei before UV irradiation results in extraction of the whole DM-sensitive H1 fraction (~25%), which in this case is not stabilized in the nucleus. A hypothesis on possible roles of the found H1 fractions in chromatin structural organization is discussed. PMID- 21314601 TI - Change in phospholipid composition and phospholipase activity of the fungus Lentinus tigrinus VKM F-3616D during growth in the presence of phenol and lignocellulosic substrates. AB - Changes in phospholipid composition, phospholipase activity, and accumulation of lipid peroxidation products in mycelium of the lignin-degrading fungus Lentinus (Panus) tigrinus VKM F-3616D in the presence of phenol and lignocellulosic substrates in the cultivation medium are reported. It is shown that in fungal mycelium in the presence of both substrates the share of lysophosphatidylcholine sharply increases. The parity between separate groups of phosphatidylinositols also changes. The lysophosphatidylcholine content increase during cultivation is connected with activation of phospholipase A(2) (EC 3.1.1.4), and phosphatidylinositol parity change is associated with distinctions in affinity of phosphoinositide-specific phospholipase C (EC 3.1.4.11) to them. PMID- 21314602 TI - Catalase activity of cytochrome C oxidase assayed with hydrogen peroxide sensitive electrode microsensor. AB - An iron-hexacyanide-covered microelectrode sensor has been used to continuously monitor the kinetics of hydrogen peroxide decomposition catalyzed by oxidized cytochrome oxidase. At cytochrome oxidase concentration ~1 uM, the catalase activity behaves as a first order process with respect to peroxide at concentrations up to ~300-400 uM and is fully blocked by heat inactivation of the enzyme. The catalase (or, rather, pseudocatalase) activity of bovine cytochrome oxidase is characterized by a second order rate constant of ~2.10(2) M(-1).sec( 1) at pH 7.0 and room temperature, which, when divided by the number of H2O2 molecules disappearing in one catalytic turnover (between 2 and 3), agrees reasonably well with the second order rate constant for H2O2-dependent conversion of the oxidase intermediate F(I)-607 to F(II)-580. Accordingly, the catalase activity of bovine oxidase may be explained by H2O2 procession in the oxygen reducing center of the enzyme yielding superoxide radicals. Much higher specific rates of H2O2 decomposition are observed with preparations of the bacterial cytochrome c oxidase from Rhodobacter sphaeroides. The observed second order rate constants (up to ~3000 M(-1).sec(-1)) exceed the rate constant of peroxide binding with the oxygen-reducing center of the oxidized enzyme (~500 M(-1).sec( 1)) several-fold and therefore cannot be explained by catalytic reaction in the a(3)/Cu(B) site of the enzyme. It is proposed that in the bacterial oxidase, H2O2 can be decomposed by reacting with the adventitious transition metal ions bound by the polyhistidine-tag present in the enzyme, or by virtue of reaction with the tightly-bound Mn2+, which in the bacterial enzyme substitutes for Mg2+ present in the mitochondrial oxidase. PMID- 21314603 TI - Study of interaction of ceruloplasmin with serprocidins. AB - This paper describes formation of complexes of ceruloplasmin (CP) with such proteins of the serprocidin family as azurocidin (CAP37), neutrophilic elastase (NE), cathepsin G (CG), and proteinase 3 (PR3). We present evidence that serprocidins form complexes with CP at a molar ratio 1 : 1. Phenylmethylsulfonyl fluoride, a serine protease inhibitor, did not prevent the interaction of serprocidins with CP in the course of SDS-free disc electrophoresis. CP affected the activities of NE, CG, and PR3 as a competitive inhibitor with K(i) ~ 1 MUM. Inhibitory effect of CP depended on ionic strength of the solution and was negligible at NaCl concentrations above 300 mM. In the mode of competitive inhibitors serprocidins suppressed oxidase activity of CP towards p phenylenediamine. CAP37 displayed the strongest inhibitory effect (K(i) ~ 20 nM). Upon adding various serprocidins to human, rat, rabbit, dolphin, dog, horse, and mouse plasma only CAP37 would form a complex with CP. Synthetic peptide RKARPRQFPRRR (5-13, 61-63 CAP37) displaced CAP37 from its complex with CP. Adding CAP37 to the triple complex formed by CP, lactoferrin, and myeloperoxidase resulted in displacement of the latter from the complex. The dissociation constant of CAP37 with immobilized CP was 13 nM. Therefore, among serprocidins CAP37 can be regarded as the specific partner of CP. PMID- 21314604 TI - Inhibition of cyclooxygenase activity of prostaglandin-H-synthase by excess substrate (molecular oxygen). AB - For the cyclooxygenase reaction of prostaglandin-H-synthase isolated from ram vesicular glands, dependences of the initial reaction rate, the maximal yield of the product, and the rate constant of enzyme inactivation in the course of reaction on oxygen concentration were studied in the absence and in the presence of electron donor in the reaction medium. It is shown that in the absence of electron donor the cyclooxygenase reaction is strictly governed by Michaelis Menten kinetics over a wide range of oxygen concentrations (5-800 uM). In the presence of electron donor in the reaction medium it was found that cyclooxygenase reaction is inhibited by an excess of dissolved oxygen: the maximal values of the initial reaction rate and yield of the product are attained at oxygen concentration 50 uM, and its increase to 500 uM causes twofold decrease in the initial rate and maximal yield. The rate constant of enzyme inactivation in the course of reaction increases on increase in oxygen concentration both in the presence and in the absence of electron donor. PMID- 21314605 TI - The quasi-equilibrium assumption for Bi-Bi ordered bisubstrate enzymatic reaction. How to discriminate the mechanism correctly. AB - Application of the quasi-equilibrium assumption for the steady-state kinetics of bisubstrate irreversible enzymatic reactions in the case of ordered binding of substrates (Bi-Bi ordered mechanism) is considered. The necessary and sufficient conditions for application of the quasi-equilibrium assumption have been found and accuracy of this assumption has been numerically evaluated. The limitations on application of the quasi-equilibrium assumption have been shown and errors of its application have been analyzed. It is shown that possible discrimination of substrate binding order using asymmetrical expressions grounded on the quasi equilibrium assumption is inconsistent because such asymmetrical expressions arise from incorrect application of the quasi-equilibrium assumption. Moreover, it has been proved in the general case that mechanisms generating such substrate asymmetrical expressions for the steady-state rate of enzymatic reaction do not exist. The error source when using graphical interpretation for discrimination of mechanisms of bisubstrate enzymatic reactions has been determined. The strategy to avoid such errors is pointed out. PMID- 21314606 TI - Effect of plastoquinone derivative 10-(6' plastoquinonyl)decyltriphenylphosphonium (SkQ1) on contents of steroid hormones and NO level in rats. AB - Introduction of the plastoquinone derivative 10-(6' plastoquinonyl)decyltriphenylphosphonium (SkQ1) into male Wistar rats once a day for two weeks in doses of 25 and 250 nmol/kg led to elevation of 17beta-estradiol level in blood serum by 33 and 41%, respectively. At the same time, nitrate and nitrite contents in the rat blood serum increased by 49 and 34%, respectively. ESR spectroscopy with diethyldithiocarbamate?iron complex as a spin trap showed more than twofold increase in NO production in lungs, but not in blood, liver, and intestines, following the SkQ1 daily introduction at a dose of 25 nmol/kg. PMID- 21314607 TI - Evidence that highly conserved residues of Delonix regia trypsin inhibitor are important for activity. AB - Delonix regia trypsin inhibitor (DrTI) consists of a single-polypeptide chain with a molecular mass of 22 kDa and containing two disulfide bonds (Cys44-Cys89 and Cys139-Cys149). Sequence comparison with other plant trypsin inhibitors of the Kunitz family reveals that DrTI contains a negatively charged residue (Glu68) at the reactive site rather than the conserved Arg or Lys found in other Kunitz type trypsin inhibitors. Site-directed mutagenesis yielded five mutants containing substitutions at the reactive site and at one of the disulfide bonds. Assay of the recombinant proteins showed mutant Glu68Leu and Glu68Lys to have only 4-5% of the wild-type activity. These provide evidence that the Glu68 residue is the reactive site for DrTI and various other Kunitz-type trypsin inhibitors. The Cys139Gly mutant lost its inhibitory activity, whereas the Cys44Gly mutant did not, indicating that the second disulfide bond (Cys139 Cys149) is critical to DrTI inhibitory activity, while the first disulfide bond (Cys44-Cys89) is not required. PMID- 21314608 TI - Interaction of plum pox virus with specific colloidal gold-labeled antibodies and development of immunochromatographic assay of the virus. AB - Two monoclonal antibodies (mABs) raised against plum pox virus (PPV) were shown to recognize its D, M, and C strains. Conjugates of the antibodies with colloidal gold (CG) nanoparticles averaging 26 nm in diameter were synthesized. The binding constants of PPV with both the native and conjugated mABs were determined using a Biacore X device. The complexes between the CG-mAB conjugates and plum pox virions were examined by means of transmission electron and atomic force microscopy. Using the conjugates with optimal component ratio, an express immunochromatographic assay of PPV was developed with a detection limit of 3 ng/ml and duration of 10 min. The assay was tested for PPV detection in samples of stone fruit tree leaves and demonstrated a good compatibility with the data obtained by "sandwich"-ELISA. The developed assay can be used in the field and applied for monitoring viral infection and for quarantine purposes. PMID- 21314609 TI - Properties of partially purified endopolyphosphatase of the yeast Saccharomyces cerevisiae. AB - Partially purified endopolyphosphatase from cytosol of the yeast Saccharomyces cerevisiae with inactivated genes PPX1 and PPN1 encoding exopolyphosphatases was obtained with ion-exchange and affinity chromatography. The enzyme activity was estimated by decrease of polyphosphate chain length determined by PAGE. The enzyme cleaved inorganic polyphosphate without the release of orthophosphate (P(i)) and was inhibited by heparin and insensitive to fluoride. Mg2+, Mn2+, and Co2+ (1.5 mM) stimulated the activity, and Ca2+ was ineffective. The molecular mass of the endopolyphosphatase determined by gel filtration was of ~20 kDa. PMID- 21314610 TI - Seasonal changes in microsomal fraction enriched with Na,K-ATPase from kidneys of the ground squirrel Spermophilus undulatus. AB - The Na,K-ATPase activity in microsomal fraction isolated from kidneys of winter hibernating ground squirrels was found to be 1.8-2.0-fold lower than that in active animals in summer. This is partially connected with a decrease in Na,K ATPase protein content in these preparations (by 25%). Using antibodies to different isoforms of Na,K-ATPase alpha-subunit and analysis of enzyme inhibition by ouabain, it was found that the decrease in Na,K-ATPase activity during hibernation is not connected with change in isoenzyme composition. Seasonal changes of Na,K-ATPase alpha-subunit phosphorylation level by endogenous protein kinases were not found. Proteins which could be potential regulators of Na,K ATPase activity were not found among phosphorylated proteins of the microsomes. Analysis of the composition and properties of the lipid phase of microsomes showed that the total level of unsaturation of fatty acids and the lipid/protein ratio are not changed significantly during hibernation, whereas the cholesterol content in preparations from kidneys of hibernating ground squirrels is approximately twice higher than that in preparations from kidneys of active animals. However, using spin and fluorescent probes it was shown that this difference in cholesterol content does not affect the integral membrane microviscosity of microsomes. Using the cross-linking agent cupric phenanthroline, it was shown that Na,K-ATPase in membranes of microsomes from kidneys of hibernating ground squirrels is present in more aggregated state in comparison with membranes of microsomes from kidneys of active animals. We suggest that the decrease in Na,K-ATPase activity in kidneys of ground squirrels during hibernation is mainly connected with the aggregation of proteins in plasma membrane. PMID- 21314611 TI - Estrogen receptors, antiestrogens, and non-small cell lung cancer. AB - This review considers data on expression of different types of estrogen receptors (ERalpha and ERbeta) in in vitro cultured cells of non-small cell lung cancer and also in human and animal lung tumors. Estrogens are shown to play an important role in genesis and development of non-small cell lung cancer because the estrogen-stimulated cell proliferation as well as antiestrogen-caused inhibition of proliferation occurred only in the cells expressing different types of estrogen receptors. In general, the situation is similar to that observed in breast cancer, but in the cells of non-small cell lung cancer not ERalpha are expressed in more than half of cases but ERbeta. Just estrogen receptors beta play the crucial role in inducing cell proliferation in response to estrogens, and ERbeta is a prognostic marker of a favorable course of non-small cell lung cancer. Data on the interactions between ER and EGFR signaling pathways, as well as on the additive antitumor effect of antiestrogens (tamoxifen and fulvestrant) combined with tyrosine kinase inhibitors (gefitinib, erlotinib, and vandetanib) are considered. The review also includes data on the influence of estrogens on genesis and development of lung cancer in humans and animals and the frequency of ERalpha and ERbeta expression in non-small cell lung cancer in tissues from patients of the two sexes. Problems of quantitative determination of alpha and beta estrogen receptors in the tumor cells are also discussed. PMID- 21314612 TI - The Wnt/Frizzled GPCR signaling pathway. AB - G protein-coupled receptors (GPCRs) represent the biggest transmembrane receptor family. The Frizzled group of GPCRs is evolutionarily conserved and serves to transduce signals from the Wnt-type lipoglycoprotein growth factors. The Wnt/Frizzled signaling cascades are repeatedly used during animal development and are mostly silent in the adult. Improper activation of these cascades, e.g. through somatic mutation, underlies cancer development in various tissues. Our research over the past years has identified the trimeric G proteins as crucial transducers of the Wnt/Frizzled cascades in insect and mammalian cells. The current mini-review summarizes our findings on the role of G proteins in Wnt/Frizzled signaling, as well as on identification of other signaling intermediates in this physiologically and pathologically important type of intracellular signal transduction. PMID- 21314613 TI - Cloning and characterization of indolepyruvate decarboxylase from Methylobacterium extorquens AM1. AB - For the first time for methylotrophic bacteria an enzyme of phytohormone indole-3 acetic acid (IAA) biosynthesis, indole-3-pyruvate decarboxylase (EC 4.1.1.74), has been found. An open reading frame (ORF) was identified in the genome of facultative methylotroph Methylobacterium extorquens AM1 using BLAST. This ORF encodes thiamine diphosphate-dependent 2-keto acid decarboxylase and has similarity with indole-3-pyruvate decarboxylases, which are key enzymes of IAA biosynthesis. The ORF of the gene, named ipdC, was cloned into overexpression vector pET-22b(+). Recombinant enzyme IpdC was purified from Escherichia coli BL21(DE3) and characterized. The enzyme showed the highest k(cat) value for benzoylformate, albeit the indolepyruvate was decarboxylated with the highest catalytic efficiency (k(cat)/K(m)). The molecular mass of the holoenzyme determined using gel-permeation chromatography corresponds to a 245-kDa homotetramer. An ipdC-knockout mutant of M. extorquens grown in the presence of tryptophan had decreased IAA level (46% of wild type strain). Complementation of the mutation resulted in 6.3-fold increase of IAA concentration in the culture medium compared to that of the mutant strain. Thus involvement of IpdC in IAA biosynthesis in M. extorquens was shown. PMID- 21314614 TI - Novel inhibitors of glyceraldehyde-3-phosphate dehydrogenase: covalent modification of NAD-binding site by aromatic thiols. AB - Glyceraldehyde-3-phosphate dehydrogenase (GAPDH, EC 1.2.1.12) is a glycolytic enzyme catalyzing the formation of 1,3-diphosphoglycerate from glyceraldehyde-3 phosphate and inorganic phosphate. In cooperation with E3 ubiquitin-kinase Siah1, GAPDH directly participates in the apoptotic death of neurons in Parkinson's disease. Potential GAPDH inhibitors were screened in silico, and three compounds with high affinity to the NAD-binding site and theoretically capable of forming a disulfide bond with amino acid residue Cys149 were found among cysteine and glutathione derivatives. The inhibitory effect of these compounds was tested on GAPDH from rabbit muscles using isothermal calorimetry and kinetic methods. As a result of experimental screening, we selected two compounds that inhibit GAPDH by forming disulfide bonds with the Cys149 residue in the enzyme active site. Since Cys149 is the key residue not only for the catalyzed reaction, but also for interaction with Siah1, the compounds can be assumed to inhibit the formation of the proapoptotic complex GAPDH-Siah1 and therefore have potential effect against Parkinson's disease. PMID- 21314615 TI - Glycosylation of purified buffalo heart galectin-1 plays crucial role in maintaining its structural and functional integrity. AB - A buffalo heart galectin-1 purified by gel filtration chromatography revealed the presence of 3.55% carbohydrate content, thus it is the first mammalian heart galectin found to be glycosylated in nature and emphasizes the need to perform deglycosylation studies. Physicochemical comparative analysis between the properties of the native and deglycosylated proteins was carried out to understand the significance of glycosylation. The deglycosylated protein exhibited lesser thermal and pH stability compared to the native galectin. When exposed to thiol blocking reagents, denaturants, and detergents, remarkable differences were observed in the properties of the native and deglycosylated protein. Compared to the native glycosylated protein, the deglycosylated galectin showed enhanced fluorescence quenching when exposed to various agents. CD and FTIR analysis showed that deglycosylation of the purified galectin and its exposure to different chemicals resulted in significant deviations from regular secondary structure of the protein, thus emphasizing the significance of glycosylation for maintaining the active conformation of the protein. The remarkable differences observed in the properties of the native and deglycosylated galectin add an important dimension to the significance of protein glycosylation and its associated biological and clinical relevance. PMID- 21314616 TI - Novel mutants of human tumor necrosis factor with dominant-negative properties. AB - Tumor necrosis factor (TNF) is a polyfunctional cytokine, one of the key mediators of inflammation and innate immunity. On the other hand, systemic or local TNF overexpression is typical of such pathological states as rheumatoid arthritis, psoriasis, Crohn's disease, septic shock, and multiple sclerosis. Neutralization of TNF activity has a marked curative effect for some diseases; therefore, the search for various TNF blockers is a promising field of protein engineering and biotechnology. According to the previously developed concept concerning the possibility of designing dominant-negative mutants, the following TNF variants have been studied: TNFY87H + A145R, TNFY87H + A96S + A145R, and TNFV91N + A145R. All of these form inactive TNF heterotrimers with the native protein. The ability of mutants to neutralize the effect of TNF was investigated. The addition of mutants to the native protein was shown to provide a concentration-dependent suppression of TNF cytotoxicity against the mouse fibroblast cell line L929. Thus, novel inhibitors of human TNF can be engineered on the basis of these muteins. PMID- 21314617 TI - Interaction of ceruloplasmin and 5-lipoxygenase. AB - The interaction between ceruloplasmin (CP), the multicopper oxidase of human plasma, and 5-lipoxygenase (5-LO), the key enzyme of leukotriene synthesis, is shown for the first time. By Western-blotting and mass spectrometry of tryptic fragments, it is shown that 5-LO from protein extract of human leukocytes binds with immobilized CP. Dose-dependent influence of intact CP on leukotrienes synthesis is found: CP reduced leukotrienes synthesis in leukocytes in a dose above 50 ug/ml (normal CP concentration in plasma is about 300-400 ug/ml). Proteolyzed CP and apo-form of CP is unable to inhibit activity of 5-LO. CP increased activity of 5-LO at low doses (5-10 ug/ml). On the whole, the influence of CP on phagocytosis index of leukocytes coordinates with influence on activity of 5-LO: the index increased in the range of 2-10 ug/ml CP and decreased at doses of CP above 40 ug/ml. The dual role of CP in regulation of cellular response of leukocytes is discussed. PMID- 21314618 TI - Proteome analysis of chloroplasts from the moss Physcomitrella patens (Hedw.) B.S.G. AB - Intact chloroplasts were prepared from protoplasts of the moss Physcomitrella patens according to an especially developed method. They were additionally separated into stroma and thylakoid fractions. The proteomes of intact plastids, stroma, and thylakoids were analyzed by 1D-electrophoresis under denaturing conditions followed by protein digestion and nano-LC-ESI-MS/MS of tryptic peptides from gel bands. A total of 624 unique proteins were identified, 434 of which were annotated as chloroplast resident proteins. The majority of proteins belonged to a photosynthetic group (21.3%) and to the group of proteins implicated in protein degradation, posttranslational modification, folding, and import (20.6%). Among proteins assigned to chloroplasts, the following groups are prominent combining proteins implicated in metabolism of: amino acids (6.9%), nucleotides (2.5%), lipids (2.2%), carbohydrates (2.4%), hormones (1.5%), isoprenoids (1.25%), vitamins and cofactors (1%), sulfur (1.25%), and nitrogen (1%); as well as proteins involved in the pentose-phosphate cycle (1.75%), tetrapyrrole synthesis (3.7%), and redox processes (3.6%). The data can be used in physiological and photobiological studies as well as in further studies of P. patens chloroplast proteome including structural and functional specifics of plant protein localization in organelles. PMID- 21314619 TI - Recombinant DNA-methyltransferase M1.BspACI from Bacillus psychrodurans AC: purification and properties. AB - A restriction-modification system from Bacillus psychrodurans AC (recognition sequence 5'-CCGC-3') comprises two DNA methyltransferases: M1.BspACI and M2.BspACI. The bspACIM1 gene was cloned in the pJW2 vector and expressed in Escherichia coli cells. High-purity M1.BspACI preparation has been obtained by chromatography on different carriers. M1.BspACI has a temperature optimum of 30 degrees C and demonstrates maximum activity at pH 8.0. M1.BspACI modifies the first cytosine in the recognition sequence 5'-CCGC-3'. The kinetic parameters of M1.BspACI DNA methylation are as follows: K(m) for phage lambda DNA is 0.053 uM and K(m) for S-adenosyl-L-methionine is 5.1 uM. The catalytic constant (k(cat)) is 0.095 min(-1). PMID- 21314620 TI - Dietary supplementation of old rats with hydrogenated peanut oil restores activities of mitochondrial respiratory complexes in skeletal muscles. AB - The effect of dietary supplementation of old rats (26-33 months) with hydrogenated peanut oil on the activity of mitochondrial enzymes in skeletal muscles has been studied. The activities of NADH-coenzyme Q1 oxidoreductase, cytochrome c oxidase, and citrate synthase were determined spectrophotometrically in muscle homogenates. The activities of respiratory complexes I and IV were shown to significantly decrease with the age compared to the activity of the same enzymes in young animals, while the activity of citrate synthase was virtually unchanged. The fatty acid composition of muscle homogenates of old rats differed from that of young animals by a reduced content of myristic, oleic, linoleic, and alpha-linolenic acids and enhanced content of dihomo-gamma-linolenic, arachidonic, and docosahexaenoic acids. Per oral supplementation of the old rats with hydrogenated peanut oil completely restored the activity of complex IV and increased the activity of complex I to 80% of the value observed in muscles of young animals, reducing the content of stearic, dihomo-gamma-linolenic, arachidonic, eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids relative to that in the groups of old and young rats. The content of oleic and linoleic acids increased relatively to that in the group of the old rats, as well as young animals. The possible mechanisms of the restoration of the activity of the respiratory enzymes under the administration of hydrogenated peanut oil are discussed. PMID- 21314621 TI - Discovery of a photosynthesizing animal that can survive for months in a light dependent manner. PMID- 21314622 TI - Psychometric comparison of standard and computerized administration of the Alzheimer's Disease Assessment Scale: Cognitive Subscale (ADASCog). AB - BACKGROUND: The Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS Cog) has become the de facto gold standard for assessing the efficacy of anti dementia treatments. However, manual administration of the ADAS-Cog is subject to procedural inconsistencies, including scoring and transcription errors, which can introduce unwanted variance and compromise data quality within and across sites and trials. To address such concerns, a computerized version was developed that integrates, rather than replaces, the examiner, standardizes administration, and uses electronic data capture at the point of patient contact. The examiner can control administration and pacing, pause or repeat digitized instructions, score verbal report and overt behavioral performance, and freely interact with the subject. PURPOSE: To conduct psychometric comparisons of traditional, paper-based administration of the standard ADAS-Cog (sADAS) with examiner- assisted administration of the computerized ADAS-Cog (cADAS). METHODS: Eighty-eight patients (39M; 49F) with mild to moderate Alzheimer's disease were tested on three occasions with each version over a period of one year with one month between paired visits. RESULTS: Intraclass Correlation Coefficients (ICC) comparisons between sADAS and cADAS were significant for total score (ICC=0.96) and all subscores (ICCs ranged 0.78-0.93), with no significant differences on paired t-tests. The mean ICCs across cADAS scores for test-retest reliability for short-term (mean ICC=0.96) and long-term (mean ICC=0.91) comparisons were significantly higher than across sADAS scores (mean ICCs were 0.87 and 0.84, respectively). CONCLUSIONS: These results indicate that examiner-assisted, computerized administration is equivalent to traditional, paper-based administration, and shows significantly greater test-retest reliability. PMID- 21314623 TI - The implication of Pseudomonas aeruginosa biofilms in infections. AB - Biofilm formation by bacteria is recognized as a major problem in chronic infections due to their recalcitrance against the immune defense and available antibiotic treatment schemes. The opportunistic pathogen Pseudomonas aeruginosa has drawn special attention in this regard due to its severity of infection in the lungs of cystic fibrosis patients and in chronic wounds. In this review we address the molecular basis of biofilm development by P. aeruginosa as well as the mechanisms employed by this bacterium in the increased tolerance displayed against antimicrobials. The complex build-up of the extracellular matrix encasing the biofilm-associated bacteria as well as the elaborate signaling mechanisms employed by the bacterium enables it to withstand the continuous stresses imposed by the immune defense and administered antibiotics resulting in a state of chronic inflammation that damages the host. The immune response leading to this chronic inflammation is described. Finally, novel treatment strategies against P. aeruginosa are described including, quorum-sensing inhibition and induced biofilm dispersion. The tolerance towards currently available antimicrobials calls for development of alternative treatment strategies where the underlying targets are less prone for resistance development as bacteria, in retrospect, have a unique ability to evade the actions of classic antibiotics. PMID- 21314624 TI - Postprandial lipemia in children and adolescents. AB - Atherosclerosis is a result of a lifelong process that has its origins in childhood. Data in adults suggest that impaired postprandial lipoprotein metabolism may contribute to, or be a marker of, the development and progression of atherosclerosis. After an 8-year follow up period, the Bogalusa Heart Study showed that children with low high density lipoprotein cholesterol, high triglyceride levels and high body mass index had a notably increased occurrence of dyslipidemia as adults. A significantly greater postprandial response of triglycerides in children with elevated fasting triglyceride levels was reported. It is well known that dietary fat is associated with higher plasma triglyceride levels. It is not clear if postprandial lipemia should be evaluated in children and adolescents. However, in special situations this may help determine the underlying lipid disorder. This review discusses the current status in this field. PMID- 21314625 TI - Proposing a "lipemic index" as a nutritional and research tool. AB - Recent studies have demonstrated the value of non-fasting serum triglycerides (TG) as risk markers for cardiovascular and cerebrovascular disease. This underscores the importance of knowing the postprandial lipid/lipoprotein responses to different foods. A systematic approach is needed to make use of postprandial lipid data as a practical nutritional tool, similar to the well known glycemic index (GI), which is a measure of the effect of carbohydrates on blood glucose levels. Using GI as a model, we propose that a similar and parallel nutritional tool called Lipemic Index (LI) be developed to facilitate the planning of a healthy diet. LI could also serve as a tool in human nutrition research. LI would refer to the postprandial increase of serum TG after a test meal with a specific food relative to a reference meal. The reference meal could take the form of a fat load that has a fixed amount (e.g. 50-70 g) of a mixture of saturated, polyunsaturated and monounsaturated fats in known proportions. It is possible that a test meal may have a greater degree of postprandial lipemia (PPL) than the reference meal and, unlike GI, the LI may exceed 100%. We recommend total plasma TG as the blood parameter to follow after consumption of the fat load. The TG incremental area under the curve (iAUC) will be calculated from the curve drawn from hourly measurements of plasma TG up to 6 hours using the trapezoid rule. The LI of the test meal (%) will equal the iAUC of the test meal divided by the iAUC of the reference meal x 100. Consideration will be given to the impact of background diet, other nutrients in the test meal and gender differences on LI testing. The establishment of LI into practice will be complicated and challenging. However, it is important for work to begin on establishing a practical and quantifiable index of PPL, in order to benefit clinical management of patients as well as research. PMID- 21314626 TI - Effects of nutrients on postprandial lipemia. AB - Numerous factors including diet, lifestyle conditions, genetic background and physio-pathological conditions modulate the amplitude and time-courses of postprandial changes in humans. This review focuses on dietary factors affecting postprandial lipemia and lipoproteins metabolism in humans. The known effects of amount or type of fat, carbohydrate, protein and fiber are summarized. Changing the habitual dietary pattern can also alter the postprandial response. This review highlights that postprandial metabolism is a key link between dietary pattern and cardiovascular health or risk. PMID- 21314627 TI - Methods to study postprandial lipemia. AB - Postprandial lipemia (PPL) refers to a dynamic sequence of plasma lipid/lipoprotein changes induced by ingestion of food. PPL results from absorption of digested dietary lipids which form chylomicrons (CM) and increased hepatic production of VLDL, stimulated by increased delivery of fats to the liver. In general, PPL occurs over 4-6 h in normal individuals, depending on the amount and type of fats consumed. The complexity of PPL changes is compounded by ingestion of food before the previous meal is fully processed. PPL testing is done to determine the impact of (a) exogenous factors such as the amount and type of food consumed, and (b) endogenous factors such as the metabolic/genetic status of the subjects, on PPL. To study PPL appropriately, different methods are used to suit the study goal. This paper provides an overview of the methodological aspects of PPL testing. It deals with markers of postprandial lipoproteins, testing conditions and protocols and interpretation of postprandial data. The influence of the meal itself will not be discussed as it is the subject of another paper in this series. PMID- 21314628 TI - Definition of postprandial lipaemia. AB - At the present time, there is no widely agreed definition of postprandial lipaemia (PPL). This lack of a shared definition limits the identification and treatment of patients with exaggerated PPL as well as the evaluation of potential therapeutic agents. PPL is a complex syndrome characterized by non-fasting hypertriglyceridaemia that is associated with an increased risk of vascular events. This review considers the definition of PPL and the methodology for assessing this process. PMID- 21314629 TI - Nutrigenetics of the postprandial lipoprotein metabolism: evidences from human intervention studies. AB - Accumulating evidence suggests that elevated plasma triglycerides concentrations, in both the fasting and the postprandial states, may pose a significant independent risk for cardiovascular disease (CVD). Both fasting and postprandial lipoprotein concentrations vary substantially among individuals, and this inter individual variability is driven by a combination of non-genetic and genetic factors. Regarding the genetic component, the efforts to elucidate the variability in postprandial response have resulted in the identification of associations with multiple lipid candidate genes. However, most reported associations are based on very simple models including one single-nucleotide polymorphism (SNP) or haplotype at a time and small sample sizes. Progress in this promising area of research requires more comprehensive experimental models, including larger sample sizes that will allow investigating gene-gene interactions. Reviews of the literature in the area of ApoA5, GCKR, and PLIN genes and postprandial lipemia are used to demonstrate the complexities of genotype-phenotype associations. Knowledge of how these and other genes influence postprandial response should increase the understanding of personalised nutrition. PMID- 21314630 TI - Clinical relevance of non-fasting and postprandial hypertriglyceridemia and remnant cholesterol. AB - Non-fasting triglycerides are measured at any time within up to 8 h (14 h) after any normal meal, while postprandial triglycerides are measured at a fixed time point within up to 8 h (14 h) of a standardised fat tolerance test. The simplest possible way of evaluating remnant cholesterol is non-fasting/postprandial total cholesterol minus low-density lipoprotein (LDL) cholesterol minus high-density lipoprotein (HDL) cholesterol. Elevated levels of non-fasting/postprandial triglycerides directly correlate with elevated remnant cholesterol. In the general population, 38% of men have non-fasting/postprandial triglycerides > 2mmol/L (>176 mg/dL) while 45% of men have non-fasting/postprandial triglyceride levels of 1-2 mmol/L (89-176 mg/dL); corresponding fractions in women are 20% and 47%. Also, 31% of men have remnant cholesterol levels > 1mmol/L (>39 mg/dL) while 46% of men have remnant cholesterol levels of 0.5-1 mmol/L (19-39 mg/dL); corresponding fractions in women are 15% and 43%. Non-fasting triglycerides >=5 mmol/L vs. <1 mmol/L marked a 17 and 5 fold increased risk of myocardial infarction, a 5 and 3 fold increased risk of ischemic stroke, and a 4 and 2 fold increased risk of early death in women and men in the general population. As all cells can degrade triglycerides it is biologically unlikely that it is the triglyceride molecules themselves that cause atherosclerosis and cardiovascular disease. However, elevated remnant cholesterol may lead to cholesterol entrapment in the arterial intima and consequently to accelerated atherosclerosis and cardiovascular disease. PMID- 21314631 TI - Diagnostic value of postprandial triglyceride testing in healthy subjects: a meta analysis. AB - BACKGROUND/AIM: Triglycerides (TGs) are measured in studies evaluating changes in non-fasting lipid profiles after a fat tolerance test (FTT); however, the optimal timing for TG measurements after the oral fat load is unclear. The aim of this study was to evaluate how non-fasting TG levels vary after an oral FTT in healthy subjects. METHODS: This meta-analysis included 113 studies with >5 participants of Caucasian race that were indexed in PubMed from its inception through March 2010, using the search term "postprandial lipemia". We only included studies that provided mean values and standard deviation (SD) (or standard error of the mean) for TG measurements at baseline (=fasting) and for at least one other time-point. Exclusion criteria included uncommon sampling time-points after the FTT, baseline TGs>=2.0 mmol/L (>=177mg/dl), and a body mass index >=30kg/m(2). RESULTS: All studies combined, weighted mean+/-SD TG values in mmol/L were 1.25+/-0.32 fasting, 1.82+/-0.40 at 2 h, 2.31+/-0.62 at 4 h, 1.87+/-0.63 at 6 h, and 1.69+/ 0.80 at 8 h. After stratifying studies based on fat quantity in the test meal (<40, >=40-<50, >=50-<60, >=60-<70, >=70-<80, >=80-<90, >=90-<100, >=100-<110, >=110-120, >=120 g), the highest standardized mean difference in TG levels from fasting levels was found in those having an oral fat load of >=70 g and <80 g, and at 4 h (difference=1.74 mmol/L; p<0.001). CONCLUSION: The 4 h time-point after an oral fat load during a FTT was the most representative measurement of TGs. The highest standardized mean difference of TGs was found after a meal containing 70-79g of fat. The relevance of these two key parameters determined in healthy subjects should be considered for further developments of an oral FFT for clinical purposes. PMID- 21314632 TI - Assessment and clinical relevance of non-fasting and postprandial triglycerides: an expert panel statement. AB - An Expert Panel group of scientists and clinicians met to consider several aspects related to non-fasting and postprandial triglycerides (TGs) and their role as risk factors for cardiovascular disease (CVD). In this context, we review recent epidemiological studies relevant to elevated non-fasting TGs as a risk factor for CVD and provide a suggested classification of non-fasting TG concentration. Secondly, we sought to describe methodologies to evaluate postprandial TG using a fat tolerance test (FTT) in the clinic. Thirdly, we discuss the role of non-fasting lipids in the treatment of postprandial hyperlipemia. Finally, we provide a series of clinical recommendations relating to non-fasting TGs based on the consensus of the Expert Panel: 1). Elevated non fasting TGs are a risk factor for CVD. 2). The desirable non-fasting TG concentration is <2 mmol/l (<180 mg/dl). 3). For standardized postprandial testing, a single FTT meal should be given after an 8 h fast and should consist of 75 g of fat, 25 g of carbohydrates and 10 g of protein. 4). A single TG measurement 4 h after a FTT meal provides a good evaluation of the postprandial TG response. 5). Preferably, subjects with non-fasting TG levels of 1-2 mmol/l (89-180 mg/dl) should be tested with a FTT. 6). TG concentration <= 2.5 mmol/l (220 mg/dl) at any time after a FTT meal should be considered as a desirable postprandial TG response. 7). A higher and undesirable postprandial TG response could be treated by aggressive lifestyle modification (including nutritional supplementation) and/or TG lowering drugs like statins, fibrates and nicotinic acid. PMID- 21314633 TI - Current pharmacologic management of pediatric heart failure in congenital heart disease. AB - Pharmacologic therapy represents the mainstay of treatment for heart failure in children. However, medical therapy for this population is not widely standardized. This is mainly due to the heterogeneity of potential etiologies, the specific challenge of patients with univentricular physiology and the lack of evidence-based prospective randomized clinical trials in pediatric patients. In fact, most current strategies are based largely on extrapolated data from adult studies. Although the classic drugs for heart failure, i.e. diuretics, angiotensin-converting enzyme inhibitors, beta -blockers and cardiac glycosides, still play a major role in the treatment of pediatric heart failure, newer alternative therapies such as levosimendan and nesiritide are increasingly utilized with promising early results. A systematic literature search of PubMed and MEDLINE databases using relevant terms was performed. All clinical trials and relevant manuscripts about the current pharmacologic treatment of heart failure in the pediatric population were reviewed. New drugs such as levosimendan and nesiritide and the treatment of single-ventricle patients were also included. PMID- 21314634 TI - What restricts the clinical use of nicotinic acid? AB - Nicotinic acid is the oldest hypolipidemic agent in use, since 1955. It possesses broad-spectrum lipidmodifying properties including reduction of total cholesterol, low density lipoprotein (LDL) cholesterol and triglycerides. In addition, nicotinic acid is the most potent available hypolipidemic agent for increasing plasma high density lipoprotein (HDL) cholesterol and decreasing lipoprotein (a) levels. Clinical trials have demonstrated that nicotinic acid can decrease cardiovascular morbidity and mortality. However, nicotinic acid is underused in the clinical setting due to its high rate of side effects, including flushing, gastrointestinal disorders, rash, hyperglycemia and hyperuricemia. The nicotinic acid-associated side effects and their management are the focus of this review. PMID- 21314635 TI - Pleiotropic effects of nicotinic acid: beyond high density lipoprotein cholesterol elevation. AB - AIMS: Treatment with statins has significantly reduced cardiovascular morbidity and mortality, an effect attributed to both the low-density lipoprotein cholesterol (LDL-C) lowering capacity and the pleiotropic actions of these drugs. However, residual risk remains even after intense LDL-C lowering. Therefore, additional treatment with lipid-lowering drugs which improve other lipid parameters and have favourable non-lipid effects may be of clinical value. The aim of the present article is to review the actions of nicotinic acid and comment on the limitations and possible benefits of this drug in clinical practice. METHODS: Relevant articles were identified through a Pubmed search up to July 2010. RESULTS: Nicotinic acid (niacin) improves the lipid profile and has been associated with reduction in morbidity and mortality from cardiovascular disease. This favourable outcome may be due to several beneficial actions of this drug, such as antithrombotic, anti-inflammatory and antioxidant. However, its use has been limited due to side effects, especially flushing. A novel formulation with a prostaglandin D2 receptor antagonist (laropiprant) appears to substantially decrease the frequency and intensity of flushing, without affecting the other properties of niacin. Some concerns regarding treatment with nicotinic acid include impaired glucose metabolism and elevations in uric acid and homocysteine levels. CONCLUSION: Nicotinic acid is a safe supplementary (to statins) lipid lowering agent which may also improve cardiovascular outcomes. Whether its combination with laropiprant will be proved equally effective and more favourable in terms of adverse effects remains to be established by large clinical trials. PMID- 21314636 TI - Atherosclerotic renal artery stenosis: an update on diagnosis and management. AB - Atherosclerotic renal artery stenosis (ARAS) is a progressive disease and it is usually associated with hypertension as well as with chronic kidney and cardiovascular disease. Although the anatomical lesions are relatively easy to depict, there is need to identify diagnostic methods to establish the functional significance of the stenosis and predict the response to revascularization. Over the last years, renal revascularization appears to be increasingly performed in patients with ARAS. However, controversy abounds as so far prospective, randomised trials did not document any benefit of revascularization with or without stenting plus optimal medical treatment over optimal medical treatment alone. In this review, we discuss the current data in the field of diagnosis and management of patients with ARAS. PMID- 21314637 TI - Platelet function and antiplatelet therapy in cardiovascular disease: implications of genetic polymorphisms. AB - Platelets play a crucial role in thrombosis, inflammation, immunity and atherogenesis. Antiplatelet agents are widely used in patients with acute coronary syndrome and other cardiovascular disorders. Aspirin and clopidogrel are the most commonly prescribed antiplatelet agents, with a relatively safe profile and efficiency in a variety of clinical conditions. Numerous prospective studies have revealed variability of antiplatelet efficacy. The so called "antiplatelet resistance" prompted a search for mechanisms implicated in poor responsiveness to aspirin and clopidogrel therapy. In this regard, genetic polymorphisms in the platelet receptor genes attracted considerable interest. Specific genetic variants in platelet receptors such as the P2Y12, glycoprotein (GP) IIb/IIIa, GPIa/IIa, GPIb/IX/V and the cytochrome P450 (CYP) family of genes are associated with variable response to antiplatelet therapy and cardiovascular events. Genetic polymorphisms and haplotypes that comprehensively capture the genetic information encoded within the platelet receptor genes can, to some extent, predict response to the antiplatelet drug better than any single genotype. Genotyping for multiple receptor variants in patients on antiplatelet therapy, complemented by standardized quantification of platelet function, can provide useful information for future drug design studies and possibly for personalized antiplatelet therapy and prevention of thrombotic events. Additional information is, however, needed to evaluate the cost-effectiveness of complex genetic and platelet function testing. PMID- 21314638 TI - Probing the S1 specificity pocket of the aminopeptidases that generate antigenic peptides. AB - ERAP1 (endoplasmic reticulum aminopeptidase 1), ERAP2 and IRAP (insulin-regulated aminopeptidase) are three homologous enzymes that play critical roles in the generation of antigenic peptides. These aminopeptidases excise amino acids from N terminally extended precursors of antigenic peptides in order to generate the correct length epitopes for binding on to MHC class I molecules. The specificity of these peptidases can affect antigenic peptide selection, but has not yet been investigated in detail. In the present study we utilized a collection of 82 fluorigenic substrates to define a detailed selectivity profile for each of the three enzymes and to probe structural and functional features of the S1 (primary specificity) pocket. Molecular modelling of the three S1 pockets reveals substrate-enzyme interactions that are critical determinants for specificity. The substrate selectivity profiles suggest that IRAP largely combines the S1 specificity of ERAP1 and ERAP2, consistent with its proposed biological function. IRAP, however, does not achieve this dual specificity by simply combining structural features of ERAP1 and ERAP2, but rather by an unique amino acid change at position 541. The results of the present study provide insights on antigenic peptide selection and may prove valuable in designing selective inhibitors or activity markers for this class of enzymes. PMID- 21314639 TI - When a module is not a domain: the case of the REJ module and the redefinition of the architecture of polycystin-1. AB - The extracellular region of a group of cell-surface receptors known as the polycystic kidney disease 1 family, containing, among others, polycystin-1, has been controversially described as containing four FNIII (fibronectin type III) domains or one REJ (receptor of egg jelly protein) module in the same portion of polypeptide. Stimulated by recent atomic force microscopy work, we re-examined the similarity of these four domains with a FNIII sequence profile showing the evolutionary relationship. Two of the predicted domains could be expressed in bacteria and refolded to give a protein suitable for biophysical study, and one of these expressed solubly. CD spectroscopy showed that both domains contain a significant amount of beta-sheet, in good agreement with theoretical predictions. Confirmation of independent folding as a domain is obtained from highly co operative thermal and urea unfolding curves. Excellent dispersion of peaks in the high-field region of one-dimensional NMR spectra confirms the presence of a hydrophobic core. Analytical ultracentrifugation and analytical gel filtration agree very well with the narrow linewidths in the NMR spectra that at least one of the domains is monomeric. On the basis of this combined theoretical and experimental analysis, we show that the extracellular portion of polycystin-1 does indeed contain beta-sheet domains, probably FNIII, and that, consequently, the REJ module is not a single domain. PMID- 21314640 TI - The suppressive effect of CD25+Treg cells on Th1 differentiation requires cell cell contact partially via TGF-beta production. AB - CD25+Treg cells (CD4+CD25+Foxp3+ regulatory T cells) play a central role in the maintenance of peripheral self-tolerance and immune homoeostasis. A previous study showed that CD25+Treg cells suppressed the differentiation and function of Th1 cells in vivo and in vitro. However, the mechanism of suppressing Th1 cell differentiation mediated by CD25+Treg cells remains unclear. In the present study, we found that CD25+Treg cells could reduce the production of IFN (interferon)-gamma and the percentage of IFN-gamma-, IL-2 and TNF-alpha-producing cells by CD25-T cells under Th1 cell culture conditions and suppress the differentiation of CD25-T cells into Th1 cells in a dose-dependent manner. Moreover, these CD25+Treg cells could inhibit the activation of CD25-T cells by down-regulating the expression of activation markers CD69 and CD25 and suppress the division and proliferation of CD25-T cells using CFSE (carboxyfluorescein diacetate succinimidyl ester)-labelling and BrdU (5-bromo-20-deoxyuridine) incorporation, respectively. Further studies showed that the suppressive effects of CD25+Treg cells on Th1 cell differentiation required cell-cell contact and was partially restored by the addition of anti-TGF-beta mAb (monoclonal antibody) but not anti-IL-10 mAb, indicating that the suppression mechanism of CD25+Treg cells was cell-cell contact dependent and partially via TGF-beta. This finding strongly indicates a therapeutic role for CD25+Treg cells in Th1-mediated diseases. PMID- 21314641 TI - Roles of the ERK, JNK/AP-1/cyclin D1-CDK4 pathway in silica-induced cell cycle changes in human embryo lung fibroblast cells. AB - Silica is a potent occupational fibrogenic agent capable of inducing lung fibrosis and many other lung diseases. Our current study focused on the signalling pathways regulating cell cycle changes in HELF (human embryo lung fibroblast) after silica (alpha-quartz) exposure. Our results showed silica exposure could lead to cell cycle changes. The cell cycle alternations were accompanied with overexpression of cyclin D1 and CDK4 (cyclin-dependent kinase 4) in a time-dependent manner. Silica exposure also decreased E2F-4 expression in HELF. These changes were blocked by overexpression of dominant-negative mutants of ERK (extracellular signal-regulated protein kinase) or the JNK (stress activated c-Jun NH2-terminal kinase), respectively. Moreover, pretreatment of cells with curcumin, an activation of AP-1 (activator protein-1) inhibitor, inhibited silica-induced cell cycle alteration, the decreased expression of E2F-4 and overexpression of cyclin D1 and CDK4. Furthermore, both antisense cyclin D1 and antisense CDK4 can block silica-induced cell cycle changes. These results suggest that silica exposure can induce cell cycle changes, which may be mediated through ERK, JNK/AP-1/cyclin D1-CDK4-dependent pathway. PMID- 21314642 TI - Epigenetic inactivation of PCDH10 in human prostate cancer cell lines. AB - PCDH10 (protocadherin-10), a novel tumour suppressor gene, is down-regulated in several human cancers due to hypermethylation of promoter CGIs (CpG islands). Here, we investigated the expression of PCDH10 in different normal adult tissues and in a panel of prostate cancer cell lines. PCDH10 was widely expressed in normal tissues with higher levels in the prostate. The expression of PCDH10 was markedly reduced or silenced in prostate cancer cell lines compared with normal adult prostate tissue. Decreased PCDH10 expression was correlated with the methylation status of the PCDH10 promoter. Furthermore, the DNA demethylating agent 5'-azacytidin restored PCDH10 expression by suppressing PCDH10 promoter methylation in prostate cancer cell lines. Treatment with Trichostatin A alone had no significant effect on the expression of PCDH10 but enhanced the effect of 5'-azacytidin. In conclusion, we found that the decreased PCDH10 expression in prostate cancer cells was associated with the aberrant methylation of PCDH10 promoter CGI. Our results may contribute to the understanding of the role of PCDH10 inactivation in the progression of prostate cancers. PMID- 21314643 TI - Strength training, walking, and social activity improve sleep in nursing home and assisted living residents: randomized controlled trial. AB - OBJECTIVES: To compare the effects of physical resistance strength training and walking (E), individualized social activity (SA), and E and SA (ESA) with a usual care control group on total nocturnal sleep time in nursing home and assisted living residents. DESIGN: Pretest-posttest experimental design with assignment to one of four groups for 7 weeks: E (n=55), SA (n=50), ESA (n=41), and usual care control (n=47). SETTING: Ten nursing homes and three assisted living facilities. PARTICIPANTS: One hundred ninety-three residents were randomly assigned; 165 completed the study. INTERVENTION: The E group participated in high-intensity physical resistance strength training 3 days a week and on 2 days walked for up to 45 minutes, the SA group received social activity 1 hour daily 5 days a week, the ESA group received both E and SA, and the control group participated in usual activities provided in the homes. MEASUREMENT: Total nocturnal sleep time was measured using 2 nights of polysomnography before and 2 nights of polysomnography after the intervention. Sleep efficiency (SE), non-rapid eye movement (NREM) sleep, rapid eye movement sleep, and sleep onset latency were also analyzed. RESULTS: Total nocturnal sleep time was significantly greater in the ESA group than in the control group (adjusted means 364.2 minutes vs 328.9 minutes), as was SE and NREM sleep. CONCLUSION: High-intensity physical resistance strength training and walking combined with social activity significantly improved sleep in nursing home and assisted living residents. The interventions by themselves did not have significant effects on sleep in this population. PMID- 21314644 TI - Effects of a month-long napping regimen in older individuals. AB - OBJECTIVES: To examine the effects of a month-long nap regimen using one of two durations (45 minutes or 2 hours) on nighttime sleep and waking function in a group of healthy older participants and to assess the degree to which healthy older individuals are willing and able to adhere to such napping regimens. DESIGN: Three laboratory sessions, with 2-week at-home recording interspersed, using a between-participants approach. SETTING: Laboratory of Human Chronobiology at Weill Cornell Medical College and participants' homes. PARTICIPANTS: Twenty two healthy men and women aged 50 to 88 (mean 70). MEASUREMENTS: Polysomnography (sleep electroencephalography), actigraphy, sleep diaries, neurobehavioral performance, sleep latency tests. RESULTS: With the exception of adherence to the protocol, there were few differences between short and long nap conditions. Napping had no negative effect on subsequent nighttime sleep quality or duration, resulting in a significant increase in 24-hour sleep amounts. Such increased sleep was associated with enhanced cognitive performance but had no effect on simple reaction time. Participants were generally able to adhere better to the 45 minute than the 2-hour nap regimen. CONCLUSION: A month-long, daily nap regimen may enhance waking function without negatively affecting nighttime sleep. Using 2 hour naps in such a regimen is unlikely to meet with acceptable adherence; a regimen of daily 1-hour naps may be more desirable for effectiveness and adherence. PMID- 21314645 TI - Histamine-2 receptor antagonist use and incident dementia in an older cohort. AB - OBJECTIVES: To examine whether histamine-2 receptor antagonist medications (H2RAs) are associated with a lower incidence of all-cause dementia or Alzheimer's disease (AD), as some studies have suggested. DESIGN: Prospective population-based cohort SETTING: Group Health, an integrated health maintenance organization, Seattle, Washington. PARTICIPANTS: Two thousand nine hundred twenty three participants aged 65 and older without dementia at baseline, with initial recruitment between 1994 and 1996. MEASUREMENTS: Follow-up occurred every 2 years to identify incident dementia and AD using standard criteria. Exposure to H2RAs was determined based on automated pharmacy data. Three aspects of exposure (time varying) were examined based on standard daily dose (SDD): cumulative use, intensity of use (highest SDD in any prior 2-year window), and cumulative use stratified according to recency (1-3 years vs >3 years before). RESULTS: Over a mean follow-up of 6.7 years, 585 subjects developed dementia (453 developed AD). Total cumulative exposure was not associated with dementia (P=.35; omnibus test) or AD (P=.23). The adjusted hazard ratios for the highest exposure category (>1,080 SDDs) compared with light or no use were 1.28 (95% confidence interval (CI)=0.95-1.72) for dementia and 1.41 (95% CI=1.00-1.97) for AD. Intensity of use was not associated with dementia (P=.39) or AD (P=.63). Examining exposure according to recent and distant cumulative use also showed no association with dementia (P=.11) or AD (P=.30). CONCLUSION: No association was found between H2RA use and risk of all-cause dementia or AD using more-detailed and -extensive information about past H2RA use than any prior study. PMID- 21314646 TI - Improvement in memory with plasticity-based adaptive cognitive training: results of the 3-month follow-up. AB - OBJECTIVES: To investigate maintenance of training effects of a novel brain plasticity-based computerized cognitive training program in older adults after a 3-month no-contact period. DESIGN: Multisite, randomized, controlled, double blind trial with two treatment groups. SETTING: Communities in northern and southern California and Minnesota. PARTICIPANTS: Four hundred eighty-seven community-dwelling adults aged 65 and older without diagnosis of clinically significant cognitive impairment. INTERVENTION: Random assignment into a broadly available brain plasticity-based computerized cognitive training program experimental group or a novelty- and intensity-matched cognitive stimulation active control. Assessments at baseline, after training, and at 3 months. MEASUREMENTS: The primary outcome was a composite of auditory subtests of the Repeatable Battery for the Assessment of Neuropsychological Status. Secondary measures included trained task performance, standardized neuropsychological assessments of overall memory and attention, and participant-reported outcomes (PROs). RESULTS: A significant difference in improvement from baseline to 3-month follow-up was seen between the experimental training and control groups on the secondary composite of overall memory and attention, (P=.01, d=0.25), the trained processing-speed measure (P<.001, d=0.80), word list total recall (P=.004, d=0.28), letter-number sequencing (P=.003, d=0.29), and the cognitive subscale of PRO (P=.006, d=0.27). Previously significant improvements became nonsignificant at the 3-month follow-up for the primary outcome, two secondary measures of attention and memory, and several PROs. Narrative memory continued to show no advantage for the experimental group. Effect sizes from baseline to follow-up were generally smaller than effect sizes from baseline to posttraining. CONCLUSION: Training effects were maintained but waned over the 3-month no contact period. PMID- 21314647 TI - Low mobility during hospitalization and functional decline in older adults. AB - OBJECTIVES: To examine the association between mobility levels of older hospitalized adults and functional outcomes. DESIGN: Prospective cohort study. SETTING: A 900-bed teaching hospital in Israel. PARTICIPANTS: Five hundred twenty five older (>=70) acute medical patients hospitalized for a nondisabling condition. MEASUREMENTS: In-hospital mobility was assessed using a previously validated scale. The main outcomes were decline from premorbid baseline functional status at discharge (activities of daily living (ADLs)) and at 1-month follow-up (ADLs and instrumental ADLs (IADLs)). Hospital mobility levels and functional outcomes were assessed according to prehospitalization functional trajectories. Logistic regressions were modeled for each outcome, controlling for functional status, morbidity, and demographic characteristics. RESULTS: Forty-six percent of participants had declined in ADLs at discharge and 49% at follow-up; 57% had declined in IADLs at follow-up. Mobility during hospitalization was twice as high in participants with no preadmission functional decline. Low versus high in-hospital mobility was associated with worse basic functional status at discharge (adjusted odds ratio (AOR)=18.03, 95% confidence interval (CI)=7.68 42.28) and at follow-up (AOR=4.72, 95% CI=1.98-11.28) and worse IADLs at follow up (AOR=2.00, 95% CI=1.05-3.78). The association with poorer discharge functional outcomes was present in participants with preadmission functional decline (AOR for low vs high mobility=15.26, 95% CI=4.80-48.42) and in those who were functionally stable (AOR for low vs high mobility=10.12, 95% CI=2.28-44.92). CONCLUSION: In-hospital mobility is an important modifiable factor related to functional decline in older adults in immediate and short-term (1-month follow up) functional outcomes. PMID- 21314648 TI - Volunteering, driving status, and mortality in U.S. retirees. AB - OBJECTIVES: To evaluate how accounting for driving status altered the relationship between volunteering and mortality in U.S. retirees. DESIGN: Observational prospective cohort. SETTING: Nationally representative sample from the Health and Retirement Study in 2000 and 2002 followed to 2006. PARTICIPANTS: Retirees aged 65 and older (N=6,408). MEASUREMENTS: Participants self-reported their volunteering, driving status, age, sex, race or ethnicity, presence of chronic conditions, geriatric syndromes, socioeconomic factors, functional limitations, and psychosocial factors. Death by December 31, 2006, was the outcome. RESULTS: For drivers, mortality in volunteers (9%) and nonvolunteers (12%) was similar; for limited or non-drivers, mortality for volunteers (15%) was markedly lower than for nonvolunteers (32%). Adjusted results showed that, for drivers, the volunteering-mortality odds ratio (OR) was 0.90 (95% confidence interval (CI)=0.66-1.22), whereas for limited or nondrivers, the OR was 0.62 (95% CI=0.49-0.78) (interaction P=.05). The effect of driving status was greater for rural participants, with greater differences between rural drivers and rural limited or nondrivers (interaction P=.02) and between urban drivers and urban limited or nondrivers (interaction P=.81). CONCLUSION: The influence of volunteering in decreasing mortality seems to be stronger in rural retirees who are limited or nondrivers. This may be because rural or nondriving retirees are more likely to be socially isolated and thus receive more benefit from the greater social integration from volunteering. PMID- 21314649 TI - Perceived effectiveness of diverse sleep treatments in older adults. AB - OBJECTIVES: To describe the different methods that older adults use to treat sleep problems and the perceived effectiveness of these methods. DESIGN: Cross sectional study of treatment patterns for sleep disorders using a mailed questionnaire that gathered information concerning sleep history, demographics, and treatment choices. SETTING: Community. PARTICIPANTS: Community-based sample of adults aged 65 and older, of whom 242 responded (67% response rate). MEASUREMENTS: Standardized questionnaires to assess sleep parameters (Pittsburgh Sleep Quality Index), demographic information, and sleep treatment options. RESULTS: Study participants engaged in a variety of treatment regimens to improve their sleep, with the average number of treatments attempted being 4.8+/-2.9. The most commonly used interventions were watching television or listening to the radio (66.4%) and reading (56.2%). The most commonly used pharmacotherapy was pain medication (40.1%). Prescription sleeping pills had the greatest self reported effectiveness. Approximately half of all study participants who used alcohol or over-the-counter sleep aids had not discussed their sleep problems with their doctor. CONCLUSION: Older adults frequently choose treatments for their sleep problems that can potentially worsen their sleep symptoms. Many patients have not spoken to their healthcare provider about their treatment choices. These findings highlight the importance of discussing sleep habits and self-treatment choices, as well as treating sleep disorders, in older adults. PMID- 21314650 TI - Screening for cognitive impairment in an elderly veteran population: acceptability and results using different versions of the Mini-Cog. AB - OBJECTIVES: To assess the feasibility of cognitive screening in older veterans presenting for routine primary care. DESIGN: Quality improvement initiative. SETTING: Seven Veterans Affairs Medical Centers. PARTICIPANTS: Veterans aged 70 and older without a prior diagnosis of cognitive impairment. MEASUREMENTS: Scores from 16 different versions of the Mini-Cog, a 5-point cognitive screen consisting of three-word recall (0-3 points) with a clock-drawing interference task (0 or 2 points). Five word lists were paired with three clock times and randomly ordered for presentation with the original Mini-Cog version. The conventional dementia screening cut point was increased to maximize sensitivity; to pass, patients had to draw the clock correctly and recall at least two of three words (score 4 or 5/5). RESULTS: Administering the Mini-Cog took 90 to 180 seconds. Of 8,342 veterans approached, 8,063 (96.7%) agreed to be screened; 2,081 (25.8%) scored less than 4 out of 5. Scores declined with age, but age did not predict pass or fail. Different word lists produced different screen failure rates, ranging from 21.2% to 33.4%. Five dementia specialists were unable to distinguish harder from easier lists. Different clock times accounted for 2% or less of the difference in failure rates. CONCLUSION: The Mini-Cog was quick and well accepted by older veterans. Many with no prior documentation of cognitive impairment failed the screen. Failure rates varied with the word list used, revealing that even apparently minor changes in test items affect screen results. Additional study is needed to establish the value of cognitive screening in shaping primary care of older veterans. PMID- 21314651 TI - Effectiveness of a multifactorial intervention to reduce physical restraints in nursing home residents. AB - OBJECTIVES: To evaluate the effectiveness of a multifactorial intervention to reduce the use of physical restraints in residents of nursing homes. DESIGN: Cluster-randomized controlled trial. SETTING: Forty-five nursing homes in Germany. PARTICIPANTS: Three hundred thirty-three residents who were being restrained at the start of the intervention. INTERVENTION: Persons responsible for the intervention in the nursing homes attended a 6-hour training course that included education about the reasons restraints are used, the adverse effects, and alternatives to their use. Technical aids, such as hip protectors and sensor mats, were provided. The training was designed to give the change agents tools for problem-solving to prevent behavioral symptoms and injuries from falls without using physical restraints. MEASUREMENTS: The main outcome was the complete cessation of physical restraint use on 3 consecutive days 3 months after the start of the intervention. Secondary outcomes were partial reductions in restraint use, percentage of fallers, number of psychoactive drugs, and occurrence of behavioral symptoms. RESULTS: The probability of being unrestrained in the intervention group (IG) was more than twice that in the control group (CG) at the end of the study (odds ratio=2.16, 95% confidence interval=1.05-4.46). A partial reduction of restraint use was also about twice as often achieved in the IG as in the CG. No negative effect was observed regarding medication or behavioral symptoms. The percentage of fallers was higher in the IG. CONCLUSION: The intervention reduced restraint use without a significant increase in falling, behavioral symptoms, or medication. PMID- 21314652 TI - Evaluation of the falls telephone: an automated system for enduring assessment of falls. AB - OBJECTIVES: To evaluate the reliability and user experiences of an automated telephone system to monitor falls during a prolonged period of time. DESIGN: Prospective cohort study. SETTING: Four neurological outpatient clinics in the Netherlands. PARTICIPANTS: One hundred nineteen community-dwelling people with Parkinson's disease without dementia, because falls are common in this population. MEASUREMENTS: Clinical and demographic data were obtained. The Falls Telephone is a computerized telephone system through which participants can enter the number of falls during a particular period. During a follow-up of 1 to 40 weekly calls, 2,465 calls were made. In total, 173 no-fall entries and 115 fall entries were verified using personal telephone interviews. User experiences were evaluated in 90 of the 119 participants using structured telephone interviews. RESULTS: All no-fall entries and 78% of fall entries were confirmed to be correct. Sensitivity to detect falls was 100%, and specificity was 87%. Users regarded the Falls Telephone as a convenient tool to monitor falls. CONCLUSION: The Falls Telephone is a convenient and reliable instrument to monitor falls. The automated system has high specificity, obviating the need for time-consuming personal follow-up calls in the majority of nonfallers. As such, the Falls Telephone lends itself well to data collection in large trials with prolonged follow-up in participants with Parkinson's disease. PMID- 21314653 TI - Protective neighborhoods: neighborhood proportion of Mexican Americans and depressive symptoms in very old Mexican Americans. AB - Research indicates that neighborhood context can have a significant effect on the health of older adults. The evidence suggests that there may be physical health benefits afforded to Mexican Americans living in ethnically homogenous neighborhoods, despite the relatively high economic risk in such neighborhoods, but few studies have considered the effect of neighborhood ethnic density on mental health outcomes in older adults. This study evaluated the association between neighborhoods with a high proportion of Mexican Americans and depressive symptoms in very old Mexican Americans. Hierarchical linear modeling was used to examine data from Wave 5 (2004/05) of the Hispanic Established Populations for the Epidemiologic Study of the Elderly. Subjects included 1,875 community dwelling Mexican Americans aged 75 and older living in 386 neighborhoods in five states in the southwestern United States (Arizona, California, Colorado, New Mexico, Texas). Depressive symptoms were measured using the Center for Epidemiologic Studies Depression Scale (alpha=0.88). Results showed that, in very old men, there was a significant negative association between percentage of Mexican Americans in the neighborhood and depressive symptoms (P=.01). In women, the direction of the association was the same, but the effect was not significant. These findings suggest that the proportion of Mexican Americans in the neighborhood matter more for very old Mexican American men than women. Further research may inform screening and treatment for depressive symptoms based on differences in neighborhood composition. Recommendations include culturally customized programs that offer older Mexican Americans greater mobility and access to programs and opportunities in culturally identifiable neighborhoods. PMID- 21314654 TI - Sustainability and scalability of the hospital elder life program at a community hospital. AB - The Hospital Elder Life Program (HELP), an effective intervention to prevent delirium in older hospitalized adults, has been successfully replicated in a community teaching hospital as a quality improvement project. This article reports on successfully sustaining the program over 7 years and expanding its scale from one to six inpatient units at the same hospital. The program currently serves more than 7,000 older patients annually and is accepted as the standard of care throughout the hospital. Innovations that enhanced scalability and widespread implementation included ensuring dedicated staffing for the program, local adaptations to streamline protocols, continuous recruitment of volunteers, and more-efficient data collection. Outcomes include a lower rate of incident delirium; shorter length of stay (LOS); greater satisfaction of patients, families, and nursing staff; and significantly lower costs for the hospital. The financial return of the program, estimated at more than $7.3 million per year during 2008, comprises cost savings from delirium prevention and revenue generated from freeing up hospital beds (shorter LOS of HELP patients with and without delirium). Delirium poses a major challenge for hospital quality of care, patient safety, Medicare no-pay conditions, and costs of hospital care for older persons. Faced with rising numbers of elderly patients, hospitals can use HELP to improve the quality and cost-effectiveness of care. PMID- 21314655 TI - Postdiarrheal hemolytic uremic syndrome in persons aged 65 and older in foodnet sites, 2000-2006. PMID- 21314656 TI - Can improved obstacle avoidance performance explain the effectiveness of a multimodal falls prevention program for persons with osteoporosis? PMID- 21314657 TI - Directing attention externally improves continuous visuomotor skill performance in older adults who have undergone cancer chemotherapy. PMID- 21314658 TI - Multiple health behaviors and mortality risk in older adults. PMID- 21314659 TI - The fall telephone for falls assessment in frail older persons; feasibility, reliability, and validity. PMID- 21314660 TI - Frailty index for patients with coronary artery disease. PMID- 21314662 TI - Neuroimaging in dementia. PMID- 21314663 TI - Guideline-driven polypharmacy in elderly, multimorbid patients is basically flawed: there are almost no guidelines for these patients. PMID- 21314665 TI - The quest for biomarkers of Alzheimer's disease. PMID- 21314666 TI - Functional abnormalities and cerebral atrophy in posttraumatic stress disorder and dementia: is there a causal link between the two diseases? PMID- 21314667 TI - Abnormal dental status? PMID- 21314668 TI - Retraction. Muscle volume and strength and arterial compliance after walk training with blood flow reduction in elderly women. PMID- 21314670 TI - Two states of active spermatogenesis switch between reproductive and non reproductive seasons in the testes of the medaka, Oryzias latipes. AB - Seasonal change in spermatogenesis was examined in the restricted spermatogonium type testes of a teleost, Oryzias latipes. Histological observation revealed that the number of each stage of germ cells during most of the non-reproductive season, from October to January (O-J period) was nearly half of that during the reproductive season, from May to July (M-J period), except for type B spermatogonia (B-gonia), which was actually equal. As a result, the ratio of primary spermatocytes (P-cytes) to B-gonia was remarkably small in the O-J period. Despite the differences between both time periods, the proliferative activity of type A spermatogonia (A-gonia), B-gonia, or P-cytes was at a similar level in both periods. Moreover, in cultured testes treated with bromodeoxyuridine as a cell-lineage tracer, P-cytes differentiated to spermatids in 11-15 days in both M-J and O-J periods. These indicate that spermatogenesis is active in each period at a different state. In the spermatogenic testis, A-gonial proliferation was maintained by human follicle stimulating hormone/luteinizing hormone in culture. Whereas cell death of B-gonia and/or P-cytes gradually increased in the M-J period in spite of those cells being constant in population sizes. In transition to the O-J period, A-gonia and P-cytes first decreased, which was accompanied by a decrease in proliferative activity of A-gonia and relative increase of dead cells from B-gonia and/or P-cytes against live P-cytes. These suggest that A-gonial proliferation and cell death of B-gonia and/or P cytes that is induced coordinately with B-gonial differentiation are critical for the spermatogenic control. PMID- 21314671 TI - Novel functions of ribosomal protein S6 in growth and differentiation of Dictyostelium cells. AB - We have previously shown that in Dictyostelium cells a 32 kDa protein is rapidly and completely dephosphorylated in response to starvation that is essential for the initiation of differentiation (Akiyama & Maeda 1992). In the present work, this phosphoprotein was identified as a homologue (Dd-RPS6) of ribosomal protein S6 (RPS6) that is an essential member for protein synthesis. As expected, Dd-RPS6 seems to be absolutely required for cell survival, because we failed to obtain antisense-RNA mediated cells as well as Dd-rps6-null cells by homologous recombination in spite of many trials. In many kinds of cell lines, RPS6 is known to be located in the nucleus and cytosol, but Dd-RPS6 is predominantly located in the cell cortex with cytoskeletons, and in the contractile ring of just-dividing cells. In this connection, the overexpression of Dd-RPS6 greatly impairs cytokinesis during axenic shake-cultures in growth medium, resulting in the formation of multinucleate cells. Much severe impairment of cytokinesis was observed when Dd-RPS6-overexpressing cells (Dd-RPS6(OE) cells) were incubated on a living Escherichia coli lawn. The initiation of differentiation triggered by starvation was also delayed in Dd-RPS6(OE) cells. In addition, Dd-RPS6(OE) cells exhibit defective differentiation into prespore cells and spores during late development. Thus, it is likely that the proper expression of Dd-RPS6 may be of importance for the normal progression of late differentiation as well as for the initiation of differentiation. PMID- 21314672 TI - The feasibility of non-viral gene transfer to the diaphragm in vivo. AB - Gene transfer using electroporation is an essential method for the study of developmental biology, especially to understand the internal control of degeneration and apoptosis of the muscle cells that occurs earlier and quicker than the usual degeneration process occurring by aging. Such experimental studies may have a role in developing new strategies for treating patients suffering from inherited primary myopathies such as Duchenne muscular dystrophy (DMD). The present study was designed to evaluate the feasibility of electroporation mediated transfer of reporter genes to the diaphragm in vivo. This is the first report of gene transfer of naked plasmid DNA into the diaphragm muscle in vivo using electroporation. Our results showed that in vivo gene transfer of naked plasmid DNA into the diaphragm muscle using electroporation is feasible. PMID- 21314674 TI - Heterogeneity of mouse primordial germ cells reflecting the distinct status of their differentiation, proliferation and apoptosis can be classified by the expression of cell surface proteins integrin alpha6 and c-Kit. AB - Primordial germ cells (PGCs) in mouse embryos likely include heterogeneous cells having distinct cellular properties. In the present study, we found that heterogeneity of PGCs can be defined by the expression of integrin alpha6 and c Kit. The changes in integrin alpha6 and c-Kit expression in PGCs were obvious as embryonic development progressed, and the PGCs became a mixture of populations consisting of cells with distinct levels of cell surface protein expression. The changes and heterogeneity of cell surface protein expression mainly reflected asynchronous differentiation of PGCs. Apoptosis of PGCs was biased in populations of c-Kit or integrin alpha6 negative PGCs at particular developmental stages, suggesting possible linkage between PGC apoptosis and the levels of expression of these cell surface proteins. Histochemical analysis confirmed the heterogeneous expression of c-Kit and integrin alpha6 in PGCs in embryonic gonads, and revealed that PGCs showing different levels of integrin alpha6 or c-Kit expression and the apoptotic PGCs were scattered and did not show specific localization within gonads. The present study enables us to analyze and isolate populations of living PGCs showing a distinct status of differentiation, or different properties of proliferation or of cell death in individual embryos, and provides a new strategy to examine the mechanisms of PGC development. PMID- 21314673 TI - Substantial changes of cellular iron homeostasis during megakaryocytic differentiation of K562 cells. AB - We investigated the remodeling of iron metabolism during megakaryocytic development of K562 cells. Differentiation was successfully verified by increase of the megakaryocytic marker CD61 and concomitant decrease of the erythroid marker gamma-globin. The reduction of erythroid properties was accompanied by changes in the cellular iron content and in the expression of proteins regulating cellular iron homeostasis. Independent of available inorganic or transferrin bound extracellular iron, total intracellular iron increases while the iron-to protein ratio decreases. The iron exporter ferroportin is downregulated within 1 6 h, followed by downregulation of transferrin receptor-1 (TfR1) and ferritin heavy chain (H-ferritin) mainly after 24-48 h. The hemochromatosis protein-1, a ligand of TfR1, peaked after 24 h. All effects were independent of iron supply with the exception of H-ferritin, which was restored by excess iron. While alterations of CD61, TfR1 and ferritin expression were revoked by a protein kinase C inhibitor, downregulation of ferroportin remained unaffected. PMID- 21314675 TI - Repressive but not activating epigenetic modifications are aberrant on the inactive X chromosome in live cloned cattle. AB - X inactivation is the process of a chromosome-wide silencing of the majority of genes on the X chromosome during early mammalian development. This process may be aberrant in cloned animals. Here we show that repressive modifications, such as methylation of DNA, and the presence of methylated histones, H3K9me2 and H3K27me3, exhibit distinct aberrance on the inactive X chromosome in live clones. In contrast, H3K4me3, an active gene marker, is obviously missing from the inactive X chromosome in all cattle studied. This suggests that the disappearance of active histone modifications (H3K4me3) seems to be more important for X inactivation than deposition of marks associated with heterochromatin (DNA methylation, H3K27me3 and H3K9me2). It also implies that even apparently normal clones may have subtle abnormalities in repressive, but not activating epigenetic modifications on the inactive X when they survive to term. We also found that the histone H3 methylations were enriched and co-localized at q21-31 of the active X chromosome, which may be associated with an abundance of LINE1 repeat elements. PMID- 21314676 TI - Xtr, a plural tudor domain-containing protein, coexists with FRGY2 both in cytoplasmic mRNP particle and germ plasm in Xenopus embryo: its possible role in translational regulation of maternal mRNAs. AB - Xtr is present exclusively in early embryonic and germline cells. We have previously shown that loss-of-function of the Xtr in embryos causes arrest of karyokinesis progression. Since Xtr contains plural tudor domains, which are known to associate with target proteins directly, we examined Xtr-interacting proteins by immunoprecipitation with an anti-Xtr monoclonal antibody and detected a few RNA-binding proteins such as FRGY2, a component of messenger ribonucleoprotein (mRNP) particle. The coexistence of Xtr with FRGY2 by constituting an mRNP particle was further confirmed by gel filtration assay. Search of mRNAs in the immunoprecipitate with Xtr suggested that the Xtr associated molecules included several mRNAs, of which translational products were known to play crucial roles in karyokinesis progression (RCC1, XRHAMM, and so on) and in germ cell development (XDead end). Immunohistochemical observation clearly showed the co-localization of Xtr with FRGY2 also in germ plasm, in which XDead end mRNA has been shown to be localized specifically. Taken together, we proposed the possible role of Xtr in translational activation of the maternal mRNAs repressed in mRNP particle. PMID- 21314677 TI - Amphetamine-associated seizures: clinical features and prognosis. AB - Forty-four patients presenting with first-ever seizure within 24 h of illicit use of amphetamine or related analogs (amphetamine-associated seizures, AAS) were identified over 8 years. Patients with AAS were compared to control groups of other first-ever seizure patients (provoked n = 126 and unprovoked n = 401). Cumulative probability of recurrence was calculated using Kaplan-Meier analysis. Seizure recurrence and development of epilepsy were less likely in patients with AAS compared to provoked or unprovoked controls. Forty percent of patients with AAS had clinical risk factors for epilepsy, epileptiform abnormalities on electroencephalography (EEG), or an epileptogenic lesion on neuroimaging. Sleep deprivation was more frequently present in those with AAS. AAS likely relate to an intrinsic proconvulsant effect of these drugs combined with patient susceptibility and environmental factors. PMID- 21314678 TI - Pregabalin effect on steady-state pharmacokinetics of carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, valproate, and tiagabine. AB - By reducing neuronal excitability through selective binding to the alpha(2)delta subunit of voltage-dependent calcium channels, pregabalin effectively treats epilepsy, chronic pain, and anxiety disorders. To evaluate if pregabalin coadministration affects pharmacokinetics of other antiepileptic drugs, population pharmacokinetic analyses using NONMEM software were performed on data from three epilepsy trials involving seven antiepileptic drugs with pregabalin as add-on therapy. Results demonstrated that pregabalin did not alter the steady state plasma concentrations of carbamazepine, lamotrigine, phenobarbital, phenytoin, tiagabine, topiramate, and valproate. Furthermore, the small percent change in the population estimate of antiepileptic drug plasma clearance values ( 2% to +7%) suggests that pregabalin coadministration exerted no significant effect on the pharmacokinetics of these antiepileptic drugs, with the possible exception of tiagabine (+34.9%). These findings are in agreement with those of previously published reports. A further clarification study is necessary for tiagabine. In conclusion, it appears that pregabalin can be coadministered with other antiepileptic drugs without concern for significantly altering their pharmacokinetic profiles. PMID- 21314679 TI - Hyponatremia and risk of seizures: a retrospective cross-sectional study. AB - This retrospective cross-sectional study was carried out to study the association between different levels of hyponatremia and the occurrence of epileptic seizures in patients without a prior epilepsy diagnosis. We identified from the hospital database, 363 inpatients of a Swedish County hospital who between March 2003 and August 2006 were found to have serum sodium levels <125 mM. Medical records were reviewed and we identified 11 patients with seizures in conjunction with their hyponatremia. Seizures were the only neurologic manifestation of hyponatremia in patients with serum sodium levels >115 mM. Of 150 patients reviewed with serum sodium levels of 120-124 mM, one had a seizure. Using 120-124 mM as reference, odds ratios (95% confidence interval) for having seizures at serum sodium levels of 115-119 mM was 3.85 (0.40-37.53), 8.43 (0.859-82.85) at 110-114 mM, and 18.06 (1.96-166.86) at <110 mM. PMID- 21314680 TI - Michael Foundation Forum 2010. PMID- 21314681 TI - Considering economic reality in calculating the financial burden of epilepsy in China. PMID- 21314682 TI - Regional collaboration in healthcare: a view from a health care initiative for people with epilepsy in rural areas of China. PMID- 21314683 TI - Announcement of a new Chinese name for epilepsy. PMID- 21314684 TI - Biogeochemical evolution of a landfill leachate plume, Norman, Oklahoma. AB - Leachate from municipal landfills can create groundwater contaminant plumes that may last for decades to centuries. The fate of reactive contaminants in leachate affected aquifers depends on the sustainability of biogeochemical processes affecting contaminant transport. Temporal variations in the configuration of redox zones downgradient from the Norman Landfill were studied for more than a decade. The leachate plume contained elevated concentrations of nonvolatile dissolved organic carbon (NVDOC) (up to 300 mg/L), methane (16 mg/L), ammonium (650 mg/L as N), iron (23 mg/L), chloride (1030 mg/L), and bicarbonate (4270 mg/L). Chemical and isotopic investigations along a 2D plume transect revealed consumption of solid and aqueous electron acceptors in the aquifer, depleting the natural attenuation capacity. Despite the relative recalcitrance of NVDOC to biodegradation, the center of the plume was depleted in sulfate, which reduces the long-term oxidation capacity of the leachate-affected aquifer. Ammonium and methane were attenuated in the aquifer relative to chloride by different processes: ammonium transport was retarded mainly by physical interaction with aquifer solids, whereas the methane plume was truncated largely by oxidation. Studies near plume boundaries revealed temporal variability in constituent concentrations related in part to hydrologic changes at various time scales. The upper boundary of the plume was a particularly active location where redox reactions responded to recharge events and seasonal water-table fluctuations. Accurately describing the biogeochemical processes that affect the transport of contaminants in this landfill-leachate-affected aquifer required understanding the aquifer's geologic and hydrodynamic framework. PMID- 21314686 TI - The making of a risk object: AIDS, gay citizenship and the meaning of blood donation in Sweden in the early 1980s. AB - In the early 1980s acquired immune deficiency syndrome (AIDS) presented a danger to the blood supply, the extent of which was difficult to ascertain before a reliable test became available in 1985. In a situation of uncertainty, the major Swedish gay organisation in early 1983 recommended voluntary exclusion from blood donation by their members, while internationally gay organisations protested and Swedish medical authorities hesitated about the appropriate action to take. At stake were definitions of gay citizenship, risk and the gift of blood. The article uses three sociological approaches to understand the controversies around blood from men-who-have-sex-with-men as a risk to public health. An institutional approach is used to situate the symbolic meaning of blood donation within the specific Swedish blood collection regime, and thus the possible stigma of exclusion from donation practices. The article then details the evolution of different risk objects, based on different actors' situated knowledge of the danger, and discusses the different framing conditions influencing decision making by the various actors involved. The analysis uses extensive archival and secondary material to trace decisions taken in the gay movement, medical authorities and blood centres, and to assess their outcome on the spread of AIDS via the blood supply. PMID- 21314687 TI - Desperately seeking cancer drugs: explaining the emergence and outcomes of accelerated pharmaceutical regulation. AB - Government regulators have increasingly accelerated new cancer drugs on to the market by granting them approval based on less clinical data supporting drug efficacy than permitted under standard regulations. With more lenient regulatory standards, pharmaceutical companies have keenly sought to develop cancer drugs. Focusing on the US, this article examines how the emergence and implementation of such accelerated approvals should be understood, particularly in relation to corporate bias and disease-politics theories. Drawing on longitudinal and case study data analysis, it is argued that the emergence of accelerated approval regulations for cancer drugs should be regarded primarily as part of a deregulatory regime driven by the interests of the pharmaceutical industry in partnership with all major aspects of the state, rather than as a response to patient activism in the aftermath of AIDS. Furthermore, even in cases when some patients successfully demand accelerated marketing approval of cancer drugs, such approval by regulators, while in manufacturers' interests, may not be in the interests of patients' health because the political culture of the regulatory agency is reluctant to uphold its own techno-regulatory standards of public health protection when that would challenge the agenda-setting influence of manufacturers, including industry collaborations with patients and the medical profession. PMID- 21314688 TI - Healthcare identities at the crossroads of service modernisation: the transfer of NHS clinicians to the independent sector? AB - Health policies increasingly support private businesses to take an active role in the organisation and delivery of public healthcare services. For the English NHS, this is exemplified by the introduction of Independent Sector Treatment Centres. A number of these facilities involve the wholesale secondment of NHS clinicians to the private sector which, we suggest, raises important questions about the identities of healthcare professionals accustomed to working in the public sector. Our paper investigates this transition highlighting three prominent discontinuities in clinical work: the ethos of private sector ownership, new lines of authority and fragmented relationships. Drawing on Giddens, we examine how clinicians experience and interpret these changes and how they keep their biographical 'narrative going'. The 'pioneers' interpreted the independent sector as an opportunity to re-invigorate their practice through new roles, relationships and higher quality care; the 'guardians' as an opportunity to replicate and protect the customs and standards of the NHS in the private sector; whilst the 'marooned' longed to return to the NHS. Our study illustrates how the sectoral context can shape healthcare identities, and how contemporary reforms aimed at promoting partnerships across public and private sectors can have profound implications for clinicians. PMID- 21314689 TI - Defending the boundaries of science: AIDS denialism, peer review and the Medical Hypotheses saga. AB - This paper explores the boundary work undertaken by HIV scientists and activists against the journal Medical Hypotheses over its lack of peer review. Their action was sparked by the publication of an article by Peter Duesberg claiming that HIV does not cause AIDS and that antiretrovirals do more harm than good. Precisely because such 'AIDS denialism' can undermine HIV prevention and treatment interventions, as was demonstrably the case in South Africa under President Mbeki, the episode raised questions about when, in the interests of public health, the boundaries of legitimate scientific debate may be drawn to exclude unreasonable and unscholarly arguments. The paper argues that normative concerns motivated the complaints which resulted in the publisher withdrawing Duesberg's paper and imposing editorial policy changes on Medical Hypotheses. Concerns were raised about the implications for academic freedom of this boundary work in defence of peer review as a core practice in science. The paper concludes, however, that Duesberg's freedom to write what he likes remains intact, but that if he wants his work to carry the imprimatur of science, he now has to subject it to peer review. PMID- 21314690 TI - Modernisation as a professionalising strategy: the case of critical care in England. AB - There has been broad agreement about how to characterise the processes of 'modernisation' of the public sector in welfare societies, but rather less consensus on the impact of this modernisation on professionals. This paper takes critical care in England as a case study to explore how professionals in one setting account for the changes associated with modernisation. In contrast to reports from other arenas, critical care professionals were positive about the processes and outcomes of 'modernisation' in general, and there was a surprising lack of nostalgia in their accounts of organisational changes. However, joking comments suggested considerable scepticism about the initiatives explicitly associated with the national organisation that was charged with 'modernising' critical care, the Modernisation Agency. We suggest that the relative optimism of staff is in part explained by historical and political contingencies which meant that critical care, as a relatively new clinical specialty, benefited in tangible ways from modernisation. Further, all staff groups were able to attribute gains, rather than losses, in autonomy and authority to the modernisation of critical care. Their accounts suggest that modernisation can be a professionalising strategy, with responses to change being neither resistant nor compliant, but sceptically strategic. PMID- 21314691 TI - Influence of post system and remaining coronal tooth tissue on biomechanical behaviour of root filled molar teeth. AB - AIM: To investigate ex vivo the influence of post system and amount of remaining coronal tooth tissue on the fracture resistance, fracture mode and strain of root filled molar teeth. METHODOLOGY: Seventy mandibular human molar teeth were divided into seven groups (n = 10), one control (sound teeth) and six experimental groups resulting from the interaction between the two study factors: post system (Pa, post absence; Gfp, glass fibre post; Cmp, cast Ni-Cr alloy post and core) and amount of remaining coronal tooth tissue (Fe, 2 mm of ferrule; NFe, no ferrule). Teeth in the experimental groups were restored with metal crowns. For the strain gauge test, two strain gauges per sample were attached on the buccal and proximal root surfaces, and the samples of each group (n = 5) were submitted to a load of 0-100N. Fracture resistance (N) was assessed in a mechanical testing device (n = 10). Strain gauge and fracture resistance data were analysed by two-way anova (3 * 2) followed by the Tukey's HSD and Duncan's test (alpha = 0.05). The failure mode was evaluated using an optical stereomicroscope and classified according to the location of the failure. RESULTS: The absence of ferrule was associated with lower fracture resistance regardless of the post system. Groups restored with glass fibre post and cast Ni Cr alloy post and core had similar fracture resistance and higher values than groups without posts, regardless of the remaining coronal tooth tissue. Teeth with no ferrule and cast Ni-Cr alloy post and core resulted in catastrophic fractures and those with no ferrule and glass fibre post or no ferrule and post absence resulted in restorable failures. Buccal strain was higher in sound teeth and lower in teeth without posts. Glass fibre post insertion decreased the buccal strain compared to the teeth with ferrule and absence of post. CONCLUSIONS: Two millimetre of ferrule had a significant influence on cusp strain, fracture resistance and failure mode. The glass fibre post was as effective as the cast Ni Cr alloy post and core in the restoration of root filled molars regardless of the remaining tooth tissue. Absence of a post decreased the fracture resistance and increased the cusp strain. PMID- 21314692 TI - Ethanol exposure in early adolescence inhibits intrinsic neuronal plasticity via sigma-1 receptor activation in hippocampal CA1 neurons. AB - BACKGROUND: We demonstrated previously that rats exposed to chronic intermittent ethanol (CIE) vapors in early adolescence show increased magnitudes of long-term potentiation (LTP) of excitatory transmission when recorded at dendritic synapses in hippocampus. Large amplitude LTP following CIE exposure is mediated by sigma-1 receptors; however, not yet addressed is the role of sigma-1 receptors in modulating the intrinsic properties of neurons to alter their action potential firing during LTP. METHODS: Activity-induced plasticity of spike firing was investigated using rat hippocampal slice recordings to measure changes in both field excitatory postsynaptic potentials (fEPSPs) and population spikes (pop. spikes) concomitantly at dendritic inputs and soma of CA1 pyramidal neurons, respectively. RESULTS: We observed unique modifications in plasticity of action potential firing in hippocampal slices from CIE exposed adolescent rats, where the induction of large amplitude LTP by 100 Hz stimulations was accompanied by reduced CA1 neuronal excitability--reflected as decreased pop. spike efficacy and impaired activity-induced fEPSP-to-spike (E-S) potentiation. In contrast, LTP induction in ethanol-naive control slices resulted in increased spike efficacy and robust E-S potentiation. E-S potentiation impairments emerged at 24 hours after CIE treatment cessation, but not before the alcohol withdrawal period, and were restored with bath-application of the sigma-1 receptor selective antagonist BD1047, but not the NMDA receptor antagonist d-AP5. Further evidence revealed a significantly shortened somatic fEPSP time course in adolescent CIE-withdrawn hippocampal slices during LTP; however, paired-pulse data show no apparent correspondence between E-S dissociation and altered recurrent feedback inhibition. CONCLUSIONS: Results here suggest that acute withdrawal from adolescent CIE exposure triggers sigma-1 receptors that act to depress the efficacy of excitatory inputs in triggering action potentials during LTP. Such withdrawal-induced depression of E-S plasticity in hippocampus probably entails sigma-1 receptor modulation of 1 or several voltage-gated ion channels controlling the neuronal input-output dynamics. PMID- 21314693 TI - Development of ethanol withdrawal-related sensitization and relapse drinking in mice selected for high- or low-ethanol preference. AB - BACKGROUND: Previous studies have shown that high alcohol consumption is associated with low withdrawal susceptibility, while at the same time, other studies have shown that exposure to ethanol vapor increases alcohol drinking in rats and mice. In the present studies, we sought to shed light on this seeming contradiction using mice selectively bred for High- (HAP) and Low- (LAP) Alcohol Preference, first, assessing these lines for differences in signs of ethanol withdrawal and second, for differences in the efficacy of intermittent alcohol vapor exposure on elevating subsequent ethanol intake. METHODS: Experiment 1 examined whether these lines of mice differed in ethanol withdrawal-induced CNS hyperexcitability and the development of sensitization to this effect following intermittent ethanol vapor exposure. Adult HAP and LAP lines (replicates 1 and 2), and the C3H/HeNcr inbred strain (included as a control genotype for comparison purposes) received intermittent exposure to ethanol vapor and were evaluated for ethanol withdrawal-induced seizures assessed by scoring handling induced convulsions (HIC). Experiment 2 examined the influence of chronic intermittent ethanol exposure on voluntary ethanol drinking. Adult male and female HAP-2 and LAP-2 mice, along with male C57BL/6J (included as comparative controls) were trained to drink 10% ethanol using a limited access (2 h/d) 2 bottle choice paradigm. After stable baseline daily intake was established, mice received chronic intermittent ethanol vapor exposure in inhalation chambers. Ethanol intake sessions resumed 72 hours after final ethanol (or air) exposure for 5 consecutive days. RESULTS: Following chronic ethanol treatment, LAP mice exhibited overall greater withdrawal seizure activity compared with HAP mice. In Experiment 2, chronic ethanol exposure/withdrawal resulted in a significant increase in ethanol intake in male C57BL/6J, and modestly elevated intake in HAP 2 male mice. Ethanol intake for male control mice did not change from baseline levels of intake. In contrast, HAP-2 female and LAP-2 mice of both sexes did not show changes in ethanol intake as a consequence of intermittent ethanol exposure. CONCLUSIONS: Overall, these results indicate that the magnitude of ethanol withdrawal-related seizures is inversely related to inherited ethanol intake preference. Additionally, intermittent ethanol vapor exposure appears more likely to affect high-drinking mice (C57BL/6J and HAP-2) than low drinkers, although these animals are less affected by ethanol withdrawal. PMID- 21314695 TI - An alcohol training program improves Chinese nurses' knowledge, self-efficacy, and practice: a randomized controlled trial. AB - BACKGROUND: Excessive alcohol use has been associated with health, social and legal problems. Helping health care providers to manage hazardous or harmful drinkers is an important worldwide issue. Alcohol is a legal and accessible substance in Taiwan and is viewed as an acceptable drink for relieving stress and enhancing socialization in Chinese culture. These cultural factors may contribute to drinking problems being easily ignored and to lack of alcohol training programs for health care providers. METHODS: For this randomized controlled clinical trial with 1- and 3-month posttests, six hospitals were randomly selected throughout Taiwan and were randomly assigned to an experimental or control group. In these hospitals, nurses were selected from the Emergency Department, psychiatric, and gastrointestinal medical-surgical units where most patients with alcohol problems are seen. For the experimental group, nurses received a 1.5-hour alcohol training program consisting of an introduction to alcohol, factors influencing alcohol drinking, impacts of high-risk drinking on a person, as well as introduction to and practice of the Alcohol Use Disorders Identification Test and brief alcohol intervention. The program also discussed Taiwanese nurses' perceived barriers and facilitators to intervening for problem alcohol use. Teaching strategies included lecture, discussion, demonstration, practice, role-playing, and sharing experiences. The control group did not receive any training. Data were collected at pretest, 1-month, and 3-month posttests using a self-report questionnaire on knowledge, self-efficacy, clinical practice scales, and a demographic form. RESULTS: The study was completed by 395 nurses, including 191 nurses in the experimental group and 204 nurses in the control group. Knowledge scores significantly improved in the experimental group at the 1- and 3-month posttests but not for the control group. Similarly, nurses' self-efficacy and clinical practice scores significantly improved in the experimental group at the 3-month posttest but not for the control group. CONCLUSIONS: Our results suggest that the alcohol training program could be used to enhance nurses' alcohol knowledge, self-efficacy, and clinical practice not only in Taiwan but also other countries. PMID- 21314694 TI - Genomewide association analysis of symptoms of alcohol dependence in the molecular genetics of schizophrenia (MGS2) control sample. AB - BACKGROUND: While genetic influences on alcohol dependence (AD) are substantial, progress in the identification of individual genetic variants that impact on risk has been difficult. METHODS: We performed a genome-wide association study on 3,169 alcohol consuming subjects from the population-based Molecular Genetics of Schizophrenia (MGS2) control sample. Subjects were asked 7 questions about symptoms of AD which were analyzed by confirmatory factor analysis. Genotyping was performed using the Affymetrix 6.0 array. Three sets of analyses were conducted separately for European American (EA, n = 2,357) and African-American (AA, n = 812) subjects: individual single nucleotide polymorphisms (SNPs), candidate genes and enriched pathways using gene ontology (GO) categories. RESULTS: The symptoms of AD formed a highly coherent single factor. No SNP approached genome-wide significance. In the EA sample, the most significant intragenic SNP was in KCNMA1, the human homolog of the slo-1 gene in C. Elegans. Genes with clusters of significant SNPs included AKAP9, phosphatidylinositol glycan anchor biosynthesis, class G (PIGG), and KCNMA1. In the AA sample, the most significant intragenic SNP was CEACAM6 and genes showing empirically significant SNPs included KCNQ5, SLC35B4, and MGLL. In the candidate gene based analyses, the most significant findings were with ADH1C, nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1) and ankyrin repeat and kinase domain containing 1 (ANKK1) in the EA sample, and ADH5, POMC, and CHRM2 in the AA sample. The ALIGATOR program identified a significant excess of associated SNPs within and near genes in a substantial number of GO categories over a range of statistical stringencies in both the EA and AA sample. CONCLUSIONS: While we cannot be highly confident about any single result from these analyses, a number of findings were suggestive and worthy of follow-up. Although quite large samples will be needed to obtain requisite power, the study of AD symptoms in general population samples is a viable complement to case-control studies in identifying genetic risk variants for AD. PMID- 21314696 TI - Item response theory analysis of binge drinking and its relationship to lifetime alcohol use disorder symptom severity in an American Indian community sample. AB - BACKGROUND: Item response theory (IRT) has been used to examine alcohol use disorder (AUD) symptoms and their psychometric properties but has not been previously applied to AUD symptoms from an American Indian sample. METHODS: Lifetime DSM-IV AUD symptoms and binge drinking (5+ drinks men/4+ drinks women) at >=1, >=4, >=8, and >=15 days per month during the period of heaviest lifetime drinking criteria were assessed in 530 American Indian participants. Exploratory factor analysis was used to examine the factor structure of the 10 AUD symptoms and each alcohol consumption criterion. Two-parameter IRT models generated marginal maximum likelihood estimates for discrimination (a) and threshold (b) parameters for 10 DSM-IV AUD symptoms and each consumption criterion. Differential item functioning (DIF) analysis was used to assess AUD symptom severity in groups defined by gender and age at interview. RESULTS: The AUD symptoms of "Withdrawal" and "Activities Given Up" were the most severe symptoms. "Tolerance" and "Social/Interpersonal Problems" were the least severe. All AUD symptoms fell on the moderate portion of the severity continuum, except "Withdrawal," which fell at the lower end of the severe portion. The consumption criterion of 5+/4+ (male/female) at >=8 times per month demarcated the portion of the severity continuum where AUD symptoms began to occur at a probability of 50%. DIF analysis showed significant gender and age at interview differences for "Hazardous Use,""Tolerance," and "Activities Given Up," but not for the other AUD symptoms. CONCLUSIONS: In this American Indian community sample, alcohol abuse and dependence did not represent distinct disorders. Only one AUD symptom was found outside the moderate portion of the underlying AUD severity continuum. Drinking 5+/4+ (male/female) drinks at a frequency of >=8 times per month during the period of heaviest lifetime drinking was found to function well as both a risk and a diagnostic criterion for lifetime DSM-IV AUD. DSM-IV AUD symptom criteria, as currently assessed, may be limited in their ability to capture the full range of symptom severity of AUDs, at least in this high-risk population. PMID- 21314698 TI - Recovery of pacemakers and defibrillators for analysis and device advance directives: electrophysiologists' perspectives. AB - BACKGROUND: Following high-profile device failures, the Heart Rhythm Society emphasized the need for postmarketing surveillance by recommending that physicians return all explanted devices to the manufacturer for analysis. METHODS: We conducted a national survey of electrophysiologists (EPs) regarding recovery for analysis of explanted pacemakers and implantable cardioverter defibrillators (devices), and attitudes toward device-specific advance directives to facilitate return of devices. Online survey invitations were sent in four waves from December 2008 to June 2009 to 300 e-mail addresses from the Heart Rhythm Society member database. RESULTS: From 250 invitations, there were 95 responses (38%). Demographics included average age 50 years (range, 31-87); 95% male; 81% Caucasian. Only 23% reported returning all explanted devices to the manufacturers. Of all the respondents, 32% discarded >10 devices/year as medical waste, 42% stored devices in a box in the electrophysiology lab, and 10% donated at least 1 device/year to charity for reuse overseas. Sixty-seven percent felt that it would not be helpful to have an advance directive specifying what the patient would want done with their device postmortem. CONCLUSIONS: Few EPs return all explanted devices or send interrogation reports to the manufacturers, though nearly all said it was easy to do so. A majority either dispose of explanted devices as medical waste or store them in laboratories or offices, and a small percentage donate for reuse in underserved nations or to veterinary hospitals. This study suggests a need for initiatives such as educational campaigns to increase the retrieval and return of devices, either for analysis or reuse. PMID- 21314697 TI - The enduring influence of drinking motives on alcohol consumption after fateful trauma. AB - OBJECTIVE: Drinking motives predict later levels of alcohol consumption and development of alcohol dependence, but their effects on stress-related drinking are less clear. Proximity to the terrorist attack on the World Trade Center (WTC) on 9/11/01 was significantly associated with alcohol consumption 1 and 16 weeks after 9/11/01. We investigated the relationship between drinking motives measured a decade earlier, proximity to the WTC, and drinking after 9/11/01. This event constitutes a natural experiment for studying the effects of previously measured drinking motives on alcohol consumption after fateful trauma. METHODS: Adult drinkers (N = 644) residing in a New Jersey county were evaluated for four drinking motives: coping with negative affect, for enjoyment, for social facilitation and social pressure. After 9/11/01, their exposure to the WTC attack and subsequent drinking were assessed. Poisson regression was used to assess the relationships between proximity to the WTC, drinking motives and post-9/11/01 drinking; models were adjusted for alcohol dependence, age, gender and race. RESULTS: Drinking to cope with negative affect predicted alcohol consumption 1 week after 9/11/01 (p = 0.04) and drinking for enjoyment predicted drinking 1 and 16 weeks after 9/11/01 (p = 0.001 and 0.01, respectively). The associations were independent of proximity to the WTC. No interactions were observed between drinking motives, proximity to the WTC or lifetime alcohol dependence. CONCLUSION: Drinking motives a decade earlier predicted higher alcohol consumption after fateful trauma independently from proximity to the WTC on 9/11/01. Results suggest that drinking motives constitute a robust, enduring influence on drinking behavior, including after traumatic experiences. PMID- 21314699 TI - Mechanical comparison of two suture constructs for extra-capsular stifle stabilization. AB - OBJECTIVE: Mechanical evaluation of 2 suture constructs for extracapsular stifle stabilization. STUDY DESIGN: In vitro study. SAMPLE POPULATION: Crimped interlocking loop constructs (ILC) of 45 kg nylon leader line (NLL) and Orthofiber(r) (OF). METHODS: ILC were tightened to 100 N, then crimp secured. Ramp to failure (n=10/group)-Data were derived from force/displacement plots. Stress-relaxation testing (n=10/group)-ILC's were nondestructively loaded and held at resultant displacement as force data were recorded. Incremental, cyclic loading (n=10/group)-ILC's were loaded (5 cycles/set) starting at 100 N and incrementally increased by 50 N (1 and 3 Hz protocols). Loop tension and elongation were recorded after each set. RESULTS: Ramp to failure-initial loop tension was similar (NLL 75.5 +/- 9.5 N; OF 68.7 +/- 10.4 N, P=.140). Tested OF constructs were stiffer (NLL 125.7 +/- 4.0; OF 234.6 +/- 25.0 N/mm, P<=.001), had lower yield load (NLL 193.6 +/- 13.8; OF 137.3 +/- 94.3 N, P<=.001), lower peak load (NLL 873.7 +/- 68.6; OF 653.6 +/- 80.2 N, P<=.001), and lower elongation at failure (NLL 19.1 +/- 1.4; OF 5.2 +/- 1.0 mm, P<=.001) and at yield (NLL 1.52 +/- 0.2; OF 0.3 +/- 0.6 mm, P=.003) than NLL constructs. Yield in NLL ILC's was variable knot tightening/crimp slippage, but only crimp-suture slippage in OF. Stress-relaxation testing-OF demonstrated greater relaxation. Incremental, cyclic loading-induced ILC elongation and tension loss in both groups, independent of loading frequency. NLL lost tension at lower rate, but elongated more than OF. CONCLUSIONS: NLL construct is mechanically superior to OF construct. PMID- 21314700 TI - Multivariate analysis of morphometric characteristics to evaluate risk factors for cranial cruciate ligament deficiency in Labrador retrievers. AB - OBJECTIVES: To determine the combination of conformation characteristics of the pelvic limbs of Labrador Retrievers that best discriminates between limb at risk to develop cranial cruciate ligament (CCL) disease and limbs at low risk using radiographs, computerized tomography (CT) images, and dual-energy X-ray absorptiometry (DEXA). STUDY DESIGN: Cross-sectional clinical study. ANIMALS: Twelve clinically normal and 9 unilaterally CCL-deficient Labrador Retrievers. METHODS: The pelvic limbs of normal dogs were considered as non-predisposed to CCL disease and the contralateral limbs of CCL-deficient dogs as predisposed. Conformation variables, obtained from femur and tibial radiographs, pelvic limb CT images and DEXA studies, of predisposed pelvic limbs were compared with the conformation variables from pelvic limbs of the low-risk group. An ROC curve analysis was used to assess the discriminating properties of conformation variables for several combinations. RESULTS: We determined that a combination of tibial plateau angle (TPA) and femoral anteversion angle (FAA) measured on radiographs was optimal for discriminating predisposed and non-predisposed limbs for CCL disease in Labrador Retrievers. CONCLUSIONS: Assessing predisposition to CCL disease with a combination of conformational measurements is better than using univariate parameters. In the future, TPA and FAA may be used to screen dogs suspected of being susceptible to CCL disease. PMID- 21314701 TI - Use of skin stretchers to elongate a peninsular thoracodorsal axial pattern flap for antebrachial wound closure in a dog. AB - OBJECTIVE: To describe preoperative use of skin stretchers to elongate a peninsular thoracodorsal axial pattern flap to close a large antebrachial wound on a dog. STUDY DESIGN: Case report. ANIMALS: A 21 kg, 7-year-old, male intact mixed breed dog. METHODS: Two skin stretchers were applied to the site of the thoracodorsal axial pattern flap 4 days before surgery. The elastic cables connecting the adhesive pads were tightened daily to increase the skin available for a peninsular thoracodorsal axial pattern flap, which was created and rotated 180 degrees to cover an antebrachial defect to a level 2 cm proximal to the carpus. RESULTS: The entire flap survived; there was a small amount of incisional separation at the distal margin of the flap that healed without further treatment. CONCLUSION: Preoperative skin stretching provided additional skin for the axial pattern flap used. PMID- 21314702 TI - Intrathecal deep digital flexor tenectomy for treatment of septic tendonitis/tenosynovitis in four horses. AB - OBJECTIVE: To describe partial removal of the intrathecal component of the deep digital flexor tendon (DDFT) in horses with chronic septic DDF tendonitis and tenosynovitis unresponsive to conventional therapy, and to report long-term outcome. STUDY DESIGN: Case series. ANIMALS: Horses (n=4). METHODS: Four horses with chronic septic DDF tendonitis and tenosynovitis were treated by surgical tenectomy of the intrathecal component of the DDFT, followed by stabilization in casts and subsequent corrective shoeing. All horses were previously managed unsuccessfully with combinations of conventional therapy consisting of systemic antibiotics, through and through tendon sheath lavage/open drainage, regional limb perfusions, tenoscopy with debridement and transection of the palmar/plantar annular ligament, and intrathecal antibiotics. RESULTS: Time from initial injury/diagnosis to tenectomy ranged from 10 to 210 days. Mean hospitalization time after surgery was 82 days. Long-term follow-up (>1.5 years; mean, 3.8 years) was available. All 4 horses were able to walk comfortably at pasture and were used as broodmares. CONCLUSIONS: Intrathecal tenectomy is a viable surgical procedure for treatment of chronic septic tenosynovitis of the digital sheath that is complicated by septic tendonitis of the DDFT. PMID- 21314703 TI - In vitro effect of ventriculocordectomy before laryngoplasty on abduction of the equine arytenoid cartilage. AB - OBJECTIVE: To determine whether ventriculocordectomy (VCE) performed before prosthetic laryngoplasty (PL) results in increased rima glottidis size compared with PL alone. STUDY DESIGN: Experimental study. ANIMALS: Equine cadaver larynges (n=13). METHODS: Right arytenoid cartilages were maximally abducted using a standard PL technique. Standard PLs were then performed on the left side and the force required to maximally abduct the left arytenoid cartilage recorded (F(max) ). Photographs were taken of the rima glottidis at zero force and at five equal levels of force up to F(max) . The force applied was released, left VCE performed, and photographs repeated. Arytenoid left:right angle quotients (LRQ) and glottic cross-sectional area ratios (CSAR) were calculated at each force level in each condition (PL and VCE-PL). RESULTS: Mean LRQ and CSAR for both PL and VCE-PL increased with increasing force, initially rapidly before plateauing at ~50% of F(max) . LRQ and CSAR were significantly greater for VCE-PL than for PL (P<.001). When VCE was performed before PL, 12% less force was required to achieve an LRQ of 0.8, and 45% less for a CSAR of 0.8. CONCLUSIONS: In vitro, VCE performed before PL enables the arytenoid cartilage to be abducted to a greater degree for a given PL suture force. PMID- 21314704 TI - In situ grazing resistance of Vibrio cholerae in the marine environment. AB - Previous laboratory experiments revealed that Vibrio cholerae A1552 biofilms secrete an antiprotozoal factor that prevents Rhynchomonas nasuta from growing and thus prevents grazing losses. The antiprotozoal factor is regulated by the quorum-sensing response regulator, HapR. Here, we investigate whether the antiprotozoal activity is ecologically relevant. Experiments were conducted in the field as well as under field-like conditions in the laboratory to assess the grazing resistance of V. cholerae A1552 and N16961 (natural frameshift mutation in hapR) biofilms to R. nasuta and Cafeteria roenbergensis. In laboratory experiments exposing the predators to V. cholerae grown in seawater containing high and low glucose concentrations, we determined that V. cholerae biofilms showed increased resistance towards grazing by both predators as glucose levels decreased. The relative resistance of the V. cholerae strains to the grazers under semi-field conditions was similar to that observed in situ. Therefore, the antipredator defense is environmentally relevant and not lost when biofilms are grown in an open system in the marine environment. The hapR mutant still exhibited some resistance to both predators and this suggests that V. cholerae may coordinate antipredator defenses by a combination of density-dependent regulation and environmental sensing to protect itself from predators in its natural habitat. PMID- 21314705 TI - The impact of different soil parameters on the community structure of dominant bacteria from nine different soils located on Livingston Island, South Shetland Archipelago, Antarctica. AB - Microorganisms inhabit very different soil habitats in the ice-free areas of Antarctica, playing a major role in nutrient cycling in cold environments. We studied the soil characteristics and the dominant bacterial composition from nine different soil profiles located on Livingston Island (maritime Antarctica). The total carbon (TC) and total nitrogen (TN) values were high for the vegetated soils, decreasing with depth, whereas the values for the mineral soils were generally low. Soil pH was more acidic for moss-covered soils and neutral to alkaline for mineral soils. Numbers of culturable heterotrophic bacteria were higher at vegetated sites, but significant numbers were also detectable in carbon depleted soils. Patterns of denaturing gradient gel electrophoresis (DGGE) revealed a highly heterogeneous picture throughout the soil profiles. Subsequent sequencing of DGGE bands revealed in total 252 sequences that could be assigned to 114 operational taxonomic units, showing the dominance of members of the Bacteroidetes and Acidobacteria. The results of phospholipid fatty acid analysis showed a lack of unsaturated fatty acids for most of the samples. Samples with a prevalence of unsaturated over saturated fatty acids were restricted to several surface samples. Statistical analysis showed that the dominant soil bacterial community composition is most affected by TC and TN contents and soil physical factors such as grain size and moisture, but not pH. PMID- 21314706 TI - Fate and efficacy of lacticin 3147-producing Lactococcus lactis in the mammalian gastrointestinal tract. AB - Gastrointestinal survival of the bacteriocin-producing strain, Lactococcus lactis DPC6520, was evaluated systematically in vitro and in vivo with a view to using this strain to deliver biologically active lacticin 3147, a broad-spectrum bacteriocin, to the gut. The activity of the lacticin 3147 producer was also evaluated against two clinically relevant pathogens: Clostridium difficile and Listeria monocytogenes. When suspended in an appropriate matrix, the lactococcal strain is capable of surviving simulated gastrointestinal juices similar to the porcine probiotic, Lactobacillus salivarius DPC6005. Upon administration of L. lactis DPC6520 to pigs (n=4), excretion rates of ~10(2) -10(5) CFU g(-1) faeces were observed by day 5. Although passage through the gastrointestinal tract (GIT) did not affect lacticin 3147 production by L. lactis DPC6520 isolates, activity was undetectable in faecal samples by an agar well diffusion assay. Furthermore, L. lactis DPC6520 had no inhibitory effect on C. difficile or other bacterial populations in a human distal colon model, while lactococcal counts declined 10,000-fold over 24 h. The lacticin 3147 producer failed to prevent L. monocytogenes infection in a mouse model, even though a mean L. lactis DPC6520 count of 4.7 * 10(4) CFU g(-1) faeces was obtained over the 5-day administration period. These data demonstrate that L. lactis DPC6520 is capable of surviving transit through the GIT, and yet lacks antimicrobial efficacy in the models of infection used. PMID- 21314707 TI - Association between masticatory performance using a colour-changeable chewing gum and jaw movement. AB - The purpose of this study was to investigate the relationship between masticatory performance as determined using a colour-changeable chewing gum and mandibular movements. Subjects comprised 45 fully dentate adults (23 men, 22 women; mean age, 28.1 years). The gum was chewed for a specified number of chewing strokes (20, 40, 60, 80, 120 or 160 strokes) without any instructions as to chewing side. A colourimeter was used to measure L*, a* and b* values (CIE-L*a*b* colour system) for the chewed gum, then the difference between two colours in the CIE L*a*b* colour space (DeltaE) for each number of chewing strokes was calculated according to a formula. Index of masticatory performance (DeltaE60) for each subject was obtained using DeltaE for 20, 40, 60, 80, 120 and 160 strokes. Mandibular movements were recorded using an opto-electric system with six degrees of freedom. Twelve parameters of mandibular movements relating to amplitude, duration, velocity and angle were computed for each cycle, and mean values for 10 cycles (from cycle 11 to 20) were calculated separately. Stepwise multiple regression analysis identified maximum closing velocity and closing angle as predictors accounting for 18% of the variation in DeltaE60. These results suggest that lower angles of approach to intercuspation and faster speed during closing duration are associated with colour changes in the colour-changeable chewing gum. PMID- 21314708 TI - Occlusal measurement method can affect SEMG activity during occlusion. AB - Occlusal indicators are widely used in dental treatment to measure tooth contacts that occur during occlusion. However, the presence of an indicator may affect the mechanics of occlusion and lead to invalid tooth contact data. The objective of this study was to determine the effect of four indicators (Parkell, silk, T Scan((r)) sensor and paper) on surface electromyography (SEMG) activity during occlusion. Twenty-three subjects performed strong bites and maximum clenches onto the four indicators and natural dentition. Surface electromyography recordings of anterior temporalis and superficial masseter activity and the subjects' perception of each indicator were measured. SEMG activity with the T-Scan((r)) sensor and paper was significantly different (higher masseter activity; P < 0.05) compared to that for natural dentition. The Parkell and silk gave no significant differences to natural dentition. Similarly, subjects perceived that T-Scan((r)) sensor and paper had the greatest effect on occlusion and were the least comfortable (P < 0.05). Thus, the very plastic T-Scan((r)) sensor and very thick articulating paper both affected SEMG activity during occlusion and, therefore, may not provide valid tooth contact information for dental treatment. In conclusion, occlusal indicators can change SEMG activity during occlusion which may affect the validity of the measurements they provide. PMID- 21314709 TI - The MAT1-2-1 mating-type gene upregulates photo-inducible carotenoid biosynthesis in Fusarium verticillioides. AB - Filamentous ascomycetes, including mitotic holomorphs, have constitutively transcribed MAT (mating type) genes. These genes encode transcription factors considered to be the major regulators of sexual communication. The proven targets of the MAT transcription factors are pheromone precursor and pheromone receptor genes. However, recent studies demonstrated that MAT proteins may also affect other genes not involved directly in the mating process. When grown in the light, Fusarium verticillioides produces the acidic xanthophyll neurosporoxanthin and lower amounts of nonpolar precursor carotenes, such as phytoene, torulene, beta carotene, and gamma-carotene. Depending on the illumination conditions, a drastic decrease or the absence of light-inducible carotenoid accumulation was detected in three independent DeltaFvMAT1-2-1 knockout mutants of F. verticillioides as compared with the parental wild-type strain. Transcript levels of the carB, carRA, and carT genes, encoding key enzymes of the carotenoid biosynthetic pathway, were also significantly reduced in the mutants. The downregulation of these genes in the DeltaFvMAT1-2-1 mutant indicates that MAT genes play a role in the control of carotenogenesis in Fusarium. The finding that mating-type genes regulate important processes unrelated to sex helps to understand the presence of functional MAT genes in asexually reproducing fungus populations. PMID- 21314710 TI - A review of prenatal home-visiting effectiveness for improving birth outcomes. AB - OBJECTIVE: To determine the effectiveness of prenatal home visiting for improving prenatal care utilization and preventing preterm birth and low birth weight. DATA SOURCES: Medline, the Cumulative Index to Nursing and Allied Health Literature, PsycINFO, and Social Work Abstract databases were searched for articles that examined prenatal home-visiting and prenatal care utilization or neonatal outcomes, with additional ascendancy and descendancy searches. Listservs were also used to identify unpublished evaluations. STUDY SELECTION: Quantitative studies meeting the following criteria were included in the analyses: published between 1985 and 2009, published in English, reported providing prenatal home visiting, and reported on prenatal care utilization or a neonatal outcome. DATA EXTRACTION: Study characteristics and findings related to prenatal care utilization, gestational age, and birth weight were abstracted independently by at least two authors. Study quality was assessed across five domains. DATA SYNTHESIS: The search yielded 28 studies comparing outcomes for women who did and did not receive prenatal home visiting, with 14 (59%) using an RCT design. Five (17%) studies reporting on prenatal care utilization found a statistically significant improvement in use of prenatal care for women with home visiting. Of 24 studies reporting an effect on birth outcomes, five (21%) found a significant positive effect on gestational age, and seven of 17 (41%) found a significant positive effect on birth weight. CONCLUSIONS: More evidence suggests that prenatal home visiting may improve the use of prenatal care, whereas less evidence exists that it improves neonatal birth weight or gestational age. These findings have implications for implementing Title II of the Affordable Care Act. PMID- 21314711 TI - On "a call for clarity in infant breast and bottle-feeding definitions for research". PMID- 21314713 TI - On "neonatal neurobehavioral organization after exposure to maternal epidural analgesia in labor". PMID- 21314715 TI - Predictors of breastfeeding exclusivity in a WIC sample. AB - OBJECTIVE: To examine predictors of breastfeeding exclusivity in low-income women who received services from a Chicago area clinic of the Special Supplemental Nutrition Program for Women, Infants and Children Program (WIC). DESIGN: A secondary data analysis of existing clinical and administrative data. SETTING: An urban community health center serving low-income families. PARTICIPANTS: Two hundred and thirty-five (235) low-income women who initiated breastfeeding and received WIC services. METHODS: Logistic regression models were fit to existing prenatal and postpartum data to determine predictors of breastfeeding exclusivity during the immediate postpartum period. RESULTS: Only 23% of the sample breastfed exclusively. Women who received first-trimester prenatal care were more likely to exclusively breastfeed than women who entered prenatal care in later trimesters (OR = 2.02, p <= 0.05). Women who declared intentions prenatally to exclusively breastfeed were more likely to exclusively breastfeed than women who did not intend to breastfeed (OR = 3.85, p <= 0.001). Overweight/obese women were less likely to exclusively breastfeed than normal/underweight women (OR = 0.50, p <= 0.05). CONCLUSION: Findings from this study can be used to develop tailored interventions to promote breastfeeding exclusivity among low-income WIC recipients. PMID- 21314716 TI - Early hospital discharge in maternal and newborn care. AB - This article highlights the historic precedence of early discharge practices and the debate regarding length of stay for new mothers and newborns in the United States. Although the documented effects of early discharge on maternal and newborn health are inconsistent, research findings universally support follow-up care for mothers and infants within 1 week of hospital discharge. Research is needed to identify the components and timing of follow-up care to optimize maternal and newborn outcomes. PMID- 21314717 TI - Scientists as stakeholders in conservation of hydrothermal vents. AB - Hydrothermal vents are deep-sea ecosystems that are almost exclusively known and explored by scientists rather than the general public. Continuing scientific discoveries arising from study of hydrothermal vents are concommitant with the increased number of scientific cruises visiting and sampling vent ecosystems. Through a bibliometric analysis, we assessed the scientific value of hydrothermal vents relative to two of the most well-studied marine ecosystems, coral reefs and seagrass beds. Scientific literature on hydrothermal vents is abundant, of high impact, international, and interdisciplinary and is comparable in these regards with literature on coral reefs and seagrass beds. Scientists may affect hydrothermal vents because their activities are intense and spatially and temporally concentrated in these small systems. The potential for undesirable effects from scientific enterprise motivated the creation of a code of conduct for environmentally and scientifically benign use of hydrothermal vents for research. We surveyed scientists worldwide engaged in deep-sea research and found that scientists were aware of the code of conduct and thought it was relevant to conservation, but they did not feel informed or confident about the respect other researchers have for the code. Although this code may serve as a reminder of scientists' environmental responsibilities, conservation of particular vents (e.g., closures to human activity, specific human management) may effectively ensure sustainable use of vent ecosystems for all stakeholders. PMID- 21314718 TI - The effect of furosemide on left atrial pressure in dogs with mitral valve regurgitation. AB - BACKGROUND: The effects of furosemide on left atrial pressure (LAP) in dogs with mitral regurgitation (MR) have not been documented in a quantitative manner and between different routes of administration. OBJECTIVE: To document LAP and echocardiographic parameters in MR dogs administered furosemide IV or PO, in order to document changes in LAP after furosemide treatment. ANIMALS: Five healthy Beagle dogs (3 males and 2 females; aged 2 years) were used. METHODS: Experimental, cross-over, and interventional study. LAP was measured before the administration of furosemide, and 30 minutes, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours after administration. Furosemide 1, 2, or 4 mg/kg IV, PO or placebo was administered. RESULTS: LAP was significantly decreased with all administrations of furosemide but not after placebo (P < .05, respectively). The max reduction was observed 1 hour (1 mg/kg IV, 15.04 +/- 7.02 mmHg), 3 hours (2, 4 mg/kg IV, 13.28 +/- 8.01, 9.23 +/- 4.92 mmHg), 4 hours (1 mg/kg PO, 14.68 +/- 11.51 mmHg), and 5 hours (2, 4 mg/kg PO, 13.19 +/- 10.52, 10.70 +/- 7.69 mmHg). E wave and E/Ea were significantly decreased corresponding to the reduction of LAP after administration of 2 and 4 mg/kg (P < .05, respectively). CONCLUSIONS AND CLINICAL IMPORTANCE: LAP was decreased in proportion to the dosage of furosemide, which did not significantly differ between IV and PO of the same dosages. E wave and E/Ea might be useful for the treatment evaluation of furosemide. PMID- 21314719 TI - Thrombelastography in horses with acute gastrointestinal disease. AB - BACKGROUND: Coagulopathies in horses with gastrointestinal disease are frequently identified and associated with morbidity and fatality. OBJECTIVE: Determine if thrombelastography (TEG) identifies abnormalities associated with lesion type, presence of systemic inflammatory response syndrome (SIRS), morbidity, and fatality more consistently than traditional coagulation testing. ANIMALS: One hundred and one horses examined for gastrointestinal disease and 20 healthy horses. METHODS: TEG, tissue factor (TF)-TEG, and traditional coagulation panels parameters and percentages of horses with coagulopathies were compared for lesion type, presence of SIRS, complications, and survival. RESULTS: Changes in individual parameters and increased incidence of coagulopathies were associated with fatality (R, P= .007; k-value [K], P= .004; clot lysis [CL]30, P= .037; CL60, P= .050; angle [Ang], P= .0003; maximum amplitude [MA], P= .006; lysis [Ly]30, P= .042; Ly60, P= .027; CI, P= .0004; >= 2 TEG coagulopathies, P= .013; >= 3 TEG coagulopathies, P= .038; TF-R, P= .037; TF-K, P= .004; TF-CL30, P < .0001; TF-CL60, P < .0001; TF-Ang, P= .005; TF-Ly30, P= .0002; TF-Ly60, P < .0001; TF-CI, P= .043; >= 1 TF-TEG coagulopathies, P= .003; >= 2 TF-TEG coagulopathies, P= .0004; prothrombin tme [PT], P < .0001; activated partial throboplastin time [aPTT], P= .021), inflammatory lesions (MA, P= .013; TF-CL30, P= .033; TF-CL60, P= .010; TF-Ly60, P= .011; >= 1 TF-TEG coagulopathy, P= .036; >= 2 TF-TEG coagulopathy, P= .0007; PT, P= .0005; fibrinogen, P= .019), SIRS (MA, P= .004; TF-CL30, P= .019; TF-CL60, P= .013; TF-Ly30, P= .020; TF-Ly60, P= .010; PT, P < .0001; aPTT, P= .032; disseminated intravascular coagulation, P= .005), and complications (ileus: aPTT, P= .020; diarrhea: TF-CL30, P= .040; TF-Ly30, P= .041; thrombophlebitis: >= 1 TF-TEG coagulopathy, P= .018; laminitis: MA, P= .004; CL60, P= .045; CI, P= .036; TF-MA, P= .019; TF-TEG CI, P= .019). Abnormalities in TEG and TF-TEG parameters were indicative of hypocoagulation and hypofibrinolysis. CONCLUSIONS AND CLINICAL IMPORTANCE: TEG identifies changes in coagulation and fibrinolysis associated with lesion type, SIRS, morbidity, and fatality in horses with gastrointestinal disease. PMID- 21314720 TI - Insulin resistance selectively alters cell-surface glucose transporters but not their total protein expression in equine skeletal muscle. AB - BACKGROUND: Insulin resistance (IR) has been widely recognized in humans, and more recently in horses, but its underlying mechanisms are still not well understood. The translocation of glucose transporter 4 (GLUT4) to the cell surface is the limiting step for glucose uptake in insulin-sensitive tissues. Although the downstream signaling pathways regulating GLUT translocation are not well defined, AS160 recently has emerged as a potential key component. In addition, the role of GLUT12, one of the most recently identified insulin sensitive GLUTs, during IR is unknown. HYPOTHESIS/OBJECTIVES: We hypothesized that cell-surface GLUT will be decreased in muscle by an AS160-dependent pathway in horses with IR. ANIMALS: Insulin-sensitive (IS) or IR mares (n = 5/group). METHODS: Muscle biopsies were performed in mares classified as IS or IR based on results of an insulin-modified frequently sampled IV glucose tolerance test. By an exofacial bis-mannose photolabeled method, we specifically quantified active cell-surface GLUT4 and GLUT12 transporters. Total GLUT4 and GLUT12 and AS160 protein expression were measured by Western blots. RESULTS: IR decreased basal cell-surface GLUT4 expression (P= .027), but not GLUT12, by an AS160-independent pathway, without affecting total GLUT4 and GLUT12 content. Cell-surface GLUT4 was not further enhanced by insulin stimulation in either group. CONCLUSIONS AND CLINICAL IMPORTANCE: IR induced defects in the skeletal muscle glucose transport pathway by decreasing active cell-surface GLUT4. PMID- 21314721 TI - Increase in minimal residual disease in peripheral blood before clinical relapse in dogs with lymphoma that achieved complete remission after chemotherapy. AB - BACKGROUND: We developed previously a minimal residual disease (MRD) monitoring system in dogs with lymphoma by exploring a highly sensitive real-time PCR system. OBJECTIVES: To identify the change in MRD before clinical relapse in dogs with lymphoma that achieved complete remission after chemotherapy. ANIMALS: Twenty dogs with multicentric high-grade B-cell lymphoma. METHODS: MRD levels in peripheral blood mononuclear cells (PBMCs) were measured by real-time PCR amplifying the rearranged immunoglobulin heavy chain gene. MRD measurement and clinical assessment were performed every 2-4 weeks for 28-601 days after completion of chemotherapy. An increase in MRD was defined as an increase by more than 0.5, calculated by log10 [copy number of MRD per 105 PBMCs], based on the uncertainty level observed in a canine lymphoma cell line. RESULTS: During the follow-up period, 15 dogs relapsed in 28-320 days (median, 120 days) after completion of chemotherapy. An increase in MRD was detected 2 weeks or more before relapse in 14 of the 15 dogs, but an increase in MRD before relapse could not be detected in the remaining 1 dog. The time from increased MRD to clinical relapse was 0-63 days (median, 42 days). In contrast, no increase in MRD was detected in 5 dogs that did not experience clinical relapse. CONCLUSION AND CLINICAL IMPORTANCE: An increase in MRD can be detected before clinical relapse in dogs with lymphoma. Application of early reinduction therapy based on an increase in MRD before clinical relapse may improve treatment outcome in canine lymphoma. PMID- 21314722 TI - Feline ureteral strictures: 10 cases (2007-2009). AB - BACKGROUND: Feline ureteral obstructions have emerged as a common problem. Ureteral strictures rarely are reported as a cause and the predisposing factors and clinical course of this condition have not been described. OBJECTIVES: Evaluate cases of feline ureteral strictures and characterize historical features, clinical signs, diagnostic imaging, surgical and endoscopic findings, histopathology, treatment modalities, and short- and long-term outcomes. ANIMALS: Ten cats diagnosed with ureteral strictures based on compatible findings from at least 2 of the following: ultrasonography, ureteropyelography, surgical exploration, or histopathology. METHODS: Retrospective study. RESULTS: Median age, serum creatinine concentration, and size of the renal pelvis were 12 years, 3.7 mg/dL, and 11.75 mm, respectively. Six of 10 cats had hyperechoic periureteral tissue on ultrasound examination at the stricture site. Four cats had evidence of a circumcaval ureter at surgery. Eight cats had an intervention including ureteral stent placement (n = 6) and traditional surgery (n = 2). Seven of 8 cats had decreases in serum creatinine concentration and renal pelvic parameters preceding discharge and 6 had persistently improved results at their last examination. All patients survived to discharge. Median survival time was > 294 days (range, 14 to > 858 days) with 6/10 cats still alive. CONCLUSIONS AND CLINICAL IMPORTANCE: Ureteral strictures may occur in cats secondary to ureteral surgery, inflammation, a circumcaval ureter, impacted ureterolithiasis, or for unknown causes. With appropriate and timely intervention, the prognosis for long term survival is good. In addition to ureteral reimplantation or ureteronephrectomy, ureteral stenting or SC ureteral bypass may be considered as future therapeutic options. PMID- 21314723 TI - Cardiac troponin I concentrations in ponies challenged with equine influenza virus. AB - BACKGROUND: Myocarditis is thought to occur secondary to equine influenza virus (EIV) infections in horses, but there is a lack of published evidence. HYPOTHESIS/OBJECTIVES: We proposed that EIV challenge infection in ponies would cause myocardial damage, detectable by increases in plasma cardiac troponin I (cTnI) concentrations. ANIMALS: Twenty-nine influenza-naive yearling ponies: 23 were part of an influenza vaccine study (11 unvaccinated and 12 vaccinated), and were challenged with 108 EID50 EIV A/eq/Kentucky/91 6 months after vaccination. Six age-matched healthy and unvaccinated ponies concurrently housed in a separate facility not exposed to influenza served as controls. METHODS: Heparinized blood was collected before and over 28 days after infection and cTnI determined. Repeated measures analysis of variance, chi-square, or clustered regression analyses were used to identify relationships between each group and cTnI. RESULTS: All EIV-infected ponies developed clinical signs and viral shedding, with the unvaccinated group displaying severe signs. One vaccinated pony and 2 unvaccinated ponies had cTnI greater than the reference range at 1 time point. At all other times, cTnI was < 0.05 ng/mL. All control ponies had normal cTnI. There were no significant associations between cTnI and either clinical signs or experimental groups. When separated into abnormal versus normal cTnI, there were no significant differences among groups. CONCLUSIONS AND CLINICAL IMPORTANCE: This study demonstrated no evidence of severe myocardial necrosis secondary to EIV challenge with 108 EID50 EIV A/eq/Kentucky/91 in these sedentary ponies, but transient increases in cTnI suggest that mild myocardial damage may occur. PMID- 21314724 TI - Effects of the insulin-sensitizing drug pioglitazone and lipopolysaccharide administration on insulin sensitivity in horses. AB - BACKGROUND: Obesity and insulin resistance increase the risk of laminitis in horses. Pioglitazone (PG) is an insulin-sensitizing drug used in humans that is absorbed after oral administration to horses. HYPOTHESIS: PG treatment will increase insulin sensitivity and transcript abundance of glucose and lipid transporters in adipose and skeletal muscle tissues. ANIMALS: Sixteen lean, healthy horses. METHODS: Eight horses were administered PG (1 mg/kg bodyweight PO) for 12 days before induction of insulin resistance through IV administration of lipopolysaccharide (LPS). Treated and untreated controls (CN; n = 8) were subjected to testing of peripheral insulin sensitivity and biopsies of both subcutaneous (nuchal ligament) adipose tissue and skeletal muscle before and after treatment, and 24 hours after LPS administration. RESULTS: PG treatment did not improve basal insulin sensitivity (CNs: 1.4 +/- 0.3, PG-treated: 1.9 +/- 1.3; P > .4) or mitigate LPS-induced insulin resistance (CNs: 0.4 +/- 0.3, PG-treated: 0.4 +/- 0.3); however, transcript abundance of glucose and lipid transporters was altered in both skeletal muscle and subcutaneous adipose tissue. CONCLUSIONS AND CLINICAL IMPORTANCE: Either a higher dose or longer treatment period might be required for physiological effects to be observed. PG is a novel therapeutic agent requiring further investigation in horses in order to determine treatment efficacy. PMID- 21314725 TI - Repetitive stimulation of the common peroneal nerve as a diagnostic aid for botulism in foals. AB - BACKGROUND: Botulism is a potentially fatal paralytic disorder for which definitive diagnosis is difficult. OBJECTIVES: To determine if repetitive stimulation of the common peroneal nerve will aid in the diagnosis of botulism in foals. ANIMALS: Four control and 3 affected foals. METHODS: Validation of the test in healthy foals for its comparison in foals with suspected botulism. Controls were anesthetized and affected foals were sedated to avoid risks of anesthesia. The common peroneal nerve was chosen for its superficial location and easy access. Stimulating electrodes were placed along the common peroneal nerve. For recording, the active and reference electrodes were positioned over the midpoint and distal end of the extensor digitorum longus muscle, respectively. Repeated supramaximal stimulation of the nerve was performed utilizing a range of frequencies (1-50 Hz). Data analysis consisted of measuring the amplitude and area under the curve for each M wave and converting these values into percentages of decrement or increment based on the comparison of subsequent potentials to the initial one (baseline) within each set. RESULTS: A decremental response was seen at all frequencies in control foals. Decremental responses also were observed in affected foals at low frequencies. An incremental response was seen in all affected foals at 50 Hz. CONCLUSIONS AND CLINICAL IMPORTANCE: Decreased baseline M wave amplitudes with incremental responses at high rates are supportive of botulism. Repetitive nerve stimulation is a safe, simple, fast, and noninvasive technique that can aid in the diagnosis of suspected botulism in foals. PMID- 21314726 TI - Hypercoagulability in dogs with protein-losing enteropathy. AB - BACKGROUND: Dogs with protein-losing enteropathy (PLE) have previously been reported to present with thromboembolism; however, the prevalence and pathogenesis of hypercoagulability in dogs with PLE have not been investigated so far. HYPOTHESIS: Dogs with PLE are hypercoagulable compared with healthy control dogs. ANIMALS: Fifteen dogs with PLE. Thirty healthy dogs served as controls (HC). METHODS: A prospective study was performed including 15 dogs with PLE. All dogs were scored using the canine chronic enteropathy activity index (CCECAI). Thromboelastography (TEG) and other measures of coagulation were evaluated. Recalcified, unactivated TEG was performed and reaction time (R), kinetic time (K), alpha angle (alpha), and maximum amplitude (M(A)) values were recorded. Nine dogs were reassessed after initiation of immunosuppressive treatment. RESULTS: All dogs with PLE in the study were hypercoagulable with decreased R (PLE: median 7.8, range [2.4-11.2]; HC: 14.1 [9.1-20.3]), decreased K (PLE: 2.5 [0.8-5.2]; HC: 8.25 [4.3-13.1]), increased alpha (PLE: 56.7 [38.5-78.3]; HC: 25.6 [17-42.4]), and increased M(A) (PLE: 68.2 [54.1-76.7]; HC: 44.1, [33.5-49]) (all P < .001). Median antithrombin (AT) concentration was borderline low in PLE dogs; however, mean serum albumin concentration was severely decreased (mean 1.67 g/dL +/- 5.1, reference range 2.8-3.5 g/dL). Despite a significant improvement in serum albumin and CCECAI, all 9 dogs with PLE were hypercoagulable at re-examination. CONCLUSIONS AND CLINICAL IMPORTANCE: The hypercoagulable state in dogs with PLE cannot be solely attributed to loss of AT. Despite good clinical response to treatment, dogs remained hypercoagulable and could therefore be predisposed to thromboembolic complications. PMID- 21314727 TI - Tolerability of metronomic administration of lomustine in dogs with cancer. AB - BACKGROUND: Metronomic chemotherapy with alkylating agents has been shown to suppress tumor angiogenesis and prevent tumor recurrence in some settings. The use of adjuvant lomustine (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea) administered in a metronomic fashion has not been evaluated in dogs. HYPOTHESIS: Oral metronomic administration of lomustine will be well tolerated in dogs with spontaneously occurring malignant neoplasms. ANIMALS: Eighty-one dogs with naturally occurring primary or metastatic tumors received metronomic administration of lomustine. METHODS: Dogs were enrolled prospectively after cytological or histological diagnosis of a tumor that was unresectable, incompletely resected, refractory to chemotherapy, or metastatic. Dogs received once daily lomustine (2.84 mg/m2 PO). End points of the trial were clinical, hematologic, or biochemical evidence of toxicosis, tumor progression, or death. RESULTS: Starting dosage (median) was 2.84 mg/m2 PO daily and treatment duration was 98 days (median, range, 1-770 days). The drug was discontinued in 22 dogs because of toxicoses. Toxicoses occurred in 13 dogs with gastrointestinal toxicosis, 4 dogs with thrombocytopenia, 3 dogs with increased alanine transaminase, 1 dog with neutropenia, and 1 dog with progressive azotemia. Eight dogs developed some degree of azotemia during treatment. Hepatotoxicosis was observed at a median of 265 days in 11 dogs. Thrombocytopenia was identified at a median of 432 days of administration. CONCLUSIONS AND CLINICAL IMPORTANCE: In dogs with metastatic or terminal neoplasms without renal compromise, metronomic administration of lomustine was well tolerated. This can provide a treatment strategy for dogs that do not have other standard-care treatment options, and warrants evaluation in primary therapy. PMID- 21314728 TI - Nested case-control study of feline calicivirus viruria, oral carriage, and serum neutralizing antibodies in cats with idiopathic cystitis. AB - BACKGROUND: The epidemiology of feline calicivirus (FCV) infection in cats with idiopathic cystitis (FIC) has not been investigated by contemporary molecular biologic methods. OBJECTIVES: To determine the prevalence of and evaluate risk factors for FCV viruria, oral carriage, and virus neutralizing (VN) antibodies in cats with and without FIC. ANIMALS: Cats with nonobstructive FIC (n = 47), obstructive FIC (n = 22), and FCV upper respiratory tract infection (URI; n = 25), and healthy client-owned (n = 18) and colony-housed (n = 24) cats. METHODS: Oropharyngeal secretions and urine were evaluated with a FCV p30 gene-based real time reverse-transcriptase polymerase chain reaction (RT-PCR) assay. Serum VN antibody titers were determined by a modified microtiter assay. Associations of risk factors with log-transformed antibody titers were determined by multivariable generalized linear regression. RESULTS: FCV viruria was detected in 4 (6%) and 3 (12%) cats with FIC and URI, respectively. In 3 FIC cats, viruria was unassociated with detectable oral virus carriage. Oral FCV carriage was detected in 7 (10%) FIC cats. Median antibody titers were significantly higher in cats with obstructive FIC (1 :256), nonobstructive FIC (1:128), and URI (1:512) compared with healthy client-owned (1:16) and colony-housed (1:4) cats (P < .001). Other than disease, multivariate analysis did not identify any other explanatory variables for increased titers in cats with FIC or URI. CONCLUSIONS AND CLINICAL IMPORTANCE: FCV viruria was detected in cats with FIC and URI, however, its etiologic significance is uncertain. Serologic results suggest increased FCV exposure in FIC cats compared with controls. Further investigations are needed to clarify the potential role of FCV in FIC. PMID- 21314729 TI - Evaluation of cytoreductive efficacy of vincristine, cyclophosphamide, and Doxorubicin in dogs with lymphoma by measuring the number of neoplastic lymphoid cells with real-time polymerase chain reaction. AB - BACKGROUND: The cytoreductive efficacy of the individual components of multidrug chemotherapy for canine lymphoma is difficult to evaluate after complete remission. OBJECTIVES: To compare the cytoreductive efficacy of vincristine (VCR), cyclophosphamide (CPA), and doxorubicin (DXR) in dogs that received a 6 month modified version of the University of Wisconsin-Madison chemotherapy protocol (UW-25). ANIMALS: Twenty-nine dogs with high-grade B-cell multicentric lymphoma. METHODS: Rearranged immunoglobulin heavy chain gene fragments from lymphoma cells were amplified by polymerase chain reaction (PCR) and sequenced to prepare clone-specific primers and probes for real-time PCR. The number of lymphoma cells in peripheral blood was measured from diagnosis to week 11 of UW 25. RESULTS: The number of lymphoma cells after the 1st administration of VCR, CPA, and DXR in weeks 1-4 was decreased in 29/29 (100%), 15/29 (51.7%), and 26/27 (96.3%) dogs, respectively. The cytoreductive efficacy of CPA was less than that of VCR and DXR. VCR, CPA, and DXR administered in weeks 6-9 were effective in 5/26 (19.2%), 5/20 (25.0%), and 14/19 (73.7%) dogs, respectively, indicating the sustained cytoreductive efficacy of DXR. CPA nonresponders were heavier and exhibited a shorter 1st remission than CPA responders. CONCLUSION AND CLINICAL IMPORTANCE: When using UW-25 for treatment of canine lymphoma, CPA was found to have less cytoreductive efficacy than VCR and DXR. Real-time PCR-based quantification of tumor cells is an objective marker of the efficacy of chemotherapeutic agents. PMID- 21314730 TI - Safety of masitinib mesylate in healthy cats. AB - BACKGROUND: Masitinib mesylate is a PO-administered tyrosine kinase inhibitor developed both for human and animal diseases with activity against both mutated and wild type forms of the c-kit receptor and platelet-derived growth factor receptors alpha and beta, and is currently registered in Europe for the treatment of mast cell tumors in dogs. HYPOTHESIS/OBJECTIVES: The objective of this study was to determine if healthy cats can tolerate administration of masitinib without clinically relevant adverse effects. ANIMALS: Twenty healthy research colony specific pathogen-free cats. METHODS: This study was a prospective, randomized phase 1 clinical trial. Masitinib was administered PO to 20 healthy cats. Ten cats received 50 mg masitinib every other day for 4 weeks, and 10 cats received 50 mg masitinib daily for 4 weeks. RESULTS: Clinically relevant proteinuria was noted in 2/20 (10%) cats (both treated daily), and neutropenia was noted in 3/20 (15%) (seen in both treatment groups). An increase in serum creatinine concentration and adverse gastrointestinal effects were noted in some cats. CONCLUSIONS AND CLINICAL IMPORTANCE: Masitinib mesylate was tolerated in the majority of cats. Long-term administration and pharmacokinetic studies are needed to further assess the use of masitinib in cats. PMID- 21314731 TI - Bronchoscopic findings in 48 cats with spontaneous lower respiratory tract disease (2002-2009). AB - BACKGROUND: Diagnosis of lower respiratory disease requires collection of airway samples to confirm the etiology of disease. Bronchoscopic evaluation is commonly performed in dogs but less information is available in cats. HYPOTHESIS: The presence and number of bronchoscopic abnormalities visualized during bronchoscopic evaluation of cats with lower respiratory disease will correlate with the type of disease and total and differential cell counts in bronchoalveolar lavage (BAL) fluid. ANIMALS: Forty-eight cats prospectively evaluated by a single bronchoscopist. METHODS: Bronchoscopy was performed during clinical evaluation of cats presenting with cough, respiratory distress, or both. Cats were evaluated for airway hyperemia, stenosis, or collapse, mucus accumulation, bronchiectasis, and epithelial irregularities. Cats were placed into groups of bronchitis/"asthma," pneumonia, or neoplasia based on BAL findings, histopathology, and response to appropriate medical therapy. Summation of bronchial abnormalities and total and differential cell counts were compared among groups. RESULTS: Endobronchial abnormalities were common in cats with feline bronchitis/asthma, pneumonia, and neoplasia and no differentiating features were found. Excessive mucus accumulation was common (83%), followed by stenosis of bronchial openings and nodular epithelial irregularities (56%), airway hyperemia (54%), airway collapse (48%), and bronchiectasis (27%). Total bronchoscopic score and total cell count did not differ among groups, although differential cell counts were significantly different. A weak correlation (R2 = 0.16, P= .006) between age and total bronchoscopic score was noted. CONCLUSIONS AND CLINICAL RELEVANCE: Bronchoscopic abnormalities are common in cats with lower respiratory tract disease, and visualization of the airways provides additional nonspecific clinical information in cats. PMID- 21314732 TI - Invasive group A streptococcal disease and association with varicella in Germany, 1996-2009. AB - A nationwide laboratory-based surveillance study was conducted to analyse the epidemiology of varicella-associated invasive group A streptococcal (iGAS) infections in Germany. A total of 1342 iGAS samples were collected between 1 January 1996 and 22 September 2009. For 21 of these isolates, an association with varicella was observed. The median age of this subgroup was 4.2 years (mean 12.1). Most of these patients presented with sepsis (42.9%), streptococcal toxic shock syndrome (23.8%) and necrotizing fasciitis (19.0%). The most common complications among patients with underlying varicella were hypotensive shock and soft-tissue necrosis (38.1% each), disseminated intravascular coagulopathy (33.3%) and renal impairment (28.6%). The overall rate of complications was higher among the patients with underlying varicella than among those without. In the varicella-positive group, emm types 1 (38.1%), 12 (19.0%) and 4 (14.3%) were predominant, while among the varicella-negative isolates, emm types 1 (32.5%), 28 (14.0%) and 3 (8.3%) were found most often. Among the varicella-positive group, the rate of ssa-positive isolates was considerably higher than that among the varicella-negative group (28.6% vs. 12.6%), as well as the coexistence of speC and ssa (14.3% vs. 3.6%). PMID- 21314733 TI - Prevotella intermedia stimulates tissue-type plasminogen activator and plasminogen activator inhibitor-2 expression via multiple signaling pathways in human periodontal ligament cells. AB - Prevotella intermedia is an important periodontal pathogen that induces various inflammatory and immune responses. In this study, we investigated the effects of P. intermedia on the plasminogen system in human periodontal ligament (hPDL) cells and explored the signaling pathways involved. Using semi-quantitative reverse transcription (RT)-PCR and quantitative real-time RT-qPCR, we demonstrated that P. intermedia challenge increased tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor (PAI)-2 expression in a concentration- and time-dependent manner, but exerted no influence on urokinase type plasminogen activator and PAI-1mRNA expression in hPDL cells. Prevotella intermedia stimulation also enhanced tPA protein secretion as confirmed by enzyme linked immunosorbent assay. Western blot results revealed that P. intermedia treatment increased phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 kinase (p38). ERK, JNK and protein kinase C inhibitors significantly attenuated the P. intermedia-induced tPA and PAI-2 expression. Furthermore, p38 and phosphatidylinositol 3-kinase inhibitors markedly decreased PAI-2 expression, whereas they showed no or little inhibition on tPA expression. In contrast, inhibition of protein kinase A greatly enhanced the upregulatory effect of P. intermedia on tPA and PAI-2 expression. Our results suggest that P. intermedia may contribute to periodontal tissue destruction by upregulating tPA and PAI-2 expression in hPDL cells via multiple signaling pathways. PMID- 21314734 TI - Influence of infection route and virulence factors on colonization of solid tumors by Salmonella enterica serovar Typhimurium. AB - Administration of facultative anaerobic bacteria such as Salmonella enterica serovar Typhimurium as anticancer treatment holds a great therapeutic potential. Here, we tested different routes of application of S. typhimurium with regard to tumor colonization and therapeutic efficacy. No differences between intravenous and intraperitoneal infection were observed, often leading to a complete tumor clearance. In contrast, after oral application, tumor colonization was inefficient and delayed. No therapeutic effect was observed under such conditions. We also showed that tumor invasion and colonization were independent of functional Salmonella pathogenicity island (SPI) 1 and SPI 2. Furthermore, tumor invasion and colonization did not require bacterial motility or chemotactic responsiveness. The distribution of the bacteria within the tumor was independent of such functions. PMID- 21314735 TI - Interleukin-10 gene promoter polymorphisms and their protein production in pleural fluid in patients with tuberculosis. AB - Associations of interleukin-10 (IL-10) gene promoter polymorphisms and pleural tuberculosis risk remain unclear. The objective of this study was to determine IL 10 gene promoter polymorphisms at -1082, -819 and -592 sites and their protein production in pleural fluid (PF) in patients with and without pleural tuberculosis. IL-10 gene promoter polymorphisms at the -1082, -819 and -592 sites were genotyped using a SNaPshot assay. Protein levels of IL-10 in PF were measured using an enzyme-linked immunosorbent assay. There were no significant differences in the genotype and allele frequencies of IL-10 gene promoter polymorphisms at position -1082 between the pleural tuberculosis and the control groups. However, the frequency of -819 T or -592 A alleles was significantly more common in patients with pleural tuberculosis than controls. The protein levels of IL-10 in PF were statistically higher in the pleural tuberculosis group than in the control group. Moreover, the polymorphisms at the -1082, -819 and -592 sites were associated with protein levels of IL-10 in PF in the pleural tuberculosis group, while in the control group, only the polymorphism at position -1082 correlated with the protein levels. These findings support the association between IL-10 promoter polymorphisms at -819 and -592 sites and their protein production with pleural tuberculosis risk. PMID- 21314736 TI - Activation of microglia in specific hypothalamic nuclei and the cerebellum of adult rats exposed to neonatal overnutrition. AB - Much attention has been drawn to the possible involvement of hypothalamic inflammation in the pathogenesis of metabolic disorders, especially in response to a high-fat diet. Microglia, the macrophages of the central nervous system, can be activated by proinflammatory signals resulting in the local production of specific interleukins and cytokines, which in turn could exacerbate the pathogenic process. Because obesity itself is considered to be a state of chronic inflammation, we evaluated whether being overweight results in microglial activation in the hypothalamus of rats on a normal diet. Accordingly, we used a model of neonatal overnutrition that entailed adjustment of litter size at birth (small litters: four pups/dam versus normal litters: 12 pups/dam) and resulted in a 15% increase in bodyweight and increased circulating leptin levels at postnatal day 60. Rats that were overnourished during neonatal life had an increased number of activated microglia in specific hypothalamic areas such as the ventromedial hypothalamus, which is an important site for metabolic control. However, this effect was not confined to the hypothalamus because significant microglial activation was also observed in the cerebellar white matter. There was no change in circulating tumour necrosis factor (TNF) alpha levels or TNFalpha mRNA levels in either the hypothalamus or cerebellum. Interleukin (IL)6 protein levels were higher in both the hypothalamus and cerebellum, with no change in IL6 mRNA levels. Because circulating IL6 levels were elevated, this rise in central IL6 could be a result of increased uptake. Thus, activation of microglia occurs in adult rats exposed to neonatal overnutrition and a moderate increase in weight gain on a normal diet, possibly representing a secondary response to systemic inflammation. Moreover, this activation could result in local changes in specific hypothalamic nuclei that in turn further deregulate metabolic homeostasis. PMID- 21314737 TI - Acute inflammation increases pituitary and hypothalamic glycoprotein hormone subunit B5 mRNA expression in association with decreased thyrotrophin receptor mRNA expression in mice. AB - The biological function of thyrostimulin, consisting of the GPA2 and GPB5 subunit, is currently poorly understood. The recent observation that pro inflammatory cytokines up-regulate the transcription of GPB5 in vitro suggested a role for thyrostimulin in the nonthyroidal illness syndrome, a state of altered thyroid hormone metabolism occurring during illness. In the present study, we used GPB5 knockout (GPB5(-/-) ) and wild-type (WT) mice to evaluate the role of GPB5 in the pituitary and hypothalamus during acute inflammation induced by lipopolysaccharide (LPS, bacterial endotoxin) administration. We evaluated serum thyroid hormones and mRNA expression of genes involved in thyroid hormone metabolism in the pituitary and in two hypothalamic regions; the periventricular region (PE) and the arcuate nucleus/median eminence region. As expected, LPS administration increased deiodinase type 2 mRNA in the PE, at the same time as decreasing pituitary thyrotrophin (TSH)beta mRNA and serum thyroxine and triiodothyronine both in GPB5(-/-) and WT mice. GPB5 mRNA, but not GPA2 mRNA, markedly increased after LPS in the pituitary (200-fold) and hypothalamus of WT mice. In addition, we found large (>50%) suppression of TSH receptor (TSHR) mRNA in the pituitary and hypothalamus of WT mice but not in GPB5(-/-) mice. In conclusion, our results demonstrate in vivo regulation of central GPB5 transcription during acute illness. The observed differences between GPB5(-/-) and WT mice point to a distinct role for GPB5 in pituitary and hypothalamic TSHR suppression during acute illness. PMID- 21314738 TI - Childhood-onset chylomicronaemia with reduced plasma lipoprotein lipase activity and mass: identification of a novel GPIHBP1 mutation. AB - OBJECTIVES: Deficiency in the catabolism of triglyceride-rich lipoproteins is the main cause of childhood-onset chylomicronaemia syndrome. Missense mutations in lipoprotein lipase (LPL) or in proteins influencing LPL activity or stability have been shown to be critical determinants of chylomicronaemia syndrome. The main objective of this study was to assess the primary deficiency in five cases of childhood-onset chylomicronaemia syndrome. SETTING: Lipid clinic at a university hospital, SUBJECTS: Subjects presenting with severe hypertriglyceridaemia and chylomicronaemia syndrome in which reduced LPL activity and mass were observed. INTERVENTIONS: Analysis of LPL and GPIHBP1 genes. RESULTS: Amongst the five patients, one novel homozygous missense mutation (p.C68Y) in exon 3 of GPIHBP1 was identified. The other four patients were homozygous for the common LPL mutation p.G188E. CONCLUSION: These findings provide further evidence that GPIHBP1 is involved in the catabolism of triglyceride-rich lipoproteins and plays a role in childhood-onset chylomicronaemia. PMID- 21314739 TI - Myeloid-derived suppressor cells: a double-edged sword? AB - Myeloid-derived suppressor cells are important cell population with an immunoregulatory potential in both adaptive and innate immunity. Their immunosuppressive activity is widely accepted. However, emerging evidence suggests that this heterogeneous cell population can be, under some circumstances, immunostimulatory rather than suppressive. This finding can shed a new light on antitumour immunity which is believed to be impaired in immunosuppressive environments. PMID- 21314740 TI - Cervical thymuses exist, but no cervical thymomas develop in thoracic thymoma prone BUF rats. AB - To confirm the existence of the cervical thymus and the development of cervical thymoma in thymoma-prone BUF/Mna (BUF) rats, we examined cervical organs and adjacent tissues, and thoracic thymic tissues of the three inbred strains, BUF, ACI/NMna (ACI), and WKY/NCrj (WKY), and 11 congenic strains, in which genetic regions of rat nude (Rnu), thymus enlargement-1 and thymus enlargement-2 (Ten1 and Ten2), thymoma susceptibility of rat-1 (Tsr1), atrophy of fast-twitch muscles 1 (Aftm1) and proteinuria of rat-1 (Pur1) were transferred into BUF, ACI or WKY rats. These organs and tissues were fixed en block in 10% formalin and cut coronally into four to six slices of 3-mm thickness, depending on the age of the rat, and embedded together in one block for each rat. Sections were cut and stained with haematoxylin and eosin and examined microscopically. Cervical thymuses were detected in 12-21% of rats from these inbred and congenic strains. No cervical thymuses were found in BUF-Rnu/Rnu rats, which were athymic. All of 42 BUF, 2 of 55 BUF-Rnu/+ and 28 of 33 ACI-Tsr1/Tsr1 rats survived more than 52 weeks, and developed thoracic thymoma, but no cervical thymomas did. It is therefore clear that cervical thymuses behave differently from thoracic thymuses in spontaneous thymomagenesis in BUF rats. PMID- 21314741 TI - Exposure to ethinylestradiol during prenatal development and postnatal supplementation with testosterone causes morphophysiological alterations in the prostate of male and female adult gerbils. AB - Steroids perform significant functions in prostatic development and growth, so that interferences of this equilibrium may predispose the gland to the development of diseases during the life. Embryonic and neonatal exposure to xenoestrogens, many of them with endocrine-disrupting potential, has been related to the induction of disturbances in reproductive system organs. Thus, this study aimed to analyse morphological and immunocytochemical aspects of prostate in both male and female adult gerbils either exposed to ethinylestradiol during the prenatal phase (pregnant females received 10 MUg/kg, by gavage) (EE group) or exposed to testosterone (1 mg/kg) during the postnatal period (EE/T group). Serological analysis revealed a rise in estradiol levels in adult males and females of the EE group. A higher incidence of prostatic intraepithelial neoplasia (PIN) was observed in the male and female prostate of the treated groups, besides an increase in collagen and reticular fibres. Immunocytochemistry showed an increase in prostatic epithelial cells immunoreactive to AR and a presence of a smooth muscle layer, evidenced by alpha actin, in injured regions this way absent in prostatic epithelial buds. These pieces of evidence suggest that the alterations verified in the prostate in adulthood of both sexes may be due to the high oestrogen levels. Either males or females of the EE/T group showed normalized estradiol levels, although prostatic lesions could be observed. While the prostatic gland of male gerbils was more affected than the female prostate, this study showed that the exposure to EE during this critical period of development disrupts the prostate of both sexes in terms of prostatic lesions. PMID- 21314742 TI - Protective effect of alpha-tocopherol on damage to rat testes by experimental cryptorchidism. AB - It is thought that the degeneration of germ cells associated with an increase in the temperature due to cryptorchidism involves oxidative stress. alpha-Tocopherol is a powerful antioxidant that prevents oxidation of polyunsaturated fats found in membranes and stabilizes peroxyl radicals. For this reason we were interested in determining the role of alpha-Tocopherol using experimental cryptorchidism, followed by orchidopexia in neonatal rats. Eighty-four, 10-day-postpartum (dpp) male rats (Wistar strain) were used and divided into 7 groups: healthy control, sham with alpha-Tocopherol treated with 30 or 100 mg/kg doses, sham vehicle, cryptorchidism treated with alpha-Tocopherol at 30 or 100 mg/kg doses and cryptorchidism vehicle. Cryptorchidism was surgically induced at 10 dpp. At 25 dpp the animals were treated with alpha-Tocopherol and the vitamin vehicle. Lipoperoxidation and testicular morphology was determined in half of the animals at 40 dpp (short term). The remaining animals underwent orchidopexia and fertility was determined at 90 dpp. Testicular morphology was determined at 120 dpp (long term) in these animals. A significant reduction of lipoperoxidation was observed in the cryptorchid group treated with alpha-Tocopherol compared to the untreated cryptorchid group, in addition to short-term histological alterations. At long term, we observed an increase in the area and maturation of the seminiferous epithelium, a decrease in apoptosis and histological alterations and an increase in fertility from alpha-Tocopherol treatment. alpha-Tocopherol treatment decreased lipoperoxidation, possibly stabilizing free radicals produced during cryptorchidism, reducing morphological testicular alterations and favoring fertility. PMID- 21314743 TI - The role of cell plasticity in progression and reversal of renal fibrosis. AB - The need for novel insights into the mechanisms of progression of renal disease has become urgent during the last several years because of the increasing incidence of chronic renal disease worldwide. Independent of the underlying disease, the subsequent progression of renal fibrosis is characterized mainly by both an exaggerated synthesis and abnormal accumulation of extracellular matrix proteins produced by mesenchymal cells within the kidney. These cells are mainly myofibroblasts deriving from a variety of renal cells such as vascular smooth muscle, mesangial, resident stem, tubular epithelial, vascular endothelial cells or pericytes. The appearance of myofibroblasts is a reversible process, as suggested by studies in experimental models showing regression of renal fibrosis during therapy with antagonists and/or blockers of the renin-angiotensin system. An additional factor that can also affect the mechanisms of progression/regression of fibrosis is the plasticity of podocytes controlling glomerular filtration. PMID- 21314747 TI - An atrial tachycardia with altered atrial activation sequences within the coronary sinus: what is the mechanism? PMID- 21314744 TI - Transgenic expression of viral capsid proteins predisposes to axonal injury in a murine model of multiple sclerosis. AB - We used transgenic expression of capsid antigens to Theiler's murine encephalomyelitis virus (TMEV) to study the influence of VP1, VP2 or VP2(121-130) to either protection or pathogenesis to chronic spinal cord demyelination, axonal loss and functional deficits during the acute and chronic phases of infection. We used both mice that are normally susceptible (FVB) and mice normally resistant (FVB.D(b) ) to demyelination. Transgenic expression of VP2(121-130) epitope in resistant FVB.D(b) mice caused spinal cord pathology and virus persistence because the VP2(121-130) epitope is the dominant peptide recognized by D(b) , which is critical for virus clearance. In contrast, all three FVB TMEV transgenic mice showed more demyelination, inflammation and axonal loss as compared with wild-type FVB mice, even though virus load was not increased. Motor function measured by rotarod showed weak correlation with total number of midthoracic axons, but a strong correlation with large-caliber axons (>10um(2) ). This study supports the hypothesis that expression of viral capsid proteins as self influences the extent of axonal pathology following Theiler's virus-induced demyelination. The findings provide insight into the role of axonal injury in the development of functional deficits that may have relevance to human demyelinating disease. PMID- 21314749 TI - Rich collaterals in clinically unsuspected basilar artery occlusion-as good as it gets. AB - Basilar artery occlusion (BAO) is generally considered an emergency and is associated with high mortality and poor functional outcome. Although cases with more benign course without thrombolysis treatment have occasionally been reported, to our knowledge there is only one previous report in which angiography, almost accidentally revealed a clinically unsuspected BAO. A 45-year old man with treated hypertension and lipidemia had three distinct isolated episodes of dizziness, 2-3 months before he was referred by an internist for an ultrasound neurovascular evaluation. Neurological examination and extensive laboratory work-up was normal; however, transcranial Doppler (TCD) unexpectedly provided findings that first raised the suspicion of BAO, alerting for further work-up. Cerebral angiography demonstrated BAO, just beyond the anterior inferior cerebellar artery origin, as well as extensive intracerebellar collateral circulation. On 6-year follow-up, he remains normal with no further episodes, although serial TCD shows persistent BAO. PMID- 21314750 TI - The epidemiology of addiction in Sub-Saharan Africa: a synthesis of reports, reviews, and original articles. AB - Use of alcohol and other psychoactive substances is associated with serious social and public health problems, but the extent of the problem in Sub-Saharan Africa is not well known. We set out to review epidemiological publications on alcohol and other psychoactive substances in Sub-Saharan Africa by performing a systematic search of electronic databases and paper records. Ten Sub-Saharan African countries are among the 22 in the world with the highest increase in per capita alcohol consumption. Cannabis, tobacco, and khat are widely used, and use of cocaine, stimulants, and heroin is increasing. More epidemiological research and implementation and evaluation of interventions is needed. Collaboration between African researchers and those in developed countries could help. PMID- 21314751 TI - The impact of drug use in social networks of patients with substance use and bipolar disorders. AB - In this exploratory analysis, we assessed the effect of drug use among social network members on recovery from drug dependence in patients with co-occurring bipolar disorder. Patients (n = 57) enrolled in a group therapy study completed assessments over 15 months. Patients with zero to one drug users in their social networks at intake had few days of drug use during treatment and follow-up, whereas those with >= 2 drug users had significantly more days of drug use. Multivariate analysis showed that patients who consistently named multiple drug users in their social networks had a marked increase in drug use over 15 months, while those who never or occasionally named multiple drug users had a small decline in drug use over time. Multiple drug users in social networks of treatment-seeking drug-dependent patients with co-occurring bipolar disorder may indicate poor drug use outcomes; efforts to reduce the association with drug users may be useful. This clinical trial has been registered in a public trials registry at clinicaltrials.gov (identifier is NCT00227838). PMID- 21314752 TI - Long-term opioid blockade and hedonic response: preliminary data from two open label extension studies with extended-release naltrexone. AB - The emergence of extended-release naltrexone (XR-NTX) raises the opportunity to explore the role of endorphin blockade on hedonic response during long-term alcohol dependence treatment. A hedonic survey was administered to 74 alcohol dependent patients treated for an average of 3.5 years with nearly continuous month-long intramuscular XR-NTX. The paper-and-pencil, one-time survey asked patients about the degree of pleasure they experienced in the past 90 days with drinking alcohol, sex, exercise and other daily activities. The data revealed lower pleasure ratings for alcohol than for sex, exercise and 10 other common activities. Mean responses to drinking alcohol and gambling were significantly lower than to listening to music, sex, reading, being with friends, eating good food, eating spicy food, and playing video/card games. This effect was independent of XR-NTX dose or duration. Although this exploratory study lacked baseline data, a comparison group or control for the impact of patient discontinuation, the data indicate the feasibility of examining long-term hedonic response in recovery. The differential hedonic ratings suggest that, in patients who persist with long-term continuous therapy, XR-NTX may selectively inhibit the pleasure associated with drinking alcohol, compared to a variety of other activities. PMID- 21314753 TI - Anxiety sensitivity as a mediator of the relationship between moderate-intensity exercise and coping-oriented marijuana use motives. AB - The present study examined the working hypothesis that moderate-intensity exercise is associated with coping-oriented marijuana use motives through its association with the fear of somatic arousal (ie, anxiety sensitivity). Using data from 146 young adult current marijuana users, we found evidence consistent with this hypothesis. Specifically, moderate-intensity exercise was associated with coping-oriented use motives, even after controlling for frequency of current marijuana use and other co-occurring marijuana use motives. This relationship became nonsignificant after entering anxiety sensitivity as an additional predictor variable, denoting a putative mediational role for this cognitive factor. These findings extend previous work and offer support for the potential utility of moderate-intensity aerobic exercise for the treatment of marijuana use problems. PMID- 21314754 TI - The effects of realistic reward and risk on simulated gambling behavior. AB - Laboratory studies on gambling may not represent an accurate analog of actual gambling behavior because they typically fail to model a meaningful level of risk and reward that is given in real-world settings. The current study sought to address this problem. One hundred and twenty college students were given the opportunity to bet valued experimental credits required for passing an introductory psychology course on the outcome of a videotaped horse race while their heart rate was monitored. Of those, 67 decided to wager, whereas 53 did not. Individuals who wagered course credits demonstrated a larger increase in heart rate and reported more subjective excitement during the race compared to individuals who did not bet. While the bettors' heart rates remained elevated after the end of the race, reports of subjective excitement depended on whether individuals had won or lost their wager. Significant gender differences and differences in personality were also found between the groups of bettors and nonbettors. These findings demonstrate that arousal in response to gambling is related to the potential for both risk and reward. PMID- 21314755 TI - gamma Hydroxybutyrate use: exploring the influence of outcome expectancies through memory modeling. AB - Gamma hydroxybutyrate (GHB) has been linked to overdose, criminal surreptitious administration, the need for emergency medical care, and fatalities worldwide. To begin to identify and understand the motivational factors that lead to the use of GHB, the present investigation utilized methods that have been successful in identifying potential expectancy targets and have been incorporated into prevention and intervention strategies successful in reducing high-risk alcohol use. In the present investigation, GHB expectancies were elicited from 926 voluntary participants aged 18-60 at a university in the southeastern United States to develop the GHB Expectancy Questionnaire (GHBEQ). The GHBEQ was subsequently administered to a different sample of 1,373 participants aged 18-55 in order to empirically derive the possible organization of GHB expectancies in memory, including likely paths of GHB expectancy activation. Findings suggest differences in GHB expectancies based on use history and sex. These results can be used to understand differences in GHB use for men and women, and to develop expectancy-based prevention and intervention programming to prevent and reduce its use in high-risk populations. PMID- 21314757 TI - Association of clinical characteristics and cessation of tobacco, alcohol, and illicit drug use during pregnancy. AB - Pregnancy is a time of relative urgency and opportunity for the treatment of substance use disorders in women, yet little is known about modifiable factors that contribute to successful abstinence. We examined self-worth, depression, anxiety, and novelty seeking in the context of substance use cessation during pregnancy in a sample of women with a high prevalence of substance abuse. Subjects were 448 birth mothers who participated in a prospective adoption study. Discontinuation rates were: tobacco 22.2%, alcohol 64.7%, marijuana 77.2%, and other drugs, 73.7-100%. Depression, anxiety, and novelty seeking were lower among women who discontinued substance use, compared to those who did not. Self-worth was higher in women who discontinued substance use. Among 110 polysubstance users, the number of substances discontinued during pregnancy was correlated with depression, anxiety, and self-worth in the hypothesized direction. Possible clinical implications are discussed. PMID- 21314756 TI - Conventional and unconventional treatments for stress among methadone-maintained patients: treatment willingness and perceived efficacy. AB - We surveyed 150 methadone maintenance treatment (MMT) program patients about willingness to use, and perceived efficacy of, conventional and unconventional nonpharmacological stress-related treatments. Although levels of treatment willingness and perceived efficacy for both conventional and unconventional treatments were high, ratings for conventional interventions were, on average, significantly higher than those for unconventional ones. Dimensions of psychiatric distress-but not demographic or MMT characteristics-predicted treatment willingness for conventional therapies and treatment willingness and perceived efficacy for unconventional therapies. These findings are likely to have implications for resource and program planning in MMT programs. PMID- 21314758 TI - Selective cocaine-related difficulties in emotional intelligence: relationship to stress and impulse control. AB - Emotional Intelligence (EI) comprises the ability to perceive, use, understand, and regulate emotions and may potentially contribute to variability in risk related factors such as stress perception and impulse control in cocaine dependent individuals. The main objective of the current study is to better define EI in cocaine dependent individuals compared with healthy controls, using the Mayer, Salovey, and Caruso Emotional Intelligence Test (MSCEIT). Secondary analysis investigates the association between EI, IQ factors, perceived stress, and impulse control in both populations. Seventy-two abstinent treatment-seeking cocaine patients and 52 healthy controls were administered the MSCEIT as well as measures of IQ, perceived stress, and impulse control. Findings showed that cocaine dependent participants demonstrated highly selective EI difficulties compared with healthy controls, specifically with regard to higher-level emotional reasoning including the understanding, management, and regulation of emotion. These EI problems were associated with increased perceived stress and impulse control difficulties. IQ was significantly associated with all MSCEIT measures in the cocaine dependent participants, but not controls. Findings indicate that specific aspects of EI may be of clinical importance to cocaine dependent populations, impacting relapse-related factors such as stress dysregulation and impulse control. PMID- 21314759 TI - Mood and cue reactivity among smokers with a history of major depression: the role of rumination and impulsivity. AB - The present study tested the influence of rumination and impulsivity on experimentally induced negative mood among a sample of smokers with a lifetime history of major depression (MDD Hx+). Participants (N = 40) were categorized into four vulnerability groups: nonvulnerable (low rumination, low impulsivity), ruminative (elevated rumination, low impulsivity), impulsive (low rumination, elevated impulsivity), and vulnerable (elevated rumination, elevated impulsivity). Participants were counterbalanced to four experimental conditions, using a combination of a mood induction (negative mood induction vs. control) and smoking cue (in vivo cigarette vs. control cue). Although all participants reported greater anger responses when exposed to the negative mood induction versus control, vulnerable and ruminative smokers reported significantly greater anger responses than impulsive and nonvulnerable smokers [F(9,87) = 2.93, p = .038, Mse = 79.38]. Implications are discussed. PMID- 21314760 TI - The co-occurrence of gambling with substance use and conduct disorder among youth in the United States. AB - The co-occurrence of gambling with substance use and conduct disorder was examined in a representative U.S. household sample of 2,274 youth 14-21 years old. The findings show that problem gambling occurs within a problem-behavior syndrome with other substance-use behaviors and conduct disorder. Male gender, being black, and being Hispanic were found to be significant in predicting problem gambling over and above the effects of all four substance use and conduct disorder variables. Clinical interventions for one specific problem behavior in youth should consider assessing the other problem behaviors as well. PMID- 21314761 TI - Herbal medicines: perfect garb for opioid abuse? A case series from India. PMID- 21314762 TI - Hazardous gambling among women court-mandated to batterer intervention programs. PMID- 21314763 TI - Less abuse potential with XR formulation of quetiapine? PMID- 21314764 TI - Safety, tolerability, and self-rated effects of aripiprazole and ropinirole treatment for cocaine dependence: a pilot study. PMID- 21314765 TI - Does lizard tail lacing heighten cannabis addiction? PMID- 21314766 TI - Housing as a motivation for seeking substance abuse treatment. PMID- 21314767 TI - Inclusion of gender in emergency medicine research. AB - BACKGROUND: Emergency physicians as front-line clinical specialists can directly advance patient care by understanding how gender-specific approaches may affect evaluation and management of diseases in the acute setting. Yet, it is unclear whether the role of gender is systematically examined in research focusing on emergency care. OBJECTIVES: The objective was to determine if the effect of gender on health outcomes is examined in published studies targeting emergency medicine (EM). METHODS: Using MEDLINE, the term "emergency" was used to identify all English-language, EM-related studies of adult human subjects published between January 2006 and April 2009 in which the first, second, or last author belonged to an EM section, division, center, or institution functioning as an emergency department (ED). The alternative chance-corrected statistic was used for intercoder reliability, and chi-square was used to calculate odds ratios (OR) with 95% confidence intervals (CIs). Articles were coded for gender composition, as well as use of gender as a control variable, independent variable, or part of the primary hypothesis. RESULTS: The search revealed 2,487 articles using the selected "emergency" terms, and 750 original studies coded as EM-related publications were reviewed. The five topics contributing the most articles (44%) were administration/crowding, cardiovascular disease, emergency medical services, trauma, and sepsis. Seventy-nine percent of articles reported the gender composition of the sample, with 11% including gender as a control variable, 18% including gender as an independent variable, and 2% including gender in the primary hypothesis. The alternative chance-corrected statistic for evaluating gender composition was 0.90 (95% CI = 0.75 to 1.00). Use of gender in the analysis did not differ between federally funded studies versus non-federally funded studies (OR = 0.86; 95% CI = 0.5 to 1.4). The number of articles analyzing the effect of gender on a health outcome increased by 5% over the study period (27%-32%). CONCLUSIONS: The majority of research articles targeted EM report gender as a demographic variable; however, few studies examined the effect of gender on health outcome. As the specialty advances into the next decade, the authors recommend that EM researchers 1) include both men and women in their study designs for appropriate gender comparisons; 2) report gender composition of study subjects and gender-specific comparisons study findings; and 3) report prognoses, outcomes, and interventions using gender as an independent variable in the study model. PMID- 21314768 TI - Introduction: special content focus: pediatrics. PMID- 21314769 TI - The role of triage liaison physicians on mitigating overcrowding in emergency departments: a systematic review. AB - OBJECTIVES: The objective was to examine the effectiveness of triage liaison physicians (TLPs) on mitigating the effects of emergency department (ED) overcrowding. METHODS: Electronic databases (Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Web of Science, HealthSTAR, Dissertation Abstracts, and ABI/INFORM Global), controlled trial registry websites, conference proceedings, study references, contact with experts in the field, and correspondence with authors were used to identify potentially relevant TLP studies. Intervention studies in which a TLP was used to influence ED overcrowding metrics (length of stay [LOS] in minutes, physician initial assessment [PIA], and left without being seen [LWBS]) were included in the review. Two reviewers independently conducted data extraction and assessed the citation relevance, inclusion, and study quality. For continuous outcomes, weighted mean differences (WMD) were calculated and reported with corresponding 95% confidence intervals (CIs). For dichotomous variables, individual and pooled statistics were calculated as relative risk (RR) with 95% CI. RESULTS: From 14,446 potentially relevant studies, 28 were included in the systematic review. Thirteen were journal publications, 12 were abstracts, and three were Web-based articles. Most studies employed before-after designs; 23 of the 28 studies were considered of weak quality. Based on the statistical pooling of data from two randomized controlled trials (RCTs), TLP resulted in shorter ED LOS compared to nurse-led triage (WMD = -36.85 min; 95% CI = -51.11 to -22.58). One of these RCTs showed a significant reduction in the PIA associated to TLP presence (WMD = 30.00 min; 95% CI = -56.91 to -3.09); the other RCT showed no change in LWBS due to a CI that included unity (RR = 0.82; 95% CI = 0.67 to 1.00). CONCLUSIONS: While the evidence summarized here suggests that to have a TLP is an effective intervention to mitigate the effects of ED overcrowding, due to the weak research methods identified, more research is required before its widespread implementation. PMID- 21314770 TI - Prior statin use is not associated with improved outcome in emergency patients admitted with infection: a prospective observational study. AB - OBJECTIVES: The objective was to determine whether prior statin use is associated with lower mortality in emergency patients admitted with infection. METHODS: A prospective observational study was conducted at the emergency department (ED) of a tertiary adult hospital with an annual census of over 73,000 patients. Patients presenting to the ED who were subsequently hospitalized with a primary diagnosis of infection were identified within 24 hours of presentation. Data were abstracted from patients' charts and from hospital electronic databases. Patients were stratified according to reported regular statin use on presentation. The outcome measure was in-hospital mortality truncated at 30 days. An association between statin use and mortality was sought using logistic regression analysis. RESULTS: Data were collected over a 60-week period from 2,642 admissions. Patients taking a statin on admission had a higher unadjusted mortality risk (odds ratio [OR] = 2.14, 95% confidence interval [CI] = 1.32 to 3.46) compared to those not on a statin. However, this result became nonsignificant (OR = 0.96, 95% CI = 0.55 to 1.69) after adjusting for age, severity of disease, comorbid status, and propensity score. CONCLUSIONS: These data do not support an independent association between current preadmission statin use and lower 30-day in-hospital mortality in emergency patients admitted with infection. This result is contrary to most previously published studies. PMID- 21314771 TI - Problems with measurement of the minimum clinically significant difference in acute pain in elders. AB - OBJECTIVES: A standard value for the minimum clinically significant difference (MCSD) in pain in nonelderly ED patients has been identified and has facilitated research in this age group. It is not clear that this value is similar in older patients. The standard method for calculating the MCSD in pain is to average scores on a numerical rating scale (NRS) over contiguous time periods. This method is based on the assumption that the MCSD remains constant over time. In an earlier hypothesis-generating study of elderly patients, this assumption was not met for the arithmetic MCSD, making it difficult to identify a single benchmark for measuring efficacy in analgesia trials in elders. The proportional MCSD was more stable, suggesting that it might constitute a better measure of analgesic efficacy in elderly patients. The objective of the study was to test the hypotheses that: 1) the arithmetic MCSD in adults 65 years and older declines over time and that 2) the proportional MCSD remains constant. METHODS: This was an observational, prospective, cohort study of emergency department (ED) patients >=65 years with acute pain. Pain intensity was rated on a standard 11-point NRS upon study entry and every 30 minutes for 2 hours. The arithmetic MCSD was defined as the mean change in pain between contiguous 30-minute intervals when change in pain was described as "a little less" or "a little more." The proportional MCSD was calculated as the arithmetic MCSD divided by pain intensity at the beginning of the interval. We used generalized estimating equations (GEEs) to test trend over time. RESULTS: A total of 214 patients were enrolled: mean (+/ standard deviation [SD]) age was 74 (+/-7.5) years, 66% were female, 63% were Hispanic, and 23% were African American. The median initial NRS was 8. The MCSD decreased 2.1 NRS units (95% confidence interval [CI] = 1.7 to 2.4) between 0 and 30 minutes, 1.4 units (95% CI = 1.0 to 1.7) between 30 and 60 minutes, 1.3 units (95% CI = 1.0 to 1.5) between 60 and 90 minutes, and 0.8 units (95% CI = 0.6 to 1.0) between 90 and 120 minutes (p < 0.001 for trend). The proportional MCSD also varied from 27% (95% CI = 23% to 32%) between 0 and 30 minutes, 19% (95% CI = 13% to 24%) between 30 and 60 minutes, 22% (95% CI = 18% to 27%) between 60 and 90 minutes, and 13% (95% CI = 9% to 18%) between 90 and 120 minutes (p < 0.001 for trend). CONCLUSIONS: Both the arithmetic and the proportional MCSD in elderly patients in acute pain declined over time. Because both measures were numerically unstable, there does not appear to be a single value for the MCSD that can be used to identify the MCSD in pain for use in analgesic efficacy trials in elderly patients. A different metric may be needed to study pain and assess comparative analgesic efficacy in elderly patients. PMID- 21314772 TI - Pain intervention for infant lumbar puncture in the emergency department: physician practice and beliefs. AB - OBJECTIVES: The objectives were to characterize physician beliefs and practice of analgesia and anesthesia use for infant lumbar puncture (LP) in the emergency department (ED) and to determine if provider training type, experience, and beliefs are associated with reported pain intervention use. METHODS: An anonymous survey was distributed to ED faculty and pediatric emergency medicine (PEM) fellows at five Midwestern hospitals. Questions consisted of categorical, yes/no, descriptive, and incremental responses. Data were analyzed using descriptive statistics with confidence intervals (CIs) and odds ratios (ORs). RESULTS: A total of 156 of 164 surveys (95%) distributed were completed and analyzed. Training background of respondents was 52% emergency medicine (EM), 30% PEM, and 18% pediatrics. Across training types, there was no difference in the belief that pain treatment was worthwhile (overall 78%) or in the likelihood of using at least one pain intervention. Pharmacologic pain interventions (sucrose, injectable lidocaine, and topical anesthetic) were used in the majority of LPs by 20, 29, and 27% of respondents, respectively. Nonpharmacologic pain intervention (pacifier/nonnutritive sucking) was used in the majority of LPs by 67% of respondents. Many respondents indicated that they never used sucrose (53%), lidocaine (41%), or anesthetic cream (49%). Physicians who thought pain treatment was worthwhile were more likely to use both pharmacologic and nonpharmacologic pain interventions than those who did not (93% vs. 53%, OR = 10.98, 95% CI = 4.16 to 29.00). The number of LPs performed or supervised per year was not associated with pain intervention use. Other than pacifiers, injectable lidocaine was the most frequently reported pain intervention. CONCLUSIONS: Provider beliefs regarding infant pain are associated with variation in anesthesia and analgesia use during infant LP in the ED. Although the majority of physicians hold the belief that pain intervention is worthwhile in this patient group, self-reported pharmacologic interventions to reduce pain associated with infant LP are used regularly by less than one-third. Strategies targeting physician beliefs on infant pain should be developed to improve pain intervention use in the ED for infant LPs. PMID- 21314773 TI - Emergency physicians' knowledge and provision of child passenger safety information. AB - OBJECTIVES: While physicians provide discharge instructions to patients and families following emergency department (ED) visits, injury prevention information may not be routinely included in these instructions. This study assessed emergency physicians' knowledge and provision of child passenger safety (CPS) information to patients following motor vehicle crashes (MVCs). METHODS: This study was both a survey of emergency physician knowledge and provision of CPS information and an examination of frequency of CPS information in discharge instructions at a single institution. Members of the American Academy of Pediatrics (AAP) Section on Emergency Medicine were invited to participate in the survey. Respondents were asked about their provision of CPS information to patients and knowledge of national AAP CPS recommendations. The institutional ED medical record chart review assessed the frequency of written CPS information for patients of MVC-related visits who were discharged home. RESULTS: There were 317 survey respondents from 1,024 eligible physicians, of whom 43 began but did not complete the survey. The data analyzed are from the 274 who completed the survey. While 85% (95% confidence interval [CI] = 81% to 89%) of physicians believed that CPS information should be included in discharge instructions, only 36% (95% CI = 31% to 42%) correctly answered all knowledge questions. Of the 51 self-identified division/department chiefs, 15 (29.4%; 95% CI = 16.9% to 41.9%) reported that their EDs routinely provide CPS information in discharge instructions for pediatric passengers in MVCs. For the medical record review, of the 152 randomly selected MVC visits, 13 (8.6%; 95% CI = 4.1% to 13.0%) had documented CPS information in the discharge instructions. Patients with documented CPS information were younger, but there were no significant differences in race, sex, or maximum abbreviated injury scale score between patients with versus without CPS information. CONCLUSIONS: While emergency physicians value the use of CPS information in discharge instructions following MVCs, they do not have adequate knowledge of, nor do they regularly disseminate, this information. PMID- 21314774 TI - Who are the children leaving the emergency department without being seen by a physician? AB - BACKGROUND: Waiting times to see a physician in emergency departments (EDs) are growing, and a greater number of patients are leaving the ED without being seen by a physician (LWBS). OBJECTIVES: The objective was to assess the characteristics of the children who left a pediatric ED without being seen by a physician. METHODS: This retrospective case-control study was performed using the computerized database of a tertiary care pediatric ED. All children aged less than 19 years old presenting to the ED between April 1, 2008, and March 31, 2009, were included. Cases were all triaged children who LWBS. Controls were all triaged children seen by a physician. Independent variables concerning the patient, the illness, and the period of consultation were assessed. A stepwise logistic regression model was constructed using significant variables identified through univariate analysis to select characteristics most predictive of patients who LWBS. The minimum sample size needed to evaluate 10 risk factors is 100 patients who LWBS. We estimated that evaluating all patients visiting the ED for 1 year would minimize seasonal variation and generate more than 10,000 patients who LWBS. RESULTS: During the study period, 60,525 patients presented to the ED. A total of 10,037 (16.6%) patients were triaged, but LWBS. On multiple logistic regression, referral by a physician (odds ratio [OR] = 0.1, 95% confidence interval [CI] = 0.08 to 0.12); summer or fall consultation (OR = 0.46, 95% CI = 0.43 to 0.45; and OR 0.42, 95% CI = 0.39 to 0.45, respectively, compared to winter); and higher acuity triage level were associated with a lower risk of patients who LWBS. Evening arrivals (OR = 2.1, 95% CI = 1.9 to 2.2, compared to night), ages between 3 months and 11 years (OR varying from 1.3 to 1.8 compared to more than 11 years of age), and living close to the hospital (OR = 1.2, 95% CI = 1.1 to 1.3) were risk factors for LWBS. The most important predictor of LWBS was triage level with rates of 0, 0, 1.5, 23, and 49% for Levels 1 to 5 according to the Canadian Triage and Acuity Scale (CTAS). CONCLUSIONS: This study shows that children who LWBS have a lower triage acuity, are less often referred by a physician, and are largely in the 3-month to 11-year-old age range. Environmental factors, such as the timing of the consultation and the proximity of patients' homes, are also associated with LWBS. PMID- 21314775 TI - Resource burden at children's hospitals experiencing surge volumes during the spring 2009 H1N1 influenza pandemic. AB - OBJECTIVES: The objective was to describe the emergency department (ED) resource burden of the spring 2009 H1N1 influenza pandemic at U.S. children's hospitals by quantifying observed-to-expected utilization. METHODS: The authors performed an ecologic analysis for April through July 2009 using data from 23 EDs in the Pediatric Health Information System (PHIS), an administrative database of widely distributed U.S. children's hospitals. All ED visits during the study period were included, and data from the 5 prior years were used for establishing expected values. Primary outcome measures included observed-to-expected ratios for ED visits for all reasons and for influenza-related illness (IRI). RESULTS: Overall, 390,983 visits, and 88,885 visits for IRI, were included for Calendar Weeks 16 through 29, when 2009 H1N1 influenza was circulating. The subset of 106,330 visits and 31,703 IRI visits made to the 14 hospitals experiencing the authors' definition of ED surge during Weeks 16 to 29 was also studied. During surge weeks, the 14 EDs experienced 29% more total visits and 51% more IRI visits than expected (p < 0.01 for both comparisons). Of ED IRI visits during surge weeks, only 4.8% were admitted to non-intensive care beds (70% of expected, p < 0.01), 0.19% were admitted to intensive care units (44% of expected, p < 0.01), and 0.01% received mechanical ventilation (5.0% of expected, p < 0.01). Factors associated with more-than-expected visits included ages 2-17 years, payer type, and asthma. No factors were associated with more-than-expected hospitalizations from the ED. CONCLUSIONS: During the spring 2009 H1N1 influenza pandemic, pediatric EDs nationwide experienced a marked increase in visits, with far fewer than expected requiring nonintensive or intensive care hospitalization. The data in this study can be used for future pandemic planning. PMID- 21314776 TI - Clinical outcomes in obese and normal-weight children undergoing ultrasound for suspected appendicitis. AB - BACKGROUND: Obesity constitutes an independent predictor for a nondiagnostic screening ultrasound (US) in suspected appendicitis. Furthermore, the imaging route consisting of the screening US with a second US if necessary has a significantly lower diagnostic accuracy in the obese children (83%) than their lean counterparts (93%). However, the effect of this association on clinical outcomes in the obese population is unknown. OBJECTIVES: In children presenting to the emergency department (ED) undergoing US for suspected appendicitis, the objective was to examine if there is a significant difference in the proportions of those with a "desirable outcome" in the obese group versus their normal-weight counterparts. METHODS: This was a reanalysis of a recent prospective cohort study conducted at a tertiary care pediatric ED. A consecutive sample of 263 previously healthy children 4-17 years of age undergoing screening US for suspected appendicitis was enrolled. Study patients were divided into obese (body mass index-for-age percentiles [BMI-FAP] >= 85%) and normal-weight groups. The main outcome was the proportion of children with the desirable outcome in the obese and normal-weight groups. Desirable outcomes for patients with a nondiagnostic screening US were defined as either 1) nonperforated appendicitis or alternate surgical diagnosis undergoing appropriate surgical procedure within 24 hours of assessment without a computed tomography (CT) scan or 2) no appendicitis, discharged from the ED within 24 hours without a CT scan. Secondary outcomes included hospitalization, CT imaging for any reason within 30 days of initial presentation, length of hospital stay, return visits, time to and length of surgery, and complications. RESULTS: Of the 263 patients, 76 (28.9%) were obese, and 187 had a normal weight. Ninety-nine children (37.6%) had appendicitis (obese = 24, normal-weight = 75). The desirable outcome was achieved in 46 (64.5%) of the obese patients versus 137 (73.3%) of the normal-weight children (95% confidence interval [CI] for the difference = -0.21 to 0.04). Compared to the normal-weight children, the obese children had similar hospitalization rates (44.7% vs. 45.5%), median length of hospital stay (20.5 hours vs. 23.0 hours), and return ED visit rates (11.8% vs. 9.1%). The median time to surgery (obese = 10.5 hours, normal-weight = 9.0 hours), complications (obese = 25%, normal-weight = 21.3%), perforations (obese = 33%, normal-weight = 31%), and length of surgery (obese 80 [+/-37] minutes, normal-weight 67 [+/-25] minutes) were also similar. The rate of CT within 30 days of initial presentation was higher in the obese compared to the normal-weight group (13/76 or 17.1% vs. 13/187 or 6.9%, 95% CI = 0.02 to 0.23). CONCLUSIONS: Previously healthy obese children undergoing screening US for suspected appendicitis experienced comparable clinical outcomes to their normal-weight counterparts. However, they were three times more likely to receive a CT scan during their investigation. These results argue for continuing current practice of using the screening US in this population, followed by a CT if clinically warranted upon reexamination. PMID- 21314777 TI - Assessment of a training curriculum for emergency ultrasound for pediatric soft tissue infections. AB - OBJECTIVES: The objective was to evaluate a training protocol for pediatric emergency physicians (EPs) learning emergency ultrasound (EUS) for the evaluation of skin and soft tissue infections (SSTIs) by assessing technical ability and interrater reliability. METHODS: Pediatric emergency medicine (EM) fellows and attending physicians completed a 1-day training course taught by an expert emergency sonologist. After the course, EPs performed proctored examinations on patients with SSTIs until they reached predefined performance criteria, after which they performed independent EUS examinations. All EUS examinations were recorded using still images and video clips that were reviewed and rated by the expert sonologist on four technical measures and combined into a composite score. The expert's opinion regarding the presence or absence of an abscess was also compared to the study sonologist's opinion and analyzed for interrater reliability. RESULTS: Seven EPs performed 107 EUS examinations. The mean (+/-SD) composite score for the evaluation of technical ability for the first EUS was 3.3 +/- 0.14 (on a 4-point scale), indicating a high level of quality following the training course. There was a small amount of improvement in the quality score (0.015, 95% confidence interval [CI] = 0.0003 to 0.03) with each consecutive EUS examination. The interrater reliability between the sonologist and the expert for the presence of an abscess as measured by the kappa statistic was 0.80 (95% CI = 0.63 to 0.97), indicating substantial agreement. CONCLUSIONS: After a brief training program, pediatric EPs can perform technically successful emergency EUS examination of SSTIs, with excellent agreement with an expert sonologist. PMID- 21314778 TI - Little's law flow analysis of observation unit impact and sizing. AB - Expanding hospital capacity by developing an observation unit may be an important strategy in congested hospitals. Understanding the principles for evaluating the potential impact and appropriate sizing of an observation unit is important. The objective of this paper is to contrast two approaches to determining observation unit sizing and profitability, real options, and a flow analysis based on Little's Law. Both methods have validity and use similar data sets. The Little's Law approach has the advantage of providing an estimate of appropriate size for the unit and a natural internal consistency check on data. The benefits of an observation unit can depend critically on assumptions regarding backfill patients, and minor changes in data or assumptions can translate into significant changes in annual financial consequences. Using both the real options and the Little's Law approaches provides some internal consistency checks on data and assumptions. Both are sufficiently simple to be easily mastered and conducted. Using these two simple and accessible methods in parallel for computing the size and financial consequences for an observation unit is recommended. PMID- 21314779 TI - Generational influences in academic emergency medicine: teaching and learning, mentoring, and technology (part I). AB - For the first time in history, four generations are working together traditionalists, baby boomers, generation Xers (Gen Xers), and millennials. Members of each generation carry with them a unique perspective of the world and interact differently with those around them. Through a review of the literature and consensus by modified Delphi methodology of the Society for Academic Emergency Medicine Aging and Generational Issues Task Force, the authors have developed this two-part series to address generational issues present in academic emergency medicine (EM). Understanding generational characteristics and mitigating strategies can help address some common issues encountered in academic EM. Through recognition of the unique characteristics of each of the generations with respect to teaching and learning, mentoring, and technology, academicians have the opportunity to strategically optimize interactions with one another. PMID- 21314780 TI - Generational influences in academic emergency medicine: structure, function, and culture (Part II). AB - Strategies for approaching generational issues that affect teaching and learning, mentoring, and technology in emergency medicine (EM) have been reported. Tactics to address generational influences involving the structure and function of the academic emergency department (ED), organizational culture, and EM schedule have not been published. Through a review of the literature and consensus by modified Delphi methodology of the Society for Academic Emergency Medicine Aging and Generational Issues Task Force, the authors have developed this two-part series to address generational issues present in academic EM. Understanding generational characteristics and mitigating strategies can address some common issues encountered in academic EM. By understanding the differences and strengths of each of the cohorts in academic EM departments and considering simple mitigating strategies, faculty leaders can maximize their cooperative effectiveness and face the challenges of a new millennium. PMID- 21314781 TI - How a bowl of beans and rice, a couple x-rays, and 8 hours of futility taught me to trust my own intuition. PMID- 21314782 TI - The role of certainty, confidence, and critical thinking in the diagnostic process: good luck or good thinking? PMID- 21314783 TI - Evaluating infant positioning for lumbar puncture using sonographic measurements. AB - OBJECTIVES: Hypoxia has been observed when infants undergo lumbar puncture in a tight flexed lateral recumbent position. This study used sonographic measurements of lumbar interspinous spaces to investigate the anatomic necessity and advantage derived from this tight flexed positioning in infants. METHODS: This was a brief, prospective, observational study of a convenience sample of patients. Twenty-one healthy infants under 1 month of age were scanned in two positions: prone in a spine-neutral position and lateral recumbent with their knees bent into their chest and their neck flexed. In each position, a 5- to 10-MHz linear array transducer was used to scan midline along the lumbar spinous processes in the sagittal plane. The distances between the spinous processes were measured near the ligamentum flavum using the ultrasound machine's calipers. Pulse oximetry was monitored on all infants during flexed positioning. RESULTS: In the spine-neutral position, all studied interspinous spaces were much wider than a 22-gauge spinal needle (diameter 0.072 cm). The mean (+/-SD) interspinous spaces for L3-4, L4-5, and L5-S1 in a spine-neutral position were 0.42 (+/-0.07), 0.37 (+/-0.06), and 0.36 (+/-0.11) cm, respectively. Flexing the infants increased the mean lumbar interspinous spaces at L3-4, L4-5, and L5-S1 by 31, 51, and 44%, respectively. CONCLUSIONS: This study verified that tight, lateral flexed positioning substantially enhances the space between the lumbar spinous processes and that a spine-neutral position also allows for a large enough anatomic interspinous space to perform lumbar puncture. However, further clinical research is required to establish the feasibility of lumbar puncture in a spine-neutral position. PMID- 21314784 TI - Relationship between B-type natriuretic peptide and adverse outcome in patients with clinical evidence of sepsis presenting to the emergency department. AB - OBJECTIVES: Myocardial dysfunction is an important aspect of sepsis pathophysiology. B-type natriuretic peptide (BNP) is a neurohormone released from the ventricles in response to myocardial stretch and volume overload. The authors hypothesized that an elevated BNP in patients presenting to the emergency department (ED) with suspected sepsis are at increased risk for development of adverse events. METHODS: This was a prospective, observational, multicenter cohort study in 10 EDs. Patients were eligible if they were older than 18 years, had two or more systemic inflammatory response syndrome (SIRS) criteria, and had suspected infection or a serum lactate level > 2.5 mmol/L. Patients were excluded if they were pregnant, had do-not-attempt-resuscitation status, sustained a cardiac arrest prior to hospital arrival, had known chronic renal insufficiency, or were on dialysis. BNP levels were obtained at arrival. The primary outcome was a composite of severe sepsis, septic shock within 72 hours, or in-hospital mortality. RESULTS: There were 825 patients enrolled (mean +/- standard deviation [SD] age = 53.5 +/- 19.6 years; 51% were female and 37% were African American). The area under the curve (AUC) for BNP to predict the triple composite outcome was 0.69, and the optimal cut-point of BNP was 49 pg/mL. Patients with a BNP > 49 pg/mL had a greater mortality rate (11.6% vs. 2.1%; p = 0.0001), a greater risk of development of severe sepsis (67.7% vs. 36.8%; p = 0.0001) and septic shock (51.7% vs. 26.4%; p = 0.0001), and a higher rate of the triple composite outcome (69% vs. 37%; unadjusted odds ratio [OR] = 1.9, 95% confidence interval [CI] = 1.6 to 2.1; p < 0.001). The sensitivity was 63% (95% CI = 58% to 67%), specificity was 69% (95% CI = 65% to 73%), negative predictive value (NPV) was 63% (95% CI = 58% to 67%), and positive predictive value (PPV) was 69% (95% CI = 65% to 74%). In multivariate modeling, after adjusting for age, sex, heart rate, white blood cell count, and creatinine, an elevated BNP was associated with increased odds of having the composite outcome. The outcome was similar in the subset of patients who did not have severe sepsis or septic shock upon arrival. CONCLUSIONS: In patients who present to the ED with SIRS criteria and suspected infection, an elevated BNP is associated with a worse prognosis but has limited diagnostic utility. PMID- 21314786 TI - Heavy air. PMID- 21314787 TI - Health legacies of war on and beyond the battlefield. PMID- 21314788 TI - Experimental wounds: science and violence in mid-century America. PMID- 21314789 TI - Surviving wartime emancipation: African Americans and the cost of Civil War. PMID- 21314790 TI - Waiting to exhale: chaos, toxicity and the origins of the U.S. Chemical Warfare Service. PMID- 21314791 TI - Toxic legacy: mustard gas in the sea around us. PMID- 21314792 TI - Veterans' welfare, the GI Bill and American demobilization. PMID- 21314793 TI - Going for the burn: medical preparedness in early Cold War America. PMID- 21314794 TI - Representations and reproductive hazards of Agent Orange. PMID- 21314795 TI - Reasonable suspicion of child abuse: finding a common language. PMID- 21314796 TI - Harmonization of ethics policies in pediatric research. PMID- 21314797 TI - Grassroots marketing in a global era: more lessons from BiDil. PMID- 21314798 TI - Currents in contemporary bioethics. Who will treat Medicaid and uninsured patients? Retired providers can help. PMID- 21314799 TI - Ban on milk labeling violates First Amendment--International Dairy Foods Ass'n v. Boggs. PMID- 21314800 TI - Use of reflectance confocal microscopy to differentiate hidrocystoma from basal cell carcinoma. PMID- 21314801 TI - Slowly-developing facial nerve paralysis. PMID- 21314802 TI - Diagnostic accuracy of sonohysterography, hysterosalpingography and diagnostic hysteroscopy in diagnosis of arcuate, septate and bicornuate uterus. AB - AIM: To evaluate the diagnostic accuracy of sonohysterography (SHG), hysterosalpingography (HSG) and diagnostic hysteroscopy (DH) in uterine anomaly detection and to assess the role of these various modalities in the differential diagnosis of arcuate, septate and bicornuate uteri. METHODS: Eighty-three women, with a history of recurrent spontaneous abortions or infertility and initial diagnosis of uterine anomaly were included in the study. Diagnostic work-up comprised of SHG, HSG and DH. To assess the accuracy of these methods all the patients underwent hysterolaparoscopy to establish the final diagnosis. The correlation between the results of each method was evaluated and diagnostic accuracy of each method was assessed in the whole group of women as well as in subgroups of arcuate, septate and bicornuate uteri using receiver operator curve (ROC) method by estimating the area under the curve (AUC). RESULTS: In the overall diagnosis of uterine anomalies, SHG with accuracy of 95.2% and correlation index of 0.873 (P < 0.001) proved to be a significantly better tool compared to DH (SHG(AUC) = 0.924 versus DH(AUC) = 0.761 P = 0.008), while no significant differences were observed between SHG versus HSG and DH versus HSG. SHG showed significantly higher accuracy (100.0%) compared to DH (80.7%) and HSG (80.7%) in differentiation of a septate (SHG(AUC) = 1.000 versus DH(AUC) = 0.816 P < 0.001 and SHG(AUC) = 1.000 versus HSG(ACC) = 0.818; P < 0.001) and bicornuate uterus (SGH(AUC) = 1.000 versus DH(ACC) = 0.707; P < 0.001 and SHG(ACC) = 1.000 versus HSG(AUC) = 0.790; P = 0.002). CONCLUSION: SHG is a noninvasive, cost effective method available in an outpatient setting that is highly accurate in identifying uterine anomalies, in particular septate and bicornuate uterus. PMID- 21314803 TI - Confidential enquiries into maternal mortality in the United Arab Emirates: a feasibility study. AB - AIM: Routine confidential enquiry into maternal deaths is not yet part of the United Arab Emirates health care system. A confidential enquiry into maternal deaths was undertaken to test the feasibility of this approach and to identify the causes and preventability of maternal deaths. MATERIAL & METHODS: Data on all maternal deaths over a six year period from 1998 to 2003 were abstracted and reviewed by a panel of experts to assign the cause if in doubt, and to determine whether the deaths were preventable. RESULTS: Over the six year period, 26 deaths were identified with 122,075 births and the maternal mortality ratio was 21.2/100,000 live births. The mean maternal age at death was 32.3 years and two thirds of the deaths occurred during the postpartum period. The leading causes of death were thromboembolic events, hemorrhage and infection. After reviewing the clinical data the expert panel concluded that one third of the deaths were avoidable. CONCLUSION: This first ever confidential enquiry has shown that it is feasible to adopt this approach in the United Arab Emirates and the causes identified would be of help in prioritizing clinical guidelines development and training programs aimed at professionals, which will ultimately lead to safer motherhood for women. PMID- 21314804 TI - Measurement of the placental total antioxidant status in preeclamptic women using a novel automated method. AB - AIM: We aimed to measure the levels of total antioxidant status (TAS) in placental samples from preeclamptic pregnant women and evaluate the relation of placental TAS, total oxidant status (TOS) and oxidative stress index (OSI) with fetomaternal compartments using the more recently designated Erel method. MATERIAL AND METHODS: Thirty four preeclamptic and 27 normotensive pregnant women were enrolled in this prospective controlled study. Subjects were selected from women attending the Obstetrics and Gynecology Department of Gaziantep University. TAS, TOS, OSI were measured from placental, maternal and cord blood samples using a novel automated method. Statistical analyses were performed with SPSS for Windows version 13.0 (SPSS Inc., Chicago, IL, USA). RESULTS: The TAS level of the placenta was evaluated as significantly lower (P<0.001) in preeclamptic women compared to normotensive women. In preeclamptic pregnancies, while the placental TAS level was not correlated with placental TOS level, the TAS levels of maternal plasma (P<0.001; r=0.584) and cord plasma (P<0.005; r=0.529) were significantly correlated with the TOS level of the placenta. CONCLUSION: Our results support the concept that placental defective response to an oxidant stimulus plays a central role in the etiopathogenesis of preeclampsia by using the novel automated Erel method. PMID- 21314805 TI - Retrospective analysis on coexisting ovarian cancer in 976 patients with clinical stage I endometrial carcinoma. AB - AIM: To evaluate the safety of ovarian preservation at the time of operation in clinical stage I endometrial carcinoma. MATERIAL AND METHODS: The data of patients with and without coexisting ovarian cancers were retrospectively collected and clinic-pathologic parameters were analyzed. RESULTS: In total, 20 (2.05%) were histologically diagnosed as coexisting ovarian cancer, including 17 (1.74%) ovarian metastases and three (0.31%) synchronous ovarian primary cancers in 976 patients. Fifty percent (10 of 20) were microscopic ovarian involvements. Ovarian involvement was significantly associated with histological type, depth of myometrial invasion, cervical invasion, uterine serosa extension, fallopian tube involvement, retroperitoneal lymph node metastasis, positive peritoneal cytology and CA125 level by univariate analysis (all P<0.05); while cervical invasion, uterine serosa extension, and fallopian tube involvement were independent high risk factors by multivariate analysis (both P<0.05). CONCLUSION: The incidence of coexisting ovarian cancer in clinical stage I endometrial carcinoma is low, but the decision for ovary preservation at the time of operation still needs to be made with caution because of occult ovarian metastasis, especially for patients with high-risk factors. PMID- 21314806 TI - Lymphangioleiomyomatosis suspected to be a gynecologic disease. AB - Lymphangioleiomyomatosis (LAM) is a rare, systemic disorder that predominantly affects women. Although patients with LAM mostly present with pulmonary symptoms, some patients may present initially with extrapulmonary symptoms. We present a case of a 30-year-old Japanese female with abdominal pain during menstrual periods was suspected of having ovarian cancer due to exaggerated ascites observed at a local clinic. Subsequently, she was transferred to our hospital for further investigations, and was diagnosed with LAM. Three years after diagnosis, she had a girl by cesarean section to avoid the progression of pulmonary LAM by vaginal delivery. The patient is undergoing follow-up treatment with the administration of gonadotropin-releasing hormone-analog. Though LAM is rare, gynecologists should know about it because it may occur with gynecological symptoms in young women. PMID- 21314808 TI - Increased arterial stiffness in mildly-hypertensive women with polycystic ovary syndrome. AB - AIM: Although risk factors for cardiovascular disease, such as obesity, hyperinsulinemia, and dyslipidemia, are commonly observed in women with polycystic ovary syndrome (PCOS), impairment of vascular function is still controversial. We evaluated the vascular function in young women with PCOS. METHODS: We evaluated arterial stiffness in 54 women with PCOS and 24 healthy control women using a volume-plethysmographic apparatus equipped with a multi element applanation tonometry sensor for the left common carotid artery and studied the correlations of various factors. RESULTS: There was no significant difference in age or body mass index between the controls and the women with PCOS. These women with PCOS had a significantly higher serum testosterone and C reactive protein levels and showed insulin resistance and dyslipidemia. The mean blood pressure in women with PCOS was within the normal range, but still significantly higher than those in the controls. Women with PCOS had a significantly higher brachial-ankle pulse wave velocity (baPWV) than that for the controls (P < 0.02), whereas there was no significant difference in the carotid augmentation index between the two groups. Stepwise multiple regression analysis revealed that blood pressure influences the baPWV in women with PCOS. Arterial stiffness evaluated using the baPWV in mildly-hypertensive women (systolic blood pressure >=120 mmHg or diastolic blood pressure >=90 mmHg) with PCOS was significantly higher than that in the controls or normotensive women with PCOS. CONCLUSIONS: Early changes in vascular function were detected in mildly hypertensive women with PCOS. Lifestyle interventions to prevent hypertension, such as diet and exercise, should be the first-line of treatment in women with PCOS. PMID- 21314807 TI - Acceptability of human papillomavirus vaccine among the urban, affluent and educated parents of young girls residing in Kolkata, Eastern India. AB - AIM: The human papillomavirus (HPV) vaccine is recommended for adolescent girls and young women; however, the social structure in India will not permit vaccination of this age-group without parental approval. Our study aimed to explore the attitude of affluent, urban Indian parents towards the HPV vaccine. METHODS: Well-to-do married couples with at least one daughter between 9-26 years of age were interviewed using a questionnaire in two parts. The first part was to assess their attitude to vaccination in general and their knowledge of cervical cancer; the second part was to assess their acceptance of the HPV vaccine. An educational fact sheet about cervical cancer and the HPV vaccine was administered in between the two parts. RESULTS: Of the 522 participants, 27% of men and 24% of women agreed to vaccinate their daughters against a cancer initially. After going through the fact sheet, 74% of both men and women were in favor of vaccination. CONCLUSIONS: The HPV vaccine seems to be well accepted among this subgroup of population if appropriately educated. PMID- 21314809 TI - Endometrial cancer implanted within a cesarean section scar. AB - Several reports have documented adenocarcinoma arising from endometriotic implants within cesarean section (C-S) scars on the serosal surface of the uterus; however, endometrial cancer invading the C-S scar from the uterine cavity has not been described. We report a case of a grade 1 endometrioid adenocarcinoma 'drop' lesion invading a previous C-S scar with resultant cervical stromal invasion. Using both MR images and a thorough review of the pathology, the tumor at the C-S scar was determined to be an implant derived from a primary lesion at the uterine fundus. With increases in the incidence of both endometrial cancer and births by C-S, it is likely we will encounter more cases of iatrogenic implants of endometrial cancers in C-S scars. PMID- 21314810 TI - Intramyometrial uterine cysts with special reference to ultrastructural findings: report of two cases. AB - An intramyometrial cyst is an extremely rare condition that is characterized by a benign, endometrial, epithelium-lined cyst within the thickened myometrium. Few cases of intramyometrial cysts have currently been reported in the literature, with or without microscopic description. We have experienced two cases of intramyometrial cysts. One was a 6.5 cm-sized cyst and the other was a 3.0 cm sized cyst accompanied by adenomyosis. Case 1 was a 41-year-old female and case 2 was a 51-year-old female who had been suffering from menorrhagia for several days. A total hysterectomy was performed for both women. Histological examination showed that the huge cysts were composed of single-layered, ciliated, cuboidal epithelia surrounded by diffusely thickened myometrium. Ultrastructural examination of case 1 showed the lining cells of the cyst consisted of the basalis-type endometrial epithelial cells that have surface microvilli. The cells were surrounded by a duplicated basal lamina and joined by well-formed desmosomes. We report here on two cases of intramyometrial cyst with special reference to the ultrastructural examination, and we discuss the pathogenesis of this rare lesion. PMID- 21314811 TI - Failure of epidural analgesia converted to epidural anesthesia for cesarean delivery in a patient with bronchial atresia in labor. AB - Bronchial atresia is a rare anomaly characterized generally by obstruction in the bronchial system, mucus accumulation, emphysematous changes and bulla formation in the peripheral lung. Regional anesthesia is the choice for cesarean delivery in a parturient patient with this anomaly. We report a patient with a diagnosis of bronchial atresia in whom the conversion of epidural analgesia to epidural anesthesia for cesarean delivery failed during labor, needing the application of general anesthesia for a successful delivery. PMID- 21314812 TI - The volume-outcome relationship for radical cystectomy in England: an analysis of outcomes other than mortality. AB - OBJECTIVE: *To evaluate the volume-outcome relationship for radical cystectomy in England using outcomes other than mortality. PATIENTS AND METHODS: *Patients undergoing an elective radical cystectomy were extracted from administrative hospital data for financial years 2000/1 to 2006/7. *Institutional and surgeon volume was assessed against postoperative re-intervention, postoperative complications and emergency readmission within 28 days, using a set of models accounting for patient case-mix, the 'clustered' nature of the data and structural and process of care measures. RESULTS: *In the final model, the odds of re-intervention within 14 and 30 days of operation for medium-volume institutions compared to low-volume institutions were found to be 63% (odds ratio, OR, 1.63; 95% CI 1.15-2.32; P= 0.01) and 52% (OR, 1.52; 95% CI, 1.13-2.04; P= 0.01) higher, respectively. *In the summary of adjusted probabilities, low volume institutions appeared to have a lower re-intervention rate than both medium- and high-volume institutions. *By contrast, high-volume surgeons were associated with a reduced odds (OR, 0.68; 95% CI, 0.51-0.91; P= 0.01) of early re intervention (within 14 days) compared to low-volume surgeons. *This surgeon volume-outcome effect became apparent only after adjusting for the influence of the institution and structural and process of care confounders. *There was no statistically significant relationship between volume and complication or readmission rates. CONCLUSIONS: *Radical cystectomy measures of re-intervention rates can be used as outcome measures to discern differences across institutional or surgeon volume providers when the institutional and surgeon volume are co examined and adjustment for structural and process of care confounders is performed. *The finding of a lower risk of re-intervention in low-volume institutions needs to be explored further. PMID- 21314813 TI - The application of pelvic osteotomy in adult female patients with exstrophy: applications and outcomes. AB - OBJECTIVE: * To apply the technique of pelvic osteotomy to a select group of adult female patients with exstrophy, in view of the low complication rate and acceptable success rate of the technique. PATIENTS AND METHODS: * We applied this technique as an adjunct to uterovaginal suspension and abdominal wall repair after our prior success in treating patients with extreme pelvic diastasis. * Bilateral innominate (transverse) and vertical iliac osteotomies were done from an anterior approach and an external fixator was placed. The fixator and pelvic bones were gradually cranked together over a period of 2-3 weeks until the diastasis was less than 4 cm. * Then sacrocolpopexy was performed with revision of the abdominal wall and revision genitoplasty along with the placement of an intrasymphyseal titanium plate. RESULTS: * Six patients presented with uterine/vaginal prolapse and concerns about the appearance of their abdominal wall and genitalia. Three patients had undergone uterine suspension before and one patient had had five prior attempts at suspension, which failed. The mean (range) age was 22.3 (18-26) years. * All the patients underwent staged reduction of pubic diastasis and sacrocolpopexy along with revision of the abdominal wall and in four cases revision genitoplasty was also performed. The mean (range) diastasis was 12.8 (8-18) cm and 2.8 (3-4) cm before and after staged reduction respectively. * Complications included transient femoral nerve palsy (two) and foot drop secondary to sciatic nerve stretch (one), which resolved with time. The symphyseal plate needed to be removed in three patients: secondary to persistent pain at the site (one), persistent discharge from the lower abdominal wound (one) and erosion into the anterior wall of the vagina (one). * At a mean (range) follow-up of 60.7 (2-137) months the cosmetic and functional outcome of the abdominal wall reconstruction and genitoplasty was good with all the patients being satisfied. Five patients are currently sexually active and none has had a recurrence of their prolapse. None has become pregnant yet. CONCLUSIONS: * Although the morbidity of this procedure in the adult is not insignificant, it is a valuable adjunct to pelvic floor reconstruction in young women of childbearing age even in those who have had prior suspension procedures. * In addition, it allows the movement of lateral previously unoperated skin into the midline, allowing scar and skin replacement with healthier more vascularized tissue. PMID- 21314814 TI - The management of residual curvature after penile prosthesis implantation in men with Peyronie's disease. AB - OBJECTIVE: * To report our experience in the management of residual curvature after implantation of a penile prosthesis in men with Peyronie's disease (PD). PATIENTS AND METHODS: * From January 1985 to June 2009, 62 (29%) of the 209 patients with PD that have undergone the insertion of a penile prosthesis have required an additional straightening procedure to correct the residual curvature after the insertion of the cylinders of the implant. * The types of additional manoeuvres, their success in correcting the residual curvature and eventual complications have been reported. RESULTS: * Among the additional straightening procedures, modelling was more successful in achieving straightening when performed on an inflatable device (84%) than on a malleable implant (54%). * If the curvature persisted after modelling or if the curvature was ventral, straightening was achieved with tunical plications or incision with or without grafting. CONCLUSION: * Although it is common for the simple implantation of cylinders alone to straighten the penis, some patients will present a residual curvature that must be successfully corrected with additional straightening procedures. PMID- 21314815 TI - The liposome-incorporating cell wall skeleton of Mycobacterium bovis bacillus Calmette-Guein can directly enhance the susceptibility of cancer cells to lymphokine-activated killer cells through up-regulation of natural-killer group 2, member D ligands. AB - OBJECTIVE: * To conduct a preclinical evaluation of the ability of natural killer cells to cytolyze bladder cancer cells that were modified to show enhanced expression of natural-killer group 2, member D (NKG2D) ligands by R8-liposome bacillus Calmette-Guein (BCG)-cell wall skeleton (CWS) treatment. MATERIALS AND METHODS: * The T24 cells and RT-112 cells were co-cultured with R8-liposome-BCG CWS and BCG for 2, 4, or 6 h, and then the surface expression of NKG2D ligands was analyzed using TaqMan real-time quantitative RT-PCR. * Peripheral blood mononuclear cells were obtained with a conventional preparation kit, and then lymphokine-activated killer (LAK) cells were generated from these purified peripheral blood mononuclear cells via interleukin-2 stimulation. * The anti tumour effect of LAK cells against untreated and R8-liposome-BCG-CWS co-cultured with cells of the human bladder cancer cell lines T24 and RT-112 was analyzed using the cytotoxic WST-8 assay method at 4 h of culture at various effector/target (E : T) ratios. RESULTS: * Major histocompatibility complex class I-related chain B (MICB) expression was increased ~1.5-fold on T24 cells and RT 112 cells with BCG. * UL-16-binding protein (ULBP) 1 expression was also increased ~1.5-fold on T24 cells and RT-112 cells with BCG. R8-liposome-BCG-CWS increased the surface expression of MICB 2.2-fold on T24 cells but did not increase it significantly on RT-112 cells. * ULBP1 expression was increased ~2.2 fold on RT-112 cells, although no differences were observed between the expression of ULBP2 and 3 with R8-liposome-BCG-CWS. * T24 cells that were co cultured with R8-liposome-BCG-CWS showed an ~1.3-fold increase in sensitivity to cytolysis by LAK cells at an E : T ratio of 4 and RT-112 cells showed an ~1.4 fold increase at an E : T ratio of 2. CONCLUSIONS: * In the present study, the induction of surface NKG2D ligands by R8-liposome-BCG-CWS rendered cancer cells more susceptible to cytolysis by LAK cells. * T24 cells and RT-112 cells, even when cultured singly in the absence of immune cells, can directly respond to R8 liposome-BCG-CWS. * The results obtained in the present study may therefore indicate a novel adoptive immunotherapy against bladder cancers. PMID- 21314816 TI - Outpatient department repair of urethrocutaneous fistulae using n-butyl cyanoacrylate (NBCA): a single-centre experience. AB - OBJECTIVES: * To evaluate urethrocutaneous fistula repair after urethroplasty using n-butyl cyanoacrylate (NBCA) in an outpatient setting. * To compare results of application of NBCA in 'early' and long-standing fistulae. PATIENTS AND METHODS: * From January 2003 to December 2006, 13 children (mean age 36 months) were treated in our Outpatient Department for urethrocutaneous fistula, which occurred after hypospadias repair. * We analysed the data dividing the patients in two groups: group A comprised six children (mean age 22.6 months) that developed a fistula within 2-3 days of catheter removal after urethroplasty ('early' fistula) and group B comprised seven children (mean age 42.6 months) with long-standing fistulae. * In all patients, a multilayer of NBCA was applied, attaching the edges of the fistula taking care to perform a scarification of the edges of the fistula in patients in group B before the application of the glue. RESULTS: * Four patients in group A and three patients in group B had definitive fistula repair (seven of 13), and six of the 13 had fistula recurrence. * Fistulae of <= 2 mm were more easily repaired than fistulae of > 2 mm (five of seven vs two of six). * Fistulae that tended to recover were those that responded to the first applications. CONCLUSIONS: * In this experience the use of NBCA as a minimally invasive treatment for fistula repair gave good results for repairing fistulae. * These preliminary results encourage the use of NBCA as a first non surgical attempt to repair urethrocutaneous fistulae especially if the fistula is <=2 mm. * The failure of this procedure does not compromise a possible subsequent surgical repair. PMID- 21314817 TI - Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY are novel substrates of fibroblast activation protein-alpha. AB - Fibroblast activation protein-alpha (FAP) is a cell surface-expressed and soluble enzyme of the prolyl oligopeptidase family, which includes dipeptidyl peptidase 4 (DPP4). FAP is not generally expressed in normal adult tissues, but is found at high levels in activated myofibroblasts and hepatic stellate cells in fibrosis and in stromal fibroblasts of epithelial tumours. FAP possesses a rare catalytic activity, hydrolysis of the post-proline bond two or more residues from the N terminus of target substrates. alpha(2)-antiplasmin is an important physiological substrate of FAP endopeptidase activity. This study reports the first natural substrates of FAP dipeptidyl peptidase activity. Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY were the most efficiently hydrolysed substrates and the first hormone substrates of FAP to be identified. In addition, FAP slowly hydrolysed other hormone peptides, such as the incretins glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which are efficient DPP4 substrates. FAP showed negligible or no hydrolysis of eight chemokines that are readily hydrolysed by DPP4. This novel identification of FAP substrates furthers our understanding of this unique protease by indicating potential roles in cardiac function and neurobiology. PMID- 21314818 TI - Deeply infiltrating disease in surgically treated endometriosis patients. AB - OBJECTIVE: To examine the incidence of deeply infiltrating endometriotic lesions among surgically treated endometriosis patients, and determine clinical parameters associated with the presence of deep disease. DESIGN: Prospective observational study. SETTING: Regional central hospital. POPULATION: Patients undergoing surgical treatment of endometriosis. METHODS: Complete excision of all visible endometriotic lesions and adhesions. MAIN OUTCOME MEASURES: The number and location of deep lesions, association between the presence of deep lesions, relevant preoperative and intraoperative factors. RESULTS: Of 201 surgically treated endometriosis patients, 103 (51.2%) had deep lesions, 43.3% had uterosacral ligament deep lesions, 18.4% intestinal, 15.4% rectovaginal, and 3.5% urinary bladder deep lesions. Patients with deep lesions had more often undergone previous operations for endometriosis (p<0.01), had been operated on for pelvic pain (p<0.01) and had a totally obliterated rectovaginal pouch (p<0.01), compared to patients without deep lesions. In multivariate analysis, pelvic pain as an indication for surgery (OR 3.9, 95%CI 1.8-8.9, p<0.01) and totally obliterated rectovaginal pouch (OR 4.0, 95%CI 1.7-9.4, p<0.01) were independent prognostic factors for the presence of deep disease. CONCLUSIONS: Deeply infiltrating endometriosis is common in surgically treated endometriosis patients and should be searched for in those with persistent pelvic pain and where obliteration of the rectovaginal pouch is detected at surgery. PMID- 21314819 TI - Efficacy of obstetric thromboprophylaxis and long-term risk of recurrence of venous thromboembolism. AB - OBJECTIVE: To study the efficacy of thromboprophylaxis with low molecular weight heparin (LMWH) in pregnant women with one previous venous thromboembolic event (VTE). Secondary aims were to study the long-term risk of secondary recurrence, bleeding and obstetric complications. DESIGN: A prospective national study of long-term LMWH thromboprophylaxis in Sweden. SETTINGS: All hospitals in Sweden during January 1998-December 2002, PARTICIPANTS: Pregnant women with one previous VTE and controls drawn from the Swedish Medical Birth Registry. The women were cross-matched with the Swedish Hospital Discharge Register to identify all recurrences and to ascertain the annual risk of recurrence. MAIN OUTCOME MEASURES: Recurrence of VTE, bleeding complications at delivery and obstetric complications. RESULTS: 326 of 393 registered women could be evaluated. The relative risk reduction in VTE was 88%. There was an absolute increased risk of VTE during the thromboprophylaxis period: 1.2% compared to 0.2% among controls (p<0.001). The risk during the immediate post-treatment period (43-100 days post partum) was increased 28-fold. The annual incidence of VTE after delivery was 1%. The risk of hematoma and major blood loss at delivery was increased during thromboprophylaxis (p<0.001). There were no differences in the incidences of preeclampsia, intrauterine growth restriction or placental abruption. CONCLUSIONS: The relative risk reduction in VTE during thromboprophylaxis was 88%. After pregnancy, the annual long-term risk of recurrence was 1%. The risk was most pronounced in the post-treatment period. There was an increased risk of bleeding complications among women given LMWH, but there was no effect on obstetric complications. PMID- 21314820 TI - Reproductive patterns and pregnancy outcomes in women with congenital heart disease--a Swedish population-based study. AB - OBJECTIVE: To study women diagnosed with congenital heart disease (CHD) with respect to characteristics related to their own births, their subsequent likelihood of giving birth and the obstetric and neonatal outcomes of their pregnancies. DESIGN: Population-based register study. POPULATION: All women born in 1973-1983 who were alive and living in Sweden at 13 years of age (n=500 245). METHODS: Women diagnosed with CHD (n=2 216) were compared with women without CHD (n=492 476). A total of 188 867 mother-firstborn-offspring pairs were identified and available for analysis. RESULTS: Mothers of women with CHD were more often older and single/unmarried. Women with CHD were more often born preterm or small for-gestational age (SGA) than women without CHD, more likely to have been born with a cesarean section, to have given birth during the study period, and to be younger at the time of their first pregnancy. Women with CHD were also more prone to give birth to children preterm or SGA and their babies were more often delivered by cesarean section with a higher frequency of congenital abnormality. CONCLUSIONS: Women with CHD were more likely to have been born preterm or SGA and these outcomes were repeated in the next generation. Women with CHD should not be discouraged from pregnancy. Prenatal diagnostics should be discussed and offered to these women, as there is an increased risk for congenital abnormalities. PMID- 21314821 TI - Micromegakaryocytes in CSF. PMID- 21314822 TI - Glasgow Rangers lymphadenopathy. PMID- 21314823 TI - Acute myeloid leukaemia in the elderly: a review. AB - The majority of patients with acute myeloid leukaemia (AML) are elderly. Advancements in supportive care and regimen intensification have resulted in improvements in clinical outcomes for younger AML patients, but analogous improvements in older patients have not been realized. While outcomes are compromised by increased comorbidities and susceptibility to toxicity from therapy, it is now recognized that elderly AML represents a biologically distinct disease that is more aggressive and less responsive to therapy. Some patients tolerate and benefit from intensive remission-induction approaches, while others are best managed with less aggressive strategies. The challenge is to differentiate these groups based on host-related and biological features, in order to maximize the therapeutic benefit and minimize toxicity. As more is understood about the complicated pathogenesis and molecular basis of AML, there are more opportunities to develop and test targeted therapies. Elderly patients, with their narrow therapeutic window, are well positioned to derive a benefit from these novel agents, and therefore, despite a difficult past, there are reasons to be optimistic about the future of elderly AML. PMID- 21314824 TI - Antibody arrays identify protein-protein interactions in chronic myeloid leukaemia. AB - Multiprotein complex formation with p210(BCR-ABL1) is likely to play a major role in determining cellular abnormalities in chronic myeloid leukaemia (CML). Although many p210(BCR-ABL1) binding partners have been identified, it is likely that many have not. We evaluated the use of co-immunoprecipitation and antibody arrays and found that this approach is capable of identifying new p210(BCR-ABL1) binding partners, and may contribute to the search for new therapeutic targets in CML. PMID- 21314825 TI - Association of serum lipids with arterial stiffness in a population-based study in Beijing. AB - BACKGROUND: Some cardiovascular risk factors such as age, hypertension and diabetes have been confirmed to be positively correlated with arterial stiffness. However, the relationship between serum lipids and arterial stiffness is incompletely understood. Recent studies have been far from conclusive and consistent data were not obtained. We investigated the relationship between serum lipids and pulse wave velocity (PWV) in community-dwelling individuals in Beijing, China. METHODS: This was a population-based, cross-sectional sample of adults (n = 2375; 48.1% men; age range, 40-96 years) from two communities in Beijing. A questionnaire was used for the risk factors of arterial stiffness. Anthropometry, blood pressure and heart rate were measured. Values of fasting plasma glucose (FPG), serum total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and uric acid were measured. Carotid-femoral PWV (cfPWV) and carotid radial PWV (crPWV) were assessed non-invasively. RESULTS: Carotid-femoral pulse wave velocity was significantly positively related to TC (r = 0.221; P < 0.0001), LDL-C (r = 0.193; P < 0.0001) and inversely related to HDL-C (r = -0.240; P < 0.0001), but not with TG (r = 0.073; P = 0.6721). crPWV was inversely related to HDL-C (r = -0.272; P < 0.0001), but not with TC (r = 0.007; P = 0.4781), LDL-C (r = 0.021; P = 0.6393) or TG (r = 0.008; P = 0.2498). The multiple regression analysis showed that LDL-C was independently associated with cfPWV and that HDL-C was inversely associated with cfPWV and crPWV. TC and TG were not independently related to cfPWV and crPWV. CONCLUSIONS: These data show the correlation between some of the parameters of serum lipids and arterial stiffness. LDL-C was independently associated with aortic stiffness, and HDL-C was independently inversely associated with aortic stiffness and peripheral stiffness. PMID- 21314826 TI - Effect of weight loss on serum pigment epithelium-derived factor levels. AB - BACKGROUND: Cumulating evidence suggests that the broadly acting neurotrophic pigment epithelium-derived factor is associated with visceral adiposity, the metabolic syndrome, diabetes and exerts beneficial effects on atherosclerosis. To further elucidate the relationship between pigment epithelium-derived factor and metabolic perturbations characteristic of obesity, we examined the effect of pronounced weight loss on serum levels of pigment epithelium-derived factor. MATERIALS AND METHODS: Thirty-six severely obese adults were examined before and 18 months after bariatric surgery. Abdominal fat distribution was determined by ultrasound, metabolic parameters by standard methods, pro-inflammatory biomarkers and serum pigment epithelium-derived factor levels by enzyme-linked immunosorbent assay. RESULTS: Bariatric surgery resulted in a mean body mass index (BMI) reduction of 9.0 +/- 5.0 kg m(-2) and concomitant improvements in glucose homoeostasis and lipid profile. Pigment epithelium-derived factor serum levels decreased from a median 11.0 MUg mL(-1) (interquartile range: 3.8) to 9.2 MUg mL( 1) (interquartile range: 4.5) (P < 0.0001). In univariate analysis, relative change in pigment epithelium-derived factor levels was significantly associated with change in weight, BMI, fat mass, visceral fat diameter, insulin, homoeostasis model for insulin resistance, triglyceride and leptin levels (all r > 0.370, P < 0.05). No associations were observed for C-reactive protein, interleukin-6 or tumour necrosis factor alpha. After adjustment for age, sex and smoking status, associations remained significant. CONCLUSIONS: The beneficial effects of bariatric surgery-induced pronounced weight loss on glucose homoeostasis may partially be attributable to visceral adipose tissue reduction and concomitantly decreasing pigment epithelium-derived factor concentrations. PMID- 21314827 TI - Arterial occlusion induces systemic changes in leucocyte composition. AB - BACKGROUND: Lack of tissue perfusion because of arterial occlusion can result in mortality and morbidity. In response to local tissue ischaemia, extravasation of leucocytes into the region at risk is initiated to facilitate matrix remodelling and subsequent perfusion recovery. However, it is unknown if local tissue ischaemia also induces a more generalized response of leucocyte trafficking and compartmentalization. This study was designed to gain insight into the temporal changes in circulating and bone marrow-derived leucocyte fractions following peripheral arterial occlusion in mice. MATERIALS AND METHODS: Mouse peripheral blood and bone marrow samples were collected at baseline and subsequently at day 1, 2, 3, 4 and 7 after femoral artery ligation. Leucocyte and bone marrow cell subsets were quantified using flow cytometry. RESULTS: After arterial occlusion, peripheral blood leucocyte numbers did not vary significantly over time. However, significant intrinsic temporal changes in cell numbers were observed for monocytes, lymphocytes, neutrophils and their subsets with fluctuations of > 50%. Granulocytes, for example, showed an initial upregulation, while monocytes and lymphocytes numbers initially decreased. These variations in the circulation were largely preceded by changes in the corresponding bone marrow lineages. Progenitor cells of the myeloid and lymphoid lineage in the bone marrow were upregulated after the decrease in the numbers of their progeny in the peripheral blood. CONCLUSIONS: Local arterial occlusion results in an orchestrated systemic response of leucocyte trafficking. This response substantiates the pivotal role of leucocytes as mediators of processes leading to perfusion recovery and tissue remodelling. PMID- 21314828 TI - Quantitative 3D profilometry and SEM analysis of the adaptation of root-end filling materials placed under an optical microscope. AB - AIM: To evaluate by 3D profilometry and scanning electron microscopy (SEM), the marginal adaptation of mineral trioxide aggregate (MTA) and Sealer 26 placed in root-end cavities with direct vision or under an optical microscope. METHODOLOGY: The root ends of 52 root filled canine teeth were filled with MTA or Sealer 26 under direct vision or optical microscope (n=13). In each group, eight specimens were analysed by profilometry for measurement of the area and depth of gaps. In the other five specimens, gap area was measured using SEM to verify marginal adaptation and surface characteristic. Data were analysed by parametric (anova and Tukey) and non-parametric (Kruskal-Wallis and Dunn) tests. RESULTS: The assessment of the adaptation of both materials to dentine was not influenced by the mode of visualization, which was confirmed by both profilometry and SEM observations. The voids measured with profilometry for Sealer 26 under direct vision were significantly wider and deeper than those for MTA under direct vision (P<0.05). In SEM, significantly larger gap areas were observed with Sealer 26 (P<0.05). CONCLUSION: Root-end cavities filled with MTA had smaller gaps and better marginal adaptation than Sealer 26. PMID- 21314829 TI - The influence of carbon content on cyclic fatigue of NiTi SMA wires. AB - AIM: To evaluate two NiTi wires with different carbon and oxygen contents in terms of mechanical resistance to rotary bending fatigue (RBF) under varied parameters of strain amplitude and rotational speed. METHODOLOGY: The wires produced from two vacuum induction melting (VIM) processed NiTi ingots were tested, Ti-49.81 at%Ni and Ti-50.33 at%Ni, named VIM 1 and VIM 2. A brief analysis related to wire fabrication is also presented, as well as chemical and microstructural analysis by energy dispersive spectroscopy (EDS) and optical microscope, respectively. A computer controlled RBF machine was specially constructed for the tests. Three radii of curvature were used: 50.0, 62.5 and 75.0 mm, respectively, R(1), R(2) and R(3), resulting in three strain amplitudes epsilon(a) : 1.00%, 0.80% and 0.67%. The selected rotational speeds were 250 and 455 rpm. RESULTS: The VIM 1 wire had a high carbon content of 0.188 wt% and a low oxygen content of 0.036 wt%. The oxygen and carbon contents of wire VIM 2 did not exceed their maximum, of 0.070 and 0.050 wt%, according to ASTM standard (ASTM F 2063-00 2001). The wire with lower carbon content performed better when compared to the one with higher carbon content, withstanding 29,441 and 12,895 cycles, respectively, to fracture. CONCLUSIONS: The surface quality of the wire was associated with resistance to cyclic fatigue. Surface defects acted as stress concentrators points. Overall, the number of cycles to failure was higher for VIM 2 wires with lower carbon content. PMID- 21314830 TI - The use of cone beam computed tomography in the management of dens invaginatus affecting a strategic tooth in a patient affected by hypodontia: a case report. AB - AIM: To report on the use of cone beam computed tomography (CBCT) in the diagnosis and management of dens invaginatus. SUMMARY: Chronic apical periodontitis of an invaginated maxillary lateral incisor was diagnosed in a patient suffering from hypodontia and awaiting active orthodontic therapy. Loss of the tooth would have complicated orthodontic treatment. Conventional periapical radiographs provided insufficient information about the nature of the invagination and its relation to the root canal to formulate an appropriate plan for treating the tooth. A small volume CBCT scan of the tooth revealed that the invagination and the root canal were completely separate, non-communicating spaces and that the wall of the invagination acted as an obstruction to the effective chemomechanical debridement of the infected root canal. An innovative method of accessing the infected root canal, based on information from the CBCT images, was adapted to permit its instrumentation, disinfection and filling. KEY LEARNING POINTS: * Teeth with dens invaginatus requiring endodontic treatment present diagnostic and technical challenges. * CBCT can provide essential information in the management of dens invaginatus. PMID- 21314831 TI - Sciatic nerve regeneration by microporous nerve conduits seeded with glial cell line-derived neurotrophic factor or brain-derived neurotrophic factor gene transfected neural stem cells. AB - Neurotrophic factors such as the glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) promote nerve cell survival and regeneration, but their efficacy in repairing a longer gap defect of rat sciatic nerve (15 mm) has not been established. In this study, two recombinant mammalian vectors containing either rat GDNF gene or BDNF gene were constructed and each was transfected into neural stem cells (NSCs). It was found that the transfection of GDNF or BDNF gene into NSCs led to significantly enhanced expression of GDNF or BDNF mRNA. The amount of GDNF or BDNF protein secreted from the transfected NSCs showed a 3.3-fold or 2.5-fold increase than that from nontransfected NSCs, respectively. The regeneration capacity of rat sciatic nerve in a poly(D,L-lactide) conduit seeded with GDNF or BDNF-transfected NSCs was evaluated by the histology, functional gait, and electrophysiology after 8 weeks of implantation. It was observed that the degree of myelination and the size of regenerated tissue in the conduits seeded with GDNF- and BDNF-transfected NSCs were higher than those seeded with the nontransfected NSCs. Conduits seeded with GDNF-transfected NSCs had the greatest number of blood vessels. The functional recovery assessed by the functional gait and electrophysiology was significantly improved for conduits seeded with GDNF or BDNF-transfected NSCs. It was concluded that the genetically modified NSCs may have potential applications in promoting nerve regeneration and functional recovery. PMID- 21314832 TI - A new way to reduce flow disturbance in endovascular stents: a numerical study. AB - Traditional commercial stents are made of wires with square or semi-circular cross-sections that lead to flow disturbance, which plays an important role in the initiation and progression of restenosis. A new stent with streamlined cross sectional wires was proposed and researched numerically for its hemodynamic performance. Simplified models of stents with square, semi-circular, or streamlined cross-sectional wires were constructed numerically. Blood flows in the three models were simulated using computational fluid dynamics methods, and compared in terms of flow pattern, wall shear stress (WSS), and oscillating shear index (OSI). The results showed that when compared with the two traditional stents, the new stent with streamlined cross-sectional wires induced almost no flow disturbance, significantly enhanced WSS, and reduced the value of OSI within the stent. The present preliminary study indicates that the optimization of the cross-sectional shape of stent wires ought to be considered in the structural design for endovascular stents. PMID- 21314833 TI - Characterization of insulin adsorption behavior of dialyzer membranes used in hemodialysis. AB - Although it has been reported that plasma insulin is removed by hemodialysis (HD), the mechanism for this has not been elucidated. We investigated the mechanism of insulin removal during HD treatment and the characteristics of insulin removal with three high-flux membranes. In our in vivo study, 20 stable diabetic patients on HD were randomly selected for three HD sessions with three different membranes: polysulfone (PS), cellulose triacetate (CTA), and polyester polymer alloy (PEPA). Blood samples were obtained from the blood tubing at the arterial (A) site at the beginning and end of the sixth HD session to investigate insulin reduction in patients. At 1 h after the initiation of dialysis, blood samples were obtained from both the A and venous sites of the dialyzer to investigate the insulin clearance with the different membranes. There was a significant reduction in patients' plasma insulin at each time point with each of the three membranes. The insulin clearance with the PS membrane was significantly higher than that with the CTA and PEPA membranes. Although no difference was observed in the plasma insulin reduction rate between the three membranes in the total subject group, there was a significantly higher reduction rate with the PS membrane in insulin-dependent diabetes mellitus subjects. The clearance of insulin in in vitro tests was significantly higher with the PS and PEPA membranes than with the CTA membrane in both new and clinically used dialyzers. Insulin was not detected in the dialysate or ultrafiltration fluids in either the in vivo or in vitro studies. The mechanism of plasma insulin clearance by HD is mainly by adsorption, and the amount of insulin adsorbed differed depending on the dialyzer membrane used. PMID- 21314834 TI - Norepinephrine and hospital mortality in critically ill patients undergoing continuous renal replacement therapy. AB - High-dose vasopressor use is associated with increasing mortality in patients with septic shock. We conducted this study to determine if the high-dose of vasopressor used before the initiation of continuous renal replacement therapy (CRRT) is associated with increasing mortality in critically ill patients. We retrospectively reviewed all patients who underwent CRRT in the medical intensive care unit of China Medical University Hospital between 2003 and 2007. The association between mortality and highest vasopressors (dopamine and norepinephrine [NE]) dose used were analyzed using Kaplan-Meier analysis and multivariate Cox regression. A total of 279 patients (170 men and 109 women) treated with CRRT in medical intensive care were reviewed and 237 (84.9%) died. In Kaplan-Meier analysis with log-rank test, dopamine dose of >=20 ug/kg/min and NE dose of >=0.3 ug/kg/min were significantly linked to mortality (P = 0.007 and <0.001). In multivariate Cox proportional hazards regression, NE dose of >=0.3 ug/kg/min, Acute Physiology and Chronic Health Evaluation II score, and low platelet count were independently linked to mortality. The hazard ratios and 95% confidence interval (CI) were 1.771 (95% CI: 1.247-2.516, P = 0.001), 1.035 (95% CI: 1.012-1.058, P = 0.003), and 0.997 (95% CI: 0.996-0.999, P = 0.003), respectively. Critically ill patients treated with very high dose of NE before the initiation of CRRT have a very high mortality rate regardless of the acute kidney injury stage. PMID- 21314835 TI - Effects of spermidine and p-cresol on polymorphonuclear cell apoptosis and function. AB - Polymorphonuclear leukocytes (PMNs) from chronic kidney disease (CKD) patients display accelerated apoptosis and dysfunction, which may predispose CKD patients to infections. In this study, we investigated the effect of spermidine and p cresol on apoptosis and function on PMN from healthy subjects. We measured the effect of spermidine and p-cresol on apoptosis, ROS production unstimulated and stimulated (S. aureus and PMA) and expression of CD95, caspase 3, and CD11b on PMN. After incubation with p-cresol and spermidine, we did not observe any changes in apoptosis, viability or expression of caspase 3 and CD95 in PMN from healthy subjects. PMN incubated for 10 minutes with spermidine demonstrated a significant reduction in spontaneous, S. aureus and PMA-stimulated ROS production. p-cresol induced a decrease in PMA-stimulated ROS production. Spermidine and p-cresol also induced a decrease in the expression of CD11b on PMN. Spermidine and p-cresol decreased the expression of CD11b and oxidative burst of PMN from healthy subjects and had no effect on PMN apoptosis and viability. PMID- 21314836 TI - Donation after cardiac death: dynamic graft reconditioning during or after ischemic preservation? AB - The benefit of gaseous oxygenation during storage of liver grafts from donors after cardiac death should be investigated as applied either during the whole period of preservation or only for the last 2 h prior to reperfusion. Rat livers were explanted 30 min after cardiac arrest of the donor and cold-stored (CS) for 20 h. Some grafts were subjected to venous systemic oxygen persufflation (VSOP) either for 20 h or for only 2 h subsequent to 18 h of CS. Viability of the livers was assessed thereafter by warm reperfusion in vitro. Twenty hours VSOP and 18 h CS + 2 h VSOP prevented mitochondrial protein breakdown of mitochondrial heat shock protein 70 and promoted a significant and approximately twofold increase in hepatic oxygen consumption, bile production, and energetic recovery upon warm reperfusion. No differences were seen whether VSOP was performed for 20 h or for only 2 h prior to reperfusion. Both techniques significantly abrogated parenchymal enzyme loss (alanine aminotransferase, aspartate aminotransferase) upon reperfusion compared with simple 20 h CS. An increase in perfusate levels of the mitochondrial enzyme glutamate dehydrogenase was observed only in the 20 h VSOP group. In conclusion, viability of donation after cardiac death liver grafts can still be augmented, similarly to continuous aerobic storage, by only endischemic reconditioning, both protocols preventing initial mitochondrial dysfunction and subsequent tissue injury. PMID- 21314837 TI - What blood temperature for an ex vivo extracorporeal circuit? AB - Ex vivo circuits are commonly used to evaluate biomaterials or devices used for extracorporeal blood purification. However, various aspects of the ex vivo circuit, apart from the circuit materials, may affect inflammation and coagulation. One such aspect is temperature. The aim of this study was to evaluate the influence of different blood temperature conditions on inflammation parameters in an ex vivo circuit. Blood was collected from 20 healthy volunteers and run through three different experimental conditions for 4 h: a miniaturized ex vivo extracorporeal circuit equipped with a blood warmer set to 37 degrees C, the same circuit without the warmer (23 degrees C), and a tube placed in an incubator at 37 degrees C (no circuit). We measured the granulocyte macrophage colony-stimulating factor, the tumor necrosis factor, and the interleukin (IL) 1beta, IL-6, IL-8, and IL-10 concentrations at baseline, 15, 60, 120, and 240 min. Human leukocyte antigen (HLA)-DR, CD11b, CD11a, CD62L, tumor necrosis factor alpha converting enzyme, annexin V expression, and NFkB DNA binding were measured in monocytes and polymorphonuclear neutrophils (PMNs) using flow cytometry at baseline, 120 min, and 240 min. While cytokine production over time was very slight at room temperature, levels increased by more than 100-fold in the two heated conditions. Differences in the expression of some surface markers were also observed between the room temperature circuit and the two heated conditions (CD11b PMN, P < 0.0001; HLA-DR Mono, P=0.0019; and CD11a PMN, P<0.0001). Evolution of annexin V expression was also different over time between the three groups (P=0.0178 for monocytes and P=0.0011 for PMNs). A trend for a greater NFkB DNA binding was observed in the heated conditions. Thus, for ex vivo studies using extracorporeal circuits, heating blood to maintain body temperature results in significant activation of inflammatory cells while hypothermia (room temperature) seems to suppress the leukocyte response. Both strategies may lead to erroneous conclusions, possibly masking some specific effects of the device being studied. Investigators in this field must be aware of the fact that blood temperature is a crucial confounding parameter and the type of "background noise" they will face depending on the strategy adopted. PMID- 21314838 TI - Five-year results of 121 consecutive patients treated with extracorporeal membrane oxygenation at Fu Wai Hospital. AB - Since 2004, our institution has adopted venoarterial (VA) extracorporeal membrane oxygenation (ECMO) for patients who otherwise could not be weaned from cardiopulmonary bypass and patients experiencing cardiogenic shock and/or pulmonary dysfunction unresponsive to conventional treatments. In this study, we reviewed our experience with ECMO support and tried to identify predictors of in hospital mortality. We retrospectively analyzed the clinical records of 121 consecutive patients receiving ECMO. Patients were divided into adult and pediatric groups and analyzed separately. Demographics, clinical characteristics at the time of ECMO implantation, ECMO-related complications, and in-hospital mortality were collected. Logistic regression analyses were performed to investigate predictors of mortality. A P value <= 0.05 was accepted as significant. Sixty-eight adult patients and 53 pediatric patients were included in this study. In adult patients, 52 were weaned from ECMO and 43 survived upon discharge. After univariate analysis, ECMO setup location, receiving cardiopulmonary resuscitation before ECMO, leg ischemia, hemolysis, acute renal failure (ARF), neurological dysfunction, and multiple organ dysfunction syndrome were associated with in-hospital death. In multiple logistic regression analyses, leg ischemia (OR 14.68, 95% CI 1.67-129.1), ARF (OR 12.14, 95% CI 2.5-58.8), and neurological dysfunction (OR 49.0, 95% CI 2.28-1051.96) were risk factors associated with in-hospital mortality. Patients put on ECMO in the operating room had a better chance of survival (OR 0.078, 95% CI 0.013-0.417). In pediatric patients, 30 were weaned from ECMO and 26 survived upon discharge. After univariate analysis, age, weight, and eight ECMO complications were associated with in-hospital death. In multiple logistic regression analyses, ARF (OR 24.0, 95% CI 4.2-137.3) was a risk factor associated with in-hospital mortality. A P value of 0.921 and >0.99 was obtained by the Hosmer-Lemeshow test, and the area under the curve was 0.863 and 0.867 for adult and pediatric patients, respectively. The overall survival rate was 57%. ECMO is a justifiable alternative treatment for refractory cardiac and/or pulmonary dysfunction which could rescue more than 50% of carefully selected patients. Higher survival rates could be achieved by preventing ECMO complications. PMID- 21314839 TI - Clinical effectiveness of centrifugal pump to produce pulsatile flow during cardiopulmonary bypass in patients undergoing cardiac surgery. AB - Although the centrifugal pump has been widely used as a nonpulsatile pump for cardiopulmonary bypass (CPB), little is known about its performance as a pulsatile pump for CPB, especially on its efficacy in producing hemodynamic energy and its clinical effectiveness. We performed a study to evaluate whether the Rotaflow centrifugal pump produces effective pulsatile flow during CPB and whether the pulsatile flow in this setting is clinically effective in adult patients undergoing cardiac surgery. Thirty-two patients undergoing CPB for elective coronary artery bypass grafting were randomly allocated to a pulsatile perfusion group (n = 16) or a nonpulsatile perfusion group (n = 16). All patients were perfused with the Rotaflow centrifugal pump. In the pulsatile group, the centrifugal pump was adjusted to the pulsatile mode (60 cycles/min) during aortic cross-clamping, whereas in the nonpulsatile group, the pump was kept in its nonpulsatile mode during the same period of time. Compared with the nonpulsatile group, the pulsatile group had a higher pulse pressure (P < 0.01) and a fraction higher energy equivalent pressure (EEP, P = 0.058). The net gain of pulsatile flow, represented by the surplus hemodynamic energy (SHE), was found much higher in the CPB circuit than in patients (P < 0.01). Clinically, there was no difference between the pulsatile and nonpulsatile groups with regard to postoperative acute kidney injury, endothelial activation, or inflammatory response. Postoperative organ function and the duration of hospital stay were similar in the two patient groups. In conclusion, pulsatile CPB with the Rotaflow centrifugal pump is associated with a small gain of EEP and SHE, which does not seem to be clinically effective in adult cardiac surgical patients. PMID- 21314840 TI - A study on moral hazard in dentistry: costs of care in the private and the public sector. AB - OBJECTIVES: The aim of this study was to evaluate the costs of subsidized care for an adult population provided by private and public sector dentists. METHODS: A sample of 210 patients was drawn systematically from the waiting list for nonemergency dental treatment in the city of Turku. Questionnaire data covering sociodemographic background, dental care utilization and marginal time cost estimates were combined with data from patient registers on treatment given. Information was available on 104 patients (52 from each of the public and the private sectors). RESULTS: The overall time taken to provide treatment was 181 days in the public sector and 80 days in the private sector (P<0.002). On average, public sector patients had significantly (P < 0.01) more dental visits (5.33) than private sector patients (3.47), which caused higher visiting fees. In addition, patients in the public sector also had higher other out-of-pocket costs than in the private sector. Those who needed emergency dental treatment during the waiting time for comprehensive care had significantly more costly treatment and higher total costs than the other patients. Overall time required for dental visits significantly increased total costs. The total cost of dental care in the public sector was slightly higher (P<0.05) than in the private sector. CONCLUSIONS: There is no direct evidence of moral hazard on the provider side from this study. The observed cost differences between the two sectors may indicate that private practitioners could manage their publicly funded patients more quickly than their private paying patients. On the other hand, private dentists providing more treatment per visit could be explained by private dentists providing more than is needed by increasing the content per visit. PMID- 21314841 TI - Tanshinone IIA suppresses lung injury and apoptosis, and modulates protein kinase B and extracellular signal-regulated protein kinase pathways in rats challenged with seawater exposure. AB - 1. Tanshinone IIA (TIIA) is one of the main active components of the Chinese herb, Danshen. In the present study, we investigated the role of apoptosis in seawater exposure-induced acute lung injury (ALI), and explored the effects of TIIA on lung injury, apoptosis, and protein kinase B (Akt) and extracellular signal-regulated protein kinase (ERK) pathways in seawater-challenged rats. The rats were randomly divided into four groups: (i) naive group, no drug was given; (ii) TIIA control group, TIIA (50 mg/kg) was given intraperitoneally; (iii) seawater (SW) group, seawater (4 mL/kg) was given; and (iv) TIIA/SW group, TIIA (50 mg/kg) was injected intraperitoneally 10 min after seawater instillation. 2. The results showed that TIIA treatment significantly improved seawater exposure induced lung histopathological changes, alleviated the decrease in PaO(2) , and reduced lung oedema, vascular leakage and cell infiltration. As shown by terminal deoxynucleotidyl transferase-mediated nick end labelling (TUNEL) assay, seawater exposure induced apoptosis in lung tissue cells. Furthermore, seawater exposure also changed apoptosis-related factors Bcl-2 and caspase-3, and caused a reduction in the activation of Akt and ERK1/2 pathways. Furthermore, TIIA treatment decreased the number of apoptotic cells, reversed changes in Bcl-2 and caspase-3, and upregulated the activation of Akt and ERK1/2 in seawater challenged rats. 3. In conclusion, the data suggest that apoptosis might play an important role in seawater exposure-induced lung injury and that TIIA could significantly attenuate the severity of ALI and apoptosis in seawater-challenged rats, which is possibly through modulation of Akt and ERK1/2 pathways. PMID- 21314842 TI - Adenovirus-mediated overexpression of cardiac troponin I-interacting kinase promotes cardiomyocyte hypertrophy. AB - 1. Cardiac troponin I-interacting kinase (TNNI3K) is a novel cardiac-specific kinase gene. Quantitative real-time reverse transcription polymerase chain reaction analysis showed a significant increase in TNNI3K mRNA expression in hypertrophic cardiomyocytes induced by endothelin-1 (ET-1). The aim of the present study was to investigate the effects of TNNI3K on neonate rat cardiomyocyte hypertrophy induced by ET-1. 2. Adenoviruses were amplified in 293A cells. To determine a reasonable adenovirus infection dose cardiomyocytes were infected with an adenovirus carrying human TNNI3K (Ad-TNNI3K) at varying multiplicity of infection (MOI) and the expression of TNNI3K was analysed by western blot. 3. Cardiomyocytes were infected with either a control adenovirus carrying green fluorescent protein (Ad-GFP) or Ad-TNNI3K. Compared with Ad-GFP, the Ad-TNNI3K induced an increase in sarcomere organization, cell surface area, (3) H-leucine incorporation and beta-MHC re-expression. This type of hypertrophic phenomenon is similar to that observed in Ad-GFP-infected hypertrophic cardiomyocytes induced by ET-1. To determine the functional role of TNNI3K in ET 1-induced hypertrophic cardiomyocytes, the cells were infected with Ad-GFP or Ad TNNI3K. Ad-TNNI3K induced an increase in sarcomere organization, cell surface area and (3) H-leucine incorporation compared with Ad-GFP. 4. These results suggest that TNNI3K overexpression induces cardiomyocytes hypertrophy and accelerates hypertrophy in hypertrophic cardiomyocytes. Therefore, TNNI3K might be an interesting target for the clinical treatment of hypertrophy. PMID- 21314843 TI - Elongated eustachian valve dividing the right atrium. AB - A 64-year-old man underwent transthoracic echocardiography after a syncopal event. Two-dimensional imaging demonstrated a linear density that appeared to divide the right atrium. Color doppler imaging demonstrated that inflow from the inferior vena cava, but not from the superior vena cava, was obstructed by this density. Injection of agitated saline through an upper extremity vein demonstrated that the linear density did create a functional separation of the right atrium. The contrast material also crossed the interatrial septum within two cardiac cycles. This constellation of findings is consistent with an elongated eustachian valve and a patent foramen ovale. PMID- 21314844 TI - WT1 mutation as a cause of 46 XY DSD and Wilm's tumour: a case report and literature review. AB - AIM: The Wilms' Tumour gene is thought to have tumour suppressor activity and to play an important role in nephrogenesis, genitourinary development, haematopoiesis and sex determination. WT1 mutations will impair gonadal and urinary tract development and have been demonstrated to cause syndromes of WAGR, Denys-Drash and Fraiser. METHODS: To elucidate the role of constitutional mutations of WT1, in the expression of the different clinical feature, we describe a 14-year-9-month nonmosaic XY sex-reversed woman with pure gonadal dysgenesis (46, XY karyotype, completely female external genitalia, normal Mullerian ducts, absence of Wolffian ducts, streak gonads) who had right kidney removed at 7 months of age because of Wilms' tumour and was diagnosed as secondary thrombocytopenia (Plt 60-80 * 10(9) /L) since she was 4 years old. We sequenced the genomic DNA of all the 10 exons of the WT1 in which mutations may occur in proposita. RESULTS: A new de novo insertion mutation in the first exon was found. A 'GCCGCCTCACTCC' is inserted between codon 138 and 139, resulting in the creation of a stop codon and a truncated protein. CONCLUSION: The present data provide further evidence to support the role of WT1 in diverse cellular functions. PMID- 21314845 TI - Current Italian practices regarding the management of hyperbilirubinaemia in preterm infants. AB - AIM: To assess the current practices existing in Italy for the management of jaundice in preterm infants as preliminary achievement to a call for national guidelines and establishment of a kernicterus registry. METHODS: A questionnaire (in Supporting Information online) was sent to the 109 level III neonatal units in Italy to ascertain existing guidelines for total bilirubin monitoring and treatment of hyperbilirubinaemia in preterm infants and occurrence of kernicterus. RESULTS: There was a 61% (67/109) response rate. Eighty-five per cent of responding units had either written guidelines coming from different literature sources or locally developed. The monitoring of bilirubin varied greatly in timing before, during and after jaundice development. Phototherapy and exchange transfusion were given to 56.0 +/- 21.0% and 0.2 +/- 0.4% of admitted preterm infants in participating centres. Five cases of kernicterus in preterm infants and eleven cases in term infants were documented over the last 10 years. CONCLUSION: The management of hyperbilirubinaemia in preterm infants is not uniform in Italy and would benefit from shared national guidance together with establishment of a kernicterus registry to guide therapy. PMID- 21314846 TI - The role(s) of astrocytes and astrocyte activity in neurometabolism, neurovascular coupling, and the production of functional neuroimaging signals. AB - Data acquired with functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) are often interpreted in terms of the underlying neuronal activity, despite mounting evidence that these signals do not always correlate with electrophysiological recordings. Therefore, considering the increasing popularity of functional neuroimaging, it is clear that a more comprehensive theory is needed to reconcile these apparent disparities and more accurately explain the mechanisms through which various PET and fMRI signals arise. In the present article, we have turned our attention to astrocytes, which vastly outnumber neurons and are known to serve a number of functions throughout the central nervous system (CNS). For example, astrocytes are known to be critically involved in neurotransmitter uptake and recycling, and empirical data suggests that brain activation increases both oxidative and glycolytic astrocyte metabolism. Furthermore, a number of recent studies imply that astrocytes are likely to play a key role in regulating cerebral blood delivery. Therefore, we propose that, by mediating neurometabolic and neurovascular processes throughout the CNS, astrocytes could provide a common physiological basis for fMRI and PET signals. Such a theory has significant implications for the interpretation of functional neuroimaging signals, because astrocytic changes reflect subthreshold neuronal activity, simultaneous excitatory/inhibitory synaptic inputs, and other transient metabolic demands that may not elicit electrophysiological changes. It also suggests that fMRI and PET signals may have inherently less sensitivity to decreases in synaptic input (i.e. 'negative activity') and/or inhibitory (GABAergic) neurotransmission. PMID- 21314847 TI - Two are better than one: unraveling the functions of cone arrestin in zebrafish (Commentary on Renninger, Gesemann and Neuhauss). PMID- 21314848 TI - Exclusive and common targets of neostriatofugal projections of rat striosome neurons: a single neuron-tracing study using a viral vector. AB - The rat neostriatum has a mosaic organization composed of striosome/patch compartments embedded in a more extensive matrix compartment, which are distinguished from each other by the input-output organization as well as by the expression of many molecular markers. The matrix compartment gives rise to the dual gamma-aminobutyric acid (GABA)ergic striatofugal systems, i.e. direct and indirect pathway neurons, whereas the striosome compartment is considered to involve direct pathway neurons alone. Although the whole axonal arborization of matrix striatofugal neurons has been examined in vivo by intracellular staining, that of striosome neurons has never been studied at the single neuron level. In the present study, the axonal arborizations of single striosome projection neurons in rat neostriatum were visualized in their entirety using a viral vector expressing membrane-targeted green fluorescent protein, and compared with that of matrix projection neurons. We found that not only matrix but also striosome compartments contained direct and indirect pathway neurons. Furthermore, only striatonigral neurons in the striosome compartment projected directly to the substantia nigra pars compacta (SNc), although they sent a substantial number of axon collaterals to the globus pallidus, entopeduncular nucleus and/or substantia nigra pars reticulata. These results suggest that striosome neurons play a more important role in the formation of reward-related signals of SNc dopaminergic neurons than do matrix neurons. Together with data from previous studies in the reinforcement learning theory, our results suggest that these direct and indirect striosome-SNc pathways together with nigrostriatal dopaminergic neurons may help striosome neurons to acquire the state-value function. PMID- 21314849 TI - An interpretative phenomenological analysis of African Caribbean women's experiences and management of emotional distress. AB - African Caribbean women are under-represented within mental health services in the United Kingdom, despite sociocontextual vulnerabilities which may increase emotional distress. This qualitative study aimed to explore individual explanatory models of experiences of distress, coping and help-seeking choices, with a view to improving cultural relevance of services. Participants were recruited following their self-referral to self-help community wellbeing workshops. Interpretative phenomenological analysis was carried out following semi-structured interviews with seven African Caribbean women in central London, who reported previously experiencing emotional distress. The study was conducted during 2009. Five super-ordinate themes emerged from the data: explanations of distress, experiences of distress, managing distress, social and cultural influences and seeking help. Each super-ordinate theme consisted of several subthemes which described participants' experiences. Gender roles and a cultural legacy of being strong and hiding distress emerged as influential in participants' beliefs about managing personal difficulties. However, this was balanced with an acknowledgement that intergenerational differences highlighted an increasing acceptance amongst the community of talking about issues and seeking professional support. The findings offered support for the notion that understandings and responses to personal distress are subject to broad-ranging and interwoven influences. This complexity may be conceptualised as an 'exploratory map' where individuals make links between their current and newly encountered knowledge and experience to guide their personal route to coping and help-seeking. The study provides support for tailoring services to individual needs using a flexible approach which empowers individuals from black and minority ethnic groups by valuing explanatory models of distress alternative to the westernised medical model. Furthermore, findings emphasise the importance of readily available and accessible information about statutory and non-statutory community resources which use language relevant to the communities they are aimed at engaging. PMID- 21314850 TI - Isocitrate dehydrogenase 1 analysis differentiates gangliogliomas from infiltrative gliomas. AB - Recent work has identified novel point mutations in isocitrate dehydrogenase 1 (IDH1) in the majority of the World Health Organization grades II and III infiltrative gliomas and secondary grade IV glioblastomas. Gangliogliomas consist of neoplastic ganglion and glial cells and, in contrast to infiltrative gliomas, are generally indolent. Yet distinguishing between a ganglioglioma and an infiltrative glioma with admixed gray matter can be difficult, perhaps accounting for some "gangliogliomas" that ultimately show aggressive behavior. In this multi institutional study, 98 cases originally diagnosed as ganglioglioma were analyzed for IDH1 mutations, 86 of which had follow-up data available. Eight cases (8.2%) were positive for R132H IDH1 mutations; six had silent IDH2 mutations and two had nonsense IDH2 mutations. The presence of mutant IDH1 in gangliogliomas correlated with a greater risk of recurrence (P=0.0007) and malignant transformation and/or death (P<0.0001) compared with tumors that were IDH1 wild type. Furthermore, the age of patients with IDH1-mutant gangliogliomas was higher than those without mutations (25.5 vs. 46.1 years, P=0.0033). IDH1/2 testing of tumors suspected of being gangliogliomas may therefore be advisable, particularly in the adult population. PMID- 21314851 TI - Low circulating CD4(+) CD25(+) Foxp3(+) T regulatory cell levels predict miscarriage risk in newly pregnant women with a history of failure. AB - PROBLEM The purpose of this study was to determine whether quantification of peripheral blood Treg cell levels could be used as an indicator of miscarriage risk in newly pregnant women with a history of immunologic reproductive failure. METHOD OF STUDY Fifty-four pregnant women with a history of immunologic infertility and/or pregnancy loss were retrospectively evaluated (mean age: 36.7 +/- 4.9 years, 2.8 +/- 2.5 previous miscarriages; 1.5 +/- 1.9 previous IVF failures). Twenty-three of these women experienced another first trimester miscarriage, and 31 of these women continued their current pregnancies past 12 weeks ('pregnancy success'). The following immunologic parameters were assessed in the first trimester: NK cell 50:1 cytotoxicity, CD56(+) 16(+) CD3(-) (NK), CD56(+) CD3(+) (NKT), TNFalpha/IL-10, IFNgamma/IL-10, CD4(+) CD25(-) Foxp3(+) , total CD4(+) Foxp3(+) (CD4(+ ) CD25(+) Foxp3 plus CD25(- ) Foxp3(+) ), and CD4(+) CD25(+) Foxp3(+) levels. RESULTS Patients with successful ongoing pregnancies experienced a mean (CD4(+) CD25(+) Foxp3(+) ) 'Treg' level of 0.72 +/- 0.52%, while those that miscarried in the first trimester experienced a mean Treg level of 0.37 +/- 0.29% (P = 0.005). Markers not significantly different between the loss and success groups were NK 50:1 cytotoxicity (P = 0.63), CD56(+) 16(+) 3(+) NK cells (P = 0.63), CD56(+) 3(+) NKT (P = 0.30), TNFalpha(+) IL 10(+) (P = 0.13), IFNg(+) IL-10(+) (P = 0.63), and CD4(+) 25(-) Foxp3(+) cells (P = 0.10), although total CD4(+) Foxp3(+) levels remained significant (P = 0.02) and CD4(+) 25(+) Foxp3(+) showed the most significant difference (P = 0.005). Mean day of blood draw was 49.2 +/- 36.1 days pregnant (median 39.0 days). In addition, patients with a low Treg level (<0.7%) in the first trimester experienced a significantly lower ongoing pregnancy rate than those with a higher Treg level (>0.7%) in the first trimester [44% (15/34) versus 80% (16/20); P = 0.01]. Of the 18 successful pregnancies with sequential Treg results, 85% (11/13) showed a T-regulatory-cell-level increase (mean Treg change 0.33 +/- 0.32), while only 40% (2/5) of the failed pregnancies showed a Treg increase (mean Treg change -0.08 +/- 0.28; P = 0.02). CONCLUSIONS From these data, we propose that CD4(+) CD25(+) Foxp3(+) T regulatory cells may serve as a superior pregnancy marker for assessing miscarriage risk in newly pregnant women. Larger follow-up studies are needed for confirmation. PMID- 21314853 TI - Commentary: how the combination of careful observation in medicine and an entrepreneurial approach serve dermato-cosmetology and dermato-surgery. PMID- 21314854 TI - Island pedicle reconstruction of partial nipple and areola defect. PMID- 21314855 TI - Response to EFNS guidelines on treatment of Dystonia article. PMID- 21314856 TI - Effect of warfarin withdrawal on thrombolytic treatment in patients with ischaemic stroke. AB - BACKGROUND AND PURPOSE: Abruptly discontinuing warfarin may induce a rebound prothrombotic state. Thrombolytic agents may also paradoxically induce prothrombotic conditions, which include platelet activation and thrombin generation. Therefore, prothrombotic states may be enhanced by withdrawing warfarin in patients under thrombolytic treatment. This study was aimed to determine whether patients with warfarin withdrawal have different clinical outcomes from those without warfarin use after thrombolytic treatment. METHODS: A total of 148 consecutive patients with atrial fibrillation who were not on anticoagulants at admission and who received thrombolysis were included in this study. We compared the outcomes between a warfarin withdrawal group and a no warfarin group. RESULTS: Fourteen patients (9.5%) were included in the warfarin withdrawal group. Although baseline National Institute of Health Stroke Scale (NIHSS) scores, recanalization rates, and hemorrhage frequencies did not differ between the groups, the warfarin withdrawal group showed poorer outcomes. Increased NIHSS scores during the first 7days were more frequent in the warfarin withdrawal group (57.1% vs. 26.9%, P=0.029). The median percent improvement in NIHSS scores at 24h after thrombolysis was also lower in the warfarin withdrawal group. After adjusting for covariates, warfarin withdrawal was a strong predictor of poor functional outcome at 3months (modified Rankin score>=3) (odds ratio, 17.067, 95% CI 2.703-107.748). CONCLUSIONS: Discontinuing warfarin was associated with early neurologic deterioration and poor long-term outcomes after thrombolytic treatment. PMID- 21314857 TI - Complementary medicine and erectile dysfunction: will you accept the charges? PMID- 21314859 TI - The HIV/AIDS crisis and the right to health. PMID- 21314860 TI - Peri-operative management of patients taking antithrombotic therapy: need for an integrated proactive approach. PMID- 21314861 TI - The right to health in practice. PMID- 21314862 TI - Could inequality in health be cured by universal coverage for all citizens? PMID- 21314863 TI - Predictive accuracy of the 'Framingham's general CVD algorithm' in a Middle Eastern population: Tehran Lipid and Glucose Study. AB - AIMS: To examine the performance of 'the Framingham's general CVD algorithm' in estimating 5-year risk of cardiovascular disease (CVD) and coronary heart disease (CHD) in an adult Middle Eastern community. METHODS: In a population-based prospective cohort, the Tehran Lipid and Glucose Study (TLGS), CVD risk estimates were calculated for 3838 individuals (2183 women) free of CVD at baseline. RESULTS: Over 8.6 years, there were 119 CVD (106 CHD) events among women, and 164 (137) among men aged >= 30 years. Standard risk factors [age, systolic blood pressure (SBP), antihypertensive treatment, total and high-density lipoprotein cholesterol, smoking and diabetes mellitus], measured at baseline, were significantly related to the incidence of CVD. The only exception, lack of significance for coefficients of SBP among women, was attributable to collinearity between age and SBP. For most risk factors, hazard ratios (HRs) for CVD were similar for the TLGS and the Framingham cohorts' participants. Few exceptions were lower HR for SBP among TLGS' women and lower HR for age among TLGS' men. The Framingham equations quite correctly discriminated participants [C statistic: CVD, 0.818 (women) and 0.774 (men); CHD: 0.822 (women) and 0.751 (men)] with good calibration (all calibration chi(2) values < 15, ps > 0.1). DISCUSSION AND CONCLUSIONS: The Framingham's CVD algorithm was effective at ranking individuals and could be used to quantify risk and to guide preventive care in Iranian adults. For regions without established cohort, recalibration using risk factors and CVD (CHD) rates may be an effective method to develop CVD (CHD) risk prediction algorithms for local practice. PMID- 21314864 TI - Comparison of metabolic syndrome subjects with and without erectile dysfunction - levels of circulating oxidised LDL and arterial elasticity. AB - BACKGROUND: Erectile dysfunction (ED) is believed to be an early sign of systemic cardiovascular disease (CVD). Elevated levels of circulating oxidised LDL (oxLDL) and impairment of arterial elasticity have been reported to predict future cardiovascular events. We studied whether metabolic syndrome subjects with and without erectile dysfunction differ in circulating levels of oxLDL and arterial elasticity. Furthermore, we assessed whether the presence of ED acts as a clinical marker of underlying atherosclerotic process. METHODS: Seventy men with metabolic syndrome, aged 35-60 years, completed the International Index of Erectile Function questionnaire. Subject was considered to have erectile dysfunction if a sum of the questions 1-5 and 15 was <= 25. OxLDL was assessed by an ELISA immunoassay and arterial elasticity by a noninvasive radial artery tonometer (HDI/PulseWaveTMCR-2000). RESULTS: Large arterial elasticity index was significantly lower among subjects with erectile dysfunction compared with those without, 15.0 +/- 3.2 ml/mmHg * 10 and 18.0 +/- 3.7 ml/mmHg * 10, respectively (p = 0.001). The presence of erectile dysfunction associated with impaired large arterial elasticity, independently of traditional CVD risk factors. Reduction in arterial elasticity was also found among those with erectile dysfunction and less than 5% risk of cardiovascular death during 10 years by the SCORE. There were no significant differences in small arterial elasticity or oxLDL levels. CONCLUSION: Erectile dysfunction truly seems to be a marker of systemic vascular disease. Aggressive primary prevention should be considered for patients with metabolic syndrome and vasculogenic ED. PMID- 21314865 TI - Male gender and chronic obstructive pulmonary disease predict a poor clinical response in patients undergoing cardiac resynchronisation therapy. AB - AIMS: Current guidelines advocate cardiac resynchronisation therapy (CRT) in patients with class III/IV New York Heart Association (NYHA) heart failure, depressed left ventricular function and a broad QRS. However, a significant proportion of patients do not derive any benefit from CRT. The aim of this study was to identify clinical, electrocardiographic and echocardiographic predictors of response to CRT. METHODS: A retrospective analysis of patients undergoing CRT in our institution was performed. A favourable clinical response to CRT was defined as an improvement in NYHA Heart failure class of >= 1 and lack of hospitalisation with heart failure. Comparisons were made between responders and non-responders in terms of baseline characteristics and potential predictors of CRT response (QRS width, presence of left bundle branch block, atrial fibrillation, evidence of mechanical dyssynchrony on echocardiography and LV lead position). RESULTS: A total of 164 patients had full follow-up data. The mean follow-up was 293 days. Of patients undergoing CRT, 90 (58.9%) had a favourable clinical response to CRT. Predictors of a lack of clinical response to CRT were male gender (p = 0.012) and chronic obstructive pulmonary disease (COPD) (0.008). Pre-implant echocardiographic dyssynchrony assessment appeared not to predict response to CRT (p = 0.87); however, there was a trend towards a positive response in those patients with significant dyssynchrony (p = 0.09) defined as interventricular delay > 40 ms or maximal LV delay of > 80 ms. CONCLUSION: Male gender and coexisting COPD were shown to be independent predictors of non response to CRT in this cohort of patients fulfilling current criteria for CRT. PMID- 21314866 TI - Cardiovascular risk, drugs and erectile function--a systematic analysis. AB - AIMS: Erectile dysfunction is a major problem with an increasing prevalence in cardiovascular high-risk patients due to its association with cardiovascular risk factors. Drugs used for evidence-based treatment of cardiovascular diseases have been reported to decrease erectile function, but possible mechanisms are poorly characterised. METHODS: MEDLINE, EMBASE and Cochrane Registry search were performed including manuscripts until January 2010. Searching terms are: 'erectile dysfunction or impotence' in combination with 'ACE-inhibitors', 'angiotensin', 'beta-blockers', 'calcium antagonist' and 'diuretics'. Animal studies, letters, reviews, case-reports and manuscripts other than English language and trials dealing with combination treatment are excluded. RESULTS: Analysis of literature revealed five epidemiological trials evaluating the effect of different cardiovascular drugs on erectile function. There were eight trials evaluating the effect of beta-blockers, five trials evaluating the effect of ace inhibitors or angiotensin-receptor-blockers and one trial evaluating the effect of diuretics on erectile function. Results of these trials demonstrate that only thiazide diuretics and beta-blockers except nebivolol may adversely influence erectile function. ACE-inhibitors, angiotensin-receptor-blockers and calcium channel-blockers are reported to have no relevant or even a positive effect on erectile function. CONCLUSION: Inappropriate patients' concerns about adverse effects of cardiovascular drugs on erectile function might limit the use of important medications in cardiovascular high-risk patients. Knowledge about the effects of drug-treatments on erectile function and about the major role of the endothelium in penile function might improve patients' adherence to evidence based treatment of cardiovascular diseases. PMID- 21314867 TI - Incidence of complications and mortality in a type 2 diabetes patient cohort study followed up from diagnosis in a primary healthcare centre. AB - AIMS: To determine the microvascular and macrovascular complications and mortality incidence rates and to identify the related factors in patients recently diagnosed with type 2 diabetes between 1991 and 2000 and followed until 2006. METHODS: Retrospective longitudinal study in a primary healthcare center. Patients without any measure of glycaemia in the 3 years previous to diabetes diagnosis were excluded. Annual incidence rates for microvascular and macrovascular complications and mortality were estimated. Analysis of KaplanMeier survival curves and Cox proportional risk models by gender were done. RESULTS: Of 469 patients [mean age: 60.4 (SD 10.7) years, 53.9% women], 80 died principally of tumoral (38.7%) and cardiovascular (30%) causes. The mean follow-up period was 8.81 years. (SD 3.21). The complication rates per 1000 patients/year (95% CI) were: microvascular complications 29.11 (22.97-36.38), macrovascular complications 24.10 (19.05-30.08) and mortality 19.23 (15.25-23.93), all of those being significantly greater in males except for cerebrovascular disease. Complications and mortality were associated with age, HbA1c, HDL-cholesterol, blood pressure and smoking with a different significance for each gender. HbA1c was related to microvascular complications in both sexes and to macrovascular complications only in women. CONCLUSION: The annual rates for death and complications in a Mediterranean type 2 diabetic patient cohort followed from diagnosis were lower than those published in Anglo-Saxon countries. Males showed higher death and complication rates except in terms of cerebrovascular disease. Predictors of complication and death were different depending on gender. In terms of mortality, unlike in other studies, only one-third of the deaths were for cardiovascular causes. PMID- 21314868 TI - Fasting hyperglycaemia and in-hospital mortality in elderly population. AB - BACKGROUND: Admission hyperglycaemia has shown to be a marker of poor clinical outcome. The prevalence of admission hyperglycaemia and its relationship with in hospital mortality in elderly population has not been clearly defined. We assessed the prevalence and prognostic significance of admission fasting hyperglycaemia in aged patients. METHODS: A total of 808 elderly patients were studied. Patients were classified into group I (serum glucose < 126 mg/dl), II (126-180 mg/dl) and III (> 180 mg/dl). Groups II and III were considered newly recognised fasting hyperglycaemia (NRFH) in non-diabetic patients. RESULTS: NRFH was present in 18.6%. After excluding diabetic patients (n = 206, 25.5%), the distribution of patients (n = 602, 74.5%) was as follows: group I (n = 452, 55.9%), group II (n = 122, 15.1%) and group III (n = 28, 3.5%). In the whole cohort, median fasting glucose was lower in patients who survived [105 mg/dl (88 135)] than in those who died [127 mg/dl (93-159), p < 0.001]. This significant difference was maintained only when non-diabetic patients were considered [100 mg/dl (87-122) vs. 118 mg/dl (92-149), p < 0.001]. In-hospital mortality rate in groups I, II and III was 8.5%, 14.1% and 22.9%, respectively (p < 0.001). Mortality rate was 8.4%, 18.0% and 32.1% (p < 0.001) in groups I, II and III, respectively in non-diabetic population. Both low albumin and high glucose serum concentrations were the only independent risk factors for in-hospital all-cause mortality in non-diabetic patients. CONCLUSIONS: In non-diabetic elderly patients admitted for acute disease, serum glucose concentration is an important, simple and independent predictor of hospital mortality. PMID- 21314869 TI - Patient adherence to medication requirements for therapy of type 2 diabetes. AB - Type 2 diabetes is a complex, progressive endocrine and metabolical disease that typically requires substantial lifestyle changes and multiple medications to lower blood glucose, reduce cardiovascular risk and address comorbidities. Despite an extensive range of available and effective treatments, < 50% of patients achieve a glycaemical target of HbA(1c) < 7.0% and about two-thirds die of premature cardiovascular disease. Adherence to prescribed therapies is an important factor in the management of type 2 diabetes that is often overlooked. Inadequate adherence to oral antidiabetes agents, defined as collecting < 80% of prescribed medication, is variously estimated to apply to between 36% and 93% of patients. All studies affirm that a significant proportion of type 2 diabetes patients exhibit poor adherence that will contribute to less than desired control. Identified factors that impede adherence include complex dosing regimens, clinical inertia, safety concerns, socioeconomic issues, ethnicity, patient education and beliefs, social support and polypharmacy. This review explores these factors and potential strategies to improve adherence in patients with type 2 diabetes. PMID- 21314870 TI - Efficacy and tolerability of mirtazapine in treating major depressive disorder with anxiety symptoms: an 8-week open-label randomised paroxetine-controlled trial. AB - AIMS: Prominent anxiety symptoms are related to poor clinical course and outcome in major depressive disorder (MDD). The aim of this randomised, open-label, controlled study is to compare the efficacy and tolerability of mirtazapine in the form of orally disintegrating tablets against paroxetine in treating MDD patients with anxiety symptoms. METHODS: A total of 60 MDD patients with a score above 18 on the Hamilton Anxiety Rating Scale (HARS) were randomly assigned to 8 weeks of fixed dosing treatment with mirtazapine (15-30 mg/day) and paroxetine (10-20 mg/day). Efficacy was primarily assessed with the HARS and with the 17 item Hamilton Depression Rating Scale (HDRS) at weeks 1, 2, 4 and 8 after treatment. Tolerability was assessed from adverse events. RESULTS: The generalised estimating equations (GEE) models showed that the rates of improvement in HDRS scores from baseline to week 8 were similar between mirtazapine and paroxetine groups. However, patients with mirtazapine exhibited earlier improvement in HARS scores at weeks 1 and 2. Week-by-week GEE models showed that these significant differences in improvement of HARS scores between the two treatment groups were detectable from the first evaluation after the treatment (week 1) and maintained through week 2. There was no difference in the overall frequency of adverse events experienced between the two treatment groups. The most common adverse event in the mirtazapine group was somnolence (n = 8), whereas that in the paroxetine group was gastrointestinal discomfort (n = 9). CONCLUSIONS: Mirtazapine and paroxetine were equally effective and well tolerated for the depressive symptoms in MDD patients with the high level of anxiety symptoms. Mirtazapine was, however, more effective in reducing the anxiety symptoms than paroxetine in the early weeks of treatment, suggesting that mirtazapine may have an earlier-onset action for the anxiety symptoms in MDD patients. PMID- 21314871 TI - Weight change with long-term duloxetine use in chronic painful conditions: an analysis of 16 clinical studies. AB - AIMS: Report weight change baseline up to 12-15 months in duloxetine-treated patients during clinical trials of chronic painful conditions of diabetic peripheral neuropathic pain (DPNP), fibromyalgia, chronic low back pain (CLBP) and chronic knee pain as a result of osteoarthritis. METHODS: Weight change data from 16 duloxetine studies in chronic painful conditions were pooled by pain condition and duration, creating 10 datasets. Datasets included placebo controlled, open-label and routine-care-controlled designs. Assessments included mean weight change from baseline, baseline body mass index category, potentially clinically significant (PCS) weight change and weight-related treatment-emergent adverse events. RESULTS: Total number of patients was 5111 with mean baseline weight ranging from 70 to 97 kg. All duloxetine groups had significant mean weight loss compared with placebo at acute phase completion (p <= 0.001). In studies > 3 months, patients from fibromyalgia and CLBP studies had overall mean weight increase (up to 1.1 kg), whereas patients in DPNP studies had overall mean weight loss (-0.33 to -1.7 kg) at end-point. Overall, the percentage of patients with PCS weight gain was 0.4-16% and PCS weight loss was 2.5-9.9%. DISCUSSION: Weight change data in clinical trials of patients with fibromyalgia or CLBP treated with duloxetine for up to 15 months were consistent with data reported in 10 clinical trials of patients with major depressive disorder (MDD) using duloxetine up to 52 weeks. Patients with DPNP had weight loss at end-point. CONCLUSION: Mean weight changes and percentages of patients with PCS weight loss and weight gain observed in DPNP, fibromyalgia and CLBP with long-term duloxetine treatment were consistent with those reported previously for MDD studies. PMID- 21314872 TI - Clinical approach to renal tubular acidosis in adult patients. AB - Renal tubular acidosis (RTA) is a group of disorders observed in patients with normal anion gap metabolic acidosis. There are three major forms of RTA: A proximal (type II) RTA and two types of distal RTAs (type I and type IV). Proximal (type II) RTA originates from the inability to reabsorb bicarbonate normally in the proximal tubule. Type I RTA is associated with inability to excrete the daily acid load and may present with hyperkalaemia or hypokalaemia. The most prominent abnormality in type IV RTA is hyperkalaemia caused by hypoaldosteronism. This article extensively reviews the mechanism of hydrogen ion generation from metabolism of normal diet and various forms of RTA leading to disruptions of normal acid-base handling by the kidneys. PMID- 21314873 TI - Peri-operative management of ophthalmic patients taking antithrombotic therapy. AB - Increasing number of patients presenting for ophthalmic surgery are using oral anti-coagulant and anti-platelet therapy. The current practice of discontinuing these drugs preoperatively because of a presumed increased risk of bleeding may not be evidence-based and could pose a significant risk to the patient's health. To provide an evidence-based review on the peri-operative management of ophthalmic patients who are taking anti-thrombotic therapy. In addition, we briefly discuss the underlying conditions that necessitate the use of these drugs as well as management of the operative field in anti-coagulated patients. A semi systematic review of literature was performed. The databases searched included MEDLINE, EMBASE, database of abstracts of reviews of effects (DARE), Cochrane controlled trial register and Cochrane systematic reviews. In addition, the bibliographies of the included papers were also scanned for evidence. The published data suggests that aspirin did not appear to increase the risk of serious postoperative bleeding in any type of ophthalmic surgery. Topical, sub tenon, peri-bulbar and retrobulbar anaesthesia appear to be safe in patients on anti-thrombotic (warfarin and aspirin) therapy. Warfarin does not increase the risk of significant bleeding in most types of ophthalmic surgery when the INR was within the therapeutic range. Current evidence supports the continued use of aspirin and with some exceptions, warfarin in the peri-operative period. The risk of thrombosis-related complications on disruption of anticoagulation may be higher than the risk of significant bleeding by continuing its use for most types of ophthalmic surgery. PMID- 21314875 TI - Two week rule. PMID- 21314876 TI - Adiponectin in non-alcoholic fatty liver disease treatment: therapeutic perspectives and unresolved dilemmas. PMID- 21314877 TI - Can one manage well without measuring? PMID- 21314878 TI - Sample contamination in clinical chemistry laboratories. PMID- 21314879 TI - Increasing liana abundance and biomass in tropical forests: emerging patterns and putative mechanisms. AB - Tropical forests are experiencing large-scale structural changes, the most apparent of which may be the increase in liana (woody vine) abundance and biomass. Lianas permeate most lowland tropical forests, where they can have a huge effect on tree diversity, recruitment, growth and survival, which, in turn, can alter tree community composition, carbon storage and carbon, nutrient and water fluxes. Consequently, increasing liana abundance and biomass have potentially profound ramifications for tropical forest composition and functioning. Currently, eight studies support the pattern of increasing liana abundance and biomass in American tropical and subtropical forests, whereas two studies, both from Africa, do not. The putative mechanisms to explain increasing lianas include increasing evapotranspirative demand, increasing forest disturbance and turnover, changes in land use and fragmentation and elevated atmospheric CO2. Each of these mechanisms probably contributes to the observed patterns of increasing liana abundance and biomass, and the mechanisms are likely to be interrelated and synergistic. To determine whether liana increases are occurring throughout the tropics and to determine the mechanisms responsible for the observed patterns, a widespread network of large-scale, long-term monitoring plots combined with observational and manipulative studies that more directly investigate the putative mechanisms are essential. PMID- 21314880 TI - Do invasive species show higher phenotypic plasticity than native species and, if so, is it adaptive? A meta-analysis. AB - Do invasive plant species have greater phenotypic plasticity than non-invasive species? And, if so, how does this affect their fitness relative to native, non invasive species? What role might this play in plant invasions? To answer these long-standing questions, we conducted a meta-analysis using data from 75 invasive/non-invasive species pairs. Our analysis shows that invasive species demonstrate significantly higher phenotypic plasticity than non-invasive species. To examine the adaptive benefit of this plasticity, we plotted fitness proxies against measures of plasticity in several growth, morphological and physiological traits to test whether greater plasticity is associated with an improvement in estimated fitness. Invasive species were nearly always more plastic in their response to greater resource availability than non-invasives but this plasticity was only sometimes associated with a fitness benefit. Intriguingly, non-invasive species maintained greater fitness homoeostasis when comparing growth between low and average resource availability. Our finding that invasive species are more plastic in a variety of traits but that non-invasive species respond just as well, if not better, when resources are limiting, has interesting implications for predicting responses to global change. PMID- 21314881 TI - Habitat structure determines resource use by zooplankton in temperate lakes. AB - While the importance of terrestrial linkages to aquatic ecosystems is well appreciated, the degree of terrestrial support of aquatic consumers remains debated. Estimates of terrestrial contributions to lake zooplankton have omitted a key food source, phytoplankton produced below the mixed layer. We used carbon and nitrogen stable isotope data from 25 Pacific Northwest lakes to assess the relative importance of particulate organic matter (POM) from the mixed layer, below the mixed layer and terrestrial detritus to zooplankton. Zooplankton and deep POM were depleted in 13C relative to mixed layer POM in lakes that can support deep primary production. A Bayesian stable isotope mixing model estimated that terrestrial detritus contributed <5% to zooplankton production, and confirms the role of lake optical and thermal properties; deep POM accounted for up to 80% of zooplankton production in the clearest lakes. These results suggest terrestrial support of lake zooplankton production is trivial. PMID- 21314883 TI - Host and gut microbiota symbiotic factors: lessons from inflammatory bowel disease and successful symbionts. AB - Humans are colonized by a diverse collection of microbes, the largest numbers of which reside in the distal gut. The vast majority of humans coexist in a beneficial equilibrium with these microbes. However, disruption of this mutualistic relationship can manifest itself in human diseases such as inflammatory bowel disease. Thus the study of inflammatory bowel disease and its genetics can provide insight into host pathways that mediate host-microbiota symbiosis. Bacteria of the human intestinal ecosystem face numerous challenges imposed by human dietary intake, the mucosal immune system, competition from fellow members of the gut microbiota, transient ingested microbes and invading pathogens. Considering features of human resident gut bacteria provides the opportunity to understand how microbes have achieved their symbiont status. While model symbionts have provided perspective into host-microbial homeostasis, high throughput approaches are becoming increasingly practical for functionally characterizing the gut microbiota as a community. PMID- 21314884 TI - Insulin-like growth factor binding protein-3 (IGFBP-3) gene variants are associated with renal cell carcinoma. AB - OBJECTIVE: * To evaluate the A to C nucleotide change located 202 bp upstream to the transcription start site, (-202 A/C polymorphism), in the insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) gene, and its association with renal carinogenesis and with clinicopathological characteristics. PATIENTS AND METHODS: * We matched 158 male patients with clear-cell renal cell carcinoma (CCRCC) to 316 healthy controls, and genotyped one single nucleotide polymorphism (rs2854744) using the polymerase chain reaction restriction fragment length polymorphism technique. RESULTS: * The alleles and genotypes differed significantly between patients with CCRCC and controls (patients with CCRCC, P= 0.82; controls, P= 0.88). * We found that the frequency of the AA genotype was significantly higher in patients with CCRCC than in controls (odds ratio [OR]= 4.62, 95% confidence interval [CI]= 3.41-7.42, P= 0.001). * The A allele had a gene dose effect in increasing the risk of CCRCC (OR = 4.75, 95% CI = 3.64-7.64, P= 0.001). * The distribution of IGFBP-3 genotypes was also significantly associated with the histological grade (P= 0.001) and clinical stage (P= 0.001). CONCLUSION: * In the Iranian population, the polymorphism of the IGFBP-3 gene plays a pivotal role in the development of CCRCC. PMID- 21314885 TI - Recreational ketamine: from pleasure to pain. AB - Ketamine has become increasingly recognized as a drug of recreational use. Individuals using significant amounts have developed symptoms including a small painful bladder, ureteric obstruction, papillary necrosis and hepatic dysfunction. The present paper examines the current literature on the relationship between ketamine use and these symptoms. Our own clinical experience and the data available clarify the causal relationship, and further data help to elucidate the mechanism of damage. On the basis of continued work and development with patients who are ketamine users we suggest an assessment and treatment regime that includes cessation of ketamine use and adequate analgesia to overcome symptoms. In conclusion, it is important for medical practitioners who encounter patients with these symptoms to ask about recreational drug use. Ketamine remains a safe and effective drug to use under appropriate medical supervision. Patients identified as suffering from this syndrome will need to be referred to a urological unit with an interest in the treatment of the condition. PMID- 21314886 TI - Pharmacokinetics and toxicity of intravesical TMX-101: a preclinical study in pigs. AB - OBJECTIVE: * To study the pharmacokinetic and toxicity profile of intravesically administered TMX-101, with its active ingredient R-837, a synthetic Toll-like receptor (TLR)-7 agonist, in a pig model. MATERIALS AND METHODS: * TLR-7 expression was determined by immunohistochemistry in human and pig bladder tissue. * Four groups of six pigs received a 1-h intravesical instillation with R 837 of different formulations. * Pharmacokinetic analysis was performed on plasma. Toxicity evaluation included monitoring the well-being of the animals, peripheral blood cell counts, and interleukin-6 and creatinine measurements. Urine was collected for R-837 measurement and dipstick analysis. * In total, three pigs per group were sacrificed 24 h post-treatment, and the remaining animals were sacrificed after 1 week. Histopathological examination of the bladder wall was performed. RESULTS: * TLR-7 was homogeneously expressed in human and pig urothelium. * R-837 and vehicle were well tolerated without deterioration in animal well-being. * Systemic R-837 absorption was low. * Mean maximum plasma concentration of R-837 differed depending on the formulation. Post-treatment, plasma levels were negligible at 24 h. * Histopathological examination of the bladders did not show significant abnormalities, apart from the intended inflammatory reaction in the R-837 treated groups. CONCLUSION: * Intravesically administered R-837 in pigs, which showed a similar TLR-7 distribution in bladder tissue as humans, is well tolerated and causes no bladder wall toxicity, and formulations with poloxamer and hydroxypropyl-beta-cyclodextrin showed less systemic absorption. PMID- 21314887 TI - Trends in the use of radiotherapy and radical surgery for patients with bladder urothelial cell carcinoma in East Anglia, 1995-2006. AB - OBJECTIVE: * To examine the use of radiotherapy and radical surgery for bladder urothelial cell carcinoma (UCC) before, during and after national initiatives for reorganization of uro-oncology services. PATIENTS AND METHODS: * Population-based data (1995-2006) from a cancer registry with stable coding practices were analysed. * Bladder UCC was defined using relevant International Classification of Disease site and morphology codes. * Time trends in the use of radiotherapy and radical surgery, and other predictors of their use were examined. RESULTS: * Of 4639 bladder UCC patients aged >=40 years (76% men), stage information was available for 4303 (93%). * Morphology and stage case mix remained stable during the study period. * Radiotherapy use decreased significantly (from 31% in 1995 1998 to 22% in 2003-2006, P < 0.001) among patients of any stage, whilst radical surgery use increased significantly (from 8 to 13%, P < 0.001), particularly among stage II-IV patients. * The proportion of patients treated by both radiotherapy and surgery also decreased notably (from 4.0 to 1.1%). * Women were significantly more likely to present in stages II-IV [odds ratio (OR) = 1.22, 95% confidence interval (CI) = 1.06-1.40, P = 0.005], and less likely to be treated with radiotherapy (OR = 0.84, 95% CI: 0.72-0.99, P = 0.036). CONCLUSIONS: * Use of radical surgery in UCC invading bladder muscle increased and use of radiotherapy decreased during the study period, most probably reflecting the increasing availability of specialist surgical management. Sociodemographic variation in treatment was limited to lower use of radiotherapy in women. * Further research should encompass treatment timeliness and other aspects of care quality, as well as exploring potential differences in endoscopic treatments for disease not invading bladder muscle. PMID- 21314888 TI - Together or alone?: foraging strategies in Caenorhabditis elegans. AB - A central goal in Life Sciences is to understand how genes encode behaviour and how environmental factors influence the expression of the genes concerned. To reach this goal a combined ecological, molecular biological and physiological approach is required in combination with a suitable model organism. Such an approach allows the elucidation of all parts of the complicated chain of events that lead from induction of gene expression to behaviour, i.e. from environmental stimulus, sensory organs and extracellular and intracellular neuronal signal processing to activation of effector organs. A particularly good model species with which to take this approach is the nematode Caenorhabditis elegans, as it has been described in great detail at the genomic, cellular and behavioural levels. Different strains of C. elegans display prominent behavioural variation in foraging behaviour. Some strains will form social feeding groups when subjected to certain environmental stimuli, while others do not. This variation is due to the existence of just two isoforms of the gene npr-1, namely 215F and 215V. Here, we describe these behavioural variations at the molecular and cellular levels to attempt to determine the environmental inputs that cause aggregation of these small nematodes. As many different stimuli affect aggregation either positively or negatively, aggregation behaviour seems to be displayed when it improves survival chances. However, not much is known about the ecological context in which C. elegans lives. Investigation of the habitats of different strains of C. elegans would help us to understand why and how a specific foraging strategy enhances survival. The relatively well-understood molecular pathways that direct its social feeding behaviour make C. elegans a highly suitable model organism to test ecological and behavioural hypotheses about the mechanisms that differentiate between aggregation and solitary behaviours. PMID- 21314889 TI - Using and writing reviews to inform your practice. AB - Reviews are seen as a way of exploiting existing data or research findings more fully and can offer a summarised insight into the current understanding of the evidence. Library and information science (LIS) workers can use reviews to inform their decision-making and service planning. Although the LIS evidence base continues to grow there will frequently be times when no published reviews are available. In these instances, you may consider undertaking your own review. Different types of review require different approaches and, by deciding from the outset what kind of review yours will be, will inform your methodology. Guidelines on writing reviews for the Health Information and Libraries Journal are presented. PMID- 21314890 TI - Evaluating clinical librarian services: a systematic review. AB - BACKGROUND: Previous systematic reviews have indicated limited evidence and poor quality evaluations of clinical librarian (CL) services. Rigorous evaluations should demonstrate the value of CL services, but guidance is needed before this can be achieved. OBJECTIVES: To undertake a systematic review which examines models of CL services, quality, methods and perspectives of clinical librarian service evaluations. METHODS: Systematic review methodology and synthesis of evidence, undertaken collaboratively by a group of 8 librarians to develop research and critical appraisal skills. RESULTS: There are four clear models of clinical library service provision. Clinical librarians are effective in saving health professionals time, providing relevant, useful information and high quality services. Clinical librarians have a positive effect on clinical decision making by contributing to better informed decisions, diagnosis and choice of drug or therapy. The quality of CL studies is improving, but more work is needed on reducing bias and providing evidence of specific impacts on patient care. The Critical Incident Technique as part of a mixed method approach appears to offer a useful approach to demonstrating impact. CONCLUSIONS: This systematic review provides practical guidance regarding the evaluation of CL services. It also provides updated evidence regarding the effectiveness and impact of CL services. The approach used was successful in developing research and critical appraisal skills in a group of librarians. PMID- 21314891 TI - Hospital clinicians' information behaviour and attitudes towards the 'Clinical Informationist': an Irish survey. AB - BACKGROUND: Hospital clinicians are increasingly expected to practice evidence based medicine (EBM) in order to minimize medical errors and ensure quality patient care, but experience obstacles to information-seeking. The introduction of a Clinical Informationist (CI) is explored as a possible solution. AIMS: This paper investigates the self-perceived information needs, behaviour and skill levels of clinicians in two Irish public hospitals. It also explores clinicians' perceptions and attitudes to the introduction of a CI into their clinical teams. METHODS: A questionnaire survey approach was utilised for this study, with 22 clinicians in two hospitals. Data analysis was conducted using descriptive statistics. RESULTS: Analysis showed that clinicians experience diverse information needs for patient care, and that barriers such as time constraints and insufficient access to resources hinder their information-seeking. Findings also showed that clinicians struggle to fit information-seeking into their working day, regularly seeking to answer patient-related queries outside of working hours. Attitudes towards the concept of a CI were predominantly positive. CONCLUSION: This paper highlights the factors that characterise and limit hospital clinicians' information-seeking, and suggests the CI as a potentially useful addition to the clinical team, to help them to resolve their information needs for patient care. PMID- 21314892 TI - Healthcare librarians and the delivery of critical appraisal training: barriers to involvement. AB - BACKGROUND: Many healthcare librarians are undertaking training in critical appraisal but a significant number are not cascading the training to their end users. OBJECTIVES: To examine the barriers to healthcare librarian involvement in delivering critical appraisal training. METHODS: A questionnaire survey of 57 library services across 48 NHS Trust Library Services in north west England followed up with 21 semi-structured interviews. RESULTS: Two types of barriers were noted: extrinsic barriers (organisational, environmental, training, role expectations) and intrinsic barriers (knowledge, skills, attitude). CONCLUSIONS: These barriers are not mutually exclusive and by overcoming one of them it does not necessarily follow that healthcare librarians will engage in delivering critical appraisal skills training. The challenge lies in developing strategies to deal effectively with these barriers to encourage and support healthcare librarians in the delivery of critical appraisal training at a level at which they feel confident and able. PMID- 21314893 TI - The Library's role and challenges in implementing an e-learning strategy: a case study from northern Australia. AB - BACKGROUND: The Northern Territory Department of Health and Families' (DHF) Library supports education programs for all staff. DHF is implementing an e learning strategy, which may be viewed as a vehicle for coordinating the education function throughout the organisation. OBJECTIVE: The objective of this study is to explore the concept of e-learning in relation to the Library's role in implementing an organisation-wide e-learning strategy. METHODS: The main findings of a literature search about the effectiveness of e-learning in health professionals' education, and the responsibility and roles of health librarians in e-learning are described. A case study approach is used to outline the current role and future opportunities and challenges for the Library. DISCUSSION: The case study presents the organisation's strategic planning context. Four areas of operational activity which build on the Library's current educational activities are suggested: the integration of library resources 'learning objects' within a Learning Management System; developing online health information literacy training programs; establishing a physical and virtual 'e Learning Library/Centre'; developing collaborative partnerships, taking on new responsibilities in e-learning development, and creating a new e-learning librarian role. CONCLUSION: The study shows that the Library's role is fundamental to developing the organisation's e-learning capacity and implementing an organisation-wide e-learning strategy. PMID- 21314894 TI - Evaluation of three point-of-care healthcare databases: BMJ Point-of-Care, Clin eguide and Nursing Reference Centre. AB - BACKGROUND: Point of care resources make it easier for clinicians to find answers to questions that arise during a clinical encounter. In order to make informed purchase decisions in times of tight budgets, librarians need to have a better understanding of which resources will meet their patrons' clinical information needs. OBJECTIVES: The goal of this study was to assess the content, interface and usability of three point-of-care tools: BMJ Point-of-Care, Clin-eguide and Nursing Reference Centre. METHODS: A questionnaire designed to gather quantitative and qualitative data was created using Survey Monkey. The survey was distributed to healthcare practitioners in Alberta's two largest health regions, and the data were analysed for emergent themes. RESULTS: The themes that arose--ease of use, validated content, relevancy to practice- generally echoed those stated in the literature. No one database fared significantly better, due to differing features, content and client preference. CONCLUSIONS: Despite the limitations of the survey, the themes that emerged provide a springboard for future research on the efficacy of information resources used at the point of care, and the need for deeper analysis of these recent additions to the medical information market. PMID- 21314895 TI - 'Quality signposting': the role of online information prescription in providing patient information. AB - BACKGROUND: Information prescriptions (IPs) are part of a Department of Health (DH) initiative to improve patient care. IPs aim to meet health information needs by providing personalised, high quality patient information about conditions and treatment. OBJECTIVES: This paper identifies current online IP provision and evaluates a sample of IP websites against the original DH aims of IP provision; British Medical Association usability criteria; and information seeking vignettes. METHODS: Five UK and one international IP website were randomly selected as a sample. Two checklists designed to appraise the websites were used to review each IP provider. Two patient information seeking vignettes were developed to enable the websites to be assessed from a patient-centred perspective. RESULTS: Information prescriptions currently vary in content, accessibility and quality. National IP websites score more highly than local IP websites, which are often weak on content for specific conditions and poorly designed but strong on signposting to local services. CONCLUSIONS: Guidelines for IP provision need to be improved to ensure higher quality, more easily accessible information is available. A synthesis of expertise included in national and local websites would improve usability for patients. IP websites should conform to standards of web design and accessibility. PMID- 21314896 TI - Searching for randomised controlled trials and clinical controlled trials in Thai online bibliographical biomedical databases. AB - BACKGROUND: Thailand is a poor but highly literate country in South-East Asia with over 60 million people. A lot of biomedical research is undertaken but dissemination is limited. OBJECTIVES: To identify relevant Thai bibliographic databases and investigate accessibility, functionality and content, particularly in relation to randomised controlled trials (RCTs) and clinical controlled trials (CCTs). METHODS: A systematic search for institutions productive of research and the databases in their libraries. Search each accessible database in both Thai and English, recording the functionality and content. Assess accessibility of the retrieved RCTs or CCTs by comparing to PubMed holdings. RESULTS: We found 32 different databases (29 accessible in UK) of various sizes, coverage and functionality but many with unique records of RCTs and CCTs (total, n=781). Two hundred and nine of 781 trials were accessible on PubMed (27%). However, 641 of the 781 trial records contain text in both English and Thai (82%) and 112 records were solely English (14%). CONCLUSIONS: Those undertaking comprehensive searches for RCTs/CCTs should, in addition to a PubMed, search the Thai Medical Index and Thai Index Medicus databases, and the Khon Kaen University Library Catalogue. PMID- 21314897 TI - Case study: library usage at an Indian medical college. AB - This issue's feature column reports on the findings of a small survey of library users carried out in an Indian medical college with a traditional curriculum. The study found that the main reason a student visited the library was to consult text books. Although the majority of students were satisfied with the library facilities, the study suggests that more needs to be done to promote self directed learning. JM. PMID- 21314898 TI - Further developing the library curriculum: skills for life delivery. AB - This feature discusses how the library curriculum was developed at Plymouth Hospitals NHS Trust Library Service to aid the delivery of Skills for Life. In particular, the feature describes how, through collaboration with learndirect, literacy and numeracy skills were embedded into the broader library and information skills training programme. The article reports on how the programme resulted in the provision of qualifications and skills development opportunities to NHS staff, and an increase in the NHS library profile. PMID- 21314899 TI - Evaluating clinical librarians: mixing apple merchants and orange sellers? AB - Clinical librarian services have been in existence for over 40 years. Although three systematic reviews have examined clinical librarian roles they continue to pose a challenge to rigorous evaluation. Difficulties can be articulated around their Population, Intervention, Comparator and Outcome (PICO) characteristics as well as within a wider evaluation framework. This feature suggests that developments within health research aimed at evaluating complex interventions may hold the key to assessing the contribution of such a variety of service models. PMID- 21314900 TI - Toxoplasma gondii infection in slaughter pigs in Serbia: seroprevalence and demonstration of parasites in blood. AB - A seroepizootiological study of Toxoplasma gondii infection involving a total of 488 slaughter pigs (468 market-weight pigs and 20 sows) in the Belgrade area, also included examination of the presence of T. gondii in the blood. Blood sampled at the slaughter line was examined for specific antibodies by modified direct agglutination, and blood clots of those seropositive at titres of 1:50 1:12800 were bioassayed in mice. The overall seroprevalence was 9.2%, significantly higher (p = 0.0063) in sows (30.0%) than in market-weight pigs (8.3%). Amongst the 22 bioassays performed, a total of 16 (72.7%) were positive, by observation of T. gondii cysts (12), seropositivity (7, including 3 in which cysts were not detected), and/or detection of T. gondii DNA by real-time PCR (12, including one otherwise negative). The positive bioassays originated from the blood of 12 market-weight pigs and 4 sows. Despite a general increase in the rate of demonstration of T. gondii with the increase in the specific antibody level, the association was not significant (p = 0.101). The risk of infection was 41 fold increased in sows vs market-weight pigs, and 15-fold in pigs from smallholders' finishing type farms vs those from large farrow-to-finish farms. The presence of viable T. gondii in a proportion of the samples indicates that some of the pigs had an active parasitaemia at the time of slaughter, which, along with the seroprevalence established, points to a potential source of human infection in Serbia. This is the first report on parasitaemia in naturally infected swine. PMID- 21314901 TI - Colostral antibody induced interference of inactivated bluetongue serotype-8 vaccines in calves. AB - Since its introduction into northern Europe in 2006, bluetongue has become a major threat to animal health. While the efficacy of commercial vaccines has been clearly demonstrated in livestock, little is known regarding the effect of maternal immunity on vaccinal efficacy. Here, we have investigated the duration and amplitude of colostral antibody-induced immunity in calves born to dams vaccinated against bluetongue virus serotype 8 (BTV-8) and the extent of colostral antibody-induced interference of vaccination in these calves. Twenty two calf-cow pairs were included in this survey. The median age at which calves became seronegative for BTV was 84 and 112 days as assayed by seroneutralisation test (SNT) and VP7 BTV competitive ELISA (cELISA), respectively. At the mean age of 118 days, 13/22 calves were immunized with inactivated BTV-8 vaccine. In most calves vaccination elicited a weak immune response, with seroconversion in only 3/13 calves. The amplitude of the humoral response to vaccination was inversely proportional to the maternal antibody level prior to vaccination. Thus, the lack of response was attributed to the persistence of virus-specific colostral antibodies that interfered with the induction of the immune response. These data suggest that the recommended age for vaccination of calves born to vaccinated dams needs to be adjusted in order to optimize vaccinal efficacy. PMID- 21314902 TI - Taxonomy of bacterial fish pathogens. AB - Bacterial taxonomy has progressed from reliance on highly artificial culture dependent techniques involving the study of phenotype (including morphological, biochemical and physiological data) to the modern applications of molecular biology, most recently 16S rRNA gene sequencing, which gives an insight into evolutionary pathways (= phylogenetics). The latter is applicable to culture independent approaches, and has led directly to the recognition of new uncultured bacterial groups, i.e. "Candidatus", which have been associated as the cause of some fish diseases, including rainbow trout summer enteritic syndrome. One immediate benefit is that 16S rRNA gene sequencing has led to increased confidence in the accuracy of names allocated to bacterial pathogens. This is in marked contrast to the previous dominance of phenotyping, and identifications, which have been subsequently challenged in the light of 16S rRNA gene sequencing. To date, there has been some fluidity over the names of bacterial fish pathogens, with some, for example Vibrio anguillarum, being divided into two separate entities (V. anguillarum and V. ordalii). Others have been combined, for example V. carchariae, V. harveyi and V. trachuri as V. harveyi. Confusion may result with some organisms recognized by more than one name; V. anguillarum was reclassified as Beneckea and Listonella, with Vibrio and Listonella persisting in the scientific literature. Notwithstanding, modern methods have permitted real progress in the understanding of the taxonomic relationships of many bacterial fish pathogens. PMID- 21314903 TI - Mesenteric lymph node cells from neonates present a prominent IL-12 response to CpG oligodeoxynucleotide via an IL-15 feedback loop of amplification. AB - At birth, the immune system is still in development making neonates more susceptible to infections. The recognition of microbial ligands is a key step in the initiation of immune responses. It can be mimicked to stimulate the immune system by the use of synthetic ligands recognising pattern recognition receptors. In human and mouse, it has been found that neonatal cytokine responses to toll like receptor (TLR) ligands differ in many ways from those of adults but the relevant studies have been limited to cord blood and spleen cells. In this study, we compared the responses in neonate and adult sheep to CpG oligodeoxynucleotides (ODN), a TLR9 ligand, in both a mucosal and a systemic organ. We observed that in response to CpG-ODN more IL-12 was produced by neonatal than adult sheep cells from mesenteric lymph nodes (MLN) and spleen. This higher IL-12 response was limited to the first 20 days after birth for MLN cells but persisted for a longer period for spleen cells. The major IL-12-producing cells were identified as CD14+CD11b+. These cells were poor producers of IL-12 in response to direct stimulation with CpG-ODN and required the cooperation of other MLN cells. The difference in response to CpG-ODN between neonates and adults can be attributed to both a higher proportion of CD14+CD11b+ cells in neonate lambs and their higher capacity to produce IL-15. The IL-15 increases IL-12 production by an amplifying feedback loop involving CD40. PMID- 21314904 TI - BSE infectivity in jejunum, ileum and ileocaecal junction of incubating cattle. AB - To establish bovine spongiform encephalopathy (BSE) public health protection measures it is important to precisely define the cattle tissues considered as specified risk materials (SRM). To date, in pre-clinical BSE infected cattle, no evidence of the BSE agent had been found in the gut outside of the ileal Peyer's Patches. This study was undertaken to determine when and where the pathological prion protein (PrPSc) and/or BSE infectivity can be found in the small intestine of cattle 4 to 6 months of age, orally challenged with BSE. Samples of the jejunum, the ileum and the ileocaecal junction from 46 BSE infected cattle, culled from 1 up to 44 months post infection (mpi) were examined by immunohistochemistry. Samples from cattle 8 mpi to 20 mpi were additionally studied by PTA Western blot, rapid tests, and by mouse (TgbovXV) bioassay. In doing so nearly all of the cattle, from 4 up to 44 mpi, had detectable amounts of PrPSc and/or infectivity in the distal ileum. In the distal ileum clear time dependent variations were visible concerning the amount of PrPSc, the tissue structures affected, and the cells involved. BSE infectivity was found not only in the ileum and ileocaecal junction but also in the jejunum. The systematic approach of this study provides new data for qualitative and quantitative risk assessments and allows defining bovine SRM more precisely. PMID- 21314905 TI - A replication analysis of foot-and-mouth disease virus in swine lymphoid tissue might indicate a putative carrier stage in pigs. AB - Foot-and-mouth disease virus (FMVD), one of the most contagious viruses of cloven hoofed animals, may cause a prolonged, asymptomatic but persistent infection in ruminants, named the "carrier state". However, it remains an open question whether this carrier state occurs in pigs. Here we present quantitative analyses of the duration of FMDV RNA and infectivity in lymphoid and epithelial tissues in experimentally infected pigs with FMDV C-S8c1. The data indicated that although FMDV RNA remained in blood until day 14 post-infection (pi), viremia was cleared by day 7 pi. However, all tissues tested were positive for FMDV until day 14-17 pi. Interestingly, the specific infectivity of FMDV in these tissues was in some cases even higher than the FMDV C-S8c1. We therefore propose that a "pseudopersistent state" may occur in pigs in which virus replicates in lymphoid tissues for a prolonged period of time, thereby representing a potential source of virus. PMID- 21314906 TI - Evaluation of immune responses following infection of ponies with an EHV-1 ORF1/2 deletion mutant. AB - Equine herpesvirus-1 (EHV-1) infection remains a significant problem despite the widespread use of vaccines. The inability to generate a protective immune response to EHV-1 vaccination or infection is thought to be due to immunomodulatory properties of the virus, and the ORF1 and ORF2 gene products have been hypothesized as potential candidates with immunoregulatory properties. A pony infection study was performed to define immune responses to EHV-1, and to determine if an EHV-1 ORF1/2 deletion mutant (DeltaORF1/2) would have different disease and immunoregulatory effects compared to wild type EHV-1 (WT). Infection with either virus led to cytokine responses that coincided with the course of clinical disease, particularly the biphasic pyrexia, which correlates with respiratory disease and viremia, respectively. Similarly, both viruses caused suppression of proliferative T-cell responses on day 7 post infection (pi). The DeltaORF1/ORF2 virus caused significantly shorter primary pyrexia and significantly reduced nasal shedding, and an attenuated decrease in PBMC IL-8 as well as increased Tbet responses compared to WT-infected ponies. In conclusion, our findings are (i) that infection of ponies with EHV-1 leads to modulation of immune responses, which are correlated with disease pathogenesis, and (ii) that the ORF1/2 genes are of importance for disease outcome and modulation of cytokine responses. PMID- 21314907 TI - Pathogenesis and transmissibility of highly (H7N1) and low (H7N9) pathogenic avian influenza virus infection in red-legged partridge (Alectoris rufa). AB - An experimental infection with highly pathogenic avian influenza virus (HPAIV) and low pathogenic avian influenza virus (LPAIV) was carried out in red-legged partridges (Alectoris rufa) in order to study clinical signs, gross and microscopic lesions, and viral distribution in tissues and viral shedding. Birds were infected with a HPAIV subtype H7N1 (A/Chicken/Italy/5093/1999) and a LPAIV subtype H7N9 (A/Anas crecca/Spain/1460/2008). Uninoculated birds were included as contacts in both groups. In HPAIV infected birds, the first clinical signs were observed at 3 dpi, and mortality started at 4 dpi, reaching 100% at 8 dpi. The presence of viral antigen in tissues and viral shedding were confirmed by immunohistochemistry and quantitative real time RT-PCR (qRRT-PCR), respectively, in all birds infected with HPAIV. However, neither clinical signs nor histopathological findings were observed in LPAIV infected partridges. In addition, only short-term viral shedding together with seroconversion was detected in some LPAIV inoculated animals. The present study demonstrates that the red-legged partridge is highly susceptible to the H7N1 HPAIV strain, causing severe disease, mortality and abundant viral shedding and thus contributing to the spread of a potential local outbreak of this virus. In contrast, our results concerning H7N9 LPAIV suggest that the red-legged partridge is not a reservoir species for this virus. PMID- 21314908 TI - Mechanisms underlying Actinobacillus pleuropneumoniae exotoxin ApxI induced expression of IL-1beta, IL-8 and TNF-alpha in porcine alveolar macrophages. AB - Actinobacillus pleuropneumoniae (A. pleuropneumoniae) causes fibrino-hemorrhagic necrotizing pleuropneumonia in pigs. Production of proinflammatory mediators in the lungs is an important feature of A. pleuropneumoniae infection. However, bacterial components other than lipopolysaccharide involved in this process remain unidentified. The goals of this study were to determine the role of A. pleuropneumoniae exotoxin ApxI in cytokine induction and to delineate the underlying mechanisms. Using real-time quantitative PCR analysis, we found native ApxI stimulated porcine alveolar macrophages (PAMs) to transcribe mRNAs of IL 1beta, IL-8 and TNF-alpha in a concentration- and time-dependent manner. Heat inactivation or pre-incubation of ApxI with a neutralizing antiserum attenuated ApxI bioactivity to induce cytokine gene expression. The secretion of IL-1beta, IL-8 and TNF-alpha protein from PAMs stimulated with ApxI was also confirmed by quantitative ELISA. In delineating the underlying signaling pathways contributing to cytokine expression, we observed mitogen-activated protein kinases (MAPKs) p38 and cJun NH2-terminal kinase (JNK) were activated upon ApxI stimulation. Administration of an inhibitor specific to p38 or JNK resulted in varying degrees of attenuation on ApxI-induced cytokine expression, suggesting the differential regulatory roles of p38 and JNK in IL-1beta, IL-8 and TNF-alpha production. Further, pre-incubation of PAMs with a CD18-blocking antibody prior to ApxI stimulation significantly reduced the activation of p38 and JNK, and subsequent expression of IL-1beta, IL-8 or TNF-alpha gene, indicating a pivotal role of beta2 integrins in the ApxI-mediated effect. Collectively, this study demonstrated ApxI induces gene expression of IL-1beta, IL-8 and TNF-alpha in PAMs that involves beta2 integrins and downstream MAPKs. PMID- 21314909 TI - Did transmission of Helicobacter pylori from humans cause a disease outbreak in a colony of Stripe-faced Dunnarts (Sminthopsis macroura)? AB - Since the discovery that Helicobacter pylori causes a range of pathologies in the stomachs of infected humans, it has become apparent that Helicobacters are found in a diverse range of animal species where they are frequently associated with disease. In 2003 and 2004, there were two outbreaks of increased mortality associated with gastric bleeding and weight-loss in a captive colony of the Australian marsupial, the Stripe-faced Dunnart (Sminthopsis macroura). The presence of gastric pathology led to an investigation of potential Helicobacter pathogenesis in these animals. Histological examination revealed the presence of gastritis, and PCR analysis confirmed the presence of Helicobacter infection in the stomachs of these marsupials. Surprisingly, sequencing of 16S rRNA from these bacteria identified the species as H. pylori and PCR confirmed the strain to be positive for the important pathogenesis factor, cagA. We therefore describe, for the first time, an apparent reverse zoonotic infection of Stripe-faced Dunnarts with H. pylori. Already prone to pathological effects of stress (as experienced during breeding season), concomitant H. pylori infection appears to be a possible essential but not sufficient co-factor in prototypic gastric bleeding and weight loss in these marsupials. The Stripe-faced Dunnart could represent a new model for investigating Helicobacter-driven gastric pathology. Infections from their human handlers, specifically of H. pylori, may be a potential risk to captive colonies of marsupials. PMID- 21314910 TI - Experimental infection of Pacific oyster Crassostrea gigas spat by ostreid herpesvirus 1: demonstration of oyster spat susceptibility. AB - In 2008 and 2009, acute mortalities occurred in France among Pacific cupped oyster, Crassostrea gigas, spat. Different hypothesis including the implication of environmental factors, toxic algae and/or pathogens have been explored. Diagnostic tests indicated that OsHV-1 including a particular genotype, termed OsHV-1 MUVar, was detected in most of samples and especially in moribund oysters with the highlighting of virus particles looking like herpes viruses by TEM examination. In this study, an experimental protocol to reproduce OsHV-1 infection in laboratory conditions was developed. This protocol was based on the intramuscular injection of filtered (0.22 MUm) tissue homogenates prepared from naturally OsHV-1 infected spat collected on French coasts during mortality outbreaks in 2008. Results of the experimental trials showed that mortalities were induced after injection. Moreover, filtered tissue homogenates induced mortalities whereas the same tissue homogenates exposed to an ultraviolet (UV) treatment did not induce any mortality suggesting that oyster spat mortalities require the presence of a UV sensitive agent. Furthermore, analysis of injected oyster spat revealed the detection of high amounts of OsHV-1 DNA by real-time quantitative PCR. Finally, TEM analysis demonstrated the presence of herpes virus particles. The developed protocol allowed to maintain sources of infective virus which can be useful for the development of further studies concerning the transmission and the development of OsHV-1 infection. PMID- 21314911 TI - Identification of the ovine mannose receptor and its possible role in Visna/Maedi virus infection. AB - This study aims to characterize the mannose receptor (MR) gene in sheep and its role in ovine visna/maedi virus (VMV) infection. The deduced amino acid sequence of ovine MR was compatible with a transmembrane protein having a cysteine-rich ricin-type amino-terminal region, a fibronectin type II repeat, eight tandem C type lectin carbohydrate-recognition domains (CRD), a transmembrane region, and a cytoplasmic carboxy-terminal tail. The ovine and bovine MR sequences were closer to each other compared to human or swine MR. Concanavalin A (ConA) inhibited VMV productive infection, which was restored by mannan totally in ovine skin fibroblasts (OSF) and partially in blood monocyte-derived macrophages (BMDM), suggesting the involvement of mannosylated residues of the VMV ENV protein in the process. ConA impaired also syncytium formation in OSF transfected with an ENV encoding pN3-plasmid. MR transcripts were found in two common SRLV targets, BMDM and synovial membrane (GSM) cells, but not in OSF. Viral infection of BMDM and especially GSM cells was inhibited by mannan, strongly suggesting that in these cells the MR is an important route of infection involving VMV Env mannosylated residues. Thus, at least three patterns of viral entry into SRLV-target cells can be proposed, involving mainly MR in GSM cells (target in SRLV-induced arthritis), MR in addition to an alternative route in BMDM (target in SRLV infections), and an alternative route excluding MR in OSF (target in cell culture). Different routes of SRLV infection may thus coexist related to the involvement of MR differential expression. PMID- 21314912 TI - Chlamydiaceae infections in pig. AB - Chlamydiaceae are Gram-negative obligate intracellular bacteria. They are responsible for a broad range of diseases in animals and humans. In pigs, Chlamydia suis, Chlamydia abortus, Chlamydia pecorum and Chlamydia psittaci have been isolated. Chlamydiaceae infections in pigs are associated with different pathologies such as conjunctivitis, pneumonia, pericarditis, polyarthritis, polyserositis, pseudo-membranous or necrotizing enteritis, periparturient dysgalactiae syndrome, vaginal discharge, return to oestrus, abortion, mummification, delivery of weak piglets, increased perinatal and neonatal mortality and inferior semen quality, orchitis, epididymitis and urethritis in boars. However, Chlamydiaceae are still considered as non-important pathogens because reports of porcine chlamydiosis are rare. Furthermore, Chlamydiaceae infections are often unnoticed because tests for Chlamydiaceae are not routinely performed in all veterinary diagnostic laboratories and Chlamydiaceae are often found in association with other pathogens, which are sometimes more easily to detect. However, recent studies have demonstrated that Chlamydiaceae infections in breeding sows, boars and piglets occur more often than thought and are economically important. This paper presents an overview on: the taxonomy of Chlamydiaceae occurring in pigs, diagnostic considerations, epidemiology and pathology of infections with Chlamydiaceae in pigs, public health significance and finally on prevention and treatment of Chlamydiaceae infections in pigs. PMID- 21314913 TI - The Incredible Years Therapeutic Dinosaur Programme to build social and emotional competence in Welsh primary schools: study protocol for a randomised controlled trial. AB - BACKGROUND: School interventions such as the Incredible Years Classroom Dinosaur Programme targets pupil behaviour across whole classrooms, yet for some children a more intense approach is needed. The Incredible Years Therapeutic Dinosaur Programme is effective for clinically referred children by enhancing social, problem-solving skills, and peer relationship-building skills when delivered in a clinical setting in small groups. The aim of this trial is to evaluate the effectiveness of the Therapeutic Programme, delivered with small groups of children at high-risk of developing conduct disorder, delivered in schools already implementing the Classroom Programme. METHODS/DESIGN: This is a pragmatic, parallel, randomised controlled trial.Two hundred and forty children (aged 4-8 years) rated by their teacher as above the 'borderline cut-off' for concern on the Strengths and Difficulties Questionnaire, and their parents, will be recruited. Randomisation is by individual within blocks (schools); 1:1 ratio, intervention to waiting list control. Twenty schools will participate in two phases. Two teachers per school will deliver the programme to six intervention children for 2-hours/week for 18 weeks between baseline and first follow-up. The control children will receive the intervention after first follow up. Phase 1 comprises three data collection points - baseline and two follow-ups eight months apart. Phase 2 includes baseline and first follow-up.The Therapeutic Programme includes elements on; Learning school rules; understanding, identifying, and articulating feelings; problem solving; anger management; how to be friendly; how to do your best in school. Primary outcomes are; change in child social, emotional and behavioural difficulties. Secondary outcomes are; teacher and parent mental wellbeing, child academic attainment, child and teacher school attendance. Intervention delivery will be assessed for fidelity. Intention to treat analyses will be conducted. ANCOVA, effect sizes, mediator and moderator analyses will be applied to establish differences between conditions, and for whom the intervention works best for and why. DISCUSSION: This trial will provide information on the delivery and effectiveness of a child centred, school-based intervention delivered in small groups of children, at risk of developing more severe conduct problems. The effects on child behaviour in school and home environments, academic attainment, peer interactions, parent and teacher mental health will be assessed. TRIAL REGISTRATION: UK Clinical Research Network UKCRNID8615. Current Controlled Trials ISRCTN96803379. PMID- 21314914 TI - Control of viral replication after cessation of HAART. AB - We describe two patients who did not experience a viral rebound after cessation of HAART which was initiated for progressive disease. CD4 T-cell count remained stable in one patient and progressively declined in the other, despite apparent viral control. We failed to identify any immune activation or genetic markers that could offer an explanation for this unusual "secondary controller" status. But their viruses are clearly less fit compared to viruses from rebounders. PMID- 21314915 TI - Translational control of cyclins. AB - Regulation of cyclin levels is important for many cell cycle-related processes and can occur at several different steps of gene expression. Translational regulation of cyclins, which occurs by a variety of regulatory mechanisms, permits a prompt response to signal transduction pathways induced by environmental stimuli. This review will summarize translational control of cyclins and its influence on cell cycle progression. PMID- 21314916 TI - Under-utilization of health care services for infectious diseases syndromes in rural Azerbaijan: a cross-sectional study. AB - BACKGROUND: Infectious diseases present a potentially substantial yet undefined burden on the health of the adult Azerbaijani population. Efforts to quantify this burden in Azerbaijan are currently based almost exclusively on passive disease surveillance, and therefore hinge on the health utilization practices of the population. Understanding the prevalence of infectious syndromes and health utilization practices is paramount to disease surveillance, public health planning, and health care system reform. METHODS: A two-stage, probability proportional to size sampling design was used to select a representative sample of three regions of northern Azerbaijan with village populations less than 500 people. Demographic, clinical, and epidemiologic parameters were assessed using prevalence odds ratios, chi-squared, and the Fisher exact test. Associations with p < 0.10 were included in the regression analysis and removed by backward elimination. Respondents included 796 adults from 39 villages. RESULTS: Self medication with antibiotics was the predominant utilization practice reported (19.4%). Only 1.3% of respondents reported seeing a health care provider for an infection, and 3.4% missed work or stayed in bed during the day in the last 5 years. In contrast, 338 illness episodes were reported in a 5 year period. Antibiotic use was significantly associated with gender, region, history of febrile illness, sleep disturbances, and arthritis controlling for age, ethnicity, and education. Influenza-like illness was the most prevalent infectious syndrome reported (33.3%). CONCLUSIONS: We observed a remarkably low utilization of health services, despite reported symptoms that would merit use. Widespread availability of antibiotics may deter health care use, and may contribute to the development of antibiotic resistance in this population. Information on utilization of health services during an infection is essential for development of effective intervention strategies, and data on the prevalence of infectious syndromes provides information not otherwise available in populations with low health care utilization. PMID- 21314917 TI - Molecular mechanisms for the destabilization and restabilization of reactivated spatial memory in the Morris water maze. AB - BACKGROUND: Memory retrieval is not a passive process. Recent studies have shown that reactivated memory is destabilized and then restabilized through gene expression-dependent reconsolidation. Molecular studies on the regulation of memory stability after retrieval have focused almost exclusively on fear memory, especially on the restabilization process of the reactivated fear memory. We previously showed that, similarly with fear memories, reactivated spatial memory undergoes reconsolidation in the Morris water maze. However, the underlying molecular mechanisms by which reactivated spatial memory is destabilized and restabilized remain poorly understood. In this study, we investigated the molecular mechanism that regulates the stability of the reactivated spatial memory. RESULTS: We first showed that pharmacological inactivation of the N methyl-D-aspartate glutamate receptor (NMDAR) in the hippocampus or genetic inhibition of cAMP-responsible element binding protein (CREB)-mediated transcription disrupted reactivated spatial memory. Finally, we showed that pharmacological inhibition of cannabinoid receptor 1 (CB1) and L-type voltage gated calcium channels (LVGCCs) in the hippocampus blocked the disruption of the reactivated spatial memory by the inhibition of protein synthesis. CONCLUSIONS: Our findings indicated that the reactivated spatial memory is destabilized through the activation of CB1 and LVGCCs and then restabilized through the activation of NMDAR- and CREB-mediated transcription. We also suggest that the reactivated spatial memory undergoes destabilization and restabilization in the hippocampus, through similar molecular processes as those for reactivated contextual fear memories, which require CB1 and LVGCCs for destabilization and NMDAR and CREB for restabilization. PMID- 21314918 TI - Repression of btuB gene transcription in Escherichia coli by the GadX protein. AB - BACKGROUND: BtuB (B twelve uptake) is an outer membrane protein of Escherichia coli. It serves as a receptor for cobalamines uptake or bactericidal toxin entry. A decrease in the production of the BtuB protein would cause E. coli to become resistant to colicins. The production of BtuB has been shown to be regulated at the post-transcriptional level. The secondary structure of 5' untranslated region of btuB mRNA and the intracellular concentration of adenosylcobalamin (Ado-Cbl) would affect the translational efficiency and RNA stability of btuB gene. The transcriptional regulation of btuB expression is still unclear. RESULTS: To determine whether the btuB gene is also transcriptionally controlled by trans acting factors, a genomic library was screened for clones that enable E. coli to grow in the presence of colicin E7, and a plasmid carrying gadX and gadY genes was isolated. The lacZ reporter gene assay revealed that these two genes decreased the btuB promoter activity by approximately 50%, and the production of the BtuB protein was reduced by approximately 90% in the presence of a plasmid carrying both gadX and gadY genes in E. coli as determined by Western blotting. Results of electrophoretic mobility assay and DNase I footprinting indicated that the GadX protein binds to the 5' untranslated region of the btuB gene. Since gadX and gadY genes are more highly expressed under acidic conditions, the transcriptional level of btuB in cells cultured in pH 7.4 or pH 5.5 medium was examined by quantitative real-time PCR to investigate the effect of GadX. The results showed the transcription of gadX with 1.4-fold increase but the level of btuB was reduced to 57%. CONCLUSIONS: Through biological and biochemical analysis, we have demonstrated the GadX can directly interact with btuB promoter and affect the expression of btuB. In conclusion, this study provides the first evidence that the expression of btuB gene is transcriptionally repressed by the acid responsive genes gadX and gadY. PMID- 21314919 TI - Management of cardiovascular risk factors with pioglitazone combination therapies in type 2 diabetes: an observational cohort study. AB - BACKGROUND: Type 2 diabetes (T2D) is strongly associated with cardiovascular risk and requires medications that improve glycemic control and other cardiovascular risk factors. The authors aimed to assess the relative effectiveness of pioglitazone (Pio), metformin (Met) and any sulfonylurea (SU) combinations in non insulin-treated T2D patients who were failing previous hypoglycemic therapy. METHODS: Over a 1-year period, two multicenter, open-labeled, controlled, 1-year, prospective, observational studies evaluated patients with T2D (n = 4585) from routine clinical practice in Spain and Greece with the same protocol. Patients were eligible if they had been prescribed Pio + SU, Pio + Met or SU + Met serving as a control cohort, once they had failed with previous therapy. Anthropometric measurements, lipid and glycemic profiles, blood pressure, and the proportions of patients at microvascular and macrovascular risk were assessed. RESULTS: All study treatment combinations rendered progressive 6-month and 12-month lipid, glycemic, and blood pressure improvements. Pio combinations, especially Pio + Met, were associated with increases in HDL-cholesterol and decreases in triglycerides and in the atherogenic index of plasma. The proportion of patients at high risk decreased after 12 months in all study cohorts. Minor weight changes (gain or loss) and no treatment-related fractures occurred during the study. The safety profile was good and proved similar among treatments, except for more hypoglycemic episodes in patients receiving SU and for the occurrence of edema in patients using Pio combinations. Serious cardiovascular events were rarely reported. CONCLUSIONS: In patients with T2D failing prior hypoglycemic therapies, Pio combinations with SU or Met (especially Pio + Met) improved blood lipid and glycemic profiles, decreasing the proportion of patients with a high microvascular or macrovascular risk. The combination of Pio with SU or Met may therefore be recommended for T2D second-line therapy in the routine clinical practice, particularly in patients with dyslipidemia. PMID- 21314920 TI - Cost-effectiveness of cognitive behaviour therapy versus talking and usual care for depressed older people in primary care. AB - BACKGROUND: Whilst evidence suggests cognitive behaviour therapy (CBT) may be effective for depressed older people in a primary care setting, few studies have examined its cost-effectiveness. The aim of this study was to compare the cost effectiveness of cognitive behaviour therapy (CBT), a talking control (TC) and treatment as usual (TAU), delivered in a primary care setting, for older people with depression. METHODS: Cost data generated from a single blind randomised controlled trial of 204 people aged 65 years or more were offered only Treatment as Usual, or TAU plus up to twelve sessions of CBT or a talking control is presented. The Beck Depression Inventory II (BDI-II) was the main outcome measure for depression. Direct treatment costs were compared with reductions in depression scores. Cost-effectiveness analysis was conducted using non-parametric bootstrapping. The primary analysis focussed on the cost-effectiveness of CBT compared with TAU at 10 months follow up. RESULTS: Complete cost data were available for 198 patients at 4 and 10 month follow up. There were no significant differences between groups in baseline costs. The majority of health service contacts at follow up were made with general practitioners. Fewer contacts with mental health services were recorded in patients allocated to CBT, though these differences were not significant. Overall total per patient costs (including intervention costs) were significantly higher in the CBT group compared with the TAU group at 10 month follow up (difference L427, 95% CI: L56 - L787, p < 0.001). Reductions in BDI-II scores were significantly greater in the CBT group (difference 3.6 points, 95% CI: 0.7-6.5 points, p = 0.018). CBT is associated with an incremental cost of L120 per additional point reduction in BDI score and a 90% probability of being considered cost-effective if purchasers are willing to pay up to L270 per point reduction in the BDI-II score. CONCLUSIONS: CBT is significantly more costly than TAU alone or TAU plus TC, but more clinically effective. Based on current estimates, CBT is likely to be recommended as a cost effective treatment option for this patient group if the value placed on a unit reduction in BDI-II is greater than L115. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN18271323. PMID- 21314921 TI - Thrombocytopenia in neonates and the risk of intraventricular hemorrhage: a retrospective cohort study. AB - BACKGROUND: The overall prevalence of thrombocytopenia in neonates admitted to neonatal intensive care units ranges from 22 to 35%. There are only a few small studies that outline the relationship between the severity of thrombocytopenia and the risk of bleeding. This makes it difficult to form an evidence-based threshold for platelet transfusions in neonatal patients. The aim of this study was to determine the prevalence of thrombocytopenia in a tertiary neonatal intensive care unit and to study the relation between thrombocytopenia and the risk of intraventricular hemorrhage (IVH). METHODS: We performed a retrospective cohort study of all patients with thrombocytopenia admitted to our neonatal tertiary care nursery between January 2006 and December 2008. Patients were divided into 4 groups according to the severity of thrombocytopenia: mild (100 149 * 109/L), moderate (50-99 * 109/L), severe (30-49 * 109/L) or very severe (< 30 * 109/L). The primary outcome was IVH >= grade 2. Pearson's chi-squared and Fischer's exact tests were used for categorical data. ANOVA, logistic regression analysis and multivariate linear regression were used for comparisons between groups and for confounding factors. RESULTS: The prevalence of thrombocytopenia was 27% (422/1569). Risk of IVH >= grade 2 was 12% (48/411) in neonates with versus 5% (40/844) in neonates without thrombocytopenia (p < 0.01). After multivariate linear regression analysis, risk of IVH >= grade 2 in the subgroups of thrombocytopenic infants was not significantly different (p = 0.3).After logistic regression analysis the difference in mortality rate in neonates with and without thrombocytopenia was not significant (p = 0.4). Similarly, we found no difference in mortality rate in the subgroups of neonates with thrombocytopenia (p = 0.7). CONCLUSION: Although IVH >= grade 2 occurs more often in neonates with thrombocytopenia, this relation is independent of the severity of thrombocytopenia. Prospective studies should be conducted to assess the true risk of hemorrhage depending on underlying conditions. Randomized controlled trials are urgently needed to determine a safe lower threshold for platelet transfusions. PMID- 21314923 TI - Genetic components of grey cattle in Estonia as revealed by microsatellite analysis using two Bayesian clustering methods. AB - BACKGROUND: It was recently postulated that a few individual grey cattle still found in Estonia might be a relict of the old native cattle stock. Genotypes at 17 microsatellite loci from a total of 243 cattle from North European breeds and 11 grey cattle in Estonia were used in an attempt to clarify the genetic composition of the grey cattle. FINDINGS: We characterize the genetic components of 11 examples of the grey cattle in Estonia at the population and individual levels. Our results show that the grey cattle in Estonia are most genetically similar to the Holstein-Friesian breed and secondarily to the Estonian Red cattle. CONCLUSIONS: Both Bayesian approaches gave similar results in terms of the identification of numbers of clusters and the estimation of proportions of genetic components. This study suggested that the Estonian grey cattle included in the analysis are a genetic composite resulting from cross-breeding of European dairy breeds. PMID- 21314922 TI - Development of a new version of the Liverpool Malaria Model. I. Refining the parameter settings and mathematical formulation of basic processes based on a literature review. AB - BACKGROUND: A warm and humid climate triggers several water-associated diseases such as malaria. Climate- or weather-driven malaria models, therefore, allow for a better understanding of malaria transmission dynamics. The Liverpool Malaria Model (LMM) is a mathematical-biological model of malaria parasite dynamics using daily temperature and precipitation data. In this study, the parameter settings of the LMM are refined and a new mathematical formulation of key processes related to the growth and size of the vector population are developed. METHODS: One of the most comprehensive studies to date in terms of gathering entomological and parasitological information from the literature was undertaken for the development of a new version of an existing malaria model. The knowledge was needed to allow the justification of new settings of various model parameters and motivated changes of the mathematical formulation of the LMM. RESULTS: The first part of the present study developed an improved set of parameter settings and mathematical formulation of the LMM. Important modules of the original LMM version were enhanced in order to achieve a higher biological and physical accuracy. The oviposition as well as the survival of immature mosquitoes were adjusted to field conditions via the application of a fuzzy distribution model. Key model parameters, including the mature age of mosquitoes, the survival probability of adult mosquitoes, the human blood index, the mosquito-to-human (human-to-mosquito) transmission efficiency, the human infectious age, the recovery rate, as well as the gametocyte prevalence, were reassessed by means of entomological and parasitological observations. This paper also revealed that various malaria variables lack information from field studies to be set properly in a malaria modelling approach. CONCLUSIONS: Due to the multitude of model parameters and the uncertainty involved in the setting of parameters, an extensive literature survey was carried out, in order to produce a refined set of settings of various model parameters. This approach limits the degrees of freedom of the parameter space of the model, simplifying the final calibration of undetermined parameters (see the second part of this study). In addition, new mathematical formulations of important processes have improved the model in terms of the growth of the vector population. PMID- 21314925 TI - Assessment of epicutaneous testing of a monovalent Influenza A (H1N1) 2009 vaccine in egg allergic patients. AB - BACKGROUND: H1N1 is responsible for the first influenza pandemic in 41 years. In the fall of 2009, an H1N1 vaccine became available in Canada with the hopes of reducing the overall effect of the pandemic. The purpose of this study was to assess the safety of administering 2 different doses of a monovalent split virus 2009 H1N1 vaccine in egg allergic patients. METHODS: Patients were skin tested to the H1N1 vaccine in the outpatient paediatric and adult allergy and immunology clinics of the Health Sciences Centre and Children's Hospital of Winnipeg, Manitoba Canada. Individuals <9 years of age were administered 1.88 MUg's of hem agglutinin antigen per 0.25 ml dose and individuals >=9 years were administered 3.75 MUg's of hemagglutinin antigen per 0.5 ml dose. Upon determination of a negative skin test, the vaccine was administered with a 30 minute observation period. RESULTS: A total of 61 patients with egg allergy (history of an allergic reaction to egg with either positive skin test &/or specific IgE to egg >0.35 Ku/L) were referred to our allergy clinics for skin testing to the H1N1 vaccine. 2 patients were excluded, one did not have a skin prick test to the H1N1 vaccine (only vaccine administration) and the other passed an egg challenge during the study period. Ages ranged from 1 to 27 years (mean 5.6 years). There were 41(69.5%) males and 18(30.5%) females. All but one patient with a history of egg allergy, positive skin test to egg and/or elevated specific IgE level to egg had negative skin tests to the H1N1 vaccine. The 58 patients with negative skin testing to the H1N1 vaccine were administered the vaccine and observed for 30 minutes post vaccination with no adverse results. The patient with the positive skin test to the H1N1 vaccine was also administered the vaccine intramuscularly with no adverse results. CONCLUSIONS: Despite concern regarding possible anaphylaxis to the H1N1 vaccine in egg allergic patients, in our case series 1/59(1.7%) patients with sensitization to egg were also sensitized to the H1N1 vaccine. Administration of the H1N1 vaccine in egg allergic patients with negative H1N1 skin tests and observation is safe. Administering the vaccine in a 1 or 2 dose protocol without skin testing is a reasonable alternative as per the CSACI guidelines. PMID- 21314924 TI - Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. AB - BACKGROUND: Bronchial thermoplasty (BT) is a bronchoscopic procedure that improves asthma control by reducing excess airway smooth muscle. Treated patients have been followed out to 5 years to evaluate long-term safety of this procedure. METHODS: Patients enrolled in the Asthma Intervention Research Trial were on inhaled corticosteroids >=200 MUg beclomethasone or equivalent + long-acting beta2-agonists and demonstrated worsening of asthma on long-acting-beta2-agonist withdrawal. Following initial evaluation at 1 year, subjects were invited to participate in a 4 year safety study. Adverse events (AEs) and spirometry data were used to assess long-term safety out to 5 years post-BT. RESULTS: 45 of 52 treated and 24 of 49 control group subjects participated in long-term follow-up of 5 years and 3 years respectively. The rate of respiratory adverse events (AEs/subject) was stable in years 2 to 5 following BT (1.2, 1.3, 1.2, and 1.1, respectively,). There was no increase in hospitalizations or emergency room visits for respiratory symptoms in Years 2, 3, 4, and 5 compared to Year 1. The FVC and FEV1 values showed no deterioration over the 5 year period in the BT group. Similar results were obtained for the Control group. CONCLUSIONS: The absence of clinical complications (based on AE reporting) and the maintenance of stable lung function (no deterioration of FVC and FEV1) over a 5-year period post BT in this group of patients with moderate to severe asthma support the long-term safety of the procedure out to 5 years. PMID- 21314926 TI - The functional expression of extracellular calcium-sensing receptor in rat pulmonary artery smooth muscle cells. AB - BACKGROUND: The extracellular calcium-sensing receptor (CaSR) belongs to family C of the G protein coupled receptors. Whether the CaSR is expressed in the pulmonary artery (PA) is unknown. METHODS: The expression and distribution of CaSR were detected by RT-PCR, Western blotting and immunofluorescence. PA tension was detected by the pulmonary arterial ring technique, and the intracellular calcium concentration ([Ca2+]i) was detected by a laser-scanning confocal microscope. RESULTS: The expressions of CaSR mRNA and protein were found in both rat pulmonary artery smooth muscle cells (PASMCs) and PAs. Increased levels of [Ca2+]o (extracellular calcium concentration) or Gd3+ (an agonist of CaSR) induced an increase of [Ca2+]i and PAs constriction in a concentration-dependent manner. In addition, the above-mentioned effects of Ca2+ and Gd3+ were inhibited by U73122 (specific inhibitor of PLC), 2-APB (specific antagonist of IP3 receptor), and thapsigargin (blocker of sarcoplasmic reticulum calcium ATPase). CONCLUSIONS: CaSR is expressed in rat PASMCs, and is involved in regulation of PA tension by increasing [Ca2+]i through G-PLC-IP3 pathway. PMID- 21314927 TI - A comparative study of clinical manifestations, haematological and serological responses after experimental infection with Anaplasma phagocytophilum in two Norwegian sheep breeds. AB - BACKGROUND: It has been questioned if the old native Norwegian sheep breed, Old Norse Sheep (also called Norwegian Feral Sheep), normally distributed on coastal areas where ticks are abundant, is more protected against tick-borne infections than other Norwegian breeds due to a continuously high selection pressure on pasture. The aim of the present study was to test this hypothesis in an experimental infection study. METHODS: Five-months-old lambs of two Norwegian sheep breeds, Norwegian White (NW) sheep and Old Norse (ON) sheep, were experimentally infected with a 16S rRNA genetic variant of Anaplasma phagocytophilum (similar to GenBank accession number M73220). The experiment was repeated for two subsequent years, 2008 and 2009, with the use of 16 lambs of each breed annually. Ten lambs of each breed were inoculated intravenously each year with 0.4 ml A. phagocytophilum-infected blood containing approximately 0.5 * 106 infected neutrophils/ml. Six lambs of each breed were used as uninfected controls. Half of the primary inoculated lambs in each breed were re-challenged with the same infectious dose at nine (2008) and twelve (2009) weeks after the first challenge. The clinical, haematological and serological responses to A. phagocytophilum infection were compared in the two sheep breeds. RESULTS: The present study indicates a difference in fever response and infection rate between breeds of Norwegian sheep after experimental infection with A. phagocytophilum. CONCLUSION: Although clinical response seems to be less in ON-lambs compared to NW-lambs, further studies including more animals are needed to evaluate if the ON breed is more protected against tick-borne infections than other Norwegian breeds. PMID- 21314928 TI - Expression of K2P5.1 potassium channels on CD4+ T lymphocytes correlates with disease activity in rheumatoid arthritis patients. AB - INTRODUCTION: CD4+ T cells express K(2P)5.1 (TWIK-related acid-sensitive potassium channel 2 (TASK2); KCNK5), a member of the two-pore domain potassium channel family, which has been shown to influence T cell effector functions. Recently, it was shown that K(2P)5.1 is upregulated upon (autoimmune) T cell stimulation. The aim of this study was to correlate expression levels of K(2P)5.1 on T cells from patients with rheumatoid arthritis (RA) to disease activity in these patients. METHODS: Expression levels of K(2P)5.1 were measured by RT-PCR in the peripheral blood of 58 patients with RA and correlated with disease activity parameters (C-reactive protein levels, erythrocyte sedimentation rates, disease activity score (DAS28) scores). Twenty patients undergoing therapy change were followed-up for six months. Additionally, synovial fluid and synovial biopsies were investigated for T lymphocytes expressing K(2P)5.1. RESULTS: K(2P)5.1 expression levels in CD4+ T cells show a strong correlation to DAS28 scores in RA patients. Similar correlations were found for serological inflammatory parameters (erythrocyte sedimentation rate, C-reactive protein). In addition, K(2P)5.1 expression levels of synovial fluid-derived T cells are higher compared to peripheral blood T cells. Prospective data in individual patients show a parallel behaviour of K(2P)5.1 expression to disease activity parameters during a longitudinal follow-up for six months. CONCLUSIONS: Disease activity in RA patients correlates strongly with K(2P)5.1 expression levels in CD4+ T lymphocytes in the peripheral blood in cross-sectional as well as in longitudinal observations. Further studies are needed to investigate the exact pathophysiological mechanisms and to evaluate the possible use of K(2P)5.1 as a potential biomarker for disease activity and differential diagnosis. PMID- 21314929 TI - Imprisoned and imperiled: access to HIV and TB prevention and treatment, and denial of human rights, in Zambian prisons. AB - BACKGROUND: Although HIV and tuberculosis (TB) prevalence are high in prisons throughout sub-Saharan Africa, little research has been conducted on factors related to prevention, testing and treatment services. METHODS: To better understand the relationship between prison conditions, the criminal justice system, and HIV and TB in Zambian prisons, we conducted a mixed-method study, including: facility assessments and in-depth interviews with 246 prisoners and 30 prison officers at six Zambian prisons; a review of Zambian legislation and policy governing prisons and the criminal justice system; and 46 key informant interviews with government and non-governmental organization officials and representatives of international agencies and donors. RESULTS: The facility assessments, in-depth interviews and key informant interviews found serious barriers to HIV and TB prevention and treatment, and extended pre-trial detention that contributed to overcrowded conditions. Disparities both between prisons and among different categories of prisoners within prisons were noted, with juveniles, women, pre-trial detainees and immigration detainees significantly less likely to access health services. CONCLUSIONS: Current conditions and the lack of available medical care in Zambia's prisons violate human rights protections and threaten prisoners' health. In order to protect the health of prisoners, prison-based health services, linkages to community-based health care, general prison conditions and failures of the criminal justice system that exacerbate overcrowding must be immediately improved. International donors should work with the Zambian government to support prison and justice system reform and ensure that their provision of funding in such areas as health services respect human rights standards, including non-discrimination. Human rights protections against torture and cruel, inhuman or degrading treatment, and criminal justice system rights, are essential to curbing the spread of HIV and TB in Zambian prisons, and to achieving broader goals to reduce HIV and TB in Zambia. PMID- 21314930 TI - Blood transfusion during cardiac surgery is associated with inflammation and coagulation in the lung: a case control study. AB - INTRODUCTION: Blood transfusion is associated with increased morbidity and mortality in cardiac surgery patients, but cause-and-effect relations remain unknown. We hypothesized that blood transfusion is associated with changes in pulmonary and systemic inflammation and coagulation occurring in patients who do not meet the clinical diagnosis of transfusion-related acute lung injury (TRALI). METHODS: We performed a case control study in a mixed medical-surgical intensive care unit of a university hospital in the Netherlands. Cardiac surgery patients (n = 45) were grouped as follows: those who received no transfusion, those who received a restrictive transfusion (one two units of blood) or those who received multiple transfusions (at least five units of blood). Nondirected bronchoalveolar lavage fluid (BALF) and blood were obtained within 3 hours postoperatively. Normal distributed data were analyzed using analysis of variance and Dunnett's post hoc test. Nonparametric data were analyzed using the Kruskal-Wallis and Mann Whitney U tests. RESULTS: Restrictive transfusion increased BALF levels of interleukin (IL)-1beta and D-dimer compared to nontransfused controls (P < 0.05 for all), and IL-1beta levels were further enhanced by multiple transfusions (P < 0.01). BALF levels of IL-8, tumor necrosis factor alpha (TNFalpha) and thrombin antithrombin complex (TATc) were increased after multiple transfusions (P < 0.01, P < 0.001 and P < 0.01, respectively) compared to nontransfused controls, but not after restrictive transfusions. Restrictive transfusions were associated with increased pulmonary levels of plasminogen activator inhibitor 1 compared to nontransfused controls with a further increase after multiple transfusions (P < 0.001). Concomitantly, levels of plasminogen activator activity (PAA%) were lower (P < 0.001), indicating impaired fibrinolysis. In the systemic compartment, transfusion was associated with a significant increase in levels of TNFalpha, TATc and PAA% (P < 0.05). CONCLUSIONS: Transfusion during cardiac surgery is associated with activation of inflammation and coagulation in the pulmonary compartment of patients who do not meet TRALI criteria, an effect that was partly dose-dependent, suggesting transfusion as a mediator of acute lung injury. These pulmonary changes were accompanied by systemic derangement of coagulation. PMID- 21314931 TI - beta-Thymosins and interstitial lung disease: study of a scleroderma cohort with a one-year follow-up. AB - BACKGROUND: beta-thymosins play roles in cytoskeleton rearrangement, angiogenesis, fibrosis and reparative process, thus suggesting a possible involvement in the pathogenesis of systemic sclerosis. The aim of the study was to investigate the presence of thymosins beta4, beta4 sulfoxide, and beta10 in bronchoalveolar lavage fluid of scleroderma patients with interstitial lung disease and the relation of these factors with pulmonary functional and radiological parameters. METHODS: beta-thymosins concentrations were determined by reverse phase-high performance liquid chromatography-electrospray-mass spectrometry in the bronchoalveolar lavage fluid of 46 scleroderma patients with lung involvement and of 15 controls. RESULTS: Thymosin beta4, beta4 sulfoxide, and beta10 were detectable in bronchoalveolar lavage fluid of patients and controls. Thymosin beta4 levels were significantly higher in scleroderma patients than in controls. In addition, analyzing the progression of scleroderma lung disease at one-year follow-up, we have found that higher thymosin beta4 levels seem to have a protective role against lung tissue damage. Thymosin beta4 sulfoxide levels were higher in the smokers and in the scleroderma patients with alveolitis. CONCLUSIONS: We describe for the first time beta-thymosins in bronchoalveolar lavage fluid and their possible involvement in the pathogenesis of scleroderma lung disease. Thymosin beta4 seems to have a protective role against lung tissue damage, while its oxidation product mirrors an alveolar inflammatory status. PMID- 21314932 TI - Ambulatory oxygen: why do COPD patients not use their portable systems as prescribed? A qualitative study. AB - BACKGROUND: Patients with COPD on long term oxygen therapy frequently do not adhere to their prescription, and they frequently do not use their ambulatory oxygen systems as intended. Reasons for this lack of adherence are not known. The aim of this study was to obtain in-depth information about perceptions and use of prescribed ambulatory oxygen systems from patients with COPD to inform ambulatory oxygen design, prescription and management. METHODS: A qualitative design was used, involving semi-structured face-to-face interviews informed by a grounded theory approach. Twenty-seven UK community-dwelling COPD patients using NHS prescribed ambulatory systems were recruited. Ambulatory oxygen systems comprised cylinders weighing 3.4 kg, a shoulder bag and nasal cannulae. RESULTS: Participants reported that they: received no instruction on how to use ambulatory oxygen; were uncertain of the benefits; were afraid the system would run out while they were using it (due to lack of confidence in the cylinder gauge); were embarrassed at being seen with the system in public; and were unable to carry the system because of the cylinder weight. The essential role of carers was also highlighted, as participants with no immediate carers did not use ambulatory oxygen outside the house. CONCLUSIONS: These participants highlighted previously unreported problems that prevented them from using ambulatory oxygen as prescribed. Our novel findings point to: concerns with the lack of specific information provision; the perceived unreliability of the oxygen system; important carer issues surrounding managing and using ambulatory oxygen equipment. All of these issues, as well as previously reported problems with system weight and patient embarrassment, should be addressed to improve adherence to ambulatory oxygen prescription and enhance the physical and social benefits of maintaining mobility in this patient group. Increased user involvement in both system development and service provision planning, could have avoided many of the difficulties highlighted by this study. PMID- 21314933 TI - Antibodies against Coxiella burnetii and pregnancy outcome during the 2007-2008 Q fever outbreaks in The Netherlands. AB - BACKGROUND: Q fever has become a major public health problem in The Netherlands. Infection with Coxiella burnetii (Q fever) during pregnancy has resulted in adverse pregnancy outcome in the majority of reported cases. Therefore, we aimed to quantify this risk by examining the earliest periods corresponding to the epidemic in The Netherlands. METHODS: Serum samples that had been collected from the area of highest incidence by an existing national prenatal screening programme and data from the Netherlands Perinatal Registry (PRN) on diagnosis and outcome were used. We performed indirect immunofluorescence assay to detect the presence of IgM and IgG antibodies against C. burnetii in the samples. The serological results were analyzed to determine statistical association with recorded pregnancy outcome. RESULTS: Evaluation of serological results for 1174 women in the PRN indicated that the presence of IgM and IgG antibodies against phase II of C. burnetii was not significantly associated with preterm delivery, low birth weight, or several other outcome measures. CONCLUSION: The present population-based study showed no evidence of adverse pregnancy outcome among women who had antibodies to C. burnetii during early pregnancy. PMID- 21314934 TI - Subacute herpes simplex virus type 1 encephalitis as an initial presentation of chronic lymphocytic leukemia and multiple sclerosis: a case report. AB - INTRODUCTION: Herpes simplex virus type 1 encephalitis presents acutely in patients who are immunocompetent. We report what we believe to be the first published case of a subacute course of herpes simplex virus type 1 encephalitis in a patient with asymptomatic chronic lymphocytic leukemia who subsequently developed multiple sclerosis. CASE PRESENTATION: A 49-year-old Caucasian woman with a history of fever blisters presented to the emergency department with a history of left temporal headache for four weeks, and numbness of the left face and leg for two weeks. A complete blood count revealed white blood cell count of 11,820 cells/mL, with an absolute lymphocyte count of 7304 cells/mL. The cerebrospinal fluid contained 6 white blood cells/MUL, 63 red blood cells/MUL, 54 mg glucose/dL, and 49 mg total protein/dL. Magnetic resonance imaging of the brain revealed meningoencephalitis and bilateral ventriculitis. Cerebrospinal fluid polymerase chain reaction for herpes simplex virus type 1 was positive, and the patient's symptoms resolved after ten days of treatment with parenteral aciclovir. Incidental findings on peripheral blood smear and flow cytometry testing confirmed chronic lymphocytic leukemia. One month later, she developed bilateral numbness of the hands and feet; a repeat cerebrospinal fluid polymerase chain reaction for herpes simplex virus type 1 at this time was negative. A repeat magnetic resonance imaging scan showed an expansion of the peri ventricular lesions, and the cerebrospinal fluid contained elevated oligoclonal bands and myelin basic protein. A brain biopsy revealed gliosis consistent with multiple sclerosis, and the patient responded to treatment with high-dose parenteral steroids. CONCLUSION: Herpes simplex virus type 1 encephalitis is a rare presentation of chronic lymphocytic leukemia. Our patient had an atypical, subacute course, presumably due to immunosuppression from chronic lymphocytic leukemia. This unusual case of herpes simplex virus type 1 encephalitis emphasizes the importance of T cell function in diseases of immune dysregulation and autoimmunity such as chronic lymphocytic leukemia and multiple sclerosis. It raises the question of whether atypical presentations of herpes simplex virus encephalitis warrant deliberations on immunocompetence. The development of multiple sclerosis in our patient so soon after she received treatment for herpes simplex virus type 1 encephalitis raises the possibility that herpes simplex virus type 1 encephalitis in an immunosuppressed patient may trigger multiple sclerosis. PMID- 21314935 TI - Patterns of unexpected in-hospital deaths: a root cause analysis. AB - BACKGROUND: Respiratory alarm monitoring and rapid response team alerts on hospital general floors are based on detection of simple numeric threshold breaches. Although some uncontrolled observation trials in select patient populations have been encouraging, randomized controlled trials suggest that this simplistic approach may not reduce the unexpected death rate in this complex environment. The purpose of this review is to examine the history and scientific basis for threshold alarms and to compare thresholds with the actual pathophysiologic patterns of evolving death which must be timely detected. METHODS: The Pubmed database was searched for articles relating to methods for triggering rapid response teams and respiratory alarms and these were contrasted with the fundamental timed pathophysiologic patterns of death which evolve due to sepsis, congestive heart failure, pulmonary embolism, hypoventilation, narcotic overdose, and sleep apnea. RESULTS: In contrast to the simplicity of the numeric threshold breach method of generating alerts, the actual patterns of evolving death are complex and do not share common features until near death. On hospital general floors, unexpected clinical instability leading to death often progresses along three distinct patterns which can be designated as Types I, II and III. Type I is a pattern comprised of hyperventilation compensated respiratory failure typical of congestive heart failure and sepsis. Here, early hyperventilation and respiratory alkalosis can conceal the onset of instability. Type II is the pattern of classic CO2 narcosis. Type III occurs only during sleep and is a pattern of ventilation and SPO2 cycling caused by instability of ventilation and/or upper airway control followed by precipitous and fatal oxygen desaturation if arousal failure is induced by narcotics and/or sedation. CONCLUSION: The traditional threshold breach method of detecting instability on hospital wards was not scientifically derived; explaining the failure of threshold based monitoring and rapid response team activation in randomized trials. Furthermore, the thresholds themselves are arbitrary and capricious. There are three common fundamental pathophysiologic patterns of unexpected hospital death. These patterns are too complex for early detection by any unifying numeric threshold. New methods and technologies which detect and identify the actual patterns of evolving death should be investigated. PMID- 21314936 TI - Neuropathic Nav1.3-mediated sensitization to P2X activation is regulated by protein kinase C. AB - BACKGROUND: Increased neuronal excitability and spontaneous firing are hallmark characteristics of injured sensory neurons. Changes in expression of various voltage-gated Na+ channels (VGSCs) have been observed under neuropathic conditions and there is evidence for the involvement of protein kinase C (PKC) in sensory hyperexcitability. Here we demonstrate the contribution of PKC to P2X evoked VGSC activation in dorsal root ganglion (DRG) neurons in neuropathic conditions. RESULTS: Using the spinal nerve ligation (SNL) model of neuropathic pain and whole-cell patch clamp recordings of dissociated DRG neurons, we examined changes in excitability of sensory neurons after nerve injury and observed that P2X3 purinoceptor-mediated currents induced by alpha,beta-meATP triggered activation of TTX-sensitive VGSCs in neuropathic nociceptors only. Treatment of neuropathic DRGs with the PKC blocker staurosporine or calphostin C decreased the alpha,beta-meATP-induced Na+ channels activity and reversed neuronal hypersensitivity. In current clamp mode, alpha,beta-meATP was able to evoke action-potentials more frequently in neuropathic neurons than in controls. Pretreatment with calphostin C significantly decreased the proportion of sensitized neurons that generated action potentials in response to alpha,beta meATP. Recordings measuring VGSC activity in neuropathic neurons show significant change in amplitude and voltage dependence of sodium currents. In situ hybridization data indicate a dramatic increase in expression of embryonic Nav1.3 channels in neuropathic DRG neurons. In a CHO cell line stably expressing the Nav1.3 subunit, PKC inhibition caused both a significant shift in voltage dependence of the channel in the depolarizing direction and a decrease in current amplitude. CONCLUSION: Neuropathic injury causes primary sensory neurons to become hyperexcitable to ATP-evoked P2X receptor-mediated depolarization, a phenotypic switch sensitive to PKC modulation and mediated by increased activity of TTX-sensitive VGSCs. Upregulation in VGSC activity after injury is likely mediated by increased expression of the Nav1.3 subunit, and the function of the Nav1.3 channel is regulated by PKC. PMID- 21314937 TI - Identification of early molecular markers for breast cancer. AB - BACKGROUND: The ductal carcinoma in situ (DCIS) of the mammary gland represents an early, pre-invasive stage in the development of invasive breast carcinoma. Since DCIS is a curable disease, it would be highly desirable to identify molecular markers that allow early detection. Mice transgenic for the WAP-SV40 early genome region were used as a model for DCIS development. Gene expression profiling was carried out on DCIS-bearing mice and control animals. Additionally, a set of human DCIS and invasive mammary tumors were analyzed in a similar fashion. Enhanced expression of these marker genes in human and murine samples was validated by quantitative RT-PCR. Besides, marker gene expression was also validated by immunohistochemistry of human samples. Furthermore in silico analyses using an online microarray database were performed. RESULTS: In DCIS mice seven genes were identified that were significantly up-regulated in DCIS: DEPDC1, NUSAP1, EXO1, RRM2, FOXM1, MUC1 and SPP1. A similar up-regulation of homologues of the murine genes was observed in human DCIS samples. Enhanced expression of these genes in DCIS and IDC (invasive ductal carcinoma) was validated by quantitative RT-PCR and immunohistochemistry. CONCLUSIONS: By comparing murine markers for the ductal carcinoma in situ (DCIS) of the mammary gland with genes up-regulated in human DCIS-samples we were able to identify a set of genes which might allow early detection of DCIS and invasive carcinomas in the future. The similarities between gene expression in DCIS and invasive carcinomas in our data suggest that the early detection and treatment of DCIS is of utmost relevance for the survival of patients who are at high risk of developing breast carcinomas. PMID- 21314938 TI - Auxin-inducible protein depletion system in fission yeast. AB - BACKGROUND: Inducible inactivation of a protein is a powerful approach for analysis of its function within cells. Fission yeast is a useful model for studying the fundamental mechanisms such as chromosome maintenance and cell cycle. However, previously published strategies for protein-depletion are successful only for some proteins in some specific conditions and still do not achieve efficient depletion to cause acute phenotypes such as immediate cell cycle arrest. The aim of this work was to construct a useful and powerful protein depletion system in Shizosaccaromyces pombe. RESULTS: We constructed an auxin inducible degron (AID) system, which utilizes auxin-dependent poly-ubiquitination of Aux/IAA proteins by SCFTIR1 in plants, in fission yeast. Although expression of a plant F-box protein, TIR1, decreased Mcm4-aid, a component of the MCM complex essential for DNA replication tagged with Aux/IAA peptide, depletion did not result in an evident growth defect. We successfully improved degradation efficiency of Mcm4-aid by fusion of TIR1 with fission yeast Skp1, a conserved F box-interacting component of SCF (improved-AID system; i-AID), and the cells showed severe defect in growth. The i-AID system induced degradation of Mcm4-aid in the chromatin-bound MCM complex as well as those in soluble fractions. The i AID system in conjunction with transcription repression (off-AID system), we achieved more efficient depletion of other proteins including Pol1 and Cdc45, causing early S phase arrest. CONCLUSION: Improvement of the AID system allowed us to construct conditional null mutants of S. pombe. We propose that the off-AID system is the powerful method for in vivo protein-depletion in fission yeast. PMID- 21314940 TI - Synthesis of some nucleosides derivatives from L- rhamnose with expected biological activity. AB - Practical procedures for production of variously blocked compounds from L rhamnose have been developed. These compounds are highly useful as indirect beta L-rhamnosyl donors. This approach represents a new method for the synthesis of aromatic nucleoside analogues and the synthesis of (3S, 4S, 5S, 6R) 3, 4, 5 triacetoxy-2-methyl-7,9-diaza-1-oxa-spiro [4,5]decane-10-one-8-thione (7). PMID- 21314939 TI - Distribution of interleukin-1 receptor complex at the synaptic membrane driven by interleukin-1beta and NMDA stimulation. AB - Interleukin-1beta (IL-1beta) is a pro-inflammatory cytokine that contributes to neuronal injury in various degenerative diseases, and is therefore a potential therapeutic target. It exerts its biological effect by activating the interleukin 1 receptor type I (IL-1RI) and recruiting a signalling core complex consisting of the myeloid differentiation primary response protein 88 (MyD88) and the IL-1R accessory protein (IL-1RAcP). This pathway has been clearly described in the peripheral immune system, but only scattered information is available concerning the molecular composition and distribution of its members in neuronal cells. The findings of this study show that IL-1RI and its accessory proteins MyD88 and IL 1RAcP are differently distributed in the hippocampus and in the subcellular compartments of primary hippocampal neurons. In particular, only IL-1RI is enriched at synaptic sites, where it co-localises with, and binds to the GluN2B subunit of NMDA receptors. Furthermore, treatment with NMDA increases IL-1RI interaction with NMDA receptors, as well as the surface expression and localization of IL-1RI at synaptic membranes. IL-1beta also increases IL-1RI levels at synaptic sites, without affecting the total amount of the receptor in the plasma membrane. Our results reveal for the first time the existence of a dynamic and functional interaction between NMDA receptor and IL-1RI systems that could provide a molecular basis for IL-1beta as a neuromodulator in physiological and pathological events relying on NMDA receptor activation. PMID- 21314941 TI - Identification of epigenetically regulated genes that predict patient outcome in neuroblastoma. AB - BACKGROUND: Epigenetic mechanisms such as DNA methylation and histone modifications are important regulators of gene expression and are frequently involved in silencing tumor suppressor genes. METHODS: In order to identify genes that are epigenetically regulated in neuroblastoma tumors, we treated four neuroblastoma cell lines with the demethylating agent 5-Aza-2'-deoxycytidine (5 Aza-dC) either separately or in conjunction with the histone deacetylase inhibitor trichostatin A (TSA). Expression was analyzed using whole-genome expression arrays to identify genes activated by the treatment. These data were then combined with data from genome-wide DNA methylation arrays to identify candidate genes silenced in neuroblastoma due to DNA methylation. RESULTS: We present eight genes (KRT19, PRKCDBP, SCNN1A, POU2F2, TGFBI, COL1A2, DHRS3 and DUSP23) that are methylated in neuroblastoma, most of them not previously reported as such, some of which also distinguish between biological subsets of neuroblastoma tumors. Differential methylation was observed for the genes SCNN1A (p < 0.001), PRKCDBP (p < 0.001) and KRT19 (p < 0.01). Among these, the mRNA expression of KRT19 and PRKCDBP was significantly lower in patients that have died from the disease compared with patients with no evidence of disease (fold change -8.3, p = 0.01 for KRT19 and fold change -2.4, p = 0.04 for PRKCDBP). CONCLUSIONS: In our study, a low methylation frequency of SCNN1A, PRKCDBP and KRT19 is significantly associated with favorable outcome in neuroblastoma. It is likely that analysis of specific DNA methylation will be one of several methods in future patient therapy stratification protocols for treatment of childhood neuroblastomas. PMID- 21314942 TI - Loss of function mutation in toll-like receptor-4 does not offer protection against obesity and insulin resistance induced by a diet high in trans fat in mice. AB - BACKGROUND: Toll-like receptor-4 (TLR4) triggers inflammatory signaling in response to microbial lipoploysaccharide. It has been reported that loss of TLR4 protected against saturated fat-induced inflammation and insulin resistance. It is not known whether loss of TLR4 function offers protection against trans fat (TF) induced obesity, inflammation, and insulin resistance. We investigated whether mice with loss of function mutation in TLR4 were resistant to TF-induced pathologies such as obesity, inflammation, hyperglycemia, and hyperinsulinemia. METHODS: C57BL/6j and C57BL/10 mice were cross bred to generate TLR4 mutant and wild type (WT). TLR4 mutant (n = 12) and WT (n = 12) mice were fed either low fat (LF) (13.5% fat energy) or high TF diets (60% fat energy) for 12 weeks. In vitro experiments were conducted on mouse macrophage cells (RAW 264.7 and J774A.1) to investigate whether elaidic (trans 18:1) or oleic acid (cis 18:1) would upregulate inflammatory markers. RESULTS: TLR4 mutant mice were ~26.4% heavier than WT mice. In both genotypes, mice that received TF diet were significantly heavier than those mice that received LF diet (P < 0.01). TLR4 mutant mice compared to WT mice had significantly higher fasting blood glucose, serum insulin, insulin resistance, serum leptin, and serum cholesterol when they received TF diet (P < 0.05). No upregulation of iNOS or COX2 in response to either elaidic or oleic acid in macrophage cells was observed. CONCLUSIONS: Loss of function mutation in TLR4 not only did not protect mice from TF-induced obesity, hyperglycemia, hyperinsulinemia, and hypercholesterolemia but also exacerbated the above pathologies suggesting that functional TLR4 is necessary in attenuating TF-induced deleterious effects. It is likely that TF induces pathologies through pathways independent of TLR4. PMID- 21314943 TI - Relapse according to antipsychotic treatment in schizophrenic patients: a propensity-adjusted analysis. AB - OBJECTIVE: To compare the rate of relapse as a function of antipsychotic treatment (monotherapy vs. polypharmacy) in schizophrenic patients over a 2-year period. METHODS: Using data from a multicenter cohort study conducted in France, we performed a propensity-adjusted analysis to examine the association between the rate of relapse over a 2-year period and antipsychotic treatment (monotherapy vs. polypharmacy). RESULTS: Our sample consisted in 183 patients; 50 patients (27.3%) had at least one period of relapse and 133 had no relapse (72.7%). Thirty eight (37.7) percent of the patients received polypharmacy. The most severely ill patients were given polypharmacy: the age at onset of illness was lower in the polypharmacy group (p = 0.03). Patients that received polypharmacy also presented a higher general psychopathology PANSS subscore (p = 0.04) but no statistically significant difference was found in the PANSS total score or the PANSS positive or negative subscales. These patients were more likely to be given prescriptions for sedative drugs (p < 0.01) and antidepressant medications (p = 0.03). Relapse was found in 23.7% of patients given monotherapy and 33.3% given polypharmacy (p = 0.16). After stratification according to quintiles of the propensity score, which eliminated all significant differences for baseline characteristics, antipsychotic polypharmacy was not statistically associated with an increase of relapse: HR = 1.686 (0.812; 2.505). CONCLUSION: After propensity score adjustment, antipsychotic polypharmacy is not statistically associated to an increase of relapse. Future randomised studies are needed to assess the impact of antipsychotic polypharmacy in schizophrenia. PMID- 21314944 TI - The effectiveness of antenatal care programmes to reduce infant mortality and preterm birth in socially disadvantaged and vulnerable women in high-income countries: a systematic review. AB - BACKGROUND: Infant mortality has shown a steady decline in recent years but a marked socioeconomic gradient persists. Antenatal care is generally thought to be an effective method of improving pregnancy outcomes, but the effectiveness of specific antenatal care programmes as a means of reducing infant mortality in socioeconomically disadvantaged and vulnerable groups of women has not been rigorously evaluated. METHODS: We conducted a systematic review, focusing on evidence from high income countries, to evaluate the effectiveness of alternative models of organising or delivering antenatal care to disadvantaged and vulnerable groups of women vs. standard antenatal care. We searched Medline, Embase, Cinahl, PsychINFO, HMIC, CENTRAL, DARE, MIDIRS and a number of online resources to identify relevant randomised and observational studies. We assessed effects on infant mortality and its major medical causes (preterm birth, congenital anomalies and sudden infant death syndrome (SIDS)) RESULTS: We identified 36 distinct eligible studies covering a wide range of interventions, including group antenatal care, clinic-based augmented care, teenage clinics, prenatal substance abuse programmes, home visiting programmes, maternal care coordination and nutritional programmes. Fifteen studies had adequate internal validity: of these, only one was considered to demonstrate a beneficial effect on an outcome of interest. Six interventions were considered 'promising'. CONCLUSIONS: There was insufficient evidence of adequate quality to recommend routine implementation of any of the programmes as a means of reducing infant mortality in disadvantaged/vulnerable women. Several interventions merit further more rigorous evaluation. PMID- 21314945 TI - Induction of strain-transcendent antibodies to placental-type isolates with VAR2CSA DBL3 or DBL5 recombinant proteins. AB - BACKGROUND: Pregnancy associated malaria is a severe clinical syndrome associated with sequestration of Plasmodium falciparum-infected erythrocytes in the placenta. Placental binding is mediated by VAR2CSA, which adheres to chondroitin sulphate A (CSA). VAR2CSA is a large and polymorphic protein that has six Duffy binding-like (DBL) domains. There is still limited understanding as to how effective individual VAR2CSA domains are at generating inhibitory antibodies or the number of domain variants needed for universal vaccine coverage. METHODS: To investigate the immunogenic properties of single domain VAR2CSA recombinant proteins, rats or rabbits were immunized with five of the six VAR2CSA domains produced in Pichia pastoris. Immune plasma was analysed against a geographically diverse panel of CSA-binding lab lines to assess antibody breadth and inhibitory activity. RESULTS: Of the five domains, DBL3, and to a lesser extent DBL5, induced antibodies that cross-reacted on five diverse CSA-binding parasite lines by flow cytometry. By comparison, anti-DBL6 antibodies were highly strain specific and anti-DBL1 and anti-DBL4 antibodies were poorly reactive by flow cytometry. From this series of recombinant proteins, adhesion-blocking activity was restricted to a single rat immunized against a DBL4 recombinant protein. CONCLUSIONS: Single domain VAR2CSA recombinant proteins produced in P. pastoris had limited efficacy in eliciting adhesion blocking antibody responses, but VAR2CSA DBL3 and DBL5 domains contain strain-transcendent epitopes that can be targeted by vaccination and may have application for vaccine development. PMID- 21314946 TI - Differences in the mannose oligomer specificities of the closely related lectins from Galanthus nivalis and Zea mays strongly determine their eventual anti-HIV activity. AB - BACKGROUND: In a recent report, the carbohydrate-binding specificities of the plant lectins Galanthus nivalis (GNA) and the closely related lectin from Zea mays (GNAmaize) were determined by glycan array analysis and indicated that GNAmaize recognizes complex-type N-glycans whereas GNA has specificity towards high-mannose-type glycans. Both lectins are tetrameric proteins sharing 64% sequence similarity. RESULTS: GNAmaize appeared to be ~20- to 100-fold less inhibitory than GNA against HIV infection, syncytia formation between persistently HIV-1-infected HuT-78 cells and uninfected CD4+ T-lymphocyte SupT1 cells, HIV-1 capture by DC-SIGN and subsequent transmission of DC-SIGN-captured virions to uninfected CD4+ T-lymphocyte cells. In contrast to GNA, which preferentially selects for virus strains with deleted high-mannose-type glycans on gp120, prolonged exposure of HIV-1 to dose-escalating concentrations of GNAmaize selected for mutant virus strains in which one complex-type glycan of gp120 was deleted. Surface Plasmon Resonance (SPR) analysis revealed that GNA and GNAmaize interact with HIV IIIB gp120 with affinity constants (KD) of 0.33 nM and 34 nM, respectively. Whereas immobilized GNA specifically binds mannose oligomers, GNAmaize selectively binds complex-type GlcNAcbeta1,2Man oligomers. Also, epitope mapping experiments revealed that GNA and the mannose-specific mAb 2G12 can independently bind from GNAmaize to gp120, whereas GNAmaize cannot efficiently bind to gp120 that contained prebound PHA-E (GlcNAcbeta1,2man specific) or SNA (NeuAcalpha2,6X specific). CONCLUSION: The markedly reduced anti HIV activity of GNAmaize compared to GNA can be explained by the profound shift in glycan recognition and the disappearance of carbohydrate-binding sites in GNAmaize that have high affinity for mannose oligomers. These findings underscore the need for mannose oligomer recognition of therapeutics to be endowed with anti HIV activity and that mannose, but not complex-type glycan binding of chemotherapeutics to gp120, may result in a pronounced neutralizing activity against the virus. PMID- 21314947 TI - In vitro susceptibility to quinine and microsatellite variations of the Plasmodium falciparum Na+/H+ exchanger (Pfnhe-1) gene: the absence of association in clinical isolates from the Republic of Congo. AB - BACKGROUND: Quinine is still recommended as an effective therapy for severe cases of Plasmodium falciparum malaria, but the parasite has developed resistance to the drug in some cases. Investigations into the genetic basis for quinine resistance (QNR) suggest that QNR is complex and involves several genes, with either an additive or a pairwise effect. The results obtained when assessing one of these genes, the plasmodial Na+/H+ exchanger, Pfnhe-1, were found to depend upon the geographic origin of the parasite strain. Most of the associations identified have been made in Asian strains; in contrast, in African strains, the influence of Pfnhe on QNR is not apparent. However, a recent study carried out in Kenya did show a significant association between a Pfnhe polymorphism and QNR. As genetic differences may exist across the African continent, more field data are needed to determine if this association exists in other African regions. In the present study, association between Pfnhe and QNR is investigated in a series of isolates from central Africa. METHODS: The sequence analysis of the polymorphisms at the Pfnhe-1 ms4760 microsatellite and the evaluation of in vitro quinine susceptibility (by isotopic assay) were conducted in 74 P. falciparum isolates from the Republic of Congo. RESULTS: Polymorphisms in the number of DNNND or NHNDNHNNDDD repeats in the Pfnhe-1 ms4760 microsatellite were not associated with quinine susceptibility. CONCLUSIONS: The polymorphism in the microsatellite ms4760 in Pfnhe-1 that cannot be used to monitor quinine response in the regions of the Republic of Congo, where the isolates came from. This finding suggests that there exists a genetic background associated with geographic area for the association that will prevent the use of Pfnhe as a molecular marker for QNR. The contribution of Pfnhe to the in vitro response to quinine remains to be assessed in other regions, including in countries with different levels of drug pressure. PMID- 21314948 TI - Combining information from surveys of several species to estimate the probability of freedom from Echinococcus multilocularis in Sweden, Finland and mainland Norway. AB - BACKGROUND: The fox tapeworm Echinococcus multilocularis has foxes and other canids as definitive host and rodents as intermediate hosts. However, most mammals can be accidental intermediate hosts and the larval stage may cause serious disease in humans. The parasite has never been detected in Sweden, Finland and mainland Norway. All three countries require currently an anthelminthic treatment for dogs and cats prior to entry in order to prevent introduction of the parasite. Documentation of freedom from E. multilocularis is necessary for justification of the present import requirements. METHODS: The probability that Sweden, Finland and mainland Norway were free from E. multilocularis and the sensitivity of the surveillance systems were estimated using scenario trees. Surveillance data from five animal species were included in the study: red fox (Vulpes vulpes), raccoon dog (Nyctereutes procyonoides), domestic pig, wild boar (Sus scrofa) and voles and lemmings (Arvicolinae). RESULTS: The cumulative probability of freedom from EM in December 2009 was high in all three countries, 0.98 (95% CI 0.96-0.99) in Finland and 0.99 (0.97-0.995) in Sweden and 0.98 (0.95-0.99) in Norway. CONCLUSIONS: Results from the model confirm that there is a high probability that in 2009 the countries were free from E. multilocularis. The sensitivity analyses showed that the choice of the design prevalences in different infected populations was influential. Therefore more knowledge on expected prevalences for E. multilocularis in infected populations of different species is desirable to reduce residual uncertainty of the results. PMID- 21314949 TI - Clinical evaluation of the function of hypothalamo-pituitary-thyroid axis in children with central nervous system infections. AB - BACKGROUND: It is well known that certain non-thyroidal critical illness may lead to euthyroid sick syndrome(ESS). There are little reports about the change of thyroid hormone in the children's central nervous system (CNS) infections. RESULTS: The results of serum TT3, TT4 and TSH in these children were compared with those in 20 cases of healthy adults and 20 cases of adults with primary hypothyroidism. Serum T3 and T4 were decreased in 34/78 children with CNS infections, T3 and T4 were much lower than those of healthy adult (p < 0.05), but still higher than that of the primary hypothyroidism (p < 0.05), and TSH levels were not significant differences among children with CNS infections and children with non-CNS infections (p > 0.05). Low T3 and T4 levels in serum and cerebrospinal fluid(CSF)were predominant in children with serious infections of CNS, 31/34 (percent 91.17) cases of serious CNS infection had low serum TT3 and/or TT4. The low T3 with low T4 was seen in 14/34 children of severe CNS infections, 3 of them died. The levels of CSF T3 (X +/- SD = 0.39 +/- 0.47 ng/ml) and T4 (x +/- SD = 1.02 +/- 1.27 ug/dl) in the serious CNS infections were lower than that of non-CNS infections T3 (x +/- SD = 0.93 +/- 1.23 ng/ml), and T4 (x +/ SD = 2.42 +/- 1.70 ug/dl), 7 died children were all in the subjects of low T3 and/or low T4. In 22 children with non-CNS infections, serum T3 and T4 levels were lower than that of healthy adult, but have not significant difference(p > 0.05). CONCLUSIONS: These results suggest that detection of TT3, TT4 and TSH in serum and/or CSF simultaneous or alone in analyses would be valuable in correctly judging thyroid function and evaluating the prognosis of the children with infections of CNS. Measuring a little amount of blood (1 ml)or CSF required for this method is a simple, convenient and accurate method. PMID- 21314950 TI - Comparative population structure of Plasmodium malariae and Plasmodium falciparum under different transmission settings in Malawi. AB - BACKGROUND: Described here is the first population genetic study of Plasmodium malariae, the causative agent of quartan malaria. Although not as deadly as Plasmodium falciparum, P. malariae is more common than previously thought, and is frequently in sympatry and co-infection with P. falciparum, making its study increasingly important. This study compares the population parameters of the two species in two districts of Malawi with different malaria transmission patterns- one seasonal, one perennial--to explore the effects of transmission on population structures. METHODS: Six species-specific microsatellite markers were used to analyse 257 P. malariae samples and 257 P. falciparum samples matched for age, gender and village of residence. Allele sizes were scored to within 2 bp for each locus and haplotypes were constructed from dominant alleles in multiple infections. Analysis of multiplicity of infection (MOI), population differentiation, clustering of haplotypes and linkage disequilibrium was performed for both species. Regression analyses were used to determine association of MOI measurements with clinical malaria parameters. RESULTS: Multiple-genotype infections within each species were common in both districts, accounting for 86.0% of P. falciparum and 73.2% of P. malariae infections and did not differ significantly with transmission setting. Mean MOI of P. falciparum was increased under perennial transmission compared with seasonal (3.14 vs 2.59, p = 0.008) and was greater in children compared with adults. In contrast, P. malariae mean MOI was similar between transmission settings (2.12 vs 2.11) and there was no difference between children and adults. Population differentiation showed no significant differences between villages or districts for either species. There was no evidence of geographical clustering of haplotypes. Linkage disequilibrium amongst loci was found only for P. falciparum samples from the seasonal transmission setting. CONCLUSIONS: The extent of similarity between P. falciparum and P. malariae population structure described by the high level of multiple infection, the lack of significant population differentiation or haplotype clustering and lack of linkage disequilibrium is surprising given the differences in the biological features of these species that suggest a reduced potential for out-crossing and transmission in P. malariae. The absence of a rise in P. malariae MOI with increased transmission or a reduction in MOI with age could be explained by differences in the duration of infection or degree of immunity compared to P. falciparum. PMID- 21314951 TI - Soluble Frizzled-7 receptor inhibits Wnt signaling and sensitizes hepatocellular carcinoma cells towards doxorubicin. AB - BACKGROUND: There are limited therapeutic options for hepatocellular carcinoma (HCC), the most common liver malignancy worldwide. Recent studies have identified the Frizzled-7 receptor (FZD7), important for activation of Wnt-mediated signaling, as a potential therapeutic target for HCC and other cancers. METHODS: We hypothesized that the extracellular domain of FZD7 (sFZD7) would be a clinically more relevant therapeutic modality than previously studied approaches to target FZD7. We expressed and purified sFZD7 from E. coli, and tested its functional activity to interact with Wnt3, its ability to inhibit Wnt3-mediated signaling, and its potential for combinatorial therapy in HCC. RESULTS: sFZD7 pulled down Wnt3 from Huh7 cells, and decreased beta-catenin/Tcf4 transcriptional activity in HCC cells. In vitro, sFZD7 dose-dependently decreased viability of three HCC cell lines (HepG2, Hep40, and Huh7, all with high FZD7 and Wnt3 mRNA), but had little effect on normal hepatocytes from three donors (all with low level FZD7 and Wnt3 mRNA). When combined with doxorubicin, sFZD7 enhanced the growth inhibitory effects of doxorubicin against HCC cells in vitro, and against Huh7 xenografts in vivo. Reduced expressions of c-Myc, cyclin D1, and survivin were observed in vitro and in vivo. Additionally, sFZD7 altered the levels of phosphorylated AKT and ERK1/2 induced by doxorubicin treatment in vitro, suggesting that several critical pathways are involved in the chemosensitizing effect of sFZD7. CONCLUSIONS: We propose that sFZD7 is a feasible therapeutic agent with specific activity, which can potentially be combined with other chemotherapeutic agents for the improved management of HCC. PMID- 21314953 TI - Validity of self-reported leisure-time sedentary behavior in adolescents. AB - BACKGROUND: To evaluate the concordance between leisure-time sedentary behavior in adolescents assessed by an activity-based questionnaire and accelerometry. A convenience sample of 128 girls and 73 boys, 11-15 years of age (12.6 +/- 1.1 years) from six states across the United States examined as part of the feasibility studies for the Trial of Activity in Adolescent Girls (TAAG). Three days of self-reported time spent watching TV/videos, using computers, playing video/computer games, and talking on the phone was assessed using a modified version of the Self-Administered Physical Activity Checklist (SAPAC). Criterion measure of sedentary behavior was via accelerometry over three days using a cut point of < 50 counts . 30 sec-1 epoch. Comparisons between sedentary behavior by the two instruments were made. RESULTS: Adolescents generally underestimated minutes of sedentary behavior compared to accelerometry-measured minutes. The overall correlation between minutes of sedentary behavior by self-report and accelerometry was weak (Spearman r = 0.14; 95% CI 0.05, 0.23). Adjustment of sedentary minutes of behavior for total minutes assessed using either percentages or the residuals method tended to increase correlations slightly. However, regression analyses showed no significant association between self-reported sedentary behavior and minutes of sedentary behavior captured via accelerometry. DISCUSSION: These findings suggest that the modified 3-day Self-Administered Physical Activity Checklist is not a reliable method for assessing sedentary behavior. It is recommended that until validation studies for self-report instruments of sedentary behavior demonstrate validity, objective measures should be used. PMID- 21314952 TI - Bioinformatic analyses identifies novel protein-coding pharmacogenomic markers associated with paclitaxel sensitivity in NCI60 cancer cell lines. AB - BACKGROUND: Paclitaxel is a microtubule-stabilizing drug that has been commonly used in treating cancer. Due to genetic heterogeneity within patient populations, therapeutic response rates often vary. Here we used the NCI60 panel to identify SNPs associated with paclitaxel sensitivity. Using the panel's GI50 response data available from Developmental Therapeutics Program, cell lines were categorized as either sensitive or resistant. PLINK software was used to perform a genome-wide association analysis of the cellular response to paclitaxel with the panel's SNP genotype data on the Affymetrix 125 k SNP array. FastSNP software helped predict each SNP's potential impact on their gene product. mRNA expression differences between sensitive and resistant cell lines was examined using data from BioGPS. Using Haploview software, we investigated for haplotypes that were more strongly associated with the cellular response to paclitaxel. Ingenuity Pathway Analysis software helped us understand how our identified genes may alter the cellular response to paclitaxel. RESULTS: 43 SNPs were found significantly associated (FDR<0.005) with paclitaxel response, with 10 belonging to protein-coding genes (CFTR, ROBO1, PTPRD, BTBD12, DCT, SNTG1, SGCD, LPHN2, GRIK1, ZNF607). SNPs in GRIK1, DCT, SGCD and CFTR were predicted to be intronic enhancers, altering gene expression, while SNPs in ZNF607 and BTBD12 cause conservative missense mutations. mRNA expression analysis supported these findings as GRIK1, DCT, SNTG1, SGCD and CFTR showed significantly (p<0.05) increased expression among sensitive cell lines. Haplotypes found in GRIK1, SGCD, ROBO1, LPHN2, and PTPRD were more strongly associated with response than their individual SNPs. CONCLUSIONS: Our study has taken advantage of available genotypic data and its integration with drug response data obtained from the NCI60 panel. We identified 10 SNPs located within protein-coding genes that were not previously shown to be associated with paclitaxel response. As only five genes showed differential mRNA expression, the remainder would not have been detected solely based on expression data. The identified haplotypes highlight the role of utilizing SNP combinations within genomic loci of interest to improve the risk determination associated with drug response. These genetic variants represent promising biomarkers for predicting paclitaxel response and may play a significant role in the cellular response to paclitaxel. PMID- 21314954 TI - Loosenin, a novel protein with cellulose-disrupting activity from Bjerkandera adusta. AB - BACKGROUND: Expansins and expansin-like proteins loosen cellulose microfibrils, possibly through the rupture of intramolecular hydrogen bonds. Together with the use of lignocellulolytic enzymes, these proteins are potential molecular tools to treat plant biomass to improve saccharification yields. RESULTS: Here we describe a new type of expansin-related fungal protein that we have called loosenin. Its corresponding gene, loos1, from the basidiomycete Bjerkandera adusta, was cloned and heterologously expressed in Saccharomyces cerevisiae. LOOS1 is distantly related to plant expansins through the shared presence of a DPBB domain, however domain II found in plant expansins is absent. LOOS1 binds tightly to cellulose and chitin, and we demonstrate that cotton fibers become susceptible to the action of a commercial cellulase following treatment with LOOS1. Natural fibers of Agave tequilana also become susceptible to hydrolysis by cellulases after loosenin treatment. CONCLUSIONS: LOOS1 is a new type of protein with disrupting activity on cellulose. LOOS1 binds polysaccharides, and given its enhancing properties on the action of hydrolytic enzymes, LOOS1 represents a potential additive in the production of fermentable sugars from lignocellulose. PMID- 21314955 TI - Higher titers of some H5N1 and recent human H1N1 and H3N2 influenza viruses in Mv1 Lu vs. MDCK cells. AB - BACKGROUND: The infectivity of influenza A viruses can differ among the various primary cells and continuous cell lines used for such measurements. Over many years, we observed that all things equal, the cytopathic effects caused by influenza A subtype H1N1, H3N2, and H5N1 viruses were often detected earlier in a mink lung epithelial cell line (Mv1 Lu) than in MDCK cells. We asked whether virus yields as measured by the 50% tissue culture infectious dose and plaque forming titer also differed in MDCK and Mv1 Lu cells infected by the same influenza virus subtypes. RESULTS: The 50% tissue culture infectious dose and plaque forming titer of many influenza A subtype H1N1, H3N2, and H5N1 viruses was higher in Mv1 Lu than in MDCK cells. CONCLUSIONS: The yields of influenza subtype H1N1, H3N2, and H5N1 viruses can be higher in Mv1 Lu cells than in MDCK cells. PMID- 21314956 TI - Deciphering the complexities of the wheat flour proteome using quantitative two dimensional electrophoresis, three proteases and tandem mass spectrometry. AB - BACKGROUND: Wheat flour is one of the world's major food ingredients, in part because of the unique end-use qualities conferred by the abundant glutamine- and proline-rich gluten proteins. Many wheat flour proteins also present dietary problems for consumers with celiac disease or wheat allergies. Despite the importance of these proteins it has been particularly challenging to use MS/MS to distinguish the many proteins in a flour sample and relate them to gene sequences. RESULTS: Grain from the extensively characterized spring wheat cultivar Triticum aestivum 'Butte 86' was milled to white flour from which proteins were extracted, then separated and quantified by 2-DE. Protein spots were identified by separate digestions with three proteases, followed by tandem mass spectrometry analysis of the peptides. The spectra were used to interrogate an improved protein sequence database and results were integrated using the Scaffold program. Inclusion of cultivar specific sequences in the database greatly improved the results, and 233 spots were identified, accounting for 93.1% of normalized spot volume. Identified proteins were assigned to 157 wheat sequences, many for proteins unique to wheat and nearly 40% from Butte 86. Alpha gliadins accounted for 20.4% of flour protein, low molecular weight glutenin subunits 18.0%, high molecular weight glutenin subunits 17.1%, gamma-gliadins 12.2%, omega-gliadins 10.5%, amylase/protease inhibitors 4.1%, triticins 1.6%, serpins 1.6%, purinins 0.9%, farinins 0.8%, beta-amylase 0.5%, globulins 0.4%, other enzymes and factors 1.9%, and all other 3%. CONCLUSIONS: This is the first successful effort to identify the majority of abundant flour proteins for a single wheat cultivar, relate them to individual gene sequences and estimate their relative levels. Many genes for wheat flour proteins are not expressed, so this study represents further progress in describing the expressed wheat genome. Use of cultivar-specific contigs helped to overcome the difficulties of matching peptides to gene sequences for members of highly similar, rapidly evolving storage protein families. Prospects for simplifying this process for routine analyses are discussed. The ability to measure expression levels for individual flour protein genes complements information gained from efforts to sequence the wheat genome and is essential for studies of effects of environment on gene expression. PMID- 21314957 TI - Evaluation of a combined index of optic nerve structure and function for glaucoma diagnosis. AB - BACKGROUND: The definitive diagnosis of glaucoma is currently based on congruent damage to both optic nerve structure and function. Given widespread quantitative assessment of both structure (imaging) and function (automated perimetry) in glaucoma, it should be possible to combine these quantitative data to diagnose disease. We have therefore defined and tested a new approach to glaucoma diagnosis by combining imaging and visual field data, using the anatomical organization of retinal ganglion cells. METHODS: Data from 1499 eyes of glaucoma suspects and 895 eyes with glaucoma were identified at a single glaucoma center. Each underwent Heidelberg Retinal Tomograph (HRT) imaging and standard automated perimetry. A new measure combining these two tests, the structure function index (SFI), was defined in 3 steps: 1) calculate the probability that each visual field point is abnormal, 2) calculate the probability of abnormality for each of the six HRT optic disc sectors, and 3) combine those probabilities with the probability that a field point and disc sector are linked by ganglion cell anatomy. The SFI was compared to the HRT and visual field using receiver operating characteristic (ROC) analysis. RESULTS: The SFI produced an area under the ROC curve (0.78) that was similar to that for both visual field mean deviation (0.78) and pattern standard deviation (0.80) and larger than that for a normalized measure of HRT rim area (0.66). The cases classified as glaucoma by the various tests were significantly non-overlapping. Based on the distribution of test values in the population with mild disease, the SFI may be better able to stratify this group while still clearly identifying those with severe disease. CONCLUSIONS: The SFI reflects the traditional clinical diagnosis of glaucoma by combining optic nerve structure and function. In doing so, it identifies a different subset of patients than either visual field testing or optic nerve head imaging alone. Analysis of prospective data will allow us to determine whether the combined index of structure and function can provide an improved standard for glaucoma diagnosis. PMID- 21314958 TI - Sodium ion channel mutations in glioblastoma patients correlate with shorter survival. AB - BACKGROUND: Glioblastoma Multiforme (GBM) is the most common and invasive astrocytic tumor associated with dismal prognosis. Treatment for GBM patients has advanced, but the median survival remains a meager 15 months. In a recent study, 20,000 genes from 21 GBM patients were sequenced that identified frequent mutations in ion channel genes. The goal of this study was to determine whether ion channel mutations have a role in disease progression and whether molecular targeting of ion channels is a promising therapeutic strategy for GBM patients. Therefore, we compared GBM patient survival on the basis of presence or absence of mutations in calcium, potassium and sodium ion transport genes. Cardiac glycosides, known sodium channel inhibitors, were then tested for their ability to inhibit GBM cell proliferation. RESULTS: Nearly 90% of patients showed at least one mutation in ion transport genes. GBM patients with mutations in sodium channels showed a significantly shorter survival compared to patients with no sodium channel mutations, whereas a similar comparison based on mutational status of calcium or potassium ion channel mutations showed no survival differences. Experimentally, targeting GBM cells with cardiac glycosides such as digoxin and ouabain demonstrated preferential cytotoxicity against U-87 and D54 GBM cells compared to non-tumor astrocytes (NTAs). CONCLUSIONS: These pilot studies of GBM patients with sodium channel mutations indicate an association with a more aggressive disease and significantly shorter survival. Moreover, inhibition of GBM cells by ion channel inhibitors such as cardiac glycosides suggest a therapeutic strategy with relatively safe drugs for targeting GBM ion channel mutations. Key Words: glioblastoma multiforme, ion channels, mutations, small molecule inhibitors, cardiac glycosides. PMID- 21314959 TI - Risk factors for posttraumatic stress reactions among Chinese students following exposure to a snowstorm disaster. AB - BACKGROUND: It is important to understand which factors increase the risk of posttraumatic stress disorder (PTSD) in adolescents. Previous studies have shown that the most important risk factors for PTSD include the type, severity, and duration of exposure to the traumatic events. METHODS: A cross-sectional survey was used to investigate the psychological symptoms associated with the aftermath of a snowstorm disaster in the Hunan province of China in January 2008. Students living in Hunan were surveyed at a three-month follow-up after the disaster. The questionnaire battery included the Impact of Event Scale-Revised (IES-R, trauma and symptoms associated with PTSD), the Chinese version of the Life Orientation Test-Revised (LOT-R, optimism and pessimism), the Chinese version of the Eysenck Personality Questionnaire (EPQ, neuroticism and extraversion), the Chinese Trait Coping Style Questionnaire (TCSQ, positive and negative coping styles), and a range of questions addressing social demographic characteristics and factors relating to the snowstorm. The survey was administered in school, and 968 students completed and returned the questionnaires. RESULTS: The results showed that 14.5% of the students had a total IES-R score >= 20. Students with greater school-to-home distances showed higher levels of posttraumatic stress symptoms than students who lived shorter distances from school. Students with emotional support from their teachers reported higher levels of posttraumatic stress symptoms (21.20%) than students without a teacher's emotional support (11.07%). The IES-R total and subscale scores correlated with all variables except extraversion. The binary logistic regression analysis results showed that the teacher's emotional support [odds ratio (OR) = 1.72, 95% confidence interval (CI) = 1.13-2.62], school-to-home distance (OR = 1.01, 95% CI = 1.00-1.01), negative coping (OR = 1.05; 95% CI = 1.02-1.08), and neuroticism (OR = 1.04, 95% CI = 1.02 1.06) were risk factors that predicted PTSD frequency and severity (percentage correct = 85.5%). CONCLUSIONS: The risk factors that significantly impacted the onset of posttraumatic stress reactions in students living in Hunan, China following a snowstorm disaster were the school-to-home distance, negative coping, neuroticism, and teacher's emotional support. PMID- 21314960 TI - Induction of heme oxygenase-1 protects against nutritional fibrosing steatohepatitis in mice. AB - BACKGROUND: Heme oxygenase-1 (HO-1), an antioxidant defense enzyme, has been shown to protect against oxidant-induced liver injury. However, its role on liver fibrosis remains unclear. This study aims to elucidate the effect and the mechanism of HO-1 in nutritional fibrosing steatohepatitis in mice. METHODS: Male C57BL/6J mice were fed with a methionine-choline deficient (MCD) diet for eight weeks to induce hepatic fibrosis. HO-1 chemical inducer (hemin), HO-1 chemical inhibitor zinc protoporphyrin IX (ZnPP-IX) and/or adenovirus carrying HO-1 gene (Ad-HO-1) were administered to mice, respectively. Liver injury was assessed by serum ALT, AST levels and histological examination; hepatic lipid peroxides levels were determined; the expression levels of several fibrogenic related genes were assayed by real-time quantitative PCR and Western blot. RESULTS: MCD feeding mice showed progressive hepatic injury including hepatic steatosis, inflammatory infiltration and fibrosis. Induction of HO-1 by hemin or Ad-HO-1 significantly attenuated the severity of liver injury. This effect was associated with the up regulation of HO-1, reduction of hepatic lipid peroxides levels, down-regulation of inflammatory factors tumor necrosis factor-alpha, interleukin-6 and suppressor of cytokine signaling-1 as well as the pro-fibrotic genes alpha-smooth muscle actin, transforming growth factor-beta1, matrix metallopeptidase-2 and matrix metallopeptidase-9. A contrary effect was observed in mice treated with ZnPP-IX. CONCLUSIONS: The present study provided the evidence for the protective role of HO-1 in ameliorating MCD diet-induced fibrosing steatohepatitis. Modulation of HO 1 expression might serve as a therapeutic approach for fibrotic steatohepatitis. PMID- 21314961 TI - Genetic variability of attachment (G) and Fusion (F) protein genes of human metapneumovirus strains circulating during 2006-2009 in Kolkata, Eastern India. AB - BACKGROUND: Human metapneumovirus (hMPV) is associated with the acute respiratory tract infection (ARTI) in all the age groups. However, there is limited information on prevalence and genetic diversity of human metapneumovirus (hMPV) strains circulating in India. OBJECTIVE: To study prevalence and genomic diversity of hMPV strains among ARTI patients reporting in outpatient departments of hospitals in Kolkata, Eastern India. METHODS: Nasal and/or throat swabs from 2309 patients during January 2006 to December 2009, were screened for the presence of hMPV by RT-PCR of nucleocapsid (N) gene. The G and F genes of representative hMPV positive samples were sequenced. RESULTS: 118 of 2309 (5.11%) clinical samples were positive for hMPV. The majority (~80%) of the positive cases were detected during July-November all through the study period. Genetic analysis revealed that 77% strains belong to A2 subgroup whereas rest clustered in B1 subgroup. G sequences showed higher diversity at the nucleotide and amino acid level. In contrast, less than 10% variation was observed in F gene of representative strains of all four years. Sequence analysis also revealed changes in the position of stop codon in G protein, which resulted in variable length (217-231 aa) polypeptides. CONCLUSION: The study suggests that approximately 5% of ARTI in the region were caused by hMPV. This is the first report on the genetic variability of G and F gene of hMPV strains from India which clearly shows that the G protein of hMPV is continuously evolving. Though the study partially fulfills lacunae of information, further studies from other regions are necessary for better understanding of prevalence, epidemiology and virus evolution in Indian subcontinent. PMID- 21314962 TI - Phase i study evaluating the treatment of patients with hepatocellular carcinoma (HCC) with carbon ion radiotherapy: the PROMETHEUS-01 trial. AB - BACKGROUND: Treatment options for patients with advanced hepatocellular carcinoma (HCC) are often limited. In most cases, they are not amenable to local therapies including surgery or radiofrequency ablation. The multi-kinase inhibitor sorafenib has shown to increase overall survival in this patient group for about 3 months.Radiation therapy is a treatment alternative, however, high local doses are required for long-term local control. However, due to the relatively low radiation tolerance of liver normal tissue, even using stereotactic techniques, delivery of sufficient doses for successful local tumor control has not be achieved to date.Carbon ions offer physical and biological characteristics. Due to their inverted dose profile and the high local dose deposition within the Bragg peak precise dose application and sparing of normal tissue is possible. Moreover, in comparison to photons, carbon ions offer an increased relative biological effectiveness (RBE), which can be calculated between 2 and 3 depending on the HCC cell line as well as the endpoint analyzed.Japanese Data on the evaluation of carbon ion radiation therapy showed promising results for patients with HCC. METHODS/DESIGN: In the current Phase I-PROMETHEUS-01-Study, carbon ion radiotherapy will be evaluated for patients with advanced HCC. The study will be performed as a dose-escalation study evaluating the optimal carbon ion dose with respect to toxicity and tumor control.Primary endpoint is toxicity, secondary endpoint is progression-free survival and response. DISCUSSION: The Prometheus-01 trial ist the first trial evaluating carbon ion radiotherapy delivered by intensity-modulated rasterscanning for the treatment of HCC. Within this Phase I dose escalation study, the optimal dose of carbon ion radiotherapy will be determined. TRIAL REGISTRATION: NCT 01167374. PMID- 21314963 TI - High interferon type I responses in the lung, plasma and spleen during highly pathogenic H5N1 infection of chicken. AB - This study shows that high pathogenic H5N1 influenza virus infection of chicken induced high levels of bioactive interferon type I in the lung (4.3 * 10(5) U/mg tissue), plasma (1.1 * 10(5) U/mL), and spleen (9.1 * 10(5) U/mg tissue). In contrast, a low pathogenic attenuated H5N1 vaccine strain only induced approximately 24 times less IFN in the lung, 441 times less in the spleen and 649 less in the plasma. This was in the same range as a reassortant carrying the HA from the vaccine strain and the remaining genes from the high pathogenic virus. On the other hand, a reassortant virus with the HA from the high pathogenic H5N1 with the remaining genes from the vaccine strain had intermediate levels of IFN. The level of interferon responses related to the viral load, and those in the spleen and blood to the spread of virus to lymphoid tissue, as well as disease severity. In vitro, the viruses did not induce interferon in chicken embryonic fibroblasts, but high levels in splenocytes, with not clear relationship to pathogenicity and virulence. This, and the responses also with inactivated viruses imply the presence of plasmacytoid dendritic cell-like leukocytes within the chicken immune system, possibly responsible for the high interferon responses during H5N1 infection. Our data also indicate that the viral load as well as the cleavability of the HA enabling systemic spread of the virus are two major factors controlling systemic IFN responses in chicken. PMID- 21314965 TI - Recovery of infectious virus from full-length cowpox virus (CPXV) DNA cloned as a bacterial artificial chromosome (BAC). AB - Transmission from pet rats and cats to humans as well as severe infection in felids and other animal species have recently drawn increasing attention to cowpox virus (CPXV). We report the cloning of the entire genome of cowpox virus strain Brighton Red (BR) as a bacterial artificial chromosome (BAC) in Escherichia coli and the recovery of infectious virus from cloned DNA. Generation of a full-length CPXV DNA clone was achieved by first introducing a mini-F vector, which allows maintenance of large circular DNA in E. coli, into the thymidine kinase locus of CPXV by homologous recombination. Circular replication intermediates were then electroporated into E. coli DH10B cells. Upon successful establishment of the infectious BR clone, we modified the full-length clone such that recombination-mediated excision of bacterial sequences can occur upon transfection in eukaryotic cells. This self-excision of the bacterial replicon is made possible by a sequence duplication within mini-F sequences and allows recovery of recombinant virus progeny without remaining marker or vector sequences. The in vitro growth properties of viruses derived from both BAC clones were determined and found to be virtually indistinguishable from those of parental, wild-type BR. Finally, the complete genomic sequence of the infectious clone was determined and the cloned viral genome was shown to be identical to that of the parental virus. In summary, the generated infectious clone will greatly facilitate studies on individual genes and pathogenesis of CPXV. Moreover, the vector potential of CPXV can now be more systematically explored using this newly generated tool. PMID- 21314964 TI - Genetic and functional characterization of the NanA sialidase from Clostridium chauvoei. AB - Clostridium chauvoei is the causative agent of blackleg, a wide spread serious infection of cattle and sheep with high mortality. In this study we have analyzed the sialidase activity of the NanA protein of C. chauvoei and cloned the sialidase gene nanA. Sialidase is encoded as a precursor protein of 722 amino acids with a 26 amino acid signal peptide. The mature sialidase has a calculated molecular mass of 81 kDa and contains the carbohydrate binding module 32 (CBM32, or F5/8 type C domain), the sialic acid binding module CBM40 and the enzymatically active sialidase domain found in all pro- and eukaryotic sialidases. Sialidase activity does not require the CBM32 domain. The NanA protein is secreted by C. chauvoei as a dimer. The nanA gene was found to be conserved and sialidase activity was found in C. chauvoei strains isolated over a period of 50 years from various geographical locations. Antiserum directed against a recombinant 40 kDa peptide containing CBM40 and part of the enzymatically active domain of NanA neutralized the secreted sialidase activity of all C. chauvoei strains tested. PMID- 21314966 TI - Quantitative assessment of the probability of bluetongue virus overwintering by horizontal transmission: application to Germany. AB - Even though bluetongue virus (BTV) transmission is apparently interrupted during winter, bluetongue outbreaks often reappear in the next season (overwintering). Several mechanisms for BTV overwintering have been proposed, but to date, their relative importance remain unclear. In order to assess the probability of BTV overwintering by persistence in adult vectors, ruminants (through prolonged viraemia) or a combination of both, a quantitative risk assessment model was developed. Furthermore, the model allowed the role played by the residual number of vectors present during winter to be examined, and the effect of a proportion of Culicoides living inside buildings (endophilic behaviour) to be explored. The model was then applied to a real scenario: overwintering in Germany between 2006 and 2007. The results showed that the limited number of vectors active during winter seemed to allow the transmission of BTV during this period, and that while transmission was favoured by the endophilic behaviour of some Culicoides, its effect was limited. Even though transmission was possible, the likelihood of BTV overwintering by the mechanisms studied seemed too low to explain the observed re emergence of the disease. Therefore, other overwintering mechanisms not considered in the model are likely to have played a significant role in BTV overwintering in Germany between 2006 and 2007. PMID- 21314967 TI - Pathogenicity of two recent Western Mediterranean West Nile virus isolates in a wild bird species indigenous to Southern Europe: the red-legged partridge. AB - West Nile virus (WNV) is an emerging zoonotic pathogen whose geographic spread and incidence in humans, horses and birds has increased significantly in recent years. WNV has long been considered a mild pathogen causing self-limiting outbreaks. This notion has changed as WNV is causing large epidemics with a high impact on human and animal health. This has been particularly noteworthy since its introduction into North America in 1999. There, native bird species have been shown to be highly susceptible to WNV infection and disease with high mortalities. For this reason, the effect of WNV infection in North American bird species has been thoroughly studied by means of experimental inoculations in controlled trials. To a lesser extent, European wild birds have been shown to be affected clinically by WNV infection. Yet experimental studies on European wild bird species are lacking. The red-legged partridge (Alectoris rufa) is a gallinaceous bird indigenous to the Iberian Peninsula, widely distributed in South Western Europe. It plays a key role in the Mediterranean ecosystem and constitutes an economically important game species. As such it is raised intensively in outdoor facilities. In this work, red-legged partridges were experimentally infected with two recent WNV isolates from the Western Mediterranean area: Morocco/2003 and Spain/2007. All inoculated birds became viremic and showed clinical disease, with mortality rates of 70% and 30%, respectively. These results show that Western Mediterranean WNV variants can be pathogenic for some European bird species, such as the red-legged partridge. PMID- 21314968 TI - Cytokine profiles and phenotype regulation of antigen presenting cells by genotype-I porcine reproductive and respiratory syndrome virus isolates. AB - The present study examined the immunological response of antigen presenting cells (APC) to genotype-I isolates of porcine reproductive and respiratory syndrome virus (PRRSV) infection by analysing the cytokine profile induced and evaluating the changes taking place upon infection on immunologically relevant cell markers (MHCI, MHCII, CD80/86, CD14, CD16, CD163, CD172a, SWC9). Several types of APC were infected with 39 PRRSV isolates. The results show that different isolates were able to induce different patterns of IL-10 and TNF-alpha. The four possible phenotypes based on the ability to induce IL-10 and/or TNF-alpha were observed, although different cell types seemed to have different capabilities. In addition, isolates inducing different cytokine-release profiles on APC could induce different expression of cell markers. PMID- 21314969 TI - Veterinary Research is now a full Open Access journal. PMID- 21314970 TI - Transcription of reference genes used for quantitative RT-PCR in Atlantic salmon is affected by viral infection. AB - Relative quantification using RT-qPCR is a widely used method for transcription profiling. Transcript levels of target genes in fish after experimental infection is often reported without documentation of stably transcribed reference genes. We present results demonstrating that transcription of typically used reference genes in Atlantic salmon is not stable during experimental infection with salmon pancreas disease virus (SPDV). Transcript levels 0 to 6 weeks after challenge revealed statistically significant changes between time-points that corresponded with a peak in viral load 3 weeks after challenge. The results emphasize the need for thorough method validation prior to transcriptional studies during viral infections. PMID- 21314971 TI - Breeding with resistant rams leads to rapid control of classical scrapie in affected sheep flocks. AB - Susceptibility to scrapie, a transmissible spongiform encephalopathy in sheep, is modulated by the genetic make-up of the sheep. Scrapie control policies, based on selecting animals of resistant genotype for breeding, have recently been adopted by the Netherlands and other European countries. Here we assess the effectiveness of a breeding programme based on selecting rams of resistant genotype to obtain outbreak control in classical scrapie-affected sheep flocks under field conditions. In six commercially-run flocks following this breeding strategy, we used genotyping to monitor the genotype distribution, and tonsil biopsies and post-mortem analyses to monitor the occurrence of scrapie infection. The farmers were not informed about the monitoring results until the end of the study period of six years. We used a mathematical model of scrapie transmission to analyze the monitoring data and found that where the breeding scheme was consistently applied, outbreak control was obtained after at most four years. Our results also show that classical scrapie control can be obtained before the frequency of non resistant animals is reduced to zero in the flock. This suggests that control at the national scale can be obtained without a loss of genetic polymorphisms from any of the sheep breeds. PMID- 21314972 TI - Highly pathogenic or low pathogenic avian influenza virus subtype H7N1 infection in chicken lungs: small differences in general acute responses. AB - Avian influenza virus can be divided into two groups, highly pathogenic avian influenza virus (HPAI) and low pathogenic avian influenza virus (LPAI) based on their difference in virulence. To investigate if the difference in clinical outcome between LPAI and HPAI in chickens is due to immunological host responses in the lung within the first 24 hours post infection (hpi), chickens were infected with LPAI or HPAI of subtype H7N1. Virus was found in the caudal and cranial part of the lung. With LPAI, virus was localised around the intrapulmonary bronchus and secondary bronchi. In sharp contrast, HPAI was detected throughout the whole lung. However, based on viral RNA levels, no quantitative difference was observed between LPAI and HPAI infected birds. In infected areas of the lungs, an influx of CD8alpha+ cells as well as KUL01+ macrophages and dendritic cells (DC) occurred as fast as 8 hpi in both infected groups. No major difference between LPAI and HPAI infected birds in the induction of cytokines and interferons at mRNA level in lung tissue was found.In conclusion, the differences in lethality for chickens infected with LPAI or HPAI could be ascribed to difference in location of the virus. However similar amounts of viral RNA, similar cytokine mRNA levels, and similar influxes of CD8alpha+ and KUL01+ macrophages and DC were found between HPAI and LPAI in the lungs. A cytokine storm at mRNA level as described for mammals was not observed in the lungs of HPAI infected birds within 24 hpi. PMID- 21314973 TI - Susceptibility of in vitro produced hatched bovine blastocysts to infection with bluetongue virus serotype 8. AB - Bluetongue virus serotype 8 (BTV-8), which caused an epidemic in ruminants in central Western Europe in 2006 and 2007, seems to differ from other bluetongue serotypes in that it can spread transplacentally and has been associated with an increased incidence of abortion and other reproductive problems. For these reasons, and also because BTV-8 is threatening to spread to other parts of the world, there is a need for more information on the consequences of infection during pregnancy. The aim of the present study was to investigate whether hatched (i.e. zona pellucida-free) in vitro produced bovine blastocysts at 8-9 days post insemination are susceptible to BTV-8 and whether such infection induces cell death as indicated by apoptosis. Exposure of hatched in vitro produced bovine blastocysts for 1 h to a medium containing 10(3.8) or 10(4.9) TCID50 of the virus resulted in active viral replication in between 25 and 100% of the cells at 72 h post exposure. The infected blastocysts also showed growth arrest as evidenced by lower total cell numbers and a significant level of cellular apoptosis. We conclude from this in vitro study that some of the reproductive problems that are reported when cattle herds are infected with BTV-8 may be attributed to direct infection of blastocysts and other early-stage embryos in utero. PMID- 21314974 TI - Variation of inflammatory dynamics and mediators in primiparous cows after intramammary challenge with Escherichia coli. AB - The objective of the current study was to investigate (i) the outcome of experimentally induced Escherichia coli mastitis in primiparous cows during early lactation in relation with production of eicosanoids and inflammatory indicators, and (ii) the validity of thermography to evaluate temperature changes on udder skin surface after experimentally induced E. coli mastitis. Nine primiparous Holstein Friesian cows were inoculated 24 +/- 6 days (d) after parturition in both left quarters with E. coli P4 serotype O32:H37. Blood and milk samples were collected before and after challenge with E. coli. The infrared images were taken from the caudal view of the udder following challenge with E. coli. No relationship was detected between severity of mastitis and changes of thromboxane B2 (TXB2), leukotriene B4 (LTB4) and lipoxin A4 (LXA4). However, prostaglandin E2 (PGE2) was related to systemic disease severity during E. coli mastitis. Moreover, reduced somatic cell count (SCC), fewer circulating basophils, increased concentration of tumor necrosis factor-alpha (TNF-alpha) and higher milk sodium and lower milk potassium concentrations were related to systemic disease severity. The thermal camera was capable of detecting 2-3 degrees C temperature changes on udder skin surface of cows inoculated with E. coli. Peak of udder skin temperature occurred after peak of rectal temperature and appearance of local signs of induced E. coli mastitis. Although infrared thermography was a successful method for detecting the changes in udder skin surface temperature following intramammary challenge with E. coli, it did not show to be a promising tool for early detection of mastitis. PMID- 21314975 TI - SPI-1-encoded type III secretion system of Salmonella enterica is required for the suppression of porcine alveolar macrophage cytokine expression. AB - Genes localized at Salmonella pathogenicity island-1 (SPI-1) are involved in Salmonella enterica invasion of host non-professional phagocytes. Interestingly, in macrophages, SPI-1-encoded proteins, in addition to invasion, induce cell death via activation of caspase-1 which also cleaves proIL-1beta and proIL-18, precursors of 2 proinflammatory cytokines. In this study we were therefore interested in whether SPI-1-encoded type III secretion system (T3SS) may influence proinflammatory response of macrophages. To test this hypothesis, we infected primary porcine alveolar macrophages with wild-type S. Typhimurium and S. Enteritidis and their isogenic SPI-1 deletion mutants. DeltaSPI1 mutants of both serovars invaded approx. 5 times less efficiently than the wild-type strains and despite this, macrophages responded to the infection with DeltaSPI1 mutants by increased expression of proinflammatory cytokines IL-1beta, IL-8, TNFalpha, IL 23alpha and GM-CSF. Identical macrophage responses to that induced by the DeltaSPI1 mutants were also observed to the infection with sipB but not the sipA mutant. The hilA mutant exhibited an intermediate phenotype between the DeltaSPI1 mutant and the wild-type S. Enteritidis. Our results showed that the SPI-1 encoded T3SS is required not only for cell invasion but in macrophages also for the suppression of early proinflammatory cytokine expression. PMID- 21314976 TI - Changes in HSP gene and protein expression in natural scrapie with brain damage. AB - Heat shock proteins (Hsp) perform cytoprotective functions such as apoptosis regulation and inflammatory response control. These proteins can also be secreted to the extracellular medium, acting as inflammatory mediators, and their chaperone activity permits correct folding of proteins and avoids the aggregation of anomalous isoforms. Several studies have proposed the implication of Hsp in prion diseases. We analysed the gene expression and protein distribution of different members of the Hsp27, Hsp70, and Hsp90 families in the central nervous system of sheep naturally infected with scrapie. Different expression profiles were observed in the areas analysed. Whereas changes in transcript levels were not observed in the cerebellum or medulla oblongata, a significant decrease in HSP27 and HSP90 was detected in the prefrontal cortex. In contrast, HSP73 was over-expressed in diencephalons of scrapie animals. Western blotting did not reveal significant differences in Hsp90 and Hsp70 protein expression between scrapie and control animals. Expression rates identified by real-time RT-PCR and western blotting were compared with the extent of classical scrapie lesions using stepwise regression. Changes in Hsp gene and protein expression were associated with prion protein deposition, gliosis and spongiosis rather than with apoptosis. Finally, immunohistochemistry revealed intense Hsp70 and Hsp90 immunolabelling in Purkinje cells of scrapie sheep. In contrast, controls displayed little or no staining in these cells. The observed differences in gene expression and protein distribution suggest that the heat shock proteins analysed play a role in the natural form of the disease. PMID- 21314977 TI - Babesias of red deer (Cervus elaphus) in Ireland. AB - Blood samples were obtained from 38 wild red deer (Cervus elaphus) at two sites in Ireland and subjected to PCR analysis of the 18S rRNA gene followed by sequencing. Two fragments of the 18S rRNA gene were generated by two different PCR protocols and subsequent sequencing suggested that at least six of the deer were infected by a babesia that, in those loci, is indistinguishable from Babesia divergens, an important tick-borne pathogen of cattle and of zoonotic significance. Additionally, a B. odocoilei-like parasite was detected in three samples and a babesia that did not match any sequences in the GenBank database was found in five samples. Neither B. capreoli nor B. venatorum (EU1) were found. There have been several reports of B. divergens occurring in deer species, including red deer, roe deer (Capreolus capreolus) and reindeer (Rangifer tarandus). However, in view of recent re-sequencing of bovine-origin samples deposited previously in GenBank, it is unlikely that any of these sequences from deer are B. divergens. The present study describes the only deer piroplasm detected so far that shows complete identity with B. divergens, in just over half of the 18S rRNA gene. The entire gene of this deer parasite should be analysed and transmission experiments undertaken before the infectivity of B. divergens for red deer can be confirmed. PMID- 21314978 TI - The reverse genetics applied to fish RNA viruses. AB - Aquaculture has expanded rapidly to become a major economic and food-producing sector worldwide these last 30 years. In parallel, viral diseases have emerged and rapidly spread from farm to farm causing enormous economic losses. The most problematic viruses encountered in the field are mainly, but not exclusively, RNA viruses belonging to the Novirhabdovirus, Aquabirnavirus, Alphavirus and Betanodavirus genera. The recent establishment of reverse genetics systems to recover infectious fish RNA viruses entirely from cDNA has made possible to genetically manipulate the viral genome. These systems have provided powerful tools to study all aspects of the virus biology and virus-host interactions but also gave the opportunity to use these viruses as live vaccines or as gene vectors. This review provides an overview on the recent breakthroughs achieved by using these reverse genetics systems in terms of viral protein function, virulence and host-specificity factor, vaccine development and vector design. PMID- 21314979 TI - Fanconi anemia protein FANCD2 inhibits TRF1 polyADP-ribosylation through tankyrase1-dependent manner. AB - BACKGROUND: Fanconi anemia (FA) is a rare autosomal recessive syndrome characterized by developmental abnormalities, progressive bone marrow failure, and predisposition to cancer. The key FA protein FANCD2 crosstalks with members of DNA damage and repair pathways that also play a role at telomeres. Therefore, we investigated whether FANCD2 has a similar involvement at telomeres. RESULTS: We reveal that FANCD2 may perform a novel function separate to the FANCD2/BRCA pathway. This function includes FANCD2 interaction with one of the telomere components, the PARP family member tankyrase-1. Moreover, FANCD2 inhibits tankyrase-1 activity in vitro. In turn, FANCD2 deficiency increases the polyADP ribosylation of telomere binding factor TRF1. CONCLUSIONS: FANCD2 binding and inhibiting tankyrase-1PARsylation at telomeres may provide an additional step within the FA pathway for the regulation of genomic integrity. PMID- 21314980 TI - Comorbid mental disorders in substance users from a single catchment area--a clinical study. AB - BACKGROUND: The optimal treatment of patients with substance use disorders (SUDs) requires an awareness of their comorbid mental disorders and vice versa. The prevalence of comorbidity in first-time-admitted SUD patients has been insufficiently studied. Diagnosing comorbidity in substance users is complicated by symptom overlap, symptom fluctuations, and the limitations of the assessment methods. The aim of this study was to diagnose all mental disorders in substance users living in a single catchment area, without any history of treatment for addiction or psychiatric disorders, admitted consecutively to the specialist health services. The prevalence of substance-induced versus substance-independent disorders according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), in SUD patients will be described. METHODS: First-time consecutively admitted patients from a single catchment area, aged 16 years or older, admitted to addiction clinics or departments of psychiatry as outpatients or inpatients will be screened for substance-related problems using the Alcohol Use Disorder Identification Test and the Drug Use Disorder Identification Test. All patients with scores above the cutoff value will be asked to participate in the study. The patients included will be diagnosed for SUD and other axis I disorders by a psychiatrist using the Psychiatric Research Interview for Substance and Mental Disorders. This interview was designed for the diagnosis of primary and substance-induced disorders in substance users. Personality disorders will be assessed according to the Structured Clinical Interview for DSM-IV axis II disorders. The Symptom Checklist-90-Revised, the Inventory of Depressive Symptoms, the Montgomery Asberg Depression Rating Scale, the Young Mania Rating Scale, and the Angst Hypomania Check List will be used for additional diagnostic assessments. The sociodemographic data will be recorded with the Stanley Foundation's Network Entry Questionnaire. Biochemical assessments will reveal somatic diseases that may contribute to the patient's symptoms. DISCUSSION: This study is unique because the material represents a complete sample of first-time admitted treatment seekers with SUD from a single catchment area. Earlier studies have not focused on first-time-admitted patients, so chronically ill patients, may have been overrepresented in those samples. This study will contribute new knowledge about mental disorders in first-time-admitted SUD patients. PMID- 21314981 TI - Elastic Stable Intramedullary Nailing (ESIN), Orthoss(r) and Gravitational Platelet Separation--System (GPS(r)): an effective method of treatment for pathologic fractures of bone cysts in children. AB - BACKGROUND: The different treatment strategies for bone cysts in children are often associated with persistence and high recurrence rates of the lesions. The safety and clinical outcomes of a combined mechanical and biological treatment with elastic intramedullary nailing, artificial bone substitute and autologous platelet rich plasma are evaluated. METHODS: From 02/07 to 01/09 we offered all children with bone cysts the treatment combination of elastic intramedullary nailing (ESIN), artificial bone substitute (Orthoss(r)) and autologous platelet rich plasma, concentrated by the Gravitational Platelet Separation (GPS(r))- System. All patients were reviewed radiologically for one year following the removal of the intramedullary nailing, which was possible because of cyst obliteration. RESULTS: A cohort of 12 children (4 girls, 8 boys) was recruited. The mean patient age was 11.4 years (range 7-15 years). The bone defects (ten humeral, two femoral) included eight juvenile and four aneurysmal bone cysts. Five patients suffered from persistent cysts following earlier unsuccessful treatment of humeral bone cyst after pathologic fracture; the other seven presented with acute pathologic fractures. No peri- or postoperative complications occurred. The radiographic findings showed a total resolution of the cysts in ten cases (Capanna Grade 1); in two cases a small residual cyst remained (Capanna Grade 2). The intramedullary nails were removed six to twelve months (mean 7.7) after the operation; in one case, a fourteen year old boy (Capanna Grade 2), required a further application of GPS(r) and Orthoss(r) to reach a total resolution of the cyst. At follow-up (20-41 months, mean 31.8 months) all patients showed very good functional results and had returned to sporting activity. No refracture occurred, no further procedure was necessary. CONCLUSIONS: The combination of elastic intramedullary nailing, artificial bone substitute and autologous platelet rich plasma (GPS(r)) enhances the treatment of bone cysts in children, with no resulting complications. PMID- 21314982 TI - Patterns of weight loss and supplement consumption of male wrestlers in Tehran. AB - BACKGROUND: To evaluate the weight loss behavior of male wrestlers in Tehran METHODS: This study was a population-based cross sectional survey. Subjects were 436 wrestlers randomly selected from the wrestling clubs in Tehran employing cluster sample setting method. Subjects were interviewed based on a designed questionnaire. Body fat levels were measured based on skin fold measurements. RESULTS: Weight loss methods practiced by 62% of all subjects during the previous year employing rapid (<=7 days before the matches) and gradual (>7 days before the matches) weight reduction methods (73% and 34% of wrestlers who reduced their weight respectively). In addition, opinions on weight reduction, the methods of weight loss used, and the side effects of the weight loss practices as well as consumption of supplements among the subjects were reported in this study. The mean percentage of body fat of subjects was 15.9%. CONCLUSIONS: Rapid weight loss for matches and the use of unsafe methods of weight reduction such as fasting, and fluid reduction methods as well as acute side effects of weight loss were prevalent among wrestlers in Tehran. Some preventive measures including education and new rules such as scheduling weigh-ins immediately prior to the competitions and mat-side weigh-in are needed to prevent these unhealthy practices. The weight loss behaviors of these wrestlers should be changed from using dehydration methods to using gradual methods of weight loss. PMID- 21314983 TI - Radioimmunotherapy of experimental head and neck squamous cell carcinoma (HNSCC) with E6-specific antibody using a novel HPV-16 positive HNSCC cell line. AB - BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide with a poor prognosis. Human papilloma virus (HPV) infection is associated with 20% HNSCC, and 50% of oropharyngeal carcinoma. HPV16 type is detected in 90% of all HPV+ HNSCC. Recently we suggested a fundamentally different approach to treatment of cancers of viral origin by targeting viral antigens on cancer cells with radiolabeled antibodies (mAbs) which promises exquisite specificity of treatment. We aimed at extending this approach to HPV related head and neck cancer by performing radioimmunotherapy (RIT) targeting E6 and E7 oncogenes with radiolabeled mAbs. METHODS: We first aimed at developing HPV16+ cell line and animal model for RIT of HNSCC as at present there are no commercially available HPV16+ HNSCC cell lines and there is only one HPV+ cell line among the collection maintained by Dusseldorf, Michigan and Turku groups. Commercially available HNSCC cell line FaDu was transfected with pLXSN16E6E7 vector containing HPV16 E6 and E7 genes. Generated novel cell lines were evaluated by PCR and western blot and the tumorigenecity was assessed in nude mice. Proof of principle RIT targeting E6 oncoprotein in 2A3 tumor-bearing nude mice was conducted using unlabeled or 188-Rhenium (188Re)-labeled C1P5 mAb to E6. RESULTS: Novel HPV16+ 2A3 cell line reliably expressed E6 oncoprotein. E6 expression was modifiable with proteasome inhibitor MG132 in a dose-dependent manner. The levels of E6 expression in 2A3 cell line were estimated to be around 200 HPV copies per cell. The HPV16+ 2A3 cell line preserved 100% tumorigenicity of parent FaDu cells in nude mice. During RIT of 2A3 tumors in nude mice the relatively low dose of 200 MUCi 188Re-C1P5 mAb was effective in decreasing the tumor growth in comparison with untreated controls. Unlabeled C1P5 mAb also caused some decrease in tumor progression, however, much less pronounced than 188Re-C1P5 mAb. CONCLUSIONS: We describe a proof-of-principle RIT study targeting HPV16 E6 oncoprotein with radiolabeled mAb to E6 in a stably transformed HPV16+ HNSCC cell line and tumor model in nude mice, and demonstrate potential utility of RIT as a novel molecular targeted therapy for HNSCC. PMID- 21314984 TI - Autotaxin is induced by TSA through HDAC3 and HDAC7 inhibition and antagonizes the TSA-induced cell apoptosis. AB - BACKGROUND: Autotaxin (ATX) is a secreted glycoprotein with the lysophospholipase D (lysoPLD) activity to convert lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA), a bioactive lysophospholipid involved in diverse biological actions. ATX is highly expressed in some cancer cells and contributes to their tumorigenesis, invasion, and metastases, while in other cancer cells ATX is silenced or expressed at low level. The mechanism of ATX expression regulation in cancer cells remains largely unknown. RESULTS: In the present study, we demonstrated that trichostatin A (TSA), a well-known HDAC inhibitor (HDACi), significantly induced ATX expression in SW480 and several other cancer cells with low or undetectable endogenous ATX expression. ATX induction could be observed when HDAC3 and HDAC7 were down-regulated by their siRNAs. It was found that HDAC7 expression levels were low in the cancer cells with high endogenous ATX expression. Exogenous over-expression of HDAC7 inhibited ATX expression in these cells in a HDAC3-dependent manner. These data indicate that HDAC3 and HDAC7 collaboratively suppress ATX expression in cancer cells, and suggest that TSA induce ATX expression by inhibiting HDAC3 and HDAC7. The biological significance of this regulation mechanism was revealed by demonstrating that TSA-induced ATX protected cancer cells against TSA-induced apoptosis by producing LPA through its lysoPLD activity, which could be reversed by BrP-LPA and S32826, the inhibitors of the ATX-LPA axis. CONCLUSIONS: We have demonstrated that ATX expression is repressed by HDAC3 and HDAC7 in cancer cells. During TSA treatment, ATX is induced due to the HDAC3 and HDAC7 inhibition and functionally antagonizes the TSA-induced apoptosis. These results reveal an internal HDACi-resistant mechanism in cancer cells, and suggest that the inhibition of ATX-LPA axis would be helpful to improve the efficacy of HDACi-based therapeutics against cancer. PMID- 21314986 TI - Recent changes in human resources for health and health facilities at the district level in Indonesia: evidence from 3 districts in Java. AB - BACKGROUND: There is continuing discussion in Indonesia about the need for improved information on human resources for health at the district level where programs are actually delivered. This is particularly the case after a central government decision to offer doctors, nurses and midwives on contract the chance to convert to permanent civil service status. Our objective here is to report changes between 2006 and 2008 in numbers and employment status of health staff in three districts following the central government decision. METHODS: Information was derived from records at the district health office and, where necessary for clarification, discussions with district officials. RESULTS: Across the three districts and all public sector provider categories there was an increase of almost 680 providers between 2006 and 2008 - more than 300 nurses, more than 300 midwives and 25 doctors. The increases for permanent public servants were proportionately much greater (43%) than the total (16%). The increase in those who are permanent civil servants was greatest for nurses (51%) and midwives (35%) with corresponding decreases in the proportion of staff on contract. There was considerable variation between the three districts. CONCLUSIONS: There has been a significant increase in the number of healthcare providers in the 3 districts surveyed and the proportion now permanent public servants has increased even more than the increase in total numbers. The changes have the effect of increasing the proportion of total public expenditure allocated to salaries and reducing the flexibility of the districts in managing their own budgets. Because public servants are allowed private practice outside office hours there has also been an increase in the number of private practice facilities offering health care. These changes illustrate the need for a much improved human resources information system and a coherent policy to guide actions on human resources for health at the national, provincial and district levels. PMID- 21314985 TI - Perceived unfairness in working conditions: the case of public health services in Tanzania. AB - BACKGROUND: The focus on the determinants of the quality of health services in low-income countries is increasing. Health workers' motivation has emerged as a topic of substantial interest in this context. The main objective of this article is to explore health workers' experience of working conditions, linked to motivation to work. Working conditions have been pointed out as a key factor in ensuring a motivated and well performing staff. The empirical focus is on rural public health services in Tanzania. The study aims to situate the results in a broader historical context in order to enhance our understanding of the health worker discourse on working conditions. METHODS: The study has a qualitative study design to elicit detailed information on health workers' experience of their working conditions. The data comprise focus group discussions (FGDs) and in depth interviews (IDIs) with administrators, clinicians and nursing staff in the public health services in a rural district in Tanzania. The study has an ethnographic backdrop based on earlier long-term fieldwork in the same part of Tanzania. RESULTS: The article provides insights into health workers' understanding and assessment of their working conditions. An experience of unsatisfactory working conditions as well as a perceived lack of fundamental fairness dominated the FGDs and IDIs. Informants reported unfairness with reference to factors such as salary, promotion, recognition of work experience, allocation of allowances and access to training as well as to human resource management. The study also revealed that many health workers lack information or knowledge about factors that influence their working conditions. CONCLUSIONS: The article calls for attention to the importance of locating the discourse of unfairness related to working conditions in a broader historical/political context. Tanzanian history has been characterised by an ambiguous and shifting landscape of state regulation, economic reforms, decentralisation and emerging democratic sentiments. Such a historic contextualisation enhances our understanding of the strong sentiments of unfairness revealed in this study and assists us in considering potential ways forward. PMID- 21314987 TI - Cellular stress-induced up-regulation of FMRP promotes cell survival by modulating PI3K-Akt phosphorylation cascades. AB - BACKGROUND: Fragile X syndrome (FXS), the most commonly inherited mental retardation and single gene cause of autistic spectrum disorder, occurs when the Fmr1 gene is mutated. The product of Fmr1, fragile X linked mental retardation protein (FMRP) is widely expressed in HeLa cells, however the roles of FMRP within HeLa cells were not elucidated, yet. Interacting with a diverse range of mRNAs related to cellular survival regulatory signals, understanding the functions of FMRP in cellular context would provide better insights into the role of this interesting protein in FXS. Using HeLa cells treated with etoposide as a model, we tried to determine whether FMRP could play a role in cell survival. METHODS: Apoptotic cell death was induced by etoposide treatment on Hela cells. After we transiently modulated FMRP expression (silencing or enhancing) by using molecular biotechnological methods such as small hairpin RNA virus-induced knock down and overexpression using transfection with FMRP expression vectors, cellular viability was measured using propidium iodide staining, TUNEL staining, and FACS analysis along with the level of activation of PI3K-Akt pathway by Western blot. Expression level of FMRP and apoptotic regulator BcL-xL was analyzed by Western blot, RT-PCR and immunocytochemistry. RESULTS: An increased FMRP expression was measured in etoposide-treated HeLa cells, which was induced by PI3K-Akt activation. Without FMRP expression, cellular defence mechanism via PI3K-Akt-Bcl xL was weakened and resulted in an augmented cell death by etoposide. In addition, FMRP over-expression lead to the activation of PI3K-Akt signalling pathway as well as increased FMRP and BcL-xL expression, which culminates with the increased cell survival in etoposide-treated HeLa cells. CONCLUSIONS: Taken together, these results suggest that FMRP expression is an essential part of cellular survival mechanisms through the modulation of PI3K, Akt, and Bcl-xL signal pathways. PMID- 21314988 TI - Antihypertensive medication versus health promotion for improving metabolic syndrome in preventing cardiovascular events: a success rate-oriented simulation study. AB - BACKGROUND: In practice, it is difficult to compare the effectiveness of traditional antihypertensive treatment with that of health promotion in reducing incidence rate of cardiovascular disease (IRCVD, events/year). This simulation study compared the effectiveness of two approaches to reducing IRCVD in a sample population: a traditional approach, in which high-risk patients are treated with conventional antihypertensive medications, and a population-based approach, in which subjects participate in a health promotion program. METHODS: We constructed a simulation model for a sample population of middle-aged Japanese men whose systolic blood pressure (SBP) levels are normally distributed (130 +/- 20 mm Hg). The principal assumption was that IRCVD increases exponentially according to SBP. The population IRCVD was calculated as the product of the distribution of SBP multiplied by IRCVD at each SBP. The cumulative IRCVD was calculated by the definite integral from the lowest to the highest SBP of IRCVD at each SBP level. The success rates were calculated according to SBP and metabolic risk profiles in the two approaches, respectively. RESULTS: The reduction in IRCVD was twice as large for antihypertensive medications as it was for health promotion in several situations. For example, if adherence to antihypertensive treatment occurred at a realistic level, the decrease in IRCVD was estimated at 9.99 * 10(-4). In contrast, even if the health program was promoted optimistically, the decrease in IRCVD was estimated at 4.69 * 10(-4). CONCLUSIONS: The success rate-oriented simulation suggests that prescribing antihypertensive medications is superior to promoting the health promotion program in reducing IRCVD in virtual middle-aged Japanese men. PMID- 21314989 TI - Stakeholder's perceptions of help-seeking behaviour among people with mental health problems in Uganda. AB - INTRODUCTION: Mental health facilities in Uganda remain underutilized, despite efforts to decentralize the services. One of the possible explanations for this is the help-seeking behaviours of people with mental health problems. Unfortunately little is known about the factors that influence the help-seeking behaviours. Delays in seeking proper treatment are known to compromise the outcome of the care. AIM: To examine the help-seeking behaviours of individuals with mental health problems, and the factors that may influence such behaviours in Uganda. METHOD: Sixty-two interviews and six focus groups were conducted with stakeholders drawn from national and district levels. Thematic analysis of the data was conducted using a framework analysis approach. RESULTS: The findings revealed that in some Ugandan communities, help is mostly sought from traditional healers initially, whereas western form of care is usually considered as a last resort. The factors found to influence help-seeking behaviour within the community include: beliefs about the causes of mental illness, the nature of service delivery, accessibility and cost, stigma. CONCLUSION: Increasing the uptake of mental health services requires dedicating more human and financial resources to conventional mental health services. Better understanding of socio cultural factors that may influence accessibility, engagement and collaboration with traditional healers and conventional practitioners is also urgently required. PMID- 21314990 TI - Is income or employment a stronger predictor of smoking than education in economically less developed countries? A cross-sectional study in Hungary. AB - BACKGROUND: In developed European countries in the last phase of the smoking epidemic, education is a stronger predictor of smoking than income or employment. We examine whether this also applies in economically less developed countries. METHODS: Data from 7218 respondents in the 25-64 age group came from two National Health Interview Surveys conducted in 2000 and 2003 in Hungary. Independent effects of educational level, income and employment status were studied in relation to smoking prevalence, initiation and continuation for all age groups combined and separately for 25-34, 35-49 and 50-64 years old. Absolute levels were evaluated by using age-standardized prevalence rates. Relative differences were assessed by means of logistic regression. RESULTS: Education and income, but not employment, were associated with equally large differences in smoking prevalence in Hungary in the 25-64 age group. Among men, smoking initiation was related to low educational level, whereas smoking continuation was related to low income. Among women, low education and low income were associated with both high initiation and high continuation rates. Considerable differences were found between the age groups. Inverse social gradients were generally strongest in the youngest age groups. However, smoking continuation among men had the strongest association with low income for the middle-aged group. CONCLUSIONS: Patterns of inequalities in smoking in Hungary can be best understood in relation to two processes: the smoking epidemic, and the additional effects of poverty. Equity orientated tobacco control measures should target the low educated to prevent their smoking initiation, and the poor to improve their cessation rates. PMID- 21314991 TI - Diet quality is positively associated with 100% fruit juice consumption in children and adults in the United States: NHANES 2003-2006. AB - BACKGROUND: One hundred percent fruit juice (100% FJ) has been viewed by some as a sweetened beverage with concerns about its effect on weight. Little regard has been given to the contribution of 100% FJ to diet quality. METHODS: In this study data from the 2003-2006 National Health and Nutrition Examination Survey were used to examine the association of 100% FJ consumption with diet quality in participants 2-5 years of age (y) (n = 1665), 6-12 y (n = 2446), 13-18 y (n = 3139), and 19+y (n = 8861). Two 24-hour dietary recalls were used to determine usual intake using the National Cancer Institute method. Usual intake, standard errors, and regression analyses (juice independent variable and Healthy Eating Index-2005 [HEI-2005] components were dependent variables), using appropriate covariates, were determined using sample weights. RESULTS: The percentage of participants 2-5 y, 6-12 y, 13-18 y, and 19+y that consumed 100% FJ was 71%, 57%, 45%, and 62%, respectively. Usual intake of 100% FJ (ounce [oz]/day) among the four age groups was: 5.8 +/- 0.6, 2.6 +/- 0.4, 3.7 +/- 0.4, and 2.4 +/- 0.2 for those in age groups 2-5 y, 6-12 y, 13-18 y, and 19+y, respectively. Consumption of 100% FJ was associated with higher energy intake in 6-12 y, 13-18 y, and 19+y; and higher total, saturated, and discretionary fats in 13-18 y participants. Consumption of 100% FJ was associated with higher total HEI-2005 scores in all age groups (< 0.0001). In 100% FJ consumers, total and whole fruit consumption was higher and intake of added sugars was lower in all age groups. CONCLUSIONS: Usual intake of 100% FJ consumption exceeded MyPyramid recommendations for children 2-5 y, but was associated with better diet quality in all age groups and should be encouraged in moderation as part of a healthy diet. PMID- 21314992 TI - Malaria rapid diagnostic kits: quality of packaging, design and labelling of boxes and components and readability and accuracy of information inserts. AB - BACKGROUND: The present study assessed malaria RDT kits for adequate and correct packaging, design and labelling of boxes and components. Information inserts were studied for readability and accuracy of information. METHODS: Criteria for packaging, design, labelling and information were compiled from Directive 98/79 of the European Community (EC), relevant World Health Organization (WHO) documents and studies on end-users' performance of RDTs. Typography and readability level (Flesch-Kincaid grade level) were assessed. RESULTS: Forty-two RDT kits from 22 manufacturers were assessed, 35 of which had evidence of good manufacturing practice according to available information (i.e. CE-label affixed or inclusion in the WHO list of ISO13485:2003 certified manufacturers). Shortcomings in devices were (i) insufficient place for writing sample identification (n=40) and (ii) ambiguous labelling of the reading window (n=6). Buffer vial labels were lacking essential information (n=24) or were of poor quality (n=16). Information inserts had elevated readability levels (median Flesch Kincaid grade 8.9, range 7.1-12.9) and user-unfriendly typography (median font size 8, range 5-10). Inadequacies included (i) no referral to biosafety (n=18), (ii) critical differences between depicted and real devices (n=8), (iii) figures with unrealistic colours (n=4), (iv) incomplete information about RDT line interpretations (n=31) and no data on test characteristics (n=8). Other problems included (i) kit names that referred to Plasmodium vivax although targeting a pan-species Plasmodium antigen (n=4), (ii) not stating the identity of the pan-species antigen (n=2) and (iii) slight but numerous differences in names displayed on boxes, device packages and information inserts. Three CE labelled RDT kits produced outside the EC had no authorized representative affixed and the shape and relative dimensions of the CE symbol affixed did not comply with the Directive 98/79/EC. Overall, RDTs with evidence of GMP scored better compared to those without but inadequacies were observed in both groups. CONCLUSION: Overall, malaria RDTs showed shortcomings in quality of construction, design and labelling of boxes, device packages, devices and buffers. Information inserts were difficult to read and lacked relevant information. PMID- 21314993 TI - The L76V mutation in HIV-1 protease is potentially associated with hypersusceptibility to protease inhibitors Atazanavir and Saquinavir: is there a clinical advantage? AB - BACKGROUND: Although being considered as a rarely observed HIV-1 protease mutation in clinical isolates, the L76V-prevalence increased 1998-2008 in some European countries most likely due to the approval of Lopinavir, Amprenavir and Darunavir which can select L76V. Beside an enhancement of resistance, L76V is also discussed to confer hypersusceptibility to the drugs Atazanavir and Saquinavir which might enable new treatment strategies by trying to take advantage of particular mutations. RESULTS: Based on a cohort of 47 L76V-positive patients, we examined if there might exist a clinical advantage for L76V-positive patients concerning long-term success of PI-containing regimens in patients with limited therapy options.Genotypic- and phenotypic HIV-resistance tests from 47 mostly multi-resistant, L76V-positive patients throughout Germany were accomplished retrospectively 1999-2009. Five genotype-based drug-susceptibility predictions received from online interpretation-tools for Atazanavir, Saquinavir, Amprenavir and Lopinavir, were compared to phenotype-based predictions that were determined by using a recombinant virus assay along with a Virtual PhenotypeTM(Virco). The clinical outcome of the L76V-adapted follow-up therapy was determined by monitoring viral load for 96 weeks. CONCLUSIONS: In this analysis, the mostly used interpretation systems overestimated the L76V-mutation concerning Atazanavir- and SQV resistance. In fact, a clear benefit in drug susceptibility for these drugs was observed in phenotype analysis after establishment of L76V. More importantly, long-term therapy success was significantly higher in patients receiving Atazanavir and/or Saquinavir plus one L76V-selecting drug compared to patients without L76V-selecting agents (p = 0.002).In case of L76V-occurrence ATV and/or SQV may represent encouraging options for patients in deep salvage situations. PMID- 21314994 TI - Newly recognized mosquito-associated viruses in mainland China, in the last two decades. AB - There are four principal arboviruses in mainland China. Two kinds of them are mosquito-borne viruses, namely Japanese encephalitis virus and dengue virus, which lead to Japanese encephalitis, and dengue fever/dengue hemorrhagic fever respectively; the other two are tick-borne viruses, namely tick-borne encephalitis virus and Crimean-Congo hemorrhagic fever virus (also known as Xinjiang hemorrhagic fever virus), which contribute to tick-borne encephalitis and Xinjiang hemorrhagic fever respectively. With exception of these four main arboviruses, many other mosquito-associated viruses have been isolated and identified in recent years. These newly isolated and identified mosquito associated viruses are probably responsible for human and animal infections and diseases. The purpose of this review is to describe the newly isolated mosquito associated viruses in mainland China which belong to five viral families, including their virological properties, phylogenetic relationships, serological evidence, as well as to appeal the public health concentration worldwide. PMID- 21314995 TI - Economic burden of illness of acute coronary syndromes: medical and productivity costs. AB - BACKGROUND: The significant economic burden associated with acute coronary syndromes (ACS) provides a need to evaluate both medical costs and productivity costs, according to evolving guideline-driven ACS treatment strategies, medical management (MM), percutaneous coronary intervention (PCI), or coronary artery bypass graft (CABG). METHODS: Commercially insured individuals, aged 18-64, with an emergency room (ER) visit or hospitalization accompanied by an ACS diagnosis (index event) were identified from a large claims database between 01/2004 and 12/2005 with a 1-year follow-up period. Patients who had an ACS diagnosis in the 12 months prior to their index event were excluded. Patients were divided into 3 groups according to treatment strategies during the index event: MM, PCI, or CABG. A subset of patients was identified for the productivity cost analysis exploring short-term disability and absenteeism costs. Multivariate generalized linear models were performed to examine the ACS costs by 3 different treatment strategies. RESULTS: A total of 10,487 patients were identified for the medical cost analysis. The total 1-year medical costs (index event costs plus the 1-year follow-up costs) were lowest for MM patients ($34,087), followed by PCI patients ($52,673) and CABG patients ($86,914). Of the 3,080 patients in the productivity costs analysis, 2,454 patients were identified in the short-term disability cohort and 626 patients were identified in the absenteeism cohort. Both the estimated mean total 1-year short-term disability and absenteeism costs were highest for CABG patients ($17,335, $14,960, respectively) compared to MM patients ($6,048, $9,826, respectively) and PCI patients ($9,221, $9,460, respectively). CONCLUSIONS: Both total 1-year medical costs and 1-year productivity costs are substantial for working-aged individuals with ACS. These costs differ according to the type of treatment strategy, with CABG having higher costs compared to either PCI or MM. PMID- 21314996 TI - Systematic search for enhancer elements and somatic allelic imbalance at seven low-penetrance colorectal cancer predisposition loci. AB - BACKGROUND: Common single-nucleotide polymorphisms (SNPs) in ten chromosomal loci have been shown to predispose to colorectal cancer (CRC) in genome-wide association studies. A plausible biological mechanism of CRC susceptibility associated with genetic variation has so far only been proposed for three loci, each pointing to variants that affect gene expression through distant regulatory elements. In this study, we aimed to gain insight into the molecular basis of seven low-penetrance CRC loci tagged by rs4779584 at 15q13, rs10795668 at 10p14, rs3802842 at 11q23, rs4444235 at 14q22, rs9929218 at 16q22, rs10411210 at 19q13, and rs961253 at 20p12. METHODS: Possible somatic gain of the risk allele or loss of the protective allele was studied by analyzing allelic imbalance in tumour and corresponding normal tissue samples of heterozygous patients. Functional variants were searched from in silico predicted enhancer elements locating inside the CRC associating linkage-disequilibrium regions. RESULTS: No allelic imbalance targeting the SNPs was observed at any of the seven loci. Altogether, 12 SNPs that were predicted to disrupt potential transcription factor binding sequences were genotyped in the same population-based case-control series as the seven tagging SNPs originally. None showed association with CRC. CONCLUSIONS: The results of the allelic imbalance analysis suggest that the seven CRC risk variants are not somatically selected for in the neoplastic progression. The bioinformatic approach was unable to pinpoint cancer-causing variants at any of the seven loci. While it is possible that many of the predisposition loci for CRC are involved in control of gene expression by targeting transcription factor binding sites, also other possibilities, such as regulatory RNAs, should be considered. PMID- 21314998 TI - The misleading simplicity of advance directives. PMID- 21314997 TI - The Collateral Source version of the Geriatric Depression Scale: evaluation of psychometric properties and discrepancy between collateral sources and patients with dementia in reporting depression. AB - BACKGROUND: Depression is under-diagnosed and under-treated in older adults. The purposes of this study were to (a) evaluate the psychometric properties of the Collateral Source Geriatric Depression Scale (CS-GDS), (b) compare collateral source scores on the CS-GDS with patient scores on the GDS, and (c) examine factors associated with any discrepancies between the CS-GDS and the GDS. METHODS: This secondary analysis used data from 132 older adults and their collateral sources attending a geriatric assessment program over a 15-month period. Scores on the 30-, 15-, and 5-item CS-GDS were compared to clinician diagnoses of depression using DSM-IV-TR criteria and patient GDS scores. RESULTS: The three forms of the CS-GDS had acceptable internal consistency, sensitivity and specificity with recommended cut-off scores of 18, 9 and 3, respectively. Collateral sources reported more depressive symptoms than patients did themselves. Simple regression analysis showed that caregiver burden significantly influenced the discrepancy between CS-GDS scores and GDS scores (beta = 0.147; p = 0.004). Functional limitations and collateral relations to the patient were not associated with these discrepancies. CONCLUSION: All three collateral versions had acceptable psychometric properties, which supports the use of the CS-GDS to assess depression in older adults. The CS-GDS provides an important alternative for depression screening with older adults who cannot complete screening tools themselves; however, alternative cut-off scores must be used for high sensitivity and specificity. PMID- 21314999 TI - [Sepsis is a disease of the microcirculation]. PMID- 21315000 TI - [Effect of inhibition of cytosolic phospholipase A2 on Leptin release from human umbilical vein endothelial cells induced by lipopolysaccharide]. AB - OBJECTIVE: To determine Leptin levels in supernatant fluid of culture of human umbilical vein endothelial cells (ECV-304) after being challenged by lipopolysaccharide (LPS) and calcium ion vector A23187, and to explore the possible relation between Leptin release and cytosolic phospholipase A(2) (cPLA(2)) activity in an inflammatory cell model. METHODS: ECV-304 cells were cultured in vitro. Experiment 1: the cells were divided into seven groups: blank control group, LPS 5, 10, 20 MUg/ml stimulation groups, A23187 0.1, 1.0, 10.0 MUmol/L stimulation groups. The supernatants were collected at 6, 12 and 24 hours.Experiment 2: according to the results of experiment 1, the cells were divided into eight groups: blank control group, LPS 20 MUg/ml stimulation group, the inhibitor of cPLA2 AACOCF3 0.1, 1.0, 10.0 MUmol/L plus LPS stimulation groups, the inhibitor of mitogen-activated protein/extracellular signal-regulated protein kinase kinase 1/2 (MEK1/2) U0126 0.1, 1.0, 5.0 MUmol/L plus LPS stimulation groups, with AACOCF3 or U0126 added 1 hour before the addition of LPS, and the supernatants were collected 24 hours after the addition of LPS. Leptin level was determined by radioimmunoassay. RESULTS: Experiment 1: with increase in LPS concentration and prolongation of time, Leptin release was decreased gradually. After 24 hours of interaction the concentration of Leptin (ng/ml) in LPS 20 MUg/ml group was decreased significantly compared with the blank control group (0.540+/-0.109 vs. 0.823+/-0.048,P<0.05). However, A23187 had no significant effect on Leptin release. Experiment 2: LPS rendered cells to release less Leptin (ng/ml: 0.558+/-0.069 vs. 0.825+/-0.067,P<0.05); by adding AACOCF3 or U0126 in different concentration before adding LPS rendered the cells to release more Leptin (ng/ml), and it showed concentration-dependent (the AACOCF3 0.1, 1.0, 10.0 MUmol/L groups were 0.673+/-0.135, 0.723+/-0.055, 0.797+/ 0.062, respectively; the U0126 0.1, 1.0, 5.0 MUmol/L groups were 0.698+/-0.112, 0.862+/-0.184, 0.935+/-0.145, respectively). The release of Leptin in AACOCF3 1.0 MUmol/L, 10.0 MUmol/L and U0126 1.0 MUmol/L, 5.0 MUmol/L groups was significantly higher than LPS 20 MUg/ml stimulation group (all P<0.05). CONCLUSION: There is a possible relation between Leptin release and cPLA 2 activity in inflammatory cells induced by LPS. PMID- 21315001 TI - [Change in number of circulating endothelial progenitor cells and its significance in septic rats]. AB - OBJECTIVE: To observe the change in number of circulating endothelial progenitor cells (cEPCs) and analyze its significance in septic rat. METHODS: Septic model of male Sprague-Dawley (SD) rats was reproduced by cecum ligation and puncture (n=80), and the normal control group (n=16) and sham operation group (n=80) were established. Nine rats in each group were used, and the cEPCs numbers in peripheral blood mononuclear cells (PBMCs, by flow cytometry), tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), D-dimer (by enzyme linked immunosorbent assay, ELISA), antithrombase-III ( AT-III , by immunonephelometry), wet/dry (W/D) ratio of liver, kidney and lung were determined at 0, 6, 12, 18 hours and 1, 2, 3, 7 days after reproduction of model. Eight rats in each group were used, and the pathologic changes in liver, kidney and lung at 1 day were observed, and the injury scores were evaluated. RESULTS: The cEPCs number was markedly increased, reaching the peak [(7 161.9+/-689.8)/10(6) PBMCs]at 18 hours. Circulating TNF-alpha, IL-10, D-dimer, AT-III were found to be increased, and the levels reached the peak at 12 hours, 12 hours, 3 days, 18 hours, respectively[(51.3+/-6.8) ng/L, (77.9+/-8.6) ng/L, (93.5+/-11.5) mg/L, (193.8+/ 43.0) mg/L]. W/D ratio was elevated and signs of injury to the liver,kidney, lung became more obvious (18-hour W/D of liver: 3.79+/-0.09, kidney: 4.25+/-0.08, lung: 4.91+/-0.09; 1-day tissue evaluation of liver:1.86+/-0.26, kidney: 5.14+/ 0.34, lung: 6.57+/-0.37). The levels of all parameters in model group were significantly higher than those in sham operation group[18-hour cEPCs numbers: (2 235.5+/-472.7)/10(6) PBMCs, 12-hour TNF-alpha: (14.3+/-5.8) ng/L, 12-hour IL-10: (35.0+/-5.8) ng/L, 3-day D-dimer: (14.2+/-4.4) mg/L, 18-hour AT-III: (100.1+/ 12.8) mg/L; 18-hour liver W/D ratio: 3.50+/-0.07, kidney: 3.96+/-0.04, lung: 4.54+/-0.14; 1-day tissue evaluation of liver:0.29+/-0.18,kidney: 0.57+/-0.20, lung: 1.14+/-0.51, P<0.05 or P<0.01]. There was positive correlation between cEPCs numbers and TNF-alpha (r=0.587), IL-10 (r=0.497), D-dimer (r=0.294), AT-III (r=0.690), and W/D ratio of liver, kidney, lung (r(1)=0.532, r(2)=0.532, r(3)=0.679, all P<0.01). CONCLUSION: The cEPCs number markedly increases in septic rats, and it shows positive correlation with the degree of inflammatory reaction, blood clotting activation, capillary leakage and tissue damage. The increase of number of cEPCs is the result of reaction to sepsis, and its change in number might be valuable in evaluating the pathogenesis of sepsis. PMID- 21315002 TI - [Effects of Hengyan medicinal recipe on the regulation of immunity in patients with severe sepsis: a prospective clinical trial]. AB - OBJECTIVE: To observe the role of Hengyan medicinal recipe on the regulation of immunity in patients with severe sepsis. METHODS: Patients with severe sepsis included in the study were randomly divided into two groups. Hengyan medicinal recipe group (n=22), in which patients were treated with Hengyan medicinal recipe 50 ml, 3 times daily, for 7 days.The recipe was composed of Bombyx batryticatus 10 g, Cicada slough 10 g, Curcuma 10 g, Rhubarb 3 g, Radix astragalus 10 g, Radix ophiopogonis 10 g, Red ginseng 10 g, Paeony 10 g, Walnut kernel 10 g, Safflower 10 g, combined with western medicine treatment.The patients in control group (n=23) were treated with western medicine same as above. In all patients the number of bowel movement and the scores of acute physiology and chronic health evaluationII (APACHEII) were recorded. Blood was taken for the determination of the levels of interleukins (IL-6, IL-10), tumor necrosis factor-alpha (TNF alpha), CD3(+), CD4(+), CD8(+) T cell before and 1, 3, 7 days after the treatment. RESULTS: Compared with the control group, the number of bowel movement, scores of APACHEII and IL-6, IL-10, IL-6/IL-10, TNF-alpha in Hengyan medicinal recipe group were decreased significantly at 7 days, while the levels of CD3(+), CD4(+), CD8(+) T cell were increased significantly [the number of bowel movement (times): 2.1+/-0.7 vs. 0.6+/-0.6, APACHEII score: 13.8+/-5.6 vs. 16.8+/-5.6, IL-6 (ng/L): 45 (32, 89) vs. 80 (41, 116), IL-10 (ng/L): 4.2 (3.6, 9.8) vs. 6.6 (3.5, 10.6), IL-6/IL-10:10.6 (7.2, 24.8) vs. 12.8 (7.6, 28.8), TNF alpha (ng/L):4.2+/-2.6 vs. 5.6+/-2.7, CD3(+): 6.59+/-2.80 vs. 5.65+/-2.92, CD4(+): 3.65+/-2.17 vs. 3.25+/-2.46, CD8(+): 2.73+/-1.29 vs. 2.26+/-1.48, P<0.05 or P<0.01]. CONCLUSION: Hengyan medicinal recipe could not only reduce the systemic inflammation, but also plays a role in bidirectional regulation of the immune disturbance to ameliorate immune suppression of sepsis patients. PMID- 21315003 TI - [Effect of continuous blood purification on endothelial cell function in patients with severe sepsis]. AB - OBJECTIVE: To investigate the effect of continuous blood purification (CBP) in patients with severe sepsis, and to evaluate the change in endothelial cell function in patients with severe sepsis during CBP therapy. METHODS: According to random principle, 45 patients were divided into control group (n=22) and CBP group (n=23). All patients of both groups received routine treatment according to international guidelines 2008 for management of severe sepsis, but the patients in the CBP group also received continuous veno-venous hemofiltration (CVVH) for 72 hours, the ultrafiltrate volume was 40 ml*kg(-1)*h(-1). Blood gas analysis was done before and 24 hours and 72 hours after CVVH therapy. The activated protein C (APC), soluble intercellular adhesion molecule-1 (sICAM-1) and von Willebrand factor (vWF) were measured. Also the length of stay in intensive care unit (ICU), time of mechanical ventilation, and death rate of patients in 28 days were observed. RESULTS: Compared with control group, the length of stay in ICU (days) and length of use of ventilator (days) in CBP group were shorter (9.12+/-3.07 vs. 11.64+/-4.82, 5.52+/-3.48 vs. 8.02+/-5.25, both P<0.05), and the death rate in 28 days was lower [13.0% (3/23) vs. 40.9% (9/22), P<0.05]. After therapy, patients in CBP group showed more reduction in the APACHEII score compared with control group (3.96+/-4.07 vs. 1.68+/-2.43, P<0.05). Patients in control group showed less change in APC, sICAM-1 and vWF. APC in CBP group increased at 72 hours, and sICAM-1 and vWF of CBP group respectively decreased at 24 hours or 72 hours, while the APC (MUg/L) and vWF (mg/L) at 72 hours showed significant change compared with that of the control group (15.12+/-7.57 vs. 10.01+/-5.83, 1.58+/ 0.73 vs. 2.64+/-1.34, P<0.05 and P<0.01). In patients who died in 28 days (12 patients) there were little changes in APC, sICAM-1 and vWF, while patients who lived for 28 days (33 patients), showed significantly more reduction in sICAM-1 (MUg/L) and vWF (mg/L, 61.03+/-45.58 vs. 104.64+/-71.08, 1.88+/-1.21 vs. 2.70+/ 0.95,both P<0.05). The APC value (MUg/L) was increased after treatment in patients who survived for 28 days (13.55+/-7.11 vs. 10.37+/-7.60, P<0.01). CONCLUSION: CBP therapy can protect endothelial cell function and ameliorate dysfunction, and it reduces the severity of the severe sepsis as well as improves the outcome of patients with severe sepsis. PMID- 21315004 TI - [The value of determination of serum myoglobin in estimation of degree of illness and prognosis of patients with sepsis in Xining area]. AB - OBJECTIVE: To investigate the value of determination of serum myoglobin (MYO) in estimation of the degree of illness and prognosis of patients with sepsis in Xining area. METHODS: Serum MYO was measured and acute physiological and chronic health estimationII (APACHEII) score was evaluated in 30 cases with sepsis within 24 hours of admission to emergency intensive care unit (EICU), and their correlation was analyzed. The patients were divided into two groups, survival group and death group according to the result within 28 days. The MYO and APACHEII score were analyzed in both groups. All cases were divided into three groups: namely <500 (n=10), 500-1 000 (n=14), >1 000 MUg/L (n=6) groups, according to serum MYO value, and APACHEII score and dead case were compared among three groups. RESULTS: Sixteen patients survived, and 14 patients died. The level of serum MYO and APACHEII score were significantly lower in survival group than death group [MYO (MUg/L): 607.85+/-499.40 vs. 976.21+/-370.10, APACHEII score: 15.50+/-4.43 vs. 18.93+/-3.63, t(1)=2.28, t(2)=2.29, both P<0.05]. With the elevation of serum MYO, the dead case was increased in sepsis patients (the dead case in MYO<500, 500-1 000, >1 000 MUg/L groups was 2, 7, 5 cases, respectively,chi(2)=5.94, P<0.05), but there was no difference in APACHEII score among three groups. There was significant positive correlation between serum MYO and APACHEII score (r=0.407, P<0.05). CONCLUSION: Determination of serum MYO can reflect degree of illness and prognosis of sepsis patients in Xining area. PMID- 21315005 TI - [Nosocomial infection caused by Pseudomonas aeruginosa in intensive care unit]. AB - OBJECTIVE: To investigate the risk factors of nosocomial infection caused by Pseudomonas aeruginosa in intensive care unit (ICU), in order to provide reference for an effective measure of infection control. METHODS: A retrospective study of cases of Pseudomonas aeruginosa infection occurring in ICU was made with multivariable Logistic regression analysis. The clinical data of 1 950 cases admitted from January 2002 to December 2006 were found to have nosocomial infection caused by Pseudomonas aeruginosa were analyzed in order to identify its independent risk factors. RESULTS: Sixty-four out of 1 950 patients were found to suffer from nosocomial infection caused by Pseudomonas aeruginosa, the morbidity rate was 3.3%. At the same time, and in the same department, 37 patients suffering from infection caused by Escherichia coli, served as control group. Univariate analysis showed that the risk factors for nosocomial infection caused by Pseudomonas aeruginosa were the use of corticosteroid, unconsciousness or craniocerebral trauma, abdominal surgery, thorax/abdomen drainage tube, mechanical ventilation, and tracheostomy [the use of corticosteroid: odds ratio (OR)=3.364, 95% confidence interval (95%CI) 1.445-7.830; unconsciousness or craniocerebral trauma: OR=4.026, 95%CI 1.545-10.490; abdominal surgery: OR=0.166, 95%CI 0.068-0.403; thorax/abdomen drainage tube: OR=0.350, 95%CI 0.150-0.818; tracheostomy: OR=4.095, 95%CI 1.638-10.740]. Multivariate analysis showed that the independent risk factors of nosocomial infection caused by Pseudomonas aeruginosa in ICU were: the use of corticosteroid and mechanical ventilation [the use of corticosteroid: OR=3.143, 95%CI 1.115-8.856; mechanical ventilation: OR=3.195, 95%CI 1.607-6.353, P<0.05 and P<0.01]. CONCLUSION: The independent risk factors of nosocomial infection caused by Pseudomonas aeruginosa in ICU are the use of corticosteroid and mechanical ventilation. Measures should be taken to take care of the risk factors in order to prevent nosocomial infection caused by Pseudomonas aeruginosa in ICU. PMID- 21315006 TI - [Effect of Tongfu granules and its constituents on barrier function of small intestine in rats with sepsis]. AB - OBJECTIVE: To investigate the effects of Tongfu granules and its constituents on barrier function of small intestine in rats with sepsis. METHODS: The male rats were divided into model group, Tongfu granules group, Rhubarb group and Magnoliae cortex group by random digits table, normal rats as control group. Intraperitoneal injection of lipopolysaccharide (LPS, 6 mg/kg) was used to reproduce sepsis model. After establishment of model, rats in Tongfu granules group were given Tongfu granules 28 g*kg(-1)*d(-1) by gavage, and Rhubarb group and Magnoliae cortex group rats were given Rhubarb or Magnoliae cortex 5 g*kg( 1)*d(-1) by gavage, while the model group was given normal saline in same quantity, once a day. Blood samples of rats were collected at 24, 48, 72 hours for measuring tumor necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8) with enzyme linked immunosorbent assay (ELISA). The pathological changes in intestinal mucosa were observed, and the pathological scores was estimated at 72 hours. RESULTS: The levels of TNF-alpha and IL-8 were significantly higher in model group than those in control group at different time points. The serum levels of TNF-alpha and IL-8 were significantly lower in treatment groups than those in model group, and the level of TNF-alpha (ng/L) in Tongfu granules group was significantly lower than that in Rhubarb and Magnoliae cortex groups at different time points (24 hours: 44.64+/-1.48 vs. 47.18+/-1.83 and 46.96+/-2.23, 48 hours: 51.38+/-1.36 vs. 57.17+/-2.23 and 59.41+/-2.01, 72 hours: 55.54+/-2.58 vs. 64.34+/-1.02 and 65.96+/-3.45, all P<0.05), and IL-8 (ng/L) level at 72 hours was significantly lower than that in Magnoliae cortex group (65.53+/-4.52 vs. 69.14+/-2.82,P<0.05). The scores of the lesions were significantly higher in model group than that in control group (3.90+/-0.17 vs. 0). The scores of Rhubarb group, Magnoliae cortex group and Tongfu granules group were 3.15+/-0.28, 3.18+/ 0.08, and 2.95+/-0.15, respectively, which were lower than those of the model group (all P<0.01), and the Tongfu granules group descended obviously than other groups. In control group, the intercellular tight junctions were normal, and the morphology of microvilli and mitochondria was also normal. In model group, the microvilli of intestinal mucosa of the small intestine were absent or disintegrated. The intercellular tight junctions were seen to be blurred in Rhubarb and Magnoliae cortex groups, and they were close to normal state in Tongfu granules group. Their integrity was better preserved compared with that of the model group. CONCLUSION: Injury of barrier function of the small intestine was found in septic rat. It was found that traditional Chinese medicine Tongfu granules, Rhubarb and Magnoliae cortex could protect the barrier function of the small intestine by decreasing the TNF-alpha and IL-8 levels in septic rats. Above mentioned effects of Tongfu granules were better than Rhubarb and Magnoliae cortex. PMID- 21315007 TI - [The protective effect of glutamine on endotoxemic intestinal injury and expression of heme oxygenase-1 in rats]. AB - OBJECTIVE: To investigate the protective effect of glutamine (Glu) pretreatment on intestinal injury induced by endotoxin and expression of heme oxygenase-1 (HO 1) in rats. METHODS: Thirty-two male Sprague-Dawley (SD) rats were randomly divided into four groups (n=8 in each group): normal control group, model group, Glu group and Glu+zinc protoporphyrin (ZnPP) group. In model group, endotoxemia was produced by intraperitoneal injection of lipopolysaccharide (LPS, 10 mg/kg). In Glu group, the rats received intragastrically 1 g/kg of Glu 12 hours before LPS intraperitoneal injection. In Glu+ZnPP group, the rats received 1 g/kg of Glu by gavage 12 hours before LPS intraperitoneal injection and ZnPP 10 mmol/kg intravenously via tail vein 1 hour before LPS injection. The distal ileum was harvested in full thickness 12 hours after LPS injection. The myeloperoxidase (MPO) activity, tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL 10) in the intestine were determined, the pathologic changes were observed and expressed in Chiu grade. The expression of HO-1 was evaluated by immunohistochemistry method. RESULTS: Compared with normal control group, the Chiu grade, MPO activity, the content of TNF-alpha and IL-10 were significantly increased in model group [Chiu grade: 3.3+/-0.4 vs. 1.1+/-0.6, MPO activity (U/g): 0.40+/-0.08 vs. 0.26+/-0.07, TNF-alpha (ng/g): 25.2+/-6.9 vs. 6.5+/-2.8, IL-10 (ng/g): 27.6+/-10.2 vs. 5.7+/-2.9, all P<0.01], and the expression of HO-1 was decreased. Compared with model group, the Chiu grade, MPO activity, the content of TNF-alpha in Glu group were significantly decreased [Chiu grade: 1.6+/ 0.5 vs. 3.3+/-0.4, MPO activity (U/g): 0.25+/-0.05 vs. 0.40+/-0.08, the content of TNF-alpha (ng/g): 13.4+/-3.2 vs. 25.2+/-6.9, all P<0.01], while the level of IL-10 (ng/g) elevated (47.3+/-5.5 vs. 27.6+/-10.2, P<0.01), and the expression of HO-1 was increased. There was no difference in above mentioned indexes between model group and Glu+ZnPP group. CONCLUSION: Glu pretreatment significantly ameliorates the expression of HO-1 of intestinal tissue induced by LPS in rats, and intestinal mucosa is protected with alleviation of inflammatory reaction in intestinal tract. PMID- 21315008 TI - [The epidemiological characteristic of 97,823 cases of pre-hospital medical care in Guangzhou city]. AB - OBJECTIVE: To investigate the epidemiological information of patients in pre hospital medical care in Guangzhou city, and to explore the characteristics of the patients. METHODS: The data in the year of 2008 were retrieved from the computer database of Guangzhou Emergency Medical Rescue Command Center. RESULTS: (1)In a total of 969 410 calls received, the time of distribution was found to be mainly between 16:00 and 18:00 [11.78% (114 224)], and least frequently between 04:00 and 06:00 [2.40% (23 237)]. (2)Among 109 682 dispatches of ambulances, Baiyun district received the most [26.77% (29 364)], and followed by Haizhu district [18.30% (20 069)], Tianhe district [18.20% (19 962)], respectively. (3)Among 97 823 cases of pre-hospital medical care, death rate of the male patients was higher than the female [amount: 57.65% (56 394) vs. 38.48% (37 641), mortality: 59.17% (3 269) vs. 33.95% (1 876)]. (4)In 9 7823 cases of pre-hospital medical care, trauma constituted the highest rate [34.57% (33 820)], especially traffic accidents [11.56% (11 307)], and the age of most of the patients ranged between 21 and 50. Disease of the nervous system ranged the second, followed by diseases of circulatory system, respiratory system and digestive system, and most of them were over 51 years old, and most frequently above 70. (5)In 97 823 cases of pre-hospital medical care, there were 5 525 deaths (5.65%), in whom the circulatory system diseases ranged first (especially sudden death) [33.07% (1 827)], followed by unclassified diseases [29.79% (1 646)], trauma [15.67% (866)], respiratory diseases [7.48% (413)], and neurological emergency illnesses [5.95% (329)]. The age of deceased was far older than 51, particularly 70. The age of most of the deceased was above 61, and age of traumatic death was 21-40. CONCLUSION: (1) It is very important to reduce the death rate of the middle-old aged patients by strengthening prevention and timely treatment of cardiovascular and cerebrovascular diseases, and improve the medical strategies in emergency care, in order to lower the death rate during emergency.(2)It is very important to emphasize safely in production lines and to strengthen traffic regulations in order to reduce the incidence of trauma, thus it is especially traffic accident, expect that the death rate of trauma could be lowered. PMID- 21315013 TI - [Anticoagulant therapy in sepsis]. PMID- 21315014 TI - [Biomarkers of endothelial cell injury and coagulopathy in sepsis]. PMID- 21315015 TI - [Microcirculation dysfunction as a result of severe sepsis and recent advances in its treatment]. PMID- 21315016 TI - [Injury of vascular endothelial cell and microcirculation disturbance in sepsis]. PMID- 21315017 TI - [Effects of p53 antisense RNA on malignant phenotype and sensitivity to cisplatin of human lung cancer cell line]. AB - BACKGROUND: To study the effects of extraneous p53 antisense RNA on malignant growth and sensitivity to cisplatin of human lung cancer cell line. METHODS: 801D cell line with p53 deletion and mutation at 248 codon was selected as a parent cell line. An 1.8 kb human p53 full length cDNA was inserted into a mammalian expression vector PEGFP to construct a p53 antisense RNA recombined plasmid PEGFP p53(AS) and GFP gene at plasmid was a report gene to monitor extraneous gene expression. The extraneous gene was detected by PCR. The p53 mutation protein was examined by immunohitochemical stain of p53 monoclonal antibody. The inhibition growth efficacy of extraneous p53 in vitro was determined by clonogenic survival assay. Sensitivity of cells to cisplatin was examined with MTT assay. FCM analysis was performed to measure the effect of p53 antisense RNA on cell cycle. RESULTS: Two cell lines, PEGFP-p53(AS)-801D and PEGFP-801D, were established after transfection of 801-D cells by lipofection and selection. Presence of extraneous p53 gene in PEGFP-p53(AS)-801D was proved by PCR and expression of extraneous p53 was estimated when green fluorescence in those cells was found out under the fluorescent microscopy. Mutated p53 protein in parent cell line 801D was positive and in PEGFP-p53(AS)-801D was negative with immunochemical stain. The inhibition rate of colony formation was 61% for PEGFP-p53(AS)-801D (P < 0.001). The sensitivity of PEGFP-p53(AS)-801D cells to cisplatin was increased. FCM analysis showed that the cell line was arrested at G1 phase. CONCLUSIONS: p53 mutation at 248 code plays an important role on malignant growth and resistance to cisplatin of human lung cancer cell line 801D. Malignant growth of cells with p53 deletion and mutation at 248 codon can be inhibited by extraneous p53 antisense RNA, and simultaneously the sensitivity to cisplatin is also increased. PMID- 21315018 TI - [Reduction of FHIT gene expression in primary lung cancer]. AB - BACKGROUND: To investigate the role of FHIT (fragile histidine triad) gene in oncogenesis and progression of human lung cancer. METHODS: The expression of FHIT gene was detected in 166 lung cancer samples and 37 benign pulmonary lesion tissues as control by immunohistochemistry. RESULTS: The positive rate of FHIT expression in lung cancer tissues was 63.03%+/-26.41%, which was significantly lower than that in tisssues adjacent to cancer (83.74%+/-17.46%) (P < 0.01 ), and both positive rates in cancer tissues and tissues adjacent to cancer were significantly lower than that in benign lesion tissues (92.98%+/-5.56%)(P < 0.01). The expression level of FHIT gene was closely related to histological classification, cancer cell differentiation, P TNM stages and lymph node involvement in lung cancer patients (P < 0.05). The positive rate of FHIT expression in smoking lung cancer patients was remarkably lower than that in non smoking ones ( 55.14% +/-27.55% vs 71.93%+/-22.05%, P < 0.01). The postoperative survival time in patients with high FHIT expression was significantly longer than those with low expression (P < 0.05). CONCLUSIONS: Reduction of FHIT gene expression might be associated with the oncogenesis and progression of human lung cancer; Smoking may be one of the important reasons of reduction of FHIT gene expression in lung cancer patients. PMID- 21315019 TI - [Molecular cloning of genes differentially expressed in human lung squamous cell carcinoma using suppression subtractive hybridization]. AB - BACKGROUND: To clone and identify genes differentially expressed in human lung squamous cell carcinoma (LSCC). METHODS: A subtracted cDNA library of human LSCC was constructed by suppression subtracted hybridization (SSH) method. After screening, the subtracted library clones representing mRNAs that were truly differentially expressed in LSCC but not in its adjacent non cancerous tissues were selected to identify by RT-PCR and DNA sequencing were performed. Nucleic acid homology searches were performed using the BLAST program. RESULTS: By this technique, 10 differentially expressed gene cDNA fragments of LSSC were obtained. Two were novel and eight were already known genes. CONCLUSIONS: SSH is a useful technique with high sensitivity for the detection of differential genes expression in LSCC and an effective method to clone novel genes. PMID- 21315020 TI - [Construction of mutant k-ras gene recombinant adenovirus]. AB - BACKGROUND: To construct the recombinant adenovirus of mutant k-ras by using the method of homogenous recombination in bacteria. METHODS: Mutant k-ras gene was liberated from the vector of pcDNA3-k-ras 12(Val) via KpnI+XhoI digestion, and subcloned into shuttle vector of pAdTrack-CMV, forming transfer vector of pAdTrack CMV/k-ras 12(Val). Then it was linearized with PmeI and cotransformed into BJ5183 cells with adenovirual geonomis plasmid of pAdEasy-1. The DNA of identified recombinant plasmid was digested with PacI and transfected to 293 cells to package adenovirus. The PCR technique was used to detect target gene. The titre and its infection rate of the Ad-k-ras 12(Val) was measured with the aid of GFP expression. RESULTS: There were over 25% positive recombinant bacterial clones after co transformation of BJ5183 bacterial cells with pAdTrack CMV/k-ras 12 (Val) and pAdEasy-1 by method of CaCl2. PCR test indicated each the recombinant adenovirus contained the insert of k-ras 12(Val). The titre of purified recombinant adenovirus was 1.2*1012 pfu/ml. CONCLUSIONS: The method of homologous recombination in bacteria is convenient and efficient, which compared with that of in cell and the pepared Ad-k-ras 12(Val) paves a sound foundation for further study. PMID- 21315021 TI - [The relationship between the CT signs and p53 abnormal expression in peripheral lung cancer]. AB - BACKGROUND: To evaluate the relationship between the CT signs and p53 protein abnormal expression in peripheral lung cancer. METHODS: Fifty-two patients with pulmonary masses underwent CT scanning before operation. Immunohistochemistry was used to detect p53 protein expression in pulmonary specimens obtained by operation. RESULTS: There were significant differences among p53 protein expression and differentiation of lung cancer cell, size of the cancer, tumor appearance, pleura excavation and lymphatic metastasis. CONCLUSIONS: p53 gene mutation indicates the biological behavior of lung cancer and might influence the morphological feature of lung cancer, which remarkably relates to CT signs of lung cancer. PMID- 21315022 TI - [Study on the specific expressions of p53, bcl-2 and c-myc in non-small cell lung cancer with neuroendocrine differentiation]. AB - BACKGROUND: To study the specific expression of tumor-related genes (p53, bcl-2 and c-myc) in non small cell lung cancer with neuroendocrine differentiation (NSCLC-NE). METHODS: The expression of neuron-specific enolase (NSE), chromogranin A (CgA), synaptophysin(Syn), c-myc, bcl-2 and p53 was detected in 60 surgically resected and paraffin-embedded non-small cell lung cancer (NSCLC) specimens by immunohistochemistry (S-P method). RESULTS: The positive rates of NSE, CgA, Syn expressed in 60 cases of NSCLC were 45.00%(27/60), 13.33%(8/60), 31.67% (19/60) respectively. According to the results of these three markers, 41.67%(25/60) of 60 specimens was proved to be as NE differentiation cancer. The NE differentiation in NSCLC was remarkably related to differentiation of tumor cells (P < 0.05). NSCLC-NE had a higher metastatic rate (P < 0.05) and a higher clinical staging (P < 0.05) than NSCLC without NE differentiation. The positive rates of bcl-2, p53 and c-myc expression in NSCLC-NE were 68.00% (17/25), 80.00% (20/25), 68.00% (17/25) respectively, and the expression of bcl-2 and p53 was closely related to NE differentiation (P < 0.05). CONCLUSIONS: A certain part of NSCLC have NE differentiation, which has different biological features from NSCLC without NE differentiation. High expression of bcl-2 and mutant p53 can be observed in NSCLC-NE, and bcl-2/Bax unbalance associated with p53 mutation may play an important role in oncogenesis and development of NSCLC-NE. PMID- 21315023 TI - [Detection of p53 gene mutation in peripheral blood in the diagnosis of patients with lung cancer]. AB - BACKGROUND: To study the diagnostic significance of detecting p53 gene mutation in peripheral blood of lung cancer patients. METHODS: PCR-SSCP was used to detect p53 gene mutation in peripheral blood of 46 samples (lung cancer 28, benign lung diseases 8, healthy people 10). RESULTS: Of the 28 lung cancer patients, 4 cases (squamous cell carcinoma 1, adenocarcinoma 1, small cell lung cancer 2) had p53 gene mutation. The positive rate was 14.29%. Of the 4 positive lung cancer patients, one patient was in stage II, one in stage III, and the other two in stage IV. No p53 mutation was found in peripheral blood of 8 benign lung disease patients and 10 healthy persons. CONCLUSIONS: Detection of p53 gene mutation in peripheral blood cells may be helpful to the diagnosis of lung cancer, especially to the accurate staging of lung cancer. PMID- 21315024 TI - [The analysis of multi-drug resistance of doxorubicin with flow cytometry]. AB - BACKGROUND: To evaluate the significance of flow cytometry (FCM) in the analysis of multi-drug resistance of doxorubicin. METHODS: The level of doxorubicin or Rh 123 in S-180R and BGC-823/DOX, which were two cell lines with different drug resistance, was measured by FCM comparatively and continuously. RESULTS: The total fluorescence profile peaks of S-180R, a high resistant cell line, were predominantly different from those of S-180, the parent cell line, by the FCM analysis. The subtle fluorescence profile differences between BGC-823/DOX (a low resistant cell line) and the parent cell line were quantitatively measured on the FCM map. The changes of each resistant cell fluorescence from the S 180R cells could be displayed by continuous tests, the more near the fluorescence level of each cell was, the more the fluorescence pike of whole cells centralized. CONCLUSIONS: FCM is a sensitive, accurate and quantitative test in the analysis of doxorubicin drug resistance. PMID- 21315025 TI - [Study on the relationship between telomerase gene and telomerase activity in lung cancer tissue]. AB - BACKGROUND: To investigate the relationship between the telomerase activity and telomerase component expression in lung cancer, and to explore whether telomerase activity is regulated at the gene or transcriptional level. METHODS: Expression of the hTR and hTERT were detected in 68 human lung cancer tissues and responsive adjacent non-neoplastic lung tissues by semi-quantitative reverse transcription polymerase chain reaction. Telomerase activity was detected by telomeric repeat amplification protocol. RESULTS: In 68 lung cancer tissues, the positive rate of the telomerase activity, hTR and hTERT expression were 79.4% (54/68), 98.5% (67/68) and 91.2% (62/68) respectively. Whereas most adjacent non-neoplastic lung tissues expressed hTR (62/68, 91.2%) also, hTERT was detected in only 7 (10.3%) normal lung tissues and no telomerase activity were detected in the 68 non neoplastic lung cancer tissues. As compared with hTR, hTERT expression was closely related to telomerase activity. The concordance was 89.0% (121/136), whereas the concordance between telomerase and hTR was 43.4% (59/136). CONCLUSIONS: The results suggest that telomerase may play an important role in tumorigenesis of lung cancer. Telomerase activity may be regulated in transcription level or translation level. PMID- 21315026 TI - [Overexpression and its clinical significance of multi-drug resistance associated genes in lung cancer tissues]. AB - BACKGROUND: To investigate the expression level and its clinical significance of the multi-drug resistance (MDR) associated protein in lung cancer specimens. METHODS: The expression levels of Pgp, MRP, GST-pi and TopoII of MDR associated protein were detected in 60 lung cancer samples and 30 paracancerous tissues by S P immunohistochemistry method. RESULTS: The positive rate of Pgp, MRP, GST-pi and Topo II in the lung cancer tissues was 40.0% (24/60), 61.7% (37/60), 45.0% (27/60) and 81.7% (49/60) respectively, which was significantly higher than those in paracancerous tissues (P < 0.01). No significant correlation was observed among the expression of multi-drug resistance-related protein and TNM staging, pathological type, cell differention and lymph node metastasis status (P > 0.05). CONCLUSIONS: Lung cancer has overexpression of multi-drug resistant-related genes during the oncogenesis. Combined detection of these genes may be useful for guiding the lung cancer chemotherapy. PMID- 21315027 TI - [Study on the clinical value of telomerase activity in exfoliated cells of sputum from lung cancer patients]. AB - BACKGROUND: To investigate the clinical value of the detection of telomerase activity in the sputum specimens of lung cancer. METHODS: The telomerase activity in sputum specimens was detected in 45 case of lung cancer and 25 cases of benign pulmonary diseases and 2 cases of metastatic carcinoma of the lung by PCR-ELISA assay. RESULTS: Twenty five sputum specimens from lung cancer patients were positive for telomerase activity, and the sensitivity was 55.6% (25/45); seven sputum specimens from benign pulmonary diseases were positive, and the sensitivity was 28.0% (7/25). Significant difference was existed between the two groups (Chi-Square=5.628, P < 0.05). CONCLUSIONS: Detection of telomerase activity in the sputum specimens may be helpful to differentiate malignant from benign pulmonary diseases. PMID- 21315028 TI - [Chemotherapy combined with radiosurgery in the treatment of non-small cell lung cancer patients with brain metastasis]. AB - BACKGROUND: To ascertain the effect of chemotherapy combined with radiosurgery therapy on the brain metastasis of lung cancer. METHODS: Twenty-four non-small cell lung cancer patients with brain metastasis who received radiosurgery and chemotherapy were prospectively observed. Main parameters of treatment program included:(1)brain tumor size range from 1.9 to 26.2m3; (2)median iso-center numbers being 3 (1-7); (3)margin dose being 13.6-22.0 Gy. Chemotherapy regimen consisted of Teniposide (VM26), CCNU and carboplatin (CBP), with VM-26 100mg IV d1-3, CCNU 80mg po d1 and CBP 300mg/m2 IV d1, repeated every 4 weeks for 2-4 cycles (CCNU used only in cycle 1 and 3). RESULTS: (1)Major neurological improvement rate was 87.0%; (2)Objective response rate of brain lesions was 58.3%; (3)Relapse rate of new lesions of the brain metastasis during 3-6 months after radiosurgical treatment was 70.8%; (4)Median survival duration was 10 months (range from 3 to 34 months); (5)l-year survival rate was 37.5%. CONCLUSIONS: (1)Chemotherapy combined with radiosurgery in the treatment of brain metastasis of non-small cell lung cancer might be an effective regimen with modest side effect; (2)Relapsing and new lesions in the brain can not be controlled with this treatment. PMID- 21315029 TI - [Diagnositic values of combined determination of carbohydrate antigen and tissue polypeptide antigen and neuron-specific enolase and carcinoembryonic antigen in the malignant pleural effusion]. AB - BACKGROUND: To evaluate the values of a new tumor marker carbohydrate antigen (CA242) and combined determination of CA242, tissue polypeptide antigen (TPA), neuron-specific enolase (NSE) and carcinoembryonic antigen (CEA) in the diagnosis of malignant pleural effusion associated with lung cancer. METHODS: The concentration of CA242, TPA, NSE and CEA in the serum and the pleural effusion was measured in 57 patients with malignant pleural effusion associated with primary lung cancer and 30 patients with tuberculous pleural effusion by enzyme linked immunosorbent assay. RESULTS: The levels of the four tumor markers in the serum and pleural effusion from patients with lung cancer were significantly higher than those with tuberculous pleural effusion (P < 0.01). The sensitivity of CA242 in the serum and the pleural effusion for lung cancer was 53.6% (31/57) and 61.4% (35/57) respectively; the sensitivity of CA242 for lung adenocarcinoma was 65.7% (23/36) and 66.7% (24/36) respectively. The specificity was 90.0%. Combined determination of the four tumor markers in serum and pleural effusion: If two or more of them were positive for evidence for diagnosis of lung cancer, the specificity for the serum and the pleural effusion was 96.7% (29/30) and 100.0% (30/30) respectively, with the sensitivity of 75.4% (43/57) and 77.2% (44/57) respectively. CONCLUSIONS: The determination of the new tumor marker CA242 in serum and pleural effusion might be useful for the diagnosis of malignant pleural effusion associated with lung cancer, especially for adenocarcinoma. The combined determination of the four tumor markers can increase the specificity and the sensitivity in the diagnosis of malignant pleural effusion. PMID- 21315030 TI - [Expression and clinicopathological significance of CD44V6 expression in non small cell lung cancer]. AB - BACKGROUND: To study the expression and clinicopathological significance of CD44V6 in non-small cell lung cancer (NSCLC). METHODS: CD44V6 expression in lung cancer tissues was detected in 90 patients with lung cancer by immunohistohemistry SABC method. RESULTS: The positive rate of CD44V6 expression in NSCLC was 51.1% (46/90), which was related to TNM stage, but not to cell differention, age and sex of the patients (P > 0.05). The positive rate of CD44V6 expression was 32.2% (10/31) in stage I+II patients and 61.0% (36/59) in stage III+IV disease. A highly significant difference was existed between the two groups (P < 0.01). The positive rate of CD44V6 expression was significantly higher in NSCLC with lymph node metastasis (61.0%, 36/59) than that without lymph node metastasis (32.2%, 10/31) (P < 0.01). The 3-year survival rate (65.5%, 19/29) in patients with low CD44V6 expression was significantly higher than that (35.0%, 7/20) with high CD44V6 expression (P < 0.05). CONCLUSIONS: Overexpression of CD44V6 may be involved in the progression and metastasis of the cancer and prognosis of the patients with lung cancer. It might be helpful to evaluate the progression of the cancer, and to predict the metastasis and progression of lung cancer. PMID- 21315031 TI - [A study on expression of p53, p27 and bcl-2 protein in non-small cell lung cancer]. AB - BACKGROUND: To study the relationship between the expression of p53, p27, bcl-2 protein and the clinical pathological characteristics of non-small cell lung cancer (NSCLC). METHODS: Expression of p53, p27 and bcl-2 protein was detected in 76 NSCLC samples by immunohistochemistry. RESULTS: The positive rate of p53, p27 and bcl-2 protein was 36.84% (28/76), 44.74% (34/76) and 48.68% (37/76) respectively, and 7 cases were positive for p53, p27 and bcl-2 protein. Positive rate of p53, p27 and bcl-2 protein was not related to the pathological type, lymph node metastasis, and TNM stage. The positive rate of p53 in higher differentiation group was significantly lower than that in lower differentiation group (P < 0.05). The positive rate of p27 and bcl-2 in higher differentiation group was significantly higher than that in lower differentiation group (P < 0.05). CONCLUSIONS: Overexpression of p53, p27 and bcl-2 genes may play an important role in the oncogenesis and development of NSCLC. PMID- 21315032 TI - [Pharmacoeconomic analysis of three new chemotherapeutic regimens for non-small cell lung cancer]. AB - BACKGROUND: To evaluate three new chemotherapeutic regimens for non-small cell lung cancer (NSCLC) by pharmacoeconomic analysis in guiding rational use of drugs. METHODS: One hundred and one cases of NSCLC in clinic stage III or IV were treated by one of the three chemotherapeutic schemes-PC: paclitaxel (135mg/m2,d1)+DDP; TC: docetetaxel (75mg/m2,d1)+DDP; VC: vinorelbine (25mg/m2,d1 and d8)+DDP, DDP were given at 80mg/m2 in 3 groups. Pharmacoeconomic cost effectiveness analysis was used to compare the efficacy of the three regimens. RESULTS: The response rate was 46.9%, 48.6% and 47.1% and median survival duration was 7.8, 7.5 and 7.6 months for PC, TC and VC regimen respectively, with 1-year survival rate of 37.5%, 37.1% and 38.2% respectively. There was remarkable difference in the response rate and median survival duration between PC and TC, but no statistical difference was observed between PC and VC. There was no statistical difference in 1-year survival rate among the three regimens. The average cost of one patient for one therapeutic cycle was RMB 15840.5, 15831.1 and 9401.8 Yuan respectively. Escalation of 1% of response rate costed RMB 337.75, 325.74 and 199.61 Yuan respectively. Prolongation of 1 month of median survival duration costed RMB 2030.83, 2110.97 and 1237.08 Yuan respectively. Escalation of 1% of one year survival rate costed RMB 422.41 , 426.71 and 246.12 Yuan respectively. CONCLUSIONS: Among these three new chemotherapeutic regimens for the advanced patients with NSCLC, the expenditure of VC is much cheaper than PC and TC. The cost effectiveness of VC is the lowest among the three regimens. PMID- 21315033 TI - [Clinical application of lung biopsy through CT-guided percutaneous paracentesis]. AB - BACKGROUND: To explore the significance of lung biopsy through CT-guided percutaneous paracentesis in the diagnosis of space-occupying lesions of the lung. METHODS: Thirty-five patients with space occupying lesions of the lung underwent lung biopsy through CT-guided percutaneous paracentesis and DLTRA-CUT 16G, 18G or 20G soft-tissue-cutting biopsy needles and PICKER IQ computerized tomograph were used. RESULTS: Of the 35 patients, 26 were confirmed by pathological examination to suffer from primary malignant tumor, 1 from metastatic carcinoma, 3 from tuberculosis and 3 from inflammatory pseudotumor. No definite diagnosis was made in two patients. The diagnostic rate was 94.3%. After operation, minor pneumothorax occurred in 5 cases and traces of blood in sputum in 2 cases, however, they didn't need any treatment. CONCLUSIONS: Lung biopsy through CT-guided percutaneous paracentesis is a safe and practical technique and may be widely used in hospitals if conditions permit. PMID- 21315034 TI - [Clinical study of ifosfamide and cisplatin in the treatment of advanced non small cell lung cancer]. AB - BACKGROUND: To evaluate the efficacy and toxicity of ifosfamide and cisplatin in the treatment of advanced non-small cell lung cancer. METHODS: Fifty-six patients with advanced non-small cell lung cancer were treated by combination chemotherapy of ifosfamide and cisplatin for two cycles: ifosfamide 1.5-2.0g/m2 iv drip on day 1-4, mesna 400mg iv at 0,4,8 hours after using ifosfamide; DDP 25-30mg/m2 iv drip on day 5-7. The response, toxicity, relievable period and survival period were evaluated. RESULTS: The total response rate was 50.0%. The response rate of patients in primary treatment was 52.8% and that of return cases was 45.0% (P > 0.05). The median relievable period was five months. The median duration of survival (MDS) was nine months. The major toxicity was inhibition of bone marrow, especially of leukocyte and platelet. CONCLUSIONS: Combination chemotherapy of ifosfamide and cisplatin is effective in the treatment of advanced non-small cell lung cancer including the return cases, and the toxicity is tolerable. If G-CSF is used as a complementary therapy, this regimen could be quite clinically valuable. PMID- 21315036 TI - [Bioinformatics analysis on CK8 full length coding sequence and eukaryotic expression in SMMC7721 cells]. AB - AIM: To construct an eukaryotic expression vector containing the coding region of human full length cytokeratin 8 gene and to detect its expression in SMMC7721 cells. METHODS: CK8 cDNA was amplified by RT-PCR and cloned to pMD18-T simple vector. After confirming the sequence, the cDNA was inserted into pEGFP-C1 and the positive clone pEGFP-CK8 was obtained. The recombinant plasmid was transfected into SMMC7721 cells with Lipofectamine(TM);2000 and the expression was detected by fluorescence microscope, real time PCR and Western blot. The physical-chemical properties, signal peptide and functional motifs were predicted by the bioinformatics software. RESULTS: PCR, restriction enzyme digestion and DNA sequencing showed that the recombinant plasmid contained the coding region of full length CK8 gene. Observation under fluorescence microscope and the results of real time PCR and western blot indicated CK8 was over-expressed in SMMC7721 cells. CONCLUSION: The eukaryotic expression vector containing the CK8 gene was successfully constructed and expressed, which provides a basis for the study for biological function of CK8. PMID- 21315035 TI - [Study on experimental systemic lupus erythematosus mouse model induced by pristane]. AB - AIM: To establish the systemic lupus erythematosus (SLE) mouse model through pristane intraperitoneal injection and discuss the pathogenesis of SLE in this mouse model. METHODS: Single intraperitoneal injection of 0.5 mL Pristane or PBS was applied on 6-8 week old female BALB/c mice. The percentage of IFN-alpha producing cells (CD11b(+);Ly6C(high);)and B cells and the expression of B cell activation surface marker(Abeta1(d);)in peripheral blood were detected by flow cytometry every 2 weeks. Serum total IgG and auto-antibodies (anti-dsDNA, anti-sm RNP, anti-ribosomal P0)were detected by ELISA at different time point. The percentage of peritoneal CD11b(+);Ly6C(high);cells and Abeta1(d);expression in spleen were also detected by flow cytometry after 6 months. glomerular IgG deposition and kidney histopathologic changes were determined by direct immunofluorescence and H&E staining respectively. RESULTS: Total IgG began to increase since 2 months after the pristane injection, while auto-antibodies were detected after 3 moths, both of which peaked after 6 moths and maintained the high level. Most of the pristane treated mice developed arthritis, glomerular immune complex deposition and kidney damage. The percentage of peripheral and peritoneal IFN-alpha producing cells was much higher in pristane group than that of the PBS control group since 2 weeks after intraperitoneal injection. The mean fluorescence intensity (MFI) of B cell activation marker(Abeta1(d);) in pristane group was also higher than PBS group in both peripheral blood and spleen indicating B cell over activation. CONCLUSION: Intraperitoneal injection of pristane can successfully establish a SLE mouse model which may be used in research of the SLE pathogenesis. Increased percentage of IFN-alphaproducing cells may play an etiopathogenic role in abnormal B cell activation and SLE development in this model. PMID- 21315037 TI - [The enhancement effect of CD59 on CD55-mediated T cell signal transduction]. AB - AIM: To study the enhancement effect of glycosylphosphatidyl inositol (GPI) anchored protein CD59 on CD55-mediated T cell signal transduction. METHODS: Human Jurkat cells were divided into 3 groups: Jurkat cells(Igroup), Jurkat cells transfected with blank plasmid(II group)and Jurkat cells transfected with siRNA plasmid (III group). CD59 mRNA level was detected by RT-PCR. The cell proliferation activity of the three groups was measured by MTTcolorimetry after crosslinking anti-CD55 mAb and anti-CD59 mAb. The phosphorylation levels of Src family of protein tyrosine kinase (PTK) were investigated by immunoblot analysis, and the kinetic changes of [Ca(2+);] in T cell endochylema were determined by Laser scanning confocal microscope imaging. RESULTS: CD59 expression was successfullyinhibited in IIIgroup cells after transfecting. The cell proliferation, phosphorylation levels of Src family of PTK and degree of [Ca(2+);] inIand IIgroups were increased compared with III group(P<0.05), after crosslinking of CD55 and CD59 antibodies, but there was no difference between I group and II group. CONCLUSION: CD59 can enhance the effect of CD55-mediated T cell signal transduction. PMID- 21315038 TI - [The role of lipid raft in TNFR1-mediated signal transduction in osteoblasts]. AB - AIM: To investigate the role of membrane cholesterol in TNFR1-mediated signal transduction in osteoblastic MC3T3 cells. METHODS: MCD binds cholesterol specifically and was commonly used to deplete cholesterol from cell plasma membrane. MC3T3 cells were serum-starved for 22 h, treated with MCD (10 g/L) for 60 min followed by TNF-alpha (10 MUg/L) for 0, 5, 10, 15 or 30 min, or TNF-alpha plus CHX (10 mg/L) for 4 h to induce apoptosis, then TNFR1-mediated IkappaBalpha degradation, phosphorylation of AKT, ERK or p38, and processing of caspase-3 were analyzed by using SDS-PAGE/Western blotting method. RESULTS: MC3T3 cell membrane cholesterol level was reduced to 35% within 60 min by MCD (10 g/L). Reduction of MC3T3 cell surface cholesterol dramatically inhibited TNFR1-mediated AKT phosphorylation, while did not affect the degradation of IkappaBalpha, activation of ERK or p38, and processing of caspase-3 induced by TNF-alpha. CONCLUSION: Cholesterol depletion can destruct lipid rafts; therefore our results suggest that lipid raft is essential for TNFR1-mediated AKT phosphorylation, but is dispensable for TNFR1-mediated degradation of IkappaBalpha, activation of ERK or p38 and processing of caspase-3. PMID- 21315039 TI - [Construction and application of inducible artificial microRNA expression vector targeting eIF3g gene]. AB - AIM: To construct an inducible artificial microRNA expression vector targeting eIF3g gene and use it to inhibit the expression of eIF3g in K562 cells. METHODS: The microRNA targeting human eIF3g was designed and obtained by PCR. After confirmed by sequencing, the microRNA was cloned into the pRevTRE2 plasmid. The Tet-off plasmids were transfected into K562 cells and selected for the stable tetracycline inducible K562/Tet-off transfectants. The pRevTRE2-eIF3g-miRNA plasmid was then transfected into stable K562/Tet-off transfectants and the expression of eIF3g was detected by Western blot. RESULTS: The microRNA targeting eIF3g was confirmed by sequencing. GFP fluorescence assay showed that the stable transfectants of Tet-off plasmids were under tetracycline control. Western blot results showed that the stable transfectants of pRevTRE2-eIF3g-microRNA inhibited eIF3g expression under the regulation of tetracycline. CONCLUSION: The tetracycline-inducible artificial microRNA expression vector targeting eIF3g gene has been successfully constructed and effectively inhibits eIF3g expression in K562 cells. PMID- 21315040 TI - [IL-1beta can promote proliferation and migration of Hepa1-6 cells and impair IFNalpha-induced cell growth inhibition in vitro]. AB - AIM: To analyze the effect of recombinant IL-1beta on proliferation, migration, and the effect on IFNalpha induced cell growth inhibtion. METHODS: The vector pLIVE-mIL-1beta was transfected into Hepa1-6 cells mediated by transIT-LT1. Gene expression level of IL-1beta was analyzed by RT-PCR and Sandwich ELISA. Cell migration was assessed using wound healing assay. RESULTS: IL-1beta significantly stimulated proliferation and migration of Hepa1-6 cells. However, expression of IL-1beta significantly down-regulated growth inhibition inducecd by IFNalpha. CONCLUSION: The recombinant vector could stably express IL-1beta and promote in vitro proliferation, migration, and impair IFNalpha-induced cell growth inhibition. PMID- 21315041 TI - [Study on construction of chimeric adenovirus vector Ad5/11 carrying human eGFP and endostatin-K5 and its experimental investigation in vitro]. AB - AIM: To construct chimeric adenoviral vector Ad5/11 carrying reporter gene eGFP and human endostatin-K5. METHODS: Chimeric adenoviral backbone vector expressing eGFP was generated by overlap PCR and homologous recombination in E.coli BJ5183. Then chimeric adenoviral vector Ad5/11-E1-CMV-endo-K5/E3-CMV-eGFP carrying eGFP and human endostatin-K5 was constructed by co-transfecting Pac I linearized chimeric adenoviral backbone and adenoviral E1 shuttle vector expressing human endostatin-K5 into HEK 293 cells. The expression of eGFP was observed under fluorescent microscope. The expression of human endostain-K5 in U87MG cells infected by chimeric adenoviral vector was detected by RT-PCR. The infection efficiency between chimeric adenovirus and unmodified control adenovirus for human glioblastoma cell line A172 and breast cancer cell line MDA-MB-231 in vitro was evaluated by the comparison of the expression of eGFP. RESULTS: Chimeric adenovirus Ad5/11-E1-CMV-endo-K5/E3-CMV-eGFP could successfully express eGFP and endostatin-K5. Chimeric adenoviral vector significantly enhances the infection efficiency for human glioblastoma cell line A172 and breast cancer cell line MDA MB-231 compared with unmodified adenoviral vector Ad5 E1-CMV-eGFP. CONCLUSION: Chimeric adenoviral vector Ad5/11-E1-CMV-endo-K5/E3-CMV-eGFP can significantly improve the infection efficiency for human glioblastoma cell line A172 and breast cancer cell line MDA-MB-231. PMID- 21315042 TI - [Construction and expression of eukaryotic expression plasmid pcDNA3.1-smac]. AB - AIM: To construct the eukaryotic expression vector of human gene Smac pcDNA3.1 Smac and express it in the lung adenocarcinoma A549 cells. METHODS: The Smac was amplified from human testis tissue by reverse transcriptase polymerase chain reaction (RT-PCR). Then recombined eukaryotic expression vector pcDNA3.1-Smac was constructed. After the reconbinant plasmid was proved to be constructed correctly by endonucleases digesting and DNA sequencing, we trasfected it into lung adenocarcinama cells A549 through liposome inducing. The expression of Smac in transfectant A549 was detected by RT-PCR and Western blot. And the cell growth inhibition ratio after trasfection was detected by MTT. RESULTS: The amplified fragment by PCR was coincident with the anticipated result, and its sequence was in concordance with that published on GenBank.Therefore, the gene Smac was cloned successfully, and the recombinant plasmid pcDNA3.1-Smac was also constructed successfully. Both on the mRNA level and the protein level, the expression of Smac gene was increased obviously in the transfected A549 detected by RT-PCR and Western blot respectively. The cell growth inhibition ratio in the group transfected pcDNA3.1-Smac was significantly higher compared with the pcDNA3.1 group after 72 hours. CONCLUSION: The recombinant eukaryotic expression vector pcDNA3.1-Smac was constructed, and it could be obviously expressed in lung adenocarcinoma cells A549. It is also proven that Smac has the function of growth inhibition. PMID- 21315043 TI - [TCRzeta gene expression in TCR gene-modified T cells specific for DLBCL associated antigen]. AB - AIM: To analyze the expression level of TCRzeta chain gene in the DLBCL associated antigen-specific T cells before and after being activated by coculture with Toledo cells (DLBCL cell line). METHODS: Real-time PCR with SYBR GreenI technique was used for detecting TCRzeta chain expression in activated and unactivated DLBCL-associated antigen-specific T cells. beta2 microglobulin gene (beta2M) was used as an endogenous reference. Relative mRNA expression level of TCRzeta gene was analyzed by the formula of both 2(-deltaCt); *100% and 2( deltadeltaCt);. RESULTS: Compared with (1.74+/-0.28)% of the relative mRNA expression level of TCRzeta gene in TCR gene-untransduced T cells, the expression level of TCRzeta gene was (1.78+/-0.22)% in unactivated TCR gene-transduced T cells and showed no obvious increase. While the expression of TCRzeta gene arrived at (11.54+/-1.98)% in the activated TCR gene-modified T cells, which was significantly higher than that in unactivated TCR gene-modified and TCR gene untransduced T cells (P<0.05), and was increased (6.59+/-0.80) and (6.48+/-0.36) times, respectively. CONCLUSION: The expression of TCRzeta chain was up regulated, when TCR gene-modified T cells were activated by the stimulation of specific antigens. PMID- 21315044 TI - [Effects of FOXP3 on the progression of atherosclerosis plaque in ApoE-knock out mice]. AB - AIM: To explore effects of FOXP3 on the progression of atherosclerosis plaque in hypercholesterolemic apoliprotein(apo)E-/- mice. METHODS: At 8 weeks of age, 32 male ApoE-/- mice were randomly divided into four groups of eight. Labeled: negative control group, positive control group, small interfering RNA (siRNA) group, and regulatory T cells transfer (Tregs) group. Lentivirus-mediated (siRNA) identified its function by Western blot was used to knock down FOXP3 and Foxp3(high+);CD4(+); CD25(+); Tregs acquired through magnetic activated cell sorting adoptive transfer assays in high fat diet ApoE-/- mice were done. The resulting atherosclerotic lesions were assessed by determining the number and function of CD4(+);CD25(+); Tregs, FOXP3 transcript levels and investigating the expression of Foxp3 protein in different tissues. Inflammatory cytokines were determined by ELISA. RESULTS: Animals treated with siRNA of FOXP3 showed a significant increase in atherosclerotic lesion formation and a reduction in the number and function of Foxp3(+);CD4(+);CD25(+); Tregs compared with other groups. Transfer of Foxp3(high+);CD4(+);CD25(+); Tregs significantly decreased atherosclerotic plaque formation and increased the number and function of Foxp3(+); CD4(+); CD25(+); Tregs. Foxp3 protein levels and FOXP3 transcript levels were lowest in the siRNA group, and were highest in tissues from the Tregs transfer group. CONCLUSION: FOXP3 plays an important role in regulating the inflammatory response within the atherosclerotic lesion. It can inhibit significant the progression of the atherosclerosis plaque in ApoE-/- mice. PMID- 21315045 TI - [Effects of H2-Bl gene transfection on biological behaviour of mouse vascular smooth muscle cell]. AB - AIM: To investigate the effects of H2-Bl gene on biological behaviour of mouse vascular smooth muscle cells (VSMCs) including apoptosis, proliferation and anti cytolysis to peripheral blood mononuclear cells (PBMCs), then speculate the possible mechanism of immunological rejection after heart transplantation in maternal-fetal immune tolerance. METHODS: The mouse VSMC were transfected with 0.5 mg/L of pEGFP-N1 plasmid vector, 0.5 mg/L of pEGFP-N1-H2B1 plasmid vector and 1.0 mg/L of pEGFP-N1-H2B1 plasmid vector, respectively. The efficiency of transfection was detected, and the H2-Bl mRNA level, the apoptosis, the proliferation and cytotoxicity of VSMCs were also investigated at 24 h, 48 h and 72 h, respectively. RESULTS: Expression of the H2-Bl gene was determined by real time quantitative PCR. Expressions of the H2-Bl in experimental groups were higher than that of the control group (P<0.001). VSMC apoptosis was observed after 24 h in the 0.5 mg/L and 1.0 mg/L H2-Bl experimental groups compared with control group (P<0.05, P<0.001, respectively). VSMC proliferation was also inhibited in the 0.5 mg/L and 1.0 mg/L H2-Bl gene groups at 24 h and 72 h (P<0.05, P<0.01, respectively). The cytotoxicity of PBMC in the 0.5 mg/L and 1.0 mg/L H2-Bl gene groups at 24 h was lower than the control group (P<0.005, P<0.001, respectively). CONCLUSION: Transfection of pEGFP-N1-H2B1 plasmid to mouse VSMC causes the over expression of H2-Bl mRNA, induces the apoptosis, inhibits the proliferation and attenuates the cytotoxicity of PBMC, leading to immune tolerance. PMID- 21315046 TI - [Effects of NAIF1 on biological behavior of esophageal carcinoma cell line EC9706 by using pTet-off system]. AB - AIM: To investigate the effects of NAIF1 on biological behavior of esophageal carcinoma cell line EC9706 by using pTet-off system. METHODS: Constructe the pTRE2-NAIF1 plasmid and co-transfected with PTK-Hyg in human inducable esophageal carcinoma cell line TF93 (derive from EC9706 cell line).After Hygromycin B selection and RT-PCR, Western blot identification we got stable inducable cell clone TF93-pTRE2-NAIF1.By using this clone, we used MTT to test the proliferation rate, flow cytometry to test the cell cycle, Transwell chamber to test the migration ability and tested the adhesion ability of EC9706 under the effect of NAIF1. RESULTS: First we got the stable inducable cell clone TF93-pTRE2-NAIF1, then we found NAIF1 could inhibit the cell proliferation, cause G0/G1 cell arrest and inhibit the migration and adhesion ability of EC9706. CONCLUSION: NAIF1 can inhibit the malignant phenotype of esophageal carcinoma cell line EC9706. PMID- 21315047 TI - [HOXA9 is direct target of miR-196a]. AB - AIM: To analyze the possible epigenetic regulation mechanism of HOXA9 gene expression and find the possible microRNA regulating HOXA9 gene expression. METHODS: Targetscan software was used to analyze potential microRNA target sites in 3'-UTR of human HOXA9. 3'-UTR fragment of HOXA9 was amplified by PCR. PCR products were cloned into Xba I/Pst I-digested pGL3-M reporter vector, placing the 3'-UTR with potential microRNA binding sites downstream of coding sequence of luciferase. Mutant 3'UTRs were generated by overlap extension PCR method. The construct was cotransfected in 293T cells with control plasmid or plasmids expressing microRNAs regulating HOXA9 potentially. Western blot and RT-PCR were used to detect the expression level of HOXA9 protein and mRNA in MV4-11 cells after transfection of miR196a. RESULTS: The results of luciferase assays revealed that overexpression of miR-196a could reduce the luciferase activity from the reporter construct containing the HOXA9 3'-UTR significantly. The activity of the reporter construct mutated at the specific miR-196a target site was unaffected. Protein and mRNA of HOXA9 was found to be downregulated by miR-196a. CONCLUSION: Theses results suggested that miR-196a regulates the expression of HOXA9 by targeting the complementary sites. PMID- 21315048 TI - [Identification of cell division of CD8+ NKT cells in vitro]. AB - AIM: To measure the in vitro cell division ability of CD8(+);NKT cells by CFSE staining and flow cytometry(FCM). METHODS: Fresh spleen lymphocytes of C57BL/J mice were separated and stained with CFSE, and then stimulated by ConA and LPS for 3 d, and by SEB for 5 d and 10 d respectively. The stimulated cells were harvested and analyzed for CD69 expression on the cell surface and the ability of cell division using FCM. The SEB-activated effector cells for 10 d further stimulated with IL-2 for the consecutive 10 days, and were analyzed for their cell division ability, CD69 expression and NKT cell subsets by FCM. RESULTS: ConA, LPS and SEB stimulated the proliferation of spleen cells. ConA and LPS made the cells divide 3 times within 3 d, and increased CD69 expression up to 74.19% and 41.56% respectively. SEB made the cells divide 5 times within 5 d and 7 times within 10 d respectively, with increased CD69 expression of 32.09% and 48.66% respectively. Ten-day IL-2 stimulation of SEB-activated cells caused population expansion for 7 times with the CD8(+);NKT cell subsets significantly increased from 0.36% to 38.58% and CD69 expression significantly increased from 0.11% to 83.74%. CONCLUSION: The SEB-activated CD8(+);NKT cells proliferated in vitro and their cell division capability could be determined by CFSE staining and FCM. PMID- 21315049 TI - [Expression of goat IL-18 mature protein in insect/baculovirus and determination of bioactivity of the recombinant protein]. AB - AIM: To express goat IL-18 in insect/baculovirus and detect the bioactivity of the recombinant protein. METHODS: The mature goat interleukin-18(gIL-18) gene was cloned into the baculovirus transfer vector pFastBac Dual, and then the resulting eukaryotic expression plasmid pFastBac Dual-gIL18 was transformed into DH10Bac, followed by the identification of Bacmid-gIL18 recombinat plosmid by three antibiotics and blue-white patch. Finally, the recombinant bacmid was transfected into sf9 insect cells by Cellfectin and the transfected cells were harvested at different times. Then the expressed protein was identified by SDS-PAGE, Western blot and bioactivity assay. RESULTS: The recombinant protein recognized and bound to its specific antibody. Bioactivity assay showed that the recombinant protein stimulated the proliferation of lymphocytes and induced IFN-gammaproduction in spleen lymphocytes. CONCLUSION: The mature gIL-18 protein has been expressed successfully in insect/baculovirus expression system, and have good immunogenicity and bioactivity. The study paves a way for application of gIL-18 as an immunomodulator or immune adjuvant. PMID- 21315050 TI - [Expression of sCD40L in peripheral blood and NF-kappaBp65 in PBMC of patients with acute progressive cerebral infarction]. AB - AIM: To study the expressional changes of soluble CD40 ligand(sCD40L) in peripheral blood serum and nuclear factor-kappaB (NF-kappaB) p65 in peripheral blood mononuclear cells (PBMC) of patients with acute progressive cerebral infarction(APCI). METHODS: We selected ninety-nine patients getting APCI less than 7 d of the onset as APCI group by prospective method. Each 100 cases of patients with acute cerebral infarction(ACI) in the same and with cerebral arteriosclerosis(CAS) in the outpatient were respectively selected as ACI and CAS group. The expressional changes of sCD40L in peripheral blood serum and NF kappaBp65 in PBMC of patients with CAS on admission, of patients with APCI and ACI when in hospital, on the course of seventh day, of fourteen and of thirtieth were detected respectively. RESULTS: The expression of sCD40L in peripheral blood serum and NF-kappaBp65 in PBMC of patients of ACI group on admission were obviously higher all than that of CAS group (P<0.05); The expression of sCD40L in peripheral blood serum and NF-kappaBp65 in PBMC of patients of APCI group when in hospital, on the course of seventh day, of fourteen and of thirtieth were obviously higher all than that of ACI group (P<0.05 ). CONCLUSION: The inflammatory and apoptotic mechanism mediated by expressional excessive increase of CD40-CD40L signal passage and NF-kappaB in PBMC might be one of the molecular biology mechanisms of onset and progress for APCI. PMID- 21315051 TI - [The clinical research of serum soluble CD40L and high sensitivie C-reactive protein in patients with acute coronary syndrome]. AB - AIM: To explore the clinical significance and mechanism of soluble CD40 Ligand (sCD40L) and high sensitive C-reactive protein (hs-CRP) in patients with acute coronary syndrome(ACS). METHODS: A total of 86 consecutive patients with ACS were included in the study, according to the selection criteria for diagnosis of acute coronary syndrome (ACS), 86 patients were divided into two groups: normal and the ACS, In all patients, sCD40L and CRP levels were evaluated within 12 h. the incidence of acute cardiovascular events were observed after two months follow up. RESULTS: The ACS group was obviously higher than control group (P<0.01), AMI group slightly higher than the UA group but had no significant difference (P>0.05). sCD40L and hs-CRP group of cardiovascular events increased more than the normal group. CONCLUSION: Acute coronary syndrome patients with early peripheral serum levels of sCD40L and hs-CRP were significantly increased, suggesting that CD40/CD40L system participate the occurrence of ACS, and the inflammatory factors such as C-reactive protein in collaboration, plays an important role on atherosclerotic plaque instability. PMID- 21315052 TI - [The study on correlativity between HLA-DQ gene polymorphism and primary Sjogren's syndrome of the Han nationality in Shanxi province]. AB - AIM: To explore the correlativity between HLA-DQ allele and primary Sjogren's syndrome(pSS) of the Han nationality in Shanxi province and to understand the pathogenesis of pSS at the gene level. METHODS: Polymerase chain reaction sequence specific primers (PCR-SSP) technique was used to determine the alleles of HLA-DQA1 and HLA-DQB1 of pSS patients and healthy populations, and the difference in their HLA-DQA1 and HLA-DQB1 allelic frequencies were analyzed by using chi-square test and Fisher's exact test. RESULTS: (1) The gene frequency of HLA-DQA1*0501 in pSS patients was significantly higher than that in healthy controls(22.0% vs 12.0%, x(2);=7.087, P<0.05, RR=2.068). (2)The gene frequency of HLA-DQA1*0301/2 in pSS patients was significantly lower than that in controls(13.0% vs 24.5%, x(2);=8.681, P<0.05, RR=0.460). (3) The gene frequency of HLA-DQB1*0201 in pSS patients was significantly higher than that in controls(28.5% vs 18.5%, x(2);=5.563, P<0.05, RR=1.756). CONCLUSION: In Han nationality of Shanxi province, HLA-DQA1*0501 and HLA-DQB1*0201 alleles probably are susceptible genes of pSS, while HLA-DQA1*0301/2 allele probably is a protective gene of pSS. PMID- 21315055 TI - Pertussis incidence among adolescents and adults surveyed in general practices in the Paris area, France, May 2008 to March 2009. AB - Since the introduction in 1998 of an adolescent pertussis vaccine booster (for persons aged 11-13 years) in France, the incidence of pertussis in adolescents and adults has been unknown. We therefore undertook a study to estimate the incidence of pertussis in these population groups and to evaluate the feasibility of a real-time electronic surveillance system for pertussis in general practices in France. The general practitioners selected for the study were located in Paris and the surrounding area. Polymerase chain reaction (PCR) or measurement of anti pertussis toxin IgG levels by enzyme-linked immunosorbent assay (ELISA) was used to confirm the infection. Among the 204 patients enrolled in the study, 46 (23%) were diagnosed as having pertussis: 21 were confirmed cases, 24 were clinical cases and one was an epidemiological case. The median age of the 204 patients was 44 years and 134 (66%) were female. The median duration of the patients' cough at enrolment was 24 days. No clinical difference was observed between those with and without a pertussis diagnosis. The incidence of pertussis was estimated to be 145 (95% confidence interval: 121-168) per 100,000 population based on the results from the 10-month study period (calculated for 12 months). Problems in sample collection were identified: pertussis sentinel surveillance cannot be developed without training the staff of medical laboratories who take the biological samples. French health authorities were alerted and training procedures were developed. PMID- 21315056 TI - Continued emergence and changing epidemiology of oseltamivir-resistant influenza A(H1N1)2009 virus, United Kingdom, winter 2010/11. AB - During the winter period 2010/11 27 epidemiologically unlinked, confirmed cases of oseltamivir-resistant influenza A(H1N1)2009 virus infection have been detected in multiple, geographically dispersed settings. Three of these cases were in community settings, with no known exposure to oseltamivir. This suggests possible onward transmission of resistant strains and could be an indication of a possibility of changing epidemiology of oseltamivir-resistant influenza A(H1N1)2009 virus. PMID- 21315057 TI - Increase in invasive Streptococcus pyogenes and Streptococcus pneumoniae infections in England, December 2010 to January 2011. AB - Increases in invasive Streptococcus pyogenes and S. pneumoniae above the seasonally expected levels are currently being seen in England. Preliminary analyses suggest that the high level of influenza activity seen this winter may be contributing to an increased risk of concurrent invasive bacterial and influenza infections in children and young adults. PMID- 21315058 TI - Group A streptococcal infections during the seasonal influenza outbreak 2010/11 in South East England. AB - We present a series of 19 cases of invasive Group A streptococcal (iGAS) infection reported to the Thames Valley Health Protection Unit from 1 December 2010 to 15 January 2011. Ten patients died and a prodrome of influenza-like illness was reported in 14 cases.Influenza B co-infection was confirmed in four cases,three of which were fatal. Our report provides further evidence that influenza B co-infection with iGAS has the potential to cause significant morbidity and mortality. PMID- 21315059 TI - Autoantibody against dendrite in Plasmodium falciparum infection: a singular auto immune phenomenon preferentially in cerebral malaria. AB - To investigate auto-reactive antibodies against dendrites of neurons (AAD) previously reported in cerebral malaria (CM) for their functional biological activity, a serological study was conducted in a larger cohort of patients with CM and uncomplicated falciparum malaria (UM). Sera from Thai adults with CM (n=22) and UM (n=21) were tested to determine the titers of AAD by indirect fluorescent antibody test and specific antibody responses to Plasmodium falciparum antigens by ELISA. Immunoreactivity against the dendrites of neurons was observed in 100% of sera from the cerebral malaria group as compared to 71% from the non-cerebral malaria group, and the median titer of AAD was higher in CM versus UM, though the difference did not reach significance. In contrast an opposite pattern was seen for anti-P. falciparum antibody titers, which were significantly lower among CM than among UM patients, both for IgG and IgM (p=0.024 and p=0.0033, respectively). Our results indicate that this auto-immune phenomenon induced by P. falciparum infection occurs preferentially in cerebral malaria despite lower responses in parasite-specific antibody responses. PMID- 21315060 TI - The importance of using the optimal plasticware and glassware in studies involving peptides. AB - The unpredictable nature of peptide binding to surfaces requires optimization of experimental containers to be used. To demonstrate the variable recoveries of peptides from multiple surfaces commonly employed in peptide research, we tested the recovery of radiolabeled (125)I endocrine peptides under different conditions and provide guidelines for determining the surfaces to use for other peptides. (125)I-labeled peptides (ghrelin, sulfated cholecystokinin-8, corticotropin releasing factor, glucagon-like peptide-1 [GLP-1], insulin, leptin, nesfatin-1, and peptide YY), representing a wide spectrum in net charge, size, end group, and modification, were incubated for 48 h in glass and plastic tubes untreated or coated with siliconizing fluid. Best surfaces were chosen and peptides were incubated with bovine serum albumin (BSA, 1%) with or without subsequent lyophilization. Recovery of (125)I-labeled peptides was determined by gamma counting. Important differences in (125)I-labeled peptide binding capacities to various types of surfaces exist. Siliconization decreased, whereas the addition of BSA improved recovery from surfaces tested. Lyophilizing solutions containing (125)I-labeled peptides and BSA in the tubes best suited for individual peptides rendered more than 89% recovery for all peptides. Ghrelin specifically displaced (125)I-ghrelin from borosilicate glass, whereas GLP-1 and Fmoc-arginine did not. Choosing the appropriate experimental container avoids unpredictable peptide loss that results in inaccurate measurements and false conclusions. PMID- 21315061 TI - Drop-out phagemid vector for switching from phage displayed affinity reagents to expression formats. AB - Affinity reagents that are generated by phage display are typically subcloned into an expression vector for further biochemical characterization. This insert transfer process is time consuming and laborious especially if many inserts are to be subcloned. To simplify the transfer process, we have constructed a "drop out" phagemid vector that can be rapidly converted to an expression vector by a simple restriction enzyme digestion with MfeI (to "drop-out" the gene III coding sequence), which generates alkaline phosphatase (AP) fusions of the affinity reagents on religation. Subsequently, restriction digestion with AscI drops out the AP coding region and religation generates affinity reagents with a C-terminal six-histidine tag. To validate the usefulness of this vector, four different human single chain Fragments of variable regions (scFv) were tested, three of which show specific binding to three zebrafish (Danio rerio) proteins, namely suppression of tumorigenicity 13, recoverin, and Ppib and the fourth binds to human Lactoferrin protein. For each of the constructs tested, the gene III and AP drop-out efficiency was between 90% and 100%. This vector is especially useful in speeding up the downstream screening of affinity reagents and bypassing the time consuming subcloning experiments. PMID- 21315062 TI - Interactions of the AT1 antagonist valsartan with dipalmitoyl-phosphatidylcholine bilayers. AB - Valsartan is a marketed drug with high affinity to the type 1 angiotensin (AT1) receptor. It has been reported that AT1 antagonists may reach the receptor site by diffusion through the plasma membrane. For this reason we have applied a combination of differential scanning calorimetry (DSC), Raman spectroscopy and small and wide angle X-ray scattering (SAXS and WAXS) to investigate the interactions of valsartan with the model membrane of dipalmitoyl phosphatidylcholine (DPPC). Hence, the thermal, dynamic and structural effects in bulk as well as local dynamic properties in the bilayers were studied with different valsartan concentrations ranging from 0 to 20 mol%. The DSC experimental results showed that valsartan causes a lowering and broadening of the phase transition. A splitting of the main transition is observed at high drug concentrations. In addition, valsartan causes an increase in enthalpy change of the main transition, which can be related to the induction of interdigitation of the lipid bilayers in the gel phase. Raman spectroscopy revealed distinct interactions between valsartan with the lipid interface localizing it in the polar head group region and in the upper part of the hydrophobic core. This localization of the drug molecule in the lipid bilayers supports the interdigitation view. SAXS measurements confirm a monotonous bilayer thinning in the fluid phase, associated with a steady increase of the root mean square fluctuation of the bilayers as the valsartan concentration is increased. At high drug concentrations these fluctuations are mainly governed by the electrostatic repulsion of neighboring membranes. Finally, valsartans' complex thermal and structural effects on DPPC bilayers are illustrated and discussed on a molecular level. PMID- 21315063 TI - Deciphering a mechanism of membrane permeabilization by alpha-hordothionin peptide. AB - alpha-Hordothionin (alphaHTH) belongs to thionins, the plant antimicrobial peptides with membrane-permeabilizing activity which is associated with broad range antimicrobial activity. Experimental data have revealed a phospholipid binding site and indicated formation of ion channels as well as membrane disruption activity of thionin. However, the mechanism of membrane permeabilization by thionin remained unknown. Here it is shown that thionin is a small water-selective channel. Unbiased high-precision molecular modeling revealed formation of a water-selective pore running through the alphaHTH double alpha-helix core when the peptide interacted with anions. Anion-induced unfolding of the C-end of the alpha2-helix opened a pore mouth. The pore started at the alpha2 C-end between the hydrophilic and the hydrophobic regions of the peptide surface and ended in the middle of the unique hydrophobic region at the C-end of the alpha1-helix. Highly conserved residues including cysteines and tyrosine lined the pore walls. A large positive electrostatic potential accumulated inside the pore. The narrow pore was, nonetheless, sufficient to accommodate at least one water molecule along the channel except for two constriction sites. Both constriction sites were formed by residues participating in the phospholipid binding site. The channel properties resembled that of aquaporins with two selectivity filters, one at the entrance, inside the alpha2 C-end cavity, and a second in the middle of the channel. It is proposed that the alphaHTH water channel delivers water molecules to the bilayer center that leads to local membrane disruption. The proposed mechanism of membrane permeabilization by thionins explains seemingly controversial experimental data. PMID- 21315064 TI - Glomerular podocytes: a study of mechanical properties and mechano-chemical signaling. AB - Kidney glomeruli function as filters, allowing the passage of small solutes and waste products into the urinary tract, while retaining essential proteins and macromolecules in the blood stream. These structures are under constant mechanical stress due to fluid pressure, driving filtration across the barrier. We mechanically stimulated adherent wildtype podocytes using the methods of magnetic tweezer and twisting as well as cell stretching. Attaching collagen IV coated or poly-l-lysine-coated magnetic beads to cell receptors allowed for the determination of cellular stiffness. Angiotensin II-treated podocytes showed slightly higher stiffness than untreated cells, the cell fluidity (i.e. internal dynamics) remained similar, and showed an increase with force. The bead detachment (a measure of the binding strength) was higher in angiotensin II treated compared to untreated podocytes. Magnetic twisting confirmed that angiotensin II treatment of podocytes increases and CDTA treatment decreases cell stiffness. However, treatment with both angiotensin II and CDTA increased the cell stiffness only slightly compared to solely CDTA-treated cells. Exposing podocytes to cyclic, uniaxial stretch showed an earlier onset of ERK(1/2) phosphorylation compared to MEF (control) cells. These results indicate that angiotensin II might free intracellularly stored calcium and affects actomyosin contraction, and that mechanical stimulation influences cell signaling. PMID- 21315065 TI - Lipoic acid ameliorates arsenic trioxide-induced HO-1 expression and oxidative stress in THP-1 monocytes and macrophages. AB - Inorganic arsenic is a common environmental contaminant; chronic exposure to arsenic can alter the physiology of various key immune cells, particularly macrophages. The aim of this research is to elucidate the key parameters associated with arsenic-induced toxicity and investigate the potential and mechanism of alpha-lipoic acid (LA), a potent thioreducant, for reducing the toxicity in human promonocytic THP-1 cells. We found that a non-lethal concentration of arsenic trioxide (1 MUM) significantly induced the expression of heme oxygenase-1 (HO-1), a response biomarker to arsenic, without stimulating measurable superoxide production. Co-treatment of cells with the HO-1 competitive inhibitor zinc protoporphyrin (Znpp) potentiated arsenic-induced cytotoxicity, indicating that HO-1 confers a cytoprotective effect against arsenic toxicity. In addition, low concentrations of arsenic trioxide (1 and 2.5 MUM) markedly inhibited monocyte-to-macrophage differentiation and expression of macrophage markers. Treatment of cells with LA attenuated arsenic trioxide-induced cytotoxicity and HO-1 over-expression and restored the redox state. In addition, LA neutralized arsenic trioxide-inhibition of monocyte maturation into macrophages and reversed the expression and activity of scavenger receptors. In conclusion, the cytotoxicity of arsenic trioxide is associated with an imbalance of the cellular redox state, and LA can protect cells from arsenic-induced malfunctions either through its reducing activity, direct interacting with arsenic or stimulating other unidentified signaling pathways. PMID- 21315066 TI - Association of haptoglobin phenotypes with ceruloplasmin ferroxidase activity in beta-thalassemia major. AB - BACKGROUND: Haptoglobin (Hp) and ceruloplasmin (CP) are 2 plasma antioxidants playing a role in preventing iron-induced oxidative damage. This study presents data related to Hp phenotypes and ceruloplasmin ferroxidase activity in relation to iron store markers in patients with beta-thalassemia major. METHODS: Blood specimens were collected from 196 subjects (124 beta-thalassemia major patients and 72 healthy controls). Serum levels of iron, total iron binding capacity (TIBC), ferritin, high sensitivity C-reactive protein (hs-CRP), ceruloplasmin, and ferroxidase activity were determined using conventional methods. Haptoglobin phenotypes were determined by polyacrylamide gel electrophoresis. RESULTS: As expected, the mean levels of iron store markers, except TIBC, were significantly higher in patients than in controls. Ceruloplasmin concentrations (mg/dl) and its ferroxidase activity (U/l) were significantly higher in patients than in controls (57.9+/-18.8 vs 46.9+/-14.2 and 159.9+/-47.8 vs 95.3+/-20.9; p<0.001, for CP and Hp, respectively). As for Hp phenotypes, no significant differences were observed between iron store markers and ferroxidase activity among the control group. In the patients group however, significantly higher concentrations of ceruloplasmin and its ferroxidase activity were observed among patients with Hp2-2 phenotype as compared to patients with the other phenotypes. Additionally, correlations according to Hp phenotypes revealed strong association between ceruloplasmin ferroxidase activity and serum ferritin in patients with Hp 2-2 phenotype and not in the others (r=0.331, p<0.05). CONCLUSION: Thalassemia patients with Hp 2-2 phenotype are under greater iron-driven oxidative stress than patients with other phenotypes. PMID- 21315067 TI - Utilize conjugated melanotropins for the earlier diagnosis and treatment of melanoma. AB - Peptides serve as effective drugs and contrast agents in the clinic today. However the inherent drawbacks of peptide structures can limit their efficacy as drugs. To overcome this we have been developing new methods to create 'tailor made' peptides and peptide mimetics with improved pharmacological and physical properties. In this work we introduce novel peptide and small molecule conjugated molecules for earlier diagnosis and treatment of melanoma. PMID- 21315068 TI - Hyaluronan suppresses prostate tumor cell proliferation through diminished expression of N-cadherin and aberrant growth factor receptor signaling. AB - Hyaluronan (HA) production has been functionally implicated in prostate tumorigenesis and metastasis. We previously used prostate tumor cells overexpressing the HA synthesizing enzyme HAS3 or the clinically relevant hyaluronidase Hyal1 to show that excess HA production suppresses tumor growth, while HA turnover accelerates spontaneous metastasis from the prostate. Here, we examined pathways responsible for effects of HAS3 and Hyal1 on tumor cell phenotype. Detailed characterization of cell cycle progression revealed that expression of Hyal1 accelerated cell cycle re-entry following synchronization, whereas HAS3 alone delayed entry. Hyal1 expressing cells exhibited a significant reduction in their ability to sustain ERK phosphorylation upon stimulation by growth factors, and in their expression of the cyclin-dependent kinase inhibitor p21. In contrast, HAS3 expressing cells showed prolonged ERK phosphorylation and increased expression of both p21 and p27, in asynchronous and synchronized cultures. Changes in cell cycle regulatory proteins were accompanied by HA induced suppression of N-cadherin, while E-cadherin expression and beta-catenin expression and distribution remained unchanged. Our results are consistent with a model in which excess HA synthesis suppresses cell proliferation by promoting homotypic E-cadherin mediated cell-cell adhesion, consequently signaling to elevate cell cycle inhibitor expression and suppress G1- to S-phase transition. PMID- 21315069 TI - Evaluation of rebound tonometry in non-human primates. AB - To determine the accuracy and reproducibility of intraocular pressure (IOP) measurements obtained with the TonoVet(r) rebound tonometer in cynomolgus macaques and to determine the effects of corneal thickness on measurements obtained by the TonoVet(r). The anterior chambers of both eyes of anesthetized monkeys were cannulated with branched 23-G needles; one branch was connected to a vertically adjustable reservoir and the other to a pressure transducer. IOP was increased by 5 mmHg increments and then decreased by 10 mmHg decrements. IOP was measured using the TonoVet(r) at each increment and decrement by 2 independent observers and at every other increment and every decrement by a single observer using 'minified' Goldmann applanation tonometry. Central corneal thickness was measured with a PachPen(TM) ultrasonic pachymeter. TonoVet(r) readings correlated well with manometric IOP (slope = 0.972, r(2) coefficient = 0.955). No significant differences were observed when comparing eyes or operators; however there was a non-significant trend for TonoVet(r) readings taken in right eyes to be closer to manometric IOP than those taken in left eyes. The TonoVet(r) had a non-significant tendency to underestimate manometric IOP. TonoVet(r) readings obtained during the decremental phase of the experiment were significantly closer (p < 0.004) to manometric IOP than those obtained during the incremental phase. Central corneal thickness significantly increased (p < 0.0001) over the course of the experiment. The TonoVet(r) rebound tonometer is a reliable and accurate tool for the measurement of IOP in cynomolgus macaques. This tonometer has several advantages, including portability, ease of use, and brief contact with the corneal surface making topical anesthetics unnecessary. PMID- 21315070 TI - Brain derived neurotrophic factor maintains Brn3a expression in axotomized rat retinal ganglion cells. AB - The transcription factor Brn3a has been reported to be a good marker for adult rat retinal ganglion cells in control and injured retinas. However, it is still unclear if Brn3a expression declines progressively by the injury itself or otherwise its expression is maintained in retinal ganglion cells that, though being injured, are still alive, as might occur when assessing neuroprotective therapies. Therefore, we have automatically quantified the whole population of surviving Brn3a positive retinal ganglion cells in retinas subjected to intraorbital optic nerve transection and treated with either brain derived neurotrophic factor or vehicle. Brain derived neurotrophic factor is known to delay retinal ganglion cell death after axotomy. Thus, comparison of both groups would inform of the suitability of Brn3a as a retinal ganglion cell marker when testing neuroprotective molecules. As internal control, retinal ganglion cells were, as well, identified in all retinas by retrogradely tracing them with fluorogold. Our data show that at all the analyzed times post-lesion, the numbers of Brn3a positive retinal ganglion cells and of fluorogold positive retinal ganglion cells are significantly higher in the brain derived neurotrophic factor treated retinas compared to the vehicle-treated ones. Moreover, detailed isodensity maps of the surviving Brn3a positive retinal ganglion cells show that a single injection of brain derived neurotrophic factor protects retinal ganglion cells throughout the entire retina. In conclusion, Brn3a is a reliable retinal ganglion cell marker that can be used to accurately measure the potential effect of a given neuroprotective therapy. PMID- 21315071 TI - Antischistosomal action of thioxo-imidazolidine compounds: an ultrastructural and cytotoxicity study. AB - Schistosomiasis is a disease caused by helminthes of the genus Schistosoma, which threatens approximately 207 million people worldwide. Recently, strains of Schistosoma mansoni appear to be developing tolerance and resistance against Praziquantel, the most commonly available drug on the market used in the treatment of disease. This worrisome development justifies studies that seek alternatives for the prevention, treatment and cure of this disease. This study aimed to evaluate the in vitro activity of new imidazolidine compounds 1-benzyl-4 [(4-chloro-phenyl)-hydrazono]-5-thioxo-imidazolidin-2-one (LPSF/PT-5) and 1-(4 chloro-benzyl)-4-[(4-fluoro-phenyl)-hydrazono]-5-thioxo-imidazolidin-2-one (LPSF/PT-11) against adult worms of S. mansoni. LPSF/PT-5 and LPSF/PT-11 imidazolidine derivatives showed relevant schistosomicidal activity in vitro and induced significant ultrastructural alterations in worms and cell death: results similar to praziquantel. Thus, it is possible that these imidazolidine derivatives can be future candidates as schistosomotic drugs, but further studies are needed to elucidate the induced mechanisms behind this response. PMID- 21315072 TI - Candida albicans Zcf37, a zinc finger protein, is required for stabilization of the white state. AB - Candida albicans, the most prevalent human fungal pathogen, can switch stochastically between white and opaque phases. In this study, we identified Zcf37, a zinc finger protein, as a new regulator of white-opaque switching. Deletion of ZCF37 increased white-to-opaque switching frequency and stabilized the opaque state. Overexpression of ZCF37 promoted conversion of opaque cells to white phase, but needed existence of Efg1, a key regulator required for maintenance of the white state. Deletion of EFG1 abolished the effect of ectopically expressed Zcf37 on opaque-to-white switching, whereas ectopic expression of EFG1 promoted white cell formation without presence of Zcf37. Our results suggest that Zcf37 acts as an activator of white cell formation and a repressor of opaque state and functions upstream of Efg1. PMID- 21315073 TI - CIDEA interacts with liver X receptors in white fat cells. AB - Cell death-inducing DNA fragmentation factor alpha-like effector A (CIDEA) is endogenously expressed in human but not rodent white adipocytes. We performed a bioinformatic analysis of the human CIDEA sequence and found conserved amino-acid motifs involved in binding to nuclear receptors. Protein-protein binding experiments and transactivation assays confirmed that CIDEA binds to liver X receptors and regulates their activity in vitro. Cell fractionation demonstrated that CIDEA localizes to both the cytoplasm and the nucleus in human white adipocytes. The interaction between CIDEA and nuclear receptors could therefore be of importance for the regulation of metabolic processes in human adipose tissue. PMID- 21315074 TI - Plasmodium ovale curtisi and Plasmodium ovale wallikeri circulate simultaneously in African communities. AB - It has been proposed that ovale malaria in humans is caused by two closely related but distinct species of malaria parasite, Plasmodium ovale curtisi and Plasmodium ovale wallikeri. It was recently shown that these two parasite types are sympatric at the country level. However, it remains possible that localised geographic, temporal or ecological barriers exist within endemic countries which prevent recombination between the genomes of the two species. Here, using conventional and real-time quantitative PCR (qPCR) methods specifically designed to discriminate P. o. curtisi and P. o. wallikeri, it is shown that both species are present among clinic attendees in Congo-Brazzaville, and occur simultaneously both in lake-side and inland districts in Uganda and on Bioko Island, Equatorial Guinea. Thus P. o. curtisi and P. o. wallikeri in these localities are exactly sympatric in both time and space. These findings are consistent with the existence of a biological barrier, rather than geographical or ecological factors, preventing recombination between P. o. curtisi and P. o. wallikeri. In cross-sectional surveys carried out in Uganda and Bioko, our results show that infections with P. ovale spp. are more common than previously thought, occurring at a frequency of 1-6% in population samples, with both proposed species contributing to ovale malaria in six sites. Malaria elimination programmes in Africa need to include strategies for control of P. o. curtisi and P. o. wallikeri. PMID- 21315075 TI - Biochemical activity and multiple locations of particulate guanylate cyclase in Rhyacophila dorsalis acutidens (Insecta: Trichoptera) provide insights into the cGMP signalling pathway in Malpighian tubules. AB - In insect renal physiology, cGMP and cAMP have important regulatory roles. In Drosophila melanogaster, considered a good model for molecular physiology studies, and in other insects, cGMP and cAMP act as signalling molecules in the Malpighian tubules (MTs). However, many questions related to cyclic nucleotide functions are unsolved in principal cells (PC) and stellate cells (SC), the two cell types that compose the MT. In PC, despite the large body of information available on soluble guanylate cyclase (sGC) in the cGMP pathway, the functional circuit of particulate guanylate cyclase (pGC) remains obscure. In SC, on the other side, the synthesis and physiological role of the cGMP are still unknown. Our biochemical data regarding the presence of cyclic nucleotides in the MTs of Rhyacophila dorsalis acutidens revealed a cGMP level above the 50%, in comparison with the cAMP. The specific activity values for the membrane-bound guanylate cyclase were also recorded, implying that, besides the sGC, pGC is a physiologically relevant source of cGMP in MTs. Cytochemical studies showed ultrastructurally that there was a great deal of pGC on the basolateral membranes of both the principal and stellate cells. In addition, pGC was also detected in the contact zone between the two cell types and in the apical microvillar region of the stellate cells bordering the tubule lumen. The pGC signal is so well represented in PC and, unexpectedly in SC of MTs, that it is possible to hypothesize the existence of still uncharacterized physiological processes regulated by the pGC-cGMP system. PMID- 21315076 TI - Phase-specific responses to different qualities of food in the desert locust, Schistocerca gregaria: developmental, morphological and reproductive characteristics. AB - Solitarious female adults are known to produce smaller hatchlings than those produced by gregarious adults of the desert locust, Schistocerca gregaria. This study investigated developmental, morphological and reproductive responses to different qualities of food in hatchlings of different phases. Mortality was higher, the duration of nymphal development longer and adult body weight lighter with a low-quality food than a high-quality food. Gregarious hatchlings showed better survivorship, grew faster and became larger adults than did solitarious ones. The incidence of locusts exhibiting extra molting, which was typically observed in the solitarious phase, was dramatically increased when a low-quality food was given to the solitarious hatchlings. Low-quality food caused locusts to shift morphometric ratios toward the values typical of gregarious forms; smaller F/C (hind femur length/maximum head width) and larger E/F (elytra length/hind femur length). Solitarious hatchlings grown at either high- or low-quality foods and then given high-quality food after adult emergence revealed that food qualities during the nymphal stage influence their progeny quality and quantity via adult body size that influenced reproductive performance. Female adults showed an overshooting response to a shift from low- to high-quality food by increasing egg production that was specific to body size. This study may suggest that gregarious hatchlings are better adapted to adverse food conditions than solitarious counterparts and extra molting is induced even among gregarious hatchlings under poor food conditions. PMID- 21315077 TI - Elevated couch potato transcripts associated with adult diapause in the mosquito Culex pipiens. AB - The couch potato (cpo) cDNA that we cloned from the northern house mosquito, Culex pipiens, encodes the C-terminus containing a highly conserved RNA recognition motif (RRM). Protein structure prediction indicates a canonical RRM structure with a betaalphabetabetaalphabeta topological structure. Northern blots indicate a single mRNA band over 9.49 kb, and Southern blot analysis suggests that the cpo gene contains large introns. Highest expression was noted in first instar larvae and pupae. A comparison of nondiapausing (long daylength) and diapausing (short daylength) adult females showed no difference immediately at adult eclosion, but by day 7 and thereafter, expression of cpo was much higher in diapausing adults. When 2-month old diapausing females were transferred from short daylength to diapausing-terminating conditions of long daylength and high temperature, expression of cpo declined. Similarly, when a topical application of JH III was used to terminate diapause abundance of the cpo transcript declined. Consistent with observations in Drosophila melanogaster and several other species levels of cpo in C. pipiens are influenced by the diapause program, although the direction of change is not the same in all species. PMID- 21315078 TI - Control of larval-pupal-adult molt in the moth Sesamia nonagrioides by juvenile hormone and ecdysteroids. AB - Sesamia nonagrioides (Lepidoptera: Noctuidae) larvae reared under long day (LD; 16L:8D) conditions pupate after 5 or 6 larval instars, whereas under short day (SD; 12L:12D) conditions they undergo up to 12 additional molts before pupating. This extended period of repeated molting is maintained by high levels of juvenile hormone (JH). Previous work demonstrated that both LD and SD larvae decapitated in the 6th instar pupate but further development is halted. By contrast, about one-third of SD larvae from which only the brain has been removed, undergo first a larval molt, then pupate and subsequently developed to the adult stage. Debrained LD larvae molt to larvae exceptionally but regularly pupate and produce adults. Implanted brains may induce several larval molts in debrained recipient larvae irrespectively of the photoperiodic conditions. The results of present work demonstrate that the prothoracic glands (PGs) and the corpora allata (CA) of debrained larvae continue to produce ecdysteroids and JHs, respectively. PGs are active also in the decapitated larvae that lack JH, consistent with the paradigm that CA, which are absent in the decapitated larvae, are the only source of this hormone. Completion of the pupal-adult transformation in both LD and SD debrained insects demonstrates that brain is not crucial for the development of S. nonagrioides but is required for diapause maintenance. Application of JH to headless pupae induces molting, presumably by activating their PGs. It is likely that JH plays this role also in the induction of pupal-adult transformation in debrained insects. Application of the ecdysteroid agonist RH 2485 (methoxyfenozide) to headless pupae also elicits molting: newly secreted cuticle is in some cases thin and indifferent, in other cases it bears distinct pupal or adult features. PMID- 21315079 TI - The complex stridulatory behavior of the cricket Eneoptera guyanensis Chopard (Orthoptera: Grylloidea: Eneopterinae). AB - Crickets produce stridulated sounds by rubbing their forewings together. The calling song of the cricket species Eneoptera guyanensis Chopard, 1931 alternates two song sections, at low and high dominant frequencies, corresponding to two distinct sections of the stridulatory file. In the present study we address the complex acoustic behavior of E. guyanensis by integrating information on the peculiar morphology of the stridulatory file, the acoustic analysis of its calling song and the forewing movements during sound production. The results show that even if E. guyanensis matches the normal cricket functioning for syllable production, the stridulation involves two different closing movements, corresponding to two types of syllables, allowing the plectrum to hit alternately each differentiated section of the file. Transition syllables combine high and low frequencies and are emitted by a complete forewing closure over the whole file. The double-teeth section of the stridulatory file may be used as a multiplier for the song frequency because of the morphological multiplication due to the double teeth, but also because of an increase of wing velocity when this file section is used. According to available phylogenetic and acoustic data, this complex stridulation may have evolved in a two-step process. PMID- 21315080 TI - Molecular architecture and structural transitions of a Clostridium thermocellum mini-cellulosome. AB - The cellulosome is a highly elaborate cell-bound multienzyme complex that efficiently orchestrates the deconstruction of cellulose and hemicellulose, two of the nature's most abundant polymers. Understanding the intricacy of these nanomachines evolved by anaerobic microbes could sustain the development of an effective process for the conversion of lignocellulosic biomass to bio-ethanol. In Clostridium thermocellum, cellulosome assembly is mediated by high-affinity protein:protein interactions (>10(9) M(-1)) between dockerin modules found in the catalytic subunits and cohesin modules located in a non-catalytic protein scaffold termed CipA. Whereas the atomic structures of several cellulosomal components have been elucidated, the structural organization of the complete cellulosome remains elusive. Here, we reveal that a large fragment of the cellulosome presents a mostly compact conformation in solution, by solving the three-dimensional structure of a C. thermocellum mini-cellulosome comprising three consecutive cohesin modules, each bound to one Cel8A cellulase, at 35 A resolution by cryo-electron microscopy. Interestingly, the three cellulosomal catalytic domains are found alternately projected outward from the CipA scaffold in opposite directions, in an arrangement that could expand the area of the substrate accessible to the catalytic domains. In addition, the cellulosome can transit from this compact conformation to a multitude of diverse and flexible structures, where the linkers between cohesin modules are extended and flexible. Thus, structural transitions controlled by changes in the degree of flexibility of linkers connecting consecutive cohesin modules could regulate the efficiency of substrate recognition and hydrolysis. PMID- 21315081 TI - Electron microscopic visualization of the filament binding mode of actin-binding proteins. AB - A large number of actin-binding proteins (ABPs) regulate various kinds of cellular events in which the superstructure of the actin cytoskeleton is dynamically changed. Thus, to understand the actin dynamics in the cell, the mechanisms of actin regulation by ABPs must be elucidated. Moreover, it is particularly important to identify the side, barbed-end or pointed-end ABP binding sites on the actin filament. However, a simple, reliable method to determine the ABP binding sites on the actin filament is missing. Here, a novel electron microscopic method for determining the ABP binding sites is presented. This approach uses a gold nanoparticle that recognizes a histidine tag on an ABP and an image analysis procedure that can determine the polarity of the actin filament. This method will facilitate future study of ABPs. PMID- 21315082 TI - Insights into metalloregulation by M-box riboswitch RNAs via structural analysis of manganese-bound complexes. AB - The M-box riboswitch couples intracellular magnesium levels to expression of bacterial metal transport genes. Structural analyses on other riboswitch RNA classes, which typically respond to a small organic metabolite, have revealed that ligand recognition occurs through a combination of base-stacking, electrostatic, and hydrogen-bonding interactions. In contrast, the M-box RNA triggers a change in gene expression upon association with an undefined population of metals, rather than responding to only a single ligand. Prior biophysical experimentation suggested that divalent ions associate with the M-box RNA to promote a compacted tertiary conformation, resulting in sequestration of a short sequence tract otherwise required for downstream gene expression. Electrostatic shielding from loosely associated metals is undoubtedly an important influence during this metal-mediated compaction pathway. However, it is also likely that a subset of divalent ions specifically occupies cation binding sites and promotes proper positioning of functional groups for tertiary structure stabilization. To better elucidate the role of these metal binding sites, we resolved a manganese-chelated M-box RNA complex to 1.86 A by X-ray crystallography. These data support the presence of at least eight well-ordered cation binding pockets, including several sites that had been predicted by biochemical studies but were not observed in prior structural analysis. Overall, these data support the presence of three metal-binding cores within the M-box RNA that facilitate a network of long-range interactions within the metal-bound, compacted conformation. PMID- 21315083 TI - Kinetics and thermodynamics of the rate-limiting conformational change in the actomyosin V mechanochemical cycle. AB - We used FRET to examine the kinetics and thermodynamics of structural changes associated with ADP release in myosin V, which is thought to be a strain sensitive step in many muscle and non-muscle myosins. We also explored essential dynamics using FIRST/FRODA starting with three different myosin V X-ray crystal structures to examine intrinsic flexibility and correlated motions. Our steady state and time-resolved FRET analysis demonstrates a temperature-dependent reversible conformational change in the nucleotide-binding pocket (NBP). Our kinetic results demonstrate that the NBP goes from a closed to an open conformation prior to the release of ADP, while the actin-binding cleft remains closed. Interestingly, we find that the temperature dependence of the maximum actin-activated myosin V ATPase rate is similar to the pocket opening step, demonstrating that this is the rate-limiting structural transition in the ATPase cycle. Thermodynamic analysis demonstrates that the transition from the open to closed NBP conformation is unfavorable because of a decrease in entropy. The intrinsic flexibility analysis is consistent with conformational entropy playing a role in this transition as the MV.ADP structure is highly flexible compared to the MV.APO structure. Our experimental and modeling studies support the conclusion of a novel post-power-stroke actomyosin.ADP state in which the NBP and actin-binding cleft are closed. The novel state may be important for strain sensitivity as the transition from the closed to open NBP conformation may be altered by lever arm position. PMID- 21315084 TI - Human spire interacts with the barbed end of the actin filament. AB - Spire is an actin nucleator that initiates actin polymerization at a specific place in the cell. Similar to the Arp2/3 complex, spire was initially considered to bind to the pointed end of the actin filament when it generates a new actin filament. Subsequently, spire was reported to be associated with the barbed end (B-end); thus, there is still no consensus regarding the end with which spire interacts. Here, we report direct evidence that spire binds to the B-end of the actin filament, under conditions where spire accelerates actin polymerization. Using electron microscopy, we visualized the location of spire bound to the filament by gold nanoparticle labeling of the histidine-tagged spire, and the polarity of the actin filament was determined by image analysis. In addition, our results suggest that multiple spires, linked through one gold nanoparticle, enhance the acceleration of actin polymerization. The B-end binding of spire provides the basis for understanding its functional mechanism in the cell. PMID- 21315085 TI - Crystal structures of Xanthomonas small heat shock protein provide a structural basis for an active molecular chaperone oligomer. AB - Small heat shock proteins (sHsps) are ubiquitous low-molecular-weight chaperones that prevent protein aggregation under cellular stresses. sHsps contain a structurally conserved alpha-crystallin domain (ACD) of about 100 amino acid residues flanked by varied N- and C-terminal extensions and usually exist as oligomers. Oligomerization is important for the biological functions of most sHsps. However, the active oligomeric states of sHsps are not defined yet. We present here crystal structures (up to 1.65 A resolution) of the sHspA from the plant pathogen Xanthomonas (XaHspA). XaHspA forms closed or open trimers of dimers (hexamers) in crystals but exists predominantly as 36mers in solution as estimated by size-exclusion chromatography. The XaHspA monomer structures mainly consist of alpha-crystallin domain with disordered N- and C-terminal extensions, indicating that the extensions are flexible and not essential for the formation of dimers and 36mers. Under reducing conditions where alpha-lactalbumin (LA) unfolds and aggregates, XaHspA 36mers formed complexes with one LA per XaHspA dimer. Based on XaHspA dimer-dimer interactions observed in crystals, we propose that XaHspA 36mers have four possible conformations, but only XaHspA 36merB, which is formed by open hexamers in 12mer-6mer-6mer-12mer with protruding dimers accessible for substrate (unfolding protein) binding, can bind to 18 reduced LA molecules. Together, our results unravel the structural basis of an active sHsp oligomer. PMID- 21315086 TI - Energetics of SecA dimerization. AB - Transport of many proteins to extracytoplasmic locations occurs via the general secretion (Sec) pathway. In Escherichia coli, this pathway is composed of the SecYEG protein-conducting channel and the SecA ATPase. SecA plays a central role in binding the signal peptide region of preproteins, directing preproteins to membrane-bound SecYEG and promoting translocation coupled with ATP hydrolysis. Although it is well established that SecA is crucial for preprotein transport and thus cell viability, its oligomeric state during different stages of transport remains ill defined. We have characterized the energetics of SecA dimerization as a function of salt concentration and temperature and defined the linkage of SecA dimerization and signal peptide binding using analytical ultracentrifugation. The use of a new fluorescence detector permitted an analysis of SecA dimerization down to concentrations as low as 50 nM. The dimer dissociation constants are strongly dependent on salt. Linkage analysis indicates that SecA dimerization is coupled to the release of about five ions, demonstrating that electrostatic interactions play an important role in stabilizing the SecA dimer interface. Binding of signal peptide reduces SecA dimerization affinity, such that K(d) increases about 9-fold from 0.28 MUM in the absence of peptide to 2.68 MUM in the presence of peptide. The weakening of the SecA dimer that accompanies signal peptide binding may poise the SecA dimer to dissociate upon binding to SecYEG. PMID- 21315087 TI - A polypeptide "building block" for the beta-trefoil fold identified by "top-down symmetric deconstruction". AB - Fibroblast growth factor-1, a member of the 3-fold symmetric beta-trefoil fold, was subjected to a series of symmetric constraint mutations in a process termed "top-down symmetric deconstruction." The mutations enforced a cumulative exact 3 fold symmetry upon symmetrically equivalent positions within the protein and were combined with a stability screen. This process culminated in a beta-trefoil protein with exact 3-fold primary-structure symmetry that exhibited excellent folding and stability properties. Subsequent fragmentation of the repeating primary-structure motif yielded a 42-residue polypeptide capable of spontaneous assembly as a homotrimer, producing a thermostable beta-trefoil architecture. The results show that despite pronounced reduction in sequence complexity, pure symmetry in the design of a foldable, thermostable beta-trefoil fold is possible. The top-down symmetric deconstruction approach provides a novel alternative means to successfully identify a useful polypeptide "building block" for subsequent "bottom-up" de novo design of target protein architecture. PMID- 21315088 TI - The ATM kinase signaling induced by the low-energy beta-particles emitted by (33)P is essential for the suppression of chromosome aberrations and is greater than that induced by the energetic beta-particles emitted by (32)P. AB - Ataxia-telangiectasia mutated (ATM) encodes a nuclear serine/threonine protein kinase whose activity is increased in cells exposed to low doses of ionizing radiation (IR). Here we examine ATM kinase activation in cells exposed to either (32)P- or (33)P-orthophosphate under conditions typically employed in metabolic labelling experiments. We calculate that the absorbed dose of IR delivered to a 5cm*5cm monolayer of cells incubated in 2ml media containing 1mCi of the high energy (1.70MeV) beta-particle emitter (32)P-orthophosphate for 30min is ~1Gy IR. The absorbed dose of IR following an otherwise identical exposure to the low energy (0.24MeV) beta-particle emitter (33)P-orthophosphate is ~0.18Gy IR. We show that low-energy beta-particles emitted by (33)P induce a greater number of ionizing radiation-induced foci (IRIF) and greater ATM kinase signaling than energetic beta-particles emitted by (32)P. Hence, we demonstrate that it is inappropriate to use (33)P-orthophosphate as a negative control for (32)P orthophosphate in experiments investigating DNA damage responses to DNA double strand breaks (DSBs). Significantly, we show that ATM accumulates in the chromatin fraction when ATM kinase activity is inhibited during exposure to either radionuclide. Finally, we also show that chromosome aberrations accumulate in cells when ATM kinase activity is inhibited during exposure to ~0.36Gy beta particles emitted by (33)P. We therefore propose that direct cellular exposure to (33)P-orthophosphate is an excellent means to induce and label the IR-induced, ATM kinase-dependent phosphoproteome. PMID- 21315089 TI - The ERCC1 N118N polymorphism does not change cellular ERCC1 protein expression or platinum sensitivity. AB - Genetic polymorphisms in ERCC1 are thought to contribute to altered sensitivity to platinum-based chemotherapy. Although ERCC1 N118N (500 C>T, rs11615) is the most studied polymorphism, the impact of this polymorphism on platinum-based chemotherapy remains unclear. This is the first study in which the functional impact of ERCC1 N118N on gene expression and platinum sensitivity was explored. The aim of this study is to investigate if the reduced codon usage frequency of AAT, which contains the variant allele of the silent mutation, has functional impact on ERCC1 in a well-controlled biological system. Specifically, the ERCC1 cDNA clone with either the C or T allele was introduced into an ERCC1 deficient cell line, UV20, and assayed for the effect of the two alleles on ERCC1 transcription, translation and platinum sensitivity. Both ERCC1 mRNA and protein expression levels increased upon cisplatin treatment, peaking at 4h post treatment, however there were no differences between the two alleles (p>0.05). Cells complemented with ERCC1 showed significantly higher survival proportion than the parental cell line following platinum exposure (p<0.0001), although no differences were observed between the cells transfected with the wild type or the polymorphic allele. These data suggest that N118N itself is not related to the phenotypic differences in ERCC1 expression or function, but rather this polymorphism may be linked to other causative variants or haplotypes. PMID- 21315090 TI - Environmental novelty causes stress-like adaptations at nucleus accumbens synapses: implications for studying addiction-related plasticity. AB - Exposure to abused drugs and stressful experience, two factors that promote the development of addiction, also modify synaptic function in the mesolimbic dopamine system. Here, we show that exposure to a novel environment produces functional synaptic adaptations in the nucleus accumbens (NAc) that mirror the effect of conventional forms of stress. We find an enhancement of excitatory synaptic strength in the NAc shell one day after exposure to a novel environment for 60 min--an effect not observed in NAc core. This effect disappeared following repeated exposure to the same environment, but then reappeared if mice are returned to the same environment 10-14 days later. There were no interactions between the effects of environmental novelty and a single exposure to cocaine (15 mg/kg), with no effect of the latter on synaptic strength in NAc shell. These results have important implications for designing studies of NAc synapses in the context of behavioral analysis, and expand our understanding of how different forms of stress modify NAc synaptic function. PMID- 21315092 TI - Music training and working memory: an ERP study. AB - While previous research has suggested that music training is associated with improvements in various cognitive and linguistic skills, the mechanisms mediating or underlying these associations are mostly unknown. Here, we addressed the hypothesis that previous music training is related to improved working memory. Using event-related potentials (ERPs) and a standardized test of working memory, we investigated both neural and behavioral aspects of working memory in college aged, non-professional musicians and non-musicians. Behaviorally, musicians outperformed non-musicians on standardized subtests of visual, phonological, and executive memory. ERPs were recorded in standard auditory and visual oddball paradigms (participants responded to infrequent deviant stimuli embedded in lists of standard stimuli). Electrophysiologically, musicians demonstrated faster updating of working memory (shorter latency P300s) in both the auditory and visual domains and musicians allocated more neural resources to auditory stimuli (larger amplitude P300), showing increased sensitivity to the auditory standard/deviant difference and less effortful updating of auditory working memory. These findings demonstrate that long-term music training is related to improvements in working memory, in both the auditory and visual domains and in terms of both behavioral and ERP measures. PMID- 21315093 TI - Top-down visual activity underlying VSTM and preparatory attention. AB - Attention and visual short-term memory (VSTM) are both associated with top-down activity in visual cortex. To-be-remembered visual input triggers persistent activity in visual cortex, and preparatory attention elicits visual activity in anticipation of an expected target stimulus. This brief review considers similarities, and differences, in top-down visual activity underlying VSTM maintenance and preparatory attention. The extant evidence suggests that top-down visual activity provides a common neural substrate for VSTM maintenance and preparatory attention, however the precise neural implementation depends on the specific task parameters. A similar neurobiological framework may also apply to other high-level visual phenomena, including visual imagery and awareness. PMID- 21315091 TI - The neural correlates of visual working memory encoding: a time-resolved fMRI study. AB - The encoding of information into visual working memory (VWM) is not only a prerequisite step for efficient working memory, it is also considered to limit our ability to attend to, and be consciously aware of, task-relevant events. Despite its important role in visual cognition, the neural mechanisms underlying visual working memory encoding have not yet been specifically dissociated from those involved in perception and/or VWM maintenance. To isolate the brain substrates supporting VWM encoding, here we sought to identify, with time resolved fMRI, brain regions whose temporal profile of activation tracked the time course of VWM encoding. We applied this approach to two different stimulus categories - colors and faces - that dramatically differ in their encoding time. While several cortical and subcortical regions were activated during the VWM encoding period, one of these regions in the lateral prefrontal cortex - the inferior frontal junction - showed a temporal activation profile associated with the duration of encoding and that could not be accounted for by either perceptual or general attentional effects. Moreover, this region corresponds to the prefrontal area previously implicated in 'attentional blink' paradigms demonstrating attentional limits to conscious perception. These results not only suggest that the inferior frontal junction is involved in VWM encoding, they also provide neural support for theories positing that VWM encoding is a rate-limiting process underlying our attentional limits to visual awareness. PMID- 21315094 TI - The time course of implicit processing of facial features: an event-related potential study. AB - In this study, we used ERPs to investigate the time course of implicit face processing. More specifically, we utilized a masked priming paradigm to investigate implicit processing of the eyes and mouth in upright and inverted faces, using a prime duration of 33ms. Two types of prime-target pairs were used: (1) congruent (e.g., open eyes only in both prime and target); (2) incongruent (e.g., open eyes only in prime and open mouth only in target). The identity of the faces changed between prime and target. Participants pressed one button to indicate whether the target face's mouth was open, and another if the eyes were open. The behavioral results indicated a congruent priming effect for upright but not for inverted faces. The ERP results indicated a face orientation effect across all ERP components studied (P1, N1, P2, N170, N2, P3) starting at about 80ms, and a congruency/priming effect on late components (N2, P3), starting at about 200ms. The functional significance of these ERP effects is discussed in relation to unconscious perception and configural face processing. PMID- 21315096 TI - Sex differences in synaptic plasticity in stress-responsive brain regions following chronic variable stress. AB - Increased stress responsiveness is implicated in the etiology of mood and anxiety disorders, including depression and post-traumatic stress disorder. Additionally, stress-related affective disorders have a higher incidence in women than men. Chronic stress in rodents produces numerous neuromorphological changes in a variety of limbic brain regions. Here, we examined the sex-dependent differences in presynaptic innervation of the paraventricular nucleus of the hypothalamus (PVN), prefrontal cortex (PFC), bed nucleus of the stria terminalis (BST), and amygdala in response to chronic variable stress (CVS). Following 14 days of CVS, the presynaptic protein synaptophysin was assessed in male and female rats. Our results demonstrate that synaptophysin staining density was higher in females than males in all brain areas evaluated, indicating sex differences in the organization of presynaptic innervation. After CVS, the PVN, principal nucleus of the BST (BSTpr), and basolateral nucleus of the amygdala (BLA) displayed significantly reduced synaptophysin density in females but not males. Furthermore, males showed an increase in synaptophysin in the PVN after CVS, suggesting a sex difference in the modulation of presynaptic inputs to the PVN following chronic stress. Overall, these data suggest marked sex differences in PVN, BSTpr, and BLA presynaptic innervation as a consequence of chronic stress, which may be associated with differential stress responsivity and perhaps susceptibility to pathologies in males and females. PMID- 21315097 TI - Circadian rhythms in metabolic variables in Caenorhabditis elegans. AB - Circadian rhythms govern a wide variety of physiological and metabolic functions in most organisms through neural networks, hormones and gene expression. In this work, we studied the circadian variation in metabolic variables of adult C. elegans such as food consumption, pharyngeal contractions, defecation and oxygen consumption. Feeding behavior was clearly rhythmic under LD conditions, with a non-significant trend under DD conditions. In addition, a daily and circadian variation in muscle contraction of the pharynx was observed. Oxygen consumption also showed a circadian fluctuation with a maximum in the middle of the night (a peak was found around ZT18/CT18). Furthermore, defecation behavior also showed a daily variation in the N2 strain (wild type). This work demonstrates that in the adult nematode C. elegans metabolic variables vary daily. In summary, our results will allow us to take full advantage of this widely used animal model (including research in genetics, ageing and developmental biology) for studies in Chronobiology. PMID- 21315095 TI - Obesity surgery and gut-brain communication. AB - The prevalence of obesity, and the cluster of serious metabolic diseases it is associated with, continues to rise globally, and hopes for effective treatment with drugs have been considerably set back. Thus, success with bariatric surgeries to induce sustained body weight loss and effectively cure most of the associated co-morbidities appears almost "miraculous" and systematic investigation of the mechanisms at work has gained momentum. Here, we will discuss the basic organization of gut-brain communication and review clinical and pre-clinical investigations on the potential mechanisms by which gastric bypass surgery leads to its beneficial effects on energy balance and glucose homeostasis. Although a lot has been learned regarding changes in energy intake and expenditure, secretion of gut hormones, and improvement in glucose homeostasis, there has not yet been the "breakthrough observation" of identifying a key signaling component common to the beneficial effects of the surgery. However, given the complexity and redundancy of gut-brain signaling and gut signaling to other relevant organs, it is perhaps more realistic to expect a number of key signaling changes that act in concert to bring about the "miracle". PMID- 21315098 TI - Children's internalizing symptoms: the role of interactions between cortisol and respiratory sinus arrhythmia. AB - We examined interactions between children's physiological activity across two systems, the hypothalamic-pituitary-adrenal (HPA)-axis and the parasympathetic nervous system (PNS), as predictors of child-reported internalizing symptoms (depression, anxiety). HPA activity was indexed by baseline salivary cortisol, and PNS activity was indexed by baseline respiratory sinus arrhythmia (RSA). Study 1 consisted of 57 children (54% girls; M age=8.81 years +/-.34), and Study 2 included 219 children (51% girls; M age=9.31 years +/-.79). Cortisol interacted with RSA to explain unique variance in children's internalizing symptoms. Across the two studies, children with higher cortisol levels in conjunction with higher RSA levels tended to exhibit the lowest levels of depression and anxiety symptoms. Findings demonstrate that contemporaneous consideration of physiological activity across multiple systems can advance understanding of internalizing symptoms in children. PMID- 21315099 TI - The independent roles of temperature and thermal perception in the control of human thermoregulatory behavior. AB - The present study independently evaluated temperature and thermal perception as controllers of thermoregulatory behavior in humans. This was accomplished using a self-paced exercise and heat stress model in which twelve physically active male subjects exercised at a constant subjective rating of perceived exertion (16, 'hard--very hard') while their face was thermally and non-thermally cooled, heated, or left alone (control trial). Thermal cooling and heating were achieved via forced convection, while non-thermal cooling and heating were accomplished via the topical application of menthol and capsaicin solutions. Evidence for thermoregulatory behavior was defined in terms of self-selected exercise intensity, and thus exercise work output. The results indicate that, in the absence of changes in temperature, non-thermal cooling and warming elicited thermal sensory and discomfort sensations similar to those observed during thermal cooling and warming. Furthermore, the perception of effort was maintained throughout exercise in all trials, while the initial and final exercise intensities were also similar. Thermal and non-thermal cooling resulted in the highest work output, while thermal warming the lowest. Non-thermal warming and control trials were similar. Heart rate, mean skin and core (rectal) temperatures, and whole body and local (neck) sweat rates were similar between all trials. These data indicate that changes in temperature are not a requirement for the initiation of thermoregulatory behavior in humans. Rather, thermal sensation and thermal discomfort are capable behavioral controllers. PMID- 21315100 TI - Blockade of androgen receptor in the medial amygdala inhibits noncontact erections in male rats. AB - Our previous work demonstrated that androgens in the medial amygdala (MeA) of castrated male rats maintained noncontact erections (NCEs), which occur during exposure to an inaccessible receptive female, for one week after implantation. The present experiments investigated the effects of implantation into the MeA of either flutamide (F), a blocker of androgen receptors, or of 1,4,6-androstatrien 3,17-dione (ATD), which blocks aromatization of testosterone. One day after implantation of F, fewer males displayed NCEs, and had longer latencies to the first NCE and fewer NCEs, and spent less total time in genital grooming, compared to the control group. ATD had only weak facilitative effects on some measures of NCEs. These results suggest that androgen receptors in the MeA play a major role in the regulation of NCEs and that the MeA is one of the neuronal structures that regulate male sexual arousal. Furthermore, it is sensitive to relatively fast changes in the level of androgen receptors stimulation. PMID- 21315102 TI - A single functional model accounts for the distinct properties of suppression in cortical area V1. AB - Cross-orientation suppression and surround suppression have been extensively studied in primary visual cortex (V1). These two forms of suppression have some distinct properties which has led to the suggestion that they are generated by different underlying mechanisms. Furthermore, it has been suggested that mechanisms other than intracortical inhibition may be central to both forms of suppression. A simple computational model (PC/BC), in which intracortical inhibition is fundamental, is shown to simulate the distinct properties of cross orientation and surround suppression. The same model has previously been shown to account for a large range of V1 response properties including orientation-tuning, spatial and temporal frequency tuning, facilitation and inhibition by flankers and textured surrounds as well as a range of other experimental results on cross orientation suppression and surround suppression. The current results thus provide additional support for the PC/BC model of V1 and for the proposal that the diverse range of response properties observed in V1 neurons have a single computational explanation. Furthermore, these results demonstrate that current neurophysiological evidence is insufficient to discount intracortical inhibition as a central mechanism underlying both forms of suppression. PMID- 21315101 TI - A comparative integrated transcript analysis and functional characterization of differential mechanisms for induction of liver hypertrophy in the rat. AB - The main goal of the present work was to better understand the molecular mechanisms underlying liver hypertrophy (LH), a recurrent finding observed following acute or repeated drug administration to animals, using transcriptomic technologies together with the results from conventional toxicology methods. Administration of 5 terminated proprietary drug candidates from participating companies involved in the EU Innomed PredTox Project or the reference hepatotoxicant troglitazone to rats for up to a 14-day duration induced LH as the main liver phenotypic toxicity outcome. The integrated analysis of transcriptomic liver expression data across studies turned out to be the most informative approach for the generation of mechanistic models of LH. In response to a xenobiotic stimulus, a marked increase in the expression of xenobiotic metabolizing enzymes (XME) was observed in a subset of 4 studies. Accumulation of these newly-synthesized proteins within the smooth endoplasmic reticulum (SER) would suggest proliferation of this organelle, which most likely is the main molecular process underlying the LH observed in XME studies. In another subset of 2 studies (including troglitazone), a marked up-regulation of genes involved in peroxisomal fatty acid beta-oxidation was noted, associated with induction of genes involved in peroxisome proliferation. Therefore, an increase in peroxisome abundance would be the main mechanism underlying LH noted in this second study subset. Together, the use of transcript profiling provides a means to generate putative mechanistic models underlying the pathogenesis of liver hypertrophy, to distinguish between subtle variations in subcellular organelle proliferation and creates opportunities for improved mechanism-based risk assessment. PMID- 21315103 TI - Sexual orientation, fraternal birth order, and the maternal immune hypothesis: a review. AB - In 1996, psychologists Ray Blanchard and Anthony Bogaert found evidence that gay men have a greater number of older brothers than do heterosexual men. This "fraternal birth order" (FBO) effect has been replicated numerous times, including in non-Western samples. More recently, strong evidence has been found that the FBO effect is of prenatal origin. Although there is no direct support for the exact prenatal mechanism, the most plausible explanation may be immunological in origin, i.e., a mother develops an immune reaction against a substance important in male fetal development during pregnancy, and that this immune effect becomes increasingly likely with each male gestation. This immune effect is hypothesized to cause an alteration in (some) later born males' prenatal brain development. The target of the immune response may be molecules (i.e., Y-linked proteins) on the surface of male fetal brain cells, including in sites of the anterior hypothalamus, which has been linked to sexual orientation in other research. Antibodies might bind to these molecules and thus alter their role in typical sexual differentiation, leading some later born males to be attracted to men as opposed to women. Here we review evidence in favor of this hypothesis, including recent research showing that mothers of boys develop an immune response to one Y-linked protein (i.e., H-Y antigen; SMCY) important in male fetal development, and that this immune effect becomes increasingly likely with each additional boy to which a mother gives birth. We also discuss other Y linked proteins that may be relevant if this hypothesis is correct. Finally, we discuss issues in testing the maternal immune hypothesis of FBO. PMID- 21315104 TI - Glutamate receptor dysfunction and drug targets across models of autism spectrum disorders. AB - There is strong evidence that metabotropic and ionotropic glutamate receptors are affected in autism spectrum disorders (ASD), but there are few candidate genes indicating involvement of these receptors. This suggests that glutamate receptor dysregulation may primarily be involved in the expression of ASD, but is an uncommon etiology. Directly implicated in models of fragile-X with ASD phenotypes is metabotropic glutamate receptor type 5 (mGluR5), which appears to be an effective pharmacologic target in a number of models of ASD. The review of other ASD models demonstrates that there is also evidence of a role for kainate, NMDA, and AMPA receptors in the neuropathophysiology of ASD, though the relationship between dysfunction in those receptors and ASD-associated phenotypes is not well understood. Current models indicate a way forward to delineate the role of glutamate receptors in ASD. Further development of preclinical models focusing on glutamate receptors may provide tools to target a clinically important subset of ASD symptoms. PMID- 21315105 TI - Impulsive choice, as measured in a delay discounting paradigm, remains stable after chronic heroin administration. AB - Heroin addicts display poorer impulse control than non-addicts, however it is not known if high impulsivity is a function of chronic heroin intake or a pre disposing vulnerability for heroin addiction. Using animal models, relatively few studies have examined changes in impulsive choice as a function of chronic drug. The objective of this study was to measure alterations in impulsive choice through a delay discounting paradigm, as a function of chronic heroin administration. Animals were trained on a series of delay discounting sessions. Each session contained 5 blocks of trials. Blocks started with 2 forced, followed by 6 free choice trials. Pressing one lever resulted in the delivery of a small immediate (1 food pellet) reward and another lever in a large delayed (5 pellets) reward. Sessions consisted of the 3 ascending delay sequences in seconds. On the terminal sequence (0, 10, 20, 40, and 60s) animals exhibited a reversal of reward choice pattern of responding that allowed for the calculation of an indifference point (IP). After animals showed stable IPs they were treated with either heroin or saline for 12 days. Three days after the last injection animals were again placed in operant chambers and experienced the terminal delay discounting sequence at which time IPs were reassessed. Heroin-treated animals exhibited significant progressive increases in locomotor activity. Groups did not differ in IPs or performance across delay conditions during either before or after chronic treatment periods. These results indicate that chronic heroin intake does not impact later impulsive responding for natural (food) reward. PMID- 21315106 TI - Immobilization of urease on nanostructured polymer membrane and preparation of urea amperometric biosensor. AB - A new matrix for enzyme immobilization of urease was obtained by incorporating rhodium nanoparticles (5% on activated charcoal) and chemical bonding of chitosan with different concentration (0.15%; 0.3%; 0.5%; 1.0%; 1.5%) in previously chemically modified AN copolymer membrane. The basic characteristics of the chitosan modified membranes were investigated. The SEM analyses were shown essential morphology change in the different modified membranes. Both the amount of bound protein and relative activity of immobilized enzyme were measured. A higher activity (about 77.44%) was measured for urease bound to AN copolymer membrane coated with 1.0% chitosan and containing rhodium nanoparticles. The basic characteristics (pH(opt), T(opt), thermal, storage and operation stability) of immobilized enzyme on this optimized modified membrane were also determined. The prepared enzyme membrane was used for the construction of amperometric biosensor for urea detection. Its basic amperometric characteristics were investigated. A calibration plot was obtained for urea concentration ranging from 1.6 to 23 mM. A linear interval was detected along the calibration curve from 1.6 to 8.2mM. The sensitivity of the constructed biosensor was calculated to be 3.1927 MUAmM(-1)cm(-2). The correlation coefficient for this concentration range was 0.998. The detection limit with regard to urea was calculated to be 0.5mM at a signal-to-noise ratio of 3. The biosensor was employed for 10 days while the maximum response to urea retained 86.8%. PMID- 21315107 TI - Probing dimer interface stabilization within a four-helix bundle of the GrpE protein from Escherichia coli via internal deletion mutants: conversion of a dimer to monomer. AB - Insight into protein stability and folding remains an important area for protein research, in particular protein-protein interactions and the self-assembly of homodimers. The GrpE protein from Escherichia coli is a homodimer with a four helix bundle at the dimer interface. Each monomer contributes a helix-loop-helix to the bundle. To probe the interface stabilization requirements, in terms of the amount of buried residues in the bundle necessary for dimer formation, internal deletion mutants (IDMs) were created that sequentially truncate each of the two helices in the helix-loop-helix region. Circular dichroism (CD) spectroscopy showed that all IDM's still contained a significant amount of alpha-helical secondary structure. IDM's that contained 11 or fewer of 22 residues originally present in the helices, or those that lost at least 50% of residues with less than 20% the solvent accessible surfaces (that is, hydrophobic residues) were unable to form a significant amount of dimer species as shown by chemical cross linking. Gel filtration studies of IDM3.0 (one that retains 10 residues in each helix) show this variant to be mainly monomeric. PMID- 21315108 TI - Epidemiology and control of chikungunya fever in Singapore. AB - OBJECTIVES: We conducted an epidemiological review of the chikungunya fever situation in Singapore and described the measures taken to prevent the chikungunya virus from becoming entrenched in the tropical city-state. METHODS: All laboratory-confirmed cases and outbreak investigation reports maintained by the Communicable Diseases Division, Ministry of Health, and Aedes mosquito surveillance data obtained by the National Environment Agency during the period 2006 and 2009 were reviewed and analysed. RESULTS: Sporadic cases were imported into Singapore until the first local transmission occurred in an urban area where Aedes aegypti was the predominant vector. Subsequent introduction of a mutant viral strain (A226V) in early 2008 resulted in the rapid spread to suburban and rural areas where Aedes albopictus was the primary vector. 1072 cases including 812 (75.7%) indigenous cases were reported. The main sources of importation were India and Malaysia. Foreign contract workers were identified as high-risk for indigenous infections. CONCLUSIONS: The disease was successfully brought under control through aggressive vector control measures directed at A. albopictus. Although the incidence has sharply declined since January 2009, a high degree of vigilance is maintained to prevent a recurrence of epidemic transmission which can occur even with a well-established nationwide mosquito control programme. PMID- 21315109 TI - Involvement of the cholinergic system in conditioning and perceptual memory. AB - The cholinergic systems play a pivotal role in learning and memory, and have been the centre of attention when it comes to diseases containing cognitive deficits. It is therefore not surprising, that the cholinergic transmitter system has experienced detailed examination of its role in numerous behavioural situations not least with the perspective that cognition may be rescued with appropriate cholinergic 'boosters'. Here we reviewed the literature on (i) cholinergic lesions, (ii) pharmacological intervention of muscarinic or nicotinic system, or (iii) genetic deletion of selective receptor subtypes with respect to sensory discrimination and conditioning procedures. We consider visual, auditory, olfactory and somatosensory processing first before discussing more complex tasks such as startle responses, latent inhibition, negative patterning, eye blink and fear conditioning, and passive avoidance paradigms. An overarching reoccurring theme is that lesions of the cholinergic projection neurones of the basal forebrain impact negatively on acquisition learning in these paradigms and blockade of muscarinic (and to a lesser extent nicotinic) receptors in the target structures produce similar behavioural deficits. While these pertain mainly to impairments in acquisition learning, some rare cases extend to memory consolidation. Such single case observations warranted replication and more in depth studies. Intriguingly, receptor blockade or receptor gene knockout repeatedly produced contradictory results (for example in fear conditioning) and combined studies, in which genetically altered mice are pharmacological manipulated, are so far missing. However, they are desperately needed to clarify underlying reasons for these contradictions. Consistently, stimulation of either muscarinic (mainly M(1)) or nicotinic (predominantly alpha7) receptors was beneficial for learning and memory formation across all paradigms supporting the notion that research into the development and mechanisms of novel and better cholinomimetics may prove useful in the treatment of neurodegenerative or psychiatric disorders with cognitive endophenotypes. PMID- 21315110 TI - Early hippocampal cell death, and late learning and memory deficits in rats exposed to the environmental toxin BMAA (beta-N-methylamino-L-alanine) during the neonatal period. AB - We have reported previously that exposure to the cyanobacterial neurotoxin beta-N methylamino-L-alanine (BMAA) during the neonatal period causes cognitive impairments in adult rats. The aim of this study was to investigate the long-term effects of neonatal BMAA exposure on learning and memory mechanisms and to identify early morphological changes in the neonatal brain. BMAA was injected subcutaneously in rat pups on postnatal days 9-10. BMAA (50 and 200 mg/kg) caused distinct deficits in spatial learning and memory in adult animals but no morphological changes. No impairment of recognition memory was detected, suggesting that neonatal exposure to BMAA preferentially affects neuronal systems that are important for spatial tasks. Histopathological examination revealed early neuronal cell death as determined by TUNEL staining in the hippocampus 24 h after a high dose (600 mg/kg) of BMAA whereas no changes were observed at lower doses (50 and 200 mg/kg). In addition, there was a low degree of neuronal cell death in the retrosplenial and cingulate cortices, areas that are also important for cognitive function. Taken together, these results indicate that BMAA is a developmental neurotoxin inducing long-term changes in cognitive function. The risk posed by BMAA as a potential human neurotoxin merits further consideration, particularly if the proposed biomagnifications in the food chain are confirmed. PMID- 21315112 TI - Regulation of IGF-1-dependent cyclin D1 and E expression by hEag1 channels in MCF 7 cells: the critical role of hEag1 channels in G1 phase progression. AB - Insulin-like Growth Factor-1 (IGF-1) plays a key role in breast cancer development and cell cycle regulation. It has been demonstrated that IGF-1 stimulates cyclin expression, thus regulating the G1 to S phase transition of the cell cycle. Potassium (K(+)) channels are involved in the G1 phase progression of the cell cycle induced by growth factors. However, mechanisms that allow growth factors to cooperate with K(+) channels in order to modulate the G1 phase progression and cyclin expression remain unknown. Here, we focused on hEag1 K(+) channels which are over-expressed in breast cancer and are involved in the G1 phase progression of breast cancer cells (MCF-7). As expected, IGF-1 increased cyclin D1 and E expression of MCF-7 cells in a cyclic manner, whereas the increase of CDK4 and 2 levels was sustained. IGF-1 stimulated p21(WAF1/Cip1) expression with a kinetic similar to that of cyclin D1, however p27(Kip1) expression was insensitive to IGF-1. Interestingly, astemizole, a blocker of hEag1 channels, but not E4031, a blocker of HERG channels, inhibited the expression of both cyclins after 6-8h of co-stimulation with IGF-1. However, astemizole failed to modulate CDK4, CDK2, p21(WAF1/Cip1) and p27(Kip1) expression. The down-regulation of hEag1 by siRNA provoked a decrease in cyclin expression. This study is the first to demonstrate that K(+) channels such as hEag1 are directly involved in the IGF-1-induced up-regulation of cyclin D1 and E expression in MCF-7 cells. By identifying more specifically the temporal position of the arrest site induced by the inhibition of hEag1 channels, we confirmed that hEag1 activity is predominantly upstream of the arrest site induced by serum deprivation, prior to the up-regulation of both cyclins D1 and E. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. PMID- 21315111 TI - Chronic injection of pansomatostatin agonist ODT8-SST differentially modulates food intake and decreases body weight gain in lean and diet-induced obese rats. AB - The aim of this study was to investigate the central actions of the stable pansomatostatin peptide agonist, ODT8-SST on body weight. ODT8-SST or vehicle was acutely (1MUg/rat) injected or chronically infused (5MUg/rat/d, 14d) intracerebroventricularly and daily food intake, body weight and composition were monitored. In lean rats, neither acute nor chronic ODT8-SST influenced daily food intake while body weight was reduced by 2.2% after acute injection and there was a 14g reduction of body weight gain after 14d compared to vehicle (p<0.01). In diet-induced obese (DIO) rats, chronic ODT8-SST increased cumulative 2-week food intake compared to vehicle (+14%, p<0.05) and also blunted body weight change ( 11g, p<0.05). ODT8-SST for 14d reduced lean mass (-22g and -25g respectively, p<0.001) and total water (-19g and -22g respectively, p<0.001) in lean and DIO rats and increased fat mass in DIO (+16g, p<0.001) but not lean rats (+1g, p>0.05) compared to vehicle. In DIO rats, ODT8-SST reduced ambulatory (-27%/24h, p<0.05) and fine movements (-38%, p<0.01) which was associated with an increased positive energy balance compared to vehicle (+50g, p<0.01). Chronic central somatostatin receptor activation in lean rats reduces body weight gain and lean mass independently of food intake which is likely related to growth hormone inhibition. In DIO rats, ODT8-SST reduces lean mass but promotes food intake and fat mass, indicating differential responsiveness to somatostatin under obese conditions. PMID- 21315113 TI - Fast preparation of fungal DNA for PCR screening. AB - Rapid DNA preparation for the quick screening is highly demanded in diverse research fields. Here, we combined an extraction buffer and heat treatment to generate DNA templates from yeast and filamentous fungal materials for PCR. This method may be widely applicable to diverse fungal species in clinical and basic studies. PMID- 21315114 TI - High-throughput screening of microbial adaptation to environmental stress. AB - We developed a microwell plate, high-throughput, screening method aimed at quantitating the tolerance of a panel of Gram-positive and Gram-negative bacteria to metals (Frankia sp., Escherichia coli, Cupriavidus metallidurans, Rhizobium leguminosarum, and Streptomyces scabies). Microbial viability was quantified using MTS; a tetrazolium salt converted to a water-soluble formazan through microbial reduction. In this paper, we present the stepwise development of the method, highlighting the main elements underlying its reliability, and compare results obtained with literature. We conclude the method is well suited to efficiently screen bacteria, including those that are filamentous and slow growing, without the need for large amounts of inoculum which may not always be available. The method allows testing of compound gradients with sufficient replicates to generate statistically robust results, and is transposable to other types of cell proliferation assays such as those for antimicrobial susceptibility, and chemoresistance. PMID- 21315115 TI - DNA immunization of pigs with foot-and-mouth disease virus minigenes: from partial protection to disease exacerbation. AB - Despite several attempts to design new vaccines, there are as of yet no available alternatives to the conventional FMDV vaccines. Here, we present the divergent results obtained in pigs after immunization with two experimental DNA vaccines encoding one B and two T cell FMDV epitopes, either expressed alone (pCMV-BTT) or fused to a strong signal peptide (pCMV-spBTT). While all pigs vaccinated with pCMV-spBTT showed both a delay in the disease onset and reduced severity of signs and lesions after FMDV challenge, pigs immunized with pCMV-BTT showed an exacerbation of the disease and most of the pigs remained viremic at 10 days post infection, the end-point of the experiment, thus opening concerns about FMDV suboptimal immunization. Interestingly, only one of the four pigs vaccinated with pCMV-spBTT showed neutralizing antibodies before challenge, demonstrating that partial protection against FMDV could be afforded in the absence of preexisting neutralizing antibodies. PMID- 21315116 TI - Generation of Salmonella-specific Th1 cells requires sustained antigen stimulation. AB - The administration of live attenuated Salmonella strains has proven to be an effective way to generate protective immunity against Salmonella infection in humans and mice. Studies in the mouse model have shown that protection requires Salmonella-specific Th1 cells, however the timing and stimulatory requirements for generating optimal Th1 responses have not been carefully examined. We used antibiotic interruption of vaccination with live attenuated Salmonella to examine the requirements for Salmonella-specific Th1 development and protective immunity. Optimal development of protective immunity to Salmonella infection required at least one week of exposure to the live attenuated Salmonella strain. In contrast, optimal development of Salmonella-specific Th1 cells required two weeks of in vivo colonization. Thus, sustained in vivo stimulation with a live vaccine strain is essential for the development of robust Salmonella-specific Th1 cells. PMID- 21315117 TI - Vaginal delivery of siRNA using a novel PEGylated lipoplex-entrapped alginate scaffold system. AB - Sustained vaginal delivery of siRNA has been precluded by the mucosal barrier lining the vaginal tract. In contrast to prior reports, we showed that conventional lipoplexes administered intravaginally are unable to reach the vaginal epithelium under normal physiological conditions. Here we have developed a novel alginate scaffold system containing muco-inert PEGylated lipoplexes to provide a sustained vaginal presence of lipoplexes in vivo and to facilitate the delivery of siRNA/oligonucleotides into the vaginal epithelium. These PEGylated lipoplex-entrapped alginate scaffolds (PLAS) were fabricated using a freeze drying method and the entrapment efficiency, release rate, and efficacy were characterized. We demonstrated that the PLAS system had an entrapment efficiency of ~50%, which released PEGylated lipoplexes gradually both in vitro and in vivo. While the presence of alginate diminished the cell uptake efficiency of PEGylated lipoplexes in vitro, as expected, we showed a six-fold increase their uptake into the vaginal epithelium compared to existing transfection systems following intravaginal administration in mice. A significant knockdown of Lamin A/C level was also observed in vaginal tissues using siLamin A/C-containing PLAS system in vivo. Overall, our results indicated the potential of the biodegradable PLAS system for the sustained delivery of siRNA/oligonucleotides to vaginal epithelium. PMID- 21315118 TI - Bone reservoir: Injectable hyaluronic acid hydrogel for minimal invasive bone augmentation. AB - A strategy has been designed to develop hyaluronic acid (HA) hydrogel for in vivo bone augmentation using minimal invasive technique. A mild synthetic procedure was developed to prepare aldehyde modified HA by incorporating an amino-glycerol side chain via amidation reaction and selective oxidation of the pendent group. This modification, upon mixing with hydrazide modified HA formed hydrazone crosslinked hydrogel within 30s that was stable at physiological pH. In vitro experiments showed no cytotoxicity of hydrogel with the controlled release of active bone morphogenic protein-2 (BMP-2). In vivo evaluation of this gel as a BMP-2 carrier was performed by injecting gels over the rat calvarium and showed bone formation in 8 weeks in correlation with the amount of BMP-2 loaded (0, 1 and 30MUg) within the gel. Furthermore, hydrogels with 30MUg of BMP-2 induced less bone formation upon subcutaneous injection in comparison with subperiosteal implantation. Histological examination showed newly formed bone with a high expression of osteocalcin, osteopontin and with angiogenic bone marrow when higher BMP-2 concentration was employed. Our result suggests that novel HA hydrogels could be used as a BMP-2 carrier and can promote bone augmentation for potential orthopedic applications. PMID- 21315119 TI - Characterisation and tumour targeting of PEGylated polylysine dendrimers bearing doxorubicin via a pH labile linker. AB - Polylysine dendrimers have potential as biodegradable vectors for the delivery of cytotoxic drugs to solid tumours. Here, the cytotoxicity, drug release and tumour targeting properties of Generation 5 PEGylated polylysine dendrimers comprising an outer generation of l-lysine or succinimyldipropyldiamine (SPN) and containing doxorubicin (DOX) linked through an acid labile 4-(hydrazinosulfonyl) benzoic acid (HSBA) linker have been characterised. Less than 10% of the DOX load was released from LYS or SPN dendrimers in pH 7.4 buffer over 3 days. In contrast approximately 100% release was evident at pH 5. The DOX-conjugated dendrimers also retained similar cytotoxic properties to free DOX in in vitro cell culture studies (presumably as a result of in situ liberation of free DOX). The clearance patterns of the DOX conjugated SPN and all-lysine dendrimers were similar to the equivalent non-DOX conjugated systems, however the SPN dendrimers showed reduced metabolic lability and increased uptake into RES organs when compared to the equivalent all-lysine dendrimers. In vivo assessment of the DOX-conjugated, PEGylated polylysine dendrimers (both SPN and LYS constructs) in rats bearing Walker 256 tumours revealed higher uptake into tumour tissue when compared with control tissue such as muscle (~8 fold) and heart (~3 fold). The data suggest that polylysine dendrimers containing DOX conjugated via an acid labile HSBA linker may provide a mechanism to target the delivery of DOX to tumours. PMID- 21315120 TI - Selective gene transfection of individual cells in vitro with plasmonic nanobubbles. AB - Gene delivery and transfection of eukaryotic cells are widely used for research and for developing gene cell therapy. However, the existing methods lack selectivity, efficacy and safety when heterogeneous cell systems must be treated. We report a new method that employs plasmonic nanobubbles (PNBs) for delivery and transfection. A PNB is a novel, tunable cellular agent with a dual mechanical and optical action due to the formation of the vapor nanobubble around a transiently heated gold nanoparticle upon its exposure to a laser pulse. PNBs enabled the mechanical injection of the extracellular cDNA plasmid into the cytoplasm of individual target living cells, cultured leukemia cells and human CD34+ CD117+ stem cells and expression of a green fluorescent protein (GFP) in those cells. PNB generation and lifetime correlated with the expression of green fluorescent protein in PNB-treated cells. Optical scattering by PNBs additionally provided the detection of the target cells and the guidance of cDNA injection at single cell level. In both cell models PNBs demonstrated a gene transfection effect in a single pulse treatment with high selectivity, efficacy and safety. Thus, PNBs provided targeted gene delivery at the single cell level in a single pulse procedure that can be used for safe and effective gene therapy. PMID- 21315121 TI - Osmotic capsules: A universal oral, controlled-release drug delivery dosage form. AB - An osmotic, oral, controlled-release capsule is described. This capsule provides drug delivery at fixed delivery rates (T(80%)=6 or 14h) independent of drug properties (e.g., solubility) or drug loading, thereby allowing rapid development of investigational or commercial drugs, especially for proof-of-concept type clinical studies. The capsule body and cap are prepared with cellulose acetate and polyethylene glycol in acetone and water using high density polyethylene molds as templates and a conventional tablet pan coater. After the shells are removed from the molds manually, a laser hole is drilled in the end of the capsule body. The drug is introduced as a shaped tablet admixed with polyethylene oxide. A "push" tablet consisting of high molecular weight polyethylene oxide, microcrystalline cellulose, and sodium chloride is also inserted into the capsule body. The capsule halves lock together due to ridges, alleviating the need for a banding operation. PMID- 21315122 TI - Nanoparticles and microparticles for skin drug delivery. AB - Skin is a widely used route of delivery for local and systemic drugs and is potentially a route for their delivery as nanoparticles. The skin provides a natural physical barrier against particle penetration, but there are opportunities to deliver therapeutic nanoparticles, especially in diseased skin and to the openings of hair follicles. Whilst nanoparticle drug delivery has been touted as an enabling technology, its potential in treating local skin and systemic diseases has yet to be realised. Most drug delivery particle technologies are based on lipid carriers, i.e. solid lipid nanoparticles and nanoemulsions of around 300 nm in diameter, which are now considered microparticles. Metal nanoparticles are now recognized for seemingly small drug like characteristics, i.e. antimicrobial activity and skin cancer prevention. We present our unpublished clinical data on nanoparticle penetration and previously published reports that support the hypothesis that nanoparticles >10nm in diameter are unlikely to penetrate through the stratum corneum into viable human skin but will accumulate in the hair follicle openings, especially after massage. However, significant uptake does occur after damage and in certain diseased skin. Current chemistry limits both atom by atom construction of complex particulates and delineating their molecular interactions within biological systems. In this review we discuss the skin as a nanoparticle barrier, recent work in the field of nanoparticle drug delivery to the skin, and future directions currently being explored. PMID- 21315123 TI - Replacement of meat by meat substitutes. A survey on person- and product-related factors in consumer acceptance. AB - What does it take to increase the consumption of meat substitutes and attract new consumers? We identified main barriers and drivers by a consumer survey (n=553) in the U.K. and the Netherlands. Person-related factors (food neophobia and food choice motives) and product-related attitudes and beliefs towards meat and meat substitutes were compared between non-users (n=324), light/medium-users (n=133) and heavy-users of meat substitutes (n=96). Consumer acceptance was largely determined by the attitudes and beliefs towards meat substitutes and food neophobia. Key barriers for non-users and light/medium-users were the unfamiliarity with meat substitutes and the lower sensory attractiveness compared to meat. In addition, non-users had a higher tendency to avoid new foods. Hence, the less consumers were using meat substitutes, the more they wanted these products to be similar to meat. Although non-users and light/medium-users did recognize the ethical and weight-control aspects of meat substitutes, this was obviously less relevant to them. Actually, only heavy-users had high motivations to choose ethical foods, which explains their choice for meat substitutes. In order to make meat substitutes more attractive to meat consumers, we would not recommend to focus on communication of ethical arguments, but to significantly improve the sensory quality and resemblance to meat. PMID- 21315124 TI - Neuropharmacological properties of neurons derived from human stem cells. AB - Human pluripotent stem cells have enormous potential value in neuropharmacology and drug discovery yet there is little data on the major classes and properties of receptors and ion channels expressed by neurons derived from these stem cells. Recent studies in this lab have therefore used conventional patch-clamp electrophysiology to investigate the pharmacological properties of the ligand and voltage-gated ion channels in neurons derived and maintained in vitro from the human stem cell (hSC) line, TERA2.cl.SP12. TERA2.cl.SP12 stem cells were differentiated with retinoic acid and used in electrophysiological experiments 28 50 days after beginning differentiation. HSC-derived neurons generated large whole cell currents with depolarizing voltage steps (-80 to 30 mV) comprised of an inward, rapidly inactivating component and a delayed, slowly deactivating outward component. The fast inward current was blocked by the sodium channel blocker tetrodotoxin (0.1 MUM) and the outward currents were significantly reduced by tetraethylammonium ions (TEA, 5 mM) consistent with the presence of functional Na and K ion channels. Application of the inhibitory neurotransmitters, GABA (0.1-1000 MUM) or glycine (0.1-1000 MUM) evoked concentration dependent currents. The GABA currents were inhibited by the convulsants, picrotoxin (10 MUM) and bicuculline (3 MUM), potentiated by the NSAID mefenamic acid (10-100 MUM), the general anaesthetic pentobarbital (100 MUM), the neurosteroid allopregnanolone and the anxiolytics chlordiazepoxide (10 MUM) and diazepam (10 MUM) all consistent with the expression of GABA(A) receptors. Responses to glycine were reversibly blocked by strychnine (10 MUM) consistent with glycine-gated chloride channels. The excitatory agonists, glutamate (1-1000 MUM) and NMDA (1-1000 MUM) activated concentration-dependent responses from hSC-derived neurons. Glutamate currents were inhibited by kynurenic acid (1 mM) and NMDA responses were blocked by MgCl(2) (2 mM) in a highly voltage-dependent manner. Together, these findings show that neurons derived from human stem cells develop an array of functional receptors and ion channels with a pharmacological profile in keeping with that described for native neurons. This study therefore provides support for the hypothesis that stem cells may provide a powerful source of human neurons for future neuropharmacological studies. PMID- 21315125 TI - Differential effect of the benzophenanthridine alkaloids sanguinarine and chelerythrine on glycine transporters. AB - Glycine transporter inhibitors modulate the transmission of pain signals. Since it is well known that extracts from medicinal plants such as Chelidonium majus exhibit analgesic properties, we investigated the effects of alkaloids typically present in this plant on glycine transporters. We found that chelerythrine and sanguinarine selectively inhibit the glycine transporter GlyT1 with comparable potency in the low micromolar range while berberine shows no inhibition at all. At this concentration both alkaloids only minimally affected transport of the closely related glycine transporter GlyT2, suggesting that the effect is not mediated by the inhibitory activity of these alkaloids on the Na(+)/K(+) ATPase. GlyT1 inhibition was time-dependent, noncompetitive and increased with glycine concentration. While chelerythrine inhibition was reversible, the effect of sanguinarine was resistant to wash out. These results suggest that benzophenanthridine alkaloids interact with glycine transporters and at low micromolar range selectively target glycine transporter GlyT1. PMID- 21315127 TI - Immunohistochemical demonstration of cholinergic structures in central ganglia of the slug (Limax maximus, Limax valentianus). AB - Immunohistochemical techniques were used to study the distribution of cholinergic neurons containing choline acetyltransferase of the common type (cChAT), the synthetic enzyme of acetylcholine, in the central nervous system of the slug Limax maximus and Limax valentianus. Because the antiserum applied here was raised against a recombinant protein encoded by exons 7 and 8 of the rat gene for ChAT, three methods were used in order to validate antibody specificity for the Limax counterpart enzyme. Western blot combined with ChAT activity assay following native gel electrophoresis and immunoprecipitation analysis both indicated that immunoreactive Limax brain molecules were capable of synthesizing acetylcholine. Western blot after denatured gel electrophoresis of Limax brain extracts revealed a single band of about 67kDa. All findings obtained with these three methods clearly indicated that the antiserum effectively recognized Limax cChAT. 1400 neuronal cell bodies positive for cChAT, mainly small to medium sized, were found in various brain regions in the buccal, cerebral, pleural, parietal, visceral and pedal ganglia. cChAT immunoreactive nerve fibers were distributed extensively in the neuropil, connectives and commissures of these central ganglia. The map of cChAT-positive cells provided here are valuable for understanding the cholinergic mechanism in the slug brain, as well as giving an important hint to clarifying the mechanisms of learning and memory in higher vertebrates including humans. PMID- 21315126 TI - Altered sensitivity of cerebellar granule cells to glutamate receptor overactivation in the Cln3(Deltaex7/8)-knock-in mouse model of juvenile neuronal ceroid lipofuscinosis. AB - The juvenile onset form of neuronal ceroid lipofuscinoses (JNCL) is a recessively inherited lysosomal storage disorder characterized by progressive neurodegeneration. JNCL results from mutations in the CLN3 gene that encodes a lysosomal membrane protein with unknown function. Utilizing a Cln3-knock-out mouse model of JNCL that was created on the 129S6/SvEv genetic background, we have previously demonstrated that CLN3-deficient cerebellar granule cells (CGCs) have a selectively increased sensitivity to AMPA-type glutamate receptor-mediated toxicity. Our recent findings that CGCs from 129S6/SvEv and C57BL/6J wild type (WT) mice have significant differences in glutamate receptor expression and in excitotoxic vulnerability indicated that the genetic background possibly have a strong influence on how glutamate receptor function is dysregulated in CLN3 deficient neurons. Indeed, here we show that in the Cln3(Deltaex7/8)-knock-in mouse model, that is on the C57BL/6J genetic background, mimics the most frequent mutation observed in JNCL patients and considered a null mutant, the sensitivity of CGCs to both AMPA- and NMDA-type glutamate receptor overactivations is altered. Cultured wild type and Cln3(Deltaex7/8) CGCs were equally sensitive to AMPA toxicity after 2 or 3 weeks in vitro, whereas the subunit-selective AMPA receptor agonist, CPW-399, induced significantly more cell death in mature, 3 week-old Cln3(Deltaex7/8) cultures. NMDA receptor-mediated toxicity changed during in vitro development: Cln3(Deltaex7/8) CGCs were less sensitive to high concentration of NMDA after 2 weeks in culture but became more vulnerable than their WT counterparts after 3 weeks in vitro. Abnormally altered glutamate receptor function in the cerebellum may result in motor deficits, and we confirmed that 7-week-old Cln3(Deltaex7/8) mice, similarly to Cln3-knock-out mice, have a motor coordination deficit as measured by an accelerating rotarod. Our results demonstrate altered glutamate receptor function in Cln3(Deltaex7/8) neurons and suggest that both AMPA and NMDA receptors are potential therapeutic targets in JNCL. PMID- 21315128 TI - A regulatory polymorphism in promoter region of TNFR1 gene is associated with Kawasaki disease in Chinese individuals. AB - Tumor necrosis factor (TNF) and the TNF receptor superfamily (TNF-TNFR) plays very important roles in the pathogenesis of Kawasaki disease (KD) by leukocyte recruitment, upregulation of matrix-degrading enzymes and proinflammatory cytokines. This study aims to investigate whether potential polymorphisms in TNF receptor superfamily member 1A gene (TNFR1) are associated with KD and its effects on transcriptions activity of TNFR1. Genetic variations of TNFR1 promoter and coding regions in 132 unrelated patients with KD and 212 age-matched healthy controls recruited from a population of Chinese individuals were screened by direct sequencing. Bioinformatics analysis and function assays were performed to investigate the association between genetic variations and KD, and its effects on transcription activity of TNFR1. Five polymorphisms, termed -609T/G, -581A/G, 421G/A, -383A/C, and +36A/G, were identified in the subjects, of which -421A/G was reported for the first time. In particular, bioinformatics analysis and function assay confirmed that -609T allele resulted in allele-specific strengthening of TNFR1 transcription and was significantly associated with KD (p = 2.951E-08, odds ratio = 2.42, 95% confidence interval = 1.76-3.13). Furthermore, the haplotype TAGAA showed a relatively higher frequency in patients with KD compared with healthy controls (p = 3.446E-07, odds ratio = 2.26, 95% confidence interval = 1.65-3.11). Therefore, our results suggested that regulatory polymorphism -609T/G and the haplotype TAGAA may be related to increased susceptibility to KD in Chinese individuals. PMID- 21315129 TI - Lymphocyte activation markers may predict the presence of donor specific alloreactivity in pediatric living related liver transplant recipients. AB - This is an observational study with the primary objective to measure donor specific immune responses by pediatric liver transplant (LT) recipients, using cell surface expression of lymphocyte activation markers and cytokine secretion in mixed lymphocyte reactions. The secondary objective was to demonstrate possible mechanism(s) involved in those who demonstrated donor-specific hyporesponsiveness. Study participants included 17 recipients, their respective parental donors, the non-donor parent, as well as unrelated third party individuals. Within the CD4(+) population, two distinct patterns of CD69 and CD71 expressions were observed: recipients who had a lower percentage of CD4(+)CD69(+) and CD4(+)CD71(+) cells after donor versus non-donor stimulation (therefore a donor/non-donor ratio <1); and recipients who had a higher percentage of CD4(+)CD69(+) and CD4(+)CD71(+) cells after donor versus non-donor stimulation (therefore a donor/non-donor ratio >=1). Eight recipients had the above defined ratio of <1, with significantly decreased interferon-gamma secretion after donor versus non-donor stimulation. CD4(+)CD25(hi.)CD127- regulatory T cells from these eight recipients suppressed donor and non-donor cell induced proliferation. Suppression of proliferation was partially abrogated by interleukin-2. In conclusion, CD69 and CD71 cell surface expression with interferon-gamma secretion can be used to identify two distinct populations in pediatric LT recipients. Both active regulation and anergy underlie donor specific hyporesponsiveness. PMID- 21315130 TI - Use of mixed-effect models and tolerance limits to evaluate control cynomolgus monkey body weight change and variability during preclinical toxicology studies. AB - Cynomolgus monkeys are an important and widely used species in preclinical toxicology studies. During the in-life phase of study, body weight effects may be indicative of toxicity; however, trends in body weight and body weight variability are often difficult to interpret due to small sample size and/or inter- and intra-animal variability. The present analysis utilizes mixed-effect modelling, which incorporates random and fixed effects into linear regression models, to evaluate control monkey body weight trends and variability relative to baseline (initial) weight and study duration. The primary aim of this analysis is to evaluate whether mixed-effect model based tolerance limits can aide in determining whether apparent test article-related changes in body weight deviate more than the predicted variability defined by the model tolerance limits. The models for this study are based on vehicle control animal body weight data from the following studies: 1-month (20 studies, 198 animals), 3-month (19 studies, 180 animals), and 9-month (17 studies, 182 animals). The analysis presented herein provides the framework for evaluating control monkey body weight change in studies with small sample size, and anticipated control monkey body weight change relative to gender and study duration. PMID- 21315131 TI - Slit2-N inhibits PDGF-induced migration in rat airway smooth muscle cells: WASP and Arp2/3 involved. AB - BACKGROUND: Slit2 has been reported to be implicated in many kinds of cell migration. However little is known about the effect of Slit2 on airway smooth muscle cell migration. This study was to detect the expression of Slit2 in rat airway smooth muscle (RASM) cells stimulated by platelet-derived growth factor (PDGF) and characterized the effect of Slit2-N on PDGF-induced migration of RASM cells in vitro. METHODS: mRNAs of Slit-Robo in RASM cells were examined by RT PCR, and the effect of exogenous Slit2-N at different doses on PDGF-induced migration of RASM cells were examined by transwell and scrape-wound assays. Actin filaments (F-actin) were stained with rhodamine-conjugated phalloidin and the levels of protein expression were detected by western blot. RESULTS: RASM cells were identified to express Slit2, Slit3, Robo1, Robo2 and Robo4 in vitro. Slit2-N caused a time- and dose-dependent inhibition of cell proliferation, while had no significantly effect on cell apoptosis. Slit2-N pretreatment attenuated the elongated morphologic characteristics, reduced lamellipodia formation, inhibited actin rearrangement and cell migration induced by PDGF. PDGF-induced increase of WASP and Arp2/3 proteins were dramatically inhibited by 100 ng/ml Slit2-N. CONCLUSION: Slit2-N inhibits RASM cells migration at least partly through attenuating the expressions of WASP and Arp2/3, inhibiting actin rearrangement in vitro. The results contribute to provide new insights into the pathogenesis of airway remodeling in asthma and may be helpful for development of effective treatments. PMID- 21315132 TI - Improved perceived general health is observed with prosthodontic treatment. AB - OBJECTIVES: Prosthodontic treatment affects not only oral health, but also general health. However, whether prosthodontic patients actually perceive a change in their general health has not been well studied. This study aims to compare self-reported general-health status in patients before and after prosthodontic treatment. METHODS: Self-reported general-health status was measured using a single-item questionnaire in a consecutive sample of 500 prosthodontic patients. Responses were recorded using a five-point scale ranging from "poor" to "excellent." RESULTS: After treatment, patients' self-reported general-health status was slightly but statistically significantly improved. Perceived general health improved in 2.3% of patients treated with fixed partial dentures, in 11.3% of patients treated with removable partial dentures, and in 4.1% of patients treated with complete dentures. Changes in self-reported general health status were not related to age or gender. CONCLUSION: Prosthodontic treatment appears to have a positive effect on perceived general health. PMID- 21315133 TI - Identification of phosphorylated oligosaccharides in cells of patients with a congenital disorders of glycosylation (CDG-I). AB - Protein N-glycosylation is initiated by the dolichol cycle in which the oligosaccharide precursor Glc(3)Man(9)GlcNAc(2)-PP-dolichol is assembled in the endoplasmic reticulum (ER). One critical step in the dolichol cycle concerns the availability of Dol-P at the cytosolic face of the ER membrane. In RFT1 cells, the lipid-linked oligosaccharide (LLO) intermediate Man(5)GlcNAc(2)-PP-Dol accumulates at the cytosolic face of the ER membrane. Since Dol-P is a rate limiting intermediate during protein N-glycosylation, continuous accumulation of Man(5)GlcNAc(2)-PP-Dol would block the dolichol cycle. Hence, we investigated the molecular mechanisms by which accumulating Man(5)GlcNAc(2)-PP-Dol could be catabolized in RFT1 cells. On the basis of metabolic labeling experiments and in comparison to human control cells, we identified phosphorylated oligosaccharides (POS), not found in human control cells and present evidence that they originate from the accumulating LLO intermediates. In addition, POS were also detected in other CDG patients' cells accumulating specific LLO intermediates at different cellular locations. Moreover, the enzymatic activity that hydrolyses oligosaccharide-PP-Dol into POS was identified in human microsomal membranes and required Mn(2+) for optimal activity. In CDG patients' cells, we thus identified and characterized POS that could result from the catabolism of accumulating LLO intermediates. PMID- 21315134 TI - Pleasant mood intensifies brain processing of cognitive control: ERP correlates. AB - The present study investigated the impact of auditory-induced mood on brain processing of cognitive control using a Stroop color-word interference task. A total of 135 positive, negative, and neutral sounds (45 of each) were presented in separate blocks for a mood induction procedure, which was then followed by a Stroop color-word task in each trial. Event-related potentials (ERPs) were recorded for color-word congruent, incongruent and neutral (color-word irrelevant) words and subjects named the printed colors of the words by pressing the appropriate key (irrespective of word meaning). Response latency was delayed during incongruent vs. neutral trials, and this cost did not interact significantly with mood states. ERP data showed prolonged peak latencies in the P200 component and more negative deflections in the Late Positive Component (LPC, 450-550 ms) during incongruent vs. neutral conditions, regardless of mood states. Moreover, the negative deflections (N450) in the 450-550 ms interval of the incongruent- neutral difference waves, which index cognitive control effect in brain potentials, was more pronounced in the pleasant, but not in the unpleasant, mood state when compared with the neutral mood state. These data suggest that, pleasant mood intensifies brain processing of cognitive control, in a situation requiring effective inhibition of task-irrelevant distracting information. In addition, N450 component serves as an affective marker, embodying not only cognitive control effect in the brain but also its interaction with mood states. PMID- 21315135 TI - From network-to-antibody robustness in a bio-inspired immune system. AB - Behavioural robustness at antibody and immune network level is discussed. The robustness of the immune response that drives an autonomous mobile robot is examined with two computational experiments in the autonomous mobile robots trajectory generation context in unknown environments. The immune response is met based on the immune network metaphor for different low-level behaviours coordination. These behaviours are activated when a robot sense the appropriate conditions in the environment in relation to the network current state. Results are obtained over a case study in computer simulation as well as in laboratory experiments with a Khepera II microrobot. In this work, we develop a set of tests where such an immune response is externally perturbed at network or low-level behavioural modules to analyse the robust capacity of the system to unexpected perturbations. Emergence of robust behaviour and high-level immune response relates to the coupling between behavioural modules that are selectively engaged with the environment based on immune response. Experimental evidence leads discussions on a dynamical systems perspective of behavioural robustness in artificial immune systems that goes beyond the isolated immune network response. PMID- 21315136 TI - Further antinociceptive effects of myricitrin in chemical models of overt nociception in mice. AB - The present work explored the antinociceptive effects of the flavonoid myricitrin in models of overt nociception triggered by intraplantar injection of chemical algogens into the hind paw of mice. The nociception induced by bradykinin (3 nmol/paw i.pl.) was abolished by prior treatment with myricitrin (10-100mg/kg, i.p.) with ID(50) of 12.4 (8.5-18.1)mg/kg. In sharp contrast, myricitrin failed to affect the nociception elicited by prostaglandin E(2) (3 nmol/paw i.pl.). Cinnamaldehyde (10 nmol/paw i.pl.)-induced nociception was reduced by myricitrin (100mg/kg, i.p.) and camphor (7.6 mg/kg,s.c.) in 43+/-10% and 57+/-8%, respectively. Myricitrin (30-100mg/kg, i.p.) and amiloride (100mg/kg, i.p.) inhibited nociceptive responses induced by acidified saline (pH 5/paw i.pl.), with ID(50) of 22.0 (16.1-30.0)mg/kg and inhibition of 71+/-6% and 64+/-5%, respectively. Moreover, myricitrin (10-30 mg/kg, i.p.) and ruthenium red (3mg/kg, i.p.) significantly reduced the nociception induced by menthol (1.2 MUmol/paw i.pl.) with the mean ID(50) of 2.4 (1.5-3.7)mg/kg and inhibition of 95+/-3% and 51+/-7%, respectively. In addition, myricitrin administration (30 and 100mg/kg, i.p.) markedly reduced menthol-induced mechanical allodynia. However, myricitrin (100mg/kg, i.p.) prevented (only in time of 60 min) cold allodynia induced by menthol. Collectively, the present results extend prior data and show that myricitrin promotes potent antinociception, an action that is likely mediated by an inhibition of the activation of nociceptors by bradykinin and TRPs agonist (i.e. cinnamaldehyde, acidified saline and menthol), probably via inhibition of PKC pathways. Thus, myricitrin could constitute an attractive molecule of interest for the development of new analgesic drugs. PMID- 21315137 TI - Stage-dependent STAT3 activation is involved in the differentiation of rat hippocampus neural stem cells. AB - Extracts of deafferented hippocampus were previously found to promote neuronal differentiation of neural stem cells (NSCs). To gain insights into the underlying molecular mechanisms we studied the potential involvement of signal transducer and activator of transcription3 (STAT3) activation in the NSCs response to hippocampal extracts. Here we report that phosphorylated STAT3 (p-STAT3) is expressed at different stages in neurons and astrocytes differentiated from rat hippocampus-derived NSCs. Deafferented hippocampal extracts produced sustained upregulation of p-STAT3 levels and promoted NSC differentiation and neurogenesis, whereas extracts of normal hippocampus were without effect. Interleukin-6 (IL-6), an activator of JAK/STAT signaling pathways, had no effect on neurogenesis, whereas the selective STAT3 inhibitor p-ip-STAT3 decreased the number of Microtubule-associated protein-2 (MAP-2)-positive cells generated by NSC differentiation. These findings argue that STAT3-related signaling pathways are likely to play a role in neuronal survival and differentiation during NSC neurogenesis stimulated by extracts of deafferented hippocampus. PMID- 21315138 TI - Neural stem/progenitor cells damaged by reactive oxygen species evolved in photosensitizing reaction. AB - We want to know how the growth of neural stem/progenitor cells and their differentiation are affected by reactive oxygen species evolved in photosensitizing reaction, because of the similarity between the stem cells and the tumor cells in central nervous system. We investigated the effects of two photosensitizers (rhodamine 123 and hematoporphyrin) on the mouse neural stem/progenitor cells cultured in vitro under the illumination. ABC transporters were expressed in the cells, and could pump rhodamine 123 and hematoporphyrin out of the cells. Under the illumination of strong actinic light with those photosensitizers, reactive oxygen species was evolved to injure the cells. Number of viable cells decreased under illumination through apoptosis and necrosis. Those cell-killing activities were not clearly dependent on the presence of inhibitors for ABC transporters. Immunocytochemical staining with showed that immature cells with markers of neural stem/progenitor cells (Sox 2, CD133, nestin) were more sensitive to the reactive oxygen species than the differentiated cells. PMID- 21315139 TI - Titanium dioxide nanoparticles impair lung mitochondrial function. AB - Titanium dioxide nanoparticles (TiO(2) NPs) are used in an increasing number of human products such as cosmetics, sunscreen, toothpaste and paints. However, there is clear evidence about effects associated to TiO(2) NPs exposure, which include lung inflammation and tumor formation and these effects are related to reactive oxygen species (ROS) formation. The ROS generation could be attributed to a mitochondrial dysfunction. Even though, it has been shown that TiO(2) NPs exposure can induce some alterations in mitochondria including cytochrome c release to cytosol, change in mitochondrial permeability and decrease of mitochondrial membrane potential (DeltaPsi(m)), there is no information about the changes in mitochondrial function induced by TiO(2) NPs. We hypothesized that TiO(2) NPs effects are associated with mitochondrial dysfunction and redox unbalance. To test our hypothesis we isolated mitochondria from lung tissue of rats and exposed them to 10(g TiO(2) NPs (particle size<25nm)/mg protein for 1h. Our results showed that TiO(2) NPs decreases NADH levels and impairs DeltaPsi(m) and mitochondrial function accompanied by ROS generation during mitochondrial respiration. PMID- 21315140 TI - Ga(III) complexes--the effect of metal coordination on potential systemic absorption after topical exposure. AB - The handling of elemental gallium is not thought to be harmful, but this assumption does not consider metal coordination which readily occurs in physiological fluids. The aim of this work was to determine Ga(III) coordination behaviour in simple solutions and assess the effects of complex formation upon skin permeation in vitro. Ga(III) coordination was modelled using metal-ligand stability constants in silico and the permeation of the metal through human and porcine skin determined using four test conditions. Ga(III) was presented to the skin as: (1) Ga3+ ions; (2) a -ve citrate complex (Ga(neg)); (3) a mixture of +ve and -ve complexes (Ga(mix)) and (4) a mixture of +ve hydroxide complexes (Ga(pos)). The permeability coefficient (Kp) of Ga(III) through human skin increased by almost 2 orders of magnitude when applied as free Ga3+ ions or a Ga(neg) complex (the two most water soluble complexes), compared to Ga(mix) or Ga(pos). This trend was not well modelled by porcine skin which proved to be less of a barrier to Ga(III) permeation compared to human skin (Kp=2 x 10-3 +/- 2 x 10 4 cm h-1). Given the significant transdermal bioavailablity of Ga(III) demonstrated by this study, it would appear prudent to re-evaluate the dermal toxicity of this metal. PMID- 21315141 TI - Doxorubicin-loaded lipid-quantum dot hybrids: surface topography and release properties. AB - A few studies have attempted to combine the physicochemical versatility offered by the liposome structure with the superior optical characteristics of quantum dots (QD) for the construction of multifunctional nanoparticles. We are reporting the construction of drug-loaded liposome-QD hybrid vesicles (L-QD) by incorporating TOPO-capped, CdSe/ZnS QD into the two types of lipid bilayers: the 'rigid' disteroylphosphatidylcholine (DSPC:Chol:DSPE-PEG(2000)) and a fluid-phase bilayer of egg PC (EPC:Chol:DSPE-PEG(2000)). Structural characterization of L-QD hybrid vesicles using atomic force microscopy (AFM) revealed that the incorporation of QD took place by hydrophobic self-association within the membranes. The encapsulation of hydrophilic small molecules in the internal aqueous phase of the L-QD hybrids showed different degrees of carboxyfluorescein (CF) release in buffer and serum, depending on the type of lipid used. The presence of QD in the lipid bilayer increased the CF release from EPC fluid bilayer. On the other hand, (DSPC) L-QD hybrids showed a higher stability under the same conditions with minimal CF leakage. Furthermore, (DSPC) L-QD hybrids showed a stable mean diameter up to three weeks stored at 4 degrees C, 25 degrees C, and 40 degrees C, determined by photo correlation spectroscopy (PCS) analysis. Finally, doxorubicin (Dox) was loaded into L-QD hybrids using the osmotic gradient technique and with at least 97% loading efficiency. The fluorescence spectrum of Dox was simultaneously detected with that of green-emitting QD that indicated the coexistence of QD and Dox in a single vesicle system. In conclusion, the drug-loaded L-QD-Dox hybrid vesicles presented here constitute a promising multifunctional delivery vector capable of transporting combinations of therapeutic and diagnostic modalities. PMID- 21315142 TI - Traditional Chinese medicine, Xue-Fu-Zhu-Yu decoction, potentiates tissue plasminogen activator against thromboembolic stroke in rats. AB - AIM OF THIS STUDY: The Xue-Fu-Zhu-Yu decoction (XFZYD) is a well-known traditional Chinese medicine for treating cardiovascular diseases. The therapeutic effects of this XFZYD have been well documented especially in treating of atherosclerosis and hyperlipidemia. Since this decoction can induce endothelial progenitor cell angiogenesis, it can provide experimental evidence for the treatment of ischemic diseases. Patients who are admitted to the hospital with acute ischemic stroke are initially considered candidates for the recombinant tissue plasminogen activator (rt-PA). However, rt-PA therapy is still lesser than ideal due to its major side effect of hemorrhaging. Therefore, medical research has been devoted to finding an alternative and/or complementary therapy for ischemic stroke. In the present study, we evaluated the protective effect of the combination of XFZYD with or without rt-PA in a rat model of thromboembolic stroke. MATERIALS AND METHODS: A cerebral thromboembolic stroke animal model and immunoblotting analysis were used to assess the effects of XFZYD and rt-PA. RESULTS: Treatment with rt-PA (8 mg/kg) or XFZYD (1.5 and 3.0 g/kg/day) alone showed slight reductions in the infarct volume compared to solvent-treated rats. However, XFZYD (1.5 and 3.0 g/kg/day) obviously potentiated rt-PA-mediated reduction in the infarct volume in cerebral ischemic regions. In addition, treatment with rt-PA significantly reduced both tumor necrosis factor (TNF)-alpha and inducible nitric oxide synthase (iNOS) but not hypoxia-inducible factor (HIF)-1 alpha or active caspase-3 expressions in ischemic regions, whereas treatment with XFZYD (3.0 g/kg/day) significantly reduced all of these protein expressions in ischemic regions. Moreover, treatment with XFZYD (1.5 and 3.0 g/kg/day) obviously potentiated rt-PA-mediated reductions in TNF-alpha, iNOS, HIF 1 alpha, and active caspase-3 expressions. CONCLUSIONS: Results of this study suggest that XFZYD potentiated rt-PA-mediated neuroprotection against thromboembolic stroke in rats. This neuroprotection is probably mediated by the inhibition of HIF-1 alpha and TNF-alpha, followed by the inhibition of inflammatory responses (i.e., iNOS) and apoptosis (active caspase-3). These results provide a better understanding of the scientific validation of the therapeutic value of the combination of XFZYD with rt-PA in ischemic stroke. PMID- 21315143 TI - Perspectives on the use of marine and freshwater hydrobiont oils for development of drug delivery systems. AB - Marine foods represent a unique source of poly-unsaturated fatty acids (PUFA) of the omega-3 (n-3) family. Today it is generally accepted that fish oil is important in a healthy and balanced omnivorous human diet. This favorable health perception of fish oil is however troubled by the high level of PUFA oxidation and low absorption in the gastro-intestinal tract. In this work we present and described various types of delivery systems which are used to improve PUFA and fish oil availability and oxidative stability. PMID- 21315144 TI - Merging bioreactor technology with 3D hepatocyte-fibroblast culturing approaches: Improved in vitro models for toxicological applications. AB - During the last years an increasing number of in vitro models have been developed for drug screening and toxicity testing. Primary cultures of hepatocytes are, by far, the model of choice for those high-throughput studies but their spontaneous dedifferentiation after some time in culture hinders long-term studies. Thus, novel cell culture systems allowing extended hepatocyte maintenance and more predictive long term in vitro studies are required. It has been shown that hepatocytes functionality can be improved and extended in time when cultured as 3D-cell aggregates in environmental controlled stirred bioreactors. In this work, aiming at further improving hepatocytes functionality in such 3D cellular structures, co-cultures with fibroblasts were performed. An inoculum concentration of 1.2*10(5) cell/mL and a 1:2 hepatocyte:mouse embryonic fibroblast ratio allowed to improve significantly the albumin secretion rate and both ECOD (phase I) and UGT (phase II) enzymatic activities in 3D co-cultures, as compared to the routinely used 2D hepatocyte monocultures. Significant improvements were also observed in relation to 3D monocultures of hepatocytes. Furthermore, hepatocytes were able to respond to the addition of beta Naphtoflavone by increasing ECOD activity showing CYP1A inducibility. The dependence of CYP activity on oxygen concentration was also observed. In summary, the improved hepatocyte specific functions during long term incubation of 3D co cultures of hepatocytes with fibroblasts indicate that this system is a promising in vitro model for long term toxicological studies. PMID- 21315145 TI - Chronic ethanol exposure and folic acid supplementation: fetal growth and folate status in the maternal and fetal guinea pig. AB - Chronic ethanol exposure (CEE) can produce developmental abnormalities in the CNS of the embryo and developing fetus. Folic acid (FA) is an important nutrient during pregnancy and low folate status exacerbates ethanol-induced teratogenicity. This study tested the hypotheses that (1) CEE depletes folate stores in the mother and fetus; and (2) maternal FA supplementation maintains folate stores. CEE decreased fetal body, brain, hippocampus weights, and brain to body weight ratio but not hippocampus to body weight ratio. These effects of CEE were not mitigated by maternal FA administration. The FA regimen prevented the CEE-induced decrease of term fetal liver folate. However, it did not affect maternal liver folate or fetal RBC folate at term, and did not mitigate the nutritional deficit-induced decrease of term fetal hippocampus folate. This study suggests that maternal FA supplementation may have differential effects on folate status in the mother and the fetus. PMID- 21315146 TI - A new duplex real-time RT-PCR assay for sensitive and specific detection of African horse sickness virus. AB - A new real-time reverse transcription-polymerase chain reaction (RT-PCR) assay for a simple and rapid diagnosis of African Horse Sickness (AHS) was developed. Primers and FAM-labeled TaqMan-MGB probes specific for African horse sickness virus (AHSV) were selected from the consensus sequence of the segment 8 of all 9 serotypes of AHSV reference strains. For the determination of the analytical sensitivity, an in vitro transcript (AHS_ns2T7) of the target region was constructed and tested. Furthermore, the AHS_ns2T7 transcript was used either as positive control or as a standard for quantifying target copies. A commercial heterologous Armored RNA was used as an internal positive control (IPC) for both RNA isolation and RT-PCR steps. The qRT-PCR AHS_ns2 was able to amplify the target sequence up to 0.71 copies/reaction. Its flexibility allowed to amplify a wide dynamic range of RNA copies from 1.5 to 0.001fg. Within this range, the Ct values varied from 18 to 38 cycles with SD values always lower than 0.5 confirming their strong and constant linear correlation with the RNA target. Furthermore the newly designed duplex real-time RT-PCR proved to be strictly AHSV specific as it did not amplify close related viruses. PMID- 21315147 TI - High-resolution melting curve analysis to establish CYP2C19*2 single nucleotide polymorphism: Comparison with hydrolysis SNP analysis. AB - Clinically significant consequences of CYP2C19 polymorphism in drug metabolism require reliable genotyping methods for assaying large numbers of blood samples. Hydrolysis single nucleotide polymorphism analysis and high-resolution melting curve (HRM) analysis successfully genotyped the 114 liver donors for CYP2C19*2. However, the HRM analysis was found to be more efficient, rapid, user- and cost friendly method. PMID- 21315148 TI - Ex vivo detection of histone H1 modified with advanced glycation end products. AB - A number of oxidative stress agents cause DNA and protein damage, which may compromise genomic integrity. Whereas oxidant-induced DNA damage has been extensively studied, much less is known concerning the occurrence and fate of nuclear protein damage, particularly of proteins involved in the regulation and maintenance of chromatin structure. Protein damage may be caused by the formation of reactive carbonyl species such as glyoxal, which forms after lipid peroxide degradation. It may also result from degradation of early protein glycation adducts and from methylglyoxal, formed in the process of glycolytic intermediate degradation. Major adducts indicative of protein damage include the advanced glycation end product (AGE) carboxymethyllysine (CML) and argpyrimidine protein adducts. Thus, the formation of CML and argpyrimidine protein adducts represents potential biomarkers for nuclear protein damage deriving from a variety of sources. The purpose of this study was to identify and quantify AGE adducts formed in vivo in a nuclear protein, specifically histone H1, using CML and argpyrimidine as biomarkers. Histone H1 was isolated from calf thymus collected immediately after slaughter under conditions designed to minimize AGE formation before isolation. Using antibodies directed against oxidative protein adducts, we identified CML, argpyrimidine, and protein crosslinks present in the freshly isolated histone H1. Detailed mass spectroscopy analysis of histone H1 revealed the presence of two specific lysine residues modified by CML adducts. Our results strongly suggest that glycation of important nuclear protein targets such as histone H1 occurs in vivo and that these oxidative changes may alter chromatin structure, ultimately contributing to chronic changes associated with aging and diseases such as diabetes. PMID- 21315149 TI - Bacterial weathering and its contribution to nutrient cycling in temperate forest ecosystems. AB - Unlike farmland, forests growing on acidic soils are among the terrestrial ecosystems that are the least influenced or amended by man. Forests which developed on acidic soils are characterized by an important stock of inorganic nutrients entrapped in poorly weatherable soil minerals. In this context, the mineral-weathering process is of great importance, since such minerals are not easily accessible to tree roots. To date, several bacterial genera have been noted for their ability to weather minerals and, in the case of some of them, to improve tree nutrition. Nevertheless, few studies have focused their analyses on mineral-weathering bacterial communities in relation to geochemical cycles and soil characteristics, their ecological origin, associated tree species and forest management practices. Here we discuss the heterogeneity of the mineral-weathering process in forest soils and present what is known concerning the taxonomic and functional characteristics of mineral-weathering bacteria, as well as the different locations where they have been isolated in forest soils. We also discuss the biotic and abiotic factors that may influence the distribution of these bacteria, such as the effect of tree species or forest management practices. PMID- 21315150 TI - Heterotetrameric forms of human phenylalanine hydroxylase: co-expression of wild type and mutant forms in a bicistronic system. AB - Hybrid forms of human phenylalanine hydroxylase (hPAH) mutants have been found to present catalytic activities lower than predicted from the individual recombinant forms, indicating that interallelic complementation could be a major determinant of the metabolic phenotype of compound heterozygous phenylketonuric (PKU) patients. To provide a molecular explanation for interallelic complementation we have here developed a bicistronic expression system and a purification strategy to obtain isolated hPAH heteromeric forms. On co-expression of WT-hPAH (~50% tetramer; ~10% dimer) and the N- and C-terminally truncated form DeltaN102/DeltaC24-hPAH (~80% dimer) no heterodimers were recovered. Moreover, by co-expression of WT-hPAH and the N-terminally truncated form DeltaN102-hPAH (~95% tetramer), heterotetramers, as a result of an assembly of two different homodimers, were isolated. The recovered (WT)/(DeltaN102)-hPAH heterotetramers revealed a catalytic activity deviating significantly from that calculated by averaging the respective recombinant homotetrameric forms. The heterotetramer assembly also results in conformational changes in the WT-hPAH protomer, as detected by trypsin limited proteolysis. The finding that the presence of two homodimers with different kinetic parameters influences the properties of the resulting heterotetrameric protein indicates that the dimers exhibit interactions which are transmitted across the assembled tetramer. The bicistronic expression system developed here allowed the isolation of hybrid forms that exhibit negative interallelic complementation, and may represent a model system for studying the molecular pathogenic mechanisms of PAH gene mutations in compound heterozygous PKU patients, providing the rationale to understand the observed inconsistencies both in genotype/phenotype correlations and in the response to BH(4) supplementation. PMID- 21315151 TI - Functional analysis of conserved sequences within a temporally restricted neural precursor cell enhancer. AB - Many of the key regulators of Drosophila CNS neural identity are expressed in defined temporal orders during neuroblast (NB) lineage development. To begin to understand the structural and functional complexity of enhancers that regulate ordered NB gene expression programs, we have undertaken the mutational analysis of the temporally restricted nerfin-1 NB enhancer. Our previous studies have localized the enhancer to a region just proximal to the nerfin-1 transcription start site. Analysis of this enhancer, using the phylogenetic footprint program EvoPrinter, reveals the presence of multiple sequence blocks that are conserved among drosophilids. cis-Decoder alignments of these conserved sequence blocks (CSBs) has identified shorter elements that are conserved in other Drosophila NB enhancers. Mutagenesis of the enhancer reveals that although each CSB is required for wild-type expression, neither position nor orientation of the CSBs within the enhancer is crucial for enhancer function; removal of less-conserved or non conserved sequences flanking CSB clusters also does not significantly alter enhancer activity. While all three conserved E-box transcription factor (TF) binding sites (CAGCTG) are required for full function, adding an additional site at different locations within non-conserved sequences interferes with enhancer activity. Of particular note, none of the mutations resulted in ectopic reporter expression outside of the early NB expression window, suggesting that the temporally restricted pattern is defined by transcriptional activators and not by direct DNA binding repressors. Our work also points to an unexpectedly large number of TFs required for optimal enhancer function - mutant TF analysis has identified at least four that are required for full enhancer regulation. PMID- 21315152 TI - Volume to dissolve applied dose (VDAD) and apparent dissolution rate (ADR): tools to predict in vivo bioavailability from orally applied drug suspensions. AB - Low solubility of drug candidates generated in research contributes to their elimination during subsequent development due to insufficient oral bioavailability (BA) of crystalline compound. Therefore, the purpose of the study was to identify critical in vitro solubility and dissolution parameter that would predict critical in vivo dissolution by means of in vitro-in vivo correlation. Thermodynamic solubility and apparent dissolution rate (ADR) were determined using the shake-flask method and mini-flow-through-cell, respectively. Oral BA studies in rats and humans were conducted from drug solution and suspension/tablets. Relative BA was calculated using F(rel) [%]=AUC(suspension)/AUC(solution)*100, representing a measure of in vivo dissolution. Roughly, F(rel) rat >50% translates into F(rel) human of >90%. Both, ADR and log volume to dissolve applied dose (VDAD), when plotted against F(rel) rat, revealed certain threshold levels, (ADR, ~150-200 MUg of compound dissolved under respective assay conditions; VDAD, ~100-500 ml/kg) which translate into F(rel) in rats of >50%. Thus, assuming that F(rel)>50% in rats is indicative of sufficient in vivo dissolution in humans after oral application, drugs should exhibit a VDAD of ~100-500 ml/kg or less in aqueous media to avoid insufficient or varying drug absorption. PMID- 21315153 TI - The role of endothelin-1 signaling in the fibrosis observed in systemic sclerosis. AB - Scleroderma (systemic sclerosis, SSc) is an autoimmune disease of unknown etiology characterized by organ fibrosis. There is no therapy for SSc. However, a recent body of evidence strongly implicates endothelin-1 (ET-1) in the pathogenesis of SSc. ET-1 is found in abundance in SSc patients. ET-1 directly induces fibrogenic effects in vitro, and is required for the ability of TGFbeta to induce fibrogenic effects both in vitro and in vivo. Moreover, endothelin receptor antagonism reverses key features of the persistent fibrotic phenotype of fibroblasts isolated from lesions of SSc patients. However, clinically, endothelin receptor antagonism alone has had mixed results. This minireview summarizes these observations. PMID- 21315154 TI - Macrolide antibiotics broadly and distinctively inhibit cytokine and chemokine production by COPD sputum cells in vitro. AB - Macrolide antibiotics are known to exert anti-inflammatory actions in vivo, including certain effects in COPD patients. In order to investigate the immunomodulatory profile of activity of macrolide antibiotics, we have studied the effects of azithromycin, clarithromycin, erythromycin and roxithromycin on the in vitro production of a panel of inflammatory mediators from cells isolated from human, steroid-naive, COPD sputum samples. Macrolide effects were compared to three other commonly used anti-inflammatory compounds, the corticosteroid dexamethasone, the PDE4 inhibitor, roflumilast and the p38 kinase inhibitor, SB203580. Three of the four tested macrolides, azithromycin, clarithromycin and roxithromycin, exhibited pronounced, concentration-related reduction of IL-1beta, IL-6, IL-10, TNF-alpha, CCL3, CCL5, CCL20, CCL22, CXCL1, CXCL5, and G-CSF release. Further slight inhibitory effects on IL-1alpha, CXCL8, GM-CSF, and PAI-1 production were also observed. Erythromycin was very weakly active. Qualitatively and quantitatively, macrolides exerted distinctive and, compared to other tested classes of compounds, more pronounced immunomodulatory effects, particularly in terms of chemokine (CCL3, CCL5, CCL20, CCL22, and CXCL5), IL-1beta, G-CSF and PAI 1 release. The described modulation of inflammatory mediators could potentially contribute to further definition of biomarkers of macrolide anti-inflammatory activity in COPD. PMID- 21315155 TI - The boundary structure in the analysis of reversibly interacting systems by sedimentation velocity. AB - Sedimentation velocity (SV) experiments of heterogeneous interacting systems exhibit characteristic boundary structures that can usually be very easily recognized and quantified. For slowly interacting systems, the boundaries represent concentrations of macromolecular species sedimenting at different rates, and they can be interpreted directly with population models based solely on the mass action law. For fast reactions, migration and chemical reactions are coupled, and different, but equally easily discernable boundary structures appear. However, these features have not been commonly utilized for data analysis, for the lack of an intuitive and computationally simple model. The recently introduced effective particle theory (EPT) provides a suitable framework. Here, we review the motivation and theoretical basis of EPT, and explore practical aspects for its application. We introduce an EPT-based design tool for SV experiments of heterogeneous interactions in the software SEDPHAT. As a practical tool for the first step of data analysis, we describe how the boundary resolution of the sedimentation coefficient distribution c(s) can be further improved with a Bayesian adjustment of maximum entropy regularization to the case of heterogeneous interactions between molecules that have been previously studied separately. This can facilitate extracting the characteristic boundary features by integration of c(s). In a second step, these are assembled into isotherms as a function of total loading concentrations and fitted with EPT. Methods for addressing concentration errors in isotherms are discussed. Finally, in an experimental model system of alpha-chymotrypsin interacting with soybean trypsin inhibitor, we show that EPT provides an excellent description of the experimental sedimentation boundary structure of fast interacting systems. PMID- 21315156 TI - Combined effects of temperature and salinity on functional responses of haemocytes and survival in air of the clam Ruditapes philippinarum. AB - The combined effects of temperature and salinity on both immune responses and survival in air of the clam, Ruditapes philippinarum, were evaluated for the first time. The animals were kept for 7 days at three differing temperature (5 degrees C, 15 degrees C, 30 degrees C) and salinity values (18 psu, 28 psu, 38 psu), and effects of the resulting 9 experimental conditions on total haemocyte count (THC), Neutral Red uptake (NRU), haemolymph protein concentration, and lysozyme activity in both haemocyte lysate (HL) and cell-free haemolymph (CFH) were evaluated. The survival-in-air test was also performed. Two-way ANOVA analysis revealed that temperature influenced significantly THC and NRU, whereas salinity and temperature/salinity interaction affected NRU only. Temperature and salinity did not influence significantly HL and CFH lysozyme activity, as well as haemolymph total protein content. Survival-in-air test is widely used to evaluate general stress conditions in clams. In the present study, temperature and salinity were shown to influence the resistance to air exposure of R. philippinarum. The highest LT50 (air exposure time resulting in 50% mortality) value was recorded in clams kept at 18 psu and 15 degrees C, whereas the lowest value was observed in clams kept at 28 psu and 30 degrees C. Overall, results obtained demonstrated that temperature and salinity can affect some functional responses of haemocytes from R. philippinarum, and suggested a better physiological condition for animals kept at 15 degrees C temperature and 18 psu salinity. PMID- 21315157 TI - Spectral signal space projection algorithm for frequency domain MEG and EEG denoising, whitening, and source imaging. AB - MEG and EEG data contain additive correlated noise generated by environmental and physiological sources. To suppress this type of spatially coloured noise, source estimation is often performed with spatial whitening based on a measured or estimated noise covariance matrix. However, artifacts that span relatively small noise subspaces, such as cardiac, ocular, and muscle artifacts, are often explicitly removed by a variety of denoising methods (e.g., signal space projection) before source imaging. Here, we introduce a new approach, the spectral signal space projection (S(3)P) algorithm, in which time-frequency (TF) specific spatial projectors are designed and applied to the noisy TF-transformed data, and whitened source estimation is performed in the TF domain. The approach can be used to derive spectral variants of all linear time domain whitened source estimation algorithms. The denoised sensor and source time series are obtained by the corresponding inverse TF-transform. The method is evaluated and compared with existing subspace projection and signal separation techniques using experimental data. Altogether, S(3)P provides an expanded framework for MEG/EEG data denoising and whitened source imaging in both the time and frequency/scale domains. PMID- 21315158 TI - Investigation of melodic contour processing in the brain using multivariate pattern-based fMRI. AB - Music perception generally involves processing the frequency relationships between successive pitches and extraction of the melodic contour. Previous evidence has suggested that the 'ups' and 'downs' of melodic contour are categorically and automatically processed, but knowledge of the brain regions that discriminate different types of contour is limited. Here, we examined melodic contour discrimination using multivariate pattern analysis (MVPA) of fMRI data. Twelve non-musicians were presented with various ascending and descending melodic sequences while being scanned. Whole-brain MVPA was used to identify regions in which the local pattern of activity accurately discriminated between contour categories. We identified three distinct cortical loci: the right superior temporal sulcus (rSTS), the left inferior parietal lobule (lIPL), and the anterior cingulate cortex (ACC). These results complement previous findings of melodic processing within the rSTS, and extend our understanding of the way in which abstract auditory sequences are categorized by the human brain. PMID- 21315159 TI - Local cortical surface complexity maps from spherical harmonic reconstructions. AB - Altered cortical surface complexity and gyrification differences may be a potentially sensitive marker for several neurodevelopmental disorders. We propose to use spherical harmonic (SPH) constructions to measure cortical surface folding complexity. First, we demonstrate that the complexity measure is accurate, by applying our SPH approach and the more traditional box-counting method to von Koch fractal surfaces with known fractal dimension (FD) values. The SPH approach is then applied to study complexity differences between 87 patients with DSM-IV schizophrenia (with stable psychopathology and treated with antipsychotic medication; 48 male/39 female; mean age=35.5 years, SD=11.0) and 108 matched healthy controls (68 male/40 female; mean age=32.1 years, SD=10.0). The global FD for the right hemisphere in the schizophrenia group was significantly reduced. Regionally, reduced complexity was also found in temporal, frontal, and cingulate regions in the right hemisphere, and temporal and prefrontal regions in the left hemisphere. These results are discussed in terms of previously published findings. Finally, the anatomical implications of a reduced FD are highlighted through comparison of two subjects with vastly different complexity maps. PMID- 21315160 TI - de Bruijn cycles for neural decoding. AB - Stimulus counterbalance is critical for studies of neural habituation, bias, anticipation, and (more generally) the effect of stimulus history and context. We introduce de Bruijn cycles, a class of combinatorial objects, as the ideal source of pseudo-random stimulus sequences with arbitrary levels of counterbalance. Neuro-vascular imaging studies (such as BOLD fMRI) have an additional requirement imposed by the filtering and noise properties of the method: only some temporal frequencies of neural modulation are detectable. Extant methods of generating counterbalanced stimulus sequences yield neural modulations that are weakly (or not at all) detected by BOLD fMRI. We solve this limitation using a novel "path guided" approach for the generation of de Bruijn cycles. The algorithm encodes a hypothesized neural modulation of specific temporal frequency within the seemingly random order of events. By positioning the modulation between the signal and noise bands of the neuro-vascular imaging method, the resulting sequence markedly improves detection power. These sequences may be used to study stimulus context and history effects in a manner not previously possible. PMID- 21315161 TI - Phylogeny and evolution of Indo-Pacific shrimp-associated gobies (Gobiiformes: Gobiidae). AB - Despite the ubiquity of obligate mutualisms on coral reef ecosystems, little is known about the evolution of many participating species. The shrimp gobies, known primarily from the coral reef habitats of the Indo-Pacific, are small benthic fishes that participate in a remarkable mutualism with alpheid shrimp. In this mutualism, the shrimp build and maintain a burrow that is guarded by the goby, and the shrimp and goby engage in an intricate tactile communication system. The mutualism is obligate for most shrimp gobies as participating species are highly vulnerable to predation when separated from a shrimp partner. We use phylogenetic analysis of nuclear and mitochondrial DNA sequence data to infer evolutionary relationships among shrimp gobies, and between shrimp gobies and their non mutualistic gobiid relatives. We show that the mutualist shrimp association has arisen twice among gobies, once in a clade composed of Amblyeleotris, Ctenogobiops, and Vanderhorstia, and a second time in a clade including Cryptocentrus, Mahidolia, Tomiamichthys and Stonogobiops. We then compare the evolution of traits within each shrimp goby clade and consider their intrarelationships. We document cryptic diversity among shrimp gobies, with three distinct clades delineated among Mahidolia mysticina specimens captured at the same locality, paired with the same shrimp species. Mahidolia is placed as sister to the Cryptocentrus species Cryptocentrus cinctus; both exhibit pronounced dichromatism, occurring in both brown and yellow (xanthic) forms. We additionally clarify species identities within Amblyeleotris, confirming that widespread similar species Amblyeleotris fasciata, Amblyeleotris steinitzi and Amblyeleotris wheeleri are all distinct. We hypothesize that the flexibility of gobiid gobies and alpheid shrimp to interact with mutualist partners, as well as the apparently highly beneficial nature of mutualism between them, has contributed to the dual evolution of shrimp-association among Indo-Pacific gobies. PMID- 21315162 TI - Phylogenomic analyses and improved resolution of Cetartiodactyla. AB - The remarkable antiquity, diversity, and significance in the ecology and evolution of Cetartiodactyla have inspired numerous attempts to resolve their phylogenetic relationships. However, previous analyses based on limited samples of nuclear genes or mitochondrial DNA sequences have generated results that were either inconsistent with one another, weakly supported, or highly sensitive to analytical conditions. Here, we present strongly supported results based upon over 1.4 Mb of an aligned DNA sequence matrix from 110 single-copy nuclear protein-coding genes of 21 Cetartiodactyla species, which represent major Cetartiodactyla lineages, and three species of Perissodactyla and Carnivora as outgroups. Phylogenetic analysis of this newly developed genomic sequence data using a codon-based model and recently developed models of the rate autocorrelation resolved the phylogenetic relationships of the major cetartiodactylan lineages and of those lineages with a high degree of confidence. Cetacea was found to nest within Artiodactyla as the sister group of Hippopotamidae, and Tylopoda was corroborated as the sole base clade of Cetartiodactyla. Within Cetacea, the monophyletic status of Odontoceti relative to Mysticeti, the basal position of Physeteroidea in Odontoceti, the non monophyly of the river dolphins, and the sister relationship between Delphinidae and Monodontidae+Phocoenidae were strongly supported. In particular, the groups of Tursiops (bottlenose dolphins) and Stenella (spotted dolphins) were validated as unnatural groups. Additionally, a very narrow time frame of ~3 My (million years) was found for the rapid diversification of delphinids in the late Miocene, which made it difficult to resolve the phylogenetic relationships within the Delphinidae, especially for previous studies with limited data sets. The present study provides a statistically well-supported phylogenetic framework of Cetartiodactyla, which represents an important step toward ending some of the often-heated, century-long debate on their evolution. PMID- 21315163 TI - Lizards from the end of the world: phylogenetic relationships of the Liolaemus lineomaculatus section (Squamata: Iguania: Liolaemini). AB - The Liolaemus lineomaculatus section is a geographically widely distributed group of lizards from the Patagonian region of southern South America, and includes 18 described species representing the most southerly distributed Liolaemus taxa (the genus includes 228 species and extends from Tierra del Fuego north to south central Peru). Despite high species diversity, the phylogenetic relationships of this section are unknown. In the present work we sampled all described species in the L. lineomaculatus section as well as currently undescribed candidate species to reconstruct the first complete phylogenetic hypothesis for the clade. Our data set included four anonymous nuclear loci, three nuclear protein-coding loci, and two mitochondrial genes. We compared results obtained with three different phylogenetic methods for the concatenated data set (Maximum Parsimony, Maximum Likelihood and Bayesian Inference) with a coalescent-based species tree approach (BEST), and recovered congruent, strongly-supported topological arrangements across all methods. We identified four main clades within the L. lineomaculatus section: the lineomaculatus, magellanicus, somuncurae, and kingii+archeforus groups, for which we estimated divergence times. We discuss the taxonomic implications of these results and how the future integration of phylogeographic, niche modeling and morphological approaches will allow testing biogeographical hypotheses in this clade. PMID- 21315164 TI - Molecular systematics of the neotropical shovelnose catfish genus Pseudoplatystoma Bleeker 1862 based on nuclear and mtDNA markers. AB - Pseudoplatystoma is a commercially important genus of Neotropical migratory catfishes widely distributed in all major river basins of South America. Historically, only three species were recognized, but a recent revision proposed eight putative morphospecies for the genus. A molecular study based on mitochondria DNA (mtDNA) provided support for recognition of only some of the species and raised questions about species boundaries in this group. We present a more encompassing analysis based on mtDNA (cytochrome b, 818bp) and nuclear DNA based phylogenies (Rag1 intron 1, 664bp and S7 intron 1, 635bp) for a more extensive sampling (279 individuals from 42 localities) of all putative species in all major river basins. Patterns generated by individual gene genealogies and a multispecies coalescent analysis provided evidence to suggest recognition of only four distinct species in this genus: Pseudoplatystoma magdaleniatum, Pseudoplatystoma corruscans, Pseudoplatystoma tigrimun (sensu lato) and Pseudoplatystoma fasciatum (sensu lato). The species phylogeny places P. magdaleniatum as the sister group to all the other species in the genus, but the relationships among P. fasciatum s.l, P. tigrimum s.l., and P. corruscans could not be resolved with confidence. PMID- 21315165 TI - Evaluation of translation in the normal and dysplastic hip using three dimensional magnetic resonance imaging and voxel-based registration. AB - OBJECTIVE: To elucidate in vivo hip instability by comparing normal hips to hips with acetabular dysplasia by evaluating three-dimensional (3D) translations of the femoral head center (FHC) at different hip positions using magnetic resonance imaging (MRI). DESIGN: Forty normal hips and 22 dysplastic female hips were examined. MRI was performed at four different positions bilaterally: neutral, 45 degrees of flexion, 15 degrees of extension, and the Patrick position. Femoral and pelvic bones were separately extracted at the neutral position and superimposed over the images of each different position using voxel-based registration. The distance between the acetabular center and FHC at neutral position was defined as 3D-migration. The distance between FHC at neutral position and that at each different position was defined as 3D-translation. Two way repeated measures analysis of variance was performed to consider the dependency between right and left-side data, and multiple linear regression analyses were performed to assess independent relationships. RESULTS: The center edge (CE) angle was the determinant for 3D-migration (beta=-0.415, P=0.001), and there was a statistical significant difference in 3D-migration between normal female hips and dysplastic hips (P=0.047). From neutral to the Patrick position, the FHC of normal and dysplastic hips translated postero-infero-medially by 1.12+/-0.39mm (0.45-1.85mm) and 1.97+/-0.84mm (0.95-4.34mm), respectively, and the difference between the groups was statistically significant (P=0.005). CE angle was the determinant for 3D-translation from neutral to the Patrick position (beta=-0.730, P<0.001). The average root mean square error in 3D-translation was 0.172mm and 0.193mm for intra- and interobserver reproducibility, respectively. CONCLUSIONS: Hip instability was increased in proportion to the severity of acetabular dysplasia. A 3D MRI voxel-based registration technique can show in vivo morphology and kinematics of the native hip without exposure to radioactivity. PMID- 21315166 TI - Time course of effects of emotion on item memory and source memory for Chinese words. AB - Although many studies have investigated the effect of emotion on memory, it is unclear whether the effect of emotion extends to all aspects of an event. In addition, it is poorly understood how effects of emotion on item memory and source memory change over time. This study examined the time course of effects of emotion on item memory and source memory. Participants learned intentionally a list of neutral, positive, and negative Chinese words, which were presented twice, and then took test of free recall, followed by recognition and source memory tests, at one of eight delayed points of time. The main findings are (within the time frame of 2 weeks): (1) Negative emotion enhances free recall, whereas there is only a trend that positive emotion enhances free recall. In addition, negative and positive emotions have different points of time at which their effects on free recall reach the greatest magnitude. (2) Negative emotion reduces recognition, whereas positive emotion has no effect on recognition. (3) Neither positive nor negative emotion has any effect on source memory. The above findings indicate that effect of emotion does not necessarily extend to all aspects of an event and that valence is a critical modulating factor in effect of emotion on item memory. Furthermore, emotion does not affect the time course of item memory and source memory, at least with a time frame of 2 weeks. This study has implications for establishing the theoretical model regarding the effect of emotion on memory. PMID- 21315167 TI - Germination response of spores of the pathogenic bacterium Clostridium perfringens and Clostridium difficile to cultured human epithelial cells. AB - Spores of pathogenic Clostridium perfringens and Clostridium difficile must germinate in the food vehicle and/or host's intestinal tract to cause disease. In this work, we examined the germination response of spores of C. perfringens and C. difficile upon incubation with cultured human epithelial cell lines (Caco-2, HeLa and HT-29). C. perfringens spores of various sources were able to germinate to different extents; while spores of a non-food-borne isolate germinated very well, spores of food-borne and animal isolates germinated poorly in human epithelial cells. In contrast, no detectable spore germination (i.e., loss of spore heat resistance) was observed upon incubation of C. difficile spores with epithelial cells; instead, there was a significant (p < 0.01) increase in heat resistant spore titers. In C. perfringens, the highest spore germination response observed with the HT-29 cell line, might be in part, due to the expression of germination factor with peptidoglycan cortex hydrolysis activity by HT-29 cells. Collectively, these findings might well have implications in understanding the mechanism of clostridial spore germination in vivo. PMID- 21315168 TI - Altered glyoxalase 1 expression in psychiatric disorders: cause or consequence? AB - Glyoxalase 1 is an enzyme, shown to protect against dicarbonyl glycation and the formation of advanced glycation end products. Recent findings suggest glyoxalase 1 as a molecular marker of psychiatric disorders. In clinical studies aberrant expression of glyoxalase 1 was shown to be involved in major depression, panic disorders and schizophrenia. In mouse models glyoxalase 1 was identified as a molecular marker of trait anxiety. However, anxiety-related behaviour in mice was inconsistently reported to correlate with elevated or reduced expression of glyoxalase 1. As yet, those findings were considered contradicting and the contribution of glyoxalase 1 to the aetiology of psychiatric disorders remained elusive. This review summarizes recent clinical and animal studies. In order to unravel the role of glyoxalase 1 in mental disease, findings are discussed with a particular focus on dicarbonyl substrate concentration. Prevailing the impact of dicarbonyl substrates on anxiety-related behaviour over the influence of glyoxalase 1 expression may consolidate findings that have been considered inconsistent. Taken together, this report suggests that physiological concentration of dicarbonyl compounds may differentiate a remedy from a poison. PMID- 21315169 TI - ASP3258, an orally active potent phosphodiesterase 4 inhibitor with low emetic activity. AB - We investigated the pharmacology of a novel phosphodiesterase (PDE) 4 inhibitor, ASP3258 (3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8 naphthyridin-3-yl] propanoic acid), comparing its potency with that of the most advanced PDE4 inhibitors, roflumilast and cilomilast. PDE4 inhibition by ASP3258 (IC(50)=0.28nM) was as potent as that achieved with roflumilast. ASP3258 inhibited lipopolysaccharide-induced tumor necrosis factor (TNF)-alpha production in rat whole blood cells (IC(50)=8.8 nM) and rat alveolar macrophages (IC(50)=2.6 nM). Orally administered ASP3258, roflumilast, and cilomilast dose-dependently inhibited production of interleukin-4, TNF-alpha, and cysteinyl leukotrienes, as well as leukocyte infiltration in bronchoalveolar lavage fluid from the airways of ovalbumin-sensitized Brown Norway rats, and these compounds showed almost complete inhibition at doses of 3, 3, and 30 mg/kg, respectively. PDE4 inhibitors induce emesis by mimicking the pharmacological action of alpha(2)-adrenoceptor antagonist. However, orally administered roflumilast (3mg/kg) and cilomilast (10mg/kg), but not ASP3258 (3mg/kg), inhibited alpha(2)-adrenoceptor agonist induced anesthesia in rats and induced emesis in ferrets. Although ASP3258 (3mg/kg) inhibited airway inflammation completely, it had no emetic activity. As such, this compound may be useful in treating airway inflammatory diseases such as asthma and COPD. PMID- 21315171 TI - Enhancement of the pulmonary allergic granulocyte recruitment in rats exposed to DMTI-II, a Kunitz-type inhibitor isolated from Dimorphandra mollis seeds. AB - DMTI-II (23-kDa trypsin inhibitor purified from Dimorphandra mollis seeds) promotes acute inflammation accompanied by an early infiltration of eosinophils, a critical cell type involved in allergic diseases. We have evaluated here the capacity of DMTI-II to enhance the allergic pulmonary inflammation, looking over time to the leukocyte trafficking from bone marrow to peripheral blood, and their recruitment into the allergic airways. Male Wistar rats were sensitized and challenged with ovalbumin (OVA). At 2 to 16h prior to OVA challenge, animals were exposed to DMTI-II (10MUg). Bronchoalveolar lavage fluid (BAL), circulating blood and bone marrow were examined at 24h post-OVA challenge. Challenge with OVA significantly increased the influx of total inflammatory cells, neutrophils and eosinophils in BAL and lung tissue. Pre-exposure to DMTI-II potentiated total inflammatory cell and neutrophil recruitment (p<0.05). Neutropoiesis and neutrophilia accompanied pulmonary cell influx. Pre-exposure to DMTI-II also significantly increased eosinophil recruitment to BAL, an effect starting at 4h, remaining markedly elevated at 16h (p<0.05). Eosinopoiesis and eosinophilia (seen within 2 to 4h) were also observed. Exposure to DMTI-II alone increased the IL-4 levels, and further increased the IL-4 levels in OVA-challenged rats. The levels of IgE, LTB(4) and eotaxin in OVA-challenged rats were greater compared with non sensitized rats, but DMTI-II exposure failed to further enhance such levels. In summary, our study shows that DMTI-II itself presents granulocytopoietic activity, and enhances allergen-induced neutrophil and eosinophil mobilization from bone marrow to lung tissues that is accompanied by enhanced IL-4 production. PMID- 21315172 TI - Linking genes to microbial growth kinetics: an integrated biochemical systems engineering approach. AB - The majority of models describing the kinetic properties of a microorganism for a given substrate are unstructured and empirical. They are formulated in this manner so that the complex mechanism of cell growth is simplified. Herein, a novel approach for modelling microbial growth kinetics is proposed, linking biomass growth and substrate consumption rates to the gene regulatory programmes that control these processes. A dynamic model of the TOL (pWW0) plasmid of Pseudomonas putida mt-2 has been developed, describing the molecular interactions that lead to the transcription of the upper and meta operons, known to produce the enzymes for the oxidative catabolism of m-xylene. The genetic circuit model was combined with a growth kinetic model decoupling biomass growth and substrate consumption rates, which are expressed as independent functions of the rate limiting enzymes produced by the operons. Estimation of model parameters and validation of the model's predictive capability were successfully performed in batch cultures of mt-2 fed with different concentrations of m-xylene, as confirmed by relative mRNA concentration measurements of the promoters encoded in TOL. The growth formation and substrate utilisation patterns could not be accurately described by traditional Monod-type models for a wide range of conditions, demonstrating the critical importance of gene regulation for the development of advanced models closely predicting complex bioprocesses. In contrast, the proposed strategy, which utilises quantitative information pertaining to upstream molecular events that control the production of rate limiting enzymes, predicts the catabolism of a substrate and biomass formation and could be of central importance for the design of optimal bioprocesses. PMID- 21315173 TI - Attenuated virulence of min operon mutants of Neisseria gonorrhoeae and their interactions with human urethral epithelial cells. AB - Neisseria gonorrhoeae, a sexually-transmitted gram-negative bacterium, causes gonorrhoea in humans. The min genes of N. gonorrhoeae are involved in cell division site selection with oxyR co-transcribed with these genes. The mutation in min genes and oxy R cause aberrant cell morphology and aggregation patterns, respectively. Our objective was to assess the contribution of neisserial min operon cell division genes i.e. minC, minD and oxyR in virulence. Compared to the N. gonorrhoeae parental strain (Ng CH811Str(R)), its isogenic mutants with insertionally inactivated minC (Ng CSRC1), minD (Ng CJSD1) or oxyR (Ng KB1) showed reduced adherence to and invasion of urethral epithelial cells. This may be explained by defective microcolony formation in the mutant strains, possibly owing to abnormal morphology and aggregation. The expression levels of surface virulence factors like Opa, pilin and lipooligosaccharide in the mutants were unchanged relative to Ng CH811Str(R). Furthermore, in urethral epithelial cells, the min and oxyR mutants induced the release of proinflammatory cytokines like IL6 and IL8 to levels similar to that induced by the parental strain. Taken together, our studies indicate that inactivation of minC, minD or oxyR in N. gonorrhoeae attenuates its ability to bind to and invade urethral epithelial cells without altering its potential to induce IL6 and IL8 release. PMID- 21315174 TI - Attenuation of human neutrophil migration and function by uropathogenic bacteria. AB - The establishment of bacterial infections at mucosal epithelial surfaces is determined by the balance of virulence attributes of the pathogen with the activity of innate host defenses. Polymorphonuclear leukocytes (PMN) are key responders in many bacterial infections, but the mechanisms by which pathogens subvert these early responses to establish infection are largely undefined. Here, we model early interactions between human PMN and the primary cause of urinary tract infections, namely uropathogenic Escherichia coli (UPEC). Our objective was to define virulence phenotypes of uropathogens that permit evasion of PMN activity. We show that UPEC strains, as compared with laboratory and commensal E. coli, resist phagocytic killing and dampen the production of antimicrobial reactive oxygen species by PMN. Analysis of the transcriptional responses of PMN to E. coli strains revealed that UPEC exposure downregulates the expression of PMN genes that direct pro-inflammatory signaling and PMN chemotaxis, adhesion, and migration. Consistent with these data, UPEC attenuated transepithelial neutrophil recruitment in an in vitro model of acute infection and in a murine model of bacterial cystitis. We propose that these UPEC strategies are important in the establishment of epithelial infection, and that the findings are germane to bacterial infections at other epithelial surfaces. PMID- 21315175 TI - Soluble extract from the nematode Strongyloides stercoralis induces CXCR2 dependent/IL-17 independent neutrophil recruitment. AB - Neutrophil recruitment via CXCR2 is required for innate and adaptive protective immunity to the larvae of Strongyloides stercoralis in mice. The goal of the present study was to determine the mechanism of CXCR2-mediated neutrophil recruitment to S. stercoralis. Mice deficient in the receptor for IL-17A and IL 17F, upstream mediators of CXCR2 ligand production, were infected with S. stercoralis larvae; there was no difference in larval survival, neutrophil recruitment, or production of CXCR2 ligands compared with wild type mice. In vivo and in vitro stimulation of neutrophils with S. stercoralis soluble extract resulted in significant neutrophil recruitment. In vitro assays demonstrated that the recruitment functioned through both chemokinesis and chemotaxis, was specific for CXCR2, and was a G protein-coupled response involving tyrosine kinase and PI3K. Finally, neutrophil stimulation with S. stercoralis soluble extract induced release of the CXCR2 ligands MIP-2 and KC from neutrophils, thereby potentially enhancing neutrophil recruitment. PMID- 21315176 TI - Coordinated involvement of cathepsins S, D and cystatin C in the commitment of hematopoietic stem cells to dendritic cells. AB - The identity of biochemical players which underpin the commitment of CD34(+) hematopoietic stem cells to immunogenic or tolerogenic dendritic cells is largely unknown. To explore this issue, we employed a previously established cell-based system amenable to shift dendritic cell differentiation from the immunogenic into the tolerogenic pathway upon supplementation with a conventional cytokine cocktail containing thrombopoietin (TPO) and IL-16. We show that stringent regulation of cathepsins S and D, two proteases involved in antigen presentation, is crucial to engage cell commitment to either route. In response to TPO+IL-16 dependent signaling, both cathepsins undergo earlier maturation and down regulation. Additionally, cystatin C orchestrates cathepsin S expression through a tight but reversible interaction that, based on a screen of adult stem cells from disparate origins, CD14(+) cells, primary fibroblasts and the MCF7 cell line, appears unique to CD34(+) stem cells from peripheral and cord blood. As shown by CD4(+) T cell proliferation in mixed-lymphocyte reactions, cell commitment to either pathway is disrupted upon cathepsin knockdown by RNAi. Surprisingly, similar effects were also observed upon gene overexpression, which prompts atypically accelerated maturation of cathepsins S and D in cells of the immunogenic pathway, similar to the tolerogenic route. Furthermore, RNAi studies revealed that cystatin C is a proteolytic target of cathepsin D and has a direct, causal impact on cell differentiation. Together, these findings uncover a novel biochemical cluster that is subject to time-controlled and rigorously balanced expression to mediate specific stem cell commitment at the crossroads towards tolerance or immunity. PMID- 21315177 TI - A novel PKC-iota inhibitor abrogates cell proliferation and induces apoptosis in neuroblastoma. AB - Protein Kinase C-iota (PKC-iota), an atypical protein kinase C isoform manifests its potential as an oncogene by targeting various aspects of cancer cells such as growth, invasion and survival. PKC-iota confers resistance to drug-induced apoptosis in cancer cells. The acquisition of drug resistance is a major obstacle to good prognosis in neuroblastoma. The focus of this research was to identify the efficacy of [4-(5-amino-4-carbamoylimidazol-1-yl)-2,3-dihydroxycyclopentyl] methyl dihydrogen phosphate (ICA-1) as a novel PKC-iota inhibitor in neuroblastoma cell proliferation and apoptosis. ICA-1 specifically inhibits the activity of PKC-iota but not that of PKC-zeta (PKC-zeta), the closely related atypical PKC family member. The IC(50) for the kinase activity assay was approximately 0.1MUM which is 1000 times less than that of aurothiomalate, a known PKC-iota inhibitor. Cyclin dependent kinase 7 (Cdk7) phosphorylates cyclin dependent kinases (cdks) and promotes cell proliferation. Our data shows that PKC iota is an in vitro Cdk7 kinase and the phosphorylation of Cdk7 by PKC-iota was potently inhibited by ICA-1. Furthermore, our data shows that neuroblastoma cells proliferate via a PKC-iota/Cdk7/cdk2 cell signaling pathway and ICA-1 mediates its antiproliferative effects by inhibiting this pathway. ICA-1 (0.1MUM) inhibited the in vitro proliferation of BE(2)-C neuroblastoma cells by 58% (P=0.01). Additionally, ICA-1 also induced apoptosis in neuroblastoma cells. Interestingly, ICA-1 did not affect the proliferation of normal neuronal cells suggesting its potential as chemotherapeutic with low toxicity. Hence, our results emphasize the potential of ICA-1 as a novel PKC-iota inhibitor and chemotherapeutic agent for neuroblastoma. PMID- 21315178 TI - Cytoplasmic ATM protein kinase: an emerging therapeutic target for diabetes, cancer and neuronal degeneration. AB - Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by cerebellar ataxia and oculocutaneous telangiectasias. The gene mutated in this disease, Atm (A-T mutated), encodes a serine/threonine protein kinase that has been traditionally considered to be a nuclear protein controlling cell-cycle progression. However, many of the growth abnormalities observed in patients with A-T, including neuronal degeneration and insulin resistance, remain difficult to explain with nuclear localization of ATM. Here, recent advances in elucidating the cytoplasmic localization and function of ATM are reviewed. Particular attention is given to the role of ATM in insulin signaling and Akt activation. The potential for cytoplasmic ATM protein kinase to be an emerging therapeutic target for treating diabetes, cancer and neuronal degeneration is discussed. PMID- 21315179 TI - Fragment screening to predict druggability (ligandability) and lead discovery success. PMID- 21315180 TI - Advances in the computational development of DNA methyltransferase inhibitors. AB - DNA methylation is an epigenetic change that results in the addition of a methyl group at the carbon-5 position of cytosine residues. The process is mediated by DNA methyltransferases (DNMTs), a family of enzymes for which inhibition is a promising strategy for the treatment of cancer and other diseases. Here, we review the current status of the computational studies directed to rationalize, at the molecular level, the enzymatic activity of DNMT inhibitors. We also review successful virtual screenings to identify inhibitors with novel scaffolds as well as the emerging efforts to characterize the dynamic behavior of DNMTs. Thus, computational approaches form part of multidisciplinary efforts to further advance epigenetic therapies. PMID- 21315181 TI - How to compute which genes control drug resistance dynamics. AB - Increasing evidence shows that genes have a pivotal role in affecting the dynamic pattern of viral loads in the body of a host. By reviewing the biochemical interactions between a virus and host cells as a dynamic system, we outline a computational approach for mapping the genetic control of virus dynamics. The approach integrates differential equations (DEs) to quantify the dynamic origin and behavior of a viral infection system. It enables geneticists to generate various testable hypotheses about the genetic control mechanisms for virus dynamics and infection. The experiment designed according to this approach will also enable researchers to gain insight into the role of genes in limiting virus abundance and the dynamics of viral drug resistance, facilitating the development of personalized medicines to eliminate viral infections. PMID- 21315182 TI - Systems-based biological concordance and predictive reproducibility of gene set discovery methods in cardiovascular disease. AB - The discovery of novel disease biomarkers is a crucial challenge for translational bioinformatics. Demonstration of both their classification power and reproducibility across independent datasets are essential requirements to assess their potential clinical relevance. Small datasets and multiplicity of putative biomarker sets may explain lack of predictive reproducibility. Studies based on pathway-driven discovery approaches have suggested that, despite such discrepancies, the resulting putative biomarkers tend to be implicated in common biological processes. Investigations of this problem have been mainly focused on datasets derived from cancer research. We investigated the predictive and functional concordance of five methods for discovering putative biomarkers in four independently-generated datasets from the cardiovascular disease domain. A diversity of biosignatures was identified by the different methods. However, we found strong biological process concordance between them, especially in the case of methods based on gene set analysis. With a few exceptions, we observed lack of classification reproducibility using independent datasets. Partial overlaps between our putative sets of biomarkers and the primary studies exist. Despite the observed limitations, pathway-driven or gene set analysis can predict potentially novel biomarkers and can jointly point to biomedically-relevant underlying molecular mechanisms. PMID- 21315184 TI - Molecular model of hexokinase binding to the outer mitochondrial membrane porin (VDAC1): Implication for the design of new cancer therapies. AB - A key feature of many cancers is the capacity and the propensity to metabolize glucose to lactic acid at a very high rate even in the presence of oxygen. This characteristic was first discovered in 1924 by Otto Heinrich Warburg. Hexokinase, the first enzyme in the glycolytic pathway, not only improves the cell's energy supply in malignant cells, but also protects cancer cells against apoptosis through direct interaction with mitochondria and with the Voltage Dependent Anion Channel 1 (VDAC1). The rupture of HK:VDAC1 protein complex provides a therapeutic opportunity, as this association appears to protect tumor cells from mitochondrial outer membrane permeabilization, an event that marks the point of no return in multiple pathways leading to cell death. In the absence of a crystallographic structure and in order to perform an in silico screening of possible small molecules able to inhibit the protein association, we are presenting a computational model of HK-I:VDAC1 complex. It appears as evident how the first 15 N-terminal residues of HK-I interact with the inner part of the barrel of VDAC1 and not with the outside walls, within the mitochondrial membrane as previously believed. This finding is in agreement with the existence of a secondary ATP binding site in the same N-terminal region of HK-I which seems to have a crucial role in HK-I interaction with VDAC1. This evidence appears to be in accord also with the high levels of ATP that are found in cancer cells. Eventually such arrangements may contribute to stabilize the tertiary structure of VDAC1 while shielding from pro-apoptotic factor binding, protecting in a synergic way the tumoral cell from programmed death. PMID- 21315185 TI - Immunological hurdles of ageing: indispensable research of the human model. AB - Census reports of many countries indicate continuing trends for the graying of their populations. For the United States alone, persons aged >=65 years are projected to comprise over 20% of the population by the year 2050. In view of the special medical needs of elders, scientific investigation into the biological aspects of ageing is key towards the improvement of geriatric care for the coming decades. This special issue of Ageing Research Reviews focuses on advances in research on the immunology of human ageing. Herein are nine articles about the age-related alterations in both the innate and adaptive arms of the immune system, and about continuing hurdles in vaccinology. These articles point to a common theme that the immunological milieu in old age is substantially different from that seen in the young. This suggests that new development and/or innovation of immune-based clinical interventions for the elderly may need to be customized for their age group, rather than the mere adoption of therapies that have been designed for and/or tested for younger persons. PMID- 21315187 TI - A comparative study of the thermal and dynamic mechanical behaviour of quenched and annealed bioresorbable poly-L-lactide/alpha-tricalcium phosphate nanocomposites. AB - Despite numerous reports on the degradation properties and biological efficacy of bioresorbable polymer nanocomposites intended for use in orthopaedics, there is currently limited literature addressing their thermal and load-bearing properties, which are of central importance to the successful design of these nanocomposites. Here we demonstrate that the storage moduli at 37 degrees C and the glass transition temperatures of quenched poly-L-lactide/alpha-tricalcium phosphate nanocomposites were lower than those of annealed nanocomposites while the damping factor tandelta values of the quenched nanocomposites were higher than those of the annealed nanocomposites. This was due to the highly crystalline structure of the annealed samples, as confirmed by wide angle X-ray diffraction. The higher storage moduli and glass transition temperatures of the annealed nanocomposites implies that higher energy will be generated to resist deformation with the possibility for reduced polymer chain mobility during in vivo use. Therefore, the decision as to whether to use quenched or annealed nanocomposites depends on the load-bearing conditions prevailing at the site of implantation. The storage moduli of the nanocomposites at 37 degrees C approached the lower range of the storage modulus for cortical bone and this may prevent stress shielding during bone regeneration. PMID- 21315186 TI - CD8 T cell responses to influenza virus infection in aged mice. AB - Influenza is one of the most common infectious diseases afflicting humans, particularly the elderly. The murine model has been widely employed for investigation of immunity to influenza virus infection. In this paper, we review the recent advances in understanding the diminished CD8 T cell immune response to influenza virus infection in aged mice. Possible mechanisms of impaired CD8 T cell responses with aging are addressed, including: (1) the role of dendritic cells (DCs); (2) the effect of age-associated changes in the T cell repertoire; and (3) the interactions with CD4 T cells, including T regulatory (Treg) cells and CD4 T helper cells. The aged murine model of the CD8 T cell response to influenza virus is helping to elucidate the mechanisms of immunosenescence which can lead to therapeutic improvements in the primary CD8 T cell response to new infections, as well as the development of new strategies for immunization to prevent influenza in the elderly. PMID- 21315188 TI - Girdlestones excision arthroplasty: current update. AB - Girdlestones procedure has become a salvage operation reserved for patients with significant co-morbidities. Recent literature addresses this infrequently used intervention inadequately. This observational study aims to update current literature and review the modern role of this intervention in orthopaedic practice. Twenty-four records were obtained from which patient demographics, indications and co-morbidities were investigated. Seventeen patients completed an abridged Harris Hip Scoring questionnaire and commented on satisfaction. The average age was 78 years and patients had multiple co-morbidities. Dementia was the most frequent condition but several patients suffered from cardiovascular and respiratory disease. The most common operative indication was persistent prosthetic infection with Staphylococcus aureus, the most common pathogen. Overall mortality was 41% but all surviving patients had complete resolution of infection and 65% had adequate pain control. No patients mobilised without aids although 29% of patients were able to manage stairs and 29% were able to mobilise outdoors. Only 29% were unsatisfied with the outcome. This study demonstrates that Girdlestones candidates are an ageing high-risk group and shows that the Girdlestones procedure can, in select cases, provide good functional outcomes. However such intervention comes at the expense of high mortality and should therefore only be used as a last resort. PMID- 21315189 TI - Clinical report: AN INTERSTITIAL deletion of 16p13.11 detected by array CGH in a patient with infantile spasms. AB - Chromosome 16p13.11 has recently been reported as a region of recurrent microdeletion/duplication, which may contribute to a specific clinical phenotype of epilepsy, significant learning difficulties and distinct facial dysmorphism. The 16p13.11 microdeletion syndrome is associated with schizophrenia, developmental delay and idiopathic generalised epilepsy. Haploinsufficiency of genes in 16p13.11 has been suggested as contributing to the pathogenicity of this microdeletion syndrome. We report a three-year-old boy with the 16p13.11 microdeletion syndrome, identified on array CGH, and describe his clinical phenotype, thereby adding to the existing literature on this newly-described microdeletion syndrome. We discuss the function and potential relevance of the genes in this region with regards to the features described in this condition. PMID- 21315190 TI - A novel frame shift mutation in the PQBP1 gene identified in a Tunisian family with X-linked mental retardation. AB - Mental retardation (MR) is the most frequent cause of serious handicap in children and young adults. Despite recent progress, in most cases the molecular defects underlying this disorder remain unknown. Linkage studies followed by mutational analysis of known X-chromosomal genes related to mental retardation (MRX genes) localized within defined genetic intervals represent a rational strategy to identify a genetic cause of the disorder. Here, we report a Tunisian family including 3 males with severe to mild mental retardation, short stature, lean body and microcephaly; we mapped the disease to a unique interval encompassing Xp21.1-Xq21.33 (with a maximum LOD score of 0.90). Subsequent mutation analysis of genes located in this interval allowed us to identify a truncating mutation in the PQBP1 gene. This mutation is an insertion of an adenosine residue in exon 5 (c.631insA). This frameshift insertion causes premature stop codon at amino acid position 226. The observed mutation was found in all males with MR in this family. Together with previously reported observations, our data further confirm that PQBP1 gene should be tested for males showing mental retardation, short stature, lean body and microcephaly. PMID- 21315191 TI - Analysis of FOXF1 and the FOX gene cluster in patients with VACTERL association. AB - VACTERL association, a relatively common condition with an incidence of approximately 1 in 20,000 -35,000 births, is a non-random association of birth defects that includes vertebral defects (V), anal atresia (A), cardiac defects (C), tracheo-esophageal fistula (TE), renal anomalies (R) and limb malformations (L). Although the etiology is unknown in the majority of patients, there is evidence that it is causally heterogeneous. Several studies have shown evidence for inheritance in VACTERL, implying a role for genetic loci. Recently, patients with component features of VACTERL and a lethal developmental pulmonary disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), were found to harbor deletions or mutations affecting FOXF1 and the FOX gene cluster on chromosome 16q24. We investigated this gene through direct sequencing and high density SNP microarray in 12 patients with VACTERL association but without ACD/MPV. Our mutational analysis of FOXF1 showed normal sequences and no genomic imbalances affecting the FOX gene cluster on chromosome 16q24 in the studied patients. Possible explanations for these results include the etiologic and clinical heterogeneity of VACTERL association, the possibility that mutations affecting this gene may occur only in more severely affected individuals, and insufficient study sample size. PMID- 21315192 TI - A founder effect at the EPCAM locus in Congenital Tufting Enteropathy in the Arabic Gulf. AB - Mutations of the EPCAM gene have been recently identified in Congenital Tufting Enteropathy (CTE), a severe autosomal recessive gastrointestinal insufficiency of childhood requiring parenteral nutrition and occasionally intestinal transplantation. Studying seven multiplex consanguineous families from the Arabic peninsula (Kuwait and Qatar) we found that most patients were homozygote for a c.498insC mutation in exon 5. The others carried a novel mutation IVS4-2A->G. Both mutations were predicted to truncate the C-terminal domain necessary to anchorage of EPCAM at the intercellular membrane. Consistently, immunohistochemistry of intestinal biopsies failed to detect the EPCAM protein at the intercellular membrane level. The c.498insC mutation was found on the background of a minimal common haplotype of 473kb suggesting a very old founder effect (5000-6000 yrs). PMID- 21315193 TI - Use of whey lactose from dairy industry for economical kefiran production by Lactobacillus kefiranofaciens in mixed cultures with yeasts. AB - To evaluate the feasibility of producing kefiran industrially, whey lactose, a by product from dairy industry, was used as a low cost carbon source. Because the accumulation of lactic acid as a by-product of Lactobacillus kefiranofaciens inhibited cell growth and kefiran production, the kefir grain derived and non derived yeasts were screened for their abilities to reduce lactic acid and promote kefiran production in a mixed culture. Six species of yeasts were examined: Torulaspora delbrueckii IFO 1626; Saccharomyces cerevisiae IFO 0216; Debaryomyces hansenii TISTR 5155; Saccharomyces exiguus TISTR 5081; Zygosaccharomyces rouxii TISTR 5044; and Saccharomyces carlsbergensis TISTR 5018. The mixed culture of L. kefiranofaciens with S. cerevisiae IFO 0216 enhanced the kefiran production best from 568 mg/L in the pure culture up to 807 and 938 mg/L in the mixed cultures under anaerobic and microaerobic conditions, respectively. The optimal conditions for kefiran production by the mixed culture were: whey lactose 4%; yeast extract 4%; initial pH of 5.5; and initial amounts of L. kefiranofaciens and S. cerevisiae IFO 0216 of 2.1*10(7) and 4.0*10(6)CFU/mL, respectively. Scaling up the mixed culture in a 2L bioreactor with dissolved oxygen control at 5% and pH control at 5.5 gave the maximum kefiran production of 2,580 mg/L in batch culture and 3,250 mg/L in fed-batch culture. PMID- 21315194 TI - Significant improvement of Geobacillus thermoleovorans CCR11 thermoalkalophilic lipase production using response surface methodology. AB - The medium optimization for the production of the Geobacillus thermoleovorans CCR11 thermoalkalophilic lipase was carried out in shake flask cultures using safflower high oleic oil. In the first step of optimization, a two level fractional factorial design allowed the identification of the concentration of nutrient broth and temperature as the main variables significantly affecting lipase production (P<0.05). In a second step, a D-optimal design was applied to determine the variables optimal values, defined as those yielding maximal lipase production in shaken flasks, thus demonstrating that the optimal concentration of nutrient broth was 3.8 g/l and the optimal culture temperature was 39.5 degrees C. The model was experimentally validated, yielding a lipase production of 2283.70 +/- 118.36 U/mL which represents a 6.7-fold increase in comparison to the non-optimized medium. PMID- 21315195 TI - Proteomic characterization of the Pseudomonas putida KT2440 global response to a monocyclic aromatic compound by iTRAQ analysis and 1DE-MudPIT. AB - Pseudomonas putida KT2440 is a metabolically versatile soil bacterium. To examine the effects of an aromatic compound on the proteome of this bacterium, cytosolic proteins induced by the presence of benzoate and succinate were analyzed using two liquid chromatography (LC)-based proteomic approaches: an isobaric tag for relative and absolute quantitation (iTRAQ) for quantitative analysis and one dimensional gel electrophoresis/multidimensional protein identification technology (1-DE MudPIT) for protein identification. In total, 1286 proteins were identified by 1-DE MudPIT; this represents around 23.3% of the total proteome. In contrast, 570 proteins were identified and quantified by iTRAQ analysis. Of these, 55 and 52 proteins were up- and down-regulated, respectively, in the presence of benzoate. The proteins up-regulated included benzoate degradation enzymes, chemotaxis-related proteins, and ABC transporters. Enzymes related to nitrogen metabolism and pyruvate metabolism were down-regulated. These data suggest that a combination of 1-DE MudPIT and iTRAQ is an appropriate method for comprehensive proteomic analysis of biodegradative bacteria. PMID- 21315196 TI - Differential proteomics of plant development. AB - In this mini-review, recent advances in plant developmental proteomics are summarized. The growing interest in plant proteomics continually produces large numbers of developmental studies on plant cell division, elongation, differentiation, and formation of various organs. The brief overview of changes in proteome profiles emphasizes the participation of stress-related proteins in all developmental processes, which substantially changes the view on functional classification of these proteins. Next, it is noteworthy that proteomics helped to recognize some metabolic and housekeeping proteins as important signaling inducers of developmental pathways. Further, cell division and elongation are dependent on proteins involved in membrane trafficking and cytoskeleton dynamics. These protein groups are less prevalently represented in studies concerning cell differentiation and organ formation, which do not target primarily cell division. The synthesis of new proteins, generally observed during developmental processes, is followed by active protein folding. In this respect, disulfide isomerase was found to be commonly up-regulated during several developmental processes. The future progress in plant proteomics requires new and/or complementary approaches including cell fractionation, specific chemical treatments, molecular cloning and subcellular localization of proteins combined with more sensitive methods for protein detection and identification. PMID- 21315197 TI - Unravelling the regulatory function of FurA in Anabaena sp. PCC 7120 through 2-D DIGE proteomic analysis. AB - The Anabaena sp. PCC 7120 ferric uptake regulator FurA controls iron homeostasis and appears implicated in a broad regulatory network, whereas failures to eliminate wild-type copies of furA gene from the polyploid genome suggest essential functions. In the present study, we comparatively analyzed the proteomes of a furA-overexpressing strain and its parental wild-type in conjunction with subsequent semi-quantitative RT-PCR and electrophoretic mobility shift assays, in order to identify direct transcriptional targets and unravel new biological roles of FurA. The results of such approach drove us to find 10 novel direct targets belonging to different functional categories including photosynthesis, energy metabolism, oxidative stress defences, redox regulation, signal transduction mechanisms, DNA replication, thiamine biosynthesis and heterocyst differentiation. Two peroxiredoxins and the thioredoxin reductase exhibited the most significant changes in both mRNA level and protein abundance under a FurA overexpression background, indicating a connection between iron metabolism, redox signalling and oxidative stress defences. A FurA box consensus sequence was ill-defined. The results suggest that particular DNA structures rather than a defined sequence govern FurA regulation of its target genes. Overall, the results provide new insights into the FurA regulon in Anabaena sp. PCC 7120. PMID- 21315198 TI - Subtle proteome differences identified between post-dormant vegetative and floral peach buds. AB - Proper development of deciduous tree species, including peach, is accomplished through an annual growth cycle. Freezing avoidance during winter is necessary for tree survival and is achieved by the enclosure of meristems in floral and vegetative buds. To elucidate the role of developmentally regulated protein networks in bud break, proteins of the two bud-types were extracted and analyzed by two-dimensional gel electrophoresis (2-DE). Of the 1107 protein spots that were picked, 475 were identified and annotated assembling the peach bud proteome reference map. The majority of these proteins are involved in stress-response, detoxification, defense, carbohydrate metabolism and energy production. The protein profiles of both bud-types bear high similarity, whereas only 11 proteins were differentially expressed. These proteins were mainly involved in carbon nitrogen homeostasis/metabolism and certain developmental processes to sustain rapid growth of the newly emerging organs. Among these are enzymes that differentially regulate the levels of H(2)O(2) between floral and vegetative buds, potentially promoting sequential bud-break. Distinct Nucleoside Diphosphate Kinase (NDPK) variants in floral and vegetative buds were detected suggesting the potential role of NDPKs in H(2)O(2)-mediated signaling for post-dormant bud break. This study provides data towards a better understanding of dormancy release and bud break. PMID- 21315199 TI - An important indirect drug interaction between dronedarone and warfarin that may be extrapolated to other drugs that can alter gastrointestinal function. PMID- 21315201 TI - Challenge of rehospitalizations for heart failure: potential of natriuretic doses of mineralocorticoid receptor antagonists. PMID- 21315202 TI - Clinical development of pharmacologic agents for acute heart failure syndromes: a proposal for a mechanistic translational phase. AB - Hospitalization for acute heart failure syndromes (AHFS) predicts a poor prognosis, with postdischarge mortality and rehospitalization rates reaching 45% within 60 to 90 days. Despite the use of evidence-based therapies and adherence to national process measures, these event rates have largely remained the same over the past decade. Given the current and growing burden of AHFS, there exists a substantial unmet need for novel therapies that improve outcomes. However, attempts to improve symptoms and/or reduce postdischarge events have failed to produce positive results, either because of safety and/or efficacy. These negative results may be related to the drug itself, the protocol in terms of patient selection and/or end points, and/or the trial execution. Although experts may not agree on the exact reasons to explain the lack of success to date of phase III trials in AHFS, there is agreement that clinical benefits observed in phase II trials were not reproduced in phase III trials. A different approach may be needed. In November of 2009, a meeting was held at the Food and Drug Administration with the primary purpose of identifying the reasons why benefits observed during phase II did not translate into benefits in phase III to improve future trial design. Although multiple domains of trial design were discussed, the participants identified a lack of in-depth understanding of novel molecules before pivotal trials in AHFS as a possible contributor to the disappointing results of recent large trials. In this brief report, we outline the T1 or translational phase of research for AHFS clinical development as an important first step toward greater success in AHFS clinical trials. PMID- 21315204 TI - Atrial fibrillation, anticoagulation, fall risk, and outcomes in elderly patients. AB - Atrial fibrillation (AF) affects 2.5 million patients in the United States. The incidence of this condition increases with age, such that approximately 5% of people > 65 years of age have AF. Because of the lack of organized atrial contraction and thrombus formation in the left atrium, patients with AF are at increased risk of stroke. The estimated risk of stroke among all AF patients is 5% per year. Among patients without mitral stenosis, there is a graded relationship of stroke risk with the number of CHADS2 risk factors. Warfarin is the recommended treatment for embolic stroke prophylaxis in AF in intermediate- to high-risk patients. However, elderly patients who are deemed to be at risk of falls are often not started on warfarin therapy secondary to a perceived higher risk of bleeding complications. These risks have been evaluated, but conclusive data regarding the risk-benefit trade-off are elusive. This review summarizes available data on the use of warfarin in elderly patients with AF, focusing on the risk of bleeding, and will specifically address the utility of falls risk assessment in the decision to initiate warfarin therapy for AF. PMID- 21315203 TI - Lessons learned from a pediatric clinical trial: the Pediatric Heart Network angiotensin-converting enzyme inhibition in mitral regurgitation study. AB - BACKGROUND: Mitral regurgitation is the most common indication for reoperation in children following repair of atrioventricular septal defect (AVSD). We hypothesized that angiotensin-converting enzyme inhibitor therapy would decrease the severity of mitral regurgitation and limit left ventricular volume overload in children following AVSD repair. METHODS: The Pediatric Heart Network designed a placebo-controlled randomized trial of enalapril in this population. The primary aim was to test the effect of enalapril on the change in left ventricular end-diastolic dimension body surface area-adjusted z score. Before the launch of the trial, a feasibility study was performed to estimate the number of patients with at least moderate mitral regurgitation following AVSD repair. TRIAL EXPERIENCE: Seventeen months after the start of the study, 349 patients were screened, 8 were trial eligible, and only 5 were enrolled. The study was subsequently terminated because of low patient accrual. Several factors led to the problems with patient accrual, including (1) the use of criteria to assess disease severity in the feasibility study that were not identical to those used in the trial, (2) failure to achieve equipoise for the study among clinicians and referring physicians, (3) reliance on methodology developed in adult populations with different disease mechanisms, and (4) absence of adequate data to define the natural history of the disease process under study. Progress in the treatment of children with cardiovascular disease will depend on the future of multicenter collaborative clinical trials. The lessons learned from this study may contribute to improvements in this research. PMID- 21315205 TI - Primary percutaneous coronary intervention for acute myocardial infarction: Is it worth the wait? The risk-time relationship and the need to quantify the impact of delay. AB - The efficacy of reperfusion therapy is dependent not only by the duration of symptoms before therapy but also by the baseline risk of the individual and the circumstances (time and context) of the occurrence. All these variables play a crucial role in determining the choice of best therapy (fibrinolysis or primary angioplasty [primary percutaneous coronary intervention, PPCI]), thereby confirming the admonition that one size does not fit all. It is generally accepted that patients are best served by PPCI when times to therapy are equal between PPCI and fibrinolysis, whereas pivotal issues that are less well supported by evidence include whether a single time interval is appropriate with regard to the "acceptable" PPCI-related delay and what degree of transfer-related delay is acceptable in patients presenting "early" to a non-percutaneous coronary intervention (PCI)-capable facility. The aim of this perspective is to use available data to individualize the approach to reperfusion therapy, taking into account temporal delays and the overall mortality risk on a case-by-case basis. PMID- 21315206 TI - Design and rationale of the radial versus femoral access for coronary intervention (RIVAL) trial: a randomized comparison of radial versus femoral access for coronary angiography or intervention in patients with acute coronary syndromes. AB - BACKGROUND: Major bleeding in acute coronary syndromes (ACS) is associated with an increased risk of subsequent mortality and recurrent ischemic events. Observational data and small randomized trials suggest that radial instead of femoral access for coronary angiography/intervention results in fewer bleeding complications, with preserved and possibly improved efficacy. Radial access versus femoral access has yet to be formally evaluated in a randomized trial adequately powered for the comparison of clinically important outcomes. OBJECTIVES: The aim of this study is to evaluate the efficacy and safety of radial versus femoral access for coronary angiography/intervention in patients with ACS managed with an invasive strategy. DESIGN: This was a multicenter international randomized trial with blinded assessment of outcomes. 7021 patients with ACS (with or without ST elevation) have been randomized to either radial or femoral access for coronary angiography/intervention. The primary outcome is the composite of death, myocardial infarction, stroke, or non-coronary artery bypass graft-related major bleeding up to day 30. The key secondary outcomes are (1) death, myocardial infarction, or stroke up to day 30 and (2) non-coronary artery bypass graft-related major bleeding up to day 30. Percutaneous coronary intervention (PCI) success rates will also be compared between the two access sites. CONCLUSIONS: The RIVAL trial will help define the optimal access site for coronary angiography/intervention in patients with ACS. PMID- 21315207 TI - A randomized, partially blinded, multicenter, active-controlled, dose-ranging study assessing the safety, efficacy, and pharmacodynamics of the REG1 anticoagulation system in patients with acute coronary syndromes: design and rationale of the RADAR Phase IIb trial. AB - Anticoagulants are the cornerstone of current acute coronary syndrome (ACS) therapy; however, anticoagulation regimens that aggressively reduce ischemic events are almost uniformly associated with more bleeding. REG1, an anticoagulation system, consists of RB006 (pegnivacogin), an RNA oligonucleotide factor IXa inhibitor, and RB007 (anivamersen), its complementary controlling agent. Phase I and IIa studies defined predictable relationships between doses of RB006, RB007, and degree of antifactor IX activity. The efficacy and safety of REG1 for the treatment of patients with ACS managed invasively and the safety of reversing RB006 with RB007 after cardiac catheterization are unknown. Randomized, partially-blinded, multicenter, active-controlled, dose-ranging study assessing the safety, efficacy, and pharmacodynamics of the REG1 anticoagulation system compared to unfractionated heparin or low molecular heparin in subjects with acute coronary syndrome (RADAR) is designed to assess both the efficacy of the anticoagulant RB006 and the safety of a range of levels of RB006 reversal with RB007. The objectives of RADAR are (1) to determine the safety of a range of levels of RB006 reversal with RB007 after catheterization, (2) to confirm whether a dose of 1 mg/kg RB006 results in near-complete inhibition of factor IXa in patients with ACS, and (3) to assess the efficacy of RB006 as an anticoagulant in patients with ACS undergoing percutaneous coronary intervention. PMID- 21315208 TI - Associations between cardiovascular parameters and uteroplacental Doppler (blood) flow patterns during pregnancy in women with congenital heart disease: Rationale and design of the Zwangerschap bij Aangeboren Hartafwijking (ZAHARA) II study. AB - BACKGROUND: Previous research has shown that women with congenital heart disease (CHD) are more susceptible to cardiovascular, obstetric, and offspring events. The causative pathophysiologic mechanisms are incompletely understood. Inadequate uteroplacental circulation is an important denominator in adverse obstetric events and offspring outcome. The relation between cardiac function and uteroplacental perfusion has not been investigated in women with CHD. Moreover, the effects of physiologic changes on pregnancy-related events are unknown. In addition, long-term effects of pregnancy on cardiac function and exercise capacity are scarce. METHODS: Zwangerschap bij Aangeboren Hartafwijking (ZAHARA) II, a prospective multicenter cohort study, investigates changes in and relations between cardiovascular parameters and uteroplacental Doppler flow patterns during pregnancy in women with CHD compared to matched healthy controls. The relation between cardiovascular parameters and uteroplacental Doppler flow patterns and the occurrence of cardiac, obstetric, and offspring events will be investigated. At 20 and 32 weeks of gestation, clinical, neurohumoral, and echocardiographic evaluation and fetal growth together with Doppler flow measurements in fetal and maternal circulation are performed. Maternal evaluation is repeated 1 year postpartum. IMPLICATIONS: By identifying the factors responsible for pregnancy related events in women with CHD, risk stratification can be refined, which may lead to better pre-pregnancy counseling and eventually improve treatment of these women. PMID- 21315209 TI - Prehospital triage in the ambulance reduces infarct size and improves clinical outcome. AB - BACKGROUND: We evaluated the effect of prehospital triage (PHT) in the ambulance on infarct size and clinical outcome and studied its relationship to the distance of patient's residence to the nearest percutaneous coronary intervention (PCI) center. METHODS: All consecutive ST-segment elevation myocardial infarction patients who were transported to the Isala klinieken from 1998 to 2008 were registered in a dedicated database. Of these, 2,288 (45%) were referred via a spoke center and 2.840 (55%) via PHT. RESULTS: PHT patients were more often treated within 3 hours after symptom onset (46.2% vs 26.8%, P < .001), more often had a post-procedural thrombolysis in myocardial infarction (TIMI) 3 flow (93.0% vs 89.7%, P < .001) had a smaller infarct size (peak creatine kinase 2,188 +/- 2,187 vs 2,575 +/- 2,259 IU/L, P < .001) and had a lower 1-year mortality (4.9% vs 7.0%, P = .002). After multivariate analysis, PHT was independently associated with ischemic time less than 3 hours (OR 2.45, 95% CI 2.13-2.83), a peak creatine kinase less than the median value (OR 1.19, 95% CI 1.04-1.36) and a lower 1-year mortality (OR 0.67, 95% CI 0.50-0.91). The observed differences between PHT patients and the spoke group were more pronounced in the subgroup of patients living >38 km from the PCI center. CONCLUSION: PHT in the ambulance is associated with a shorter time to treatment, a smaller infarct size and a more favorable clinical outcome, especially with longer distance from the patient's residence to the nearest PCI center. Therefore, PHT in the ambulance may reduce the negative effect of living at a longer distance from the PCI center. PMID- 21315210 TI - The influence of time from symptom onset and reperfusion strategy on 1-year survival in ST-elevation myocardial infarction: a pooled analysis of an early fibrinolytic strategy versus primary percutaneous coronary intervention from CAPTIM and WEST. AB - BACKGROUND: The CAPTIM trial suggested a survival benefit of prehospital fibrinolysis (FL) compared to primary percutaneous coronary intervention (PCI) in patients with ST-elevation myocardial infarction (STEMI) with a presentation delay of <2 hours. We examined the relationship between reperfusion strategy and time from symptom onset on 1-year mortality in a combined analysis of 1,168 patients with STEMI. METHODS: Individual patient data from CAPTIM (n = 840, 1997 2000) and the more recent WEST trial (n = 328, 2003-2005) were pooled. RESULTS: Median age was 58 years, 81% were men, and 41% had anterior myocardial infarction; 640 patients were randomized to FL versus 528 patients to PCI. Both arms received contemporary adjunctive medical therapy. Presentation delay (ie, symptom onset to randomization) was similar in FL and PCI patients (median 105 [72-158] vs 106 [74-162] minutes, P = .712). Rescue PCI after FL occurred in 26% and 27%, and 30-day PCI, in 70% and 71% in CAPTIM and WEST, respectively. Mortality was not different between FL and PCI (4.6% vs 6.5%, P = .263); however, the interaction between presentation delay and treatment was significant (P = .043). Benefit with FL was observed with time <2 hours (2.8% [FL] vs 6.9% [PCI], P = .021, hazard ratio [HR] 0.43, 95% CI 0.20-0.91), whereas beyond 2 hours, no treatment difference was observed (6.9% [FL] vs 6.0% [PCI], P = .529, HR 1.23, 95% CI 0.61-2.46). CONCLUSIONS: A strategy of early FL demonstrated a reduction in 1-year mortality compared to primary PCI in early presenters. Time from symptom onset should be a key consideration when selecting reperfusion therapy for STEMI. PMID- 21315211 TI - Has the ClOpidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) of early beta-blocker use in acute coronary syndromes impacted on clinical practice in Canada? Insights from the Global Registry of Acute Coronary Events (GRACE). AB - BACKGROUND: The COMMIT/CCS-2 trial, published in 2005, demonstrated no net benefit of early beta-blocker (BB) therapy in acute coronary syndromes (ACS). We sought to assess the short-term impact of this landmark trial by comparing the use of early BB therapy in patients with a broad spectrum of ACS before and after 2005. METHODS: Using data from the Global Registry of Acute Coronary Events and Canadian Registry of Acute Coronary Events, we compared the rates of BB use within the first 24 hours of presentation in the periods 1999 to 2005 and 2006 to 2008, after stratifying patients by the type of ACS (ST-segment elevation myocardial infarction [STEMI] and non-ST-segment elevation ACS [NSTEACS]) and clinical presentation. RESULTS: Of the 14,231 patients with ACS, 77.7% received BB therapy within 24 hours of presentation (78.5% and 77.4% in the STEMI and NSTEACS groups, respectively). The early use of BB declined in the STEMI group (80.3% to 76.7%, P = .005) but increased in the NSTEACS group (75.4% to 78.9%, P < .001) after 2005. Long-term BB use, higher systolic blood pressure, and higher heart rate were independent predictors of early BB use. Conversely, patients who were female, older, Killip class >1, and had cardiac arrest at presentation were less likely to receive early BB. Multivariable analysis showed a trend toward lower use of BB among patients with STEMI (adjusted odds ratio 0.76, 95% CI 0.57 1.00, P = .055) and a trend toward more frequent BB use among patients with NSTEACS (adjusted odds ratio 1.22, 95% CI 0.96-1.55, P = .11) after 2005. The temporal trends in the early use of BB differed between patients with STEMI and patients with NSTEACS (P for interaction with period <.001). CONCLUSIONS: Most patients with STEMI or NSTEACS were treated with early BB therapy. In accordance with the COMMMIT/CCS-2 trial, patients with lower systolic blood pressure and higher Killip class in the "real world" less frequently received early BB therapy. Since the publication of COMMIT/CCS-2, there has been no significant change in the use of BB in patients with STEMI or NSTEACS after controlling for their clinical characteristics. PMID- 21315212 TI - Incidence and clinical consequences of acquired thrombocytopenia after antithrombotic therapies in patients with acute coronary syndromes: results from the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial. AB - BACKGROUND: The aim of the study was to investigate the incidence and clinical consequences of acquired thrombocytopenia in patients with acute coronary syndromes (ACS) in the ACUITY trial. METHODS: We examined 10,836 patients with ACS randomized to receive heparin plus glycoprotein (GP) IIb/IIIa inhibitor, bivalirudin plus GP IIb/IIIa inhibitor, or bivalirudin monotherapy. RESULTS: Acquired thrombocytopenia developed in 740 (6.8%) patients; mild (100,000-150,000 platelets/mm3), moderate (50,000-100,000 platelets/mm3), and severe (< 50,000 platelets/mm3) developed in 656 (6%), 51 (0.5%), and 33 (0.3%) patients, respectively. Patients with acquired thrombocytopenia, compared with those without, were more likely to develop major bleeding (14% vs 4.3%, P < .0001) at 30 days and had higher rates of mortality (6.5% vs 3.4%, P < .0001) at 1 year. By multivariate analysis, acquired thrombocytopenia was an independent predictor of major bleeding at 30 days (hazard ratio [HR] 1.68, 95% CI 1.04-2.72, P = .03). Moderate and severe acquired thrombocytopenia were predictors of mortality at 1 year (HR 2.89, 95% CI 0.92-9.06, P = .06, and HR 3.41, 95% CI 1.09-10.68, P = .03, respectively). Compared to heparin plus GP IIb/IIIa inhibitor, bivalirudin monotherapy was associated with less declines in platelet count by >25% (7.6% vs 5.6%, P = .0009) and >50% (1.4% vs 0.7%, P = .004) from baseline. CONCLUSIONS: Acquired thrombocytopenia occurs in approximately 1 in 14 patients with ACS treated with antithrombin and antiplatelet medications and is strongly associated with hemorrhagic and ischemic complications. Compared to an anticoagulant regimen including a GP IIb/IIIa inhibitor, administration of bivalirudin monotherapy appears to be associated with less frequent declines in platelet count. PMID- 21315213 TI - Pregnancy in women with corrected tetralogy of Fallot: occurrence and predictors of adverse events. AB - BACKGROUND: In women with corrected tetralogy of Fallot (ToF), pregnancy is associated with maternal cardiac, obstetric, and offspring complications. Our aim is to investigate the magnitude and determinants of pregnancy outcome in women with corrected ToF. METHODS: In this retrospective international multicenter study using 2 congenital heart disease registries, 204 women with corrected ToF were identified. Within this group, 74 women had 157 pregnancies, including 30 miscarriages and 4 terminations of pregnancy. Detailed information on each completed pregnancy (n = 123) was obtained using medical records and supplementary interviews. RESULTS: Cardiovascular events occurred during 10 (8.1%) pregnancies, mainly (supra)ventricular arrhythmias. Obstetric and offspring events occurred in 73 (58.9%) and 42 (33.9%) pregnancies, respectively, including offspring mortality in 8 (6.4%). The most important predictor was use of cardiac medication before pregnancy (odds ratio for cardiac events 11.7, 95% CI 2.2-62.7; odds ratio for offspring events 8.4, 95% CI 1.4-48.6). In pregnancies with cardiovascular events, significantly more small-for-gestational age children were born (P value < .01). CONCLUSIONS: Cardiovascular, obstetric, and offspring events occur frequently during pregnancies in women with ToF. Maternal use of cardiovascular medication is associated with pregnancy outcome, and maternal cardiovascular events during pregnancy are highly associated with offspring events. PMID- 21315214 TI - Left atrial reverse remodeling and functional improvement after mitral valve repair in degenerative mitral regurgitation: a real-time 3-dimensional echocardiography study. AB - BACKGROUND: Severe mitral regurgitation is often associated with left atrium (LA) enlargement, which is a well-known predictor of adverse cardiovascular outcomes. However, only few data are available on the effect of mitral valve (MV) repair on LA size. The aim of this study was to evaluate, using real-time 3-dimensional echocardiography, the changes in LA volumes after MV repair. METHODS: A total of 65 patients with severe mitral regurgitation due to MV prolapse and scheduled for repair at an early stage were enrolled. Before the procedure, real-time 3 dimensional echocardiography was performed to assess LA volumes (maximum, before atrial active contraction [preA], and minimum). The same evaluation was repeated 6 months and 1 year after MV repair. Twenty healthy subjects matched for age and gender were enrolled as a control group. RESULTS: Before MV repair, patients showed significantly higher values of LA volumes (maximum 43 +/- 14 mL/m2, preA 33 +/- 12 mL/m2, minimum 23 +/- 11 mL/m2) as compared to controls (maximum 22 +/- 6 mL/m2, preA 13 +/- 4 mL/m2, minimum 8 +/- 3 mL/m2). Six months after the operation, LA volumes significantly decreased (maximum 25 +/- 8 mL/m2, preA 18 +/ 8 mL/m2, minimum 13 +/- 5 mL/m2), with a further reduction at 1-year follow-up (maximum 23 +/- 7 mL/m2, preA 15 +/- 7 mL/m2, minimum 11 +/- 5 mL/m2), resulting in values similar to controls. The extent of LA reverse remodeling was inversely correlated with age (r = -0.42) and postoperative transmitral mean pressure gradient (r = -0.32), whereas a positive correlation was found with the reduction in left ventricular volume after MV repair (r = 0.35). DISCUSSION: In patients with severe mitral regurgitation due to MV prolapse, MV repair, when performed at an early stage, results in a significant LA reverse remodeling. PMID- 21315215 TI - Certoparin versus unfractionated heparin to prevent venous thromboembolic events in patients hospitalized because of heart failure: a subgroup analysis of the randomized, controlled CERTIFY study. AB - BACKGROUND: Despite the elevated risk for developing venous thromboembolic events in patients with heart failure, there are no randomized, double-blind, controlled trial data on the comparison of low-molecular-weight heparin with unfractionated heparin (UFH) in this patient population. METHODS: This was a subgroup analysis of the CERTIFY trial, which included 3,239 nonsurgical, acutely ill medical patients 70 years or older. Patients were randomized to receive 3,000-U anti-Xa certoparin once daily or 5,000-IU UFH 3 times a day. The analysis was performed on a subgroup of 542 patients diagnosed with heart failure at hospital admission. RESULTS: Patients with heart failure differed from patients without heart failure in that they were more likely using antiplatelets (67.2% vs 48.9%; P < .0001) and had a lower glomerular filtration rate (8.0% vs 5.5%; <= 30 mL/min per 1.73 m2; P = .0232). Thromboembolic risk was comparable except for a higher incidence of distal deep venous thrombosis (DVT) in patients with heart failure (10.80% vs 7.26%; P = .0144). Within the heart failure population, patient characteristics were comparable between randomized treatment groups. The incidence of the primary end point (proximal DVT, symptomatic nonfatal pulmonary embolism, and venous thromboembolism-related death combined) was numerically, slightly smaller with certoparin (3.78% vs 4.74% with UFH; odds ratio 0.79, 95% CI 0.32-1.94), and the incidence of major bleeding was 0.72% with certoparin versus 0.38% with UFH. CONCLUSIONS: Patients hospitalized for heart failure are at high risk for developing distal DVT and bleeding complications compared with acutely ill medical patients without heart failure. Within the heart failure population, the observed differences in prophylactic efficacy between 3,000-U anti-Xa certoparin once daily and 5,000-IU UFH 3 times a day were similar to those observed in the overall study population; this suggests that certoparin might be at least as effective as UFH also in this subgroup. There were no relevant differences in bleeding risk or frequency of adverse events. PMID- 21315216 TI - A randomized controlled trial evaluating the safety and efficacy of cardiac contractility modulation in advanced heart failure. AB - BACKGROUND: Cardiac contractility modulation (CCM) delivers nonexcitatory electrical signals to the heart during the absolute refractory period intended to improve contraction. METHODS: We tested CCM in 428 New York Heart Association class III or IV, narrow QRS heart failure patients with ejection fraction (EF) <= 35% randomized to optimal medical therapy (OMT) plus CCM (n = 215) versus OMT alone (n = 213). Efficacy was assessed by ventilatory anaerobic threshold (VAT), primary end point, peak Vo2 (pVo2), and Minnesota Living with Heart Failure Questionnaire (MLWFQ) at 6 months. The primary safety end point was a test of noninferiority between groups at 12 months for the composite of all-cause mortality and hospitalizations (12.5% allowable delta). RESULTS: The groups were comparable for age (58 +/- 13 vs 59 +/- 12 years), EF (26% +/- 7% vs 26% +/- 7%), pVo2 (14.7 +/- 2.9 vs 14.8 +/- 3.2 mL kg-1 min-1), and other characteristics. While VAT did not improve at 6 months, CCM significantly improved pVo2 and MLWHFQ (by 0.65 mL kg-1 min-1 [P = .024] and -9.7 points [P < .0001], respectively) over OMT. Forty-eight percent of OMT and 52% of CCM patients experienced a safety end point, which satisfied the noniferiority criterion (P = .03). Post hoc, hypothesis-generating analysis identified a subgroup (characterized by baseline EF >= 25% and New York Heart Association class III symptoms) in which all parameters were improved by CCM. CONCLUSIONS: In the overall target population, CCM did not improve VAT (the primary end point) but did improve pVo2 and MLWHFQ. Cardiac contractility modulation did not have an adverse affect on hospitalizations or mortality within the prespecified boundaries. Further study is required to clarify the role of CCM as a treatment for medically refractory heart failure. PMID- 21315217 TI - Effects of n-3 polyunsaturated fatty acids on malignant ventricular arrhythmias in patients with chronic heart failure and implantable cardioverter defibrillators: A substudy of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca (GISSI-HF) trial. AB - BACKGROUND: The antiarrhythmic effects of n-3 polyunsaturated fatty acids (n 3PUFA) in ischemic heart disease have been demonstrated; however, studies in patients surviving malignant ventricular arrhythmias of different etiologies treated with an implantable cardioverter-defibrillator (ICD) have given conflicting results. The purpose of this study was to assess the antiarrhythmic effect of n-3PUFA versus placebo in 566 patients with heart failure enrolled in the GISSI-HF trial who received an ICD for secondary or primary prevention of ventricular fibrillation (VF) or tachycardia (VT). METHODS: Clinical data and arrhythmic event recordings extracted from the device memory were obtained. We tested the treatment effect by a multivariate Cox model adjusting for all clinical parameters associated with the primary end point defined as time to first appropriate ICD discharge for VT/VF. RESULTS: In the 566 patients with at least one recorded follow-up visit, 1363 VT and 316 VF episodes were terminated by ICD pacing or shock over a median follow-up of 928 days. The incidence of the primary end point event was 27.3% in the n-3PUFA group and 34.0% in the placebo group (adjusted hazard rate = 0.80, 95% CI 0.59-1.09, P = .152). Patients who received 1, 2 to 3, or >3 ICD discharges were 8.9%, 7.1%, and 11.1% in the n 3PUFA group, compared with slightly higher rates of 11.1%, 10.7%, and 12.1% in the placebo group (overall P = .30). Patients with the highest 3-month increase in plasma n-3PUFA had a somewhat lower incidence of arrhythmic events. CONCLUSIONS: The results of this study, though not statistically significant, support prior evidences of an antiarrhythmic effect of n-3PUFA in patients with ICD, although they leave open the issue of whether this effect leads to a survival benefit. PMID- 21315218 TI - Common oral mucosal diseases, systemic inflammation, and cardiovascular diseases in a large cross-sectional US survey. AB - BACKGROUND: Inflammation of the gingivae (periodontitis) has been associated with raised serum biomarkers of inflammation, sub-clinical markers of atherosclerosis, and increased risk of and/or mortality from cardiovascular disease (CVD). There remain little information regarding the association between other common oral inflammatory disease, systemic inflammation, and CVD. The objective of the study was to assess the association between common oral mucosal diseases, circulating markers of inflammation, and increased prevalence of CVD in a cross-sectional survey of a nationally representative sample of the noninstitutionalized civilians in the United States. METHODS: Data for this study are from 17,223 men and women aged >= 17 years who received oral examination as part of the Third National Health and Nutrition Examination Survey. The primary and secondary outcome measures were the association of oral mucosal diseases with raised serum levels of C-reactive protein/fibrinogen and increased prevalence of CVD, respectively. Adjustment for common confounding factors was performed. RESULTS: Having oral mucosal disease was associated with systemic inflammation (serum levels of C-reactive protein >= 10 mg/dL) (odds ratio 1.41, 95% CI 1.02-1.94). Individuals with oral mucosal disease were 1.36 times (95% CI 1.02-1.80) more likely to have history of myocardial infarction and 1.33 times (95% CI 1.03-1.71) more likely to report angina than unaffected individuals. All associations were independent of common confounding factors. CONCLUSIONS: This is the first study to suggest that common oral mucosal diseases are independently associated with raised markers of systemic inflammation and history of CVD. PMID- 21315219 TI - Reducing cardiovascular disease risk in medically underserved urban and rural communities. AB - OBJECTIVES: The aim of this study is to evaluate methods for lowering cardiovascular disease (CVD) risk in asymptomatic urban and rural underserved subjects. BACKGROUND: Medically underserved populations are at increased CVD risk, and systems to lower CVD risk are needed. Nurse management (NM) and telemedicine (T) systems may provide low-cost solutions for this care. METHODS: We randomized 465 subjects without overt CVD, with Framingham CVD risk >10% to NM with 4 visits over 1 year, or NM plus T to facilitate weight, blood pressure (BP), and physical activity reporting. The study goal was to reduce CVD risk by 5%. RESULTS: Three hundred eighty-eight subjects completed the study. Cardiovascular disease risk fell by >= 5% in 32% of the NM group and 26% of the T group (P, nonsignificant). In hyperlipidemic subjects, total cholesterol decreased (NM -21.9 +/- 39.4, T -22.7 +/- 41.3 mg/dL) significantly. In subjects with grade II hypertension (systolic BP >= 160 mm Hg, 24% of subjects), both NM and T groups had a similar BP response (average study BP: NM 147.4 +/- 17.5, T 145.3. +/- 18.4, P is nonsignificant), and for those with grade I hypertension (37% of subjects), T had a lower average study BP compared to NM (NM 140.4 +/- 16.9, T 134.6 +/- 15.0, P = .058). In subjects at high risk (Framingham score >= 20%), risk fell 6.0% +/- 9.9%; in subjects at intermediate risk (Framingham score >= 10, < 20), risk fell 1.3% +/- 4.5% (P < .001 compared to high-risk subjects). Medication adherence was similar in both high- and intermediate-risk subjects. CONCLUSIONS: In 2 underserved populations, CVD risk was reduced by a nurse intervention; T did not add to the risk improvement. Reductions in BP and blood lipids occurred in both high- and intermediate-risk subjects with greatest reductions noted in the high-risk subjects. Frequent communication using a nurse intervention contributes to improved CVD risk in asymptomatic, underserved subjects with increased CVD risk. Telemedicine did not change the effectiveness of the nurse intervention. PMID- 21315220 TI - Incidence and clinical outcome of minor surgery in the year after drug-eluting stent implantation: results from the Evaluation of Drug-Eluting Stents and Ischemic Events Registry. AB - BACKGROUND: The aim of the study was to describe the incidence and consequences of minor surgery after drug-eluting stent (DES) implantation. METHODS: The Evaluation of Drug-Eluting Stents and Ischemic Events (EVENT) Registry prospectively enrolled unselected patients undergoing percutaneous coronary intervention at 47 US centers between July 2004 and December 2007. We examined 8,323 patients who received a DES in EVENT to determine the frequencies of minor surgery and postoperative adverse events. RESULTS: Minor surgery (defined as procedures not requiring a major surgical incision) was performed in 164 (2.0%) of 8,323 patients <1 year after stenting, as follows: pacemaker/defibrillator implantation (46%), eye surgery (17%), orthopedic (9%), dermatologic (8%), endovascular (6%), and gastrointestinal procedures (5%). Compared with patients who did not undergo minor surgery, those who did were older, had more comorbidities, had more extensive coronary disease, and were more likely to have received warfarin after stenting. Only 1 (0.6%, 95% CI 0.0%-3.4%) of 164 patients had an event (stent thrombosis causing myocardial infarction) during the first week after minor surgery; this rate was slightly higher than the background rate of ischemic events in the study population (exact mid P = .01). Clopidogrel use at 12 months was similar between patients who did and those who did not undergo minor surgery (65.2% vs 65.5%, P = .95). CONCLUSIONS: In the EVENT Registry, minor surgery was performed in 2% of patients in the first year after DES implantation. The risk of stent thrombosis during the first week after surgery was increased slightly compared with background rates, but the absolute event rate was low (0.6%). PMID- 21315221 TI - Qualitative assessment of neointimal tissue after drug-eluting stent implantation: comparison between follow-up optical coherence tomography and intravascular ultrasound. AB - BACKGROUND: Characterization of neointimal tissue is essential to understand the pathophysiology of in-stent restenosis after drug-eluting stent (DES) implantation. We compared the morphological characteristics of neointimal tissue as assessed by optical coherence tomography (OCT) and intravascular ultrasound (IVUS) in patients treated with DES. METHODS: A total of 243 patients (250 lesions) underwent follow-up OCT and IVUS after DES implantation. RESULTS: Mean time interval from DES implantation to follow-up OCT/IVUS was 12.0 +/- 9.3 (range 2.8-68.5) months. Percent neointimal hyperplasia (NIH) cross-sectional area (CSA) was calculated as (NIH CSA/stent CSA) * 100 for receiver-operating characteristic analysis of NIH detection by IVUS; the optimal cutoff value of percent NIH CSA was 14.7%, as determined by OCT (sensitivity 0.887, specificity 0.790). Neointimal hyperplasia was detected by both OCT and IVUS in 121 of 250 lesions and categorized as homogenous (OCT n = 74, IVUS n = 107), heterogeneous (OCT n = 34, IVUS n = 4), or layered (OCT n = 13, IVUS n = 10). Of the 121 NIH lesions, nonhomogenous NIH was detected in 14 (11.6%) by IVUS and 47 (38.8%) by OCT. Optical coherence tomography and IVUS assessments of NIH morphology showed a moderate correlation (P < .001, r = 0.455); however, assessments differed in 37 (30.6%) of 121 lesions. CONCLUSION: Optical coherence tomography-assessed NIH morphology might be different from that by IVUS in about 30% of the lesions that were treated with DES implantation. PMID- 21315222 TI - Standard versus high loading doses of clopidogrel in Asian ST-segment elevation myocardial infarction patients undergoing percutaneous coronary intervention: insights from the Korea Acute Myocardial Infarction Registry. AB - BACKGROUND: The optimal loading dose of clopidogrel in Asian patients with ST segment elevation myocardial infarction (STEMI) has not been fully investigated. We compared bleeding, vascular complications, and midterm outcomes of a 300-mg versus a 600-mg loading dose of clopidogrel in a large series of Korean patients with STEMI undergoing primary percutaneous coronary intervention (PCI). METHODS: A total of 2,664 STEMI patients (age 61.96 +/- 11.91 years, men 70.4%) who underwent primary PCI were enrolled in this study. The patients were divided into a standard loading dose group (300 mg; n = 1,447 patients) and a high loading dose group (600 mg; n = 1,217 patients). Bleeding and vascular complications, and in-hospital and clinical outcomes up to 12 months were compared between the 2 groups. RESULTS: In-hospital bleeding and vascular complications were similar between the 2 groups. There were no differences in bleeding and vascular complications and in 1- and 12-month clinical outcomes, including mortality, myocardial infarction, repeated PCI, and major adverse cardiac events, between the 2 groups. These findings were consistent even after the propensity score matched analysis. CONCLUSIONS: The standard loading dose of clopidogrel may be as safe and similarly effective as the high loading dose in Asian STEMI patients undergoing primary PCI. PMID- 21315223 TI - Comparison of 2 point-of-care platelet function tests, VerifyNow Assay and Multiple Electrode Platelet Aggregometry, for predicting early clinical outcomes in patients undergoing percutaneous coronary intervention. AB - BACKGROUND: Various platelet function tests are currently used to measure responsiveness to antiplatelet therapy. We sought to compare 2 point-of-care platelet function tests, VerifyNow Assay (Accumetrics, San Diego, CA) and Multiple Electrode Platelet Aggregometry (MEA) (Dynabyte, Munich, Germany), for predicting early clinical outcomes after percutaneous coronary intervention. METHODS: Platelet reactivity in the arachidonic acid-induced and adenosine diphosphate (ADP)-induced platelet aggregation was measured simultaneously with the VerifyNow Assay and MEA in 222 patients undergoing percutaneous coronary intervention between August and October 2009. We investigated the correlations between the 2 tests and performed receiver operating characteristic curve analysis for major adverse cardiovascular events (MACE), a composite of death, myocardial infarction (MI), stroke, and target vessel revascularization, at 30 days. RESULTS: Major adverse cardiovascular events occurred in 19 patients (8.6%), including 14 patients with periprocedural MI and 5 patients with stroke. Correlations were weak between the 2 tests in the arachidonic acid-induced (Spearman r = 0.189, P = .006) and ADP-induced platelet reactivity (Spearman r = 0.390, P < .001). Although the VerifyNow P2Y12 Assay (Accumetrics) was able to predict periprocedural MI (area under the aggregation curve 0.680, P = .024) and 30-day MACE (area under the aggregation curve 0.649, P = .032), VerifyNow Aspirin Assay (Accumetrics), MEA ASPI test, and MEA ADP test failed to predict such clinical events. Hyporesponsiveness to clopidogrel based on the VerifyNow Assay was associated with about a 6-fold increased risk of MACE at 30 days. CONCLUSIONS: Hyporesponsiveness to clopidogrel measured by VerifyNow Assay was able to identify patients with dual antiplatelet therapy who were at higher risk for periprocedural MI and MACE at 30 days. Further randomized studies are required to validate the effectiveness of different platelet function tests for predicting long-term clinical outcomes. PMID- 21315224 TI - Impact of baseline thrombocytopenia on the early and late outcomes after ST elevation myocardial infarction treated with primary angioplasty: analysis from the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial. AB - BACKGROUND: Thrombocytopenia (TP) is a common abnormality in patients presenting with acute coronary syndrome. Whether baseline TP has any influence on the outcome of patients treated with primary angioplasty for acute myocardial infarction is unknown. METHODS: We sought to detect the impact of baseline TP on the early and late outcomes of patients with ST-elevation myocardial infarction in the HORIZONS-AMI trial that included a protocol of immediate angiography and primary percutaneous coronary intervention. RESULTS: Baseline TP was found in 4.2% of patients and was associated with a higher incidence of cardiovascular mortality, major bleeding, and major cardiovascular events at short- and long term follow-up. The 30-day rates of death, major bleeding, major cardiac events, and major cardiac events plus major bleeding were 6.2%, 11.9%, 9.6%, and 18.5% in the TP group, respectively, compared with 2.1%, 7%, 5.2%, and 10.8% in those without TP (P < .05 for all). Similarly, event rates at 2 years were 11.3%, 12.7%, 24.7%, and 30.8% compared with 5.1%, 7.9%, 18.5%, and 23.3% (P < .05). By multivariate analysis, baseline TP was an independent predictor of 30-day net adverse clinical events but not of any 2-year events. CONCLUSIONS: We found that baseline TP in patients with ST-elevation myocardial infarction undergoing routine angiography and primary percutaneous coronary intervention is strongly associated with early adverse events and is a maker of late events, related to both ischemia and bleeding. PMID- 21315225 TI - Temporal changes in the outcomes of patients with diabetes mellitus undergoing percutaneous coronary intervention in the National Heart, Lung, and Blood Institute dynamic registry. AB - BACKGROUND: Patients with diabetes mellitus (DM) are at higher risk for adverse outcomes following percutaneous coronary intervention (PCI). METHODS: To determine whether outcomes have improved over time, we analyzed data from 2,838 consecutive patients with medically treated DM, including 1,066 patients (37.6%) treated with insulin, in the National Heart, Lung, and Blood Institute Dynamic Registry undergoing PCI registered in waves 1 (1997-1998), 2 (1999), 3 (2001 2002), 4 (2004), and 5 (2006). We compared baseline demographics and 1-year outcomes in the overall cohort and in analyses stratified by recruitment wave and insulin use. RESULTS: Crude mortality rates by chronological wave were 9.5%, 12.5%, 8.9%, 11.6%, and 6.6% (P value(trend) = .33) among those treated with insulin and, respectively, 9.7%, 6.5%, 4.1%, 5.4%, and 4.7% (P value(trend) = .006) among patients treated with oral agents,. The adjusted hazard ratios of death, myocardial infarction (MI), and overall major adverse cardiovascular events (death, MI, revascularization) in insulin-treated patients with DM in waves 2 to 5 as compared with wave 1 were either higher or the same. In contrast, the similar adjusted hazard ratios for oral agent-treated patients with DM were either similar or lower. CONCLUSIONS: Significant improvements over time in adverse events by 1 year were detected in patients with DM treated with oral agents. In insulin-treated diabetic patients, despite lower rates of repeat revascularization over time, death and MI following PCI have not significantly improved. These findings underscore the need for continued efforts at optimizing outcomes among patients with DM undergoing PCI, especially those requiring insulin treatment. PMID- 21315226 TI - Clopidogrel loading dose and bleeding outcomes in patients undergoing urgent coronary artery bypass grafting. AB - BACKGROUND: Coronary artery bypass grafting (CABG) performed within 5 days of clopidogrel administration is associated with increased bleeding. The impact of clopidogrel loading dose is unknown. We examined the effect of clopidogrel loading dose on bleeding outcomes in patients undergoing urgent CABG. METHODS: Clinical outcomes were examined retrospectively for 196 consecutive patients undergoing urgent CABG within 5 days of a clopidogrel loading dose between January 2003 and June 2009. Major bleeding was defined as a fall in hemoglobin > 5 g/dL, fatal or intracranial bleeding, or cardiac tamponade. RESULTS: One hundred forty-eight patients received 300 mg and 48 patients received >= 600 mg clopidogrel loading. Patients were predominantly male (78%) with a mean age of 66 +/- 10 years. Mean duration from clopidogrel loading to CABG was 3.0 +/- 1.5 and 3.0 +/- 1.6 days for the 300 and 600 mg loading doses, respectively. Major bleeding occurred in 47% of patients receiving 300 mg and 73% of patients receiving >= 600 mg clopidogrel loading (P = .002). Compared with 300 mg, patients receiving >= 600 mg had greater 24-hour chest tube output (391 +/- 251 vs 536 +/- 354 mL, P = .01), stayed longer in surgical intensive care (4.3 +/- 4.1 vs 5.0 +/- 3.1 days, P = .0001), and trended toward greater reoperation for bleeding (5% vs 12%, P = .09). Following multivariate analysis, clopidogrel loading dose >= 600 mg (odds ratio 2.8, CI 1.2-6.6), preoperative hemoglobin (3.4, 2.7-5.0 per 1 g/dL increase), and female gender (2.9, 1.1-7.4) predicted major bleeding. CONCLUSIONS: Higher clopidogrel loading doses are associated with increased bleeding when administered within 5 days of CABG. The development of shorter-acting, reversible, oral antiplatelet agents may reduce perioperative bleeding in this population. PMID- 21315227 TI - Factors associated with the physical activity level of children who have the Fontan procedure. AB - BACKGROUND: Children with complex heart defects are sedentary, with activity level unrelated to exercise capacity. We sought to identify factors associated with physical activity level for children who have the Fontan procedure. METHODS: We used a cross-sectional study, 64 children (25 female, 5-11 years) after Fontan. Measurements were weekly minutes of moderate-to-vigorous physical activity, cardiac status, resting/exercise cardiopulmonary capacity, gross motor skill, health-related endurance/strength/body composition, and parent/child activity perceptions. RESULTS: Participants performed 361 +/- 137 minutes per week of moderate-to-vigorous physical activity. Increased activity related to antithrombotic medication use (86 min/wk), lower resting heart rate (3 min/wk), higher weekday outdoor time (0.7 minutes per outside minute), lower family income (13 minutes per $10,000), and higher parent rating of child's activity relative to peers (36 min/wk). Factors related to decreased activity were winter season ( 84 min/wk), history of arrhythmia (-96 min/wk), and greater child confidence in own ability to be active (-113 min/wk). CONCLUSIONS: Physical activity after the Fontan procedure is primarily associated with factors unrelated to cardiac status. Interventions that impact these modifiable factors would be expected to enable these children to achieve the recommended activity levels associated with optimal health. PMID- 21315230 TI - The CREST results: another piece to an unfinished puzzle. PMID- 21315231 TI - A long-term survival score improves preoperative prediction of survival following major vascular surgery. AB - BACKGROUND: In a previous study it has been shown that a long-term survival score (LTSS), composed of Lee's Revised Cardiac Risk Index (RCRI) criteria supplemented by age, preoperative electrocardiography (EKG) features, and all types of diabetes to the RCRI criteria, predicts long-term (3-15 years) survival after major vascular surgery. The present study aimed to investigate the performance of LTSS in predicting earlier survival (3 months-3 years) as compared with the RCRI. METHODS: Data from 921 consecutive patients undergoing major vascular surgery (624 patients at Hadassah Medical Center [HMC] and 296 patients in Beth Israel Deaconess Medical Center [BIDMC]) were collected retrospectively. The LTSS was seven points that included the five RCRI factors as well as age >65 years and ST segment depression on preoperative EKG. Logistic regression and receiver operating characteristic curve (ROC) curve analyses were used to compare the 3 months-3 years mortality between the RCRI and LTSS. RESULTS: The Beth Israel Deaconess Medical Center patients were sicker than the Hadassah Medical Center patients, with higher RCRI (1.2 +/- 1.0 vs. 0.81 +/- 0.83, p < 0.001) and LTSS (2.6 +/- 1.4 vs. 1.7 +/- 1.2, p < 0.001) and higher 3-years mortality (36.3% vs. 20.7%, p = 0.005). The LTSS predicted mortality better than RCRI as measured by the area under the ROC curves at all time points between 6 months (0.66 +/- 0.03 vs. 0.57 +/- 0.04, p = 0.02) and 3 years (0.70 +/- 0.02 vs. 0.61 +/- 0.02, p < 0.0001) in both institutions, but not 3-months mortality. The LTSS also provided better discrimination between each adjacent two-risk score than the RCRI. CONCLUSIONS: Age >65 years, ST-segment depression on preoperative 12-lead EKG, and all types of diabetes added to the RCRI significantly improved the preoperative prediction of mortality after 6 months following major vascular surgery. PMID- 21315232 TI - Impact of race on infrainguinal angioplasty and stenting. AB - BACKGROUND: Over the last decade, catheter-based interventions on lower extremity arteries have been used with increasing frequency. However, the effect of racial background on the outcome of lower extremity endovascular interventions for peripheral arterial disease is unknown. The purpose of this study was to determine the effect of patients' race on the durability of angioplasty and stenting performed on the superficial femoral and popliteal arteries. METHODS: The records of all patients undergoing percutaneous intervention on the lower extremity arteries during a 14-year period were reviewed. During a 44-month period (2003-2007), all patients underwent primary stenting as part of a prospective study protocol. Indication for intervention, TransAtlantic InterSociety Consensus II classification, runoff anatomy, site of intervention, and the placement of stents were noted. Results were analyzed by race. Kaplan Meier life survival curves were plotted and differences between groups tested by log-rank method. Cox proportional hazards regression model was used to perform the multivariate analysis. RESULTS: Between 1994 and 2007, a total of 374 percutaneous interventions were performed on the superficial femoral and popliteal arteries in 280 patients. Of these, 182 procedures were angioplasties and 192 included both angioplasty and stenting. The study group consisted of 60% Caucasians, 23% Hispanics, 12% African Americans, and 5% Asians. No difference in primary patency rates was noted between individuals belonging to different races. However, in those undergoing angioplasty alone, Caucasians had the highest rate of failure, followed by Hispanics, African Americans, and then Asians (p < 0.002). No difference in patency rates between races was seen in patients undergoing angioplasty with stenting. For the entire group, dyslipidemia, TransAtlantic InterSociety Consensus II C and D lesions, and angioplasty without stenting negatively affected primary patency. CONCLUSIONS: Race does not appear to influence the durability of catheter-based procedures performed on the superficial femoral and popliteal arteries. However, in patients who underwent angioplasty alone, it was noted that Caucasians had the highest rates of failure and Asians the lowest. However, this difference was no longer apparent when stents were used. PMID- 21315233 TI - Endovascular nitinol stenting for long occlusive disease of the superficial femoral artery in critical limb ischemia: a single-center, mid-term result. AB - BACKGROUND: The aim of the present study was to assess the mid-term patency rate of nitinol stent implantation in patients with long superficial femoral artery (SFA) stenosis or occlusion. This is a retrospective, single-center study. METHODS: The data of 138 patients were retrospectively assessed in our center to determine the patency rate after nitinol stenting of the SFA. MATERIALS: Data for 165 limbs from 138 patients were collected. Each limb showed a long lesion with a total occlusion of >10 cm and mean lesion length of 20.35 +/- 9.46 cm (range, 10 32 cm). Nitinol self-expanding stent implantations were performed in each limb. A total of 258 stents were implanted into 165 limbs (average, 1.56 stents/limb). Each patient received clinical and ultrasound/computerized tomographic angiography/magnetic resonance angiography evaluations before the procedure and underwent clinical status evaluation and an ankle-brachial index test at discharge and at 12, 24, and 36 months thereafter. RESULTS: The initial technical success rate of revascularization was 91.51% (151/163). During follow-up, nine patients died because of myocardial infarction, cerebral infarction, and pneumonia, and 14 patients were lost to follow-up. The mean follow-up period for 150 limbs from 124 patients was 25.46 months (range, 6-51). During follow-up, 19 in-stent restenoses and 15 occlusions were diagnosed. In all, 30 re-interventions were performed, including six balloon angioplasties, three secondary cutting balloon angioplasties, 10 restenting procedures, four bypass surgeries, two bone marrow stem cell transplantations, and five limb amputations. Analysis showed the primary patency rates at 12, 24, and 36 months were 92.4%, 78.3%, and 62.1%, respectively, and the overall assisted-primary patency rates were 94.4%, 84.6%, and 75.8%, respectively. CONCLUSIONS: Nitinol self-expanding stent implantation seems to be a good choice for older patients with long SFA occlusions. Although the short- and mid-term patency results were good, more observations are needed to assess its long-term efficiency. PMID- 21315234 TI - Quantification and location of Chlamydia pneumoniae-specific antigen in the walls of abdominal aortic aneurysms. AB - BACKGROUND: To evaluate the prevalence and quantity of Chlamydia pneumoniae specific antigen in the three layers (intima, media, and adventitia) of abdominal aortic aneurysms (AAAs), so as to further investigate the pathogenesis of AAAs. METHODS: Aortic walls were collected from 20 patients with AAA and 11 healthy organ donors. Immunohistochemistry was used to identify the C pneumoniae-specific antigen, and image analysis system was used to quantify and locate it. RESULTS: The positive rate of C pneumoniae-specific antigen was higher in the AAA group than in the control group (100% vs. 54.54%, p = 0.003), positive intensity decreased from the tunica intima to the adventitia in the AAA group (16.32% +/- 2.13%, 14.84% +/- 1.80%, and 14.25% +/- 1.67%, respectively, p = 0.003). In the control group, positive cells were mainly found in focal lesion areas. CONCLUSION: We have demonstrated the presence and differentiation of C pneumoniae specific antigen in the three layers of AAAs, which are in accordance with pathology, thus suggesting a pathogenic role of the antigen. PMID- 21315235 TI - Dislodged self-expanding carotid stent delivery sheath marker ring leading to emergent surgery. AB - Endovascular carotid artery stenting has evolved over recent years to become a favorable alternative treatment option for cervical carotid artery stenosis. Potential complications include procedural embolism, carotid artery dissection, and hemodynamic instability. Events caused by device defect are unusual. We hereafter present a case in which the metallic marker ring on the delivery sheath dislodged and emergent surgery had to be performed to retrieve the locked stent. PMID- 21315236 TI - Preaortic left primitive iliac vein: two case studies. AB - Although congenital abnormalities of the inferior vena cava (IVC) are rare, they can lead to serious hemorrhagic complications, especially during aortoiliac surgery. The most frequent complications include the double IVC, left-sided IVC, and the left retroaortic renal vein isolated or associated with a preaortic renal vein forming a periaortic venous collar. Preaortic primitive iliac vein represents an exceptional anatomic entity and only a few cases have been reported in previously published data (Ruemenapf et al., J Vasc Surg 1998;27:767-771; Schiavetta et al., J Vasc Surg 1998;28:719-722; Shindo et al., Ann Vasc Surg 2000;14:393-396; Balbridge and Canos, Arch Surg 1987;122:1184-1188; Honkasalo et al., Acta Chir Scand 1983;149:717-719; Brener et al., Arch Surg 1974;108:159-165; Vohra and Leiberman, Eur J Vasc Surg 1991;5:209-211; McClure and Huntington, Am Anat Memoirs 1929;15:1-55). In this study, we report two cases of preaortic left primitive iliac vein. The first patient was a male who was operated on for an aortobiiliac aneurysm. The second was of a female patient who was operated on for an interaortocaval lymphadenopathy that resulted from ganglion curettage performed for ovarian cancer. PMID- 21315237 TI - Carotid artery stenting. PMID- 21315238 TI - Monitoring epidemic of tobacco use, promote tobacco control. PMID- 21315239 TI - Findings from 2010 Global Adult Tobacco Survey: implementation of MPOWER policy in China. AB - OBJECTIVE: To assess the implementation of five key tobacco control policies in China: protection from second-hand smoke (SHS); offering help to quit; health warnings regarding tobacco use; the enforcement of bans on tobacco advertising, promotion, and sponsorship; and increasing tobacco taxes and prices. METHODS: Using 2010 Global Adults Tobacco Survey in China (GATS-China), 10 indicators are used to assess the implementation of five key tobacco control policies of MPOWER in China. RESULTS: Overall, 63.3% and 72.7% of adults noticed people smoking indoor workplaces and public places, respectively. Approximately 60% of smokers were not asked about their smoking habits and approximately 67% were not advised to quit on their visit to a health worker. Sixty percent of adults noticed health warning messages on cigarette packaging and in the media in the last 30 days, 63.6% stated that they would not consider quitting. Twenty percent of respondents noticed tobacco advertising, promotion, and/or sponsorship activities in the 30 days prior to the survey. Among them, 76.3% noticed the direct advertising and 50% noticed from TV programs. Although purchasing price of one pack of cigarettes ranged from 1 to 200 RMB, 50% of current smokers (about 150 million) spent 5 RMB or less on one pack of cigarette. The expenditure on 100 packets of cigarettes represents 2% of 2009 GDP per capita. CONCLUSION: The average score for the implementation of the 5 policies of MPOWER in China is 37.3 points, indicating tobacco control policies in China is poor and there is a large gaps from the FCTC requirements. PMID- 21315240 TI - Population-based survey of secondhand smoke exposure in China. AB - OBJECTIVE: To determine the extent of secondhand smoke exposure in China, and to explore the potential associated factors. METHODS: This study was a nationally representative household survey examining secondhand smoke exposure of non institutionalized men and women aged 15 and older using a global standardized geographically clustered sample design. A total of 13,354 people completed the individual questionnaire with questions on gender, age, educational level, residence, profession, potential factors associated with secondhand smoke exposure, and workplace smoking policy. The data were used to determine whole population estimates of secondhand smoke exposure. RESULTS: Among non-smokers aged 15 years and older, it was estimated that 72.4% (556 million) were exposed to secondhand smoke, with 52.5% (292 million) exposed to secondhand smoke daily. The prevalence of secondhand smoke exposure was 74.1% for men, 71.6% for women, 70.5% for urban populations, and 74.2% for rural populations. The rates were 67.3%, 63.3%, and 72.7% respectively, within the household, indoor workplaces and public places. Secondhand smoke exposure was significantly reduced in workplaces with a smoking ban but not in workplaces with a partial smoking ban. CONCLUSION: Although China has made some progress toward a smoke-free environment there remains a high degree of exposure to secondhand smoke. PMID- 21315241 TI - Awareness of tobacco-related health hazards among adults in China. AB - OBJECTIVE: To determine the level of awareness of the hazards of tobacco smoking and secondhand smoke inhalation among adults in China. METHODS: Household surveys were conducted with a total of 13,354 respondents aged 15 years or over from 100 counties of 28 Chinese provinces using a stratified multi-stage geographically clustered sample design. RESULTS: The findings revealed that 81.8% of the population was aware that smoking causes serious diseases, and 27.2% and 38.7% were aware that smoking causes stroke and heart attack, respectively. Only 64.3% of respondents were aware that secondhand smoke can cause serious diseases, and 27.5%, 51.0%, and 52.6% were aware that secondhand smoke causes heart disease in adults, lung disease in children and lung cancer in adults, respectively. Awareness regarding smoking-related hazards across all participants was significantly associated with several factors, including gender, smoking status, urban/rural residency, education level and exposure to tobacco control publicity in the last 30 days. Awareness regarding tobacco-related hazards in smokers was significantly associated with urban/rural residency, education level, exposure to tobacco control publicity in the last 30 days, and physician's advice. Awareness relating to the hazards of inhaling secondhand smoke was associated with smoking status, urban/rural residency, age, education level, and exposure to tobacco control publicity in the last 30 days. Medical professionals were found to know more about the health hazards of tobacco compared with people in other types of employment. CONCLUSIONS: Overall awareness of the health hazards of tobacco has improved in the last 15 years in China, but is still relatively poor. Improved means of communicating information and more effective warning labels on cigarette packaging are necessary for increasing public awareness of tobacco hazards, particularly among rural residents and people with less education. PMID- 21315242 TI - Methodology of the Global Adult Tobacco Survey in China, 2010. PMID- 21315243 TI - Current trends of the prevalence of childhood asthma in three Chinese cities: a multicenter epidemiological survey. AB - OBJECTIVE: To analyze the prevalence of asthma and asthma related symptoms among children aged 0-14 years in three Chinese cities and to obtain a crude estimation of the trend of childhood asthma prevalence in China. METHODS: A cross-sectional, population-based survey of prevalence of asthma was conducted in children aged from 0 to 14 years in 3 major cities of China (Beijing, Chongqing, and Guangzhou) with different geographic locations. All the subjects were randomly selected by a multi-stage sampling method. Three to five schools and kindergartens in 2 urban districts in each city were randomly selected for the survey, and a validated questionnaire that included the core questions of the International Study of Asthma and Allergies in Childhood, Phase III questionnaire and several additional questions were used. All questionnaires were completed by parents or guardians of the selected children. Children whose parents responded affirmatively to the question "Has your child ever been diagnosed as asthma by a doctor" were recognized as victims of asthma. RESULTS: The prevalence of asthma in Beijing, Chongqing, and Guangzhou was 3.15%, 7.45%, and 2.09%, respectively. These values were significantly higher than those obtained 10 years ago in the national epidemiological survey in 2000 which used the same method of investigation and the same diagnotic criteria (chi2=3.938, P=0.047; chi2=73.506, P<=0.001; chi2=11.956, P=0.001, in each city). Of the asthmatic children 57.21%, 69.91%, and 60.00% had their first attack before the age of 3 in Beijing, Chongqing, and Guangzhou, respectively. Wheezing was the primary clinical manifestation for all asthmatic children, followed by persistent cough and repeated respiratory infections. Both the prevalence of asthma and asthma-related symptoms were statistically higher in males than in females. CONCLUSION: The prevalence of childhood asthma is statistically higher than that 10 years ago in the three Chinese cities. PMID- 21315244 TI - Maternal and fetal exposure to four carcinogenic environmental metals. AB - OBJECTIVE: To examine maternal and fetal exposure levels to four carcinogenic metals, arsenic (As), cadmium (Cd), nickel (Ni), and beryllium (Be), and to investigate their environmental influences. METHODS: Metal concentrations in maternal and umbilical cord blood were measured by inductively coupled plasma mass spectrometry (ICP-MS). Environmental factors that might play a role in exposure were analyzed using Mann-Whitney nonparametric U-tests and multiple linear regression. RESULTS: The concentrations of As, Cd, and Ni in umbilical cord blood (5.41, 0.87, and 139.54 MUg/L) were significantly lower than those in maternal blood (6.91, 1.93, and 165.93 MUg/L). There were significant positive correlations between the maternal and cord concentrations of each carcinogen. Our results showed that: (i) exposures to potentially harmful occupational factors during pregnancy were associated with high levels of maternal As, Cd, and Ni; (ii) living close to major transportation routes (<500 m) or exposure to second hand smoke during pregnancy increased the maternal Cd levels and (iii) living close to industrial chimneys induced high maternal Ni levels. Multiple linear regression analysis showed that these environmental factors remained significant in models of the influences of these four carcinogens. CONCLUSION: Both mothers and fetuses had been exposed to As, Cd, Ni, and Be. The increased levels of these carcinogens in pregnant women were associated with some detrimental environmental factors, such as occupational exposure, contact with second-hand smoke and living close to major transportation routes or industrial chimneys. PMID- 21315245 TI - Reported willingness and associated factors related to utilization of voluntary counseling and testing services by female sex workers in Shandong Province, China. AB - OBJECTIVE: To explore reported willingness and factors associated with utilization of voluntary counseling and testing services by female sex workers (FSWs) in China and to offer recommendations to optimize use of such services. METHODS: A questionnaire to explore willingness to use VCT was designed based on social ecological theory and formative qualitative research. A cross-sectional survey was conducted among FSWs from entertainment venues. Single and multiple logistic regression analyses were employed to examine factors associated with reported willingness to utilize VCT. RESULTS: A total of 970 FSWs provided valid questionnaires, with 69% (669) expressing willingness to utilize VCT. Factors at the interpersonal level associated with reported willingness included knowledge about VCT, desire to get help if diagnosed as HIV positive, ability to imagine life after an HIV positive diagnosis, and perceived support for VCT from peers, managers, and family members. Availability of free antiretroviral (ARV) treatment represented a factor at policy level. Other factors included intention to leave sex work in the near future, having had a previous HIV test, and lack of a suspected STD history. CONCLUSIONS: The rate of reported willingness to use VCT among FSWs was substantially higher than that of actual VCT utilization (11%). The next step is to explore the connection between reported willingness and actual use. Based on these findings, peer education, VCT knowledge dissemination, and free ARV treatment should be emphasized to increase FSWs' willingness to use VCT. PMID- 21315246 TI - Comparative study on inorganic composition and crystallographic properties of cortical and cancellous bone. AB - OBJECTIVE: To comparatively investigate the inorganic composition and crystallographic properties of cortical and cancellous bone via thermal treatment under 700 degrees C. METHODS: Thermogravimetric measurement, infrared spectrometer, X-ray diffraction, chemical analysis and X-ray photo-electron spectrometer were used to test the physical and chemical properties of cortical and cancellous bone at room temperature 250 degrees C, 450 degrees C, and 650 degrees C, respectively. RESULTS: The process of heat treatment induced an extension in the a-lattice parameter and changes of the c-lattice parameter, and an increase in the crystallinity reflecting lattice rearrangement after release of lattice carbonate and possible lattice water. The mineral content in cortical and cancellous bone was 73.2wt% and 71.5wt%, respectively. For cortical bone, the weight loss was 6.7% at the temperature from 60 degrees C to 250 degrees C, 17.4% from 250 degrees C to 450 degrees C, and 2.7% from 450 degrees C to 700 degrees C. While the weight loss for the cancellous bone was 5.8%, 19.9%, and 2.8 % at each temperature range, the Ca/P ratio of cortical bone was 1.69 which is higher than the 1.67 of stoichiometric HA due to the B-type CO32- substitution in apatite lattice. The Ca/P ratio of cancellous bone was lower than 1.67, suggesting the presence of more calcium deficient apatite. CONCLUSION: The collagen fibers of cortical bone were arrayed more orderly than those of cancellous bone, while their mineralized fibers ollkded similar. The minerals in both cortical and cancellous bone are composed of poorly crystallized nano-size apatite crystals with lattice carbonate and possible lattice water. The process of heat treatment induces a change of the lattice parameter, resulting in lattice rearrangement after the release of lattice carbonate and lattice water and causing an increase in crystal size and crystallinity. This finding is helpful for future biomaterial design, preparation and application. PMID- 21315247 TI - Toxicity reduction of municipal wastewater by anaerobic-anoxic-oxic process. AB - OBJECTIVE: This study was conducted to optimize the operational parameters of anaerobic-anoxic-oxic (A2/O) processes to reduce the toxicity of municipal wastewater and evaluate its ability to reduce toxicity. METHODS: A luminescent bacterium toxicity bioassay was employed to assess the toxicity of influent and effluent of each reactor in the A2/O system. RESULTS: The optimum operational parameters for toxicity reduction were as follows: anaerobic hydraulic retention time (HRT) = 2.8 h, anoxic HRT = 2.8 h, aerobic HRT = 6.9 h, sludge retention time (SRT) = 15 days and internal recycle ratio (IRR) = 100%. An important toxicity reduction (%) was observed in the optimized A2/O process, even when the toluene concentration of the influent was 120.7 mg.L-1. CONCLUSIONS: The toxicity of municipal wastewater was reduced significantly during the A2/O process. A2/O process can be used for toxicity reduction of municipal wastewater under toxic shock loading. PMID- 21315248 TI - Increased levels of p53 and PARP-1 in EL-4 cells probably related with the immune adaptive response induced by low dose ionizing radiation in vitro. AB - OBJECTIVE: This paper is to explore the DNA repair mechanism of immune adaptive response (AR) induced by low dose radiation (LDR), the changes of mRNA levels and protein expressions of p53, ATM, DNA-PK catalytic subunit (DNA-PKcs) and PARP-1 genes in the LDR-induced AR in EL-4 cells. METHODS: The apoptosis and cell cycle progression of EL-4 cells were detected by flow cytometry in 12 h after the cells received the pre-exposure of 0.075 Gy X-rays (inductive dose, D1) and the succeeding high dose irradiation (challenge dose, D2; 1.0, 1.5, and 2.0 Gy X rays, respectively) with or without wortmannin (inhibitor of ATM and DNA-PK) and 3-aminobenzamid (inhibitor of PARP-1). And the protein expressions and mRNA levels related to these genes were detected with flow cytometry and reverse transcription-polymerase chain reaction in 12 h after irradiation with D2. RESULTS: The mRNA and protein expressions of p53 and PARP-1 in EL-4 cells in the D1 + D2 groups were much lower than those in the D2 groups, and those of PARP-1 in the 3-AB + D2 and the 3-AB + D1 + D2 groups were much lower than those in the D2 and the D1 + D2 groups. The percentage of apoptotic EL-4 cells in the 3-AB + D1 + D2 groups was much higher than that in the D1 + D2 groups, that in the G0/G1 and the G2 + M phases was much higher, and that in the S phase were much lower. Although the ATM and DNA-PKcs mRNA and protein expressions in wortmannin + D1 + D2 groups were much lower than those in the D1 + D2 groups, there were no significant changes in the apoptosis and cell cycle progression between the wortmannin + D1 + D2 and the D1 + D2 groups. CONCLUSION: PARP-1 and p53 might play important roles in AR induced by LDR. PMID- 21315249 TI - A convenient fluorescent-labeled assay for in vitro measurement of DNA mismatch repair activity. AB - OBJECTIVE: The assay of DNA mismatch repair (MMR) activity can be used as a biomarker for environmental condition detection and human disease diagnosis. Radioactive 32P-endlabeled DNA containing mismatch is extensively used as the substrate for MMR activity analyses. The aim of the present study is to develop a simple non-radioactive, but equally specific and sensitive method for the MMR activity assay. METHODS: A fluorescent label was chosen to replace the radioactive isotope label. Sensitive evaluation of the fluorescent label was carried out for the first time, and then the fluorescent label was compared with the isotope label in the MMR activity and DNA binding assays. RESULT: LOD (limit of detection) of the fluorescent label was about 0.1 fmol and the relative signal strength displayed a pretty good linear relationship. Moreover, the fluorescent label method has equivalent sensitivity and performance as compared with the classical radioactive method in experiments. CONCLUSION: In light of the sensitivity, reproducibility, safety, rapidity and long lifespan of the fluorescent label, this improved method can be applied to evaluation of biologic and toxic effects of environmental pollutants on man and other forms of life. PMID- 21315250 TI - Decision making: singin' in the brain. AB - Which neurons in the brain "decide" to initiate particular behaviors in response to sensory information? In this issue of Neuron, two papers (Kohatsu et al. and von Philipsborn et al.) identify candidates in the courtship circuitry of Drosophila. The activity of these neurons is both regulated by sex pheromones and necessary and sufficient to trigger male love song. PMID- 21315251 TI - Synaptotagmin 4: a new antiobesity target? AB - In this issue of Neuron, Zhang et al. show that Synaptotagmin 4 (Syt4) is specifically induced in adult hypothalamic oxytocin neurons by high-fat diet. Evidence is provided to support a critical role for Syt4 in negative regulation of oxytocin release, which in turn is responsible for diet-induced obesity, raising the possibility of using Syt4 as a new antiobesity target. PMID- 21315252 TI - Decision time for free will. AB - In this issue of Neuron, Fried et al. report electrical recordings from single neurons in several areas of the human medial frontal lobe prior to voluntary movement. These data shed important new light on the neuronal mechanisms of human volition and on the hotly debated relation between consciousness and will. PMID- 21315253 TI - Sensorimotor integration in speech processing: computational basis and neural organization. AB - Sensorimotor integration is an active domain of speech research and is characterized by two main ideas, that the auditory system is critically involved in speech production and that the motor system is critically involved in speech perception. Despite the complementarity of these ideas, there is little crosstalk between these literatures. We propose an integrative model of the speech-related "dorsal stream" in which sensorimotor interaction primarily supports speech production, in the form of a state feedback control architecture. A critical component of this control system is forward sensory prediction, which affords a natural mechanism for limited motor influence on perception, as recent perceptual research has suggested. Evidence shows that this influence is modulatory but not necessary for speech perception. The neuroanatomy of the proposed circuit is discussed as well as some probable clinical correlates including conduction aphasia, stuttering, and aspects of schizophrenia. PMID- 21315255 TI - Activity-induced Notch signaling in neurons requires Arc/Arg3.1 and is essential for synaptic plasticity in hippocampal networks. AB - Notch signaling in the nervous system has been most studied in the context of cell fate specification. However, numerous studies have suggested that Notch also regulates neuronal morphology, synaptic plasticity, learning, and memory. Here we show that Notch1 and its ligand Jagged1 are present at the synapse, and that Notch signaling in neurons occurs in response to synaptic activity. In addition, neuronal Notch signaling is positively regulated by Arc/Arg3.1, an activity induced gene required for synaptic plasticity. In Arc/Arg3.1 mutant neurons, the proteolytic activation of Notch1 is disrupted both in vivo and in vitro. Conditional deletion of Notch1 in the postnatal hippocampus disrupted both long term potentiation (LTP) and long-term depression (LTD), and led to deficits in learning and short-term memory. Thus, Notch signaling is dynamically regulated in response to neuronal activity, Arc/Arg3.1 is a context-dependent Notch regulator, and Notch1 is required for the synaptic plasticity that contributes to memory formation. PMID- 21315254 TI - Huntington's disease: can mice lead the way to treatment? AB - Mouse models for Huntington's Disease (HD) and HD patients demonstrate motor and behavioral dysfunctions, such as progressive loss of coordination and memory, and share similar transcriptional profiles and striatal neuron atrophy. Clear differences between the mouse and human diseases include almost complete striatal degeneration and rarity of intranuclear inclusions in HD, and the fact that mice expressing full-length mutant huntingtin do not demonstrate a shortened life span characteristic of HD. While no clinical interventions tested in mouse models to date have delayed disease progression, the mouse models provide an invaluable tool for both investigating the underlying pathogenic processes and developing new effective therapies. Inherent differences between humans and mice must be considered in the search for efficacious treatments for HD, but the striking similarities between human HD and mouse models support the view that these models are a biologically relevant system to support the identification and testing of potential clinical therapies. PMID- 21315256 TI - Habenula "cholinergic" neurons co-release glutamate and acetylcholine and activate postsynaptic neurons via distinct transmission modes. AB - Acetylcholine is an important neurotransmitter, and the habenulo-interpeduncular projection is a major cholinergic pathway in the brain. To study the physiological properties of cholinergic transmission in the interpeduncular nucleus (IPN), we used a transgenic mouse line in which the light-gated cation channel ChannelRhodopsin-2 is selectively expressed in cholinergic neurons. Cholinergic axonal terminals were activated by light pulses, and postsynaptic responses were recorded from IPN neurons. Surprisingly, brief photostimulation produces fast excitatory postsynaptic currents that are mediated by ionotropic glutamate receptors, suggesting wired transmission of glutamate. By contrast, tetanic photostimulation generates slow inward currents that are largely mediated by nicotinic acetylcholine receptors, suggesting volume transmission of acetylcholine. Finally, vesicular transporters for glutamate and acetylcholine are coexpressed on the same axonal terminals in the IPN. These results strongly suggest that adult brain "cholinergic" neurons can corelease glutamate and acetylcholine, but these two neurotransmitters activate postsynaptic neurons via different transmission modes. PMID- 21315257 TI - Early functional impairment of sensory-motor connectivity in a mouse model of spinal muscular atrophy. AB - To define alterations of neuronal connectivity that occur during motor neuron degeneration, we characterized the function and structure of spinal circuitry in spinal muscular atrophy (SMA) model mice. SMA motor neurons show reduced proprioceptive reflexes that correlate with decreased number and function of synapses on motor neuron somata and proximal dendrites. These abnormalities occur at an early stage of disease in motor neurons innervating proximal hindlimb muscles and medial motor neurons innervating axial muscles, but only at end-stage disease in motor neurons innervating distal hindlimb muscles. Motor neuron loss follows afferent synapse loss with the same temporal and topographical pattern. Trichostatin A, which improves motor behavior and survival of SMA mice, partially restores spinal reflexes, illustrating the reversibility of these synaptic defects. Deafferentation of motor neurons is an early event in SMA and may be a primary cause of motor dysfunction that is amenable to therapeutic intervention. PMID- 21315258 TI - DSL-Notch signaling in the Drosophila brain in response to olfactory stimulation. AB - Delta/Serrate/Lag2 (DSL) ligands and their Notch family receptors have profound and pervasive roles in development. They are also expressed in adult tissues, notably in mature neurons and glia in the brain, where their roles are unknown. Here, focusing on the sense of smell in adult Drosophila, we show that Notch is activated in select olfactory receptor neurons (ORNs) in an odorant-specific fashion. This response requires olfactory receptor activity and the Notch ligand Delta. We present evidence that Notch activation depends on synaptic transmission by the ORNs in which the receptors are active and is modulated by the activity of local interneurons in the antennal lobe. It is also subject to regulatory inputs from olfactory receptor activity in other ORNs. These findings identify a correlate of stimulus-dependent brain activity and potentially new forms of neural integration and plasticity. PMID- 21315260 TI - Female contact activates male-specific interneurons that trigger stereotypic courtship behavior in Drosophila. AB - We determined the cellular substrate for male courtship behavior by quasinatural and artificial stimulation of brain neurons. Activation of fruitless (fru) expressing neurons via stimulation of thermosensitive dTrpA1 channels induced an entire series of courtship acts in male Drosophila placed alone without any courting target. By reducing the number of neurons expressing dTrpA1 by MARCM, we demonstrated that the initiation of courtship behavior is significantly correlated with the activation of the transmidline P1 interneurons, the descending P2b interneurons, or both, indicating that these interneurons trigger courtship. Using an experimental paradigm in which a tethered male can be stimulated to initiate courtship by touching his foreleg tarsus to a female's abdomen, we found that P1 neurites of tethered males showed a transient Ca(2+) rise after tarsal stimulation with the female-associated sensory cues. These observations strongly suggest that P1 neurons are the prime components of the neural circuitry that initiates male courtship. PMID- 21315259 TI - Reelin regulates cadherin function via Dab1/Rap1 to control neuronal migration and lamination in the neocortex. AB - Neuronal migration is critical for establishing neocortical cell layers and migration defects can cause neurological and psychiatric diseases. Recent studies show that radially migrating neocortical neurons use glia-dependent and glia independent modes of migration, but the signaling pathways that control different migration modes and the transitions between them are poorly defined. Here, we show that Dab1, an essential component of the reelin pathway, is required in radially migrating neurons for glia-independent somal translocation, but not for glia-guided locomotion. During migration, Dab1 acts in translocating neurons to stabilize their leading processes in a Rap1-dependent manner. Rap1, in turn, controls cadherin function to regulate somal translocation. Furthermore, cell autonomous neuronal deficits in somal translocation are sufficient to cause severe neocortical lamination defects. Thus, we define the cellular mechanism of reelin function during radial migration, elucidate the molecular pathway downstream of Dab1 during somal translocation, and establish the importance of glia-independent motility in neocortical development. PMID- 21315261 TI - Neuronal control of Drosophila courtship song. AB - The courtship song of the Drosophila male serves as a genetically tractable model for the investigation of the neural mechanisms of decision-making, action selection, and motor pattern generation. Singing has been causally linked to the activity of the set of neurons that express the sex-specific fru transcripts, but the specific neurons involved have not been identified. Here we identify five distinct classes of fru neuron that trigger or compose the song. Our data suggest that P1 and pIP10 neurons in the brain mediate the decision to sing, and to act upon this decision, while the thoracic neurons dPR1, vPR6, and vMS11 are components of a central pattern generator that times and shapes the song's pulses. These neurons are potentially connected in a functional circuit, with the descending pIP10 neuron linking the brain and thoracic song centers. Sexual dimorphisms in each of these neurons may explain why only males sing. PMID- 21315262 TI - Neuropeptide exocytosis involving synaptotagmin-4 and oxytocin in hypothalamic programming of body weight and energy balance. AB - Hypothalamic neuropeptides play essential roles in regulating energy and body weight balance. Energy imbalance and obesity have been linked to hypothalamic signaling defects in regulating neuropeptide genes; however, it is unknown whether dysregulation of neuropeptide exocytosis could be critically involved. This study discovered that synaptotagmin-4, an atypical modulator of synaptic exocytosis, is expressed most abundantly in oxytocin neurons of the hypothalamus. Synaptotagmin-4 negatively regulates oxytocin exocytosis, and dietary obesity is associated with increased vesicle binding of synaptotagmin-4 and thus enhanced negative regulation of oxytocin release. Overexpressing synaptotagmin-4 in hypothalamic oxytocin neurons and centrally antagonizing oxytocin in mice are similarly obesogenic. Synaptotagmin-4 inhibition prevents against dietary obesity by normalizing oxytocin release and energy balance under chronic nutritional excess. In conclusion, the negative regulation of synaptotagmin-4 on oxytocin release represents a hypothalamic basis of neuropeptide exocytosis in controlling obesity and related diseases. PMID- 21315263 TI - Neural mechanisms of tactile motion integration in somatosensory cortex. AB - How are local motion signals integrated to form a global motion percept? We investigate the neural mechanisms of tactile motion integration by presenting tactile gratings and plaids to the fingertips of monkeys, using the tactile analogue of a visual monitor and recording the responses evoked in somatosensory cortical neurons. The perceived directions of the gratings and plaids are measured in parallel psychophysical experiments. We identify a population of somatosensory neurons that exhibit integration properties comparable to those induced by analogous visual stimuli in area MT and find that these neural responses account for the perceived direction of the stimuli across all stimulus conditions tested. The preferred direction of the neurons and the perceived direction of the stimuli can be predicted from the weighted average of the directions of the individual stimulus features, highlighting that the somatosensory system implements a vector average mechanism to compute tactile motion direction that bears striking similarities to its visual counterpart. PMID- 21315264 TI - Internally generated preactivation of single neurons in human medial frontal cortex predicts volition. AB - Understanding how self-initiated behavior is encoded by neuronal circuits in the human brain remains elusive. We recorded the activity of 1019 neurons while twelve subjects performed self-initiated finger movement. We report progressive neuronal recruitment over ~1500 ms before subjects report making the decision to move. We observed progressive increase or decrease in neuronal firing rate, particularly in the supplementary motor area (SMA), as the reported time of decision was approached. A population of 256 SMA neurons is sufficient to predict in single trials the impending decision to move with accuracy greater than 80% already 700 ms prior to subjects' awareness. Furthermore, we predict, with a precision of a few hundred ms, the actual time point of this voluntary decision to move. We implement a computational model whereby volition emerges once a change in internally generated firing rate of neuronal assemblies crosses a threshold. PMID- 21315265 TI - Fear-conditioning mechanisms associated with trait vulnerability to anxiety in humans. AB - Investigations of fear conditioning in rodents and humans have illuminated the neural mechanisms underlying cued and contextual fear. A critical question is how personality dimensions such as trait anxiety act through these mechanisms to confer vulnerability to anxiety disorders, and whether humans' ability to overcome acquired fears depends on regulatory skills not characterized in animal models. In a neuroimaging study of fear conditioning in humans, we found evidence for two independent dimensions of neurocognitive function associated with trait vulnerability to anxiety. The first entailed increased amygdala responsivity to phasic fear cues. The second involved impoverished ventral prefrontal cortical (vPFC) recruitment to downregulate both cued and contextual fear prior to omission (extinction) of the aversive unconditioned stimulus. These two dimensions may contribute to symptomatology differences across anxiety disorders; the amygdala mechanism affecting the development of phobic fear and the frontal mechanism influencing the maintenance of both specific fears and generalized anxiety. PMID- 21315266 TI - Neuronal dynamics underlying high- and low-frequency EEG oscillations contribute independently to the human BOLD signal. AB - Work on animals indicates that BOLD is preferentially sensitive to local field potentials, and that it correlates most strongly with gamma band neuronal synchronization. Here we investigate how the BOLD signal in humans performing a cognitive task is related to neuronal synchronization across different frequency bands. We simultaneously recorded EEG and BOLD while subjects engaged in a visual attention task known to induce sustained changes in neuronal synchronization across a wide range of frequencies. Trial-by-trial BOLD fluctuations correlated positively with trial-by-trial fluctuations in high-EEG gamma power (60-80 Hz) and negatively with alpha and beta power. Gamma power on the one hand, and alpha and beta power on the other hand, independently contributed to explaining BOLD variance. These results indicate that the BOLD-gamma coupling observed in animals can be extrapolated to humans performing a task and that neuronal dynamics underlying high- and low-frequency synchronization contribute independently to the BOLD signal. PMID- 21315267 TI - Balancing at survival's edge: the structure and adaptive benefits of prokaryotic toxin-antitoxin partners. AB - Many prokaryotes express toxin-antitoxin (TA) pairs that are harmful to their hosts if not maintained in delicate balance. The maintenance of potentially lethal toxin-antitoxin pairs could be viewed as a high-risk strategy. However, accumulating evidence suggests that toxin-antitoxin pairs can confer selective evolutionary benefits such as adaptive stress responses, starvation recovery and herd immunity to predation. Many of the known TA pairs interact as proteins, but recent work has identified a new class of antitoxins that are RNA cleavage products. Structural studies have revealed common folds for diverse toxins, highlighting unexpected evolutionary relationships within different toxin classes. TA pairs appear to have diverged in function considerably, to meet the specialised requirements of their varied prokaryotic hosts. PMID- 21315269 TI - Internal radiotherapy with copper-64-diacetyl-bis (N4-methylthiosemicarbazone) reduces CD133+ highly tumorigenic cells and metastatic ability of mouse colon carcinoma. AB - INTRODUCTION: (64)Cu-diacetyl-bis (N(4)-methylthiosemicarbazone) ((64)Cu-ATSM) is an imaging agent for positron emission tomography (PET) that targets hypoxic tumors. (64)Cu-ATSM is also reported to be a potential agent for internal radiotherapy. In a mouse colon carcinoma (Colon-26) model, we have shown that (64)Cu-ATSM preferentially localizes in intratumoral regions with a high density of CD133(+) cells, which show characteristics of cancer stem cells or cancer stem cell-like cells (collectively referred here as CSCs). In this study, we evaluated the therapeutic effect of (64)Cu-ATSM in relation to CD133 expression using this model. METHODS: Systemic administration of 37 MBq (64)Cu-ATSM or saline was conducted twice within a 1-week interval to mice bearing 1-week-old Colon-26 tumors (days 0-7). At day 19, tumor size measurement, flow cytometry analysis and experimental lung metastatic assay were performed. The therapeutic effect of (64)Cu-ATSM on sorted CD133(+) and CD133(-) Colon-26 cells was also examined in vitro. RESULTS: In vivo studies showed that (64)Cu-ATSM treatment inhibited tumor growth. The percentage of CD133(+) cells and metastatic ability in (64)Cu-ATSM treated tumors was decreased compared with that in control animals. In vitro studies demonstrated that (64)Cu-ATSM accumulated in cells under hypoxic conditions and incorporation of (64)Cu-ATSM under hypoxia caused cell death in both CD133(+) and CD133(-) cells in a similar extent. CONCLUSIONS: (64)Cu-ATSM administration reduced tumor volume as well as the percentage of CD133(+) cells and the metastatic ability of Colon-26 tumors. Together with our data, it is suggested that (64)Cu-ATSM accumulates in regions high in CD133(+) highly tumorigenic cells and kills such regions by radiation, resulting in a decrease of the percentage of CD133(+) cells. PMID- 21315270 TI - Unexpected side products in the conjugation of an amine-derivatized morpholino oligomer with p-isothiocyanate benzyl DTPA and their removal. AB - In connection with pretargeting, an amine-derivatized morpholino phosphorodiamidate oligomer (NH(2)-cMORF) was conjugated conventionally with p isothiocyanate benzyl-DTPA (p-SCN-Bn-DTPA). However, after (111)In radiolabeling, unexpected label instability was observed. To understand this instability, the NH(2)-cMORF and, as control, the native cMORF without the amine were conjugated in the conventional manner. Surprisingly, the (111)In labeling of the native cMORF conjugate was equally effective as that of the NH(2)-cMORF conjugate (>95%) despite the absence of the amine group. Furthermore, heating the radiolabeled NH(2)-cMORF and native cMORF conjugates resulted in a 35% loss and a complete loss of the label, respectively. Since the (111)In labeled DTPA is known to be stable, the instability in both cases must be due to some unstable association of DTPA to the cMORF, presumably unstable association to some endogenous sites in cMORF. Based on this assumption, a postconjugation-prepurification heating step was introduced, and labeling efficiency and stability were again investigated. By introducing the heating step, the side products were dissociated, and after purification and labeling, the NH(2)-cMORF conjugate provided a stable label and high labeling efficiency with no need for postlabeling purification. The biodistribution of this radiolabeled conjugate in normal mice showed significantly lower backgrounds compared with the labeled unstable native cMORF conjugate. In conclusion, the conventional conjugation procedure to attach the p SCN-Bn-DTPA to NH(2)-cMORF resulted in side product(s) that were responsible for the (111)In label instability. Adding a postconjugation-prepurification heating step dissociated the side products, improved the label stability and lowered tissue backgrounds in mice. PMID- 21315271 TI - Fully automated SPE-based synthesis and purification of 2-[18F]fluoroethyl choline for human use. AB - INTRODUCTION: 2-[(18)F]Fluoroethyl-choline ([(18)F]FECH) is a promising tracer for the detection of prostate cancer as well as brain tumors with positron emission tomography (PET). [(18)F]FECH is actively transported into mammalian cells, becomes phosphorylated by choline kinase and gets incorporated into the cell membrane after being metabolized to phosphatidylcholine. So far, its synthesis is a two-step procedure involving at least one HPLC purification step. To allow a wider dissemination of this tracer, finding a purification method avoiding HPLC is highly desirable and would result in easier accessibility and more reliable production of [(18)F]FECH. METHODS: [(18)F]FECH was synthesized by reaction of 2-bromo-1-[(18)F]fluoroethane ([(18)F]BFE) with dimethylaminoethanol (DMAE) in DMSO. We applied a novel and very reliable work-up procedure for the synthesis of [(18)F]BFE. Based on a combination of three different solid-phase cartridges, the purification of [(18)F]BFE from its precursor 2-bromoethyl-4 nitrobenzenesulfonate (BENos) could be achieved without using HPLC. Following the subsequent reaction of the purified [(18)F]BFE with DMAE, the final product [(18)F]FECH was obtained as a sterile solution by passing the crude reaction mixture through a combination of two CM plus cartridges and a sterile filter. The fully automated synthesis was performed using as well a Raytest SynChrom module (Raytest, Germany) or a Scintomics HotboxIII module (Scintomics, Germany). RESULTS: The radiotracer [(18)F]FECH can be synthesized in reliable radiochemical yields (RCY) of 37+/-5% (Synchrom module) and 33+/-5% (Hotbox III unit) in less than 1 h using these two fully automated commercially available synthesis units without HPLC involvement for purification. Detailed quality control of the final injectable [(18)F]FECH solution proved the high radiochemical purity and the absence of Kryptofix2.2.2, DMAE and DMSO used in the course of synthesis. Sterility and bacterial endotoxin testing following standard procedures verified that the described production method for [(18)F]FECH is suitable for human applications. CONCLUSIONS: The routine production of [(18)F]FECH with sufficient RCYs was established by reliable and fast solid-phase extraction purifications of both the secondary labeling precursor [(18)F]BFE and the final product [(18)F]FECH, avoiding complex and sensitive HPLC equipment. The purity of the product was >95%, rendering the tracer suitable for human application. The newly developed purification procedure for [(18)F]BFE significantly reduces the complexity of the automated synthesis unit, hence reducing the cost for routine production in a clinical setup and allowing easy transfer to different synthesis modules. PMID- 21315272 TI - Influence of biological assay conditions on stability assessment of radiometal labelled peptides exemplified using a 177Lu-DOTA-minigastrin derivative. AB - INTRODUCTION: Lack of correlation between in vitro and in vivo stability is a general problem for the development of radiopeptides especially in the case of minigastrin derivatives for therapeutic applications. In this study, we compared the influence of experimental conditions on radiopeptide stability results in vitro using a model Minigastrin (MG) analogue labelled with Lu-177. Additionally, we attempted to characterize the main serum enzymatic cleavage sites by matrix assisted laser desorption/ionization (MALDI) time-of-flight (TOF) mass spectrometry (MS) analysis. METHODS: In vitro stability of a DOTA-minigastrin derivative ((177)Lu-DOTA-His-His-Glu-Ala-Tyr-Gly-Trp-NIe-Asp-Phe-NH(2)) was tested in serum, rat tissue homogenates and two different standardised enzymatic mixtures. Quantification of the metabolised radiopeptides at different time intervals was performed using reversed-phase high-performance liquid chromatography (RP-HPLC). Metabolites were characterised by MALDI-TOF-MS. Urine was collected after 15 min p.i. into the mice and compared with in vitro metabolites by RP-HPLC. RESULTS: Faster degradation of the radiopeptide was found in blood in comparison with plasma and serum incubation and in components from rats faster than from human origin. Fast degradation was observed in kidney and liver homogenates as well as in standardised enzymatic mixtures, also revealing variations in the metabolic profile. In urine, no intact peptide was detected already 5 min post injection. MALDI-TOF-MS revealed major cleavage sites at the carboxy terminus of the peptide. CONCLUSION: Very variable results may be found when different kind of incubation media for testing radiopeptide stabilities is used. Serum incubation studies may overestimate stability; therefore, results should be interpreted with care and combined with alternative in vitro and in vivo investigations. PMID- 21315273 TI - [11C]diclofenac sodium: synthesis and PET assessment of transdermal penetration. AB - The aim of this work was to study the feasibility of using Positron Emission Tomography (PET) imaging as a new tool to detect transdermal penetration of topical drugs in human subjects. The compound used in the study is sodium 2-[(2,6 dichlorophenyl)amino]phenyl]acetate, better known as diclofenac sodium. This molecule belongs to the family of non-steroidal anti-inflammatory drugs and is considered one of the first choices among non-steroidal anti-inflammatory drugs for the treatment of inflammatory diseases; it is widely used and commercially present in a large number of pharmaceutical forms and formulations. (11)C-labeled diclofenac has been synthesized and coformulated, as an internal indicator, with a proprietary preparation based on the use of a sprayer. The radiolabeled preparation was topically administered to healthy volunteers, and PET imaging was used to evaluate transdermal penetration. Results obtained have demonstrated the efficacy of PET and radiolabeled tracers for the evaluation of transdermal penetration of active pharmaceutical ingredients as topical formulations. PMID- 21315274 TI - PET imaging of thin objects: measuring the effects of positron range and partial volume averaging in the leaf of Nicotiana tabacum. AB - INTRODUCTION: PET imaging in plants is receiving increased interest as a new strategy to measure plant responses to environmental stimuli and as a tool for phenotyping genetically engineered plants. PET imaging in plants, however, poses new challenges. In particular, the leaves of most plants are so thin that a large fraction of positrons emitted from PET isotopes ((18)F, (11)C, (13)N) escape while even state-of-the-art PET cameras have significant partial-volume errors for such thin objects. Although these limitations are acknowledged by researchers, little data have been published on them. METHODS: Here we measured the magnitude and distribution of escaping positrons from the leaf of Nicotiana tabacum for the radionuclides (18)F, (11)C and (13)N using a commercial small animal PET scanner. Imaging results were compared to radionuclide concentrations measured from dissection and counting and to a Monte Carlo simulation using GATE (Geant4 Application for Tomographic Emission). RESULTS: Simulated and experimentally determined escape fractions were consistent. The fractions of positrons (mean+/-S.D.) escaping the leaf parenchyma were measured to be 59+/ 1.1%, 64+/-4.4% and 67+/-1.9% for (18)F, (11)C and (13)N, respectively. Escape fractions were lower in thicker leaf areas like the midrib. Partial-volume averaging underestimated activity concentrations in the leaf blade by a factor of 10 to 15. CONCLUSIONS: The foregoing effects combine to yield PET images whose contrast does not reflect the actual activity concentrations. These errors can be largely corrected by integrating activity along the PET axis perpendicular to the leaf surface, including detection of escaped positrons, and calculating concentration using a measured leaf thickness. PMID- 21315275 TI - Automated synthesis of 2'-deoxy-2'-[18F]fluoro-5-methyl-1-beta-D arabinofuranosyluracil ([18F]-FMAU) using a one reactor radiosynthesis module. AB - 2'-Deoxy-2'-[(18)F]fluoro-5-methyl-1-beta-D-arabinofuranosyluracil ([(18)F]-FMAU) is an established PET probe used to monitor cellular proliferation. For clinical applications, a fully automated cGMP-compliant radiosynthesis would be preferred. However, the current synthesis of [(18)F]-FMAU requires a multistep procedure, making the development of an automated protocol difficult and complicated. Recently, we have developed a significantly simplified one-pot reaction condition for the synthesis of [(18)F]-FMAU in the presence of Friedel-Crafts catalysts. Here, we report a fully automated synthesis of [(18)F]-FMAU based on a one reactor radiosynthesis module using our newly developed synthetic method. The product was purified on a semi-preparative high-performance liquid chromatography integrated with the synthesis module using 6% EtOH in 10 mM phosphate buffer or 8% MeCN/water. [(18)F]-FMAU was obtained in 12+/-3% radiochemical yield (decay corrected overall yield based on [(18)F]-F(-), n=4) with 383+/-33 mCi/MUmol specific activity at the time of injection. The alpha/beta anomer ratio was 4:6. The overall reaction time was about 150 min from the end of bombardment and the radiochemical purity was >99%. This automated synthesis should also be suitable for the production of other 5-substituted thymidine analogues. PMID- 21315276 TI - Automated preparation of Re-188 lipiodol for the treatment of hepatocellular carcinoma. AB - The iodinated oil lipiodol is commonly used as a carrier for in situ delivery of drugs or radioactivity to hepatic tumors. Recently, we reported a new kit formulation for high-activity labeling of lipiodol with the beta-emitting radionuclide Re-188. Since the whole preparation involves different steps and complex manipulations of high-activity samples, we describe here an automated synthesis module that allows the easy preparation of sterile and pyrogen-free samples of Re-188 lipiodol ready to be administered to the patient. Important advantages include the possibility to incorporate high Re-188 activity into the lipiodol hydrophobic phase and a sharp reduction of radiation exposure of the operator assisting the labelling procedure. Application of this modular reaction system could be also extended to the preparation of other Re-188 radiopharmaceuticals and to compound labelled with different beta-emitting therapeutic radionuclides. PMID- 21315277 TI - [11C]GR103545: novel one-pot radiosynthesis with high specific activity. AB - INTRODUCTION: GR103545 is a potent and selective kappa-opioid receptor agonist. Previous studies in non-human primates demonstrated favorable properties of [(11)C]GR103545 as a positron emission tomography tracer for in vivo imaging of cerebral kappa-opioid receptor. Nonetheless, advancement of [(11)C]GR103545 to imaging studies in humans was hampered by difficulties of its multiple-step radiosynthesis, which produces a final product with low specific activity (SA), which in turn could induce undesirable physiological side effects resulting from the mass associated with an injected amount of radioactivity. We report herein an alternative radiosynthesis of [(11)C]GR103545 with higher SA and radiochemical yields. METHODS: The TRACERLab FXC automated synthesis module was used to carry out the two-step, one-pot procedure. In the first step, the desmethoxycarbonyl precursor was converted to the carbamic acid intermediate desmethyl-GR103545 via transcarboxylation with the zwitterionic carbamic complex, 1,8 diazabicyclo[5.4.0]undec-7-ene-carbon dioxide, in the presence and/or absence of cesium carbonate and tetrabutylammonium triflate. In the second step, the intermediate was radiolabeled at the carboxyl oxygen with [(11)C]methyl trifluoromethanesulfonate to give [(11)C]GR103545. RESULTS: This novel synthesis produced [(11)C]GR103545 with >=90% chemical and radiochemical purities and an SA of 290.45+/-99.9 MBq/nmol at the end of synthesis (n=26). Injectable radioactivity was 1961+/-814 GBq/MUmol with 43 min of average synthesis time from the end of beam. CONCLUSION: We have developed a practical one-pot method for the routine production of [(11)C]GR103545 with reliably high SA and radiochemical yield, thus allowing the advancement of this radiotracer to imaging applications in humans. PMID- 21315279 TI - Synthesis of hypoxia imaging agent 1-(5-deoxy-5-fluoro-alpha-D-arabinofuranosyl) 2-nitroimidazole using microfluidic technology. AB - INTRODUCTION: Microfluidic technology allows fast reactions in a simple experimental setup, while using very low volumes and amounts of starting material. Consequently, microfluidic technology is an ideal tool for radiolabeling reactions involving short-lived positron emitters. Optimization of the complex array of different reaction conditions requires knowledge of the different reaction parameters linked to the microfluidic system as well as their influence on the radiochemical yields. 1-(5-Deoxy-5-fluoro-alpha-d arabinofuranosyl)-2-nitroimidazole ([(18)F]FAZA) is a frequently used radiotracer for PET imaging of tumor hypoxia. The present study describes the radiosynthesis of [(18)F]FAZA by means of microfluidic technology and subsequent small animal PET imaging in EMT-6 tumor-bearing mice. METHODS: Radiosyntheses were performed using the NanoTek Microfluidic Synthesis System (Advion BioSciences, Inc.). Optimal reaction conditions were studied through screening different reaction parameters like temperature, flow rate, residency time, concentration of the labeling precursor (1-(2,3-di-O-acetyl-5-O-tosyl-alpha-d-arabinofuranosyl)-2 nitroimidazole) and the applied volume ratio between the labeling precursor and [(18)F]fluoride. RESULTS: Optimized reaction conditions at low radioactivity levels (1 to 50 MBq) afforded 63% (decay-corrected) of HPLC-purified [(18)F]FAZA within 25 min. Higher radioactivity levels (0.4 to 2.1 GBq) gave HPLC-purified [(18)F]FAZA in radiochemical yields of 40% (decay-corrected) within 60 min at a specific activity in the range of 70 to 150 GBq/MUmol. Small animal PET studies in EMT-6 tumor-bearing mice showed radioactivity accumulation in the tumor (SUV(20min) 0.74 +/- 0.08) resulting in an increasing tumor-to-muscle ratio over time. CONCLUSIONS: Microfluidic technology is an ideal method for the rapid and efficient radiosynthesis of [(18)F]FAZA for preclinical radiopharmacological studies. Careful analysis of various reaction parameters is an important requirement for the understanding of the influence of different reaction parameters on the radiochemical yield using microfluidic technology. Exploration of microfluidic technology for the radiosynthesis of other PET radiotracers in clinically relevant radioactivity levels is currently in progress. PMID- 21315278 TI - Engineering an antibody with picomolar affinity to DOTA chelates of multiple radionuclides for pretargeted radioimmunotherapy and imaging. AB - INTRODUCTION: In pretargeted radioimmunotherapy (PRIT), a bifunctional antibody is administered and allowed to pre-localize to tumor cells. Subsequently, a chelated radionuclide is administered and captured by cell-bound antibody while unbound hapten clears rapidly from the body. We aim to engineer high-affinity binders to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelates for use in PRIT applications. METHODS: We mathematically modeled antibody and hapten pharmacokinetics to analyze hapten tumor retention as a function of hapten binding affinity. Motivated by model predictions, we used directed evolution and yeast surface display to affinity mature the 2D12.5 antibody to DOTA, reformatted as a single chain variable fragment (scFv). RESULTS: Modeling predicts that for high antigen density and saturating bsAb dose, a hapten-binding affinity of 100 pM is needed for near-maximal hapten retention. We affinity matured 2D12.5 with an initial binding constant of about 10 nM to DOTA-yttrium chelates. Affinity maturation resulted in a 1000-fold affinity improvement to biotinylated DOTA-yttrium, yielding an 8.2+/-1.9 picomolar binder. The high-affinity scFv binds DOTA complexes of lutetium and gadolinium with similar picomolar affinity and indium chelates with low nanomolar affinity. When engineered into a bispecific antibody construct targeting carcinoembryonic antigen, pretargeted high-affinity scFv results in significantly higher tumor retention of a (111)In-DOTA hapten compared to pretargeted wild-type scFv in a xenograft mouse model. CONCLUSIONS: We have engineered a versatile, high-affinity, DOTA-chelate-binding scFv. We anticipate it will prove useful in developing pretargeted imaging and therapy protocols to exploit the potential of a variety of radiometals. PMID- 21315280 TI - [11C]CURB: Evaluation of a novel radiotracer for imaging fatty acid amide hydrolase by positron emission tomography. AB - INTRODUCTION: Fatty acid amide hydrolase (FAAH) is the enzyme responsible for metabolising the endogenous cannabinoid, anandamide, and thus represents an important target for molecular imaging. To date, no radiotracer has been shown to be useful for imaging of FAAH using either positron emission tomography (PET) or single photon emission computed tomography (SPECT). We here determine the suitability of a novel carbon-11-labeled inhibitor of FAAH via ex vivo biodistribution studies in rat brain in conjunction with pharmacological challenges. METHODS: A potent irreversible inhibitor of FAAH, URB694, radiolabeled with carbon-11 in the carbonyl position ([(11)C]CURB), was administered to male rats via tail-vein injection. Rats were sacrificed at various time points postinjection, and tissue samples were dissected, counted and weighed. Specific binding to FAAH was investigated by pretreatment of animals with URB694 or URB597. For metabolism and mechanism of binding studies, whole brains were excised post-radiotracer injection, homogenised and extracted exhaustively with 80% aq. acetonitrile to determine the time course and fraction of radioactivity that was irreversibly bound to brain parenchyma. RESULTS: Upon intravenous injection into rats, [(11)C]CURB showed high brain uptake [standard uptake value (SUV) of 1.6-2.4 at 5 min] with little washout over time, which is characteristic of irreversible binding. Highest uptake of radioactivity was seen in the cortex, intermediate in the cerebellum and lowest in the hypothalamus, reflecting the reported distribution of FAAH. Brain uptake of radioactivity was decreased in a dose-dependent manner by pretreatment with increasing amounts of URB694, demonstrating that binding was saturable. Pretreatment with the well characterised FAAH inhibitor, URB597, reduced binding in all brain regions by 70 80%. Homogenised brain extraction experiments demonstrated unequivocally that [(11)C]CURB was irreversibly bound to FAAH. CONCLUSIONS: The title radiotracer demonstrates favourable properties such as good brain uptake, regional heterogeneity and specificity of binding based on ex vivo biodistribution studies in conscious rat brain. [(11)C]CURB represents a highly promising radiotracer for the imaging of FAAH using PET. PMID- 21315281 TI - Evaluation of 99mTc-glucarate as a breast cancer imaging agent in a xenograft animal model. AB - INTRODUCTION: The use of [(99m)Tc]glucarate has been reported as an infarct-avid agent with the potential for very early detection of myocardial infarction. [(99m)Tc]Glucarate has also been postulated as an agent for non-invasive detection of tumors. The aim of our study was to develop a Glucarate kit and evaluate [(99m)Tc]glucarate as a potential cancer imaging agent in female SCID mice bearing human MDA-MB-435 breast tumors. METHODS: Glucarate in a kit formulation was labeled with (99m)Tc and evaluated for radiolabelling efficiency and radiochemical purity. The Glucarate kit stability was assessed by monthly quality controls. The pharmacokinetics of [(99m)Tc]glucarate were determined in female SCID mice bearing MDA-MB-435 human breast carcinoma tumors at 0.5, 1, 2, 4 and 24 h. Nuclear imaging studies were performed with a micro-single photon emission tomography (SPECT)/computed tomography (CT) system at 2 h post injection, while magnetic resonance imaging (MRI) was employed for tumor morphology analysis and metastatic deposit localization. RESULTS: The Glucarate kits exhibited a stable shelf life of 6 months. [(99m)Tc]Glucarate was obtained with radiochemical purity greater than 95%. Biodistribution studies demonstrated moderate tumor uptake coupled with high renal clearance. Tumor-to-muscle ratios were 4.85 and 5.14 at 1 and 4 h post injection. MRI analysis showed tumors with dense cellular growth and moderate central necrosis. [(99m)Tc]Glucarate uptake in the primary MDA-MB-435 shoulder tumors and metastatic lesions were clearly visualized with micro-SPECT/CT imaging. CONCLUSIONS: Selective tumor uptake and rapid clearance from nontarget organs makes [(99m)Tc]glucarate a potential agent for breast cancer imaging that awaits validation in a clinical trial. PMID- 21315282 TI - Development of a PET radioligand for the central 5-HT1B receptor: radiosynthesis and characterization in cynomolgus monkeys of eight radiolabeled compounds. AB - INTRODUCTION: The serotonin 1B (5-HT(1B)) receptor has been implicated in several psychiatric disorders and is a potential pharmacological target in the treatment of depression. The aim of this study was to develop a radioligand for positron emission tomography (PET) imaging of the 5-HT(1B) receptor in the primate brain in vivo. METHODS: Eight carboxamide radioligands (1-8) from three different core structures were radiolabeled with carbon-11 employing N-methylation with [(11)C]methyl triflate on the piperazine structural moiety. In vivo PET evaluation of each radioligand was performed in cynomolgus monkeys and included analysis of radioactive metabolites measured in plasma using high-performance liquid chromatography. RESULTS: In a total of 12 radiosynthesis of the eight radioligands, the mean decay corrected yield was 11%, and the mean specific radioactivity was 299 GBq/MUmol (8075 Ci/mmol) at time of administration. Of the eight tested candidates, [(11)C]6 demonstrated the most promising in vivo characteristics, showing high binding in 5-HT(1B) receptor-rich regions and low binding in the cerebellum. When inspecting data from all eight compounds, lipophilicity appeared as a physicochemical property that could be related to favorable in vivo imaging characteristics. CONCLUSION: Candidate [(11)C]6, i.e., [(11)C]AZ10419369, exhibited high binding potentials in regions known to contain 5-HT(1B) receptors and was nominated for further preclinical characterization and PET examination in human subjects. PMID- 21315283 TI - In vitro assessment of the agonist properties of the novel 5-HT1A receptor ligand, CUMI-101 (MMP), in rat brain tissue. AB - INTRODUCTION: Development of agonist positron emission tomography (PET) radioligands for the 5-HT neurotransmitter system is an important target to enable the understanding of human 5-HT function in vivo. [(11)C]CUMI-101, proposed as the first 5-HT(1A) receptor agonist PET ligand, has been reported to behave as a potent 5-HT(1A) agonist in a cellular system stably expressing human recombinant 5-HT(1A) receptors. In this study, we investigate the agonist properties of CUMI-101 in rat brain tissue. METHODS: [(35)S]-GTPgammaS binding studies were used to determine receptor function in HEK (human embryonic kidney) 293 cells transfected with human recombinant 5-HT(1A) receptors and in rat cortex and rat hippocampal tissue, following administration of CUMI-101 and standard 5 HT1A antagonists (5-HT, 5-CT and 8-OH-DPAT). RESULTS: CUMI-101 behaved as an agonist at human recombinant 5-HT(1A) receptors (pEC(50) 9.2). However, CUMI-101 did not show agonist activity in either rat cortex or hippocampus at concentrations up to 10 MUM. In these tissues, CUMI-behaved as an antagonist with pK(B)s of 9.2 and 9.3, respectively. CONCLUSIONS: Our studies demonstrate that as opposed to its behavior in human recombinant system, in rat brain tissue CUMI-101 behaves as a potent 5-HT(1A) receptor antagonist. PMID- 21315284 TI - Biological studies in animal models using [99mTc](CO)3 recombinant annexin V as diagnostic agent of apoptotic processes. AB - INTRODUCTION: There are many diseases associated with variations in the expression of apoptosis such as organ rejection after transplantation, myocardial ischemia or infarct and neurodegenerative diseases. For this reason, the early visualization of this process is relevant to set fast and effective therapeutic strategies. METHODS: The precursor was prepared according to the procedure reported by R. Alberto, R. Schibli, P. Schubiger, U. Abram, and T. Kaden [Reactions with the technetium and rhenium carbonyl complexes (NEt(4))[MX(3)(CO)(3)]. Synthesis and structure of Tc(CN-But)(3)(CO)(3)](NO(3)) and (Net(4))[Tc(2)(MU-SCH(2)CH(2)OH)(3)(CO)(3)], Polyhedron 1996;15: 1079-89]. Recombinant annexin V was incubated with [(99m)Tc](H(2)O)3(CO)(3)(+) solution, previously neutralized with buffer. Biodistribution studies were performed in 8 week-old female Wistar rats. Animals were housed and treated in compliance with institutional guidelines related to animal experimentation. Work protocol was previously approved by the Animal Ethics Committee of the university. Two groups of rats were defined. One was used as control and the other group was previously injected with 150 mg/kg ip of cyclophosphamide to induce apoptosis. RESULTS: The synthesis of carbonyl precursor achieved yields higher than 90%, and the radiolabeled protein was obtained with 92% of radiochemical purity and high stability in vitro. An important uptake in apoptotic tissues was confirmed by biodistributions, scintigraphic images and histological studies. CONCLUSIONS: Biodistribution studies revealed hepatobiliary elimination, high stability in vivo and important uptake in the reticuloendothelial system. In the pathologic model, higher uptake values correspond to the liver, spleen, lungs and femur. Histological studies confirmed the development of apoptosis at 8 and 24 h postinduction in the spleen and lymphocyte bulks in the peribronchial area. Scintigraphic images confirmed high uptake both the spleen and the lungs. PMID- 21315285 TI - Reduction of stimulated sodium iodide symporter expression by estrogen receptor ligands in breast cancer cells. AB - PURPOSE: The sodium iodide symporter (NIS) mediates active iodide uptake in lactating breast tissue, and when its levels are enhanced by all-trans retinoic acid (atRA), NIS has been proposed as a target for the imaging and radiotherapy of breast cancer. Importantly, the estrogen receptor alpha (ERalpha) is an important regulator of atRA induced NIS gene expression in breast cancer cells. In this study, we investigated the effect of an ER agonist (17beta-estradiol, E(2)) or antagonist [trans-hydroxytamoxifen (TOT) or raloxifene (RAL)] treatment on the regulation of NIS gene expression and iodide uptake in an ERalpha-positive breast cancer (MCF-7) model. METHODS: NIS functional activity was measured in vitro by (125)I uptake assay after incubation with E(2) (from 10(-15) to 10(-5) M), TOT (from 5*10(-8) to 5*10(-6) M), or RAL (from 5*10(-8) to 5*10(-6) M) in the presence or absence of atRA (10(-7) M). Under the same conditions, NIS mRNA expression was examined by reverse transcriptase polymerase chain reaction. Athymic mice with MCF-7 xenograft tumors were treated with atRA alone or atRA together with E(2) to evaluate the change of (125)I uptake in tumor tissues in vivo. RESULTS: In the iodide uptake study in cells, E(2), TOT, or RAL treatment alone did not stimulate (125)I uptake. However, when iodide uptake was stimulated by atRA, cotreatment with E(2), TOT or RAL decreased (125)I uptake in a concentration-dependent manner. The hormone effects on NIS mRNA expression levels in MCF-7 cells were similar. The results of the in vivo biodistribution study showed that (125)I uptake was reduced 50% in tumor tissues of mice treated with atRA/E(2) as compared to tumors treated only with atRA. CONCLUSION: Our results suggest that combination treatment of atRA and ER ligands could limit the functional activity of the NIS gene induced by atRA, thereby compromising its use as a target for diagnosis or radiotherapy in breast cancer. PMID- 21315286 TI - PET imaging of blood flow and glucose metabolism in localized musculoskeletal tumors of the extremities. AB - INTRODUCTION: Little is known about blood flow in sarcomas. Our purpose was to study glucose metabolism and blood flow in untreated localized musculoskeletal tumors of the extremities using [(18)F]fluorodeoxyglucose (FDG), oxygen-15 labeled water ([15O]H(2)O) and positron emission tomography (PET). METHODS: Six patients with high-grade osteosarcoma (OS), two with soft-tissue sarcoma (STS) and one with aneurysmal bone cyst had PET studies with [15O]H(2)O and FDG. Arterial blood sampling and autoradiography calculation method were used to define blood flow as milliliters per 100 g times minutes. Tumor FDG uptake was measured as standardized uptake values (SUVs) and regional metabolic rates for FDG (rMRFDG). Two patients also had FDG PET studies during (one patient) and after (two patients) preoperative chemotherapy. All patients underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). The PET findings were compared with the clinical follow-up data and results of DCE-MRI. RESULTS: Blood flow in bone tumors was 31.7-75.2 ml/(100 g*min) and in STS 9.0-45.9 ml/(100 g*min). [(18)F]-Fluorodeoxyglucose uptake and rMRFDG in untreated bone tumors were 5.4-18.4 and 10.9-57.4 MUmol/100 g/min, respectively. [(18)F] Fluorodeoxyglucose uptake and rMRFDG in STS were 2.6-11.5 and 5.6-32.2 MUmol/100 g/min, respectively. Four of five sarcomas with SUV>9.0 have already relapsed. High blood flow in untreated OS was related to long overall survival, while the predictive power of glucose metabolism was less apparent. Good histopathological response to therapy was not associated with long survival. CONCLUSIONS: Measurement of blood flow in musculoskeletal tumors appears to be feasible by PET and [(15)O]H(2)O. The influence of tumor blood flow and glucose metabolism on the final outcome in sarcoma is variable and needs further research. PMID- 21315287 TI - From the editor's perspective... PMID- 21315289 TI - Improving antibiotic treatment outcomes through the implementation of a midline: piloting a change in practice for cystic fibrosis patients. AB - Midline catheters have many advantages for chronically ill patients needing up to six weeks intravenous therapy and medications, and when inserted in a sterile environment and correctly monitored and maintained, have a significantly lower association of infection and thrombus than previously suggested. Furthermore, there is a reduction in central collateral vessel formation from incursions into the superior vena cava, associated with peripherally inserted central catheters. Midline use was examined in a cystic fibrosis control group. Lines were checked daily until removal. All midline catheter tips were sent for culture on removal and data from 42 midlines placed in 2006 were retrieved from the hospital scientist for analysis. Twenty-seven inpatients with cystic fibrosis were identified and informed of the trial and possible risks of midline use. Outcome variables included infection and thrombus rates. On conclusion of the trial, data demonstrated both zero infection and thrombus rates in the study patient population. Midline catheters were monitored for a further 12 months following conclusion of the trial and infection rates continued to be below 1% and thrombus rates lower than 2%. In the specified group, the parameters of use for midlines fit with international cystic fibrosis intravenous antibiotic protocols currently adhered to. The study has begun to generate evidence to inform clinical practice, improve patient outcomes and supports the role of the specialist nurse in implementing midlines for cystic fibrosis patients. PMID- 21315288 TI - A study of 90-day outcomes for a cohort of patients admitted to an Australian metropolitan acute stroke unit. AB - This study investigated patients' 90-day outcomes poststroke following an admission to one Australian metropolitan Acute Stroke Unit (ASU) and examined premorbid risk factors associated with these outcomes. Data from patients consecutively admitted from January 2006 to July 2007 (n = 54) to an acute stroke unit within 48 hours of onset of symptoms were linked with the Quality in Acute Stroke Care research project data and were analyzed to identify associations between premorbid risk factors (atrial fibrillation, hypertension, high cholesterol, smoking and diabetes); demographic, clinical and stroke characteristics; and death, disability (modified Rankin Score >= 2), dependency (Barthel Index score >= 95) and health status (SF-36) poststroke. Within 90 days, 4 participants had died and 45.5% were classified as dependent. Of the total participants, 56.8% were classified as disabled. The SF-36 mean scores indicated that the cohort had less than optimal physical health (46.7, SD = 9.8) and mental health (46.4, SD = 13.1). Analysis of baseline variables showed that participants with atrial fibrillation were more likely to have a severe stroke (p = 0.037). Patients presenting with intracerebral haemorrhage (p = 0.017) and those with subsequent strokes (p = 0.000) had significantly lower Barthel Index scores. A lower SF-36 physical component score at 90 days was significantly associated with intracerebral haemorrhages (p = 0.018) and subsequent strokes (p = 0.026). Although most patients were alive at 90 days poststroke, there were variable levels of morbidity-associated stroke type, subsequent strokes and premorbid risk factors, particularly atrial fibrillation. The findings provide insight into the 90-day outcomes of patients discharged from an ASU, which may be of use to plan appropriate postdischarge support for this group. In particular, aggressive management of stroke risk factors to prevent recurrent stroke is warranted. PMID- 21315290 TI - Aortic aneurysm with valvular insufficiency: is it due to Marfan syndrome or hypertension? A case report and review of literature. AB - Aortic aneurysm can result from both Marfan syndrome (MFS) and hypertension. Hypertension is more easily detected by the use of ubiquitous sphygmomanometer but MFS diagnosis requires a summation of a set of clinical features, including increased cardiac output from aortic regurgitation. A common complication of aortic aneurysm may result in apparent elevation in systolic pressure in a MFS patient with aortic root dilatation and regurgitation. Thus a patient with MFS presenting with aortic regurgitation may be misdiagnosed as having hypertensive heart disease. Clinical case presentation of a 47-year-old woman referred to the cardiology unit with the diagnosis of aortic aneurysm with regurgitation secondary to hypertension was found to have MFS. Relevant literature on diagnostic criteria of MFS and differences in aortic root disease secondary to MFS and that secondary to hypertension was reviewed. Physicians should have a high index of suspicion and consider MFS as a differential diagnosis of aortic aneurysm, especially in younger patients. PMID- 21315291 TI - ACCF/AHA/ACR/SCAI/SIR/SVM/SVN/SVS 2010 performance measures for adults with peripheral artery disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Performance Measures, the American College of Radiology, the Society for Cardiac Angiography and Interventions, the Society for Interventional Radiology, the Society for Vascular Medicine, the Society for Vascular Nursing, and the Society for Vascular Surgery (Writing Committee to Develop Clinical Performance Measures for Peripheral Artery Disease). PMID- 21315292 TI - Surgical site infection initiative: implementations and observations. PMID- 21315293 TI - Review of an article: Son, H, Min, S, Min, S, et al. (2010). Evaluation of the efficacy of the forearm basilic vein transposition arteriovenous fistula. Journal of Vascular Surgery, 51(3), 667-72. PMID- 21315294 TI - Designing computerized decision support that works for clinicians and families. Foreword. PMID- 21315296 TI - Potential dangers of accelerant use in arson. AB - Accelerant-enhanced combustion often characterizes a fire that has been deliberately set to disguise a murder scene or to destroy property for insurance purposes. The intensity and rapidity of spread of fires where accelerants have been used are often underestimated by perpetrators who may sustain heat-related injuries. The case of a 49-year-old male who was using gasoline (petrol) as an accelerant is reported to demonstrate another danger of this type of activity. After ignition, an explosion occurred that destroyed the building and caused the death of the victim who was crushed beneath a rear wall of the commercial premises. Gasoline vapour/air mixtures are extremely volatile and may cause significant explosions if exposed to flame. Given the potential danger of explosion, arsonists using accelerants do so at significant risk to themselves and to others in the vicinity. PMID- 21315295 TI - Designing computerized decision support that works for clinicians and families. AB - Evidence-based decision-making is central to the practice of pediatrics. Clinical trials and other biomedical research provide a foundation for this process, and practice guidelines, drawing from their results, inform the optimal management of an increasing number of childhood health problems. However, many clinicians fail to adhere to guidelines. Clinical decision support delivered using health information technology, often in the form of electronic health records, provides a tool to deliver evidence-based information to the point of care and has the potential to overcome barriers to evidence-based practice. An increasing literature now informs how these systems should be designed and implemented to most effectively improve outcomes in pediatrics. Through the examples of computerized physician order entry, as well as the impact of alerts at the point of care on immunization rates, the delivery of evidence-based asthma care, and the follow-up of children with attention deficit hyperactivity disorder, the following review addresses strategies for success in using these tools. The following review argues that, as decision support evolves, the clinician should no longer be the sole target of information and alerts. Through the Internet and other technologies, families are increasingly seeking health information and gathering input to guide health decisions. By enlisting clinical decision support systems to deliver evidence-based information to both clinicians and families, help families express their preferences and goals, and connect families to the medical home, clinical decision support may ultimately be most effective in improving outcomes. PMID- 21315297 TI - Postmortem degradation of porcine articular cartilage. AB - Postmortem decompositional changes to articular cartilage were analysed to help establish a new methodology in determining the postmortem interval. The cartilage was collected from porcine trotters buried in simulated shallow graves for different time periods. The trotters were dissected to expose the cartilage located at the metatarsal joint. Numerous macroscopic changes including a colour change, gradual degradation of cartilage and adjacent soft tissues and a loss of cartilage covering articular facets were observed. Further analysis was conducted using light microscopy (LM) and scanning electron microscopy (SEM) to assess microstructural changes. Both LM and SEM showed gradual morphological and structural changes to the tissue over time, along with loss of nuclear material. Tissue surface analysis with SEM highlighted orthorhombic shaped crystals that appear at approximately three weeks postmortem and persist until six weeks postmortem. Both microscopic and macroscopic characteristics followed a recognisable succession over the burial times observed. These results indicate that postmortem degradation of articular cartilage may be useful for estimating a presumptive postmortem interval. PMID- 21315298 TI - The work of forensic physicians with police detainees in the Canberra City Watchhouse. AB - Forensic physicians provide both medical care and forensic consultations to detainees in police custody. There is a paucity of Australian data regarding characteristics of detainees and the type of work provided by forensic physicians in this setting. This retrospective audit of a clinical forensic service in Canberra, Australia will assist with service planning, future data collection and the training of forensic physicians. PMID- 21315299 TI - Age estimation from pulp/tooth area ratio in maxillary incisors among Egyptians using dental radiographic images. AB - Age estimation from dental radiographs is a non-destructive, simple method to obtain information. The aim of this study was to determine the reliability of age estimation from Egyptians' incisors radiographs. 144 periapical radiographs of maxillary (central & lateral) incisors (both sexes) aged 12-60 were used. Digital camera was used to image the radiographs. Images were computed and pulp/tooth area ratios were determined by AutoCAD Program. Data were subjected to correlation and regression analysis which showed statistically significant correlation (r = 0.23 &P = 0.006 for maxillary central incisors and r = -0.2 &P = 0.05 for maxillary lateral incisors) between age and pulp tooth area ratio. Linear regression equations were determined separately for both central and lateral incisors along with the corresponding Standard Error of Estimate, which ranged from 1.2 to 5.08 years. Consequently, it was concluded that pulp/tooth area ratios of incisors are reliable for estimation of age among Egyptians in forensic work. PMID- 21315300 TI - Causes of premature mortality in Swedish drug abusers: a prospective longitudinal study 1970-2006. AB - AIMS: To evaluate premature mortality and causes of death from young adulthood to middle age in a cohort of drug users followed during almost four decades. DESIGN: Follow-up study of a consecutive cohort of patients with drug abuse/dependence. METHODS: A cohort of 561 drug abusers, admitted to a detoxification and short term rehabilitation unit 1970-1978 was followed to December 31st, 2006. Standardized interviews and hospital records with toxicological analyses were used for demographic data, substance use and psychiatric diagnoses at admission. For Follow-up analyses, autopsy protocols including toxicology tests and death certificates were obtained for assessment of causes of death which were coded according to ICD-10. Age-group standardized mortality ratios were calculated independently for both sexes. RESULTS: 204 persons (36.4%) were deceased by 2006. SMR was 5.94 for the cohort. Compared to an age- and gender-matched population, the risk of premature death was about eighteen times higher between the ages of 20-44 and about five times higher from 45 up to the age of 69. Of 120 (59%) drug related deaths, 43 were opiate overdoses, and 3 were overdose from amphetamine. A total of 53 (26%) persons died violent deaths: 39 suicides, of which 25 were drug related, 3 homicides and 12 accidents. The Swedish national causes of death register underestimated drug-related death by 37% and suicide by 85% compared to the results from this study. CONCLUSIONS: The cohort of drug abusers had an increased risk of premature often drug-related and violent death well into middle age, and to a great extent the drug addicts died from the same drug they had abused when they were first admitted for treatment. The underestimation of drug related death and suicide in some national death cause registers could be reduced if the doctor routinely records ICD codes when issuing death certificates and autopsy protocols. PMID- 21315301 TI - A new classification of zoophilia. AB - Zoophilia is a paraphilia whereby the perpetrator gets sexual pleasure in having sex with animals. Most jurisdictions and nations have laws against this practice. Zoophilia exists in many variations, and some authors have attempted to classify zoophilia previously. However unanimity does not exist among various classifications. In addition, sexual contact between humans and animals has been given several names such as zoophilia, zoophilism, bestiality, zooerasty and zoorasty. These terms continue to be used in different senses by different authors, creating some amount of confusion. A mathematical classification of zoophilia, which could group all shades of zoophilia under various numerical classes, could be a way to end this confusion. Recently a ten-tier classification of necrophilia has been proposed to bring an end to a similar confusion extant among various terms referring to necrophilia. It is our proposition that various shades of zoophilia exist on a similar continuum. Thus, each proposed class of zoophilia can be "mapped" to a similar class of necrophilia already proposed. This classification has an intuitive appeal, as it grades all shades of zoophilia from the least innocuous behavior to the most criminal. It is hoped that it would also bring an end to the existing confusion among several zoophilia related terms. In addition, since each proposed class of zoophilia can be exactly "mapped" to classes of another paraphilia (necrophilia), it may point to an "equivalence" among all paraphilias not yet explored fully. This area needs further exploration. PMID- 21315302 TI - Gender differentiation by finger ridge count among South Indian population. AB - The goal of this study is to determine the gender based on finger ridge count within a well-defined area. Rolled fingerprints were taken from 550 subjects (275 men and 275 women) belonging to South Indian population all within the age range of 18-65 years. Results show that women have a significantly higher ridge count than men. Application of Baye's theorem suggests that a fingerprint possessing ridge density <13 ridges/25 mm(2) is most likely to be of male origin. Likewise, a fingerprint having ridge count >14 ridges/25 mm(2) are most likely to be of female origin. These results are helpful as a tool for fingerprint experts as they can be used as a presumptive indicator of gender based on the degree of ridge density. PMID- 21315303 TI - Age estimation from clavicular epiphyseal union sequencing in a Northwest Indian population of the Chandigarh region. AB - Medial clavicular epiphysis is the long bone epiphysis to fuse last and therefore, is useful for estimating age in the post-pubertal period. Age estimation was done from clavicles obtained from 343 cadavers (252 males and 91 females) of known age. The data was subjected to statistical analysis to see whether the difference obtained in the various ages was significant or not. Commencement of fusion was seen as early as 18 years of age in both male and female clavicles. No clavicle showed complete fusion until the age of 22 years. Complete fusion of the medial end of the clavicle was seen latest at 32 years in the male clavicles while the same was observed at 31 years in the female bones, i.e., the medial epiphysis of female clavicles fused one year earlier than their male counterparts. Advanced stages of clavicular epiphyseal union were seen in most of the clavicles after 24 years of age in females and 23 years of age in males. No significant difference was noticed in both sexes for the right and left clavicles as regards to the occurrence of various stages of epiphyseal union. PMID- 21315304 TI - Pistol thrown to the ground by shooter after fatal self inflicted gunshot wound to the chest. AB - We report the case of a 46-year-old man found dead in his apartment in a chair with a gunshot wound in his chest. All circumstances pointed to suicide as the manner of death. Finding the weapon, a SIG Sauer P228 pistol, about 2 m away from the decedent with an obstacle between weapon and corpse however generated speculation about third party involvement. Scene investigations and ballistic calculations showed that with a high probability the weapon must have been purposefully thrown away by the decedent after he fired the lethal gunshot. PMID- 21315305 TI - Fatal hypernatremia due to drinking a large quantity of shoyu (Japanese soy sauce). AB - We report a case of fatal salt poisoning in a 55-year-old woman who suffered from depression and drank a large quantity of shoyu (Japanese soy sauce). She presented with the highest ever documented serum sodium level of 187 mmol/L. This was associated with symptoms of cerebral damage which developed within hours after drinking the soy sauce. She died as a result of massive pulmonary edema, despite intensive medical treatment. Viewing the results of clinical and postmortem investigations together, her death could clearly be attributed to drinking a large quantity of soy sauce. PMID- 21315306 TI - Naphyrone: analytical profile of the new "legal high" substitute for mephedrone. PMID- 21315307 TI - Effects of abscisic acid and nitric oxide on trap formation and trapping of nematodes by the fungus Drechslerella stenobrocha AS6.1. AB - The in vitro effects of abscisic acid (ABA) and nitric oxide (NO) on the nematode trapping fungus Drechslerella stenobrocha AS6.1 were examined. The average number of traps (constricting rings) per colony and the percentage of nematodes (Caenorhabditis elegans) trapped were greatly increased by addition of ABA but greatly suppressed by addition of sodium nitroprusside (SNP, an NO donor) to corn meal agar. The suppressive effect of SNP was not negated by addition of an NO synthase competitive inhibitor (l-naphthylacetic acid, L-NNA) or an NO-specific scavenger [2-(4-carboxyphenyl)-4,4, 5,5-tetramethylimidazoline-1-oxyl-3-oxide, cPTIO]. When added without SNP, however, L-NNA and cPTIO caused moderate increases in trap number and trapping. The results indicate that the trap formation and nematode-trapping ability of D. stenobrocha were enhanced by ABA but decreased by exogenous NO. PMID- 21315308 TI - Evidence for high degrees of specialisation, evolutionary diversity, and morphological distinctiveness in the genus Bremia. AB - Bremia lactucae is one of the most important pathogens in lettuce production. Recent molecular studies revealed considerable genetic variation in this species complex. However, only few accessions from the same host have been examined for most species and no study investigating the morphological distinctiveness of phylogenetic lineages of Bremia has so far been reported. Thus it is believed that morphological species delimitation in Bremia is not feasible. In the present study, multiple accessions of neglected species, which had been described decades ago, but have not been widely accepted, were investigated, considering both multi gene phylogenies and morphological characters. All previously described species from host genera other than Lactuca investigated, Bremia microspora, Bremia ovata, Bremia saussureae, and Bremia sonchicola, could be confirmed as distinct, host-specific entities. Also, morphological characteristics of their conidiophores and conidia allowed delimitation of these species. Therefore, not only the wide species concept to merge all Bremia species on the Asteraceae under B. lactucae is inappropriate but also their delimitation on the basis of morphological characters seems feasible. In addition, it has been shown that Bremia elliptica is phylogenetically distinct from the other species infecting the genus Lactuca, B. lactucae. It is therefore concluded that B. lactucae is most likely limited to Lactuca sativa and closely-related species, and that most species of Bremia are highly host specific. This finding might stimulate the search for durable resistance genes in genera closely related to the genus Lactuca and in divergent species of the genus itself. PMID- 21315309 TI - FUM cluster divergence in fumonisins-producing Fusarium species. AB - Fumonisins are polyketide-derived mycotoxins, produced by several Fusarium species, and its biosynthetic pathway is controlled by the FUM cluster--a group of genes exhibiting a common expression pattern during fumonisin biosynthesis. The most common are the B analogues with fumonisin B(1) (FB(1)) being the most prevalent. At least a part of the inter- and intraspecific variation in FBs synthesis level can be explained by the sequence differences inside FUM cluster. The aim of our study was to evaluate the toxin production and sequence variability in FUM genes and intergenic regions among thirty isolates of seven species reported as potential fumonisins producers: Fusarium anthophilum, Fusarium fujikuroi, Fusarium nygamai, Fusarium oxysporum, Fusarium proliferatum, Fusarium subglutinans and Fusarium verticillioides, particularly with respect to FBs synthesis. Fumonisins were produced in high amounts (over 1mg g(-1)) by one isolate of F. subglutinans, three of F. verticillioides and all F. proliferatum isolates except one, regardless of the host organism. The remaining isolates produced low amounts of FBs and two F. verticillioides isolates didn't produce it at all. The lowest variation in amount of toxin produced was found among F. proliferatum isolates. Based on the translation elongation factor 1alpha (tef 1alpha) sequence of F. fujikuroi, a species-specific marker was developed. The intergenic region presents similar opportunity for F. nygamai identification. The phylogenetic reconstruction based on FUM1 gene generally reflects the scenario presented by tef-1alpha sequences. Although the sequence similarities for intergenic regions were lower than in coding regions, there are clearly conserved patterns enabling separation of different subsets of species, including the non producer species. PMID- 21315310 TI - Integration of additional copies of Trichoderma reesei gene encoding protein O mannosyltransferase I results in a decrease of the enzyme activity and alteration of cell wall composition. AB - In fungi, transfer of the first mannosyl residue to proteins during their O glycosylation is catalyzed by protein O-mannosyltransferases. Integration of additional copies of the pmt1 gene into Trichoderma reesei genome unexpectedly resulted in the silencing of pmt1 expression. Strains carrying the additional copies of pmt1 gene exhibited lower total activity of protein O mannosyltransferases, lower O- and N-glycosylation of secreted proteins and showed defects in their cell wall composition. Moreover, the strains grew slowly on solid medium and were hypersensitive to an antifungal reagent, Calcofluor white. These results indicate that protein O-mannosyltransferases are required for proper cell wall formation, and their decreased activity influences not only O- but also N-glycosylation. PMID- 21315311 TI - Bioactive metabolites from Stenocarpella maydis, a stalk and ear rot pathogen of maize. AB - Stenocarpella maydis is a fungal pathogen of major importance that causes a dry rot of maize ears and is associated with a neuromycotoxicosis in cattle grazing harvested maize fields in southern Africa and Argentina. In an effort to investigate the potential roles of S. maydis metabolites in the fungal disease cycle, ethyl acetate extracts of solid-substrate fermentations of several S. maydis isolates from maize grown in the United States were found to exhibit significant phytotoxic, antifungal, and antiinsectan activity. Chemical investigations of extracts of S. maydis isolates from Illinois and Nebraska led to the isolation or detection of the known metabolites diplodiatoxin, chaetoglobosins K and L, and (all-E)-trideca-4,6,10,12-tetraene-2,8-diol as major components. A culture of Stenocarpella macrospora from maize grown in Zambia produced diplosporin and chaetoglobosins K and L as major components that were isolated. Diplodiatoxin produced significant lesions in a maize leaf puncture wound assay. Diplosporin and chaetoglobosin K displayed moderate antiinsectan activity in dietary assays against the fall armyworm Spodoptera frugiperda, while chaetoglobosin K exhibited significant antifungal activity against Aspergillus flavus and Fusarium verticillioides. Using LC-ESIMS and (1)H NMR data, diplodiatoxin was detected as a major component in S. maydis-rotted grain, stalks, and stalk residues. This constitutes the first report of chaetoglobosins K and L from S. maydis, of (all-E)-trideca-4,6,10,12-tetraene-2,8-diol from Stenocarpella, and the first reported detection of diplodiatoxin, or any other Stenocarpella metabolite, in diseased maize seeds and stalk tissues. PMID- 21315312 TI - Molecular phylogeny and paclitaxel screening of fungal endophytes from Taxus globosa. AB - We studied the endophytic mycoflora associated with Taxus globosa, the Mexican yew. The study localities; Las Avispas (LA), San Gaspar (SG), and La Mina (LM) were three segments of cloud forest within the range of Sierra Gorda Biosphere Reserve, Mexico. Overall, 245 endophytes were isolated and 105 representative Ascomycota (morphotaxons) were chosen for phylogenetic and genotypic characterization. Maximum likelihood analyses of large subunit of ribosomal RNA (LSU) rDNA showed well-supported clades of Dothideomycetes, Eurotiomycetes, Leotiomycetes, Pezizomycetes, and Sordariomycetes. Analyses of ITS rDNA groups showed 57 genotypes (95% sequence similarity), in general consistent with the phylogenetically delimitated taxa based on LSU rDNA sequences. The endophyte diversity measured by Fisher's alpha, Shanonn, and Simpson indices was ca. three fold and ca. two-fold greater in LM than in LA and SG respectively. A screening for paclitaxel using a competitive inhibition enzyme immunoassay showed 16 positive isolates producing between 65 and 250 ng l(-1). The isolates included Acremonium, Botryosphaeria, Fusarium, Gyromitra, Nigrospora, Penicillium, three novel Pleosporales, and Xylaria. PMID- 21315313 TI - Oogonial biometry and phylogenetic analyses of the Pythium vexans species group from woody agricultural hosts in South Africa reveal distinct groups within this taxon. AB - Pythium vexans fits into the internal transcribed spacer (ITS) clade K sensu Levesque & De Cock (2004). Within clade K, P. vexans forms a distinct clade containing two enigmatic species, Pythium indigoferae and Pythium cucurbitacearum of which no ex-type strains are available. In South Africa, as well as in other regions of the world, P. vexans isolates are known to be heterogeneous in their ITS sequences and may consist of more than one species. This study aimed to investigate the diversity of South African P. vexans isolates, mainly from grapevines, but also citrus and apple using (i) phylogenetic analyses of the ITS, cytochrome c oxidase (cox) I, cox II, and beta-tubulin regions and (ii) seven biometric oogonial parameters. Each of the phylogenies clustered P. vexans isolates into a single well-supported clade, distinct from other clade K species. The beta-tubulin region was phylogenetically uninformative regarding the P. vexans group. The ITS phylogeny and combined cox I and II phylogenies, although each revealing several P. vexans subclades, were incongruent. One of the most striking incongruences was the presence of one cox subclade that contained two distinct ITS subclades (Ib and IV). Three groups (A-C) were subjectively identified among South African P. vexans isolates using (i) phylogenetic clades (ITS and cox), (ii) univariate analysis of oogonial diameters, and (iii) multivariate analyses of biometric oogonial parameters. Group A is considered to be P. vexans s. str. since it contained the P. vexans CBS reference strain from Van der Plaats-Niterink (1981). This group had significantly smaller oogonial diameters than group B and C isolates. Group B contained the isolates from ITS subclades Ib and IV, which formed a single cox subclade. The ITS subclade IV isolates were all sexually sterile or produced mainly abortive oospores, as opposed to the sexually fertile subclade Ib isolates, and may thus represent a distinct assemblage within group B. Although ITS subclade Ib included the P. indigoferae ex-type sequence, this group was considered to be P. vexans since South African isolates in this clade produced globose sporangia. Group C contained four apple isolates that were related to, but distinct from P. cucurbitacearum. Although P. vexans groups A-C might be distinct species, they are not described here as such due to (i) these groups only representing some of the known diversity in P. vexans, (ii) conflicting gene tree phylogenies preventing phylogenetic species identification, and (iii) sexually sterile isolates preventing the broad application of biometrical data. PMID- 21315314 TI - Species-specific PCR-DGGE markers to distinguish Pyrenophora species associated to cereal seeds. AB - Pyrenophora species, toxigenic cereal pathogens, and causal agents of leaf and kernel diseases, bring about economic and food safety concerns. Traditionally, Pyrenophora taxa have been identified microscopically after a period of incubation on culture media. In this study, a simple nested PCR-denaturing gel electrophoresis (DGGE) method was developed to detect, differentiate and identify six Pyrenophora species in plant tissues. A primer, specific to Pyrenophora species and able to amplify a fragment of the ribosomal RNA (rRNA), following first round amplification with universal ITS primers, was designed by reviewing Pyrenophora ribosomal DNA sequences deposited in GenBank. The specificity of the primer was assessed by submitting its sequence to the GenBank Basic Local Alignment Search Tool (BLAST) algorithm, and was also tested with DNA extracted from several ascomycetous, basidiomycetous, and zygomycetous taxa. No PCR product was obtained from non-Pyrenophora species. PCR amplification of DNA extracted from pure cultures of the different Pyrenophora species generated amplicons of an approximate 350bp. DGGE effectively separated between all six Pyrenophora amplicons. Subsequently, amplicons of known Pyrenophora species were used as molecular markers when Pyrenophora infected wheat seed was analyzed by PCR-DGGE. The molecular-based approach described herein can be used to identify different Pyrenophora species directly from infected plant material. PMID- 21315315 TI - The obligately lichenicolous genus Lichenoconium represents a novel lineage in the Dothideomycetes. AB - Lichenicolous fungi are obligately lichen-associated organisms that have evolved many times throughout the Ascomycota and Basidiomycota. Approximately 20% of lichenicolous ascomycetes are recognized only from asexual (anamorphic) characteristics, so the phylogenetic position of many groups has never been resolved. Here we present the first molecular phylogeny of Lichenoconium, a genus of strictly asexual, obligately lichenicolous species with broad geographic distributions and diverse host ecologies. We obtained nuclear and mitochondrial rDNA sequences from fungal cultures isolated from four species in the genus, including a new species, Lichenoconium aeruginosum sp. nov., collected in France, Luxembourg and Netherlands. Our multilocus phylogeny supports the monophyly of fungi in the genus Lichenoconium, and places the genus in the Dothideomycetes, an ascomycete class made up mainly of saprobes and plant-associated endophytes and pathogens. There are only a few recognized groups of lichen-formers in the Dothideomycetes, but Lichenoconium is not supported as being closely related to any of these, nor to any other recognized order within the Dothideomycetes. Given that Lichenoconium is but one of over 100 genera of anamorphic lichenicolous fungi, most of which have never been studied phylogenetically, we suggest that asexual lichenicolous fungi may represent novel and evolutionarily significant phylogenetic groups in the Kingdom Fungi. PMID- 21315316 TI - Sinomyces: a new genus of anamorphic Pleosporaceae. AB - Sinomyces gen. nov. is described for Ulocladium alternariae and two new species from China. These three species differ from Ulocladium in producing simple conidiophores with a single, cicatrized apical pore or 1 or 2 short, uniperforate, geniculate sympodial proliferations. Phylogenetic analysis of partial DNA sequences of the glyceraldehyde-3-phosphate dehydrogenase gene (gpd) gene and a fragment of the Alternaria alternata major allergen (Alt a 1) gene, using Maximum-Parsimony (MP), Maximum-Likelihood (ML) and Bayesian approaches, indicates that Sinomyces is distinct within the Alternaria-Stemphylium complex, although its closest relatives could not be determined. Sinomyces alternariae comb. nov. and the new species Sinomyces obovoideus and Sinomyces fusoideus are proposed. PMID- 21315317 TI - [Myringoplasties. A retrospective analysis of our surgical outcomes]. AB - OBJECTIVE: The aim of this study was to present, myringoplasty case results in our department. Different factors were studied to confirm their prognostic value. MATERIALS AND METHODS: A total of 126 myringoplasties from 2006 until 2010 were reviewed, collecting patient-related details, descriptions of the anatomical defect and the most interesting surgical aspects. RESULTS: Subtotal perforations (35.7%) were the most frequently observed. In 89.7% of the operations, the transcanal approach was preferred. The medial technique (underlay) to the tympanic membrane was the most performed (97.6%). Cartilage was the principal graft used (82.5%). Complete closure of the perforation was obtained in 71.1% of the cases at 6 months follow-up. Recurrences of the perforations were of minimal size in 11.9% of the cases, partial in 11.1% and with a cartilage fragment gap in 4.8%. The mean time in which these defects were registered was 3.82 months. The mean post-operative auditory gain was 12.8 decibels at 6 months. CONCLUSIONS: Myringoplasty is an appropriate technique for restoring tympanic integrity and obtaining functional benefit. Dried middle ear mucosa and posterior perforations seem to be related with better functional results. PMID- 21315318 TI - In honour of the 65th birthday of Valentin B. Fainerman. AB - This Honorary Note is dedicated to the 65th birthday of Valentin Fainerman and summarizes some of his contributions to the field of interfacial dynamics. First of all, he made the maximum bubble pressure tensiometry the most frequently used methodology in the short time range of surfactant adsorption at liquid surfaces. This work allows us now to use experimental data down to the time range of sub milliseconds for analyzing adsorption mechanisms of surfactants and polymers and their mixtures. The contributions of V.B. Fainerman to the quantitative understanding of the thermodynamics of adsorption represent a significant step ahead and describe adsorption layers even of rather complex nature, such as mixed protein-surfactant layers. These models consider molecular interfacial reorientation and aggregation. His thermodynamic approach is able to explain various interfacial systems which includes for example also phase transitions in insoluble monolayers. Based on diffusional transport and the proposed thermodynamic models, the adsorption kinetics and dilational rheology of liquid interfacial layers have reached a new level of understanding. PMID- 21315319 TI - Effects of exercise training on gingival oxidative stress in obese rats. AB - OBJECTIVE: The purpose of the present study was to investigate the effects of exercise training on serum reactive oxygen species (ROS) level and gingival oxidative stress in obese rats fed a high-fat diet. DESIGN: Rats were divided into three groups (n = 14/group): one control group (fed a regular diet) and two experimental groups (fed a high-fat diet with and without exercise training [treadmill: 5 days/week]). The rats were sacrificed at 4 or 8 weeks. The level of serum reactive oxidative metabolites (ROM) was measured as an indicator of circulating ROS. The level of 8-hydroxydeoxyguanosine (8-OHdG) and reduced-form glutathione (GSH)/oxidised-form glutathione (GSSG) ratio were determined to evaluate gingival oxidative stress. RESULTS: The obese rats fed a high-fat diet without exercise training showed higher serum ROM levels [Carratelli Units (CARR U)] (mean +/- SD; 413 +/- 64) than the control (333 +/- 12) at 4 weeks (p = 0.023). Such a condition resulted in higher 8-OHdG levels (ng/mg mtDNA) (0.97 +/- 0.18) (p < 0.05) and a lower GSH/GSSG ratio (17.0 +/- 3.1) (p < 0.05) in gingival tissues, compared to the control (0.55 +/- 0.13 for 8-OHdG and 23.6 +/- 5.8 for GSH/GSSG ratio) at 8 weeks. In addition, the obese rats fed a high-fat diet with exercise training showed lower serum ROM (623 +/- 103) (p < 0.001) and gingival 8 OHdG levels (0.69 +/- 0.17) (p = 0.012) than those without exercise training (1105 +/- 95 for ROM and 0.55 +/- 0.13 for 8-OHdG) at 8 weeks. CONCLUSIONS: Obesity prevention by exercise training may effectively suppress gingival oxidative stress by decreasing serum ROS in rats. PMID- 21315320 TI - Acid-promoted synthesis of per-O-sulfated fucooligosaccharides related to fucoidan fragments. AB - The synthesis of per-O-sulfated derivatives of di-, tetra-, hexa-, octa-, dodeca , and hexadecafucosides related to natural fucoidans of different types has been performed with the use of previously reported acid-promoted protocol for per-O sulfation of polyols by SO(3) complexes. During the treatment of (1->3)-linked oligofucosides under these conditions with the promotion by TfOH, the unusual rearrangement of the reducing pyranose residue into furanose one was observed. To avoid the formation of rearrangement by-products, the use of a series of strong acids as promoters of sulfation of large oligofucosides was studied and the improved protocol was developed based on the use of TFA instead of TfOH. The efficiency of the new method was demonstrated by the syntheses of per-O-sulfated derivatives of dodeca- and hexadecafucosides. The described method of O-sulfation opens access to the preparation of the oligosaccharides related to fucoidan fragments and their per-O-sulfated derivatives interesting for elucidation of the relationship between their structure and biological activity. PMID- 21315321 TI - Aldobiouronic acid domains in Helicobacter pylori. AB - Helicobacter pylori cell-surface glycans exert strong influences in host-microbe interplays and define the strain's immunological signature. Envisaging the development of a carbohydrate-based vaccine against the gastroduodenal pathogen H. pylori, several clinical isolates are being screened for their cell-surface glycan profile. The present work concerns H. pylori clinical specimen PTAV79 that abundantly expressed amylose-like glycans. These polysaccharides were isolated in glycan-rich fractions resultant from phenol-water extractions and purified by Bio Gel P2. Structural studies showed that the glycans are linked to glycerol and present aldobiouronic acid domains composed of [->3)-alpha-D-GlcA-(1->4)-alpha-D Glc-(1->] repeating units. The amylose domains were constituted by an average of 19 Glc residues and the acidic moieties had an average number of 10 aldobiouronic acid repeating units. These polysaccharides were isolated in fractions that, although hydrophilic, were rich in stearic acid, strongly suggesting that they are present as glycerolipids anchored to cell-surface. PMID- 21315322 TI - [Laparoscopic recto-sigmoidal resection with transanal extraction of the surgical specimen (NOSE) as a treatment for early colorectal cancer (description of the technique)]. PMID- 21315323 TI - Re.: Radiation-reduction strategies in cardiac computed tomographic angiography. PMID- 21315324 TI - The paradox of moral focus. AB - When we evaluate moral agents, we consider many factors, including whether the agent acted freely, or under duress or coercion. In turn, moral evaluations have been shown to influence our (non-moral) evaluations of these same factors. For example, when we judge an agent to have acted immorally, we are subsequently more likely to judge the agent to have acted freely, not under force. Here, we investigate the cognitive signatures of this effect in interpersonal situations, in which one agent ("forcer") forces another agent ("forcee") to act either immorally or morally. The structure of this relationship allowed us to ask questions about both the "forcer" and the "forcee." Paradoxically, participants judged that the "forcer" forced the "forcee" to act immorally (i.e. X forced Y), but that the "forcee" was not forced to act immorally (i.e. Y was not forced by X). This pattern obtained only for human agents who acted intentionally. Directly changing participants' focus from one agent to another (forcer versus forcee) also changed the target of moral evaluation and therefore force attributions. The full pattern of judgments may provide a window into motivated moral reasoning and focusing bias more generally; participants may have been motivated to attribute greater force to the immoral forcer and greater freedom to the immoral forcee. PMID- 21315325 TI - Making tools isn't child's play. AB - Tool making evidences intelligent, flexible thinking. In Experiment 1, we confirmed that 4- to 7-year-olds chose a hook tool to retrieve a bucket from a tube. In Experiment 2, 3- to 5-year-olds consistently failed to innovate a simple hook tool. Eight-year-olds performed at mature levels. In contrast, making a tool following demonstration was easy for even the youngest children. In Experiment 3, children's performance did not improve given the opportunity to manipulate the objects in a warm-up phase. Children's tool innovation lags substantially behind their ability to learn how to make tools by observing others. PMID- 21315326 TI - Neural system for heartbeats recognition using genetically integrated ensemble of classifiers. AB - This paper presents the application of genetic algorithm for the integration of neural classifiers combined in the ensemble for the accurate recognition of heartbeat types on the basis of ECG registration. The idea presented in this paper is that using many classifiers arranged in the form of ensemble leads to the increased accuracy of the recognition. In such ensemble the important problem is the integration of all classifiers into one effective classification system. This paper proposes the use of genetic algorithm. It was shown that application of the genetic algorithm is very efficient and allows to reduce significantly the total error of heartbeat recognition. This was confirmed by the numerical experiments performed on the MIT BIH Arrhythmia Database. PMID- 21315327 TI - Short-term association between exposure to ozone and mortality in Oporto, Portugal. AB - Exposures to air pollution in developed countries have generally decreased over the last two decades. However, many recent epidemiological studies have consistently shown positive associations between low-level exposure to air pollutants and health outcomes. In Portugal, very few studies have analysed the acute effect of air pollutants on health. The present study evaluates the association between exposure to air pollution and daily mortality in the Oporto Metropolitan Area, Portugal. Generalised additive models were used for this analysis. Pollutants assessed were ozone, nitrogen dioxide, and particulate matter (PM(10)). Models were adjusted for time trend, seasonality, and weather. We report that an increase of 10 MUg/m(3) in the daily ozone 8-h maximum moving average corresponds to an increase of 0.95% (95%CI: 0.30, 1.60) and 1.58% (95%CI: 0.45, 2.73) in non-accidental mortality and cardiovascular mortality, respectively, in the summer season. A significant effect of 0.67% (95% CI: 0.03:1.32) was also found for the association between PM(10) and non-accidental mortality in the summer season. Associations with ozone and PM(10) exposures were higher in the elderly people. No significant effects on mortality were observed during the summer season with nitrogen dioxide exposures. Our analyses provide the first significant evidence in Oporto that exposures to O(3) and PM(10) have adverse effects on the health of the general population in the summer months. PMID- 21315328 TI - Phthalates in cosmetic and personal care products: concentrations and possible dermal exposure. AB - Phthalates are multifunctional chemicals that are used in a variety of consumer products including cosmetic and personal care products. This study aims at determining phthalate levels in cosmetic and personal care products obtained from the Canadian market. Overall 252 products including 98 baby care products were collected at retail stores in several provinces across Canada in year 2007. These products included fragrances, hair care products (hair sprays, mousses, and gels), deodorants (including antiperspirants), nail polishes, lotions (body lotions and body creams), skin cleansers, and baby products (oils, lotions, shampoos and diaper creams). Samples were extracted with different organic solvents, depending on the types of the products, followed by gas chromatography mass spectrometry (GC-MS) analysis. Of the 18 investigated phthalates, diethyl phthalate (DEP), dimethyl phthalate (DMP), diisobutyl phthalate (DiBP), di-n butyl phthalate (DnBP) and di(2-ethylhexyl) phthalate (DEHP) were detected. The detection frequencies were in the following order: DEP (103 out of 252 products)>DnBP (15/252)>DiBP (9/252)>DEHP (8/252)>DMP (1/252). DEP was detected in almost all types of surveyed products with the highest levels (25,542 MUg/g, equal to 2.6%) found in fragrances. DnBP was largely present in nail polish products with the highest concentration of 24,304 MUg/g (2.4%). DnBP was also found in other products such as hair sprays, hair mousses, skin cleansers and baby shampoos at much lower concentrations (36 MUg/g and less). Levels of other detected phthalates were generally low in the products. Based on these values, daily dermal exposure dosage to five phthalates was estimated for three age groups, female adults (60 kg); toddlers (0.5-4 years) and infants (0-6 months), through the use of cosmetic and personal care products. The exposure estimation, however, was based on existing products use pattern data, instead of probabilistic model based population use distribution. For female adults, the maximal daily exposure of 78 MUg/kg bw/d was determined for DEP. The maximal daily exposure was much lower for the other four phthalates (DEHP, 0.82 MUg/kg bw/d; DnBP, 0.36 MUg/kg bw/d; and DMP, 0.03 MUg/kg bw/d). The exposure for DiBP was not calculated due to its very low levels (<10 MUg/g) in products. Toddlers and infants in this case had a maximal daily exposure to DEP of 20 and 42 MUg/kg bw/d, respectively. PMID- 21315329 TI - [Malakoplakia of the middle ear]. PMID- 21315330 TI - [Burnout syndrome and medical residents: reflections on the magnitude of the phenomena]. PMID- 21315331 TI - [Electronic calendar as an organization element in Internal Medicine services]. AB - The growing volume of information and introduction of new technologies in the Internal Medicine hospital department mare making the traditional updating "methods" of knowledge and organization obsolete. The development of new tools could help the management of information and organization of the medical departments is outdated. Electronic calendar such as the Google calendar facilitate adequate coordination among health care professionals. Our experience suggests that the Google calendar is a simple and useful tool that helps planning and organization of the clinical, educational, and research activities of the different medical departments, limits loss of information and improves efficacy with a close to zero cost of infrastructure. PMID- 21315332 TI - Myomectomy reduces endometrial T2 relaxation times. AB - Magnetic resonance imaging was used to measure the endometrial T2 relaxation times of patients with infertility with fibroma. Although the location of fibromas did not influence the T2 relaxation times, we did observe a significant decrease in endometrial T2 relaxation times after myomectomy. PMID- 21315333 TI - Antimullerian hormone as a predictor of controlled ovarian hyperstimulation outcome: comparison of two commercial immunoassay kits. AB - This study was performed to compare antimullerian hormone (AMH) levels measured by two commercially available AMH measuring kits currently available, and to evaluate the AMH levels as predictor of controlled ovarian hyperstimulation (COH) outcome using the two different kits. The two assays for AMH measurement provide similar results, and serum AMH levels measured by the two kits both could be used as COH outcome predictors with similar reference values. PMID- 21315334 TI - Should the myometrial free margin still be considered a limiting factor for hysteroscopic resection of submucous fibroids? A possible answer to an old question. AB - OBJECTIVE: To evaluate the feasibility of the hysteroscopic resection of type II submucous fibroids regardless of the myometrial free margin separating them from the serosa and to report the dynamic changes the margin undergoes after the various phases of resection. DESIGN: A prospective observational study. SETTING: A tertiary-level university hospital. PATIENT(S): Thirteen women with single type II submucous fibroids of <= 5 cm in diameter regardless of the myometrial free margin. INTERVENTION(S): Hysteroscopic myomectomy and ultrasound evaluation of myometrial free margin before and after each phase of the procedure. MAIN OUTCOME MEASURE(S): The possibility of a complete one-step resection, the incidence of intraoperative or postoperative complications, and the analysis of the dynamic changes occurring in myometrial free margin. RESULT(S): Complete resection was performed successfully in all patients. No complications were registered. The myometrial free margin decreased on the distension of the uterine cavity and then increased progressively and significantly after the various phases of resection. CONCLUSION(S): In selected cases and in experienced hands, hysteroscopic myomectomy of type II submucous fibroids may be performed successfully and safely regardless of the myometrial free margin. Myometrial free margin increases progressively with each step of the procedure probably leading to an increasing margin of safety. PMID- 21315335 TI - Comparison of revised American Fertility Society and ENZIAN staging: a critical evaluation of classifications of endometriosis on the basis of our patient population. AB - OBJECTIVE: To develop a classification that takes deep infiltrating endometriosis into account, the ENZIAN score was introduced. The ENZIAN classification supplements the revised American Fertility Society (AFS) score with regard to the description of deep infiltrating endometriosis, retroperitoneal structures, and other organs. The null hypothesis was that classifying a lesion by the revised AFS as well as the ENZIAN system is not meaningful, because the two systems express different locations. DESIGN: Retrospective. SETTING: Hospital admissions. PATIENT(S): Two hundred nineteen women admitted for endometriosis. INTERVENTION(S): Surgical interventions. MAIN OUTCOME MEASURE(S): Classification of the severity of endometriosis according to the revised AFS and the ENZIAN classification, focusing on the distribution pattern in deep infiltrating endometriosis, and the identification of duplicate classifications of the same lesions in the revised AFS as well as the ENZIAN systems. RESULT(S): Deep infiltrating endometriosis was diagnosed in 160 of 219 patients (73%). These patients had 236 lesions of deep infiltrating endometriosis, which were classified by ENZIAN as follows: compartment a (vertical): 26%; compartment b (horizontal): 41%; compartment c (dorsal): 24%; uterine adenomyosis: 4%; bladder disease: 2%; ureter disease: 1%; and bowel disease: 2%. The severity of deep infiltrating endometriosis according to ENZIAN (grades 1 = mild to 4 = severe) was as follows: grade 1: 45%; grade 2: 26%; grade 3: 19%; grade 4: 10%. Fifty eight patients were classified according to ENZIAN although they did not fulfill the criteria of deep infiltrating endometriosis and had previously been classified according to the revised AFS classification. Adaptation of the ENZIAN score would reduce the diagnoses of deep infiltrating endometriosis by 36% (95% confidence interval [CI] 29%-44%). CONCLUSION(S): The ENZIAN score is a helpful aid to describe deep infiltrating endometriosis, but needs to be adapted. PMID- 21315336 TI - Changes in serum anti-Mullerian hormone levels may predict damage to residual normal ovarian tissue after laparoscopic surgery for women with ovarian endometrioma. AB - We measured serum anti-Mullerian hormone levels before and after surgery in women undergoing unilateral and monolocular cystectomy for benign ovarian diseases. Comparing to control benign cysts, we found a significant decline in serum anti Mullerian hormone levels with consequent depletion of follicles in tissue specimens after surgery for women with ovarian endometrioma. PMID- 21315337 TI - Is uterine-sparing surgical management of persistent postpartum hemorrhage truly a fertility-sparing technique? AB - Among 23 women who underwent diagnostic hysteroscopy after triple uterine artery ligation with or without hemostatic multiple square suturing for the management of postpartum hemorrhage (PPH), five had abnormal findings. Endometritis was statistically significantly associated with abnormal diagnostic hysteroscopy findings. Twelve patients developed subsequent pregnancies, and four had abnormal obstetric outcomes: one placenta percreta, one placenta accreta, one recurrent postpartum hemorrhage, and one intrauterine growth retardation. PMID- 21315338 TI - Rupture of endometriotic ovarian cyst causes acute hemoperitoneum in twin pregnancy. AB - OBJECTIVE: To present a case of an acute hemoperitoneum caused by a ruptured ovarian cyst in a late twin pregnancy. DESIGN: Case report study. SETTING: Department of Obstetrics and Gynecology, Medical University of Graz, Austria. PATIENT(S): A woman with a history of surgery for endometriosis and currently pregnant with dichorionic twins after IVF presented with acute abdominal pain. INTERVENTION(S): Serial ultrasound assessment revealed a massive hemoperitoneum that was caused by a ruptured endometriotic ovarian cyst. Emergency laparotomy was performed. MAIN OUTCOME MEASURE(S): Hemostasis. RESULT(S): Laparotomy led to operative hemostasis and preterm cesarean section of healthy twins at 27 weeks of gestation. CONCLUSION(S): Endometriosis occurs in about 10% of women of reproductive age and carries an infertility rate of up to 50%. Severe endometriosis used to be a rare event in patients with spontaneously conceived pregnancies. However, during the last decade, the increased use of assisted reproductive technologies has led to higher fertility rates in patients with endometriosis and to a higher incidence of multiple gestations. Therefore, the number of pregnant women with endometriosis and associated complications may rise. PMID- 21315339 TI - Vitrified-warmed blastocyst transfer cycles yield higher pregnancy and implantation rates compared with fresh blastocyst transfer cycles--time for a new embryo transfer strategy? AB - OBJECTIVE: To compare the clinical outcome of fresh versus vitrified-warmed blastocyst transfer (BT) cycles. DESIGN: Retrospective study. SETTING: Medical university affiliated hospital. PATIENT(S): Women aged less than 40 years undergoing BT cycles. INTERVENTION(S): Vitrification and warming of blastocyst with the Cryotop system. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate (CPR), implantation rate (IR), and multiple pregnancy rate (MPR). RESULT(S): In 110 fresh BT cycles versus 136 vitrified-warmed BT cycles performed from January 2007 to March 2010, the IR and CPR of vitrified-warmed BT cycles were 37.0% and 55.1%, respectively, which were statistically significantly higher than the corresponding values of 25.2% and 36.4% obtained for fresh BT cycles. Additionally, the MPR was not statistically significantly different between vitrified-warmed and fresh BT cycles when a similar number of blastocysts was transferred to patients. CONCLUSION(S): Vitrified-warmed BT cycles resulted in statistically significantly higher CPR and IR compared with fresh BT cycles. A new embryo transfer strategy is therefore proposed whereby fresh BT would be avoided in the initial ovarian stimulation cycle. Instead, all the patient's available blastocysts would be vitrified-warmed and transferred in subsequent cycles. PMID- 21315340 TI - Fat tissue morphology of long-term sex steroid deficiency and estrogen treatment in female rats. AB - After long-term estradiol deficiency, female rats displayed body mass gain accompanied by an increase in the size of adipocytes, an increase in hyperglycemia, and a decrease in insulinemia. The effects were reversed by daily estradiol treatment. Adiposity was suggested by the increased vascular endothelial growth factor expression in castrated rats, whereas the proliferative effect of estradiol was suggested by the increased fibronectin expression in treated rats. PMID- 21315341 TI - Follicle-stimulating hormone administered at the time of human chorionic gonadotropin trigger improves oocyte developmental competence in in vitro fertilization cycles: a randomized, double-blind, placebo-controlled trial. AB - OBJECTIVE: To determine whether an additional follicle-stimulating hormone (FSH) bolus administered at the time of the human chorionic gonadotropin (hCG) trigger can improve the developmental competence of the oocyte. DESIGN: Randomized, double-blind, placebo-controlled, clinical trial. SETTING: Academic medical center. PATIENT(S): Women undergoing a long agonist suppression in vitro fertilization (IVF) protocol for treatment of infertility. INTERVENTION(S): FSH bolus at time of hCG trigger versus placebo. MAIN OUTCOME MEASURE(S): Primary outcome; fertilization; secondary outcomes: oocyte recovery, implantation rate, and clinical and ongoing pregnancy/live birth rates. RESULT(S): A total of 188 women (mean age: 36.2 years; range: 25 to 40 years) were randomized. Fertilization (2PN/#oocyte) was statistically significantly improved in the treatment arm (63% vs. 55%) as was the likelihood of oocyte recovery (70% vs. 57%). There was no statistically significant difference in clinical pregnancy rate (56.8% vs. 46.2%) or ongoing/live birth rate (51.6% vs. 43.0%). CONCLUSION(S): Improvements in IVF success rates have largely been due to optimization of embryo culture and stimulation protocols; less attention has been directed toward methods to improve induction of final oocyte maturation. This was the first randomized, double-blind, placebo-controlled trial to modify the ovulation trigger to improve oocyte competence, as demonstrated by the statistically significant improvement in fertilization. PMID- 21315342 TI - Expression of endometrial protein markers in infertile women and the association with subsequent in vitro fertilization outcome. AB - Endometrial biopsies were performed during the luteal phase just before an IVF cycle in 104 infertile women, and immunohistochemical staining was performed to investigate expression patterns of hCG-LH receptor, leukemia-inhibitory factor, macrophage colony-stimulating factor, HOXA-10, vascular endothelial growth factor A, and their relation to subsequent IVF pregnancy. Only glandular expression of vascular endothelial growth factor A in early luteal endometrium was significantly higher in the pregnant group compared with the nonpregnant group (6.0 +/- 3.9 vs. 2.9 +/- 3.4) and thus could be a predicting marker for subsequent IVF pregnancy. PMID- 21315343 TI - A unique peri-prosthetic fracture pattern in well fixed femoral stems with polished, tapered, collarless design of total hip replacement. AB - Peri-prosthetic fractures (PPF) are a recognised complication following hip arthroplasty. Prosthesis design and type influence PPF pattern. Surgeons rely on classification systems, such as the Vancouver, to aid treatment planning. This study highlights a specific fracture pattern that occurs with cemented well-fixed polished, tapered, collarless (PTC) stems. We reviewed a consecutive series of 21 PPF around well fixed PTC stems. The majority of the fractures were classified pre-operatively as Vancouver B2 (14/21), but there were also B1 (6/21) and A type fractures. The B2 fractures had common radiological and intra-operative findings: a spiral fracture with extensive fragmentation of bone and cement, debonding of cement from the implant, cement fracture, and a well-fixed cement-bone interface. Reconstruction of these fractures was more difficult than suggested by the radiographs. Two of the six patients who were considered to have a Vancouver B1 fracture underwent open reduction and internal fixation (ORIF), and had treatment related complications. Retrospective review of the radiographs showed subtle features, such as subsidence of the stem into the centraliser, that are characteristic of a B2 fracture pattern. In summary, it is important to recognise this fracture pattern around secure PTC stems in order to prevent misinterpretation of the fracture as a Vancouver B1 rather than a B2, leading to failure of treatment, and to alert the surgeon that complex reconstruction will be required because of the extensive fragmentation. PMID- 21315344 TI - Early-onset severe growth restriction and placental abruption associated with Breus mole. PMID- 21315345 TI - Cervical leukorrhea is correlated with bacterial vaginosis. PMID- 21315346 TI - Complications of mid-urethral slings for treatment of stress urinary incontinence. AB - OBJECTIVE: To compare the incidence of complications associated with the use of retropubic tension-free vaginal tape (TVT) and transobturator tension-free vaginal tape (TVT-O) for the management of stress urinary incontinence (SUI). METHODS: In a cross-sectional study, 1081 patients were treated for SUI via mid urethral slings, and the outcomes of those treated via TVT and those treated via TVT-O were compared. Patients who suffered from recurrent or mixed urinary incontinence were excluded. RESULTS: Group 1 included patients treated via TVT (n=207) and group 2 included those treated with TVT-O (n=570). There was a higher incidence of bladder perforation (5.4% versus 0.6%; P=0.001) and hematoma formation (9.1% versus 1.5%; P=0.001) in group 1 than in group 2. Compared with group 1, there was higher incidence of vaginal wall perforation in group 2 (0.0% versus 3.8%, P=0.044). The rate of intraoperative complications was not related to patient age, body mass index, or parity. Of the patients who did not leak urine during a cough test 1 month after surgery, 90.9% still had a negative cough test at the long-term follow-up. CONCLUSION: TVT-O was superior to TVT with regard to the incidence of bladder perforation and hematoma formation, but it resulted in more vaginal wall injuries. PMID- 21315347 TI - Implementation of the Zambia electronic perinatal record system for comprehensive prenatal and delivery care. AB - OBJECTIVE: To characterize prenatal and delivery care in an urban African setting. METHODS: The Zambia Electronic Perinatal Record System (ZEPRS) was implemented to record demographic characteristics, past medical and obstetric history, prenatal care, and delivery and newborn care for pregnant women across 25 facilities in the Lusaka public health sector. RESULTS: From June 1, 2007, to January 31, 2010, 115552 pregnant women had prenatal and delivery information recorded in ZEPRS. Median gestation age at first prenatal visit was 23weeks (interquartile range [IQR] 19-26). Syphilis screening was documented in 95663 (83%) pregnancies: 2449 (2.6%) women tested positive, of whom 1589 (64.9%) were treated appropriately. 111108 (96%) women agreed to HIV testing, of whom 22% were diagnosed with HIV. Overall, 112813 (98%) of recorded pregnancies resulted in a live birth, and 2739 (2%) in a stillbirth. The median gestational age was 38weeks (IQR 35-40) at delivery; the median birth weight of newborns was 3000g (IQR 2700 3300g). CONCLUSION: The results demonstrate the feasibility of using a comprehensive electronic medical record in an urban African setting, and highlight its important role in ongoing efforts to improve clinical care. PMID- 21315348 TI - Treatment and outcome of stage Ia1 squamous cell carcinoma of the uterine cervix. AB - OBJECTIVE: To evaluate the treatment and clinical outcome of patients with FIGO stage IA1 cervical squamous cell carcinoma (SCC). METHODS: Medical records, including 5-year follow-up, were reviewed for 276 patients with stage IA1 SCC. RESULTS: As definitive surgery, 152 (55.1%), 72 (26.1%), 40 (14.5%), and 12 (4.3%) patients underwent conization, hysterectomy, hysterectomy with pelvic lymphadenectomy (PL), and radical hysterectomy with PL, respectively. Among these groups, the 5-year recurrence-free rate was 94.1%, 98.6%, 95%, and 100%, respectively, and the survival rate was 98.7%, 98.6%, 100%, and 100%, respectively. Recurrent disease was identified among 12 (4.3%) patients, and was related to the depth of invasion (P<0.001). Eleven (4.0%) of 276 patients were found to have lymph vascular space invasion (LVSI). There were no positive lymph nodes among 52 patients who underwent PL, including those with LVSI. Conization was followed by hysterectomy in 49 patients. In these patients, residual intraepithelial neoplasia was found in 18 women, 3 of whom had no involved margins on previous conization. In the group of patients treated by conization, recurrence correlated with the status of the endocervical and lateral cone margin (P<0.001). CONCLUSION: As a conservative approach, conization is an effective and reasonable treatment option for stage IA1 SCC, especially in actively reproductive women. PMID- 21315349 TI - Hypericum perforatum for the treatment of premenstrual syndrome. PMID- 21315350 TI - Task shifting and sharing in Tigray, Ethiopia, to achieve comprehensive emergency obstetric care. AB - OBJECTIVE: To assess the contribution of nonphysician clinicians (NPCs) to comprehensive emergency obstetric care (CEmOC) in Tigray, Ethiopia. METHODS: We conducted a retrospective review of the obstetric records of all women treated from January 1, 2006, to December 31, 2008, at the 11 hospitals and 2 health centers with CEmOC status in Tigray. Data were collected using 2 questionnaires, one concerning the facility and the other concerning the patient. RESULTS: During the studied period 25,629 deliveries and 11,059 obstetric procedures (3369 of which were major surgical interventions) were performed at these 13 institutions. Overall, NPCs performed 63.3% of these procedures, which included 1574 (55.5%) of a total of 2835 cesarean deliveries. Whereas the cesarean deliveries performed by physicians were more often elective, those performed by NPCs were more often indicated by an emergency. Maternal deaths, fetal deaths, and length of hospital stay did not statistically differ by type of attending staff. CONCLUSION: Not only do NPCs perform a significant proportion of emergency obstetric procedures in Tigray, but the postoperative outcomes achieved under their care are similar to those attained by physicians. Strengthening NPC training programs in emergency obstetric surgery should further reduce maternal and fetal mortality and morbidity in Ethiopia. PMID- 21315351 TI - Pandemic (H1N1) 2009 virus infection during pregnancy in South India. AB - OBJECTIVE: To assess the clinical profile of pregnant/puerperal women from a semi urban Indian population who were infected with pandemic (H1N1) 2009 virus (P[H1N1]2009v) and to evaluate their outcome. METHODS: In a cross-sectional study, 566 women (79 pregnant/puerperal, 487 nonpregnant) who presented to a tertiary care hospital with influenza-like illness were tested for P(H1N1)2009v by real-time reverse transcriptase polymerase chain reaction. Outcomes measures were the maternal mortality and the perinatal mortality rate (PMR). RESULTS: Twenty (25%) pregnant/puerperal and 144 (30%) nonpregnant women tested positive for P(H1N1)2009v, with 5 pregnant and 3 postpartum women requiring admission to the intensive care unit (ICU). P(H1N1)2009v-related mortality was higher in pregnant than nonpregnant women (25% versus 8%; P=0.04). In the pregnant/puerperal cohort, factors associated with death included delayed presentation (median 6days versus 1.5days in survivors; P=0.007), need for ICU admission (P=0.004), need for ventilation (P=0.001), and renal failure (P=0.001). The PMR was 55.5/1000 births compared with 33.5/1000 births in the hospital overall during the study period. CONCLUSION: In a low-income country, P(H1N1)2009v infection in pregnancy is associated with considerable mortality. Delayed presentation to a tertiary care center, lack of awareness, and restricted access to treatment might have contributed to the high mortality. PMID- 21315352 TI - Long-term treatment with low-dose metoprolol CR/XL is associated with increased plaque echogenicity: the Beta-blocker Cholesterol-lowering Asymptomatic Plaque Study (BCAPS). AB - OBJECTIVES: To examine whether the decrease in IMT progression rate in the carotid bulb induced by metoprolol CR/XL treatment (25mg once daily) observed in the beta-blocker Cholesterol-lowering Asymptomatic Plaque Study (BCAPS) was accompanied by an effect on carotid plaque echogenicity. METHODS: Gray scale median (GSM) in carotid plaques, used as a score of echogenicity, was measured at baseline and after 36 months in those 341 subjects (aged 49-69 years) with an asymptomatic moderate- to large-sized carotid plaque present at baseline and at follow-up. Participants were in a factorial design assigned to treatment with metoprolol CR/XL (25mg once daily), fluvastatin (40 mg once daily) or corresponding placebo. RESULTS: After 36 months plaques were more echogenic in participants treated compared to those not treated with metoprolol CR/XL (57.3 +/ 16.8 versus 51.8 +/- 20.0, p=0.006). GSM had increased more from baseline in the metoprolol CR/XL treated subjects (25 +/- 15 versus 18 +/- 20, p<0.001), and plaques that had become more echolucent were less frequent in the metoprolol CR/XL treated subjects (3.6% versus 17.0%, p<0.001). CONCLUSIONS: Long-term treatment with low dose metoprolol CR/XL in clinically healthy subjects with moderate-sized carotid plaques was associated with increase in plaque echogenicity, suggesting a potential beneficial effect of the beta-blocker treatment on plaque stability. PMID- 21315353 TI - Native high-density lipoproteins inhibit platelet activation via scavenger receptor BI: role of negatively charged phospholipids. AB - OBJECTIVES: HIGH-density lipoproteins (HDL) are a negative predictor of platelet dependent thrombus formation and reduced platelet activation has been observed in vitro in the presence of HDL3, a major HDL fraction. However, mechanisms underlying the anti-thrombotic effects of HDL3 are poorly understood. Scavenger receptors class B represent possible HDL3 binding partners on platelets. We here investigated the role of scavenger receptor class B type I (SR-BI) and CD36 in mediating inhibitory effects of native HDL3 on thrombin-induced platelet activation. METHODS AND RESULTS: Rhodamine isothiocyanate-labeled HDL3 bound specifically to platelets and HDL3 binding was inhibited by scavenger receptor class B ligands such as phosphatidylserine (PS)- or phosphatidylinositol (PI) containing liposomes or maleylated albumin (mBSA). By contrast, scavenger receptor class A ligands failed to displace HDL3 from platelets. HDL3, PS- and PI liposomes, and mBSA inhibited thrombin-induced platelet aggregation, fibrinogen binding, P-selectin expression and mobilization of intracellular Ca(2+). In addition, PS- and PI-liposomes emulated HDL3-induced intracellular signaling cascades including diacylglycerol production and protein kinase C activation. The reduction of platelet activation by liposomes was related to their PS or PI content. Moreover, inhibitory effects of native HDL3 were enhanced after enriching lipoproteins with PS, while PS- and PI-poor HDL2 failed to inhibit platelet aggregation and Ca(2+) mobilization. Both, HDL3 and PS-containing liposomes failed to inhibit thrombin-induced activation of platelets obtained from SR-BI-deficient mice but not CD36-deficient mice. CONCLUSION: We suggest that SR-BI is a functional receptor for native HDL3 on platelets that generates an inhibitory signal for platelet activation. The content of negatively charged phospholipids (PS, PI) in HDL may be an important determinant of their anti thrombotic potential. PMID- 21315354 TI - Effects of smoking on coronary microcirculatory function: a twin study. AB - BACKGROUND: In asymptomatic smokers, coronary microcirculatory dysfunction, assessed by coronary flow reserve (CFR), is an early indicator of cardiovascular risk. Inflammation and oxidative stress may be the mechanisms through which smoking affects the microvasculature. OBJECTIVES: The purpose of this study was to determine the relationship between smoking and CFR, taking into account potential shared genetic effects. METHODS: We examined 360 male middle aged twins (288 non-smokers and 72 smokers), including 46 twin pairs discordant for current smoking. Coronary flow reserve (CFR) in response to adenosine was measured with positron emission tomography [N(13)] ammonia and quantitation of coronary blood flow at rest and after adenosine stress. Inflammation was assessed by measuring interleukin-6 and C-reactive protein, and oxidative stress was determined by measuring plasma hydroperoxides, glutathione (GSH), the oxidized form of GSH, GSSG, and the ratio of GSH to GSSG. RESULTS: CFR was significantly lower in smokers compared to nonsmokers (2.25 vs. 2.75, p<0.01). This relationship persisted after accounting for known cardiovascular disease risk factors, and was marginally affected by adjusting for inflammatory and oxidative stress biomarkers. In addition, in smoking-discordant twin pairs, CFR in the smoking twin was significantly lower than in the non-smoking co-twin (2.25 vs. 2.67, p=0.03) even after adjustment for cardiovascular risk factors. CONCLUSIONS: Our results demonstrate the adverse effects of smoking in the early phases of cardiovascular disease. Mechanisms other than peripherally measured inflammation and oxidative stress are involved. PMID- 21315355 TI - Deferoxamine promotes angiogenesis via the activation of vascular endothelial cell function. AB - BACKGROUND: Deferoxamine (DFO), an iron chelator for disorders of excess iron, upregulates the expression of angiogenic factors, such as vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2), indicating that it affects angiogenesis. Herein, we clarify the effect and mechanism of action of DFO on angiogenesis. METHODS AND RESULTS: In an in vitro study, DFO increased endothelial nitric oxide synthesis (eNOS) phosphorylation in human aortic endothelial cells (HAECs), which were inhibited by the phosphatidylinositol 3 kinase inhibitor LY294002. Tube formation, cell proliferation, and cell migration in HAECs were promoted by DFO, which were significantly reduced by LY294002. In an in vivo study, DFO promoted blood flow recovery in response to the hindlimb ischemia in mice with unilateral hindlimb surgery. The density of capillaries and arterioles in ischemic muscle was higher in DFO-treated mice compared to vehicle treated mice. Endothelial cell proliferation increased and oxidative stress and apoptosis decreased in ischemic muscles of DFO-treated mice. The phosphorylation of Akt and eNOS on the ischemic side was elevated and urinary nitric oxide/nitric dioxide (NOx) excretion was higher in DFO-treated mice compared to vehicle treated mice. The effect of DFO on angiogenesis was abolished in eNOS-deficient mice with hindlimb ischemia. CONCLUSION: These findings indicate that DFO promotes revascularization via the activation of vascular endothelial cell function by an Akt-eNOS-dependent mechanism. PMID- 21315356 TI - Prognostic importance of baseline and serial changes in microalbuminuria in patients with resistant hypertension. AB - OBJECTIVE: The prognostic value of microalbuminuria is unsettled in resistant hypertension. The objective was to evaluate the importance of baseline and serial changes in albuminuria as predictors of cardiovascular morbidity and mortality in patients with resistant hypertension. METHODS: 531 resistant hypertensives had urinary albumin excretion rate (UAER) measured prospectively at baseline and at the 2nd year of follow-up. Primary endpoints were a composite of fatal and non fatal cardiovascular events, all-cause and cardiovascular mortalities. Total strokes and coronary heart disease (CHD) events were secondary endpoints. Multiple Cox regression assessed the associations between UAER and endpoints. RESULTS: After a median follow-up of 4.9 years, 72 patients died, 42 from cardiovascular causes; 96 cardiovascular events occurred, 42 strokes and 47 CHD events. After adjustment for several cardiovascular risk factors, baseline UAER, either analyzed as a continuous variable or dichotomized at different cut-off values, was an independent predictor of the composite endpoint, all-cause and cardiovascular mortality, strokes and CHD events. Each 10-fold increase in UAER implied a significant 1.6, 1.5, 2.0, 1.5 and 1.6-fold higher risk, respectively, for each of the above endpoints. Serial changes in microalbuminuria status during follow-up tended to parallel changes in cardiovascular risk, regression of microalbuminuria was associated with a 27% lower risk and development with a 65% higher risk of having a cardiovascular event. CONCLUSIONS: Baseline albuminuria strongly predicts cardiovascular morbidity and mortality in resistant hypertensive patients and serial changes in microalbuminuria may translate into changes in risk. Microalbuminuria reduction may be a goal of anti-hypertensive treatment. PMID- 21315357 TI - Proteinuria in early childhood due to familial LCAT deficiency caused by loss of a disulfide bond in lecithin:cholesterol acyl transferase. AB - INTRODUCTION: Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare recessive disorder of cholesterol metabolism characterized by the absence of high density lipoprotein (HDL) and the triad of corneal opacification, hemolytic anemia and glomerulopathy. PATIENTS: We here report on FLD in three siblings of a kindred of Moroccan descent with HDL deficiency. In all cases (17, 12 and 3 years of age) corneal opacification and proteinuria were observed. In the 17-year-old female proband, anemia with target cells was observed. RESULTS: Homozygosity for a mutation in LCAT resulted in the exchange of cysteine to tyrosine at position 337, disrupting the second disulfide bond in LCAT. LCAT protein and activity were undetectable in the patients' plasma and in media of COS7 cells transfected with an expression vector with mutant LCAT cDNA. Upon treatment with an ACE inhibitor and a thiazide diuretic, proteinuria in the proband decreased from 6g to 2g/24h. CONCLUSION: This is the first report that FLD can cause nephropathy at a very early age. PMID- 21315358 TI - The non-synonymous Arg230Cys variant (R230C) of the ATP-binding cassette transporter A1 is associated with low HDL cholesterol concentrations in Mexican adults: a population based nation wide study. AB - OBJECTIVE: To search for an association between the non-synonymous Arg230Cys variant (R230C) of the ATP-binding cassette transporter A1 and low HDL cholesterol levels in a Mexican, population-based nation wide survey. METHODS: The 2000 National Health Survey is a cross sectional study that included individuals from 400 cities. All individuals who had a 9-12-h fasted blood sample and a DNA sample were selected (n = 1729). These cases were randomly distributed; no bias was detected for sex, education, region or socioeconomic status. The R230C variant was genotyped using TaqMan assays. RESULTS: In individuals with the R230C/C230C genotypes (39.03 mg/dl (36.63-41.43)) lower HDL-C levels (p < 0.001) were observed compared to those with the R230R genotype (44.7 mg/dl (43.31 46.24)). The difference remained significant after adjusting for gender, body mass index and waist circumference; the mean difference in HDL cholesterol levels between alleles was 5.73 +/- 1.4 mg/dl. The magnitude of the effect was significantly greater in males. The C230 allele of ABCA1 was associated with an increased risk for hypoalphalipoproteinemia (OR 1.66 (95%CI 1.08-2.54), p < 0.05). The population attributable risk (PAR) for having hypoalphalipoproteinemia of the C230 allele of the ABCA1, after considering the confounding effect of waist circumference and gender, was 12.2% (95%CI 1.4-24.2%). CONCLUSION: The non synonymous Arg230Cys variant of ABCA1 is associated with low levels of HDL cholesterol levels in Mexican adults. The HDL cholesterol lowering effect of the variant is greater in males. The size of the effect is greater compared to that reported for other ABCA1 variants. PMID- 21315360 TI - Hydrophilic interaction chromatography of nucleoside triphosphates with temperature as a separation parameter. AB - Eight deoxynucleoside triphosphates (dNTPs) and nucleoside triphosphates (NTPs): ATP, CTP, GTP, UTP, dATP, dCTP, dGTP and dTTP, were separated with two 15 cm ZIC pHILIC columns coupled in series, using LC-UV instrumentation. The polymer-based ZIC-pHILIC column gave significantly better separations and peak shape than a silica-based ZIC-HILIC column. Better separations were obtained with isocratic elution as compared to gradient elution. The temperature markedly affected the selectivity and could be used to fine tune separation. The analysis time was also affected by temperature, as lower temperatures surprisingly reduced the retention of the nucleotides. dNTP/NTP standards could be separated in 35 min with a flow rate of 200 MUL/min. In Escherichia coli cell culture samples dNTP/NTPs could be selectively separated in 7 0min using a flow rate of 100 MUL/min. PMID- 21315359 TI - Preparation of polypyrrole-coated magnetic particles for micro solid-phase extraction of phthalates in water by gas chromatography-mass spectrometry analysis. AB - In this work, polypyrrole (PPy)-coated Fe(3)O(4) magnetic microsphere were successfully synthesized, and applied as a magnetic sorbent to extract and concentrate phthalates from water samples. The PPy-coated Fe(3)O(4) magnetic microspheres had the advantages of large surface area, convenient and fast separation ability. The PPy coating of magnetic microspheres contributed to preconcentration of phthalates from water sample, due to the pi-pi bonding between PPy coating and the analytes. Also, the coating could prevent aggregation of the microspheres, and improve their dispersibility. In this study, seven kinds of phthalates were selected as model analytes, including dimethyl phthalate (DMP), diethyl phthalate (DEP), di-iso-butyl phthalate (DIBP), di-n-butyl phthalate (DBP), benzylbutyl phthalate (BBP), di-(2-ethylhexyl) phthalate (DEHP) and di-n-octyl phthalate (DNOP), and gas chromatography-mass spectrometry (GC-MS) was introduced to detect the phthalates after sample pretreatment. Important parameters of the extraction procedure were investigated, and optimized including eluting solvent, the amount of Fe(3)O(4)@PPy particles, and extraction time. After optimization, the procedure took only 15 min to extract and concentrate analytes with high efficiency. Validation experiments showed that the optimized method had good linearity (0.985-0.998), precision (3.4-11.7%), high recovery (91.1-113.4%), and the limits of detection were from 0.006 to 0.068 MUg/L. The results indicated that the novel method had advantages of convenience, good sensitivity, high efficiency, and it could also be applied successfully to analyze phthalates in real water sample. PMID- 21315361 TI - Comparison of the response of four aerosol detectors used with ultra high pressure liquid chromatography. AB - The responses of four different types of aerosol detectors have been evaluated and compared to establish their potential use as a universal detector in conjunction with ultra high pressure liquid chromatography (UHPLC). Two charged aerosol detectors, namely Corona CAD and Corona Ultra, and also two different types of light-scattering detectors (an evaporative light scattering detector, and a nano-quantity analyte detector [NQAD]) were evaluated. The responses of these detectors were systematically investigated under changing experimental and instrumental parameters, such as the mobile phase flow-rate, analyte concentration, mobile phase composition, nebulizer temperature, evaporator temperature, evaporator gas flow-rate and instrumental signal filtering after detection. It was found that these parameters exerted non-linear effects on the responses of the aerosol detectors and must therefore be considered when designing analytical separation conditions, particularly when gradient elution is performed. Identical reversed-phase gradient separations were compared on all four aerosol detectors and further compared with UV detection at 200 nm. The aerosol detectors were able to detect all 11 analytes in a test set comprising species having a variety of physicochemical properties, whilst UV detection was applicable only to those analytes containing chromophores. The reproducibility of the detector response for 11 analytes over 10 consecutive separations was found to be approximately 5% for the charged-aerosol detectors and approximately 11% for the light-scattering detectors. The tested analytes included semi-volatile species which exhibited a more variable response on the aerosol detectors. Peak efficiencies were generally better on the aerosol detectors in comparison to UV detection and particularly so for the light-scattering detectors which exhibited efficiencies of around 110,000 plates per metre. Limits of detection were calculated using different mobile phase compositions and the NQAD detector was found to be the most sensitive (LOD of 10 ng/mL), followed by the Corona CAD (76 ng/mL), then UV detection at 200 nm (178 ng/mL) using an injection volume of 25 MUL. PMID- 21315362 TI - On-line hyphenation of centrifugal partition chromatography and high pressure liquid chromatography for the fractionation of flavonoids from Hippophae rhamnoides L. berries. AB - Centrifugal Partition Chromatography (CPC), a liquid-liquid preparative chromatography using two immiscible solvent systems, benefits from numerous advantages for the separation or purification of synthetic or natural products. This study presents the on-line hyphenation of CPC-Evaporative Light Scattering Detector (CPC-ELSD) with High Performance Liquid Chromatography-UV (HPLC-UV) for the fractionation of flavonols from a solvent-free microwave extract of sea buckthorn (Hippophae rhamnoides L., Elaeagnaceae) berries. An Arizona G system was used for the fractionation of flavonoids by CPC and a fused core Halo C18 column allowed the on-line analyses of collected fractions by HPLC. The on-line CPC/HPLC procedure allowed the simultaneous fractionation step at preparative scale combined with the HPLC analyses which provide direct fingerprint of collected fractions. Thus the crude extract was simplified and immediate information on the composition of fractions could be obtained. Furthermore, this methodology reduced the time of post-fractionation steps and facilitated identification of main molecules by Mass Spectrometry (MS). Rutin, isorhamnetin-3 O-rutinoside, isorhamnetin-3-O-glucoside, quercetin-3-O-glucoside, isorhamnetin rhamnoside, quercetin and isorhamnetin were identified. CPC-ELSD/HPLC-UV could be considered as a high-throughput technique for the guided fractionation of bioactive natural products from complex crude extracts. PMID- 21315363 TI - On the shape of a hydrostatic meniscus attached to a corrugated plate or wavy cylinder. AB - The shape of a hydrostatic meniscus attached at a fixed contact angle to a vertical plate or circular cylinder with periodic corrugations is studied by analytical and numerical methods, and the effect of wall irregularities on the shape of the contact line and vertical component of the capillary force is discussed. An asymptotic analysis for a plate with small-amplitude sinusoidal corrugations is carried out to first order with respect to the corrugation amplitude, and a boundary-value problem is formulated and solved by a shooting method to determine the meniscus shape and elevation of the contact line. The meniscus attached to a corrugated plate with rounded corners produced by a Schwarz-Christoffel mapping function for a triangular wave is considered by numerical methods. The Laplace-Young equation determining the meniscus shape is solved in orthogonal curvilinear coordinates generated by conformal mapping using a finite-difference method. The numerical results are successfully compared with the predictions of the perturbation expansion for small amplitudes and discussed with reference to the rise of a meniscus inside a dihedral angle for large amplitudes. A companion asymptotic analysis is presented for a meniscus outside a vertical circular cylinder with small-amplitude sinusoidal corrugations. The analytical predictions are successfully compared with numerical solutions of the Laplace-Young equation for a meniscus outside an elliptical cylinder with aspect ratio near unity, regarded as a deformed circle. PMID- 21315364 TI - In situ growth of CuS thin films on functionalized self-assembled monolayers using chemical bath deposition. AB - Nano-structured CuS thin films were deposited on the functionalized -NH(2) terminated self-assembled monolayers (SAMs) surface by chemical bath deposition (CBD). The deposition mechanism of CuS on the -NH(2)-terminated group was systematically investigated using field emission scanning electron microscope (FESEM), X-ray photoelectron spectroscope (XPS), UV-vis absorption. The optical, electrical and photoelectrochemical performance of CuS thin films incorporating with the X-ray diffraction (XRD) analysis confirmed the nanocrystalline nature of CuS with hexagonal crystal structure and also revealed that CuS thin film is a p type semiconductor with high electrical conductivity (12.3Omega/?). The functionalized SAMs terminal group plays a key role in the deposition of CuS thin films. The growth of CuS on the varying SAMs surface shows different deposition mechanisms. On -NH(2)-terminated surfaces, a combination of ion-by-ion growth and cluster-by-cluster deposition can interpret the observed behavior. On -OH- and CH(3)-terminated surfaces, the dominant growth mechanism on the surface is cluster-by-cluster deposition in the solution. According to this principle, the patterned CuS microarrays with different feature sizes were successfully deposited on -NH(2)-terminated SAMs regions of -NH(2)/-CH(3) patterned SAMs surface. PMID- 21315365 TI - The imaging ammeter. AB - A method for measuring local current density, not requiring segmentation of the electrode or spatial scanning, is presented. The motion of colloidal particles in response to local current density, characterized by the intensity of the light they scatter, is the fundamental phenomenon of the technique. The scattering was produced and measured with the electrochemical total internal reflection microscope, a tool that places an electrochemical cell within a total internal reflection apparatus. The electrolysis of water and the oxidation of ferrocene monocarboxylic acid were used as test reactions. Light scattered by a probe particle produced an "image" of current density; scattered light was converted to local current density by a function derived herein. Numerical simulations supplemented experimental evidence that local current density controlled the probe particle's vertical motion. The spatial resolution of the method was approximately the length scale of the probe particle, in this case 5.7 MUm. The resolution of current density was better than 100 nA cm(-2). The method might find use in high throughput screening of electrocatalysts. PMID- 21315367 TI - Electrical potentials of two identical particles with fixed surface charge density in a salt-free medium. AB - The electrical potentials of two identical planar, cylindrical, and spherical particles immersed in a salt-free dispersion are solved analytically by a perturbation approach for the case of constant surface charge density. The system under consideration simulates, for example, micelles, where the ionic species in the liquid phase come mainly from the dissociation of the functional groups on the droplet surface. We show that for planar particles, the present zero-order perturbation solution is exact, and for cylindrical and spherical particles, the first-order perturbation solution provides sufficiently accurate results, with an averaged percentage deviation on the order of 1% under typical conditions. In general, the higher the surface charge density, the higher the valence of counterions, the smaller the separation distance between two particles, and the smaller the curvature of particle surface, the better the performance of the perturbation solution. PMID- 21315366 TI - Interactions of biomacromolecules with reverse hexagonal liquid crystals: drug delivery and crystallization applications. AB - Recently, self-assembled lyotropic liquid crystals (LLCs) of lipids and water have attracted the attention of both scientific and applied research communities, due to their remarkable structural complexity and practical potential in diverse applications. The phase behavior of mixtures of glycerol monooleate (monoolein, GMO) was particularly well studied due to the potential utilization of these systems in drug delivery systems, food products, and encapsulation and crystallization of proteins. Among the studied lyotropic mesophases, reverse hexagonal LLC (H(II)) of monoolein/water were not widely subjected to practical applications since these were stable only at elevated temperatures. Lately, we obtained stable H(II) mesophases at room temperature by incorporating triacylglycerol (TAG) molecules into the GMO/water mixtures and explored the physical properties of these structures. The present feature article summarizes recent systematic efforts in our laboratory to utilize the H(II) mesophases for solubilization, and potential release and crystallization of biomacromolecules. Such a concept was demonstrated in the case of two therapeutic peptides cyclosporin A (CSA) and desmopressin, as well as RALA peptide, which is a model skin penetration enhancer, and eventually a larger macromolecule-lysozyme (LSZ). In the course of the study we tried to elucidate relationships between the different levels of organization of LLCs (from the microstructural level, through mesoscale, to macroscopic level) and find feasible correlations between them. Since the structural properties of the mesophase systems are a key factor in drug release applications, we investigated the effects of these guest molecules on their conformations and the way these molecules partition within the domains of the mesophases. The examined H(II) mesophases exhibited great potential as transdermal delivery vehicles for bioactive peptides, enabling tuning the release properties according to their chemical composition and physical properties. Furthermore, we showed a promising opportunity for crystallization of CSA and LSZ in single crystal form as model biomacromolecules for crystallographic structure determination. The main outcomes of our research demonstrated that control of the physical properties of hexagonal LLC on different length scales is key for rational design of these systems as delivery vehicles and crystallization medium for biomacromolecules. PMID- 21315368 TI - Titania-silver and alumina-silver composite nanoparticles: novel, versatile synthesis, reaction mechanism and potential antimicrobial application. AB - Titania-silver (TiO(2)-Ag) and alumina-silver (Al(2)O(3)-Ag) composite nanoparticles were synthesised by a simple, reproducible, wet chemical method under ambient conditions. The surface of the oxides was modified with oleic acid, which acted as an intermediate between the oxide surface and the silver nanoparticles. The resulting composite nanoparticles were thoroughly characterised by XRD, TEM, XPS, FTIR and TGA to elucidate the mode of assembly of Ag nanoparticles on the oxide surfaces. Epoxy nanocomposites were formulated with TiO(2)-Ag and Al(2)O(3)-Ag to examine potential applications for the composite nanoparticles. Preliminary results from disc diffusion assays against Escherichia coli DH5alpha and Staphylococcus epidermidis NCIMB 12721 suggest that these TiO(2)-Ag and Al(2)O(3)-Ag composite nanoparticles have potential as antimicrobial materials. PMID- 21315369 TI - Poorly water-soluble drug nanoparticles via an emulsion-freeze-drying approach. AB - Low water solubility of a high percentage of pharmaceuticals is a big issue for pharmaceutical applications due to the resulting low bioabsorption and hence limited therapeutic efficacy. Preparation of drug nanoparticles has been one of the mostly investigated routes to address this problem. In this study, we reported the preparation of nanoparticles via an emulsion-freeze-drying approach. Indomethacin (IMC, a poorly water-soluble drug) nanoparticles were formed in situ within porous poly(vinyl alcohol). The IMC nanoparticles could be released into water to form stable nanodispersions simply by rapid dissolution of the porous polymeric scaffold. This study focused on how preparation conditions including phase volume ratios in the emulsions and the concentrations of polymer, surfactant and drug influenced the formation of IMC nanoparticles. It was concluded that the loading and size of IMC nanoparticles could be easily tuned by changing the preparation conditions. PMID- 21315370 TI - Aerosol-assisted self-assembly of hybrid Layered Double Hydroxide particles into spherical architectures. AB - Acetate intercalated NiAl-Layered Double Hydroxide nanoparticles were prepared by polyol process and further used as building blocks to form hybrid LDH spheres by a spray drying technique. The spherical aggregated LDH particles display a polydispersed size with a diameter ranging from 47 nm to 2 MUm. The analysis of the thermal behavior evidenced that the spherical form was maintained upon calcination up to 1100 degrees C, giving rise to derived mixed oxide (NiO+NiAl(2)O(4)) nanospheres. Interestingly, the spherical morphology of the LDH materials was also retained during anion exchange process. The replacement of the intercalated acetate anion by of a voluminous anion such as dodecylsulfate induces an increase of the nanosphere mean diameter of 65%. The different materials were deeply characterized using X-ray diffraction, FTIR spectroscopy, scanning and transmission electron microscopies, dynamic light scattering, thermal analysis and nitrogen sorption. PMID- 21315371 TI - Age and schooling effects on early literacy and phoneme awareness. AB - Previous research on age and schooling effects is largely restricted to studies of children who begin formal schooling at 6years of age, and the measures of phoneme awareness used have typically lacked sensitivity for beginning readers. Our study addresses these issues by testing 4 to 6year-olds (first 2years of formal schooling in the United Kingdom) on a sensitive dynamic measure of phoneme awareness and tests of early literacy. There were significant effects of both age and schooling on the dynamic measure of phoneme awareness, word reading, spelling, and letter name knowledge, but there were no significant Age*Time interactions. This indicates that older children within this age group generally outperform their younger classmates (although they do not make faster progress) and that this advantage is developed prior to the start of school. PMID- 21315372 TI - Context effects on orthographic learning of regular and irregular words. AB - The self-teaching hypothesis proposes that orthographic learning takes place via phonological decoding in meaningful texts, that is, in context. Context is proposed to be important in learning to read, especially when decoding is only partial. However, little research has directly explored this hypothesis. The current study looked at the effect of context on orthographic learning and examined whether there were different effects for novel words given regular and irregular pronunciations. Two experiments were conducted using regular and irregular novel words, respectively. Second-grade children were asked to learn eight novel words either in stories or in a list of words. The results revealed no significant effect of context for the regular items. However, in an orthographic decision task, there was a facilitatory effect of context on irregular novel word learning. The findings support the view that contextual information is important to orthographic learning, but only when the words to be learned contain irregular spelling-sound correspondences. PMID- 21315374 TI - Concerns regarding power and other analysis issues. PMID- 21315373 TI - Extensive limb swelling after vaccination. PMID- 21315375 TI - Melatonin and mental capacities in newborn infants. AB - OBJECTIVES: To investigate the role of melatonin in the emergence of mental capacities in the newborn infant. STUDY DESIGN: Assessment of Preterm Infant Behavior examination was performed at 2 weeks post-term age for 39 (21 preterm and 18 term) infants. 6-Suphatoxymelatonin from nocturnal urine samples was analyzed by enzyme-linked immunosorbent assays, and the Mental Developmental Index, assessed by Bayley scales, was correlated at 4, 6, and 9 months' corrected age. RESULTS: Multivariate analysis of variance with repeated measures showed that improved autonomic function at 2 weeks of age was associated with higher Mental Developmental Index scores at 9 months when related to the amount of melatonin at 4, 6, and 9 months of age. CONCLUSIONS: Early compromised autonomic system function in preterm infants is associated with lower mental capacities and is related to lower melatonin levels at later ages. PMID- 21315376 TI - White matter changes in dementia with Lewy bodies and Alzheimer's disease: a tractography-based study. AB - Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) are different types of dementia. However, their clinical symptoms partially overlap and differential diagnosis is occasionally difficult. There is need for additional diagnostic criteria to reliably differentiate between these two conditions. Meanwhile, several imaging studies have showed inconsistent results between DLB and AD. The aim of this study was to use a tractography-based analysis to elucidate white matter alterations in subjects with DLB compared to those with AD and to controls. An understanding of the white matter connectivity differences between AD, DLB and controls will be helpful for differential diagnosis and an understanding of the pathophysiology. Twenty-six subjects with DLB, 26 with AD and 26 controls underwent magnetic resonance diffusion tensor imaging and neuropsychological assessment. Diffusion tensors were computed and fiber-tract maps were created using "dTV II" software. We measured mean fractional anisotropy (FA) values along the uncinate fasciculus (UNC), the inferior occipitofrontal fasciculus (IOFF) and the inferior longitudinal fasciculus (ILF). Both subjects with DLB and AD had lower FA values for the bilateral UNC than controls. Subjects with DLB exhibited significantly lower FA values on both sides of the IOFF and the left side of the ILF than those of controls. Although there were no significant differences between subjects with DLB and AD for any measurements, those with DLB exhibited lower FA values especially in visual-related white matter. These different changes in white matter tracts among groups could be helpful for differential diagnosis and an understanding of the pathophysiology. PMID- 21315378 TI - [Down syndrome: a 21st Century medical challenge]. PMID- 21315377 TI - Friedreich's ataxia: pathology, pathogenesis, and molecular genetics. AB - The pathogenic mutation in Friedreich's ataxia (FRDA) is a homozygous guanine adenine-adenine (GAA) trinucleotide repeat expansion on chromosome 9q13 that causes a transcriptional defect of the frataxin gene. Deficiency of frataxin, a small mitochondrial protein, is responsible for all clinical and morphological manifestations of FRDA. This autosomal recessive disease affects central and peripheral nervous systems, heart, skeleton, and endocrine pancreas. Long expansions lead to early onset, severe clinical illness, and death in young adult life. Patients with short expansions have a later onset and a more benign course. Some are not diagnosed during life. The neurological phenotype reflects lesions in dorsal root ganglia (DRG), sensory peripheral nerves, corticospinal tracts, and dentate nuclei (DN). Most patients succumb to cardiomyopathy, and many become diabetic during the course of their disease. This review seeks to reconcile the diverse clinical features with pathological and molecular data. In the pathogenesis of the lesion in DRG, dorsal spinal roots, and sensory peripheral nerves, developmental defects and atrophy occur in combination. The progressive lesion of the DN lacks a known developmental component. Destruction of the DN, optic atrophy, and degeneration of the corticospinal tracts are intrinsic central nervous system lesions. Fiber loss in dorsal columns and spinocerebellar tracts, and atrophy of the neurons in the dorsal nuclei of Clarke are secondary to the lesion in DRG. The role of frataxin deficiency in the pathogenesis of FRDA is still unclear because the protein has multiple functions in the normal state, including biogenesis of iron-sulfur clusters; iron chaperoning; iron storage; and control of iron-mediated oxidative tissue damage. PMID- 21315379 TI - Eremophilane-type sesquiterpene lactones from Ligularia hodgsonii Hook. AB - A dimeric eremophilane sesquiterpene lactone with a cyclobutane ring, biliguhodgsonolide (1) and an uncommon seco-sesquiterpene derivative, (4S,5S,6R,10R)-8,9-seco-12-hydroxyeremophil-7(11)-en-14,6;12,8-diolid-9-al (2), were isolated from the roots and rhizomes of Ligularia hodgsonii Hook. Their structures, including the absolute stereochemistry, were elucidated by spectroscopic data and CD analysis. The cyclobutane ring was confirmed by single crystal X-ray diffraction. PMID- 21315380 TI - Metabolic profile of wound-induced changes in primary carbon metabolism in sugarbeet root. AB - Injury to plant products by harvest and postharvest operations induces respiration rate and increases the demand for respiratory substrates. Alterations in primary carbon metabolism are likely to support the elevated demand for respiratory substrates, although the nature of these alterations is unknown. To gain insight into the metabolic changes that occur to provide substrates for wound-induced increases in respiration, changes in the concentrations of compounds that are substrates, intermediates or cofactors in the respiratory pathway were determined in sugarbeet (Beta vulgaris L.) roots in the 4days following injury. Both wounded and unwounded tissues of wounded roots were analyzed to provide information about localized and systemic changes that occur after wounding. In wounded tissue, respiration increased an average of 186%, fructose, glucose 6-phosphate, ADP and UDP concentrations increased, and fructose 1,6-bisphosphate, triose phosphate, citrate, isocitrate, succinate, ATP, UTP and NAD(+) concentrations decreased. In the non-wounded tissue of wounded roots, respiration rate increased an average of 21%, glucose 6-phosphate, fructose 6 phosphate, glucose 1-phosphate and ADP concentrations increased, and isocitrate, UTP, NAD(+), NADP(+), and NADPH concentrations declined. Changes in respiration rate and metabolite concentrations indicated that localized and systemic changes in primary carbon metabolism occurred in response to injury. In wounded tissue, metabolite concentration changes suggested that activities of the early glycolytic enzymes, fructokinase, phosphofructokinase, phosphoglucose isomerase, and phosphoglucomutase were limiting carbon flow through glycolysis. These restrictions in the respiratory pathway, however, were likely overcome by use of metabolic bypasses that allowed carbon compounds to enter the pathway at glycolytic and tricarboxylic acid (TCA) cycle downstream locations. In non wounded tissue of wounded roots, metabolic concentration changes suggested that glycolysis and the TCA cycle were generally capable of supporting the small systemic elevation in respiration rate. Although the mechanism by which respiration is regulated in wounded sugarbeet roots is unknown, localized and systemic elevations in respiration were positively associated with one or more indicators of cellular redox status. PMID- 21315381 TI - Peach fruit ripening: A proteomic comparative analysis of the mesocarp of two cultivars with different flesh firmness at two ripening stages. AB - A proteomic analysis was conducted on peach fruit mesocarp in order to better elucidate the biochemical and physiological events which characterize the transition of fruit from the "unripe" to the "ripe" phase. The first goal of the present work was to set-up a protocol suitable for improving protein extraction from peach mesocarp. The use of freeze-dried powdered tissue, together with the addition of phenol prior to the extraction with an aqueous buffer, significantly increased the protein yield and the quality of 2-DE gels. The proteomic profiles of the mesocarp from peach fruit of a non-melting flesh (NMF; 'Oro A') and a melting flesh (MF; 'Bolero') cultivar, at "unripe" and "ripe" stages as defined by some parameters typical of ripening, were then analyzed. The comparative analysis of the 2-DE gels showed that in NMF and MF peaches the relative volumes of 53 protein spots significantly changed in relation to both the ripening stage ("unripe" versus "ripe") and/or the genetic background of the cultivar ('Oro A' versus 'Bolero'). Thirty out of the 53 differently abundant spots were identified by LC-ESI-MS/MS. The analysis revealed enzymes involved in primary metabolism (e.g. C-compounds, carbohydrates, organic acids and amino acids) and in ethylene biosynthesis as well as proteins involved in secondary metabolism and responses to stress. Among these, 1-aminocyclopropane-1-carboxylic acid oxidase (ACO) appeared to be one of the proteins with the largest change in relative abundance during the fruit transition from the pre-climacteric ("unripe") to the climacteric ("ripe") phase. Other proteins, such as S-adenosylmethionine synthetase and beta-cyanoalanine synthase involved in ethylene metabolism, were also identified. Moreover, the changes in the relative abundances of a sucrose synthase and an alpha-amylase suggested differences between the two cultivars in the carbohydrate import activity of ripe fruit. The different accumulation of a few typical ROS-scavenger enzymes suggested that a higher oxidative stress occurred in MF with respect to NMF fruit. This result, together with data concerning the levels of total proteins and free amino acids and those regarding proteins involved in the maintenance of tissue integrity, was consistent with the hypothesis that the last phase of ripening in MF fruit is characterized by the appearance of a senescence status. The present study appears to define well some of the biochemical and physiological events that characterize the ripening of peach and, at the same time, provides interesting indications that could be employed in future marker assisted selection (MAS) programmes aimed to obtain MF fruits with higher ability to preserve tissue functionality maintaining for a longer time their organoleptic characteristics. PMID- 21315382 TI - Aporphine alkaloids and cytotoxic lignans from the roots of Illigera luzonensis. AB - Six aporphine alkaloids, (+)-(S)-N-butyrylcaaverine (1), (+)-(S)-N propionylcaaverine (2), (+)-(S)-N-acetylcaaverine (3), (+)-(6aR,7R)-N butyrylnorushinsunine (4), (+)-(6aR,7R,E)-N-(but-2-enoyl)norushinsunine (5), and N-formyldehydrocaaverine (6) were isolated from the roots of Illigera luzonensis, together with 16 known compounds. Their structures were determined through spectroscopic and MS analyses. Among the isolates, (-)-deoxypodophyllotoxin (13) was the most cytotoxic, with IC(50) values of 0.0057, 0.0067, 0.00004, and 0.0035MUg/mL, respectively, against DLD-1, CCRF-CEM, HL-60, and IMR-32 cell lines. In addition, (-)-yatein (12) exhibited cytotoxic effects, with IC(50) values of 0.81, 0.20, and 0.59MUg/mL, respectively, against DLD-1, CCRF-CEM, and HL-60 cell lines. PMID- 21315383 TI - Chemical constituents from fruits of Harrisonia perforata. AB - Eight limonoids (1-8) including three A, B and D-seco-16-nor-type ones, 5,6 dehydrodesepoxyharperforin C2 (1), harrpernoid B (2), and its C-9S epimer, harrpernoid C (3), along with six known compounds (9-14), were isolated from fruits of Harrisonia perforata. Extensive spectroscopic analysis was used to elucidate their structures and stereochemistries. Further confirmation of structures of 1 and 2 were obtained by single-crystal X-ray diffraction. Limonoids (1-8) were evaluated for their anti-tobacco mosaic virus activity and in vitro cytotoxicity against A549 and HL60 cell lines; only compound 2 showed weak activity. PMID- 21315384 TI - Unusual withanolides from aeroponically grown Withania somnifera. AB - In an attempt to maximize production and the structural diversity of plant metabolites, the effect of growing the medicinal plant Withania somnifera under soil-less aeroponic conditions on its ability to produce withaferin A and withanolides was investigated. It resulted in the isolation and characterization of two compounds, 3alpha-(uracil-1-yl)-2,3-dihydrowithaferin A (1) and 3beta (adenin-9-yl)-2,3-dihydrowithaferin A (2), in addition to 10 known withanolides including 2,3-dihydrowithaferin A-3beta-O-sulfate. 3beta-O-Butyl-2,3 dihydrowithaferin A (3), presumably an artifact formed from withaferin A during the isolation process was also encountered. Reaction of withaferin A with uracil afforded 1 and its epimer, 3beta-(uracil-1-yl)-2,3-dihydrowithaferin A (4). The structures of these compounds were elucidated on the basis of their high resolution mass and NMR spectroscopic data. PMID- 21315385 TI - Phytochemicals of Brassicaceae in plant protection and human health--influences of climate, environment and agronomic practice. AB - In this review, we provide an overview of the role of glucosinolates and other phytochemical compounds present in the Brassicaceae in relation to plant protection and human health. Current knowledge of the factors that influence phytochemical content and profile in the Brassicaceae is also summarized and multi-factorial approaches are briefly discussed. Variation in agronomic conditions (plant species, cultivar, developmental stage, plant organ, plant competition, fertilization, pH), season, climatic factors, water availability, light (intensity, quality, duration) and CO(2) are known to significantly affect content and profile of phytochemicals. Phytochemicals such as the glucosinolates and leaf surface waxes play an important role in interactions with pests and pathogens. Factors that affect production of phytochemicals are important when designing plant protection strategies that exploit these compounds to minimize crop damage caused by plant pests and pathogens. Brassicaceous plants are consumed increasingly for possible health benefits, for example, glucosinolate derived effects on degenerative diseases such as cancer, cardiovascular and neurodegenerative diseases. Thus, factors influencing phytochemical content and profile in the production of brassicaceous plants are worth considering both for plant and human health. Even though it is known that factors that influence phytochemical content and profile may interact, studies of plant compounds were, until recently, restricted by methods allowing only a reductionistic approach. It is now possible to design multi-factorial experiments that simulate their combined effects. This will provide important information to ecologists, plant breeders and agronomists. PMID- 21315386 TI - A dynamic role for sterols in embryogenesis of Pisum sativum. AB - Molecular roles of sterols in plant development remain to be elucidated. To investigate sterol composition during embryogenesis, the occurrence of 25 steroid compounds in stages of developing seeds and pods of Pisum sativum was examined by GC-MS analysis. Immature seeds containing very young embryos exhibited the greatest concentrations of sterols. Regression models indicated that the natural log of seed or pod fr. wt was a consistent predictor of declining sterol content during embryonic development. Although total sterol levels were reduced in mature embryos, the composition of major sterols sitosterol and campesterol remained relatively constant in all 12 seed stages examined. In mature seeds, a significant decrease in isofucosterol was observed, as well as minor changes such as increases in cycloartenol branch sterols and campesterol derivatives. In comparison to seeds and pods, striking differences in composition were observed in sterol profiles of stems, shoots, leaves, flowers and flower buds, as well as cotyledons versus radicles. The highest levels of isofucosterol, a precursor to sitosterol, occurred in young seeds and flower buds, tissues that contain rapidly dividing cells and cells undergoing differentiation. Conversely, the highest levels of stigmasterol, a derivative of sitosterol, were found in fully differentiated leaves while all seed stages exhibited low levels of stigmasterol. The observed differences in sterol content were correlated to mRNA expression data for sterol biosynthesis genes from Arabidopsis. These findings implicate the coordinated expression of sterol biosynthesis enzymes in gene regulatory networks underlying the embryonic development of flowering plants. PMID- 21315387 TI - Phosphoproteomics perspective on plant signal transduction and tyrosine phosphorylation. AB - Plants and animal cells use intricate signaling pathways to respond to a diverse array of stimuli. These stimuli include signals from environment, such as biotic and abiotic stress signals, as well as cell-to-cell signaling required for pattern formation during development. The transduction of the signal often relies on the post-translational modification (PTM) of proteins. Protein phosphorylation in eukaryotic cells is considered to be a central mechanism for regulation and cellular signaling. The classic view is that phosphorylation of serine (Ser) and threonine (Thr) residues is more abundant, whereas tyrosine (Tyr) phosphorylation is less frequent. This review provides an overview of the progress in the plant phosphoproteomics field and how this progress has lead to a re-evaluation of the relative contribution of tyrosine phosphorylation to the plant phosphoproteome. In relation to this appreciated contribution of tyrosine phosphorylation we also discuss some of the recent progress on the role of tyrosine phosphorylation in plant signal transduction. PMID- 21315388 TI - Biochemical characterisation of MdCXE1, a carboxylesterase from apple that is expressed during fruit ripening. AB - Esters are an important component of apple (Malus*domestica) flavour. Their biosynthesis increases in response to the ripening hormone ethylene, but their metabolism by carboxylesterases (CXEs) is poorly understood. We have identified 16 members of the CXE multigene family from the commercial apple cultivar, 'Royal Gala', that contain all the conserved features associated with CXE members of the alpha/beta hydrolase fold superfamily. The expression of two genes, MdCXE1 and MdCXE16 was characterised in an apple fruit development series and in a transgenic line of 'Royal Gala' (AO3) that is unable to synthesise ethylene in fruit. In wild-type MdCXE1 is expressed at low levels during early stages of fruit development, rising to a peak of expression in apple fruit at harvest maturity. It is not significantly up-regulated by ethylene in the skin of AO3 fruit. MdCXE16 is expressed constitutively in wild-type throughout fruit development, and is up-regulated by ethylene in skin of AO3 fruit. Semi-purified recombinant MdCXE1 was able to hydrolyse a range of 4-methyl umbelliferyl ester substrates that included those containing acyl moieties that are found in esters produced by apple fruit. Kinetic characterisation of MdCXE1 revealed that the enzyme could be inhibited by organophosphates and that its ability to hydrolyse esters showed increasing affinity (K(m)) but decreasing turnover (k(cat)) as substrate acyl carbon length increases from C2 to C16. Our results suggest that MdCXE1 may have an impact on apple flavour through its ability to hydrolyse relevant flavour esters in ripe apple fruit. PMID- 21315390 TI - Hydroperoxide lyase cascade in pea seedlings: Non-volatile oxylipins and their age and stress dependent alterations. AB - The profiles of non-volatile oxylipins of pea (Pisum sativum) seedlings were examined by gas chromatography-mass spectrometry after invitro incubation with alpha-linolenic acid. The 13-lipoxygenase/hydroperoxide lyase (HPL) products were predominant in the leaves, while the roots possess both 13- and 9-HPL products. Allene oxide synthase (AOS) and divinyl ether synthase (DES) products were not detected in the leaves or in the roots of any age. The HPL cascade produces a diversity of oxylipins, including the compounds (2E)-4-hydroxy-traumatic, (10E) 9,12-dihydroxy-10-dodecenoic and 9,12-dihydroxydodecanoic acids, as well as (2E) 4-hydroxy-2-nonenoic acid, which has not yet been detected in plants. Oxylipin patterns were altered by infection, water deficit, as well as by plant age. Infection caused the specific strong accumulation of azelaic (nonane-1,9-dioic) acid in the leaves. The azelaic acid content in the aged (14 and 18day-old) leaves was significantly higher than in the younger leaves. Water deficit induced the accumulation of (2E)-4-hydroxy-2-nonenoic acid and (2E)-traumatic acid in the roots. Results demonstrate that: (1) the HPL cascade is the predominant branch of the lipoxygenase pathway in pea seedlings; (2) the HPL products may have the regulatory role both in growth control and adaptation. PMID- 21315389 TI - ent-Rosane and abietane diterpenoids as cancer chemopreventive agents. AB - Two ent-rosane- (cuzcol, 1 and 6-dehydroxycuzcol, 2) and a abietatriene- (salvadoriol, 3) type diterpenoids have been isolated from Maytenus cuzcoina and Crossopetalum uragoga, respectively, along with five known diterpene compounds (4 8). Their stereostructures have been elucidated on the basis of spectroscopic analysis, including 1D and 2D NMR techniques, and computational data. The absolute configuration of cuzcol was determined by application of Riguera ester procedure. This is the first instance of isolation of ent-rosane diterpenoids from species of the Celastraceae. The isolated diterpenes were found to be potent anti-tumour-promoter agents, and carnosol (7) also showed a remarkable chemopreventive effect in an in vivo two-stage carcinogenesis model. PMID- 21315391 TI - Relative and accurate measurement of protein abundance using 15N stable isotope labeling in Arabidopsis (SILIA). AB - In the quantitative proteomic studies, numerous in vitro and in vivo peptide labeling strategies have been successfully applied to measure differentially regulated protein and peptide abundance. These approaches have been proven to be versatile and repeatable in biological discoveries. (15)N metabolic labeling is one of these widely adopted and economical methods. However, due to the differential incorporation rates of (15)N or (14)N, the labeling results produce imperfectly matched isotopic envelopes between the heavy and light nitrogen labeled peptides. In the present study, we have modified the solid Arabidopsis growth medium to standardize the (15)N supply, which led to a uniform incorporation of (15)N into the whole plant protein complement. The incorporation rate (97.43+/-0.11%) of (15)N into (15)N-coded peptides was determined by correlating the intensities of peptide ions with the labeling efficiencies according to Gaussian distribution. The resulting actual incorporation rate (97.44%) and natural abundance of (15)N/(14)N-coded peptides are used to re calculate the intensities of isotopic envelopes of differentially labeled peptides, respectively. A modified (15)N/(14)N stable isotope labeling strategy, SILIA, is assessed and the results demonstrate that this approach is able to differentiate the fold change in protein abundance down to 10%. The machine dynamic range limitation and purification step will make the precursor ion ratio deriving from the actual ratio fold change. It is suggested that the differentially mixed (15)N-coded and (14)N-coded plant protein samples that are used to establish the protein abundance standard curve should be prepared following a similar protein isolation protocol used to isolate the proteins to be quantitated. PMID- 21315392 TI - Estrogenic and anti-estrogenic compounds from the Thai medicinal plant, Smilax corbularia (Smilacaceae). AB - From the rhizomes of Smilax corbularia Kunth. (Smilacaceae), 11 compounds, (2R,3R)-2"-acetyl astilbin, (2R,3R)-3"-acetyl astilbin, (2R,3R)-4"-acetyl astilbin, (2R,3R)-3"-acetyl engeletin, (2R,3S)-4"-acetyl isoastilbin, 2-(4 hydroxyphenyl)-3,4,9,10-tetrahydro-3,5-dihydroxy-10-(3,4-dihydroxyphenyl) (2R,3R,10R)-2H,8H-benzo [1,2-b:3,4-b'] dipyran-8-one, 2-(4-hydroxyphenyl) 3,4,9,10-tetrahydro-3,5-dihydroxy-10-(3,4-dihydroxyphenyl)-(2R,3R,10S)-2H, 8H benzo [1,2-b:3,4-b'] dipyran-8-one, 3,4-dihydro-7-hydroxy-4-(3,4-dihydroxyphenyl) 5-[(1E)-2-(4-hydroxyphenyl) ethenyl]-2H-1-benzopyran-2-one, 3,4-dihydro-7-hydroxy 4-(3,4-dihydroxy-phenyl)-5-[(1E)-2-(3,4-dihydroxyphenyl) ethenyl]-2H-1-benzopyran 2-one, 3,4-dihydro-7-hydroxy-4-(4-hydroxy-3-methoxyphenyl)-5-[(1E)-2-(4 hydroxyphenyl) ethenyl]-2H-1-benzopyran-2-one, and 5,7,3',4'-tetrahydroxy-3 phenylcoumarin along with 34 known compounds were isolated and characterized as 19 flavonoids, 14 catechin derivatives, 6 stilbene derivatives, and 6 miscellaneous substances. All isolates had their estrogenic and anti-estrogenic activities determined using the estrogen-responsive human breast cancer cell lines MCF-7 and T47D. The major constituents were recognized as flavanonol rhamnosides by the suppressive effect on estradiol induced cell proliferation at a concentration of 1MUM. Meanwhile, flavanonol rhamnoside acetates demonstrated estrogenic activity in both MCF-7 and T47D cells at a concentration of 100MUM, and they enhanced the effects of co-treated E2 on T47D cell proliferation at concentrations of more than 0.1MUM. PMID- 21315393 TI - Absolute configuration of labdanes and ent-clerodanes from Chromolaena pulchella by vibrational circular dichroism. AB - The aerial parts of Chromolaena pulchella biosynthesize two groups of diterpenes belonging to opposite enantiomeric series, specifically, the furanoid ent clerodanes (5R,8R,9S,10R)-(-)-hardwikiic acid (1), methyl (5R,8R,9S,10R)-(-) hardwikiate (2), (5S,8R,9S,10R)-(-)-hautriwaic acid lactone (3), methyl (5R,8R,9S,10R)-(-)-nidoresedate (4) and methyl (8R,9R)-(-)-strictate (5), as well as the labdanes (5S,8R,9R,10S)-(+)-(13E)-labd-13-ene-8,15-diol (6) and (5S,8R,9R,10S)-(+)-isoabienol (7). The absolute configuration of the two groups of diterpenes was unambiguously assigned by comparison of the vibrational circular dichroism spectra of 3 for ent-clerodanes, and of 7 for labdanes with their theoretical spectra obtained by density functional theory calculations. The results support a biogenetic proposal to diterpenes found in the studied botanical species. PMID- 21315394 TI - Self-reported health problems of asylum seekers and their understanding of the national health service: a pilot study. PMID- 21315395 TI - Regional price differences and food consumption frequency among elementary school children. AB - OBJECTIVE: Food prices may affect diet and weight gain among youth and lead to geographic disparities in obesity. This paper examines the association between regional prices and consumption frequency of fruit/vegetables and snack items among elementary school children in the USA. STUDY DESIGN: Observational study using individual-level survey data of fifth-grade children (average age 11 years) and regional food prices based on store visits in 2004. METHODS: Dependent variables are self-reported consumption frequency in fifth grade; primary explanatory variables are metropolitan area food prices relative to cost of living. Multivariate regression analysis. RESULTS: Price variation across metropolitan areas exists, and lower real prices for vegetables and fruits predict significantly higher intake frequency. Higher dairy prices predict lower frequency of milk consumption, while higher meat prices predict increased milk consumption. Similar price effects were not found for fast food or soft drink consumption. DISCUSSION: The geographic variation in food prices across the USA is sufficiently large to affect dietary patterns among youth for fruit, vegetables and milk. The price variation is either too small to affect children's consumption frequency of fast food or soft drinks, or the consumption of these foods is less price sensitive. PMID- 21315396 TI - [Inflammatory pseudotumor of the urinary bladder]. PMID- 21315397 TI - [Challenges and opportunities in scientific publications in 2011: an analysis by the editors of the journals of the Radiological Society of North America (RSNA)]. PMID- 21315398 TI - [Semiautomatic quantification of left and right ventricular function in cardiac magnetic resonance imaging: a preliminary study]. AB - OBJECTIVES: The aim of this study was to compare a semiautomatic segmentation method to quantify the function of both ventricles in magnetic resonance imaging (MRI) with the manual tracing method. MATERIAL AND METHODS: We examined 17 patients with diverse cardiovascular diseases on a 1.5 Tesla MRI unit (Magnetom Symphony Quantum; Siemens Medical Systems, Erlangen, Germany) using the following parameters: maximum gradient, 30 mT/m; and slew rate, 125 T/m/s. In all studies, we acquired images in cine mode in the short axis (SSFP, 6mm slice thickness, from the base to the ventricular apex) with breath holding. To reduce the user interaction, we used only one image per patient to initiate the semiautomatic method. The semiautomatic method was based on a specifically designed algorithm of regional growth and border detection. We quantified the end-diastolic volume (EDV), end-systolic volume (ESV), and the ejection fraction (EF) for both ventricles in all patients. RESULTS: No significant differences between the two segmentation techniques were found in the quantification of either ventricle (p>0.05). The difference in the volumes, although nearly significant, are clinically irrelevant. The correlation for the estimation of left ventricular function was excellent (r>0.9), and the correlation for the estimation of right ventricular function was good (r>0.7). CONCLUSIONS: Our semiautomatic segmentation method enables the function of both ventricles to be quantified as accurately as the conventional method. PMID- 21315399 TI - Physical therapy assessment tools to evaluate disease progression and phenotype variability in Golden Retriever muscular dystrophy. AB - Dogs suffering from Golden Retriever muscular dystrophy (GRMD) present symptoms that are similar to human patients with Duchenne muscular dystrophy (DMD). Phenotypic variability is common in both cases and correlates with disease progression and response to therapy. Physical therapy assessment tools were used to study disease progression and assess phenotypic variability in dogs with GRMD. At 5 (T0), 9 (T1), 13 (T2) and 17 (T3)months of age, the physical features, joint ranges of motion (ROM), limb and thorax circumferences, weight and creatine kinase (CK) levels were assessed in 11 dogs with GRMD. Alterations of physical features were higher at 13 months, and different disease progression rates were observed. Passive ROM decreased until 1 year old, which was followed by a decline of elbow and tarsal ROM. Limb and thorax circumferences, which were corrected for body weight, decreased significantly between T0 and T3. These measurements can be used to evaluate disease progression in dogs with GRMD and to help discover new therapies for DMD patients. PMID- 21315400 TI - Lysosomal localization and mechanism of membrane penetration influence nonenveloped virus activation of the NLRP3 inflammasome. AB - Adenovirus (Ad) endosomal membrane penetration activates the NLRP3 inflammasome by releasing lysosomal cathepsin B (catB) into the cytoplasm. We therefore examined the extent to which inflammasome activation correlates with Ad colocalization with catB-enriched lysosomes. Inflammasome activation, is greater during infections with Ad5 possessing an Ad16 fiber (Ad5F16gfp), or Ad5gfp neutralized by human serum, than Ad5gfp alone. Enhanced IL-1beta release by Ad5F16gfp is partially due to increased TLR9 signaling but also correlates with greater release of catB into the cytoplasm. This increased TLR9 signaling and catB release correlates with a greater localization of Ad5F16gfp to lysosomes prior to endosomal escape. Another nonenveloped virus, reovirus, requires catB to penetrate cell membranes. However, reovirus did not release catB into the cytoplasm despite significantly greater colocalization with lysosomes compared to Ad5gfp and efficient membrane penetration. Thus, not only lysosomal localization, but the mechanism of membrane penetration influences viral activation of the NLRP3 inflammasome. PMID- 21315401 TI - A post-entry role for CD63 in early HIV-1 replication. AB - Macrophages and CD4(+) lymphocytes are the major reservoirs for HIV-1 infection. CD63 is a tetraspanin transmembrane protein, which has been shown to play an essential role during HIV-1 replication in macrophages. In this study, we further confirm the requirement of CD63 in early HIV-1 replication events in both macrophages and a CD4(+) cell line. Further analysis revealed that viral attachment and cell-cell fusion were unaffected by CD63 silencing. However, CD63 depleted macrophages showed a significant decrease in the initiation and completion of HIV-1 reverse transcription, affecting subsequent events of the HIV 1 life cycle. Integration of HIV-1 cDNA as well as the formation of 2-LTR circles was notably reduced. Reporter assays showed that CD63 down regulation reduced production of the early HIV protein Tat. In agreement, CD63 silencing also inhibited production of the late protein p24. These findings suggest that CD63 plays an early post-entry role prior to or at the reverse transcription step. PMID- 21315403 TI - Reply to comment on "Using Bayesian statistics to estimate the coefficients of a two-component second-order chlorine bulk decay model for a water distribution system" by Huang, J.J., McBean E.A. Water Res. (2007). PMID- 21315402 TI - Genetic bases of the temperature-sensitive phenotype of a master donor virus used in live attenuated influenza vaccines: A/Leningrad/134/17/57 (H2N2). AB - Trivalent live attenuated influenza vaccines whose type A components are based on cold-adapted A/Leningrad/134/17/57 (H2N2) (caLen17) master donor virus (MDV) have been successfully used in Russia for decades to control influenza. The vaccine virus comprises hemagglutinin and neuraminidase genes from the circulating viruses and the remaining six genes from the MDV. The latter confer temperature sensitive (ts) and attenuated (att) phenotypes. The ts phenotype of the vaccine virus is a critical biological determinant of attenuation of virulence. We developed a plasmid-based reverse genetics system for MDV caLen17 to study the genetic basis of its ts phenotype. Mutations in the polymerase proteins PB1 and PB2 played a crucial role in the ts phenotype of MDV caLen17. In addition, we show that caLen17-specific ts mutations could impart the ts phenotype to the divergent PR8 virus, suggesting the feasibility of transferring the ts phenotype to new viruses of interest for vaccine development. PMID- 21315404 TI - Characterization of ACC deaminase-producing endophytic bacteria isolated from copper-tolerant plants and their potential in promoting the growth and copper accumulation of Brassica napus. AB - One hundred Cu-resistant-endophytic bacteria were isolated from Cu-tolerant plants grown on Cu mine wasteland, of which, eight Cu-resistant and 1 aminocyclopropane-1-carboxylate (ACC) deaminase-producing endophytic bacteria were obtained based on the ACC deaminase activity of the bacteria and characterized with respect to metal resistance, production of ACC deaminase, indole-3-acetic acid (IAA) as well as siderophores and mineral phosphate solubilization. Ralstonia sp. J1-22-2, Pantoea agglomerans Jp3-3, and Pseudomonas thivervalensis Y1-3-9 with higher ACC deaminase activity (ranging from 213 to 370 MUM alpha-ketobutyrate mg(-1)h(-1)) were evaluated for promoting plant growth and Cu uptake of rape grown in quartz sand containing 0, 2.5, and 5 mg kg(-1) of Cu in pot experiments. The eight bacteria were found to exhibit different multiple heavy metal resistance characteristics, to show different levels of ACC deaminase activity and to produce indole acetic acid. Seven bacteria produced siderophores and solubilized inorganic phosphate. Pot experiments showed that inoculation with the strains (J1-22-2, Jp3-3, and Y1-3-9) was found to increase the biomass of rape. Increases in above-ground tissue Cu contents of rape cultivated in 2.5 and 5 mg kg(-1) of Cu-contaminated substrates varied from 9% to 31% and from 3 to 4 fold respectively in inoculated-rape plants compared to the uninoculated control. The maximum Cu uptake of rape was observed after inoculation with P. agglomerans Jp3-3. The results show that metal-resistant and plant growth promoting endophytic bacteria play an important role in plant growth and Cu uptake which may provide a new endophytic bacterial-assisted phytoremediation of Cu contaminated environment. PMID- 21315405 TI - Chromate-reducing activity of Hansenula polymorpha recombinant cells over producing flavocytochrome b2. AB - In spite of the great interest to studies of the biological roles of chromium, as well as the toxic influence of Cr(VI)-species on living organisms, the molecular mechanisms of chromate bioremediation remain vague. A reductive pathway resulting in formation of less toxic Cr(III)-species is suggested to be the most important among possible mechanisms for chromate biodetoxification. The yeast l lactate:cytochrome c-oxidoreductase (flavocytochrome b(2), FC b(2)) has absolute specificity for l-lactate, yet is non-selective with respect to its electron acceptor. These properties allow us to consider the enzyme as a potential candidate for chromate reduction by living cells in the presence of l-lactate. A recombinant strain of thermotolerant, methylotrophic yeast Hansenula polymorpha with sixfold increased FC b(2) enzyme activity (up to 3MUmolmin(-1)mg(-1) protein in cell-free extract) compared to the parental strain was used for approval our suggestion. The recombinant cells, stored in dried state, as well as living yeast cells were tested for chromate-reducing activity in vitro in the presence of l lactate (as an electron donor for chromate reduction) and different low molecular weight, redox-active mediators facilitating electron transfer from the reduced form of the enzyme to chromate (as a final electron acceptor): dichlorophenolindophenol (DCPIP), Methylene blue, Meldola blue, and Nile blue. It was shown that the highest chromate-reducing activity of the cells was achieved in the presence of DCPIP. The ability of chromate to catch electrons from the reduced flavocytochrome b(2) was confirmed using purified enzyme immobilized on the surface of a platinum electrode. The increasing concentration of Cr(VI) resulted in a decrease of enzyme-mediated current generated on the electrode during l-lactate oxidation. The shift and drop in amplitude of the peak in the cyclic voltammogram are indicative of Cr(VI)-dependent competition between reaction of chromate with reduced FC b(2) and direct electron transfer from the enzyme to the electrode surface. The application of the chromate-reducing ability of FC b(2)-over-producing recombinant cells of H. polymorpha toward chromate bioremediation and the construction of cells-based biosensor for chromate monitoring in the environment are discussed. PMID- 21315406 TI - Enantioselective bioaccumulation and toxic effects of metalaxyl in earthworm Eisenia foetida. AB - Knowledge about the enantioselective bioavailability of chiral pesticides in soil invertebrates facilitates more accurate interpretation of their environmental behaviors. In this study, the acute toxicities of R-metalaxyl and rac-metalaxyl to earthworm (Eisenia foetida) were assayed by filter paper contact test. After 48 h of exposure, the calculated LC(50) values for R- and rac-metalaxyl were 0.052 and 0.022 mg cm(-2), respectively, resulting in a two fold difference in toxicity. For uptake experiment, earthworms were exposed in soil at two dose levels (10 and 50 mg kg(dwt)(-1)). The concentrations of two enantiomers in soil and earthworm were determined by high-performance liquid chromatography based on cellulose tri-(3,5-dimethylphenyl-carbamate) chiral stationary phase. The results showed that metalaxyl was taken up by earthworm rapidly, and the bioaccumulation of metalaxyl in earthworm was enantioselective with preferential accumulation of S-enantiomer. In addition, biota to soil accumulation factor (BSAF) used to express the bioaccumulation of metalaxyl enantiomers was investigated, and significant difference was observed between rac-metalaxyl and R-metalaxyl. PMID- 21315407 TI - Change of genotoxicity for raw and finished water: role of purification processes. AB - In China, the safety of drinking water becomes a significant issue due to serious aquatic environmental pollution. The genotoxic levels of raw and finished water from seven typical waterworks located in the five basins in China were then evaluated using umu test. Effect of conventional treatment processes (coagulation, filtration and disinfection) on the genotoxicity and the fate of dissolved organic matter (DOM) was discussed. The results showed that most of the selected finished water presented genotoxicity at or lower than 300 mL water sample exposure dose. The genotoxic effects of finished water were significantly higher than those of raw water. It also exhibited that there existed higher correlation between genotoxic effect and Br(-) than the other water quality parameters. The brominated trihalomethanes played a more important role in finished water genotoxicity than brominated haloacetic acids. The treatment processes could increase the genotoxic effects of finished water, especially for the chlorination treatment. The fluorescence spectra and high performance size exclusion chromatogram analysis of DOM characters indicated that the proportion of low molecular weight acids, nitrogen containing aromatics, proteinaceous and microbially derived organic matters (200-300 Da) increased during purification processes, which indicated probably the release or formation of drinking water genotoxins. PMID- 21315408 TI - Class III beta-tubulin expression in advanced-stage serous ovarian carcinoma effusions is associated with poor survival and primary chemoresistance. AB - The objective of this study was to analyze the clinical role of nestin, a stem cell marker, and class III beta-tubulin in advanced-stage serous ovarian carcinoma. Nestin and class III beta-tubulin protein expression were investigated in 217 effusions using immunohistochemistry. Results were analyzed for association with clinicopathologic parameters including chemotherapy response and survival. Class III beta-tubulin and nestin were expressed in tumor cells in 98.6% and 95.6% of specimens, respectively. Staining extent was comparable in prechemotherapy and postchemotherapy effusions. No association was found with patient age, histologic grade, International Federation of Gynecology and Obstetrics stage, primary surgery versus secondary debulking, or residual disease volume. High class III beta-tubulin expression in prechemotherapy effusions was significantly associated with primary chemoresistance (progression-free survival <6 months; P = .036) and with a trend for less favorable response to first-line treatment (P = .054). In univariate survival analysis, high class III beta tubulin expression in prechemotherapy effusions was significantly associated with poor overall survival (P = .021), with a trend for poor progression-free survival (P = .067). These associations did not have independent prognostic value in Cox multivariate analysis. Nestin expression was unrelated to chemoresistance or survival. Both class III beta-tubulin and nestin are frequently expressed in serous ovarian carcinoma cells in effusions. Nestin does not provide predictive or prognostic data in this patient group, whereas class III beta-tubulin expression in prechemotherapy effusions is associated with poor chemoresponse and shorter survival, suggesting that it may be a therapeutic target in ovarian cancer. PMID- 21315409 TI - Certification and maintenance of certification: updates from the American Board of Pathology. AB - The American Board of Pathology continues to update the certification process to ensure that all candidates have appropriate training and credentials and meet the competency requirements of the Accreditation Council for Graduate Medical Education. The maintenance of certification process, instituted in 2006, has gone through 2 reporting cycles; and the American Board of Pathology is preparing for administration of the first maintenance of certification examination in 2014. This article updates the pathology community on these changes. PMID- 21315410 TI - Nuclear Snail1 and nuclear ZEB1 protein expression in invasive and intraductal human breast carcinomas. AB - Snail1 and ZEB1 are transcriptional repressors that drive tumor initiation and metastasis in animal models. Snail1 and ZEB1 are frequently coexpressed in tumor cell lines, suggesting that these factors may cooperate to promote tumor progression. However, coexpression of these transcriptional repressors in primary human cancer specimens has not been investigated. Previous studies assessed expression in primary breast cancers of Snail1 messenger RNA, which does not reflect Snail1 activity because Snail1 is subject to posttranslational modifications that inhibit its nuclear localization/activity. In the current study, using breast tumor cell lines of known Snail1 and ZEB1 expression status, we developed immunohistochemistry protocols for detecting nuclear Snail1 and nuclear ZEB1 proteins. Using these protocols, we assessed nuclear Snail1 and nuclear ZEB1 expressions in primary human breast cancers of varying subtypes (n = 78). Nuclear Snail1 and estrogen receptor alpha expressions were inversely associated in primary breast cancers, and nuclear Snail1 was expressed in approximately 80% of triple-negative breast cancers (lacking estrogen receptor alpha, progesterone receptor, and human epidermal growth factor receptor 2 overexpression). In contrast, nuclear ZEB1 was expressed at a significantly lower frequency in these breast cancers. Notably, nuclear Snail1 protein was detected in 45% of ductal carcinoma in situ specimens (n = 29), raising the important possibility that nuclear Snail1 expression in early stage breast lesions may predict future development of invasive breast cancer. Collectively, our studies demonstrate frequent expression of nuclear Snail1, but not nuclear ZEB1, in invasive, triple-negative breast cancers as well as in intraductal carcinomas. PMID- 21315411 TI - Tubular nuclear accumulation of Snail and epithelial phenotypic changes in human myeloma cast nephropathy. AB - The transcription factor Snail is an important repressor of E-cadherin gene expression. It plays a key role in the induction of epithelial-mesenchymal transition, an essential process important not only in embryonic development and tumor progression but also in organ fibrogenesis. We studied the expression of Snail by immunohistochemistry, along with several epithelial phenotypic changes suggestive of epithelial-mesenchymal transition, in 14 patients with multiple myeloma cast nephropathy. This nephropathy is characterized by a rapid progression toward fibrosis. As controls, we used normal kidneys and kidneys from patients displaying an idiopathic nephrotic syndrome, a syndrome unassociated with renal fibrosis. We discovered that, in all patients with multiple myeloma nephropathy, a drastic accumulation of Snail is seen in the nuclei from tubular epithelial cells showing epithelial phenotypic changes. In contrast, normal and idiopathic nephrotic syndrome kidneys did not exhibit either of these markers. Snail, a major player in the process of epithelial-to-mesenchymal transition, is highly expressed by tubular epithelial cells during multiple myeloma nephropathy. It is, therefore, a potential target to prevent multiple myeloma kidneys from fibrosing. Intranuclear accumulation of Snail is a characteristic in phenotypically altered tubular cells from multiple myeloma kidneys. The epithelial-mesenchymal transition pathway could, therefore, be involved in the rapid renal fibrogenesis observed in this setting. PMID- 21315412 TI - Proliferative capacity of stem/progenitor-like cells in the kidney may associate with the outcome of patients with acute tubular necrosis. AB - Animal studies indicate that adult renal stem/progenitor cells can undergo rapid proliferation in response to renal injury, but whether the same is true in humans is largely unknown. To examine the profile of renal stem/progenitor cells responsible for acute tubular necrosis in human kidney, double and triple immunostaining was performed using proliferative marker and stem/progenitor protein markers on sections from 10 kidneys with acute tubular necrosis and 4 normal adult kidneys. The immunopositive cells were recorded using 2-photon confocal laser scanning microscopy. We found that dividing cells were present in the tubules of the cortex and medulla, as well as the glomerulus in normal human kidney. Proliferative cells in the parietal layer of Bowman capsule expressed CD133, and dividing cells in the tubules expressed immature cell protein markers paired box gene 2, vimentin, and nestin. After acute tubular necrosis, Ki67 positive cells in the cortex tubules significantly increased compared with normal adult kidney. These Ki67-positive cells expressed CD133 and paired box gene 2, but not the cell death marker, activated caspase-3. In addition, the number of dividing cells increased significantly in patients with acute tubular necrosis who subsequently recovered, compared with patients with acute tubular necrosis who consequently developed protracted acute tubular necrosis or died. Our data suggest that renal stem/progenitor cells may reside not only in the parietal layer of Bowman capsule but also in the cortex and medulla in normal human kidney, and the proliferative capacity of renal stem/progenitor cells after acute tubular necrosis may be an important determinant of a patient's outcome. PMID- 21315413 TI - A novel case of rhabdoid colon carcinoma associated with a positive CpG island methylator phenotype and BRAF mutation. AB - Colon carcinoma with rhabdoid characteristics is a rare, malignant tumor whose molecular alterations have not been clarified yet. We report a novel case of a colon adenocarcinoma with rhabdoid features in a 71-year-old woman, localized to the right colon and associated with local lymph node and liver metastasis. The patient died within 8 months from surgery despite target chemotherapy. The tumor was enriched in cells with a typical rhabdoid-type morphology displaying a marked and diffuse vimentin staining. Cells were also positive for epidermal growth factor receptor (EGFR), p53, Ki67, and beta-catenin and negative for cytokeratin 20/cytokeratin 7, E-cadherin, and CDX2. Remarkably, the promoter regions of 4 of 5 specific genes that define the so-called "CpG island methylator phenotype," including mutL homolog 1 (MLH1), were methylated. Consistently, microsatellite instability was detected. A BRAF V600E mutation and no KRAS mutations were identified. Finally, 4 tumor suppressor gene promoters CDH1, CDKN1B, CDKN1C, and MGMT were not methylated. This is the first case of a colorectal carcinoma with rhabdoid features, "CpG island methylator phenotype," high microsatellite instability associated with a BRAF mutation, and patient poorer outcome. PMID- 21315414 TI - Biomarker expression in cervical intraepithelial neoplasia: potential progression predictive factors for low-grade lesions. AB - The aim of this study was to reveal whether 3 biomarkers (p16INK4a, ProEx C, and human papilloma virus DNA) are useful in the diagnosis of cervical intraepithelial neoplasia and whether they could predict disease progression of cervical intraepithelial neoplasia-1. We analyzed 252 cervical specimens: nondysplastic mucosa (n = 9), cervical intraepithelial neoplasia (n = 229), and squamous cell carcinoma (n = 14). Immunostaining for p16INK4a and ProEx C, and the hybridcapture II assay for human papilloma virus DNA were performed. Expression of p16INK4a and staining for ProEx C were significantly higher in intraepithelial neoplasia 2/3 (96%-100%) than in nondysplastic mucosa (11%) or intraepithelial neoplasia 1 (40%-53%). Human papilloma virus DNA was detected in 69% of intraepithelial neoplasia-1, 95% of intraepithelial neoplasia-2, and 100% of intraepithelial neoplasia 3. Of 99 patients with intraepithelial neoplasia 1 for whom follow-up data was available, 62 (73%) showed spontaneous regression, 17 (20%) demonstrated persistent low-grade lesion, and 7 (7%) progressed to intraepithelial neoplasia 2/3. Expressions of p16INK4a and staining with ProEx C were significantly higher in the progression group than in the regression group. Testing for p16INK4a and ProEx C was sensitive (86%) and moderately specific (60% and 61%, respectively) in predicting the progression of cervical intraepithelial neoplasia 1. Human papilloma virus DNA testing was highly sensitive (100%) but less specific (37%). In conclusion, this study revealed that p16INK4a and ProEx C are useful biomarkers for the diagnosis of cervical intraepithelial neoplasia, and have potential as predictors of progression of low-grade lesions. PMID- 21315415 TI - Atypical tumor-stromal fibroblasts in invasive ductal carcinomas of the breast treated with neoadjuvant therapy. AB - Tumor-stromal fibroblasts have recently been reported to play important roles in the tumor progression of cancer in various organs. The purpose of the present study was to investigate whether any characteristic histologic features of tumor stromal fibroblasts could accurately predict the outcome of 318 patients with invasive ductal carcinoma of the breast who had received neoadjuvant therapy. We observed a small number of tumor-stromal fibroblasts with characteristic nuclear features existing in the tumor stroma and named these cells "atypical tumor stromal fibroblasts." We then assessed the absence or presence of atypical tumor stromal fibroblasts in biopsy (taken before neoadjuvant therapy) and surgical (taken after neoadjuvant therapy) materials and analyzed the outcome predictive powers of the presence of atypical tumor-stromal fibroblasts in biopsy and surgical materials using multivariate analyses that included well-known clinicopathological factors. The multivariate analyses demonstrated that the presence of atypical tumor-stromal fibroblasts assessed using biopsy materials had significantly higher hazard ratios for tumor recurrence and tumor-related death in patients with nodal metastasis and also significantly higher hazard ratios for tumor recurrence and tumor-related death independent of the hormone receptor status of the tumors. The results of this study clearly indicated that the presence of atypical tumor-stromal fibroblasts, especially in biopsy materials, is significantly associated with tumor recurrence and the tumor related death of patients with invasive ductal carcinoma of the breast who have received neoadjuvant therapy. PMID- 21315416 TI - Adult T-cell leukemia/lymphoma with Epstein-Barr virus-positive Hodgkin-like cells. AB - Hodgkin-like cells have been described in a variety of non-Hodgkin lymphomas including chronic lymphocytic leukemia and peripheral T-cell lymphoma. There have been rare reports in the Japanese population of human T-cell lymphotrophic virus 1-associated adult T-cell leukemia/lymphoma harboring Hodgkin-like cells; however, no similar cases have been described in Western patients. We report a 53 year-old African American man who presented with progressive weakness and lethargy, and was found to have generalized lymphadenopathy and hypercalcemia. A lymph node biopsy showed involvement by adult T-cell leukemia/lymphoma with scattered Epstein-Barr virus-positive cells, some of which resembled Hodgkin cells that had a B-cell phenotype, consistent with an Epstein-Barr virus lymphoproliferative disorder. The patient had stage 4 disease with bone marrow involvement. In light of the associated B-cell lymphoproliferative process, the patient was treated with 6 cycles of intensive chemotherapy that targeted both the adult T-cell leukemia/lymphoma and the Epstein-Barr virus-lymphoproliferative disorder that resulted in a complete response. An awareness of the association of Epstein-Barr virus-lymphoproliferative disorder with Hodgkin-like cells in the context of adult T-cell leukemia/lymphoma is necessary to avoid potential misdiagnosis and to aid in therapeutic decisions. PMID- 21315417 TI - Adrenal lymphangioma: clinicopathologic and immunohistochemical characteristics of a rare lesion. AB - Adrenal lymphangiomas, also known as cystic adrenal lymphangiomas, are rare, benign vascular lesions that usually remain asymptomatic throughout life. Although previously adrenal lymphangioma lesions were primarily found at autopsy, they are currently detected during imaging work-up for unrelated causes and are likely to imitate other adrenocortical or adrenal medullary neoplasms. We aimed to retrospectively review all adrenal lymphangioma cases at our hospital and further document their lymphatic origin by immunohistochemical staining. A search of surgical pathology records (1984-2008) was conducted. All hematoxylin and eosin sections were retrieved from archives and reviewed by 2 pathologists in the study. Clinical information was gathered from electronic medical records. Representative paraffin-embedded sections from each case were selected for immunohistochemical analysis using monoclonal antibodies D2-40 and AE1/AE3. A total of 9 adrenal lymphangioma cases were identified (6 women and 3 men). All 9 patients were adults at time of diagnosis with a mean age of 42 years (range, 28 56 years). There were 7 white patients, 1 African American patient, and 1 Asian patient. The average size of an adrenal lymphangioma lesion was 4.9 cm (range, 2.0-13.5 cm). Adrenal lymphangioma was twice more frequently located on the right side (6 right-sided and 3 left-sided). Clinically, 4 (44%) of the 9 lesions presented with abdominal, flank, or back pain. One lymphangioma was found during work-up for labile hypertension. The remaining 4 lesions (44%) were asymptomatic and incidentally found during imaging studies for unrelated causes. Surgical removal was achieved by total adrenalectomy in 8 of the 9 lesions and by partial adrenalectomy in the remaining case. No evidence of recurrence or development of a contralateral lesion was encountered in any of the patients. Histologically, our adrenal lymphangiomas showed a typical multicystic architecture with dilated spaces lined by flattened, bland, simple lining. The cystic channels/spaces occasionally contained proteinaceous material and lacked red blood cell content. On immunohistochemical stains, D2-40 cytoplasmic staining was positive in all 9 examined lesions, whereas AE1/AE3 was negative, thus, confirming their lymphatic nature. D2-40 staining was diffuse in 2 and focal in the 7 remaining lesions. Adrenal lymphangiomas are very rare, benign lymphatic neoplasms with a female, right-sided predominance in our current series. They may clinically present with abdominal pain or can be incidentally found during adulthood as a mass, necessitating surgical removal to rule out other types of adrenal neoplasms. PMID- 21315418 TI - Deletion of the inhibitor of growth 4 (ING4) tumor suppressor gene is prevalent in human epidermal growth factor 2 (HER2)-positive breast cancer. AB - Inhibitor of growth 4 (ING4) is a candidate tumor suppressor gene that was shown to be deleted in 10% to 20% of breast cancers by array comparative genome hybridization analysis. We developed fluorescent in situ hybridization to detect the ING4 gene directly in the tissue samples on tumor tissue microarrays. We evaluated the ING4 gene status in 1033 breast cancer tissue samples and observed that ING4 was deleted in 16.5% (170/1033) of all breast cancers. ING4 deletion was significantly associated with Her2 overexpression: of the tumors with ING4 deletion, 23.8% (39/164) were human epidermal growth factor 2 (HER2) positive, as compared with 14.1% (115/814) of the tumors without ING4 deletion (P = .002). In addition, the tumors with ING4 deletion were more likely to belong to the HER2 molecular subtype (estrogen receptor negative/progesterone receptor negative/human epidermal growth factor positive) of breast cancer, compared with the other subtypes (28.4% HER2 versus 15.7% all, P = .002). ING4 deletion did not affect survival outcome of all patients with breast cancer (P = .797) or of the patients with HER2-positive tumors (P = .792). We conclude that ING4 deletion in breast cancer is relatively common, as 1 in 6 breast cancer harbors ING4 deletion. Furthermore, ING4 deletion is more prevalent in HER2-positive tumors, suggesting a functional antagonistic relationship between the ING4 tumor suppressor and the HER2 oncogene. These results sustain the view that ING4 is a tumor suppressor in breast cancer and suggest that ING4 deletion may contribute to the pathogenesis of HER2-positive breast cancer. PMID- 21315419 TI - Down-regulation of MU-protocadherin expression is a common event in colorectal carcinogenesis. AB - We have previously reported that treatment of colorectal cancer cells with mesalazine results in the up-regulated expression of a novel member of the cadherin protein superfamily, named MU-protocadherin, which is able to sequester beta-catenin on plasmatic membrane of treated cells inhibiting its proliferation signalling pathway. This finding suggests that MU-protocadherin could exert an oncosuppressive effect on colorectal epithelium. The purpose of our study was to assess whether MU-protocadherin expression is down-regulated during colorectal carcinogenesis. This issue was addressed by analyzing the messenger RNA and protein expression of MU-protocadherin in normal and tumor colorectal cell samples using a combination of quantitative real-time polymerase chain reaction, microarray analysis, and immunohistochemical examination. To better contextualize the role played by MU-protocadherin in the pathogenesis of colorectal cancer, this last assay was also extended to beta-catenin, E-cadherin, and Ki-67 proteins. The results obtained evidenced that (1) levels of MU-protocadherin transcript were down-regulated in all the analyzed colorectal cancer samples as compared with normal mucosa; (2) expression of MU-protocadherin protein was completely lost in most analyzed colorectal cancer samples (71%); (3) MU protocadherin retains beta-catenin on the plasmatic membrane of normal colon enterocytes, which implies that beta-catenin is released from this site and translocated to the nucleus in colorectal cancer cells. Our data consequently suggest that down-regulation of MU-protocadherin expression is a common event in colorectal carcinogenesis and might therefore play an important role in this pathologic process. PMID- 21315420 TI - Increased expression of activating transcription factor 3 is related to the biologic behavior of cutaneous squamous cell carcinomas. AB - Activating transcription factor 3, a member of the activating transcription factor/cyclic adenosine monophosphate response element-binding family of transcription factors, is an adaptive response gene that plays an oncogenic role in the development of various cancers. To our knowledge, few information are available on the possible role of activating transcription factor 3 in skin cancer. In this study, we investigated the expression of activating transcription factor 3 in basal cell carcinomas (n = 5), actinic keratoses (n = 7), squamous cell carcinomas (n = 19), and Bowen disease (n = 14) by immunohistochemistry. In results, activating transcription factor 3 was significantly expressed in squamous cell carcinomas (15/19), suggesting that it is involved in the pathogenesis of squamous cell carcinomas but not in basal cell carcinomas (0/5). In addition, higher expression of activating transcription factor 3 was observed in squamous cell carcinomas that were metastatic (P < .01) or arose in organ transplant recipients (P < .05). Therefore, activating transcription factor 3 appears to play an oncogenic role in the development of squamous cell carcinomas and may be related to the biologic behavior of them. PMID- 21315421 TI - Parafibromin expression is an independent prognostic factor for colorectal carcinomas. AB - Parafibromin is a protein encoded by hyperparathyroidism 2, and its down regulated expression is involved in the pathogenesis of parathyroid, breast, and gastric carcinomas. This study aimed to clarify the roles of parafibromin expression in tumorigenesis, progression, and prognosis of colorectal carcinomas. Parafibromin-expressing plasmid was transfected into DLD-1 cells with the phenotypes, and related molecules were examined. Parafibromin expression was examined in colorectal samples by immunohistochemistry, in situ hybridization, Western blot, or reverse transcription polymerase chain reaction. It was found that parafibromin overexpression could cause G1 arrest and enhance differentiation of DLD-1 cells. There was a high expression of p21, p27, and cyclin E, but low expression of cyclin D1 messenger RNA, phospho-cdc2, and phospho-cdc25c proteins. Parafibromin could inhibit c-myc messenger RNA expression by binding to c-myc promoter. Expression levels of nuclear parafibromin and parafibromin messenger RNA were decreased from colorectal nonneoplastic mucosa and adenomas to carcinomas (P < .05). Immunohistochemically, parafibromin expression was inversely correlated with tumor size, depth of invasion, lymph node metastasis, clinicopathologic staging, and poor prognosis of carcinomas (P < .05). It was suggested that parafibromin overexpression might suppress cell cycle progression and promote differentiation of DLD-1 cells. Aberrant parafibromin expression possibly contributes to the pathogenesis, growth, invasion, and metastasis of colorectal carcinomas and could be regarded as an independent factor to indicate a favorable prognosis for patients with colorectal carcinomas. PMID- 21315422 TI - Distinguishing features of endometrial pathology after exposure to the progesterone receptor modulator mifepristone. AB - There is growing interest in the use of progesterone receptor modulators such as mifepristone for treatment of gynecologic and other conditions, but interest in progesterone receptor modulators is dampened by the effects of the agents on the endometrium. In this study, we examined the endometria of women exposed to mifepristone for treatment of leiomyomas in doses of 2.5 and 5 mg and compared them to unexposed endometria. We assessed the reliability of these features by comparing agreement in ratings between pathologists who were blinded to each other's readings. We assessed distinguishing features between exposed and unexposed groups by comparing frequency of features between groups. We found that key features could be reliably assessed by pathologists experienced in endometrial pathology. We observed several features (nonsynchronous endometrium, large fluid filled glands, and abnormal blood vessels) that distinguished endometrial samples that were and were not exposed to the drug. These findings suggest several features that can be tracked during studies involving mifepristone and, potentially, other progesterone receptor modulators. PMID- 21315423 TI - Expression of serine 194-phosphorylated Fas-associated death domain protein correlates with proliferation in B-cell non-Hodgkin lymphomas. AB - Fas-associated death domain protein is a key component of the extrinsic apoptotic pathway. In addition, in animal models, Fas-associated death domain protein phosphorylation at serine 194 has been shown to affect cell proliferation, especially in T lymphocytes. The importance of Fas-associated death domain protein phosphorylation at serine 194 for the proliferation of B lymphocytes, however, is uncertain. Here we show in reactive lymph nodes that serine 194 phosphorylated Fas-associated death domain protein is expressed predominantly in the dark (proliferative) zone of germinal centers. In B-cell non-Hodgkin lymphoma cell lines, serine 194 phosphorylated Fas-associated death domain protein levels are substantially higher in highly proliferating cells and lower in serum-starved cells. We also used immunohistochemical analysis to assess Fas-associated death domain protein phosphorylation at serine 194 expression in 122 B-cell non-Hodgkin type lymphomas. The mean percentage of serine 194 phosphorylated Fas-associated death domain protein positive tumor cells was 81% in Burkitt lymphoma, 41% in diffuse large B-cell lymphoma, 18% in follicular lymphoma, 18% in plasma cell myeloma, 12% in extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, 11% in mantle cell lymphoma, and 2% in chronic lymphocytic leukemia/small lymphocytic lymphoma (P < .0001, Kruskal-Wallis test). Furthermore, in chronic lymphocytic leukemia/small lymphocytic lymphoma, serine 194 phosphorylated Fas-associated death domain protein was detected predominantly in proliferation centers. In the entire study group, the percentage of cells positive for serine 194 phosphorylated Fas-associated death domain protein correlated significantly with the proliferation index Ki-67 (Spearman R = 0.9, P < .0001). These data provide evidence that serine 194 phosphorylated Fas associated death domain protein is involved in the proliferation of normal and neoplastic B cells and has features of a novel proliferation marker. PMID- 21315424 TI - Osteopontin expression in ovarian carcinoma effusions is related to improved clinical outcome. AB - Osteopontin, a soluble protein present in all body fluids, is involved in signaling pathways related to adhesion and extracellular matrix interactions, affecting multiple cellular functions, including inflammation, angiogenesis, and tumor metastasis. We studied osteopontin expression by immunohistochemistry and its clinical relevance in 170 effusions (140 peritoneal, 30 pleural) from women with advanced-stage ovarian carcinoma. Carcinoma cells expressed osteopontin in 126 (74%) of 170 effusions. Osteopontin expression was more frequent in effusions from patients with high-grade tumors (P = .036) but was significantly associated with better debulking at primary surgery (P = .019) and complete response to chemotherapy at diagnosis (P = .021). Osteopontin expression was positively associated to that of the previously studied nuclear factor kappaB inhibitor IkappaB (P = .019) and negatively related to expression of the inhibitor of apoptosis family member XIAP (P = .008) and the angiogenic marker endoglin (CD105; P = .018). In univariate survival analysis, the presence of osteopontin in carcinoma cells in primary diagnosis prechemotherapy effusions was associated with longer progression-free survival (P = .037), a finding that did not retain its significance in multivariate Cox analysis. This study demonstrates that osteopontin is frequently expressed in ovarian carcinoma effusions. However, its presence in tumor cells at this anatomical site is unexpectedly associated with less aggressive clinical course, suggesting different and yet undefined biological roles for this protein in serous effusions. PMID- 21315425 TI - New Anchomomys (Adapoidea, Primates) from the Robiacian (Middle Eocene) of northeastern Spain. Taxonomic and evolutionary implications. PMID- 21315426 TI - Pharmaceuticals, hormones and bisphenol A in untreated source and finished drinking water in Ontario, Canada--occurrence and treatment efficiency. AB - The Ontario Ministry of the Environment (MOE) conducted a survey in 2006 on emerging organic contaminants (EOCs) which included pharmaceuticals, hormones and bisphenol A (BPA). The survey collected 258 samples over a 16 month period from selected source waters and 17 drinking water systems (DWSs), and analyzed them for 48 EOCs using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and isotope dilution mass spectrometry (IDMS) for the highest precision and accuracy of analytical data possible. 27 of the 48 target EOCs were detected in source water, finished drinking water, or both. DWSs using river and lake source water accounted for>90% detections. Of the 27 EOCs found, we also reported the first detection of two antibiotics roxithromycin and enrofloxacin in environmental samples. The most frequently detected compounds (>= 10%) in finished drinking water were carbamazepine (CBZ), gemfibrozil (GFB), ibuprofen (IBU), and BPA; with their concentrations accurately determined by using IDMS and calculated to be 4 to 10 times lower than those measured in the source water. Comparison of plant specific data allowed us to determine removal efficiency (RE) of these four most frequently detected compounds in Ontario DWSs. The RE of CBZ was determined to be from 71 to 93% for DWSs using granulated activated carbon (GAC); and was 75% for DWSs using GAC followed by ultraviolet irradiation (UV). The observed RE of GFB was between 44 and 55% in DWSs using GAC and increased to 82% when GAC was followed by UV. The use of GAC or GAC followed by UV provided an RE improvement of BPA from 80 to 99%. These detected concentration levels are well below the predicted no effect concentration or total allowable concentration reported in the literature. Additional targeted, site specific comparative research is required to fully assess the effectiveness of Ontario DWSs to remove particular compounds of concern. PMID- 21315427 TI - Have the bioavailabilities of trace metals to a suite of biomonitors changed over three decades in SW England estuaries historically affected by mining? AB - Many estuaries of southwest England were heavily contaminated with toxic metals associated with the mining of copper and other metals, particularly between 1850 and 1900. The question remains whether the passage of time has brought remediation to these estuaries. In 2003 and 2006 we revisited sites in 5 metal contaminated estuaries sampled in the 1970s and 1980s - Restronguet Creek, Gannel, West Looe, East Looe and Tavy. We evaluate changes in metal contamination in sediments and in metal bioavailabilities in sediments and water to local organisms employed as biomonitors. We find that the decline in contamination in these estuaries is complex. Differences in bioavailable contamination in the water column were detectable, as were significant detectable changes in at least some estuaries in bioavailable metal contamination originating from sediments. However, in the 100 years since mining activities declined, bioavailable contamination has not declined to the regional baseline in any estuary affected by the mine wastes. The greatest decline in contamination occurred in the one instance (East Looe) where a previous industrial source of (Ag) contamination was considered. We used the macroalgae Fucus vesiculosus and Ascophyllum nodosum as biomonitors of dissolved metal bioavailabilities and the deposit feeders Nereis diversicolor and Scrobicularia plana as biomonitors of bioavailable metal in sediments. We found no systematic decrease in the atypically high Ag, Cu, Pb and Zn concentrations in the estuarine sediments over a 26 year period. Accumulated metal (Ag, As, Cu, Pb, and Zn) concentrations in the deposit feeders are similarly still atypically high in at least one estuary for each metal, and there is no consistent evidence for general decreases in sediment metal bioavailabilities over time. We conclude that the legacy of mining in sheltered estuaries of southwest England is the ongoing presence of sediments rich in metals bioavailable to deposit feeders, while dissolved metal bioavailabilities from this historical source alone are no longer atypically high. PMID- 21315428 TI - Addition of bevacizumab to weekly paclitaxel significantly improves progression free survival in heavily pretreated recurrent epithelial ovarian cancer. AB - OBJECTIVE: Weekly paclitaxel has been shown to be an effective cytotoxic regimen for recurrent epithelial ovarian cancer (EOC), and may act through inhibition of angiogenesis. Bevacizumab, a potent angiogenesis inhibitor, has also been shown to have activity in patients with EOC. Therefore, we sought to determine if the addition of bevacizumab to weekly paclitaxel led to an increased survival compared to weekly paclitaxel alone. METHODS: A single institutional review was conducted for patients with recurrent EOC treated with weekly paclitaxel (60 70mg/m(2)) on days 1, 8, 15, and 22 of a 28day cycle and those treated with weekly paclitaxel and bevacizumab (10-15mg/kg on day 1 and 15). Response rates (RR) were calculated, and progression-free survival (PFS), and overall survival (OS) were compared using Kaplan-Meier survival analysis. RESULTS: Twenty-nine patients treated with weekly paclitaxel and 41 patients treated with paclitaxel/bevacizumab were identified. The groups were similar in demographics, initial optimal cytoreduction, stage, histology, grade, platinum sensitivity, and median number of previous regimens (4 vs. 4, p=0.69).The overall response rate (ORR) was 63% (complete response (CR) 34% and partial response (PR) 29%) for paclitaxel/bevacizumab and 48% (CR 17% and PR 31%) for weekly paclitaxel (p=0.23). Improvement in PFS was seen in those treated with paclitaxel/bevacizumab in comparison to weekly paclitaxel alone (median PFS 13.2 vs. 6.2months, p<.01). There was a trend towards improved OS for paclitaxel/bevacizumab (median OS 20.6 vs. 9.1months; p=0.12). Toxicities were similar between the two regimens although more bowel perforations (2 vs. 0) were seen in the paclitaxel/bevacizumab group. CONCLUSION: A significant increase in PFS with a trend towards improved OS was demonstrated in this heavily pretreated population treated with paclitaxel/bevacizumab as compared to weekly paclitaxel alone. This data should be helpful in guiding future trials to determine the optimal care for women with recurrent EOC. PMID- 21315429 TI - Initial failure site according to primary treatment with or without para-aortic lymphadenectomy in endometrial cancer. AB - OBJECTIVE: The objective of this study was to compare the initial failure sites in patients with endometrial cancer who underwent surgical treatment including pelvic lymphadenectomy with or without para-aortic lymphadenectomy. METHODS: A retrospective chart review was carried out for 657 endometrial cancer patients with no residual disease after initial treatments including lymphadenectomy at two tertiary centers between 1987 and 2004. Surgical treatment at one institute included pelvic lymphadenectomy (PLX) without para-aortic lymphadenectomy (PALX), while surgical treatment including PLX+PALX was routinely performed at the other institute. We identified patients with recurrence and evaluated initial failure sites. Rates of recurrence in the respective sites were compared according to the type of lymphadenectomy. RESULTS: Of the 657 patients, 103 (15.7%) suffered recurrence. There was no significant difference between the rate of intrapelvic recurrence in the PLX alone group and that in the PLX+PALX group (4.7% vs. 2.9%, p=0.22). The rate of extrapelvic recurrence in the PLX alone group was significantly higher than that in the PLX+PALX group (16.1% vs. 6.2%, p<0.0001), and the rate of para-aortic node (PAN) recurrence in the PLX alone group was also significantly higher than that in the PLX+PALX group (5.1% vs. 0.6%, p=0.0004). In the analysis of patients who received adjuvant chemotherapy, the rate of PAN recurrence in the PLX alone group was significantly higher than that in the PLX+PALX group (9.5% vs. 1.3%, p=0.0036). CONCLUSION: PAN recurrence was a failure pattern peculiar to the PLX alone group. Adjuvant chemotherapy might not be able to replace surgical removal as a treatment for metastatic lymph nodes. PMID- 21315430 TI - Targeted eicosanoid lipidomics of exhaled breath condensate provide a distinct pattern in the aspirin-intolerant asthma phenotype. AB - BACKGROUND: Eicosanoids, important signaling and inflammatory molecules, are present in exhaled breath condensate (EBC) in very low concentrations, requiring highly sensitive analytic methods for their quantification. OBJECTIVE: We sought to assess a vast platform of eicosanoids in different asthma phenotypes, including aspirin-intolerant asthma, by means of a recently developed analytic approach based on mass spectrometry. METHODS: EBC from 115 adult asthmatic subjects (62 with aspirin intolerance) and 38 healthy control subjects were assessed quantitatively for 19 eicosanoids by using complementary HPLC, gas chromatography-mass spectrometry, or both. Palmitic acid concentrations were used as a marker for dilution of condensate samples. RESULTS: Asthma was characterized by an increase in arachidonate lipoxygenase products and cysteinyl leukotrienes. The COX pathway was also significantly upregulated in asthmatic subjects. Subjects with aspirin-intolerant asthma were distinguished by a sharp increase in the level of prostaglandin D(2) and E(2) metabolites; their 5- and 15 hydroxyeicosateraenoic acid levels were also higher than in aspirin-tolerant subjects. A classical discriminant analysis permitted us to classify correctly 99% of asthmatic subjects within the study population; the specificity of the analysis was 97%. The eicosanoid profiling allowed for 92% correct classification of aspirin-intolerant subjects. CONCLUSIONS: The highly sensitive eicosanoid profiling in EBC makes it possible to detect alterations in asthma, especially in its distinct phenotype characterized by hypersensitivity to aspirin and other nonsteroidal anti-inflammatory drugs. This permits us to discriminate asthmatic subjects from healthy subjects, as well as to distinguish the 2 asthma phenotypes based on the presence or absence of aspirin hypersensitivity. PMID- 21315431 TI - Celiac disease confers a 1.6-fold increased risk of asthma: a nationwide population-based cohort study. PMID- 21315432 TI - Omalizumab is effective in nonautoimmune urticaria. PMID- 21315433 TI - Vitamin D supplementation in children may prevent asthma exacerbation triggered by acute respiratory infection. PMID- 21315434 TI - Factors associated with severe versus mild immunotherapy-related systemic reactions: a case-referent study. PMID- 21315435 TI - Eosinophil and neutrophil extracellular DNA traps in human allergic asthmatic airways. AB - BACKGROUND: Asthma is a heterogeneous inflammatory airway disorder that involves eosinophilic and noneosinophilic phenotypes. Unlike in healthy lungs, eosinophils are often present in atopic asthmatic airways, although a subpopulation of asthmatic subjects predominantly experience neutrophilic inflammation. Recently, it has been demonstrated that eosinophils and neutrophils generate bactericidal extracellular traps consisting of DNA and cytotoxic granule proteins. OBJECTIVE: We sought to explore whether living eosinophils and neutrophils infiltrating human atopic asthmatic airways actively form extracellular DNA traps in vivo. METHODS: Quantitative analysis of eosinophils releasing DNA was performed in endobronchial biopsy specimens from 20 human subjects with mild atopic asthma at baseline and after local allergen challenge and 10 healthy subjects. DNA was stained with propidium iodine and major basic protein with specific antibody. Differential cell counts and cytokines/chemokines were assessed in bronchoalveolar lavage fluid. RESULTS: Asthmatic airways were infiltrated with a significantly higher number of eosinophils than healthy airways (39.3 +/- 4.6 vs 0.4 +/- 0.9, P < .0001). All asthmatic subjects but only 1 control subject expressed eosinophils releasing DNA that colocalized with major basic protein (33.65 +/- 20.33 vs 0.3 +/- 0.9 per high-power field, P < .0001). Four asthmatic subjects mostly expressed neutrophilic inflammation and neutrophil DNA traps. Allergen challenge had no significant quantitative effect on eosinophil or neutrophil DNA traps. Airway eosinophils or DNA traps did not correlate with either bronchoalveolar lavage levels of IL-5, IFN-gamma, or eotaxin or the provoking doses of methacholine or allergen in asthmatic subjects. CONCLUSIONS: Extracellular DNA traps are generated by eosinophils and neutrophils in human atopic asthmatic airways in vivo. The mechanism and role of this new finding will necessitate further investigation. PMID- 21315438 TI - Regional differences in the listener's phonemic inventory affect semantic processing: A mismatch negativity (MMN) study. AB - Using the mismatch negativity (MMN) response, we examined how Standard French and Southern French speakers access the meaning of words ending in /e/ or /epsilon/ vowels which are contrastive in Standard French but not in Southern French. In Standard French speakers, there was a significant difference in the amplitude of the brain response after the deviant-minus-standard subtraction between the frontocentral (FC) and right lateral (RL) recording sites for the final-/epsilon/ word but not the final-/e/ word. In contrast, the difference in the amplitude of the brain response between the FC and RL recording sites did not significantly vary as a function of the word's final vowel in Southern French speakers. Our findings provide evidence that access to lexical meaning in spoken word recognition depends on the speaker's native regional accent. PMID- 21315436 TI - Identification of aneuploidy-selective antiproliferation compounds. AB - Aneuploidy, an incorrect chromosome number, is a hallmark of cancer. Compounds that cause lethality in aneuploid, but not euploid, cells could therefore provide new cancer therapies. We have identified the energy stress-inducing agent AICAR, the protein folding inhibitor 17-AAG, and the autophagy inhibitor chloroquine as exhibiting this property. AICAR induces p53-mediated apoptosis in primary mouse embryonic fibroblasts (MEFs) trisomic for chromosome 1, 13, 16, or 19. AICAR and 17-AAG, especially when combined, also show efficacy against aneuploid human cancer cell lines. Our results suggest that compounds that interfere with pathways that are essential for the survival of aneuploid cells could serve as a new treatment strategy against a broad spectrum of human tumors. PMID- 21315437 TI - Semantic dementia and persisting Wernicke's aphasia: linguistic and anatomical profiles. AB - Few studies have directly compared the clinical and anatomical characteristics of patients with progressive aphasia to those of patients with aphasia caused by stroke. In the current study we examined fluent forms of aphasia in these two groups, specifically semantic dementia (SD) and persisting Wernicke's aphasia (WA) due to stroke. We compared 10 patients with SD to 10 age- and education matched patients with WA in three language domains: language comprehension (single words and sentences), spontaneous speech and visual semantics. Neuroanatomical involvement was analyzed using disease-specific image analysis techniques: voxel-based morphometry (VBM) for patients with SD and overlays of lesion digitized lesion reconstructions in patients with WA. Patients with SD and WA were both impaired on tasks that involved visual semantics, but patients with SD were less impaired in spontaneous speech and sentence comprehension. The anatomical findings showed that different regions were most affected in the two disorders: the left anterior temporal lobe in SD and the left posterior middle temporal gyrus in chronic WA. This study highlights that the two syndromes classically associated with language comprehension deficits in aphasia due to stroke and neurodegenerative disease are clinically distinct, most likely due to distinct distributions of damage in the temporal lobe. PMID- 21315439 TI - Corkscrew oesophagus on virtual endoscopy. PMID- 21315440 TI - Telemonitoring of fluid status in heart failure: CHAMPION. PMID- 21315442 TI - Tobacco companies expand their epidemic of death. PMID- 21315443 TI - Phenotypic and genetic differentiation in young-of-the-year common sole (Solea solea) at differentially contaminated nursery grounds. AB - Growth-related characters, condition factor, and genetic differentiation were investigated for a single cohort of young-of-the-year (YOY) sole within and among nurseries with differing levels of heavy metals (Cd, Cu and Zn) contamination in the two Charentais Straits, Bay of Biscay, France. Analyses were performed when individuals recruited (May), then after a full summer spent in each nursery (October). Levels of phenotypic and genetic diversity were compared, together with genetic differentiation at a candidate metallothionein (MT) locus and three putatively neutral microsatellite loci. No phenotypic or genetic differentiation was detected among nurseries in May, but significant variation at each phenotypic trait and at the multilocus level in October (P < 0.001). Single locus analysis demonstrated that only the MT locus was significantly differentiated among nurseries, whether corrected for null alleles or not (theta=0.0401 and theta(corr.FreeNA)=0.0326, respectively; P < 0.001). Results indicate that phenotypic differences among YOY sole nurseries present a molecular correlate acting at identical spatio-temporal scales among nurseries, potentially reflecting differential selective pressure among nurseries in response to contamination. PMID- 21315444 TI - Encapsulation of 2-methoxyestradiol within multifunctional poly(amidoamine) dendrimers for targeted cancer therapy. AB - We report here a general approach to using multifunctional poly(amidoamine) (PAMAM) dendrimer-based platform to encapsulate a potential anticancer drug for targeted cancer therapy. In this approach, amine-terminated generation 5 (G5) PAMAM dendrimers were sequentially modified with fluorescein isothiocyanate (FI) and folic acid (FA) via covalent conjugation, followed by an acetylation reaction to neutralize the remaining amines of the dendrimer surfaces. The synthesized multifunctional dendrimers (G5.NHAc-FI-FA) were then used to complex a potential anticancer drug, 2-methoxyestradiol (2-ME) for targeted delivery of the drugs to cancer cells overexpressing high-affinity folic acid receptors (FAR). We show that the formed G5.NHAc-FI-FA/2-ME complexes with each dendrimer encapsulating approximately 3.7 2-ME molecules are water soluble and stable. In vitro release studies show that 2-ME complexed with the multifunctional dendrimers can be released in a sustained manner. 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay in conjunction with cell morphology observation demonstrates that the G5.NHAc-FI-FA/2-ME complexes can specifically target and display specific therapeutic efficacy to cancer cells overexpressing high-affinity FAR. Findings from this study suggest that multifunctional dendrimers may be used as a general drug carrier to encapsulate various cancer drugs for targeted therapy of different types of cancer. PMID- 21315441 TI - Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. AB - BACKGROUND: Results of previous studies support the hypothesis that implantable haemodynamic monitoring systems might reduce rates of hospitalisation in patients with heart failure. We undertook a single-blind trial to assess this approach. METHODS: Patients with New York Heart Association (NYHA) class III heart failure, irrespective of the left ventricular ejection fraction, and a previous hospital admission for heart failure were enrolled in 64 centres in the USA. They were randomly assigned by use of a centralised electronic system to management with a wireless implantable haemodynamic monitoring (W-IHM) system (treatment group) or to a control group for at least 6 months. Only patients were masked to their assignment group. In the treatment group, clinicians used daily measurement of pulmonary artery pressures in addition to standard of care versus standard of care alone in the control group. The primary efficacy endpoint was the rate of heart-failure-related hospitalisations at 6 months. The safety endpoints assessed at 6 months were freedom from device-related or system-related complications (DSRC) and freedom from pressure-sensor failures. All analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00531661. FINDINGS: In 6 months, 83 heart-failure-related hospitalisations were reported in the treatment group (n=270) compared with 120 in the control group (n=280; rate 0.31 vs 0.44, hazard ratio [HR] 0.70, 95% CI 0.60-0.84, p<0.0001). During the entire follow-up (mean 15 months [SD 7]), the treatment group had a 39% reduction in heart-failure-related hospitalisation compared with the control group (153 vs 253, HR 0.64, 95% CI 0.55-0.75; p<0.0001). Eight patients had DSRC and overall freedom from DSRC was 98.6% (97.3-99.4) compared with a prespecified performance criterion of 80% (p<0.0001); and overall freedom from pressure-sensor failures was 100% (99.3-100.0). INTERPRETATION: Our results are consistent with, and extend, previous findings by definitively showing a significant and large reduction in hospitalisation for patients with NYHA class III heart failure who were managed with a wireless implantable haemodynamic monitoring system. The addition of information about pulmonary artery pressure to clinical signs and symptoms allows for improved heart failure management. FUNDING: CardioMEMS. PMID- 21315445 TI - Co-encapsulation of magnetic nanoparticles and doxorubicin into biodegradable microcarriers for deep tissue targeting by vascular MRI navigation. AB - Magnetic tumor targeting with external magnets is a promising method to increase the delivery of cytotoxic agents to tumor cells while reducing side effects. However, this approach suffers from intrinsic limitations, such as the inability to target areas within deep tissues, due mainly to a strong decrease of the magnetic field magnitude away from the magnets. Magnetic resonance navigation (MRN) involving the endovascular steering of therapeutic magnetic microcarriers (TMMC) represents a clinically viable alternative to reach deep tissues. MRN is achieved with an upgraded magnetic resonance imaging (MRI) scanner. In this proof of-concept preclinical study, the preparation and steering of TMMC which were designed by taking into consideration the constraints of MRN and liver chemoembolization are reported. TMMC were biodegradable microparticles loaded with iron-cobalt nanoparticles and doxorubicin (DOX). These particles displayed high saturation magnetization (Ms = 72 emu g(-1)), MRI tracking compatibility (strong contrast on T2*-weighted images), appropriate size for the blood vessel embolization (~50 MUm), and sustained release of DOX (over several days). The TMMC were successfully steered in vitro and in vivo in the rabbit model. In vivo targeting of the right or left liver lobes was achieved by MRN through the hepatic artery located 4 cm beneath the skin. Parameters such as flow velocity, TMMC release site in the artery, magnetic gradient and TMMC properties, affected the steering efficiency. These data illustrate the potential of MRN to improve drug targeting in deep tissues. PMID- 21315446 TI - Osteoconductive properties of poly(96L/4D-lactide)/beta-tricalcium phosphate in long term animal model. AB - The objective of this study was to determine the effect of calcium phosphate mineral content on the bone in-growth at the expense of composite of co polylactide polymer charged with 2 different ratios of beta-TCP granules (10 and 24 w-% of beta-TCP). The evaluation was realized in a long term rabbit bone model. After 24, 48 and 76 weeks, the implants were examined by micro CT, scanning electron microscopy (SEM) using backscattered electron (BSE) and light microscopy (polarized and blue light microscopy). No foreign body reaction was detected during the 76 weeks follow-up in any of the test samples. Polymer hydrolysis began at approximately 24 weeks, by 76 weeks, the pure polymer implant had begun to release P(96L/4D)LA particles and show signs of peripheral localized bone resorption. A decrease in the amount of CaP was noticed between 24 and 76 weeks in both 10 wt-% and 24 wt-% beta-TCP/P(96L/4D)LA composites. The study showed that the highest bone in-growth was with 24 wt-% beta-TCP/P(96L/4D)LA composite. Bone in-growth and mineralization were evident for the composites associated with specific peripheral bone architecture. Fluorescent labelling demonstrated high bone in-growth and remodeling at the interface, while for pure co-polymer no bone remodeling or bone activity was maintained after 48 weeks. The study demonstrated the positive effect of calcium phosphate content into P(96L/4D)LA. This kind of composite is a suitable resorbable osteoconductive matrix, which provides long term stability required for ligament fixation device. PMID- 21315447 TI - The use of leukemia inhibitory factor immobilized on virus-derived polyhedra to support the proliferation of mouse embryonic and induced pluripotent stem cells. AB - Human leukemia inhibitory factor (LIF) was immobilized into insect virus-derived microcrystals (polyhedra) to generate LIF polyhedra (LIF-PH) that can slowly release LIF into embryonic stem (ES) cell culture media and thus maintain ES cells in an undifferentiated state. Assays of the biological activities of LIF-PH indicated that a single addition of LIF-PH to the ES cell culture medium can support the proliferation of mouse ES and induced pluripotent stem (iPS) cells continuously for 14 days, and suggest that LIF-PH can be successfully used in the place of a periodic addition of recombinant LIF to the media every 2-3 days. The release of LIF protein from LIF-PH was determined by enzyme-linked immunosorbent assay (ELISA). Maintenance of undifferentiated state of mouse ES and iPS cells cultured with LIF-PH was determined by the detection of pluripotency-related biomarkers Oct3/4 and stage-specific embryonic antigen-1 (SSEA-1) through immunostaining and measurement of alkaline phosphatase activity. In this paper, we propose a closed culture system for mass production of ES and iPS cells that utilize a slow-releasing agent of LIF. PMID- 21315448 TI - Fludarabine and cytarabine in patients with acute myeloid leukemia refractory to two different courses of front-line chemotherapy. AB - The most effective regimen for acute myeloid leukemia (AML) patients who do not achieve complete remission (CR) after two different courses of front-line chemotherapy has not been established. We therefore evaluated the efficacy, toxicity, and prognostic factors for achieving CR following treatment with fludarabine and cytarabine in 25 newly diagnosed AML patients who did not respond to initial therapy with idarubicin and cytarabine followed by mitoxantrone and etoposide. CR was achieved in 32% of patients; in 55% of patients with intermediate-risk karyotype and in 14% with unfavorable-risk. Eight percent died of infectious complications. Median duration of overall survival was 6.6 months (95% CI 3.4 months to infinity); 3.4 months (95% CI 0.8-8.6 months) for patients with an unfavorable-risk karyotype and 18.1 months (95% CI 5.0 months to infinity) with an intermediate-risk karyotype (p=0.02). Our data suggest that poor-risk karyotype patients are unlikely to benefit from third course treatment with fludarabine-cytarabine, and that this regimen merits further investigation in AML patients with good or intermediate-risk karyotype that have persistent leukemia after two courses of front-line chemotherapy. PMID- 21315449 TI - Vaginal lacerations from consensual intercourse in adolescents. AB - OBJECTIVE: (1) To describe lacerations of the vaginal fornices, an injury known to be associated with consensual sexual intercourse, including known complications and treatment course, (2) to contrast these injuries with injuries sustained during sexual assault, and (3) to discuss the assessment of adolescent patients for sexual injuries. METHODS: We present a case series of 4 female adolescent patients seen at a children's hospital over a period of 6 months. Each patient developed significant vaginal bleeding after sexual intercourse, and 3 of the patients presented to the emergency department with vital signs consistent with compensated shock. RESULTS: Each patient was evaluated by pediatric surgery, and found to have a laceration of the vagina. Three of the patients described consensual intercourse prior to the onset of bleeding, and had lacerations of the vaginal fornices; these patients were determined to have injuries resulting from consensual sexual intercourse. The fourth patient reported sexual assault as the cause of her injuries, and was treated for longitudinal lacerations of the vaginal wall. CONCLUSIONS: Lacerations of the upper vagina are not frequently reported in forced vaginal intercourse, but are occasionally reported as injuries sustained during consensual coitus. In the absence of reported sexual assault, a severe vaginal fornix laceration is consistent with the diagnosis of coital injury from consensual intercourse. Diagnosis and treatment of this injury can be delayed due to the sensitive nature of these injuries. Bleeding can be profuse, leading to hemorrhagic shock, and these injuries may require transfusion of blood products and surgical repair in some cases. Complications may include hemoperitoneum, pneumoperitoneum, or retroperitoneal hematoma, even in the absence of complete vaginal perforation. PRACTICE IMPLICATIONS: Knowledge of the consensual sexual injuries that may occur in adolescent patients can guide diagnosis, treatment, and counseling for the patient and her family, preventing long-term medical complications and legal consequences. PMID- 21315450 TI - Abusive head trauma: A perpetrator confesses. AB - OBJECTIVES: To present a detailed confession from a perpetrator of Shaken Baby syndrome. METHODS: Case study. RESULTS: We present a confession of Shaken Baby syndrome describing how the perpetrator severely injured a 3 year old with repeated bursts of acceleration-deceleration (shaking). The child sustained retinal and intracranial hemorrhage. Details of the confession and circumstances by which it was obtained lead us to believe its accuracy. CONCLUSIONS: Accurate perpetrator confessions offer useful windows into realities and pathophysiology of abusive head trauma. PMID- 21315451 TI - Genotoxic damages in zebrafish submitted to a polymetallic gradient displayed by the Lot River (France). AB - Genotoxic effects of a polymetallic pollution gradient displayed by the Lot River and one of its tributary have been assessed on zebrafish Danio rerio. Three methods were compared: RAPD-PCR, the comet assay, and 8-oxo-7, 8-dihydro-2' deoxyguanosine (8-oxodG) formation. The fishes were exposed for 14 days to waters collected from three stations: Joanis, a site polluted by cadmium (Cd) and zinc (Zn) (mean concentrations: 15 MUg Cd/L and 550 MUg Zn/L), Bouillac (mean concentrations: 0.55 MUg Cd/L and 80 MUg Zn/L), and Boisse-Penchot, a reference station (mean concentrations: <0.05 MUg Cd/L and 7 MUg Zn/L). The quantitative RAPD-PCR methodology proved to be sensitive enough to unmask metal genotoxicity after 3 and 7 days of exposure to Joanis water and after 14 days to Bouillac water, whereas the comet assay only detected DNA damages at the most contaminated station (Joanis). The 8-oxodG quantification was not sensitive enough to be used in zebrafish under these environmental conditions. PMID- 21315452 TI - Iron plaque formation on roots of different rice cultivars and the relation with lead uptake. AB - The relationships between lead (Pb) uptake and iron/manganese plaque formation on rice roots were investigated with three cultivars. The results showed that the rice cultivars with indica consanguinity were more sensitive to soil Pb stress than the cultivar with japonica consanguinity. Pb concentrations and distribution ratios in root tissues were in the order: Shanyou 63 > Yangdao 6 > Wuyunjing 7, but Pb and Fe concentrations and distribution ratios in the plaques showed a reverse order. Mn concentrations and distribution ratios in the plaques of Wuyunjing 7 were significantly higher (P < 0.01 or 0.05) than those of Shanyou 63 and Yangdao 6. The results indicate that iron/manganese plaque on rice root can provide a barrier to soil Pb stress. The plaque will increase sequestration of Pb on rice root surface and in the rhizosphere, providing a means of external exclusion of soil Pb to some extent. PMID- 21315453 TI - A risk assessment approach to identifying constituents in oilfield produced water for treatment prior to beneficial use. AB - A risk assessment approach incorporating exposure pathways and calculated risk quotients was applied to identifying constituents requiring treatment prior to beneficial use of oilfield produced water (OPW). In this study, risk quotients are ratios of constituent concentrations in soil or water to guideline concentrations for no adverse effects to receptors. The risk assessment approach is illustrated by an example of an oilfield water produced from non-marine geologic strata of a rift basin in sub-Saharan Africa. The OPW studied has the following characteristics: 704-1370 mg L(-1) total dissolved solids (TDS), 45-48 mg L(-1) chloride, and 103.8 mg L(-1) oil and grease. Exposure pathways of constituents in OPW used for irrigation include: ingestion of plant tissue, ingestion and direct contact of irrigated soil by livestock, inhalation of aerosols or volatilized constituents, and ingestion of OPW directly by livestock. Applying risk quotient methods for constituents in soil and water, constituents of concern (COCs) identified for irrigation and livestock watering using the OPW studied include: iron (Fe), manganese (Mn), nickel (Ni), zinc (Zn), and oil and grease. Approximately 165,000 barrels d(-1) (26,233 m(3) d(-1)) of OPW from the study site are available for use. Identification of COCs and consideration of water quantity allows for development of reliable treatment design criteria to ensure effective and consistent treatment is achieved to meet guideline levels required for irrigation, livestock watering, or other uses. This study illustrates the utility of risk assessment for identifying the COCs in OPW for treatment, the level of treatment required, and viable options for use of the treated water. PMID- 21315454 TI - Effects of short time UV-A exposures on compound eyes and haematological parameters in Procambarus clarkii (Girad, 1852). AB - The amount of ultraviolet radiation (UVR) reaching the Earth's surface has been increasing as a result of an increasingly thinner ozone layer. The UV-A component of the UVR is able to generate oxidative stress in the compound eye and haemolymph of Procambarus clarkii when the latter was exposed for as little as 15 min daily for one week to UV-A. Changes in the eye involved corneal material, crystalline cones, pigments in cone stalks and retinula cells, rhabdom integrity, haemocyte infiltration, and haemal spaces. UV-A had significant impacts on haemolymph iron and glucose, whereas Ca ions were unaffected. Total protein and Cu-ions showed only insignificant changes following UV-A radiation. Involvement of lipid peroxidation and DNA fragmentation was significant with regard to the tissue damage cause by the UV-A. UV-A furthermore induced biological effects on serum electrophoretic patterns: some fractions either increased in size or others decreased. The described changes can be used as reference guidelines in evaluations of UV-A induced stress effects in P. clarkii. PMID- 21315455 TI - Infant's psychophysiological profile and temperament at 3 and 12 months. AB - This study is intended to analyze (1) differences in infant temperament at 3 and 12 months according to infants' psychophysiological profiles: "withdrawn" "extroverted", and "underaroused" and (2) changes in infant temperament from 3 to 12 months, namely according to the infant psychophysiological profile and the quality of mother-infant interaction. Ninety-four 8-week-old infants were assessed using the Neonatal Behavioral Assessment Scale (NBAS, Brazelton & Nugent, 1995) and the Alarm Distress Baby Scale (ADBB, Guedeney & Fermanian, 2001). Saliva samples were collected at 8-12 weeks old, both before and after a routine inoculation for cortisol reactivity measurement. Mother-infant interaction was evaluated at 12-16 weeks, using the Global Rating Scales (GRS, Murray, Fiori-Cowley, Hooper, & Cooper, 1996). Mothers' reports on infant temperament at 3 and 12 months were collected using the Infant Behavior Questionnaire (IBQ, Rothbart, 1981). Significant differences in mothers' perception of infant temperament were found at both 3 and 12 months in infants with distinct psychophysiological profiles. Stability was observed in most of the temperament's dimensions from 3 to 12 months old; still, there were changes in mothers' perception of infant temperament in terms of level of distress, cuddliness, sadness and approach. Infant psychophysiological profile and mother infant interaction both influence with the pattern of those changes. The results corroborate that infant's characteristics early in life as well as contextual factors influence with mothers' perception of infant temperament and with changes across the 1st year of life. PMID- 21315456 TI - Validation of a classification system of obsessive-compulsive spectrum disorder symptoms in a non-clinical sample. AB - Controversy surrounds the classification of obsessive-compulsive spectrum disorder (OCSD) symptoms. In this study, we tested whether a broad OCSD symptoms model consisting of obsessive-compulsive, body dysmorphic, health anxiety, trichotillomania, pathological skin picking, impulsivity, and anxiety symptoms displayed sufficient data fit. Alternatively, we tested whether a reduced OCSD symptoms model consisting of obsessive-compulsive, body dysmorphic, health anxiety, trichotillomania, and pathological skin picking symptoms demonstrated superior fit. The reduced OCSD symptoms model demonstrated good data fit. However, the broader OCSD symptoms model only displayed marginal data fit. In context with other findings, results of this study support an OCSD symptoms dimension that includes obsessive-compulsive, body dysmorphic, health anxiety, trichotillomania, and pathological skin picking symptoms. Implications of these findings are discussed as they relate to proposed changes in the forthcoming edition of the Diagnostic and Statistical Manual. PMID- 21315457 TI - Thin-plate spline analysis of craniofacial morphology in subjects with adenoid or tonsillar hypertrophy. AB - OBJECTIVE: To compare the skeletal features of subjects with adenoid hypertrophy with those of children with tonsillar hypertrophy using thin-plate spline (TPS) analysis. MATERIALS AND METHODS: A group of 20 subjects (9 girls and 11 boys; mean age 8.4 +/- 0.9 years) with adenoid hypertrophy (AG) was compared with a group of 20 subjects (10 girls and 10 boys; mean age 8.2 +/- 1.1 years) with tonsillar hypertrophy (TG). Craniofacial morphology was analyzed on the lateral cephalograms of the subjects in both groups by means of TPS analysis. A cross sectional comparison was performed on both size and shape differences between the two groups. RESULTS: AG exhibited statistically significant shape and size differences in craniofacial configuration with respect to TG. Subjects with adenoid hypertrophy showed an upward dislocation of the anterior region of the maxilla, a more downward/backward position of the anterior region of the mandibular body and an upward/backward displacement of the condylar region. Conversely, subjects with tonsillar hypertrophy showed a downward dislocation of the anterior region of the maxilla, a more upward/forward position of the anterior region of the mandibular body and a downward/forward displacement of the condylar region. CONCLUSIONS: Subjects with adenoid hypertrophy exhibited features suggesting a more retrognathic mandible while subjects with tonsillar hypertrophy showed features suggesting a more prognathic mandible. PMID- 21315458 TI - Slitrks as emerging candidate genes involved in neuropsychiatric disorders. AB - Slitrks are a family of structurally related transmembrane proteins belonging to the leucine-rich repeat (LRR) superfamily. Six family members exist (Slitrk1-6) and all are highly expressed in the central nervous system (CNS). Slitrks have been implicated in mediating basic neuronal processes, ranging from neurite outgrowth and dendritic elaboration to neuronal survival. Recent studies in humans and genetic mouse models have led to the identification of Slitrks as candidate genes that might be involved in the development of neuropsychiatric conditions, such as obsessive compulsive spectrum disorders and schizophrenia. Although these system-level approaches have suggested that Slitrks play prominent roles in CNS development, key questions remain regarding the molecular mechanisms through which they mediate neuronal signaling and connectivity. PMID- 21315459 TI - Development and cancer of the cerebellum. AB - Medulloblastoma (MB) is the most common malignant pediatric brain tumor and is thought to arise from genetic anomalies in developmental pathways required for the normal maturation of the cerebellar cortex, notably developmental pathways for granule cell progenitor (GCP) neurogenesis. Over the past decade, a wide range of studies have identified genes and their regulators within signaling pathways, as well as noncoding RNAs, that have crucial roles in both normal cerebellar development and pathogenesis. These include the Notch, Wnt/beta catenin, bone morphogenic proteins (Bmp) and Sonic Hedgehog (Shh) pathways. In this review, we highlight the function of these pathways in the growth of the cerebellum and the formation of MB. A better understanding of the developmental origins of these tumors will have significant implications for enhancing the treatment of this important childhood cancer. PMID- 21315460 TI - Evaluation of aortic root for definition of prosthesis size by magnetic resonance imaging and cardiac computed tomography: implications for transcatheter aortic valve implantation. AB - BACKGROUND: This study sought to compare cardiac magnetic resonance imaging (CMR) with dual source computed tomography (DSCT) for analysis of aortic root dimensions prior to transcatheter aortic valve implantation (TAVI). In addition, the potential impact of CMR and DSCT measurements on TAVI strategy defined by 2D transesophageal echocardiography (TEE) was evaluated. METHODS: Aortic root dimensions were measured using CMR and DSCT in 58 patients referred for evaluation of TAVI. The TAVI strategy (choice of prosthesis size and decision to implant) was based on 2D-TEE annulus measurements. RESULTS: CMR and DSCT aortic root measurements showed an overall good correlation (r=0.86, p<0.001 for coronal aortic annulus diameters). There was also a good correlation between TEE and CMR as well as between TEE and DSCT for measurement of sagittal aortic annulus diameters (r=0.69, p<0.001). However, annulus diameters assessed by TEE (22.1+/ 2.3mm) were significantly smaller than coronal aortic annulus diameters assessed by CMR (23.4+/-1.8mm, p<0.001) or DSCT (23.6+/-1.8, p<0.001). Regarding TAVI strategy, the agreement between TEE and sagittal CMR (kappa=0.89) as well as sagittal DSCT measurements (kappa=0.87) was statistically perfect. However, decision based on coronal CMR- or MSCT measurements would have modified TAVI strategy as compared to a TEE based choice in a significant number of patients (22% to 24%). CONCLUSION: In patients referred for TAVI, CMR measurements of aortic root dimensions show a good correlation with DSCT measurements and thus CMR may be an alternative 3D-imaging modality. Aortic annulus measurements using TEE, CMR and DSCT were close but not identical and the method used has important potential implications on TAVI strategy. PMID- 21315461 TI - Twelve-month clinical outcomes of everolimus-eluting stent as compared to paclitaxel- and sirolimus-eluting stent in patients undergoing percutaneous coronary interventions. A meta-analysis of randomized clinical trials. AB - BACKGROUND: It is well established that both PES and SES reduce the need for reintervention as compared with bare-metal stents. Whether everolimus-eluting stent (EES) a "second-generation" drug-eluting stent, further improves clinical outcomes compared to PES and SES still remains uncertain. The aim of this study was to perform a meta-analysis of randomized trials evaluating safety and efficacy of EES compared with paclitaxel- (PES) and sirolimus-eluting stent (SES), in patients undergoing percutaneous coronary intervention (PCI). METHODS: We undertook a literature search using Medline, EMBASE, the Cochrane Central Register of Controlled Trials, scientific session abstracts and relevant websites, until August 2010. Included studies comprised randomized trials evaluating EES vs PES/SES, in patients undergoing PCI, at 1-year follow-up. RESULTS: Five studies, enrolling 8058 patients, were included. At 12-month follow up, patients treated with EES, as compared with PES/SES, experienced lower target lesion revascularization (OR [95% CI] = 0.56 [0.45-0.70], p<0.00001) and myocardial infarction rates (OR [95% CI] = 0.57 [0.43-0.77], p = 0.0002), without difference in mortality (OR [95% CI] = 0.88 [0.62-1.24], p = 0.46). A trend towards lower stent thrombosis rates in favour of EES vs PES/SES was found (OR [95% CI] = 0.45 [0.20-1.01], p = 0.05). However, after the exclusion of SES, EES significantly reduced stent thrombosis as compared with PES (OR [95% CI] = 0.35 [0.14-0.86], p = 0.02). CONCLUSIONS: At 12-month follow-up, treatment with EES is associated with decreased target-lesion revascularization and myocardial infarction rates, without differences in mortality, as compared with PES/SES. EES vs PES/SES use is associated with a trend towards lower stent thrombosis rates. Moreover, EES significantly reduce stent thrombosis with respect to PES. PMID- 21315462 TI - Post-interventional three-dimensional dark blood MRI in the adult with congenital heart disease. AB - BACKGROUND: Investigate a novel three-dimensional (3D) turbo spin echo (TSE) magnetic resonance imaging (MRI) sequence to assess stented segments in adults with congenital heart disease (CHD) after transcatheter intervention. METHODS: Adults with CHD referred for computed tomography (CT) after transcatheter intervention underwent MR exam with a 3D respiratory gated TSE sequence. Data obtained at the time of the study included type of CHD, radiation dose, length of time between exams, and luminal diameters of stented segments from each exam. Continuous variables were analyzed using Student'st and Bland-Altman plots performed to analyze measurements obtained from both examinations. RESULTS: Eleven patients underwent both examinations. Type of defects included coarctation of the aorta (n=6) and tetralogy of Fallot. Average radiation dose was 19.6 mSv and average time between CT and MRI was 99 +/- 160 days. Luminal diameters of stented vessels correlated closely between TSE MRI and CT (r(2)=.85) with a bias toward overestimation with MRI (mean 22.4 +/- 4.3mm and 20.9 +/- 3.7 mm, p<.01). CONCLUSION: This novel 3D respiratory gated TSE MR technique provides a feasible method to reduce metallic artifact and improve visualization of stented segments and surrounding anatomic structures without exposure to radiation. PMID- 21315463 TI - Different effects of rosuvastatin and simvastatin on myocardial high-energy phosphate metabolism. PMID- 21315464 TI - And what about epidermal growth factor (EGF) as the bridge between survivin and cardiac remodelling? PMID- 21315465 TI - Association between brachial-ankle pulse wave velocity and occult coronary artery disease detected by multi-detector computed tomography. AB - BACKGROUND: Arterial stiffness, assessed by aortic pulse wave velocity (PWV), has been reported to predict cardiovascular morbidity and mortality. We assessed the association between arterial stiffness, as determined by PWV, and occult coronary artery disease (CAD), as detected by multi-detector computed tomography (MDCT), in asymptomatic individuals. METHOD: We retrospectively enrolled 615 consecutive South Korean individuals who had undergone both brachial-ankle PWV (baPWV) and coronary CT angiography during general routine health evaluations at the Asan Medical Center in 2008. RESULTS: We found that baPWV was positively correlated with age; body mass index; blood pressure; total cholesterol, homocysteine, and fasting blood glucose concentrations; and coronary artery calcium score. When we divided subjects into two groups according to the results of MDCT, we found that baPWV was significantly higher in subjects with (diameter of stenosis >50%) than without CAD (1573.2 +/- 275.6 cm/s vs. 1409.6 +/- 235.6 cm/s, p<0.01). The optimal baPWV cutoff value for detection of significant coronary arterial stenosis was 1426.0 cm/s, which had a sensitivity of 77% and a specificity of 63% (area under curve=0.71). After adjusting for age, smoking status, hypertension, diabetes, and dyslipidemia, the odds ratio for significant occult CAD was 3.30 (95% CI=1.47-7.41, p<0.01). CONCLUSION: We found that baPWV was associated with risk factors for cardiovascular disease, including CACS, in asymptomatic individuals, and the optimal baPWV cutoff value for occult CAD detected by MDCT was 1426 cm/s. These findings suggest that baPWV may be a useful screening tool for predicting occult CAD. PMID- 21315466 TI - Hypertension in the elderly: where are we? PMID- 21315467 TI - Aortic and left ventricular remodeling in patients with bicuspid aortic valve without significant valvular dysfunction: a prospective study. AB - BACKGROUND: Bicuspid aortic valve (BAV) represents the most common cardiac congenital malformation in the adult age. It is frequently associated with dilatation, aneurysm and dissection of the ascending aorta. The purpose of the following study was to evaluate in patients with BAV: 1) the elastic properties of the ascending aorta, 2) the mechanical function of the left ventricle and 3) stiffness, elasticity and strain of the epi-aortic vessels wall. METHODS: Forty BAV patients (28M/12F; age 20.9 +/- 4.7 years; range 17-26) with no or mild valvular impairment were recruited with 40 control subjects (25M/15F; age 23.4 +/ 3.4 years; range 15-31) matched for age, gender and body surface area (BSA). Aortic strain, aortic distensibility (AoDIS) and aortic stiffness index (AoSI) were derived. Left ventricular strain was acquired. Elastic properties of epi aortic vessels were evaluated. RESULTS: BAVs vs. controls had increased systolic and diastolic aortic diameters (p<0.001). Aortic strain (%) was lower in BAVs than in controls (8.3 +/- 3.6 vs. 11.2 +/- 2.6; p<0.001) as well as AoDIS (10( 6)cm(2)dyn(-1)) (6.5 +/- 2.8 vs. 8.8 +/- 2.9; p=0.002), while AoSI was greater in BAVs (6.4 +/- 3.5 vs. 3.9 +/- 1.2; p<0.001). Both AoDIS and aortic strain were related to aortic size in BAVs and controls. Left ventricular longitudinal (p=0.01), circumferential (p=0.01) and radial (p<0.001) strain (%) were lower in BAVs. No significant differences were found in elastic properties of epi-aortic vessels. CONCLUSIONS: Bicuspid aortic valve is associated with an increased aortic stiffness and with a reduction of the aortic and left ventricular deformation properties. Epi-aortic vessels do not seem to be interested by the disease. The use of an echocardiographic method that can estimate the degree of aortic and left ventricular remodeling can provide great benefits in the selection of patients with BAV to be treated and in determining the time for beginning drug therapy. PMID- 21315468 TI - Applications of neural networks in training science. AB - Training science views itself as an integrated and applied science, developing practical measures founded on scientific method. Therefore, it demands consideration of a wide spectrum of approaches and methods. Especially in the field of competitive sports, research questions are usually located in complex environments, so that mainly field studies are drawn upon to obtain broad external validity. Here, the interrelations between different variables or variable sets are mostly of a nonlinear character. In these cases, methods like neural networks, e.g., the pattern recognizing methods of Self-Organizing Kohonen Feature Maps or similar instruments to identify interactions might be successfully applied to analyze data. Following on from a classification of data analysis methods in training-science research, the aim of the contribution is to give examples of varied sports in which network approaches can be effectually used in training science. First, two examples are given in which neural networks are employed for pattern recognition. While one investigation deals with the detection of sporting talent in swimming, the other is located in game sports research, identifying tactical patterns in team handball. The third and last example shows how an artificial neural network can be used to predict competitive performance in swimming. PMID- 21315469 TI - Bacterial species associated with sound and Botrytis-infected grapes from a Greek vineyard. AB - Grape bacterial microbiota plays central roles in the quality of grapes and wine, yet its diversity remains poorly described. In the present study, bacterial species associated with sound and Botrytis-infected grapes of two cultivars originating from the same vineyard were assessed. Isolates were identified by PCR Denaturing Gradient Gel Electrophoresis (PCR-DGGE) and sequence analysis of partial 16S rRNA gene. Comparable counts were recorded between Botrytis-infected and sound grape samples. In all cases, the majority of isolates belonged to different species of Enterobacteriaceae. The dominant species in the vineyard was Klebsiella oxytoca that was found in different combinations with Citrobacter freundii, Enterobacter spp., Erwinia sp., Pantoea dispersa, Tatumella ptyseos or other species. In fermenting musts, those populations declined while other species evolved, like Lactobacillus plantarum and Enterobacter ludwigii. Populations in botrytised samples persisted longer during spontaneous fermentations. Present study suggests that bacterial diversity on grapes may be wider than previously described. PMID- 21315470 TI - Probiotic assessment of Enterococcus faecalis CP58 isolated from human gut. AB - A total of seventy lactic acid bacteria (LAB) were isolated from the faeces of healthy humans and their identities were confirmed by sequencing of their 16S rDNA genes. Of these only 5 isolates were found to resist bile salts and indicated survival in the simulated in vitro digestion assay which reproduces the stomach and intestinal digestion indicating their tolerance to gastric enzymes and the low pH conditions. Species that showed the best resistance to these conditions were: Lactobacillus casei, Lactobacillus sp., uncultured bifidobacteria, Enterococcus faecalis and Streptococcus anginosus. These strains were investigated further to study their capacity to adhere to human intestinal Caco-2 cells. E. faecalis was the most adherent strain. Examination of the virulence determinants for this strain indicated that it was positive for efaAfs, gelE, agg, cpd, cob, ccf and cad, a profile that is similar to that of many E. faecalis isolates from food sources. The cytolysin biosynthetic genes cylA, cylB and cylM that are more associated with the clinical isolates of E. faecium were not detected in this strain. The antibiotic susceptibility tests indicated that the strain was sensitive to vancomycin, tetracycline, rifampicin and erythromycin but resistant only to kanamycin and chloramphenicol. These data suggest that the strain E. faecalis CP58 may be tested further for beneficial properties and developed as a new probiotic. PMID- 21315471 TI - A combination system for prediction of Chinese Materia Medica properties. AB - Identifying and explaining the property of Chinese Materia Medica (CMM) is an important and urgent mission in recent CMM researches. In the present work, we built a combination system for predicting the cold/hot property of CMM based on chemical material basis. A novel strategy, weight center treatment, was used to solve the problem that the chemical description was unable to be applied to CMM. As the results of prediction, the accuracy of 83.3% and 81.0% for the training and the test set, respectively, indicates that this system is a useful tool to predict the property of unidentified folk herbs and foreign herbs. It will characterize these herbs with traditional Chinese medicine properties so as to design new CMM formulas for better therapeutics. Moreover, we found some interesting explanation about the property of CMM based on chemical information by using the selected descriptors. It will give new insight into the CMM property from the standpoint of chemistry. PMID- 21315472 TI - Expression of selected gene for acquired drug resistance to EGFR-TKI in lung adenocarcinoma. AB - BACKGROUND: Individualized treatment is an attractive challenge that may allow for more effective and safer treatment of human disease. Activating mutations in the epidermal growth factor receptor (EGFR) gene in lung adenocarcinoma are associated with a dramatic clinical response to EGFR-tyrosine kinase inhibitors (TKIs). However, patients often experience a relapse after treatment with EGFR TKIs, even when the tumors are initially highly sensitive. However, the "whole picture" regarding acquired resistance remains unclear. METHODS: Tumor specimens were collected from 11 lung adenocarcinoma patients before and after treatment with gefitinib. The status of the EGFR and K-ras genes were investigated by PCR based analyses. Immunohistochemistry and real-time PCR assays were used to evaluate the MET gene in terms of its tyrosine phosphorylation and amplification, respectively. The expression of HGF, PTEN, and EGR-1, and changes in the epithelial-mesenchymal transition (EMT) status including the expression of E cadherin and gamma-catenin as epithelial markers, and vimentin and fibronectin as mesenchymal markers, were evaluated by immunohistochemistry. RESULTS: Seven (64%) of the gefitinib refractory tumors exhibited a secondary threonine-to-methionine mutation at codon 790 in EGFR (T790M). All of the tumors had wild type K-ras gene expression. No MET amplification was detected in any of the samples, nor was there phosphorylation of MET detected in any of the resistant samples. Neither MET gene amplification, nor the overexpression of HGF was observed in samples without the T790M mutation. A strong expression of HGF was detected in 6 of 8 specimens with the T790M mutation. Three (38%) of 8 cases showed a loss of PTEN in samples with the T790M mutation. A loss of EGR-1 was detected in 2 (29%) of 7 cases, including one tumor without PTEN. Four (57%) of 7 cases showed positive expression of phosphorylated Akt (p-Akt). A change in the EMT status between pre and post-treatment was observed in 4 (44%) of 9 cases. In all examined samples cases, some alterations of gene or proteins were observed. CONCLUSIONS: The current results showed that these alterations in gene or protein expression can account for all resistant mechanisms. This phenomenon suggests the existence of complicated relationships among acquired resistance-related genes. PMID- 21315473 TI - Screening for EGFR mutations in lung cancer, a report from India. AB - Epidermal growth factor receptor (EGFR) is one of the targeted molecular markers in many cancers including the lung malignancy. Genetic modifications such as deletions, insertions and Single Nucleotide Polymorphisms in the tyrosine kinase (TK) domain of EGFR is a common feature observed in most lung cancers. Gefitinib and erlotinib are commonly available therapeutic drugs which act as specific inhibitors for the tyrosine kinase domain of EGFR and associated with EGFR mutations in exons 18-21. However the prevalence of mutation varies among ethnicity, grade, age and gender. This is the first report on the prevalence of EGFR mutation in non-small cell lung cancer patients using DNA obtained from samples such as biopsy/cytology/pleural fluid and Fine Needle Aspiration (FNA), across India. We have screened for 29 somatic mutations which span exons 18, 19, 20 and 21 of EGFR gene using Scorpion probe based ARMS-PCR technique. DNA from 220 NSCLC tissue samples were analyzed for EGFR mutations and mutations were detected in 51.8% of the study population. Among the mutant positive cases, the deletions in exon 19 (52%) and a missense mutation L858R in exon 21 (26%) were most predominant. There was a significant increase in overall mutations (p=0.01) as a function of age, mutation in exons 19 and 21 together (p=0.003), mutations in exons 18, 19 and 21 (p=0.04) and mutations in exons 18 and 19 (p=0.03) in females. Mutations did not seem to significantly correlate metastases or disease progression. Mutations in exons [19] and 21 together were significant in non smokers compared to smokers (p=0.01) using Mann-Whitney tests. The study suggests high prevalence of EGFR positivity in NSCLC in Indian sub-population and provides opportunities for targeted therapies for this group. PMID- 21315474 TI - Arabidopsis CYP82C4 expression is dependent on Fe availability and circadian rhythm, and correlates with genes involved in the early Fe deficiency response. AB - Under conditions of reduced iron availability, most frequent in calcareous soils, plants induce the "Fe Deficiency Response" to improve root Fe uptake. The transcription factor FIT is essential for such a response in strategy I plants, such as Arabidopsis thaliana. From microarray analysis of Arabidopsis roots, it is known that three different cytochrome P450 genes, CYP82C4, CYP82C3 and CYP71B5 are up-regulated under Fe deficiency through a FIT-dependent pathway. We show that, out of these three P450 genes, only CYP82C4 strongly correlates with genes involved in metal uptake/transport. The CYP82C4 promoter, unlike those of CYP82C3 and CYP71B5, contains several IDE1-like sequences (iron deficiency-responsive element) as well as an RY element. While confirming that the CYP82C4 transcript accumulates in Fe-deficient Arabidopsis seedlings, with circadian fluctuations in a light-dependent way, we also demonstrate that such accumulation is suppressed under Fe excess. Full suppression of CYP82C4 expression, as observed in the atc82c4-1 KO mutant, is associated with longer roots at the seedling stage. We propose that CYP82C4 is involved in the early Fe deficiency response, possibly through an IDE1-like mediated pathway. PMID- 21315475 TI - Root release and metabolism of organic acids in tea plants in response to phosphorus supply. AB - Self-rooted, 10-month-old, uniform tea [Camellia sinensis (L.) O. Kuntze cv. Huangguanyin] plants were supplied for 17 weeks with 0, 40, 80, 160, 400, or 1000MUM phosphorus (P) to investigate the effects of P supply on root citrate and malate release, the concentrations of malate and citrate and the activities of acid-metabolizing enzymes in leaves and roots. Root malate release and accumulation was induced by both 0 and 40MUM P, while root citrate release and accumulation was induced only by 0MUM P. Phosphorus-deficiency-induced malate and citrate release coincided with higher concentrations of root malate and citrate. The higher concentrations of malate and citrate were accompanied by increased activities of phosphoenolpyruvate carboxylase (PEPC), phosphoenolpyruvate phosphatase (PEPP), citrate synthase (CS) and NAD-malic enzyme (NAD-ME) and decreased activities of pyruvate kinase (PK), NADP-ME and NADP-isocitrate dehydrogenase (NADP-IDH) in roots. In contrast to roots, malate accumulated in the leaves only in response to 0MUM P, and no change was observed in citrate levels. The P-deficiency-induced leaf malate accumulation coincided with increased activities of NADP-ME, NAD-ME and PK. Overall, the P-deficiency-induced changes in organic acid (OA) metabolism differed between roots and leaves. The high tolerance of tea plants to P-deficiency might be involved in two major processes: (a) increasing the availability of P by inducing root release of OA anions; and (b) improving the ability to use P efficiently by inducing bypass enzymes involved in tissue P economy. PMID- 21315476 TI - The Barley stripe mosaic virus system used for virus-induced gene silencing in cereals differentially affects susceptibility to fungal pathogens in wheat. AB - Barley stripe mosaic virus (BSMV) has emerged as a vector for virus-induced gene silencing (VIGS) in cereals, having been used to study a number of genes involved in resistance in both wheat and barley. However, the effects of the BSMV vector on plant physiology and disease resistance in plants remains unexplored. The BSMV inoculation control vector, BSMV:GFP was shown to cause severe viral symptoms in wheat, displaying chlorosis, leaf curling and growth inhibition typical of the symptoms seen in BSMV-infected barley. These viral symptoms were accompanied by induction of genes implicated in defense against pathogens, namely PR1, PR4, PR5, PR10 and PAL. Subsequent inoculation of BSMV:GFP-infected wheat with a wheat pathotype of Magnaporthe oryzae, the blast pathogen, resulted in decreased susceptibility. Penetration of epidermal cells and subsequent multiple cell colonization by M. oryzae was significantly reduced. This increased restriction of pathogen growth observed for BSMV:GFP infections with and without the viral coat protein gene. However, prior infection with BSMV:GFP had no effect on the development of a compatible isolate of Blumeria graminis f. sp. tritici, the causal agent of powdery mildew. PMID- 21315477 TI - Analysis of predictive factors for the outcome of complete lymph node dissection in melanoma patients with metastatic sentinel lymph nodes. AB - BACKGROUND: Sentinel lymph node biopsy (SLNB) is a widely accepted procedure to accurately stage patients with melanoma. However, there is no consensus concerning the practical consequences of a positive SLN, since a survival benefit of a complete lymph node dissection (CLND) has not yet been demonstrated. OBJECTIVE: We wondered whether we could identify a subgroup of patients with metastatic involvement of the SLN who could be excluded from the recommendation to undergo CLND. METHODS: At the Department of Dermatology at the University of Munich, a total of 213 patients with metastatic SLNs (24.9%) were identified among 854 patients who had undergone SLNB between 1996 and 2007. All SLN-positive patients had been advised to have CLND. Survival analyses were performed by using the Kaplan-Meier approach. RESULTS: A total of 176 (82.6%) of 213 SLN-positive patients underwent CLND. In this group, 26 patients (14.8%) showed metastatic disease in non-sentinel lymph nodes (NSLN). The 5-year overall survival (OS) was 26.1% in NSLN-positive patients and 74% in NSLN-negative patients. SLN-positive patients who refused CLND had a better prognosis than patients with CLND. Breslow tumor thickness was significantly associated with positive CLND status with higher median values in CLND-positive than CLND-negative patients (3.03 vs 2.22 mm). LIMITATIONS: The subgroup of patients with metastatic disease in CLND may have been too small to reach statistical significance for other tumor- or patient related parameters. Mitotic indices of the primary melanomas had not been determined in this retrospective study; thus a possible correlation with lymph node status could not be tested. CONCLUSION: Among SLN-positive patients, the presence of metastatic NSLN is a highly significant poor prognostic factor. Tumor thickness is a significant prognostic parameter for positive CLND status and might be considered in the decision to perform CLND in case of metastatic SLN. PMID- 21315478 TI - A novel mutation in MBTPS2 causes a broad phenotypic spectrum of ichthyosis follicularis, atrichia, and photophobia syndrome in a large Chinese family. AB - BACKGROUND: Ichthyosis follicularis, atrichia, and photophobia (IFAP) syndrome is a rare congenital disorder. Missense mutations in the membrane-bound transcription factor protease, site 2 (MBTPS2) gene have recently been identified in patients with IFAP. OBJECTIVE: To determine whether Chinese patients with IFAP have MBTPS2 mutations. METHODS: We observed a large IFAP pedigree of 5 generations in a Chinese family and performed MBTPS2 molecular analysis. RESULTS: The male proband was severely affected. He presented with hyperextensibility of the interphalangeal joints of the fingers in addition to previously reported clinical manifestations. Clinically affected female patients had hairless patches on the scalp, ichthyosiform skin changes, hypotrichosis, hyperkeratosis, nail dystrophy, and brown scaly plaques, some of which were arranged in a linear pattern following the lines of Blaschko. Molecular analysis identified a novel missense mutation in exon 11 and confirmed cosegregation of the missense mutation with the disease in this family. LIMITATIONS: It is unclear whether hyperextensibility of the fingers was nosologically related to IFAP syndrome or was a coincidental finding. CONCLUSION: This report provides further evidence for the genetic basis of IFAP syndrome and enlarges the phenotypic spectrum and number of MBTPS2 mutations. We confirm that MBTPS2 mutations cause IFAP in patients of Chinese origin. PMID- 21315479 TI - Validity assessment of the cutaneous T-cell lymphoma severity index to predict prognosis in advanced mycosis fungoides/Sezary syndrome. AB - BACKGROUND: There is a need for standardized quantitative disease assessment measures in mycosis fungoides/Sezary syndrome. In 2005, a cutaneous T-cell lymphoma (CTCL)-severity index (SI) that not only measures disease extent (on a scale of 0-75) independent of the classic TNM(B) staging system but can also be used to estimate individual 5-year survival (SR5) was reported. OBJECTIVE: We sought to assess the generalizability of the CTCL-SI/SR5 equation (SR5 equation) to predict prognosis in our cohort of patients with advanced mycosis fungoides/Sezary syndrome (n = 50, photopheresis service, 1984-2001). METHODS: TNM(B) staging, CTCL-SI score (based on skin involvement, presence of tumors, lymph node/visceral/blood involvement), and SR5 (SR5 equation = 124 - 2 * [CTCL SI]%) at initial diagnosis were calculated retrospectively and compared with overall survival by the Kaplan-Meier method. The prognostic significance of TNM(B) staging versus the CTCL-SI was determined by Cox proportional hazards models and Brier scores. RESULTS: Patients had stage IIA to IVA disease with a median actuarial overall survival of 58 months. By disease stage, the overall 5 year survival was 70% (stage IIA), 48% (stage IIB-IIIB), and 36% (stage IVA). In our cohort, the CTCL-SI itself was predictive of overall survival (P = .028) but the SR5 equation was not predictive of survival (Brier score of 0.29). LIMITATIONS: Small sample size, single academic center population, and retrospective design are limitations. CONCLUSIONS: The CTCL-SI is a relatively simple-to-use quantitative tool that measures disease activity in all compartments (skin, nodes, blood, viscera) and has prognostic significance in multivariate analysis. The CTCL-SI may be a useful adjunct to the TNM(B) staging for tracking disease activity quantitatively in all disease compartments (skin, nodes, blood, viscera) in clinical practice and trials, but the predictive ability of the SR5 equation needs further validation at other centers in larger groups of patients. PMID- 21315480 TI - Markedly elevated serum levels of calcium-binding S100A8/A9 proteins in psoriatic arthritis are due to activated monocytes/macrophages. AB - BACKGROUND: Serum levels of S100A8/A9 may correlate with disease activity in psoriasis. OBJECTIVE: We sought to elucidate the association of serum levels of S100A8/A9 heterodimers with the clinical subtypes of psoriasis and the major cell source. METHODS: Serum samples were collected from patients with psoriasis vulgaris (n = 30), psoriatic arthritis (PA) (n = 16), pustular psoriasis (n = 24), and atopic dermatitis (n = 14) and from healthy control subjects (n = 21). Serum concentrations of S100A8/A9 were measured, and the expression levels were examined in psoriatic lesions. The messenger RNA levels were quantified in circulating monocytes and neutrophils. RESULTS: Serum levels of S100A8/A9 were significantly increased in all subtypes of psoriasis as compared with healthy controls and atopic dermatitis. Among the psoriatic subtypes, PA and pustular psoriasis showed remarkably high concentrations of S100A8/A9 heterodimers. The higher serum levels were associated with the presence of articular symptoms, but not significantly correlated with body surface areas of psoriatic lesions. S100A8 was expressed by both keratinocytes and infiltrating mononuclear cells, whereas S100A9 was predominantly expressed by neutrophils. The expression levels of S100A8 and S100A9 messenger RNA in monocytes were increased by approximately 2.25 and 1.91-fold in PA, respectively, whereas no significant increase was observed in psoriasis vulgaris and pustular psoriasis. LIMITATIONS: Difficulty in acquisition of clinical and laboratory samples in untreated patients, and of a sufficient number of subjects, were limitations. CONCLUSIONS: Although serum levels of S100A8/A9 were increased in all types of psoriasis examined, patients with PA had higher levels of S100A8/A9, probably because of an activated monocyte/macrophage system. PMID- 21315481 TI - Papular epidermal nevus with "skyline" basal cell layer (PENS). AB - BACKGROUND: Several types of epidermal keratinocytic nevus are recognized. OBJECTIVE: We sought to describe a previously unreported keratinocytic nevus with distinctive clinical and histopathologic features in 5 patients. METHODS: We performed a clinical and photographic review, and obtained skin biopsy samples for histopathologic examination from each patient. Genetic analysis to screen for fibroblast growth factor receptor 3 and phosphatidylinositol 3-kinase, catalytic, alpha hotspot mutations was performed on lesional skin from two patients. RESULTS: Five infants (2 male, 3 female) had from 1 to 11 lesions present since birth. These consisted of 1- to 7-mm hyperkeratotic papules with a rough, flat surface and a round, commalike, rectangular, or polygonal shape. Histopathologic examination showed acanthosis with broad and rectangular rete ridges, and strikingly arranged basal cells with palisaded nuclei. Genetic testing on paraffin-embedded specimens from two patients ruled out hotspot mutations in the fibroblast growth factor receptor 3 and phosphatidylinositol 3-kinase, catalytic, alpha genes. LIMITATIONS: A small number of patients are presented. CONCLUSION: We propose the name "papular epidermal nevus with 'skyline' basal cell layer" (PENS) for this newly recognized condition. PMID- 21315482 TI - Ungual and periungual human papillomavirus-associated squamous cell carcinoma: a review. AB - BACKGROUND: Human papillomavirus (HPV)-associated squamous cell carcinoma (SCC) and SCC in situ are often reported in the genital region. The association of HPV with SCC in the ungual and periungual skin is less well recognized, and verrucous lesions may undergo years of therapeutic attempts without a diagnostic biopsy. OBJECTIVES: To review the epidemiology, associations, and role of HPV in digital SCC and SCC in situ. METHODS: The English-language literature reporting HPV associated SCC and SCC in situ of the digits was reviewed. RESULTS: HPV associated SCC and SCC in situ were almost equally represented. The patients' ages ranged from 22 to 89 years, with men affected twice as often as women. HPV16 was the most common subtype. The tumors presented as persistent verrucae, present for an average of 5.3 years. Immune suppression was documented in only 6.8% of patients. Approximately 6% of cases required digital amputation. LIMITATIONS: Most of the information was obtained from case reports, some of which had limited data regarding the exact location of the tumor and the diagnostic and treatment course. HPV subtyping is not commonly performed in these tumors, which limited the number of reports that could be evaluated. CONCLUSIONS: The majority of digital HPV-associated SCCs or SCCs in situ involves the nailbed region. The clinical appearance is most commonly that of a periungual verruca. Tumors have a higher rate of recurrence after excision than SCC in other sites. Periungual and subungual warts caused by high-risk HPV subtypes pose a risk for malignant transformation in both immunocompetent and immunocompromised hosts. PMID- 21315484 TI - Factors affecting bacterial biofilm expression in chronic rhinosinusitis and the influences on prognosis. AB - PURPOSE: The purpose of the study was to investigate the expression of bacterial biofilm (BF) for chronic rhinosinusitis (CRS) and to find out factors affecting BF expression and the influences on its prognosis. MATERIALS AND METHODS: All specimens were analyzed by a scanning electron microscope and bacterial cultivation from a panel of 93 patients with CRS, 20 with nasal septum deviation, and 17 with nasal bone fractures as the control group. Referring to the grade classification criteria from the sinusitis-specific questionnaire Sino-Nasal Outcome Test-20, patients were assessed preoperatively based on common clinical manifestations. Patients were followed up for condition improvement as assessed by visual analogue scale and nasal endoscopic examination. RESULTS: In the experimental group, among all the patients, 3 were lost (lost 3.2%). Bacterial biofilm was positive in 64 (71.1%) of 90 patients. Mucosal cilia were observed in varying degrees of injury. Bacterial culture was positive in 60 (66.7%) patients. In the control group, no BF was found and no bacterium was cultured. Bacterial biofilm expression was correlated with the bacterial culture. The BF(+) patients' visual analogue scale scores 6 months and 1 year postoperation were lower than the BF(-) patients' scores (P < .05). The BF(+) patients' Lund-Kennedy scores at 6 months and 1 year postoperation were higher than the BF(-) patients' scores (P < .05). CONCLUSIONS: Bacterial biofilm is involved in the pathogenesis of CRS and is associated with the bacterial culture. Bacterial biofilm has a certain impact on patients' prognosis. PMID- 21315483 TI - The risk of infection and malignancy with tumor necrosis factor antagonists in adults with psoriatic disease: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: There is a need to better understand the safety of tumor necrosis factor (TNF) inhibitors in patients with psoriatic disease in whom TNF inhibitors are frequently used as monotherapy. OBJECTIVE: We sought to examine the risks of infection and malignancy with the use of TNF antagonists in adult patients with psoriatic disease. METHODS: We conducted a systematic search for trials of TNF antagonists for adults with plaque psoriasis and psoriatic arthritis. We included randomized, placebo-controlled trials of etanercept, infliximab, adalimumab, golimumab, and certolizumab for the treatment of plaque psoriasis and psoriatic arthritis. Twenty of 820 identified studies with a total of 6810 patients were included. Results were calculated using fixed effects models and reported as pooled odds ratios. RESULTS: Odds ratios for overall infection and serious infection over a mean of 17.8 weeks were 1.18 (95% confidence interval [CI] 1.05 1.33) and 0.70 (95% CI 0.40-1.21), respectively. When adjusting for patient years, the incidence rate ratio for overall infection was 1.01 (95% CI 0.92 1.11). The odds ratio for malignancy was 1.48 (95% CI 0.71-3.09) and 1.26 (95% CI 0.39-4.15) when nonmelanoma skin cancer was excluded. LIMITATIONS: Short duration of follow-up and rarity of malignancies and serious infections are limitations. CONCLUSIONS: There is a small increased risk of overall infection with the short term use of TNF antagonists for psoriasis that may be attributable to differences in follow-up time between treatment and placebo groups. There was no evidence of an increased risk of serious infection and a statistically significant increased risk in cancer was not observed with short-term use of TNF inhibitors. PMID- 21315485 TI - The effect of hypoxia and cycloxygenase inhibitors on nasal polyp derived fibroblasts. AB - BACKGROUND AND PURPOSE: The pathogenesis of chronic rhinosinusitis with nasal polyposis is unknown. Chronic inflammation along with local tissue hypoxia may effect polyp's growth. Activation of Cycloxygenases may also be involved. COX-2 up-regulates in response to different stimuli including hypoxia. Its activation is associated with enhanced cell proliferation. Histologically, besides inflammatory cells, increased stromal fibrosis is seen in nasal polyposis. The aims of this study were to test whether hypoxia amplifies nasal polyp fibroblasts proliferation, whether treatment with various COX inhibitors could influence fibroblasts, and whether this effect may be modulated in response to different oxygenation conditions. MATERIALS AND METHODS: Polyp fibroblasts were incubated under hypoxic or normoxic conditions with or without NSAIDs at different concentrations for 12 or 24 hours. Cell proliferation was quantified using BrdU ELISA. Metabolic activity was evaluated using MTT assay. Cell death was measured using Annexin V staining and FACS scan. RESULTS: No significant difference was found between proliferation of fibroblasts treated under hypoxia or normoxia. Cells incubated with indomethacin proliferated in a slightly enhanced manner compared with non-treated cells. Celecoxib inhibited fibroblast proliferation (P < .001) but did not influence cell survival. Metabolic activity of cells treated with celecoxib was significantly reduced (P < .003), unlike cells treated with indomethacin or rofecoxib. CONCLUSION: Hypoxia does not affect fibroblasts proliferation. It may contribute to nasal polyposis pathogenesis in other ways. The anti-proliferative effect of celecoxib may be associated with cell cycle arrest rather than with pro-apoptotic activity. Celecoxib may be considered for treating nasal polyposis. PMID- 21315486 TI - Point-of-care rapid intraoperative parathyroid hormone assay of needle aspirates from parathyroid tissue: a substitute for frozen sections. AB - BACKGROUND: The intraoperative parathyroid hormone (IOPTH) assay is an important tool that facilitates targeted parathyroidectomy and may increase surgical cure rates. We sought to evaluate the utility of a point-of-care assay to distinguish parathyroid adenomas from nonparathyroid tissues, which can sometimes pose a challenge during parathyroidectomy and is commonly achieved with the use of frozen sections. We hypothesized that point-of-care rapid IOPTH assays of needle aspirates from suspected adenomas would be faster and equal in accuracy to frozen sections. METHODS: Parathyroid and nonparathyroid lesions were excised, and the tissues were needle aspirated, diluted in saline, and submitted to a rapid IOPTH assay located in the operating room. Frozen sections were simultaneously sent for analysis. The time intervals to result availability were tracked and compared using a paired t test. RESULTS: Point-of-care IOPTH assays of needle aspirates were available in a mean (+/-SD) of 11.6 +/- 1.5 minutes compared to 18.7 +/- 4.0 minutes for frozen sections (P = .005). The findings were concordant 100% of the time for both parathyroid (mean parathyroid hormone [PTH] > 3338.9 pg/mL) and parathyroid tissues (mean PTH = 8.7 pg/mL). CONCLUSION: Point-of-care IOPTH assay of needle aspirates is an accurate method of distinguishing parathyroid from nonparathyroid tissues. It is suggested that this would be particularly useful in instances where use of IOPTH is planned for assessment of a drop in serum PTH. PMID- 21315487 TI - Quality of life in patients with smell loss due to upper respiratory tract infections. AB - PURPOSE: Upper respiratory tract infections (URTIs) are among the most frequent causes of dysosmias. It has been reported that acute anosmic patients often experience a feeling of personal isolation, display less interest in eating, and feel emotionally impaired. Our goal is to describe the quality of life (QOL) in patients with URTI olfactory loss. MATERIAL AND METHODS: A retrospective and descriptive patient-based study was performed. From 2002 to 2007, 51 patients with URTI olfactory loss (40 women [78.4%] and 11 men [21.6%]) were studied. The mean age was 53.3 +/- 1.8 years. Olfactory function was assessed using the Connecticut Chemosensorial Clinical Research Center test. All patients completed the QOL questionnaire Rhinosinusitis Disability Index. The following were determined: total score; visual analogue scale from 1 to 10; and functional, emotional, and physical domains. Descriptive analysis and Mann-Whitney U nonparametric test were used. RESULTS: Rhinosinusitis Disability Index data showed that questions f2, f4, p8, and p20 reached the highest score. The patients' mean overall rating of the severity of olfactory impairment was 3.9 +/- 2.8, which fell into the moderate category. CONCLUSIONS: The patients' mean overall rating of the severity of olfactory impairment fell into the moderate category. The follow-up time span is important to assess the QOL of patients. PMID- 21315488 TI - Down-regulation of cyclin D1 by small interfering RNA inhibits cell growth and induces apoptosis of laryngeal squamous cell carcinoma. AB - OBJECTIVE: The objective of the study was to explore the inhibitive role of cyclin D1 gene silence in laryngeal squamous cell carcinoma by lentivirus mediated RNA interference. MATERIALS AND METHODS: Cd1-RNAi-Lentivirus and the control lentivirus (GFP-Lentivirus) were transfected into Hep-2 cells. Reverse transcriptase polymerase chain reaction was performed to explore the cyclin D1 expression level in Cd1-RNAi-Lentivirus-transfected Hep 2 cells. The apoptosis and viability of Cd1-RNAi-Lentivirus-treated Hep-2 cells were measured with flow cytometry and methyl thiazolyl tetrazoliym assay. In an animal experiment, 10 mice bearing Hep-2 cell tumor were intratumorally injected with Cd1-RNAi Lentivirus; and the other 10 mice were injected with GFP-Lentivirus. Terminal deoxytransferase-mediated dUTP nick end labeling stains and transmission electron microscope were used to observe the apoptosis in the xenografts. RESULTS: Cyclin D1 was knocked down after Cd1-RNAi-Lentivirus was transfected into Hep-2 cells. The proliferative ability of Hep-2 cells was significantly inhibited by Cd1-RNAi Lentivirus, and a significant apoptosis of Hep-2 cells was also observed after Cd1-RNAi-Lentivirus transfection. The average weight and volume of tumors in the Cd1-RNAi-Lentivirus-treated group were significantly lower than those in the control group (P < .01). The significant apoptosis was detected with terminal deoxytransferase-mediated dUTP nick end labeling stain and transmission electron microscope. CONCLUSIONS: The present findings suggest that cyclin D1 gene silence by lentivirus-mediated RNA interference can inhibit growth and promote apoptosis of laryngeal squamous cell carcinoma. PMID- 21315489 TI - [The use of antipsychotics in patients with dementia]. PMID- 21315490 TI - Relationship between the type and side of motor symptoms with the prevalence of non-motor symptoms in Parkinson's disease. AB - INTRODUCTION: the relationship between laterality and asymmetry of Parkinson's disease and non-motor dysfunction has been studied mainly from the perspective of cognitive functions, and the few studies that have included other symptoms have mixed reports. The relationship between non-motor symptoms and the type of onset of the disease has not been studied in detail. OBJECTIVE: to analyse the association between the side and type of motor onset and the prevalence of non motor symptoms. PATIENTS AND METHODS: we included 232 patients diagnosed with Parkinson's disease. Type of onset and the side initially affected were documented. The presence of non-motor symptoms was determined by applying the non motor symptom questionnaire (NMSQuest). RESULTS: when analysing the side of onset and presence of each non-motor symptom explored, statistically significant differences were found in the frequency of hallucinations (P=0.04) and sleep behaviour disorder (P<0.01) in subjects with right side onset. The motor type of onset differences were not statistically significant. CONCLUSIONS: subjects with right side onset seem to have a higher risk of having hallucinations and sleep behaviour disorders. These symptoms should be intentionally sought in order to provide treatment and improve the patient's quality of life. PMID- 21315491 TI - [Social networks for teaching and learning: the case of the telemedicine laboratory]. AB - This article analyzes the possibility of using social networks for teaching and learning telemedicine. The Telemedicine Laboratory is presented as a case study that offers a learning model supported by the development of a social network in a higher education environment. We performed a qualitative research study through an anonymous survey and participant observation. The results show that the Telemedicine Laboratory allows the generation of new knowledge from a holistic approach to reality, through communication and information technology, supported by the development of a social network. The presence of "invited experts" in the teaching and learning process and the linking of this process to problematic situations that members can "recognize" and perceive as true for their domain increase motivation and constitute success factors in the learning and teaching process. PMID- 21315492 TI - Gender differences in sexual risk behaviour among adolescents in Catalonia, Spain. AB - OBJECTIVE: To analyze the factors associated with sexual risk behavior in adolescent girls and boys in order to plan future school health interventions. METHODS: A cross-sectional study with two-stage cluster sampling that included 97 schools and 9,340 students aged between 14 and 16 years old was carried out in 2005-2006 in Catalonia (Spain). For the survey, a self-administered paper-based questionnaire was used. The questionnaire contained items on sociodemographic variables, use of addictive substances and mood states, among other items. These variables were tested as risk factors for unsafe sexual behavior. RESULTS: This study included 4,653 boys and 4,687 girls with a mean age of 15 years. A total of 38.7% of students had had sexual relations at least once and 82.3% of boys and 63.0% of girls were engaged in sexual risk behaviors. The prevalence of sexual relations and risk behaviors was generally higher in boys than in girls, independently of the variables analyzed. Boys had more sexual partners (P<.001) and used condoms as a contraceptive method less frequently than girls (P<.001). Foreign origin was related to unsafe sexual activity in both genders. Alcohol consumption was also a risk factor in boys. CONCLUSIONS: Sexual risk behaviors among adolescents in Catalonia are higher in boys than in girls. Factors related to unsafe sexual activity in boys were foreign origin and alcohol consumption. In girls only foreign origin was a significant risk factor. PMID- 21315493 TI - [Tuberculosis surveillance in the Balearic Islands and characteristics of unreported cases from 2005 to 2007]. AB - We performed a descriptive study of tuberculosis cases detected by the Epidemiological Surveillance System in the Balearic Islands in the triennium 2005 2007. Our goal was to characterize underreported cases in sociodemographic terms and their contact with primary care. Overall, underreporting of tuberculosis was approximately 20%. Significant factors in multivariate analysis were social marginality (consisting of alcoholism, intravenous drug use or indigence) (aOR: 2.6 [1.2 to 5.3]), contact with primary care (aOR: 3.2 [1.4 to 7.1]), and extrapulmonary tuberculosis (aOR: 5.5[3.2-9.6]). We recommend strengthening notification by hospital specialists through the use of hospital electronic records. Our findings show that the information obtained from the primary care computerized history is helpful in improving the epidemiological surveillance of tuberculosis. PMID- 21315494 TI - [Influence of immigration on tuberculosis transmission patterns in Castellon, Spain (2004-2007)]. AB - BACKGROUND: This study aimed to identify tuberculosis transmission patterns in Castellon in a period of major demographic changes. METHODS: A prospective study of patients with positive culture in the province of Castellon over a 4-year period (2004-2007) was carried out. Cases were described by year and nationality and were compared with those reported to the Department of Public Health. We studied the population with available molecular patterns, identified through restriction fragment length polymorphism (RFLP) and analyzed the variables from patient clusters, based on data collected in surveys of the Department of Health and the Laboratory Management Program. RESULTS: According to data from the Department of Public Health, the overall rate of tuberculosis per 100,000 inhabitants in the province of Castellon was 15.7 in 2004, 19.9 in 2005, 18.2 in 2006 and 17.5 in 2007. In our laboratory, strains were identified from 301 patients, representing 77% (301/390) of reported cases and 94% (301/321) of reported cases with a positive culture. The percentage of tuberculosis among foreigners increased with age, exceeding 50% in 2007. Molecular studies were available in 95% of patients (286); 58% were Spanish and 42% were foreigners, of whom 54% were Romanians. The cluster percentage was 40%, with 30% of mixed clusters. According to conventional contact studies, 85% of patients in clusters had been considered isolated cases. CONCLUSIONS: The increased rate of tuberculosis in Castellon was mainly due to the increasing number of cases among foreigners, mostly Romanians. The availability of molecular studies in all patients with a positive culture allowed us to analyze how and where tuberculosis is transmitted in our province. Forty percent of the patients were grouped into clusters; of these, mixed clusters accounted for one third, indicating the high integration of immigrants in our area. PMID- 21315495 TI - Synthesis and anticancer effects of some novel pyrazolo[3,4-d]pyrimidine derivatives by generating reactive oxygen species in human breast adenocarcinoma cells. AB - A series of novel substituted pyrazolo[3,4-d]pyrimidines (compounds 2-12) were synthesized starting with pyrimidinone derivative 1. Their in vitro cytotoxicity against human breast adenocarcinoma (MCF-7) cell lines has been investigated and most of the tested compounds exploited potent cytotoxic activity against MCF-7 cell lines comparable to the activity of the commonly used anticancer drug cisplatin. Treatment of MCF-7 cells with increased doses (2, 5, 10, 20 MUg/ml) of the tested compounds revealed that the activity of superoxide dismutase and the level of hydrogen peroxide were significantly increased, while the activities of catalase and glutathione peroxidase and the levels of reduced glutathione were significantly lowered compared with control MCF-7 cells. In general, acyclic nucleoside derivative 4 revealed the highest anticancer activity among the other tested compounds. PMID- 21315496 TI - Cobalt bis(dicarbollide) derivatives: solubilization and self-assembly suppression. AB - Cobalt bis(dicarbollide) derivatives are promising therapeutic agents however their utilization is complicated due to their low solubility and self-assembling in water. Earlier we have shown that their solubility can be increased by using of suitable biocompatible excipients--carriers of pharmaceutically active compounds. Expected mechanism of solubilization was disassembling of self assemblies and complexation of unimers. Newly our results of time-dependent light scattering study correct this presumption. Poor solubility of all derivatives can be easily improved by using various excipients, however only heptakis(2,6-di-O methyl)-beta-cyclodextrin displays ability to disassemble self-assemblies of all derivatives and suppress their self-assembling. Surprisingly, the other excipients participate on formation of mixed assemblies of derivative/excipient complex or cover assemblies to make them more soluble without decreasing their size. PMID- 21315497 TI - Using entropy of drug and protein graphs to predict FDA drug-target network: theoretic-experimental study of MAO inhibitors and hemoglobin peptides from Fasciola hepatica. AB - There are many drugs described with very different affinity to a large number of receptors. In this work, we selected Drug-Target pairs (DTPs/nDTPs) of drugs with high affinity/non-affinity for different targets like proteins. Quantitative Structure-Activity Relationships (QSAR) models become a very useful tool in this context to substantially reduce time and resources consuming experiments. Unfortunately, most QSAR models predict activity against only one protein. To solve this problem, we developed here a multi-target QSAR (mt-QSAR) classifier using the MARCH-INSIDE technique to calculate structural parameters of drug and target plus one Artificial Neuronal Network (ANN) to seek the model. The best ANN model found is a Multi-Layer Perceptron (MLP) with profile MLP 32:32-15-1:1. This MLP classifies correctly 623 out of 678 DTPs (Sensitivity = 91.89%) and 2995 out of 3234 nDTPs (Specificity = 92.61%), corresponding to training Accuracy = 92.48%. The validation of the model was carried out by means of external predicting series. The model classifies correctly 313 out of 338 DTPs (Sensitivity = 92.60%) and 1411 out of 1534 nDTP (Specificity = 91.98%) in validation series, corresponding to total Accuracy = 92.09% for validation series (Predictability). This model favorably compares with other LDA and ANN models developed in this work and Machine Learning classifiers published before to address the same problem in different aspects. These mt-QSARs offer also a good opportunity to construct drug-protein Complex Networks (CNs) that can be used to explore large and complex drug-protein receptors databases. Finally, we illustrated two practical uses of this model with two different experiments. In experiment 1, we report prediction, synthesis, characterization, and MAO-A and MAO-B pharmacological assay of 10 rasagiline derivatives promising for anti Parkinson drug design. In experiment 2, we report sampling, parasite culture, SEC and 1DE sample preparation, MALDI-TOF MS and MS/MS analysis, MASCOT search, MM/MD 3D structure modeling, and QSAR prediction for different peptides of hemoglobin found in the proteome of the human parasite Fasciola hepatica; which is promising for anti-parasite drug targets discovery. PMID- 21315498 TI - Developing clinical scenarios from a European perspective: successes and challenges. AB - This paper presents developmental work involving students from the University College Dublin (UCD), Ireland (n=9), University of Surrey, England (n=8) and University of Ljubljana and University of Maribor, Slovenia (n=5) participating in the Erasmus Intensive Programme. The Erasmus programme offers a two week 'Summer School' in the Faculty of Health Sciences, University of Maribor, Slovenia. Using a participatory approach, facilitators from both the UCD and Surrey engaged with students from all of the universities to develop scenarios for simulated learning experiences, in the care of older people, for utilisation on an e learning facility and within the simulated clinical learning environment. Students developed key transferable skills in learning, such as information literacy, cultural diversity, team working, communication, and clinical skills acquisition whilst exploring differences in healthcare delivery in other European countries. PMID- 21315499 TI - Assessing the impact of Cross Compliance measures on nitrogen fluxes from European farmlands with DNDC-EUROPE. AB - We investigated the effects of the agricultural Cross Compliance measures for European cultivated lands, focusing on nitrogen (N) fluxes from corn fields. Four scenarios have been designed according to some conservation farming practices, namely no-till, max manure, catch crop and N splitting. Results indicated that (1) in the no-till scenario the N(2)O fluxes are decreased during the first simulated years, with a return to default fluxes in following years; no-till particularly decreased N(2)O emission in the dryer and colder simulation spatial units (HSMUs); (2) the no-till and the N splitting scenarios slightly increased the N surplus because of a decrease in plant uptake; (3) introducing a rotation with alfalfa decreased the N leaching in the corn crops following the catch crops; and (4) the application of fertilizer and manure during the cold and wet seasons led to an increase of N leaching. PMID- 21315501 TI - Defibrillator implantation for the primary prevention of sudden death in patients awaiting cardiac transplantation: one center's experience. AB - Patients who are on a waiting list for cardiac transplantation often have a clinical profile that satisfies current recommendations for the implantation of an implantable cardioverter-defibrillator for the primary prevention of sudden death. The prospect that transplantation may take place within the short-to medium term puts the effectiveness of this therapy in doubt. We investigated the incidence of therapy delivered by implantable cardioverter-defibrillators implanted for primary prevention in patients awaiting cardiac transplantation. Recent changes in the incidence of sudden death at our center were also investigated. Data on 308 patients listed for heart transplantation between 1998 and 2008 were reviewed. An implantable cardioverter-defibrillator was indicated for primary prevention at initial evaluation in 17 patients. Of these, 53% received appropriate implantable cardioverter-defibrillator therapy while carrying an implantable cardioverter-defibrillator for a mean period of 7.8 months (+/-4.8). Only one patient received inappropriate therapy and none had any complications associated with device use. The frequency of sudden death has decreased over the course of recent years. PMID- 21315502 TI - EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. AB - OBJECTIVES: Our aim is to present a summary of the 2010 version of the European Association of Urology (EAU) guidelines on the treatment of advanced, relapsing, and castration-resistant prostate cancer (CRPC). METHODS: The working panel performed a literature review of the new data emerging from 2007 to 2010. The guidelines were updated, and the levels of evidence (LEs) and/or grades of recommendation (GR) were added to the text based on a systematic review of the literature, which included a search of online databases and bibliographic reviews. RESULTS: Luteinising hormone-releasing hormone (LHRH) agonists are the standard of care in metastatic prostate cancer (PCa). Although LHRH antagonists decrease testosterone without any testosterone surge, their clinical benefit remains to be determined. Complete androgen blockade has a small survival benefit of about 5%. Intermittent androgen deprivation (IAD) results in equivalent oncologic efficacy when compared with continuous androgen-deprivation therapy (ADT) in well-selected populations. In locally advanced and metastatic PCa, early ADT does not result in a significant survival advantage when compared with delayed ADT. Relapse after local therapy is defined by prostate-specific antigen (PSA) values >0.2 ng/ml following radical prostatectomy (RP) and >2 ng/ml above the nadir after radiation therapy (RT). Therapy for PSA relapse after RP includes salvage RT at PSA levels <0.5 ng/ml and salvage RP or cryosurgical ablation of the prostate in radiation failures. Endorectal magnetic resonance imaging and (11)C-choline positron emission tomography/computed tomography (CT) are of limited importance if the PSA is <2.5 ng/ml; bone scans and CT can be omitted unless PSA is >20 ng/ml. Follow-up after ADT should include screening for the metabolic syndrome and an analysis of PSA and testosterone levels. Treatment of castration-resistant prostate cancer (CRPC) includes second-line hormonal therapy, novel agents, and chemotherapy with docetaxel at 75 mg/m(2) every 3 wk. Cabazitaxel as a second-line therapy for relapse after docetaxel might become a future option. Zoledronic acid and denusomab can be used in men with CRPC and osseous metastases to prevent skeletal-related complications. CONCLUSION: The knowledge in the field of advanced, metastatic, and CRPC is rapidly changing. These EAU guidelines on PCa summarise the most recent findings and put them into clinical practice. A full version is available at the EAU office or online at www.uroweb.org. PMID- 21315503 TI - The devil is in the details. PMID- 21315504 TI - Fatal ischemic stroke in a patient receiving lenalidomide for multiple myeloma. PMID- 21315505 TI - Targeting apoptosis pathways in cancer stem cells. AB - There is a significant void in cancer biology with regard to the elucidation of the mechanisms that underlie tumor formation and progression. Recently, the existence of a hierarchy within cancer cell populations has been demonstrated experimentally for several tumor types. The identification of a tumor cell subset that is capable of self-renewal and, concurrently, generation into more differentiated progeny has engendered new perspectives toward selective targeting of tumors. Although the identification of the so-called "cancer stem cells" (CSCs) is a leap in the study of cancer ontogenesis, therapeutic targeting of such cells is plagued by significant difficulties. CSCs are able to evade the control mechanisms that regulate cell survival and proliferation. Apoptosis is one of the most critical and well-studied mechanisms, governing tissue development and homeostasis through a complex network of molecules that mediate death and survival signals. Escape from such a finely tuned death program is a prerequisite for any tumor-initiating cell. Thus, many compounds have been developed to target cancer cells and induce apoptosis directly or indirectly. Several TRAIL receptor agonists are in Phase I or II trials, and IAP inhibitors are undergoing clinical examination to exploit their ability to enhance ionizing radiation- and chemotherapy-induced apoptosis. Further, the EGF-R/Akt pro survival signaling axis is one of the most frequently explored sources of targets for indirect apoptosis induction, as evidenced by the significant amount of molecules designed to target this pathway and have been approved by the FDA or are under clinical evaluation. Despite the promise of these magic bullets, the absence of reliable clinical models has considerably diminished the therapeutic potential of targeted therapies considerably. A more systematic molecular characterization of the tumor-initiating cell population in many tumors will allow us to refine the stimuli that force CSCs to die, thus accelerating the development of more effective treatment for cancer. PMID- 21315506 TI - Inhibition of topoisomerase IIalpha: novel function of wedelolactone. AB - The naturally occurring coumestan wedelolactone has been previously shown to reduce growth of various cancer cells. So far, the growth-suppressing effect of wedelolactone has been attributed to the inhibition of the NFkappaB transcription factor and/or androgen receptors. We found that wedelolactone suppressed growth and induced apoptosis of androgen receptor-negative MDA-MB-231 breast cancer cells at concentrations that did not inhibit the NFkappaB activity. The cells responded to wedelolactone by the S and G2/M phase cell cycle arrest and induction of the DNA damage signaling. Wedelolactone interacted with dsDNA and inhibited the activity of DNA topoisomerase IIalpha. We conclude that wedelolactone can act as growth suppressor independently of NFkappaB and androgen receptors. PMID- 21315507 TI - Ozonation of Cationic Red X-GRL in aqueous solution: kinetics and modeling. AB - Ozonation of Cationic Red X-GRL was investigated in a semi-batch column reactor under various operating conditions such as gas flow rate Q(G), temperature T, initial concentration C(D,0), and pH. The relative contributions of ozone direct oxidation and OH-facilitated indirect oxidation of the dyestuff were quantified, and the overall rate constant k(T) and the kinetic regime of the reaction were determined by interpreting the experimental data with a newly derived kinetic model. The Hatta number of the reaction was found between 0.053 and 0.080, indicating that the reaction occurred in the liquid bulk, i.e. the slow kinetic regime. The ratio gamma of indirect oxidation rate constant k(R) to k(T) decreased from 11.50% at pH 9.24 to 2.47% at pH 3.15. A mechanistically sounder model was derived to describe the reaction kinetics, which takes into account mechanisms of ozone decomposition and dyestuff degradation, and gas-liquid mass transfer. Good agreements were obtained between the experimental and calculated concentrations of Cationic Red X-GRL C(D), dissolved ozone C(A), ozone in off gas C(A,G), and nitrate. Furthermore, a model-based sensitivity analysis of C(D)/C(D,0), C(A), and C(A,G) was performed with respect to various model parameters. PMID- 21315508 TI - Deep oxidation of pollutants using gold deposited on a high surface area cobalt oxide prepared by a nanocasting route. AB - Gold deposited on a cobalt oxide with high surface area (138 m(2)g(-1)), obtained through a nanocasting route using a siliceous KIT-6 mesoporous material as a hard template, has demonstrated high activity for the total oxidation of propane and toluene, and ambient temperature CO oxidation. The addition of gold promotes the activity when compared to a gold-free Co(3)O(4) catalyst prepared using the same nanocasting technique. The enhanced catalytic activity when gold is present has been explained for the deep oxidation of propane and toluene in terms of the improved reducibility of cobalt oxide when gold is added, rather than to the intrinsic activity of metallic gold particles. The improved behaviour for CO oxidation has been linked to the simultaneous presence of Au(delta+) and Au degrees . PMID- 21315509 TI - Responses of Ceriodaphnia dubia to TiO2 and Al2O3 nanoparticles: a dynamic nano toxicity assessment of energy budget distribution. AB - The in vivo responses of C. dubia to nanoparticles exemplified by a photoactive titanium oxide (TiO(2)) and a non-photocatalytic aluminum oxide (Al(2)O(3)) were studied. Both nanomaterials inhibited the growth of C. dubia at concentrations ca. >100mg/L. The EC50 value was 42 and 45 mg/L in the presence of TiO(2) and Al(2)O(3), respectively, based on 3-brood reproduction assay. Results implied that reactive oxygen species (ROS) may not be totally responsible for the adverse effects exerted on the invertebrate. Aggregation and interaction among nanoparticles, C. dubia, and algal cells, major food source of Daphnia, played a significant role on the responses of C. dubia to nanoparticles. Dynamic energy budget (DEB) analysis was used to assess the impact of nanoparticles on the energy allocation of C. dubia. Results indicated that nanoparticles could disrupt the assimilation and consumption of energy in C. dubia dramatically. The assimilation energy was negatively correlated to the concentration of nanomaterials, a reduction from 11 to near 0 MUg-C/animal/day in the presence of TiO(2) or Al(2)O(3) nanoparticles at a nanoparticle concentration of 200mg/L. The energy consumed for life-maintenance increased also with increase in the concentration of nanomaterials. Results clearly demonstrated the importance of energy disruption in determining the toxicity of nanoparticles toward C. dubia. PMID- 21315510 TI - Removal of arsenic from water using Fe-exchanged natural zeolite. AB - An elevated arsenic (As) content in groundwater imposes a great threat to people worldwide. Thus, developing new and cost-effective methods to remove As from groundwater and drinking water becomes a priority. Using iron/aluminum hydroxide to remove As from water is a proven technology. However, separation of As-bearing fine particles from treated water presented a challenge. An alternative method was to use coarse-grained sorbents to increase the flow rate and throughput. In this research, a natural zeolite (clinoptilolite) was exchanged with iron(III) to enhance its As removal. Batch test results showed a Fe(III) sorption capacity of 144 mmol/kg on the zeolite. The As sorption on the Fe-exchanged zeolite (Fe-eZ) could reach up to 100mg/kg. Columns packed with Fe-eZ were tested for As removal from water collected from acid mine drainage (AMD) and groundwater containing high natural organic matter and high As(III). With an initial concentration of 147 MUg/L in the AMD water, a complete As removal was achieved up to 40 pore volumes. However, the Fe-eZ was not effective to remove As from Chia-Nan Plain groundwater due to its high initial As concentration (511 MUg/L), high amounts of natural organic matter, as well as its low oxidation-reduction potential, under which the As was in reduced As(III) form. PMID- 21315511 TI - The occurrence and fate of anti-inflammatory and analgesic pharmaceuticals in sewage and fresh water: treatability by conventional and non-conventional processes. AB - The presence of pharmaceutical (PhAC) residues in the environment is an emerging issue due to their continuous and uncontrolled release (via excretion from medical care) to the water environment and detrimental effects on aquatic organisms at low concentrations. A large fraction of PhAC pollution in water is composed of anti-inflammatory (AI) and analgesic (AN) drugs, which are rapidly excreted in urine. The present review is aimed to emphasize the occurrence of AI/AN wastes in sewage and fresh water bodies, their impacts on non-target organisms, and conversion or elimination by chemical, biochemical and physical treatment methods. The first part of the study is devoted to a critical review of most common AI/AN drugs and the relative efficiency of some selected sewage and drinking water treatment operations for their elimination/separation from aqueous systems. The second part focuses on pilot- or lab-scale applications of various advanced oxidation processes that are promising solutions to the ultimate degradation and/or conversion of such medical residues in effluents of drinking water treatment plants (DWTPs) and wastewater treatment plants (WWTPs) to less harmful and non-toxic products. PMID- 21315512 TI - Enhanced visible light photocatalytic activity of novel Pt/C-doped TiO2/PtCl4 three-component nanojunction system for degradation of toluene in air. AB - C-doped TiO(2) nanoparticles prepared by partial oxidation of TiC were modified with Pt species by impregnation-calcination method in order to enhance the visible light photocatalytic activity. The physicochemical properties of as prepared samples were characterized by various techniques in detail. The results indicated that a novel Pt/C-doped TiO(2)/PtCl(4) three-component nanojunction system was formed, where C-doped TiO(2) and PtCl(4) behaved as two visible light responsive components, and Pt metal as electron-transfer system. The three component nanojunctioned photocatalyst system exhibited six times higher visible light activity than that of the pristine C-doped TiO(2) in degradation of toluene in air. The dramatically enhanced activity can be attributed to the increased utilization of visible light, the enhanced charge carrier separation and transfer process. Further more, the band structure and photocatalysis mechanism over the three-component nanojunction system was proposed and discussed. This work may provide new insights into the design of novel multi-component photocatalyst system with efficient visible light activity. PMID- 21315513 TI - Decolorization of synthetic dyes by crude laccase from a newly isolated Trametes trogii strain cultivated on solid agro-industrial residue. AB - A new dye-decolorizing white-rot fungus was isolated and identified as Trametes trogii based on its ITS-5.8S rRNA gene sequence analysis and morphological characteristics. Laccase was the only lignolytic enzyme produced by this strain during solid substrate fermentation (SSF) in soybean cake, a solid agro industrial residue used for the first time in enzyme production. The extracellular crude enzyme from T. trogii in solid substrate fermentation showed good activity in synthetic dye color removal, decolorizing 85.2% Remazol Brilliant Blue R (50 mg l(-1)), 69.6% Reactive Blue 4 (35 mg l(-1)), and 45.6% Acid Blue 129 (83.3 mg l(-1)) without the addition of redox mediators, 90.2% Acid Red 1 (10 mg l(-1)), and 65.4% Reactive Black 5 (18.3 mg l(-1)) with the addition of 1mM 1-hydroxybenzotriazole in 30 min. Native polyacrylamide gel electrophoresis (Native-PAGE) of the crude enzyme and effects of laccase inhibitors on decolorization corroborated the laccase as the major enzyme involved in the decolorization of dyes. The comparison of color removal by the crude culture filtrates and by the whole fungal culture on the solid substrate revealed the former was more advantageous. PMID- 21315514 TI - Opioids around the clock? PMID- 21315515 TI - Does emotional disclosure about stress improve health in rheumatoid arthritis? Randomized, controlled trials of written and spoken disclosure. AB - Studies of the effects of disclosing stressful experiences among patients with rheumatoid arthritis (RA) have yielded inconsistent findings, perhaps due to different disclosure methods--writing or speaking--and various methodological limitations. We randomized adults with RA to a writing (n=88) or speaking (to a recorder) sample (n=93), and within each sample, to either disclosure or 1 of 2 control groups (positive or neutral events), which conducted four 20-minute, at home sessions. Follow-up evaluations at 1, 3, and 6 months included self reported, behavioral, physiological, and blinded physician-assessed outcomes. In both writing and speaking samples, the disclosure and control groups were comparably credible, and the linguistic content differed as expected. Covariance analyses at each follow-up point indicated that written disclosure had minimal effects compared with combined controls--only pain was reduced at 1 and 6 months, but no other outcomes improved. Spoken disclosure led to faster walking speed at 3 months, and reduced pain, swollen joints, and physician-rated disease activity at 6 months, but there were no effects on other outcomes. Latent growth curve modeling examined differences in the trajectory of change over follow-up. Written disclosure improved affective pain and walking speed; spoken disclosure showed only a marginal benefit on sensory pain. In both analyses, the few benefits of disclosure occurred relative to both positive and neutral control groups. We conclude that both written and spoken disclosure have modest benefits for patients with RA, particularly at 6 months, but these effects are limited in scope and consistency. PMID- 21315516 TI - Evolving options for the treatment of metastatic breast cancer: progression-free survival as an endpoint. AB - Because of its direct clinical relevance, overall survival is the gold standard endpoint for measuring clinical efficacy. However, achieving improvements in overall survival can be confounded by factors such as crossover to active treatment arms and subsequent treatment with non-experimental active therapies. Powering studies to detect significant overall survival increases requires prohibitively large patient numbers and long follow-up and may not always be practical. Trials incorporating progression free survival (PFS) or time to progression (TTP) as primary outcome measures are likely to be shorter, require fewer patients and are usually more affordable, which may ultimately translate into a more rapid evaluation of potentially effective experimental therapies. In heavily pretreated metastatic breast cancer, significant improvements in progression-free survival may indicate a clinically meaningful benefit for patients with otherwise limited salvage therapy options available. Approval for several newer agents in the advanced resistant or refractory metastatic breast cancer setting has been based on prolonged progression-free survival or time to progression as primary trial endpoints. In this paper, clinical trial data relating to OS, PFS and TTP endpoints are reviewed and the use of surrogate markers of survival for the evaluation of new drugs is considered. PMID- 21315517 TI - Past year treatment status and alcohol abuse symptoms among US adults with alcohol dependence. AB - OBJECTIVE: We tested whether the number and type of alcohol abuse symptoms were associated with an increased likelihood of treatment seeking among respondents with alcohol dependence. METHODS: Data from 4027 adult respondents from 2006 and 2007 National Survey on Drug Use and Health (NSDUH) who met DSM-IV criteria for the past year alcohol dependence were used. Respondents were classified according to the number of past year alcohol abuse symptoms endorsed, as well as type of abuse symptom. Associations were estimated using weighted multivariate logistic regressions that controlled for severity of alcohol dependence, other drug use disorders and other characteristics. RESULTS: Twenty-eight percent of individuals with alcohol dependence had one alcohol abuse symptom, 20% had two and 19% had three or four. Individuals with more alcohol abuse symptoms differed from those without alcohol abuse symptoms in a number of sociodemographic characteristics and severity of alcohol and drug dependence. Even after adjusting for these factors, individuals with three or four alcohol abuse symptoms had 2.67 times increased odds of treatment seeking, as compared to those without alcohol abuse symptoms [95% CI=1.65-4.30]. However, individuals with one or two alcohol abuse symptoms were no more likely to seek treatment than those without alcohol abuse symptoms. Majority of those with one or two alcohol abuse symptoms endorsed the hazardous abuse symptom. CONCLUSION: Alcohol abuse symptoms are important factors for treatment seeking in individuals with alcohol dependence, but only among certain subset of individuals with three or four alcohol abuse symptoms. Examining structural and psychosocial differences across these subgroups may help inform and reduce barriers to treatment seeking among this population. PMID- 21315518 TI - The associations between early alcohol use and suicide attempts among adolescents with a history of major depression. AB - OBJECTIVE: Previous studies have identified significant associations between alcohol initiation before the age of 13 years and risk for suicide attempts. However, these associations have not been extensively tested using data obtained from populations with clinically significant psychopathology. The current study seeks to extend knowledge of the associations between early alcohol initiation and risk for suicide by identifying the associations between age of first alcohol use and suicide attempts among a sample of youth age 13 to 15 years with a history of major depression. METHODOLOGY: Data were obtained from the National Study of Drug Use and Health (NSDUH), a household-based survey of U.S. adolescents and adults age 12 years and older. RESULTS: Results from these analyses confirm previous reports of significant associations between age of first alcohol use and suicide attempts and extend previous understanding of risk by using data obtained from a household-based survey and from adolescents with clinically relevant psychopathology. CONCLUSIONS: These findings provide further support for the implementation, enforcement, and continued support of both targeted and universal prevention strategies designed to reduce underage drinking. PMID- 21315519 TI - Drinking motives as mediators between PTSD symptom severity and alcohol consumption in persons with severe mental illnesses. AB - Research has consistently shown that drinking to alleviate negative emotional states predicts alcohol use and relapse among clients with co-occurring disorders including depressive and posttraumatic stress disorders. However, studies examining the mediating role of drinking motives in persons with severe mental illness (SMI) are few. The current survey of 116 community mental health clients (51.7% men; 47.4% women) diagnosed with either a schizophrenia spectrum disorder (41, 35.3%) or major mood disorder (75, 64.7%) tested the hypothesis that convivial drinking and drinking to cope with negative emotions would mediate posttraumatic stress symptoms (PSS-I) and alcohol consumption (QF). A series of path models revealed that convivial drinking fully mediated hyper-arousal symptoms and alcohol consumption, and negative coping fully mediated total posttraumatic stress symptoms, avoidance and hyper-arousal symptoms and alcohol consumption. The results support an emotional distress reduction model of alcohol use in people with severe mental illness, and highlight the need to assess specific drinking motives and target them in cognitive-behavioral treatment approaches. The cross sectional design employed limits cause-effect inferences regarding mediation, and highlights the need for longitudinal designs to sort out causal pathways among symptoms, drinking motives and alcohol consumption in clients with SMI. PMID- 21315520 TI - Association of cigarette smoking with drug use and risk taking behaviour in Irish teenagers. AB - BACKGROUND: Cigarette smoking has been shown to act as a 'gateway' to cannabis use and further risk taking behaviours. This study aims to (1) establish the prevalence of cigarette smoking and cannabis use in Irish teenagers, (2) to quantify the strength and significance of the association of cigarette smoking and cannabis use and other high risk behaviours and (3) examine whether the above associations are independent of the extent of social networking. METHODS: Adolescent students across five urban, non-fee paying schools completed an abridged European schools survey project on alcohol and other drugs (ESPAD) questionnaire. RESULTS: 370/417 (88.7%) students completed the questionnaire. 228 (61.6%) were female, 349 (94.3%) were aged 15-16 years. 48.4% of those surveyed had smoked tobacco at some stage in their lifetime, 18.1% in the last 30 days. 15.1% have used cannabis with 5.7% using it in the last 30 days. 29.6% of cigarette smokers have used cannabis in comparison to 1.6% of non-smokers. On multivariate analysis lifetime cigarette smoking status was independently associated with hard drug use, adjusted OR=6.0, p<0.01; soft drug use, adjusted OR=4.6, p<0.01 and high risk sex practises, adjusted OR=10.6, p<0.05. CONCLUSIONS: Cigarette smoking prevalence remains high in Irish teenagers and is significantly associated with drug use and other risk taking behaviours. Specific teenage smoking cessation strategies need to be developed targeting these combined high risk health behaviours. PMID- 21315521 TI - Articularly placed interfragmentary screw fixation of difficult condylar fractures of the hand. AB - PURPOSE: To retrospectively review the outcomes of intra-articularly placed interfragmentary screws for fixation of difficult condylar fractures of the metacarpal and proximal phalangeal heads. METHODS: We placed interfragmentary screws intra-articularly in 10 patients with 11 fractures to achieve a rigid fixation construct in which the non-articular portion of the bone fragment is too small to allow a stable fixation, or where the bone fragment is entirely osteochondral. RESULTS: The mean duration of follow-up was 15.9 months (range, 6 45 mo). All fractures united within 16 weeks (average, 8.1 wk). We observed subsidence in 1 case; another patient had screw protrusion that required removal. The range of motion of the involved metacarpophalangeal joints for the metacarpal head fractures was 79 degrees (range, 60 degrees to 90 degrees ). The range of motion of the involved proximal interphalangeal joints for the proximal phalangeal head fractures was 86 degrees (range, 80 degrees to 90 degrees ). CONCLUSIONS: Intra-articularly placed interfragmentary screw fixation is a good technique for treating difficult condylar fractures of the hand. PMID- 21315522 TI - [The confidential enquiries into maternal deaths, 1996-2006 in France: what consequences for the obstetrical care?]. AB - The national confidential enquiry into maternal deaths (ENCMM) and its committee (CNEMM) have the target to study all maternal deaths occurring in France, in order to expertise the care provided. The current report covers the 1996--year of the ENCMM establishment--to 2006 years. After being informed of the potential maternal deaths by the Epidemiological center on medical causes of deaths (CepiDC), and agreement from the medical doctors concerned, two assessors (one anesthetist and one obstetrician) gather the medical or obstetrical information near the team involved in the care of the women, by the mean of a detailed and specific questionnaire. The completely anonymous files are expertised by the CNEMM. Maternal mortality rates have been calculated by periods, the distribution of the obstetrical causes and the characteristics of the dead women were calculated too. The substandard care and the avoidability of deaths were estimated by subgroup. Since 1996 to 2006, 729 maternal deaths were included of which 553 were expertised. The majority of maternal deaths were due to direct obstetrical causes (73%) mainly haemorrhages (22%), amniotic fluid embolism (12%), complications of hypertension (10 %), and venous thrombo-embolism (around 10 % each). Half of maternal deaths were considered preventable by the CNEMM, particularly haemorrhage and sepsis. The factors of avoidability are delay to treat (31%) inadapted therapeutics (28%), even professional default (20%) no diagnosis (15%) or reluctant patient (7%). Seven deaths are discussed in a specific section including a detailed description of, and recommendations on how the quality of care may be improved. PMID- 21315523 TI - The relationship between social network factors, HIV, and Hepatitis C among injection drug users in Chennai, India. AB - OBJECTIVE: The purpose of this study was to examine whether social network factors predict HIV and Hepatitis C (HCV) serostatus after controlling for individual-level factors at baseline among a cohort of male injection drug users in Chennai, India. METHODS: The sample, which was recruited through street outreach, consists of 1078 males who reported having injected drugs in the last 6 months. RESULTS: The participants reported 3936 social support and risk network members. HIV and HCV positive serostatus were negatively associated with network member providing emotional support, and positively associated with network member providing material support. In addition, HCV positivity was associated with network member being an active drug user known for more than 10 years and network member being male kin networks, even after adjusting for individual demographic factors and risk behaviors. CONCLUSIONS: These findings suggest that social network factors are significantly linked to HIV and HCV status among IDUs in Southern India and highlight the mixed effects of social capital on health. Future HIV/HCV prevention efforts should incorporate IDU peers to alter drug network injection risk norms. For drug users who have minimal network support, support groups and other informal and formal support mechanisms may be need to help them with health care and psychological support needs for dealing with HIV/HCV. PMID- 21315524 TI - Effect of resistin on granulosa and theca cell function in cattle. AB - Resistin is an adipokine that has not been extensively studied in cattle but is produced by adipocytes in greater amounts in lactating versus non-lactating cattle. Seven experiments were conducted to determine the effect of resistin on proliferation, steroidogenesis, and gene expression of theca and granulosa cells from small (1-5mm) and/or large (8-22 mm) cattle follicles. Resistin had no effect on IGF-I-induced proliferation of large-follicle theca cells or small follicle granulosa cells, but decreased IGF-I-induced proliferation of large follicle granulosa cells. Resistin weakly stimulated FSH plus IGF-I-induced estradiol production by large-follicle granulosa cells, but had no effect on IGF I- or insulin-induced progesterone and androstenedione production by theca cells or progesterone production by granulosa cells of large follicles. In small follicle granulosa cells, resistin attenuated the stimulatory effect of IGF-I on progesterone and estradiol production of small-follicle granulosa cells. RT-PCR measuring abundance of side-chain cleavage enzyme (CYP11A1), aromatase (CYP19A1), FSH receptor (FSHR) and LH receptor (LHCGR) mRNA in large- and small-follicle granulosa cells indicated that resistin reduced the stimulatory effect of IGF-I on CPY11A1 mRNA abundance in large-follicle granulosa cells but had no effect on CYP19A1, FSHR or LHCGR mRNA abundance in large- or small-follicle granulosa cells. Resistin had no effect on CYP11A1, CYP17A1 or LHCGR mRNA abundance in theca cells. These results indicate that resistin preferentially inhibits steroidogenesis of undifferentiated (small follicle) granulosa cells and inhibits proliferation of differentiated (large follicle) granulosa cells, indicating that the ovarian response to resistin is altered during follicular development. PMID- 21315525 TI - Predictors of cervical lymph node involvement in patients with pharyngeal carcinoma undergoing endoscopic mucosal resection. AB - OBJECTIVE: Although detection of pharyngeal carcinoma remaining in the epithelium or subepithelial tissue layer has been difficult by routine examinations, recent advances in endoscopic technology have enabled us to detect these lesions. These patients can receive endoscopic mucosal resection (EMR) and generally have a good prognosis, but some patients have nodal involvement. The purpose was to investigate predictors of nodal involvement in patients with pharyngeal carcinoma undergoing EMR at our hospital. STUDY DESIGN: Outcomes research. METHODS: Lymph node involvement, endoscopic morphology, and tumor thickness were investigated in 152 patients treated between 2001 and 2009. RESULTS: Pathological examination revealed carcinoma in situ (CIS) for 77 patients and subepithelial invasion (SEPI) for 75 patients. There were no patients with muscular invasion. Nodal involvement was found in none of CIS but in 7 of 75 patients (9.3%) with SEPI. In patients with SEPI, the mean tumor thickness was significantly higher in patients with lymph node involvement (1311.4 +/- 300.0 MUm) than those without involvement (692.6 +/- 495.7 MUm) (p=0.002). Significant risk factors for nodal involvement included the tumor thickness over 1000 MUm (p<0.001) and the presence of venous or lymphatic invasion (p<0.05). Based on analysis in relation to sensitivity and specificity, the tumor thickness over 1000 MUm may serve as the most predictive factor for nodal involvement. CONCLUSION: Tumor thickness can be a simple predictor for nodal involvement in cases of SEPI. Careful follow-up including neck palpation and annual imaging diagnostics such as computed tomography or ultrasonography are recommended for these patients. PMID- 21315526 TI - A systematic review and Number Needed to Treat analysis to guide the management of the neck in patients with squamous cell carcinoma of the head and neck. AB - OBJECTIVES: To systematically review the literature to identify studies from which it is possible to perform a Number Needed to Treat (NNT) analysis to identify, in a more clinically intuitive manner, neck node levels for which treatment is essential in the N0 and N+ neck with respect to the primary site of tumour. METHODS: Systematic literature review using a defined search strategy; data extraction from studies meeting the inclusion criteria; calculation of NNT for individual neck node levels with respect to primary site. RESULTS: A total of 6169 articles were identified from searches of Embase, Medline, The Cochrane library of randomised control trials, conference proceedings and the bibliographies of retrieved papers. Titles and abstracts were screened; from these, 219 studies were retrieved for detailed review. One hundred and ninety six papers were excluded and 23 studies were included in the final analysis. Following review of the data from these studies, and accepting a NNT cut-off of 5 we confirmed that the following lymph node levels should be treated: CONCLUSIONS: NNT is a clinically intuitive parameter to guide appropriate lymph node level treatment in patients presenting with squamous cell carcinoma of the head and neck. PMID- 21315527 TI - Quantitative T2 evaluation at 3.0T compared to morphological grading of the lumbar intervertebral disc: a standardized evaluation approach in patients with low back pain. AB - BACKGROUND: The purpose of our investigation was to compare quantitative T2 relaxation time measurement evaluation of lumbar intervertebral discs with morphological grading in young to middle-aged patients with low back pain, using a standardized region-of-interest evaluation approach. PATIENTS AND METHODS: Three hundred thirty lumbar discs from 66 patients (mean age, 39 years) with low back pain were examined on a 3.0T MR unit. Sagittal T1-FSE, sagittal, coronal, and axial T2-weighted FSE for morphological MRI, as well as a multi-echo spin echo sequence for T2 mapping, were performed. Morphologically, all discs were classified according to Pfirrmann et al. Equally sized rectangular regions of interest (ROIs) for the annulus fibrosus were selected anteriorly and posteriorly in the outermost 20% of the disc. The space between was defined as the nucleus pulposus. To assess the reproducibility of this evaluation, inter- and intraobserver statistics were performed. RESULTS: The Pfirrmann scoring of 330 discs showed the following results: grade I: six discs (1.8%); grade II: 189 (57.3%); grade III: 96 (29.1%); grade IV: 38 (11.5%); and grade V: one (0.3%). The mean T2 values (in milliseconds) for the anterior and the posterior annulus, and the nucleus pulposus for the respective Pfirrmann groups were: I: 57/30/239; II: 44/67/129; III: 42/51/82; and IV: 42/44/56. The nucleus pulposus T2 values showed a stepwise decrease from Pfirrmann grade I to IV. The posterior annulus showed the highest T2 values in Pfirrmann group II, while the anterior annulus showed relatively constant T2 values in all Pfirrmann groups. The inter- and intraobserver analysis yielded intraclass correlation coefficients (ICC) for average measures in a range from 0.82 (anterior annulus) to 0.99 (nucleus). CONCLUSIONS: Our standardized method of region-specific quantitative T2 relaxation time evaluation seems to be able to characterize different degrees of disc degeneration quantitatively. The reproducibility of our ROI measurements is sufficient to encourage the use of this method in future investigations, particularly for longitudinal studies. PMID- 21315528 TI - Spatial relationship between intrahepatic artery and portal vein based on the fusion image of CT-arterial portography (CTAP) and CT-angiography (CTA): new classification for hepatic artery at hepatic hilum and the segmentation of right anterior section of the liver. AB - PURPOSE: To clarify the variations of the intrahepatic artery and portal vein and to verify the proper segmentation for the right anterior section of the liver. MATERIALS AND METHODS: CT during arterial portography and CT angiography were performed on 64-slice multi detector row CT in 147 patients. All images were transferred to a workstation for analysis using multi-image-fusion mode. We investigated the spatial relationship between hepatic artery and portal vein in the right hemiliver and the segmentation of the right anterior hepatic artery and portal vein. RESULTS: The spatial anatomy of right hepatic arteries and portal vein was (1) anterior and posterior hepatic artery run superior and inferior to anterior portal vein, respectively (47.6%), (2) one anterior hepatic artery runs superior to and another one runs inferior to anterior portal vein (15%), (3) anterior and posterior hepatic arteries run superior to anterior portal vein (11.6%), (4) anterior and posterior hepatic arteries run inferior to anterior portal vein (7.5%), and (5) one posterior hepatic artery runs superior to and another one runs inferior to anterior portal vein (6.8%). The combined anatomy of right anterior artery and portal vein with regard to segmentation was classified as (1) dorso-ventral (26.5%), (2) dorso-ventral and inferior (10.9%), (3) multiple (18.4%), and (4) superior and inferior segments (1.4%). CONCLUSION: There are various types of spatial anatomy of intrahepatic artery and portal vein. The hepatic arteries as well as portal veins of right anterior section of the liver could be divided into dorsal and ventral, not superior and inferior. PMID- 21315529 TI - Gd-EOB-DTPA-enhanced MR imaging: evaluation of hepatic enhancement effects in normal and cirrhotic livers. AB - OBJECTIVE: The purpose of this study was to assess differences in enhancement effects of liver parenchyma between normal and cirrhotic livers on contrast enhanced MR imaging (CE-MRI) obtained with Gd-EOB-DTPA. METHODS: A total of 99 patients with cirrhotic liver (n=58; Child-Pugh class A, n=30; B, n=22; C, n=6) and normal liver (n=41) underwent Gd-EOB-DTPA-enhanced MR imaging. CE images were obtained before contrast injection, in the arterial phase (AP) at 25s or modified scan delay, in the portal phase (PP) at 70s, in the equilibrium phase (EP) at 3 min, and in the hepatobiliary phase (HP) at 3 times (10, 15 and 20 min). Signal intensity of the liver in all phases was defined using region-of-interest measurements for relative enhancement (RE) calculation. RESULTS: In normal-liver and Child-Pugh class A and B patients, mean RE of liver parenchyma increased significantly (P<0.03-0.001) with time until 20-min HP. Conversely, mean RE for Child-Pugh class C patients did not show any increasing tendency after PP. Mean RE of liver parenchyma at EP and HP (10-, 15- and 20-min) was highest in normal liver, followed by Child-Pugh class A, B and C cirrhosis (P<0.02-0.001). CONCLUSION: Hepatic parenchymal enhancement on CE-MR images obtained using Gd-EOB DTPA is affected by the severity of cirrhosis. PMID- 21315530 TI - Comparison of automated 4-chamber cardiac views versus axial views for measuring right ventricular enlargement in patients with suspected pulmonary embolism. AB - PURPOSE: Compare the right ventricle to left ventricle (RV/LV) diameter ratio obtained from axial pulmonary CT angiograms (CTPA) with those derived from automatically generated 4-chamber (4-CH) reformats in patients with suspected pulmonary embolism (PE). METHODS: In this institutional review board-approved study we included 120 consecutive non ECG-gated CTPA from 3 institutions (mean age 60 +/- 16 years; 71 women). Twenty 64-slice CTPA with PE and 20 without PE were selected per institution. For each patient the RV/LV diameter ratio was obtained from both axial CTPA images and automatically generated 4-CH reformats. Measurements were performed twice in two separated sessions by 2 experienced radiologists and 2 residents. The differences between the measurements on both views were evaluated. RESULTS: The 4-CH view was successfully obtained in 113 patients. The mean axial and 4-CH diameter ratios were comparable for three of the four readers (p = 0.56, p = 0.13, p = 0.08). Although the mean diameters (1.0 and 1.03 respectively) for one resident were significantly different (p = 0.013), the difference of 0.03 seems negligible in clinical routine. Three readers achieved equally high intra-reader agreements with both measurements (ICCs of 0.94, 0.95 and 0.96), while one reader showed a different variability with ICCs of 0.96 for the axial view and 0.91 for the 4-CH view. The inter-reader agreement was equally high for both measurement types with ICCs of 0.95 and 0.94, respectively. CONCLUSION: In patients with suspected PE, RV/LV diameters ratio can be measured with the same reproducibility and accuracy using an automatically generated 4-CH view compared to the axial view. PMID- 21315531 TI - Tracheal morphology and collapse in COPD: correlation with CT indices and pulmonary function test. AB - OBJECTIVES: To assess the tracheal morphologic changes using CT in COPD (chronic obstructive lung disease) patients and to assess correlation between them and PFT (pulmonary function test) and CT parameters. MATERIALS AND METHODS: Ninety-two healthy individuals and 115 patients with COPD who underwent volumetric inspiration/expiration CT scanning were included. The Lsag, Lcor, and the tLA were measured. The TI was defined as the ratio of Lcor/Lsag. The tracheal morphologic changes (tLA, TI, and collapsibility) were compared in healthy individuals and COPD. In COPD patients, correlation of the tracheal morphologic change with PFT and CT parameters was assessed. RESULTS: The TIs in the COPD patients were significantly lower than those in the control group (0.80+/-0.15 vs. 0.88+/-0.11, Mean+/-SD) (p<0.01). In COPD patients, TI correlated with FEV1 (r=0.29, p=<0.01), FEV1/FVC (r=0.26, p<0.01), and the GOLD stage (r=-0.26, p<0.01). TI showed significant correlation with EI on both inspiration and expiration CT (r=-0.19, p=0.04 and r=-0.23, p=0.02), MLD on expiration CT (r=0.27, p<0.01), CT-ATI (r=0.34, p<0.01), and with LV on expiration CT (r=-0.25, p<0.01). CONCLUSION: Among the tracheal morphologic changes, the most significant change in COPD patients compared with that in the control group, was the TI. In COPD patients, the tracheal morphologic change showed clinically significant correlation with severity of emphysema and CT indices. PMID- 21315532 TI - On the positive correlation between the percentage of acute fracture of medial orbital wall and the degree of injury of affected medial rectus muscle by CT image. AB - AIM: To study the correlation between the percentage of acute fracture of unilateral medial orbital wall and the degree of injury of medial rectus muscle on the same side and to explore the possibility of evaluating the degree of injury of medial rectus muscle according to the percentage of fracture of medial orbital wall on the same side undergoing examination and diagnosis of ocular trauma by use of CT scan. METHOD: To measure the span length of fracture of medial orbital wall, to calculate the fracture percentage, to measure the maximum widths of muscle belly of medial rectus muscle on affected and contralateral sides on CT images and to analyse statistically. RESULTS: There is a significant positive correlation between the fracture percentage of medial orbital wall and the increase in amplitude of width of medial rectus muscle on the same side. CONCLUSION: The injury of medial rectus muscle was aggravated by the greater percentage of fracture of medial orbital wall, which could be used to assess the degree of injury of medial rectus muscle suffering fracture of lamina orbitalis. PMID- 21315533 TI - Arterial spin-labeling MR imaging in moyamoya disease compared with SPECT imaging. AB - OBJECTIVE: Arterial spin-labeling (ASL) is a noninvasive magnetic resonance (MR) imaging method used to obtain brain perfusion information on various cerebrovascular diseases. We retrospectively compared the use of ASL-MRI and single-photon emission CT (SPECT) imaging to determine absolute cerebral blood flow (CBF) in moyamoya disease. MATERIALS AND METHODS: CBF examinations using ASL MRI on 3-T MRI and SPECT imagings with iodine-123-N-isopropyl-p-iodoamphetamine at resting (rest-IMP) and after acetazolamide challenge (ACZ-IMP) were performed on 12 patients with moyamoya disease (men, 5; women, 7; age range/average (year), 7-66/35.0). The CBF values determined by ASL-MRI (ASL-value), rest-IMP (rest-IMP value), and ACZ-IMP (ACZ-IMP-value) of cerebral hemispheres (24 sides) were measured with normalized CBF maps created from data of those 3 perfusion imaging methods. Cerebrovascular reactivity (CVR) was calculated as follows: {(ACZ-IMP value)-(rest-IMP-value)}/(rest-IMP-value)*100 (%). The ASL-value was compared with the rest-IMP-value, ACZ-IMP-value, and CVR. RESULTS: The ASL-value, rest-IMP value, ACZ-IMP-value, and CVR (average+/-standard deviation) were 26.6+/-14.8 (mL/100 g/min), 27.5+/-6.4 (mL/100 g/min), 37.1+/-13.2 (mL/100 g/min), and 35.9+/ 44.3 (%), respectively. Significant relationships between the ASL-value versus (vs.) the rest-IMP-value (rs=0.500, p<0.05), the ASL-value vs. the ACZ-IMP-value (rs=0.863, p<0.01), and the ASL-value vs. the CVR (rs=0.699, p<0.01) were observed. CONCLUSION: Although the ASL-value was lower than the rest-IMP-value, the significant relationship between the ASL-value and the rest-IMP-value may suggest that perfusion imaging by ASL-MRI could be used to recognize the condition of brain perfusion. In particular, the stronger correlation coefficient between the ASL-value and ACZ-IMP-value might suggest that perfusion imaging by ASL-MRI could show the potentially dangerous zone for ischemia. PMID- 21315534 TI - Quantitative combination of volumetric MR imaging and MR spectroscopy data for the discrimination of meningiomas from metastatic brain tumors by means of pattern recognition. AB - The analysis of information derived from magnetic resonance imaging (MRI) and spectroscopy (MRS) has been identified as an important indicator for discriminating among different brain pathologies. The purpose of this study was to investigate the efficiency of the combination of textural MRI features and MRS metabolite ratios by means of a pattern recognition system in the task of discriminating between meningiomas and metastatic brain tumors. The data set consisted of 40 brain MR image series and their corresponding spectral data obtained from patients with verified tumors. The pattern recognition system was designed employing the support vector machines classifier with radial basis function kernel; the system was evaluated using an external cross validation process to render results indicative of the generalization performance to "unknown" cases. The combination of MR textural and spectroscopic features resulted in 92.15% overall accuracy in discriminating meningiomas from metastatic brain tumors. The fusion of the information derived from MRI and MRS data might be helpful in providing clinicians a useful second opinion tool for accurate characterization of brain tumors. PMID- 21315535 TI - Treatment of laryngeal hereditary angioedema. AB - BACKGROUND: In the emergency department, patients with laryngeal swelling and an inconclusive patient history may receive treatment for allergy-mediated angioedema. Intubation may be necessary if the patient does not respond to treatment. Because angioedema subtypes respond to different interventions, a correct diagnosis is vital. OBJECTIVES: Review the differential diagnosis of angioedema and characteristics differentiating subtypes. Discuss therapies for angioedema subtypes. Introduce therapies for prevention and acute treatment of hereditary angioedema (HAE). CASE REPORT: A 10-year-old girl presented with laryngeal swelling unresponsive to diphenhydramine, methylprednisolone, and epinephrine. It was later revealed that she had a family history of HAE, was C1 inhibitor deficient, and enrolled in a clinical study of acute HAE treatment. She was given 1000 units of nanofiltered C1 inhibitor and was able to swallow within 30 min. She was prescribed routine prophylaxis with C1 inhibitor concentrate and has had no subsequent severe HAE swelling attacks. CONCLUSION: This case illustrates the need for providers to consider HAE in light of available diagnostic testing and recent Food and Drug Administration approval of specific therapies for HAE. PMID- 21315536 TI - Images in emergency medicine: wall-echo-shadow (WES) complex. PMID- 21315537 TI - Thermometer of warmth in the patient-provider relationship (WARMOMETER)--theory based development of a patient self-report measure and initial validation using cognitive interview methodology. AB - OBJECTIVE: The aims of this study are twofold: (1) the theory-based development of a patient self-report measure of physician warmth and (2) the application of cognitive interview methodology to understand patients' perception and interpretation of this new measure. METHODS: A draft measure was developed based on an in-depth literature review of the concept of human warmth by a multidisciplinary expert group. Sixteen cognitive probing interviews were conducted to examine how patients perceive and interpret this new measure and to identify potential problems. A content analysis of the interviews was used to evaluate findings. RESULTS: Findings indicate that the WARMOMETER is a short patient self-report assessment of physician warmth, which seems easy and intuitive to understand. In addition, most respondents were found to share a common concept of physician warmth. CONCLUSIONS: Verification of our study hypotheses and confirmation of the theoretical assumptions of human warmth give basic indications that the WARMOMETER seems to be a valid and sensitive patient self-report instrument for assessing the socio-emotional quality of physicians. PRACTICE IMPLICATIONS: These first promising results of our cognitive interviews suggest that the WARMOMETER may also be used and further validated in future health communication studies, also with other healthcare professionals. PMID- 21315538 TI - Lingering questions and doubts: online information-seeking of support forum members following their medical visits. AB - OBJECTIVE: To examine the prevalence and predictors of patients' post-appointment online health information-seeking and the reasons behind their information searches. METHODS: Survey of 274 Internet support community members who had been seen by a physician within 30 days. The questionnaire included measures of trust in the physician, health worries, changes in amount of worrying following the visit, online health information-seeking, and standard demographic and visit characteristics. RESULTS: A majority of respondents (68%) went online in search of information after their visits. In a logistic regression analysis, going online was associated with lower trust (P=.002), greater worrying (P=.049), and becoming more (P=.024) or less worried (P=.05) by the visit. Among those who went online, the most common reasons for doing so were sheer curiosity (71%) and disappointment with some aspect of the physician's behavior (32%). CONCLUSION: Patients in this online forum routinely turned to the Internet after their medical visits, but were especially likely to do so when trust in the physician was low, anxieties were high, and the visit altered (for better or worse) their anxiety levels. PRACTICE IMPLICATIONS: Since many patients seek online information after their appointments, physicians should suggest credible websites suited to the circumstances of each patient. PMID- 21315539 TI - The impact of pay-for-performance on therapists' intentions to deliver high quality treatment. AB - This article examined the extent to which assignment to a pay-for-performance (P4P) experimental condition impacted therapists' intentions to deliver high quality treatment and the extent to which therapists' intentions could be explained by the theory of planned behavior. Data were collected from 95 therapists who agreed to participate in a P4P experiment related to their implementation of an evidence-based treatment (EBT) for adolescents with substance use problems. Relative to those in the control condition, therapists in the P4P condition reported significantly greater intentions to achieve monthly competence (B = 1.41, p < .001) and deliver a targeted threshold level of treatment to clients (B = 1.31, p < .001). In addition, therapists' intentions could be partially explained by the theory of planned behavior. Meta-analyses have found intentions to be one of the best predictors of behavior; thus, these findings provide initial support for using P4P approaches as a method of increasing the quality of substance use treatment. PMID- 21315540 TI - The relative effectiveness of women-only and mixed-gender treatment for substance abusing women. AB - Following research indicating that the treatment needs of women are different from those of men, researchers and clinicians have argued that drug treatment programs for women should be designed to take their needs into account. Such programs tend to admit only women and incorporate philosophies and activities that are based on a social, peer-based model that is responsive to women's needs. To assess the relative effectiveness of women-only (WO) outpatient programs compared with mixed-gender (MG) outpatient programs, 291 study volunteers were recruited (152 WO, 139 MG), and a 1-year follow-up was completed with 259 women (135 WO, 124 MG). Using bivariate, logistic regression, and generalized estimating equation analysis, the following four outcomes were examined: drug and alcohol use, criminal activity, arrests, and employment. In both groups, women showed improvement in the four outcome measures. Comparison of the groups on outcomes yielded mixed results; women who participated in the WO treatment reported significantly less substance use and criminal activity than women in the MG treatment, but there were no differences in arrest or employment status at follow-up compared with those in the MG treatment. PMID- 21315541 TI - The impact of craving and impulsivity on aggression in detoxified cocaine dependent patients. AB - Patients with substance use disorders are frequently associated with impulsivity that may underlie elevated levels life-threatening types of behavior, including aggression. In addition, craving is a prominent feature of addiction and appears to be closely related to impulsivity. This study assessed the unique contribution of cocaine craving and impulsivity in predicting aggression by means of correlational and mediational analyses. Forty inpatient detoxified cocaine dependent patients and 40 matched healthy controls were enrolled. These participants filled out the Obsessive Compulsive Drug Use Scale, the Dickman Impulsivity Inventory, and the Aggression Questionnaire. The patient group showed elevated levels of impulsivity and aggression as compared with the control group. Although cocaine craving is positively correlated with both impulsivity and aggression, craving did not mediate the relationship between both constructs. It is concluded that craving does not have an impact on the relationship between impulsivity and trait aggression in this patient sample. PMID- 21315542 TI - A case of atherosclerotic inferior mesenteric artery aneurysm secondary to high flow state. AB - Inferior mesenteric artery aneurysms are very rare and they are among the rarest of visceral artery aneurysms. Sometimes, the distribution of the blood flow due to chronic atherosclerotic occlusion of some arteries can establish an increased flow into a particular supplying district (high flow state). A high flow state in a stenotic inferior mesenteric artery in compensation for a mesenteric occlusive disease can produce a rare form of aneurysm. We report the case of an atherosclerotic inferior mesenteric aneurysm secondary to high flow state (association with occlusion of the celiac trunk and severe stenosis of the superior mesenteric artery), treated by open surgical approach. PMID- 21315543 TI - Extrinsic compression of the external iliac artery following internal fixation of an acetabular fracture. AB - Vascular injuries following fixation of acetabular injuries are becoming increasingly recognized. Most case reports describe thrombosis or rupture of the adjacent artery. Repair of these injuries is most often described by open technique with endovascular repair rarely reported. Here, we present a case of injury to the external iliac artery caused by extrinsic compression from orthopedic hardware following acetabular fracture repair. Diagnosis of this injury was difficult with angiography, but on duplex ultrasonography, the injury was more clearly seen. The injury was treated with endovascular angioplasty and stenting, with restoration of normal arterial flow to the lower extremity. PMID- 21315544 TI - Evolution of operative strategies in open thoracoabdominal aneurysm repair. AB - OBJECTIVE: During a 24-year interval, we managed >90% of thoracoabdominal aortic aneurysm (TAA) repairs with a clamp-and-sew (clamp/sew) approach supplemented with protective adjuncts, including renal hypothermia and epidural cooling with aggressive intercostal reconstruction for spinal cord protection. A finite paraplegia rate led to operative modifications using distal aortic perfusion (DAP) through atriofemoral bypass to support cord collateral circulation and selective intercostal reconstruction based on motor evoked potential (MEP) monitoring. This study evaluated the effect of DAP/MEP on perioperative outcomes. METHODS: Consecutive patients undergoing repair of nonruptured Crawford extent I III TAA using DAP/MEP were compared with propensity-matched patients treated with the clamp/sew technique. Outcomes included 30-day mortality and paraplegia. RESULTS: There were 52 patients in the DAP cohort vs 127 undergoing clamp/sew. The DAP and clamp/sew cohorts differed in age (62.6 vs 69.5 years, P = .0003), presence of Marfan disease (10% vs 2%, P = .01), and chronic dissection (37% vs 8%, P = .001). Operative mortality was low (DAP, 2%; clamp/sew, 5%; P = .38). Postoperative renal insufficiency, although doubled in clamp/sew (17%) vs DAP (8%; P = .10), was not significant. DAP patients had a significantly lower incidence of intercostal reconstruction than the clamp/sew group (10% vs 34%, P < .0001), yet there was no paraplegia in the DAP cohort vs 5% in clamp/sew (P = .11). The composite death/paraplegia rate was decreased with DAP at 1 of 52 (2%) vs clamp/sew at 11 of 127 (9%; P = .01). Paraparesis with complete recovery occurred in 5 of 52 (10%) of the DAP group. CONCLUSIONS: Elective TAA repair was accomplished with a low mortality in the DAP and clamp/sew cohorts. The use of MEP in the DAP cohort (despite a higher spinal cord ischemic risk due to the number of chronic dissection patients) decreased the need for intercostal reconstruction, with no paraplegia to date. DAP with MEP is the preferred operative strategy for extent I to III TAA repair. PMID- 21315545 TI - Endovascular stent-graft placement and coil embolization for an anomalous splenic artery aneurysm. AB - Aneurysms of the splenic artery originating anomalously from the superior mesenteric artery are extremely rare; however, they are clinically important because of the potential for fatal rupture and particular anatomical location. Most previous cases were managed by open surgical intervention. We present a case of an anomalous splenic artery aneurysm, which was successfully treated with endovascular stent graft placement and coil embolization. This appears to be a promising minimally invasive approach to manage this rare entity. Also, we review the literature of aneurysms of the splenic artery arising from the superior mesenteric artery. PMID- 21315546 TI - Carotid endarterectomy for treatment of in-stent restenosis after carotid angioplasty and stenting. AB - OBJECTIVE: Carotid angioplasty and stenting (CAS) has emerged as an alternative for carotid endarterectomy (CEA) in the prevention of stroke. The benefit of the procedure, however, is hampered by a suggested higher incidence of in-stent restenosis (ISR) for CAS relative to CEA during follow-up. ISR management remains a challenge for clinicians. In this observational retrospective analysis, we evaluated the operative management of ISR by standard CEA with stent removal, including midterm follow-up in 15 patients. METHODS: The present analysis included 15 patients from three Dutch vascular centers who underwent CEA for symptomatic (n = 10) or hemodynamically significant (>=80%) asymptomatic ISR (n = 5). Median time between CAS and CEA was 18.3 months (range, 0-51 months). RESULTS: Standard CEA with stent removal was performed in all 15 patients. A Javid shunt was used in two procedures. One patient sustained an intraoperative minor ischemic stroke, with complete recovery during the first postoperative days. No neurologic complications occurred in the other 14 patients. Two patients required a reoperation to evacuate a neck hematoma. There were no peripheral nerve complications. After a median follow-up of 21 months (range, 3-100 months), all 15 patients remained asymptomatic and without recurrent restenosis (>=50%) on duplex ultrasound imaging. CONCLUSION: CEA with stent explantation for ISR after CAS seems an effective and durable therapeutic option, albeit with potential cerebral and bleeding complications, as in this study. The optimal treatment for carotid ISR, however, has yet to be defined. PMID- 21315547 TI - Carotid artery stenting by direct percutaneous puncture. AB - Carotid artery stenting is usually performed by a femoral approach. When the patient's anatomy forbids this or other distal access to the carotids, a direct access by percutaneous puncture may be used. We present two cases in which a successful stenting of the carotids with the use of a cerebral protection device was performed. PMID- 21315548 TI - Double-chimney technology for treating secondary type I endoleak after endovascular repair for complicated thoracic aortic dissection. AB - Endovascular repair continues to pose a formidable technical challenge in the cases of aneurysm, dissection, and proximal type I endoleak involving the aortic arch. During the process of covering the aortic arch by stent graft to achieve better sealing, maintaining blood flow to the vital supra-aortic branches is difficult. We present a case of successful endovascular treatment of secondary type I endoleak by a double-chimney technique in a 36-year-old woman who had previously undergone a complicated descending aortic dissection repair. This endovascular technology might offer a new option to simultaneously preserve the innominate artery and the left carotid artery for total reconstruction of the aortic arch. PMID- 21315549 TI - [Intrathoracic hernia of the liver: an unusual cause of extubation failure in a trauma patient]. PMID- 21315550 TI - The relations between social anxiety and social intelligence: a latent variable analysis. AB - Social anxiety has been associated with biases in cognitive processing and deficits in social performances. Yet, it remains unclear if these variations may be partly attributable to deficits in fundamental social abilities: for example, social intelligence (SI). Using the Magdeburg Test of Social Intelligence (MTSI) as an objective and performance based SI measure, we examined the relationship between social anxiety and SI in a general population sample (N=110) using Structural Equation Modeling. Dimensions of social anxiety as postulated by Clark and Wells (1995) and facets of SI (social understanding, social memory, and social perception), were negatively correlated. Use of safety-behavior in particular was related to deficits in social understanding (r=-0.25; p<0.05) and social perception and memory (r=-0.24; p<0.05). Results suggest small to medium sized relationships between specific facets of social anxiety and certain domains of SI. Therapeutic implications for socially anxious individuals concerning SI are discussed. PMID- 21315551 TI - The discovery of chlordiazepoxide and the clinical introduction of benzodiazepines: half a century of anxiolytic drugs. AB - The clinical introduction of chlordiazepoxide half a century ago was one of the major breakthroughs in the history of psychopharmacology, as it opened the door for the benzodiazepine saga, the pharmacological family par excellence in the treatment of anxiety disorders. This review analyses the discovery of this drug, which was filled with chance events, and numerous chemical and clinical errors of approach. Chlordiazepoxide, initially called methaminodiazepoxide, was patented in 1958 and introduced in clinical treatment in 1960 under the brand name Librium(r). The benzodiazepines became the most widely prescribed drugs worldwide, provided truly effective treatment for "minor forms" (neuroses) of mental disorders for the first time, increased the quality of scientific methodology in clinical research, and enabled the development of new etiopathogenic theories for anxiety disorders, especially after the discovery in 1977 of their high-affinity receptor complex. PMID- 21315552 TI - Fear factors: cross validation of specific phobia domains in a community-based sample of African American adults. AB - The current study attempted a cross-validation of specific phobia domains in a community-based sample of African American adults based on a previous model of phobia domains in a college student sample of African Americans. Subjects were 100 African American community-dwelling adults who completed the Fear Survey Schedule-Second Edition (FSS-II). Domains of fear were created using a similar procedure as the original, college sample of African American adults. A model including all of the phobia domains from the FSS-II was initially tested and resulted in poor model fit. Cross-validation was subsequently attempted through examining the original factor pattern of specific phobia domains from the college sample (Chapman, Kertz, Zurlage, & Woodruff-Borden, 2008). Data from the current, community based sample of African American adults provided poor fit to this model. The trimmed model for the current sample included the animal and social anxiety factors as in the original model. The natural environment-type specific phobia factor did not provide adequate fit for the community-based sample of African Americans. Results indicated that although different factor loading patterns of fear may exist among community-based African Americans as compared to African American college students, both animal and social fears are nearly identical in both groups, indicating a possible cultural homogeneity for phobias in African Americans. Potential explanations of these findings and future directions are discussed. PMID- 21315553 TI - Changes in kinetics and kinematics of handwriting during a prolonged writing task in children with and without dysgraphia. AB - Handwriting difficulties or dysgraphia have a profound impact on children's psychosocial development, and yet, 10-30% of school-aged children are reported to experience difficulties mastering this skill. Several studies have examined the nature and biomechanical underpinnings of handwriting difficulties in children with and without dysgraphia. While the majority of these studies have considered short handwriting activities involving a sentence or a paragraph, handwriting quality and speed are reported to vary with the length of the writing task. Further, it is suggested that the biomechanics of handwriting also evolve over extended writing periods, and that these changes may be distinct between children with and without dysgraphia. The nature and specificity of these biomechanical alterations remain unknown. To address this knowledge gap, we examined changes in writing speed, grip forces on the pen barrel, and normal forces on the writing surface, over the course of a 10-min writing task, in a large cohort of 4th grade children with and without dysgraphia. Horizontal stroke speed, grip force and normal force increased over time while vertical stroke speed decreased in all children. These biomechanical changes may be attributable to physical and psychological fatigue and the corresponding compensatory processes invoked by the motor system. PMID- 21315554 TI - A generalized diffusion frame for parsimonious representation of functions on data defined manifolds. AB - One of the now standard techniques in semi-supervised learning is to think of a high dimensional data as a subset of a low dimensional manifold embedded in a high dimensional ambient space, and to use projections of the data on eigenspaces of a diffusion map. This paper is motivated by a recent work of Coifman and Maggioni on diffusion wavelets to accomplish such projections approximately using iterates of the heat kernel. In greater generality, we consider a quasi-metric measure space X (in place of the manifold), and a very general operator T defined on the class of integrable functions on X (in place of the diffusion map). We develop a representation of functions on X in terms of linear combinations of iterates of T. Our construction obviates the need to compute the eigenvalues and eigenfunctions of the operator. In addition, the local smoothness of a function f is characterized by the local norm behavior of the terms in our representation of f. This property is similar to that of the classical wavelet representations. Although the operator T utilizes the values of the target function on the entire space, this ability results in automatic "feature detection", leading to a parsimonious representation of the target function. In the case when X is a smooth compact manifold (without boundary), our theory allows T to be any operator that commutes with the heat operator, subject to certain conditions on its eigenvalues. In particular, T can be chosen to be the heat operator itself, or a Green's operator corresponding to a suitable pseudo-differential operator. PMID- 21315555 TI - A modeling study suggesting how a reduction in the context-dependent input on CA1 pyramidal neurons could generate schizophrenic behavior. AB - The neural mechanisms underlying schizophrenic behavior are unknown and very difficult to investigate experimentally, although a few experimental and modeling studies suggested possible causes for some of the typical psychotic symptoms related to this disease. The brain region most involved in these processes seems to be the hippocampus, because of its critical role in establishing memories for objects or events in the context in which they occur. In particular, a hypofunction of the N-methyl-D-aspartate (NMDA) component of the synaptic input on the distal dendrites of CA1 pyramidal neurons has been suggested to play an important role for the emergence of schizophrenic behavior. Modeling studies have investigated this issue at the network and cellular level. Here, starting from the experimentally supported assumption that hippocampal neurons are very specific, sparse, and invariant in their firing, we explore an experimentally testable prediction at the single neuron level. The model shows how and to what extent a pathological hypofunction of a context-dependent distal input on a CA1 neuron can generate hallucinations by altering the normal recall of objects on which the neuron has been previously tuned. The results suggest that a change in the context during the recall phase may cause an occasional but very significant change in the set of active dendrites used for feature recognition, leading to a distorted perception of objects. PMID- 21315556 TI - Utility of Doppler myocardial imaging, cardiac biomarkers, and clonal immunoglobulin genes to assess left ventricular performance and stratify risk following peripheral blood stem cell transplantation in patients with systemic light chain amyloidosis (Al). AB - BACKGROUND: Cardiac dysfunction is a well-recognized complication of light chain amyloidosis (AL). Autologous stem cell transplant (auto-SCT) has emerged as a successful treatment modality for AL patients. In this study, we examined the effect of clonal immunoglobulin light chain genes (VL), which encodes the immunoglobulin light chain protein that ultimately forms amyloid, on cardiac function, in the context of auto-SCT and its impact on overall survival. METHODS: Longitudinal Doppler myocardial imaging parameters along with cardiac biomarkers were used to assess for cardiac function pre and post auto-SCT. RESULTS: VL gene analysis revealed that Vl genes, in particular VlVI, were associated with worse cardiac function parameters than Vk genes. Clonal VL genes appeared to have an impact on left ventricular (LV) function post-transplant and also influenced mortality, with specific VL gene families associated with lower survival. Another key predictor of mortality in this report was change in tricuspid regurgitant flow velocity following auto-SCT. Correlations were also observed between systolic strain rate, systolic strain and VL genes associated with amyloid formation. CONCLUSIONS: Clonal VL gene usage influences global cardiac function in AL, with patients having VlVI and VlII-III-associated amyloid more severely affected than those having Vk or VlI amyloid. Pulsed wave tissue Doppler imaging along with immunoglobulin gene analysis offers novel insights into prediction of mortality and cardiac dysfunction in AL after auto-SCT. PMID- 21315557 TI - Validation of noninvasive measurements of cardiac output in mice using echocardiography. AB - BACKGROUND: Although multiple echocardiographic methods exist to calculate cardiac output (CO), they have not been validated in mice using a reference method. METHODS: Echocardiographic and flow probe measurements of CO were obtained in mice before and after albumin infusion and inferior vena cava occlusions. Echocardiography was also performed before and after endotoxin injection. Cardiac output was calculated using left ventricular volumes obtained from an M-mode or a two-dimensional view, left ventricular stroke volume calculated using the pulmonary flow, or estimated by the measurement of pulmonary velocity time integral (VTI). RESULTS: Close correlations were demonstrated between flow probe-measured CO and all echocardiographic measurements of CO. All echocardiographic-derived CO overestimated the flow probe-measured CO. Two dimensional image-derived CO was associated with the smallest overestimation of CO. Interobserver variability was lowest for pulmonary VTI-derived CO. CONCLUSION: In mice, CO calculated from two-dimensional parasternal long-axis images is most accurate when compared with flow probe measurements; however, pulmonary VTI-derived CO is subject to less variability. PMID- 21315558 TI - Do epileptic seizures predict outcome in patients with oligodendroglioma? AB - BACKGROUND: Many patients with an oligodendroglioma (OD) experience seizures, some of which become refractory to anti-epileptic drugs (AEDs). This study aims (1) to quantify the rate of seizures and medically refractory epilepsy in patients with ODs; and (2) to determine if there is any association between short term and long-term survival, and the presence and drug-responsiveness of seizures. METHODS: A retrospective review was conducted of the medical records of patients who had been pathologically identified as having an OD at the London Health Sciences Centre or the London Regional Cancer Program in London, Ontario from January 1996 to July 2008. Deaths were ascertained by reviewing all hospital records. Survival analysis was performed. RESULTS: One-hundred sixty-six patients met inclusion criteria. Epileptic seizures were the presenting feature or occurred as part of the initial manifestation of the OD in 75.3% of patients, with 90.4% (n=150) experiencing at least one seizure and 76.5% developing epilepsy over the course of observation. Of the 150 patients with seizures, 23 experienced a single seizure (13.9% of the 166), whereas 127 patients experienced multiple seizures (76.5%). In those with multiple seizures, the epilepsy was refractory to drug treatment slightly more than half the time (54.3%). Survival analysis demonstrated consistently superior survival among those with a single seizure. Those without seizures had the worst survival rates over the first few years post-diagnosis; but then no further deaths occurred. Survival among those with refractory seizures tended to be better than among those whose seizures were drug responsive, over the first 10 years post-diagnosis. CONCLUSIONS: Seizures are common and may influence survival in patients with oligodendogliomas. Those who experience just one seizure appear to do best. PMID- 21315559 TI - Persistence and outcome of auditory hallucinations in adolescence: a longitudinal general population study of 1800 individuals. AB - BACKGROUND: Auditory hallucinations are common in adolescents. However, it has been suggested that not the presence of low-grade psychotic experiences per se, but rather the level of persistence and associated clinical complications over time may lead to psychotic illness. The current paper investigated, in a large representative sample of adolescents, to what degree hallucinations persist, and whether persistence of hallucinations increases the risk of developing secondary delusional ideation and affective dysregulation. METHODS: Data were derived from a general health screening of all 1912 adolescents living in the Maastricht area. Baseline assessment was in the second grade of secondary school (T0) and follow up occurred 2 years later (T1). Questions included the psychosis screening questions (Poulton et al., 2000), the SDQ assessing general psychopathology and a question assessing depression. RESULTS: Five percent of adolescents reported hallucinations at T0 and 27% of these hallucinations were still present 2 years later. Hallucinations at T0 were associated with increased levels of depressed mood and general psychopathology at T1, and the degree of persistence of hallucinations was associated with a progressively greater risk for T1 delusional ideation as well as increased levels of follow-up depressed mood and general psychopathology. CONCLUSION: Although hallucinations in adolescents are a common and mainly transitory phenomenon, the persistence rate over time is far from negligible, and associated with clinical deterioration. PMID- 21315560 TI - Insight into illness in patients and caregivers during early psychosis: a pilot study. AB - BACKGROUND: Impaired insight into illness is common during early psychosis and has been associated with treatment delays and poorer long-term outcomes. The relationship between patients' insight into illness and their caregivers' knowledge about psychosis is putatively associated with treatment outcome but there is limited research about this. This pilot study was designed to test the hypothesis that caregivers' levels of insight into illness is associated with patients' insight into illness in early psychosis and would be related to caregivers' levels of critical, rejecting attitudes toward patients. METHODS: Patients with schizophrenia or schizoaffective disorder within 5 years of psychosis onset (n=14) and caregivers (n=14) of the patients' choosing were studied. Insight into illness was assessed in patients using the Scale to assess Unawareness of Mental Disorder (SUMD). Caregiver insight into illness was assessed with a modified version of the SUMD with questions rephrased to probe caregivers' understanding of the patients' illness. Caregivers' critical attitudes toward patients were assessed with the Patient Rejection Scale (PRS). RESULTS: Significant correlations were found between patients' and caregivers' awareness of need for treatment (r=.55, p=.02), awareness of symptoms (r=.48, p=.04) and between caregivers' awareness of illness and critical attitudes toward patients (r=.65, p=.01). CONCLUSIONS: These findings suggest that caregivers' emotional characteristics and levels of insight into illness may be related to insight into illness in patients. Implications for family psychoeducational approaches to impairments of insight into illness during early psychosis are discussed. PMID- 21315561 TI - ERK activation in the amygdala and hippocampus induced by fear conditioning in ethanol withdrawn rats: modulation by MK-801. AB - The extracellular signal-regulated kinase (ERK) pathway, which can be activated by NMDA receptor stimulation, is involved in fear conditioning and drug addiction. We have previously shown that withdrawal from chronic ethanol administration facilitated the formation of contextual fear memory. In order to explore the neural substrates and the potential mechanism involved in this effect, we examined: 1) the ERK1/2 activation in the central (CeA) and basolateral (BLA) nuclei of the amygdala and in the dorsal hippocampus (dHip), 2) the effect of the NMDA receptor antagonist MK-801 on fear conditioning and ERK activation and 3) the effect of the infusion of U0126, a MEK inhibitor, into the BLA on fear memory formation in ethanol withdrawn rats. Rats made dependent via an ethanol-containing liquid diet were subjected to contextual fear conditioning on day 3 of ethanol withdrawal. High basal levels of p-ERK were found in CeA and dHip from ethanol withdrawn rats. ERK activation was significantly increased both in control (60min) and ethanol withdrawn rats (30 and 60min) in BLA after fear conditioning. Pre-training administration of MK-801, at a dose that had no effect on control rats, prevented the increase in ERK phosphorylation in BLA and attenuated the freezing response 24h later in ethanol withdrawn rats. Furthermore, the infusion of U0126 into the BLA, but not the CeA, before fear conditioning disrupted fear memory formation. These results suggest that the increased fear memory can be linked to changes in ERK phosphorylation, probably due to NMDA receptor activation in BLA in ethanol withdrawn rats. PMID- 21315562 TI - Defensive self-presentation style is associated with reduced prepulse inhibition. AB - Prepulse inhibition (PPI) of the startle response is a cross-species measure of sensorimotor gating that provides a valuable tool for assessing the capacity to effectively screen out irrelevant sensory input. Accumulating evidence suggests that PPI deficits may correlate with impairments in social cognition, i.e. the ability to construct representation about others, oneself and the relations between others and oneself. Social cognition deficits are commonly encountered within the framework of psychiatric disorders. In this study 113 healthy volunteers completed psychopyhsiological measures of sensorimotor gating (PPI) and social self-presentation style (the Concern for Appropriate (CAS) and the Revised Self-Monitoring (RSMS) scales). CAS measures a defensive and fearful social approach aiming at avoiding social threats; RSMS measures an active and flexible social approach aiming at gaining power and status. Analyses revealed an inverse correlation between PPI at the 120 ms prepulse-to-pulse interval and total CAS scores (r=-0.19, p=0.04), as well as with the Attention to Social Comparison Information (ASCI) subscale of the CAS (r=-0.23, p=0.01). These findings suggest that reduced PPI may contribute to the tendency to adopt a defensive and fearful "getting along" social approach. This study is, to our knowledge, the first to assess the relationship between sensorimotor gating and self-presentational style in humans. Its findings suggest that very basic perceptual deficits that can be assessed using the PPI paradigm, may reflect information processing abnormalities that impact negatively upon the perception of complex social interactions. PMID- 21315563 TI - Cyclodextrin-mediated entrapment of curcuminoid 4-[3,5-bis(2-chlorobenzylidene-4 oxo-piperidine-1-yl)-4-oxo-2-butenoic acid] or CLEFMA in liposomes for treatment of xenograft lung tumor in rats. AB - We recently reported a novel curcuminoid 4-[3,5-bis(2-chlorobenzylidene-4-oxo piperidine-1-yl)-4-oxo-2-butenoic acid] or CLEFMA as a potent anti-proliferative agent, and showed that it induces autophagic cell death in lung cancer cells. We are now reporting a drug-in-CD-in-liposome approach to formulate CLEFMA liposomes that could be labeled with Tc-99m radionuclide for non-invasive imaging of their biodistribution. CLEFMA encapsulation was enabled by hydroxypropyl-beta cyclodextrin. In vitro studies showed that CLEFMA possessed more potent anti proliferative activity in lung adenocarcinoma H441 cells than naturally occurring curcumin. At the same time, it had no effect on the proliferative capacity of normal lung fibroblasts. CLEFMA liposomes retained the antiproliferative potency of free CLEFMA, while maintaining its non-toxic nature in normal lung fibroblasts. In nude rats bearing xenograft H441 tumors, the tumor volume significantly reduced after i.v. treatment with CLEFMA liposomes (p<0.05); the tumor inhibition was determined to be 94%. The anti-tumor activity of CLEFMA liposomes was confirmed by the observation that F-18-fluorodeoxyglucose uptake in tumors of treated rats was reduced as compared to those of control rats. Tc-99m labeled CLEFMA liposomes accumulated in liver (33.7%); spleen showed the largest accumulation on per gram tissue basis (6.2%/g). Upon histopathological examination of liver, lung and kidney, we found no apparent toxicity from multiple CLEFMA liposome administrations. The results demonstrate the utility of liposomes to serve as a carrier for CLEFMA. This study is the first to demonstrate the efficacy of novel curcuminoid CLEFMA in a preclinical model. PMID- 21315564 TI - Successful preferential formation of a novel macromolecular assembly--trilayered polymeric micelle--that can incorporate hydrophilic compounds: the optimization of factors affecting the micelle formation from amphiphilic block copolymers. AB - We have developed a novel macromolecular assembly, trilayered polymeric micelle, which can incorporate hydrophilic compounds. The micelle can be prepared from the amphiphilic block copolymers without regard to their properties such as the copolymer's charges and the homogeneity of the copolymers forming the micelle's inner and outer parts. In this study, we investigated the optimal condition for the preferential formation of the trilayered polymeric micelle. GPC results clarified that the composition of the block copolymer, the concentration of PVA in the aqueous bulk phase, and the temperature during the preparation were the important preparation factors affecting preferential formation of the trilayered polymeric micelles. We successfully achieved the preferential formation of the trilayered polymeric micelles under optimal conditions. Furthermore, we confirmed that the model hydrophilic compound, FITC-dextran, was successfully encapsulated into the hydrophilic core of the trilayered polymeric micelles. The novel micelle that can incorporate hydrophilic compounds can have a variety of future medical applications such as a protein delivery-based therapy. PMID- 21315565 TI - Coronary disease risk prediction algorithm warranting incorporation of C-reactive protein in Turkish adults, manifesting sex difference. AB - BACKGROUND AND AIM: An algorithm is needed for predicting coronary heart disease (CHD) risk in Turkish adults who have a high prevalence of metabolic syndrome (MetS). METHODS AND RESULTS: Ten-year risk of CHD was estimated in 2232 middle aged adults free of CHD at baseline, followed over 7.6-years. Cox proportional hazard regression was used to predict CHD. Discrimination was assessed with area under receiver operating characteristics curve (AROC). CHD developed in 302 subjects. In multivariable analysis, high-density lipoprotein (HDL)-cholesterol levels were borderline predictive in men; smoking status and HDL-and low-density lipoprotein (LDL)-cholesterol levels were not predictive in women. Age, presence of diabetes, systolic blood pressure and C-reactive protein (CRP) were predictors in both sexes, while smoking status and LDL-cholesterol were so in men only. AROC of the model was 0.789 in men, and 0.806 in women (p < 0.001 each). An algorithm using the stated seven variables was derived separately for each sex. After age adjustment, men and women in the highest quintile of risk score were significantly and 20-27-fold more likely to develop CHD than those in the lowest quintile. CONCLUSIONS: In a population with prevalent MetS, low-grade inflammation is independently relevant for CHD, as are serum lipoproteins and smoking status. The derived algorithm is effective in estimating CHD risk among Turkish adults. PMID- 21315566 TI - Type 2 diabetes and polymorphisms on chromosome 9p21: a meta-analysis. AB - BACKGROUND AND AIMS: Genome-wide association studies found some variants on chromosome 9p21 associated with type 2 diabetes (T2D). We performed a meta analysis to estimate strength, accuracy and feature of the association of polymorphisms in 9p21 with T2D. METHODS AND RESULTS: Articles were retrieved screening electronic databases and cross references. Twenty-two publications were identified, for a total of 38,455 T2D patients and 60,516 controls. Twenty-one studies investigated the role of the SNP rs10811661; in some studies three additional SNPs (rs564398, rs10757278, rs1333040) were genotyped. Population attributable risk (PAR) was computed as: risk allele frequency*(OR-1)/OR, using the per-allele odds ratio (OR). The risk allele (T) of rs10811661 was associated with T2D in most of the studies. In meta-analysis the overall per-allele OR was 1.24 (95% CI: 1.21-1.27; P < 10(-15)), with no difference according to ethnicity (P = 0.45), and low heterogeneity (P = 0.040) across studies partly explained by sample size. Modeling of inheritance suggested an additive effect of the T allele. PAR of T2D related to this polymorphism was 15% for Caucasians and 13% for Asians. The overall odds ratio for the T allele of the SNP rs564398 was 1.08 (95% CI: 1.05-1.12; PAR = 6%). The other SNPs showed negligible associations. CONCLUSIONS: This meta-analysis provides accurate and comprehensive estimates of the association of some genetic variants at chromosome 9p21 and T2D. A relatively small but significant role of the T allele of the rs10811661 SNP in increasing by 21-27% the risk of T2D in an additive way was apparent. PMID- 21315567 TI - Protective effect of Sonchus asper extracts against experimentally induced lung injuries in rats: a novel study. AB - In this study, protective effects of methanol extract (SAME) were evaluated against carbon tetrachloride induced oxidative stress in lungs. Male Sprague Dawley rats were orally fed with various doses (100, 200 mg/kg body weight) of SAME and (50 mg/kg body weight) of rutin after 48 h of CCl(4) treatment (3 ml/kg body weight, 30% in olive oil) biweekly for 4 weeks. The results showed that administration of extracts and rutin significantly restored lung contents of reduced glutathione and activities of catalase, peroxidase, superoxide dismutase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase, quinine reductase were reduced while lipid peroxide, hydrogen peroxide, nitrite, DNA fragmentation% and activity of gamma-glutamyl transferase, increased by CCl(4), were reversed towards the control levels by the supplement of Sonchus asper extracts and rutin. Lung histopathology showed that S. asper extracts and rutin reduced the incidence of lung lesions induced by CCl(4) in rats. These results suggest that S. asper fractions and rutin could protect lung against the CCl(4) induced oxidative damage in rats. PMID- 21315568 TI - Vincamine-producing endophytic fungus isolated from Vinca minor. AB - Vinca minor is a plant containing the alkaloid vincamine, which is used in the pharmaceutical industry as a cerebral stimulant and vasodilator. The objective of this study was to determine whether endophytic fungi isolated from V. minor produce vincamine. Primary screening was carried out using Dragendorff's and Mayer's reactions, and strain re-selection was made by thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) to identify the fermentation products of the selected strain. We isolated 10 endophytic fungal strains from V. minor. An extract from one (Vm-J2), showed positive reactions with both Dragendorff's and Mayer's reagents. The strain had a component with the same TLC R(f) value and HPLC retention time as authentic vincamine. Therefore, the fungus appeared to produce the same bioactive ingredient, vincamine, as the host plant. The prospect of using endophytic fungi to produce the phytoactive compound by fungal fermentation is discussed. PMID- 21315569 TI - Antiobesity and lipid lowering effects of Glycyrrhiza chalcones: experimental and computational studies. AB - Twelve flavonoids (1-12), isolated from Glycyrrhiza glabra roots were evaluated for their pancreatic lipase (PL) inhibitory activity in vitro. The structures of the isolated compounds were elucidated by spectroscopic methods. Amongst all the compounds 7, 8, 10 and 11 showed strong inhibition against PL with IC(50) values of 7.3 MUM, 35.5 MUM, 14.9 MUM and 37.6 MUM, respectively. Molecular docking studies on the most active compound 7 revealed that it binds with the key amino acid residues of the PL active site. In silico absorption, distribution, metabolism and excretion (ADME) parameters were also computed on the active compounds to determine their preliminary pharmacokinetic properties. Further, investigations were carried out to determine the antiobesity and lipid lowering effects of 7 and 10 in high fat diet (HFD) fed male SD rats. In the rats supplemented with compound 7 the body weight increase was only 23.2+/-3.6 g as compared to 64.2+/-0.5 g in the HFD control group while in the rats treated with compound 10 showed 23.2+/-3.6 g weight gain only. Compound 7 decreased the levels of plasma total cholesterol (TC) to 84.6+/-1.4 mg/dl and plasma total triglycerides (TG) to 128.8+/-6.0 mg/dl. Compound 10 also lowered the plasma TC and TG levels considerably. The results indicate the potential of the chalcone scaffold as a source of PL inhibitors for preventing obesity. PMID- 21315570 TI - The aqueous extract, not organic extracts, of Terminalia arjuna bark exerts cardiotonic effect on adult ventricular myocytes. AB - The bark of Terminalia arjuna (TA) has been used for centuries in ayurvedic medicine as cardiotonics for treatment of cardiac disorders. It became recently available as over-the-counter supplements marketed for maintaining a healthy heart. However, the cellular mechanism of its cardiotonic effect remains undefined. The present study was designed to investigate the physicochemical property and inotropic effect of the aqueous extract of TA bark (TA(AqE)) on adult rat ventricular myocytes in comparison with extracts prepared sequentially with organic solvents (organic extracts). The kinetics of myocyte contraction and caffeine-induced contraction were analyzed to assess the effect of TA(AqE) on sarcoplasmic reticular (SR) function. The inotropic effect of TA(AqE) was also compared with that of known cardiotonics, isoproterenol (ISO) and ouabain (Ouab). We found that TA(AqE) decoctions exerted positive inotropy, accelerated myocyte relaxation and increased caffeine-induced contraction concentration-dependently. In contrast, TA organic extracts caused interruption of excitability and arrhythmias without consistent inotropic action. In conclusion, TA(AqE)-induced cardiotonic action via enhancing SR function, a unique action minimizing the occurrence of arrhythmias, makes TA(AqE) a promising and relatively safe cardiotonic beneficial to the healthy heart and the treatment for chronic heart disease. The cardiotonic effect of TA(AqE) is consistent with the therapeutic property of TA bark used in ayurvedic medicine. The method of administration and/or selective omission of hydrophobic components from bark powder could be crucial to the efficacy and safety of TA bark in cardiac therapy and uses as over the-counter supplements. PMID- 21315571 TI - Diallyl trisulfide (DATS) inhibits mouse colon tumor in mouse CT-26 cells allograft model in vivo. AB - Our earlier studies showed that DATS induced apoptosis in human colon cancer HT29 and colo 205 cell lines in vitro. However, there is no report to show that DATS induced apoptosis in vitro and inhibited CT26 cancer cells in vivo on a murine allograft animal model. In vitro studies, the results indicated that DATS induced morphological changes and induction of apoptosis in CT26 cells. In vivo studies, CT26 cancer cells were implanted into BALB/c mice and groups of mice were treated with vehicle, DATS (10 and 50 mg/kg of body weight). DATS were injected once per four days intraperitoneally (i.p.), with treatment starting 4 weeks prior to cells inoculation. Treatment with vehicle or with 10 and 50 mg/kg of DATS resulted in a reduction in tumor volume and weight. Tumor volume and total hemoglobin in allograft mice treated with 50 mg/kg DATS were significantly smaller than that in the control group. These findings indicated that DATS inhibits tumor growth in an allograft animal model. Thus, DATS may represent a colon cancer preventive agent and can be used in the future. PMID- 21315572 TI - Analgesic effect and mechanism of the three TCM-herbal drug-combination Tou Feng Yu pill on treatment of migraine. AB - It is well known that pain is one of the most important characteristics of migraine. Therefore, it is important and interesting to investigate the analgesic effect and mechanism of drugs which are used to treat migraine. Tou Feng Yu pill (TFY) is a traditional Chinese herbal medicine, consisting of the three Chinese herbal drugs Radix Angelicae dahuricae (Baizhi), Rhizome Ligustici (Chuanxiong) and Folium Camelliae sinensis (green tea) for the treatment of migraine. In this study, we found that TFY could significantly reduce the writhing times induced by acetic acid and licking foot response induced by formalin, and extend the writhing latent period. But the analgesic effect was not observed at hot-plate test. Meanwhile, experimental migrainous model induced by nitroglycerin was used to investigate the therapeutic effect of TFY. Compared with the control group, the levels of plasma calcitonin gene related to peptide (CGRP), serum nitric oxide (NO) and contents of brain dopamine (DA) in TFY administration groups were significantly decreased, and the levels of plasma endothelin (ET) and contents of brain 5-hydroxytryptamine (5-HT) and norepinephrine (NE) were remarkably increased, also the ratio of ET/NO was clearly corrected. Furthermore, the improving effect of behavior abnormality was observed in TFY administration rats. Meanwhile, isolated vascular ring test indicated that TFY had an significant effect on vasomotion, and antagonize vasospasm; moreover TFY also could increase cerebral blood flow (CBF) and reduce cerebrovascular resistance index (RI) in normal rabbits, which verified the effect of TFY on vasomotion and abnormal hemorheology. All the results indicate that TFY has an effective therapeutical action on migraine, which may be related to three aspects as following: firstly, adjusting the level of neurotransmitters, neuropeptides and vasoactive substances, relieving neurogenic inflammation; secondly, improving vasomotion, increase cerebral blood flow, then improving hemorheology; finally, increasing pain threshold, relieving or preventing headache. These findings provide additional pharmacological information and may contribute for the further study and use of TFY as a phytomedicine. PMID- 21315573 TI - Papermill industrial waste as a sustainable source for high efficiency absorbent production. AB - Papermill sludge (PMS) is generated during the wastewater treatment process of paper production. Its handling and disposal techniques are of great concern for the environment. It can be landfilled as a waste, or it can be recycled and converted into useful products of high value. It has a very promising application as an absorbing agent for the cleaning of water surfaces polluted with hydrophobic substances (vegetable, synthetic and mineral oils, animal fats, fuels, organic chemicals and even coal dust). Here, we present the pretreatment procedure (hydrophobation, mechanical and thermal treatments) of PMS that produces a lightweight absorbent material (HAWSC - high efficiency absorbent for water surface cleaning), which floats on the water surface and binds hydrophobic pollutants with considerably higher efficiency than commercially available mineral and synthetic absorbents. After its application, it can be incinerated, due to its high caloric value, to produce energy. The incineration residues can then be formed into granules that can be used as an efficient absorbent for fluids spilled onto solid surfaces. PMID- 21315574 TI - DNA probe functionalized QCM biosensor based on gold nanoparticle amplification for Bacillus anthracis detection. AB - The rapid detection of Bacillus anthracis, the causative agent of anthrax disease, has gained much attention since the anthrax spore bioterrorism attacks in the United States in 2001. In this work, a DNA probe functionalized quartz crystal microbalance (QCM) biosensor was developed to detect B. anthracis based on the recognition of its specific DNA sequences, i.e., the 168 bp fragment of the Ba813 gene in chromosomes and the 340 bp fragment of the pag gene in plasmid pXO1. A thiol DNA probe was immobilized onto the QCM gold surface through self assembly via Au-S bond formation to hybridize with the target ss-DNA sequence obtained by asymmetric PCR. Hybridization between the target DNA and the DNA probe resulted in an increase in mass and a decrease in the resonance frequency of the QCM biosensor. Moreover, to amplify the signal, a thiol-DNA fragment complementary to the other end of the target DNA was functionalized with gold nanoparticles. The results indicate that the DNA probe functionalized QCM biosensor could specifically recognize the target DNA fragment of B. anthracis from that of its closest species, such as Bacillus thuringiensis, and that the limit of detection (LOD) reached 3.5 * 10(2)CFU/ml of B. anthracis vegetative cells just after asymmetric PCR amplification, but without culture enrichment. The DNA probe functionalized QCM biosensor demonstrated stable, pollution-free, real-time sensing, and could find application in the rapid detection of B. anthracis. PMID- 21315575 TI - Heart valve tissue engineering: quo vadis? AB - Surgical replacement of diseased heart valves by mechanical and tissue valve substitutes is now commonplace and generally enhances survival and quality of life. However, a fundamental problem inherent to the use of existing mechanical and biological prostheses in the pediatric population is their failure to grow, repair, and remodel. A tissue engineered heart valve could, in principle, accommodate these requirements, especially somatic growth. This review provides a brief overview of the field of heart valve tissue engineering, with emphasis on recent studies and evolving concepts, especially those that establish design criteria and key hurdles that must be surmounted before clinical implementation. PMID- 21315576 TI - Anaesthesia for caesarean section in a patient with Sturge-Weber syndrome following acute neurological deterioration. AB - Sturge-Weber syndrome consists of facial capillary malformation (port-wine stain) and abnormal blood vessels in the brain or eye. Seizures, developmental delay and intracranial and airway angiomata are principal concerns. We report a 28-year-old primiparous woman at 41 weeks of gestation with Sturge-Weber syndrome who developed unilateral weakness, aphasia, blurred vision and confusion. Preeclampsia was excluded. Neuroimaging showed left sided cerebral oedema and a right parieto-occipital lesion, most likely an angioma. Caesarean section was planned to avoid the risk of angioma rupture during labour. General anesthesia was avoided due to the haemodynamic response to laryngoscopy and reports of seizure-related mortality. Despite the possibility of raised intracranial pressure and precipitation of cerebral herniation, a lumbar epidural block was administered but failed. A subarachnoid block was successfully performed and a healthy infant delivered. The choice of anaesthesia was strongly influenced by detailed radiological investigations and multidisciplinary participation. PMID- 21315577 TI - Topical vasoconstrictor use for nasal intubation during pregnancy complicated by cardiomyopathy and preeclampsia. AB - Ankylosing spondylitis presents challenges for the obstetric anesthesiologist in administering neuraxial anesthesia or managing the airway. A pregnant patient with ankylosing spondylitis, cardiomyopathy and preeclampsia requiring cesarean delivery was managed with an awake nasotracheal fiberoptic intubation. The use of topical cocaine, epinephrine, phenylephrine, and oxymetazoline to produce nasal vasoconstriction is discussed. Selective alpha-2 agonists that can potentially provide nasal mucosa vasoconstriction and placental vasculature vasodilation are also discussed. PMID- 21315578 TI - Transthoracic echocardiography in obstetric anaesthesia and obstetric critical illness. AB - Transthoracic echocardiography (TTE) is a powerful non-invasive diagnostic, monitoring and measurement device in medicine. In addition to cardiologists, many other specialised groups, including emergency and critical care physicians and cardiac anaesthetists, have recognised its ability to provide high quality information and utilise TTE in the care of their patients. In obstetric anaesthesia and management of obstetric critical illness, the favourable characteristics of pregnant women facilitate TTE examination. These include anterior and left lateral displacement of the heart, frequent employment of the left lateral tilted position to avoid aortocaval compression, spontaneous ventilation and wide acceptance of ultrasound technology by women. Of relevance to obstetric anaesthetists is that maternal morbidity and mortality due to cardiovascular disease is significant worldwide. This makes TTE an appropriate, important and applicable device in pregnant women. Clinician-performed TTE enables differentiation between the life-threatening causes of hypotension. In the critically ill woman this improves diagnostic accuracy and allows treatment interventions to be instituted and monitored at the point of patient care. This article outlines the application of TTE in the specialty of obstetric anaesthesia and in the management of obstetric critical illness. It describes the importance of TTE education, quality assurance and outcome recording. It also discusses how barriers to the routine implementation of TTE in obstetric anaesthesia and management of obstetric critical illness can be overcome. PMID- 21315579 TI - Interscapular pain during cesarean delivery under epidural anesthesia. PMID- 21315580 TI - Acute starvation in pregnancy: a cause of severe metabolic acidosis. AB - We report a case of starvation-induced metabolic ketoacidosis in a previously healthy 29-year-old, nulliparous woman at 32 weeks of gestation. She was admitted to hospital with mild preeclampsia associated with persistent nausea and vomiting that progressed to severe preeclampsia requiring urgent control of hypertension before caesarean delivery. Prolonged and severe vomiting limited oral caloric intake and led to starvation ketoacidosis, characterised by ketonuria and a raised anion gap metabolic acidosis that required intensive care support. Despite significant metabolic derangement the patient appeared clinically well. Intravascular volume was replenished. Fluid restriction used as part of our preeclampsia treatment regimen delayed the therapeutic administration of sufficient dextrose, which rapidly corrected her metabolic derangement when commenced after delivery. Electrolyte supplementation was given to prevent re feeding syndrome. Both mother and baby were discharged without sequelae. PMID- 21315581 TI - The protein shells of bacterial microcompartment organelles. AB - Details are emerging on the structure and function of a remarkable class of capsid-like protein assemblies that serve as simple metabolic organelles in many bacteria. These bacterial microcompartments consist of a few thousand shell proteins, which encapsulate two or more sequentially acting enzymes in order to enhance or sequester certain metabolic pathways, particularly those involving toxic or volatile intermediates. Genomic data indicate that bacterial microcompartment shell proteins are present in a wide range of bacterial species, where they encapsulate varied reactions. Crystal structures of numerous shell proteins from distinct types of microcompartments have provided keys for understanding how the shells are assembled and how they conduct molecular transport into and out of microcompartments. The structural data emphasize a high level of mechanistic sophistication in the protein shell, and point the way for further studies on this fascinating but poorly appreciated class of subcellular structures. PMID- 21315582 TI - Odours and volatile organic compounds emitted from municipal solid waste at different stage of decomposition and relationship with biological stability. AB - Odours (OU(E)) and volatile organic compounds (VOC) emission during biological process used to treat MSW were studied under standardized conditions in order to detect potential risk for workers and population. Results obtained indicated that odours and VOCs emitted depend on the biological stability of waste measured by the dynamic respiration index (DRI) and a very good correlation were found between these parameters (OU(E) vs. DRI, r=0.96, p<0.001, n=6; VOC vs. DRI, r=0.97, p<0.001, n=6). GC-MS study of the VOCs indicated the presence of a group of molecules that were degraded during the process. On the other hand, a second group of molecules, i.e. aromatic and halogenated compounds, and furan persisted in the waste sample, although molecule concentrations were always lower than Threshold Limit Value-Time Weighted Average (TLV-TWA). PMID- 21315583 TI - Treatment of APMP pulping effluent based on aerobic fermentation with Aspergillus niger and post-coagulation/flocculation. AB - A novel two-stage biological/flocculation process was developed for treating the pulping effluent from the alkaline peroxide mechanical pulping (APMP) process. In the first biological stage, the aerobic fermentation by using Aspergillus niger can decrease the chemical oxygen demand (COD) by about 60% while producing about 7 g/l of solid biomass. In the second stage (post-coagulation/flocculation), the residual COD, turbidity and color, can be further decreased by using alum and polyacrylamide (PAM). The overall removal efficiencies of COD, color and turbidity from the APMP pulping effluent by the above two-stage biological coagulation/flocculation process were 93%, 92% and 99%, respectively, under the conditions studied. PMID- 21315584 TI - Discovery of ((1S,3R)-1-isopropyl-3-((3S,4S)-3-methoxy-tetrahydro-2H-pyran-4 ylamino)cyclopentyl)(4-(5-(trifluoromethyl)pyridazin-3-yl)piperazin-1 yl)methanone, PF-4254196, a CCR2 antagonist with an improved cardiovascular profile. AB - We describe the systematic optimization, focused on the improvement of CV-TI, of a series of CCR2 antagonists. This work resulted in the identification of 10 (((1S,3R)-1-isopropyl-3-((3S,4S)-3-methoxy-tetrahydro-2H-pyran-4 ylamino)cyclopentyl)(4-(5-(trifluoromethyl)pyridazin-3-yl)piperazin-1 yl)methanone) which possessed a low projected human dose 35-45mg BID and a CV TI=3800-fold. PMID- 21315585 TI - Synthesis and SAR of centrally active mGlu5 positive allosteric modulators based on an aryl acetylenic bicyclic lactam scaffold. AB - This Letter describes the hit-to-lead progression and SAR of a series of biphenyl acetylene compounds derived from an HTS screening campaign targeting the mGlu(5) receptor. 'Molecular switches' were identified that modulated modes of pharmacology, and several compounds within this series were shown to be efficacious in reversal of amphetamine induced hyperlocomotion in rats after ip dosing, a preclinical model that shows similar positive effects with known antipsychotic agents. PMID- 21315586 TI - Solution-phase parallel synthesis and screening of anti-tumor activities from fenbufen and ethacrynic acid libraries. AB - The derivatives with fenbufen and ethacrynic acid core compounds was synthesized through a facial preparation of 1-amino-4-azidobutane. The subsequent coupling with 102 members of carboxylic acids afforded amide products. The in situ screening using colorimetric assay with 3-(4.5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide showed that fenbufen but not ethacrynic acid butyl amide members displayed the cytotoxicities to tumor cells substantially, including two human cell lines (MCF7 and A549) and two murine cell lines (C26 and TRAMP-C1). Three fenbufen analogs were found to have a good anti-tumor activity comparable to cisplatin. PMID- 21315587 TI - Chroman and tetrahydroquinoline ureas as potent TRPV1 antagonists. AB - Novel chroman and tetrahydroquinoline ureas were synthesized and evaluated for their activity as TRPV1 antagonists. It was found that aryl substituents on the 7 or 8-position of both bicyclic scaffolds imparted the best in vitro potency at TRPV1. The most potent chroman ureas were assessed in chronic and acute pain models, and compounds with the ability to cross the blood-brain barrier were shown to be highly efficacious. The tetrahydroquinoline ureas were found to be potent CYP3A4 inhibitors, but replacement of bulky substituents at the nitrogen atom of the tetrahydroisoquinoline moiety with small groups such as methyl can minimize the inhibition. PMID- 21315588 TI - Discovery of benzimidazole pyrrolidinyl amides as prolylcarboxypeptidase inhibitors. AB - A series of benzimidazole pyrrolidinyl amides containing a piperidinyl group were discovered as novel prolylcarboxypeptidase (PrCP) inhibitors. Low-nanomolar IC(50)'s were achieved for several analogs, of which compound 9b displayed modest ex vivo target engagement in eDIO mouse plasma. Compound 9b was also studied in vivo for its effect on weight loss and food intake in an eDIO mouse model and the results will be discussed. PMID- 21315589 TI - Simple phosphonic inhibitors of human neutrophil elastase. AB - Herein, we describe the synthesis and resulting activity of a complex series of alpha-aminophosphonate diaryl esters as irreversible human neutrophil elastase inhibitors and their selectivity preference for human neutrophil elastase over several other serine proteases such as porcine pancreatic elastase, trypsin, and chymotrypsin. We synthesized and examined the inhibitory potency of several new simple Cbz-protected alpha-aminoalkylphosphonate diaryl esters that yielded several new HNE inhibitors, where one of the obtained compounds Cbz Val(P)(OC(6)H(4)-4-COOMe)(2) displayed an apparent second-order inhibition value at 33,015 M(-1) s(-1). PMID- 21315590 TI - HY251, a novel decahydrocyclopenta[a]indene analog, from Aralia continentalis induces apoptosis via down-regulation of AR expression in human prostate cancer LNCaP cells. AB - In the course of screening for a novel anticancer drug candidate, we previously isolated HY251 with the molecular structure of 3-propyl-2-vinyl 1,2,3,3a,3b,6,7,7a,8,8a-decahydrocyclopenta[a]indene-3,3a,7a,8a-tetraol from the roots of Aralia continentalis. The current study was designed to evaluate the detailed mechanisms of apoptotic induction of HY251 in androgen-sensitive prostate cancer LNCaP cells. TUNEL assay and Western blot analysis revealed an appreciable apoptotic induction in LNCaP cells treated with 95MUM of HY251 for 24h. This apoptotic induction is also associated with cytochrome c release from mitochondria which, in turn, resulted in the activation of caspase-9 and -3, and the cleavage of poly(ADP-ribose) polymerase (PARP). Moreover, we found that HY251 significantly inhibited the expression levels of androgen receptor (AR) and prostate-specific antigen (PSA) in a time-dependent manner, as well as abrogated up-regulation of AR and PSA genes with and without androgen. Therefore, we suggest that HY251, a novel androgen antagonist, may be a potent cancer chemotherapeutic candidate for the treatment of both androgen-sensitive and hormone-refractory prostate cancer. PMID- 21315591 TI - Syntheses and studies of amamistatin B analogs reveals that anticancer activity is relatively independent of stereochemistry, ester or amide linkage and select replacement of one of the metal chelating groups. AB - A series of analogs of the amamistatin natural products was designed and synthesized to facilitate additional anticancer structure-activity relationships. The results indicate that the anticancer activity is relatively independent of stereochemistry, ester or amide linkage and replacement of the oxazoline/oxazole based iron-binding group with a catechol. PMID- 21315592 TI - Rhythmic TMS over parietal cortex links distinct brain frequencies to global versus local visual processing. AB - Neural networks underlying visual perception exhibit oscillations at different frequencies (e.g.,). But how these map onto distinct aspects of visual perception remains elusive. Recent electroencephalography data indicate that theta or beta frequencies at parietal sensors increase in amplitude when conscious perception is dominated by global or local features, respectively, of a reversible visual stimulus. But this provides only correlative, noninterventional evidence. Here we show via transcranial magnetic stimulation (TMS) interventions that short rhythmic bursts of right-parietal TMS at theta or beta frequency can causally benefit processing of global or local levels, respectively, for hierarchical visual stimuli, especially in the context of salient incongruent distractors. This double dissociation between theta and beta TMS reveals distinct causal roles for particular frequencies in processing global versus local visual features. PMID- 21315593 TI - The capsaicin receptor TRPV1 is a crucial mediator of the noxious effects of mustard oil. AB - Mustard oil (MO) is a plant-derived irritant that has been extensively used in experimental models to induce pain and inflammation. The noxious effects of MO are currently ascribed to specific activation of the cation channel TRPA1 in nociceptive neurons. In contrast to this view, we show here that the capsaicin receptor TRPV1 has a surprisingly large contribution to aversive and pain responses and visceral irritation induced by MO. Furthermore, we found that this can be explained by previously unknown properties of this compound. First, MO has a bimodal effect on TRPA1, producing current inhibition at millimolar concentrations. Second, it directly and stably activates mouse and human recombinant TRPV1, as well as TRPV1 channels in mouse sensory neurons. Finally, physiological temperatures enhance MO-induced TRPV1 stimulation. Our results refute the dogma that TRPA1 is the sole nocisensor for MO and motivate a revision of the putative roles of these channels in models of MO-induced pain and inflammation. We propose that TRPV1 has a generalized role in the detection of irritant botanical defensive traits and in the coevolution of multiple mammalian and plant species. PMID- 21315594 TI - Extreme aggression in male squid induced by a beta-MSP-like pheromone. AB - Male-male aggression is widespread in the animal kingdom and subserves many functions related to the acquisition or retention of resources such as shelter, food, and mates. These functions have been studied widely in the context of sexual selection, yet the proximate mechanisms that trigger or strengthen aggression are not well known for many taxa. Various external sensory cues (visual, audio, chemical) acting alone or in combination stimulate the complex behavioral interactions of fighting behaviors. Here we report the discovery of a 10 kDa protein, termed Loligo beta-microseminoprotein (Loligo beta-MSP), that immediately and dramatically changes the behavior of male squid from calm swimming and schooling to extreme fighting, even in the absence of females. Females synthesize Loligo beta-MSP in their reproductive exocrine glands and embed the protein in the outer tunic of egg capsules, which are deposited on the open sea floor. Males are attracted to the eggs visually, but upon touching them and contacting Loligo beta-MSP, they immediately escalate into intense physical fighting with any nearby males. Loligo beta-MSP is a distant member of the chordate beta-microseminoprotein family found in mammalian reproductive secretions, suggesting that this gene family may have taxonomically widespread roles in sexual competition. PMID- 21315595 TI - A sparse object coding scheme in area V4. AB - Sparse coding has long been recognized as a primary goal of image transformation in the visual system. Sparse coding in early visual cortex is achieved by abstracting local oriented spatial frequencies and by excitatory/inhibitory surround modulation. Object responses are thought to be sparse at subsequent processing stages, but neural mechanisms for higher-level sparsification are not known. Here, convergent results from macaque area V4 neural recording and simulated V4 populations trained on natural object contours suggest that sparse coding is achieved in midlevel visual cortex by emphasizing representation of acute convex and concave curvature. We studied 165 V4 neurons with a random, adaptive stimulus strategy to minimize bias and explore an unlimited range of contour shapes. V4 responses were strongly weighted toward contours containing acute convex or concave curvature. In contrast, the tuning distribution in nonsparse simulated V4 populations was strongly weighted toward low curvature. But as sparseness constraints increased, the simulated tuning distribution shifted progressively toward more acute convex and concave curvature, matching the neural recording results. These findings indicate a sparse object coding scheme in midlevel visual cortex based on uncommon but diagnostic regions of acute contour curvature. PMID- 21315596 TI - Split introns in the genome of Giardia intestinalis are excised by spliceosome mediated trans-splicing. AB - Spliceosomal introns are hallmarks of most eukaryotic genomes and are excised from premature mRNAs by a spliceosome that is among the largest, and most complex, molecular machine in cells. The divergent unicellular eukaryote Giardia intestinalis, the causative agent of giardiasis, also possesses spliceosomes, but only four canonical (cis-spliced) introns have been identified in its genome to date. We demonstrate that this organism has a novel form of spliceosome-mediated trans-splicing of split introns that is essential for generating mature mRNAs for at least two important genes: one encoding a heat shock protein 90 (HSP90), which controls the conformation of a suite of cellular proteins, and the other encoding a dynein molecular motor protein, involved in the motility of eukaryotic flagella. These split introns have properties that distinguish them from other trans-splicing systems known within eukaryotes, suggesting that Giardia independently evolved a unique system to splice split introns. PMID- 21315597 TI - PIN polarity maintenance by the cell wall in Arabidopsis. AB - A central question in developmental biology concerns the mechanism of generation and maintenance of cell polarity, because these processes are essential for many cellular functions and multicellular development. In plants, cell polarity has an additional role in mediating directional transport of the plant hormone auxin that is crucial for multiple developmental processes. In addition, plant cells have a complex extracellular matrix, the cell wall, whose role in regulating cellular processes, including cell polarity, is unexplored. We have found that polar distribution of PIN auxin transporters in plant cells is maintained by connections between polar domains at the plasma membrane and the cell wall. Genetic and pharmacological interference with cellulose, the major component of the cell wall, or mechanical interference with the cell wall disrupts these connections and leads to increased lateral diffusion and loss of polar distribution of PIN transporters for the phytohormone auxin. Our results reveal a plant-specific mechanism for cell polarity maintenance and provide a conceptual framework for modulating cell polarity and plant development via endogenous and environmental manipulations of the cellulose-based extracellular matrix. PMID- 21315599 TI - Regulation of response properties and operating range of the AFD thermosensory neurons by cGMP signaling. AB - BACKGROUND: The neuronal mechanisms that encode specific stimulus features in order to elicit defined behavioral responses are poorly understood. C. elegans forms a memory of its cultivation temperature (T(c)) and exhibits distinct behaviors in different temperature ranges relative to T(c). In particular, C. elegans tracks isotherms only in a narrow temperature band near T(c). T(c) memory is in part encoded by the threshold of responsiveness (T*(AFD)) of the AFD thermosensory neuron pair to temperature stimuli. However, because AFD thermosensory responses appear to be similar at all examined temperatures above T*(AFD), the mechanisms that generate specific behaviors in defined temperature ranges remain to be determined. RESULTS: Here, we show that the AFD neurons respond to the sinusoidal variations in thermal stimuli followed by animals during isothermal tracking (IT) behavior only in a narrow temperature range near T(c). We find that mutations in the AFD-expressed gcy-8 receptor guanylyl cyclase (rGC) gene result in defects in the execution of IT behavior and are associated with defects in the responses of the AFD neurons to oscillating thermal stimuli. In contrast, mutations in the gcy-18 or gcy-23 rGCs alter the temperature range in which IT behavior is exhibited. Alteration of intracellular cGMP levels via rGC mutations or addition of cGMP analogs shift the lower and upper ranges of the temperature range of IT behavior in part via alteration in T*(AFD). CONCLUSIONS: Our observations provide insights into the mechanisms by which a single sensory neuron type encodes features of a given stimulus to generate different behaviors in defined zones. PMID- 21315600 TI - Case-control study of the UCH-L1 S18Y variant in sporadic Parkinson's disease in the Chinese population. AB - The ubiquitin carboxy-terminal hydrolase L1 gene (UCH-L1) has been implicated in the etiology of Parkinson's disease (PD). In several previous studies, an S18Y (C54A) polymorphism in exon 3 of the UCH-L1 gene has been found to be protective against PD. We performed polymerase chain reaction-restriction fragment length polymorphism analysis for DNA samples from 408 Chinese patients with PD and 398 Chinese healthy controls. For the S18Y variant, there was no significant difference either in the individual allele or genotype frequencies between cases and control subjects. Possession of the S18Y variant did not alter the risk of developing PD (odds ratio: 0.827; 95% confidence interval=0.596-1.147). There was no statistically significant difference in terms of age or sex distribution between the patients and controls (p>0.05). Overall, considering our present results together with those of our previous studies, we now have access to data from more than 1000 patients from different regions of China, supporting the conclusion that the S18Y polymorphism may not have a protective effect against PD in the Chinese population. PMID- 21315598 TI - Red and green algal monophyly and extensive gene sharing found in a rich repertoire of red algal genes. AB - The Plantae comprising red, green (including land plants), and glaucophyte algae are postulated to have a single common ancestor that is the founding lineage of photosynthetic eukaryotes. However, recent multiprotein phylogenies provide little or no support for this hypothesis. This may reflect limited complete genome data available for red algae, currently only the highly reduced genome of Cyanidioschyzon merolae, a reticulate gene ancestry, or variable gene divergence rates that mislead phylogenetic inference. Here, using novel genome data from the mesophilic Porphyridium cruentum and Calliarthron tuberculosum, we analyze 60,000 novel red algal genes to test the monophyly of red + green (RG) algae and their extent of gene sharing with other lineages. Using a gene-by-gene approach, we find an emerging signal of RG monophyly (supported by ~50% of the examined protein phylogenies) that increases with the number of distinct phyla and terminal taxa in the analysis. A total of 1,808 phylogenies show evidence of gene sharing between Plantae and other lineages. We demonstrate that a rich mesophilic red algal gene repertoire is crucial for testing controversial issues in eukaryote evolution and for understanding the complex patterns of gene inheritance in protists. PMID- 21315601 TI - The clinical value of laryngeal electromyography in laryngeal immobility. AB - Although laryngeal electromyography (LEMG) is commonly performed, there are no data confirming its efficacy. We evaluated 40 patients with a laryngoscopic diagnosis of unilateral vocal-fold immobility who underwent LEMG of the thyroarytenoid (TA) and cricothyroid (CT) muscle, with the immobile side of each muscle being compared to the normal side. The immobile side compared to the normal side showed more fibrillation potentials and positive sharp waves for the TA (p=0.04), longer MUAP duration for the TA (p=0.04) and CT (p=0.01), more polyphasic potentials for the TA (p=0.002), and more frequent decreased recruitment for the TA (p<0.01) and CT (p=0.008). Specificity and positive predictive value were around 90%. Sensitivity, negative predictive value and accuracy were around 50%. These results suggest that altered LEMG findings are reliable and they can be used to determine the innervation status of an immobile muscle. Conversely, when the LEMG is normal, the results should be reviewed. PMID- 21315602 TI - Cerebral reactive oxygen species assessed by electron spin resonance spectroscopy in the initial stage of ischemia-reperfusion are not associated with hypothermic neuroprotection. AB - Using an in vivo L-band electron spin resonance (ESR) system, we determined changes in reactive oxygen species (ROS) levels during the early stage (within 60 minutes) of global cerebral ischemia-reperfusion (IR) under normothermic and hypothermic conditions in rats. To confirm the neuroprotective role of hypothermia in this IR model, we immunohistochemically evaluated the levels of active caspase-3 in the hippocampal CA1 sector. ROS levels increased within the first 15 minutes following IR under both normothermic and hypothermic conditions; however, the ROS levels did not differ significantly between normothermic and hypothermic conditions. In the later periods of IR, there were no significant changes in ROS levels for either normothermic or hypothermic conditions relative to the control. As expected, normothermia increased the number of active caspase 3 immunoreactive nuclei in the IR model. However, this induction was prevented by hypothermia. These results suggest that the neuroprotective role of hypothermia does not correlate with the early ROS-induced oxidative stress following IR as measured by ESR. PMID- 21315603 TI - Cement augmented anterior reconstruction with short posterior instrumentation: a less invasive surgical option for Kummell's disease with cord compression. AB - We report the surgical procedure and clinical outcomes of a cement augmented anterior reconstruction with pedicle screw fixation for osteoporotic vertebral collapse with an intravertebral cleft (Kummell's disease). Ten consecutive patients with cord compression were enrolled in this study. The mean number of fused segments was 3.2. Instrumentation and posterolateral bone grafts were performed for one level above and below the collapsed vertebra with the exception of one patient. Polymethylmethacrylate (PMMA) cement was then injected into the intravertebral cleft and posterior decompression was performed when needed. The visual analog scale (VAS) pain score and Frankel grade were used to evaluate the clinical results and radiological parameters were also assessed. The mean VAS score before vertebroplasty was 7.5, which was reduced to 3.2 postoperatively, and was 3.7 at the most recent follow-up. The mean follow-up duration was 12.1 months. Seven (83%) of the eight patients with motor deficits showed an improvement in neurological function by at least 1 Frankel grade. The mean decrease in the kyphosis (Cobb) angle was 12.6 degrees and the wedge angle was 12.1 degrees (p<0.05). However, the angle improvement regressed slightly during follow-up. None of the patients showed vertebral collapse, or loss or leakage of PMMA into the canal. One patient developed wound dehiscence. There was no need for revision or evidence of instrument failure. Based on the preliminary results, we advocate the use of short instrumentation in combination with vertebroplasty with PMMA and posterolateral fusion for Kummell's disease in patients who are elderly or medically compromised. PMID- 21315604 TI - Two patients with rare causes of Weber's syndrome. AB - We report two patients with rare causes of Weber's syndrome and review the relevant literature. The first patient presented with Weber's syndrome caused by a partially thrombosed giant aneurysm of the posterior cerebral artery. The second patient was an immunocompetent patient who presented with progressive hemiparesis and subsequently developed Weber's syndrome. Primary central nervous system lymphoma (PCNSL) was eventually diagnosed. To our knowledge, the association between Weber's syndrome and PCNSL is rare. PMID- 21315605 TI - Significance of minor traumatic lesions in focal head injuries. AB - We investigated the significance of minor traumatic lesions associated with focal head injuries. Patients included in the study were admitted between January 2003 and December 2007 and had sustained a head injury with focal injury and undergone MRI examination including T2(*)-weighted imaging. Patients were divided into two groups: (i) a T2(*)-positive group - those who had hypointense lesions at sites other than the original injury site as shown by T2(*)-weighted MRI (n=12); and (ii) a control group without hypointense lesions at sites other than the original injury (n=25). The median Glasgow Outcome Scale score was significantly lower in the T2(*)-positive group (median=4; range=4-5) than in the control group (median=5; range=4-5; p=0.003). We conclude that patients with a focal head injury and minor traumatic lesions are likely to have a poorer prognosis than patients without additional minor traumatic lesions. PMID- 21315606 TI - Therapeutic efficacy of double filtration plasmapheresis in patients with anti aquaporin-4 antibody-positive multiple sclerosis. AB - Multiple sclerosis (MS) in Asian countries, including Japan, is classified into two types: conventional MS (C-MS), characterized mainly by cerebral lesions, and opticospinal MS (OS-MS) or neuromyelitis optica (NMO), characterized by selective involvement of the optic nerve and spinal cord. Recently, a serum immunoglobulin G-antibody was discovered in patients with NMO that targets aquaporin-4 (AQP4). The existence of the anti-AQP4 antibody shows the pathogenetic role of humoral immune factors in OS-MS/NMO. We treated eight patients with anti-AQP4 antibody positive MS with double filtration plasmapheresis (DFPP) to remove the antibody. Improvement of vision was observed in two patients. Motion improvement was seen in seven patients. Sensory improvement was observed in four patients. In total, six out of eight patients (75%) showed therapeutic improvement after DFPP treatment. We propose that DFPP might be an effective therapeutic option for patients with anti-AQP4 antibody-positive MS. PMID- 21315607 TI - Nuclear receptor coregulators merge transcriptional coregulation with epigenetic regulation. AB - Members of the nuclear steroid/thyroid hormone receptor (NR) gene superfamily are DNA-binding transcription factors that regulate target genes in a spatiotemporal manner, depending on the promoter context. In vivo observations of ligand responses in NR-mediated gene regulation led to the identification of ligand dependent coregulators that directly interact with NRs. Functional dissection of NR coregulators revealed that their transcriptional coregulation was linked to histone acetylation. However, recent work in the fields of reversible histone modification and chromatin remodeling indicates that histone-modifying enzymes, including histone methylases and chromatin remodelers, are potential transcriptional coregulators that interact directly and indirectly with NRs. PMID- 21315608 TI - Synthesis and evaluation of cyclic RGD-boron cluster conjugates to develop tumor selective boron carriers for boron neutron capture therapy. AB - Boron-containing agents play a key role in successful boron neutron capture therapy (BNCT). Icosahedral boron cluster-Arg-Gly-Asp (RGD) peptide conjugates were designed, synthesized, and evaluated for the biodistribution to develop tumor-selective boron carriers. Integrin alphavbeta3 is an attractive target for anti-tumor drug delivery because of its specific expression in proliferating endothelial and tumor cells of various origins. We, therefore, selected a c(RGDfK) moiety recognizing alphavbeta3 as an active tumor-targeting device to conjugate with icosahedral boron-10 clusters, disodium mercaptododecaborate (BSH) or o-carborane as a thermal neutron-sensitizing unit. Preparation of o-carborane derivatives involved microwave irradiation, and resulted in high yields in a short time. An in vitro cell adhesion assay on alphavbeta3-positive U87MG and SCCVII cells demonstrated the high binding affinity of conjugates to integrin alphavbeta3 (IC(50)=0.19-2.66 MUM). Biodistribution experiments using SCCVII bearing mice indicated that GPU-201 showed comparable tumor uptake and a significantly longer retention in tumors compared with BSH. These results suggest that GPU-201 is a promising candidate for use in BNCT. PMID- 21315609 TI - Radiosynthesis and in vivo evaluation of [11C]MP-10 as a PET probe for imaging PDE10A in rodent and non-human primate brain. AB - 2-((4-(1-[(11)C]Methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-quinoline (MP-10), a specific PDE10A inhibitor (IC(50)=0.18 nM with 100-fold selectivity over other PDEs), was radiosynthesized by alkylation of the desmethyl precursor with [(11)C]CH(3)I, ~45% yield, >92% radiochemical purity, >370 GBq/MUmol specific activity at end of bombardment (EOB). Evaluation in Sprague-Dawley rats revealed that [(11)C]MP-10 had highest brain accumulation in the PDE10A enriched striatum, the 30 min striatum: cerebellum ratio reached 6.55. MicroPET studies of [(11)C]MP-10 in monkeys displayed selective uptake in striatum. However, a radiolabeled metabolite capable of penetrating the blood-brain-barrier may limit the clinical utility of [(11)C]MP-10 as a PDE10A PET tracer. PMID- 21315610 TI - Cytotoxic 3,6-bis((imidazolidinone)imino)acridines: synthesis, DNA binding and molecular modeling. AB - New acridine derivatives bearing two symmetrical imidazolidinone rings, 3,6 bis((1-alkyl-5-oxo-imidazolidin-2-yliden)imino)acridine hydrochlorides 6a-6e (alkyl=ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl), have been prepared and their interactions with calf thymus DNA and selected cell lines were studied. The DNA binding of 6a-6e to ctDNA was examined by UV-vis, fluorescence, and CD spectroscopy. The binding constants determined by UV-vis spectroscopy were found in the range 1.9*10(5)-7.1*10(5) M(-1). An electrophoretic separation proved that ligands 6a-6e inhibited topoisomerase I in 40 MUM concentration although only those with longer alkyl chains were able to penetrate the membranes and efficiently suppress the cell proliferation. The highest activity in cytotoxic tests was found for 3,6-bis((1-n-hexyl-5-oxo-imidazolidin-2-yliden)imino)acridine hydrochloride (6e) with IC(50)=2.12 MUM (HL 60) and 5.28 MUM (L1210) after 72 h incubation. Molecular dynamics simulations and calculations of solvent-accessible surface areas (SASAs) were used to explore the intercalation mechanism. MD simulations favor stacking between adjacent C:G base pairs from the minor groove side. MD and SASAs calculations indicate that the decrease of K with alkyl extension is due to negative entropic change upon binding. PMID- 21315611 TI - Huprines as a new family of dual acting trypanocidal-antiplasmodial agents. AB - A series of 19 huprines has been evaluated for their activity against cultured bloodstream forms of Trypanosoma brucei and Plasmodium falciparum. Moreover, cytotoxicity against rat myoblast L6 cells was assessed for selected huprines. All the tested huprines are moderately potent and selective trypanocidal agents, exhibiting IC(50) values against T. brucei in the submicromolar to low micromolar range and selectivity indices for T. brucei over L6 cells of approximately 15, thus constituting interesting trypanocidal lead compounds. Two of these huprines were also found to be active against a chloroquine-resistant strain of P. falciparum, thus emerging as interesting trypanocidal-antiplasmodial dual acting compounds, but they exhibited little selectivity for P. falciparum over L6 cells. PMID- 21315612 TI - Synthesis and biological activity of splitomicin analogs targeted at human NAD(+) dependent histone deacetylases (sirtuins). AB - Small molecules interfering with posttranslational modification of histones are of interest as tools to study epigenetic regulation of gene transcription. Specifically, drugs that interfere with histone deacetylation could be useful to induce differentiation, growth arrest as well as apoptotic cell death in tumor cells. One class of histone deacetylases is known as sirtuins some of which (Saccharomyces cerevisiae Sir2) are for example inhibited by the lactone splitomicin leading to telomeric silencing in yeast. However, splitomicin is only a micromolar inhibitor of yeast Sir2 and does not inhibit human subtypes and the lactone is prone to hydrolytic ring opening. In preliminary SAR-studies, splitomicin analogs lacking this hydrolytically labile ring were described as inactive while the naphthalene moiety could successfully be replaced by smaller aromatic rings in a fragment-like dihydrocoumarin. Here we report the synthesis and biological activity of a series of hydrolytically stable analogs with activity against human SIRT1 and 2. These comparatively small compounds characterized by high ligand efficiency are used as a starting point toward the development of specific inhibitors of histone deacetylases from the class of sirtuins. PMID- 21315613 TI - Biological activity and ligand binding mode to the progesterone receptor of A homo analogues of progesterone. AB - The biological activity of two seven-membered A-ring (A-homo) analogues of progesterone was evaluated by transactivation assays in Cos-1 cells and by determination of Bcl-x(L) expression levels in T47D cells. The results show that both compounds act as selective progesterone receptor (PR) agonists but lack mineralocorticoid receptor (MR) activity. Molecular modelling using semiempirical AM1 and ab initio HF/6-31G** calculations, showed that the A-ring of the A-homo steroids may adopt five different conformations, although only three correspond to low energy conformers. The low energy conformers of each analogue were introduced into the ligand binding pocket of the PR ligand binding domain (LBD) obtained from the PR LBD-progesterone crystal structure. The steroid binding mode was then analyzed using 10 ns of molecular dynamics (MD) simulation. The PR LBD progesterone complex was also simulated as a control system. The MD results showed that both A-homo steroids have one conformer that may be properly recognized by the PR, in agreement with the observed progestagen activity. Moreover, the simulation revealed the importance of a water molecule in the formation of a hydrogen bonding network among specific receptor residues and the steroid A-ring carbonyl. PMID- 21315614 TI - Unexpected stereochemical tolerance for the biological activity of tyroscherin. AB - Here we describe the concise syntheses of the 15 diastereomers and key analogs of the natural product tyroscherin. While systematic analysis of the analogs clearly demonstrated that the hydrocarbon tail is important for biological activity, structure-activity relationship studies of the complete tyroscherin diastereoarray revealed a surprisingly expansive stereochemical tolerance for the cytotoxic activity. Our results represent a departure from the tenet that biological activity is constrained to a narrow pharmacophore, and highlight the recently emerging appreciation for stereochemical flexibility in defining the essential structural elements of biologically active small molecules. PMID- 21315615 TI - Total arch repair versus hemiarch repair in the management of acute DeBakey type I aortic dissection. AB - OBJECTIVE: In acute DeBakey type I aortic dissection, it is still controversial whether to perform extended aortic replacement to improve long-term outcome or to use a conservative strategy with ascending aortic and hemiarch replacement to palliate a life-threatening condition. METHODS: Between 1999 and 2009, 188 consecutive patients (93 women; mean age, 57.4+/-11.7 years) with acute DeBakey type I aortic dissection underwent hemiarch (Hemiarch group; n=144) or total arch replacement (Total arch group; n=44) in conjunction with ascending aorta replacement. Clinical outcomes were compared after adjustment for baseline characteristics using inverse-probability-of-treatment weighting. RESULTS: Median follow-up was 47.5 months (range 0-130.4 months) and was 92.0% (n=173) complete. Five-year unadjusted survival and permanent-neurologic-injury-free survival rates were 65.8+/-8.3% and 43.1+/-9.7% in the Total arch group, and 83.2+/-3.3% and 75.2+/-4.0% in the Hemiarch group, respectively (P=0.013 and <0.001). After adjustment, the Total arch group patients were at greater risks of death (hazard ratio (HR) 2.38, 95% confidence interval (CI) 1.21-4.67; P=0.012), and permanent neurologic injury (HR 3.25, 95% CI 1.31-8.04; P=0.011) compared to the Hemiarch group patients. The risks of the re-operation for aortic pathology or distal aortic dilatation (>55 mm) were similar for both groups (HR 0.33, 95% CI 0.08 1.43; P=0.14). CONCLUSIONS: Total arch repair was associated with greater morbidity and mortality compared with hemiarch repair in acute DeBakey type I aortic dissection. Rates of aortic re-operation or aortic dilatation were not significantly different between the two surgical strategies. These findings support a conservative surgical approach to circumvent this life-threatening situation. PMID- 21315616 TI - Th1/Th2 cytometric bead array can discriminate cytokine secretion from endogenously activated cells in pulmonary disease, recent and remote infection in tuberculosis. AB - Differential T cell trafficking through the blood compartment towards infected foci may be occurring in different stages of tuberculosis disease and infection. The aim of the present study was to identify cytokine signatures in the blood compartment in tuberculosis patients with pulmonary disease (PTB=19), recently exposed household contacts (HC=27) and nonexposed community controls (EC=37). Diluted (1:10) whole blood was cultured for 2 days and cytokine secretion was assessed using Cytometric Bead Array (Th1/Th2 kit II; BD Biosciences) which included IL-2, TNF-alpha, IFN-gamma (Type1/T1), IL-4, IL-6 and IL-10 (Type2/T2). All T1/T2 cytokines were elevated in PTB (AUROC>0.9) while HC showed selective elevation of IL-6 (AUROC>0.7) compared to EC. Principal component analysis (PCA) extracted two groupings with Eigen values >1; IL-6 separated into the second component for PTB, HC and EC. After rotation, IFN-gamma was correlated with the first component for PTB and EC and the second component for HC indicating an absence of T1/T2 dichotomy. Therefore endogenous cytokine signatures may indicate differential T cell trafficking in different stages of tuberculosis infection and disease. PMID- 21315617 TI - Relationship influence and health risk behavior among re-entering women offenders. AB - BACKGROUND: Studies have shown that relationships can influence health risk behaviors such as drug use among women offenders. This study takes an exploratory look at the positive and negative influences of parents, peers, and partners for women prisoners to better understand their health risk behavior for HIV, including risky sex and drug use. METHODS: The current study includes secondary analysis of cross-sectional data from women offenders enrolled in three protocols of the National Institute on Drug Abuse-funded Criminal Justice Drug Abuse Treatment Studies cooperative agreement. Baseline interviews were completed with incarcerated women preparing for community re-entry and focused on behaviors during the 6 months before incarceration. Relationship influences during the 6 months before prison were categorized as "positive" or "negative" for the women offenders. FINDINGS: Multivariate regression models suggested that positive parental influence was significantly associated with reduced HIV risk and reduced drug use in the 6 months before incarceration. However, negative peer influence increased drug use including both risky needle behavior and any drug use in the 6 months before incarceration. CONCLUSION: These data suggest that, although relationships are generally important to women, particular types of relationship influences may be related to risky behavior. Implications for targeting re-entry interventions for women offenders are discussed. PMID- 21315618 TI - Are the point-of-care diagnostics MULTIPLATE and ROTEM valid in the setting of high concentrations of heparin and its reversal with protamine? AB - OBJECTIVES: To evaluate the in vitro effects of high concentrations of heparin and its reversal with protamine on routine laboratory parameters as well as on modified thromboelastogram (ROTEM; TEM International, Munich, Germany) and impedance aggregometry (MULTIPLATE; Dynabyte, Munich, Germany). DESIGN: An observational, nonrandomized in vitro study. SETTING: A single-center, university hospital. PARTICIPANTS: Ten healthy volunteers. INTERVENTIONS: Heparinization of whole blood to levels of 2, 4, 6, and 8 IU/mL of heparin and reversal with protamine. For MULTIPLATE measurements, heparin levels up to 20 IU/mL were tested. MEASUREMENTS AND MAIN RESULTS: The present results show that the prothrombin time (PT) and fibrinogen measurements are altered significantly by heparin concentrations above 2 IU/mL. Protamine reversal also affected coagulation tests except for the fibrinogen. The INTEM test using the ROTEM system was influenced significantly by heparin concentrations of 2 IU/mL or higher, whereas EXTEM measurements remained stable up to 4 IU/mL. The findings for the FIBTEM test were stable up to 6 IU/mL but then declined to values less than 50% of baseline at 8 IU/mL. HEPTEM results remained valid under all concentrations of heparin tested. The effect of protamine on ROTEM was seen mainly in the INTEM and HEPTEM measurements. Heparin concentrations up to a level of 20 U/mL had no effect on MULTIPLATE measurements. Effects of protamine on MULTIPLATE became significant at heparin-to-protamine ratios below 1:1 and were more pronounced for adenosine diphosphate than for thrombin receptor-activated protein testing. CONCLUSIONS: Neither fibrinogen (Clauss) nor derived fibrinogen or FIBTEM testing is valid in the setting of high concentrations of heparin unless antagonized by heparinase. Reversal of heparin with protamine worsens platelet function at all ratios as detected by aggregometry (MULTIPLATE) and thromboelastography (ROTEM), starting at a 1:1 ratio. Therefore, appropriate coagulation testing under cardiopulmonary bypass conditions should be selected carefully according to heparin levels. In particular, fibrinogen values are falsely low at heparin levels of 2 IU/mL and above. Therefore, newer algorithms promoting the correction of fibrinogen levels on cardiopulmonary bypass should be based on appropriate testing. PMID- 21315619 TI - Arterial injury complicating subclavian central venous catheter insertion. PMID- 21315620 TI - The allograft sleeve: a case report of the surgical management of an interprosthetic fracture between a shoulder and elbow joint replacement. PMID- 21315621 TI - Electroclinical features of idiopathic generalized epilepsies in the elderly: a geriatric hospital-based study. AB - PURPOSE: Idiopathic generalized epilepsies (IGE) are age-related epileptic syndromes mainly described in children and adolescence. Our aim is to describe their electroclinical features in the elderly. METHODS: Patients aged 70 years or more were prospectively selected in a geriatric EEG laboratory on the basis of rhythmic generalized spikes and waves discharges. Their clinical data were then examined to ascertain the syndromic diagnosis. RESULTS: Among 1181 geriatric patients referred for EEG over a 30-month period, IGE were identified in 10 cases. Eight patients began seizures in childhood or adulthood (3 childhood absence epilepsies, 2 juvenile/adult myoclonic epilepsies and 3 epilepsies with generalized-tonic-clonic-seizures alone (EGTCS)) and 2 very late in life with EGTCS. The early-onset IGE cases had usually experienced a quiescent long period in adulthood before relapsing late in life. This relapse, mostly severe, consisted of absence status, myoclonic status or repeated generalized tonic clonic seizures and was often not-situation related. Absence status and myoclonic status were stopped by Clonazepam. The two late-onset IGE cases had familial history of epilepsy. Inappropriate antiepileptic drugs (AED) previously given in four patients with two worsenings were corrected. CONCLUSIONS: In this study, the non-negligible number of elderly cases observed over a short period of time suggests that IGE are frequent in the elderly but underestimated until recently. IGE may be lifelong with late severe exacerbations. A few very late-onset IGE cases exist. EEG remains useful in contributing to diagnose IGE and AED adjustment continues to be beneficial at extreme age. PMID- 21315622 TI - Overexpression of MU-calpain in the anterior temporal neocortex of patients with intractable epilepsy correlates with clinicopathological characteristics. AB - PURPOSE: This study aims to investigate MU-calpain expression profiles in the anterior temporal neocortex in patients with intractable epilepsy, and to determine whether its pattern of expression is related to pathological changes seen in these patients. METHODS: The study subjects consisted of 30 patients with intractable epilepsy and a control group of 10 patients with brain trauma who underwent resection of the anterior temporal lobe. MU-Calpain expression in surgically resected anterior temporal cortices of patients with intractable epilepsy were analyzed using the RT-PCR, Western blot, immunohistochemistry and immunofluorescence staining. GFAP expression was detected by immunohistochemical staining. The related pro-inflammatory cytokines were quantified by elisa. Clinicopathological characteristics were evaluated by HE staining. RESULTS: Analysis by Western blot and RT-PCR revealed that inactive MU-calpain expression and the calpain-cleaved spectrin fragment in surgically resected anterior temporal cortices of patients with intractable epilepsy were significantly increased compared to the tissues from corresponding regions of the control group. Immunohistological staining demonstrated that MU-calpain was overexpressed in the cell cytoplasm of neurons and glial cells in patients with intractable epilepsy and GFAP was overexpressed in the cell cytoplasm of glial cells in patients with intractable epilepsy. The level of pro-inflammatory cytokines, such as IL-1beta, IL-6 and TGF-beta1 were significantly increased in patients with intractable epilepsy. HE staining indicated MU-calpain overexpression is an independent prognostic factor for pathological changes such as neuronal loss, neuronal degeneration, gliosis and astrocytosis. CONCLUSION: These data suggest that overexpression of MU-calpain is relationship with intractable epilepsy as well as the clinicopathological characteristics in these patients. PMID- 21315623 TI - Immunization with HIV-1 gp41 subunit virosomes induces mucosal antibodies protecting nonhuman primates against vaginal SHIV challenges. AB - Human immunodeficiency virus (HIV)-1 is mainly transmitted mucosally during sexual intercourse. We therefore evaluated the protective efficacy of a vaccine active at mucosal sites. Macaca mulatta monkeys were immunized via both the intramuscular and intranasal routes with an HIV-1 vaccine made of gp41-subunit antigens grafted on virosomes, a safe delivery carrier approved in humans with self-adjuvant properties. Six months after 13 vaginal challenges with simian-HIV (SHIV)-SF162P3, four out of five vaccinated animals remained virus-negative, and the fifth was only transiently infected. None of the five animals seroconverted to p27gag-SIV. In contrast, all 6 placebo-vaccinated animals became infected and seroconverted. All protected animals showed gp41-specific vaginal IgAs with HIV-1 transcytosis-blocking properties and vaginal IgGs with neutralizing and/or antibody-dependent cellular-cytotoxicity activities. In contrast, plasma IgGs totally lacked virus-neutralizing activity. The protection observed challenges the paradigm whereby circulating antiviral antibodies are required for protection against HIV-1 infection and may serve in designing a human vaccine against HIV-1 AIDS. PMID- 21315624 TI - Childhood pregnancy as a result of incest: a case report and literature review with suggested management strategies. AB - BACKGROUND: Childhood pregnancy presents multiple challenges, which are compounded when the pregnancy is a result of abuse. While there is ample information regarding the psychological manifestations of childhood sexual abuse, a review of the literature provides modest information on childhood pregnancy, as distinct from teen pregnancy. CASE: A 10-year-old pregnant female reports for medical care at 28-30 weeks gestation. CONCLUSION: Sensitivity to the patient's and family's needs and having a care team who followed a well defined care plan appeared to be the key to optimizing the management of this patient. Although decisions should be based on medical standards, the psychological, social, and, at times, criminal concerns must be considered in every aspect of the patient's care and variations from established patterns of care should be allowed when needed. PMID- 21315625 TI - In vitro expansion and differentiation of fresh and revitalized adult canine bone marrow-derived and adipose tissue-derived stromal cells. AB - The objective of this study was to determine the tissue density, in vitro expansion and differentiation of canine adipose tissue-derived (ASC) and bone marrow-derived (BMSC) stromal cells. Primary (P0) and cell passages 1-6 (P1-6) cell doubling numbers (CD) and doubling times (DT) were determined in fresh cells. The P0, P3, and P6 adipogenic (CFU-Ad), osteogenic (CFU-Ob), and fibroblastic (CFU-F) colony forming unit frequencies, lineage specific mRNA levels in differentiated P3 cells and composition of P3 and P6 chondrogenic pellets were assessed in cryogenically preserved cells. Cell yields from bone marrow were significantly higher than adipose tissue. Overall ASC and BMSC CDs and DTs and P3 and P6 CFU-F, CFU-Ad, and CFU-Ob were comparable. The P0 BMSC CFU Ob was significantly higher than ASC. Lineage specific mRNA levels were higher in differentiated versus control cells, but similar between cell types. Protein was significantly greater in P3 versus P6 ASC chondrogenic pellets. Based on these findings, fresh and revitalized canine ASCs are viable alternatives to BMSCs for stromal cell applications. PMID- 21315626 TI - Lower shedding of strongylid eggs by Warmblood horses with recurrent airway obstruction compared to unrelated healthy horses. AB - An association between equine recurrent airway obstruction (RAO) and increased resistance to intestinal parasites has been demonstrated in descendants of an RAO affected stallion. It was hypothesised that members of another high-incidence RAO family (F) and unrelated RAO-affected Warmblood horses (UA) would shed fewer strongylid eggs than unrelated RAO-unaffected pasture mates (PM) under the same environmental conditions. Faecal worm egg counts were performed on faecal samples (63 F, 86 UA, 149 PM) and classified into three categories: 0, 1-100 and >100 eggs per gram. While results for F did not differ from PM, UA were 2.5-times less likely to shed strongylid eggs than PM. RAO-affected Warmblood horses may be more resistant to strongylid nematodes than unrelated unaffected pasture mates and a family history of RAO does not necessarily confer protection against helminth infections. PMID- 21315628 TI - A positron emission tomography study of wind-up pain in chronic postherniotomy pain. AB - Many neuropathic pain conditions are characterized by abnormal responses to noxious or innocuous mechanical stimulation, including wind-up pain. Whereas previous brain imaging studies have explored the cerebral correlates of hyperalgesia and allodynia, no studies are available on mechanical-induced wind up pain in neuropathic pain patients. We therefore used positron emission tomography (PET) to investigate the cerebral response pattern of mechanical wind up pain in a homogenous group of 10 neuropathic pain patients with long-standing postherniotomy pain in the groin area. Patients were scanned in the following conditions: (1) rest; (2) wind-up pain, induced by 2 Hz von Frey stimulation in the painful area; (3) non-painful 2 Hz von Frey stimulation in the homologous contralateral area and (4) tonic pressure pain in the homologous contralateral area. A direct comparison between wind-up pain and non-painful von Frey stimulation revealed that the former more strongly activated contralateral secondary somatosensory cortex, insula, anterior cingulate cortex, right dorsolateral prefrontal cortex, thalamus and cerebellum. In addition, wind-up pain also activated the sublenticular extended amygdala (SLEA) and the brain stem. A direct comparison between wind-up pain and pressure pain revealed that both activated a largely overlapping network. Since no de novo brain areas were activated by wind-up pain, our data suggest that the processes specific to wind up pain do not occur at the cerebral level. PMID- 21315627 TI - Brain activity for chronic knee osteoarthritis: dissociating evoked pain from spontaneous pain. AB - Chronic pain is a hallmark of osteoarthritis (OA), yet little is known about its properties and representation in the brain. Here we use fMRI combined with psychophysics to study knee pain in fourteen OA patients and nine healthy controls. Mechanical painful pressure stimuli were applied to the knee in both groups and ratings of evoked pain and related brain activity examined. We observe that psychophysical properties and brain activation patterns of evoked pain are essentially the same between OA patients and healthy subjects, and between worse and better OA knees. In OA patients, stimulus-related brain activity could be distinguished from brain activity associated with spontaneous pain. The former activated brain regions commonly observed for acute painful stimuli in healthy subjects, while the spontaneous pain of OA engaged prefrontal-limbic regions closely corresponding to areas observed for spontaneous pain in other chronic pain conditions, such as chronic back pain and post-herpetic neuralgia. Arthritis related clinical characteristics of knee OA also mapped to prefrontal-limbic regions. In a subgroup of patients (n=6) we examined brain activity changes for a 2-week, repeat measure, cyclooxygenase-2 inhibitor (valdecoxib) therapy. Treatment decreased spontaneous pain for the worse knee and clinical characteristics of OA, and increased blood and csf levels of the drug which correlated positively with prefrontal-limbic brain activity. These findings indicate dissociation between mechanically induced and spontaneous OA knee pain, the latter engaging brain regions involved in emotional assessment of the self, and challenge the standard clinical view regarding the nature of OA pain. PMID- 21315629 TI - Bilateral optic nerve drusen and gliomas in Klippel-Trenaunay syndrome. AB - Klippel-Trenaunay syndrome (KTS) consists of a vascular nevus involving an extremity, varicosities of that extremity, and hypertrophy of bone and soft tissue. When arteriovenous malformation is also present, it is called Klippel Trenaunay-Weber syndrome (KTWS). Ophthalmic features of these syndromes include vascular anomalies of the orbit, iris, retina, choroid, and optic nerve. We report a case of a 16-year-old girl with KTS who was found to have bilateral optic nerve and chiasmal gliomas, optic disk drusen, and acquired myelination of the retinal nerve fiber layer. These findings have not been previously reported to be associated with KTS or KTWS. PMID- 21315630 TI - Abducens nerve palsy associated with a clival epidural hematoma. AB - A clival epidural hematoma is a rare lesion that usually develops after a hyperflexion or hyperextension injury of the neck, often in a child. A 5-year-old girl presented after a motor vehicle accident with multiple cranial neuropathies, including bilateral abducens nerve pareses and right facial, glossopharyngeal, and hypoglossal cranial nerve palsies. Neuroimaging identified a clival epidural hematoma. The child was observed and the hematoma resolved. The abducens nerve palsies resolved during the ensuing 14 months. PMID- 21315631 TI - Spectacle wear in children reduces parental health-related quality of life. AB - PURPOSE: To investigate whether spectacle wear in children affects responses on the Intermittent Exotropia Questionnaire (IXTQ) or the Pediatric Quality of Life Inventory (PedsQL). METHODS: We recruited 49 children, median age 8 years (range, 5-13 years), presenting with visual acuity 20/40 or better and an otherwise normal eye examination (no strabismus), who either had no refractive error (n=29) or had refractive error corrected with spectacles (n=20). The IXTQ and PedsQL were completed, each comprising a child report (Child IXTQ, Child PedsQL) and a parent proxy report (Proxy IXTQ, Proxy PedsQL). In addition, the IXTQ contains a parent self-report (Parent IXTQ). Each questionnaire is scored from 0 (worst health-related quality of life [HRQOL]) to 100 (best HRQOL). Median scores were compared using Wilcoxon rank-sum tests. RESULTS: Child IXTQ and Proxy IXTQ scores were similar between groups; nevertheless, Parent IXTQ scores were lower for spectacle wearers (90.4 vs 97.1, p=0.01). Parent IXTQ questions that scored lower in the spectacle group were related to parental worry about permanent damage to their child's eyes, long-term eyesight, surgery, self-consciousness, and teasing. The PedsQL composite scores and all subscale scores were similar between spectacle wearers and nonspectacle wearers, both for Child PedsQL and Proxy PedsQL. CONCLUSIONS: Parental HRQOL, measured with the use of the Parent IXTQ, was lower for children wearing spectacles than for children who did not wear spectacles. There was no difference between spectacle and no-spectacle groups when either Child IXTQ, Proxy IXTQ, Child PedsQL, or Proxy PedsQL was used. PMID- 21315632 TI - Germinoma presenting as a fourth cranial nerve palsy in a patient with adenomatous polyposis coli (APC) gene mutation. AB - A 17-year-old boy with adenomatous polyposis and a history of an adenomatous polyposis coli (APC) gene mutation (IVS13(-2) A>G) presented for evaluation of vertical, binocular diplopia. Examination was suggestive of a fourth (trochlear) nerve palsy. A history of headaches was elicited and led to further investigation with neuroimaging, which identified a germinoma in the tectal plate and secondary hydrocephalus. We report the clinical, radiological, and histopathological findings of this patient, who to our knowledge is the first reported case of a germinoma occurring in association with adenomatous polyposis. PMID- 21315633 TI - Comparison of proliferating cell nuclear antigen, thyroid transcription factor-1, Ki-67, p63, p53 and high-molecular weight cytokeratin expressions in papillary thyroid carcinoma, follicular carcinoma, and follicular adenoma. AB - The searching of the reliable and repeatable immunohistochemical markers in the differential diagnosis of the thyroid's differentiated follicular epithelial neoplasms has been continuing. Recently, the studies have majored on immunohistochemical markers such as high-molecular weight cytokeratin (HMW-CK), galectin-3, cytokeratin 19, and p27. We aimed to evaluate the differences of the expressions of the proliferating cell nuclear antigen (PCNA), thyroid transcription factor-1 (TTF-1), Ki-67, p63, p53, and HMW-CK among the papillary thyroid carcinomas (PTCs), follicular carcinomas (FCs), and follicular adenomas (FAs). Thirty-nine patients with the diagnoses of the PTC, FC, and FA in the archives of the Izmir Tepecik Training and Research Hospital Pathology Laboratory registries in between 2004 and 2009 were included in the study. Immunohistochemical stains for PCNA, TTF-1, Ki-67, p63, p53, and HMW-CK were applied. The results were analyzed statistically by using Statistical Package for the Social Sciences (SPSS) for Windows 16.0 program (SPSS Inc., IBM, Somers, New York, USA). In all 3 groups, all tumors showed PCNA and TTF-1 positivity. Ki-67 proliferation index varied in a wide range in all groups. Although it was not statistically significant, 19 of 39 tumors (7 PTCs, 2 FCs, and 10 FAs) were stained with p63. The results of the immunoreactivity seen in PTCs with p53 (41.2%) and HMW-CK (52.9%) were statistically significant. The tumors in the other 2 groups (FC and FA) showed no reactivity with HMW-CK. Although the differential diagnosis of the thyroid follicular neoplasms are based on the histologic and cytomorphological criteria, p53 and HMW-CK positivity might be undertaken in favor of the diagnosis of the PTC. PMID- 21315634 TI - An inverse docking approach for identifying new potential anti-cancer targets. AB - Inverse docking is a relatively new technique that has been used to identify potential receptor targets of small molecules. Our docking software package MDock is well suited for such an application as it is both computationally efficient, yet simultaneously shows adequate results in binding affinity predictions and enrichment tests. As a validation study, we present the first stage results of an inverse-docking study which seeks to identify potential direct targets of PRIMA 1. PRIMA-1 is well known for its ability to restore mutant p53's tumor suppressor function, leading to apoptosis in several types of cancer cells. For this reason, we believe that potential direct targets of PRIMA-1 identified in silico should be experimentally screened for their ability to inhibit cancer cell growth. The highest-ranked human protein of our PRIMA-1 docking results is oxidosqualene cyclase (OSC), which is part of the cholesterol synthetic pathway. The results of two followup experiments which treat OSC as a possible anti-cancer target are promising. We show that both PRIMA-1 and Ro 48-8071, a known potent OSC inhibitor, significantly reduce the viability of BT-474 and T47-D breast cancer cells relative to normal mammary cells. In addition, like PRIMA-1, we find that Ro 48-8071 results in increased binding of p53 to DNA in BT-474 cells (which express mutant p53). For the first time, Ro 48-8071 is shown as a potent agent in killing human breast cancer cells. The potential of OSC as a new target for developing anticancer therapies is worth further investigation. PMID- 21315635 TI - Another study showing that two preference-based measures of health-related quality of life (EQ-5D and SF-6D) are not interchangeable. But why should we expect them to be? AB - OBJECTIVES: Studies have shown that preference-based measures of health-related quality of life (utility measures) fail to provide interchangeable values, which raises concerns for the cross-study comparability of cost-effectiveness estimates. This study offers generalizable and condition-specific insight into why (rather than if) there are discrepancies between two widely used measures, the EQ-5D and SF-6D. METHODS: Comparisons focused on practical considerations and the respective descriptive and valuation components of the measures, addressing empirical and conceptual issues. More specifically, we addressed instrument completion, item-completion, contextual framing of questions, dimension-to dimension correlations, floor and ceiling effects, and construct validity. Data came from randomized controlled trial participants with nonspecific neck pain (n = 346). RESULTS: The descriptive classification systems do not permit respondents to describe their health state in the same manner, due, primarily, to contextual differences and the number of available response options. Specific to neck pain populations, "vitality" was a unique contributor to the SF-6D, although both measures identified the same significant linear trends across theoretical constructs. Rates of instrument completion were significantly better for the EQ 5D over the course of the randomized controlled trial. CONCLUSIONS: The EQ-5D and SF-6D do not provide interchangeable utility estimates for patients with nonspecific neck pain-a finding that is common to other clinical areas. However, this result, and the results from previous studies, should not be surprising given the extent of between-measure differences relating to the descriptive content of health dimensions across the two measures. Given the consistent messages emerging from method comparison studies for the EQ-5D and SF-6D, new and/or novel approaches are necessary to drive this research area forward. PMID- 21315636 TI - The long-term outcomes and costs of diabetes mellitus among renal transplant recipients: tacrolimus versus cyclosporine. AB - Anti-rejection regimens for renal transplants have changed dramatically during the past 20 years, but there are few long-term studies relating cost, mortality, or graft failure simultaneously to disease-pharmacotherapy couplets. We analyzed US Renal Data System data on a matched-pair cohort of first, single organ kidney transplants from 1998 through 2002 over up to 5 years following transplantation for patients on tacrolimus or low-dose cyclosporine, stratifying by whether the recipient had pre-existing or new onset diabetes. Kaplan-Meier survival curves show mortality and survival differences associated with diabetes, but no additional incremental effects of immune suppression regimen. Significant cost increases are reported for patients receiving tacrolimus above and beyond the extra costs associated with diabetes. PMID- 21315637 TI - Patient-reported Pediatric Quality of Life InventoryTM 4.0 Generic Core Scales in pediatric patients with attention-deficit/hyperactivity disorder and comorbid psychiatric disorders: feasibility, reliability, and validity. AB - OBJECTIVES: The primary objective of the study was to evaluate the feasibility, reliability, and validity of the Pediatric Quality of Life InventoryTM (PedsQL) 4.0 Generic Core Scales as a patient self-reported health-related quality of life measurement instrument in pediatric patients with attention-deficit/hyperactivity disorder (ADHD) and physician-diagnosed comorbid psychiatric disorders being seen in a pediatric psychiatric clinic. The secondary objective was to evaluate parent proxy-reported PedsQL in this population. METHODS: One hundred seventy-nine children with ADHD and comorbid psychiatric disorders ages 5 to 18 years and 181 parents completed the PedsQL 4.0 Generic Core Scales and parents also completed the Vanderbilt ADHD Diagnostic Rating Scales. Known-groups discriminant validity comparisons were made between the sample of pediatric patients with ADHD and comorbid psychiatric disorders and healthy, cancer, and type 1 diabetes samples. RESULTS: The PedsQL evidenced minimal missing responses for patient self-report and parent proxy-report (0.2% and 0.5%, respectively), demonstrated no significant floor or ceiling effects, and achieved excellent reliability for the Total Scale Score (alpha = 0.85 patient self-report, 0.92 parent proxy-report). Pediatric patients with ADHD and comorbid psychiatric disorders and their parents reported statistically significantly worse PedsQL scores than healthy children, with large effect sizes across all domains, supporting known-groups discriminant validity. Pediatric patients with ADHD and comorbid psychiatric disorders and their parents reported worse PedsQL scores compared to pediatric patients with cancer and diabetes with the exception of physical health, in which pediatric cancer patients manifested lower physical health, indicating the relative severe impact of ADHD and comorbid psychiatric disorders. More severe ADHD symptoms were generally associated with more impaired PedsQL scores, supporting construct validity. CONCLUSIONS: These data demonstrate the feasibility, reliability, and validity of patient self-reported PedsQL 4.0 Generic Core Scales in this high risk population of pediatric patients and highlight the profound negative impact of ADHD and comorbid psychiatric disorders on generic health-related quality of life, comparable to or worse than serious pediatric chronic physical diseases. PMID- 21315638 TI - [The end of life in the intensive care unit from the nursing perspective: a phenomenological study]. AB - INTRODUCTION: Intensive Care Units do not adapt to the social and health reality regarding the phenomenon of death and this results in a high degree of dissatisfaction among professional, relatives and patients. The special characteristics of these units give the nursing staff a main roll as carers of critical dying patients. The principal aim of this study is to know the nursing staffs' experiences and attitudes towards the phenomenon of death in the intensive care units. PARTICIPANTS AND METHOD: A descriptive qualitative study of phenomenological character was performed. Constant comparison and progressive incorporation of participants was made, using intentional sampling up to data saturation (n=16). The data collection technique used was a semi-structured in depth interview, which were recorded and literally transcribed. The data collected was verified by the informants and analyzed according to the steps proposed by Taylor-Bogdan. RESULTS: The analysis shows 5 thematic categories: death and beliefs, emotional work, environmental factors, decision-making management of death in intensive care units and relationships with relatives. CONCLUSIONS: The management model of death in intensive care units focuses on medical intervention and overlooks the opinions of the nurses, relatives and patients. This study shows the contributions that can be provided by the nursing staff in decision making and in the care of the dying patients in these wards. PMID- 21315639 TI - [Quality criteria of scientific publications: a backward step in the development of the nursing discipline?]. PMID- 21315640 TI - [Impact index or translation into clinical practice: a difficult decision]. PMID- 21315641 TI - [Strategy to increase screening for cardiovascular risk factors among young people]. AB - OBJECTIVE: To evaluate the effectiveness of an intervention to increase the participation among young people in the Health Prevention and Promotion Activities Programme (PAPPS) and the register of their variables. To evaluate differences in registering based on age and sex. METHOD: DESIGN: randomized, controlled clinical trial. SETTING: Palamos primary care centre. PARTICIPANTS: A total of 828 people between the ages of 25 and 40 assigned to a nurse with one of the PAPPS variables improperly completed: 415 in control group and 413 in intervention group. INTERVENTION: letter to complete the PAPPS and phone call if the response after three weeks was less than 10%. VARIABLES: age, sex, nationality, clinic attendance, number of variables of PAPPS variables properly completed and the correct registration of each one at the beginning and end of the period. STATISTICAL ANALYSIS: univariate and bivariate analysis, 95% confidence interval, RRR and NNT. RESULTS: Heterogeneous groups as regards clinic attendance: 5 (1.2%) of control and 85 (20.6%) of intervention group, NNT=5 (95% CI, 4-7); and properly completed registration of PAPPS (P<.001): 5 (1.2%) of control and 73 (17.7%) of intervention, NNT=6 (95% CI, 5-8). At the end, there were differences with regard to age and sex in the number of variables completed and in the registration of cholesterol (P<.001), and only in regard to age in body mass index (P=.005). CONCLUSIONS: The strategy significantly increased the number of people who completed the PAPPS and their registration. Sex and age influenced the completion. PMID- 21315642 TI - [Application of amniotic membrane dressings in patients with skin damage]. AB - The application of amniotic membranes in patients diagnosed with skin damage is a valid treatment option. A care plan following the Virginia Henderson model and NANDA, NOC and NIC taxonomy was applied to 36 patients admitted to the Dr. Miguel Enriquez hospital with different cutaneous lesions. This membrane has already been used for years due to its healing properties. These are attributed to antimicrobial properties reducing infection risk and promoting epithelial activity. They can decrease the need for the use of antibiotics, expendable materials, and can be applied during long periods of healing. This decreases the cost of wide spectrum antibiotic treatments, as well as the time patients spend in hospital. We present the results of this application in cases with several types of skin lesions. PMID- 21315643 TI - [Production, circulation and access to information beyond the impact factor]. PMID- 21315644 TI - [Locally advanced unresectable pancreatic cancer: Induction chemoradiotherapy followed by maintenance gemcitabine versus gemcitabine alone: Definitive results of the 2000-2001 FFCD/SFRO phase III trial]. AB - PURPOSE: To compare chemoradiation with systemic chemotherapy to chemotherapy alone in locally advanced pancreatic cancer. PATIENTS AND METHODS: One hundred and nineteen patients with locally advanced pancreatic cancer, with World Health Organization performance status of zero to two were randomly assigned to either the induction chemoradiation group (60 Gy, 2 Gy/fraction; concomitant 5-fluoro uracil infusion, 300 mg/m(2) per day, days 1-5 for 6 weeks; cisplatin, 20 mg/m(2) per day, days 1-5 during weeks 1 and 5) or the induction gemcitabine group (GEM: 1000 mg/m(2) weekly for 7 weeks). Maintenance gemcitabine (1000 mg/m(2) weekly, 3/4 weeks) was given in both arms until disease progression or toxicity. RESULTS: Overall survival was shorter in the chemoradiation than in the gemcitabine arm (median survival 8.6 [99% confidence interval 7.1-11.4] and 13 months [8,9,9-18], p=0.03). One-year survival was, respectively, 32 and 53%. These results were confirmed in a per-protocol analysis for patients who received 75% or more of the planned dose of radiotherapy. More overall grades 3-4 toxic effects were recorded in the chemoradiation arm, both during induction (36 versus 22%) and maintenance (32 versus 18%). CONCLUSION: This intensive induction schedule of chemoradiation was more toxic and less effective than gemcitabine alone. PMID- 21315645 TI - Simultaneous determination of seven informative Y chromosome SNPs to differentiate East Asian, European, and African populations. AB - Identification of the population origin of an individual is very useful for crime investigators who need to narrow down a suspect based on specimens left at a crime scene. Single nucleotide polymorphisms of the Y chromosome (Y-SNPs) are a class of markers of interest to forensic investigators because many of the markers indicate regional specificity, thus providing useful information about the geographic origin of a subject. We selected seven informative Y-SNPs (M168, M130, JST021355, M96, P126, P196, and P234) to differentiate the three major population groups (East Asian, European, and African) and used them to develop forensic application. SNP genotyping was carried out by multiplex PCR reaction and multiplex single base extension (MSBE) reaction followed by capillary electrophoresis of extension products. This method can be used to assign a haplogroup from both degraded male DNA samples and DNA samples containing a mixture of female and male DNA through PCR primers that generate small amplicons (less than about 150 bp) and are highly specific for targets on the Y chromosome. The allelic state of each marker was definitively determined from a total of 791 males from the three major population groups. As expected, samples from the three major population groups showed Y-haplogroups common in the region of provenance: Y haplogroups C, D, and O for East Asians; IJ and R1 for Europeans; and AB and E for Africans. PMID- 21315646 TI - Postmortem pulmonary edema: a comparison between immediate and delayed postmortem computed tomography. AB - OBJECTIVE: Postmortem CT (PMCT) findings may change with the passage of time after death. The aim of this study was to investigate time-dependent PMCT findings of the lung in order to aid the interpretation of postmortem images obtained at various times. MATERIALS AND METHODS: Our subjects were three non traumatically deceased male subjects (25, 44, and 76 years old) who underwent whole body PMCT scan at two time points: one immediately after death and the other several hours after death but before the autopsy. The causes of death of the subjects were acute cardiac insufficiency (so-called sudden manhood death syndrome, 2 subjects), ischemic heart disease (acute coronary syndrome, 1 subject). The immediate and delayed PMCT findings of the lung were compared, and the differences between them were investigated. RESULTS: Compared with immediate PMCT, delayed PMCT showed advanced dependent opacity and consolidation corresponding to congestive pulmonary edema. CONCLUSION: PMCT images of the lung change as the time after death increases due to the natural postmortem changes of the corpse. Immediate PMCT is more suitable than delayed PMCT for discerning cause of death. Delayed PMCT reflects the autopsy findings more accurately than immediate PMCT. PMID- 21315647 TI - One-pot sonochemical fabrication of hierarchical hollow CuO submicrospheres. AB - Hierarchical hollow CuO submicrospheres have been fabricated on a large scale by a facile one-pot sonochemical process in the absence of surfactants and additives. The as-prepared products were investigated by XRD, FESEM, EDX, TEM, SAED, HRTEM and BET nitrogen adsorption-desorption isotherms. The results reveal that hollow pumpkin-shaped structures possess a monoclinic phase CuO with the diameters ranging from 400 to 500 nm, and their walls with around 45 nm in thickness are composed of numerous single crystalline CuO nanoribbons with a width of about 8 nm. The BET specific surface area of the as-synthesized CuO hollow structures was measured to be 59.60 m(2)/g, and the single point adsorption total pore volume was measured to be 0.1036 cm(3)/g. A possible growth mechanism for the formation of hierarchical hollow CuO structures was proposed, which is considered to be a sonohydrolysis - oriented aggregation - Ostwald ripening process. The novel hollow CuO spherical structures may utilize applications in biosensors, photonics, electronics, and catalysts. PMID- 21315648 TI - The acute antiparkinsonian and antidyskinetic effect of AFQ056, a novel metabotropic glutamate receptor type 5 antagonist, in L-Dopa-treated parkinsonian monkeys. AB - Overactivity of glutamatergic transmission has been implicated in Parkinson's disease (PD) and levodopa (L-Dopa)-induced dyskinesias. Striatal metabotropic glutamate receptors type 5 (mGluR5) are abundant and provide specific targets to modulate glutamatergic activity. This study investigated the acute effects of the novel mGluR5 antagonist AFQ056 on motor behavior in L-Dopa-treated monkeys with a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion to model PD. Six Macaca fascicularis MPTP monkeys were treated repeatedly with L-Dopa; this treatment increased their locomotion and reduced their parkinsonian scores, but also induced dyskinesias. When AFQ056 (doses of 5, 25, 125 or 250mg/kg) was administered one hour prior to a high dose of L-Dopa, the antiparkinsonian activity of L-Dopa was maintained as measured with locomotion and antiparkinsonian scores, whereas dyskinesias were significantly reduced at 25, 125 and 250mg/kg AFQ056 for peak dyskinesia score and at 125 and 250mg/kg for the 1h peak period of dyskinesia score. Administration of AFQ056 one hour before L Dopa led to peak or elevated plasma AFQ056 concentrations occurring close to L Dopa peak-dose dyskinesias. We next investigated AFQ056 25mg/kg combined with a low dose of L-Dopa. The antiparkinsonian activity of L-Dopa was increased as measured with locomotion, while dyskinesias remained low at these doses. Our results show a beneficial motor effect of AFQ056 with L-Dopa in MPTP monkeys. This supports the therapeutic use of an mGluR5 antagonist to restore normal glutamatergic neurotransmission in PD and decrease dyskinesias. PMID- 21315649 TI - The validity and accuracy of clinical diagnostic tests used to detect labral pathology of the hip: a systematic review. AB - Acetabular labral tears are an area of increasing interest to clinicians involved in the diagnosis of musculoskeletal complaints of the hip. This review systematically evaluated the evidence for the diagnostic accuracy and validity of reported symptoms, physical examination and imaging in this complex population. Studies published in English prior to May 2010 were included. One reviewer searched information sources to identify relevant articles. Two reviewers independently assessed studies for inclusion, extracted data and evaluated quality using the Quality Assessment of Diagnostic Studies Tool. Twenty one studies were included. Meta-analysis was limited owing to heterogeneity between studies. Results showed Magnetic Resonance Arthrography to consistently outperform Magnetic Resonance Imaging. Computerised Tomography also showed high accuracy levels for the few studies identified. Studies investigating physical tests were of poor quality demonstrating a need for further research in this area. Symptoms likely to be present in patients presenting with acetabular labral tears were found to be anterior groin pain and mechanical hip symptoms; however, additional good quality studies are needed to consolidate findings. PMID- 21315650 TI - A spatiotemporal statistical atlas of motion for the quantification of abnormal myocardial tissue velocities. AB - In this paper, we present a new method for the automatic comparison of myocardial motion patterns and the characterization of their degree of abnormality, based on a statistical atlas of motion built from a reference healthy population. Our main contribution is the computation of atlas-based indexes that quantify the abnormality in the motion of a given subject against a reference population, at every location in time and space. The critical computational cost inherent to the construction of an atlas is highly reduced by the definition of myocardial velocities under a small displacements hypothesis. The indexes we propose are of notable interest for the assessment of anomalies in cardiac mobility and synchronicity when applied, for instance, to candidate selection for cardiac resynchronization therapy (CRT). We built an atlas of normality using 2D ultrasound cardiac sequences from 21 healthy volunteers, to which we compared 14 CRT candidates with left ventricular dyssynchrony (LVDYS). We illustrate the potential of our approach in characterizing septal flash, a specific motion pattern related to LVDYS and recently introduced as a very good predictor of response to CRT. PMID- 21315651 TI - Penetrating cardiac injury following sewing needle ingestion. AB - Penetrating cardiac injuries are common in South Africa. Reports describing traumatic lesions to the heart caused by caudo-cranial migration of ingested foreign bodies are however extremely rare. Delayed presentation and intervention are associated with poor outcome in these patients; cardiac tamponade remains the most serious complication. We present the case of a 19 year-old man who sustained a left ventricular injury after intentionally swallowing eight sewing needles. The impacted needle was removed through a median sternotomy and the patient recovered uneventfully. PMID- 21315652 TI - Angioembolisation of pulmonary artery pseudoaneurysm arising in H1N1 influenza viral pneumonia. AB - A 51 year-old Aboriginal woman was diagnosed with H1N1 influenza virus and methicillin-resistant Staphylococcus aureus. Contrasted CT of the pulmonary and bronchial vasculature undertaken for investigation for of haemoptysis revealed an 11 mm left upper lobe pulmonary artery pseudoaneurysm (PAP). The PAP was successfully treated with angioembolisation of the parent artery with two platinum coils. Pulmonary artery pseudoaneurysms are uncommon but potentially life-threatening and have not previously been reported in association with H1N1 influenza viral pneumonia, which has been prominent in recent times in both medical literature and popular press. PMID- 21315653 TI - Opinions and experiences with cancer patients in educational settings. PMID- 21315654 TI - Preladenant in patients with Parkinson's disease and motor fluctuations: a phase 2, double-blind, randomised trial. AB - BACKGROUND: Preladenant is an adenosine 2A (A2(A)) receptor antagonist. In animal models of Parkinson's disease, preladenant monotherapy improves motor function without causing dyskinesia and, as an adjunct to levodopa, it improves motor function without worsening dyskinesia. We aimed to assess the efficacy and safety of preladenant in patients with Parkinson's disease and motor fluctuations who were receiving levodopa and other antiparkinsonian drugs. METHODS: In this phase 2, dose-finding trial, patients with Parkinson's disease who were receiving levodopa were enrolled and treated at 44 sites in 15 countries between December, 2006, and November, 2008. Assignment to treatment was done centrally with an interactive voice response system, according to a block randomisation schedule that was computer generated by the sponsor. Patients were assigned to receive 1, 2, 5, or 10 mg oral preladenant twice daily, or matching placebo for 12 weeks. Patients, study staff, investigators, and all sponsor personnel were masked to treatment assignment. The primary outcome was change in mean daily off time from baseline to week 12, as assessed by home diaries. Efficacy analysis included all patients who received at least one dose of study drug and had data for assessments after baseline. This trial is registered with ClinicalTrials.gov, number NCT00406029. FINDINGS: 253 patients were randomised to receive preladenant (1 mg [n=49], 2 mg [n=49], 5 mg [n=49], 10 mg [n=57]) or placebo (n=49), of whom 234 on preladenant (1 mg [n=47], 2 mg [n=48], 5 mg [n=45], 10 mg [n=49]) and placebo (n=45) were eligible for the efficacy analysis. Mean daily off time from baseline to week 12 was reduced versus placebo in patients on 5 mg preladenant (difference -1.0 h, 95% CI -2.1 to 0.0; p=0.0486) and 10 mg preladenant (-1.2 h, 2.2 to -0.2; p=0.019). Changes in mean daily off time versus placebo were not significant for 1 mg preladenant (0.2 h, -0.9 to 1.2; p=0.753) or 2 mg preladenant (-0.7 h, -1.7 to 0.3; p=0.162). The most common adverse events in the combined preladenant group versus placebo were worsening of Parkinson's disease (22 [11%] vs 4 [9%]), somnolence (20 [10%] vs 3 [6%]), dyskinesia (18 [9%] vs 6 [13%]), nausea (17 [9%] vs 5 [11%]), constipation (15 [8%] vs 1 [2%]), and insomnia (15 [8%] vs 4 [9%]). INTERPRETATION: 5 and 10 mg preladenant twice daily might be clinically useful to reduce off time in patients with Parkinson's disease and motor fluctuations. FUNDING: Schering-Plough, a subsidiary of Merck. PMID- 21315655 TI - Another trial, another hour. PMID- 21315657 TI - Do trends in physical activity, sedentary, and dietary behaviors support trends in obesity prevalence in 2 border regions in Texas? AB - OBJECTIVE: The aim of the study was to compare the change in energy balance related behaviors from 2000-2002 to 2004-2005 between 2 Texas regions with distinct patterns in obesity prevalence (decrease in the El Paso region [EP] and leveling off in the Rio Grande Valley region [RGV]) and to determine the role of the behaviors in the difference in obesity prevalence between the regions. DESIGN: Cross-sectional measurements of the School Physical Activity and Nutrition Study. SETTING: Elementary schools. PARTICIPANTS: 3,949 children (9-10 years). VARIABLES MEASURED: Body mass index (objectively measured) and behaviors (self-assessed). ANALYSIS: Probability and post-stratification weighting procedures and mediation analysis. RESULTS: Compared to students in the RGV, students in the EP experienced a smaller decrease in sports team participation, an increase in regular meal consumption, and an increase in the frequency of milk/yogurt, cereal, sweet snacks, and frozen dessert consumption between measurement periods. Prevalence of frequent television viewing was lower in the EP. The lower body mass index in the EP was associated with regular meal consumption, and higher milk/yogurt and sweet snack consumption. CONCLUSIONS AND IMPLICATIONS: Improvement of physical activity, sedentary behaviors, and healthful diet, but not unhealthful diet like sweet snack consumption, seem to be related to the decrease in obesity in the EP. PMID- 21315656 TI - Bacterial protein structures reveal phylum dependent divergence. AB - Protein sequence space is vast compared to protein fold space. This raises important questions about how structures adapt to evolutionary changes in protein sequences. A growing trend is to regard protein fold space as a continuum rather than a series of discrete structures. From this perspective, homologous protein structures within the same functional classification should reveal a constant rate of structural drift relative to sequence changes. The clusters of orthologous groups (COG) classification system was used to annotate homologous bacterial protein structures in the Protein Data Bank (PDB). The structures and sequences of proteins within each COG were compared against each other to establish their relatedness. As expected, the analysis demonstrates a sharp structural divergence between the bacterial phyla Firmicutes and Proteobacteria. Additionally, each COG had a distinct sequence/structure relationship, indicating that different evolutionary pressures affect the degree of structural divergence. However, our analysis also shows the relative drift rate between sequence identity and structure divergence remains constant. PMID- 21315658 TI - Emotional trauma and abuse in patients with psychogenic nonepileptic seizures. AB - A history of childhood trauma and the presence of dissociative phenomena are considered to be the most important risk factors for psychogenic nonepileptic seizure disorder (PNESD). This case-control study investigated 20 patients with PNESD and 20 with temporal lobe epilepsy (TLE) diagnosed by video/EEG monitoring who were matched for gender and age. Patients with both conditions were not included in the study. Groups were evaluated for age at onset and at diagnosis, worst lifetime weekly seizure frequency, trauma history, and presence of dissociative phenomena. Age at onset (P=0.007) and age at diagnosis (P<0.001) were significantly higher in the PNESD group than the control group, as were the scores on the Dissociative Experiences Scale (P<0.001) and Childhood Trauma Questionnaire (P=0.014). Only the differences in scores on the Childhood Trauma Questionnaire subscales Emotional Neglect (P=0.013) and Emotional Abuse (P=0.014) reached statistical significance. Dissociative phenomena and a reported history of childhood trauma are more common in patients with PNESD than in those with TLE. However, only emotional neglect and abuse were associated with PNESD in this study. PMID- 21315659 TI - Consciousness impairment and diagnostic criteria for nonconvulsive status epilepticus. PMID- 21315660 TI - Psychiatric and neurodevelopmental disorders in childhood-onset epilepsy. AB - Childhood-onset epilepsy is associated with psychiatric and cognitive difficulties and with poor social outcomes in adulthood. In a prospective cohort of young people with epilepsy, we studied psychiatric and neurodevelopmental disorders and epilepsy-related characteristics, all factors that may influence long-term social outcomes. Five hundred one subjects, 159 with complicated (IQ <80 or brain lesion) and 342 with uncomplicated epilepsy, were included. Psychiatric disorders and neurodevelopmental disorders were more common in complicated epilepsy (P<0.005). In uncomplicated epilepsy, externalizing but not internalizing disorders were strongly associated with neurodevelopmental disorders. Internalizing disorders and neurodevelopmental disorders were associated with lack of 5-year remission. Type of epilepsy was not associated with neurodevelopmental disorders or psychiatric disorders. Various comorbid conditions in epilepsy cluster together and are modestly associated with imperfect seizure control. These need to be considered together in evaluating and managing young people with epilepsy and may help explain long-term social outcomes above and beyond poor seizure control. PMID- 21315661 TI - The opioid debate-missing the point. PMID- 21315662 TI - Transumbilical 2-site laparoscopic Roux-en-Y gastric bypass: initial results of 100 cases and comparison with traditional laparoscopic technique. AB - BACKGROUND: Single-site or single-incision laparosopic surgery has recently been developed, but it is difficult to use in more complicated gastric bypass surgery. We have introduced a 2-site modified single-incision laparosopic surgery technique for laparoscopic Roux-en-Y gastric bypass (LRYGB). METHODS: We used the umbilical site incision to place 2 ports (12 and 10 mm) to serve as the video port and working port for the stapler. Another small skin incision was placed at a left lateral abdominal site for the 5-mm working port. Through these working channels, we could use conventional laparoscopic instruments to perform LRYGB. The data from 100 consecutive 2-site LRYGB procedures (February 2009 to September 2009) were compared with the data from 100 traditional LRYGB procedures (September 2008 to January 2009). RESULTS: The mean body mass index for the study group was 43 kg/m(2) (range 32-61), and mean age was 34 years (range 18-55). The procedures were successfully performed in all but 18 patients. These 18 patients had required an extra skin incision for a 5-mm port to complete the procedures. The mean operating time was 144 minutes (range 95-160), and blood loss was 56 mL (range 20-150). A total of 3 perioperative major complications (3%) occurred, and 6 patients (6%) had minor complications. The 2-site LRYGB group had a significantly longer operating time and more blood loss than the traditional LRYGB group but less pain and better cosmesis. CONCLUSION: Two-site LRYGB generated minimal somatic pain and achieved excellent cosmetic results. We believe it can be applied as routine LRYGB surgery. PMID- 21315663 TI - Mismatch and base excision repair proficiency in murine embryonic stem cells. AB - Accumulation of mutations in embryonic stem (ES) cells would be detrimental to an embryo derived from these cells, and would adversely affect multiple organ systems and tissue types. ES cells have evolved multiple mechanisms to preserve genomic integrity that extend beyond those found in differentiated cell types. The present study queried whether mismatch repair (MMR) and base-excision repair (BER) may play a role in the maintenance of murine ES cell genomes. The MMR proteins Msh2 and Msh6 are highly elevated in mouse ES cells compared with mouse embryo fibroblasts (MEFs), as are Pms2 and Mlh1, albeit to a lesser extent. Cells transfected with an MMR reporter plasmid showed that MMR repair capacity is low in MEFs, but highly active in wildtype ES cells. As expected, an ES cell line defective in MMR was several-fold less effective in repair level than wildtype ES cells. Like proteins that participate in MMR, the level of proteins involved in BER was elevated in ES cells compared with MEFs. When BER activity was examined biochemically using a uracil-containing oligonucleotide template, repair activity was higher in ES cells compared with MEFs. The data are consistent with the suggestion that ES cells have multiple mechanisms, including highly active MMR and BER that preserve genetic integrity and minimize the accumulation of mutations. PMID- 21315664 TI - Potential application of hydrogel-based strong anion-exchange membrane for plasmid DNA purification. AB - The potential application of a hydrogel-based strong anion-exchange (Q) membrane to purify plasmid DNAs was evaluated. The maximum binding capacity of plasmid DNA was estimated to be 12.4 mg/ml of membrane volume with a plasmid recovery yield of ~90%. The effect of the inherent properties of plasmid DNA, membrane adsorbent, and the ionic environment on membrane performance was systematically investigated. Plasmid DNAs with smaller tertiary structure tended to have a better recovery than those with larger tertiary structure. Environmental Scanning Electron Microscopy (ESEM) revealed that the hydrogel structure is more porous on one side of membrane than the other. Membrane pre-treatment significantly improved pore distribution and increased membrane porosity resulting in a better adsorption, recovery, and higher flux. The selection of proper operating pH led to further improvement. The relative contribution of these factors to improve membrane chromatography of plasmid DNAs was analyzed using statistical modeling. It was found that the adsorption of plasmid DNA was mainly affected by the available adsorptive area associated with membrane porosity, whereas the recovery of plasmid DNAs was mainly affected by the environmental pH. PMID- 21315665 TI - High tumor levels of IL6 and IL8 abrogate preclinical efficacy of the gamma secretase inhibitor, RO4929097. AB - Interest continues to build around the early application of patient selection markers to prospectively identify patients likely to show clinical benefit from cancer therapies. Hypothesis generation and clinical strategies often begin at the preclinical stage where responder and nonresponder tumor cell lines are first identified and characterized. In the present study, we investigate the drivers of in vivo resistance to the gamma-secretase inhibitor RO4929097. Beginning at the tissue culture level, we identified apparent IL6 and IL8 expression differences that characterized tumor cell line response to RO4929097. We validated this molecular signature at the preclinical efficacy level identifying additional xenograft models resistant to the in vivo effects of RO4929097. Our data suggest that for IL6 and IL8 overexpressing tumors, RO4929097 no longer impacts angiogenesis or the infiltration of tumor associated fibroblasts. These preclinical data provide a rationale for preselecting patients possessing low levels of IL6 and IL8 prior to RO4929097 dosing. Extending this hypothesis into the clinic, we monitored patient IL6 and IL8 serum levels prior to dosing with RO4929097 during Phase I. Interestingly, the small group of patients deriving some type of clinical benefit from RO4929097 presented with low baseline levels of IL6 and IL8. Our data support the continued investigation of this patient selection marker for RO4929097 and other types of Notch inhibitors undergoing early clinical evaluation. PMID- 21315666 TI - Validation of the Italian translation of the Inflammatory Bowel Disease Questionnaire. AB - BACKGROUND: Health-related quality of life is an important measure of treatment outcome; its evaluation requires the use of internationally validated ad hoc questionnaires. The McMaster Inflammatory Bowel Disease Questionnaire (IBDQ) is the most used specific instrument. AIM: To assess the validity and reliability of the Italian translation of the IBDQ. METHODS: The IBDQ underwent forward and backward translation; 13 patients were enrolled for cognitive testing of the Italian version to increase clarity. For field testing, 113 patients (65 with Crohn's disease and 48 with ulcerative colitis) completed both the IBDQ and the generic instrument 36-item Short Form Health Survey scale (SF-36). RESULTS: Data quality was optimal with high completeness and low floor and ceiling effect. Item internal consistency was satisfied for 100% of patients, while discriminant validity showed a few items with higher correlations with other scales. Cronbach's alpha coefficient was 0.96. Test-retest correlations indicated good reliability (Pearson R 0.81). Exploratory factor analysis indicated that the original grouping of the item was suboptimal. The score proved sensitive to disease activity, gender and quality of life as measured by the SF-36. CONCLUSIONS: The Italian translation of the McMaster Inflammatory Bowel Disease Questionnaire sounds natural and is easy to understand. A field test gave results comparable to other international validations, supporting its use in cross national surveys. PMID- 21315667 TI - [Environment and paediatric cancer in the Region of Murcia (Spain): integrating clinical and environmental history in a geographic information system]. AB - INTRODUCTION: Environment and Paediatric Cancer (PC) in the Region of Murcia (RM) is an on-going research project that has the following aims: to collect a careful paediatric environmental history (PEH) and to use geographical information systems (GIS) to map the incidence and analyze the geographic distribution of the PC incidence in the RM. The objectives are to present the methodology used for the collection and processing of data and disseminate initial results on the spatial and temporal incidence of PC in the RM (Spain). MATERIAL AND METHODS: A descriptive and georeference study of all PC cases under 15 years, diagnosed from 1 January 1998 to December 31, 2009. Three postal addresses were assigned to each case, residence during pregnancy, postnatal, and at the time of diagnosis. Other variables such as sex, date of birth, date of diagnosis, and histopathology classification were collected. RESULTS: No increase was observed in the trend of incidence of PC. The crude annual incidence rate was 14.3 cases per 100,000 children under 15 years. The standardised incidence ratio was higher in the north west of the RM. Before diagnosis, 30% of cases had a different postal address than during the pregnancy. CONCLUSIONS: Integrating the spatial and temporal information through the PEH in a GIS should allow the identification and study of space-time clusters through an environmental monitoring system in order to know the importance of associated risk factors. PMID- 21315668 TI - [1p36 microdeletion syndrome]. PMID- 21315669 TI - [Spanish paediatric research in ANALES DE PEDIATRIA: research groups and research areas (2003-2009)]. AB - INTRODUCTION: Authorships of scientific papers are a significant milestone for researchers. Quantification of authors' contribution in research papers makes it possible to investigate patterns of research collaboration and interactions in scientific community. The objective of this paper is to analyse scientific collaboration and to identify research groups and research areas of ANALES DE PEDIATRIA. MATERIAL AND METHODS: Papers published in ANALES DE PEDIATRIA between 2003 and 2009 period were selected from Medline. An author name normalization process was carried out. Productivity and scientific collaboration indexes have been determined. Research groups have been identified through co-authorships networks analysis. Thematic areas of research and major domains of research groups have been characterised by means of quantification of Medical Subject Headings terms assigned to documents. RESULTS: An analysis was made of 1,828 documents published by 4,695 authors. The collaboration index (articles) was 5.3 +/- 2.3. A total of 97 research groups consisting of between 2 and 80 researchers, which add up 415 researchers have been identified. The main diseases and medical signs studied were asthma (n = 35), multiple abnormalities (n = 28), premature diseases (n = 25), sepsis (n = 24), congenital heart defects (n = 23), respiratory insufficiency (n = 22), HIV infections (n = 21), streptococcal infections (n = 20) and gastroenteritis (n = 20). CONCLUSIONS: ANALES DE PEDIATRIA is one of the most productive Spanish medical journals. Author's collaboration was similar to those observed in other Spanish clinical journals included in Journal Citation Reports. A remarkable number of paediatric research groups publishing on many topics have been identified. PMID- 21315670 TI - [Paroxysmal supraventricular tachycardia and severe respiratory syncytial virus infection in the neonatal period]. PMID- 21315671 TI - Growth of cranial volume: an anthropometric study. AB - The aim of the study is to follow the growth dynamics of cranial volume from birth to 18 years of age among 1623 central Indian subjects. Anthropometric technique was adopted to estimate the cranial volume using maximum length, width and auricular height of head. The mean cranial volume at birth is 376 cc in male and 308 cc in female i.e. 28% and 26% of the 18 years old volume. Within a year the volume reaches 65% in male and 59% in female of the adult size due to very rapid growth during the first six months after birth. The adult cranial volume at 18 years is 1329 cc in males and 1193 cc in females, approximately 3.5 and 4 times of the birth size respectively. The cranial volume reaches its adult size in females at 16 years of age and a year later in males. The present study has generated metrical norms for all growing ages and also the growth dynamics for cranial volume of Indian subjects which will be useful to physicians as a guideline in correcting cranial deformity. PMID- 21315672 TI - Color-coded longitudinal interventricular septal tissue velocity imaging, strain and strain rate in healthy Doberman Pinschers. AB - OBJECTIVE: To determine reference values for septal longitudinal tissue Doppler imaging (TDI) in Doberman Pinschers. BACKGROUND: TDI includes several new techniques, such as tissue velocity imaging (TVI), strain, and strain rate that might be used to detect early myocardial dysfunction. However, before these techniques can be used, breed specific reference ranges need to be established. ANIMALS, MATERIALS AND METHODS: One-hundred healthy Doberman Pinschers >= 4 years of age were prospectively evaluated using electrocardiography, Holter recording, and echocardiography. Systolic, early and late diastolic parameters of septal longitudinal color-coded TVI, strain, and strain rate were analyzed in three myocardial segments (basal, middle, and apical). RESULTS: TDI was feasible in all Doberman Pinschers. Reference values were established for every myocardial segment. There was a significant velocity gradient from the basal to the apical segment for all TVI parameters. No differences between the three segments were found for systolic strain and strain rate. Several diastolic strain rate values were significantly different between myocardial segments. Influence of age, weight, and gender was not clinically relevant. CONCLUSIONS: This study provides reference values for TVI, strain, and strain rate in Doberman Pinschers. The parameters established here can be used for a supportive diagnostic approach. PMID- 21315673 TI - Ventilatory disorders and facial growth: benefits of early genioplasty. AB - AIM: The purpose of this prospective study was to determine whether combined functional genioplasty and orthodontic treatment in patients with vertical mandibular growth can be beneficial not only in achieving an esthetic outcome and orthodontic stability but also for the multi-disciplinary management of oral ventilation. METHODS: Twenty-five non-obese adolescents (mean age: 14.6 +/- 1.4 years) with vertical excess of the lower third requiring genioplasty received surgery following orthodontic treatment. All were predominantly mouth-breathers despite ENT treatment and rehabilitation. The functional before-after impact of genioplasty was examined in a clinical setting using polysomnography. RESULTS: Before genioplasty, 52% of the adolescents presented an upper airways resistance syndrome (UARS) with obstructive hypopnea and poor sleep quality. Three to 6 months after genioplasty, the mode of ventilation shifted from oral to nasal (p < 0.001). Lip seal was significantly restored with no contraction of the labio mental muscles. All nighttime symptoms improved. The proportion of patients suffering from ronchopathy (pathological snoring), dry mouth and disturbed sleep dropped significantly (p = 0.08, p = 0.001, p = 0.0009, respectively). Respiratory events and sleep pattern became normal. Below, we present two clinical reports involving obstructive sleep apnea syndrome (OSAS). CONCLUSIONS: Genioplasty performed during puberty promotes spontaneous lip closure and helps restore nasal ventilation. It improves the obstructive disorder and its manifestations during sleep. PMID- 21315675 TI - Developing a best practice model of refugee maternity care. AB - BACKGROUND: About one third of refugee and humanitarian entrants to Australia are women age 12-44 years. Pregnant women from refugee backgrounds may have been exposed to a range of medical and psychosocial issues that can impact maternal, fetal and neonatal health. RESEARCH QUESTION: What are the key elements that characterise a best practice model of maternity care for women from refugee backgrounds? This paper outlines the findings of a project which aimed at developing such a model at a major maternity hospital in Brisbane, Australia. PARTICIPANTS AND METHODS: This multifaceted project included a literature review, consultations with key stakeholders, a chart audit of hospital use by African born women in 2006 that included their obstetric outcomes, a survey of 23 African born women who gave birth at the hospital in 2007-08, and a survey of 168 hospital staff members. RESULTS: The maternity chart audit identified complex medical and social histories among the women, including anaemia, female circumcision, hepatitis B, thrombocytopenia, and barriers to access antenatal care. The rates of caesarean sections and obstetric complications increased over time. Women and hospital staff surveys indicated the need for adequate interpreting services, education programs for women regarding antenatal and postnatal care, and professional development for health care staff to enhance cultural responsiveness. DISCUSSION AND CONCLUSIONS: The findings point towards the need for a model of refugee maternity care that comprises continuity of carer, quality interpreter services, educational strategies for both women and healthcare professionals, and the provision of psychosocial support to women from refugee backgrounds. PMID- 21315676 TI - Case report of a fatal bear attack documented by forensic wildlife genetics. AB - Fatal bear attacks on humans are extremely rare across Europe. Here we report a fatal bear attack on a man in Bulgaria. We used microsatellite analysis for bear individualization based on hair samples found near the man's corpse. The genetic profile of the killing bear was compared to that of a bear shot three days later near the killing scene. Our results show that the wrong bear has been shot. Shortly after our results were reported a second person was attacked by a bear nearby. This case documents the importance of forensic DNA analysis following severe wildlife attacks in order to improve wildlife management actions in regions were direct human-bear conflicts are likely to happen. PMID- 21315677 TI - Tibial component rotation assessment using CT scan in medial and lateral unicompartmental knee arthroplasty. AB - BACKGROUND: Rotation of tibial component has not been analysed in literature for unicompartmental knee arthroplasty. The purpose of the study was to determine and compare the rotation of medial and lateral unicompartmental knee arthroplasty (UKA) tibial components. We assumed both components (lateral and medial) were positioned with external rotation. PATIENTS AND METHODS: Eighteen lateral and 19 medial UKA patients were scanned postoperatively in neutral position with computed tomography enabling lower extremity three-dimensional image acquisition from the hip to the ankle. All the patients were operated by three different senior surgeons using the same surgical technique. From the reconstructions we measured the two-dimensional (2D) rotation of the tibial components. RESULTS: The rotation of the tibial component was external (mean 6.5 degrees , SD 5.1 degrees ) for the medial UKA and external (mean 7.3 degrees , SD 10.3 degrees ) as well for the lateral UKA. The difference was statistically insignificant (P=0.717). DISCUSSION: This study presents the first 2D in vivo analysis accurately determining and comparing medial and lateral UKA component rotation. Despite a wide range of value, we found both components were indeed externally rotated. The variability in implant positioning was observed despite the rigorous performance of an experienced surgeon using routine techniques in patients selected under routine criteria. Further analysis of these patients for satisfaction and implant survivorship in relation to implant rotation may give us an optimal range for the tibial component. If it is found that this ideal range cannot be consistently obtained with current surgical techniques then there may be a case for the use of a navigation system. PMID- 21315678 TI - A 12-month moderate-intensity exercise intervention does not alter serum prolactin concentrations. AB - INTRODUCTION: Many studies have investigated the immediate impact of physical activity on prolactin concentrations; however, it is currently unclear what impact exercise may have on prolactin concentrations in the long-term, particularly among women. Understanding the role of exercise on prolactin is important because epidemiologic studies have reported increased risks of breast cancer in association with high prolactin concentrations. We investigated whether exercise alters serum prolactin concentrations at two time points within a one year exercise intervention. METHODS: Out of 96 women aged 40-75 years, 47 were randomized to a 12-month regimen of moderate-intensity physical activity and 49 were randomized to the control group. Participants in the exercise group (exercisers) took part in exercise at gym facilities 3 times per week and 3 times per week on their own. Serum prolactin was collected from participants at baseline, 3 and 12 months. Using generalized linear models, we compared the percent change in prolactin concentrations from baseline to the two follow-up time points in the exercisers versus the control group. RESULTS: While we observed the suggestion of differences in the change in serum prolactin concentrations in some subgroups, overall there was no difference in the change in prolactin concentrations between exercisers and controls at 3 months (p=0.57) or 12 months (p=0.42). CONCLUSION: Our study does not support the hypothesis that long-term exercise influences serum prolactin concentrations. PMID- 21315680 TI - Evaluation of the pyrrole insecticide chlorfenapyr for the control of Culex quinquefasciatus Say. AB - Culex quinquefasciatus Say (Diptera: Culicidae) is a widely distributed mosquito vector species in India and also in other tropical regions of the world. This species is implicated in the transmission of lymphatic filariasis in many countries. This species is reported to be widely resistant to insecticides of different classes in current use. In the present study, bio-efficacy of chlorfenapyr, an insecticide of pyrrole class with a novel mode of action was tested for the control of Cx. quinquefasciatus. Studies were performed to determine the diagnostic dosage; residual efficacy on different artificially fabricated substrates, namely wood, mud, mud+lime, cement and cement+distemper; to assess cross-resistance with different insecticides; and synergism/antagonism using piperonyl butoxide (PBO). A dosage of 5.0% chlorfenapyr was determined as diagnostic dosage with 2 h exposure and 48 h holding period for assessing the susceptibility of mosquitoes. The residual efficacy was observed up to 34 weeks on wood and mud+lime substrates while on other substrates, it was about 15 weeks at a dosage of 400mg a.i./m(2). Laboratory-reared strains of Cx. quinquefasciatus showed cross-resistance, whereas field-collected mosquitoes showed absence of cross-resistance to chlorfenapyr. Potentiation bioassays showed antagonistic effect of PBO to chlorfenapyr toxicity owing to the involvement of oxidases in the initial step of a conversion of pro-insecticide chlorfenapyr to toxic form CL 303268. The present study results have shown that chlorfenapyr can be a potential insecticide for the control of multiple insecticide resistant strains of Cx. quinquefasciatus. However, in countries where indoor residual spray (IRS) is not targeted for the control of this species, like in India, chlorfenapyr used in IRS for the control of malaria vectors in rural and peri-urban areas can additionally provide control of Cx. quinquefasciatus also. PMID- 21315679 TI - Green tea consumption, inflammation and the risk of primary hepatocellular carcinoma in a Chinese population. AB - OBJECTIVE: Green tea has been found to possess anti-inflammatory, anti-oxidative and anti-carcinogenic properties. The present study examines the association between green tea drinking and hepatocellular carcinoma (HCC) and its interactions with other risk or protective factors and single nucleotide polymorphisms (SNP) of inflammation and oxidative stress related genes. METHODS: A population-based case-control study with 204 primary HCC cases and 415 healthy controls was conducted in Taixing, China. Epidemiological data were collected using a standard questionnaire. SNPs of genes of the inflammation and metabolic pathways were genotyped at the UCLA Molecular Epidemiology Laboratory. Logistic regression was performed to estimate adjusted odds ratios and 95% confidence intervals. RESULTS: Longer duration and larger quantities of green tea consumption were inversely associated with primary HCC. Individuals who drank green tea longer than 30 years were at lowest risk (adjusted OR=0.44, 95% CI: 0.19-0.96) compared with non-drinkers. A strong interaction was observed between green tea drinking and alcohol consumption (adjusted OR for interaction=3.40, 95% CI: 1.26-9.16). Green tea drinking was also observed to have a potential effect modification on HBV/HCV infection, smoking and polymorphisms of inflammation related cytokines, especially for IL-10. CONCLUSION: Green tea consumption may protect against development of primary HCC. Potential effect modifications of green tea on associations between primary HCC and alcohol drinking, HBV/HCV infection, and inflammation-related SNPs were suggested. PMID- 21315681 TI - Quantitative, small-scale, fluorophore-assisted carbohydrate electrophoresis implemented on a capillary electrophoresis-based DNA sequence analyzer. AB - Fluorophore-assisted carbohydrate electrophoresis (FACE) is an analytical method for characterizing carbohydrate chain length that has been applied to neutral, charged, and N-linked oligosaccharides and that has been implemented using diverse separation platforms, including polyacrylamide gel electrophoresis and capillary electrophoresis. In this article, we describe three substantial improvements to FACE: (i) reducing the amount of starch and APTS required in labeling reactions and systematically analyzing the effect of altering the starch and 8-amino-1,3,6-pyrenetrisulfonic acid (APTS) concentrations on the reproducibility of the FACE peak area distributions; (ii) implementing FACE on a multiple capillary DNA sequencer (an ABI 3130xl), enabling higher throughput than is possible on other separation platforms; and (iii) developing a protocol for producing quantitative output of peak heights and areas using genetic marker analysis software. The results of a designed experiment to determine the effect of decreasing both the starch and fluorophore concentrations on the sensitivity and reproducibility of FACE electrophoregrams are presented. Analysis of the peak area distributions of the FACE electrophoregrams identified the labeling reaction conditions that resulted in the smallest variances in the peak area distributions while retaining strong fluorescence signals from the capillary-based DNA sequencer. PMID- 21315682 TI - An amperometric uric acid biosensor based on multiwalled carbon nanotube-gold nanoparticle composite. AB - An amperometric uric acid biosensor was fabricated by immobilizing uricase (EC 1.7.3.3) onto gold nanoparticle (AuNP)/multiwalled carbon nanotube (MWCNT) layer deposited on Au electrode via carbodiimide linkage. Determination of uric acid was performed by oxidation of enzymically generated H(2)O(2) at 0.4V. The sensor showed optimal response within 7s at 40 degrees C in 50mM Tris-HCl buffer (pH 7.5). The linear working range of the biosensor was 0.01-0.8mM. The limit of detection (LOD) was 0.01mM. The sensor measured uric acid levels in serum of healthy individuals and persons suffering from gout. The analytical recoveries of the added uric acid, 10 and 20mgL(-1), were 98.0% and 96.5%, respectively. Within and between-batch coefficients of variation were less than 5.6% and less than 4.7%, respectively. A good correlation (r=0.998) was obtained between serum uric acid values by the standard enzymic colorimetric method and the current method. A number of serum substances had practically no interference. The sensor was used in more than 200 assays and had a storage life of 120 days at 4 degrees C. PMID- 21315683 TI - Involvement of lipid rafts in macrophage apoptosis induced by cationic liposomes. AB - We have demonstrated that protein kinase Cdelta (PKCdelta) could be involved in macrophage apoptosis induced by cationic liposomes composed of stearylamine (SA liposomes), but the detailed mechanism of how SA-liposomes activate PKCdelta has remained unclear. In this paper, we clarified whether lipid rafts are involved in the PKCdelta activation induced by SA-liposomes. Co-localization of SA-liposomes and Cholera toxin B subunit (CBT), which specifically binds to ganglioside GM1 on lipid rafts, was found by microscopic observation. The incorporation of SA liposomes into lipid rafts was clearly inhibited by the pretreatment of cells with an agent, 2,6-di-O-methyl-alpha-cyclodextrin (DM-alpha-CD) which disrupts lipid rafts. Activation of PKCdelta and externalization of phosphatidylserine induced by SA-liposomes were also suppressed by DM-alpha-CD, which extracts sphingolipids and proteins from lipid rafts. Reactive oxygen species (ROS) generation, which could be involved in the macrophage apoptosis, was also inhibited by DM-alpha-CD. Furthermore, apoptosis induced by SA-liposomes was clearly inhibited when the cells were pre-treated with DM-alpha-CD, but not nystatin, a cholesterol-sequestering agent that disrupt lipid rafts. These findings suggest that sphingolipids in lipid rafts are involved in the activation of PKCdelta which leads to apoptosis induced by cationic liposomes, SA-liposomes. PMID- 21315684 TI - Heterologous expression and characterization of the sterol 14alpha-demethylase CYP51F1 from Candida albicans. AB - Lanosterol 14alpha-demethylase (CYP51F1) from Candida albicans is known to be an essential enzyme in fungal sterol biosynthesis. Wild-type CYP51F1 and several of its mutants were heterologously expressed in Escherichia coli, purified, and characterized. It exhibited a typical reduced CO-difference spectrum with a maximum at 446 nm. Reconstitution of CYP51F1 with NADPH-P450 reductase gave a system that successfully converted lanosterol to its demethylated product. Titration of the purified enzyme with lanosterol produced a typical type I spectral change with K(d)=6.7 MUM. The azole antifungal agents econazole, fluconazole, ketoconazole, and itraconazole bound tightly to CYP51F1 with K(d) values between 0.06 and 0.42 MUM. The CYP51F1 mutations F105L, D116E, Y132H, and R467K frequently identified in clinical isolates were examined to determine their effect on azole drug binding affinity. The azole K(d) values of the purified F105L, D116E, and R467K mutants were little altered. A homology model of C. albicans CYP51F1 suggested that Tyr132 in the BC loop is located close to the heme in the active site, providing a rationale for the modified heme environment caused by the Y132H substitution. Taken together, functional expression and characterization of CYP51F1 provide a starting basis for the design of agents effective against C. albicans infections. PMID- 21315685 TI - Stabilization of the peroxy intermediate in the oxygen splitting reaction of cytochrome cbb(3). AB - The proton-pumping cbb(3)-type cytochrome c oxidases catalyze cell respiration in many pathogenic bacteria. For reasons not yet understood, the apparent dioxygen (O(2)) affinity in these enzymes is very high relative to other members of the heme-copper oxidase (HCO) superfamily. Based on density functional theory (DFT) calculations on intermediates of the oxygen scission reaction in active-site models of cbb(3)- and aa(3)-type oxidases, we find that a transient peroxy intermediate (I(P), Fe[III]-OOH(-)) is ~6kcal/mol more stable in the former case, resulting in more efficient kinetic trapping of dioxygen and hence in a higher apparent oxygen affinity. The major molecular basis for this stabilization is a glutamate residue, polarizing the proximal histidine ligand of heme b(3) in the active site. PMID- 21315687 TI - Water permeation dynamics of AqpZ: a tale of two states. AB - Molecular dynamics simulations of aquaporin Z homotetramer which is a membrane protein facilitating rapid water movement through the plasma membrane of Escherichia coli were performed. Initial configurations were taken from the open and closed states of crystal structures separately. The resulting water osmotic permeability (pf) and diffusive permeability (pd) displayed distinct features. Consistent with previous studies, the side chain conformation of arginine189 was found to mediate the water permeability. A potential of mean force (PMF) as a function of the distance between NH1 of R189 and carbonyl oxygen of A117 was constructed based on the umbrella sampling technique. There are multiple local minima and transition states on the PMF. The assignment of the open or closed state was supported by the permeability pf, calculated within trajectories in umbrella sampling simulations. Our study disclosed a detailed mechanism of the gated water transport. PMID- 21315686 TI - Glutamine residues in Q-loops of multidrug resistance protein MRP1 contribute to ATP binding via interaction with metal cofactor. AB - Structural analyses of bacterial ATP-binding-cassette transporters revealed that the glutamine residue in Q-loop plays roles in interacting with: 1) a metal cofactor to participate in ATP binding; 2) a putative catalytic water molecule to participate in ATP hydrolysis; 3) other residues to transmit the conformational changes between nucleotide-binding-domains and transmembrane-domains, in ATP dependent solute transport. We have mutated the glutamines at 713 and 1375 to asparagine, methionine or leucine to determine the functional roles of these residues in Q-loops of MRP1. All these single mutants significantly decreased Mg.ATP binding and increased the K(m) (Mg.ATP) and V(max) values in Mg.ATP dependent leukotriene-C4 transport. However, the V(max) values of the double mutants Q713N/Q1375N, Q713M/Q1375M and Q713L/Q1375L were lower than that of wtMRP1, implying that the double mutants cannot efficiently bind Mg.ATP. Interestingly, MRP1 has higher affinity for Mn.ATP than for Mg.ATP and the Mn.ATP dependent leukotriene-C4 transport activities of Q713N/Q1375N and Q713M/Q1375M are significantly higher than that of wtMRP1. All these results suggest that: 1) the glutamine residues in Q-loops contribute to ATP-binding via interaction with a metal cofactor; 2) it is most unlikely that these glutamine residues would play crucial roles in ATP hydrolysis and in transmitting the conformational changes between nucleotide-binding-domains and transmembrane-domains. PMID- 21315688 TI - Anti-diabetic and anti-adipogenic effects of a novel selective 11beta hydroxysteroid dehydrogenase type 1 inhibitor, 2-(3-benzoyl)-4-hydroxy-1,1-dioxo 2H-1,2-benzothiazine-2-yl-1-phenylethanone (KR-66344). AB - The selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta HSD1) have considerable potential for treating type 2 diabetes mellitus and metabolic syndrome. In the present study, we investigated the anti-diabetic and anti-adipogenic effects of 2-(3-benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine 2-yl-1-phenylethanone (KR-66344), as a 11beta-HSD1 inhibitor; we also investigated the underlying molecular mechanisms in the cortisone-induced 3T3-L1 adipogenesis model system and C57BL/6-Lep(ob/ob) mice. KR-66344 concentration dependently inhibited 11beta-HSD1 activity in human liver microsome, mouse C2C12 myotube and human SW982 cells. In the C57BL/6-Lep(ob/ob) mice study, the administration of KR-66344 (200mg/kg/d, orally for 5 days) improved the glucose intolerance as determined by the oral glucose tolerance test, in which the area under the curve (AUC) of the plasma glucose concentration was significantly reduced by 27% compared with the vehicle treated group. Further, KR-66344 suppressed adipocyte differentiation on cortisone-induced adipogenesis in 3T3-L1 cells is associated with the suppression of the cortisone-induced mRNA levels of FABP4, G3PD, PPARgamma2 and Glut4, and 11beta-HSD1 expression and activity. Our results additionally demonstrate evidence showing that KR-66344 improved glycemic control and inhibited adipogenesis via 11beta-HSD1 enzyme activity. Taken together, these results may provide evidence of the therapeutic potential of KR 66344, as a 11beta-HSD1 inhibitor, in obesity and type 2 diabetes patients with metabolic syndrome. PMID- 21315689 TI - Effects of treadmill exercise on behavioral recovery and neural changes in the substantia nigra and striatum of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine lesioned mouse. AB - Our goal was to extend our understanding of the neural changes behind motor recovery with treadmill exercise in the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-lesioned mouse. We determined the extent of dopamine (DA) terminal changes using Western immunoblotting [striatal dopamine transporter (DAT) and tyrosine hydroxylase (TH)] and alterations in the mean number of DA cells/section by immunohistochemistry and Nissl staining [TH-labeled cells and thionin-stained cells in the substantia nigra pars compacta (SN-PC)]. We measured recovery of gait performance and amount of spontaneous physical activity using the parallel rod activity chamber (PRAC). We hypothesized that the decrease in TH labeled neurons in the SN-PC due to MPTP will be partially reversed by treadmill exercise, leading to recovery of motor behavior as measured by the PRAC. Following MPTP or vehicle administration, mice ran on the treadmill for 1h/day at 18cm/s, 5days/week. Results showed that treadmill exercise improves gait performance and increases physical activity while promoting increased protein expression of striatal DAT and TH. Exercise was effective for all mice; however, effects of early treadmill-based intervention appear to have an additional and unique benefit in mice who received MPTP. We are the first to show that, even following a nearly 50% decrease in the mean number of TH-labeled neurons/section in the SN-PC following MPTP, treadmill exercise leads to an increase of neurons in the SN-PC and improved motor behavior. PMID- 21315690 TI - Toll-like receptor 4 is involved in ischemic tolerance of postconditioning in hippocampus of tree shrews to thrombotic cerebral ischemia. AB - BACKGROUND: Toll-like receptor 4 (TLR4) is an important mediator of the innate immune response. It significantly contributes to neuroinflammation and may be involved in ischemic tolerance. It is unknown how cerebral ischemia in the cortex and postconditioning might affect inflammatory reactions in the hippocampus or whether TLR4 expression plays a role. OBJECTIVE: This study explored the mechanistic hypothesis that postconditioning modulates TLR4 expression and thus improves inflammatory reactions in the hippocampus. METHODS: Thrombotic focal cerebral ischemia was induced by a photochemical reaction in tree shrews. Four hours after the photochemical reaction onset, ischemic postconditioning was established with three repeated five minute cycles of temporary right carotid artery clipping and a five minute reperfusion. Histological changes were assessed over 72h in hippocampal morphology (hematoxylin-and-eosin), myeloperoxidase (MPO) expression (immunohistochemistry), TLR4 expression (Western blot analysis and immunohistochemistry), and TLR4 mRNA expression (semiquantitative RT-PCR). RESULTS: We found extensive neuronal degeneration in the hippocampus that peaked at 24h after cerebral ischemia. This was significantly attenuated after postconditioning. Cerebral ischemia caused a predominant increase in TLR4 protein expression from 4 to 24h (P<0.05). In contrast, postconditioning caused a decrease in TLR4 protein expression from 4 to 24h (P<0.05), which increased at 72h (P<0.05). Hippocampal TLR4 mRNA levels showed the same trends as those observed in protein expression. CONCLUSION: These findings indicated that TLR4 signaling and innate immunity may be involved in the protective mechanisms of postconditioning and ischemic tolerance. PMID- 21315691 TI - Icilin-evoked behavioral stimulation is attenuated by alpha2-adrenoceptor activation. AB - Icilin is a transient receptor potential cation channel subfamily M (TRPM8) agonist that produces behavioral activation in rats and mice. Its hallmark overt pharmacological effect is wet-dog shakes (WDS) in rats. The vigorous shaking associated with icilin is dependent on NMDA receptor activation and nitric oxide production, but little else is known about the biological systems that modulate the behavioral phenomenon. The present study investigated the hypothesis that alpha(2)-adrenoceptor activation inhibits icilin-induced WDS. Rats injected with icilin (0.5, 1, 2.5, 5mg/kg, i.p.) displayed dose-related WDS that were inhibited by pretreatment with a fixed dose of clonidine (0.15 mg/kg, s.c.). Shaking behavior caused by a fixed dose (2.5mg/kg) of icilin was also inhibited in a dose related manner by clonidine pretreatment (0.03-0.15 mg/kg, s.c.) and reduced by clonidine posttreatment (0.15 mg/kg, s.c.). Pretreatment with a peripherally restricted alpha(2)-adrenoceptor agonist, ST91 (0.075, 0.15 mg/kg), also decreased the incidence of shaking elicited by 2.5mg/kg of icilin. Pretreatment with yohimbine (2mg/kg, i.p.) enhanced the shaking induced by a low dose of icilin (0.5mg/kg). The imidazoline site agonists, agmatine (150mg/kg, i.p.) and 2 BFI (7 mg/kg, i.p.), did not affect icilin-evoked shaking. These results suggest that alpha(2)-adrenoceptor activation inhibits shaking induced by icilin and that increases in peripheral, as well as central, alpha(2)-adrenoceptor signaling oppose the behavioral stimulant effect of icilin. PMID- 21315692 TI - Effects of propofol on proliferation and anti-apoptosis of neuroblastoma SH-SY5Y cell line: new insights into neuroprotection. AB - Recently, it has been suggested that anesthetic agents may have neuroprotective potency. The notion that anesthetic agents can offer neuroprotection remains controversial. Propofol, which is a short-acting intravenous anesthetic agent, may have potential as a neuroprotective agent. In this study, we tried to determine whether propofol affected the viability of human neuroblastoma SH-SY5Y cells by using the MTT assay. Surprisingly, our results showed that propofol at a dose of 1-10 MUM could improve cell proliferation. However, at higher doses (200 MUM), propofol appears to be cytotoxic. On the other hand, propofol could up regulate the expression of key proteins involved in neuroprotection including B cell lymphoma 2 at a dose range of 1-10 MUM, activation of phospho serine/threonine protein kinase at a dose range of 0.5-10 MUM, and activation of phospho-extracellular signal-regulated kinases at a dose range of 5-10 MUM. Similarly, we demonstrate that propofol (10 MUM) could elevate protein levels of heat shock protein 90 and heat shock protein 70. Therefore, we choose to utilize a 10 MUM concentration of propofol to assess neuroprotective activities in our studies. In the following experiments, we used dynorphin A to generate cytotoxic effects on SH-SY5Y cells. Our data indicate that propofol (10 MUM) could inhibit the cytotoxicity in SH-SY5Y cells induced by dynorphin A. Furthermore, propofol (10 MUM) could decrease the expression of the p-P38 protein as well. These data together suggest that propofol may have the potential to act as a neuroprotective agent against various neurologic diseases. However, further delineation of the precise neuroprotective effects of propofol will need to be examined. PMID- 21315693 TI - Preventing H2O2-induced apoptosis in cerebellar granule neurons by regulating the VEGFR-2/Akt signaling pathway using a novel dimeric antiacetylcholinesterase bis(12)-hupyridone. AB - Oxidative stress-induced apoptosis plays a critical role in the pathogenesis of various neurodegenerative disorders. In this study, the neuroprotective properties of bis(12)-hupyridone (B12H), a novel dimeric acetylcholinesterase (AChE) inhibitor modified from a naturally occurring monomeric analogue, huperzine A, on H2O2-induced neurotoxicity were investigated in cerebellar granule neurons (CGNs). Exposure of CGNs to H2O2 resulted in apoptosis which could be attenuated by the pre-treatment of B12H (0.3-5 nM) in a concentration dependent manner. Moreover, tacrine and neostigmine failed to prevent neurotoxicity, indicating that the neuroprotection of B12H might not be due to its inhibitory property of AChE enzymatic activity. Increased activation of extracellular signal-regulated kinase (ERK) and decreased activation of glycogen synthase kinase (GSK) 3beta were observed after H2O2 exposure, and B12H reversed the altered activation of GSK3beta, but not that of ERK. Furthermore, using vascular endothelial growth factor (VEGF), phospho-VEGF receptor-2 (VEGFR-2) antibody, a specific VEGFR-2 inhibitor (PTK787/ZK222584) and specific phosphoinositide 3-kinase inhibitors (LY294002 and wortmannin), it was found that VEGF prevented H2O2-induced neuronal loss from activating the VEGF/VEGFR-2 system and that the observed B12H neuroprotective effects might share the same signaling pathway. These findings strongly suggest that B12H prevents H2O2-induced neuronal apoptosis independent of inhibiting AChE, but through regulating VEGFR 2/Akt/GSK3beta signaling pathway. PMID- 21315694 TI - Behavioral and social science in HIV vaccine clinical research: Workshop report. AB - In May 2009, a workshop was held in Washington DC to identify ways in which HIV vaccine clinical research could benefit from and better incorporate behavioral and social science (BSS) considerations. Seventy-one people from government, non government, and private organizations participated, including HIV vaccine researchers, clinical trial scientists, BSS researchers, community representatives, and sponsors. This workshop elucidated the opportunities and challenges for integrating BSS in HIV vaccine research by highlighting insights gained from previous BSS research on HIV prevention and highlighting new BSS approaches and methodologies. Meeting participants identified priority areas where BSS methodologies could significantly impact HIV research and developed concrete recommendations for addressing current challenges encountered in HIV vaccine research relating to social impact, risk assessment, community engagement, informed consent, risk reduction, and special populations. These recommendations address the need for improving the accuracy of participant data; standardizing data collection to enable comparisons across studies; engaging the community at all levels; using evidenced-based counseling techniques; understanding the needs and concerns of target populations; and considering the impacts of macro-level forces and influences. The importance of establishing collaborations that can carry out these recommendations and facilitate necessary changes in thinking and practice was emphasized throughout the meeting. PMID- 21315695 TI - Combined protective effects of anti-PhtD and anti-pneumococcal polysaccharides. AB - In the past years, a significant rise in the proportion of childhood complicated pneumonia cases related to pneumococcal serotypes 1 and 3 has been observed. PhtD is a vaccine candidate protein antigen. By using a pneumococcal lethal intranasal challenge mouse model, a significant additive effect on protection was observed with the combination of vaccination-induced anti-PhtD and injected anti polysaccharide antibodies specific for serotypes 1 and 3. PMID- 21315696 TI - Induction of protective Th1 immune responses in mice by vaccination with recombinant Toxoplasma gondii nucleoside triphosphate hydrolase-II. AB - The Toxoplasma gondii nucleoside triphosphate hydrolase (TgNTPase) has apyrase activity, degrading ATP to the di- and mono-phosphate forms and may be used by the parasite to salvage purines from the host cell for survival and replication. To study the immune-protective value of TgNTPase-II, BALB/c mice were immunized with a recombinant form of the antigen rTgNTPase-II combined with alum. All immunized mice produced specific anti-rTgNTPase-II immunoglobulins, with high IgG antibody titers and a mixed IgG1/IgG2a response, with predominance of IgG2a production. The cellular immune response was associated with the production of IFN-gamma and IL-2 cytokines and the increase of the percentage of CD8+ T cells. Vaccinated mice displayed significant protection against acute infection with the virulent RH strain (P<0.05 in survival rate) and also chronic infection with PRU cyst (62.9% and 57.6% reduction in brain parasite load for rTgNTPase-II+alum and rTgNTPase-II alone vaccinated groups) compared to the non-vaccinated control group. In conclusion, rTgNTPase-II elicits a strong specific Th1 immune response providing partial protection against both T. gondii acute and chronic infection. PMID- 21315697 TI - Varicella breakthrough infection and vaccine effectiveness in Taiwan. AB - We performed this nationwide retrospective investigation among the recipients of varicella vaccine to evaluate the breakthrough varicella infection rate, factors associated with breakthrough infection and the vaccine effectiveness. The recipients of these vaccinations were identified through Taiwan's National Immunization Information System and data on breakthrough infections among these recipients were collected by using Taiwan's National Health Insurance Claims Database. From 2000 to 2007, 1,057,345 persons received varicella vaccinations in Taiwan. Varicella breakthrough infection occurred among 22,640 (2.1%) vaccinees and 170 (0.016%) required hospitalization for varicella disease. Annual breakthrough infection rates ranged from 0.12% to 2.04%. The mean age of vaccination was 1.6 years (median 1.3 years) and the mean age at breakthrough infection was 3.9 years. The mean interval between vaccination and the breakthrough infection was 2.3 years. The rate was significantly lower in regions where free varicella vaccinations were available than in regions where they were not (P<0.001). Varicella breakthrough infection was significantly more likely to occur at 5 and 6 years of age among the vaccinees, who received vaccination between 12 months and 23 months of age (P<0.001). The vaccine effectiveness against varicella was 82.6% and against varicella-related hospitalization was 85.4% from 2000 to 2005. PMID- 21315698 TI - Formaldehyde-inactivated human enterovirus 71 vaccine is compatible for co immunization with a commercial pentavalent vaccine. AB - In this study we tested the effectiveness of a formaldehyde-inactivated EV71 vaccine and its compatibility for co-immunization with a pentavalent vaccine that contained inactivated poliovirus (PV) vaccine. The inactivated EV71 vaccine (C2 genogroup) elicited an antibody response which broadly neutralized homologous and heterologous genogroups, including B4, C4, and B5. Pups from vaccinated dams were resistant to the EV71 challenge and had a high survival rate and a low tissue viral burden when compared to those from non-vaccinated counterparts. Co immunization with pentavalent and inactivated EV71 vaccines elicited antibodies against the major components of the pentavalent vaccine including the PV, Bordetella pertussis, Haemophilus influenzae type b, diphtheria toxoid, and tetanus toxoid at the same levels as in mice immunized with pentavalent vaccine alone. Likewise, EV71 neutralizing antibody titers were comparable between EV71 vaccinated mice and mice co-immunized with the two vaccines. These results indicate that formaldehyde-inactivated whole virus EV71 vaccine is feasible for designing multivalent vaccines. PMID- 21315699 TI - Adenovirus-vectored Plasmodium vivax ookinete surface protein, Pvs25, as a potential transmission-blocking vaccine. AB - Adjuvants or delivery vehicles are essential components to expedite malaria vaccine development. In this study, replication-defective human adenovirus serotype 5 (rAd) was genetically engineered to express the Plasmodium vivax ookinete surface protein (OSP), Pvs25 (AdPvs25). BALB/c mice immunized with the AdPvs25 through various routes including intramuscular, subcutaneous and intranasal routes were analyzed for induction of antigen-specific transmission blocking immunity. Parenteral but not mucosal immunization induced high serum immunoglobulin G (IgG) responses specific to P. vivax ookinetes isolated from P. vivax volunteer patients from Thailand. The membrane feeding assay revealed that antisera conferred a transmission blockade of up to 99% reduction in the average oocyst numbers per mosquito, while immunization with a rAd expressing Pfs25 from Plasmodium falciparum, a homolog of Pvs25, conferred only a background level of blockade, suggesting that a species-specific transmission-blocking immunity was induced. Vaccine efficacy of AdPvs25 was slightly higher than to a recombinant Pvs25 protein mixed with aluminum hydroxide, but less efficacious than the protein emulsified with incomplete Freund's adjuvant. This study, the first preclinical evaluation of adenovirus-vectored malaria OSPs, implicates a potential inclusion of malaria transmission-blocking vaccine antigens in viral vector systems. PMID- 21315700 TI - Gastroprotective potential of risperidone, an atypical antipsychotic, against stress and pyloric ligation induced gastric lesions. AB - Risperidone has been used in some stress disorders and may be potentially protective against stress-induced gastric lesions. Thus, the aim of the present study is to investigate, whether risperidone, a D(2) receptor and 5-HT(2A) receptor antagonist, would be able to result in gastroprotective effect in stress induced lesions and also explore the possible mechanism of action behind its gastroprotective activity. Gastroprotective activity of risperidone was evaluated both by single treatment and 21 days repeated (0.03, 0.1, 0.3 and 1mg/kg, p.o.) treatment in the cold restraint stress (CRS) model and 21 days repeated treatment in the pyloric ligation (PL) model and compared with that of sulpiride (D(2) receptor antagonist) and ketanserin (5-HT(2) receptor antagonist) as standard. Histopathological assessment was done to evaluate the gastroprotective activity of risperidone in CRS model. The roles of nitric oxide (NO), sulfhydryl (SH) group, ATP-sensitive K(+) channels (K(ATP) channels) and prostaglandins (PGs) in the gastroprotective effect of risperidone against CRS were also investigated. PGE(2), hexosamine as a marker of mucus barrier and microvascular permeability were also estimated. Results show that repeated treatment of risperidone, sulpiride and ketanserin exhibited a gastroprotective effect against CRS-induced lesions while single administration of risperidone was found to be ineffective. Moreover, repeated treatment of risperidone and ketanserin was found to be ineffective in case of PL in contrast to sulpiride. Risperidone pretreatment reverses the stress induced alteration in hexosamine, PGE(2) and microvascular permeability. Pretreatment with l-NAME, NEM, glibenclamide and indomethacin reversed the gastroprotective effect of risperidone. The results suggest that risperidone has significant gastroprotective effects in CRS-induced gastric lesions models, which appears to be mediated by endogenous NO, SH, PGs and K(ATP) channel opening. PMID- 21315701 TI - Lipase-catalyzed synthesis and characterization of 1-butanoyl-2-palmitoyl phosphatidylcholine, a potential lipidic prodrug of butyric acid. AB - 1-Butanoyl-2-palmitoyl phosphatidylcholine was synthesized from dipalmitoylphosphatidylcholine (DPPC) and butyric acid using a lipase catalyzed transesterification in toluene at controlled water activity. A high fatty acid concentration and low water activity were essential for the enzymatic synthesis. The transesterification resulted in 97.3% incorporation of butyric acid in the sn 1 position with negligible incorporation in the sn-2-position. In mixtures with water, a liquid crystalline phase was formed in equilibrium with a micellar phase. The prepared phospholipid derivative could find applications as a lipidic anticancer prodrug of butyric acid. PMID- 21315702 TI - Prognostic cytokine markers in peripheral blood for oral cavity squamous cell carcinoma identified by multiplexed immunobead-based profiling. AB - BACKGROUND: Oral cavity squamous cell carcinoma (OSCC) is one of the most common cancers worldwide and has been considered to be highly associated with altered biological processes, including immunocyte chemotaxis, inflammatory response, angiogenesis, and/or immune regulation, suggesting that the levels of the tumor related cytokines and chemokines will be dysregulated in the tumor microenvironment as well as in the systemic circulation and might be associated with some OSCC phenotypes. METHODS: To profile cytokines in OSCC patients, the plasma levels of 48 proteins (26 cytokines, 10 chemokines, and 12 growth factors) were measured in 111 untreated OSCC patients, 112 healthy individuals, and 107 individuals with oral premalignant lesion (OPL). RESULT: Compared to the plasma levels in the healthy individuals and OPL group, the levels of 12 proteins were significantly dysregulated in the OSCC patients. Further analysis demonstrated that the levels of IFN-alpha2, IL-2RA, and SCF were significantly lower in patients with higher pT status. IFN-alpha2 levels also decreased in patients with higher tumor depths. Moreover, OSCC patients with greater levels of VEGF (>4.87 pg/ml) before treatment had worse prognoses for overall survival after treatment (P=0.035). CONCLUSIONS: This is the first report showing that the plasma VEGF levels may be a useful prognostic indicator of OSCC. PMID- 21315703 TI - Multiplexed genotyping of beta globin mutations with MALDI-TOF mass spectrometry. AB - BACKGROUND: Beta thalassemia represents a great heterogeneity as over 300 mutations have been identified and each population at-risk has its own spectrum of mutations. Molecular characterization with high accuracy, sensitivity and economics is required for population screening and genetic counseling. METHODS: We used the MALDI-TOF mass spectrometry (MS) platform to develop novel multiplex assays for comprehensive detection of 27 mutations in beta-thalassemia patients. Six multiplex assays were designed to detect 13 common known beta-mutations, namely CD41/42, CD71/72, IVS1-5, IVS1-1, CD26, IVS2-654, CAP+1, CD19, -28, -29, IVS1-2, InCD (T-G) and CD17; and 14 rare beta-mutations, i.e. InCD (A-C), CD8/9, CD43, -86, CD15, Poly A, Poly T/C, IVS2-1, CD1, CD35/36, CD27/28, CD16, CD37, and 619bpDEL in 165 samples. We compared the efficiencies of genotyping by MS and Amplification Refractory Mutation System (ARMS). Discrepant results were confirmed by sequencing analysis. RESULTS: A total of 88.7% (260/293 allele) of MS and ARMS results was in agreement. More than fifty percent of the discrepant result was due to the false interpretation of ARMS results. Failed CD19 assay by MS method might be due to the assay design. The MS method detected 5 rare beta mutations (CD15, CD35/36, CD8/9, Poly A and Poly T/C) presented in 13 alleles, which were not included in the ARMS screening panel. CONCLUSION: We revealed that the MS method is a sensitive, high-throughput, highly automated, flexible, and cost-effective alternative to conventional beta-thalassemia genotyping methods. PMID- 21315704 TI - An overview of a recent court challenge to the protection of biomarkers as intellectual property. AB - BACKGROUND: We present an intellectual property case in the United States to demonstrate the recent developments concerning patenting novel biomarker discoveries. A court struck down several patents owned by Myriad Genetics, which were related to breast cancer (BRCA1 and BRCA2). This decision can affect patent eligibility for inventions related to biomarkers, particularly genetic biomarkers. METHODS: The court proceedings for the Myriad Genetics case were reviewed by two patent attorneys (SCH and JMT). Relevant discussions applicable to the scientist involved with biomarker discovery were also prepared. RESULTS: In this case, the Plaintiff had argued that the analysis and comparison of various gene mutations merely involved natural phenomena, and, therefore, could not be eligible for patent protection. The patent holder (Myriad) argued that the claimed gene compositions did not exist in nature, and that the claimed methods provided practical utility for science and medicine. The Court held that the patent claims did not meet patent eligibility requirements under United States patent law. It held that the patent claims at issue were merely abstract mental processes of analyzing and comparing gene sequences, and that such abstract mental processes are not patentable. On June 22, 2010, Myriad appealed the ruling. CONCLUSIONS: This case provides guidance to inventors in the biomarker field who may be interested in obtaining intellectual property protection for their inventive work, as well as their patent counsel. However, the case also presented unique factors that may not be present in all situations involving biomarker patents. PMID- 21315705 TI - A primer design strategy for PCR amplification of GC-rich DNA sequences. AB - OBJECTIVES: To establish a primer design method for amplification of GC-rich DNA sequences. DESIGN AND METHODS: A group of 15 pairs of primers with higher T(m) (>79.7 degrees C) and lower level DeltaT(m) (<1 degrees C) were designed to amplify GC-rich sequences (66.0%-84.0%). The statistical analysis of primer parameters and GC content of PCR products was performed and compared with literatures. Other control experiments were conducted using shortened primers for GC-rich PCR amplifications in this study, and the statistical analysis of shortened primer parameters and GC content of PCR products was performed compared with primers not shortened. A group of 26 pairs of primers were designed to test the applicability of this primer designing strategy in amplifications of non-GC rich sequences (35.2%-53.5%). RESULTS: All the DNA sequences in this study were successfully amplified. Statistical analyses show that the T(m) and DeltaT(m) were the main factors influencing amplifications. CONCLUSIONS: This primer designing strategy offered a perfect tool for amplification of GC-rich sequences. It proves that the secondary structures cannot be formed at higher annealing temperature conditions (>65 degrees C), and we can overcome this difficulty easily by designing primers and using higher annealing temperature. PMID- 21315706 TI - Cryobanking the genetic diversity in the critically endangered Iberian lynx (Lynx pardinus) from skin biopsies. Investigating the cryopreservation and culture ability of highly valuable explants and cells. AB - Cryobanking skin samples permit preserving a maximum of genetic representation from the population biodiversity. This is a relevant aspect for threatened species, potentially menaced by an epizooty and from which it is difficult to obtain gametes. As a first step for properly cryobanking skin samples of a given species, the optimal conditions of culture and freezing have to be studied by covering a broad range of possibilities. This paper presents, for the first time, a systematic study of such conditions for the Iberian lynx (Lynx pardinus). To that end, we have analyzed twenty different culture conditions and fifteen different freezing solutions for skin explants, as well as three freezing solutions for isolated cells derived from them. The culture conditions included both two different culture strategies and several combinations of nutritional supplements and mitotic agents. For the freezing solutions, we have considered different concentrations of the permeating cryoprotectant dimethyl sulfoxide (Me(2)SO) either alone (5%, 7.5%, 10%, 12.5% and 15% v/v for explants, 10% for isolated cells) or along with the non-permeating cryoprotectant sucrose (0.1 or 0.2M). Our results have been analyzed through several quantitative parameters and show that only thawed explants cryopreserved in Me(2)SO (10%) either alone or with sucrose (0.2M) presented similar properties to those in optimal fresh cultures. In addition, for these freezing conditions, isolated thawed cells also presented high survival rates (90%) and percentages of cellular functionality (85%). These results, focussed on the most endangered felid in the world, could be also useful for other threatened/endangered species. PMID- 21315707 TI - Machine perfusion at 20 degrees C reduces preservation damage to livers from non heart beating donors. AB - We previously reported that machine perfusion (MP) performed at 20 degrees C enhanced the preservation of steatotic rat livers. Here, we tested whether rat livers retrieved 30 min after cardiac arrest (NHBDs) were better protected by MP at 20 degrees C than with cold storage. We compared the recovery of livers from NHBDs with organs obtained from heart beating donors (HBDs) preserved by cold storage. MP technique: livers were perfused for 6h with UW-G modified at 20 degrees C. Cold storage: livers were perfused in situ and preserved with UW solution at 4 degrees C for 6h. Both MP and cold storage preserved livers were reperfused with Krebs-Heinselet buffer (2h at 37 degrees C). AST and LDH release and mitochondrial glutamate dehydrogenase (GDH) levels were evaluated. Parameters assessed included: bile production and biliary enzymes; tissue ATP; reduced and oxidized glutathione (GSH/GSSG); protein-SH group concentration. Livers preserved by MP at 20 degrees C showed significantly lower hepatic damage at the end of reperfusion compared with cold storage. GDH release was significantly reduced and bile production, ATP levels, GSH/GSSG and protein-SH groups were higher in livers preserved by MP at 20 degrees C than with cold storage. The best preserved morphology and high glycogen content was obtained with livers submitted to MP at 20 degrees C. Liver recovery using MP at 20 degrees C was comparable to recovery with HBDs. MP at 20 degrees C improves cell survival and gives a better-quality of preservation for livers obtained from NHBDs and may provide a new method for the successful utilization of marginal livers. PMID- 21315709 TI - Desirable properties of beta3-adrenoceptor agonists: implications for the selection of drug development candidates. AB - beta3-adrenoceptor agonists are currently in clinical development for the treatment of overactive bladder and considered for several other indications. This Perspective discusses desirable properties of such drugs mainly based on the example of overactive bladder, but at least partly they should also be applicable to other indications of beta(3)-adrenoceptor agonists or other drug classes and therapeutic areas. These include degree of selectivity for the molecular target in terms of affinity, intrinsic efficacy and ligand-directed signaling. The ability to cause agonist-induced desensitization and the potential impact of gene polymorphisms also need to be considered. Depending on intended indication, specific pharmacokinetic considerations may also apply. These findings challenge the usefulness of high-throughput screening assays based upon a single molecular response in an artificial system and emphasize the need for early use of in vivo testing in species considered to be predictive for the human situation. PMID- 21315708 TI - Lrrn1 is required for formation of the midbrain-hindbrain boundary and organiser through regulation of affinity differences between midbrain and hindbrain cells in chick. AB - The midbrain-hindbrain boundary (MHB) acts as an organiser/signalling centre to pattern tectal and cerebellar compartments. Cells in adjacent compartments must be distinct from each other for boundary formation to occur at the interface. Here we have identified the leucine-rich repeat (LRR) neuronal 1 (Lrrn1) protein as a key regulator of this process in chick. The Lrrn family is orthologous to the Drosophila tartan/capricious (trn/caps) family. Differential expression of trn/caps promotes an affinity difference and boundary formation between adjacent compartments in a number of contexts; for example, in the wing, leg and eye imaginal discs. Here we show that Lrrn1 is expressed in midbrain cells but not in anterior hindbrain cells. Lrrn1 is down-regulated in the anterior hindbrain by the organiser signalling molecule FGF8, thereby creating a differential affinity between these two compartments. Lrrn1 is required for the formation of MHB--loss of function leads to a loss of the morphological constriction and loss of Fgf8. Cells overexpressing Lrrn1 violate the boundary and result in a loss of cell restriction between midbrain and hindbrain compartments. Lrrn1 also regulates the glycosyltransferase Lunatic Fringe, a modulator of Notch signalling, maintaining its expression in midbrain cells which is instrumental in MHB boundary formation. Thus, Lrrn1 provides a link between cell affinity/compartment segregation, and cell signalling to specify boundary cell fate. PMID- 21315710 TI - Synthesized pyridine compound derivatives decreased TNF alpha and adhesion molecules and ameliorated HSV-induced inflammation in a mouse model. AB - Synthesized pyridine compound derivatives (SK94, SK126) from a natural lead source were administered to mice to test for possible anti-TNF alpha and anti inflammatory activities. Lipopolysaccharide (LPS)-induced TNF alpha production was analyzed in the endothelial cells, Raw 264.7 cells, and serum of normal mice after treatment with SK compounds. These compounds were also orally administered to a herpes simplex virus (HSV)-induced Behcet's disease mouse model to investigate their anti-inflammatory therapeutic effect. TNF alpha production was inhibited in a dose-dependent manner in the SK94 treated cells. E-selectin, VCAM 1, and ICAM-1 mRNA levels were also down-regulated. Treatment with 30mg/kg SK94 inhibited 55% of the TNF alpha production in LPS challenged Balb/c mice (n=8). SK94 and SK126 were administered to the Behcet's disease-like mice for five consecutive days and SK94 improved in five out of six mice (83%), while it only improved in one out of nine mice (11%) in the pH 1.2 saline (artificial gastric juice) group (P<0.005), four out of ten mice (40%) in the thalidomide group (P<0.05), and six out of seven (86%) in the SK126 group (P<0.005). Soluble ICAM-1 was inhibited by 23.8% in the sera of SK94 treated mice and by 34.6% in SK126 treated mice when compared to artificial gastric juice. Based on these findings, SK compounds could be candidates for clinical trials. PMID- 21315711 TI - Bupivacaine induces apoptosis via mitochondria and p38 MAPK dependent pathways. AB - Mitochondria and the p38 mitogen-activated protein kinase (MAPK) pathways play important roles in apoptosis. Although the effect of bupivacaine on apoptosis is known, it remains unclear whether bupivacaine induces apoptosis via mitochondrial depolarization and the p38 MAPK activity. In this study, SH-SY5Y cells were pretreated respectively with 50MUM 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), 10MUM 4-(4-Fluorophenyl)-2-[4-(methylsulfinyl)phenyl]-5-(4-pyridyl) 1H-imidazole (SB203580), and 50MUM DIDS plus 10MUM SB203580 30min prior to the treatment with either 1mM bupivacaine or an equivalent amount of medium. The cell viability, mitochondrial membrane potential, phospho-p38 MAPK (p-p38 MAPK) and cell apoptosis were investigated with MTT assay, western blots, Hoechst 33258 staining and flow cytometry assay. In addition, the roles of chloridion (Cl(-)) channel and reactive oxygen species were studied to explore the molecular mechanism of bupivacaine-induced mitochondrial injury. Pretreatment with DIDS could attenuate reactive oxygen species production, the phosphorylation of p38MAPK, dissipation of mitochondrial membrane potential and apoptosis of SH-SY5Y cells induced by bupivacaine. Pretreatment with SB203580 could attenuate apoptosis, but could not attenuate reactive oxygen species production, or dissipation of mitochondrial membrane potential induced by bupivacaine. These findings indicate that the mitochondrial anion channel and p38 MAPK pathway are implicated in bupicavaine-induced apoptosis. Bupivacaine-induced reactive oxygen species production results in an alteration in the permeability of the mitochondrial membranes and Cl(-) influx into mitochondria, which seems to be responsible for mitochondrial depolarization and the p38 MAPK activation. PMID- 21315712 TI - Antibody inhibiting enzymatic activity of tumour-associated carbonic anhydrase isoform IX. AB - Carbonic anhydrase IX (CAIX) is a hypoxia-induced, membrane-tethered enzyme that is highly expressed in many cancers. It catalyses the hydration of CO(2) to HCO(3)(-) and H(+), and the reverse dehydration reaction. Recent studies have shown an important role for CAIX in pH regulation and it has been speculated that CAIX may play a role in supporting cancer progression towards more aggressive forms of the disease. Clinical correlative studies in many tumours have shown that high expression is related to poor outcome. In the present study, we have selected antigen-binding antibody fragments (Fab) against human CAIX by phage display, and tested these for inhibitory potency on CAIX catalytic activity. Inhibition was assessed from the kinetics of the CAIX-catalysed reaction, using assays performed on intact cells over-expressing CAIX, and their CAIX-containing membrane fragments. Inhibition was also assessed in multi-cellular tissue-models (spheroids) from the kinetics of CO(2) venting. We have identified a Fab antibody, labelled MSC8, and its corresponding full-length IgG that inhibited CAIX by up to 57% and 76%, respectively, with half-maximal inhibition at 0.3MUg/ml. Incubation of CAIX-expressing cells with MSC8 IgG produced a lasting inhibitory effect. The inhibitory effect was prompt and was also observed in isolated membrane-fragments, suggesting that a direct inhibitory interaction takes place between the antibody and CAIX. The inhibitory effects in spheroids argue for a physiological relevance of the antibody. Biologically-active antibodies against CAIX can be used as selective, high-affinity inhibitors in experimental studies to dissect the role of CAIX and, possibly, therapeutically by targeting a catalytically-active cancer-related protein. PMID- 21315713 TI - Expression Of Ki-67 and MUC1 In mucoepidermoid carcinomas of young and adult patients: prognostic implications. AB - Mucoepidermoid cancer (MEC) is the most malignant neoplasm of minor salivary glands. The aim of this study was to compare the expression of Ki-67 and MUC1 and clinicopathological data of mucoepidermoid carcinoma (MEC) in minor salivary glands of young and adult patients. The MEC cases in patients under 25 years old (n=8) and over 26 year old (n=8) were matched by gender, location and TNM staging. Immunohistochemical analysis of Ki-67 and MUC1 was carried out and correlated with clinicopathological data. The expression of Ki-67 and MUC1 was similar between the groups, although a tendency towards higher Ki-67 and MUC1 expression was observed in the younger group. Despite no significant differences, survival time was shorter in adults (71.37+/-17.44 months) compared to the younger group (97.62+/-25.81). While no patient deaths or tumor recurrences were found in the younger patient group, the adult group presented recurrence in 25% of cases and one patient died. In conclusion, our findings showed that age can be an important factor in MEC prognosis. PMID- 21315714 TI - Correcting a misrepresentation of hypervitaminosis A attributed to Herbalife product consumption. PMID- 21315715 TI - Giardia intestinalis: DNA extraction approaches to improve PCR results. AB - Difficulty in disrupting cysts of Giardia intestinalis, a cosmopolitan protozoan parasite, decreases the yield of DNA extracted and reduces the effectiveness of the polymerase chain reaction (PCR). To improve the detection of the Giardia Glutamate Dehydrogenase (gdh) gene, we re-evaluated the effects of deoxyribonucleic acid (DNA) extraction methods. Purified and concentrated cysts from 33 fecal samples were disrupted using conventional methods, and DNA extraction was conducted using two protocols: the QIAamp Stool Mini Kit and phenol/chloroform/isoamyl alcohol (PCI). PCR amplification was successful for 12 extracted DNA samples (36%) using PCI following a glass bead and freeze/thaw pretreatment and for all 33 samples (100%) using the QIAamp Stool Mini Kit following the aforementioned pretreatment. Consequently, the pretreatment of cysts with glass beads and freeze/thaw cycles followed by extraction of DNA with the QIAamp Stool Mini kit was the more effective protocol. PMID- 21315716 TI - Ubiquitination of mRNA cycling sequence binding protein from Leishmania donovani (LdCSBP) modulates the RNA endonuclease activity of its Smr domain. AB - In trypanosomatid parasites, an octanucleotide sequence (C/A)AUAGAA(G/A) in the UTRs primarily determines the stability of S-phase specific mRNAs. A multi-domain protein LdCSBP from Leishmania donovani interacts with the UTR of an S-phase RNA containing the octanucleotide sequence through its unique CCCH-type Zn-finger motifs. Interestingly, the RNA binding protein contains a previously characterized DNA endonuclease domain - Smr. It has been demonstrated here that the LdCSBP Smr domain independently possesses both DNA and RNA endonuclease activities, but the full-length LdCSBP exhibits only riboendonuclease activity. Moreover, LdCSBP protein has been shown to be ubiquitinated, resulting in the down-regulation of its riboendonuclease activity. In conclusion, the results described here suggest a novel regulatory mechanism of mRNA degradation through ubiquitination in eukaryotes. PMID- 21315717 TI - The Zollinger-Ellison syndrome and mismeasurement of gastrin. AB - BACKGROUND & AIMS: Zollinger-Ellison syndrome (ZES) is characterized by hypersecretion of gastric acid, severe peptic ulcerations in the upper small intestine, and diarrhea. It is usually diagnosed by measuring increased levels of gastrin in plasma. METHODS: We examined the accuracy of commercial kits to measure gastrin (7 radioimmunoassays and 5 enzyme-linked immunosorbent assays), using plasma from 40 patients suspected or known to have ZES. Each sample was analyzed using the 12 kits and a reference assay that measures bioactive gastrin in plasma, irrespective of size and amino acid derivatization. Known concentrations of peptides with identical sequences to circulating gastrins were also assessed by all assays. Molecular patterns in plasma from patients with ZES were examined by chromatography and monitored by kits that measure false-low or false-high concentrations of gastrin. RESULTS: Failure to diagnose gastrinomas has serious consequences. Four kits found false-low concentrations of gastrin in 20% to 80% of the patients. Specificity assessment showed that the antibodies used in these kits bound only gastrin-17. Three kits found false-high concentrations of gastrin, because the reagents had increased reactions to sulfated gastrins or to unspecific factors in plasma. Thus, only 5 of 12 kits tested accurately measure plasma concentrations of gastrin. CONCLUSIONS: Seven of 12 tested commercial kits inaccurately measure plasma concentrations of gastrin; these assays used antibodies with inappropriate specificity that were insufficiently validated. Misdiagnosis of gastrinoma based on lack of specificity of assays for gastrin results in ineffective or inappropriate therapy for patients with ZES. PMID- 21315718 TI - NPC2 regulates biliary cholesterol secretion via stimulation of ABCG5/G8-mediated cholesterol transport. AB - BACKGROUND & AIMS: Biliary cholesterol secretion helps maintain cholesterol homeostasis; it is regulated by the cholesterol exporter adenosine triphosphate binding cassettes G5 and G8 (ABCG5/G8) and the cholesterol importer Niemann-Pick C1-like 1 (NPC1L1). We studied another putative regulator of cholesterol secretion into bile, Niemann-Pick C2 (NPC2)--a cholesterol-binding protein secreted by the biliary system--and determined its effects on transporter mediated biliary secretion of cholesterol. METHODS: Mice with hepatic knockdown of Npc2 or that overexpressed NPC2 were created using adenovirus-mediated gene transfer; biliary lipids were characterized. The effects of secreted NPC2 on cholesterol transporter activity were examined in vitro using cells that overexpressed ABCG5/G8 or NPC1L1. RESULTS: Studies of mice with altered hepatic expression of NPC2 revealed that this expression positively regulates the biliary secretion of cholesterol, supported by the correlation between levels of NPC2 protein and cholesterol in human bile. In vitro analysis showed that secreted NPC2 stimulated ABCG5/G8-mediated cholesterol efflux but not NPC1L1-mediated cholesterol uptake. Consistent with these observations, no significant changes in biliary cholesterol secretion were observed on hepatic overexpression of NPC2 in ABCG5/G8-null mice, indicating that NPC2 requires ABCG5/G8 to stimulate cholesterol secretion. Analyses of NPC2 mutants showed that the stimulatory effect of biliary NPC2 was independent of the function of lysosomal NPC2 as a regulator of intracellular cholesterol trafficking. CONCLUSIONS: NPC2 is a positive regulator of biliary cholesterol secretion via stimulation of ABCG5/G8 mediated cholesterol transport. PMID- 21315719 TI - The nuclear pore complex protein Elys is required for genome stability in mouse intestinal epithelial progenitor cells. AB - BACKGROUND & AIMS: Elys is a conserved protein that directs nuclear pore complex (NPC) assembly in mammalian cell lines and developing worms and zebrafish. Related studies in these systems indicate a role for Elys in DNA replication and repair. Intestinal epithelial progenitors of zebrafish elys mutants undergo apoptosis early in development. However, it is not known whether loss of Elys has a similar effect in the mammalian intestine or whether the NPC and DNA repair defects each contribute to the overall phenotype. METHODS: We developed mice in which a conditional Elys allele was inactivated in the developing intestinal epithelium and during preimplantation development. Phenotypes of conditional mutant mice were determined using immunohistochemical analysis for nuclear pore proteins, electron microscopy, and immunoblot analysis of DNA replication and repair proteins. RESULTS: Conditional inactivation of the Elys locus in the developing mouse intestinal epithelium led to a reversible delay in growth in juvenile mice that was associated with epithelial architecture distortion and crypt cell apoptosis. The phenotype was reduced in adult mutant mice, which were otherwise indistinguishable from wild-type mice. All mice had activated DNA damage responses but no evidence of NPC assembly defects. CONCLUSIONS: In mice, Elys maintains genome stability in intestinal epithelial progenitor cells, independent of its role in NPC assembly in zebrafish. PMID- 21315720 TI - Impaired uptake of serotonin by platelets from patients with irritable bowel syndrome correlates with duodenal immune activation. AB - BACKGROUND & AIMS: Patients with irritable bowel syndrome with diarrhea (IBS-D) have increased mucosal serotonin (5-hydroxytryptamine [5-HT]) availability, possibly because immune activation reduces activity of the 5-HT transporter (SERT). We investigated the relationship between mucosal and platelet SERT and immune activation of the duodenal mucosa in patients with IBS-D. METHODS: We quantified mucosal intraepithelial lymphocytes (IELs), mast cells, and enterochromaffin cells in blood samples, measured levels of SERT messenger RNA (mRNA) in mucosal samples, and assessed platelet uptake of 5-HT and platelet membrane binding of (3)H-paroxetine in samples from 29 healthy volunteers (HVs), 20 patients with IBS-D, and 20 untreated patients with celiac disease. RESULTS: Patients with IBS-D or celiac disease had increased numbers of IELs and mast cells compared with HVs (both P < .001). Levels of SERT mRNA were reduced in the mucosa of patients with IBS-D or celiac disease and were inversely correlated with numbers of IELs (r = -0.72, P < .0001). Uptake of 5-HT by platelets from patients with IBS-D or celiac disease was reduced (mean, 17.1 +/- 3.5 and 28.3 +/ 4.1 nmol.min(-1).mg(-1), respectively) compared with HVs (50.8 +/- 8.0 nmol.min( 1).mg(-1), P < .01 and P = .05, respectively). Binding of paroxetine to membranes of platelets from patients with IBS-D (median [interquartile range], 226 [92-405] fmol/mg protein) was significantly greater than that from HVs (109 [69-175] fmol/mg protein) and correlated inversely with platelet uptake of 5-HT (r = 0.62, P = .03). Tryptase release from incubated biopsy samples was significantly increased in patients with IBS-D (2.2 [0.42-3.5] vs 0.50 [0.25-0.86] ng.mL( 1).mg(-1) for HVs; P = .03). CONCLUSIONS: Platelet SERT is reduced in IBS-D and associated with reduced levels of SERT mRNA and duodenal immune activation. PMID- 21315721 TI - Survivors of childhood cancer have increased risk of gastrointestinal complications later in life. AB - BACKGROUND & AIMS: Children who receive cancer therapy experience numerous acute gastrointestinal (GI) toxicities. However, the long-term GI consequences have not been extensively studied. We evaluated the incidence of long-term GI outcomes and identified treatment-related risk factors. METHODS: Upper GI, hepatic, and lower GI adverse outcomes were assessed in cases from participants in the Childhood Cancer Survivor Study, a study of 14,358 survivors of childhood cancer who were diagnosed between 1970 and 1986; data were compared with those from randomly selected siblings. The median age at cancer diagnosis was 6.8 years (range, 0 21.0 years), and the median age at outcome assessment was 23.2 years (5.6-48.9 years) for survivors and 26.6 years (1.8-56.2 years) for siblings. Rates of self reported late GI complications (occurred 5 or more years after cancer diagnosis) were determined and associated with patient characteristics and cancer treatments, adjusting for age, sex, and race. RESULTS: Compared with siblings, survivors had increased risk of late-onset complications of the upper GI tract (rate ratio [RR], 1.8; 95% confidence interval [CI], 1.6-2.0), liver (RR, 2.1; 95% CI, 1.8-2.5), and lower GI tract (RR, 1.9; 95% CI, 1.7-2.2). The RRs for requiring colostomy/ileostomy, liver biopsy, or developing cirrhosis were 5.6 (95% CI, 2.4-13.1), 24.1 (95% CI, 7.5-77.8), and 8.9 (95% CI, 2.0-40.0), respectively. Older age at diagnosis, intensified therapy, abdominal radiation, and abdominal surgery increased the risk of certain GI complications. CONCLUSIONS: Individuals who received therapy for cancer during childhood have an increased risk of developing GI complications later in life. PMID- 21315722 TI - Development of a multi-product leached protein A assay for bioprocess samples containing recombinant human monoclonal antibodies. AB - The detection of low level of protein A leached from monoclonal antibody downstream purification process is often interfered by the presence of excess amount of product antibody. In order to prevent this interference, we developed a new multi-product leached protein A assay that used acidification to completely dissociate the IgG-ProteinA complex, followed by neutralization under selected condition to prevent re-formation of the IgG-ProteinA complex. The amount of protein A was then determined by a sandwich immunoassay using Meso Scale Discovery technology. The assay takes approximately 3h to complete for one 96 well plate of samples, and this has been successfully applied to samples containing different monoclonal antibody products examined so far. The data demonstrates that this assay is robust and efficient in determining leached protein A contamination during purification of recombinant monoclonal antibodies. PMID- 21315723 TI - Quantification of mucosal mononuclear cells in tissues with a fluorescent bead based polychromatic flow cytometry assay. AB - Since the vast majority of infections occur at mucosal surfaces, accurate characterization of mucosal immune cells is critically important for understanding transmission and control of infectious diseases. Standard flow cytometric analysis of cells obtained from mucosal tissues can provide valuable information on the phenotype of mucosal leukocytes and their relative abundance, but does not provide absolute cell counts of mucosal cell populations. We developed a bead-based flow cytometry assay to determine the absolute numbers of multiple mononuclear cell types in colorectal biopsies of rhesus macaques. Using 10-color flow cytometry panels and pan-fluorescent beads, cells were enumerated in biopsy specimens by adding a constant ratio of beads per mg of tissue and then calculating cell numbers/mg of tissue based on cell-to-bead ratios determined at the time of sample acquisition. Testing in duplicate specimens showed the assay to be highly reproducible (Spearman R=0.9476, P<0.0001). Using this assay, we report enumeration of total CD45(+) leukocytes, CD4(+) and CD8(+) T cells, B cells, NK cells, CD14(+) monocytes, and myeloid and plasmacytoid dendritic cells in colorectal biopsies, with cell numbers in normal rhesus macaques varying from medians of 4486 cells/mg (T cells) to 3 cells/mg (plasmacytoid dendritic cells). This assay represents a significant advancement in rapid, accurate quantification of mononuclear cell populations in mucosal tissues and could be applied to provide absolute counts of a variety of different cell populations in diverse tissues. PMID- 21315724 TI - Novel roles for the corpus allatum hormone in the cost of sexual interactions in the linden bug Pyrrhocoris apterus. AB - The cost of sexual interactions, usually expressed as a reduction of life-span, is a fundamental but poorly understood aspect of life. According to a widely accepted view, a rise in the "pro-aging" juvenile hormone (JH) might contribute to the decrease of life span caused by sexual interactions. We tested this hypothesis using the linden bug Pyrrhocoris apterus by removing the corpus allatum (CA), the source of JH. If JH is causally involved in the cost of sexual interactions, then the absence of CA (JH) should decrease the negative effect of sexual interactions on survival. As expected, ablating the CA significantly prolonged life-span of both virgin females and virgin males. Mated insects of both sexes lived significantly shorter than virgins. However, contrary to prediction, the decrease of life span by sexual interactions was similar in control and CA-ablated males, and was even enhanced in CA-ablated females. Another unexpected finding was that males paired with CA-ablated females lived almost as long as virgin males and significantly longer than did males paired with control females, although ablating the female CA did not cause any decrease in mating activity. On the other hand, females paired with CA-ablated males lived only slightly longer than did females paired with control males. These results highlight several important points. (1) In both genders, the negative effect of sexual interactions on insect's survival is not mediated by the insect's own CA. (2) The male CA has only minor effect on female survival, while (3) the female CA (JH) is principally responsible for the sex-induced reduction in the male survival. PMID- 21315725 TI - Function and immuno-localization of aquaporins in the Antarctic midge Belgica antarctica. AB - Aquaporin (AQP) water channel proteins play key roles in water movement across cell membranes. Extending previous reports of cryoprotective functions in insects, this study examines roles of AQPs in response to dehydration, rehydration, and freezing, and their distribution in specific tissues of the Antarctic midge, Belgica antarctica (Diptera, Chironomidae). When AQPs were blocked using mercuric chloride, tissue dehydration tolerance increased in response to hypertonic challenge, and susceptibility to overhydration decreased in a hypotonic solution. Blocking AQPs decreased the ability of tissues from the midgut and Malpighian tubules to tolerate freezing, but only minimal changes were noted in cellular viability of the fat body. Immuno-localization revealed that a DRIP-like protein (a Drosophila aquaporin), AQP2- and AQP3 (aquaglyceroporin) like proteins were present in most larval tissues. DRIP- and AQP2-like proteins were also present in the gut of adult midges, but AQP4-like protein was not detectable in any tissues we examined. Western blotting indicated that larval AQP2-like protein levels were increased in response to dehydration, rehydration and freezing, whereas, in adults DRIP-, AQP2-, and AQP3-like proteins were elevated by dehydration. These results imply a vital role for aquaporin/aquaglyceroporins in water relations and freezing tolerance in B. antarctica. PMID- 21315726 TI - The VD1 neutralizing antibody to vascular endothelial growth factor-D: binding epitope and relationship to receptor binding. AB - Vascular endothelial growth factor-D (VEGF-D) is a secreted protein that promotes tumor growth and metastatic spread in animal models of cancer. Expression of VEGF D in prevalent human cancers was reported to correlate with lymph node metastasis and patient outcome-hence, this protein is a potential target for novel anticancer therapeutics designed to restrict tumor growth and spread. Here, we define the binding site in VEGF-D of a neutralizing antibody, designated VD1, which blocks the interaction of VEGF-D with its cell surface receptors vascular endothelial growth factor receptor (VEGFR)-2 and VEGFR-3 and is being used for the development of therapeutic antibodies. We show by peptide-based mapping and site-directed mutagenesis that the VD1 binding site includes the five residues (147)NEESL(151) and that immunization with a synthetic peptide containing this motif generates antibodies that neutralize VEGF-D. The tertiary structure of VEGF D indicates that the (147)NEESL(151) epitope is located in the L2 loop of the growth factor, which is important for receptor binding. Mutation of any of these five residues influences receptor binding; for example, mutations to E148, which abolished binding to VD1, impaired the interaction with VEGFR-2 but enhanced binding to VEGFR-3. This structure/function study indicates that the VD1 binding epitope is part of the receptor binding site of VEGF-D, identifies a region of VEGF-D critical for binding of receptors and explains why VD1 does not bind other members of the VEGF family of growth factors. PMID- 21315727 TI - SDS-facilitated in vitro formation of a transmembrane B-type cytochrome is mediated by changes in local pH. AB - The folding and stabilization of alpha-helical transmembrane proteins are still not well understood. Following cofactor binding to a membrane protein provides a convenient method to monitor the formation of appropriate native structures. We have analyzed the assembly and stability of the transmembrane cytochrome b(559)', which can be efficiently assembled in vitro from a heme-binding PsbF homo-dimer by combining free heme with the apo-cytochrome b(559)'. Unfolding of the protein dissolved in the mild detergent dodecyl maltoside may be induced by addition of SDS, which at high concentrations leads to dimer dissociation. Surprisingly, absorption spectroscopy reveals that heme binding and cytochrome formation at pH 8.0 are optimal at intermediate SDS concentrations. Stopped-flow kinetics revealed that genuine conformational changes are involved in heme binding at these SDS concentrations. GPS (Global Protein folding State mapping) NMR measurements showed that optimal heme binding is intimately related to a change in the degree of histidine protonation. In the absence of SDS, the pH curve for heme binding is bell-shaped with an optimum at around pH 6-7. At alkaline pH values, the negative electrostatic potential of SDS lowers the local pH sufficiently to restore efficient heme binding, provided the amount of SDS needed for this does not denature the protein. Accordingly, the higher the pH value above 6-7, the more SDS is needed to improve heme binding, and this competes with the inherent tendency of SDS to dissociate cytochrome b(559)'. Our work highlights that, in addition to its denaturing properties, SDS can affect protein functions by lowering the local pH. PMID- 21315728 TI - The alternating-access mechanism of MFS transporters arises from inverted topology repeats. AB - Lactose permease (LacY) is the prototype of the major facilitator superfamily (MFS) of secondary transporters. Available structures of LacY reveal a state in which the substrate is exposed to the cytoplasm but is occluded from the periplasm. However, the alternating-access transport mechanism requires the existence of a periplasm-facing state. We recently showed that inverted-topology structural repeats provide the foundation for the mechanisms of two transporter families with folds distinct from the MFS. Here, we generated a structural model of LacY by swapping the conformations of inverted-topology repeats identified in its two domains. The model exhibits all required properties of an outward-facing conformation, i.e., closure of the binding site to the cytoplasm and exposure to the periplasm. Furthermore, the model agrees with double electron-electron resonance distance changes, accessibility to cysteine-modifying reagents, cysteine cross-linking data, and a recent structure of a distantly related transporter. Analysis of the intradomain differences between the two states suggests a role for conserved sequence motifs in occluding the central pathway through kinking of the pore-lining helices. In addition, predicted re-pairing of critical salt-bridging residues in the binding sites agrees remarkably well with previous proposals, allowing a description of the proton/sugar transport mechanism. More fundamentally, our model demonstrates that inverted-topology repeats provide the foundation for the alternating-access mechanisms of MFS transporters. PMID- 21315729 TI - A new classification of membrane protein crystals. AB - Although being much smaller than the number of soluble proteins in the Protein Data Bank, the number of membrane proteins therein now approaches 700, and a statistical analysis becomes meaningful. Such an analysis showed that the conventional subdivision into monotopic, beta-barrel and alpha-helical membrane proteins is appropriate but should be amended by a classification according to the detergent micelle structure in the crystal, which can be derived from the packing of the membrane-immersed parts of the proteins. The crystal packing density is specific for the three conventional types of membrane proteins and soluble proteins. It is also specific for three observed detergent arrangements that are micelle pockets, micelle filaments and micelle sheets, demonstrating that the detergent structure affects crystallization. The packing density distribution of crystals from integral membrane proteins has approximately the same shape as that of soluble proteins but is by a factor of two broader and shifted to lower density. It seems unlikely that the differences can be explained by a mere solvent expansion due to the required detergent. The crystallized membrane proteins were further analyzed with respect to protein mass, oligomerization and crystallographic asymmetric unit, space group, crystal ordering and symmetry. The results provide a new view on membrane proteins. PMID- 21315730 TI - The challenges and scope of theoretical biology. AB - Scientific theories seek to provide simple explanations for significant empirical regularities based on fundamental physical and mechanistic constraints. Biological theories have rarely reached a level of generality and predictive power comparable to physical theories. This discrepancy is explained through a combination of frozen accidents, environmental heterogeneity, and widespread non linearities observed in adaptive processes. At the same time, model building has proven to be very successful when it comes to explaining and predicting the behavior of particular biological systems. In this respect biology resembles alternative model-rich frameworks, such as economics and engineering. In this paper we explore the prospects for general theories in biology, and suggest that these take inspiration not only from physics, but also from the information sciences. Future theoretical biology is likely to represent a hybrid of parsimonious reasoning and algorithmic or rule-based explanation. An open question is whether these new frameworks will remain transparent to human reason. In this context, we discuss the role of machine learning in the early stages of scientific discovery. We argue that evolutionary history is not only a source of uncertainty, but also provides the basis, through conserved traits, for very general explanations for biological regularities, and the prospect of unified theories of life. PMID- 21315731 TI - Paradoxical suppression of poly-specific broadly neutralizing antibodies in the presence of strain-specific neutralizing antibodies following HIV infection. AB - One of the first immunologic responses against HIV infection is the presence of neutralizing antibodies that seem able to inactivate several HIV strains. Moreover, in vitro studies have shown the existence of monoclonal antibodies that exhibit broad crossclade neutralizing potential. Yet their number is low and slow to develop in vivo. In this paper, we investigate the potential benefits of inducing poly-specific neutralizing antibodies in vivo throughout immunization. We develop a mathematical model that considers the activation of families of B lymphocytes producing poly-specific and strain-specific antibodies and use it to demonstrate that, even if such families are successful in producing neutralizing antibodies, the competition between them may limit the poly-specific response allowing the virus to escape. We modify this model to account for viral evolution under the pressure of antibody responses in natural HIV infection. The model can reproduce viral escape under certain conditions of B lymphocyte competition. Using these models we provide explanations for the observed antibody failure in controlling natural infection and predict quantitative measures that need to be satisfied for long-term control of HIV infection. PMID- 21315732 TI - Extinction threshold for spatial forest dynamics with height structure. AB - We present a pair-approximation model for spatial forest dynamics defined on a regular lattice. The model assumes three possible states for a lattice site: empty (gap site), occupied by an immature tree, and occupied by a mature tree, and considers three nonlinearities in the dynamics associated to the processes of light interference, gap expansion, and recruitment. We obtain an expression of the basic reproduction number R(0) which, in contrast to the one obtained under the mean-field approach, uses information about the spatial arrangement of individuals close to extinction. Moreover, we analyze the corresponding survival extinction transition of the forest and the spatial correlations among gaps, immature and mature trees close to this critical point. Predictions of the pair approximation model are compared with those of a cellular automaton. PMID- 21315733 TI - Slow variable dominance and phase resetting in phantom bursting. AB - Bursting oscillations are common in neurons and endocrine cells. One type of bursting model with two slow variables has been called 'phantom bursting' since the burst period is a blend of the time constants of the slow variables. A phantom bursting model can produce bursting with a wide range of periods: fast (short period), medium, and slow (long period). We describe a measure, which we call the 'dominance factor', of the relative contributions of the two slow variables to the bursting produced by a simple phantom bursting model. Using this tool, we demonstrate how the control of different phases of the burst can be shifted from one slow variable to another by changing a model parameter. We then show that the dominance curves obtained as a parameter is varied can be useful in making predictions about the resetting properties of the model cells. Finally, we demonstrate two mechanisms by which phase-independent resetting of a burst can be achieved, as has been shown to occur in the electrical activity of pancreatic islets. PMID- 21315734 TI - Vanillin induces adipocyte differentiation in 3T3-L1 cells by activating extracellular signal regulated kinase 42/44. AB - AIMS: To investigate the effect of vanillin, a dietary component, on adipocyte differentiation and the mechanism involved in the process using 3T3-L1 murine preadipocytes. MAIN METHODS: The effect of vanillin on adipocyte differentiation was detected by Oil Red O analysis. The activation of extracellular signal regulated kinase 42/44 (ERK 42/44), Akt, expression of the key regulator of adipocyte differentiation peroxisome proliferators-activated receptor (PPARgamma) and its target gene glucose transporter 4 (GLUT4) were detected by western blotting. Glucose uptake assay was used to determine the insulin sensitivity of adipocytes differentiated by vanillin treatment. To confirm the role of ERK 42/44 and Akt, Oil Red O analysis was performed with cells differentiated in the presence or absence of ERK inhibitor U0126 or Akt kinase 1/2 inhibitor. KEY FINDINGS: Vanillin induced adipocyte differentiation in 3T3-L1 cells in a dose dependent manner and also increased the expression levels of PPARgamma and its target gene GLUT4. The adipocytes differentiated by vanillin exhibited insulin sensitivity as demonstrated by a significant increase in glucose uptake. Vanillin treatment activated the phosphorylation of ERK 42/44 during the initial phase of adipocyte differentiation but there was no significant change in the Akt phosphorylation status. SIGNIFICANCE: The data show that vanillin induces adipocyte differentiation in 3T3-L1 cells by activating ERK42/44 and these adipocytes are insulin sensitive in nature. PMID- 21315735 TI - Claudin-2 knockdown decreases matrix metalloproteinase-9 activity and cell migration via suppression of nuclear Sp1 in A549 cells. AB - AIMS: Claudin expression is altered in lung cancer, but the pathophysiological role of claudin is not well understood. We examined the effect of claudin-2 expression on cell migration using human adenocarcinoma A549 cells. MAIN METHODS: The mRNA level was measured by real time polymerase chain reaction. To knockdown claudin-2 expression, we made the cells expressing doxycycline-inducible claudin 2 shRNA vector. The protein level was examined by Western blotting. Cell migration was measured by wound-healing assay. The enzymatic activity of MMP-9 was assessed by gelatin zymography. KEY FINDINGS: In A549 cells, claudin-2 expression was higher than in normal lung tissue. Claudin-2 knockdown did not affect the expression of other junctional proteins including claudin-1, occludin and E-cadherin. Claudin-2 knockdown decreased cell migration concomitant with a decrease in the mRNA level and enzymatic activity of MMP-9. The expression level of Sp1 in the nuclei was decreased by claudin-2 knockdown. In contrast, the expression levels of c-Fos, c-Jun and NF-kB p65 in the nuclei were not changed by claudin-2 knockdown. The knockdown of Sp1 expression by siRNA decreased cell migration, and the mRNA expression, enzymatic activity, and promoter activity of MMP-9. SIGNIFICANCE: Claudin-2 may increase the mRNA level and enzymatic activity of MMP-9 mediated by the elevation of nuclear distribution of Sp1, resulting in the up-regulation of A549 cell migration. PMID- 21315736 TI - Aberrant expression of imprinted genes in post-implantation rat embryos. AB - AIM: Imprinted genes are known regulators of embryo growth. Studies from our laboratory have demonstrated that treatment of adult male rats with tamoxifen increased post-implantation loss at around midgestation. Expression of insulin like growth factor 2 (Igf2), a paternally expressed imprinted gene was down regulated in the resorbing embryos obtained at embryonic day 13. Hypomethylation of Igf2-H19 imprint control region was observed in the resorbing embryo sires and spermatozoa obtained from tamoxifen-treated rats thereby suggesting that errors in imprint acquisition during spermatogenesis can result in embryo loss. The present study aims at studying the expression of other imprinted genes, besides Igf2 in the embryos sired by tamoxifen-treated males. MAIN METHODS: Gene expression profiles of resorbing versus normal embryos were assessed by microarrays. Real time quantitative RT-PCR for six imprinted genes and four genes involved in cell cycle was done to validate gene expression data. The affected pathways and functions were identified in the resorbing embryos and effect on cell cycle was confirmed by flow cytometry. KEY FINDINGS: Aberrant expression of a number of imprinted genes was observed in the resorbing embryos when compared to the normal embryos at embryonic days 11 and 13. Down-regulation of Notch signaling, Wnt signaling and cell cycle pathway was observed in the resorbing embryos. SIGNIFICANCE: The study suggests that exposure of male germ cells to tamoxifen during adulthood results in aberrant expression of imprinted genes and down-regulation of development associated pathways in the F(1) progeny thereby causing embryo loss. PMID- 21315737 TI - Effects of high-fat diet on insulin receptor function in rat hippocampus and the level of neuronal corticosterone. AB - AIM: Chronic consumption of a high-fat (HF) diet contributes to peripheral insulin resistance and elevated plasma corticosterone. However, the effect of HF consumption on the neurofunctional insulin receptors and neuronal corticosterone level is unclear. We tested the hypothesis that HF consumption can lead to peripheral insulin resistance, elevated neuronal corticosterone, and impaired neuronal responses to insulin. MAIN METHODS: Male Wistar rats were fed with normal diet or HF diet for 4, 8 or 12weeks. At the end of each dietary period, plasma was collected for investigating peripheral insulin resistance parameters and corticosterone. Brains were then rapidly removed for studying the function of neuronal insulin receptors (IRs) by extracellular recording in CA1 hippocampus, neuronal IR signaling by immunoblot technique and neuronal corticosterone. KEY FINDINGS: Elevated plasma corticosterone level was initially seen in 4-week HF fed rats. Peripheral insulin resistance developed at 8-week HF-fed rats. However, the elevated neuronal corticosterone level was found at 12-week HF consumption. The neuronal IR response demonstrated by insulin-mediated long-term depression in CA1 hippocampus was diminished in 12-week HF-fed rats. The phosphorylation levels of neuronal IR, IR substrate 1 and Akt/PKB were decreased in 12-week HF-fed rats with no change in these proteins. There was a correlation among peripheral insulin resistance, neuronal stress (elevated neuronal corticosterone), and neuronal insulin resistance in HF group. SIGNIFICANCE: Our findings suggest that HF consumption can lead to the elevation of corticosterone and peripheral insulin resistance, which could contribute to neuronal insulin resistance and neuronal stress. PMID- 21315738 TI - Role of decoy molecules in neuronal ischemic preconditioning. AB - AIMS: Decoy receptors bind with TNF related apoptosis inducing ligands (TRAIL) but do not contain the cytoplasmic domains necessary to transduce apoptotic signals. We hypothesized that decoy receptors may confer neuronal protection against lethal ischemia after ischemic preconditioning (IPC). MAIN METHOD: Mixed cortical neurons were exposed to IPC one day prior to TRAIL treatment or lethal ischemia. KEY FINDINGS: IPC increased decoy receptor but reduced death receptor expression compared to lethal ischemia. IPC-induced increase in decoy receptor expression was reduced by prior treatment with CAPE, a nuclear factor-kappa B inhibitor (NFkappaB). SIGNIFICANCE: Expression of decoy molecules, dependent on NFkappaB, may mediate neuronal survival induced by IPC. PMID- 21315739 TI - Chronic magnesium deficiency decreases tolerance to hypoxia/reoxygenation injury in mouse heart. AB - AIMS: Magnesium (Mg) deficiency has been reported to be associated with the development of the metabolic syndrome, cardiovascular diseases, and sudden death. We examined the influence of chronic Mg deficiency on cardiac tolerance to hypoxia/reoxygenation injury. MAIN METHODS: Mice were fed an Mg-deficient diet for 4 weeks, and then their hearts were excised for Langendorff perfusion experiments. The levels of total Mg in the blood and heart were quantified by atomic absorption spectrometry. KEY FINDINGS: In Mg-deficient mice, the Mg concentration in whole blood was markedly decreased; however, that in the heart remained unchanged. When the hearts of control mice were exposed to hypoxia/reoxygenation, removal of extracellular Mg from a normal Krebs solution containing 1.2 mM Mg resulted in a significant decrease in the recovery of the tension-rate product (TRP) upon reoxygenation. In Mg-deficient mice, the recovery of TRP in the heart was reduced significantly in the absence of extracellular Mg compared to that in controls. The addition of Mg to the perfusate did not improve TRP recovery. During hypoxia/reoxygenation, cardiac damage evaluated by myocardial aspartate amino transferase (AST) release was greater in hearts of Mg deficient mice than in that of control mice. SIGNIFICANCE: These results indicate that chronic Mg deficiency causes severe hypomagnesemia and a decrease in cardiac tolerance to hypoxia, without changing the intracellular Mg content. The decreased tolerance to hypoxia was not affected by the presence or absence of extracellular Mg, suggesting that some intracellular metabolic abnormalities develop in the cardiac myocytes of Mg-deficient mice. PMID- 21315740 TI - Central melanocortin receptor agonist reduces hepatic lipogenic gene expression in streptozotocin-induced diabetic mice. AB - AIMS: The central melanocortin system regulates a variety of metabolic functions including lipid metabolism and hepatic lipogenic gene expression. The objective of the present study was to determine whether central melanocortin regulates hepatic lipogenic gene expression under insulin insufficient condition. MAIN METHODS: We examined the effect of intracerebroventricular (i.c.v.) injection of MTII, a melanocortin agonist, on hepatic gene expression in a mouse model of the insulin-deficient diabetes. Diabetes was induced in male C57BL/6J mice by intraperitoneal injections of streptozotocin (STZ). Diabetic mice received daily i.c.v. injections of MTII (3 nmol) for 11 days. Hepatic expression levels of lipogenic genes and their transcription factors were measured. KEY FINDINGS: MTII treatment significantly reduced hepatic expression levels of genes encoding lipid biosynthetic enzymes, stearoyl-CoA desaturase 1 (SCD1), glycerol-3-phosphate acyltransferase 1 (GPAT1), acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), and DGAT2 mRNA without significant changes in serum insulin levels, homeostasis model assessment of insulin resistance (HOMA-IR) and glucose tolerance in STZ-induced diabetic mice. MTII treatment also reduced fatty acid synthase (FAS) and SCD1 protein levels in the liver of diabetic mice. Expression levels of genes encoding transcription factors of these lipogenic genes, sterol regulatory element-binding protein 1c (SREBP-1c) and peroxisome proliferator-activated receptor gamma2 (PPARgamma2) were also significantly reduced by MTII treatment. SIGNIFICANCE: These data suggest that the insulin-independent mechanism is involved in the regulation of hepatic lipogenic gene expression. Enhanced central melanocortin signaling may be effective in improving abnormal lipid metabolism associated with insulin-deficiency or insulin-insufficiency. PMID- 21315741 TI - Differential trafficking of adenosine receptors in hippocampal neurons monitored using GFP- and super-ecliptic pHluorin-tagged receptors. AB - Adenosine receptors (ARs) modulate many cellular and systems-level processes in the mammalian CNS. However, little is known about the trafficking of ARs in neurons, despite their importance in controlling seizure activity and in neuroprotection in cerebral ischaemia. To address this we examined the agonist dependent internalisation of C-terminal GFP-tagged A(1)Rs, A(2A)Rs and A(3)Rs in primary hippocampal neurons. Furthermore, we developed a novel super-ecliptic pHluorin (SEP)-tagged A(1)R which, via the N-terminal SEP tag, reports the cell surface expression and trafficking of A(1)Rs in real-time. We demonstrate the differential trafficking of ARs in neurons: A(3)Rs internalise more rapidly than A1Rs, with little evidence of appreciable A(2A)R trafficking over the time-course of the experiments. Furthermore, the novel SEP-A(1)R construct revealed the time course of internalisation and recovery of cell-surface expression to occur within minutes of agonist exposure and removal, respectively. These observations highlight the labile nature of A(1)R and A(3)Rs when expressed at the neuronal plasma membrane. Given the high levels of adenosine in the brain during ischaemia and seizures, internalisation of the inhibitory A(1)R may result in hyperexcitability, increased brain damage and the development of chronic epileptic states. PMID- 21315742 TI - Post stroke intervention: is the window widening? PMID- 21315743 TI - Adenosine hypothesis of schizophrenia--opportunities for pharmacotherapy. AB - Pharmacotherapy of schizophrenia based on the dopamine hypothesis remains unsatisfactory for the negative and cognitive symptoms of the disease. Enhancing N-methyl-D-aspartate receptors (NMDAR) function is expected to alleviate such persistent symptoms, but successful development of novel clinically effective compounds remains challenging. Adenosine is a homeostatic bioenergetic network modulator that is able to affect complex networks synergistically at different levels (receptor-dependent pathways, biochemistry, bioenergetics, and epigenetics). By affecting brain dopamine and glutamate activities, it represents a promising candidate for reversing the functional imbalance in these neurotransmitter systems believed to underlie the genesis of schizophrenia symptoms, as well as restoring homeostasis of bioenergetics. Suggestion of an adenosine hypothesis of schizophrenia further posits that adenosinergic dysfunction might contribute to the emergence of multiple neurotransmitter dysfunctions characteristic of schizophrenia via diverse mechanisms. Given the importance of adenosine in early brain development and regulation of brain immune response, it also bears direct relevance to the aetiology of schizophrenia. Here, we provide an overview of the rationale and evidence in support of the therapeutic potential of multiple adenosinergic targets, including the high affinity adenosine receptors (A(1)R and A(2A)R), and the regulatory enzyme adenosine kinase (ADK). Key preliminary clinical data and preclinical findings are reviewed. PMID- 21315746 TI - Lateralisation for processing facial emotion and anxiety: contrasting state, trait and social anxiety. AB - Recent neuropsychological studies have attempted to distinguish between different types of anxiety by contrasting patterns of brain organisation or activation; however, lateralisation for processing emotional stimuli has received relatively little attention. This study examines the relationship between strength of lateralisation for the processing of facial expressions of emotion and three measures of anxiety: state anxiety, trait anxiety and social anxiety. Across all six of the basic emotions (anger, disgust, fear, happiness, sadness, surprise) the same patterns of association were found. Participants with high levels of trait anxiety were more strongly lateralised to the right hemisphere for processing facial emotion. In contrast, participants with high levels of self reported physiological arousal in response to social anxiety were more weakly lateralised to the right hemisphere, or even lateralised to the left hemisphere, for the processing of facial emotion. There were also sex differences in these associations: the relationships were evident for males only. The finding of distinct patterns of lateralisation for trait anxiety and self-reported physiological arousal suggests different neural circuitry for trait and social anxiety. PMID- 21315744 TI - Mutant DISC1 affects methamphetamine-induced sensitization and conditioned place preference: a comorbidity model. AB - Genetic factors involved in neuroplasticity have been implicated in major psychiatric illnesses such as schizophrenia, depression, and substance abuse. Given its extended interactome, variants in the Disrupted-In-Schizophrenia-1 (DISC1) gene could contribute to drug addiction and psychiatric diseases. Thus, we evaluated how dominant-negative mutant DISC1 influenced the neurobehavioral and molecular effects of methamphetamine (METH). Control and mutant DISC1 mice were studied before or after treatment with non-toxic escalating dose (ED) of METH. In naive mice, we assessed METH-induced conditioned place preference (CPP), dopamine (DA) D2 receptor density and the basal and METH-induced activity of DISC1 partners, AKT and GSK-3beta in the ventral striatum. In ED-treated mice, 4 weeks after METH treatment, we evaluated fear conditioning, depression-like responses in forced swim test, and the basal and METH-induced activity of AKT and GSK-3beta in the ventral striatum. We found impairment in METH-induced CPP, decreased DA D2 receptor density and altered METH-induced phosphorylation of AKT and GSK-3beta in naive DISC1 female mice. The ED regimen was not neurotoxic as evidenced by unaltered brain regional monoamine tissue content. Mutant DISC1 significantly delayed METH ED-produced sensitization and affected drug-induced phosphorylation of AKT and GSK-3beta in female mice. Our results suggest that perturbations in DISC1 functions in the ventral striatum may impact the molecular mechanisms of reward and sensitization, contributing to comorbidity between drug abuse and major mental diseases. PMID- 21315747 TI - Selection within visual memory representations activates the oculomotor system. AB - Humans tend to create and maintain internal representations of the environment that help guiding actions during the everyday activities. Previous studies have shown that the oculomotor system is involved in coding and maintenance of locations in visual-spatial working memory. In these studies selection of the relevant location for maintenance in working memory took place on the screen (selecting the location of a dot presented on the screen). The present study extended these findings by showing that the oculomotor system also codes selection of location from an internal memory representation. Participants first memorized two locations and after a retention interval selected one location for further maintenance. The results show that saccade trajectories deviated away from the ultimately remembered location. Furthermore, selection of the location from the memorized representation produced sustained oculomotor preparation to it. The results show that oculomotor system is very flexible and plays an active role for coding and maintaining information selected within internal memory representations. PMID- 21315745 TI - Behavioral and neurochemical consequences of cortical oxidative stress on parvalbumin-interneuron maturation in rodent models of schizophrenia. AB - Oxidative stress, in response to the activation of the superoxide-producing enzyme Nox2, has been implicated in the schizophrenia-like behavioral dysfunction that develops in animals that were subject to either neonatal NMDA receptor antagonist treatment or social isolation. In both of these animal models of schizophrenia, an environmental insult occurring during the period of active maturation of the fast-spiking parvalbumin-positive (PV+) interneuronal circuit leads to a diminished expression of parvalbumin in GABA-inhibitory neurons when animals reach adulthood. The loss of PV+ interneurons in animal models had been tentatively attributed to the death of these neurons. However, present results show that for the perinatal NMDA-R antagonist model these interneurons are still alive when animals are 5-6 weeks of age even though they have lost their phenotype and no longer express parvalbumin. Alterations in parvalbumin expression and sensory-evoked gamma-oscillatory activity, regulated by PV+ interneurons, are consistently observed in schizophrenia. We propose that cortical networks consisting of faulty PV+ interneurons interacting with pyramidal neurons may be responsible for the aberrant oscillatory activity observed in schizophrenia. Thus, oxidative stress during the maturation window for PV+ interneurons by alteration of normal brain development, leads to the emergence of schizophrenia-like behavioral dysfunctions when subjects reach early adulthood. PMID- 21315748 TI - Looking to the future: automatic regulation of attention between current performance and future plans. AB - We investigated neuro-cognitive mechanisms involved with coordination of attention between current task performance and future action plans in prospective memory. We developed a novel task paradigm with continuous performance of a prospective memory task, where trial intervals of prospective memory targets were systematically manipulated in a periodic cycle of expanding and contracting target intervals. We found that subjects' behaviour was significantly modulated without awareness of this temporal sequence of the targets: remembering to perform a prospective memory response to target events was more successful and faster in the expanding target interval phase, at the cost of lower and slower performance of ongoing tasks, while an opposite direction of this trade-off effect was observed in the contracting target interval phase. By using functional magnetic resonance imaging (fMRI), we identified the similar trade-off effect in activations in the anterior medial prefrontal cortices (activation elevation at the target responses as well as deactivation at the ongoing responses in the expanding phase as compared with the contracting phase). The opposite direction of the trade-off was observed in the anterior cingulate cortex. These results show a clear case in which attention between current task performance and future action plans in prospective memory tasks is automatically regulated without particular task instructions or strategic control processes initiated by subjects. We suggest that medial areas of the frontal cortex specifically mediate the automatic coordination of attentional resources between current task performance and future action plans. PMID- 21315749 TI - The role of negative affectivity and social inhibition in perceiving social threat: an fMRI study. AB - Personality is associated with specific emotion regulation styles presumably linked with unique brain activity patterns. By using functional magnetic resonance imaging (fMRI) in 26 individuals, the neural responses to threatening (fearful and angry) facial and bodily expressions were investigated in relation to negative affectivity and social inhibition. A negative correlation was observed between negative affectivity and activation of the amygdala, fusiform gyrus, insula and hippocampus. Increased activation following threatening stimuli was observed in the left temporo-parietal junction and right extrastriate body area correlating with more social inhibition traits. Interestingly, the orbitofrontal cortex, superior temporal sulcus, inferior frontal gyrus (Brodmann area 45) and temporal pole correlated negatively with negative affectivity and positively with social inhibition. Whereas individuals with increased negative affectivity tend to de-activate the core emotion system, socially inhibited people tend to over-activate a broad cortical network. Our findings demonstrate effects of personality traits on the neural coding of threatening signals. PMID- 21315750 TI - Prospective memory in patients with closed head injury: a review. AB - This paper aimed to review the limited, but growing literature on prospective memory (PM) following closed head injury (CHI). Search of two commonly used databases yielded studies that could be classified as: self- or other-report of PM deficits; behavioral PM measures in adults with CHI, behavioral PM measures in children and adolescents with CHI, and treatment of PM in adults with CHI. The methodology and findings of these studies were critically reviewed and discussed. Because of the small number of studies, meta-analysis was only conducted for studies that used behavioral PM measures in adults to integrate findings. PM deficits were found to be commonly reported by patients with CHI and their significant others and they could be identified using behavioral measures in adults, children and adolescents with CHI. However, more work is needed to clarify the nature and mechanisms of these deficits. Although some promising results have been reported by studies that evaluated PM treatment, most studies lack tight experimental control and used only a small number of participants. The paper concluded with some suggestions for future research. PMID- 21315751 TI - Intestinal feedback signaling and satiety. AB - Peptidergic and neural signals arising from the presence of food in the gastrointestinal track provide feedback signals to the brain about the nature and quantity of consumed nutrients. Peptide secreting cells are differentially distributed along the gastrointestinal tract. How ingested nutrients activate or inhibit peptide secretion is complex and depends upon local, hormonal and neural mechanisms. The mode of action of the various peptides is equally complex involving endocrine, paracrine and neurocrine signaling. The success of bariatric surgical approaches to obesity treatment is secondary to alterations in gastrointestinal feedback signaling and roles of increased secretion of lower gut peptides such as peptide YY (PYY) and glucagon like peptide 1 (GLP-1) in mediating the superior effects of Roux-en-Y gastric bypass (RYGB) surgery are becoming evident. Direct nutrient delivery to jejunal sites that models the site of gastric-jejunal anastamosis in RYGB is especially effective at inhibiting food intake. Such infusions also stimulate the release of lower gut peptides suggesting a role for increased gut peptide signaling in sustaining such feeding inhibitions. Thus, gut peptides are clear targets for future obesity therapeutic developments. PMID- 21315752 TI - How eating affects mood. AB - IOAKIMIDIS I, M. ZANDIAN, F. ULBL, C. BERGH, M LEON, AND P. SODERSTEN. How eating affects mood. PHYSIOL BEHAV 2011 (000) 000-000. We hypothesize that the changes in mood that are associated with eating disorders are caused by a change in eating behavior. When food is in short supply, the rhythm of the neural network for eating, including orbitofrontal cortex and brainstem, slows down and we suggest that this type of neural activity activates a partially overlapping neural network for mood, including dorsal raphe serotonin projections to the orbitofrontal and prefrontal cortex. As a consequence, people who restrict the amount of food that they consume, either by choice or by their limited access to food, become preoccupied with food and food-related behavior. Most eating disorders emerge from a history of dietary restriction and we suggest that disordered eating consequent upon food restriction produces the altered mental state of patients with eating disorders. Based on the present hypothesis, eating disorders are not the result of a primary mental disorder. Rather, this notion suggests that the patients should be treated by learning to eat an appropriate amount of food at an appropriate rate. PMID- 21315753 TI - Rates of cultural change and patterns of cultural accumulation in stochastic models of social transmission. AB - Cultural variation in a population is affected by the rate of occurrence of cultural innovations, whether such innovations are preferred or eschewed, how they are transmitted between individuals in the population, and the size of the population. An innovation, such as a modification in an attribute of a handaxe, may be lost or may become a property of all handaxes, which we call "fixation of the innovation." Alternatively, several innovations may attain appreciable frequencies, in which case properties of the frequency distribution-for example, of handaxe measurements-is important. Here we apply the Moran model from the stochastic theory of population genetics to study the evolution of cultural innovations. We obtain the probability that an initially rare innovation becomes fixed, and the expected time this takes. When variation in cultural traits is due to recurrent innovation, copy error, and sampling from generation to generation, we describe properties of this variation, such as the level of heterogeneity expected in the population. For all of these, we determine the effect of the mode of social transmission: conformist, where there is a tendency for each naive newborn to copy the most popular variant; pro-novelty bias, where the newborn prefers a specific variant if it exists among those it samples; one-to-many transmission, where the variant one individual carries is copied by all newborns while that individual remains alive. We compare our findings with those predicted by prevailing theories for rates of cultural change and the distribution of cultural variation. PMID- 21315754 TI - Regulation of brain copper homeostasis by the brain barrier systems: effects of Fe-overload and Fe-deficiency. AB - Maintaining brain Cu homeostasis is vital for normal brain function. The role of systemic Fe deficiency (FeD) or overload (FeO) due to metabolic diseases or environmental insults in Cu homeostasis in the cerebrospinal fluid (CSF) and brain tissues remains unknown. This study was designed to investigate how blood brain barrier (BBB) and blood-SCF barrier (BCB) regulated Cu transport and how FeO or FeD altered brain Cu homeostasis. Rats received an Fe-enriched or Fe depleted diet for 4 weeks. FeD and FeO treatment resulted in a significant increase (+55%) and decrease (-56%) in CSF Cu levels (p<0.05), respectively; however, neither treatment had any effect on CSF Fe levels. The FeD, but not FeO, led to significant increases in Cu levels in brain parenchyma and the choroid plexus. In situ brain perfusion studies demonstrated that the rate of Cu transport into the brain parenchyma was significantly faster in FeD rats (+92%) and significantly slower (-53%) in FeO rats than in controls. In vitro two chamber Transwell transepithelial transport studies using primary choroidal epithelial cells revealed a predominant efflux of Cu from the CSF to blood compartment by the BCB. Further ventriculo-cisternal perfusion studies showed that Cu clearance by the choroid plexus in FeD animals was significantly greater than control (p<0.05). Taken together, our results demonstrate that both the BBB and BCB contribute to maintain a stable Cu homeostasis in the brain and CSF. Cu appears to enter the brain primarily via the BBB and is subsequently removed from the CSF by the BCB. FeD has a more profound effect on brain Cu levels than FeO. FeD increases Cu transport at the brain barriers and prompts Cu overload in the CNS. The BCB plays a key role in removing the excess Cu from the CSF. PMID- 21315755 TI - Carcinogenic heavy metals, As3+ and Cr6+, increase affinity of nuclear mono ubiquitinated annexin A1 for DNA containing 8-oxo-guanosine, and promote translesion DNA synthesis. AB - To elucidate the biological roles of mono-ubiquitinated annexin A1 in nuclei, we investigated the interaction of purified nuclear mono-ubiquitinated annexin A1 with intact and oxidatively damaged DNA. We synthesized the 80mer 5' GTCCACTATTAAAGAACGTGGACTCCAACGTCAAAGGGCGAAAAACCGTCTATCAGGGCGATGGCCCACTACGTGAACCA 3' (P0G), and four additional 80mers, each with a selected single G in position 14, 30, 37 or 48 replaced by 8-oxo-guanosine (8-oxo-G) to model DNA damaged at a specific site by oxidation. Nuclear mono-ubiquitinated annexin A1 was able to bind oligonucleotides containing 8-oxo-G at specific positions, and able to anneal damaged oligonucleotide DNA to M13mp18 in the presence of Ca(2+) or heavy metals such as As(3+) and Cr(6+). M13mp18/8-oxo-G-oligonucleotide duplexes were unwound by nuclear annexin A1 in the presence of Mg(2+) and ATP. The binding affinity of nuclear annexin A1 for ssDNA was higher for oxidatively damaged oligonucleotides than for the undamaged oligonucleotide P0G, whereas the maximal binding was not significantly changed. The carcinogenic heavy metals, As(3+) and Cr(6+), increased the affinity of mono-ubiquitinated annexin A1 for oxidatively damaged oligonucleotides. Nuclear mono-ubiquitinated annexin A1 stimulated translesion DNA synthesis by Pol beta. Nuclear extracts of L5178Y tk(+/-) lymphoma cells also promoted translesion DNA synthesis in the presence of the heavy metals As(3+) and Cr(6+). This DNA synthesis was inhibited by anti-annexin A1 antibody. These observations do not prove but provide strong evidence for the hypothesis that nuclear mono-ubiquitinated annexin A1 is involved in heavy metal promoted translesion DNA synthesis, thereby exhibiting the capacity to increase the introduction of mutations into DNA. PMID- 21315757 TI - Cortical tonotopic map plasticity and behavior. AB - Central topographic representations of sensory epithelia have a genetic basis, but are refined by patterns of afferent input and by behavioral demands. Here we review such experience-driven map development and plasticity, focusing on the auditory system, and giving particular consideration to its adaptive value and to the putative mechanisms involved. Recent data have challenged the widely held notion that only the developing auditory brain can be influenced by changes to the prevailing acoustic environment, unless those changes convey information of behavioral relevance. Specifically, it has been shown that persistent exposure of adult animals to random, bandlimited, moderately loud sounds can lead to a reorganization of auditory cortex not unlike that following restricted hearing loss. The mature auditory brain is thus more plastic than previously supposed, with potentially troubling consequences for those working or living in noisy environments, even at exposure levels considerably below those presently considered just-acceptable. PMID- 21315758 TI - The reticular-activating hypofrontality (RAH) model of acute exercise. AB - We present here a comprehensive, neurocognitive model to account for the psychological consequences of acute exercise. There is a substantial amount of disparate research and the proposed mechanistic explanation meaningfully integrates this body of brain and behavioral data into a single, unified model. The model's central feature is a cascading, two-step process. First, exercise engages arousal mechanisms in the reticular-activating system. This activation process, which involves a number of neurotransmitter systems, has several interrelated effects on cognition and emotion but, in general, has evolved to facilitate implicit information processing. Second, exercise disengages the higher-order functions of the prefrontal cortex. This deactivation process, which is caused in part by resource limitations, also has several interrelated effects but, in general, has evolved to keep the inefficient explicit system and unhelpful emotional processes from compromising the implicit system's functioning when optimal motor execution is needed most. In this article, we review evidence in support of this reticular-activating hypofrontality (RAH) model of acute exercise and place it into a larger evolutionary context. PMID- 21315756 TI - Alzheimer's disease and age-related memory decline (preclinical). AB - An unfortunate result of the rapid rise in geriatric populations worldwide is the increasing prevalence of age-related cognitive disorders such as Alzheimer's disease (AD). AD is a devastating neurodegenerative illness that is characterized by a profound impairment of cognitive function, marked physical disability, and an enormous economic burden on the afflicted individual, caregivers, and society in general. The rise in elderly populations is also resulting in an increase in individuals with related (potentially treatable) conditions such as "Mild Cognitive Impairment" (MCI) which is characterized by a less severe (but abnormal) level of cognitive impairment and a high-risk for developing dementia. Even in the absence of a diagnosable disorder of cognition (e.g., AD and MCI), the perception of increased forgetfulness and declining mental function is a clear source of apprehension in the elderly. This is a valid concern given that even a modest impairment of cognitive function is likely to be associated with significant disability in a rapidly evolving, technology-based society. Unfortunately, the currently available therapies designed to improve cognition (i.e., for AD and other forms of dementia) are limited by modest efficacy and adverse side effects, and their effects on cognitive function are not sustained over time. Accordingly, it is incumbent on the scientific community to develop safer and more effective therapies that improve and/or sustain cognitive function in the elderly allowing them to remain mentally active and productive for as long as possible. As diagnostic criteria for memory disorders evolve, the demand for pro-cognitive therapeutic agents is likely to surpass AD and dementia to include MCI and potentially even less severe forms of memory decline. The purpose of this review is to provide an overview of the contemporary therapeutic targets and preclinical pharmacologic approaches (with representative drug examples) designed to enhance memory function. PMID- 21315759 TI - In vitro Pb exposure disturbs the balance between Abeta production and elimination: the role of AbetaPP and neprilysin. AB - Metabolism of beta-amyloid peptide (Abeta) is closely associated with the pathology and etiology of Alzheimer's disease (AD). Our previous studies on aging primates and rodents have revealed that early life lead exposure increases the expression of the beta-amyloid precursor protein (AbetaPP), elevates Abeta levels, and promotes neurodegeneration in old age. These effects were attributed to de novo synthetic pathways; however, the impact on Abeta degradation was not explored. Neprilysin (NEP), a rate-limiting catabolic peptidase is involved in Abeta metabolism in vivo. In the present study we sought to investigate whether accumulation of Abeta induced by Pb exposure is partially due to its ability to subdue NEP expression and consequently NEP activity. SH-SY5Y cells were exposed to Pb concentrations of 0, 5, 10, 20, and 50 MUM for 48 h and AbetaPP, NEP protein and mRNA levels were measured. Additionally, NEP enzymatic activity and Abeta levels were also assessed. Western blot and RT-PCR analysis indicated significant increases in the protein and mRNA expression of AbetaPP, which appeared to be concentration and time-dependent, while the protein and mRNA expression of NEP as well as NEP activity declined. These actions of Pb were specific and were not observed when substituted by another metal. These results suggest that Pb causes both the overexpression of AbetaPP and repression of NEP resulting in the buildup of Abeta. PMID- 21315761 TI - The role of oxidative stress in fetal alcohol spectrum disorders. AB - The ingestion of alcohol/ethanol during pregnancy can result in abnormal fetal development in both humans and a variety of experimental animal models. Depending on the pattern of consumption, the dose, and the period of exposure to ethanol, a myriad of structural and functional deficits can be observed. These teratogenic effects are thought to result from the ethanol-induced dysregulation of a variety of intracellular pathways ultimately culminating in toxicity and cell death. For instance, ethanol exposure can lead to the generation of reactive oxygen species (ROS) and produce an imbalance in the intracellular redox state, leading to an overall increase in oxidative stress. In the present review we will provide an up to-date summary on the effects of prenatal/neonatal ethanol exposure on the levels of oxidative stress in the central nervous system (CNS) of experimental models of fetal alcohol spectrum disorders (FASD). We will also review the evidence for the use of antioxidants as potential therapeutic strategies for the treatment of some of the neuropathological deficits characteristic of both rodent models of FASD and children afflicted with these disorders. We conclude that an imbalance in the intracellular redox state contributes to the deficits seen in FASD and suggest that antioxidants are potential candidates for the development of novel therapeutic strategies for the treatment of these developmental disorders. PMID- 21315760 TI - The role of the central noradrenergic system in behavioral inhibition. AB - Although the central noradrenergic system has been shown to be involved in a number of behavioral and neurophysiological processes, the relation of these to its role in depressive illness has been difficult to define. The present review discusses the hypothesis that one of its chief functions that may be related to affective illness is the inhibition of behavioral activation, a prominent symptom of the disorder. This hypothesis is found to be consistent with most previous neuropsychopharmacological and immunohistochemical experiments on active behavior in rodents in a variety of experimental conditions using manipulation of neurotransmission at both locus coeruleus and forebrain adrenergic receptors. The findings support a mechanism in which high rates of noradrenergic neural activity suppress the neural activity of principal neurons in forebrain regions mediating active behavior. The suppression may be mediated through postsynaptic galaninergic and adrenergic receptors, and via the release of corticotrophin releasing hormone. The hypothesis is consistent with clinical evidence for central noradrenergic system hyperactivity in depressives and with the view that this hyperactivity is a contributing etiological factor in the disorder. A similar mechanism may underlie the ability of the noradrenergic system to suppress seizure activity suggesting that inhibition of the spread of neural activation may be a unifying function. PMID- 21315762 TI - Detection of early locomotor abnormalities in a Drosophila model of Alzheimer's disease. AB - Behavioural assays represent sensitive methods for detecting neuronal dysfunction in model organisms. A number of manual methods have been established for Drosophila, however these are time-consuming and generate parameter-poor phenotype descriptors. Here, we have developed an automated computer vision system to monitor accurately the three-dimensional locomotor trajectories of flies. This approach allows the quantitative description of fly trajectories, using small fly cohorts and short acquisition times. The application of this approach to a Drosophila model of Alzheimer's disease enables the early detection of progressive locomotor deficits and the quantitative assessment of phenotype severity. The approach can be widely applied to different disease models in a number of model organisms. PMID- 21315763 TI - Generation of murine monoclonal antibodies which cross-neutralize human enterovirus genogroup B isolates. AB - A live enterovirus 71 (EV71) isolate designated, EV71/E59, with genotype B4 produced in Vero cells and purified over a sucrose gradient was used as the immunogen to generate EV71-specific murine monoclonal antibodies. Four hybridoma clones derived from the fusion of splenocytes of EV71/E59-preimmunized BALB/c (H 2(d)) mice and the NS-1 myeloma cells that exhibit stable growth were selected for detailed characterization. The proof that the hybridomas produced are indeed true independent clones was based on the obervations that they expressed different complementarity-determining regions (CDRs) in their kappa light chain genes. Purified ascitic fluids produced by the individual clones reacted against the viral capsid protein, VP1, in Western blot; and recognized distinct sites of a common epitope localized at the C-terminal half of VP1. Each of the monoclonal antibodies exhibited potent neutralizing activities against the immunizing virus strain, as well as two other isolates namely, N0781-TW-01, and N2838, of subgenogroups B4 and B5, respectively, that were found commonly in recent outbreaks in Taiwan. It was also observed the monoclonal antibodies acted cooperatively in neutralizing the EV71/E59 virus. PMID- 21315764 TI - A dendritic cell-based assay for measuring memory T cells specific to dengue envelope proteins in human peripheral blood. AB - Dengue envelope (E) protein is a dominant immune inducer and E protein-based vaccines elicited partial to complete protection in non-human primates. To study the immunogenicity of these vaccines in humans, an enzyme linked immunospot (ELISPOT) assay for measuring interferon gamma (IFN-gamma) production was developed. Cells from two subject groups, based on dengue-exposure, were selected for assay development. The unique feature of the IFN-gamma ELISPOT assay is the utilization of dendritic cells pulsed with E proteins as antigen presenting cells. IFN-gamma production, ranging from 53-513 spot forming units per million peripheral blood mononuclear cells (PBMCs), was observed in dengue-exposed subjects as compared to 0-45 IFN-gamma spot forming units in dengue-unexposed subjects. Further, both CD4(+) and CD8(+) T cells, and cells bearing CD45RO memory marker, were the major sources of IFN-gamma production. The assay allowed quantification of E-specific IFN-gamma-secreting memory T cells in subjects 9 years after exposure to a live-attenuated virus vaccine and live-virus challenge. Results suggested that the dendritic cell-based IFN-gamma assay is a useful tool for assessing immunological memory for clinical research. PMID- 21315765 TI - An analysis of nicotine conditioned place conditioning in early postweanling and adolescent rats neonatally treated with quinpirole. AB - This study investigated nicotine place conditioning in early postweanling and adolescent male and female rats neonatally treated with quinpirole, a dopamine D(2)/D(3) agonist. Previous research has shown that neonatal quinpirole treatment results in an increase of dopamine D(2)-like receptor sensitivity that persists throughout the animal's lifetime, relevant to psychosis. Rats were neonatally treated with quinpirole or saline from postnatal day (P)1-21, and animals were conditioned with nicotine or saline daily from P23-30 as early postweanlings or P32-39 as adolescents in a two- or three-chambered place conditioning apparatus. A drug free test was given on P31 for early postweanlings, and P40 for adolescents. Results on the two chamber apparatus revealed that nicotine increased time spent in the drug-paired context at both ages tested. Neonatal quinpirole treatment resulted in less time spent in the drug-paired context in early postweanling males and increased time spent in the drug-paired context in adolescent females conditioned with nicotine. Adolescent females neonatally treated with saline and conditioned with nicotine on the two chamber apparatus did not differ from controls. On the three-chambered apparatus, nicotine increased time spent in the drug-paired context in both ages tested, which was blocked by neonatal quinpirole in early postweanling males, but enhanced by neonatal quinpirole treatment in adolescents. These results demonstrate both age and sex differences in the effects of nicotine and point to significant differences in performance depending on the apparatus used. Additionally, neonatal quinpirole enhanced the effects of nicotine, but this is true only in adolescents and task-dependent. PMID- 21315766 TI - The hydrophobic dipeptide Leu-Ile inhibits immobility induced by repeated forced swimming via the induction of BDNF. AB - Depression has recently become a serious problem in society worldwide. However, we lack appropriate therapeutic tools, since the causes of depression remain unclear. Degeneration of neuronal cells and a decrease in neurogenesis have been suggested recently as two of the factors responsible for depression-like behavior. Furthermore, brain-derived neurotrophic factor (BDNF) is also suggested to be an important factor in recovering from such behavior. We have previously demonstrated that the hydrophobic dipeptide leucyl-isoleucine (Leu-Ile) induces BDNF in cultured neuronal cells. We therefore investigated possible antidepressant-like effects of Leu-Ile in an animal model using the repeated forced swim test (FST). Mice were forced to swim for 6 min once a day in a cylinder containing water. The mice were treated with Leu-Ile s.c. or p.o. immediately after each FST. Five-day repeated Leu-Ile treatment significantly increased BDNF mRNA levels and activated the BDNF/Akt/mTOR signaling pathway in the hippocampi of the mice. While 2-week repeated FST increased immobility time, Leu-Ile treatment for 2 weeks offset this increase. In C57BL/6J-BDNF heterozygous knockout (BDNF(+/-)) mice, Leu-Ile failed to reduce the immobility time increased by repeated FST. We next investigated the extent of cell proliferation in the hippocampus as 5-bromo-2'-deoxy-uridine (BrdU) uptake into hippocampal cells. Repeated FST significantly reduced the number of BrdU-positive cells in the hippocampal dentate gyrus, while this deficit was prevented by repeated Leu-Ile treatment. These results suggest that Leu-Ile has an antidepressant-like effect, at least in part by supporting cell proliferation through the BDNF signaling pathway. PMID- 21315767 TI - Lesions of the entopeduncular nucleus in rats prevent apomorphine-induced deficient sensorimotor gating. AB - Dopamine-induced hyperactivity and deficient sensorimotor gating, measured as prepulse inhibition (PPI) of the acoustic startle response (ASR), are used as animal models for neuropsychiatric disorders such as schizophrenia and Tourette's syndrome. We here investigated whether excitotoxic lesions of the rat entopeduncular nucleus (EPN), the equivalent to the human globus pallidus internus (GPi), would improve apomorphine-induced PPI-deficits and hyperactivity. Additionally, we investigated the effect of EPN lesions on cognition, motivation and motor skills. In male Sprague Dawley rats bilateral EPN lesions were induced by stereotactic injection of ibotenate (4 MUg in 0.4 MUl phosphate buffered saline, PBS) or sham-lesions by injection of vehicle PBS. After one week, rats were tested for learning and memory (continuous and delayed alternation, T-maze), for motivation (progressive ratio test with breakpoint of 3 min inactivity, Skinner box), and for motor skills (rotating rod). Thereafter, rats were tested for PPI of ASR (startle response system) after subcutaneous injection of apomorphine (1.0mg/kg and vehicle) and for locomotor activity (0.5mg/kg and vehicle). Ibotenate-induced EPN lesions did not affect learning and memory, motivation or motor skills. Basal locomotor activity and PPI was also not affected, but EPN lesions ameliorated apomorphine-induced hyperlocomotion and deficient PPI. This work indicates an important role of the EPN for the modulation of dopamine agonist-induced deficient sensorimotor gating and hyperlocomotion, without affecting normal behavioral function. PMID- 21315768 TI - Pre- and post-conditioning treatment with an ultra-low dose of Delta9 tetrahydrocannabinol (THC) protects against pentylenetetrazole (PTZ)-induced cognitive damage. AB - Preconditioning, a phenomenon where a minor noxious stimulus protects from a subsequent more severe insult, and post-conditioning, where the protective intervention is applied following the insult, offer new insight into the neuronal mechanism(s) of neuroprotection and may provide new strategies for the prevention and treatment of brain damage. We have previously reported that a single administration of an extremely low dose of Delta(9)-tetrahydrocannabinol (THC; the psychoactive ingredient of marijuana) to mice induced minor long-lasting cognitive deficits. In the present study we examined the possibility that such a low dose of THC will protect the mice from more severe cognitive deficits induced by the epileptogenic drug pentylenetetrazole (PTZ). THC (0.002 mg/kg, a dose that is 3-4 orders of magnitude lower than the doses that induce the conventional effects of THC) was administered 1-7 days before, or 1-3 days after the injection of PTZ (60 mg/kg). The consequences of this treatment were studied 3-7 weeks later by various behavioral tests that evaluated different aspects of memory and learning. We found that a single administration of THC either before or after PTZ abolished the PTZ-induced long-lasting cognitive deficits. Biochemical studies indicated a concomitant reduction in phosphorylated-ERK (extracellular signal regulated kinase) in the cerebella of mice 7 weeks following the injection of THC. Our results suggest that a pre- or post-conditioning treatment with extremely low doses of THC, several days before or after brain injury, may provide safe and effective long-term neuroprotection. PMID- 21315769 TI - Acute and chronic anxiogenic-like response to fluoxetine in rats in the elevated plus-maze: modulation by stressful handling. AB - While antidepressants are widely prescribed to humans for the treatment of anxiety, the results achieved with animal anxiety models are conflicting. The experimental procedure and the prior test history of the animals are critical parameters that are largely susceptible to influence the results and their interpretation. We compared the effect of 5mg fluoxetine administered to six groups of rats subjected to the psychopharmacological test of the elevated plus maze, under experimental conditions designed to demonstrate the effect of handling and one daily injection on the response to fluoxetine. The results show that for animals with the same recent experience, fluoxetine, when administered once or over a period of 15 days, induces anxiogenic-like behaviour. On the other hand, our results also show that stressful handling has an anxiolytic-like effect modulating the anxiogenic-like effect of fluoxetine, without eliminating it altogether. PMID- 21315770 TI - Autophagy in parasitic protists: unique features and drug targets. AB - Eukaryotic cells can degrade their own components, cytosolic proteins and organelles, using dedicated hydrolases contained within the acidic interior of their lysosomes. This degradative process, called autophagy, is used under starvation conditions to recycle redundant or less important macromolecules, facilitates metabolic re-modeling in response to environmental cues, and is also often important during cell differentiation. In this review, we discuss the role played by autophagy during the life cycles of the major parasitic protists. To provide context, we also provide an overview of the different forms of autophagy and the successive steps in the autophagic processes, including the proteins involved, as revealed in recent decades by studies using the model organism Saccharomyces cerevisiae, methylotrophic yeasts and mammalian cells. We describe for trypanosomatid parasites how autophagy plays a role in the differentiation from one life cycle stage to the next one and, in the case of the intracellular parasites, for virulence. For malarial parasites, although only a limited repertoire of canonical autophagy-related proteins can be detected, autophagy seems to play a role in the removal of redundant organelles important for cell invasion, when sporozoites develop into intracellular trophozoites inside the hepatocytes. The complete absence of a canonical autophagy pathway from the microaerophile Giardia lamblia is also discussed. Finally, the essential role of autophagy for differentiation and pathogenicity of some pathogenic protists suggests that the proteins involved in this process may represent new targets for drug development. Opportunities and strategies for drug design targeting autophagy proteins are discussed. PMID- 21315771 TI - A survey of schistosome protein domain types: insights into unique biological properties. AB - Using the PROSITE database and search tools, we conducted a comprehensive bioinformatic analysis of the predicted protein sequences of the flatworm parasites Schistosoma mansoni and Schistosoma japonicum and seven other animal genomes in order to identify novel schistosome-specific features. Our analyses revealed a relative paucity of proline-rich domains in schistosomes in comparison with their human host and a corresponding enrichment in schistosomes of asparagine-rich, serine-rich, and threonine-rich domains. Domain types found in both schistosome species but not in human included the two-component system sensor histidine kinase/response regulator; C83 family peptidase; DyP-type peroxidase; and densovirus NS1-type domain. Unique features of the schistosome proteome may help guide development of new drugs, while the presence of a densovirus-derived protein in S. mansoni suggests that this species may be infected by a virus of this group, which might be useful as a biological control agent. PMID- 21315772 TI - Malaria drug resistance is associated with defective DNA mismatch repair. AB - Malarial parasites exhibit striking genetic plasticity, a hallmark of which is an ever-increasing rate of resistance to new drugs, especially in Southeast Asia where multi-drug resistance (MDR) threatens the last line of antimalarial drugs, the artesunate compounds. Previous studies quantified the accelerated resistance to multiple drugs (ARMD) phenomenon, but the underpinning mechanism(s) remains unknown. We utilize a forward genetic assay to investigate a new hypothesis that defective DNA mismatch repair (MMR) contributes to the development of MDR by Plasmodium falciparum parasites. We report that two ARMD parasites, W2 and Dd2, have defective MMR, as do the chloroquine-resistant parasites T9-94, 7C12, and 7G8. By contrast, the chloroquine-sensitive parasites HB3, D6 and 3D7 were MMR proficient. Interestingly, W2 was unable to repair substrates with a strand break located 3' to the mismatch, which is attributable to a large observed decrease in PfMutLalpha content. These data imply that antimalarial drug resistance can result from defective MMR. PMID- 21315773 TI - Human T-cell leukemia virus type 1 tax transactivates the matrix metalloproteinase 7 gene via JunD/AP-1 signaling. AB - Adult T-cell leukemia (ATL) is a T-cell malignancy associated with human T-cell leukemia virus type 1 (HTLV-1) and characterized by visceral invasion. Degradation of the extracellular matrix by matrix metalloproteinases (MMPs) is a crucial process in invasion of tumors and metastasis. MMP-7 (or matrilysin), is a "minimal domain MMP" with proteolytic activity against components of the extracellular matrix. To determine the involvement of MMP-7 in visceral spread in ATL, this study investigated MMP-7 expression in ATL. MMP-7 expression was identified in HTLV-1-infected T-cell lines, peripheral blood ATL cells and ATL cells in lymph nodes, but not in uninfected T-cell lines or normal peripheral blood mononuclear cells. MMP-7 expression was induced following infection of a human T-cell line with HTLV-1, and specifically by the viral protein Tax. Functionally, MMP-7 promoted cell migration of HTLV-1-infected T cells. The MMP-7 promoter activity was increased by Tax and reduced by deletion of the activator protein-1 (AP-1) binding site. Electrophoretic mobility shift assay showed high levels of AP-1 binding proteins, including JunD, in HTLV-1-infected T-cell lines and ATL cells, and Tax elicited JunD binding to the MMP-7 AP-1 element. Tax induced MMP-7 activation was inhibited by dominant negative JunD and augmented by JunD/JunD homodimers. Short interfering RNA against JunD inhibited MMP-7 mRNA expression in HTLV-1-infected T-cell lines. These results suggest that the induction of MMP-7 by Tax is regulated by JunD and that MMP-7 could facilitate visceral invasion in ATL. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. PMID- 21315774 TI - Ataxin-1 occupies the promoter region of E-cadherin in vivo and activates CtBP2 repressed promoter. AB - Ataxin-1 is a polyglutamine protein of unknown function that is encoded by the ATXN1 gene in humans. To gain insight into the function of ataxin-1, we sought to identify proteins that interact with ataxin-1 through yeast two-hybrid screening. In this study, transcriptional corepressor CtBP2 was identified as a protein that interacted with ataxin-1. CtBP2 and ataxin-1 colocalized in the nucleus of mammalian cells. Since the E-cadherin promoter is a target of CtBP-mediated repression, the relationship between ataxin-1 and the E-cadherin promoter was investigated. Chromatin immunoprecipitation assays showed that CtBP2 and ataxin-1 were recruited to the E-cadherin promoter in mammalian cells. Luciferase assays using E-cadherin promoter reporter constructs revealed that the luciferase activity was enhanced as the level of ataxin-1 protein expression increased. CtBP2 overexpression decreased E-cadherin expression, but expression of ataxin-1 inversely increased the mRNA and protein levels of endogenous E-cadherin. Interestingly, siRNA experiments showed that the transcriptional activation of ataxin-1 was associated with the presence of CtBP2. This study demonstrates that ataxin-1 occupies the promoter region of E-cadherin in vivo and that ataxin-1 activates the promoter in a CtBP2-mediated transcriptional regulation manner. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. PMID- 21315775 TI - Single actomyosin motor interactions in skeletal muscle. AB - We present a study of intramuscular motion during contraction of skeletal muscle myofibrils. Myofibrillar actin was labeled with fluorescent dye so that the ratio of fluorescently labeled to unlabeled protein was 1:10(5). Such sparse labeling assured that there was on average only one actin-marker present in the focus at a given time. From the intensity signal in the two orthogonal detection channels, significant fluctuations, similar to fluorescent burst in diffusion-based single molecule detection schemes, were identified via a threshold algorithm and analyzed with respect to their intensity and polarization. When only rigor complexes were formed, the fluctuations of polarized intensity were characterized by unimodal Gaussian photon distributions. During contraction, in contrast, bimodal Gaussian photon distributions were observed above the rigor background threshold. This suggests that the bimodal Gaussian photon distributions represent pre- and post-power stroke conformations. Clusters of polarized photons indicated an anisotropy decay of single actomyosin motors of ~9s during muscle contraction. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. PMID- 21315776 TI - HuR and myogenesis: being in the right place at the right time. AB - The process of muscle cell differentiation into myotubes, termed myogenesis, depends on a complex coordination of myogenic factors, many of which are regulated post-transcriptionally. HuR, an mRNA-binding protein, is responsible for regulating the expression of several such myogenic factors by stabilizing their mRNAs. The critical role for HuR in myogenesis also involves the nucleocytoplasmic shuttling ability of this protein. Indeed, in order to perform its stabilizing functions, HuR must accumulate in the cytoplasm. This requires its dissociation from the import factor Transportin 2 (TRN2) which is actually caused by the cleavage of a portion of cytoplasmic HuR. In this review, we describe the roles of HuR during myogenesis, and the mechanisms regulating its cytoplasmic accumulation. This article is part of a Special Issue entitled: Regulation of Signaling and Cellular Fate through Modulation of Nuclear Protein Import. PMID- 21315777 TI - Predictors of performance monitoring abilities following traumatic brain injury: the influence of negative affect and cognitive sequelae. AB - Performance monitoring is a cognitive control process modulated by both cognitive and affective variables. This study examined the relative contributions of negative affect (NA) and cognitive sequelae to performance monitoring dysfunction following severe traumatic brain injury (TBI). We used the error-related negativity (ERN) and post-error positivity (Pe) components of the event-related potential (ERP) to test the hypothesis that NA and cognitive sequelae would predict performance monitoring dysfunction beyond time since injury, and injury severity. Nineteen survivors of severe TBI completed neuropsychological tests, measures of NA, and a computerized Stroop task. Scores on NA and neuropsychological measures were standardized to form magnitude of cognitive sequelae and negative affect composite scores. Separate hierarchical regression analyses with ERN and Pe amplitudes as dependent variables and injury severity, time since injury, magnitude of cognitive sequelae, and NA as independent variables indicated that NA and cognitive sequelae significantly predicted ERN amplitude, with a larger relative contribution of NA than cognitive sequelae. Increased levels of NA were associated with decreased amplitude ERN. Cognitive sequelae, but not NA, predicted Pe amplitude. Injury severity and time since injury were not significant predictors. Results suggest that both NA and cognitive sequelae play critical roles in performance monitoring decrements following TBI and indicate a possible dissociation between the ERN and Pe, with the ERN more related to affective processes and the Pe to cognitive processes. PMID- 21315778 TI - The influence of attention and arousal on emotion perception in adults with severe traumatic brain injury. AB - Many people with traumatic brain injury (TBI) have poor emotion recognition, with negative emotions more frequently impaired. They can also display abnormal affective responses to emotionally charged material, however, the mechanisms underpinning such deficits are unclear. This study examined whether affective responsivity can be improved by focusing attention and whether responsivity is associated with perception accuracy. Eighteen adults with moderate-to-severe TBI and 18 control participants viewed facial expressions while skin conductance (SCR) and evoked cardiac deceleration (ECD) (used as indices of orientation) and skin conductance levels (SCL) (used as an index of phasic arousal) were monitored. They viewed two blocks of faces (8 angry and 8 happy per block), passively in the first block and with the instruction to identify the emotional expression in the second. No differences between conditions, emotions or groups were found using SCR. Both groups demonstrated increasing ECD for the attend condition relative to the passive condition. For the passive task the control group showed increasing SCL (sensitisation) over trials when viewing angry faces and decreasing SCL (habituation) to happy faces. No differences between emotions were shown for the TBI group who rapidly habituated to both expressions. For the attend task, there was no evidence of habituation for either expression for either the control or TBI participants. Physiological measures did not correlate to accuracy in recognising emotions. The results suggest that increasing attentional demands improves orientation and emotional engagement (arousal) to emotional faces following TBI. However, the relationship to this and emotion perception accuracy remains unclear. PMID- 21315779 TI - Adjuvant effect of cationic liposomes and CpG depends on administration route. AB - In this study we explored the immunization route-dependent adjuvanticity of cationic liposomes loaded with an antigen (ovalbumin; OVA) and an immune potentiator (CpG). Mice were immunized intranodally, intradermally, transcutaneously (with microneedle pre-treatment) and nasally with liposomal OVA/CpG or OVA/CpG solution. In vitro, OVA/CpG liposomes showed enhanced uptake by DCs of both OVA and CpG compared to OVA+CpG solution. A similar enhanced uptake by DCs was observed in vivo when fluorescent OVA/CpG liposomes were administered intranodally. However, after transcutaneous and nasal application a lower uptake of OVA/CpG liposomes compared to an OVA+CpG solution was observed. Moreover, the IgG titers after nasal and transcutaneous administration of OVA/CpG liposomes were reduced compared to administration of an OVA+CpG solution. Although serum IgG titers may suggest limited added value of liposomes to the immunogenicity, for all routes, OVA/CpG liposomes resulted in elevated IgG2a levels, whereas administration of OVA+CpG solutions did not. These data show that encapsulation of antigen and adjuvant into a cationic liposome has a beneficial effect on the quality of the antibody response in mice after intranodal or intradermal immunization, but impairs proper delivery of antigen and adjuvant to the lymph nodes when the formulations are administered transcutaneously or nasally. PMID- 21315780 TI - Modified Tat peptide with cationic lipids enhances gene transfection efficiency via temperature-dependent and caveolae-mediated endocytosis. AB - The HIV-1 Tat peptide has been successfully used for intracellular gene delivery. Likewise, various lipid-based methods have shown increased endocytosis and can influence endosomal escape. This study combines the favorable properties of Tat peptide with that of lipid systems for DNA delivery. We combined the lipid FuGENE HD (FH) with the Tat peptide sequence modified with histidine and cysteine residues (mTat). mTat/FH transfection was evaluated by luciferase expression plasmid in five cell types. mTat/FH produced significant improvement in transfection efficiency of all cell lines when compared to FH or mTat. Treatment with chloroquine, associated with energy-dependent endocytosis, significantly increased transfection efficiency with mTat/FH while incubation at low temperature decreased it. The zeta potential of mTat/FH/DNA was significantly higher compared to FH, mTat, or their DNA combination in the presence of serum, and it was correlated with transfection efficiency. The particle size of the FH/DNA complex was significantly reduced by addition of mTat. Filipin III, an inhibitor of caveolae-mediated endocytosis, significantly inhibited mTat/FH transfection, but transfection was increased by chlorpromazine, an inhibitor of clathrin-mediated endocytosis. These findings demonstrated the feasibility of using a combination of mTat with lipids, utilizing temperature-dependent and caveolae-mediated endocytosis, as a potentially attractive non-viral gene vector. PMID- 21315781 TI - Physical and chemical stability of drug nanoparticles. AB - As nano-sizing is becoming a more common approach for pharmaceutical product development, researchers are taking advantage of the unique inherent properties of nanoparticles for a wide variety of applications. This article reviews the physical and chemical stability of drug nanoparticles, including their mechanisms and corresponding characterization techniques. A few common strategies to overcome stability issues are also discussed. PMID- 21315782 TI - HIV-1 Tat upregulates expression of histone deacetylase-2 (HDAC2) in human neurons: implication for HIV-associated neurocognitive disorder (HAND). AB - Histone deacetylases (HDACs) play a pivotal role in epigenetic regulation of transcription and homeostasis of protein acetylation in histones and other proteins involved in chromatin remodeling. Histone hypoacetylation and transcriptional dysfunction have been shown to be associated with a variety of neurodegenerative diseases. More recently, neuron specific overexpression of HDAC2 has been shown to modulate synaptic plasticity and learning behavior in mice. However, the role of HDAC2 in development of HIV-associated neurocognitive disorders (HAND) is not reported. Herein we report that HIV-1 Tat protein upregulate HDAC2 expression in neuronal cells leading to transcriptional repression of genes involved in synaptic plasticity and neuronal function thereby contributing to the progression of HAND. Our results indicate upregulation of HDAC2 by Tat treatment in dose and time dependant manner by human neuroblastoma SK-N-MC cells and primary human neurons. Further, HDAC2 overexpression was associated with concomitant downregulation in CREB and CaMKIIa genes that are known to regulate neuronal activity. These observed effects were completely blocked by HDAC2 inhibition. These results for the first time suggest the possible role of HDAC2 in development of HAND. Therefore, use of HDAC2 specific inhibitor in combination with HAART may be of therapeutic value in treatment of neurocognitive disorders observed in HIV-1 infected individuals. PMID- 21315783 TI - MDSC as a mechanism of tumor escape from sunitinib mediated anti-angiogenic therapy. AB - Sunitinib is a receptor tyrosine kinase inhibitor (TKI) that is front-line therapy for metastatic renal cell carcinoma (mRCC). Its antitumor activity is related to its ability to block tumor cell and tumor vasculature cell signaling via several TKI receptors (i.e. vascular endothelial growth factor receptors VEGFRs, platelet-derived growth factors (PDGFs), and stem cell factors). Sunitinib also targets myeloid derived suppressor cells (MDSCs) significantly reducing their accumulation in the peripheral blood and reversing T cell (IFNgamma) suppression in both mRCC patients and in murine tumor models. This reduction in immune suppression provides a rationale for combining sunitinib with immunotherapy for the treatment of certain tumor types. Despite these encouraging findings, however, we have observed that sunitinib has variable impact at reducing MDSCs and restoring T cell function within the tumor microenvironment. Given the immunosuppressive and proangiogenic activities of MDSC, it seems plausible that their persistence may contribute to the resistance that develops in sunitinib-treated patients. While sunitinib reduced tumor infiltrating MDSCs in Renca and CT26-bearing mice, coinciding with strong to modest decreases in tumor size respectively, it was ineffective at reducing MDSCs (<35% reduction in Gr1+CD11b+) or tumor burden in 4T1-bearing mice. Persistence of intratumor MDSCs was paralleled by depressed intratumor T cell IFNgamma response and increased GM CSF expression. Additionally, in vitro and in vivo experiments showed that GM-CSF prolongs survival of MDSCs, thus protecting them from the effects of sunitinib via a pSTAT5-dependent pathway. Although preliminary, there is evidence of intratumor MDSC resistance in some mRCC patients following sunitinib treatment. Intratumor MDSC persistence and T cell IFNgamma response post nephrectomy in patients receiving sunitinib in a neoadjuvant setting are being compared to RCC patients undergoing nephrectomy without prior sunitinib treatment. Tumors from untreated patients showed suppressed T cell IFNgamma response along with substantial expression of MDSCs (5% of total digested cells). Thus far, tumors from 5/8 neoadjuvant patients showed persistence of intratumor MDSCs and low T cell IFNgamma production post sunitinib treatment, findings that parallel results from untreated tumors. In the remaining 3 neoadjuvant patients, intratumor MDSCs were detected at low levels which coincided with a T cell IFNgamma response similar to that observed with normal donor peripheral T cells. GM-CSF's role in promoting MDSC survival in patient tumors is supported by the observation that GM CSF is produced in short-term RCC cultures at levels capable of protecting MDSCs from sunitinib-induced cell death. Additionally, persistence of MDSC also may be associated with increased expression of proangiogenic proteins, such as MMP9, MMP8, and IL-8 produced by tumor stromal cells or infiltrating MDSCs. Indeed our findings suggest that the most dominate MDSC subset in RCC patients is the neutrophilic population that produces proangiogenic proteins. We propose that the development of sunitinib resistance is partly mediated by the survival of MDSCs intratumorally, thereby providing sustained immune suppression and angiogenesis. PMID- 21315784 TI - Meeting report: regulatory myeloid cells. AB - Recent investigations of regulatory myeloid cell mobilization and amplification in response to cancer and chronic inflammation associated with infectious disease and autoimmunity have provided numerous insights into the suppressive mechanisms, pathobiology and potential pharmaceutical modulation of MDSC. Controversies have emerged as hematology investigators, have suggested that regulatory myeloid cells, including MDSC merely reflect normal physiological responses to inflammatory and growth factor stimuli. A recurring theme at the recent "International Immunopharmacology Conference on Regulatory Myeloid cells" held in Arlington, Virginia, October 21-24, 2010, focused on efforts to more clearly elucidate molecular features of MDSC from the immature myeloid cells observed in the circulation in response to acute infection and inflammatory responses. Evidence for the potential contribution of regulatory myeloid cells to pathologic processes and sequelae associated with numerous inflammatory and malignant diseases also suggested that these cells may represent a significant deviation from the normal physiologic responses to acute inflammatory stimuli. The relevance of these research efforts was evident from the discussions by numerous clinical investigations regarding their efforts to modulate MDSC in cancer patients to augment immunotherapeutic treatments. PMID- 21315785 TI - The role of glucocorticoids in the immediate vs. delayed effects of acute ethanol exposure on cytokine production in a binge drinking model. AB - BACKGROUND: Acute ethanol administration just prior to a stimulus, such as the viral mimic poly I:C, results in decreased proinflammatory cytokine production. Studies have indicated that this suppression is not primarily mediated by glucocorticoids (corticosterone in mice) released in the ethanol-induced stress response. Fewer studies have been done on the effects of acute ethanol administration 12 or more hours prior to a stimulus. The purpose of this study was to determine the role of corticosterone on these effects. Also, since gender differences occur in immune responses, separate experiments were performed using male and female mice. METHODS: Mice were treated with ethanol 15 min or 12h before stimulation by poly I:C to demonstrate immunosuppressive effects of ethanol on cytokine production. A glucocorticoid synthesis inhibitor was used to manipulate corticosterone levels. RESULTS: Short-term and persistent effects of acute ethanol exposure on corticosterone and cytokine levels were nearly identical in males and females. Blocking glucocorticoid synthesis altered the inhibition of some cytokines, particularly IL-6, in females, but not in males. CONCLUSION: These results indicate that the short-term effects of acute ethanol on poly I:C-induced cytokine production are not primarily mediated by corticosterone in male or female mice. In female mice, however, corticosterone does appear to mediate the persistent effects of acute ethanol administration on poly I:C- induced IL-6 levels. Since many IL-6 related disorders are gender associated, further research into the bidirectional effects of the HPG and HPA axes on alterations in cytokine production mediated by ethanol is warranted. PMID- 21315786 TI - Aberrant PGE2 metabolism in bladder tumor microenvironment promotes immunosuppressive phenotype of tumor-infiltrating myeloid cells. AB - Bladder cancer is associated with enhanced inflammation and characterized by deregulated prostanoid metabolism. Here we examined prostaglandin E2 (PGE2) metabolism and myeloid cell subsets that infiltrate tumor tissue using two xenograft models of human bladder cancer. Human bladder tumor xenografts implanted into athymic nude mice become highly infiltrated with host CD11b myeloid cells of bone marrow origin. Fast growing SW780 bladder tumor xenografts were infiltrated with heterogeneous CD11b myeloid cell subsets including tumor associated macrophages and myeloid-derived suppressor cells. In contrast, majority of myeloid cells in tumor tissue from slow growing bladder cancer Urothel 11 displayed more immature, homogenous phenotype and comprised mostly MHC II class-negative myeloid-derived suppressor cells. We demonstrate that human bladder tumors secrete substantial amounts of PGE2. Normal bone marrow myeloid cell progenitors cultured in the presence of a bladder tumor-conditioned medium, which is enriched for PGE2, failed to differentiate into mature APCs and acquired phenotype of the myeloid-derived suppressor cells or inflammatory macrophages with up-regulated chemokine receptor CXCR4. Collectively our data demonstrate that enhanced cancer-related inflammation and deregulated PGE2 metabolism in tumor microenvironment promote immunosuppressive pro-tumoral phenotype of myeloid cells in bladder cancer. These data also suggest that not only local tumor microenvironment but other factors such as stage of cancer disease and pace of tumor growth could markedly influence the phenotype, differentiation and immune function of myeloid cells in tumor tissue. PMID- 21315787 TI - A comparative study of paliperidone palmitate and risperidone long-acting injectable therapy in schizophrenia. AB - This open-label, rater-blinded, parallel-group study was designed to evaluate noninferiority of paliperidone palmitate (PP), a once-monthly injectable atypical antipsychotic, to once-biweekly risperidone long-acting injectable (RIS-LAI) in adult Chinese patients with acute schizophrenia. Eligible Chinese adults (N=452) with schizophrenia were randomized (1:1) to either PP (N=229; deltoid injections on day 1 [150 mg eq.] and day 8 [100 mg eq.]; then once-monthly deltoid or gluteal injections, flexibly dosed [50, 100, or 150 mg eq.]), or RIS-LAI (N=223; once-biweekly gluteal injections, flexibly dosed [25, 37.5 or 50 mg]). RIS-LAI treated patients received oral risperidone supplementation (1-6 mg/day) at initiation and with RIS-LAI dose increases. Mean (SD) Positive and Negative Syndrome Scale (PANSS) total score at baseline was 83.2 (12.44). Mean (SD) change from baseline to endpoint in PANSS total scores (primary efficacy measure) was: 23.6 (16.28) for PP group and -26.9 (15.43) for RIS-LAI group. PP was noninferior to RIS-LAI (least squares mean difference [95% CI]: -2.3 [-5.20; 0.63]; predetermined non-inferiority margin: -5.5). Mean (SD) change from baseline to endpoint in Clinical Global Impression-Severity scale score was: -1.5 (1.24; PP group), -1.7 (1.16; RIS-LAI group) and in Personal and Social Performance Scale scores was: 16.8 (14.76; PP group), 18.6 (13.92; RIS-LAI group). The incidence of treatment-emergent adverse events (TEAEs) was similar between the two groups (73% [PP]; 75% [RIS-LAI]). The most common TEAEs were akathisia, tremor, and insomnia. The study demonstrated the noninferiority of PP (50-150 mg eq., flexibly dosed, without oral paliperidone supplementation) to risperidone-LAI (25-50 mg, flexibly dosed, with oral risperidone supplementation) for the treatment of acute schizophrenia in adult Chinese patients. PP injections were generally tolerable, and no new safety signals were detected in this population. PMID- 21315788 TI - Fisetin, a novel flavonol attenuates benzo(a)pyrene-induced lung carcinogenesis in Swiss albino mice. AB - Lung cancer is the foremost cause of cancer mortality and is a growing economic burden worldwide. Fisetin (3,7,3',4'-tetrahydroxyflavone), a naturally occurring flavonoid is found in vegetables and fruits possesses anti-oxidative, anti inflammatory and anti-proliferative effects in a wide variety of cancer. In the present study it is hypothesized that fisetin may provide chemopreventive as well as chemotherapeutic effects against experimental lung carcinogenesis. The present study was designed to investigate whether fisetin confers anti-cancer action against benzo(a)pyrene [B(a)P] induced lung carcinogenesis. Treatment with fisetin significantly reduced the degree of histological lesions, restored the levels of lipid peroxidation (LPO), enzymic and non-enzymic anti-oxidants in B(a)P-induced mice. Anti-proliferative efficacy of fisetin was assessed by immunohistochemical analysis of proliferating cell nuclear antigen (PCNA) in B(a)P induced mice showed increased PCNA expression which is restored upon fisetin administration. Together, our results depicts that fisetin can be used as chemopreventive agent against lung cancer. PMID- 21315789 TI - Genotoxicity testing of a Hoodia gordonii extract. AB - Hoodia gordonii extract consists of a mixture of steroid glycosides, fatty acids, plant sterols and alcohols. As part of the overall safety assessment H. gordonii extract was assessed for genotoxicity in two assays in vitro: a bacterial mutation assay; and a gene mutation assay using mouse lymphoma cells. H. gordonii extract showed no evidence of genotoxic activity in either of these assays. In addition, H. gordonii extract was assessed for mutagenic activity in a bone marrow micronucleus (MN) assay in the mouse, with 400mg/kg selected as the high dose group, based on observations in a dose-range-finding study. The group mean frequencies of micronucleated polychromatic erythrocytes of treated animals were similar to those of the vehicle control group, indicating H. gordonii extract to be non-genotoxic under the conditions of this test. All assays were performed in compliance with the Good Laboratory Practice Regulations and in accordance with standard guidelines for genotoxicity tests. H. gordonii extract was shown to be non-genotoxic in 3 independent assays (a bacterial mutation test, a gene mutation assay using mouse lymphoma cells and a bone marrow micronucleus assay in the mouse). PMID- 21315790 TI - Effect of garlic on liver phosphatidate phosphohydrolase and plasma lipid levels in hyperlipidemic rats. AB - Studies on the effects of garlic (Allium sativum) on hyperlipidemia have demonstrated somewhat controversial results and there have been few studies on its enzymatic mechanism. The purpose of this study was to assess the effect of garlic on the liver phosphatidate phosphohydrolase (PAP) activity, plasma lipid levels, malondialdehyde (MDA) and plasma antioxidant in rats fed either by normal or high-lipogenic diet with or without garlic. Male Wistar rats were fed by standard pellet diet (group I), standard diet supplemented with 4% garlic (group II), lipogenic diet (containing sunflower oil, cholesterol and ethanol) plus 4% garlic (group III) and only lipogenic diet (group IV). Results showed that garlic significantly reduced total cholesterol (TC), plasma triglyceride (TG), LDL-C, VLDL-C, liver triglyceride, plasma malondialdehyde (MDA) and elevated plasma antioxidant in garlic treated rats (groups II and III) compared to group IV (lipogenic diet group). Also, liver PAP activity was decreased in group II than group I whereas, the decrease in its activity in groups III and IV was due to the accumulation of triglyceride in liver. Therefore, the results are clearly indicative of the beneficial effects of garlic in reducing lateral side effects of hyperlipidemia. PMID- 21315791 TI - Marginal iodide deficiency and thyroid function: dose-response analysis for quantitative pharmacokinetic modeling. AB - Severe iodine deficiency (ID) results in adverse health outcomes and remains a benchmark for understanding the effects of developmental hypothyroidism. The implications of marginal ID, however, remain less well known. The current study examined the relationship between graded levels of ID in rats and serum thyroid hormones, thyroid iodine content, and urinary iodide excretion. The goals of this study were to provide parametric and dose-response information for development of a quantitative model of the thyroid axis. Female Long Evans rats were fed casein based diets containing varying iodine (I) concentrations for 8 weeks. Diets were created by adding 975, 200, 125, 25, or 0 MUg/kg I to the base diet (~25 MUg I/kg chow) to produce 5 nominal I levels, ranging from excess (basal+added I, Treatment 1: 1000 MUg I/kg chow) to deficient (Treatment 5: 25 MUg I/kg chow). Food intake and body weight were monitored throughout and on 2 consecutive days each week over the 8-week exposure period, animals were placed in metabolism cages to capture urine. Food, water intake, and body weight gain did not differ among treatment groups. Serum T4 was dose-dependently reduced relative to Treatment 1 with significant declines (19 and 48%) at the two lowest I groups, and no significant changes in serum T3 or TSH were detected. Increases in thyroid weight and decreases in thyroidal and urinary iodide content were observed as a function of decreasing I in the diet. Data were compared with predictions from a recently published biologically based dose-response (BBDR) model for ID. Relative to model predictions, female Long Evans rats under the conditions of this study appeared more resilient to low I intake. These results challenge existing models and provide essential information for development of quantitative BBDR models for ID during pregnancy and lactation. PMID- 21315792 TI - 2-Methyl-pyran-4-one-3-O-beta-D-glucopyranoside isolated from leaves of Punica granatum inhibits the TNFalpha-induced cell adhesion molecules expression by blocking nuclear transcription factor-kappaB (NF-kappaB). AB - Here, we report bioactivity-guided isolation, purification and characterization of a novel compound, 2-methyl-pyran-4-one-3-O-beta-d-glucopyranoside (MPG) from the leaves of Punica granatum. The structure of MPG was established on the basis of its detailed spectral analyses. We demonstrated that MPG not only inhibited the expression of cell adhesion molecules but also significantly blocked its functional consequence, that is, the adhesion of neutrophils on human endothelial cells monolayer. To elucidate the molecular mechanism of action of MPG, we showed that MPG decreased the transcript levels of ICAM-1, VCAM-1 and E-selectin genes. Using electrophoretic mobility shift assay (EMSA) and western blot analyses, we demonstrated that MPG significantly blocked both the TNFalpha-induced translocation and activation of nuclear transcription factor-kappaB (NF-kappaB). Thus, MPG could be useful as a novel lead molecule for developing future anti inflammatory agents. PMID- 21315793 TI - Explicit and implicit memory in female college students with schizotypal traits: an event-related potential study. AB - The explicit and implicit memory of nonclinical individuals with schizotypal traits was investigated using event-related potentials. Explicit and implicit memory was measured with continuous recognition and categorization tasks, respectively. On the recognition task, the control group demonstrated a greater old/new effect in response to the old than to the new words during the 250-750 ms post-stimulus period, whereas schizotypal trait group did not exhibit an old/new effect during the 550-650 ms period. The control group demonstrated faster response times to the old than to the new words, whereas the schizotypal group demonstrated longer response times to the old than to the new words. On the categorization task, both groups showed old/new effects during the 250-550 ms after stimulus onset and responded more rapidly and with fewer errors to the old than to the new words. These results suggest that individuals with schizotypal traits have impaired explicit but preserved implicit memory. PMID- 21315794 TI - Is contextual cueing more than the guidance of visual-spatial attention? AB - When search displays are repeatedly presented, participants become faster in finding the target (contextual cueing, CC). It has been debated whether a more liberal response criterion might contribute to CC. In the current experiment, participants had to search through target-absent and target-present trials to compute d-prime as the measurement of sensitivity and beta as the measurement of response bias. Results showed that participants' sensitivity was not affected by the repetition of search displays. Although repeated displays led to both faster RTs and a more liberal response criterion, these effects were uncorrelated. In the event-related potential, RT effects were reflected by a late positive activity, which reflects response-related processes, but not by differences in the N2pc as electrophysiological correlate of focused attention. These results indicate that a more liberal response criterion is not the cause for CC effects in RTs but that other response-related processes might still contribute to the effect. PMID- 21315795 TI - Neural co-activation as a yardstick of implicit motor learning and the propensity for conscious control of movement. AB - Two studies examined EEG co-activation (coherence) between the verbal-analytical (T3) and motor planning (Fz) regions during a golf putting task. In Study 1, participants with a strong propensity to consciously monitor and control their movements, determined psychometrically by high scores on a movement specific Reinvestment Scale, displayed more alpha2 T3-Fz co-activation than participants with a weak propensity. In Study 2, participants who practiced a golf putting task implicitly (via an errorless learning protocol) displayed less alpha2 T3-Fz co-activation than those who practiced explicitly (by errorful learning). In addition, explicit but not implicit motor learners displayed more T3-Fz co activation during golf putting under pressure, implying that verbal-analytical processing of putting movements increased under pressure. These findings provide neuropsychological evidence that supports claims that implicit motor learning can be used to limit movement specific reinvestment. PMID- 21315796 TI - Meta-analysis and meta-regression of hypothalamic-pituitary-adrenal axis activity in functional somatic disorders. AB - Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is the most investigated biological risk marker in functional somatic disorders (FSDs), such as chronic fatigue syndrome (CFS), fibromyalgia (FM), and irritable bowel syndrome (IBS). Our aim was to assess whether there is an association between basal hypocortisolism and FSD and to identify potential moderators of this association. Meta-analysis on 85 studies revealed that although basal cortisol levels were generally lower in FSD subjects compared to controls, this association did not reach statistical significance (SMD -0.07, 95% CI -0.17 to 0.04, p=0.241). However, when the three FSD were assessed separately, statistically significant basal hypocortisolism was observed in CFS subjects compared to controls (SMD -0.14, 95% CI -0.28 to 0.00, p=0.047), but not in FM or IBS. When all potential moderators were entered into a meta-regression analysis, only type of FSD and female gender were significant independent predictors of basal hypocortisolism. In conclusion, we did not find evidence to consider all three main FSD as hypocortisolemic disorders, as significant reduction in basal cortisol compared to healthy controls was only found in CFS and in females with FM, but not in IBS. PMID- 21315797 TI - An application programming interface for CellNetAnalyzer. AB - CellNetAnalyzer (CNA) is a MATLAB toolbox providing computational methods for studying structure and function of metabolic and cellular signaling networks. In order to allow non-experts to use these methods easily, CNA provides GUI-based interactive network maps as a means of parameter input and result visualization. However, with the availability of high-throughput data, there is a need to make CNA's functionality also accessible in batch mode for automatic data processing. Furthermore, as some algorithms of CNA are of general relevance for network analysis it would be desirable if they could be called as sub-routines by other applications. For this purpose, we developed an API (application programming interface) for CNA allowing users (i) to access the content of network models in CNA, (ii) to use CNA's network analysis capabilities independent of the GUI, and (iii) to interact with the GUI to facilitate the development of graphical plugins. Here we describe the organization of network projects in CNA and the application of the new API functions to these projects. This includes the creation of network projects from scratch, loading and saving of projects and scenarios, and the application of the actual analysis methods. Furthermore, API functions for the import/export of metabolic models in SBML format and for accessing the GUI are described. Lastly, two example applications demonstrate the use and versatile applicability of CNA's API. CNA is freely available for academic use and can be downloaded from http://www.mpi magdeburg.mpg.de/projects/cna/cna.html. PMID- 21315799 TI - The thyroid hormone transporters MCT8 and MCT10 transport the affinity-label N bromoacetyl-[(125)I]T3 but are not modified by it. AB - Thyroid hormone (TH) transporter proteins mediate transport of TH across the plasma membrane, thereby facilitating its intracellular bioavailability. As only a few transporters have been identified which are relatively specific for TH, including monocarboxylate transporter (MCT) 8 and MCT10, the need for identification of novel specific TH transporters is obvious. A possible strategy to identify TH transporters is their modification with a ligand-derived affinity label and subsequent identification by mass spectrometry. Previously, N bromoacetyl (BrAc)-iodothyronines have been reported as useful affinity-labels for human (h) MCT8. In the present study we reinvestigated possible BrAc[(125)I]T3-labeling of hMCT8 and hMCT10. The present study demonstrates that hMCT8 and hMCT10 both facilitate BrAc[(125)I]T3 transport, but are not labeled by BrAc[(125)I]T3. We provide evidence that human protein disulfide isomerase, which molecular mass is similar to hMCT8, is labeled by BrAc[(125)I]T3. In addition, differential inhibitory effects were observed of iodothyronines derivatives with different side chains on T3 transport by hMCT8 and hMCT10. In conclusion, we demonstrated that not hMCT8 and hMCT10, but human protein disulfide isomerase, is labeled by BrAc[(125)I]T3. The usefulness of BrAc[(125)I]T3 as a tool for the identification of novel TH transporters remains to be explored. PMID- 21315798 TI - Stability analysis and optimal control of an SIR epidemic model with vaccination. AB - This paper focuses on the study of a nonlinear mathematical SIR epidemic model with a vaccination program. We have discussed the existence and the stability of both the disease free and endemic equilibrium. Vaccine induced reproduction number is determined and the impact of vaccination in reducing the vaccine induced reproduction number is discussed. Then to achieve control of the disease, a control problem is formulated and it is shown that an optimal control exists for our model. The optimality system is derived and solved numerically using the Runge-Kutta fourth order procedure. PMID- 21315800 TI - Estradiol modulates TGF-beta1 expression and its signaling pathway in thyroid stromal cells. AB - The higher prevalence of thyroid disease in women suggests that estrogen (E2) might be involved in the pathophysiology of thyroid dysfunction. To approach the question of the effect of stromal cells in the modulation of thyroid epithelial cells activity, we established and characterized a homogeneous stromal cell population (TS7 cells) of rat thyroid gland. These fibroblastic cells synthesize the cytoskeleton proteins alpha-smooth muscle actin and vimentin, produce basement membrane components and express the cytokine transforming growth factor beta 1 (TGF-beta1). Here, we hypothesized that the effects of E2 on follicular thyroid cells are mediated by TGF-beta1 synthesis and secretion by stromal cells (paracrine action). Thus we investigated the effect of E2 on TGF-beta1 synthesis and its signaling pathway in TS7 cells. In addition, we analyzed the role of TGF beta1 signaling pathway as mediator of TS7-PC CL3 thyroid epithelial cells interactions. We report that TS7 stromal cells expressed alpha and beta estrogen receptors (ERalpha and ERbeta). Further, both isoforms of TGF-beta1 receptors, TGFRI and TGFRII, were also identified in TS7 cells, suggesting that these cells might be a target for this cytokine in vitro. Treatment of TS7 cells with E2 induced both synthesis and secretion of TGF-beta1. This event was followed by phosphorylation of the transcription factor Smad2, a hallmark of TGF-beta1 pathway activation. Co-culture of PC CL3 cells onto TS7 cells monolayers yielded round aggregates of PC CL3 cells surrounded by TS7 cells. TS7 cells induced a decrease in iodide uptake by PC CL3 cells, probably by a mechanism involving TGF beta1. Moreover, E2 affected synthesis and organization of the extracellular matrix (ECM) components, tenascin C and chondroitin sulfate, in these co-culture cells. Our results point to the TGF-beta1/Smad-2 signaling pathway as a putative target of estrogen actions on thyroid stromal cells and contribute to understanding the interplay between stromal and follicular cells in thyroid physiology. PMID- 21315801 TI - Dorsal as well as ventral striatal lesions affect levels of intravenous cocaine and morphine self-administration in rats. AB - While the ventral striatum has long been implicated in the rewarding properties of psychomotor stimulants and opiates, little attention has been paid to the possible contribution of more dorsal regions of the striatum. We have thus examined the effects of lesions in three different striatal subregions on cocaine and morphine self-administration. Different groups of rats were trained to self administer intravenous cocaine (1.0mg/kg/infusion) or morphine (0.5mg/kg/infusion) first under fixed ratio (FR) and then under progressive ratio (PR) schedules of reinforcement. Upon completion of the training, independent groups received bilateral electrolytic or sham lesions of the dorsal portion of the caudate-putamen (dCPu), the ventral portion of the caudate-putamen (vCPu) or the more ventral nucleus accumbens (NAS). Following recovery, they were tested for self-administration of cocaine (0.25, 0.5, 1.0 and 1.5mg/kg/infusion) or morphine (0.125, 0.25, 0.5 and 0.75mg/kg/infusion) under the PR schedule. The PR responding for each drug was significantly reduced in a dose-dependent manner following lesions of dCPu, vCPu and NAS. While the relative effectiveness of these lesions is likely to be specific to the conditions of this experiment, NAS lesions reduced self-administration of each drug to a greater extent than did dCPu or vCPu lesions. PMID- 21315802 TI - Role of transient receptor potential ankyrin subfamily member 1 in pruritus induced by endothelin-1. AB - Noxious cold reduces pruritus and transient receptor potential ankyrin subfamily member 1 (TRPA1), a non-selective cation channel, is known as a noxious cold activated ion channel. Recent findings implicated the involvement of TRPA1 in pain induced by endothelin-1 (ET-1). Therefore, we evaluated its potential role in pruritus induced by ET-1. We found that ruthenium red (RR; a nonselective TRP inhibitor) and AP18 (a TRPA1 antagonist) significantly increased scratching bouts caused by ET-1, while capsazepine (a TRPV1 antagonist) and morphine showed no effects in the ET-1-induced scratching response. However, RR and capsazepine significantly reduced scratching bouts caused by histamine. Our results suggested that activation of TRPA1 could suppress itch induced by ET-1 and this is not related to pain induced by ET-1. PMID- 21315803 TI - Neural correlates of near-misses effect in gambling. AB - The present study investigated the cognitive and neural mechanisms underlying the gambling near-miss effect by measuring event-related-potentials. Using a simple gambling task, we measured behavioral response and electrophysiological activity of gambling outcomes. Self-rating results showed that when compared to full-miss outcome, near-miss outcome were rated as less pleasant, but yielded higher motivation to play. Whereas the feedback-related negativity (FRN) amplitude did not reflect the motivation rating differences between near-miss and full-miss, the P300 amplitude mirrored the motivation rating differences between near-miss and full-miss, with larger amplitudes for near-miss outcomes. Dipole source analysis of the difference wave (near-miss minus full-miss) indicated that two generators of the P300, localized in the putamen and orbitofrontal cortex, might be involved in motivational evaluation and regret, respectively. Our findings indicated that the near-miss effect stems from sources: higher levels of motivation and the presence of regret, caused by counterfactual thinking. PMID- 21315804 TI - T(H)17 cells in asthma and inflammation. AB - BACKGROUND: The chronic airway disease asthma causes significant burden to patients as well as the healthcare system with limited options for prevention or cure. Inadequate treatment strategies are most likely due to the complex heterogeneous nature of asthma. Furthermore, the severe asthma phenotype is characterized by the lack of a response to standard medication, namely, corticosteroids. SCOPE OF REVIEW: In the last several years it has been shown that the eosinophilic/atopic phenotype of asthma driven by T(H)2 mechanisms is not the only immunologic pathway contributing to disease. In fact, there has been evidence revealing that severe asthmatics in particular have neutrophilic inflammation, and this is associated with corticosteroid resistance. T(H)17 cells, a recently discovered lineage of T helper cells, play an important role in lung host defense against multiple pathogens via production of the cytokine IL 17. IL-17 promotes neutrophil production and chemotaxis via multiple factors. MAJOR CONCLUSIONS: Mouse and human studies provide robust evidence that T(H)17 cells and IL-17 play a role in severe asthma and may contribute to corticosteroid resistance. GENERAL SIGNIFICANCE: As we learn more about T(H)17 cells in severe asthma, the goal is to potentially target this pathway for treatment in the hope of significantly improving the quality of life for those children and adults affected with this disease. This article is part of a Special Issue entitled: Biochemistry of Asthma. PMID- 21315805 TI - Spatiotemporal dynamics of visual vertical judgments: early and late brain mechanisms as revealed by high-density electrical neuroimaging. AB - Constructing and updating an internal model of verticality is fundamental for maintaining an erect posture and facilitating visuo-spatial processing. The judgment of the visual vertical (VV) has been intensively studied in psychophysical investigations and relies mainly on the integration of visual and vestibular signals, although a contribution of postural and somatosensory signals has been reported. Here we used high-density 192-channel evoked potential (EP) mapping and distributed source localization techniques to reveal the neural mechanisms of VV judgments. VV judgments (judging the orientation of visual lines with respect to the subjective vertical) were performed with and without a tilted visual frame. EP mapping revealed a sequence of neural processing steps (EP maps) of which two were specific for VV judgments. An early EP map, observed at ~75-105 ms post-stimulus, was localized in right lateral temporo-occipital cortex. A later EP map (~260-290 ms) was localized in bilateral temporo-occipital and parieto-occipital cortex. These data suggest that early VV-related neural processing involves the lateral and ventral visual stream and is related to visual processing concerning orientation, attention and comparison. The later, more dorsal, activation involves multimodal cortex subtending a constantly available and updated internal model of the vertical that we can refer to for the control of one's posture, actions, and visuo-spatial processing. PMID- 21315806 TI - Nucleoside triphosphate diphosphohydrolases role in the pathophysiology of cognitive impairment induced by seizure in early age. AB - Studies have shown that seizures in young animals lead to later cognitive deficits. There is evidence that long-term potentiation (LTP) and long-term depression (LTD) might contribute to the neural basis for learning and memory mechanism and might be modulated by ATP and/or its dephosphorylated product adenosine produced by a cascade of cell-surface transmembrane enzymes, such as E NTPDases (ecto-nucleoside triphosphate diphosphohydrolases) and ecto-5' nucleotidase. Thus, we have investigated if hippocampal ecto-nucleotidase activities are altered at different time periods after one episode of seizure induced by kainic acid (KA) in 7 days old rats. We also have evaluated if 90 day old rats previously submitted to seizure induced by KA at 7 days of age presented cognitive impairment in Y-maze behavior task. Our results have shown memory impairment of adult rats (Postnatal day 90) previously submitted to one single seizure episode in neonatal period (Postnatal day 7), which is accompanied by an increased ATP hydrolysis in hippocampal synaptosomes. The metabolism of ATP evaluated by HPLC confirmed that ATP hydrolysis was faster in adult rats treated with KA in neonatal period than in controls. Surprisingly, the mRNA and protein levels as seen by PCR and Western blot, respectively, were not altered by the KA administration in early age. Since we have found an augmented hydrolysis of ATP and this nucleotide seems to be important to LTP induction, we could assume that impairment of memory and learning observed in adult rats which have experienced a convulsive episode in postnatal period may be a consequence of the increased ATP hydrolysis. These findings correlate the purinergic signaling to the cognitive deficits induced by neonatal seizures and contribute to a better understanding about the mechanisms of seizure-induced memory dysfunction. PMID- 21315808 TI - Central glial activation mediates cancer-induced pain in a rat facial cancer model. AB - Peripheral and central glial activation plays an important role in development of pain hypersensitivity induced by inflammation and nerve injury. However, the involvement of glial cells in cancer pain is not well understood. The present study evaluated the peripheral and central glial activation and the effect of an inhibitor of glial activation, propentofylline, on pain-related behaviors in a rat facial cancer model of the growth of Walker 256B cells in the unilateral vibrissal pad until days 3-4 post-inoculation. As compared with sham animals, the facial grooming period was prolonged, the withdrawal latency to radiant heat stimulation was shortened, and the withdrawal threshold by von Frey hair stimulation was decreased at the inoculated region, indicating the development of spontaneous pain, thermal hyperalgesia and mechanical allodynia. In immunostainings for Iba1 and glial fibrillary acidic protein (GFAP), although there were no morphological changes of GFAP-immunopositive satellite glial cells in the trigeminal ganglion, Iba1-immunopositive microglia and GFAP-immunopositive astrocytes in the medullary dorsal horn showed large somata with cell proliferation. After the daily i.p. administration of propentofylline beginning pre-inoculation, the central glial activation was attenuated, the prolonged facial grooming was partially suppressed, and the induced allodynia and hyperalgesia from day 2 were prevented, without a change in tumor size. These results suggest that glial activation in the CNS, but not in the peripheral nervous system, mediates the enhancement of spontaneous pain and the development of allodynia and hyperalgesia at an early stage in the facial cancer model. PMID- 21315807 TI - The moderating role of the dopamine transporter 1 gene on P50 sensory gating and its modulation by nicotine. AB - Although schizophrenia has been considered primarily a disease of dopaminergic neurotransmission, the role of dopamine in auditory sensory gating deficits in this disorder and their amelioration by smoking/nicotine is unclear. Hypothesizing that individual differences in striatal dopamine levels may moderate auditory gating and its modulation by nicotine, this preliminary study used the mid-latency (P50) auditory event-related potential (ERP) to examine the single dose (6 mg) effects of nicotine (vs. placebo) gum on sensory gating in 24 healthy nonsmokers varying in the genetic expression of the dopamine transporter (DAT). Consistent with an inverted-U relationship between dopamine level and the drug effects, individuals carrying the 9R (lower gene expression) allele, which is related to greater striatal dopamine levels, tended to evidence increased baseline gating compared to 10R (higher gene expression) allele carriers and showed a reduction in gating with acute nicotine. The present results may help to understand the link between excessive smoking and sensory gating deficits in schizophrenia and to explain the potential functional implications of genetic disposition on nicotinic treatment in schizophrenia. PMID- 21315810 TI - Sadness as a passion of the soul: a psychopathological consideration of the Cartesian concept of melancholy. AB - The relationship between the "passions" (emotions or feelings) and psychopathology has been a constant throughout the history of medicine. In this context, melancholy was considered a perversion of the soul (corruption of the passions). One of the most influential authors on this subject was Rene Descartes, who discussed it in his work The Treatise on the Passions of the Soul (1649). Descartes believed that "passions" were sensitive movements that the soul experienced due to its union with the body (res extensa). According to this theory, the soul was located in the pineal gland, where it was actively involved in overseeing the functions of the "human machine" and kept its dysfunctions under control, by circulating animal spirits. Descartes described sadness as one of "the six primitive passions of the soul", which leads to melancholy if not remedied. Cartesian theories had a great deal of influence on the way that mental pathologies were considered throughout the entire 17th century (Spinoza, Willis, Pitcairn) and during much of the 18th century (Le Cat, Tissot). From the 19th century onwards, emotional symptomatology finally began to be used in diagnostic criteria for mood disorders. PMID- 21315809 TI - Lesions of the dorsomedial striatum disrupt prepulse inhibition. AB - Prepulse inhibition (PPI) of startle is an experimentally tractable measure of sensorimotor gating that can be readily evaluated in mice, rats, monkeys, and humans. PPI is the inhibitory effect of a low-intensity stimulus, the prepulse, on the startle response to a subsequent high-intensity stimulus. PPI has garnered great interest as a marker of clinically relevant information processing abnormalities, because it is impaired in such neuropsychiatric conditions as schizophrenia, Tourette syndrome, and obsessive compulsive disorder (OCD). Pathology of the basal ganglia has been described in all three of these disorders, and it is therefore of great interest to determine the role of the basal ganglia in PPI. Previous work in rats described a PPI deficit after excitotoxic ventral striatal lesions and a more subtle attenuation after caudodorsal lesion, but no effect of other large lateral dorsal lesions. However, previous studies have not specifically investigated the role of the dorsomedial striatum in PPI. We investigated this issue using excitotoxic lesions in mice. We describe a marked reduction in PPI, at a variety of prepulse intensities, after bilateral lesions of dorsomedial striatum. There was no effect of lesion on baseline startle or habituation. In contrast, comparably sized lesions of the central dorsal striatum had no effect on PPI. These results reveal a role for the dorsomedial striatum in prepulse inhibition, which may have relevance for the abnormalities observed in this region in such disorders as Tourette syndrome and OCD. PMID- 21315811 TI - Modulation of constitutive androstane receptor (CAR) and pregnane X receptor (PXR) by 6-arylpyrrolo[2,1-d][1,5]benzothiazepine derivatives, ligands of peripheral benzodiazepine receptor (PBR). AB - Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) regulate xenobiotic sensing and metabolism through interactions with multiple exogenous and endogenous chemicals. Compounds that activate CAR are often ligands of PXR; attention is therefore given to discovery of new, receptor-specific chemical entities that may be exploited for therapeutic and basic research purposes. Recently, ligands of the peripheral benzodiazepine receptor (PBR), PK11195 and FGIN-1-27, were shown to modulate both CAR and PXR. PBR is a mitochondrial transport protein responsible for multiple regulatory functions, including heme biosynthesis, a major component in cytochrome P450 (CYP) enzymes. To investigate possible new roles for PBR involvement in metabolic regulation, expression of the CAR and PXR target genes, CYP2B6 and CYP3A4, was measured in human hepatocytes following treatment with a targeted PBR ligand set. Luciferase reporter assays with transiently expressed wild-type CAR (CAR1), splice variant CAR3, or PXR in HuH-7 cells were used to further study activation of these receptors. Four structurally related PBR ligands (benzothiazepines) differentially modulate CAR1, CAR3 and PXR activity. Benzothiazepine NF49 is an agonist ligand of CAR3, a partial agonist of PXR, exhibits greater inverse agonist activity on CAR1 than does PK11195, and is a new tool for studying these closely related nuclear receptors. PMID- 21315812 TI - Study of gene-specific DNA repair in the comet assay with padlock probes and rolling circle amplification. AB - We used padlock probes to study the rate of gene specific repair of three genes, OGG1 (8-oxoguanine-DNA glycosylase-1), XPD (xeroderma pigmentosum group D), and HPRT (hypoxanthine-guanine phosphoribosyltransferase) in human lymphocytes, in relation to the repair rate of Alu repeats and total genomic DNA. Padlock probes offer highly specific detection of short target sequences by combining detection by ligation and signal amplification. In this approach only genes in sequences containing strand breaks, which become single-stranded in the tail, are available for hybridisation. Thus the total number of signals from the padlock probes per comet gives a direct measure of the amount of damage (strand-breaks) present and allows the repair process to be monitored. This method could provide insights on the organisation of genomic DNA in the comet tail. Alu repeat containing DNA was repaired rapidly in comparison with total genomic DNA, and the studied genes were generally repaired more rapidly than the Alu repeats. PMID- 21315813 TI - Novel magnetic iron oxide nanoparticles coated with poly(ethylene imine)-g poly(ethylene glycol) for potential biomedical application: synthesis, stability, cytotoxicity and MR imaging. AB - Magnetic iron oxide nanoparticles have found application as contrast agents for magnetic resonance imaging (MRI) and as switchable drug delivery vehicles. Their stabilization as colloidal carriers remains a challenge. The potential of poly(ethylene imine)-g-poly(ethylene glycol) (PEGPEI) as stabilizer for iron oxide (gamma-Fe2O3) nanoparticles was studied in comparison to branched poly(ethylene imine) (PEI). Carrier systems consisting of gamma-Fe2O3-PEI and gamma-Fe2O3-PEGPEI were prepared and characterized regarding their physicochemical properties including magnetic resonance relaxometry. Colloidal stability of the formulations was tested in several media and cytotoxic effects in adenocarcinomic epithelial cells were investigated. Synthesized gamma-Fe2O3 cores showed superparamagnetism and high degree of crystallinity. Diameters of polymer-coated nanoparticles gamma-Fe2O3-PEI and gamma-Fe2O3-PEGPEI were found to be 38.7 +/- 1.0 nm and 40.4 +/- 1.6 nm, respectively. No aggregation tendency was observable for gamma-Fe2O3-PEGPEI over 12 h even in high ionic strength media. Furthermore, IC50 values were significantly increased by more than 10-fold when compared to gamma-Fe2O3-PEI. Formulations exhibited r2 relaxivities of high numerical value, namely around 160 mM-1 s-1. In summary, novel carrier systems composed of gamma-Fe2O3-PEGPEI meet key quality requirements rendering them promising for biomedical applications, e.g. as MRI contrast agents. PMID- 21315814 TI - Kudzu root: traditional uses and potential medicinal benefits in diabetes and cardiovascular diseases. AB - Kudzu root (Gegen in Chinese) is the dried root of Pueraria lobata (Willd.) Ohwi, a semi-woody, perennial and leguminous vine native to South East Asia. It is often used interchangeably in traditional Chinese medicine with thomson kudzu root (Fengen in Chinese), the dried root of P. thomsonii, although the Chinese Pharmacopoeia has separated them into two monographs since the 2005 edition. For more than 2000 years, kudzu root has been used as a herbal medicine for the treatment of fever, acute dysentery, diarrhoea, diabetes and cardiovascular diseases. Both English and Chinese literatures on the traditional applications, phytochemistry, pharmacological activities, toxicology, quality control and potential interactions with conventional drugs of both species have been included in the present review. Over seventy phytochemicals have been identified in kudzu root, with isoflavonoids and triterpenoids as the major constituents. Isoflavonoids, in particular puerarin, have been used in most of the pharmacological studies. Animal and cellular studies have provided support for the traditional uses of kudzu root on cardiovascular, cerebrovascular and endocrine systems, including diabetes and its complications. Further studies to define the active phytochemical compositions, quality standards and clinical efficacy are warranted. Strong interdisciplinary collaboration to bridge the gap between traditional medicine and modern biomedical medicine is therefore needed for the development of kudzu root as an effective medicine for the management of diabetes and cardiovascular diseases. PMID- 21315815 TI - Evaluation of mutagenic and antimutagenic activities of neem (Azadirachta indica) seed oil in the in vitro Ames Salmonella/microsome assay and in vivo mouse bone marrow micronucleus test. AB - AIM OF THE STUDY: The possible mutagenic and antimutagenic activity of neem oil (NO) and its DMSO extract (NDE) were, examined in the Ames Salmonella/microsome mutagenicity test and the mouse bone marrow micronucleus assay. MATERIALS AND METHODS: Eight different strains of Salmonella typhimurium were, used to study the genotoxicity of neem oil both in the presence and absence of Aroclor-1254 induced rat liver homogenate (S9). Two-dose treatment protocol was, employed to study the cytogenetic activity in micronucleus assay. Similarly, the antimutagenic activity of neem oil and NDE was studied against mitomycin (MMC) and 7,12-dimethylbenz[a]anthracene (DMBA) in the above two test systems. RESULTS: Neem oil was non-mutagenic in all the eight tester strains of Salmonella typhimurium both in the presence and absence of S9 mix. In the present study, there was no significant increase in the frequency of micronucleated polychromatic erythrocytes (MNPCEs) in neem oil treated groups over the negative control (DMSO) group of animals, indicating the non-clastogenic activity of neem oil in the micronucleus test. Neem oil showed good antimutagenic activity against DMBA induced mutagenicity compared to its DMSO extract. However, neem oil showed comparatively less antimutagenicity against MMC in the Ames assay. In vivo anticlastogenic assays shows that neem oil exhibited better activity against DMBA induced clastogenicity. CONCLUSION: These results indicate non-mutagenic activity of neem oil and significant antimutagenic activity of neem oil suggesting its pharmacological importance for the prevention of cancer. PMID- 21315816 TI - Silver nanoparticles alter zebrafish development and larval behavior: distinct roles for particle size, coating and composition. AB - Silver nanoparticles (AgNPs) act as antibacterials by releasing monovalent silver (Ag(+)) and are increasingly used in consumer products, thus elevating exposures in human and wildlife populations. In vitro models indicate that AgNPs are likely to be developmental neurotoxicants with actions distinct from those of Ag(+). We exposed developing zebrafish (Danio rerio) to Ag(+) or AgNPs on days 0-5 post fertilization and evaluated hatching, morphology, survival and swim bladder inflation. Larval swimming behavior and responses to different lighting conditions were assessed 24h after the termination of exposure. Comparisons were made with AgNPs of different sizes and coatings: 10nm citrate-coated AgNP (AgNP C), and 10 or 50nm polyvinylpyrrolidone-coated AgNPs (AgNP-PVP). Ag(+) and AgNP-C delayed hatching to a similar extent but Ag(+) was more effective in slowing swim bladder inflation, and elicited greater dysmorphology and mortality. In behavioral assessments, Ag(+) exposed fish were hyperresponsive to light changes, whereas AgNP-C exposed fish showed normal responses. Neither of the AgNP-PVPs affected survival or morphology but both evoked significant changes in swimming responses to light in ways that were distinct from Ag(+) and each other. The smaller AgNP-PVP caused overall hypoactivity whereas the larger caused hyperactivity. AgNPs are less potent than Ag(+) with respect to dysmorphology and loss of viability, but nevertheless produce neurobehavioral effects that highly depend on particle coating and size, rather than just reflecting the release of Ag(+). Different AgNP formulations are thus likely to produce distinct patterns of developmental neurotoxicity. PMID- 21315817 TI - A proposal to facilitate weight-of-evidence assessments: Harmonization of Neurodevelopmental Environmental Epidemiology Studies (HONEES). AB - The ability to conduct weight-of-evidence assessments to inform the evaluation of potential environmental neurotoxicants is limited by lack of comparability of study methods, data analysis, and reporting. There is a need to establish consensus guidelines for conducting, analyzing, and reporting neurodevelopmental environmental epidemiologic studies, while recognizing that consistency is likewise needed for epidemiology studies examining other health outcomes. This paper proposes a set of considerations to be used by the scientific community at large as a tool for systematically evaluating the quality of proposed and/or published studies in terms of their value for weight-of-evidence assessments. Particular emphasis is placed on evaluating factors influencing the risk of incorrect conclusions at the level of study findings. The proposed considerations are the first step in what must be a larger consensus-based process and can serve to catalyze such a discussion. Achieving consensus in these types of endeavors is difficult; however, opportunities exist for further interdisciplinary discussion, collaboration, and research that will help realize this goal. Broad acceptance and application of such an approach can facilitate the expanded use of environmental epidemiology studies of potential neurodevelopmental toxicants in the protection of public health, and specifically children's health. PMID- 21315818 TI - Transgenic plants expressing the quorum quenching lactonase AttM do not significantly alter root-associated bacterial populations. AB - The possible impact of genetically engineered plants that degrade the quorum sensing (QS) signal of the plant pathogen Pectobacterium carotovorum was evaluated on non-target plant-associated bacterial populations and communities using Nicotiana tabacum lines expressing the lactonase AttM that degrades QS signals (AttM), and the wild type (WT) parent line. Cell densities of total culturable bacteria and those of selected populations (pseudomonads, agrobacteria) isolated from plant rhizospheres and rhizoplanes were comparable whatever the genotype of the plants (AttM or WT). Similarly, cell densities of members of the bacterial communities relying upon acyl-homoserine-lactones (AHLs) to communicate, or naturally degrading AHL signals, were identical and independent of plant genotype. Bacterial populations isolated from the two plant genotypes were also analyzed irrespective of their culturability status. DGGE analyses targeting the rrs gene (16S rRNA gene) did not reveal any significant differences within these populations. All these data indicate that bacterial population changes that could have resulted from the genetic modification of the plants are non-existent or very limited, as no changes linked to the plant genotype were observed. PMID- 21315819 TI - MicroRNAs and the cell cycle. AB - The control of cell proliferation by microRNAs (miRNAs) is well established and the alteration of these small, non-coding RNAs may contribute to tumor development by perturbing critical cell cycle regulators. Oncogenic miRNAs may facilitate cell cycle entry and progression by targeting CDK inhibitors or transcriptional repressors of the retinoblastoma family. On the other hand, tumor suppressor miRNAs induce cell cycle arrest by downregulating multiple components of the cell cycle machinery. Recent data also suggest that miRNAs act co ordinately with transcriptional factors involved in cell cycle regulation such as c-MYC, E2F or p53. These miRNAs not only can potentiate the function of these factors but they may also limit the excessive translation of cell cycle proteins upon mitogenic or oncogenic stimuli to protect cells from replicative stress. The implications of these regulatory networks in cell proliferation and human disease are discussed. PMID- 21315820 TI - Enhancement of transdermal apomorphine delivery with a diester prodrug strategy. AB - Diester prodrugs of apomorphine, diacetyl apomorphine (DAA), and diisobutyryl apomorphine (DIA) were synthesized, and their partition coefficients, capacity factor (log K'), enzymatic hydrolysis, and in vitro permeation across nude mouse skin were characterized. The lipophilicity of the diesters was between that of apomorphine HCl and the apomorphine base. The prodrugs were chemically stable, but enzymatically unstable in esterase medium, skin homogenate, and human plasma. DAA showed a faster hydrolysis in plasma compared to DIA. Total fluxes (nmol/cm(2)/h) of the parent drug and prodrug were significantly greater after topical treatment with the diesters in aqueous solutions (water, 30% polyethylene glycol in water, and 30% glycerol in water) compared to treatment with HCl and base forms of apomorphine. DIA flux from deionized water was 51 nmol/cm(2)/h, which exceeded the flux of apomorphine HCl by 10-fold. The extent of parent drug regeneration after topical application ranged 51-88% and 34-61% for DAA and DIA, respectively, depending on the vehicles selected. Permeation measurements using intact and stratum corneum-stripped skins demonstrated that the viable epidermis/dermis was an important barrier to prodrug permeation. Nano-sized lipid emulsions were also used as carriers for apomorphine and its prodrugs. Diester prodrugs exhibited superior skin permeation compared to the parent drug when formulated into the emulsions. DAA and DIA fluxes from lipid emulsions were 11- and 3-fold higher than that of apomorphine HCl. The results in the present work suggest the feasibility of diester prodrugs for the transdermal delivery of apomorphine. PMID- 21315821 TI - Unique gene expression patterns indicate microglial contribution to neural stem cell recovery following irradiation. AB - Ionizing radiation results in damage to neural stem cells and reduced neurogenesis. The aim of the present study was to determine intrinsic and extrinsic factors that influence neural stem cell survival following irradiation, using qPCR. Gene expression of hippocampal and SVZ neurospheres were analyzed following irradiation, and results demonstrated that irradiated hippocampal and SVZ stem cells displayed similar gene expression profiles for intrinsic genes. Irradiated microglia (extrinsic factor) isolated from the SVZ exhibited increased gene expression of growth factors involved in stem cell maintenance, proliferation, and survival. However, microglial genes in the irradiated hippocampus responded less favorably with respect to stem cell recovery. This might explain the superior recovery of SVZ compared to hippocampal stem cells following in vivo irradiation. In addition, our results show that a combination of growth factors, which were upregulated in SVZ microglia, increased the proliferation and decreased cell death of irradiated neurospheres in vitro. PMID- 21315822 TI - Expression and purification of full-length anti-apoptotic Bcl-2 using cell-free protein synthesis. AB - The anti-apoptotic B cell CLL/lymphoma-2 (Bcl-2) protein is a key player in the regulation of programmed cell death and is linked to various types of cancer and their resistance to drug treatment. Biophysical and structural studies of the full-length intact Bcl-2 have been hampered due to difficulties in expression and severe solubility problems, precluding isolation of this hydrophobic membrane protein. Therefore, previous work has so far mainly been carried out using structurally modified Bcl-2 variants, lacking the transmembrane region. Thus, biophysical information regarding the full-length protein is still missing. Here, a protocol is presented for expression and purification of preparative amounts of the full-length human isoform 2 of Bcl-2 (Bcl-2(2)). A batch-based cell-free expression system, using extract isolated from Escherichia coli (E. coli) was employed to produce recombinant protein encoded by an optimized gene sequence. Presence of polyoxyethylene-(20)-cetyl-ether (Brij-58) in the reaction mixture and subsequently in the immobilized metal-affinity purification steps was crucial to keep Bcl-2(2) soluble. The obtained yield was 0.25-0.3mg per ml of cell-free reaction. Far-UV circular dichroism (CD) spectroscopy confirmed the alpha-helical structure of the purified protein, characteristic for members of the Bcl-2 protein family. PMID- 21315823 TI - Phylogenetic structure and species boundaries in the mountain pitviper Ovophis monticola (Serpentes: Viperidae: Crotalinae) in Asia. AB - We investigated phylogenetic structure and morphological variation in Asian mountain pitvipers of the genus Ovophis (comprising 3-4 species some of which are considered polytypic) by sequencing four mitochondrial markers (cytochrome b, NADH dehydrogenase subunit 4, 12S and 16S rRNA) from 72 specimens, and analysed them in a Bayesian framework together with another 26 sequences from closely related genera. We reconstructed the region of origin and direction of dispersal of the major clades, and of Ovophis as a whole, using likelihood framework analysis. We also defined morphogroups from 280 specimens from across the range of Ovophis to allow the geographic extent of the major clades to be determined, as well as to allow inclusion of specimens lacking sequence data. Phylogenetic analyses confirmed the monophyly of Ovophis as currently defined, and revealed that it contains two major lineages, eastern (mainly Chinese) and western, with both occurring in southwestern China, central and northern Viet Nam. The most likely origin of the genus, and of individual lineages, coincides with the northeastern boundary of the Indomalayan hotspot. Major diversification in this species group likely corresponded to major climatic changes arising from the uplift of the Tibetan Plateau in the early to mid Miocene. With reference to the defined morphogroups, we suggest that at least five species are present and provide appropriate names. With a few exceptions, the newly defined species boundaries do not correspond to the existing taxonomy. PMID- 21315824 TI - Basolateral amygdala inactivation impairs learned (but not innate) fear response in rats. AB - Numerous studies have suggested that the amygdala is involved in the formation of aversive memories, but the possibility that this structure is merely related to any kind of fear sensation or response could not be ruled out in previous studies. The present study investigated the effects of bilateral inactivation of the amygdaloid complex in rats tested in the plus-maze discriminative avoidance task. This task concomitantly evaluates aversive memory (by discrimination of the two enclosed arms) and innate fear (by open-arm exploration). Wistar rats (3-5 months-old) were implanted with bilateral guide cannulae into basolateral amygdala. After surgery, all subjects were given 1 week to recover before behavioral experiments. Afterwards, in experiment 1, 15 min prior to training, 0.5 MUl of saline or muscimol (1 mg/ml) was infused in each side via microinjection needles. In experiment 2 the animals received injections immediately after the training session and in experiment 3 rats were injected prior to testing session (24 h after training). The main results showed that (1) pre-training muscimol prevented memory retention (evaluated by aversive arm exploration in the test session), but did not alter innate fear (evaluated by percent time in open arms); (2) post-training muscimol impaired consolidation, inducing increased percent in aversive arm exploration in the test session and (3) pre-testing muscimol did not affect retrieval (evaluated by aversive enclosed arm exploration in the test session). The results suggest that amygdala inactivation specifically modulated the learning of the aversive task, excluding a possible secondary effect of amygdala inactivation on general fear responses. Additionally, our data corroborate the hypothesis that basolateral amygdala is not the specific site of storage of aversive memories, since retention of the previously learned task was not affected by pre-testing inactivation. PMID- 21315825 TI - Post-training disruption of Arc protein expression in the anterior cingulate cortex impairs long-term memory for inhibitory avoidance training. AB - The activity-regulated-cytoskeletal-associated protein (Arc) has a well established role in memory consolidation and synaptic plasticity in the hippocampus and amygdala. However the role of Arc within the anterior cingulate cortex (ACC), an area of the brain involved in processing memory for pain, has yet to be examined. Here we sought to determine if Arc protein within neurons of the rat ACC is necessary for the consolidation of a single-trial, contextual inhibitory avoidance (IA) task. Immunohistochemistry and western blotting revealed an increase in Arc protein within the ACC following IA training in a shock-specific manner, suggesting that ACC Arc expression may play a critical role in the consolidation of the aversive task. To directly test this hypothesis, male Sprague-Dawley rats were trained on the IA task and given post-training intra-ACC infusions of Arc antisense oligodeoxynucleotides (ODNs), designed to suppress Arc translation, or control scrambled ODNs that do not suppress Arc translation. Memory retention was tested 48h after training. Arc antisense induced disruption of Arc protein expression in the ACC impaired long-term memory for the IA task as compared to rats given intra-ACC infusions of the scrambled control ODNS, suggesting that Arc expression in the ACC is important for the consolidation of emotional memory. Results further indicate that knock down of Arc 6h after training impairs IA memory. This is consistent with time course findings indicating elevated Arc expression at 3 and 6h after IA training but not 12 or 48h. Taken together, these findings support the hypothesis that Arc expression in the ACC participates in synaptic plasticity that underlies long term memory. PMID- 21315826 TI - Glyoxalase in tumourigenesis and multidrug resistance. AB - Since the discovery by Warburg of high aerobic glycolysis in most tumours in the 1920s, it has remained unclear how to exploit this in chemotherapy. The aim of this review is to assess the evidence for the involvement of the glyoxalase system in tumour growth and multidrug resistance and the importance of the glyoxalase system as a target for anticancer drug development and a source of biomarkers for tumour diagnosis. Increased expression of glyoxalase 1 appears to support the viability of tumour cells with high glycolytic rates. Multidrug resistance conferred by overexpression of glyoxalase 1 suggests mechanisms of toxicity of most current antitumour agents involve, in some part, accumulation of methylglyoxal to cytotoxic levels. The recent finding of glyoxalase 1 gene amplification in tumours and induction of increased glyoxalase 1 expression by malignant transformation and conventional antitumour drug treatment implies a critical role of glyoxalase 1 in innate and acquired multidrug resistance in cancer treatment. Improved understanding of glyoxalase 1 in cancer chemotherapy multidrug resistance is likely vital to achieve improvement of cancer patient survival rates. Advances made to counter glyoxalase 1-linked multidrug resistance with glyoxalase 1 inhibitors and related prodrugs has been translated from in vitro to pre-clinical in vivo studies. Further research is required urgently for next stage clinical translation. Finally, overexpression of glyoxalase 1 may be linked to multidrug resistance in chemotherapy of other disease - such as microbial infections. PMID- 21315827 TI - HIV-1 does not significantly influence Chlamydia trachomatis serovar L2 replication in vitro. AB - Individuals with lymphogranuloma venereum (LGV), caused by Chlamydia trachomatis serovar L2, are commonly co-infected with human immunodeficiency virus type 1 (HIV-1), for reasons that remain unknown. One hypothesis is that a biological synergy exists between the two pathogens. We tested this by characterising for the first time in vitro C. trachomatis L2 replication in the presence of HIV-1. The human epithelial cell-line, MAGI P4R5 was infected with C. trachomatis L2 and HIV-1 (MN strain). Co-infected cultures contained fewer and larger chlamydial inclusions, but the inclusions did not contain morphologically aberrant organisms. C. trachomatis remained infectious in the presence of HIV-1 and showed neither an alteration in genome accumulation, nor in the acumulation of ompA, euo or unprocessed 16S rRNA transcripts. However, omcB was slightly elevated. Taken together, these data indicate that HIV-1 co-infection did not significantly alter C. trachomatis replication and the association between HIV-1 and LGV is likely due to other factors that require further investigation. The fewer, larger inclusions observed in co-infected cultures probably result from the fusion of multiple inclusions in HIV-1 induced syncytia and indicate that C. trachomatis host-cell interactions continue to function, despite considerable host-cell re modelling. PMID- 21315828 TI - Permissivity of Vero cells, human pneumocytes and human endometrial cells to Waddlia chondrophila. AB - Growing evidence suggests that the bacterium Waddlia chondrophila, a novel member of the Chlamydiales order, is an agent of miscarriage in humans and abortion in ruminants. We thus investigated the permissivity of three epithelial cell lines, primate Vero kidney cells, human A549 pneumocytes and human Ishikawa endometrial cells to this strict intracellular bacteria. Bacterial growth kinetics in these cell lines was assessed by quantitative PCR and immunofluorescence and our results demonstrated that W. chondrophila enters and efficiently multiplies in these epithelial cell lines. Additionally, confocal and electron microscopy indicated that the bacteria co-localize with host cell mitochondria. Within Vero and A549 cells, intracellular growth of W. chondrophila was associated with a significant decrease in host cell viability while no such cytophatic effect was detected in Ishikawa cells. Bacterial cell growth in this endometrial cell line stopped 48 h after infection. This stop in the replication of W. chondrophila coincided with the appearance of large aberrant bodies, a form of the bacteria also observed in Chlamydiaceae and associated with persistence. This persistent state of W. chondrophila may explain recurrent episodes of miscarriage in vivo, since the bacteria might reactivate within endometrial cells following hormonal changes that occur during pregnancy. PMID- 21315829 TI - The role of ficolins in the lectin pathway of innate immunity. AB - Ficolins are a family of oligomeric proteins consisting of an N-terminal collagen like domain and a C-terminal globular fibrinogen-like domain. They are novel lectins that employ the fibrinogen-like domain as a functional domain. Ficolins specifically recognize N-acetyl compounds such as N-acetylglucosamine, components of bacterial and fungal cell walls, and certain bacteria. Like mannose-binding lectin (MBL), ficolins circulate in complexes with MBL-associated serine proteases (MASPs). MASP complexes form with ficolins and MBL, thereby activating the complement through the lectin pathway. Upon binding of ficolins and MBL to carbohydrates on pathogens, MASPs convert to active forms, and subsequently activate the complement. The activated complements lead to pathogen phagocytosis, aggregation and lysis. In humans, three ficolins (L-, M- and H-ficolins) have been identified, which exhibit differences in tissue expression, protein location site, ligand-binding and bacteria-recognition, suggesting a specific role of each ficolin. In addition, these ficolins form complexes with three MASPs (MASP-1, MASP-2 and MASP-3) and two nonenzymatic proteins (sMAP and MAP-1), suggesting a highly sophisticated organization and regulated activation of the ficolin dependent lectin pathway. This review provides an overview of our current knowledge of ficolins, especially human ficolins and their mouse homologues. We also discuss their possible physiological roles in innate immunity, especially their defensive role against bacterial infection. PMID- 21315830 TI - Targeting cancer-initiating cell drug-resistance: a roadmap to a new-generation of cancer therapies? AB - The occurrence of drug resistance in oncology accounts for treatment failure and relapse of diverse tumor types. Cancers contain cells at various stages of differentiation together with a limited number of 'cancer-initiating cells' able to self-renew and divide asymmetrically, driving tumorigenesis. Cancer-initiating cells display a range of self-defense systems that include almost all mechanisms of drug-resistance. Different molecular pathways and markers, identified in this malignant sub-population, are becoming targets for novel compounds and for monoclonal antibodies, which may be combined with conventional drugs. These interventions might eliminate drug-resistant cancer-initiating cells and lead to remission or cure of cancer patients. PMID- 21315831 TI - Omics-current applications in toxicology. PMID- 21315832 TI - A new view of insect-crustacean relationships II. Inferences from expressed sequence tags and comparisons with neural cladistics. AB - The enormous diversity of Arthropoda has complicated attempts by systematists to deduce the history of this group in terms of phylogenetic relationships and phenotypic change. Traditional hypotheses regarding the relationships of the major arthropod groups (Chelicerata, Myriapoda, Crustacea, and Hexapoda) focus on suites of morphological characters, whereas phylogenomics relies on large amounts of molecular sequence data to infer evolutionary relationships. The present discussion is based on expressed sequence tags (ESTs) that provide large numbers of short molecular sequences and so provide an abundant source of sequence data for phylogenetic inference. This study presents well-supported phylogenies of diverse arthropod and metazoan outgroup taxa obtained from publicly-available databases. An in-house bioinformatics pipeline has been used to compile and align conserved orthologs from each taxon for maximum likelihood inferences. This approach resolves many currently accepted hypotheses regarding internal relationships between the major groups of Arthropoda, including monophyletic Hexapoda, Tetraconata (Crustacea + Hexapoda), Myriapoda, and Chelicerata sensu lato (Pycnogonida + Euchelicerata). "Crustacea" is a paraphyletic group with some taxa more closely related to the monophyletic Hexapoda. These results support studies that have utilized more restricted EST data for phylogenetic inference, yet they differ in important regards from recently published phylogenies employing nuclear protein-coding sequences. The present results do not, however, depart from other phylogenies that resolve Branchiopoda as the crustacean sister group of Hexapoda. Like other molecular phylogenies, EST-derived phylogenies alone are unable to resolve morphological convergences or evolved reversals and thus omit what may be crucial events in the history of life. For example, molecular data are unable to resolve whether a Hexapod-Branchiopod sister relationship infers a branchiopod-like ancestry of the Hexapoda, or whether this assemblage originates from a malacostracan-like ancestor, with the morphologically simpler Branchiopoda being highly derived. Whereas this study supports many internal arthropod relationships obtained by other sources of molecular data, other approaches are required to resolve such evolutionary scenarios. The approach presented here turns out to be essential: integrating results of molecular phylogenetics and neural cladistics to infer that Branchiopoda evolved simplification from a more elaborate ancestor. Whereas the phenomenon of evolved simplification may be widespread, it is largely invisible to molecular techniques unless these are performed in conjunction with morphology based strategies. PMID- 21315833 TI - The origins of the arthropod nervous system: insights from the Onychophora. AB - A revision of evolutionary relationships of the Arthropoda has provided fresh impetus to tracing the origins of the nervous system of this group of animals: other members of the Ecdysozoa possess a markedly different type of nervous system from both the arthropods and the annelid worms, with which they were previously grouped. Given their status as favoured sister taxon of the arthropods, Onychophora (velvet worms) are a key group for understanding the evolutionary changes that have taken place in the panarthropod (Arthropoda + Onychophora + Tardigrada) lineage. This article reviews our current knowledge of the structure and development of the onychophoran nervous system. The picture that emerges from these studies is that the nervous system of the panarthropod ancestor was substantially different from that of modern arthropods: this animal probably possessed a bipartite, rather than a tripartite brain; its nerve cord displayed only a limited degree of segmentation; and neurons were more numerous but more uniform in morphology than in living arthropods. These observations suggest an evolutionary scenario, by which the arthropod nervous system evolved from a system of orthogonally crossing nerve tracts present in both a presumed protostome ancestor and many extant worm-like invertebrates, including the onychophorans. PMID- 21315834 TI - Ablation of atrioventricular nodal reentrant tachycardia in the elderly: results from the German Ablation Registry. AB - BACKGROUND: Catheter ablation (CA) is considered the treatment of choice for patients with atrioventricular nodal reentrant tachycardia (AVNRT). However, there is a tendency to avoid CA in the elderly because of a presumed increased risk of periprocedural atrioventricular (AV) nodal block. OBJECTIVE: The purpose of this prospective registry was to assess age-related differences in the efficacy and safety of CA within a large population with AVNRT. METHODS: A total of 3,234 consecutive patients from 48 German trial centers who underwent CA of AVNRT between March 2007 and May 2010 were enrolled in this study. The cohort was divided into three age groups: <50 years (group 1, n = 1,268 [39.2%]; median age = 40 [30.0-45.0] years, 74.1% women), 50-75 years old (group 2, n = 1,707 [52.8%]; 63.0 [58.0-69.0] years, 63.0% women), and > 75 years old (group 3, n = 259 [8.0%]; 79.0 [77.0-82.0] years, 50.6% women). RESULTS: CA was performed with radiofrequency current (RFC) in 97.7% and cryoablation technology in 2.3% of all cases. No differences were observed among the three groups with regard to primary CA success rate (98.7% vs. 98.8 % vs. 98.5%; P = .92) and overall procedure duration (75.0 minutes [50.0-105.0]; P = .93). Hemodynamically stable pericardial effusion occurred in five group 2 (0.3%) and two group 3 (0.8%) patients but in none of the group 1 (P <.05) patients. Complete AV block requiring permanent pacemaker implantation occurred in two patients in group 1 (0.2%) and six patients in group 2 (0.4%) but none in group 3 (P = 0.41). During a median follow up period of 511.5 days (396.0-771.0), AVNRT recurrence occurred in 5.7% of all patients. Patients >75 years (group 3) had a significantly longer hospital stay (3.0 days [2.0-5.0]) compared with group 1 (2.0 days [1.0-2.0]) or group 2 (2.0 days [1.0-3.0]) patients (P <.0001). CONCLUSION: CA of AVNRT is highly effective and safe and does not pose an increased risk for complete AV block in patients over 75 years of age, despite a higher prevalence of structural heart disease. Antiarrhythmic drug therapy is often ineffective in this age group; thus, CA for AVNRT should be considered the preferred treatment even in elderly patients. PMID- 21315835 TI - Balloon occlusion of the distal coronary sinus facilitates mitral isthmus ablation. AB - BACKGROUND: Mitral isthmus ablation is challenging. Blood flow in the coronary sinus (CS) may act as a heat sink and reduce the efficacy of radiofrequency ablation. OBJECTIVE: This study investigates whether balloon occlusion of CS facilitates mitral isthmus ablation. METHODS: This single-center, prospective, randomized controlled trial included patients undergoing ablation for atrial fibrillation. After circumferential pulmonary vein isolation and roof line ablation, mitral isthmus ablation was performed during left atrial appendage pacing using an irrigated ablation catheter (endocardium: maximum power: 40/50 W, maximum temperature: 48 degrees C; CS: maximum power: 25/30 W, maximum temperature: 48 degrees C). An air-filled 40 * 10-mm percutaneous transluminal angioplasty balloon (Opta Pro, Cordis Europa, LJ Roden, The Netherlands) was used to occlude the CS on the epicardial aspect of the ablation line. Left coronary and CS angiography were performed before and after the procedure. RESULTS: Forty six patients were studied. The balloon was successfully positioned in the distal CS in 20 of 23 patients (87%). Mitral isthmus block was achieved in 41 of 46 patients (91%). According to intention-to-treat analysis, there was significant reduction in the need for epicardial CS ablation (48% vs. 83%, P = .01) in the CS occlusion group but no difference in acute success rate. Secondary analysis showed reduction in mean total ablation time (9.4 +/- 5.5 vs. 13.3 +/- 4.6 minutes, P <.02) and mean CS ablation time (1.5 +/- 2.8 vs. 3.4 +/- 2.7 minutes, P <.05) in patients who had CS occlusion. CONCLUSION: Balloon occlusion of the CS during mitral isthmus ablation is feasible and safe. It significantly reduces ablation time and the need for CS ablation to achieve mitral isthmus block. The results support the hypothesis that heat sink is one of the obstacles to successful mitral isthmus ablation. PMID- 21315836 TI - Cryoballoon temperature predicts acute pulmonary vein isolation. AB - BACKGROUND: Cryoballoon pulmonary vein isolation (PVI) currently requires a long cryoballoon application (CBA) time of 240 to 300 seconds, thus repeated ineffective CBA prolongs procedure duration. We hypothesized that cryoballoon temperature (CBT) may be used to discriminate between effective and ineffective CBA during freezing. OBJECTIVE: This study sought to evaluate CBT as a predictor of CBA efficiency. METHODS: Sixty-six patients with atrial fibrillation underwent PVI using the single big (28 mm) cryoballoon technique. CBT was continuously recorded. After each CBA (300 seconds), a Lasso catheter (Biosense Webster, Inc., Diamond Bar, California) was placed into the target pulmonary vein (PV) to determine whether electrical PV disconnection was present. Only the first CBA at each PV was analyzed to avoid cumulative effects. RESULTS: The CBT was lower during CBA at superior compared with inferior PVs. When individual CBAs were grouped according to successful/failed PVI, CBT was lower for those CBAs that resulted in successful PVI at all time points analyzed. To test the performance of CBT to predict failed CBA, receiver-operator curves were constructed. A minimal CBT of >= -42 degrees C/ -39 degrees C (superior/inferior PVs) predicted failed PVI with 73%/92% specificity (area under the curve 0.82/0.81); positive predictive value (PPV) 74%/74%. A minimal CBT of < -51 degrees C was invariably associated with PVI. After 120 seconds of freezing, a CBT of >= -36 degrees C/ 33 degrees C (superior/inferior PVs) predicted failed PVI with 97%/95% specificity (area under the curve 0.82/0.76); PPV 82%/80%. CONCLUSION: Balloon temperature predicts successful target PVI during cryoablation and may serve in the early identification of noneffective balloon applications. PMID- 21315837 TI - Epsilon-like waves and ventricular conduction abnormalities in subjects with type 1 ECG pattern of Brugada syndrome. AB - BACKGROUND: Previous studies have demonstrated an overlap between the arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) and Brugada syndrome (BS). Conduction delay in the right ventricle has been demonstrated in both entities. OBJECTIVE: This study investigated specific ARVC/D electrocardiographic (ECG) markers in subjects with spontaneous or drug-induced type 1 ECG pattern of BS. METHODS: The study population consisted of 47 apparently healthy individuals (38 men, mean age 44.1 +/- 13.3 years) with spontaneous (n = 17) or drug-induced (n = 30) type 1 ECG phenotype of BS. The clinical records of these individuals were retrospectively analyzed. RESULTS: Fifteen subjects (31.9%) were symptomatic, with a history of syncope. A family history of BS or sudden cardiac death was reported in 10 (21.3%) and 8 (17.0%) cases, respectively. Epsilon-like waves in leads V1-V3 were observed in 6 subjects (12.7%). Epsilon-like waves were seen in spontaneous type 1 ECGs in 2 cases and after sodium channel blocking test in 4 cases. In baseline ECGs, localized prolongation (>110 ms) of the QRS complex in leads V1-V3, QRS duration ratio in (V1+V2+V3)/(V4+V5+V6) >= 1.2, and prolonged S wave upstroke (>55 ms) in leads V1-V3 were seen in 48.8%, 29.8%, and 40.4% of subjects, respectively. Epsilon-like waves and delayed S wave upstroke were more commonly observed in subjects with family history of BS (P = .014 and P = .038, respectively). CONCLUSION: Specific ECG markers that reflect ventricular conduction delay in ARVC/D are commonly observed in subjects with spontaneous or drug-induced type 1 ECG pattern of BS as well. These depolarization abnormalities may be related to subtle underlying structural abnormalities. PMID- 21315838 TI - Spontaneous electrocardiogram alterations predict ventricular fibrillation in Brugada syndrome. AB - BACKGROUND: Patients with Brugada syndrome (BS) often have spontaneous changes in their electrocardiogram (ECG). OBJECTIVE: To evaluate the significance of ECG alterations, we investigated the relationships between the ECG and the occurrence of ventricular fibrillation (VF) in both patients and an experimental model of BS. METHODS: In study 1, we evaluated ECG alterations in BS patients with (VF+, n = 33) and without (VF-, n = 41) spontaneous VF. We defined type 0 ECG as coved type ST elevation without a negative T wave, which represents the existence of loss-of-dome (LOD) type action potentials (APs). In study 2, we optically mapped epicardial APs and recorded transmural ECGs in 34 canine right ventricular tissues with a drug-induced BS model by a combination of pinacidil and pilsicainide. RESULTS: In study 1, changes in ST level >=0.2 mV were more frequent in the VF+ group than in the VF- group (P <.01). Spontaneous ECG alterations and appearances of types 1 and 0 ECGs were more frequent in the VF+ group than in the VF- group (P <.01). In study 2, BS model with spike-and-dome (SAD) epicardial APs exhibited type 1 ECG. Deepening of the phase 1 notch of the APs induced heterogeneous conversion of the APs (SAD->LOD) and resulted in ECG conversion from type 1 to type 0. Significant AP heterogeneity often appeared during AP alterations and initiated phase 2 reentry. Tissues having ventricular tachycardia (VT; n = 20) had more frequent alterations in APs and ECG than in tissues without VT (n = 14; P <.01). CONCLUSION: ECG alterations, especially conversion between types 0 and 1, are associated with significant AP heterogeneity that can initiate VF in BS. PMID- 21315839 TI - Prevalence and characteristics of asymptomatic excessive transmural injury after radiofrequency catheter ablation of atrial fibrillation. AB - BACKGROUND: Even with a low energy setting, radiofrequency energy applications on the left atrial (LA) posterior wall may cause excessive transmural injury (ETI) during catheter ablation of atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to clarify the prevalence and characteristics of ETI. METHODS: This study included 104 patients with AF who underwent extensive encircling pulmonary vein isolation (EEPVI) followed by an endoscopic examination (<=48 hours after EEPVI). EEPVI was performed under conscious sedation, and the ablation settings at the LA posterior wall were a maximum energy of 20 to 25 W and duration of <=30 seconds. The ETI was defined as any injury that resulted from EEPVI, including esophageal damage or periesophageal nerve injury. RESULTS: ETIs were found in 10 (9.6%) patients and were all asymptomatic; esophageal damage in 4 patients and periesophageal nerve injury in the remaining 6. All patients with ETI were below normal weight (body mass index [BMI] < 24.9 kg/m(2)), and consisted of 17% of those below normal weight. The procedural parameters such as the type of energy source, total duration of energy applications to the LA posterior wall, additional LA linear ablation, and biochemical markers were not related to the ETI. In the logistic multiadjusted model, the BMI (per 1 kg/m(2)) was the only independent predictor of ETI (odds ratio = 0.76; 95% confidence interval = 0.59 to 0.97, P < .05). CONCLUSION: Asymptomatic ETIs were not rare even with a low energy setting in patients below normal weight. Tailored energy settings based on the patient's BMI may be required when performing EEPVI. PMID- 21315840 TI - Extraction of transvenous leads in the operating room versus electrophysiology laboratory: a comparative study. AB - BACKGROUND: Although risks and life-threatening complications associated with lead extraction are well characterized, practice patterns vary regarding whether procedures are performed in an operating room (OR) or electrophysiology (EP) laboratory with cardiothoracic surgical backup. OBJECTIVE: Our objective was to compare procedural outcomes and complications associated with lead extraction in the OR vs. EP laboratory. METHODS: Prospectively acquired data were pooled from 2 referral centers. Lead extraction procedures were performed between 2000 and 2010, encompassing a transition phase from the OR to EP laboratory. Analyses were conducted using generalized estimating equations. RESULTS: A total of 1,364 leads (533 OR; 831 EP laboratory) were targeted in 684 consecutive procedures, 41.2% of which were in the OR. Laser sheaths and snares were used for 699 (51.2%) and 101 (7.4%) leads, respectively. Overall, 775 (93.1%) vs. 487 (91.4%) leads were completely extracted in the EP laboratory vs. OR [odds ratio 1.3, 95% confidence interval 0.9 to 2.1]. Complications occurred in 2.24% vs. 2.84%, respectively (P = .431). Two patients died because of superior vena caval lacerations (0.29%), 1 in each group. Rapid surgical intervention was helpful in 6 (0.9%) patients [4 OR (2 subclavian vein lacerations, 1 tricuspid valve laceration, 1 tamponade); 2 EP laboratory (tamponades)], with subsequently favorable outcomes. The only independent predictor of complications was older lead age [odds ratio 1.11 per year, 95% confidence interval 1.02 to 1.20]. CONCLUSION: Lead extraction in the EP laboratory with surgical backup is associated with a similarly low rate of complications and mortality as procedures performed in the OR. PMID- 21315841 TI - Temporal stability of defibrillation thresholds with cardiac resynchronization therapy. AB - BACKGROUND: Defibrillation thresholds (DFTs) are typically stable over time among patients with implantable cardioverter-defibrillators (ICDs). However, the impact of cardiac resynchronization therapy (CRT) on DFTs has not been studied systematically. OBJECTIVE: This study prospectively evaluated the effect of CRT and left ventricular (LV) chamber reverse remodeling on DFTs. METHODS: This prospective, multicenter study evaluated 54 cardiac resynchronization therapy defibrillator (CRT-D) patients. Echocardiography and DFTs were performed both at implantation and at 6 months after implantation. All patients received dual-coil leads and a CRT-D pulse generator. DFTs were measured using a binary search method and tuned biphasic waveforms, where the shock pulse widths were determined by the measured shock impedance. Echocardiograms were analyzed by an independent core laboratory with a responder defined as a decrease of left ventricular end systolic volume >15%. RESULTS: The study cohort was 74% male, with a mean age of 68.7 +/- 10.9 years. The baseline ejection fraction was 0.245 +/- 0.076, and the mean New York Heart Association class was 2.9 +/- 0.4. In CRT responders (n = 32) the mean DFT was 415.6 +/- 108.1 V at implantation vs. 415.6 +/- 124.7 V at 6 months (P = .9), and in nonresponders (n = 19) the mean DFT was 452.6 +/- 102 V at implantation vs. 447.4 +/- 112.4 V at 6 months (P = .8). There was no significant change in DFT peak voltage, delivered energy, or shock impedance over time. CONCLUSION: DFTs were unchanged at 6 months in CRT patients with or without LV chamber reverse remodeling. PMID- 21315842 TI - Wide complex tachycardia: an unusual presentation. PMID- 21315843 TI - Phrenic nerve monitoring with diaphragmatic electromyography during cryoballoon ablation for atrial fibrillation: the first human application. PMID- 21315844 TI - T-wave morphology abnormalities in benign, potent, and arrhythmogenic I(kr) inhibition. AB - BACKGROUND: There is a consensus on the limited value of the QTc interval prolongation as a surrogate marker of drug cardiotoxicity and as a risk stratifier in inherited long QT syndrome (LQTS) patients. OBJECTIVE: We investigated the interest of repolarization morphology in the acquired and the inherited LQTS. METHODS: We analyzed 2 retrospective electrocardiographic (ECG) datasets from healthy on/off moxifloxacin and from genotyped KCNH2 patients. We measured QT, RR, and T-peak to T-end intervals, early repolarization duration (ERD) and late repolarization duration, T-roundness, T-amplitude, left (alphaL) and right slopes of T-waves. We designed multivariate logistic models to predict the presence of the KCNH2 mutation or moxifloxacin while adjusting for the level of QTc prolongation and the level of heart rate in LQT2 patients. Independent learning and validation sets were used. A list of 4,874 ECGs from 411 healthy individuals, 293 from 143 LQT2 carriers and 150 noncarrier family members were analyzed. RESULTS: In the moxifloxacin model, ERD was associated with the presence of the drug (odds ratio = 1.15 per ms increase, confidence interval 1.04 to 1.26, P = .0001) after adjustment for QTc. The model for the LQT2 revealed that left slope was associated with the presence of the KCNH2 mutation (odds ratio = 0.38 per 1.5 MUV/ms decrease, confidence interval 0.23 to 0.64, P = .0002). Only T-roundness complemented QTc in the model investigating cardiac events in LQT2. CONCLUSIONS: These observations demonstrate that the phenotypic expression of KCNH2 mutations and the effect of IKr-inhibitory drug on the surface electrocardiogram are specific. Future research should investigate whether this phenomenon is linked to different level/form of loss functions of Ikr channels, and whether they could result in different arrhythmogenic mechanisms. PMID- 21315845 TI - Interventricular dyssynchrony due to unilateral atrioventricular conduction block in a patient with right atrial isomerism and twin atrioventricular nodes. PMID- 21315846 TI - Arrhythmia characterization and long-term outcomes in catecholaminergic polymorphic ventricular tachycardia. AB - BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by adrenergically induced ventricular tachycardia (VT) associated with syncope and sudden death. OBJECTIVE: This study sought to characterize arrhythmias associated with CPVT with respect to provocation by exercise and drugs, electrocardiographic characteristics, and association with long-term outcomes; and to explore the relation between age and clinical presentation. METHODS: Seventy patients from 16 families were evaluated with exercise and selective adrenaline challenge, and screened for RyR2 mutations. CPVT was diagnosed in probands with symptoms and stress- or adrenaline-provoked VT, or in asymptomatic relatives with provoked VT or RyR2 mutations. Patients were followed up for recurrent syncope, VT, and sudden death. RESULTS: Twenty-seven patients including 16 probands were identified (median age 35 years, 67% female). Presentation was cardiac arrest in 33% and syncope in 56%, and 11% were asymptomatic. Polymorphic or bidirectional VT was provoked with exercise in 63% and adrenaline in 82%. The initiating beat of VT was late-coupled and wide (coupling interval 418 +/- 42 ms; QRSd 131 +/- 17 ms), and QRS morphology suggested an outflow tract origin in 59%. During follow-up of 6.2 +/- 5.7 years, 2 patients died despite an implantable cardioverter-defibrillator (ICD), 4 patients received ICD therapy for VT, and 5 patients had inappropriate therapy for supraventricular tachycardia. Patients presenting with late-onset CPVT (age > 21; n = 10) were often female (80%) and less likely to have RyR2 (Ryanodine receptor type 2) mutations (33%), and fatal events were not observed during follow-up (4.1 +/- 3.6 years). CONCLUSION: Ventricular arrhythmia in CPVT is often initiated from the outflow tract region. Despite beta-blocker therapy and selective ICD implantation, breakthrough arrhythmias occur and may be associated with adverse outcomes. PMID- 21315847 TI - The biatrial substrate properties in different types of paroxysmal atrial fibrillation. AB - BACKGROUND: The biatrial substrate properties in patients with paroxysmal atrial fibrillation (AF) originating from the pulmonary veins (PVs) and superior vena cava (SVC) are not available. OBJECTIVE: The purpose of this study is to characterize the differences of biatrial substrate properties in patients with different types of AF. METHODS: A total of 36 patients with paroxysmal AF originating from the PV (PV-AF) and 9 patients with paroxysmal AF initiating from the SVC (SVC-AF) were included. Regional electrogram voltage, conduction velocity (CV), and spectral analysis to identify the AF nest were performed to characterize the biatrial, PVs, and SVC substrate. RESULTS: In the left atrial (LA) body, the bipolar voltage, total activation time, CV, and dominant frequency (DF) were similar between the PV-AF and SVC-AF. However, in the PV regions, the electrogram voltage, CV, and DF were decreased in the PV-AF. The proportions of AF nest in the LA body (72.2% vs. 22.2%, P = .008) and PV regions (100% vs. 22.2%, P <.001) were higher in PV-AF compared with SVC-AF, respectively. On the other hand, lower bipolar voltage, longer total activation time, and slower CV of RA body were recognized in the SVC-AF as compared with the PV-AF. In the SVC, lower bipolar voltage, slower CV, higher DF, and higher proportions of AF nest in SVC (16.7% vs. 66.7%, P = .002) were identified in SVC-AF. CONCLUSION: These most remodeled substrates in different types of paroxysmal AF indicated the importance of the atrial substrate in the vicinity of the arrhythmogenic thoracic veins. PMID- 21315848 TI - How dormant is Mycobacterium tuberculosis during latency? A study integrating genomics and molecular epidemiology. AB - Mycobacterium tuberculosis may survive for decades in the human body in a state termed latent tuberculosis infection (LTBI). We investigated the occurrence during LTBI of insertion/deletion events in a selected set of mononucleotide simple sequence repeats, DNA sequence changes in four M. tuberculosis genes, and large sequence variations in 4750 M. tuberculosis open reading frames. We studied 13 paired M. tuberculosis clinical isolates, with each pair representing a reactivation of LTBI more than three decades after primary infection. Absence of sequence variations between paired isolates in nearly all investigated loci suggests a low likelihood of bacterial replication during LTBI. PMID- 21315850 TI - Impaired migration and cell volume regulation in aquaporin 5-deficient SPC-A1 cells. AB - BACKGROUND: Aquaporin 5 (AQP5) is widely expressed in various organ and tissues. In light of the novel oncogenic properties of aquaporins (AQPs), here we investigated the effect of AQP5 knockdown by RNAi on transmembrane osmotic water permeability, cell migration potential and cell volume regulation ability. METHODS: AQP5 expression was inhibited by short hairpin RNA in SPC-A1 cells, a lung adenocarcinoma cell line. Cells loaded with a fluoroprobe (calcein-AM) were immersed in either isosmotic, hyperosmotic or hyposmotic solutions, and fluorescence intensity was recorded using confocal microscopy. These measurements were used to calculate osmotic water permeability coefficients (Pf) and to monitor regulated volume decrease (RVD). Tumor cell migration and invasion assays were performed in a modified Boyden chamber. Wound healing and colony forming ability were also tested. RESULTS: Although self-quenching was not found in SPC A1 cells, we observed a linear relationship between fluorescence intensity and cell water volume, suggesting that this method is a sensitive and reproducible way to measure single-cell transmembrane water permeability. Cells in which the AQP5 gene was silenced showed a 49.4% decrease in osmotic water permeability, a 55.3% decrease in migration and a 28.4% decrease in invasion potential. In addition, RVD decreased remarkably with reduced osmotic water permeability. CONCLUSION: Our results suggest that AQP5, which mediates water permeability and thus regulates cell shape and volume, is a potentially important determinant in cell migration. PMID- 21315849 TI - The benzodiazepine Midazolam mitigates the breathing defects of Mecp2-deficient mice. AB - Rett syndrome is a severe neurodevelopmental disease caused by mutations of the transcriptional repressor methyl-CpG-binding protein 2 (MeCP2) that induce complex, disabling symptoms, including breathing symptoms. Males of Mecp2 deficient mice (Mecp2(-/y)) normally breathe at birth but develop first altered breathing regulations, thereafter erratic breathing with severe apnoeas, aggravating until respiratory distress and premature death. Mecp2(-/y) mice also develop early GABA deficits. To examine whether GABA deficits contributed to breathing defects of Mecp2(-/y) mice, mice were subjected to acute administration of Midazolam, a benzodiazepine of clinical use known to enhance GABA effects. For the first time, we showed that Midazolam abolished, although transiently, the breathing defects of Mecp2(-/y) mice, confirming a crucial role of GABA deficits in their breathing defects. PMID- 21315851 TI - N-linked glycosylation of G. mellonella juvenile hormone binding protein - comparison of recombinant mutants expressed in P. pastoris cells with native protein. AB - Juvenile hormone (JH) regulates insect growth and development. JH present in the hemolymph is bound to juvenile hormone binding protein (hJHBP) which protects JH from degradation. In G. mellonella, this protein is glycosylated only at one (Asn(94)) of the two potential N-linked glycosylation sites (Asn(4) and Asn(94)). To investigate the function of glycosylation, each of the two potential glycosylation sites in the rJHBP molecule was examined by site-directed mutagenesis. MS analysis revealed that rJHBP overexpressed in the P. pastoris system may appear in a non-glycosylated as well as in a glycosylated form at both sites. We found that mutation at position Asn(94) reduces the level of protein secretion whereas mutation at the Asn(4) site has no effect on protein secretion. Purified rJHBP and its mutated forms (N4W and N94A) have the same JH binding activities similar to that of hJHBP. However, both mutants devoid of the carbohydrate chain are more susceptible to thermal inactivation. It is concluded that glycosylation of JHBP molecule is important for its thermal stability and secretion although it is not required for JH binding activity. PMID- 21315853 TI - Mechanistic enzymology of serine palmitoyltransferase. AB - Serine palmitoyltransferase, which is one of the alpha-oxamine synthase family enzymes, catalyzes the condensation reaction of L-serine and palmitoyl-CoA to form 3-ketodihydrosphingosine, the first and rate-determining step of the sphingolipid biosynthesis. As with other alpha-oxamine synthase family enzymes, the catalytic reaction is composed of multiple elementary steps, and the mechanism to control these steps to avoid side reactions has been the subject of intensive research in recent years. Combined spectroscopic, kinetic, and structural studies have revealed the finely controlled stereochemical mechanism, in which the His residue conserved among the alpha-oxamine synthase family enzymes plays a central and critical role. This article is part of a Special Issue entitled: Pyridoxal Phosphate Enzymology. PMID- 21315852 TI - Mechanisms and structures of vitamin B(6)-dependent enzymes involved in deoxy sugar biosynthesis. AB - PLP is well-regarded for its role as a coenzyme in a number of diverse enzymatic reactions. Transamination, deoxygenation, and aldol reactions mediated by PLP dependent enzymes enliven and enrich deoxy sugar biosynthesis, endowing these compounds with unique structures and contributing to their roles as determinants of biological activity in many natural products. The importance of deoxy aminosugars in natural product biosynthesis has spurred several recent structural investigations of sugar aminotransferases. The structure of a PMP-dependent enzyme catalyzing the C-3 deoxygenation reaction in the biosynthesis of ascarylose was also determined. These studies, and the crystal structures they have provided, offer a wealth of new insights regarding the enzymology of PLP/PMP dependent enzymes in deoxy sugar biosynthesis. In this review, we consider these recent achievements in the structural biology of deoxy sugar biosynthetic enzymes and the important implications they hold for understanding enzyme catalysis and natural product biosynthesis in general. This article is part of a Special Issue entitled: Pyridoxal Phosphate Enzymology. PMID- 21315855 TI - Identification of novel rhoptry proteins in Neospora caninum by LC/MS-MS analysis of subcellular fractions. AB - Apicomplexan parasites possess an apical complex that is composed of two secretory organelles recognized as micronemes and rhoptries. Rhoptry contents are secreted into the parasitophorous vacuole during the host cell invasion process. Several rhoptry proteins have been identified in Toxoplasma gondii and seem to be involved in host-pathogen interactions and some of them are considered to be important virulence factors. Only one rhoptry protein, NcROP2, has been identified and extensively characterized in the closely related parasite Neospora caninum, and this has showed immunoprotective properties. Thus, with the aim of increasing knowledge of the rhoptry protein repertoire in N. caninum, a subcellular fractionation of tachyzoites was performed to obtain fractions enriched for this secretory organelle. 2-D SDS-PAGE followed by MS and LC/MS-MS were applied for fraction analysis and 8 potential novel rhoptry components (NcROP1, 5, 8, 30 and NcRON2, 3, 4, 8) and several kinases, proteases and phosphatases proteins were identified with a high homology to those previously found in T. gondii. Their existence in N. caninum tachyzoites suggests their involvement in similar events or pathways that occur in T. gondii. These novel proteins may be considered as targets that could be useful in the future development of immunoprophylactic measures. PMID- 21315854 TI - PLP-dependent H(2)S biogenesis. AB - The role of endogenously produced H(2)S in mediating varied physiological effects in mammals has spurred enormous recent interest in understanding its biology and in exploiting its pharmacological potential. In these early days in the field of H(2)S signaling, large gaps exist in our understanding of its biological targets, its mechanisms of action and the regulation of its biogenesis and its clearance. Two branches within the sulfur metabolic pathway contribute to H(2)S production: (i) the reverse transsulfuration pathway in which two pyridoxal 5'-phosphate dependent (PLP) enzymes, cystathionine beta-synthase and cystathionine gamma lyase convert homocysteine successively to cystathionine and cysteine and (ii) a branch of the cysteine catabolic pathway which converts cysteine to mercaptopyruvate via a PLP-dependent cysteine aminotransferase and subsequently, to mercaptopyruvate sulfur transferase-bound persulfide from which H(2)S can be liberated. In this review, we present an overview of the kinetics of the H(2)S generating reactions, compare the structures of the PLP-enzymes involved in its biogenesis and discuss strategies for their regulation. This article is part of a Special Issue entitled: Pyridoxal Phospate Enzymology. PMID- 21315856 TI - [Epidemiology of contact allergy in Europe: current situation and outlook for the future]. PMID- 21315857 TI - [Importance of epidemiologic surveillance in contact dermatitis: Spanish surveillance system on contact allergies]. AB - The high prevalence of contact dermatitis means that this common medical problem has considerable personal, societal, and economic impact. Clinical and epidemiologic research is needed if we are to shed light on the real situation of contact dermatitis in Spain. In this article we will look at epidemiologic research from a practical point of view and analyze the role of the dermatologist in planning and designing studies. The advantages of multicenter studies are discussed, along with the roles of national and international surveillance networks. We present the Spanish Surveillance System on Contact Allergies, which serves as a bridge between Spanish dermatologists and the European Surveillance System on Contact Allergies. The present and future aims of the Spanish network are described. PMID- 21315858 TI - [Salmon patch: a descriptive study]. AB - BACKGROUND AND OBJECTIVES: salmon patch is a congenital venous malformation that usually affects the midline. Although it is very common, few studies have analyzed its prevalence or predisposing factors. The aim of this study was to determine the prevalence and clinical characteristics of salmon patch in a group of newborn infants from a health care area in northwest Spain and to assess its association with neonatal and maternal variables. PATIENTS AND METHODS: a descriptive study was undertaken of live newborn children seen in the neonatal unit of the Department of Pediatrics at Hospital Arquitecto Marcide, Ferrol, Spain between May 1, 2008 and January 31, 2009. The study protocol included collection of data on neonatal variables (including gestational age, sex, ethnic origin, weight, and presence and anatomical site of salmon patch) and maternal variables (including age and number of previous pregnancies). RESULTS: of the 600 newborn infants included in the study, 59% had salmon patches. The most commonly affected sites were the nape of the neck (226 infants, 37.6%) and eyelids (211 infants, 35.1%). In a number of cases, more than one part of the body was affected. There was a higher prevalence of salmon patch in full-term or post-term births, in girls, white children, heavier children, and infants born to mothers aged between 30 and 34 years or who had not been pregnant previously. CONCLUSIONS: salmon patch occurred most frequently on the nape of the neck, the eyelids, and the glabella. Its prevalence was associated with certain neonatal and maternal factors. PMID- 21315860 TI - [Dermatology consultations in an emergency department prior to establishment of emergency dermatology cover]. AB - BACKGROUND AND OBJECTIVE: an increasing number of patients seek emergency treatment for dermatologic complaints. The aim of this study was to assess the characteristics of skin complaints seen in an emergency department prior to establishment of specialist dermatology cover. MATERIALS AND METHODS: a retrospective, descriptive study was undertaken using data on urgent dermatology cases seen by nonspecialist physicians in the emergency department of Hospital General Universitario de Albacete, Spain, in 2008. RESULTS: a total of 3662 patients with skin diseases were seen (2.59% of all emergency cases; approximately 10 patients per day). The mean age was 27.73 years and there was a slight predominance of female patients. Children and adolescents accounted for 5.85% of cases. A total of 96 different conditions were diagnosed and 84% of cases corresponded to one of 21 different diagnostic entities, urticaria being the most frequent (19.27%). The 96 diagnoses were grouped into 16 categories to facilitate analysis. According to this classification, most patients had infectious diseases (47.49%), followed by urticaria and angioedema (20.13%), "nonspecific diagnosis" (11.93%), and "descriptive diagnosis" (6.49%). In 4.8% of cases, the patient was admitted, most frequently for cellulitis. CONCLUSIONS: in nonspecialist emergency services, the number of different diagnoses is small in relation to the number of patients seen and the proportion of nonspecific and descriptive diagnoses is relatively large. In our opinion, an on-call dermatologist should be made available within emergency departments in order to offer a higher quality of care to patients with skin conditions. PMID- 21315861 TI - [Effectiveness of primary care physicians and dermatologists in the diagnosis of skin cancer: a comparative study in the same geographic area]. AB - BACKGROUND: skin cancer is the most common malignant tumor in white individuals. Early diagnosis and treatment are key factors in reducing morbidity. We performed a prospective observational study throughout 2008 to assess the ability of primary care physicians to diagnose nonmelanoma skin cancer. METHODS: the study was undertaken in a single geographic area corresponding to the region served by a primary health care center. Patients who were referred to a dermatologist were included if the primary care physician indicated skin cancer in the differential diagnosis on the referral form. Patients were also included if the dermatologist suspected skin cancer even if the referral from primary care had not indicated it. RESULTS: primary care physicians had a sensitivity of 0.45 and a specificity of 0.16 for the diagnosis of skin cancer, whereas dermatologists had a sensitivity of 0.97 and a specificity of 0.75. The alpha statistic as a measure of agreement was -0.56. CONCLUSIONS: The ability of primary care physicians to diagnose skin cancer was appreciably lower than that of dermatologists. This may result in substantial delays in the provision of appropriate care for patients with skin cancer considering the role played by primary care physicians in screening for the disease in the Spanish national health system. PMID- 21315862 TI - [Metastatic Basal cell carcinoma in the axilla: reconstruction with a lateral pectoral island flap]. AB - Although basal cell carcinoma (BCC) is one of the most common forms of cancer worldwide, it rarely occurs in the axilla. Only 31 cases have been reported in the literature. The incidence of metastatic BCC, particularly in areas not exposed to the sun, is very low. We present a new case of axillary BCC with lymph node metastases and the results of an extensive review of cases previously reported in the literature. BCC in the axilla is rare and metastasis is exceptional. Factors other than UV radiation probably contribute to its development. The lateral pectoral island flap was used for surgical closure. This method is useful for the reconstruction of axillary defects, obtaining excellent cosmetic and functional results. This flap should therefore be considered for the repair of large surgical defects in the axilla. PMID- 21315863 TI - [Non-follicular papules with a cobblestone appearance]. PMID- 21315859 TI - [Design and validation of a questionnaire to measure treatment satisfaction in patients with moderate-to-severe psoriasis: the NEODERMA study]. AB - BACKGROUND AND OBJECTIVES: the aim of this study was to design and assess the validity, reliability, and sensitivity to change of the Spanish Satisfaction With Treatment of Psoriasis Questionnaire (SSTPQ) for use in patients with moderate-to severe psoriasis. PATIENTS AND METHODS: a prospective, multicenter, observational, naturalistic study was designed. The instrument consisted of 12 items scored on a 5-point Likert scale with scores from 0 (very satisfied) to 5 (very unsatisfied), generating a total score of 0 to 48. Patients completed the questionnaire at baseline and then at 3-, 6-, 9-, and 12-month follow-up. At each visit, data were also collected on the Psoriasis Area and Severity Index (PASI), treatment adherence (Morisky-Green questionnaire), and overall treatment satisfaction on a Visual Analogue Scale (VAS) from 0 to 100. RESULTS: a total of 423 patients were included in the study and 68% completed 12 months of follow-up. Responses were provided to all items in 98.8% of cases. There was a weak correlation between changes in treatment satisfaction on the SSTPQ and changes in PASI score (r = 0.38 to 0.33); in contrast, there were strong correlations with changes in the VAS score for overall treatment satisfaction (r = -0.75 to -0.81). Good internal consistency was observed (Cronbach alpha = 0.92). The intraclass correlation coefficient was 0.89, with a mean difference in score at 3- and 6 month follow-up of 0.07. CONCLUSIONS: The results obtained suggest that the SSTPQ is a feasible, valid, and reliable tool for the assessment of treatment satisfaction in patients with moderate-to-severe psoriasis. PMID- 21315864 TI - [Ulcerated tumor of the lip]. PMID- 21315865 TI - [Non-sexually transmitted acute ulcer of the vulva associated with influenza A virus infection]. PMID- 21315866 TI - [Patch testing increases the likelihood of recognizing lamotrigine as a cause of drug-induced rash]. PMID- 21315867 TI - [Pregnancy-related erythema annulare centrifugum]. PMID- 21315868 TI - [Dermoscopic features of multinucleate cell angiohistiocytoma: a variant of dermatofibroma?]. PMID- 21315869 TI - [Keloid development on skin lesions after the application of a cream purchased over the internet]. PMID- 21315870 TI - [Granular parakeratosis: disease or reactive response?]. PMID- 21315871 TI - [Agave americana causing irritant contact dermatitis with a purpuric component]. PMID- 21315872 TI - [Carbon dioxide-laser treatment of trichoepitheliomas in Brooke-Spiegler syndrome]. PMID- 21315873 TI - Reduction of verbally learned fear in children: a comparison between positive information, imagery, and a control condition. AB - This study explored the effects of positive information and imagery as ways of reducing a verbally installed fear in children. Seventy-two primary school children aged 9-13 years were first exposed to negative information to induce fear of a novel animal, and were then randomly assigned to three interventions: positive information, imagery, or a control condition. Outcome of various interventions was assessed by means of a standardized scale of fear beliefs and an index of confirmation bias (defined as the tendency to search for threat information in relation to the feared stimulus). Results indicated that both positive information and imagery were more effective in reducing fear than the control condition. Some evidence was also obtained showing that positive information was more effective than imagery, which suggests that this intervention represents the most optimal treatment approach when dealing with verbally acquired fears in children. PMID- 21315874 TI - Schizotypy, self-referential thinking and the Barnum effect. AB - BACKGROUND AND OBJECTIVES: The tendency for people to endorse, as an accurate description of themselves, personality descriptions that are essentially bogus is well-attested. The study tested whether the so-called 'Barnum' effect could be predicted by individual differences in self-referential thinking, and beyond this, schizotypy more generally. METHODS: 130 Participants completed four different measures of the Barnum effect followed by measures of schizotypy and self-referential thinking. RESULTS: Both self-referential thinking and positive schizotypy independently predicted the degree of agreement with several Barnum measures including both favorable and unfavorable personality descriptions, as well as computer-generated and horoscope-based readings. LIMITATIONS: The sample is heavily represented by students and is not representative of the general population. Testing at a single point in time may have reduced differences between different indices of the Barnum effect. CONCLUSIONS: Self-referential thinking and schizotypy more generally are key contributors to the Barnum effect across a wide range of indices. PMID- 21315875 TI - Effect of a context of concrete and abstract words on hallucinatory content in individuals scoring high in schizotypy. AB - The present study examined the occurrence and content of auditory hallucinatory experiences in 41 non-clinical participants scoring high or low on the Oxford Liverpool Inventory of Feelings and Experiences (brief version; OLIFE-B) measure of schizotypy. Participants listened to 10 1-min recordings of white noise, some of which contained embedded concrete or abstract words, and were asked to record the words that they had heard. High scorers on the unusual experiences (UE) scale of the OLIFE-B reported hearing more words, not actually present, relative to low scorers on that measure. In addition, high UE scorers showed a bias toward making hallucinatory reports of an abstract type over a concrete type. These results suggest a bias toward more auditory hallucinatory reports in high scorers in schizotypy, and particularly to those of an abstract type. PMID- 21315876 TI - Behavioral theory of depression: reinforcement as a mediating variable between avoidance and depression. AB - Behavioral theory posits that certain environmental changes and avoidant behaviors inhibit individuals from experiencing environmental reward and reinforcement and subsequently leads to the development and maintenance of depressive symptoms. Using self-report and behavioral (daily diary) indices of environmental reward as proxy measures for positive reinforcement, this investigation examined whether environmental reward mediated the relationship between avoidance and depression. When controlling for anxiety, both indices of environmental reward significantly mediated the relationships of depression with cognitive, behavioral and total avoidance. Post-hoc mediation analyses were conducted to examine potential gender differences. Self-reported environmental reward significantly mediated the relationship between avoidance and depression across both genders. Among females, however, daily diary-measured reward only mediated the relation between cognitive avoidance and depression. In males daily diary reward was a mediator with all three forms of avoidance and depression. This investigation provides initial support for reinforcement as a significant mediator between avoidance and depression and further highlights the relevance of avoidance and reinforcement in behavioral conceptualizations of depression. PMID- 21315877 TI - Coping and experiential avoidance: unique or overlapping constructs? AB - The present study examined associations between coping as measured by the Brief COPE and experiential avoidance as measured by the AAQ-II and the role of both constructs in predicting psychological distress and well-being. Specifically, associations between experiential avoidance and other types of coping were examined, and factor analysis addressed the question of whether experiential avoidance is part of coping or a related but independent construct. Results showed that experiential avoidance loads on the same factor as other emotion focused and avoidant types of coping. The higher people are in experiential avoidance, the more they tend to utilize these types of coping strategies. Both experiential avoidance and coping predicted psychological distress and well being, with most variance explained by coping but some additional variance explained by experiential avoidance. ANOVAS also showed gender differences in experiential avoidance and coping approaches. Results are discussed in light of previous relevant findings and future treatment relevant implications. PMID- 21315878 TI - The relationship between the maladaptive self-beliefs characteristic of social anxiety and avoidance. AB - The Clark and Wells (1995) model of social phobia proposes that there are three types of maladaptive self-beliefs responsible for persistent social anxiety (high standard, conditional, and unconditional beliefs). Another prominent feature of social phobia is the avoidance of social-evaluative situations. To our knowledge, there have been no studies that have examined the relationship between these specific maladaptive self-belief types and avoidance. We hypothesised that while accounting for potential confounding variables (i.e., fear of negative evaluation and general symptomology), each of the three maladaptive self-belief types would be significantly and positively associated with cognitive and behavioural avoidance in the social domain, but not these forms of avoidance in the non social domain. In a sample of undergraduates (N = 361), we found only partial support for our hypotheses. In the social domain, stronger high standard beliefs predicted less behavioural avoidance, stronger unconditional beliefs predicted more behavioural avoidance, and stronger conditional beliefs predicted more cognitive avoidance. In the non-social domain, stronger unconditional beliefs predicted more cognitive avoidance. These relationships were obtained at all levels of social anxiety. Additionally, the unconditional beliefs partially mediated the relationship between social anxiety and behavioural avoidance in the social domain, and the conditional beliefs fully mediated the relationship between social anxiety and cognitive avoidance in the social domain. These results emphasise the distinct nature of each of the maladaptive self-belief types and the need to elucidate their relationship with other components in theoretical models of social phobia. PMID- 21315879 TI - One-session computer-based exposure treatment for spider-fearful individuals- efficacy of a minimal self-help intervention in a randomised controlled trial. AB - Computer-based self-help treatments have been proposed to provide greater access to treatment while requiring minimum input from a therapist. The authors employed a randomised controlled trial to investigate the efficacy of one-session computer based exposure (CBE) as a self-help treatment for spider-fearful individuals. Spider-fearful participants in a CBE group underwent one 27-min session of standardised exposure to nine fear-eliciting spider pictures. Treatment outcome was compared to spider-fearful control participants exposed to nine neutral pictures. Fear reduction was quantified on a subjective level by the Fear of Spiders Questionnaire (FSQ) and complemented with a behavioural approach test (BAT). Results demonstrate that compared to control participants, CBE participants showed greater fear reduction from pre- to posttreatment on both the subjective level (FSQ) and the behavioural level (BAT). Moreover, in contrast to the control group, the obtained subjective fear reduction effect remained stable in the CBE group at 1-month follow-up. These findings highlight the role of computer-based self-help as a minimal but effective intervention to reduce fear of spiders. PMID- 21315880 TI - When does jumping-to-conclusions reach its peak? The interaction of vulnerability and situation-characteristics in social reasoning. AB - BACKGROUND AND OBJECTIVES: Persons with delusions tend to display a jumping-to conclusions (JTC) bias which is considered relevant to delusion formation. However, its contribution in real life social scenarios is unknown. This study investigates whether JTC increases when decisions have to be made in delusion relevant situations and whether the increase is uniquely moderated by delusion proneness. METHODS: JTC was assessed by a social reasoning paradigm in 92 healthy participants that were classified as high, medium or low in paranoid ideation and social anxiety. Decisions had to be made for emotionally salient scenarios without direct self-relevance, self-relevant scenarios and delusion-relevant scenarios, by successively drawing pieces of information. RESULTS: All participants drew less information in the scenarios that were self-relevant and delusion-relevant compared to non-self-relevant scenarios. Participants with higher paranoid ideation generally drew less information than persons with medium or low levels of paranoid ideation. However, the hypothesized interaction of delusion-proneness and type of scenario was not significant. Social anxiety had no effect on draws to decision in any of the task types. LIMITATIONS: The description of social encounters in the task does still not capture the full perceptual experience in real life encounters. CONCLUSIONS: The data support the assumption that the formation of persecutory delusions might arise as a function of a delusion-specific JTC-bias in combination with a normal and functional tendency to collect less information in self-relevant situations. PMID- 21315881 TI - Evaluating implicit attractiveness beliefs in body dysmorphic disorder using the Go/No-go Association Task. AB - Cognitive-behavioral models of body dysmorphic disorder (BDD) suggest the disorder is characterized by exaggerated beliefs about the significance of appearance. However, previous studies assessing automatic associations regarding the importance of attractiveness failed to find any differences between individuals with BDD and healthy control participants using the Implicit Association Test (IAT; Greenwald, McGhee, & Schwartz, 1998). An open question is whether the BDD and control groups indeed implicitly evaluate attractiveness comparably, or whether methodological factors (e.g., the IAT design requirement of a relative comparison category for attractiveness) made it difficult to observe group differences. To address this question, we evaluated explicit and implicit attractiveness beliefs among individuals with BDD (n = 36), individuals with a dermatological condition (n = 36), and psychiatrically healthy control participants (n = 36) using the single target category Go/No-go Association Task (GNAT; Nosek, & Banaji, 2001). Indeed, BDD participants had significantly stronger implicit associations between attractive and important, relative to the other groups, whereas there was no difference between the dermatology and control groups. Further, the GNAT was effective at classifying individuals with BDD above and beyond the prediction offered by an explicit measure of attractiveness beliefs. The GNAT may be a useful tool for assessing implicit associations in clinical populations because it does not require an explicit comparison target category, which is a restriction of many implicit measures. PMID- 21315882 TI - The role of magical thinking in Obsessive-Compulsive Disorder symptoms and cognitions in an analogue sample. AB - BACKGROUND AND OBJECTIVES: In addition to clinical observations exemplifying biased reasoning styles (e.g., overemphasis of thoughts) and particular ritualistic behaviors, it is also empirically supported that magical beliefs are also associated with Obsessive-Compulsive Disorder (OCD) symptoms and some cognitions. It should be noted, however, that most empirical studies have been carried out on the samples from Western cultures, even though these beliefs were culturally determined. Thus, more research is needed in order to understand their roles in the OCD symptoms in different cultural contexts. The present study aimed to examine the impact of magical beliefs in OCD symptoms, cognitions and thought control in a non-Western analogue sample from Turkey. METHOD: The measures of paranormal beliefs, fusion of thoughts-actions, obsessive beliefs, strategies of thought control and OCD symptoms were administered to an undergraduate sample. RESULT: Consistent with findings in the literature, the analyses of group comparisons, correlation and regression showed that even after controlling general negative affect, magical beliefs were still associated with OCD symptoms, some beliefs and control strategies, namely the symptoms of obsessional thoughts and checking, fusions of thoughts and actions in likelihood, faulty beliefs in perfectionism-certainty and punishment. LIMITATIONS: Some methodological concerns such as cross-sectional nature, inclusion of only non-clinical sample were major restrictions of the present study. CONCLUSION: Evidence that magical thinking is a critical factor in the OCD is supported once more in a different cultural context. PMID- 21315883 TI - Absence of a positive bias in social anxiety: the application of a directed forgetting paradigm. AB - The present study used a directed forgetting paradigm to investigate whether socially anxious individuals show a memory bias for social information. Socially anxious and non-anxious participants viewed three types of words: socially negative, socially positive, and neutral. Each word was presented on a computer screen and was followed by a cue instructing participants to either remember or forget the word. A free recall test and a recognition test were then administered by asking participants to recall and recognize both "to-be-remembered" and "to-be forgotten" words. When compared to non-anxious participants, socially anxious participants showed a greater directed forgetting effect for socially positive words in the free recall test, indicating that socially anxious individuals more easily forget socially positive words than do non-anxious individuals. This result suggests that socially anxious individuals lack the positive bias (i.e., difficulty in forgetting socially positive information) displayed by non-anxious individuals. PMID- 21315884 TI - Effects of attention training on self-reported, implicit, physiological and behavioural measures of spider fear. AB - Cognitive theories hold that biased attention to threat plays a prominent role in the development and maintenance of anxiety disorders. In support of this view, attention training has been shown to affect emotional reactivity. An important limitation of most attention training studies is that they almost exclusively rely on self-report measures to assess changes in fear. In the present study, we trained attention towards or away from spiders. We assessed not only self reported spider fear, but also implicit spider associations, physiological, and behavioural measures of spider fear. Although we successfully changed the attentional processing of spiders, attention training had no effect on any of the outcome variables. These results indicate that changes in attentional bias are not necessarily associated with changes in fear, suggesting that attention training may be unsuitable as a clinical intervention for spider fear. PMID- 21315885 TI - Eye movement assessment in individuals with social phobia: differential usefulness for varying presentation times? AB - Visual dot probe tasks are used to examine attentional biases towards threat faces in social phobia. Based on eye movement assessments, short presentation times of stimuli have been proposed to investigate initial attentional processes. However, it remains unclear if eye movements contribute to anxiety related biases as measured in dot probe tasks when presentation times below 200 ms are used. In this study the electrooculogram (EOG) was recorded in a sample of 17 participants with social phobia and 13 controls performing a visual dot probe task in two presentation time conditions. In the 175 ms condition, half of the participants moved their eyes in only 10% of the trials. Significantly more participants moved their eyes in the 600 ms condition and individuals with social phobia directed their gaze more often to the threat faces than to the neutral faces. Eye movement measures were not related to reaction time measures but the number of initial eye movements towards threatening faces correlated with measures of social anxiety. For dot probe paradigms, the additional use of eye movement measures seems to be particularly appropriate for longer presentation times. The dissociation between attentional bias scores as measured with reaction time versus eye movement measures and their relation to different presentation times underlines the need for both measures when conducting visual probe studies. PMID- 21315886 TI - The Perseverative Thinking Questionnaire (PTQ): validation of a content independent measure of repetitive negative thinking. AB - Repetitive negative thinking (RNT) has been found to be involved in the maintenance of several types of emotional problems and has therefore been suggested to be a transdiagnostic process. However, existing measures of RNT typically focus on a particular disorder-specific content. In this article, the preliminary validation of a content-independent self-report questionnaire of RNT is presented. The 15-item Perseverative Thinking Questionnaire was evaluated in two studies (total N = 1832), comprising non-clinical as well as clinical participants. Results of confirmatory factor analyses across samples supported a second-order model with one higher-order factor representing RNT in general and three lower-order factors representing (1) the core characteristics of RNT (repetitiveness, intrusiveness, difficulties with disengagement), (2) perceived unproductiveness of RNT and (3) RNT capturing mental capacity. High internal consistencies and high re-test reliability were found for the total scale and all three subscales. The validity of the Perseverative Thinking Questionnaire was supported by substantial correlations with existing measures of RNT and associations with symptom levels and clinical diagnoses of depression and anxiety. Results suggest the usefulness of the new measure for research into RNT as a transdiagnostic process. PMID- 21315887 TI - Cognitive-evaluative features of childhood social anxiety in a performance task. AB - Using an experimental design, we analysed differences in the occurrence of cognitive-evaluative distortions and performance deficits across children with social anxiety disorder, with subclinical anxiety and without any anxiety symptoms. Twenty-one children with full syndrome social phobia, 18 children with partial syndrome social phobia and 20 children without any symptoms of social phobia were compared with respect to their degree of anxiety, negative thinking and task performance during two social-evaluative tasks. In addition, self ratings of task performance, performance estimations for other children and objective behavioural ratings by two independent observers were obtained. Children with social anxiety disorder and subclinical social anxiety showed higher degrees of experienced anxiety and negative thinking than healthy control children. There was no group difference in respect to actual task performance. Findings are discussed with regard to the continuum assumption of childhood social anxiety disorder and the need of well-adapted early interventions. PMID- 21315888 TI - Odors eliciting fear: a conditioning approach to Idiopathic Environmental Intolerances. AB - Patients suffering from Idiopathic Environmental Intolerances (IEI) report health symptoms, referable to multiple organ systems, which are triggered by harmless odors and therefore medically unexplainable. In line with previous research that predominantly points towards psychological explanations, the present study tests the hypothesis that IEI symptoms result from learning via classical conditioning of odors to fear. A differential conditioning paradigm was employed. Hedonically different odors were compared on ease of fear acquisition. Conditioned stimuli (CSs) were Dimethyl Sulfide (unpleasant) and peach (pleasant). The unconditioned stimulus (US) was an electrical shock. During acquisition one odor (CS+) was followed by shock, while the other odor (CS-) was not. Next, fear extinction was tested by presenting both CS+ and CS- without US. Electrodermal response, odor evaluation, and sniffing behavior were monitored. Results showed successful fear conditioning irrespective of hedonic character as evidenced by electrodermal response. Acquired fear did not extinguish. There was no evidence of evaluative conditioning taking place, as CS evaluation did not change during fear acquisition. Early avoidance of the CS+, as deduced from odor inhalation measures, was demonstrated, but did not sustain during the entire acquisition phase. This study suggests that a fear conditioning account of IEI is only partially satisfactory. PMID- 21315889 TI - A new disposable ionic liquid based coating for headspace solid-phase microextraction of methyl tert-butyl ether in a gasoline sample followed by gas chromatography-flame ionization detection. AB - A new ionic liquid (IL) based solid-phase microextraction (SPME) fiber was investigated and used for headspace (HS) extraction of methyl tert-butyl ether (MTBE) in a gasoline sample. Using the new IL coated HS-SPME fiber with the combination of gas chromatography-flame ionization detection (GC-FID); sub-to-low MUg L(-1) concentrations of MTBE were detected. Four different ILs including 1 butyl-3-methylimidazolium tetraflouroborate ([C(4)C(1)IM] [BF(4)]), 1-octyl-3 methylimidazolium tetraflouroborate ([C(8)C(1)IM] [BF(4)]), 1-octyl-3 methylimidazolium hexaflourophosphate ([C(8)C(1)IM] [PF(6)]) and 1-ethyl-3 methylimidazolium ethylsulphate ([C(2)C(1)IM] [ETSO(4)]) were synthesized and examined for extraction, preconcentration and determination of MTBE. It was observed that [C(8)C(1)IM] [BF(4)] showed the highest extraction efficiency and possessed the best extractability for MTBE. The fiber coating takes up the compounds from the sample by absorption in the case of liquid coatings. The calibration graph was linear in a concentration range of 1-120 MUg L(-1) (R(2)>0.994) with the detection limit of 0.09 MUg L(-1) level. The new IL-coated fiber was applied successfully for the determination of MTBE in a gasoline sample with good recoveries between 90 and 95%. PMID- 21315890 TI - A sensitive, rapid and inexpensive way to assay pesticide toxicity based on electrochemical biosensor. AB - We reported a rapid toxicity assay method using electrochemical biosensor for pesticides, Escherichia coli (E. coli) was taken as a model microorganism for test. In this method, we adopted ferricyanide instead of natural electron acceptor O(2), and then microbial oxidation was substantially accelerated. Toxicity assays measured the effect of toxic materials on the metabolic activity of microorganisms. The current signal of ferrocyanide produced from the metabolism was proven to be directly related to the toxicity, which could be amplified by ultramicroelectrode array (UMEA). The ratio of the electrochemical signals, recorded in the presence and absence of toxin, provided an index of inhibition. Accordingly, a direct toxicity assessment (DTA) based on chronoamperometry was proposed to detect the effect of toxic chemicals on microorganisms. 3,5-Dichlorophenol (DCP) was taken as the reference toxicant, its IC50 was estimated to be 8.0mg/L. Three pesticides were examined using this method. IC50 values of 6.5mg/L for Ametryn, 22 mg/L for Fenamiphos and 5.7 mg/L for Endosulfan were determined and in line with EC50 values reported in the literature. Atomic force microscopy (AFM) was also used for morphology characterization of E. coli induced by three pesticides. These results confirmed the present electrochemical method used is reliable. In addition, the electrochemical method is a sensitive, rapid and inexpensive way for toxicity assays of pesticides. PMID- 21315891 TI - Adaptive variable-weighted support vector machine as optimized by particle swarm optimization algorithm with application of QSAR studies. AB - Representing a compound by a numerous structural descriptors becomes common in quantitative structure-activity relationship (QSAR) studies. As every descriptor carries molecular structure information more or less, it seems more advisable to investigate all the possible descriptor vectors rather than traditional variable selection when building a QSAR model. Based on particle swarm optimization (PSO) algorithm, a more flexible descriptor selection and model construction method variable-weighted support vector machine (VW-SVM) is proposed. The new strategy adopted in this paper is to weight all structural descriptors with continuous non negative values rather than removing or reserving any ones arbitrarily. The manner of invoking PSO to seek non-negative weights of variables can be regarded as a process of searching optimized rescaling for every molecular structural descriptor. Moreover, PSO is employed to search the optimal parameters of VW-SVM model besides variable weights, enables the construction of a rational and adaptive parameter-free QSAR model according to the performance of the total model. Results obtained by investigating glycogen synthase kinase-3alpha inhibitors and carbonic anhydrase II inhibitors indicate VW-SVM can hold more useful structure information of compounds than other methods as optimally weighting all the descriptors, consequently leading to precisely QSAR models coupled with developed performance both in training and in prediction. PMID- 21315892 TI - A simple and sensitive LC-ESI-MS (ion trap) method for the determination of bupropion and its major metabolite, hydroxybupropion in rat plasma and brain microdialysates. AB - A specific and highly sensitive liquid chromatography-electrospray mass spectrometry (LC-ESI-MS) method for the direct determination of bupropion (BUP) and its main metabolite hydroxybupropion (HBUP) in rat plasma and brain microdialysate has been developed and validated. The analysis was performed on a Bonus RP C18 (100 mm * 2.1mm i.d., 3.5 MUm particles) column using gradient elution with the mobile phase consisting of acetonitrile and ammonium formate buffer (10mM, pH 4). Plasma samples were analyzed after a simple, one-step protein precipitation clean-up with trichloroacetic acid (TCA), however clean-up for microdialysis samples was not necessary, enabling direct injection of the samples into the LC-ESI-MS system. Signals of the compounds were monitored under the multiple reaction monitoring (MRM) mode of the LC-ESI-MS (ion trap) for quantification. The precursor to product ion transitions of m/z 240-184 and m/z 256-238 were used to measure BUP and HBUP, respectively. The method was validated in both plasma and microdialysate samples, and the obtained lower limit of quantification (LLOQ) was 1.5 ng mL(-1) for BUP and HBUP in both matrices. The intra- and inter-day assay variability was less than 15% for both analytes. This LC-ESI-MS method provided simple sampling, rapid clean-up and short analysis time (<9 min), applicable to the routine therapeutic monitoring and pharmacokinetic studies of BUP and HBUP. PMID- 21315893 TI - Determination of melamine in different milk batches using a novel chemosensor based on the luminescence quenching of Ru(II) carbonyl complex. AB - A novel, simple, sensitive and precise spectrofluorimetric method was developed for measuring the melamine concentration in different milk batch samples. The method was based upon measuring the quenching of the luminescence intensity of the produced yellow colored ruthenium((II)) carbonyl complex of the general formula [Ru(CO)(2)(L)] (where L=anion of tetradentate Schiff base). The Ru((II)) complex exhibited characteristic luminescence band in the visible region. The remarkable quenching of the luminescence intensity of [Ru(CO)(2)(L)] complex by various concentrations of melamine was successfully used as a chemosensor for the assessment of melamine in different milk samples at lambda(ex)=400 nm and pH 7.4 in DMSO with a linear dynamic range 1.0 * 10(-6) to 3.0 * 10(-9) mol L(-1) and lower detection limit (LOD) and quantification detection limit (QOD) of 3.3 * 10( 10) and 1.0 * 10(-9) mol L(-1), respectively. PMID- 21315894 TI - Construction of a new Cu2+ coated wire ion selective electrode based on 2-((2-(2 (2-(2-hydroxy-5-methoxybenzylidene amino)phenyl)disufanyl)phenylimino)methyl)-4 methoxyphenol Schiff base. AB - In this article a new coated platinum Cu(2+) ion selective electrode based on 2 ((2-(2-(2-(2-hydroxy-5-methoxybenzylideneamino)phenyl)disufanyl)phenylimino) methyl)-4-methoxyphenol Schiff base (L(1)) as a new ionophore is described. This sensor has a wide linear range of concentration (1.2 * 10(-7)-1.0 * 10(-1) mol L( 1)) and a low detection limit of 9.8 * 10(-8) mol L(-1)of Cu(NO(3))(2). It has a Nernstian response with slope of 29.54 +/- 1.62 mV decade(-1) and it is applicable in the pH range of 4.0-6.0 without any divergence in potential. The coated electrode has a short response time of approximately 9s and is stable at least for 3.5 months. The electrode shows a good selectivity for Cu(2+) ion toward a wide variety of metal ions. The proposed sensor was successfully applied for the determination of Cu(2+) ion in different real and environmental samples and as indicator electrode for potentiometric titration of Cu(2+) ion with EDTA. PMID- 21315895 TI - Application of a low impedance contactless conductometric detector for the determination of inorganic cations in capillary monolithic column chromatography. AB - Poly(glycidyl methacrylate) cation exchange monolithic column was prepared in fused-silica capillaries of 320 MUm i.d. by thermally initiated radical polymerization and utilized in capillary ion chromatography. With 15 mM methanesulfonic acid as the mobile phase, the separations of a mixture of inorganic cations (Li(+), Na(+), NH(4)(+), K(+)) was tested by using a capacitively coupled contactless conductivity detector (C(4)D) and a low impedance C(4)D (LIC(4)D). The LIC(4)D is the series combination of a C(4)D and a quartz crystal resonator. At the resonant frequency of the series combination, the capacitor impedance from capillary wall was offset by the inductance impedance from the quartz crystal resonator. A minimum impedance was obtained in the impedance-frequency curve of the combination. The responses of the C(4)D and LIC(4)D were analyzed based on an equivalent circuit model. It was shown that the sensitivity of the C(4)D to the change in analyte concentration is rather poor due to the high ratio of the impedance from the capillary wall capacitor to the solution impedance. The LIC(4)D has the similar sensitivity as a contact conductivity detector but a much smaller cell volume. The on-column detection model was realized by LiC(4)D without preparation of optical detection window in monolithic column. PMID- 21315896 TI - Application of cement as new electrode material and solid-phase microextraction material demonstrated by electrochemiluminescent detection of perphenazine. AB - Because of its unique pore network, good strength, and low cost, cement was used as a new electrode material and solid-phase microextraction (SPME) material for the first time. It was mixed with carbon to make a new electrode, cement carbon electrode (CCE). The as-prepared CCE was used to demonstrate the application of cement in SPME by Ru(bpy)(3)(2+) electrochemiluminescent detection of perphenazine (PPZ). The calibration plot for PPZ is linear from 1.0 * 10(-9) to 3.0 * 10(-6)M with a detection limit of 3.1 * 10(-10)M. The method was successfully applied to the detection of PPZ in urine sample. Cement-based electrode material may also find broad applications in electrochemistry industry, such as electrochemical wastewater treatment. PMID- 21315897 TI - A hybrid mesoporous material functionalized by 1,8-naphthalimide-base receptor and the application as chemosensor and absorbent for Hg2+ in water. AB - A novel hybrid material (SBA-P1) is prepared through the functionalization of mesoporous silica (SBA-15) with a 1,8-naphthalimide-based dye by sol-gel reaction. The characterization results of elemental analysis (EA), X-ray powder diffractometer (XRD) and spectroscopic methods demonstrate the fluorescence dye P1 is successfully grafted onto the inner surface of SBA-15 and the organized structure is preserved. SBA-P1 can detect Hg(2+) with high selectivity to Cu(2+), Zn(2+), Cd(2+), Pb(2+), Mn(2+), Ni(2+), Co(2+), Ag(+), Cr(3+), and Mg(2+), Ca(2+), Li(+), Na(+), K(+) in water and sensitivity to environmentally relevant mercury in complex natural samples. The quenching fluorescence detection is also reversible by treating with EDTA/base. Furthermore, its fluorescence intensity keeps stable in the physiologically relevant pH range. The extraction ability of SBA-P1 is also estimated by inductively coupled plasma source mass spectrometer (ICP), showing that approximately 90% of the Hg(2+) ion is extracted. These results imply that the hybrid material has potential application for sensing and removing of Hg(2+) ions in waste water and working as toxicide for acute mercury poisoning. PMID- 21315898 TI - Cyclodextrin-graphene hybrid nanosheets as enhanced sensing platform for ultrasensitive determination of carbendazim. AB - In this paper, cyclodextrin-graphene hybrid nanosheets (CD-GNs) for the first time have been used as an enhanced material for ultrasensitive detection of carbendazim by electrochemistry method. The peak currents of carbendazim on the GNs modified glassy carbon electrode (GNs/GCE) and the CD-GNs/GCE are increased by 11.7 and 82.0 folds compared to the bare GCE, respectively. This indicates the nanocomposite film not only shows the excellent electrical properties of GNs but also exhibits high supramolecular recognition capability of CDs. At the CD GNs/GCE, the peak currents increase linearly with the concentration of carbendazim in the range of 5 nM-0.45 MUM. The detection limit of carbendazim reached to 2 nM on the basis of the signal-to-noise characteristics (S/N=3) and the recoveries were between 98.9% and 104.5%. The developed electrochemical sensor exhibited good stability and reproducibility for the detection of carbendazim. And the CD-GNs based electrochemical sensor was also successfully demonstrated for the detection of carbendazim in water sample with satisfactory results. Furthermore, this simple sensing platform can in principle be extended to the detection of other benzimidazole fungicide which can form host-guest complexes with cyclodextrin. PMID- 21315899 TI - Dual optical sensor for oxygen and temperature based on the combination of time domain and frequency domain techniques. AB - In measuring specific conditions in the real world, there are many situations where both the oxygen concentration and the temperature have to be determined simultaneously. Here we describe a dual optical sensor for oxygen and temperature that can be adapted for different applications. The measurement principle of this sensor is based on the luminescence decay times of the oxygen-sensitive ruthenium complex tris-4,7-diphenyl-1,10-phenanthroline ruthenium(III) [Rudpp] and the temperature-sensitive europium complex tris(dibenzoylmethane) mono(5-amino-1,10 phenanthroline)europium(III) [Eudatp]. The excitation and emission spectra of the two luminophores overlap significantly and cannot be discriminated in the conventional way using band pass filters or other optical components. However, by applying both the frequency and time domain techniques, we can separate the signals from the individual decay time of the complexes. The europium complex is entrapped in a poly(methyl methacrylate) (PMMA) layer and the ruthenium complex is physically adsorbed on silica gel and incorporated in a silicone layer. The two layers are attached to each other by a double sided silicone based tape. The europium sensing film was found to be temperature-sensitive between 10 and 70 degrees C and the ruthenium oxygen-sensitive layer can reliably measure between 0 and 21% oxygen. PMID- 21315900 TI - Amperometric hydrogen peroxide biosensor based on the immobilization of heme proteins on gold nanoparticles-bacteria cellulose nanofibers nanocomposite. AB - A novel matrix, gold nanoparticles-bacterial cellulose nanofibers (Au-BC) nanocomposite was developed for enzyme immobilization and biosensor fabrication due to its unique properties such as satisfying biocompatibility, good conductivity and extensive surface area, which were inherited from both gold nanoparticles (AuNPs) and bacterial cellulose nanofibers (BC). Heme proteins such as horseradish peroxidase (HRP), hemoglobin (Hb) and myoglobin (Mb) were successfully immobilized on the surface of Au-BC nanocomposite modified glassy carbon electrode (GCE). The immobilized heme proteins showed electrocatalytic activities to the reduction of H(2)O(2) in the presence of the mediator hydroquinone (HQ), which might be due to the fact that heme proteins retained the near-native secondary structures in the Au-BC nanocomposite which was proved by UV-vis and IR spectra. The response of the developed biosensor to H(2)O(2) was related to the amount of AuNPs in Au-BC nanocomposite, indicating that the AuNPs in BC network played an important role in the biosensor performance. Under the optimum conditions, the biosensor based on HRP exhibited a fast amperometric response (within 1s) to H(2)O(2), a good linear response over a wide range of concentration from 0.3 MUM to 1.00 mM, and a low detection limit of 0.1 MUM based on S/N=3. The high performance of the biosensor made Au-BC nanocomposite superior to other materials as immobilization matrix. PMID- 21315901 TI - Simultaneous determination of epinephrine and norepinephrine in human blood plasma and urine samples using nanotubes modified edge plane pyrolytic graphite electrode. AB - The simultaneous determination of catecholamines - epinephrine and norepinephrine by square wave voltammetry (SWV) at physiological pH 7.2 is reported using multi walled carbon nanotubes modified edge plane pyrolytic graphite electrode (MWNT/EPPGE). A broad bump at ~ 250 mV is appeared for the oxidation of epinephrine (EP) and norepinephrine (NE) at bare EPPGE whereas at MWNT/EPPGE two well-separated peaks at ~ 150 and ~ 215 mV are appeared for the oxidation of EP and NE, respectively. The oxidation peak current of both the neurotransmitters also increased significantly along with the negative shift of peak potentials using MWNT/EPPGE. The oxidation of both compounds occurred in a pH dependent, 2e and 2H(+) process and the electrode reaction followed diffusion controlled pathway. Linear calibration curves were obtained for epinephrine and norepinephrine in the range 0.5-100 nM with limits of detection 0.15 * 10(-9) and 0.90 * 10(-10)M, respectively. The developed protocol is implemented for the simultaneous determination of epinephrine and norepinephrine in blood plasma and urine samples of smokers as well as in athletes. PMID- 21315902 TI - Qualitative analysis by online nuclear magnetic resonance using Carr-Purcell Meiboom-Gill sequence with low refocusing flip angles. AB - The Carr-Purcell-Meiboom-Gill (CPMG) pulse sequence has been used in many applications of magnetic resonance imaging (MRI) and low-resolution NMR (LRNMR) spectroscopy. Recently, CPMG was used in online LRNMR measurements that use long RF pulse trains, causing an increase in probe temperature and, therefore, tuning and matching maladjustments. To minimize this problem, the use of a low-power CPMG sequence based on low refocusing pulse flip angles (LRFA) was studied experimentally and theoretically. This approach has been used in several MRI protocols to reduce incident RF power and meet the specific absorption rate. The results for CPMG with LRFA of 3pi/4 (CPMG(135)), pi/2 (CPMG(90)) and pi/4 (CPMG(45)) were compared with conventional CPMG with refocusing pi pulses. For a homogeneous field, with linewidth equal to Deltaupsilon=15 Hz, the refocusing flip angles can be as low as pi/4 to obtain the transverse relaxation time (T(2)) value with errors below 5%. For a less homogeneous magnetic field, Deltaupsilon=100 Hz, the choice of the LRFA has to take into account the reduction in the intensity of the CPMG signal and the increase in the time constant of the CPMG decay that also becomes dependent on longitudinal relaxation time (T(1)). We have compared the T(2) values measured by conventional CPMG and CPMG(90) for 30 oilseed species, and a good correlation coefficient, r=0.98, was obtained. Therefore, for oilseeds, the T(2) measurements performed with pi/2 refocusing pulses (CPMG(90)), with the same pulse width of conventional CPMG, use only 25% of the RF power. This reduces the heating problem in the probe and reduces the power deposition in the samples. PMID- 21315903 TI - Preparation of anti-CD4 monoclonal antibody-conjugated magnetic poly(glycidyl methacrylate) particles and their application on CD4+ lymphocyte separation. AB - Novel immunomagnetic particles have been prepared for separation of CD4(+) lymphocytes. The magnetic nanoparticles with a diameter of approximately 5-6 nm were first synthesized by co-precipitation from ferrous and ferric iron solutions and subsequently encapsulated with poly(glycidyl methacrylate) (PGMA) by precipitation polymerization. Monoclonal antibody specific to CD4 molecules expressed on CD4(+) lymphocytes was conjugated to the surface of magnetic PGMA particles through covalent bonding between epoxide functional groups on the particle surface and primary amine groups of the antibodies. The generated immunomagnetic particles have successfully separated CD4(+) lymphocytes from whole blood with over 95% purity. The results indicated that these particles can be employed for cell separation and provide a strong potential to be applied in various biomedical applications including diagnosis, and monitoring of human diseases. PMID- 21315904 TI - Field measurement of nitrate in marine and estuarine waters with a flow analysis system utilizing on-line zinc reduction. AB - A sensitive reagent-injection flow analysis method for the spectrophotometric determination of nitrate in marine, estuarine and fresh water samples is described. The method is based on the reduction of nitrate in a micro column containing zinc granules at pH 6.5. The nitrite formed is reacted with sulfanilamide and N-(1-naphthyl)ethylene diamine (Griess reagent), and the resulting azo compound is quantified spectrophotometrically at 520 nm. Water samples in the range of 3-700 MUg L(-1) NO(3)(-)-N can be processed with a throughput of up to 40 samples per hour, a detection limit of 1.3 MUg L(-1) and reproducibility of 1.2% RSD (50 MUg L(-1) NO(3)(-)-N, n=10). The proposed method was successfully applied for the determination of nitrate in estuarine waters and the reliability was assessed by the analyses of certified reference materials and recovery experiments. The method is suitable for waters with a wide range of salinities, and was successfully used for more than 3200 underway nitrate measurements aboard SV Pelican1 in the "Two Bays" cruise in January 2010. PMID- 21315905 TI - Electropolymerized multiwalled carbon nanotubes/polypyrrole fiber for solid-phase microextraction and its applications in the determination of pyrethroids. AB - A novel solid-phase microextraction (SPME) fiber coated with multiwalled carbon nanotubes/polypyrrole (MWCNTs/Ppy) was prepared with an electrochemical method and used for the extraction of pyrethroids in natural water samples. The results showed that the MWCNTs/Ppy coated fiber had high organic stability, and remarkable acid and alkali resistance. In addition, the MWCNTs/Ppy coated fiber was more effective and superior to commercial PDMS and PDMS/DVD fibers in extracting pyrethroids in natural water samples. Under optimized conditions, the calibration curves were found to be linear from 0.001 to 10 MUg mL(-1) for five of the six pyrethroids studied, the exception being fenvalerate (which was from 0.005 to 10 MUg mL(-1)), and detection limits were within the range 0.12-0.43 ng mL(-1). The recoveries of the pyrethroids spiked in water samples at 10 ng mL(-1) ranged from 83 to 112%. PMID- 21315906 TI - Ion pair-based dispersive liquid-liquid microextraction for gold determination at ppb level in solid samples after ultrasound-assisted extraction and in waters by electrothermal-atomic absorption spectrometry. AB - A new methodology was developed for the determination of ultratrace levels of gold in water samples, soils and river sediments. Dispersive liquid-liquid microextraction was used to preconcentrate the ion pair formed between AuCl(4)(-) and [CH(3)(CH(2))(3)](4)N(+) in a microliter-range volume of chlorobenzene using acetone as disperser solvent. When solid samples were analyzed, the method consisted of a combination of ultrasound-assisted extraction and dispersive liquid-liquid microextraction with final detection by electrothermal-atomic absorption spectrometry. Since an HCl medium was required for the formation of the AuCl(4)(-) complex, HCl together with HNO(3) was used as extractants for ultrasound-assisted extraction. After optimization, the enrichment factor obtained was 220 for water samples. Moreover, the extraction efficiency was around 96%. The repeatability, expressed as relative standard deviation ranged from 3.6% to 9.7%. The instrumental detection limit was 8.4 ng L(-1), whereas the procedural detection limits were 42 ng L(-1) for water samples and 1.5 ng g(-1) for environmental solid samples. PMID- 21315907 TI - The effect of humidity on sensitivity of amine detection in ion mobility spectrometry. AB - Vaporized water molecules are unavoidably present in every ion mobility spectrometry (IMS) measurement. In general, this humidity is seen in positive mode IMS-spectra as protonated water clusters producing reactant ions. Clusters containing water molecules are also abundant among ions generated by an analyte. In this paper the influence of humidity on IMS-spectra was systematically investigated and determined by measuring different concentrations of a selected amine at various levels of humidity. The selected amine, trimethylamine (TMA), was chosen as the model analyte due to its atmospheric importance. During the measurements, surplus water vapor was introduced into the drift section inside the IMS instrument; the concentrations of both amine and water were adjusted by controlling the gas flows. The simultaneous presence of water vapor and analyte at various predefined concentrations revealed the sensitivity of the IMS technique to water and the effect of moisture on the ion mobility distribution. The results indicated that the existence, positions and shapes of the peaks are strongly dependent on the amount of moisture. However, the sensitivity of detection is weakly dependent on humidity if this detection is based on monomer ion peak or the sum of peaks generated by the analyte, In addition, the main principles of the adjustment of sample and water concentrations are presented here. PMID- 21315908 TI - Germanium determination by flame atomic absorption spectrometry: an increased vapor pressure-chloride generation system. AB - A new chloride generation system was designed for the direct, sensitive, rapid and accurate determination of the total germanium in complex matrices. It was aimed to improve the detection limit of chloride generation technique by increasing the vapor pressure of germanium tetrachloride (GeCl(4)). In order to do so, a novel joint vapor production and gas-liquid separation unit equipped with a home-made oven was incorporated to an ordinary nitrous oxide-acetylene flame atomic absorption spectrometer. Several variables such as reaction time, temperature and acid concentration have been investigated. The linear range for germanium determination was 0.1-10 ng mL(-1) for 1 mL sampling volume with a detection limit (3s) of 0.01 ng mL(-1). The relative standard deviation (RSD) was 2.4% for nine replicates of a 1 ng mL(-1) germanium solution. The method was validated by the analysis of one non-certified and two certified geochemical reference materials, respectively, CRM GSJ-JR-2 (Rhyolite), and GSJ-JR-1 (Rhyolite), and GBW 07107 (Chinese Rock). Selectivity of the method was investigated for Cd(2+), Co(2+), Cu(2+), Fe(3+), Ga(3+), Hg(2+), Ni(2+), Pb(2+), Sn(2+), and Zn(2+) ions and ionic species of As(III), Sb(III), Te(IV), and Se(IV). PMID- 21315909 TI - Identification and quantification of lignans in wheat bran by gas chromatography electron capture detection. AB - Whole grain cereals are an important source of bioavailable lignans, the group of compounds with potential anti-cancerogenic, antioxidant, anti-proliferative, pro apoptotic, and antiangiogenic properties. The aim of this work was to develop a sensitive method for determination of wheat bran lignans. The analysis of lignans secoisolariciresinol, hydroxymatairesinol, lariciresinol, matairesinol, pinoresinol, syringaresinol is based on derivatization with pentafluoropropionic anhydride (PFPA) and gas chromatography-electron capture detection (GC-ECD), using styrene glycol as internal standard. To our knowledge, this is the first time that EC detection has been used for lignan analysis. The results show that the technique is reproducible and sensitive enough for detecting lignans in wheat at parts-per-billion (ppb) levels, except for hydroxymatairesinol. The method developed showed good recovery (85-105%) and precision (4-20%) for five types of lignans and thus represents a simpler and more affordable alternative to state-of the-art wheat lignan liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. PMID- 21315910 TI - A new method to analyze copolymer based superplasticizer traces in cement leachates. AB - Enhancing the flowing properties of fresh concrete is a crucial step for cement based materials users. This is done by adding polymeric admixtures. Such additives have enabled to improve final mechanicals properties and the development of new materials like high performance or self compacting concrete. Like this, the superplasticizers are used in almost cement based materials, in particular for concrete structures that can have a potential interaction with drinking water. It is then essential to have suitable detection techniques to assess whether these organic compounds are dissolved in water after a leaching process or not. The main constituent of the last generation superplasticizer is a PolyCarboxylate-Ester copolymer (PCE), in addition this organic admixture contains polyethylene oxide (free PEO) which constitutes a synthesis residue. Numerous analytical methods are available to characterize superplasticizer content. Although these techniques work well, they do not bring suitable detection threshold to analyze superplasticizer traces in solution with high mineral content such as leachates of hardened cement based materials formulated with superplasticizers. Moreover those techniques do not enable to distinguish free PEO from PCE in the superplasticizer. Here we discuss two highly sensitive analytical methods based on mass spectrometry suitable to perform a rapid detection of superplasticizer compounds traces in CEM I cement paste leachates: MALDI-TOF mass spectrometry, is used to determine the free PEO content in the leachate. However, industrial copolymers (such as PCE) are characterized by high molecular weight and polymolecular index. These two parameters lead to limitation concerning analysis of copolymers by MALDI-TOFMS. In this study, we demonstrate how pyrolysis and a Thermally assisted Hydrolysis/Methylation coupled with a triple-quadrupole mass spectrometer, provides good results for the detection of PCE copolymer traces in CEM I cement paste leachates. PMID- 21315911 TI - Determination of 17 pyrethroid residues in troublesome matrices by gas chromatography/mass spectrometry with negative chemical ionization. AB - An analytical method with the technique of QuEChERS (quick, easy, cheap, effective, rugged and safe) and gas chromatography (GC)/mass spectrometry (MS) in negative chemical ionization (NCI) has been developed for the determination of 17 pyrethroid pesticide residues in troublesome matrices, including garlic, onion, spring onion and chili. Pyrethroid residues were extracted with acidified acetonitrile saturated by hexane. After a modified QuEChERS clean-up step, the extract was analyzed by GC-NCI/MS in selected ion monitoring (SIM) mode. An isotope internal standard of trans-cypermethrin-D(6) was employed for quantitation. Chromatograms of pyrethroids obtained in all these matrices were relatively clean and without obvious interference. The limits of detection (LODs) ranged from 0.02 to 6 MUg kg(-1) and recovery yields were from 54.0% to 129.8% at three spiked levels (20, 40 and 60 MUg kg(-1) for chili, and 10, 20 and 30 MUg kg(-1) for others) in four different matrices depending on the compounds determined. The relative standard deviations (RSDs) were all below 14%. Isomerization enhancement of pyrethroids in chili extract was observed and preliminarily explained, especially for acrinathrin and deltamethrin. PMID- 21315912 TI - Direct probing of the folding/unfolding event of bovine hemoglobin at montmorillonite clay modified electrode by adsorptive-transfer voltammetry. AB - An efficient way was proposed for probing the folding/unfolding event of bovine hemoglobin (Hb) through adsorptive-transfer voltammetry. Hb molecules in native and pre-unfolded in different urea conditions for 23 h were adsorbed onto the montmorillonite clay modified glassy carbon electrode (Hb/clay/GCE and uHb/clay/GCE, respectively). Cyclic voltammograms of Hb/clay/GCE and uHb/clay/GCE showed that the unfolding of Hb caused great change in the direct electron transfer between the heme irons within Hb and electrode surface, which was facilitated on clay film. From the amount of the electroactive Hb (W(Hbe)) and the adsorbed Hb (Gamma) on clay per unit mass, the minimal electroactive portion (MEP) of the adsorbed Hb was calculated to assess the unfolding state of Hb. With the increase of urea concentration, MEP showed a sigmoid curve. Thermodynamic parameters related to the unfolding event of Hb were also obtained based on the linear free energy model (LEM), including the free energy of folding in water (DeltaG(U)(water)), the slope of the Santoro-Bolen equation (m), and the urea concentration required in for achieving half of the total change (S(m)) in the unfolding curves. This work gave the first try for investigating protein unfolding at nano-materials modified electrode using adsorptive-transfer voltammetry, which improved the sensitivity of analysis and avoided the disadvantages involved in the existing electrochemical methods for protein unfolding. The proposed method will benefit the electrochemical studies of protein. PMID- 21315913 TI - Separation and sweeping of flavonoids by microemulsion electrokinetic chromatography using mixed anionic and cationic surfactants. AB - In this report, a novel means for the separation and sweeping of flavonoids (quercetin, rutin, calycosin, ononin and calycosin-7-O-beta-D-glucoside) by microemulsion electrokinetic chromatography using mixed anionic and cationic surfactants as modified pseudostationary phase was presented. The optimized background electrolyte consisted of 0.5% (w/v) ethyl acetate, 2.0% (w/v) SDS, 9 mM DTAC, 4.0% (w/v) 1-butanol and 10mM sodium borate or 25 mM phosphoric acid. We systematically investigated the separation and preconcentration conditions, including the concentrations of surfactant, types of sweeping, sample matrix, the effect of high salt or acetonitrile, and sample injection volume. It was found that the use of mixed surfactants significantly enhanced the separation efficiency through the change of the efficient electrophoretic mobility of analytes. Compared with normal sample injection, 185-508-fold sensitivity enhancement in terms of limit of detection was achieved through effective sweeping of large sample volume at 50 mbar pressure (up to 45% capillary length). At last, the proposed method was suitable for the determination of Radix Astragali sample. PMID- 21315914 TI - Sensitive voltammetric determination of baicalein at DNA Langmuir-Blodgett film modified glassy carbon electrode. AB - The present paper describes to modify a double stranded DNA-octadecylamine (ODA) Langmuir-Blodgett film on a glassy carbon electrode (GCE) surface to develop a voltammetric sensor for the detection of trace amounts of baicalein. The electrode was characterized by atomic force microscopy (AFM) and cyclic voltammetry (CV). Electrochemical behaviour of baicalein at the modified electrode had been investigated in pH 2.87 Britton-Robinson buffer solutions by CV and square wave voltammetry (SWV). Compared with bare GCE, the electrode presented an electrocatalytic redox for baicalein. Under the optimum conditions, the modified electrode showed a linear voltammetric response for the baicalein within a concentration range of 1.0 * 10(-8)-2.0 * 10(-6) mol L(-1), and a value of 6.0 * 10(-9) mol L(-1) was calculated for the detection limit. And the modified electrode exhibited an excellent immunity from epinephrine, dopamine, glucose and ascorbic acid interference. The method was also applied successfully to detect baicalein in the medicinal tablets and spiked human blood serum samples with satisfactory results. PMID- 21315915 TI - Industrial application of green chromatography--I. Separation and analysis of niacinamide in skincare creams using pure water as the mobile phase. AB - In this work, chromatographic separation of niacin and niacinamide using pure water as the sole component in the mobile phase has been investigated. The separation and analysis of niacinamide have been optimized using three columns at different temperatures and various flow rates. Our results clearly demonstrate that separation and analysis of niacinamide from skincare products can be achieved using pure water as the eluent at 60 degrees C on a Waters XTerra MS C18 column, a Waters XBridge C18 column, or at 80 degrees C on a Hamilton PRP-1 column. The separation efficiency, quantification quality, and analysis time of this new method are at least comparable with those of the traditional HPLC methods. Compared with traditional HPLC, the major advantage of this newly developed green chromatography technique is the elimination of organic solvents required in the HPLC mobile phase. In addition, the pure water chromatography separations described in this work can be directly applied in industrial plant settings without further modification of the existing HPLC equipment. PMID- 21315916 TI - Spectrofluorometric determination and chemical speciation of trace concentrations of chromium (III & VI) species in water using the ion pairing reagent tetraphenyl phosphonium bromide. AB - A highly selective, and low cost extractive spectrofluorometric method has been developed for determination of trace concentrations of chromium (III & VI) in water samples using the fluorescent reagent tetraphenylphosphonium bromide (TPP(+) . Br(-)). The method was based upon solvent extraction of the produced ion associate [TPP(+) . CrO(3)Cl(-)] of TPP(+) . Br(-) and halochromate in aqueous HCl and measuring the fluorescence quenching of TPP(+) . Br(-) in chloroform at lambda(ex/em)=242/305 nm. The fluorescence intensity of TPP(+)Br(-) decreased linearly on increasing the chromium (VI) concentration in the range of 1-114 MUg L(-1). The limits of detection (LOD) and quantification (LOQ) of chromium (VI) were 0.43 and 1.42 MUg L(-1), respectively. Chromium (III) species after oxidation to chromium (VI) with H(2)O(2) in alkaline solution were also determined. Chemical speciation of chromium (III & VI) species at trace levels was achieved. The method was applied for analysis of chromium in certified reference material (IAEA Soil-7) and in tap- and wastewater samples and compared successfully (>95%) with the inductively coupled plasma-mass spectrometry (ICP MS) results. PMID- 21315917 TI - Carbohydrates electrocatalytic oxidation using CNT-NiCo-oxide modified electrodes. AB - A new sensor for an amplified electrochemical detection of carbohydrates is proposed, where carbohydrates are oxidized by CNT-NiCo-oxide composite in basic solutions. Cyclic voltammograms of the modified electrode show a stable and well defined redox couple in alkaline media due to the synergy of Ni(II)/Ni(III) system with Co(II)/Co(III). The modified electrode shows excellent electrocatalytic activity towards monosaccharides oxidation at reduced overpotential in alkaline solutions. Six monosaccharides were determined amperometrically at the surface of this modified electrode with high sensitivity over a wide range of concentrations, from 0.02 up to 12.12 mM. Low detection limit of 5 MUM for glucose could be obtained. PMID- 21315918 TI - A novel fused-silica capillary dropping mercury electrode with long drop-time and its application on determination of critical micelle concentration. AB - A novel long drop time mercury electrode has been constructed from common fused silica capillary (50 MUm I.D., 360 MUm E.D.). Proposed device provides reproducible mercury drops with typical lifetime 40-120 s. The electrode was used for a set of electrocapillary measurements aimed at determination of critical micelle concentration of anionic surfactants by a convection controlled drop-time technique. A critical micelle concentration of sodium dodecyl sulfate 5.6 +/- 0.4 mmol L(-1) and 4.3 +/- 0.4 mmol L(-1) were obtained in 1 mmol L(-1) and 5 mmol L( 1) phosphate buffer (pH 7.0), respectively. The values were comparable to those obtained from conductometric measurements under the same conditions (7.0 +/- 0.1 mmol L(-1) and 5.2 +/- 0.1 mmol L(-1), respectively) and the difference was explained in accordance with theory of hemi-micelle formation. PMID- 21315919 TI - A new non-destructive method for chemical analysis of particulate matter filters: the case of manganese air pollution in Vallecamonica (Italy). AB - Total Reflection X-ray Fluorescence (TXRF) is a well-established technique for chemical analysis, but it is mainly employed for quality control in the electronics semiconductor industry. The capability to analyze liquid and uniformly thin solid samples makes this technique suitable for other applications, and especially in the very critical field of environmental analysis. Comparison with standard methods like inductively coupled plasma (ICP) and atomic absorption spectroscopy (AAS) shows that TXRF is a practical, accurate, and reliable technique in occupational settings. Due to the greater sensitivity necessary in trace heavy metal detection, TXRF is also suitable for environmental chemical analysis. In this paper we show that based on appropriate standards, TXRF can be considered for non-destructive routine quantitative analysis of environmental matrices such as air filters. This work has been developed in the frame of the EU-FP6 PHIME (Public Health Impact of long-term, low-level Mixed element Exposure in susceptible population strata) Integrated Project (www.phime.org). The aim of this work was to investigate Mn air pollution in the area of Vallecamonica (Italy). PMID- 21315920 TI - Phosphate additives determination in meat products by 31-phosphorus nuclear magnetic resonance using new internal reference standard: hexamethylphosphoroamide. AB - New (31)P NMR internal reference standard - hexamethylphosphoroamide (HMPA) was applied for determination of added polyphosphates and their ionic forms in raw pork meat and meat products. Phosphate species were determined after extraction with a boric acid buffer (pH=9) and EDTA solution, using internal standard (HMPA) procedure. Hexamethylphosophoroamide was also used as the NMR reference standard. Linear correlations between phosphates and polyphosphate concentrations and (31)P NMR signal areas were found in the range 81-5236 mg P/dm(3), presenting 95-99% recovery and variation coefficient (CV) <= 5%. Studied HMPA procedure revealed shorter analysis time and the same recovery (>95%) and precision (CV=1.3-2.7%) in comparison to MDPA method. Results of phosphate determination by both (31)P NMR methods were tested against the molybdenumvanadate yellow spectrophotometric method (standard PN-ISO 13730, 1999) using standard reference material (certified phosphate solution). PMID- 21315921 TI - A monoclonal antibody-based immunosensor for detection of Sudan I using electrochemical impedance spectroscopy. AB - Sudan I monoclonal antibodies (Mabs) were prepared by hybridoma technique and firstly used to develop a Sudan I immunosensor by immobilizing the Mabs on a gold electrode. o-Mercaptobenzoic acid (MBA) was covalently conjugated on the gold electrode to form a self-assembled monolayer (SAM). The immobilization of Sudan I Mabs to the SAM was carried out through a stable acyl amino ester intermediate generated by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and N hydrosuccinimide (NHS), which could condense antibodies reproducibly and densely on the SAM. The changes of the electrode behavior after each assembly step were investigated by cyclic voltammetric (CV) technique. The Sudan I concentration was measured through the increase of impedance values in the corresponding specific binding of Sudan I and Sudan I antibody. A linear relationship between the increased electron-transfer resistance (Ret) and the logarithmic value of Sudan I concentrations was found in the range of 0.05-50 ng mL(-1) with the detection limit of 0.03 ng mL(-1). Using hot chili as a model sample, acceptable recovery of 96.5-107.3% was obtained. The results were validated by conventional HPLC method with good correlation. The proposed method was proven to be a feasible quantitative method for Sudan I analysis with the properties of stability, highly sensitivity and selectivity. PMID- 21315922 TI - Separation and preconcentration of Pb(II) using ionic liquid-modified silica and its determination by flame atomic absorption spectrometry. AB - A new method based on microcolumn packed with ionic liquid-modified silica combined with flame atomic absorption spectrometry has been developed for the determination of lead in environmental samples. Several factors influencing the preconcentration efficiency of lead and its subsequent determination, such as pH of the sample, flow rate, mass of ionic liquid, and interfering effect, have been investigated. Lead could be quantitatively retained by ionic liquid-modified silica in the pH range of 5-7, and then eluted completely with 3.0 mL 1.0 mol L( 1) HCl. The detection limit of this method for lead was 0.7 MUg L(-1) with preconcentration factor of 185, and the relative standard deviation (RSD) was 4.2% at 0.1 MUg mL(-1) Pb(II). This method has been applied for the determination of trace amount of lead in NIST standard reference material 2709 (San Joaquin Soil) and river water samples with satisfactory results. PMID- 21315923 TI - Micro-plate chemiluminescence enzyme immunoassay for aflatoxin B1 in agricultural products. AB - In this work, a micro-plate chemiluminescence enzyme immunoassay by antibody coated for the determination of aflatoxin B1 (AFB1) in agricultural products has been established. Aflatoxin B1 antibody (AFB1-Ab) was adsorbed physically on polystyrene micro-plate hole as solid phase antibody, which took place immunity reaction between antigen and antibody with AFB1 standard solution or samples by direct competition. Luminol-hydrogen peroxide chemiluminescence system catalyzed by horseradish peroxidase (HRP) with p-iodophenol enhancement was used as signal detecting system. The effects of several factors, including composition and pH of coating solution, dilution ratio and amount of antibody and enzyme labeled antigen, time of antibody-coating, incubation and chemiluminescence reaction, and other relevant variables upon the immunoassay were studied and optimized. The linear range of proposed method for AFB1 was 0.05-10.0 ng g(-1) with a correlative coefficient of -0.9997. The sensitivity of the proposed method was 0.01 ng g(-1). The RSDs of intra- and inter-assay were less than 12.2% and 10.0%, respectively. This method has been successfully applied to the evaluation of AFB1 in agricultural products with recoveries of 79.8%, 101.9% and 115.4% for low, middle and high concentration samples, respectively. It shows a good correlation with the commercial available ELISA kit for AFB1 with correlative coefficient of 0.9098 indicating that the established CLEIA method can be used to determine AFB1 in real samples. PMID- 21315924 TI - Stripping voltammetric determination of silymarin in formulations and human blood utilizing bare and modified carbon paste electrodes. AB - Silymarin is one of the most powerful natural substances that have the ability to protect and rebuild the liver cells damaged by alcohol and other toxic substances. Silymarin showed two irreversible anodic peaks in buffered solutions (pH 2.5-8.0) at either the bare carbon paste electrode or the montmorillonite-Ca modified carbon paste one. These two peaks have been attributed to oxidation of the two phenolic OH groups at positions C-20 and C-7 of silymarin molecule. A square-wave adsorptive anodic stripping voltammetry method was optimized for determination of silymarin utilizing the bare and the modified carbon paste electrodes. The method was fully validated and successfully applied for the determination of silymarin in commercial formulations and human serum without prior extraction utilizing both carbon paste electrodes. Limits of quantitation of 1 * 10(-7) and 7 * 10(-9) mol L(-1) silymarin have been achieved in bulk form or in formulations while 2 * 10(-7) and 8 * 10(-9) mol L(-1) silymarin were achieved in spiked human serum utilizing the bare carbon paste electrode and the modified one, respectively. The two electrodes exhibited excellent selectivity towards silymarin even in the presence of 10(2)to 10(3)-fold excess of its co formulated drugs, common excipients, and common metal ions. The pharmacokinetic parameters of silymarin in plasma of healthy human volunteers were estimated following the administration of a single oral dose of 120 mg silymarin utilizing the modified carbon paste electrode. The estimated pharmacokinetic parameters were favorably compared with those reported in literature. PMID- 21315925 TI - Nanomolar detection with high sensitivity microfluidic absorption cells manufactured in tinted PMMA for chemical analysis. AB - We describe a novel, cost effective and simple technique for the manufacture of high sensitivity absorption cells for microfluidic analytical systems. The cells are made from tinted polymethyl methacrylate (PMMA) in which microfluidic channels are fabricated. Two windows (typically 250 MUm thick, resulting in little optical power loss) are formed at either end of the channel through which light is coupled. Unwanted stray light from the emitter passes through a greater thickness of the tinted substrate (typically the length of the cell) and is preferentially absorbed. In effect, this creates a pin-hole configuration over the length of the absorption cell, providing improved performances (sensitivity, S/N ratios, baseline noise and limit of detection) when used as an absorption cell compared to clear substrates. The method is used to achieve a LOD of 20 nM with a colourimetric iron assay and a LOD of 0.22 milli-absorption units with a pH assay. PMID- 21315926 TI - Simultaneous cloud point extraction and spectrophotometric determination of carmoisine and brilliant blue FCF in food samples. AB - A novel simultaneous cloud point extraction method for the determination of carmoisine and brilliant blue FCF by spectrophotometry has been developed. The method is based on the cloud point extraction of carmoisine and brilliant blue FCF from aqueous solution using Triton X-100, diluting the extracted surfactant rich phase with water and measuring the absorbance at 522 and 640 nm for carmoisine and brilliant blue FCF, respectively. The effects of different parameters such as pH, concentration of surfactant and temperature on the cloud point extraction of both dyes were investigated and optimum conditions were established. Linear calibration curves were obtained in the range of 0.02-3.50 MUg mL(-1) for carmoisine and 0.05-3.50 MUg mL(-1) for brilliant blue FCF under optimum conditions. Detection limit based on three times the standard deviation of the blank (3S(b)) was 0.017 and 0.016 MUg mL(-1) (n=10) for carmoisine and brilliant blue FCF, respectively. The relative standard deviation (RSD) for 0.1 MUg mL(-1) was 4.14 and 3.30% (n=10), for carmoisine and brilliant blue FCF, respectively. The method was applied to the simultaneous determination of the dyes in different food samples. PMID- 21315927 TI - Designing drugs to avoid toxicity. PMID- 21315928 TI - Prostaglandin D2 receptor CRTH2 antagonists for the treatment of inflammatory diseases. PMID- 21315929 TI - Progress in the development of small molecule therapeutics targeting Th17 cell function for the treatment of immune-inflammatory diseases. PMID- 21315930 TI - Therapeutic applications of iminosugars: current perspectives and future opportunities. PMID- 21315931 TI - An epidemic of risk factors for cardiovascular disease. PMID- 21315932 TI - School: a place for children to learn their HIV status? PMID- 21315935 TI - Hermaphrodite. PMID- 21315936 TI - Drugs and harm to society. PMID- 21315937 TI - Drugs and harm to society. PMID- 21315938 TI - Drugs and harm to society. PMID- 21315939 TI - Drugs and harm to society. PMID- 21315940 TI - Drugs and harm to society. PMID- 21315941 TI - Drugs and harm to society. PMID- 21315942 TI - Drugs and harm to society. PMID- 21315943 TI - Identification of incestuous parental relationships by SNP-based DNA microarrays. PMID- 21315944 TI - Medical student electives: potential for global health? PMID- 21315946 TI - Heat, Oriental sore, and HIV. PMID- 21315949 TI - Systemic lupus erythematosus induced by cefepime. PMID- 21315950 TI - Superantigens in dermatology. AB - Superantigens (SAgs) are virulent polypeptides that are produced by a variety of infectious organisms. They are capable of causing nonspecific T cell activation by circumventing normal antigen processing in the human host. The genetic makeup of the host plays a role in conferring susceptibility or protection against SAgs. They are linked to a variety of conditions, ranging from toxic shock syndrome to recurrent toxin-mediated perineal erythema. The early recognition of signs and symptoms of SAg-mediated illnesses is important to ensure prompt medical treatment. PMID- 21315952 TI - Catastrophic cutaneous carcinomatosis in the non-organ transplant patient. AB - BACKGROUND: The increased frequency of nonmelanoma skin cancers (NMSCs) in organ transplant recipients has been termed "catastrophic cutaneous carcinomatosis" (CCC). We have treated a cohort of immunocompetent patients with an increased number of NMSCs that meets the definition of CCC whom we have termed "catastrophic cutaneous carcinomatosis-immunocompetent" (CCC-IC). OBJECTIVE: We sought to further understand the epidemiologic characteristics of this subset of immunocompetent patients with a high burden of NMSCs. METHODS: Our pathology database was searched over a 4-year experience of a Mohs surgeon to identify patients with greater than 10 basal cell carcinomas (BCCs) and/or squamous cell carcinomas (SCCs) in a 12-month period who had no underlying systemic cause of immunosuppression or genetic predisposition to form NMSCs. Information regarding the 13 patients who met inclusion criteria was collected by questionnaire and analyzed. RESULTS: There was no statistically significant difference in the constitutional variables of this patient population. Patients with CCC-IC had a SCC:BCC ratio of 2.5:1, similar to what is seen in organ transplant recipients where the SCC:BCC ratio is 2:1 with SCC predominance. There was a statistically significant increase in the number of SCCs in patients with CCC-IC (8.77/patient) as compared with control patients (2.27/patient). Most strikingly, a 13.8-fold higher incidence of malignant melanoma in the CCC-IC group was found as compared with the general population. LIMITATIONS: Limitations to this study include a small sample size and recall bias. CONCLUSION: Our data suggest that patients with CCC-IC have skin cancer profiles of SCC and BCC similar to organ transplant recipients and have a markedly higher incidence of malignant melanoma than the general population. These patients require strict monitoring and combination therapeutic approaches toward management of cutaneous carcinomas. PMID- 21315951 TI - Radiofrequency facial rejuvenation: evidence-based effect. AB - BACKGROUND: Multiple therapies involving ablative and nonablative techniques have been developed for rejuvenation of photodamaged skin. Monopolar radiofrequency (RF) is emerging as a gentler, nonablative skin-tightening device that delivers uniform heat to the dermis at a controlled depth. OBJECTIVE: We evaluated the clinical effects and objectively quantified the histologic changes of the nonablative RF device in the treatment of photoaging. METHODS: Six individuals of Fitzpatrick skin type III to IV and Glogau class I to II wrinkles were subjected to 3 months of treatment (6 sessions at 2-week intervals). Standard photographs and skin biopsy specimens were obtained at baseline, and at 3 and 6 months after the start of treatment. We performed quantitative evaluation of total elastin, collagen types I and III, and newly synthesized collagen using computerized histometric and immunohistochemical techniques. Blinded photographs were independently scored for wrinkle improvement. RESULTS: RF produced noticeable clinical results, with high satisfaction and corresponding facial skin improvement. Compared with the baseline, there was a statistically significant increase in the mean of collagen types I and III, and newly synthesized collagen, while the mean of total elastin was significantly decreased, at the end of treatment and 3 months posttreatment. LIMITATIONS: A limitation of this study is the small number of patients, yet the results show a significant improvement. CONCLUSIONS: Although the results may not be as impressive as those obtained by ablative treatments, RF is a promising treatment option for photoaging with fewer side effects and downtime. PMID- 21315953 TI - Angioplasmocellular hyperplasia: a clinicopathologic study of 10 patients. AB - BACKGROUND: Angioplasmocellular hyperplasia is rarely reported. OBJECTIVE: The purpose of this study is to describe and analyze the clinicopathologic features of angioplasmocellular hyperplasia. METHODS: The records of 10 patients (mean age, 45 years; range, 17 to 71 years) with characteristic histologic features of angioplasmocellular hyperplasia were reviewed and the histopathologic findings, clinical features, and medical histories analyzed. Formalin-fixed, paraffin embedded specimens were examined by immunohistochemical staining. RESULTS: The most common clinical appearance was a single nodule with an erythematous rim. Histologically, the inflammatory infiltrate comprised mainly polyclonal plasma cells. There was vascular proliferation of capillaries and venules with varying numbers of plump endothelial cells. There were no definite predisposing factors. LIMITATIONS: The number of cases was limited and all patients were Asian. CONCLUSIONS: Angioplasmocellular hyperplasia had a distinct clinical appearance characterized by its inflammatory rim. The nature of the infiltrating cells and distribution of blood vessels indicates that it is a form of reactive plasmocytic inflammatory vascular hyperplasia. PMID- 21315954 TI - Quantification of melanocytes in sun-damaged skin. AB - BACKGROUND: The density of melanocytes varies by anatomic site and degree of sun damage. OBJECTIVE: To determine the density of melanocytes and frequency of confluence in specimens adjacent to nonmelanoma skin cancers. METHODS: Two hundred final layer specimens from Mohs surgery for basal cell carcinomas were analyzed by using MART-1. RESULTS: Data for 162 skin specimens from the head demonstrated an average keratinocyte to melanocyte ratio of 7.12 and 8.19 for epidermis and adnexal structures, respectively. The 23 specimens from the trunk demonstrated respective ratios of 7.54 and 7.46, and 13 specimens from extremities demonstrated ratios of 8.69 and 12.38. LIMITATIONS: Margins from Mohs micrographic surgery for nonmelanoma skin cancers were utilized as a proxy for chronically sun-damaged skin. CONCLUSION: Our results suggest that chronically sun-exposed skin demonstrates increased melanocytic density, but confluence of melanocytes is rare. Occasionally intraepidermal pagetoid scatter and isolated melanocytic nests were rarely noted. These findings alone should not support an unequivocal diagnosis of melanoma in situ. PMID- 21315955 TI - Clinical and photographic assessment of lichen planopilaris treatment efficacy. PMID- 21315957 TI - Cutaneous cribriform carcinoma: a short comment. PMID- 21315958 TI - CD34+ connective tissue nevi: are they unusual? PMID- 21315960 TI - Law of unintended consequences. PMID- 21315961 TI - Hyperhidrotic and control subjects have similar sweating responses to pilocarpine administration. PMID- 21315962 TI - Permanent chemotherapy-induced alopecia: a review. PMID- 21315963 TI - Superior efficacy of oral fluconazole 400 mg daily versus oral fluconazole 200 mg daily in the treatment of cutaneous leishmania major infection: a randomized clinical trial. PMID- 21315964 TI - Fixed drug eruption caused by dimenhydrinate. PMID- 21315965 TI - Adult-onset multiple myofibromas. PMID- 21315966 TI - Complete basal cell carcinoma remission with imiquimod in a patient with nevoid basal cell carcinoma syndrome and associated basal cell carcinoma of the scalp and invasive ductal breast cancer. PMID- 21315967 TI - Platelike osteoma cutis. PMID- 21315969 TI - A successful pregnancy outcome in a woman with Haemoglobin J Biskra. PMID- 21315970 TI - SPORE2009 spore-forming bacteria in foods. PMID- 21315971 TI - Origin of bacterial spores contaminating foods. AB - Bacterial spores (=endospores) are common contaminants in foods. Sources of contamination in the food chain may include soil, faeces, animal feeds and food ingredients and processing chain themselves. Sporulation may occur in very diverse environments. The environment of sporulation has a strong influence on spore properties relevant for food quality and safety. PMID- 21315972 TI - Clostridium botulinum in the post-genomic era. AB - Foodborne botulism is a severe neuroparalytic disease caused by consumption of botulinum neurotoxin formed by strains of proteolytic Clostridium botulinum and non-proteolytic C. botulinum during their growth in food. The botulinum neurotoxin is the most potent substance known, with as little as 30-100 ng potentially fatal, and consumption of just a few milligrams of neurotoxin containing food is likely to be sufficient to cause illness and potentially death. In order to minimise the foodborne botulism hazard, it is necessary to extend understanding of the biology of these bacteria. This process has been recently advanced by genome sequencing and subsequent analysis. In addition to neurotoxin formation, endospore formation is also critical to the success of proteolytic C. botulinum and non-proteolytic C. botulinum as foodborne pathogens. The endospores are highly resistant, and enable survival of adverse treatments such as heating. To better control the botulinum neurotoxin-forming clostridia, it is important to understand spore resistance mechanisms, and the physiological processes involved in germination and lag phase during recovery from this dormant state. PMID- 21315973 TI - Novel insights into the epidemiology of Clostridium perfringens type A food poisoning. AB - Clostridium perfringens food poisoning ranks among the most common gastrointestinal diseases in developed countries. The disease is caused by C. perfringens enterotoxin (CPE) encoded by cpe and produced by less than 5% of C. perfringens type A strains. Molecular epidemiological research in the past 15 years has focused on the reservoirs and routes of cpe-positive C. perfringens aiming to clarify the role and epidemiology of chromosomal and plasmid-borne cpe carrying strains. This literature review highlights novel aspects in the epidemiology of CPE-mediated diseases. We suggest that (1) chromosomal and plasmid-borne cpe-carrying C. perfringens strains are genetically and epidemiologically distinct and have adapted to different environments; (2) not only chromosomal but also plasmid-borne cpe-carrying C. perfringens strains cause food poisonings; (3) other CPE-mediated diseases, such as antibiotic-associated and sporadic diarrhea, associated with plasmid-borne cpe-positive strains, may be food-related; (4) the role of animals as the main reservoir of cpe-positive C. perfringens needs to be reconsidered; (5) humans serve as an important reservoir of cpe-positive C. perfringens, introducing a contamination risk into foods through handling; and (6) the current standard procedures to diagnose C. perfringens food poisoning fail to detect and isolate many C. perfringens strains, distorting the epidemiological understanding of C. perfringens food poisoning. PMID- 21315974 TI - Germination and outgrowth of spores of Bacillus cereus group members: diversity and role of germinant receptors. AB - Bacillus cereus is a gram-positive, facultative anaerobic, endospore-forming toxicogenic human pathogen. Endospores are highly specialized, metabolically dormant cell types that are resistant to extreme environmental conditions, including heat, dehydration and other physical stresses. B. cereus can enter a range of environments, and can in its spore form, survive harsh conditions. If these conditions become favorable, spores can germinate and grow out and reach considerable numbers in a range of environments including processed foods. Certainly the last decade, when consumer preferences have shifted to mildly processed food, new opportunities arose for spore-forming spoilage and pathogenic organisms. Only rigorous methods have been shown to be capable of destroying all spores present in food, thus a shift toward e.g., milder heat preservation strategies, may result in low but significant amounts of viable spores in food products. Hence, the need for a mild spore destruction strategy is eminent including control of spore outgrowth. Consequently, there is a large interest in triggering spore germination in foodstuffs, since germinated spores have lost the extreme resistance of dormant spores and are relatively easy to kill. Another option could be to prevent germination so that no dangerous levels can be reached. This contribution will focus on germination and outgrowth characteristics of B. cereus and other members of the B. cereus group, providing an overview of the niches these spore-formers can occupy, the signals that trigger germination, and how B. cereus copes with these wake-up calls in different environments including foods, during food processing and upon interaction with the human host. PMID- 21315975 TI - Challenges in risk assessment and predictive microbiology of foodborne spore forming bacteria. AB - Mathematical description of the behavior of bacterial foodborne pathogens and concepts of risk assessment were first applied to spore-forming bacteria and specially to Clostridium botulinum with numerous works dealing with spores heat destruction to ensure the safety of canned foods or with their germination and growth probability in foods. This paper discusses two aspects which appear specific to pathogenic sporeformers in comparison to vegetative microorganisms, that is, firstly, the extreme intra-species biodiversity of spore-forming bacteria and its consequences for risk assessment and, secondly, the modeling of spore germination and outgrowth processes. The intra-species biodiversity of spore-forming bacteria has a great impact on hazard identification, exposure assessment and hazard characterization leading thus to an extremely variable individual poisoning risk for consumers. The germination and outgrowth processes were shown independent at the single cell level and although numerous studies were performed to study the effect of spores treatments and growth conditions on these two events, the mathematical modeling and the prediction of these processes is still challenging today. The difficulties to accurately assess the biodiversity and the germination and outgrowth processes of spore-forming bacteria lead to a substantial uncertainty in risk estimates related to the exposure to these microorganisms. Nevertheless, significant progress have been made these last years improving the relevance of quantitative risk assessments for spore-forming bacteria and decreasing the risk uncertainty. Despite these difficulties, risk assessment still constitutes a valuable tool to justify the implementation of management options. PMID- 21315976 TI - Bacillus probiotics. AB - Bacterial spore formers are being used as probiotic supplements for use in animal feeds, for human dietary supplements as well as in registered medicines. Their heat stability and ability to survive the gastric barrier makes them attractive as food additives and this use is now being taken forward. While often considered soil organisms this conception is misplaced and Bacilli should be considered as gut commensals. This review summarises the current use of Bacillus species as probiotics, their safety, mode of action as well as their commercial applications. PMID- 21315977 TI - Challenges and advances in systems biology analysis of Bacillus spore physiology; molecular differences between an extreme heat resistant spore forming Bacillus subtilis food isolate and a laboratory strain. AB - Bacterial spore formers are prime organisms of concern in the food industry. Spores from the genus Bacillus are extremely stress resistant, most notably exemplified by high thermotolerance. This sometimes allows surviving spores to germinate and grow out to vegetative cells causing food spoilage and possible intoxication. Similar issues though more pending toward spore toxigenicity are observed for the anaerobic Clostridia. The paper indicates the nature of stress resistance and highlights contemporary molecular approaches to analyze the mechanistic basis of it in Bacilli. A molecular comparison between a laboratory strain and a food borne isolate, very similar at the genomic level to the laboratory strain but generating extremely heat resistant spores, is discussed. The approaches cover genome-wide genotyping, proteomics and genome-wide expression analyses studies. The analyses aim at gathering sufficient molecular information to be able to put together an initial framework for dynamic modelling of spore germination and outgrowth behaviour. Such emerging models should be developed both at the population and at the single spore level. Tools and challenges in achieving the latter are succinctly discussed. PMID- 21315978 TI - Lag time variability in individual spores of Clostridium botulinum. AB - Quantifying lag times from individual spores and the associated variability is an important part of understanding the hazard associated with spore-forming pathogens such as Clostridium botulinum. Knowledge of the underlying distribution would allow greater refinement of risk assessments. To date most studies have either examined lag time indirectly by measuring time to growth or have only examined the first stage of lag, germination. Recent studies have attempted to quantify the variability of spores during the different stages of lag phase and to examine the relationships between these stages. The effect of incubation temperature (22 degrees C, 15 degrees C, 10 degrees C or 8 degrees C), heat treatment (unheated or 80 degrees C for 20 s) and sodium chloride concentration in both the sporulation medium (0 or 3% w/v) or growth medium (0 or 2% w/v) on growth from individual spores has been examined. These studies found spores within a single population are very heterogeneous with large variability in all stages of lag. The duration and variability of times for germination, outgrowth and first doubling depended on both the historic treatment of the spores and the prevailing growth conditions, and the stage of lag most affected was treatment dependant. PMID- 21315979 TI - Extended and global phylogenetic view of the Bacillus cereus group population by combination of MLST, AFLP, and MLEE genotyping data. AB - The Bacillus cereus group of bacteria includes species that can cause food poisoning or spoilage, such as B. cereus, as well as Bacillus anthracis, the cause of anthrax. In the present report we have conducted a multi-datatype analysis using tools from the HyperCAT database (http://mlstoslo.uio.no/) that we recently developed, combining data from multilocus sequence typing (Tourasse et al., 2010), amplified fragment length polymorphism, and multilocus enzyme electrophoresis typing techniques. We provide a comprehensive snapshot of the B. cereus group population, incorporating 2213 isolates including 450 from food and dairy products, in the form of both phylogenetic supertrees and superclusters of genetically closely related isolates. Our main findings include the detection of phylogenetically separated groups of isolates possibly representing novel evolutionary lineages within the B. cereus group, a putative new branch of B. anthracis, as well as new groups of related strains containing both environmental and clinical isolates. In addition, the multi-datatype analysis revealed to a larger extent than previously recognized that food-borne isolates can share identical genotyping profiles with strains from various other origins. Altogether, the global analysis confirms and extends the results underlining the opportunistic nature of B. cereus group organisms, and the fact that isolates responsible for disease outbreaks and contamination of foodstuffs can originate from various genetic backgrounds. PMID- 21315980 TI - A mixed-species microarray for identification of food spoilage bacilli. AB - Failure of food preservation is frequently caused by thermostable spores of members of the Bacillaceae family, which show a wide spectrum of resistance to cleaning and preservation treatments. We constructed and validated a mixed species genotyping array for 6 Bacillus species, including Bacillus subtilis, Bacillus licheniformis, Bacillus pumilus, Bacillus sporothermodurans, Bacillus cereus and Bacillus coagulans, and 4 Geobacillus species, including Geobacillus stearothermophilus, Geobacillus thermocatenulatus, Geobacillus toebii and Geobacillus sp., in order to track food spoilage isolates from ingredient to product. The discriminating power of the array was evaluated with sets of 42 reference and 20 test strains. Bacterial isolates contain a within-species conserved core genome comprising 68-88% of the entire genome and a non-conserved accessory genome comprising 7-22%. The majority of the core genome markers do not hybridise between species, thus they allow for efficient discrimination at the species level. The accessory genome array markers provide high-resolution discrimination at the level of individual isolates from a single species. In conclusion, the reported mixed-species microarray contains discriminating markers that allow rapid and cost-effective typing of Bacillus food spoilage bacteria in a wide variety of food products. PMID- 21315981 TI - Biodiversity and characterization of aerobic spore-forming bacteria in surimi seafood products. AB - The microbial quality and safety of surimi seafood products was assessed by studying the prevalence and biodiversity of aerobic spore-forming bacteria at the beginning and end of shelf life in 100 surimi samples. Low levels of total flora and sporulated flora were numerated at the beginning of storage, however, residual spores were detected in the majority of samples during storage. Furthermore, for 34 samples, total flora counts>10(4) CFU/g were observed at the end of shelf life which could lead to non-compliance with good practice recommendations or product spoilage. In total, 460 strains were isolated, fingerprinted by M13-PCR and grouped into 98 different clusters. Representative strains were then identified at the species level via 16S rRNA gene sequencing. Overall, dominant species belonged to Bacillus simplex, Bacillus subtilis and Bacillus licheniformis; while B. simplex, B. subtilis as well as Sporosarcina aquimarina were clearly the dominant species found in samples with higher total flora counts. Amylolytic and proteolytic activities were very frequent amongst tested strains (80 and 92.5%, respectively). Heat resistance parameters of 4 strains in a surimi-based medium were determined. B. simplex and B. subtilis strains were the most heat resistant (delta(96 degrees C)= 27.6 and 23.3 min and z(T)=8.6 and 7.9, respectively) which can explain their dominance in surimi samples exhibiting higher microbial counts. The heat resistance data obtained can now be used to model thermal destruction of strains using predictive microbiology tools (Sym'Previus). PMID- 21315982 TI - Biodiversity of psychrotrophic bacteria of the Bacillus cereus group collected on farm and in egg product industry. AB - The aim of the present study was (i) to type, by genotypic and phenotypic methods, a collection of psychrotrophic bacteria belonging to the Bacillus cereus group collected in a farm and in 6 egg breaking industries during a period covering a warm and a cold season, and (ii) to characterize the egg product spoilage (growth in liquid whole egg) and the sanitary risk potential (cytotoxic activity on Caco-2 cells and adhesion on stainless steel) of each isolate of the collection. The investigation of specific psychrotrophic and mesophilic signatures together with the study of ability to grow at 6 degrees C and/or at 43 degrees C on optimal agar medium allowed highlighting twelve profiles, the major one corresponding to the species Bacillus weihenstephanensis (46.2% of the collection). The diversity of the profiles depended on the season and on the origin of the isolates. In terms of food spoilage, all the isolates were able to grow at the same level in liquid whole egg and in optimal medium, even at low temperature. Under the same conditions, the cytotoxic activity depended on the isolate, the medium and the temperature. At 10 degrees C, no isolate was cytotoxic at 10 degrees C in liquid whole egg and only one, belonging to the Bacillus weihenstephansensis species, in the optimal medium. All the isolates were able to adhere on stainless steel at various levels, from 2.6+/-0.2 log cfu/cm(2) to 4.9+/-0.1 log cfu/cm(2). A large majority (80.8%) was strongly adhering and could lead to the formation of biofilms in industrial equipments. PMID- 21315983 TI - Clostridial spore germination versus bacilli: genome mining and current insights. AB - Bacilli and clostridia share the characteristic of forming metabolically inactive endospores. Spores are highly resistant to adverse environmental conditions including heat, and their ubiquitous presence in nature makes them inevitable contaminants of foods and food ingredients. Spores can germinate under favourable conditions, and the following outgrowth can lead to food spoilage and foodborne illness. Germination of spores has been best studied in Bacillus species, but the process of spore germination is less well understood in anaerobic clostridia. This paper describes a genome mining approach focusing on the genes related to spore germination of clostridia. To this end, 12 representative sequenced Bacillus genomes and 24 Clostridium genomes were analyzed for the distribution of known and putative germination-related genes and their homologues. Overall, the number of ger operons encoding germinant receptors is lower in clostridia than in bacilli, and some Clostridium species are predicted to produce cortex-lytic enzymes that are different from the ones encountered in bacilli. The in silico germination model constructed for clostridia was linked to recently obtained experimental data for selected germination determinants, mainly in Clostridium perfringens. Similarities and differences between germination mechanisms of bacilli and clostridia will be discussed. PMID- 21315984 TI - Characterization of germination and outgrowth of sorbic acid-stressed Bacillus cereus ATCC 14579 spores: phenotype and transcriptome analysis. AB - Sorbic acid (SA) is widely used as a preservative, but the effect of SA on spore germination and outgrowth has gained limited attention up to now. Therefore, the effect of sorbic acid on germination of spores of Bacillus cereus strain ATCC 14579 was analyzed both at phenotype and transcriptome level. Spore germination and outgrowth were assessed at pH 5.5 without and with 0.75, 1.5 and 3.0 mM (final concentrations) undissociated sorbic acid (HSA). This resulted in distinct HSA concentration-dependent phenotypes, varying from reduced germination and outgrowth rates to complete blockage of germination at 3.0 mM HSA. The phenotypes reflecting different stages in the germination process could be confirmed using flow cytometry and could be recognized at transcriptome level by distinct expression profiles. In the absence and presence of 0.75 and 1.5 mM HSA, similar cellular ATP levels were found up to the initial stage of outgrowth, suggesting that HSA-induced inhibition of outgrowth is not caused by depletion of ATP. Transcriptome analysis revealed the presence of a limited number of transcripts in dormant spores, outgrowth related expression, and genes specifically associated with sorbic acid stress, including alterations in cell envelope and multidrug resistance. The potential role of these HSA-stress associated genes in spore outgrowth is discussed. PMID- 21315985 TI - Transcriptional kinetic analyses of cereulide synthetase genes with respect to growth, sporulation and emetic toxin production in Bacillus cereus. AB - In light of the increasing number of serious food borne outbreaks caused by emetic Bacillus cereus, a better understanding of the cereulide synthetase (ces) gene expression and toxin synthesis is required. Here, the relative expression levels of three ces genes (cesP, cesA and cesB) were investigated using quantitative real-time reverse transcription PCR in relation to growth, degree of sporulation and toxin production of the emetic reference strain B. cereus F4810/72 and the weakly emetic strain IH41385. The strict co-transcription of all three genes confirmed the operon structure of the ces gene cluster responsible for cereulide formation. ces transcription turned out to be highly temporal and tightly regulated; ces mRNA was only detectable during mid to late exponential growth in both strains. The low toxigenic potential of the weakly emetic strain IH41385 correlated well with its respective ces transcripts, showing reduced activity at a transcriptional level. Two non-sporulating mutants (F4810/72Deltaspo0A and F4810/72INsigH) demonstrated that cereulide synthesis is part of the Spo0A regulon but independent of later sporulation processes. Besides strain specific intrinsic factors, ces transcription was found to be significantly influenced by the cellular growth state as well as by extrinsic abiotic factors, like salt. An increase of sodium chloride in the media resulted in lower ces transcription and coincided with lower cereulide toxin levels. Interestingly, at 25 gl(-1) NaCl, toxin levels were already reduced without strongly affecting the growth of B. cereus, indicating an inhibitory effect of NaCl on cereulide biosynthesis independent of growth. This illustrates that ces gene expression and toxicity cannot be predicted solely from growth rates or cell numbers, but is influenced by complex interactions of various intrinsic as well as extrinsic factors, which remain to be clarified in detail. PMID- 21315986 TI - Spores of Bacillus cereus strain KBAB4 produced at 10 degrees C and 30 degrees C display variations in their properties. AB - Spores of the psychrotrophic Bacillus cereus KBAB4 strain were produced at 10 degrees C and 30 degrees C in fermentors. Spores produced at 30 degrees C were more resistant to wet heat at 85 degrees C, 1% glutaraldehyde, 5% hydrogen peroxide, 1M NaOH and pulsed light at fluences between 0.5 and 1.75 Jcm(-2) and to a lesser extent to monochromatic UV-C at 254 nm. No difference in resistance to 0.25 mM formaldehyde, 1M nitrous acid and 0.025 gl(-1) calcium hypochlorite was observed. Spores produced at 10 degrees C germinated more efficiently with 10 mM and 100 mM l-alanine than spores produced at 30 degrees C, while no difference in germination was observed with inosine. Dipicolinic acid (DPA) content in the spore was significantly higher for spores prepared at 30 degrees C. Composition of certain fatty acids varied significantly between spores produced at 10 degrees C and 30 degrees C. PMID- 21315987 TI - The influence of headspace and dissolved oxygen level on growth and haemolytic BL enterotoxin production of a psychrotolerant Bacillus weihenstephanensis isolate on potato based ready-to-eat food products. AB - The major objective of this study was to determine the influence of the initial headspace and dissolved O(2) level and vacuum packaging on growth and diarrhoeal enterotoxin production by Bacillus weihenstephanensis on potato based ready-to eat food products. In general, the lower the initial headspace or dissolved O(2) level the slower the maximum growth rate (MU(max), log(10) CFU g(-1) d(-1)), the longer the lag phase duration (lambda, d) and the smaller the maximum population density (N(max), log(10) CFU g(-1)) became. The slowest MU(max), the longest lambda and the smallest N(max) were generally found for growth under vacuum packaging. This implies shorter shelf-lives will occur at higher initial headspace or dissolved O(2) levels as the growth of B. weihenstephanensis to the infective dose of 10(5) CFU g(-1) in such atmospheres takes a shorter time. Significant consumption of dissolved O(2) only occurred when growth shifted from the lag to the exponential phase and growth generally transitioned from the exponential to the stationary phase when the dissolved O(2) levels fell below ca. 75 ppb. Diarrhoeal enterotoxin production (determined via detection of the L2 component of haemolytic BL) was similar for growth under initial headspace O(2) levels of 1-20.9%, and was only reduced when growth took place under vacuum packaging. The reduction in L2 production when growth took place under vacuum was most probably related to the low final cell densities observed under this condition. Both growth and L2 production were inhibited over a 32-day incubation period at 7 degrees C by 40% CO(2) irrespective of the headspace or dissolved O(2) levels. The results illustrate the importance of residual O(2) and CO(2) on the shelf-stability and safety of modified atmosphere packaged potato based ready to-eat food products with regards to B. weihenstephanensis. PMID- 21315988 TI - Combined effect of lysozyme and nisin at different incubation temperature and mild heat treatment on the probability of time to growth of Bacillus cereus. AB - Stochastic models can be useful to predict the risk of foodborne illness. The presence of Bacillus cereus in liquid egg can pose a serious hazard to the food industry, since a mild heat treatment cannot guarantee its complete inactivation. However, most of the information available in the scientific literature is deterministic, including growth of B. cereus. In this paper, a stochastic approach to evaluate growth of B. cereus cells influenced by different stresses (presence of nisin and lysozyme separately or in combination) was performed, using an individual-based approach of growth through OD measurements. Lag phase duration was derived from the growth curves obtained. From results obtained, histograms of the lag phase were generated and distributions were fitted. Normal and Weibull distributions were ranked as the bestfit distributions in experiments performed at 25 degrees C. At 16 degrees C, lag values (obtained in presence of combinations of both antimicrobials) were also fitted by a Gamma distribution. Predictions were compared with growth curves obtained in liquid egg exposed to mild heat, nisin and/or lysozyme to assess their validity. PMID- 21315989 TI - Bayesian modeling of Clostridium perfringens growth in beef-in-sauce products. AB - Models on Clostridium perfringens growth which have been published to date have all been deterministic. A probabilistic model describing growth under non isothermal conditions was thus proposed for predicting C. perfringens growth in beef-in-sauce products cooked and distributed in a French hospital. Model parameters were estimated from different types of data from various studies. A Bayesian approach was proposed to model the overall uncertainty regarding parameters and potential variability on the 'work to be done' (h(0)) during the germination, outgrowth and lag phase. Three models which differed according to their description of this parameter h(0) were tested. The model with inter-curve variability on h(0) was found to be the best one, on the basis of goodness-of-fit assessment and validation with literature data on results obtained under non isothermal conditions. This model was used in two-dimensional Monte Carlo simulations to predict C. perfringens growth throughout the preparation of beef in-sauce products, using temperature profiles recorded in a hospital kitchen. The median predicted growth was 7.8*10(-2) log(10) cfu.g(-1) (95% credibility interval [2.4*10(-2), 0.8]) despite the fact that for more than 50% of the registered temperature profiles cooling steps were longer than those required by French regulations. PMID- 21315990 TI - Quantitative risk assessment for hazards that arise from non-proteolytic Clostridium botulinum in minimally processed chilled dairy-based foods. AB - A modular process risk model has been constructed that describes the manufacture of dairy dessert products and hazards that arise from non-proteolytic Clostridium botulinum. The model describes batch manufacture and consumer storage of a family size generic dairy dessert but includes a realistic quantification that could apply to a specific food product. The dairy dessert sector is an expanding part of the UK market. The model includes modules that describe spore loads in raw materials, spore inactivation during thermal processing, volume partition and the population kinetics for non-proteolytic C. botulinum during sequential isothermal storage regimes. Where possible elements of uncertainty and variability are identified explicitly. The model is constructed as a belief network from published data and expert opinions. The model provides marginal probabilities, and associated sensitivities, for a range of endpoint measures centred on the toxicity of a single retail unit after an extended period of storage. The decimal reduction time for non-proteolytic C. botulinum spore populations at the highest (hold) temperature of the primary thermal process and the highest temperature experienced during poorly controlled (consumer) storage are dominant factors determining risks. Priorities for additional information to support risk assessments have been identified. PMID- 21315991 TI - Infection prevention and control in the hospital. Preface. PMID- 21315992 TI - Building a successful infection prevention program: key components, processes, and economics. AB - Infection control is the discipline responsible for preventing nosocomial infections. There has been an increasing focus on prevention rather than control of hospital-acquired infections. Individuals working in infection control have seen their titles change from infection control practitioner to infection control professional and most recently to infection preventionist (IP), emphasizing their critical role in protecting patients. The responsibilities of IPs span multiple disciplines including medicine, surgery, nursing, occupational health, microbiology, pharmacy, sterilization and disinfection, emergency medicine, and information technology. This article discusses the structure and responsibilities of an infection control program and the regulatory pressures and opportunities the program faces. PMID- 21315993 TI - Hand hygiene. AB - The toll of health care-associated infections on patients and the seeming ease of the procedure thought best able to prevent them have focused a spotlight onto hand hygiene performance. Poor performance of hand hygiene by health care workers inspires outrage in the general public. Much is understood regarding barriers to and motivators of hand hygiene performance. Guidelines encouraging use of alcohol based hand hygiene agents have facilitated hand hygiene improvement efforts. These efforts and evidence that improved hand hygiene performance is associated with a reduction in health care-associated infections should encourage those in the hand hygiene campaigns. PMID- 21315994 TI - Sterilization, high-level disinfection, and environmental cleaning. AB - Failure to perform proper disinfection and sterilization of medical devices may lead to introduction of pathogens, resulting in infection. New techniques have been developed for achieving high-level disinfection and adequate environmental cleanliness. This article examines new technologies for sterilization and high level disinfection of critical and semicritical items, respectively, and because semicritical items carry the greatest risk of infection, the authors discuss reprocessing semicritical items such as endoscopes and automated endoscope reprocessors, endocavitary probes, prostate biopsy probes, tonometers, laryngoscopes, and infrared coagulation devices. In addition, current issues and practices associated with environmental cleaning are reviewed. PMID- 21315995 TI - Central line-associated bloodstream infections: prevention and management. AB - Approximately 80,000 central venous line-associated bloodstream infections (CLA BSI) occur in the United States each year. CLA-BSI is most commonly caused by coagulase-negative staphylococci, Staphylococcus aureus, Candida spp, and aerobic gram-negative bacilli. These organisms commonly gain entrance in into the bloodstream via the catheter-skin interface (insertion site) or via the catheter hub. Use of strict aseptic technique for insertion is the key method for the prevention of CLA-BSI. Various methods can be used to reduce unacceptably high rates of CLA-BSI, including use of an antiseptic- or antibiotic-impregnated catheter, daily chlorhexidine baths/washes, and placement of a chlorhexidine impregnated sponge over the insertion site. PMID- 21315996 TI - Urinary tract infections. AB - Catheter-associated urinary tract infections (CAUTIs) account for approximately 40% of all health care-associated infections. Despite studies showing benefit of interventions for prevention of CAUTI, adoption of these practices has not occurred in many healthcare facilities in the United States. As urinary catheters account for the majority of healthcare-associated UTIs, the most important interventions are directed at avoiding placement of urinary catheters and promoting early removal when appropriate. Alternatives to indwelling catheters such as intermittent catheterization and condom catheters should be considered. If indwelling catheterization is appropriate, proper aseptic practices for catheter insertion and maintenance and use of a closed catheter collection system are essential for preventing CAUTI. The use of antimicrobial catheters also may be considered when the rates of CAUTI remain persistently high despite adherence to other evidence-based practices, or in patients deemed to be at high risk for CAUTI or its complications. Attention toward prevention of CAUTI will likely increase as Center for Medicare and Medicaid Services and other third-party payers no longer reimburse for hospital-acquired UTI. PMID- 21315997 TI - Prevention of health care-acquired pneumonia and transmission of Mycobacterium tuberculosis in health care settings. AB - Health care-acquired pneumonia (HAP) is associated with significant morbidity and mortality. These infections most frequently arise from a patient's indigenous flora, although occasionally they result from exposure to environmental pathogens such as Legionella and Aspergillus. This article reviews infection prevention strategies to reduce the incidence of HAP. Successful implementation of these prevention strategies usually requires a multidisciplinary approach and standardization of protocols. This article also discusses strategies to prevent transmission of Mycobacterium tuberculosis within health care settings. PMID- 21315998 TI - Surgical site infections. AB - Surgical site infections (SSIs) lead to adverse patient outcomes, including prolonged hospitalization and death. Wound contamination occurs with each incision, but proven strategies exist to decrease the risk of SSIs. In particular, improved adherence to evidence-based preventative measures related to appropriate antimicrobial prophylaxis can decrease the rate of SSI. Aggressive surgical debridement and effective antimicrobial therapy are needed to optimize the treatment of SSIs. PMID- 21315999 TI - Control of methicillin-resistant Staphylococcus aureus. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of nosocomial infections worldwide. Different approaches to the control of this pathogen have met with varying degrees of success in different health care settings. Controversies exist with regards to various MRSA control strategies. The implementation and outcomes of control measures depend on several factors, including scientific, economic, administrative, governmental, and political influences. It is clear that flexibility to adapt and institute these measures in the context of local epidemiology and resources is required. PMID- 21316000 TI - Common approaches to the control of multidrug-resistant organisms other than methicillin-resistant Staphylococcus aureus (MRSA). AB - Curbing antibiotic resistance is a challenge in health care today. Infections caused by multidrug-resistant organisms are estimated to cause 12,000 deaths and cost 3.5 billion dollars in excess health care costs in the United States annually. This article focuses on relevant infection control measures for vancomycin-resistant enterococci, multidrug-resistant gram-negative infections, and Clostridium difficile. Common control strategies targeting these pathogens are reviewed and opportunities for research and more effective deployment of existing tools are highlighted. When there is less extensive evidence available from the published literature, the experience with methicillin-resistant Staphylococcus aureus is discussed as it might apply to other pathogens. PMID- 21316001 TI - Nosocomial fungal infections: epidemiology, infection control, and prevention. AB - Fungal infections are an increasing cause of morbidity and mortality in hospitalized patients. This article reviews the current epidemiology of nosocomial fungal infections in adult patients, with an emphasis on invasive candidiasis and aspergillosis. Recently published recommendations and guidelines for the control and prevention of these nosocomial fungal infections are summarized. PMID- 21316003 TI - Antimicrobial stewardship. AB - The overuse and misuse of antimicrobial agents has detrimental effects on patients, the health care system, and society. Inappropriate antimicrobial use contributes to the rising cost of health care, the emergence of multidrug resistant organisms, and adverse drug reactions. Antimicrobial stewardship programs provide standard, evidence-based approaches to encourage judicious use of antimicrobial agents. This review summarizes the goals of antimicrobial stewardship programs, the members needed to initiate and sustain them, antimicrobial stewardship strategies, barriers to the implementation and maintenance of the programs, approaches to measure their effects, and the basic steps needed to initiate them. PMID- 21316002 TI - Health care-acquired viral respiratory diseases. AB - Health care-associated viral respiratory infections, common among hospitalized children, also occur among adults and institutionalized persons and result in increased patient morbidity, mortality, and health care costs. Approximately 20% of patients with healthcare-associated pneumonia have viral respiratory infections, with 70% of these infections caused by adenovirus, influenza virus, parainfluenza virus, and respiratory syncytial virus (RSV). These infections typically reflect the level of viral activity within the community. This article focuses on the epidemiology, transmission, and control of health care-associated RSV and influenza virus. PMID- 21316004 TI - Informatics and epidemiology in infection control. AB - Increasing amounts of hospital data are available electronically and offer new possibilities in performing surveillance for health care-associated infections. To use electronic information effectively, health care epidemiologists need to be aware of potential sources of data, issues with data integrity, and the trade offs in using electronic data for surveillance as opposed to traditional manual surveillance. In reality, a combined surveillance approach may provide the best possible result. A clear understanding of the epidemiologic principles, such as prevalence and incidence, and some of the nuances behind these principles are essential for the proper interpretation of the epidemiologic data. PMID- 21316005 TI - Infection prevention in alternative health care settings. AB - With the changing health care delivery, patients receive care at various settings, including acute care hospitals, skilled nursing facilities (SNFs), and ambulatory clinics, thus becoming exposed to pathogens. Various health care settings face unique challenges requiring individualized infection control programs. The programs in SNFs should address surveillance for infections and antimicrobial resistance, outbreak investigation and control plan for epidemics, isolation precautions, hand hygiene, staff education, and employee and resident health programs. In ambulatory clinics, the program should address triage and standard transmission-based precautions; cleaning, disinfection, and sterilization principles; surveillance in surgical clinics; safe injection practices; and bioterrorism and disaster planning. PMID- 21316006 TI - Recent advances in the treatment of metastatic colorectal cancer in Taiwan. PMID- 21316007 TI - Antimicrobial drug resistance in Taiwan. AB - Antimicrobial resistance is a major global health threat associated with high mortality rates and high medical costs. Geographic variations in resistance profiles of bacterial and fungal pathogens have had a considerable impact on antimicrobial prescription. In Taiwan, there is an alarmingly high prevalence of penicillin-resistant Streptococcus pneumoniae, multidrug-resistant and extensively drug-resistant (XDR) Pseudomonas aeruginosa and Acinetobacter baumannii, extended-spectrum beta-lactamase-producing Klebsiella pneumoniae, penicillin- and fluoroquinolone-resistant Neisseria gonorrhoeae, and azole resistant Candida species. In addition, the emergence of XDR Mycobacterium tuberculosis has illustrated the need for regular monitoring of the resistance profiles of clinical isolates. A few clones of XDR A. baumannii and methicillin resistant Staphylococcus aureus of unique sequence type (ST 59) have disseminated in Taiwanese hospital settings. Besides, the existence of a transposon-harboring carbapenemase gene has been verified in XDR P aeruginosa strains throughout Taiwan. An end to the worsening trends in the emergence of antimicrobial resistance will require continuous survey of resistance data from clinical isolates and effective implementation of strict infection control policies in healthcare settings and animal husbandry. PMID- 21316008 TI - Cyclic vomiting syndrome in Taiwanese children. AB - BACKGROUND/PURPOSE: Cyclic vomiting syndrome (CVS) is a periodic and Stereotypic pattern of intractable nausea or vomiting episodes, which has been well recognized in previous decades, although the actual pathogenesis is still unclear. Recurrent, discrete, but self-limited symptoms of nausea and vomiting bother children, and increase the cost of family and health care. This report described the clinical features of patients who fulfill the diagnostic criteria for CVS. METHODS: This was a retrospective study that reviewed the medical records of children with CVS in our department from 1992 to 2008. The clinical features and results of long-term follow-up of these children were analyzed. RESULTS: Twenty-four patients (16 boys and 8 girls) were enrolled in this study. The mean age of onset was 6.8 +/- 3.3 years (2.2-15.4 years), and the mean interval from onset to proper diagnosis was 2.1 +/- 2.2 years. Comparing initial presentation and latest condition, the duration of attack was 4.1 +/- 2.2 days and 0.8 +/- 1.4 days, respectively, and the admission/emergency department visit dropped from 2.3 +/- 2.0 to 0.6 +/- 1.1 times per year. Twenty-three of 24 patients had been treated with amitriptyline, cyproheptadine, or propranolol. Nine patients (38%) had no symptoms in the past 12 months. CONCLUSION: The diagnosis of CVS must be based on the detailed history of the clinical manifestations of vomiting pattern, complete symptom-free intervals between the attacks, and absence of neurological, gastrointestinal, or metabolic abnormalities. Most of our patients improve when they grow up, but prompt diagnosis and early intervention may improve quality of life. PMID- 21316009 TI - Long-term clinical outcomes following elective stent implantation for unprotected left main coronary artery disease. AB - BACKGROUND/PURPOSE: Percutaneous coronary intervention (PCI) has been increasingly adopted for unprotected left main coronary artery (LMCA) disease. The aim of this study was to evaluate the predictors of long-term clinical outcomes in patients after elective stent implantation for unprotected LMCA disease. METHODS: A total of 122 patients with medically refractory angina who received coronary stenting for unprotected LMCA disease between August 1997 and December 2008 were included. RESULTS: During the follow-up period of 45 +/- 35 months (range: 1-137 months), the incidence of repeated PCI and/or coronary artery bypass grafting (CABG), and cardiovascular and total mortality were 28% (34 patients), 20% (24 patients), and 25% (31 patients), respectively. Multivariate analysis revealed that young age [p = 0.02; hazard ratio (HR): 2.19, 95% confidence interval (CI): 1.11-4.30] and bare-metal stent (BMS) use (p = 0.02; HR: 5.35, 95% CI: 1.27-22.57) were the independent predictors of repeated PCI and/or CABG. Only lower left ventricular ejection fraction (LVEF) could predict both cardiovascular mortality (p = 0.003; HR: 4.25, 95% CI: 1.63-11.08) and total mortality (p = 0.002; HR: 3.95, 95% CI: 1.65-9.45). Lower LVEF (p = 0.001; HR: 0.31, 95% CI: 0.16-0.61) and small stent size (p = 0.01; HR: 5.95, 95% CI: 1.43-24.80) could predict the composite endpoint, including target vessel revascularization and total mortality. CONCLUSION: We showed that young age and BMS implantation could predict repeated PCI and/or CABG after stent implantation for unprotected LMCA disease. Only lower LVEF could predict both cardiovascular and total mortality. Lower LVEF and small stent size but not BMS implantation could predict composite target vessel revascularization/total mortality. PMID- 21316010 TI - Odontogenic fibroma: a clinicopathological study of 15 cases. AB - BACKGROUND/PURPOSE: Odontogenic fibroma (ODF) is a rare odontogenic tumor. It can be further divided into peripheral odontogenic fibroma (PODF) and central odontogenic fibroma (CODF). This retrospective study evaluated the clinical and histopathological features of 15 ODFs in Taiwanese patients. METHODS: Fifteen consecutive cases of ODF were collected from 1984 to 2009. The clinical data and microscopic features of these cases were reviewed and analyzed. RESULTS: Twelve PODFs were excised from six male and six female patients (mean age: 35 years) and three CODFs from two male and one female patients (mean age: 11 years). Eight of the 12 PODFs were found on the mandibular gingiva and four on the maxillary gingiva, with the most common site being the mandibular anterior and premolar region (5 cases). Two CODFs were located in the molar region of the mandible and one in the anterior maxilla. Two CODFs showed a mixed lesion and one a radiolucent lesion. No recurrence of the 15 ODFs was found after total excision or enucleation. Microscopically 58.3% of the PODFs showed surface ulceration. Calcified foci composed of osteoid, cementoid, or cementicle-like materials were noted in all 15 ODFs. Nests or strands of odontogenic epithelium were found in all 15 ODFs. The stromal component was mainly fibro-collagenous in nine of the 12 PODFs, whereas two of the three CODFs contained predominantly myxomatous stroma. CONCLUSION: PODFs occurred more commonly than CODFs. PODF showed an equal sex distribution and was found more frequently in patients in the third to fourth decades of life. The most commonly affected site was the mandibular gingiva, especially the anterior and premolar gingiva. Only three CODFs were found; therefore, we could not draw any conclusions about CODF in Taiwanese patients. PMID- 21316011 TI - Use of two-dimensional multiple-slice magnetic resonance hydrography for diagnosis of hepatic hemangiomas and cysts. AB - BACKGROUND/PURPOSE: Although hepatic hemangiomas and cysts display very high signal intensities on conventional T2 images, their appearances are quite distinct using magnetic resonance hydrography (MRH). We examined the feasibility of using MRH in distinguishing hepatic cysts from hemangiomas. METHODS: We recruited 97 patients with hepatic hemangiomas and 65 with hepatic cysts. All patients underwent magnetic resonance imaging (including two-dimensional multiple slice MRH, TR/TE: 8000/800) and the results were reviewed independently by two radiologists. The signal intensities of the lesions were measured. For each lesion, the variation in signal to noise ratio between MRH and the fat-saturated T2-weighted images was calculated, and the results were validated using a receiver operating characteristic curve. RESULTS: There was a significant difference between the signal to noise ratio of hepatic hemangiomas and cysts using MRH (p < 0.001). This difference could be identified by visual inspection. The receiver operating characteristic curve revealed that the ideal cut-off value for the signal intensity reduction ratio between hepatic cysts and hemangiomas was -0.1. Using this ratio, the derived sensitivity was 95.4%, specificity 99.0%, and accuracy 99.7%. CONCLUSION: Hepatic hemangiomas and cysts have significantly different signal intensities on non-contrast two-dimensional multiple-slice MRH. This approach uses a non-invasive, reliable, and accurate imaging technique to differentiate the two diagnoses. PMID- 21316012 TI - Sex differences in conscious sedation during upper gastrointestinal panendoscopic examination. AB - BACKGROUND/PURPOSE: Sex differences in response to noxious stimuli or analgesia have been demonstrated. We investigated sex differences in conscious sedation during upper gastrointestinal panendoscopic examination with regard to drug dose and entropy scores. METHODS: We investigated sex differences in 30 men and 30 women who were undergoing conscious sedation during upper gastrointestinal panendoscopic examination. The drug mixture was prepared as 5 mg midazolam plus 1 mg alfentanil diluted with normal saline to a volume of 10 mL. An initial injection of 4 mL was followed by an additional 1 mL every 1 minute, until the modified Observer Assessment of Alertness and Sedation (OAAS) rating scale was <= 3 when the panendoscope was inserted. Further injection was allowed thereafter. Entropy values, including state entropy (SE) and response entropy (RE), were monitored from baseline to full recovery. RESULTS: The volume of mixture needed to achieve an OAAS score of <= 3 was significantly lower in men than in women (4.4 +/- 0.7 mL vs. 4.8 +/- 0.8 mL, p = 0.034). The initial drug demand was not significantly influenced by age, body weight, or body height. The RE and SE values at the time of panendoscope insertion were not significantly different between men and women. The total volume for men was also significantly lower than that for women (5.7 +/- 1.1 mL vs. 6.5 +/- 1.4 mL, p < 0.01). The lowest RE and SE values during the procedure were not significantly different between men and women. CONCLUSION: Women need more analgesic agents than men during panendoscopic examination. There was no significant difference between men and women with regard to anesthetic depth and response to noxious stimuli, as revealed by similar SE and RE values. PMID- 21316013 TI - Expression of vascular endothelial growth factor is significantly associated with progression and prognosis of oral squamous cell carcinomas in Taiwan. AB - BACKGROUND/PURPOSE: Expression of vascular endothelial growth factor (VEGF) correlates with progression and prognosis of several human cancers. The main purposes of this study were to assess expression of VEGF in specimens of oral squamous cell carcinoma (OSCC) and to evaluate the possible influence of VEGF on the progression and prognosis of OSCC in Taiwan. METHODS: An immunohistochemical technique was used to examine the expression of VEGF in 100 specimens of OSCC, 66 specimens of oral epithelial dysplasia, and 36 specimens of normal oral mucosa. RESULTS: We found that the mean labeling indices (Lis) of VEGF increased significantly from normal oral mucosa (13 +/- 6%), through mild (22 +/- 8%), moderate (24 +/- 13%), and severe oral epithelial dysplasia (32 +/- 14%), to OSCC samples (50 +/- 18%, p < 0.001). The higher mean VEGF LI was significantly related to OSCC with positive lymph node metastasis (p = 0.022) and with more advanced clinical stages (p = 0.046). In addition, positive lymph node metastasis (p = 0.008) and VEGF LI > 40% (p = 0.046) were identified as independent unfavorable prognosis factors for OSCC patients by multivariate analysis with the Cox regression model. Moreover, the Kaplan-Meier curve showed that OSCC patients with a VEGF LI > 40% had a significantly poorer cumulative survival than those with a VEGF LI <= 40% (log-rank test, p = 0.016). CONCLUSION: We conclude that VEGF may be a biomarker for prediction of the progression and prognosis of OSCC in Taiwan. PMID- 21316014 TI - Congenital hypopituitarism due to POU1F1 gene mutation. AB - POU1F1 (Pit-1; Gene ID 5449) is an anterior pituitary transcriptional factor, and POU1F1 mutation is known to cause anterior pituitary hypoplasia, growth hormone and prolactin deficiency and various degree of hypothyroidism. We report here a patient who presented with growth failure and central hypothyroidism since early infancy. However, treatment with thyroxine gave no effect and he subsequently developed calf muscle pseudohypertrophy (Kocher-Debre-Semelaigne syndrome), elevation of creatinine kinase, dilated cardiomyopathy and pericardial effusion. Final diagnosis was made by combined pituitary function test and sequencing analysis that revealed POU1F1 gene C.698T > C (p.F233S) mutation. The rarity of the disease can result in delayed diagnosis and treatment. PMID- 21316015 TI - Escitalopram for psychogenic nausea and vomiting: a report of two cases. AB - Psychogenic nausea and vomiting is defined as vomiting without any obvious organic pathology or vomiting with a psychological etiology. The treatment for such a condition is a challenge in clinical practice. The first patient was a 46 year-old married factory worker who was repeatedly hospitalized for recurring bouts of nausea and vomiting. After consultation, she was diagnosed with major depressive disorder. The frequency of nausea and vomiting decreased after treatment with daily doses of 10-20 mg escitalopram. The second patient was a 37 year-old married teacher who had bouts of nausea and vomiting and was also hospitalized repeatedly. She was diagnosed with mixed anxiety-depressive disorder. After treatment with 10 mg/day escitalopram, her episodes of nausea and vomiting decreased. Escitalopram may be an effective treatment for psychogenic nausea and vomiting associated with depression. PMID- 21316016 TI - [Electroencephalogram of the full-term newborn. Normal features and hypoxic ischemic encephalopathy]. AB - The objective of this work is to specify, by reference to the normal newborn, the current contribution of the electroencephalogram in the hypoxic-ischemic encephalopathy of the full-term newborn. Both digitized traditional EEG and cerebral function monitoring (CFM) will be considered. We first describe the main features of normal and pathological EEGs. A good knowledge of the organization of the sleep-wakefulness cycles, in relationship with the EEG, is essential. Very early recordings (before 6 hours of life) are needed to put the indications of neuroprotective treatments (hypothermia). Between the normal or near-normal tracings, which are associated with a good prognosis, and the very pathological tracings (inactive, paroxysmal), which are associated with a poor vital or functional prognosis, the interpretation of "intermediate" tracings - mainly represented by other types of discontinuous tracings - must take into account characteristics of bursts and discontinuities, postnatal age, the evolution of successive tracings, and pharmacological treatments. A flowchart is used to illustrate our strategy of EEG watching over a full-term newborn after an acute fetal distress. PMID- 21316017 TI - Influence of hypothermia on the prognostic value of early EEG in full-term neonates with hypoxic ischemic encephalopathy. AB - OBJECTIVE: To determine the prognostic value of early electroencephalograms (EEG) in full-term neonates suffering from hypoxic ischemic encephalopathy (HIE) exposed to whole-body hypothermia (cooled group), compared to neonates treated conventionally (control group). METHODS: The study included all term neonates born at Grenoble Hospital between 2000 and 2006 with symptoms of HIE. The first two EEGs were reviewed retrospectively and classified according to current electrophysiological criteria. In the cooled group, EEGs were recorded with a mean body temperature of 33 degrees C. Neurological outcome was correlated with EEG pattern. RESULTS: An EEG inactive or paroxysmal pattern was associated with death in 60% of the controls, while all survivors had neurological sequels. In the cooled group, this EEG pattern was only predictive of death in 40% while survivors had normal examination at 1 year of age. Mild abnormalities on the first EEG correlated with a good prognosis in both groups. The second EEG had a high predictive value, particularly in the cooled group. Persistence of inactivity at 3 days after birth was always associated with death. CONCLUSIONS: After HIE, the first two EEGs are good prognostic indicators, also in the cooled group. Strong discontinuity in the EEG observed on the first hours after hypothermia induction can be associated with a good outcome. SIGNIFICANCE: Early Stage 4 EEGs recorded during the hypothermia may not always indicate a poor prognosis in HIE. PMID- 21316018 TI - Study of accessory deep peroneal nerve motor conduction in a population of healthy subjects. AB - AIM OF THE STUDY: The short extensor muscle of the toes (extensor digitorum brevis) is innervated by the deep peroneal nerve (DPN) but can also receive innervation from an accessory deep peroneal nerve (ADPN), a branch of the superficial peroneal nerve (SPN). PATIENTS AND METHODS: We conducted a systematic electrophysiological study of the DPN and ADPN in 200 healthy subjects (400 legs). RESULTS: We found the presence of an ADPN in 13.5% of the subjects (8.5% of the legs). On average, ADPN amplitudes and motor potential areas were one fifth of those for the corresponding DPN. Without this systematic search, most of the ADPN would not have been detected. Comparative study of electrophysiological parameters in patients with and without ADPN showed a significantly higher (P<0.0001) DPN motor potential area ratio (distal/proximal ratio) in subjects without an ADPN. CONCLUSION: Even though electrophysiological identification of the ADPN is generally not easy (in simple DPN motor conduction studies), the nerve can sometimes be clinically symptomatic (ankle pain). Evaluation of the DPN motor potential area ratio (distal/proximal ratio) heightens the detection of ADPN. PMID- 21316019 TI - Correlation between functional and structural assessments of the optic nerve and retina in multiple sclerosis patients. PMID- 21316020 TI - Part one: for the motion. Serial sac pressure measurements can determine which type II endoleaks can be treated. PMID- 21316021 TI - Part two: against the motion. Measuring intra-sac pressure measurements is of no benefit to the patient. PMID- 21316026 TI - Animal model of human maturity onset diabetes of the young--type 2: similar but different? PMID- 21316027 TI - Long-term renal changes in the liver-specific glucokinase knockout mouse: implications for renal disease in maturity-onset diabetes of the young 2. AB - To investigate the functional and structural renal changes in a long-term liver specific glucokinase (gck) knockout mouse, a model was developed of maturity onset diabetes of the young (MODY2). Hemizygous gck knockout mice, gck(w/-) groups, were compared at 6, 10, and 14 months with their age-matched normal littermates, gck(w/w) groups. To examine changes, we compared body weight, fasting blood glucose, serum insulin, and creatinine levels, as well as 24-h urine samples that were collected for urine volume and protein analysis between the 2 groups. Renal tissues were collected and stained with hemotoxylin-eosin and periodic-acid Schiff for light microscopic observation. The expression of renal transforming growth factor beta1 (TGF-beta1) was determined by Western blot. Our results show that fasting blood glucose levels were significantly higher in gck(w/-) mice compared with gck(w/w) mice (P < 0.01) for all age groups. Compared with age-matched gck(w/w) mice, 10-month old gck(w/-) mice have significantly elevated body weights (P < 0.01) and protein contents (P < 0.001). A gradual increase in mesangial matrix and a thickening of the glomerular basement membrane was observed in gck(w/-) mice at 10 and 14 months. The levels of renal TGF-beta1 expression are increasing in both gck(w/-) and gck(w/w) mice. Our results indicate that renal changes occur in the liver-specific gck knockout mouse model of MODY2 and suggest that TGF-beta1 may play a key role in pathogenesis of these renal changes. PMID- 21316028 TI - Inflammation and reduced endothelial function in the course of severe acute heart failure. AB - Systemic inflammation and elevated circulating levels of the endogenous nitric oxide inhibitor asymmetrical dimethylarginine (ADMA) have been associated with increased risk in cardiogenic shock (CS). In this prospective study, we assessed, over 4 consecutive days, the changes and possible associations between vascular function, markers of inflammation, and circulating ADMA levels in patients with CS (n = 12) and postcardiotomy heart failure (n = 12, PC-HF). Vasodilator function was measured as a reactive hyperemia index (RH-index) using a finger plethysmograph. Blood samples were analyzed for plasma ADMA, interleukine-6, interleukine-8, intracellular adhesion molecule-1, and vascular adhesion molecule 1. Baseline RH-index was significantly attenuated compared with healthy controls (2.28) for both CS and PC-HF (1.35 and 1.45, respectively, P = 0.001). Although vasodilator function improved in PC-HF patients, it remained attenuated in CS. Inflammatory markers were markedly elevated followed by a significant fall during the observation period in both groups. ADMA levels increased significantly during the observation period for PC-HF, whereas no pattern of change was observed for CS. No association was found between the longitudinal changes in RH-index, markers of inflammation, or ADMA in CS. However, an improved RH-index was associated with decreasing inflammatory markers in PC-HF. ADMA correlated to arterial lactate levels and the degree of organ dysfunction in CS. In conclusion, CS and PC-HF were characterized by a marked inflammatory activation accompanied by an attenuated vasodilator function. ADMA was related to organ dysfunction and degree of hypoperfusion during CS but showed no correlations to inflammation or hampered vasodilator function. The pathogenic significance of these responses needs clarification. PMID- 21316029 TI - Reduction of arterial graft smooth muscle mass by moderate heat therapy. AB - Radial artery (RA) graft spasm is a major cause of early graft failure in coronary artery bypass grafting surgeries. We explored the feasibility of thermal reduction of smooth muscle mass to attenuate vasoconstriction. Rat and rabbit femoral arteries were treated thermally in situ (45 degrees C to 65 degrees C; 0 s to 120 s) and then excised at various time points for histological and physiological study (pressure-diameter relationships). Human radial arteries were treated in vitro and studied in similar fashion. Weeks after thermal treatment, no overt indication was noted of vasospasm, thrombosis, or scarring in the arterial wall; however, this intervention led to a thermal dose-dependent reduction of vasoconstriction (to phenylephrine or potassium chloride) and to a conspicuous loss of smooth muscle. Pressure-diameter relationships showed no aneurismal dilation of these demuscularized arteries up to 200 mmHg. Qualitatively identical results were obtained in human radial arteries. Thermal ablation of RAs may provide a simple, safe, and effective solution to postsurgical vasospasm. PMID- 21316031 TI - Analysis of cosegregation of intragenic DNA sequence variations as markers of maternal cell contamination in prenatal diagnosis of beta-thalassemia. AB - Prenatal diagnosis of 3 HBB gene mutations causing beta-thalassemia and hemoglobin D Punjab segregated in a South Indian nuclear family is reported along with a method identified as control for maternal cell contamination (MCC). Amplicons of the HBB gene from genomic DNA obtained from the blood of a thalassemic first child (proband), both parents, and a chorionic villus sample of their second pregnancy were directly sequenced. A test for MCC was performed by genotyping polymorphic microsatellite markers (D21S11 and D21S1270) by quantitative fluorescence polymerase chain reaction (QF-PCR) and capillary gel electrophoresis. The pedigree analysis showed proband as a compound heterozygote of NG_000007.3:g.70691G>C and NG_000007.3:g.72128T>C mutations; showed the father as a compound heterozygote of NG_000007.3:g.72128T>C and NG_000007.3:g.71938G>C mutations; and showed the mother as a heterozygous carrier of the NG_000007.3:g.70691G>C mutation. The fetus inherited a normal maternal allele and a mutant paternal allele NG_000007.3:g.72128T>C and was ascertained a carrier of beta-thalassemia. Analysis of cosegregation of 5 other single nucleotide polymorphisms (SNPs) in the family, including NG_000007.3:g.70603T>C, NG_000007.3:g.71055G>C, NG_000007.3:g.71113T>G, NG_000007.3:g.72332G>A, and NG_000007.3:g.72334A>C, defined the disease allele haplotypes. QF-PCR showed no extra maternal alleles in the fetal sample. Prenatal diagnosis of mutations and an absence of MCC was confirmed by cosegregation of the SNPs, suggesting the utility of a panel of such polymorphisms that can serve to identify MCC quickly and reliably. PMID- 21316030 TI - Redistribution of labile plasma zinc during mild surgical stress in the rat. AB - Zinc is an essential trace element and cofactor for many cellular processes. Uptake of ionized divalent zinc (Zn(2+)) in peripheral tissues depends on its total content in the circulation and on mechanisms facilitating delivery to tissues in its labile form. Understanding mechanisms of Zn(2+) delivery has been hindered by the absence of techniques to detect labile Zn(2+) in the circulation. In this study, we report the use of the fluorescent zinc-binding dye (ZnAF-2) to detect changes in labile Zn(2+) in the circulating plasma of the rat under standardized conditions, including exogenous infusions to increase plasma Zn(2+) and an infusion of the chelator, citrate, to decrease labile Zn(2+) in the plasma without altering total Zn(2+) content. In a model of mild surgical stress (unilateral femoral arterial ligation), plasma levels of total and labile Zn(2+) decreased significantly 24 h after the operation. Ultrafiltration of plasma into high- and low-molecular weight macromolecule fractionations indicated that binding capacity of zinc in the high-molecular weight fraction is impaired for the entire 24-h interval after induction of mild surgical stress. Affinity of the filtrate fraction was rapidly and reversibly responsive to anesthesia alone, decreasing significantly at 4 h and recovering at 24 h; in animals subjected to moderate surgical stress, this responsiveness was lost. These findings are the first reported measurements of labile Zn(2+) in the circulation in any form of mild systemic stress. Zinc undergoes substantial redistribution in the plasma as a response to surgical stress, leading to increased availability in lower molecular weight fractions and in its labile form. PMID- 21316032 TI - A step toward hemodynamic assessment with CT angiography. PMID- 21316033 TI - President's page: Looking back at 2010 and ahead to 2011. PMID- 21316034 TI - Regulation of antimicrobial peptide expression in human gingival keratinocytes by interleukin-1alpha. AB - In the oral cavity, mucosal keratinocytes resist bacterial infection, in part, by producing broad-spectrum antimicrobial peptides (AMPs) including defensin, adrenomedullin and calprotectin. Epidermal keratinocyte expression of many AMPs increases in response to interleukin-1alpha (IL-1alpha). IL-1alpha is produced by epidermal keratinocytes and regulates cell differentiation. To better understand innate immunity in the oral cavity, we sought to determine how IL-1alpha might regulate expression of AMPs by human gingival keratinocytes (HGKs) using DNA microarray and Western blot analyses. HGKs from three subjects expressed eleven AMPs, including S100A7, S100A8, S100A9, S100A12, secretory leucocyte protease inhibitor, lipocalin 2 (LCN2), cystatin C and beta-defensin 2. Of the expressed AMPs, S100A7, S100A12 and LCN2 were up-regulated by IL-1alpha (inducible AMPs); the other AMPs were considered to be constitutive. Human gingival keratinocytes, therefore, express constitutive and IL-1alpha-inducible AMPs to provide a rapid and robust innate response to microbial infection. PMID- 21316035 TI - Animal models of obsessive-compulsive disorder. PMID- 21316038 TI - The first ferrocene analogues of muramyldipeptide. AB - The two structurally interesting bioorganometallic analogues of muramyldipeptide (MDP) with potential immunomodulatory activity were synthesized starting from the O-protected N-acetylmuramic acid (MurNAc), L- or D-Ala and 1'-aminoferrocene-1 carboxylic acid (Fca). They were fully characterized by IR, (1)H NMR, (13)C NMR and CD spectroscopy as well as by FD mass spectrometry. PMID- 21316037 TI - A review of functional brain imaging correlates of successful cognitive aging. AB - Preserved cognitive performance is a key feature of successful aging. Several theoretical models have been proposed to explain the putative underlying relationship between brain function and performance. We aimed to review imaging studies of the association between brain functional response and cognitive performance among healthy younger and older adults to understand the neural correlates of successful cognitive aging. MEDLINE-indexed articles published between January 1989 and December 2009 and bibliographies of these articles and related reviews were searched. Studies that measured brain function with functional magnetic resonance imaging or positron emission tomography, evaluated cognitive performance, analyzed how cognitive performance related to brain response, and studied healthy older individuals were included. Eighty of 550 articles met these criteria. Seventy percent of the studies reported some brain regions in which greater activation related to better cognitive performance among older participants. This association was not universal, however, and was seen mainly in frontal cortex brain response and seemed to be more common among older compared with younger individuals. This review supports the notion of compensatory increases in brain activity in old age resulting in better cognitive performance, as suggested by hemispheric asymmetry reduction and posterior anterior shift models of functional brain aging. However, a simple model of bigger structure -> greater brain response -> better cognitive performance might not be accurate. Suggestions for future research are discussed. PMID- 21316039 TI - Elucidation of the full O-polysaccharide structure and identification of the core type of the lipopolysaccharide of Providencia alcalifaciens O9. AB - Opportunistic human pathogens of the genus Providencia from the family Enterobacteriaceae are serotyped by their O-antigens, which represent the O polysaccharide chains of the lipopolysaccharides (LPSs) on the cell surface. In this work, the O-polysaccharide of Providencia alcalifaciens O9 was obtained by mild acid degradation of a long-chain S-form LPS. The structure of the hexasaccharide repeat (O-unit) of the O-polysaccharide containing one D-Gal, two D-Glc, and three D-GalNAc residues was established by sugar and methylation analyses along with one- and two-dimensional (1)H and (13)C NMR spectroscopy. Another degradation product was derived from a short-chain SR-form LPS and found to consist of a core oligosaccharide bearing one O-unit. Its studies by NMR spectroscopy and electrospray ionization mass spectrometry enabled identification of one of the GalNAc residues as the first monosaccharide of the O-unit, whose glycosidic linkage links the O-units to each other and the first O-unit to the core. The core is distinguished by the occurrence of two glycoforms differing in the nature of a lateral monosaccharide, which is either D-Glc or D-GlcNAc. Although composed of common monosaccharides, the O-polysaccharide of P. alcalifaciens O9 has a unique structure among bacterial polysaccharides, whereas the oligosaccharide region belongs to one of several core types recognized in the LPSs of Providencia. PMID- 21316040 TI - The FRCR 2B examination: a survey of candidate perceptions and experiences. AB - AIM: To survey the views of recent candidates of the Fellowship of the Royal College of Radiologists (FRCR) 2B examination with reference to assessment validity, reliability, and acceptability. MATERIALS AND METHODS: One thousand, two hundred and four UK radiology trainees and consultants were invited to complete an automated internet questionnaire regarding their experiences and perceptions of the FRCR 2B examination. The questionnaire was informed by a review of the literature. Eligible participants were candidates who had taken the examination within the previous 3 years. RESULTS: Four hundred and ninety-seven out of 1204 (41%) responses were received; of which 258/497 (52% of respondents) were eligible for inclusion into the study. The rapid reporting component is perceived to be significantly fairer than the oral section (82 versus 70% agree; p<0.001). The oral component fared poorly in perceived performance-reducing anxiety levels but well in questions relating to validity and reliability. Female candidates are more likely to find the FRCR 2B unfair (p=0.01) and experience performance-reducing anxiety (p<0.001) than males. No gender differences were observed in first-time pass rates (p=0.6). Candidate first language did not affect anxiety levels (p=0.9) or first-time pass rates (p=0.06). Only 12% of candidates agreed that the oral examination should move to an objective structured clinical format. CONCLUSION: Candidates score the FRCR 2B examination well in test validity with little desire for change to the oral examination format. Efforts to help reduce anxiety levels in the oral component would improve perceived fairness. PMID- 21316041 TI - Mindset changes lead to drastic impairments in rule finding. AB - Rule finding is an important aspect of human reasoning and flexibility. Previous studies associated rule finding failure with past experience with the test stimuli and stable personality traits. We additionally show that rule finding performance is severely impaired by a mindset associated with applying an instructed rule. The mindset was established in Phase 1 (manipulation) of the experiment, before rule finding ability was assessed in Phase 2 (testing). The impairment in rule finding was observed even when Phase 1 involved executing a single trial (Experiment 2), and when entirely different stimuli and rules were used in the two phases of the experiment (Experiments 3-6). Experiments 4-6 show that applying an instructed rule in Phase 1 impaired subsequent (Phase 2) feedback evaluation, rule generation, and attention switching between rules, which are the three component processes involved in rule finding according to COVIS (Ashby, Alfonso-Reese, Turken, & Waldron, 1998). PMID- 21316042 TI - E-shaver: an improved DullRazor((r)) for digitally removing dark and light colored hairs in dermoscopic images. AB - We present an efficient and improved method for hair removal from dermoscopic images, which is faster and can remove hairs more effectively as compared to the existing and widely used DullRazor((r)). To do so, we first detect the predominant orientation of hairs in the image by using Radon transform, followed by filtering the image by Prewitt filters using the orientation of existing hairs. Undesirable effects, such as non-hair structures and noise are removed from the image by thresholding-averaging-thresholding, followed by smoothing. The proposed scheme has the advantage of removing bubbles, as well. Implementation of our proposed scheme on different dermoscopic images validates its improved performance. PMID- 21316043 TI - Root-induced changes to cadmium speciation in the rhizosphere of two rice (Oryza sativa L.) genotypes. AB - Our aim was to investigate rhizosphere effects on the chemical behavior of Cd. This was done in a glasshouse experiment, where two rice cultivars (Zhenong54 and Sixizhan) were grown in soil spiked with cadmium (Cd) at two levels, 3.9 +/- 0.5 and 8.3 +/- 0.5 mg kg(-1) soil, placed in a rhizobox until ripening stage. Chemical forms of cadmium near the root surface were then assessed using a sequential extraction procedure (SEP). There were significant differences in Cd species, especially exchangeable Cd (EXC-Cd) between the two rice cultivars as affected by rice roots. The lowest EXC-Cd with Zhenong54 appeared in the near rhizosphere area with little difference between tillering stage and ripening stage while Sixizhan had its lowest EXC-Cd concentration in the root compartment. Both cultivars had slight changes in the Fe/Mn oxide-bound fraction of Cd (FMO Cd) at the grain ripening stage while the control treatments without plants had a significant increase in FMO-Cd at the same time, indicating a transformation from a less bioavailable form (FMO-Cd) to more bioavailable forms (EXC-Cd). Soil microbial biomass in the vicinity of the root surface had opposite trends to some extent with EXC-Cd, partly because of the root-induced changes to bioavailable Cd. Unlike Zhenong54, Sixizhan had a higher Cd concentration in the root, but only a small proportion of Cd translocated from the root to grain. PMID- 21316044 TI - Distribution of toenail selenium levels in young adult Caucasians and African Americans in the United States: the CARDIA Trace Element Study. AB - BACKGROUND: Data on selenium (Se) levels in American young adults, especially in African Americans, are lacking. OBJECTIVE: This study presented toenail Se distributions in American young adults of both genders, including both Caucasians and African Americans; and explored potential predictors of toenail Se levels. DATA AND METHODS: Data from the Coronary Artery Risk Development in Young Adults study among 4252 American young adults, aged 20-32 in 1987 was used to examine toenail Se levels by instrumental neutron-activation analysis. The distribution of Se levels was described and multivariable linear regression was used to examine potential modifiers of toenail Se concentration within ethnicity-gender subgroups. RESULTS: The geometric mean of toenail Se in this cohort was 0.844 MUg/g (95% CI, 0.840-0.849 MUg/g) and the median was 0.837 MUg/g (95% CI, 0.833 0.844 MUg/g). Median levels from lowest to highest quintile were 0.691, 0.774, 0.838, 0.913 and 1.037 MUg/g. Se levels varied geographically, and were generally in accordance with its concentrations in local soil. Males, African Americans, current smokers, heavy drinkers and less educated participants were more likely to have low Se levels. CONCLUSION: This study suggests that toenail Se levels vary geographically depending on soil Se concentrations. In addition to gender, ethnicity and education level, smoking status and alcohol consumption are two important indicators of Se status since they are modifiable lifestyle factors. Findings from this study might aid public health professionals in identifying people at relatively high or low Se levels, so that chronic disease prevention efforts can be directed toward these subgroups. PMID- 21316045 TI - Morphological embryo assessment: reevaluation. AB - OBJECTIVE: To assess whether the pronuclear score and embryo nuclear scoring have an additive value to day 2 morphology criteria in the prediction of the implantation rate (IR). DESIGN: Retrospective clinical study. SETTING: IVF Unit, Soroka University Medical Center. PATIENT(S): Analysis of all homogenous IVF fresh embryo transfers from 2008-2010. INTERVENTION(S): Morphological evaluation of pronuclear scoring, embryo nuclear scoring, and day 2 embryo morphology scoring on embryos obtained from IVF or intracytoplasmic sperm injection (ICSI) cycles. MAIN OUTCOME MEASURE(S): Implantation rate of homogeneous transfers. RESULT(S): No statistical association was found between the pronuclear scoring system (Z) and IR. The pronuclear score Z3 had a significantly better performance than Z1, Z2, and Z4 (IR = 25.2%, 22%, 21.4%, and 11.8%, respectively). Assessment of the second day embryo morphology scoring (index [IDX]) was found to associate with IR. IDX1, IDX2, IDX3, IDX4, and IDX5 had an IR of 36.1%, 28%, 21.9%, 14.2%, and 0, respectively. The nuclear scoring including: 1 nucleus in all blastomeres, 1 nucleus in part of the blastomeres, no visualization, and multinucleation showed high association with IR = 32.7%, 22.9%, 14.8%, and 9.1%, respectively. The effect of the nuclear scoring on IR was lost in a multivariable analysis that included day 2 embryo morphology scoring. CONCLUSION(S): Our results suggest that there is no additive value in grading the zygote on day 1 or embryo nuclear scoring on day 2 to day 2 embryo morphology for the prediction of IR. PMID- 21316046 TI - Contrast-enhanced ultrasound reveals real-time spatial changes in vascular perfusion during early implantation in the macaque uterus. AB - OBJECTIVE: To use contrast-enhanced ultrasound (CEU) to quantify blood flow in the macaque uterus during early pregnancy. DESIGN: Prospective nonhuman primate study. SETTING: Oregon National Primate Research Center. ANIMALS: Naturally cycling female rhesus macaques (Macaca mulatta). INTERVENTION(S): Female macaques were mated on days 11-14 of the cycle. Females were then imaged by CEU and Doppler ultrasound once every 3 days from day 21 through day 39 of the fertile cycle. MAIN OUTCOME MEASURE(S): Visualization and quantification of uterine vascular perfusion. RESULT(S): CEU identified the primary placental disc and underlying vessels approximately 2 days earlier than Doppler ultrasound was able to observe endometrial thickening. CEU revealed spatial differences in vascular perfusion between the endometrium, myometrium, and endometrial-myometrial (junctional) zone. Myometrium displayed the highest rate of blood flow (>10 mL/min/g tissue). There was less blood flow in the endometrium and junctional zone (<3 mL/min/g). A brief fall in progesterone was observed during early implantation, which was correlated with reduced blood flow to all three uterine compartments, but did not reduce flow to the placenta. CONCLUSIONS: CEU provides a sensitive, noninvasive method to assess vascular perfusion of the uterus during embryo implantation in macaques. We propose CEU as a new diagnostic tool to monitor vascular changes associated with early pregnancy in women. PMID- 21316048 TI - Anastrozole single-dose protocol in women with oligo- or anovulatory infertility: results of a randomized phase II dose-response study. AB - OBJECTIVE: To compare the effects of anastrozole and clomiphene citrate (CC) on follicular development and ovulation in infertile women with ovulatory dysfunction. DESIGN: Phase II, prospective, randomized, assessor-blind, multicenter, dose-finding, noninferiority study. SETTING: Outpatient. PATIENT(S): Infertile women with ovulatory dysfunction, aged 18-35 years, and body mass index <35 kg/m(2). INTERVENTION(S): Single-dose anastrozole at 5 mg (n = 39), 10 mg (n = 39), 20 mg (n = 39), or 30 mg (n = 38) or a 5-day course of CC at 50 mg/d (n = 39) as starting doses. MAIN OUTCOME MEASURE(S): The primary endpoint was the ovulation rate in the first treatment cycle (cycle 1). Ovulation was defined as a midluteal phase serum P level >= 10 ng/mL or clinical pregnancy. RESULT(S): In cycle 1 the ovulation rates for a single dose of anastrozole at 5, 10, 20, and 30 mg were 46.2%, 41.0%, 23.1%, and 28.9%, respectively, whereas that for CC at 50 mg/d was 61.5%. Among women with fewer than six menses per year, the cumulative ovulation rates over three cycles were comparable in the anastrozole 5 mg (52.4%) and CC 50 mg/d (42.3%) groups. CONCLUSION(S): In terms of ovulation rates in cycle 1, single-dose anastrozole at 5, 10, 20, and 30 mg was not as effective as CC at 50 mg/d for 5 days (noninferiority was not shown). PMID- 21316047 TI - In vivo delivery of FTY720 prevents radiation-induced ovarian failure and infertility in adult female nonhuman primates. AB - OBJECTIVE: To determine whether sphingosine-1-phosphate (S1P), or the S1P mimetic FTY720 shields ovaries of adult female rhesus monkeys from damage caused by 15 Gy of targeted radiotherapy, allowing for the retention of long-term fertility, and to evaluate whether S1P protects human ovarian tissue (xenografted into mice) from radiation-induced damage. DESIGN: Research animal study. SETTING: Research laboratory and teaching hospital. PATIENT(S): Adult female rhesus macaques (8-14 years of age; n = 21) and two women (24 and 27 years of age) undergoing gynecologic surgery for benign reasons, after informed consent and approval. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Ovarian histologic analysis, ovarian reserve measurements, and fertility in mating trials. RESULT(S): Rapid ovarian failure was induced in female macaques by ovarian application of 15 Gy of radiation. Females given S1P or FTY720 by direct intraovarian cannulation for 1 week before ovarian irradiation rapidly resumed menstrual cycles because of maintenance of follicles, with greater beneficial effects achieved using FTY720. Monkeys given the S1P mimetic before ovarian irradiation also became pregnant in mating trials. Offspring conceived and delivered by radioprotected females developed normally and showed no evidence of genomic instability, as measured by micronucleus frequency in reticulocytes. Adult human ovarian cortical tissue xenografted into mice also exhibited a reduction in radiation-induced primordial oocyte depletion when preexposed to S1P. CONCLUSION(S): S1P and its analogs hold clinical promise as therapeutic agents to preserve ovarian function and fertility in female cancer patients exposed to cytotoxic treatments. PMID- 21316049 TI - The role of intraductal US in the management of idiopathic recurrent pancreatitis without a definite cause on ERCP. AB - BACKGROUND: The cause of pancreatitis is unknown in as many as 30% of cases of recurrent acute pancreatitis, even after ERCP. OBJECTIVE: To investigate the role of intraductal US (IDUS) for managing idiopathic recurrent pancreatitis (IRP). DESIGN: Prospective study. SETTING: Tertiary referral hospital. PATIENTS: Thirty one patients with suspicious IRP with negative findings on ERCP. INTERVENTIONS: IDUS during ERCP. MAIN OUTCOME MEASUREMENTS: IDUS findings showing any possible cause of pancreatitis. RESULTS: IDUS revealed small bile duct stones (<=3 mm) in 5 patients (16.1%) and sludge in 3 patients (9.7%). The detection rate for a bile duct stone and sludge was significantly higher in patients with a dilated CBD than a nondilated CBD on ERCP (71.4 vs 12.5%; P < .05). Recurrent pancreatitis did not develop in 7 of 8 patients with biliary stones or sludge after an endoscopic sphincterotomy (EST). Two patients (6.5%) demonstrated a small polypoid lesion on the distal end of the pancreatic duct. One patient underwent surgery for intra-ampullary cancer, and another one underwent EST without another attack of pancreatitis. Three patients (9.7%) showed evidence of chronic pancreatitis with small pancreatic stones and/or calcifications on IDUS. LIMITATIONS: Small number of patients. IDUS results were not compared with those of conventional EUS. There was no reference standard for chronic pancreatitis as diagnosed by IDUS. CONCLUSIONS: IDUS identified a possible cause of idiopathic recurrent pancreatitis in 42% of patients with negative findings on ERCP. The IDUS-guided approach combined with ERCP and EST may be useful for decreasing recurring attacks of pancreatitis. PMID- 21316050 TI - Endoscopic prediction of tumor invasion depth in early gastric cancer. AB - BACKGROUND: Although conventional endoscopy is a good diagnostic tool to evaluate tumor depth (T staging) in early gastric cancer (EGC), its accuracy has not been determined and no consensus has been reached regarding standard endoscopic criteria. OBJECTIVE: To evaluate the diagnostic accuracy of endoscopic T staging and to identify the characteristic endoscopic features for mucosal (T1m) and submucosal (T1sm) tumors. DESIGN: Retrospective study. PATIENTS: A consecutive 2105 patients with EGC who underwent either surgical (n=1624) or endoscopic (n=481) resection. INTERVENTION: Endoscopic staging was performed by consensus of 2 endoscopists based on the characteristic endoscopic criteria of T1m (smooth surface protrusion or depression, slight marginal elevation, and the smooth tapering of converging folds) and T1sm (irregular surface, marked marginal elevation, and clubbing/abrupt cutting/fusion of converging folds). The endoscopic staging was compared with the pathologic staging of the resected specimen. RESULTS: The overall accuracy of endoscopic staging was 78.0% (1642/2105). The sensitivity, specificity, and positive and negative predictive values of T1m endoscopic staging were 85.5%, 73.9%, 82.0%, and 78.5%, whereas those for T1sm were 72.6%, 81.9%, 71.9%, and 82.4%, respectively. LIMITATIONS: Retrospective study. Endoscopic predictions for T1sm tumors were correct in only 72% of cases. CONCLUSIONS: Conventional endoscopy was found to provide reliable accuracy for T staging in EGC and may be an effective method for assessing penetration depth. A detailed endoscopic evaluation regarding tumor base, margin, and converging folds may provide useful information to determine tumor depth and to select the optimal therapeutic strategy, particularly for endoscopic resection. PMID- 21316052 TI - What can qualitative approaches bring to trauma outcome research? PMID- 21316051 TI - Femoral shaft fractures in the elderly--role of prior bisphosphonate therapy. AB - INTRODUCTION: There is a recent surge in interest on bisphosphonate related femoral fractures. Most studies have examined subtrochanteric fractures in patients on long-term bisphosphonates. This study evaluates the characteristics of low-impact femoral shaft fractures in elderly patients on long-term alendronate. MATERIALS AND METHODS: All patients above 60 years old admitted to the National University Hospital for femoral shaft fracture from January 2003 to January 2007 were retrospectively analysed. Of the 55 patients included, 7 had prior alendronate therapy and were examined in detail. RESULTS: All 7 patients on prior alendronate therapy sustained their fractures by low-impact or atraumatic mechanisms of injury. 5 of these 7 patients exhibited a characteristic fracture pattern of thickened lateral cortices at the proximal fracture fragment (p<0.05) and all 7 patients had either transverse or short oblique fractures. Notably, none of the 7 patients had bone mineral density scans prior to their fractures. One patient was started on alendronate after a vertebral compression fracture, whilst the other 6 patients were started on alendronate without any clear clinical indication. All 7 patients reported prodromal thigh pain 3 weeks to 2 years prior to the fracture. CONCLUSIONS: Low-impact femoral shaft fractures in elderly patients on long-term alendronate therapy represent a new entity of insufficiency fractures, with characteristic low-impact modes of injury and fracture patterns on radiograph. Prodromal thigh pain is a warning sign for impending fracture in this group of patients and should be evaluated closely. Teriparatide is a possible alternative to alendronate following such a fracture though more long-term clinical studies are required. PMID- 21316053 TI - A six-strand technique for zone II flexor-tendon repair in children younger than 2 years of age. AB - INTRODUCTION: A six-strand repair for zone II flexor-tendon repair in children younger than 2 years of age has not been reported in the literature because of the small size of the flexor tendon in this very young age group. PURPOSE: The aim is to introduce the use of a six-strand repair in zone II flexor-tendon repair in children younger than 2 years of age. METHODS: A total of 12 children younger than 2 years, with 12 injured fingers, were treated over a 10-year period. A 'profundus only' repair was done using three separate 'figure of eight' core sutures and a continuous epitendinous suture. The repair site was bulky and 'venting' of the pulley system proximal to the repair site was done. The hand was immobilised for 3.5 weeks after surgery and then physiotherapy exercises were started. The final net range of motion at the interphalangeal joints was measured and the outcome was assessed as per the Strickland-Glogovac criteria. RESULTS: There were no ruptures. The final outcome in range of motion was excellent in nine children and good in the remaining three children. None of the children required tenolysis. CONCLUSION: Our six-strand technique is an alternative technique for zone II flexor-tendon repair in children younger than 2 years of age, but the bulky repair site requires a 'profundus only' repair and 'venting' of the pulley system. PMID- 21316054 TI - Short-term progression of maximum intima-media thickness of carotid plaque is associated with future coronary events in patients with coronary artery disease. AB - OBJECTIVE: This study examined whether changes in maximum intima-media thickness of carotid plaque (plaque-IMTmax) over 6 months predict future coronary events in patients with carotid plaque and coronary artery disease (CAD). METHODS: This study included 240 patients with CAD who had a carotid plaque (IMT >= 1.1mm) at entry. A carotid ultrasound examination was performed at entry (1st test) and after 6 months (2nd test). The carotid plaque with the greatest axial thickness at the 1st test was selected as the target plaque for monitoring the change in plaque-IMTmax. After the 2nd test, patients were prospectively followed-up for 3 years or until the occurrence of one of the following coronary events: cardiac death, non-fatal myocardial infarction, or unstable angina pectoris requiring coronary revascularization. RESULTS: The change in plaque-IMTmax over 6 months ranged from -0.85 to 0.97 mm (mean, -0.006 +/- 0.319 mm). There were 41 events during follow-up. In a stepwise multivariate Cox proportional hazards model, the change in plaque-IMTmax was a significant predictor of coronary events after adjustment for known risk factors (HR per 0.1mm increase over 6 months, 1.21; 95%CI, 1.10-1.33, p=0.0001). Analysis of receiver operating characteristic (ROC) curves showed that the addition of the change in plaque-IMTmax to conventional risk factors resulted in a greater area under the ROC curve compared with conventional risk factors alone (0.81 and 0.70, respectively, p=0.02). CONCLUSION: Short-term progression of carotid plaque-IMTmax was associated with future coronary events in patients with CAD. PMID- 21316055 TI - Association of systemic inflammatory activity with coronary and carotid atherosclerosis in the very elderly. AB - OBJECTIVE: To verify the existence of association between plasma levels of pro- or anti-inflammatory mediators and atherosclerotic burden at coronary and carotid arteries in individuals aged of 80 or more years old. METHODS: Healthy individuals aged between 80 and 102 years old (n = 178) underwent evaluation of plasma cytokines and acute phase proteins, intima-media thickness (IMT) and presence of plaques in carotid arteries by ultrasound and coronary artery calcification (CAC) by cardiac computed tomography. RESULTS: There was no association between CAC and carotid plaques (p = 0.8), maximum (p = 0.06) or mean IMT (p = 0.2). No association was found between the presence of carotid plaques and CRP (p = 0.4), TNF-alpha (p = 0.8) or IL-10 (p = 0.2). Likewise, individuals in the first three quartiles for CRP, TNF-alpha or IL-10 had similar values of CAC, mean and maximum IMT. In contrast, individuals above the 75th percentile for CRP or for TNF-alpha had enhanced maximum IMT (p = 0.017 and p < 0.0001) and CAC (p = 0.026 and p = 0.01) and subjects with IL-10 levels above the 75th percentile had lower maximum IMT (p = 0.027) and CAC (p = 0.006) as compared with those below this percentile. There was no difference in mean IMT for individuals above or below the 75th percentile for CRP, TNF-alpha or IL-10. CONCLUSION: In very old individuals, CAC and maximum IMT were positively associated with systemic inflammatory activity only in those above the 75th percentile. The markers of atherosclerotic burden at coronary and carotid arteries were not related to each other and were distinctly associated with pro- and anti-inflammatory mediators, suggesting that atherosclerosis development is different in these vascular beds. PMID- 21316057 TI - Biomechanical modeling of eye trauma for different orbit anthropometries. AB - In military, automotive, and sporting safety, there is concern over eye protection and the effects of facial anthropometry differences on risk of eye injury. The objective of this study is to investigate differences in orbital geometry and analyze their effect on eye impact injury. Clinical measurements of the orbital aperture, brow protrusion angle, eye protrusion, and the eye location within the orbit were used to develop a matrix of simulations. A finite element (FE) model of the orbit was developed from a computed tomography (CT) scan of an average male and transformed to model 27 different anthropometries. Impacts were modeled using an eye model incorporating lagrangian-eulerian fluid flow for the eye, representing a full eye for evaluation of omnidirectional impact and interaction with the orbit. Computational simulations of a Little League (CD25) baseball impact at 30.1m/s were conducted to assess the effect of orbit anthropometry on eye injury metrics. Parameters measured include stress and strain in the corneoscleral shell, internal dynamic eye pressure, and contact forces between the orbit, eye, and baseball. The location of peak stresses and strains was also assessed. Main effects and interaction effects identified in the statistical analysis illustrate the complex relationship between the anthropometric variation and eye response. The results of the study showed that the eye is more protected from impact with smaller orbital apertures, more brow protrusion, and less eye protrusion, provided that the orbital aperture is large enough to deter contact of the eye with the orbit. PMID- 21316056 TI - Nitric oxide activates PI3-K and MAPK signalling pathways in human and rat vascular smooth muscle cells: influence of insulin resistance and oxidative stress. AB - OBJECTIVE: Vascular smooth muscle cells (VSMCs) from the animal model of insulin resistance obese Zucker rats (OZR) show impaired ability of nitric oxide (NO) to increase cGMP and of cGMP to activate its specific kinase PKG, these defects being attributable to oxidative stress. We aimed to investigate the intracellular signalling downstream PKG in human and rat VSMC, and to clarify whether it is modified by insulin resistance and oxidative stress. METHODS: In aortic VSMC from humans, lean Zucker rats (LZR) and OZR, we measured by Western blots the activation induced by NO and cGMP of signalling molecules of PI3-K and MAPK pathways, with or without PKG inhibition, hydrogen peroxide and antioxidants. We explored the mechanism of the increased oxidative stress in VSMC from OZR by measuring superoxide anion concentrations (luminescence method) with or without inhibition of NADPH oxidase, xanthine oxidase, and mitochondrial electron transport chain complex and by measuring superoxide dismutase (SOD) expression (Western blot) and activity. RESULTS: In VSMC from humans and LZR, the NO/cGMP/PKG pathway activates both PI3-K (Akt, mTOR) and MAPK (ERK-1/2, p38MAPK) signalling. This effect is attenuated in VSMC from OZR, in which the greater oxidative stress is mediated by NADPH oxidase and mitochondrial complex and by a reduced synthesis/activity of SOD. Impairment of the NO/cGMP/PKG signalling is reproduced in VSMC from LZR by hydrogen peroxide and reverted in VSMC from OZR by antioxidants. CONCLUSIONS: In VSMC from an animal model of insulin resistance the NO/cGMP/PKG intracellular signalling is impaired due to an increased oxidative stress. PMID- 21316058 TI - The effects of step width and arm swing on energetic cost and lateral balance during running. AB - In walking, humans prefer a moderate step width that minimizes energetic cost and vary step width from step-to-step to maintain lateral balance. Arm swing also reduces energetic cost and improves lateral balance. In running, humans prefer a narrow step width that may present a challenge for maintaining lateral balance. However, arm swing in running may improve lateral balance and help reduce energetic cost. To understand the roles of step width and arm swing, we hypothesized that net metabolic power would be greater at step widths greater or less than preferred and when running without arm swing. We further hypothesized that step width variability (indicator of lateral balance) would be greater at step widths greater or less than preferred and when running without arm swing. Ten subjects ran (3m/s) at four target step widths (0%, 15%, 20%, and 25% leg length (LL)) with arm swing, at their preferred step width with arm swing, and at their preferred step width without arm swing. We measured metabolic power, step width, and step width variability. When subjects ran at target step widths less (0% LL) or greater (15%, 20%, and 25% LL) than preferred, both net metabolic power demand (by 3%, 9%, 12%, and 15%) and step width variability (by 7%, 33%, 46%, and 69%) increased. When running without arm swing, both net metabolic power demand (by 8%) and step width variability (by 9%) increased compared to running with arm swing. It appears that humans prefer to run with a narrow step width and swing their arms so as to minimize energetic cost and improve lateral balance. PMID- 21316059 TI - Application of hydrophilic interaction chromatography for the analysis of polar contaminants in food and environmental samples. AB - For the analysis of highly hydrophilic and polar compounds, Hydrophilic Interaction Chromatography (HILIC) has been established as a valuable complementary approach to reversed-phase liquid chromatography (RPLC). Moreover, the use of mobile phases with a high percentage of organic solvent in HILIC separation is beneficial for mass spectrometric (MS) detection, because of enhanced ionization which results in an increased sensitivity. In this review, various applications of HILIC are described for a number of environmental and food contaminants together with detailed methodological descriptions and the advantages or drawbacks of HILIC compared to other LC methods are critically discussed. In the first part of the review, an overview is given of the work that has been carried out with HILIC for the analysis of pharmaceuticals and pesticides in environmental samples. HILIC has shown its applicability for polar pharmaceuticals, such as antibiotics, estrogens and their metabolites, drugs of abuse, cytostatics, metformin and contrast agents. In the pesticide group, HILIC chromatography was helpful for polar phenylurea and organophosphorus pesticides. The second part of the review focuses on the analysis of antibiotic residues in food and feed with HILIC, while in the pesticide group, HILIC experiments have been reported for dithiocarbamates and quaternary ammonium compounds. The last chapter gives an overview of the analysis by HILIC of miscellaneous analytes in aquatic and food/feed samples. PMID- 21316060 TI - Covalently bonded polysaccharide-modified stationary phase for per aqueous liquid chromatography and hydrophilic interaction chromatography. AB - The mixed sulfated/methacryloyl polysaccharide derivative was prepared and successfully immobilized onto the surface of porous silica particles by polymerization. Polysaccharide derivative was calculated as 10.33% in the stationary phase prepared. The new stationary phase (PMSP) showed both hydrophilic interaction (HILIC) and per aqueous liquid chromatography (PALC) characteristics. The effects of column temperature, the water content, pH and ion strength of mobile phase on the retention time of test compounds in highly aqueous eluents were investigated to evaluate the PALC features of PMSP. The column efficiency is about 31,000 plates/m for benzoic acid in water/ACN (97/3, v/v) mobile phase at a flow rate of 1.0 mL/min. Compared with C18 column, the PMSP had shorter retention time for weak polar and non-polar compounds, but also showed stronger retention for strong polar compounds. It indicated that PALC was a suitable mode of chromatography as replacement of HILIC and complementarity of reversed-phase liquid chromatography (RPLC). PMID- 21316061 TI - Effect of Ni cations and microwave hydrothermal treatment on the related properties of layered double hydroxide-ethylene vinyl acetate copolymer composites. AB - The effect of Ni cations and synthetic methods on the crystallinity, morphology, thermal stability and hydrophobic properties of carbonate-containing layered double hydroxides (LDHs) was investigated. The conventional hydrothermal treatment (CHT) and microwave hydrothermal treatment (MHT) methods were used to synthesize LDHs. The microwave treatment LDHs (MgAl-MHT and NiMgAl-MHT) have higher crystallinity and smaller crystal sizes than the conventional hydrothermal treatment LDHs (MgAl-CHT and NiMgAl-CHT). IR results indicate that the interactions of both OH(-)-CO(3)(2-) and CO(3)(2-)-CO(3)(2-) in NiMgAl-MHT are weaker. Furthermore, the thermal decomposition of OH(-) and CO(3)(2-) in the NiMgAl-MHT sample occurred earlier and faster than that of other LDHs. The contact angle values indicate that NiMgAl-MHT has the highest hydrophobicity. The influences of the LDHs on the thermal degradation and flame retardance of ethylene vinyl acetate copolymer (EVA)-LDH composites have also been studied in detail. NiMgAl-MHT has the more homogeneous nano-dispersed layers in EVA matrix. All composites enhance the thermal stability compared with the pure EVA because of the release of H(2)O and CO(2). Flame retardance of NiMgAl-MHT-EVA was obviously higher than that of the pure EVA and other composites. PMID- 21316062 TI - Dual-stimuli responsive behaviors of diblock polyampholyte PDMAEMA-b-PAA in aqueous solution. AB - Two poly(2-(dimethylamino)ethyl methacrylate)-b-poly(acrylic acid) diblock copolymers, PDMAEMA(84)-b-PAA(18) and PDMAEMA(50)-b-PAA(18), were synthesized by the atom transfer radical polymerization (ATRP) and their dual-stimuli responsive behaviors to the changes in temperature and pH in aqueous solutions were investigated by UV-vis spectroscopy, dynamic light scattering (DLS), (1)H NMR spectroscopy and surface tension measurement. Different from PDMAEMA(84)-b PAA(18) solutions where no aggregation is observed between pH 7.0 and 9.5, the PDMAEMA(50)-b-PAA(18) aggregates can exist in this broad pH range due to the hydrophobic interactions among the charge-balanced polyampholyte chains. At high pH, e.g., 11.0, the DMAEMA segments collapse to form the core of micelles due to the hydrophobic property of the de-protonized DMAEMA stabilized with the highly ionized AA segments on the surface of the micelles upon heating. At pH around the IEP, e.g., 9.5, large micelles can be formed in PDMAEMA(84)-b-PAA(18) solution upon heating, just like that at pH 11.0, while PDMAEMA(50)-b-PAA(18) first formed the micelles due to the electrostatic attraction between ionized AA segments and protonated DMAEMA segments, but the aggregation of the micelles was hardly happened upon heating due to the smaller DMAEMA segment. Moreover, LCST can be exactly estimated by surface tension experiment. PMID- 21316063 TI - Adsorption on montmorillonite prevents oligomerization of Bt Cry1Aa toxin. AB - The adsorption of the insecticidal Cry1Aa protein from Bacillus thuringiensis (Bt toxin) on a model clay surface was studied to understand the structural changes of the protein induced by the clay surface. We studied the adsorption of the monomeric and soluble oligomeric forms of the Cry1Aa toxin as a function of pH and ionic strength conditions on montmorillonite, which is an electronegative phyllosilicate. Cry1Aa secondary structure was determined from the amide I' FTIR absorption profiles. Accessibility to the solvent was determined by NH/ND exchange to characterize conformational flexibility of the different states of the Cry1Aa protein. The size distribution of Cry1Aa solutions was obtained by dynamic light scattering (DLS). From combined DLS and FTIR measurements, we conclude that montmorillonite traps the Cry1Aa toxin in its monomeric state, preventing the oligomerization of the protein. The oligomeric forms were adsorbed onto the clay without significant structural changes. PMID- 21316064 TI - Letter names and phonological awareness help children to learn letter-sound relations. AB - Two experimental training studies with Portuguese-speaking preschoolers in Brazil were conducted to investigate whether children benefit from letter name knowledge and phonological awareness in learning letter-sound relations. In Experiment 1, two groups of children were compared. The experimental group was taught the names of letters whose sounds occur either at the beginning (e.g., the letter /be/) or in the middle (e.g., the letter /'eli/) of the letter name. The control group was taught the shapes of the letters but not their names. Then both groups were taught the sounds of the letters. Results showed an advantage for the experimental group, but only for beginning-sound letters. Experiment 2 investigated whether training in phonological awareness could boost the learning of letter sounds, particularly middle-sound letters. In addition to learning the names of beginning- and middle-sound letters, children in the experimental group were taught to categorize words according to rhyme and alliteration, whereas controls were taught to categorize the same words semantically. All children were then taught the sounds of the letters. Results showed that children who were given phonological awareness training found it easier to learn letter sounds than controls. This was true for both types of letters, but especially for middle sound letters. PMID- 21316065 TI - Insect herbivore counteradaptations to the plant glucosinolate-myrosinase system. AB - The glucosinolate-myrosinase system found in plants of the Brassicales order is one of the best studied plant chemical defenses. Glucosinolates and their hydrolytic enzymes, myrosinases, are stored in separate compartments in the intact plant tissue. Upon tissue disruption, bioactivation of glucosinolates is initiated, i.e. myrosinases get access to their glucosinolate substrates, and glucosinolate hydrolysis results in the formation of toxic isothiocyanates and other biologically active products. The defensive function of the glucosinolate myrosinase system has been demonstrated in a variety of studies with different insect herbivores. However, a number of generalist as well as specialist herbivores uses glucosinolate-containing plants as hosts causing large agronomical losses in oil seed rape and other crops of the Brassicaceae. While our knowledge of counteradaptations in generalist insect herbivores is still very limited, considerable progress has been made in understanding how specialist insect herbivores overcome the glucosinolate-myrosinase system and even exploit it for their own defense. All mechanisms of counteradaptation identified to date in insect herbivores specialized on glucosinolate-containing plants ensure that glucosinolate breakdown to toxic isothiocyanates is avoided. This is accomplished in many different ways including avoidance of cell disruption, rapid absorption of intact glucosinolates, rapid metabolic conversion of glucosinolates to harmless compounds that are not substrates for myrosinases, and diversion of plant myrosinase-catalyzed glucosinolate hydrolysis. One of these counteradaptations, the nitrile-specifier protein identified in Pierid species, has been used to demonstrate mechanisms of coevolution of plants and their insect herbivores. PMID- 21316066 TI - The health of disabled people and the social determinants of health. PMID- 21316067 TI - [Intrathoracic manifestations of breast cancer]. AB - Breast cancer continues to be the most common malignant neoplasm in women in Spain. The radiological study of intrathoracic manifestations, often secondary to complications, is of great interest because intrathoracic manifestations have a high prevalence and diagnosing them early significantly improves the patient's prognosis. The imaging techniques in current use for this purpose include plain film chest X-rays, computed tomography (CT), magnetic resonance imaging (MRI), thoracic ultrasonography, and hybrid techniques like positron emission tomography combined with CT (PET/CT). In this article, we review the imaging findings for the different types of intrathoracic complications of breast cancer, classified as: a) complications related to tumor dissemination, b) complications related to treatment, and c) idiopathic complications. PMID- 21316068 TI - Identification of urinary sex pheromones in female buffaloes and their influence on bull reproductive behaviour. AB - The present study was carried out to identify the urinary sex pheromones of buffaloes and their role in relation to bull reproductive behaviour. Urinary samples were collected from 12 buffalo heifers at four different phases of estrous cycles. Fourteen compounds were identified throughout the cycle, which included phenol, ketone, alkane, alcohol, amide, acid and aldehyde. Among the 14 chemical profiles, three compounds were only found on the day of estrus, viz. 1 chlorooctane, 4-methylphenol and 9-octadecenoic acid. Behavioural investigation clearly showed that bulls were attracted and exhibited repeated flehmen behaviour towards the 4-methyl phenol. The bulls displayed penile erection and mounting behaviour while exposed to 9-octadecenoic acid. However, the other compound, 1 chlorooctane, did not influence such sexual behaviours. The present results provide evidence that the estrus-specific urinary volatile compounds appear to be sex pheromones which initiate the bull's reproductive behaviour. PMID- 21316069 TI - SV40 host-substituted variants: a new look at the monkey DNA inserts and recombinant junctions. AB - The available monkey genomic data banks were examined in order to determine the chromosomal locations of the host DNA inserts in 8 host-substituted SV40 variant DNAs. Five of the 8 variants contained more than one linked monkey DNA insert per tandem repeat unit and in all cases but one, the 19 monkey DNA inserts in the 8 variants mapped to different locations in the monkey genome. The 50 parental DNAs (32 monkey and 18 SV40 DNA segments) which spanned the crossover and flanking regions that participated in monkey/monkey and monkey/SV40 recombinations were characterized by substantial levels of microhomology of up to 8 nucleotides in length; the parental DNAs also exhibited direct and inverted repeats at or adjacent to the crossover sequences. We discuss how the host-substituted SV40 variants arose and the nature of the recombination mechanisms involved. PMID- 21316070 TI - Immunological properties of the transmembrane envelope protein of the feline foamy virus and its use for serological screening. AB - The transmembrane envelope (TM) proteins of retroviruses are used as antigen in diagnostic immunoassays and they represent a conserved target for neutralizing antibodies. To analyze the situation in infections with the feline foamy virus (FFV), its recombinant TM protein was produced and used for ELISA and Western blot analyses. Screening sera from 404 German cats showed that 39% reacted against the TM protein, the same infection rate was determined using the Gag protein. Epitope mapping showed antibodies against the membrane proximal external region (MPER) of the TM protein in the sera from infected cats, but attempts to induce neutralizing antibodies by immunization with the recombinant TM protein failed. This is the first report demonstrating that the TM protein of the FFV is highly immunogenic and valuable for serological screening. Similar to HIV-1, but in contrast to different gammaretroviruses, immunization with the TM protein of FFV did not induce neutralizing antibodies. PMID- 21316071 TI - Nitrate reduction using nanosized zero-valent iron supported by polystyrene resins: role of surface functional groups. AB - To probe the role of host chemistry in formation and properties of the inside nano-zero valent iron (nZVI), we encapsulated nZVI within porous polystyrene resins functionalized with -CH(2)Cl and -CH(2)N(+)(CH(3))(3) respectively and obtained two hybrid nZVIs denoted Cl-S-ZVI and N-S-ZVI. 14.5% (in Fe mass) of nZVI particles were distributed in N-S within a ring-like region (about 0.10 mm in thickness) of size around ~ 5 nm, whereas only 4.0% of nZVI particles were entrapped near the outer surface of Cl-S of size > 20 nm. -CH(2)N(+)(CH(3))(3) is more favorable than -CH(2)Cl to inhibit nZVI dissolution into Fe(2+) ions under acidic pH (3.0-5.5). 97.2% of nitrate was converted into ammonium when introducing 0.12 g N-S-ZVI into 50 mL 50 mg N/L nitrate solution, while that for Cl-S-ZVI was 79.8% under identical Fe/N molar ratio. Under pH = 2 of the effectiveness of nZVI was 88.8% for nitrate reduction, whereas that for Cl-S-ZVI was only 14.6% under similar conditions. Nitrate reduction by N-S-ZVI exhibits relatively slower kinetics than Cl-S-ZVI, which may be related to different nZVI distribution of both composites. The coexisting chloride and sulfate co-ions are favorable for the reactivity enhancement of N-S-ZVI whereas slightly unfavorable for Cl-S-ZVI. The results demonstrated that support chemistry plays a significant role in formation and reactivity of the encapsulated nZVI, and may shed new light on design and fabrication of hybrid nZVIs for environmental remediation. PMID- 21316072 TI - Degradation of pentachlorophenol by a novel peroxidase-catalyzed process in the presence of reduced nicotinamide adenine dinucleotide. AB - A novel horseradish peroxidase (HRP)-catalyzed H2O2 process in the presence of reduced nicotinamide adenine dinucleotide (NADH) was applied to remove aqueous pentachlorophenol (PCP). Parameters (pH, H2O2 concentration, HRP activity and NADH dosage) on PCP removal were investigated. It was found that initial 0.05mM PCP was removed by 98% in HRP-NADH-H2O2 system at pH 5.0 and 30 degrees C for 1h. Addition of O2 in HRP-NADH-H2O2 system enhanced the removal rate of PCP due to promoting hydroxyl radicals (.OH) and superoxide anion radical (.O2-) generation, which were confirmed by electron paramagnetic resonance (EPR)-spin trapping method. PCP removal efficiency decreased when .O2- and H2O2 were scavenged by superoxide dismutase and catalase in HRP-NADH-O2 system, indicating that .OH/.O2- played a great role in the degradation of PCP. Gas chromatography-mass spectrometry (GC-MS) analysis revealed that octachlorinated dibenzodioxin (OCDD) in residual solution was reduced after treated by the HRP-NADH-O2 process, resulting in lower toxicity of treated solution than conventional enzymatic process. Two enzymatic-catalysis pathways were proposed for PCP removal in HRP NADH-H2O2/O2 system: (i) OH/.O2- free radical oxidation (ii) conventional phenoxy polymerization. PMID- 21316073 TI - An overview of the methods used in the characterisation of natural organic matter (NOM) in relation to drinking water treatment. AB - Natural organic matter (NOM) is found in all surface, ground and soil waters. During recent decades, reports worldwide show a continuing increase in the color and NOM of the surface water, which has an adverse affect on drinking water purification. For several practical and hygienic reasons, the presence of NOM is undesirable in drinking water. Various technologies have been proposed for NOM removal with varying degrees of success. The properties and amount of NOM, however, can significantly affect the process efficiency. In order to improve and optimise these processes, the characterisation and quantification of NOM at different purification and treatment processes stages is important. It is also important to be able to understand and predict the reactivity of NOM or its fractions in different steps of the treatment. Methods used in the characterisation of NOM include resin adsorption, size exclusion chromatography (SEC), nuclear magnetic resonance (NMR) spectroscopy, and fluorescence spectroscopy. The amount of NOM in water has been predicted with parameters including UV-Vis, total organic carbon (TOC), and specific UV-absorbance (SUVA). Recently, methods by which NOM structures can be more precisely determined have been developed; pyrolysis gas chromatography-mass spectrometry (Py-GC-MS), multidimensional NMR techniques, and Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS). The present review focuses on the methods used for characterisation and quantification of NOM in relation to drinking water treatment. PMID- 21316074 TI - Pleiotropic effects of hexavalent chromium (CrVI) in Mytilus galloprovincialis digestive gland. AB - Hexavalent Chromium Cr(VI) is an important contaminant considered as a model oxidative toxicant released from both domestic and industrial effluents, and represents the predominant chemical form of the metal in aquatic ecosystems. On the other hand, in mammals the reduced form Cr(III) is considered an essential microelement, involved in regulation of lipid and carbohydrate metabolism; moreover, recent evidence suggests that Cr may have endocrine effects. In this work, the effects of Cr(VI) were investigated in the digestive gland of the marine bivalve Mytilus galloprovincialis. Mussels were exposed to 0.1-1-10-100 MUg Cr(VI) L(-1) animal(-1) for 96 h. At 100 MUg L(-1), a large increase in total Cr tissue content was observed; in these conditions, the lysosomal membranes were completely destabilized, whereas other lysosomal biomarkers (neutral lipids-NL and lipofuscin-LF), as well as different enzyme activities and gene expression were unaffected, this indicating severe stress conditions in the tissue. On the other hand, at lower concentrations, changes in other histochemical, biochemical and molecular endpoints were observed. In particular, at both 1 and 10 MUg L(-1), lysosomal destabilization was associated with significant NL and LF accumulation; however, no changes in catalase and GSH transferase (GST) activities were observed. At the same concentrations, GSSG reductase (GSR) activity was significantly increased, this probably reflecting the recycling of GSSG produced in the GSH-mediated intracellular reduction of Cr(VI). Increased activities of the key glycolytic enzymes PFK (phosphofructokinase) and PK (pyruvate kinase) were also observed, indicating that Cr(VI) could affect carbohydrate metabolism. Cr(VI) induced downregulation or no effects on the expression of metallothioneins MT10 and MT20, except for an increase in MT20 transcription in males. Moreover, significant up-regulation of the Mytilus estrogen receptor MeER2 and serotonin receptor (5-HTR) were observed in both sexes. The results demonstrate that exposure to Cr(VI) in the low ppb range did not result in strong toxicity or oxidative stress conditions in mussel digestive gland. On the other hand, our data support the hypothesis that low concentrations of the metal can exert pleiotropic effects on mussel physiology, from modulation of lipid and carbohydrate metabolism, to effects on the expression of estrogen-responsive genes. PMID- 21316076 TI - The effect of nitrate concentration on sulfide-driven autotrophic denitrification in marine sediment. AB - The effect of nitrate concentration on denitrification rate, microbial community and byproduct accumulation in sulfide-driven autotrophic denitrification, one of the dominant processes during anoxic marine sediment remediation, was investigated in this study. Microorganisms which were phylogenetically closely related with Sulfurimonas denitrificans of epsilon-Proteobacteria and Thiohalomonas denitrificans of gamma-Proteobacteria were the major autotrophic denitrifiers in this study. Nitrate concentration was demonstrated to have selective effect on denitrifying microbial community as revealed by denaturing gradient gel electrophoresis. Denitrifiers enriched at 30 mM NO(3)(-) have higher diversity than other two groups (10, and 80 mM NO(3)(-)) according to Shannon index. Denitrification showed zero-order reaction kinetics when nitrate concentration was higher than 4mM. Neither absolute nitrate concentration nor overall nitrate/sulfide ratio acted as the determinant for denitrification byproduct (i.e. N(2)O and NO(2)(-)) accumulation. The limitation of sulfide due to low mass transfer might be the reason for the byproduct accumulation. PMID- 21316075 TI - Assessment of the environmental fate and effects of the PPARgamma receptor agonist, pioglitazone. AB - The environmental fate and effects of pioglitazone prescribed for the treatment of type 2 diabetes were evaluated in an environmental risk assessment following the European Medicines Agency (EMA) "Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use"; EMEA/CHMP/SWP/4447/00. A predicted environment concentration (PEC) for surface water was estimated at 0.023MUgL(-1), (action limit of 0.01MUgL(-1)) triggering a comprehensive battery of laboratory evaluations. Pioglitazone and its major metabolites were determined not to significantly adsorb to sewage solids, were not persistent in the aquatic environment, did not bioaccumulate and were non-toxic to aquatic organisms. Pioglitazone does not pose an unacceptable risk to groundwater supplies, with concentrations not anticipated to be a risk to aquatic organisms or human drinking water supplies. Pioglitazone does not pose a risk of secondary poisoning. PMID- 21316077 TI - Development and evolution of The Knowledge Hub for Pathology and related electronic resources. AB - The Knowledge Hub for Pathology was created to provide authenticated and validated knowledge for United States and Canadian Academy of Pathology members and pathologists worldwide with access to the Web. Using the material presented at the annual meeting of the United States and Canadian Academy of Pathology with existing selection and review procedures ensured that these criteria were met without added costly procedures. Further submissions for courses and research papers are provided in electronic format and funded by universities and hospitals for their creation; thus, the principal costs borne by the United States and Canadian Academy of Pathology are Web site-posting costs. Use has escalated rapidly from 2 million hits in 2002 to 51 million in 2009 with use by 35,000 pathologists from now a total of 180 countries. This true "freemium" model is a successful process as are more traditional continuing professional development course structures such as Anatomic Pathology Electronic Case Series, a "premium" model for learning electronically also sponsored by the United States and Canadian Academy of Pathology. PMID- 21316078 TI - DEK expression in melanocytic lesions. AB - The diagnosis of malignant melanoma presents a clinical challenge and relies principally on histopathological evaluation. Previous studies have indicated that increased expression of the DEK oncogene, a chromatin-bound factor, could contribute to the development of melanoma and may be a frequent event in melanoma progression. Here, we investigated DEK expression by immunohistochemistry in a total of 147 melanocytic lesions, including ordinary nevi, dysplastic nevi, Spitz nevi, melanoma in situ, primary invasive melanomas, and metastatic melanomas. Most benign nevi (ordinary, dysplastic, and Spitz nevi) were negative or exhibited weak staining for DEK, with only 4 of 49 cases showing strong staining. Similar to benign nevi, melanoma in situ also demonstrated low levels of DEK expression. In contrast, the expression of DEK in primary invasive melanomas was significantly higher than benign nevi (P < .0001). Moreover, DEK expression was significantly increased in deep melanomas (Breslow depth >1 mm) and metastatic melanomas as compared with superficial melanomas (Breslow depth <=1 mm) (P < .05). Our findings indicate that DEK overexpression may be a frequent event in invasive melanomas, and further augmentation of DEK expression may be associated with the acquisition of ominous features such as deep dermal invasion and metastasis. These data suggest a role of DEK in melanoma progression. PMID- 21316079 TI - JAZF1 and JJAZ1 gene fusion in primary extrauterine endometrial stromal sarcoma. AB - Endometrial stromal sarcoma predominantly occurs as a primary tumor of the uterus. The most common cytogenetic abnormality in these tumors is t(7;17)(p15;q21), which occurs in 33% to 80% of cases and results in a JAZF1 JJAZ1 gene fusion. Rare cases of primary extrauterine endometrial stromal sarcoma have been reported, but it remains uncertain whether the genetic features of uterine endometrial stromal sarcoma are also characteristic of extrauterine tumors. The present study evaluates the prevalence of the t(7;17)(p15;q21) and JAZF1-JJAZ1 gene fusion in a series of 6 cases of primary extrauterine endometrial stromal sarcoma. Conventional nested reverse transcriptase-polymerase chain reaction was performed using primers complementary to sense and antisense JAZF1 and JJAZ1 sequences. Interphase fluorescence in situ hybridization was performed to detect t(7;17)(p15;q21) using a break-apart strategy for both JAZF1 and JJAZ1. In one of the 6 extrauterine endometrial stromal sarcoma cases, JAZF1 JJAZ1 fusion transcripts were detected by reverse transcriptase-polymerase chain reaction. The same case showed evidence of both JAZF1 and JJAZ1 rearrangements by interphase fluorescence in situ hybridization. The remaining 5 cases were negative for the t(7;17)(p15;q21) by both reverse transcriptase-polymerase chain reaction and fluorescence in situ hybridization analysis. These findings demonstrate that the t(7;17)(p15;q21) and associated JAZF1-JJAZ1 fusion transcripts are present in only a subset of primary extrauterine endometrial stromal sarcoma. Although molecular testing for the t(7;17)(p15;q21) and associated gene fusion may be useful for confirming primary extrauterine endometrial stromal sarcoma, the low prevalence of the genetic aberration limits the clinical utility of the testing. PMID- 21316080 TI - Respiratory effects of indoor particles in young children are size dependent. AB - BACKGROUND: Extensive epidemiological studies have provided evidence of an association between elevated outdoor particulate air pollution and adverse health effects. However, while people typically spend majority of time indoors, there is limited knowledge on airborne indoor particles and on the correlation between the concentrations of indoor particles and health effects. Even insights into the influence of differently sized indoor particles on human health are still rare. OBJECTIVE: The association between differentially sized indoor air particles and the development of respiratory diseases was studied for three year aged children. METHODS: Short-term measurements of particle mass and number concentrations were carried out in children's rooms. Information on possible particle sources (smoking habits, type of heating, and traffic) and respiratory outcomes were obtained from questionnaires. Measured indoor particle concentrations were correlated with possible sources of indoor particles and with respiratory health impacts. RESULTS: Daily smoking, smoking more than 5 cigarettes per day at home and traffic density in front of the window of children's room were found to be related to indoor exposure by particles of different diameters. High indoor particle exposures were associated with an increased risk for the development of obstructive bronchitis and in some extent of non-obstructive bronchitis. The strongest impact was observed for the mass concentration of particles <1 MUm and the number concentration of particles >0.5 MUm. The risk increases still remain significant if tested for stability changing the number of adjustment variables or omitting randomly selected cases, respectively. CONCLUSION: Our results show significant associations between indoor particle concentrations and the risks for respiratory diseases in young children. The applied short-term measurements can help to assess the health risks of indoor particles with different sizes within epidemiological studies. PMID- 21316081 TI - Association between metabolic syndrome and male lower urinary tract symptoms in Japanese subjects using three sets of criteria for metabolic syndrome and International Prostate Symptom Score. AB - OBJECTIVES: To investigate whether the metabolic syndrome is a risk factor for lower urinary tract symptoms (LUTS), as defined by the International Prostate Symptom Score (IPSS). METHODS: A total of 900 men underwent digital rectal examination of the prostate and completed an IPSS questionnaire. These men had visited our hospital for metabolic screening from April 2008 to March 2009. The IPSS includes scores for 3 questions on voiding symptoms, 3 on storage symptoms, and 1 on postmicturition symptoms. The relationships of the LUTS (determined from the IPSS subscores) with the metabolic syndrome diagnosed using the Japan Society for the Study of Obesity, 2005 National Cholesterol Education Program-Adult Treatment Panel III, and 2005 International Diabetes Federation criteria were examined. The severity of LUTS was compared among the younger, middle-age, and older men (<50, 50-64, and >=65 years old, respectively) with and without the metabolic syndrome. RESULTS: A diagnosis of the metabolic syndrome was made in 16.7%, 16.6%, and 11.7% of the men using the Japan Society for the Study of Obesity, 2005 National Cholesterol Education Program-Adult Treatment Panel III, and 2005 International Diabetes Federation criteria, respectively. Regardless of the presence of the metabolic syndrome, aging was significantly associated with an increased rate of moderate or severe LUTS, except for postmicturition symptoms. In the middle-age men, the metabolic syndrome had a significant negative correlation with storage symptoms (odds ratio 0.258-0.426). In the younger and older men, LUTS was observed equally in those with and without the metabolic syndrome. CONCLUSIONS: A relationship between age and LUTS was observed; however, the metabolic syndrome did not show a clear association with LUTS. Our results suggest that LUTS is associated with aging, regardless of the presence of the metabolic syndrome. PMID- 21316082 TI - Laparoscopic single-stage Fowler-Stephens orchidopexy in a case of orchidogastric fusion. AB - This report describes laparoscopic Fowler-Stephens orchidopexy for cryptorchidism resulting from orchidogastric fusion in an infant born with gastroschisis. At 11 months of age, the left testicle remained impalpable, and diagnostic laparoscopy was performed. Intraoperatively, a normal-appearing testicle was found attached to the stomach. The testicle was dissected, mobilized down to the left inguinal ring, exteriorized through a transscrotal trocar, and subsequently fixated in the lower left scrotum. On follow-up 5 months later, both testicles were normal in size and location. Single-stage laparoscopic Fowler-Stephens orchidopexy is easily accomplished in cases of orchidogastric fusion resulting from a long vas deferens. PMID- 21316083 TI - Tumor size is a potential predictor of response to tyrosine kinase inhibitors in renal cell cancer. AB - OBJECTIVES: To investigate the correlations between the initial tumor size and size reduction rate in patients treated with targeted agents. To select the patients who can benefit the most from treatment with targeted agents, it will be necessary to find a tumor characteristic that predicts their effectiveness. METHODS: The data from 139 metastatic and 16 primary lesions treated with the targeted agents were retrospectively analyzed. They consisted of 86 sunitinib treated and 69 sorafenib-treated lesions in 54 patients with metastatic renal cell carcinoma who had undergone treatment from April 2008 to July 2010. The relationship between the longest tumor diameter at baseline and the rate of reduction in tumor size was assessed using the Spearmancorrelation test. RESULTS: A linear, moderate to strong association between the initial tumor size and tumor size reduction rate was shown (correlation coefficient -0.441, P < .001). When these tumors were divided into 2 groups at the threshold value (23.95 mm), which was decided by the receiver operating characteristic curve analysis, the smaller tumors demonstrated a significantly greater size reduction than the larger tumors according to the Mann-Whitney U test (P < .001). Both univariate and multivariate linear regression analyses revealed that only the initial tumor size was associated with the rate of reduction in individual tumors (P < .001). CONCLUSIONS: The initial tumor size was a good predictor of the tumor size reduction. This simple observation could be useful for physicians who treat patients with metastatic renal cell carcinoma. In addition, in assessing clinical trials of targeted agents for metastatic renal cell carcinoma using the ResponseEvaluation Criteria in Solid Tumors, perhaps this association should be considered. PMID- 21316084 TI - Risk factors for recurrent urinary tract infection in infants with vesicoureteral reflux during prophylactic treatment: effect of delayed contrast passage on voiding cystourethrogram. AB - OBJECTIVES: To investigate the risk factors for recurrent urinary tract infection (UTI) in infants with vesicoureteral reflux (VUR) because little is known regarding the risk factors for breakthrough infection. METHODS: We compared children with infantile VUR with (20 boys, mean age 2.7 months) and without (20 boys and 4 girls, mean age 4.7 months) recurrent UTI. The factors compared included sex, timing of UTI episode, degree and bilaterality of the reflux, hydronephrosis, renal scar, associated congenital anomalies, voiding dysfunction, and delayed ureteral excretion of refluxed contrast on the voiding cystourethrogram. RESULTS: Univariate Cox survival-time regression analysis showed that a younger mean age at the first UTI, bilateral reflux, and grade 4-5 VUR and hydronephrosis on the initial ultrasound scan significantly increased the risk of recurrent UTI (P<.05 each). On multivariate analysis, high-grade (P=.009) and bilateral (P=.016) VUR were independently associated with an increased risk of recurrent UTI. Of the infants with and without recurrent UTI, 80% and 0%, respectively, presented with high-grade VUR, as shown by delayed contrast passage on the voiding cystourethrogram. A urodynamic study of 11 infants with recurrent UTI showed decreased bladder capacity in 2 infants and a larger residual volume in 1 infant. CONCLUSIONS: During the first year after birth, high-grade and bilateral VUR significantly increased the risk of recurrent UTI. Delayed contrast passage on the voiding cystourethrogram was significantly associated with an increased risk of recurrent UTI. PMID- 21316085 TI - Outcomes of percutaneous nephrolithotomy in patients with solitary kidneys: a single-center experience. AB - OBJECTIVES: To evaluate the outcomes, complications, and early and late postoperative kidney function of percutaneous nephrolithotomy (PCNL) in patients with solitary kidneys. METHODS: Between 2002 and 2009, 47 patients with a solitary kidney (congenital in 10 patients, 21.3%; contralateral nephrectomy in 22 patients, 46.8%; and nonfunctional kidney in 15 patients, 31.9%) underwent PCNL. Serum creatinine was measured preoperatively, on postoperative day 1, and at each follow-up visit at regular intervals. The 4-variable modification of diet in renal disease equation was used to calculate the estimated glomerular filtration rate (eGFR). The 5-stage classification of chronic kidney disease (CKD) was used according to the National Kidney Foundation published guidelines. Of 47 patients, 44 were followed least 6 months, whereas 3 patients were lost to follow-up. RESULTS: Success was achieved in 84.5% (40/47) of patients after 1 session of PCNL. Complex stones were detected in 32 (68.1%) patients. Among all patients, 23.4% (n = 11) of them required multiple accesses. Complications developed in 5 (10.6%) patients. At a mean follow-up time of 18.7 +/- 11.8 (6-60) months, the overall success rate improved to 97.7% after auxiliary treatments. eGFR was 76.4 +/- 27.1, 73.4 +/- 26.1, and 83.5 +/- 29.4 per 1.73 m(2) during preoperative period, immediate postoperative period, and at the last follow-up visit (>6 months), respectively (P < .001). According to CKD classification, kidney function was stable, improved and worse in 63.6% (n = 28), 29.5% (n = 13), and 6.8% (n = 3) of patients, respectively, compared with preoperative levels. CONCLUSIONS: PCNL is safe and has an acceptably low complication rate in patients with solitary kidneys. At long-term follow-up, renal function had stabilized or improved in more than 90% of patients with a solitary kidney after PCNL. PMID- 21316086 TI - Comparison between lidocaine and glyceryl trinitrate ointment for perianal intrarectal local anesthesia before transrectal ultrasonography-guided prostate biopsy: a placebo-controlled trial. AB - OBJECTIVE: To evaluate the use of topical lidocaine gel and glyceryl trinitrate ointment (GTN) vs placebo, in reducing anal pain and discomfort as an adjunct to periprostatic anesthesia because of probe insertion, during the use of transrectal ultrasonography (TRUS) prostate-guided biopsy in young patients. PATIENTS AND METHODS: Two-hundred twenty-three men who underwent prostate biopsy were divided into 3 groups. Seventy-four patients (first group) and 76 patients (second group) received perianal local anesthesia with lidocaine gel 2%, and 1 g of 0.4% GTN ointment, respectively, whereas 73 patients (third group) received lubricant gel as perianal local anesthesia. All patients also underwent periprostatic nerve block (PPNB). Visual analogue scales (VAS 1 and VAS 2) were used to estimate the pain and discomfort during probe insertion and biopsy. RESULTS: Men in the first and second groups reported significantly less pain score (mean, 1.7 and 1.6, respectively) vs men from the third group (mean, 5.7) during probe insertion. Comparing the 3 different groups subsequently with the periprostatic anesthesia, no significant difference in VAS scores between the first and the third groups (mean, 1.9 and 2.1, respectively) was found; in addition, patients from the second group reported significantly less pain score (mean, 1.3) during biopsy. CONCLUSIONS: Lidocaine gel and GTN ointment is safe and effective in reducing anal pain associated with the insertion of an ultrasound probe. Furthermore, men with GTN ointment also reported less pain during biopsy. We suggest that analgesia before PPNB could significantly reduce anal pain and improve tolerance during TRUS prostate-guided biopsy. PMID- 21316087 TI - Molecular analysis of clear cell sarcoma with translocation (1;6)(p32.3;q21). AB - A 23-month-old boy presented with an 11-month history of abdominal distention. Examination disclosed a large tumor in the right kidney and transabdominal radical nephrectomy was performed. Histopathological study demonstrated clear cell sarcoma of the kidney (CCSK). Cytogenetic analyses performed with blood lymphocytes showed translocation (1;6) (p32.3;q21). This is the first case of CCSK showing chromosomal translocation in blood lymphocytes. In addition, molecular analyses demonstrated high expression levels of EGFR and KIT proteins in the tumor tissue of CCSK. These molecular findings suggest that tyrosine kinase receptors may be potential therapeutic targets for CCSK in the future. PMID- 21316088 TI - Efficacy and tolerability of tadalafil for treatment of erectile dysfunction in men taking serotonin reuptake inhibitors. AB - OBJECTIVES: To evaluate the efficacy and safety of tadalafil in men with treatment-emergent sexual dysfunction due to serotonin reuptake inhibitors. METHODS: The present prospective, double-blind, 12-week study, randomized in a 1:1 ratio to tadalafil 20 mg or placebo taken on demand, included 50 men. The efficacy measures were the changes in total and domain scores of the International Index of Erectile Function questionnaire, Sexual Encounter Profile diary questions 2-6, and the Global Assessment questions (GAQs) 1 and 2. The safety analyses included the evaluation of adverse events, vital signs, serum chemistry results, and electrocardiography findings. RESULTS: For the patients who took tadalafil 20 mg, the net median score change from baseline to the endpoint compared with placebo was 26 for the 15-item International Index of Erectile Function; 10, 4, 4, 3, and 3 for the erectile function, intercourse satisfaction, overall satisfaction, orgasmic function, and sexual desire domains; and 3 and 5 points for "yes" responses to the Sexual Encounter Profile 2 and Sexual Encounter Profile 3 questions, respectively. All comparisons between tadalafil and placebo were significant (P < .001). At the endpoint, 92% of the tadalafil group responded affirmatively to both GAQs 1 and 2 compared with 8% of the placebo group (P < .001, for each). In the safety measures, no clinically significant changes attributable to tadalafil use were found. CONCLUSIONS: Tadalafil 20-mg treatment significantly improved sexual function in patients who were taking serotonin reuptake inhibitors for depression, with mild to moderate, well-tolerable adverse events. PMID- 21316089 TI - Doppler ultrasound-guided percutaneous nephrolithotomy: a prospective randomized study. AB - OBJECTIVE: To evaluate the role, safety, and effectiveness of Doppler ultrasound guided percutaneous nephrolithotomy (PCNL). METHODS: The present study was a prospectively randomized controlled trial performed from March 2007 to February 2010. A total of 131 patients, scheduled for PCNL to remove huge renal stones (diameter>35 mm) and staghorn stones, were enrolled and prospectively randomized using a random numbers table into 2 groups. Of the 131 patients, 54 were randomized to ultrasound-guided puncture PCNL (group 1). Group 2 included 57 patients who received Doppler ultrasound-guided PCNL. A total of 30 patients were excluded from the study. The preoperative data included urinalysis, urine culture, complete blood count, biochemistry study, renal ultrasonography, intravenous urography, and technetium-99m diethylenetriaminepentaacetic acid to determine the selective glomerular filtration rate. The intraoperative findings, operative time (from insertion of the puncture needle to the end of the procedure), and outcomes were also recorded. The complete blood count and serum creatinine were also checked. The modified Clavien grading system was used to evaluate the perioperative morbidity of PCNL. RESULTS: No difference was found between the 2 groups with regard to the serum creatinine change, length of stay, return to normal activity, Clavien grade, relative perfusion rate, or glomerular filtration rate, as determined by technetium-99m diethylenetriaminepentaacetic acid clearance, preoperatively and postoperatively. However, the hemoglobin decrease (2.33+/-0.46 g/dL) in the ultrasound-guided puncture group was greater than that in the Doppler ultrasound-guided group, with statistically significant difference. CONCLUSION: Doppler ultrasound-guided PCNL is accurate and safe and was associated with less blood loss. We believe that Doppler ultrasound can be an important alternative to B-mode ultrasound guidance. PMID- 21316091 TI - Relationship between nocturnal urine volume, leg edema, and urinary antidiuretic hormone in older men. AB - OBJECTIVE: To evaluate the relationship between leg edema, nocturnal urine volume (NUV), and the secretion of antidiuretic hormone (ADH) during the night, and to investigate the principal factors affecting nocturnal polyuria in older men. METHOD: A total of 74 male inpatients more than 50 years of age were enrolled in this study. Blood count, standard chemistry panel, brain natriuretic peptide (BNP), urinary ADH (u-ADH), urinary creatinine (u-Cre), and urinary osmolarity were measured at 6:00 am. Keeping a frequency volume chart, bioelectric impedance analysis was performed at 5 pm. Leg edema was measured as an edema ratio, using the following formula: extracellular water [L)/(extracellular water [L) + intracellular water [L)) in legs. RESULTS: A total of 66 patients were evaluated. NUV had a significant positive correlation with leg edema (r = 0.32, P = .008), negative correlation with u-ADH/u-Cre (r = -0.37, P = .003) but not BNP. Leg edema had a significant positive correlation with the level of BNP (r = 0.33, P = .012) and negative correlation with u-ADH/u-Cre (r = -0.4, P = .001). However a partial correlation showed that there was no significant correlation between NUV and leg edema. A multivariate logistic model showed that only u-ADH/u-Cre was an independent predictive variable of nocturnal polyuria. CONCLUSIONS: This study suggested that leg edema influenced nocturnal urine volume with an associated decrease in ADH secretion but not directly. ADH secretion during the night was the principal factor affecting NP in older men. PMID- 21316090 TI - Prevalence of baseline chronic kidney disease in patients presenting with solid renal tumors. AB - OBJECTIVES: To evaluate the prevalence of baseline chronic kidney disease (CKD) in a large cohort of patients presenting with renal masses to a tertiary care center, comparing serum creatinine (sCr) and estimated glomerular filtration rate (eGFR). sCr inadequately reflects renal function. eGFR and chronic kidney disease CKD stage are more clinically relevant parameters to reflect the risk of morbidity and mortality in patients after nephron loss. METHODS: Using the prospectively maintained Fox Chase Kidney Cancer Database, we identified patients undergoing kidney surgery between January 2000 and May 2010. eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) and the CKD-Epidemiology formulas. CKD stages I-V were defined using the National Kidney Foundation definitions. RESULTS: A total of 1114 patients had adequate data available to calculate a preoperative eGFR (mL/min). Although 88% of all patients presenting for surgery at our institution had a "normal" baseline sCr (<=1.4 mg/dL), 22% of patients had CKD stage III or greater. Moreover, of the 282 patients 70 years and older, 40% (113/282) had CKD stage III. Twenty-three percent (51/220) of patients older than 70 years had CKD stage III with a seemingly normal sCr. CONCLUSIONS: Many patients with a normal sCr have CKD stage III or higher, particularly patients older than 70 years old. Given the high prevalence of baseline CKD in patients with a solid renal tumor, a concerted effort must be made to preserve renal function when surgically treating solid renal masses. PMID- 21316092 TI - Castleman's disease in the left suprarenal region, mimicking an adrenal neoplasm. AB - We present a rare case of a 16-year-old male patient with Castleman's disease (CD) manifest by a suspicious mass within the left suprarenal region abutting the left adrenal gland, mimicking an adrenal neoplasm. CD is an uncommon and poorly understood lymphoproliferative disorder that, when observed, typically occurs as a mediastinal mass. Two percent of cases reportedly occur in the pararenal region. Although rare, Castleman's disease should be considered in the differential diagnosis of a retroperitoneal mass. PMID- 21316093 TI - Morbidity of prostate biopsy after simplified versus complex preparation protocols: assessment of risk factors. AB - OBJECTIVE: To determine whether prostate biopsy complications were affected by 2 varying prebiospy protocols implemented at our institution. Although transrectal ultrasound (TRUS) guided prostate biopsy is considered generally safe, it is associated with significant complications. METHODS: We retrospectively evaluated a total of 1438 TRUS-guided prostate biopsies between January 2001 and June 2008. In group A, 931 men had only one dose of a quinolone antibiotic immediately before the procedure, and no enema was performed. In group B, 507 men who underwent a prebiopsy enema and were given oral antibiotics starting the day before the procedure for 3 days. We analyzed demographics and biopsy complications between the 2 groups. RESULTS: The overall complication rates were categorized as infection (2.2%), urine retention (0.8%), hematuria (4.4%), rectal bleeding (1.5%), sepsis (0.2%). There was no significant statistical difference in the incidence of infection or sepsis between the 2 groups (2.7% vs 1.4%, P = .157 and 0.1% vs 0.4%, P = .285 respectively, for group A vs B). Both hematuria and hematospermia were more common in group B (2.5% vs 7.9%, P < .001 and 0.2% vs 2%, P < .001 respectively, for group A vs B). Prostate size was a significant risk for both hematuria (odds ratio = 1.7, 95% confidence interval = 1.2-2.44, P = .003) and acute urinary retention (odds ratio = 4.45, 95% confidence interval = 2.01-9.84, P < .001). CONCLUSIONS: This study demonstrates that a single antibiotic dose before prostate biopsy may be sufficient. In addition, use of prebiopsy enemas is unnecessary to decrease overall complication rates. PMID- 21316094 TI - Clavien classification of complications after 150 laparoscopic pyeloplasties. AB - OBJECTIVES: To compare the complications of laparoscopic pyeloplasty observed in 3 periods of our learning curve using the Clavien classification. METHODS: We reviewed and retrospectively analyzed the records of 150 cases of laparoscopic pyeloplasty performed for primary ureteropelvic junction obstruction at our center. All patients were divided into 3 groups according to the order of the case number (1-50, 51-100, 101-150) to compare the intergroup differences in the preoperative data and perioperative parameters. The postoperative complications were subdivided according to the 5-grade Clavien classification of surgical complications. The groups of patients with and without complications were compared with respect to age, degree of hydronephrosis, positive urine culture before surgery, concomitant nephrolithiasis, crossing vessel, and the type of operation performed (dismembered vs nondismembered). RESULTS: The success rate was 90.5%. The mean follow-up was 53.7 months (range 5-103). Intraoperative complications occurred in 9 (6%) of 150 patients and postoperative complications in 27 (18%) of 150 patients. No statistically significant differences were seen between the incidence of intra- and postoperative complications among the compared groups. The only statistically significant difference among the groups with and without complications was the presence of a positive urine culture (19% vs 6%, respectively). CONCLUSIONS: The most common complications were connected with stent obstruction, and they did not seem dependent on surgeon experience. Patients with a preoperative positive urine culture might have a greater risk of postoperative complications. PMID- 21316095 TI - Primary mature teratoma presenting as an adrenal tumor in a child. AB - Teratomas, rare germ tumors usually found in the ovaries and testes, are potentially malignant. Adrenal teratomas are extremely rare, and their diagnosis relies on the findings from radiologic examinations. Early diagnosis and surgical resection are important for effective treatment. The success of the treatment determines the need for postoperative chemotherapy. Because the prognosis is currently difficult to predict, close, lifelong follow-up is recommended. The present review discusses the character of mature teratomas of the adrenal gland. We report 1 case of a primary mature teratoma presenting as an adrenal tumor in a child and review the published data. PMID- 21316097 TI - Cardiovascular safety and diabetes drug development. PMID- 21316098 TI - Europe and the century of biomedical discovery and implementation. PMID- 21316099 TI - The effect of artificial feed on blood biochemistry profile and liver histology of wild saddled bream, Oblada melanura (Sparidae). AB - Floating fish farms attract a great number of wild fish species, changing their behaviour and physiology. The saddled bream, Oblada melanura, sampled from populations aggregated around the Adriatic fish farm and from natural/control populations, were analysed for differences in eleven blood biochemistry parameters and liver histomorphology. The levels of lactate dehydrogenase (LDH), alkaline phosphatase (ALKP) and urea (URE) in cage-associated saddled bream (428.00+/-SD 321.56 U/L, 86.13+/-SD 39.87 U/L and 0.05+/-SD 0.16 mmol/L, respectively) were significantly lower than those observed in the control specimens (1047.06+/-SD 505.56 U/L, 125.75+/-SD 34.70 U/L and 1.99+/-SD 0.73 mmol/L, respectively). In contrast to that, concentrations of aspartate aminotransferase (AST) in cage-associated fish (87.63+/-SD 132.34 U/L) were higher than values noted for the control population (6.55+/-SD 5.90 U/L). URE and AST presented the main variables contributing to the discrimination between two analysed populations. One-way ANOSIM based on the blood parameters showed significant difference between saddled bream that fed around cages and those from the remote waters (R=0.697; P < 0.01). Hepatocytes of cage-associated fish contained large cytoplasmatic clear spaces indicating excessive accumulation of fat in the hepatocyte cytoplasm. All observed differences can be attributed to contrasting feeding behaviour of sampled populations but basic nutritional differences between them should be quantified in the future. Moreover, further research is necessary to detect their impact on the health status of the fish. PMID- 21316100 TI - Neither normal nor diseased placentas contain lymphatic vessels. AB - BACKGROUND: Scant data on placental lymphatic vessels have pointed to the absence of lymphatic circulation. A recent study on mesenchymal dysplasia (MD), however, has identified pathologic lymphangiogenesis using the D2-40 lymphatic marker. These conflicting data have prompted us to investigate whether lymphatic vessels are present in normal developing placentas and in placental disorders characterized by cistern formation. DESIGN: Seventeen human placentas without significant pathological abnormality ranging from 12 to 39 weeks of gestational age were studied. Cisternal placental disorders were represented by mesenchymal dysplasia (n = 1), partial hydatitiform mole (n = 2), spontaneous abortion (n = 3) and complete hydatiform mole (n = 2). To identify lymphatic vessels, we used lymphatic endothelial markers Prox-1 and D2-40. The pan-endothelial marker CD31 was used to highlight overall placental vasculature and to determine if the lining cells of cisterns were of endothelial origin. Lymphatic marker positivity was assessed in maternal (decidual) as well as in fetal (chorionic villous) vasculature. RESULTS: No staining with Prox-1 or D2-40 was identified in fetal vessels in developing or term placentas, or in selected cisternal placental disorders, although both markers highlighted a number of thin-walled decidual vessels. Cistern lining cells were negative for Prox-1, D2-40 and CD31. D2-40 consistently marked stromal cells in chorionic villi and highlighted perivascular/pericellular extracellular matrix. CONCLUSION: We established that no lymphatic vasculature is present in the chorionic villi during development, at term or in selected edematous placental disorders. The cisternal lining cells are not endothelial cells; most likely they are of stromal cell origin. Lymphangiogenesis is a part of decidual vascular remodeling during gestation. PMID- 21316101 TI - Ca(2+) signalling in the Golgi apparatus. AB - The Golgi apparatus plays a central role in lipid and protein post-translational modification and sorting. Morphologically the organelle is heterogeneous and it is possible to distinguish stacks of flat cysternae (cis- and medial Golgi), tubular-reticular networks and vesicles (trans-Golgi). These morphological differences parallel a distinct functionality with a selective distribution and complementary roles of the enzymes found in the different compartments. The Golgi apparatus has been also shown to be involved in Ca(2+) signalling: it is indeed endowed with Ca(2+) pumps, Ca(2+) release channels and Ca(2+) binding proteins and is thought to participate in determining the spatio-temporal complexity of the Ca(2+) signal within the cell, though this role is still poorly understood. Recently, it has been demonstrated that the organelle is heterogeneous in terms of Ca(2+) handling and selective reduction of Ca(2+) concentration, both in vitro and in a genetic human disease, within one of its sub-compartment results in alterations of protein trafficking within the secretory pathway and of the entire Golgi morphology. In this paper we review the available information on the Ca(2+) toolkit within the Golgi, its heterogeneous distribution in the organelle sub compartments and discuss the implications of these characteristics for the physiopathology of the Golgi apparatus. PMID- 21316102 TI - Comparative pre-clinical evaluation of receptor tyrosine kinase inhibitors for the treatment of multiple myeloma. AB - BACKGROUND: Fibroblast growth factor receptor 3 (FGFR3) is up-regulated as a result of the t(4;14)(p16;q32) translocation that occurs in up to 20% of multiple myeloma (MM) patients. Recent studies have demonstrated that up-regulation of FGFR3 promotes cell survival, growth and drug resistance in malignant plasma cells, both in vitro and in vivo. Therefore, inhibition of FGFR3 signalling is potential target for the chemotherapeutic intervention in t(4;14) MM. METHODS: Small molecule receptor tyrosine kinase inhibitors (PD173074, sunitinib (SU 11248), vandetanib (ZD6474) and vatalanib (PTK-787)) with varying degrees of inhibitory activity and selectivity against FGFR, were assessed in Ba/f3 cells expressing ZNF198-FGFR1 and MM cell lines. Cell viability, FGFR3 and ZNF198-FGFR1 phosphorylation and apoptosis were evaluated by growth inhibition assays, immunoblotting and fluorescence-activated cell sorting analysis, respectively. An in vivo study was performed with sunitinib in t(4;14)-positive and t(4;14) negative human MM tumour xenograft models. RESULTS: PD173074 and sunitinib differentially inhibited the growth of Ba/f3 cells expressing ZNF198-FGFR1 (GI(50)=10 nM and 730 nM, versus GI(50) >1 MUM and 2.7 MUM for parental cells; p<0.0001) and t(4;14) positive MM cell lines (GI(50)=4-10 MUM and 1-3 MUM, versus GI(50)=14-15 MUM and 4-5 MUM for t(4;14) negative MM cells; p<=0.002). In addition, both PD173074 and sunitinib inhibited the activation of FGFR3 in t(4;14)-positive MM cells. PD173074 and sunitinib induced an apoptotic response in a concentration and time-dependent manner in a t(4;14)-positive (PD174073 and sunitinib) but not a t(4;14)-negative MM cell line (sunitinib only); however, in in vivo tumours derived from the same cell lines, sunitinib was only active in the t(4;14)-negative model. CONCLUSIONS: These data demonstrate that PD173074 and sunitinib are inhibitors of FGFR3 in MM cell lines, and that sunitinib has in vivo activity in a human MM tumour xenograft model. However, caution should be exercised in using the t(4;14) translocation as a predictive biomarker for patient selection in clinical trials with sunitinib. PMID- 21316103 TI - Isolated central nervous system relapse after nine years of complete molecular remission in a lymphoid blast crisis of chronic myeloid leukemia treated with imatinib. PMID- 21316104 TI - Identification of ICD codes suggestive of child maltreatment. AB - OBJECTIVE: In order to be reimbursed for the care they provide, hospitals in the United States are required to use a standard system to code all discharge diagnoses: the International Classification of Disease, 9th Revision, Clinical Modification (ICD-9). Although ICD-9 codes specific for child maltreatment exist, they do not identify all maltreatment-related hospital and emergency department discharges. To increase the usefulness of medical data for public health surveillance of child maltreatment, this project sought to identify ICD-9 codes that are suggestive of child maltreatment. METHODS: After review of the literature and discussions with experts, injuries and conditions that should raise suspicion of child maltreatment (physical or sexual abuse or neglect) were identified and a list of corresponding ICD codes was compiled. Using a statewide electronic database of hospital discharges and emergency department (ED) visits for the year 2000, visits by children assigned these ICD codes were identified, a sample of visits was selected, and medical records were reviewed to assess the circumstances of the injury or illness that led to the visit. Based on information in the medical record, the injury or illness was classified as maltreatment-related, or not. RESULTS: There were 3,684 visits selected for review. Of these, 2,826 records were reviewed and classified; 1,200 (43%) records met the criteria for being maltreatment-related, 1,419 (50%) contained adequate information indicating the injury/condition was not likely maltreatment-related, and 207 (7%) records did not contain enough information to classify. Sixty-eight ICD codes had >66% of visits classified as maltreatment-related, the a priori criteria for a code to be considered suggestive of maltreatment. Codes suggestive of maltreatment include specific fractures, burns, and injuries of undetermined intent, among others. CONCLUSION: Several ICD codes were found that, when used with age restrictions and other specific exclusion criteria, are suggestive of maltreatment. This information may increase the usefulness of hospital discharge data for public health surveillance of child maltreatment. PRACTICE IMPLICATIONS: Use of these suggestive codes facilitates identifying conditions and injuries that are likely maltreatment-related in hospital discharge and ED visit data. When used in conjunction with ICD maltreatment-specific codes, these suggestive codes may enhance the use of medical data for monitoring child maltreatment trends. PMID- 21316105 TI - Accidental death from take home methadone maintenance doses: A report of a case and suggestions for prevention. PMID- 21316106 TI - Pediatric health assessments of young children in child welfare by placement type. AB - OBJECTIVES: To describe health-related problems across placement types (unrelated foster, kin foster, in-home with birth parent); to examine the association of placement and demographic/child welfare variables (child gender, age, race/ethnicity; caregiver language; type of maltreatment, and length of time receiving services from child welfare) with health-related problems. METHODS: This study utilized a retrospective medical chart review of children less than 6 years old (n=449) seen at an outpatient child welfare pediatric clinic. Logistic regression modeling was used to estimate odds of having a weight, medical, or provisional developmental delay problem by placement and demographic/child welfare characteristics. RESULTS: Almost 13% of children in the sample were obese (>=95% age-gender specific percentile) and more than a quarter were overweight/obese (>=85%) while only 7% were underweight (<=5%). Most children (78%) had a physical health diagnosis and 25% were provisionally identified with a developmental delay. No differences between weight diagnoses, type of medical diagnoses, and provisional developmental delay by placement type were found, although children with 3 or more medical diagnoses were more likely to be with kin (p<.05). Children 2 years old or older were more likely to be overweight/obese than children under 2 years old (p<.05) and Hispanic children were more likely to be overweight/obese than non-Hispanic children (p<.01). Length of stay in child welfare was positively related with a medical diagnosis or provisional developmental delay (p<.01). CONCLUSIONS: Results argue for careful assessment of weight, medical, and developmental problems in children active to child welfare, whether residing in their home of origin, with kin, or with unrelated foster parents. The increasing problem of obesity among young children in child welfare warrants further investigation and intervention. PRACTICE IMPLICATIONS: The comprehensive health examination and enhanced health maintenance schedule for children in foster care should be extended to children who remain at home with child welfare services as child welfare involvement rather than placement is related to health-related problems. PMID- 21316107 TI - The effects of abuse history on sexually intrusive behavior by children: An analysis of child justice records. AB - OBJECTIVES: A commonly cited risk factor for sexually intrusive behavior (SIB) among children and adolescents is a history of abuse. Based on a large and non clinical nationwide sample of children who were investigated as abuse victims and suspects of SIBs in Israel over a decade, the present study examines the rate of abuse history among child suspects who have admitted SIBs. In addition, this study compares some personal and family characteristics as well as selected aspects of SIBs reported by children with and without a history of abuse. Abuse history is then used to predict the nature of SIBs after controlling for other predictors. METHODS: National data files of the investigation of alleged child victims and child suspects aged 14 or under were electronically merged, allowing the identification of a sub-group of suspects, out of all suspects, who had a record of child abuse. Using only confirmed cases of boys with SIBs, child suspects with a record of abuse were compared to the larger group of child suspects with no record of abuse. RESULTS: Of 3,554 child suspects of SIBs, 345 or 9.7% had a formal record of abuse. Boys with a record of abuse engaged in SIBs at a younger age; were more likely to display mental disabilities; more often belonged to large size, single-parent, low SES, and immigrant families and were more likely to be removed from home to alternative care than boys with no record of abuse. The nature of SIBs varied across the groups, with victim-suspects more likely than their counterparts to act repeatedly, and to do so alone rather than in the presence of others. Victim-suspects were more likely to involve in SIBs with younger children, with siblings, and with unrelated children. Most aspects of SIBs were predicted by abuse history after controlling for other predictors, with some differences between age groups being evident. CONCLUSIONS: Although abuse history is uncommon among children displaying SIBs in this sample, it seems to affect the involvement of children at a younger age in more severe SIBs, posing a higher risk to other children. PRACTICAL IMPLICATIONS: The low rate of abuse history among boys with SIBs suggests that clinical assessors of SIBs in children should not assume that these children have been victims of abuse or that abuse is a necessary component in the development of SIBs. This implies that the exploration of past abuse in the assessment of children with SIBs is not always relevant and that trauma-related components in the treatment of these children should be selective. As past-abuse is less related to SIB's for older children, the clinical focus on abuse is even less relevant for older children. However, when boys with SIBs have been past-victims, they seem to be in greater need for treatment than other boys with SIBs. Moreover, the dynamics of SIBs by past victims should raise more concern for older than for younger children. PMID- 21316108 TI - The relationship between time spent living with kin and adolescent functioning in youth with a history of out-of-home placement. AB - OBJECTIVE: Many children in the US who are court-ordered to live in out-of-home care are placed with kinship caregivers. Few studies have examined the impact of living with kin on child well-being. This study examined the relationship between length of time living with kin and indices of adolescent well-being in a cohort of children who were initially court-ordered into out-of-home care. METHODS: Prospective cohort design with 148 youth, ages 7-12, who entered out-of-home care between May, 1990, and October, 1991. Seventy-five percent of those interviewed at T1 (6 months following placement) were interviewed at T2 (5 years later). RESULTS: Bivariate analyses did not demonstrate significant relationships between length of time living with kin and the outcome variables. In multivariate analyses, longer length of time living with kin was related to: (1) greater involvement in risk behaviors including: delinquency (beta=.22, p<.05), sexual risk behaviors (beta=.31, p<.05), substance use (beta=.26, p<.05), and total risk behaviors (beta=.27, p<.05), and (2) poorer life-course outcomes including: Tickets/Arrests (OR=1.4, p<.05) and lower grades (beta=-.24, p<.05). Time living with kin was not related to total competence, or self-destructive, internalizing, externalizing, or total behavior problems. There were trends (p<.10) for time living with kin to predict greater trauma symptomatology (beta=.17) and suspensions (OR=1.1). CONCLUSIONS: There were no significant bivariate findings. The multivariate findings suggested a pattern of poorer functioning for youth who spent more time living with kin. No differences were found in current symptomatology. PRACTICE IMPLICATIONS: Although findings from a single study should not dictate changes in practice or policy, the current study's findings do suggest that the field needs to conduct more methodologically sophisticated research on the impact of kinship care. PMID- 21316109 TI - Lipid mobilization and inflammatory responses during the transition period of dairy cows. AB - The transition period of dairy cattle is characterized by dramatic changes in metabolism and host defense mechanisms that are associated with increased disease. Intense lipid mobilization from tissue stores is an important metabolic adaptation during the transition period that results in significant release of non-esterified fatty acids (NEFA) into the blood stream. Whereas these fatty acids are important sources of energy during times of increased metabolic demands, elevated concentrations of NEFA are known to disrupt several immune and inflammatory functions. This review will discuss the implications of lipid mobilization on inflammatory responses with special emphasis on leukocytes and endothelial cell functions during the transition period of dairy cows. PMID- 21316110 TI - The influence of attachment and temperament on venipuncture distress in 14-month old infants: the Generation R Study. AB - OBJECTIVE: This study examined the effects of attachment and temperament on infant distress during venipuncture. METHOD: The study was embedded in the Generation R Study, a prospective population-based study. Two different research procedures (i.e., blood sampling and the Ainsworth Strange Situation Procedure) yielded measures of venipuncture distress and attachment security and disorganization in 246 infants aged 14 months. Four temperament traits (distress to limitations, fear, recovery from distress, and sadness) were assessed using the maternally reported Infant Behavior Questionnaire-Revised, at the age of 6 months. RESULTS: There were no differences between mean levels of distress during venipuncture in infants classified as having insecure attachment, but there was a trend for disorganized attachment. The temperament traits were not related to distress. However, children with a disorganized attachment and higher temperamental fear had more venipuncture distress. CONCLUSION: When different risk factors are present simultaneously, infant distress is heightened. PMID- 21316111 TI - Expression of CXCR7 chemokine receptor in human meningioma cells and in intratumoral microvasculature. AB - CXCR4 and CXCR7 chemokine receptors, and their ligands CXCL11 and CXCL12, have been often involved in tumor cell proliferation and survival. We report the expression pattern of these ligand/receptor pairs in 22 human meningiomas. High CXCR7 and CXCL12 expression was associated with high-proliferative tumors. CXCR7 levels were correlated to the content of both ligands, suggesting a possible autocrine regulation. CXCR4 and CXCL12 were homogeneously expressed within tumor cells, while CXCR7 was mainly detected in tumor endothelial cells and CXCL11 in pericytes. Our results highlight the preferential CXCR7 and CXCL12 expression within more aggressive tumors and the possible role of CXCR7 in meningioma vascularization. PMID- 21316112 TI - Temporal dynamics of cerebrospinal fluid anti-aquaporin-4 antibodies in patients with neuromyelitis optica spectrum disorders. AB - Neuromyelitis optica spectrum disorders (NMOSD) are associated with anti aquaporin-4 autoantibodies (AQP4-IgG). Limited data is available on longitudinal cerebrospinal fluid (CSF) AQP4-IgG and their relation to disease activity and inflammatory parameters. AQP4-IgG titers were measured in matched longitudinal serum and CSF samples of 12 patients with NMOSD by an immunofluorescence assay and correlated with clinical parameters. CSF AQP4-IgG were present in patients with high serum titers and correlated with spinal MRI lesion length and CSF parameters. Clinical improvement was associated with a decrease in CSF, but not serum, AQP4-IgG titers. Thus, CSF AQP4-IgG were associated with clinical activity and neuroinflammation. PMID- 21316113 TI - Unexpected pathologies in pediatric parotid lesions: management paradigms revisited. AB - OBJECTIVES: To present case vignettes of unusual pediatric parotid pathologies and discuss management paradigms in the context of these lesions. STUDY DESIGN: Retrospective case series. SETTING: Free-standing, academic tertiary care pediatric hospital. METHODS: All patients over the past 18 months undergoing parotidectomy for a parotid mass were reviewed (N=5). RESULTS: Ages ranged from 17 months to 16 years. All presented with a remarkably similar clinical course, consisting of a persistent parotid mass for more than 3 months which was usually painless. Most (4/5 patients) had been treated with antibiotics prior to Otolaryngology consultation. Fine-needle aspiration (FNA) was performed on 3 patients and was diagnostic in one. Complete excision of the mass was performed in each child through a parotidectomy approach (3 total, 2 lateral lobe). The final pathology showed metastatic neuroblastoma (17 months old), undifferentiated primitive sarcoma (22 months old), mucoepidermoid carcinoma (11 years old), nodular fasciitis (12 years old), and hyperplastic lymph node (16 years old). The patient with neuroblastoma died from complications of bone marrow transplant. CONCLUSIONS: The differential diagnosis for a persistent pediatric parotid mass is expansive and differs from that found in the adult population. As this series highlights, in many cases, it is impossible to discern the pathology, or rule out malignancy, based upon the clinical course, imaging, or FNA results. Surgical excision remains the standard for management of these patients and is both diagnostic and therapeutic. Our anecdotal case series highlights the importance of having a low threshold for parotidectomy in these children. PMID- 21316115 TI - Is echo-guided optimization of biventricular devices time practical? PMID- 21316114 TI - Differences in coronary plaque composition with aging measured by coronary computed tomography angiography. AB - BACKGROUND: Little is known about the independent impact of aging on coronary plaque morphology and composition in the era of cardiac computed tomography angiography (CCTA). METHODS: We studied 1015 consecutive asymptomatic South Korean subjects (49 +/- 10 years, 64% men) who underwent 64-slice CCTA during routine health evaluation. Coronary plaque characteristics were analyzed on a per segment basis according to the modified AHA classification. Plaques with >50% calcified tissue were classified as calcified (CAP), plaques with <50% calcified tissue were classified as mixed (MCAP), and plaques without calcium were classified as non-calcified (NCAP). Multiple regression analysis was employed to describe the cross-sectional association between age tertile and plaque type burden (>= 2 affected segments) after adjustment for other cardiovascular risk factors. RESULTS: The prevalence of coronary plaque increased with age, (1st tertile: 7.5%, 3rd tertile: 38.5% [p<0.001]). The relative contribution of NCAP to overall plaque burden decreased with age from nearly 50% in the first tertile to approximately 20% in the third, while there was a reciprocal increase in both MCAP and CAP subtypes. In multivariable analysis, patients in the oldest tertile had a 2.5-fold increase in burden of NCAP, yet a nearly 40-fold increase in MCAP and 16-fold increase in CAP compared to the youngest tertile. In conclusion, CCTA is an effective method for measuring age-related differences in the burden of individual coronary plaque subtypes. Future research is needed to determine whether the increase in mixed and calcified plaques seen with aging produce an independent contribution to the age-related increase in cardiovascular risk. PMID- 21316117 TI - Systematized nomenclature of medicine clinical terms (SNOMED CT) to represent computed tomography procedures. AB - OBJECTIVE: To evaluate the ability of systematized nomenclature of medicine clinical terms (SNOMED CT) to represent computed tomography procedures in computed tomography dictionaries used in the Canadian province of Newfoundland and Labrador. METHODS: This study was conducted in two stages. In the first stage computed tomography dictionaries were collected and consolidated to one master list. The duplicated procedure names were deleted from the list. In the second stage the unique data items from the master list were matched with the SNOMED CT concepts. Sensitivity, specificity, and positive and negative predictive values of SNOMED CT were investigated. RESULTS: After eliminating 680 duplicate procedures from the total of 833, the study sample consisted of 153 data items. For pre-coordination, SNOMED CT had sensitivity of 56% and for post-coordination SNOMED CT had sensitivity of 98%. CONCLUSION: Our results suggest that SNOMED CT is a valid nomenclature for representing computed tomography procedures. PMID- 21316116 TI - Origin of Vibrio parahaemolyticus O3:K6 pandemic clone. AB - O3:K6 pandemic clone of Vibrio parahaemolyticus has caused outbreaks in coastal countries since 1996. Mutilocus sequence typing (MLST) is an important tool to trace the source and analysis the evolution of bacteria. Based on MLST, the first pandemic clonal complex (CC) of V. parahaemolyticus has been confirmed. In this study, 57 pandemic strains, 27 pathogenic strains (tdh or trh positive) and 36 nonpathogenic strains isolated from China were analyzed with MLST. Forty-seven unique sequence types, one clonal complex (CC) and one doublet (D) were identified by eBURST and Mega4 analyses. CC corresponded to not only the known O3:K6 pandemic clone (including ST-3, ST-192, ST-227) but nonpathogenic clone (including ST-3, S-T2, ST-196, ST-220, ST-226). ST-3 was the founder of the complex. STs of the isolates were not inevitably associated with the presence or number of the accessory genes or the serotypes of the isolates. The ancestor strain of O3:K6 pandemic clone was originated from an environmental nonpathogenic O3:K6, ST-3 strain. The pandemic O3:K6 clone was developed from this strain in approximately 1996 by laterally transferring large fragments of genes including systematic functional genes and genomic islands. PMID- 21316119 TI - Applicability of a sharp-interface model for estimating steady-state salinity at pumping wells--validation against sand tank experiments. AB - A numerical sharp-interface model of saltwater and freshwater behavior was validated against experiments conducted in two small scale sand tanks. A simple algorithm was proposed to determine saltwater and freshwater withdrawal rates at a pumping well at which a total pumping rate was specified. Model estimates were compared with transient salinity breakthroughs and steady-state salinities of water extracted from pumping wells in the sand tanks. Experimental scenarios included various combinations of freshwater pumping and injection and saltwater pumping. The corresponding Nash-Sutcliffe model efficiency was 0.95, which showed that the agreement between observations and computed results was satisfactory. PMID- 21316118 TI - p53 codon 72 polymorphism and the risk of lung cancer in a Korean population. AB - The aim of this study was to assess whether p53 codon 72 polymorphism is associated with an increased risk of lung cancer (LC) in a South Korean population. We conducted a population-based, large-scale, case-control study including 3939 patients with LC and 1700 controls. P53 codon 72 polymorphism was determined by real-time polymerase chain reaction (PCR). The frequencies of p53 codon 72 polymorphisms (Arg/Arg, Arg/Pro, and Pro/Pro) in LC were 37.0%, 46.2%, and 16.7%, respectively; frequencies in the controls were 43.2%, 45.6%, and 11.2%, respectively (p<0.01). The Arg/Pro and Pro/Pro genotype were significantly associated with increased risk of LC (odds ratio (OR)=1.22, 95% confidence interval (CI)=1.06-1.14 and OR=1.83, 95% CI=1.48-2.26, respectively) compared with the Arg/Arg genotype. Risk was compared in different subgroups. The OR of Pro/Pro genotype was significantly higher in small cell lung cancer (SCC) and squamous cell carcinoma (SQC) than in adenocarcinoma (ADC). Higher OR of Pro/Pro genotype was also seen among males. However, relationships between gender, age, smoking, and genotypes were not found. P53 codon 72 polymorphism was associated with an increased risk of LC in this Korean population; the association was especially noteworthy in SQC, SCC, and males. PMID- 21316120 TI - Growth advantage in stationary phase phenomenon in Gram-positive bacteria. PMID- 21316121 TI - Impact of observation and analysis methodology when reporting hand hygiene data. PMID- 21316122 TI - Routine hand hygiene audit by direct observation: has nemesis arrived? AB - Infection prevention and control experts have expended valuable health service time developing and implementing tools to audit health workers' hand hygiene compliance by direct observation. Although described as the 'gold standard' approach to hand hygiene audit, this method is labour intensive and may be inaccurate unless performed by trained personnel who are regularly monitored to ensure quality control. New technological devices have been developed to generate 'real time' data, but the cost of installing them and using them during routine patient care has not been evaluated. Moreover, they do not provide as much information about the hand hygiene episode or the context in which hand hygiene has been performed as direct observation. Uptake of hand hygiene products offers an inexpensive alternative to direct observation. Although product uptake would not provide detailed information about the hand hygiene episode or local barriers to compliance, it could be used as a continuous monitoring tool. Regular inspection of the data by infection prevention and control teams and clinical staff would indicate when and where direct investigation of practice by direct observation and questioning of staff should be targeted by highly trained personnel to identify local problems and improve practice. PMID- 21316123 TI - Auricular cartilage: harvest technique and versatility in rhinoplasty. AB - OBJECTIVES/HYPOTHESIS: This study aims to present an improved technique for auricular cartilage harvest that maximizes graft volume while preserving auricular cosmesis. Also discussed is the versatility of auricular cartilage utilization in rhinoplasty. STUDY DESIGN: A retrospective review of a single surgeon's experience. METHODS: All auricular cartilage harvest and rhinoplasty operations performed by the senior author (CSC) from December 2006 through December 2009 cartilage were reviewed. RESULTS: Twenty-two cases were identified in which the described technique was used to harvest auricular cartilage for the purpose of functional or aesthetic rhinoplasty. There was sufficient tissue harvested in all operations, and no patients required costal cartilage harvest. Pain at the donor site after surgery was minimal and well controlled with oral medication. There were no donor-site complications and no cases of wound infection. CONCLUSIONS: The proposed technique allows for optimal auricular cartilage harvest. By applying this method, the ear retains the preoperative appearance while the surgeon is able to obtain the largest graft possible. Auricular cartilage is a versatile source of grafting material in primary and secondary rhinoplasty. PMID- 21316124 TI - [Knowledge of gender-based violence in the population seen in primary care]. AB - OBJECTIVE: To determine the knowledge and attitudes towards gender-based violence in the Primary Care patient population and their relationship with sociodemographic factors and personal experience. DESIGN: A descriptive, cross sectional study. SETTING: Urban Health Centres. PARTICIPANTS: Patients >=18 years old who were seen in a Primary Care clinic. MATERIALS AND METHOD: A questionnaire was used that included questions associated with knowledge, attitudes and experience of gender-based violence in the domestic environment. Variables such as, age, sex, education level, marital state were recorded, as well as the detection of personal experiences of Gender-Based Violence using the short Woman Abuse Screening Tool (WAST). RESULTS: A total of 673 people, from 18-86 years, responded, of which 68% were women. Only 18.2% had sufficient knowledge on who is considered to exercise gender-based violence. Half of the participants believed that gender-based violence included physical and psychological injuries, inhibition of freedom and rape. In the logistic regression analysis an independent relationship was found with the knowledge of the correct response on what is gender-based violence by marital state, being less likely in married people as regards widowers (OR: 0.28; CI 95%: 0.11-0.72), to consider that gender based violence involves physical injury (OR: 2.55; CI 95%: 1.28-5.08), but not psychological injury (OR: 0.52; CI 95%: 0.28-0.96), and not giving the correct response on what is domestic violence (OR:0.06; CI 95%: 0.03-0.12). CONCLUSIONS: There is a wide variation in the results as regards what patients believe gender based violence is and what aspects it covers. PMID- 21316125 TI - Acute myeloid leukemia detected on fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography imaging in a patient with fever of unknown origin. PMID- 21316126 TI - [Cost comparison of three treatments for localized prostate cancer in Spain: radical prostatectomy, prostate brachytherapy and external 3D conformal radiotherapy]. AB - OBJECTIVE: To compare the initial costs of the three most established treatments for clinically localized prostate cancer according to risk, age and comorbidity groups, from the healthcare provider's perspective. METHODS: We carried out a cost comparison study in a sample of patients consecutively recruited between 2003 and 2005 from a functional unit for prostate cancer treatment in Catalonia (Spain). The use of services up to 6 months after the treatment start date was obtained from hospital databases and direct costs were estimated by micro-cost calculation. Information on the clinical characteristics of patients and treatments was collected prospectively. Costs were compared by using nonparametric tests comparing medians (Kruskall-Wallis) and a semi-logarithmic multiple regression model. RESULTS: Among the 398 patients included, the cost difference among treatments was statistically significant: medians were ? 3,229.10, ? 5,369.00 and ? 6,265.60, respectively, for the groups of patients treated with external 3D conformal radiotherapy, brachytherapy and radical retropublic prostatectomy, (p<0.001). In the multivariate analysis (adjusted R(2)=0.8), the average costs of brachytherapy and external radiotherapy were significantly lower than that of prostatectomy (coefficient -0.212 and -0.729, respectively). CONCLUSIONS: Radical prostatectomy proved to be the most expensive treatment option. Overall, the estimated costs in our study were lower than those published elsewhere. Most of the costs were explained by the therapeutic option and neither comorbidity nor risk groups showed an effect on total costs independent of treatment. PMID- 21316128 TI - [Abdominal pain]. PMID- 21316127 TI - Synthesis and application of a bromomethyl substituted scaffold to be used for efficient optimization of anti-virulence activity. AB - Pilicides are a class of compounds that attenuate virulence in Gram negative bacteria by blocking the chaperone/usher pathway in Escherichia coli. It has also been shown that compounds derived from the peptidomimetic scaffold that the pilicides are based on can prevent both Abeta aggregation and curli formation. To facilitate optimizations towards the different targets, a new synthetic platform has been developed that enables fast and simple introduction of various substituents in position C-7 on the peptidomimetic scaffold. Importantly, this strategy also enables introduction of previously unattainable heteroatoms in this position. Pivotal to the synthetic strategy is the synthesis of a C-7 bromomethyl substituted derivative of the ring-fused dihydrothiazolo 2-pyridone pilicide scaffold. From this versatile and reactive intermediate various heteroatom-linked substituents could be introduced on the scaffold including amines, ethers, amides and sulfonamides. In addition, carbon-carbon bonds could be introduced to the sp(3)-hybridized bromomethyl substituted scaffold by Suzuki-Miyaura cross couplings. Evaluation of the 24 C-7 substituted compounds in whole-bacterial assays provided important structure-activity data and resulted in the identification of a number of new pilicides with activity as good or better than those developed previously. PMID- 21316129 TI - A biomechanical investigation of vertebral staples for fusionless scoliosis correction. AB - BACKGROUND: Fusionless scoliosis surgery is an early-stage treatment for idiopathic scoliosis which claims potential advantages over current fusion-based surgical procedures. Anterior vertebral stapling using a shape memory alloy staple is one such approach. Despite increasing interest in this technique, little is known about the effects on the spine following insertion, or the mechanism of action of the staple. The purpose of this study was to investigate the biomechanical consequences of staple insertion in the anterior thoracic spine, using in vitro experiments on an immature bovine model. METHODS: Individual calf spine thoracic motion segments were tested in flexion, extension, lateral bending and axial rotation. Changes in motion segment rotational stiffness following staple insertion were measured on a series of 14 specimens. Strain gauges were attached to three of the staples in the series to measure forces transmitted through the staple during loading. A micro-CT scan of a single specimen was performed after loading to qualitatively examine damage to the vertebral bone caused by the staple. FINDINGS: Small but statistically significant decreases in bending stiffness (P<0.05) occurred in flexion, extension, lateral bending away from the staple, and axial rotation away from the staple. Each strain-gauged staple showed a baseline compressive loading following insertion which was seen to gradually decrease during testing. Post-test micro-CT showed substantial bone and growth plate damage near the staple. INTERPRETATION: Based on our findings it is possible that growth modulation following staple insertion is due to tissue damage rather than sustained mechanical compression of the motion segment. PMID- 21316130 TI - Urban forests and pollution mitigation: analyzing ecosystem services and disservices. AB - The purpose of this paper is to integrate the concepts of ecosystem services and disservices when assessing the efficacy of using urban forests for mitigating pollution. A brief review of the literature identifies some pollution mitigation ecosystem services provided by urban forests. Existing ecosystem services definitions and typologies from the economics and ecological literature are adapted and applied to urban forest management and the concepts of ecosystem disservices from natural and semi-natural systems are discussed. Examples of the urban forest ecosystem services of air quality and carbon dioxide sequestration are used to illustrate issues associated with assessing their efficacy in mitigating urban pollution. Development of urban forest management alternatives that mitigate pollution should consider scale, contexts, heterogeneity, management intensities and other social and economic co-benefits, tradeoffs, and costs affecting stakeholders and urban sustainability goals. PMID- 21316131 TI - The removal of microorganisms and organic micropollutants from wastewater during infiltration to aquifers after irrigation of farmland in the Tula Valley, Mexico. AB - The Tula Valley receives untreated wastewater from Mexico City for agricultural irrigation, half of which infiltrates to aquifers from where drinking water is extracted. Samples of wastewater and infiltrated water from three areas of the valley were analyzed for microorganisms, organic micropollutants, and some basic parameters. Concentrations of microorganisms in the infiltrated water were generally very low but the incidence of fecal coliforms (present in 68% of samples), somatic bacteriophages (36%), Giardia spp. (14%), and helminth eggs (8%) suggested a health risk. Organic micropollutants, often present at high concentrations in the wastewater, were generally absent from the infiltrated water except carbamazepine which was in 55% of samples (up to 193 ng/L). There was no correlation between carbamazepine concentrations and the presence of microorganisms but highest concentrations of carbamazepine and boron coincided. A treatment such as nanofiltration would be necessary for the infiltrated water to be a safe potable supply. PMID- 21316132 TI - The 2011 ESRD prospective payment system: perspectives from a for-profit small- to medium-sized dialysis organization. PMID- 21316133 TI - Association of the malnutrition-inflammation score with clinical outcomes in kidney transplant recipients. AB - BACKGROUND: The combination of chronic malnutrition and inflammation, often termed malnutrition-inflammation complex syndrome or protein-energy wasting, is common in patients with chronic kidney disease. It is associated with increased mortality in patients on maintenance dialysis therapy. We assessed the association of malnutrition-inflammation score (MIS) with all-cause mortality and death-censored transplant loss or death with a functioning transplant in a sample of kidney transplant recipients. STUDY DESIGN: Prospective prevalent cohort study. SETTING & PARTICIPANTS: Data from 993 prevalent transplant recipients were analyzed. Sociodemographic parameters, laboratory data, medical and transplant history, comorbid conditions, estimated glomerular filtration rate, and MIS were tabulated at baseline and annually thereafter. PREDICTOR: MIS, a 30-point scale expressed per 1 standard deviation (1 SD) unit or categorized as <3 (reference), 3-5, 6-8, and >8. The MIS is derived from 10 components, each with 4 levels of severity from 0 (normal) to 3 (severely abnormal). Higher score reflects more severe degree of malnutrition and inflammation status. OUTCOMES: All-cause mortality and death-censored transplant loss or death with a functioning transplant. Association of MIS with total mortality was assessed using time dependent Cox regression analysis, and the association of MIS with death-censored transplant loss or death with a functioning transplant was assessed using semiparametric competing-risks regression analysis. RESULTS: Mean age was 51 +/- 13 years, 57% of patients were men, and 21% had diabetes. Percentages of patients in the MIS categories <3, 3-5, 6-8, and >8 were 40%, 32%, 20%, and 8%, respectively. In multivariable time-dependent Cox regression analyses, time varying MIS score was a significant predictor of all-cause mortality (HR per 1-SD increase, 1.59; 95% CI, 1.37-1.85), death with a functioning transplant (HR per 1 SD increase, 1.48; 95% CI, 1.23-1.78), and death-censored transplant loss (HR per 1-SD increase, 1.34; 95% CI, 1.04-1.71). Compared with MIS <3, HRs for all-cause mortality for MIS of 3-5, 6-8, and >8 were 1.53 (95% CI, 0.74-3.15), 3.66 (95% CI, 1.87-7.14), and 6.82 (95% CI, 3.34-13.91), respectively. LIMITATIONS: Single center study, small number of outcomes. CONCLUSIONS: The MIS, a simple tool to assess the presence of malnutrition-inflammation complex syndrome, predicts mortality in kidney transplant recipients. PMID- 21316134 TI - It's not just who you are but where you live: an exploration of community influences on individual HIV status in rural Malawi. AB - Approximately 1 million people are infected with Human Immunodeficiency Virus (HIV) in Malawi. Despite efforts aimed at changing individual risk behaviors, HIV prevalence continues to rise among rural populations. Both previous research and the Political Economy of Health framework suggest that community-based socio economic factors and accessibility may influence HIV transmission; however, these community factors have received little empirical investigation. To fill this gap, this research uses data from a nationally representative probability sample of rural Malawians combined with small area estimates of community socio-economic and accessibility data in logistic regression models to: 1) reveal relationships between community factors and individual HIV status; 2) determine whether these relationships operate through individual HIV risk behaviors; and 3) explore whether these associations vary by gender. Community socio-economic factors include relative and absolute poverty; community accessibility factors include distance to roads, cities, and public health facilities. Individual HIV risk behaviors include reported condom use, sexually transmitted infections, multiple partnerships, and paid sex. Results show that higher community income inequality, community proximity to a major road, and community proximity to a public health clinic are associated with increased odds of HIV for women. For men, community proximity to a major road and community proximity to a public health clinic are associated with increased odds of HIV infection. These direct relationships between community factors and individual HIV status are not mediated by individual HIV risk behaviors. The Political Economy of Health frames the discussion. This study provides evidence for expanding HIV prevention efforts beyond individual risk behaviors to consideration of community factors that may drive the HIV epidemic in rural Malawi. PMID- 21316135 TI - Primary study of the use of an internal, self-activated shape memory alloy distraction device in the dog mandible: alveolar ridge distraction and implant placement. AB - PURPOSE: To investigate the use of an internal self-activated distraction device made of titanium-nickel memory alloy to augment the mandibular alveolar ridge. MATERIALS AND METHODS: Twelve adult mongrel canines were randomly divided into 4 groups. Groups I and II were sacrificed 1 month and 3 months after distraction, respectively. In group III (distraction-planting group), 2 implants were placed on both sides of the mandible 3 months after distraction. In group IV (control group), no implants were placed. X-rays were taken and histologic research was performed. RESULTS: When the distraction device was in place, the transport segments were lifted up 3.0 to 4.5 mm immediately, and a range of 7.5 to 11.5 mm of augmentation was reached after 3 to 5 days of device activation. X-rays showed that bone mineral density increased, and new bone formed in the distraction area 1 month after distraction. Three months later, the bone mineral density of the distraction area was close to that of the surrounding alveolar bone. Histologic observation showed that collagen bundles initially formed in the distraction region and were followed by calcification and osteogenesis. X-rays showed that the implants were well integrated 3 months after implant placement. The implant bone interface showed bony integration, and there was no significant difference in the implant-bone contact rate between the distraction and control sides. CONCLUSION: The titanium-nickel memory alloy distractor can be used successfully to augment the posterior mandibular alveolar ridge of canines. New bone formed between the buccal and lingual periosteal layers. A conventional implant surgical procedure could be performed 3 months later and the desirable implant-bone integration was produced. PMID- 21316136 TI - Preventive protocol for tooth extractions in patients treated with zoledronate: a case series. AB - PURPOSE: We report on an observational longitudinal noncontrolled study of a case series of consecutive patients treated with zoledronate who underwent tooth extractions. The tooth extractions were performed after a preventive protocol to minimize the risk of bisphosphonate-related osteonecrosis of the jaw. PATIENTS AND METHODS: A total of 43 patients who had received zoledronate and required single or multiple dental extractions were treated. The preventive protocol provided a surgical approach for dental extractions, characterized by the removal of alveolar bone (alveolectomy), and supported by correct antimicrobial therapy (antibiotics and mouthwash). RESULTS: A total of 102 tooth extractions in 43 patients were performed. The follow-up was 12 months. No signs of inflamed tissue or necrotic exposed bone in any patient were observed. CONCLUSIONS: With the limits of the present study, we observed that the removal of the alveolar bone after the tooth extractions and correct antimicrobial prophylaxis (antibiotics and mouthwash) could reduce the risk of occurrence of osteonecrosis in patients taking zoledronate. PMID- 21316137 TI - [Pyoderma gangrenosum: spontaneous healing after early diagnosis. Three cases and general review]. AB - INTRODUCTION: Pyoderma gangrenosum (PG) is a rare chronic inflammatory skin disease characterized by the recurring development of necrotizing and painful ulcers and therefore, often misinterpreted. This condition can simulate fulminant infection, particularly after surgery. The presentation is often impressive in extensive ulcerations and scarring and lead to significant sequelae. A rapid initial management avoids a dramatic evolution. PATIENTS AND METHODS: We report the case of three PG for patients followed for breast reconstruction after breast cancer. DISCUSSION: PG is a neutrophilic dermatosis that can occur after injuries of varying intensity. Its shape after surgery is a rare disease whose presentation loud and fast pace "infectious" contrasts with the absence of inflammatory lymphangitis or lymphadenopathy. Be aware of prescribing high doses of corticosteroids. CONCLUSION: These three cases illustrate the importance for early diagnosis and treatment of PG, who can allow spontaneous healing without complex surgery, always feared in this context. PMID- 21316138 TI - Wall abscess due to Mycobacterium avium intracellulare (MAI) in a patient with pneumoconiosis. PMID- 21316139 TI - Lung cancer in women: a comparison with men and an analysis of cases diagnosed in Ourense (Spain) 1999-2006. AB - INTRODUCTION AND OBJECTIVE: To analyse frequency, characteristics and survival of women with lung cancer (LC), in contrast to male patients. PATIENTS AND METHODS: A retrospective study was performed in patients with LC diagnosed by histocytology from 1999 to 2006. Survival was estimated by the Kaplan-Meier method. The chi-squared test was used to compare variables. RESULTS: A total of 1,290 patients were diagnosed, 190 (14.7%) of them were women, with a mean age of 67+/-13 years. The percentage of smokers was 17%. Histological types: adenocarcinoma 53%, small cell 21%, squamous cell carcinoma 13%. Surgery was performed (20%) in a higher percentage of women than in men. There were no differences in survival between the two groups. CONCLUSIONS: Of the total cases diagnosed, 14.7% were women, with a lower percentage of smokers. Adenocarcinoma was the most common histological type in women. There was no differences in survival compared to men. PMID- 21316140 TI - Experiences and the use of Cardiocerebral Resuscitation by a Chinese Emergency Department. PMID- 21316141 TI - Emerging pharmaceutical therapies in cardiopulmonary resuscitation and post resuscitation syndrome. AB - OBJECTIVE: The medication used in cardiopulmonary resuscitation (CPR) has by no means yielded the expected prognostic benefit. This review focuses on drugs that are currently under investigation as part of novel therapeutic strategies in CPR and post-resuscitation care. DATA SOURCES: The main categories of drugs under investigation were identified in position papers regarding gaps in scientific knowledge and research priorities in CPR. The electronic bases of Medline via PubMed and the ClinicalTrials.gov registry were searched. Research terms were identified using the MESH database and were combined thereafter. Initial search terms were "cardiac arrest", "cardiopulmonary resuscitation", "post-cardiac arrest syndrome" combined with "drugs" and also the names of pharmaceutical categories and related drugs. RESULTS: Novel pharmaceutical approaches rely on a better understanding of the pathophysiology of cardiac arrest and post resuscitation syndrome. Some medications are targeted primarily towards enhancing the return of spontaneous circulation and increasing survival rates, while others mostly aim at the attenuation of post-arrest myocardial and neurological impairment. Only a few of these therapies are currently being evaluated for clinical use. Despite the remarkable variability in study quality and success in achieving therapeutic targets, results for most therapies seem encouraging and support the continuation of research. CONCLUSION: New pharmaceutical modalities are being investigated for future use in CPR. Currently, none has been unequivocally accepted for clinical use, while only a few of them are undergoing clinical testing. This research is likely to continue, in view of the unsatisfactory results of current pharmaceutical therapies and the encouraging results of preliminary studies. PMID- 21316142 TI - Recurrent versus isolated pre-eclampsia and risk of feto-infant morbidity outcomes: racial/ethnic disparity. AB - OBJECTIVE: We examined the association between recurrent versus isolated pre eclampsia and feto-infant morbidity outcomes. STUDY DESIGN: This is a population based retrospective study on Florida hospital discharge data linked to the birth cohort files from 1998 through 2007. The study population comprised women with singleton first and second births who experienced pre-eclampsia in both pregnancies, and a comparison group consisting of women who were normotensive during their first pregnancy but developed pre-eclampsia in their second pregnancy. Feto-infant morbidities (low birth weight, very low birth weight, preterm, very preterm and small for gestational age) were the outcome of interest. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association between recurrent pre-eclampsia and feto-infant morbidity outcomes were obtained from logistic regression models. RESULT: Women who experienced recurrent pre-eclampsia were at elevated risk for low birth weight, very low birth weight, preterm and very preterm. The risk was most pronounced for preterm infants (OR=1.58 CL=1.42-1.76). Subgroup analysis demonstrated that infants born to black mothers with recurrent pre-eclampsia experienced the most elevated risk across all the racial/ethnic subgroups and this was most pronounced for very low birth weight and very preterm with a more than three-fold increase in risk (OR=3.77, 95% CI=2.77-5.13 and OR=3.66, 95% CI=2.66-5.03, respectively) as compared to the referent category (white mothers who were normotensive in first pregnancy but developed pre-eclampsia in their second pregnancy). CONCLUSION: Pre eclampsia is very severe when it recurs and black women are affected more than white or Hispanic women. PMID- 21316143 TI - Developmental regulation of somatic imprints. AB - Genomic imprinting is an epigenetic phenomenon guiding the allele-specific marking of parental alleles. Genes regulated by imprinting are only or preferentially expressed from a single allele during development and in the adult, and the transcriptional activity of each allele is dictated by its parental origin. Consequently, active and repressed alleles of imprinted genes are marked by activating and repressive histone marks, respectively. Whether these marks are implicated in the germline imprints distinguishing maternal and paternal alleles at fertilization or indeed in the mitotic inheritance of the two transcriptional states is currently unknown. The only epigenetic modification which is known to fulfill these roles is DNA methylation. Most but not all imprinted genes are marked by regions of allele-specific DNA methylation termed differentially methylated regions (DMRs). Whereas some DMRs, the gametic DMRs, are directly inherited from the mature gametes at fertilization, others, the somatic DMRs, are only acquired in postimplantation embryos. Although all somatic imprints are thought to emerge as a consequence of the cis-activity of a nearby gametic imprint, the molecular mechanisms guiding the de novo methylation at somatic DMRs are not fully understood. Here we review the known characteristics of gametic and somatic DMRs, with an emphasis on the factors implicated in the initiation and maintenance of these epigenetic marks. The analysis of somatic DMRs offers the opportunity to study the mechanism of de novo DNA methylation outside the context of the germline and as such might help to elucidate common mechanisms implicated in epigenetic silencing during development and differentiation. Moreover, studies on genes directly silenced by somatic DMRs may be informative in understanding the significance of controlling gene dosage in the adult. PMID- 21316144 TI - Re-fermentation of washed spent solids from batch hydrogenogenic fermentation for additional production of biohydrogen from the organic fraction of municipal solid waste. AB - In the first batch solid substrate anaerobic hydrogenogenic fermentation with intermittent venting (SSAHF-IV) of the organic fraction of municipal solid waste (OFMSW), a cumulative production of 16.6 mmol H(2)/reactor was obtained. Releases of hydrogen partial pressure first by intermittent venting and afterward by flushing headspace of reactors with inert gas N(2) allowed for further hydrogen production in a second to fourth incubation cycle, with no new inoculum nor substrate nor inhibitor added. After the fourth cycle, no more H(2) could be harvested. Interestingly, accumulated hydrogen in 4 cycles was 100% higher than that produced in the first cycle alone. At the end of incubation, partial pressure of H(2) was near zero whereas high concentrations of organic acids and solvents remained in the spent solids. So, since approximate mass balances indicated that there was still a moderate amount of biodegradable matter in the spent solids we hypothesized that the organic metabolites imposed some kind of inhibition on further fermentation of digestates. Spent solids were washed to eliminate organic metabolites and they were used in a second SSAHF-IV. Two more cycles of H(2) production were obtained, with a cumulative production of ca. 2.4 mmol H(2)/mini-reactor. As a conclusion, washing of spent solids of a previous SSAHF-IV allowed for an increase of hydrogen production by 15% in a second run of SSAHF-IV, leading to the validation of our hypothesis. PMID- 21316145 TI - Long-term infection rates in diabetic patients implanted with antibiotic impregnated versus nonimpregnated inflatable penile prostheses: 7-year outcomes. AB - BACKGROUND: Diabetic patients may be more prone to penile-implant infections than other men. OBJECTIVE: We sought to determine whether revision surgeries due to infection were less common in diabetic men after implantation of an inflatable penile prosthesis (IPP) impregnated with minocycline and rifampin (M/R) versus a nonimpregnated prosthesis. DESIGN, SETTING, AND PARTICIPANTS: Infection-related revisions for M/R-impregnated and nonimpregnated implants were compared during a retrospective review of patient-implant and removal data recorded in the manufacturer's database. The data set included men with diabetes as an etiology of erectile dysfunction and who were implanted with their first IPPs between 2001 and 2008. INTERVENTION: All men received three-piece IPPs. MEASUREMENTS: The number of first revisions due to infection reported at any time during the study period were summarized for each group. Freedom from infection-related revisions for initial M/R-impregnated implants were compared to nonimpregnated implants with <= 84 mo of follow-up using life-table survival analysis. Infection-free survival was also compared for diabetics versus nondiabetics. RESULTS AND LIMITATIONS: Mean age was 59.1 yr for the 6071 diabetic men in the M/R impregnated group. The nonimpregnated group included 624 diabetics with a mean age of 57.6 yr. Initial revisions due to infection were reported for 1.47% of M/R impregnated versus 4.17% of nonimpregnated implants. At 7 yr, the rate of infection-related revisions was significantly lower for M/R-impregnated (1.62%) than for nonimpregnated implants (4.24%; log-rank p < 0.0001). Diabetic men had a significantly higher rate of revisions due to infection at 7 yr (1.88%) than men without diabetes (1.53%; log-rank p = 0.0052). CONCLUSIONS: This long-term evidence from the largest known database of diabetic IPP recipients establishes that the use of an antibiotic-impregnated IPP can decrease revisions due to infection. Reducing the incidence of this devastating complication represents a significant medical advance in erectile restoration for diabetic patients. PMID- 21316147 TI - Mineralogical characterization of municipal solid waste incineration bottom ash with an emphasis on heavy metal-bearing phases. AB - Municipal solid waste incineration (MSWI) bottom ash contains a considerable amount of heavy metals. The occurrence and uneven distribution of these heavy metals in bottom ash can increase the complexity of such residues in terms of long-term behavior upon landfilling or recycling. Bottom ashes sampled from three stoker-type incinerators in Japan were analyzed in this paper. This study presents detailed information on the mineralogical characterization of bottom ash constituents and the weathering behavior of these constituents by means of optical microscopy and scanning electron microscopy. It was revealed that bottom ash mainly consists of assorted silicate-based glass phases (48-54 wt% of ash) and mineral phases including melilites, pseudowollastonite, spinels, and metallic inclusions (Fe-P, Fe-S, Fe-Cu, Cu-Sn, Cu-Zn, Cu-S, and Cu-Pb dominated phases), as melt products formed during the incineration process. The compounds embedded in the glass matrix, e.g. spinels and metallic inclusions, played the most important role in concentration of heavy metals (Pb, Zn, Cu, Cr, Mn, Ni, etc.). Other phases such as refractory minerals and ceramics, frequently found in ash, were of less significance in terms of their influence on the involvement of heavy metals. Analysis of lab-scale artificially weathered and 10-year landfilled bottom ash samples revealed that secondary mineralization/alteration of the bottom ash constituents principally carbonation and glass evolution substantially decreased the potential risk of the heavy metals to the surrounding environment. PMID- 21316148 TI - Deep brain stimulation of the subthalamic nucleus improves temperature sensation in patients with Parkinson's disease. AB - Patients with Parkinson's disease (PD) reportedly show deficits in sensory processing in addition to motor symptoms. However, little is known about the effects of bilateral deep brain stimulation of the subthalamic nucleus (STN-DBS) on temperature sensation as measured by quantitative sensory testing (QST). This study was designed to quantitatively evaluate the effects of STN-DBS on temperature sensation and pain in PD patients. We conducted a QST study comparing the effects of STN-DBS on cold sense thresholds (CSTs) and warm sense thresholds (WSTs) as well as on cold-induced and heat-induced pain thresholds (CPT and HPT) in 17 PD patients and 14 healthy control subjects. The CSTs and WSTs of patients were significantly smaller during the DBS-on mode when compared with the DBS-off mode (P<.001), whereas the CSTs and WSTs of patients in the DBS-off mode were significantly greater than those of healthy control subjects (P<.02). The CPTs and HPTs in PD patients were significantly larger on the more affected side than on the less affected side (P<.02). Because elevations in thermal sense and pain thresholds of QST are reportedly almost compatible with decreases in sensation, our findings confirm that temperature sensations may be disturbed in PD patients when compared with healthy persons and that STN-DBS can be used to improve temperature sensation in these patients. The mechanisms underlying our findings are not well understood, but improvement in temperature sensation appears to be a sign of modulation of disease-related brain network abnormalities. PMID- 21316149 TI - Psychological approaches have not been demonstrated to be effective for fibromyalgia. PMID- 21316151 TI - Response to the editorial commentary: "A cure for back pain?". PMID- 21316150 TI - Pain catastrophizing is related to temporal summation of pain but not temporal summation of the nociceptive flexion reflex. AB - Pain catastrophizing is associated with enhanced temporal summation of pain (TS Pain). However, because prior studies have found that pain catastrophizing is not associated with a measure of spinal nociception (nociceptive flexion reflex [NFR] threshold), this association may not result from changes in spinal nociceptive processes. The goal of the present study in healthy participants was to examine the relationship between trait (traditional) and state (situation-specific) pain catastrophizing and temporal summation of NFR (TS-NFR) and TS-Pain. A secondary goal was to replicate prior findings concerning relationships between catastrophizing and NFR threshold, electrocutaneous pain threshold, and sensory and affective ratings of electrocutaneous stimuli. All analyses controlled for depression symptoms, pain-related anxiety, and participant sex. As expected, multiple regression analyses indicated that neither trait nor situation-specific catastrophizing was associated with NFR threshold, but that situation-specific catastrophizing was associated with pain ratings. Multilevel linear growth models of TS data indicated that situation-specific catastrophizing was associated with TS-Pain but not TS-NFR. Trait catastrophizing was not related to TS-Pain or TS NFR. Together, these results confirm prior studies that indicate that catastrophizing enhances pain via supraspinal processes rather than spinal processes. Moreover, because catastrophizing was associated with TS-Pain but not TS-NFR, caution is warranted when using pain ratings to infer temporal summation of spinal nociceptive processes. PMID- 21316153 TI - Neuropathic pain- and glial derived neurotrophic factor-associated regulation of cadherins in spinal circuits of the dorsal horn. AB - Neuropathic pain is associated with reorganization of spinal synaptic circuits, implying that adhesion proteins that normally build and modify synapses must be involved. The adhesion proteins E- and N-cadherin delineate different synapses furnished by nociceptive primary afferents, but dynamic aspects of cadherin localization in relationship to onset, maintenance or reversibility of neuropathic pain are uncharacterized. Here, we find very different responses of these cadherins to L5 spinal nerve transection (SNT)-induced mechanical allodynia and to intrathecal glial derived neurotrophic factor (GDNF), which has potent analgesic effects in this pain model. In L5, E-cadherin is rapidly eliminated in patches within lamina IIi contemporaneously with the onset of mechanical allodynia. Intrathecal GDNF in conjunction with, or at 7 days after, L5 SNT prevents or reverses both the loss of E-cadherin and abnormal pain sensation. In contrast, N-cadherin undergoes a delayed and transient increase uniformly across lamina I-II that is insensitive to GDNF. Some N-cadherin-labeled profiles codistribute with GAP-43, suggesting a role in axon sprouting. Patterns of immunolabeling for GDNF receptor components GFRalpha1, NCAM, and RET after L5 SNT suggest that GFRalpha1 and NCAM are the principal receptors operative in this model. In addition, GFRalpha1 codistributes with E-cadherin, but not N-cadherin, profiles. Together, these data indicate strikingly divergent patterns of temporal and molecular regulation of different cadherins at distinct nociceptive circuits in response to spinal nerve injury, suggesting that the two cadherins and the circuits with which they are affiliated participate in different aspects of synaptic and circuit reorganization associated with neuropathic pain. PMID- 21316154 TI - Use of split thickness plantar skin grafts in the treatment of hyperpigmented skin-grafted fingers and palms in previously burned patients. AB - Palmar and finger burns are often seen in children, and are usually as a result of contact burns. Some patients with deep hand burns are treated with full thickness or split-thickness skin grafts. Skin graft is commonly used for hand reconstruction. However, the grafted skin would be more pigmented than the adjacent skin and different from skin texture. 19 patients who showed hyperpigmentation after skin graft of finger and palm were treated. They all were injured by hand burns. We performed mechanical dermabrasion of the hyperpigmentation scar and application of a split thickness skin harvested from medial aspect of plantar of foot. Patients were asked about their level of satisfaction with the procedure and scar appearance was assessed using a five point Likert scale. Also scar appearances were assessed using a Vancouver Scar Scale (VSS). The grafts were completely taken in all 19 patients. The color of the graft became similar to adjacent tissue. 15 patients were very satisfied, and four patients were relatively satisfied. The average score of the patients postoperative appearance improvement was 4.5 (improved to significantly improved postoperative appearance). Average VSS score was improved from 9.53 to 2.53. There was no hypertrophic scar on plantar donor site. The technique of the split thickness plantar skin graft after mechanical dermabrasion is simple and provided good results in both color and texture for the patients who showed hyperpigmentation after grafting. PMID- 21316152 TI - Brain P450 epoxygenase activity is required for the antinociceptive effects of improgan, a nonopioid analgesic. AB - The search for the mechanism of action of improgan (a nonopioid analgesic) led to the recent discovery of CC12, a compound that blocks improgan antinociception. Because CC12 is a cytochrome P450 inhibitor, and brain P450 mechanisms were recently shown to be required in opioid analgesic signaling, pharmacological and transgenic studies were performed in rodents to test the hypothesis that improgan antinociception requires brain P450 epoxygenase activity. Intracerebroventricular (i.c.v.) administration of the P450 inhibitors miconazole and fluconazole, and the arachidonic acid (AA) epoxygenase inhibitor N-methylsulfonyl-6-(2 propargyloxyphenyl)hexanamide (MS-PPOH) potently inhibited improgan antinociception in rats at doses that were inactive alone. MW06-25, a new P450 inhibitor that combines chemical features of CC12 and miconazole, also potently blocked improgan antinociception. Although miconazole and CC12 were weakly active at opioid and histamine H(3) receptors, MW06-25 showed no activity at these sites, yet retained potent P450-inhibiting properties. The P450 hypothesis was also tested in Cpr(low) mice, a viable knock-in model with dramatically reduced brain P450 activity. Improgan (145 nmol, i.c.v.) antinociception was reduced by 37% to 59% in Cpr(low) mice, as compared with control mice. Moreover, CC12 pretreatment (200 nmol, i.c.v.) abolished improgan action (70% to 91%) in control mice, but had no significant effect in Cpr(low) mice. Thus, improgan's activation of bulbospinal nonopioid analgesic circuits requires brain P450 epoxygenase activity. A model is proposed in which (1) improgan activates an unknown receptor to trigger downstream P450 activity, and (2) brainstem epoxygenase activity is a point of convergence for opioid and nonopioid analgesic signaling. PMID- 21316155 TI - Prediction of maximal aerobic capacity in severely burned children. AB - INTRODUCTION: Maximal oxygen uptake (VO2 peak) is an indicator of cardiorespiratory fitness, but requires expensive equipment and a relatively high technical skill level. PURPOSE: The aim of this study is to provide a formula for estimating VO2 peak in burned children, using information obtained without expensive equipment. METHODS: Children, with >= 40% total surface area burned (TBSA), underwent a modified Bruce treadmill test to assess VO(2) peak at 6 months after injury. We recorded gender, age, %TBSA, %3rd degree burn, height, weight, treadmill time, maximal speed, maximal grade, and peak heart rate, and applied McHenry's select algorithm to extract important independent variables and Robust multiple regression to establish prediction equations. RESULTS: 42 children; 7-17 years old were tested. Robust multiple regression model provided the equation: VO2 =10.33-0.62 * age (years)+1.88 * treadmill time (min)+2.3 (gender; females = 0, males = 1). The correlation between measured and estimated VO2 peak was R = 0.80. We then validated the equation with a group of 33 burned children, which yielded a correlation between measured and estimated VO2 peak of R = 0.79. CONCLUSIONS: Using only a treadmill and easily gathered information, VO2 peak can be estimated in children with burns. PMID- 21316156 TI - Comparative analysis of waterpipe and cigarette suppression of abstinence and craving symptoms. AB - This study's objective is to examine the relative effectiveness of cigarettes and waterpipe (WP) in reducing tobacco abstinence symptoms in dual cigarette/WP smokers. Sixty-one dual cigarette/WP smokers participated (mean age+/-SD 22.0+/ 2.6 year; mean cigarettes/day 22.4+/-10.1; mean WPs/week 5.2+/-5.6). After 12 hour abstinence participants completed two smoking sessions (WP or cigarette), while they responded to subjective measures of withdrawal, craving, and nicotine effects administered before smoking and 5, 15, 30 and 45 min thereafter. For both tobacco use methods, scores on measures of withdrawal and craving were high at the beginning of session (i.e., before smoking) and were reduced significantly and comparably during smoking. Analysis of smoking and recovery (post-smoking) phases showed similarity in the way both tobacco use methods suppressed withdrawal and craving, but the recovery of some of these symptoms can be faster with cigarette use. This study is the first to show the ability of WP to suppress abstinence effects comparably to cigarettes, and its potential to thwart cigarette cessation. PMID- 21316157 TI - Electronic screening and brief intervention for risky drinking in Swedish university students--a randomized controlled trial. AB - BACKGROUND: The limited number of electronic screening and brief intervention (e SBI) projects taking place in young adult student populations has left knowledge gaps about the specific methods needed to motivate reduced drinking. The aim of the present study was to compare differences in alcohol consumption over time after a series of e-SBIs was conducted with two groups of young adult students who were considered risky drinkers. The intervention group (IG) (n=80) received extensive normative feedback; the control group (CG) (n=78) received very brief feedback consisting of only three statements. METHOD: An e-SBI project was conducted in naturalistic settings among young adult students at a Swedish university. This study used a randomized controlled trial design, with respondents having an equal chance of being assigned to either the IG or the CG. The study assessed changes comparing the IG with the CG on four alcohol-related measurements: proportion with risky alcohol consumption, average weekly alcohol consumption, frequency of heavy episodic drinking (HED) and peak blood alcohol concentration (BAC). Follow-up was performed at 3 and 6 months after baseline. RESULTS: The study documented a significant decrease in the average weekly consumption for the IG over time but not for the CG, although the differences between the groups were non-significant. The study also found that there were significant decreases in HED over time within both groups; the differences were about equal in both groups at the 6-month follow-up. The proportion of risky drinkers decreased by about a third in both the CG and IG at the 3- and 6-month follow-ups. CONCLUSIONS: As the differences between the groups at 6 months for all alcohol-related outcome variables were not significant, the shorter, generic brief intervention appears to be as effective as the longer one including normative feedback. However, further studies in similar naturalistic settings are warranted with delayed assessment groups as controls in order to increase our understanding of reactivity assessment in email-based interventions among students. PMID- 21316158 TI - Retail colour display life of chilled lamb as affected by processing conditions and storage temperature. AB - This study explored the impact of i) processing conditions (electrical stimulation and pre rigor temperatures), and ii) storage temperature prior to retail display on the colour stability of lamb which had been vacuum-packaged for seven weeks before retail packaging in high-oxygen modified atmosphere (80% O(2)/20% CO(2)). A high pre rigor temperature (42 degrees C) reduced colour stability while differences in colour stability between pre rigor temperatures of 5 degrees C, 15 degrees C and 25 degrees C were limited. It was not affected by electrical stimulation, and did not interact with pre rigor temperature. In contrast, an increase in the storage temperature from the ideal temperature of 1.5 degrees C to 2 degrees C significantly decreased the colour stability of lamb loins. Even one week at 2 degrees C at the end of the storage period had a substantial negative impact on the retail colour display life. The variability in colour increased over time, and the variability increased more for the temperature abuse treatments. PMID- 21316159 TI - [Obstetrical outcome and risk of uterine rupture following a caesarean section before 32 weeks]. AB - OBJECTIVE: Our aim was to evaluate the subsequent obstetrical outcome and rate of uterine rupture following a caesarean section before 32 weeks of gestation. PATIENTS AND METHODS: A retrospective cohort study of 200 consecutive women with a prior caesarean section performed between 25 and 32 weeks were contacted by questionnaire or followed through medical charts to determine the subsequent mode of delivery. RESULTS: Two hundred caesarean section were performed between 25 and 32 weeks from January 1997 to March 2000. Thirty-nine patients (19.2%) were lost to follow-up. Seventy-one patients had a subsequent delivery. Thirty-two attempted vaginal birth and the success rate was 87.5%. Thirty-nine patients had a subsequent caesarean. One case of uterine rupture occurred before labour at 31 weeks (1.4%, % IC 95% [0.25; 7.56]). CONCLUSION: After a previous caesarean delivery before 32 weeks, a trial of labour may be proposed when obstetrical conditions are optimal. However, uterine rupture may occur prior to labor. PMID- 21316160 TI - [Hysteroscopic myomectomy: recurrence and satisfaction survey at short- and long term]. AB - OBJECTIVES: To assess the postoperative results at short- and long-term after hysteroscopic resection of submucosal myoma giving rise to symptoms. PATIENTS AND METHODS: Retrospective study (University Hospital Estaing, Clermont-Ferrand, France) including patients operated by hysteroscopy in 2004 for one or more submucosal myomas giving rise to symptoms. A survey concerning relapse of symptoms and patient satisfaction was made by phone 4 and 6 years after surgery. RESULTS: Seventy-two patients (mean age: 45.6 years [18-70]) underwent hysteroscopy. At the time of the first survey, the rate of recurrence was 22% (n=15) with 87.5% of cases of recurrence in the first year. Nineteen percent of the patients needed subsequent treatment. The significant factors for the risk of failure of treatment included younger age, number and large size myoma, intramural extension and incomplete resection. In 2010, the overall failure rate was 31.7% (n=20). Fifty percent of the patients who had an incomplete resection required no further treatment. CONCLUSION: In 70% of cases, hysteroscopic resection remains efficient at long-term. Repeat surgery should not be systematic after incomplete resection. The patients must be fully informed, and especially with respect to the risk factors for recurrence. PMID- 21316162 TI - Synthetic cannabinoid JWH-018 and psychosis: an explorative study. AB - BACKGROUND: Aroma, Spice, K2 and Dream are examples of a class of new and increasingly popular recreational drugs. Ostensibly branded "herbal incense", they have been intentionally adulterated with synthetic cannabinoids such as JWH 018 in order to confer on them cannabimimetic psychoactive properties while circumventing drug legislation. JWH-018 is a potent cannabinoid receptor agonist. Little is known about its pharmacology and toxicology in humans. This is the first research considering the effects of JWH-018 on a psychiatric population and exploring the relationship between JWH-018 and psychotic symptoms. METHOD: This paper presents the results of semi-structured interviews regarding the use and effects of JWH-018 in 15 patients with serious mental illness in a New Zealand forensic and rehabilitative service. RESULTS: All 15 subjects were familiar with a locally available JWH-018 containing product called "Aroma" and 86% reported having used it. They credited the product's potent psychoactivity, legality, ready availability and non-detection in drug testing as reasons for its popularity, with most reporting it had replaced cannabis as their drug of choice. Most patients had assumed the product was "natural" and "safe". Anxiety and psychotic symptoms were common after use, with 69% of users experiencing or exhibiting symptoms consistent with psychotic relapse after smoking JWH-018. Although psychological side effects were common, no one reported becoming physically unwell after using JWH-018. Three subjects described developing some tolerance to the product, but no one reported withdrawal symptoms. CONCLUSION: It seems likely that JWH-018 can precipitate psychosis in vulnerable individuals. People with risk factors for psychosis should be counseled against using synthetic cannabinoids. PMID- 21316161 TI - [Quantitative assessment of medical students' clinical practical learning in department of obstetrics and gynecology of Brest Hospital University]. AB - OBJECTIVE: The main objective of this study was to describe how medical students got progressively trained to perform the most frequent medical procedures in obstetrics and gynecology. The secondary objective was to rationalize and plan the training. METHODS: The medical students in our University Hospital were contacted either directly or by e-mail. They were given an anonymous simple choice questionnaire relating to eight most important acts in the specialty. RESULTS: Three hundred and eighty-two medical students have been consulted. We got 173 answers which means a participation rate of 45.3%. The survey showed up that the considered procedures were progressively put into practice with the exception of two: the insertion of an intrauterine contraceptive device (coil) and of an implant. CONCLUSION: The study showed off some insufficiency in the training in two of the considered procedures. An amendment was proposed with simulated performances of the acts and the setting up of a training course booklet. PMID- 21316163 TI - Prevalence of alcohol and other substances of abuse among injured patients in a Norwegian emergency department. AB - BACKGROUND: Studies have found a high prevalence of both alcohol and other impairing psychoactive drugs in injured patient populations. The aim of this study was to assess the prevalence of potentially impairing psychoactive substances in all patients admitted to a hospital emergency department with injuries from accidents, assault or deliberate self harm. METHODS: A total of 1272 patients over 18 years of age, admitted to the hospital within 12h of injury, were included. Presence of alcohol was determined by an enzymatic method and other drugs by liquid chromatography-mass spectrometry (LC-MS) or gas chromatography-mass spectrometry (GC-MS), both highly specific analytical methods for determining recent intake. RESULTS: There were 510 (40%) women in the sample. Of the patients, 38% of the women and 48% of the men had a positive blood sample for psychoactive substances on admission. The most prevalent psychoactive substance was alcohol (27%) with an average concentration of 1.5 g/kg. A further 21% of patients tested showed use of medicinal drugs, and 9% showed use of illicit substances. Cannabis was the most prevalent illicit drug (6.2%). Diazepam (7.4%) and zopiclone (5.3%) were the most prevalent medicinal drugs. In road traffic accidents, 25% of the car drivers had positive findings, about half of them for alcohol. CONCLUSION: Psychoactive substances were found in nearly half the patients admitted with injuries. The most common substance was alcohol. Alcohol was particularly related to violence, whereas medicinal drugs were most prevalent in accidents at home. PMID- 21316164 TI - The phylogenetic analysis of avipoxvirus in New Zealand. AB - Avipoxvirus is known to be endemic in New Zealand and it is a cause of ongoing mortalities in the endangered black robin and shore plover populations. There is no information on the strains of avipoxvirus occurring in New Zealand and their likely origin or pathogenicity. This study was designed to identify the phylogenetic relationships of pathogenic avipoxvirus strains infecting introduced, native, and endemic bird species in New Zealand. Avipoxvirus 4b core protein gene was detected in tissue samples from 25/48 birds (52.1%) from 15 different species in New Zealand. Bootstrap analysis of avipoxvirus 4b core protein gene revealed that the New Zealand avipoxvirus isolates comprised of three different subclades. The majority of New Zealand avipoxvirus isolates (74%) belonged to A1 subclade which shared 100% genetic similarity with the fowlpox HPB strain. An isolate from a wood-pigeon (kereru) belonged to subclade A3, displaying 100% sequence homology to albatrosspox virus. An additional group, isolated from two shore plovers and one South Island saddleback, grouped within subclade B1 and presented 99% sequence homology to European PM33/2007 and Hawaiian HAAM 22.10H8 isolates. The results suggest that a variety of New Zealand bird species are susceptible to avipoxvirus infection, that there are more than two distinctive avipoxvirus subclades in New Zealand, and that the most prevalent A1 strain may have been introduced to New Zealand through introduced avian hosts such as passerines or poultry. PMID- 21316165 TI - Normalized spectral power of fetal heart rate variability is associated with fetal scalp blood pH. AB - BACKGROUND: Spectral power of fetal heart rate variability is related to fetal condition. Previous studies found an increased normalized low frequency power in case of severe fetal acidosis. AIMS: To analyze whether absolute or normalized low or high frequency power of fetal heart rate variability is associated with fetal scalp blood pH. STUDY DESIGN: Prospective cohort study, performed in an obstetric unit of a tertiary care teaching hospital. SUBJECTS: Consecutive singleton term fetuses in cephalic presentation that underwent one or more scalp blood samples, monitored during labour using ST-analysis of the fetal electrocardiogram. Ten-minute continuous beat-to-beat fetal heart rate segments, preceding the scalp blood measurement were used. OUTCOME MEASURES: Absolute and normalized spectral power in the low frequency band (0.04-0.15 Hz) and in the high frequency band (0.4-1.5 Hz). RESULTS: In total 39 fetal blood samples from 30 patients were studied. We found that normalized low frequency and normalized high frequency power of fetal heart rate variability is associated with fetal scalp blood pH. The estimated beta of normalized low frequency power was -0.37 (95% confidence interval -0.68 to -0.06) and the relative risk was 0.69 (95% confidence interval 0.51-0.94). The estimated beta of normalized high frequency power was 0.33 (95% confidence interval 0.01-0.65) and the relative risk was 1.39 (95% confidence interval 1.01-1.92). CONCLUSIONS: Normalized low and normalized high frequency power of fetal heart rate variability is associated with fetal scalp blood pH. PMID- 21316166 TI - Spectroscopic characterization of 3,4-methylenedioxypyrrolidinobutyrophenone: a new designer drug with alpha-pyrrolidinophenone structure. AB - This study presents and discusses the infrared spectroscopic, the nuclear magnetic resonance spectroscopic and mass spectrometric data of the designer drug 3,4 methylenedioxypyrrolidinobutyrophenone (MDPBP), a homolog of 3,4 methylenedioxypyrovalerone (MDPV). MDPBP was first seized in Germany in the year 2009. The structure elucidation of the aliphatic part of MDPBP was carried out by product ion spectrometry of the immonium ion with m/z=112 formed after electron ionization, and by one- and two-dimensional (1)H- and (13)C NMR spectroscopy. PMID- 21316167 TI - Single-stage laryngotracheoplasty in children. AB - OBJECTIVE: To review the outcomes of pediatric patients with laryngotracheal stenosis treated by single-stage laryngotracheoplasty. METHODS: A single surgeon personal series retrospective review of 15 children undergoing single-stage laryngotracheoplasty for laryngeal stenosis over 4-year period (2004-2008). RESULTS: 15 patients (9 boys and 6 girls), with ages ranging from 1 month to 18 years, were operated. Using the Myer-Cotton grading system, 2 patients were diagnosed with grade 4 stenosis, 6 patients with grade 3 and 7 patients with grade 2. In10 cases, an LTP with anterior costal cartilage graft was performed; in one case an anterior and posterior LTP; in one case a partial cricotracheal resection and in 3 cases an anterior cricoids split. The overall success rate was 94%. CONCLUSION: Single stage laryngotracheoplasty is a safe and effective method for laryngotracheal stenosis in children. PMID- 21316168 TI - Isolated otosclerosis of the incus in a Korean woman. AB - We report an isolated otosclerosis of the incus that was removed using a transcanal approach and the ossicular chain was reconstructed using a total ossicular replacement prosthesis due to a tilted stapes. PMID- 21316169 TI - Clinical utility of quantitative magnetic resonance angiography in the assessment of the underlying pathophysiology in a variety of cerebrovascular disorders. AB - BACKGROUND: Quantitative MRA (qMRA) is a relatively new technique that uses traditional time-of-flight and phase-contrast MRI to visualize extracranial and intracranial vascular anatomy and measure volumetric blood flow. We aimed to assess the clinical utility of qMRA in assessing the hypothesized pathophysiology (HP) in a range of cerebrovascular diseases. Moreover, we postulated that evaluation of the arterial waveforms, can improve the evaluation of the hypothesized pathophysiology by qMRA. METHODS: We reviewed studies from 10 patients who underwent qMRA examinations before and after their treatments. Two reviewers assessed the anatomy, volumetric flow rates and arterial waveforms for each vessel sampled and reached a consensus as to whether the above parameters supported the clinical diagnosis/hypothesized pathophysiology and the subsequent management. FINDINGS: All 20 qMRA studies were technically adequate. qMRA supported the HP in all 10 patients as determined by abnormal volumetric flow values in the affected vessels before treatment and by the correction of these abnormal values in the patients whose treatment was successful. Each of our five patients with occlusive disease/vasoconstriction demonstrated evidence of dampening of the arterial waveforms distally to the narrowed artery (parvus tardus phenomenon). The parvus-tardus effect disappeared after treatment. CONCLUSION: qMRA is unique in combining time-of-flight MRA in a complementary manner with phase-contrast MRA to obtain volumetric flow values and potentially important physiologic information from arterial waveform analysis in patients with a range of cerebrovascular diseases during the course of a single MR examination. PMID- 21316170 TI - Comparison of grey matter atrophy between patients with neuromyelitis optica and multiple sclerosis: a voxel-based morphometry study. AB - PURPOSE: Previous studies have established regional grey matter (GM) loss in multiple sclerosis (MS). However, whether there is any regional GM atrophy in neuromyelitis optica (NMO) and the difference between NMO and MS is unclear. The present study addresses this issue by voxel-based morphometry (VBM). METHODS: Conventional magnetic resonance imaging (MRI) and T1-weighted three-dimensional MRI were obtained from 26 NMO patients, 26 relapsing-remitting MS (RRMS) patients, and 26 normal controls. An analysis of covariance model assessed with cluster size inference was used to compare GM volume among three groups. The correlations of GM volume changes with disease duration, expanded disability status scale (EDSS) and brain T2 lesion volume (LV) were analyzed. RESULTS: GM atrophy was found in NMO patients in several regions of frontal, temporal, parietal lobes and insula (uncorrected, p < 0.001). While extensive GM atrophy was found in RRMS patients, including most cortical regions and the deep grey matter (corrected for multiple comparisons, p < 0.01). Compared with NMO, those with RRMS had significant GM loss in bilateral thalami, caudate, left parahippocampal gyrus, right hippocampus and insula (corrected, p < 0.01). In RRMS group, regional GM loss in right caudate and bilateral thalami were strongly correlated with brain T2LV. CONCLUSIONS: Our study found the difference of GM atrophy between NMO and RRMS patients mainly in deep grey matter. The correlational results suggested axonal degeneration from lesions on T2WI may be a key pathogenesis of atrophy in deep grey matter in RRMS. PMID- 21316171 TI - Role of magnetic resonance imaging in evaluation of the activity of perianal Crohn's disease. AB - AIM: To evaluate the diagnostic ability of contrast-enhanced Magnetic Resonance Imaging (MRI) in assessment of the activity of perianal fistulas in Crohn's disease (CD) patients, compared to clinical data. MATERIALS AND METHODS: Fifty CD patients (25 men; mean[SD] age: 40.4[12.6] years) with known or suspected perianal fistulas underwent perianal space MRI. Radiological activity of disease was measured as the percentage increase (PI) of ROI values of fistulas in relation to ROI values of healthy local fat, after contrast administration. Clinical activity of disease was defined according to Perianal Disease Activity Index (PDAI) and Fistula Drainage Assessment (FDA). RESULTS: Forty-two patients presented perianal disease at MRI (55 fistulas identified). An association between both fistula's PI and PDAI (Pearson's coefficient 0.512, p<0.0001) and between PI and FDA (p=0.003) was demonstrated. Areas under ROC curves of PI values in relation to PDAI and FDA were respectively 0.876 [95%CI=(0.743-1.00), p<0.001] and 0.784 [95%CI=(0.588-0.980), p=0.003]. A cut-off value of PI, calculated on these preliminary data, correctly classified more than 90% of fistulas. CONCLUSIONS: Contrast-enhanced MRI with PI calculation offered practical information about activity of perianal fistulas and might be helpful in providing a comprehensive evaluation of CD perianal disease. PMID- 21316172 TI - Demonstration of the dorsal pancreatic artery by CTA to facilitate superselective arterial infusion of stem cells into the pancreas. AB - PURPOSE: To investigate the diagnostic performance of 64-section CTA in the detection of dorsal pancreatic artery before interventional therapy for patients with diabetes. MATERIALS AND METHODS: The study was approved by the institutional ethics committee; written informed consent was obtained. Forty-two consecutive patients with diabetes received an experimental treatment of autologous bone marrow-derived stem cell transplantation by means of infusion into the dorsal pancreatic artery. All cases underwent abdominal CTA before angiography of pancreatic arteries in order to locate the origin and course of dorsal pancreatic artery. Angiography of coeliac artery, splenic artery, common hepatic artery and superior mesenteric artery were performed both in CTA and DSA. Superselective catheterization of dorsal pancreatic artery was carried out for the infusion of stem cell. Sensitivity, specificity and accuracy for the detection of dorsal pancreatic artery with CTA were calculated using DSA images as the reference standard. RESULTS: Thirty-five and thirty-six dorsal pancreatic arteries were detected by CTA and DSA respectively. Dorsal pancreatic artery was not visualized in either CTA or DSA in 5 patients. The sensitivity, specificity and accuracy for CTA were 94.4%, 83.3% and 92.9%. CONCLUSION: 64-section CTA is accurate for the detection of dorsal pancreatic artery. It may be useful for the facilitation of superselective arterial infusion of stem cells to pancreas. PMID- 21316173 TI - Applying value stream mapping techniques to eliminate non-value-added waste for the procurement of endovascular stents. AB - OJECTIVES: To eliminate non-value-adding (NVA) waste for the procurement of endovascular stents in interventional radiology services by applying value stream mapping (VSM). MATERIALS AND METHODS: The Lean manufacturing technique was used to analyze the process of material and information flow currently required to direct endovascular stents from external suppliers to patients. Based on a decision point analysis for the procurement of stents in the hospital, a present state VSM was drawn. After assessment of the current status VSM and progressive elimination of unnecessary NVA waste, a future state VSM was drawn. RESULTS: The current state VSM demonstrated that out of 13 processes for the procurement of stents only 2 processes were value-adding. Out of the NVA processes 5 processes were unnecessary NVA activities, which could be eliminated. The decision point analysis demonstrated that the procurement of stents was mainly a forecast driven push system. The future state VSM applies a pull inventory control system to trigger the movement of a unit after withdrawal by using a consignment stock. CONCLUSION: VSM is a visualization tool for the supply chain and value stream, based on the Toyota Production System and greatly assists in successfully implementing a Lean system. PMID- 21316174 TI - A direct ELISA assay for quantitative determination of the inhibitory potency of small molecules inhibitors for JNK3. AB - The c-jun N-terminal kinase 3 (JNK3) is a promising drug target for the treatment of neurological disorders. Here we report a direct ELISA including the optimization of a nonradioactive immunosorbent JNK3 activity assay to determine inhibitory potency of small-molecule inhibitors. Based on our previous JNK3 assay and our recently optimized p38alpha mitogen activated protein kinase (MAPK) protocol for monitoring the phosphorylation of activating-transcription factor 2 (ATF-2), we present a rapid and straightforward alternative to conventional radioactive and indirect ELISA kinase assays. To validate the assay with the optimized assay conditions we used reference compounds and achieved well comparable IC(50) results to published data. The use of a linked monoclonal antibody increased the specificity and the sensitivity of the assay, reducing the required antibody concentration by approximately 100-fold. The novel protocol is an accurate, easy-to-handle and robust screening assay for JNK3 and the assay performance was reduced from 7.5 to 3h. PMID- 21316175 TI - Gradient RP-HPLC method for the determination of potential impurities in atazanavir sulfate. AB - This paper proposes a simple and selective RP-HPLC method for the determination of process impurities and degradation products (degradants) of atazanavir sulfate (ATV) drug substance. Chromatographic separation was achieved on Ascentis((r)) Express C8, (150mm*4.6mm, 2.7MUm) column thermostated at 30 degrees C under gradient elution by a binary mixture of potassium dihydrogen phosphate (pH 3.5, 0.02M) and ACN at a flow rate of 1.0ml/min. A photodiode array (PDA) detector set at 250nm was used for detection. Stress testing (forced degradation) of ATV was carried out under acidic, alkaline, oxidative, photolytic, thermal and humidity conditions. In presence of alkali, ATV transformed into cyclized products and the order of degradation reaction is determined by the method of initial rates. The unknown process impurities and alkaline degradants are isolated by preparative LC and characterized by ESI-MS/MS, (1)H NMR, and FT-IR spectral data. The developed method is validated with respect to sensitivity (lod and loq), linearity, precision, accuracy and robustness and can be implemented for routine quality control analysis and stability testing of ATV. PMID- 21316176 TI - Mass spectrometric characterization of gentamicin components separated by the new European Pharmacopoeia method. AB - Liquid chromatography combined with pulsed electrochemical detection (LC-PED) is the method of choice in the European Pharmacopoeia for the determination of gentamicin and its related substances. A recently approved improved LC-PED method, with a reversed-phase C(18) column and a mobile phase consisting of trifluoroacetic acid (TFA), pentafluoropropionic acid (PFPA), sodium hydroxide and acetonitrile, showed better separation and more sensitive detection of the gentamicin components than the previous method using a polymer column. More unknown peaks can be separated from the main components and from each other. As the LC-PED method cannot be directly coupled to a mass spectrometer (MS), the unknown substances were collected after the LC column, desalted and analyzed by MS. The structures of the unknown compounds were deduced based on comparison of their fragmentation patterns with those of reference substances investigated by MS(n) experiments using an electrospray ion trap mass spectrometer. A comparison was also made with an already previously published LC-MS method using a volatile mobile phase. PMID- 21316177 TI - Rapid and simultaneous measurement of midazolam, 1'-hydroxymidazolam and digoxin by liquid chromatography/tandem mass spectrometry: application to an in vivo study to simultaneously measure P-glycoprotein and cytochrome P450 3A activity. AB - In order to simultaneously determine in vivo P-glycoprotein (P-gp) and Cytochrome P450 3A (CYP3A) activity, a new, rapid and sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) method has been developed and fully validated to simultaneously determine midazolam (MDZ, as CYP3A substrate), 1'-hydroxymidazolam (1'-OHMDZ) and digoxin (DG, as P-gp substrate) in rat plasma using digitoxin as the internal standard (IS). After a single step liquid-liquid extraction with tert-butyl methyl ether/dichloromethane (75:25, v/v), analytes were subjected to LC-MS/MS analysis using positive electro-spray ionization (ESI(+)) under selected reaction monitoring mode (SRM). Chromatographic separation was performed on an XTerra MS C18 column (50mm*2.1mm, i.d. 3.5MUm). The MS/MS detection was conducted by monitoring the fragmentation of 326.05 -> 244.00 (m/z) for MDZ, 342.02 >168.01 (m/z) for 1'-OHMDZ, 798.33 -> 651.36(m/z) for DG and 782.67 -> 635.24 (m/z) for IS. The method had a chromatographic running time of 3min and linear calibration curves over the concentrations of 2-400ng/mL for MDZ and 1'-OHMDZ and 0.5-100ng/mL for DG. The recoveries of the method were 86.8-96.3% for MDZ, 84.6 86.4% for 1'-OH MDZ, and 81.7-85.1% for DG. The lower limit of quantification (LLOQ) of the method was 2ng/mL for MDZ and 1'-OHMDZ and 0.5ng/mL for DG. The intra- and inter-batch precision were less than 15% for all quality control samples at concentrations of 5, 50 and 320ng/mL for MDZ and 1'-OHMDZ and 1, 10 and 80ng/mL for DG. The validated LC-MS/MS method has been successfully used to analyze the concentrations of MDZ, 1'-OH MDZ and DG in rat plasma for simultaneous measurement of in vivo P-gp and CYP 3A activity. PMID- 21316178 TI - Development and validation of a capillary electrophoresis method for the enantiomeric purity determination of RS86017 using experimental design. AB - A selective capillary electrophoresis method for determination of enantiomeric purity of RS86017, a new antiarrhythmic agent with two chiral centers, was developed and validated using sulfobutyl ether-beta-cyclodextrin as chiral selector. The concentration of the chiral selector and organic modifier, pH of background electrolyte (BGE), capillary temperature, and applied voltage were systematically optimized by using orthogonal design and concentration of chiral selector was further optimized. The optimal conditions included 25mM phosphate buffer at pH 8.0, containing 28mg/mL sulfobutyl ether-beta-cyclodextrin and 20% acetonitrile as running buffer, an applied voltage of 22kV, and a temperature of 20 degrees C. The detection wavelength was 206nm. The obtained method was capable of separating RS86017 from its potential chiral impurities, the S,R-enantiomer, the R,R-diastereomer and the S,S-diastereomer with a short analysis time of 10min. The separation was validated with respect to its selectivity, repeatability, linearity, precision, accuracy, limits of detection (LOD), limits of quantitation (LOQ) and robustness testing. The LODs and LOQs were 0.8MUg/mL and 2.5MUg/mL for all isomers of RS86017, respectively. Finally, the method was used to investigate the chiral purity of RS86017 in bulk samples. PMID- 21316179 TI - Prevalence of hypokalemia in ED patients with diabetic ketoacidosis. AB - OBJECTIVE: Although patients with diabetic ketoacidosis (DKA) are expected to have total body potassium depletion, measured levels may be normal or elevated due to extracellular shifts of potassium secondary to acidosis. Because insulin therapy decreases serum potassium levels, which creates potential to precipitate a fatal cardiac arrhythmia in a patient with hypokalemia, the American Diabetes Association (ADA) recommends obtaining a serum potassium level before giving insulin. Although the ADA guidelines are clear, the evidence on which they are based is largely anecdotal. The purpose of this study was to estimate the prevalence of hypokalemia in patients with DKA before initiation of fluid resuscitation and insulin therapy. METHODS: This is a prospective cross-sectional descriptive study of patients with a capillary blood glucose level of 250 mg/dL or higher (at risk for DKA) seen in an urban county emergency department over a 1 year period. Those who consented provided basic demographic information and had a venous blood gas and chemistry panel drawn. Diabetic ketoacidosis and hypokalemia were defined using ADA recommendations. RESULTS: The mean age in our sample was 40.2 years, and 81% of patients were Hispanic. Of 503 analyzable patients with hyperglycemia, 54 (10.7%) met all criteria for DKA. Of patients with DKA, 3 (5.6%) of 54 (95% confidence interval, 1.2%-15.4%) had hypokalemia. Two of these patients had values of 3.0 mmol/L, and 1 had a value of 2.8 mmol/L. CONCLUSION: Hypokalemia was observed in 5.6% of patients with DKA. These findings support the ADA recommendation to obtain a serum potassium before initiating intravenous insulin therapy in a patient with DKA. PMID- 21316180 TI - Are adults with developmental disabilities more likely to visit EDs? PMID- 21316181 TI - Longer-term influence of breast cancer genetic counseling on cognitions and distress: smaller benefits for affected versus unaffected women. AB - OBJECTIVE: To evaluate outcomes of breast cancer genetic counseling in women with and without breast cancer. METHODS: Seventy-seven first-time attendees (n=44 affected) completed questionnaires assessing cognitions (risk accuracy, knowledge, perceived personal control [PPC]) and distress (state anxiety [STAI], cancer-related stress reactions [IES]) from immediately before to immediately and six months after completing counseling. Data were analyzed using multilevel repeated measures and trend analyses. RESULTS: In affected counselees, mean cognitions did not significantly differ over time, anxiety significantly decreased, and IES levels were increased immediately post-counseling. In unaffected counselees, cognitions significantly improved over time except for knowledge. Distress levels showed similar patterns as in affected women. Improvements in cognitions and distress were significantly smaller in affected versus unaffected women. CONCLUSION: Overall, counseling educates women about breast cancer risk and alleviates their anxiety. Importantly, benefits gained at immediate follow-up seem maintained over time. PRACTICE IMPLICATION: Affected women seem to benefit less from counseling. Counselors may need to devote more effort into educating these women and addressing their anxieties. Future studies should confirm the unexpected finding that cancer-related distress increased immediately post-counseling. PMID- 21316182 TI - The advantages and challenges of unannounced standardized patient methodology to assess healthcare communication. AB - OBJECTIVE: This paper provides an overview of the implementation of using unannounced standardized patients (USPs) to conduct health communication research in clinical settings. METHODS: Certain types of health communication situations are difficult to capture because of their rarity or unpredictable nature. In primary care the real reasons for a visit are frequently unknown until the consultation is well under way. Therefore, it is logistically difficult for communication studies to capture many real-time communications between patients and their physicians. Although the USP methodology is ideal for capturing these communication behaviors, challenges to using this method include developing collaborative relationships with clinical practices, logistical issues such as safeguarding the identity of the USP, training USPs and creating their identities, maintaining fidelity to the role, and analyzing the resultant data. RESULTS: This paper discusses the challenges and solutions to USP implementation. We provide an example of how to implement a USP study using an on-going study being conducted in primary care practices. CONCLUSION: This paper explores the advantages and challenges as well as strategies to overcome obstacles to implementing a USP study. PRACTICE IMPLICATIONS: Despite the challenges, USP methodology can contribute much to our understanding of health communication and practice. PMID- 21316183 TI - A criterion-based stepwise approach for training counselors in motivational interviewing. AB - This pilot study evaluated a criterion-based stepwise approach for training counselors in motivational interviewing (MI). Three sequential steps of training in MI were provided to 26 counselors who worked within the U.S. State of Connecticut Veterans Administration addiction treatment programs: a distance learning Web course (Step 1), a skill-building workshop (Step 2), and a competency-based individual supervision (Step 3). Counselors first participated in the course and then only received the next step of training if they failed to meet an independently rated criterion level of adequate MI performance. The results showed that counselors who showed inadequate MI performance immediately after taking the Web course and who subsequently participated in a workshop or supervision improved their adherence to fundamental MI strategies over time, whereas those who performed MI adequately following the Web course continued to demonstrate similar levels of fundamental and advanced MI adherence and competence over a 24-week period without additional training. The pilot study's findings, although preliminary, suggest that different counselors likely require different types and amounts of training to perform a behavioral treatment well. PMID- 21316184 TI - Successful management of renal artery aneurysm rupture after cesarean section. AB - Renal artery aneurysm is a rare entity, and patients are usually asymptomatic at the time of presentation. These aneurysms are rare among pregnant patients, especially after childbirth, and usually form due to changes in vascular wall integrity secondary to hormonal and hemodynamic changes. Here we describe a patient with an intraparenchymal renal artery aneurysm that ruptured after a cesarean section but was immediately identified and managed appropriately, allowing for a successful outcome. PMID- 21316185 TI - Meta-analysis of predictive factors for non-sentinel lymph node metastases in breast cancer patients with a positive SLN. AB - AIMS: A meta-analysis was performed to identify the clinicopathological variables most predictive of non-sentinel node (NSN) metastases when the sentinel node is positive. METHODS: A Medline search was conducted that ultimately identified 56 candidate studies. Original data were abstracted from each study and used to calculate odds ratios. The random-effects model was used to combine odds ratios to determine the strength of the associations. FINDINGS: The 8 individual characteristics found to be significantly associated with the highest likelihood (odds ratio >2) of NSN metastases are SLN metastases >2mm in size, extracapsular extension in the SLN, >1 positive SLN, <=1 negative SLN, tumour size >2cm, ratio of positive sentinel nodes >50% and lymphovascular invasion in the primary tumour. The histological method of detection, which is associated with the size of metastases, had a correspondingly high odds ratio. CONCLUSIONS: We identified 8 factors predictive of NSN metastases that should be recorded and evaluated routinely in SLN databases. These factors should be included in a predictive model that is generally applicable among different populations. PMID- 21316186 TI - Letter to the editor relating to the editorial EJSO 36 (2010) 1162-1164. PMID- 21316188 TI - [Vigilance in May, prudence in November]. PMID- 21316187 TI - Characteristics of and therapeutic options for contralateral axillary lymph node metastasis in breast cancer. AB - AIM: Contralateral axillary metastasis (CAM) from breast cancer is uncommon. This papers aims to identify the features of our patients with CAM, as well as clarify management options. METHODS: We reviewed all of our breast cancer patients during the period from 2004 to 2009. All patients with a proven pathological diagnosis of CAM were included. Patients were evaluated for demographics, tumor features and management modalities. RESULTS: A total of 21 patients were included, forming 1.9% of our breast cancer population. The median age was 51 years (range 29-71). Twelve patients had large central or diffuse tumors. Most of the tumors were of invasive ductal type (95%), of high grade (81%) and with lymphovascular invasion (81%). The majority of cases were locally advanced (stage III: 90%). Hormonal receptor positivity and HER-2 overexpression were seen in 48% and 42% of cases, respectively. Those pathological features were significantly worse than those of patients without CAM. Ten patients had synchronous and 11 patients had metachronous CAM. Treatment modalities included axillary dissection, chemotherapy and hormonal therapy. Four patients died from metastatic disease and 5 patients are still alive without evidence of metastasis. CONCLUSION: CAM is associated with tumors with aggressive pathological features. Hormonal therapy is associated with an excellent response in patients whose tumors are hormone-receptor positive. Axillary dissection is indicated in patients with early-stage tumors, when there is no response to systemic therapy, or for palliation. It is associated with excellent local control. PMID- 21316189 TI - Treating the cause of illness rather than the symptoms: parental causal beliefs and treatment choices in autism spectrum disorder. AB - OBJECTIVES: To explore the relationship between causal beliefs on autism (CBA) and treatment choices. DESIGN AND METHODS: A cross-sectional design was employed. Parents of a child with autism spectrum disorder (ASD) were asked to complete the Lay-Beliefs about Autism Questionnaire (LBA-Q) and answer questions about treatments used. Only items inquiring about a cause of autism were retained for analysis. Series of forward stepwise logistic regressions were performed with each treatment as dependent variable and the scores given to each of the CBA items as independent variables. RESULTS: 78 parents were included. The most strongly held causal beliefs were brain abnormalities and genetic factors. Parents who had more beliefs in the causal role of very early traumatic experiences were less likely to use behavior therapy and PECS. Higher beliefs in illness during pregnancy increased the odds of medication use. Stronger beliefs on the role of food allergy were associated with higher use of detoxification treatments, special diets, and vitamins. On the contrary, these beliefs reduced the odds of drug use. CONCLUSIONS: Causal beliefs are associated with treatment choices. Such preliminary results highlight the value of continued studies, not only to establish the causal nature of these associations, but also to demonstrate the utility of modifying such beliefs for both parents' and child's benefits. Identifying parents' beliefs about their child's illness may be an important step in formulating interventions facilitating appropriate care. PMID- 21316190 TI - Scales for the identification of adults with attention deficit hyperactivity disorder (ADHD): a systematic review. AB - Attention deficit hyperactivity disorder (ADHD) is prevalent in the adult population. The associated co-morbidities and impairments can be relieved with treatment. Therefore, several rating scales have been developed to identify adults with ADHD who may benefit from treatment. No systematic review has yet sought to evaluate these scales in more detail. The present systematic review was undertaken to describe the properties, including psychometric statistics, of the currently available adult ADHD rating scales and their scoring methods, along with the procedure for development. Descriptive synthesis of the data is presented and study quality has been assessed by an objective quality assessment tool. The properties of each scale are discussed to make judgements about their validity and usefulness. The literature search retrieved 35 validation studies of adult ADHD rating scales and 14 separate scales were identified. The majority of studies were of poor quality and reported insufficient detail. Of the 14 scales, the Conners' Adult ADHD Rating scale and the Wender Utah Rating Scale (short version) had more robust psychometric statistics and content validity. More research into these scales, with good quality studies, is needed to confirm the findings of this review. Future studies of ADHD rating scales should be reported in more detail so that further reviews have more support for their findings. PMID- 21316191 TI - Modeling eye movements in visual agnosia with a saliency map approach: bottom-up guidance or top-down strategy? AB - Two recent papers (Foulsham, Barton, Kingstone, Dewhurst, & Underwood, 2009; Mannan, Kennard, & Husain, 2009) report that neuropsychological patients with a profound object recognition problem (visual agnosic subjects) show differences from healthy observers in the way their eye movements are controlled when looking at images. The interpretation of these papers is that eye movements can be modeled as the selection of points on a saliency map, and that agnosic subjects show an increased reliance on visual saliency, i.e., brightness and contrast in low-level stimulus features. Here we review this approach and present new data from our own experiments with an agnosic patient that quantifies the relationship between saliency and fixation location. In addition, we consider whether the perceptual difficulties of individual patients might be modeled by selectively weighting the different features involved in a saliency map. Our data indicate that saliency is not always a good predictor of fixation in agnosia: even for our agnosic subject, as for normal observers, the saliency-fixation relationship varied as a function of the task. This means that top-down processes still have a significant effect on the earliest stages of scanning in the setting of visual agnosia, indicating severe limitations for the saliency map model. Top-down, active strategies-which are the hallmark of our human visual system-play a vital role in eye movement control, whether we know what we are looking at or not. PMID- 21316192 TI - Getting to grips with GRADE-perspective from a low-income setting. PMID- 21316193 TI - Associations of positive T wave in lead aVR with hemodynamic, coronary, and left ventricular angiographic findings in anterior wall old myocardial infarction. AB - BACKGROUND: No information is available on the clinical significance of a positive T wave in lead aVR in myocardial infarction (MI). Accordingly, in the present study, we sought to clarify the associations of the positive T wave in lead aVR with hemodynamic, coronary angiographic, and left ventriculographic findings in anterior wall old MI. METHODS: We examined 122 patients with anterior wall old MI who underwent diagnostic or follow-up cardiac catheterization including coronary angiography and left ventriculography. The patients were classified into the following 2 groups: patients with a positive (>= 1mm) T wave in lead aVR (n=20, group A) and those without (n=102, group B). RESULTS: Group A had higher pulmonary arterial, pulmonary capillary wedge, and left ventricular (LV) end-diastolic pressures and a lower cardiac index than group B. The prevalence of a long left anterior descending coronary artery (LAD) was higher in group A than in group B (60% vs 30.4%, p=0.01), and none of group A patients had an LAD that did not reach the apex. Group A had a lower LV ejection fraction than group B (36.4 +/- 11.6% vs 48.4 +/- 12.7%, p<0.001). CONCLUSIONS: The positive T wave in lead aVR is related to severely reduced cardiac function, with an LAD wrapping the apex, in anterior wall old MI. Further studies are needed to clarify whether the positive T wave in lead aVR is associated with an adverse outcome in patients with anterior wall old MI. PMID- 21316194 TI - Do risk factors for schizophrenia predispose to emigration? AB - OBJECTIVE: Increased incidence rates of schizophrenia in immigrants still lack a satisfactory explanation. The aim of this study was to examine the hypothesis that risk factors for schizophrenia also increase the risk of emigration to a foreign country. If valid, Danes emigrating from Denmark carry a higher predisposition to develop schizophrenia compared to Danes living in Denmark. METHODS: Utilizing data from the Danish Civil Registration System, we established a population-based cohort of 1.10 million native Danes. We assessed relative risks of emigration to a foreign country in relation to sex, age, urban birth, parental age, and a history of mental illness. RESULTS: Urban birth in Denmark was a significant predictor of emigration to a foreign country. A maternal history of psychiatric contact during childhood and a parental history of bipolar affective disorder increased the risks of emigration. A personal history of mental illness decreased the risk of emigration, mostly for people diagnosed with schizophrenia. CONCLUSIONS: Our study provided evidence that Danish emigrants residing in a foreign country have both a higher predisposition of schizophrenia due to differential exposure to birth in urban areas and a lower predisposition of schizophrenia due to differential exposure to a history of mental illness. Although competing selection mechanisms operate, the combined effect of these different selection mechanisms was limited, thus suggesting a potential role for yet to be identified adverse environmental effects operating either before or after emigration. PMID- 21316195 TI - General coping strategies and their impact on quality of life in older adults with schizophrenia. AB - BACKGROUND: Both symptom specific and general coping strategies may affect the well-being of persons with schizophrenia. There are little data on how older adults with schizophrenia employ various coping styles. This study examines the types of general coping strategies used by older persons with schizophrenia and examines the extent to which the various coping strategies affect quality of life. METHODS: The schizophrenia group consisted of 198 persons aged 55 and over living in the community who developed schizophrenia before age 45. A community comparison group (n=113) was recruited using randomly selected block-groups. Cognitive, instrumental, and avoidant coping scales were created based on a principal component analysis with equamax rotation of items from a self-report coping inventory. A modified version of Yanos and Moos' integrative model was used to assess the direct and mediating effects of each of the coping strategies scales on the Quality of Life Index. RESULTS: Older adults with schizophrenia and their age peers in the general community most commonly use cognitive coping strategies, and there was no significant difference in their scores on this scale. For persons with schizophrenia, the active coping strategies--cognitive and instrumental--were used more frequently than the avoidant strategies. Both active and avoidant strategies mediated the impact of psychiatric symptoms on quality of life as well as contributing independently to improving life quality; however, they had no impact on the other stressor variables. CONCLUSION: This study suggests that general coping strategies, especially more active approaches, may be useful in diminishing the adverse impact of psychiatric symptoms on quality of life as well as having direct effects on life quality. Such strategies can complement symptom specific approaches. PMID- 21316197 TI - Synergistic effect of lipopeptide biosurfactant with antibiotics against Escherichia coli CFT073 biofilm. AB - Biofilms are microcolonies of microbes adherent to biotic and abiotic surfaces, often responsible for chronic infections and medical device contamination. Escherichia coli is one of the prevalent pathogens involved in uropathogenic infections and contamination of catheters. A biosurfactant produced by Bacillus licheniformis V9T14 was tested alone and in association with various antibiotics against a mature 24-h uropathogenic E. coli CFT073 biofilm. Biofilm was grown on polystyrene pegs of a Calgary Biofilm Device, providing a tool to evaluate the efficacy of antimicrobial agents. Antibiotics tested were ampicillin, cefazolin, ceftriaxone, ciprofloxacin, piperacillin, tobramycin and trimethoprim/sulfamethoxazole (19:1). Biosurfactant alone at the concentrations tested was not able to remove the adherent cells of the pre-formed biofilm. However, the difference between the effect of antibiotic alone and in combination with the biosurfactant was significant and exceeded 1log(10) (90%) reduction in most cases. Results of this study indicate that V9T14 biosurfactant in association with antibiotics leads to a synergistic increase in the efficacy of antibiotics in biofilm killing, and in some combinations leads to total eradication of E. coli CFT073 biofilm. PMID- 21316198 TI - Molecular epidemiology and resistance mechanisms involved in reduced susceptibility to amoxicillin/clavulanic acid in Klebsiella pneumoniae isolates from a chronic care centre. AB - The aim of this work was to investigate the molecular epidemiology and mechanisms responsible for reduced susceptibility to amoxicillin/clavulanic acid (AMC) amongst cefazolin-susceptible Klebsiella pneumoniae isolates from patients admitted to a chronic care institution. In total, 51 (29.8%) of 171 K. pneumoniae isolates recovered between 2006 and 2008 were non-susceptible to AMC, of which 45 were susceptible to cefazolin. Nucleotide sequencing analysis revealed that 19 produced IRT-11 and the remaining 26 were OXA-1-producers. All of the OXA-1 producing isolates harboured the aac(6')-Ib-cr-bla(OXA-1) cassette array, which in 23 isolates was located together with catB3 and arr3 within a class 1 integron and associated with qnrS2 (in 3 cases the integron lacked the qacEDelta1 and sul1 or sul3 genes). Genotyping analysis performed by enterobacterial repetitive intergenic consensus polymerase chain reaction (ERIC-PCR) identified three different patterns amongst IRT-11-producing isolates (E1 to E3), with E1 being the most prevalent (63.2%), whilst the OXA-1-producing isolates were assigned to patterns E3 and E3a (isolates carrying typical class 1 integrons), E4 (isolates carrying defective integrons) and E5 (isolates without integrons). Genes encoding IRT-11 and OXA-1 were transferred by conjugation, and aac(6')-Ib-cr and qnrS2 were systematically co-transferred with bla(OXA-1). These results demonstrate that the high prevalence of decreased susceptibility to AMC amongst K. pneumoniae isolates from a chronic care hospital was mainly due to the simultaneous spread of two different clones, one of which comprised isolates producing IRT-11 and the other one comprised isolates that had acquired either the bla(OXA-1) gene located in a class 1 integron and linked to qnrS2 or the bla(IRT-11) gene. PMID- 21316199 TI - Death by request in Switzerland: posttraumatic stress disorder and complicated grief after witnessing assisted suicide. AB - BACKGROUND: Despite continuing political, legal and moral debate on the subject, assisted suicide is permitted in only a few countries worldwide. However, few studies have examined the impact that witnessing assisted suicide has on the mental health of family members or close friends. METHODS: A cross-sectional survey of 85 family members or close friends who were present at an assisted suicide was conducted in December 2007. Full or partial Post-Traumatic Distress Disorder (PTSD; Impact of Event Scale-Revised), depression and anxiety symptoms (Brief Symptom Inventory) and complicated grief (Inventory of Complicated Grief) were assessed at 14 to 24 months post-loss. RESULTS: Of the 85 participants, 13% met the criteria for full PTSD (cut-off>=35), 6.5% met the criteria for subthreshold PTSD (cut-off>=25), and 4.9% met the criteria for complicated grief. The prevalence of depression was 16%; the prevalence of anxiety was 6%. CONCLUSION: A higher prevalence of PTSD and depression was found in the present sample than has been reported for the Swiss population in general. However, the prevalence of complicated grief in the sample was comparable to that reported for the general Swiss population. Therefore, although there seemed to be no complications in the grief process, about 20% of respondents experienced full or subthreshold PTSD related to the loss of a close person through assisted suicide. PMID- 21316200 TI - Electrocardiographic signs of autonomic imbalance in medicated patients with first-episode schizophrenia spectrum disorders--relations to first treatment discontinuation and five-year remission status. AB - PURPOSE: To explore measures in electrocardiograms (ECG) influenced by autonomic balance in early schizophrenia spectrum disorders and to examine their relation to subsequent first antipsychotic pharmacotherapy discontinuation and five-year remission status. SUBJECTS AND METHODS: Twelve-lead ECGs were recorded at baseline in 58 patients with first-episode schizophrenia spectrum disorders and in 47 healthy controls of similar age. Selected ECG variables included heart rate and measures of repolarization. Pharmacotherapy data were extracted from medical records. At a five-year follow-up the patients were interviewed and assessed with the positive and negative syndrome scale. RESULTS: Patients had higher heart rate and a different ST-T pattern than the controls. High T-wave amplitudes in the leads aVF and V5 and ST-elevations in V5 were associated both with higher risk of an earlier discontinuation of first antipsychotic pharmacotherapy and with non remission five years later. DISCUSSION AND CONCLUSION: In this longitudinal cohort study, simple ECG measures influenced by autonomic balance in the early phase of schizophrenia spectrum disorders contained prognostic information. As this is the first report of this association and is based on a relatively small sample, the results should be interpreted with caution. PMID- 21316201 TI - Circadian clock gene Per3 variants influence the postpartum onset of bipolar disorder. AB - Postpartum depression can mark the onset of bipolar disorder. The coding region of Per3 gene contains a variable-number tandem-repeat polymorphism, which has been shown to influence bipolar disorder onset and to affect breast cancer risk. We showed a relationship between Per3 polymorphism and postpartum depressive onset in bipolar disorder. PMID- 21316202 TI - Use of the Hypomania Checklist-32 and the Mood Disorder Questionnaire for detecting bipolarity in 1051 patients with major depressive disorder. AB - PURPOSE: To use the hypomania checklist (HCL-32) and the mood disorder questionnaire (MDQ), for detecting bipolarity in depressed patients. PATIENTS: One thousand and fifty-one patients fulfilling ICD-10 criteria for unipolar major depressive episode, single or recurrent, were studied. Patients were assessed using a structured demographic and clinical data interview, and by the Polish versions of the HCL-32 and MDQ questionnaires. RESULTS: Hypomanic symptoms exceeding cut-off criteria for bipolarity by HCL-32 were found in 37.5% of patients and, by MDQ, in 20% of patients. Patients with HCL-32 (+) or MDQ (+) differed significantly from patients with HCl-32 (-) and MDQ (-) respectively, by being less frequently married, having more family history of depression, bipolar disorder, alcoholism and suicide, earlier onset of illness, and more depressive episodes and psychiatric hospitalizations. The percentage of patients resistant to treatment with antidepressant drugs was significantly higher in HCL-32 (+) vs. HCL-32 (-) and in MDQ (+) vs. MDQ (-): 43.9% vs. 30.0%, and 26.4% vs. 12.4%, respectively. CONCLUSIONS: The results confirm a substantial percentage of bipolarity in major depressive disorder. Such patients have a number of clinical characteristics pointing on a more severe form of the illness and their depression is more resistant to treatment with antidepressants. PMID- 21316203 TI - Longitudinal changes in brain structure following the first episode of psychosis. AB - Both schizophrenia and bipolar disorder have been associated with progressive changes in grey matter (GM) volume. However, the temporal trajectories of these changes are poorly understood. The aim of this study was to assess longitudinal changes in grey matter volume subsequent to the first episode of schizophrenia and of affective psychoses. Adolescent patients with a first episode psychosis (n=26) were scanned twice using magnetic resonance imaging, at first presentation and after a 3-year follow-up period. An age-matched group of healthy volunteers (n=17) was scanned at the same time points. Within-group and between-group changes in regional grey matter volume were examined using voxel-based morphometry. There were significant group by time interactions (p(FDRcorr)<0.05) in the frontal, temporal, parietal, cerebellar cortex, and in the thalamus, mainly reflecting longitudinal reductions in the controls but not in the patients. Subdivision of the patient group revealed that there were similar longitudinal reductions in patients with affective psychoses as in the controls but no volumetric changes in patients with schizophrenia. Psychosis with onset in adolescence or early adulthood may be associated with a delay or a loss of longitudinal reductions in regional grey matter volume that normally occur at this stage of development. These changes may be specific to schizophrenia. PMID- 21316204 TI - Amygdala hyperreactivity in restrictive anorexia nervosa. AB - Functional imaging studies had often investigated heterogeneous samples of anorexia nervosa (AN) patients with varying paradigms and methodologies that had resulted in divergent results. The present study aimed to examine these issues by studying a well-defined sample of restrictive AN patients with a disorder specific paradigm which had been used previously. Subjects showed increased blood oxygen level dependent responses of the cingulate, frontal, insular and parietal cortices. Group comparisons demonstrated increased activity of the right amygdala in the sample of restrictive AN patients. Our results are in support of other recently published functional imaging studies and point to a pivotal role of the right amygdala in AN. Signals of the midcingulum were reduced in comparison to healthy controls. The constellation of increased activity of the amygdala and decreased activity of the cingulate cortex likely represents parts of a negative feedback loop of emotional processing. Disgust ratings correlated with the amygdala signal negatively, which points to the complex role of this structure within eating disorders. PMID- 21316205 TI - DNA copy number alterations in radiation-induced thyroid cancer. AB - For many years, gene alterations of the mitogen activated protein kinase pathway have been investigated in papillary thyroid carcinomas (PTC) and the radiation specific induction of Ret/PTC rearrangements has been discussed in the published literature. According to recent studies, these alterations are now considered as age-related changes rather than radiation-specific changes in PTC. Thus, there is a strong motivation to search for novel alterations that might represent radiation-specific markers in PTC. DNA copy number alterations (CNAs) are frequent in human cancers and are also prevalent in PTC. However, the only way to tease out radiation-specific CNAs is a comparative analysis of CNAs from closely matched tumour cohorts, as various factors such as the age of patients or the histology of tumours also influence the type and frequency of CNA. Therefore, this review focuses on the current knowledge on CNAs in PTC and on future strategies to identify radiation-specific changes in these tumours. PMID- 21316206 TI - Histamine induces the neuronal hypertrophy and increases the mast cell density in gastrointestinal tract. AB - Histamine is an endogenous biogenic amine that is synthesized from the basic amino acid histidine. Ability to mimic anaphylaxis is one of the first described functions of histamine and it has been demonstrated that histamine plays a significant role in the regulation of immune system and neuronal function, influences neuronal morphology and is involved in mast cells (MCs) chemotaxis. MCs as histamine releasers, may thus also interact with neuronal function. In the present study, we aimed to evaluate the role of histamine on mast cell density and neuronal morphology in the gastrointestinal tract of the mouse. Ten mice were daily injected intraperitoneally for 7 days with 20 mg/kg of histamine diluted in 0.5 ml physiological serum. After 7 days, mice were euthanised and samples from stomach, small bowel, colon and appendix were processed for histological examination. Immunohistochemistry was performed employing primary antibodies directed against triptase for mast cells and PGP 9.5 antigen for neuronal structures. The density of triptase and PGP 9.5 positive cells and the morphology of the ganglia were quantitatively evaluated by digital image analysis. The number of ganglia was higher in stomach, small bowel, colon and appendices of the histamine group when compared with the control group. Only in appendices and colon, the number of Schwann cells was significantly higher than that of the control group. The PGP 9.5 expression and the mean area of ganglia showed a significant increase only in appendices. In histamine group the MCs were clustered especially in the lamina propria. Mast cell density (MCD) was significantly higher than the control group in the small bowel, colon and appendices tissues. The intraperitoneally injection histamine increases the MCD and induces the neuronal hypertrophy and after the comparison of the organs in the gastrointestinal tract the results indicated the most effected organ as the appendices. PMID- 21316207 TI - Oral administration of gamma-aminobutyric acid and gamma-oryzanol prevents stress induced hypoadiponectinemia. AB - Metabolic syndrome is a cluster of risk factors including insulin resistance and type 2 diabetes and is found to associate partly with chronic stress at work in human. Adiponectin circulates in mammal blood mainly as a low molecular weight (LMW) trimer, hexamer, and a high molecular weight (HMW) multimers. Low circulating levels of adiponectin are related to metabolic syndrome. We have then investigated the influence of immobilization stress on plasma adiponectin concentrations in mice. Relative LMW and HMW adiponectin levels were markedly reduced by immobilization stress (0.66+/-0.07 and 0.59+/-0.06 after 102 h, respectively), significantly different from the control values (p<0.01 and 0.05, respectively). gamma-Aminobutyric acid (GABA) and gamma-oryzanol abundantly contained in germinated brown rice have some physiological functions. We further investigated the effect of GABA, gamma-oryzanol, GABA plus gamma-oryzanol on adiponectin levels in mice subjected to immobilization stress. GABA and gamma oryzanol significantly increased the relative LMW and HMW adiponectin levels under immobilization stress (1.10+/-0.11 and 0.99+/-0.19 after 102 h, respectively, for GABA; 1.08+/-0.17 and 1.15+/-0.17 after 102 h, respectively, for gamma-oryzanol). Additionally, the co-administration of GABA and gamma oryzanol also increased both relative LMW and HMW adiponectin levels (1.02+/-0.07 and 0.99+/-0.10 after 102 h, respectively) and was effective in an earlier phase from 30 to 54 h. The results indicate that the co-administration of GABA and gamma-oryzanol might be effective in preventing stress-induced hypoadiponectinemia in mice and be also a promising tool for improving metabolic syndrome aggravated by chronic stress. PMID- 21316208 TI - The influence of supplemental docosahexaenoic and arachidonic acids during pregnancy and lactation on neurodevelopment at eighteen months. AB - Docosahexaenoic acid (DHA) and arachidonic acid (AA) are important for neurodevelopment. The effects of DHA (220 mg/day, n=41), DHA+AA (220 mg/day, n=39) or placebo (n=34) during pregnancy and lactation on neurodevelopment at 18 months, and the relations between umbilical cord DHA, AA and Mead acid and neurodevelopment were studied. An age-specific, standardized neurological assessment for the evaluation of minor neurological dysfunction (MND), and the Bayley Scales of Infant Development (BSID) were used. The intervention did not influence any of the outcomes. Umbilical venous (UV) Mead acid was negatively and n-6 fatty acids were weakly positively associated to the BSID mental developmental index. Children with simple MND had lower UV DHA compared to normally classified children. We conclude that relatively short-term maternal DHA or DHA+AA supplementation does not influence neurodevelopment at toddler age, although some parameters of brain development are related to perinatal DHA and AA status. PMID- 21316209 TI - Propofol mitigates systemic oxidative injury during experimental cardiopulmonary cerebral resuscitation. AB - Effects of propofol, an intravenous anesthetic agent that exerts potent antioxidant properties, were investigated in an experimental model of cardiac arrest and cardiopulmonary resuscitation. An extended cardiac arrest with 15 randomized piglets was studied to assess the effect of propofol or its solvent intralipid as the control group. Oxidative stress (as measured by a major F(2) isoprostane) and inflammation (a major metabolite of PGF(2alpha)) were evaluated in addition to the hemodynamic evaluation, protein S-100beta and in situ tissue brain damage by immunochemistry at sacrifice after 3h of reperfusion following cardiac arrest and restoration of spontaneous circulation (ROSC). ROSC increased jugular bulb plasma levels of F(2)-isoprostane and PGF(2alpha) metabolite significantly more in controls than in the propofol-treated group. In situ tissue damage after ischemia-reperfusion was variable among the pigs at sacrifice, but tended to be greater in the control than the propofol-treated group. Propofol significantly reduced an ROSC-mediated oxidative stress in the brain. PMID- 21316210 TI - Environmental assessment of garden waste management in the Municipality of Aarhus, Denmark. AB - An environmental assessment of six scenarios for handling of garden waste in the Municipality of Aarhus (Denmark) was performed from a life cycle perspective by means of the LCA-model EASEWASTE. In the first (baseline) scenario, the current garden waste management system based on windrow composting was assessed, while in the other five scenarios alternative solutions including incineration and home composting of fractions of the garden waste were evaluated. The environmental profile (normalised to Person Equivalent, PE) of the current garden waste management in Aarhus is in the order of -6 to 8 mPE Mg(-1) ww for the non-toxic categories and up to 100 mPE Mg(-1) ww for the toxic categories. The potential impacts on non-toxic categories are much smaller than what is found for other fractions of municipal solid waste. Incineration (up to 35% of the garden waste) and home composting (up to 18% of the garden waste) seem from an environmental point of view suitable for diverting waste away from the composting facility in order to increase its capacity. In particular the incineration of woody parts of the garden waste improved the environmental profile of the garden waste management significantly. PMID- 21316211 TI - Chip-based impedance measurement on single cells for monitoring sub-toxic effects on cell membranes. AB - There is a lack of methods suitable for generation of data about the dynamics of effects on cell membranes with a high sensitivity. Such methods are urgently needed to support the optimisation of interaction of substances, particles or materials with cell. The goal of this article is to use an improved microhole chip system to monitor the alterations of cells due to the interactions of polymer-DNA complexes. This should demonstrate exemplarily that subtoxic effect of biological relevant particles or substances at relevant concentrations can be monitored for several hours. By using a microhole cell chip and a microfluidic unit single cells can be electrically interfaced via microholes and the use of small electrodes with high impedances is not necessary. For separation and positioning of the cells onto the hole negative pressure is applied on the reverse side of the chip. Under cell culture conditions the cell starts to spread on the biocompatible insulating chip membrane resulting in a stable interface to an adherent growing cell. After the spreading process is finished, the polymer/polyplex solution is added and the impedance is measured with respect to time. To illustrate the cellular parameter which can affect the measured impedance a simple simulation based on the finite element method (FEM) is performed. It was shown for the first time that the impedance-based method predicated on the microhole chip can be used for biological relevant substances at relevant concentrations and that it is more sensitive than the well established biological marker. PMID- 21316212 TI - Percutaneous resection of calcaneo-navicular coalition with interposition of synthetic graft. AB - BACKGROUND: Surgical resection of calcaneo-navicular coalition (CNC) with interposition of fat or muscle graft is indicated when there is failure of conservative treatment. OBJECTIVES: to evaluate the clinical and functional of outcome of a new mini-invasive technique for resection of CNC and interposition of synthetic graft. METHODS: This is a prospective case series study on 9 patients (12 feet) with symptomatic CNC. Percutaneous resection of the CNC was done using a motorized bone burr through a small incision in the sinus tarsi under image intensifier control. After complete resection a synthetic graft of Teflon or Dacron measuring 15 mm * 30 mm was interposed to prevent re-union of the bone bar. RESULTS: The mean follow up period was 26.44 months (+/-1.5 SD). There was statistically significant improvement in the mean total AOFAS score from 47.89 (+/-8.49 SD) preoperatively to 90.22 (+/- 5.26 SD) at two years follow up (P<0.05). The mean time to return to full daily activity was 7.44 weeks (+/ 0.88 SD) CONCLUSION: Percutaneous resection of calcaneo-navicular bar with interposition of synthetic graft is an effective mini-invasive method for treatment of calcaneo-navicular coalition with good results in 44.4% of patients and excellent results in 55.6% of patients. PMID- 21316213 TI - The combined reverse scarf and opening wedge osteotomy of the proximal phalanx for the treatment of iatrogenic hallux varus. AB - BACKGROUND: [Corrected] Hallux varus is a complication of hallux valgus surgery. Historically the standard treatment has been to arthrodese the first metatarso phalangeal (MTP) joint. More recently other options have come to light, including reverse osteotomies and tendon-transfer procedures. OBJECTIVES: This paper presents a small retrospective audit of patients who developed hallux varus following the combined rotation scarf and Akin osteotomy for hallux valgus, and their subsequent treatment with a stepwise approach of soft tissue release and ultimately reverse scarf osteotomy and opening wedge osteotomy of the proximal phalanx. METHOD: Five patients attended for a retrospective audit including reasons for revision surgery, review of intermetatarsal (IM) and first metatarso phalangeal joint (MTPA) angles, AOFAS scores and patient satisfaction. RESULTS: At a mean follow up of 38 months, mean IM angle and MTP joint angle improved from 5 to 9 degrees and -10 degrees to 11 degrees respectively. Mean first MTP joint dorsiflexion and plantarflexion was 26 degrees and 19 degrees respectively. One patient was completely satisfied and four were satisfied with reservations with their surgical outcome and 100% felt they were better off as a result of their surgery. CONCLUSION: The stepwise approach to the reverse scarf and opening wedge osteotomy of the proximal phalanx for iatrogenic hallux varus is an alternative to first MTP joint arthrodesis for those with a viable joint. PMID- 21316214 TI - An observational study of factors leading to difficulty in resident anaesthesiologists identifying the epidural space in obstetric patients. AB - BACKGROUND: Multiple attempts at needle placement for neuraxial block may cause patient discomfort, a higher incidence of spinal haematomas, postdural puncture headache and nerve trauma. The aim of this study was to evaluate the factors predicting difficult epidural analgesia for inexperienced residents. METHODS: In this prospective observational study, conducted in a teaching hospital, four anaesthesiology residents without prior experience in obstetric anaesthesia performed all epidural procedures. A difficult epidural was defined as a need for more than one attempt at catheter placement. The following patient data were recorded: body mass index, abdominal circumference (classified as <105 or >= 105 cm), ability to palpate anatomical landmarks and spinal abnormality. RESULTS: Four hundred and twelve pregnant women in labour were recruited. Residents achieved successful cannulation of the epidural space in 74% of attempts. Factors associated with difficult epidural placement in the univariate analysis were body mass index > 30 kg/m(2), an abdominal circumference > 105 cm, inability to palpate spinous processes and spinal abnormality. With the exception of abdominal circumference, all factors were independently predictive of difficult placement in the multivariate analysis with spinal abnormality being the most significant factor. CONCLUSIONS: For residents with no prior experience in obstetric anaesthesia, the most reliable factor in predicting difficult epidural cannulation was spinal abnormality. PMID- 21316215 TI - Lessons on transcriptional control from the serum response network. AB - Response to environmental stimuli is critical for cell survival and function and requires high fidelity signal transduction into the nucleus to facilitate the coordinated transcriptional regulation of appropriate gene networks. The cellular response to mitogenic stimuli provides an excellent paradigm to decipher the mechanisms mediating precise gene expression control at the transcriptional level. Here we review recent advances in our understanding of this so-called serum response network, which illuminate novel aspects of nuclear signaling mechanisms, combinatorial control by DNA binding proteins and regulation of RNA polymerase II (RNAPII) elongation. PMID- 21316216 TI - Chromatin states in pluripotent, differentiated, and reprogrammed cells. AB - The pluripotent state of embryonic stem cells is maintained by a core network of transcription factors, and by chromatin remodelling factors that support an environment permissive for transcription. Polycomb and trithorax Group proteins enable 'bivalent' chromatin to be established at lineage-specific genes within pluripotent cells that is thought to poise genes for rapid activation upon induction of differentiation. As differentiation proceeds, chromatin condenses and there is a genome-wide increase in the abundance of repressive histone modifications, alterations in the subnuclear organisation of particular genomic regions, and changes in DNA methylation profiles within genes. Reprogramming of somatic cells provides a platform to investigate the role of chromatin-based factors in establishing and maintaining pluripotency. PMID- 21316217 TI - The ribosomal tunnel as a functional environment for nascent polypeptide folding and translational stalling. AB - As the nascent polypeptide chain is being synthesized, it passes through a tunnel within the large ribosomal subunit and emerges at the solvent side where protein folding occurs. Despite the universality and conservation of dimensions of the ribosomal tunnel, a functional role for the ribosomal tunnel is only beginning to emerge: Rather than a passive conduit for the nascent chain, accumulating evidence indicates that the tunnel plays a more active role. In this article, we discuss recent structural insights into the role of the tunnel environment, and its implications for protein folding, co-translational targeting and translation regulation. PMID- 21316218 TI - Design and synthesis of novel allosteric MEK inhibitor CH4987655 as an orally available anticancer agent. AB - The MAP kinase pathway is one of the most important pathways involved in cell proliferation and differentiation, and its components are promising targets for antitumor drugs. Design and synthesis of a novel MEK inhibitor, based on the 3D structural information of the target enzyme, and then multidimensional optimization including metabolic stability, physicochemical properties and safety profiles were effectively performed and led to the identification of a clinical candidate for an orally available potent MEK inhibitor, CH4987655, possessing a unique 3-oxo-oxazinane ring structure at the 5-position of the benzamide core structure. CH4987655 exhibits slow dissociation from the MEK enzyme, remarkable in vivo antitumor efficacy both in mono- and combination therapy, desirable metabolic stability, and insignificant MEK inhibition in mouse brain, implying few CNS-related side effects in human. An excellent PK profile and clear target inhibition in PBMC were demonstrated in a healthy volunteer clinical study. PMID- 21316219 TI - Optimisation of ITK inhibitors through successive iterative design cycles. AB - Based on a hit cluster of compounds inhibiting interleukin-2 inducible T-cell kinase (ITK) in the submicromolar range a series of ITK inhibitor libraries were synthesized. Through iterative design cycles including kinase crystal structure information, indolylindazole libraries were identified which showed low nanomolar activity in enzymatic and cellular assays. The potential of these novel lead series was confirmed through in vivo tests in an anti-CD3-IL2 mouse model. The intravenous administration of highly potent ITK inhibitor 11o resulted in dose dependent, efficient suppression of IL-2. PMID- 21316220 TI - Design and synthesis of novel CCR2 antagonists: investigation of non aryl/heteroaryl binding motifs. AB - This report describes the design and synthesis of a series of CCR2 antagonists incorporating novel non-aryl/heteroaryl RHS (right hand side) motifs. Previous SAR in the area has suggested an aryl/heteroaryl substituent as a necessary structural feature for binding to the CCR2 receptor. Herein we describe the SAR with regards to potency (binding to hCCR2), dofetilide activity and metabolic stability (in vitro HLM) for this series. The resulting outcome was the identification of compounds with excellent properties for the investigation of the role of CCR2 in disease. PMID- 21316222 TI - Thienopyrrole acetic acids as antagonists of the CRTH2 receptor. AB - The bioisosteric replacement of the indole core of CRTH2 antagonists using thienopyrroles was investigated, resulting in potent antagonists with good selectivity over DP1. Early ADME/PK assessment of this chemotype demonstrated bioavailability in mice. PMID- 21316221 TI - Synthesis and SAR of novel quinazolines as potent and brain-penetrant c-jun N terminal kinase (JNK) inhibitors. AB - Quinazoline 3 was discovered as a novel c-jun N-terminal kinase (JNK) inhibitor with good brain penetration and pharmacokinetic (PK) properties. A number of analogs which were potent both in the biochemical and cellular assays were discovered. Quinazoline 13a was found to be a potent JNK3 inhibitor (IC(50)=40 nM), with >500-fold selectivity over p38, and had good PK and brain penetration properties. With these properties, 13a is considered a potential candidate for in vivo evaluation. PMID- 21316223 TI - The synthesis and structure-activity relationship of pyridazinones as glucan synthase inhibitors. AB - A structure-activity relationship study of the lead 5-[4 (benzylsulfonyl)piperazin-1-yl]-4-morpholino-2-phenyl-pyridazin-3(2H)-one 1 has resulted in the identification of 2-(3,5-difluorophenyl)-4-(3 fluorocyclopentyloxy)-5-[4-(isopropylsulfonyl)piperazin-1-yl]-pyridazin-3(2H)-one 11c as a beta-1,3-glucan synthase inhibitor. Compound 11c exhibited significant efficacy in an in vivo mouse model of Candida glabrata infection. PMID- 21316224 TI - Structure-activity relationship studies on 1-(5-carboxyindol-1-yl)-propan-2-one inhibitors of human cytosolic phospholipase A2alpha: variation of the activated ketone moiety. AB - Indole-5-carboxylic acids with 3-aryloxy-2-oxopropyl residues in position 1 have been found to be potent inhibitors of human cytosolic phospholipase A(2)alpha (cPLA(2)alpha). In course of structure-activity relationship studies, we investigated the effect of the substitution of the electrophilic ketone group in the middle part of the molecule by other polar residues, such as hydroxyimino, azido, acyloxy, acylamino, urea and carbamate, on enzyme inhibition. With an IC(50) of 1.7 MUM against cPLA(2)alpha from human platelets, the 4 fluorophenylcarbamate derivative 23f was the most active of the compounds tested. PMID- 21316225 TI - Oxindole derivatives as inhibitors of TAK1 kinase. AB - Several series of oxindole analogues were synthesized and screened for inhibitory activity against transforming growth factor-beta-activating kinase 1 (TAK1). Modifications around several regions of the lead molecules were made, with a distal hydroxyl group in the D region being critical for activity. The most potent compound 10 shows an IC(50) of 8.9 nM against TAK1 in a biochemical enzyme assay, with compounds 3 and 6 showing low micromolar cellular inhibition. PMID- 21316226 TI - Pyridyl amides as potent inhibitors of T-type calcium channels. AB - A novel series of amide T-type calcium channel antagonists were prepared and evaluated using in vitro and in vivo assays. Optimization of the screening hit 3 led to identification of the potent and selective T-type antagonist 37 that displayed in vivo efficacy in rodent models of epilepsy and sleep. PMID- 21316227 TI - Design, synthesis and in vitro cytotoxicity of novel dinuclear platinum(II) complexes. AB - Five dinuclear platinum(II) complexes with a novel chiral ligand, 2-(((1R,2R)-2 aminocyclohexylamino)methyl)phenol (HL), were designed, prepared and spectrally characterized. In vitro cytotoxicity of all the resulting platinum(II) compounds was evaluated against human HEPG-2, A549 and HCT-116 cell lines, respectively. Results indicated that all compounds showed positive biological activity. Particularly, compound D4 has lower IC(50) values than carboplatin toward HEPG-2 and A549, while compound D5 shows better activity than carboplatin against A549. PMID- 21316228 TI - Discovery of a potent, orally bioavailable pyrimidine VLA-4 antagonist effective in a sheep asthma model. AB - A series of N-(pyrimidin-4-yl)-phenylalanine VLA-4 antagonists is described. Optimization of substituents at the 2 and 5 positions of the pyrimidine ring gave 14, a very potent VLA-4 inhibitor which is orally active in a sheep asthma model. PMID- 21316229 TI - Discovery and biological activity of a novel class I PI3K inhibitor, CH5132799. AB - Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase and a promising therapeutic target for cancer. Using structure-based drug design (SBDD), we have identified novel PI3K inhibitors with a dihydropyrrolopyrimidine skeleton. Metabolic stability of the first lead series was drastically improved by replacing phenol with aminopyrimidine moiety. CH5132799, a novel class I PI3K inhibitor, exhibited a strong inhibitory activity especially against PI3Kalpha (IC(50)=0.014 MUM). In human tumor cell lines with PI3K pathway activation, CH5132799 showed potent antiproliferative activity. CH5132799 is orally available and showed significant antitumor activity in PI3K pathway-activated human cancer xenograft models in mice. PMID- 21316230 TI - Lead detoxification activities and ADMET hepatotoxicities of a class of novel 5 (1-carbonyl-L-amino-acid)-2,2-dimethyl-[1,3]dithiolane-4-carboxylic acids. AB - By linking the mercapto groups with isopropyl and introducing L-amino acid into the 5-carboxyl of DMSA a class of novel 5-(1-carbonyl-L-amino-acid)-2,2- dimethyl [1,3]dithiolane-4-carboxylic acids were prepared. Their in vivo activities were evaluated on lead loaded mice at the dose of 0.4 mmol/kg. The results showed that the lead levels of the livers, kidneys, femurs and brains in particular could be efficiently decreased by 0.4 mmol/kg of 5-(1-carbonyl-L-amino-acid)-2,2-dimethyl [1,3]dithiolane-4-carboxylic acids. The benefit of 5-(1-carbonyl-L-amino-acid) 2,2-dimethyl-[1,3]dithiolane-4-carboxylic acids to the detoxification of the brain lead was attributed to their transmembrane ability. Compared with the lead detoxification efficacy, they did not affect the essential metals such as Fe, Cu, Zn, and Ca of the treated mice. Silico molecular modeling predicted that 5-(1 carbonyl-L-amino-acid)-2,2-dimethyl-[1,3]dithiolane-4-carboxylic acids had no hepatotoxicity. PMID- 21316231 TI - Organelle-selective energy transfer: a fluorescent indicator of intracellular environment. AB - A dye cassette fluoresces green (ca 520 nm) in the cytoplasm, endoplasmic reticulum (ER), and lysosomes, but red in mitochondria, that is, it illustrates 'organelle specific energy transfer'. This phenomenon may open new horizons in intracellular imaging. PMID- 21316232 TI - 4-aminopyrimidine-5-carbaldehyde oximes as potent VEGFR-2 inhibitors. Part II. AB - A series of 4-aminopyrimidine-5-carbaldehyde oxime was discovered to have potent VEGFR-2 inhibitory activity. Described here are the chemistry for analogue synthesis and SAR study results. The PK properties, kinase profiling, and in vivo efficacy study for compound 4b are also discussed. PMID- 21316233 TI - Novel dihydrothieno[2,3-e]indazole derivatives as IkappaB kinase inhibitors. AB - Synthesis, and structure-activity relationship (SAR) studies of the novel IKK beta inhibitors 2 and 3 characterized by a dihydrothieno[2,3-e]indazole core are presented. Compound 2t was efficacious in a mouse model of LPS-stimulated TNF alpha production. PMID- 21316234 TI - Design and synthesis of a novel, orally active, brain penetrant, tri-substituted thiophene based JNK inhibitor. AB - The SAR of a series of tri-substituted thiophene JNK3 inhibitors is described. By optimizing both the N-aryl acetamide region of the inhibitor and the 4-position of the thiophene we obtained single digit nanomolar compounds, such as 47, which demonstrated an in vivo effect on JNK activity when dosed orally in our kainic acid mouse model as measured by phospho-c-jun reduction. PMID- 21316235 TI - Hepatitis C NS5B polymerase inhibitors: functional equivalents for the benzothiadiazine moiety. AB - A series of quinoline derivatives was synthesized as potential bioisosteric replacements for the benzothiadiazine moiety of earlier Hepatitis C NS5B polymerase inhibitors. Several of these compounds exhibited potent activity in enzymatic and replicon assays. PMID- 21316236 TI - Synthesis, characterization and anti-tumor activity of moxifloxacin-copper complexes against breast cancer cell lines. AB - Novel moxifloxacin-copper complexes were synthesized, characterized and screened for anti-proliferative and apoptosis-inducing activity against multiple human breast cancer cell lines (hormone-dependent MCF-7 and T47D as well as hormone independent MDA-MB-231 and BT-20). The results indicated that the parent compound moxifloxacin (1) does not exert any inhibitory activity against breast cancer cell lines examined. On the other hand, the copper conjugate 2 and its nitrogen adducts 3-5 exerted growth inhibitory and apoptosis-inducing activity against breast cancer cell lines without any substantial effect on non-tumorigenic breast epithelial cells MCF-10A at equimolar concentration, suggesting a cancer cell specific activity. BT-20 cells were more sensitive to compounds 2 and 3, while compounds 4 and 5 exerted significant anti-proliferative and apoptosis-inducing effects on T47D, MDA-MB-231 and BT-20 cell lines. Our results suggest that these novel compounds could be useful for the treatment of breast cancer in the future. PMID- 21316237 TI - Synthesis and evaluation of 1,5-diaryl-substituted tetrazoles as novel selective cyclooxygenase-2 (COX-2) inhibitors. AB - A series of 1,5-diaryl-substituted tetrazole derivatives was synthesized via conversion of readily available diaryl amides into corresponding imidoylchlorides followed by reaction with sodium azide. All compounds were evaluated by cyclooxygenase (COX) assays in vitro to determine COX-1 and COX-2 inhibitory potency and selectivity. Tetrazoles 3a-e showed IC(50) values ranging from 0.42 to 8.1 mM for COX-1 and 2.0 to 200 MUM for COX-2. Most potent compound 3c (IC(50) (COX-2)=2.0 MUM) was further used in molecular modeling docking studies. PMID- 21316238 TI - Phenotypic heterogeneity in a large Thai slow-channel congenital myasthenic syndrome kinship. AB - The slow-channel congenital myasthenic syndrome (SCCMS) is an autosomal dominant neuromuscular disorder caused by mutations in different subunits of the acetylcholine receptor (AChR). We here report our clinical findings in three generations of a large Thai kinship suffering from SCCMS and trace the disease to the p.Gly153Ser mutation in the AChR alpha subunit. The same mutation had previously been reported only in Caucasian but not in Asian patients. The clinical features include ptosis, ophthalmoparesis, and weakness of the cervical and finger extensor muscles as well as marked phenotypic heterogeneity. PMID- 21316239 TI - Survey of utilization of multidisciplinary management tumor boards in Arab countries. AB - Multidisciplinary management (MDM) of cancer patients provides better care and is recommended by all authorities and published guidelines. There is very little documentation of MDM practices in low and middle income countries. A survey of 338 practicing oncology specialists from various Arab countries was conducted at four major pan-Arab oncology conferences in the first half of 2010. While 72% of respondents reported having an MDM tumor board, only 49% reported that their tumor boards met on a weekly basis. Of those who do not have a tumor board, 57% attend a tumor board meeting at another hospital within their country. 60% of respondents attend tumor board meetings to seek group opinion and help in the management of their patients. 93% of physicians surveyed agreed that tumor boards should be mandatory. The vast majority of physicians agreed that in the absence of all specialties, "mini tumor boards" should be organized between available specialists at all hospitals that treat cancer patients. PMID- 21316240 TI - Step length asymmetry is representative of compensatory mechanisms used in post stroke hemiparetic walking. AB - Post-stroke hemiparetic subjects walk with asymmetrical step lengths that are highly variable between subjects and may be indicative of the underlying impairments and compensatory mechanisms used. The goal of this study was to determine if post-stroke hemiparetic subjects grouped by step length asymmetry have similar abnormal walking biomechanics compared to non-impaired walkers. Kinematic and ground reaction force data were recorded from 55 hemiparetic subjects walking at their self-selected speed and 21 age and speed-matched non impaired control subjects. Hemiparetic subjects were grouped by paretic step ratio, which was calculated as the paretic step-length divided by the sum of paretic and nonparetic step-lengths, into high (>0.535), symmetric (0.535-0.465) and low (<0.465) groups. Non-parametric Wilcoxin signed-rank tests were used to test for differences in joint kinetic measures between hemiparetic groups and speed-matched control subjects during late single-leg stance and pre-swing. The paretic leg ankle moment impulse was reduced in all hemiparetic subjects regardless of their paretic step ratio. The high group had increased nonparetic leg ankle plantarflexor and knee extensor moment impulses, the symmetric group had increased hip flexor moment impulses on both the paretic and nonparetic leg and the low group had no additional significant differences in joint moment impulses. These results suggest that the direction of asymmetry can be used to identify both the degree of paretic plantarflexor impairment and the compensatory mechanisms used by post-stroke hemiparetic subjects. PMID- 21316241 TI - Correlation between idiopathic hemifacial spasm and the MRI characteristics of the vertebral artery. AB - We studied the correlation between the anatomy of the vertebral artery (VA) and the symptoms of primary hemifacial spasm (HFS). Between June and October 2009, 88 patients with primary HFS underwent a preoperative MRI and subsequent microvascular decompression surgery. Each patient's VA was categorized into one of three types according to their MRI findings. In Type I, the bilateral VA that join to form the basilar artery in the mid line appear symmetrical. In Type II, the VA distribute asymmetrically and deviate to one side (Type IIa deviate to the symptomatic side; Type IIb to the contralateral side). In Type III, both VA occur on the same side (Type IIIa occur on the symptomatic side; Type IIIb on the contralateral side). The correlation between deviation of the VA and the symptomatic side of primary HFS was analyzed statistically. Of the 88 patients, the number of patients with each type of VA, as identified by three-dimensional time-of-flight MRI was: Type I=3, Type II=48 (Type IIa=40, Type IIb=8) and Type III=37 (Type IIIa=36, Type IIIb=1). The anatomical characteristics of the VA (lateral deviation) were significantly related to the symptomatic side of the primary HFS (chi-squared [chi(2)]=102.14; p<0.01; relative risk=8.44). The likelihood that the VA deviated to the symptomatic side was 86.4%, while the likelihood of deviation to the asymptomatic side was 10.2%. Thus, anatomical variation of the VA (lateral deviation) is one of the risk factors for primary HFS. PMID- 21316242 TI - Association of diffusion weighted imaging abnormalities and recurrence in transient global amnesia. AB - Since the first description of transient global amnesia (TGA) in 1964, its etiology has remained obscure. Reversible diffusion weighted imaging (DWI) hyperintensities in the hippocampus have been found on MRI of some patients with TGA during acute events. The implication of this is not well understood. We identified 47 patients with TGA between November 2004 and November 2009, and enrolled 27 patients with brain MRI within 72 hours of symptom onset for analysis and recorded subsequent relapse or stroke occurrence during follow-up. Nine of the 27 patients had reversible hippocampal punctuate hyperintensities, with complete resolution noted on a second MRI on average 4 months after the initial TGA. Patients with a first relapse (their second TGA attack) had a significantly higher association of DWI hippocampal abnormalities (p=0.03) compared to patients with their first TGA event. None of the 27 patients had a stroke or further relapse during the mean follow-up period of 32.6 months. Thus, patients with recurrent TGA have a significantly higher association of reversible DWI abnormality. PMID- 21316243 TI - Comment on "A report of the natural history of leptomeningeal gliomatosis". PMID- 21316244 TI - Myositis ossificans of bilateral hip joints in a patient with diplegic cerebral palsy. AB - Myositis ossificans (MO) occurs in association with musculoskeletal trauma, traumatic and non-traumatic neurologic conditions, joint surgery and rarely as a hereditary disorder. We report a 6-year-old boy with diplegic cerebral palsy who developed MO of his bilateral hip joints after initiating physiotherapy. He responded well to conservative management. PMID- 21316245 TI - Mutation and haplotype analysis of oculopharyngeal muscular dystrophy in Thai patients. AB - Oculopharyngeal muscular dystrophy (OPMD) is an inherited neuromuscular disease associated with a short trinucleotide repeat expansion in Exon 1 of the PABPN1 gene. OPMD is uncommon in East Asian populations, and there have been no previous reports of Thai patients. We studied clinical and molecular genetic features of six unrelated Thai patients with autosomal dominant OPMD. All patients had expansions of the guanine-cytosine-guanine (GCG) repeat ranging from three to seven additional repeats in the PABPN1 gene. Haplotype analysis showed that these mutations might have originated independently. Analysis of the size of the GCG repeat in the PABPN1 gene in 200 Thai control patients showed that 0.5% of the control subjects possessed (GCG)(7), thereby suggesting that the prevalence of autosomal recessive OPMD in the Thai population was approximately 1 in 160,000. In conclusion, our data suggest that OPMD in Thailand may be more common than previously thought. PMID- 21316246 TI - A report of the natural history of leptomeningeal gliomatosis. AB - Primary leptomeningeal gliomatosis (PLG) is a rare condition, with fewer than 50 patients reported. Our report illustrates the natural history of PLG in full, from the prodromal phase of subacute meningitis to the final stages characterised by extensive nerve root infiltration, cranial nerve palsies and widespread peripheral neurogenic muscle wasting. We provide correlative neuroimaging with serial MRI, and present the first published positron emission tomography imaging of this condition. We emphasise the importance of considering PLG in the differential diagnosis of chronic aseptic meningitis, the difficulties of making the diagnosis ante mortem, and the utility and potential limitations of early meningeal biopsy in this condition. PMID- 21316247 TI - Two-dimensional high-end ultrasound imaging compared to intraoperative MRI during resection of low-grade gliomas. AB - Ultrasound (US) is being used increasingly in intraoperative imaging. Its reliability in identifying low-grade gliomas (LGG), however, has not been shown definitively. We compared the quality and reliability of high-end two-dimensional (2D) ultrasound (US) and 1.5 Tesla intraoperative MRI (iopMRI) images in 11 patients with LGG. The parameters evaluated were: tumor border; internal structure; vascularity, location, and relation to landmarks and vessels; and accuracy in detecting remnants. Both methods allowed good visualization of internal characteristics of the tumor and its location. The tumor border was clear on 10 of 11 MRI and on 9 of 11 US. During surgery, however, the quality of US images diminished, leading to some difficulties in interpretation. One small superficial remnant was not identified and in one patient an artifact was falsely interpreted as a remnant. While iopMRI appeared superior for visualizing different stages of hemispheric LGG resection, 2D US still allows accurate initial tumor delineation and for almost real-time control of tumor resection. PMID- 21316248 TI - Computer- and structure-based lead design for epigenetic targets. AB - The term epigenetics is defined as inheritable changes that influence the outcome of a phenotype without changes in the genome. Epigenetics is based upon DNA methylation and posttranslational histone modifications. While there is much known about reversible acetylation as a posttranslational modification, research on reversible histone methylation is still emerging, especially with regard to drug discovery. As aberrant epigenetic modifications have been linked to many diseases, inhibitors of histone modifying enzymes are very much in demand. This article will summarize the progress on small molecule epigenetic inhibitors identified by structure- and computer-based approaches. PMID- 21316249 TI - EMCD real space maps of Magnetospirillum magnetotacticum. AB - In this study we combine energy loss magnetic circular dichroism (EMCD) and energy filtered transmission electron microscopy (EFTEM) to map magnetic properties of nanoparticles. We show that it is a functional tool for investigating the magnetic behaviour of bio-mineralized magnetite crystals of Magnetospirillum magnetotacticum. We find that the spatial resolution of our experimental set-up is in the range of less than 2 nm. The results are compared with EMCD studies of abiogenic magnetite. PMID- 21316250 TI - Effects of curcumin on the dorsal root ganglion structure and functional recovery after sciatic nerve crush in rat. AB - BACKGROUND: Curcumin has protective effects on a variety of CNS injury models. Our purpose was to assess the effects of curcumin on the dorsal root ganglion (DRG) and functional recovery in sciatic nerve crush (SNC) of rats. METHODS: The fifth lumbar DRG was removed 28 days after SNC. Sciatic functional index (SFI) and also the DRG structure were evaluated, using stereological methods to assess the effects of curcumin. RESULTS: The volume and number of A- and B-cells were reduced in the SNC as compared with the sham-operated animals. In curcumin treated rats, the volume decreased but in a lesser extent and it was ~10% and ~15% higher on the average in comparison with the non-treated SNC (P<0.04). In curcumin treated rats, the number of cells also decreased but in a lesser extent and it was ~17% and ~36% higher in comparison with the non-treated crushed animals (P<0.02). The surface area of A- and B-cells reduced in the SNC and SNC plus curcumin in comparison with the sham-operated rats (P<0.01). The number of satellite cells was reduced in the SNC as compared with the sham-operated animals. In curcumin treated rats, the number of satellite cells decreased but in a lesser extent and the number of satellite cells was ~19% higher in comparison with the non-treated (P<0.02). SFI test shows that the motor function of the rats treated with curcumin significantly improved at 21st days after sciatic nerve crush. CONCLUSION: The results demonstrate that curcumin promotes the functional recovery and has a neuroprotective effect on the DRG after sciatic nerve injury in the rats. PMID- 21316251 TI - SOLANG: A user-friendly code to calculate the geometry factor using Monte Carlo simulations. Application to alpha-particle spectrometry. AB - Monte Carlo simulation was applied to calculate the effective solid angle (or geometry factor) presented by a plane radioactive source at a detector entrance window. A fast and user-friendly computer program SOLANG was written to perform the calculations for disk or rectangular sources and circular non-coaxial detector disks. Results can be achieved with great precision, depending on the number of simulated trajectories. Some checks and applications to the calculation of efficiencies of semiconductor detectors and gas ionization chambers used to measure alpha particles are presented. Their results were very reliable. The code is available free of charge on request to the authors. PMID- 21316252 TI - A large HPGe detector for the non-destructive radioassay of an ultra-low background counting facility. AB - We present the use of a low background counting facility, equipped with a p-type 80% relative efficiency HPGe detector, protected by active and passive shielding, and large enough to count a 10 in photo-multiplier tube (PMT). A GEANT4 Monte Carlo of this detector was developed and tuned to 3% accuracy. We report the U, Th, and K content in three different types of PMTs used in current neutrino experiments, with accuracies of ~10ppb for U and Th and of ~15ppm for K. PMID- 21316253 TI - Towards the final BSA modeling for the accelerator-driven BNCT facility at INFN LNL. AB - Some remarkable advances have been made in the last years on the SPES-BNCT project of the Istituto Nazionale di Fisica Nucleare (INFN) towards the development of the accelerator-driven thermal neutron beam facility at the Legnaro National Laboratories (LNL), aimed at the BNCT experimental treatment of extended skin melanoma. The compact neutron source will be produced via the (9)Be(p,xn) reactions using the 5 MeV, 30 mA beam driven by the RFQ accelerator, whose modules construction has been recently completed, into a thick beryllium target prototype already available. The Beam Shaping Assembly (BSA) final modeling, using both neutron converter and the new, detailed, Be(p,xn) neutron yield spectra at 5 MeV energy recently measured at the CN Van de Graaff accelerator at LNL, is summarized here. PMID- 21316254 TI - A new model involving ethylene, nitric oxide and Fe to explain the regulation of Fe-acquisition genes in Strategy I plants. AB - In previous work it has been shown that both ethylene and NO (nitric oxide) participate in a similar way in the up-regulation of several Fe-acquisition genes of Arabidopsis and other Strategy I plants. This raises the question as to whether NO acts through ethylene or ethylene acts through NO, or whether both act in conjunction. One possibility is that NO could increase ethylene production. Conversely, ethylene could increase NO production. By using Arabidopsis and cucumber plants, we have found that both possibilities occur: NO greatly induces the expression in roots of genes involved in ethylene synthesis: AtSAM1, AtSAM2, AtACS4, AtACS6, AtACO1, AtACO2, AtMTK; CsACS2 and CsACO2; on the other hand, ethylene greatly enhances NO production in the subapical region of the roots. These results suggest that each substance influences the production of the other and that both substances could be necessary for up-regulation of Fe-acquisition genes. This has been further confirmed in experiments with simultaneous application of the NO donor GSNO (S-nitrosoglutathione) and ethylene inhibitors; or with simultaneous application of the ethylene precursor ACC (1 aminocyclopropane-1-carboxylic acid) and an NO scavenger. Both GSNO and ACC enhanced ferric reductase activity in control plants, but not in those plants simultaneously treated with the ethylene inhibitors or the NO scavenger, respectively. To explain all these results and previous ones we have proposed a new model involving ethylene, NO, and Fe in the up-regulation of Fe-acquisition genes of Strategy I plants. PMID- 21316255 TI - Molecular cloning, characterization, and expression of an alfalfa (Medicago sativa L.) heme oxygenase-1 gene, MsHO1, which is pro-oxidants-regulated. AB - It has been documented that plant heme oxygenase-1 (HO-1; EC 1.14.99.3) is both development- and stress-regulated, thus it plays a vital role in light signalling and stress responses. In this study, an alfalfa (Medica sativa L.) HO-1 gene MsHO1 was isolated and sequenced. It contains four exons and three introns within genomic DNA sequence and encodes a polypeptide with 283 amino acids. MsHO1 had a conserved HO signature sequence and showed high similarity to other HOs in plants, especially HO-1 isoform. The MsHO1:GFP fusion protein was localized in the chloroplast. Further biochemical activity analysis of mature MsHO1, which was expressed in Escherichia coli, showed that the Vmax was 48.78 nmol biliverdin IXalpha (BV) h-1 nmol-1 protein with an apparent Km value for hemin of 2.33 MUM, and the optimum Tm and pH were 37 degrees C and 7.2, respectively. Results of semi-quantitative RT-PCR and western blot showed that the expressions of MsHO1 were higher in alfalfa stems and leaves than those in germinating seeds and roots. Importantly, MsHO1 gene expression and protein level were induced significantly by some pro-oxidant compounds, including hemin and nitric oxide (NO) donor sodium nitroprusside (SNP). In conclusion, MsHO1 may play an important role in oxidative responses. PMID- 21316256 TI - Assessment of the perfusion and morbidity of the buccal mucosal donor site for grafting of urethral strictures. AB - Buccal mucosal grafting has become the gold standard for reconstruction of urethral strictures. The aim of this study was to investigate donor site morbidity with a unique emphasis on objective measurements of perfusion and oxygenation. METHODS: In a prospective study 15 male patients with recurrent urethral strictures, underwent urethroplasty using an intraoral mucosal graft. Donor site was closed primarily (group 1) or left to granulation (group 2). Clinical examinations of recipient and donor sites, urograms and the modified SF 8TM health questionnaire were carried out 1, 3 and 24 weeks postoperatively. Oxygenation and perfusion parameters of the donor site were measured by the O2C (oxygen-to-see) monitoring device - a combined technique of laser Doppler flowmetry and tissue spectroscopy. RESULTS: No recurrence of strictures at recipient site or infections at either sites occurred. 24 weeks after operation, haemoglobin oxygenation (72.1+/-5.9%) and deep flow (177.2 Arbitrary Units (AU)) of the donor site were slightly, but not significantly, lower compared to the contralateral unoperated buccal mucosa (haemoglobin oxygenation: 75.4+/-5.2%, deep flow: 187.3 AU). Significant differences between the two groups of different wound healing could not be revealed. CONCLUSIONS: Using free mucosal grafts for urethroplasty is a simple and safe method in the interdisciplinary treatment of urethral strictures. Donor site morbidity within the first 3 weeks after operation is noticeable, but tolerable measured by a validated Quality of Life tool. Six months after the operation, perfusion and oxygenation of the former graft harvest site are equal to the contralateral unoperated mucosa. PMID- 21316257 TI - The aortic interleaflet triangles annuloplasty: a multidisciplinary appraisal. AB - OBJECTIVE: Aortic interleaflets triangles annuloplasty (AITA) reduces interleaflet triangles' circumferential extent through properly placed sutures. To achieve aortic root functional unit (ARFU) stabilization, we aimed at quantifying the effect of suture extent (SE) on aortic valve function and at finding general optimization criteria. METHODS: A previously published ARFU finite element model was modified to simulate ARFU dilation and AITA, systematically varying the SE and quantifying the corresponding regurgitant orifice (RO), leaflets co-aptation area (CA) and annular diameter (D(a)). Computational outcomes were tested by comparison with postoperative virtual basal ring echo data of 105 successfully corrected ARFUs. RESULTS: According to our finite element simulations of AITA, RA and CA depended linearly on SE, through a relationship that predicted optimal surgical results when SE was equal to 48% of the interleaflet triangle height (ITH). Follow-up data showed that, after AITA, ARFU diameter decreased from 23.4 +/- 3.93 to 20.1 +/- 1.8mm, (p<0.05) at the annulus, from 41.53 +/- 6.347 to 38.2 +/- 4.0 mm, (p<0.01) at the sinuses, and from 41.3 +/- 6.47 to 35.25 +/- 5.95 mm (p=ns) at the sinotubular junction (STJ). The mean ITH was 11.18 +/- 1.74 mm and the mean SE predicted by our model was 5.34 +/- 0.6mm, that is, 47.76% of the ITH, comparable to 48% of the computational model. Leaflet co-aptation length (CL) increased from 2.73 +/- 1.25 to 7.56 +/- 2.36 mm (p<0.001), while the CA evaluated via finite element modeling changed from 8% to 48%. CONCLUSIONS: So far, the AITA seems to be a valuable technique to increase leaflet CL in aortic valve repair and in silico models seem to be able to predict the principles of the phenomena but not the individual complexity. PMID- 21316258 TI - Right aortic arch with mirror image aplasia of brachiocephalic trunk presented as subclavian steal syndrome. PMID- 21316260 TI - Targeting phosphoinositide 3-kinase signalling in lung cancer. AB - Lung cancer is the leading cause of cancer-related mortality worldwide and more than 1 million people annually die in consequence of lung cancer. Although an improvement in lung cancer treatment could be achieved, especially in the last decade, the development of additional therapeutic strategies is urgently required in order to provide improved survival benefit for patients. Lung cancer formation is caused by genetic modifications commonly caused by tobacco smoking. Numerous studies have demonstrated the role of extracellular growth factors in lung cancer cell proliferation, metastasis, and chemoresistance. Mutations and amplifications in molecules related to receptor tyrosine signalling, such as EGFR, ErbB2, c-Met, c-Kit, VEGFR, PI3K, and PTEN are only some of the alterations known to contribute to the development of lung cancer. The phosphoinositide 3-kinase (PI3K) pathway, fundamental for cell development, growth, and survival, is known to be frequently altered in neoplasia, including carcinomas of the lung. Based on the high frequency of alterations, which include mutations and amplifications, leading to over-activation of certain upstream/downstream mediators, targeting components of the PI3K signalling pathway is considered to be a promising therapeutic approach in cancer treatment. In this article we will summarize the current knowledge about the involvement of PI3K signalling in lung cancer and discuss the development of targeted therapies involving PI3K pathway inhibitors. PMID- 21316259 TI - The efficacy of paravertebral block using a catheter technique for postoperative analgesia in thoracoscopic surgery: a randomized trial. AB - OBJECTIVE: The analgesic scheme combining paravertebral block (PVB) and intravenous non-steroidal anti-inflammatory drug (NSAID) has proven to be effective for postoperative pain control after thoracotomy. The hypothesis tested in this study was that this policy was also suitable to improve pain control after video-assisted thoracic surgery (VATS). METHODS: This was a prospective randomized study on 40 patients submitted to three-ports' VATS for pneumothorax or solitary pulmonary nodule. The sample size was calculated to detect one point of minimum pain score difference with 80% statistical power. Patients were randomly assigned to two groups: (1) paravertebral block group (PVB) (n=20) - At the end of surgery, a catheter was placed in patients in the thoracic paravertebral space under camera control; they received a bolus of 15 ml of local anesthetic (ropivacaine 0.2%) every 6h, combined with endovenous metamizol (1g); and (2) alternate NSAIDs group (AN) (n=20) - They were treated with paracetamol (1g) combined with metamizol (1g) every 6h. Subcutaneous meperidine (synthetic opioid) was employed as rescue drug. Both groups were comparable in terms of age, sex, pathology, and co-morbidity. Pain level was measured with the visual analog scale (VAS) at 1, 6, 24, and 48 h. RESULTS: No side effects related to any of the two analgesic techniques were noted. Two patients needed rescue meperidine in the AN group, and none in the PVB group. VAS scores were the following: PVB group, VAS 1h: 1.4+/-0.8, VAS 6h: 3.4+/-1.2, VAS 24h: 2.6+/-1.0, VAS 48 h: 2.2+/-0.9, and mean VAS: 2.4+/-1.3; AN group, VAS 1h: 2.8+/-1.0, VAS 6h: 4.9+/-1.3, VAS 24h: 3.9+/-1.4, VAS 48 h: 3.3+/-1.0, and mean VAS: 3.8+/-1.4. VAS scores were significantly lower at any time in the PVB patients (p<0.01). CONCLUSIONS: The analgesic regimen combining PVB and NSAID provided an excellent level of pain control. Thoracoscopy assisted positioning of the paravertebral catheter is simple and effective, and allows direct visualization of correct delivery of local anesthetic. It represents a valuable addition to any VATS procedure. PMID- 21316261 TI - Harnessing dendritic cells to improve allogeneic hematopoietic cell transplantation outcome. AB - In clinical practice, hematopoietic cell transplantation (HCT) is now recognized as a powerful means of delivering effective cellular immunotherapy for malignant and non-malignant diseases. In patients with severe hematological malignancies, the success of allogeneic HCT is largely based on immunologic graft-versus-tumor (GVT) effects mediated by allogeneic T lymphocytes present in the graft. Unfortunately, this beneficial effect is counterbalanced by the occurrence of graft versus host reactions directed against normal host tissues resulting in graft versus host disease (GVHD), a potentially life-threatening complication that limits the success of allogeneic HCT. Therefore, while preserving beneficial GVT effects, a major objective in allogeneic HCT is the prevention of GVHD. Studies in the last decade revealed the central role of dendritic cells and macrophages in modulating graft versus host immune reactions after allogeneic HCT. In this review, we summarize recent progress and potential new therapeutic avenues using dendritic cell-based strategies to improve allogeneic HCT outcome. PMID- 21316262 TI - Aortoesophageal fistula after stent-graft treatment of an aortic arch mycotic aneurysm: treatment with embolization and covered esophageal stent. PMID- 21316263 TI - Compression of the celiac trunk caused by median arcuate ligament in children and adolescent subjects: evaluation with contrast-enhanced MR angiography and comparison with Doppler US evaluation. AB - PURPOSE: Compression of the celiac trunk by the median arcuate ligament can lead to clinically significant reduction in celiac blood flow and cause clinical symptoms. Doppler ultrasound (US) can be used to screen for stenoses of the celiac trunk and to reduce unnecessary catheter angiography. A noninvasive alternative method is magnetic resonance (MR) angiography. MATERIALS AND METHODS: A series of 32 children and adolescent patients were evaluated retrospectively; 22 had a positive history of abdominal angina and the other 10 were referred for abdominal imaging including MR angiography for other reasons and were used as a control group. RESULTS: In the patient group, all evaluated patients showed the typical hook-shaped appearance of the celiac trunk and focal narrowing with high grade stenosis on MR angiography, which were eliminated after laparoscopic treatment. In the control group, no typical signs of median arcuate ligament syndrome were detected. US measurement of the mean preoperative peak velocity in the patient group was 304 cm/s +/- 49. The mean postoperative peak velocity was 163 cm/s +/- 29. In the control group without symptoms, the mean peak velocity was 140 cm/s +/- 25. The difference in pre- and postoperative peak velocities in the patient group was highly significant (P <.0001). CONCLUSIONS: MR angiography can confirm the diagnosis of median arcuate ligament syndrome by demonstrating the characteristic focal narrowing of the celiac artery in children presenting with the appropriate clinical symptoms and is an excellent alternative to catheter angiography, especially in a pediatric population. PMID- 21316264 TI - Iatrogenic hepatic puncture while placing a peritoneal drain: percutaneous direct embolization under ultrasound guidance. PMID- 21316265 TI - Autoscopic phenomena and one's own body representation in dreams. AB - Autoscopic phenomena (AP) are complex experiences that include the visual illusory reduplication of one's own body. From a phenomenological point of view, we can distinguish three conditions: autoscopic hallucinations, heautoscopy, and out-of-body experiences. The dysfunctional pattern involves multisensory disintegration of personal and extrapersonal space perception. The etiology, generally either neurological or psychiatric, is different. Also, the hallucination of Self and own body image is present during dreams and differs according to sleep stage. Specifically, the representation of the Self in REM dreams is frequently similar to the perception of Self in wakefulness, whereas in NREM dreams, a greater polymorphism of Self and own body representation is observed. The parallels between autoscopic phenomena in pathological cases and the Self-hallucination in dreams will be discussed to further the understanding of the particular states of self awareness, especially the complex integration of different memory sources in Self and body representation. PMID- 21316266 TI - Psychiatric comorbidity in patients with two prototypes of focal versus generalized epilepsy syndromes. AB - The frequency of psychiatric disorders (PD) in a homogeneous series of patients with temporal lobe epilepsy with mesial temporal sclerosis (TLE-MTS) compared to patients with juvenile myoclonic epilepsy (JME) was evaluated, aiming to determine the frequency of PD and possible differences in psychiatric diagnoses between these two epileptic syndromes. Data from 248 patients with refractory TLE MTS and from 124 JME patients were reviewed and compared. There was a high prevalence of PD in both groups of epilepsy patients, present in 100 TLE-MTS (41%) and in 58 JME patients (46.7%). Mood (23.7%), anxiety (13.7%) and psychotic (11.6%) disorders were the most frequent diagnoses in TLE-MTS group, while mood and anxiety disorders (25% and 21%, respectively) were the most common PD among JME. Psychoses were significantly associated with TLE-MTS (p=0.01). These observations are concordant with our previous study, reforcing the existence of a possible anatomic correlation of PD and brain structures involved in both epilepsy syndromes. PMID- 21316267 TI - The effect of levetiracetam monotherapy on subjective sleep quality and objective sleep parameters in patients with epilepsy: compared with the effect of carbamazepine-CR monotherapy. AB - PURPOSE: There is relatively little known about the effects of new antiepileptic drugs (AEDs) on sleep. This study was done to evaluate the effect of levetiracetam (LEV) on subjective sleep quality and sleep architecture in patients with epilepsy, and the results were compared with the effects of carbamazepine-CR (CBZ-CR). METHODS: This is a longitudinal randomized controlled trial using two different treatments, LEV (1000 mg/day) or CBZ-CR (400mg/day). Thirty-one subjects (16 LEV and 15 CBZ-CR) had partial epilepsy and were tested with an overnight polysomnography (PSG) with full 10-20 electrodes. Sleep questionnaires and National Hospital Seizure severity Scale (NHS3) were evaluated. PSG and the questionnaires were repeated after 4-6 weeks of treatment. RESULTS: In the LEV group, when treatment PSG findings were compared with baseline, there was a significant increase in sleep efficiency (p=0.039) but no changes in subjective sleep parameters. In the CBZ-CR group, there was a significant increase in the percentage of slow wave sleep (p=0.038) while other sleep parameters were not significantly changed after treatment. There were no significant differences in effects on sleep between the LEV and CBZ-CR groups. CONCLUSION: LEV may increase sleep efficiency without major effects on sleep structure with an overall effect on sleep parameters comparable to CBZ-CR. PMID- 21316268 TI - Lack of association of ABCB1 and PXR polymorphisms with response to treatment in epilepsy. AB - It is proposed that overexpression of P-glycoprotein (P-gp), encoded by the ABC subfamily B member 1 (ABCB1) gene, is involved in resistance to antiepileptic drugs (AEDs) in about 30% of patients with epilepsy. Genetic variation and haplotype patterns are population specific which may cause different phenotypes such as response to AEDs. Although several studies examined the link between the common polymorphisms in the ABCB1 gene with resistance to AEDs, the results have been conflicting. This controversy may be caused by the effect of some confounders such as ethnicity and polytherapy. Moreover, expression of the ABCB1 gene is under the control of pregnane X receptor (PXR). Evidence showed that PXR gene contribute to the response to treatment. The aim of this study was to assess the association of ABCB1 and PXR genetic polymorphisms with response to the carbamazepine (CBZ) or sodium valproate (VPA) monotherapy in epilepsy. Genotypes were assessed in 685 Chinese, Indian, and Malay epilepsy patients for ABCB1 (C1236T, G2677T, C3435T) and PXR (G7635A) polymorphisms. No association between these polymorphisms and their haplotypes, and interaction between them, with response to treatment was observed in the overall group or in the Chinese, Indian, and Malay subgroups. Our data showed that these polymorphisms may not contribute to the response to CBZ or VPA monotherapy treatment in epilepsy. PMID- 21316269 TI - Cerebral arteriogenesis is enhanced by pharmacological as well as fluid-shear stress activation of the Trpv4 calcium channel. AB - OBJECTIVES: This study aimed to determine the importance of the shear-stress sensitive calcium channels Trpc1, Trpm7, Trpp2, Trpv2 (transient receptor potential cation channel, subfamily V, member 2) and Trpv4 for cerebral arteriogenesis. The expression profiles were analysed, comparing the stimulation of collateral growth by target-specific drugs to that achieved by maximum increased fluid shear stress (FSS). DESIGN: A prospective, controlled study wherein rats were subjected to bilateral carotid artery ligature (BCL), or BCL + arteriovenous fistula, or BCL + drug application. METHODS: Messenger RNA (mRNA) abundance and protein expression were determined in FSS-stimulated cerebral collaterals by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry. Drugs were applied via osmotic mini pumps and arteriogenesis was evaluated by post-mortem angiograms and Ki67 immunostaining. RESULTS: Trpv4 was the only mechanosensitive Trp channel showing significantly increased mRNA abundance and protein expression after FSS stimulation. Activation of Trpv4 by 4alpha-phorbol-12,13-didecanoate caused significantly enhanced collateral growth (length: 4.43 +/- 0.20 mm and diameter: 282.6 +/- 8.1 MUm) compared with control (length: 3.80 +/- 0.06 mm and diameter: 237.3 +/- 5.3 MUm). Drug application stimulated arteriogenesis to almost the same extent as did maximum FSS stimulation (length: 4.61 +/- 0.07 mm and diameter: 327.4 +/- 12.6 MUm). CONCLUSIONS: Trpv4 showed significantly increased expression in FSS stimulated cerebral collaterals. Pharmacological Trpv4 activation enhanced cerebral arteriogenesis, pinpointing Trpv4 as a possible candidate for the development of new therapeutic concepts. PMID- 21316270 TI - Rhinitis and sleep. AB - Allergic rhinitis is a very prevalent disease in developed nations and has been increasing throughout the world. Nasal congestion is one of the most common and bothersome symptoms of rhinitis in both children and adults. Congestion is associated with sleep-disordered breathing and is thought to be a key cause of sleep impairment in rhinitis. The end result is decrease in quality of life and productivity and increased daytime sleepiness. Treatment with intranasal corticosteroids has been shown to reduce nasal congestion. Data on sleep-related endpoints from clinical trials of intranasal corticosteroids indicate that this reduction is associated with improved sleep, reduced daytime fatigue, and improved quality of life. Other therapies, such as montelukast, also have a positive influence on congestion and sleep, while still other therapies for rhinitis do not affect either symptom. This review examines nasal congestion and the associated sleep impairment with allergic rhinitis. It explores the adverse effects of disturbed sleep on patients' quality of life and how these disturbances can be reduced by therapies that address nasal congestion. PMID- 21316271 TI - The burden of symptoms predicts early retirement: a twin cohort study on fibromyalgia-associated symptoms. AB - OBJECTIVE: To assess whether symptoms of fibromyalgia (FM) predict disability retirement or mortality. METHODS: All Finnish Twin Cohort members and diagnosed FM-patients who had answered the same health questionnaire in 1990-1992 were studied. A sample of 10,608 working aged individuals of the cohort was classified in homogenous groups based on symptom profile with latent class analysis, using a battery of questions addressing FM-associated symptoms validated between FM patients and twins. This resulted in three classes: no or few symptoms (LC1), some symptoms (LC2), and high load of FM-symptoms (LC3). In a 14-year follow-up, 1990-2004, information on disability retirement was obtained from official pension registers. Further linkage with Population Register Centre data for 1990 2009 yielded information on the vital status of the cohort subjects. Those with malignancies or inflammatory rheumatic diseases were excluded. RESULTS: Cumulative incidence of early disability retirement was 9.5% among all 8448 individuals (after exclusions), and 26% in LC3. Adjusted hrs for early retirement were 1.0 (reference class) in LC1, 1.5 (95%CI 1.2-1.7) in LC2, and 2.9 (2.4-3.6) in LC3 for all causes and 1.8 (1.4-2.5) in LC2 and 5.0 (3.6-6.9) in LC3 for musculoskeletal disorders. In 173,675 person-years, the high symptom class (LC3) had a 43% (95% CI 17-75%) increased overall mortality risk, which was fully accounted for by adjustment for lifestyle factors, mainly smoking. CONCLUSION: Symptoms associated with FM strongly correlate with early disability retirement. Lifestyle problems associated with high symptom load need prompt management to avoid increased risk of mortality. PMID- 21316272 TI - Representation of dynamic mechanical allodynia in the ventral medial prefrontal cortex of trigeminal neuropathic rats. AB - Trigeminal neuropathic pain is due to lesion or dysfunction of the nervous system. Dynamic mechanical allodynia is a widespread symptom of neuropathic pain for which mechanisms are still poorly understood. Recent studies demonstrate that forebrain neurons, including neurons in the medial prefrontal cortex (mPFC) are important for the perception of acute and chronic pain. Using the phosphorylation of the extracellular-signal regulated kinase (pERK-1/2) as an anatomical marker of neuronal activation, the present study investigated how dynamic mechanical allodynia is processed in the rat ventral mPFC (prelimbic and infralimbic cortex) after chronic constriction injury to the infraorbital nerve (IoN-CCI). Two weeks after unilateral IoN-CCI, rats showed a dramatic bilateral trigeminal dynamic mechanical allodynia. Light, moving stroking of the infraorbital skin resulted in strong, bilateral upregulation of pERK-1/2 in the ventral mPFC of IoN-CCI animals. pERK-1/2 was located in neuronal cells only. Stimulus-evoked pERK-1/2 immunopositive cell bodies displayed a rostrocaudal gradient and layer-selective distribution in the ventral mPFC, being predominant in the rostral ventral mPFC and in layers II-III and V-VI of the ventral mPFC. In layers II-III, intense pERK 1/2 also extended into distal dendrites, up to layer I. These results demonstrate that trigeminal nerve injury induces a significant alteration in the ventral mPFC processing of tactile stimuli and suggest that ERK phosphorylation contributes to the mechanisms underlying abnormal pain perception under this condition. PMID- 21316273 TI - The menacing phantom: what pulls the trigger? AB - Phantom phenomena are frequent following amputation, but how this often painful experience is modified or triggered by spontaneous events or sensations often puzzles amputees and clinicians alike. We explored triggers of phantom phenomena in a heterogeneous sample of 264 upper and lower limb adult amputees with phantom sensations. Participants completed a structured questionnaire to determine the prevalence and nature of the triggers of phantom phenomena. The four categories of triggers identified include: (a) a quarter of participants experiencing psychological, emotional or autonomic triggers; (b) half experiencing behavioral triggers, "forgetting" the limb's absence and attempting to use the phantom; (c) one-fifth experiencing weather-induced triggers; and (d) one-third experiencing sensations referred from parts of the body. Upper limb amputees; and were more likely to experience weather-induced phantom phenomena than lower limb amputees; and upper and lower limb amputees were equally likely to experience referred sensations from the genitals, contradicting the homuncular remapping hypothesis. Traumatic amputees were more likely to report emotional triggers. Further, while those with emotional triggers exhibited poorer acceptance of the limitations of amputation, they were more likely to employ adaptive coping mechanisms. Finally, habitual "forgetting" behaviors were most common soon after amputation, whereas other more adaptive schemata (e.g., self-defense) were equally likely to be performed at any time following amputation. Various likely inter-related mechanisms are discussed in relation to phantom triggers. Ultimately, optimizing stump and neuroma management, as well as restoring function of central networks for pain, limb movement, and amputation-related memories, should help manage spontaneously triggered phantom phenomena. PMID- 21316274 TI - Fast and accurate algorithm for the simulation of NMR spectra of large spin systems. AB - The computational cost for the simulation of NMR spectra grows exponentially with the number of nuclei. Today, the memory available to store the Hamiltonian limits the size of the system that can be studied. Modern computers enable to tackle systems containing up to 13 spins [1], which obviously does not allow to study most molecules of interest in research. This issue can be addressed by identifying groups of spins or fragments that are not or only weakly interacting together, i.e., that only share weakly coupled spin pairs. Such a fragmentation is only permitted in the weak coupling regime, i.e., when the coupling interaction is weak compared to the difference in chemical shift of the coupled spins. Here, we propose a procedure that removes weak coupling interactions in order to split the spin system efficiently and to correct a posteriori for the effect of the neglected couplings. This approach yields accurate spectra when the adequate interactions are removed, i.e., between spins only involved in weak coupling interactions, but fails otherwise. As a result, the computational time for the simulation of 1D spectra grows linearly with the size of the spin system. PMID- 21316275 TI - A general assignment method for oriented sample (OS) solid-state NMR of proteins based on the correlation of resonances through heteronuclear dipolar couplings in samples aligned parallel and perpendicular to the magnetic field. AB - A general method for assigning oriented sample (OS) solid-state NMR spectra of proteins is demonstrated. In principle, this method requires only a single sample of a uniformly 15N-labeled membrane protein in magnetically aligned bilayers, and a previously assigned isotropic chemical shift spectrum obtained either from solution NMR on micelle or isotropic bicelle samples or from magic angle spinning (MAS) solid-state NMR on unoriented proteoliposomes. The sequential isotropic resonance assignments are transferred to the OS solid-state NMR spectra of aligned samples by correlating signals from the same residue observed in protein containing bilayers aligned with their normals parallel and perpendicular to the magnetic field. The underlying principle is that the resonances from the same residue have heteronuclear dipolar couplings that differ by exactly a factor of two between parallel and perpendicular alignments. The method is demonstrated on the membrane-bound form of Pf1 coat protein in phospholipid bilayers, whose assignments have been previously made using an earlier generation of methods that relied on the preparation of many selectively labeled (by residue type) samples. The new method provides the correct resonance assignments using only a single uniformly 15N-labeled sample, two solid-state NMR spectra, and a previously assigned isotropic spectrum. Significantly, this approach is equally applicable to residues in alpha helices, beta sheets, loops, and any other elements of tertiary structure. Moreover, the strategy bridges between OS solid-state NMR of aligned samples and solution NMR or MAS solid-state NMR of unoriented samples. In combination with the development of complementary experimental methods, it provides a step towards unifying these apparently different NMR approaches. PMID- 21316276 TI - Compressed sensing and the reconstruction of ultrafast 2D NMR data: Principles and biomolecular applications. AB - A topic of active investigation in 2D NMR relates to the minimum number of scans required for acquiring this kind of spectra, particularly when these are dictated by sampling rather than by sensitivity considerations. Reductions in this minimum number of scans have been achieved by departing from the regular sampling used to monitor the indirect domain, and relying instead on non-uniform sampling and iterative reconstruction algorithms. Alternatively, so-called "ultrafast" methods can compress the minimum number of scans involved in 2D NMR all the way to a minimum number of one, by spatially encoding the indirect domain information and subsequently recovering it via oscillating field gradients. Given ultrafast NMR's simultaneous recording of the indirect- and direct-domain data, this experiment couples the spectral constraints of these orthogonal domains - often calling for the use of strong acquisition gradients and large filter widths to fulfill the desired bandwidth and resolution demands along all spectral dimensions. This study discusses a way to alleviate these demands, and thereby enhance the method's performance and applicability, by combining spatial encoding with iterative reconstruction approaches. Examples of these new principles are given based on the compressed-sensed reconstruction of biomolecular 2D HSQC ultrafast NMR data, an approach that we show enables a decrease of the gradient strengths demanded in this type of experiments by up to 80%. PMID- 21316277 TI - Exact solution of the CPMG pulse sequence with phase variation down the echo train: application to R2 measurements. AB - An implicit exact algebraic solution of CPMG experiments is presented and applied to fit experiments. Approximate solutions are also employed to explore oscillations and effective decay rates of CPMG experiments. The simplest algebraic approximate solution has illustrated that measured intensities will oscillate in the conventional CPMG experiments and that using even echoes can suppress errors of measurements of R2 due to the imperfection of high-power pulses. To deal with low-power pulses with finite width, we adapt the effective field to calculate oscillations. An optimization model with the effective field approximation and dimensionless variables is proposed to quantify oscillations of measured intensities of CPMG experiments of different phases of the pi pulses. We show, as was known using other methods, that repeating one group of four pulses with different phases in CPMG experiments, which we call phase variation, but others call phase alternation or phase cycling, can significantly smooth the dependence of measured intensities on frequency offset in the range of +/ 1/2gammaB1. In this paper, a second-order expression with respect to the ratio of frequency offset to pi-pulse amplitude is developed to describe the effective R2 of CPMG experiments when using a group phase variation scheme. Experiments demonstrate that (1) the exact calculation of CPMG experiments can remarkably eliminate systematic errors in measured R2s due to the effects of frequency offset, even in the absence of phase variation; (2) CPMG experiments with group phase variation can substantially remove oscillations and effects of the field inhomogeneity; (3) the second-order expression of the effective decay rate with phase variation is able to provide reliable estimates of R2 when offsets are roughly within +/-1/2gammaB1; and, most significantly, (4) the more sophisticated optimization model using an exact solution of the discretized CPMG experiment extends, to +/-gammaB1, the range of offsets for which reliable estimates of R2 can be obtained when using the preferred phase variation scheme. PMID- 21316278 TI - Inhomogeneity-free heteronuclear iMQC. AB - Intermolecular dipolar interactions between proton and carbon spins can be used to indirectly detect carbon spectra with high sensitivity. In this communication, we present a modified sequence that, in addition to the high sensitivity of heteronuclear intermolecular multiple quantum coherence (iMQC) experiments, retains the line narrowing capability characteristic of homonuclear zero-quantum coherences. We demonstrate that this sequence can be used to obtain high resolution (13)C spectra in the presence of magnetic field inhomogeneities, both for thermal and hyperpolarized samples, and discuss applications to water hyperpolarized carbon imaging. PMID- 21316279 TI - Radio frequency assisted homonuclear recoupling - a Floquet description of homonuclear recoupling via surrounding heteronuclei in fully protonated to fully deuterated systems. AB - We present a Floquet theory approach for the analysis of homonuclear recoupling assisted by radio frequency (RF) irradiation of surrounding heteronuclear spins. This description covers a broad range of systems from fully protonated to deuterated proteins, focusing in detail on recoupling via protons and deuterons separately as well as simultaneously by the double nucleus enhanced recoupling (DONER) scheme. The theoretical description, supported by numerical simulations and compared to experimental results from a partially deuterated model compound, indicates that in perdeuterated systems setting the RF amplitude equal to the magic angle spinning (MAS) frequency is not necessarily optimal for recoupling via (1)H and/or (2)H nuclei and modified recoupling conditions are identified. PMID- 21316280 TI - Application of double spin echo spiral chemical shift imaging to rapid metabolic mapping of hyperpolarized [1-13C]-pyruvate. AB - Undersampled spiral CSI (spCSI) using a free induction decay (FID) acquisition allows sub-second metabolic imaging of hyperpolarized 13C. Phase correction of the FID acquisition can be difficult, especially with contributions from aliased out-of-phase peaks. This work extends the spCSI sequence by incorporating double spin echo radiofrequency (RF) pulses to eliminate the need for phase correction and obtain high quality spectra in magnitude mode. The sequence also provides an added benefit of attenuating signal from flowing spins, which can otherwise contaminate signal in the organ of interest. The refocusing pulses can potentially lead to a loss of hyperpolarized magnetization in dynamic imaging due to flow of spins through the fringe field of the RF coil, where the refocusing pulses fail to provide complete refocusing. Care must be taken for dynamic imaging to ensure that the spins remain within the B1-homogeneous sensitive volume of the RF coil. PMID- 21316281 TI - Construction and performance of an NMR tube with a sample cavity formed within magnetic susceptibility-matched glass. AB - We describe the construction and performance of an NMR tube with a magnetic susceptibility matched sample cavity that confines the solution within the detection zone in the axial direction and in a quasi-rectangular region in the radial direction. The slot-like sample cavity provides both good sample volume efficiency and tolerance to sensitivity loss in the sample space. The signal-to noise ratio per unit volume of the constructed tube was 2.2 times higher than that of a cylindrical tube of 5mm outer diameter with a sample containing 300 mM NaCl at a static magnetic field of 14.1T. Even the overall signal-to-noise ratio of the slot tube was 35% higher than that of the conventional 5mm tube for a sample containing 300 mM NaCl. Similar improvements over existing sample tube geometries were obtained at 950 MHz. Moreover the temperature rise resulting from RF heating was found to be significantly lower for the slot tube even when compared to 3 and 4mm outer diameter cylindrical tubes as measured in a 5mm cryoprobe. A further advantage of this type of tube is that a sample cavity of any desired size and shape can be formed within a cylindrical tube for use in a single cryogenic probe. PMID- 21316282 TI - Pediatric Metarrhizium anisopliae keratitis. AB - Metarrhizium anisopliae (M. anisopliae) is an entomopathogenic fungus used as an agricultural pesticide in many countries, including the United States. M. anisopliae grows optimally at 25 degrees C and is therefore considered safe to humans. We report a case of a 12-year-old girl who is a soft contact lens wearer with M. anisopliae corneal ulcer who was treated effectively with topical natamycin after identification of the organism by corneal culture. Topical amphotericin B was not effective. PMID- 21316283 TI - [Confined placental mosaicisms a priori from meiotic origin: analysis of 10 cases]. AB - This retrospective monocenter study focused on confined placental mosaicisms a priori from meiotic origin (i.e. non-mosaic type 3 confined placental mosaicisms). From a series of 14,967 chorionic villus samplings performed in our Fetal Medicine Center, 10 non-mosaic type 3 confined placental mosaicisms were identified. These abnormalities only involved chromosomes 15, 16 or 22. Pregnancies complicated by these confined placental mosaicisms were associated with prematurity and neonatal hypotrophy. Thus, when a confined placental mosaicism is suspected, this retrospective study highlighted the need to characterize the type of confined placental mosaicism to prevent the probable intra-uterine growth retardation and to adapt the obstetrical monitoring if necessary. PMID- 21316284 TI - [Outcome of elective single or double embryo transfer in first and second IVF/ICSI cycles]. AB - BACKGROUND: The aim of the study is to compare the incidence of eSET (elective single embryo transfer) and DET (double embryo transfer) and their results about live birth and twin pregnancies between first and second IVF/ICSI cycles, in a selective population. These data allow analysing whether the extension of elective single embryo transfer in the second cycle is efficient. PATIENTS AND METHODS: Retrospective study about embryo transfers performed in first and second IVF/ICSI cycles in the IVF unity (CHU Clermont-Ferrand) between 1 January 2004 and 31 December 2006. Women belonging to couples considered have less than 36 years. On the second day of embryo development, at least two good quality embryos have been observed. After information about eSET and DET, couples give their written consent to the transfer of one or two embryos. Couples who have no live birth at the end of the first cycle have been followed up for the second cycle whether they correspond to the inclusions criteria. Analysis is performed with live birth rates by tentative (overall rate) and after one or two embryo transfer, cumulative live birth rate (including fresh and frozen embryo transfer, and twin pregnancy rate. RESULTS: An embryo transfer at the first IVF/ICSI cycle (report eSET/DET=0.5) has been performed for 513 patients. The overall cumulative live birth rate is 37.1%, without significant difference between eSET and DET (36.2% vs 35.7%, p=ns). The twin pregnancies rate is 12% (including 0% in eSET vs 24% in DET, p<0001). Two hundred and five patients have a second IVF/ICSI cycle (92.3% in DET and 7.7% in eSET). The overall cumulative live birth rate is 34.1% without difference between eSET and DET (31.3% vs 34.3%). The twin pregnancies rate is 22.5% and it is significantly higher compared with the first attempt (including 0% in ESET and 24.6% in DET). DISCUSSION AND CONCLUSION: The increased twin pregnancies rate during the second cycle is explained by the higher rate of DET. This may be explained by the non-acceptance by couples of a new eSET, despite acceptable results for live birth rate. We have to search for solutions to encourage its development like the reimbursement of more cycles when eSET is performed, or with regulations as in Belgium, because the information to the couples is not efficient. PMID- 21316285 TI - [How I do... The Lefort colpocleisis procedure?]. PMID- 21316286 TI - Therapeutic ultrasound an overview. AB - Therapeutic ultrasound is defined as the use of ultrasound for the treatment of diseased or injured organs or bodily structures and is quite distinct from diagnostic ultrasound. There were many early attempts in the past to use ultrasound in therapy for a variety of applications and while some of these have not been pursued others have led on to clinical applications which are now used routinely. Such progress has been made possible by a number of factors including advances in transducer design, more accurate measurement and calibration of acoustic power and careful experiments to determine the precise nature of chemical processes taking place during and following the exposure of tissue to ultrasound. Major advances have been made in some fields where ultrasound is used such as physiotherapy, surgical instruments, chemotherapy, drug delivery and more recently, high intensity focused ultrasound (HIFU). The last of these has seen enormous activity leading to the formation of the International Society of Therapeutic Ultrasound and a number of very well attended regular specialist meetings. In this review some historical perspectives of therapeutic ultrasound and progress in the field since the early 1990's will be presented. PMID- 21316287 TI - A novel and convenient synthesis of 4-hydroxy-6-methyl-3-(1-(phenylimino) ethyl) 2H-pyran-2-one derivatives under ultrasound irradiation. AB - A facile, efficient and environment-friendly protocol for the synthesis of 4 hydroxy-6-methyl-3-(1-(phenylimino)ethyl)-2H-pyran-2-one derivatives has been developed by the convenient ultrasound-mediated condensation of amine with dehydroacetic acid. This method provides several advantages over current reaction methodologies including a simple work-up procedure, shorter reaction times and higher yields. PMID- 21316288 TI - The role of vapour pressure in multibubble sonoluminescence from organic solvents. AB - The action of high intensity cavitation on several liquid halocarbons (C(2)Cl(4) CCl(4), CHCl(3), C(2)H(2)Br(4)) and other organic solvents (acetone, benzene and their mixtures) was investigated by recording multibubble sonoluminescence UV-Vis spectra over the temperature range between 246 and 298 K. The temperature induced variation of some thermophysical properties of the solvents Favours the interpretations of their role in determining the salient characteristics of the recorded spectra. We observed that high volatility does not necessarily quench sonoluminescence emission and that argon flow plays a key role in the appearance of radical emission lines. While for each investigated substance the intensity of C*(2) emission lines was clearly correlated to temperature, a comparative test between different halocarbons did not show a clear correlation with vapour pressure. Following recently reported results which evidenced the formation of dynamically differentiated populations of emitting bubbles in sulphuric acid, we performed MBSL experiments in liquid mixtures of halocarbons and sulphuric acid to investigate the correlation between the production of emitting species and the halocarbon volatility. PMID- 21316289 TI - Low resource processing algorithms for laser Doppler blood flow imaging. AB - The emergence of full field laser Doppler blood flow imaging systems based on CMOS camera technology means that a large amount of data from each pixel in the image needs to be processed rapidly and system resources need to be used efficiently. Conventional processing algorithms that are utilized in single point or scanning systems are therefore not an ideal solution as they will consume too much system resource. Two processing algorithms that address this problem are described and efficiently implemented in a field programmable gate array. The algorithms are simple enough to use low system resource but effective enough to produce accurate flow measurements. This enables the processing unit to be integrated entirely in an embedded system, such as in an application-specific integrated circuit. The first algorithm uses a short Fourier transformation length (typically 8) but averages the output multiple times (typically 128). The second method utilizes an infinite impulse response filter with a low number of filter coefficients that operates in the time domain and has a frequency-weighted response. The algorithms compare favorably with the reference standard 1024 point fast Fourier transform in terms of both resource usage and accuracy. The number of data words per pixel that need to be stored for the algorithms is 1024 for the reference standard, 8 for the short length Fourier transform algorithm and 5 for the algorithm based on the infinite impulse response filter. Compared to the reference standard the error in the flow calculation is 1.3% for the short length Fourier transform algorithm and 0.7% for the algorithm based on the infinite impulse response filter. PMID- 21316290 TI - Impairment of motor cortex plasticity in Parkinson's disease, as revealed by theta-burst-transcranial magnetic stimulation and transcranial random noise stimulation. PMID- 21316291 TI - Autopsy-confirmed, co-existent CADASIL and multiple system atrophy. PMID- 21316292 TI - Cognitive outcome and reliable change indices two years following bilateral subthalamic nucleus deep brain stimulation. AB - Subthalamic nucleus deep brain stimulation (STN-DBS) is currently the treatment of choice for medication-resistant levodopa-related motor complications in patients with Parkinson's disease (PD). While STN-DBS often results in meaningful motor improvements, consensus regarding long-term neuropsychological outcome continues to be debated. We assessed the cognitive outcomes of 19 STN-DBS patients compared to a group of 18 medically-managed PD patients on a comprehensive neuropsychological battery at baseline and two years post-surgery. Patients did not demonstrate changes in global cognitive functioning on screening measures. However, neuropsychological results revealed impairments in nonverbal recall, oral information processing speed, and lexical and semantic fluency in STN-DBS patients compared to PD controls 2 years post-surgery in these preliminary analyses. Additionally, reliable change indices revealed that approximately 50% of STN-DBS patients demonstrated significant declines in nonverbal memory and oral information processing speed compared to 25-30% of PD controls, and 26% of STN-DBS patients declined on lexical fluency compared to 11% of PD patients. Approximately 30% of both groups declined on semantic fluency. The number of STN-DBS patients who converted to dementia 2 years following surgery was not significantly different from the PD participants (32% versus 16%, respectively). Our results suggest that neuropsychological evaluations may identify possible mild cognitive changes following surgery. PMID- 21316293 TI - Social determinants of state variation in special education participation among preschoolers with developmental delays and disabilities. AB - Children with developmental disabilities are at risk for secondary complications and lower academic performance, which contributes to lower health and well-being and may be ameliorated by access to special education services. This paper examines state variability in preschool special education participation among a United States population-based cohort with parent-reported developmental delays and disabilities. Analyses explore the extent to which observed variability can be explained by state socio-economic attributes and special education policy and funding. Rates of special education varied significantly across states and were highest in states with least income inequality and lowest in states with most income inequality. Place variation in preschool special education participation stems, in part, from child characteristics, but to a larger extent, from state socio-economic attributes. PMID- 21316294 TI - A novel, dynamic, in vivo, non-contact method of measuring oxygen depletion rate of the anterior eye. AB - PURPOSE: Despite the importance of oxygen measurements, techniques have been limited by their invasive nature and small corneal area of assessment. The aim of this study was to assess a non-contact way of measuring oxygen uptake of the whole anterior eye. METHOD: The device consisted of a goggle with an oxygen sensitive material on the inner surface. As the output is affected by temperature, a second probe was inserted into the goggle to compensate. The goggle was positioned over the eye on 10 subjects (mean age 30.5+/-5.0 years, 3:2 male:female) to assess the oxygen depletion of the unrestricted, blinking eye. Measurements were taken over a 3 min period. The volume contained within the goggle and bone structure of individual eyes was measured by water volume displacement and the output corrected to O(2)% reduction/cm(3) over a 30s period. To check the discriminatory ability of the device, measurements were taken in open-eye and closed-eye conditions, along with on the subjects' skin (cheek) for comparisons. RESULTS: The oxygen depletion measure over 30s was on average 3.10+/ 1.51 O(2)%cm(3) during open eye condition, significantly more than during closed eye conditions (1.26+/-1.52 O(2)%cm(3)). The skin (control) showed a negligible oxygen uptake (0.19+/-0.33 O(2)%cm(3)). The results demonstrated good repeatability with a mean standard deviation of around 0.4 O(2)%cm(3) (equating to 11%). CONCLUSIONS: The technique demonstrated a non-invasive, non-contact method of measuring consumption of oxygen within the goggle (oxygen depletion rate) and showed good within-visit repeatability. PMID- 21316295 TI - Recurrent erosion syndrome--the patient's perspective. AB - AIM: The purpose of this study was to investigate the symptomatic effect of bandage contact lens (BCL) wear along with regular lubrication for the treatment of recurrent erosion syndrome (RES) resistant to simple measures alone (lubrication, artificial tears, or ointment). A patient satisfaction questionnaire assessed the longer term impact on RES symptoms and recurrence rate following the period of BCL wear. METHOD: A retrospective case note review of all patients presenting with RES to a regional Ophthalmology department and referred for therapeutic BCL fitting over a one year period. An audit of 50 clinical records was performed and a patient satisfaction questionnaire survey completed before, during and following treatment. RESULT: Thirty four patients responded to a satisfaction questionnaire which was sent to the fifty patients identified with RES. These patients were identified over a one-year period and all had been treated with BCLs. The predominant RES symptoms were pain (n=31), photosensitivity (n=5) and reduced vision (n=4). The majority of patients (n=30) felt that RES significantly affected their professional or social life. The average duration of BCL wear for RES was 6 months (range 2-15 months). On completion of treatment 79% (27/34) of patients felt that overall there had been some improvement in their RES symptoms, and 13 of these patients defined this improvement as being "cured". CONCLUSION: Overall we found that RES patients were satisfied that BCL wear was beneficial in relieving their RES symptoms. The predominant symptom of RES was ocular pain. No patient developed a sight threatening complication secondary to BCL wear. PMID- 21316296 TI - Give children and adolescents the gift of a good night's sleep: a call to action. PMID- 21316297 TI - Fragmentary myoclonus in sleep revisited: a polysomnographic study in 62 patients. AB - STUDY OBJECTIVES: To investigate the frequency of fragmentary myoclonus (FM) in a sleep-disorder population, to analyze its distribution across sleep stages and to examine potential associations with clinical correlates and night-to-night variability. DESIGN: Retrospective review of 102 polysomnographic records. SETTING: Sleep laboratory at a University Hospital Neurology Department. PATIENTS: Sixty-two sleep-disorder patients. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Fragmentary myoclonus (FM) was counted according to published criteria. Sleep stage specific FM indices (FMI) were calculated for each patient. Median FMI was 39.5/h sleep. FMI was the highest in REM sleep, followed by similar indices in wakefulness, S1 and S2 sleep, and was the lowest in S3/S4 sleep (n.s.). FMI increased with age (rho=0.350, P=0.005). Men had a higher FMI than women (median 55.8/h vs. 24.1/h, P=0.042). In addition, FMI was positively correlated with the presence of sleep-related breathing disorders (rho=0.270, P=0.036), respiratory indices (apnea-hypopnea index: rho=0.403, P=0.002; oxygen desaturation index: rho=0.378, P=0.004) and body mass index (rho=0.28, P=0.028). In a linear regression model, age, male sex and oxygen desaturation index were significant (P<0.05). FMI night-to-night variability was 1.6 (range: 1.0-3.9). CONCLUSION: Fragmentary myoclonus was present in every patient of this sleep disorder population. Its clinical significance is unknown, but the association with oxygen desaturation index points to an association with sleep-related breathing disorders. Since FMI was similar during wakefulness and light sleep, these data challenge the concept of a primarily sleep-related phenomenon. PMID- 21316298 TI - Obstructive sleep apnea in shift workers. AB - OBJECTIVE: In modern society, the number of people working night shifts is increasing. The aim of the study was to investigate effects of shift work on obstructive sleep apnea syndrome (OSAS) and oxygen desaturation index (ODI) during daytime and nighttime sleep in patients with OSAS. METHODS: Twenty-nine male and two female shift workers (SW) with OSAS were investigated. Their mean age was 47+/-10years, BMI 32+/-4kg/m(2). The control group consisted of 10 male patients with OSAS, matched for age, BMI, and hours of night sleep, not working on shifts. Nocturnal and diurnal after night shift or sleep deprivation polysomnographies (PSG) were performed in all subjects. RESULTS: Comparison of diurnal and nocturnal PSG recordings in the SW group demonstrated a significantly higher AHI in diurnal PSG after the night shift vs. nocturnal PSG (50+/-27 vs. 32+/-22, P<0.05). During daytime sleep SW OSAS patients demonstrated higher AHI than sleep-deprived controls (49.7+/-26.6 vs. 30.1+/-21.9, P<0.05) and higher ODI (44.1+/-25.1 vs. 21.6+/-18.5, P<0.05). CONCLUSIONS: Significantly higher severity of OSAS during daytime sleep after night shift may intensify unfavorable health effects of OSAS. Patients with OSAS if not effectively treated should avoid nighttime work. PMID- 21316299 TI - Validation in the context of commercialization: the white rabbit effect. PMID- 21316300 TI - Correlates of adolescent sleep time and variability in sleep time: the role of individual and health related characteristics. AB - OBJECTIVES: Adolescents are predisposed to short sleep duration and irregular sleep patterns due to certain host characteristics (e.g., age, pubertal status, gender, ethnicity, socioeconomic class, and neighborhood distress) and health related variables (e.g., ADHD, asthma, birth weight, and BMI). The aim of the current study was to investigate the relationship between such variables and actigraphic measures of sleep duration and variability. METHOD: Cross-sectional study of 247 adolescents (48.5% female, 54.3% ethnic minority, mean age of 13.7years) involved in a larger community-based cohort study. RESULTS: Significant univariate predictors of sleep duration included gender, minority ethnicity, neighborhood distress, parent income, and BMI. In multivariate models, gender, minority status, and BMI were significantly associated with sleep duration (all p<.05), with girls, non-minority adolescents, and those of a lower BMI obtaining more sleep. Univariate models demonstrated that age, minority ethnicity, neighborhood distress, parent education, parent income, pubertal status, and BMI were significantly related to variability in total sleep time. In the multivariate model, age, minority status, and BMI were significantly related to variability in total sleep time (all p<.05), with younger adolescents, non minority adolescents, and those of a lower BMI obtaining more regular sleep. CONCLUSIONS: These data show differences in sleep patterns in population sub groups of adolescents which may be important in understanding pediatric health risk profiles. Sub-groups that may particularly benefit from interventions aimed at improving sleep patterns include boys, overweight, and minority adolescents. PMID- 21316301 TI - Tyrosine phosphorylation of actin during microcyst formation and germination in Polysphondylium pallidum. AB - High osmolarity causes amoebae of the cellular slime mould Polysphondylium pallidum to individually encyst, forming microcysts. During microcyst differentiation, actin is tyrosine phosphorylated. Tyrosine phosphorylation of actin is independent of encystment conditions and occurs during the final stages of microcyst formation. During microcyst germination, actin undergoes dephosphorylation prior to amoebal emergence. Renewed phosphorylation of actin in germinating microcysts can be triggered by increasing the osmolarity of the medium which inhibits emergence. Immunofluorescence reveals that actin is dispersed throughout the cytoplasm in dormant microcysts. Following the onset of germination, actin is observed around vesicles where it co-localizes with phosphotyrosine. Prior to emergence, actin localizes to patches near the cell surface. Increasing osmolarity disrupts this localization and causes actin to redistribute throughout the cytoplasm, a situation similar to that observed in dormant microcysts. The tyrosine phosphorylation state of actin does not appear to influence the long-term viability of dormant microcysts. Together, these results indicate an association between actin tyrosine phosphorylation, organization of the actin cytoskeleton, and microcyst dormancy. PMID- 21316302 TI - An assessment of potential public health risk associated with the extended survival of indicator and pathogenic bacteria in freshwater lake sediments. AB - Microcosm studies were performed to evaluate the survival of Escherichia coli, Salmonella paratyphi and Vibrio parahaemolyticus in water and sediment collected from the freshwater region of Vembanad Lake (9'35 degrees N 76'25 degrees E) along the south west coast of India. All three test microorganisms showed significantly (p < 0.01) higher survival in sediment compared to overlying water. The survival in different sediment types with different particle size and organic carbon content revealed that sediment with small particle size and high organic carbon content could enhance their extended survival (p < 0.05). The results indicate that sediments of the Lake could act as a reservoir of pathogenic bacteria and exhibit a potential health hazard from possible resuspension and subsequent ingestion during recreational activities. Therefore, the assessment of bacterial concentration in freshwater Lake sediments used for contact and non contact recreation has of considerable significance for the proper assessment of microbial pollution of the overlying water, and for the management and protection of related health risk at specific recreational sites. Besides, assessment of the bacterial concentration in sediments can be used as a relatively stable indicator of long term mean bacterial concentration in the water column above. PMID- 21316303 TI - Bacterial colonization patterns in neonates transferred from neonatal intensive care units. AB - After an outbreak with Enterobacter cloacae we decided to routinely nurse all neonates in isolation who were transferred from a neonatal intensive care unit (NICU) to the neonatal unit of the Diakonessenhuis until cultures for MRSA and antibiotic-resistant gram-negative bacteria were negative. The goal of this study was to determine (1) the colonization patterns with (antibiotic-resistant) bacteria; (2) whether there is a trend in time and (3) to identify predictors for colonization. Neonates from 2001 till 2006 transferred from a NICU to our neonatal unit were included. Patients were monitored for infections. In total 287 neonates were included. The average birth weight was 1990 g and gestational age 33 weeks and 3 days. Only one patient was colonized with a highly resistant microorganism (HRMO) and no MRSA was isolated. A NICU-stay longer than one week was the only independent risk factor for bacterial colonization. Twenty-six percent of neonates were colonized with bacteria resistant to amoxicillin/clavulanate. Five neonates (1.7%) developed a bacterial infection after transfer, none of them caused by an antibiotic-resistant microorganism present at transfer. No significant trends in time were found. In conclusion, we found a low prevalence of HRMO and a low incidence of bacterial infections in neonates after transfer from a NICU. There was no significant increase in time in the prevalence of colonization with (resistant) bacteria. A NICU-stay longer than a week was an independent predictor for colonization with bacteria. Based on these observations we have ended standard culturing and nursing in isolation of these patients. PMID- 21316304 TI - Tissue Doppler Em and instantaneous end-diastolic stiffness: validation against pressure-volume loops in patients undergoing coronary artery bypass surgery. AB - The assessment of diastolic function using trans-mitral Doppler and tissue Doppler imaging during coronary artery bypass surgery (CABG) is complex, with anaesthesia, blood loss and ischaemia all contributing to altered loading conditions. Ten patients undergoing coronary artery bypass grafting underwent simultaneous transoesophageal and pressure volume loop analysis of diastolic function at different loading conditions (baseline, preload reduction, afterload increase, increased heart rate and post cardiopulmonary bypass). The mean age was 59+/-9 years and 3 (range 2-5) grafts. Altered loading conditions resulted in no significant changes in Tau or the end diastolic pressure volume relationship. dP/dtmin varied significantly across loading conditions (p<0.001). Tissue Doppler peak Em measured at the lateral mitral annulus was affected significantly with increased heart rate (p<0.01), but was insensitive to changes in preload and afterload. Instantaneous end diastolic stiffness (IEDS=log(10)PCWP/EDA) did not alter during loading conditions (p=0.99). Peak Em (lateral annulus) and IEDS appear promising as measures of diastolic function over a range of haemodynamic alterations, although changes in Peak Em may not reflect diastolic function accurately if the heart rate substantially changes. PMID- 21316305 TI - A hammock in the left atrium. AB - Shone's anomaly describes a complex involving multiple left sided cardiac obstructions, namely, parachute deformity of the mitral valve, supravalvular ring of the left atrium, subaortic stenosis and aortic coarctation. We are reporting a case of Shone's anomaly characterised by aortic recoarctation, mitral supravalvular membrane, bicuspid aortic valve, complicated complete atrioventricular block and bradycardia-induced nonsustained polymorphic ventricular tachycardia. We revealed mitral supravalvular membrane by 3D transoesophageal echocardiography. PMID- 21316306 TI - Use of complementary medicines by cardiac surgery patients; undisclosed and undetected. AB - BACKGROUND: Some complementary medicines (CMs) confer benefits in people with cardiovascular disease, yet they also pose risks such as drug interactions and haemorrhage. OBJECTIVES: To determine cardiac surgery patients' perioperative use of CMs, disclosure about their use and interest in hospitals providing access to complementary therapies. METHOD: An anonymous survey of 205 elective cardiac surgery inpatients at Cabrini Hospital, Victoria. RESULTS: Of the 161 respondents (78% response rate), 51% took CMs and 92% took prescription medicines in the two weeks before admission. Of those taking CMs, 42% intended to continue this use in hospital. Medical doctors were the main prescribers and 25% of patients were taking fish oils and 25% multivitamins. Use was not significantly associated with gender, education or income. In hospital, the main reason for non-disclosure about CM use was not being asked. Of those asked about their use, 52% reported being asked by a nurse, 12% a surgeon, 12% a pharmacist and 8% an anaesthetist. Most (85%) of the total sample would consider using complementary therapies if offered by hospitals. CONCLUSIONS: CMs are used by cardiac surgery patients but communication with surgeons and anaesthetists is poor. There is substantial patient interest in hospital-based complementary therapies. PMID- 21316307 TI - Genome-wide analysis shows no genomic predictors of ovarian response to stimulation by exogenous FSH for IVF. AB - The current proof of principle study explores the possibility that a genetic single-nucleotide polymorphism (SNP) profile is associated with ovarian response to standardized stimulation for IVF using exogenous FSH. Such a pharmacogenomic approach could aid in rendering ovarian stimulation for IVF more tailored to the patient, potentially improving the delicate balance between efficacy, side effects and chances for complications. Genome-wide association (GWA) analysis using Illumina Human 610-Quad BeadChips was used in a homogeneous group of 102 healthy, Caucasian, regularly cycling, non-smoking women aged 38 years or less with a body mass index <30 kg/m2 with a regular indication for IVF in a tertiary referral University Hospital. Genetic profiles were associated with the number of oocytes obtained. Ovarian response varied widely, ranging from cancellation (less than three follicles) to more than 20 oocytes. After correction for multiple testing, no SNPs were observed to be significantly correlated to ovarian response, embryo quality or pregnancy. Restricting the information to SNPs involved in granulosa cell function, cell cycle regulation or apoptosis also did not yield significant associations for ovarian response. A study in a larger cohort is warranted, aiming to further explore subtle genetic variants with greater power. PMID- 21316308 TI - Assisted reproduction for the validation of gestational age assessment methods. AB - Despite major achievements in medicine, preterm birth (PTB) remains a leading cause of infant morbidity and mortality, worldwide. Research efforts have been devoted towards a better understanding of the multifactorial aetiology of PTB and its subtypes, with the purpose of prevention and control. The availability of valid and reliable gestational age data is a prerequisite for PTB classification. Pregnancies conceived through assisted reproduction treatments provide an opportunity for the exact determination of gestational age using date of delivery and dates of fertilization or implantation. The purpose of this review article is to evaluate the current evidence for or against the various methods that can be applied to measure gestational age, namely the first day of the last menstrual period, ultrasound before 20 weeks of gestation and post-natal assessments, and to propose the use of assisted reproduction treatments populations for further validation of these methods. PMID- 21316309 TI - Metformin modulates IL-8, IL-1beta, ICAM and IGFBP-1 expression in human endometrial stromal cells. AB - To evaluate the effects of metformin on endometrial stromal cell gene expression and on the decidualization process, endometrial biopsies were collected from five healthy, regularly cycling women. Stromal cell culture was performed and decidualized with oestrogen/progesterone in the presence or absence of metformin and thereafter stimulated with insulin. The effect of metformin on decidualization was analysed by prolactin determination in the cell culture supernatant. Gene expression of insulin-like growth factor binding protein 1 (IGFBP-1), interleukin (IL) 8 and 1beta and intercellular adhesion molecule (ICAM) was analysed by real-time PCR. Decidualization was significantly diminished in cells incubated with metformin (P<0.05) accompanied by a significant reduction of prolactin secretion in the supernatant (day 10: 2.2 fold, P<0.05; day 15: 3.1 fold, P<0.05). IGFBP-1 gene expression was reduced after long-term metformin exposure (7.7 fold, P<0.05). The negative effect of insulin on IL-8 (4.8 fold) and IL-1beta (9.3 fold) gene expression was similarly found in cells incubated with metformin. As far as is known, this is the first demonstration of a change in endometrial gene and protein expression after in vitro stimulation with metformin, including a diminished decidualization process and changes in genes relevant to implantation. PMID- 21316310 TI - Patients diagnosed with nonepileptic seizures: their perspectives and experiences. AB - The objective of this qualitative study was to examine how patients with nonepileptic seizures (NES) make sense of their illness experience in light of the many obstacles they may face when seeking treatment. We conducted semistructured interviews with five patients with NES to explore their illness perspectives and different modes of reasoning in regard to their illness and treatment experiences. The data were examined using thematic content analysis. The participants who implicitly incorporated epilepsy as an illness prototype demonstrated less effective treatment expectations and imposed greater life constraints on themselves than the participant who used anxiety attacks. The participants who defined an explanatory model with a psychosocial basis for illness onset were receptive and demanding of psychotherapeutic intervention. Emergent themes included accounts of adverse and positively perceived life events coinciding with illness onset, head injury, presence of caregivers during events, comorbid illness, and previously witnessing epilepsy in others. PMID- 21316311 TI - Combined intensity-modulated radiation therapy vs. three-dimensional highly conformal radiotherapy after (125)I prostate permanent seed brachytherapy: a comparative treatment planning study. AB - PURPOSE: A comparative treatment planning study was conducted to analyze combined intensity-modulated radiation therapy (IMRT) vs. three-dimensional highly conformal radiotherapy (3D-hCRT) after (125)I permanent seed brachytherapy in patients with localized prostate cancer. METHODS AND MATERIALS: We optimized an IMRT and a 3D-hCRT treatment plan to 45Gy in 9 patients 2 months after (125)I seed brachytherapy (110Gy) implant. IMRT and 3D-hCRT were planned using eight and seven nonopposed coplanar fields of 6- and 23-MV. Dose-volume histograms for target volume and organs at risk were compared for both techniques. RESULTS: IMRT provided similar conformality but better homogeneity (p=0.021) than 3D-hCRT plans, despite slightly higher maximal point dose rates (101.9% vs. 100.9%, p=0.050). 3D-hCRT plans required fewer monitor units than did IMRT (289 vs. 607, p=0.008). Dose to bladder, penile bulb, and femoral heads were lower with IMRT than with 3D-hCRT (p=0.008-0.028). No differences were observed for dose to urethra and the entire rectum. Mean dose to rectal wall was lower with IMRT than with 3D-hCRT (25.1 vs. 26.5Gy, p=0.028). CONCLUSION: IMRT plans result in more homogeneous dose distribution and in reduced doses to most organs at risk at the expense of needing more than twice the monitor units compared with 3D-hCRT. PMID- 21316312 TI - Autonomic dysfunction with mutations in the gene that encodes methyl-CpG-binding protein 2: insights into Rett syndrome. AB - Rett syndrome (RTT) is an autism spectrum disorder with an incidence of ~1:10,000 females (reviewed in Bird, 2008; Chahrour et al., 2007; Francke, 2006). Affected individuals are apparently normal at birth. Between 6-18 months of age, however, RTT patients begin to exhibit deceleration of head growth, replacement of purposeful hand movements with stereotypic hand wringing, loss of speech, social withdrawal and other autistic features. RTT is caused by loss of function mutations in the gene that encodes methyl-CpG-binding protein 2 (Mecp2) (Amir et al., 1999), a transcriptional repressor that targets genes essential for neuronal survival, dendritic growth, synaptogenesis, and activity dependent plasticity. MECP2 is X-linked, and males die soon after birth. Included in the RTT phenotype are cardiorespiratory disorders involving the autonomic nervous system. The respiratory disorders, including the roles of bioaminergic and brain derived neurotrophic factor (BDNF) signaling in the respiratory pathophysiology of RTT have been recently reviewed (Bissonnette et al., 2007a; Ogier et al., 2008; Katz et al., 2009). Here we will cover the work on RTT regarding respiration that has appeared since 2009 as well as cardiovascular abnormalities. PMID- 21316313 TI - Acute effects of ganglionated plexi ablation on sinoatrial nodal and atrioventricular nodal functions. AB - Ganglionated plexus (GP) ablation has been shown effective for eliminating atrial fibrillation (AF), the most common clinical tachyarrhythmia. However, the safety of destroying the main cardiac autonomic structures remains unclear. This study investigated the acute effects of GP ablation on the sinoatrial nodal (SAN) and atrioventricular nodal (AVN) functions in a canine model. In 10 open-chest dogs, multiple electrode catheters were sutured at both atria for recording and pacing. SAN and AVN function were evaluated. GP ablation caused no significant change of sinus rate immediately after GP ablation compared with the baseline state. After GP ablation, the sinus node recovery time (SNRT) and corrected SNRT did not show significant changes at long pacing cycle lengths (CLs), and only showed significant decrease at shorter pacing CLs. The AH interval at different pacing CLs, the Wenckebach atrioventricular block (AVB) CL, 2:1 AVB CL or the ventricular rate during AF were not significantly altered by GP ablations. Vagal suppression of SAN and AVN functions was eliminated by GP ablation. GP staining showed abundant choline acetyl transferase or tyrosine hydroxylase positive neurons. These findings suggest the functions of the SAN and AVN are mainly retained after GP ablation. These results may be partially related to destroying both parasympathetic and sympathetic elements in the GP by ablation. PMID- 21316314 TI - Development of an ionic liquid-based ultrasonic-assisted liquid-liquid microextraction method for sensitive determination of biogenic amines: application to the analysis of octopamine, tyramine and phenethylamine in beer samples. AB - A simple and efficient method, ionic liquid-based ultrasound-assisted liquid liquid microextraction, has been developed for the determination of three biogenic amines including octopamine (OCT), tyramine (TYR) and phenethylamine (PHE). Fluorescence probe 2,6-dimethyl-4-quinolinecarboxylic acid N hydroxysuccinimide ester was applied for derivatization of biogenic amines and high-performance liquid chromatography coupled with fluorescence detection was used for the determination of the derivatives. The factors affecting the extraction efficiency, such as the type and volume of ionic liquid, ultrasonication time and centrifugation time have been investigated in detail. Under the optimum conditions, linearity of the method was observed in the range of 0.5-50 MUgmL(-1) for OCT and TYR, and 0.025-2.5 MUgmL(-1) for PHE, respectively, with correlation coefficients (gamma)>0.996. The limits of detection ranged from 0.25-50 ngmL(-1) (S/N=3). The spiked recoveries of three target compounds in beer samples were in the range of 90.2-114%. As a result, this method has been successfully applied for the sensitive determination of OCT, TYR and PHE in beer samples. PMID- 21316315 TI - Secular changes in the height of the inhabitants of Anatolia (Turkey) from the 10th millennium B.C. to the 20th century A.D. AB - We use human-skeleton samples to estimate the height of adults living in Anatolia during the Neolithic period. We also report the results of surveys taken in the 20th century on the height of the Turkish population. Neolithic and the Chalcolithic (5000-3000 B.C.) male heights are estimated as 170.9 cm and 165.0 cm, respectively. Pronounced increases were observed for both sexes between the Chalcolithic and Iron (1000-580 B.C.) periods and sharp decreases among both males and females in the Hellenistic-Roman period (333 B.C. to 395 A.D.). Moreover, recovery to the Iron Age levels was achieved in the Anatolian Medieval period (395-1453 A.D.) for both sexes (169.4 cm for males and 158.0 cm for females). In 1884 the mean height of men was 162.2 cm and by the beginning of the 1930s it increased to 166.3 cm. In the first nationwide survey in 1937 males mean height was 165.3 cm, and females was 152.3 cm, where today current heights are 174.0 cm and 158.9 cm, respectively. PMID- 21316316 TI - [DiGeorge syndrome with mild episodic hypocalcemia]. PMID- 21316317 TI - The role of endoscopic ultrasound in the evaluation of chronic mesenteric ischaemia. AB - INTRODUCTION: Doppler transabdominal ultrasound is a validated screening test for chronic mesenteric ischaemia, but gas and obesity are limitations. Endoscopic ultrasound has been proposed as a comprehensive test to evaluate chronic upper abdominal pain and is capable of Doppler measurement. We aim to evaluate the accuracy of Doppler endoscopic ultrasound (D-EUS) as a single screening test to rule out chronic mesenteric ischaemia in patients with abdominal pain and compare it with Doppler transabdominal ultrasound (D-TUS). METHODS: We enrolled all patients >=50 years with chronic upper abdominal pain and vascular risk referred for endoscopic ultrasound. All were scheduled for D-EUS and D-TUS plus a confirmatory test if one of the previous resulted positive. We estimated the accuracy of both techniques comparing them using McNemar test. RESULTS: 68 patients completed the study. Fifty-three (78%) underwent D-EUS, D-TUS, and a confirmatory test. Fifteen (38%) underwent follow-up after negative results. Three (4%) in the D-EUS group and 14 in the D-TUS (21%) were excluded due to artefacts. D-EUS presented a sensitivity of 63%, specificity of 84%, whilst D-TUS presented a sensitivity of 80% and a specificity of 78%. Specificity of D-EUS was not significantly different to D-TUS. CONCLUSIONS: These results support the role of Doppler endoscopic ultrasound to exclude chronic mesenteric ischaemia as cause of chronic abdominal pain. PMID- 21316318 TI - [Continuous monitoring of a guideline: Bell's palsy]. AB - INTRODUCTION: The preparation and review of child neurology guidelines can reduce the variability of our medical practice, thus improving health care. We present the continuous monitoring of our Bell's palsy guideline. MATERIAL AND METHODS: Emergency and medical reports of the children seen in Child Neurology surgery from July 2006 to August 2009 (group 2) are reviewed for the purpose of finding out the present level of compliance with guideline quality criteria and compare it with the previously reviewed period (group 1, from March 2003 to June 2006). Scientific evidence on this topic is also updated. RESULTS: Comparing the compliance rate in group 1 with group 2 shows a rise in group 2 from 85.1% to 100% in facial expression description, from 11.1% to 31.6% on whether or not there is evidence of Herpes Zoster vesicles, from 77.7% to 84.2% whether or not there is evidence fundoscopic examination, and from 77.7% to 86.8% as regards cranial nerve function remaining normal. The rate of fact sheet issue, recorded for the first time in group 2, is 21.1%. DISCUSSION: Medical auditing allows us to evaluate our medical practice and set up ways for improvement according to the deficiencies found. We insist on striving to improve the written record of the most relevant data and never overlook the importance of issuing the fact sheets to parents and paediatricians, to ensure continuity of medical care. PMID- 21316319 TI - Rapid methods for targeted prenatal diagnosis of common chromosome aneuploidies. AB - Improvements in non-invasive screening methods for trisomy 21 (Down syndrome) and other aneuploidies during the first and second trimester of pregnancy have radically changed the indications for prenatal diagnosis over the last decade. Consequently, there was a need for rapid tests for the detection of common chromosome aneuploidies resulting in the development of molecular methods for the rapid, targeted detection of (an)euploidies of the chromosomes 13, 18, 21 and the sex chromosomes. The analysis of large series of prenatal samples has shown that such tests can detect the great majority of chromosome abnormalities in prenatal diagnosis. This resulted in lively discussions on whether conventional karyotyping should remain the standard method for the majority of prenatal cases or can be replaced by rapid tests only. This review gives an overview of different aspects of the three most common tests for rapid, targeted prenatal detection of (an)euploidies, i.e. interphase fluorescence in-situ hybridisation (iFISH), quantitative fluorescent polymerase chain reaction (QF-PCR) and multiplex ligation-dependent probe amplification (MLPA). PMID- 21316320 TI - Treatment options for cutaneous pyogenic granulomas: a review. AB - Pyogenic granuloma (PG) is a common benign vascular proliferation that commonly occurs on the skin. Various treatment options exist in the literature with no clear consensus. Our objective was to review the literature associated with PGs and their management, and based on recurrence rates, suggest management options. A retrospective literature review examining the treatment of cutaneous PG and their associated recurrence rates was conducted. A total of 34 manuscripts were included in our review; with 1162 PGs managed using 19 different treatment modalities with 53 recurrences observed. Among the surgical management options, surgical excision offers the lowest overall recurrence rates (2.94%). Of the medical treatments, cryotherapy offered the lowest overall recurrence rate (1.62%). We concluded that surgical excision and primary closure should be the treatment of choice for small cutaneous PGs in non-cosmetically sensitive areas; however if non-surgical management is undertaken, cauterization with silver nitrate should be the first line treatment. When comparing recurrence rates of surgical excision vs. cauterization, we found no statistical difference between the two (p-value 0.426). PMID- 21316321 TI - Nostril alar rim threshold flap for columellar reconstruction. AB - The reconstruction of the columella poses a significant challenge to the plastic surgeon. A multitude of techniques have been developed to address this issue; however, the end result is often unsatisfactory or comes at too high a morbid cost. Gillies described an alar margin flap in 1949 that never gained significant popularity. This technique had been refined by Servant over the past two decades in his work on Noma noses in Africa. We describe a two-stage columella reconstruction technique with a nostril alar rim threshold flap and provide the results of our case series. Under local anaesthesia, a full-thickness alar flap is raised by placing an incision along the alar-facial groove and carrying it around the lateral crus. This flap is then rotated on its medial pedicle and inserted into the nasal tip. Three weeks after the first stage, the flap is divided to the desired columellar length and the remaining ala relocated to the alar-facial groove. At the same time, the contralateral ala can be adjusted to match the donor side. We performed a retrospective study of all our columellar reconstructions using this local flap. Our case series consisted of seven patients, and satisfactory cosmetic results were obtained in all cases. The nostril alar rim threshold flap is a useful technique for columellar reconstruction, producing near-anatomic results that can be performed as a two stage outpatient procedure under local anaesthesia. This technique is particularly well suited for columellar reconstruction in patients of African descent. PMID- 21316323 TI - Vascular exclusion of the liver. PMID- 21316322 TI - [Plasma malondialdehyde may not predict mortality in patient with chronic kidney disease]. AB - The role of oxidative stress in patients with chronic kidney disease (CKD) as a potential marker of morbidity and mortality remains poorly evaluated. The aim of the present study aims was thus: to determine plasma levels of malondialdehyde (MDA), end product of lipid peroxidation in patients at different CKD stages (predialysis and dialysis); to evaluate the association between plasma MDA levels and vascular disease or overall and cardiovascular mortality. Plasma MDA levels evaluated by HPLC, pulse wave velocity, aortic calcification score were evaluated in 94 CKD patients (67+/-13 years, 54% males, 29% at CKD stages 2-3, 32% at stages 4-5, 39% at stage 5D) prospectively followed for mortality. We observed that the plasma MDA levels were increased in patient with CKD and augmented progressively with CKD stages. However, we did not find any independent association between plasma levels of MDA and pulse wave velocity, aortic calcification score, or overall and cardiovascular mortality. Our results suggest that plasma MDA is not a useful biomarker in CKD patients. PMID- 21316324 TI - Panoramic Implant Notation System--a method to denote implant positions and prosthodontic modalities. AB - PURPOSE: This article describes a method to express implant positions in the dental arch as well as the type and extent of superstructures. METHODS: Basic signs, a 'O' (circle) and a '[symbol: see text]' (dot), which denote an implant and a single standing implant, respectively, are utilized to construct the Panoramic Implant Notation System (PIN System), which allows graphical representation of implants and implant-supported prostheses. The use of the PIN System is described by means of its application to common dental implant situations. While the Universal Numbering System is applied principally, examples of use of FDI Two-Digit Notation and Palmer Notation are also illustrated. CONCLUSION: By employing the PIN System, implant positions as well as information pertaining to the type and extent of implant prosthodontics can be easily visualized, and, therefore, practically described, which leads to the avoidance of misunderstanding and ambiguity in communication. PMID- 21316325 TI - Acute pancreatitis after transcatheter arterial chemoembolization for liver metastases of carcinoid tumors. AB - Acute pancreatitis is a rare side effect of non-selective transcatheter arterial chemoembolization (TACE) of hepatocellular carcinoma with an incidence ranging from 2% (clinical pancreatitis) to 40% (biological pancreatitis). This complication, due to embolization of extrahepatic arterial collaterals, has never been reported for treatment of well-differentiated endocrine carcinoma. We report here a case of acute clinical pancreatitis developing within 24 hours after a first selective TACE into the proper hepatic artery, with two peaks of hyperlypasemia, and intend to discuss its mechanism. Since it may clinically mimic a postembolization syndrome, dosage of serum pancreatic enzymes should be performed systematically in case of abdominal pain following TACE. PMID- 21316326 TI - Role of nuclear receptors in hepatitis B and C infections. AB - Nuclear receptors are key regulators of many cellular functions including energy supply by the direct control of the expression of target genes. They constitute a super-family of transcription factors activated by ligands, hormones or metabolites, and therefore, sensible to host metabolic stimuli. Viral replication and production requires energy and elementary building blocks from the infected cells. Hepatitis B and C virus replication is modulated in part by liver nuclear receptors that regulate the glucose and lipid metabolism. However, nuclear receptors control the two viruses' replication by different mechanisms. The expression of hepatitis B virus genes is directly under the control of nuclear receptors, which bind to the viral genome regulatory regions. Viral replication and production may, therefore, be optimal when cells receive the correct metabolic signals. Hepatitis C virus replication and production depend to a large extent on lipidogenesis and lipoprotein secretion. The role of nuclear receptors in controlling hepatitis C replication may be to turn on the cellular mode that would provide the appropriate metabolic environment for viral replication. PMID- 21316327 TI - Evaluation of nitrite/nitrate levels in relation to oxidative stress parameters in liver cirrhosis. AB - BACKGROUND AND OBJECTIVE: Nitric oxide and reactive oxygen species have been implicated in several pathophysiological events leading to fibrosis and cirrhosis. The aim of the present study was to investigate the possible contribution of peroxynitrite (formed by the interaction of nitric oxide and superoxide anion) in the pathophysiology of cirrhosis. METHODS: Twenty-six cirrhotic patients classified as Child-Pugh A, and seven as Child-Pugh B, were included in the study, and nine healthy volunteers served as controls. Levels of nitrite/nitrate (NOx), thiobarbituric acid-reactive substances (TBARS), nitrotyrosine (peroxynitrite marker), superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) were measured in blood samples. RESULTS: NOx, TBARS, CAT, SOD and GSH levels were higher in cirrhosis patients than in the controls (NOx: 0.17 +/- 0.02, 0.95 +/- 0.12, 1.3 +/- 0.1; TBARS: 2.0 +/- 0.05, 4.6 +/- 0.3, 5 +/ 0.3; CAT: 1.8 +/- 0.1, 4 +/- 0.3, 4.5 +/- 0.4; SOD: 1.8 +/- 0.2, 4.8 +/- 0.5, 7 +/- 0.4; and GSH: 1.3 +/- 0.05, 3.6 +/- 0.3, 4.5 +/- 0.6 in controls, and Child Pugh A and B patients, respectively). However, there were no differences in nitrotyrosine levels across these groups (controls: 11.4 +/- 0.4; Child-Pugh A: 11.1 +/- 0.4; Child-Pugh B: 11.9 +/- 1.6). NOx levels showed significant and strongly positive correlations with TBARS, SOD, CAT and GSH levels. In contrast, no correlations were found between either NOx or TBARS and nitrotyrosine levels. CONCLUSION: Nitric oxide and reactive oxygen species, but not peroxynitrite, are overproduced in patients with cirrhosis in spite of evidence of an increase in antioxidant defenses. This suggests that therapeutic measures aimed at attenuating oxidative stress as well as increasing antioxidant defenses may well benefit patients with cirrhosis. PMID- 21316328 TI - Minimization of radiation exposure due to computed tomography in inflammatory bowel disease. AB - Exposure to ionising radiation as a result of diagnostic imaging is increasing among patients with inflammatory bowel disease (IBD), primarily due to the more widespread use of computed tomography (CT). The potentially harmful effects of ionising radiation are a major cause for concern and radiologists, technologists and referring physicians who have a responsibility to the patient to ensure judicious use of those imaging modalities which result in exposure to ionising radiation and, when imaging is necessary, to ensure that a diagnostic quality imaging examination is acquired with lowest possible radiation exposure. This can be achieved by limiting the use of those imaging studies which involve ionising radiation to clinical situations where they are likely to change management, by implementing advances in low-dose CT technology, and, where feasible, by using alternative imaging modalities, such as ultrasonography or magnetic resonance imaging, which avoid radiation exposure. PMID- 21316329 TI - Periportal hypodensity on CT: significance and differential diagnosis of an overlooked sign. PMID- 21316330 TI - Acinar cell carcinoma of the pancreas: a rare tumor with a particular clinical and paraclinical presentation. AB - Acinar cell carcinoma (ACC) of the pancreas is a rare tumor with an extremely low incidence rate. While the number of reported patients with ACC is relatively small, a long-term survival rate has been noted in patients with neuroendocrine differentiation. A 39-year-old woman visited our emergency department for upper gastrointestinal bleeding. Endoscopy indicated extrinsic compression of the posterior body of the stomach, together with a large, 10-cm, central ulcer covered with necrotic tissue. Abdominal computed tomography (CT) indicated a lesion that involved the whole of the pancreas, with a fistula in the stomach, which was suspected of being a degenerative intraductal papillary mucinous tumor of the pancreas. Magnetic resonance imaging (MRI) of the pancreas was performed, and the results further strengthened our suspicions by demonstrating the presence of cystic lesions and tumor buds. A total duodenopancreatectomy, including total splenectomy and gastrectomy, was performed, along with two independent Roux-en-Y anastomoses (one esojejunal and one hepaticojejunal). The tumor also had a wide opening in the stomach. The patient's postoperative course was marked by partial thrombosis of the portal vein, which was treated medically. Histopathological examination provided evidence of pancreatic ACC. The diagnosis of ACC should be considered in the presence of cutaneous lesions, which were absent in the case of our patient, and colonoscopy is also highly desirable because of the various forms associated with familial adenomatous polyposis. The prognosis, which includes a 5-year survival rate of 45%, in the population with an R0 resection is better than that for ductular adenocarcinoma, thus prompting the more aggressive management of this type of tumor. PMID- 21316332 TI - Rapid measurement of deoxyribonuclease I activity with the use of microchip electrophoresis based on DNA degradation. AB - Deoxyribonuclease I (DNase I) activity in serum has been shown to be a novel diagnostic marker for the early detection of acute myocardial infarction (AMI). However, the conventional method to measure DNase I activity is time-consuming. In the current study, to develop a rapid assay method for DNase I activity for clinical purposes, a microchip electrophoresis device was used to measure DNase I activity. Because DNase I is an endonuclease that degrades double-stranded DNA endo-nucleolytically to produce oligonucleotides, degradation of the DNA standard caused by DNase I action was detected using microchip electrophoresis. We detected DNase I activity within 10 min. This is the first study to apply microchip electrophoresis for the detection of DNase I activity; furthermore, it seems plausible that reduction of analysis time for DNase I activity could make this novel assay method using microchip electrophoresis applicable in clinical use. PMID- 21316331 TI - Activity of OZ78 analogues against Fasciola hepatica and Echinostoma caproni. AB - The rapid spread of triclabendazole resistance in veterinary medicine is an important motivation for the discovery and development of novel fasciocidal drugs. The aim of this study was to characterize the fasciocidal properties of 1,2,4,5-tetraoxane (MT04 and MT14) and 1,2,4-trioxane (ST16 and ST28) analogues of the fasciocidal drug candidate OZ78, a 1,2,4-trioxolane. Dose response relationships were determined against juvenile and adult Fasciola hepatica in rats and Echinostoma caproni in mice. The temporal effects of MT04, MT14, ST16, and ST28 compared to OZ78 on the viability of F. hepatica were tested in vitro. The heat flow of OZ78 and MT04 treated flukes was studied with isothermal microcalorimetry. Finally, surface changes to adult flukes were monitored by scanning electron microscopy (SEM) 18, 24, and 48 h post-treatment of rats with 50 mg/kg MT04. Administration of 50-100 mg/kg of the synthetic peroxides resulted in complete elimination of adult F. hepatica from rats. SEM pictures revealed sloughing and blebbing already 18 h post-treatment with MT04. MT04 (100mg/kg) cured infections with juvenile F. hepatica, whereas MT14, ST16, and ST28 showed only low to moderate worm burden reductions. At 300 mg/kg, MT14 was the only compound to completely eliminate worms from E. caproni infected mice. MT14 showed the highest activity against juvenile F. hepatica in vitro. MT04 was very active against adult F. hepatica in vitro, which was confirmed by heat flow measurements. In conclusion, we have identified MT04 as another lead compound with potential against F. hepatica, hence further preclinical studies are necessary to determine if MT04 can be considered a drug development candidate. PMID- 21316333 TI - Detection of inducible nitric oxide synthase using a suite of electrochemical, fluorescence, and surface plasmon resonance biosensors. AB - A suite of biosensors for rapid detection of inducible nitric oxide synthase (iNOS) is described. First, a metal-enhanced electrochemical detection (MED) sensor, which relied on the redox properties of a silver monolayer, was developed. The linear detection range was between 8.64*10(-2) and 5.4*10(1)ng/ml with a detection limit of 1.69*10(-4)ng/ml. This method was compared with surface plasmon resonance (SPR) biosensors in which polyclonal mouse anti-iNOS was covalently immobilized onto a gold surface using an iNOS antigen. The linear detection range recorded was between 3.37*10(1) and 5.4*10(-2)ng/ml with a detection limit of 2*10(-3)ng/ml. Finally, an ultrasensitive portable capillary (UPAC) fluorescence immunosensor, in which a mouse anti-iNOS antibody was covalently immobilized onto the inner surface of a capillary and a rabbit anti iNOS antibody was employed as the secondary antibody, was developed. The resulting signals were found to be directly proportional to iNOS concentrations between 1.52*10(-1) and 1.52*10(-2)ng/ml with a detection limit of 1.05*10( 3)ng/ml. These immunosensors exhibit low cross-reactivity toward potential interferents such as human serum albumin and ovalbumin. The SPR and UPAC biosensors were validated using simulated blood spiked with recombinant iNOS, resulting in recoveries of 85% and 88.5%, respectively. The research presented in this article could potentially provide new ways of detecting NO for diagnostic and biomarker purposes in medical research. PMID- 21316334 TI - Hit proteins, mitochondria and cancer. AB - The histidine triad (HIT) superfamily comprises proteins that share the histidine triad motif, His-phi-His-phi-His-phi-phi, where phi is a hydrophobic amino acid. HIT proteins are ubiquitous in prokaryotes and eukaryotes. HIT proteins bind nucleotides and exert dinucleotidyl hydrolase, nucleotidylyl transferase or phosphoramidate hydrolase enzymatic activity. In humans, 5 families of HIT proteins are recognized. The accumulated epidemiological and experimental evidence indicates that two branches of the superfamily, the HINT (Histidine Triad Nucleotide Binding) members and FHIT (Fragile Histidine Triad), have tumor suppressor properties but a conclusive physiological role can still not be assigned to these proteins. Aprataxin forms another discrete branch of the HIT superfamily, is implicated in DNA repair mechanisms and unlike the HINT and FHIT members, a defective protein can be conclusively linked to a disease, ataxia with oculomotor apraxia type 1. The scavenger mRNA decapping enzyme, DcpS, forms a fourth branch of the HIT superfamily. Finally, the GalT enzymes, which exert specific nucleoside monophosphate transferase activity, form a fifth branch that is not implicated in tumorigenesis. The molecular mechanisms by which the HINT and FHIT proteins participate in bioenergetics of cancer are just beginning to be unraveled. Their purported actions as tumor suppressors are highlighted in this review. PMID- 21316335 TI - Destabilization exerted by peptides derived from the membrane-proximal external region of HIV-1 gp41 in lipid vesicles supporting fluid phase coexistence. AB - The human immunodeficiency virus (HIV) envelope is enriched in cholesterol and sphingomyelin, two lipids that sustain the formation of laterally segregated liquid-ordered fluid domains in model systems. Several evidences indicate that the high lipid order existing at the envelope may play a role in HIV pathogenesis. A putative mechanism might involve the modulation of the membrane perturbing function of the gp41 membrane-proximal external region (MPER). To test such hypothesis, we investigate here the effect of lipid phase coexistence on the membrane-restructuring properties of NpreTM and CpreTM, two peptides based on the amino- and carboxy-terminal MPER sequences, respectively. Fluid phase coexistence elicited the fusogenic activity of NpreTM at high membrane doses and stimulated "graded" leakage at low doses. By comparison, the effect on CpreTM was restricted to an enhancement of "all-or-none" leakage that was consistent with the promotion of its surface aggregation. Confocal microscopy of single vesicles revealed the preference of both peptides for liquid-disordered domains. Accordingly, we speculate that confinement into envelope fluid nanodomains might boost the distinct capacities of HIV MPER hydrophobic modules for inducing membrane defects during fusion. PMID- 21316336 TI - Adenosine receptor containing oligomers: their role in the control of dopamine and glutamate neurotransmission in the brain. AB - While the G protein-coupled receptor (GPCR) oligomerization has been questioned during the last fifteen years, the existence of a multi-receptor complex involving direct receptor-receptor interactions, called receptor oligomers, begins to be widely accepted. Eventually, it has been postulated that oligomers constitute a distinct functional form of the GPCRs with essential receptorial features. Also, it has been proven, under certain circumstances, that the GPCR oligomerization phenomenon is crucial for the receptor biosynthesis, maturation, trafficking, plasma membrane diffusion, and pharmacology and signalling. Adenosine receptors are GPCRs that mediate the physiological functions of adenosine and indeed these receptors do also oligomerize. Accordingly, adenosine receptor oligomers may improve the molecular mechanism by which extracellular adenosine signals are transferred to the G proteins in the process of receptor transduction. Importantly, these adenosine receptor-containing oligomers may allow not only the control of the adenosinergic function but also the fine-tuning modulation of other neurotransmitter systems (i.e. dopaminergic and glutamatergic transmission). Overall, we underscore here recent significant developments based on adenosine receptor oligomerization that are essential for acquiring a better understanding of neurotransmission in the central nervous system under normal and pathological conditions. PMID- 21316337 TI - L-selectin transmembrane and cytoplasmic domains are monomeric in membranes. AB - A recombinant protein termed CLS, which corresponds to the C-terminal portion of human L-selectin and contains its entire transmembrane and cytoplasmic domains (residues Ser473-Arg542), has been produced and its oligomeric state in detergents characterized. CLS migrates in the SDS polyacrylamide gel at a pace that is typically expected from a complex twice of its molecular weight. Additional studies revealed, however, that this is due to residues in the cytoplasmic domain, as mutations in this region or its deletion significantly increased the electrophoretic rate of CLS. Analytical ultracentrifugation and fluorescence resonance energy transfer studies indicated that CLS reconstituted in dodecylphosphocholine detergent micelles is monomeric. When the transmembrane domain of L-selectin is inserted into the inner membrane of Escherichia coli as a part of a chimeric protein in the TOXCAT assay, little oligomerization of the chimeric protein is observed. Overall, these results suggest that transmembrane and cytoplasmic domains of L-selectin lack the propensity to self-associate in membranes, in contrast to the previously documented dimerization of the transmembrane domain of closely related P-selectin. This study will provide constraints for future investigations on the interaction of L-selectin and its associating proteins. PMID- 21316338 TI - Genome-wide screen identifies PVT1 as a regulator of Gemcitabine sensitivity in human pancreatic cancer cells. AB - Gemcitabine has been a first-line chemotherapy agent for advanced pancreatic cancer, which is associated with one of the lowest 5 years survival rates among human cancers. Due to our lack of understanding of the genetic determinants of Gemcitabine sensitivity in pancreatic cancer, the therapeutic effectiveness of Gemcitabine chemotherapy is typically unpredictable. Using a genome-wide and piggyBac transposon-based genetic screening platform, we identified the PVT1 gene as a regulator of Gemcitabine sensitivity and showed that functional inactivation of the PVT1 gene led to enhanced Gemcitabine sensitivity in human pancreatic cancer ASPC-1 cells. The integration of the piggyBac transposon-based vector system into intron 3 of PVT1 was within a common site of oncogenic retroviral insertions and chromosomal translocations. PVT1 is a non-protein encoding gene; the genomic arrangement of PVT1 and its co-amplification with MYC have been implicated in the tumorigenesis of a variety of cancers. The molecular mechanism of PVT1 transcripts in gene regulation remains a puzzle. We demonstrated that overexpression of a full length PVT1 cDNA in the antisense orientation reconstituted enhanced sensitivity to Gemcitabine in naive ASPC-1 cells, whereas overexpression of a full length PVT1 cDNA in the sense orientation resulted in decreased sensitivity to Gemcitabine. Our results identified PVT1 as a regulator of Gemcitabine sensitivity in pancreatic cancer cells and validated the genome wide genetic screening approach for the identification of genetic determinants as well as potential biomarkers for the rational design of Gemcitabine chemotherapies for pancreatic cancer. PMID- 21316339 TI - Characterization of band 3-ankyrin-Protein 4.2 complex by biochemical and mass spectrometry approaches. AB - The elastic property of red blood cell is supported by interaction between red cell membrane and the intricate cytoskeleton network underlying the membrane bilayer cytoplasmic face. One of the major scaffold protein linkers is band 3 ankyrin complex. Defects occurring in this complex have been found in many inherited diseases, causing red blood cell abnormalities. Here we combined the power of mass spectrometry with conventional biochemical purification methods in order to study the native interactions among band 3, ankyrin and Protein 4.2. This approach provided in vivo evidence for the association between band 3 and N terminal ankyrin purified directly from the cell membrane. The C-terminal regions of ankyrin were not found to be a stable partner of the band 3 complex. Protein 4.2 was shown here to be an integral part of the complex. Its association to the band 3-ankyrin complex could withstand harsh purification conditions. Our findings lend additional support to the interaction between band 3 and ankyrin N terminal domain previously shown by in vitro binding assays and provide evidence for a band 3 core complex comprising of band 3, ankyrin and Protein 4.2. PMID- 21316340 TI - Abnormal expression of ADAR1 isoforms in Chinese pediatric acute leukemias. AB - The posttranscriptional RNA editing by the type 1 adenosine deaminase acting on RNAs (ADAR1), expressed as p110 and p150 isoforms, is important for both physiological and pathological processes. Their expression and significance in leukemias remain unknown. Here, we investigated the expression of ADAR1 in Chinese pediatric acute leukemias by real-time PCR and Western blot. The results showed that significant high expression of p110 was detected in leukemias, especially in B-ALL, whereas a slight increase of p150 could be observed. Furthermore, the decrease of p110 expression was observed in B-ALL patients achieving complete remission. Moreover, among prognostic risk groups in ALL, the highest expressions of p110 and p150 were detected in standard-risk group, whereas their lowest expressions were in high-risk group. This observation was further confirmed in comparisons between good and poor prognostic groups based on prognostic related clinical features. These results demonstrated that ADAR1 isoforms showed different expression patterns, suggesting that they might play different roles in pediatric leukemias. Our results will help us for the better understanding of RNA editing, exploring the potential target for the treatment, and making prognostic evaluation in childhood leukemias. PMID- 21316341 TI - Activation of calcium-sensing receptor increases TRPC3 expression in rat cardiomyocytes. AB - Transient receptor potential (TRP) channels are expressed in cardiomyocytes, which gate a type of influx of extracellular calcium, the capacitative calcium entry. TRP channels play a role in mediating Ca(2+) overload in the heart. Calcium-sensing receptors (CaR) are also expressed in rat cardiac tissue and promote the apoptosis of cardiomyocytes by Ca(2+) overload. However, data about the link between CaR and TRP channels in rat heart are few. In this study, reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting were used to examine the expression of the TRP canonical proteins TRPC1 and TRPC3 in adult and neonatal rat cardiomyocytes. Laser scan confocal microscopy was used to detect intracellular [Ca(2+)](i) levels in isolated adult rat ventricular myocytes. The results showed that, in adult rat cardiomyocytes, the depletion of Ca(2+) stores in the endoplasmic/sarcoplasmic reticulum (ER/SR) by thapsigargin induced a transient increase in [Ca(2+)](i) in the absence of [Ca(2+)](o) and the subsequent restoration of [Ca(2+)](o) sustained the increased [Ca(2+)](i) for a few minutes, whereas, the persisting elevation of [Ca(2+)](i) was reduced in the presence of the TRPC inhibitor SKF96365. The stimulation of CaR by its activator gadolinium chloride (GdCl(3)) or spermine also resulted in the same effect and the duration of [Ca(2+)](i) increase was also shortened in the absence of [Ca(2+)](o). In adult and neonatal rat cardiomyocytes, GdCl(3) increased the expression of TRPC3 mRNA and protein, which were reversed by SKF96365 but not by inhibitors of the L-type channels and the Na(+)/Ca(2+) exchangers. However, GdCl(3) had no obvious effect on the expression of TRPC1 protein. These results suggested that CaR stimulation induced activation of TRP channels and promoted the expression of TRPC3, but not TRPC1, that sustained the increased [Ca(2+)](i). PMID- 21316342 TI - Enzymes involved in hepatic acylglycerol metabolism in the chicken. AB - In laying hens, massive hepatic mobilization of fatty acids is required for the synthesis of oocyte-targeted very-low density lipoproteins (VLDL). The current study aims at identification of enzymes that hydrolyze hepatic acylglycerol stores regulated in a fashion compatible with supporting enhanced VLDL synthesis. We show that unlike mammals, chickens express adipose triglyceride lipase (ATGL) also in liver, where it is upregulated by fasting, while the enzyme patatin-like phospholipase domain-containing lipase 3 (PNPLA3) is suppressed. For the first time in any system, we show that hepatic arylacetamide deacetylase (AADA) is upregulated by fasting, and that its affinity for an insoluble carboxylester substrate is compatible with an in-vivo function similar to that of ATGL. Unknown heretofore, hepatic expression of chicken AADA is estrogen-responsive, and is induced to the same degree as the stimulation of VLDL-production by estrogen. These observations support roles of chicken ATGL, PNPLA3, and AADA in acylglycerol metabolism related to the high rates of VLDL synthesis that are essential for reproduction. PMID- 21316343 TI - Sindbis virus replication, is insensitive to rapamycin and torin1, and suppresses Akt/mTOR pathway late during infection in HEK cells. AB - Genetically engineered Sindbis viruses (SIN) are excellent oncolytic agents in preclinical models. Several human cancers have aberrant Akt signaling, and kinase inhibitors including rapamycin are currently tested in combination therapies with oncolytic viruses. Therefore, it was of interest to delineate possible cross regulation between SIN replication and PI3K/Akt/mTOR signaling. Here, using HEK293T cells as host, we report the following key findings: (a) robust SIN replication occurs in the presence of mTOR specific inhibitors, rapamycin and torin1 or Ly294002--a PI3K inhibitor, suggesting a lack of requirement for PI3K/Akt/mTOR signaling; (b) suppression of phosphorylation of Akt, mTOR and its effectors S6, and 4E-BP1 occurs late during SIN infection: a viral function that may be beneficial in counteracting cellular drug resistance to kinase inhibitors; (c) Ly294002 and SIN act additively to suppress PI3K/Akt/mTOR pathway with little effect on virus release; and (d) SIN replication induces host translational shut off, phosphorylation of eIF2alpha and apoptosis. This first report on the potent inhibition of Akt/mTOR signaling by SIN replication, bolsters further studies on the development and evaluation of engineered SIN genotypes in vitro and in vivo for unique cytolytic functions. PMID- 21316344 TI - Acute suppression of apo B secretion by insulin occurs independently of MTP. AB - Secretion of apolipoprotein (apo) B-containing lipoproteins by the liver depends mainly upon apo B availability and microsomal triglyceride transfer protein (MTP) activity and is subject to insulin regulation. Hepatic MTP mRNA expression is negatively regulated by insulin which correlates with inhibition of apo B secretion suggesting that insulin might suppress apo B secretion through an MTP dependent mechanism. To investigate this possibility, we examined the acute effect of insulin on hepatic MTP expression and activity levels in vivo utilizing apobec-1(-/-) mice. Insulin did not significantly alter hepatic MTP mRNA levels or lipid transfer activity 2h following injection, but suppressed expression of genes important in gluconeogenesis. To study the specific role of MTP, we expressed human MTP (hMTP) in primary rat hepatocytes using adenoviral gene transfer. Increased expression of hMTP resulted in a 47.6+/-17.9% increase in total apo B secreted. Incubation of hepatocytes with insulin suppressed apo B secretion by 50.1+/-10.8% in cells over-expressing hMTP and by 53.0+/-12.4% in control transfected hepatocytes. Results indicate that even under conditions of increased hepatic apo B secretion mediated by MTP, responsiveness of hepatocytes to insulin to suppress apo B secretion is maintained. PMID- 21316345 TI - Involvement of Rac GTPase activation in phosphatidylcholine hydroperoxide-induced THP-1 cell adhesion to ICAM-1. AB - Increasing evidence indicates that phospholipid oxidation plays important roles in atherosclerosis. Here, we investigated the involvement of Rho-family GTPases inphosphatidylcholine hydroperoxide (PCOOH)-induced THP-1 cell adhesion to ICAM 1. Isoprenoid depletion by fluvastatin and geranylgeranyltransferase inhibition by GGTI-286 suppressed PCOOH-induced cell adhesion to ICAM-1 and F-actin-rich membrane protrusion formation. Pull-down assays demonstrated the activation of Rac1 and Rac2 in PCOOH-treated cells. Pan-Rho-family GTPase inhibitor Clostridium difficile toxin B, Rac-specific inhibitor NSC23776, and RNA interference of the Rac isoforms suppressed the cell adhesion. These findings indicate the involvement of Rac GTPase activation in PCOOH-induced cell adhesion to ICAM-1 via actin reorganization. PMID- 21316346 TI - Retinoids synergized with insulin to induce Srebp-1c expression and activated its promoter via the two liver X receptor binding sites that mediate insulin action. AB - We have reported that the rat liver lipophilic extract (LE) synergized with insulin to induce Gck and Srebp-1c in primary rat hepatocytes. After identification of retinol and retinal in LE, only their effects in the absence or presence of insulin on Gck, but not that on Srebp-1c, were investigated subsequently. The retinoid effects on the Srebp-1c expression and the activation of its promoter were examined with real-time PCR and reporter gene assays, respectively. In primary hepatocytes, retinal and retinoic acid (RA) synergized with insulin to induce Srebp-1c expression. This induction was followed by the elevation of its target gene, fatty acid synthase. Activation of retinoid X receptor, but not retinoic acid receptor, was responsible for the induction of Srebp-1c expression. RA, but not retinal, also induced Srebp-1c expression in a dose dependent manner in INS-1 cells. The RA responsive elements in Srebp-1c promoter were determined as previously identified two liver X receptor elements responsible for mediating insulin action. We conclude that retinoids regulate hepatic Srebp-1c expression through activation of retinoid X receptor. The RA- and insulin-induced Srebp-1c expression converged at the same sites in its promoter, indicating the roles of vitamin A in regulation of hepatic gene expression. PMID- 21316347 TI - The nucleolar SUMO-specific protease SMT3IP1/SENP3 attenuates Mdm2-mediated p53 ubiquitination and degradation. AB - SUMO (small ubiquitin-like modifier) modification plays multiple roles in several cellular processes. Sumoylation is reversibly regulated by SUMO-specific proteases. SUMO-specific proteases have recently been implicated in cell proliferation and early embryogenesis, but the underlying mechanisms remain unknown. Here, we show that a nucleolar SUMO-specific protease, SMT3IP1/SENP3, controls the p53-Mdm2 pathway. We found that SMT3IP1 interacts with p53 and Mdm2, and desumoylates both proteins. Overexpression of SMT3IP1 in cells resulted in the accumulation of Mdm2 in the nucleolus and increased stability of the p53 protein. In addition, SMT3IP1 bound to the acidic domain of Mdm2, which also mediates the p53 interaction, and competed with p53 for binding. Increasing expression of SMT3IP1 suppressed Mdm2-mediated p53 ubiquitination and subsequent proteasomal degradation. Interestingly, the desumoylation activity of SMT3IP1 was not necessary for p53 stabilization. These results suggest that SMT3IP1 is a new regulator of the p53-Mdm2 pathway. PMID- 21316348 TI - Osthole, a natural coumarin, improves neurobehavioral functions and reduces infarct volume and matrix metalloproteinase-9 activity after transient focal cerebral ischemia in rats. AB - Previously we demonstrated that Osthole, a natural coumarin, protects against focal cerebral ischemia/reperfusion-induced injury in rats. In the present study, the effects of Osthole on neurobehavioral functions, infarct volume and matrix metalloproteinase-9 (MMP-9) in a rat 2h focal cerebral ischemia model were investigated. Osthole (100mg/kg per dose) was administrated intraperitoneally 30min before ischemic insult and immediately after reperfusion. Osthole treatment significantly reduced neurological deficit score and infarct volume by 38.5% and 33.8%, respectively, as compared with the untreated animals. Osthole reversed ischemia-reperfusion-induced increase in MMP-9 protein level/activity as evidenced by Western blotting and gelatin zymography. Taken together, these results for the first time demonstrate that Osthole reduces infarct volume, restores neurobehavioral functions and downregulates MMP-9 protein level/activity in ischemia/reperfused brain. PMID- 21316349 TI - Reading for sound with dyslexia: evidence for early orthographic and late phonological integration deficits. AB - Deteriorated phonological representations are widely assumed to be the underlying cause of reading difficulties in developmental dyslexia; however, existing evidence also implicates degraded orthographic processing. Here, we used event related potentials whilst dyslexic and control adults performed a pseudoword-word priming task requiring deep phonological analysis to examine phonological and orthographic priming, respectively. Pseudowords were manipulated to be homophonic or non-homophonic to a target word and more or less orthographically similar. Since previous ERP research with normal readers has established phonologically driven differences as early as 250 ms from word presentation, degraded phonological representations were expected to reveal reduced phonological priming in dyslexic readers from 250 ms after target word onset. However, phonological priming main effects in both the N2 and P3 ranges were indistinguishable in amplitude between groups. Critically, we found group differences in the N1 range, such that orthographic modulations observed in controls were absent in the dyslexic group. Furthermore, early group differences in phonological priming transpired as interactions with orthographic priming (in P2, N2 and P3 ranges). A group difference in phonological priming did not emerge until the P600 range, in which the dyslexic group showed significantly attenuated priming. As the P600 is classically associated with online monitoring and reanalysis, this pattern of results suggest that during deliberate phonological processing, the phonological deficit in reading may relate more to inefficient monitoring rather than deficient detection. Meanwhile, early differences in perceptual processing of phonological information may be driven by the strength of engagement with orthographic information. PMID- 21316351 TI - Glibenclamide ameliorates ischemia-reperfusion injury via modulating oxidative stress and inflammatory mediators in the rat hippocampus. AB - Stroke remains a debilitating disease with high incidence of morbidity and mortality, where many reports provide promising venues for prevention/treatment of such ailment. Glibenclamide, a selective blocker of KATP channels, was reported to protect against ischemia and ischemia-reperfusion (IR) injury in several experimental models. Hence, the present study aimed to investigate the possible involvement of free radicals as well as inflammatory and anti inflammatory mediators in the hippocampus of rats exposed to IR. To this end, male Wistar rats were divided into 3 groups: group I served as sham operated controls; group II was subjected to 15 min ischemia by occlusion of both common carotid arteries, followed by 60 min reperfusion; group III was injected with glibenclamide (1mg/kg, i.p.) 10 min before ischemic-reperfusion injury. IR increased lipid peroxides, myeloperoxidase activity, TNF-alpha and PGE(2), while decreasing glutathione, total antioxidant capacity, nitric oxide and IL-10 levels in the hippocampus. Glibenclamide reversed all the former alterations, thus highlighting a potential therapeutic utility for this sulphonyl urea in IR brain injury via modulating oxidative stress and inflammatory mediators. PMID- 21316350 TI - Brain glucose transporter (Glut3) haploinsufficiency does not impair mouse brain glucose uptake. AB - Mouse brain expresses three principal glucose transporters. Glut1 is an endothelial marker and is the principal glucose transporter of the blood-brain barrier. Glut3 and Glut6 are expressed in glial cells and neural cells. A mouse line with a null allele for Glut3 has been developed. The Glut3(-/-) genotype is intrauterine lethal by 7days post-coitis, but the heterozygous (Glut3(+/-)) littermate survives, exhibiting rapid post-natal weight gain, but no seizures or other behavioral aberrations. At 12weeks of age, brain uptake of tail vein injected ((3))H-2-deoxy glucose in Glut3(+/-) mice was not different from Glut3(+/+) littermates, despite 50% less Glut3 protein expression in the brain. The brain uptake of injected ((18))F-2-fluoro-2-deoxy glucose was similarly not different from Glut3(+/-) littermates in the total amount, time course, or brain imaging in the Glut3(+/-) mice. Glut1 and Glut6 protein expressions evaluated by immunoblots were not affected by the diminished Glut3 expression in the Glut3(+/ ) mice. We conclude that a 50% decrease in Glut3 is not limiting for the uptake of glucose into the mouse brain, since Glut3 haploinsufficiency does not impair brain glucose uptake or utilization. PMID- 21316352 TI - Whole body hypothermia broadens the therapeutic window of intranasally administered IGF-1 in a neonatal rat model of cerebral hypoxia-ischemia. AB - To investigate whether whole body hypothermia after neonatal cerebral hypoxia ischemia (HI) could broaden the therapeutic window of intranasal treatment of IGF 1 (iN-IGF-1), postnatal day 7 rat pups were subjected to right common carotid artery ligation, followed by 8% oxygen inhalation for 2h. After HI, one group of pups were returned to their dams and kept at room temperature (24.5+/-0.2 degrees C). A second group of pups were subjected to whole body hypothermia in a cool environment (21.5+/-0.3 degrees C) for 2 or 4h before being returned to their dams. Two doses of 50 MUg recombinant human IGF-1 were administered intranasally at a 1h interval starting at 0, 2 or 4h after hypothermia. Hypothermia decreased the rectal temperature of pups by 4.5 degrees C as compared to those kept at room temperature. While hypothermia or iN-IGF-1 administered 2h after HI alone did not provide neuroprotection, the combined treatment of hypothermia with iN-IGF-1 significantly protected the neonatal rat brain from HI injury. Hypothermia treatment extended the therapeutic window of IGF-1 to 6h after HI. The extended IGF-1 therapeutic window by hypothermia was associated with decreases in infiltration of polymorphonuclear leukocytes and activation of microglia/macrophages and with attenuation of NF-kappaB activation in the ipsilateral hemisphere following HI. PMID- 21316353 TI - Auditory signal detection appears to depend on temporal integration of subthreshold activity in auditory cortex. AB - The threshold of hearing decreases with increasing sound duration up to a limit of a few hundred milliseconds, whereas other auditory time constants are orders of magnitude shorter. A possible solution to this resolution-integration paradox is that temporal integration occurs more centrally than computations depending on high temporal resolution. But this would require information about subthreshold events in the periphery to reach higher centers. Here we show that this prerequisite is fulfilled. The auditory evoked response to a just perceptible pulse series does basically not depend on whether single pulses are below or above behavioral threshold. The failure to find evidence of temporal integration up to response latencies of 30 ms suggests that the integrator is located more centrally than primary auditory cortex. By using noise to its advantage, the auditory system apparently has established a central integration mechanism that is about as efficient as the peripheral one in the visual system. PMID- 21316354 TI - P300 as a measure of processing capacity in auditory and visual domains in specific language impairment. AB - This study examined the electrophysiological correlates of auditory and visual working memory in children with Specific Language Impairments (SLI). Children with SLI and age-matched controls (11;9-14;10) completed visual and auditory working memory tasks while event-related potentials (ERPs) were recorded. In the auditory condition, children with SLI performed similarly to controls when the memory load was kept low (1-back memory load). As expected, when demands for auditory working memory were higher, children with SLI showed decreases in accuracy and attenuated P3b responses. However, children with SLI also evinced difficulties in the visual working memory tasks. In both the low (1-back) and high (2-back) memory load conditions, P3b amplitude was significantly lower for the SLI as compared to CA groups. These data suggest a domain-general working memory deficit in SLI that is manifested across auditory and visual modalities. PMID- 21316355 TI - An event-related potential investigation of lexical pitch-accent processing in auditory Japanese. AB - Lexical prosody plays an important role in speech comprehension. However, the electrophysiological nature and time course of processing lexical prosody in mora timed languages are rarely known in contrast to the wealth of knowledge in stress timed languages and syllable-timed languages like German and French. In the present study, lexical pitch-accent processing in Japanese is investigated using event-related potentials. Participants listened to sentences with verbs either correct or incorrect with respect to pitch-accent (phonological condition), word meaning (semantic condition) or sentence type (syntactic condition). When the brain potentials of correct and incorrect sentences were compared within conditions, the phonological and semantic conditions showed a negativity and positivity (P600), while the syntactic condition displayed a P600. Furthermore, the negativity in response to pitch-accent violations (pitch-accent negativity) appeared approximately 60ms earlier than the response to semantic violations (N400), while no significant topographical distributions were found between the two components. These results suggest that the pitch-accent negativity reflects initial phonological processing followed by lexical access and word recognition. Moreover, the P600 displayed in all conditions was interpreted as a general integration process that is common across the three domains. PMID- 21316356 TI - Transient receptor potential (TRP) A1 activated currents in TRPV1 and cholecystokinin-sensitive cranial visceral afferent neurons. AB - Culinary use of the pungent spices has potential health benefits including a reduction in food intake. Pungent spices often contain ingredients that activate members of the transient receptor potential (TRP) family A1 and evoke pain from capsaicin-sensitive somatosensory neurons. TRPA1 channel have also been identified on cranial visceral afferent neurons but their distribution and functional contributions are poorly understood. Visceral vagal neurons transduce mechanical and chemical signals from peripheral organs to the nucleus tractus solitarii. Many capsaicin-sensitive vagal afferents participate in peripheral satiety signaling that includes cholecystokinin (CCK) sensitive neurons. To assess signaling, the TRPA1 selective agonist allyl isothiocyanate (AITC) was tested together with CCK and capsaicin (200nM), a TRPV1 specific agonist. In isolated nodose neurons, AITC (0.05-0.2mM) evoked concentration-dependent inward currents in 38% of the tested neurons. The TRPA1 specific antagonist HC-030031 (10MUM) blocked AITC responses. TRPA1 responses were mixed across neurons that were capsaicin-sensitive and -insensitive. However CCK evoked inward currents only on capsaicin-sensitive neurons and 28% of the CCK-sensitive neurons expressed TRPA1. Our results indicate that TRPA1 is co-expressed with TRPV1 in CCK-sensitive nodose neurons. The findings indicate a potential mechanism by which spices can act within cranial visceral afferent pathways mediating satiety and contribute to the reduction of the food intake associated with spiced diets. PMID- 21316357 TI - The role of dopamine receptors in ventrolateral orbital cortex-evoked antinociception in a rat formalin test model. AB - The present study examined the roles of dopamine and D(1)- and D(2)-like dopamine receptors in ventrolateral orbital cortex (VLO)-evoked antinociception in rats with persistent inflammatory pain. Following formalin injection into the rat unilateral hindpaw pad, the effects of dopamine receptor agonist and antagonist microinjections into the VLO on nociceptive behavior were observed. Results demonstrated that VLO microinjection of the non-selective dopamine receptor agonist apomorphine (R(-)-apomorphine hydrochloride, 1.0, 2.5 and 5.0MUg) depressed later-phase nociceptive behavior induced by formalin injection; this effect was attenuated by the D(2)-like dopamine receptor antagonist S(-) raclopride(+)-tartrate salt (raclopride, 3.0MUg), but not by the D(1)-like dopamine receptor antagonist R(+)-SCH-23390 hydrochloride (SCH-23390, 1.0MUg). Apomorphine-induced antinociception was mimicked by microinjection of the D(2) like dopamine receptor agonist (-)-quinpirole hydrochloride (2.0 and 5.0MUg) into the same VLO site, and this effect was antagonized by raclopride (3.0MUg). In addition, microinjection of the D(1)-like dopamine receptor agonist R(+)-SKF 38393 hydrochloride (5.0MUg) had no effect on formalin-induced nociceptive behavior during the later phase. However, the D(1)-like dopamine receptor antagonist SCH-23390 (2.5, 5.0 and 10MUg) depressed nociceptive behavior in a dose-dependent manner. These results suggested that dopamine mediated VLO-induced antinociception via different mechanisms in the persistent inflammatory pain model; D(2)-like receptors mediated dopamine-induced antinociception, while D(1) like dopamine receptors exhibited tonic facilitatory action on nociceptive behavior, thereby blocking D(1)-like dopamine receptors could induce antinociception. PMID- 21316358 TI - Tumor necrosis factor-alpha induces increased lung vascular permeability: a role for GSK3alpha/beta. AB - We tested the hypothesis that glycogen synthase kinase 3alpha/beta (GSK3alpha/beta) modulates tumor necrosis factor-a (TNF) induced increased lung vascular permeability. Rats were treated with TNF (i.v., ~100ng/ml) or vehicle 0.5h, 4.0h and 24.0h prior to lung isolation. Rats were co-treated with the GSK3alpha/beta inhibitors SB216763 (0.6mg/kg) or TDZD-8 (1.0mg/kg). After TNF, the isolated lung was assessed for hemodynamics, wet-dry/dry weight (W-D/D) and extravascular albumin. Extravascular albumin significantly increased at TNF-24h compared to Control. In the GSK3alpha/beta-inhibited+TNF groups, extravascular albumin was similar to the Control and respective SB216763 and TDZD-8 groups. In separate studies, to assess GSK3alpha/beta-activity, lung lysate was assessed for phospho-GSK3alpha/beta-Ser(21/9), total GSK3alpha/beta, un-phospho-beta-catenin Ser(33/37) and total beta-catenin. In the TNF-4.0h group, there was no change in GSK3alpha/phospho-GSK3alpha-Ser(21) but there was an increase in GSK3beta/GSK3beta-Ser(9) compared to Control, indicating GSK3beta activation at TNF-4.0h. GSK3beta activation was verified because there was a decrease in un phospho-beta-catenin-Ser(33/37)/beta-catenin in the TNF-4.0 group, a specific outcome for GSK3beta activation. In the SB216763+TNF group, un-phospho-beta catenin-Ser(33/37) was similar to Control, indicating prevention of TNF-induced GSK3beta activation. In the TNF-24h group, there were increases in the biomarkers of inflammation phospho-eNOS-Ser (1117) and oxidized protein, which did not occur in the SB216763+TNF-24h and TDZD-8+TNF-24h groups. In the SB216763+TNF-24h and TDZD-8+TNF-24h groups, un-phospho-beta-catenin-Ser(33/37) was greater than in the Control, indicating continued inhibition of GSK3beta. The data indicates that pharmacologic inhibition of GSK3beta inhibits TNF induced increased endothelial permeability associated with lung inflammation. PMID- 21316359 TI - Therapeutic efficacy of stemazole in a beta-amyloid injection rat model of Alzheimer's disease. AB - Alzheimer's disease is one of the most devastating neurodegenerative disorders and is characterized by severe memory and cognitive decline. The deposition of beta-amyloid (Abeta) protein is the primary pathology associated with Alzheimer's disease. Current treatments for Alzheimer's disease only offer limited symptomatic alleviation, and more effective therapies are needed for Alzheimer's disease. Our primary data showed that stemazole, a novel small molecule, protected SH-SY5Y cells from toxicity induced by hydrogen peroxide and Abeta aggregates in vitro. In this study, we evaluated the therapeutic effects of a 14 day stemazole treatment in Abeta1-40 aggregate injection rat model of Alzheimer's disease. Administration of stemazole reversed learning and memory deficits induced by the Abeta1-40 aggregates in a dose-dependent manner, as assessed by a Morris water maze task. In addition, the number of Abeta1-40 aggregates was reduced in the hippocampus, as demonstrated by micro-positron emission tomography/computerized tomographic scanning. Finally, stemazole treatment reduced degeneration and the loss of neurons in the hippocampus, as shown by histology and immunohistochemical analysis. The neuroprotective effects of stemazole may be important for its therapeutic efficacy. These results demonstrate that stemazole is effective in the treatment of Abeta1-40 aggregates injection rat model, suggesting that this compound may be used as a therapeutic agent against Alzheimer's disease. PMID- 21316361 TI - Increased synapsin expression and neurite sprouting in lamprey brain after spinal cord injury. AB - Spinal cord injury induces structural plasticity throughout the mammalian nervous system, including distant locations in the brain. Several types of injury-induced plasticity have been identified, such as neurite sprouting, axon regeneration, and synaptic remodeling. However, the molecular mechanisms involved in injury induced plasticity are unclear as is the extent to which injury-induced plasticity in brain is conserved across vertebrate lineages. Due to its robust roles in neurite outgrowth and synapse formation during developmental processes, we examined synapsin for its potential involvement in injury-induced plasticity. We used lamprey, a vertebrate that undergoes robust anatomical plasticity and functional recovery after spinal cord injury. At 3 and 11 weeks after spinal cord transection, synapsin I mRNA was upregulated >2-fold in lamprey brain, as assayed by semi-quantitative RT-PCR. Other synaptic vesicle-associated genes remained unchanged. In situ hybridization revealed that synapsin I mRNA was increased globally throughout the lamprey brain. Immunolabeling for synapsin I protein revealed a significant increase in both the intensity and density of synapsin I positive structures in lamprey hindbrain at 11 weeks post-transection, relative to controls. Moreover, the number of structures immunolabeled for phospho synapsin (serine 9) increased after injury, suggestive of neurite sprouting. Indeed, at the ultrastructural level, there was an increase in neurite density at 11 weeks post-transection. Taken together, these data show that neurite sprouting in the brain is an evolutionarily conserved response to a distant spinal cord injury and suggest that synapsin and its phosphorylation at serine 9 play key roles in the sprouting mechanism. PMID- 21316363 TI - Broad-spectrum neuroprotection against traumatic brain injury by agonism of peroxisome proliferator-activated receptors. AB - In a recent issue of Experimental Neurology, Sauerbeck and colleagues demonstrated that treatment with the peroxisome proliferator-activated receptor (PPAR) agonist Pioglitazone after experimental traumatic brain injury (TBI) in rats was protective against mitochondrial dysfunction, cognitive impairment, cortical tissue loss and microglial activation. In this commentary, we review the key findings of this work and their relevance to previous and future neurotrauma research. More broadly, we speculate about their significance in the context of developing therapeutic strategies for a wide range of neuroinflammatory conditions. PMID- 21316362 TI - GDNF modifies reactive astrogliosis allowing robust axonal regeneration through Schwann cell-seeded guidance channels after spinal cord injury. AB - Reactive astrogliosis impedes axonal regeneration after injuries to the mammalian central nervous system (CNS). Here we report that glial cell line-derived neurotrophic factor (GDNF), combined with transplanted Schwann cells (SCs), effectively reversed the inhibitory properties of astrocytes at graft-host interfaces allowing robust axonal regeneration, concomitant with vigorous migration of host astrocytes into SC-seeded semi-permeable guidance channels implanted into a right-sided spinal cord hemisection at the 10th thoracic (T10) level. Within the graft, migrated host astrocytes were in close association with regenerated axons. Astrocyte processes extended parallel to the axons, implying that the migrated astrocytes were not inhibitory and might have promoted directional growth of regenerated axons. In vitro, GDNF induced migration of SCs and astrocytes toward each other in an astrocyte-SC confrontation assay. GDNF also enhanced migration of astrocytes on a SC monolayer in an inverted coverslip migration assay, suggesting that this effect is mediated by direct cell-cell contact between the two cell types. Morphologically, GDNF administration reduced astrocyte hypertrophy and induced elongated process extension of these cells, similar to what was observed in vivo. Notably, GDNF treatment significantly reduced production of glial fibrillary acidic protein (GFAP) and chondroitin sulfate proteoglycans (CSPGs), two hallmarks of astrogliosis, in both the in vivo and in vitro models. Thus, our study demonstrates a novel role of GDNF in modifying spinal cord injury (SCI)-induced astrogliosis resulting in robust axonal regeneration in adult rats. PMID- 21316364 TI - Disordered TPPP/p25 binds GTP and displays Mg2+-dependent GTPase activity. AB - The disordered Tubulin Polymerization Promoting Protein/p25 (TPPP/p25) modulates the dynamics and stability of the microtubule system and plays a crucial role in differentiation of oligodendrocytes. Here we first demonstrated by multinuclear NMR that the extended disordered segments are localized at the N- and C-terminals straddling a flexible region. We showed by affinity chromatography, fluorescence spectroscopy and circular dichroism that GTP binds to TPPP/p25 likely within the flexible region; neither positions nor intensities of the peaks in the assigned terminals were affected by GTP. In addition, we demonstrated that TPPP/p25 specifically hydrolyses GTP in an Mg(2+)-dependent manner. The GTPase activity is comparable with the intrinsic activities of small G proteins suggesting its potential role in multiple physiological processes. PMID- 21316365 TI - Chronotype changes during puberty depend on gonadal hormones in the slow developing rodent, Octodon degus. AB - During puberty, human adolescents develop a later chronotype, exhibiting a delay in the timing of rest and activity as well as other daily physiological rhythms. The purpose of this study was to determine whether similar changes in chronotype occur during puberty in a laboratory rodent species, and, if so, to determine whether they are due to pubertal hormones acting on the circadian timekeeping system. To test this hypothesis, we carefully tracked daily activity rhythms across puberty in the slow-developing rodent Octodon degus. We confirmed that male degus showed a large reorganization of activity rhythms that correlated with secondary sex development during puberty, including a loss of bimodality and a 3 5 h phase-advance. Similar to humans, this circadian reorganization showed distinct sex differences, with females showing little change during puberty in two separate experiments. Prepubertal gonadectomy (GDX) eliminated the changes, whereas SHAM gonadectomy had little impact. Therefore, gonadal hormones are likely to play a role in pubertal changes in chronotype in this rodent species. Using evidence from a variety of species, including our recent studies in the rat, we conclude that chronotype changes during puberty are a well-demonstrated phenomenon in mammals. PMID- 21316366 TI - Chemosensory and hormone information are relayed directly between the medial amygdala, posterior bed nucleus of the stria terminalis, and medial preoptic area in male Syrian hamsters. AB - In many rodent species, including Syrian hamsters, the expression of appropriate social behavior depends critically on the perception and identification of conspecific odors. The behavioral response to these odors is mediated by a network of steroid-sensitive ventral forebrain nuclei including the medial amygdala (Me), posterior bed nucleus of the stria terminalis (BNST), and medial preoptic area (MPOA). Although it is well-known that Me, BNST, and MPOA are densely interconnected and each uniquely modulates odor-guided social behaviors, the degree to which conspecific odor information and steroid hormone cues are directly relayed between these nuclei is unknown. To answer this question, we injected the retrograde tracer, cholera toxin B (CTB), into the BNST or MPOA of male subjects and identified whether retrogradely-labeled cells in Me and BNST 1) expressed immediate early genes (IEGs) following exposure to male and/or female odors or 2) expressed androgen receptor (AR). Although few retrogradely-labeled cells co-localized with IEGs, a higher percentage of BNST- and MPOA-projecting cells in the posterior Me (MeP) expressed IEGs in response to female odors than to male odors. The percentage of retrogradely-labeled cells that expressed IEGs did not, however, differ between and female and male odor-exposed groups in the anterior Me (MeA), posterointermediate BNST (BNSTpi), or posteromedial BNST (BNSTpm). Many retrogradely-labeled cells co-localized with AR, and a higher percentage of retrogradely-labeled MeP and BNSTpm cells expressed AR than retrogradely-labeled MeA and BNSTpi cells, respectively. Together, these data demonstrate that Me, BNST, and MPOA interact as a functional circuit to process sex-specific odor cues and hormone information in male Syrian hamsters. PMID- 21316368 TI - Post-weaning social isolation induces abnormal forms of aggression in conjunction with increased glucocorticoid and autonomic stress responses. AB - We showed earlier that social isolation from weaning (a paradigm frequently used to model social neglect in children) induces abnormal forms of attack in rats, and assumed that these are associated with hyperarousal. To investigate this hypothesis, we deprived rats of social contacts from weaning and studied their behavior, glucocorticoid and autonomic stress responses in the resident-intruder paradigm at the age of 82 days. Social isolation resulted in abnormal attack patterns characterized by attacks on vulnerable targets, deficient social communication and increased defensive behaviors (defensive upright, flight, freezing). During aggressive encounters, socially deprived rats rapidly switched from one behavior to another, i.e. showed an increased number of behavioral transitions as compared to controls. We tentatively term this behavioral feature "behavioral fragmentation" and considered it a form of behavioral arousal. Basal levels of plasma corticosterone regularly assessed by radioimmunoassay between 27 and 78 days of age were not affected. In contrast, aggression-induced glucocorticoid responses were approximately doubled by socially isolation. Diurnal oscillations in heart rate assessed by in vivo biotelemetry were not affected by social isolation. In contrast, the aggression-induced increase in heart rate was higher in socially isolated than in socially housed rats. Thus, post-weaning social isolation induced abnormal forms of aggression that developed on the background of increased behavioral, endocrine and autonomic arousal. We suggest that this paradigm may be used to model aggression-related psychopathologies associated with hyperarousal, particularly those that are triggered by adverse rearing conditions. PMID- 21316367 TI - Estradiol effects on behavior and serum oxytocin are modified by social status and polymorphisms in the serotonin transporter gene in female rhesus monkeys. AB - Despite the well-documented relation between estradiol (E2) and behavior, exposure to stressors may modify sensitivity to E2. The effects of E2 on behavior are, in part, likely related to their modulation of the serotonin (5HT) and oxytocin systems. The short allele (s-variant) polymorphism found in the promoter region of the SLC6A4 gene that encodes the 5HT transporter (5HTT) modulates responsivity to stressors. The current study used ovariectomized adult female rhesus monkeys to evaluate how exposure to the psychosocial stressor of social subordination and polymorphisms in the gene encoding 5HTT influence the behavioral effects of E2 and immunoreactive serum oxytocin. Dominant females had higher levels of oxytocin than subordinate animals even though E2 increased immunoreactive serum oxytocin in all females. E2 increased affiliative behaviors in all animals, with even more of these prosocial behaviors directed at dominant females. S-variant females, regardless of social status, were more aggressive toward more subordinate cage mates and these behaviors too were increased by E2. Subordinate s-variant females are most often involved in agonistic behavior, less affiliative behavior, and were less responsive to the anxiolytic action of E2. The results show that the short allele of the 5HTT gene synergizes with psychosocial stress exposure to affect the behavioral efficacy of E2 while confirming the actions of E2 for producing generalized behavioral arousal in females. Whether differences in the central action of 5HT and/or oxytocin are responsible for this effect requires further study. PMID- 21316369 TI - Identification of targeting peptides for ischemic myocardium by in vivo phage display. AB - Therapies selectively targeting ischemic myocardium could be applied by intravenous injection. Here, we report an approach for ischemic tissue-selective targeting based on in vivo screening of random peptide sequences using phage display. We performed in vivo biopanning using a phage library in a rat model of ischemia-reperfusion and identified three peptide motifs, CSTSMLKAC, CKPGTSSYC, and CPDRSVNNC, that exhibited preferential binding to ischemic heart tissue compared to normal heart as well as other control organs. The CSTSMLKAC sequence was capable of mediating selective homing of phage to ischemic heart tissue. The CSTSMLKAC peptide was then made as a fusion protein with Sumo-mCherry and injected intravenously in a mouse model of myocardial ischemia-reperfusion injury; subsequently, bio-distribution of Sumo-mCherry-CSTSMLKAC was measured with quantitative ELISA. The targeting peptide led to a significant increase in homing to ischemic left ventricle compared to tissues from non-ischemic left ventricle, the right ventricle, lung, liver, spleen, skeletal muscle, and brain (all p<0.001). These results indicate that the peptide sequence CSTSMLKAC represents a novel molecular tool that may be useful in targeting ischemic tissue and delivering bioengineered proteins into the injured myocardium by systemic intravenous administration. PMID- 21316370 TI - Modulating iNOS-uncoupling: a new therapeutic avenue to tackle reperfusion injury? PMID- 21316371 TI - A proteomic study of myosin II motor proteins during tumor cell migration. AB - Myosin II motor proteins play important roles in cell migration. Although myosin II filament assembly plays a key role in the stabilization of focal contacts at the leading edge of migrating cells, the mechanisms and signaling pathways regulating the localized assembly of lamellipodial myosin II filaments are poorly understood. We performed a proteomic analysis of myosin heavy chain (MHC) phosphorylation sites in MDA-MB 231 breast cancer cells to identify MHC phosphorylation sites that are activated during integrin engagement and lamellar extension on fibronectin. Fibronectin-activated MHC phosphorylation was identified on novel and previously recognized consensus sites for phosphorylation by protein kinase C and casein kinase II (CK-II). S1943, a CK-II consensus site, was highly phosphorylated in response to matrix engagement, and phosphoantibody staining revealed phosphorylation on myosin II assembled into leading-edge lamellae. Surprisingly, neither pharmacological reduction nor small inhibitory RNA reduction in CK-II activity reduced this stimulated S1943 phosphorylation. Our data demonstrate that S1943 phosphorylation is upregulated during lamellar protrusion, and that CK-II does not appear to be the kinase responsible for this matrix-induced phosphorylation event. PMID- 21316372 TI - Consequences of the overexpression of a eukaryotic membrane protein, the human KDEL receptor, in Escherichia coli. AB - Escherichia coli is the most widely used host for producing membrane proteins. Thus far, to study the consequences of membrane protein overexpression in E. coli, we have focussed on prokaryotic membrane proteins as overexpression targets. Their overexpression results in the saturation of the Sec translocon, which is a protein-conducting channel in the cytoplasmic membrane that mediates both protein translocation and insertion. Saturation of the Sec translocon leads to (i) protein misfolding/aggregation in the cytoplasm, (ii) impaired respiration, and (iii) activation of the Arc response, which leads to inefficient ATP production and the formation of acetate. The overexpression yields of eukaryotic membrane proteins in E. coli are usually much lower than those of prokaryotic ones. This may be due to differences between the consequences of the overexpression of prokaryotic and eukaryotic membrane proteins in E. coli. Therefore, we have now also studied in detail how the overexpression of a eukaryotic membrane protein, the human KDEL receptor, affects E. coli. Surprisingly, the consequences of the overexpression of a prokaryotic and a eukaryotic membrane protein are very similar. Strain engineering and likely also protein engineering can be used to remedy the saturation of the Sec translocon upon overexpression of both prokaryotic and eukaryotic membrane proteins in E. coli. PMID- 21316373 TI - Inhibition of Escherichia coli RNAp by T7 Gp2 protein: role of negatively charged strip of amino acid residues in Gp2. AB - Gp2, a 7 kDa protein encoded by T7 bacteriophage, is a potent inhibitor of Escherichia coli RNA polymerase (RNAp), the enzyme responsible for transcription of all bacterial genes and early viral genes. A prominent feature in the structure of Gp2 is a contiguous strip of seven negatively charged amino acid residues (negatively charged strip or NCS), located along one side of the molecule. The role of the NCS in Gp2 function is not known. Here, the in vivo and in vitro properties of altered forms of Gp2 with amino acid substitutions in the NCS are described. While mutations in the NCS do not compromise the folding or the ability of Gp2 to bind to the RNAp beta' subunit, disruption of the NCS significantly attenuates Gp2 function in vivo and its ability to inhibit RNAp in vitro. Efficient inhibition of the RNAp by Gp2 also involves the amino terminal region 1 domain of the RNAp promoter specificity subunit sigma(70), located in the vicinity of the primary Gp2 binding site in beta'. The results are discussed in the context of hypothetical molecular mechanisms of RNAp inhibition by Gp2. PMID- 21316374 TI - Sigma(70)-dependent transcription pausing in Escherichia coli. AB - After promoter escape in Escherichia coli, the initiating sigma(70) factor is retained by core RNA polymerase (RNAP) for at least tens of nucleotides. While it is bound, sigma(70) can engage a repeat of a promoter DNA element located downstream of the promoter and thereby induce a transcription pause. The sigma(70)-dependent promoter-proximal pause that occurs at all lambdoid phage late gene promoters is essential to regulation of the late gene operons. Several, and possibly many, E. coli promoters have associated sigma(70)-dependent pauses. Clearly characterized sigma(70)-dependent pauses occur within 25 nucleotides of the start site, but sigma(70)-dependent pausing might occur farther downstream as well. In this review, we summarize evidence for sigma(70)-dependent promoter proximal and promoter-distal pausing, and we discuss its potential regulatory function and mechanistic basis. PMID- 21316375 TI - Born to dance but beat deaf: a new form of congenital amusia. AB - Humans move to the beat of music. Despite the ubiquity and early emergence of this response, some individuals report being unable to feel the beat in music. We report a sample of people without special training, all of whom were proficient at perceiving and producing the musical beat with the exception of one case ("Mathieu"). Motion capture and psychophysical tests revealed that people synchronized full-body motion to music and detected when a model dancer was not in time with the music. In contrast, Mathieu failed to period- and phase-lock his movement to the beat of most music pieces, and failed to detect most asynchronies of the model dancer. Mathieu's near-normal synchronization with a metronome suggests that the deficit concerns beat finding in the context of music. These results point to time as having a distinct neurobiological origin from pitch in music processing. PMID- 21316376 TI - Haptic perception and body representation in lateral and medial occipito-temporal cortices. AB - Although vision is the primary sensory modality that humans and other primates use to identify objects in the environment, we can recognize crucial object features (e.g., shape, size) using the somatic modality. Previous studies have shown that the occipito-temporal areas dedicated to the visual processing of object forms, faces and bodies also show category-selective responses when the preferred stimuli are haptically explored out of view. Visual processing of human bodies engages specific areas in lateral (extrastriate body area, EBA) and medial (fusiform body area, FBA) occipito-temporal cortex. This study aimed at exploring the relative involvement of EBA and FBA in the haptic exploration of body parts. During fMRI scanning, participants were asked to haptically explore either real size fake body parts or objects. We found a selective activation of right and left EBA, but not of right FBA, while participants haptically explored body parts as compared to real objects. This suggests that EBA may integrate visual body representations with somatosensory information regarding body parts and form a multimodal representation of the body. Furthermore, both left and right EBA showed a comparable level of body selectivity during haptic perception and visual imagery. However, right but not left EBA was more activated during haptic exploration than visual imagery of body parts, ruling out that the response to haptic body exploration was entirely due to the use of visual imagery. Overall, the results point to the existence of different multimodal body representations in the occipito-temporal cortex which are activated during perception and imagery of human body parts. PMID- 21316377 TI - Introduction to the festschrift. PMID- 21316378 TI - Leap of faith: voluntary emersion behaviour and physiological adaptations to aerial exposure in a non-aestivating freshwater fish in response to aquatic hypoxia. AB - Lowland stream fauna in areas of intensive agriculture are increasingly under threat from anthropogenic activities leading to eutrophication and subsequent hypoxia. Survival of hypoxic episodes depends upon a combination of behavioural and physiological adaptations. Responses of inanga (Galaxias maculatus: Galaxiidae) to aquatic hypoxia were investigated in the laboratory. Contrary to expectation inanga did not display behaviour that might reduce energy expenditure during oxygen limitation, with swimming activity slightly, but significantly elevated relative to normoxia. Instead, as dissolved oxygen concentrations decreased, the fish moved higher in the water column, increased their swimming speed and exhibited aquatic surface respiration. Physiological changes such as enhanced opercular frequency were also noted. As hypoxia deepened inanga started to leap out of the water, emersing themselves on a floating platform. Once emersed, fish exhibited an enhanced oxygen consumption rate compared to hypoxic fish. Thus inanga appear better adapted to escape hypoxia (a behavioural adaptation) rather than tolerate it (physiological adaptation). The emersion strategy used for inanga in response to severe hypoxia is in agreement with their ability to take up more oxygen from the air than from hypoxic water and therefore may justify the potentially increased risks of desiccation and predation associated with leaving the water. PMID- 21316380 TI - The final problem. PMID- 21316379 TI - Comparisons of insulin related parameters in commercial-type chicks: Evidence for insulin resistance in broiler chicks. AB - The aim of this study is to elucidate whether insulin acts differentially within the central nervous system (CNS) of two types of commercial chicks to control ingestive behavior. Male layer and broiler chicks (4-day-old) were intracerebroventricularly (ICV) injected with saline or insulin under satiated and starved conditions. Feed intake was measured at 30, 60 and 120 min after treatment. Secondly, blood and hypothalamus were collected from both chick types under ad libitum feeding and fasting for 24 h. Plasma insulin concentration was measured by time-resolved fluoro-immunoassay. Hypothalamic insulin receptor mRNA expression levels were measured by quantitative RT-PCR. The ICV injection of insulin significantly inhibited feed consumption in layer chicks when compared with saline (P<0.05), but not broiler chicks (P>0.1). Plasma insulin concentration of both chick types significantly decreased following 24 h of fasting, while insulin concentrations in the broiler chicks were significantly higher compared to the layers fed under ad libitum conditions. Hypothalamic insulin receptor mRNA expression levels were significantly lower (P<0.05) in broiler chicks than in layer ones under ad libitum feeding. Feed deprivation significantly decreased insulin receptor mRNA levels in layer chicks (P<0.01), but not in broiler chicks (P>0.1). Moreover, plasma insulin concentrations correlated negatively with hypothalamic insulin receptor protein expression in the two types of chicks fed ad libitum (P<0.05). These results suggest that insulin resistance exists in the CNS of broiler chicks, possibly due to persistent hyperinsulinemia, which results in a down-regulation of CNS insulin receptor expression compared to that in layer chicks. PMID- 21316381 TI - Alteration in contractile G-protein coupled receptor expression by moist snuff and nicotine in rat cerebral arteries. AB - The cardiovascular risk for users of use of Swedish snus/American snuff (moist tobacco) has been debated for a long time. The present study was designed to examine the effects of water- or lipid-soluble (DMSO-soluble) snus and nicotine, the most important substance in tobacco, on the expression of vasocontractile G protein coupled receptors (GPCR), such as endothelin ET(B), serotonin 5-HT(1B), and thromboxane A(2) TP receptors, in rat cerebral arteries. Studies show that these vasocontractile GPCR show alterations by lipid-soluble cigarette smoke particles via activation of mitogen-activated protein kinases (MAPK). However, the effects of moist tobacco on the expression of GPCR are less studied. Rat middle cerebral arteries were isolated and organ cultured in serum-free medium for 24h in the presence of water-soluble snus (WSS), DMSO-soluble snus (DSS), or nicotine. The dose of snus and nicotine was kept at plasma level of snus users (25ng nicotine/ml). A high dose (250ng nicotine/ml) was also included due to the previous results showing alteration in the GPCR expression by nicotine at this concentration. Contractile responses to the ET(B) receptor agonist sarafotoxin 6c, 5-HT(1B) receptor agonist 5-carboxamidotryptamine, and TP receptor agonist U46619 were investigated by a sensitive myograph. The expression of ET(B), 5 HT(1B), and TP receptors was studied at mRNA and protein levels using quantitative real-time PCR and immunohistochemistry, respectively. Organ culture with WSS or DSS (25ng nicotine/ml) lowered the 5-HT(1B) receptor-mediated contraction. Furthermore, DSS shifted the TP receptor-mediated contraction curve left-wards with a stronger contraction. High dose of nicotine (250ng nicotine/ml) increased the ET(B) receptor-mediated contraction. The combined 5-HT(1B) and 5 HT(2A) receptor-mediated contraction was increased, and both the 5-CT and TxA2 induced contractions were left-ward shifted by WSS, DSS, or nicotine (250ng nicotine/ml). Only the DSS group showed that the increase of 5-HT(1B) receptor mediated contraction occurred at the transcriptional level, demonstrated by an increased mRNA expression for the receptor. Thus, snus and nicotine alter the GPCR expression in the cerebral arteries, which may be involved in cerebral vascular disease. PMID- 21316382 TI - Comparison of imatinib, nilotinib and silymarin in the treatment of carbon tetrachloride-induced hepatic oxidative stress, injury and fibrosis. AB - Effective and well-tolerated anti-fibrotic drugs are currently lacking. Therefore, this study was carried out to investigate the potential anti-fibrotic effects of imatinib, nilotinib and silymarin on established hepatic fibrosis in the carbon tetrachloride (CCl(4)) rat model. Male Wistar rats received intraperitoneal injections of CCl(4) twice weekly for 8weeks, as well as daily intraperitoneal treatments of imatinib (10 and 20mg/kg), nilotinib (10 and 20mg/kg) and silymarin (100mg/kg) during the last 4weeks of CCl(4)-intoxication. At the end of the study, hepatic damage was evaluated by analysis of liver function tests and hepatic oxidative stress parameters. Hepatic fibrosis was evaluated by histopathology and morphometry, as well as collagen and 4 hydroxyproline contents. Nilotinib (20mg/kg) was the most effective treatment to counteract CCl(4)-induced hepatic injury as indicated by liver function tests and histopathology. Nilotinib (10mg/kg), nilotinib (20mg/kg) and silymarin (100mg/kg) treatments reduced the mean score of hepatic fibrosis by 31%, 68% and 47%, respectively, and hepatic collagen content by 47%, 49% and 18%, respectively in CCl(4)-treated rats. Hepatic morphometric evaluation and 4-hydroxyproline content revealed that CCl(4)-induced fibrosis was ameliorated significantly by nilotinib (20mg/kg) and imatinib (20mg/kg). Unlike nilotinib, imatinib (20mg/kg) showed some sort of hepatic injury evidenced by elevation of serum aminotransferases and total bilirubin levels, and hepatic total nitrate/nitrite content, as well as characteristic anisonucleosis visualized with the hematoxylin-eosin staining. In conclusion, this study provides the evidence that nilotinib exerts anti-fibrotic activity and suggests that it may be valuable in the treatment of hepatic fibrosis in humans. PMID- 21316383 TI - Acetaminophen hepatotoxicity and HIF-1alpha induction in acetaminophen toxicity in mice occurs without hypoxia. AB - HIF-1alpha is a nuclear factor important in the transcription of genes controlling angiogenesis including vascular endothelial growth factor (VEGF). Both hypoxia and oxidative stress are known mechanisms for the induction of HIF 1alpha. Oxidative stress and mitochondrial permeability transition (MPT) are mechanistically important in acetaminophen (APAP) toxicity in the mouse. MPT may occur as a result of oxidative stress and leads to a large increase in oxidative stress. We previously reported the induction of HIF-1alpha in mice with APAP toxicity and have shown that VEGF is important in hepatocyte regeneration following APAP toxicity. The following study was performed to examine the relative contribution of hypoxia versus oxidative stress to the induction of HIF 1alpha in APAP toxicity in the mouse. Time course studies using the hypoxia marker pimonidazole showed no staining for pimonidazole at 1 or 2h in B6C3F1 mice treated with APAP. Staining for pimonidazole was present in the midzonal to periportal regions at 4, 8, 24 and 48h and no staining was observed in centrilobular hepatocytes, the sites of the toxicity. Subsequent studies with the MPT inhibitor cyclosporine A showed that cyclosporine A (CYC; 10mg/kg) reduced HIF-1alpha induction in APAP treated mice at 1 and 4h and did not inhibit the metabolism of APAP (depletion of hepatic non-protein sulfhydryls and hepatic protein adduct levels). The data suggest that HIF-1alpha induction in the early stages of APAP toxicity is secondary to oxidative stress via a mechanism involving MPT. In addition, APAP toxicity is not mediated by a hypoxia mechanism. PMID- 21316384 TI - Perceptual learning in visual hyperacuity: A reweighting model. AB - Improvements of visual hyperacuity are a key focus in research of perceptual learning. Of particular interest has been the specificity of visual hyperacuity learning to the particular features of the trained stimuli as well as disruption of learning that occurs in some cases when different stimulus features are trained together. The implications of these phenomena on the underlying learning mechanisms are still open to debate; however, there is a marked absence of computational models that explore these phenomena in a unified way. Here we implement a computational learning model based on reweighting and extend it to enable direct comparison, by means of simulations, with a variety of existing psychophysical data. We find that this very simple model can account for a diversity of findings, such as disruption of learning of one task by practice on a similar task, as well as transfer of learning across both tasks and stimulus configurations under certain conditions. These simulations help explain existing results in the literature as well as provide important insights and predictions regarding the reliability of different hyperacuity tasks and stimuli. Our simulations also shed light on the model's limitations, for example in accounting for temporal aspects of training procedures or dependency of learning with contextual stimuli, which will need to be addressed by future research. PMID- 21316385 TI - Dissociation between intentional and automatic remapping: different levels of inter-hemispheric transfer. AB - In order to efficiently interact with our environment we need to constantly to update the spatial representation of visual targets for movement. This is required not only when we move our eyes but also when we want to reach toward a location different from the actual physical target (for example symmetrical). These two types of remapping are very different in nature, one being automatic, and the other intentional. However, they both have been shown to involve the posterior parietal cortex (PPC). To further investigate the role of this brain region in automatic and intentional remapping processes and the level of inter hemispheric transfer of visuo-motor information in these two conditions of reaching, we tested two patients with unilateral optic ataxia (OA) in two different tasks: reaching to a memorised visual target after an intervening eye movement (trans-saccadic remapping) and an anti-reaching task. We showed that lesions of the PPC had different implications for these two tasks. In the trans saccadic remapping task, movements toward the contralesional field were disrupted, even when the visual target was presented in the ipsilesional field. In contrast, in the anti-reaching task, the patients were mostly impaired in conditions where the target was presented in the contralesional field, even if the movement was executed toward the ipsilesional field. We postulate that the transfer of the visuo-motor information between hemispheres occurs before the parietal cortex in trans-saccadic remapping (transfer of visual information), and at the parietal level or after in anti-reaching (transfer of visuo-motor information). PMID- 21316386 TI - A 2-dimensional geometry for biological time. AB - This paper proposes an abstract mathematical frame for describing some features of biological time. The key point is that usual physical (linear) representation of time is insufficient, in our view, for the understanding key phenomena of life, such as rhythms, both physical (circadian, seasonal...) and properly biological (heart beating, respiration, metabolic...). In particular, the role of biological rhythms do not seem to have any counterpart in mathematical formalization of physical clocks, which are based on frequencies along the usual (possibly thermodynamical, thus oriented) time. We then suggest a functional representation of biological time by a 2-dimensional manifold as a mathematical frame for accommodating autonomous biological rhythms. The "visual" representation of rhythms so obtained, in particular heart beatings, will provide, by a few examples, hints towards possible applications of our approach to the understanding of interspecific differences or intraspecific pathologies. The 3-dimensional embedding space, needed for purely mathematical reasons, allows to introduce a suitable extra-dimension for "representation time", with a cognitive significance. PMID- 21316387 TI - Cognitive enhancers for the treatment of neuropsychiatric disorders: clinical and preclinical investigations. PMID- 21316388 TI - Effects of LPS and serotonergic drugs on hygienic behavior in mice. AB - Hygienic self-grooming is a behavioral adaptation for removing litter particles and pathogenic agents from animal fur and skin. We studied contribution of brain serotonin system into mechanisms regulating hygienic behavior in intact mice and mice with LPS(lipopolysaccharide)-induced sickness. A spot of fluorescent dye was applied on the back of a mouse, and the decrease in its fluorescence served as an index of fur cleaning efficiency estimated using original classifier algorithm. Agonist of 5-HT(1A) receptor (8-OH-DPAT) or 5-HT(2A/2C) receptor (DOI) attenuated fur cleaning at a dose of 1 mg/kg but not of 0.2 mg/kg. MAO-A inhibitor clorgyline decreased hygienic self-grooming at a dose of 10 but not of 5 mg/kg. SSRI paroxetine had no effect while fluoxetine diminished hygienic behavior at the higher dose used (20 mg/kg). Inhibitory effect of LPS treatment (50 MUg/kg) on fur cleaning was not altered by administration of p-MPPI (5-HT(1A) receptor antagonist, 1mg/kg) or DOI (1mg/kg) while 8-OH-DPAT (1 mg/kg) produced additive effect. The results suggest the involvement of 5-HT(1A) and 5-HT(2A/2C) brain serotonin receptors and MAO-A in the inhibition of hygienic behavior in mice. However, LPS-induced depression of fur cleaning appeared to be mediated via different mechanisms and enhanced by 5-HT(1A) receptor activation. PMID- 21316389 TI - Depletion of CD8 alpha cells from tissues of Atlantic salmon during the early stages of infection with high or low virulent strains of infectious salmon anaemia virus (ISAV). AB - The virulence of an infectious salmon anaemia virus (ISAV) isolate is influenced by the response of the host's immune system to virus infection. Here we report the fate of immune responsive cells in head kidney, spleen and gills of Atlantic salmon during infection with high and low virulent strains of ISAV. A comparison of real-time PCR detection of virus and immunohistochemical detection of immune responsive cells revealed that peak viral load was coincident with both an elevated presence of MHC class I cells and a marked depletion of CD8 alpha cells. There was a larger CD8 alpha population in tissues from salmon infected with the low virulent strain compared with tissues from salmon infected with the high virulent strain at early stages of infection. These findings suggest a protective role for the CD8 alpha cell population in immune defences against ISAV. PMID- 21316390 TI - Report on the 22nd annual meeting of the Japanese Association for Developmental and Comparative Immunology (JADCI), August 2-4, 2010, Nishijin Plaza, Kyushu University, Fukuoka (Local Organizer: Shun-ichiro Kawabata, Kyushu University). PMID- 21316391 TI - Stress revisited: a critical evaluation of the stress concept. AB - With the steadily increasing number of publications in the field of stress research it has become evident that the conventional usage of the stress concept bears considerable problems. The use of the term 'stress' to conditions ranging from even the mildest challenging stimulation to severely aversive conditions, is in our view inappropriate. Review of the literature reveals that the physiological 'stress' response to appetitive, rewarding stimuli that are often not considered to be stressors can be as large as the response to negative stimuli. Analysis of the physiological response during exercise supports the view that the magnitude of the neuroendocrine response reflects the metabolic and physiological demands required for behavioural activity. We propose that the term 'stress' should be restricted to conditions where an environmental demand exceeds the natural regulatory capacity of an organism, in particular situations that include unpredictability and uncontrollability. Physiologically, stress seems to be characterized by either the absence of an anticipatory response (unpredictable) or a reduced recovery (uncontrollable) of the neuroendocrine reaction. The consequences of this restricted definition for stress research and the interpretation of results in terms of the adaptive and/or maladaptive nature of the response are discussed. PMID- 21316392 TI - Bioluminescence technologies to detect calicivirus protease activity in cell-free system and in infected cells. AB - Feline calicivirus (FCV) is an important veterinary pathogen and causes respiratory disease in cats. Because it grows well in cell culture, FCV is often used as a model virus of non-culturable caliciviruses. In this study, a cell-free and two cell culture-based biosensor assay systems were established to detect FCV protease activity. The assays utilize luciferase sensor technology or second generation bioluminescence resonance energy transfer (BRET2). A luciferase sensor was designed to contain an FCV protease cleavage motif within the permutated luciferase (GloSensor). The BRET2-based probe contained the same cleavage motif flanked by a renilla luciferase and a variant of green fluorescent protein. To confirm the specificity of these assay systems, GloSensor or a BRET2-based probe containing a mutation in the cleavage motif was also constructed. In a cell-free assay, GloSensor showed increased luminescence in proportion to the amount of FCV protease, while no signal change was observed when the construct harboring the mutant cleavage motif was used. A feline cell line stably expressing GloSensor or the BRET2-based probe was established. Increased levels of GloSensor luminescence, and decreased levels of BRET2 signals were observed according to input FCV titers. In contrast, no significant signal change was observed in the cells stably expressing the mutant cleavage motif. GloSensor and the BRET2-based probe were capable of detecting the inhibitory activity of ribavirin in FCV infected cells. Our results demonstrate that these biosensors are useful to detect FCV protease activity induced in infected cells, and well worth consideration for screening of anti-FCV protease compounds in cell-free system as well as anti-FCV compounds in cultured cells. PMID- 21316393 TI - A single intramuscular injection of neuraminidase inhibitor peramivir demonstrates antiviral activity against novel pandemic A/California/04/2009 (H1N1) influenza virus infection in mice. AB - New and emerging influenza virus strains, such as the pandemic influenza A (H1N1) virus require constant vigilance for antiviral drug sensitivity and resistance. Efficacy of intramuscularly (IM) administered neuraminidase (NA) inhibitor, peramivir, was evaluated in mice infected with recently isolated pandemic A/California/04/2009 (H1N1, swine origin, mouse adapted) influenza virus. A single IM injection of peramivir (four dose groups), given 1h prior to inoculation, significantly reduced weight loss (p < 0.001) and mortality (p < 0.05) in mice infected with LD90 dose of pandemic A/California/04/2009 (H1N1) influenza virus compared to vehicle group. There was 20% survival in the vehicle treated group, whereas in the peramivir-treated groups, survival increased in a dose-dependent manner with 60, 60, 90 and 100% survivors for the 1, 3, 10, and 30 mg/kg doses, respectively. Weight loss on day 4 in the vehicle-treated group was 3.4 gm, and in the peramivir-treated groups was 2.1, 1.5, 1.8 and 1.8 g for the 1, 3, 10 and 30 mg/kg dose groups, respectively. In the treatment model, peramivir given 24h after infection as a single IM injection at 50mg/kg dose, showed significant protection against lethality and weight loss. There was 13% survival in the vehicle-treated group while in the peramivir-treated group at 24, 48, and 72 h post infection, survival was 100, 40, and 50%, respectively. Survival in the oseltamivir groups (10 mg/kg/d twice a day, orally for 5 days) was 90, 30 and 20% at 24, 48 and 72 h, respectively. These data demonstrate efficacy of parenterally administered peramivir against the recently isolated pandemic influenza virus in murine infection models. PMID- 21316394 TI - Predictive validity of a non-induced mouse model of compulsive-like behavior. AB - A key to advancing the understanding of obsessive-compulsive disorder (OCD)-like symptoms is the development of spontaneous animal models. Over 55 generations of bidirectional selection for nest-building behavior in house mice, Mus musculus, resulted in a 40-fold difference in the amount of cotton used for a nest in high (BIG) and low (SMALL) selected lines. The nesting behavior of BIG mice appears to be compulsive-like and has initial face validity as an animal model for OCD in humans. Compulsive-like digging behavior was assessed; BIG male mice buried about three times as many marbles as SMALL male mice, strengthening face validity. Using the open field and elevated plus maze, SMALL male mice showed higher levels of anxiety/fear-like behavior than BIG male mice, indicating that compulsive-like and not anxiety-like behavior was measured. To establish predictive validity, chronic (4 weeks) oral administration of fluoxetine (30, 50 and 100mg/kg/day) and clomipramine (80 mg/kg/day), both effective in treating OCD, significantly reduced compulsive-like nest-building behavior in BIG male mice. Compulsive-like digging behavior was also significantly reduced by chronic oral fluoxetine (30 and 80 mg/kg/day) treatment in BIG male mice. General locomotor activity was not affected by chronic oral fluoxetine (30 and 80 mg/kg/day) treatment; chronic oral treatment with desipramine (30 mg/kg/day), an antidepressant not effective in treating OCD, had no effect on nesting behavior of BIG male mice, strengthening predictive validity. Together, the results indicate that these mice have good face and predictive validity as a non-induced mouse model of compulsive-like behavior relevant to OCD. PMID- 21316395 TI - Sensory mismatch induces autonomic responses associated with hippocampal theta waves in rats. AB - Hippocampal (HIP) theta power increases during sensory mismatch, which has been suggested to induce motion sickness with autonomic abnormality (Zou et al., 2009 [29]). To investigate relationships between hippocampal theta rhythm and autonomic functions, theta waves in the HIP and electrocardiograms (ECGs) were recorded during sensory mismatch by backward translocation in awake rats. The rats were placed on a treadmill affixed to a motion stage that was translocated along a figure 8-shaped track. The rats were trained to run forward on the treadmill at the same speed as that of forward translocation of the motion stage (a forward condition) before the experimental (recording) sessions. In the experimental sessions, the rats were initially tested in the forward condition, and then tested in a backward (mismatch) condition, in which the motion stage was turned around by 180 degrees before translocation. That is, the rats were moved backward by translocation of the stage although the rats ran forward on the treadmill. In this condition, proprioceptive information indicated forward movements while vestibular and visual information indicated backward movements. The theta (6-9 Hz) power was significantly increased in the backward condition compared with the forward condition. Spectral analysis of heart rate variability indicated that sympathetic nervous activity increased in the backward condition. These data (theta power and sympathetic nervous activity) were positively correlated. Furthermore, electrical stimulation of the HIP at theta rhythm (8 Hz) increased heart rate. These results suggest that sensory mismatch information activates the HIP to induce autonomic alteration in motion sickness. PMID- 21316396 TI - Increased anxiety-related behaviour in Hint1 knockout mice. AB - Several reports have implicated a role for the histidine triad nucleotide-binding protein-1 (Hint1) in psychiatric disorders. We have studied the emotional behaviour of male Hint1 knockout (Hint1 KO) mice in a battery of tests and performed biochemical analyses on brain tissue. The behavioural analysis revealed that Hint1 KO mice exhibit an increased emotionality phenotype compared to wildtype (WT) mice, while no significant differences in locomotion or general exploratory activity were noted. In the elevated plus-maze (EPM) test, the Hint1 KO animals entered the open arms of the apparatus less often than WT littermates. Similarly, in the dark-light box test, Hint1 KO mice spent less time in the lit compartment and the number of entries were reduced, which further confirmed an increased anxiety-related behaviour. Moreover, the Hint1 KO animals showed significantly more struggling and less floating behaviour in the forced swim test (FST), indicating an increased emotional arousal in aversive situations. Hint1 is known as a protein kinase C (PKC) interacting protein. Western blot analysis showed that PKCgamma expression was elevated in Hint1 KO compared to WT mice. Interestingly, PKCgamma mRNA levels of the two groups did not show a significant difference, implying a post-transcriptional PKCgamma regulation. In addition, PKC enzymatic activity was increased in Hint1 KO compared to WT mice. In summary, our results indicate a role for Hint1 and PKCgamma in modulating anxiety-related and stress-coping behaviour in mice. PMID- 21316397 TI - Individual variation in the propensity to attribute incentive salience to an appetitive cue predicts the propensity to attribute motivational salience to an aversive cue. AB - It has been proposed that animals that attribute high levels of incentive salience to reward-related cues may be especially vulnerable to addiction. Individual variation has also been observed in the motivational value attributed to aversive cues, which may confer vulnerability to anxiety disorders such as post-traumatic stress disorder (PTSD). There may be a core behavioral trait that contributes to individual variation in the motivational value assigned to predictive cues regardless of emotional valence. To test this hypothesis, we used a Pavlovian conditioned approach procedure to classify rats based on whether they learned to approach and interact with a cue predicting food reward (sign trackers) or learned upon cue presentation to go to the location of impending food delivery (goal-trackers), and then examined Pavlovian fear conditioning in the same animals. It has recently been proposed that sign-trackers are more vulnerable to substance abuse because they attribute greater incentive motivational value to drug cues. Here we show that sign-trackers also have a tendency to be more fearful of discrete cues that predict footshock. In addition, we found that goal-trackers exhibited greater contextual fear when placed back into the original fear-conditioning context in the absence of temporally discrete cues. These results suggest that there may be a subset of individuals who tend to attribute high levels of motivational salience to predictive cues regardless of emotional valence, which may predispose them to a number of psychiatric comorbidities including PTSD and substance abuse. Other individuals use contexts to appropriately modify their reactions to such salient stimuli. PMID- 21316398 TI - Lesions of the basolateral, but not central, amygdala impair flavour-taste learning based on fructose or quinine reinforcers. AB - The current studies examined basolateral (BLA) and central nucleus (CNA) amygdala lesioned rats in flavour-taste learning. In Experiment 1 rats received access to a flavour paired with the palatable sweet taste of fructose while in Experiment 2 the same rats received access to a different flavour paired with the unpalatable bitter taste of quinine. BLA, but not CNA, lesions disrupted appetitive flavour taste learning and prevented aversive flavour-taste learning. PMID- 21316399 TI - The dorsomedial striatum mediates flexible choice behavior in spatial tasks. AB - The dorsomedial striatum plays a critical role in action selection and evaluation as well as in value-based decision making. Rodent studies implicated the posterior subregion of the dorsomedial striatum (pDMS) in acquisition and expression of action-outcome associations and in choosing actions that lead to rewarded locations. However, it is not clear whether the pDMS is involved in action selection based on an assessment of the efforts and outcomes of the available response options. Here we investigated in rats the effects of pDMS cell body lesions on effort-based decision making in a cost-benefit T-maze task. In this task, subjects could either choose to climb a barrier to obtain a high reward in one arm or a low reward in the other arm without a barrier. Furthermore, the effects of pDMS cell body lesions were examined in this task after a spatial alteration of reward allocation to analyze flexibility of choice behavior. Results revealed that choice behavior based on an assessment of cost benefit ratios of the available response options was intact in rats with pDMS lesions. However, relative to sham controls, choice behavior in rats with pDMS lesions was less flexible after a spatial reversal of the high and low reward goal arm. Thus, in a T-maze task as used here, the pDMS may not support effort related decision making, but flexibility of spatially guided behavior. PMID- 21316400 TI - Population genetic analysis and sub-structuring in Babesia bovis. AB - The tick-borne protozoan parasite, Babesia bovis is one of the causes of bovine babesiosis, an economically important disease of cattle in tropical and sub tropical countries. Using the recently published genome sequence of the parasite, we developed a panel of eight mini- and micro-satellite markers and used these to investigate the role of genetic exchange in the population structure and diversity of the parasite using isolates from Zambia and Turkey. This population genetic analysis showed that genetic exchange occurs and that there are high levels of genetic diversity, with geographical sub-structuring quantified using Wright's F Index. Linkage disequilibrium was observed when isolates from both countries were treated as one population, but when isolates from Zambia were analysed separately linkage equilibrium was observed. The Turkish isolates were sub-structured, containing two genetically distinct sub-groups, both of which appeared to be in linkage equilibrium. The results of the Zambian study suggest that a sub-set of the parasite population is responsible for the westward spread of babesiosis into the previously disease-free central region of the country. The Zambian isolates had a significantly higher number of genotypes per sample than those from Turkey and age was found to be a significant predictor of the multiplicity of infection. The high levels of diversity seen in the Zambian and Turkish B. bovis populations have implications in the development of subunit vaccines against the disease and the spread of drug resistance. PMID- 21316401 TI - A malaria gametocytocidal assay using oxidoreduction indicator, alamarBlue. AB - Efforts to move from malaria control to eradication will require new approaches to block malaria transmission, such as the development of anti-malarial drugs with gametocytocidal activity. Here fluorescent oxidoreduction indicator alamarBlue is used to develop a screen for gametocyte viability. The fluorescent signal increases linearly with gametocyte number (R(2)=0.99) and determination of the IC(50) of epoxomicin demonstrated the assay was reproducible and sensitive (IC(50) 2.16+/-0.57 nM, Z'-factor 0.81+/-0.01). Six anti-malarials were also tested and at 10 MUM only primaquine and dihydroartemisinin (DHA) had gametocytocidal activity. This new assay provides an important tool to efficiently screen compounds for gametocytocidal activity. PMID- 21316402 TI - Hepatitis E virus cell culture models. AB - Early studies reported the propagation of hepatitis E virus (HEV) in either primary hepatocytes or several established cell lines, but replication was inefficient. Efficient cell culture systems for HEV in PLC/PRF/5 and A549 cells have recently been established, using inoculum of fecal suspensions with high HEV loads, originally obtained from patients with genotype 3 HEV (the JE03-1760F strain, 2.0*10(7) copies/ml) or genotype 4 HEV (the HE-JF5/15F strain, 1.3*10(7) copies/ml), and many generations were successfully propagated in serial passages of culture supernatant. In addition, a full-length infectious cDNA clone (pJE03 1760F/wt) of the JE03-1760F strain was constructed, which can replicate efficiently in PLC/PRF/5 and A549 cells. A derivative ORF3-deficient mutant revealed that the ORF3 protein of HEV is responsible for virion egress from infected cells and is present on the surface of released HEV particles, which is associated with lipids. Various HEV strains with high loads of >=10(5) copies/ml in circulating blood were also propagated efficiently in PLC/PRF/5 and A549 cells. This paper reviews the road map toward the development of efficient cell culture systems for a wide variety of HEV strains and introduces the current knowledge on virion egress obtained by cell culture models. PMID- 21316403 TI - Current strategies for subunit and genetic viral veterinary vaccine development. AB - Developing vaccines for livestock provides researchers with the opportunity to perform efficacy testing in the natural hosts. This enables the evaluation of different strategies, including definition of effective antigens or antigen combinations, and improvement in delivery systems for target antigens so that protective immune responses can be modulated or potentiated. An impressive amount of knowledge has been generated in recent years on vaccine strategies and consequently a wide variety of antigen delivery systems is now available for vaccine research. This paper reviews several antigen production and delivery strategies other than those based on the use of live viral vectors. Genetic and protein subunit vaccines as well as alternative production systems are considered in this review. PMID- 21316404 TI - From barnyard to food table: the omnipresence of hepatitis E virus and risk for zoonotic infection and food safety. AB - Hepatitis E virus (HEV) is an important but extremely understudied pathogen. The mechanisms of HEV replication and pathogenesis are poorly understood, and a vaccine against HEV is not yet available. HEV is classified in the family Hepeviridae consisting of at least four recognized major genotypes. Genotypes 1 and 2 HEV are restricted to humans and associated with epidemics in developing countries, whereas genotypes 3 and 4 HEV are zoonotic and responsible for sporadic cases worldwide. The identification and characterization of a number of animal strains of HEV from pigs, chickens, rabbits, rats, mongoose, deer, and possibly cattle and sheep have significantly broadened the host range and diversity of HEV. The demonstrated ability of cross-species infection by some animal strains of HEV raises public health concerns for zoonotic HEV infection. Pigs are a recognized reservoir for HEV, and pig handlers are at increased risk of zoonotic HEV infection. Sporadic cases of hepatitis E have been definitively linked to the consumption of raw or undercooked animal meats such as pig livers, sausages, and deer meats. In addition, since large amounts of viruses excreted in feces, animal manure land application and runoffs can contaminate irrigation and drinking water with concomitant contamination of produce or shellfish. HEV RNA of swine origin has been detected in swine manure, sewage water and oysters, and consumption of contaminated shellfish has also been implicated in sporadic cases of hepatitis E. Therefore, the animal strains of HEV pose not only a zoonotic risk but also food and environmental safety concerns. PMID- 21316405 TI - Infection of cultured bovine cells with bovine herpesvirus 1 (BHV-1) or Sendai virus induces different beta interferon subtypes. AB - In contrast to mice or humans, cattle contain three beta interferon (IFN-beta) genes with distinct transcriptional promoters suggesting IFN-beta gene expression is not stimulated the same by different viruses. To test this hypothesis, we compared expression of the three IFN-beta subtypes after infection with a RNA virus, Sendai, versus a large DNA virus, bovine herpesvirus 1 (BHV-1). Infection of low passage bovine kidney (BK) or established bovine kidney cells (CRIB) with Sendai virus has consistently led to high levels of IFN-beta1 RNA. Conversely, infection of CRIB cells, but not BK cells, with BHV-1 increased IFN-beta3 RNA levels and to a lesser extent the other two IFN-beta subtypes. Inhibition of de novo protein synthesis with cycloheximide resulted in higher levels of IFN-beta1 and IFN-beta2 RNA levels after BHV-1 infection. Further studies demonstrated that BHV-1 immediate early and/or early genes were primarily responsible for inhibiting the IFN response in BK cells. The three bovine IFN-beta promoters were cloned upstream of a reporter gene construct, and their properties analyzed in transient transfection assays. Only the IFN-beta3 promoter was trans-activated by IRF3 (interferon responsive factor 3). IRF7 and double stranded RNA (polyI:C) stimulated IFN-beta1 and IFN-beta3 promoter activity, but not IFN-beta2. Relative to the human IFN-beta promoter, the IFN-beta3 promoter contained fewer nucleotide differences in the positive regulatory domain III (PRD III), PRD IV, and PRD I compared to the IFN-beta1 and IFN-beta2 promoter. Collectively, these studies provide evidence that virus infection differentially stimulates expression of the three bovine IFN-beta genes. PMID- 21316406 TI - Distinct, alcohol-modulated effects of PNPLA3 genotype on progression of chronic hepatitis C. PMID- 21316409 TI - Do fatigue and UDCA therapy truly have independent effects on mortality in PBC? PMID- 21316410 TI - Negative affect-induced food intake in non-dieting women is reward driven and associated with restrained-disinhibited eating subtype. AB - In humans the presence of negative affect is thought to promote food intake, although widespread variability surrounds this issue. Susceptibility to negative affect-induced eating may depend on trait eating behaviours, notably 'emotional eating', 'restrained eating' and 'disinhibited eating', but the evidence is not consistent. In the present study, 30 non-obese, non-dieting women were given access to palatable food while in a state of negative or neutral affect, induced by a validated autobiographical recall technique. As predicted, food intake was higher in the presence of negative affect; however, this effect was moderated by the pattern of eating behaviour traits and enhanced wanting for the test food. Specifically, high restraint and high disinhibition in combination with higher scores on emotional eating and food wanting was able to predict negative-affect intake (adjusted R(2)=.61), suggesting that individuals who are both restrained and vulnerable to disinhibited eating are particularly susceptible to negative affect food intake via stimulation of food wanting. Identification of traits that predispose individuals to overconsume and a more detailed understanding of the specific behaviours driving such overconsumption may help to optimise strategies to prevent weight gain. PMID- 21316411 TI - Does prolonged chewing reduce food intake? Fletcherism revisited. AB - Horace Fletcher (1849-1919) spread his doctrine to chew each mouthful thoroughly in order to prevent gaining weight. We sought to test this idea by manipulating chewing instructions whilst using electromyography to monitor chewing behaviour. Comparing 35 with 10 chews per mouthful, we showed that higher chewing counts reduced food intake despite increasing chewing speed, and despite doubling meal duration for achieving a subjective reference point for feeling 'comfortably full'. Although limited by a low sample size, our preliminary findings confirm Mr. Fletcher's doctrine, and provide a basis for further research in this area. Outcomes and implications are discussed. PMID- 21316412 TI - Relationships between temperament and eating behaviours in young children. AB - This study examined the associations between eating behaviours and temperament in a sample of young children. Mothers (N=241) of children aged 3-8 years completed measures of their children's eating behaviours and temperament and reported their child's height and weight. Children with more emotional temperaments were reported to display more food avoidant eating behaviours. Shyness, sociability and activity were not related to children's eating behaviours. Higher child BMI was related to more food approach eating behaviours but BMI was unrelated to child temperament. Future research should explore more specifically how emotional temperaments might influence child eating behaviour. PMID- 21316413 TI - Predicting mothers' decisions to introduce complementary feeding at 6 months. An investigation using an extended theory of planned behaviour. AB - In Australia and other developed countries there is poor adherence to guidelines recommending the introduction of complementary feeding to infants at 6 months of age. We aimed to investigate, via adopting a theory of planned behaviour framework and incorporating additional normative and demographic influences, mothers' complementary feeding intentions and behaviour. Participants were 375 primiparas who completed an initial questionnaire (infant age 13+/-3 weeks) that assessed the theory of planned behaviour constructs of attitude, subjective norm, and perceived behavioural control, as well as group norm and additional maternal and infant variables of mothers' age, education level, weight status perception, current maternal feeding practices, and infant birth weight. Approximately, 3 months after completion of the main questionnaire, mothers completed a follow-up questionnaire that assessed the age in months at which the infant was first introduced to solids. The theory of planned behaviour variables of attitude and subjective norm, along with group norm, predicted intentions, with intention, mothers' age (older more likely), and weight status perception (overweight less likely) predicting behaviour. Overall, the results highlight the importance of attitudes, normative influences, and individual characteristics in complementary feeding decision-making which should be considered when designing interventions aimed at improving adherence to current maternal feeding guidelines. PMID- 21316414 TI - The role of glia in neuronal recovery following anoxia: In vitro evidence of neuronal adaptation. AB - We investigated the effects of 3h of anoxia on metabolism of neurons and astrocytes, using a robust cell-based model system that mimics closely the living tissue milieu, i.e., in 3D neural aggregates cultured in bioreactors. Cells were incubated simultaneously with [1-(13)C]glucose and [1,2-(13)C]acetate; and, the gliotoxin fluorocitrate (FC) was used for glial tricarboxylic acid (TCA) cycle inhibition to assess the role of astrocytes for neuronal metabolism after oxygen deprivation. Results show that culture viability was not compromised by exposure to anoxia with and without FC. Interaction between astrocytes and glutamatergic neurons was altered due to anoxia: labeling in glutamine from [1-(13)C]glucose was decreased, whereas that in glutamate from [1,2-(13)C]acetate was increased. In contrast, GABA labeling was not affected by anoxia. It was shown that anoxia did not affect astrocytic capacity to synthesize glutamine in the reoxygenation period. The selective action of FC on astrocytes was confirmed. However, the presence of small amounts of glutamate and GABA labeled from acetate indicated residual activity of the glial TCA cycle. Although major metabolic changes were found due to FC-treatment, the intracellular pool of GABA was kept unchanged. Overall, our data clearly confirm that the glutamate-glutamine cycle depends on astrocytic TCA cycle activity and that mitochondrial impairment of astrocytes will ultimately stop metabolic trafficking between astrocytes and glutamatergic neurons. Additionally, our data suggest a metabolic independence of GABAergic neurons from astrocytes even after situations of complete oxygen depletion. PMID- 21316415 TI - Assessing the human carcinogenic potential of tetrahydrofuran: I. Mode of action and human relevance analysis of the male rat kidney tumor. AB - In 1998, the National Toxicology Program concluded that inhalation exposure to tetrahydrofuran resulted in increased incidences of renal adenomas and carcinomas (combined) in male F344 rats and of hepatocellular adenomas and carcinomas (combined) in female B6C3F1 mice. In the present paper, the bioassay results and additional information are evaluated using the IPCS/ILSI Mode of Action/Human Relevance Framework to determine if the data are sufficient to describe the possible mode(s) of action (MOA) underlying the reported results for the rat renal tumor and to determine if any of these modes of action could be operative in humans. Preliminary analysis of the rat renal tumor data and related information suggested that a MOA could be described, but questions remained concerning the role that chronic progressive nephropathy (CPN) may play in the development of the lesions. In 2009, a Pathology Working Group concluded that the rat renal lesions resulted primarily from regenerative processes associated with advanced CPN. The renal tumor finding is considered not relevant to humans and should not be considered in any further risk assessment efforts on this chemical. A companion paper describes a similar analysis of the female mouse liver tumor finding. PMID- 21316416 TI - Gene expression profile of ADAMs and ADAMTSs metalloproteinases in normal and malignant plasma cells and in the bone marrow environment. AB - OBJECTIVE: The ADAM (a disintegrin and metalloproteinases) and the related ADAMTS (a disintegrin and metalloproteinases with thrombospondin) motifs metalloproteinases are membrane-anchored and secreted proteins exhibiting key roles in mediating cell adhesion, proteolytic shedding, and cell signaling. Dysregulation of these proteins has been observed in some pathologic states, including cancers. Their contribution to multiple myeloma, a plasma-cell neoplasia strongly dependent on bone marrow environment, has been poorly characterized. MATERIALS AND METHODS: We analyzed the expression of genes encoding for these proteins and their inhibitors (tissue inhibitor of metalloproteinases [TIMP], reversion-inducing cysteine-rich protein with kazal motifs) in normal B-cell differentiation, primary malignant plasma cells, human myeloma cell lines, and various bone marrow environment cells. The prognostic value of the expression of these genes was analyzed in two independent series of newly diagnosed patients. RESULTS: ADAM28 and ADAMTS6 were overexpressed in normal memory B cells, ADAM10 and ADAM19 in plasmablasts, and TIMP1 and TIMP2 in normal bone marrow plasma cells. ADAMTS9 was aberrantly expressed by primary malignant plasma cells and ADAM23 expression was associated with a bad prognosis, its expression being spiked in some primary myeloma cell samples. Bone marrow environment cells displayed distinct expression profiles for genes encoding for ADAMs and their inhibitors. They expressed ADAMTSs genes at a low level, with the exception of bone marrow stromal cells. CONCLUSIONS: This study provides an overview of expression data related to ADAMs and ADAMTSs genes potentially involved in myeloma pathogenesis. PMID- 21316417 TI - Inhibitory mechanism of MMP-9 gene expression by ethyl pyruvate in lipopolysaccharide-stimulated BV2 microglial cells. AB - Ethyl pyruvate (EP) is a stable derivative of pyruvate and has been identified as a therapeutic agent for various inflammatory diseases. In the present study, we showed that EP and sodium pyruvate (SP) inhibited the production of TNF-alpha, nitric oxide (NO), or reactive oxygen species (ROS) in LPS-stimulated BV2 microglial cells. The inhibitory effects of EP were more potent than SP. Because matrix metalloproteinase-9 (MMP-9) plays a key role in neuroinflammation, as well as in neuronal cell death, we examined the effect of EP on MMP-9 expression. RT PCR and Western blot analyses revealed that EP inhibits MMP-9 expression at mRNA and protein levels in LPS-stimulated BV2 cells. In addition, EP suppressed MMP-9 secretion, as demonstrated by gelatin zymography analysis. In contrast, SP did not affect MMP-9 expression at an equivalent concentration of EP. Further mechanistic studies revealed that EP inhibits MMP-9 promoter activity by reducing the binding of NF-kappaB and AP-1 to its cognitive binding sites. In addition, EP suppressed LPS-induced phosphorylation of p38 MAPK, ERK, and Akt, which are upstream signaling molecules in MMP-9 gene expression. Taken together, our data suggest that the inhibition of MMP-9 may be one of the factors contributing to anti-inflammatory activity of EP in LPS-stimulated microglia. PMID- 21316418 TI - Interleukin-17 levels in rat models of nerve damage and neuropathic pain. AB - In the present study, we assessed IL-17 levels at 3 and 8 days following various forms of injuries to the sciatic nerve and related the cytokine levels to the pain behaviors associated with the injuries. The four experimental models employed were chronic constriction injury (CCI), partial sciatic ligation (PSL), complete sciatic transection (CST) and perineural inflammation (Neuritis). Behavior withdrawal thresholds for mechanical stimulus and withdrawal latency for thermal stimulation were used to measure mechanical allodynia and thermal hyperalgesia. IL-17 levels of the affected, contralateral and naive rats' sciatic nerve were assessed employing enzyme-linked immunosorbent assay (ELISA). Rats exposed to CCI and Neuritis displayed significant mechanical allodynia and thermal hyperalgesia 3, 5 and 8 days following the procedure, rats exposed to PSL displayed significant mechanical allodynia 5 and 8 days following the procedure and rats exposed to CST developed significant hypoesthesia. Three days following the procedure, IL-17 levels increased significantly compared to naive rats only in the PSL model. Eight days following the procedure, IL-17 levels in nerves exposed to CCI, CST, PSL and Neuritis were significantly elevated compare to intact nerve levels. It is likely that IL-17 has a limited role in the acute phase of nerve injury and the associated acute pain, but may have a role in later phases of the processes of the development of neuropathic pain. PMID- 21316419 TI - Is somatosensory excitability more affected by the perspective or modality content of motor imagery? AB - Beneficial effects of mental practice likely arise because motor imagery involves largely similar neural networks as physical execution of the same movement. While it is known that the involvement of the motor system is favoured by focusing on the kinaesthetic modality and by the first person perspective, little is known about the impact of these factors on the somatosensory system. The present paper examines the effects on the somatosensory excitability of both perspective (the point of view of the person imagining a motor act) and modality (visual versus kinaesthetic) during mental practice. Seventeen healthy subjects participated. Quality of mental practice was controlled using chronometric tests and a subjective questionnaire. Excitability of the somatosensory system was assessed through the steady-state electroencephalographical response to a continuous train of electrical stimuli applied to the radial nerve, at the same time subjects were instructed to perform one of five tasks designed to separate the effects of perspective, modality and motor versus non-motor imagery. Kinaesthetic motor imagery exerts the largest effect on somatosensory excitability whereas visual motor imageries (1st and 3rd person perspectives) produce the same lower effect that static visual imagery does. Strikingly, specific effect of kinaesthetic motor imagery correlates with the selfselected speed to imagine and execute the same movement. These findings suggest a key role of the kinaesthetic content of motor imagery in recruiting the sensorimotor system. PMID- 21316420 TI - Reduced gamma range activity at REM sleep onset and termination in fear conditioned Wistar-Kyoto rats. AB - Recent investigations of rapid eye movement sleep (REMS) continuity have emphasized the importance of transitions both into and out of REMS. We have previously reported that, compared to Wistar rats (WIS), Wistar-Kyoto rats (WKY) responded to fear conditioning (FC) with more fragmented REMS. Gamma oscillations in the electroencephalogram (EEG) are synchronized throughout the brain in periods of focused attention, and such synchronization of cell assemblies in the brain may represent a temporal binding mechanism. Therefore, we examined the effects of FC on EEG gamma range activity (30-50Hz) at REMS transitions in WKY compared to WIS. Relative power in the gamma range (measured as a percent of total power) at Baseline and upon re-exposure to the fear-inducing conditioning stimulus was measured 35s before REMS onset to 105s after REMS onset (ARO) and 85s before REMS termination (BRT) to 35s after REMS termination. After baseline recording, rats received 10 tones, each co-terminating with an electric foot shock. On Days 1 and 14 post-conditioning, rats were re-exposed to three tones. Fast-Fourier transforms created power spectral data in the gamma frequency domain. Relative power was extracted from an average of 4-5 REMS transitions. Relative gamma power was always higher in WIS. On Day 14, at 15s and 25s ARO, WKY had significant increases in relative gamma power from Baseline. WIS had a significant increase on Day 1 at 25s ARO. Despite the increases in relative gamma power, WKY never achieved levels attained by WIS. Moreover, at 5s BRT, only WKY had a significant decrease in relative gamma power from Baseline to Day 14. Gamma range activity may indicate neural activity underlying maintenance of REMS continuity. Low relative gamma power at REMS transitions may be associated with increased REMS fragmentation in WKY after FC. PMID- 21316421 TI - MicroRNA181a plays a key role in hair cell regeneration in the avian auditory epithelium. AB - Specialized sensory-transducing hair cells regenerate in response to injury in non-mammalian vertebrates such as birds and fish but not in mammals. Previous work has shown that overexpression of microRNA181a (miR181a) in cultured chicken basilar papillae, the avian counterpart of the cochlea, is sufficient to stimulate proliferation with production of new hair cells. The present study investigates the role of miR181a in hair cell regeneration after injury in explants of chicken auditory epithelia. Basilar papillae were explanted from 0 day-old chickens and transfected with either anti-miR181a, which knocks down endogenous miR181a, or a non-targeting miRNA and cultured with streptomycin to eliminate all hair cells from the epithelium. Labeling with BrdU was used to quantify proliferation. Explants exposed to streptomycin and transfected with anti-miR181a had significantly fewer BrdU positive cells than basilar papillae treated with streptomycin and transfected with a non-targeting miRNA. Activated caspase-3 and myosin VI labeling were used to show that the pattern of hair cell death and loss, respectively, were not affected by anti-miR181a transfection. MiR181a downregulation therefore seems to dimish the proliferative component of hair cell regeneration rather than prevent hair cell death following ototoxic injury. PMID- 21316422 TI - Primary motor cortex activity is elevated with incremental exercise intensity. AB - While the effects of exercise on brain cortical activity from pre-to post exercise have been thoroughly evaluated, few studies have investigated the change in activity during exercise. As such, it is not clear to what extent changes in exercise intensity influence brain cortical activity. Furthermore, due to the difficulty in using brain-imaging methods during complex whole-body movements like cycling, it is unclear to what extent the activity in specific brain areas is altered with incremental exercise intensity over time. Latterly, active electroencephalography (EEG) electrodes combined with source localization methods allow for the assessment of brain activity, measured as EEG current density, within specific cortical regions. The present study aimed to investigate the application of this method during exercise on a cycle ergometer, and to investigate the effect of increasing exercise intensity on the magnitude and location of any changes in electrocortical current density. Subjects performed an incremental cycle ergometer test until subjective exhaustion. Current density of the EEG recordings during each test stage, as well as before and after exercise, was determined. Spatial changes in current density were localized using low resolution brain electromagnetic tomography (LORETA) to three regions of interest; the primary motor cortex, primary sensory cortex and prefrontal cortex, and were expressed relative to current density within the local lobe. It was demonstrated that the relative current density of the primary motor cortex was intensified with increasing exercise intensity, whereas activity of the primary sensory cortex and that of the prefrontal cortex were not altered with exercise. The results indicate that the combined active EEG/LORETA method allows for the recording of brain cortical activity during complex movements and incremental exercise. These findings indicate that primary motor cortex activity is elevated with incremental exercise intensity during a whole-body movement, like cycling. PMID- 21316425 TI - Stilbenes and flavonoids from Artocarpus nitidus subsp. lingnanensis. AB - The first stilbene possessing a gamma-aminobutyric acid lactam function, artocarpene (1), and a new flavanone, 2-hydroxynaringenin 4'-O-beta-d glucopyranoside (2), were isolated from the stems of Artocarpus nitidus subsp. lingnanensis along with four known compounds, 2-hydroxynaringenin (3), oxyresveratrol (4), 3,4',5-trihydroxy-3'-prenylstilbene (5) and norartocarpetin (6). Their structures were elucidated on the basis of spectroscopic data. Compounds 1 exhibited weak antioxidant activity and 2 displayed weak cytotoxicity against human lung cancer A549 cell line. PMID- 21316424 TI - Anti-inflammatory, antioxidant and antifungal furanosesquiterpenoids isolated from Commiphora erythraea (Ehrenb.) Engl. resin. AB - The topical anti-inflammatory, free radical scavenging and antifungal activities of essential oils and extracts of Commiphora erythraea (Ehrenb.) Engl. resin were investigated. The hexane extract significantly inhibited oedema when applied topically in Croton oil-induced ear oedema assay in mice. The same extract showed antioxidant activity in DPPH radical scavenging assay. A bioguided separation of the hexane extract led to the isolation of furanosesquiterpenoids 1 and 2 that showed a weak antifungal activity, while compounds 3-5 resulted to be antioxidant (EC(50) 4.28, 2.56 and 1.08 mg/mL, respectively) and anti-inflammatory (30, 26 and 32% oedema reduction, respectively). PMID- 21316423 TI - The role of NR4A transcription factors in memory formation. AB - In various physiological contexts, Nr4a genes are transcribed in response to external stimuli as part of an immediate early response that initiates a cascade of gene expression ultimately leading to distinct physiological outcomes in each of these contexts. The signaling pathway that initiates Nr4a gene expression in most of these contexts consists of elevated intracellular cAMP activating PKA, which in turn leads to phosphorylation of CREB and new gene synthesis. This cAMP PKA-CREB pathway is a central molecular pathway in the formation of a long-term memory. Indeed, learning induces Nr4a family gene expression, and long-term memory formation requires at least two waves of transcription after learning, suggesting that NR4A nuclear receptors may contribute to the second of these waves of gene expression. In this article, we review insights gained in other physiological contexts regarding Nr4a function and regulation, and highlight how these lessons can be applied to the study of memory formation. PMID- 21316426 TI - Kaurane-type diterpenoids from Chromoleana odorata, their X-ray diffraction studies and potent alpha-glucosidase inhibition of 16-kauren-19-oic acid. AB - A new diterpenoid, 15-angeloyloxy-16,17-epoxy-19-kauronic acid (1), along with five known metabolites, 16-kauren-19-oic acid (2), 6'-hydroxy-2',3',4,4' tetramethoxychalcone (3), isosakuranetin (4), acacetin (5), and kaempferide (6) was isolated from the organic extracts of the roots of Chromoleana odorata. Their structures were determined by spectroscopic evidences. The structures of 1 and 2 were further confirmed by single-crystal X-ray diffraction studies. Compound 2 exhibited significant alpha-glucosidase inhibitory and antibacterial activities against Escherichia coli and Bacillus subtilis. PMID- 21316427 TI - Phytochemical potential of Eruca sativa for inhibition of melanoma tumor growth. AB - Solvent extracts from the aerial and root parts and seed oil from E. sativa (rocket salad) were assayed for anticancer activity against melanoma cells. The seed oil (isothiocyanates rich) significantly (p<0.01) reduced the tumor growth comparable to the control. Remarkably, the seed oil inhibited melanoma growth and angiogenesis in mice without any major toxicity. The findings qualify seed oil for further investigations in the real of cancer prevention and treatment. PMID- 21316428 TI - Construction, screening and evaluation of a derivative recombinant adenovirus for the optimal siRNA targeting of a novel gene (HA117). AB - At this study, we screened for an optimal siRNA to target a novel gene named HA117 and constructed and evaluated a recombinant adenovirus carrying the DNA template for the transcription of the optimal HA117 siRNA to examine the function of HA117 and its possible mechanism of action in CW-2 cell lines. An HAi5 carrying recombinant adenovirus (Ad-HAi5) was successfully constructed and evaluated. The results show that, among five pairs of DNA templates, siRNA transcribed from HAi5 gave the strongest interference with the novel gene HA117. The expression of the exogenous HA117 gene increased drug resistance in CW-2 cells. We hypothesized that this action may be a result of HA117 through inhibiting apoptosis in CW-2 cells. PMID- 21316429 TI - Self-assembly of cyclodextrins: the effect of the guest molecule. AB - The principle action by which cyclodextrins solubilize compounds is via inclusion complex formation. However, data suggest that cyclodextrins and their complexes also aggregate in solution and this aggregation contributes to their ability to solubilize poorly water-soluble materials. The current effort aims at better understanding the role of guest molecule nature (i.e. its structural and functional peculiarities) in cyclodextrin complex aggregation as well as in the aggregate stability assessed using a cellophane membrane permeability assay. A test set of 11 acidic, basic and neutral drugs and antibacterial agents (i.e. guests) were examined with regard to their interaction with hydroxypropyl-beta cyclodextrin (HPbetaCD) and the resulting ability of the formed aggregates to move through a semi-permeable membrane of various molecular weight cut-off values. The data suggested that the interaction of HPbetaCD with certain guests resulted in the formation of structure large enough to poorly penetrate semi permeable membrane. The aggregates appeared to be highly dynamic in that there were no qualitative differences between systems that were diluted immediately prior to permeation experiments and those allowed to equilibrate. Pharmaceutical polymers which have been shown to enhance solubilizing efficiency of cyclodextrins had little or no effect on the stability of the aggregates using the permeability paradigm as an endpoint with the exception of carboxymethylcellulose. PMID- 21316430 TI - Skin penetration and deposition of carboxyfluorescein and temoporfin from different lipid vesicular systems: In vitro study with finite and infinite dosage application. AB - The aim of the present research is to evaluate the influence of different lipid vesicular systems as well as the effect of application mode on skin penetration and deposition behaviors of carboxyfluorescein (hydrophilic model drug) and temoporfin (lipophilic model drug). All of the lipid vesicular systems, including conventional liposomes, invasomes and ethosomes, were prepared by film hydration method and characterized for particle size distribution, zeta-potential, vesicular shape and surface morphology, in vitro human skin penetration and skin deposition. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) defined that all of lipid vesicles had almost spherical structures with low polydispersity (PDI < 0.2) and nanometric size range (z-average no more than 150 nm). In addition, all lipid vesicular systems exhibited a negative zeta potential. In vitro skin penetration and deposition experiments demonstrated that, in the case of CF with finite dose application (10 MUl/cm2) and infinite dose application (160 MUl/cm2), lipid vesicular systems, especially ethosomes and invasomes, compared with non-vesicular systems, can significantly improve the delivery of hydrophilic drug such as carboxyfluorescein into skin deep layers or across the skin. While in the case of mTHPC with finite and infinite dose application, most of drug accumulation was observed in the skin superficial layer for both lipid vesicular systems and non-vesicular systems. The results also revealed that the factors influencing the drug skin distribution concern the physicochemical characteristics of the drug, the choice of the vehicle formulation and the application mode applied. PMID- 21316431 TI - Electrospun fiber mats containing shikonin and derivatives with potential biomedical applications. AB - Alkannin, shikonin (A/S) and their derivatives are naturally occurring hydroxynaphthoquinones with a well-established spectrum of wound healing, antimicrobial, anti-inflammatory, antioxidant and antitumor activity. Clinical studies over the years revealed that A/S derivatives-based wound healing preparations (such as HELIXDERM((r))) are among a very small group of therapeutics that modulate both the inflammatory and proliferative phases of wound healing and present significant tissue regenerative activity. The purpose of the present work was to combine the biological properties of A/S and the advantages of electrospun meshes to prepare a potent topical/transdermal biomaterial for A/S. Four biocompatible polymers (cellulose acetate, poly(L lactide), poly(lactide-co-glycolide) LA/GA:50/50 and 75/25) were used for the first time, to produce electrospun fiber mats containing either shikonin or A/S mixture in various amounts. Both drugs were effectively loaded into the above biomaterials. The incorporation of drugs did not considerably affect fibers morphology and their mean diameter size varied from 315 to 670 nm. High drug entrapment efficiencies (ranged from 74% to 95%) and appropriate release profiles were achieved, that render these fibers as potential A/S topical/transdermal wound healing dressings. Given the multifunctional activity of the natural products alkannins and shikonins, their consideration as bioactive constituents for tissue engineering scaffolds seems a promising strategy for repairing and regenerating tissues and mainly skin. PMID- 21316432 TI - Development of natural-based wound dressings impregnated with bioactive compounds and using supercritical carbon dioxide. AB - Film- and foam-like structures of N-carboxybutylchitosan (CBC) and of agarose (AGA) were prepared and characterized in order to evaluate their potential application as topical membrane-type wound dressing materials, mostly regarding their sustained release capacities and fluid handling properties. Polymeric biomaterials were loaded with two natural-origin bioactive compounds (quercetin and thymol, which present anti-inflammatory and anaesthetic properties, respectively), separately or as a mixture of these two substances, and using a supercritical solvent impregnation (SSI) method. Impregnation experiments were carried out with supercritical carbon dioxide (scCO2) at 10 and 20 MPa, and at 303 and 323 K. Ethanol (10%, v/v) was employed as a co-solvent whenever quercetin was used. Release kinetic studies were performed for all prepared systems and the obtained results showed that higher amounts of quercetin and/or thymol were loaded when higher pressures and temperatures were employed. Results showed that the separated and the simultaneous SSI loading of these two bioactive substances into CBC and AGA is a feasible and advantageous process and that the relative loaded amounts of these substances can be "tuned" simply by changing the operational pressure-temperature conditions. Quercetin presented more sustained release profiles which can be justified by its higher molecular volume and by its lower water solubility as well as by the specific favourable interactions that can be established between quercetin and CBC. Obtained results showed that the employed SSI process also promoted the size reduction of loaded quercetin particles which can significantly improve the solubility of this compound in aqueous solutions. In addition, prepared systems presented adequate water sorption and water vapor sorption capacities as well as water vapor transmission rates that were in the typical and desired ranges for commercial wound dressings. PMID- 21316433 TI - Theoretical and experimental investigations into the delamination tendencies of bilayer tablets. AB - Delamination is one major problem in the production of layered tablets, yet there is little knowledge about the physical reasons for this to occur. The aim of this work was to explore the theoretical influence of thermal stresses and strains that can develop during tabletting and to devise an experimental method that can be used to detect delamination tendencies in bilayered tablets. Theoretical considerations have shown that thermal stresses due to development of heat during powder compaction can result in delamination, and this effect is the more pronounced the larger the Young's modulus for the individual layer materials is. Elastic mismatch further enhances delamination tendencies. Experiments on mixed powder beams showed that there is only limited adhesion between particle surfaces of a model drug (acetylsalicylic acid) and model excipient (lactose monohydrate), indicative of limited adhesion between similar interfaces in layered tablets. A three-point bending test was developed to determine the far field stress intensity factor for bilayered compacts. Under the test conditions employed, lactose monohydrate behaved as a brittle material, whereas acetylsalicylic acid demonstrated ductility, which resulted in considerable differences in the far field stress intensity factor values, depending on whether the excipient or the drug formed the downward facing layer during the bending test. Ductile phase toughening was observed when the drug formed the downward facing layer, and hence for bilayer tablets made from these two powders lactose monohydrate must form the downward facing layer during the test. Using the correct test configuration the far field stress intensity factor correctly predicted practically observed delamination between the two material layers. Hence, the proposed fracture mechanics approach could become a formulation tool in the development of bilayered tablets. PMID- 21316434 TI - PEGylated thermo-sensitive poly(amidoamine) dendritic drug delivery systems. AB - Thermo-sensitive dendrimers hold promise in various biomedical and pharmaceutical applications due to their stimuli-responsive properties. However, for such systems there are still certain unaddressed issues e.g. the undesired toxicity, immunogenicity and short blood circulation time. PEGylation is a potential approach to solve these above problems. The aims of this study were to engineer PEGylated thermo-sensitive dendritic derivatives and to investigate their temperature sensitivity and drug release behaviour therein. Linear poly(N isopropylacrylamide) (PNIPAAm) and methoxy poly(ethylene glycol) (MPEG) were attached to the surface of polyamidoamine (PAMAM) dendrimers to generate PAMAM-g PNIPAAm and PAMAM-g-PNIPAAm-co-PEG. PAMAM-g-PNIPAAm exhibited the lowest critical solution temperature (LCST) of ca. 32 degrees C, whereas PAMAM-g-PNIPAAm-co-PEG showed a LCST of ca. 35 degrees C. Indomethacin was used as a model molecule to examine the drug release profiles from both types of dendritic polymers. Results showed that such thermo-sensitive PAMAM derivatives could manipulate drug release simply by controlling the temperature above or below the LCST. At 37 degrees C a prolonged drug release was obtained for both systems with less than 30% of drug was released over 12 h, whilst the release rate is much faster at 30 degrees C and ca. 90% of drug was released over 12 h. The results obtained suggest that these thermo-sensitive PAMAM derivatives could be potential drug delivery systems to achieve controlled drug release. PMID- 21316436 TI - Passive exposure of adult cats to bandlimited tone pip ensembles or noise leads to long-term response suppression in auditory cortex. AB - We have recently demonstrated that persistent, passive exposure of adult cats to bandlimited tone pip ensembles at moderate intensities (~70 dB SPL) leads to a long-term suppression of neural activity in auditory cortex, in the absence of hearing loss. With wideband ensembles (4-20 kHz), the suppression is limited to the exposure frequency range; with narrowband ensembles (2-4 kHz, or third-octave bands centered at 4 and 16 kHz), suppression occurs not only within but also well beyond the exposure range, at least in primary auditory cortex (AI). (In secondary cortex (AII) suppression remains limited mostly to the exposure range even for narrowband ensembles.) We report here on two additional experiments. First, we demonstrate suppression in both AI and AII upon exposure to 4-20 kHz bandlimited noise, thus generalizing our previous results obtained with tonal ensembles. However, we found a somewhat different suppression pattern with noise. Whereas 4-20 kHz tone exposure produced relatively uniform suppression over the 4 20 kHz range, save for a small local minimum at ~10 kHz, 4-20 kHz noise produced maximal suppression over ~4-10 kHz, which then progressively weakened with frequency up to 20 kHz. Second, we outline the time course of the emergence of response suppression in AI, using the above-mentioned pair of third-octave bands as the exposure stimulus. Suppression emerged relatively rapidly, within a week of exposure onset, and was initially confined to frequencies close to the 4 and 16 kHz stimulus bands. Over the course of several more weeks, the suppression broadened to cover the entire 4-16 kHz range. We discuss these new findings with reference to the putative mechanisms underlying exposure-induced auditory cortical plasticity. PMID- 21316435 TI - Impact of polymer tacticity on the physico-chemical behaviour of polymers proposed as therapeutics. AB - Although water-soluble polymers are finding increasing use as polymer therapeutics, there has been little consideration of the effect of polymer stereochemistry on their physico-chemical and biological properties. The aim of this study was to investigate these properties using polymethacrylic acids (PMAs) of similar molecular weights with a difference in syndiotacticity of about 20% of rr triad content. Experiments to characterize the solution behaviour were conducted at pHs encountered during the transport, endocytic uptake and intracellular trafficking (7.4-3.0). These showed that with increasing rr triads, the polymer become less hydrophobic, a stronger acid, displayed a locally ordered solution conformation at pH 5.5, and interacted more strongly with dodecyl trimethylammonium bromide (DTAB) micelles. Preliminary cytotoxicity experiments using B16F10 melanoma cells showed lower toxicity in the concentration range of 1 100 MUg/mL with increased rr triads. These observations indicate that the higher content of rr triads could drive a chain organization that minimize the influence of negative charges and so underline the importance of further, systematic studies to investigate the effect of tacticity on the behaviour of polymers in respect of their pharmacokinetics, toxicity and efficacy. PMID- 21316437 TI - Lipid-lowering and antioxidant activities of Jiang-Zhi-Ning in Traditional Chinese Medicine. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Jiang-Zhi-Ning (JZN) is composed of four Chinese herbs, i.e., Fleeceflower Root, Fructus Crataegi, Folium Nelumbinis and Semen Cassiae. It was used to strengthen blood circulation of coronary artery, arrhythmia and hyperlipidemia. AIM OF THE STUDY: The main objective of this paper is to evaluate lipid-lowering and antioxidant activities of extract and effective fraction of JZN by using in vitro experiments on hyperlipidemic rats. Moreover, in vivo experiments on cells were performed to investigate lipid-lowering and antioxidant activities of effective fraction and active constituents of JZN. MATERIALS AND METHOD: Wistar rats with high fat diet-induced hyperlipidemia were used as in vitro models to study biological effects of lipid-lowering and antioxidant activities of extract and effective fraction of JZN. Serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), Coronary Index and Atherogenic Index were investigated to evaluate lipid-lowering effects of extract and effective fraction of JZN. Serum total nitric oxide synthase (NOS), nitric oxide (NO), endothelin-1 (ET-1), malondialdehyde (MDA), superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) were detected to measure antioxidant effects of extract and effective fraction of JZN. Furthermore, oxidized low-density lipoprotein (Ox-LDL) injured human umbilical vein endothelial cell (HUVEC) model was employed as in vivo experiment to study lipid-lowering and antioxidant effects of effective fraction and active constituents of JZN. NO, ET-1, MDA SOD and T-AOC in HUVECs or culture media were investigated to evaluate antioxidant activity of effective fraction and active constituents of JZN. Using human hepatoma cell line Bel-7402, reverse transcription polymerase chain reaction (RT PCR) technology was performed to investigate cholesterol metabolism effects of effective fraction and active constituents of JZN. Expressions of low density lipoprotein receptor (LDL-R), 3-hydroxy-3-methyl-HMG-coenzyme A reductase (HMG CoAR), and cholesterol 7alpha-hydroxylase (CYP7A1) mRNA of the liver cells were investigated to evaluate JZN on associated receptor and enzymes of cholesterol metabolism. High-performance liquid chromatography (HPLC) and spectrophotometry were used to study the impact of effective fraction and active constituents of JZN on synthesis and translation of cholesterol during the process of metabolism by measuring inside and extracellular contents of total bile acid (TBA) of Bel 7402. RESULTS: Extract and effective fraction of JZN significantly reduced contents of TC, TG and LDL-C, CRI and AI in hyperlipidemic rats as well as significantly increased contents of HDL-C in the rats. Moreover, they significantly enhanced the activity of NOS and increased contents of NO. They also caused significant reductions in contents of ET-1 and MDA as well as significant increase in SOD activity and T-AOC in the hyperlipidemic rats. Several indicators were found to be concentration-dependent. As far as in vivo experiments to investigate biological activities of effective fraction and active constituents of JZN were concerned, it was found that they restored and enhanced the vitality of HUVECs with a concentration-dependent manner as well as content of NO in the culture media of HUVEC. They caused reductions in the contents of ET 1 in the culture media of HUVEC and contents of MDA in HUVECs. They also caused an increase in the vitality of SOD and T-AOC in HUVECs. Furthermore, they enhanced LDL-RmRNA expression, with a concentration-dependent manner. Low and medium concentrations of effective fraction and active constituents of JZN could inhibit expression of HMG-CoAR mRNA. High concentration counterpart could enhance expression of the HMG-CoAR mRNA. They enhanced expression of CYP7A1 mRNA in a concentration-dependent manner. Finally, they caused reductions in the contents of cholesterol in Bel-7402. They also increased intercellular content of total bile acid as well as lowered extracellular contents of TBA in the cells in a concentration-dependent manner. CONCLUSION: We demonstrated for the first time lipid-lowering and antioxidant activities of extract and effective fractions as well as active constituents of JZN. Active constituents of JZN had the same biological effects with effective fraction and extract of JZN. Therefore, this study supports its ethnopharmacological use in Traditional Chinese Medicine to manage hyperlipidemia and paves a basis for establishing quality control method of Chinese medicine. PMID- 21316438 TI - CpG-ODN+IFN-gamma confer pro- and anti-inflammatory properties to peritoneal macrophages in aged mice. AB - Aging is accompanied by a disturbance in the homeostasis of the immune system. However, research into the behavior of macrophages in aging has shown disagreements about the functional status of these cells in aged mice. In this work, we studied the influence of aging on macrophage functions by evaluating the pro- and anti-inflammatory parameters of peritoneal macrophages preserved in their natural microenvironment. Resident peritoneal macrophages from old mice, in the context of their natural milieu, were found to respond with a similar phenotype and functional pattern to macrophages from young mice. In addition, we evaluated the macrophage response to CpG-ODN, a well-known Th1 promoter. CpG ODN+IFN-gamma were able to activate not only nitric oxide to initiate the inflammatory response, but also IL-12 in resident and inflammatory peritoneal macrophages from aged mice in the context of their natural milieu, although some quantitative differences were found in IL-10 and IL-12 secretion. With this stimulus, NO secretion and arginase activation were maintained in peritoneal macrophages during aging. These results will help to elucidate potential immunization strategies with CpG-ODN in the elderly. PMID- 21316439 TI - Antioxidant-rich food intakes and their association with blood total antioxidant status and vitamin C and E levels in community-dwelling seniors from the Quebec longitudinal study NuAge. AB - A cross-sectional study was designed to investigate the association between current consumption of a series of 26 common antioxidant-rich foods (ARF) with serum total antioxidant status (TAS) and plasma vitamin C and E levels in community-dwelling older adults. A convenience sample of the first 94 non-smoking Caucasian men (54%) and women (46%) enrolled in the Quebec Longitudinal Study NuAge were selected. The "Functional Foods Consumption Frequency Questionnaire" (FFCFQ) was administered at recruitment (T1) to ascertain patterns of consumption of ARF over the lifetime. The total Oxygen Radical Antioxidant Capacity (ORAC) of 25 ARF reported by subjects was estimated using published values. Serum TAS was determined based on the Trolox equivalent antioxidant capacity (TEAC) assay while plasma vitamins C and E (alpha- and gamma-tocopherol) levels were analyzed by HPLC. The numbers of ARF eaten daily at T1, estimated from the FFCFQ and calculated from the diet recalls, were significantly correlated (r=0.51, P<0.0001) and each measure was associated with total ORAC content (r=0.34, P<0.001 and r=0.59, P<0.0001 for FFCFQ and recalls, respectively). No significant association was found between TAS and the total ORAC value of ARF determined from the quantitative 24-h diet recalls. However, daily ARF consumption at T1 obtained from the FFCFQ was significantly and positively correlated with TAS (r=0.26, P<0.05) and circulating levels of vitamin C (r=0.25, P<0.02) and alpha-tocopherol (r=0.22, p<0.05) and negatively correlated with plasma gamma-tocopherol (r=-0.25, P<0.025). These results highlight associations between ARF consumption and circulating levels of antioxidants in the elderly and suggest benefits from antioxidant-rich foods during aging. PMID- 21316440 TI - Granzyme B contributes to extracellular matrix remodeling and skin aging in apolipoprotein E knockout mice. AB - Apolipoprotein E knockout (apoE-KO) mice have been utilized for decades as a model of atherosclerosis. However, in addition to atherosclerosis, apoE-KO mice develop extensive cutaneous xanthomatosis, accelerated skin aging and frailty when fed a high fat diet. Granzyme B (GrB) is a pro-apoptotic serine protease that has recently been shown to exhibit extracellular proteolytic activity in certain pathologies. In the present study, the role of GrB in skin aging and pathology was assessed using the apoE-KO model of skin aging. Male C57BL/6 wild type and apoE-KO mice were grown for 0, 5, 15 or 30 weeks on either a high fat (21.2% fat, 0.2% cholesterol) or regular chow diet (7% fat). ApoE/GrB double knockout (DKO) mice were also generated and assessed after being fed either diet for 30 weeks. Skin was removed from the mid to lower back and examined for age related changes such as hair loss, skin thinning and collagen remodeling and disorganization. ApoE-KO mice exhibited signs of frailty, hair graying, hair loss, skin thinning, loss of collagen density and increased skin pathologies featuring collagen remodeling and reduced decorin compared to wild type controls. These phenotypes occurred earlier and were more severe when fed a high fat diet. In addition, we also observed increased GrB expression in proximity to areas of decorin degradation and reduced collagen density in the skin of apoE-KO mice. DKO mice exhibited protection against skin thinning, ECM degradation and loss of dermal collagen density. In summary, our results provide novel insights into the effects of a high fat diet and apoE deficiency on skin aging and pathology and suggest a role for GrB in age-related skin thinning and frailty. PMID- 21316441 TI - Pyridoxamine prevents age-related aortic stiffening and vascular resistance in association with reduced collagen glycation. AB - An increase in oxidative chemical modifications of tissue proteins by advanced glycation end products (AGEs) and advanced lipoxidation end products (ALEs) has been implicated in normal aging. Pyridoxamine (PM), one of the three natural forms of vitamin B(6), has been identified as an inhibitor of AGE/ALE products formed during the autoxidation of carbohydrates and peroxidation of lipids. The current study seeks to determine whether PM intervention could prevent the age related aortic stiffening and vascular resistance through its ability to inhibit the pathogenic cross-linking of glycated collagen. Male Fisher 344 rats at 15 months were treated daily with PM (1 g l(-1) in drinking water) for 5 months and compared with the age-matched, untreated controls at 20 months. Pulsatile aortic pressure and flow signals were measured to perform the vascular impedance analysis. The anti-AGE antibody 6D12 was used to detect glycation-derived modification of aortic collagen, using protein blotting analysis. PM therapy attenuated the age-related increase in total peripheral resistance. An increase in wave transit time and aortic compliance by PM indicated that the drug improved aortic distensibility of the aged vasculature. This paralleled its reduction of AGE-collagen cross-links on aortas. Treatment of the old animals with PM also prevented the age-induced augmentation in vascular load imposed on the heart, as evidenced by an increased wave transit time and a decreased wave reflection factor. These findings suggest a partial role of PM in improving arterial mechanics by targeting the pathogenic formation of AGE-induced aortic collagen cross-links in old rats. PMID- 21316442 TI - Effects of resistance and aerobic exercise on physical function, bone mineral density, OPG and RANKL in older women. AB - This study compared the effects of a resistance training protocol and a moderate impact aerobic training protocol on bone mineral density (BMD), physical ability, serum osteoprotegerin (OPG), and receptor activator of nuclear factor kappa B ligand (RANKL) levels. Seventy-one older women were randomly assigned to resistance exercise (RE), aerobic exercise (AE) or a control group (CON). Both interventions were conducted 3 times per week for 8 months. Outcome measures included proximal femur BMD, muscle strength, balance, body composition, serum OPG, and RANKL levels. Potential confounding variables included dietary intake, accelerometer-based physical activity (PA), and molecularly defined lactase nonpersistence. After 8 months, only RE group exhibited increases in BMD at the trochanter (2.9%) and total hip (1.5%), and improved body composition. Both RE and AE groups improved balance. No significant changes were observed in OPG and RANKL levels, and OPG/RANKL ratio. Lactase nonpersistence was not associated with BMD changes. No group differences were observed in baseline values or change in dietary intakes and daily PA. Data suggest that 8 months of RE may be more effective than AE for inducing favourable changes in BMD and muscle strength, whilst both interventions demonstrate to protect against the functional balance control that is strongly related to fall risk. PMID- 21316443 TI - Age-related changes in renal expression of oxidant and antioxidant enzymes and oxidative stress markers in male SHR and WKY rats. AB - Oxidative stress has been hypothesized to play a role in aging and age-related disorders, such as hypertension. This study compared levels of oxidative stress and renal expression of oxidant and antioxidant enzymes in male normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) at different ages (3 and 12 months). In the renal cortex of 3-month old SHR increases in hydrogen peroxide (H(2)O(2)) were accompanied by augmented expression of NADPH oxidase subunit Nox4 and decreased expression of antioxidant enzymes SOD1 and SOD3. A further increase in renal H(2)O(2) production and urinary TBARS was observed in 12-month old WKY and SHR as compared with 3-month old rats. Similarly, expressions of NADPH oxidase subunit p22(phox), SOD2 and SOD3 were markedly elevated with age in both strains. When compared with age-matched WKY, catalase expression was increased in 3-month old SHR, but unchanged in 12-month old SHR. Body weight increased with aging in both rat strains, but this increase was more pronounced in WKY. In conclusion, renal oxidative stress in 12-month old SHR is an exaggeration of the process already observed in the 3-month old SHR, whereas the occurrence of obesity in 12-month old normotensive rats may partially be responsible for the age-related increase in oxidative stress. PMID- 21316444 TI - Generalized F accelerated failure time model for mapping survival trait loci. AB - As the two most popular models in survival analysis, the accelerated failure time (AFT) model can more easily fit survival data than the Cox proportional hazards model (PHM). In this study, we develop a general parametric AFT model for identifying survival trait loci, in which the flexible generalized F distribution, including many commonly used distributions as special cases, is specified as the baseline survival distribution. EM algorithm for maximum likelihood estimation of model parameters is given. Simulations are conducted to validate the flexibility and the utility of the proposed mapping procedure. In analyzing survival time following hyperoxic acute lung injury (HALI) of mice in an F(2) mating population, the generalized F distribution performed best among the six competing survival distributions and detected four QTLs controlling differential HALI survival. PMID- 21316445 TI - Efficient generation of gene knockout plasmids for Dictyostelium discoideum using one-step cloning. AB - The amoeba Dictyostelium discoideum is a well-established model organism for studying numerous aspects of cellular and developmental functions. Its rather small (~34Mb) chromosomal genome and the high efficiency of gene disruption by homologous recombination have enabled researchers to dissect various specific gene functions. We describe here the use of one-step cloning for the fast and efficient generation of deletion vectors that are produced in a one-step reaction by inserting two PCR products into an organism-specific, generic acceptor system. This worked efficiently for all 16 tested constructs directed against genes in the amoeba Dictyostelium discoideum. Saving cost and time, the used protocol represents a significant advancement in the generation of such plasmids compared to the conventionally applied restriction enzyme/ligation approach. Using appropriate selection markers, similar systems could also be useful in other organisms, where genes can be knocked out by homologous recombination. PMID- 21316446 TI - Release of theophylline and carbamazepine from matrix tablets--consequences of HPMC chemical heterogeneity. AB - The release of theophylline and carbamazepine from matrix tablets composed of microcrystalline cellulose, lactose and hydroxypropyl methylcellulose (HPMC) was studied. The aim was to investigate the effect of different substituent heterogeneities of HPMC on the drug release from matrix tablets composed of either 35% or 45% HPMC. The release of the poorly soluble carbamazepine was considerably affected by the HPMC heterogeneity, and the time difference at 80% drug release was more than 12h between the formulations of different HPMC batches. This was explained by slower polymer erosion of the heterogeneous HPMC and the fact that carbamazepine was mainly released by erosion. In addition, results from magnetic resonance imaging showed that the rate of water transport into the tablets was similar. This explained the comparable results of the release of the sparingly soluble theophylline from the two formulations even though the polymer erosion and the swelling of the tablets were considerably different. Thus, it can be concluded that the drug release was highly affected by the substituent heterogeneity, especially in the case of carbamazepine, which was released mainly by erosion. PMID- 21316447 TI - Antitumoral and antimetastatic effect of antiangiogenic plasmids in B16 melanoma: Higher efficiency of the recombinant disintegrin domain of ADAM 15. AB - BACKGROUND: Despite the discovery of novel inhibitors of tumor angiogenesis, protein-based antiangiogenic cancer therapy suffers some limitations that antiangiogenic gene therapy could overcome. We investigated whether intra-tumoral electrotransfer of three angiogenic plasmids could inhibit tumor growth and metastasis. METHODS: Plasmids encoding recombinant disintegrin domain of ADAM-15 (RDD), thrombospondin 1 (TSP-1), and the soluble isoform of the VEGF receptor 1 (sFlt-1) were injected into B16F10 melanoma-bearing C57BL/6 mice followed by electroporation. Tumor volume was measured daily using a digital caliper. Metastasis was monitored by in vivo bioluminescence after surgical removal of the primary luciferase-encoding B16F10 tumor 5 days after intra-tumoral electrotransfer. Markers of vascularization and cell proliferation were quantified by immunohistochemistry. RESULTS: Intra-tumoral electrotransfer of the antiangiogenic plasmids induced a significant inhibition of tumor growth, doubling of mean survival time and long-term survivors (~40% vs 0% in control). When the tumor was removed by surgery after intra-tumoral plasmid electrotransfer, a significant decrease in tumor metastasis was observed leading to long-term tumor-free survival especially after treatment with pRDD plasmid (84% vs 0% in control). Unlike pTSP-1 and psFlt-1, pRDD significantly decreased cell proliferation in B16F10 primary tumors which express alphavbeta3 and alpha5beta1 integrins. No effect of antiangiogenic plasmid electrotransfer on normal skin blood flow was detected. CONCLUSION: The intra-tumoral electrotransfer of the three antiangiogenic plasmids is a promising method for the treatment of melanoma. The plasmid encoding RDD seems to be particularly effective due to its direct antitumoral activity combined with angiogenesis suppression, and its marked inhibition of metastasis. PMID- 21316448 TI - The aggregative stability of beta-lactoglobulin in glassy mixtures with sucrose, trehalose and dextran. AB - The aim of this study was to investigate the effect of the addition of different carbohydrates on the thermally induced aggregation of a model globular protein, beta-lactoglobulin (BLG), in the glass state. Amorphous mixtures of BLG with trehalose, sucrose and dextran were prepared by freeze-drying, their glass behaviour was characterised using calorimetry and thermally induced aggregation was measured using size exclusion chromatography. Pure BLG shows increasing levels of aggregation when heated in the temperature range 70-100 degrees C for 48-144 h. The addition of the disaccharides sucrose and trehalose both resulted in a decrease in aggregation rate which approached negligible rates at 50 wt.% carbohydrate. The effect of dextran addition was similar to that of the disaccharides when preparations containing 9wt.% carbohydrate were heated at 70 degrees C for 2 days. However, when the concentration exceeded 23 wt.%, the reaction temperature was 70 degrees C or above or the reaction time was longer than 48 h, the addition of the polysaccharide did not protect the protein from thermally induced aggregation, suggesting that protein-polymer phase separation could have occurred during freeze-drying. Overall the results support the proposal that one aspect of carbohydrate additive functionality is as a diluent with the added condition that the carbohydrate remains miscible with the protein during processing. PMID- 21316449 TI - Drug-carrier/hydrogel scaffold for controlled growth of cells. AB - In this work, a novel functional drug-carrier/hydrogel scaffold was prepared to control the growth of cells for tissue engineering. The drug-carrier/hydrogel scaffold was constructed from a micelle/Ca-alginate microparticles (Alg MPs)/poly(vinyl alcohol) (PVA) hydrogel composite. In such a system, paclitaxel (PTX) is encapsulated in the micelles formed by poly(L-glutamic acid)-b poly(propylene oxide)-b-poly(L-glutamic acid) (GPG), while human vascular endothelial growth factor-165 (VEGF(165)) is loaded in the Alg-MPs. The designed function of this scaffold is to encourage the fast growth of cells such as endothelial cells (ECs) in the early period to reduce the rejection and inhibit the growth of cells such as smooth muscle cells (SMCs) in late period to prevent the vascular intimal hyperplasia. The effect of VEGF(165) is to encourage the growth of ECs, while PTX is used to inhibit the growth of smooth muscle cells (SMCs). Structure characterizations show that the drug carriers are well dispersed in the PVA hydrogel. Independent release behaviors of the two drugs are observed. VEGF(165) shows a short-term release behavior, while PTX shows a long term release behavior from the drug-carrier/hydrogel scaffolds. Further study shows a controllable cell growth behavior on this functional drug carrier/hydrogel scaffold via the MTT assay. PMID- 21316450 TI - Quantitative determination of dehydroepiandrosterone fatty acyl esters in human female adipose tissue and serum using mass spectrometric methods. AB - Dehydroepiandrosterone-fatty acyl esters (DHEA-FAE) are naturally occurring water insoluble metabolites of DHEA, which are transported in plasma exclusively by lipoproteins. To find out whether DHEA, like estradiol, might be stored in adipose tissue in FAE form, we set up a mass spectrometric method to quantify DHEA-FAE and free DHEA in human adipose tissue and serum. The method consists of chromatographic purification steps and final determination of hydrolyzed DHEA-FAE and free DHEA, which was carried out by gas chromatography-mass spectrometry (GC MS) or liquid chromatography-tandem mass spectrometry (LC-MS/MS). Our results showed that no detectable amounts of DHEA-FAE could be found in adipose tissue although 32-178 pmol/g of free DHEA were determined by GC-MS and LC-MS/MS. The DHEA-FAE concentrations in serum quantified by GC-MS were 1.4+/-0.7 pmol/ml in premenopausal women (n=7), and 0.9+/-0.4 pmol/ml in postmenopausal women (n=5). Correspondingly, the free DHEA concentrations were 15.2+/-6.3 pmol/ml and 6.8+/ 3.0 pmol/ml. In addition, the mean proportions of DHEA-FAE of total DHEA (DHEA FAE+free DHEA) in serum were 8.6% and 11.2% in pre- and postmenopausal women, respectively. Serum DHEA-FAE concentration was below quantification limit for LC MS/MS (signal-to-noise ratio, S/N=10), while free DHEA concentrations varied between 5.8 and 23.2 pmol/ml. In conclusion, the proportion of DHEA-FAE of total DHEA in serum was approximately 9%. However, in contrast to our previous findings for estradiol fatty acid esters in adipose tissue which constituted about 80% of total estradiol (esterified+free), the proportion of DHEA-FAE of total DHEA was below 5%. Four to ten times higher concentrations of free DHEA were quantified in adipose tissue compared to those in serum. PMID- 21316451 TI - The N-terminus of ecdysteroid receptor isoforms and ultraspiracle interacts with different ecdysteroid response elements in a sequence specific manner to modulate transcriptional activity. AB - The functional insect ecdysteroid receptor is comprised of two nuclear receptors, the ecdysteroid receptor (EcR) and the RXR homologue, ultraspiracle (USP), which form a heterodimer. The dimer recognizes various hormone response elements and the effect of these elements on transcriptional activity of EcR isoforms was determined in vertebrate cells transfected with EcR and USP. Only constitutive activity mediated by the core response elements was preserved after elimination of nonspecific binding sites on the DNA of the vector. The constitutive transcriptional activity was regulated in a complex manner by the N-termini of both EcR and USP, the DBD of USP and the type and number of hormone response elements (HRE). Cooperative effects at oligomeric response elements particularly DR1 depended on the type of ecdysteroid response element and the N-termini of EcR and USP. The DBD of USP abolishes or attenuates synergistic effects. The data show that in the absence of hormone, transcriptional activity is regulated in a complex manner that offers additional possibilities for ecdysteroid receptor mediated gene regulation during development. PMID- 21316452 TI - AFQ056, a new mGluR5 antagonist for treatment of fragile X syndrome. AB - Fragile X syndrome, the most common form of inherited intellectual disability, is caused by a lack of FMRP, which is the product of the Fmr1 gene. FMRP is an RNA binding protein and a component of RNA-granules found in the dendrites of neurons. At the synapse, FMRP is involved in regulation of translation of specific target mRNAs upon stimulation of mGluR5 receptors. In this study, we test the effects of a new mGluR5 antagonist (AFQ056) on the prepulse inhibition of startle response in mice. We show that Fmr1 KO mice have a deficit in inhibition of the startle response after a prepulse and that AFQ056 can rescue this phenotype. We also studied the effect of AFQ056 on cultured Fmr1 KO hippocampal neurons; untreated neurons showed elongated spines and treatment resulted in shortened spines. These results suggest that AFQ056 might be a potent mGluR5 antagonist to rescue various aspects of the fragile X phenotype. PMID- 21316453 TI - Activity-dependent interactions of NSF and SNAP at living synapses. AB - As core components of the neurotransmitter release apparatus, SNAREs, NSF and SNAPs mediate fusion of neurotransmitter-filled synaptic vesicles within specialized regions of the presynaptic plasma membrane known as active zones (AZs). The present study combines genetic approaches in Drosophila with biochemical and live-imaging methods to provide new insights into the in vivo behavior and interactions of NSF and SNAP in neurotransmitter release. This work employs a temperature-sensitive (TS) paralytic NSF mutant, comatose, to show that disruption of NSF function results in activity-dependent redistribution of NSF and SNAP to periactive zone (PAZ) regions of the presynaptic plasma membrane and accumulation of protein complexes containing SNAREs, NSF and SNAP. Fluorescence Resonance Energy Transfer (FRET) and Fluorescence Recovery After Photobleaching (FRAP) studies in comatose revealed that NSF and SNAP exhibit activity-dependent binding to each other within living presynaptic terminals as well as distinctive interactions and mobilities. These observations extend current models describing the spatial organization of NSF, SNAP and SNARE proteins in synaptic vesicle trafficking. PMID- 21316454 TI - Excitotoxic neuroprotection and vulnerability with CaMKII inhibition. AB - Aberrant calcium signaling is a common feature of ischemia and multiple neurodegenerative diseases. While activation of calcium-calmodulin (CaM) dependent protein kinase II (CaMKII) is a key event in calcium signaling, its role in excitotoxicity is controversial. Our findings demonstrate neuroprotection in neuronal cultures treated with the small molecule (KN-93) and peptide (tat-AIP and tat-CN21) inhibitors of CaMKII immediately prior to excitotoxic glutamate/glycine insult. Unlike KN-93 which blocks CaMKII activation, but not constitutively active forms of CaMKII, tat-CN21 and tat-AIP significantly reduced excitotoxicity in cultured neurons when applied post-insult. We observed that the neuroprotective effects of tat-CN21 are greatest when applied before the toxic glutamate challenge and diminish with time, with the neuroprotection associated with CaMKII inhibition diminishing back to control 3h post glutamate insult. Mechanistically, tat-CN21 inhibition of CaMKII resulted in an increase in CaMKII activity and the percentage of soluble alphaCaMKII observed in neuronal lysates 24h following glutamate stimulation. To address the impact of prolonged CaMKII inhibition prior to excitotoxic insult, neuronal cultures were treated with CaMKII inhibitors overnight and then subjected to a sub-maximal excitotoxic insult. In this model, CaMKII inhibition prior to insult exacerbated neuronal death, suggesting that a loss of CaMKII enhances neuronal vulnerability to glutamate. Although changes in alphaCaMKII or NR2B protein levels are not responsible for this enhanced glutamate vulnerability, this process is blocked by the protein translation inhibitor cycloheximide. In total, the neuroprotection afforded by CaMKII inhibition can be seen as neuroprotective immediately surrounding the excitotoxic insult, whereas sustained CaMKII inhibition produced by excitotoxicity leads to neuronal death by enhancing neuronal vulnerability to glutamate. PMID- 21316455 TI - Characterization of a TiO2 enrichment method for label-free quantitative phosphoproteomics. AB - Phosphorylation is a protein post-translational modification with key roles in the regulation of cell biochemistry and signaling. In-depth analysis of phosphorylation using mass spectrometry is permitting the investigation of processes controlled by phosphorylation at the system level. A critical step of these phosphoproteomics methods involves the isolation of phosphorylated peptides from the more abundant unmodified peptides produced by the digestion of cell lysates. Although different techniques to enrich for phosphopeptides have been reported, there are limited data on their suitability for direct quantitative analysis by MS. Here we report a TiO(2) based enrichment method compatible with large-scale and label-free quantitative analysis by LC-MS/MS. Starting with just 500 MUg of protein, the technique reproducibly isolated hundreds of peptides, >85% of which were phosphorylated. These results were obtained by using relatively short LC-MS/MS gradient runs (45 min) and without any previous separation step. In order to characterize the performance of the method for quantitative analyses, we employed label-free LC-MS/MS using extracted ion chromatograms as the quantitative readout. After normalization, phosphopeptides were quantified with good precision (coefficient of variation was 20% on average, n=900 phosphopeptides), linearity (correlation coefficients >0.98) and accuracy (deviations <20%). Thus, phosphopeptide ion signals correlated with the concentration of the respective phosphopeptide in samples, making the approach suitable for in-depth relative quantification of phosphorylation by label-free LC MS/MS. PMID- 21316456 TI - Polyclonal hypergammaglobulinemia and autoantibody production induced by vaccination in farmed Atlantic salmon. AB - The introduction of oil-adjuvanted vaccines in salmon aquaculture made large scale production feasible by reducing the impact of infections. Vaccines given intraperitoneally (ip) contain oil adjuvant such as mineral oil. However, in rodents, a single ip injection of adjuvant hydrocarbon oil induces lupus-like systemic autoimmune syndrome. We have recently reported that autoimmune disease in farmed salmon, characterized by production of various autoantibodies, immune complex glomerulonephritis, liver thrombosis, and spinal deformity, are previously unrecognized side effects of vaccination. In the present study, we examined whether vaccination-induced autoantibody production in farmed Atlantic salmon is a mere result of polyclonal B-cell activation. Sera were collected from 205 vaccinated and unvaccinated Atlantic salmon (experimental, 7 farms) and wild salmon. Total IgM levels and autoantibodies to salmon blood cell (SBC) extract in sera were measured by ELISA and the relationship between hypergammaglobulinemia and autoantibody production was analyzed. Comparison of endpoint titers vs levels/units using a single dilution of sera in detection of autoantibodies to SBC showed near perfect correlation, justifying the use of the latter for screening. Both total IgM and anti-SBC antibodies are increased in vaccinated salmon compared with unvaccinated controls, however, they do not always correlate well when compared between groups or between individuals, suggesting the involvement of antigen-specific mechanisms in the production of anti-SBC autoantibodies. The primary considerations of successful vaccine for aquaculture are cost-effectiveness and safety. Vaccination-induced autoimmunity in farmed Atlantic salmon may have consequences on future vaccine development and salmon farming strategy. Evaluation for polyclonal hypergamamglobulinemia and autoimmunity should be included as an important trait when vaccine efficacy and safety are evaluated in future. PMID- 21316458 TI - Mast cell responses to Ergasilus (Copepoda), a gill ectoparasite of sea bream. AB - Immunocytochemical, light microscopy and ultrastructural studies were conducted on gill of sea bream, Sparus aurata L., naturally parasitized with the important parasitic copepod Ergasilus sp. to assess pathology and cellular responses. Thirty-seven S. aurata were examined from a fish farm; 26 (70%) were parasitized, with infection intensity ranging from 3 to 55 parasites per fish. Hosts were divided into two groups, lightly infected fish (<15 parasites per fish) and heavily infected fish (>15 parasites per fish). In histological sections, the copepod encircled gill lamellae with its second antennae, compressed the epithelium, provoked hyperplasia and hemorrhage, occluded arteries and often caused lamellar disruption. Fusion of the secondary lamellae due to epithelial hyperplasia was common in all infected fish; heavily infected fish showed more intense branchial inflammation. In both healthy and infected fish, mast cells (MCs) were free within the connective tissue inside and outside the blood vessels of the primary lamellae and made close contact with vascular endothelial cells, mucous cells and rodlet cells (RCs). MCs were irregular in shape with a cytoplasm filled by numerous electron-dense, membrane-bound granules. Immunostaining of primary and secondary gill filaments with an antibody against the antimicrobial peptide (AMP) piscidin 3 (anti-piscidin 3 antibody, anti-HAGR) revealed a subpopulation of MCs that were positive. These MCs were more abundant in gills of heavily infected fish than in either lightly infected or uninfected fish (ANOVA, P<0.05). Our report documents the response of gill to ectoparasite infection and provides further evidence that mast cells and their AMPs may play a role in responding to branchial ectoparasite infections. PMID- 21316457 TI - Anti-viral effects of interferon administration on sevenband grouper, Epinephelus septemfasciatus. AB - Interferon (IFN) plays crucial roles in innate immune responses against viral infections. In the present study, we report cloning and characterization of the IFN gene from the sevenband grouper (Epinephelus septemfasciatus), and the anti viral effects of its recombinant IFN protein in vivo. The isolated cDNA from sevenband grouper IFN encoded a protein consisting of 178 amino acids, and its first 22 amino acids represented a putative signal peptide. We named the identified sevenband grouper IFN gene as SgIFNa1 based on the result from phylogenetic analysis that categorized the deduced protein sequence into fish IFNa family. The expression of SgIFNa1 mRNA in the head kidney cells was induced by synthetic Poly(I:C), which is known as an inducer of IFN. It has also been confirmed that injection of recombinant SgIFNa1 protein (rSgIFNa1) upregulates expression of the Mx gene, which is known as an IFN-responsive gene, in head kidney cells. Moreover, we observed that preliminarily injection of rSgIFNa1 provided significant protection against a lethal challenge of nervous necrosis virus (NNV), which is a serious disease of sevenband grouper. These results demonstrate that SgIFNa1 has anti-viral activity and the administration of rSgIFNa1 to sevenband grouper is effective in preventing severe symptom development after NNV infection. PMID- 21316459 TI - Cloning, expression analysis and promoter structure of TBK1 (TANK-binding kinase 1) in Atlantic cod (Gadus morhua L.). AB - TBK1, also termed NAK or T2K, is a ubiquitous member of the IkappaB kinase (IKK) family that is required for innate and adaptive immune responses. We have identified and characterized the full-length TBK1 cDNA in Atlantic cod. The cod TBK1 gene consists of 2190 bp open reading frame encoding a polypeptide of 729 amino acids. According to a BLAST search, the cloned TBK1 gene has a high degree of sequence similarity (80.7-92%) to the various members of the TBK1 family, indicating that it is conserved during evolution. RT-PCR showed that the largest quantity of TBK1 transcripts was found in spleen, followed by the liver, gill, head kidney, gut, pyloric caeca, while the expression of TBK1 mRNA in muscle and skin was low. Both PMA, poly I:C and beta-glucan promoted expression of TBK1 transcripts in vivo. Furthermore, we determined an 875 bp sequence upstream of the transcriptional start site (TSS) and found a number of sequence motifs that matched known transcription factor-binding sites. Activities of the presumptive regulatory regions of this gene were assessed by transfecting different 5' deletion constructs in CHSE-214 cells. After the expression experiments, the results showed that the basal promoters and positive transcriptional regulator activities of cod TBK1 gene were dependent by sequences located from -875 to -425 bp and from -245 to +28 bp upstream of TSS. This study provides further insights into the transcriptional regulation of cod TBK1. PMID- 21316460 TI - Characterization of large yellow croaker (Pseudosciaena crocea) beta-actin promoter supports beta-actin gene as an internal control for gene expression modulation and its potential application in transgenic studies in fish. AB - As a housekeeping gene, beta-actin is one of the most commonly used reference gene and its promoter is widely used in transgenic studies in mammals and fish. In this study, we used genomic walker technology to clone the beta-actin gene (Lycbeta-actin) promoter sequence from large yellow croaker, an economically important marine fish in China. The Lycbeta-actin promoter region spans 3350 nucleotides (nt) and contains several transcription factor binding sites and a conserved enhancer motif (ATGGTAATAA) in the first intron. A promoter activity assay showed that this promoter region can drive enhanced green fluorescent protein (EGFP) gene expression in the fish cell line, EPC. Luciferase activity analysis demonstrated that the activity of the Lycbeta-actin promoter is not affected by poly(I:C) or lipopolysaccharide (LPS) stimulation. Absolute real-time PCR analysis of various tissues revealed that Lycbeta-actin expression levels are not significantly altered by poly(I:C) or inactivated trivalent bacterial vaccine (P > 0.05). These results suggest that beta-actin can be used as a suitable internal control for gene expression modulation in response to immune stimulations in large yellow croaker. In vivo transgenic experiments showed that the Lycbeta-actin promoter region can drive efficient EGFP expression in large yellow croaker fries or fertilized zebrafish eggs, supporting its potential application in transgenic studies in fish. PMID- 21316461 TI - Embryonic exposure to cypermethrin induces apoptosis and immunotoxicity in zebrafish (Danio rerio). AB - Cypermethrin (CYP) is widely used for control of indoor and field pests. As a result, CYP is one of the most common contaminants in freshwater aquatic systems. In the present study, we investigated the effects of CYP exposure on the induction of apoptosis and immunotoxicity in zebrafish during the embryo developmental stage. The mRNA levels of some key genes including P53, Puma, Bax, Apaf1, Cas9 and Cas3 on the mitochondrial pathway of cell apoptosis were significantly up-regulated at the concentration of 3 and 10 MUg/l CYP. Correspondingly, the activities of Cas3 and Cas9 increased significantly after exposure to 3 or 10 MUg/l CYP. In addition, the mRNA levels of iNOS and the total content of NO were also up-regulated significantly after CYP exposure. Moreover, it was also observed that the mRNA levels of IFN, CXCL-Clc, CC-chem and C3, which are closely related to the innate immune system, were affected in newly hatched zebrafish when exposed to 3 and 10 MUg/l CYP, exhibiting CYP's prominent impacts on the innate immune system of zebrafish. Taken together, our results suggest that CYP has the potential to induce cell apoptosis and cause innate immune system disruption in zebrafish during the embryo stage. The information presented in this study will help elucidate the mechanism of CYP-induced toxicity in fish. PMID- 21316462 TI - Characterization of the anterior cingulate's role in the at-risk mental state using graph theory. AB - The onset of positive symptoms in schizophrenia is often preceded by a prodromal phase characterized by neurocognitive abnormalities as well as changes in brain structure and function. Increasing efforts have been made to identify individuals at elevated risk of developing schizophrenia, as early intervention may help prevent progression towards psychosis. The present study uses functional MRI and graph theoretical analysis to characterize the organization of a functional brain network in at-risk mental state patients with varying symptoms assessed with the PANSS and healthy volunteers during performance of a verbal fluency task known to recruit frontal lobe networks and to be impaired in psychosis. We first examined between-groups differences in total network connectivity and global network compactness/efficiency. We then addressed the role of specific brain regions in the network organization by calculating the node-specific "betweeness centrality", "degree centrality" and "local average path length" metrics; different ways of assessing a region's importance in a network. We focused our analysis on the anterior cingulate cortex (ACC); a region known to support executive function that is structurally and functionally impaired in at-risk mental state patients. Although global network connectivity and efficiency were maintained in at-risk patients relative to the controls, we report a significant decrease in the contribution of the ACC to task-relevant network organization in at risk subjects with elevated symptoms (PANSS >= 45) relative to both the controls and the less symptomatic at-risk subjects, as reflected by a reduction in the topological centrality of the ACC. These findings provide evidence of network abnormalities and anterior cingulate cortex dysfunction in people with prodromal signs of schizophrenia. PMID- 21316463 TI - Symmetric diffeomorphic registration of fibre orientation distributions. AB - Registration of diffusion-weighted images is an important step in comparing white matter fibre bundles across subjects, or in the same subject at different time points. Using diffusion-weighted imaging, Spherical Deconvolution enables multiple fibre populations within a voxel to be resolved by computing the fibre orientation distribution (FOD). In this paper, we present a novel method that employs FODs for the registration of diffusion-weighted images. Registration was performed by optimising a symmetric diffeomorphic non-linear transformation model, using image metrics based on the mean squared difference, and cross correlation of the FOD spherical harmonic coefficients. The proposed method was validated by recovering known displacement fields using FODs represented with maximum harmonic degrees (l(max)) of 2, 4 and 6. Results demonstrate a benefit in using FODs at l(max)=4 compared to l(max)=2. However, a decrease in registration accuracy was observed when l(max)=6 was used; this was likely caused by noise in higher harmonic degrees. We compared our proposed method to fractional anisotropy driven registration using an identical code base and parameters. FOD registration was observed to perform significantly better than FA in all experiments. The cross-correlation metric performed significantly better than the mean squared difference. Finally, we demonstrated the utility of this method by computing an unbiased group average FOD template that was used for probabilistic fibre tractography. This work suggests that using crossing fibre information aids in the alignment of white matter and could therefore benefit several methods for investigating population differences in white matter, including voxel based analysis, tensor based morphometry, atlas based segmentation and labelling, and group average fibre tractography. PMID- 21316464 TI - Evoked and induced oscillatory activity contributes to abnormal auditory sensory gating in schizophrenia. AB - The ratio of magnetoencephalogram-recorded brain responses occurring 50ms after paired clicks (S2-evoked M50/S1-evoked M50) serves as a measure of sensory gating. An abnormally large ratio is commonly found in schizophrenia. Whether this abnormality indicates impaired gating is debated. Using event-related oscillations the present study sought to elucidate processes contributing to the phenomenon of altered M50 gating ratio. Schizophrenia inpatients (n=50) showed the expected large M50 gating ratio relative to 48 healthy controls, which correlated with less induced frontally generated activity in the 10-15Hz frequency band starting 200ms before the onset of S2. Patients also produced smaller alpha (8-12Hz) and gamma (60-80Hz) responses to S1. Results suggest that the deviant gating ratio in schizophrenia is a consequence of a complex alteration in the processing of incoming information that cannot be attributed to impaired gating alone. PMID- 21316465 TI - Stability of fMRI striatal response to alcohol cues: a hierarchical linear modeling approach. AB - In functional magnetic resonance imaging (fMRI) studies of alcohol-dependent individuals, alcohol cues elicit activation of the ventral and dorsal aspects of the striatum (VS and DS), which are believed to underlie aspects of reward learning critical to the initiation and maintenance of alcohol dependence. Cue elicited striatal activation may represent a biological substrate through which treatment efficacy may be measured. However, to be useful for this purpose, VS or DS activation must first demonstrate stability across time. Using hierarchical linear modeling (HLM), this study tested the stability of cue-elicited activation in anatomically and functionally defined regions of interest in bilateral VS and DS. Nine non-treatment-seeking alcohol-dependent participants twice completed an alcohol cue reactivity task during two fMRI scans separated by 14 days. HLM analyses demonstrated that, across all participants, alcohol cues elicited significant activation in each of the regions of interest. At the group level, these activations attenuated slightly between scans, but session-wise differences were not significant. Within-participants stability was best in the anatomically defined right VS and DS and in a functionally defined region that encompassed right caudate and putamen (intraclass correlation coefficients of .75, .81, and .76, respectively). Thus, within this small sample, alcohol cue-elicited fMRI activation had good reliability in the right striatum, though a larger sample is necessary to ensure generalizability and further evaluate stability. This study also demonstrates the utility of HLM analytic techniques for serial fMRI studies, in which separating within-participants variance (individual changes in activation) from between-participants factors (time or treatment) is critical. PMID- 21316466 TI - Mapping the flow of information within the putative mirror neuron system during gesture observation. AB - The putative mirror neuron system may either function as a strict feed-forward system or as a dynamic control system. A strict feed-forward system would predict that action observation leads to a predominantly temporal->parietal->premotor flow of information in which a visual representation is transformed into motor programs which contribute to action understanding. Instead, a dynamic feedback control system would predict that the reverse direction of information flow predominates because of a combination of inhibitory forward and excitatory inverse models. Here we test which of these conflicting predictions best matches the information flow within the putative mirror neuron system (pMNS) and between the pMNS and the rest of the brain during the observation of comparatively long naturalistic stretches of communicative gestures. We used Granger causality to test the dominant direction of influence. Our results fit the predictions of the dynamic feedback control system: we found predominantly an information flow within the pMNS from premotor to parietal and middle temporal cortices. This is more pronounced during an active guessing task than while passively reviewing the same gestures. In particular, the ventral premotor cortex sends significantly more information to other pMNS areas than it receives during active guessing than during passive observation. PMID- 21316468 TI - How specific is specific phobia? Different neural response patterns in two subtypes of specific phobia. AB - Specific phobia of the animal subtype has been employed as a model disorder exploring the neurocircuitry of anxiety disorders, but evidence is lacking whether the detected neural response pattern accounts for all animal subtypes, nor across other phobia subtypes. The present study aimed at directly comparing two subtypes of specific phobia: snake phobia (SP) representing the animal, and dental phobia (DP) representing the blood-injection-injury subtype. Using functional magnetic resonance imaging (fMRI), brain activation and skin conductance was measured during phobogenic video stimulation in 12 DP, 12 SP, and 17 healthy controls. For SP, the previously described activation of fear circuitry structures encompassing the insula, anterior cingulate cortex and thalamus could be replicated and was furthermore associated with autonomic arousal. In contrast, DP showed circumscribed activation of the prefrontal and orbitofrontal cortex (PFC/OFC) when directly compared to SP, being dissociated from autonomic arousal. Results provide preliminary evidence for the idea that snake and dental phobia are characterized by distinct underlying neural systems during sustained emotional processing with evaluation processes in DP being controlled by orbitofrontal areas, whereas phobogenic reactions in SP are primarily guided by limbic and paralimbic structures. Findings support the current diagnostic classification conventions, separating distinct subtypes in DSM-IV-TR. They highlight that caution might be warranted though for generalizing findings derived from animal phobia to other phobic and anxiety disorders. If replicated, results could contribute to a better understanding of underlying neurobiological mechanisms of specific phobia and their respective classification. PMID- 21316467 TI - Boys do it the right way: sex-dependent amygdala lateralization during face processing in adolescents. AB - Previous studies have observed a sex-dependent lateralization of amygdala activation related to emotional memory. Specifically, it was shown that the activity of the right amygdala correlates significantly stronger with memory for images judged as arousing in men than in women, and that there is a significantly stronger relationship in women than in men between activity of the left amygdala and memory for arousing images. Using a large sample of 235 male adolescents and 235 females matched for age and handedness, we investigated the sex-specific lateralization of amygdala activation during an emotional face perception fMRI task. Performing a formal sex by hemisphere analysis, we observed in males a significantly stronger right amygdala activation as compared to females. Our results indicate that adolescents display a sex-dependent lateralization of amygdala activation that is also present in basic processes of emotional perception. This finding suggests a sex-dependent development of human emotion processing and may further implicate possible etiological pathways for mental disorders most frequent in adolescent males (i.e., conduct disorder). PMID- 21316469 TI - The effect of intra- and inter-subject variability of hemodynamic responses on group level Granger causality analyses. AB - Granger causality analyses aim to reveal the direction of influence between brain areas by analyzing temporal precedence: if a signal change in area A consistently precedes a signal change in area B, then A Granger-causes B. fMRI-based Granger causality inferences are mediated by the hemodynamic response function which can vary across brain regions. This variability might induce a bias in Granger causality analyses. Here we use simulations to investigate the effect of hemodynamic response variability on Granger causality analyses at the level of a group of twenty participants. We used a set of hemodynamic responses measured by Handwerker et al. (Neuroimage, 2004) and simulated 200 experiments in which time series with known directions of influence are convolved with these hemodynamic responses and submitted to Granger causality analysis. Results show that the average chance to find a significant Granger causality effect when no actual influence is present in the data stays well below the p-level imposed on the second level statistics. Most importantly, when the analyses reveal a significant directed influence, this direction was accurate in the vast majority of the cases. The sensitivity of the analyses however depended on the neuronal delay between the source and target regions and their relative hemodynamic delay. Influences flowing from regions to one with the same or a slower hemodynamic response function were detected in over 80% of the cases when the neuronal delay was at least 100 ms. Influences flowing to a region with a faster hemodynamic delay were detected in over 80% of the cases when delays are above 1s. PMID- 21316470 TI - LoAd: a locally adaptive cortical segmentation algorithm. AB - Thickness measurements of the cerebral cortex can aid diagnosis and provide valuable information about the temporal evolution of diseases such as Alzheimer's, Huntington's, and schizophrenia. Methods that measure the thickness of the cerebral cortex from in-vivo magnetic resonance (MR) images rely on an accurate segmentation of the MR data. However, segmenting the cortex in a robust and accurate way still poses a challenge due to the presence of noise, intensity non-uniformity, partial volume effects, the limited resolution of MRI and the highly convoluted shape of the cortical folds. Beginning with a well-established probabilistic segmentation model with anatomical tissue priors, we propose three post-processing refinements: a novel modification of the prior information to reduce segmentation bias; introduction of explicit partial volume classes; and a locally varying MRF-based model for enhancement of sulci and gyri. Experiments performed on a new digital phantom, on BrainWeb data and on data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) show statistically significant improvements in Dice scores and PV estimation (p<10(-3)) and also increased thickness estimation accuracy when compared to three well established techniques. PMID- 21316471 TI - Quantification of accuracy and precision of multi-center DTI measurements: a diffusion phantom and human brain study. AB - The inter-site and intra-site variability of system performance of MRI scanners (due to site-dependent and time-variant variations) can have significant adverse effects on the integration of multi-center DTI data. Measurement errors in accuracy and precision of each acquisition determine both the inter-site and intra-site variability. In this study, multiple scans of an identical isotropic diffusion phantom and of the brain of a traveling human volunteer were acquired at MRI scanners from the same vendor and with similar configurations at three sites. We assessed the feasibility of multi-center DTI studies by direct quantification of accuracy and precision of each dataset. Accuracy was quantified via comparison to carefully constructed gold standard datasets while precision (the within-scan variability) was estimated by wild bootstrap analysis. The results from both the phantom and human data suggest that the inter-site variation in system performance, although relatively small among scanners of the same vendor, significantly affects DTI measurement accuracy and precision and therefore the effectiveness for the integration of multi-center DTI measurements. Our results also highlight the value of a DTI-specific phantom in identifying and quantifying measurement errors due to site-dependent variations in the system performance, and its usefulness for quality assurance/quality control in multi center DTI studies. In addition, we observed that the within-scan variability of each data acquisition, as assessed by wild bootstrap analysis, is of the same magnitude as the inter-site and intra-site variability. We propose that by weighing datasets based on their variability, as evaluated by wild bootstrap analysis, one can improve the quality of the dataset. This approach will provide a more effective integration of datasets from multi-center DTI studies. PMID- 21316472 TI - Accurate epileptogenic focus localization through time-variant functional connectivity analysis of intracranial electroencephalographic signals. AB - Epilepsy is a neurological disorder characterized by seizures, i.e. abnormal synchronous activity of neurons in the brain. During a focal seizure, the abnormal synchronous activity starts in a specific brain region and rapidly propagates to neighboring regions. Intracranial ElectroEncephaloGraphy (IEEG) is the recording of brain activity at a high temporal resolution through electrodes placed within different brain regions. Intracranial electrodes are used to access structures deep within the brain and to reveal brain activity that cannot be observed with scalp EEG recordings. In order to identify the pattern of propagation across brain areas, a connectivity measure named the Adapted Directed Transfer Function (ADTF) has been developed. This measure reveals connections between different regions by exploiting statistical dependencies within multichannel recordings. The ADTF can be derived from the coefficients of a time variant multivariate autoregressive (TVAR) model fitted to the data. In this paper the applicability to locate the epileptogenic focus by time-variant connectivity analysis of seizure onsets based on the ADTF is shown. Furthermore, different normalizations of the ADTF (the integrated ADTF, the masked ADTF and the full frequency ADTF) are compared to investigate whether one is more suitable to describe the spreading of epileptic activity during an epileptic seizure. We quantified the performance of different connectivity measures during simulations of an epileptic seizure onset. The full frequency ADTF outperforms the integrated ADTF and masked ADTF. Accordingly, we applied this full frequency ADTF to 4 seizure onset and 29 subclinical seizure IEEG recordings of a patient with refractory epilepsy. Hereby, we showed that connectivity patterns derived from IEEG recordings can provide useful information about seizure propagation and may improve the accuracy of the pre-surgical evaluation in patients with refractory epilepsy. PMID- 21316473 TI - The development of future-oriented control: an electrophysiological investigation. AB - Cognitive control, or the ability to focus attention and select task-appropriate responses, is not static but can be dynamically adjusted in the face of changing environmental circumstances. Several models suggest a role for conflict monitoring in triggering these adjustments, whereby instances of response uncertainty are detected by the anterior cingulate cortex and strengthen attention-guiding rules actively maintained by lateral prefrontal cortex. Given the continued development of active maintenance mechanisms into adolescence, these models predict that the capacity to dynamically modulate control should be protracted in its development. The present study tested this prediction by examining age-related differences in behavioral and electrophysiological adaptations to prior conflict. Children, adolescents, and adults were administered the Dimensional Change Card Sort (DCCS; Zelazo, 2006) - a developmentally-appropriate task modified so that response conflict varied from trial to trial - as cortical activity was measured by means of event-related potentials (ERPs). Although all groups showed a robust conflict effect, there were pronounced age-related differences in behavioral and electrophysiological adaptations to prior conflict. First, responses to incongruent trials were faster following incongruent trials than following congruent trials, but only for adults and adolescents. Second, ERP components that indexed response conflict, and the cortical source of these components, were modulated by preceding conflict for adults and adolescents, but not children. Taken together, the findings suggest that adults and adolescents take advantage of prior conflict to prepare for the future, whereas children respond to cognitive challenges as they occur. Theoretical implications are discussed. PMID- 21316474 TI - Axon diameter mapping in the presence of orientation dispersion with diffusion MRI. AB - Direct measurement of tissue microstructure with diffusion MRI offers a new class of markers, such as axon diameters, that give more specific information about tissue than measures derived from diffusion tensor imaging. The existing techniques of this kind assume a single axon orientation in the tissue model, which may be a reasonable approximation only for the most coherently oriented brain white matter, such as the corpus callosum. For most other areas, orientation dispersion is not negligible and, if unaccounted for, leads to overestimation of the axon diameters, prohibiting their accurate mapping over the whole brain. Here we propose a new model that captures the effect of orientation dispersion explicitly. A numerical scheme is developed to compute the diffusion signal prescribed by the proposed model efficiently, which supports the simultaneous estimation of the axon diameter and orientation dispersion. Synthetic data experiments demonstrate that the new model provides an axon diameter index that is robust to the presence of orientation dispersion. Results on in vivo human data show reduced axon diameter index and better agreement with histology compared to previous methods suggesting improvements in the axon diameter estimate. PMID- 21316475 TI - Cortical and striatal contributions to automaticity in information-integration categorization. AB - In information-integration categorization, accuracy is maximized only if information from two or more stimulus components is integrated at some pre decisional stage. In many cases the optimal strategy is difficult or impossible to describe verbally. Evidence suggests that success in information-integration tasks depends on procedural learning that is mediated largely within the striatum. Although many studies have examined initial information-integration learning, little is known about how automaticity develops in information integration tasks. To address this issue, each of ten human participants received feedback training on the same information-integration categories for more than 11,000 trials spread over 20 different training sessions. Sessions 2, 4, 10, and 20 were performed inside an MRI scanner. The following results stood out. 1) Automaticity developed between sessions 10 and 20. 2) Pre-automatic performance depended on the putamen, but not on the body and tail of the caudate nucleus. 3) Automatic performance depended only on cortical regions, particularly the supplementary and pre-supplementary motor areas. 4) Feedback processing was mainly associated with deactivations in motor and premotor regions of cortex, and in the ventral lateral prefrontal cortex. 5) The overall effects of practice were consistent with the existing literature on the development of automaticity. PMID- 21316476 TI - Task relevance modulates successful retrieval effects during explicit and implicit memory tests. AB - The successful retrieval effect refers to greater activation for items identified as old compared to those identified as new. This effect is particularly apparent in the ventral posterior parietal cortex (vPPC), though its functional properties remain unclear. In two experiments, we assessed the activation for old and new items during explicit and implicit tests of memory. In Experiment 1, significant effects were observed during explicit recognition performance and during an implicit lexical decision task. In both tasks, determining mnemonic status provides relevant information to task goals. Experiment 2 included a second implicit task in which determining mnemonic status was not relevant (color discrimination task). In this case, vPPC activation did not distinguish between old and new items. These findings suggest that automatic or implicit processes can drive retrieval-related activation in the vPPC, though such processes are gated by stimulus relevancy and task goals. PMID- 21316477 TI - A multi-locus molecular phylogeny of the Lepidoziaceae: laying the foundations for a stable classification. AB - The Lepidoziaceae, with over 700 species in 30 genera, is one of the largest leafy liverwort families. Despite receiving considerable attention, the composition of subfamilies and genera remains unsatisfactorily resolved. In this study, 10 loci (one nuclear 26S, two mitochondrial nad1 and rps3, and seven chloroplast atpB, psbA, psbT-psbH, rbcL, rps4, trnG and trnL-trnF) are used to estimate the phylogeny of 93 species of Lepidoziaceae. These molecular data provide strong evidence against the monophyly of three subfamilies; Lepidozioideae, Lembidioideae and Zoopsidoideae, and seven of the 20 sampled genera; Lepidozia, Telaranea, Kurzia, Zoopsis, Lembidium, Paracromastigum and Chloranthelia. Several robust clades are recognised that might provide the basis for a revised subfamily circumscription including a narrower circumscription of the Lepidozioideae and a more inclusive Lembidioideae. Neogrollea notabilis is returned to the Lepidoziaceae and Megalembidium insulanum is placed in the Lembidioideae. PMID- 21316478 TI - Biogeography and diversification of hermit spiders on Indian Ocean islands (Nephilidae: Nephilengys). AB - The origin of the terrestrial biota of Madagascar and, especially, the smaller island chains of the western Indian Ocean is relatively poorly understood. Madagascar represents a mixture of Gondwanan vicariant lineages and more recent colonizers arriving via Cenozoic dispersal, mostly from Africa. Dispersal must explain the biota of the smaller islands such as the Comoros and the chain of Mascarene islands, but relatively few studies have pinpointed the source of colonizers, which may include mainland Africa, Asia, Australasia, and Madagascar. The pantropical hermit spiders (genus Nephilengys) seem to have colonized the Indian Ocean island arc stretching from Comoros through Madagascar and onto Mascarenes, and thus offer one opportunity to reveal biogeographical patterns in the Indian Ocean. We test alternative hypotheses on the colonization route of Nephilengys spiders in the Indian Ocean and simultaneously test the current taxonomical hypothesis using genetic and morphological data. We used mitochondrial (COI) and nuclear (ITS2) markers to examine Nephilengys phylogenetic structure with samples from Africa, southeast Asia, and the Indian Ocean islands of Madagascar, Mayotte, Reunion and Mauritius. We used Bayesian and parsimony methods to reconstruct phylogenies and haplotype networks, and calculated genetic distances and fixation indices. Our results suggest an African origin of Madagascar Nephilengys via Cenozoic dispersal, and subsequent colonization of the Mascarene islands from Madagascar. We find strong evidence of gene flow across Madagascar and through the neighboring islands north of it, while phylogenetic trees, haplotype networks, and fixation indices all reveal genetically isolated and divergent lineages on Mauritius and Reunion, consistent with female color morphs. These results, and the discovery of the first males from Reunion and Mauritius, in turn falsify the existing taxonomic hypothesis of a single widespread species, Nephilengys borbonica, throughout the archipelago. Instead, we diagnose three Nephilengys species: Nephilengys livida (Vinson, 1863) from Madagascar and Comoros, N. borbonica (Vinson, 1863) from Reunion, and Nephilengys dodo new species from Mauritius. Nephilengys followed a colonization route to Madagascar from Africa, and on through to the Mascarenes, where it speciated on isolated islands. The related golden orb-weaving spiders, genus Nephila, have followed the same colonization route, but Nephila shows shallower divergencies, implying recent colonization, or a moderate level of gene flow across the archipelago preventing speciation. Unlike their synanthropic congeners, N. borbonica and N. dodo are confined to pristine island forests and their discovery calls for evaluation of their conservation status. PMID- 21316479 TI - Osteoarthritis year 2010 in review. PMID- 21316480 TI - The glyoxalase system--from microbial metabolism, through ageing to human disease and multidrug resistance. PMID- 21316481 TI - von Hippel-Lindau protein adjusts oxygen sensing of the FIH asparaginyl hydroxylase. AB - Hypoxia inevitably develops in rapidly growing tumors and acts as an important microenvironment that forces changes in tumor behavior. Hypoxia-inducible factor 1alpha (HIF-1alpha) is activated during hypoxia and promotes the progression of malignancy by stimulating angiogenesis and by augmenting the ability of tumors to survive. In aerobic conditions, HIF-1alpha is destabilized by the PHD prolyl hydroxylases that target HIF-1alpha for proteolysis via the von Hippel-Lindau protein (pVHL) and further inactivated by the FIH asparaginyl-hydroxylase that precludes the recruitment of transcription coactivators. Although HIF-1alpha degradation is well understood, little is known about how its transcriptional activity increases gradually in response to decreasing oxygen. In particular, it has been questioned how FIH having a high affinity for oxygen regulates the HIF 1alpha activity in moderate hypoxia. We here found that the HIF-1alpha-FIH interaction is disrupted in 1-5% oxygen. Both in vitro and in vivo binding analyses revealed that pVHL acts as an adaptor for FIH to bind HIF-1alpha. Furthermore, because the pVHL-FIH interaction depends on oxygen tension, the FIH mediated inactivation of HIF-1alpha can be exquisitely regulated according to the severity of hypoxia. Based on these findings, we propose that pVHL fine-tunes the transcriptional activity of HIF-1alpha in graded oxygen tensions. PMID- 21316482 TI - The combined effects of BDE47 and BaP on oxidatively generated DNA damage in L02 cells and the possible molecular mechanism. AB - Polybrominated diphenyl ethers (PBDEs) and polycyclic aromatic hydrocarbons (PAHs) coexist widely in the environment and have generated adverse effects on the environment and human health. The purpose of this study was to investigate the combined toxic effects of these chemicals and the related mechanism. L02 cells were exposed to BDE47 (5, 10MUmol/L) or/and BaP (50MUmol/L) in different administration order. The cell growth and survival, DNA strand breaks, oxidative stress index (ROS, SOD, GSH, and MDA), LDH release and the expression level of CYP1 family members were measured. The result showed that BDE47 or/and BaP had no effect on the cell growth and survival under the present conditions. However, compared with the groups treated with BDE47 or BaP alone, the combined-treated groups induced significantly elevated DNA strand breaks, ROS production, and MDA level. Especially, pretreatment with BDE47 followed by BaP led to the strongest effects. Addition of the antioxidant N-acetyl-l-cysteine (NAC) markedly reduced the ROS level and partly suppressed the DNA strand breaks induced by BDE47 or/and BaP. Meanwhile, the combined treatment groups also markedly increased the SOD activity, GSH content, and LDH release level compared with the control group. The real-time PCR results showed that BaP could significantly induce the expression of CYP1A1 and CYP1B1, however, the pre-treatment with BDE47 appeared to attenuate the BaP-induced CYP1 expression. All of above findings indicated that BDE47 and BaP had a synergistic effect on oxidatively generated DNA damage in L02 cells via regulation on the oxidative stress response and the expression of CYP1 metabolism enzymes. PMID- 21316483 TI - Virtual enteroscopic images of Meckel's diverticulum. PMID- 21316484 TI - Diverticular bleeding: the imaging-endoscopy corroboration. PMID- 21316485 TI - Radiofrequency ablation of atrial fibrillation in patients with mitral or aortic mechanical prosthetic valves: a feasibility, safety, and efficacy study. AB - BACKGROUND: Patients with prosthetic valves have a high prevalence of atrial fibrillation (AF). We report a multicenter experience of performing pulmonary vein antral isolation (PVAI) in this challenging, high-risk cohort of patients. OBJECTIVE: The purpose of this study was to assess the feasibility, safety, and efficacy of radiofrequency (RF) ablation for sinus rhythm restoration in AF patients with mitral or aortic mechanical prosthetic valves. METHODS: A total of 50 patients with prosthetic valves (group I) who underwent RF ablation for AF between January 1, 2007, and April 30, 2009, were identified prospectively at four tertiary care centers. A matched group of 50 patients (group II) acted as controls. RESULTS: Total procedural time (199.4 +/- 49 minutes vs 166.6 +/- 27.5 minutes, P <.001) and fluoroscopy time (60 +/- 17 minutes vs 53.8 +/- 6.8 minutes, P <.01) were prolonged, with a higher incidence of atrial flutter at 3 months in group I (18% vs 6%, P = .1) compared to group II. At 12 months, 80% of patients in the valve group were in sinus rhythm after an average of 1.3 procedures, and 82% of controls were in sinus rhythm after an average 1.2 procedures (P = .9). There was a trend toward a higher nonfatal complication rate in the valve group than in the control group (8% vs 4%, P = .1). CONCLUSION: In patients with prosthetic valves, RF ablation for AF is feasible, safe, and efficacious, with a trend toward a higher nonfatal complication rate and an increased rate of postablation atrial flutter. PMID- 21316486 TI - Spinal cord stimulators for treatment of ventricular arrhythmias: antiarrhythmic in a can. PMID- 21316487 TI - Evaluation of prognostic factors for Peg Interferon alfa-2b plus ribavirin treatment on HCV infected patients in Pakistan. AB - The effective standard therapeutic regimen for patients with chronic hepatitis C is pegylated interferon plus ribavirin. The efficacy of treatment in chronic hepatitis C is defined as absence of detectable virus at six months after treatment. Analysis of patient dependent and virus related factors that enable us to predict the response to antiviral treatment is very important. We prospectively studied 403 patients who received PEG-IFN alpha-2b 1.5 MUg/kg/body weight plus ribavirin. Treatment was administrated for 24 weeks and 48 weeks for hepatitis C virus (HCV) genotypes 3 and 1, respectively. Out of 403 treated patients, 301 patients (74.7%) showed a sustained virologic response (SVR). Seven variables (age, sex, ethnic group, pretreatment viral load, HCV genotyping and pretreatment ALT) were chosen as possible predictors of SVR and were analysed by means of univariable and multivariable logistic regression analysis. Five variables were statistically significant (p<0.005) on univariable analysis: age, ethnic group, pretreatment viral load, response rate at week 4, and HCV genotype. In multivariable analysis independent factors associated with SVR were low pretreatment viral load (1.97; 95%CI, 1.06-3.66; p=0.03) and attainment of rapid virological response (RVR) (7.19; 95%CI, 4.15-12.45; p<0.001). Our findings support the association between viral load and SVR to PEG-IFN-alpha-2b plus ribavirin therapy. No achievement of RVR is an unfavorable marker for SVR. These findings suggest that all patients considered for treatment should have quantification of serum HCV RNA levels. The result can be used to counsel patients on the likelihood of achieving SVR and may influence the patient's decision on treatment. Future studies should confirm and explore this observation in other ethnic groups and in relation to HCV genotypes 1 and 3. PMID- 21316488 TI - In vitro aerobic and anaerobic muscle capacities in the European eel, Anguilla anguilla: effects of a swimming session. AB - In order to have a general view of metabolic requirements during swimming, in vitro aerobic and anaerobic fluxes were measured in red and white muscles from silver eels and yellow eels which differ in activity levels and nutritional states. These measurements were performed in control eels and after a 4 day swimming session (70% U(crit) in yellow eels, 80% U(crit) in silver eels). A swimming session significantly increases U(crit) from 12% to 18%, depending on the stage, with a significantly higher in vitro energy cost during the yellow stage at the muscle level. In vitro, the swimming session brings about a gain in anaerobic capacities rather than in aerobic ones. Some in vivo hypotheses are proposed. PMID- 21316489 TI - Evaluation of 3-D bioactive glass scaffolds dissolution in a perfusion flow system with X-ray microtomography. AB - Bioactive glass has high potential for bone regeneration due to its ability to bond to bone and stimulate osteogenesis whilst dissolving in the body. Although three-dimensional (3-D) bioactive glass scaffolds with favorable pore networks can be made from the sol-gel process, compositional and structural evolutions in their porous structures during degradation in vivo, or in vitro, have not been quantified. In this study, bioactive glass scaffolds were put in a simulated body fluid flow environment through a perfusion bioreactor. X-ray microtomography (MUCT) was used to non-destructively image the scaffolds at different degradation stages. A new 3-D image processing methodology was developed to quantify the scaffold's pore size, interconnect size and connectivity from MUCT images. The accurate measurement of individual interconnect size was made possible by a principal component analysis-based algorithm. During 28 days of dissolution, the modal interconnect size in the scaffold was reduced from 254 to 206 MUm due to the deposition of mineral phases. However, the pore size remained unchanged, with a mode of 682 MUm. The data presented are important for making bioactive glass scaffolds into clinical products. The technique described for imaging and quantifying scaffold pore structures as a function of degradation time is applicable to most scaffold systems. PMID- 21316490 TI - In vitro and in vivo degradation profile of aliphatic polyesters subjected to electron beam sterilization. AB - Degradation characteristics in response to electron beam sterilization of designed and biodegradable aliphatic polyester scaffolds are relevant for clinically successful synthetic graft tissue regeneration. Scaffold degradation in vitro and in vivo were documented and correlated to the macroscopic structure and chemical design of the original polymer. The materials tested were of inherently diverse hydrophobicity and crystallinity: poly(L-lactide) (poly(LLA)) and random copolymers from L-lactide and epsilon-caprolactone or 1,5-dioxepan-2 one, fabricated into porous and non-porous scaffolds. After sterilization, the samples underwent hydrolysis in vitro for up to a year. In vivo, scaffolds were surgically implanted into rat calvarial defects and retrieved for analysis after 28 and 91days. In vitro, poly(L-lactide-co-1,5-dioxepan-2-one) (poly(LLA-co-DXO)) samples degraded most rapidly during hydrolysis, due to the pronounced chain shortening reaction caused by the sterilization. This was indicated by the rapid decrease in both mass and molecular weight of poly(LLA-co-DXO). Poly(L-lactide-co epsilon-caprolactone) (poly(LLA-co-CL)) samples were also strongly affected by sterilization, but mass loss was more gradual; molecular weight decreased rapidly during hydrolysis. Least affected by sterilization were the poly(LLA) samples, which subsequently showed low mass loss rate and molecular weight decrease during hydrolysis. Mechanical stability varied greatly: poly(LLA-co-CL) withstood mechanical testing for up to 182 days, while poly(LLA) and poly(LLA-co-DXO) samples quickly became too brittle. Poly(LLA-co-DXO) samples unexpectedly degraded more rapidly in vitro than in vivo. After sterilization by electron beam irradiation, the three biodegradable polymers present widely diverse degradation profiles, both in vitro and in vivo. Each exhibits the potential to be tailored to meet diverse clinical tissue engineering requirements. PMID- 21316491 TI - The bone tissue compatibility of a new Ti-Nb-Sn alloy with a low Young's modulus. AB - A Ti-Nb-Sn alloy was developed as a new beta-type titanium alloy which had a low Young's modulus and high strength. The Young's modulus of the Ti-Nb-Sn alloy was reduced to about 45 GPa by cold rolling, much closer to human cortical bone (10 30 GPa) than that of Ti-6Al-4V alloy (110 GPa) and other beta-type titanium alloys developed for biomedical applications. The tensile strength of the Ti-Nb Sn alloy was increased to a level greater than that of Ti-6Al-4V alloy by heat treatment after severe cold rolling. In this study the cytotoxicity of Ti-25Nb 11Sn alloy was evaluated in direct contact cell culture tests using metal disks and the bone tissue compatibility - examined using metal rods inserted into the medullary canal of rabbit femurs. The remarkable findings were that: (1) there were no significant differences in the relative growth ratio and relative absorbance ratio between cells grown with the Ti-Nb-Sn alloy, Ti-6Al-4V alloy and CP-Ti in direct contact cell culture tests; (2) there were no significant differences in the load at failure between the Ti-Nb-Sn alloy and Ti-6Al-4V alloy in pull-out metal rods tests; (3) there were no significant differences in new bone formation around metal rods between the Ti-Nb-Sn alloy and Ti-6Al-4V alloy in histological evaluations. The new Ti-Nb-Sn alloy with an elasticity closer to that of human bone is thus considered to be bioinert while also having a high degree of bone compatibility similar to that of Ti-6Al-4V alloy. PMID- 21316492 TI - Mesoporous bioactive glasses: mechanical reinforcement by means of a biomimetic process. AB - Mesoporous bioactive glasses (MBGs) constitute a new family of bioceramics with the fastest in vitro bioactivity studied so far. In this work, pieces with the composition 85SiO(2)-10CaO-5P(2)O(5) (mol.%) were prepared as MBGs and also by the conventional sol-gel method. After in vitro tests in simulated body fluid, the MBG pieces exhibited compression resistance twice as great than before, whereas conventional sol-gel glasses showed similar values. Scanning and transmission electron microscopy demonstrate the development of an apatite-like phase not only on the external surface, but also on the grains located within the MBGs pieces. In contrast, conventional sol-gel glasses only developed an apatite like phase on the external surface. This work presents for the first time a new property of MBGs: the mechanical reinforcement of a bioactive glass through a biomimetic process. This ability is explained in terms of the outstanding bioactive behavior and the three-dimensional mesoporous structure that is exclusive for this bioceramics family. PMID- 21316493 TI - Introduction of antibacterial function into biomedical TiNi shape memory alloy by the addition of element Ag. AB - A new kind of biomedical shape memory TiNiAg alloy with antibacterial function was successfully developed in the present study by the introduction of pure Ag precipitates into the TiNi matrix phase. The microstructure, mechanical property, corrosion resistance, ion release behavior in simulated body fluid, cytotoxicity and antibacterial properties were systematically investigated. The typical microstructural feature of TiNiAg alloy at room temperature was tiny pure Ag particles (at submicrometer or micrometer scales with irregular shape) randomly distributed in the TiNi matrix phase. The presence of Ag precipitates was found to result in a slightly higher tensile strength and larger elongation of TiNiAg alloy in comparison with that of TiNi binary alloy. Furthermore, a maximum shape recovery strain of ~6.4% was obtained with a total prestrain of 7% in the TiNiAg alloy. In electrochemical and immersion tests, TiNiAg alloy presented good corrosion resistance in simulated body fluid, comparable with that of CP Ti and TiNi alloy. The cytotoxicity evaluation revealed that TiNiAg alloy extract induced slight toxicity to cells, but the viability of experimental cells was similar to or higher than that of TiNi alloy extract. In vitro bacterial adhesion study indicated a significantly reduced number of bacteria (S. aureus, S. epidermidis and P. gingivalis) on the TiNiAg alloy plate surface when compared with that on TiNi alloy plate surface, and the corresponding antibacterial mechanism for the TiNiAg alloy is discussed. PMID- 21316494 TI - A new insight into the dissociating effect of strontium on bone resorption and formation. AB - Calcium phosphates are widely used as biomaterials and strontium (Sr) is known to have the ability to modify the bone balance towards osteosynthesis. In the present study we investigated the capacity of Sr-substituted sol-gel calcium phosphate to modify the expression of genes and proteins involved in extracellular matrix synthesis by primary bone cells. We first determined the most effective concentration of strontium using human primary bone cells. Sol-gel biphasic calcium phosphate (BCP) powders were then synthesised to obtain release of the optimal concentration of strontium. Finally, human osteoblasts obtained from explant cultures were cultured in the presence of sol-gel BCP, Sr substituted BCP (5% Sr-substituted BCP, corresponding to a release of 5*10(-5)M [Sr(2+)] under the culture conditions (BCP(5%))) and medium containing strontium chloride (SrCl(2)). Viability, proliferation, cell morphology, protein production and protein activity were studied. We demonstrated that 5*10(-5)M SrCl(2) and BCP(5%) increased the expression of type I collagen and SERPINH1 mRNA and reduced the production of matrix metalloproteinases (MMP-1 and MMP-2) without modifying the levels of the tissue inhibitors of MMPs (TIMPs). Thus strontium has a positive effect on bone formation. PMID- 21316495 TI - Characterization of sSMC by FISH and molecular techniques. AB - Small supernumerary marker chromosome (sSMC) is a structurally altered additional chromosome that may not be explicitly clarified by conventional karyotyping alone. About one third of sSMC carriers have abnormal phenotypes and its clinical correlation is difficult, especially in prenatal studies. The present study was aimed at characterizing 19 sSMC identified in 15 patients with dysmorphic features with or without multiple congenital anomalies, conspicuous family history, short stature and/or ambiguous genitalia. All the sSMC were primarily identified by routine cytogenetics studies (performed with banding techniques) from peripheral blood except in one patient, where amniotic fluid was used. All sSMCs were further characterized by array-CGH (using 44 K oligonucleotide probe) and/or fluorescence in situ hybridization (FISH) using multicolor banding (MCB), centromere specific multicolor FISH (cenM-FISH), subcentromere-specific multicolor FISH (subcenM-FISH), micro-dissection and/or reverse FISH. This report demonstrates the worth of advanced molecular (cyto)genetic techniques in characterizing sSMC, their utility in genotype-phenotype correlation and risk of clinical presentation. PMID- 21316496 TI - Transcriptomics and proteomics in human African trypanosomiasis: current status and perspectives. AB - Human African trypanosomiasis, or sleeping sickness, is a neglected vector-borne parasitic disease caused by protozoa of the species Trypanosoma brucei sensu lato. Within this complex species, T. b. gambiense is responsible for the chronic form of sleeping sickness in Western and Central Africa, whereas T. b. rhodesiense causes the acute form of the disease in East Africa. Presently, 1.5 million disability-adjusted life years (DALYs) per year are lost due to sleeping sickness. In addition, on the basis of the mortality, the disease is ranked ninth out of 25 human infectious and parasitic diseases in Africa. Diagnosis is complex and needs the intervention of a specialized skilled staff; treatment is difficult and expensive and has potentially life-threatening side effects. The use of transcriptomic and proteomic technologies, currently in rapid development and increasing in sensitivity and discriminating power, is already generating a large panel of promising results. The objective of these technologies is to significantly increase our knowledge of the molecular mechanisms governing the parasite establishment in its vector, the development cycle of the parasite during the parasite's intra-vector life, its interactions with the fly and the other microbial inhabitants of the gut, and finally human host-trypanosome interactions. Such fundamental investigations are expected to provide opportunities to identify key molecular events that would constitute accurate targets for further development of tools dedicated to field work for early, sensitive, and stage-discriminant diagnosis, epidemiology, new chemotherapy, and potentially vaccine development, all of which will contribute to fighting the disease. The present review highlights the contributions of the transcriptomic and proteomic analyses developed thus far in order to identify potential targets (genes or proteins) and biological pathways that may constitute a critical step in the identification of new targets for the development of new tools for diagnostic and therapeutic purposes. PMID- 21316497 TI - Management of hepatitis C virus genotype 4: recommendations of an international expert panel. AB - HCV has been classified into no fewer than six major genotypes and a series of subtypes. Each HCV genotype is unique with respect to its nucleotide sequence, geographic distribution, and response to therapy. Genotypes 1, 2, and 3 are common throughout North America and Europe. HCV genotype 4 (HCV-4) is common in the Middle East and in Africa, where it is responsible for more than 80% of HCV infections. It has recently spread to several European countries. HCV-4 is considered a major cause of chronic hepatitis, cirrhosis, hepatocellular carcinoma, and liver transplantation in these regions. Although HCV-4 is the cause of approximately 20% of the 170 million cases of chronic hepatitis C in the world, it has not been the subject of widespread research. Therefore, this document, drafted by a panel of international experts, aimed to review current knowledge on the epidemiology, natural history, clinical, histological features, and treatment of HCV-4 infections. PMID- 21316498 TI - Immunity to hepatitis B vaccine among health care workers. AB - The aim of this study was to determine the level of anti-HBsAg (hepatitis B surface antigen) in vaccinated high risk group. We measured anti-HBsAg concentration in blood sera of adult students aged from 19 to 37 years old. Five milliliters (5ml) of blood sample was taken from 210 cases four months after the second dose and 126 out of 210 cases three months after the third dose of hepatitis B vaccination. All blood samples were analyzed for anti-HBsAg by ELISA method. 125 out of 210 samples (59.5%) showed anti-HBsAg concentrations higher than 20mIu/ml and considered immune after the second dose of hepatitis B vaccination. Also, 99.2% of samples had anti-HBsAg higher than 20mIu/ml three months after the third dose of the vaccination. Non-immune cases in males were more than females (41.2% vs.40.1%). In conclusions, our results reinforce the importance of hepatitis B vaccine in adolescents and suggest that three dose of hepatitis B vaccine is necessary to increase the seropositive rate of anti-HBsAg in adults. PMID- 21316499 TI - Efficacy of vaccination strategies against intranasal challenge with Brucella abortus in BALB/c mice. AB - Brucellosis is a zoonotic disease affecting 500,000 people worldwide annually. Inhalation of aerosol containing a pathogen is one of the major routes of disease transmission in humans. Currently there are no licensed human vaccines available. Brucella abortus strain RB51 is a USDA approved live attenuated vaccine against cattle brucellosis. In a mouse model, strain RB51 over-expressing superoxide dismutase (SOD) administered intraperitoneally (IP) has been shown to be more protective than strain RB51 against an IP challenge with B. abortus pathogenic strain 2308. However, there is lack of information on the ability of these vaccine strains to protect against intranasal challenge. With the long-term goal of developing a protective vaccine for animals and people against respiratory challenge of Brucella spp., we tested a number of different vaccination strategies against intranasal infection with strain 2308. We employed strains RB51 and RB51SOD to assess the efficacy of route, dose, and prime-boost strategies against strain 2308 challenge. Despite using multiple protocols to enhance mucosal and systemic protection, neither rough RB51 vaccine strains provided respiratory protection against intranasal pathogenic Brucella infection. However, intranasal (IN) administration of B. abortus vaccine strain 19 induced significant (p<=0.05) pulmonary clearance of strain 2308 upon IN challenge infection compared to saline. Further studies are necessary to address host pathogen interaction in the lung microenvironment and elucidate immune mechanisms to enhance protection against aerosol infection. PMID- 21316500 TI - Effect of thiomersal on dissociation of intact (146S) foot-and-mouth disease virions into 12S particles as assessed by novel ELISAs specific for either 146S or 12S particles. AB - Intact (146S) foot-and-mouth disease virions (FMDVs) can dissociate into specific (12S) viral capsid degradation products. Using two single-domain antibody fragments that bind specifically to either 146S or 12S particles we developed two ELISAs for the quantification of these particles in FMDV antigen preparations used for vaccine manufacturing. Only O serotype strains are detected in the 146S specific ELISA whereas strains of most serotypes are detected in the 12S specific ELISA. However, the 146S concentration of A and Asia 1 serotype strains could be measured indirectly using the 12S specific ELISA by prior conversion of 146S into 12S particles by heat treatment. This allowed us to demonstrate that addition of the preservative thiomersal to FMDV antigens stimulates the dissociation into 12S particles of O, A and Asia 1 serotype strains upon prolonged storage at 4 degrees C. FMDV dissociation is known to result in a strongly reduced immunogenicity, which was experimentally confirmed here. Therefore, we recommend to omit thiomersal from FMD vaccines to increase its shelf life. PMID- 21316501 TI - CD4+CD25+ regulatory T cell-mediated changes in the expression of endocytic receptors and endocytosis process of human dendritic cells. AB - CD4+CD25+ regulatory T cells (Tregs) are known to inhibit immune responses to antigens. Since, the process of antigen uptake by dendritic cells (DC) is central to induction of immune responses, we analyzed the effect of Tregs on the expression of endocytic receptors on DC and its repercussion on antigen uptake. Our results demonstrate that Tregs down-regulate the expression and uptake of antigens via C-type lectin-like receptors CD206 and DC-SIGN, restrain the pinocytosis process of DC and augment the expression of FcgammaRIIB, an inhibitory Fcgamma receptor the engagement of which by IgG-bound antigens leads to inhibition of DC activation. Our results thus provide an additional insight on the pertinence of strategies aimed at blocking Treg functions towards improved vaccination protocols. PMID- 21316502 TI - Local innate and adaptive immune responses regulate inflammatory cell influx into the lungs after vaccination with formalin inactivated RSV. AB - Inactivated respiratory syncytial virus (RSV) vaccines tend to predispose for immune mediated enhanced disease, characterized by Th2 responses and airway hypersensitivity reactions. We show in a C57BL/6 mouse model that the early innate response elicited by the challenge virus (RSV versus influenza virus) influences the outcome of the Th1/Th2 balance in the lung after intramuscular priming with inactivated vaccine. Priming of CD4(+)/IFN-gamma(+) T cells by mature dendritic cells administered intravenously and/or priming of a virus specific CD8(+) T cell response ameliorated the Th2-mediated inflammatory response in the lung, suggesting that vaccination procedures are feasible that prevent vaccine induced immune pathology. PMID- 21316503 TI - Intussusception following rotavirus vaccine administration: post-marketing surveillance in the National Immunization Program in Australia. AB - INTRODUCTION: In Australia, post-marketing surveillance for intussusception following vaccination commenced with funding of RotaTeq((r)) and Rotarix((r)) vaccines under the National Immunization Program (NIP) in July 2007. METHODS: Two active surveillance mechanisms (hospital-based case ascertainment and monthly reports from paediatricians) identified intussusception cases between 1st July 2007 and 31st December 2008 in four states. Linkage to vaccination records identified cases occurring within 1-7 and 1-21 days of rotavirus vaccination. Expected cases within the post-vaccination windows were calculated by applying rates of intussusception from national hospitalisation data over 6 years (mid 2000 to mid-2006), by age and state, to numbers vaccinated (by dose) according to the Australian Childhood Immunization Register. RESULTS: Combining exposure windows associated with all doses of rotavirus vaccine from 1 to 9 months of age, there was no evidence of an increased risk of intussusception following vaccination for either vaccine. However, in infants 1 to <3 months of age, there was suggestive evidence of excess intussusception cases 1-7 and 1-21 days following dose 1 (1-7 days: RotaTeq((r)) relative risk (RR)=5.3, 95% confidence interval [CI] 1.1,15.4; Rotarix((r)) RR 3.5, 95% CI 0.7,10.1; 1-21 days: RotaTeq((r)) RR 3.5, 95% CI 1.3, 7.6; Rotarix((r))RR 1.5, 95% CI 0.4, 3.9). There was no evidence that clinical outcome of intussusception occurring within 21 days of rotavirus vaccination differed from that in cases occurring later post vaccination. CONCLUSION: Although we found no overall increase in intussusception following receipt of rotavirus vaccine, there was some evidence of an elevated risk following the first dose of both vaccines. Larger population-based studies using linked databases are required to provide more definitive evidence. PMID- 21316504 TI - C reactive protein as a predictor of neutrophil recovery in autoimmune neutropenia. AB - Primary autoimmune neutropenia (AIN) is more common in newborns, and usually benign or self-limiting, so most cases require no specific therapy. In adults, however, for little tendency toward spontaneous remission, they require certain treatments and careful managements. Here we report a successful management of primary AIN patient by estimating the granulopoiesis according to CRP levels without administration of G-CSF or increase of prednisolone when peripheral neutrophil counts dropped down. Transient elevation of CRP associated with severe drop down in neutrophil count, and subsequent dramatic neutrophil increase was occasionally observed during the follow up with minimal dose of prednisolone. Coexistence of decreased neutrophil counts and elevated CRP levels was accompanied by increase of serum levels of IL-6 and IL-8. Although this is the report of only one patient, these elevated CRP levels combined with severe drop down and subsequently spontaneous rapid recovery in neutrophil count, were repetitively observed, suggesting the preceding CRP elevation before neutrophil recovery. We propose the important part of CRP as a predictor of granulopoiesis in patients with neutropenia. PMID- 21316505 TI - Patterns of ventricular tachyarrhythmias associated with training, deconditioning and retraining in elite athletes without cardiovascular abnormalities. AB - Ventricular tachyarrhythmias commonly occur in trained athletes during ambulatory Holter electrocardiography and are usually associated with a benign course. Such arrhythmias have been demonstrated to be sensitive to short periods of athletic deconditioning; however, their response to retraining is not known. Twenty-four hour Holter electrocardiographic monitoring was performed at peak training and after 3 to 6 months of deconditioning and was repeated in the present study after 2, 6, and 12 months of retraining in 37 athletes with frequent and complex ventricular tachyarrhythmias and without cardiovascular abnormalities. These subjects showed partial (101 to 500 ventricular premature complexes [VPCs]/24 hours) or marked (<100 VPCs) reversibility of arrhythmias after deconditioning. Retraining initially resulted in a significant increase in arrhythmia frequency compared with deconditioning (from 280 +/- 475 to 1,542 +/- 2,186 VPCs; p = 0.005), couplets (0.14 +/- 0.42 to 4.4 +/- 8.2; p = 0.005), and nonsustained ventricular tachycardia (from 0 to 0.8 +/- 1.8; p = 0.02). Subsequently, a progressive reduction was seen in the frequency of all ventricular arrhythmias during the 1 year of training to well below that at the peak training levels (VPCs 917 +/- 1,630, couplets 1.8 +/- 4.2, and nonsustained ventricular tachycardia 0.4 +/- 1.2). Such annual arrhythmia reduction was significantly greater statistically in those athletes with marked reversibility after deconditioning than in the athletes with partial reversibility (69 +/- 139 vs 1,496 +/- 1,917 VPCs/24 hours, respectively; p = 0.007). No cardiac events or symptoms occurred during 1 year of follow-up. In conclusion, in elite athletes without cardiovascular disease, a resumption in intense training after deconditioning was associated with variable, but prolonged, suppression of ventricular ectopy. The absence of adverse clinical events or symptoms associated with the resumption of training supports the continued eligibility in competitive sports for such athletes and is also consistent with the benign nature of physiologic athlete's heart syndrome. PMID- 21316506 TI - Differential effect of elevated blood pressure on left ventricular geometry types in black and white young adults in a community (from the Bogalusa Heart Study). AB - Hypertension and left ventricular (LV) hypertrophy are both more common in blacks than in whites. The aim of the present study was to test the hypothesis that blood pressure (BP) has a differential effect on the LV geometry types in black versus white asymptomatic young adults. As a part of the Bogalusa Heart Study, echocardiography and cardiovascular risk factor measurements were performed in 780 white and 343 black subjects (aged 24 to 47 years). Four LV geometry types were identified as normal, concentric remodeling, eccentric, and concentric hypertrophy. Compared to the white subjects, the black subjects had a greater prevalence of eccentric (15.7% vs 9.1%, p <0.001) and concentric (9.3% vs 4.1%, p <0.001) hypertrophy. On multivariate logistic regression analyses, adjusting for age, gender, body mass index, lipids, and glucose, the black subjects showed a significantly stronger association of LV concentric hypertrophy with BP (systolic BP, odds ratio [OR] 3.74, p <0.001; diastolic BP, OR 2.86, p <0.001) than whites (systolic BP, OR 1.50, p = 0.037; and diastolic BP, OR 1.35, p = 0.167), with p values for the race difference of 0.007 for systolic BP and 0.026 for diastolic BP. LV eccentric hypertrophy showed similar trends for the race difference in the ORs; however, the association between eccentric hypertrophy and BP was not significant in the white subjects. With respect to LV concentric remodeling, its association with BP was not significant in either blacks or whites. In conclusion, elevated BP levels have a greater detrimental effect on LV hypertrophy patterns in the black versus white young adults. These findings suggest that blacks might be more susceptible than whites to BP-related adverse cardiac remodeling. PMID- 21316507 TI - Predictive value of depressive symptoms and B-type natriuretic peptide for new onset heart failure and mortality. AB - Depression and natriuretic peptides predict heart failure (HF) progression, but the unique contributions of depression and biomarkers associated with HF outcomes are not known. The present study determined the additive predictive value of depression and aminoterminal pro-B-type natriuretic peptide (NT-proBNP) for new onset HF in HF-free subjects and mortality in patients with HF. The participants in the Cardiovascular Health Study were assessed for depressive symptoms using the Center for Epidemiologic Studies Depression Scale and NT-proBNP using an electrochemiluminescence immunoassay. The validated cutoff values for depression (Center for Epidemiologic Studies Depression Scale >=8) and NT-proBNP (>=190 pg/ml) were used. The risks of incident HF and mortality (cardiovascular disease related and all-cause) were examined during a median follow-up of 11 years, adjusting for demographics, clinical factors, and health behaviors. In patients with HF (n = 208), depression was associated with an elevated risk of cardiovascular disease mortality (hazard ratios [HR] 2.07, 95% confidence interval [CI] 1.31 to 3.27) and all-cause mortality (HR 1.49, 95% CI 1.05 to 2.11), independent of the NT-proBNP level and covariates. The combined presence of depression and elevated NT-proBNP was associated with substantially elevated covariate-adjusted risks of cardiovascular disease mortality (HR 5.42, 95% CI 2.38 to 12.36) and all-cause mortality (HR 3.72, 95% CI 2.20 to 6.37). In the 4,114 HF-free subjects, new-onset HF was independently predicted by an elevated NT-proBNP level (HR 2.27, 95% CI 1.97 to 2.62) but not depression (HR 1.08, 95% CI 0.92 to 1.26) in covariate-adjusted analysis. In conclusion, depression and NT proBNP displayed additive predictive value for mortality in patients with HF. These associations can be explained by complementary pathophysiologic mechanisms. The presence of both elevated depression and NT-proBNP levels might improve the identification of patients with HF with a high risk of mortality. PMID- 21316508 TI - Incidence, epidemiology, and prognosis of residual pulmonary hypertension after mitral valve repair for degenerative mitral regurgitation. AB - Pulmonary hypertension (PH) is a common sequela of degenerative mitral valve disease, but the regression of PH after mitral surgery is often incomplete. We sought to identify the preoperative risk factors for residual PH after mitral valve repair and its effect on the clinical outcome. The outcomes in 71 patients with preoperative PH (mean pulmonary arterial pressure >=25 mm Hg) were compared according to the presence or absence of residual PH 24 hours after mitral valve surgery. Of 71 patients, 33 (46%) had residual PH. The remainder experienced significant reductions in the mean pulmonary arterial pressure without changes in pulmonary vascular resistance. Patients with residual PH had significantly elevated postoperative pulmonary vascular resistance (despite a significant decrease from the preoperative baseline) compared to those without residual PH. Residual PH was an independent risk factor for postoperative morbidity, mortality, and a prolonged intensive care unit stay (odds ratio 4.0, 95% confidence interval 1.2 to 13.1, p = 0.02), independent of the preoperative mean pulmonary arterial pressure. A decreased left ventricular ejection fraction (odds ratio 0.9, 95% confidence interval 0.8 to 1.0, p = 0.007) and fibroelastic deficiency (odds ratio 3.6, 95% confidence interval 1.1 to 11.8, p = 0.03) were independent predictors of residual PH. In conclusion, residual PH is a clinically important entity common after mitral valve repair for degenerative disease and is associated with clinical variables that aid in the preoperative prediction of at risk patients. PMID- 21316509 TI - Carcinoid heart disease without the carcinoid syndrome but with quadrivalvular regurgitation and unsuccessful operative intervention. AB - A 53-year-old woman is described who underwent mitral and aortic valve replacement and tricuspid valve annuloplasty for pure regurgitation at all 3 valve sites for unrecognized carcinoid heart disease without the carcinoid syndrome 22 days before death. Metastatic carcinoid was not recognized until necropsy, which disclosed a probable ovarian primary but with large hepatic metastases and left-sided cardiac involvement either greater than or equal to the right-sided involvement. Pulmonary hypertension, very unusual in carcinoid heart disease, persisted postoperatively and probably played a role in the patient's early death. Hepatic metastasis with ovarian primary is most unusual in this circumstance. PMID- 21316510 TI - Usefulness of serial of B-type natriuretic peptide and troponin-I levels to predict left ventricular remodeling after primary coronary angioplasty. PMID- 21316511 TI - Re: QRS duration as a predictor of permanent pacemaker implantation. PMID- 21316512 TI - Paul Dudley White on echocardiography. "Nobody is perfect". PMID- 21316513 TI - Gating in schizophrenia: from genes to cognition (to real world function?). PMID- 21316514 TI - Pharmacological enhancement of cognition in individuals with schizophrenia. PMID- 21316515 TI - Evidence-based recommendations for the use of Negative Pressure Wound Therapy in traumatic wounds and reconstructive surgery: steps towards an international consensus. AB - Negative pressure wound therapy (NPWT) has become widely adopted over the last 15 years and over 1000 peer reviewed publications are available describing its use. Despite this, there remains uncertainty regarding several aspects of usage. In order to respond to this gap a global expert panel was convened to develop evidence-based recommendations describing the use of NPWT. In this paper the results of the study of evidence in traumatic wounds (including soft tissue defects, open fractures and burns) and reconstructive procedures (including flaps and grafts) are reported. Evidence-based recommendations were obtained by a systematic review of the literature, grading of evidence, drafting of the recommendations by a global expert panel, followed by a formal consultative consensus development program in which 422 independent healthcare professionals were able to agree or disagree with the recommendations. The criteria for agreement were set at 80% approval. Evidence and recommendations were graded according to the SIGN (Scottish Intercollegiate Guidelines Network) classification system. Twelve recommendations were developed in total; 4 for soft tissue trauma and open fracture injuries, 1 for burn injuries, 3 for flaps and 4 for skin grafts. The present evidence base is strongest for the use of NPWT on skin grafts and weakest as a primary treatment for burns. In the consultative process, 11/12 of the proposed recommendations reached the 80% agreement threshold. The development of evidence-based recommendations for NPWT with direct validation from a large group of practicing clinicians offers a broader basis for consensus than work by an expert panel alone. PMID- 21316523 TI - A change in the pediatric leadership landscape. PMID- 21316527 TI - Systemic hypothermia is beneficial for infants with hypoxic-ischemic encephalopathy. PMID- 21316528 TI - 5% hypertonic saline with epinephrine is safe and may be effective in the treatment of bronchiolitis. PMID- 21316529 TI - Age and symptoms affect the prevalence of group A beta-hemolytic streptococcus in pharyngeal cultures of school-age children. PMID- 21316530 TI - Lactobacillus reuteri DSM 17938 appears to be effective in reducing crying time for colic. PMID- 21316531 TI - Electrocardiography does not reliably detect left ventricular hypertrophy in high risk children. PMID- 21316532 TI - A review of the treatment of chronic hepatitis C virus infection in cirrhosis. AB - BACKGROUND: Cirrhosis developing during chronic infection with the hepatitis C virus (HCV) poses a risk of anticipated liver-related death, therefore representing a dominant indication to anti-HCV therapy. OBJECTIVE: This review highlights the efficacy and safety of treatment of HCV infection in cirrhotic patients with respect to the clinical stage of the disease. METHODS: The PubMed, MEDLINE, EMBASE, and Cochrane databases, as well as the conference proceedings from the annual meetings of the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver, and the Asian Pacific Association for the Study of the Liver, were searched for articles published in English from January 1990 through May 2010, fulfilling the following criteria: (1) randomized, prospective observational, retrospective, or meta analysis; (2) involving adult patients with chronic HCV infection; and (3) data (fibrosis stage, treatment regimen, efficacy, safety) available for cirrhotics. Reviews were excluded. Search terms included chronic hepatitis C, fibrosis, cirrhosis, interferon alfa, ribavirin, hepatocellular carcinoma, and liver decompensation. RESULTS: Forty-five studies were identified. The rates of sustained virologic response to pegylated interferon in combination with ribavirin ranged from 10% to 44% for HCV genotypes 1/4 to 33% to 72% for genotypes 2/3 in compensated cirrhosis, while falling to 0% to 16% and 44% to 57%, respectively, in the decompensated stage, compared with 29% to 55% for genotypes 1/4 and 70% to 80% for genotypes 2/3 in noncirrhotic patients (compensated cirrhosis vs no cirrhosis: P < 0.001 for genotypes 1/4 and P = 0.002 for genotypes 2/3; decompensated cirrhosis vs no cirrhosis: P < 0.001 for all genotypes). HCV clearance was associated with a reduced risk of liver decompensation, hepatocellular carcinoma development, liver-related mortality, and hepatitis recurrence after liver transplantation. Treatment during compensated cirrhosis proved to be most cost-effective versus treatment after decompensation or a no-treatment strategy. Headache (54%), irritability (38%), fatigue (34%), and nausea (30%) were the most common adverse events in compensated patients, while anorexia (100%), fatigue (59%), neutropenia (53%), and thrombocytopenia (50%) were most common in decompensated patients. CONCLUSIONS: Anti-HCV treatment in cirrhotic patients was less effective than in noncirrhotic patients. Viral eradication reduced the risk of liver complications and improved survival in noncirrhotics. Based on effectiveness and tolerability data, therapy has a significant effect in patients with compensated cirrhosis, while decompensated patients need to weigh the risks versus benefits of treatment. PMID- 21316533 TI - Effectiveness and tolerability of combination treatment of chronic hepatitis C in illicit drug users: meta-analysis of prospective studies. AB - BACKGROUND: Hepatitis C virus (HCV) infection is a global health problem. In Western countries, illicit drug users (IDUs) constitute the largest proportion of HCV patients. International guidelines no longer regard ongoing illicit drug use as a contraindication to antiviral therapy for chronic hepatitis C (CHC). Nonetheless, in clinical practice, few IDUs have access to HCV treatment, likely because many physicians believe these patients will have poor adherence or a lack of treatment efficacy. OBJECTIVE: The aim of this study was to assess effectiveness and tolerability of combination treatment with ribavirin plus recombinant or pegylated interferon-alpha in the treatment of CHC in IDUs. METHODS: MEDLINE, EMBASE, and the Cochrane Library were searched for relevant studies published in English between 2000 and December 2008. The following terms were searched: chronic hepatitis C, interferons, antiviral agents, methadone, and substance-related disorders. Full-text articles and abstracts were searched using predefined criteria. A manual search of abstracts from 8 international meetings of hepatologists was also conducted. Only prospective studies with a sample size >15 and a homogeneous treatment schedule were included. Articles were extracted independently by 2 of the authors using an electronic standardized form including study quality indicators. RESULTS: Sixteen prospective studies were included, and data from a cohort of 953 IDUs were analyzed. The estimated overall sustained virologic response (SVR) and dropout (DO) rates in IDUs were 52% (95% CI, 44% 60%) and 26% (18%-35%, 95% CI), respectively. The rate of psychiatric severe adverse events (SAEs) that led to treatment discontinuation was 2% (95% CI, 1% 3%). These prevalences were not significantly different from those reported in registration trials of treatment of CHC that excluded IDUs from the study population (SVR, 50% [95% CI, 39%-61%]; DO, 26% [95% CI, 12%-41%]; and psychiatric SAEs, 2% [95% CI, 0%-6%]). By subgroup analysis, active ongoing drug use negatively affected the rate of treatment success (39% [95% CI, 30%-49%] vs 55% [95% CI, 45%-64%]; P = 0.02). CONCLUSION: Based on data from 16 prospective clinical studies of CHC treatment in IDUs published in the past 10 years, findings on effectiveness and tolerability are comparable to those in the general population. PMID- 21316534 TI - Telavancin: a lipoglycopeptide antimicrobial for the treatment of complicated skin and skin structure infections caused by gram-positive bacteria in adults. AB - BACKGROUND: Telavancin, a lipoglycopeptide antibiotic, is a semisynthetic derivative of vancomycin. It was approved by the US Food and Drug Administration (FDA) in 2009 for the treatment of complicated skin and skin structure infections (cSSSIs) caused by gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. OBJECTIVE: This article summarizes the pharmacology, in vitro and in vivo activity, pharmacokinetic properties, and clinical efficacy and tolerability of telavancin. METHODS: Relevant information was identified through a search of MEDLINE (1966-August 2010), Iowa Drug Information Service (1966 August 2010), International Pharmaceutical Abstracts (1970-August 2010), and Google Scholar using the terms telavancin, lipoglycopeptide, and TD-6424. Abstracts and posters from scientific meetings, as well as documents submitted by the manufacturer of telavancin to the FDA as part of the approval process, were consulted. In vivo and in vitro experimental and clinical studies and review articles that provided information on the activity, mechanism of action, pharmacologic and pharmacokinetic properties, clinical efficacy, and tolerability of telavancin were reviewed. RESULTS: In vitro, telavancin has potent activity against S aureus, including methicillin-resistant strains; Streptococcus pneumoniae; and vancomycin-susceptible enterococci with MICs generally <1 MUg/mL. Telavancin appears to have a dual mechanism of action, inhibiting cell wall formation and disrupting the cell membrane. In Phase III studies (ATLAS 1 and ATLAS 2), telavancin was found to be noninferior to vancomycin, with clinical cure rates of 88.3% and 87.1%, respectively, in clinically evaluable patients in the treatment of cSSSIs (difference, 1.2%; 95% CI, -2.1 to 4.6; P = NS). The effectiveness of telavancin in the treatment of hospital-acquired pneumonia was assessed in 2 Phase III studies (ATTAIN 1 and ATTAIN 2). Preliminary findings were that the effectiveness of telavancin was not significantly different from that of vancomycin, with cure rates of 82.7% and 80.9% in the clinically evaluable population, respectively (difference, 1.8%; 95% CI, -4.1 to 7.7; P = NS). The most commonly (>10%) reported adverse events included taste disturbances, nausea, headache, vomiting, foamy urine, constipation, and insomnia. CONCLUSION: In clinical trials, the effectiveness of telavancin was not significantly different from that of vancomycin in the treatment of cSSSIs, and telavancin was generally well tolerated. PMID- 21316535 TI - A phase III, randomized, open-label study to assess the tolerability and immunogenicity of an H5N1 influenza vaccine administered to healthy adults with a 1-, 2-, 3-, or 6-week interval between first and second doses. AB - BACKGROUND: Preparedness for an H5N1 influenza pre-pandemic requires effective and well-tolerated emergency vaccination strategies that provide both pandemic strain-specific and heterologous protection. OBJECTIVES: This was a pivotal study for the regulatory approval process for a candidate MF59-adjuvanted H5N1 vaccine. Its goals were to identify the preferred primary 2-dose vaccination schedule in adults and to assess whether the vaccine met European Committee for Medicinal Products for Human Use (CHMP) licensure criteria. METHODS: Healthy volunteers aged 18 to 60 years received 1 of 4 randomized schedules in which the 2 doses of vaccine were separated by a 1-, 2-, 3-, or 6-week interval. Three blood samples (~20 mL(-1)) were obtained from each subject: the first sample, immediately before administration of the first dose of vaccine; the second, immediately before administration of the second dose; and the third, 21 days after administration of the second dose. Hemagglutination inhibition (HI), microneutralization (MN), and single radial hemolysis (SRH) were assayed after each dose. Immunogenicity was assessed based on the CHMP licensure criteria for annual influenza vaccines (number of seroconversions or significant increase in HI titer >40%; mean geometric increase >2.5; and proportion of subjects achieving an HI titer >=40 or SRH titer >25 mm(2) should be >70% [seroprotection]). Subjects recorded all adverse events occurring within 7 days of vaccine administration; information on any serious adverse events was collected throughout the study (duration, 202 days). RESULTS: All study participants (N = 240) were white, with a mean age of 33 years and a mean body mass index of 24.6 kg/m(2). Equal numbers of men and women were assigned to each vaccination schedule. The CHMP criterion for seroprotection was achieved when the 2 doses of vaccine were separated by 2 (76%), 3 (72%), and 6 (79%) weeks; similar results were obtained on MN and SRH analysis. On the SRH analysis, the candidate vaccine showed a heterologous immune response to the H5N1/turkey/Turkey/1/05 (NIBRG-23; clade 2) influenza antigen. The vaccine met 2 of the 3 European licensure criteria, with seroconversion rates of 69% and 65% in the groups assigned to a 2- and 3-week interval between doses, respectively, and geometric mean ratios of 4.3 and 4.5. There were no serious adverse events related to vaccination. The most common adverse events reported within 7 days of the first and second doses of vaccine were mild to moderate injection-site pain (63%-73% and 34%-48%, respectively) and fatigue (25%-30% and 13%-24%). CONCLUSIONS: Two 7.5-MUg doses of MF59-adjuvanted H5N1 influenza vaccine given 2, 3, or 6 weeks apart afforded H5N1-specific immunity and met the CHMP licensure criterion for seroprotection in these healthy volunteers. Clinically relevant levels of heterologous immunity were observed when the 2 doses of vaccine were administered either 2 or 3 weeks apart; however, the licensure criterion for seroprotection was not met in this case. PMID- 21316536 TI - Combined retrospective analysis of seven phase II and III trials of the efficacy of linezolid in the treatment of pneumonia caused by multidrug-resistant Streptococcus pneumoniae. AB - BACKGROUND: Antimicrobial resistance among Streptococcus pneumoniae is of concern. Up to 30% of pneumococcal isolates worldwide are multidrug resistant. OBJECTIVE: The objective of this analysis was to assess the effectiveness of linezolid for the treatment of pneumonia caused by S pneumoniae, including multidrug-resistant S pneumoniae (MDRSP). METHODS: Data from 7 Phase II and III clinical trials that assessed the efficacy of linezolid in community- or hospital acquired pneumonia were pooled. Adults and children (aged <=12 years) received linezolid 600 mg and 10 mg/kg, respectively, IV or PO q12h for 7 to 14 days, with the exception of patients with documented bacteremia who could be treated for up to 28 days. Patients with a confirmed baseline isolate of S pneumoniae, including MDRSP, were assessed for clinical and microbiological outcomes. MDRSP was defined as an isolated strain of S pneumoniae that was resistant to >=3 classes of antibiotics. Clinical cure was defined as the resolution of clinical signs and symptoms of pneumonia compared with baseline, with either improvement or absence of progression of abnormalities on chest radiography. Microbiological eradication was defined as documented or presumed eradication at the test-of-cure (TOC) visit. Results from patients with indeterminate or missing outcomes at TOC were not included in the analyses. RESULTS: Of the patients with no bacteremia and treated with linezolid, 19 adults had MDRSP and 165 had non-MDRSP, and 3 children had MDRSP and 7 had non-MDRSP. Clinical cure and microbiological eradication rates were not significantly different between those infected with an MDRSP or non-MDRSP pathogen, respectively, in adults (16/19 [84%] and 150/164 [91%]) and children (3/3 [100%] and 7/7 [100%]). CONCLUSION: Linezolid was efficacious for the treatment of pneumonia caused by S pneumoniae, including multidrug-resistant strains. PMID- 21316537 TI - Long-term visual safety of voriconazole in adult patients with paracoccidioidomycosis. AB - BACKGROUND: Voriconazole is an antifungal agent with in vitro activity and clinical efficacy against yeasts, molds, and dimorphic fungi (eg, Paracoccidioides brasiliensis). The safety profile of voriconazole includes transient visual adverse events (VAEs) that resolve while undergoing treatment or after its discontinuation. OBJECTIVE: The goal of this study was to assess the long-term (ie, 6-12 months) visual safety of voriconazole in adult patients with paracoccidioidomycosis. METHODS: Ophthalmic data were prospectively collected as part of a multicenter, open-label, comparative study. Patients aged >=18 years with paracoccidioidomycosis were randomized in a 2:1 ratio to receive either voriconazole (200 mg BID orally, after the loading dose of 400 mg BID on day 1) or itraconazole (100 mg BID orally, with no loading dose). Patients were expected to receive treatment for a minimum of 6 months, or longer if needed as determined by the investigator (maximum duration, 1 year). Visual function tests and safety assessments were performed at baseline, week 12, week 24, end of treatment (EOT), and 8 weeks post-EOT. Ophthalmic examinations included visual acuity, color vision, contrast sensitivity, visual field, funduscopy, and slit lamp biomicroscopy. Treatment compliance was monitored via pill counts at each study visit. RESULTS: Thirty-five patients (mean age, 48 years; 96.2% male; 83.0% white) were randomized to receive voriconazole and 18 to receive itraconazole. Fourteen voriconazole-treated patients received >6 months of treatment (median, 169 days). Efficacy and overall safety results have been published previously. Sixteen voriconazole-treated patients and 2 itraconazole-treated patients experienced drug-related VAEs; none was considered serious or severe or led to dose reductions or resulted in discontinuation. Overall, visual examination results were not clinically significantly different between patients treated with voriconazole or itraconazole. There was no apparent relationship between changes in visual function test results and the occurrence of VAEs in either treatment group. CONCLUSION: Clinical assessment in this study found no evidence of an effect of voriconazole on long-term visual function in these adult patients with paracoccidioidomycosis. PMID- 21316538 TI - Respiratory syncytial virus testing during bronchiolitis episodes of care in an integrated health care delivery system: a retrospective cohort study. AB - BACKGROUND: Bronchiolitis has the highest incidence rate of any lower respiratory infection among infants and children <2 years of age. Respiratory syncytial virus (RSV) is the most common etiology of bronchiolitis. The American Academy of Pediatrics does not recommend routine RSV testing for infants and children with bronchiolitis. The clinical predictors of RSV testing are unknown. OBJECTIVES: The aims of this study were to identify the rates and predictors of RSV testing during bronchiolitis and to explore the relationship between RSV test results and antibiotic treatment among infants and children aged <2 years. METHODS: A retrospective study was conducted of 123,264 infants >=32 weeks' gestational age (GA) who were born at 1 of 6 Northern California Kaiser Permanente Medical Center Program hospitals between 1996 and 2004. A bronchiolitis episode of care (EOC) was defined as >=1 medical encounters with a bronchiolitis diagnosis code followed by 14 clear days without a bronchiolitis-related medical encounter. Descriptive statistics were used to report the frequency of tests, and logistic regression was used to assess the effect of hospitalization, chronologic age, gestational age, and season on the frequency of testing for RSV. Rapid direct fluorescent antibody testing was performed during the study. RESULTS: The birth cohort was 51.2% male and 42.7% white, 20.8% Hispanic, 20.3% Asian, 8.4% African American, and 7.9% other. Of 23,748 bronchiolitis EOCs, 4969 (20.9%) had >=1 test for RSV. Overall, 44.2% of all tests were positive for RSV. Physicians ordered RSV tests in 30.4% and 26.7% of bronchiolitis EOCs for infants born at 32 to 33 and 34 to 36 weeks' GA, respectively, compared with 17.9% of bronchiolitis EOCs for infants born at >=41 weeks' GA. Bronchiolitis hospitalization, younger chronologic age, prematurity, and RSV season were associated with RSV testing in a multivariate model controlling for other variables, with an adjusted odds ratio (AOR) of 28.55 (95% CI, 24.99-36.62) for hospitalization status; AOR of 6.89 (95% CI, 5.19-9.15) for chronologic age <1 month; AOR of 0.85 (95% CI, 0.76-0.95) for GA >41 weeks; and AOR of 2.48 (95% CI, 2.24-2.74) for RSV season (December March). Among hospitalized infants who were tested and had a diagnostic code suggesting treatment with antibiotics, use of antibiotics was significantly lower among those with a positive RSV test (63.4%) than those with a negative RSV test (75.5%) (chi(2) test; P < 0.001). CONCLUSIONS: Approximately 20% of these children with bronchiolitis EOCs were tested for RSV; of those tested, about half were positive. In this integrated health care system, hospitalization with bronchiolitis, chronologic age, gestational age <37 weeks, neonatal oxygen exposure, and bronchiolitis EOC during the RSV season were the factors associated with testing for RSV. PMID- 21316539 TI - Cost-effectiveness of optimized background therapy plus maraviroc for previously treated patients with R5 HIV-1 infection from the perspective of the Spanish health care system. AB - OBJECTIVE: The aim of this work was to evaluate the cost-effectiveness, from the perspective of the Spanish health care system, of optimized background therapy (OBT) plus maraviroc 300 mg BID versus OBT plus placebo in previously treated patients with R5 HIV-1 infection. METHODS: A lifetime cohort model was developed, based on 24- and 48-week pooled results from the Maraviroc Versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) studies 1 and 2, to reflect the Spanish health care system's perspective. Treatment duration was based on clinical trial follow-up from MOTIVATE 1 and 2. Clinical data, cohort characteristics, success probability, CD4 increase rate, CD4 cell status link to disease states, and adverse-event probability were taken from the MOTIVATE trials and other published literature. Other input parameters were taken from published sources. Antiretroviral (ARV) costs were derived from local sources. Non-ARV drug costs were obtained from published literature and a cost database. All costs were calculated as year-2009 euros. The annual discount rate was set at 3.0%. The main outcomes were cost per life-year gained (LYG) and cost per quality-adjusted life-year (QALY) gained. Uncertainty was assessed with one-way and probabilistic sensitivity analyses. RESULTS: In the model analysis, adding maraviroc to OBT was associated with an increase of 0.952 LYG and 0.909 QALY. Total costs were ?275,970 for maraviroc plus OBT and ?254,655 for placebo plus OBT (difference: ?21,315). The incremental cost per LYG was ?22,398 and the incremental cost per QALY gained was ?23,457. The model appeared to be robust for variations in key parameters. Results from the probabilistic sensitivity analyses indicated that the probability of the cost per QALY being below ?30,000 was 99%. CONCLUSION: Despite the limitations of the model, our analysis suggested that OBT plus maraviroc 300 mg BID is a clinically valuable option, and cost-effective from the perspective of the Spanish health care system, for previously treated patients with R5 HIV-1 infection. PMID- 21316540 TI - Nonadherence to oral linezolid after hospitalization: a retrospective claims analysis of the incidence and consequence of claim reversals. AB - BACKGROUND: Linezolid is available in an oral as well as an intravenous formulation. It is an oxazolidinone antibiotic and is effective in treating resistant gram-positive organisms such as methicillin-resistant Staphylococcus aureus and multidrug-resistant Streptococcus pneumoniae. OBJECTIVES: The goals of this study were to identify the incidence of claim reversals for oral linezolid in members who were recently discharged from a hospital and to study the subsequent pattern of health care utilization to quantify the consequences for members who have a reversed linezolid claim. METHODS: This study was a retrospective claims analysis of Humana Medicare Advantage Prescription Drug patients who had a claim for oral linezolid after an inpatient discharge between April 1, 2006, and June 30, 2008. The incidence of reversed claims among those with a linezolid prescription was measured as a proxy for medication adherence. Propensity scores were calculated to account for differences in patients' propensity to have a reversed claim. The association of the claim reversal with subsequent expenditures was assessed through 3 multivariate regression models wherein the dependent variables were drug, medical, and total costs for the 60 day period after discharge. The key independent variable was the occurrence of a reversed linezolid claim, and control variables included the propensity score quartiles and other clinical and demographic characteristics. All costs were provided in US dollars and from the year in which they occurred. RESULTS: Of 1046 patients identified (mean [SD] age, 69 [12] years; 51% male), 252 patients (24.1%) had a claim reversal for linezolid. Among these, 125 patients (49.6%) received linezolid within 10 days of the initial reversal, 39 patients (15.5%) received other antibiotics, and 88 patients (34.9%) did not receive any antibiotics. The unadjusted, mean outpatient drug costs were $696 and $2265 for patients with and without a reversal, respectively, whereas mean medical costs were $13,567 and $9355. Multivariable analyses revealed that members who did not receive linezolid after the claim reversal had significantly higher medical expenditures (Wald chi(2), 8.370; P = 0.004) and lower drug expenditures (Wald chi(2), 122.630; P < 0.01). The total costs did not differ significantly between the 2 groups (Wald chi(2), 1.540; P = 0.215), however, as the medical savings were partially negated by the higher drug costs. CONCLUSION: These patients with a reversed outpatient claim for linezolid had lower outpatient drug costs and higher medical costs in the 60-day period after the reversal. PMID- 21316541 TI - Relative bioavailability of two formulations of nevirapine 200-mg tablets in healthy Chinese male volunteers: a single-dose, randomized-sequence, open-label, two-way crossover study. AB - BACKGROUND: Nevirapine was the first member of the nonnucleoside reverse transcriptase inhibitor class to be approved for the treatment of HIV infection. It binds directly to the allosteric site on the reverse transcriptase and inhibits the activity of both RNA- and DNA-dependent DNA polymerases. OBJECTIVE: This study compared the pharmacokinetics and relative bioavailability of a test and reference formulation of nevirapine 200-mg tablets after single oral doses in healthy Chinese men to meet regulatory criteria for marketing of the new generic formulation. METHODS: This single-dose, randomized-sequence, open-label, 2-way crossover study was conducted at the Nanjing First Hospital of Nanjing Medical University, Nanjing, China. Healthy male Chinese volunteers were randomized in a 1?1 ratio to receive a single 200-mg (3.2-mg/kg) tablet of the test or reference formulation, followed by a 2-week washout period and administration of the alternate formulation. The study drugs were administered after a 10-hour overnight fast. Concentrations of nevirapine were assayed using an HPLC-UV method. For analysis of nevirapine pharmacokinetic parameters, blood samples were obtained before dosing and at regularly scheduled intervals over 168 hours after administration. The 2 formulations would be assumed to be bioequivalent for regulatory purposes if the 90% CIs for the log-transformed ratios of nevirapine AUC and C(max) were within the range established by the US Food and Drug Administration (0.80-1.25). Tolerability was evaluated throughout the study based on vital signs, physical examinations, 12-lead ECGs, and subject interviews concerning adverse events (AEs). RESULTS: Twenty Chinese male subjects were enrolled in and completed the study. Their mean age was 23 years (range, 21-25 years), mean weight was 63 kg (range, 56-70 kg), and mean height was 171 cm (range, 166-176 cm). No period or sequence effect was observed. The mean (SD) t(1/2) was 38.12 (2.23) hours for the test tablet and 36.79 (5.06) hours for the reference tablet; T(max) was 3.1 (0.7) and 3.0 (0.7) hours, respectively; C(max) was 2.52 (0.31) and 2.60 (0.48) mg . L(-1); AUC(0-168) was 155.66 (22.41) and 150.66 (22.11) mg . h . L(-1); and AUC(0-infinity) was 163.30 (22.88) and 157.75 (22.87) mg . h . L(-1). Mean relative bioavailability was 103.6% (8.6%). The 90% CIs for the log-transformed ratios of C(max) (93.51-102.13) and AUC(0-168) ( 99.84-106.74) were within the predetermined range for the assumption of bioequivalence. One subject reported mild headache after receiving the test formulation; the relationship of this AE to study drug was considered uncertain. No serious or clinically significant AEs were observed or reported during the study. CONCLUSIONS: In this single-dose study in healthy fasted Chinese males, the test tablet met the regulatory criterion for assumption of bioequivalence to the reference tablet. Both formulations were well tolerated in the population studied. SFDA registration no: 2009L04358. PMID- 21316542 TI - [Interventional bronchoscopy]. AB - In the last decade, major advances have been made in interventional bronchoscopy. Notable techniques are tracheobronchial laser, endoprosthesis placement and endobronchial ultrasound bronchoscopy. The indications and applications for these three bronchoscopic techniques are reviewed. I. PMID- 21316543 TI - [Asthma control. Possible obstacles along the way]. AB - With current therapeutic regimens, asthma should be well controlled in most patients. However, although asthma-related hospital admissions and mortality have decreased, the potential efficacy of treatments is not translating into optimal asthma control and quality of life. This discrepancy may be due to several factors and is complex to analyze. Poor asthma control can be caused by diverse reasons such as the patient's failure to understand how to take the medication, the presence of an untreated, underlying comorbid condition that aggravates the asthma, and the possibility that the patient has a severe form of glucocorticosteroid-insensitive asthma. The present article reviews the situations in which poor asthma control occurs for human-related reasons. These situations can be due to patients themselves and be independent of the disease or can be due to inadequate intervention by health professionals in specific areas and circumstances linked to asthma. A small but important group of patients with asthma is also analyzed; in this group, the asthma per se is severe and is refractory to routine treatments. PMID- 21316544 TI - [Non-invasive ventilation]. AB - The advent of non-invasive mechanical ventilation (NIMV) has radically changed the management of acute and chronic respiratory failure. Over the last few years, the number of possible applications of NIMV has progressively increased, both in the hospital and extrahospital setting. NIMV is now used in all hospitals and resident physicians currently receive specific training -nonexistent until a few years ago- in this modality. It falls to all of us to push forward the clinical and scientific advances represented by the development of NIMV, by promoting the events that accompany better knowledge of the physiopathological bases of ventilation and of its continuous applications in daily clinical practice and by perfecting the elements required for the correct application of this technique. The present review aims to provide a broad overview of NIMV, from the most theoretical knowledge (the physiopathology of NIMV) to the most practical skills (recognition of patient-ventilator asynchrony). Through this progression from the complex to the most basic, or from the basics to the most complex, depending on the perspective taken, we aim to provide deeper knowledge of the concepts required to understand the technical functioning of the ventilator, describing its distinct modes and parameters and the abilities that must be developed for the correct indication, use and monitoring of the technique. We provide a final reflection on other forms of respiratory support that can be offered to patients with ventilatory failure. PMID- 21316545 TI - [New challenges in community-acquired pneumonia]. AB - Community-acquired pneumonia is a major cause of morbidity and mortality. Severity assessment is a fundamental tool in the management of pneumonia that allows patients to be stratified according to risk of death and the most appropriate treatment intensity to be provided. The most widely used scales are the PSI/Fine and CURB-65 scales, which have been widely validated and are easy to calculate in clinical practice. Biomarkers can additionally be used to increase accuracy in predicting complications and mortality. Etiologic diagnosis of pneumonia continues to pose a challenge to clinicians. With the experience acquired in the 2009 AH1/N1 influenza pandemic, virological diagnosis of pneumonia by rapid polymerase chain reaction techniques has recently begun to be used. Experience has also been gained in antiviral treatment and complications, especially bacterial superinfection as the main unfavorable event in viral pneumonias. Just as the use of antibiotics to treat infections radically changed their prognosis and treatment, reports in the literature have progressively began to appear of the immunomodulatory effect of drugs that were not initially designed for the treatment of pneumonia, leading to hope for the potential modification of outcome in these patients. PMID- 21316546 TI - [Exacerbation of chronic obstructive pulmonary disease]. AB - Exacerbations of chronic obstructive pulmonary disease (COPD) are considered to be episodes of instability that favor disease progression, reduce quality of life, increase the risk of death and cause substantial healthcare resource use. These exacerbations are due to bacterial and viral infections and environmental stressors. However, other concomitant diseases such as heart disease, other lung diseases (e.g. pulmonary embolism, aspiration or pneumothorax) and other systemic processes can trigger or complicate these exacerbations. The two factors with the greatest influence on the physiopathology of exacerbations are dynamic overinflation and local and systemic inflammation. In most patients, drug treatment includes short-acting bronchodilators, systemic corticosteroids and antibiotics. Hypoxemic respiratory failure requires controlled oxygen therapy. In hypercapnic respiratory failure, non-invasive positive pressure ventilation may allow time to be gained until other treatments begin to take effect and can thus avoid endotracheal intubation. The use of non-invasive mechanical ventilation should never delay intubation, if indicated. Hospital discharge criteria are based on both clinical and gasometric stabilization and on the patient's ability to manage his or her disease at home. Hospitalization at home can be a treatment option in COPD exacerbations and is as effective as conventional hospitalization. PMID- 21316547 TI - [Community-acquired pneumonia]. AB - Given the inherent difficulty of determining the cause of community-acquired pneumonia (CAP) (an etiological diagnosis is only established in 40-60 % of cases), assessment of severity plays a key role in stratifying CAP patients arriving at the emergency department in three groups according to the need for hospitalization: outpatient, hospitalization, and the need for intensive care unit (ICU) admission. The two most common severity scales used to assess the need for hospital admission in CAP are the Pneumonia Severity Index (PSI) and CURB-65 score while ATS-IDSA 2007 criteria are specific to evaluate the need for ICU admission. Because of the possible etiological differences between the three groups, distinct etiological tests and empiric antibiotic treatments will be required in each subgroup, although a possible pneumococcal etiology should always be considered, since Streptococcus pneumoniae is the most common etiology of CAP in all three groups. Clinical status must be reassessed 48 hours after empirical antibiotic treatment is started. PMID- 21316548 TI - [Pulmonary thromboembolism]. AB - Pulmonary thromboembolism is a frequent disease in emergency departments and often poses a diagnostic challenge that requires appropriate strategies. Clinical information, laboratory tests such as a D-dimer and imaging techniques such as computed tomography (CT) angiography, ventilation-perfusion scintigraphy or echocardiography help to establish clinical probability and the severity of the disease. With all this information, risk scores can be constructed, such as the Pulmonary Embolism Severity Index (PESI) score, which has high sensitivity in predicting mortality. Treatment should be started immediately with heparin, usually low molecular weight heparin. If the patient is at high risk, thrombolytic therapy is indicated, although possible contraindications should be thoroughly assessed. Supportive treatment may be considered in a few patients. PMID- 21316549 TI - [Pharmacological treatment of COPD. Where are we now?]. AB - Current clinical guidelines recommend a step-wise approach to the pharmacological treatment of chronic obstructive pulmonary disease (COPD), with drugs being added according to the severity of airflow obstruction, symptoms, and the number of acute exacerbations in patients with severe disease. However, greater knowledge of the physiopathogenesis of this disease has led to COPD being considered a heterogeneous process in which therapeutic decisions should not be based exclusively on the results of spirometry. Treatment is increasingly individualized according to the patient's characteristics. The present article reviews the scientific evidence on the aims of treatment in COPD and the benefits achieved by the various pharmacological options available. PMID- 21316550 TI - [Limitations of current treatment: unmet needs in the treatment of COPD]. AB - In the last few years, considerable interest has been aroused in the treatment of chronic obstructive pulmonary disease (COPD) and the dearth of therapeutic options has been replaced by a far more proactive treatment approach, reflected in the development of the various guidelines and recommendations of the scientific societies. There are three main steps in the treatment of COPD: prevention of the disease, treatment of its symptoms, progression and complications, and recovery of physical function through respiratory rehabilitation. Considerable advances have been produced in these three dimensions, but limitations have been detected, indicating areas for improvement. The most effective means to prevent the disease is smoking cessation. While there are moderately effective drugs to help individuals quit, no drugs are available to prevent relapses. Moreover, due to health policies, most patients with COPD do not receive drug treatment for smoking. The treatment of COPD and its complications is based on the use of bronchodilators, which improve symptoms and quality of life and, to a greater or lesser extent, prevent exacerbations. However, treatment aimed at the underlying pathogenic causes of the disease, which should be antiinflammatory treatment, remains an unresolved issue due to the discouraging results obtained with inhaled corticosteroids, which should always be used in combination with a bronchodilator. The development of new antiinflammatory agents, such as roflumilast, could improve the management of patients with the most severe disease and repeated exacerbations. Lastly, although respiratory rehabilitation is highly effective in helping patients recover their ability to exercise, few patients have access to this option. As with the treatment of smoking, there is a need to implement respiratory rehabilitation through simple and effective programs and with the support of the health administration. PMID- 21316551 TI - [Toward personalized and integrated treatment of patients with COPD]. AB - The concept of chronic obstructive pulmonary disease (COPD) is broad and generic. In clinical practice and research, the definition of COPD is based on the extent of airflow obstruction measured through spirometry. However, it is currently known that this disease encompasses a complex variety of cellular, anatomical, functional and clinical manifestations that could allow distinct COPD phenotypes to be defined. Moreover, the severity of COPD depends not only on pulmonary function evaluated through spirometry but also on other variables such as clinical symptoms, exacerbations and the presence of complications and comorbidities, which contribute to distinguishing among the distinct phenotypes. Phenotypic heterogeneity may affect treatment response and the clinical course of the disease. COPD is, therefore, a complex entity requiring comprehensive and multidimensional evaluation to establish more personalized and integrated treatment. PMID- 21316552 TI - [Pharmacological profile of roflumilast]. AB - Roflumilast (3-cyclopropylmethoxy-4-difluoromethoxy-n-(3,5-dichloropyrid-4 yl)benzamide) was the first agent of a novel pharmacological class, selective phosphodiesterase 4 (PDE(4)) inhibitors, approved for the use of chronic obstructive pulmonary disease (COPD). The molecular mechanism of action of roflumilast is inhibition of the PDE(4) isoenzyme with a consequent increase of cyclic adenosine monophosphate. Roflumilast evidently has several pharmacological effects: antiinflammatory, anti-emphysema, and antibiotic actions. This drug also inhibits pulmonary hypertension and reduces mucus hypersecretion. The pharmacological actions leading to these effects are: a) inhibition of reactive oxygen species formation in epithelial cells, neutrophils and smooth muscle cells; b) inhibition of smooth muscle cell proliferation in the pulmonary artery, endothelial cells and probably some inflammatory cells causing pulmonary vascular remodeling; c) inhibition of fibroblasts, with a consequent reduction in pulmonary remodeling and, finally, d) inhibition of mucus production and improved ciliary beat frequency. In summary, roflumilast is the first non-steroidal anti inflammatory drug that can be used in the treatment of COPD. PMID- 21316553 TI - [Clinical profile of roflumilast]. AB - Patients with chronic obstructive pulmonary disease (COPD) and associated bronchitis are at higher risk of exacerbations, which are a major cause of morbidity and impaired quality of life. Moreover, exacerbations are associated with more rapid disease progression and higher mortality. The typical symptoms of chronic bronchitis (chronic cough and sputum production) are correlated with inflammatory markers in COPD. Roflumilast is an anti-inflammatory drug belonging to the novel therapeutic class of phosphodiesterase-4 inhibitors and is the first drug to be developed for the treatment of a specific COPD phenotype (COPD associated with chronic bronchitis). The results of clinical trials indicate that, in patients with COPD associated with chronic bronchitis and a history of exacerbations, roflumilast improves pulmonary function and reduces the symptoms and frequency of exacerbations requiring medical intervention. This effect is maintained when regular treatment with a long-acting bronchodilator or an inhaled corticosteroid is added. PMID- 21316554 TI - [Role of inflammation in the etiopathogenesis of COPD]. AB - Inflammation is one of the first immune system responses to any type of aggression. As with any type of aggression, the lesion produced by inhalation of tobacco smoke prompts an innate inflammatory response. Subsequently, this lesion is stimulated by the release of various chemical factors that enhance the inflammatory response and, finally--depending on the type of aggression--acquired immunity is activated, which, mediated by lymphocyte participation, serves to establish a physical barrier against the propagation of the lesion and to aid repair of the damaged pulmonary tissue. However, the balance between inflammation and repair is not always maintained, as is the case in chronic obstructive pulmonary disease (COPD), in which marked changes appear in the architecture of the airways, alveolar spaces and pulmonary arteries, forming the structural background of the functional changes characteristic of this disease. COPD is basically a pulmonary disease but data are available on the existence of associated systemic inflammation. The origins of this systemic inflammation are unclear: some information indicates that tobacco smoke is a direct origin common to local and systemic inflammation, while other data point to primary pulmonary inflammation that secondarily produces systemic involvement. The present review describes the main mechanisms involved in both pulmonary and systemic inflammation in COPD. PMID- 21316555 TI - [Clinical phenotypes of COPD]. AB - Chronic obstructive pulmonary disease (COPD) is a complex, multifaceted disease. The clinical presentation is highly heterogeneous and consequently, within what is known today as COPD, there may be some groups (phenotypes) of patients who share clinical and/or biological characteristics but who have distinct prognoses and/or who require different therapeutic approaches. In its broadest sense, phenotype is defined as any observable characteristic in the body, but "clinical phenotype" is defined as a characteristic or set of characteristics of a disease that can be used to distinguish individuals with COPD and are related to significant clinical outcomes, such as symptoms, exacerbations, treatment response, disease progression or death. The present article reviews current knowledge of this topic. PMID- 21316556 TI - [Multidimensional impact of COPD exacerbations]. AB - One of the inherent characteristics of chronic obstructive pulmonary disease (COPD) is the occurrence of exacerbations. These episodes of clinical decompensation, which used to be considered epiphenomena of the disease, are now viewed as key elements in the natural history of COPD. Exacerbations generate huge clinical workload and enormous costs, impair patients' quality of life, make a decisive contribution to the multidimensional progression of the disease and affect prognosis. The present article reviews the current scientific evidence on the multifaceted impact of COPD exacerbations. However, the effects of exacerbations are not homogeneous. Not all patients suffer exacerbations and not all exacerbations have the same repercussions. This review highlights the need to standardize the definition of exacerbation, as well as that of concepts such as the frequency, severity, and duration of the episode. These factors influence the effect of the exacerbation itself and introduce variables that may affect treatment. Indeed, there is an increasing need to identify specific clinical phenotypes and personalize treatment. Consequently, an "exacerbating" phenotype is postulated as a therapeutic target of special importance. PMID- 21316557 TI - [Comorbidities in COPD]. AB - The comorbidities of chronic obstructive pulmonary disease (COPD) consist of all the alterations and disorders associated, for one reason or another, with this disease. These comorbidities may be causal (other diseases also caused by smoking, such as ischemic heart disease or lung cancer), a complication (pulmonary hypertension or heart failure), a concurrence (disorders related to advanced age such as hypertension, diabetes mellitus, depression or osteoarthritis) or an intercurrent process (an acute process, generally time limited, such as a respiratory infection). Of all these comorbidities, those most frequently associated with COPD are hypertension, diabetes mellitus, infections, cancer and cardiovascular diseases. Comorbidities in COPD not only increase the social repercussions and annual cost of the disease but are also a prognostic factor for mortality in affected individuals. Indeed, in addition to respiratory failure, frequent causes of death in patients with COPD are ischemic heart disease and malignancies. The present article discusses the comorbidities of COPD with the greatest impact due to their frequency or influence on mortality. Although not precisely known, the common mechanism of all these comorbidities could be systemic inflammation and its mediators, which play an important role in the pathogenesis of COPD. PMID- 21316558 TI - Self-directed learning: does it affect team performance? PMID- 21316559 TI - Three-dimensional high-frequency backscatter and envelope quantification of cancerous human lymph nodes. AB - Quantitative imaging methods using high-frequency ultrasound (HFU) offer a means of characterizing biological tissue at the microscopic level. Previously, high frequency, 3-D quantitative ultrasound (QUS) methods were developed to characterize 46 freshly-dissected lymph nodes of colorectal-cancer patients. 3-D ultrasound radiofrequency data were acquired using a 25.6 MHz center-frequency transducer and each node was inked before tissue fixation to recover orientation after sectioning for 3-D histological evaluation. Backscattered echo signals were processed using 3-D cylindrical regions-of-interest (ROIs) to yield four QUS estimates associated with tissue microstructure (i.e., effective scatterer size, acoustic concentration, intercept and slope). These QUS estimates, obtained by parameterizing the backscatter spectrum, showed great potential for cancer detection. In the present study, these QUS methods were applied to 112 lymph nodes from 77 colorectal and gastric cancer patients. Novel QUS methods parameterizing the envelope statistics of the ROIs using Nakagami and homodyned-K distributions were also developed; they yielded four additional QUS estimates. The ability of these eight QUS estimates to classify lymph nodes and detect cancer was evaluated using receiver operating characteristics (ROC) curves. An area under the ROC curve of 0.996 with specificity and sensitivity of 95% were obtained by combining effective scatterer size and one envelope parameter based on the homodyned-K distribution. Therefore, these advanced 3-D QUS methods potentially can be valuable for detecting small metastatic foci in dissected lymph nodes. PMID- 21316560 TI - Reduced local perfusion after shock wave treatment of rotator cuff tendinopathy. AB - A marked neovascularity has been demonstrated in tendinopathies, due to the inflammatory-degenerative process. The aim of this study was to assess the effect of extracorporeal shock wave therapy (ESWT) on tissue perfusion in the treatment of tendinopathy. An observational clinical study was made of 30 patients undergoing ESWT for tendinopathy of the rotator cuff. A clinical improvement was obtained in 65.6% of patients at 2 and 6 months. This was associated with a statistically significant reduction in the oxygen tissue saturation, measured by oxymetry that was apparent already during treatment, as well as at subsequent follow-up visits. The reduced perfusion achieved with ESWT supports the hypothesis that this treatment can regulate the inflammatory process and offset increased vascularization, restoring physiologic tendon conditions. PMID- 21316561 TI - Augmentation of HIFU-induced heating with fibers embedded in a phantom. AB - The effect of fibers on the rate of heat deposition in the focal region of high intensity focused ultrasound (HIFU) beams was investigated. Nylon, stainless steel and copper fibers of diameters 0.23-0.25, 0.33 and 0.51-0.53 mm embedded in a phantom were exposed to HIFU. The total energy deposited was quantified by measuring the volumes of the lesions formed. The average volumes of the lesions normalized to the average volume of control lesions were 1.19+/-0.19, 1.43+/-0.19 and 2.67+/-0.21 for increasing nylon fiber diameter, indicating an augmented rate of heating. The maximum normalized volume of lesions at the metal fibers was 0.655. These results are consistent with the material properties, which suggest that the mechanism is increased acoustic absorption along with reduction of heat loss by the nylon fiber. The study supports the possibility of improving the efficacy of HIFU-induced hemostasis in vivo by use of a specially designed, nylon fiber-based medical appliance. PMID- 21316562 TI - In vitro and preliminary in vivo validation of echo particle image velocimetry in carotid vascular imaging. AB - Noninvasive, easy-to-use and accurate measurements of wall shear stress (WSS) in human blood vessels have always been challenging in clinical applications. Echo particle image velocimetry (Echo PIV) has shown promise for clinical measurements of local hemodynamics and wall shear rate. Thus far, however, the method has only been validated under simple flow conditions. In this study, we validated Echo PIV under in vitro and in vivo conditions. For in vitro validation, we used an anatomically correct, compliant carotid bifurcation flow phantom with pulsatile flow conditions, using optical particle image velocimetry (optical PIV) as the reference standard. For in vivo validation, we compared Echo PIV-derived 2-D velocity fields obtained at the carotid bifurcation in five normal subjects against phase-contrast magnetic resonance imaging (PC-MRI)-derived velocity measurements obtained at the same locations. For both studies, time-dependent, 2 D, two-component velocity vectors; peak/centerline velocity, flow rate and wall shear rate (WSR) waveforms at the common carotid artery (CCA), carotid bifurcation and distal internal carotid artery (ICA) were examined. Linear regression, correlation analysis and Bland-Altman analysis were used to quantify the agreement of different waveforms measured by the two techniques. In vitro results showed that Echo PIV produced good images of time-dependent velocity vector maps over the cardiac cycle with excellent temporal (up to 0.7 ms) and spatial (~0.5 mm) resolutions and quality, comparable with optical PIV results. Further, good agreement was found between Echo PIV and optical PIV results for velocity and WSR measurements. In vivo results also showed good agreement between Echo PIV velocities and phase contrast MRI velocities. We conclude that Echo PIV provides accurate velocity vector and WSR measurements in the carotid bifurcation and has significant potential as a clinical tool for cardiovascular hemodynamics evaluation. PMID- 21316563 TI - Enhanced shock wave-assisted transformation of Escherichia coli. AB - The objective of the study was to demonstrate that shock wave-induced transfer of DNA into bacteria can be increased by enhancing cavitation using dual-pulse (tandem) shock waves. Escherichia coli and plasmid were transferred to test vials. Competent cells were prepared at different concentrations of CaCl(2). Single pulses and tandem shock waves were compared as were three treatment temperatures: 0, 10 and 25 degrees C. Three delays (250, 500, 750 MUs) between double pulses were tested. Characterization was achieved by using a plasmid that provided green fluorescent protein expression. At 0 degrees C double pulses generated at a delay of 750 MUs significantly increased the number of fluorescent colonies compared with single pulses. In general, the lowest temperature enhanced the mean number of transformants compared with the two higher temperatures. A strong influence of the CaCl(2) concentration on the transformation efficiency was also found. The main conclusion is that gene transfer to target cells may be increased up to 50 times at 0 degrees C by enhancing cavitation using pairs of shock waves. PMID- 21316564 TI - Sepsis. Preface. PMID- 21316565 TI - The evolution of the understanding of sepsis, infection, and the host response: a brief history. AB - Sepsis is the ultimate clinical expression of the deleterious clash between the host immune response and invasive microorganisms.(72,73) At the beginning of the twentieth century, infections were by far the most common causes of death of Americans. By the beginning of the twenty-first century, the average lifespan of United States citizens had increased by over 30 years, with infections now accounting for a small minority of death.(74,75) Despite advances in public health, sanitation, vaccines, and antituberculosis chemotherapy and other antimicrobial agents, sepsis continues to account for an increasing number of deaths in critically ill patients. Future advances are anticipated when the genomics era and the promise of systems biology and personalized medicine are fully realized in the next few decades. A remarkable history of scientific inquiry into the fundamental nature of microbes and immune defenses preceded much of the current advances in the treatment of infectious diseases. Much work remains before the benefits of these discoveries can be thoughtfully applied to the management of severe sepsis and septic shock worldwide. PMID- 21316566 TI - Evolving concepts in sepsis definitions. AB - Developing effective therapies for any disease process relies on the ability to clearly define the population of patients who will benefit from that intervention. Advances in our understanding of sepsis pathogenesis have made it clear that the global definition or concept of sepsis as a single, homogeneous disease process is inadequate. The idea that all patients who have severe sepsis will respond positively to any single therapeutic intervention is probably too simple, although some interventions may target more general pathways and be globally beneficial. For example, drotrecogin alfa (activated) was shown to be effective at reducing mortality in a clinical trial with a heterogeneous patient population,(28) although even here positive results were restricted to patients who had severe sepsis, highlighting the importance of being able to better characterize patients. Our approach to sepsis and its definition has evolved as we increasingly recognize the complex nature of the process and the importance of targeting treatments according to individual patients' characteristics. Clinical variables are too sensitive and nonspecific and improved biologic and biochemical tools need to be incorporated into current definitions to provide precise and accurate methods of diagnosis. Systems, such as PIRO, that can characterize patients according to their likely prognosis and response to a specific therapy need to be further developed so that treatments can be appropriately directed for individual patients. PMID- 21316567 TI - The pathophysiology of septic shock. AB - Septic shock remains a significant challenge for clinicians. Recent advances in cellular and molecular biology have significantly improved our understanding of its pathogenetic mechanisms. These improvements in understanding should translate to better care and improved outcomes for these patients. PMID- 21316568 TI - Microcirculatory dysfunction in sepsis. AB - Septic shock is a common and deadly disease that traditionally has been diagnosed and treated by evaluation and optimization of global hemodynamic indices. However, microcirculatory dysfunction is a critically important element in the pathophysiology of this disease. New techniques of in vivo video microscopy permit the assessment of microcirculatory function in human subjects. With the advent of these techniques, the microcirculation may represent a new frontier for developing novel therapies for sepsis. PMID- 21316569 TI - Optimizing antimicrobial therapy in sepsis and septic shock. AB - Every patient with sepsis and septic shock must be evaluated thoroughly at presentation before the initiation of antibiotic therapy. However, in most situations, an abridged initial assessment focusing on critical diagnostic and management planning elements is sufficient. Intravenous antibiotics should be administered as early as possible, and always within the first hour of recognizing severe sepsis and septic shock. Broad-spectrum antibiotics must be selected with one or more agents active against likely bacterial or fungal pathogens and with good penetration into the presumed source. Antimicrobial therapy should be reevaluated daily to optimize efficacy, prevent resistance, avoid toxicity, and minimize costs. Consider combination therapy in Pseudomonas infections, and combination empiric therapy in neutropenic patients. Combination therapy should be continued for no more than 3 to 5 days and de-escalation should occur following availability of susceptibilities. The duration of antibiotic therapy typically is limited to 7 to 10 days; longer duration is considered if response is slow, if there is inadequate surgical source control, or in the case of immunologic deficiencies. Antimicrobial therapy should be stopped if infection is not considered the etiologic factor for a shock state. PMID- 21316570 TI - Principles of source control in the management of sepsis. AB - This brief overview of the role of source control in sepsis emphasizes the underlying principles rather than the empiric evidence from well-performed clinical studies. The reasons for this are several. First there is a paucity of high-level published evidence, with few rigorous large clinical series, and even fewer clinical trials. Second, the decision-making process in the individual patient is complex, and often not amenable to study using the design of a randomized controlled trial, for decisions involve consideration not only of the underlying disease but of the stability of the patient, the presence of comorbidities, and the prior surgical history, all factors that can heavily influence the decision to choose one therapeutic option rather than another. The scope of the topic is large, and the space limited. Interested readers are referred to more detailed discussions such as that found in the background to the recommendations on source control in the guidelines of the Surviving Sepsis Campaign.(1) Source control is a core treatment modality in the management of the patient with severe sepsis or septic shock. Its optimal use assumes a comprehensive knowledge of biologic principles, the complexities of the septic response, and the range of surgical and nonsurgical options, and a combination of therapeutic aggressiveness and judicious caution in the clinician charged with making the decision. As every intensivist learns, appropriate source-control intervention can rapidly alter the course of sepsis to a more favorable direction, and suboptimal decision-making can change a difficult clinical challenge into a nightmare. PMID- 21316571 TI - Sepsis-induced tissue hypoperfusion. AB - The understanding of sepsis is continuously evolving. An overview of sepsis induced tissue hypoperfusion has been provided herein. It is of critical importance that the clinician understands the pathophysiology of this emergent condition and is able to synthesize the available data in a rapid fashion so that tissue hypoperfusion is readily detected. Once detected, aggressive and endpoint directed resuscitation should be implemented to reverse the hypoperfusion and to prevent further deterioration, organ dysfunction, and death. PMID- 21316572 TI - Inotrope and vasopressor therapy of septic shock. AB - The ultimate goals of hemodynamic therapy in shock are to restore effective tissue perfusion and to normalize cellular metabolism. In sepsis, both global and regional perfusion must be considered. In addition, mediators of sepsis can perturb cellular metabolism, leading to inadequate use of oxygen and other nutrients despite adequate perfusion; one would not expect organ dysfunction mediated by such abnormalities to be corrected by hemodynamic therapy. Despite the complex pathophysiology of sepsis, an underlying approach to its hemodynamic support can be formulated that is particularly pertinent with respect to vasoactive agents. Both arterial pressure and tissue perfusion must be taken into account when choosing therapeutic interventions and the efficacy of hemodynamic therapy should be assessed by monitoring a combination of clinical and hemodynamic parameters. It is relatively easy to raise blood pressure, but somewhat harder to raise cardiac output in septic patients. How to optimize regional blood and microcirculatory blood flow remains uncertain. Specific end points for therapy are debatable and are likely to evolve. Nonetheless, the idea that clinicians should define specific goals and end points, titrate therapies to those end points, and evaluate the results of their interventions on an ongoing basis remains a fundamental principle. The practice parameters were intended to emphasize the importance of such an approach so as to provide a foundation for the rational choice of vasoactive agents in the context of evolving monitoring techniques and therapeutic approaches. PMID- 21316573 TI - Hemodynamic monitoring in sepsis. AB - Arterial waveform analysis that does not require continuous calibration, impedance cardiography, electrical cardiometry, velocity-encoded phase contrast magnetic resonance imaging (MRI), pulsed dye densitometry, noninvasive pulse pressure analysis using tonometry, suprasternal Doppler, partial CO2 rebreathing techniques, and transcutaneous Doppler are just some of the other emerging technologies not described in this review that may be used routinely in the management of sepsis and septic shock in the very near future. These innovative approaches may further increase our ability to optimize patients' fluid status and hemodynamics. We also have ability to monitor the microcirculation. This increasingly sophisticated approach to the management of sepsis and septic shock will hopefully translate into better patient outcomes. However, optimal use of any hemodynamic monitoring requires an understanding of its physiologic underpinnings. Accurate interpretation of the hemodynamic information coupled with a protocolized management algorithm is the cornerstone of an effective resuscitation effort. Many forms of hemodynamic monitoring have emerged over the past 20 to 30 years with no convincing evidence for the superiority of any single techniques (Table 2). The goal of hemodynamic monitoring and optimization is to combat the systemic imbalance between tissue oxygen supply and demand ranging from global tissue hypoxia to overt shock and multiorgan failure. It remains unproven that hemodynamic monitoring of disease progression can effectively change patient outcome. However, despite our increased understanding of sepsis pathophysiology, mortality and morbidity from the disease remains high. Therefore, the search for the optimal parameters in resuscitation and the best way they can be monitored will continue. PMID- 21316574 TI - Steroid therapy of septic shock. AB - Steroid therapy in patients with septic shock has been controversial for decades. Although treatment with high-doses of corticosteroids for patients with septic shock has been shown not to be beneficial, it was believed that therapy with low doses would be helpful. Recent studies document that steroids are beneficial only in adult septic shock patients whose blood pressure is poorly responsive to fluid resuscitation and vasopressor therapy. For the majority of septic shock patients, corticosteroids should not be used, as the benefit of reversing shock is not worth the complications of superinfection, new sepsis, and septic shock. Finally, steroid therapy should not be guided by corticotropin test results. PMID- 21316575 TI - Genetic polymorphisms in sepsis. AB - The number of genetic polymorphisms shown to play a role in sepsis continues to increase. At the same time, platforms for genetic sequencing and expression analysis are being refined, allowing unprecedented data generation. International databases may soon facilitate synchrony of genotypic and phenotypic data using enormous numbers of septic patients. If this occurs, 2 strategies for investigating polymorphisms in sepsis are likely to gain favor. In the first strategy, sepsis will continue to be viewed as a single entity. High-throughput genetic techniques will be used to evaluate numerous polymorphisms, each with fractional disease responsibility. Nongenetic variables, such as pathogen characteristics, underlying host medical conditions, and type and timing of resuscitation, will be considered cofactors. Using this approach, principal components that predict susceptibility to and outcomes during sepsis are likely to be identified. In the second strategy, sepsis will be divided into subtypes based on the concentration of specific variables. Categories will be based on features like the presence or absence of specific polymorphisms, gram-positive or gram-negative staining of causative organisms, age and comorbid conditions of the host, recent administration of chemotherapeutic agents, and hospital setting (ie, community vs teaching institution). Each category will be used to create homogenous sepsis subgroups for detailed evaluation. This approach will increase the odds of finding single dominant factors responsible for predilection and/or outcome within well-defined groups among those with sepsis. Several elements will be essential for the success of both these strategies. Firstly, databases that are extremely detailed will have to be generated. Secondly, better clinical information technology systems will be needed to facilitate large-scale phenotyping. Thirdly, standardization of protocols will need to take place to ensure uniformity of data sets. If the rapid advances in technology and informatics continue, they may catalyze paradigm shifts with regard to how clinicians address sepsis. Clinicians may change their focus from aggressive uniform treatment strategies to rapid stratification and subcategorization, with subsequent aggressive targeted therapeutic interventions. Advances in technology have the potential to change our primary goal in sepsis from rapid treatment to prevention for those most at risk. The cost savings to the US health care systems from such changes could be substantial. PMID- 21316576 TI - Performance improvement in the management of sepsis. AB - Sepsis guidelines, although creating a base to allow change in health care practitioner behavior, do not, in and of themselves, effect change. Change only comes with institution of a PI program, converting a core of key goals of guideline recommendations to quality indicators, and giving feedback on performance. These quality indicators are tracked before or during (recommended approach) initiation of hospital-wide education to evaluate baseline performance. When combining multispecialty and multidisciplinary champions in the ED, hospital wards, ICU, and hospital administrative leadership with timely performance feedback, case failure analysis, and re-education, an opportunity to succeed in decreasing mortality in severe sepsis can be achieved. Sepsis bundle indicators require updating as new evidence emerges and new guidelines are published.(30,31) PMID- 21316577 TI - Multicenter clinical trials in sepsis: understanding the big picture and building a successful operation at your hospital. AB - Only through adequately designed and adequately conducted clinical trials can new treatments be found for the benefit of the septic patient. Over the past 20 years, tens of thousands of patients have been enrolled in sepsis clinical trials with little success. These efforts, however, have not been without worth. Much has been learned and the knowledge gained has changed our approach to trial design in this very difficult field. Animal studies are better designed to match the clinical picture of severe sepsis. Phase II studies are more carefully engineered to answer questions about the most suitable target population and end points. Trial conduct likely benefits from use of CROs and a CCC. The future of clinical trials may include more standardization of sepsis management across investigative sites. Before the decision is made to become an investigative site in a multicenter industry-sponsored clinical trial in sepsis or severe sepsis, it is important to recognize what is required to succeed. Once these key-to-success elements are in place, members of the investigative team are more likely to realize the satisfaction and career growth from becoming a successful site. The most professional satisfaction comes from the knowledge of contributing to original science in the field of the sepsis. PMID- 21316578 TI - Shedding light on mysterious microtubules. PMID- 21316579 TI - What developmental biologists can learn from plant pathogens. PMID- 21316580 TI - The only constant is change. PMID- 21316581 TI - Mitochondrial fusion: bax to the fussure. AB - Mitochondria can be organized into highly interconnected networks through continuous cycles of fission and fusion. A recent study by Hoppins et al. (2011) published in Molecular Cell now suggests that Bax, more commonly known for its role in apoptosis, can promote mitochondrial fusion in a Mitofusin 2-dependent manner. PMID- 21316582 TI - A CRY in the Night. AB - CRY1 is essential for normal circadian clock function, but its transcriptional regulation by the clock has not been considered an important feature for its function. However, reporting in Cell, Ukai-Tadenuma et al. (2011) now show that rhythmic Cry1 expression in the early night is critical for clock function. PMID- 21316583 TI - A new piece to the unsolved planar cell polarity puzzle. AB - Wnt-Frizzled/Planar cell polarity (PCP) signaling is a conserved mechanism establishing cellular orientation across animal species. Many aspects of PCP signaling regulation remain, however, poorly understood. A new paper establishes a potential link from Wnt5a to asymmetric PCP-factor localization via their phosphorylation. PMID- 21316584 TI - The many faces of RNAi. AB - Small non-coding RNAs, through association with Argonaute protein family members, have a variety of functions during the development of an organism. Although there is increased mechanistic understanding of the RNA interference (RNAi) pathways surrounding these small RNAs, how their effects are modulated by subcellular compartmentalization and cross-pathway functional interactions is only beginning to be explored. This review examines the current understanding of these aspects of RNAi pathways and the biological functions of these pathways. PMID- 21316585 TI - Wnt signaling gradients establish planar cell polarity by inducing Vangl2 phosphorylation through Ror2. AB - It is fundamentally important that signaling gradients provide positional information to govern morphogenesis of multicellular organisms. Morphogen gradients can generate different cell types in specific spatial order at distinct threshold concentrations. However, it is largely unknown whether and how signaling gradients also control cell polarities by acting as global cues. Here, we show that Wnt signaling gradient provides directional information to a field of cells. Vangl2, a core component in planar cell polarity, forms Wnt-induced receptor complex with Ror2 to sense Wnt dosages. Wnts dose-dependently induce Vangl2 phosphorylation of serine/threonine residues and Vangl2 activities depend on its levels of phosphorylation. In the limb bud, Wnt5a signaling gradient controls limb elongation by establishing PCP in chondrocytes along the proximal distal axis through regulating Vangl2 phosphorylation. Our studies have provided new insight to Robinow syndrome, Brachydactyly Type B1, and spinal bifida which are caused by mutations in human ROR2, WNT5A, or VANGL. PMID- 21316586 TI - Vangl2 promotes Wnt/planar cell polarity-like signaling by antagonizing Dvl1 mediated feedback inhibition in growth cone guidance. AB - Although a growing body of evidence supports that Wnt-Frizzled signaling controls axon guidance from vertebrates to worms, whether and how this is mediated by planar cell polarity (PCP) signaling remain elusive. We show here that the core PCP components are required for Wnt5a-stimulated outgrowth and anterior-posterior guidance of commissural axons. Dishevelled1 can inhibit PCP signaling by increasing hyperphosphorylation of Frizzled3 and preventing its internalization. Vangl2 antagonizes that by reducing Frizzled3 phosphorylation and promotes its internalization. In commissural axon growth cones, Vangl2 is predominantly localized on the plasma membrane and is highly enriched on the tips of the filopodia as well as in patches of membrane where new filopodia emerge. Taken together, we propose that the antagonistic functions of Vangl2 and Dvl1 (over Frizzled3 hyperphosphorylation and endocytosis) allow sharpening of PCP signaling locally on the tips of the filopodia to sense directional cues, Wnts, eventually causing turning of growth cones. PMID- 21316587 TI - ERK5 regulates muscle cell fusion through Klf transcription factors. AB - In skeletal muscle differentiation, muscle-specific genes are regulated by two groups of transcription factors, the MyoD and MEF2 families, which work together to drive the differentiation process. Here, we show that ERK5 regulates muscle cell fusion through Klf transcription factors. The inhibition of ERK5 activity suppresses muscle cell fusion with minimal effects on the expression of MyoD, MEF2, and their target genes. Promoter analysis coupled to microarray assay reveals that Klf-binding motifs are highly enriched in the promoter regions of ERK5-dependent upregulated genes. Remarkably, Klf2 and Klf4 expression are also upregulated during differentiation in an ERK5-dependent manner, and knockdown of Klf2 or Klf4 specifically suppresses muscle cell fusion. Moreover, we show that Sp1 transcription factor links ERK5 to Klf2/4, and that nephronectin, a Klf transcriptional target, is involved in muscle cell fusion. Therefore, an ERK5/Sp1/Klf module plays a key role in the fusion process during skeletal muscle differentiation. PMID- 21316589 TI - IKKepsilon regulates cell elongation through recycling endosome shuttling. AB - IKK-related kinases are key regulators of innate immunity and oncogenesis. While their effects on transcription are well characterized, their cytoplasmic functions remain poorly understood. Drosophila IKK-related kinase, IKKE, regulates cytoskeletal organization and cell elongation. Here, we demonstrate that IKKE is activated locally at the tip of growing mechanosensory bristles and regulates the rapid shuttling of recycling endosomes, independent of its roles in F-actin organization and caspase signaling. IKKE regulates the localization of recycling endosome regulators Rab11 and Dynein and phosphorylates their adaptor molecule, Nuclear fallout (Nuf). Nuf's negative regulation by IKKE suggests that local activation of IKKE inhibits Dynein on incoming recycling endosomes, converting them for outward transport. Mammalian IKK-related kinases also regulate the recycling endosomes' distribution by phosphorylating the Nuf homolog Rab11-FIP3. Our results establish an evolutionarily conserved function of IKK related kinases in regulating recycling endosome dynamics and point to a key role of endosome dynamics in cell morphogenesis. PMID- 21316588 TI - Synaptojanin 1-mediated PI(4,5)P2 hydrolysis is modulated by membrane curvature and facilitates membrane fission. AB - Phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] plays a fundamental role in clathrin-mediated endocytosis. However, precisely how PI(4,5)P2 metabolism is spatially and temporally regulated during membrane internalization and the functional consequences of endocytosis-coupled PI(4,5)P2 dephosphorylation remain to be explored. Using cell-free assays with liposomes of varying diameters, we show that the major synaptic phosphoinositide phosphatase, synaptojanin 1 (Synj1), acts with membrane curvature generators/sensors, such as the BAR protein endophilin, to preferentially remove PI(4,5)P2 from curved membranes as opposed to relatively flat ones. Moreover, in vivo recruitment of Synj1's inositol 5 phosphatase domain to endophilin-induced membrane tubules results in fragmentation and condensation of these structures largely in a dynamin-dependent fashion. Our study raises the possibility that geometry-based mechanisms may contribute to spatially restricting PI(4,5)P2 elimination during membrane internalization and suggests that the PI(4,5)P2-to-PI4P conversion achieved by Synj1 at sites of high curvature may cooperate with dynamin to achieve membrane fission. PMID- 21316591 TI - Trophectoderm lineage determination in cattle. AB - The trophectoderm (TE) and inner cell mass (ICM) are committed and marked by reciprocal expression of Cdx2 and Oct4 in mouse late blastocysts. We find that the TE is not committed at equivalent stages in cattle, and that bovine Cdx2 is required later, for TE maintenance, but does not repress Oct4 expression. A mouse Oct4 (mOct4) reporter, repressed in mouse TE, remained active in the cattle TE; bovine Oct4 constructs were not repressed in the mouse TE. mOct4 has acquired Tcfap2 binding sites mediating Cdx2-independent repression-cattle, humans, and rabbits do not contain these sites and maintain high Oct4 levels in the TE. Our data suggest that the regulatory circuitry determining ICM/TE identity has been rewired in mice, to allow rapid TE differentiation and early blastocyst implantation. These findings thus emphasize ways in which mice may not be representative of the earliest stages of mammalian development and stem cell biology. PMID- 21316590 TI - Peroxiredoxin stabilization of DE-cadherin promotes primordial germ cell adhesion. AB - Regulated adhesion between cells and their environment is critical for normal cell migration. We have identified mutations in a gene encoding the Drosophila hydrogen peroxide (H2O2)-degrading enzyme Jafrac1, which lead to germ cell adhesion defects. During gastrulation, primordial germ cells (PGCs) associate tightly with the invaginating midgut primordium as it enters the embryo; however, in embryos from jafrac1 mutant mothers this association is disrupted, leaving some PGCs trailing on the outside of the embryo. We observed similar phenotypes in embryos from DE-cadherin/shotgun (shg) mutant mothers and were able to rescue the jafrac1 phenotype by increasing DE-cadherin levels. This and our biochemical evidence strongly suggest that Jafrac1-mediated reduction of H2O2 is required to maintain DE-cadherin protein levels in the early embryo. Our results present in vivo evidence of a peroxiredoxin regulating DE-cadherin-mediated adhesion. PMID- 21316592 TI - Translocation of the cytoplasmic domain of ADAM13 to the nucleus is essential for Calpain8-a expression and cranial neural crest cell migration. AB - ADAMs are transmembrane metalloproteases that control cell behavior by cleaving both cell adhesion and signaling molecules. The cytoplasmic domain of ADAMs can regulate the proteolytic activity by controlling the subcellular localization and/or the activation of the protease domain. Here, we show that the cytoplasmic domain of ADAM13 is cleaved and translocates into the nucleus. Preventing this translocation renders the protein incapable of promoting cranial neural crest (CNC) cell migration in vivo, without affecting its proteolytic activity. In addition, the cytoplasmic domain of ADAM13 regulates the expression of multiple genes in CNC, including the protease Calpain8-a. Restoring the expression of Calpain8-a is sufficient to rescue CNC migration in the absence of the ADAM13 cytoplasmic domain. This study shows that the cytoplasmic domain of ADAM metalloproteases can perform essential functions in the nucleus of cells and may contribute substantially to the overall function of the protein. PMID- 21316593 TI - Transcriptional activation of Arabidopsis axis patterning genes WOX8/9 links zygote polarity to embryo development. AB - In most flowering plants, the apical-basal body axis is established by an asymmetric division of the polarized zygote. In Arabidopsis, early embryo patterning is regulated by WOX homeobox genes, which are coexpressed in the zygote but become restricted to apical (WOX2) and basal (WOX8/9) cells. How the asymmetry of zygote division is regulated and connected to the daughter cell fates is largely unknown. Here, we show that expression of WOX8 is independent of the axis patterning signal auxin, but, together with the redundant gene WOX9, is activated in the zygote, its basal daughter cell, and the hypophysis by the zinc finger transcription factor WRKY2. In wrky2 mutants, egg cells polarize normally but zygotes fail to reestablish polar organelle positioning from a transient symmetric state, resulting in equal cell division and distorted embryo development. Both defects are rescued by overexpressing WOX8, indicating that WRKY2-dependent WOX8 transcription links zygote polarization with embryo patterning. PMID- 21316595 TI - New insights into the origin and the genetic basis of rhabdomyosarcomas. PMID- 21316594 TI - Mechanistic basis of otolith formation during teleost inner ear development. AB - Otoliths, which are connected to stereociliary bundles in the inner ear, serve as inertial sensors for balance. In teleostei, otolith development is critically dependent on flow forces generated by beating cilia; however, the mechanism by which flow controls otolith formation remains unclear. Here, we have developed a noninvasive flow probe using optical tweezers and a viscous flow model in order to demonstrate how the observed hydrodynamics influence otolith assembly. We show that rotational flow stirs and suppresses precursor agglomeration in the core of the cilia-driven vortex. The velocity field correlates with the shape of the otolith and we provide evidence that hydrodynamics is actively involved in controlling otolith morphogenesis. An implication of this hydrodynamic effect is that otolith self-assembly is mediated by the balance between Brownian motion and cilia-driven flow. More generally, this flow feature highlights an alternative biological strategy for controlling particle localization in solution. PMID- 21316596 TI - One NOTCH Further: Jagged 1 in Bone Metastasis. AB - The outgrowth of metastatic cells to bone depends on the interaction between multiple intrinsic and host factors. In this issue of Cancer Cell, Sethi and colleagues report Notch signaling in bone cells as responsible for promoting this outgrowth and provide evidence for a beneficial treatment effect of NOTCH inhibitors. PMID- 21316597 TI - HiJAKing the methylosome in myeloproliferative disorders. AB - JAK2 gain-of-function mutations have been shown to cause myeloproliferative neoplasms. In this issue of Cancer Cell, Liu et al. (2011) demonstrate that these JAK2 mutants, but not wild-type JAK2, directly phosphorylate PRMT5 and inhibit its arginine methyltransferase activity, establishing a link between mutant JAK2 and histone arginine methylation. PMID- 21316598 TI - Monoallelic deletion of NFKBIA in glioblastoma: when less is more. AB - Bredel et al. (2010) recently identified a subset of glioblastomas that harbor monoallelic loss of NFKBIA, which negatively affects patient prognosis. This finding raises new questions as to the role of IkappaBalpha and NF-kappaB in glioblastoma, the relationship between EGFR and NF-kappaB signaling, and potential therapeutic targets. PMID- 21316599 TI - PARP inhibitors in cancer therapy: promise, progress, and puzzles. AB - A recent article in the New England Journal of Medicine by O'Shaughnessy et al. provides evidence that a treatment strategy aimed at inducing DNA damage with chemotherapy while simultaneously disabling repair using a PARP inhibitor might offer hope for patients with a treatment-refractory form of breast cancer. PMID- 21316600 TI - NEDD8 pathways in cancer, Sine Quibus Non. AB - There are 17 known ubiquitin-like proteins (UBLs) from nine phylogenetically distinct classes (NEDD8, SUMO, ISG15, FUB1, FAT10, Atg8, Atg12, Urm1, and UFM1) that have been identified to conjugate to substrates in a manner analogous to ubiquitin. NEDD8 is one of the most studied UBLs and shares the highest amino acid similarity to ubiquitin. Here, we review the current knowledge of the NEDD8 conjugation cascade derived from functional studies in genetic model organisms, structural insights from crystallographic studies, biochemical studies identifying a growing list of NEDD8 substrates with oncogenic implications, and attempts to pharmacologically target the NEDD8 pathway in cancer. PMID- 21316601 TI - Evidence for an unanticipated relationship between undifferentiated pleomorphic sarcoma and embryonal rhabdomyosarcoma. AB - Embryonal rhabdomyosarcoma (eRMS) shows the most myodifferentiation among sarcomas, yet the precise cell of origin remains undefined. Using Ptch1, p53 and/or Rb1 conditional mouse models and controlling prenatal or postnatal myogenic cell of origin, we demonstrate that eRMS and undifferentiated pleomorphic sarcoma (UPS) lie in a continuum, with satellite cells predisposed to giving rise to UPS. Conversely, p53 loss in maturing myoblasts gives rise to eRMS, which have the highest myodifferentiation potential. Regardless of origin, Rb1 loss modifies tumor phenotype to mimic UPS. In human sarcomas that lack pathognomic chromosomal translocations, p53 loss of function is prevalent, whereas Shh or Rb1 alterations likely act primarily as modifiers. Thus, sarcoma phenotype is strongly influenced by cell of origin and mutational profile. PMID- 21316602 TI - Identification of miRNomes in human liver and hepatocellular carcinoma reveals miR-199a/b-3p as therapeutic target for hepatocellular carcinoma. AB - The full scale of human miRNome in specific cell or tissue, especially in cancers, remains to be determined. An in-depth analysis of miRNomes in human normal liver, hepatitis liver, and hepatocellular carcinoma (HCC) was carried out in this study. We found nine miRNAs accounted for ~88.2% of the miRNome in human liver. The third most highly expressed miR-199a/b-3p is consistently decreased in HCC, and its decrement significantly correlates with poor survival of HCC patients. Moreover, miR-199a/b-3p can target tumor-promoting PAK4 to suppress HCC growth through inhibiting PAK4/Raf/MEK/ERK pathway both in vitro and in vivo. Our study provides miRNomes of human liver and HCC and contributes to better understanding of the important deregulated miRNAs in HCC and liver diseases. PMID- 21316603 TI - A functional role for tumor cell heterogeneity in a mouse model of small cell lung cancer. AB - Small cell lung cancer (SCLC) is the lung neoplasia with the poorest prognosis, due to its high metastatic potential and chemoresistance upon relapse. Using the previously described mouse model for SCLC, we found that the tumors are often composed of phenotypically different cells with either a neuroendocrine or a mesenchymal marker profile. These cells had a common origin because they shared specific genomic aberrations. The transition from neuroendocrine to mesenchymal phenotype could be achieved by the ectopic expression of oncogenic Ras(V12). Crosstalk between mesenchymal and neuroendocrine cells strongly influenced their behavior. When engrafted as a mixed population, the mesenchymal cells endowed the neuroendocrine cells with metastatic capacity, illustrating the potential relevance of tumor cell heterogeneity in dictating tumor properties. PMID- 21316604 TI - Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. AB - Carcinoma-associated fibroblasts (CAFs) that express alpha-smooth muscle actin (alphaSMA) contribute to cancer progression, but their precise origin and role are unclear. Using mouse models of inflammation-induced gastric cancer, we show that at least 20% of CAFs originate from bone marrow (BM) and derive from mesenchymal stem cells (MSCs). alphaSMA+ myofibroblasts (MFs) are niche cells normally present in BM and increase markedly during cancer progression. MSC derived CAFs that are recruited to the dysplastic stomach express IL-6, Wnt5alpha and BMP4, show DNA hypomethylation, and promote tumor growth. Moreover, CAFs are generated from MSCs and are recruited to the tumor in a TGF-beta- and SDF-1alpha dependent manner. Therefore, carcinogenesis involves expansion and relocation of BM-niche cells to the tumor to create a niche to sustain cancer progression. PMID- 21316605 TI - The MDM2 promoter SNP285C/309G haplotype diminishes Sp1 transcription factor binding and reduces risk for breast and ovarian cancer in Caucasians. AB - MDM2 plays a key role in modulating p53 function. The MDM2 SNP309T > G promoter polymorphism enhances Sp1 binding and has been linked to cancer risk and young age at diagnosis although with conflicting evidence. We report a second MDM2 promoter polymorphism, SNP285G > C, residing on the SNP309G allele. SNP285C occurs in Caucasians only, where 7.7% (95% CI 7.6%-7.8%) of healthy individuals carry the SNP285C/309G haplotype. In vitro analyses reveals that SNP309G enhances but SNP285C strongly reduces Sp1 promoter binding. Comparing MDM2 promoter status among different cohorts of ovarian (n = 1993) and breast (n = 1973) cancer patients versus healthy controls (n = 3646), SNP285C reduced the risk of both ovarian (OR 0.74; CI 0.58-0.94) and breast cancer (OR 0.79; CI 0.62-1.00) among SNP309G carriers. PMID- 21316606 TI - JAK2V617F-mediated phosphorylation of PRMT5 downregulates its methyltransferase activity and promotes myeloproliferation. AB - The JAK2V617F constitutively activated tyrosine kinase is found in most patients with myeloproliferative neoplasms. While examining the interaction between JAK2 and PRMT5, an arginine methyltransferase originally identified as JAK-binding protein 1, we found that JAK2V617F (and JAK2K539L) bound PRMT5 more strongly than did wild-type JAK2. These oncogenic kinases also acquired the ability to phosphorylate PRMT5, greatly impairing its ability to methylate its histone substrates, and representing a specific gain-of-function that allows them to regulate chromatin modifications. We readily detected PRMT5 phosphorylation in JAK2V617F-positive patient samples, and when we knocked down PRMT5 in human CD34+ cells using shRNA, we observed increased colony formation and erythroid differentiation. These results indicate that phosphorylation of PRMT5 contributes to the mutant JAK2-induced myeloproliferative phenotype. PMID- 21316608 TI - Exploring the positional importance of aromatic residues and lysine in the interactions of peptides with the Plasmodium falciparum Hsp70-1. PMID- 21316607 TI - Protein biochemistry: don't forget the cell biology. PMID- 21316609 TI - The effect of keratoconus on the structural, mechanical, and optical properties of the cornea. AB - Keratoconus is an eye disorder wherein the cornea weakens due to structural and/or compositional anomalies. This weakened cornea is no longer able to preserve its normal shape against the intraocular pressure in the eye and therefore bulges outward, leading to a conical shape and subsequent distorted vision. Changes in structure and composition often manifest as a change in shape (or geometry) as well as in mechanical and optical properties. Thus, understanding the properties and structure of keratoconic corneas could help elucidate etiology and pathogenesis, to develop treatments, and to understand other diseases of the eye. In this review, we discuss the changes in structure, composition, and mechanical and optical properties of the cornea with keratoconus. Current treatments for keratoconus and a novel proposed treatment using two-photon excitation therapy are also discussed. The intended audiences are mechanical engineers, materials engineers, optical engineers, and bioengineers. PMID- 21316610 TI - Two-body wear of dental restorative materials. AB - AIM: The aim of this in vitro study was to determine the two-body wear resistance of modern direct dental restorative materials. METHODS: Eight standardized specimens were prepared from 14 dental restorative materials (nano-, micro-, hybrid-, macrofilled composites; compomer, silorane, ormocer); a veneering composite (Sinfony) and enamel were used for reference. Vickers hardness (HV) and inorganic filler weight were determined. Specimens were subjected to mastication simulation using a mastication simulator (50 N, 1.2*10(5) cycles, 1.2 Hz) in a pin-on-block design and simultaneous thermal cycling (600 cycles, 5/55 degrees C, 2 min/cycle). Steatite balls were used as antagonists. Vertical substance and volume loss were determined using cast replicas and a 3D laser scanning device. Means and standard deviations were calculated, and statistical analysis was performed using one-way ANOVA and the Games-Howell test for post hoc analysis (alpha=.05). RESULTS: HV ranged between 19 and 76; inorganic filler weight ranged between 44% and 88%. Significantly lowest vertical substance and volume loss were detected for the microfilled composite Heliomolar; enamel yielded similar vertical substance and volume loss. Intermediate wear was found for the other microfilled and hybrid composites as well as the silorane and the ormocers. Significantly highest wear was found for the macrofilled composite Quixfil and the compomer Compoglass F. DISCUSSION: Within the limitations of an in vitro study, the findings indicate similar wear behaviour for silorane- and ormocer based dental restorative materials. However, correlations between HV, filler content, and wear resistance were poor. PMID- 21316611 TI - Bond strength of five dental adhesives using a fracture mechanics approach. AB - OBJECTIVES: The adhesion tests utilized in dentistry are unable to separate the effects of adhesive composition, substrate properties, joint geometry and type of loading on the measured bond strength. This makes it difficult for the clinician to identify the most suitable adhesive for a given procedure and for the adhesive manufacturer to optimize its composition. Thus, an adhesion test protocol based on the fracture mechanics has been proposed to generate data for which separation of the effect of composition from that of the joint geometry on the shear (tau(a)) and tensile (sigma(a)) bond strengths was possible for five commercial dental adhesives. METHODS: Planar 40*5*5 mm(3) sections of bovine femur were used as model adherends. The adhesive thickness (h) was varied from 15 to 500 MUm. Commercial adhesives with fracture toughness (K(IC)) ranging from 0.3 to 1.6 MPa m(1/2) were used. Double lap joint (DLJ) and modified compact tension (MCT) specimens were conditioned for 24 h in 37 degrees C distilled water, then dried in a vacuum oven at 37 degrees C for 24 h prior to testing. The thickness dependence of sigma(a) and tau(a) was measured at constant strain rate and analyzed using the interface corner stress intensity factor model. RESULTS: Both tau(a) and sigma(a) increased with increasing adhesive thickness, exhibiting a maximum bond strength at the optimum thickness (h(opt)). For h R <--> B19 transformation in Highland Metal wire and B2 <--> B19(') transformation in Copper NiTi wire. Three point bending (TPB) tests in the certain designed fixture were performed at 37 degrees C to evaluate the mechanical behavior of the wires. The experimental results revealed the superelastic behavior of the Highland Metal wire after 60 min ageing at 400 and 500 degrees C and the plastic deformation of the Copper NiTi wire after annealing due to the effect of copper in the alloy composition. PMID- 21316618 TI - Reliability assessment in advanced nanocomposite materials for orthopaedic applications. AB - Alumina-zirconia nano-composites were recently developed as alternative bearing materials for orthopedics. Previous, preliminary reports show that such alumina zirconia nanocomposites exhibit high crack resistance and low wear rate. In this paper, additional information is given in terms of wear, crack resistance and ageing behaviour: femoral heads are inspected after 7 million cycles of wear testing on a hip simulator, crack resistance is measured and compared to other ceramics used today in orthopedics, slow crack growth is reported under static and cyclic fatigue, and aging resistance is assessed. We also report on the load to failure of femoral heads prototypes during compression tests. This overall reliability assessment ensures a potential future development for these kinds of new nanocomposites in the orthopedic field. PMID- 21316619 TI - On the chipping and splitting of teeth. AB - One of the most frequent fracture modes in teeth is chipping. It can lead to deterioration and ultimate loss of tooth function. Chips in enamel can also be used to gain insight into the evolutionary history of extant animal and fossil hominin species. In this study, chipping tests are performed on the surfaces of as-received or flattened human molars using hard indenters. The chips exhibit a characteristic scallop shape, with some influence from tooth curvature as well as from enamel anisotropy and inhomogeneity. Chipping fracture tends to follow easy interprism pathways, but inevitably involves breakage of bundles of mineralized prisms in the last stages of spallation. A simple relation describes how critical loads for chipping scale with distance of the occlusal contact from the specimen edge. Measured loads fall well within the range of biting forces exerted during normal oral function. A transition from chipping to splitting occurs at higher loads for contacts nearer the central axis of the tooth. PMID- 21316620 TI - A multiparametric evaluation of post-restored teeth with simulated bone loss. AB - Endodontically-treated teeth are prone to fracture due to loss of tooth structure and altered mechanical behaviors. The stability and rigidity of post-restored teeth, particularly in cases involving periodontal destruction, has not been adequately investigated. This study examined the influence of post material on teeth with simulated bone reduction by a multiparametric evaluation. Sixty extracted premolars of similar sizes were endodontically treated then divided into six groups. Each group was restored with one of the combinations of three posts (a glass-fiber, a prefabricated titanium post, and a cast post) and two simulated bone conditions (2 or 6 mm below crown margins). After crown restorations, they were loaded with a 100 N force then the displacements were examined by the digital-image-correlation technique. Marginal integrity on the buccal and lingual crown margins was examined before and after the thermocycling. Finally, the teeth were loaded until failure to examine the strength and fracture patterns. The digital-image-correlation measurements revealed that tooth deformation was related to the support conditions, especially for the fiber post groups. The cast post groups showed less altered marginal integrity after thermomechanical loading than the fiber and titanium post groups did. In the fracture test, the fiber-post/reduced-support group exhibited inferior fracture strength. The reduced support significantly affected fracture strength and incidence of repairable root fracture. The marginal integrity was not correlated with tooth deformation, since the tooth flexed at the crest of the simulated bone. The root fracture resistance was determined mainly by post materials but was concurrently affected by the support conditions. PMID- 21316621 TI - Reinforcement of calcium phosphate cement with multi-walled carbon nanotubes and bovine serum albumin for injectable bone substitute applications. AB - This paper presents the development of novel alternative injectable calcium phosphate cement (CPC) composites for orthopaedic applications. The new CPC composites comprise beta-tri-calcium phosphate (beta-TCP) and di-calcium phosphate anhydrous (DCPA) mixed with bovine serum albumin (BSA) and incorporated with multi-walled carbon nanotubes (MWCNTs) or functionalized MWCNTs (MWCNTs-OH and MWCNTs-COOH). Scanning electron microscopy (SEM), compressive strength tests, injectability tests, Fourier transform infrared spectroscopy and X-ray diffraction were used to evaluate the properties of the final products. Compressive strength tests and SEM observations demonstrated particularly that the concomitant admixture of BSA and MWCNT improved the mechanical properties, resulting in stronger CPC composites. The presence of MWCNTs and BSA influenced the morphology of the hydroxyapatite (HA) crystals in the CPC matrix. BSA was found to act as a promoter of HA growth when bounded to the surface of CPC grains. MWCNT-OH-containing composites exhibited the highest compressive strengths (16.3 MPa), being in the range of values for trabecular bone (2-12 MPa). PMID- 21316622 TI - Nano/micro electro-spun polyethylene terephthalate fibrous mat preparation and characterization. AB - Electro-spun polyethylene terephthalate (PET) fibrous mats are potential substrates for biotechnological and biomedical applications. In this regard, substrate characteristics including, fiber diameter, orientation and mechanical properties play an important role in controlling the interaction of substrate with biological entities. However, few studies reporting the preparation of electro-spun PET substrates with such controlled characteristics have been published. In this study, electro-spun PET fibrous mats with fiber diameters in the nanometer and micrometer range were produced by varying polymer solution concentration and flow rate. Fiber orientation within the mats was also varied by varying collector surface velocities in rotation and translation. Their morphological, mechanical, thermal and structural properties were evaluated as a function of fiber diameter and collector speed using scanning electron microscopy (SEM), a micromechanical tester, differential scanning calorimetry (DSC) and X ray diffraction (XRD), respectively. Varying polymer solution concentration and flow rate allowed the production of matrices with fiber diameters ranging from 400 nm to 2 MUm. Tensile properties increased with fiber diameter and collector surface velocity. Thermal properties of electro-spun PET fibers were different from the structure of as received raw PET in the form of pellets, revealing an amorphous structure for the entire electro-spun PET. This was also confirmed by XRD analysis. No considerable differences were observed between electro-spun PET fibers, in terms of crystalline and thermal properties, produced under various conditions. These electro-spun mats with different fiber diameters, orientation and mechanical properties can be used for various applications including tissue engineering scaffolds. PMID- 21316623 TI - Continuum damage model for bioresorbable magnesium alloy devices - Application to coronary stents. AB - The main drawback of a conventional stenting procedure is the high risk of restenosis. The idea of a stent that "disappears" after having fulfilled its mission is very intriguing and fascinating, since it can be expected that the stent mass decreases in time to allow the gradual transmission of the mechanical load to the surrounding tissues owing to controlled dissolution by corrosion. Magnesium and its alloys are appealing materials for designing biodegradable stents. The objective of this work is to develop, in a finite element framework, a model of magnesium degradation that is able to predict the corrosion rate, thus providing a valuable tool for the design of bioresorbable stents. Continuum damage mechanics is suitable for modeling several damage mechanisms, including different types of corrosion. In this study, the damage is assumed to be the superposition of stress corrosion and uniform microgalvanic corrosion processes. The former describes the stress-mediated localization of the corrosion attack through a stress-dependent evolution law, while the latter affects the free surface of the material exposed to an aggressive environment. Comparisons with experimental tests show that the developed model can reproduce the behavior of different magnesium alloys subjected to static corrosion tests. The study shows that parameter identification for a correct calibration of the model response on the results of uniform and stress corrosion experimental tests is reachable. Moreover, three-dimensional stenting procedures accounting for interaction with the arterial vessel are simulated, and it is shown how the proposed modeling approach gives the possibility of accounting for the combined effects of an aggressive environment and mechanical loading. PMID- 21316624 TI - Multi-axial loading micromechanics of the cement-bone interface in postmortem retrievals and lab-prepared specimens. AB - Maintaining adequate fixation between cement and bone is important for successful long term survival of cemented total joint replacements. Mixed-mode loading conditions (combination of tension/compression and shear) are present during in vivo loading, but the micromotion response of the interface to these conditions is not fully understood. Non-destructive, multi-axial loading experiments were conducted on laboratory prepared (n=6) and postmortem (n=6) human cement-bone interfaces. Specimens were mounted in custom loading discs and loaded at 0 degrees , 30 degrees , 60 degrees , and 90 degrees relative to the interface plane where 0 degrees represents normal loading to the interface, and 90 degrees represents shear loading along the longitudinal axis of the femur. Axial compliance did not depend on loading angle for laboratory prepared (p=0.96) or postmortem specimens (p=0.62). The cement-bone interface was more compliant under tensile than compressive loading at the 0 degrees loading angle only (p=0.024). The coupled transverse to axial compliance ratio, which is a measure of the coupled motion, was small for laboratory prepared (0.115 +/- 0.115) and postmortem specimens (0.142 +/- 0.101). There was a moderately strong inverse relationship between interface compliance and contact index (r(2)=0.65). From a computational modeling perspective, the results of the current study support the concept that the cement-bone interface could be numerically implemented as a compliant layer with the same initial stiffness in tension and shear directions. The magnitude of the compliance could be modified to simulate immediate post operative conditions (using laboratory prepared data set) or long-term remodeling (using postmortem data set). PMID- 21316625 TI - Porcine extracellular matrix scaffolds in reconstructive urology: An ex vivo comparative study of their biomechanical properties. AB - Functional reconstruction of the human urinary bladder has been attempted by replacing defective bladder tissue with tissue-engineered xenogenic extracellular matrix (ECM) scaffolds. However, experimental studies that demonstrate the effects of implanted ECMs on important biomechanical properties such as total bladder capacity (TBC) and compliance (C) are lacking. In the current study, the effects of ECM scaffold surface area (SA) on TBC and C was assessed, ex vivo, in an ovine model (n=5). TBC and C were measured at pressures (P) of 5, 10, 15 and 20 mm Hg prior to performing a 3*3 cm (9 cm(2)) partial cystectomy defect. Equal sized 3*3 cm (9 cm(2)) and larger 6*6 cm (36 cm(2)) urinary bladder matrix (UBM) scaffolds of porcine origin replaced the 3*3 cm cystectomy defect, and TBC and C were re-recorded for comparative analysis. The results showed that TBC decreased by 39.6%+/-0.005% (122.9 ml+/-15 ml, p<0.05) and C by 38.9%+/-0.51%, (DeltaP=0 5mmHg, p<0.05) in ovine bladders reconstructed with 3*3 cm UBM scaffolds compared to their native values. It was also found that TBC increased by 25.6+/-0.64% (64.2 ml +/- 8.8 ml, p>0.05) and C by 24.5+/-0.43% (DeltaP=0-5mmHg, p>0.05) in the 6*6 cm UBM scaffold group compared to the 3*3 cm UBM scaffold group; however, these values were not statistically significant. The present work demonstrates that a fourfold increase in ECM scaffold SA relative to its intended defect does not lead to a significant improvement in TBC and C values. PMID- 21316626 TI - Non-destructive characterization of microdamage in cortical bone using low field pulsed NMR. AB - The microcracking and damage accumulation process in human cortical bone was characterized by performing cyclic loading under four-point bending at ambient temperature. A non-destructive nuclear magnetic resonance (NMR) spin-spin (T(2)) relaxation technique was applied to quantify the apparent changes in bone porosity as a function of cyclic loading and prior damage accumulation, first to unloaded cortical bone to quantify the initial porosity and then to fatigued cortical bone that was subjected to cyclic loading to various levels of modulus degradation and microdamage in the form of microcracks. The NMR T(2) relaxation time and amplitude data of the fatigued bone were compared against the undamaged state. The difference in the T(2) relaxation time data was taken as a measure of the increase in pore size, bone porosity or microcrack density due to microdamage induced by cyclic loading. A procedure was developed to deduce the number and size distributions of microcracks formed in cortical bone. Serial sectioning of the fatigued bone showed the formation of microcracks along the cement lines or within the interstitial tissue. The results on the evolution of microdamage derived from NMR measurements were verified by independent experimental measurements of microcrack density using histological characterization techniques. The size distribution and population of the microcracks were then utilized in conjunction with an analytical model to predict the degradation of the elastic modulus of cortical bone as a function of damage accumulation. PMID- 21316627 TI - Mechanical and histological characterization of the abdominal muscle. A previous step to modelling hernia surgery. AB - The aims of this study are to experimentally characterize the passive elastic behaviour of the rabbit abdominal wall and to develop a mechanical constitutive law which accurately reproduces the obtained experimental results. For this purpose, tissue samples from New Zealand White rabbits 2150+/-50 (g) were mechanically tested in vitro. Mechanical tests, consisting of uniaxial loading on tissue samples oriented along the craneo-caudal and the perpendicular directions, respectively, revealed the anisotropic non-linear mechanical behaviour of the abdominal tissues. Experiments were performed considering the composite muscle (including external oblique-EO, internal oblique-IO and transverse abdominis-TA muscle layers), as well as separated muscle layers (i.e., external oblique, and the bilayer formed by internal oblique and transverse abdominis). Both the EO muscle layer and the IO-TA bilayer demonstrated a stiffer behaviour along the transversal direction to muscle fibres than along the longitudinal one. The fibre arrangement was measured by means of a histological study which confirmed that collagen fibres are mainly responsible for the passive mechanical strength and stiffness. Furthermore, the degree of anisotropy of the abdominal composite muscle turned out to be less pronounced than those obtained while studying the EO and IO-TA separately. Moreover, a phenomenological constitutive law was used to capture the measured experimental curves. A Levenberg-Marquardt optimization algorithm was used to fit the model constants to reproduce the experimental curves. PMID- 21316628 TI - Strength enhancement of a biomedical titanium alloy through a modified accumulative roll bonding technique. AB - The strength of a biomedical beta-type alloy, Ti-25Nb-3Zr-3Mo-2Sn, was enhanced through severe plastic deformation using a modified accumulative roll bonding technique. Incremental strength increases were observed after each cycle, while ductility initially fell but showed some recovery with further cycles. After 4 cycles there was a 70% improvement in the ultimate tensile strength to 1220 MPa, a two-fold increase in the 0.5% proof stress to 946 MPa and the ductility was 4.5%. The microstructure comprised of ultrafine grain beta grains heavily elongated in the rolling direction with a fine dispersion of nanocrystalline alpha phase precipitates on the beta grain boundaries. Shear bands formed in order to accommodate large plastic strains during processing and the grains within the bands were significantly finer than the surrounding matrix. PMID- 21316629 TI - Fatigue endurance of Ti-6Al-4V alloy with electro-eroded surface for improved bone in-growth. AB - Ti-6Al-4V hour-glass shaped rotating beam specimens with duplex microstructure were processed by electric discharge machining (EDM). A comparatively high peak current of 29A was utilized in order to increase surface roughness for improved osteointegration. High cycle fatigue (HCF) tests were performed in rotating beam loading (R=-1) on these EDM specimens and results were compared with electrolytically polished specimens serving as reference. As expected, the HCF performance of EDM specimens was inferior to the electrolytically polished specimens. A detailed study of fatigue crack nucleation and microcrack growth was carried out on failed specimens by SEM. The poor HCF strength of EDM specimens is explained by early crack nucleation due to the high notch sensitivity of Ti-6Al 4V. In addition, process-induced residual tensile stresses and microstructural effects may also account for the drastic loss in HCF performance relative to the electropolished baseline. PMID- 21316630 TI - Sub-10-micrometer toughening and crack tip toughness of dental enamel. AB - In previous studies, enamel showed indications to occlude small cracks in-vivo and exhibited R-curve behaviors for bigger cracks ex-vivo. This study quantifies the crack tip's toughness (K(I0),K(III0)), the crack's closure stress and the cohesive zone size at the crack tip of enamel and investigates the toughening mechanisms near the crack tip down to the length scale of a single enamel crystallite. The crack-opening-displacement (COD) profile of cracks induced by Vickers indents on mature bovine enamel was studied using atomic force microscopy (AFM). The mode I crack tip toughness K(I0) of cracks along enamel rod boundaries and across enamel rods exhibit a similar range of values: K(I0,Ir)=0.5-1.6MPa m(0.5) (based on Irwin's 'near-field' solution) and K(I0,cz)=0.8-1.5MPa m(0.5) (based on the cohesive zone solution of the Dugdale-Muskhelishvili (DM) crack model). The mode III crack tip toughness K(III0,Ir) was computed as 0.02-0.15MPa m(0.5). The crack-closure stress at the crack tip was computed as 163-770 MPa with a cohesive zone length and width 1.6-10.1MUm and 24-44 nm utilizing the cohesive zone solution. Toughening elements were observed under AFM and SEM: crack bridging due to protein ligament and hydroxyapatite fibres (micro- and nanometer scale) as well as microcracks were identified. PMID- 21316631 TI - Effect of fluid resins on the surface roughness and topography of resin composite restorations analyzed by atomic force microscope. AB - The aim of the study was to verify the influence of surface sealants on the surface roughness of resin composite restorations before and after mechanical toothbrushing, and evaluate the superficial topography using atomic force microscope. Five surface sealers were used: Single Bond, Opti Bond Solo Plus, Fortify, Fortify Plus and control, without any sealer agent. The lowest values of surface roughness were obtained for control, Single Bond and Fortify groups before toothbrushing. Fortify and Fortify Plus were the sealer agents that support the abrasive action caused by the toothbrushing although Fortify Plus group remained with high values of surface roughness. The application of specific surface sealants could be a useful clinical procedure to maintain the quality of resin-based composite restorations. PMID- 21316632 TI - Poro-viscoelastic constitutive modeling of unconfined creep of hydrogels using finite element analysis with integrated optimization method. AB - Hydrogels are cross-linked polymer networks swollen with water and are being considered as potential replacements for deceased load bearing tissues such as cartilage. Hydrogels show nonlinear time dependent behavior, and are a challenge to model. A three-element poro-viscoelastic constitutive model was developed based on the structure and nature of the hydrogel. To identify the material parameters, an inverse finite element (FE) technique was used that combines experimental results with FE modeling and an optimization method. Unconfined compression creep tests were conducted on poly(vinyl alcohol) (PVA) and poly(ethylene-co-vinyl alcohol)-poly(vinyl pyrrolidone) (EVAL-PVP) hydrogels manufactured by injection molding. Results from the creep experiments showed that for PVA hydrogels, an increase in polymer concentration correlates with a decrease in the equilibrium water content (EWC) and the creep strain. In EVAL-PVP hydrogels, an increase in the hydrophobic segments (EVAL) correlates with a decrease in the EWC as well as the creep strain. An inverse FE method was used to identify the viscoelastic material parameters of the hydrogels in combination with creep testing using the poro-viscoelastic three-element constitutive model. The elastic modulus estimated from the inverse FE technique showed good agreement with the modulus estimated directly from the test data. PMID- 21316633 TI - Mechanical study of PLA-PCL fibers during in vitro degradation. AB - The aliphatic polyesters are widely used in biomedical applications since they are susceptible to hydrolytic and/or enzymatic chain cleavage, leading to alpha hydroxyacids, generally metabolized in the human body. This is particularly useful for many biomedical applications, especially, for temporary mechanical supports in regenerative medical devices. Ideally, the degradation should be compatible with the tissue recovering. In this work, the evolution of mechanical properties during degradation is discussed based on experimental data. The decrease of tensile strength of PLA-PCL fibers follows the same trend as the decrease of molecular weight, and so it can also be modeled using a first order equation. For each degradation stage, hyperelastic models such as Neo-Hookean, Mooney-Rivlin and second reduced order, allow a reasonable approximation of the material behavior. Based on this knowledge, constitutive models that describe the mechanical behavior during degradation are proposed and experimentally validated. The proposed theoretical models and methods may be adapted and used in other biodegradable materials, and can be considered fundamental tools in the design of regenerative medical devices where strain energy is an important requirement, such as, for example, ligaments, cartilage and stents. PMID- 21316634 TI - Microtensile bond strength of etch and rinse versus self-etch adhesive systems. AB - The aim of this study was to compare the microtensile bond strength of the etch and rinse adhesive versus one-component or two-component self-etch adhesives. Twelve intact human molar teeth were cleaned and the occlusal enamel of the teeth was removed. The exposed dentin surfaces were polished and rinsed, and the adhesives were applied. A microhybride composite resin was applied to form specimens of 4 mm height and 6 mm diameter. The specimens were sectioned perpendicular to the adhesive interface to produce dentin-resin composite sticks, with an adhesive area of approximately 1.4 mm(2). The sticks were subjected to tensile loading until failure occurred. The debonded areas were examined with a scanning electron microscope to determine the site of failure. The results showed that the microtensile bond strength of the etch and rinse adhesive was higher than that of one-component or two-component self-etch adhesives. The scanning electron microscope examination of the dentin surfaces revealed adhesive and mixed modes of failure. The adhesive mode of failure occurred at the adhesive/dentin interface, while the mixed mode of failure occurred partially in the composite and partially at the adhesive/dentin interface. It was concluded that the etch and rinse adhesive had higher microtensile bond strength when compared to that of the self-etch adhesives. PMID- 21316635 TI - Prediction of mechanical properties of composites of HDPE/HA/EAA. AB - In this investigation, the behavior of the mechanical properties of composites of high-density polyethylene/hydroxyapatite (HDPE/HA) with and without ethylene acrylic acid copolymer (EAA) as possible compatibilizer, was studied. Different mathematical models were used to predict their Young's modulus, tensile strength and elongation at break. A comparison with the experimental results shows that the theoretical models of Guth and Kerner modified can be used to predict the Young's modulus. On the other hand, the values obtained by the Verbeek model do not show a good agreement with the experimental data, since different factors that influence the mechanical properties are considered in this model such as: aspect ratio of the reinforcement, interfacial adhesion, porosity and binder content. TEM analysis confirms the discrepancies obtained between the experimental Young's modulus values and those predicted by the Verbeek model. The values of "P", "a" and "sigma(A)" suggest that an interaction among the carboxylic groups of the copolymer and the hydroxyl groups of hydroxyapatite might be present. In composites with 20 and 30 wt% of filler, this interaction does not improve the Young's modulus values, since the deviations of the Verbeek model are significant. PMID- 21316636 TI - Strength and reliability of alumina ceramic femoral heads: Review of design, testing, and retrieval analysis. AB - Ceramic components are used increasingly in total hip arthroplasty (THA). Compared with metallic components, ceramic femoral heads for THA have the potential advantage of lower wear rates in articulations with acetabular liners. However, the use of ceramic components is also associated with unique risks, including sudden fracture and intolerable bearing noise or squeaking. This review paper summarizes the published literature regarding alumina ceramic femoral heads and tries to identify areas where uncertainties remain. We will discuss the following topics: (1) the fracture mechanics of ceramic materials; (2) design related stresses acting on the femoral head, especially at the interface between the stem trunnion and the head; (3) gradual loss of strength in service by fatigue or slow crack growth and simulation using a proof test; and (4) information that can be gathered from examination of fractured explants. PMID- 21316637 TI - Age-dependence of intracranial viscoelastic properties in living rats. AB - To explore the effect of maturation on intracranial mechanical properties, viscoelastic parameters were determined in 44 live rats at ages 1-2, 10-12, 21, 56-70, and 180 days using instrumented indentation. With the dura mater intact, the apparent modulus of elasticity, the indentation modulus, and viscous behavior were measured in vivo, as well as 1 h after death. In a separate group of 25 rats, brain water, and protein content were determined. A significant increase of the elastic and indentation moduli beginning at 10-12 days after birth and continuing to 180 days was observed. The creep behavior decreased in the postnatal period and stabilized at 21 days. Changes in intracranial biomechanical properties corresponded to a gradual decrease of brain water, and an increase in total protein content, including glial fibrillary acidic protein, myelin basic protein, and neurofilament light chain. Elastic properties were not significantly different comparing the live and dead states. However, there were significant postmortem changes in viscous behavior. Viscoelastic properties of living rat intracranial contents are shown to be age dependent, reflecting the physical and biochemical changes during postnatal development. This may be important for understanding why young and mature brains respond differently in situations of brain trauma and hydrocephalus. PMID- 21316638 TI - Ratchetting of porcine skin under uniaxial cyclic loading. AB - Skin soft tissue (e.g., porcine skin) was tested in vitro under uniaxial cyclic loading, and its biomechanical responses were investigated to realize some basic properties which are very significant in assessing the fatigue life of skin soft tissue. The results show that a cyclic accumulation of peak and valley strain, which can be terminologically called as ratchetting in terms of material science of metals, occurs in the porcine skin during cyclic tension-unloading, tension tension and compression-unloading tests. Observed ratchetting of porcine skin depends on load level and loading orientation greatly and also presents remarkable rate dependence due to the viscosity of skin soft tissue. The ratchetting is much more remarkable during the test at lower loading rate than that at higher loading rate. Moreover, some basic properties of porcine skin were also investigated by monotonic tension, compression and creep tests in order to address the ratchetting more comprehensively. Finally, collagen fiber bundles in the porcine skin and their variation during monotonic and cyclic tension tests were observed microscopically in term of standard iron-hematoxylin staining method. The observations are useful to realize the micro-mechanism of ratchetting deformation. PMID- 21316639 TI - In vivo feasibility case study for evaluating abdominal aortic aneurysm tissue properties and rupture potential using acoustic radiation force impulse imaging. AB - An abdominal aortic aneurysm (AAA) is defined as a permanent and irreversible localized dilatation of the abdominal aorta. A reliable, non-invasive method to assess the wall mechanics of an aneurysm may provide additional information regarding their susceptibility to rupture. Acoustic radiation force impulse (ARFI) imaging is a phenomenon associated with the propagation of acoustic waves in attenuating media. This study was a preliminary evaluation to explore the feasibility of using ARFI imaging to examine an AAA in vivo. A previously diagnosed in vivo aneurysm case study was imaged to demonstrate the viability of excitation of the abdominal aorta using ARFI imaging. Ex vivo experiments were used to assess an artificially induced aneurysm to establish its development and whether ARFI was able to capture the mechanical changes during artificial aneurysm formation. A combination of in vivo and ex vivo results demonstrated a proposed hypothesis of estimation of the tissue's stiffness properties. The study details a method for non-invasive rupture potential prediction of AAAs using patient-specific moduli to generate a physiological stiffness rupture potential index (PSRPI) of the AAA. Clinical feasibility of ARFI imaging as an additional surgical tool to interrogate AAAs was verified and methods to utilize this data as a diagnostic tool was demonstrated with the PSRPI. PMID- 21316640 TI - Evidence-based diuretic therapy for improving cardiovascular prognosis in systemic hypertension. AB - Diuretics are among the most commonly prescribed cardiovascular (CV) medications. The strength of evidence supporting the effectiveness of diuretics in lowering blood pressure and for preventing major adverse CV events in patients with hypertension varies considerably among diuretic classes and even among agents within the same class. Unfortunately, common prescribing habits among American physicians, including specialists in CV diseases, are not in line with the existing evidence regarding diuretic therapy for improving CV prognosis. In conclusion, although hydrochlorothiazide is the standard diuretic used for hypertension, the outcomes data suggest that chlorthalidone, indapamide, and possibly even the aldosterone receptor blockers (spironolactone and eplerenone) may be superior agents. PMID- 21316641 TI - Improving pregnancy drug warnings to promote patient comprehension. AB - OBJECTIVE: We sought to evaluate the effectiveness of a pharmaceutical labeling strategy intended to improve comprehension of a teratogen warning. STUDY DESIGN: This is a secondary analysis that evaluated women of childbearing age who were assigned prescription containers with the current teratogen warning, a label with simplified text, or a label with simplified text and icons. The association between label type and understanding of label instructions was assessed. RESULTS: A total of 132 women were interviewed. Comprehension of the icon label (94%) was higher than for the standard and enhanced text-only labels (76% and 79%), respectively (P < .05). Adjustment for age, race/ethnicity, education, literacy, and number of current medications revealed that the label with the enhanced text and icon yielded superior comprehension (risk ratio vs standard, 1.26; 95% confidence interval, 1.04-1.53; risk ratio vs enhanced, 1.22; 95% confidence interval, 1.02-1.46). CONCLUSION: In our study, a teratogen warning label that had easy-to-read messages with icons significantly improved comprehension. PMID- 21316643 TI - Analysis of shoulder dystocia maneuvers using a computer model. PMID- 21316642 TI - Accreta complicating complete placenta previa is characterized by reduced systemic levels of vascular endothelial growth factor and by epithelial-to mesenchymal transition of the invasive trophoblast. AB - OBJECTIVE: We sought to characterize serum angiogenic factor profile of women with complete placenta previa and determine if invasive trophoblast differentiation characteristic of accreta, increta, or percreta shares features of epithelial-to-mesenchymal transition. STUDY DESIGN: We analyzed gestational age-matched serum samples from 90 pregnant women with either complete placenta previa (n = 45) or uncomplicated pregnancies (n = 45). Vascular endothelial growth factor (VEGF), placental growth factor, and soluble form of fms-like tyrosine-kinase-1 were immunoassayed. VEGF and phosphotyrosine immunoreactivity was surveyed in histological specimens relative to expression of vimentin and cytokeratin-7. RESULTS: Women with previa and invasive placentation (accreta, n = 5; increta, n = 6; percreta, n = 2) had lower systemic VEGF (invasive previa: median 0.8 [0.02-3.4] vs control 6.5 [2.7-10.5] pg/mL, P = .02). VEGF and phosphotyrosine immunostaining predominated in the invasive extravillous trophoblasts that coexpressed vimentin and cytokeratin-7, an epithelial-to mesenchymal transition feature and tumorlike cell phenotype. CONCLUSION: Lower systemic free VEGF and a switch of the interstitial extravillous trophoblasts to a metastable cell phenotype characterize placenta previa with excessive myometrial invasion. PMID- 21316645 TI - Main sequence: an index for detecting mental workload variation in complex tasks. AB - The primary aim of this study was to validate the saccadic main sequence, in particular the peak velocity [PV], as an alternative psychophysiological measure of Mental Workload [MW]. Taking the Wickens' multiple resource model as the theoretical framework of reference, an experiment was conducted using the Firechief(r) microworld. MW was manipulated by changing the task complexity (between groups) and the amount of training (within groups). There were significant effects on PV from both factors. These results provide additional empirical support for the sensitivity of PV to discriminate MW variation on visual-dynamic complex tasks. These findings and other recent results on PV could provide important information for the development of a new vigilance screening tool for the prevention of accidents in several fields of applied ergonomics. PMID- 21316646 TI - Fluoride concentration in dentine as a biomarker of fluoride intake in European roe deer (Capreolus capreolus) - an electron-microprobe study. AB - OBJECTIVE: Fluoride concentration in dentine has been recommended as the best marker for the level of chronic fluoride intake and the most suitable indicator of an individual's total body burden of fluoride. We analysed fluoride concentrations in the dentine of cheek teeth of European roe deer from fluoride polluted habitats to retrospectively assess the level of fluoride uptake into the tissue. Thereby, we tested the hypothesis of the existence of mechanisms that limit fluoride intake of individuals and fluoride exposure of forming dental hard tissues during the late foetal and early postnatal periods in the species. DESIGN: Using electron-microprobe analysis, fluoride profiles were obtained on sectioned P(4)s, M(1)s, and M(3)s from individuals exhibiting pronounced dental fluorosis. Fluoride concentrations were compared between early formed (peripheral) and late-formed (juxtapulpal) dentine both within single teeth and amongst the three different teeth studied. RESULTS: Peripheral dentine of the M(1), which is formed during the late foetal and early postnatal periods, exhibited markedly lower fluoride concentrations than juxtapulpal dentine of the same tooth and both, peripheral and juxtapulpal dentine of P(4) and M(3) that are formed post-weaning. CONCLUSIONS: Our study provides strong support for the hypothesis that in the European roe deer the prenatal and early postnatal (pre weaning) stages of dental development are (largely) protected against exposure to excess fluoride. This is attributed to the operation of certain protective mechanisms during these periods. PMID- 21316647 TI - "I feel fat": an experimental induction of body displacement in disordered eating. AB - Body displacement, the theory that predicts that individuals with eating disorders will displace negative feelings about themselves onto their body, was tested experimentally in this study. Unrestrained eaters (n = 61), restrained eaters (n = 33), and individuals with eating disorders (n = 26) were randomly assigned to a control condition or an ineffectiveness induction. In the ineffectiveness condition participants were asked to recall and reflect on a past experience when they felt useless or incapable (i.e., ineffective). Results showed that individuals with eating disorders who were made to feel ineffective reported more implicit appearance/body concern than those in the control condition. Unrestrained and restrained eaters did not show this effect. This is the first experimental study to support body displacement theory. These data can be used clinically to educate and encourage patients with eating disorders to address thoughts and feelings related to ineffectiveness directly, instead of displacing this distress onto their body and potentially perpetuating their eating disorder. PMID- 21316649 TI - Symbolic magnitude modulates perceptual strength in binocular rivalry. AB - Basic aspects of magnitude (such as luminance contrast) are directly represented by sensory representations in early visual areas. However, it is unclear how symbolic magnitudes (such as Arabic numerals) are represented in the brain. Here we show that symbolic magnitude affects binocular rivalry: perceptual dominance of numbers and objects of known size increases with their magnitude. Importantly, variations in symbolic magnitude acted like variations in luminance contrast: we found that an increase in numerical magnitude of adding one lead to an equivalent increase in perceptual dominance as a contrast increment of 0.32%. Our results support the claim that magnitude is extracted automatically, since the increase in perceptual dominance came about in the absence of a magnitude-related task. Our findings show that symbolic, acculturated knowledge about magnitude interacts with visual perception and affects perception in a manner similar to lower-level aspects of magnitude such as luminance contrast. PMID- 21316648 TI - Synthesis and antibacterial properties of carbohydrate-templated lysine surfactants. AB - The synthesis of four dicationic glucose-templated D-lysine-derived surfactants and their two unmodified D-lysine-analogs is described. Replacement of D-lysine by D-glucose-templated-D-lysine provides a general tool to introduce chemical diversity into the side chain of lysine. The presence of the polyfunctional D gluco-configured polyol scaffold provides rich opportunities to study structure activity relationships in lysine-lipid conjugates. All cationic lipids were tested for inhibition of bacterial growth using a panel of clinically relevant Gram-positive and Gram-negative strains. Our results show that substitution of D lysine by D-glucose-templated D-lysine surfactants retains, but does not improve, the antibacterial activity. Similarly, conversion of the D-gluco-based polyol scaffold into a hydrophobically enhanced tri-O-phenylcarbamate scaffold does not further enhance the antibacterial activity of the cationic lipid. However, improvements in the antibacterial activity were observed by guanidinylation of the two lysine-based amino groups. PMID- 21316650 TI - Eye contact facilitates awareness of faces during interocular suppression. AB - Eye contact captures attention and receives prioritized visual processing. Here we asked whether eye contact might be processed outside conscious awareness. Faces with direct and averted gaze were rendered invisible using interocular suppression. In two experiments we found that faces with direct gaze overcame such suppression more rapidly than faces with averted gaze. Control experiments ruled out the influence of low-level stimulus differences and differential response criteria. These results indicate an enhanced unconscious representation of direct gaze, enabling the automatic and rapid detection of other individuals making eye contact with the observer. PMID- 21316651 TI - Identity-specific face adaptation effects: evidence for abstractive face representations. AB - The effects of selective adaptation on familiar face perception were examined. After prolonged exposure to photographs of a celebrity, participants saw a series of ambiguous morphs that were varying mixtures between the face of that person and a different celebrity. Participants judged fewer of the morphs to resemble the celebrity to which they had been adapted, implying that they were now less sensitive to that particular face. Similar results were obtained when the adapting faces were highly dissimilar in viewpoint to the test morphs; when they were presented upside-down; or when they were vertically stretched to three times their normal height. These effects rule out explanations of adaptation effects solely in terms of low-level image-based adaptation. Instead they are consistent with the idea that relatively viewpoint-independent, person-specific adaptation occurred, at the level of either the "Face Recognition Units" or "Person Identity Nodes" in Burton, Bruce and Johnston's (1990) model of face recognition. PMID- 21316652 TI - A combined approach to investigate the toxicity of an industrial landfill's leachate: chemical analyses, risk assessment and in vitro assays. AB - Solid wastes constitute an important and emerging problem. Landfills are still one of the most common ways to manage waste disposal. The risk assessment of pollutants from landfills is becoming a major environmental issue in Europe, due to the large number of sites and to the importance of groundwater protection. Furthermore, there is lack of knowledge for the environmental, ecotoxicological and toxicological characteristics of most contaminants contained into landfill leacheates. Understanding leachate composition and creating an integrated strategy for risk assessment are currently needed to correctly face the landfill issues and to make projections on the long-term impacts of a landfill, with particular attention to the estimation of possible adverse effects on human health and ecosystem. In the present study, we propose an integrated strategy to evaluate the toxicity of the leachate using chemical analyses, risk assessment guidelines and in vitro assays using the hepatoma HepG2 cells as a model. The approach was applied on a real case study: an industrial waste landfill in northern Italy for which data on the presence of leachate contaminants are available from the last 11 years. Results from our ecological risk models suggest important toxic effects on freshwater fish and small rodents, mainly due to ammonia and inorganic constituents. Our results from in vitro data show an inhibition of cell proliferation by leachate at low doses and cytotoxic effect at high doses after 48 h of exposure. PMID- 21316653 TI - Temporal variability in trihalomethane and haloacetic acid concentrations in Massachusetts public drinking water systems. AB - Previous epidemiological studies in Massachusetts have reported a risk of adverse health outcomes in relation to disinfection by-product (DBP) exposures. Measurement error due to the use of indirect exposure surrogates can lead to misclassification bias in epidemiological studies; therefore, it is important to characterize exposure variability in these populations to assess the potential for exposure misclassification. We used 19,944 trihalomethane (THM) samples and 9291 haloacetic acid (HAA) samples collected in 201 public water systems (PWSs) in Massachusetts to examine temporal variability under different drinking water sources and disinfection types. Annual and seasonal variability was also examined in 46 PWSs with complete quarterly THM4 (i.e., the sum of 4 individual THMs) data from 1995 to 2004 and 19 PWSs with complete HAA5 (i.e., the sum of 5 individual HAAs) data from 2001 to 2004. The quarterly ratio of THM4 and HAA5 and correlations between THM4, HAA5 and individual DBP species were examined to determine the adequacy of using different exposure surrogates in epidemiological studies. Individual PWSs were used to examine monthly variability in relation to quarterly averages. Based on all available matched samples (n=9003) from 1995 to 2004 data, we found a correlation of 0.52 for THM4 and HAA5. The correlation was stronger among the 62 ground water systems (r(s)=0.62) compared to the 81 surface water (r(s)=0.45) and 40 mixed water (r(s)=0.39) systems. Mean THM4 levels were fairly stable over the 10-year study period for 46 PWSs including 39 PWSs that did not change disinfection. Large reductions (~40 MUg/L) in mean THM4 data were found among seven systems that switched from chlorination to alternative disinfectants. As expected, the highest mean THM4 values were detected for Quarter 3, while the lowest values were found in Quarter 1. The highest HAA5 values were detected in Quarters 2 and 3 and the lowest was found in Quarter 4. Data from four systems showed mean differences up to 66 MUg/L (67% change) in successive months and by 46 MUg/L compared to quarterly mean concentrations. Although longer-term disinfection by-product temporality may be minimal in this study population, the use of monthly average concentrations for exposure assessment may be needed for some PWSs to minimize misclassification of narrow critical periods of exposure in epidemiological studies. PMID- 21316655 TI - A response to "A quantitative assessment of the carcinogenicity of hexavalent chromium by the oral route and its relevance to human exposure". PMID- 21316656 TI - [Troponin-I in hemodynamically-stable pulmonary embolism: correlation with echocardiography and computed tomography angiography]. AB - BACKGROUND: Troponin-I (TnI) is a marker of severe pulmonary thromboembolism (PTE) in unselected patients. There are few articles that assess its usefulness in hemodynamically-stable patients. OBJECTIVES: To assess the correlation between TnI levels and both echocardiographic/radiologic signs of right ventricle (RV) dysfunction or pulmonary hypertension (PH), and the severity of the pulmonary vascular obstruction. METHODS: We selected patients from a prospective cohort of 103 consecutive patients with PTE and systolic arterial pressure >= 90 mmHg. Computed tomography pulmonary angiography (CTPA) and echocardiography were performed in all patients. We performed a post hoc study, analyzing the 68 cases in which TnI was measured, at the discretion of the emergency room physician. RESULTS: Patients included had a median age of 74 years and 50% were male. The patients with elevated TnI had a differentiated clinical profile, suggestive of more severe PTE. There was a significant correlation between TnI levels and systolic pulmonary artery pressure (r=0.46, P<.001), the CTPA-measured pulmonary artery diameter (r=0.48, P<.001), the CTPA-measured RV diameter (r=0.47, P=.001) and the pulmonary vascular obstruction index (r=0.39, P=.001). CONCLUSION: The higher levels of TnI in patients with hemodynamically stable PTE predicts the existence of more severe PE in hemodynamically-stable patients. This biomarker could be used in the clinical practice to select those patients who might require more intensive monitoring or additional complementary studies. PMID- 21316657 TI - [Hematoma of the rectus abdominis. experience of a primary care hospital]. AB - OBJECTIVE: To describe patients diagnosed with hematoma of the rectus abdominis (HRA) muscle. MATERIAL AND METHODS: A retrospective analysis of patients diagnosed with HRA over the past 8 years in our center. RESULTS: A total of 17 patients (9 women) with mean age of 73 years were included in the study. In 52% of the cases the HRA was the cause of hospitalization. Anticoagulant therapy was documented in 70%. More than half of patients treated with low molecular weight heparin had renal insufficiency. In the group receiving oral anticoagulants (OA), 86% had INR greater than 4. Paroxysmal cough appeared in 13. The most common presentation was abdominal pain and palpable mass. CT scan sensitivity was superior to that of the ultrasound. The most common location was the lower right. Treatment was conservative in all but one. Two patients died. Mean decrease in hemoglobin was 4.7 g/dl. Average stay was 19 days. CONCLUSIONS: In our center, HRA almost equally affects both genders and appears in older people with excessive anticoagulation and cough. The clinical presentation, increased diagnostic sensitivity of CT scan and predominance in the right abdominal involvement are similar to other series. Mortality and hospital stay are higher than described. PMID- 21316658 TI - [The positive side of the burnout: a starting point]. PMID- 21316659 TI - [Hematoma of the rectus abdominis muscle in patients treated with low-molecular weight heparin: four clinical cases]. PMID- 21316660 TI - How effective is in vitro fertilization, and how can it be improved? AB - OBJECTIVE: To measure IVF effectiveness, which is defined as the cumulative incidence of live delivery over real time in women after commencing IVF treatment. DESIGN: Population-based retrospective cohort study. SETTING: IVF clinics in Western Australia (WA). PATIENT(S): All women ages 20-44 years inclusive at start of treatment, commencing IVF in 1982-1992 and 1993-2002 at clinics in WA (n = 8,275). INTERVENTION(S): Data on IVF cycles were extracted from hospital records and a statutory reproductive technology register and linked to records of births. MAIN OUTCOME MEASURE(S): Cumulative incidence of an IVF attributed live delivery and cumulative incidence of an IVF-attributed or IVF treatment-independent live delivery. RESULT(S): IVF effectiveness in the 1993 2002 cohort was 47% overall. It was highest in women ages 20-29 years at the start of treatment, measuring 58%; and 79% with the inclusion of IVF treatment independent deliveries, and declined to 22% and 33%, respectively, in women ages 40-44 years. Couples underwent, on average, only three cycles, even though the cumulative probability of a live delivery increased with each successive cycle for at least the first five cycles. CONCLUSION(S): IVF effectiveness could be improved if women, particularly those over 35, underwent more cycles. PMID- 21316661 TI - Serum complement C3 has a stronger association with insulin resistance than high sensitivity C-reactive protein in women with polycystic ovary syndrome. AB - OBJECTIVE: To compare the association of complement C3 (C3) versus high sensitivity C-reactive protein (hs-CRP) with insulin resistance (IR) in women with polycystic ovary syndrome (PCOS). DESIGN: Cross-sectional analysis. SETTING: Clinical research center in China. PATIENT(S): One hundred thirty-three women with PCOS and 116 healthy, age-matched controls were recruited. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): One hundred one women with PCOS and 20 controls underwent hyperinsulinemic-euglycemic clamp to assess their insulin sensitivity, which was expressed as an M value. RESULT(S): Compared with controls, women with PCOS had a lower M value and higher C3 (1.37 +/- 0. 34 vs. 1.10 +/- 0.22 g/L) and hs-CRP levels (1.46 +/- 2.29 vs. 0.49 +/- 0.88 mg/L). In women with PCOS, C3 and hs-CRP negatively correlated with M value (r = -0.61 and r = -0.47, respectively). By regression analysis, C3 was found to have a greater impact on the M value (standardized coefficient beta = -0.24) than did hs-CRP (standardized coefficient beta = -0.13). After adjusting for body mass index (BMI), women with PCOS in the upper quartile were 4.30 times more likely to exhibit IR compared with those in the lower quartiles, whereas hs-CRP was not a statistically significant predictor of IR in women with PCOS. CONCLUSION(S): Compared with hs CRP, serum C3 might be a stronger inflammatory marker of IR in women with PCOS. PMID- 21316662 TI - Diabetes risk score in the diagnostic categories of polycystic ovary syndrome. AB - OBJECTIVE: To assess the Finnish Diabetes Risk Score in polycystic ovary syndrome (PCOS) and in different phenotypes of PCOS and controls. DESIGN: Cross-sectional study. SETTING: General community. PATIENT(S): Overweight premenopausal women with National Institutes of Health (NIH) PCOS (n = 29), non-NIH PCOS (n = 25), or controls (n = 27). INTERVENTION(S): No intervention provided. MAIN OUTCOME MEASURE(S): Finnish Diabetes Risk Score, anthropometrics, oral glucose tolerance test (OGTT), glucose, insulin, and reproductive hormone levels. RESULT(S): The women with NIH PCOS had higher adiposity, abdominal adiposity and 120-minute OGTT glucose. The women with NIH and non-NIH PCOS had elevated 120-minute OGTT insulin compared with controls. The women with NIH (11.3 +/- 0.7) and non-NIH PCOS (10.4 +/- 0.7) had similar diabetes risk scores, but both had higher diabetes risk score compared with controls (7.6 +/- 0.8) maintained on adjustment for age and body mass index (BMI). The women with NIH (4%) and non-NIH PCOS (12%) had a lower prevalence of low risk of diabetes scores compared with controls (50%). CONCLUSION(S): We report for the first time that women with NIH and non-NIH PCOS have similar Finnish Diabetes Risk Scores and elevated scores relative to controls independent of age and adiposity. Similar clinical screening and treatment practices for type 2 diabetes are warranted for both phenotypes of PCOS. PMID- 21316663 TI - Retrovirus-mediated multidrug resistance gene (MDR1) overexpression inhibits chemotherapy-induced toxicity of granulosa cells. AB - OBJECTIVE: To protect granulosa cells from chemotherapy-induced toxicity by retrovirus-mediated multidrug resistance (MDR1) gene transfection. DESIGN: Laboratory study. SETTING: Academic research laboratory in a university hospital. PATIENT(S): None. INTERVENTION(S): KK15 immortalized murine granulosa cell line transiently transduced with sf91m3 retrovirus vector carrying MDR1 complementary DNA that encodes P-glycoprtoein (P-gp); transduced cells selected with colchicine and treated with doxorubicin or paclitaxel for 24-72 hours; expression and function of MDR1 and the messenger RNA (mRNA) expression of selected steroidogenesis enzymes evaluated by flow cytometry, cell viability assays, Western blot, and reverse-transcriptase polymerase chain reaction (RT-PCR). MAIN OUTCOME MEASURE(S): Viability of sf91m3-transduced KK15 cells after treatment with doxorubicin and paclitaxel. RESULT(S): The sf91m3-transduced KK15 demonstrated high expression of biologically active MDR1, as shown by flow cytometry analysis and immunoblotting using P-gp monoclonal antibody and Rhodamine 123 efflux assays. The sf91m3-transduced KK15 exhibited statistically significant resistance to toxicity of 10 MUM paclitaxel. The MDR1-transduced KK15 cells were also protected from doxorubicin toxicity (10 nM to 2.5 MUM), as shown by cell viability assay. Both flow cytometry and cell viability assays showed that the protection of KK15 from doxorubicin toxicity was lost at 5 MUM of doxorubicin; equivalent to 500 times LD50. The sf91m3-transduced KK15 showed normal mRNA expression of a panel of selected steroidogenesis enzymes. CONCLUSION(S): Retroviral gene delivery of human MDR1 inhibited chemotherapy induced granulosa cell toxicity and offered chemoprotection in an in vitro model. PMID- 21316664 TI - Copy number variants on the X chromosome in women with primary ovarian insufficiency. AB - OBJECTIVE: To investigate whether submicroscopic copy number variants (CNVs) on the X chromosome can be identified in women with primary ovarian insufficiency (POI), defined as spontaneous secondary amenorrhea before 40 years of age accompanied by follicle-stimulating hormone levels above 40 IU/L on at least two occasions. DESIGN: Analysis of intensity data of single nucleotide polymorphism (SNP) probes generated by genomewide Illumina 370k CNV BeadChips, followed by the validation of identified loci using a custom designed ultra-high-density comparative genomic hybridization array containing 48,325 probes evenly distributed over the X chromosome. SETTING: Multicenter genetic cohort study in the Netherlands. PATIENT(S): 108 Dutch Caucasian women with POI, 97 of whom passed quality control, who had a normal karyogram and absent fragile X premutation, and 235 healthy Dutch Caucasian women as controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Amount and locus of X chromosomal microdeletions or duplications. RESULT(S): Intensity differences between SNP probes identify microdeletions and duplications. The initial analysis identified an overrepresentation of deletions in POI patients. Moreover, CNVs in two genes on the Xq21.3 locus (i.e., PCDH11X and TGIF2LX) were statistically significantly associated with the POI phenotype. Mean size of identified CNVs was 262 kb. However, in the validation study the identified putative Xq21.3 deletions samples did not show deviations in intensities in consecutive probes. CONCLUSION(S): X chromosomal submicroscopic CNVs do not play a major role in Caucasian POI patients. We provide guidelines on how submicroscopic cytogenetic POI research should be conducted. PMID- 21316665 TI - Deoxyribonucleic acid methyltransferases and methyl-CpG-binding domain proteins in human endometrium and endometriosis. AB - OBJECTIVE: To determine [1] expression levels of both DNA methyltransferases (DNMTs) and methyl-CpG-binding domain proteins (MBDs) in human endometrium throughout the menstrual cycle and in eutopic and ectopic endometrium of patients with endometriosis and [2] hormone responsiveness of DNMT and MBD expression in explant cultures of proliferative phase endometrium. DESIGN: In vitro study. SETTING: Academic medical center. PATIENT(S): Premenopausal women with and without endometriosis. INTERVENTION(S): Explant cultures of proliferative phase endometrium were treated with vehicle, 17beta-E(2), or a combination of E(2) and P (E(2) + P) for 24 hours. MAIN OUTCOME MEASURE(S): Expression levels of DNMT1, DNMT2, and DNMT3B and MBD1, MBD2, and MeCP2 with use of real-time quantitative polymerase chain reaction. RESULT(S): Expression levels of DNMT1 and MBD2 were significantly higher in secretory-phase endometrium compared with proliferative endometrium and menstrual endometrium. In explant cultures, treatment with E(2) + P resulted in significant up-regulation of DNMT1 and MBD2. Expression levels of several DNMTs and MBDs were significantly lower in endometriotic lesions compared with eutopic endometrium of women with endometriosis and disease-free controls. CONCLUSION(S): These findings suggest a role for DNMTs and MBDs in the growth and differentiation of the human endometrium and support the notion that endometriosis may be an epigenetic disease. PMID- 21316666 TI - Feasibility of salvage endoscopic mucosal resection by using a cap for remnant rectal carcinoids after primary EMR. AB - BACKGROUND: Secondary endoscopic treatment for remnant lesions of rectal carcinoid tumors after primary EMR or polypectomy is technically difficult because of fibrosis of residual tissues. EMR by using a cap (EMR-C), a method to resect the submucosal layer by suction by using a transparent cap, may be feasible as a salvage treatment. OBJECTIVE: To assess the feasibility of salvage EMR-C. DESIGN: Retrospective analysis. SETTING: Tertiary academic health care system. PATIENTS: Thirty-one patients who were referred for salvage treatment of a failed en bloc excision of rectal carcinoid tumors after primary EMR or polypectomy between January 2007 and December 2009. INTERVENTIONS: Salvage EMR-C for remnant carcinoid tumors in the rectum. MAIN OUTCOME MEASUREMENTS: Rate of complete resection, complications, length of procedure, and recurrence rate. RESULTS: The mean age of the patients was 52.0+/-11.8 years (range 30-78 years). The mean tumor size was 8.9+/-3.2 mm (range 5.0-13.0 mm). The mean procedure time was 9.1+/-3.7 minutes, and clear resection margins were pathologically confirmed in all 31 patients. The most common complication of salvage EMR-C was bleeding (7 patients, 22.6%), which was successfully treated by hemoclipping in all cases. The 1-year follow-up colonoscopy and CT results for all patients were negative for recurrence. LIMITATIONS: Retrospective design and limited cases at a single center. CONCLUSIONS: EMR-C is a feasible salvage therapeutic option for failed en bloc excision after primary endoscopic treatment of rectal carcinoid tumors. PMID- 21316667 TI - Clinical feasibility of direct peroral cholangioscopy-guided photodynamic therapy for inoperable cholangiocarcinoma performed by using an ultra-slim upper endoscope (with videos). AB - BACKGROUND: Photodynamic therapy (PDT) has emerged as a promising palliative treatment for inoperable cholangiocarcinoma. Cholangioscopy-guided PDT can be useful for identification of tumor margins, determination of the appropriate location for placement of the diffuser, and evaluation of the patient's response to therapy. OBJECTIVE: To evaluate the feasibility of PDT under direct peroral cholangioscopy (POC) by using an ultra-slim upper endoscope in patients with inoperable cholangiocarcinoma. DESIGN: Prospective, observational, pilot study. SETTING: Single tertiary-care referral center. PATIENTS: This study involved 9 patients with inoperable extrahepatic cholangiocarcinoma. INTERVENTION: Photofrin II was administered intravenously 48 hours before PDT. Additional PDT was performed up to 48 hours after the initial application of therapy. A successful direct POC-guided PDT was defined as advancement of the endoscope into the distal margin of the tumor and maintenance of endoscope position until PDT was completed. MAIN OUTCOME MEASUREMENTS: The clinical feasibility, usefulness, and complications of direct POC for PDT. RESULTS: Seventeen sessions of direct POC for PDT were performed in 9 patients. PDT was performed successfully in 15 of 17 sessions (88.2%) and 7 of 9 patients (77.8%). Biliary drainage under direct POC, if necessary after PDT, was possible in 100% of patients (7/7). Follow-up direct POC confirmed significant tumor ablation after PDT in 5 patients. One patient reported mild skin redness; no major procedure-related complications were observed. LIMITATIONS: Small sample size, pilot study. CONCLUSION: Direct POC guided PDT by using an ultra-slim upper endoscope seems to be both feasible and safe in select patients with inoperable extrahepatic cholangiocarcinoma. PMID- 21316668 TI - Prospective, randomized study of conventional versus HybridKnife endoscopic submucosal dissection methods for the esophagus: an animal study. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) increases en bloc and histologically complete resection rate of neoplastic mucosal tumors but is technically more demanding than EMR. Limited data are available comparing the efficacy and safety of a new ESD designed to overcome these limitations and conventional ESD (C-ESD) techniques. OBJECTIVE: To compare the safety, efficacy, and operation time of the new HybridKnife ESD (HK-ESD) with C-ESD in the esophagus. DESIGN: Prospective, randomized, controlled study. SETTING: Animal research laboratory. SUBJECTS: Seventeen anesthetized Yorkshire pigs. INTERVENTIONS: Removal of a 4-cm length of half-circumference esophageal mucosa by C-ESD with Hook knife or Flexknife versus HK-ESD. MAIN OUTCOME MEASUREMENTS: Procedure time, en bloc and complete resection rate, and complications (bleeding and perforation). RESULTS: All resections were completed en bloc. Procedure time was shorter in C-ESD. However, it was similar after 12 procedures. Significantly more bleeding occurred during C-ESD (28 vs 12, P = .0007). Histological muscularis propria injuries occurred with equal frequency (16 vs 17) and were mostly seen during the first 11 procedures. There were 3 perforations (2 endoscopic, 1 histological), all with C-ESD. LIMITATIONS: Nonsurvival study, use of 2 conventional knives, no training period for a new procedure. CONCLUSIONS: The HK-ESD technique was equally effective as the C-ESD technique for successful en bloc resection and was safer with less bleeding and perforation. Although procedure time was longer in HK-ESD, the difference became nonsignificant after 12 procedures. PMID- 21316669 TI - A prospective assessment of sedation-related adverse events and patient and endoscopist satisfaction in ERCP with anesthesiologist-administered sedation. AB - BACKGROUND: Despite the increasing use of anesthesiologist-administered sedation for monitored anesthesia care (MAC) or general anesthesia in patients undergoing ERCP, limited prospective data exist on the effectiveness, safety, and cost of this approach. OBJECTIVE: To prospectively assess sedation-related adverse events (SRAEs), patient- and procedure-related risk factors associated with SRAEs, and endoscopist and patient satisfaction with anesthesiologist-administered sedation. DESIGN: Single-center, prospective cohort study. SETTING: Tertiary-care referral center. PATIENTS: A total of 528 consecutive patients undergoing ERCP. INTERVENTIONS: Anesthesiologist-administered MAC or general anesthesia. MAIN OUTCOME MEASUREMENTS: SRAEs, endoscopist and patient satisfaction. RESULTS: There were 120 intraprocedure SRAEs during 109 of the 528 ERCPs (21% of cases). Intraprocedure SRAEs included hypotension (38 events), arrhythmia (20 events), O(2) desaturation to less than 85% (66 events), unplanned intubation (16 events), and procedure termination (1 event). Thirty postprocedure SRAEs occurred in a total of 22 patients (4% of cases), including hypotension (5 events), endotracheal intubation (2 events), and arrhythmia (12 events). Patient-related variables associated with adverse intraprocedure events were American Society of Anesthesiologists class (P = .004) and body mass index (kg/m(2)) (P = .02). On a 10-point scale, mean endoscopist satisfaction with sedation was 9.2 (standard deviation 1.8) and patient satisfaction with sedation was 9.9 (standard deviation 0.7). LIMITATIONS: The approach to sedation was not randomized. CONCLUSIONS: Higher American Society of Anesthesiologists class and body mass index are associated with an increased rate of cardiac and respiratory events during ERCP. Cardiac and respiratory events are generally minor, and MAC can be considered a safe option for most ERCP patients. Despite the frequency of minor sedation related events, procedure interruption or premature termination was rare in the setting of anesthesiologist-administered sedation. PMID- 21316671 TI - The FIGO classification of causes of abnormal uterine bleeding: Malcolm G. Munro, Hilary O.D. Crithcley, Ian S. Fraser, for the FIGO Working Group on Menstrual Disorders. PMID- 21316670 TI - Is MRCP equivalent to ERCP for diagnosing biliary obstruction in orthotopic liver transplant recipients? A meta-analysis. AB - BACKGROUND: Biliary complications are the second leading cause of morbidity and mortality in orthotopic liver transplant (OLT) recipients. Endoscopic retrograde cholangiography (ERC) is considered the diagnostic criterion standard for post orthotopic liver transplantation biliary obstruction, but incurs significant risks. OBJECTIVE: To determine the diagnostic accuracy of MRCP for biliary obstruction in OLT patients. DESIGN: A systematic literature search identified studies primarily examining the utility of MRCP in detecting post-orthotopic liver transplantation biliary obstruction. A meta-analysis was then performed according to the Quality of Reporting Meta-Analyses statement. SETTING: Meta analysis of 9 studies originally performed at major transplantation centers. PATIENTS: A total of 382 OLT patients with clinical suspicion of biliary obstruction. INTERVENTIONS: MRCP and ERCP or clinical follow-up. MAIN OUTCOME MEASUREMENTS: Sensitivity and specificity of MRCP for diagnosis of biliary obstruction. RESULTS: The composite sensitivity and specificity were 0.96 (95% CI, 0.92-0.98) and 0.94 (95% CI, 0.90-0.97), respectively. The positive and negative likelihood ratios were 17 (95% CI, 9.4-29.6) and 0.04 (95% CI, 0.02 0.08), respectively. LIMITATIONS: All but 1 included study had significant design flaws that may have falsely increased the reported diagnostic accuracy. CONCLUSIONS: The high sensitivity and specificity demonstrated in this meta analysis suggest that MRCP is a promising test for diagnosing biliary obstruction in patients who have undergone liver transplantation. However, given the significant design flaws in most of the component studies, additional high quality data are necessary before unequivocally recommending MRCP in this setting. PMID- 21316672 TI - Nurse prescribing for inpatient pain in the United Kingdom: a national questionnaire survey. AB - BACKGROUND: Nurses make a valuable contribution to pain services and have the potential to improve the safety and effectiveness of pain management. A recent addition to the role of the specialist pain nurse in the United Kingdom has been the introduction of prescribing rights, however there is a lack of literature about their role in prescribing pain medication. OBJECTIVE: The aim of this study was to develop a profile of the experience, role and prescribing practice of these nurses. DESIGN: A descriptive questionnaire survey. SETTING: 192 National Health Service public hospital inpatient pain services across the United Kingdom. PARTICIPANTS: 161 qualified nurse prescribers were invited to participate, representing 98% of known nurse prescribers contributing to inpatient pain services. The survey was completed in November 2009 by 137 nurses; a response rate of 85%. RESULTS: Compared with nurse prescribers in the United Kingdom in general, participants were highly qualified and experienced pain specialists. Fifty-six percent had qualified as a prescriber in the past 3 years and 22% reported that plans were underway for more nurses to undertake a nurse prescribing qualification. Although all participants worked in inpatient pain services, 35% also covered chronic pain (outpatient) services and 90% treated more than one pain type. A range of pain medications were prescribed, averaging 19.5 items per week. The role contained a strong educational component and contributed to informing organisational policy on pain management. Prescribing was said to improve nurses' ability to promote evidence-based practice but benefits were limited by legislation on prescribing controlled drugs. CONCLUSIONS: Findings demonstrate that pain nurses are increasingly adopting prescribing as part of their advanced nurse role. This has implications for the development needs of pain nurses in the United Kingdom and the future role development of nurses in other countries. PMID- 21316673 TI - Malnutrition and cognitive impairment among people 60 years of age and above living in regular housing and in special housing in Sweden: a population-based cohort study. AB - BACKGROUND: Malnutrition is a common problem among older people and associated with reduced functional and cognitive ability. Furthermore, malnutrition among people living in special housing, i.e. in nursing homes or sheltered accommodation, appears to be more common than among those living in regular housing, i.e. in their own homes. However, it is still unclear if the relationship between malnutrition and impaired cognitive ability is connected to living arrangement, i.e. if the relationship is stronger among those who live alone compared to those who cohabit in regular housing. OBJECTIVES: The purpose with the present study was to describe the relationship between nutritional status and cognitive ability among people 60 years of age and above in Sweden, with a focus on housing and living arrangement. DESIGN: Population-based cohort study. SETTING AND PARTICIPANTS: The study focused on people living in regular or in special housing and comprised 1,402 randomly selected individuals (60-96 years of age) who lived in one municipality in south-eastern Sweden and participated in SNAC-B (the Swedish study on Aging and Care - Blekinge), 2001-2003. METHODS: Data regarding demography, nutrition and functional and cognitive ability were collected through questionnaires, medical examinations and structured interviews. RESULTS: The relationship was the strongest between cognitive ability and nutritional status among those living in special housing. Regardless of housing and living arrangement, older people with a moderate or severe cognitive impairment risked (OR 2.59-16.00) being malnourished, irrespective of functional ability. CONCLUSION: This study highlights that those with a moderate and severe cognitive impairment suffer a risk of developing malnutrition, irrespective of living and housing arrangement. The findings suggest that nurses in the social service and health care system need to consider changes in weight and nutritional intake as well as the individual needs of older people with cognitive impairment to avoid malnutrition. PMID- 21316674 TI - Cytokines and metabolic syndrome: the perfect storm for arterial aging. PMID- 21316675 TI - Association of haptoglobin genotype and common cardiovascular risk factors with the amount of iron in atherosclerotic carotid plaques. AB - INTRODUCTION: The aim of this study was to evaluate the iron burden of carotid atherosclerotic plaques removed from patients treated for carotid disease and find any relation with haptoglobin genotype and other common cardiovascular risk factors. METHODS: Consecutive patients undergoing carotid endarterectomy were included in the study. All patients had high-grade carotid stenosis (>70%). The clinical characteristics and serum parameters of the study population were recorded and the haptoglobin genotype was determined. The presence of hemosiderin deposits in the plaques was identified using Perl's stain on adjacent serial sections. RESULTS: 70 specimens were processed for histologic examination: 27 plaques from diabetic patients (16 with the Hp 1-1 or 2-1 genotype and 11 with the Hp 2-2 genotype) and 43 plaques from non diabetic patients (20 with the Hp 1 1 or 2-1 genotype and 23 with the Hp 2-2 genotype). In plaques from diabetic patients the density of Perl's iron stain was significantly higher in the Hp 2-2 group compared with that in the Hp 1-1 or 2-1 group (p = 0.008). The correlation and regression analysis of all possible clinical and laboratory predictors of intraplaque iron deposition showed that four factors were independently associated with intraplaque iron deposition: male gender, serum homocysteine, Hp 2-2 genotype and diabetes mellitus treatment. CONCLUSIONS: Male diabetic patients with increased plasma levels of homocysteine and the Hp 2-2 genotype had higher carotid plaque iron deposition. Current evidence and pathophysiological considerations suggest that the increased intraplaque iron deposition may be associated with increased oxidative stress, affecting the stability of the carotid plaque. PMID- 21316676 TI - 12- and 15-lipoxygenases in human carotid atherosclerotic lesions: associations with cerebrovascular symptoms. AB - Lipoxygenase (ALOX) enzymes are implicated in both pro- and anti-atherogenic processes. The aim of this study was to investigate mRNA expression of 12- and 15 lipoxygenases (ALOX12, ALOX12B, ALOX15, ALOX15B) and the atypical ALOXE3 in human carotid atherosclerotic lesions, in relation to cerebrovascular symptoms and risk factors. The Biobank of Karolinska Endarterectomies (BiKE) collection of human carotid plaque tissue and associated clinical data was utilized (n=132). Lesion mRNA levels were analyzed by TaqMan qPCR (n=132) and microarray hybridization (n=77). Of the investigated mRNAs, only ALOX15B (15-LOX-2; epidermis-type 15-LOX) was readily detected in all plaque samples by qPCR, and thus suitable for quantitative statistical evaluation. ALOX12, ALOX12B, ALOX15 and ALOXE3 were detected with lower frequency and at lower levels, or virtually undetected. Microarray analysis confirmed ALOX15B as the most abundant 12- or 15-lipoxygenase mRNA in carotid lesions. Comparing plaques with or without attributable cerebrovascular symptoms (amaurosis fugax, transient ischemic attack, or stroke), ALOX15B mRNA levels were higher in symptomatic than asymptomatic plaques (1.31 [1.11-1.56], n=102; and 0.79 [0.55-1.15], n=30, respectively; p=0.008; mean [95% CI], arbitrary units). Multiple regression analysis confirmed symptomatic/asymptomatic status as a significant determinant of ALOX15B mRNA levels, independently of potentially confounding factors. Immunohistochemical analyses showed abundant ALOX15B expression in macrophage-rich areas of carotid lesions, and lipidomic analyses demonstrated the presence of typical ALOX15B products in plaque tissue. In summary, we observed associations between high ALOX15B expression in carotid lesions and a history of cerebrovascular symptoms. These findings suggest a link between ALOX15B and atherothrombotic events that merits further investigation. PMID- 21316677 TI - Association of serum soluble receptor for advanced glycation end-products with subclinical cerebrovascular disease: the Northern Manhattan Study (NOMAS). AB - OBJECTIVE: Serum levels of the soluble receptor for advanced glycation end products (sRAGE) have been associated with risk of cardiovascular disease. We hypothesized that sRAGE levels are associated with subclinical cerebrovascular disease in an ethnically diverse population. METHODS: Clinically stroke-free participants in the multi-ethnic Northern Manhattan Study (NOMAS) underwent brain MRI to quantify subclinical brain infarcts (SBI) and white matter hyperintensity volume (WMHV) (n = 1102). Serum levels of sRAGE were measured by ELISA. Logistic and multiple linear regression were employed to estimate associations of sRAGE with SBI and WMHV, after adjusting for demographics and vascular risk factors. RESULTS: Median sRAGE levels were significantly lower in Hispanics (891.9 pg/ml; n = 708) and non-Hispanic blacks (757.4 pg/ml; n = 197) than in non-Hispanic whites (1120.5 pg/ml; n = 170), and these differences remained after adjusting for other risk factors. Interactions were observed by race-ethnicity between sRAGE levels and MRI measurements, including for SBI in Hispanics (p = 0.04) and WMHV among blacks (p = 0.03). In Hispanics, increasing sRAGE levels were associated with a lower odds of SBI, with those in the upper sRAGE quartile displaying a 50% lower odds of SBI after adjusting for sociodemographic and vascular risk factors (p = 0.05). Among blacks, those in the upper quartile of sRAGE had a similarly reduced increased risk of SBI (p = 0.06) and greater WMHV (p = 0.04). CONCLUSION: Compared to whites, Hispanics and blacks have significantly lower sRAGE levels, and these levels were associated with more subclinical brain disease. Taken together, these findings suggest sRAGE levels may be significantly influence by ethnicity. Further studies of sRAGE and stroke risk, particularly in minorities, are warranted. PMID- 21316678 TI - Attenuated atherogenesis in apolipoprotein E-deficient mice lacking amyloid precursor protein. AB - OBJECTIVE: Recent evidence suggests that amyloid precursor protein (APP) is overexpressed in atherosclerosis-prone regions of mouse aorta. We therefore investigated in the present study whether APP has a role in the progression and composition of atherosclerotic plaques. METHODS AND RESULTS: Apolipoprotein E deficient (apoE(-/-)) mice were crossbred with animals lacking APP (APP(-/-)). After 16 weeks on a Western-type diet, apoE(-/-) and APP(-/-)/apoE(-/-) mice showed similar cholesterol levels. However, atherosclerotic plaque size was significantly reduced in the distal thoracic aorta (90% reduction) and abdominal aorta (75% reduction) of APP(-/-)/apoE(-/-) mice as compared to apoE(-/-). Plaques at the level of the aortic valves were not different in size, but showed a more stable phenotype in APP(-/-)/apoE(-/-) mice, as indicated by a reduced macrophage content, an increased amount of collagen and a thicker fibrous cap. CONCLUSION: Our findings provide evidence that lack of APP attenuates atherogenesis and leads to plaque stability. PMID- 21316679 TI - Associations between common genetic polymorphisms in the liver X receptor alpha and its target genes with the serum HDL-cholesterol concentration in adolescents of the HELENA Study. AB - OBJECTIVE: Genetic variability in the NR1H3 gene (encoding LXRalpha) and in several of its target genes is associated with serum HDL-cholesterol (HDL-C) concentrations. We sought to assess if these associations could be detected in adolescents. METHODS: Thirty-nine polymorphisms in NR1H3, ABCA1, APOE, CETP, PLTP and LPL were analysed in the HELENA study (n = 1144 European adolescents). RESULTS: The minor alleles of rs11039155 in NR1H3, rs2575879 in ABCA1, rs708272, rs17231506 and rs5882 in CETP and rs328 in LPL were associated with higher serum HDL-C concentrations (p <= 0.0012). The minor alleles of rs12221497 in NR1H3, rs1800978 in ABCA1 and the APOE E4 allele were associated with lower HDL-C concentrations (p <= 0.01). The combined set of associated polymorphisms accounted for ~6.6% of the variance in HDL-C. CONCLUSION: We report for the first time that polymorphisms in NR1H3 and its target genes ABCA1, APOE, CETP and LPL contribute to the genetic variance for HDL-C concentrations in adolescence. PMID- 21316680 TI - (Pro)renin receptors and angiotensin converting enzyme 2/angiotensin-(1-7)/Mas receptor axis in human aortic valve stenosis. AB - BACKGROUND: There is increasing evidence that renin-angiotensin system (RAS) may play a major role in the actively regulated fibrocalcific process in aortic valve stenosis (AS), but the gene expression or function of (pro)renin receptor ((P)RR), prorenin and renin or angiotensin converting enzyme 2(ACE2)/angiotensin (1-7)/Mas receptor axis in calcific aortic valve disease is not known. METHODS AND RESULTS: We characterized expression of (P)RR, ACE2 and Mas receptor as well as renin, prorenin and angiotensin II type 2 (AT(2)) receptors in human aortic valves, and compared normal control valves (n = 11) with valves obtained from patients with aortic regurgitation (AR, n = 14), AR with fibrosis (n = 20) and AS (n = 61). By immunohistochemistry (P)RR positive staining was seen in the valvular endothelial cells of control and in the neovessels of stenotic valves. By RT-PCR, renin mRNA levels were 72% (P = 0.001) and prorenin mRNA levels 64% lower (P = 0.002) in stenotic aortic valves compared to control valves. ACE2, Mas receptor and AT(2)-receptor mRNA levels were 69% (P < 0.001), 58% (P = 0.008) and 75% (P = 0.001) lower, respectively, in stenotic valves. ACE2 positive staining, existing to lesser extent in stenotic aortic valves, was localized mainly to stromal area in spongiosa layer in control valves. CONCLUSIONS: (P)RR, prorenin and renin are expressed in human aortic valves. We also report for the first time expression of ACE2/angiotensin-(1-7)/-Mas receptor axis in human aortic valve cusps. The downregulation of ACE2/angiotensin-(1-7)/-Mas receptor axis as well as AT(2)-receptors may promote fibrosis, proliferation and inflammation in patients with AS. PMID- 21316681 TI - Dependence of nanoscale friction and adhesion properties of articular cartilage on contact load. AB - Boundary lubrication of articular cartilage by conformal, molecularly thin films reduces friction and adhesion between asperities at the cartilage-cartilage contact interface when the contact conditions are not conducive to fluid film lubrication. In this study, the nanoscale friction and adhesion properties of articular cartilage from typical load-bearing and non-load-bearing joint regions were studied in the boundary lubrication regime under a range of physiological contact pressures using an atomic force microscope (AFM). Adhesion of load bearing cartilage was found to be much lower than that of non-load-bearing cartilage. In addition, load-bearing cartilage demonstrated steady and low friction coefficient through the entire load range examined, whereas non-load bearing cartilage showed higher friction coefficient that decreased nonlinearly with increasing normal load. AFM imaging and roughness calculations indicated that the above trends in the nanotribological properties of cartilage are not due to topographical (roughness) differences. However, immunohistochemistry revealed consistently higher surface concentration of boundary lubricant at load-bearing joint regions. The results of this study suggest that under contact conditions leading to joint starvation from fluid lubrication, the higher content of boundary lubricant at load-bearing cartilage sites preserves synovial joint function by minimizing adhesion and wear at asperity microcontacts, which are precursors for tissue degeneration. PMID- 21316682 TI - An elasto-hydrodynamical model of friction for the locomotion of Caenorhabditis elegans. AB - Caenorhabditis elegans (C. elegans) is one of the most studied organisms by biologists. Composed of around one thousand cells, easy to culture and to modify genetically, it is a good model system to address fundamental physiological questions and in particular to investigate neuromuscular processes. Many C. elegans mutants can be distinguished by their locomotion phenotype and it then important to understand the biomechanics of their locomotion and in particular the mechanics of their undulating crawling motion on agar aqueous gels where they are commonly grown and observed. In this article, we present a mechanical model of the friction of the worms on their substrate where we have included capillarity (which pins the worm of the gel), the hydrodynamics of the lubrication film (between worm and gel) and the substrate/body elasticity. We determine the ratio of the transverse to longitudinal friction coefficients of the worm body on the culture gel as a function of a control parameter which describes the relative role of the deformation of the gel and the viscous dissipation in the lubrication film. Experimentally this ratio is - for soft gels - larger than the maximal value predicted by our model (this maximum is equal to 2, the value for an infinite cylinder in bulk liquid) and we propose to include the plasticity of the gel (i.e. the dissipation of the deformation of the gel) for a better description of the worm/gel interaction. PMID- 21316683 TI - The ventilation distribution of helium-oxygen mixtures and the role of inertial losses in the presence of heterogeneous airway obstructions. AB - The regional distribution of inhaled gas within the lung is affected in part by normal variations in airway geometry or by obstructions resulting from disease. In the present work, the effects of heterogeneous airway obstructions on the distribution of air and helium-oxygen were examined using an in vitro model, the two compartments of a dual adult test lung. Breathing helium-oxygen resulted in a consistently more uniform distribution, with the gas volume delivered to a severely obstructed compartment increased by almost 80%. An engineering approach to pipe flow was used to analyze the test lung and was extrapolated to a human lung model to show that the in vitro experimental parameters are relevant to the observed in vivo conditions. The engineering analysis also showed that helium oxygen can decrease the relative weight of the flow resistance due to obstructions if they are inertial in nature (i.e., density dependent) due to either turbulence or laminar convective losses. PMID- 21316684 TI - A new method research for determination of natural pigment crocin yellow in foods by solid-phase extraction ultrahigh pressure liquid chromatography. AB - Crocin yellow was determined in soft drinks, sausages and sauces by ultra performance liquid chromatography coupled with ultraviolet detector and analyzed within 5 min using a short analytical column ACQUITY UPLC HSS T3 2.1 x 100 mm 1.8 MUm) with gradient elution. An innovative pretreatment method based on homemade macroporous resin solid-phase extraction (SPE) column was established. The SPE column packed with macroporous resins could simplify the sample preparation of multi-matrices and be reused by regeneration steps. The recoveries of crocin yellow added to soft drinks, sausages and sauces at three levels ranged from 81.3% to 106.2%, and relative standard deviations (RSDs) were within 8.8%. The limits of quantitation of soft drinks, sausages and sauces were 0.5 mg/kg, 5 mg/kg and 5 mg/kg, respectively. PMID- 21316685 TI - Prediction of the physicochemical properties of gasoline by comprehensive two dimensional gas chromatography and multivariate data processing. AB - The estimation of physicochemical parameters such as distillation points and relative densities still plays an important role in the quality control of gasoline and similar fuels. Their measurements according to standard ASTM procedures demands specific equipments and are time and work consuming. An alternative method to predict distillation points and relativity density by multivariate analysis of comprehensive two-dimensional gas chromatography with flame ionization detection (GC*GC-FID) data is presented here. Gasoline samples, previously tested according to standard methods, were used to build regression models, which were evaluated by external validation. The models for distillation points were built using variable selection methods, while the model for relativity density was built using the whole chromatograms. The root mean square prediction differences (RMSPD) obtained were 0.85%, 0.48%, 1.07% and 1.71% for 10, 50 and 90% v/v of distillation and for the final point of distillation, respectively. For relative density, the RMSPD was 0.24%. These results suggest that GC*GC-FID combined with multivariate analysis can be used to predict these physicochemical properties of gasoline. PMID- 21316686 TI - Metabolic profiling of Actaea species extracts using high performance liquid chromatography coupled with electrospray ionization time-of-flight mass spectrometry. AB - Despite persistent questions about the safety of black cohosh (Actaea racemosa L., syn. Cimicifuga racemosa L.), its products continue to be one of the most popular botanical supplements in the United States market. Black cohosh products have been associated with cases of liver toxicity, but subsequent evaluation found some products to be adulterated with other related plants from the same genus. US FDA regulations require that black cohosh products be unadulterated, and correct identification of different species of Actaea is a key first step for their good manufacturing practice. We have developed a phytochemical method to distinguish four different groups of Actaea, including: species other than A. racemosa, Asian species, A. racemosa, and North American species other than A. racemosa. Using HPLC-TOF-ESI-MS technique and principal component analysis, we identified 15 chemical markers (1-3, 5-6, 8-10, 12, 16-21). Three marker compounds were unambiguously identified using authentic standards, and 12 marker compounds were tentatively identified by comparison of fragmentation patterns with previously reported data. The presence of these marker compounds is critical for discrimination among the four groups of closely related plants. The use of metabolic profiling to distinguish black cohosh from related species of Actaea has broader implications in the identification of markers to help authenticate other important medicinal plants. PMID- 21316687 TI - Influence of physical properties and operating parameters on hydrodynamics in Centrifugal Partition Chromatography. AB - Besides the selection of a suitable biphasic solvent system the separation efficiency in Centrifugal Partition Chromatography (CPC) is mainly influenced by the hydrodynamics in the chambers. The flow pattern, the stationary phase retention and the interfacial area for mass transfer strongly depend on physical properties of the solvent system and operating parameters. In order to measure these parameters we visualized the hydrodynamics in a FCPC-chamber for five different solvent systems with an optical measurement system and calculated the stationary phase retention, interfacial area and the distribution of mobile phase thickness in the chamber. Although inclined chambers were used we found that the Coriolis force always deflected the mobile phase towards the chamber wall reducing the interfacial area. This effect increased for systems with low density difference. We also have shown that the stability of phase systems (stationary phase retention) and its tendency to disperse increased for smaller values of the ratio of interfacial tension and density difference. But also the viscosity ratio and the flow pattern itself had a significant effect on retention and dispersion of the mobile phase. As a result operating parameters should be chosen carefully with respect to physical properties for a CPC system. In order to reduce the effect of the Coriolis force CPC devices with greater rotor radius are desirable. PMID- 21316688 TI - Affinity capillary electrophoresis and density functional theory applied to binding constant determination and structure elucidation of hexaarylbenzene-based receptor complex with ammonium cation. AB - Affinity capillary electrophoresis (ACE) and quantum mechanical density functional theory (DFT) calculations have been employed for the investigation of noncovalent interactions between hexaarylbenzene-based receptor (R) and ammonium cation NH(4)(+). Firstly, by means of ACE, the binding constant of the NH(4)R(+) complex in methanol was estimated from the dependence of the effective electrophoretic mobility of the receptor R (in advance corrected by our earlier developed procedure to a reference temperature of 25 degrees C) on the concentration of ammonium ion in the background electrolyte using non-linear regression analysis. The logarithmic form of the apparent binding (stability) constant of NH(4)R(+) complex in the methanolic background electrolyte (25 mM Tris, 50 mM chloroacetate, pH(MeOH) 7.8) was evaluated as log K(NH(4)R) = 4.03 +/ 0.15. Secondly, the structural characteristics of NH(4)R(+) complex were determined by DFT calculations. PMID- 21316689 TI - A new approach based on a combination of direct and headspace cold-fiber solid phase microextraction modes in the same procedure for the determination of polycyclic aromatic hydrocarbons and phthalate esters in soil samples. AB - This study describes a new approach to cold-fiber solid-phase microextraction (CF SPME) based on a combination of different extraction modes in the same extraction procedure. Also, the high quantity of water required to facilitate both the desorption of analytes from the matrix and their transport to the fiber coating is reported. The extraction mode was changed from the direct to the headspace mode in a single extraction while manipulating the extraction times and coating temperature to improve the extraction of compounds with different volatilities. Compounds with low volatility were better extracted in the direct mode, while the headspace mode was more appropriate for volatile compounds. Polycyclic aromatic hydrocarbons (PAHs) and phthalic acid esters (PEs) in sand or soil samples were used as model compounds and matrices in this study. The optimized conditions were: sample pH in the range of 4-7, addition of 12 mL of 194 g L(-1) aqueous NaCl solution in a 15 mL vial, and 80 min total extraction time with a sample temperature of 90 degrees C (50 min in direct mode with coating at 90 degrees C followed by 30 min in headspace mode with coating at 30 degrees C). The proposed procedure was compared with conventional CF-SPME (with and without addition of water) and was found to be more effective for all the analytes, since it is capable of extracting both heavier and lighter compounds from soil samples in a single extraction procedure. The use of an excess of water and a combination of extraction modes in the same CF-SPME procedure are the main factors responsible for this enhancement. The proposed method was applied to the extraction of PAHs and PEs in spiked soil samples and excellent results were obtained for most of the compounds evaluated. PMID- 21316690 TI - Environmental analysis of chlorinated and brominated polycyclic aromatic hydrocarbons by comprehensive two-dimensional gas chromatography coupled to high resolution time-of-flight mass spectrometry. AB - A method for the analysis of chlorinated and brominated polycyclic aromatic hydrocarbon (Cl-/Br-PAHs) congeners in environmental samples, such as a soil extract, by comprehensive two-dimensional gas chromatography coupled to a high resolution time-of-flight mass spectrometry (GC*GC-HRTOF-MS) is described. The GC*GC-HRTOF-MS method allowed highly selective group type analysis in the two dimensional (2D) mass chromatograms with a very narrow mass window (e.g. 0.02Da), accurate mass measurements for the full mass range (m/z 35-600) in GC*GC mode, and the calculation of the elemental composition for the detected Cl-/Br-PAH congeners in the real-world sample. Thirty Cl-/Br-PAHs including higher chlorinated 10 PAHs (e.g. penta, hexa and hepta substitution) and ClBr-PAHs (without analytical standards) were identified with high probability in the soil extract. To our knowledge, highly chlorinated PAHs, such as C(14)H(3)Cl(7) and C(16)H(3)Cl(7), and ClBr-PAHs, such as C(14)H(7)Cl(2)Br and C(16)H(8)ClBr, were found in the environmental samples for the first time. Other organohalogen compounds; e.g. polychlorinated biphenyls (PCBs), polychlorinated naphthalenes (PCNs), and polychlorinated dibenzofurans (PCDFs) were also detected. This technique provides exhaustive analysis and powerful identification for the unknown and unconfirmed Cl-/Br-PAH congeners in environmental samples. PMID- 21316691 TI - Analysis of biodiesel conversion using thin layer chromatography and nonlinear calibration curves. AB - Biodiesel (BD) is a fuel produced by the (trans)esterification reaction between the components of vegetable oil (or animal fat) and an alcohol. The presence of several substrates complicates analytical separation of the mixture, yet understanding of the complex reaction kinetics requires acquisition of a large body of data. The two well-established methods of gas chromatography (GC) and HPLC are time consuming and expensive when analyzing multiple samples. Additionally, it is not always possible to record all the reactants on one elution profile. We examined applicability of thin layer chromatography (TLC) for this purpose, where the detection was based on either flame ionization detector (FID) or a modified staining procedure. The suggested staining method gave no background and appeared well suited for quantitative analysis. The relevant calibrations are presented, and the general principles of analysis of nonlinear responses are discussed. Several experimental samples were produced by enzymatic conversion of rapeseed oil to BD. One reaction step resulted in 85-95% conversion (6h). The second step (after removal of glycerol and water) increased the yield to 97-98%. All components of the mixtures were separated and quantified. Relation of the BD contents measured by TLC and GC gave the values of 1.03+/-0.07 (TLC staining) and 0.95+/-0.04 (TLC-FID), indicating applicability of the TLC-methods. PMID- 21316692 TI - Unexpected differences in the behavior of ovotransferrin at the air-water interface at pH 6.5 and 8.0. AB - Adsorption of purified apo-ovotransferrin at the air-water interface was studied by ellipsometry, surface tension, polarization-modulation infrared reflection absorption spectroscopy (PM-IRRAS), and shear elastic constant measurements. No significant difference was observed between pH 6.5 and 8.0 as regards the final value of surface concentration and surface pressure. However at low concentration, a weak barrier to adsorption is evidenced at pH 6.5 and confirmed by PM-IRRAS measurements. At a pH where the protein net charge is negative (pH 8.0), the behavior of ovotransferrin at the air-water interface is more influenced by charge effects rather than bulk concentration effects. At this pH, the interface exhibits a low shear elastic constant and a spectral signature not usual for globular proteins. PMID- 21316693 TI - Influence of surface conductivity on the apparent zeta potential of TiO2 nanoparticles. AB - Zeta potential is a physico-chemical parameter of particular importance in describing ion adsorption and electrostatic interactions between charged particles. Nevertheless, this fundamental parameter is ill-constrained, because its experimental interpretation is complex, particularly for very small and charged TiO(2) nanoparticles. The excess of electrical charge at the interface is responsible for surface conductance, which can significantly lower the electrophoretic measurements, and hence the apparent zeta potential. Consequently, the intrinsic zeta potential can have a larger amplitude, even in the case of simple 1:1 electrolytes like NaCl and KCl. Surface conductance of TiO(2) nanoparticles immersed in a NaCl solution is estimated using a surface complexation model, and this parameter and particle size are incorporated into Henry's model in order to determine a constrained value of the zeta potential from electrophoresis. Interior conductivity of the agglomerates is calculated using a differential self-consistent model. The amplitude of estimated zeta potential is greater than that derived from the von Smoluchowski equation and corresponds to the electric potential at the outer Helmholtz plane calculated by our surface complexation model. Consequently, the shear plane may be located close to the OHP, contradicting the assumption of the presence of a stagnant diffuse layer at the TiO(2)/water interface. PMID- 21316694 TI - Crystallization of calcium sulfate on polymeric surfaces. AB - Surface crystallization of calcium sulfate dihydrate (gypsum) on a series of polymeric surfaces was studied using a quartz microbalance system. Polyelectrolyte multilayer films (positively and negatively charged surfaces) were formed on the quartz crystal microbalance (QCM) sensors utilizing a layer-by layer spin-assembly method. The kinetics of gypsum surface crystallization was quantified in terms of the evolution of gypsum mineral scale on the different surfaces. For comparison mineral scaling was also evaluated on silica and polyamide surfaces. For surfaces of the same charge polarity (+/-), the mass density of gypsum scale was lower (PSS 100 MUM and PO4 > 1 MUM) resulted in high chl a and BB, whereas nutrient-depleted offshore waters (DIN < 5 MUM and PO4 < 0.5 MUM) had low biomass. Temperature (> 26 degrees C) was not the controlling factor of BA. BB was significantly correlated with chl a biomass both in PRE and NSCS. The bacteria to phytoplankton biomass (BB/PB) ratio increased clearly along the gradient from near-shore PRE (0.15) to offshore CSNP (0.93) and deep OP (2.75), indicating the important role of small cells in the open ocean compared to estuarine and coastal zones. PMID- 21316715 TI - [Accidental hypothermia]. AB - Accidental hypothermia is an infrequent and under-diagnosed pathology, which causes fatalities every year. Its management requires thermometers to measure core temperature. An esophageal probe may be used in a hospital situation, although in moderate hypothermia victims epitympanic measurement is sufficient. Initial management involves advance life support and body rewarming. Vigorous movements can trigger arrhythmia which does not use to respond to medication or defibrillation until the body reaches 30 degrees C. External, passive rewarming is the method of choice for mild hypothermia and a supplementary method for moderate or severe hypothermia. Active external rewarming is indicated for moderate or severe hypothermia or mild hypothermia that has not responded to passive rewarming. Active internal rewarming is indicated for hemodynamically stable patients suffering moderate or severe hypothermia. Patients with severe hypothermia, cardiac arrest or with a potassium level below 12 mmol/l may require cardiopulmonary bypass treatment. PMID- 21316716 TI - [Efficacy of screening for lung cancer. Systematic review]. PMID- 21316717 TI - [Advanced glycation end-products: new markers of renal dysfunction in patients with chronic heart failure]. AB - BACKGROUND AND OBJECTIVES: Advanced glycation end-products (AGE) are implicated in the physiopathology and prognosis of heart failure (HF) and they accumulate in situations such as kidney failure (KF). Our objective was to analyze the relation between AGE and KF in patients with chronic HF. MATERIALS AND METHODS: 102 consecutive patients of our medical center were included. Clinical and analytical data were obtained, with measurement of glycated haemoglobin, brain natriuretic peptide, cystatin C and fluorescent AGE. Glomerular filtration rate (GFR) was estimated for each patient. RESULTS: 40.2% of patients presented GFR < 60 mL/min/1.73 m(2) and 11.7% had hidden kidney disease (HKD). AGE correlated positively with creatinine (r=0.685, p<0.001) and cystatin C (r=0.682, p<0.001) and negatively with GFR (r=-0.720, p<0.001). Medium value of fluorescent AGE in patients with KF was higher than those without KF (83.4 [3.3] URF vs 56.8 [2.1] URF, p<0.001). With regard to the diagnostic value for HKD, fluorescent AGE presented an area under the ROC curve higher than other parameters for KD such as cystatin C. In the multivariate analysis, fluorescent AGE were an independent biomarker of KD (OR 1.060; 95% CI 1.024-1.097; p=0.001). CONCLUSIONS: AGE act as a biomarker of KD in patients with chronic HF, both diabetics and non diabetics, being better than cystatin C in the detection of HKD. PMID- 21316718 TI - Identification and functional characterisation of genes encoding the omega-3 polyunsaturated fatty acid biosynthetic pathway from the coccolithophore Emiliania huxleyi. AB - The Prymnesiophyceae coccolithophore Emiliania huxleyi is one of the most abundant alga in our oceans and therefore plays a central role in marine foodwebs. E. huxleyi is notable for the synthesis and accumulation of the omega-3 long chain polyunsaturated fatty acid docosahexaenoic acid (DHA; 22:6Delta(4,7,10,13,16,19), n-3) which is accumulated in fish oils and known to have health-beneficial properties to humans, preventing cardiovascular disease and related pathologies. Here we describe the identification and functional characterisation of the five E. huxleyi genes which direct the synthesis of docosahexaenoic acid in this alga. Surprisingly, E. huxleyi does not use the conventional Delta6-pathway, instead using the alternative Delta8-desaturation route which has previously only been observed in a few unrelated microorganisms. Given that E. huxleyi accumulates significant levels of the Delta6-desaturated fatty acid stearidonic acid (18:4Delta(6,9,12,15), n-3), we infer that the biosynthesis of DHA is likely to be metabolically compartmentalised from the synthesis of stearidonic acid. PMID- 21316719 TI - The effect of lemongrass oil and its major components on clinical isolate mastitis pathogens and their mechanisms of action on Staphylococcus aureus DMST 4745. AB - The aims of this study were to investigate the antibacterial activity of lemongrass oil (LG) and its major components which were citral, geraniol and myrcene, against four strains of clinically isolated bovine mastitis pathogens, including Staphylococcus aureus, Streptococcus agalactiae, Bacillus cereus and Escherichia coli by the broth microdilution method, as well as their activity on S. aureus biofilm formation. Attempts to clarify their mechanisms of action by investigation of the effects on intracellular material leakage and morphological changes of S. aureus DMST 4745 were also made. The results demonstrate that S. agalactiae and B. cereus are more susceptible to LG, citral and geraniol than S. aureus and E. coli. Moreover, they also inhibit S. aureus biofilm formation and exhibit effective killing activities on preformed biofilms. The LG appears to have multiple targets in the bacterial cell, depending on concentration used as well as the amount of its components. PMID- 21316720 TI - Analysis of 2735 canine uroliths in Spain and Portugal. A retrospective study: 2004-2006. AB - The objective of the study was to evaluate epidemiological data derived from 2735 canine uroliths received by Hill's Pet Nutrition from Spain and Portugal between January 2004 and December 2006. The results of quantitative analysis from Minnesota Urolith Center (MUC) were compared with that from other countries and interrelations of mineral composition, age, breed, and gender were determined. The most frequent calculus was calcium oxalate (38.1%) followed by struvite (32.9%). Eighty-three breeds plus crossbreeds (25%) were identified. In all of them, but Dalmatians, calcium oxalate and struvite accounted for 71-78%. The mean age of urolith appearance was 7.6 years. There was a significant difference in the frequency of different uroliths composition among the six most common breeds presenting urolithiasis in Spain and Portugal (Yorkshire terrier, Miniature Schnauzer, Cocker Spaniel, Poodle, Shih Tzu and Dalmatian). This is the first report on xanthine urolithiasis found in Spain. Prevalence of cystine calculi was significantly lower (3.2%) than that reported previously in parts of Spain (26%). PMID- 21316721 TI - Serological response of guinea pigs to oily and aqueous inactivated vaccines containing a Brazilian isolate of the Bovine Viral Diarrhea Virus (BVDV). AB - Bovine Viral Diarrhea Virus (BVDV) is widespread in cattle in Brazil and research shows its large antigenic variability. Available vaccines are produced with virus strains isolated in other countries and may not be effective. In this study, inactivated vaccines containing the Brazilian BVDV-Ib IBSP11 isolate were developed and tested on 6 groups of 10 guinea pigs (Cavia porcellus). Animals in groups A and C received an aqueous vaccine (aluminum hydroxide); B and D groups received an oily vaccine (Montanide ISA50); Group E positive-control animals were given an imported commercial vaccine with BVDV-Ia Singer; Group F animals were sham vaccinated (negative control). Groups A, B and E received two doses, and Groups C and D, three, every 21 days. Twelve blood samples were taken, at 21-day intervals over 231 days, and evaluated for antibody titer through virus neutralization (VN), using a homologous strain (IBSP11), and a heterologous strain (BVDV-Ia NADL). Most animals, 42 days following the first dose, seroconverted to both strains and, after the second dose, there was a significant increase of titers in all groups. The oily formulation induced greater response after the third administration. This increase was not observed with the aqueous vaccines, regardless of the virus used in the VN. Antibody decline was more rapid in animals that received aqueous vaccines. The results showed the importance of studying the influence of endemic strains of commercial vaccines, to improve the efficacy of BVD vaccination. Use of the endemic strain in vaccine formulation presented promising results, as well as the use of guinea pigs as a laboratory model. PMID- 21316722 TI - Metabolic correlates of tumour hypoxia in malignant canine mammary carcinoma. AB - Given its importance in human and canine tumour biology, a profound understanding of tumour hypoxia is of paramount importance. Therefore, the aim of this work was to investigate the relationship between tumour hypoxia and the expression of a number of hypoxia-induced proteins that play a role in tumour metabolism. The hypoxia marker pimonidazole was administered to dogs affected by spontaneous mammary carcinoma and compared with immunohistochemical staining for GLUT1 and 3, HK 2 and CA IX. A statistically significant correlation was found between pimonidazole staining and GLUT1-expression (R=0.607; p=0.001). These results indicate a strong interaction between tumour hypoxia and tumour metabolism by the induction of proteins essential to maintain a stable tumour microenvironment. PMID- 21316723 TI - Genotyping of Cryptosporidium parvum isolates in bovine population in Kolkata and characterization of new bovine genotypes. AB - Cryptosporidium infection may have adverse effect in health and production potential of cattle herd. The exact profile of Cryptosporidium infection in bovine population of India in general, particularly from Kolkata is scarce. We here report systematic investigation of clinical and genetic profiling of promiscuous Cryptosporidium infection in selected representative cattle farms from Kolkata as well as some surrounding local areas. The current study was conducted in the period of October to September, 2000-2001 with 149 diarrhoeic and non-diarrhoeic cattle of different age groups from two Government cattle farms, Harringhata Cattle Unit and Kalyani State Livestock Farm and animals raised by local farmers. Among these 149 samples, diarrhoea was recorded in 79 cases (53%) and non-diarrhoeic in 70 (46.9%). Out of 149 faecal samples screened microscopically, 32.9% from diarrhoeic faecal samples and 7.1% from healthy faecal samples revealed the presence of oocysts. Cryptosporidium genus was confirmed by DNA typing with nested PCR. The PCR-RFLP analysis was carried out for genotype identification. In course of PCR-RFLP, unique band patterns were obtained in two of our samples. The unusual RFLP products were characterized by DNA sequencing and homology analysis with other reported variants. This is the first report of identification and characterization of such a variant from the area of present investigation. Further study will be required to understand the phylogenetic origin and functional significance in virulence and morbidity of this genotype. PMID- 21316724 TI - Single artery reconstruction in left liver transplantation. AB - BACKGROUND: A left liver graft in living donor liver transplantation often has 2 arterial stumps. The indication for multiple arterial reconstructions remains controversial. The aim of this retrospective study was to investigate whether single anastomosis of a left liver graft affects the outcome of living donor liver transplantation. METHODS: When a hepatic graft had 2 arterial stumps, the thicker (dominant) stump was reconstructed first. After the initial reconstruction, another reconstruction was performed only if no pulsating flow was observed from the remnant stump. A total of 134 left liver grafts were divided into 3 groups: Group 1 (n = 70), 1 arterial stump on a graft with 1 arterial reconstruction; Group 2 (n = 59), 2 stumps with 1 arterial reconstruction; Group 3 (n = 5), 2 stumps with 2 arterial reconstructions. The incidence of hepatic arterial thrombosis, biliary stenosis, and patient survival was compared between Groups 1 and 2. RESULTS: The incidence of arterial thrombosis and biliary stenosis, and the patient survival curves, were equivalent between Groups 1 and 2. CONCLUSION: When the criteria were satisfied, single arterial reconstruction in a left liver graft with 2 arterial stumps did not affect the patient survival or biliary complications. PMID- 21316725 TI - Bile leakage after hepatobiliary and pancreatic surgery: a definition and grading of severity by the International Study Group of Liver Surgery. AB - BACKGROUND: Despite the potentially severe impact of bile leakage on patients' perioperative and long-term outcome, a commonly used definition of this complication after hepatobiliary and pancreatic operations has not yet been established. The aim of the present article is to propose a uniform definition and severity grading of bile leakage after hepatobiliary and pancreatic operative therapy. METHODS: An international study group of hepatobiliary and pancreatic surgeons was convened. A consensus definition of bile leakage after hepatobiliary and pancreatic operative therapy was developed based on the postoperative course of bilirubin concentrations in patients' serum and drain fluid. RESULTS: After evaluation of the postoperative course of bilirubin levels in the drain fluid of patients who underwent hepatobiliary and pancreatic operations, bile leakage was defined as bilirubin concentration in the drain fluid at least 3 times the serum bilirubin concentration on or after postoperative day 3 or as the need for radiologic or operative intervention resulting from biliary collections or bile peritonitis. Using this criterion severity of bile leakage was classified according to its impact on patients' clinical management. Grade A bile leakage causes no change in patients' clinical management. A Grade B bile leakage requires active therapeutic intervention but is manageable without relaparotomy, whereas in Grade C, bile leakage relaparotomy is required. CONCLUSION: We propose a simple definition and severity grading of bile leakage after hepatobiliary and pancreatic operative therapy. The application of the present proposal will enable a standardized comparison of the results of different clinical trials and may facilitate an objective evaluation of diagnostic and therapeutic modalities in the field of hepatobiliary and pancreatic operative therapy. PMID- 21316727 TI - Involvement of the UL24 protein in herpes simplex virus 1-induced dispersal of B23 and in nuclear egress. AB - UL24 of herpes simplex virus 1 (HSV-1) is widely conserved within the Herpesviridae family. Herein, we tested the hypothesis that UL24, which we have previously shown to induce the redistribution of nucleolin, also affects the localization of the nucleolar protein B23. We found that HSV-1-induced dispersal of B23 was dependent on UL24. The conserved N-terminal portion of UL24 was sufficient to induce the redistribution of B23 in transient transfection assays. Mutational analysis revealed that the endonuclease motif of UL24 was important for B23 dispersal in both transfected and infected cells. Nucleolar protein relocalization during HSV-1 infection was also observed in non-immortalized cells. Analysis of infected cells by electron microscopy revealed a decrease in the ratio of cytoplasmic versus nuclear viral particles in cells infected with a UL24-deficient strain compared to KOS-infected cells. Our results suggest that UL24 promotes nuclear egress of nucleocapsids during HSV-1 infection, possibly though effects on nucleoli. PMID- 21316728 TI - Parameters predictive of Legionella contamination in hot water systems: association with trace elements and heterotrophic plate counts. AB - The contamination of hot water samples with Legionella spp. was studied in relation to temperature, total hardness, trace element concentrations (iron, zinc, manganese, and copper) and heterotrophic plate counts (HPC) at both 22 and 37 degrees C. Factor analysis and receiver operating characteristic (ROC) curves were used to establish the cut-off of water parameters as predictors for Legionella contamination. Legionella spp. was isolated in 194 out of 408 samples (47.5%), with Legionella pneumophila being the most common (92.8%). After multiple logistic regression analysis, the risk for legionellae colonisation was positively associated with Mn levels >6 MUg l(-1), HPC at 22 degrees C >27 CFU l(-1), and negatively with temperature >55 degrees C and Cu levels >50 MUg l( 1). Multiple regression analysis revealed that Legionella spp. counts were positively associated with Mn, HPC at 37 degrees C and Zn and negatively associated with temperature. Only 1 out of the 97 samples (1%) having a Mn concentration, an HPC at 22 degrees C and an HPC at 37 degrees C below the respective median values exhibited a Legionella spp. concentration exceeding 10(4) CFU l(-1)vs. 41 out of the 89 samples (46.1%) with the three parameters above the medians. Our results show a qualitative and quantitative relationship between Legionella spp., the Mn concentration and heterotrophic plate counts in hot water samples from different buildings, suggesting that these parameters should be included in a water safety plan. The role of manganese in biofilm formation and its possible involvement in the mechanisms favouring Legionella survival and growth in water niches should be investigated further. PMID- 21316726 TI - Enhanced proliferation of primary rat type II pneumocytes by Jaagsiekte sheep retrovirus envelope protein. AB - Jaagsiekte sheep retrovirus (JSRV) is the causative agent of a contagious lung cancer in sheep. The envelope protein (Env) is the oncogene, as it can transform cell lines in culture and induce tumors in animals, although the mechanisms for transformation are not yet clear because a system to perform transformation assays in differentiated type II pneumocytes does not exist. In this study we report culture of primary rat type II pneumocytes in conditions that favor prolonged expression of markers for type II pneumocytes. Env-expressing cultures formed more colonies that were larger in size and were viable for longer periods of time compared to vector control samples. The cells that remained in culture longer were confirmed to be derived from type II pneumocytes because they expressed surfactant protein C, cytokeratin, displayed alkaline phosphatase activity and were positive for Nile red. This system will be useful to study JSRV Env in the targets of transformation. PMID- 21316729 TI - Design and fabrication of an innovative and environmental friendly adsorbent for boron removal. AB - Boron can pose adverse effects on human beings and plants species. It exists in various water environments and is difficult to be removed by conventional technologies. In this study, an efficient and environmental friendly sorbent was fabricated by the functionalization of a natural biopolymer, chitosan, with N methylglucamine through atom transfer radical polymerization. The SEM and BET studies revealed that the sorbent had a rougher surface and a more porous structure than the chitosan. At the optimum neutral pH, the maximum sorption capacity was as high as 3.25 mmol/g, much higher than the commercial boron selective resins (e.g., Amberlite IRA-743) and many other synthesized sorbents. Almost 90% of boron sorption occurred within 8 h and the equilibrium was established in 12 h, which was well described by an intraparticle surface diffusion model. The presence of sodium chloride and sodium nitrate had no effect on the boron removal. The boron concentration in seawater could be reduced to less than 0.5 mg/L from 4.8 mg/L when a sorbent dosage of 1.2 g/L was used. It was therefore concluded that the sorption technology from this study could be promising for boron removal from aqueous solutions. PMID- 21316730 TI - Natural variability and correlations in the metabolic profile of healthy Eisenia fetida earthworms observed using 1H NMR metabolomics. AB - 1H NMR metabolomics can be used to assess the sub-lethal toxicity of contaminants to earthworms by identifying alterations in the metabolic profiles of contaminant exposed earthworms in contrast to those of healthy (control) individuals. In support of this method this study sought to better characterize the baseline metabolic profile of healthy, mature earthworms of the species, Eisenia fetida, which is recommended for both acute and sub-lethal toxicity testing for soil contaminants. Profiles of D(2)O-buffer extracted metabolites were determined using (1)H NMR spectroscopy and both inter-individual metabolic variability and pair-wise metabolic correlations were assessed. The control earthworm extracts exhibited low overall inter-individual metabolic variability, with a spectrum wide median relative standard deviation (%RSD=standard deviation/mean*100) of 14%, which suggests that the metabolic profile of E. fetida earthworms is well controlled in laboratory conditions and supports further use of this organism in environmental metabolomics research. In addition, strong positive correlations were detected between the levels of maltose, betaine, glycine, and glutamate as well as between the levels of lactate, valine, leucine, alanine, lysine, tyrosine, and phenylalanine which had not previously been reported. Since comparison of pair-wise metabolic correlations between control and treated organisms can reveal changes in the underlying pattern of biochemical relationships between the metabolites, identification of these significant metabolic correlations in control earthworms provides an additional characteristic that may be applied to delineate between control and treated earthworms in future NMR-based metabolomic studies. PMID- 21316731 TI - Fenton based remediation of polycyclic aromatic hydrocarbons-contaminated soils. AB - This paper aims to review the applications of Fenton based treatments specifically for polycyclic aromatic hydrocarbons-contaminated soils. An overview of the background and principles of Fenton treatment catalysed by both homogenous (conventional and modified Fenton) and heterogeneous (Fenton-like) catalysts is firstly presented. Laboratory and field soil remediation studies are then discussed in terms of efficiency, kinetics and associated factors. Four main scopes of integrated Fenton treatments, i.e. physical-Fenton, biological-Fenton, electro-Fenton and photo-Fenton are also reviewed in this paper. For each of these integrated remediation technologies, the theoretical background and mechanisms are detailed alongside with achievable removal efficiencies for polycyclic aromatic hydrocarbons in contaminated soils compared to sole Fenton treatment. Finally, the environmental impacts of Fenton based soil treatments are documented and discussed. PMID- 21316732 TI - Significance of metal exchange in EDDS-flushing column experiments. AB - Chelating agents have been widely studied for extracting heavy metals from contaminated soils, and the effectiveness of EDDS ([S,S]-ethylene-diamine disuccinic acid) has aroused extensive attention because of its biodegradability in the natural environment. However, in the course of EDDS-flushing, metal exchange of newly extracted metal-EDDS complexes with other sorbed metals and mineral cations may result in metal re-adsorption on the soil surfaces. Therefore, this study investigated the relative significance of metal exchange under different travel distances of chelant complexes, characteristics of soil contamination, and solution pH in the column experiments. As a result of metal exchange, the elution of Zn and Pb was retarded and the cumulative extraction was lower than those of Ni and Cu, especially over a longer travel distance. Compared with the field-contaminated soils, the effects of metal exchange were even more substantial in the artificially contaminated soil because of a greater amount of extractable metals and a larger proportion of weakly bound fractions. By contrast, metal exchange was insignificant at pH 8, probably due to less adsorption of metal-EDDS complexes. These findings highlight the conditions under which metal exchange of metal-EDDS complexes and the resulting impacts are more significant during EDDS-flushing. PMID- 21316733 TI - Photophysical and photochemical properties of the pharmaceutical compound salbutamol in aqueous solutions. AB - Salbutamol is a potent beta(2)-adrenergic receptor agonist widely used in the treatment of bronchial asthma and chronic obstructive pulmonary disease. An increasing number of studies have detected salbutamol in natural water systems worldwide. Studies have shown that sunlight degrades salbutamol resulting in the formation of products; some showing higher toxicity to bacteria Vibrio fischeri than the parent compound. In this contribution, steady-state absorption and emission techniques, high-performance liquid chromatography, and transient absorption spectroscopy are used to investigate the photochemistry of salbutamol in aqueous buffer solutions at controlled pH values. Ground- and excited-state calculations that include solvent effects are performed to guide the interpretation of the experimental results. Salbutamol is sensitive to UVB light absorption in the pH range from 3 to 12, forming products that absorb light at longer wavelengths than the parent compound. Quantum yields of degradation reveal that the deprotonated species is 10-fold more photo-active than the protonated species. In line with this result, the fluorescence quantum yield of the protonated species is more than an order of magnitude higher than that of the deprotonated species. Transient absorption spectroscopy shows that population of the triplet state occurs with a rate constant of 7.1*10(8)s(-1) in the protonated species, while a rate constant of 1.7*10(10)s(-1) is measured for the deprotonated species. While degradation of the deprotonated species is not affected by the presence of molecular oxygen, a twofold increase in the photodegradation yield of the protonated species in air-saturated conditions is observed. PMID- 21316734 TI - The adsorption of short single-stranded DNA oligomers to mineral surfaces. AB - We studied the adsorption of short single-stranded deoxyribonucleic acid (ssDNA) oligomers, of approximately 30 nucleotides (nt) in length, of varying sequence, adenine+guanine+cytosine (AGC) content, and propensity to form secondary structure, to equal surface area samples of olivine, pyrite, calcite, hematite, and rutile in 0.1M NaCl, 0.05M pH 8.1 KHCO(3) buffer. Although the mineral surfaces have widely varying points of zero charge, under these conditions they show remarkably similar adsorption of ssDNA regardless of oligomer characteristics. Mineral surfaces appear to accommodate ssDNA comparably, or ssDNA oligomers of this length are able to find binding sites of comparable strength and density due to their flexibility, despite the disparate surface properties of the different minerals. This may partially be due charge shielding by the ionic strength of the solutions tested, which are typical of many natural environments. These results may have some bearing on the adsorption and accumulation of biologically derived nucleic acids in sediments as well as the abiotic synthesis of nucleic acids before the origin of life. PMID- 21316735 TI - Metacarpal head biomechanics: a comparative backscattered electron image analysis of trabecular bone mineral density in Pan troglodytes, Pongo pygmaeus, and Homo sapiens. AB - Great apes and humans use their hands in fundamentally different ways, but little is known about joint biomechanics and internal bone variation. This study examines the distribution of mineral density in the third metacarpal heads in three hominoid species that differ in their habitual joint postures and loading histories. We test the hypothesis that micro-architectural properties relating to bone mineral density reflect habitual joint use. The third metacarpal heads of Pan troglodytes, Pongo pygmaeus, and Homo sapiens were sectioned in a sagittal plane and imaged using backscattered electron microscopy (BSE-SEM). For each individual, 72 areas of subarticular cortical (subchondral) and trabecular bone were sampled from within 12 consecutive regions of the BSE-SEM images. In each area, gray levels (representing relative mineralization density) were quantified. Results show that chimpanzee, orangutan, and human metacarpal III heads have different gray level distributions. Weighted mean gray levels (WMGLs) in the chimpanzee showed a distinct pattern in which the 'knuckle-walking' regions (dorsal) and 'climbing' regions (palmar) are less mineralized, interpreted to reflect elevated remodeling rates, than the distal regions. Pongo pygmaeus exhibited the lowest WMGLs in the distal region, suggesting elevated remodeling rates in this region, which is loaded during hook grip hand postures associated with suspension and climbing. Differences among regions within metacarpal heads of the chimpanzee and orangutan specimens are significant (Kruskal-Wallis, p < 0.001). In humans, whose hands are used for manipulation as opposed to locomotion, mineralization density is much more uniform throughout the metacarpal head. WMGLs were significantly (p < 0.05) lower in subchondral compared to trabecular regions in all samples except humans. This micro-architectural approach offers a means of investigating joint loading patterns in primates and shows significant differences in metacarpal joint biomechanics among great apes and humans. PMID- 21316736 TI - Impacts of rainfall events on runoff water quality in an agricultural environment in temperate areas. AB - Since a rise in dissolved organic carbon (DOC) concentrations has been observed for surface waters at least over the last two decades, a change in weather conditions (temperature and precipitations) has been proposed to partly explain this increase. While the majority of DOC delivery from soils to stream occurs during rainfall events, a better understanding of the rainfall influence on DOC release is needed. This study has been conducted in Brittany, western France, on agricultural experimental plots receiving either cattle manure (CM) or pig slurry (PS) as fertilizers in accordance with local practices. Each plot was instrumented with a flow meter and an auto sampler for runoff measurements. The results show that export of DOC during high intensity events is higher than during lower intensity rainfalls. Fertilization has a noticeable impact on total organic carbon (TOC) fluxes with an increase of five to seven folds for PS and CM respectively. If TOC shock load occurs shortly after the rainfall peak, DOC maximum appears with the first flush of the event. Organic carbon (OC) is mainly under colloidal (41.2%) and soluble (23.9%) forms during the first stage of a rainfall event and a control of rainfall intensity on OC colloidal transport is suggested. These findings highlight the potential risk of receiving water quality degradation due to the increase of heavier rainfall events with climate change in temperate areas. PMID- 21316737 TI - Biodiesel emissions profile in modern diesel vehicles. Part 1: Effect of biodiesel origin on the criteria emissions. AB - This paper presents the regulated emissions profile of a Euro 4 compliant common rail passenger car, fuelled with low concentration biodiesel blends. Four biodiesels of different origin and quality blended with a typical automotive diesel fuel at proportions of 10, 20, and 30% v/v. Emission and fuel consumption measurements were conducted on a chassis dynamometer with constant volume sampling (CVS) technique, over the New European Driving Cycle (NEDC) and the real traffic-based Artemis driving cycles. Limited effects were observed on CO(2) emissions, while fuel consumption marginally increased with biodiesel. PM, HC and CO emissions improved with the addition of biodiesel, with some exceptions. Some increases with biodiesel were observed over the NEDC, as a consequence of biodiesel characteristics and engine conditions. NO(x) emissions were increased with the use of biodiesel blends and positively correlated with fuel unsaturation levels. PMID- 21316738 TI - Sediment yield as a desertification risk indicator. AB - Soil erosion is often regarded as one of the main processes of desertification. This has led to the use of various desertification indicators that are related to soil erosion. Most of these indicators focus, however, on small spatial units, while little attention has been given to the amount of sediment exported at the catchment scale. Such a small spatial unit approach neglects the transfer of sediment through catchments as well as the scale-dependency of erosion processes. Furthermore, this approach does not consider important off-site impacts of soil erosion, such as sediment deposition in reservoirs, flooding as well as ecological impacts. This study aims to illustrate the importance of also considering catchment sediment yield (SY, t km(-2) y(-1)) in desertification assessment studies. Based on recently established databases of SY and soil loss rates in Europe and examples from previous studies, we illustrate that soil erosion rates at the plot scale are not representative for catchment SY, as they are often several orders of magnitude smaller. Also, the erosion response of catchments to changes in land use or climate often differs strongly from responses to those changes at the plot scale. We further discuss several of the impacts of SY and their link with desertification: i.e. the sedimentation of reservoirs, problems related to flooding, catchment hydrology, export of nutrients and ecological implications. Using earlier established criteria we evaluate the potential for using catchment SY as a desertification indicator and conclude that this could give an important added value to desertification studies. SY, used in combination with other indicators, allows the identification of other sediment sources than those considered at the plot scale and can reflect the results of desertification processes over longer time periods than periods over which assessments at the plot scale have been made. We argue therefore, that SY is a strong complementary indicator of desertification providing valuable information on the catchment response to changes in drivers of desertification. PMID- 21316739 TI - Evidences of non-reactive mercury-selenium compounds generated from cultures of Pseudomonas fluorescens. AB - This work was designed to determine chemically inert mercury-selenium (Hg-Se) compounds formed in a culture of Pseudomonas fluorescens exposed to Hg(2+) and Se(IV) (selenite). To isolate these compounds, different digestion methods were studied and sodium dodecyl sulfate (SDS) lysis was selected. The Hg(0) and non reactive Hg were determined in two series of cultures containing 0.0-6.00 MUg L( 1) Se(IV) (0.0-76.0 MUmol L(-1)) in combination with low 5.00 MUg L(-1) (0.025 MUmol L(-1)) or high 100 MUg L(-1) (0.500 MUmol L(-1)) Hg(2+). It was found that Hg(0) formed in the culture decreased with the increase of initial Se(IV), while the non-reactive Hg increased with the Se(IV). In cultures with low initial [Hg(2+)], a median Se(IV) (2.0 MUg L(-1) or 25.3 MUmol L(-1)) resulted in about 70% of the added Hg(2+) sequestered as non-reactive Hg, and in culture with high initial Hg(2+), about 40% was sequestered. P. fluorescens was proved to be indispensible for the formation of the non-reactive Hg-Se compounds. The Hg:Se molar ratio in the non-reactive Hg-Se compounds was close to 1, suggesting the existence of mercuric selenide in cells. Mechanisms for the formation of the non reactive Hg-Se compounds are proposed. PMID- 21316740 TI - Organic matter recycling in a beach environment influenced by sunscreen products and increased inorganic nutrient supply (Sturla, Ligurian Sea, NW Mediterranean). AB - The beaches are sites where the human influence may be strong and the beach ecosystems have often shown a high sensibility to environmental alterations. These zones may be affected by a large series of anthropogenic-derived pressures, such as unbalanced inorganic nutrient input, that may cause anomalous development of primary production, altering the structure of the trophic webs. Furthermore, the utilisation of cosmetic sunscreen products is reaching unexpected levels, thus assuming a potentially important as well as unknown role in the contamination of marine environments. The present study was planned to test the response of the beach ecosystem to increases in inorganic nutrients (nitrate and phosphate) and to the input of a widely used cosmetic sunscreen product. A short term laboratory experiment was carried out on microsystems consisting of sediments and seawater from the swash zone of a Ligurian city beach (Sturla). The processes related to organic matter (OM) recycling and some microbial food web components (bacteria and micro-autotrophic organisms) were analysed. The multivariate statistical analysis of the results showed that the increase in inorganic nutrients and sunscreen caused only a transient alteration in the OM recycling processes in the seawater. The sedimentary processes, instead, were different in the different systems, although starting from the same condition. In the sediment, surprisingly, an increase in inorganic nutrients did not lead to an increase in the primary biomass nor to significantly higher bacterial abundance, while the sunscreen caused increased OM recycling, especially devoted to protein and lipid mobilisation, supporting a growing bacterial and autotrophic community by reducing the bottom-up pressure. Additional toxicity tests performed on protozoa highlighted that, while the inorganic nutrients seemed to show no effects, sunscreen decreased the protozoan viability, thus likely favouring microautotrophic and bacterial increases by reducing the top-down pressure. PMID- 21316741 TI - Transformation of metals speciation in a combined landfill leachate treatment. AB - Landfill leachate was treated by a combined sequential batch reactor (SBR), coagulation, Fenton oxidation and biological aerated filter (BAF) technology. The metals in treatment process were fractionated into three fractions: particulate and colloidal (size charge filtration), free ion/labile (cation exchange) and non labile fractions. Fifty percent to 66% Cu, Ni, Zn, Mn, Pb and Cd were present as particulate/colloidal matter in raw leachate, whereas Cr was present 94.9% as non labile complexes. The free ion/labile fractions of Ni, Zn, Mg, Mn, Pb and Cd increased significantly after treatment except Cr. Fifty-nine percent to 100% of Al was present mainly as particulate/colloidal matter >0.45 MUm and the remaining portions were predicted as non-labile complexes except in coagulation effluent. The speciation of Fe varied significantly in various individual processes. Visual MINTEQ simulation showed that 95-100% colloidal species for Cu, Cd and Pb were present as metal-humic complexes even with the lower dissolved organic carbon. Optimum agreements for the free ion/labile species were within acidic solution, whereas under-estimated in alkaline effluents. Overestimated particulate/colloidal fraction consisted with the hypothesis that a portion of colloids in fraction <0.45 MUm were considered as dissolved. PMID- 21316742 TI - Homocysteinylated fibrinogen forms disulfide-linked complexes with albumin. AB - We have shown that homocysteinemic rabbits have altered fibrinogen that forms fibrin clots with increased resistance to fibrinolysis. Homocysteine thiolactone is a metabolite of homocysteine (Hcys) that can react with amines and introduce a new sulfhydryl group into proteins. Recent evidence suggests that Hcys thiolactone-lysine adducts form in vivo. We have shown that in vitro reaction of Hcys thiolactone with human fibrinogen (Hcys-fibrinogen) alters fibrinogen function in a manner similar to that in homocysteinemic rabbits. Several naturally-occurring mutations that introduce a new cysteine into fibrinogen are associated with clinical thrombosis due to increased resistance of clots to fibrinolysis. In those cases the new cysteine mediates disulfide formation between the mutant fibrinogen and albumin. We now report that Hcys-fibrinogen similarly forms disulfides with albumin in vitro, specifically through sites in its D-domain. However, fibrin clots formed from Hcys-fibrinogen-albumin show a similarly reduced ability to support plasminogen activation and a similar resistance to fibrinolysis as clots formed from Hcys-fibrinogen. Thus, fibrinogen albumin conjugates may result from N-homocysteinylation of fibrinogen in vivo. However, there is no evidence that conjugation to albumin further impairs fibrinogen function above the defect induced by homocysteinylation of critical lysines. Similar to the utility of glycated hemoglobin as a marker for the deleterious effects of hyperglycemia, the level of fibrinogen-albumin complexes might possibly be a clinically useful marker for the level of homocysteine associated damage in vivo. PMID- 21316743 TI - Thromboxane metabolite excretion during pregnancy--influence of preeclampsia and aspirin treatment. PMID- 21316745 TI - Persistent platelet activation after simultaneous pancreas-kidney transplantation (SPKT) in patients with end-stage renal disease (ESRD) and diabetes type I (DM I). PMID- 21316744 TI - Regulation of coagulation factors during liver regeneration in mice: mechanism of factor VIII elevation in plasma. AB - INTRODUCTIONS: The profiles of coagulation factor production during liver regeneration process remains to be fully elucidated. The present study was aimed to perform a comprehensive analysis whether hepatic gene expression was differentially regulated relative to the secretion of biologically active coagulation factors using a mouse model of liver regeneration. MATERIALS AND METHODS: Liver regeneration was induced by performing a 2/3 partial hepatectomy (PHx). Plasma samples were assessed for coagulation factor activities (fibrinogen, prothrombin, V, VII, VIII, IX, X, XI, XII, and XIII) and the liver mRNA levels of coagulation, anti-coagulation, and fibrinolytic factors were quantified by real-time RT-PCR during the phase of liver regeneration. RESULTS: At the peak of liver regeneration, the expression levels for all of the genes analyzed were found to be reduced in a time-dependent manner. Consistent with the gene expression levels, plasma activities of all coagulation factors, except for FVIII, were temporally declined during the same time frame. FVIII paradoxically demonstrated a significant increase (P<0.05) in plasma activities concomitant with the decrease of liver mRNA expression levels. We found that the increase in plasma FVIII activities might be associated with (1) a delay in the inactivation of plasma FVIII caused by increased VWF in plasma and decreased FVIII clearance in the liver, (2) the rapid release of FVIII from the storage sites, and (3) the alteration of intracellular trafficking pathway of FVIII. CONCLUSIONS: The present study demonstrated that the process of liver regeneration involves a general reduction for many of the coagulation cascade proteins, but there are paradoxical increases in plasma levels of FVIII and VWF. PMID- 21316746 TI - Simultaneous thrombin and plasmin generation capacities in normal and abnormal states of coagulation and fibrinolysis in children and adults. AB - INTRODUCTION: Thrombin and plasmin are the key enzymes involved in coagulation and fibrinolysis, respectively. Plasma coagulative and fibrinolytic potentials in normal children and adults, and in representative pathologically altered hemostatic states, were evaluated via simultaneous assessment of thrombin and plasmin generation. MATERIALS AND METHODS: An assay of Simultaneous Thrombin and Plasmin generation (STP) was developed to measure thrombin and plasmin in plasma using individual fluorometric substrates. Coagulation is initiated with dilute tissue factor, phospholipid, and calcium in platelet-poor plasma; fibrinolysis is accelerated via tissue plasminogen activator (tPA). Abnormal states of hemostasis were investigated. RESULTS: STP assay reproducibility and normal adult and pediatric values for measured and calculated parameters have been established. Onset of both thrombin and plasmin generation was significantly delayed in children relative to adults (p<0.001) and the maximum amplitudes of thrombin and plasmin generation were less in children than adults (p<0.01). No significant differences were measured among pediatric age groups. The most profound impairments in thrombin generation were observed for extrinsic and common pathway factor deficiencies, with the exception of afibrinogenemia. Plasmin generation was severely impaired in deficiencies of fibrinogen and plasminogen as well as with decreased tPA reagent concentration and addition of aminocaproic acid. Plasmin generation was greatly enhanced by alpha-2-antiplasmin deficiency and excess tPA reagent. CONCLUSION: Simultaneous assessment of thrombin and plasmin generation in plasma shows promise for affording an enhanced understanding of overall coagulative and fibrinolytic functions in physiological and pathologically altered states of hemostasis in children and adults. PMID- 21316747 TI - Uterine leiomyosarcomas: tumor size, mitotic index, and biomarkers Ki67, and Bcl 2 identify two groups with different prognosis. AB - BACKGROUND: Prognostic factors for uterine leiomyosarcomas are not well established. Although most tumors are associated with poor prognosis even when apparently confined to the uterus (stage I), some cases that exhibited morphologic features of malignancy had prolonged survival. METHODS: Using tissue microarrays of 84 uterine leiomyosarcomas, we investigated conventional clinico pathologic parameters, including International Federation of Gynecology and Obstetrics (FIGO) stage, together with expression of Ki67, p53, p16, and Bcl-2, attempting to distinguish leiomyosarcomas with different prognosis. The rate of CD163 immunoreactive tumor macrophages was also investigated. RESULTS: Tumor size and mitotic index were significant prognostic factors by univariate (p=0.018 and p=0.003, respectively) and multivariate (p=0.006 and p=0.001) analyses. Of the biomarkers investigated, only Ki67 immunoreaction was significant by univariate analysis and was associated with adverse prognosis (p=0.01). However, combination of tumor size, mitotic index, Ki67, and Bcl-2 worked even better. Using these 4 parameters, unsupervised hierarchical clustering identified 2 groups of tumors with different prognosis (p=0.001): group 1 consisted mostly of smaller leiomyosarcomas (<10cm) with mitotic index <20 MF/10 HPF, negative Ki67, and positive or negative Bcl-2 immunostaining. These tumors were associated with better prognosis. In contrast, group 2 leiomyosarcomas which were mostly>=10cm in diameter had higher mitotic index (>= 20 MF/10 HPF), and were positive for Ki67 and negative for Bcl-2 had worse prognosis. Also, the number of CD163-macrophages was greater in group 2 than group 1 (p=0.007). CONCLUSIONS: Tumor size and mitotic index are morphologic predictors of malignancy in uterine leiomyosarcomas. Combination of tumor size, mitotic index, Ki67, and Bcl-2 protein expression allows distinguishing 2 groups of leiomyosarcomas with different survival. Leiomyosarcomas associated with poor outcome had a higher number of CD163 stromal macrophages. PMID- 21316748 TI - Heterogeneous distribution of LOH (loss of heterozygosity) and tumor progression. PMID- 21316749 TI - Xenogeneic transplantation of equine testicular cells into seminiferous tubules of immunocompetent rats. AB - The objectives were to develop a transplantation assay for equine testicular cells using busulfan-treated prepubertal immunocompetent rats as recipients, and to determine if putative equine spermatogonial stem cells (SSCs) could be enriched by flow cytometric cell sorting (based on light scattering properties), thereby improving engraftment efficiency. Four weeks after transplantation of frozen/thawed PKH26-labeled equine testicular cells, 0.029 +/- 0.045% (mean +/- SD) of viable donor cells transplanted had engrafted. Donor cells were present in seminiferous tubules of all recipient rats forming chains, pairs, mesh structures, or clusters (with two to >30 cells/structure). Cells were localized to the basal compartment by the basement membrane. Although equine cells proliferated within rat seminiferous tubules, no donor-derived spermatogenesis was evident. Furthermore, there was no histologic evidence of acute cellular rejection. No fluorescent cells were present in control testes. When equine testicular cells were sorted based on light scattering properties, the percentage of transplanted donor cells that engrafted was higher after injection of cells from the small, low complexity fraction (II; 0.169 +/- 0.099%) than from either the large, high complexity fraction (I; 0.046 +/- 0.051%) or unsorted cells (0.009 +/- 0.007%; P < 0.05). Seminiferous tubules of busulfan-treated prepubertal immunocompetent rats provided a suitable niche for engraftment and proliferation, but not differentiation, of equine testicular cells. Sorting equine testicular cells based on light scattering properties resulted in a 19 fold improvement in colonization efficiency by cells with high forward scatter and low side scatter, which may represent putative equine SSCs. PMID- 21316750 TI - Quality of boar spermatozoa from the sperm-peak portion of the ejaculate after simplified freezing in MiniFlatpacks compared to the remaining spermatozoa of the sperm-rich fraction. AB - Boar sperm viability post-thaw differs depending on the ejaculate fraction used, with spermatozoa present in the first 10 mL of the sperm-rich fraction (SRF) (portion 1, P1, sperm-peak portion) displaying the best cryosurvival in vitro compared with that of spermatozoa from the rest of the ejaculate (portion 2 of the SRF plus the post-spermatic fraction), even when using simplified freezing routines. This viability apparently relates to the specific profile of seminal plasma in P1 (i.e., glycoprotein and bicarbonate concentrations, and pH). However, spermatozoa from P1 have not been compared with spermatozoa from the rest of the SRF (SRF-P1, usually 30-40 mL of the SRF), which is routinely used for freezing. We compared P1 with SRF-P1 in terms of sperm kinematics (using the QualiSpermTM system), while membrane integrity (SYBR-14/PI), acrosome integrity (FITC PNA/PI), and sperm membrane stability (Annexin-V) were explored using flow cytometry. As well, total protein concentration and the proteomics of the seminal plasma (SP) of both portions of the SRF were studied using two-dimensional electrophoresis (2DE), mass fingerprinting (MALDI-TOF), and collision-induced dissociation tandem mass spectrometry (CID-MS/MS) on selected peptides. The SRF portions were collected weekly from four mature boars (4-5 replicates per boar, sperm concentration: P1, 1.86 +/- 0.20; SRF-P1, 1.25 +/- 0.14 * 10(9) spz/mL) and processed using a quick freezing method in MiniFlatPacks. Post-thaw sperm motility reached 50%, without differences between SRF portions, but with clear inter-boar variation. Neither plasma membrane nor acrosome integrity differed (ns) between fractions. These results indicate that there are no differences in cryosurvival after quick freezing of boar spermatozoa derived from either of the two SRF portions. While P1 and SRF-P1 clearly differed in relative total protein contents, as expected, they displayed very similar protein profiles as assessed using 2DE and mass spectrometry (tryptic peptide mass fingerprint analysis and CID-MS/MS), indicating a similar emission of epididymal protein content. PMID- 21316751 TI - Dual promoter lentiviral vector generates transgenic mice expressing E2-CSFV glycoprotein in their milk, but impairs early identification of transgenic embryos. AB - Lentiviral vectors containing the green fluorescent protein gene have been successfully used to select transgenic embryos before transfer to a surrogate mother. However, there are apparently no reports regarding early detection of transgenic embryos using a lentiviral vector carrying an additional transcription unit for tissue-specific expression of a valuable protein. In this study, two HIV based lentiviral vectors were constructed. The first one contained the green fluorescent protein (GFP) coding sequence driven by the early SV40 promoter (Lv G), whereas the other contained an additional transcription unit for the expression of E2 glycoprotein from classical swine fever virus, driven by a 1.5 kb alphaS1casein promoter from water buffalo (Lv-alphaS1cE2hisG). Microinjection of single-cell mouse embryos with Lv-G lentiviral vector rendered embryos which were GFP-positive, beginning at the four-cell stage. Of 33 mice born, 28 (81%) carried the transgene DNA and 15 (55.5%) were GFP-positive. Microinjection of Lv alphaS1cE2hisG lentiviral vector yielded 28 mice born; although 24 (85%) carried the transgene DNA, none were GFP-positive, suggesting that the tissue-specific expression cassette interfered with expression of the ubiquitous trancriptional unit. In Lv-alphaS1cE2hisG transgenic mice, E2his was expressed in milk as a homodimer (at concentrations <= 0.422 mg/mL). This was apparently the first report of expression of a recombinant protein in the milk of transgenic animals generated by lentiviral transgenesis. PMID- 21316753 TI - Lowering blood pressure in acute stroke: the SCAST trial. PMID- 21316754 TI - Changes in the nutrient ratios and phytoplankton community after declines in nutrient concentrations in a semi-enclosed bay in Hong Kong. AB - Tolo Harbour is a landlocked bay with poor tidal flushings in the northeastern part of Hong Kong. During the 1980s, excessive nutrient loading led to dramatic increase in nutrient concentrations, accompanied by lower N:P ratios, higher algal biomass and shifts in the phytoplankton community. We studied the effects of nutrient loading reduction measures on nutrient concentrations, nutrient ratios and phytoplankton dynamics in Tolo Harbour by comparing data collected before the full implementation of nutrient loading reduction measures (1986-1997) to those after the implementation (1998-2008). Such measures led to declines in nutrient concentrations, changes in N:P and N:Si ratios, lower chlorophyll-a concentrations and fewer algal blooms. Diatoms were the most abundant phytoplankton group in Tolo Harbour both before and after declines in nutrient concentrations. The density of dinoflagellates did not change, but substantial increase in other algal group abundance was recorded. PMID- 21316752 TI - The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebo-controlled, double-blind trial. AB - BACKGROUND: Raised blood pressure is common in acute stroke, and is associated with an increased risk of poor outcomes. We aimed to examine whether careful blood-pressure lowering treatment with the angiotensin-receptor blocker candesartan is beneficial in patients with acute stroke and raised blood pressure. METHODS: Participants in this randomised, placebo-controlled, double blind trial were recruited from 146 centres in nine north European countries. Patients older than 18 years with acute stroke (ischaemic or haemorrhagic) and systolic blood pressure of 140 mm Hg or higher were included within 30 h of symptom onset. Patients were randomly allocated to candesartan or placebo (1:1) for 7 days, with doses increasing from 4 mg on day 1 to 16 mg on days 3 to 7. Randomisation was stratified by centre, with blocks of six packs of candesartan or placebo. Patients and investigators were masked to treatment allocation. There were two co-primary effect variables: the composite endpoint of vascular death, myocardial infarction, or stroke during the first 6 months; and functional outcome at 6 months, as measured by the modified Rankin Scale. Analyses were by intention to treat. The study is registered, number NCT00120003 (ClinicalTrials.gov), and ISRCTN13643354. FINDINGS: 2029 patients were randomly allocated to treatment groups (1017 candesartan, 1012 placebo), and data for status at 6 months were available for 2004 patients (99%; 1000 candesartan, 1004 placebo). During the 7-day treatment period, blood pressures were significantly lower in patients allocated candesartan than in those on placebo (mean 147/82 mm Hg [SD 23/14] in the candesartan group on day 7 vs 152/84 mm Hg [22/14] in the placebo group; p<0.0001). During 6 months' follow-up, the risk of the composite vascular endpoint did not differ between treatment groups (candesartan, 120 events, vs placebo, 111 events; adjusted hazard ratio 1.09, 95% CI 0.84-1.41; p=0.52). Analysis of functional outcome suggested a higher risk of poor outcome in the candesartan group (adjusted common odds ratio 1.17, 95% CI 1.00-1.38; p=0.048 [not significant at p<=0.025 level]). The observed effects were similar for all prespecified secondary endpoints (including death from any cause, vascular death, ischaemic stroke, haemorrhagic stroke, myocardial infarction, stroke progression, symptomatic hypotension, and renal failure) and outcomes (Scandinavian Stroke Scale score at 7 days and Barthel index at 6 months), and there was no evidence of a differential effect in any of the prespecified subgroups. During follow-up, nine (1%) patients on candesartan and five (<1%) on placebo had symptomatic hypotension, and renal failure was reported for 18 (2%) patients taking candesartan and 13 (1%) allocated placebo. INTERPRETATION: There was no indication that careful blood-pressure lowering treatment with the angiotensin-receptor blocker candesartan is beneficial in patients with acute stroke and raised blood pressure. If anything, the evidence suggested a harmful effect. FUNDING: South-Eastern Norway Regional Health Authority; Oslo University Hospital Ulleval; AstraZeneca; Takeda. PMID- 21316755 TI - Engineering spatial control of multiple differentiation fates within a stem cell population. AB - The capability to engineer microenvironmental cues to direct a stem cell population toward multiple fates, simultaneously, in spatially defined regions is important for understanding the maintenance and repair of multi-tissue units. We have previously developed an inkjet-based bioprinter to create patterns of solid phase growth factors (GFs) immobilized to an extracellular matrix (ECM) substrate, and applied this approach to drive muscle-derived stem cells toward osteoblasts 'on-pattern' and myocytes 'off-pattern' simultaneously. Here this technology is extended to spatially control osteoblast, tenocyte and myocyte differentiation simultaneously. Utilizing immunofluorescence staining to identify tendon-promoting GFs, fibroblast growth factor-2 (FGF-2) was shown to upregulate the tendon marker Scleraxis (Scx) in C3H10T1/2 mesenchymal fibroblasts, C2C12 myoblasts and primary muscle-derived stem cells, while downregulating the myofibroblast marker alpha-smooth muscle actin (alpha-SMA). Quantitative PCR studies indicated that FGF-2 may direct stem cells toward a tendon fate via the Ets family members of transcription factors such as pea3 and erm. Neighboring patterns of FGF-2 and bone morphogenetic protein-2 (BMP-2) printed onto a single fibrin-coated coverslip upregulated Scx and the osteoblast marker ALP, respectively, while non-printed regions showed spontaneous myotube differentiation. This work illustrates spatial control of multi-phenotype differentiation and may have potential in the regeneration of multi-tissue units. PMID- 21316756 TI - Modulation of immune responses by the antimicrobial peptide, epinecidin (Epi)-1, and establishment of an Epi-1-based inactivated vaccine. AB - Current efforts to improve the effectiveness of vaccines include incorporating antimicrobial peptides mixed with a virus. The antimicrobial peptide, epinecidin (Epi)-1, was reported to have an antiviral function, and an Epi-1-based inactivated vaccine was postulated as a model and discussed. In this report, we demonstrated modulation of immune responses by Epi-1 and an Epi-1-based Japanese encephalitis virus (JEV)-inactivated vaccine against JEV infection in mice. Under in vitro conditions, Epi-1 prevented JEV infection-mediated loss of cell viability in BHK-21 cells. When Epi-1 and JEV were co-injected into mice and mice were re-challenged with JEV after 14 days, all mice survived. In addition, Epi-1 modulated the expressions of immune-responsive genes like interleukin (IL)-6, IL 10, MCP-1, tumor necrosis factor-alpha, interferon-gamma and IL-12, and elevated the levels of anti-JEV-neutralizing antibodies in the serum. The presence of Epi 1 suppressed the multiplication of JEV in brain sections at 4 days after an injection. Mice immunized with the developed vaccine showed complete survival against JEV infection, and it was superior to the traditional formalin-based JEV inactivated vaccine. This study demonstrates the use of Epi-1 to develop an inactivated vaccine can provide guidelines for the future design of Epi-1-virus formulations for various in vivo applications. PMID- 21316757 TI - Keratin films for ocular surface reconstruction. AB - Human amniotic membrane (AM) is frequently used as a substrate for ocular surface reconstruction. Its disadvantages (e.g., reduced transparency and biomechanical strength, heterogeneity depending on donor) create the need for standardized alternatives. Keratin from hair or wool has been proposed as an appropriate material for producing films or cell cultivation scaffolds. The current study was performed to develop transparent, stable and transferable films based on human hair keratin that support cellular adhesion and proliferation. The films were engineered by a multi-step procedure including keratin extraction, neutral and alkaline dialysis, drying and a curing process. Keratin films were investigated by SDS-PAGE, SEM and X-ray analyses. Furthermore, swelling and water absorption of the films were studied, as were tensile strength and light transmission (UV/VIS). Finally, the growth behavior of corneal epithelial cells on the keratin films and AM was estimated in proliferation studies. In addition, we assessed the seeding efficiency and cell detachment behavior during trypsinization. The film forming process resulted in transparent films composed of nanoparticulate keratin structures. The film characteristics could be varied by changing the protein composition, adding softening agents or varying the curing temperature and duration. Based on these findings, an optimized protocol was developed. The films showed improved light transmission and biomechanical strength in comparison to AM. Furthermore, cell behavior on the films was similar to that found on AM. We conclude that keratin films may represent a new, promising alternative for ocular surface reconstruction. PMID- 21316758 TI - Targeting glycolysis in leukemia: a novel inhibitor 3-BrOP in combination with rapamycin. AB - Rapidly proliferating solid tumor cells are often dependent on glycolysis for ATP production even in normoxia (the Warburg effect), however it is not yet clear whether acute leukemias have a similarly increased dependence on aerobic glycolysis. We report that all acute leukemia subtypes (pre-B ALL, T-ALL and AML) demonstrated growth arrest and cell death when treated the novel glycolysis inhibitor 3-BrOP. Potentiated ATP depletion and pro-apoptotic effects were seen for 3-BrOP combinations with the cytochrome-c-reductase inhibitor antimycin A and the mTOR inhibitor rapamycin. These results reveal a potential role for glycolysis inhibition in acute leukemia subtypes and suggest potential combinations. PMID- 21316759 TI - Some novel features of IDH1-mutated acute myeloid leukemia revealed in Chinese patients. AB - Mutations of isocitrate dehydrogenase 1 (IDH1) have recently been reported in acute myeloid leukemia (AML). However, the characteristics of IDH1-mutated AML are still not known clearly. We analyzed 416 Chinese AML patients and found 28 patients (6.7%) carried this mutation. One homozygous IDH1 mutant in AML was found. The IDH1 mutations were associated with NPM1 mutations (P=0.043) and could coexist with recurrent transcription factor aberrations including AML1-ETO (6/50), PML-RARalpha (3/77) and CBFbeta-MYH11 (1/15). For AML with AML1-ETO fusion gene, IDH1(mut) patients may have worse disease-free survival (DFS) than IDH1(wild-type) patients. PMID- 21316760 TI - Evaluation of tolerability and efficacy of imatinib mesylate in elderly patients with chronic phase CML: ELDERGLI study. AB - Imatinib mesylate (IM) is the treatment of choice in patients with newly diagnosed chronic myeloid leukemia (CML), irrespectively of their age. Nevertheless, information regarding tolerability and responses in advanced-age patients, a subgroup in which co-morbidities and other factors may influence outcome, is scarce, since they were excluded from most clinical trials. In this observational study (ELDERGLI), information regarding demographics, concomitant medication, physical examination, performance status, hemogram, biochemistry, hematologic, cytogenetic and molecular responses, time to progression, adverse events (AE) and severe adverse events (SAE) were prospectively recorded in a series of 36 elderly patients with CML, with a median age of 76.6 years. Most patients had cardiovascular co-morbidities, especially hypertension. Regarding IM toxicity, around one third of patients required treatment interruptions because of adverse events, especially hematologic toxicity (66% of cases that needed dose interruptions). When analyzing non hematologic adverse events, the most frequent ones were superficial edemas and GI symptoms. Of note, 9 of patients experienced an infection episode during the follow-up, and 4 were diagnosed during the study period of another type of cancer. Finally, cardiovascular events were reported in 7 patients, most of them with prior cardiovascular risk factors. Regarding responses, after 12 months of imatinib therapy, the rate of complete hematologic response (CHR), complete cytogenetic response (CCyR) and major molecular response (MMolR) were 89%, 72% and 55% respectively. In summary, IM display, in advanced age patients with chronic phase CML, an efficacy and safety profile comparable to younger patients. PMID- 21316761 TI - The validity and utility of the California Family Risk Assessment under practice conditions in the field: A prospective study. AB - OBJECTIVE: Analysis of the validity and implementation of a child maltreatment actuarial risk assessment model, the California Family Risk Assessment (CFRA). QUESTIONS ADDRESSED: (1) Is there evidence of the validity of the CFRA under field operating conditions? (2) Do actuarial risk assessment results influence child welfare workers' service delivery decisions? (3) How frequently are CFRA risk scores overridden by child welfare workers? (4) Is there any difference in the predictive validity of CFRA risk assessments and clinical risk assessments by child welfare workers? METHOD: The study analyzes 7,685 child abuse/neglect reports originating in 5 California counties followed prospectively for 2 years to identify further substantiated child abuse/neglect. Measures of model calibration and discrimination were used to assess CFRA validity and compare its accuracy with the accuracy of clinical predictions made by child welfare workers. The extent of use of an override feature of the CFRA and child welfare worker reliance on CFRA risk scores for making service decisions were analyzed. RESULTS: Imperfect but better-than-chance predictive validity was found for the CFRA on a range of measures in a large temporal validation sample (n=6,543). For 114 cases where both CFRA risk assessments and child welfare worker clinical risk assessments were available, the CFRA exhibited evidence of imperfect but better than-chance predictive validity, while child welfare worker risk assessments were found to be invalid. Child welfare workers overrode CFRA risk assessments in only 114 (1.5%) of 7,685 cases and provided in-home services in statistically significantly larger proportions of higher- versus lower-risk cases, consistent with heavy reliance on the CFRA. CONCLUSIONS/PRACTICE IMPLICATIONS: Until research identifies actuarial models exhibiting superior predictive validity when applied in every-day practice, the CFRA is, and will be a valuable tool for assessing risk in order to make in-home service-provision decisions. PMID- 21316762 TI - Trace element accumulation and distribution in the organs of Phragmites australis (common reed) and biomonitoring applications. AB - The concentrations of trace elements were studied in roots, rhizomes, stems, and leaves of Phragmites australis stands (common reeds), and in the corresponding samples of water and sediment from the mouth of the Imera Meridionale River (Sicily, Italy), an area affected by massive urbanization and intensive agriculture. The elements considered were Ag, Al, As, B, Ba, Be, Co, Fe, Mo, Pd, Pt, Rh, Sb, Se, Sr, Tl, and V. Concentrations in belowground organs were usually higher than aboveground tissues, and the general decreasing trend of element content was root>rhizome>leaf>stem. Trace element mobility was generally higher within the organs than in sediment to plant. Regarding Al, Fe, and V, the phytotoxic levels in roots and the low plant/root mobility, may indicate that roots are inherently tolerant to these metals, and act as filters to prevent toxic distribution in the plant. The high uptake of Pd and Rh showed that emissions of catalytic converters are one of the main health hazards of the study area. P. australis showed a direct response to the environmental conditions, and its application as a biomonitor should be considered. PMID- 21316763 TI - Effects of copper on phenology and reproduction in Rumex dentatus from metalliferous and non-metalliferous sites. AB - The responses of phenology and reproductive traits to copper stress in two populations of Rumex dentatus were comparatively studied with pot culture experiments. Seeds used for the experiments were, respectively, collected from metalliferous and normal soils. It was found that the responses of phenology and reproductive traits to Cu treatment between the two populations were significantly different. Compared to the non-metallicolous population, the metallicolous population of R. dentatus had a short life cycle, large reproductive effort, and high fertility under Cu stress. In addition, the reproductive effort in metallicolous population of R. dentatus was maintained at the expense of a curtailment of vegetative development. The results suggested that change in phenological traits and more resources allocation to reproduction might play an important role in the adaptation of metallicolous population of R. dentatus to the Cu-enriched mine soils. PMID- 21316764 TI - Versions of vesalius. AB - Andreas Vesalius reformed anatomical knowledge and teaching in the Renaissance by adopting Galenic methods from the classical past. His careful drawings revealed the human body in unprecedented and realistic detail, but the images of himself were more ambiguous. PMID- 21316765 TI - Molecular characterization of two novel cases of complete complement inhibitor Factor I deficiency. AB - Factor I (FI) is the major complement inhibitor that degrades activated complement components C3b and C4b in the presence of specific cofactors. Complete FI deficiency results in secondary complement deficiency due to uncontrolled spontaneous alternative pathway activation. In this study we describe two unrelated patients with complete FI deficiency and undetectable alternative complement pathway activity. Both patients had experienced recurrent infections and arthralgia/arthritis. In one patient, analysis of genomic DNA revealed deletion of two adenine nucleotides in exon 2 of the CFI gene (c.133-134delAA), causing a frame shift and premature STOP codon/termination in the FIMAC (FI membrane attack complex) domain (p.K45SfsX11). The other patient carried an A>T substitution in exon 6 (c.866A>T) encoding the LDLr2 (low density lipoprotein receptor) domain (p.D289V), resulting in an aspartic acid to valine change. Both patients were homozygous for the mutations while their healthy parents were heterozygous carriers. The mutations were introduced into recombinant FI, causing lack of FI expression and secretion upon transient transfection. Mutation p.K45SfsX11 theoretically allows expression of a 55 amino acid fragment of FI that lacks the serine protease domain, preventing proteolytic activity. In contrast, aspartic acid D289 is crucial for folding of FI. This report describes the molecular and functional consequences of two novel mutations of FI, providing a unique insight into the pathogenesis of complete FI deficiency in these patients. PMID- 21316766 TI - Signal peptides and trans-membrane regions are broadly immunogenic and have high CD8+ T cell epitope densities: Implications for vaccine development. AB - Cell mediated immune response has a major role in controlling the elimination of infectious agents. The rational design of sub-unit peptide vaccines against intracellular pathogens or cancer requires the use of antigenic sequence/s that can induce highly potent, long lasting and antigen-specific responses in the majority of the population. A promising peptide selection strategy is the detection of multi-epitope peptide sequences with an ability to bind multiple MHC alleles. While past research sought the best epitopes based on their specific antigenicity, we ask whether specific defined domains have high epitope densities. Signal peptides and trans-membrane domains were found to have exceptionally high epitope densities. The improved MHC binding of these domains relies on their hydrophobic nature and, in signal peptides, also on their specific sequence. The high epitope density of SP was computed using in-silico methods and corroborated by the high percentage of identified SP epitope in the IEDB (immune epitope database). The enhanced immunogenicity of SP was then experimentally confirmed using a panel of nine peptides derived from Mycobacterium tuberculosis (MTb) proteins used in human PBMC proliferation assays and T cell lines functional assays. Our results show the exceptionally high antigen specific response rates and population coverage to SP sequences compared with non-SP peptide antigens derived from the same proteins. The results suggest a novel scheme for the rational design of T cell vaccines using a domain based rather than an epitope based approach. PMID- 21316767 TI - Do young infants respond socially to human hands? AB - This study revealed that 4- and 6-month-old infants produced social-communicative behaviours only in response to faces, and not in response to hands. However, infants' spontaneous responses to hands were unique in that they scanned the space above the hands, perhaps searching for a face. PMID- 21316768 TI - Quasi-experimental study on the effectiveness of psychoanalysis, long-term and short-term psychotherapy on psychiatric symptoms, work ability and functional capacity during a 5-year follow-up. AB - BACKGROUND: Psychotherapy is apparently an insufficient treatment for some patients with mood or anxiety disorder. In this study the effectiveness of short term and long-term psychotherapies was compared with that of psychoanalysis. METHODS: A total of 326 psychiatric outpatients with mood or anxiety disorder were randomly assigned to solution-focused therapy, short-term psychodynamic and long-term psychodynamic psychotherapies. Additionally, 41 patients suitable for psychoanalysis were included in the study. The patients were followed from the start of the treatment and assessed 9 times during a 5-year follow-up. The primary outcome measures on symptoms were the Beck Depression Inventory, the Hamilton Depression and Anxiety Rating Scales, and the Symptom Check List, anxiety scale. Primary work ability and functional capacity measures were the Work Ability Index, the Work-subscale of the Social Adjustment Scale, and the Perceived Psychological Functioning Scale. RESULTS: A reduction in psychiatric symptoms and improvement in work ability and functional capacity was noted in all treatment groups during the 5-year follow-up. The short-term therapies were more effective than psychoanalysis during the first year, whereas the long-term therapy was more effective after 3years of follow-up. Psychoanalysis was most effective at the 5-year follow-up, which also marked the end of the psychoanalysis. CONCLUSIONS: Psychotherapy gives faster benefits than psychoanalysis, but in the long run psychoanalysis seems to be more effective. Results from trials, among patients suitable for psychoanalysis and with longer follow-up, are needed before firm conclusions about the relative effectiveness of psychoanalysis and psychotherapy in the treatment of mood and anxiety disorders can be drawn. PMID- 21316770 TI - Rewiring the brain with cell transplantation in Parkinson's disease. AB - Cell replacement therapy has been proposed as a means to replace lost dopaminergic neurons in Parkinson's disease (PD). In most studies, the transplanted cells have been placed within the target site, the striatum, and not within the lesioned site, the substantia nigra, as the adult nigrostriatal pathway was thought to constitute a non-permissive environment for long distance axonal outgrowth of transplanted neuroblasts. Here, we discuss recent findings showing that intranigral transplanted dopaminergic neuroblasts can form axonal projections to the striatum, resulting in increased striatal dopamine levels and ameliorating behavioral deficits in animal models of PD. Such findings have raised new hopes and opened new avenues for cell replacement therapy in patients with PD. PMID- 21316769 TI - Cardiac electrical remodeling in health and disease. AB - Electrical remodeling of the heart takes place in response to both functional (altered electrical activation) and structural (including heart failure and myocardial infarction) stressors. These electrophysiological changes produce a substrate that is prone to malignant ventricular arrhythmias. Understanding the cellular and molecular mechanisms of electrical remodeling is important in elucidating potential therapeutic targets designed to alter maladaptive electrical remodeling. For example, altered patterns of electrical activation lead primarily to electrical remodeling, without significant structural remodeling. By contrast, secondary remodeling arises in response to a structural insult. In this article we review cardiac electrical remodeling (predominantly in the ventricle) with an emphasis on the mechanisms causing these adaptations. These mechanisms suggest novel therapeutic targets for the management or prevention of the most devastating manifestation of heart disease, sudden cardiac death (SCD). PMID- 21316771 TI - The protective role of hydrogen sulfide in myocardial ischemia-reperfusion induced injury in diabetic rats. AB - BACKGROUND: Hydrogen sulfide (H(2)S) displays anti-inflammatory and cytoprotective activities to attenuate myocardial ischemia-reperfusion (MIR) induced injury, but its role in MIR in diabetics is not known. This study was undertaken to investigate whether H(2)S plays a protective role in MIR in diabetic rats. METHODS: Diabetes was induced by streptozocin in Wistar rats, which were subjected to myocardial ischemia by blocking the left circumflex artery for 30 min, followed by 2h reperfusion. dl-propargylglycine (PAG) and sodium hydrosulfide (NaHS) were administered to the rats to investigate their effects on severity of MIR-induced injury. RESULTS: Diabetic rats had smaller myocardial infarct sizes and higher serum levels of H(2)S (both P < 0.05) than non-diabetics when they underwent MIR. MIR significantly increased the serum level of H(2)S (49.5 +/- 7.1 MUM), H(2)S-synthesizing activity (7.4 +/- 1.6 nmol/mg) and the myocardial infarct size (44.0 +/- 7.2%), compared with sham operated diabetic rats (21.7 +/- 2.1 MUM, 0.15 +/- 0.4 nmol/mg and 1.2 +/- 0.4%, respectively). Administration of NaHS increased the H(2)S level (65.8 +/- 6.9 MUM) and had little effect on H(2)S production activity (6.5 +/- 2.2 nmol/mg), while PAG reduced both the H(2)S level (29.2 +/- 5.0 MUM) and H(2)S-synthesizing activity (2.2 +/- 1.8 nmol/mg). NaHS significantly reduced the myocardial infarct size (31.2 +/- 4.7%), inhibited the production of lipid peroxidation, MPO activity, and cell apoptosis, and downregulated expression of caspase-3, Fas, FasL, and TNF-alpha, which had been elevated by MIR, while PAG further increased the myocardial infarct size (58.3 +/- 5.9%), and displayed opposite effects. CONCLUSIONS: The study indicates that H(2)S may play a protective role in MIR induced myocardial injury in diabetics by its anti-apoptotic, anti-oxidative and anti-inflammatory activities. PMID- 21316772 TI - Electrocardiographic intricacies clarified by echocardiography--should the electrocardiogram be interpreted echocardiographically? AB - BACKGROUND: During the past century the electrocardiogram (ECG) has established itself as an integral part of the cardiovascular examination. Since the first direct recordings of cardiac potentials by Waller in 1887, to the invention of the string galvanometer by Willem Einthoven in 1901, to use in the clinic by 1910, the electrocardiogram has become the most widely used clinical tool in the diagnosis of virtually every type of heart disease. Currently up to 20 million ECGs are performed annually in the United States alone. HYPOTHESIS: However, in this era of readily available echocardiography, an important caveat in the interpretation of the electrocardiogram has emerged: variants of intracardiac structures which might mimic disease on the ECG. METHODS: In this perspective various structural variants of intracardiac structures, specifically variants of papillary muscles and subaortic muscular bands, will be shown, together with their associated electrocardiographic changes, mimicking disease. CONCLUSION: It is concluded that in this era of readily available echocardiography, the electrocardiogram should be interpreted echocardiographically in instances where intricate variations are seen on the surface electrocardiogram. PMID- 21316773 TI - Successful treatment of coronary artery steal with an Amplatzer Vascular Plug 4. PMID- 21316774 TI - Increased plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) levels are related to good collateral development in patients with isolated left coronary artery disease. PMID- 21316775 TI - Aging and arterial-cardiac interactions in the elderly. AB - Cardiovascular system changes with aging, and these changes are modified by arteriosclerosis-risk factors, i.e., hypertension and diabetes, as well as arterial-cardiac interactions. Regarding age-related changes in the cardiovascular system, Lakatta et al. reported morphological and functional changes that are specific to the cardiovascular aging and are distinct from arteriosclerotic changes. After then, various studies on the mechanism of aging of the cardiovascular system have been performed from the viewpoint of cellular aging, endothelial or endocardial function, and fibroblast. Aging-related changes in the cardiovascular system include death and dysfunction of cell, and matrix fibrosis, but these can also be induced by various causes other than aging. To elucidate the relationship between aging and remodeling of the cardiovascular system, firstly, it is necessary to clarify the phenomena of cellular aging. Changes also differ between the heart and arteries, and there are time lags between aging and aging-associated morphological and functional changes in the cardiovascular system: some changes appear early (early type) or later (delayed type) and some changes occur at the same speed with aging (linear type). In this report, the latest findings concerning aging-associated functional and morphological changes in the arteries and the heart are reviewed and the studies are summarized. Arteries and the heart change with aging while interacting with each other. These arterial-cardiac interactions are also described. PMID- 21316776 TI - MiR-204 regulate cardiomyocyte autophagy induced by hypoxia-reoxygenation through LC3-II. PMID- 21316777 TI - Rare and atypical forms of Tako-Tsubo cardiomyopathy diagnosed by contrast echocardiography during subarachnoid haemorrhage: confirming the appropriateness of the new Tako-Tsubo classification. PMID- 21316778 TI - Estimation of the clinical and economic consequences of non-compliance with antimicrobial treatment of canine skin infections. AB - The goal of this study was to estimate the health and economic consequences of non-compliance with oral antimicrobial treatment in dogs with superficial pyoderma, wounds or abscesses in the US. A mathematical model (Markov model) which simulated treatment with long-term injectable cefovecin versus oral amoxicillin/clavulanic acid was developed and accounted for the effect of non compliance on clinical outcomes and mean total treatment costs per patient. Efficacy parameters considered in the model were derived from clinical studies. Treatment failure due to oral antimicrobial treatment non-compliance was approximated from published data at 13.6%. US cost data for 2009 were derived from public sources. When non-compliance was considered as a cause of treatment failure with oral medication, the long-term injectable antibiotic was more effective than oral comparator (162 versus 158 days without clinical signs). Mean total treatment costs were lower with cefovecin (USD 376.74) versus amoxicillin/clavulanic acid (USD 382.34) in dogs of 25 kg; and cefovecin remained cost-saving up to a body weight of 31 kg. In large dogs, cefovecin was more costly; however, total therapy costs were less than 6% greater than with amoxicillin/clavulanic acid. Accordingly the higher drug and administration costs of the long-term injectable antibiotic were totally or substantially offset when non-compliance was considered as reason for treatment failure with oral medication. The model also allowed for the estimation of the impact of various non-compliance scenarios. PMID- 21316780 TI - Computational design of peptide ligands. AB - Peptides possess several attractive features when compared to small molecule and protein therapeutics, such as high structural compatibility with target proteins, the ability to disrupt protein-protein interfaces, and small size. Efficient design of high-affinity peptide ligands via rational methods has been a major obstacle to the development of this potential drug class. However, structural insights into the architecture of protein-peptide interfaces have recently culminated in several computational approaches for the rational design of peptides that target proteins. These methods provide a valuable alternative to experimental high-resolution structures of target protein-peptide complexes, bringing closer the dream of in silico designed peptides for therapeutic applications. PMID- 21316779 TI - The effects of maternal employment on the health of school-age children. AB - The effects of maternal employment on children's health are theoretically ambiguous and challenging to identify. There are trade-offs between income and time, and a mother's decision to work reflects, in part, her children's health and her underlying preferences. I utilize exogenous variation in each child's youngest sibling's eligibility for kindergarten as an instrument. Using the restricted-access National Health Interview Survey (1985-2004), I identify the effects on overnight hospitalizations, asthma episodes, and injuries/poisonings for children ages 7-17. Maternal employment increases the probability of each adverse health event by nearly 200 percent. These effects are robust and do not reflect a non-representative local effect. PMID- 21316781 TI - Measuring enzyme activity in single cells. AB - Seemingly identical cells can differ in their biochemical state, function and fate, and this variability plays an increasingly recognized role in organism level outcomes. Cellular heterogeneity arises in part from variation in enzyme activity, which results from interplay between biological noise and multiple cellular processes. As a result, single-cell assays of enzyme activity, particularly those that measure product formation directly, are crucial. Recent innovations have yielded a range of techniques to obtain these data, including image-, flow- and separation-based assays. Research to date has focused on easy to-measure glycosylases and clinically-relevant kinases. Expansion of these techniques to a wider range and larger number of enzymes will answer contemporary questions in proteomics and glycomics, specifically with respect to biological noise and cellular heterogeneity. PMID- 21316782 TI - Breast cancer patients receiving postoperative radiotherapy: distress, depressive symptoms and unmet needs of psychosocial support. AB - BACKGROUND AND PURPOSE: The diagnosis and treatment of breast cancer can cause considerable psychological consequences, which may remain unrecognized and untreated. In this study, the prevalence of depressive symptoms and distress, and unmet needs for psychosocial support were assessed among breast cancer patients receiving postoperative radiotherapy. MATERIAL AND METHODS: Out of 389 consecutive patients, 276 responded and comprised the final study group. Depressive symptoms were assessed with the Beck Depression Inventory. Distress was measured with the Distress Thermometer. Hospital records of the patients were examined for additional information. RESULTS: Nearly one third of patients (32.1%) displayed depressive symptoms, and more than a quarter of patients (28.4%) experienced distress. Younger age (p=0.001) and negative hormone receptor status (p=0.008) were independent factors associated with distress. One quarter of the patients expressed an unmet need for psychosocial support, which was independently associated with depressive symptoms and/or distress (p=0.001) and younger age (p=0.006). CONCLUSIONS: During radiotherapy for breast cancer, the staff should have awareness of the higher risk of depression and distress in their patients and should consider screening tools to recognise distress and depressive symptoms. Special attention should be paid to younger patients. PMID- 21316783 TI - Dosimetric comparison of left-sided whole breast irradiation with 3DCRT, forward planned IMRT, inverse-planned IMRT, helical tomotherapy, and topotherapy. AB - BACKGROUND AND PURPOSE: To compare left-sided whole breast conventional and intensity-modulated radiotherapy (IMRT) treatment planning techniques. MATERIALS AND METHODS: Treatment plans were created for 10 consecutive patients. Three dimensional conformal radiotherapy (3DCRT), forward-planned IMRT (for-IMRT), and inverse-planned IMRT (inv-IMRT) used two tangent beams. For-IMRT utilized up to four segments per beam. For helical tomotherapy (HT) plans, beamlet entrance and/or exit to critical structures was blocked. Topotherapy plans, which used static gantry angles with simultaneous couch translation and inverse-planned intensity modulation, used two tangent beams. Plans were normalized to 50Gy to 95% of the retracted PTV. RESULTS: Target max doses were reduced with for-IMRT compared to 3DCRT, which were further reduced with HT, topotherapy, and inv-IMRT. HT resulted in lowest heart and ipsilateral lung max doses, but had higher mean doses. Inv-IMRT and topotherapy reduced ipsilateral lung mean and max doses compared to 3DCRT and for-IMRT. CONCLUSIONS: All modalities evaluated provide adequate coverage of the intact breast. HT, topotherapy, and inv-IMRT can reduce high doses to the target and normal tissues, although HT results in increased low doses to large volume of normal tissue. For-IMRT improves target homogeneity compared with 3DCRT, but to a lesser degree than the inverse-planned modalities. PMID- 21316784 TI - The effect of local breast radiotherapy on circulating CD34(+) cells. AB - The number of circulating CD34(+) (hematopoietic stem) cells (HSCs) was observed to decline by 15% in breast cancer patients after starting adjuvant radiation therapy, regardless of age or preceding chemotherapy. These data demonstrate that local radiation therapy can profoundly affect HSC homeostasis, which might have a myriad of important implications. PMID- 21316785 TI - Palliative radiotherapy for cervical carcinoma, a systematic review. AB - PURPOSE: Worldwide, particularly in developing countries, many women present with advanced stage cervical cancer for which palliative radiotherapy is the treatment of choice or may be the only available treatment. The purpose of this study was to determine from the literature the optimal palliative radiation scheme for the treatment of advanced cervical cancer. DESIGN: A systematic literature review up to January 2010 was performed in Medline, Embase, the Cochrane database, CinHL and Google Scholar using a combination of synonyms for: cervical cancer, palliative treatment and radiation therapy. No limitations were applied for language or study types. For included papers data were extracted and described. RESULTS: Only eight papers were identified and none compared the results of different fractionation schemes. Most used observational retrospective study design with considerable sources of bias. No studies used validated endpoints for symptom relief nor did they include measures of the quality of life. Several papers described the experience with single or multiple monthly 10Gy doses or with a higher total dose delivered in 2-4 fractions within 48 h to 1 week. Studies report varying amounts of relief from bleeding. The effect on other symptoms such as pain and discharge is not evaluable. Acute and late toxicity is poorly documented. CONCLUSION: There is a dearth of information in the current literature to guide selection of an optimal palliative radiation schedule for treatment of patients with advanced cervical cancer. Based on this review and information from other solid tumors, there is no evidence to support the common belief that better and longer palliation is achieved with a high dose delivered in multiple smaller fractions. There is a clear need for comparative studies of different radiation fractionation schedules in order to identify an optimal palliative radiation scheme. These studies require the use of validated endpoints to measure specific symptom relief as well as accompanying quality of life. PMID- 21316786 TI - Geometric accuracy of a novel gimbals based radiation therapy tumor tracking system. AB - PURPOSE: VERO is a novel platform for image guided stereotactic body radiotherapy. Orthogonal gimbals hold the linac-MLC assembly allowing real-time moving tumor tracking. This study determines the geometric accuracy of the tracking. MATERIALS AND METHODS: To determine the tracking error, an 1D moving phantom produced sinusoidal motion with frequencies up to 30 breaths per minute (bpm). Tumor trajectories of patients were reproduced using a 2D robot and pursued with the gimbals tracking system prototype. Using the moving beam light field and a digital-camera-based detection unit tracking errors, system lag and equivalence of pan/tilt performance were measured. RESULTS: The system lag was 47.7 ms for panning and 47.6 ms for tilting. Applying system lag compensation, sinusoidal motion tracking was accurate, with a tracking error 90% percentile E(90%)<0.82 mm and similar performance for pan/tilt. Systematic tracking errors were below 0.14 mm. The 2D tumor trajectories were tracked with an average E(90%) of 0.54 mm, and tracking error standard deviations of 0.20 mm for pan and 0.22 mm for tilt. CONCLUSIONS: In terms of dynamic behavior, the gimbaled linac of the VERO system showed to be an excellent approach for providing accurate real-time tumor tracking in radiation therapy. PMID- 21316787 TI - Dose-effect relation in stereotactic radiotherapy for brain metastases. A systematic review. AB - PURPOSE: Stereotactic radiotherapy (SRT) of brain metastases is considered effective when long-term local control is obtained. However, dose-effect data are scarce. We, therefore, performed a systematic literature search to assess the evidence concerning the relation of SRT dose and local control probability. METHODS AND MATERIALS: A search was performed for papers describing patients treated with SRT for brain metastases, published from 1990 through 2009, in the electronic databases Medline (Pubmed) and Embase. We selected only papers reporting actuarial local control probability, in which a fixed dose had been prescribed and in which the size of the metastases was given. Series with SRT as a boost after whole brain irradiation (WBI) or with SRT after surgery were excluded. From the selected papers we extracted data on dose, local control rates and necrosis rates. Biological effective doses of the linear-quadratic-cubic model, using an alpha/beta of 12Gy (BED(12)), were calculated and a dose-response curve was constructed. RESULTS: Eleven papers fulfilled the selection criteria for further analysis. Six-month local control rates were higher than 80% in almost all the series irrespective of dose. Twelve-month local control rates, however, varied and were higher than 80%, higher than 60% and lower than 50% with single doses of >=21Gy, >=18Gy and <=15Gy, respectively, and 70% or higher with fractionated SRT (FSRT). A BED(12) of at least 40Gy was associated with a twelve month local control rate of 70% or more. CONCLUSION: Local control after single fraction SRT is highly dependent upon dose and is high (>80%) after 21Gy or more, but low (<50%) after 15Gy or less. We conclude that SRT for brain metastases should preferably be applied with a BED(12) of at least 40Gy corresponding with a single fraction of 20Gy, two fractions of 11.6Gy or three fractions of 8.5Gy. PMID- 21316788 TI - A pilot structured behavioural intervention trial to increase physical activity among women with recent gestational diabetes. AB - Forty-three women were recruited into a 1-year randomised controlled trial to test the feasibility of a structured behavioural intervention to increase physical activity after gestational diabetes. Increases in achievement of physical activity targets were not attained. Recruitment and subject retention were identified as major challenges. PMID- 21316789 TI - Impact of aortic repair based on flow field computer simulation within the thoracic aorta. AB - Purpose of this computational study is to examine the hemodynamic parameters of velocity fields and shear stress in the thoracic aorta with and without aneurysm, based on an individual patient case and virtual surgical intervention. These two cases, case I (with aneurysm) and II (without aneurysm), are analyzed by computational fluid dynamics. The 3D Navier-Stokes equations and the continuity equation are solved with an unsteady stabilized finite element method. The vascular geometries are reconstructed based on computed tomography angiography images to generate a patient-specific 3D finite element mesh. The input data for the flow waveforms are derived from MR phase contrast flow measurements of a patient before surgical intervention. The computed results show velocity profiles skewed towards the inner aortic wall for both cases in the ascending aorta and in the aortic arch, while in the descending aorta these velocity profiles are skewed towards the outer aortic wall. Computed streamlines indicate that flow separation occurs at the proximal edge of the aneurysm, i.e. computed flow enters the aneurysm in the distal region, and that there is essentially a single, slowly rotating, vortex within the aneurysm during most of the systole. In summary, after virtual surgical intervention in case II higher shear stress distribution along the descending aorta could be found, which may produce more healthy reactions in the endothelium and benefit of vascular reconstruction of an aortic aneurysm at this particular location. PMID- 21316790 TI - Exercise intervention to improve exercise capacity and health related quality of life for patients with Non-small cell lung cancer: a systematic review. AB - CONTEXT: The role of exercise intervention for patients with Non-small cell lung cancer (NSCLC) has not been systematically reviewed to date. OBJECTIVE: To identify, evaluate and synthesize the evidence examining (1) the effect of exercise intervention on exercise capacity, health related quality of life (HRQoL), physical activity levels, cancer symptoms and mortality for patients with NSCLC; and (2) the safety and feasibility of exercise intervention for a population with NSCLC. DATA SOURCES: A systematic review of articles using the electronic databases MEDLINE (1950-2010), CINAHL (1982-2010), EMBASE (1980-2010), TRIP (1997-2010), Science Direct (1994-2010), PubMed (1949-2010), Cochrane Library (2010), Expanded Academic ASAP (1994-2010), Meditext Informit (1995 2010), PEDRO (1999-2010) and DARE (2010). Additional studies were identified by manually cross referencing all full text reports and personal files were searched. No publication date restrictions were imposed. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Randomised controlled trials (RCTs), case-control studies and case series assessing exercise intervention to improve exercise capacity, HRQoL, level of daily physical activity, cancer symptoms or mortality of patients with NSCLC were included. Only articles available in English and published in a peer reviewed journal were included. DATA EXTRACTION: A data collection form was developed by one reviewer and data extracted. Data extraction was cross checked by a second reviewer. RESULTS AND DATA SYNTHESIS: 16 studies on 13 unique patient groups totalling 675 patients with NSCLC met the inclusion criteria. The majority of studies were case series (n=9) and two RCTs were included. Studies exercising participants pre-operatively reported improvements in exercise capacity but no change in HRQoL immediately post exercise intervention. Studies exercising participants post-treatment (surgery, chemotherapy or radiotherapy) demonstrated improvements in exercise capacity but conflicting results with respect to the impact on HRQoL immediately post exercise intervention. Heterogeneity among studies was observed and a meta-analysis was deemed inappropriate. PRISMA guidelines were followed in reporting this systematic review. CONCLUSION: Exercise intervention for patients with NSCLC is safe before and after cancer treatment. Interventions pre-operatively or post-cancer treatment are associated with positive benefits on exercise capacity, symptoms and some domains of HRQoL. The majority of studies are small case series therefore results should be viewed with caution until larger RCTs are completed. Further research is required to establish the effect of exercise during and after cancer treatment and in the advanced stage of disease, the optimum type of exercise training and the optimum setting for delivery. PMID- 21316791 TI - Species differences in captivity: where are the invertebrates? PMID- 21316792 TI - Review of unsaturated-zone transport and attenuation of volatile organic compound (VOC) plumes leached from shallow source zones. AB - Reliable prediction of the unsaturated zone transport and attenuation of dissolved-phase VOC (volatile organic compound) plumes leached from shallow source zones is a complex, multi-process, environmental problem. It is an important problem as sources, which include solid-waste landfills, aqueous-phase liquid discharge lagoons and NAPL releases partially penetrating the unsaturated zone, may persist for decades. Natural attenuation processes operating in the unsaturated zone that, uniquely for VOCs includes volatilisation, may, however, serve to protect underlying groundwater and potentially reduce the need for expensive remedial actions. Review of the literature indicates that only a few studies have focused upon the overall leached VOC source and plume scenario as a whole. These are mostly modelling studies that often involve high strength, non aqueous phase liquid (NAPL) sources for which density-induced and diffusive vapour transport is significant. Occasional dissolved-phase aromatic hydrocarbon controlled infiltration field studies also exist. Despite this lack of focus on the overall problem, a wide range of process-based unsaturated zone - VOC research has been conducted that may be collated to build good conceptual model understanding of the scenario, particularly for the much studied aromatic hydrocarbons and chlorinated aliphatic hydrocarbons (CAHs). In general, the former group is likely to be attenuated in the unsaturated zone due to their ready aerobic biodegradation, albeit with rate variability across the literature, whereas the fate of the latter is far less likely to be dominated by a single mechanism and dependent upon the relative importance of the various attenuation processes within individual site - VOC scenarios. Analytical and numerical modelling tools permit effective process representation of the whole scenario, albeit with potential for inclusion of additional processes - e.g., multi mechanistic sorption phase partitioning, and provide good opportunity for further sensitivity analysis and development to practitioner use. There remains a significant need to obtain intermediate laboratory-scale and particularly field scale (actual site and controlled release) datasets that address the scenario as a whole and permit validation of the available models. Integrated assessment of the range of simultaneous processes that combine to influence leached plume generation, transport and attenuation in the unsaturated zone is required. Component process research needs are required across the problem scenario and include: the simultaneous volatilisation and dissolution of source zones; development of appropriate field-scale dispersion estimates for the unsaturated zone; assessment of transient VOC exchanges between aqueous, vapour and sorbed phases and their influence upon plume attenuation; development of improved field methods to recognise and quantify biodegradation of CAHs; establishment of the influence of co-contaminants; and, finally, translation of research findings into more robust practitioner practice. PMID- 21316793 TI - The transcription machineries of plant mitochondria and chloroplasts: Composition, function, and regulation. AB - Although genomes of mitochondria and plastids are very small compared to those of their bacterial ancestors, the transcription machineries of these organelles are of surprising complexity. With respect to the number of different RNA polymerases per organelle, the extremes are represented on one hand by chloroplasts of eudicots which use one bacterial-type RNA polymerase and two phage-type RNA polymerases to transcribe their genes, and on the other hand by Physcomitrella possessing three mitochondrial RNA polymerases of the phage type. Transcription of genes/operons is often driven by multiple promoters in both organelles. This review describes the principle components of the transcription machineries (RNA polymerases, transcription factors, promoters) and the division of labor between the different RNA polymerases. While regulation of transcription in mitochondria seems to be only of limited importance, the plastid genes of higher plants respond to exogenous and endogenous cues rather individually by altering their transcriptional activities. PMID- 21316794 TI - Methyl jasmonate, gibberellic acid, and auxin affect transcription and transcript accumulation of chloroplast genes in barley. AB - Phytohormones control growth and development of plants. Their effects on the expression of nuclear genes are well investigated. Although they influence plastid-related processes, it is largely unknown whether phytohormones exert their control also by regulating the expression of plastid/chloroplast genes. We have therefore studied the effects of methyl jasmonate (MeJA), gibberellic acid (GA(3)), an auxin (indole-3-acetic acid, IAA), a brassinosteroid (24 epibrassinolide, BR) and a cytokinin (6-benzyladenine) on transcription (run-on assays) and transcript levels (RNA blot hybridization) of chloroplast genes after incubation of detached barley leaves in hormone solutions. BR was the only hormone without significant influence on chloroplast transcription. It showed, however, a weak reducing effect on transcript accumulation. MeJA, IAA and GA(3) repressed both transcription and transcript accumulation, while BA counteracted the effects of the other hormones. Effects of phytohormones on transcription differed in several cases from their influence on transcript levels suggesting that hormones may act via separate signaling pathways on transcription and transcript accumulation in chloroplasts. We observed striking differences in the response of chloroplast gene expression on phytohormones between the lower (young cells) and the upper segments (oldest cells) of barley leaves. Quantity and quality of the hormone effects on chloroplast gene expression seem to depend therefore on the age and/or developmental stage of the cells. As the individual chloroplast genes responded in different ways on phytohormone treatment, gene- and transcript-specific factors should be involved. Our data suggest that phytohormones adjust gene expression in the nucleo-cytoplasmic compartment and in plastids/chloroplasts in response to internal and external cues. PMID- 21316796 TI - Elucidation of structure-function relationships in photosynthetic light harvesting antenna complexes by non-linear polarization spectroscopy in the frequency domain (NLPF). AB - Photosynthetically active pigments are usually organized into pigment-protein complexes. These include light-harvesting antenna complexes (LHCs) and reaction centers. Site energies of the bound pigments are determined by interactions with their environment, i.e., by pigment-protein as well as pigment-pigment interactions. Thus, resolution of spectral substructures of the pigment-protein complexes may provide valuable insight into structure-function relationships. By means of conventional (linear) and time-resolved spectroscopic techniques, however, it is often difficult to resolve the spectral substructures of complex pigment-protein assemblies. Nonlinear polarization spectroscopy in the frequency domain (NLPF) is shown to be a valuable technique in this regard. Based on initial experimental work with purple bacterial antenna complexes as well as model systems NLPF has been extended to analyse the substructure(s) of very complex spectra, including analyses of interactions between chlorophylls and "optically dark" states of carotenoids in LHCs. The paper reviews previous work and outlines perspectives regarding the application of NLPF spectroscopy to disentangle structure-function relationships in pigment-protein complexes. PMID- 21316795 TI - OsDOG, a gibberellin-induced A20/AN1 zinc-finger protein, negatively regulates gibberellin-mediated cell elongation in rice. AB - The A20/AN1 zinc-finger proteins (ZFPs) play pivotal roles in animal immune responses and plant stress responses. From previous gibberellin (GA) microarray data and A20/AN1 ZFP family member association, we chose Oryza sativa dwarf rice with overexpression of gibberellin-induced gene (OsDOG) to examine its function in the GA pathway. OsDOG was induced by gibberellic acid (GA(3)) and repressed by the GA-synthesis inhibitor paclobutrazol. Different transgenic lines with constitutive expression of OsDOG showed dwarf phenotypes due to deficiency of cell elongation. Additional GA(1) and real-time PCR quantitative assay analyses confirmed that the decrease of GA(1) in the overexpression lines resulted from reduced expression of GA3ox2 and enhanced expression of GA2ox1 and GA2ox3. Adding exogenous GA rescued the constitutive expression phenotypes of the transgenic lines. OsDOG has a novel function in regulating GA homeostasis and in negative maintenance of plant cell elongation in rice. PMID- 21316797 TI - Ammonia production and assimilation: its importance as a tolerance mechanism during moderate water deficit in tomato plants. AB - Nitrate assimilation diminishes under water stress. This can augment the photorespiratory rate as a protection mechanism, increasing the ammonium concentration, which must be rapidly assimilated. We therefore examined the effect of moderate water stress in photorespiration and N assimilation, as possible tolerance mechanisms in cherry tomato. Five cherry tomato cultivars with different degrees of water stress tolerance were submitted to two water treatments: well-watered (100% FC) and water stress (50% FC). In the susceptible cultivars, nitrate assimilation declined but without stimulating photorespiration. Zarina, a stress-tolerant cultivar, showed increased activity of the main enzymes involved in photorespiration, together with greater assimilation of nitrates and of the resulting ammonium. This translates as higher concentrations of N as well as amino acids and proteins. We characterize these mechanisms in the cv. Zarina (tolerant) as essential to water stress tolerance, acting on N metabolism as well as helping to maintain or augment biomass. PMID- 21316798 TI - Drought tolerance through over-expression of the expansin gene TaEXPB23 in transgenic tobacco. AB - Expansins are proteins that are the key regulators of wall extension during plant growth. To investigate the role of TaEXPB23, a wheat expansin gene, we analyzed TaEXPB23 mRNA expression levels in response to water stress in wheat and examined the drought resistance of transgenic tobaccos over-expressing TaEXPB23. We found that the expression of TaEXPB23 corresponded to wheat coleoptile growth and the response to water stress. The results also indicated that the transgenic tobacco lines lost water more slowly than the wild-type (WT) plants under drought stress; their cells could sustain a more integrated structure under water stress than that of WT. Other physiological and biochemical parameters under water stress, such as electrolyte leakage, malondialdehyde (MDA) level, photosynthetic rate, F(v)/F(m) and PhiPSII, also suggested that the transgenic tobaccos were more drought resistant than WT plants. PMID- 21316799 TI - Inpatient mortality and death reporting associated with Clostridium difficile infection in a large teaching hospital. PMID- 21316800 TI - Changes in the incidence of candidaemia during 2000-2008 in a tertiary medical centre in northern Taiwan. AB - Candidaemia is associated with high mortality and high healthcare costs. The incidence of candidaemia in Taiwan rose markedly during the period 1980-2000. We conducted this hospital-based surveillance study in order to explore the secular trend in incidence of candidaemia during the period 2000 to 2008. In our study, Candida spp. were the fourth most common cause of bloodstream infections, with a 30-day crude mortality rate of 36.7%. Candida albicans was the most common species identified, although mortality rate did not differ significantly among species. The incidence of candidaemia began to decrease in 2004. Risk factors related to higher mortality included longer hospital stay before onset of candidaemia, liver cirrhosis, malignancy, end-stage renal disease requiring renal dialysis, dependence on mechanical ventilation and urinary catheterisation. PMID- 21316801 TI - Risk of pandemic (H1N1) 2009 virus infection among healthcare workers caring for critically ill patients with pandemic (H1N1) 2009 virus infection. PMID- 21316802 TI - Taiwan's traffic control bundle and the elimination of nosocomial severe acute respiratory syndrome among healthcare workers. AB - The traffic control bundle consists of procedures designed to help prevent epidemic nosocomial infection. We retrospectively studied the serial infection control measures to determine factors most effective in preventing nosocomial infections of healthcare workers (HCWs) during the 2003 Taiwanese severe acute respiratory syndrome (SARS) epidemic. Fever screening stations, triage of fever patients, separating SARS patients from other patients, separation of entrances and passageways between patients and HCWs, and increasing hand-washing facilities all demonstrated a protective effect for HCWs (univariate analysis; P<0.05). By multiple logistic regression: (i) checkpoint alcohol dispensers for glove-on hand rubbing between zones of risk, and (ii) fever screening at the fever screen station outside the emergency department, were the significant methods effectively minimising nosocomial SARS infection of HCWs (P<0.05). The traffic control bundle should be implemented in future epidemics as a tool to achieve strict infection control measures. PMID- 21316803 TI - Determination of factors required to increase uptake of influenza vaccination among hospital-based healthcare workers. AB - A questionnaire study was performed in all eight University Medical Centers in The Netherlands to determine the predictors of influenza vaccination compliance in hospital-based healthcare workers (HCWs). Demographical, behavioural and organisational determinants were assessed based on behavioural and implementation models. Multivariable regression analysis was applied to assess the independent predictors for influenza vaccine uptake. Age >40 years, the presence of a chronic illness, awareness of personal risk and awareness of risk of infecting patients, trust in the effectiveness of the vaccine to reduce the risk of infecting patients, the HCWs' duty to do no harm and their duty to ensure continuity of care, finding vaccination useful despite the constant flow of visitors and having knowledge of the Health Council's advice, social influence and convenient time for vaccination were all independently associated with vaccine uptake. The accuracy of the prediction model was very high (area under the receiver operating curve: 0.95). Intervention programmes to increase influenza vaccine uptake among HCWs should target the relevant determinants identified in this study. PMID- 21316804 TI - Tuberculosis screening programme using the QuantiFERON-TB Gold test and chest computed tomography for healthcare workers accidentally exposed to patients with tuberculosis. AB - Healthcare workers (HCWs) have an increased incidence of tuberculosis (TB). Periodic and as-needed screenings of HCWs exposed to patients with TB are important. We integrated chest computed tomography (CT) and the QuantiFERON-TB Gold (QFT-G) test into our TB screening programme for HCWs. First, contacts were tested using the QFT-G test. Those positive for the QFT-G test were investigated by CT and classified as having active, latent (LTBI), or old TB. Between April 2005 and April 2010, 11 patients who had not been diagnosed with active TB on admission were found to have the disease. A total of 512 close or high risk contacts were identified, and underwent screening. Out of those, 34 (6.64%) were QFT-G positive, whereas 478 (93.36%) were negative. Of the 34 QFT-G-positive HCWs, four had CT findings compatible with active TB and received multidrug treatment; 24 showed no findings of active TB and received isoniazid for six months. All completed their regimens without any adverse effects. The TB screening programme integrating CT and the QFT-G test was safe and feasible. The efficacy of the programme needs to be confirmed by large scale clinical trials. PMID- 21316805 TI - Imipenem and ciprofloxacin consumption as factors associated with high incidence rates of resistant Pseudomonas aeruginosa in hospitals in northern France. AB - In France, Pseudomonas aeruginosa is the third most common isolate from nosocomial infections. To determine whether high consumption rates of some antibiotics are risk factors for resistance to ceftazidime, imipenem, ciprofloxacin and amikacin in P. aeruginosa, we conducted a study based on data from the Antimicrobial Surveillance Network in northern France and the French public reporting system of infection control indicators. These data were related to hospital characteristics (size, type, proportion of non-acute care beds), antibiotic consumption, incidence rates of some key resistances and quality indicators of healthcare-associated infection (HAI) control. In univariate analysis, high total and specific antibiotic consumption (except amoxicillin/clavulanate and imidazoles) were associated with high P. aeruginosa resistance rates. In multivariate analysis, high resistance rates were related to high imipenem and ciprofloxacin consumption [odds ratio (95% confidence interval): 7.9 (2.24-28.09), P<0.05 for both], but were not significantly related to quality indicators of HAI control. These findings suggest that imipenem and ciprofloxacin use could play a major role in driving P. aeruginosa resistance, independent of other infection control performance. PMID- 21316806 TI - Outbreak in Croatia caused by a new carbapenem-resistant clone of Acinetobacter baumannii producing OXA-72 carbapenemase. PMID- 21316807 TI - Complicated infections with meticillin-resistant Staphylococcus aureus in Hong Kong. PMID- 21316808 TI - Death certificates provide a poor estimation of attributable mortality due to Clostridium difficile when compared to a death review panel using defined criteria. PMID- 21316809 TI - Paediatric viral respiratory polymerase chain reaction testing: more sensitive but less rapid and with infection control implications. PMID- 21316810 TI - Surgical site infection rates in robotic and laparoscopic colorectal surgery: a retrospective, case-control audit. PMID- 21316811 TI - Flavobacterium sepsis outbreak due to contaminated distilled water in a neonatal intensive care unit. AB - Outbreaks of sepsis due to water or contaminated equipment can cause significant mortality and morbidity in neonatal intensive care units. We studied an outbreak among neonates caused by flavobacterium and investigated the characteristics of the infected neonates, antimicrobial susceptibilities, and the source of the outbreak. Forty-five neonates with documented flavobacterium sepsis were evaluated in this descriptive study. Data including sex, vaginal delivery or caesarean, preterm or term, birth weight, results of blood cultures and antibiograms were recorded and cases followed up until death or recovery. Environmental sampling for detecting the source of contamination was performed. Among the 45 patients, 28 (62.2%) were male and 17 (37.8%) female (P<0.001). The commonest clinical manifestation was respiratory distress (60%). Eighteen neonates (40%) were low birth weight. Thirty-seven neonates (82.2%) were born via caesarean section. Twenty (44.4%) of them were preterm whereas 25 (55.6%) were term (P<0.001). Mortality was 17.7%. All strains were resistant to ampicillin, and susceptible to amikacin. The source of outbreak was contaminated distilled water. PMID- 21316812 TI - Systematic review and meta-analysis of the effect of warming local anesthetics on injection pain. AB - STUDY OBJECTIVE: Local anesthetics are the main class of analgesics used for pain management during laceration repair and other minor surgeries; however, they are administered by injection, which is painful. Warming local anesthetics has been proposed as a cost-free intervention that reduces injection pain. A systematic review of the effectiveness of this technique has not yet been undertaken. We determine the effectiveness of warming local anesthetics to reduce pain in adults and children undergoing local anesthetic infiltration into intradermal or subcutaneous tissue. METHODS: We used published articles from MEDLINE (1950 to June 2010), EMBASE (1980 to June 2010), CINAHL (1982 to June 2010), the Cochrane Library (second quarter 2010), International Pharmaceutical Abstracts (1970 to June 2010), and ProQuest Dissertations and Theses database (1938 to June 2010). We included studies with randomized or pseudorandomized designs and healthy subjects or patients receiving subcutaneous or intradermal injection of local anesthetics that were warmed (body temperature) or not (room temperature). Studies of regional anesthesia and intraarticular, spinal, or periorbital administration of local anesthetics were excluded. Data were extracted onto predesigned forms and verified by 2 reviewers. Quality was assessed with the Cochrane risk of bias tool. The primary outcome was self-reported pain as assessed by a visual analog or numeric rating scale. Data were combined with mean differences with 95% confidence intervals (CIs) by using a random-effects model. RESULTS: Twenty-nine studies were retrieved for close examination and 19 studies met inclusion criteria. A total of 18 studies with 831 patients could be included in a meta-analysis. Seventeen studies had an unclear risk of bias and 1 had a high risk of bias. A mean difference of -11 mm (95% CI -14 to -7 mm) on a 100-mm scale was found in favor of warming local anesthetics. Subgroup analysis of 8 studies investigating the effect of warming on buffered local anesthetics yielded similar results: -7 mm (95% CI -12 to -3 mm). CONCLUSION: Warming local anesthetics leads to less pain during injection and therefore should be done before administration. PMID- 21316813 TI - Cortical thinning related to periventricular and deep white matter hyperintensities. AB - Previous studies showed that white matter hyperintensities (WMH) are related to cognitive decline in patients with mild cognitive impairment (MCI) or dementia. Moreover, periventricular WMH (periventricular white matter hyperintensities (PWMH)) and deep WMH (deep white matter hyperintensities (DWMH)) may have different effects on cognition. The purpose of this study is to investigate the contributions of PWMH and DWMH to the topography of cortical thinning and to investigate the relationship among WMH, cortical thinning, and cognitive impairments. Participants included 226 patients with Alzheimer's disease or subcortical vascular dementia, and 135 patients with amnestic MCI or subcortical vascular MCI. Cortical thickness was measured using the surface based method. The topography of cortical thinning related to WMH was distributed in the frontal and perisylvian regions, which was similar to that of PWMH. In contrast, there were only small areas of cortical thinning inversely associated with DWMH, which were distributed in medial frontal and lingual gyrus. PWMH, but not DWMH, were associated with the frontal thinning and executive dysfunction; where both PWMH and frontal thinning were independently associated with executive dysfunction. Our results suggest that PWMH are associated with frontal thinning, which is further associated with frontal executive dysfunction. PMID- 21316815 TI - "Lest we forget you--methylene blue...". AB - Methylene blue (MB), the first synthetic drug, has a 120-year-long history of diverse applications, both in medical treatments and as a staining reagent. In recent years there was a surge of interest in MB as an antimalarial agent and as a potential treatment of neurodegenerative disorders such as Alzheimer's disease (AD), possibly through its inhibition of the aggregation of tau protein. Here we review the history and medical applications of MB, with emphasis on recent developments. PMID- 21316814 TI - Structural brain changes in normal individuals with a maternal history of Alzheimer's. AB - Having a parent affected with late-onset Alzheimer's disease (LOAD) is a major risk factor for developing the disease among cognitively normal (NL) individuals. This magnetic resonance imaging (MRI) study examines whether NL with a LOAD affected parent show preclinical brain atrophy, and whether there are parent-of origin effects. Voxel-based morphometry (VBM) on Statistical parametric mapping (SPM8) was used to examine volumetric T1-MRI scans of 60 late-middle-aged NL subjects, divided into 3 size-matched, demographically balanced groups of 20 subjects each, including NL with a maternal (FHm), paternal (FHp), or negative family history (FH-) of LOAD. There were no group differences for clinical and neuropsychological measures, and ApoE status. On VBM, FHm showed reduced gray matter volumes (GMV) in frontal, parietal, and temporal cortices and precuneus as compared with FH-, and in precuneus compared with FHp (p < 0.05, family-wise error [FWE]-corrected). Results remained significant controlling for age, gender, education, ApoE, and total intracranial volume. No differences were observed between FHp and FH- in any regions. NL FHm showed reduced GMV in LOAD-affected brain regions compared with FH- and FHp, indicating higher risk for Alzheimer's disease. Our findings support the use of regional brain atrophy as a preclinical biomarker for LOAD among at-risk individuals. PMID- 21316817 TI - Synthesis, human monoamine oxidase inhibitory activity and molecular docking studies of 3-heteroarylcoumarin derivatives. AB - Monoamine oxidase (MAO) is an important drug target for the treatment of neurological disorders. Series of 3-indolyl and 3-thiophenylcoumarins were synthesized and evaluated as inhibitors of the two human MAO isoforms, hMAO-A and hMAO-B. In general, the derivatives were found to be selective hMAO-B inhibitors with IC(50) values in the nanoMolar (nM) to microMolar (MUM) range. Docking experiments were carried out in order to compare the theoretical and experimental affinity of these compounds to the hMAO-B protein. According to our results, docking experiments could be an interesting approach to try to predict the activity of this class of coumarins against MAO-B receptors. PMID- 21316816 TI - [Men inequalities and liver cirrhosis mortality (Zaragoza, Spain, 1996-2003)]. AB - OBJECTIVES: The aim of this study was to identify geographical differences in mortality from liver cirrhosis in men living in the province of Zaragoza, Spain, as well as its possible association with socioeconomic factors. The utility of the MEDEA project's deprivation index in rural areas was also explored. METHODS: Census tracts were used in Zaragoza city as analysis units and municipalities were used for the rest of the province. Crude and smoothed standardized mortality ratios were calculated for each analysis unit through a Bayesian generalized mixed linear model. A deprivation index was obtained and was included in the model in quartiles. An exploratory analysis was also conducted, including a rural index in the province of Zaragoza. RESULTS: In Zaragoza city, mortality from liver cirrhosis and other chronic liver diseases [code 571 of the 9th International Classification of Diseases (ICD) and K70, K72.1, K73, K74, K76.1.9 of the ICD-10] increased as the deprivation index increased. Mortality in the most deprived areas was twice that in the less deprived areas (relative risk [RR] 2.09, credible interval (CI): 1.53-2.83). In the rest of the province, geographical differences in mortality could not be explained by the deprivation index used. Nevertheless, municipalities with the highest values in the rural index showed a RR of 0.47 (CI: 0.18-0.92) compared with those with the lowest values. CONCLUSIONS: In Zaragoza city, mortality from liver cirrhosis and other chronic liver diseases was higher in the most deprived census tracts than in the most affluent areas. This association was not found in the rest of the province, probably because of the low variability explained by the deprivation index. Municipalities with high rural values had the lowest risk of death from these diseases. PMID- 21316818 TI - Biological evaluation of polyhalo 1,3-diazaheterocycle fused isoquinolin-1(2H) imine derivatives. AB - A series of polyhalo 1,3-diazaheterocycle fused isoquinolin-1(2H)-imines were evaluated in vitro against human tumour cell lines including A431, K562, HL60, HepG2 and Skov-3. As a result, some of the target compounds such as 5b, 5c, 5i, 5o, 6c, 6h and 7f showed stronger cytotoxicity against K562, H562 and Skov-3 cells in comparison with cisplatin, and the others displayed moderate cytotoxicity to A431 and HepG2. Biological investigations using the representative compounds 5c, 6c and 6h were also performed in mice bearing S(180) and H(22) tumours. The results indicated that these three compounds inhibit S(180) and H(22) growth. In addition, compounds 6c and 6h have very low acute toxicities. The preliminary analysis of structure-activity relationships is also discussed. PMID- 21316819 TI - Synthesis, stereochemistry, antimicrobial evaluation and QSAR studies of 2,6 diaryltetrahydropyran-4-one thiosemicarbazones. AB - A series of 2,6-diaryltetrahydropyran-4-one thiosemicarbazones (11-27) were synthesized and characterized for evaluation of potential antibacterial activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi, Bacillus subtilis and Klebsiella pneumonia and antifungal activity against Cryptococcus neoformans, Candida albicans, Rhizopus sp., Aspergillus niger and Aspergillus flavus were evaluated. Compounds 21 and 22 showed maximum inhibition potency at low concentration (6.25 MUg/ml) against P. aeruginosa. For antifungal activity, 20 and 21 were effective against C. neoformans and 22-24 against C. albicans at minimum concentration. Further, the results of QSAR studies of these synthesized compounds indicated the importance of weakly polar component of surface area, hydrophobicity and ionization potential parameters in defining their antimicrobial activity. PMID- 21316820 TI - Determination of U, Pu and Am isotopes in Irish Sea sediment by a combination of AMS and radiometric methods. AB - Samples from a marine sediment core from the Irish Sea (54.416 N, 3.563 W) were analyzed for the isotopic composition of uranium, plutonium and americium by a combination of radiometric methods and AMS. The radiochemical procedure consisted of a Pu separation step by anion exchange, subsequent U separation by extraction chromatography using UTEVA(r) and finally Am separation with TRU(r) Resin. Additionally to radiometric determination of these isotopes by alpha spectrometry, the separated samples were also used for the determination of (236)U/(238)U and plutonium isotope ratios by Accelerator Mass Spectrometry (AMS) at the VERA facility. PMID- 21316821 TI - Review of evidence for the use of steroids in orthognathic surgery. AB - Primarily, steroids are used routinely in orthognathic surgery to reduce swelling, but there is no nationally accepted regimen for the use of glucocorticoids in the UK. This article examines the evidence base for the use of steroids to reduce swelling, nausea, vomiting, and pain, and looks at evidence of the ratio of risks:benefits in orthognathic surgery and related publications. Evidence supports their use preoperatively, but the timing of this and their postoperative use may be contentious. The current regimens are associated with little morbidity and low cost. A well designed multi-centre study whose design would allow objective measures of swelling is required to resolve the areas of debate. PMID- 21316822 TI - Load on the shoulder complex during wheelchair propulsion and weight relief lifting. AB - BACKGROUND: This study focuses on the relationship between overuse in association with wheelchair activities of daily living and risks for osteoarthrosis in the acromioclavicular and sternoclavicular joints. The aim is to quantify the joint moments and joint reaction forces in all three joints of the shoulder complex during wheelchair-related activities of daily living. METHODS: A convenience sample of 17 subjects performed two tasks (wheelchair propulsion and weight relief lifting). Three-dimensional kinematics and kinetics were measured and position and force data were used as input for a musculoskeletal model of the arm and shoulder. Output variables of the model were the moments and the joint reaction forces on the sternoclavicular, acromioclavicular and glenohumeral joints. FINDINGS: Moments on the sternoclavicular joint were higher than on the acromioclavicular and glenohumeral joint, but the joint reaction forces on the sternoclavicular and acromioclavicular joints were only one third of those on the glenohumeral joint (peak forces around 96N compared to 315N for wheelchair propulsion and around 330N compared to 1288N for weight relief lifting). INTERPRETATION: Based on the results found in this study, net joint moments are likely a better measure to describe the load on the acromioclavicular and sternoclavicular joints due to the passive stabilization. Prospective studies on wheelchair overuse injuries should also look at the acromioclavicular and sternoclavicular joints since the load of wheelchair tasks might be a risk factor for osteoarthrosis in these joints. PMID- 21316823 TI - Current practice and future directions for optimization of platelet transfusions in patients with severe therapy-induced cytopenia. AB - Platelet transfusions are mainly used for patients with thrombocytopenia due to bone marrow failure, especially cancer patients developing severe chemotherapy induced thrombocytopenia (e.g. patients with acute leukemia or other hematologic malignancies). A prophylactic transfusion strategy is now generally accepted in developed countries. Some clinical data, however, support the use of a therapeutic transfusion strategy at least for certain subsets of these patients. Several methodological approaches can then be used to evaluate the outcome of platelet transfusions, including peripheral blood platelet increments and bleeding assessments. Several factors will influence the efficiency of platelet transfusions; fever and ongoing hemorrhage are among the most important patient dependent factors, but the number and quality of the transfused platelets are also important. The quality of transfused platelets can be evaluated by analyzing platelet activation, metabolism or senescence/apoptosis. Only evaluation of metabolism is included in international guidelines, but high-throughput methods for evaluation of activation and senescence/apoptosis are available and should be incorporated into routine clinical practice if future studies demonstrate that they reflect clinically relevant platelet characteristics. Finally, platelet transfusions have additional biological effects that may cause immunomodulation or altered angioregulation; at present it is not known whether these effects will influence the long-time prognosis of cancer patients. Thus, several questions with regard to the optimal use of platelet transfusions in cancer patients still need to be answered. PMID- 21316824 TI - The performance of passive flow monitors and phosphate accumulating passive samplers when exposed to pulses in external water flow rate and/or external phosphate concentrations. AB - Passive samplers are typically calibrated under constant flow and concentration conditions. This study assessed whether concentration and/or flow pulses could be integrated using a phosphate passive sampler (P-sampler). Assessment involved three 21-day experiments featuring a pulse in flow rate, a pulse of filterable reactive phosphate (FRP) concentration and a simultaneous concentration and flow pulse. FRP concentrations were also determined by parallel grab sampling and the P-sampler calibrated with passive flow monitors (PFMs) and direct measurement of flow rates. The mass lost from the PFM over the deployment periods predicted water velocity to within 5.1, 0.48 and 7.1% when exposed to a flow rate pulse (7.5-50 cm s(-1)), concentration pulse (5-100 MUg P L(-1)), or both simultaneously. For the P-sampler, good agreement was observed between the grab and passive measurements of FRP concentration when exposed to a pulse in flow (6% overestimation) or concentration (2% underestimation). PMID- 21316825 TI - Determination of PM10 deposition based on antimony flux to selected urban surfaces. AB - Deposition of PM(10) particles to several types of urban surfaces was investigated within this study. Antimony was chosen as a tracer element to calculate dry deposition velocities for PM(10), since antimony proved to be present almost exclusively in PM(10) particles in ambient urban air. During 18 months, eight sampling sites in Berlin and Karlsruhe, two cities in Germany, were operated. PM(10) concentrations and dry deposition were routinely sampled as two week averages. Additionally, leaf-samples were collected at three sites with tall vegetation. The obtained deposition velocities ranged from 0.8 to 1.3 cms(-1) at roadside sites and from 0.4 to 0.5 cms(-1) at the other sites. With reference to the whole canopy, additional deposition velocities of about 0.5 cms(-1) were obtained for leaf surfaces. As a consequence, it can be concluded that vegetation covered areas beside streets show the highest potential to capture particles in urban areas. PMID- 21316826 TI - Salting our landscape: an integrated catchment model using readily accessible data to assess emerging road salt contamination to streams. AB - A new integrated catchment model for salinity has been developed to assess the transport of road salt from upland areas in watersheds to streams using readily accessible landscape, hydrologic, and meteorological data together with reported salt applications. We used Fishkill Creek (NY) as a representative watershed to test the model. Results showed good agreement between modeled and measured stream water chloride concentrations. These results suggest that a dominant mode of catchment simulation that does not entail complex deterministic modeling is an appropriate method to model salinization and to assess effects of future applications of road salt to streams. We heuristically increased and decreased salt applications by 100% and results showed that stream chloride concentrations increased by 13% and decreased by 7%, respectively. The model suggests that future management of salt application can reduce environmental concentrations, albeit over some time. PMID- 21316827 TI - Identification of magnetic particulates in road dust accumulated on roadside snow using magnetic, geochemical and micro-morphological analyses. AB - The aim of this study is to test the applicability of snow surveying in the collection and detailed characterization of vehicle-derived magnetic particles. Road dust extracted from snow, collected near a busy urban highway and a low traffic road in a rural environment (southern Finland), was studied using magnetic, geochemical and micro-morphological analyses. Significant differences in horizontal distribution of mass specific magnetic susceptibility (chi) were noticed for both roads. Multi-domain (MD) magnetite was identified as the primary magnetic mineral. Scanning electron microscope (SEM) analyses of road dust from both roads revealed: (1) angular-shaped particles (diameter~-300 MUm) mostly composed of Fe, Cr and Ni, derived from circulation of motor vehicles and (2) iron-rich spherules (d~2-70 MUm). Tungsten-rich particles (d<2 MUm), derived from tyre stud abrasion were also identified. Additionally, a decreasing trend in chi and selected trace elements was observed with increasing distance from the road edge. PMID- 21316828 TI - A process for the inclusion of Aboriginal People in health research: lessons from the Determinants of TB Transmission project. AB - The Determinants of TB Transmission (DTT) project, a federally-funded study covering the period April 1, 2006-March 31, 2013, and examining the determinants of TB transmission amongst the Canadian-born population (Aboriginal and non Aboriginal) in the prairie provinces of Canada, took a novel approach to health research involving Aboriginal people. The methodology aligned itself with the recently published Canadian Institutes of Health Research (CIHR) Guidelines for Health Research Involving Aboriginal People and the established principles of Ownership, Control, Access, and Possession (OCAP). This article details the process by which collaboration with Aboriginal peoples was achieved, including the involvement of Aboriginal researchers, the development of Provincial Network Committees (PNCs), and communications with First Nations Chiefs and Council. Strengths of this methodology included Aboriginal organizational and community support with a high rate of participation; PNC leadership, which brought together Aboriginal stakeholders with provincial and federal TB program planners; and the exploration of both on and off-reserve transmission factors. Challenges of the methodology included meeting funding agency timelines and expectations given the gradual process of trust development and PNC-reviewed publication; respecting both community and individual participants' autonomy regarding study participation; and political discomfort with strong Aboriginal involvement. While the methodology required a dedicated investment from researchers and funding agencies alike, the process was worthwhile and achieved a high degree of support from its major collaborators: the Aboriginal peoples. PMID- 21316829 TI - Neighborhood socioeconomic status predictors of physical activity through young to middle adulthood: the CARDIA study. AB - Neighborhood socioeconomic status (SES) is related to a wide range of health outcomes, but existing research is dominated by cross-sectional study designs, which are particularly vulnerable to bias by unmeasured characteristics related to both residential location decisions and health-related outcomes. Further, little is known about the mechanisms by which neighborhood SES might influence health. Therefore, we estimated longitudinal relationships between neighborhood SES and physical activity (PA), a theorized mediator of the neighborhood SES health association. We used data from four years of the Coronary Artery Risk Development in Young Adults (CARDIA) study (n = 5115, 18-30 years at baseline, 1985-1986), a cohort of U.S. young adults followed over 15 years, and a time varying geographic information system. Using two longitudinal modeling strategies, this is the first study to explicitly examine how the estimated association between neighborhood SES (deprivation) and PA is biased by (a) measured characteristics theorized to influence residential decisions (e.g., controlling for individual SES, marriage, and children in random effects models), and (b) time-invariant, unmeasured characteristics (e.g., controlling for unmeasured motivation to exercise that is constant over time using repeated measures regression modeling, conditioned on the individual). After controlling for sociodemographics (age, sex, race) and individual SES, associations between higher neighborhood deprivation and lower PA were strong and incremental in blacks, but less consistent in whites. Furthermore, adjustment for measured characteristics beyond sociodemographics and individual SES had little influence on the estimated associations; adjustment for unmeasured characteristics attenuated negative associations more strongly in whites than in blacks. PMID- 21316830 TI - Socioeconomic variation in recall and perceived effectiveness of campaign advertisements to promote smoking cessation. AB - There are large disparities in cigarette smoking rates by socioeconomic status (SES) in many countries. There is mixed evidence about the relative effectiveness of smoking cessation media campaigns in promoting quitting between lower and higher SES populations, and studies suggest that some types of ad content may have differential effects by SES. We analyzed data from five waves of the New York Media Tracking Survey Online (MTSO), a web survey involving over 7000 adult smokers conducted between 2007 and 2009, to assess SES variation in response to smoking cessation ads. Smokers with low levels of education and income less often recalled ads focused on how to quit, and perceived them as less effective, than ads using graphic imagery or personal testimonials to convey why to quit. Contrary to predictions offered by the Stages of Change Model, we found no evidence that variation in readiness to quit smoking explained patterns of response by education. Results offer guidance for theorists and campaign planners in developing campaigns that are likely to promote cessation among less educated populations. PMID- 21316831 TI - In the mood for science: a discussion of emotion management in a pharmacogenomics research encounter in Denmark. AB - We investigated the practices through which patients in treatment for depression become research subjects in pharmacogenomics research in Denmark. On the basis of an ethnographic study of research subject participation taking place between May 2006 and August 2007, we conceptualized the efforts made by both researchers and research subjects at the research encounter as emotion management, through which the raw material of pharmacogenomics research is created. The study demonstrates that management of emotions in the research encounter is necessary to secure high quality data and simultaneously produces new relations of exchange - exchanges we view as important fuel in the generation of biovalue. In bringing this analysis into dialogue with the bioethical emphasis on altruism, we challenge the assumption that research participation comes about by linking already available, that is, 'altruistic', individuals to research institutions. We suggest that the emotion management taking place in the research encounter and the relations of exchange established through it actualize behavior we recognize as 'altruistic'. We conclude that there is no morally relevant conflict between 'altruistic behaviour' and the production of exchange relations. PMID- 21316832 TI - Deliberation to enhance awareness of and prioritize socioeconomic interventions for health. AB - Health disparities are, to a large extent, the result of socio-economic factors that cannot be entirely mitigated through the health care system. While an array of social services are thought to be necessary to address the social determinants of health, budget constraints, particularly in difficult economic times, limit the availability of such services. It is therefore necessary to prioritize interventions through some fair process. While it might be appropriate to engage in public deliberation to set priorities, doing so requires that the public accept such a deliberative process and appreciate the social determinants of health. We therefore analyzed the results of a study in which groups deliberated to prioritize socio-economic interventions to examine whether these two requirements can possibly be met and to explore the basis for their priorities. A total of 431 residents of Washington, D.C. with incomes under 200% of the federal poverty threshold participated in 43 groups to engage in a hypothetical exercise to prioritize interventions designed to ameliorate the social determinants of health within the constraints of a limited budget. Findings from pre- and post exercise questionnaires demonstrate that the priority setting exercise was perceived as a fair deliberative process, and that following the deliberation, participants became more likely to agree that a broad number of determinants contribute to their health. Qualitative analysis of the group discussions indicate that participants prioritized interventions that would provide for basic necessities and improve community conditions, while at the same time addressing more macro-structural factors such as homelessness and unemployment. We conclude that engaging small groups in deliberation about ways to address the social determinants of health can both change participant attitudes and yield informed priorities that might guide public policy aimed at most affordably reducing health disparities. PMID- 21316833 TI - COPD exacerbation: mortality prognosis factors in a respiratory care unit. AB - OBJECTIVE: The aim of our study was to investigate the mortality predictive factors after a severe exacerbations of COPD admitted to a Spanish respiratory intermediate care unit (IRCU). PATIENTS AND METHODS: Prospective observational 2 years study, where we included all episodes of acute exacerbations of COPD with hypercapnic respiratory failure admitted in an IRCU. We analyzed different sociodemographic, functional and clinical variables including physical activity. RESULTS: We collected data from 102 consecutive episodes admitted to IRCU (90.1% men). Mean age was 69.4+/-10.6. The mean APACHE II was 19.6+/-5.0 and 9.5% presented a failure of other non respiratory organ. Non invasive ventilation was applied in 75.3% of the episodes and this treatment failed in 11.6% of them. The duration of stay in the IRCU was 3.5+/-2.1 days and 8.0+/-5.3 days in the hospital. The hospital mortality rate was 6.9%, and another 12.7% after 90 days of discharged. In order to predict hospital mortality, multivariant statistics identified a model with AUC of 0.867, based in 3 variables: the number of previous year admission for COPD exacerbation (p=0,048), the respiratory rate after 2 hours of treatment in the IRCU (p=0.0484) and the severity of the disease established with ADO score (p=0.0241). CONCLUSIONS: The number of previous year admission for COPD exacerbation, the severity of the disease established with ADO score, the respiratory rate after 2 hours of treatment, allow us to identify what patients with a COPD exacerbation admitted in a IRCU can die during this episode. PMID- 21316834 TI - Usefulness of the INTERMACS Scale for predicting outcomes after urgent heart transplantation. AB - INTRODUCTION AND OBJECTIVES: Our aim was to assess the prognostic value of the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) scale in patients undergoing urgent heart transplantation (HT). METHODS: Retrospective analysis of 111 patients treated with urgent HT at our institution from April, 1991 to October, 2009. Patients were retrospectively assigned to three levels of the INTERMACS scale according to their clinical status before HT. RESULTS: Patients at the INTERMACS 1 level (n=31) more frequently had ischemic heart disease (P=.03) and post-cardiothomy shock (P=.02) than patients at the INTERMACS 2 (n=55) and INTERMACS 3-4 (n=25) levels. Patients at the INTERMACS 1 level showed higher preoperative catecolamin doses (P=.001), a higher frequency of use of mechanical ventilation (P<.001), intraaortic balloon (P=.002) and ventricular assist devices (P=.002), and a higher frequency of preoperative infection (P=.015). The INTERMACS 1 group also presented higher central venous pressure (P=.02), AST (P=.002), ALT (P=.006) and serum creatinine (P<.001), and lower hemoglobin (P=.008) and creatinine clearance (P=.001). After HT, patients at the INTERMACS 1 level had a higher incidence of primary graft failure (P=.03) and postoperative need for renal replacement therapy (P=.004), and their long term survival was lower than patients at the INTERMACS 2 (log rank 5.1, P=.023; HR 3.1, IC 95% 1.1-8.8) and INTERMACS 3-4 level (log rank 6.1, p=0.013; HR 6.8, IC 95% 1.2-39.1). CONCLUSIONS: Our results suggest that the INTERMACS scale may be a useful tool to stratify postoperative prognosis after urgent HT. PMID- 21316835 TI - Comment on 'Comment on "Another look at the molecular mechanism of the resistance of H5N1 influenza A virus neuraminidase (NA) to oseltamivir (OTV)"'. PMID- 21316836 TI - Surgery for stress urinary incontinence: so near and yet so far. PMID- 21316837 TI - Antithrombin III associated with fibrinogen predicts the risk of cerebral ischemic stroke. AB - BACKGROUND AND PURPOSE: The purpose of this study is to examine the feasibility of developing plasma predictive value biomarkers of cerebral ischemic stroke before imaging evidence is acquired. METHODS: Blood samples were obtained from 198 patients who attended our neurology department as emergencies - with symptoms of vertigo, numbness, limb weakness, etc. - within 4.5 h of symptom onset, and before imaging evidence was obtained and medical treatment. After the final diagnosis was made by MRI/DWI/MRA or CTA in the following 24-72 h, the above cases were divided into two groups: stroke group and non-stroke group according to the imaging results. The levels of baseline plasma antithrombin III (AT-III), thrombin-antithrombin III (TAT), fibrinogen, D-dimer and high-sensitivity C reactive protein (hsCRP) in the two groups were assayed. RESULTS: The level of the baseline AT-III in the stroke group was 118.07+/-26.22%, which was lower than that of the non-stroke group (283.83+/-38.39%). The levels of TAT, fibrinogen, hsCRP were 7.24+/-2.28 MUg/L, 5.49+/-0.98 g/L, and 2.17+/-1.07 mg/L, respectively, which were higher than those of the non-stroke group (2.53+/-1.23 MUg/L, 3.35+/-0.50 g/L, 1.82+/-0.67 mg/L). All the P-values were less than 0.001. The D-dimer level was 322.57+/-60.34 MUg/L, which was slightly higher than that of the non-stroke group (305.76+/-49.52 MUg/L), but the P-value was 0.667. The sensitivities of AT-III, TAT, fibrinogen, D-dimer and hsCRP for predicting ischemic stroke tendency were 97.37%, 96.05%, 3.29%, 7.89%, but the specificity was 93.62%, 82.61%, 100% and 100%, respectively, and all the P-values were less than 0.001. High levels of D-dimer and hsCRP were mainly seen in the few cases with severe large-vessel infarction. CONCLUSIONS: Clinical manifestations of acute focal neurological deficits were associated with plasma AT-III and fibrinogen. These tests might help the risk assessment of acute cerebral ischemic stroke and/or TIA with infarction tendency in the superacute stage before positive imaging evidence is obtained. PMID- 21316838 TI - Helicobacter pylori may play an important role in both axonal type Guillain-Barre syndrome and acute inflammatory demyelinating polyradiculoneuropathy. PMID- 21316839 TI - BAG3 (BCL2-associated athanogene 3) interacts with MMP-2 to positively regulate invasion by ovarian carcinoma cells. AB - BAG3 (BCL2-associated athanogene 3) is a member of the BAG family proteins, which interact with and regulate Hsp70. Our aim in the present study was to correlate BAG3 expression in ovarian cancer with invasion and progression-free survival. We found that BAG3 interacts with MMP2 in cultured ovarian cancer cells, and that knockdown of BAG3 expression downregulated MMP2 expression and diminished cell motility and invasiveness. The incidence of BAG3 positivity was significantly higher at advanced clinical stages of ovarian cancer than at early stages. We suggest that BAG3 binds to MMP2 to positively regulate the process of cell invasion. PMID- 21316840 TI - Molecular competition between plasminogen activator inhibitors type -1 and -2 for urokinase: Implications for cellular proteolysis and adhesion in cancer. AB - Up-regulation of the urokinase plasminogen activation (uPA) system leads to increased cancer invasion and metastasis. Plasminogen activator inhibitors type-1 (PAI-1/SERPINE1) and type-2 (PAI-2/SERPINB2) have similar uPA inhibitory properties yet PAI-1 promotes cell invasion by modulating cell adhesion and migration. High tumour PAI-2 levels are associated with improved prognoses. Herein we show that PAI-2 is capable of inhibiting uPA in the presence of PAI-1, particularly on adherent cells in the presence of vitronectin. This suggests that elevated levels of PAI-2 in the tumour microenvironment could outcompete PAI-1 for uPA inhibition through its inhibitory serpin function. However, PAI-1 modulated cell adhesion in a largely uPA-independent manner consequently PAI-2 could not counteract the effects of PAI-1 on adhesion/migration. Thus studies aimed at further characterising the interplay between PAI-1 and PAI-2 on uPA dependent pro-invasive processes are warranted. PMID- 21316841 TI - Pentamidine reduces expression of hypoxia-inducible factor-1alpha in DU145 and MDA-MB-231 cancer cells. AB - Pentamidine is an aromatic diamine used for the treatment of human protozoa infections. Recently, pentamidine has been reported to exhibit anticancer properties. In this study, we report that pentamidine inhibits expression of hypoxia-inducible factor (HIF)-1alpha in cancer cells. Pentamidine decreased HIF 1alpha protein translation and enhanced its protein degradation in DU145 prostate cancer and MDA-MB-231 breast cancer cells. In parallel with reduction of de novo synthesis of HIF-1alpha, pentamidine was able to suppress global protein translation, an effect accompanied by the reduction of eIF4F complex formation and also the induction of eIF2alpha phosphorylation. These results show that pentamidine is a potential inhibitor of HIF-1alpha and its potential as a cancer therapeutic reagent warrants further study. PMID- 21316842 TI - Enhanced photocatalytic activity of C-N-codoped TiO2 films prepared via an organic-free approach. AB - An organic-free sol-gel method was developed to synthesize crack-free, high surface roughness and visible-light-active C-N-codoped TiO(2) films. These films were subsequently evaluated for its photodegradation efficient using stearic acid as the model pollutant compound. The current approach avoids the use of hazardous organic solvents and employs carbon black as the carbon source as well as a template to increase the surface roughness. The presence of carbon and nitrogen species in TiO(2) was studied and discussed. The concentrations of carbon and nitrogen dopants in the TiO(2) films were affected by calcination temperature and the concentration of carbon black. Optimal visible light photocatalytic activity was observed for C-N-codoped TiO(2) film at 10.0 wt.% C, which was more than double that of the N-doped TiO(2) film. The enhancement in visible light photocatalytic activities of the C-N-codoped TiO(2) films was attributed to the synergistic effects of carbon and nitrogen dopants, and high surface roughness of the prepared films. PMID- 21316843 TI - Nitrification activity and community structure of nitrite-oxidizing bacteria in the bioreactors operated with addition of pharmaceuticals. AB - Pharmaceuticals represent a group of the new emerging contaminants, which might influence microbial communities in the activated sludge. Nitrification activity and Nitrospira community structure in the small-scale reactors supplied with different concentrations (0, 50, 200, 500 MUg L(-1)) of the selected pharmaceuticals (ibuprofen, naproxen, ketoprofen, diclofenac and clofibric acid) were evaluated. Ammonia removal was not influenced by selected pharmaceuticals. However, in the two reactors operated with 50 MUg L(-1) of pharmaceuticals (R50 and R50P), the effluent concentration of N-(NO(2)(-)+NO(3)(-)) was significantly higher than in the other reactors. Nitrospira community structure was assessed by terminal restriction fragment length polymorphism (T-RFLP) and by cloning and sequencing of the partial genes for 16S rRNA. Nitrospira spp. were detected in all reactors. The two dominant T-RFs represented the sublineages I and II of the genus Nitrospira. Main shifts were observed in the reactors R50 and R50P, where the T-RF representing sublineage II was much higher as compared to the other reactors. Consistent with this, the Nitrospira sublineage II was detected only in the clone libraries from the reactors R50 and R50P. Our results suggest that the relative abundance of Nitrospira sublineage II could be related to the effluent N (NO(2)(-)+NO(3)(-)) concentration. PMID- 21316844 TI - Which emission sources are responsible for the volatile organic compounds in the atmosphere of Pearl River Delta? AB - A field measurement study of volatile organic compounds (VOCs) was simultaneously carried out in October-December 2007 at an inland Pearl River Delta (PRD) site and a Hong Kong urban site. A receptor model i.e. positive matrix factorization (PMF) was applied to the data for the apportionment of pollution sources in the region. Five and six sources were identified in Hong Kong and the inland PRD region, respectively. The major sources identified in the region were vehicular emissions, solvent use and biomass burning, whereas extra sources found in inland PRD included liquefied petroleum gas and gasoline evaporation. In Hong Kong, the vehicular emissions made the most significant contribution to ambient VOCs (48 +/ 4%), followed by solvent use (43 +/- 2%) and biomass burning (9 +/- 2%). In inland PRD, the largest contributor to ambient VOCs was solvent use (46 +/- 1%), and vehicular emissions contributed 26 +/- 1% to ambient VOCs. The percentage contribution of vehicular emission in Hong Kong in 2007 is close to that obtained in 2001-2003, whereas in inland PRD the contribution of solvent use to ambient VOCs in 2007 was at the upper range of the results obtained in previous studies and twice the 2006 PRD emission inventory. The findings advance our knowledge of ozone precursors in the PRD region. PMID- 21316845 TI - Preparation and characterization of photoactive composite kaolinite/TiO(2). AB - Preparation of nanocomposite kaolinite/TiO(2), using hydrolysis of titanyl sulfate in the presence of kaolin was addressed. A variable (kaolin)/(titanyl sulfate) ratio has been used in order to achieve the desired TiO(2) content in prepared nanocomposites. Calcination of the composites at 600 degrees C led to the transformation of the kaolinite to metakaolinite and to origination of metakaolinite/TiO(2) composites. The prepared samples were investigated using X ray fluorescence spectroscopy, X-ray powder diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, thermogravimetry and diffuse reflectance spectroscopy in the UV-VIS region. Structural ordering of TiO(2) on the kaolinite particle surface was modeled using empirical force field atomistic simulations in the Material Studio modeling environment. Photodegradation activity of the composites prepared was evaluated by the discoloration of Acid Orange 7 aqueous solution. PMID- 21316846 TI - Sulfide oxidation and acid mine drainage formation within two active tailings impoundments in the Golden Quadrangle of the Apuseni Mountains, Romania. AB - Sulfidic mine tailings have to be classified as one of the major source of hazardous materials leading to water contamination. This study highlights the processes leading to sulfide oxidation and acid mine drainage (AMD) formation in the active stage of two tailings impoundments located in the southern part of the Apuseni Mountains, in Romania, a well-known region for its long-term gold-silver and metal mining activity. Sampling was undertaken when both impoundments were still in operation in order to assess their actual stage of oxidation and long term behavior in terms of the potential for acid mine drainage generation. Both tailings have high potential for AMD formation (2.5 and 3.7 wt.% of pyrite equivalent, respectively) with lesser amount of carbonates (5.6 and 3.6 wt.% of calcite equivalent) as neutralization potential (ABA=-55.6 and -85.1 tCaCO(3)/1000 t ) and showed clear signs of sulfide oxidation yet during operation. Sequential extraction results indicate a stronger enrichment and mobility of elements in the oxidized tailings: Fe as Fe(III) oxy-hydroxides and oxides (transformation from sulfide minerals, leaching in oxidation zone), Ca mainly in water soluble and exchangeable form where gypsum and calcite are dissolved and higher mobility of Cu for Ribita and Pb for Mialu. Two processes leading to the formation of mine drainage at this stage could be highlighted (1) a neutral Fe(II) plume forming in the impoundment with ferrihydrite precipitation at its outcrop and (2) acid mine drainage seeping in the unsaturated zone of the active dam, leading to the formation of schwertmannite at its outcrop. PMID- 21316847 TI - Benzene and toluene biodegradation down gradient of a zero-valent iron permeable reactive barrier. AB - This study simulated benzene and toluene biodegradation down gradient of a zero valent iron permeable reactive barrier (ZVI PRB) that reduces trichloroethylene (TCE). The effects of elevated pH (10.5) and the presence of a common TCE dechlorination by product [cis-1,2-dichloroethene (cis-1,2-DCE)] on benzene and toluene biodegradation were evaluated in batch experiments. The data suggest that alkaline pH (pH 10.5), often observed down gradient of ZVI PRBs, inhibits Fe(III) mediated biotransformation of both benzene and toluene. Removal was reduced by 43% for benzene and 26% for toluene as compared to the controls. The effect of the addition of cis-1,2-DCE on benzene and toluene biodegradation was positive and resulted in removal that was greater than or equal to the controls. These results suggest that, at least for cis-1,2-DCE, its formation may not be toxic to iron-reducing benzene and toluene degrading bacteria; however, for microbial benzene and toluene removal down gradient of a ZVI PRB, it may be necessary to provide pH control, especially in the case of a biological PRB that is downstream from a ZVI PRB. PMID- 21316848 TI - Carbons prepared from Spartina alterniflora and its anaerobically digested residue by H3PO4 activation: characterization and adsorption of cadmium from aqueous solutions. AB - Two series of activated carbons were prepared from Spartina alterniflora and from its anaerobically digested residue by H(3)PO(4) activation at various process conditions, and used as adsorbents for the removal of cadmium (II) in aqueous solutions. The surface areas and pore volumes of carbons were derived from adsorption isotherms (N(2) at 77K). The surface chemistry of carbons was investigated by infrared spectroscopy. Comparison study indicated that physicochemical properties of the activated carbons were strongly dependent not only on activation conditions but also on biopolymer contents of precursors. Several isotherm models were investigated and the adsorption isotherm data were best represented by the Langmuir isotherm model, with a maximum monolayer adsorption capacity of 47.85 mg/g at 25 degrees C. The results showed that the activated carbon produced from S. alterniflora could be employed as a promising adsorbent for removing cadmium (II) from aqueous solutions. PMID- 21316849 TI - Electro-enzymatic degradation of chlorpyrifos by immobilized hemoglobin. AB - Electro-enzymatic processes, which are enzyme catalysis combined with electrochemical reactions, have been used in the degradation of many environment pollutants. For some pollutants, the catalytic mechanisms of the electrochemical enzyme reaction are still poorly understood. In this paper, the degradation of chlorpyrifos by a combination of immobilized hemoglobin and in situ generated hydrogen peroxide is reported for the first time. Hemoglobin was immobilized on graphite felts to catalyze the removal of chlorpyrifos in an electrochemical enzyme system. Under the optimal conditions, more than 98% of the chlorpyrifos was degraded. Furthermore, the degradation products of chlorpyrifos were also studied and identified using liquid chromatography-mass spectrometry analysis. The results suggest a possible degradation mechanism for chlorpyrifos with low power and high efficiency, reveal the feasibility of hemoglobin as a substitute for some expensive natural enzymes, and demonstrate the application of an electro enzymatic process in the treatment of organophosphorus compounds in wastewater. PMID- 21316850 TI - Metal precipitation in an ethanol-fed, fixed-bed sulphate-reducing bioreactor. AB - A batch upflow fixed-bed sulphate-reducing bioreactor has been set up and monitored for the treatment of synthetic solutions containing divalent iron (100mg/L and 200mg/L), zinc (100mg/L and 200mg/L), copper (100mg/L and 200mg/L), nickel (100mg/L and 200mg/L) and sulphate (1700 mg/L and 2130 mg/L) at initial pH 3-3.5, using ethanol as the sole electron donor. The reactor has been operated at the theoretical stoichiometric ethanol/sulphate ratio. Complete oxidation of ethanol has been achieved through complete oxidation of the intermediately, microbially produced acetate. This is mainly attributed to the presence of Desulfobacter postgatei species which dominated the sulphate-reducing community in the reactor. The reduction of sulphate was limited to about 85%. Quantitative precipitation of the soluble metal ions has been achieved. XRD and SEM-EDS analyses performed on samples of the produced sludge showed poorly crystalline phases of marcasite, covellite and wurtzite as well as several mixed metal sulphides. PMID- 21316851 TI - Reduction of the short-term availability of copper, lead and zinc in a contaminated soil amended with municipal solid waste compost. AB - The effect of two municipal solid waste composts on the availability of Cu, Pb and Zn in a soil contaminated in the laboratory was evaluated. An agricultural acid soil developed on granite was amended with the composts at two rates (3% and 6% dry weight), contaminated with 1000 mg kg(-1) of Cu, Pb and Zn, and incubated in the laboratory for three months. Determinations of soil pH, CaCl(2) extractable and EDTA-extractable Cu, Pb, and Zn were run monthly during the incubation. At the end, a leaching test (TCLP) and selective extractions were performed for these elements. The analysis of the CaCl(2)-extractable elements demonstrated a strong capacity of both composts to decrease the solubility of the metals added to the soil, specially for Cu and Pb. The percentage of reduction of the soluble forms with respect to the initial addition was higher at the highest rate of compost, and reached 99% for Cu and Pb, and 80% for Zn in the compost amended soil, whereas the soil without amendment was able to reduce Cu availability by a 94%, but not Zn or Pb availability. The TCLP test showed that compost also reduced the leachability of the three elements. Nevertheless, EDTA extracted a major amount (around 90%) of the elements added in all the treatments. Given that EDTA has a strong ability to extract elements bound to organic matter, it can be hypothesized that the main mechanism of the observed insolubilization was the formation of low-solubility organo-metallic complexes with both soil and compost organic matter. The selective extractions confirmed that compost reduced the exchangeable fraction of the elements, and that the organically bound fraction (pyrophosphate-extractable) was the main one for the three elements. PMID- 21316852 TI - Utilization of petrochemical wastewater for the production of poly(3 hydroxybutyrate) by Haloarcula sp. IRU1. AB - Wastewater of petrochemical industries contains high amounts of emulsified aliphatic or aromatic hydrocarbons that lead to the contamination of almost all environmental resources. The ability of Haloarcula sp. IRU1 isolated from Urmia lake, Iran for utilization of petrochemical wastewater and production of poly(3 hydroxybutyrate) (PHB) from it was evaluated and optimized by Taguchi experimental method. The optimium conditions for the maximum production of PHB were petrochemical wastewater 2% (as carbon source), tryptone 0.8% (as nitrogen source), KH(2)PO(4) 0.001% (as phosphorus source) and temperature 47 degrees C. In conclusion, Haloarcula sp. IRU1 can degrade petrochemical wastewater and produce PHB from it in different conditions. PMID- 21316853 TI - Artificial neural network modeling in competitive adsorption of phenol and resorcinol from water environment using some carbonaceous adsorbents. AB - This paper illustrates the application of artificial neural network (ANN) for prediction of performances in competitive adsorption of phenol and resorcinol from aqueous solution by conventional and low cost carbonaceous adsorbent materials, such as activated carbon (AC), wood charcoal (WC) and rice husk ash (RHA). The three layer's feed forward neural network with back propagation algorithm in MATLAB environment was used for estimation of removal efficiencies of phenol and resorcinol in bi-solute water environment based on 29 sets of laboratory batch study results. The input parameters used for training of the neural network include amount of adsorbent (g/L), initial concentrations of phenol (mg/L) and resorcinol (mg/L), contact time (h), and pH. The removal efficiencies of phenol and resorcinol were considered as an output of the neural network. The performances of the developed ANN models were also measured using statistical parameters, such as mean error, mean square error, root mean square error, and linear regression. The comparison of the removal efficiencies of pollutants using ANN model and experimental results showed that ANN modeling in competitive adsorption of phenolic compounds reasonably corroborated with the experimental results. PMID- 21316854 TI - Thermal hazard assessment of nitrobenzene/dinitrobenzene mixtures. AB - During the production of nitrobenzene by an adiabatic nitration process, the main byproducts are mono and dinitrophenols as well as 2,4,6-trinitrophenol (picric acid) and 1,3-dinitrobenzene. The byproducts can become concentrated if a distillation step to remove high boiling point impurities is used. In the present work, representative samples of nitrobenzene containing 20-30% dinitrobenzene and less than 1% dinitrophenol, 1% picric acid, and 1% sodium hydroxide were tested by Differential Scanning Calorimetry (DSC) and Accelerating Rate Calorimetry (ARC) to investigate their thermal stability relative to the pure substances. The DSC thermal curves for pure nitrobenzene and the various nitrobenzene dinitrobenzene mixtures exhibited exothermic activity from about 300 degrees C to 500 degrees C and enthalpy changes of about -2.5 * 10(3)Jg(-1), which is very energetic. The impurities (dinitrophenol, picric acid, and sodium hydroxide) had no significant effect on the DSC results. During the ARC experiments, the various nitrobenzene-dinitrobenzene mixtures were found to be less thermally stable than pure nitrobenzene and pure dinitrobenzene, with exotherms beginning in the 263 280 degrees C temperature range. Analysis of ARC data indicates that short-term exposure of nitrobenzene mixtures containing up to 20 mass% dinitrobenzene to temperatures up to 208 degrees C should not pose a serious runaway reaction hazard. PMID- 21316855 TI - Safety and efficacy of pregabalin in patients with central post-stroke pain. AB - Pregabalin has demonstrated efficacy in several forms of neuropathic pain, but its long-term efficacy in central post-stroke pain (CPSP) is unproven. We evaluated the efficacy and safety of pregabalin versus placebo in patients with CPSP. A 13-week, randomized, double-blind, multicenter, placebo-controlled, parallel group study of 150 to 600 mg/day pregabalin was conducted in patients aged >=18 years with CPSP. The primary efficacy endpoint was the mean pain score on the Daily Pain Rating Scale over the last 7 days on study drug up to week 12 or early termination visit. Secondary endpoints included other pain parameters and patient-reported sleep and health-related quality-of-life measures. A total of 219 patients were treated (pregabalin n=110; placebo n=109). A mean pain score at baseline of 6.5 in the pregabalin group and 6.3 in the placebo group reduced at endpoint to 4.9 in the pregabalin group and 5.0 in the placebo group (LS mean difference=-0.2; 95% CI=-0.7, 0.4; P=0.578). Treatment with pregabalin resulted in significant improvements, compared with placebo, on secondary endpoints including MOS-sleep, HADS-A anxiety, and clinician global impression of change (CGIC) P<0.05. Adverse events were more frequent with pregabalin than with placebo and caused discontinuation in 9 (8.2%) of pregabalin patients versus 4 (3.7%) of placebo patients. Although pain reductions at endpoint did not differ significantly between pregabalin and placebo, improvements in sleep, anxiety, and CGIC suggest some utility of pregabalin in the management of CPSP. PMID- 21316856 TI - Neuropathic pain after thoracic surgery. PMID- 21316857 TI - Similarity of suffering: equivalence of psychological and psychosocial factors in neuropathic and non-neuropathic orofacial pain patients. AB - The degree to which neuropathic and non-neuropathic pain conditions differ in psychological and psychosocial status remains largely unexplored. A better understanding of these aspects would be of considerable benefit in helping to define whether similar psychological treatment strategies (eg, cognitive behavioural therapy) can be adopted in the management of neuropathic pain as in non-neuropathic pain conditions. Chronic orofacial pain disorders present a unique opportunity to compare nociceptive and neuropathic pain in the same body region. Twenty-four patients with trigeminal neuropathic pain, 21 patients with temporomandibular disorder, and 38 healthy controls were assessed with a psychological/psychosocial battery encompassing the 4 dimensions of the pain experience; sensory-discriminative, affective-motivational, cognitive-evaluative, and psychosocial. Although patients with trigeminal neuropathic pain (neuropathic pain) and temporomandibular disorder (non-neuropathic pain) described the sensory aspects of their pain differently, they exhibited comparable negative affective motivational, cognitive-evaluative, and psychosocial states, although these were significantly different compared to healthy controls. These findings support growing evidence that the negative affective, cognitive, and psychosocial state of chronic pain is universal, regardless of a neuropathic or nociceptive nature. Further characterisation of these 4 dimensions of the pain experience in different chronic pain subtypes may improve the efficacy of cognitive-behavioural therapy. PMID- 21316858 TI - A new method of trimming the fat from a full thickness skin graft. PMID- 21316860 TI - Genetics of cortisol secretion and depressive symptoms: a candidate gene and genome wide association approach. AB - BACKGROUND: Depressive patients often have altered cortisol secretion, but few studies have investigated genetic variants in relation to both cortisol secretion and depression. To identify genes related to both these conditions, we: (1) tested the association of single nucleotide polymorphisms (SNPs) in hypothalamic pituitary-adrenal-axis (HPA-axis) candidate genes with a summary measure of total cortisol secretion during the day (cortisol(AUC)), (2) performed a genome wide association study (GWAS) of cortisol(AUC), and (3) tested the association of identified cortisol-related SNPs with depressive symptoms. METHODS: We analyzed data on candidate SNPs for the HPA-axis, genome-wide scans, cortisol secretion (n=1711) and depressive symptoms (the Centre for Epidemiology Studies Depression Scale, CES-D) (n=2928) in elderly persons of the Rotterdam Study. We used data from the Whitehall II study (n=2836) to replicate the GWAS findings. RESULTS: Of the 1456 SNPs in 33 candidate genes, minor alleles of 4 SNPs (rs9470080, rs9394309, rs7748266 and rs1360780) in the FKBP5 gene were associated with a decreased cortisol(AUC) (p<1*10(-4) after correction for multiple testing using permutations). These SNPs were also associated with an increased risk of depressive symptoms (rs9470080: OR 1.19 (95%CI 1.0; 1.4)). The GWAS for cortisol yielded 2 SNPs with p-values of 1*10(-06) (rs8062512, rs2252459), but these associations could not be replicated. CONCLUSIONS: These results suggest that variation in the FKBP5 gene is associated with both cortisol(AUC) and the likelihood of depressive symptoms. PMID- 21316861 TI - The influence of client behavior during motivational interviewing on marijuana treatment outcome. AB - Psychotherapy process research continues to be important in identifying within session client and therapist behaviors related to outcome. Motivational Interviewing (MI) assumes that the type of client language elicited within session is important. Client behavior was coded from 61 MI sessions with marijuana dependent adults. Sessions were coded for client language using the Client Language and Commitment Scale. Client statements indicating desire and reasons for change were significantly predictive of marijuana treatment outcome through the 34-month follow-up above and beyond baseline levels of marijuana use or motivation for change. Commitment language was not associated with outcomes. These findings suggest specific types of client language statements predict marijuana treatment outcome and are durable to a 34-month follow-up. PMID- 21316862 TI - Prevention of alcohol use in middle school students: psychometric assessment of the decisional balance inventory. AB - A measurement model should be equivalent across the different subgroups of a target population. The Decisional Balance Inventory for the Prevention of Alcohol Use is a 2-factor correlated model with 3 items for Pros of alcohol use and 3 items for Cons. The measure is part of a tailored intervention for middle school students. This study evaluated the important psychometric assumptions of factorial invariance and scale reliability with a large sample of sixth grade students (N=3565) from 20 schools. A measure is factorially invariant when the model is the same across subgroups. Three levels of invariance were assessed, from least restrictive to most restrictive: 1) Configural Invariance (unconstrained nonzero factor loadings); 2) Pattern Identity Invariance (equal factor loadings); and 3) Strong Factorial Invariance (equal factor loadings and measurement errors). Structural equation modeling was used to assess invariance over two levels of gender (male and female), race (white and black), ethnicity (Hispanic and non-Hispanic), and school size (large, indicating >200 students per grade, or small). The strongest level of invariance, Strong Factorial Invariance, was a good fit for the model across all of the subgroups: gender (CFI: 0.94), race (CFI: 0.96), ethnicity (CFI: 0.93), and school size (CFI: 0.97). Coefficient alpha was 0.61 for the Pros and 0.67 for Cons. Together, invariance and reliability provide strong empirical support for the validity of the measure. PMID- 21316863 TI - Human cytomegalovirus infection is a novel etiology for essential hypertension. AB - Essential hypertension is a major risk factor for cardiovascular, cerebrovascular, and renal diseases. However, the underlying cause and pathologic mechanisms of essential hypertension are poorly understood. Vascular inflammation and endothelial dysfunction are implicated in the pathogenesis of hypertension based on associations with elevated expression of adhesion molecules and chemokines and dysfunctional nitric oxide synthase. Human cytomegalovirus (HCMV) has been implicated in several cardiovascular disorders, including atherosclerosis, coronary heart disease, and cardiac transplant arteriopathy. Recent studies have suggested that HCMV is associated with cardiovascular disorders through impaired endothelial nitric oxide synthase function and subsequent endothelial dysfunction, which manifest as impaired vasculature dilation in vivo. However, direct links between human cytomegalovirus infection and essential hypertension remain undefined. Based on current studies, we present a hypothesis that human cytomegalovirus is an opportunistic pathogen that causes essential hypertension by disrupting nitric oxide synthesis and immune defense and by activating inflammation and the renin-angiotensin system. PMID- 21316864 TI - A hypothesis of local intrinsic cortical signal processing. AB - Nearly a century ago, Ramon y Cajal [1] speculated that cortical interneurones underlie specific functions that are fundamental to human thought. Here we develop a computational analysis of the function of local cortical loops and their synaptic connections. Specifically, we propose that the function of cortical interneurones is to reduce redundancy and to contribute to compute saliency of information represented in neurones by implementing divisive normalization and multiplicative filtering functions. This contextual filtering by cortical interneurones reduces the energy of locally homogeneous information flowing between different cortical areas, in a non-linear manner and along various event spaces, thereby ensuring a homeostatic level of informational selectivity. Dysregulations of the synaptic transmission in this ubiquitous basic building block of the functional architecture of the brain are correspondingly associated with disturbances of informational selectivity. Perturbations of synaptic transmission in local intrinsic connections of the cerebral cortex consequently lead to various kinds of cognitive and/or affective disorders, depending on the exact nature, the extension and the specific localization of the distortion. PMID- 21316865 TI - Diabetes mellitus type 2 through oncology lens. PMID- 21316866 TI - Production of biogenic amines by lactic acid bacteria and enterobacteria isolated from fresh pork sausages packaged in different atmospheres and kept under refrigeration. AB - The occurrence of in vitro amino acid activity in bacterial strains associated with fresh pork sausages packaged in different atmospheres and kept in refrigeration was studied. The presence of biogenic amines in decarboxylase broth was confirmed by ion-exchange chromatography and by the presence of the corresponding decarboxylase genes by PCR. From the 93 lactic acid bacteria and 100 enterobacteria strains analysed, the decarboxylase medium underestimates the number of biogenic amine-producer strains. 28% of the lactic acid bacteria produced tyramine and presented the tdc gene. All the tyramine-producer strains were molecularly identified as Carnobacterium divergens. Differences on the relative abundance of C. divergens were observed among the different packaging atmospheres assayed. After 28 days of storage, the presence of argon seems to inhibit C. divergens growth, while packing under vacuum seems to favour it. Among enterobacteria, putrescine was the amine more frequently produced (87%), followed by cadaverine (85%); agmatine and tyramine were only produced by 13 and 1%, respectively, of the strains analysed. Packing under vacuum or in an atmosphere containing nitrogen seems to inhibit the growth of enterobacteria which produce simultaneously putrescine, cadaverine, and agmatine. Contrarily, over-wrapping or packing in an atmosphere containing argon seems to favour the growth of agmatine producer-enterobacteria. The production of putrescine and cadaverine was associated with the presence of the corresponding amino acid decarboxylase genes. The biogenic amine-producer strains were included in a wide range of enterobacterial species, including Kluyvera intermedia, Enterobacter aerogenes, Yersinia kristensenii, Serratia grimesii, Serratia ficaria, Yersinia rodhei, Providencia vermicola and Obesumbacterium proteus. PMID- 21316867 TI - Quality control of Toxoplasma gondii in meat packages: standardization of an ELISA test and its use for detection in rabbit meat cuts. AB - Toxoplasma gondii causes severe disease both to man and livestock and its detection in meat after slaughtering requires PCR or biological tests. Meat packages contain retained exudate that could be used for serology due to its blood content. Similar studies reported false negative assays in those tests. We standardized an anti-T. gondii IgG ELISA in muscle juices from experimentally infected rabbits, with blood content determination by cyanhemoglobin spectrophotometry. IgG titers and immunoblotting profiles were similar in blood, serum or meat juice, after blood content correction. These assays were adequate regardless of the storage time up to 120 days or freeze-thaw cycles, without false negative results. We also found 1.35% (1/74) positive sample in commercial Brazilian rabbit meat cuts, by this assay. The blood content determination shows ELISA of meat juice may be useful for quality control for toxoplasmosis monitoring. PMID- 21316868 TI - Carotenoid, colour and reflectance measurements in bovine adipose tissue to discriminate between beef from different feeding systems. AB - Our hypothesis was that carotenoids in bovine subcutaneous adipose tissue (SAT) together with colour and reflectance spectra could be used to differentiate between beef production systems based on grass, concentrates or combinations thereof. SAT was sampled from the carcasses of heifers fed pasture (P), a barley based concentrate (C), silage followed by pasture (SiP) or silage followed by pasture with concentrate (SiPC). beta-carotene in the SAT from the C group (0.09 MUg g(-1)) was lower (P<0.05) than that from the P (0.54 MUg g(-1)), SiP (0.49 MUg g(-1)) and SiPC (0.49 MUg g(-1)) groups. Lutein in the SAT differed (P<0.05) between all groups with 0.13, 0.10, 0.08 and 0.04 MUg g(-1) for the P, SiP, SiPC and C groups, respectively. Principal component analysis of the carotenoid data, SAT colour variables ['L', 'a', 'b', 'C', 'H'] and the reflectance data made it possible to distinguish between the animals fed a barley-based concentrate diet and the animals fed pasture-based diets, but not between different pasture-based groups. PMID- 21316869 TI - Vacuum skin pack of beef--a consumer friendly alternative. AB - The aim of this study was to assess how beef quality traits are affected by skin packaging compared with vacuum and high-oxygen modified atmosphere packaging (MAP; 80% O(2) and 20% CO(2)). Both M. longissimus dorsi from 6 young bulls were cut and aged in vacuum for 7 days and then cut into 3.5-cm steaks, thereafter either frozen directly day 7 or stored in skin pack, vacuum pack or MAP for an additional 7 or 14 days and then frozen. Warner-Bratzler shear force, loss and colour were measured and sensory analysis was performed. The results showed no differences in shear force, sensory analysis and total loss between steaks packed in skin pack or vacuum, but skin packed steaks had lower purge loss. MAP steaks had lower sensory scores than the other treatments at days 14 and 21. Raw MAP steaks were bright red, but showed signs of premature browning when cooked. PMID- 21316870 TI - Effects on the development of blown pack spoilage of the initial numbers of Clostridium estertheticum spores and Leuconostoc mesenteroides on vacuum packed beef. AB - Beef steaks were inoculated with Clostridium estertheticum spores and Leuconostoc mesenteroides cells at all combinations of numbers of 0, 10, 100 or 1000/cm(2) for each organism. After vacuum packaging the steaks were stored at 4, 1, or -1.5 degrees C. Pack volumes were determined by water displacement at suitable intervals. Irrespective of L. mesenteroides numbers, for packs containing meat inoculated with 0, 10, 100 or 1000 spores/cm(2), 60, 16, 3 and 1 of 60 packs did not swell. The times of onset of swelling were twice as long at -1.5 as at 4 degrees C, but they were not affected by the inoculated numbers of L. mesenteroides. Rates of pack swelling increased with increasing storage temperature and number of spores, but decreased with increasing numbers of inoculated L. mesenteroides. Lactic acid bacteria can apparently prevent development of blown pack spoilage of vacuum packs containing meat contaminated with low numbers of C. estertheticum. PMID- 21316871 TI - High prevalence of substance use among heterosexuals living in communities with high rates of AIDS and poverty in Washington, DC. AB - OBJECTIVES: To assess the prevalence and patterns of substance use, HIV prevalence, and sexual risk behaviors in a community-based sample of heterosexuals recruited from areas at high risk for HIV/AIDS and poverty in Washington, DC. METHODS: Community-recruited heterosexuals aged 18-50 from areas of high AIDS and poverty rates in DC were analyzed. Based on past 12 months use, participants were hierarchically classified into five groups: (1) ever injection drug use (IDU); (2) non-injection crack; (3) non-injection heroin and cocaine; (4) marijuana; and (5) no drug use. Sexual behaviors and HIV serology were also assessed. RESULTS: Of 862 participants, 40% were men, most were Black and unemployed, and more than half had ever been incarcerated. Prevalence of past year substance use was high: binge drinking (59%); marijuana (50%); non-injection crack (28%); heroin and/or cocaine injection (28%), non-injection cocaine (13%); and ecstasy (13%). In the hierarchical classification, 25% were ever IDU, 15% non injection crack users, 2% non-injection heroin and/or cocaine users, 31% marijuana users, and 27% reported no drug use. Overall HIV seroprevalence was 5.7% and differed by drug use group-9.5%, 11.1%, 1.8%, 1.6%, and 3.2%, respectively. Nearly half reported having >=3 sex partners in the past year; 20% reported exchange partners, and 69% had concurrent sex partners. CONCLUSION: Estimated prevalence of substance use in this heterosexual population was high. HIV prevalence among IDUs and non-injection crack users was higher than the estimated population prevalence in Washington, DC. Sexual behaviors above and beyond drug use are likely to be driving HIV transmission. PMID- 21316872 TI - Antimicrobial susceptibility of Actinobacillus pleuropneumoniae isolates from clinical outbreaks of porcine respiratory diseases. AB - Limited data regarding the susceptibility of Actinobacillus pleuropneumoniae to antimicrobials has been published during recent years. Accordingly, the aim of the present study was to investigate the distribution of MICs for the isolates of A. pleuropneumoniae from diseased pigs in the Czech Republic between 2007 and 2009. A total of 242 isolates were tested for susceptibility to 16 antimicrobial agents by a broth microdilution method. A low degree of resistance was observed for florfenicol (0.8%), amoxicillin and clavulanic acid (0.8%), tilmicosin (1.2%), tiamulin (1.7%) and ampicillin (3.3%), whereas resistance to tetracycline was detected more frequently, 23.9% of isolates. Interestingly, resistance to florfenicol has not yet been reported in any study investigating antimicrobial resistance of A. pleuropneumoniae. By PCR the presence of the floR gene was confirmed in all florfenicol resistant isolates. PMID- 21316873 TI - A unique novel reptilian paramyxovirus, four atadenovirus types and a reovirus identified in a concurrent infection of a corn snake (Pantherophis guttatus) collection in Germany. AB - In 2009, 26 clinical samples (organs and oral/cloacal swabs) from a total of 24 corn snakes (Pantherophis guttatus) from a single owner were sent to our laboratory to be tested for the presence of viruses. Paramyxoviruses (PMV), adenoviruses (AdV) and reoviruses were detected by RT-PCR, PCR and virus isolation methods. Three snakes were infected with all three viruses at the same time, while two other snakes had a double infection (PMV and reo, AdV and reo) and nine other snakes had a single infection with any of the three viruses. No viruses were detected in 10 animals. All isolated reoviruses were identical to one another and to the reptilian orthoreovirus isolate 55-02 in the partial RNA dependent RNA polymerase (RDRP) gene sequence. AdV partial polymerase sequences represented four different types, one of which was first described here: most similar to SnAdV-1, while the other three were identical to known types: SnAV-1, 2 and -3. However, the detected single PMV differed distinctly from described reptile PMV and was a new type. According to partial L gene, HN gene and U gene sequences it may be the first described representative of a third squamatid PMV cluster: "group C" within the proposed reptilian PMV genus "Ferlavirus". Nucleotide identity values for the L gene of the new PMV compared to group A viruses range between 76.5 and 80.3%, and between 80.5 and 81.2% compared to group B viruses. For the HN gene, these values were similar: 78.2-80% (A) and 79.9-80.5% (B) and somewhat lower for the U gene: 72.7-75.4% (A) and 69.7-70% (B). No reports on the prevalence of concurrent viral infection in captive snake populations have been published so far. The possibility of concurrent infection with several different viruses and subsequent consequences for animal health should be kept in mind when testing reptile samples for viruses. PMID- 21316874 TI - Reach on sound: a key to object permanence in visually impaired children. AB - BACKGROUND: The capacity to reach an object presented through sound clue indicates, in the blind child, the acquisition of object permanence and gives information over his/her cognitive development. AIM: To assess cognitive development in congenitally blind children with or without multiple disabilities. STUDY DESIGN: Cohort study. SUBJECTS: Thirty-seven congenitally blind subjects (17 with associated multiple disabilities, 20 mainly blind) were enrolled. OUTCOME MEASURES: We used Bigelow's protocol to evaluate "reach on sound" capacity over time (at 6, 12, 18, 24, and 36 months), and a battery of clinical, neurophysiological and cognitive instruments to assess clinical features. RESULTS: Tasks n.1 to 5 were acquired by most of the mainly blind children by 12 months of age. Task 6 coincided with a drop in performance, and the acquisition of the subsequent tasks showed a less agehomogeneous pattern. In blind children with multiple disabilities, task acquisition rates were lower, with the curves dipping in relation to the more complex tasks. CONCLUSIONS: The mainly blind subjects managed to overcome Fraiberg's "conceptual problem"--i.e., they acquired the ability to attribute an external object with identity and substance even when it manifested its presence through sound only--and thus developed the ability to reach an object presented through sound. Instead, most of the blind children with multiple disabilities presented poor performances on the "reach on sound" protocol and were unable, before 36 months of age, to develop the strategies needed to resolve Fraiberg's "conceptual problem". PMID- 21316875 TI - Behavior problems of 9-16 year old preterm children: biological, sociodemographic, and intellectual contributions. AB - BACKGROUND: Preterm children are at risk for behavior problems. Studies examining contributions of intellectual and environmental factors to behavior outcomes in preterm children are mixed. AIMS: (1) To identify the nature of maladaptive behaviors in preterm children age 9 to 16 years born across the spectrum of gestational age and birth weight (BW). (2) To examine contributions of BW as a biological factor, socioeconomic status as an environmental factor, and intelligence quotient (IQ) as indicative of intellectual ability to behavior outcomes. METHOD: Using the Child Behavior Checklist, parent reports of behavior for 63 preterm children (gestational age 24 to <36 weeks) were compared to 29 full term children of similar age, gender and socioeconomic status. Multiple regression models evaluated effects of prematurity, socioeconomic status, and intellectual ability on behavioral symptom scores. RESULTS: Preterm children had higher total and internalizing problem scores compared to full term children. They also had lower IQ. BW was a significant predictor of total and internalizing behavior problems. Among the syndrome scales, anxious/depressed and attention problems were elevated. Socioeconomic status did not contribute to behavior scores. IQ contributed to total, but not to internalizing or externalizing, scores. IQ contributed to attention problems, but not to anxious/depressed scores. CONCLUSION: Preterm children had increased behavior problems, especially symptoms of inattention and anxiety. Lower BW predicted more behavior problems. IQ acted as a mediator between BW and attention scores, but not anxiety scores. These findings alert health care providers to assess anxiety in all preterm children regardless of intellectual ability and additional study on the influence of intellectual ability on behavioral outcomes in preterm children is needed. PMID- 21316876 TI - Pertinence of the self-report mother-to-infant bonding scale in the neonatal unit of a maternity ward. AB - OBJECTIVE: To assess the relevance of the self-report Mother-to-Infant Bonding Scale (MIBS) to evaluate mother-infant bonding in the neonatal unit of a maternity ward. MATERIAL AND METHODS: Forty-eight hours after delivery, 78 mothers responded to the MIBS, the Edinburgh Postnatal Depression Scale (EPDS), the Adult Attachment Questionnaire (AAQ), and the Mother's Assessment of the Behavior of her Infant (MABI) questionnaire. They were then interviewed 24h later by a pediatric psychiatrist, who assessed the mother-infant relationship. The neonatology nurses also filled out the MIBS, imagining the mothers' responses, and responded anonymously to questionnaires on the use of the MIBS in their daily practice. RESULTS: MIBS satisfactorily detected difficulties in mother-child bonding: the area under the ROC curve was 0.93, with a sensitivity of 0.9 and a specificity of 0.8 for a threshold score >=2. MIBS was independent of EPDS (r=0.11, p=0.29) and AAQ (r=0.05, p=0.63). However, it was influenced by the infant's behavioral characteristics (r=0.3, p=0.01). MIBS scores of the mothers and nurses showed low correlation (r=0.31, p=0.004) and the item-by-item responses were rarely concordant. Fully 100% of the nurses stated that the MIBS was helpful in evaluating mother-child bonding and 85% of the mothers found it beneficial. CONCLUSION: New mothers need to express their feelings about their babies, as hospital staff observation of mother-infant interactions is not sufficiently reliable for assessing the attachment process. The self-report MIBS is a useful tool for detecting difficulties in early mother-infant bonding. PMID- 21316877 TI - Psychological distress and early lactation performance in mothers of late preterm infants. AB - Late preterm infants are a vulnerable population susceptible to early breastfeeding failure and lactation-associated morbidities. We have found that late preterm gestation has a negative effect on mothers' psychological profiles in the puerperium, with the resulting levels of anxiety, depression, and psychological distress correlating negatively with their early lactation performance. PMID- 21316878 TI - Very preterm children free of disability or delay at age 2: predictors of schooling at age 8: a population-based longitudinal study. AB - AIM: To study the predictive value of a developmental assessment at 2 years corrected age (CA) for schooling at age 8 in children born very preterm and free of disability or delay; to identify other factors associated with schooling in this population. METHODS: 244 children born before 33 weeks in 1997, part of the population-based EPIPAGE cohort study, free of disability or delay, had their developmental quotient (DQ) evaluated with the Brunet-Lezine scale at 2 years CA. The mental processing composite (MPC) score was evaluated at age 5 with the K-ABC battery. Data on schooling were obtained at age 8 by postal questionnaire. Schooling was considered appropriate if the child was attending age-appropriate grade level in a regular classroom environment without support at school. RESULTS: Schooling was appropriate for 172 (70%) children. The predictive value of a DQ>=100 for appropriate schooling was 0.80 [0.75;0.85]. In children with a DQ at age 2<100, schooling varied significantly according to their MPC score at age 5 whereas it didn't in children with a DQ>=100. In multivariate analysis, the rate of appropriate schooling was significantly related to global DQ at age 2 (p<0.01), gestational age>=29 weeks (p<0.05), head circumference at age 2 (p<0.05) and mother's educational level (p<0.05). CONCLUSION: A DQ>=100 cannot be solely used for the prediction of appropriate schooling at age 8. Mother's educational level, gestational age and head circumference at age 2 could be taken account. These factors could be used to individualise follow-up. PMID- 21316879 TI - Immunosenescence: Implications for vaccination programmes in adults. AB - Vaccination is crucially important in preventing infection and protecting vulnerable population from infectious diseases. However, a multitude of changes in the immune system occurring with advancing age, termed immunosenescence, lead to limit the protective effects of vaccination in older adults. While it is widely believed that the current immunization strategies saves many lives, vaccine preventable infectious diseases (VPDs) still place a considerable burden, not only on older individuals, but also on the adult population and healthcare systems of developed countries. This review will first examine the evidence linking the contribution of immunosenescence to a less than optimal vaccine response in aged individuals in order to demonstrate that strategy of promoting vaccination in these populations is not sufficient to reduce the burden associated with VPDs. Furthermore, based upon the side effects of the herd immunity when vaccine-policies are mainly childhood-centered, considerations will be given on the imperative necessity to frame shift our thinking and efforts away from a nearly complete childhood-centered vaccine programme toward a life-span immunization programmes. PMID- 21316880 TI - Psychopathology and weapon choice: a study of 103 perpetrators of homicide or attempted homicide. AB - The aim of this study was to ascertain if a relationship between weapon choice and psychopathology existed. The perpetrators (103) were evaluated at the Department of Criminology and Forensic Psychiatry of the University of Bari in southern Italy. Psychiatric examination and psycho-diagnostic tests were administered for each of the perpetrators and a database was subsequently formulated. The results showed a significant correlation between some types of mental disorder and weapon choice. A strong correlation was found between delusional disorders and the use of sharp weapons, whereas depressive disorders were more strongly associated with asphyxia. Organic disorders were found to be highly correlated with the use of blunt instruments. In cases where the homicide was the result of an impulsive reaction, the use of sharp weapons was most often observed. PMID- 21316881 TI - 1H NMR spectroscopic identification of a glue sniffing biomarker. AB - Organic solvent abuse typically involves sniffing organic solvents to experience the mind-altering conditions they induce. In Republic of Korea, organic solvent abuse is a serious social problem, especially among teenagers. Several studies have addressed the effects of organic solvent abuse on mind and body, but there are no simple methods by which such abuse can be positively identified. In this report, we describe a method for analyzing toluene metabolites (toluene is the main ingredient of glue) in glue-sniffers' urine using (1)H NMR spectroscopy. Toluene is a commonly used solvent in the rubber, paint, plastics, leather, printing, and chemical industries. Inhaled toluene is metabolized to hippuric acid in the liver and excreted in the urine. Hippuric acid is known as a good biomarker for biological monitoring of toluene exposure. We have scanned hippuric acid and other toluene metabolites by NMR spectroscopy and performed statistical multivariate analysis of the data. Based on this analysis, we sought to determine parameters by which glue-sniffing (toluene inhalation) behavior may be verified. We also demonstrate the use of a pattern recognition method for accurate and efficient analysis of NMR data. In comparison to conventional methods, such as mass spectroscopy coupled with liquid chromatography or gas chromatography, nuclear magnetic resonance spectroscopy has several advantages, including simple sample preparation, non-destructive sampling, accuracy, short acquisition time, and reproducibility in the determination of urinary hippuric acid. PMID- 21316882 TI - Bone anchored hearing aid in single sided deafness: outcome in right-handed patients. AB - OBJECTIVE: To assess the benefits in terms of sound localization, to evaluate speech discrimination in noise, to appraise the prosthesis benefit and to identify outcome in right and left handed patients when BAHA are implanted on the right or on the left deaf side. METHODS: Two years prospective study in a tertiary referral center. Tests consist on Hearing in Noise Test (HINT) and sound localization after 6 months of BAHA use. Quality of life was assessed by the Abbreviated Profile of Hearing Aid Benefit (APHAB) questionnaire. The paired T test and the analysis of variance were used for the statistical measures. RESULTS: Twenty-one subjects participated in this study. HINT: patients score better when speech and noise are spatially separated and noise is not presented to the healthy ear. In the right-handed group (left dominant brain), unaided left implanted patients performed better than right-implanted patient when speech is in front and noise to the good ear; when speech is presented to the good ear and noise to the front, aided right-implanted patients performed better than aided left-implanted patients. Sound localization: correct answers attain 35% at best. No statistical difference between the frequencies was found, neither between the left and right implanted patients. APHAB: the score improvement is statistically significant for the global score, the background noise subscale at 5 weeks and for the reverberation subscale at 6 months. CONCLUSION: It seems that left dominant hemisphere is able to filter crossed noise better than the right hemisphere. Results of uncrossed speech to the dominant left brain are better than the uncrossed speech to the non-dominant right brain. PMID- 21316883 TI - Temporomandibular joint herniation into the external ear canal through foramen of Huschke. AB - Foramen of Huschke, which is also known as the foramen tympanicum, is an anatomical variation of the tympanic portion of the temporal bone. This foramen is located on the anteroinferior aspect of the external auditory canal, posteromedial to the temporomandibular joint. Herein, a rare case of foramen Huschke with a herniation of the soft tissues around the temporomandibular joint that result in severe otalgia and its treatment are presented. PMID- 21316884 TI - Paradoxical increase in seizure frequency with valproate in nonketotic hyperglycinemia. AB - Nonketotic hyperglycinemia (NKH), or glycine encephalopathy, is an autosomal recessive disorder caused by a defect in the glycine cleavage enzyme system. In neonatal-onset NKH, patients manifest lethargy, hypotonia, apnea, and intractable epileptic seizures that are not specific to this disease. We experienced a 6-year old girl with spastic quadriplegia, intractable epilepsy, and mental retardation, all initially regarded as sequelae of neonatal meningitis. The seizure frequency was transiently increased when valproate was started. Head MRI revealed progressive brain atrophy and white matter loss with high intensity signals on T2 weighted and diffusion-weighted images, which prompted us to conduct further metabolic workups. High glycine levels led us to suspect NKH, and we confirmed this diagnosis by the non-invasive, (13)C-glycine breath test. DNA sequencing revealed novel Leu885Pro/Trp897Cys mutations in the glycine decarboxylase gene that were transmitted from both parents. Sodium benzoate and dextromethorphan dramatically decreased her hypertonicity. Our case shows that paradoxical increases in seizure frequency following valproate can be a clue for a diagnosis of NKH, and that a correct diagnosis of NKH can greatly alter the quality of life in such patients. PMID- 21316885 TI - The "communication line" suggests occult posterior malleolar fracture associated with a spiral tibial shaft fracture. AB - OBJECTIVES: To demonstrate radiographical characteristics of the relationship between distal spiral tibial shaft fractures and associated occult posterior malleolar fractures (PMF) that confirmed by CT and MRI. MATERIALS AND METHODS: X rays for a ninety-six patients with spiral tibia fracture and associated PMF were reviewed. All patients additionally had an ankle CT. Patients with a negative CT scans underwent an ankle MRI. Radiographic observations included fracture location, characteristics, and a presence of a fracture line between the two injuries. RESULTS: The spiral tibia fracture line was contiguous with PMF in 89 of 96 cases after evaluation with the CT and MRI. The line connecting the two injuries, which occurs between the medial inferior apex of the spiral tibia fracture line and the posterior superior apex of the PMF was identified as the "communication line". In 47 of the 89 conjunction fractures, the "communication line" was detectable preoperatively and in 12 cases postoperatively by anteroposterior radiograph. By using the CT and MRI scans, we found that no "communication line" was present in only 7 cases. CONCLUSION: It is important to understand the nature of the association between distal spiral tibial shaft fractures and occult posterior malleolar fractures for optimal stabilization of the fracture and for appropriate rehabilitation. The "communication line" is a useful diagnostic clue for early recognition the occult PMF and alerts a closer evaluation of the lateral view and further CT examination. PMID- 21316886 TI - Detection and classification of focal liver lesions in patients with colorectal cancer: retrospective comparison of diffusion-weighted MR imaging and multi-slice CT. AB - OBJECTIVES: To compare the diagnostic performance of diffusion-weighted MR imaging (DWI) with multi-slice CT (MS-CT) in the detection and classification of focal liver lesions in patients with colorectal cancer. METHODS: In a retrospective study 68 patients who underwent DWI at 1.5 T (b-values of 50, 300 and 600s/mm(2)) and contrast-enhanced MS-CT were analysed by two radiologists blinded to the clinical results. Imaging results were correlated with intraoperative surgical and ultrasound findings (n=24), imaging follow-up or PET (n=44). Sensitivity of DWI and MS-CT in detection of focal liver lesions was compared on a per-lesion and a per-segment basis. Receiver operator characteristic (ROC) curves to determine the diagnostic performance and the sensitivities of correctly identifying liver metastases on a segmental base were calculated. RESULTS: For lesion detection, DWI was significantly superior to MS CT both on a per-lesion (difference in sensitivities for reader 1 and 2 22.65% and 19.06%, p<0.0001) and a per-segment basis (16.86% and 11.76%, p<0.0001). Especially lesions smaller than 10mm were better detected with DWI compared to MS CT (difference 41.10% and 29.45%, p<0.0001). ROC-analysis showed superiority for lesions classification (p<0.0001) of DWI (AUC: 0.949 and 0.951) as compared to MS CT (AUC: 0.879 and 0.892, p<0.0001 and p=0.005). DWI was able to filter out metastatic segments with a higher sensitivity (88.2 and 86.5%) compared to MS-CT (68.0 and 67.4%, p<0.0001 and p=0.005, respectively). CONCLUSION: Compared to MS CT DWI is both more sensitive in the detection of liver lesions and more accurate in determining the extent of metastatic disease in patients with colorectal cancer and therefore might help to optimize therapeutic management in those patients. PMID- 21316887 TI - Prospective versus retrospective ECG-gated multislice CT coronary angiography: a systematic review of radiation dose and diagnostic accuracy. AB - PURPOSE: To perform a systematic review of the radiation dose and diagnostic accuracy of prospective versus retrospective ECG-gated multislice CT coronary angiography. MATERIALS AND METHODS: A search of Pubmed/Medline and Sciencedirect databases for English literature was performed to identify studies comparing prospective and retrospective ECG-gated multislice CT angiography in the diagnosis of coronary artery disease. Effective dose, dose length product, image quality and diagnostic value were compared between two groups of studies. RESULTS: 22 studies were included for analysis. The mean effective dose of prospective ECG-gated scans was 4.5 mSv (95% CI: 3.6, 5.3 mSv), which is significantly lower than that of retrospective scans, which is 13.8 mSv (95% CI: 11.5, 16.0 mSv) (p<0.001). The mean dose length product was 225 mGycm (95% CI: 188, 262 mGycm) and 822 mGycm (95% CI: 630, 1013 mGycm) for the prospective and retrospective ECG-gated scans, respectively, indicating a statistically significant difference between these two protocols (p<0.0001). The mean sensitivity and specificity of multislice CT angiography in the diagnosis of coronary artery disease was 97.7% (95% CI: 93.7%, 100%) and 92.1% (95% CI: 87.2%, 97%) for prospective ECG-gated scans; 95.2% (95% CI: 91%, 99.5%) and 94.4% (95% CI: 88.5%, 100%) for retrospective ECG-gated scans, respectively, with no significant difference for sensitivity but significant difference for specificity (p=0.047). CONCLUSION: Multislice CT coronary angiography with prospective ECG gating leads to a significant reduction of radiation dose when compared to that of retrospective ECG-gating, while offering comparable image quality and diagnostic value. PMID- 21316888 TI - Relationships of clinical protocols and reconstruction kernels with image quality and radiation dose in a 128-slice CT scanner: study with an anthropomorphic and water phantom. AB - PURPOSE: The aim of this study was to explore the relationship of scanning parameters (clinical protocols), reconstruction kernels and slice thickness with image quality and radiation dose in a DSCT. MATERIALS AND METHODS: The chest of an anthropomorphic phantom was scanned on a DSCT scanner (Siemens Somatom Definition flash) using different clinical protocols, including single- and dual energy modes. Four scan protocols were investigated: 1) single-source 120kV, 110mAs, 2) single-source 100kV, 180mAs, 3) high-pitch 120kV, 130mAs and 4) dual energy with 100/Sn140kV, eff.mAs 89, 76. The automatic exposure control was switched off for all the scans and the CTDIvol selected was in between 7.12 and 7.37mGy. The raw data were reconstructed using the reconstruction kernels B31f, B80f and B70f, and slice thicknesses were 1.0mm and 5.0mm. Finally, the same parameters and procedures were used for the scanning of water phantom. Friedman test and Wilcoxon-Matched-Pair test were used for statistical analysis. RESULTS: The DLP based on the given CTDIvol values showed significantly lower exposure for protocol 4, when compared to protocol 1 (percent difference 5.18%), protocol 2 (percent diff. 4.51%), and protocol 3 (percent diff. 8.81%). The highest change in Hounsfield Units was observed with dual-energy Sn140-kV (Hounsfield unit 15.18) compared to protocol 2 (24.35HU). The differences in noise between the different clinical protocol data sets were statistically significant [protocol 3 vs. dual-energy 100-kV (p<0.01) and protocol 3 vs. dual-energy Sn140-kV (p<0.01)]. The dual-energy Sn140-kV protocol shows the highest image noise (14.5HU for 5.0mm slice (B31f) and 162HU for 1.0mm slice (B70f) thickness). The difference between reconstruction kernel B31f and B80f images made using 5.0mm reconstruction thickness was statistically significant (p<0.0312) and 1.0mm slice thickness shows the significance of p<0.0312 between B31f and B70f reconstructions. In both cases, the lowest image noise was obtained from B31f reconstructed images. Again the slice thickness significantly affects image noise (p<0.03) and the noise was higher at 1.0mm compared to that at 5.0mm slice thickness. CONCLUSION: The clinical protocol, reconstruction kernel, slice thickness and phantom diameter or the density of material it contains directly affects the image quality. Dual energy protocol shows the lowest dose-length product compared to all other protocols examined, the fused image shows excellent image quality and the noise is same as that of single or high-pitch mode protocol images. Advanced CT technology improves image quality and considerably reduces radiation dose. PMID- 21316889 TI - Features of time-intensity curve parameters of colorectal adenocarcinomas evaluated by double-contrast enhanced ultrasonography: initial observation. AB - PURPOSE: This study is to investigate the value of double contrast-enhanced ultrasonography (DCEU) in assessing microcirculation of colorectal adenocarcinomas and to describe the perfusion features of the tumours. MATERIAL AND METHODS: DCEUS was performed in 42 patients with adenocarcinoma. The time intensity curve parameters (arrival time (AT), time-to-peak (TTP), peak intensity (PI) and area under the curve (AUC)) within the tumours were extracted. The parameters were compared among the tumours with different CEUS features and stages. RESULTS: The mean values of AT, TTP, PI and AUC of the colorectal adenocarcinomas were 13.68+/-13.36s, 32.61+/-19.56s, 19.82+/-16.54dB and 271.10+/ 159.19dBs, respectively. In the adenocarcinomas with necrosis, the mean values of AUC was significantly lower than that of the adenocarcinomas without (231.10+/ 219.27dBs, 278.10+/-123.20dBs, p=0.004). In the adenocarcinomas with necrosis, the AUC and PI of the non-necrotic part were significantly higher than that of the necrotic part (p=0.007, 0.0025, respectively). AUC increased progressively in the subgroups of T2, T3 and T4 and the difference of AUC between T2 and T4 subgroup was significant (p=0.008). CONCLUSIONS: Double contrast-enhanced ultrasonography is a valuable technique for quantifying tumour vascularity of colorectal adenocarcinomas. AUC was significantly different in the subgroups of different T stage. AUC and PI could reflect the different perfusion status of tumours with or without necrosis. PMID- 21316890 TI - Juxta-adrenal schwannoma: dynamic multi-slice CT and MRI findings. AB - BACKGROUND: We retrospectively analyzed the MSCT and MRI findings of three cases of juxta-adrenal schwannoma and reviewed literature. METHODS AND RESULTS: Three patients were male, and showed no signs for endocrine activity. The three cases of juxta-adrenal schwannoma were all well-circumscribed, oval masses with cystic components, and one case with hemorrhage. Hypointense signal capsules were observed on T2-weighted images in two cases, and the capsule in one case showed rim enhancement. The tumors displayed mild enhancement in the arterial phase and progressive enhancement during the portal venous phase and equilibrium phase. Computed tomography angiography clearly showed the tumor feeding vessels arising from the abdominal aorta. CONCLUSIONS: MSCT and MRI are valuable imaging modalities for diagnosis of juxta-adrenal schwannoma. PMID- 21316891 TI - Tumor disease and associated congenital abnormalities on prenatal MRI. AB - OBJECTIVE: Fetal tumors can have a devastating effect on the fetus, and may occur in association with congenital malformations. In view of the increasing role of fetal magnetic resonance imaging (MRI) as an adjunct to prenatal ultrasonography (US), we sought to demonstrate the visualization of fetal tumors, with regard to congenital abnormalities, on MRI. MATERIALS AND METHODS: This retrospective study included 18 fetuses with tumors depicted on fetal MRI after suspicious US findings. An MRI standard protocol was used to diagnose tumors judged as benign or malignant. All organ systems were assessed for tumor-related complications and other congenital malformations. Available US results and histopathology were compared with MRI. RESULTS: There were 13/18 (72.2%) benign and 5/18 (27.8%) malignant tumors diagnosed: a cerebral primitive neuroectodermal tumor in 1/18, head-neck teratomas in 4/18; ventricular rhabdomyomas in 4/18; a cardiac teratoma in 1/18; a hepatoblastoma in 1/18; neuroblastomas in 2/18; a cystic hemorrhagic adrenal hyperplasia in 1/18; a pelvic leiomyoma in 1/18; sacrococcygeal teratomas in 3/18. Tumor-related complications were present in 13/18 (72.2%) cases; other congenital abnormalities in 3/18 (16.7%). MRI diagnosis and histology were concordant in 8/11 (72.7%) cases. In 6/12 (50%) cases, US and MRI diagnoses were concordant, and, in 6/12 (50%) cases, additional MRI findings changed the US diagnosis. CONCLUSION: Our MRI results demonstrate the visualization of fetal tumors, with frequently encountered tumor-related complications, and other exceptional congenital abnormalities, which may provide important information for perinatal management. Compared to prenatal US, MRI may add important findings in certain cases. PMID- 21316892 TI - RGD-targeted paramagnetic liposomes for early detection of tumor: in vitro and in vivo studies. AB - Magnetic resonance molecular imaging has emerged as a potential approach for tumor diagnosis in the last few decades. This approach consists of the delivery of MR contrast agents to the tumor by specific targeted carriers. For this purpose, a lipopeptide was constructed by using a cyclic RGD peptide headgroup coupled to palmitic acid anchors via a KGG tripeptide spacer. Targeted paramagnetic liposomes were then prepared by the incorporation of RGD-coupled lipopeptides into lipid bilayers for specific bounding to tumor. In vitro, study demonstrated that RGD-targeted liposomes exhibited a better binding affinity to targeted cells than non-targeted liposomes. MR imaging of mice bearing A549 tumors with the RGD-targeted paramagnetic liposomes also resulted in a greater signal enhancement of tumor compared to non-targeted liposomes and pure contrast agents groups. In addition, biodistribution study also showed specific tumor targeting of RGD-targeted paramagnetic liposomes in vivo. Therefore, RGD-targeted paramagnetic liposomes prepared in the present study may be a more promising method for early tumor diagnosis. PMID- 21316893 TI - Aortic volume as an indicator of disease progression in patients with untreated infrarenal abdominal aneurysm. AB - OBJECTIVE: The maximal diameter of an abdominal aortic aneurysm (AAA) and the change in diameter over time reflect rupture risk and are used for surgical planning. However, evidence has emerged that aneurysm volume may be a better indicator of AAA remodeling. The purpose of this study was to assess the relationship between the volume and maximal diameter of the abdominal aorta in patients with untreated infrarenal AAA. MATERIALS AND METHODS: This was a retrospective study of 100 patients with infrarenal AAA who were followed for more than 6 months. We examined 2 sets of computed tomography images for each patient, acquired >= 6 months apart. The maximal diameter and volume of the infrarenal abdominal aorta were determined by semiautomated segmentation software. RESULTS: At baseline, mean maximal infrarenal diameter was 5.1 +/- 1.0 cm and mean aortic volume was 139 +/- 72 mL. There was good correlation between the maximal diameter and aortic volume at baseline (r(2) = 0.55; P<0.001). The mean change in maximal diameter between studies was 0.2 +/- 0.3 cm and the mean volume change was 19 +/- 19 mL. However, the correlation between diameter change and volume change was modest (r(2) = 0.34; P=0.001). Most patients (n = 64) had no measurable change in maximal diameter between studies (<= 2 mm), but the change in volume was found to vary widely (-2 to 69 mL). CONCLUSION: In patients with untreated infrarenal AAA, a change in aortic volume can occur in the absence of a significant change in maximal diameter. Additional work is needed to examine the relationship between change in AAA volume and outcomes in this patient group. PMID- 21316894 TI - Changes in bacterial cells induced by high pressure at subzero temperature. AB - The aim of this study was to examine the effect of pressure treatment at 193MPa and -20 degrees C on membrane damage, changes in activity of membrane-bound ATPases and degradation of nucleic acids. The experiments were carried out with three Escherichia coli strains, in the exponential and stationary phases of growth, and differing in sensitivity to pressure. All E. coli strains subjected to pressure in the exponential phase of growth were inactivated by 6 log cycles, independently of the strain, which was accompanied by a total loss of ability to plasmolyse, an increase in irreversible membrane permeability to PI, and a reduction of cellular ATP by more than 80%. After pressure treatment of stationary phase cells, the relationship between the inactivation level and the ability to plasmolyse was not as evident as in the case of exponential phase cells. Pressure treatment of two strains of E. coli K-12 and Ec160/59 in the stationary phase that decreased viability by no more than one log cycle led only to reversible permeabilization of bacterial membranes, while irreversible permeabilization was observed in the pressure sensitive E. coli IBA72 strain phase that was inactivated by 4.6 log cycles. The reduction of ATP and changes in ATPase activity after pressure treatment of tested E. coli strains in the stationary phase of growth depended on the stage of inactivation of the particular strain. Electrophoretic analysis showed degradation of RNA isolated after pressure treatment from cells of all E. coli strains tested in the exponential phase of growth. The changes of RNA induced by pressure were not visible in the case of cells in the stationary phase. The degradation of DNA isolated from pressure treated E. coli strains from the exponential as well as from the stationary phase of growth was not observed. PMID- 21316895 TI - Physico-chemical characterization and in vitro/in vivo evaluation of loratadine:dimethyl-beta-cyclodextrin inclusion complexes. AB - A tricyclic, piperidine derivative of antihistamines, loratadine, which belongs in class II of the Biopharmaceutical Classification System, was investigated. It is an ionizable drug, whose solubility depends on the gastrointestinal pH, and the bioavailability is therefore very variable. Inclusion complexes were prepared by kneading method, containing loratadine (LOR) and dimethyl-beta-cyclodextrin (DIMEB) in two different molar ratios in an attempt to achieve better dissolution and therefore the better bioavailability of loratadine. The formation and physicochemical properties of the inclusion complexes were investigated by means of dissolution tests, pH-dependent solubility studies, electrospray ionization mass spectrometry and diffusion-ordered 1H NMR spectroscopy. The in vivo efficiency of the complexes was examined in rat animal experiments to confirm the better in vitro dissolution. The instrumental examinations proved the presence of total complexes in 1:1 ratio in both compositions. However, the in vitro pH dependent solubility results, the in vivo blood levels and the greater pharmacological effect prove that excess DIMEB is needed to achieve the pH independent and complete solubility of LOR, and therefore better and more consistent bioavailability. PMID- 21316896 TI - When coders are reliable: the application of three measures to assess inter-rater reliability/agreement with doctor-patient communication data coded with the VR CoDES. AB - OBJECTIVE: To investigate whether different measures of inter-rater reliability will compute similar estimates with nominal data commonly encountered in communication studies. To make recommendations how reliability should be computed and described for communication coding instruments. METHODS: The raw data from an inter-rater study with three coders were analysed with; Cohen's kappa, sensitivity and specificity measures, Fleiss's multirater kappaj, and an intraclass correlation coefficient (ICC). RESULTS: Minor differences were found between Cohen's kappa and an ICC model across paired data (largest margin=0.01). There were negligible differences between the multirater estimates e.g. kappaj (0.52) and ICC (0.53). Sensitivity analyses were in general agreement with the multirater estimates. CONCLUSION: It is more practical to analyse nominal data with >2 raters with an appropriate model ICC for inter-rater studies, and little difference exists between Cohen's kappa or an ICC. PRACTICE IMPLICATION: Alternatives to Cohen's kappa are readily available, but researchers need to be aware of the different ICC definitions. An ICC model should be fully described in reports. Investigators are encouraged to supply confidence limits with inter rater data, and to revisit guidance regarding the relative strengths of agreement of reliability coefficients. PMID- 21316897 TI - Effects of counseling techniques on patients' weight-related attitudes and behaviors in a primary care clinic. AB - OBJECTIVE: Examine primary care physicians' use of counseling techniques when treating overweight and obese patients and the association with mediators of behavior change as well as change in nutrition, exercise, and weight loss attempts. METHODS: We audio recorded office encounters between 40 physicians and 461 patients. Encounters were coded for physician use of selected counseling techniques using the Motivational Interviewing Treatment Integrity (MITI) scale. Patient motivation and confidence as well as Fat and Fiber Diet score (1-4), Framingham physical activity questionnaire (MET-minutes), and weight loss attempts (yes/no) were assessed by surveys. Generalized linear models were fit, including physician, patient, and visit level covariates. RESULTS: Patients whose physicians were rated higher in empathy improved their Fat and Fiber intake 0.18 units (95% CI 0, 0.4). When physicians used "MI consistent" techniques, patients reported higher confidence to improve nutrition (OR 2.57, 95% CI 1.2, 5.7). CONCLUSION: When physicians used counseling techniques consistent with MI principles, some of their patients' weight-related attitudes and behaviors improved. PRACTICE IMPLICATIONS: Physicians may not be able to employ formal MI during a clinic visit. However, use of counseling techniques consistent with MI principles, such as expression of empathy, may improve patients' weight-related attitudes and behaviors. PMID- 21316898 TI - Diabetes education in mainland China- a systematic review of the literature. AB - OBJECTIVE: In this review, we assess and summarize evidence and gaps in the literature regarding diabetes education in mainland China. METHODS: Using China/Chinese, diabetes and education as key words, articles were obtained from the National Science and Technology Library (NSTL), Chongqing Weipu and Qinghua Tongfang databases. Articles included in this review were further selected based on pre-determined criteria, including studying duration, outcome measurements, and inclusion of control groups. RESULTS: Based on the 34 articles, we found that studies often took place in inpatient and outpatient department. Popular methods used were class teaching, or one-on-one teaching, and knowledge and glycemic control were mostly selected as the outcome measurements. Beneficial effects of diabetes education on knowledge, and glycemic control were demonstrated in studies during a relatively short follow-up (3-6 months). Limitations to the studies selected were that the effects of interventions on behavior change, BMI, blood pressure, lipids, and medical costs were not clearly addressed, and long term outcomes and adherence to diabetes education was unknown. CONCLUSIONS: Diabetes education had positive impact on glycemic control in mainland China in short duration. PRACTICE IMPLICATIONS: Future studies should use more creative ways of education, and the long-term impact of diabetes education should be evaluated. PMID- 21316899 TI - Advance care planning for patients with COPD: past, present and future. AB - OBJECTIVE: To discuss the importance, current status and directions for improvement of advance care planning and communication about end-of-life care for patients with Chronic Obstructive Pulmonary Disease (COPD). METHODS: Narrative review of the currently available literature regarding advance care planning and communication about end-of-life care in COPD. RESULTS: Advance care planning, including patient-clinician communication about end-of-life care, can improve outcomes for patients and their families and may be particularly important for patients with COPD. Patient-clinician communication is needed to inform and prepare patients about their diagnosis, treatment, prognosis, and what dying might be like. It is necessary to help patients and their clinicians understand patient preferences for life-sustaining treatments. Despite these advantages, advance care planning and conversations about end-of-life care in current practice are limited and their quality is often poor. CONCLUSION: Advance care planning can improve outcomes for patients and their relatives. Recent studies provide directions for how to facilitate advance care planning for patients with COPD. PRACTICE IMPLICATIONS: Advance care planning ought to be part of care for patients with advanced COPD. Future studies should focus on interventions to facilitate advance care planning in patients with COPD with the goal of improving the quality of end-of-life care. PMID- 21316900 TI - Stenting of chronically obstructed inferior vena cava filters. AB - OBJECTIVES: A protective inferior vena cava (IVC) filter may later be incorporated into a chronic postthrombotic ilio-caval obstruction (occlusive, requiring recanalization, or nonocclusive). This study aims to assess the safety and stent-related outcome following stenting across an obstructed filter. METHODS: From 1997 to 2009, 708 limbs had stenting for postthrombotic ilio-caval outflow obstruction (occlusion in 121 limbs). In 25 patients, an IVC filter was obstructed (Group X). The site was crossed by a guidewire and balloon dilated. The filter was markedly displaced sidewise or remodeled. A stent was placed across the IVC filter and redilated. In 28 other patients, the cephalad stenting terminated below a patent IVC filter (Group B). The remaining 655 patients had no previous IVC filter placement (Group no IVC filter present [NF]). The patients were followed to assess patency. The types of reintervention were noted. RESULTS: The stenting maneuver through a variety of previously inserted IVC filters was safely performed without an apparent tear of the IVC, no clinical bleeding or abdominal symptoms, or pulmonary embolism. Mortality was nil; morbidity minimal. The primary and secondary cumulative patency rates at 54 months for limbs with postthrombotic obstruction were with and without IVC filter (38% and 40%; P = .1701 and 79% and 86%; P = .1947, respectively), and for limbs with stenting across the filter (Group X) and stent termination below the filter (Group B; 32% and 42%; P = .3064 and 75% and 84%; P = .2788, respectively), not statistically different. When Group X alone was compared with Group NF, the secondary patency rate was, however, significantly lower (75% vs 86%; P = .0453), suggesting that crossing of the stent was associated with reduced patency. Occlusive postthrombotic disease requiring recanalization was more frequent in Group X than in Group B and Group NF (68%, 25%, and 15%, respectively; P = .004). A comparison was therefore performed only between limbs stented for recanalized occlusions with (n = 23) and without IVC filters (n = 92) showing no difference (cumulative primary and secondary patency rates 30% and 35%; P = .9678 and 71% and 73%; P = .9319, respectively). Multiple logistic regression analysis also supported a significant association between patency rate and occlusive disease (odds ratio, 6.9; 95% confidence interval, 3.4-13.9; P < .0001), but not between patency rate and presence of an IVC filter (P = .5552). CONCLUSIONS: Stenting across an obstructed IVC filter is safe. It appears that patency is not influenced by the fact that an IVC filter is crossed by a stent, but is related to the severity of postthrombotic disease (occlusive or nonocclusive obstruction) and the associated recanalization procedure. PMID- 21316901 TI - Clinical and kidney morphologic predictors of outcome for renal artery stenting: data to inform patient selection. AB - BACKGROUND: The purpose of the current study was to identify clinical and kidney morphologic features that predict a favorable blood pressure (BP) response to renal artery stenting (RAS). METHODS: The study cohort consisted of 149 patients who underwent primary RAS over 9 years. Patients were categorized as "responders" based on modified American Heart Association guidelines: BP <160/90 mm Hg on fewer antihypertensive medications or diastolic BP <90 mm Hg on the same medications. All other patients were deemed "nonresponders." Renal volume was estimated as kidney length * width * depth/2 based on preoperative computed tomography or magnetic resonance scans. Median follow-up was 19 months (interquartile range [IQR] 10.0-29.5 months). RESULTS: The median age of the cohort was 68 years (IQR, 60-74 years). A favorable BP response was observed in 50 of 149 patients (34%). Multivariate analysis identified three independent predictors of a positive BP response: (1) requirement for four or more medications (odds ratio, 29.9; P = .0001), (2) preoperative diastolic BP >90 mm Hg (OR, 31.4; P = .0011), and (3) preoperative clonidine use (OR, 7.3; P = .029). The BP response rate varied significantly based on the number of predictors present per patient (P < .0001). Among patients with three-drug hypertension, a larger ipsilateral kidney (volume >=150 cm(3)) increased the BP response rate more than threefold compared with patients with smaller kidneys (63% vs 18% BP response rate; P = .018). CONCLUSIONS: The current study demonstrated that three clinical predictors (>=4 antihypertensive medications, diastolic BP >=90 mm Hg, and clonidine use) are preoperative predictors of BP response to RAS. Kidney volume may help in discriminating responders from nonresponders among those patients with three-drug hypertension. These parameters may assist clinicians in patient selection and provide more concrete data with which to counsel patients on the likely outcomes for RAS. PMID- 21316902 TI - Acute aortic occlusion in a child secondary to lap-belt injury treated with thromboendarterectomy and primary repair. AB - Abdominal aortic injury as a result of blunt trauma is a rare event and has been described in few children. A 6-year-old girl presented with acute bilateral lower extremity ischemia, and a triad of acute aortic occlusion, intra-abdominal visceral injury, and a lumbar chance fracture after sustaining a seat belt injury from a motor vehicle collision. An emergency aortic thromboendarterectomy and primary repair were performed. This represents one of the few reports of acute traumatic aortic thrombosis in a child and highlights the surgical treatment of acute abdominal aortic injury in a pediatric patient. PMID- 21316903 TI - In situ versus extra-anatomic reconstruction for primary infected infrarenal abdominal aortic aneurysms. AB - BACKGROUND: There is no standard procedure for revascularization after infected infrarenal abdominal aortic aneurysm resection. This study examines the outcomes of two contemporary methods. METHODS: We retrospectively reviewed medical records for patients who underwent repair of infected infrarenal abdominal aortic aneurysms from January 1998 to December 2007 at a single institution. Patients with infected prosthetic aortic grafts were excluded. RESULTS: Twenty-eight patients (22 men; mean age, 65 +/- 12) had in situ graft (group I, n = 13) or extra-anatomic bypass (group II, n = 15), with a mean follow-up of 22 months. Mean hospital lengths of stay were 36 +/- 16 days for group I and 46 +/- 17 days for group II. Overall perioperative mortality was 5 of 28 (18%), comprising 1 of 13 in group I (8%) and 4 of 15 in group II (27%; P = .333). No early or late vascular-related complications occurred in group I. In group II, three patients had early vascular-related complications, including, graft infection, graft occlusion and ischemia colitis, and five patients had late vascular-related complications, including graft infection and graft occlusion. One patient ultimately lost a limb. Group I had a 0% late complication rate vs 33% in group II (P = .044). For cumulative survival rates, Kaplan-Meier analysis and log-rank testing revealed no significant differences between groups I and II. CONCLUSION: In situ graft revascularization is viable in afebrile patients or patients who have good response to preoperative antibiotic therapy. Extra-anatomic bypass grafting for infected infrarenal abdominal aneurysm resection has a similar long term survival rate and should be considered in patients who are unsuitable for in situ graft revascularization; however, the postoperative complication rate is higher. Further prospective study with large patient populations is needed to determine the selection criteria for using in situ revascularization as alternative methods for treatment of infected abdominal aneurysms. PMID- 21316904 TI - Hypothenar syndrome. PMID- 21316906 TI - [Perioperative management of chronic treatment and medical devices. Neurological and psychiatric diseases]. PMID- 21316907 TI - [Perioperative management of chronic treatment and medical devices. Phytotherapy]. PMID- 21316908 TI - [Perioperative management of chronic treatment and medical devices. Endocrine pathology]. PMID- 21316909 TI - [Severe and acute pancreatitis admitted in intensive care: a prospective epidemiological multiple centre study using CClin network database]. AB - OBJECTIVES: To describe the demographic characteristics, incidence of extra abdominal hospital-acquired infections and outcome of patients admitted to intensive care unit (ICU) with severe acute pancreatitis. STUDY DESIGN: A retrospective, observational multiple center (65 centers) analysis of prospectively acquired data. PATIENTS AND METHODS: During 2 years, all consecutive admitted patients to ICU for severe acute pancreatitis in the centers participating in the nosocomial infections surveillance network CClin Sud-Est were included. Patients whose ICU stay was less than 48 hours were not included. Demographic characteristics, extra-abdominal hospital-acquired infections and clinical course were described. RESULTS: During the study period, 510 patients were included which represented 2 % of patients with a length of stay longer than 48 hours in the 65 participating ICUs. The global attack rate of extra-abdominal hospital-acquired infections (pneumonia, bacteremia, urinary tract or central venous catheter infection) was 23 % in overall patients and it was 33 % in the 294 mechanically ventilated patients. ICU mortality was 20 % in overall patients and it was 34 % in mechanically ventilated patients. CONCLUSION: Severe acute pancreatitis represents 2 % of ICU stay longer than 48 hours. Its clinical course is frequently complicated by hospital-acquired infections and is associated with an high ICU mortality rate. This epidemiological observational study may be used for calculating sample size for future multicenter interventional therapeutic studies. PMID- 21316910 TI - The incidence of venous thromboembolism before and after total knee arthroplasty using 16-row multidetector computed tomography. AB - We performed a prospective study to determine the incidence of venous thromboembolism (VTE) using 16-row multidetector computed tomography (MDCT). The study included 71 patients who underwent total knee arthroplasty between September 2004 and March 2009. Multidetector computed tomography was performed 4 days before and after surgery. No patient had any presurgical symptoms of VTE. Presurgical and postsurgical incidences of pulmonary thromboembolism plus deep vein thrombosis were 0% and 13%, respectively; pulmonary thromboembolism alone, 1% and 3%, respectively; and deep vein thrombosis alone, 8% and 34%, respectively. Because asymptomatic VTE was noted in 9% of patients before surgery and 51% after surgery, we conclude that performing MDCT before and after total knee arthroplasty may be useful to clarify the incidence of VTE and to develop appropriate strategies for treatment and prevention. PMID- 21316911 TI - Straight tapered titanium stem with alumina bearing in cementless primary total hip arthroplasty: a minimum 5-year follow-up. AB - The aim of this study was to assess the midterm results of primary cementless total hip arthroplasty using a tapered stem and alumina bearing couple in active patients. After a minimum of 5 years of follow-up, 78 arthroplasties in 72 patients were reviewed retrospectively. The mean Harris hip score was 94 points, and 2 hips had thigh pain. All components radiographically demonstrated stable fixation by bone ingrowth and mild stress shielding of the proximal femur were noted in 14% of hips. There was no significant osteolysis or aseptic loosening. There was a ceramic head fracture in 1 hip and audible sounds in 2 hips. The results of total hip arthroplasty with a straight, tapered, proximally porous coated stem and alumina-on-alumina bearing were encouraging for active patients. PMID- 21316913 TI - Three-dimensional component alignment and functional outcome in computer navigated total knee arthroplasty: a prospective, randomized study comparing two navigation systems. AB - Computer navigation in total knee arthroplasty produces better component alignment than conventional techniques. Different navigation systems exist. We undertook a prospective, randomized study comparing 2 navigations systems (Stryker Full Navigation and Stryker Articular Surface Mounted [ASM] navigation systems). Three-dimensional component alignment (Perth computed tomographic knee protocol) and function at 1 year (Knee Society Scores) were assessed. Forty patients participated (20 fully navigated and 20 ASM-navigated total knee arthroplasties). Cohorts were well matched according to sex, age, and body mass index. No statistically significant difference was seen in any parameter of 3 dimensional component alignment or function between cohorts. Operative time for the ASM cohort was significantly less than the fully navigated cohort (P = .001). Both systems performed equally well, and therefore, surgeon preference should determine which system is used. PMID- 21316914 TI - Prewarming operating rooms for prevention of intraoperative hypothermia during total knee and hip arthroplasties. AB - Prewarming operating rooms has been shown to limit hypothermia in pediatric surgical patients but may be associated with extreme discomfort for surgeons. We examined the effect of prewarming operating rooms on core temperatures during knee and hip arthroplasties. Sixty-six patients were randomized to the prewarmed group at 24 degrees C or control group at 17 degrees C. The prewarmed group core temperature (mean, 36.14 degrees C) before active warming was significantly higher (P = .018) than that of the control group (mean, 35.83 degrees C). By the start of surgery, the difference was 36.01 degrees C prewarmed vs 35.83 degrees C control, P = .038. There was no significant difference in the last recorded mean temperatures between groups: 36.35 degrees C (prewarmed) vs 36.16 degrees C (control). A prewarmed operating room for adults undergoing knee or hip arthroplasty had minimal effect on preventing intraoperative hypothermia. PMID- 21316915 TI - Effect of surgical fit on integration of cancellous bone and implant cortical bone shear strength for a porous titanium. AB - Porous scaffold dowels of Ti(6)Al(4)V were prepared and implanted into cancellous and cortical bone sites in adult sheep. Cancellous implants were examined under gap, line-to-line, and press-fit conditions, whereas line-to-line implantation was used in cortical sites. Cortical shear strength increased significantly with time and reached 26.1 +/- 8.6 MPa at 12 weeks, accompanied by a concomitant increase in bone integration and remodeling. In cancellous sites, bone integration was well established at 4 and 12 weeks under conditions of press-fit and line-to-line match between implant and surgical defect. New bone growth was also found in the gap conditions, although to a lesser extent. These findings suggest that the porous Ti(6)Al(4)V could prove an effective scaffold material for uncemented fixation in cortical and cancellous sites. PMID- 21316916 TI - Alignment of computer-assisted total knee arthroplasty in patients with altered hip center. AB - This study aimed to determine limb and component alignment after computer assisted total knee arthroplasty in 30 patients (32 limbs) with an altered hip center due to a prior hip implant or deformed femoral head. There were no outliers greater than +/-3 degrees in the postoperative coronal alignment of the limb and the femoral component in relation to the altered hip center. Two limbs (8%) were more than +/-3 degrees for coronal alignment of the femoral component in relation to the anatomical hip center and 96% of limbs had less than 2 degrees deviation in relation to the altered hip center. Computer-navigated total knee arthroplasty results in accurate restoration of lower limb and component alignment in patients with prior hip implants or deformed femoral heads where accurate restoration of alignment may be challenging due to altered hip center. PMID- 21316917 TI - Intraoperative morphometric study of gender differences in Asian femurs. AB - Sixty-two male and 290 female knees from the Singapore population were measured intraoperatively for anteroposterior (AP) height of both medial and lateral femoral condyles, mediolateral (ML) width, and AP/ML ratio (aspect ratio). Median AP/ML ratio for the medial condyle was 1.00 (range, 0.91-1.18) in men and 1.09 (range, 0.92-1.39) in women. Median AP/ML ratio for the lateral condyle was 0.98 (range, 0.84-1.14) in men and 1.06 (range, 0.89-1.36) in women. Both aspect ratios showed significant differences according to sex (P < .001). We conclude that women generally have narrower femurs than men for any given AP height. The aspect ratios of Asians also appear narrower than that reported in white populations. PMID- 21316918 TI - Work stress, burnout, and social and personal resources among direct care workers. AB - Work stress is endemic among direct care workers (DCWs) who serve people with intellectual and developmental disabilities. Social resources, such as work social support, and personal resources, such as an internal locus of control, may help DCWs perceive work overload and other work-related stressors as less threatening and galvanize them to cope more effectively to prevent burnout. However, little is known about what resources are effective for coping with what types of work stress. Thus, we examined how work stress and social and personal resources are associated with burnout for DCWs. We conducted a survey of DCWs (n = 323) from five community-based organizations that provide residential, vocational, and personal care services for adults with intellectual and developmental disabilities. Participants completed a self-administered survey about their perceptions of work stress, work social support, locus of control, and burnout relative to their daily work routine. We conducted multiple regression analysis to test both the main and interaction effects of work stress and resources with respect to burnout. Work stress, specifically work overload, limited participation decision-making, and client disability care, was positively associated with burnout (p < .001). The association between work social support and burnout depended on the levels of work overload (p < .05), and the association between locus of control and burnout depended on the levels of work overload (p < .05) and participation in decision-making (p < .05). Whether work social support and locus of control make a difference depends on the kinds and the levels of work stressors. The findings underscore the importance of strong work-based social support networks and stress management resources for DCWs. PMID- 21316919 TI - The Screening Tool of Feeding Problems applied to children (STEP-CHILD): psychometric characteristics and associations with child and parent variables. AB - The present study evaluated the 23-item Screening Tool for Feeding Problems (STEP; Matson & Kuhn, 2001) with a sample of children referred to a hospital based feeding clinic to examine the scale's psychometric characteristics and then demonstrate how a children's revision of the STEP, the STEP-CHILD is associated with child and parent variables. Participants included 142 children (95 boys, 47 girls; mean age = 61.4 months; 43 with autism, 51 with other special needs, 48 with no special needs). Children ranged in age from 24 months to 18 years. Factor analysis revealed a 15-item STEP-CHILD with six subscales of child feeding problems: chewing problems, rapid eating, food refusal, food selectivity, vomiting, and stealing food. Mediation analysis documented that "overly permissive" actions by parents (such as infrequent insistence on eating during meals, or frequent preparation of Special Meals for children different than the family meal) explained over 34% of the links between children's feeding problems and poor weight and diet outcomes. PMID- 21316920 TI - Low vision aids for visually impaired children: a perception-action perspective. AB - It is a widely accepted belief in clinical practice that children with a visual impairment can profit from the use of a low vision aid (LVA). However, we found a considerable gap in our scientific understanding of LVA use, particularly in young children. This is the reason for the analysis presented in this paper. A selected overview of LVA use in adults is given, from which valuable insights are taken. Additionally, an action perspective for analysing LVA use is discussed as well as the results of tool-use studies in children. Mainly based on these three ingredients, we developed a conceptual framework for LVA use. The framework consists of three interacting relations between LVA, child and task. Performance of a particular child on a specific task with a certain LVA is constrained by the following three reciprocal and dynamic relations: the Child-to-Task relation (related to goal-information), the Child-to-LVA relation (related to control information), and the LVA-to-Task relation (related to topology information). PMID- 21316921 TI - Graphical modeling can be used to illustrate associations between variables describing functioning in head and neck cancer patients. AB - OBJECTIVE: To examine the associations between variables of functioning measured by the International Classification of Functioning, Disability and Health (ICF) in head and neck cancer (HNC) patients by means of graphical modeling. STUDY DESIGN AND SETTING: Graphical modeling was used on a data set of a cross sectional multicentric study of 145 patients with HNC. Functioning was qualified using the extended ICF checklist. Multiple imputation was used to handle missing data. The least absolute shrinkage and selection operator for generalized linear models was used to identify conditional associations between the ICF categories. Bootstrap aggregating was used to enhance the accuracy and validity of model selection. RESULTS: The resulting graph shows largely meaningful associations between the ICF categories. One central point could be visualized consisting of a circular path of d330 Speaking, d350 Conversation, b510 Ingestion functions, s320 Structure of mouth, and b310 Voice functions. Another important structure in the graph were the bow-shaped associations beginning with d335 Producing nonverbal messages to b130 Energy and drive functions. CONCLUSION: Graphical modeling can be used to describe associations between different areas of functioning in HNC patients. They found associations can be the basis for improved rehabilitation and gives a deeper understanding of functioning in HNC patients. PMID- 21316922 TI - Human T cells induce their own regulation through activation of B cells. AB - Regulatory functions for B lymphocytes have been reported in murine models of autoimmune diseases in which B-cell deficient mice were shown to exhibit exacerbated disease. The B cells responsible for the immune regulations were identified as a subpopulation of interleukin 10-secreting cells. However, the mechanism of induction and the characteristics of regulatory B cells in humans have been hardly studied. This study reports that regulation of T cell responses can be induced by B cells following CD40-dependent cognate interaction. T cell proliferation and cytokine production were differentially regulated. Thus, CD40 induced regulatory B cells partially inhibited T cell proliferation following CD40 interaction without requirement of soluble factor. In contrast, modulation of Th1 differentiation resulted from CD80- and CD86-dependent interactions and from IL-10 production. The suppressive effects were mediated by CD19(high)IgD+CD38(high)CD24(high)CD5(high) B cells and appeared to be indirect, through the induction of regulatory T cells as indicated by the appearance of Foxp3+CD4+CD25+T cells. These data suggest that activation signals from T cells initiate regulatory properties in B cells that modulate T cell responses involving regulatory T cells. Finally, studies in autoimmune patients revealed that regulation of T cell proliferation was defective in systemic lupus erythematosus but efficient in other diseases. Restoration of efficient B-cell regulatory activity could provide innovative B-cell based treatment of autoimmune diseases. PMID- 21316924 TI - Association between T-lymphocyte regulatory gene CTLA4 single nucleotide polymorphism at position 49 in exon 1 and HLA-DRB1*08 in Japanese patients with psoriasis vulgaris. PMID- 21316923 TI - Schizophrenia, "Just the Facts" 6. Moving ahead with the schizophrenia concept: from the elephant to the mouse. AB - The current construct of schizophrenia as a unitary disease is far from satisfactory, and is in need of reconceptualization. The first five papers in our "facts" series reviewed what is known about schizophrenia to date, and a limited number of key facts appear to stand out. Schizophrenia is characterized by persistent cognitive deficits, positive and negative symptoms typically beginning in youth, substantive heritability, and brain structural, functional and neurochemical alterations including dopaminergic dysregulation. Several pathophysiological models have been proposed with differing interpretations of the illness, like the fabled six blind Indian men groping different parts of an elephant coming up with different conclusions. However, accumulating knowledge is integrating the several extant models of schizophrenia etiopathogenesis into unifying constructs; we discuss an example, involving a neurodevelopmental imbalance in excitatory/inhibitory neural systems leading to impaired neural plasticity. This imbalance, which may be proximal to clinical manifestations, could result from a variety of genetic, epigenetic and environmental causes, as well as pathophysiological processes such as inflammation and oxidative stress. Such efforts to "connect the dots" (and visualizing the elephant) are still limited by the substantial clinical, pathological, and etiological heterogeneity of schizophrenia and its blurred boundaries with several other psychiatric disorders leading to a "fuzzy cluster" of overlapping syndromes, thereby reducing the content, discriminant and predictive validity of a unitary construct of this illness. The way ahead involves several key directions: a) choosing valid phenotype definitions increasingly derived from translational neuroscience; b) addressing clinical heterogeneity by a cross-diagnostic dimensional and a staging approach to psychopathology; c) addressing pathophysiological heterogeneity by elucidating independent families of "extended" intermediate phenotypes and pathophysiological processes (e.g. altered excitatory/inhibitory, salience or executive circuitries, oxidative stress systems) that traverse structural, functional, neurochemical and molecular domains; d) resolving etiologic heterogeneity by mapping genomic and environmental factors and their interactions to syndromal and specific pathophysiological signatures; e) separating causal factors from consequences and compensatory phenomena; and f) formulating or reformulating hypotheses that can be refuted/tested, perhaps in the mouse or other experimental models. These steps will likely lead to the current entity of schizophrenia being usefully deconstructed and reconfigured into phenotypically overlapping, but etiopathologically unique and empirically testable component entities (similar to mental retardation, epilepsy or cancer syndromes). The mouse may be the way to rescue the trapped elephant! PMID- 21316925 TI - An environmental contaminant, benzo(a)pyrene, induces oxidative stress-mediated interleukin-8 production in human keratinocytes via the aryl hydrocarbon receptor signaling pathway. AB - BACKGROUND: Benzo(a)pyrene (BaP) is an environmental contaminant found in cigarette smoke. It is well known that cigarette smoking exacerbates interleukin 8 (IL-8)-related inflammatory skin diseases such as psoriasis, palmoplantar pustulosis and acne. Although BaP has been shown to exert its biological effects via the aryl hydrocarbon receptor (AhR) signaling pathway, the mechanism of its inflammatory effects on skin remains unanswered. OBJECTIVE: To elucidate whether or not BaP cause AhR activation and subsequent oxidative stress leading to IL-8 production in normal human epidermal keratinocytes (NHEKs). METHODS: NHEKs exposed to BaP were analyzed. Immunofluorescence, real-time PCR, Western blotting, ELISA, reactive oxygen species (ROS) detection using H2DCFDA and RNA interference using si (small interfering) RNA were employed. RESULTS: Immunofluorescence analysis clearly demonstrated that BaP induced nuclear translocation of AhR from cytoplasm. The AhR activation subsequently induced CYP1A1 mRNA and protein expression in a dose-dependent manner. In addition, ROS and IL-8 production were coordinately augmented by BaP, whereas this was not the case in IL-1alpha, IL-6, TNF-alpha or GM-CSF production. Knockdown of AhR expression using siRNA transfection inhibited BaP-induced-ROS and IL-8 production, suggesting that these responses are strongly dependent on the AhR signaling pathway. Furthermore, the addition of N-acetyl cystein or catalase cancelled the IL-8 production by BaP, indicating that ROS production is essential for IL-8 production. RESULTS: This data highlights AhR-ROS-dependent regulation of IL-8 in NHEKs by BaP, providing a plausible explanation, at least in part, for why cigarette smoking exacerbates IL-8-related skin diseases such as psoriasis, palmoplantar pustulosis and acne. PMID- 21316926 TI - Topical application of emollients prevents dry skin-inducible intraepidermal nerve growth in acetone-treated mice. PMID- 21316927 TI - Optimising vancomycin doses in continuous infusion for septic patients. PMID- 21316928 TI - Emergence of Klebsiella pneumoniae ST258 with KPC-2 in Hong Kong. PMID- 21316929 TI - Effects of olanzapine on extracellular concentrations and tissue content of neurotensin in rat brain regions. AB - We have previously shown that both the psychostimulant d-amphetamine and the antipsychotics haloperidol and risperidone affect extracellular concentrations and tissue content of neurotensin (NT) in distinct brain regions. This study investigated the effects of acute olanzapine (1, 5mg/kg, s.c.) on extracellular NT-like immunoreactivity (-LI) concentrations in the ventral striatum (vSTR) and the medial prefrontal cortex (mPFC), and the effects of acute d-amphetamine (1.5mg/kg, s.c.) on extracellular NT-LI in these brain regions after a 30-day olanzapine (15mg/kg, p.o.) administration in rats. The effects of a 30-day olanzapine (3, 15mg/kg, p.o.) administration and d-amphetamine (1.5mg/kg, s.c.) coadministration during either the last day (acute) or the last 8days (chronic) on NT-LI tissue content in distinct rat brain regions were also studied. Acute olanzapine increased extracellular NT-LI, in both the vSTR and the mPFC. Chronic olanzapine increased and decreased basal extracellular NT-LI in the vSTR and the mPFC, respectively, and abolished the stimulatory effects of acute d-amphetamine on extracellular NT-LI in these brain regions. Chronic olanzapine as well as acute and chronic d-amphetamine affected NT-LI tissue content in a brain region dependent manner. Chronic olanzapine prevented the effects of acute and chronic d amphetamine on NT-LI tissue content in certain brain regions. The fact that olanzapine and d-amphetamine affected extracellular NT-LI in the vSTR and mPFC as well as NT-LI tissue content in distinct brain regions further supports the notion that NT plays a role in the therapeutic actions of antipsychotic drugs and possibly also in the pathophysiology of schizophrenia. PMID- 21316930 TI - Involvement of the neurotrophin and cannabinoid systems in the mechanisms of action of neurokinin receptor antagonists. AB - The anxiolytic- and antidepressant-like effects of the neurokinin (NK) receptor antagonists have been shown in behavioral studies. According to the involvement of neurotrophin signaling in the mechanisms of action of psychotropic agents, we aimed to investigate whether the selective NK(1), NK(2), or NK(3) receptor antagonists (GR-205171, SR48968, and SR142801, respectively) affect nerve growth factor (NGF) contents in the brain regions involved in the modulation of emotions. To gain a mechanistical insight into the process by which the NK antagonists regulate brain NGF levels, we evaluated the role of the cannabinoid system which is linked to depression and/or antidepressant effects and appears to interact with neurotrophin signaling. According to the results, single injection of the NK receptor antagonists (3, 5, and 10mg/kg, i.p.) into gerbils did not alter NGF or endocannabinoid (eCB) levels quantified by Bio-Rad protein assay and isotope-dilution liquid chromatography/mass spectrometry, respectively. Three week administration of 10mg/kg NK antagonists significantly elevated both NGF and eCB levels in brain-region specific fashion. Pre-application of the CB(1) receptor neutral antagonist AM4113 (5.6mg/kg) prevented the elevation of NGF or eCB induced by the NK antagonists. AM4113 showed no effect by itself. We conclude that the cannabinoid system is implicated in the mechanisms of action of NK receptor antagonists including the upregulation of brain NGF levels. PMID- 21316931 TI - Efficient design of multituned transmission line NMR probes: the electrical engineering approach. AB - Transmission line-based multi-channel solid state NMR probes have many advantages regarding the cost of construction, number of RF-channels, and achievable RF power levels. Nevertheless, these probes are only rarely employed in solid state NMR-labs, mainly owing to the difficult experimental determination of the necessary RF-parameters. Here, the efficient design of multi-channel solid state MAS-NMR probes employing transmission line theory and modern techniques of electrical engineering is presented. As technical realization a five-channel ((1)H, (31)P, (13)C, (2)H and (15)N) probe for operation at 7 Tesla is described. This very cost efficient design goal is a multi port single coil transmission line probe based on the design developed by Schaefer and McKay. The electrical performance of the probe is determined by measuring of Scattering matrix parameters (S-parameters) in particular input/output ports. These parameters are compared to the calculated parameters of the design employing the S-matrix formalism. It is shown that the S-matrix formalism provides an excellent tool for examination of transmission line probes and thus the tool for a rational design of these probes. On the other hand, the resulting design provides excellent electrical performance. From a point of view of Nuclear Magnetic Resonance (NMR), calibration spectra of particular ports (channels) are of great importance. The estimation of the pi/2 pulses length for all five NMR channels is presented. PMID- 21316932 TI - Role of lipid rafts in innate immunity and phagocytosis of polystyrene latex microspheres. AB - Understanding of the association of phagocytosis of polymers with signaling of innate immunity of macrophages is the major purpose of this study. Polymer conjugates have been utilized for clinical therapy of cancer and infections, such as Mycobacterium tuberculosis, as effective vectors of drug-delivery systems. They are incorporated through phagocytosis into macrophages and activate innate immunity signaling, which plays a crucial role in its therapeutic and side effects. Macrophage phagocytosis of polystyrene latex microspheres was examined and assayed by treatment of macrophages with the cholesterol depletor methyl-beta cyclodextrin (MbetaCD) or the sphingolipid depletor n-octyl-beta-D glucopyranoside (OGP). Expressions of various mRNAs during phagocytosis were quantified by real-time PCR. Phagocytosis of polystyrene latex microspheres by various macrophages, such as murine monocyte-derived macrophage J774, rat alveolar macrophage NR8383, and murine Kupffer cell KC13-2, was suppressed by treatment with MbetaCD or OGP in a concentration-dependent manner. The expression of mRNAs of TNFalpha, IL-1beta, IL-6 and CXCL10 genes induced by lipopolysaccharide (LPS) was not suppressed by treatment with MbetaCD in J774 cells. Moreover, genes that were induced by LPS were up-regulated even in the absence of LPS by the phagocytosis of polymer conjugates, but such up-regulations were not suppressed by the treatment with MbetaCD. It was shown that lipid rafts play a significant role in incorporation of polymer conjugates through phagocytosis of macrophages, but their association with signal transduction in innate immunity is very limited. PMID- 21316933 TI - Biomimetic preparation of polymer-supported free radical scavenging, cytocompatible and antimicrobial "green" silver nanoparticles using aqueous extract of Citrus sinensis peel. AB - In the pursuit of making the nanoscale-research greener, the utilization of the reductive potency of a common byproduct of food processing industry i.e. orange peel is reported here to prepare biopolymer-templated "green" silver nanoparticles. Aqueous extract of orange peel at basic pH was exploited to prepare starch supported nanoparticles under ambient conditions. The compositional abundance of pectins, flavonoids, ascorbic acid, sugars, carotenoids and myriad other flavones may be envisaged for the effective reductive potential of orange peel to generate silver nanoparticles. The nanoparticles were distributed within a narrow size spectrum of (3-12 nm) with characteristic Bragg's reflection planes of fcc structure, and surface plasmon resonance peak at 404 nm. Anti-lipid peroxidation assay using goat liver homogenate and DPPH scavenging test established the anti-oxidant potency of the silver nanoparticles. Their synergy with rifampicin against Bacillus subtilis MTCC 736 and cytocompatibility with the human leukemic monocytic cell line, THP-1 were also investigated. Thus, the present work deals with the preparation of starch assisted anti-microbial, cytocompatible and free radical scavenging "green" silver nanoparticles. PMID- 21316934 TI - Phytosterols supplementation decreases plasma small and dense LDL levels in metabolic syndrome patients on a westernized type diet. AB - BACKGROUND AND AIMS: Several studies have observed a hypocholesterolemic effect of plant sterols in hypercholesterolemic patients on a balanced diet. The aim of this study was to examine the effect of phytosterol supplementation on risk factors of coronary artery disease in metabolic syndrome patients on a Westernized type diet. METHODS AND RESULTS: In a randomized placebo-controlled design 108 patients with metabolic syndrome were assigned to consume either 2 plant sterol-enriched yogurt mini drink which provided 4 g phytosterols per day, or a yogurt beverage without phytosterols (control). The duration of the study was 2 months and the patients in both groups followed their habitual westernized type diet and recording it on food diaries. Blood samples were drawn at baseline and after 2 months of intervention. After 2 months supplementation with phytosterols, a significant reduction in total cholesterol, LDL-cholesterol, small and dense LDL (sdLDL) levels, as well as, apoB and triglycerides concentrations were observed in the intervention group (P < 0.05) compared to the control group. In addition, phytosterol supplementation lowered serum total cholesterol by 15.9%, LDL-cholesterol by 20.3% and triglyceride levels by 19.1% (P = 0.02, P < 0.001 and P < 0.001, respectively), although the patients kept their habitual westernized type diet. No differences were observed in HDL cholesterol, apoA1, glucose, C-reactive protein, fibrinogen levels and blood pressure. CONCLUSIONS: Phytosterol supplementation improves risk factors of coronary artery disease even if the diet is a westernized type. PMID- 21316936 TI - Leachate recirculation in a landfill: some insights obtained from the development of a simple 1-D model. AB - The re-introduction of leachate back into the waste can play an important part in landfill management. It can encourage biodegradation by raising the water content and transporting bacteria, nutrients and waste products. It also enables leachate to be stored within the body of the landfill, for example to help minimise temporal variations in the load on a leachate treatment plant. It is helpful for a landfill operator to be able to estimate the rate at which the landfill can accept leachate (the maximum infiltration or injection rate), the storage capacity of the landfill and the leachate retention time. This paper discusses some of the insights obtained from the development and application of a simple conceptual model of leachate recirculation that can be used to estimate key parameter values on the basis of the hydraulic properties of the waste. The model is described, partly validated against a more rigorous numerical analysis, and then used to interpret data obtained from field tests on a real site. The shortcomings of the model in its current form are discussed, and suggestions are made as to how these might be addressed in the context of developing the model as a design tool. PMID- 21316935 TI - Amphetamine-type stimulant use and HIV/STI risk behaviour among young female sex workers in Phnom Penh, Cambodia. AB - BACKGROUND: Use of amphetamine-type substances (ATS) has been linked to increased risk of HIV and other sexually transmitted infections (STI) worldwide. In Cambodia, recent ATS use is independently associated with incident STI infection among young female sex workers (FSWs). METHODS: We conducted 33 in-depth interviews with women (15-29 years old) engaged in sex work to explore ATS use and vulnerability to HIV/STI. RESULTS: Participants reported that ATS, primarily methamphetamine in pill and crystalline forms (yama), were cheap, widely available and commonly used. Yama was described as a "power drug" (thnam kamlang) which enabled women to work long hours and serve more customers. Use of ATS by clients was also common, with some providing drugs for women and/or encouraging their use, often resulting in prolonged sexual activity. Requests for unprotected sex were also more common among alternatives intoxicated clients and strategies typically employed to negotiate condom use were less effective. CONCLUSION: ATS use was highly functional for young women engaged in sex work, facilitating a sense of power and agency and highlighting the occupational significance and normalization of ATS in this setting. This highly gendered dynamic supports the limited but emerging literature on women's use of ATS, which to date has been heavily focused on men. Results indicate an urgent need to increase awareness of the risks associated with ATS use, to provide women with sustainable alternatives for income generation, to better regulate the conditions of sex work, and to work with FSWs and their clients to develop and promote culturally appropriate harm reduction interventions. PMID- 21316937 TI - Eco-efficiency for greenhouse gas emissions mitigation of municipal solid waste management: a case study of Tianjin, China. AB - The issue of municipal solid waste (MSW) management has been highlighted in China due to the continually increasing MSW volumes being generated and the limited capacity of waste treatment facilities. This article presents a quantitative eco efficiency (E/E) analysis on MSW management in terms of greenhouse gas (GHG) mitigation. A methodology for E/E analysis has been proposed, with an emphasis on the consistent integration of life cycle assessment (LCA) and life cycle costing (LCC). The environmental and economic impacts derived from LCA and LCC have been normalized and defined as a quantitative E/E indicator. The proposed method was applied in a case study of Tianjin, China. The study assessed the current MSW management system, as well as a set of alternative scenarios, to investigate trade-offs between economy and GHG emissions mitigation. Additionally, contribution analysis was conducted on both LCA and LCC to identify key issues driving environmental and economic impacts. The results show that the current Tianjin's MSW management system emits the highest GHG and costs the least, whereas the situation reverses in the integrated scenario. The key issues identified by the contribution analysis show no linear relationship between the global warming impact and the cost impact in MSW management system. The landfill gas utilization scenario is indicated as a potential optimum scenario by the proposed E/E analysis, given the characteristics of MSW, technology levels, and chosen methodologies. The E/E analysis provides an attractive direction towards sustainable waste management, though some questions with respect to uncertainty need to be discussed further. PMID- 21316938 TI - A longitudinal study of hallux valgus surgical outcomes using a validated patient centred outcome measure. AB - BACKGROUND: Hallux valgus is a common chronic condition affecting up to a third of the population. Progressive disruption to the complex anatomy of the first ray involving metatarsal, sesamoids and hallux impose both structural and functional alteration to the foot which underpin the secondary pathologies associated with this condition. It is common for patients to seek correction of the deformity in order to alleviate pain and improve footwear tolerance. Surgical intervention remains the only viable means to restore osseous alignments. To date there remains no universally accepted standards for procedure selection. METHODS: A total of 179 consecutive participants were recruited into the study. Ethical approval was obtained and all participants consented to participate in the study, in accordance with the Helsinki Declaration. All patients attending the Department of Podiatric Surgery, between July 2004 and October 2007 for the surgical management of hallux valgus were invited to complete a Foot Health Status Questionnaire. Pre-operative data collection on all participants was undertaken on the day of admission, using the validated Foot Health Status Questionnaire measurement tool as with previous studies. RESULTS: A total of 179 complete data sets were recorded in this longitudinal study with an average participant age of 49.4 years (SD 14.5). The group comprised 164 females and 15 males. The mean days for administration of the Foot Health Status Questionnaire post operative follow up was 1045 days (149 weeks or 2.9 years). The results demonstrated that within all four foot specific domains, the minimal important differences were achieved by the majority of the group. Meanwhile, in domains relating to general health, physical activity, vigour and social capacity, the majority of participants failed to attain the calculated minimal important difference (94 [53%], 96 [54%], 93 [52%], 93 [52%], respectively). CONCLUSIONS: The authors have presented for the first time minimal important difference for all eight domains for the Foot Health Status Questionnaire quality of life tool in respect to hallux valgus surgery. Results demonstrate that surgical correction of hallux valgus undertaken under local anaesthetic as a Day Case procedure is an effective intervention directly benefiting patients by reducing perceived foot pain, improving foot function and general foot health for the majority of patients. PMID- 21316939 TI - Transcription modulation chromosome-wide: universal features and principles of dosage compensation in worms and flies. AB - Dosage compensation processes in flies and worms provide a unique opportunity to study common regulatory principles of thousands of genes. Technological advancement in the recent years has allowed for the comprehensive description of key aspects such as the targeting of the regulatory factors, the emerging chromatin structure changes and the ensuing subtle transcriptional alterations. With plenty of data at hand the challenge remains to integrate the findings into coherent models that appreciate the global nature of the underlying principles leaving the experimental anecdotes behind while avoiding the numerical burlesque. PMID- 21316940 TI - Microwave-assisted pyrolysis of microalgae for biofuel production. AB - The pyrolysis of Chlorella sp. was carried out in a microwave oven with char as microwave reception enhancer. The results indicated that the maximum bio-oil yield of 28.6% was achieved under the microwave power of 750 W. The bio-oil properties were characterized with elemental, GC-MS, GPC, FTIR, and thermogravimetric analysis. The algal bio-oil had a density of 0.98 kg/L, a viscosity of 61.2 cSt, and a higher heating value (HHV) of 30.7 MJ/kg. The GC-MS results showed that the bio-oils were mainly composed of aliphatic hydrocarbons, aromatic hydrocarbons, phenols, long chain fatty acids and nitrogenated compounds, among which aliphatic and aromatic hydrocarbons (account for 22.18% of the total GC-MS spectrum area) are highly desirable compounds as those in crude oil, gasoline and diesel. The results in this study indicate that fast growing algae are a promising source of feedstock for advanced renewable fuel production via microwave-assisted pyrolysis (MAP). PMID- 21316941 TI - Optimization of culture conditions for Aspergillus sojae expressing an Aspergillus fumigatus alpha-galactosidase. AB - Using Response Surface Methodology, carbon and nitrogen sources and agitation speed for cultivation of Aspergillus sojae expressing the alpha-galactosidase gene, aglB of Aspergillus fumigatus IMI 385708 were optimized. Compared to cultivation in modified YpSs medium, cultivation in 250-mL Erlenmeyer flasks agitated at 276 rpm and containing 100 mL of optimized medium consisting of 10.5% molasses (w/v) and 1.3% NH(4)NO(3) (w/v), 0.1% K(2)HPO(4), and 0.005% MgSO(4).7H(2)O achieved a 4-fold increase in alpha-galactosidase production (10.4 U/mL). These results suggest the feasibility of industrial large scale production of an alpha-galactosidase known to be valuable in galactomannan modification. PMID- 21316942 TI - Change in the fouling propensity of sludge in membrane bioreactors (MBR) in relation to the accumulation of biopolymer clusters. AB - A membrane bioreactor (MBR) and an activated sludge process (ASP) were operated side by side to evaluate the change of sludge supernatant characteristics and the evolution of the sludge fouling propensity. The MBR sludge had a higher organic concentration and more biopolymer clusters (BPC) in the supernatant compared with ASP. BPC increased in both concentration and size in the MBR. The results show that the change in the liquid-phase property had a profound effect on the sludge fouling propensity. MBR operation transformed typical activated sludge to MBR sludge with a higher fouling propensity. Distinct from the ASP, membrane filtration retained soluble microbial products (SMP) within the MBR, and the vast membrane surface provided a unique environment for the transformation of SMP to large size BPC, leading to further sludge deposition on the membrane surface. Thus, membrane filtration is the crucial cause of the inevitable fouling problem in submerged MBRs. PMID- 21316943 TI - Column bioleaching of uranium embedded in granite porphyry by a mesophilic acidophilic consortium. AB - A mesophilic acidophilic consortium was enriched from acid mine drainage samples collected from several uranium mines in China. The performance of the consortium in column bioleaching of low-grade uranium embedded in granite porphyry was investigated. The influences of several chemical parameters on uranium extraction in column reactor were also investigated. A uranium recovery of 96.82% was achieved in 97 days column leaching process including 33 days acid pre-leaching stage and 64 days bioleaching stage. It was reflected that indirect leaching mechanism took precedence over direct. Furthermore, the bacterial community structure was analyzed by using Amplified Ribosomal DNA Restriction Analysis. The results showed that microorganisms on the residual surface were more diverse than that in the solution. Acidithiobacillus ferrooxidans was the dominant species in the solution and Leptospirillum ferriphilum on the residual surface. PMID- 21316944 TI - Use of near infrared spectroscopy in online-monitoring of feeding substrate quality in anaerobic digestion. AB - In order to keep the anaerobic process stably and uniformly producing biogas it needs to be supplied with either an even amount of substrate of stable quality or varying amounts according to variations in quality. Feeding amounts are usually adjusted manually as a reaction to changing rates of biogas production. Continuous information about the actual substrate quality is not available and feedstuff analyses are costly. Aim of this study was to assess the feasibility of near infrared spectroscopic (NIRS) online monitoring of substrate quality in order to find ways towards more exact control of biogas plant feeding. A NIRS sensor system was designed, constructed and calibrated for continuous monitoring of (RMSECV in brackets) dry matter (DM) (0.75%fresh matter (FM)), volatile solids (0.74%FM), crude fat (0.09%FM), crude protein (0.22%FM), crude fiber (1.50%DM) and nitrogen-free extracts (0.93%FM) of maize silage. PMID- 21316945 TI - Improvement in HPLC separation of acetic acid and levulinic acid in the profiling of biomass hydrolysate. AB - 5-Hydroxymethylfurfural (HMF) and furfural could be separated by the Aminex HPX 87H column chromatography, however, the separation and quantification of acetic acid and levulinic acid in biomass hydrolysate have been difficult with this method. In present study, the HPLC separation of acetic acid and levulinic acid on Aminex HPX-87H column has been investigated by varying column temperature, flow rate, and sulfuric acid content in the mobile phase. The column temperature was found critical in resolving acetic acid and levulinic acid. The resolution for two acids increased dramatically from 0.42 to 1.86 when the column temperature was lowered from 60 to 30 degrees C. So did the capacity factors for levulinic acid that was increased from 1.20 to 1.44 as the column temperature dropped. The optimum column temperature for the separation was found at 45 degrees C. Variation in flow rate and sulfuric acid concentration improved not as much as the column temperature did. PMID- 21316946 TI - Hydrothermal liquefaction of the brown macro-alga Laminaria saccharina: effect of reaction conditions on product distribution and composition. AB - The brown macro-alga Laminaria saccharina was converted into bio-crude by hydrothermal liquefaction in a batch reactor. The influence of reactor loading, residence time, temperature and catalyst (KOH) loading was assessed. A maximum bio-crude yield of 19.3 wt% was obtained with a 1:10 biomass:water ratio at 350 degrees C and a residence time of 15 min without the presence of the catalyst. The bio-crude had an HHV of 36.5 MJ/kg and is similar in nature to a heavy crude oil or bitumen. The solid residue has high ash content and contains a large proportion of calcium and magnesium. The aqueous phase is rich in sugars and ammonium and contains a large proportion of potassium and sodium. PMID- 21316947 TI - Butanol production from thin stillage using Clostridium pasteurianum. AB - The production of butanol from thin stillage by Clostridium pasteurianum DSM 525 was evaluated in the paper. At initial pH values ranging from 5.0 to 7.0 C. pasteurianum DSM 525 produced 6.2-7.2 g/L of butanol utilizing glycerol in thin stillage as the main carbon source, with yields of 0.32-0.44 g butanol produced/g glycerol consumed, which are higher than previously reported yields (e.g., 0.14 0.31 g butanol/g glycerol, Biebl, 2001). Lactic acid in the thin stillage acted as a buffering agent, maintaining the pH of the medium within a range of 5.7-6.1. Lactic acid was also utilized along with glycerol, enhancing butanol production (6.5 g/L butanol vs. 8.7 g/L butanol with 0 and 16 g/L lactic acid, respectively). These results demonstrate the feasibility of cost-effective butanol production using thin stillage as a nutrient-containing medium with a pH buffering capacity. PMID- 21316948 TI - Dynamic transition of microbial communities in response to acidification in fixed bed anaerobic baffled reactors (FABR) of two different flow directions. AB - Two five-compartment fixed-bed anaerobic baffled reactors (FABRs) were operated under deteriorative and stable conditions. The FABRs were identical except for flow direction: one was horizontal (H-reactor) and the other was vertical (V reactor). The microbial community dynamics in 1, 3 and 5 compartments were analyzed using denaturing gradient gel electrophoresis (DGGE), 16S rRNA gene clone library screening and quantitative PCR. After start-up, the Methanomicrobiales were typically dominant in adhering sludge of 5th compartments of two reactors. Because methanogenesis mainly occurred in the latter compartment, Methanomicrobiales were likely to play important roles in FABRs. FABRs recovered from performance deterioration very quickly. Meanwhile, methanogens and dominant methanogens greatly increased in every compartment of two reactors. Our results indicated that 16S rRNA levels of methanogens in the adhering sludge were higher than those in the deposited sludge and the adhering fraction of V-reactor held up more acid-resistant bacteria and methanogens than that of H-reactor. PMID- 21316949 TI - Effect of chitosan on UASB treating POME during a transition from mesophilic to thermophilic conditions. AB - The effects of chitosan addition on treatment of palm oil mill effluent were investigated using two lab-scale upflow anaerobic sludge bed (UASB) reactors: (1) with chitosan addition at the dosage of 2 mg chitosan per g volatile suspended solids on the first day of the operation (R1), (2) without chitosan addition (the control, R2). The reactors were inoculated with mesophilic anaerobic sludge which was acclimatized to a thermophilic condition with a stepwise temperature increase of 5 degrees C from 37 to 57 degrees C. The OLR ranged from 2.23 to 9.47 kg COD m(-3) day(-1). The difference in biogas production rate increased from non significant to 18% different. The effluent volatile suspended solids of R1 was 65 mg l(-1) lower than that of R2 on Day 123. 16S rRNA targeted denaturing gradient gel electrophoresis (DGGE) fingerprints of microbial community indicated that some methanogens in the genus Methanosaeta can be detected in R1 but not in R2. PMID- 21316950 TI - An evaluation of the potential of Acacia dealbata as raw material for bioethanol production. AB - In this work, the potential of Acacia dealbata as raw material for ethanol production was evaluated, as well as its composition with regard to cellulose, hemicelluloses, lignin, extractives and ash. The tree samples were subjected to several dilute acid pretreatments using a combined severity parameter ranging from 0.7 to 3.7. The highest ethanol concentration obtained was 10.31 g ethanol/L within 24 h by using a separate hydrolysis and fermentation of the water insoluble fraction after pretreatment at 180 degrees C with 0.8% of sulfuric acid for 15 min. With simultaneous saccharification and fermentation, results obtained for the washed solids of water insoluble fraction were better than those obtained with the whole slurry. PMID- 21316951 TI - An integrated UASB-sludge digester system for raw domestic wastewater treatment in temperate climates. AB - To improve the performance of an upflow anaerobic sludge blanket (UASB) reactor treating raw domestic wastewater under temperate climates conditions, the addition of a sludge digester to the process was investigated. With the decrease in temperature, the COD removal decreased from 78% at 28 degrees C to 42% at 10 degrees C for the UASB reactor operating alone at a hydraulic retention time of 6 h. The decrease was attributed to low hydrolytic activity at lower temperatures that reduced suspended matter degradation and resulted in solids accumulation in the top of the sludge blanket. Solids removed from the upper part of the UASB sludge were treated in an anaerobic digester. Based on sludge degradation kinetics at 30 degrees C, a digester of 0.66 l per liter of UASB reactor was design operating at a 3.20 days retention time. Methane produced by the sludge digester is sufficient to maintain the temperature at 30 degrees C. PMID- 21316952 TI - Dioxin-like polychlorinated biphenyl adsorbent obtained from enzymatic saccharification residue of lignocellulose. AB - In this study, the effective utilization of lignocellulose residue as an adsorbent was investigated. Japanese cypress wood flour subjected to hydrothermal pretreatment and ball-mill grinding was saccharified with an enzyme. The residual wood flour was carbonized and activated by physical and chemical activation to produce adsorbents for persistent organic pollutant removal. The adsorption properties were investigated by pore analysis using the N(2) adsorption/desorption isotherm and adsorption tests for dioxin-like polychlorinated biphenyls in a hexane solution. The obtained adsorbents showed high production yields and adsorption properties for dioxin-like polychlorinated biphenyls. PMID- 21316953 TI - Two-stage anaerobic digestion of tomato, cucumber, common reed and grass silage in leach-bed reactors and upflow anaerobic sludge blanket reactors. AB - Anaerobic digestion of tomato, cucumber, common reed and grass silage was studied in four separate two-stage reactor configuration consisting of leach bed reactor (LBR) and upflow anaerobic sludge blanket reactor (UASB). LBR studies showed that COD solubilization for cucumber and grass silage was higher (50%) than tomato (35%) and common reed (15%). Results also showed that 31-39% of initial TKN present in tomato and cucumber was solubilized in the leachates and 47-54% of the solubilized TKN was converted to NH(4)-N. The corresponding values for common reed and grass silage were 38-50% and 18-36%, respectively. Biomethanation of the leachates in UASB reactors resulted in methane yields of 0.03-0.14 m(3) CH(4) kg( 1)VS(fed) for the studied crop materials. Thus, high COD solubilization, high nitrogen mineralization and solubilization rates were feasible during anaerobic digestion of lignocellulosic materials in a two-stage LBR-UASB reactor system. PMID- 21316954 TI - Field scale evaluation of bovine-specific DNA as an indicator of tissue degradation during cattle mortality composting. AB - Currently, mortality compost is managed by temperature as extent of tissue degradation is difficult to assess. In the present study, field-scale mortality compost was constructed with composted brain tissue (Brain) and compost adjacent to brain tissue (CAB) sampled over 230 d. Following genomic DNA extraction, bovine-specific mitochondrial DNA (Mt-DNA) and bacterial 16S rDNA fragments were quantified using real-time PCR. Genomic DNA yield of Brain and CAB decreased rapidly (89-98%) and stabilized after 7 d. Compared to d 0, Brain Mt-DNA rapidly decreased (84-91% reduction on d 7). In CAB, Mt-DNA dramatically increased until d 28 (up to 34,500 times) thereafter decreasing by 77-93% on d 112. Quantification of bovine Mt-DNA indicates tissue degradation was initially characterized by rapid decomposition and release of cell contents into surrounding compost matrix followed by further degradation of Mt-DNA by flourishing microorganisms. Consequently, bovine Mt-DNA copies in compost matrix were reliable indicators of tissue degradation. PMID- 21316956 TI - Upgrading of low-boiling fraction of bio-oil in supercritical methanol and reaction network. AB - In this work, the low-boiling fraction (LBF) of bio-oil was used as feed stock. LBF is a very complex mixture, and the three groups in LBF: acids, aldehydes and phenols, are primarily responsible for deterioration in the quality. The upgrading reactions were carried out over Pt/Al(2)(SiO(3))(3), Pt/C or Pt/MgO in supercritical methanol. It is demonstrated that supercritical condition can greatly facilitate the esterification process, and after 6 h reaction, all the acids can be converted into esters even without adding any catalyst. The total amount of the three groups left in products was much less exhibited on Pt supported on active carbon and MgO in the presence of hydrogen. By investigating the model reactions, the relations between the representative compounds and major products were identified, and the conversion scheme of the upgrading reactions is proposed. PMID- 21316955 TI - Low temperature alkali pretreatment for improving enzymatic digestibility of sweet sorghum bagasse for ethanol production. AB - A low temperature alkali pretreatment method was proposed for improving the enzymatic hydrolysis efficiency of lignocellulosic biomass for ethanol production. The effects of the pretreatment on the composition, structure and enzymatic digestibility of sweet sorghum bagasse were investigated. The mechanisms involved in the digestibility improvement were discussed with regard to the major factors contributing to the biomass recalcitrance. The pretreatment caused slight glucan loss but significantly reduced the lignin and xylan contents of the bagasse. Changes in cellulose crystal structure occurred under certain treatment conditions. The pretreated bagasse exhibited greatly improved enzymatic digestibility, with 24-h glucan saccharification yield reaching as high as 98% using commercially available cellulase and beta-glucosidase. The digestibility improvement was largely attributed to the disruption of the lignin-carbohydrate matrix. The bagasse from a brown midrib (BMR) mutant was more susceptible to the pretreatment than a non-BMR variety tested, and consequently gave higher efficiency of enzymatic hydrolysis. PMID- 21316957 TI - Degradation of phorbol esters by Pseudomonas aeruginosa PseA during solid-state fermentation of deoiled Jatropha curcas seed cake. AB - Large amount of seed cake is generated as by-product during biodiesel production from Jatropha seeds. Presence of toxic phorbol esters restricts its utilization as livestock feed. Safe disposal or meaningful utilization of this major by product necessitates the degradation of these phorbol esters. The present study describes the complete degradation of phorbol esters by Pseudomonas aeruginosa PseA strain during solid state fermentation (SSF) of deoiled Jatropha curcas seed cake. Phorbol esters were completely degraded in nine days under the optimized SSF conditions viz. deoiled cake 5.0 g; moistened with 5.0 ml distilled water; inoculum 1.5 ml of overnight grown P. aeruginosa; incubation at temperature 30 degrees C, pH 7.0 and RH 65%. SSF of deoiled cake seems a potentially viable approach towards the complete degradation of the toxic phorbol esters. PMID- 21316958 TI - Maintaining potent HTLV-I protease inhibition without the P3-cap moiety in small tetrapeptidic inhibitors. AB - The human T cell lymphotropic/leukemia virus type 1 (HTLV-I) causes adult T cell lymphoma/leukemia. The virus is also responsible for chronic progressive myelopathy and several inflammatory diseases. To stop the manufacturing of new viral components, in our previous reports, we derived small tetrapeptidic HTLV-I protease inhibitors with an important amide-capping moiety at the P(3) residue. In the current study, we removed the P(3)-cap moiety and, with great difficulty, optimized the P(3) residue for HTLV-I protease inhibition potency. We discovered a very potent and small tetrapeptidic HTLV-I protease inhibitor (KNI-10774a, IC(50)=13 nM). PMID- 21316959 TI - Synthesis, in vitro antimalarial and cytotoxicity of artemisinin-aminoquinoline hybrids. AB - Dihydroartemisinin (DHA) was coupled to different aminoquinoline moieties forming hybrids 9-14, which were then treated with oxalic acid to form oxalate salts (9a 14a). Compounds 9a, 10a, 12, 12a, and 14a showed comparable potency in vitro to that of chloroquine (CQ) against the chloroquine sensitive (CQS) strain, and were found to be more potent against the chloroquine resistant CQR strain. Hybrids 12 and its oxalate salt 12a were the most active against CQR strain, being 9- and 7 fold more active than CQ, respectively (17.12 nM; 20.76 nM vs 157.9 nM). An optimum chain length was identified having 2 or 3 Cs with or without an extra methylene substituent. PMID- 21316961 TI - Phellinstatin, a new inhibitor of enoyl-ACP reductase produced by the medicinal fungus Phellinus linteus. AB - A new trimeric hispidin derivative, phellinstatin, was isolated from a culture broth of the medicinal fungus Phellinus linteus and its structure was established by various spectral analysis. Phellinstatin strongly inhibited Staphylococcus aureus enoyl-ACP reductase with an IC(50) of 6 MUM and also showed antibacterial activity against S. aureus and MRSA. PMID- 21316960 TI - 5-oxo-15-HETE: total synthesis and bioactivity. AB - The first total synthesis of 6(E),8(Z),11(Z),13(E) 5-oxo-15-HETE 4 was accomplished. The synthetic material was evaluated with calcium mobilization assay and compared with 5-oxo-ETE the natural ligand for the OXE receptor. PMID- 21316962 TI - Discovery of potent and orally bioavailable heterocycle-based cannabinoid CB1 receptor agonists. AB - Novel 3-(1H-indol-3-yl)-1,2,4-oxadiazoles and -thiadiazoles were synthesized and found to be potent CB1 cannabinoid receptor agonists. The oral bioavailability of these compounds could be dramatically improved by optimization studies of the side chains attached to the indole and oxadiazole cores, leading to identification of a CB1 receptor agonist with good oral activity in a range of preclinical models of antinociception and antihyperalgesia. PMID- 21316963 TI - Novel potent pyrimido[4,5-c]quinoline inhibitors of protein kinase CK2: SAR and preliminary assessment of their analgesic and anti-viral properties. AB - We describe the discovery of novel potent substituted pyrimido[4,5-c]quinoline ATP-competitive inhibitors of protein kinase CK2. A binding model of the inhibitors with the protein was elaborated on the basis of SAR and revealed various modes of interaction with the hinge region. Representative analog 14k (CK2 IC(50)=9 nM) showed anti-viral activity at nanomolar concentrations against HIV-1. Orally available compound 7e (CK2 IC(50)=3 nM) reduced pain in the phase II of a murine formalin model. These preliminary data confirm that properly optimized CK2 inhibitors may be used for anti-viral and pain therapy. PMID- 21316964 TI - Discovery of orally available tetrahydroquinoline-based glucocorticoid receptor agonists. AB - A series of tetrahydroquinoline derivatives were synthesized and profiled for their ability to act as glucocorticoid receptor selective modulators. Structure activity relationships of the tetrahydroquinoline B-ring lead to the discovery of orally available GR-selective agonists with high in vivo activity. PMID- 21316965 TI - Discovery of novel mGluR1 antagonists: a multistep virtual screening approach based on an SVM model and a pharmacophore hypothesis significantly increases the hit rate and enrichment factor. AB - Development of glutamate non-competitive antagonists of mGluR1 (Metabotropic glutamate receptor subtype 1) has increasingly attracted much attention in recent years due to their potential therapeutic application for various nervous disorders. Since there is no crystal structure reported for mGluR1, ligand-based virtual screening (VS) methods, typically pharmacophore-based VS (PB-VS), are often used for the discovery of mGluR1 antagonists. Nevertheless, PB-VS usually suffers a lower hit rate and enrichment factor. In this investigation, we established a multistep ligand-based VS approach that is based on a support vector machine (SVM) classification model and a pharmacophore model. Performance evaluation of these methods in virtual screening against a large independent test set, M-MDDR, show that the multistep VS approach significantly increases the hit rate and enrichment factor compared with the individual SB-VS and PB-VS methods. The multistep VS approach was then used to screen several large chemical libraries including PubChem, Specs, and Enamine. Finally a total of 20 compounds were selected from the top ranking compounds, and shifted to the subsequent in vitro and in vivo studies, which results will be reported in the near future. PMID- 21316966 TI - The identification of Landouzy-Dejerine disease: an investigative history. PMID- 21316967 TI - Breast cancer in a multi-ethnic Asian setting: results from the Singapore Malaysia hospital-based breast cancer registry. AB - Two hospital-based breast cancer databases (University Malaya Medical Center, Malaysia [n = 1513] and National University Hospital, Singapore [n = 2545]) were merged into a regional registry of breast cancer patients diagnosed between 1990 and 2007. A review of the data found 51% of patients diagnosed before the age of 50 years. and 72% percent of the women were Chinese followed by Malays (16%), Indians (8%), and other races (4%). Median tumor size at presentation was 26 mm and about 25% of patients presented with TNM stage III or IV disease. Most tumors were of ductal histology (87%). Fifty-seven percent of tumors were estrogen receptor positive and 40% were poorly differentiated. Of those patients who had surgery, 70% had mastectomy while 30% had breast conserving surgery. Overall, chemotherapy was administered to 56% of patients and hormonal treatment to 60%. Five-year overall survival was 82.5% in patients with TNM stage 0 to stage II cancer, and 30.2% in those with later stages. PMID- 21316968 TI - Barriers and opportunities for early detection of breast cancer in Gaza women. AB - A survey of 100 women living inside Gaza (WIG) and 55 Gaza women residing outside Gaza (WOG) was conducted to investigate barriers and opportunities for breast cancer screening, and to better understand possible differences based on residency. The survey found that over 90% of both groups were willing to undergo a diagnostic mammogram for a breast complaint and 86% of WIG and 85% of WOG believed survival was increased with early detection. However, only 27% of WIG and 50% WOG were willing to undergo screening mammography. Religion and culture were not barriers to mammography for over 94% of WIG and 98% of WOG. Limited resources and lack of access to medical facilities were identified as barriers in up to 55% of WIG compared to 15% of WOG. Misconceptions about breast cancer were reported more frequently by WIG, including beliefs that breast cancer is not very common and that breast cancer can be contagious. PMID- 21316969 TI - Polymorphisms of the vascular endothelial growth factor A gene and susceptibility to sporadic brain arteriovenous malformation in a Chinese population. AB - Human brain arteriovenous malformation (BAVM) tissue contains increased levels of vascular endothelial growth factor A (VEGFA). We carried out a case-control study to determine whether polymorphisms in the VEGFA gene are associated with sporadic BAVM. Nine selected VEGFA single-nucleotide polymorphisms (SNP) were genotyped in 319 patients with BAVM and 333 controls from a Chinese population using the MassARRAY genotyping system. We found four single variants in the VEGFA gene (rs1547651, rs2010963, rs833069 and rs3025010), with one haplotype, ACT, possibly associated with the risk of developing BAVM. PMID- 21316970 TI - Management of recurrent craniopharyngioma. AB - Craniopharyngioma accounts for approximately 1.2% to 4.6% of all intracranial tumours. Their close proximity to vital structures such as the hypothalamic pituitary axis and optic apparatus makes them one of the most challenging and controversial management dilemmas in neurosurgery. Recurrence following initial transcranial resection is reported as 9% to 51% at a median time of 26 months to 96 months. Treatment options for recurrent craniopharyngioma include repeat surgery, radiotherapy, radiosurgery and intracystic therapies. We present a series of 54 recurrent craniopharyngiomas treated at The Royal Melbourne Hospital between 1991 and 2008 and discuss the management options now available. PMID- 21316971 TI - En bloc excision of a dermal sinus tract. AB - Dermal sinus tracts are a form of spinal dysraphism that arises from a failure of dysjunction early in embryogenesis. They are diagnosed in pediatric patients and who present with a dimple, infection, or neurologic deficit. The tract is surgically excised en bloc to avoid contamination from the tract, which harbors bacteria. However, dermal sinus tracts typically terminate intradurally, rendering their en bloc excision difficult. To avoid entering the tract, allowing for an en bloc excision, we modified the usual technique employed for accessing the spinal intradural space. An en bloc excision of the dermal sinus tract was successfully performed. The patient recovered from the procedure neurologically intact and her postoperative course was uncomplicated. We conclude that en bloc excision of a dermal sinus tract down to the intradural space is feasible with modifications to standard operative technique. PMID- 21316972 TI - Evaluation of tibial rotational stability of single-bundle vs. anatomical double bundle anterior cruciate ligament reconstruction during a high-demand activity - a quasi-randomized trial. AB - The purpose of this study was to compare the tibial rotational stability of anatomical double-bundle anterior cruciate ligament reconstructed knees with single-bundle anterior cruciate ligament reconstructed knees during a high-demand activity. Total of 66 subjects, (22 with double-bundle anterior cruciate ligament reconstruction, 22 with single-bundle anterior cruciate ligament reconstruction, and 22 healthy control individuals) were examined in this study. Using a 9-camera motion analysis system, motion subjects were recorded performing during a drop landing and cutting. Using the point cluster technique, the internal-external tibial rotation of both knees was calculated. The mean maximum range of motion for each knee was evaluated for 3 groups (double-bundle group, single-bundle group, and control group). Clinical assessment, including Tegner score, Lysholm score, and knee arthrometric measurement, revealed restoration of the reconstructed knee stability with no differences between the two anterior cruciate ligament reconstruction groups. The results showed that both groups resulted in tibial rotation values that were significantly smaller than those in the intact legs and those in the healthy controls. There were no significant differences in tibial rotation between the DB group and the SB group. Therefore anatomical double-bundle reconstruction restores normal tibial rotation no more than single-bundle reconstruction during this high-demand dynamic activity. These results suggest a trend towards dynamic overcorrection after the ACL reconstruction. PMID- 21316973 TI - X-ray and molecular modelling in fragment-based design of three small quinoline scaffolds for HIV integrase inhibitors. AB - Crystal structures of three small molecular scaffolds based on quinoline, 2 methylquinoline-5,8-dione, 5-hydroxy-quinaldine-6-carboxylic acid and 8-hydroxy quinaldine-7-carboxylic acid, were characterised. 5-Hydroxy-quinaldine-6 carboxylic acid was co-crystallized with cobalt(II) chloride to form a model of divalent metal cation-ligand interactions for potential HIV integrase inhibitors. Molecular docking into active site of HIV IN was also performed on 1WKN PDB file. Selected ligand-protein interactions have been found specific for active compounds. Studied structures can be used as scaffolds in fragment-based design of new potent drugs. PMID- 21316974 TI - An automated, polymer-assisted strategy for the preparation of urea and thiourea derivatives of 15-membered azalides as potential antimalarial chemotherapeutics. AB - A series of 15-membered azalide urea and thiourea derivatives has been synthesized and evaluated for their in vitro antimalarial activity against chloroquine-sensitive (D6), chloroquine/pyremethamine resistant (W2) and multidrug resistant (TM91C235) strains of Plasmodium falciparum. We have developed an effective automated synthetic strategy for the rapid synthesis of urea/thiourea libraries of a macrolide scaffold. Compounds have been synthesized using a solution phase strategy with overall yields of 50-80%. Most of the synthesized compounds had inhibitory effects. The top 10 compounds were 30-65 times more potent than azithromycin, an azalide with antimalarial activity, against all three strains. PMID- 21316975 TI - 2-aminomethylphenylamine as a novel scaffold for factor Xa inhibitor. AB - We have been researching orally active factor Xa inhibitor for a long time. We explored the new diamine linker using effective ligands to obtain a new attractive original scaffold 2-aminomethylphenylamine derivative. Compound 1D showed very strong in vitro and in vivo factor Xa inhibitory activity, as well as favorable PK profiles in po administration to monkeys. PMID- 21316976 TI - 17,20-lyase inhibitors. Part 4: design, synthesis and structure-activity relationships of naphthylmethylimidazole derivatives as novel 17,20-lyase inhibitors. AB - A novel series of naphthylmethylimidazole derivatives and related compounds have been investigated as selective 17,20-lyase inhibitors. Optimization of the substituent at the 6-position on the naphthalene ring was performed to yield a methylcarbamoyl derivative, which exhibited potent inhibitory activity against human 17,20-lyase and promising selectivity (>200-fold) for 17,20-lyase over CYP3A4. Further modifications of the methylcarbamoyl derivative led to the discovery of the corresponding tricyclic compound, which showed highly potent activity against human 17,20-lyase (IC(50) 19 nM) and good selectivity (>1000 fold) for inhibition of 17,20-lyase over CYP3A4. Additional biological evaluation revealed that the tricyclic compound had potent in vivo efficacy in monkeys and favorable pharmacokinetic profiles when administered in rats. Asymmetric synthesis of the selective tricyclic inhibitor was also achieved using a chiral alpha-hydroxy ketone. PMID- 21316977 TI - Synthesis, in vitro anti-inflammatory and cytotoxic evaluation, and mechanism of action studies of 1-benzoyl-beta-carboline and 1-benzoyl-3-carboxy-beta-carboline derivatives. AB - In the present study, various 1-substituted and 1,3-disubstituted beta-carboline derivatives were synthesized by a modified single-step Pictet-Spengler reaction. The compounds were examined for cytotoxicity and anti-inflammatory activity, as measured by the inhibition of prostaglandin E(2) (PGE(2)) production and nitric oxide (NO) production. While only two compounds (28 and 31) showed marginal cytotoxicity against four human cancer cell lines, most of the tested compounds exhibited potent inhibitory activity of both NO and PGE(2) production. Moreover, compounds 6 and 16 significantly reduced the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2), suggesting that beta-carboline analogs can inhibit NO and PGE(2) production at the translational level. In addition, several of the beta-carboline derivatives (1, 2, 4-8, 11, 13, 22, 25, 27, 31, and 41-43) displayed significant inhibitory activity of superoxide anion (O(2)(.-)) generation or elastase release compared to the reference compound, with 6 being the most potent. N-Formyl-L-methionyl-phenylalanine (FMLP)-induced phosphorylation of c-JunN-terminal kinase (JNK) and protein kinase B (AKT) were also inhibited by 6, suggesting that it suppresses human neutrophil functions by inhibiting the activation of JNK and AKT signaling pathways. Therefore, the synthetic 1-benzoyl-3-carboxy beta-carboline analogs may have great potential to be developed as anti-inflammatory agents. PMID- 21316978 TI - First tomographic image of neutron capture rate in a BNCT facility. AB - This work discusses the development of online dosimetry of the boron dose via Single Photon Emission Computed Tomography (SPECT) during a BNCT treatment irradiation. Such a system will allow the online computation of boron dose maps without the large current uncertainties in the assessment of the boron concentration in different tissues. The first tomographic boron dose image with a SPECT prototype is shown. PMID- 21316979 TI - Over-expression of HAP3b enhances primary root elongation in Arabidopsis. AB - HAPs, similar to Heme Activator Proteins (HAP) or nuclear factor-Y (NF-Y) in yeast and animals, play versatile roles in plant growth, development, and responses to environmental cues. HAP3b in Arabidopsis is a member in the HAP3 gene family and is involved in regulating flowering time through the long-day photoperiod pathway (Cai et al., 2007, Plant Physiol 145: 98-105). In this study, we report that overexpression of HAP3b enhances primary root elongation. Detailed analysis showed that HAP3b-overexpression did not affect the length of the root elongation zone and the cell length profiles in the elongation zone. Kinematic analysis indicated that root cells in HAP3b-overexpressors elongate faster than the cells in wild-type roots. Using GUS as a reporter gene, we showed that HAP3b is specifically expressed in the tip region of the root, where cell division and elongation occur. Our results provide evidence to support a role of HAP3b in regulation of root growth. PMID- 21316980 TI - 'Six sigma approach' - an objective strategy in digital assessment of postoperative air leaks: a prospective randomised study. AB - OBJECTIVE: Until now, only way to report air leaks (ALs) has been with an analogue score in an inherently subjective manner. The Six Sigma quality improvement methodology is a data-driven approach applicable to evaluate the quality of the quantification method of repetitive procedures. We applied the Six Sigma concept to improve the process of AL evaluation. METHODS: A digital device for AL measurement (Drentech PALM, Redax S.r.l., Mirandola (MO), Italy) was applied to 49 consecutive patients, who underwent pulmonary intervention, compared with a similar population with classical chest drainage. Data recorded were postoperative AL, chest-tube removal days, number of chest roentgenograms, hospital length of stay; device setup time, average time rating AL and patient satisfaction. Bivariable comparisons were made using the Mann-Whitney test, the chi2 test and Fisher's exact test. Analysis of quality was conducted using the Six Sigma methodology. RESULTS: There were no significant differences regarding AL (p=0.075), although not statistically significant; there was a reduction of postoperative chest X-rays (four vs five) and of hospital length of stay (6.5 vs 7.1 days); and a marginally significant difference was found between chest-tube removal days (p=0.056). There were significant differences regarding device setup time (p=0.001), average time rating AL (p=0.001), inter-observer variability (p=0.001) and patient satisfaction (p=0.002). Six Sigma analyses revealed accurate assessment of AL. CONCLUSIONS: Continuous digital measurement of AL reduces degree of variability of AL score, gives more assurance for tube removal, and reports AL without the apprehension of observer error. Efficiency and effectiveness improved with the use of a digital device. We have noted that the AL curves depict actually sealing of AL. The clinical importance of AL curves requires further study. PMID- 21316981 TI - The management of post-intubation tracheal stenoses with self-expandable stents: early and long-term results in 11 cases. AB - OBJECTIVE: The optimal management of post-intubation tracheal stenoses is surgical reconstruction of the airway. Stenting of the trachea using silastic T tubes or one of the various types of tracheal stents are the alternative ways to surgical reconstruction for the management of post-intubation tracheal stenoses. The early and long-term results of 11 patients with post-intubation tracheal stenosis, who underwent tracheal stenting with self-expandable metallic stents (SEMSs), are presented. METHODS: Twelve patients (10 men, mean age: 47.8+/-20.4 years) with post-intubation tracheal stenosis were referred for tracheal stenting with SEMS (2000-2004). In three cases, the upper tracheal stenosis extended within the subglottic larynx. Stenting was successful in 11 patients, while, in one patient with involvement of the subglottic larynx, the attempt to insert the stent failed. Follow-up time varied from 6 to 96 months, and it was made with virtual and fiberoptic bronchoscopy. RESULTS: Immediate relief of obstructive symptoms was observed in all the 11 patients, where an SEMS was successfully inserted. Stent dislodgement occurred shortly after the procedure in two patients, and it was treated with insertion of a new stent in the first case and a stent-on-stent insertion in the second. Good patency of the stent was observed in three patients for 60-96 months. Three patients with good patency of the stent died from other reasons 24-48 months after stent insertion. Four patients developed obstructive granulation tissue at the ends of the stent after 12-43 months, requiring further treatment with thermal lasers and/or tracheostomy. One patient underwent stent removal and successful laryngotracheal reconstruction 6 months after stent insertion. CONCLUSIONS: The application of SEMS in post intubation tracheal stenoses results in immediate improvement of obstructive symptoms without significant perioperative complications. SEMSs have the potential risks of migration and of granulation tissue formation at the end of the stent. SEMS should be applied only in strictly selected patients with post intubation tracheal stenosis, who are considered unfit for surgery and/or with limited life expectancy. PMID- 21316982 TI - Pulmonary arteriovenous fistula in an aged patient. PMID- 21316984 TI - Recent theoretical studies of water oxidation in photosystem II. AB - In the present mini-review, computational work over the past decade on water oxidation in photosystem II (PSII) is summarized. The size of the chemical model used for the oxygen evolving complex (OEC) has during this time increased from the initial 20 atoms to the present day 220 atoms. The electronic structure methods used have during the same period only undergone minor improvements. It is concluded that the results have now reached a high level of convergence and the predictions for both the structure of the OEC and the O-O bond formation mechanism are most probably of higher accuracy than presently available from experiments. PMID- 21316983 TI - PsbO, the manganese-stabilizing protein: analysis of the structure-function relations that provide insights into its role in photosystem II. AB - The minireview presented here summarizes current information on the structure and function of PsbO, the photosystem II (PSII) manganese-stabilizing protein, with an emphasis on the protein's assembly into PSII, and its function in facilitating rapid turnovers of the oxygen evolving reaction. Two putative mechanisms for functional assembly of PsbO, which behaves as an intrinsically disordered polypeptide in solution, into PSII are proposed. Finally, a model is presented for the role of PsbO in relation to the function of the Mn, Ca(2+), and Cl(-) cofactors that are required for water oxidation, as well as for the action of hydroxide and small Mn reductants that inhibit the function of the active site of the oxygen-evolving complex. PMID- 21316985 TI - Serum TNF-alpha, sTNFR1, IL-6, IL-8 and IL-10 levels in Weil's syndrome. AB - Studies on cytokine levels in Weil's syndrome are lacking. In this study, TNF alpha, sTNFR1, IL-6, IL-8 and IL-10 levels were measured in 44 serum samples of patients diagnosed with Leptospira interrogans serovar icterohaemorrhagiae infection. TNF-alpha levels linked with pulmonary hemorrhagic implications, while elevated sTNFR1 and IL-10 levels linked with fatal cases. IL-6 and IL-8 did not seem to affect the outcome of the disease. Immune response pattern in Weil's syndrome bears resemblance to other patterns described for hemorrhagic fevers. IL 10/TNF-alpha ratio is proposed as a marker for prognosis. PMID- 21316986 TI - Asymptomatic migration of a first-generation AMPLATZER vascular plug into the abdominal aorta: conservative management may be an option. PMID- 21316987 TI - Update in hematology: heparin-induced thrombocytopenia and bivalirudin. AB - Heparin-induced thrombocytopenia (HIT) is important because it is common, and it significantly increases mortality after cardiac surgery. Although thrombocytopenia after cardiac surgery is common, it predicts serious adverse outcome when it is severe. Despite the high prevalence of heparin/platelet factor 4 antibodies in cardiac surgical patients, they typically do not indicate a higher perioperative risk. Recent evidence suggests, however, that when these antibodies are in the immunoglobulin M class, there is an increased risk of nonthrombotic adverse outcomes after cardiac surgery. According to the guidelines from the American College of Chest Physicians, patients with HIT require parenteral anticoagulation with a direct thrombin inhibitor such as lepirudin, argatroban, or bivalirudin. The transition to oral anticoagulation must be undertaken cautiously and only after the platelet count has recovered. Patients with a remote history of HIT can have cardiac surgery safely with unfractionated heparin. Patients with clinically active HIT who require cardiac surgery before the resolution of the HIT preferably should be anticoagulated with bivalirudin, dosed according to body weight and the goal-activated coagulation time. Given that bivalirudin is an established alternative to heparin as a thrombin inhibitor for cardiac surgery, it is likely that future trials will investigate which anticoagulant confers better outcomes after cardiac surgery, as is the case in percutaneous coronary intervention. PMID- 21316988 TI - Device closure of an atrial septal defect: an unexpected stumbling block. PMID- 21316989 TI - Presence of high grade tertiary Gleason pattern upgrades the Gleason sum score and is inversely associated with biochemical recurrence-free survival. AB - OBJECTIVES: Tumor heterogeneity is a common finding and led to realization of a tertiary Gleason component (TGC) in prostate cancer. In an attempt to further investigate its prognostic value, we analyzed the association of tertiary Gleason pattern in Gleason score <= 7 tumors with pathologic stage and biochemical disease-free survival. MATERIAL AND METHODS: A total of 331 radical prostatectomy specimens were analyzed retrospectively. The primary, secondary, and the tertiary patterns were evaluated by reviewing all of the pathologic slides. TGC was defined as Gleason grade pattern 4 or 5 for Gleason score < 7 tumors and Gleason grade pattern 5 for Gleason score 7 tumors. The pathologic prognostic factors, (extraprostatic extension, seminal vesicle and lymph node invasion, surgical margin status) of Gleason score < 7, 3+4, and 4+3 tumors with or without TGC were compared. Biochemical recurrence-free survival (BRFS) was calculated using Kaplan Meier method with log rank test, and the influence of TGC was assessed in a Cox regression model. RESULTS: TGC observed more frequently with higher Gleason scores (21% of the GS < 7 cases, 23% of the GS 3+4 cases, and 58% of the GS 4+3 cases). In terms of adverse pathologic prognostic factors and BRFS, GS < 7 tumors with TGC behaved significantly worse than GS < 7 tumors without TGC (P = 0.01 and P = 0.001, respectively) with properties similar to GS 3+4 tumors without TGC. Gleason score 3+4 and 4+3 tumors without TGC were statistically similar and had better features than corresponding tumors of same Gleason score with TGC. Furthermore, Gleason score 7 tumors with TGC had similar features with GS 8-10 tumors. During follow-up, 73 (22%) subjects had PSA recurrence. In the Cox regression model TGC was an independent variable for BRFS (HR = 2.63, 95% CI = 1.39-4.98, P = 0.003). CONCLUSION: According to the present study, 3 different prognostic groups were observed; good prognostic group: GS < 7, intermediate prognostic group: GS < 7+TGC, GS 3+4, and GS 4+3, and finally bad prognostic group: GS (3+4)+TGC, GS (4+3)+TGC, GS > 7. Presence of a TGC appears to upgrade the total score and adjuvant treatment decisions may further be refined by considering the tertiary pattern. PMID- 21316990 TI - Surgical hand antisepsis in veterinary practice: evaluation of soap scrubs and alcohol based rub techniques. AB - Recent studies have shown that hydro-alcoholic solutions are more efficient than traditional medicated soaps in the pre-surgical hand antisepsis of human surgeons but there is little veterinary literature on the subject. The aim of this study was to compare the efficiency of medicated soaps and a hydro-alcoholic solution prior to surgery using an in-use testing method in a veterinary setting. A preliminary trial was performed that compared the mean log(10) number of bacterial colony forming units (CFU) and the reduction factors (RF) between two 5 min hand-scrubbing sessions using different soaps, namely, povidone iodine (PVP) and chlorhexidine gluconate (CHX), and the 1.5-min application of a hydro alcoholic rub. A clinical in-use trial was then used to compare the hydro alcoholic rub and CHX in a surgical setting. Sampling was performed using finger printing on agar plates. The hydro-alcoholic rub and CHX had a similar immediate effect, although the sustained effect was significantly better for the hydro alcoholic rub, while PVP had a significantly lower immediate and sustained effect. The hydro-alcoholic rub showed good efficiency in the clinical trial and could be considered as a useful alternative method for veterinary surgical hand antisepsis. PMID- 21316991 TI - Effects of iatrogenic hypercortisolism on gallbladder sludge formation and biochemical bile constituents in dogs. AB - An association between gallbladder mucoceles and hypercortisolism (HC) was recently described in dogs. Because the formation of a mucocele from clear bile without the transitional formation of microprecipitates appears unlikely, the aim of this study was to investigate the effects of iatrogenic HC on sludge formation and changes in the biochemical composition of bile. Bile samples from 6 dogs obtained by percutaneous ultrasound-guided cholecystocentesis before (day 0), during (days 28, 56, and 84), and after (days 28p, 56p, and 84p) oral administration of hydrocortisone (8 mg/kg every 12 h) were analysed for calcium, cholesterol and bilirubin concentrations and pH. In addition the gallbladder was examined ultrasonographically for sludge. Six dogs receiving a placebo served as controls. Although gallbladder sludge was observed in all treated dogs at day 56, it was also noted in 50% of control dogs, and no significant differences were seen between groups at any sampling time. Bilirubin and cholesterol concentrations decreased significantly and reversibly during treatment, and calcium concentration showed a similar trend. Bile pH was consistently slightly alkaline during iatrogenic HC, whereas it was slightly acidic in control animals. A 3-month period of iatrogenic HC does not lead to ultrasonographically detectable gallbladder sludge or to an increase in bile constituents that are commonly implicated in sludge formation in humans. PMID- 21316992 TI - A retrospective study of serum beta-hydroxybutyric acid in 215 ill cats: clinical signs, laboratory findings and diagnoses. AB - Serum concentrations of beta-hydroxybutyric acid (sBHBA) are increased in cats with diabetes mellitus (DM), diabetic ketoacidosis (DKA) and hepatic lipidosis (HL). This study assessed sBHBA as a diagnostic tool in 215 consecutively enrolled ill cats in the general population in a veterinary hospital. At the time of presentation, sBHBA was within the reference range in 158/215 (73.5%) cats (median 0.27; range 0.00-0.49 mmol/L) and elevated in 57/215 (26.5%) cats (median 0.87; range 0.51-21.45 mmol/L). Compared to cats with normal sBHBA, those with increased sBHBA had higher frequencies of anorexia, weight loss, icterus, polyuria/polydipsia, hyperbilirubinaemia, hypertriglyceridaemia, pancreatitis, HL, DM and DKA. They had higher concentrations of bilirubin and triglycerides and lower concentrations of potassium, chloride and total protein. There were positive correlations (P<0.01) between sBHBA and urinary glucose (r=0.42) and ketones (r=0.76), but there were no group differences in dipstick levels of urinary ketones. Cats with DM/DKA and with HL had significantly higher sBHBA compared to other cats. Receiver operator characteristics analysis of sBHBA as a predictor of HL showed that sBHBA was a good predictor of HL. Increased sBHBA occurs frequently in ill cats and provides useful diagnostic information, especially in DM/DKA and HL. PMID- 21316993 TI - Juvenile parkinsonism associated with heterozygous frameshift ATP13A2 gene mutation. AB - We report a case of levodopa-responsive juvenile parkinsonism (JP) associated with a heterozygous ATP13A2 gene frameshift mutation. The clinical phenotype of our case is more severe when compared with other published reports of symptomatic heterozygous ATP13A2 mutation carriers. To our knowledge, this is the youngest reported patient with JP associated with a heterozygous ATP13A2 mutation. Our findings expand the clinical phenotypic spectrum of JP associated with heterozygous ATP13A2 mutation. PMID- 21316994 TI - Fast measurements of average flow velocity by Low-Field 1H NMR. AB - In this paper, we describe a method for measuring the average flow velocity of a sample by means of Nuclear Magnetic Resonance. This method is based on the Carr Purcell-Meiboom-Gill (CPMG) sequence and does not require the application of any additional static or pulsed magnetic field gradients to the background magnetic field. The technique is based on analyzing the early-time behavior of the echo amplitudes of the CPMG sequence. Measurements of average flow velocity of water are presented. The experimental results show a linear relationship between the slope/y-intercept ratio of a linear fit of the first echoes in the CPMG sequence, and the average flow velocity of the flowing fluid. The proposed method can be implemented in low-cost Low-Field NMR spectrometers allowing a continuous monitoring of the average velocity of a fluid in almost real-time, even if the flow velocity changes rapidly. PMID- 21316995 TI - Enhancing time-suspension sequences for the measurement of weak perturbations. AB - We detail key features for implementation of time-suspension multiple-pulse line narrowing sequences. This sequence class is designed to null the average Hamiltonian (H-(0)) over the period of the multiple-pulse cycle, typically to provide for high-resolution isolation of evolution from a switched interaction, such as field gradients for imaging or small sample perturbations. Sequence designs to further ensure null contributions from correction terms (H-((1)) and H (2)) of the Magnus expansion are also well known, as are a variety of approaches to second averaging, the process by which diagonal content is incorporated in H (0) to truncate unwanted terms. In spite of such designs, we observed spin evolution not explicable by H-(0) using 16-, 24- and 48-pulse time-suspension sequences. We found three approaches to effectively remove artifacts that included splitting of the lineshape into unexpected multiplets as well as chirped evolution. The noted approaches are simultaneously compatible for combination of their benefits. The first ensures constant power deposition from RF excitation as the evolution period is incremented. This removes chirping and allows more effective 2nd averaging. Two schemes for the latter are evaluated: the noted introduction of a diagonal term in H-(0), and phase-stepping the line-narrowing sequence on successive instances during the evolution period. Either of these was sufficient to remove artifactual splittings and to further enhance resolution, while in combination enhancements were maintained. Finally, numerical simulations provide evidence that our experimental line-narrowing results with 75As in crystalline GaAs approach performance limits of idealized sequences (e.g., with ideal square pulses, etc.). The three noted experimental techniques should likewise benefit ultimate implementation with switched interactions and corresponding new error contributions, which place further demand on sequence performance. PMID- 21316996 TI - Kocher-Debre-Semelaigne syndrome diagnosed by autopsy associated with disseminated intravascular coagulation. AB - Kocher-Debre-Semelaigne syndrome is a rare disease with little literature, which develops with myopathy in infancy associated with neuromuscular alterations, polymyositis with symmetrical proximal muscle weakness, pseudohypertrophy, muscular rigidity and spasms, exercise intolerance, myxoedema, short stature, and cretinism. Male patient aged 18 years old, 1.52 m in height, admitted in the General Hospital of Triangulo Mineiro Federal University on November 11, 2003, complaining of intense diffuse abdominal pain like severe cramps, without triggering factors, associated with asthenia and hyporexia. This seems to be one of the few reports of KDS syndrome diagnoses by autopsy, where alterations in the thyroid gland connected with hypotrophy and probable congenital hypothyroidism were described and resulted in complications such as disseminated intravascular coagulation and hemophagocytic syndrome with fast progression to death of an 18 year-old patient. PMID- 21316997 TI - Investigation of LRP8 gene in 1p31 QTL linked to LDL peak particle diameter in the Quebec family study. AB - The small, dense LDL phenotype is associated with an increased cardiovascular disease risk. A genome-wide scan performed on 236 nuclear families of the Quebec Family Study (QFS) revealed a quantitative trait locus affecting LDL peak particle diameter (LDL-PPD) and density on the 1p31 region. This region contains the low-density lipoprotein receptor-related protein 8 (LRP8) gene. LRP8, a receptor for apolipoprotein (apo) E, modulates apoE levels, thus contributing to plasma cholesterol and triglyceride (TG) concentrations. We investigate the effects of LRP8 polymorphisms on LDL-PPD, on the relative proportion of small LDL (<255A) and the absolute concentration of cholesterol among the small LDL particles. LRP8 rs5174 was associated with LDL-PPD and estimated cholesterol concentrations in the small LDL particles adjusted for the effects of age and sex (p=0.008, p=0.04, respectively). LRP8 rs3820198 was associated with total and LDL cholesterol levels as well as with apoB concentrations adjusted for the effects of age and sex (p=0.005, p=0.004 and p=0.01, respectively) but not with LDL size related variables. These results suggest that LRP8 gene polymorphisms influence plasma cholesterol levels as well as size and composition of LDL particles. PMID- 21316998 TI - A polymorphism in the angiotensin II type 1 receptor gene has different effects on the risk of diabetic nephropathy in men and women. AB - BACKGROUND: The etiology of diabetic nephropathy depends partly on genetic factors. Elevated systemic and intraglomerular blood pressure and glomerular filtration rate, partly regulated by the renin-angiotensin system, increase the risk of diabetic nephropathy. METHODS: The present case-control study investigated the association of the rs5186 polymorphism, in the angiotensin II type 1 receptor gene (AGTR1), with diabetic nephropathy. The study included 3561 patients with type 1 diabetes from Denmark, Finland, France and Sweden. Microalbuminuria was defined as albumin excretion rate (AER) >=20 to <200 MUg/min or albumin concentration >=30 to <300 mg/l (n=707), macroalbuminuria was defined as AER>=200 MUg/min or >=300 mg/l (n=1546), and patients with renal replacement therapy were also included in this group. The controls had >15 years diabetes duration, AER <20 MUg/min or <30 mg/l, and no antihypertensive treatment (n=1308). RESULTS: AA genotype of the rs5186 polymorphism significantly increased the risk of diabetic nephropathy in male patients, OR=1.27 (95% CI=1.02-1.58), P=0.03, adjusted for age at diabetes onset, HbA1c, diabetes duration, smoking and country of origin. Among the women, there were no significant associations between rs5186 and diabetic nephropathy, OR=0.89 (0.71-1.11), P=0.30. CONCLUSION: We conclude that the AGTR1 gene may be associated with increased risk of diabetic nephropathy in men with type 1 diabetes. PMID- 21316999 TI - Lysosomal enzyme activities in phenylketonuria. PMID- 21317000 TI - [Quality analysis by external users of the non-medical health transport unit of Alicante]. AB - Non-medical health transport has great health, media and social repercussions and requires a very considerable amount of human and economic resources. OBJECTIVE: To describe the quality, evaluated by external users of our Health Department, in order to know what are the most important elements for external users. METHODS: Cross-sectional, descriptive observational study. Population to study: patients with a social security health card who come to the Hospital of Alicante and are non-medical health transport unit users. RESULTS: Waiting time to be delivered to hospital in 92.7% of the cases was less than an hour, and was between one and two hours for 7.2%. The most frequent destinations were rehabilitation service and outpatient clinics. When users were asked if the would recommend this service, 60.9% said "for sure" and 39.1% said "probably yes". CONCLUSIONS: This study allows us to know patient needs and expectations, as well as the factors they value the most and which of our work areas to improve. PMID- 21317001 TI - [Validity and reliability of the personalised nursing care index in a hospital medical unit]. AB - OBJECTIVES: To determine the validity and reliability of the personalised nursing care index (PNCI). METHODS: A descriptive study was carried out in the Puerta del Mar Hospital (Cadiz) of the Andalusian Health Service, which included all patients admitted to an Internal Medicine ward from May 2007 to July 2008. A descriptive analysis was performed on the population included in the study. Furthermore, reliability was analysed with the 20-Kuder-Richardson coefficient and a correlation matrix between PNCI items; and validity via a maximum likelihood factorial analysis, and a ROC curve to determine sensitivity and specificity. RESULTS: A total of 219 people were included in the survey, of whom 74.4% were patients and 26.6% caregivers. The percentages of males and females were similar with a mean age of 62.5 years and 48.4% finished basic school education. The 20-Kuder-Richarson value was 0.835; and a positive correlation between items, which corresponded to 3 groups of items (factors). The maximum likelihood factorial analysis confirmed the 3 items-factor groups with a Promax rotation due to the high correlation between them. The maximum explained variance was 91.42%. The ROC curve area was 90.1% with a cut-off point of 8, for a sensitivity of 79.9% and a specificity of 90.6%. CONCLUSIONS: The PCNI is reliable, with the internal consistency coefficient value in between an optimum range. Furthermore, factors obtained from the matrix correlation inter-items were confirmed with a factorial analysis, resulting in a high explained variance. The curve ROC area is excellent compared to the gold standard, considered as the perception of confidence relationship. PMID- 21317002 TI - [Opinion of healthcare professionals on patient safety in a primary level hospital]. AB - OBJECTIVE: To identify the patient safety (PS) culture perceived by health professionals of the Hospital Universitario Virgen de las Nieves (HUVN) in Granada. METHODOLOGY: A descriptive cross-sectional study of professionals working in HUVN using the Spanish version of the questionnaire Hospital Survey On Patient Safety Culture (AHRQ), in July-August 2008. The sample size was estimated as 476 surveys (included 60% losses). RESULTS: The response rate was 62.8% (299 questionnaires). In the previous 12 months, 90.2% of professionals had not notified any adverse event (AE). The average perception of PS was 6.57 +/- 1.82 (scale 0-10). Teamwork in the unit for PS was the best rated dimension (66.9%). There was a positive correlation (c. Pearson) between the perception of PS and the years that professionals had worked in specialisation (0.21), hospital (0.197) and unit (0.138), respectively (all, p < 0.05). According to category, the physicians have reported an AE with a likelihood 32.26 times greater than the assistants and technicians (p < 0.05). The PS perception dimension was viewed favourably by 34.1%. The management support (3.7%) and staffing (9%) were the main areas for improvement. CONCLUSIONS: The perception of PS at HUVN is good, even if the communication of errors is poor. The main area for improvement is a non-punitive communication of errors. It is advisable to promote a campaign to raise public awareness of the problem, to perform training programs for professionals and to implement systems for recording adverse events. PMID- 21317003 TI - [Health management must contribute to reduce (not increase) problems associated with the induced prescription]. PMID- 21317005 TI - The case of the disappearing mycobacteria in Ziehl-Neelsen-stained smears. PMID- 21317004 TI - Increasing drug resistance of Mycobacterium tuberculosis in Sinaloa, Mexico, 1997 2005. AB - BACKGROUND: In 1997 the US Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) reported high proportions of drug-resistant Mycobacterium tuberculosis in three Mexican states: Sinaloa, Baja California, and Oaxaca. In 2006, we showed that resistance to anti-tuberculosis drugs remained frequent in Sinaloa. OBJECTIVES: The objectives of this study were to describe drug-resistant tuberculosis (TB) trends and to investigate the probability that patients acquire resistance to first-line anti-TB drugs on recurrence after treatment in Sinaloa. METHODS: Sputum specimens were collected from patients diagnosed with TB at all the health care institutions of Sinaloa during 1997 2005. Isolates were tested for susceptibility to first-line drugs. RESULTS: Among 671 isolates tested from 1997 to 2002, the overall resistance rate was 34.9% (95% confidence interval (CI) 31.2-38.4) with a 1.2% increase per year (Chi square=4.258, p=0.03906). The prevalence of multi-drug resistance (MDR) was 17.9% (95% CI 14.9-20.7) with a 1.2% increase per year (Chi-square=8.352, p=0.00385). Of 50 patients registered twice between 1997 and 2005, 15 were fully susceptible at first registration, of whom six (40%) acquired drug resistance. Of 35 cases with any drug resistance at first registration, 21 (60%) came to acquire resistance to at least one other drug. CONCLUSIONS: The proportion of drug resistant TB increased during 1997-2005 in Sinaloa. Major efforts are needed to prevent the further rise and spread of drug-resistant and MDR TB. PMID- 21317006 TI - Outcome in AN adult patients: a 13-year follow-up in 484 patients. AB - BACKGROUND: To study the long-term prognosis of anorexia nervosa (AN), 484 adult AN patients were followed on a mean duration of 13 years. RESULTS: The mortality rate was 1.2%. Eight factors were linked to the lack of recovery at 2 years: low BMI at discharge, low energy and fat intakes, high drive for excessive exercising, high score for perfectionism, for interpersonal distrust and for anxiety, use of tube-feeding and adhesion to treatment (P<0.02). Four factors explained the risk of the binge/purging form at 2 years: having had binge-eating disorder and overweight before AN, having had purging episodes within the first 2 years of AN; having had very high energy intakes through meals and being not treated by tube-feeding. During the 13-year follow-up, very few binge/purging patients turned out to have the restrictive form. Two main factors explained 67% of the variance of menses recovery: having a BMI>18.5 kg/m(2); and having no physical hyperactivity. The recovery rate increased with the elapsing of relapse free time (P=0.02). After a 13.5-year follow-up, 292 out of the 484 patients were recovered (60.3%), 25.8% had a relatively good outcome, 6.4% a bad outcome and 6.4% a severe outcome. Very few factors were identified as predictors of a good outcome (binge-eating/purging subtype, personality disorder). PMID- 21317007 TI - [Research during residency]. PMID- 21317008 TI - [How I do... a fetal ultrasound? Probe and fetal manipulation in order to increase the accuracy]. PMID- 21317009 TI - [Obesity and pregnancy]. AB - Obesity during pregnancy increases the risk of complications for both the mother (gestational hypertension, diabetes mellitus) and the newborn (malformations and macrosomia). Deliveries are also more difficult with more c-section and failure in peridural analgesia. A specific organization supported by the perinatal network should improve the management of these women, especially for morbid obesity. PMID- 21317010 TI - [The therapeutic contribution of proteomic approaches in cancers]. AB - Up to now, there are no protein tumor markers with a specificity and sensitivity sufficient to have a utility in prognosis and early diagnosis of cancer. Recent advances in proteomics approaches have led to the identification of novel tumor markers of cancer that may have a utility in screening strategies and treatment. The purpose of the current review is to describe the major advances in cancer proteomics, especially those related to the study of serum biomarkers, immune related responses (autoantibodies) and alterations in cellular proteins. PMID- 21317011 TI - [Being a specialty registrar in Aquitaine]. PMID- 21317012 TI - [Is it really necessary to delete the anonymous of gamete donations in France?]. PMID- 21317013 TI - [Training of residents in obstetrical-gynaecology in Region Aquitaine]. PMID- 21317014 TI - A novel liquid plasma AOP device integrating microwaves and ultrasounds and its evaluation in defluorinating perfluorooctanoic acid in aqueous media. AB - A simplified and energy-saving integrated device consisting of a microwave applicator and an ultrasonic homogenizer has been fabricated to generate liquid plasma in a medium possessing high dielectric factors, for example water. The microwave waveguide and the ultrasonic transducer were interconnected through a tungsten/titanium alloy stick acting both as the microwave antenna and as the horn of the ultrasonic homogenizer. Both microwaves and ultrasonic waves are simultaneously transmitted to the aqueous media through the tungsten tip of the antenna. The microwave discharge liquid plasma was easily generated in solution during ultrasonic cavitation. The simple device was evaluated by carrying out the degradation of the perfluorooctanoic acid (PFOA), a system highly recalcitrant to degradation by conventional advanced oxidation processes (AOPs). PFOA is 59% degraded in an aqueous medium after only 90 s of irradiation by the plasma. Intermediates were identified by electrospray mass spectral techniques in the negative ion mode. PMID- 21317015 TI - Continuous and pulsed ultrasound-assisted extractions of antioxidants from pomegranate peel. AB - There is a great demand for developing efficient extraction methods in order to reduce extraction time and increase the yield and activity of functional antioxidants. The yields, activities, and extraction kinetics of antioxidants from dry peel of pomegranate marc were studied using ultrasound-assisted extraction in continuous and pulsed modes and the results were compared with conventional extraction (CE) at a temperature of 25+/-2 degrees C and water/peel ratio of 50/1, w/w. The studied factors were intensity level and treatment time for continuous ultrasound-assisted extraction (CUAE), and intensity level, number of pulse repetition, and pulse duration and interval for pulsed ultrasound assisted extraction (PUAE). The results showed that all factors significantly affected the antioxidant yield, but only treatment time had a significant effect on the antioxidant activity. Compared to CE, PUAE at intensity level of 59.2 W/cm(2), and the 5 and 5s of pulse duration and interval increased the antioxidant yield by 22% and reduced the extraction time by 87%. Similarly, CUAE at the same intensity level increased the antioxidant yield by 24% and reduced the extraction time by 90%. Since PUAE had 50% energy saving compared to CUAE, we recommend using PUAE for the extraction with antioxidant yield of 14.5% and DPPH scavenging activity of 5.8 g/g. A second-order kinetic model was successfully developed for describing the mechanism of ultrasound-assisted extractions under PUAE and CUAE. This research clearly demonstrated the superiority of PUAE for producing antioxidants from peel of pomegranate marc. PMID- 21317017 TI - Improved characterisation of aortic tortuosity. AB - Tortuosity can be described as the variation in blood vessel curvature. Abnormal tortuosity is an important clinical indicator of various conditions. Despite considerable research, there has been very little agreement on an accurate, unique measure of this phenomenon for clinical applications. It has been demonstrated that a single value is insufficient to describe vessel tortuosity. In this work, the fast Fourier transform of the vessel's curvature as a measure of tortuosity is introduced. Spectral analysis of a suite of computed-simulated vessels, a phantom and clinical data is carried out. Observation of the acquired spectra permits detection of the local curvature variations. Spectral analysis of curvature provides a compact and graphic representation of tortuosity. This paper also describes two new highly automated MATLAB algorithms for obtaining the vessel centrelines: a heuristic image processing algorithm, and an algorithm based on the probabilistic Hough transform. We demonstrate the accuracy of both algorithms comparing with a manual method to extract the vessel centreline. Both algorithms reduce potential errors and user time and only require the manual selection of one centroid. PMID- 21317016 TI - Dynamics of counterion binding during acoustic nebulisation of surfactant solutions. AB - A metal ion (Cu(2+)) and a complex copper species, copper (II) bis-bipyridine, were used as alternate counterions in an aqueous surfactant solution of sodium dodecylbenzenesulfonate (SDBS) to investigate the dynamics of counterion interactions in an acoustic field. Sonoluminescence spectral studies showed that such counterions were able to replace sodium ions at the interface, even when the interface was rapidly oscillating under the acoustic field. Ultrasound induced nebulisation was then used to probe the interfacial profile of surfactant and bound counterions in a dynamic environment. At low bulk concentrations, the copper (II) bis-bipyridine cation was more effective at enhancing the loading of the dodecylbenzenesulfonate anion on the interface, due to its documented greater binding ability. However, at higher bulk concentrations, the movement of this cation is limited by its larger size and the smaller Cu(2+) cation is more effective in enhancing the loading of the dodecylbenzenesulfonate anion. The results show that under dynamic conditions, the surface concentrations are governed by mass transfer kinetics rather than equilibrium thermodynamics. PMID- 21317018 TI - SPECT perfusion patterns distinguish psychogenic from essential tremor. AB - BACKGROUND: Psychogenic movement disorders pose formidable challenges to diagnosis and treatment reflecting our limited understanding of the basic brain mechanisms that cause them. Recently, functional brain imaging has been utilized to study psychogenic movement disorders. OBJECTIVES: To identify characteristic patterns of cerebral perfusion distinguishing psychogenic tremor (PT) from essential tremor (ET). METHODS: We studied five patients each with PT, ET and normal controls. SPECT imaging was performed at rest and during a tremor-inducing motor task. RESULTS: In ET, rest imaging revealed increased rCBF (relative cerebral blood flow) in cerebellar hemispheres and left inferior frontal gyrus. During the motor task, ET patients demonstrated increased rCBF in the supplementary motor area (SMA) and contralateral motor cortex and reduced rCBF in the cerebellum and visual cortex. In contrast, PT images at rest revealed increased rCBF in left inferior frontal gyrus and left insula. Motor task imaging revealed increased rCBF in the cerebellum and reduced rCBF in anterior regions of the default mode network. CONCLUSIONS: Our study revealed distinct patterns of cerebral perfusion during rest and motor task that distinguish PT from ET. Deactivation of the default mode network may serve as a marker for psychogenic movement disorders. PMID- 21317019 TI - Architecture for the silver generation: exploring the meaning of appropriate space for ageing in a Swedish municipality. AB - This paper focuses on an architecture competition for the silver generation, namely those aged 65 years and older. Twenty-seven Swedish informants were interviewed using an interviewing guide that included a photographic survey. The informants emphasised aesthetic dimensions in architecture for the prolongation of ageing in place and independent living in a residential home. This study highlights the individual adjustment of space, and the integrated location in existing urban settings near nature. Based on the findings, a habitational model for exploring the appropriate space for ageing is formulated. It suggests that architecture through location and spatial features needs to generate positive associations with the users. PMID- 21317020 TI - A molecular evolutionary concept connecting nonhost resistance, pathogen host range, and pathogen speciation. AB - Any given pathogenic microbial species typically colonizes a limited number of plant species. Plant species outside of this host range mount nonhost disease resistance to attempted colonization by the, in this case, non-adapted pathogen. The underlying mechanism of nonhost immunity and host immunity involves the same non-self detection systems, the combined action of nucleotide-binding and leucine rich repeat (NB-LRR) proteins and pattern recognition receptors (PRRs). Here we hypothesize that the relative contribution of NB-LRR- and PRR-triggered immunity to nonhost resistance changes as a function of phylogenetic divergence time between host and nonhost. Similarly, changes in pathogen host range, e.g. host range expansions, appear to be driven by variation in pathogen effector repertoires, in turn leading to reproductive isolation and subsequent pathogen speciation. PMID- 21317021 TI - An MRI digital brain phantom for validation of segmentation methods. AB - Knowledge of the exact spatial distribution of brain tissues in images acquired by magnetic resonance imaging (MRI) is necessary to measure and compare the performance of segmentation algorithms. Currently available physical phantoms do not satisfy this requirement. State-of-the-art digital brain phantoms also fall short because they do not handle separately anatomical structures (e.g. basal ganglia) and provide relatively rough simulations of tissue fine structure and inhomogeneity. We present a software procedure for the construction of a realistic MRI digital brain phantom. The phantom consists of hydrogen nuclear magnetic resonance spin-lattice relaxation rate (R1), spin-spin relaxation rate (R2), and proton density (PD) values for a 24 * 19 * 15.5 cm volume of a "normal" head. The phantom includes 17 normal tissues, each characterized by both mean value and variations in R1, R2, and PD. In addition, an optional tissue class for multiple sclerosis (MS) lesions is simulated. The phantom was used to create realistic magnetic resonance (MR) images of the brain using simulated conventional spin-echo (CSE) and fast field-echo (FFE) sequences. Results of mono parametric segmentation of simulations of sequences with different noise and slice thickness are presented as an example of possible applications of the phantom. The phantom data and simulated images are available online at http://lab.ibb.cnr.it/. PMID- 21317022 TI - What drives the organization of object knowledge in the brain? AB - Various forms of category-specificity have been described at both the cognitive and neural levels, inviting the inference that different semantic domains are processed by distinct, dedicated mechanisms. In this paper, we argue for an extension of a domain-specific interpretation to these phenomena that is based on network-level analyses of functional coupling among brain regions. On this view, domain-specificity in one region of the brain emerges because of innate connectivity with a network of regions that also process information about that domain. Recent findings are reviewed that converge with this framework, and a new direction is outlined for understanding the neural principles that shape the organization of conceptual knowledge. PMID- 21317023 TI - Arecoline stimulated Cyr61 production in human gingival epithelial cells: inhibition by lovastatin. AB - Cyr61 is associated with growth and progression of many types of tumors and is an independent poor prognostic indicator for oral cancer patients. Areca nut (AN) chewing is the most important etiological factor in the pathogenesis of oral cancer in India and many Southeast Asian countries. Yet, the molecular mechanisms involved in the AN-induced oral cancer remain largely unknown. In this study, we show that arecoline, a main alkaloid found in AN, stimulated Cyr61 synthesis in human gingival epithelial S-G cells. Constitutive overexpression of Cyr61 protein in oral epithelial cells during AN chewing may play a role in the pathogenesis of oral cancer. ERK inhibitor PD98059, N-acetyl-L-cysteine, Rho-associated protein kinase (ROCK) selective inhibitor Y-27632 and a geranylgeranyltransferase inhibitor reduced the arecoline-stimulated levels of Cyr61 protein by ~31%, 47%, 65% and 100%, respectively. Lovastatin also completely inhibited arecoline induced Cyr61 synthesis and the inhibition is dose-dependent. Decreased of geranylgeranylated proteins could be the mechanism that lovastatin regulates Cyr61 synthesis and lovastatin could serve as a useful agent in controlling AN induced oral cancer. PMID- 21317024 TI - Comment on a letter written by Ribeiro DA ''Risk assessment of oral cancer in patients with pre-cancerous states of the oral cavity using micronucleus test and challenge assay'' [Saran R, Tiwari RK, Reddy PP, Ahuja YR. Oral Oncol 2008;44:354 60]. PMID- 21317025 TI - IR, 1H NMR, mass, XRD and TGA/DTA investigations on the ciprofloxacin/iodine charge-transfer complex. AB - The charge-transfer complex (CTC) of ciprofloxacin drug (CIP) as a donor with iodine (I(2)) as a sigma acceptor has been studied spectrophotometrically in CHCl(3). At maximum absorption bands, the stoichiometry of CIP:iodine system was found to be 1:1 ratio according to molar ratio method. The essential spectroscopic data like formation constant (K(CT)), molar extinction coefficient (E(CT)), standard free energy (DeltaG degrees ), oscillator strength (f), transition dipole moment (MU), resonance energy (R(N)) and ionization potential (I(D)) were estimated. The spectroscopic techniques such as IR, (1)H NMR, mass and UV-vis spectra and elemental analyses (CHN) as well as TG-DTG and DTA investigations were used to characterize the chelating behavior of CIP/iodine charge-transfer complex. The iodine CT interaction was associated with a presence of intermolecular hydrogen bond. The X-ray investigation was carried out to investigate the iodine doping in the synthetic CT complex. PMID- 21317026 TI - Micro-Raman spectroscopic identification of natural mineral phases and their weathering products inside an abandoned zinc/lead mine. AB - Mining activities provide a good source of minerals of different nature. On the one hand, the primary minerals for whose formation a geological time-scale is required. On the other hand, secondary minerals, formed from removed products after the earlier weathering and alteration states. These are characteristic of the local geology and the environment context that commonly appears due to the low chemical stability of their original primary minerals. This work shows how quickly the reactions promoting secondary minerals may have taken place, due to the fact that these were found in newly formed solid materials called efflorescences. To achieve this purpose, the sampling is crucial. It was carried out in such a way that tried to guarantee that the samples collected consisted in the very top soil matter (first 2 cm depth). Thus, unlike the deeper soil, the material analysed may have been newly formed due to the interactions that they had with the place weathering agents (i.e. air oxygen, humidity, and microbial activities). Raman spectroscopy has emerged as a good and fast non-destructive technique that provides molecular information of the local mineralogy without the need of any pre-treatment of the samples. At the same time, the work looked for information on the variety of non-stable lead and-or zinc containing minerals due to the possible health and environmental risks they convey. Among the different minerals identified, 16 were of primary nature while 23 may be classified as secondary minerals, probably formed in the last decades as the result of the extractive activities. PMID- 21317027 TI - A model of awareness to enhance our understanding of interprofessional collaborative care delivery and health information system design to support it. AB - BACKGROUND: As more healthcare delivery is provided by collaborative teams there is a need for enhanced design of health information systems (HISs) to support collaborative care delivery. The purpose of this study was to develop a model of the different types of awareness that exist in interprofessional collaborative care (ICC) delivery to inform HIS design to support ICC. METHODS: Qualitative data collection and analysis was done. The data sources consisted of 90 h of non participant observations and 30 interviews with nurses, physicians, medical residents, volunteers, and personal support workers. RESULTS: Many of the macro level ICC activities (e.g. morning rounds, shift change) were constituted by micro-level activities that involved different types of awareness. We identified four primary types of ICC awareness: patient, team member, decision making, and environment. Each type of awareness is discussed and supported by study data. We also discuss implication of our findings for enhanced design of existing HISs as well as providing insight on how HISs could be better designed to support ICC awareness. CONCLUSION: Awareness is a complex yet crucial piece of successful ICC. The information sources that provided and supported ICC awareness were varied. The different types of awareness from the model can help us understand the explicit details of how care providers communicate and exchange information with one another. Increased understanding of ICC awareness can assist with the design and evaluation of HISs to support collaborative activities. PMID- 21317028 TI - Disrupted rhythms and mobile ICT in a surgical department. AB - PURPOSE: This study presents a study of mobile information and communication technology (ICT) for healthcare professionals in a surgical ward. The purpose of the study was to create a participatory design process to investigate factors that affect the acceptance of mobile ICT in a surgical ward. METHODS: Observations, interviews, a participatory design process, and pilot testing of a prototype of a co-constructed application were used. RESULTS: Informal rhythms existed at the department that facilitated that people met and interacted several times throughout the day. These gatherings allowed for opportunistic encounters that were extensively used for dialogue, problem solving, coordination, message and logistics handling. A prototype based on handheld mobile computers was introduced. The tool supported information seeking functionality that previously required local mobility. By making the nurses more freely mobile, the tool disrupted these informal rhythms. This created dissatisfaction with the system, and lead to discussion and introduction of other arenas to solve coordination and other problems. CONCLUSIONS: Mobile ICT tools may break down informal communication and coordination structures. This may reduce the efficiency of the new tools, or contribute to resistance towards such systems. In some situations however such "disrupted rhythms" may be overcome by including additional sociotechnical mechanisms in the overall design to counteract this negative side effect. PMID- 21317029 TI - Predicting comatose patients with acute stroke outcome using middle-latency somatosensory evoked potentials. AB - OBJECTIVE: To evaluate the prognostic value of middle-latency somatosensory evoked potential (MLSEP) in comatose patients with acute severe supratentorial stroke, considering both unfavourable outcome and death. METHODS: Eighty-eight patients with acute severe supratentorial stroke underwent MLSEP, short-latency somatosensory evoked potential (SLSEP), Glasgow Coma Scale (GCS) and cerebral computed tomography (CCT) within 1 week from onset. MLSEP and SLSEP were recorded in 25 normal controls. All patients were evaluated with two criteria of outcome as unfavourable outcome (modified Rankin Scale 4-6) and death 6 months after onset. N60 of MLSEP predictive value was compared with N20 of SLSEP, GCS and CCT. RESULTS: Sixty-seven patients (76.1%) suffered from cerebral infarction; and 21 patients (23.9%) suffered from intracerebral haemorrhage. Seventy-one patients (80.7%) had unfavourable outcomes and 39 patients (44.3%) died. The peak latencies of MLSEP were prolonged and some waves of MLSEP were absent in stroke patients, and the proportion of absent waves in lesion-ipsilateral MLSEP was higher than in contralateral MLSEP. By using the prognostic authenticity analysis of predictors, the lesion-ipsilateral absence of N60 showed the highest sensitivity for unfavourable outcome (97.2%, confidence interval (CI): 89.3 99.5%) and death (100%, CI: 88.8-100%), which was superior to GCS, CCT and N20. Bilateral absence of N60 showed a high specificity of 100% for unfavourable outcome, which was as good as bilateral absence of N20. However, it showed a specificity of 89.8% (CI: 77.0-96.2%) for death, not as good as bilateral absence of N20 (98%, CI: 87.8-99.9%). The false positive rate of lesion-ipsilateral absence of N60 for unfavourable outcome and death was 12.7% (CI: 6.6-22.5%) and 50.6% (CI: 39.2-62.0%), respectively, and that of bilateral absence of N60 was 0 (CI: 0-12.3%) and 14.3% (CI: 5.4-31.0%), respectively. CONCLUSIONS: We confirm the high predictive value of MLSEP in severe stroke. MLSEP showed higher sensitivity than SLSEP for predicting unfavourable outcome and death. Combined MLSEP with SLSEP results produced even greater predictive value. SIGNIFICANCE: The combination of MLSEP and SLSEP would increase the sensitivity and maintain the high specificity not only for predicting outcome in coma after cardiopulmonary resuscitation but also after severe stroke. PMID- 21317030 TI - The sleep in our eyes. PMID- 21317031 TI - Gene cloning and biochemical characterization of a catalase from Gluconobacter oxydans. AB - Gluconobacter oxydans has a large number of membrane-bound dehydrogenases linked to the respiratory chain that catalyze incomplete oxidation of a wide range of organic compounds by oxidative fermentation. Because the respiratory chain is a primary site of reactive oxygen species (ROS) production, the bacterium is expected to have a high capacity to detoxify nascent ROS. In the present study, a gene that encodes a catalase of G. oxydans, which might act as a potential scavenger of H(2)O(2), was cloned, and the expression product (termed rGoxCat) was characterized biochemically. rGoxCat is a heme b-containing tetrameric protein (molecular mass, 320 kDa) consisting of identical subunits. The recombinant enzyme displayed a strong catalase activity with a k(cat) of 6.28*10(4) s(-1) and a K(m) for H(2)O(2) of 61 mM; however, rGoxCat exhibited no peroxidase activity. These results, along with the phylogenetic position of the enzyme, provide conclusive evidence that rGoxCat is a monofunctional, large subunit catalase. The enzyme was most stable in the pH range of 4-9, and greater than 60% of the original activity was retained after treatment at pH 3.0 and 40 degrees C for 1h. Moreover, the enzyme exhibited excellent thermostability for a catalase from a mesophilic organism, retaining full activity after incubation for 30 min at 70 degrees C. The observed catalytic properties of rGoxCat, as well as its stability in a slightly acidic environment, are consistent with its role in the elimination of nascent H(2)O(2) in a bacterium that produces a large amount of organic acid via oxidative fermentation. PMID- 21317032 TI - Molecular characterization of the PEX14 gene from the methylotrophic yeast Pichia methanolica. AB - In this study, we describe the molecular characterization of the PmPEX14 gene encoding the peroxisomal membrane protein from the methylotrophic yeast Pichia methanolica. The pex14Delta strain of P. methanolica lost its ability to grow on methanol and oleate but grew normally on glucose. Disruption of the PmPEX14 caused a decrease in the activities of peroxisomal methanol-metabolizing enzymes and mislocalization of those proteins into the cytosol and vacuole. Taken together, these findings show that PmPex14p has an essential physiological role in methanol metabolism in P. methanolica. PMID- 21317033 TI - Self-reported sleep duration, all-cause mortality, cardiovascular mortality and morbidity in Finland. AB - OBJECTIVE: The U-shaped association of self-reported sleep duration with all cause mortality is generally accepted. Findings on cardiovascular (CVD) mortality and morbidity are inconsistent. We aimed to further clarify the associations of the self-reported sleep duration with CVD mortality and morbidity. METHODS: In two population based surveys in 1972 and 1977 the levels of coronary risk factors in Finland and habitual sleep duration were measured; 25,025 individuals were followed-up until 2006 by the national register data. The outcome variables were death (for any reason), CVD death, and non-fatal CVD event (non-fatal myocardial infarction or stroke). Participants with former non-fatal CVD event at baseline were excluded from CVD analyses, and socio-demographic and health-related confounders were considered in the final Cox proportional hazard models for both genders. RESULTS: The U-shaped association of total mortality with self-reported sleep duration was confirmed in both genders. The association of CVD mortality with self-reported sleep duration was independent of pertinent cardiovascular risk factors in women. The highest CVD mortality risk was found in both extreme ends of sleep duration distribution (?5 and ?10h sleepers). CONCLUSIONS: Sleep duration is an independent risk factor for CVD mortality and morbidity in women but not in men. The highest CVD mortality risk is associated with the extreme ends of sleep duration distribution. Thus, in epidemiological studies, combining adjacent (6 and 9h) sleep duration groups with the extreme groups may partly mask the mortality risks, especially in the long run. PMID- 21317034 TI - Usefulness of the SINBAR electromyographic montage to detect the motor and vocal manifestations occurring in REM sleep behavior disorder. AB - OBJECTIVE: In a previous study we showed that simultaneous electromyographic (EMG) recording of the mentalis, flexor digitorum superficialis and extensor digitorum brevis (SINBAR EMG montage) detected the highest rates of rapid eye movement (REM) sleep phasic EMG activity in subjects with REM sleep behavior disorder (RBD). As a next step, in the present study we evaluated the usefulness of the SINBAR EMG montage to detect the movements and vocalizations occurring in RBD. METHODS: Polysomnographic studies with synchronized audiovisual monitoring of 11 patients with idiopathic RBD were analyzed. Phasic EMG activity in REM sleep was scored and quantified in 3-s mini-epochs while the video was reviewed to detect motor events and vocalizations. RESULTS: A total of 64.8% (11,562 out of 17,848) of all mini-epochs contained phasic EMG activity, whereas 28.8% (5135 out of 17,848) contained movements or vocalizations. Using the SINBAR EMG montage, 94.4% of the mini-epochs containing behavioral events were linked to phasic EMG activity. The sensitivity of the SINBAR EMG montage was 94.4%, specificity was 47.2%, negative predictive value was 95.4% and positive predictive value was 41.9%. Isolated EMG recording of the mentalis did not show phasic EMG activity in 35.5% of the behavioral events seen in the video. CONCLUSIONS: The SINBAR EMG montage is a useful approach for the diagnosis of RBD showing that simultaneous EMG recording of the mentalis, flexor digitorum superficialis and extensor digitorum brevis muscles detected the majority (94.4%) of the motor and vocal manifestations occurring in RBD. For clinical purposes, this means that it is efficient to screen the video when increased phasic EMG activity is seen on the polysomnography. PMID- 21317035 TI - Changing demographics in REM sleep behavior disorder: possible effect of autoimmunity and antidepressants. AB - BACKGROUND: Rapid eye movement (REM) sleep behavior disorder (RBD) has been described predominantly in elderly men and in association with neurodegenerative disease. But an increasing proportion of cases in recent reports and in clinical practice do not fit this description; thus we sought to describe a current RBD population and possibly identify new subgroups with RBD. METHODS: Records of 115 consecutive patients with polysomnogram-confirmed RBD at an academic sleep center were retrospectively reviewed. RESULTS: Male to female ratio was 2:1, and 1.25:1 for early-onset (age <50) cases. Mean age at diagnosis was 53.7+/-16.4years. Most (60%) cases were idiopathic, and neurodegenerative disease was coincident primarily in older men. Autoimmune disease was unexpectedly common in women (20%) particularly in the 30-49 age groups (40%). Antidepressant use was frequent (46.1%), especially in early-onset cases (57.8%). CONCLUSIONS: RBD is diagnosed more equally between men and women and in younger individuals than previously reported. While neurodegenerative disease is frequently co-incident with RBD in older men, most women and early-onset cases have "idiopathic" RBD. High prevalence of autoimmune disease among women with RBD suggests an intriguing link between immune dysfunction and RBD. A high rate of antidepressant use provides support for a potentially causal role for antidepressants in RBD. PMID- 21317036 TI - Iron status and chronic kidney disease predict restless legs syndrome in an older hospital population. AB - BACKGROUND: Iron deficiency is important in the pathogenesis of restless legs syndrome (RLS), and serum ferritin measurement, using a cutoff of 45-50ng/ml, is widely recommended as the optimal screening test for iron deficiency in RLS. Serum ferritin often increases with inflammation, and a higher cutoff may be better in those with acute and chronic inflammatory conditions, including those with chronic kidney disease (CKD). METHODS: The relationships between RLS and potential secondary causes were examined in hospital patients aged 50years or more. Diagnosis of RLS was based on a clinician interview. RESULTS: Of 301 patients, 55 (18.3%) had RLS. Ferritin levels less than 40ng/ml and between 40 and 69ng/ml and Stage 4 CKD (estimated glomerular filtration rate [eGFR] between 15 and 29ml/min and not on dialysis) were associated with significantly higher odds for RLS in univariate and multivariate analyses. CONCLUSION: Iron deficiency and chronic kidney disease are the strongest predictors of RLS in older hospital patients. Ferritin less than 70ng/ml is the best cutoff for identifying possible iron deficiency in RLS patients with inflammatory conditions. Independent of iron status, RLS is strongly associated with chronic kidney disease that is not severe enough to require dialysis, and the results of this study suggest that eGFR values and stages of CKD should be reported in future studies of RLS. PMID- 21317037 TI - Normal sleep in African-Americans and Caucasian-Americans: A meta-analysis. AB - OBJECTIVE: This meta-analysis was designed to estimate the average magnitude of ethnic differences between African-Americans and Caucasian-Americans in normal sleep and to identify moderators of these differences. METHODS: Included studies had to have (1) sufficient information to estimate the difference between African Americans and Caucasian-Americans on measures of subjective or objective sleep, (2) adult samples, and (3) samples of normal sleepers. Fourteen studies representing 1010 African-Americans and 3156 Caucasian-Americans aged 18years and older met these criteria. RESULTS: Significant ethnic differences were found, with mean effect sizes ranging from -.23 to .57. African-Americans had poorer sleep continuity and duration, less slow wave sleep, and a greater proportion of stage 2 sleep. Differences in sleep continuity and duration variables were moderated by several biopsychosocial factors, whereas sleep architecture differences were not influenced by any examined moderating factor. CONCLUSIONS: African-Americans slept worse objectively and subjectively than Caucasian Americans. Sleep continuity and duration were moderated by biopsychosocial factors whereas sleep architecture was not. Implications and future research are discussed. PMID- 21317038 TI - Role of angiotensin II type I receptor agonistic autoantibodies (AT1-AA) in preeclampsia. AB - Despite being one of the leading causes of maternal death and a major contributor of maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of preeclampsia are unclear. One important initiating event in preeclampsia is thought to be reduced placental perfusion leading to the production of a variety of factors that cause widespread dysfunction of the maternal vasculature. The major objective of this review is to discuss the potential role of a novel agonistic autoantibody to the angiotensin II type I receptor (AT1-AA) in mediating hypertension during pregnancy. Although animal studies suggest that increasing plasma AT1-AA concentration in pregnant rats to levels observed in preeclamptic women or placental ischemic rats result in significant increases in arterial pressure, the quantitative importance of AT1-AA in the pathophysiology of preeclampsia in humans has yet to be fully elucidated. PMID- 21317039 TI - Regulating neutrophil apoptosis: new players enter the game. AB - Recently, unexpected biological features of polymorphonuclear neutrophils have been revealed. In addition to their pivotal role in the defence against pathogens, neutrophils display a high degree of plasticity and contribute to control of adaptive immune responses. An emerging aspect of neutrophils is their ability to modulate their survival in response to both intrinsic and extrinsic factors. This review focuses on recent advances that have uncovered proliferating cell nuclear antigen (PCNA) and other cell cycle regulatory proteins as novel players regulating neutrophil survival. A better understanding of the mechanisms involved in neutrophil fate might pave the way for the identification of new anti inflammatory molecules. PMID- 21317040 TI - Immune reconstitution after a decade of combined antiretroviral therapies for human immunodeficiency virus. AB - The introduction of combined antiretroviral therapies (HAART) has reversed the fatal course of human immunodeficiency virus (HIV) infection. HAART controls virus production and, in most cases, allows the quantitative and functional immune defects caused by HIV to be reversed. Here, we review T cell homeostatic mechanisms that drive immune recovery. These homeostatic mechanisms, as well as differences in T cell antigen exposure, explain the distinct patterns of recovery for HIV-specific T cells versus T cells specific for other pathogens. Immune restoration during HAART can, however, have adverse effects. Immune restoration syndrome occurs in some patients as a result of successful but unbalanced immunity. PMID- 21317041 TI - Anti-Mullerian hormone-based prediction model for a live birth in assisted reproduction. AB - Prediction of assisted reproduction treatment outcome has been the focus of clinical research for many years, with a variety of prognostic models describing the probability of an ongoing pregnancy or a live birth. This study assessed whether serum anti-Mullerian hormone (AMH) concentrations may be incorporated into a model to enhance the prediction of a live birth in women undergoing their first IVF cycle, by analysing a database containing clinical and laboratory information on IVF cycles carried out between 2005 and 2008 at the Mother-Infant Department of University Hospital, Modena. Logistic regression was used to examine the association of live birth with baseline patient characteristics. Only AMH and age were demonstrated in regression analysis to predict live birth, so a model solely based on these two criteria was generated. The model permitted the identification of live birth with a sensitivity of 79.2% and a specificity of only 44.2%. In the prediction of a live birth following IVF, a distinction, however moderate, can be made between couples with a good and a poor prognosis. The success of IVF was found to mainly depend on maternal age and serum AMH concentrations, one of the most relevant and valuable markers of ovarian reserve. PMID- 21317042 TI - alpha-Synuclein and tau concentrations in cerebrospinal fluid of patients presenting with parkinsonism: a cohort study. AB - BACKGROUND: Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy are brain disorders characterised by intracellular alpha-synuclein deposits. We aimed to assess whether reduction of alpha-synuclein concentrations in CSF was a marker for alpha-synuclein deposition in the brain, and therefore diagnostic of synucleinopathies. METHODS: We assessed potential extracellular fluid markers of alpha-synuclein deposition in the brain (total alpha-synuclein and total tau in CSF, and total alpha-synuclein in serum) in three cohorts: a cross-sectional training cohort of people with Parkinson's disease, multiple system atrophy, dementia with Lewy bodies, Alzheimer's disease, or other neurological disorders; a group of patients with autopsy-confirmed dementia with Lewy bodies, Alzheimer's disease, or other neurological disorders (CSF specimens were drawn ante mortem during clinical investigations); and a validation cohort of patients who between January, 2003, and December, 2006, were referred to a specialised movement disorder hospital for routine inpatient admission under the working diagnosis of parkinsonism. CSF and serum samples were assessed by ELISA, and clinical diagnoses were made according to internationally established criteria. Mean differences in biomarkers between diagnostic groups were assessed with conventional parametric and non-parametric statistics. FINDINGS: In our training set, people with Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies had lower CSF alpha-synuclein concentrations than patients with Alzheimer's disease and other neurological disorders. CSF alpha synuclein and tau values separated participants with synucleinopathies well from those with other disorders (p<0.0001; area under the receiver operating characteristic curve [AUC]=0.908). In the autopsy-confirmed cases, CSF alpha synuclein discriminated between dementia with Lewy bodies and Alzheimer's disease (p=0.0190; AUC=0.687); in the validation cohort, CSF alpha-synuclein discriminated Parkinson's disease and dementia with Lewy bodies versus progressive supranuclear palsy, normal-pressure hydrocephalus, and other neurological disorders (p<0.0001; AUC=0.711). Other predictor variables tested in this cohort included CSF tau (p=0.0798), serum alpha-synuclein (p=0.0502), and age (p=0.0335). CSF alpha-synuclein concentrations of 1.6 pg/MUL or lower showed 70.72% sensitivity (95% CI 65.3-76.1%) and 52.83% specificity (39.4-66.3%) for the diagnosis of Parkinson's disease. At this cutoff, the positive predictive value for any synucleinopathy was 90.7% (95% CI 87.3-94.2%) and the negative predictive value was 20.4% (13.7-27.2%). INTERPRETATION: Mean CSF alpha-synuclein concentrations as measured by ELISA are significantly lower in Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy than in other neurological diseases. Although specificity was low, the high positive predictive value of CSF alpha-synuclein concentrations in patients presenting with synucleinopathy-type parkinsonism might be useful in stratification of patients in future clinical trials. FUNDING: American Parkinson Disease Association, Stifterverband fur die Deutsche Wissenschaft, Michael J Fox Foundation for Parkinson's Research, National Institutes of Health, Parkinson Research Consortium Ottawa, and the Government of Canada. PMID- 21317043 TI - Biochemical diagnosis of neurodegenerative diseases gets closer. PMID- 21317044 TI - Global energy minimization of alanine dipeptide via barrier function methods. AB - This paper presents an interior point method to determine the minimum energy conformation of alanine dipeptide. The CHARMM energy function is minimized over the internal coordinates of the atoms involved. A barrier function algorithm to determine the minimum energy conformation of peptides is proposed. Lennard-Jones 6-12 potential which is used to model the van der Waals interactions in the CHARMM energy equation is used as the barrier function for this algorithm. The results of applying the algorithm for the alanine dipeptide structure as a function of varying number of dihedral angles are reported, and they are compared with that obtained from genetic algorithm approach. In addition, the results for polyalanine structures are also reported. PMID- 21317045 TI - Effect of apolipoprotein epsilon4 allele on hippocampal and brain volume in intractable temporal lobe epilepsy. AB - This study investigated the relationship between the apolipoprotein (APOE) epsilon4 allele and brain volumes in patients with medically intractable temporal lobe epilepsy (TLE). MRI-based volumetric analyses of the hippocampi, cerebral hemispheres, and whole brain were conducted in 59 patients with TLE (31 with left TLE, 28 with right TLE) with hippocampal sclerosis (HS). There were no differences in hippocampal, hemispheric, or whole brain volumes as a function of epsilon4 status even after correcting for hemispheric and total brain volumes. However, APOE epsilon4 carriers showed a trend toward having a smaller discrepancy between ipsilateral and contralateral hippocampal volumes than patients without this allele, and post hoc analyses suggest there may be an increased incidence of bilateral HS in epsilon4 carriers. In summary, APOE epsilon4 is not associated with significant hippocampal, hemispheric, or whole brain atrophy in patients with medically intractable TLE. However, epsilon4 carriers may be more likely to have bilateral HS, with an apparent dose-dependent effect. PMID- 21317046 TI - Poly(ADP-ribosyl)ation affects stabilization of Che-1 protein in response to DNA damage. AB - Poly(ADP-ribose) polymerase 1 (PARP-1) catalyzes a post-translational modification that plays a crucial role in coordinating the signalling cascade in response to stress stimuli. During the DNA damage response, phosphorylation by ataxia telangiectasia mutated (ATM) kinase and checkpoint kinase Chk2 induces the stabilization of Che-1 protein, which is critical for the maintenance of G2/M arrest. In this study we showed that poly(ADP-ribosyl)ation, beyond phosphorylation, is involved in the regulation of Che-1 stabilization following DNA damage. We demonstrated that Che-1 accumulation upon doxorubicin treatment is reduced after the inhibition of PARP activity in HCT116 cells and in PARP-1 knock out or silenced cells. In accordance, impairment in Che-1 accumulation by PARP inhibition reduced Che-1 occupancy at p21 promoter and affected the expression of the corresponding gene. Epistasis experiments showed that the effect of poly(ADP ribosyl)ation on Che-1 stabilization is independent from ATM kinase activity. Indeed we demonstrated that Che-1 protein co-immunoprecipitates with ADP-ribose polymers and that PARP-1 directly interacts with Che-1, promoting its modification in vitro and in vivo. PMID- 21317048 TI - Splicing defects in the CFTR gene: minigene analysis of two mutations, 1811+1G>C and 1898+3A>G. AB - BACKGROUND: Cystic fibrosis is caused by mutations of the Cystic Fibrosis Transmembrane conductance Regulator gene (CFTR). Among the 1795 reported mutations, 221 (12.31%) are believed to affect pre-mRNA splicing. Nevertheless, not all splicing mutations have been demonstrated, by functional assays, to affect splicing in living cells. METHODS: We have used a minigene-based approach, coupled to site-specific mutagenesis, to analyze the effects of presumptive pre mRNA splicing mutations. RESULTS: We show here that the intron 11 1811+1G>C and the intron 12 1898+3A>G mutations strongly affected CFTR pre-mRNA splicing. The encoded proteins are predicted to be defective, which would thus participate in the disease phenotype of carrier individuals. CONCLUSIONS: These results further validate the minigene strategy for the study of presumptive splice mutations, and report unanticipated defects in splicing. Such assays should improve the analysis of genotype-phenotype correlations. PMID- 21317047 TI - RAD51-independent inverted-repeat recombination by a strand-annealing mechanism. AB - Recombination between inverted repeats is RAD52 dependent, but reduced only modestly in the rad51Delta mutant. RAD59 is required for RAD51-independent inverted-repeat recombination, but no clear mechanism for how recombination occurs in the absence of RAD51 has emerged. Because Rad59 is thought to function as an accessory factor for the single-strand annealing activity of Rad52 one possible mechanism for spontaneous recombination could be by strand annealing between repeats at a stalled replication fork. Here we demonstrate the importance of the Rad52 single-strand annealing activity for generating recombinants by showing suppression of the rad52Delta, rad51Delta rad52Delta and rad52Delta rad59Delta inverted-repeat recombination defects by the rfa1-D228Y mutation. In addition, formation of recombinants in the rad51Delta mutant was sensitive to the distance between the inverted repeats, consistent with a replication-based mechanism. Deletion of RAD5 or RAD18, which are required for error-free post replication repair, reduced the recombination rate in the rad59Delta mutant, but not in wild type. These data are consistent with RAD51-independent recombinants arising by a faulty template switch mechanism that is distinct from nascent strand template switching. PMID- 21317049 TI - Quantification of 2-hydrazinopyridine derivatized steroid hormones in fathead minnow (Pimephales promelas) blood plasma using LC-ESI+/MS/MS. AB - Fathead minnows (Pimephales promelas) comprise a species-of-choice for the hazard assessments of various environmental contaminants, including compounds capable of disrupting endocrine function. Towards this end, the use of liquid chromatography coupled with mass spectrometry (LC-MS) and/or tandem mass spectrometry (MS/MS) is gaining common use for the quantification of steroid hormones as biomarkers of endocrine stress in small-fish toxicological studies. In this work, 2 hydrazinopyridine (2-HP) was used to derivatize and quantify the physiologically relevant steroid hormones of: 17alpha-hydroxypregnenolone, progesterone, 11 ketotestosterone, 11-deoxycortisol and 17alpha,20beta-dihydroxypregnenone, in the blood plasma of male and female fathead minnows. Liquid chromatographic separation was achieved using a WatersTM Sunfire C(18) column (2.1 mm*50 mm with a 3.5 MUm particle size) and Milli-Q water:methanol (both with 0.1% formic acid) mobile phase over a gradient of 15 min. All mass analyses were conducted using electrospray ionization in the positive mode with tandem mass spectrometry (ESI+/MS/MS). This is the first such application of 2-HP derivatization for the quantifications of the structurally and functionally diverse C19 androgen of 11 ketotestosterone; C21 progestogens of 17alpha-hydroxypregnenolone, progesterone and17alpha,20beta-dihydroxypregnenone; and C21 corticosteroid of 11 deoxycortisol, in fathead minnow blood plasma. The limits of detection (LOD) were set to the lowest calibration standard that gave a signal-to-background response of >=3, and were: 0.16 ng/ml for progesterone, 0.63 ng/ml for 17alpha hydroxypregnenolone, 11-deoxycortisol and 17alpha,20beta-dihydroxypregnenone, and 1.25 ng/ml for 11-ketotestosterone. This study demonstrates the application of 2 HP derivatization for the analysis of a variety of steroid hormones representative of endocrine function in a species of fish commonly used in toxicological studies. PMID- 21317050 TI - Development and validation of a highly sensitive LC-MS/MS method for organic cation transporter (OCT) substrate tetraethylammonium (TEA) in rabbits. AB - Tetraethylammonium is widely used as a probe in organic cation transporters studies. A simple, highly sensitive, and specific method using direct protein precipitation was developed using Hydrophilic Interaction Liquid Chromatography coupled with positive electrospray ionization tandem mass spectrometry for the determination of tetraethylammonium (TEA) in rabbit plasma. Isocratic separation was achieved using a ZIC-HILIC column with acetonitrile and 5mM ammonium acetate in the ratio of 8:2 containing 0.1% formic acid. Acquisition was performed in multiple reaction monitoring mode with the transitions: m/z 130->100 and 130->86 for TEA and m/z 276.1->142.2 for internal standard (homatropine). This method was validated to determine selectivity, linearity, sensitivity, precision, accuracy, recovery and stability. A good linearity was found within a range of 1.53-784.6 ng/mL. The above method has been demonstrated for its capability to estimate the plasma levels of TEA after its topical instillation in rabbit eyes. This method provides an accurate, precise and sensitive tool for determining TEA levels for transporter studies. PMID- 21317051 TI - [Primary adrenal insufficiency due to bilateral adrenal lymphoma]. PMID- 21317052 TI - [Childhood bullous pemphigoid]. PMID- 21317053 TI - A new approach to the treatment of nasal bone fracture: the clinical usefulness of closed reduction using a C-arm. AB - Closed reduction is commonly conducted for the treatment of a nasal bone fracture unless a concurrent fracture or a severe nasal septum fracture is observed. As the reduction, however, is not conducted through the direct gross observation of the fracture site, it is difficult to obtain a good result from it. Accordingly, a supplementary process is required. Closed reduction with a C-arm was conducted within the period from March 2009 to January 2010 on 50 patients with nasal bone fractures, to treat these fractures or to evaluate the postoperative conditions of such. The usefulness of the C-arm was evaluated by comparing the aforementioned closed reduction with a C-arm with the closed reduction without a C-arm that was conducted on 64 patients with nasal bone fractures within the period from January 2008 to February 2009. The complication morbidity and re operation rate were significantly lower in the patient group with closed reduction with a C-arm, and the radiologic examination also showed a significant difference. If closed reduction is conducted on patients with nasal bone fractures using a C-arm, an accurate result can be obtained by observing the fractured bone indirectly with continuous imaging during the operation, and the operation result can be immediately assessed in the operating room, thereby reducing the frequencies of complications and re-operation. PMID- 21317054 TI - Medium-term cost analysis of breast reconstructions in a single Dutch centre: a comparison of implants, implants preceded by tissue expansion, LD transpositions and DIEP flaps. AB - BACKGROUND: Free flap breast reconstruction (BR) is generally believed to be more expensive than implant BR, but costs were previously shown to level out over time due to complications and re-operations. The aim of this study was to assess the economic implications of four BR techniques: silicone prosthesis (SP), implant preceded by tissue expansion (TE/SP), latissimus dorsi transposition with or without implant (LD +/- SP) and deep inferior epigastric perforator (DIEP) flap. METHODS: A prospective historic cohort study was performed to evaluate intramural medical costs in 427 patients, who had undergone BR between 2002 and 2009. Short- and medium-term complications were incorporated. In addition, 58 patients, who had recently undergone BR, participated in a questionnaire study to prospectively evaluate extramural medical and non-medical costs. Estimates of mean short- and medium-term costs are presented per patient. RESULTS: Intramural medical costs for BR and short-term complications for unilateral DIEP flaps (? 12,848) and TE/SP reconstructions (? 12,400) were significantly higher than those for LD +/- SP reconstructions (? 5804), which, in turn, were more expensive than SP reconstructions (? 4731). In bilateral cases, costs of TE/SP (? 12,723) and LD +/ SP (? 10,760) reconstructions were comparable, while DIEP flaps (? 15,747) were significantly more expensive and SP reconstructions were significantly cheaper (? 6784). Overall, the medium-term costs for complications and additional operations were not significantly different (? 3017-? 4503). Extramural medical costs and non-medical costs were approximately ? 9300 per stage, regardless of technique. CONCLUSIONS: Differences in short-term costs between techniques did not level out during follow-up and SP reconstructions remained least expensive. Single-stage SP reconstructions, however, are not suitable for all patients due to high complication rates. Definite implant placement is therefore increasingly preceded by tissue expansion at more comparable costs to autologous BR. Incorporation of non-medical costs into the cost analysis would render two-stage procedures more costly than autologous BR. To achieve the optimal result, careful patient selection is critical. Only in select cases where two options are equally applicable, cost comparison becomes a valid argument for treatment selection. PMID- 21317055 TI - New protocols for the manufacture of surgical splints in surgical-orthodontic treatment. AB - The role of the orthodontist is important in the management of surgical orthodontic treatment. It is particularly vital during the preoperative stage when the arches are prepared for surgery, but also in the manufacture of the surgical splints. Many tools are available to help forecast the surgical outcome and prepare the surgical splints. Some, although time-consuming and difficult to implement are still being used but are most often delegated to the prosthetics laboratory. Here, we present two innovations which provide the most precise surgical simulation achievable and which, most importantly, are the easiest to implement. The first involves the making of a set of articulator set-up plates. The second is computer-based and entails the creation of a user-friendly virtual surgical set-up. PMID- 21317057 TI - [Living-donor kidney transplantation in the European countries and in North America (2001-2009)]. AB - In front of kidney transplants shortage, the alternative of living donor renal transplantation is discussed. The purpose of this work is to compare, in 16 European countries and of North America having a consequent activity, the levels of living donor renal transplantation activities and their possible impact on kidney shortage, usually reported in a fragmented and punctual way. In 2009 and in spite of a light growth, the French rate of 3,5 living donor kidney transplantation per million people (pmp) was one of the weakest just before Italy and Finland. Numerous countries exceeded the rate of 14 pmp. Others as Spain and Portugal know a regular growth while their transplant activity was mainly based on brain dead donor. This growth is also observed in Germany and in Austria. France, in spite of an increase of kidney transplantation activity, had a high level of kidney shortage (2,7 patients registered on the waiting list in 2009 for one kidney transplant) before Italy which has low rate of living kidney transplant activity, Portugal, with a recent growth of transplant activity, but also the United States with high incidence of end stage renal disease and the United Kingdom which has a low rate of brain dead donors. For these last ones, France have one of the highest rates but it seems to reach a ceiling for 3 years. This report should lead a real strategy of the transplant from kidney living donor with a support for the healthcare professionals, the information of the general public, the patients and their family. PMID- 21317058 TI - [Patients treated by peritoneal dialysis: a heterogeneous group of patients. Profile of PD patients]. AB - Often, one gathers together under the denomination "peritoneal dialysis" patients with various clinical profiles. To quantify this "heterogeneity" we analysed the clinical characteristics of 32,975 patients treated by dialysis at 31 December 2008 in 22 French regions, participating to the REIN registry. This cross sectional study confirms our initial hypothesis of a great heterogeneity of patients' profiles in peritoneal dialysis. As in hemodialysis, there is a gradation between modalities: from assisted continuous ambulatory peritoneal dialysis which concerns the frailty patients to autonomous automated peritoneal dialysis for more healthy patients, through assisted automated peritoneal dialysis and autonomous continuous ambulatory peritoneal dialysis. PMID- 21317060 TI - Cost of pretherapeutic staging of patients with colorectal cancer metastases in a French population. AB - BACKGROUND: Little is known about the economic burden of pretherapeutic staging of patients presenting colorectal cancer metastases. OBJECTIVE: The aim of this study was to estimate the cost of pretherapeutic staging and identify cost determinants for 132 patients presenting colorectal metastases and living in the north-east of France. METHOD: Staging cost was estimated using direct medical costs from the point of view of the French Health Insurance System. Independent factors were identified using a linear regression model, and bootstrap resampling was used to estimate unbiased standard errors and 95% confidence intervals. RESULTS: The overall mean cost for pretherapeutic staging was estimated to be 1534? [95% CI: 1250?-1818?]. Staging costs increased significantly with the number of medical procedures performed during the staging, and according to health care patterns (in-patient hospital stay versus out-patient episodes, public versus private care). CONCLUSION: These results could now be used to estimate the impact of new imaging techniques on clinical practices and pretherapeutic staging costs. PMID- 21317062 TI - Conversation on technoethics and cyborgs. PMID- 21317061 TI - New plays in the p53 theater. AB - The p53 tumor suppressor and its paralogs p63 and p73 are at the crux of a network modulating cellular responses against potentially tumorigenic events. p53 acts primarily as a transcription factor, regulating the expression of both coding and non-coding RNAs, as well as the activity of RNA processing complexes. In line with their anti-tumorigenic function, p53 and p63 have recently been implicated in restricting tumor cell invasion. In parallel, a growing number of non-canonical target genes have been added to the p53 repertoire. These include genes encoding for proteins that impinge on a broad spectrum of cellular functions, from cell metabolism to stem cell renewal. The p53 story is still far from being fully told. PMID- 21317063 TI - Engineering global health. PMID- 21317064 TI - In pursuit of the newt. PMID- 21317065 TI - Innovative engineering solutions. "Lessons learned from medical systems development" workshop--32nd Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBS). PMID- 21317066 TI - Vital signs. PMID- 21317067 TI - Optimization of ECG classification by means of feature selection. AB - This study tackles the ECG classification problem by means of a methodology, which is able to enhance classification performance while simultaneously reducing the computational resources, making it specially adequate for its application in the improvement of ambulatory settings. For this purpose, the sequential forward floating search (SFFS) algorithm is applied with a new criterion function index based on linear discriminants. This criterion has been devised specifically to be a quality indicator in ECG arrhythmia classification. Based on this measure, a comprehensive feature set is analyzed with the SFFS algorithm, and the most suitable subset returned is additionally evaluated with a multilayer perceptron (MLP) to assess the robustness of the model. Aiming at obtaining meaningful estimates of the real-world performance and facilitating comparison with similar studies, the present contribution follows the Association for the Advancement of Medical Instrumentation standard EC57:1998 and the same interpatient division scheme used in several previous studies. Results show that by applying the proposed methods, the performance obtained in similar studies under the same constraints can be exceeded, while keeping the requirements suitable for ambulatory monitoring PMID- 21317068 TI - A point process model for auditory neurons considering both their intrinsic dynamics and the spectrotemporal properties of an extrinsic signal. AB - We propose a point process model of spiking activity from auditory neurons. The model takes account of the neuron's intrinsic dynamics as well as the spectrotemporal properties of an input stimulus. A discrete Volterra expansion is used to derive the form of the conditional intensity function. The Volterra expansion models the neuron's baseline spike rate, its intrinsic dynamics-spiking history-and the stimulus effect which in this case is the analog of the spectrotemporal receptive field (STRF). We performed the model fitting efficiently in a generalized linear model framework using ridge regression to address properly this ill-posed maximum likelihood estimation problem. The model provides an excellent fit to spiking activity from 55 auditory nerve neurons. The STRF-like representation estimated jointly with the neuron's intrinsic dynamics may offer more accurate characterizations of neural activity in the auditory system than current ones based solely on the STRF. PMID- 21317069 TI - Optical assay for biotechnology and clinical diagnosis. AB - In this paper, we present an optical diagnostic assay consisting of a mixture of environmental-sensitive fluorescent dyes combined with multivariate data analysis for quantitative and qualitative examination of biological and clinical samples. The performance of the assay is based on the analysis of spectrum of the selected fluorescent dyes with the operational principle similar to electronic nose and electronic tongue systems. This approach has been successfully applied for monitoring of growing cell cultures and identification of gastrointestinal diseases in humans. PMID- 21317070 TI - A skin-contact-actuated micropump for transdermal drug delivery. AB - In this paper, a skin-contact-actuated dispenser/micropump for transdermal drug delivery applications is presented. The micropump consists of stacked polydimethylsiloxane layers mounted on a silicon substrate and operates based on the evaporation and condensation of a low-boiling-point liquid. Therefore, there is no need for a heater and a power source, since only the thermal energy provided by skin contact is required for the actuation. A prototype device with overall dimensions of 14 mm * 14 mm * 8 mm is fabricated and characterized. For a perfluoro compound working fluid (3M FC-3284), a flow rate of 28.8 MU L/min and a maximum back pressure of 28.9 kPa is measured. PMID- 21317071 TI - Identification of time-varying intrinsic and reflex joint stiffness. AB - Dynamic joint stiffness defines the dynamic relationship between the position of a joint and the torque acting about it and can be separated into intrinsic and reflex components. Under stationary conditions, these can be identified using a nonlinear parallel-cascade algorithm that models intrinsic stiffness-a linear dynamic response to position-and reflex stiffness-a nonlinear dynamic response to velocity-as parallel pathways. Experiments using this method show that both intrinsic and reflex stiffness depend strongly on the operating point, defined by position and torque, likely because of some underlying nonlinear behavior not modeled by the parallel-cascade structure. Consequently, both intrinsic and reflex stiffness will appear to be time-varying whenever the operating point changes rapidly, as during movement. This paper describes and validates an extension of the parallel-cascade algorithm to time-varying conditions. It describes the ensemble method used to estimate time-varying intrinsic and reflex stiffness. Simulation results demonstrate that the algorithm can track rapid changes in joint stiffness accurately. Finally, the performance of the algorithm in the presence of noise is tested. We conclude that the new algorithm is a powerful new tool for the study of joint stiffness during functional tasks. PMID- 21317072 TI - Targeted tissue ablation with nanosecond pulses. AB - In-vivo porcine studies on the effect of nanosecond high voltage pulses on liver tissue have shown that cell death can be induced in well-defined tissue volumes without damaging collagen-predominant structures. Comparison of the experimental results with the results of a three-dimensional finite element model allowed us to determine the threshold electric field for cell death. For 30, 100 nanosecond long pulses this was found to be in the range from 12 to 15 kV/cm. Modelling of the temperature distribution in the tissue using Pennes' bioheat equation showed that the lethal effect of nanosecond pulses on cells is non-thermal. Muscle contractions, generally caused by high voltage pulses, were significantly reduced for the 100 nanosecond pulses compared to microsecond long pulses. The results of these studies indicate that high voltage nanosecond pulses reliably kill normal liver cells in vivo and therefore may be useful for liver tumor treatments. PMID- 21317073 TI - Selective classification for improved robustness of myoelectric control under nonideal conditions. AB - Recent literature in pattern recognition-based myoelectric control has highlighted a disparity between classification accuracy and the usability of upper limb prostheses. This paper suggests that the conventionally defined classification accuracy may be idealistic and may not reflect true clinical performance. Herein, a novel myoelectric control system based on a selective multiclass one-versus-one classification scheme, capable of rejecting unknown data patterns, is introduced. This scheme is shown to outperform nine other popular classifiers when compared using conventional classification accuracy as well as a form of leave-one-out analysis that may be more representative of real prosthetic use. Additionally, the classification scheme allows for real-time, independent adjustment of individual class-pair boundaries making it flexible and intuitive for clinical use. PMID- 21317074 TI - A wideband spiral antenna for ingestible capsule endoscope systems: experimental results in a human phantom and a pig. AB - This paper presents the design of a wideband spiral antenna for ingestible capsule endoscope systems and a comparison between the experimental results in a human phantom and a pig under general anesthesia. As wireless capsule endoscope systems transmit real-time internal biological image data at a high resolution to external receivers and because they operate in the human body, a small wideband antenna is required. To incorporate these properties, a thick-arm spiral structure is applied to the designed antenna. To make practical and efficient use of antennas inside the human body, which is composed of a high dielectric and lossy material, the resonance characteristics and radiation patterns were evaluated through a measurement setup using a liquid human phantom. The total height of the designed antenna is 5 mm and the diameter is 10 mm. The fractional bandwidth of the fabricated antenna is about 21% with a voltage standing-wave ratio of less than 2, and it has an isotropic radiation pattern. These characteristics are suitable for wideband capsule endoscope systems. Moreover, the received power level was measured using the proposed antenna, a circular polarized receiver antenna, and a pig under general anesthesia. Finally, endoscopic capsule images in the stomach and large intestine were captured using an on-off keying transceiver system. PMID- 21317075 TI - Classification of paroxysmal and persistent atrial fibrillation in ambulatory ECG recordings. AB - The problem of classifying short atrial fibrillatory segments in ambulatory ECG recordings as being either paroxysmal or persistent is addressed by investigating a robust approach to signal characterization. The method comprises preprocessing estimation of the dominant atrial frequency for the purpose of controlling the subbands of a filter bank, computation of the relative subband (harmonics) energy, and the subband sample entropy. Using minimum-error-rate classification of different feature vectors, a data set consisting of 24-h ambulatory recordings from 50 subjects with either paroxysmal (26) or persistent (24) atrial fibrillation (AF) was analyzed on a 10-s segment basis; a total of 212,196 segments were classified. The best performance in terms of area under the receiver operating characteristic curve was obtained for a feature vector defined by the subband sample entropy of the dominant atrial frequency and the relative harmonics energy, resulting in a value of 0.923, whereas that of the dominant atrial frequency was equal to 0.826. It is concluded that paroxysmal and persistent AFs can be discriminated from short segments with good accuracy at any time of an ambulatory recording. PMID- 21317076 TI - Automated off-line respiratory event detection for the study of postoperative apnea in infants. AB - Previously, we presented automated methods for thoraco-abdominal asynchrony estimation and movement artifact detection in respiratory inductance plethysmography (RIP) signals. This paper combines and improves these methods to give a method for the automated, off-line detection of pause, movement artifact, and asynchrony. Simulation studies demonstrated that the new combined method is accurate and robust in the presence of noise. The new procedure was successfully applied to cardiorespiratory signals acquired postoperatively from infants in the recovery room. A comparison of the events detected with the automated method to those visually scored by an expert clinician demonstrated a higher agreement (kappa = 0.52) than that amongst several human scorers (kappa = 0.31) in a clinical study . The method provides the following advantages: first, it is fully automated; second, it is more efficient than visual scoring; third, the analysis is repeatable and standardized; fourth, it provides greater agreement with an expert scorer compared to the agreement between trained scorers; fifth, it is amenable to online detection; and lastly, it is applicable to uncalibrated RIP signals. Examples of applications include respiratory monitoring of postsurgical patients and sleep studies. PMID- 21317077 TI - Tracking of vessels in intra-operative microscope video sequences for cortical displacement estimation. AB - This article presents a method designed to automatically track cortical vessels in intra-operative microscope video sequences. The main application of this method is the estimation of cortical displacement that occurs during tumor resection procedures. The method works in three steps. First, models of vessels selected in the first frame of the sequence are built. These models are then used to track vessels across frames in the video sequence. Finally, displacements estimated using the vessels are extrapolated to the entire image. The method has been tested retrospectively on images simulating large displacement, tumor resection, and partial occlusion by surgical instruments and on 21 video sequences comprising several thousand frames acquired from three patients. Qualitative results show that the method is accurate, robust to the appearance and disappearance of surgical instruments, and capable of dealing with large differences in images caused by resection. Quantitative results show a mean vessel tracking error (VTE) of 2.4 pixels (0.3 or 0.6 mm, depending on the spatial resolution of the images) and an average target registration error (TRE) of 3.3 pixels (0.4 or 0.8 mm). PMID- 21317078 TI - Shear elastic modulus estimation from indentation and SDUV on gelatin phantoms. AB - Tissue mechanical properties such as elasticity are linked to tissue pathology state. Several groups have proposed shear wave propagation speed to quantify tissue mechanical properties. It is well known that biological tissues are viscoelastic materials; therefore, velocity dispersion resulting from material viscoelasticity is expected. A method called shearwave dispersion ultrasound vibrometry (SDUV) can be used to quantify tissue viscoelasticity by measuring dispersion of shear wave propagation speed. However, there is not a gold standard method for validation. In this study, we present an independent validation method of shear elastic modulus estimation by SDUV in three gelatin phantoms of differing stiffness. In addition, the indentation measurements are compared to estimates of elasticity derived from shear wave group velocities. The shear elastic moduli from indentation were 1.16, 3.40, and 5.6 kPa for a 7%, 10%, and 15% gelatin phantom, respectively. SDUV measurements were 1.61, 3.57, and 5.37 kPa for the gelatin phantoms, respectively. Shear elastic moduli derived from shear wave group velocities were 1.78, 5.2, and 7.18 kPa for the gelatin phantoms, respectively. The shear elastic modulus estimated from the SDUV, matched the elastic modulus measured by indentation. On the other hand, shear elastic modulus estimated by group velocity did not agree with indentation test estimations. These results suggest that shear elastic modulus estimation by group velocity will be bias when the medium being investigated is dispersive. Therefore, a rheological model should be used in order to estimate mechanical properties of viscoelastic materials. PMID- 21317079 TI - A maximum NEC criterion for Compton collimation to accurately identify true coincidences in PET. AB - In this work, we propose a new method to increase the accuracy of identifying true coincidence events for positron emission tomography (PET). This approach requires 3-D detectors with the ability to position each photon interaction in multi-interaction photon events. When multiple interactions occur in the detector, the incident direction of the photon can be estimated using the Compton scatter kinematics (Compton Collimation). If the difference between the estimated incident direction of the photon relative to a second, coincident photon lies within a certain angular range around colinearity, the line of response between the two photons is identified as a true coincidence and used for image reconstruction. We present an algorithm for choosing the incident photon direction window threshold that maximizes the noise equivalent counts of the PET system. For simulated data, the direction window removed 56%-67% of random coincidences while retaining > 94% of true coincidences from image reconstruction as well as accurately extracted 70% of true coincidences from multiple coincidences. PMID- 21317081 TI - Prediction of the spatial resolution of magnetic particle imaging using the modulation transfer function of the imaging process. AB - The magnetic particle imaging method allows for the quantitative determination of spatial distributions of superparamagnetic nanoparticles in vivo. Recently, it was shown that the 1-D magnetic particle imaging process can be formulated as a convolution. Analyzing the width of the convolution kernel allows for predicting the spatial resolution of the method. However, this measure does not take into account the noise of the measured data. Furthermore, it does not consider a reconstruction step, which can increase the resolution beyond the width of the convolution kernel. In this paper, the spatial resolution of magnetic particle imaging is investigated by analyzing the modulation transfer function of the imaging process. An expression for the spatial resolution is derived, which includes the noise level and which is validated in simulations and experiments. PMID- 21317080 TI - Total variation regularization for fMRI-based prediction of behavior. AB - While medical imaging typically provides massive amounts of data, the extraction of relevant information for predictive diagnosis remains a difficult challenge. Functional magnetic resonance imaging (fMRI) data, that provide an indirect measure of task-related or spontaneous neuronal activity, are classically analyzed in a mass-univariate procedure yielding statistical parametric maps. This analysis framework disregards some important principles of brain organization: population coding, distributed and overlapping representations. Multivariate pattern analysis, i.e., the prediction of behavioral variables from brain activation patterns better captures this structure. To cope with the high dimensionality of the data, the learning method has to be regularized. However, the spatial structure of the image is not taken into account in standard regularization methods, so that the extracted features are often hard to interpret. More informative and interpretable results can be obtained with the l(1) norm of the image gradient, also known as its total variation (TV), as regularization. We apply for the first time this method to fMRI data, and show that TV regularization is well suited to the purpose of brain mapping while being a powerful tool for brain decoding. Moreover, this article presents the first use of TV regularization for classification. PMID- 21317082 TI - Fiber continuity: an anisotropic prior for ODF estimation. AB - The accurate and reliable estimation of fiber orientation distributions, based on diffusion-sensitized magnetic resonance images is a major prerequisite for tractography algorithms or any other derived statistical analysis. In this work, we formulate the principle of fiber continuity (FC), which is based on the simple observation that the imaging of fibrous tissue implies certain expectations for the measured images. From this principle we derive a prior for the estimation of fiber orientation distributions based on high angular resolution diffusion imaging (HARDI). We demonstrate on simulated, phantom, and in vivo data the superiority of the proposed approach. Further, we propose another application of the FC principle, named FC flow, a method to resolve complex crossing regions solely based on diffusion tensor imaging (DTI). The idea is to infer directional information in crossing regions from adjacent anisotropic areas. PMID- 21317083 TI - Hybrid small animal imaging system combining magnetic resonance imaging with fluorescence tomography using single photon avalanche diode detectors. AB - The high sensitivity of fluorescence imaging enables the detection of molecular processes in living organisms. However, diffuse light propagation in tissue prevents accurate recovery of tomographic information on fluorophore distribution for structures embedded deeper than 0.5 mm. Combining optical with magnetic resonance imaging (MRI) provides an accurate anatomical reference for fluorescence imaging data and thereby enables the correlation of molecular with high quality structural/functional information. We describe an integrated system for small animal imaging incorporating a noncontact fluorescence molecular tomography (FMT) system into an MRI detector. By adopting a free laser beam design geometrical constraints imposed by the use of optical fibers could be avoided allowing for flexible fluorescence excitation schemes. Photon detection based on a single-photon avalanche diode array enabled simultaneous FMT/MRI measurements without interference between modalities. In vitro characterization revealed good spatial accuracy of FMT data and accurate quantification of dye concentrations. Feasibility of FMT/MRI was demonstrated in vivo by simultaneous assessment of protease activity and tumor morphology in murine colon cancer xenografts. PMID- 21317084 TI - Observer-Based Adaptive Fuzzy Backstepping Dynamic Surface Control for a Class of MIMO Nonlinear Systems. AB - In this paper, an adaptive fuzzy backstepping dynamic surface control (DSC) approach is developed for a class of multiple-input-multiple-output nonlinear systems with immeasurable states. Using fuzzy-logic systems to approximate the unknown nonlinear functions, a fuzzy state observer is designed to estimate the immeasurable states. By combining adaptive-backstepping technique and DSC technique, an adaptive fuzzy output-feedback backstepping-control approach is developed. The proposed control method not only overcomes the problem of "explosion of complexity" inherent in the backstepping-design methods but also overcomes the problem of unavailable state measurements. It is proved that all the signals of the closed-loop adaptive-control system are semiglobally uniformly ultimately bounded, and the tracking errors converge to a small neighborhood of the origin. Simulation results are provided to show the effectiveness of the proposed approach. PMID- 21317085 TI - Hybrid Training Method for MLP: Optimization of Architecture and Training. AB - The performance of an artificial neural network (ANN) depends upon the selection of proper connection weights, network architecture, and cost function during network training. This paper presents a hybrid approach (GaTSa) to optimize the performance of the ANN in terms of architecture and weights. GaTSa is an extension of a previous method (TSa) proposed by the authors. GaTSa is based on the integration of the heuristic simulated annealing (SA), tabu search (TS), genetic algorithms (GA), and backpropagation, whereas TSa does not use GA. The main advantages of GaTSa are the following: a constructive process to add new nodes in the architecture based on GA, the ability to escape from local minima with uphill moves (SA feature), and faster convergence by the evaluation of a set of solutions (TS feature). The performance of GaTSa is investigated through an empirical evaluation of 11 public-domain data sets using different cost functions in the simultaneous optimization of the multilayer perceptron ANN architecture and weights. Experiments demonstrated that GaTSa can also be used for relevant feature selection. GaTSa presented statistically relevant results in comparison with other global and local optimization techniques. PMID- 21317086 TI - Detection of abnormal living patterns for elderly living alone using support vector data description. AB - In this study, we developed an automated behavior analysis system using infrared (IR) motion sensors to assist the independent living of the elderly who live alone and to improve the efficiency of their healthcare. An IR motion-sensor based activity-monitoring system was installed in the houses of the elderly subjects to collect motion signals and three different feature values, activity level, mobility level, and nonresponse interval (NRI). These factors were calculated from the measured motion signals. The support vector data description (SVDD) method was used to classify normal behavior patterns and to detect abnormal behavioral patterns based on the aforementioned three feature values. The simulation data and real data were used to verify the proposed method in the individual analysis. A robust scheme is presented in this paper for optimally selecting the values of different parameters especially that of the scale parameter of the Gaussian kernel function involving in the training of the SVDD window length, T of the circadian rhythmic approach with the aim of applying the SVDD to the daily behavior patterns calculated over 24 h. Accuracies by positive predictive value (PPV) were 95.8% and 90.5% for the simulation and real data, respectively. The results suggest that the monitoring system utilizing the IR motion sensors and abnormal-behavior-pattern detection with SVDD are effective methods for home healthcare of elderly people living alone. PMID- 21317087 TI - Automatic detection of temporal gait parameters in poststroke individuals. AB - Approximately one-third of people who recover from a stroke require some form of assistance to walk. Repetitive task-oriented rehabilitation interventions have been shown to improve motor control and function in people with stroke. Our long term goal is to design and test an intensive task-oriented intervention that will utilize the two primary components of constrained-induced movement therapy: massed, task-oriented training and behavioral methods to increase use of the affected limb in the real world. The technological component of the intervention is based on a wearable footwear-based sensor system that monitors relative activity levels, functional utilization, and gait parameters of affected and unaffected lower extremities. The purpose of this study is to describe a methodology to automatically identify temporal gait parameters of poststroke individuals to be used in assessment of functional utilization of the affected lower extremity as a part of behavior enhancing feedback. An algorithm accounting for intersubject variability is capable of achieving estimation error in the range of 2.6-18.6% producing comparable results for healthy and poststroke subjects. The proposed methodology is based on inexpensive and user-friendly technology that will enable research and clinical applications for rehabilitation of people who have experienced a stroke. PMID- 21317088 TI - Vessel tree segmentation in presence of interstitial lung disease in MDCT. AB - The automated segmentation of vessel tree structures is a crucial preprocessing stage in computer aided diagnosis (CAD) schemes of interstitial lung disease (ILD) patterns in multidetector computed tomography (MDCT). The accuracy of such preprocessing stages is expected to influence the accuracy of lung CAD schemes. Although algorithms aimed at improving the accuracy of lung fields segmentation in presence of ILD have been reported, the corresponding vessel tree segmentation stage is under-researched. Furthermore, previously reported vessel tree segmentation methods have only dealt with normal lung parenchyma. In this paper, an automated vessel tree segmentation scheme is proposed, adapted to the presence of pathologies affecting lung parenchyma. The first stage of the method accounts for a recently proposed method utilizing a 3-D multiscale vessel enhancement filter based on eigenvalue analysis of the Hessian matrix and on unsupervised segmentation. The second stage of the method is a texture-based voxel classification refinement to correct possible over-segmentation. The performance of the proposed scheme, and of the previously reported technique, in vessel tree segmentation was evaluated by means of area overlap (previously reported: 0.715 +/- 0.082, proposed: 0.931 +/- 0.027), true positive fraction (previously reported: 0.968 +/- 0.019, proposed: 0.935 +/- 0.036) and false positive fraction (previously reported: 0.400 +/- 0.181, proposed: 0.074 +/- 0.031) on a dataset of 210 axial slices originating from seven ILD affected patient scans (used for performance evaluation out of 15). The proposed method demonstrated a statistically significantly ( p < 0.05) higher performance as compared to the previously reported vessel tree segmentation technique. The impact of suboptimal vessel tree segmentation in a reticular pattern quantification system is also demonstrated. PMID- 21317089 TI - Spike sorting by stochastic simulation. AB - The decomposition of multiunit signals consists of the restoration of spike trains and action potentials in neural or muscular recordings. Because of the complexity of automatic decomposition, semiautomatic procedures are sometimes chosen. The main difficulty in automatic decomposition is the resolution of temporally overlapped potentials. In a previous study , we proposed a Bayesian model coupled with a maximum a posteriori (MAP) estimator for fully automatic decomposition of multiunit recordings and we showed applications to intramuscular EMG signals. In this study, we propose a more complex signal model that includes the variability in amplitude of each unit potential. Moreover, we propose the Markov Chain Monte Carlo (MCMC) simulation and a Bayesian minimum mean square error (MMSE) estimator by averaging on samples that converge in distribution to the joint posterior law. We prove the convergence property of this approach mathematically and we test the method representatively on intramuscular multiunit recordings. The results showed that its average accuracy in spike identification is greater than 90% for intramuscular signals with up to 8 concurrently active units. In addition to intramuscular signals, the method can be applied for spike sorting of other types of multiunit recordings. PMID- 21317091 TI - 30 years--starting out, attaining and maintaining excellence, new beginnings. PMID- 21317090 TI - Diffusion-weighted MRI in head and neck radiology: applications in oncology. AB - Extracranial application of diffusion-weighted magnetic resonance imaging (MRI) has gained increasing importance in recent years. As a result of technical advances, this new non-invasive functional technique has also been applied in head and neck radiology for several clinical indications. In cancer imaging, diffusion-weighted MRI can be performed for tumour detection and characterization, monitoring of treatment response as well as the differentiation of recurrence and post-therapeutic changes after radiotherapy. Even for lymph node staging promising results have been reported recently. This review article provides overview of potential applications of diffusion-weighted MRI in head and neck with the main focus on its applications in oncology. PMID- 21317092 TI - Neonatal Resuscitation Program (NRP) 2011: new science, new strategies. AB - In spring 2011, the American Academy of Pediatrics (AAP) will release sixth edition materials for the Neonatal Resuscitation Program (NRP). This edition brings changes in resuscitation practice and a new education methodology that shifts the instructor from "teacher" to "learning facilitator" and requires the NRP course participant to assume more responsibility for learning. The change from a lecture format to simulation-based learning requires instructors to learn new skills and meet new requirements to maintain instructor status. The sixth edition of the Textbook of Neonatal Resuscitation and the fifth edition of the Instructor's Manual for Neonatal Resuscitation are currently in press. The AAP granted permission to use material from these forthcoming publications in this article. PMID- 21317093 TI - The Circle of Caring Model for Neonatal Transport. AB - The Circle of Caring Model serves as a guide that superimposes nursing and medical practice models. This transformative template was formulated for advanced practice nursing in all health care settings, including neonatal care. This article proposes an extension of this model specific to neonatal transport. It also shows how the Circle of Caring Model for Neonatal Transport functions within the framework of a hypothetical patient case. PMID- 21317094 TI - Mothers' breastfeeding experiences in the NICU. AB - PURPOSE: There is extensive literature on the physical and physiologic benefits of breastfeeding premature infants. Less is known about mothers' perceptions of their own breastfeeding experience. This study explored the maternal experience of breastfeeding initiation and progression in the NICU. DESIGN: A qualitative, descriptive design. SAMPLE: A convenience sample of ten mothers was recruited from a Level III NICU. The sample included mothers of infants between 33 and 36 weeks gestational time at the time of the interview who had been in the NICU for at least five days. MAIN OUTCOME VARIABLE: Mothers' breastfeeding experiences with preterm infants in an NICU. RESULTS: Mothers described their breastfeeding experiences in terms of maintaining milk production, the regimen of the NICU , mother as learner, personal motivation, and forming attachments. PMID- 21317095 TI - Induced hypothermia for neonatal hypoxic-ischemic encephalopathy: pathophysiology, current treatment, and nursing considerations. AB - Hypoxic-ischemic encephalopathy (HIE) can lead to devastating neurodevelopmental consequences such as cerebral palsy, seizure disorders, and significant developmental delays. HIE in the newborn is often the result of a hypoxic event, such as uterine rupture, placental abruption, or cord prolapse. Biphasic brain injury occurs in HIE. The first phase involves activation of the sympathetic nervous system as a compensatory mechanism. The second phase, known as reperfusion brain injury, occurs hours later. Induced hypothermia, a neuroprotective strategy for treating HIE, targets the second phase to prevent reperfusion injury. NICU nurses are in a unique position to detect patient instability and to maintain the therapeutic interventions that contribute to the healing process. This article highlights the significant role nurses play in the management of infants diagnosed with HIE who are treated with induced hypothermia. PMID- 21317096 TI - Developmental considerations in working with newborn infants of mothers with diabetes. AB - Infants of diabetic mothers (IDMs) are at risk for an altered developmental course beginning with physiologic alterations in utero. This article describes physiologic and behavioral factors that impact the fetus and newborn infant and may have long-term developmental consequences. A clinical reasoning process to support development optimizes the outcomes of IDMs while in the NICU. Specific interventions are suggested. PMID- 21317098 TI - Blood types and ABO incompatibility. AB - Using the Punnett square and having an understanding of the relationship between genes and blood types will assist you in explaining blood type inheritance to parents and answering their many questions. Using this tool, nurses can show parents what is happening during the division of genes and how blood type genes are expressed. PMID- 21317099 TI - Neonatal pharmacology--pharmacokinetics. AB - The goal of drug therapy is a defined clinical response. Drug therapy in the vulnerable preterm and term newborn population is complicated by developmental limitations that affect the pharmacokinetics of most drugs. It is important that, in any therapy, care providers maintain a keen awareness of the expected response while monitoring the infant's clinical response throughout drug administration. This column has addressed pharmacologic principles, especially the pharmacokinetics of drug therapy, to guide clinical assessments of patients' responses to drug therapy. PMID- 21317101 TI - Creative learning ideas from around the U.S. AB - Moving education away from a teacher-centered "sage on the stage" approach to learner-centered methodologies in which the instructor is more like a "guide on the side" enhances learning and retention of material. When preparing educational materials, nurse educators should focus on engaging learners, stimulating multiples senses, and taking steps to make learning fun. The innovative teaching strategies presented here have hopefully stimulated creative thinking among both educators and learners. Thank you to the nurses who were willing to share their creative ideas in this column. PMID- 21317102 TI - Nurturing touch helps mothers with postpartum depression and their infants. Interview by Deb Discenza. PMID- 21317104 TI - Re. The experiences of NICU nurses in caring for infants with neonatal abstinence syndrome. PMID- 21317105 TI - Tribute to neonatal nursing and Neonatal Network(r). PMID- 21317106 TI - How strong are passwords used to protect personal health information in clinical trials? AB - BACKGROUND: Findings and statements about how securely personal health information is managed in clinical research are mixed. OBJECTIVE: The objective of our study was to evaluate the security of practices used to transfer and share sensitive files in clinical trials. METHODS: Two studies were performed. First, 15 password-protected files that were transmitted by email during regulated Canadian clinical trials were obtained. Commercial password recovery tools were used on these files to try to crack their passwords. Second, interviews with 20 study coordinators were conducted to understand file-sharing practices in clinical trials for files containing personal health information. RESULTS: We were able to crack the passwords for 93% of the files (14/15). Among these, 13 files contained thousands of records with sensitive health information on trial participants. The passwords tended to be relatively weak, using common names of locations, animals, car brands, and obvious numeric sequences. Patient information is commonly shared by email in the context of query resolution. Files containing personal health information are shared by email and, by posting them on shared drives with common passwords, to facilitate collaboration. CONCLUSION: If files containing sensitive patient information must be transferred by email, mechanisms to encrypt them and to ensure that password strength is high are necessary. More sophisticated collaboration tools are required to allow file sharing without password sharing. We provide recommendations to implement these practices. PMID- 21317107 TI - LC/MS/MS method for analysis of E2 series prostaglandins and isoprostanes. AB - 15-series prostaglandins (PGE2s) and isoprostanes (isoPGE2s) are robust biomarkers of oxidative stress, possess potent biological activity, and may be derived through cyclooxygenase or free radical pathways. Thus, their quantification is critical in understanding many biological processes where PG, isoPG, or oxidative stress are involved. LC/MS/MS methods allow a highly selective, sensitive, simultaneous analysis for prostanoids without derivatization. However, the LC/MS/MS methods currently used do not allow for simultaneous separation of the major brain PGE2/D2) and isoPGE2 without derivatization and multiple HPLC separations. The developed LC/MS/MS method allows for the major brain PGE2/PGD2/isoPGE2 such as PGE2, entPGE2, 8-isoPGE2, 11beta-PGE2, PGD2, and 15(R)-PGD2 to be separated and quantified without derivatization. The method was validated by analyzing free and esterified isoPGE2 in mouse brains fixed with head-focused microwave irradiation before or after global ischemia. Using the developed method, we report for the first time the esterified isoPGE2 levels in brain tissue under basal conditions and upon global ischemia and demonstrate a nonreleasable pool of esterified isoPG upon ischemia. In addition, we demonstrated that PGE2s found esterified in the sn-2 position in phospholipids are derived from a free radical nonenzymatic pathway under basal conditions. Our method for brain PG analysis provides a high level of selectivity to detect changes in brain PG and isoPG mass under both basal and pathological conditions. PMID- 21317108 TI - DGAT enzymes are required for triacylglycerol synthesis and lipid droplets in adipocytes. AB - The total contribution of the acyl CoA:diacylglycerol acyltransferase (DGAT) enzymes, DGAT1 and DGAT2, to mammalian triacylglycerol (TG) synthesis has not been determined. Similarly, whether DGAT enzymes are required for lipid droplet (LD) formation is unknown. In this study, we examined the requirement for DGAT enzymes in TG synthesis and LDs in differentiated adipocytes with genetic deletions of DGAT1 and DGAT2. Adipocytes with a single deletion of either enzyme were capable of TG synthesis and LD formation. In contrast, adipocytes with deletions of both DGATs were severely lacking in TG and did not have LDs, indicating that DGAT1 and DGAT2 account for nearly all TG synthesis in adipocytes and appear to be required for LD formation during adipogenesis. DGAT enzymes were not absolutely required for LD formation in mammalian cells, however; macrophages deficient in both DGAT enzymes were able to form LDs when incubated with cholesterol-rich lipoproteins. Although adipocytes lacking both DGATs had no TG or LDs, they were fully differentiated by multiple criteria. Our findings show that DGAT1 and DGAT2 account for the vast majority of TG synthesis in mice, and DGAT function is required for LDs in adipocytes, but not in all cell types. PMID- 21317111 TI - Browpexy through the upper lid (BUL): a new technique of lifting the brow with a standard blepharoplasty incision. AB - BACKGROUND: Browpexy returns the brow to an anatomical, aesthetically-appealing location on the upper face. Recently, browlifting techniques have evolved from aggressive, open approaches toward less invasive, limited-incision techniques. Browpexy through the upper lid (BUL), an innovative technique based on earlier practices, anchors the underlying brow soft tissue to the bone, allowing for stabilization. Furthermore, this procedure can be performed concomitantly with an upper eyelid blepharoplasty through the same access incision. OBJECTIVE: The authors evaluate the efficacy of BUL in patients with ptotic eyebrows requiring stabilization and/or elevation and in patients with prominent brow fat pads. METHODS: The charts of 21 patients who were treated with BUL by the senior author (HMS) between February 2007 and October 2008 were retrospectively reviewed. RESULTS: The age range of the 21 patients in this study was 54 to 70 years. Twelve patients were men; nine were women. Each patient presented with complaints of tired-appearing or "weighed-down" upper eyelids. All patients were uniformly happy with their postoperative aesthetic results. There were no major immediate or long-term complications (including, but not limited to, uneven postoperative brow position, loss of suspension, frontal nerve injury, hematoma, infection, or wound dehiscence). No patients required reoperation for recurrent brow ptosis or upper lid deformity. CONCLUSIONS: BUL is ideal for patients with ptotic eyebrows who need brow stabilization and/or elevation, as well as for patients with prominent brow fat pads who require stabilization. BUL achieves excellent results through a standard upper eyelid blepharoplasty incision, and allows the surgeon to perform a concomitant upper eyelid blepharoplasty and browpexy without a traditional coronal, scalp, or forehead incision. PMID- 21317112 TI - Commentary on: browpexy through the upper lid (BUL): a new technique of lifting the brow with a standard blepharoplasty incision. PMID- 21317113 TI - Case studies in Asian blepharoplasty. AB - Many techniques have been reported for rejuvenation of the upper eyelids. As the facial structure and skin of Asians differ from those of other races and nationalities (specifically, Caucasians), the operative strategy and technique for treating these patients should take into account their specific anatomy. In this article, the author illustrates his techniques for Asian blepharoplasty (including skin-muscle resection, subeybrow resection, filler or fat injections, double eyelid procedures, block fat grafting, and/or levator shortening), concluding that thorough preoperative evaluation and proper technique selection are key for successful results. PMID- 21317114 TI - Commentary on: case studies in Asian blepharoplasty. PMID- 21317115 TI - Silent sinus syndrome: a rare presentation after botulinum toxin injection. AB - Silent sinus syndrome is a unique diagnosis characterized by spontaneous enophthalmos and hypoglobus resulting from collapse of the orbital floor secondary to chronic subclinical sinusitis. Although reported in the ophthalmology and otolaryngology literature, there is no mention of silent sinus syndrome in the plastic surgery literature. The authors present a case report, along with a brief overview of silent sinus syndrome, so that knowledge of this rare but potentially devastating clinical entity may supplement plastic surgeons' differential to ensure proper diagnosis and treatment. PMID- 21317116 TI - Packing and postoperative rhinoplasty management: a survey report. AB - BACKGROUND: Postoperative management following rhinoplasty varies greatly among aesthetic surgeons. Few studies have addressed practice trends in postoperative rhinoplasty care or questioned the frequency of packing and splinting. Many conventional postoperative techniques remain controversial (eg, packing). OBJECTIVE: To investigate current postoperative practices in the United States, correlating the results with surgical education, practice type, and complication rates. METHODS: An online survey was distributed to members of the American Society for Aesthetic Plastic Surgery. Respondents were polled about their background, route of education, type of practice, frequency and preference of postoperative nasal care, and most frequent rhinoplasty complications. Statistical analysis was performed with the chi(2) test. RESULTS: Of the 1550 total surveys sent, 126 responses were received (8.1%). The majority of respondents were in private practice (86%) and trained in plastic surgery (83%). Approximately 33% continue to regularly employ packing following rhinoplasty, but data show that surgeons performing 21 or more rhinoplasties per year were less likely to utilize packing (P = .06). Those surgeons with higher rhinoplasty case volumes were significantly more likely to utilize a secondary therapy (eg, steroids, arnica) in combination with ice packs (P = .03) to prevent postoperative ecchymosis. Finally, surgeons with lower rhinoplasty case volumes reported more frequent postoperative nasal tip deformities (P = .01). CONCLUSIONS: Postoperative rhinoplasty care varies greatly among practicing aesthetic surgeons. Importantly, a high percentage of private practice aesthetic surgeons continue to utilize nasal packing following rhinoplasty. However, these numbers trend downward in surgeons who perform rhinoplasties more frequently. PMID- 21317117 TI - Aesthetic and technical refinements in latissimus dorsi implant breast reconstruction: a 15-year experience. AB - BACKGROUND: The latissimus dorsi myocutaneous flap and implant breast reconstruction procedure has undergone many refinements over its lifetime. In fact, the authors have made many aesthetic and technical refinements to their own approach to breast reconstruction. OBJECTIVES: The authors review the historical progression of latissimus flap and breast reconstruction techniques and compare these to their own 15-year experience. METHODS: A retrospective chart review was conducted for all latissimus and implant breast reconstructions performed by the senior author (MAC) from July 1994 to June 2009, for a total of 52 procedures in 31 patients. Surgical and oncological data, complications, and outcomes data were recorded. RESULTS: The mean age of the patients at time of surgery was 47.6 years. Average mastectomy weight was 283 grams and average final implant volume was 364 cc. Average follow-up was three years, four months. Of the 52 total procedures, 34.6% were immediate breast reconstructions utilizing skin-sparing mastectomy (SSM); 13.5% of the reconstructed breasts also had preservation of the areola (areolar-sparing mastectomy [ASM]). The most common complication was donor site seroma (40.4%). Aesthetic and surgical refinements identified over the time period included the adoption of SSM and ASM techniques, immediate nipple reconstruction, the placement of an adjustable saline implant to allow for postoperative size adjustment, and implant placement in the prepectoral position. The overall latissimus dorsi implant reconstruction success rate was 94.2% (49/52). CONCLUSIONS: The data demonstrated a successful outcome for latissimus dorsi and implant breast reconstruction for patients with a low or normal body mass index and a small (A to C cup) breast size. The aesthetic outcome of latissimus dorsi breast reconstruction has been improved over the past 15 years by the adoption of SSM and ASM techniques. Immediate nipple reconstruction and the placement of an adjustable saline implant potentially render this procedure a true single-stage reconstruction. Prepectoral implant position provides good aesthetics while preserving the subpectoral space for future management of capsular contracture if required. PMID- 21317118 TI - Contouring the gluteal region with tumescent liposculpture. AB - BACKGROUND: For quite some time, plastic surgeons have experimented with novel techniques for enhancing the gluteal region. However, all of the previously described techniques have the disadvantage of postoperative scarring, most of which is visible. As an alternative, fat injection in the gluteal region has been shown to have permanent and satisfactory results. OBJECTIVES: The authors discuss the results of liposuction and lipoinjection in the gluteal region. METHODS: Between March 2000 and March 2007, 300 female patients who presented with lipodystrophy of the gluteal and paragluteal regions underwent liposuction with a modified tumescent technique. The treated sites were classified into six anatomical zones, and the patients were retrospectively grouped into types based on the frequency of treatment in each zone. RESULTS: The patients ranged in age from 16 to 54 years. The follow-up period ranged from six to 36 months. Fifty percent of patients underwent liposuction in Zone I, 90% in Zone II, 0% in Zone III, 40% in Zone IV, 30% in Zone V, and 75% in Zone VI. The largest percentage of patients underwent treatment in Zones I, II, and V, with subsequent lipoinjection. Comparison of pre- and postoperative photographs and measurements revealed gluteal lifting in all patients at the point of greatest projection. Improved contour was shown in Zones I, II, and IV when all zones were treated in a combined form. CONCLUSIONS: The concept of refining techniques for liposuction and lipoinjection according to individual anatomical zones is essential to the evolution of the procedure. In this series, the results indicated that improving the intraoperative treatment of the hip region resulted in improved aesthetic contouring. Therefore, the authors believe that this technique can reduce the need for more aggressive surgical procedures, which thereby decreases the risk of complications, recovery time, and sequelae. PMID- 21317119 TI - The American Society for Aesthetic Plastic Surgery (ASAPS) survey: current trends in liposuction. AB - BACKGROUND: The emergence of new technologies necessitates a study of current trends in liposuction and other methods for fat removal. OBJECTIVE: The American Society for Aesthetic Plastic Surgery (ASAPS) conducted a survey of its members to gain valuable information from Board-certified plastic surgeons about their experience with new technologies for fat removal and managing complications after liposuction. METHODS: The ASAPS Current Trends in Liposuction Survey was emailed to 1713 ASAPS members. Data were tabulated and examined to determine current trends in liposuction and other fat removal techniques performed by ASAPS members. RESULTS: The response rate for the survey was 28.7% (n = 492). Most ASAPS respondents reported performing between 50 and 100 liposuction procedures annually. Most plastic surgeons currently employ or have previous experience with suction-assisted lipectomy/liposuction (SAL), ultrasound-assisted liposuction (UAL), and power-assisted liposuction, but fewer reported experience with laser assisted liposuction (LAL), mesotherapy, or external, noninvasive devices. SAL was the preferred method of fat removal for 51.4%. UAL, LAL, and SAL were most commonly associated with complications. Only 10.5% of ASAPS members employ LAL; 38% have treated a patient with complications secondary to LAL. CONCLUSIONS: Valuable information about current trends in liposuction and other fat removal techniques has been gained from this survey. Although many studies have been published that review issues related to safety, morbidity, aesthetics, and recovery after different methods of fat removal, more prospective studies with standardized objective outcome measures comparing these techniques, particularly newer modalities, are needed to continue improving safety-related standards of care. PMID- 21317120 TI - Treatment of the tear trough deformity with hyaluronic acid. AB - BACKGROUND: Volume loss and muscular hyperactivity are two major components of the aging process that contribute to the formation of the folds and wrinkles. Tear trough deformity is one of the most difficult depressions to correct surgically. OBJECTIVE: The authors evaluate the results of periorbital filling with hyaluronic acid (HA) in a small series of patients. METHODS: Between June 2008 and December 2009, 25 patients were treated with HA to correct tear trough deformities. The HA was administered into the preperiosteal tissues with a serial puncture technique and approximately 0.1 mL was injected at each pass. Each patient's before and after photographs were reviewed by three surgeons; to objectively assess the outcomes, a quantitative scale was used to grade the pre- and postinjection results. The significance of subjective aesthetic evaluation of the photographs was evaluated with the Mann-Whitney U-test. Differences were regarded as significant if probabilities were less than 0.05. RESULTS: The mean (SD) volume per side needed to achieve correction was 0.54 (0.27) mL on the right and 0.61 (0.30) mL on the left. Complications included some degree of bruising, erythema, and local swelling. Most patients (88%) had cosmetic improvement according to the independent evaluation. CONCLUSIONS: All patients were very satisfied with their results. During the course of the study, the authors determined that the ideal candidates for this treatment are young, with thick skin and a definite hollow. PMID- 21317121 TI - An in vivo comparison of barbed suture devices and conventional monofilament sutures for cosmetic skin closure: biomechanical wound strength and histology. AB - BACKGROUND: Very little biomechanical or histological data exist in the peer reviewed literature comparing absorbable monofilament sutures to commercially available knotless, absorbable barbed suture devices for cosmetic closure of skin incisions. OBJECTIVES: The authors compare two commercially-available knotless, barbed suture devices against a conventional monofilament suture in a porcine model for biomechanical wound strength and histological quality of healing. METHODS: This prospective randomized trial included 18 animals randomly assigned among three groups, with six in each. A total of 192 incisions were closed in a porcine in vivo model and assessed for biomechanical strength and histology at postoperative Days 0, 3, 10, and 21. Each animal received all three test devices in a randomized, three-way matched design. Immediately following euthanasia, the skin incisions were excised for ex vivo biomechanical testing. RESULTS: In the ex vivo analysis, Biosyn proved significantly stronger than the V-Loc 90 device at Day 0 and Quill Monoderm at Day 3. At no time point was there any difference in biomechanical strength between the two barbed suture devices. Differences in barb geometry, barb number, and helicity between the two barbed suture devices resulted in failure modes that were significantly different. All three test articles resulted in mild tissue reaction scores on histology. The V-Loc 90 device consistently had the lowest tissue reaction scores at all time periods, with the difference between the V-Loc 90 device and Quill being significant at postoperative Day 10. CONCLUSIONS: Knotless, absorbable barbed suture devices are a safe and efficacious alternative for cosmetic skin closures and yield wound strength and tissue reaction scores that are comparable to those from closures performed with absorbable monofilament sutures and secured with knots. PMID- 21317122 TI - The crooked nose: principles of treatment. AB - Correction of the crooked nose is one of the most challenging procedures in rhinoplasty. The goals of the surgery are creation of a rigid and straight cartilaginous L-strut, correction of the deviated bony structures, and improvement of the nasal airway. Curvatures of the dorsal septum can be corrected with several techniques. Spreader grafts, cartilage batten grafts, or ethmoid bone grafts can be utilized for internal stenting to straighten the dorsal deviations. The surgical treatment for a deformed caudal septum with the most predictable and successful outcome is resection and replacement with a straight septal cartilage graft. In severe deviations of septum cartilage involving both dorsal and caudal portions of the L-strut, extracorporeal reconstruction of the septal cartilage may be the required method. For correction of the deviated bony pyramid, several osteotomy methods can be employed. Medial osteotomy, low-to-low or low-to -high internal lateral osteotomy, double-level lateral osteotomies, and external lateral osteotomy are the options, depending on the deformity. Dorsal onlay grafts can provide camouflage for any residual asymmetries after septal reconstruction or can be applied for dorsal augmentation. PMID- 21317124 TI - Discussing the advantages of saline and silicone implants in clinical practice. PMID- 21317125 TI - Advanced neonatal nurse practitioners in the workforce: a review of the evidence to date. AB - The last decade has seen dramatic changes in the working arrangements and training requirements of junior medical staff employed in neonatal units. As a result, there is a need for the professional roles in service provision to be reappraised. In many neonatal services, advanced neonatal nurse practitioners (ANNPs) have been introduced and have been shown to be effective in providing an alternative option for the provision of neonatal care at both junior and middle grade medical staffing level. One of the key factors of the success of this role is the underpinning years spent in clinical practice, a foundation that provides a valuable and unique perspective for professional functioning at a senior level. For this potential to be fully exploited, a more integrated approach to the development of career pathways for ANNPs is needed. However, there are challenges related to recruitment, and the relatively small numbers of ANNPs available means that they are unlikely to provide an immediate solution for many units. The introduction of physicians' assistants (PAs) would seem to be worthy of consideration as part of the neonatal workforce, but it is likely that their functioning will be best integrated with that of ANNPs. In the longer term, economic factors will be a powerful determinant of the relative proportion of consultants, trainee doctors, ANNPs and PAs in the workforce. PMID- 21317126 TI - Question 1. Is cerebral function monitoring as accurate as conventional EEG in the detection of neonatal seizures? PMID- 21317128 TI - Question 2. Is Doppler ultrasound superior to upper gastrointestinal contrast study for the diagnosis of malrotation? PMID- 21317129 TI - Question 3. Topiramate for chronic migraine in children. PMID- 21317130 TI - A spider in the web: role of the palliative care nurse specialist in Uganda--an ethnographic field study. AB - BACKGROUND: Palliative care is not a priority in developing countries. Hospice Africa Uganda (HAU), where nurses complete a course in clinical palliative care, is considered a model for other African countries. AIM: To explore the role of the palliative care nurse specialist (PCNS) in Uganda. METHODS: This ethnographic field study uses observations, interviews, and group interviews. PARTICIPANTS: In total, 20 participants are included in this study. RESULT: The role of the palliative care nurse specialist is multifaceted. Beyond prescribing drugs, their role is to deliver holistic care. They encounter numerous challenges in their work, but they also have the possibility to improve the quality of the patient's life. PMID- 21317131 TI - When to say "yes" and when to say "no": boundary issues for hospice palliative care volunteers. AB - A total of 79 hospice palliative care volunteers from 2 community-based hospice programs responded to a 27-item Boundary Issues Questionnaire that was specifically developed for this study. Volunteers were asked to indicate whether or not they considered each item (eg, "Lend personal belongings to a patient or family," "Agree to be a patient's power of attorney," "Attend/go into a patient's medical appointment") to be something they should not do and to indicate whether or not they have ever done it. On the basis of the volunteers' responses, the authors distinguished between "definite boundary issues" (things volunteers should never do, for example, "Accept money from a patient or family"), "potential boundary issues" (things volunteers should stop and think twice about doing, for example, "Accept a gift from a patient or family"), and "questionable boundary issues" (things volunteers should be aware of doing, for example, "Give your home phone number to a patient or family"). The implications of these findings for training volunteers are discussed and the need for clear and unambiguous organizational policies and procedures to preserve boundaries is stressed. Without clear policies, etc, community-based hospice programs may be putting themselves at legal risk. PMID- 21317132 TI - Trends in hospice utilization across age among the veteran population. AB - Hospice is a major expansion area within the Veterans Health Administration (VHA). The objective of this retrospective study was to explore trends in hospice utilization among older veterans receiving services at the end of life over a 4 year (2006-2009) time period. Reviewing trends, the number of veterans receiving hospice services increased annually, with 5779 veterans receiving services during 2009, up from 1742 veterans in 2006. The total cost of providing hospice rose dramatically, increasing from $1.98 million in 2006 to $5.91 million in 2009. More funds were spent on younger veterans, with an average of $1.5 million spent on veterans aged 55 to 64 and less than $400,000 spent on veterans aged 85 and older. Findings highlight the growing need and demand for hospice within the VHA to provide end-of-life services. PMID- 21317133 TI - The effect of applying NICE guidelines for the investigation of stable chest pain on out-patient cardiac services in the UK. AB - BACKGROUND: The National Institute for Health and Clinical Excellence (NICE) recently released guidelines for the investigation of chest pain of recent onset. There is no published data regarding their impact on out-patient cardiac services. AIM: This study was undertaken to assess the likelihood of coronary artery disease (CAD) in Rapid Access Chest Pain Clinic (RACPC) patients and the resultant investigation burden if NICE guidance was applied. METHODS: Five hundred and ninety-five consecutive patients attending two RACPCs over 6 months preceding release of the NICE guidelines [51% male; median age 55 (range 22-94) years] were risk stratified using NICE criteria and the resultant investigations evaluated. RESULTS: One hundred and six (18%) patients had a likelihood of CAD <10%, 123 (21%) between 10% and 29%, 175 (29%) between 30% and 60%, 141 (24%) between 61% and 90% and 50 (8%) >90%. NICE would have recommended 443 (74%) patients for no cardiac investigation, 10 (2%) for cardiac computed tomography (CCT), 69 (12%) for functional cardiac testing and 73 (12%) for invasive angiography. Relative to existing practice, there would have been a trend towards reduced functional cardiac testing (-24%, P = 0.06), no significant change in CCT (43%, P = 0.436) and a significant increase in invasive angiography (508%, P < 0.001). The cost of investigations recommended by NICE would have been L15,881 greater than existing practice. CONCLUSION: This study suggests patients attending RACPC will have a greater likelihood of CAD than predicted by NICE. Differences between recommended investigations and existing practice will guide investment in cardiac services. Individual hospitals should assess their RACPC cohorts prior to implementing the NICE guidelines. PMID- 21317134 TI - Surfer's myelopathy. PMID- 21317136 TI - Comments on 'Bayesian variable selection for disease classification using gene expression data'. PMID- 21317135 TI - Ultrasound discloses entheseal involvement in inactive and low active inflammatory bowel disease without clinical signs and symptoms of spondyloarthropathy. AB - OBJECTIVE: To investigate the presence of lower limb entheseal abnormalities in IBD patients without clinical signs and symptoms of SpA and their correlation with IBD clinical variables. METHODS: A total of 81 IBD patients [55 Crohn's disease (CD) and 26 ulcerative colitis (UC), 43 females and 38 males, mean age 41.3 (12.4) years, BMI 24 (2)] with low active (12) and inactive (67) disease were consecutively studied with US (LOGIQ5 General Electric 10-MHz linear array transducer) of lower limb entheses and compared with 40 healthy controls matched for sex, age and BMI. Quadriceps, patellar, Achilleon and plantar fascia entheses were scored according to the 0-36 Glasgow Ultrasound Enthesitis Scoring System (GUESS) and power Doppler (PD). Correlations of GUESS and PD with IBD features [duration, type (CD/UC) and activity (disease activity index for CD/Truelove score for UC)] were investigated. The intra- and inter-reader agreements for US were estimated in all images detected in patients and controls. RESULTS: Of the 81 patients, 71 (92.6%) presented almost one tendon alteration with mean GUESS 5.1 (3.5): 81.5% thickness (higher than controls P < 0.05), 67.9% enthesophytosis, 27.1% bursitis and 16.1% erosions. PD was positive in 13/81 (16%) patients. In controls, US showed only enthesophytes (5%) and no PD. GUESS and PD were independent of duration, activity or type (CD/UC) of IBD. The intra- and inter-reader agreements were high (>0.9 intra-class correlation variability). CONCLUSIONS: US entheseal abnormalities are present in IBD patients without clinical signs and symptoms of SpA. US enthesopathy is independent of activity, duration and type of gut disease. PMID- 21317137 TI - Bases adjacent to mononucleotide repeats show an increased single nucleotide polymorphism frequency in the human genome. AB - Mononucleotide repeats (MNRs) are abundant in eukaryotic genomes and exhibit a high degree of length variability due to insertion and deletion events. However, the relationship between these repeats and mutation rates in surrounding sequences has not been systematically investigated. We have analyzed the frequency of single nucleotide polymorphisms (SNPs) at positions close to and within MNRs in the human genome. Overall, we find a 2- to 4-fold increase in the SNP frequency at positions immediately adjacent to the boundaries of MNRs, relative to that at more distant bases. This relationship exhibits a strong asymmetry between 3' and 5' ends of repeat tracts and is dependent upon the repeat motif, length and orientation of surrounding repeats. Our analysis suggests that the incorporation or exclusion of bases adjacent to the boundary of the repeat through substitutions, in which these nucleotides mutate towards or away from the base present within the repeat, respectively, may be another mechanism by which MNRs expand and contract in the human genome. PMID- 21317138 TI - Automated analysis of biological oscillator models using mode decomposition. AB - MOTIVATION: Oscillating signals produced by biological systems have shapes, described by their Fourier spectra, that can potentially reveal the mechanisms that generate them. Extracting this information from measured signals is interesting for the validation of theoretical models, discovery and classification of interaction types, and for optimal experiment design. RESULTS: An automated workflow is described for the analysis of oscillating signals. A software package is developed to match signal shapes to hundreds of a priori viable model structures defined by a class of first-order differential equations. The package computes parameter values for each model by exploiting the mode decomposition of oscillating signals and formulating the matching problem in terms of systems of simultaneous polynomial equations. On the basis of the computed parameter values, the software returns a list of models consistent with the data. In validation tests with synthetic datasets, it not only shortlists those model structures used to generate the data but also shows that excellent fits can sometimes be achieved with alternative equations. The listing of all consistent equations is indicative of how further invalidation might be achieved with additional information. When applied to data from a microarray experiment on mice, the procedure finds several candidate model structures to describe interactions related to the circadian rhythm. This shows that experimental data on oscillators is indeed rich in information about gene regulation mechanisms. AVAILABILITY: The software package is available at http://babylone.ulb.ac.be/autoosc/. PMID- 21317139 TI - eGOB: eukaryotic Gene Order Browser. AB - A large number of genomes have been sequenced, allowing a range of comparative studies. Here, we present the eukaryotic Gene Order Browser with information on the order of protein and non-coding RNA (ncRNA) genes of 74 different eukaryotic species. The browser is able to display a gene of interest together with its genomic context in all species where that gene is present. Thereby, questions related to the evolution of gene organization and non-random gene order may be examined. The browser also provides access to data collected on pairs of adjacent genes that are evolutionarily conserved. AVAILABILITY: eGOB as well as underlying data are freely available at http://egob.biomedicine.gu.se SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. CONTACT: tore.samuelsson@medkem.gu.se. PMID- 21317140 TI - SiGN-SSM: open source parallel software for estimating gene networks with state space models. AB - SiGN-SSM is an open-source gene network estimation software able to run in parallel on PCs and massively parallel supercomputers. The software estimates a state space model (SSM), that is a statistical dynamic model suitable for analyzing short time and/or replicated time series gene expression profiles. SiGN SSM implements a novel parameter constraint effective to stabilize the estimated models. Also, by using a supercomputer, it is able to determine the gene network structure by a statistical permutation test in a practical time. SiGN-SSM is applicable not only to analyzing temporal regulatory dependencies between genes, but also to extracting the differentially regulated genes from time series expression profiles. AVAILABILITY: SiGN-SSM is distributed under GNU Affero General Public Licence (GNU AGPL) version 3 and can be downloaded at http://sign.hgc.jp/signssm/. The pre-compiled binaries for some architectures are available in addition to the source code. The pre-installed binaries are also available on the Human Genome Center supercomputer system. The online manual and the supplementary information of SiGN-SSM is available on our web site. CONTACT: tamada@ims.u-tokyo.ac.jp. PMID- 21317141 TI - Network clustering: probing biological heterogeneity by sparse graphical models. AB - MOTIVATION: Networks and pathways are important in describing the collective biological function of molecular players such as genes or proteins. In many areas of biology, for example in cancer studies, available data may harbour undiscovered subtypes which differ in terms of network phenotype. That is, samples may be heterogeneous with respect to underlying molecular networks. This motivates a need for unsupervised methods capable of discovering such subtypes and elucidating the corresponding network structures. RESULTS: We exploit recent results in sparse graphical model learning to put forward a 'network clustering' approach in which data are partitioned into subsets that show evidence of underlying, subset-level network structure. This allows us to simultaneously learn subset-specific networks and corresponding subset membership under challenging small-sample conditions. We illustrate this approach on synthetic and proteomic data. AVAILABILITY: go.warwick.ac.uk/sachmukherjee/networkclustering. PMID- 21317142 TI - Topological entropy of DNA sequences. AB - MOTIVATION: Topological entropy has been one of the most difficult to implement of all the entropy-theoretic notions. This is primarily due to finite sample effects and high-dimensionality problems. In particular, topological entropy has been implemented in previous literature to conclude that entropy of exons is higher than of introns, thus implying that exons are more 'random' than introns. RESULTS: We define a new approximation to topological entropy free from the aforementioned difficulties. We compute its expected value and apply this definition to the intron and exon regions of the human genome to observe that as expected, the entropy of introns are significantly higher than that of exons. We also find that introns are less random than expected: their entropy is lower than the computed expected value. We also observe the perplexing phenomena that introns on chromosome Y have atypically low and bimodal entropy, possibly corresponding to random sequences (high entropy) and sequences that posses hidden structure or function (low entropy). AVAILABILITY: A Mathematica implementation is available at http://www.math.psu.edu/koslicki/entropy.nb CONTACT: koslicki@math.psu.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21317143 TI - Cross-platform comparison of microarray data using order restricted inference. AB - MOTIVATION: Titration experiments measuring the gene expression from two different tissues, along with total RNA mixtures of the pure samples, are frequently used for quality evaluation of microarray technologies. Such a design implies that the true mRNA expression of each gene, is either constant or follows a monotonic trend between the mixtures, applying itself to the use of order restricted inference procedures. Exploiting only the postulated monotonicity of titration designs, we propose three statistical analysis methods for the validation of high-throughput genetic data and corresponding preprocessing techniques. RESULTS: Our methods allow for inference of accuracy, repeatability and cross-platform agreement, with minimal required assumptions regarding the underlying data generating process. Therefore, they are readily applicable to all sorts of genetic high-throughput data independent of the degree of preprocessing. An application to the EMERALD dataset was used to demonstrate how our methods provide a rich spectrum of easily interpretable quality metrics and allow the comparison of different microarray technologies and normalization methods. The results are on par with previous work, but provide additional new insights that cast doubt on the utility of popular preprocessing techniques, specifically concerning the EMERALD projects dataset. AVAILABILITY: All datasets are available on EBI's ArrayExpress web site http://www.ebi.ac.uk/microarray-as/ae/) under accession numbers E-TABM-536, E-TABM-554 and E-TABM-555. Source code implemented in C and R is available at: http://statistics.msi.meduniwien.ac.at/float/cross_platform/. Methods for testing and variance decomposition have been made available in the R-package orQA, which can be downloaded and installed from CRAN http://cran.r-project.org. PMID- 21317144 TI - Equipment performance and radiation protection status in X-ray fluoroscopy units in Sudan. AB - The number of fluoroscopy and fluoroscopically guided procedures has been substantially growing in developing countries at the same time advanced and sophisticated equipment are used in some hospitals. However, radiation protection requirements are not necessarily well adopted. In this study nine fluoroscopy X ray units in Sudan were examined for compliance with international standards. The tests included: beam quality, entrance surface air kerma, image quality and radiation field measurements. Staff radiation protection tools such as lead aprons and eye glasses were also visually examined to find out whether international recommendations were fulfilled and to determine the level of staff awareness. The measured peak tube voltage deviation exceeded the recommended tolerance level in 30 % of the measurements. The results of patient doses measurements exceeded the recommended reference dose levels in 43 % of the measurements; however image quality and radiation field generally fulfilled the requirements for most units. The study revealed that a considerable number of fluoroscopy units were not performing according to the international standards and highlights the need of optimisation of radiation protection. PMID- 21317145 TI - Induced radioactive nuclides of 10-MeV radiotherapy accelerators detected by using a portable HP-Ge survey meter. AB - The radioactivation of linear accelerator components for radiation therapy is interest for radiation protection in general, and particularly, when decommissioning these structures. The energy spectra of gamma rays emitted from the heads of two accelerator models, EXL-15SP and Clinac iX, after 10-MeV X-ray irradiation, were measured using a high-purity germanium semiconductor survey meter. After spectrum analyses, activities of (24)Na, (28)Al, (54)Mn, (56)Mn, (57)Ni, (58)Co, (60)Co, (64)Cu, (65)Zn, (122)Sb, (124)Sb, (181)W, (187)W, (196)Au, and (198)Au were detected. One centimetre deep dose-equivalent rate of the heads of the linear accelerator was measured using the survey meter. The dose rate decreased to ~10 % of its initial rate after 1 week. Long-term activations were few, the radioactivity level was low, and a cooling time of several days was effective for reducing dose rate to an acceptable level for decommissioning. PMID- 21317146 TI - Evolution of polyploid triticum wheats under cultivation: the role of domestication, natural hybridization and allopolyploid speciation in their diversification. AB - The evolution of the polyploid Triticum wheats is distinctive in that domestication, natural hybridization and allopolyploid speciation have all had significant impacts on their diversification. In this review, I outline the phylogenetic relationships of cultivated wheats and their wild relatives and provide an overview of the recent progress and remaining issues in understanding the genetic and ecological factors that favored their evolution. An attempt is made to view the evolution of the polyploid Triticum wheats as a continuous process of diversification that was initiated by domestication of tetraploid emmer wheat and driven by various natural events ranging from interploidy introgression via hybridization to allopolyploid speciation of hexaploid common wheat, instead of viewing it as a group of discrete evolutionary processes that separately proceeded at the tetraploid and hexaploid levels. This standpoint underscores the important role of natural hybridization in the reticulate diversification of the tetraploid-hexaploid Triticum wheat complex and highlights critical, but underappreciated, issues that concern the allopolyploid speciation of common wheat. PMID- 21317147 TI - Are we using cardiovascular medications and coronary angiography appropriately in men and women with chest pain? AB - AIMS: The main purpose of the present study was to analyse the contemporary use of cardiovascular medications and diagnostic coronary angiography in men and women with suspected coronary artery disease (CAD). Furthermore, we examined the association of outcomes (death, myocardial infarction, repeat coronary angiography, procedural complications) with angiographic findings. METHODS: All patients with stable chest pain (n = 12 200) referred for a first-time elective diagnostic coronary angiography during 2006-08 and registered in the Swedish Coronary Angiography and Angioplasty Register (SCAAR) were included. Significant CAD was defined as >= 50% luminal narrowing in any epicardial coronary artery. RESULTS: In the youngest age group (<= 59 years), more women than men (78.8 vs. 42.3%, P< 0.001) had normal/non-significant CAD, whereas more men had either left main or three-vessel disease (18.2 vs. 4.2%, P < 0.001). Event rates were similarly low for men and women with normal/non-significant CAD, except for a higher procedural complication rate in women. Prior to angiography, fewer women than men with high-risk features were prescribed aspirin (83 vs. 86.1%, P = 0.001). CONCLUSION: In women, normal/non-significant CAD was highly prevalent, especially among younger women, and associated cardiovascular event rates were low. In men, findings of advanced disease were more common than in women, even younger men. Fewer high-risk women than men were initially prescribed aspirin. The observed sex differences suggest a need for improved identification of women appropriate for investigation with coronary angiography, earlier diagnostics in men, and heightened attention in the evidence-based use of aspirin in risk patients, especially women. PMID- 21317148 TI - Effect of the direct renin inhibitor aliskiren on left ventricular remodelling following myocardial infarction with systolic dysfunction. AB - AIMS: Direct renin inhibitors provide an alternative approach to inhibiting the renin-angiotensin-aldosterone system (RAAS) at the most proximal, specific, and rate-limiting step. We tested the hypothesis that direct renin inhibition would attenuate left ventricular remodelling in patients following acute myocardial infarction receiving stable, individually optimized therapy, including another inhibitor of the RAAS. METHODS AND RESULTS: We randomly assigned 820 patients between ~2 and 8 weeks following acute myocardial infarction, with the left ventricular ejection fraction (LVEF) <=45%, and regional wall motion abnormalities (>=20% akinetic area), to receive aliskiren (n = 423), titrated to 300 mg, or matched placebo (n = 397), added to the standard therapy. All patients were required to be on a stable dose of an ACE-inhibitor or ARB, and beta-blocker unless contraindicated or not tolerated. Echocardiograms were obtained at baseline, and following 26-36 weeks of treatment. The primary endpoint was change in left ventricular end-systolic volume from baseline to 36 weeks, and was evaluable in 329 patients in the placebo group and 343 patients in the aliskiren group. We observed no difference in the primary endpoint of end-systolic volume change between patients randomized to aliskiren (-4.4 +/- 16.8 mL) or placebo ( 3.5 +/- 16.3 mL), or in secondary measures of end-diastolic volume, or LVEF. We also observed no differences in a composite endpoint of cardiovascular death, hospitalization for heart failure, or reduction in LVEF >6 points. There were more investigator reported adverse events in the aliskiren group, including hypotension, increases in creatinine and hyperkalaemia. CONCLUSION: Adding the direct renin inhibitor aliskiren to the standard therapy, including an inhibitor of the RAAS, in high-risk post-MI patients did not result in further attenuation of left ventricular remodelling, and was associated with more adverse effects. These findings do not suggest that dual RAAS blockade with aliskiren would provide additional benefit in these high-risk post-MI patients. PMID- 21317149 TI - Volume reduction rate by surgical ventricular restoration determines late outcome in ischaemic cardiomyopathy. AB - AIMS: Surgical ventricular restoration (SVR) effectively reduces left ventricular (LV) volume in ischaemic cardiomyopathy (ICM), but the recent Surgical Treatment of Ischemic Heart Failure (STICH) Trial questions its importance. We report 8 year SVR experience in patients with ICM. METHODS AND RESULTS: Between 2000 and 2008, 135 patients underwent SVR for ICM. This report analyses data from 90 patients who underwent accurate pre- and post-operative assessment of LV volumes by left ventriculogram or scintigram. All patients also had echocardiograms. Pre operative LV end-systolic volume index (ESVI) was 123.5 +/- 53.2 mL/m(2) (range 92-310). Overall, 63 patients were in NHYA class III and 27 were in class IV. The SVR procedure was endoventricular circular patch plasty in 33 patients, septal anterior ventricular exclusion in 43, and 14 patients had posterior exclusion. Coronary artery bypass grafting was performed in 78 patients (87%) and 50 underwent mitral procedures. Eighteen follow-up late deaths occurred owing to chronic heart failure (n = 12) and sudden death (n = 6). Post-operative ESVI was < 90 mL/m(2) (Group-S) in 54 patients, 90-120 mL/m(2) (Group-M) in 16, and >120 mL/m(2) (Group-L) in 20 patients. The 8-year survival rate was 82.4% in group-S following a > 33% LV volume reduction. In contrast, in Group-M and Group-L, the volume reduction was ~ 15%, and 100% of patients died within 7 years following the SVR procedure (or 0% 8-year survival). CONCLUSIONS: SVR is most effective when a >33% volume reduction rate achieves an ESVI of < 90 mL/m(2). No long-term benefits occur when SVR induces an LV volume reduction of < 15% leaving a residual ESVI >90 mL/m(2). This database contradicts the STICH trial findings. PMID- 21317150 TI - A prospective study of the standardized diagnostic evaluation of syncope. AB - AIMS: To evaluate the aetiology and the diagnostic yield of the standardized diagnostic work-up based on European Society of Cardiology guidelines in the syncope unit. METHODS AND RESULTS: A total of 501 patients (191 men and 310 women), mean age 65 years (44-75 years), were prospectively evaluated. They underwent initial evaluation (history, physical evaluation, and a 12-lead electrocardiogram) and subsequently targeted tests that differed according to suspected aetiology. Initial evaluation resulted in diagnosis in 155 patients- reflex syncope (93), arrhythmogenic syncope (62), and pacemaker malfunction (7). In 22 patients with solitary syncope, a diagnostic algorithm was stopped after initial evaluation. In 139 patients with organic heart disease, cardiac syncope was found in 83 patients and reflex syncope in 30 patients. In 185 patients without organic heart disease, reflex syncope was diagnosed in 127 patients, cardiac syncope in 30 patients, and vascular syncope in 2 patients. Vasovagal syncope was the most common type of syncope (43%), followed by bradyarrhythmias (25%), tachyarrhythmias (9%), and orthostatic hypotension (5%). Aetiology of syncope remained unknown in 11% of patients. Diagnostic yield of specific examinations was as follows: head-up tilt 52%, implantable loop recorder 51%, electrophysiologic study 33%, initial evaluation 31%, EKG Holter 12%, orthostatic test 10%, transoesophageal stimulation 9%, carotid sinus massage 4%, and echocardiography 2%. CONCLUSION: Standardized diagnostic evaluation determined the aetiology of syncope in 89% of patients. Diagnostic yield of specific diagnostic procedures was different. Initial evaluation resulted in diagnosis in one-third of patients. PMID- 21317151 TI - Constitutional change of Italian legislation on assisted reproduction technology improves pregnancy rate especially in older patients. PMID- 21317152 TI - Patient-centred infertility care: a qualitative study to listen to the patient's voice. AB - BACKGROUND High-quality care for patients faced with infertility should be patient-centred. Few studies have provided in-depth insights into the patient's perspective on care and, to the best of our knowledge, no study has provided a model of the complex concept 'patient-centred infertility care'. Therefore, a qualitative study aimed at understanding 'patient-centred infertility care' from the patient's perspective was conducted. METHODS Fourteen focus group discussions were organized with patients (n = 103) from two European countries to find out about patients' positive and negative experiences with infertility care. Content analysis of the transcripts and analysis of patients' priority lists were conducted. RESULTS The patient-centredness of infertility care depends on 10 detailed dimensions, which can be divided into system and human factors, and there is a two-way interaction between both kinds of factors. System factors, in order of patient's priority, are: provision of information, competence of clinic and staff, coordination and integration, accessibility, continuity and transition and physical comfort. Human factors, in order of patient's priority, are: attitude of and relationship with staff, communication, patient involvement and privacy and emotional support. CONCLUSIONS This study provides a detailed patient's description of the concept 'patient-centred infertility care' and an interaction model that aids understanding of the concept. Fertility clinics are encouraged to improve the patient-centredness of their care by taking into account the detailed description of the dimensions of patient-centred infertility care, and by paying attention to both system and human factors and their interaction when setting up 'patient-centred improvement projects'. PMID- 21317153 TI - Supportive care for women with unexplained recurrent miscarriage: patients' perspectives. AB - BACKGROUND Supportive care is currently the only 'therapy' that can be offered to women with unexplained recurrent miscarriage (RM). What these women themselves prefer as supportive care in their next pregnancy has never been substantiated. Therefore the aim of this study was to explore what women with unexplained RM prefer as supportive care during their next pregnancy. METHODS We performed explorative, semi-structured, in-depth interviews. The interviews were performed with 15 women with unexplained RM who were actively seeking conception. All interviews were conducted by telephone. The interviews were fully transcribed and two researchers independently identified text segments from the transcribed interviews and categorized them in the appropriate domain. RESULTS Women identified 20 different supportive care options; 16 of these options were preferred for their next pregnancy. Examples of the preferred supportive care were early and frequently repeated ultrasounds, betaHCG monitoring, practical advice concerning life style and diet, emotional support in the form of counselling, a clear policy for the upcoming 12 weeks and medication. The four supportive care options that were not preferred by the women were admittance to a hospital ward at the same gestational age as previous miscarriages, Complementary Alternative Medicine, ultrasound every other day and receiving supportive care from their general practitioner. CONCLUSIONS Our study identified several relevant preferences for supportive care in women with unexplained RM. Many of these can be offered by the gynaecologist and will help in guaranteeing high quality patient-centred care. PMID- 21317154 TI - Extra-anatomic lateral bypass combined with embolization of the femoral stump for management of groin infection and bleeding due to metastatic carcinoma of the penis. AB - We report a possible treatment strategy for a patient with squamous cell carcinoma of the penis in hemorrhagic shock, due to erosion of the right femoral artery by metastatic inguinal lymph nodes. Because of coexistent groin infection and the inability to perform radical excision, the patient was treated with a lateral extra-anatomic iliac femoral prosthetic bypass; to prevent further bleeding, the femoral stump was embolized percutaneously. The patient was discharged home and did not experience any vascular complications during the follow-up, until death due to pulmonary metastasis. PMID- 21317155 TI - Partial resection of the aorta and patch plasty with a simple clamping technique in a lung cancer patient. AB - A 59-year-old male patient was diagnosed as having lung cancer with a suspected invasion of the descending aorta. A significant response was not obtained after chemotherapy. A left pneumonectomy with partial resection of the aortic wall with simple clamping was done. The postoperative course was uneventful. PMID- 21317156 TI - Risk factors for morbidity after pulmonary resection for lung cancer in younger and elderly patients. AB - The aim of this study was to evaluate the perioperative morbidity, mortality, and risk factors for morbidity after lung cancer resection in younger and elderly patients. This study retrospectively reviewed 1073 patients with non-small cell lung cancers (NSCLC) who underwent pulmonary resection. The risk factors for morbidity were analyzed independently in groups of 664 younger (<70 years) patients and 409 elderly (>= 70 years) patients. Co-morbidities, such as hypertension, ischemic heart disease, and renal insufficiency were more frequently observed in the elderly group in comparison to the younger group. However, there were no statistical differences in the rates of overall morbidity and 30-day mortality between the younger and elderly groups (36% vs. 42% and 0.3% vs. 0.5%, respectively). Multivariate analyses revealed the risk factors for morbidity to be % forced expiratory volume in 1 s (FEV(1)), the extent of pulmonary resection and tumor histology in the younger group, and smoking, hypertension, renal insufficiency and % diffusing capacity of the lung to carbon monoxide (DLCO) in the elderly group, respectively. In conclusion, the rate of morbidity and mortality in elderly patients were similar to those observed in younger patients. However, perioperative management should be cautiously performed while taking into account the risk factors for morbidity especially in elderly patients because they frequently have various co-morbidities. PMID- 21317157 TI - Lack of global dosage compensation in Schistosoma mansoni, a female-heterogametic parasite. AB - Many species have morphologically and genetically differentiated sex chromosomes, such as the XY pair of mammals. Y chromosomes are often highly degenerated and carry few functional genes, so that XY males have only one copy of most X-linked genes (whereas females have two). As a result, chromosome-wide mechanisms of dosage compensation, such as the mammalian X-inactivation, often evolve to reestablish expression balance. A similar phenomenon is expected in female heterogametic species, where ZW females should suffer from imbalances due to W chromosome degeneration. However, no global dosage compensation mechanisms have been detected in the two independent ZW systems that have been studied systematically (birds and silkworm), leading to the suggestion that lack of global dosage compensation may be a general feature of female-heterogametic species. However, analyses of other independently evolved ZW systems are required to test if this is the case. In this study, we use published genomic and expression data to test for the presence of global dosage compensation in Schistosoma mansoni, a trematode parasite that causes schistosomiasis in humans. We find that Z-linked expression is reduced relative to autosomal expression in females but not males, consistent with incomplete or localized dosage compensation. This gives further support to the theory that female-heterogametic species may not require global mechanisms of dosage compensation. PMID- 21317160 TI - Apoptotic gene expression in potentially fertile and subfertile men. AB - Human sperm contain similar amounts of protamine-1 (P1) and protamine-2 (P2). Although an aberrant protamine ratio have been observed in subfertile men, functional evidence is provided by protamine knockout mice exhibiting male infertility. As sperm DNA integrity is known to be linked with DNA fragmentation and apoptosis, we investigated whether the DNA fragmentation factor 40 (DFF40) ratio or caspase (Casp4, Casp6) and tumor necrosis factor superfamily member 10 (TNFSF10) ratio together with the P1/P2 ratio represents a reliable biomarker to discriminate between fertile and subfertile men. Real-time quantitative RT-PCR was used for amplification of P1, P2 and DFF40 in 49 testicular biopsies. Casp4, Casp6 and TNFSF10 have been selected from a PCR apoptosis array and were further investigated in another group of testicular biopsies (22 subfertile men versus 11 potentially fertile men). Using Spearman's rank correlation coefficient analysis, we did not find a correlation between DFF40 and P1, P2, P1/P2, score, fertilization rate and age. In addition, logistic regression analysis demonstrated no statistically significant effect of the analyzed variables on pregnancy. A two-way analysis of variance with repeated measures of relative expression of Casp4, Casp6 and TNFSF10 versus P1 or P2 in potentially fertile men and subfertile patients demonstrated statistically significant differences between both groups, all tested gene combinations and the interaction between two genes and both groups in all cases analyzed. Furthermore, significant differences in the expression of Casp4 and TNFSF10 between the groups of potentially fertile and subfertile men could be demonstrated. In addition, the means of differences of selected gene combinations revealed that the protamine to apoptotic gene ratio is statistically different between both groups. Our data suggest that Casp4, Casp 6 and TNFSF10 are differentially expressed in potentially fertile and subfertile men and represent useful biomarkers for predicting male fertility in combination with P1 and P2. PMID- 21317158 TI - Absence of disturbed axonal transport in spinal and bulbar muscular atrophy. AB - Spinal and bulbar muscular atrophy (SBMA), or Kennedy's disease, is a late-onset motor neuron disease (MND) caused by an abnormal expansion of the CAG repeat in the androgen receptor (AR) gene on the X-chromosome, encoding a polyglutamine (poly-Q) sequence in the protein product. Mutant poly-Q-expanded AR protein is widely expressed but leads to selective lower motoneuron death. Although the mechanisms that underlie SBMA remain unclear, defective axonal transport has been implicated in MND and other forms of poly-Q disease. Transcriptional dysregulation may also be involved in poly-Q repeat pathology. We therefore examined axonal transport in a mouse model of SBMA recapitulating many aspects of the human disease. We found no difference in the expression levels of motor and the microtubule-associated protein tau, in the spinal cord and sciatic nerve of wild-type (WT) and SBMA mice at various stages of disease progression. Furthermore, we found no alteration in binding properties of motor proteins and tau to microtubules. Moreover, analysis of axonal transport rates both in cultured primary motoneurons in vitro and in vivo in the sciatic nerve of adult WT and mutant SBMA mice demonstrated no overt axonal transport deficits in these systems. Our results therefore indicate that unlike other motoneuron and poly-Q diseases, axonal transport deficits do not play a significant role in the pathogenesis of SBMA. PMID- 21317159 TI - Zebrafish Fukutin family proteins link the unfolded protein response with dystroglycanopathies. AB - Allelic mutations in putative glycosyltransferase genes, fukutin and fukutin related protein (fkrp), lead to a wide range of muscular dystrophies associated with hypoglycosylation of alpha-dystroglycan, commonly referred to as dystroglycanopathies. Defective glycosylation affecting dystroglycan-ligand interactions is considered to underlie the disease pathogenesis. We have modelled dystroglycanopathies in zebrafish using a novel loss-of-function dystroglycan allele and by inhibition of Fukutin family protein activities. We show that muscle pathology in embryos lacking Fukutin or FKRP is different from loss of dystroglycan. In addition to hypoglycosylated alpha-dystroglycan, knockdown of Fukutin or FKRP leads to a notochord defect and a perturbation of laminin expression before muscle degeneration. These are a consequence of endoplasmic reticulum stress and activation of the unfolded protein response (UPR), preceding loss of dystroglycan-ligand interactions. Together, our results suggest that Fukutin family proteins may play important roles in protein secretion and that the UPR may contribute to the phenotypic spectrum of some dystroglycanopathies in humans. PMID- 21317161 TI - Comparison of the Effectiveness of Low-Dose Indinavir/Ritonavir (IDV/r)- versus Atazanavir/Ritonavir (ATV/r)-Based Generic Antiretroviral Therapy in NNRTI Experienced HIV-1-Infected Patients in India. AB - BACKGROUND: Currently, data on the effectiveness of second-line antiretroviral regimens using indinavir/ritonavir (IDV/r) and atazanavir/ritonavir (ATV/r) along with 2 nucleoside reverse transcriptase inhibitor (NRTI) in resource-poor settings is limited. METHODS: Observational follow-up study on 441 patients who experienced treatment failure to first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)-based treatment. Multivariate Cox Proportional Hazards Model was used to assess comparative effectiveness of treatment regimens. RESULTS: A total of 63 patients (14.8%) had failed second line treatments, of which 53 patients (17.2%) were using IDV/r while 10 patients (8.5%) were on ATV/r. After adjusting for age, weight, gender, and baseline CD4 count, patients who took IDV/r were more than twice as likely to experience treatment failure as compared to those who were on ATV/r (hazard ratio [HR] 2.18; 95% confidence interval [CI] 1.14, 4.15). Successful response to second-line therapy was not different between the 2 treatment groups when patients weighed less than 55 kg at baseline (log rank P value = 1.00) in contrast to the individuals weighing >=55 kg (P < .0001). CONCLUSION: We found that successful response to second-line therapy was twice as likely in the ATV/r group; however, this difference was eliminated in patients less than 55 kg. PMID- 21317162 TI - Barriers to antiretroviral treatment in ethiopia: a qualitative study. AB - OBJECTIVE: Ethiopia has made meaningful headway in improving access to HIV care and treatment but client attrition remains a daunting challenge. The objective of this study was to describe the major reasons of patient attrition from treatment at hospital and health center levels in Oromia region of Ethiopia. METHODS: This qualitatively designed study was based on semistructured interview with antiretroviral therapy (ART) service providers and focus group discussions with ART clients. The participants were recruited purposively to obtain robust and programmatically important information on in retention HIV care and treatment. FINDINGS: The analysis identified four major themes: antiretroviral (ARV) medications as ''long-term life support,'' free ART as ''expensive,'' regular follow up as ''devotion to a life-long crisis management,'' and expansion of free ART as ''sharing the new hope,'' CONCLUSION: The finding clearly illustrated that while financial constraints and some sociocultural factors impede adherence, disclosure, community support, and decentralization of ART to primary health care units enhance retention in care and treatment. PMID- 21317163 TI - Efficacy of Interventions for Improving Antiretroviral Therapy Adherence in HIV/AIDS Cases at PIMS, Islamabad. AB - It is imperative to prove efficacy of tailored interventions and translate the efficacious ones into clinical strategies for achieving good ART adherence. ART adherence among registered HIV/AIDS cases at HIV treatment centre, Pakistan Institute of Medical Sciences, Islamabad was assessed through RCT. Study duration was 10 weeks; eligible subjects (N = 76) were randomly halved; Intervention Group (IG) received trial interventions i.e. subject involvement, weekly phone reminders in addition to routine counselling, while Comparison group received routine counselling only. Self-reported adherence (SRA) questionnaire and pill identification test (PIT) conducted at both baseline and follow-up in addition to CD4 count and viral load. ITT using ANOVA; McNemar's test for variables with before-after assessments within a group. Results showed significant differences in >=95% SRA, >=95% Adherence on PIT, Viral load test of <50 copies per cubic mm. These interventions should be included in the overall treatment strategy for HIV/AIDS in Pakistan. PMID- 21317164 TI - Cryptococcal Meningitis in an HIV-Positive Pregnant Woman. AB - Cryptococcal meningitis is uncommon in pregnant HIV-infected women. The clinical care of an HIV-1 positive pregnant woman with cryptococcal meningitis whose pathology has been previously reported is reviewed to highlight the treatment of the disease and some of the challenges associated with antifungal therapy during pregnancy, including the teratogenicity of antifungal agents, their variable pharmacokinetics in pregnancy, the lack of well-defined treatment duration for such infections, and host factors including compliance. This patient's disease relapsed due to nonadherence after an initial course of intravenous amphotericin. Subsequently, she was successfully treated, with a favorable fetal outcome, with another 2 weeks of amphotericin B, followed by consolidation and maintenance with fluconazole and antiretroviral treatment. This case highlights and reviews the complexities of the management of cryptococcal meningitis in HIV-infected pregnant women. PMID- 21317166 TI - Pharmacological dose of {alpha}-tocopherol induces cardiotoxicity in Wistar rats determined by echocardiography and histology. AB - The effect of pharmacological dose of alpha-tocopherol on heart health was determined in Wistar rats. Animals were randomly assigned to either C (control, n = 11) or E (alpha-tocopherol, n = 11) group. Animals received corn oil (C) or alpha-tocopherol dissolved in corn oil (250 mg alpha-tocopherol/[kg body wt/day]) (E) by gavage for a 7-week period. Rats underwent echocardiogram and were analyzed for cardiomyocyte histology and cardiac alpha-tocopherol absorption at the end of the study period. As compared to the C group, alpha-tocopherol supplemented group showed significantly (p < 0.05) lower body weight (E, 412.8 g vs C, 480.3 g) and total cardiac weight (E, 0.94 g vs C, 1.08 g); cardiomyocyte histological impairment; smaller left ventricle (LV) (LV end-diastolic diameter (E, 7.22 mm vs C, 7.37 mm), lower LV systolic [left ventricle fractional shortening (E, 47.6% vs C, 53.6%) and ejection fraction ratio (E, 85.4 vs C, 89.9)] and diastolic [early peak velocities of diastolic transmitral flow (E, 64.6 cm/sec vs C, 75.1 cm/sec)] function. The alpha-tocopherol uptake in target tissue was confirmed by determination of alpha-tocopherol concentration medians in cardiac tissue (E, 109.91 nmol/kg vs C, 52.09 nmol/kg). The current study indicates that pharmacological dose of alpha-tocopherol supplementation can induce cardiotoxicity in healthy rats. PMID- 21317165 TI - A double-blind, randomized, multicenter study of MP4OX for treatment of perioperative hypotension in patients undergoing primary hip arthroplasty under spinal anesthesia. AB - BACKGROUND: MP4OX (oxygenated polyethylene glycol-modified hemoglobin) is a novel oxygen therapeutic agent specifically developed to perfuse and oxygenate tissue at risk for ischemia and hypoxia. In this study, we investigated the ability of MP4OX to treat hypotensive episodes. In addition, the tolerability profile of MP4OX in a large surgical population was established. METHODS: Patients from 21 study sites in 5 countries, scheduled to undergo primary hip arthroplasty under spinal anesthesia, were randomized in a double-blind manner to receive MP4OX or hydroxyethyl starch (HES) solution (Voluven(r); HES 130/0.4). Patients received the first 250-mL dose of investigational product when systolic blood pressure decreased to the predefined dosing trigger. A second 250-mL dose was given only if the systolic blood pressure decreased to the same trigger level after administration of the first dose. The primary efficacy outcome was total duration of all hypotensive episodes during surgery and the first 6 hours after skin closure. RESULTS: Of the 474 patients randomized, 405 reached the dosing trigger and received at least 1 dose. The mean total duration of all hypotensive episodes was significantly shorter (P < 0.0001) in the MP4OX group (52.4 +/- 71.50 minutes; range, 3-442 minutes) compared with the HES group (137.6 +/- 120.21 minutes; range, 5-435 minutes). The overall incidence of adverse events (AEs) in the intent-to-treat population was similar between the MP4OX and HES groups (75.2% vs 73.4%; P = 0.733). Transient increases in laboratory values were reported in more patients in the MP4OX group versus HES controls for aspartate aminotransferase (13.4% vs 7.4%; P = 0.052), alanine aminotransferase (6.9% vs 4.9%; P = 0.409), lipase (9.7% vs 3.6%; P = 0.015), and troponin (8.1% vs 2.0%; P = 0.006). There was no significant difference in the incidence of serious AEs reported (6.4% in MP4OX group vs 3.0% in HES controls; P = 0.106). Certain AEs did occur more frequently in the MP4OX group, including nausea (23.8% vs 14.3%; P = 0.016), bradycardia (14.9% vs 5.9%; P = 0.003), hypertension (8.4% vs 2.5%; P = 0.009), and oliguria (5.9% vs 1.5%; P = 0.019). The composite morbidity and ischemia end points did not reveal any differences between the 2 treatment groups. CONCLUSIONS: Administration of MP4OX achieved the end point of treating perioperative hypotension in patients undergoing primary hip arthroplasty under spinal anesthesia. The study was not powered to demonstrate clinical benefit based on the composite morbidity or ischemia outcomes. Although efficacy end points with sufficient power were met, MP4OX is not being proposed for use in routine surgery where the risk-benefit profile would not be favorable based on the safety profile demonstrated in this study. PMID- 21317167 TI - Diet and sleep in children with attention deficit hyperactivity disorder: preliminary data in Australian children. AB - Sleep disturbances are common and consequential in children with attention deficit hyperactivity disorder (ADHD). Diet also influences ADHD symptoms. Interrelationships between diet, sleep and behaviour in children diagnosed with ADHD are little studied. We investigated, via parental report, the relationships between sleep and diet in 88 Australian children aged 6-13 years old (M = 8.94, SD = 1.78). This pilot data shows that 30 per cent of the children had sleep disturbance (>= 2 standard deviations above the mean) with significant relationships between ADHD symptoms, sleep disturbance and diet. Parents who reported more sleep disturbance also reported a higher intake of carbohydrate, fats, and, most particularly, sugar which was also a significant predictor of night time sweating. These findings suggest an interrelationship between diet and sleep in children with ADHD. Given that both sleep and dietary intake are potentially modifiable behaviours within treatment regimes of children with ADHD, further investigation is needed. PMID- 21317168 TI - Health disparities in low-income families with infants and toddlers: needs and challenges related to disability. AB - This study examines disparities in health status, health care utilization, insurance coverage and satisfaction in US low-income parents of infants and toddlers with disabilities compared to low-income parents of children without disabilities. The Early Head Start Research and Evaluation Project is a longitudinal study involving 2087 families in 17 communities across the United States. Families completed interviews at enrollment and at 7, 16, and 28 months after enrollment. Descriptive analyses were conducted to characterize children's status in terms of health, health care use, and insurance coverage. Children with disabilities were more likely to experience poor health and to use more health care services. Parents of children with disabilities were more likely to report that medical care was inadequate. Hispanic children were less likely to experience excellent health. Hispanic parents were less likely to have health insurance or to report that their medical care was adequate. Low-income parents of young children with disabilities perceived their children as less healthy, more vulnerable and needing more health services. This study demonstrates the importance of providing accessible, culturally-competent services to this vulnerable population. PMID- 21317169 TI - Health-related quality of life (HRQOL) in Latino families experiencing pediatric asthma. AB - The purpose of the present study was to examine health-related quality of life (HRQOL) in Latino children with asthma and their parents. Twenty-six parents completed the Pediatric Asthma Caregivers Quality of Life Questionnaire (PACQLQ), the Health Status and Activities Questionnaire for Children with Asthma (HSAQ) and four subscales from the Family Environment Scale. The results indicated that, overall, neither children with asthma nor their parents showed significant impairments in their HRQOL, though higher illness severity was associated with lower child quality of life and lower parent quality of life related to activity limitations. Other child and family variables, including dimensions of family functioning, did not correlate significantly with HRQOL. However, child and parent HRQOL were significantly associated with each other. This study provides additional context for understanding the experiences of Latino families dealing with pediatric asthma. PMID- 21317170 TI - Randomised placebo-controlled trial of teduglutide in reducing parenteral nutrition and/or intravenous fluid requirements in patients with short bowel syndrome. AB - BACKGROUND AND AIMS: Teduglutide, a GLP-2 analogue, may restore intestinal structural and functional integrity by promoting repair and growth of the mucosa and reducing gastric emptying and secretion, thereby increasing fluid and nutrient absorption in patients with short bowel syndrome (SBS). This 24-week placebo-controlled study evaluated the ability of teduglutide to reduce parenteral support in patients with SBS with intestinal failure. METHODS: In 83 patients randomised to receive subcutaneous teduglutide 0.10 mg/kg/day (n = 32), 0.05 mg/kg/day (n = 35) or placebo (n = 16) once daily, parenteral fluids were reduced at 4-week intervals if intestinal fluid absorption (48 h urine volumes) increased >= 10%. Responders were subjects who demonstrated reductions of >= 20% in parenteral volumes from baseline at weeks 20 and 24. The primary efficacy end point, a graded response score (GRS), took into account higher levels and earlier onset of response, leading to longer duration of response. The intensity of the response was defined as a reduction from baseline in parenteral volume (from 20% to 100%), and the duration of the response was considered the response at weeks 16, 20 and 24. The results were tested according to a step-down procedure starting with the 0.10 mg/kg/day dose. RESULTS: Using the GRS criteria, teduglutide in a dose of 0.10 mg/kg/day did not have a statistically significant effect compared with placebo (8/32 vs 1/16, p=0.16), while teduglutide in a dose of 0.05 mg/kg/day had a significant effect (16/35, p = 0.007). Since parenteral volume reductions were equal (353 +/- 475 and 354 +/- 334 ml/day), the trend towards higher baseline parenteral volume (1816 +/- 1008 vs 1374 +/- 639 ml/day, p=0.11) in the 0.10 mg/kg/day group compared with the 0.05 mg/kg/day group may have accounted for this discrepancy. Three teduglutide-treated patients were completely weaned off parenteral support. Serious adverse events were distributed similarly between active treatment groups and placebo. Villus height, plasma citrulline concentration and lean body mass were significantly increased with teduglutide compared with placebo. CONCLUSIONS: Teduglutide was safe, well tolerated, intestinotrophic and suggested pro-absorptive effects facilitating reductions in parenteral support in patients with SBS with intestinal failure. ClinicalTrials.gov number NCT00172185. PMID- 21317171 TI - Breaking down haem attenuates acute pancreatitis: a new treatment option? PMID- 21317172 TI - The benefits of diagnostic ERCP in autoimmune pancreatitis. PMID- 21317175 TI - EGILS consensus report. Gastric extranodal marginal zone B-cell lymphoma of MALT. AB - This consensus report of the EGILS (European Gastro-Intestinal Lymphoma Study) group includes recommendations on the management of gastric extranodal marginal zone B-cell lymphoma of MALT. They are based on data from the literature and on intensive discussions and votings of the experts during their annual meetings. PMID- 21317176 TI - A randomised trial of sheathed versus standard forceps for obtaining uncontaminated biopsy specimens of microbiota from the terminal ileum. AB - BACKGROUND: The study of intestinal microbiota has been revolutionised by the use of molecular methods, including terminal restriction fragment length polymorphism (T-RFLP) analysis. Microbiota studies of Crohn's disease patients have examined samples from stool or from the neoterminal ileum with a standard biopsy forceps, which could be contaminated by colonic bacteria when the forceps passes through the colonoscope channel. OBJECTIVE: To determine whether sheathed biopsy forceps are able to obtain terminal ileal microbiota samples with less colonic bacterial contamination compared with unsheathed (standard) biopsy forceps. DESIGN: Prospective randomised single-centre study. PATIENTS AND METHODS: Four (paired) biopsy specimens were obtained from adjacent locations in the terminal ileum using the sheathed and standard forceps of 27 consecutive subjects undergoing colonoscopy and the microbiota were characterised using T-RFLP. The Bray-Curtis similarity index between samples (sheathed vs unsheathed forceps) was calculated within patients and significant differences were tested for across all patients. RESULTS: There was not a significant difference in the microbial diversity of samples obtained using sheathed versus unsheathed forceps. The difference in microbial diversity between patients was much greater than the variability within patients by proximal versus distal site or by forceps type. LIMITATIONS: T-RFLP is based on PCR amplification, so it is not always sensitive to rare bacterial species. CONCLUSION: Standard unsheathed forceps appear to be sufficient for microbiota sample collection from the terminal ileum. PMID- 21317177 TI - The mucosal addressin cell adhesion molecule antibody PF-00547,659 in ulcerative colitis: a randomised study. AB - BACKGROUND AND AIMS: Leucocyte migration to gut mucosa, mediated by integrin binding to mucosal addressin cell adhesion molecule (MAdCAM), is a promising target for therapeutic intervention in inflammatory bowel disease. This first-in human study of a monoclonal antibody to MAdCAM, PF-00547,659, aimed to explore the safety and preliminary efficacy of this gut-specific mechanism in ulcerative colitis. METHODS: In this randomised, double-blind placebo-controlled study, 80 patients with active ulcerative colitis received single or multiple (three doses, 4-week intervals) doses of PF-00547,659 0.03-10 mg/kg IV/SC, or placebo. Safety was assessed by adverse events, laboratory tests, and immunogenicity. Exploratory efficacy analyses were based on Mayo score and endoscopic responder rates at weeks 4 and 12. Faecal calprotectin was quantified as a measure of disease activity, and the number of alpha4beta7+ lymphocytes was measured to demonstrate drug activity. RESULTS: No obvious drug-related side effects were observed in the PF-00547,659 group, while patient numbers, especially those fully exposed, were small. Overall responder/remission rates at 4 and 12 weeks were 52%/13% and 42%/22%, respectively with combined PF-00547,659 doses compared with 32%/11% and 21%/0%, respectively with placebo. Equivalent endoscopic responder rates were 50% and 42% versus 26% and 29%, respectively. Faecal calprotectin levels decreased to a greater extent with PF-00547,659 than placebo (week 4: 63% vs 18%). Despite variability, there was a trend for an increase in alpha4beta7+ lymphocytes in patients receiving PF-00547,659. CONCLUSIONS: The favourable short-term safety profile and preliminary efficacy findings for PF-00547,659 in this first-in-human study pave the way for further investigation in larger trials, to establish the role of PF-00547,659 in ulcerative colitis treatment. Trial Register No: NCT00928681. PMID- 21317178 TI - Intestinal transplantation and the European implication: impact of experience and study design. PMID- 21317179 TI - UK Lung Screen (UKLS) nodule management protocol: modelling of a single screen randomised controlled trial of low-dose CT screening for lung cancer. AB - The UK Lung Screen (UKLS) is a randomised controlled trial of the use of low-dose multidetector CT for lung cancer screening. It completed the Health Technology Appraisal (HTA)-funded feasibility stage in October 2009 and the pilot UKLS will be initiated in early 2011. The pilot will randomise 4000 subjects to either low dose CT screening or no screening. The full study, due to start in September 2012, if progression criteria are met, will randomise a further 28,000 subjects from seven centres in the UK. Subjects will be selected if they have sufficient risk of developing lung cancer according to the Liverpool Lung Project risk model. The UKLS employs the 'Wald Single Screen Design', which was modelled in the UKLS feasibility study. This paper describes the modelling of nodule management in UKLS by using volumetric analysis with a single initial screen design and follow-up period of 10 years. This modelling has resulted in the development and adoption of the UKLS care pathway, which will be implemented in the planned CT screening trial in the UK. PMID- 21317180 TI - Utilising improvement science methods to optimise medication reconciliation. AB - BACKGROUND: In 2005, The Joint Commission included medication reconciliation as a National Patient Safety Goal to reduce medication errors related to omissions, duplications and interactions. Hospitals continue to struggle to implement successful programmes that meet these objectives. METHODS: The authors used improvement methods and reliability principles to develop and implement a process for medication reconciliation completion at admission at a large, paediatric medical centre. Medication reconciliation was defined as recording a complete and accurate list of each patient's medications within 20 min of admission by the nurse and reconciliation of those medications within 24 h of admission by the physician. Interventions focused on five main areas: leadership and support from senior physicians and nurses to sustain a culture of safety; simplification and standardisation of the electronic medication reconciliation application; clarifying roles and responsibilities; creating a highly reliable and visible system; and sustainability. RESULTS: At baseline, only 62% of patients had their medications reconciled within 24 h of admission. Over a 9-month period, >=90% medication reconciliation was achieved within 24 h of admission. These results have been sustained for 27 months. CONCLUSIONS: Through the use of improvement methods and reliability science, a sustainable process for medical reconciliation completion at admission was successfully achieved at a large, busy academic children's hospital. PMID- 21317181 TI - The role of theory in research to develop and evaluate the implementation of patient safety practices. AB - Theories provide a way of understanding and predicting the effects of patient safety practices (PSPs), interventions intended to prevent or mitigate harm caused by healthcare or risks of such harm. Yet most published evaluations make little or no explicit reference to theory, thereby hindering efforts to generalise findings from one context to another. Theories from a wide range of disciplines are potentially relevant to research on PSPs. Theory can be used in research to explain clinical and organisational behaviour, to guide the development and selection of PSPs, and in evaluating their implementation and mechanisms of action. One key recommendation from an expert consensus process is that researchers should describe the theoretical basis for chosen intervention components or provide an explicit logic model for 'why this PSP should work.' Future theory-driven evaluations would enhance generalisability and help build a cumulative understanding of the nature of change. PMID- 21317182 TI - Effectiveness of collaborative improvement: evidence from 27 applications in 12 less-developed and middle-income countries. AB - INTRODUCTION: The improvement collaborative approach has been widely promoted in developed countries as an effective method to spread clinical practices, but little has been published on its effectiveness in developing country settings. Between 1998 and 2008, the United States Agency for International Development funded 54 collaboratives in 14 low- and middle-income countries, adapting the approach to resource-constrained environments. METHODS: The authors analysed data on provider compliance with standards and outcomes from 27 collaboratives in 12 countries that met study inclusion criteria (at least 12 months of data available for analysis and indicators measured as percentages). The dataset, representing 1338 facility-based teams, consisted of 135 time-series charts related to maternal, newborn and child health, HIV/AIDS, family planning, malaria and tuberculosis. An average of 28 months of data was available for each chart. RESULTS: Eighty-seven per cent of these charts achieved performance levels of 80% or higher, and 76% reached at least 90% performance, even though two-thirds had a baseline performance below 50%. Teams achieved average increases of 51.9 percentage points (SE = 28.0) per chart, with baseline value being the main determinant of absolute increase. Teams consistently maintained this level of performance for an average of 13 months (69% of months of observation). The average time to reach 80% performance was 9.2 months (SE 8.5), and to reach 90% performance, 14.4 months (SE = 12.0). CONCLUSION: Collaborative improvement can produce significant, sustained gains in compliance with standards and outcomes in less-developed settings and merits wider application as a strategy for health systems strengthening. PMID- 21317183 TI - Translation and standardization of the HoNOSCA (Health of the Nation Outcome Scales for Children and Adolescents) scale in a Greek sample. AB - The Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA) is a brief measure of outcomes. Evidence for the effectiveness of patient treatments conducted in mental health services is limited in Greece. Thus, in an attempt to employ an easily administered and valid outcome measure, to assess outcomes in clinical practice for children and adolescents, but also to be able to compare the results across countries, the HoNOSCA was the measure of choice. In this study we have translated and validated it in a Greek sample. We have investigated the inter-rater reliability, intraclass correlation, concurrent validity, and clinical change across time, of the HoNOSCA Greek translation. The results show that the Greek translation of HoNOSCA is a reliable and valid instrument. It can be used for clinical, managerial, research and audit purposes, but, most importantly, to facilitate multinational clinical research and comparison of data with other countries. PMID- 21317184 TI - Understanding the experiences and emotional needs of unaccompanied asylum-seeking adolescents in the UK. AB - For adolescents who flee to the UK seeking asylum, the experience of leaving their home country puts them at risk of developing mental health problems. Although there is a research base exploring the mental health of asylum-seeking children and adolescents who arrive with their families, there is in contrast very little focusing on the mental health needs of children and adolescents who arrive in the UK alone. There has been ongoing debate about whether current theoretical models for understanding reactions to trauma and loss are helpful in supporting unaccompanied asylum-seeking children and adolescents with complex psychological and social issues as a result of fleeing their home countries. This article draws on young people's own understanding of their experiences of seeking asylum in the UK using a qualitative semi-structured interview. It attempts to develop a more contextually relevant understanding of their emotional reactions to adversity and to consider the sorts of support required. Interpretative Phenomenological Analysis was used to provide an in-depth understanding of six young asylum seekers' experiences, exploring themes of loss, negotiating a new life, psychological distress and the process of adjustment. Psychological interventions and future service provision for this group are discussed. PMID- 21317185 TI - Exploring views on satisfaction with life in young children with chronic illness: an innovative approach to the collection of self-report data from children under 11. AB - The objective of this study was to explore young children's views on the impact of chronic illness on their life in order to inform future development of a patient-based self-report health outcome measure. We describe an approach to facilitating self-report views from young children with chronic illness. A board game was designed in order to obtain qualitative data from 39 children with a range of chronic illness conditions and 38 healthy controls ranging in age from 3 to 11 years. The format was effective in engaging young children in a self-report process of determining satisfaction with life and identified nine domains. The board game enabled children aged 5-11 years with chronic illness to describe the effects of living with illness on home, family, friends, school and life in general. It generated direct, non-interpreted material from children who, because of their age, may have been considered unable or limited their ability to discuss and describe how they feel. Obtaining this information for children aged 4 and under continues to be a challenge. PMID- 21317186 TI - Comparative whole genome sequencing reveals phenotypic tRNA gene duplication in spontaneous Schizosaccharomyces pombe La mutants. AB - We used a genetic screen based on tRNA-mediated suppression (TMS) in a Schizosaccharomyces pombe La protein (Sla1p) mutant. Suppressor pre-tRNA(Ser)UCA C47:6U with a debilitating substitution in its variable arm fails to produce tRNA in a sla1-rrm mutant deficient for RNA chaperone-like activity. The parent strain and spontaneous mutant were analyzed using Solexa sequencing. One synonymous single-nucleotide polymorphism (SNP), unrelated to the phenotype, was identified. Further sequence analyses found a duplication of the tRNA(Ser)UCA-C47:6U gene, which was shown to cause the phenotype. Ninety percent of 28 isolated mutants contain duplicated tRNA(Ser)UCA-C47:6U genes. The tRNA gene duplication led to a disproportionately large increase in tRNA(Ser)UCA-C47:6U levels in sla1-rrm but not sla1-null cells, consistent with non-specific low-affinity interactions contributing to the RNA chaperone-like activity of La, similar to other RNA chaperones. Our analysis also identified 24 SNPs between ours and S. pombe 972h- strain yFS101 that was recently sequenced using Solexa. By including mitochondrial (mt) DNA in our analysis, overall coverage increased from 52% to 96%. mtDNA from our strain and yFS101 shared 14 mtSNPs relative to a 'reference' mtDNA, providing the first identification of these S. pombe mtDNA discrepancies. Thus, strain-specific and spontaneous phenotypic mutations can be mapped in S. pombe by Solexa sequencing. PMID- 21317187 TI - Measurable impact of RNA quality on gene expression results from quantitative PCR. AB - Compromised RNA quality is suggested to lead to unreliable results in gene expression studies. Therefore, assessment of RNA integrity and purity is deemed essential prior to including samples in the analytical pipeline. This may be of particular importance when diagnostic, prognostic or therapeutic conclusions depend on such analyses. In this study, the comparative value of six RNA quality parameters was determined using a large panel of 740 primary tumour samples for which real-time quantitative PCR gene expression results were available. The tested parameters comprise of microfluidic capillary electrophoresis based 18S/28S rRNA ratio and RNA Quality Index value, HPRT1 5'-3' difference in quantification cycle (Cq) and HPRT1 3' Cq value based on a 5'/3' ratio mRNA integrity assay, the Cq value of expressed Alu repeat sequences and a normalization factor based on the mean expression level of four reference genes. Upon establishment of an innovative analytical framework to assess impact of RNA quality, we observed a measurable impact of RNA quality on the variation of the reference genes, on the significance of differential expression of prognostic marker genes between two cancer patient risk groups, and on risk classification performance using a multigene signature. This study forms the basis for further rational assessment of reverse transcription quantitative PCR based results in relation to RNA quality. PMID- 21317188 TI - Ranking causal variants and associated regions in genome-wide association studies by the support vector machine and random forest. AB - We study the number of causal variants and associated regions identified by top SNPs in rankings given by the popular 1 df chi-squared statistic, support vector machine (SVM) and the random forest (RF) on simulated and real data. If we apply the SVM and RF to the top 2r chi-square-ranked SNPs, where r is the number of SNPs with P-values within the Bonferroni correction, we find that both improve the ranks of causal variants and associated regions and achieve higher power on simulated data. These improvements, however, as well as stability of the SVM and RF rankings, progressively decrease as the cutoff increases to 5r and 10r. As applications we compare the ranks of previously replicated SNPs in real data, associated regions in type 1 diabetes, as provided by the Type 1 Diabetes Consortium, and disease risk prediction accuracies as given by top ranked SNPs by the three methods. Software and webserver are available at http://svmsnps.njit.edu. PMID- 21317189 TI - Isoform-level microRNA-155 target prediction using RNA-seq. AB - Computational prediction of microRNA targets remains a challenging problem. The existing rule-based, data-driven and expression profiling approaches to target prediction are mostly approached from the gene-level. The increasing availability of RNA-seq data provides a new perspective for microRNA target prediction on the isoform-level. We hypothesize that the splicing isoform is the ultimate effector in microRNA targeting and that the proposed isoform-level approach is capable of predicting non-dominant isoform targets as well as their targeting regions that are otherwise invisible to many existing approaches. To test the hypothesis, we used an iterative expectation maximization (EM) algorithm to quantify transcriptomes at the isoform-level. The performance of the EM algorithm in transcriptome quantification was examined in simulation studies using FluxSimulator. We used joint evidence from isoform-level down-regulation and seed enrichment to predict microRNA-155 targets. We validated our computational approach using results from 149 in-house performed in vitro 3'-UTR assays. We also augmented the splicing database using exon-exon junction evidence, and applied the EM algorithm to predict and quantify 1572 cell line specific novel isoforms. Combined with seed enrichment analysis, we predicted 51 novel microRNA 155 isoform targets. Our work is among the first computational studies advocating the isoform-level microRNA target prediction. PMID- 21317190 TI - Human microRNA hsa-miR-125a-5p interferes with expression of hepatitis B virus surface antigen. AB - MicroRNAs are small non-coding RNAs that modulate gene expression at post transcriptional level, playing a crucial role in cell differentiation and development. Recently, some reports have shown that a limited number of mammalian microRNAs are also involved in anti-viral defense. In this study, the analysis of the hepatitis B virus (HBV) genome by the computer program MiRanda led to the identification of seven sites that are potential targets for human liver microRNAs. These sites were found to be clustered in a 995-bp segment within the viral polymerase ORF and the overlapping surface antigen ORF, and conserved among the most common HBV subtypes. The HBV genomic targets were then subjected to a validation test based on cultured hepatic cells (HepG2, HuH-7 and PLC/PRF/5) and luciferase reporter genes. In this test, one of the selected microRNAs, hsa-miR 125a-5p, was found to interact with the viral sequence and to suppress the reporter activity markedly. The microRNA was then shown to interfere with the viral translation, down-regulating the expression of the surface antigen. Overall, these results support the emerging concept that some mammalian microRNAs play a role in virus-host interaction. Furthermore, they provide the basis for the development of new strategies for anti-HBV intervention. PMID- 21317191 TI - Retinoic acid-related orphan receptor gamma directly regulates neuronal PAS domain protein 2 transcription in vivo. AB - Retinoic acid-related orphan receptors (RORs) and the basic helix-loop-helix-PAS transcription factor Npas2 have been implicated in the control of circadian rhythm. In this study, we demonstrate that RORgamma directly regulates Npas2 expression in vivo. Although the rhythmicity of Npas2 mRNA expression was maintained in RORgamma(-/-) mice, the peak level of expression was significantly reduced in several tissues, while loss of RORalpha had little effect. Inversely, overexpression of RORgamma in hepatoma Hepa1-6 cells greatly induced the expression of Npas2. RORgamma-activated Npas2 transcription directly by binding two ROREs in its proximal promoter. ChIP analysis demonstrated that RORgamma was recruited to this promoter in the liver of wild-type mice, but not RORgamma deficient mice. Activation of Npas2 correlated positively with chromatin accessibility and level of H3K9 acetylation. The activation of Npas2 by RORgamma was repressed by co-expression with Rev-Erbalpha or addition of the ROR inverse agonist T0901317. Npas2 expression was also significantly enhanced during brown adipose differentiation and that this induction was greatly suppressed in adipose cells lacking RORgamma. Our results indicate that RORgamma and Rev-Erbalpha are part of a feed-back loop that regulates the circadian expression of Npas2 suggesting a regulatory role for these receptors in Npas2-dependent physiological processes. PMID- 21317192 TI - Integrated genome-wide chromatin occupancy and expression analyses identify key myeloid pro-differentiation transcription factors repressed by Myb. AB - To gain insight into the mechanisms by which the Myb transcription factor controls normal hematopoiesis and particularly, how it contributes to leukemogenesis, we mapped the genome-wide occupancy of Myb by chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-Seq) in ERMYB myeloid progenitor cells. By integrating the genome occupancy data with whole genome expression profiling data, we identified a Myb-regulated transcriptional program. Gene signatures for leukemia stem cells, normal hematopoietic stem/progenitor cells and myeloid development were overrepresented in 2368 Myb regulated genes. Of these, Myb bound directly near or within 793 genes. Myb directly activates some genes known critical in maintaining hematopoietic stem cells, such as Gfi1 and Cited2. Importantly, we also show that, despite being usually considered as a transactivator, Myb also functions to repress approximately half of its direct targets, including several key regulators of myeloid differentiation, such as Sfpi1 (also known as Pu.1), Runx1, Junb and Cebpb. Furthermore, our results demonstrate that interaction with p300, an established coactivator for Myb, is unexpectedly required for Myb-mediated transcriptional repression. We propose that the repression of the above mentioned key pro-differentiation factors may contribute essentially to Myb's ability to suppress differentiation and promote self-renewal, thus maintaining progenitor cells in an undifferentiated state and promoting leukemic transformation. PMID- 21317193 TI - Streptococcus mutans diacylglycerol kinase homologue: a potential target for anti caries chemotherapy. AB - Aciduricity is a major cariogenic characteristic of Streptococcus mutans, and various genes have been implicated in this ability of S. mutans. Sixteen S. mutans mutant strains, each defective in a different gene, were constructed and their aciduricity was assessed. Of the mutants, the diacylglycerol kinase (Dgk) homologue mutant and the glucose-1-phosphate uridylyltransferase mutant strains displayed distinctly attenuated aciduricity when grown at pH 5.5. Considering the delayed growth rate of the latter at neutral pH, the dgk homologue appeared to be a gene responding specifically to pH reduction among the 16 genes tested. Two known eukaryotic Dgk inhibitors, R59949 and R59022, were selected as candidate inhibitors of the S. mutans Dgk homologue. R59949, but not R59022, significantly reduced the growth of S. mutans at pH <5.4. R59949 did not affect either the final pH of the medium or the internal pH of the organism. Furthermore, R59949 inhibited about 20 % of Dgk kinase activity. Novel derivatives of R59949 may be useful for preventing the development of dental caries caused by S. mutans. PMID- 21317194 TI - Colonization and transmission of meticillin-susceptible and meticillin-resistant Staphylococcus aureus in a murine nasal colonization model. AB - Nasal colonization by Staphylococcus aureus is an important risk factor for the development of a nosocomial infection. Acquisition of nasal colonization by S. aureus increases mortality in hospitalized patients, but little is known about the transmission dynamics of S. aureus. To study S. aureus transmission, colonization and colonization persistence, we developed a murine transmission model. In 20 cages, 2 out of 10 mice were nasally inoculated (at 5*10(8) c.f.u. per mouse) with either meticillin-susceptible S. aureus (MSSA) (10 cages) or meticillin-resistant S. aureus (MRSA) (10 cages). On days 5, 15, 25 and 40, all mice in a cage were swabbed or sacrificed and nasal colonization and c.f.u. were determined in all 10 mice by nasal dissection or by nasal swab. Spread and subsequent stable colonization by both MSSA and MRSA from colonized to uncolonized mice within a cage was seen. At day 5, an increased number of colonized mice were observed in the MSSA group compared to the MRSA group (P = 0.003). On day 40, the mean number of c.f.u. per mouse was higher for MRSA than for MSSA (P = 0.06). Faecal-oral transmission was shown to be a possibly important transmission route in this model. These results suggest a more rapid spread of MSSA compared to MRSA. However, MRSA shows a more stable nasal colonization after a longer period of time. PMID- 21317195 TI - High prevalence of mupirocin-resistant staphylococci in a dialysis unit where mupirocin and chlorhexidine are routinely used for prevention of catheter-related infections. PMID- 21317196 TI - Trace elements and vitamins at diagnosis in pediatric-onset inflammatory bowel disease. AB - AIM: To compare serum vitamin and mineral levels at diagnosis in children with inflammatory bowel disease (IBD) versus a control group without. METHODS: In a retrospective cohort study, serum levels of iron, zinc, folate, selenium, vitamin B( 12), vitamin A, and vitamin E in children with IBD at diagnosis were compared with gender- and age-matched controls. RESULTS: A total of 154 patients with IBD (mean age 11.27 +/- 3.74 years, 83 boys, 80 with Crohn's disease) were recruited. The mean duration of symptoms prior to diagnosis was 5.4 +/- 3.2 months for patients with Crohn's disease and 4.6 +/- 2.9 months for patients with ulcerative colitis. A control group of 64 children was recruited. The mean serum zinc levels were 11.33 +/- 4.16 umol/L for ulcerative colitis, 8.74 +/- 2.08 umol/L for Crohn's disease and 11.49 +/- 1.63 umol/L for controls (P < .001). CONCLUSIONS: In newly diagnosed children with IBD, serum zinc levels are significantly lower compared with children without IBD. PMID- 21317197 TI - A pilot program to identify and reverse childhood obesity in a primary care clinic. AB - This pilot study is an innovative approach to addressing the issue of childhood obesity that starts with the primary care physician and involves group education with peers. The primary care physician assesses the child's well-being at each interaction, whether for a scheduled well-child visit or for an acute illness. At each office visit the vital signs are taken, including the height, weight, and the calculated body mass index (BMI). The BMI is a tool that helps the provider identify children who are overweight or obese. Using the patient empowerment readiness model, the provider addresses obesity with the patient and the parent to determine if they are ready to implement behavioral changes. During a 10-month period, 68 patients were enrolled in the pilot program. The initial results after the 10 months showed that when the provider identified the issue of obesity and the child was assessed for readiness and integrated in the behavioral modification program the outcome was 63% of the group reduced their BMI. It was also noted that asthma was the most frequent comorbidity in the overweight/obese children. Whereas BMI increased in a matched control group, participants in the pilot program succeeded in reducing BMI. PMID- 21317198 TI - Treatment of streptococcal pharyngitis with once-daily amoxicillin versus intramuscular benzathine penicillin G in low-resource settings: a randomized controlled trial. AB - BACKGROUND: Primary prevention of acute rheumatic fever is achieved by proper antibiotic treatment of group A beta -hemolytic streptococcal (GAS) pharyngitis. METHODS: To assess noninferiority of oral amoxicillin to intramuscular benzathine penicillin G (IM BPG). Children (2 to 12 years) meeting enrollment criteria were randomized 1:1 to receive antibiotic treatment in 2 urban outpatient clinics in Egypt and Croatia. RESULTS: A total of 558 children (Croatia = 166, Egypt = 392) were randomized, with 368 evaluable in an intention-to-treat (ITT) analysis, and 272 evaluable in the per protocol (PP) analysis. In Croatia, ITT and PP treatment success rates were comparable for IM BPG and amoxicillin (2.5% difference vs 1.1% difference, respectively). In Egypt, amoxicillin was not comparable with IM BPG in ITT analysis (15.1% difference), but was comparable in PP analysis (-9.3% difference). CONCLUSION: If compliance is a major issue, a single dose of IM BPG may be preferable for treatment of GAS pharyngitis. PMID- 21317199 TI - Treatment of breast infection. PMID- 21317201 TI - Association of genetic polymorphisms in ESR2, HSD17B1, ABCB1, and SHBG genes with colorectal cancer risk. AB - The incidence rates and relative risks for colorectal cancer (CRC) are higher in men than in women. Sex steroids may play a role in this gender-associated difference in CRC risk. This study was conducted to explore the relationship of single nucleotide polymorphisms (SNPs) in steroid hormone signaling (ESR1, ESR2, PGR, NR1I2, and SHBG), phase I- and II-metabolizing enzyme (COMT, HSD17B1, CYP1A1, CYP17A1, CYP1A2, CYP1B1, CYP2C9, CYP3A4, CYP2C19, and GSTP1), and hormone transporter (ABCB1) genes with the risk of CRC in German women and men, separately. From the population-based DACHS study (South Germany), 47 putatively functional SNPs were genotyped in 1798 CRC cases (746 women and 1052 men) and 1810 controls (732 women and 1078 men). Significant allele dose-response associations were observed with ESR2_rs1255998, ESR2_rs928554, HSD17B1_rs605059, and ABCB1_rs2229109 in women (P trend=0.004, 0.05, 0.03, and 0.05 respectively) and with ABCB1_rs1045642, ABCB1_rs9282564, and SHBG_rs6259 in men (P trend=0.01, 0.03, and 0.02 respectively). The ESR2_rs1255998_G allele showed the most significant association with risk for CRC in women, with a per-allele odds ratio (OR) of 0.68 (95% confidence interval (CI) 0.52-0.88). This finding was replicated in an independent study from North Germany including 1076 female CRC cases and 1151 controls (OR=0.84, 95% CI 0.71-1.04), yielding a per-allele OR of 0.80 (95% CI 0.69-0.93, P trend=0.003) in the pooled sample. These findings implicate a role of ESR2 in the risk for developing CRC in women and suggest that HSD17B1, ABCB1, and SHBG genes may contribute to sex steroid-mediated effects on CRC development. PMID- 21317202 TI - The novel Raf inhibitor Raf265 decreases Bcl-2 levels and confers TRAIL sensitivity to neuroendocrine tumour cells. AB - The tumour-selective death receptor ligand tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for the treatment of human cancer. However, many tumours have evolved mechanisms to resist TRAIL-induced apoptosis. A number of studies have demonstrated that aberrant PI(3)K-Akt-mTOR survival signalling may confer TRAIL resistance by altering the balance between pro- and anti-apoptotic proteins. Here, we show that neuroendocrine tumour (NET) cell lines of heterogeneous origin exhibit a range of TRAIL sensitivities and that TRAIL sensitivity correlates with the expression of FLIP(S), caspase-8, and Bcl-2. Neither single mTOR inhibition by everolimus nor dual mTOR/PI(3)K inhibition by NVP-BEZ235 was able to enhance TRAIL susceptibility in any of the tested cell lines. In contrast, dual PI(3)K-Akt-mTOR and Raf-MEK-Erk pathway inhibition by the IGF-1R inhibitor NVP-AEW541 effectively restored TRAIL sensitivity in NCI-H727 bronchus carcinoid cells. Furthermore, blocking Raf-MEK Erk signalling by the novel Raf inhibitor Raf265 significantly enhanced TRAIL sensitivity in NCI-H727 and CM insulinoma cells. While having no effect on FLIP(S) or caspase-8 expression, Raf265 strongly decreased Bcl-2 levels in those cell lines susceptible to its TRAIL-sensitizing action. Taken together, our findings suggest that combinations of Raf-MEK-Erk pathway inhibitors and TRAIL might offer a novel therapeutic strategy in NET disease. PMID- 21317203 TI - Combination of trastuzumab and letrozole after resistance to sequential trastuzumab and aromatase inhibitor monotherapies in patients with estrogen receptor-positive, HER-2-positive advanced breast cancer: a proof-of-concept trial (SAKK 23/03). AB - A sequential treatment design was chosen in this trial to ensure complete resistance to single-agent non-steroidal aromatase inhibitor (AI) and trastuzumab both given as monotherapy before receiving the combination of a non-steroidal AI and trastuzumab. Key eligibility criteria included postmenopausal patients with advanced, measurable, human epidermal growth factor receptor-2 (HER-2)-positive disease (assessed by FISH, ratio (>=2)), hormone receptor (HR)-positive disease, and progression on prior treatment with a non-steroidal AI, e.g. letrozole or anastrozole, either in the adjuvant or in the advanced setting. Patients received standard dose trastuzumab monotherapy in step 1 and upon disease progression continued trastuzumab in combination with letrozole in step 2. The primary endpoint was clinical benefit rate (CBR) in step 2. Totally, 13 patients were enrolled. In step 1, six patients (46%) achieved CBR. Median time to progression (TTP) was 161 days (95% confidence interval (CI): 82-281). In step 2, CBR was observed in eight out of the 11 evaluable patients (73%), including one patient with partial response. Median TTP for all the 11 patients was 188 days (95% CI: 77-not reached). Results of this proof-of-concept trial suggest that complete resistance to both AI and trastuzumab can be overcome in a proportion of patients by combined treatment of AI and trastuzumab, as all patients served as their own control. Our results appear promising for a new treatment strategy that offers a chemotherapy-free option for at least a subset of patients with HR-positive, HER 2-positive breast cancer over a clinically relevant time period. PMID- 21317204 TI - Androgen receptor levels are upregulated by Akt in prostate cancer. AB - Multiple lines of evidence suggest a functional link between the androgen receptor (AR) and the serine/threonine kinase Akt in the development and progression of prostate cancer. To investigate the impact of Akt activity on AR homeostasis, we treated androgen-dependent LNCaP and LAPC-4 prostate cancer cells with Akt inhibitor. Akt inhibition decreased AR expression, suggesting that Akt activity was required for regulation of AR protein levels. However, while androgen-independent LNCaP-abl cells also showed diminished AR protein levels in response to Akt inhibition, treatment of androgen-independent LNCaP-AI cells failed to alter AR protein levels upon similar treatment, suggesting that AR protein levels in these androgen-independent prostate cells were regulated by mechanisms independent of Akt activation. Regulation of AR, downstream of activated Akt, also was observed in vivo when examining transgenic mice that overexpress constitutively active mutant myristoylated (myr)-Akt1 in the prostate. Transgenic mice expressing activated myr-Akt1 exhibited higher levels of AR mRNA and protein. Expression of activated myr-Akt1 did not alter prostate cell growth and no significant size differences between prostate tissues derived from transgenic animals were observed when comparing transgenic mice with wild type mice. Still, transgenic mice overexpressing Akt exhibited higher levels of gammaH2AX and phosphorylated Chk2 in prostate tissue. These changes in markers associated with oncogene-induced senescence confirmed significant altered signaling in the transgenic mouse model. Overall, results presented here suggest that AR levels are regulated by the Akt pathway. PMID- 21317206 TI - Ireland has record fall in number of organ donations. PMID- 21317209 TI - Effects of a fluoride-containing casein phosphopeptide-amorphous calcium phosphate complex on the shear bond strength of orthodontic brackets. AB - The purpose of this study was to investigate the effects of enamel pre-treatment with a new fluoride-containing casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) complex on the shear bond strength (SBS) of brackets bonded with etch and-rinse or self-etching adhesive systems. The material comprised 66 extracted human premolars randomly divided into six equal groups with respect to the enamel pre-treatment and adhesive system employed: 1. No pre-treatment and brackets bonded with the etch-and-rinse adhesive system (Transbond XT). 2. Pre-treatment with fluoride-containing CPP-ACP paste (MI Paste Plus) and Transbond XT. 3. Pre treatment with non-fluoride CPP-ACP paste (MI Paste) and Transbond XT.4. No pre treatment and brackets bonded with the self-etching adhesive system (Transbond Plus). 5 and 6. Enamel pre-treated as for groups 2 and 3, respectively, and the Transbond Plus. Bonded specimens were subjected to thermal cycling (*1000) before SBS testing. The residual adhesive on the enamel surface was evaluated after debonding with the adhesive remnant index (ARI). Data evaluation was made using one-way analysis of variance and Tukey test for SBS results, and Kruskal-Wallis test for ARI results. The results showed that enamel pre-treatment with either fluoride or non-fluoride CPP-ACP paste had no significant effect on the SBS of the self-etching adhesive system (P > 0.05). Enamel pre-treatment with non fluoride CPP-ACP in group 3 significantly reduced the SBS of the etch-and-rinse adhesive (P < 0.001), while pre-treatment with fluoride-containing CPP-ACP paste (groups 2 and 5) did not affect debonding values (P > 0.05). The fluoride containing CPP-ACP did not compromise the SBS of brackets bonded with the tested etch-and-rinse and self-etching systems, but its non-fluoride version significantly decreased the SBS of the etch-and-rinse adhesive system. PMID- 21317208 TI - Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide. AB - Due to its molecular heterogeneity and infiltrative nature, glioblastoma multiforme (GBM) is notoriously resistant to traditional and experimental therapeutics. To overcome these hurdles, targeted agents have been combined with conventional therapy. We evaluated the preclinical potential of a novel, orally bioavailable PI3K/mTOR dual inhibitor (XL765) in in vitro and in vivo studies. In vivo serially passaged human GBM xenografts that are more genetically stable than GBM cell lines in culture were used for all experiments. Biochemical downstream changes were evaluated by immunoblot and cytotoxicity by colorimetric ATP-based assay. For in vivo experiments, human xenograft GBM 39 grown intracranially in nude mice was altered to express luciferase to monitor tumor burden by optical imaging. XL765 resulted in concentration-dependent decreases in cell viability in vitro. Cytotoxic doses resulted in specific inhibition of PI3K signaling. Combining XL765 with temozolomide (TMZ) resulted in additive toxicity in 4 of 5 xenografts. In vivo, XL765 administered by oral gavage resulted in greater than 12-fold reduction in median tumor bioluminescence compared with control (Mann Whitney test p = 0.001) and improvement in median survival (logrank p = 0.05). TMZ alone showed a 30-fold decrease in median bioluminescence, but the combination XL765 + TMZ yielded a 140-fold reduction in median bioluminescence (Mann-Whitney test p = 0.05) with a trend toward improvement in median survival (logrank p = 0.09) compared with TMZ alone. XL765 shows activity as monotherapy and in combination with conventional therapeutics in a range of genetically diverse GBM xenografts. PMID- 21317210 TI - Acupuncture and heart rate variability. PMID- 21317211 TI - Pp6-FEH1 encodes an enzyme for degradation of highly polymerized levan and is transcriptionally induced by defoliation in timothy (Phleum pratense L.). AB - The ability of grasses to regrow after defoliation by cutting or grazing is a vital factor in their survival and an important trait when they are used as forage crops. In temperate grass species accumulating fructans, defoliation induces the activity of a fructan exohydrolase (FEH) that degrades fructans to serve as a carbon source for regrowth. Here, a cDNA from timothy was cloned, named Pp6-FEH1, that showed similarity to wheat fructan 6-exohydrolase (6-FEH). The recombinant enzyme expressed in Pichia pastoris completely degraded fructans that were composed mainly of beta(2,6)-linked and linear fructans (levan) with a high degree of polymerization (DP) in the crown tissues of timothy. The substrate specificity of Pp6-FEH1 differed from previously characterized enzymes with 6-FEH activity in fructan-accumulating plants: (i) Pp6-FEH1 showed 6-FEH activity against levan (mean DP 20) that was 4-fold higher than against 6-kestotriose (DP 3), indicating that Pp6-FEH1 has a preference for beta(2,6)-linked fructans with high DP; (ii) Pp6-FEH1 had significant activity against beta(2,1)-linked fructans, but considerably less than against beta(2,6)-linked fructans; (iii) Pp6 FEH1 had weak invertase activity, and its 6-FEH activity was inhibited slightly by sucrose. In the stubble of seedlings and in young haplocorms from adult timothy plants, transcripts of Pp6-FEH1 were significantly increased within 3 h of defoliation, followed by an increase in 6-FEH activity and in the degradation of fructans. These results suggest that Pp6-FEH1 plays a role in the degradation of fructans and the mobilization of carbon sources for regrowth after defoliation in timothy. PMID- 21317212 TI - Cysteine-rich peptides (CRPs) mediate diverse aspects of cell-cell communication in plant reproduction and development. AB - Cell-cell communication in plants is essential for the correct co-ordination of reproduction, growth, and development. Studies to dissect this mode of communication have previously focussed primarily on the action of plant hormones as mediators of intercellular signalling. In animals, peptide signalling is a well-documented intercellular communication system, however, relatively little is known about this system in plants. In recent years, numerous reports have emerged about small, secreted peptides controlling different aspects of plant reproduction. Interestingly, most of these peptides are cysteine-rich, and there is convincing evidence suggesting multiple roles for related cysteine-rich peptides (CRPs) as signalling factors in developmental patterning as well as during plant pathogen responses and symbiosis. In this review, we discuss how CRPs are emerging as key signalling factors in regulating multiple aspects of vegetative growth and reproductive development in plants. PMID- 21317213 TI - Clinical signs in dematiaceous and hyaline fungal keratitis. PMID- 21317214 TI - Detection of early functional changes in diabetic retina using slow double stimulation mfERG paradigm. AB - Aim Diabetes mellitus (DM) is a systemic disease with insufficient secretion of insulin or poor response to insulin. This typically causes poor control of blood glucose level leading to a range of complications. Early detection of the retinal function alteration in DM is needed. Methods A newly modified paradigm-slow double-stimulation multifocal electroretinogram (mfERG)-was introduced to measure early changes of retinal function in DM and to investigate changes in the adaptation mechanisms in the diabetic retina. The mfERG was measured by using a slow double-stimulation mfERG paradigm (M(1)M(2)OOO). Results The m1 amplitude of M(1) stimulation from diabetic subjects was significantly reduced in ring 1 in contrast to that of a control group. The m2 amplitude of M(2) stimulation from diabetic subjects was also significantly reduced in ring 1 and 2 as compared with those of the control group. The m1/m2 ratio which minimises intersubject variation shows a reasonable differentiation between the control and diabetic groups. There was a significant increase in the amplitude ratio from diabetic subjects in ring 2 and 3 as compared with those of the control group. Conclusions The present findings suggest that the new mfERG paradigm is a fast and sensitive test for the detection of early functional changes in the diabetic retina. PMID- 21317215 TI - The effect of head tilt on the measurements of retinal nerve fibre layer and macular thickness by spectral-domain optical coherence tomography. AB - BACKGROUND/AIMS: To evaluate the effect of head tilt on retinal nerve fibre layer (RNFL) and macular thickness measured by the Cirrus HD spectral-domain optical coherence tomography (Cirrus HD OCT). METHODS: A total of 30 right eyes from 30 healthy young subjects underwent RNFL and macular thickness measurements with the Cirrus HD OCT. The measurements were performed at a baseline head position and at right and left head tilt positions. The differences in RNFL and macular thickness between the baseline head position and the positions with head tilt were analysed. RESULTS: The right and left head tilt induced counter-clockwise (mean 8.27 degrees ) and clockwise (mean 8.47 degrees ) rotation of the optic disc. The right head tilt caused superior-temporal RNFL thickening, inferior-temporal RNFL thinning, superior outer macular thickening and inferior outer macular thinning (all p values <0.05). The left head tilt induced superior-temporal RNFL thinning, inferior-temporal RNFL thickening, superior outer macular thinning, nasal outer macular thickening and inferior outer macular thickening (all p values <0.05). CONCLUSIONS: RNFL and macular thickness measured with the Cirrus HD OCT was affected by head tilt. Artefacts caused by head tilt should be considered in the analysis of the Cirrus HD OCT measurements. PMID- 21317216 TI - Expanded polytetrafluoroethylene as a substrate for retinal pigment epithelial cell growth and transplantation in age-related macular degeneration. AB - BACKGROUND: Retinal pigment epithelial (RPE) transplantation presents a potential treatment for age-related macular degeneration (AMD). A suitable transplant membrane that can support an intact functioning RPE monolayer is required. Expanded polytetrafluoroethylene (ePTFE) possesses the physical properties required for a transplanting device; however, cells do not attach and spread on ePTFE. This study investigated the ability of surface-modified ePTFE to optimise the growth and function of healthy RPE monolayers. METHODS: ePTFE discs were modified by ammonia gas plasma treatment. ARPE-19 cells were seeded on the membranes and maintained in media supplemented with retinoic acid and reduced serum. Cell number, morphology and proliferation were analysed. RPE monolayer function was investigated through formation of cell-cell junctions and phagocytosis of photoreceptor outer segments (POS). RESULTS: Ammonia gas plasma treatment resulted in enhanced cell growth and good monolayer formation with evidence of cell-cell junctional proteins. Furthermore, RPE monolayers were able to phagocytose POS in a time-dependent manner. CONCLUSIONS: ePTFE can be surface modified to support an intact functional monolayer of healthy RPE cells with normal morphology and the ability to perform RPE-specific functions. Following further investigation ePTFE may be considered for use in transplantation. PMID- 21317217 TI - The transcriptome of the medullary area postrema: the thirsty rat, the hungry rat and the hypertensive rat. AB - The area postrema (AP) is a sensory circumventricular organ characterized by extensive fenestrated vasculature and neurons which are capable of detecting circulating signals of osmotic, cardiovascular, immune and metabolic status. The AP can communicate these messages via efferent projections to brainstem and hypothalamic structures that are able to orchestrate an appropriate response. We have used microarrays to profile the transcriptome of the AP in the Sprague Dawley (SD) and Wistar-Kyoto rat and present here a comprehensive catalogue of gene expression, focusing specifically on the population of ion channels, receptors and G protein-coupled receptors expressed in this sensory tissue; of the G protein-coupled receptors expressed in the rat AP, we identified ~36% that are orphans, having no established ligand. We have also looked at the ways in which the AP transcriptome responds to the physiological stressors of 72 h dehydration (DSD) and 48 h fasting (FSD) and have performed microarrays in these conditions. Comparison between the DSD and SD or between FSD and SD revealed only a modest number of AP genes that are regulated by these homeostatic challenges. The expression levels of a much larger number of genes are altered in the spontaneously hypertensive rat AP compared with the normotensive Wistar-Kyoto control rat, however. Finally, analysis of these 'hypertension-related' elements revealed genes that are involved in the regulation of both blood pressure and immune function and as such are excellent targets for further study. PMID- 21317219 TI - Relationship between force and size in human single muscle fibres. AB - When the contractile properties of single muscle fibres are studied, force is typically normalized by fibre cross-sectional area and expressed as specific force. We studied a set of 2725 chemically skinned human single muscle fibres from 119 healthy adults to determine whether specific force is the optimal way to express the relationship between single-fibre force and size. A linear mixed effects model was used to estimate the slope and slope variability among individuals of log-log plots of force and diameter. For type I fibres, the slope estimate was 0.99 (95% confidence interval 0.36-1.62), and for type IIa fibres it was 0.94 (95% confidence interval 0.77-1.11), indicating that force is proportional to fibre diameter, rather than to cross-sectional area. If force were proportional to cross-sectional area, the slope estimate would be 2.0. In future studies using the chemically skinned single fibre preparation, force may be normalized to fibre diameter rather than cross-sectional area. We propose that a new term, 'normalized force', be used for this variable, with units of newtons per metre. We demonstrate using our data set that when populations of single fibres are compared with one another, the determination of whether the size and force relationship is the same or different is dependent upon the method used to account for fibre size (i.e. specific force versus 'normalized force'). PMID- 21317218 TI - Spinal opioid receptor-sensitive muscle afferents contribute to the fatigue induced increase in intracortical inhibition in healthy humans. AB - We investigated the influence of spinal opioid receptor-sensitive muscle afferents on cortical changes following fatiguing unilateral knee-extensor exercise. On separate days, seven subjects performed an identical five sets of intermittent isometric right-quadriceps contractions, each consisting of eight submaximal contractions [63 +/- 7% maximal voluntary contraction (MVC)] and one MVC. The exercise was performed following either lumbar interspinous saline injection or lumbar intrathecal fentanyl injection blocking the central projection of spinal opioid receptor-sensitive lower limb muscle afferents. To quantify exercise-induced peripheral fatigue, quadriceps twitch force (Q(tw,pot)) was assessed via supramaximal magnetic femoral nerve stimulation before and after exercise. Motor evoked potentials and cortical silent periods (CSPs) were evaluated via transcranial magnetic stimulation of the motor cortex during a 3% MVC pre-activation period immediately following exercise. End-exercise quadriceps fatigue was significant and similar in both conditions (Q(tw,pot) -35 and -39% for placebo and fentanyl, respectively; P = 0.38). Immediately following exercise on both days, motor evoked potentials were similar to those obtained prior to exercise. Compared with pre-exercise baseline, CSP in the placebo trial was 21 +/ 5% longer postexercise (P < 0.01). In contrast, CSP following the fentanyl trial was not significantly prolonged compared with the pre-exercise baseline (6 +/- 4%). Our findings suggest that the central effects of spinal opioid receptor sensitive muscle afferents might facilitate the fatigue-induced increase in CSP. Furthermore, since the CSP is thought to reflect inhibitory intracortical interneuron activity, which may contribute to central fatigue, our findings imply that spinal opioid receptor-sensitive muscle afferents might influence central fatigue by facilitating intracortical inhibition. PMID- 21317220 TI - Angiogenic factors in maternal circulation and the risk of severe fetal growth restriction. AB - Maternal angiogenic factors (placental growth factor, soluble fms-like tyrosine kinase 1 (Flt-1), and soluble endoglin) may be associated with fetal growth restriction, and the associations may differ according to stage of pregnancy. Among children born to pregnant women without preeclampsia in Norway between 1992 and 1994, 217 singletons with severe growth restriction (small for gestational age (SGA), <2.5th percentile) were compared with 378 singleton controls. For each angiogenic factor, SGA risk was related to concentrations in maternal serum collected in the first 2 trimesters, by using women with a serum concentration in the middle third at both samplings as reference. A low placental growth factor (lowest third) at both samplings was associated with high risk of SGA (odds ratio=3.8, 95% confidence interval: 1.6, 8.8). An increase from the lowest to the highest third of soluble Flt-1 was associated with high SGA risk (odds ratio=6.2, 95% confidence interval: 2.4, 16.1). Women with high soluble endoglin (highest third) at the second sampling had approximately a 3.5-fold increased risk of SGA. Low maternal soluble Flt-1 in early pregnancy followed by a strong subsequent increase in soluble Flt-1 and soluble endoglin was associated with a particularly high risk of severe fetal growth restriction. PMID- 21317221 TI - Evaluating the indirect effect of infant weight velocity on insulin resistance in young adulthood: a birth cohort study from the Philippines. AB - The authors assessed the relation between infant weight velocity and adult insulin resistance, specifically evaluating whether adult size and body fat distribution mediated the association. Data were from the Cebu Longitudinal Health and Nutrition Survey (Cebu, the Philippines), in which a birth cohort was followed to age 22 years (n=1,409; 1983-2005). Insulin resistance was measured using homeostasis model assessment of insulin resistance (HOMA-IR). Weight velocity (g/month) from 0 to 4 months and from 0 to 24 months was assessed. The authors examined direct and total associations between early growth and adult HOMA-IR in linear regression models and used a nonparametric bootstrapping procedure to test indirect effects through adult body mass index (BMI; weight (kg)/height (m)(2)) and waist circumference. Infant weight velocity was positively associated with adult BMI and waist circumference, which positively predicted HOMA-IR. There were no total or direct effects of immediate postnatal weight velocity (0-4 months) on adult HOMA-IR, although indirect effects through BMI and waist circumference were significant. Weight velocity from 0 to 24 months positively predicted HOMA-IR among males only, while indirect effects were significant in both sexes. In a relatively lean sample of young adults from a population with rising rates of diabetes and cardiovascular disease, the authors found evidence for small indirect effects of infant weight velocity on adult insulin resistance mediated through adult BMI and waist circumference. PMID- 21317222 TI - Hemorrhagic complications in a phase II study of sunitinib in patients of nasopharyngeal carcinoma who has previously received high-dose radiation. AB - BACKGROUND: We aimed to evaluate the safety and efficacy of single-agent sunitinib in nasopharyngeal carcinoma (NPC). METHODS: Eligible patients had progressive disease after prior platinum-based chemotherapy. Sunitinib was given as continuous once-daily dosing of 37.5 mg in 4-week cycles until progression. RESULTS: Thirteen patients were enrolled. Recruitment was stopped after two patients died of hemorrhagic events. All patients had previously received curative radiotherapy (RT) to nasopharynx/neck (including nine patients who had chemoradiotherapy). Patients received a median of three cycles of sunitinib. One patient was still on sunitinib with stable disease after 24 cycles. Hemorrhagic events occurred in nine patients (64%), including epistaxis in six, hemoptyses in three and hematemesis in two patients. Prior RT to thorax was significantly associated with hemoptyses (P = 0.03). Two patients with local tumor invasion into the carotid sheath developed fatal epistaxis/hematemesis within the first cycle of sunitinib, likely due to internal carotid blowout after tumor shrinkage. CONCLUSIONS: Sunitinib demonstrated modest clinical activity in heavily pretreated NPC patients. However, the high incidence of hemorrhage from the upper aerodigestive tract in NPC patients who received prior high-dose RT to the region is of concern. Direct vascular invasion by tumors appeared to increase the risk of serious bleeding. PMID- 21317223 TI - Survival and human papillomavirus in oropharynx cancer in TAX 324: a subset analysis from an international phase III trial. AB - BACKGROUND: The association between human papillomavirus (HPV) and overall survival (OS) in oropharynx cancer (OPC) was retrospectively examined in TAX 324, a phase III trial of sequential therapy for locally advanced head and neck cancer. METHODS: Accrual for TAX 324 was completed in 2003 and data updated through 2008. Pretherapy tumor biopsies were studied by PCR for human papillomavirus type 16 and linked to OS, progression-free survival (PFS) and demographics. RESULTS: Of 264 patients with OPC, 111 (42%) had evaluable biopsies; 56 (50%) were HPV+ and 55 (50%) were HPV-. HPV+ patients were significantly younger (54 versus 58 years, P = 0.02), had T1/T2 primary cancers (49% versus 20%, P = 0.001), and had a performance status of zero (77% versus 49%, P = 0.003). OS and PFS were better for HPV+ patients (OS, hazard ratio = 0.20, P < 0.0001). Local-regional failure was less in HPV+ patients (13% versus 42%, P = 0.0006); at 5 years, 82% of HPV+ patients were alive compared with 35% of HPV- patients (P < 0.0001). CONCLUSIONS: HPV+ OPC has a different biology compared with HPV- OPC; 5-year OS, PFS, and local-regional control are unprecedented. These results support the possibility of selectively reducing therapy and long-term morbidity in HPV+ OPC while preserving survival and approaching HPV- disease with more aggressive treatment. PMID- 21317226 TI - Why is the surgical high-risk patient still at risk? PMID- 21317224 TI - PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. AB - This study addresses the role of PTEN loss in intrinsic resistance to the BRAF inhibitor PLX4720. Immunohistochemical staining of a tissue array covering all stages of melanocytic neoplasia (n = 192) revealed PTEN expression to be lost in >10% of all melanoma cases. Although PTEN expression status did not predict for sensitivity to the growth inhibitory effects of PLX4720, it was predictive for apoptosis, with only limited cell death observed in melanomas lacking PTEN expression (PTEN-). Mechanistically, PLX4720 was found to stimulate AKT signaling in the PTEN- but not the PTEN+ cell lines. Liquid chromatography multiple reaction monitoring mass spectrometry (LC-MRM) was performed to identify differences in apoptosis signaling between the two cell line groups. PLX4720 treatment significantly increased BIM expression in the PTEN+ (>14-fold) compared with the PTEN- cell lines (four-fold). A role for PTEN in the regulation of PLX4720-mediated BIM expression was confirmed by siRNA knockdown of PTEN and through reintroduction of PTEN into cells that were PTEN-. Further studies showed that siRNA knockdown of BIM significantly blunted the apoptotic response in PTEN+ melanoma cells. Dual treatment of PTEN- cells with PLX4720 and a PI3K inhibitor enhanced BIM expression at both the mRNA and protein level and increased the level of apoptosis through a mechanism involving AKT3 and the activation of FOXO3a. In conclusion, we have shown for the first time that loss of PTEN contributes to intrinsic BRAF inhibitor resistance via the suppression of BIM mediated apoptosis. PMID- 21317227 TI - Anaesthetic management of patients with severe sepsis. PMID- 21317228 TI - Etomidate for induction of the septic patient. PMID- 21317230 TI - Some old truths are still true ... succinylcholine in spinal cord injury. PMID- 21317233 TI - Role of rocuronium and sugammadex in rapid sequence induction in pregnancy. PMID- 21317235 TI - Teaching epidural insertion: a modified approach to combined spinal-epidural anaesthesia. PMID- 21317236 TI - Haemodynamic effects of negative pressure ventilation. PMID- 21317238 TI - Low-flow anaesthesia in paediatric patients. PMID- 21317239 TI - EZH1 and EZH2 cogovern histone H3K27 trimethylation and are essential for hair follicle homeostasis and wound repair. AB - Polycomb protein group (PcG)-dependent trimethylation on H3K27 (H3K27me3) regulates identity of embryonic stem cells (ESCs). How H3K27me3 governs adult SCs and tissue development is unclear. Here, we conditionally target H3K27 methyltransferases Ezh2 and Ezh1 to address their roles in mouse skin homeostasis. Postnatal phenotypes appear only in doubly targeted skin, where H3K27me3 is abolished, revealing functional redundancy in EZH1/2 proteins. Surprisingly, while Ezh1/2-null hair follicles (HFs) arrest morphogenesis and degenerate due to defective proliferation and increased apoptosis, epidermis hyperproliferates and survives engraftment. mRNA microarray studies reveal that, despite these striking phenotypic differences, similar genes are up-regulated in HF and epidermal Ezh1/2-null progenitors. Featured prominently are (1) PcG controlled nonskin lineage genes, whose expression is still significantly lower than in native tissues, and (2) the PcG-regulated Ink4a/Inkb/Arf locus. Interestingly, when EZH1/2 are absent, even though Ink4a/Arf/Ink4b genes are fully activated in HF cells, they are only partially so in epidermal progenitors. Importantly, transduction of Ink4b/Ink4a/Arf shRNAs restores proliferation/survival of Ezh1/2-null HF progenitors in vitro, pointing toward the relevance of this locus to the observed HF phenotypes. Our findings reveal new insights into Polycomb-dependent tissue control, and provide a new twist to how different progenitors within one tissue respond to loss of H3K27me3. PMID- 21317240 TI - Zeppo1 is a novel metastasis promoter that represses E-cadherin expression and regulates p120-catenin isoform expression and localization. AB - Amplification of 8p11-12 in human breast cancers is associated with increased proliferation and tumor grade and reduced metastasis-free patient survival. We identified Zeppo1 (zinc finger elbow-related proline domain protein 1) (FLJ14299/ZNF703) within this amplicon as a regulator of cell adhesion, migration, and proliferation in mammary epithelial cells. Overexpression of Zeppo1 reduces cell-cell adhesion and stimulates migration and proliferation. Knockdown of Zeppo1 induces adhesion and lumen formation. Zeppo1 regulates transcription, complexing with Groucho and repressing E-cadherin expression and Wnt and TGFbeta reporter expression. Zeppo1 promotes expression of metastasis associated p120-catenin isoform 1 and alters p120-catenin localization upon cell contact with the extracellular matrix. Significantly, Zeppo1 overexpression in a mouse breast cancer model increases lung metastases, while reducing Zeppo1 expression reduces both tumor size and the number of lung metastases. These results indicate that Zeppo1 is a key regulator of breast cancer progression. PMID- 21317241 TI - Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. AB - Autophagy is a catabolic pathway used by cells to support metabolism in response to starvation and to clear damaged proteins and organelles in response to stress. We report here that expression of a H-ras(V12) or K-ras(V12) oncogene up regulates basal autophagy, which is required for tumor cell survival in starvation and in tumorigenesis. In Ras-expressing cells, defective autophagosome formation or cargo delivery causes accumulation of abnormal mitochondria and reduced oxygen consumption. Autophagy defects also lead to tricarboxylic acid (TCA) cycle metabolite and energy depletion in starvation. As mitochondria sustain viability of Ras-expressing cells in starvation, autophagy is required to maintain the pool of functional mitochondria necessary to support growth of Ras driven tumors. Human cancer cell lines bearing activating mutations in Ras commonly have high levels of basal autophagy, and, in a subset of these, down regulating the expression of essential autophagy proteins impaired cell growth. As cancers with Ras mutations have a poor prognosis, this "autophagy addiction" suggests that targeting autophagy and mitochondrial metabolism are valuable new approaches to treat these aggressive cancers. PMID- 21317242 TI - Combined impact of geriatric syndromes and cardiometabolic diseases on measures of functional impairment. AB - BACKGROUND: Examine the independent and joint effects of geriatric syndromes (GS) and cardiometabolic diseases (CMDs) on functional impairment. METHODS: Cross sectional analysis of baseline data from the Women's Health Initiative, including 62,829 women aged 65 years or older. GS (urinary incontinence, falls, and depression measured by the shortened Center for Epidemiological Studies Depression scale/Diagnostic Interview Schedule screening instrument) and CMD (coronary artery disease, coronary heart failure, and diabetes) were self reported. Physical and social functioning and general health subscales of the Short Form-36 dichotomized at the median for the study sample were used to assess functional impairment. Additive interaction between burden of GS and CMD was assessed using logistic regression models. RESULTS: Forty-three percent of women had at least one GS; 14.1% had at least one CMD; and 6.9% had at least one of each. Compared with women with no GS or CMD, women with one or more GS but no CMD were as likely to have physical functioning impairments (odds ratio [OR] = 1.79; 95% confidence interval [CI] = 1.73, 1.86) as those with CMD alone (OR = 1.97; CI = 1.84, 2.10). The association with social functioning was stronger for GS alone (OR = 2.10; CI = 2.02, 2.18) compared with CMD (OR = 1.60; CI = 1.50, 1.71). The association with general health was stronger for CMD alone (OR = 2.15; CI = 2.01, 2.29) compared with GS (OR = 1.68; CI = 1.62, 1.74). Significant interactions between GS and CMD were observed for all functional measures with 20%-30% of observed ORs attributable to additive interaction. CONCLUSION: GSs alone are associated with functional impairment in older women; the association is stronger in the presence of even one CMD. PMID- 21317243 TI - N-glycosylation engineering of plants for the biosynthesis of glycoproteins with bisected and branched complex N-glycans. AB - Glycoengineering is increasingly being recognized as a powerful tool to generate recombinant glycoproteins with a customized N-glycosylation pattern. Here, we demonstrate the modulation of the plant glycosylation pathway toward the formation of human-type bisected and branched complex N-glycans. Glycoengineered Nicotiana benthamiana lacking plant-specific N-glycosylation (i.e. beta1,2-xylose and core alpha1,3-fucose) was used to transiently express human erythropoietin (hEPO) and human transferrin (hTF) together with modified versions of human beta1,4-mannosyl-beta1,4-N-acetylglucosaminyltransferase (GnTIII), alpha1,3 mannosyl-beta1,4-N-acetylglucosaminyltransferase (GnTIV) and alpha1,6-mannosyl beta1,6-N-acetylglucosaminyltransferase (GnTV). hEPO was expressed as a fusion to the IgG-Fc domain (EPO-Fc) and purified via protein A affinity chromatography. Recombinant hTF was isolated from the intracellular fluid of infiltrated plant leaves. Mass spectrometry-based N-glycan analysis of hEPO and hTF revealed the quantitative formation of bisected (GnGnbi) and tri- as well as tetraantennary complex N-glycans (Gn[GnGn], [GnGn]Gn and [GnGn][GnGn]). Co-expression of GnTIII together with GnTIV and GnTV resulted in the efficient generation of bisected tetraantennary complex N-glycans. Our results show the generation of recombinant proteins with human-type N-glycosylation at great uniformity. The strategy described here provides a robust and straightforward method for producing mammalian-type N-linked glycans of defined structures on recombinant glycoproteins, which can advance glycoprotein research and accelerate the development of protein-based therapeutics. PMID- 21317244 TI - Making a case for defining osteonecrosis of the jaw. PMID- 21317245 TI - ONJ in two dental practice-based research network regions. AB - The incidence of osteonecrosis of the jaw (ONJ) in the population is low, but specifics are unknown. Potential risk factors include bisphosphonate treatment, steroid treatment, osteoporosis, and head/neck radiation. This Dental Practice Based Research Network study estimated ONJ incidence and odds ratios from bisphosphonate exposure and other risk factors using a key word search and manual chart reviews of electronic records for adults aged >= 35 yrs enrolled during 1995-2006 in two large health-care organizations. We found 16 ONJ cases among 572,606 cohort members; seven additional cases were identified through dental plan resources. Among 23 cases (0.63 per 100,000 patient years), 20 (87%) had at least one risk factor, and six (26%) had received oral bisphosphonates. Patients with oral bisphosphonates were 15.5 (CI, 6.0-38.7) more likely to have ONJ than non-exposed patients; however, the sparse number of ONJ cases limits firm conclusions and suggests that the absolute risks for ONJ from oral bisphosphonates is low. PMID- 21317247 TI - Marker removal system for Thermoanaerobacterium saccharolyticum and development of a markerless ethanologen. AB - Marker removal strategies were developed for Thermoanaerobacterium saccharolyticum to select against the pyrF gene and the pta and ack genes. The pta- and ack-based haloacetate selective strategy was subsequently used to create strain M0355, a markerless Deltaldh Deltapta Deltaack strain that produces ethanol at a high yield. PMID- 21317248 TI - WITHDRAWN: Wide distribution ranges of several microbial eukaryotes of nanofaunal size at abyssal depths of the South-East Atlantic and the Mediterranean. AB - This article has been withdrawn. PMID- 21317246 TI - Risk factors for osteonecrosis of the jaws: a case-control study from the CONDOR dental PBRN. AB - Case reports and cohort studies have linked bisphosphonate therapy and osteonecrosis of the jaws (ONJ), but neither causality nor specific risks for lesion development have been clearly established. We conducted a 1:3 case-control study with three dental Practice-based Research Networks, using dentist questionnaires and patient interviews for collection of data on bisphosphonate therapy, demographics, co-morbidities, and dental and medical treatments. Multivariable logistic regression analyses tested associations between bisphosphonate use and other risk factors with ONJ. We enrolled 191 ONJ cases and 573 controls in 119 dental practices. Bisphosphonate use was strongly associated with ONJ (odds ratios [OR] 299.5 {95%CI 70.0-1282.7} for intravenous [IV] use and OR = 12.2 {4.3-35.0} for oral use). Risk markers included local suppuration (OR = 7.8 {1.8-34.1}), dental extraction (OR = 7.6 {2.4-24.7}), and radiation therapy (OR = 24.1 {4.9-118.4}). When cancer patients (n = 143) were excluded, bisphosphonate use (OR = 7.2 {2.1-24.7}), suppuration (OR = 11.9 {2.0-69.5}), and extractions (OR = 6.6 {1.6-26.6}) remained associated with ONJ. Higher risk of ONJ began within 2 years of bisphosphonate initiation and increased four-fold after 2 years. Both IV and oral bisphosphonate use were strongly associated with ONJ. Duration of treatment > 2 years; suppuration and dental extractions were independent risk factors for ONJ. PMID- 21317249 TI - Inhibitory spectra and modes of antimicrobial action of gallotannins from mango kernels (Mangifera indica L.). AB - This study investigated the antimicrobial activities and modes of action of penta , hexa-, hepta-, octa-, nona-, and deca-O-galloylglucose (gallotannins) isolated from mango kernels. The MICs and minimum bactericidal concentrations (MBCs) against food-borne bacteria and fungi were determined using a critical dilution assay. Gram-positive bacteria were generally more susceptible to gallotannins than were Gram-negative bacteria. The MICs of gallotannins against Bacillus subtilis, Bacillus cereus, Clostridium botulinum, Campylobacter jejuni, Listeria monocytogenes, and Staphylococcus aureus were 0.2 g liter(-1) or less; enterotoxigenic Escherichia coli and Salmonella enterica were inhibited by 0.5 to 1 g liter(-1), and lactic acid bacteria were resistant. The use of lipopolysaccharide mutants of S. enterica indicated that the outer membrane confers resistance toward gallotannins. Supplementation of LB medium with iron eliminated the inhibitory activity of gallotannins against Staphylococcus aureus, and siderophore-deficient mutants of S. enterica were less resistant toward gallotannins than was the wild-type strain. Hepta-O-galloylglucose sensitized Lactobacillus plantarum TMW1.460 to hop extract, indicating inactivation of hop resistance mechanisms, e.g., the multidrug resistance (MDR) transporter HorA. Carbohydrate metabolism of Lactococcus lactis MG1363, a conditionally respiring organism, was influenced by hepta-O-galloylglucose when grown under aerobic conditions and in the presence of heme but not under anaerobic conditions, indicating that gallotannins influence the respiratory chain. In conclusion, the inhibitory activities of gallotannins are attributable to their strong affinity for iron and likely additionally relate to the inactivation of membrane-bound proteins. PMID- 21317250 TI - Inhibition of predation by Bdellovibrio bacteriovorus and Micavibrio aeruginosavorus via host cell metabolic activity in the presence of carbohydrates. AB - Bdellovibrio bacteriovorus and Micavibrio aeruginosavorus are highly motile Gram negative predatory bacteria with the potential of being used as biocontrol agents or living antibiotics. It was suggested previously that sugar-binding proteins play a role in M. aeruginosavorus and B. bacteriovorus host specificity and predator-prey interactions. The effect of carbohydrates on predation was reexamined in this study. It was demonstrated that the presence of carbohydrates could indeed block predation. However, further investigation demonstrated that inhibition of predation was due to medium acidification by the metabolic activity of the host and not to a blocking of a putative sugar-binding protein. The data presented here might be of value when storing, growing, and cultivating predatory bacteria, as well as when considering environmental conditions that might influence predation in the field. PMID- 21317251 TI - Spatial genetic structure of a vector-borne generalist pathogen. AB - Vector-borne generalist pathogens colonize several reservoir species and are usually dependent on polyphagous arthropods for dispersal; however, their spatial genetic structure is generally poorly understood. Using fast-evolving genetic markers (20 simple sequence repeat loci, resulting in a total of 119 alleles), we studied the genetic structure of the vector-borne plant-pathogenic bacterium Xylella fastidiosa in Napa Valley, CA, where it causes Pierce's disease when it is transmitted to grapevines from reservoir plants in adjacent riparian vegetation. Eighty-three different X. fastidiosa multilocus microsatellite genotypes were found in 93 isolates obtained from five vineyards, resulting in an index of clonal fraction closer to 0 and a Simpson's genotypic diversity index (D) closer to a maximum value of 1. Moderate values of Nei's gene diversity (H(Nei); average H(Nei) = 0.41) were observed for most of the X. fastidiosa populations. The low Wright's index of genetic diversity among populations calculated by the FSTAT software (Wright's F(ST) index) among population pairs (0.0096 to 0.1080) indicated a weak or absent genetic structure among the five populations; a panmictic population was inferred by Bayesian analyses (with the STRUCTURE and BAPS programs). Furthermore, a Mantel test showed no significant genetic isolation by distance when both Nei (r = -0.3459, P = 0.268) and linearized (r = -0.3106, P = 0.269) indices were used. These results suggest that the riparian vegetation from which vectors acquire the pathogen prior to inoculation of grapevines supports a diverse population of X. fastidiosa. PMID- 21317252 TI - The probiotic Escherichia coli Nissle 1917 reduces pathogen invasion and modulates cytokine expression in Caco-2 cells infected with Crohn's disease associated E. coli LF82. AB - Increased numbers of adherent invasive Escherichia coli (AIEC) have been found in Crohn's disease (CD) patients. In this report, we investigate the potential of the probiotic Escherichia coli Nissle 1917 (EcN) to reduce features associated with AIEC pathogenicity in an already established infection with AIEC reference strain LF82. PMID- 21317253 TI - Identification of genetic markers for differentiation of Shiga toxin-producing, enteropathogenic, and avirulent strains of Escherichia coli O26. AB - Shiga toxin-producing Escherichia coli (STEC) O26 is one of the top five enterohemorrhagic E. coli (EHEC) O groups most often associated with hemorrhagic colitis and hemolytic uremic syndrome (HUS) worldwide. STEC O26 is considered to have evolved from enteropathogenic (EPEC) O26 strains through the acquisition of Shiga toxin (Stx)-encoding genes. Our PCR data identified several STEC-like strains expressing all features of STEC except Stx production and carrying remnants of Stx phages that were probably derivatives of EHEC O26. EHEC and EPEC O26 strains phenotypically resemble O26 EHEC-like and apathogenic E. coli O26 strains and are therefore undistinguishable by cultural methods. A clear discrimination between the different O26 groups is required for diagnostics in patients and for control of food safety. To develop an assay for specific detection of EHEC and EHEC-like O26 strains, we used a high-throughput PCR approach for selection of discriminative genetic markers among 33 tested genes mostly encoding type III secretion system effector proteins. The genes ECs1822, nleH1-2, nleA, nleC, nleH1-1, nleG, nleG2, nleG6-1, nleG6-2, espJ, espM2, nleG8 2, espG, ent (or espL2), nleB, nleE, efa1, and espB were detected at different frequencies in O26 EHEC, EHEC-like, and EPEC strains, indicating the possible role of these genes in virulence of human pathogenic O26 strains. The espK and espN genes were detected only in EHEC and EHEC-like O26 strains. espK was present in 99.14% of EHEC and 91.14% of EHEC-like O26 strains and was hence the best candidate as a genetic marker for characterizing these pathogroups. These data were corroborated by a genotyping real-time PCR test based on allelic discrimination of the arcA (aerobic respiratory control protein A) gene. The results indicate that a combination of molecular detection tools for O26 wzx (wzx(O26)), eae-beta, stx, espK, and arcA genotyping is highly discriminative for clear identification of EHEC and EHEC-like E. coli O26 strains. This simple diagnostic test might be applicable in hospital service laboratories or public health laboratories to test strains isolated from stools of patients suffering from diarrhea. PMID- 21317254 TI - Pathogenicity island markers, virulence determinants malX and usp, and the capacity of Escherichia coli to persist in infants' commensal microbiotas. AB - Virulence-associated genes in bacteria are often located on chromosomal regions, termed pathogenicity islands (PAIs). Several PAIs are found in Escherichia coli strains that cause extraintestinal infections, but their role in commensal bowel colonization is unknown. Resident strains are enriched in adhesins (P fimbriae and type 1 fimbriae), capsular antigens (K1 and K5), hemolysin, and aerobactin and mostly belong to phylogenetic group B2. Here, we investigated whether six pathogenicity islands and the virulence determinants malX and usp are associated with fitness of E. coli in the infant bowel microbiota. E. coli strains isolated from stools of 130 Swedish infants during the first year of life were examined for their carriage of PAI markers, malX, and usp by PCR. Carriage was related to strain persistence: long-term colonizers (>=12 months) carried significantly more of PAI II from strain CFT703 (II(CFT703)), IV(536,) and II(J96) and malX and usp than intermediate colonizers (1 to 11 months) and transient strains (<3 weeks). The accumulation of PAI markers in each individual strain correlated positively with its time of persistence in the colon. Phylogenetic group B2 accounted for 69% of long-term colonizers, 46% of intermediate colonizers and 14% of transient strains. These results support the hypothesis that some bacterial traits contributing to extraintestinal infections have in fact evolved primarily because they increase the fitness of E. coli in its natural niche, the colon; accordingly, they may be regarded as fitness islands in the gut. PMID- 21317255 TI - Temperature adaptation markedly determines evolution within the genus Saccharomyces. AB - The present study uses a mathematical-empirical approach to estimate the cardinal growth temperature parameters (T(min), the temperature below which growth is no longer observed; T(opt), the temperature at which the MU(max) equals its optimal value; MU(opt), the optimal value of MU(max); and T(max), the temperature above which no growth occurs) of 27 yeast strains belonging to different Saccharomyces and non-Saccharomyces species. S. cerevisiae was the yeast best adapted to grow at high temperatures within the Saccharomyces genus, with the highest optimum (32.3 degrees C) and maximum (45.4 degrees C) growth temperatures. On the other hand, S. kudriavzevii and S. bayanus var. uvarum showed the lowest optimum (23.6 and 26.2 degrees C) and maximum (36.8 and 38.4 degrees C) growth temperatures, respectively, confirming that both species are more psychrophilic than S. cerevisiae. The remaining Saccharomyces species (S. paradoxus, S. mikatae, S. arboricolus, and S. cariocanus) showed intermediate responses. With respect to the minimum temperature which supported growth, this parameter ranged from 1.3 (S. cariocanus) to 4.3 degrees C (S. kudriavzevii). We also tested whether these physiological traits were correlated with the phylogeny, which was accomplished by means of a statistical orthogram method. The analysis suggested that the most important shift in the adaptation to grow at higher temperatures occurred in the Saccharomyces genus after the divergence of the S. arboricolus, S. mikatae, S. cariocanus, S. paradoxus, and S. cerevisiae lineages from the S. kudriavzevii and S. bayanus var. uvarum lineages. Finally, our mathematical models suggest that temperature may also play an important role in the imposition of S. cerevisiae versus non-Saccharomyces species during wine fermentation. PMID- 21317256 TI - Distribution and diversity of Gallionella-like neutrophilic iron oxidizers in a tidal freshwater marsh. AB - Microbial iron oxidation is an integral part of the iron redox cycle in wetlands. Nonetheless, relatively little is known about the composition and ecology of iron oxidizing communities in the soils and sediments of wetlands. In this study, sediment cores were collected across a freshwater tidal marsh in order to characterize the iron-oxidizing bacteria (FeOB) and to link their distributions to the geochemical properties of the sediments. We applied recently designed 16S rRNA primers targeting Gallionella-related FeOB by using a nested PCR-denaturing gradient gel electrophoresis (DGGE) approach combined with a novel quantitative PCR (qPCR) assay. Gallionella-related FeOB were detected in most of the samples. The diversity and abundance of the putative FeOB were generally higher in the upper 5 to 12 cm of sediment than in deeper sediment and higher in samples collected in April than in those collected in July and October. Oxygen supply by macrofauna appears to be a major force in controlling the spatial and temporal variations in FeOB communities. The higher abundance of Gallionella-related FeOB in April coincided with elevated concentrations of extractable Fe(III) in the sediments. Despite this coincidence, the distributions of FeOB did not exhibit a simple relationship to the redox zonation inferred from the geochemical depth profiles. PMID- 21317257 TI - Determination of adhesin gene sequences in, and biofilm formation by, O157 and non-O157 Shiga toxin-producing Escherichia coli strains isolated from different sources. AB - Biofilm formation by Shiga toxin-producing Escherichia coli (STEC) has been associated with the expression of different adhesins (type 1 fimbria, curli, Ag43, Cah, and EhaA). In this study, biofilm formation and the presence of adhesin-related gene sequences were determined by PCR in 18 O157 strains and 33 non-O157 strains isolated from different sources (human, animal, food, and water). The expression of different adhesins was also assessed by reverse transcription-PCR (RT-PCR), Congo red agar plates, and mannose-sensitive hemagglutination (MSHA) assay. Biofilm formation occurred in 5/18 (28%) O157 STEC strains and 17/33 (51%) non-O157 STEC strains from different serotypes and sources, when the assays were performed at 28 degrees C for 48 h. Among the non O157 biofilm-producing isolates, 12/17 (71%) expressed type 1 fimbriae and 11/17 (65%) expressed curli and produced cellulose, while 8/17 (47%) were considered to be Ag43(+) by RT-PCR. Among O157 strains, a close correlation was observed between biofilm formation and expression of curli and cellulose. In non-O157 strains, it seems that, in addition to the presence of curli, the ability to form biofilm is associated with the presence of other factors such as type 1 fimbriae and autotransporter proteins, which may contribute to the persistence of these organisms in the environment. PMID- 21317258 TI - Activity and distribution of thermophilic prokaryotes in hydrothermal fluid, sulfidic structures, and sheaths of alvinellids (East Pacific Rise, 13 degrees N). AB - Processes of inorganic carbon assimilation, methanogenesis, sulfate reduction, and acetate oxidation to CO(2) occurring in samples from the East Pacific Rise at 13 degrees N were traced, using radioisotopically labeled substrates, at temperatures ranging from 65 to 100 degrees C. Molecular hydrogen stimulated lithotrophic methanogenesis and sulfate reduction but inhibited inorganic carbon assimilation. Active mineralization of acetate was observed in an organic-rich Alvinella-associated system at 80 degrees C. Members of the Thermococcales were the most numerous hyperthermophilic archaea in these samples, their density achieving 10(8) cells per cm(3), while the numbers of cultured hydrogen-utilizing thermophilic lithotrophs were several orders of magnitude lower. PMID- 21317259 TI - Natural competence in the hyperthermophilic archaeon Pyrococcus furiosus facilitates genetic manipulation: construction of markerless deletions of genes encoding the two cytoplasmic hydrogenases. AB - In attempts to develop a method of introducing DNA into Pyrococcus furiosus, we discovered a variant within the wild-type population that is naturally and efficiently competent for DNA uptake. A pyrF gene deletion mutant was constructed in the genome, and the combined transformation and recombination frequencies of this strain allowed marker replacement by direct selection using linear DNA. We have demonstrated the use of this strain, designated COM1, for genetic manipulation. Using genetic selections and counterselections based on uracil biosynthesis, we generated single- and double-deletion mutants of the two gene clusters that encode the two cytoplasmic hydrogenases. The COM1 strain will provide the basis for the development of more sophisticated genetic tools allowing the study and metabolic engineering of this important hyperthermophile. PMID- 21317260 TI - Genetic diversity of O-antigen biosynthesis regions in Vibrio cholerae. AB - O-antigen biosynthetic (wbf) regions for Vibrio cholerae serogroups O5, O8, and O108 were isolated and sequenced. Sequences were compared to those of other published V. cholerae O-antigen regions. These wbf regions showed a high degree of heterogeneity both in gene content and in gene order. Genes identified frequently showed greater similarities to polysaccharide biosynthesis genes from species other than V. cholerae. Our results demonstrate the plasticity of O antigen genes in V. cholerae, the diversity of the genetic pool from which they are drawn, and the likelihood that new pandemic serogroups will emerge. PMID- 21317261 TI - Metagenomic analysis of kimchi, a traditional Korean fermented food. AB - Kimchi, a traditional food in the Korean culture, is made from vegetables by fermentation. In this study, metagenomic approaches were used to monitor changes in bacterial populations, metabolic potential, and overall genetic features of the microbial community during the 29-day fermentation process. Metagenomic DNA was extracted from kimchi samples obtained periodically and was sequenced using a 454 GS FLX Titanium system, which yielded a total of 701,556 reads, with an average read length of 438 bp. Phylogenetic analysis based on 16S rRNA genes from the metagenome indicated that the kimchi microbiome was dominated by members of three genera: Leuconostoc, Lactobacillus, and Weissella. Assignment of metagenomic sequences to SEED categories of the Metagenome Rapid Annotation using Subsystem Technology (MG-RAST) server revealed a genetic profile characteristic of heterotrophic lactic acid fermentation of carbohydrates, which was supported by the detection of mannitol, lactate, acetate, and ethanol as fermentation products. When the metagenomic reads were mapped onto the database of completed genomes, the Leuconostoc mesenteroides subsp. mesenteroides ATCC 8293 and Lactobacillus sakei subsp. sakei 23K genomes were highly represented. These same two genera were confirmed to be important in kimchi fermentation when the majority of kimchi metagenomic sequences showed very high identity to Leuconostoc mesenteroides and Lactobacillus genes. Besides microbial genome sequences, a surprisingly large number of phage DNA sequences were identified from the cellular fractions, possibly indicating that a high proportion of cells were infected by bacteriophages during fermentation. Overall, these results provide insights into the kimchi microbial community and also shed light on fermentation processes carried out broadly by complex microbial communities. PMID- 21317262 TI - Synechococcus sp. strain PCC 7002 nifJ mutant lacking pyruvate:ferredoxin oxidoreductase. AB - The nifJ gene codes for pyruvate:ferredoxin oxidoreductase (PFOR), which reduces ferredoxin during fermentative catabolism of pyruvate to acetyl-coenzyme A (acetyl-CoA). A nifJ knockout mutant was constructed that lacks one of two pathways for the oxidation of pyruvate in the cyanobacterium Synechococcus sp. strain PCC 7002. Remarkably, the photoautotrophic growth rate of this mutant increased by 20% relative to the wild-type (WT) rate under conditions of light dark cycling. This result is attributed to an increase in the quantum yield of photosystem II (PSII) charge separation as measured by photosynthetic electron turnover efficiency determined using fast-repetition-rate fluorometry (F(v)/F(m)). During autofermentation, the excretion of acetate and lactate products by nifJ mutant cells decreased 2-fold and 1.2-fold, respectively. Although nifJ cells displayed higher in vitro hydrogenase activity than WT cells, H(2) production in vivo was 1.3-fold lower than the WT level. Inhibition of acetate-CoA ligase and pyruvate dehydrogenase complex by glycerol eliminated acetate production, with a resulting loss of reductant and a 3-fold decrease in H(2) production by nifJ cells compared to WT cells. Continuous electrochemical detection of dissolved H(2) revealed two temporally resolved phases of H(2) production during autofermentation, a minor first phase and a major second phase. The first phase was attributed to reduction of ferredoxin, because its level decreased 2-fold in nifJ cells. The second phase was attributed to glycolytic NADH production and decreased 20% in nifJ cells. Measurement of the intracellular NADH/NAD(+) ratio revealed that the reductant generated by PFOR contributing to the first phase of H(2) production was not in equilibrium with bulk NADH/NAD(+) and that the second phase corresponded to the equilibrium NADH-mediated process. PMID- 21317263 TI - Molecular characterization of a novel N-acetylneuraminate lyase from Lactobacillus plantarum WCFS1. AB - N-Acetylneuraminate lyases (NALs) or sialic acid aldolases catalyze the reversible aldol cleavage of N-acetylneuraminic acid (Neu5Ac) to form pyruvate and N-acetyl-d-mannosamine (ManNAc). In nature, N-acetylneuraminate lyase occurs mainly in pathogens. However, this paper describes how an N-acetylneuraminate lyase was cloned from the human gut commensal Lactobacillus plantarum WCFS1 (LpNAL), overexpressed, purified, and characterized for the first time. This novel enzyme, which reaches a high expression level (215 mg liter(-1) culture), shows similar catalytic efficiency to the best NALs previously described. This homotetrameric enzyme (132 kDa) also shows high stability and activity at alkaline pH (pH > 9) and good temperature stability (60 to 70 degrees C), this last feature being further improved by the presence of stabilizing additives. These characteristics make LpNAL a promising biocatalyst. When its sequence was compared with that of other, related (real and putative) NALs described in the databases, it was seen that NAL enzymes could be divided into four structural groups and three subgroups. The relation of these subgroups with human and other mammalian NALs is also discussed. PMID- 21317264 TI - Construction of a bacterial assay for estrogen detection based on an estrogen sensitive intein. AB - Escherichia coli strain DIER was constructed for estrogen detection by inserting an estrogen-sensitive intein (VMA(ER) intein) into the specific site of the constitutively expressed chromosomal lacZ gene. This VMA(ER) intein was generated by replacing the endonuclease region of the Saccharomyces cerevisiae VMA intein with the estrogen binding region of the human estrogen receptor alpha (hERalpha). When there were estrogens or analogs, the splicing of the VMA(ER) intein was induced to produce the mature LacZ protein, which was detected through a beta galactosidase colorimetric assay. Eight typical chemicals (17-beta-estradiol, bisphenol A, chrysene, 6-OH-chrysene, benz[a]anthracene, pyrene, progesterone, and testosterone) were detected using this DIER strain, and the whole detection procedure was accomplished in 2 h. Their 50% effective concentrations (EC(50)), relative estrogenic activities, and estradiol equivalency factors were calculated and were quite consistent with those detected with the yeast estrogen screening (YES) system. Furthermore, the estrogenic activities of the synthetic musk samples extracted from the wastewater and waste sludge of a sewage treatment plant of Shanghai (China) were detected, and their results were comparable to those obtained from the YES system and gas chromatography-mass spectrometry (GC MS). In conclusion, the DIER bioassay could fill a niche for the efficient, rapid, high-throughput screening of estrogenic compounds and has potential for the remote, near-real-time monitoring of environmental estrogens. PMID- 21317265 TI - Contribution of rapid evolution of the luxR-luxI intergenic region to the diverse bioluminescence outputs of Vibrio fischeri strains isolated from different environments. AB - Vibrio fischeri serves as a valuable model of bacterial bioluminescence, its regulation, and its functional significance. Light output varies more than 10,000 fold in wild-type isolates from different environments, yet dim and bright strains have similar organization of the light-producing lux genes, with the activator-encoding luxR divergently transcribed from luxICDABEG. By comparing the genomes of bright strain MJ11 and the dimmer ES114, we found that the lux region has diverged more than most shared orthologs, including those flanking lux. Divergence was particularly high in the intergenic sequence between luxR and luxI. Analysis of the intergenic lux region from 18 V. fischeri strains revealed that, with one exception, sequence divergence essentially mirrored strain phylogeny but with relatively high substitution rates. The bases conserved among intergenic luxR-luxI sequences included binding sites for known regulators, such as LuxR and ArcA, and bases of unknown significance, including a striking palindromic repeat. By using this collection of diverse luxR-luxI regions, we found that expression of P(luxI)-lacZ but not P(luxR)-lacZ transcriptional reporters correlated with the luminescence output of the strains from which the promoters originated. We also found that exchange of a small stretch of the luxI luxR intergenic region between two strains largely reversed their relative brightness. Our results show that the luxR-luxI intergenic region contributes significantly to the variable luminescence output among V. fischeri strains isolated from different environments, although other elements of strain backgrounds also contribute. Moreover, the lux system appears to have evolved relatively rapidly, suggesting unknown environment-specific selective pressures. PMID- 21317266 TI - Proof of concept for recombinant cellular controls in quantitative molecular pathogen detection. AB - In this study, we present the concept of internal sample process controls (ISPCs) to monitor the efficiency of an analytical chain using sample preparation and quantitative PCR (qPCR). A recombinant Listeria monocytogenes DeltaprfA (targeted deletion) strain containing a competitive artificial single-copy genomic target was applied to naturally contaminated samples to demonstrate its analytical suitability as an ISPC. PMID- 21317267 TI - Cellulose- and xylan-degrading thermophilic anaerobic bacteria from biocompost. AB - Nine thermophilic cellulolytic clostridial isolates and four other noncellulolytic bacterial isolates were isolated from self-heated biocompost via preliminary enrichment culture on microcrystalline cellulose. All cellulolytic isolates grew vigorously on cellulose, with the formation of either ethanol and acetate or acetate and formate as principal fermentation products as well as lactate and glycerol as minor products. In addition, two out of nine cellulolytic strains were able to utilize xylan and pretreated wood with roughly the same efficiency as for cellulose. The major products of xylan fermentation were acetate and formate, with minor contributions of lactate and ethanol. Phylogenetic analyses of 16S rRNA and glycosyl hydrolase family 48 (GH48) gene sequences revealed that two xylan-utilizing isolates were related to a Clostridium clariflavum strain and represent a distinct novel branch within the GH48 family. Both isolates possessed high cellulase and xylanase activity induced independently by either cellulose or xylan. Enzymatic activity decayed after growth cessation, with more-rapid disappearance of cellulase activity than of xylanase activity. A mixture of xylan and cellulose was utilized simultaneously, with a significant synergistic effect observed as a reduction of lag phase in cellulose degradation. PMID- 21317268 TI - Quantitative metagenomic analyses based on average genome size normalization. AB - Over the past quarter-century, microbiologists have used DNA sequence information to aid in the characterization of microbial communities. During the last decade, this has expanded from single genes to microbial community genomics, or metagenomics, in which the gene content of an environment can provide not just a census of the community members but direct information on metabolic capabilities and potential interactions among community members. Here we introduce a method for the quantitative characterization and comparison of microbial communities based on the normalization of metagenomic data by estimating average genome sizes. This normalization can relieve comparative biases introduced by differences in community structure, number of sequencing reads, and sequencing read lengths between different metagenomes. We demonstrate the utility of this approach by comparing metagenomes from two different marine sources using both conventional small-subunit (SSU) rRNA gene analyses and our quantitative method to calculate the proportion of genomes in each sample that are capable of a particular metabolic trait. With both environments, to determine what proportion of each community they make up and how differences in environment affect their abundances, we characterize three different types of autotrophic organisms: aerobic, photosynthetic carbon fixers (the Cyanobacteria); anaerobic, photosynthetic carbon fixers (the Chlorobi); and anaerobic, nonphotosynthetic carbon fixers (the Desulfobacteraceae). These analyses demonstrate how genome proportionality compares to SSU rRNA gene relative abundance and how factors such as average genome size and SSU rRNA gene copy number affect sampling probability and therefore both types of community analysis. PMID- 21317269 TI - Amount but not pattern of protective sensory stimulation alters recovery after permanent middle cerebral artery occlusion. AB - BACKGROUND AND PURPOSE: Using a rodent model of ischemia (permanent middle cerebral artery occlusion), our laboratory previously demonstrated that 4.27 minutes of patterned single-whisker stimulation delivered over 120 minutes can fully protect from impending damage when initiated within 2 hours of permanent middle cerebral artery occlusion ("early"). When initiated 3 hours postpermanent middle cerebral artery occlusion ("late"), stimulation resulted in irreversible damage. Here we investigate the effect of altering pattern, distribution, or amount of stimulation in this model. METHODS: We assessed the cortex using functional imaging and histological analysis with altered stimulation treatment protocols. In 2 groups of animals we administered the same number of whisker deflections but in a random rather than patterned fashion distributed either over 120 minutes or condensed into 10 minutes postpermanent middle cerebral artery occlusion. We also tested increased (full-whisker array versus single-whisker) stimulation. RESULTS: Early random whisker stimulation (condensed or dispersed) resulted in protection equivalent to early patterned stimulation. Early full whisker array patterned stimulation also resulted in complete protection but promoted faster recovery. Late full-whisker array patterned stimulation, however, resulted in loss of evoked function and infarct volumes larger than those sustained by single-whisker counterparts. CONCLUSIONS: When induced early on after ischemic insult, stimulus-evoked cortical activity, irrespective of the parameters of peripheral stimulation that induced it, seems to be the important variable for neuroprotection. PMID- 21317270 TI - Interrater reliability of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a multicenter study. AB - BACKGROUND AND PURPOSE: Stroke is an important cause of death and disability among children. Clinical trials for childhood stroke require a valid and reliable acute clinical stroke scale. We evaluated interrater reliability (IRR) of a pediatric adaptation of the National Institutes of Health Stroke Scale. METHODS: The pediatric adaptation of the National Institutes of Health Stroke Scale was developed by pediatric and adult stroke experts by modifying each item of the adult National Institutes of Health Stroke Scale for children, retaining all examination items and scoring ranges of the National Institutes of Health Stroke Scale. Children 2 to 18 years of age with acute arterial ischemic stroke were enrolled in a prospective cohort study from 15 North American sites from January 2007 to October 2009. Examiners were child neurologists certified in the adult National Institutes of Health Stroke Scale. Each subject was examined daily for 7 days or until discharge. A subset of patients at 3 sites was scored simultaneously and independently by 2 study neurologists. RESULTS: IRR testing was performed in 25 of 113 a median of 3 days (interquartile range, 2 to 4 days) after symptom onset. Patient demographics, total initial pediatric adaptation of the National Institutes of Health Stroke Scale scores, risk factors, and infarct characteristics in the IRR subset were similar to the non-IRR subset. The 2 raters' total scores were identical in 60% and within 1 point in 84%. IRR was excellent as measured by concordance correlation coefficient of 0.97 (95% CI, 0.94 to 0.99); intraclass correlation coefficient of 0.99 (95% CI, 0.97 to 0.99); precision measured by Pearson rho of 0.97; and accuracy measured by the bias correction factor of 1.0. CONCLUSIONS: There was excellent IRR of the pediatric adaptation of the National Institutes of Health Stroke Scale in a multicenter prospective cohort performed by trained child neurologists. PMID- 21317272 TI - What is your guess? The case of the blue-green urine. PMID- 21317271 TI - Endothelial nitric oxide synthase mediates endogenous protection against subarachnoid hemorrhage-induced cerebral vasospasm. AB - BACKGROUND AND PURPOSE: Vasospasm-induced delayed cerebral ischemia remains a major source of morbidity in patients with aneurysmal subarachnoid hemorrhage (SAH). We hypothesized that activating innate neurovascular protective mechanisms by preconditioning (PC) may represent a novel therapeutic approach against SAH induced vasospasm and neurological deficits and, secondarily, that the neurovascular protection it provides is mediated by endothelial nitric oxide synthase (eNOS). METHODS: Wild-type mice were subjected to hypoxic PC or normoxia followed 24 hours later by SAH. Neurological function was analyzed daily; vasospasm was assessed on post-surgery Day 2. Nitric oxide availability, eNOS expression, and eNOS activity were also assessed. In a separate experiment, wild type and eNOS-null mice were subjected to hypoxic PC or normoxia followed by SAH and assessed for vasospasm and neurological deficits. RESULTS: PC nearly completely prevented SAH-induced vasospasm and neurological deficits. It also prevented SAH-induced reduction in nitric oxide availability and increased eNOS activity in mice with and without SAH. PC-induced protection against vasospasm and neurological deficits was lost in wild-type mice treated with the nitric oxide synthase inhibitor N(G)-nitro-l-arginine methyl ester and in eNOS-null mice. CONCLUSIONS: Endogenous protective mechanisms against vasospasm exist, are powerful, and can be induced by PC. eNOS-derived nitric oxide is a critical mediator of PC-induced neurovascular protection. These data provide strong "proof of-principle" evidence that PC represents a promising new strategy to reduce vasospasm and delayed cerebral ischemia after SAH. PMID- 21317273 TI - Proposed serum cholesterol reference measurement procedure by gas chromatography isotope dilution mass spectrometry. AB - BACKGROUND: Our purpose was to establish a mass spectrometry reference measurement procedure (RMP) for cholesterol to use in the CDC's standardization programs. We explored a gas chromatography-isotope dilution mass spectrometry (GC IDMS) procedure using a multilevel standard calibration curve to quantify samples with varying cholesterol concentrations. METHODS: We calibrated the mass spectrometry instrument by isotope dilution with a pure primary standard reference material and an isotopically enriched cholesterol analog as the internal standard (IS). We diluted the serum samples with Tris-HCl buffer (pH 7.4, 0.05 mol/L, 0.25% Triton X-100) before analysis. We used 17 serum pools, 10 native samples, and 2 standard reference materials (SRMs). We compared the GC IDMS measurements with the CDC's modified Abell-Levy-Brodie-Kendall (AK) RMP measurements and assessed method accuracy by analyzing 2 SRMs. We evaluated the procedure for lack of interference by analyzing serum spiked with a mixture of 7 sterols. RESULTS: The mean percent bias between the AK and the GC-IDMS RMP was 1.6% for all samples examined. The mean percent bias from NIST's RMP was 0.5% for the SRMs. The total %CVs for SRM 1951b levels I and II were 0.61 and 0.73%, respectively. We found that none of the sterols investigated interfered with the cholesterol measurement. CONCLUSIONS: The low imprecision, linear response, lack of interferences, and acceptable bias vs the NIST primary RMP qualifies this procedure as an RMP for determining serum cholesterol. The CDC will adopt and implement this GC-IDMS procedure for cholesterol standardization. PMID- 21317274 TI - Psychrobacter sanguinis sp. nov., recovered from four clinical specimens over a 4 year period. AB - An analysis of 16S rRNA gene sequences from archived clinical reference specimens identified a novel species of the genus Psychrobacter, of which four strains have been independently isolated from human blood. On the basis of 16S rRNA gene sequence similarity, the closest relatives with validly published names were Psychrobacter arenosus R7(T) (98.7%), P. pulmonis CECT 5989(T) (97.7%), P. faecalis Iso-46(T) (97.6%) and P. lutiphocae IMMIB L-1110(T) (97.2%). Maximum likelihood phylogenetic analysis of 16S rRNA gene sequences showed that the isolates belonged to the genus Psychrobacter and were members of a cluster associated with Psychrobacter sp. PRwf-1, isolated from a silk snapper fish. DNA DNA relatedness and partial 23S rRNA gene sequences also supported the finding that the isolates belonged to a species distinct from its closest phylogenetic neighbours. The predominant cellular fatty acids were C(18:1)omega9c, C(16:0), summed feature 3 (C(16:1)omega7c and/or iso-C(15:0) 2-OH), summed feature 5 (C(18:2)omega6,9c and/or anteiso-C(18:0)) and C(18:0). Biochemical and morphological analysis further supported the assignment of the four isolates to a novel species. The name Psychrobacter sanguinis sp. nov. is proposed. The type strain is 13983(T) (=DSM 23635(T)=CCUG 59771(T)). PMID- 21317275 TI - Maritalea porphyrae sp. nov., isolated from a red alga (Porphyra yezoensis), and transfer of Zhangella mobilis to Maritalea mobilis comb. nov. AB - Three Gram-negative, motile, aerobic bacteria were isolated from cultures of the marine red alga Porphyra yezoensis. Phylogenetic analysis based on 16S rRNA gene sequences revealed that the novel strains were closely related to Maritalea myrionectae CL-SK30(T) (97.9% 16S rRNA gene sequence similarity) and Zhangella mobilis E6(T) (96.2 %). 16S rRNA gene sequence similarity between Z. mobilis E6(T) and M. myrionectae CL-SK30(T) was 97.9%. The DNA G+C contents of the isolates (49.4-50.0 mol%) were similar to those of M. myrionectae DSM 19524(T) (52.3 mol%) and Z. mobilis JCM 15144(T) (50.3 mol%). From these results, it was difficult to differentiate the genus Zhangella from the genus Maritalea. DNA-DNA hybridization demonstrated that the isolates belonged to a single species. The isolates could also be distinguished from M. myrionectae and Z. mobilis on the basis of chemotaxonomic and phenotypic features, including fatty acid composition (particularly C(16:1)omega7c), growth with 6-9% (w/v) NaCl, carbon utilization, oxidation patterns and so on. A novel species of the genus Maritalea is proposed to accommodate the three isolates, with the name Maritalea porphyrae sp. nov. The type strain is LCM-3(T) (=LMG 25872(T)=NBRC 107169(T)). Furthermore, it is proposed that Zhangella mobilis should be transferred from the genus Zhangella to the genus Maritalea, with the name Maritalea mobilis comb. nov. (type strain E6(T)=CGMCC 1.7002(T)=JCM 15144(T)). PMID- 21317276 TI - Laceyella sediminis sp. nov., a thermophilic bacterium isolated from a hot spring. AB - A thermophilic bacterium, designated strain RHA1(T), was isolated from a sediment sample collected from a hot spring in Tengchong county, Yunnan province, south west China, and was characterized by using a polyphasic approach. Based on its phenotypic and phylogenetic characteristics, strain RHA1(T) was affiliated to the genus Laceyella. The strain formed white aerial and yellow-white substrate mycelia, bearing single endospores on short sporophores. The cell-wall peptidoglycan contained meso-diaminopimelic acid. Whole-cell hydrolysates contained ribose and glucose. The major fatty acids were iso-C(15:0) (62.39%) and anteiso-C(15:0) (17.55%)(.) The predominant menaquinone was MK-9. The G+C content of the genomic DNA of strain RHA1(T) was 47.9 mol%. Based on DNA-DNA hybridization data, chemotaxonomic characteristics and differential physiological properties, strain RHA1(T) is considered to represent a novel species of the genus Laceyella, for which the name Laceyella sediminis sp. nov. is proposed; the type strain is RHA1(T) (=DSM 45263(T)=CCTCC AA 208058(T)). PMID- 21317277 TI - Desulfovibrio arcticus sp. nov., a psychrotolerant sulfate-reducing bacterium from a cryopeg. AB - A psychrotolerant sulfate-reducing bacterium, designated B15(T), was isolated from supercooled water brine from within permafrost of the Varandey Peninsula, on the southern coast of the Barents Sea. Cells were Gram-negative, motile vibrions (3.0-4.0*0.4-0.5 um) with a single polar flagellum. The isolate was positive for desulfoviridin as a bisulfite reductase. Strain B15(T) grew at -2 to 28 degrees C (optimum 24 degrees C) and with 0-2.0% NaCl (optimum 0.2%). The isolate used H(2) plus acetate, formate, ethanol, lactate, pyruvate and choline as electron donors and used sulfate, sulfite, thiosulfate, elemental sulfur, DMSO and Fe(3+) as electron acceptors. Pyruvate and lactate were not fermented in the absence of sulfate. The G+C content of genomic DNA was 55.2 mol%. Analysis of the 16S rRNA gene sequence showed that the isolate belonged to the genus Desulfovibrio. Its closest relatives were Desulfovibrio idahonensis CY1(T) (98.8% 16S rRNA gene sequence similarity) and Desulfovibrio mexicanus Lup1(T) (96.5%). On the basis of genotypic, phenotypic and phylogenetic characteristics, the isolate represents a novel species, for which the name Desulfovibrio arcticus sp. nov. is proposed; the type strain is B15(T) (=VKM B-2367(T)=DSM 21064(T)). PMID- 21317278 TI - Altererythrobacter xinjiangensis sp. nov., isolated from desert sand, and emended description of the genus Altererythrobacter. AB - A Gram-negative, rod-shaped, non-motile, strictly aerobic bacterium, strain S3 63(T), was isolated from desert sand of Xinjiang, China. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain S3-63(T) had highest similarity to type strains of the genus Altererythrobacter, i.e. Altererythrobacter marinus H32(T) (97.2% similarity), Altererythrobacter marensis MSW-14(T) (95.9%), Altererythrobacter aestuarii KCTC 22735(T) (95.5%), Altererythrobacter epoxidivorans JCS350(T) (95.1%), Altererythrobacter namhicola KCTC 22736(T) (95.1%), Altererythrobacter luteolus SW-109(T) (95.0%) and Altererythrobacter indicus LMG 23789(T) (93.5%). Growth occurred at 20-37 degrees C (optimum 30 degrees C), at pH 7.0-9.0 (optimum pH 8.0) and in 0-3% (w/v) NaCl (optimum 1%). The major respiratory quinone was ubiquinone-10 and the predominant cellular fatty acids were C(18:1)omega7c (50.8%), summed feature 3 (C(16:1)omega7c and/or C(16:1)omega6c; 12.6%), C(16:0) (12.3%), C(14:0) 2-OH (7.3%) and C(17:1)omega6c (4.5%). The DNA G+C content was 64.6 mol%. Therefore, the phylogenetic, physiological and chemotaxonomic data demonstrated that strain S3-63(T) represents a novel species of the genus Altererythrobacter, for which the name Altererythrobacter xinjiangensis sp. nov. is proposed; the type strain is S3-63(T) (=CCTCC AB 207166(T)=CIP 110125(T)). An emended description of the genus Altererythrobacter is provided. PMID- 21317279 TI - Amycolatopsis salitolerans sp. nov., a filamentous actinomycete isolated from a hypersaline habitat. AB - A novel actinomycete strain, designated TRM F103(T), was isolated from a hypersaline habitat of the Tarim basin in Xinjiang province, north-west China. Phylogenetic analysis based on 16S rRNA gene sequences showed that the isolate belonged to the genus Amycolatopsis and was most closely related to Amycolatopsis halophila YIM 93223(T) (99.3% 16S rRNA gene sequence similarity). However, DNA DNA relatedness between these two strains, based on triplicate experiments, was only 31.6%. The isolate contained meso-diaminopimelic acid and ribose, glucose and galactose as the major whole-cell sugars. The predominant menaquinone was MK 8(H(4)). The major fatty acids were iso-C(16:0) and C(16:0). The polar lipids were diphosphatidylglycerol, phosphatidylmethylethanolamine, phosphatidylethanolamine and glucosamine-containing phospholipids. The G+C content of the genomic DNA was 66.4 mol%. The phenotypic data clearly distinguished the isolate from its closest relatives. The combined phylogenetic, chemotaxonomic and phenotypic data indicate that the isolate represents a novel species of the genus Amycolatopsis. The proposed name is Amycolatopsis salitolerans sp. nov., with TRM F103(T) (=JCM 15899(T)=CCTCC AB 208326(T)) as the type strain. PMID- 21317280 TI - Phenotypic variability and phylogenetic relationships of the genera Tolypothrix and Calothrix (Nostocales, Cyanobacteria) from running water. AB - The taxonomy of heterocystous cyanobacteria belonging to the genera Calothrix and Tolypothrix has long been a matter of debate, but their phylogenetic relationships are still not well understood. Our aim was to compare the phylogeny and morphology of members of these genera, which exhibit basal-apical polarity. A phylogeny was reconstructed on the basis of 16S rRNA gene sequences and compared with the morphological characterization of new isolates and environmental samples. Strains isolated from several rivers and streams showed a high degree of tapering when they were cultured in a nutrient-rich medium. However, clear differences were apparent when they were transferred to a nutrient-poor medium. Some strains showed a low degree of tapering and other morphological features corresponding to the genus Tolypothrix, such as false branching, whereas others maintained the morphological characteristics of the genus Calothrix. Phylogenetic analysis was congruent with the phenotypic characterization, in which the strains and environmental samples of the Tolypothrix and Calothrix morphotypes could be clearly separated. Isolates with a low degree of tapering and natural samples of Tolypothrix distorta were grouped in the same cluster, but strains of the genus Calothrix fell into well separated clades. Results from this study showed that representatives of the genus Tolypothrix share most morphological and developmental properties and a high degree of 16S rRNA gene sequence similarity. However, although similar and sometimes overlapping morphologies may occur in isolates of the genus Calothrix, these morphotypes may be distinguished on the basis of their clear genetic divergence. PMID- 21317281 TI - Mucilaginibacter angelicae sp. nov., isolated from the rhizosphere of Angelica polymorpha Maxim. AB - A Gram-negative-staining, non-motile rod, designated GG-w14(T), was isolated from the rhizosphere of Angelica polymorpha Maxim. Phylogenetic analysis of 16S rRNA gene sequences revealed that the isolate belonged to the genus Mucilaginibacter and exhibited 93.9-97.4% 16S rRNA gene sequence similarity with recognized members of the genus Mucilaginibacter (closest relative Mucilaginibacter gossypii Gh-67(T)). DNA-DNA relatedness between strain GG-w14(T) and M. gossypii KCTC 22380(T) was <41%. Strain GG-w14(T) grew at 4-35 degrees C, at pH 5.0-8.0 and with 0-1% (w/v) NaCl. The isolate hydrolysed casein, CM-cellulose and starch and contained menaquinone 7 as the major menaquinone. The major cellular fatty acids were summed feature 3 (C(16:1)omega7c and/or iso-C(15:0) 2-OH; 39.9%), iso C(15:0) (24.2%) and iso-C(17:0) 3-OH (12.4%). The DNA G+C content was 42.5 mol%. These data suggest that strain GG-w14(T) should be considered as a representative of a novel species of the genus Mucilaginibacter, for which the name Mucilaginibacter angelicae sp. nov. is proposed. The type strain is GG-w14(T) (=KCTC 23250(T)=NCAIM B 02415(T)). PMID- 21317282 TI - A meta-analysis of the associations between common variation in the PDE8B gene and thyroid hormone parameters, including assessment of longitudinal stability of associations over time and effect of thyroid hormone replacement. AB - OBJECTIVE: Common variants in PDE8B are associated with TSH but apparently without any effect on thyroid hormone levels that is difficult to explain. Furthermore, the stability of the association has not been examined in longitudinal studies or in patients on levothyroxine (l-T(4)). DESIGN: Totally, four cohorts were used (n=2557): the Busselton Health Study (thyroid function measured on two occasions), DEPTH, EFSOCH (selective cohorts), and WATTS (individuals on l-T(4)). METHODS: Meta-analysis to clarify associations between the rs4704397 single nucleotide polymorphism in PDE8B on TSH, tri-iodothyronine (T(3)), and T(4) levels. RESULTS: Meta-analysis confirmed that genetic variation in PDE8B was associated with TSH (P=1.64 * 10(-10) 0.20 s.d./allele, 95% confidence interval (CI) 0.142, 0.267) and identified a possible new association with free T(4) (P=0.023, -0.07 s.d./allele, 95% CI -0.137, -0.01), no association was seen with free T(3) (P=0.218). The association between PDE8B and TSH was similar in 1981 (0.14 s.d./allele, 95% CI 0.04, 0.238) and 1994 (0.20 s.d./allele, 95% CI 0.102, 0.300) and even more consistent between PDE8B and free T(4) in 1981 (-0.068 s.d./allele, 95% CI -0.167, 0.031) and 1994 (-0.07 s.d./allele, 95% CI -0.170, 0.030). No associations were seen between PDE8B and thyroid hormone parameters in individuals on l-T(4). CONCLUSION: Common genetic variation in PDE8B is associated with reciprocal changes in TSH and free T(4) levels that are consistent over time and lost in individuals on l-T(4). These findings identify a possible genetic marker reflecting variation in thyroid hormone output that will be of value in epidemiological studies and provides additional evidence that PDE8B is involved in TSH signaling in the thyroid. PMID- 21317283 TI - Efficacy and safety of oral tolvaptan therapy in patients with the syndrome of inappropriate antidiuretic hormone secretion. AB - OBJECTIVE: Tolvaptan, an oral antagonist of the vasopressin V(2) receptor, has been found to improve hyponatremia in patients with mixed etiologies. This study analyzed a subgroup of patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) to evaluate the efficacy and safety of tolvaptan in this group. DESIGN AND PATIENTS: Hyponatremic patients in the SALT-1 and SALT-2 studies with a diagnosis of SIADH were identified based on clinical diagnosis by individual study investigators. Subjects were randomized to receive oral placebo (n=52) or tolvaptan 15 mg daily, with further titration to 30 and 60 mg daily, if necessary, based on the response of serum [Na(+)] (n=58). RESULTS: In patients with SIADH, improvement in serum [Na(+)] was significantly greater (P<0.0001) with tolvaptan than placebo over the first 4 days of therapy as well as the entire 30-day study, with minimal side effects of increased thirst, dry mouth, and urination. Only 5.9% of tolvaptan-treated patients had overly rapid correction of hyponatremia as defined by current guidelines. After discontinuation of tolvaptan, serum [Na(+)] declined to values similar to placebo. A significant positive treatment effect favoring tolvaptan on the physical component, and a near-significant trend on the mental component, was found using the SF-12 Health Survey. Tolvaptan was associated with a significantly reduced incidence of fluid restriction. CONCLUSIONS: Results for the SIADH subgroup were analogous to those of the combined SALT population regarding efficacy and safety but demonstrated a greater improvement in the physical component of the SF-12 Health Survey than in the full mixed etiology SALT patient group. PMID- 21317284 TI - Mapping of the SecA.SecY and SecA.SecG interfaces by site-directed in vivo photocross-linking. AB - The two major components of the Eubacteria Sec-dependent protein translocation system are the heterotrimeric channel-forming component SecYEG and its binding partner, the SecA ATPase nanomotor. Once bound to SecYEG, the preprotein substrate, and ATP, SecA undergoes ATP-hydrolytic cycles that drive the stepwise translocation of proteins. Although a previous site-directed in vivo photocross linking study (Mori, H., and Ito, K. (2006) Proc. Natl. Acad. Sci. U.S.A. 103, 16159-16164) elucidated residues of SecY needed for interaction with SecA, no reciprocal study for SecA protein has been reported to date. In the present study we mapped residues of SecA that interact with SecY or SecG utilizing this approach. Our results show that distinct domains of SecA on two halves of the molecule interact with two corresponding SecY partners as well as with the central cytoplasmic domain of SecG. Our data support the in vivo relevance of the Thermotoga maritima SecA.SecYEG crystal structure that visualized SecYEG interaction for only one-half of SecA as well as previous studies indicating that SecA normally binds two molecules of SecYEG. PMID- 21317285 TI - WIPI1 coordinates melanogenic gene transcription and melanosome formation via TORC1 inhibition. AB - Recent studies implicate a role for WD repeat domain, phosphoinositide interacting 1 (WIPI1) in the biogenesis of melanosomes, cell type-specific lysosome-related organelles. In this study, we determined that WIPI1, an ATG18 homologue that is shown to localize to both autophagosomes and early endosomes, inhibited mammalian target of rapamycin (MTOR) signaling, leading to increased transcription of melanogenic enzymes and the formation of mature melanosomes. WIPI1 suppressed the target of rapamycin complex 1 (TORC1) activity, resulting in glycogen synthase kinase 3beta inhibition, beta-Catenin stabilization, and increased transcription of microphthalmia transcription factor and its target genes. WIPI1-depleted cells accumulated stage I melanosomes but lacked stage III IV melanosomes. Inhibition of TORC1 by rapamycin treatment resulted in the accumulation of stage IV melanosomes but not autophagosomes, whereas starvation resulted in the formation of autophagosomes but not melanin accumulation. Taken together, our studies define a distinct role for WIPI1 and TORC1 signaling in controlling the transcription of melanogenic enzymes and melanosome maturation, a process that is distinct from starvation-induced autophagy. PMID- 21317286 TI - BAD contributes to RAF-mediated proliferation and cooperates with B-RAF-V600E in cancer signaling. AB - BAD (Bcl-2 antagonist of cell death) belongs to the proapoptotic BH3-only subfamily of Bcl-2 proteins. Physiological activity of BAD is highly controlled by phosphorylation. To further analyze the regulation of BAD function, we investigated the role of recently identified phosphorylation sites on BAD mediated apoptosis. We found that in contrast to the N-terminal phosphorylation sites, the serines 124 and 134 act in an antiapoptotic manner because the replacement by alanine led to enhanced cell death. Our results further indicate that RAF kinases represent, besides PAK1, BAD serine 134 phosphorylating kinases. Importantly, in the presence of wild type BAD, co-expression of survival kinases, such as RAF and PAK1, leads to a strongly increased proliferation, whereas substitution of serine 134 by alanine abolishes this process. Furthermore, we identified BAD serine 134 to be strongly involved in survival signaling of B-RAF V600E-containing tumor cells and found that phosphorylation of BAD at this residue is critical for efficient proliferation in these cells. Collectively, our findings provide new insights into the regulation of BAD function by phosphorylation and its role in cancer signaling. PMID- 21317287 TI - Deletion of the dual specific phosphatase-4 (DUSP-4) gene reveals an essential non-redundant role for MAP kinase phosphatase-2 (MKP-2) in proliferation and cell survival. AB - Mitogen-activated protein kinase phosphatase-2 (MKP-2) is a type 1 nuclear dual specific phosphatase (DUSP) implicated in a number of cancers. We examined the role of MKP-2 in the regulation of MAP kinase phosphorylation, cell proliferation, and survival responses in mouse embryonic fibroblasts (MEFs) derived from a novel MKP-2 (DUSP-4) deletion mouse. We show that serum and PDGF induced ERK-dependent MKP-2 expression in wild type MEFs but not in MKP-2(-/-) MEFs. PDGF stimulation of sustained ERK phosphorylation was enhanced in MKP-2(-/ ) MEFs, whereas anisomycin-induced JNK was only marginally increased. However, marked effects upon cell growth parameters were observed. Cellular proliferation rates were significantly reduced in MKP-2(-/-) MEFs and associated with a significant increase in cell doubling time. Infection with adenoviral MKP-2 reversed the decrease in proliferation. Cell cycle analysis revealed a block in G(2)/M phase transition associated with cyclin B accumulation and enhanced cdc2 phosphorylation. MEFs from MKP-2(-/-) mice also showed enhanced apoptosis when stimulated with anisomycin correlated with increased caspase-3 cleavage and gammaH2AX phosphorylation. Increased apoptosis was reversed by adenoviral MKP-2 infection and correlated with selective inhibition of JNK signaling. Collectively, these data demonstrate for the first time a critical non-redundant role for MKP-2 in regulating cell cycle progression and apoptosis. PMID- 21317288 TI - Identification of the atypical MAPK Erk3 as a novel substrate for p21-activated kinase (Pak) activity. AB - The class I p21-activated kinases (Pak1-3) regulate many essential biological processes, including cytoskeletal rearrangement, cell cycle progression, apoptosis, and cellular transformation. Although many Pak substrates, including elements of MAPK signaling cascades, have been identified, it is likely that additional substrates remain to be discovered. Identification of such substrates, and determination of the consequences of their phosphorylation, is essential for a better understanding of class I Pak activity. To identify novel class I Pak substrates, we used recombinant Pak2 to screen high density protein microarrays. This approach identified the atypical MAPK Erk3 as a potential Pak2 substrate. Solution-based in vitro kinase assays using recombinant Erk3 confirmed the protein microarray results, and phospho-specific antisera identified serine 189, within the Erk3 activation loop, as a site directly phosphorylated by Pak2 in vitro. Erk3 protein is known to shuttle between the cytoplasm and the nucleus, and we showed that selective inhibition of class I Pak kinase activity in cells promoted increased nuclear accumulation of Erk3. Pak inhibition in cells additionally reduced the extent of Ser(189) phosphorylation and inhibited the formation of Erk3-Prak complexes. Collectively, our results identify the Erk3 protein as a novel class I Pak substrate and further suggest a role for Pak kinase activity in atypical MAPK signaling. PMID- 21317289 TI - Dual Phosphorylation of suppressor of fused (Sufu) by PKA and GSK3beta regulates its stability and localization in the primary cilium. AB - Suppressor of fused (Sufu) is an essential negative regulator of the sonic hedgehog (Shh) pathway, but little is known about how Sufu itself is normally regulated. Here, we report that Sufu is phosphorylated at Ser-342 and Ser-346 by GSK3beta and cAMP-dependent protein kinase A (PKA), respectively, and phosphorylation at this dual site stabilizes Sufu against Shh signaling-induced degradation. We further show that localization of Sufu in the primary cilium is induced by Shh signaling and is required for the turnover of both phosphorylated and total Sufu. Perturbing Sufu phosphorylation with PKA inhibitors or replacing Ser-346 with alanine reduced the stay and replacing Ser-342 and Ser-346 with aspartic acid prolonged the stay of Sufu in the cilia. Finally, ciliary localization of Gli2/3 also required Smo and was similarly influenced by perturbations of PKA activity or mutations at the dual Sufu phosphorylation site. Thus, Shh likely induced trafficking of phospho-Sufu into the primary cilium in a complex with Gli2/3, and dephosphorylation triggered a retrograde export, allowing Sufu to be degraded by the ubiquitin-proteasome system. PMID- 21317290 TI - The GAS41-PP2Cbeta complex dephosphorylates p53 at serine 366 and regulates its stability. AB - The p53 tumor suppressor is principally regulated by post-translational modifications and proteasome-dependent degradation. Various kinases have been shown to phosphorylate p53, but little is known about the counteracting phosphatases. We demonstrate here that the newly identified complex GAS41 PP2Cbeta, and not PP2Cbeta alone, is specifically required for dephosphorylation of serine 366 on p53. Ectopic expression of GAS41 and PP2Cbeta reduces UV radiation-induced p53 up-regulation, thereby increasing the cell survival upon genotoxic DNA damage. To our knowledge, the GAS41-PP2Cbeta complex is the first example in which substrate specificity of a PP2C family member is controlled by an associated regulatory subunit. Because GAS41 is frequently amplified in human gliomas, our finding illustrates a novel oncogenic mechanism of GAS41 by p53 dephosphorylation. PMID- 21317291 TI - A twin-track approach has optimized proton and hydride transfer by dynamically coupled tunneling during the evolution of protochlorophyllide oxidoreductase. AB - Protein dynamics are crucial for realizing the catalytic power of enzymes, but how enzymes have evolved to achieve catalysis is unknown. The light-activated enzyme protochlorophyllide oxidoreductase (POR) catalyzes sequential hydride and proton transfers in the photoexcited and ground states, respectively, and is an excellent system for relating the effects of motions to catalysis. Here, we have used the temperature dependence of isotope effects and solvent viscosity measurements to analyze the dynamics coupled to the hydride and proton transfer steps in three cyanobacterial PORs and a related plant enzyme. We have related the dynamic profiles of each enzyme to their evolutionary origin. Motions coupled to light-driven hydride transfer are conserved across all POR enzymes, but those linked to thermally activated proton transfer are variable. Cyanobacterial PORs require complex and solvent-coupled dynamic networks to optimize the proton donor acceptor distance, but evolutionary pressures appear to have minimized such networks in plant PORs. POR from Gloeobacter violaceus has features of both the cyanobacterial and plant enzymes, suggesting that the dynamic properties have been optimized during the evolution of POR. We infer that the differing trajectories in optimizing a catalytic structure are related to the stringency of the chemistry catalyzed and define a functional adaptation in which active site chemistry is protected from the dynamic effects of distal mutations that might otherwise impact negatively on enzyme catalysis. PMID- 21317292 TI - Expanding the nucleotide and sugar 1-phosphate promiscuity of nucleotidyltransferase RmlA via directed evolution. AB - Directed evolution is a valuable technique to improve enzyme activity in the absence of a priori structural knowledge, which can be typically enhanced via structure-guided strategies. In this study, a combination of both whole-gene error-prone polymerase chain reaction and site-saturation mutagenesis enabled the rapid identification of mutations that improved RmlA activity toward non-native substrates. These mutations have been shown to improve activities over 10-fold for several targeted substrates, including non-native pyrimidine- and purine based NTPs as well as non-native D- and L-sugars (both alpha- and beta-isomers). This study highlights the first broadly applicable high throughput sugar-1 phosphate nucleotidyltransferase screen and the first proof of concept for the directed evolution of this enzyme class toward the identification of uniquely permissive RmlA variants. PMID- 21317293 TI - Characterization of the interactions between the nucleoprotein and the phosphoprotein of Henipavirus. AB - The Henipavirus genome is encapsidated by the nucleoprotein (N) within a helical nucleocapsid that recruits the polymerase complex via the phosphoprotein (P). In a previous study, we reported that in henipaviruses, the N-terminal domain of the phosphoprotein and the C-terminal domain of the nucleoprotein (N(TAIL)) are both intrinsically disordered. Here we show that Henipavirus N(TAIL) domains are also disordered in the context of full-length nucleoproteins. We also report the cloning, purification, and characterization of the C-terminal X domains (P(XD)) of Henipavirus phosphoproteins. Using isothermal titration calorimetry, we show that N(TAIL) and P(XD) form a 1:1 stoichiometric complex that is stable under NaCl concentrations as high as 1 M and has a K(D) in the MUM range. Using far-UV circular dichroism and nuclear magnetic resonance, we show that P(XD) triggers an increase in the alpha-helical content of N(TAIL). Using fluorescence spectroscopy, we show that P(XD) has no impact on the chemical environment of a Trp residue introduced at position 527 of the Henipavirus N(TAIL) domain, thus arguing for the lack of stable contacts between the C termini of N(TAIL) and P(XD). Finally, we present a tentative structural model of the N(TAIL)-P(XD) interaction in which a short, order-prone region of N(TAIL) (alpha-MoRE; amino acids 473-493) adopts an alpha-helical conformation and is embedded between helices alpha2 and alpha3 of P(XD), leading to a relatively small interface dominated by hydrophobic contacts. The present results provide the first detailed experimental characterization of the N-P interaction in henipaviruses and designate the N(TAIL)-P(XD) interaction as a valuable target for rational antiviral approaches. PMID- 21317294 TI - Drosophila Upf1 and Upf2 loss of function inhibits cell growth and causes animal death in a Upf3-independent manner. AB - Nonsense-mediated RNA decay (NMD) is a surveillance mechanism that degrades transcripts containing nonsense mutations, preventing the translation of truncated proteins. NMD also regulates the levels of many endogenous mRNAs. While the mechanism of NMD is gradually understood, its physiological role remains largely unknown. The core NMD genes upf1 and upf2 are essential in several organisms, which may reflect an important developmental role for NMD. Alternatively, the lethality of these mutants might arise from their function in NMD-independent processes. To analyze the developmental importance of NMD, we studied Drosophila mutants of the other core NMD gene, upf3. We compare the resulting upf3 phenotype with those defects observed in upf1 and upf2 loss-of function mutants, as well as with flies expressing a mutant Upf2 protein unable to bind Upf3. Our results show that Upf3 is an NMD effector in the fly but, unlike Upf1 and Upf2, plays a peripheral role in the degradation of most NMD targets and is not required for development or viability. Furthermore, Upf1 and Upf2 loss-of-function inhibits cell growth and induces apoptosis through a Upf3 independent pathway. Accordingly, disruption of Upf2-Upf1 interaction causes death, while the Upf2-Upf3 complex is dispensable for viability. Our findings suggest that NMD is essential for cell growth and animal development, and that the lethality of upf1 and upf2 mutants is not due to disrupting their roles during NMD-independent processes, but to their function in the degradation of specific mRNAs by the NMD pathway. Furthermore, our results show that Upf3 is not always essential in NMD. PMID- 21317295 TI - Retinal microglial activation and inflammation induced by amadori-glycated albumin in a rat model of diabetes. AB - OBJECTIVE: During diabetes, retinal microglial cells are activated to release inflammatory cytokines that initiate neuronal loss and blood-retinal barrier breakdown seen in diabetic retinopathy (DR). The mechanism by which diabetes activates microglia to release those inflammatory mediators is unclear and was therefore elucidated. RESEARCH DESIGN AND METHODS: Microglia activation was characterized in streptozocin-injected rats and in isolated microglial cells using immunofluorescence, enzyme-linked immunosorbent assay, RT-PCR, and Western blot analyses. RESULTS: In 8-week diabetic retina, phospho-extracellular signal related kinase (ERK) and P38 mitogen-activated protein kinases were localized in microglia, but not in Mueller cells or astrocytes. At the same time, Amadori glycated albumin (AGA)-like epitopes were featured in the regions of microglia distribution, implicating a pathogenic effect on microglial activation. To test this, diabetic rats were treated intravitreally with A717, a specific AGA neutralizing antibody, or murine IgG. Relative to nondiabetic rats, diabetic rats (IgG-treated) manifested 3.9- and 7.9-fold increases in Iba-1 and tumor necrosis factor (TNF)-alpha mRNAs, respectively. Treatment of diabetic rats with A717 significantly attenuated overexpression of these mRNAs. Intravitreal injection of AGA per se in normal rats resulted in increases of Iba-1 expression and TNF-alpha release. Guided by these results, a cultured retinal microglia model was developed to study microglial response after AGA treatment and the mechanistic basis behind this response. The results showed that formation of reactive oxygen species and subsequent activation of ERK and P38, but not Jun NH2-terminal kinase, are molecular events underpinning retinal microglial TNF-alpha release during AGA treatment. CONCLUSIONS: These results provide new insights in understanding the pathogenesis of early DR, showing that the accumulated AGA within the diabetic retina elicits the microglial activation and secretion of TNF alpha. Thus, intervention trials with agents that neutralize AGA effects may emerge as a new therapeutic approach to modulate early pathologic pathways long before the occurrence of vision loss among patients with diabetes. PMID- 21317296 TI - Insulin resistance impairs circulating angiogenic progenitor cell function and delays endothelial regeneration. AB - OBJECTIVE: Circulating angiogenic progenitor cells (APCs) participate in endothelial repair after arterial injury. Type 2 diabetes is associated with fewer circulating APCs, APC dysfunction, and impaired endothelial repair. We set out to determine whether insulin resistance adversely affects APCs and endothelial regeneration. RESEARCH DESIGN AND METHODS: We quantified APCs and assessed APC mobilization and function in mice hemizygous for knockout of the insulin receptor (IRKO) and wild-type (WT) littermate controls. Endothelial regeneration after femoral artery wire injury was also quantified after APC transfusion. RESULTS: IRKO mice, although glucose tolerant, had fewer circulating Sca-1(+)/Flk-1(+) APCs than WT mice. Culture of mononuclear cells demonstrated that IRKO mice had fewer APCs in peripheral blood, but not in bone marrow or spleen, suggestive of a mobilization defect. Defective vascular endothelial growth factor-stimulated APC mobilization was confirmed in IRKO mice, consistent with reduced endothelial nitric oxide synthase (eNOS) expression in bone marrow and impaired vascular eNOS activity. Paracrine angiogenic activity of APCs from IRKO mice was impaired compared with those from WT animals. Endothelial regeneration of the femoral artery after denuding wire injury was delayed in IRKO mice compared with WT. Transfusion of mononuclear cells from WT mice normalized the impaired endothelial regeneration in IRKO mice. Transfusion of c-kit(+) bone marrow cells from WT mice also restored endothelial regeneration in IRKO mice. However, transfusion of c-kit(+) cells from IRKO mice was less effective at improving endothelial repair. CONCLUSIONS: Insulin resistance impairs APC function and delays endothelial regeneration after arterial injury. These findings support the hypothesis that insulin resistance per se is sufficient to jeopardize endogenous vascular repair. Defective endothelial repair may be normalized by transfusion of APCs from insulin-sensitive animals but not from insulin-resistant animals. PMID- 21317297 TI - Cells lacking IKKalpha show nuclear cyclin D1 overexpression and a neoplastic phenotype: role of IKKalpha as a tumor suppressor. AB - The catalytic subunits of IkappaB kinase (IKK) complex, IKKalpha and IKKbeta, are involved in activation of NF-kappaB and in mediating a variety of other biological functions. Though these proteins have a high-sequence homology, IKKalpha exhibits different functional characteristics as compared with IKKbeta. Earlier, we have shown that cyclin D1 is overexpressed and predominantly localized in the nucleus of IKKalpha(-/-) cells, indicating that IKKalpha regulates turnover and subcellular distribution of cyclin D1, which is mediated by IKKalpha-induced phosphorylation of cyclin D1. Because cyclin D nuclear localization is implicated in tumor development, we examined whether the absence of IKKalpha leads to tumor development as well. In the current study, we show that IKKalpha plays a critical role in tumorigenesis. Though IKKalpha(-/-) MEF cells show a slower anchorage-dependent growth, they are clonogenic in soft agar. These cells are tumorigenic in nude mice. Microarray analysis of IKKalpha(-/-) cells indicates a differential expression of genes involved in proliferation and apoptosis. Furthermore, analysis of microarray data of human lung cancer cell lines revealed decreased IKKalpha RNA expression level as compared with cell lines derived from normal bronchial epithelium. These results suggest that IKKalpha may function as a tumor suppressor gene. Absence of IKKalpha may induce tumorigenicity by nuclear localization of cyclin D1 and modulating the expression of genes involved in neoplastic transformation. PMID- 21317298 TI - An exploration of listener variability in intelligibility judgments. AB - PURPOSE: This study was designed to assess potential contributors to listener variability in judgments of intelligibility. METHOD: A total of 228 unfamiliar everyday listeners judged speech samples from 3 individuals with dysarthria. Samples were the single-word phonetic contrast test, the Sentence Intelligibility Test, an unpredictable sentence intelligibility test, and conversational speech. RESULTS: Across speakers, significant variability was found for all samples except the phonetic contrast test. Across tasks, significant variability was found for all speakers. There were no significant differences in age, gender, or education between the highest and lowest scoring listeners on the phonetic contrast test. CONCLUSIONS: These findings suggest that seemingly objective intelligibility tests are subject to a number of factors that affect scores. PMID- 21317299 TI - Milk-borne lactocrine-acting factors affect gene expression patterns in the developing neonatal porcine uterus. AB - Lactocrine communication of milk-borne bioactive factors (MbFs) from mother to offspring through nursing can affect neonatal development with lasting consequences. Relaxin (RLX), a lactocrine-active peptide found in porcine colostrum, stimulates estrogen receptor-alpha (ESR1) expression required for uterine development shortly after birth (postnatal day=PND 0). Whether other MbFs or cooperative lactocrine mechanisms affect the neonatal uterine developmental program is unknown. To determine the effects of age, nursing, and exogenous RLX on gene expression associated with uterine development, gilts (n=4-5/group) were assigned to nurse ad libitum or to receive milk replacer, with or without exogenous RLX (20 MUg/kg BW i.m./6 h for 48 h), from birth to PND 2 when uteri were collected. Body weight and uterine weight increased (P<0.05) similarly from birth to PND 2 in all gilts. However, colostrum consumption was required for normal uterine ESR1, vascular endothelial growth factor (VEGFA), matrix metalloproteinase 9 (MMP9), and RLX receptor (RXFP1) protein and/or transcript expression on PND 2. Uterine ESR1, VEGFA, and MMP9 protein levels were below (P<0.01) the assay sensitivity in replacer-fed gilts. Supplemental RLX increased (P<0.05) uterine ESR1 protein and mRNA in nursed gilts, as well as VEGFA protein in nursed and VEGFA mRNA in both nursed and replacer-fed gilts. RLX treatment did not affect uterine MMP9 mRNA levels. When compared with replacer-fed gilts on PND 2, uterine RXFP1 mRNA was reduced (P<0.05) in nursed gilts and in RLX supplemented replacer-fed gilts. These results constitute the first evidence that establishment of the neonatal porcine uterine developmental program requires maternal lactocrine support. PMID- 21317300 TI - Activation of autophagy in mesenchymal stem cells provides tumor stromal support. AB - Recent studies have implicated multipotential mesenchymal stem cells (MSCs) as an aid to breast cancer cell proliferation and metastasis, partly as a result of the MSCs secretome. As the tumor gets beyond 2 mm in diameter, the stromal cells could undergo starvation due to the lack of sufficient nutrients in solid tumor microenvironment. In this study, we investigated the survival mechanisms used by stressed stromal cells in breast cancers. We used serum-deprived mesenchymal stem cells (SD-MSCs) and MCF-7 breast cancer cells as model system with a hypothesis that stromal cells in the nutrient-deprived core utilize survival mechanisms for supporting surrounding cells. We tested this hypothesis using in vivo tumor xenografts in immunodeficient mice, which indicated that SD-MSCs supported MCF-7 tumor growth by protection from apoptosis. Histochemical assays showed that SD MSCs-injected tumors exhibited higher cellularity, decreased apoptosis and decreased differentiation. Beclin-1 staining indicated autophagic areas surrounded by actively proliferating cells. Furthermore, in vitro studies demonstrate that SD-MSCs survive using autophagy and secrete paracrine factors that support tumor cells following nutrient/serum deprivation. Western blot and immunocytochemistry analysis of SD-MSCs demonstrated upregulation and perinuclear relocation of autophagy key regulators such as beclin-1, ATG10, ATG12, MAP-LC3 and lysosomes. Electron microscopic analysis detected a time-dependent increase in autophagosome formation and HDAC6 activity assays indicated the upregulation of autophagy. Taken together, these data suggest that under nutrient-deprived conditions that can occur in solid tumors, stromal cells utilize autophagy for survival and also secrete anti-apoptotic factors that can facilitate solid tumor survival and growth. PMID- 21317302 TI - FTO polymorphisms are associated with adult body mass index (BMI) and colorectal adenomas in African-Americans. AB - Obesity is a known risk factor for colon cancer and higher body mass index (BMI) has been associated with colorectal adenomas, which are precursor lesions to most colorectal cancers. Polymorphisms in the fat-mass and obesity-associated (FTO) gene have been associated with BMI and larger effects in older versus younger children have been reported. However, no studies have examined associations between FTO polymorphisms, BMI throughout adulthood and colorectal adenomas. Therefore, we evaluated associations between FTO polymorphisms (rs1421085, rs17817449, rs8050136, rs9939609, rs8044769), adult BMI (at recruitment, 50s, 40s, 30s, 20s age decades) and colorectal adenomas in 759 Caucasians and 469 African-Americans. We found that the highest versus the lowest BMI tertile at recruitment [odds ratio (OR) = 1.82; 95% confidence interval (CI): 1.07-2.16] and in the 30s (OR = 1.50; 95% CI: 1.04-2.15) was associated with higher adenoma risk. Stratification by ethnicity revealed that these associations only remained significant in Caucasians. We found that, in Caucasians, having two versus no copies of the variant allele in rs17817449, rs8050136 and rs9939609, which are all in strong linkage disequilibrium, was associated with higher BMI in the 30s and 40s but none of the polymorphisms were associated with adenomas. In African Americans, having one or two copies of the variant in rs17817449 (OR = 0.61; 95% CI: 0.39-0.95) and rs8050136 (OR = 0.59; 95% CI: 0.38-0.93) was associated with colorectal adenomas and, having two variant copies in rs17817449 and rs8050136 was associated with higher BMI at recruitment and in the 40s, respectively. Our results are consistent with prior studies and show for the first time that FTO polymorphisms are associated with colorectal adenomas in African-Americans. PMID- 21317301 TI - The multiple roles of autophagy in cancer. AB - Autophagy is an evolutionarily conserved, catabolic process that involves the entrapment of cytoplasmic components within characteristic vesicles for their delivery to and degradation within lysosomes. Autophagy is regulated via a group of genes called AuTophaGy-related genes and is executed at basal levels in virtually all cells as a homeostatic mechanism for maintaining cellular integrity. The levels and cargos of autophagy can be modulated in response to a variety of intra- and extracellular cues to bring about specific and selective events. Autophagy is a multifaceted process and alterations in autophagic signalling pathways are frequently found in cancer and many other diseases. During tumour development and in cancer therapy, autophagy has paradoxically been reported to have roles in promoting both cell survival and cell death. In addition, autophagy has been reported to control other processes relevant to the aetiology of malignant disease, including oxidative stress, inflammation and both innate and acquired immunity. It is the aim of this review to describe the molecular basis and the signalling events that control autophagy in mammalian cells and to summarize the cellular functions that contribute to tumourigenesis when autophagy is perturbed. PMID- 21317303 TI - Coffee phenolic phytochemicals suppress colon cancer metastasis by targeting MEK and TOPK. AB - Epidemiological studies suggest that coffee consumption reduces the risk of cancers, including colon cancer, but the molecular mechanisms and target(s) underlying the chemopreventive effects of coffee and its active ingredient(s) remain unknown. Based on serving size or daily units, coffee contains larger amounts of phenolic phytochemicals than tea or red wine. Coffee or chlorogenic acid inhibited CT-26 colon cancer cell-induced lung metastasis by blocking phosphorylation of ERKs. Coffee or caffeic acid (CaA) strongly suppressed mitogen activated MEK1 and TOPK activities and bound directly to either MEK1 or TOPK in an ATP-noncompetitive manner. Coffee or CaA, but not caffeine, inhibited ERKs phosphorylation, AP-1 and NF-kappaB transactivation and subsequently inhibited TPA-, EGF- and H-Ras-induced neoplastic transformation of JB6 P+ cells. Coffee consumption was also associated with a significant attenuation of ERKs phosphorylation in colon cancer patients. These results suggest that coffee and CaA target MEK1 and TOPK to suppress colon cancer metastasis and neoplastic cell transformation. PMID- 21317304 TI - Ventilatory baroreflex sensitivity in humans is not modulated by chemoreflex activation. AB - Increasing arterial blood pressure (AP) decreases ventilation, whereas decreasing AP increases ventilation in experimental animals. To determine whether a "ventilatory baroreflex" exists in humans, we studied 12 healthy subjects aged 18 26 yr. Subjects underwent baroreflex unloading and reloading using intravenous bolus sodium nitroprusside (SNP) followed by phenylephrine ("Oxford maneuver") during the following "gas conditions:" room air, hypoxia (10% oxygen)-eucapnia, and 30% oxygen-hypercapnia to 55-60 Torr. Mean AP (MAP), heart rate (HR), cardiac output (CO), total peripheral resistance (TPR), expiratory minute ventilation (V(E)), respiratory rate (RR), and tidal volume were measured. After achieving a stable baseline for gas conditions, we performed the Oxford maneuver. V(E) increased from 8.8 +/- 1.3 l/min in room air to 14.6 +/- 0.8 l/min during hypoxia and to 20.1 +/- 2.4 l/min during hypercapnia, primarily by increasing tidal volume. V(E) doubled during SNP. CO increased from 4.9 +/- .3 l/min in room air to 6.1 +/- .6 l/min during hypoxia and 6.4 +/- .4 l/min during hypercapnia with decreased TPR. HR increased for hypoxia and hypercapnia. Sigmoidal ventilatory baroreflex curves of V(E) versus MAP were prepared for each subject and each gas condition. Averaged curves for a given gas condition were obtained by averaging fits over all subjects. There were no significant differences in the average fitted slopes for different gas conditions, although the operating point varied with gas conditions. We conclude that rapid baroreflex unloading during the Oxford maneuver is a potent ventilatory stimulus in healthy volunteers. Tidal volume is primarily increased. Ventilatory baroreflex sensitivity is unaffected by chemoreflex activation, although the operating point is shifted with hypoxia and hypercapnia. PMID- 21317306 TI - Mechanics of left ventricular relaxation, early diastolic lengthening, and suction investigated in a mathematical model. AB - We investigated the determinants of ventricular early diastolic lengthening and mechanics of suction using a mathematical model of the left ventricle (LV). The model was based on a force balance between the force represented by LV pressure (LVP) and active and passive myocardial forces. The predicted lengthening velocity (e') from the model agreed well with measurements from 10 dogs during 5 different interventions (R = 0.69, P < 0.001). The model showed that e' was increased when relaxation rate and systolic shortening increased, when passive stiffness was decreased, and when the rate of fall of LVP during early filling was decreased relative to the rate of fall of active stress. We first defined suction as the work the myocardium performed to pull blood into the ventricle. This occurred when contractile active forces decayed below and became weaker than restoring forces, producing a negative LVP. An alternative definition of suction is filling during falling pressure, commonly believed to be caused by release of restoring forces. However, the model showed that this phenomenon also occurred when there had been no systolic compression below unstressed length and therefore in the absence of restoring forces. In conclusion, relaxation rate, LVP, systolic shortening, and passive stiffness were all independent determinants of e'. The model generated a suction effect seen as lengthening occurring during falling pressure. However, this was not equivalent with the myocardium performing pulling work on the blood, which was performed only when restoring forces were higher than remaining active fiber force, corresponding to a negative transmural pressure. PMID- 21317305 TI - Preemptive conditioning of the swine heart by H11 kinase/Hsp22 provides cardiac protection through inducible nitric oxide synthase. AB - The second window of ischemic preconditioning (SWOP) provides maximal protection against ischemia through regulation of the inducible nitric oxide synthase (iNOS), yet its application is limited by the inconvenience of the preliminary ischemic stimulus required for prophylaxis. Overexpression of H11 kinase/Hsp22 (Hsp22) in a transgenic mouse model provides cardioprotection against ischemia that is equivalent to that conferred by SWOP. We hypothesized that short-term, prophylactic overexpression of Hsp22 would offer an alternative to SWOP in reducing ischemic damage through a nitric oxide (NO)-dependent mechanism. Adeno mediated overexpression of Hsp22 was achieved in the area at risk of the left circumflex (Cx) coronary artery in chronically instrumented swine and compared with LacZ controls (n = 5/group). Hsp22-injected myocardium showed an average fourfold increase in Hsp22 protein expression compared with controls and a doubling in iNOS expression (both P < 0.05). Four days after ischemia reperfusion, regional wall thickening was reduced by 58 +/- 2% in the Hsp22 group vs. 82 +/- 7% in the LacZ group, and Hsp22 reduced infarct size by 40% (both P < 0.05 vs. LacZ). Treatment with the NOS inhibitor N(G)-nitro-L-arginine (L-NNA) before ischemia suppressed the protection induced by Hsp22. In isolated cardiomyocytes, Hsp22 increased iNOS expression through the transcription factors NF-kappaB and STAT, the same effectors activated by SWOP, and reduced by 60% H(2)O(2)-mediated apoptosis, which was also abolished by NOS inhibitors. Therefore, short-term, prophylactic conditioning by Hsp22 provides NO-dependent cardioprotection that reproduces the signaling of SWOP, placing Hsp22 as a potential alternative for preemptive treatment of myocardial ischemia. PMID- 21317307 TI - Atorvastatin suppresses LPS-induced rapid upregulation of Toll-like receptor 4 and its signaling pathway in endothelial cells. AB - In the present study, we tested our hypothesis that atorvastatin exerts its anti inflammation effect via suppressing LPS-induced rapid upregulation of Toll-like receptor 4 (TLR4) mRNA and its downstream p38, ERK, and NF-kappaB signaling pathways in human umbilical-vein endothelial cells (HUVECs) and human aortic endothelial cells (HAECs). TLR4 mRNA expression and its downstream kinase activities induced by LPS alone or atorvastatin + LPS in endothelial cells were quantified using quantitative real-time PCR and enzyme-linked immunosorbent assay. Preincubation of LPS-stimulated endothelial cells with TLR4 siRNA was conducted to identify the target of the anti-inflammatory effects of atorvastatin. Atorvastatin incubation resulted in the reduction of LPS-induced TLR4 mRNA expression, ERK1/2 and P38 MAPK phosphorylation, and NF-kappaB binding activity. Pretreatment with MEK/ERK1/2 inhibitor PD98059 attenuated atorvastatin + LPS-induced NF-kappaB activity but had no effect on P38 MAPK phosphorylation. In contrast, pretreatment with P38 MAPK inhibitor SB203580 resulted in upregulation of atorvastatin + LPS-induced ERK1/2 phosphorylation but had no significant effects on NF-kappaB activity. On the other hand, blocking NF-kappaB with SN50 produced no effects on atorvastatin + LPS-induced ERK1/2 and P38 MAPK phosphorylation. Moreover, TLR4 gene silencing produced the same effects as the atorvastatin treatment. In conclusion, atorvastatin downregulated TLR4 mRNA expression by two distinct signaling pathways. First, atorvastatin stabilized Ikappa-Balpha, which directly inhibited NF-kappaB activation. Second, atorvastatin inactivated ERK phosphorylation, which indirectly inhibited NF kappaB activation. Suppression of p38 MAPK by atorvastatin upregulates ERK but exerts no effect on NF-kappaB. PMID- 21317308 TI - Exercise limits the production of endothelin in the coronary vasculature. AB - We previously demonstrated that endothelin (ET)-mediated coronary vasoconstriction wanes with increasing exercise intensity via a nitric oxide- and prostacyclin-dependent mechanism (Ref. 23). Therefore, we hypothesized that the waning of ET coronary vasoconstriction during exercise is the result of decreased production of ET and/or decreased ET receptor sensitivity. We investigated coronary ET receptor sensitivity using intravenous infusion of ET and coronary ET production using intravenous infusion of the ET precursor Big ET, at rest and during continuous treadmill exercise at 3 km/h in 16 chronically instrumented swine. In the systemic vasculature, Big ET and ET induced similar changes in hemodynamic parameters at rest and during continuous exercise at 3 km/h, indicating that exercise does not alter ET production or receptor sensitivity in the systemic vasculature. In the coronary vasculature, infusion of ET resulted in similar dose-dependent decreases in coronary blood flow and coronary venous oxygen tension and saturation at rest and during exercise. In contrast, administration of Big ET resulted in dose-dependent decreases in coronary blood flow, as well as coronary venous oxygen tension and saturation at rest. These effects of Big ET were significantly reduced during exercise. Altogether, our data indicate that continuous exercise at 3 km/h attenuates ET-mediated coronary vasoconstriction through reduced production of ET from Big ET rather than through reduced ET sensitivity of the coronary vasculature. The decreased ET production during exercise likely contributes to metabolic coronary vasodilation. PMID- 21317309 TI - Differential vulnerability of skeletal muscle feed arteries to dysfunction in insulin resistance: impact of fiber type and daily activity. AB - Functional and structural heterogeneity exists among skeletal muscle vascular beds related, in part, to muscle fiber type composition. This study was designed to delineate whether the vulnerability to vascular dysfunction in insulin resistance is uniformly distributed among skeletal muscle vasculatures and whether physical activity modifies this vulnerability. Obese, hyperphagic Otsuka Long-Evans Tokushima fatty rats (20 wk old) were sedentary (OSED) or physically active (OPA; access to running wheels) and compared with age-matched sedentary Long-Evans Tokushima Otsuka (LSED) rats. Vascular responses were determined in isolated, pressurized feed arteries from fast-twitch gastrocnemius (GFAs) and slow-twitch soleus (SFAs) muscles. OSED animals were obese, insulin resistant, and hypertriglyceridemic, traits absent in LSED and OPA rats. GFAs from OSED animals exhibited depressed dilation to ACh, but not sodium nitroprusside, and enhanced vasoconstriction to endothelin-1 (ET-1), but not phenylephrine, compared with those in LSED. Immunoblot analysis suggests reduced endothelial nitric oxide synthase phosphorylation at Ser1177 and endothelin subtype A receptor expression in OSED GFAs. Physical activity prevented reduced nitric oxide-dependent dilation to ACh, but not enhanced ET-1 vasoconstriction, in GFA from OPA animals. Conversely, vasoreactivity of SFAs to ACh and ET-1 were principally similar in all groups, whereas dilation to sodium nitroprusside was enhanced in OSED and OPA rats. These data demonstrate, for the first time, that SFAs from insulin resistant rats exhibit reduced vulnerability to dysfunction versus GFAs and that physical activity largely prevents GFA dysfunction. We conclude that these results demonstrate that vascular dysfunction associated with insulin resistance is heterogeneously distributed across skeletal muscle vasculatures related, in part, to muscle fiber type and activity level. PMID- 21317310 TI - Plasmodium falciparum var gene silencing is determined by cis DNA elements that form stable and heritable interactions. AB - Antigenic variation in the human malaria parasite Plasmodium falciparum depends on the transcriptional regulation of the var gene family. In each individual parasite, mRNA is expressed exclusively from 1 var gene out of ~60, while the rest of the genes are transcriptionally silenced. Both modifications to chromatin structure and DNA regulatory elements associated with each var gene have been implicated in the organization and maintenance of the silent state. Whether silencing is established at the level of entire chromosomal regions via heterochromatin spreading or at the level of individual var promoters through the action of a silencing element within each var intron has been debated. Here, we consider both possibilities, using clonal parasite lines carrying chromosomally integrated transgenes. We confirm a previous finding that the loss of an adjacent var intron results in var promoter activation and further show that transcriptional activation of a var promoter within a cluster does not affect the transcriptional activity of neighboring var promoters. Our results provide more evidence for the hypothesis that var genes are primarily silenced at the level of an individual gene, rather than by heterochromatin spreading. We also tested the intrinsic directionality of an intron's silencing effect on upstream or downstream var promoters. We found that an intron is capable of silencing in either direction and that, once established, a var promoter-intron pair is stably maintained through many generations, suggesting a possible role in epigenetic memory. This study provides insights into the regulation of endogenous var gene clusters. PMID- 21317311 TI - Mitosis in the human malaria parasite Plasmodium falciparum. AB - Malaria is caused by intraerythrocytic protozoan parasites belonging to Plasmodium spp. (phylum Apicomplexa) that produce significant morbidity and mortality, mostly in developing countries. Plasmodium parasites have a complex life cycle that includes multiple stages in anopheline mosquito vectors and vertebrate hosts. During the life cycle, the parasites undergo several cycles of extreme population growth within a brief span, and this is critical for their continued transmission and a contributing factor for their pathogenesis in the host. As with other eukaryotes, successful mitosis is an essential requirement for Plasmodium reproduction; however, some aspects of Plasmodium mitosis are quite distinct and not fully understood. In this review, we will discuss the current understanding of the architecture and key events of mitosis in Plasmodium falciparum and related parasites and compare them with the traditional mitotic events described for other eukaryotes. PMID- 21317312 TI - Cigarette smoke suppresses Bik to cause epithelial cell hyperplasia and mucous cell metaplasia. AB - RATIONALE: Aberrant regulation of airway epithelial cell numbers in airways leads to increased mucous secretions in chronic lung diseases such as chronic bronchitis. Because the Bcl-2 family of proteins is crucial for airway epithelial homeostasis, identifying the players that reduce cigarette smoke (CS)-induced mucous cell metaplasia can help to develop effective therapies. OBJECTIVES: To identify the Bcl-2 family of proteins that play a role in reducing CS-induced mucous cell metaplasia. METHODS: We screened for dysregulated expression of the Bcl-2 family members. MEASUREMENTS AND MAIN RESULTS: We identified Bik to be significantly reduced in bronchial brushings of patients with chronic epithelial cell hyperplasia compared with nondiseased control subjects. Reduced Bik but increased MUC5AC mRNA levels were also detected when normal human airway epithelial cells (HAECs) were exposed to CS or when autopsy tissues from former smokers with and without chronic bronchitis were compared. Similarly, exposure of C57Bl/6 mice to CS resulted in increased numbers of epithelial and mucous cells per millimeter of basal lamina, along with reduced Bik but increased Muc5ac expression, and this change was sustained even when mice were allowed to recover in filtered air for 8 weeks. Restoring Bik expression significantly suppressed CS induced mucous cell metaplasia in differentiated primary HAEC cultures and in airways of mice in vivo. Bik blocked nuclear translocation of phospho-ERK1/2 to induce apoptosis of HAECs. The conserved Leu61 within Bik and ERK1/2 activation were essential to induce cell death in hyperplastic mucous cells. CONCLUSIONS: These studies show that CS suppresses Bik expression to block airway epithelia cell death and thereby increases epithelial cell hyperplasia in chronic bronchitis. PMID- 21317313 TI - Leptin promotes fibroproliferative acute respiratory distress syndrome by inhibiting peroxisome proliferator-activated receptor-gamma. AB - RATIONALE: Diabetic patients have a lower incidence of acute respiratory distress syndrome (ARDS), and those who develop ARDS are less likely to die. The mechanisms that underlie this protection are unknown. OBJECTIVES: To determine whether leptin resistance, a feature of diabetes, prevents fibroproliferation after lung injury. METHODS: We examined lung injury and fibroproliferation after the intratracheal instillation of bleomycin in wild-type and leptin-resistant (db/db) diabetic mice. We examined the effect of leptin on transforming growth factor (TGF)-beta(1)-mediated transcription in primary normal human lung fibroblasts. Bronchoalveolar lavage fluid (BAL) samples from patients with ARDS and ventilated control subjects were obtained for measurement of leptin and active TGF-beta(1) levels. MEASUREMENTS AND MAIN RESULTS: Diabetic mice (db/db) were resistant to lung fibrosis. The db/db mice had higher levels of peroxisome proliferator-activated receptor-gamma (PPARgamma), an inhibitor of the transcriptional response to TGF-beta(1), a cytokine critical in the pathogenesis of fibroproliferative ARDS. In normal human lung fibroblasts, leptin augmented the transcription of profibrotic genes in response to TGF-beta(1) through a mechanism that required PPARgamma. In patients with ARDS, BAL leptin levels were elevated and correlated with TGF-beta(1) levels. Overall, there was no significant relationship between BAL leptin levels and clinical outcomes; however, in nonobese patients, higher BAL leptin levels were associated with fewer intensive care unit- and ventilator-free days and higher mortality. CONCLUSIONS: Leptin signaling is required for bleomycin-induced lung fibrosis. Leptin augments TGF-beta(1) signaling in lung fibroblasts by inhibiting PPARgamma. These findings provide a mechanism for the observed protection against ARDS observed in diabetic patients. PMID- 21317315 TI - Breaking habits with implementation intentions: a test of underlying processes. AB - Implementation intentions specifying the replacement of a habitual response with an alternative response in a critical situation can overrule habits. In three experiments the cognitive effects of such counterhabitual implementation intentions were investigated. Results showed that implementation intentions eliminated the cognitive advantage of the habitual means in the "horse race" with the alternative response. That is, in the control condition, the habitual means was more accessible than the alternative means on encountering the critical situation, but this was no longer the case when implementation intentions were formulated. However, the cognitive advantage of the habitual means was not immediately replaced by an automatic activation of the alternative means. This suggests that formulating counterhabitual implementation intentions increases individuals' flexibility to choose which behavior to perform in the critical situation but that actual behavior will depart from their habits only to the extent that individuals have strong alternative goal intentions. PMID- 21317314 TI - Natural killer T cell-derived IL-17 mediates lung ischemia-reperfusion injury. AB - RATIONALE: We recently implicated a role for CD4(+) T cells and demonstrated elevated IL-17A expression in lung ischemia-reperfusion (IR) injury. However, identification of the specific subset of CD4(+) T cells and their mechanistic role in IR injury remains unknown. OBJECTIVES: We tested the hypothesis that invariant natural killer T (iNKT) cells mediate lung IR injury via IL-17A signaling. METHODS: Mice underwent lung IR via left hilar ligation. Pulmonary function was measured using an isolated lung system. Lung injury was assessed by measuring edema (wet/dry weight) and vascular permeability (Evans blue dye). Inflammation was assessed by measuring proinflammatory cytokines in lungs, and neutrophil infiltration was measured by immunohistochemistry and myeloperoxidase levels. MEASUREMENTS AND MAIN RESULTS: Pulmonary dysfunction (increased airway resistance and pulmonary artery pressure and decreased pulmonary compliance), injury (edema, vascular permeability), and inflammation (elevated IL-17A; IL-6; tumor necrosis factor-alpha; monocyte chemotactic protein-1; keratinocyte-derived chemokine; regulated upon activation, normal T-cell expressed and secreted; and neutrophil infiltration) after IR were attenuated in IL-17A(-/-) and Rag-1(-/-) mice. Anti-IL-17A antibody attenuated lung dysfunction in wild-type mice after IR. Reconstitution of Rag-1(-/-) mice with wild-type, but not IL-17A(-/-), CD4(+) T cells restored lung dysfunction, injury, and inflammation after IR. Lung dysfunction, injury, IL-17A expression, and neutrophil infiltration were attenuated in Jalpha18(-/-) mice after IR, all of which were restored by reconstitution with wild-type, but not IL-17A(-/-), iNKT cells. Flow cytometry and enzyme-linked immunosorbent spot assay confirmed IL-17A production by iNKT cells after IR. CONCLUSIONS: These results demonstrate that CD4(+) iNKT cells play a pivotal role in initiating lung injury, inflammation, and neutrophil recruitment after IR via an IL-17A-dependent mechanism. PMID- 21317316 TI - Decisions for others are more creative than decisions for the self. AB - Four studies investigate whether decisions for others produce more creative solutions than do decisions for the self and if construal level explains this relation. In Study 1, participants carried out a structured imagination task by drawing an alien for a story that they would write, or alternatively for a story that someone else would write. As expected, drawing an alien for someone else produced a more creative alien. In Studies 2a and 2b, construal level (i.e., psychological distance) was independently manipulated. Participants generated more creative ideas on behalf of distant others than on behalf of either close others or themselves. Finally, in Study 3, a classic insight problem was investigated. Participants deciding for others were more likely to solve the problem; furthermore, this result was mediated by psychological distance. These findings demonstrate that people are more creative for others than for themselves and shed light on differences in self-other decision making. PMID- 21317317 TI - An Enterotoxin-Bearing Pathogenicity Island in Staphylococcus epidermidis. AB - Cocolonization of human mucosal surfaces causes frequent encounters between various staphylococcal species, creating opportunities for the horizontal acquisition of mobile genetic elements. The majority of Staphylococcus aureus toxins and virulence factors are encoded on S. aureus pathogenicity islands (SaPIs). Horizontal movement of SaPIs between S. aureus strains plays a role in the evolution of virulent clinical isolates. Although there have been reports of the production of toxic shock syndrome toxin 1 (TSST-1), enterotoxin, and other superantigens by coagulase-negative staphylococci, no associated pathogenicity islands have been found in the genome of Staphylococcus epidermidis, a generally less virulent relative of S. aureus. We show here the first evidence of a composite S. epidermidis pathogenicity island (SePI), the product of multiple insertions in the genome of a clinical isolate. The taxonomic placement of S. epidermidis strain FRI909 was confirmed by a number of biochemical tests and multilocus sequence typing. The genome sequence of this strain was analyzed for other unique gene clusters and their locations. This pathogenicity island encodes and expresses staphylococcal enterotoxin C3 (SEC3) and staphylococcal enterotoxin like toxin L (SElL), as confirmed by quantitative reverse transcription-PCR (qRT PCR) and immunoblotting. We present here an initial characterization of this novel pathogenicity island, and we establish that it is stable, expresses enterotoxins, and is not obviously transmissible by phage transduction. We also describe the genome sequence, excision, replication, and packaging of a novel bacteriophage in S. epidermidis FRI909, as well as attempts to mobilize the SePI element by this phage. PMID- 21317318 TI - Structure of the periplasmic stress response protein CpxP. AB - CpxP is a novel bacterial periplasmic protein with no homologues of known function. In gram-negative enteric bacteria, CpxP is thought to interact with the two-component sensor kinase, CpxA, to inhibit induction of the Cpx envelope stress response in the absence of protein misfolding. CpxP has also been shown to facilitate DegP-mediated proteolysis of misfolded proteins. Six mutations that negate the ability of CpxP to function as a signaling protein are localized in or near two conserved LTXXQ motifs that define a class of proteins with similarity to CpxP, Pfam PF07813. To gain insight into how these mutations might affect CpxP signaling and/or proteolytic adaptor functions, the crystal structure of CpxP from Escherichia coli was determined to 2.85-A resolution. The structure revealed an antiparallel dimer of intertwined alpha-helices with a highly basic concave surface. Each protomer consists of a long, hooked and bent hairpin fold, with the conserved LTXXQ motifs forming two diverging turns at one end. Biochemical studies demonstrated that CpxP maintains a dimeric state but may undergo a slight structural adjustment in response to the inducing cue, alkaline pH. Three of the six previously characterized cpxP loss-of-function mutations, M59T, Q55P, and Q128H, likely result from a destabilization of the protein fold, whereas the R60Q, D61E, and D61V mutations may alter intermolecular interactions. PMID- 21317319 TI - Subpopulation-specific transcriptome analysis of competence-stimulating-peptide induced Streptococcus mutans. AB - Competence-stimulating-peptide (CSP)-mediated competence development in Streptococcus mutans is a transient and biphasic process, since only a subpopulation induces the expression of ComX in the presence of CSP, and the activation of the DNA uptake machinery in this fraction shuts down ~3 to 4 h postinduction. Here, we combine for the first time, to our knowledge, the bacterial flow-cytometric sorting of cells and subpopulation-specific transcriptome analysis of both the competent and noncompetent fraction of CSP treated S. mutans cells. Sorting was guided by a ComX-green fluorescent protein (ComX-GFP) reporter, and the transcriptome analysis demonstrated the successful combination of both methods, because a strong enrichment of transcripts for comX and its downstream genes was achieved. Three two-component systems were expressed in the competent fraction, and among them was ComDE. Moreover, the recently identified regulator system ComR/S was expressed exclusively in the competent fraction. In contrast, the expression of bacteriocin-related genes was at the same level in all cells. GFP reporter strains for ComE and CipB (mutacin V) confirmed this expression pattern on the single-cell level. Fluorescence microscopy revealed that some ComX-expressing cells committed autolysis in an early stage of competence initiation. In viable ComX-expressing cells, the uptake of DNA could be shown on the single-cell level. This study demonstrates that all cells in the population respond to CSP through the activation of bacteriocin related genes. Some of these cells start to activate ComX expression but then segregate into two subpopulations, one becoming competent and another one that lyses, resulting in intrapopulation diversity. PMID- 21317320 TI - Regulation and consequence of serine catabolism in Streptococcus pyogenes. AB - The Gram-positive bacterium Streptococcus pyogenes (also called group A Streptococcus [GAS]), is found strictly in humans and is capable of causing a wide variety of infections. Here we demonstrate that serine catabolism in GAS is controlled by the transcriptional regulator Spy49_0126c. We have designated this regulator SerR (for serine catabolism regulator). Microarray and transcriptional reporter data show that SerR acts as a transcriptional repressor of multiple operons, including sloR and sdhBA. Purified recombinant SerR binds to the promoters of both sloR and sdhB, demonstrating that this regulation is direct. Deletion of serR results in a lower culture yield of the mutant than of the wild type when the strains are grown in defined medium unless additional serine is provided, suggesting that regulation of serine metabolism is important for maximizing bacterial growth. Deletion of sloR or sdhB in the DeltaserR mutant background restores growth to wild-type levels, suggesting that both operons have roles in serine catabolism. While reports have linked sloR function to streptolysin O expression, transport experiments with radiolabeled l-serine reveal that the sloR operon is required for rapid acquisition of serine, suggesting a novel role for this operon in amino acid metabolism. PMID- 21317322 TI - Anomalous spatial redistribution of competing bacteria under starvation conditions. AB - Bacterial cells evolved under prolonged stress often have a growth advantage in stationary phase (GASP); we expect GASP cells to maintain a proliferative state and dominate wild-type cells during starvation, especially when nutrients are limited and the medium has been conditioned. However, when we compete GASP mutants against wild-type cells in a chain of microfluidic microhabitat patches (MHPs) with alternating nutrient-rich and nutrient-limited regions, we observe the reverse effect: wild-type cells achieve maximum relative density under nutrient-limited conditions, while GASP cells dominate nutrient-rich regions. We explain this surprising observation in terms of ideal free distributions, where we show that wild-type cells maximize their fitness at high cell density by redistributing themselves to sparsely populated MHPs. At the microscopic level, we describe how biofilm formation also contributes to the population redistribution. We conclude by discussing the implications of these results for social interactions of more complex organisms. PMID- 21317321 TI - Identification of a chitin-induced small RNA that regulates translation of the tfoX gene, encoding a positive regulator of natural competence in Vibrio cholerae. AB - The tfoX (also called sxy) gene product is the central regulator of DNA uptake in the naturally competent bacteria Haemophilus influenzae and Vibrio cholerae. However, the mechanisms regulating tfoX gene expression in both organisms are poorly understood. Our previous studies revealed that in V. cholerae, chitin disaccharide (GlcNAc)2 is needed to activate the transcription and translation of V. cholerae tfoX (tfoX(VC)) to induce natural competence. In this study, we screened a multicopy library of V. cholerae DNA fragments necessary for translational regulation of tfoX(VC). A clone carrying the VC2078-VC2079 intergenic region, designated tfoR, increased the expression of a tfoX(VC)::lacZ translational fusion constructed in Escherichia coli. Using a tfoX(VC)::lacZ reporter system in V. cholerae, we confirmed that tfoR positively regulated tfoX(VC) expression at the translational level. Deletion of tfoR abolished competence for exogenous DNA even when (GlcNAc)2 was provided. The introduction of a plasmid clone carrying the tfoR(+) gene into the tfoR deletion mutant complemented the competence deficiency. We also found that the tfoR gene encodes a 102-nucleotide small RNA (sRNA), which was transcriptionally activated in the presence of (GlcNAc)2. Finally, we showed that this sRNA activated translation from tfoX(VC) mRNA in a highly purified in vitro translation system. Taking these results together, we propose that in the presence of (GlcNAc)2, TfoR sRNA is expressed to activate the translation of tfoX(VC), which leads to the induction of natural competence. PMID- 21317323 TI - Complete genome sequence of Bacillus subtilis BSn5, an endophytic bacterium of Amorphophallus konjac with antimicrobial activity for the plant pathogen Erwinia carotovora subsp. carotovora. AB - Here, we present the complete genome sequence of Bacillus subtilis strain BSn5, isolated from Amorphophallus konjac calli tissue and showing strong inhibitory activity to Erwinia carotovora subsp. carotovora, which causes Amorphophallus soft rot disease and affects the industry development of this organism. PMID- 21317324 TI - The interplay of ClpXP with the cell division machinery in Escherichia coli. AB - ClpXP is a two-component protease composed of ClpX, an ATP-dependent chaperone that recognizes and unfolds specific substrates, and ClpP, a serine protease. One ClpXP substrate in Escherichia coli is FtsZ, which is essential for cell division. FtsZ polymerizes and forms the FtsZ ring at midcell, where division occurs. To investigate the role of ClpXP in cell division, we examined the effects of clpX and clpP deletions in several strains that are defective for cell division. Together, our results suggested that ClpXP modulates cell division through degradation of FtsZ and possibly other cell division components that function downstream of FtsZ ring assembly. In the ftsZ84 strain, which is temperature sensitive for filamentation due to a mutation in ftsZ, we observed that deletion of clpX or clpP suppresses filamentation and reduces FtsZ84 degradation. These results are consistent with ClpXP playing a role in cell division by modulating the level of FtsZ through degradation. In another division defective strain, DeltaminC, the additional deletion of clpX or clpP delays cell division and exacerbates filamentation. Our results demonstrate that ClpXP modulates division in cells lacking MinC by a mechanism that requires ATP dependent degradation. However, antibiotic chase experiments in vivo indicate that FtsZ degradation is slower in the DeltaminC strain than in the wild type, suggesting there may be another cell division component degraded by ClpXP. Taken together these studies suggest that ClpXP may degrade multiple cell division proteins, thereby modulating the precise balance of the components required for division. PMID- 21317325 TI - Extremely variable conservation of gamma-type small, acid-soluble proteins from spores of some species in the bacterial order Bacillales. AB - gamma-Type small, acid-soluble spore proteins (SASP) are the most abundant proteins in spores of at least some members of the bacterial order Bacillales, yet they remain an enigma from both functional and phylogenetic perspectives. Current work has shown that the gamma-type SASP or their coding genes (sspE genes) are present in most spore-forming members of Bacillales, including at least some members of the Paenibacillus genus, although they are apparently absent from Clostridiales species. We have applied a new method of searching for sspE genes, which now appear to also be absent from a clade of Bacillales species that includes Alicyclobacillus acidocaldarius and Bacillus tusciae. In addition, no gamma-type SASP were found in A. acidocaldarius spores, although several of the DNA-binding alpha/beta-type SASP were present. These findings have elucidated the phylogenetic origin of the sspE gene, and this may help in determining the precise function of gamma-type SASP. PMID- 21317326 TI - Lactococcus lactis ZitR is a zinc-responsive repressor active in the presence of low, nontoxic zinc concentrations in vivo. AB - In the family Streptococcaceae, the genes encoding zinc ABC uptake systems (called zit or adc) are regulated by a coencoded MarR family member (i.e., ZitR or AdcR), whereas in the great majority of bacteria, these genes are regulated by Zur, the Fur-like zinc-responsive repressor. We studied the zit operon from Lactococcus lactis and its regulation in response to Zn(II) in vivo. zit transcription is repressed by Zn(II) in a wide concentration range starting from nontoxic micromolar levels and is derepressed at nanomolar concentrations. The level of zit promoter downregulation by environmental Zn(II) is correlated with the intracellular zinc content. The helix-turn-helix domain of ZitR is required for downregulation. In vitro, the purified protein is a dimer that complexes up to two zinc ligands per monomer and specifically binds two intact palindromic operator sites overlapping the -35 and -10 boxes of the zit promoter. DNA binding is abolished by the chelator EDTA or TPEN and fully restored by Zn(II) addition, indicating that the active repressor complexes Zn(II) with high affinity. These results suggest that derepression under starvation conditions could be an essential emergency mechanism for preserving Zn(II) homeostasis by uptake; under Zn(II)-replete conditions, the function of ZitR repression could be to help save energy rather than to avoid Zn(II) toxicity. The characterization of a MarR family zinc-responsive repressor in this report gives insight into the way Streptococcaceae efficiently adapt to Zn(II) fluctuations in their diverse ecological niches. PMID- 21317327 TI - Fatty acid-related phylogeny of myxobacteria as an approach to discover polyunsaturated omega-3/6 Fatty acids. AB - In an analysis of 47 aerobic myxobacterial strains, representing 19 genera in suborders Cystobacterineae, Nannocystineae, Sorangiineae, and a novel isolate, "Aetherobacter" SBSr008, an enormously diverse array of fatty acids (FAs) was found. The distribution of straight-chain fatty acids (SCFAs) and branched-chain fatty acids (BCFAs) supports the reported clustering of strains in the phylogenetic tree based on 16S rRNA genes. This finding additionally allows the prediction and assignment of the novel isolate SBSr008 into its corresponding taxon. Sorangiineae predominantly contains larger amounts of SCFA (57 to 84%) than BCFA. On the other hand, Cystobacterineae exhibit significant BCFA content (53 to 90%), with the exception of the genus Stigmatella. In Nannocystineae, the ratio of BCFA and SCFA seems dependent on the taxonomic clade. Myxobacteria could also be identified and classified by using their specific and predominant FAs as biomarkers. Nannocystineae is remarkably unique among the suborders for its absence of hydroxy FAs. After the identification of arachidonic (AA) FA in Phaselicystidaceae, eight additional polyunsaturated fatty acids (PUFAs) belonging to the omega-6 and omega-3 families were discovered. Here we present a comprehensive report of FAs found in aerobic myxobacteria. Gliding bacteria belonging to Flexibacter and Herpetosiphon were chosen for comparative analysis to determine their FA profiles in relation to the myxobacteria. PMID- 21317328 TI - Complete genome sequences of two hemotropic mycoplasmas, Mycoplasma haemofelis strain Ohio2 and Mycoplasma suis Strain Illinois. AB - We report the complete and fully assembled genomes of Mycoplasma haemofelis strain Ohio2 and Mycoplasma suis strain Illinois, which are the first available genomes of these uncultivatable hemoplasma species. The single circular chromosomes of 1,152,484 bp and 742,431 bp for M. haemofelis and M. suis, respectively, are typical of mycoplasma species, having reduced size and low G+C content (38.8% for M. haemofelis and 31.1% for M. suis). Their metabolic pathways are reduced, with evidence of adaption to the blood environment. PMID- 21317329 TI - A glutathione redox effect on photosynthetic membrane expression in Rhodospirillum rubrum. AB - The formation of intracytoplasmic photosynthetic membranes by facultative anoxygenic photosynthetic bacteria has become a prime example for exploring redox control of gene expression in response to oxygen and light. Although a number of redox-responsive sensor proteins and transcription factors have been characterized in several species during the last several years in some detail, the overall understanding of the metabolic events that determine the cellular redox environment and initiate redox signaling is still poor. In the present study we demonstrate that in Rhodospirillum rubrum, the amount of photosynthetic membranes can be drastically elevated by external supplementation of the growth medium with the low-molecular-weight thiol glutathione. Neither the widely used reductant dithiothreitol nor oxidized glutathione caused the same response, suggesting that the effect was specific for reduced glutathione. By determination of the extracellular and intracellular glutathione levels, we correlate the GSH/GSSG redox potential to the expression level of photosynthetic membranes. Possible regulatory interactions with periplasmic, membrane, and cytosolic proteins are discussed. Furthermore, we found that R. rubrum cultures excrete substantial amounts of glutathione to the environment. PMID- 21317330 TI - The sigE gene is required for normal expression of heterocyst-specific genes in Anabaena sp. strain PCC 7120. AB - The filamentous cyanobacterium Anabaena (Nostoc) sp. strain PCC 7120 produces specialized cells for nitrogen fixation called heterocysts. Previous work showed that the group 2 sigma factor sigE (alr4249; previously called sigF) is upregulated in differentiating heterocysts 16 h after nitrogen step-down. We now show that the sigE gene is required for normal heterocyst development and normal expression levels of several heterocyst-specific genes. Mobility shift assays showed that the transcription factor NtcA binds to sites in the upstream region of sigE and that this binding is enhanced by 2-oxoglutarate (2-OG). Deletions of the region containing the NtcA binding sites in P(sigE)-gfp reporter plasmids showed that the sites contribute to normal developmental regulation but are not essential for upregulation in heterocysts. Northern RNA blot analysis of nifH mRNA revealed delayed and reduced transcript levels during heterocyst differentiation in a sigE mutant background. Quantitative reverse transcription PCR (qRT-PCR) analyses of the sigE mutant showed lower levels of transcripts for nifH, fdxH, and hglE2 but normal levels for hupL. We developed a P(nifHD)-gfp reporter construct that showed strong heterocyst-specific expression. Time-lapse microscopy of the P(nifHD)-gfp reporter in a sigE mutant background showed delayed development and undetectable green fluorescent protein (GFP) fluorescence. Overexpression of sigE caused accelerated heterocyst development, an increased heterocyst frequency, and premature expression of GFP fluorescence from the P(nifHD)-gfp reporter. PMID- 21317331 TI - Expanding the definition of class 3 inteins and their proposed phage origin. AB - Inteins are the protein equivalent of introns. Their protein splicing activity is essential for the host protein's maturation and function. Inteins are grouped into three classes based on sequence signature and splicing mechanism. The sequence signature of the recently characterized class 3 inteins is a noncontiguous Trp-Cys-Thr (WCT) motif and the absence of the standard class 1 Cys1 or Ser1 N-terminal nucleophile. The intein N-terminal Cys1 or Ser1 residue is essential for splicing in class 1 inteins. The mycobacteriophage Catera Gp206, Nocardioides sp. strain JS614 TOPRIM, and Thermobifida fusca YX Tfu2914 inteins have a mixture of class 1 and class 3 motifs. They carry the class 3 Trp-Cys-Thr motif and have the standard class 1 N-terminal Ser1 or Cys1. This study determined which class the mycobacteriophage Catera Gp206 and Nocardioides sp. JS614 TOPRIM inteins belong to based on catalytic mechanism. The mycobacteriophage Catera Gp206 intein (starting with Ser1) is a class 3 intein, and its Ser1 residue is not required for splicing. Based on phylogenetic analysis, we propose that class 3 inteins arose from a single mutated intein that was spread by phage into predominantly helicase genes in various phages and their hosts. PMID- 21317332 TI - Genome sequence of Citromicrobium strain JLT1363, isolated from the South China Sea. AB - Citromicrobium is a member of the alpha-4 subcluster in the Alphaproteobacteria and is identified as a typical aerobic anoxygenic phototrophic bacterium (AAPB). Here we report the draft genome sequence of a non-AAPB strain, Citromicrobium sp. JLT1363. The genome sequence reveals a multimechanism of horizontal gene transfer, as well. PMID- 21317333 TI - Draft genome sequences of six Escherichia coli isolates from the stepwise model of emergence of Escherichia coli O157:H7. AB - Enterohemorrhagic Escherichia coli (EHEC) of serotype O157:H7 has been implicated in food-borne illnesses worldwide. An evolutionary model was proposed in which the highly pathogenic EHEC O157:H7 serotype arose from its ancestor, enteropathogenic E. coli (EPEC) O55:H7 (sorbitol fermenting [SOR(+)] and beta glucuronidase positive [GUD(+)]), through sequential gain of virulence, phenotypic traits, and serotype change. Here we report six draft genomes of strains belonging to this evolutionary model: two EPEC O55:H7 (SOR(+) GUD(+)) strains, two nonmotile EHEC O157:H(-) strains (SOR(+) GUD(+)) containing plasmid pSFO157, one EHEC O157:H7 (SOR(-) GUD(+)) strain, and one O157:H7 strain containing plasmid pSFO157 (SOR(+) GUD(+)). PMID- 21317334 TI - Complete genome sequence of Mycoplasma haemofelis, a hemotropic mycoplasma. AB - Here, we present the genome sequence of Mycoplasma haemofelis strain Langford 1, representing the first hemotropic mycoplasma (hemoplasma) species to be completely sequenced and annotated. Originally isolated from a cat with hemolytic anemia, this strain induces severe hemolytic anemia when inoculated into specific pathogen-free-derived cats. The genome sequence has provided insights into the biology of this uncultivatable hemoplasma and has identified potential molecular mechanisms underlying its pathogenicity. PMID- 21317335 TI - Regulation of sulfur assimilation pathways in Burkholderia cenocepacia through control of genes by the SsuR transcription factor. AB - The genome of Burkholderia cenocepacia contains two genes encoding closely related LysR-type transcriptional regulators, CysB and SsuR, involved in control of sulfur assimilation processes. In this study we show that the function of SsuR is essential for the utilization of a number of organic sulfur sources of either environmental or human origin. Among the genes upregulated by SsuR identified here are the tauABC operon encoding a predicted taurine transporter, three tauD type genes encoding putative taurine dioxygenases, and atsA encoding a putative arylsulfatase. The role of SsuR in expression of these genes/operons was characterized through (i) construction of transcriptional reporter fusions to candidate promoter regions and analysis of their expression in the presence/absence of SsuR and (ii) testing the ability of SsuR to bind SsuR responsive promoter regions. We also demonstrate that expression of SsuR activated genes is not repressed in the presence of inorganic sulfate. A more detailed analysis of four SsuR-responsive promoter regions indicated that ~44 bp of the DNA sequence preceding and/or overlapping the predicted -35 element of such promoters is sufficient for SsuR binding. The DNA sequence homology among SsuR "recognition motifs" at different responsive promoters appears to be limited. PMID- 21317336 TI - Evolutionarily conserved orthologous families in phages are relatively rare in their prokaryotic hosts. AB - We have identified conserved orthologs in completely sequenced genomes of double strand DNA phages and arranged them into evolutionary families (phage orthologous groups [POGs]). Using this resource to analyze the collection of known phage genomes, we find that most orthologs are unique in their genomes (having no diverged duplicates [paralogs]), and while many proteins contain multiple domains, the evolutionary recombination of these domains does not appear to be a major factor in evolution of these orthologous families. The number of POGs has been rapidly increasing over the past decade, the percentage of genes in phage genomes that have orthologs in other phages has also been increasing, and the percentage of unknown "ORFans" is decreasing as more proteins find homologs and establish a family. Other properties of phage genomes have remained relatively stable over time, most notably the high fraction of genes that are never or only rarely observed in their cellular hosts. This suggests that despite the renowned ability of phages to transduce cellular genes, these cellular "hitchhiker" genes do not dominate the phage genomic landscape, and a large fraction of the genes in phage genomes maintain an evolutionary trajectory that is distinct from that of the host genes. PMID- 21317337 TI - Enzymatic and mutational analyses of a class II 3',5'-cyclic nucleotide phosphodiesterase, PdeE, from Myxococcus xanthus. AB - Myxococcus xanthus PdeE, an enzyme homologous to class II 3',5'-cyclic nucleotide phosphodiesterases, hydrolyzed cyclic AMP (cAMP) and cGMP with K(m) values of 12 MUM and 25 MUM, respectively. A pdeE mutant exhibited delays in fruiting body and spore formation compared with the wild type when cultured on starvation medium. PMID- 21317338 TI - Complete genome sequence of Vibrio vulnificus MO6-24/O. AB - Vibrio vulnificus is the causative agent of life-threatening septicemia and severe wound infections. Here, we announce the complete annotated genome sequence of V. vulnificus MO6-24/O, isolated from a patient with septicemia. When it is compared with previously known V. vulnificus genomes, the genome of this bacterium shows a unique genetic makeup, including phagelike elements, carbohydrate metabolism-related genes, and the superintegron. PMID- 21317339 TI - LEAF TIP NECROSIS1 plays a pivotal role in the regulation of multiple phosphate starvation responses in rice. AB - Although phosphate (Pi) starvation signaling is well studied in Arabidopsis (Arabidopsis thaliana), it is still largely unknown in rice (Oryza sativa). In this work, a rice leaf tip necrosis1 (ltn1) mutant was identified and characterized. Map-based cloning identified LTN1 as LOC_Os05g48390, the putative ortholog of Arabidopsis PHO2, which plays important roles in Pi starvation signaling. Analysis of transgenic plants harboring a LTN1 promoter::beta glucuronidase construct revealed that LTN1 was preferentially expressed in vascular tissues. The ltn1 mutant exhibited increased Pi uptake and translocation, which led to Pi overaccumulation in shoots. In association with enhanced Pi uptake and transport, some Pi transporters were up-regulated in the ltn1 mutant in the presence of sufficient Pi. Furthermore, the elongation of primary and adventitious roots was enhanced in the ltn1 mutant under Pi starvation, suggesting that LTN1 is involved in Pi-dependent root architecture alteration. Under Pi-sufficient conditions, typical Pi starvation responses such as stimulation of phosphatase and RNase activities, lipid composition alteration, nitrogen assimilation repression, and increased metal uptake were also activated in ltn1. Moreover, analysis of OsmiR399-overexpressing plants showed that LTN1 was down-regulated by OsmiR399. Our results strongly indicate that LTN1 is a crucial Pi starvation signaling component downstream of miR399 involved in the regulation of multiple Pi starvation responses in rice. PMID- 21317341 TI - Effects of diet and Aspergillus oryzae extract or Saccharomyces cervisiae on growth and carcass characteristics of lambs and steers fed to meet requirements of natural markets. AB - Two studies were conducted to determine the effects of diet and feed additive on growth and carcass characteristics of lambs and cattle destined for all natural markets. In Exp. 1, 48 Dorset * Hampshire lambs (initial BW 29.4 +/- 0.1 kg) were used in a randomized complete block experiment to determine the effects of Aspergillus oryzae extract, Amaferm (AMF) supplementation (1 g/d) in an 85% concentrate diet on growth and carcass characteristics. Lambs were allotted to 12 pens (4 lambs per pen), and blocked by sex and BW. Lambs were fed until the average BW of each pen reached a target BW (55.4 kg for wethers and 50.0 kg for ewes), at which time the entire pen of lambs was slaughtered. Amaferm resulted in a greater (P=0.07) G:F. In Exp. 2, 168 crossbred steers (initial BW 300 +/- 0.7 kg) were used in a trial with a 3 * 2 factorial arrangement of treatments to examine the effects of 0.5 g/d of Saccaromyces cervisiae boulardii CNCM 1079 Levucell SB (LEV), or 3 g/d of AMF with 2 corn sources, dry whole-shelled corn or high moisture corn, on growth and carcass characteristics. Neither LEV nor AMF improved (P>0.10) carcass characteristics compared with control or non-feed supplemented steers. Addition of LEV to high-concentrate, corn-based diets did not improve (P>0.10) growth performance of feedlot steers. However, addition of AMF to a diet composed of dry whole-shelled corn resulted in an improvement (P<0.05) in G:F (0.208 vs. 0.194). Results indicate that at the amounts fed, AMF may improve G:F for lambs and steers fed dry corn-based finishing diets. PMID- 21317340 TI - Whole genome analysis of gene expression reveals coordinated activation of signaling and metabolic pathways during pollen-pistil interactions in Arabidopsis. AB - Plant reproduction depends on the concerted activation of many genes to ensure correct communication between pollen and pistil. Here, we queried the whole transcriptome of Arabidopsis (Arabidopsis thaliana) in order to identify genes with specific reproductive functions. We used the Affymetrix ATH1 whole genome array to profile wild-type unpollinated pistils and unfertilized ovules. By comparing the expression profile of pistils at 0.5, 3.5, and 8.0 h after pollination and applying a number of statistical and bioinformatics criteria, we found 1,373 genes differentially regulated during pollen-pistil interactions. Robust clustering analysis grouped these genes in 16 time-course clusters representing distinct patterns of regulation. Coregulation within each cluster suggests the presence of distinct genetic pathways, which might be under the control of specific transcriptional regulators. A total of 78% of the regulated genes were expressed initially in unpollinated pistil and/or ovules, 15% were initially detected in the pollen data sets as enriched or preferentially expressed, and 7% were induced upon pollination. Among those, we found a particular enrichment for unknown transcripts predicted to encode secreted proteins or representing signaling and cell wall-related proteins, which may function by remodeling the extracellular matrix or as extracellular signaling molecules. A strict regulatory control in various metabolic pathways suggests that fine-tuning of the biochemical and physiological cellular environment is crucial for reproductive success. Our study provides a unique and detailed temporal and spatial gene expression profile of in vivo pollen-pistil interactions, providing a framework to better understand the basis of the molecular mechanisms operating during the reproductive process in higher plants. PMID- 21317342 TI - Triennial Growth Symposium: dietary regulation of growth and development. PMID- 21317343 TI - Hypothermia in neonatal piglets: interactions and causes of individual differences. AB - Hypothermia is a major cause of mortality in neonatal piglets. However, there are considerable individual differences in the successful recovery from postnatal hypothermia in the common farrowing environment, and so far the causes and interactions of causes have not been studied in detail. Using 635 crossbred neonatal piglets, the aim of this study was to identify the links among different physiological and behavioral measures and their connections to the ability of piglets to overcome initial postnatal hypothermia, with rectal temperature at 2 h as the response variable. The data included birth weight, hypoxia at birth (viability score and lactate in umbilical cord blood), latency to first udder contact and first suckle, scans of individual piglet position during the first 2 h after birth, and rectal temperature at birth and 2 h postpartum. A graphical chain model was used to analyze data. The statistical variables were divided into blocks according to level (design and litter) and chronological order (prenatal, birth, perinatal, and thermoregulatory success at 2 h) before applying the graphical model to the data. Bayesian information criteria (BIC) was used for model selection. The BIC relates to maximum likelihood, but introduces an additional penalty term for the number of variables. The strength of an association between 2 variables is reported as the increase in BIC (BICinc) due to removing the link. Results indicate that at 2 h, 22.1% of the piglets had a rectal temperature below 37 degrees C. Out of the 16 variables included in the model, only 3 had direct links to the response variable of rectal temperature at 2 h. There was a positive relationship between rectal temperature at 2 h and birth weight (BICinc=26), and between being observed more often by the udder as opposed to alone during both the first (BICinc=8) and second hours (BICinc=19) after birth. Lighter piglets and piglets that had experienced hypoxia took longer to achieve first suckle, which in turn affected where the piglet positioned itself during the first and second hours after birth. Variables related to the birth process had no direct connection to thermoregulatory success, but were additive in the explanation of piglet behavior. The rectal temperature of individual piglets at 2 h depends largely on piglet birth weight and on piglet position in relation to sow and littermates. Birth weight is the most important single factor in successful recovery from postnatal hypothermia. PMID- 21317344 TI - Effect of fermentation of cereals on the degradation of polysaccharides and other macronutrients in the gastrointestinal tract of growing pigs. AB - The main objective of the present investigation was to study the impact of fermentation of cereals on the degradation of polysaccharides and other macronutrients in the small intestine and total tract of growing pigs. Eight pigs (initial BW, 34.5 +/- 0.9 kg) were used in a replicated 4 * 4 Latin square design. Pigs were cannulated and housed individually in metabolism pens during sample collection. The 4 cereal-based diets were nonfermented liquid barley (NFLB), nonfermented liquid wheat (NFLW), fermented liquid barley (FLB), and fermented liquid wheat (FLW). The fermented feeds were prepared by storing the dietary cereals (barley and wheat) and water [1:2.75 (wt/wt)] in a closed tank at 25 degrees C for 2 d, after which 50% of the volume was removed and replaced with an equal amount of fresh cereals and water after each afternoon meal. At the time of feeding (0730 and 1430 h), the remaining dietary ingredients were added. Water was added to the dry nonfermented feeds [1:1 (wt/wt)] immediately before feeding. The fermentation process reduced the amount of DM in both cereals (P<0.001), whereas the amount of DM was similar (P=0.626) between the fermented cereals. There was an interaction of cereal and treatment for ileal flow of DM (P=0.014), OM (P=0.013), and protein (P=0.006), which were less in pigs fed the NFLB than the FLB diets, but unchanged in pigs fed the NFLW and FLW diets. Conversely, the ileal flow of protein was similar (P=0.605) in pigs fed the barley diets (average, 47.5 +/- 1.7 g/kg of DMI) and increased with the FLW diet compared with the NFLW diet (43 vs. 35 g/kg of DMI, respectively). Ileal fat and CH(2)O digestibilities were 7.6 (P=0.002) and 8.9% (P<0.001) greater, respectively, when pigs were fed wheat compared with the barley-based diets, and the ileal digestibility of CH(2)O was greater when pigs were fed the fermented than nonfermented diets (86.5 vs. 84.5%, respectively; P<0.001). Fermentation reduced (P<0.0001) the fecal excretion of DM, OM, and protein in pigs fed the barley diet, but not when fed the wheat-based diet (P=0.305). Fermentation had no effect (P=0.243) on the fecal digestibility of nonstarch polysaccharides in either of the cereals but their digestibility was 10.0% greater (P<0.001) in pigs fed wheat than the barley-based diets. In conclusion, fermentation of cereal before feeding altered the dietary composition and influenced flow and composition of polysaccharides and other macronutrients at the ileum and in feces to a larger extent for barley than wheat. PMID- 21317345 TI - Evaluation of 2 sources of Angus cattle under South Florida subtropical conditions. AB - The objective of this study was to compare performance and aspects of adaptability attributes of cattle from a Florida Angus bloodline (local source from a mostly closed herd for over 50 yr) to cattle that are representative of modern Angus bloodlines (outside source) in US subtropical conditions. Embryos from both sources were transferred to Brahman-crossbred cows in South Florida, and calves (n=82) were born in 3 yr. Before weaning, summer tympanic temperatures were recorded hourly for 3 d in each year. Heifers were placed with fertile bulls until diagnosed pregnant. Traits relative to sexual maturation of bulls were recorded at 1- or 2-mo intervals until approximately 17 mo of age. Calves from outside sources had greater hip height at weaning than calves from the local source (P<0.001; 108.8 +/- 0.62 and 104.7 +/- 0.68 cm, respectively). Local source calves (n=37) had greater (P=0.03) exit velocity (2.7 +/- 0.3 m/s) than outside-source (n=45) calves (2.0 +/- 0.29 m/s), which may be indicative of more nervous or temperamental disposition. However, no source differences were detected for other assessments of disposition (chute or pen score, P>0.8). Few source differences for minimum, maximum, or range of daily tympanic (inner ear) temperatures were detected. At 17 mo of age, outside-source heifers were heavier (P = 0.05) and had greater (P<0.001) hip height than Angus heifers from the local source. Heifers from the outside source were younger (P<0.001) at the time of their first conception (454 +/- 17.5 d) than heifers from the local source (550 +/- 16.9 d). Outside-source heifers also had greater (P<0.02) pregnancy and calving rates (0.7 +/- 0.119 and 0.62 +/- 0.125, respectively) from exposure to bulls within a year from weaning than the heifers from the local source (0.29 +/- 0.089 and 0.19 +/- 0.077, respectively). Bulls from the outside source were heavier (P=0.05) at 320 d of age than local-source bulls. From 14 through 17 mo of age, outside-source bulls had greater (P<=0.05) scrotal circumference and tended (P<=0.15) to be heavier than local-source bulls. There appeared to be no performance or adaptation advantages for the local-source Angus through 17 mo of age. The large source difference for age at first conception in heifers merits additional attention and comparison with cow lifetime production performance for the 2 sources. PMID- 21317346 TI - Energy and protein allowances and requirements in stallions during the breeding season, comparing different nutritional systems. AB - This study was conducted to estimate the nutritional value of diets given to stallions of different breeds during the reproductive season, and comparing allowances with requirements. The systems compared were the French INRA, the 1989 NRC, and the 2007 NRC. Data on reproductive activity, daily exercise, BW, BCS, feed intake, and feed composition during 4 mo (from March to June) were recorded on 12 stallions used for commercial AI programs. Stallions belonged to 3 different breeds: Italian Haflinger (IH, n=4), Holstein (HOL, n=4), and Italian Heavy Draft horse (IHDH, n=4). Data recorded were used to estimate the actual energy and protein intakes and theoretical requirements of the stallions using the aforementioned systems. A deviation index [DI = (intake - requirement)/intake * -1] was calculated to allow a comparison among methods as a proportion of under or overestimates of theoretical requirements. All data were statistically analyzed with a mixed model for repeated measurements. The reproductive activity of the stallions was affected by month (less in March and greater in subsequent months; P<0.05). Daily exercise was generally low during the middle breeding season, and the intensity and kinds of exercise differed according to the breeds. Changes of BW and BCS of the stallions were not statistically significant (P=0.69 and P=0.17, respectively) during the experimental period, and therefore diets could be considered balanced to support all animal needs. However, the energy and protein allowances were not always consistent with the theoretical requirements considering all 3 nutritional systems. Energy and protein INRA recommendations showed, on average, +0.90 and +0.27 greater DI than actual intakes, respectively, for IH and HOL stallions, whereas the theoretical requirements were much closer to allowances for the IHDH stallions (DI close to 0). The 1989 NRC energy and protein recommendations, respectively, were +0.67 and +0.87 greater than intake for IH, +0.28 and +0.43 greater for HOL, and only +0.06 and +0.17 greater for IHDH stallions. The 2007 NRC energy and protein recommendations, respectively, were +0.70 and +0.52 greater for IH, +0.33 and +0.17 greater for HOL, and +0.52 and +0.49 greater for IHDH than actual intakes. Therefore, all systems overestimated the requirements of the stallion, particularly in lighter breeds. Further studies to validate requirements for breeding stallions of different sizes are recommended. PMID- 21317347 TI - Effect of compensatory growth on forms of glycogen, postmortem proteolysis, and meat quality in pigs. AB - The current experiment was designed to examine if a compensatory feed regimen influenced storage of glycogen forms, activity of proteolytic systems, and meat quality. Female pigs (Large White * Landrace * Duroc cross) with an initial age of 74 d were allocated to 6 feeding treatment groups (n=8 for each group). Groups then consumed feed ad libitum for 40 (A40), 42 (A42), or 82 d (A82). The compensatory growth groups were fed 0.70 of ad libitum intake for 40 d (R40) followed by refeeding for ad libitum intake for 2 (R40A2) or 42 d (R40A42). Pigs were slaughtered at the end of the restriction period (SL1), then after refeeding for 2 (SL2) and 42 d (SL3). The feeding regimen caused restricted animals at SL2 to have a decreased BW (P=0.039), with the refed animals undergoing compensatory growth by SL3 so BW was not different (P=0.829). At SL1 there was a trend for the R40 pigs to have less intramuscular fat than A40 (P=0.084). There was a trend for macroglycogen (MG; P=0.051) and a significant effect for proglycogen (ProG; P=0.014) to be greater at slaughter in R40 than A40, along with a greater postmortem decline in both MG (P=0.033) and ProG (P=0.022) over the first 2 h in R40, which was associated with the R40 having a lower pH at 24 h postmortem (P=0.043). After refeeding for 2 d (SL2), only MG of R40A2 was greater (P=0.030) than A42 and had a trend for a greater difference of decline at 24 h postmortem (P=0.091), which was associated with lower pH at 24 h (P=0.012). The data suggest that the concentrations of ProG are more labile and recovered to the concentrations of pigs fed for ad libitum intake sooner than MG. After full compensation in SL3, there was no difference for MG content (at 0 h, P=0.721; at 2 h, P=0.987; at 24 h, P=0.343), ProG content (at 0 h, P=0.879; at 2 h, P=0.946; at 24 h, P=0.459), and muscle pH (at 45 min, P=0.373; at 24 h, P=0.226). At all slaughter points, there was no difference in shear force (at SL1, P=0.101; at SL2, P=0.420; at SL3, P=0.167). There were no significant effects of the feeding regimen on micro- and milli-calpain large subunit gene expression (for micro calpain at SL1, P=0.450; at SL2, P=0.171; at SL3, P=0.281; for milli-calpain at SL1, P=0.666; at SL2, P=0.123; at SL3, P=0.617) or the activity of the 2 proteolytic enzymes at any of the slaughter dates (for micro-calpain at SL1, P=0.238; at SL2, P =0.238; at SL3, P=0.222; for milli-calpain at SL1, P=0.296; at SL2, P=0.230; at SL3, P=0.615). In R40 there was a trend (P=0.070) for greater gene expression of caspase 3, whereas in R40A2 the increase was significant (P=0.009) relative to pigs consuming feed ad libitum. However, gene expression of the E3 ligase, MuRF1, at SL3 was less in R40A42 (P=0.019). Although compensatory growth does appear to influence the expression of various proteolytic systems, the changes do not appear to be associated with meat quality as measured by shear force. PMID- 21317348 TI - Effect of dietary fermented garlic by Weissella koreensis powder on growth performance, blood characteristics, and immune response of growing pigs challenged with Escherichia coli lipopolysaccharide. AB - Two experiments were conducted to investigate the effect of fermented garlic by Weissella koreensis powder (WKG) on pig growth performance and immune responses after an Escherichia coli lipopolysaccharide (LPS) challenge. In Exp. 1, 120 growing barrows (23.5 +/- 0.5 kg of BW and 56 d of age) were used in a 35-d experiment to determine the optimal amounts of WKG. Pigs were randomly allotted to 1 of 5 treatments with 6 replicate pens and 4 pigs per pen. Dietary treatments included 1) NC (negative control; basal diet without antibiotics), 2) PC (positive control; basal diet + 1 g of tylosin/kg), 3) WKG1 (basal diet + 1 g of WKG/kg), 4) WKG2 (basal diet + 2 g of WKG/kg), and 5) basal diet + 4 g of WKG/kg. At the end of the feeding period, 12 pigs each were selected from the NC and WKG2 treatment groups, and 6 pigs were injected with LPS (50 MUg/kg of BW) and the other 6 pigs with an equivalent amount of sterile saline, resulting in a 2 * 2 factorial arrangement of treatments. Blood samples and rectal temperature data were collected at 0, 2, 4, 6, 8, and 12 h after challenge. The ADG of pigs fed WKG- and antibiotic-supplemented diets was greater (P<0.05) than NC from d 14 to 35 and the overall phase, but no dosage-dependent effects were observed. At the end of the experiment, the fecal E. coli count was linearly reduced by the increasing amounts of WKG at d 35 (P=0.01). Challenge with LPS increased white blood cell counts at 6 and 8 h (P<0.01) and depressed lymphocyte concentration at 4, 8, and 12 h (P<0.01). During challenge, LPS injection increased rectal temperature at 2, 4, 6, and 8 h postchallenge (P<0.05), and WKG2 alleviated (P<0.05) the increase in the temperature at 2 h postchallenge. The LPS injection increased plasma tumor necrosis factor-alpha and IGF-1 concentrations at 2, 4, 6, 8, and 12 h (P<0.01), whereas an alleviating effect of WKG was observed at 4, 6, and 8 h after LPS challenge (P<0.05). At 2, 4, and 6 h postchallenge, concentration of cluster of differentiation-antigen-4-positive cells and cluster of differentiation-antigen-8-positive cells (CD4(+) and CD8(+), respectively) increased in the LPS treatments (P<0.05), and the WKG2 boosted this effect (P<0.05). In conclusion, dietary supplementation of WKG2 in growing pigs can improve ADG and have a beneficial effect on the immune response during an inflammatory challenge. PMID- 21317349 TI - Comparison of varying doses and durations of ractopamine hydrochloride on late finishing pig carcass characteristics and meat quality. AB - The objective was to investigate the effect of various doses and durations of ractopamine hydrochloride (RAC) on pig HCW, cutting yields, and meat quality. Late-finishing pigs (approximately 93 kg) were allotted to 12 treatments 35 d before slaughter. Treatments consisted of negative control (NEG; 13.1% CP, 0.64 TID Lys), positive control (POS; 17.8% CP, 0.94 TID Lys), and 2 RAC doses (5 and 7.4 mg/kg) with 5 different feeding durations for each dose (7, 14, 21, 28, or 35 d). Pigs on ractopamine-duration diets were fed NEG until incorporation of RAC, and then the diet was switched to POS to comply with label requirements. A subset of 240 pigs was utilized to determine the effects of RAC on carcass cutting yields. This subset was selected by taking the 5 pigs closest to the average pen weight from 4 complete replicates. Differences in response to RAC between 5 and 7.4 mg/kg were not significant. Therefore, RAC dosages were pooled, resulting in an average dose of 6.2 mg/kg, which was then compared with NEG and POS diets. Ractopamine increased (P < 0.05) HCW by 2.5 and 2.3 kg compared with the NEG and POS diets, respectively. Hot carcass weight also increased linearly (P=0.003) as RAC duration increased. Indicators of carcass leanness increased with RAC compared with NEG. Estimated carcass lean percentage increased (P=0.010) 1 percentage unit from 54.79 to 55.79%, carcass cut yield increased (P<0.001) 1.23 percentage units from 50.61 to 51.84%, and (P=0.006) boneless lean cut yield increased 1.27 percentage units from 36.71 to 37.98%. Ractopamine decreased (P=0.002) subjective marbling scores 0.49 units from the NEG value of 3.0, but RAC did not differ (P=0.203) from POS. Subjective color values and shear force aging curves for RAC were not significantly different from NEG or POS. Overall, RAC had greater responses in carcass weight and cut yield than NEG, and had minimal effects on meat quality. PMID- 21317350 TI - Short-term effects of maternal feed restriction during pregnancy on goat kid morphology, metabolism, and behavior. AB - Morphometric, metabolic, and behavioral modifications were studied in goat kids after maternal feed restriction during the last one-third of pregnancy. At birth, only kids from twin and triplet litters were studied [n=40 kids born to control dams (CONT) and n=38 born to restricted dams (REST)] and only males thereafter (n=13 CONT and 15 REST kids) until slaughter at 6 wk of age. Kids born to restricted goats had a smaller abdominal girth at birth (P<0.01) and tended to have a smaller body mass index (P=0.10) and a smaller density index (P=0.09) than kids born to CONT goats. Male REST kids had a lighter birth weight (P=0.03) than male CONT kids, but no differences (all P>0.10) were found for BW and morphometric measurements thereafter. Decreased NEFA concentrations suggested that male REST kids mobilized their body reserves less than CONT kids at birth (P<0.01). No modifications in drinking tests at 3 and 5 wk of age were observed, or in feeding behavior and emotional reactivity at 5 wk of age (all P>0.10). In conclusion, maternal feed restriction in the last one-third of pregnancy resulted in a decrease in birth size, but male kids rapidly caught up, and there were no changes in behavior, morphology, or metabolism during rearing. PMID- 21317351 TI - Mapping genes for hypertension using experimental models: a challenging and unanticipated very long journey. PMID- 21317353 TI - A view on imaging in drug research and development for respiratory diseases. AB - With the incidence of respiratory diseases increasing throughout the world, new therapies are needed. This review provides a short overview of different imaging techniques of interest for drug discovery and development within the pulmonary disease area. The focus is on studies performed in both animals and humans, which are of importance for understanding pathophysiological aspects and evaluating new drugs. Rather than emphasizing particular lung diseases, the noninvasive diagnosis and quantification of a number of characteristics related to several pathological conditions of the lung are addressed: inflammation, mucus secretion and clearance, emphysema, ventilation, perfusion, fibrosis, airway remodeling, and pulmonary arterial hypertension. Techniques are discussed based on their present use or potential future utilization in the context of drug studies. PMID- 21317354 TI - Nonhuman primate positron emission tomography neuroimaging in drug abuse research. AB - Positron emission tomography (PET) neuroimaging in nonhuman primates has led to significant advances in our current understanding of the neurobiology and treatment of stimulant addiction in humans. PET neuroimaging has defined the in vivo biodistribution and pharmacokinetics of abused drugs and related these findings to the time course of behavioral effects associated with their addictive properties. With novel radiotracers and enhanced resolution, PET neuroimaging techniques have also characterized in vivo drug interactions with specific protein targets in the brain, including neurotransmitter receptors and transporters. In vivo determinations of cerebral blood flow and metabolism have localized brain circuits implicated in the effects of abused drugs and drug associated stimuli. Moreover, determinations of the predisposing factors to chronic drug use and long-term neurobiological consequences of chronic drug use, such as potential neurotoxicity, have led to novel insights regarding the pathology and treatment of drug addiction. However, similar approaches clearly need to be extended to drug classes other than stimulants. Although dopaminergic systems have been extensively studied, other neurotransmitter systems known to play a critical role in the pharmacological effects of abused drugs have been largely ignored in nonhuman primate PET neuroimaging. Finally, the study of brain activation with PET neuroimaging has been replaced in humans mostly by functional magnetic resonance imaging (fMRI). There has been some success in implementing pharmacological fMRI in awake nonhuman primates. Nevertheless, the unique versatility of PET imaging will continue to complement the systems-level strengths of fMRI, especially in the context of nonhuman primate drug abuse research. PMID- 21317355 TI - Assessing antibody pharmacokinetics in mice with in vivo imaging. AB - Recent advances in small-animal molecular imaging instrumentation combined with well characterized antibody-labeling chemistry have enabled detailed in vivo measurements of antibody distribution in mouse models. This article reviews the strengths and limitations of in vivo antibody imaging methods with a focus on positron emission tomography and single-photon emission computed tomography and a brief discussion of the role of optical imaging in this application. A description of the basic principles behind the imaging techniques is provided along with a discussion of radiolabeling methods relevant to antibodies. Practical considerations of study design and execution are presented through a discussion of sensitivity and resolution tradeoffs for these techniques as defined by modality, signaling probe (isotope or fluorophore) selection, labeling method, and radiation dosimetry. Images and analysis results from a case study are presented with a discussion of output data content and relevant informatics gained with this approach to studying antibody pharmacokinetics. PMID- 21317356 TI - Potentials and challenges for arterial spin labeling in pharmacological magnetic resonance imaging. AB - Pharmacological magnetic resonance imaging (phMRI) is increasingly being used in drug discovery and development to speed the translation from the laboratory to the clinic. The two primary methods in phMRI include blood-oxygen-level-dependent (BOLD) contrast and arterial spin-labeled (ASL) perfusion MRI. BOLD contrast has been widely applied in existing phMRI studies. However, because of the lack of absolute quantification and poor reproducibility over time scales longer than hours or across scanning sessions, BOLD fMRI may not be suitable to track oral and other long-term drug effects on baseline brain function. As an alternative method, ASL provides noninvasive, absolute quantification of cerebral blood flow both at rest and during task activation. ASL perfusion measurements have been shown to be highly reproducible over minutes and hours to days and weeks. These two characteristics make ASL an ideal tool for phMRI for studying both intravenous and oral drug action as well as understanding drug effects on baseline brain function and brain activation to cognitive or sensory processing. When ASL is combined with BOLD fMRI, drug-induced changes in cerebral metabolic rate of oxygen may also be inferred. Representative phMRI studies using ASL perfusion MRI on caffeine, remifentanil, and metoclopramide (dopamine antagonist) are reviewed here, with an emphasis on the methodologies used to control for potentially confounding vascular and systemic effects. Both the potentials and limitations of using ASL as an imaging marker of drug action are discussed. PMID- 21317357 TI - Effect of triiodothyronine on antidepressant screening tests in mice and on presynaptic 5-HT1A receptors: mediation by thyroid hormone alpha receptors. AB - Although triiodothyronine (T3) is widely used clinically, preclinical support for its antidepressant-like effects is limited, and the mechanisms are unknown. We evaluated 1) the antidepressant-like effects of T3 in the novelty suppressed feeding test (NSFT), tail suspension test (TST), and forced swim test (FST), 2) the role of presynaptic 5-HT(1A) receptors in the antidepressant-like mechanism of T3 by the hypothermic response to the 5-HT(1A) receptor agonist, 8-hydroxy-N,N dipropyl-2-aminotetralin (8-OH-DPAT), 3) the thyroid hormone receptor type mediating the antidepressant-like effects by concurrent administration of the specific thyroid hormone alpha receptor (TRalpha) antagonist, dronedarone, and 4) the presence of these effects in both genders. Male and female BALB/c mice were administered 1) T3 (20, 50, 200, or 500 MUg/kg per day) or vehicle or 2) T3 (50 MUg/kg per day), dronedarone (100 MUM/day), or the combination intraperitoneally for 21 days and then underwent a behavioral test battery. The NSFT showed a shortened latency to feed in males at the two lower T3 doses. The TST and FST showed decreased immobility in male mice at T3 doses >20 MUg/kg per day and in females at all T3 doses. Concurrent dronedarone prevented T3 effects in males on the NSFT and in the TST and FST in both genders. Attenuation of 8-OH-DPAT-induced hypothermia was observed in males only and may be reduced by concurrent dronedarone. These findings support an antidepressant-like effect of T3. Attenuation of 8-OH-DPAT-induced hypothermia in males only suggests the need to evaluate a possible gender disparity in the role of presynaptic 5-HT(1A) receptors in T3 antidepressant mechanisms. Blockade by dronedarone of the antidepressant-like effects of T3 suggests that these effects are TRalpha receptor-mediated. PMID- 21317358 TI - Motion processing with two eyes in three dimensions. AB - The movement of an object toward or away from the head is perhaps the most critical piece of information an organism can extract from its environment. Such 3D motion produces horizontally opposite motions on the two retinae. Little is known about how or where the visual system combines these two retinal motion signals, relative to the wealth of knowledge about the neural hierarchies involved in 2D motion processing and binocular vision. Canonical conceptions of primate visual processing assert that neurons early in the visual system combine monocular inputs into a single cyclopean stream (lacking eye-of-origin information) and extract 1D ("component") motions; later stages then extract 2D pattern motion from the cyclopean output of the earlier stage. Here, however, we show that 3D motion perception is in fact affected by the comparison of opposite 2D pattern motions between the two eyes. Three-dimensional motion sensitivity depends systematically on pattern motion direction when dichoptically viewing gratings and plaids-and a novel "dichoptic pseudoplaid" stimulus provides strong support for use of interocular pattern motion differences by precluding potential contributions from conventional disparity-based mechanisms. These results imply the existence of eye-of-origin information in later stages of motion processing and therefore motivate the incorporation of such eye-specific pattern-motion signals in models of motion processing and binocular integration. PMID- 21317359 TI - Development of an artificial cell, from self-organization to computation and self reproduction. AB - This article describes the state and the development of an artificial cell project. We discuss the experimental constraints to synthesize the most elementary cell-sized compartment that can self-reproduce using synthetic genetic information. The original idea was to program a phospholipid vesicle with DNA. Based on this idea, it was shown that in vitro gene expression could be carried out inside cell-sized synthetic vesicles. It was also shown that a couple of genes could be expressed for a few days inside the vesicles once the exchanges of nutrients with the outside environment were adequately introduced. The development of a cell-free transcription/translation toolbox allows the expression of a large number of genes with multiple transcription factors. As a result, the development of a synthetic DNA program is becoming one of the main hurdles. We discuss the various possibilities to enrich and to replicate this program. Defining a program for self-reproduction remains a difficult question as nongenetic processes, such as molecular self-organization, play an essential and complementary role. The synthesis of a stable compartment with an active interface, one of the critical bottlenecks in the synthesis of artificial cell, depends on the properties of phospholipid membranes. The problem of a self replicating artificial cell is a long-lasting goal that might imply evolution experiments. PMID- 21317360 TI - Identifying organic aerosol sources by comparing functional group composition in chamber and atmospheric particles. AB - Measurements of submicron particles by Fourier transform infrared spectroscopy in 14 campaigns in North America, Asia, South America, and Europe were used to identify characteristic organic functional group compositions of fuel combustion, terrestrial vegetation, and ocean bubble bursting sources, each of which often accounts for more than a third of organic mass (OM), and some of which is secondary organic aerosol (SOA) from gas-phase precursors. The majority of the OM consists of alkane, carboxylic acid, hydroxyl, and carbonyl groups. The organic functional groups formed from combustion and vegetation emissions are similar to the secondary products identified in chamber studies. The near absence of carbonyl groups in the observed SOA associated with combustion is consistent with alkane rather than aromatic precursors, and the absence of organonitrate groups can be explained by their hydrolysis in humid ambient conditions. The remote forest observations have ratios of carboxylic acid, organic hydroxyl, and nonacid carbonyl groups similar to those observed for isoprene and monoterpene chamber studies, but in biogenic aerosols transported downwind of urban areas the formation of esters replaces the acid and hydroxyl groups and leaves only nonacid carbonyl groups. The carbonyl groups in SOA associated with vegetation emissions provides striking evidence for the mechanism of esterification as the pathway for possible oligomerization reactions in the atmosphere. Forest fires include biogenic emissions that produce SOA with organic components similar to isoprene and monoterpene chamber studies, also resulting in nonacid carbonyl groups in SOA. PMID- 21317361 TI - Clustering to identify RNA conformations constrained by secondary structure. AB - RNA often folds hierarchically, so that its sequence defines its secondary structure (helical base-paired regions connected by single-stranded junctions), which subsequently defines its tertiary fold. To preserve base-pairing and chain connectivity, the three-dimensional conformations that RNA can explore are strongly confined compared to when secondary structure constraints are not enforced. Using three examples, we studied how secondary structure confines and dictates an RNA's preferred conformations. We made use of Macromolecular Conformations by SYMbolic programming (MC-Sym) fragment assembly to generate RNA conformations constrained by secondary structure. Then, to understand the correlations between different helix placements and orientations, we robustly clustered all RNA conformations by employing unique methods to remove outliers and estimate the best number of conformational clusters. We observed that the preferred conformation (as judged by largest cluster size) for each type of RNA junction molecule tested is consistent with its biological function. Further, the improved quality of models in our pruned datasets facilitates subsequent discrimination using scoring functions based either on statistical analysis (knowledge based) or experimental data. PMID- 21317362 TI - Free-energy cost for translocon-assisted insertion of membrane proteins. AB - Nascent membrane proteins typically insert in a sequential fashion into the membrane via a protein-conducting channel, the Sec translocon. How this process occurs is still unclear, although a thermodynamic partitioning between the channel and the membrane environment has been proposed. Experiment- and simulation-based scales for the insertion free energy of various amino acids are, however, at variance, the former appearing to lie in a narrower range than the latter. Membrane insertion of arginine, for instance, requires 14-17 kcal/mol according to molecular dynamics simulations, but only 2-3 kcal/mol according to experiment. We suggest that this disagreement is resolved by assuming a two-stage insertion process wherein the first step, the insertion into the translocon, is energized by protein synthesis and, therefore, has an effectively zero free energy cost; the second step, the insertion into the membrane, invokes the translocon as an intermediary between the fully hydrated and the fully inserted locations. Using free-energy perturbation calculations, the effective transfer free energies from the translocon to the membrane have been determined for both arginine and leucine amino acids carried by a background polyleucine helix. Indeed, the insertion penalty for arginine as well as the insertion gain for leucine from the translocon to the membrane is found to be significantly reduced compared to direct insertion from water, resulting in the same compression as observed in the experiment-based scale. PMID- 21317364 TI - H4K20 monomethylation faces the WNT. PMID- 21317363 TI - Human transcriptome array for high-throughput clinical studies. AB - A 6.9 million-feature oligonucleotide array of the human transcriptome [Glue Grant human transcriptome (GG-H array)] has been developed for high-throughput and cost-effective analyses in clinical studies. This array allows comprehensive examination of gene expression and genome-wide identification of alternative splicing as well as detection of coding SNPs and noncoding transcripts. The performance of the array was examined and compared with mRNA sequencing (RNA-Seq) results over multiple independent replicates of liver and muscle samples. Compared with RNA-Seq of 46 million uniquely mappable reads per replicate, the GG H array is highly reproducible in estimating gene and exon abundance. Although both platforms detect similar expression changes at the gene level, the GG-H array is more sensitive at the exon level. Deeper sequencing is required to adequately cover low-abundance transcripts. The array has been implemented in a multicenter clinical program and has generated high-quality, reproducible data. Considering the clinical trial requirements of cost, sample availability, and throughput, the GG-H array has a wide range of applications. An emerging approach for large-scale clinical genomic studies is to first use RNA-Seq to the sufficient depth for the discovery of transcriptome elements relevant to the disease process followed by high-throughput and reliable screening of these elements on thousands of patient samples using custom-designed arrays. PMID- 21317365 TI - Unlocking the time resolved nature of electron microscopy. PMID- 21317366 TI - Pan-genome of the dominant human gut-associated archaeon, Methanobrevibacter smithii, studied in twins. AB - The human gut microbiota harbors three main groups of H(2)-consuming microbes: methanogens including the dominant archaeon, Methanobrevibacter smithii, a polyphyletic group of acetogens, and sulfate-reducing bacteria. Defining their roles in the gut is important for understanding how hydrogen metabolism affects the efficiency of fermentation of dietary components. We quantified methanogens in fecal samples from 40 healthy adult female monozygotic (MZ) and 28 dizygotic (DZ) twin pairs, analyzed bacterial 16S rRNA datasets generated from their fecal samples to identify taxa that co-occur with methanogens, sequenced the genomes of 20 M. smithii strains isolated from families of MZ and DZ twins, and performed RNA-Seq of a subset of strains to identify their responses to varied formate concentrations. The concordance rate for methanogen carriage was significantly higher for MZ versus DZ twin pairs. Co-occurrence analysis revealed 22 bacterial species-level taxa positively correlated with methanogens: all but two were members of the Clostridiales, with several being, or related to, known hydrogen producing and -consuming bacteria. The M. smithii pan-genome contains 987 genes conserved in all strains, and 1,860 variably represented genes. Strains from MZ and DZ twin pairs had a similar degree of shared genes and SNPs, and were significantly more similar than strains isolated from mothers or members of other families. The 101 adhesin-like proteins (ALPs) in the pan-genome (45 +/- 6 per strain) exhibit strain-specific differences in expression and responsiveness to formate. We hypothesize that M. smithii strains use their different repertoires of ALPs to create diversity in their metabolic niches, by allowing them to establish syntrophic relationships with bacterial partners with differing metabolic capabilities and patterns of co-occurrence. PMID- 21317367 TI - Transient binding of dynein controls bidirectional long-range motility of early endosomes. AB - In many cell types, bidirectional long-range endosome transport is mediated by the opposing motor proteins dynein and kinesin-3. Here we use a fungal model system to investigate how both motors cooperate in early endosome (EE) motility. It was previously reported that Kin3, a member of the kinesin-3 family, and cytoplasmic dynein mediate bidirectional motility of EEs in the fungus Ustilago maydis. We fused the green fluorescent protein to the endogenous dynein heavy chain and the kin3 gene and visualized both motors and their cargo in the living cells. Whereas kinesin-3 was found on anterograde and retrograde EEs, dynein motors localize only to retrograde organelles. Live cell imaging shows that binding of retrograde moving dynein to anterograde moving endosomes changes the transport direction of the organelles. When dynein is leaving the EEs, the organelles switch back to anterograde kinesin-3-based motility. Quantitative photobleaching and comparison with nuclear pores as an internal calibration standard show that single dynein motors and four to five kinesin-3 motors bind to the organelles. These data suggest that dynein controls kinesin-3 activity on the EEs and thereby determines the long-range motility behavior of the organelles. PMID- 21317368 TI - In vivo investigation in pigs of intestinal absorption, hepatobiliary disposition, and metabolism of the 5alpha-reductase inhibitor finasteride and the effects of coadministered ketoconazole. AB - The overall aim of this detailed investigation of the pharmacokinetics (PK) and metabolism of finasteride in pigs was to improve understanding of in vivo PK for this drug and its metabolites. Specific aims were to examine the effects of ketoconazole coadministration on the PK in three plasma compartments (the portal, hepatic, and femoral veins), bile, and urine and to use these data to study in detail the intestinal absorption and the liver extraction ratio and apply a semiphysiological based PK model to the data. The pigs received an intrajejunal dose of finasteride (0.8 mg/kg) either alone (n = 5) or together with ketoconazole (10 mg/kg) (n = 5) or an intravenous dose (0.2 mg/kg) (n = 3). Plasma, bile, and urine (collected from 0 to 6 h) were analyzed with ultraperformance liquid chromatography-tandem mass spectrometry. Ketoconazole increased the bioavailability of finasteride from 0.36 +/- 0.23 to 0.91 +/- 0.1 (p < 0.05) and the terminal half-life from 1.6 +/- 0.4 to 4.0 +/- 1.1 h (p < 0.05). From deconvolution, it was found that the absorption rate from the intestine to the portal vein was rapid, and the product of the fraction absorbed and the fraction that escaped gut wall metabolism was high (f(a) . F(G) ~ 1). Interestingly, the apparent absorption rate constant (k(a)) to the femoral vein was lower than that to the portal vein, probably because of binding and distribution within the liver. The liver extraction ratio was time-dependent and varied with the two routes of administration. After intrajejunal administration, from 1 to 6 h, the liver extraction ratio was significantly (p < 0.05) reduced by ketoconazole treatment from intermediate (0.41 +/- 0.21) to low (0.21 +/- 0.10). PMID- 21317369 TI - Liver-selective expression of human arylamine N-acetyltransferase NAT2 in transgenic mice. AB - Human arylamine N-acetyltransferase 2 (NAT2) mediates the biotransformation of arylamine drugs and procarcinogens into either innocuous or reactive DNA-damaging metabolites and is expressed predominantly in liver. Interspecies differences and incongruous results between in vitro, in vivo, and epidemiological studies make it difficult to extrapolate animal results to human risk. We have generated human NAT2 transgenic mice on both C57BL/6 (hNAT2(tg)) and Nat1/2 null backgrounds [hNAT2(tg)Nat1/2(-/-)], in which liver-selective expression of human NAT2 is driven by the mouse albumin promoter. We detected expression of the human NAT2 transcript and protein in mouse liver by real-time PCR and Western blot analysis. NAT2 enzyme activity, measured using the human NAT2-selective substrate sulfamethazine (SMZ), was 40- to 80-fold higher in liver cytosols from hNAT2(tg)Nat1/2(-/-) mice than in wild-type mice. An unexpected gender difference was observed, with males displaying 2-fold higher activity than females. Transgenic mice also had an increased in vivo plasma clearance of SMZ and higher levels of N-acetylated SMZ than wild-type mice. Liver expression of human NAT2 did not affect the disposition of the human NAT1-selective substrate p aminosalicylic acid (PAS), because hNAT2(tg)Nat1/2(-/-) mice displayed in vivo PAS pharmacokinetic profiles similar to those of Nat1/2(-/-) mice. The metabolism of 4-aminobiphenyl was similar between hNAT2(tg)Nat1/2(-/-) and wild-type mice with the exception of a more liver-restricted pattern in hNAT2(tg)Nat1/2(-/-) mice and lower activity in females. Overall, the hNAT2(tg)Nat1/2(-/-) mouse mimics human expression of NAT2 and may thus be of value in clarifying the role of human NAT2 in arylamine clearance, detoxification, and bioactivation. PMID- 21317370 TI - On the foundations of beliefs in free will: intentional binding and unconscious priming in self-agency. AB - The concept of an ability to make choices and to determine one's own outcomes fits well with experiences that most people have, and these experiences form the basis for beliefs in free will. However, the existence of conscious free will is challenged by modern research findings highlighting the unconscious origins of goal-directed behavior that gives rise to free-will beliefs. This report expands on these insights by revealing that both conscious and unconscious processes play an important role in free-will beliefs. Specifically, Experiment 1 demonstrates that free-will beliefs are strengthened when conscious intentions to produce action outcomes bind the perception of action and outcome together in time. Experiment 2 shows that these beliefs are strengthened when unconscious priming of action outcomes creates illusory experiences of self-agency when the primed outcomes occur. Together, these findings suggest that beliefs in free will are associated with self-agency and are enhanced by both conscious and unconscious information processing of goal-directed behavior. PMID- 21317371 TI - Contextual illusions reveal the limit of unconscious visual processing. AB - The perception of even the most elementary features of the visual environment depends strongly on their spatial context. In the study reported here, we asked at what level of abstraction such effects require conscious processing of the context. We compared two visual illusions that alter subjective judgments of brightness: the simultaneous brightness contrast illusion, in which two circles of identical physical brightness appear different because of different surround luminance, and the Kanizsa triangle illusion, which occurs when the visual system extrapolates a surface without actual physical stimulation. We used a novel interocular masking technique that allowed us to selectively render only the context invisible. Simultaneous brightness contrast persisted even when the surround was masked from awareness. In contrast, participants did not experience illusory contours when the inducing context was masked. Our findings show that invisible context is resolvable by low-level processes involved in surface brightness perception, but not by high-level processes that assign surface borders through perceptual completion. PMID- 21317372 TI - Ego threat and intergroup bias: a test of motivated-activation versus self regulatory accounts. PMID- 21317374 TI - Metabolic engineering in Nicotiana benthamiana reveals key enzyme functions in Arabidopsis indole glucosinolate modification. AB - Indole glucosinolates, derived from the amino acid Trp, are plant secondary metabolites that mediate numerous biological interactions between cruciferous plants and their natural enemies, such as herbivorous insects, pathogens, and other pests. While the genes and enzymes involved in the Arabidopsis thaliana core biosynthetic pathway, leading to indol-3-yl-methyl glucosinolate (I3M), have been identified and characterized, the genes and gene products responsible for modification reactions of the indole ring are largely unknown. Here, we combine the analysis of Arabidopsis mutant lines with a bioengineering approach to clarify which genes are involved in the remaining biosynthetic steps in indole glucosinolate modification. We engineered the indole glucosinolate biosynthesis pathway into Nicotiana benthamiana, showing that it is possible to produce indole glucosinolates in a noncruciferous plant. Building upon this setup, we demonstrate that all members of a small gene subfamily of cytochrome P450 monooxygenases, CYP81Fs, are capable of carrying out hydroxylation reactions of the glucosinolate indole ring, leading from I3M to 4-hydroxy-indol-3-yl-methyl and/or 1-hydroxy-indol-3-yl-methyl glucosinolate intermediates, and that these hydroxy intermediates are converted to 4-methoxy-indol-3-yl-methyl and 1-methoxy indol-3-yl-methyl glucosinolates by either of two family 2 O-methyltransferases, termed indole glucosinolate methyltransferase 1 (IGMT1) and IGMT2. PMID- 21317375 TI - Evolution and functional diversification of MIRNA genes. AB - MicroRNAs (miRNAs) are small regulatory RNAs found in diverse eukaryotic lineages. In plants, a minority of annotated MIRNA gene families are conserved between plant families, while the majority are family- or species-specific, suggesting that most known MIRNA genes arose relatively recently in evolutionary time. Given the high proportion of young MIRNA genes in plant species, new MIRNA families are likely spawned and then lost frequently. Unlike highly conserved, ancient miRNAs, young miRNAs are often weakly expressed, processed imprecisely, lack targets, and display patterns of neutral variation, suggesting that young MIRNA loci tend to evolve neutrally. Genome-wide analyses from several plant species have revealed that variation in miRNA foldback expression, structure, processing efficiency, and miRNA size have resulted in the unique functionality of MIRNA loci and resulting miRNAs. Additionally, some miRNAs have evolved specific properties and functions that regulate other transcriptional or posttranscriptional silencing pathways. The evolution of miRNA processing and functional diversity underscores the dynamic nature of miRNA-based regulation in complex regulatory networks. PMID- 21317377 TI - Rapid and reversible light-mediated chromatin modifications of Arabidopsis phytochrome A locus. AB - Recent genome-wide surveys showed that acetylation of H3K9 and H3K27 is correlated with gene activation during deetiolation of Arabidopsis thaliana seedlings, but less is known regarding changes in the histone status of repressed genes. Phytochrome A (phyA) is the major photoreceptor of deetiolation, and phyA expression is reversibly repressed by light. We found that in adult Arabidopsis plants, phyA activation in darkness was accompanied by a significant enrichment in the phyA transcription and translation start sites of not only H3K9/14ac and H3K27ac but also H3K4me3, and there was also moderate enrichment of H4K5ac, H4K8ac, H4K12ac, and H4K16ac. Conversely, when phyA expression was repressed by light, H3K27me3 was enriched with a corresponding decline in H3K27ac; moreover, demethylation of H3K4me3 and deacetylation of H3K9/14 were also seen. These histone modifications, which were focused around the phyA transcription/translation start sites, were detected within 1 h of deetiolation. Mutant analysis showed that HDA19/HD1 mediated deacetylation of H3K9/14 and uncovered possible histone crosstalk between H3K9/14ac and H3K4me3. Neither small RNA pathways nor the circadian clock affected H3 modification status of the phyA locus, and DNA methylation was unchanged by light. The presence of activating and repressive histone marks suggests a mechanism for the rapid and reversible regulation of phyA by dark and light. PMID- 21317378 TI - Cigarette smoke differentially affects eosinophilia and remodeling in a model of house dust mite asthma. AB - Although a similar prevalence of smoking is evident among patients with asthma and the general population, little is known about the impact of cigarette smoke on the immune inflammatory processes elicited by common environmental allergens. We investigated the impact of exposure to cigarette smoke on house dust mite (HDM)-induced allergic airway inflammation and its consequences for tissue remodeling and lung physiology in mice. BALB/c mice received intranasal HDMs daily, 5 days per week, for 3 weeks to establish chronic airway inflammation. Subsequently, mice were concurrently exposed to HDMs plus cigarette smoke, 5 days per week, for 2 weeks (HDMs + smoke). We observed significantly attenuated eosinophilia in the bronchoalveolar lavage of mice exposed to HDMs + smoke, compared with animals exposed only to HDMs. A similar activation of CD4 T cells and expression of IL-5, IL-13, and transforming growth factor-beta was observed between HDM-treated and HDM + smoke-treated animals. Consistent with an effect on eosinophil trafficking, HDMs + smoke exposure attenuated the HDM-induced expression of eotaxin-1 and vascular cell adhesion molecule-1, whereas the survival of eosinophils and the numbers of blood eosinophils were not affected. Exposure to cigarette smoke also reduced the activation of B cells and the concentrations of serum IgE. Although the production of mucus decreased, collagen deposition significantly increased in animals exposed to HDMs + smoke, compared with animals exposed only to HDMs. Although airway resistance was unaffected, tissue resistance was significantly decreased in mice exposed to HDMs + smoke. Our findings demonstrate that cigarette smoke affects eosinophil migration without affecting airway resistance or modifying Th2 cell adaptive immunity in a murine model of HDM-induced asthma. PMID- 21317376 TI - The Arabidopsis multistress regulator TSPO is a heme binding membrane protein and a potential scavenger of porphyrins via an autophagy-dependent degradation mechanism. AB - TSPO, a stress-induced, posttranslationally regulated, early secretory pathway localized plant cell membrane protein, belongs to the TspO/MBR family of regulatory proteins, which can bind porphyrins. This work finds that boosting tetrapyrrole biosynthesis enhanced TSPO degradation in Arabidopsis thaliana and that TSPO could bind heme in vitro and in vivo. This binding required the His residue at position 91 (H91), but not that at position 115 (H115). The H91A and double H91A/H115A substitutions stabilized TSPO and rendered the protein insensitive to heme-regulated degradation, suggesting that heme binding regulates At-TSPO degradation. TSPO degradation was inhibited in the autophagy-defective atg5 mutant and was sensitive to inhibitors of type III phosphoinositide 3 kinases, which regulate autophagy in eukaryotic cells. Mutation of the two Tyr residues in a putative ubiquitin-like ATG8 interacting motif of At-TSPO did not affect heme binding in vitro but stabilized the protein in vivo, suggesting that downregulation of At-TSPO requires an active autophagy pathway, in addition to heme. Abscisic acid-dependent TSPO induction was accompanied by an increase in unbound heme levels, and downregulation of TSPO coincided with the return to steady state levels of unbound heme, suggesting that a physiological consequence of active TSPO downregulation may be heme scavenging. In addition, overexpression of TSPO attenuated aminolevulinic acid-induced porphyria in plant cells. Taken together, these data support a role for TSPO in porphyrin binding and scavenging during stress in plants. PMID- 21317379 TI - Innate inflammatory responses of pediatric cystic fibrosis airway epithelial cells: effects of nonviral and viral stimulation. AB - There is controversy regarding whether cystic fibrosis (CF) airway epithelial cells (AECs) are intrinsically proinflammatory. The objective of the current study was to characterize the inflammatory profiles of AECs from children with CF compared with cells from healthy control subjects. We obtained AECs from healthy children (12) and children with CF (27). Biochemical and functional characteristics were assessed by stimulating cells with IFNgamma, LPS, a cocktail referred to as cytomix, which consists of IFNgamma, IL-1beta, TNF-alpha, and LPS, or with human rhinovirus (HRV). Cytokine production was assessed using ELISA. Apoptotic responses to HRV infection were measured via production of single stranded DNA. Our results indicated that CF and healthy cells exhibited similar morphology in monolayer culture. CF cells constitutively produced greater amounts of IL-6, IL-1beta, and prostaglandin E(2), but similar levels of IL-8 and soluble intracellular adhesion molecule-1 compared with healthy cells, and this profile was maintained through repeated passage. Stimulation with LPS or cytomix elicited similar levels of IL-8 in CF and non-CF cells. In contrast, exposure to HRV1b resulted in a marked increase in IL-8 production from CF compared with non-CF cells. CF cells also exhibited reduced apoptosis and increased viral replication compared with non-CF cells after exposure to HRV1b. We conclude that CF and healthy AECs have similar basal and stimulated expression of IL-8 in response to proinflammatory stimuli, but elevated IL-8 release in response to HRV infection. The elevated IL-8, together with dampened apoptotic responses by CF cells to HRV, could contribute to augmented airway inflammation in the setting of recurrent viral infections early in life. PMID- 21317380 TI - Neuregulin receptor ErbB4 functions as a transcriptional cofactor for the expression of surfactant protein B in the fetal lung. AB - Sufficient pulmonary surfactant production is required for the fetal-neonatal transition, especially in preterm infants. Neuregulin (NRG) and its transmembrane receptor ErbB4 positively regulate the onset of fetal surfactant synthesis. Details of this signaling process remain to be elucidated. ErbB4 is known to regulate gene expression in the mammary gland, where the receptor associates with the signal transducer and activator of transcription Stat5a to transactivate the beta-casein gene promoter. We hypothesized that in the fetal lung, ErbB4 functions as a transcriptional regulator for surfactant protein B (Sftpb), the most critical surfactant protein gene. Re-expressing full-length ErbB4 in primary fetal ErbB4-depleted Type II epithelial cells led to an increased expression of Sftpb mRNA. This stimulatory effect required the nuclear translocation of ErbB4 and association with Stat5a, with the resultant binding to and activation of the Sftpb promoter. We conclude that ErbB4 directly regulates important aspects of fetal lung maturation that help prepare for the fetal-neonatal transition. PMID- 21317381 TI - Accrual to clinical trials: let's look at the physicians. PMID- 21317382 TI - A population-based assessment of specialty physician involvement in cancer clinical trials. AB - BACKGROUND: Clinical trials are critical for evaluating new cancer therapies, but few adult patients participate in them. Physicians have an important role in facilitating patient participation in clinical trials. We examined the characteristics of specialty physicians who participate in clinical trials by enrolling or referring patients, the types of trials in which they participate, and factors associated with physicians who report greater involvement in clinical trials. METHODS: We analyzed data from the Cancer Care Outcomes Research and Surveillance Consortium. The study included 1533 specialty physicians who cared for colorectal and lung cancer patients (496 medical oncologists, 228 radiation oncologists, and 809 surgeons) and completed a survey conducted during 2005-2006 (response rate = 61.0%). Descriptive statistics were used to characterize physicians' personal and practice characteristics, and regression models were used to examine associations between these characteristics and physician participation in clinical trials. All statistical tests were two-sided. RESULTS: A total of 87.8% of medical oncologists, 66.1% of radiation oncologists, and 35.0% of surgeons reported referring or enrolling one or more patients in clinical trials during the previous 12 months. The mean number of patients referred or enrolled by these physicians was 17.2 (95% confidence interval [CI] = 15.5 to 18.9) for medical oncologists, 9.5 (95% CI = 7.7 to 11.3) for radiation oncologists, and 12.2 (95% CI = 9.8 to 14.6) for surgeons (P < .001). Specialty type, involvement in teaching, and affiliation with a Community Clinical Oncology Program (CCOP) and/or a National Cancer Institute-designated cancer center were associated with physician trial participation and enrolling more patients (all Ps < .05). Two-thirds of physicians with a CCOP or National Cancer Institute designated cancer center affiliation reported participating in trials. CONCLUSIONS: Features of specialty physicians' practice environments are associated with their trial participation, but many physicians at CCOPs and cancer centers do not participate. PMID- 21317383 TI - T cell development critically depends on prethymic stromal patched expression. AB - We recently described that T cell specification in mice deficient in the Hedgehog (Hh) receptor Patched (Ptch) is blocked at the level of the common lymphoid progenitor in the bone marrow (BM). Adoptive transfer of wild-type BM in Ptch deficient mice provides evidence that T cell development strictly depends on Ptch expression in the nonhematopoietic compartment. Transplantation experiments using BM deficient in the glucocorticoid receptor exclude any involvement of the stress hormone corticosterone in our model. Using cell-type-specific knockout mice, we show that T cell development is independent of T cell-intrinsic Ptch expression. Furthermore, Ptch expression by the thymus stroma is dispensable, as revealed by fetal thymus organ culture and thymus transplantation. In contrast, analysis of the earliest thymic progenitors in Ptch-deficient mice indicated that Ptch is required for the development or supply of thymic homing progenitors that give rise to earliest thymic progenitors. Collectively, our findings identified Ptch as an exclusive T cell-extrinsic factor necessary for proper development of T cells at their prethymic stage. This observation may be important for current considerations using Hh inhibitors upstream of Ptch in diseases accompanied by aberrant Hh signaling. PMID- 21317384 TI - Impaired wound healing with defective expression of chemokines and recruitment of myeloid cells in TLR3-deficient mice. AB - Skin injury evokes both innate and adaptive immune responses to restore tissue integrity. TLRs play a critical role in host responses to injurious insults. Previous studies demonstrated that RNAs released from damaged tissues served as endogenous ligands for TLR3. In this study, we investigated the involvement of TLR3 in skin restoration after injury. Full excisional wounds were created on the skin of mice with TLR3 deficiency. We found that skin wound closure in TLR3(-/-) mice was significantly delayed compared with control littermates. Wound healing parameters, including re-epithelialization, granulation formation, and neovascularization, were decreased in TLR3(-/-) mice. Further studies revealed that the absence of TLR3 led to defective recruitment of neutrophils and macrophages, in association with decreased expression of the chemokines, MIP 2/CXCL2, MIP-1alpha/CCL3, and MCP-1/CCL2, in the wound. Moreover, in wild type mice, the mRNA level and protein content of TLR3 was significantly upregulated in wounded skins and silencing of TLR3 signal adaptor Toll/IL-1R domain-containing adapter inducing IFN-beta with small interfering RNA retarded wound closure. These results indicate an essential role for TLR3 and Toll/IL-1R domain containing adapter inducing IFN-beta in wound healing by regulating chemokine production and recruitment of myeloid cells to wound for tissue repair. PMID- 21317385 TI - A barrier-type insulator forms a boundary between active and inactive chromatin at the murine TCRbeta locus. AB - In CD4(-)CD8(-) double-negative thymocytes, the murine Tcrb locus is composed of alternating blocks of active and inactive chromatin containing Tcrb gene segments and trypsinogen genes, respectively. Although chromatin structure is appreciated to be critical for regulated recombination and expression of Tcrb gene segments, the molecular mechanisms that maintain the integrity of these differentially regulated Tcrb locus chromatin domains are not understood. We localized a boundary between active and inactive chromatin by mapping chromatin modifications across the interval extending from Prss2 (the most 3' trypsinogen gene) to D(beta)1. This boundary, located 6 kb upstream of D(beta)1, is characterized by a transition from repressive (histone H3 lysine 9 dimethylation [H3K9me2]) to active (histone H3 acetylation [H3ac]) chromatin and is marked by a peak of histone H3 lysine 4 dimethylation (H3K4me2) that colocalizes with a retroviral long terminal repeat (LTR). Histone H3 lysine 4 dimethylation is retained and histone H3 lysine 9 dimethylation fails to spread past the LTR even on alleles lacking the Tcrb enhancer (E(beta)) suggesting that these features may be determined by the local DNA sequence. Notably, we found that LTR-containing DNA functions as a barrier-type insulator that can protect a transgene from negative chromosomal position effects. We propose that, in vivo, the LTR blocks the spread of heterochromatin, and thereby helps to maintain the integrity of the E(beta) regulated chromatin domain. We also identified low-abundance, E(beta)-dependent transcripts that initiate at the border of the LTR and an adjacent long interspersed element. We speculate that this transcription, which extends across D(beta), J(beta) and C(beta) gene segments, may play an additional role promoting initial opening of the E(beta)-regulated chromatin domain. PMID- 21317387 TI - Supplemental and highly elevated tocopherol doses differentially regulate allergic inflammation: reversibility of alpha-tocopherol and gamma-tocopherol's effects. AB - We have reported that supplemental doses of the alpha- and gamma-tocopherol isoforms of vitamin E decrease and increase, respectively, allergic lung inflammation. We have now assessed whether these effects of tocopherols are reversible. For these studies, mice were treated with Ag and supplemental tocopherols in a first phase of treatment followed by a 4-wk clearance phase, and then the mice received a second phase of Ag and tocopherol treatments. The proinflammatory effects of supplemental levels of gamma-tocopherol in phase 1 were only partially reversed by supplemental alpha-tocopherol in phase 2, but were completely reversed by raising alpha-tocopherol levels 10-fold in phase 2. When gamma-tocopherol levels were increased 10-fold (highly elevated tocopherol) so that the lung tissue gamma-tocopherol levels were equal to the lung tissue levels of supplemental alpha-tocopherol, gamma-tocopherol reduced leukocyte numbers in the lung lavage fluid. In contrast to the lung lavage fluid, highly elevated levels of gamma-tocopherol increased inflammation in the lung tissue. These regulatory effects of highly elevated tocopherols on tissue inflammation and lung lavage fluid were reversible in a second phase of Ag challenge without tocopherols. In summary, the proinflammatory effects of supplemental gamma tocopherol on lung inflammation were partially reversed by supplemental levels of alpha-tocopherol but were completely reversed by highly elevated levels of alpha tocopherol. Also, highly elevated levels of gamma-tocopherol were inhibitory and reversible in lung lavage but, importantly, were proinflammatory in lung tissue sections. These results have implications for future studies with tocopherols and provide a new context in which to review vitamin E studies in the literature. PMID- 21317386 TI - Estriol generates tolerogenic dendritic cells in vivo that protect against autoimmunity. AB - Chronic inflammation contributes to numerous diseases, and regulation of inflammation is crucial for disease control and resolution. Sex hormones have potent immunoregulatory abilities. Specifically, estrogen influences immune cells and inflammation, which contributes to the sexual dimorphism of autoimmunity and protection against disease seen during pregnancy in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Although long thought to act primarily on T cells, recent evidence demonstrated that myeloid cells, such as dendritic cells (DCs), are essential in mediating estrogen's protective effects. Estriol (E3), a pregnancy-specific estrogen, has therapeutic efficacy in MS and EAE, and we evaluated whether E3 could act exclusively through DCs to protect against the inflammatory autoimmune disease EAE. Levels of activation markers (CD80 and CD86) and inhibitory costimulatory markers (PD-L1, PD-L2, B7-H3, and B7-H4) were increased in E3 DCs. E3 DCs had decreased proinflammatory IL-12, IL-23, and IL-6 mRNA expression, increased immunoregulatory IL-10 and TGF-beta mRNA expression, and a decreased ratio of IL 12/IL-10 protein production. Importantly, transfer of E3 DCs to mice prior to active induction of EAE protected them from developing EAE through immune deviation to a Th2 response. This protection was apparent, even in the face of in vitro and in vivo inflammatory challenge. In summary, our results showed that E3 generates tolerogenic DCs, which protect against the inflammatory autoimmune disease EAE. Targeted generation of tolerogenic DCs with immunomodulatory therapeutics, such as E3, has potential applications in the treatment of numerous autoimmune and chronic inflammatory diseases. PMID- 21317388 TI - Cutting edge: intravenous Ig inhibits invariant NKT cell-mediated allergic airway inflammation through FcgammaRIIIA-dependent mechanisms. AB - Despite their increasing use in autoimmune, inflammatory, and allergic conditions, the mechanism of action of i.v. Igs (IVIg) is poorly understood. On the basis of the critical role of invariant NKT (iNKT) cells in allergic airway inflammation (AAI) and their constitutive expression of the low-affinity IgG receptor FcgammaRIIIA, we surmised that IVIg targets iNKT cells to exert their anti-inflammatory effect. We found that IVIg treatment significantly inhibited AAI in OVA-sensitized C57BL/6 mice and downregulated alpha-galactosylceramide induced iNKT cell activation and cytokine production. Allergic responses were restored in iNKT cell-deficient mice by transferring iNKT cells from PBS- but not from IVIg-treated mice, suggesting that IVIg acts directly on activated iNKT cells that have a critical role in AAI. The inhibitory effects of IVIg on both iNKT cell activation/function and OVA-driven AAI were lost in FcgammaRIIIA(-/-) mice. Our data unravel an FcgammaRIIIA-dependent inhibitory effect of IVIg on activated iNKT cells that confers protection in AAI. PMID- 21317389 TI - Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. AB - Stimulated CD4(+) T lymphocytes can differentiate into effector T cell (Teff) or inducible regulatory T cell (Treg) subsets with specific immunological roles. We show that Teff and Treg require distinct metabolic programs to support these functions. Th1, Th2, and Th17 cells expressed high surface levels of the glucose transporter Glut1 and were highly glycolytic. Treg, in contrast, expressed low levels of Glut1 and had high lipid oxidation rates. Consistent with glycolysis and lipid oxidation promoting Teff and Treg, respectively, Teff were selectively increased in Glut1 transgenic mice and reliant on glucose metabolism, whereas Treg had activated AMP-activated protein kinase and were dependent on lipid oxidation. Importantly, AMP-activated protein kinase stimulation was sufficient to decrease Glut1 and increase Treg generation in an asthma model. These data demonstrate that CD4(+) T cell subsets require distinct metabolic programs that can be manipulated in vivo to control Treg and Teff development in inflammatory diseases. PMID- 21317391 TI - Uridine 5'-diphosphate induces chemokine expression in microglia and astrocytes through activation of the P2Y6 receptor. AB - Chemokines play critical roles in inflammation by recruiting inflammatory cells to injury sites. In this study, we found that UDP induced expression of chemokines CCL2 (MCP-1) and CCL3 (MIP-1alpha) in microglia, astrocytes, and slice cultures by activation of P2Y(6). Interestingly, CCL2 was more highly expressed than CCL3. However, CCL2 synthesis kinetics in response to UDP differed in microglia and astrocytes; microglia rapidly produced small amounts of CCL2, whereas astrocytes continuously synthesized large amounts of CCL2, resulting in a high ultimate level of the chemokine. UDP-induced chemokine expression was reduced in the presence of a specific antagonist of P2Y(6) (MRS2578) or small interfering RNA directed against the P2Y(6) gene. Inhibition of phospholipase C and calcium increase, downstream signaling pathways of Gq-coupled P2Y(6), reduced UDP-induced chemokine expression. UDP activated two calcium-activated transcription factors, NFATc1 and c2. Furthermore, inhibitors of calcineurin (a phosphatase activating NFAT) and NFAT reduced UDP-induced chemokine synthesis. We also found, using a transmigration assay, that UDP-treated astrocytes recruited monocytes. These results suggest that UDP induces chemokine expression in microglia and astrocytes of the injured brain by activation of P2Y(6) receptors. PMID- 21317390 TI - Long-term control of simian immunodeficiency virus mac251 viremia to undetectable levels in half of infected female rhesus macaques nasally vaccinated with simian immunodeficiency virus DNA/recombinant modified vaccinia virus Ankara. AB - The efficacy of two SIV DNA plus recombinant modified vaccinia virus Ankara nasal vaccine regimens, one combined with plasmids expressing IL-2 and IL-15, the other with plasmids expressing GM-CSF, IL-12, and TNF-alpha, which may better stimulate humoral responses, was evaluated in two female rhesus macaque groups. Vaccination stimulated significant SIV-specific mucosal and systemic cell-mediated immunity in both groups, whereas SIV-specific IgA titers were sporadic and IgG titers negative. All vaccinated animals, except one, became infected after intravaginal SIV(mac251) low-dose challenge. Half of the vaccinated, infected animals (7/13) promptly controlled virus replication to undetectable viremia for the duration of the trial (130 wk) and displayed virological and immunological phenotypes similar to those of exposed, uninfected individuals. When all vaccinated animals were considered, a 3-log viremia reduction was observed, compared with controls. The excellent viral replication containment achieved in vaccinated animals translated into significant preservation of circulating alpha4beta7(high+)/CD4(+) T cells and of circulating and mucosal CD4(+)/C(M) T cells and in reduced immune activation. A more significant long-term survival was also observed in these animals. Median survival was 72 wk for the control group, whereas >50% of the vaccinated animals were still disease free 130 wk postchallenge, when the trial was closed. There was a statistically significant correlation between levels of CD4(+)/IFN-gamma(+) and CD8(+)/IFN-gamma(+) T cell percentages on the day of challenge and the control of viremia at week 60 postchallenge or survival. Postchallenge immunological correlates of protection were systemic anti-SIV Gag + Env CD4(+)/IL-2(+), CD4(+)/IFN-gamma(+), and CD8(+)/TNF-alpha(+) T cells and vaginal anti-SIV Gag + Env CD8(+) T cell total monofunctional responses. PMID- 21317392 TI - Highly activated cytotoxic CD8 T cells express protective IL-10 at the peak of coronavirus-induced encephalitis. AB - Acute viral encephalitis requires rapid pathogen elimination without significant bystander tissue damage. In this article, we show that IL-10, a potent anti inflammatory cytokine, is produced transiently at the peak of infection by CD8 T cells in the brains of coronavirus-infected mice. IL-10(+)CD8 and IL-10(-)CD8 T cells interconvert during acute disease, possibly based on recent Ag exposure. Strikingly, IL-10(+)CD8 T cells were more highly activated and cytolytic than IL 10(-)CD8 T cells, expressing greater levels of proinflammatory cytokines and chemokines, as well as cytotoxic proteins. Even though these cells are highly proinflammatory, IL-10 expressed by these cells was functional. Furthermore, IL 10 produced by CD8 T cells diminished disease severity in mice with coronavirus induced acute encephalitis, suggesting a self-regulatory mechanism that minimizes immunopathological changes. PMID- 21317393 TI - Simian immunodeficiency virus-induced changes in T cell cytokine responses in cynomolgus macaques with latent Mycobacterium tuberculosis infection are associated with timing of reactivation. AB - Understanding the early immunologic events accompanying reactivated tuberculosis (TB) in HIV-infected individuals may yield insight into causes of reactivation and improve treatment modalities. We used the cynomolgus macaque (Macaca fascicularis) model of HIV-Mycobacterium tuberculosis coinfection to investigate the dynamics of multifunctional T cell responses and granuloma T cell phenotypes in reactivated TB. CD4(+) and CD8(+) T cells expressing Th1 cytokines (IFN-gamma, IL-2, TNF) and Th2 cytokines (IL-4 and IL-10) were followed from latent M. tuberculosis infection to reactivation after coinfection with a pathogenic SIV. Coinfected animals experienced increased Th1 cytokine responses to M. tuberculosis Ags above the latent-response baseline 3-5 wk post-SIV infection that corresponded with peak plasma viremia. Th2 cytokine expression was not Ag specific, but strong, transient IL-4 expression was noted 4-7 wk post-SIV infection. Animals reactivating <17 wk post-SIV infection had significantly more multifunctional CD4(+) T cells 3-5 wk post-SIV infection and more Th2-polarized and fewer Th0-, Th1-polarized CD8(+) T cells during weeks 1-10 post-SIV infection than animals reactivating >26 wk post-SIV infection. Granuloma T cells included Th0-, Th1-, and Th2-polarized phenotypes but were particularly rich in cytolytic (CD107(+)) T cells. When combined with the changes in peripheral blood T cells, these factors indicate that events during acute HIV infection are likely to include distortions in proinflammatory and anti-inflammatory T cell responses within the granuloma that have significant effects on reactivation of latent TB. Moreover, it appears that mycobacteria-specific multifunctional T cells are better correlates of Ag load (i.e., disease status) than of protection. PMID- 21317394 TI - NK cell adoptive transfer combined with Ontak-mediated regulatory T cell elimination induces effective adaptive antitumor immune responses. AB - Previous work from our laboratory showed that hydrocortisone (HC) combined with IL-15 induces expansion of activated human NK cells. We set up an experimental tumor model to evaluate the use of adoptively transferred, HC plus IL-15 (HC/IL 15)-activated and -expanded murine NK cells in the treatment of syngeneic mice carrying established lung metastases of the CT26 transplantable tumor. We also examined the effect of denileukin diftitox (Ontak) on the depletion of regulatory T cells to enhance the in vivo antitumor immunity induced by the adoptively transferred NK cells. Our results clearly demonstrate that murine DX5(+) NK cells are largely expanded in the presence of IL-15 plus HC while retaining intact their functional status. Moreover, when intravenously infused, they mediated significant antitumor responses against CT26 lung tumors in syngeneic BALB/c animals that were further enhanced upon pretreatment of the tumor-bearing animals with Ontak. Total splenocytes and isolated splenic T cells from NK-treated mice responded in vitro against CT26 tumor cells as evidenced by IFN-gamma-based ELISPOT, proliferation, and cytotoxicity assays. Importantly, animals treated with Ontak plus adoptive transfer of HC/IL-15-expanded NK cells significantly retarded CT26 tumor growth after a rechallenge with the same tumor s.c. in their flanks. Taken altogether, our data suggest that NK cell adoptive transfer can trigger adaptive antitumor T cell responses, and regulatory T cell depletion by Ontak is mandatory for enabling HC/IL-15-activated NK cells to promote long lasting adaptive antitumor immunity. PMID- 21317395 TI - Inhibition of type 1 diabetes correlated to a Lactobacillus johnsonii N6.2 mediated Th17 bias. AB - Although it is known that resident gut flora contribute to immune system function and homeostasis, their role in the progression of the autoimmune disease type 1 diabetes (T1D) is poorly understood. Comparison of stool samples isolated from Bio-Breeding rats, a classic model of T1D, shows that distinct bacterial populations reside in spontaneous Bio-Breeding diabetes-prone (BBDP) and Bio Breeding diabetes-resistant animals. We have previously shown that the oral transfer of Lactobacillus johnsonii strain N6.2 (LjN6.2) from Bio-Breeding diabetes-resistant to BBDP rodents conferred T1D resistance to BBDP rodents, whereas Lactobacillus reuteri strain TD1 did not. In this study, we show that diabetes resistance in LjN6.2-fed BBDP rodents was correlated to a Th17 cell bias within the mesenteric lymph nodes. The Th17 bias was not observed in the non-gut draining axillary lymph nodes, suggesting that the Th17 bias was because of immune system interactions with LjN6.2 within the mesenteric lymph node. LjN6.2 interactions with the immune system were observed in the spleens of diabetes resistant, LjN6.2-fed BBDP rats, as they also possessed a Th17 bias in comparison with control or Lactobacillus reuteri strain TD1-fed rats. Using C57BL/6 mouse in vitro assays, we show that LjN6.2 directly mediated enhanced Th17 differentiation of lymphocytes in the presence of TCR stimulation, which required APCs. Finally, we show that footpad vaccination of NOD mice with LjN6.2-pulsed dendritic cells was sufficient to mediate a Th17 bias in vivo. Together, these data suggest an interesting paradigm whereby T1D induction can be circumvented by gut flora mediated Th17 differentiation. PMID- 21317396 TI - Inducible adeno-associated virus-mediated IL-2 gene therapy prevents autoimmune diabetes. AB - IL-2 and TGF-beta1 play key roles in the immunobiology of Foxp3-expressing CD25(+)CD4(+) T cells (Foxp3(+)Treg). Administration of these cytokines offers an appealing approach to manipulate the Foxp3(+)Treg pool and treat T cell-mediated autoimmunity such as type 1 diabetes. However, efficacy of cytokine treatment is dependent on the mode of application, and the potent pleiotropic effects of cytokines like IL-2 may lead to severe side effects. In the current study, we used a gene therapy-based approach to assess the efficacy of recombinant adeno associated virus vectors expressing inducible IL-2 or TGF-beta1 transgenes to suppress ongoing beta cell autoimmunity in NOD mice. Intramuscular vaccination of recombinant adeno-associated virus to 10-wk-old NOD female mice and a subsequent 3 wk induction of IL-2 was sufficient to prevent diabetes and block the progression of insulitis. Protection correlated with an increased frequency of Foxp3(+)Treg in the periphery as well as in the draining pancreatic lymph nodes and islets. IL-2 induced a shift in the ratio favoring Foxp3(+)Treg versus IFN gamma-expressing T cells infiltrating the islets. Induction of IL-2 had no systemic effect on the frequency or activational status of T cells and NK cells. Induction of TGF-beta1 had no effect on the Foxp3(+)Treg pool or the progression of beta cell autoimmunity despite induced systemic levels of activated TGF-beta1 that were comparable to IL-2. These results demonstrate that inducible IL-2 gene therapy is an effective and safe approach to manipulate Foxp3(+)Treg and suppress T cell-mediated autoimmunity and that under the conditions employed, IL-2 is more potent than TGF-beta1. PMID- 21317397 TI - Recombinant dimeric IgA antibodies against the epidermal growth factor receptor mediate effective tumor cell killing. AB - Dimeric IgA Abs contribute significantly to the humoral part of the mucosal immune system. However, their potential as immunotherapeutic agent has hardly been explored. In this article, we describe the production, purification, and functional evaluation of recombinant dimeric IgA against the epidermal growth factor receptor. Human joining chain-containing IgA was produced by nonadherent Chinese hamster ovarian (CHO)-K1 cells under serum-free conditions. Purification by anti-human kappa and anti-His-tag affinity, as well as size exclusion chromatography, resulted in a homogenous preparation of highly pure IgA dimers. Functional studies demonstrated dimeric IgA to be at least as effective as monomeric IgA in triggering Ab-dependent cellular cytotoxicity by isolated monocytes or polymorphonuclear cell and in human whole-blood assays. Importantly, dimeric IgA was more effective in F(ab)-mediated killing mechanisms, such as inhibition of ligand binding, receptor downmodulation, and growth inhibition. Furthermore, only dimeric but not monomeric IgA or IgG was directionally transported by the polymeric Ig receptor through an epithelial cell monolayer. Together, these studies demonstrate that recombinant dimeric IgA Abs recruit a distinct repertoire of effector functions compared with monomeric IgA or IgG1 Abs. PMID- 21317399 TI - Recurrent wound botulism among injection drug users in California. AB - BACKGROUND: Botulism is an acute neurologic illness characterized by cranial nerve palsies and descending flaccid paralysis. Botulism is a rare disease and recurrent botulism even more rare. We review cases of recurrent wound botulism (WB) among injection drug users (IDUs) in California from 1993 through 2006 and describe 2 case patients. METHODS: From botulism surveillance data for 1993-2006, we identified patients with >1 episode of clinical WB, defined as acute descending paralysis with a visible wound or recent history of injection drug use. For each patient, >=1 of their WB episodes was laboratory confirmed. We extracted demographic, clinical, and laboratory information from case and laboratory reports and compared clinical characteristic frequency of initial and second WB episodes. RESULTS: During 1993-2006, 17 IDUs had recurrent WB, 14 with 1 recurrence and 3 with 2 recurrences. Of 25 laboratory-confirmed episodes, 22 were confirmed through serum testing and 3 through wound testing. Patients were 32-61 years old, and 94% were male. All patients reported heroin injections; 88% specified black tar heroin use and 76% reported subcutaneous injection. The most common presentations were having a visible wound, speech difficulty, double vision, respiratory difficulty, and trouble swallowing. There were no significant differences in clinical presentation between initial and second episodes. CONCLUSIONS: As the California epidemic of WB among IDUs continues, WB episodes are recurring. Both clinicians and IDUs should be aware of the potential for WB to recur among IDUs to enable timely diagnosis and early botulinum antitoxin administration and supportive care. PMID- 21317398 TI - Containment of a country-wide outbreak of carbapenem-resistant Klebsiella pneumoniae in Israeli hospitals via a nationally implemented intervention. AB - BACKGROUND: During 2006, Israeli hospitals faced a clonal outbreak of carbapenem resistant Klebsiella pneumoniae that was not controlled by local measures. A nationwide intervention was launched to contain the outbreak and to introduce a strategy to control future dissemination of antibiotic-resistant bacteria in hospitals. METHODS: In March 2007, the Ministry of Health issued guidelines mandating physical separation of hospitalized carriers of carbapenem-resistant Enterobacteriaceae (CRE) and dedicated staffing and appointed a professional task force charged with containment. The task force paid site visits at acute-care hospitals, evaluated infection-control policies and laboratory methods, supervised adherence to the guidelines via daily census reports on carriers and their conditions of isolation, provided daily feedback on performance to hospital directors, and intervened additionally when necessary. The initial intervention period was 1 April 2007-31 May 2008. The primary outcome measure was incidence of clinically diagnosed nosocomial CRE cases. RESULTS: By 31 March 2007, 1275 patients were affected in 27 hospitals (175 cases per 1 million population). Prior to the intervention, the monthly incidence of nosocomial CRE was 55.5 cases per 100,000 patient-days. With the intervention, the continuous increase in the incidence of CRE acquisition was halted, and by May 2008, the number of new monthly cases was reduced to 11.7 cases per 100,000 patient-days (P<.001). There was a direct correlation between compliance with isolation guidelines and success in containment of transmission (P=.02). Compliance neutralized the effect of carrier prevalence on new incidence (P=.03). CONCLUSIONS: A centrally coordinated intervention succeeded in containing a nationwide CRE outbreak after local measures failed. The intervention demonstrates the importance of strategic planning and national oversight in combating antimicrobial resistance. PMID- 21317400 TI - The development of a Spanish language instrument to measure genetic knowledge of diabetes mellitus type 2. AB - PURPOSE: The purpose of this study was to develop a Spanish-language measure of genetic knowledge relevant to type 2 diabetes for use with members of the ethnically heterogeneous U.S. Latino community. DESIGN: Review of the literature and expert content analysis guided initial instrument development. The instrument was pretested in three cognitive interview waves with 36 Latinos representative of Mexican, Central and South American, and Cuban heritage. Interview analysis indicated potential sources of response error and guided an iterative process of instrument refinement. RESULTS: Difficulties associated with item interpretation, grammatical structure, and comprehension were identified. Analysis indicated that revisions improved item quality and enhanced cultural and linguistic appropriateness of the instrument. CONCLUSIONS: Field testing suggested initial validity of a Spanish-language instrument to measure genetic knowledge relative to type 2 diabetes. IMPLICATIONS: A Spanish-language measure of genetic knowledge can guide nursing interventions that support culturally appropriate integration of genetics into health care. PMID- 21317401 TI - An integrative review of the current knowledge of cardiovascular disease and associated risk factors in the Old Order Amish. AB - PURPOSE: To review the uniqueness of the Amish culture and evaluate the published research on cardiovascular disease and associated risk factors in the Amish. METHOD: A computerized database search from January 1999 to January 2009 was conducted using the search terms Amish and cardiovascular. RESULTS: The majority of published research is based on the Amish in Lancaster County, Pennsylvania; is genetically based; and did not make recommendations for health care practices in the Amish. CONCLUSIONS: Studies that focus on cardiovascular disease in the Amish outside Lancaster County, Pennsylvania, and that study cardiovascular health care practices of the Amish are needed to develop culturally specific educational interventions. PMID- 21317402 TI - The work of language interpretation in health care: complex, challenging, exhausting, and often invisible. AB - The value of qualified language interpretation services for limited-English proficient patients is gaining increasing recognition by policy makers and researchers in the United States. Yet the actual work experiences of health care interpreters have not been adequately studied. The purpose of this qualitative research was to explore the work experiences of formal and informal interpreters (n = 27). The core narrative finding from the interview data was the complex, challenging, exhausting, and often invisible work of language interpretation. Critical examination of health care interpreters' complex work and interactions with patients, providers, and administrators is needed to provide more effective and integrated services for limited-English proficient patients. PMID- 21317403 TI - How to prescribe Tai chi therapy. AB - Exercise has been shown to positively influence quality of life for people with a wide variety of medical illnesses. Tai chi,a slow and graceful form of exercise and meditation, has been offered as the ideal exercise for diverse conditions such as chronic heart failure and for breast cancer survivors. In one recent study, tai chi was found to improve exercise capacity,sleep stability, and quality of life in heart failure patients. Another study focusing on breast cancer survivors revealed tai chi to be superior to psychosocial support in increasing aerobic capacity, muscular strength, flexibility, and quality of life. Primary care providers can play a vital role in encouraging their patients with chronic illnesses to participate in safe forms of exercise such as tai chi in order to improve their healing experience, physical function, and overall quality of life. PMID- 21317404 TI - Lessons learned from translators and interpreters from the Dinka tribe of southern Sudan. AB - This article discusses the methodological challenges associated with working with translators and interpreters from the Dinka tribe of southern Sudan during an ethnographic study with refugee Dinka women who were resettled with their children in the United States. Navigating the cultural differences between the researcher, the translator, and the interpreters provided a deeper understanding about the culture of the study population. The lessons learned included the importance of cultural congruence between the interpreters and participants; the education, training, and experience of the interpreters; and the difficulties encountered in preparing interpreters according to university institutional review board requirements. Cultural differences such as time perception and communication and literacy styles were negotiated throughout each phase of the study. The most valuable lesson learned from this experience was the importance of the relationship between the researcher, the translator, and the interpreters as well as between the interpreters and participants to achieve credibility and trustworthiness of the study results. PMID- 21317405 TI - Using American sign language interpreters to facilitate research among deaf adults: lessons learned. AB - BACKGROUND: Health care providers commonly discuss depressive symptoms with clients, enabling earlier intervention. Such discussions rarely occur between providers and Deaf clients. Most culturally Deaf adults experience early-onset hearing loss, self-identify as part of a unique culture, and communicate in the visual language of American Sign Language (ASL). Communication barriers abound, and depression screening instruments may be unreliable. PURPOSE: To train and use ASL interpreters for a qualitative study describing depressive symptoms among Deaf adults. METHOD: Training included research versus community interpreting. During data collection, interpreters translated to and from voiced English and ASL. RESULTS: Training eliminated potential problems during data collection. Unexpected issues included participants asking for "my interpreter" and worrying about confidentiality or friendship in a small community. CONCLUSIONS: Lessons learned included the value of careful training of interpreters prior to initiating data collection, including resolution of possible role conflicts and ensuring conceptual equivalence in real-time interpreting. PMID- 21317406 TI - Obstructive sleep apnea: a stand-alone risk factor for chronic kidney disease. AB - BACKGROUND: Previous studies have found an association between obstructive sleep apnea (OSA) and chronic kidney disease (CKD). However, subjects with confounding factors such as diabetes and hypertension were not excluded. The purpose of the present study was to determine whether patients with OSA without meeting criteria for diabetes or hypertension would also show increased likelihood of CKD. METHODS: We prospectively enrolled adult patients with a chief complaint of habitual snoring. Overnight polysomnography, fasting blood triglyceride, cholesterol, glucose, insulin, creatinine, albumin and hemoglobin A1c, and first voiding urine albumin and creatinine were examined. Estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (UACR), homeostatic model assessment-insulin resistance and percentage of CKD were calculated. RESULTS: The final analyses involved 40 patients who were middle-aged [44.8 (8.6) years] predominantly male (83%), obese [body mass index, 28.2 (5.1) kg/m(2)] and more severe OSA, with an apnea-hypopnea index (AHI) of 51.6 (39.2)/h. The mean eGFR and UACR were 85.4 (18.3) mL/min/1.73m(2) and 13.4 (23.4) mg/g, respectively. The prevalence of CKD in severe OSA subjects is 18%. With stepwise multivariate linear regression analysis, AHI and desaturation index were the only independent predictor of UACR (beta = 0.26, P = 0.01, R(2) = 0.17) and eGFR (beta = 0.32, P < 0.01, R(2) = 0.32), respectively. CONCLUSIONS: High prevalence of CKD is present in severe OSA patients without hypertension or diabetes. Significantly positive correlations were found between severity of OSA and renal function impairment. PMID- 21317407 TI - Targets of blood pressure. PMID- 21317408 TI - Effects of arteriovenous fistula formation on arterial stiffness and cardiovascular performance and function. AB - BACKGROUND: Native arteriovenous fistula (AVF) is the vascular access of choice and its use cf. catheters is associated with sustained reduction in mortality. This may be due to factors beyond dialysis catheter-associated sepsis. This study aimed to investigate the impact of AVF formation on the spectrum of cardiovascular factors that might be important in the pathophysiology of cardiovascular diseases in chronic kidney disease (CKD) patients. METHODS: We recruited 43 pre-dialysis patients who underwent AVF formation. Patients were studied 2 weeks prior to AVF operation and 2 weeks and 3 months post-operatively. Haemodynamic variables were measured using pulse wave analysis, carotid femoral pulse wave velocity (CF-PWV) by applanation tonometry and AVF blood flow by Doppler ultrasound. Bioimpedence analysis was performed and patients underwent serial transthoracic echocardiography. RESULTS: AVF formation was successful in 30/43 patients. Two weeks post-operatively, total peripheral resistance decreased (-17 +/- 18%, P = 0.001), stroke volume tended to rise (12 +/- 30 mL, P = 0.053) and both heart rate (4 +/- 8 bpm, P = 0.01) and cardiac output (1.1 +/- 1.5 L/min, P = 0.001) increased. Systolic and diastolic blood pressures (BPs) reduced (-9 +/- 18 mmHg; -9 +/- 10 mmHg; <= P = 0.006) and CF-PWV reduced (-1.1 +/- 1.5 m/s, P = 0.004). Left ventricular ejection fraction (LVEF) increased (6 +/- 8%, P < 0.001). All the observed changes were largely maintained after 3 months. No change in hydration status/body composition was observed. CONCLUSIONS: AVF formation resulted in a sustained reduction in arterial stiffness and BP as well as an increase in LVEF. Overall, post-AVF adaptations might be characterized as potentially beneficial in these patients and supports the widespread use of native vascular access, including older or cardiovascular compromised individuals. PMID- 21317409 TI - Evalutation of mycophenolic acid systemic exposure by limited sampling strategy in kidney transplant recipients receiving enteric-coated mycophenolate sodium (EC MPS) and cyclosporine. AB - BACKGROUND: Enteric-coated mycophenolate sodium (EC-MPS) and mycophenolate mofetil (MMF) are prodrugs of mycophenolic acid (MPA). Although many patients still receive MMF as an inosine monophosphate dehydrogenase inhibitor, EC-MPS could be considered a reliable alternative to MMF in the immunosuppressive protocols of kidney transplant recipients. MPA shows high pharmacokinetic variability and consequently a 12-h area under the curve (AUC(0-12)) should be used to guide the therapeutic dosage. However, patient compliance and economic costs make MPA AUC(0-12) an unpractical approach. Limited sampling strategies or predictive systemic drug exposure equation models based on limited sampling times are available only for MMF but lack for EC-MPS. METHODS: The present study enrolled 26 kidney transplant recipients receiving EC-MPS as part of their immunosuppressive therapy. Twenty-six full MPA AUC(0-12) were performed. By using multiple stepwise regression analysis, we obtained several predictive equations of MPA systemic exposure in this group of patients. The value of the selected equations was tested in a subsequently enrolled group of 26 kidney transplant recipients. RESULTS: The best equations obtained in the first group of patients were the following: 22.906 + 3.880.C(0) + 1.117.C(1) + 7.527.C(8) (r = 0.901) and 35.064 +3.784.C(0) + 1.002.C(1) + 1.192.C(2) (r = 0.846). These equation models showed an optimal agreement between the full AUCs and estimated AUCs by using the validation group of patients. CONCLUSIONS: Limited sampling strategies are useful for MPA AUC(0-12) estimation in patients receiving EC-MPS and cyclosporine. The choice of one or the other equation model depends on the pharmacokinetic characteristics of the patients, in particular the potential presence of enterohepatic recirculation. PMID- 21317410 TI - The association of pneumococcal vaccination with hospitalization and mortality in hemodialysis patients. AB - BACKGROUND: Few studies have examined the effectiveness of pneumococcal vaccination (alone or with influenza vaccination) in improving hemodialysis patient outcomes. We aimed to describe vaccination rates between 2003-2005 and to study the effects on outcomes. METHODS: For 118,533 prevalent patients who initiated hemodialysis >=90 days before 1 November 2003, had Medicare Part A and Part B and were aged >=18 years, and alive through 31 October 2005, Cox proportional hazards models were used to assess pneumococcal vaccination effects on subsequent hospitalization and mortality, adjusting for demographics and comorbidity. RESULTS: The 21% of patients who received vaccinations were older; a higher proportion were white, with diabetes as cause of end-stage renal disease and more comorbidity. Pneumococcal vaccination was associated with a statistically significant decreased mortality hazard [hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.90-0.98], cardiac death (HR 0.91, 95% CI 0.85-0.97) and hospitalization for bacteremia/viremia/septicemia (HR 0.95, 95% CI 0.91 1.00). The mortality hazard was 0.73 (95% CI 0.68-0.78) for patients who received pneumococcal and influenza vaccinations. CONCLUSIONS: The small but significant association between pneumococcal vaccination and lower mortality risk was seen despite factors associated with poor outcomes in patients most likely to be vaccinated. Pneumococcal and influenza vaccines may have beneficial synergistic effects. Hemodialysis patients may benefit from revaccination more frequently than the recommended 5-year intervals. PMID- 21317412 TI - Mindful staffing: a qualitative description of charge nurses' decision-making behaviors. AB - Patient outcomes are linked to nurse staffing. Although charge nurses are responsible for intrashift staffing decisions, little is known about their decision-making behaviors. This study describes the behaviors of charge nurses from the perspective of charge nurses, nurse managers, and staff nurses. This qualitative descriptive study was conducted with a sample of 24 nurses. The findings revealed that staffing the unit was the most important role for charge nurses. Charge nurses reported spending up to 90% of a shift resolving intrashift staffing issues. Five effective decision-making behaviors emerged: (a) resourcefulness, (b) tactful communication, (c) flexibility, (d) decisiveness, and (e) awareness of the big picture. These behaviors of charge nurses are similar to mindful behaviors of workers in hazardous work environments, and are therefore described as mindful staffing. Practice implications and considerations for the education of charge nurses in relation to safe intrashift staffing are suggested by the findings of this study. PMID- 21317411 TI - Full loss of residual renal function causes higher mortality in dialysis patients; findings from a marginal structural model. AB - BACKGROUND: Declining residual renal function, as indicated by the glomerular filtration rate (GFR), is associated with an increased mortality risk in patients with end-stage renal disease (ESRD) on dialysis. METHODS: We monitored GFR and mortality in 1800 haemodialysis (HD) and peritoneal dialysis (PD) patients in 1996-2006. We used a marginal structural model to estimate the causal effects both of GFR when it was not completely lost and of the subsequent full loss of GFR on mortality, avoiding the drawbacks of standard regression models that include covariates to adjust for confounding. Instead, effect estimates were adjusted for possible baseline and time-varying confounders using inverse probability weighting. RESULTS: We estimated a hazard ratio (HR) corresponding to the effect of the full loss of GFR on mortality, as compared to not having fully lost GFR, of 1.50 [95% confidence interval (CI) 1.09-2.07]. The HR corresponding to the effect of GFR when GFR is not (yet) fully lost on mortality was 0.97 (95% CI 0.92-1.02) (per mL/min/1.73 m(2)). We found no significant difference in the effect of GFR on mortality between patients starting on PD and HD. CONCLUSIONS: Preventing or delaying the full loss of GFR can improve survival in dialysis patients. This supports the importance that is given to the effect of treatment options for patients with ESRD on the rate of decline of the residual renal function. PMID- 21317413 TI - Moving on: researching, surviving, and thriving in the evidence-saturated world of health care. AB - In the worlds inhabited by qualitative inquirers working in health-related areas, health care, evidence, qualitative research, and qualitative researchers are four areas of potential tension and, at times, collision. These areas, or at least aspects of them, are constantly reinvented and realigned as the effects of such encounters are navigated. This article is about some of these close encounters, what we might learn from them, and how we might use this to "survive" as qualitative inquirers in an evidence-based world of health care and health care delivery. PMID- 21317414 TI - Tizanidine (Zanaflex): a muscle relaxant that may prolong the QT interval by blocking IKr. AB - BACKGROUND: Tizanidine (Zanaflex) is a centrally acting imidazoline muscle relaxant that is structurally similar to clonidine (alpha(2)-adrenergic agonist) but not to other myorelaxants such as baclofen or benzodiazepines. Interestingly, cardiac arrhythmias and QT interval prolongation have been reported with tizanidine. OBJECTIVE: To evaluate the effects of tizanidine on cardiac ventricular repolarization. METHODS: (1) Whole-cell patch-clamp experiments: HERG or KCNQ1+KCNE1-transfected cells were exposed to tizanidine 0.1-100 umol/L (n = 29 cells, total) to assess drug effect on the rapid (I(Kr)) and slow (I(Ks)) components of the delayed rectifier potassium current. (2) Langendorff retroperfusion experiments: isolated hearts from male Hartley guinea pigs (n = 6) were exposed to tizanidine 1 umol/L to assess drug-induced prolongation of monophasic action potential duration measured at 90% repolarization (MAPD(90)). (3) In vivo wireless cardiac telemetry experiments: guinea pigs (n = 6) implanted with radio transmitters were injected a single intraperitoneal (ip) dose of tizanidine 0.25 mg/kg and 24 hours electrocardiography (ECG) recordings were made. RESULTS: (1) Patch-clamp experiments revealed an estimated IC(50) for tizanidine on I(Kr) above 100 umol/L. Moreover, tizanidine 1 umol/L had hardly any effect on I(Ks) (5.23% +/- 4.54% inhibition, n = 5 cells). (2) While pacing the hearts at stimulation cycle lengths of 200 or 250 ms, tizanidine 1 umol/L prolonged MAPD(90) by 8.22 +/- 2.03 (6.7%) and 11.70 +/- 3.08 ms (8.5%), respectively (both P < .05 vs baseline). (3) Tizanidine 0.25 mg/kg ip caused a maximal 11.93 +/- 1.49 ms prolongation of corrected QT interval (QTc), 90 minutes after injection. CONCLUSION: Tizanidine prolongs the QT interval by blocking I(Kr). Patients could be at risk of cardiac proarrhythmia during impaired drug elimination, such as in case of CYP1A2 inhibition during drug interactions. PMID- 21317415 TI - Fibroids not encroaching the endometrial cavity and IVF success rate: a prospective study. AB - BACKGROUND The impact of fibroids, not encroaching the endometrial cavity, have on the rate of success of IVF is still controversial. Recent meta-analyses suggest a detrimental effect of intramural lesions but not subserosal lesions. However, they also emphasize the need for further evidence. In order to elucidate this, we designed a prospective cohort study to compare the rate of success of IVF in women with and without fibroids. METHODS Exposed women were those with asymptomatic intramural or subserosal fibroids with a diameter below 50 mm and who were selected for IVF. Unexposed women were those free of fibroids, who were matched to cases by age and number of previous IVF cycles. All recruited patients underwent hystero-sonography to rule out intra-cavitary lesions. RESULTS There were 119 cases and 119 controls recruited. The number of clinical pregnancies in women with and without fibroids was 28 (24%) and 22 (19%), respectively (P= 0.43). The adjusted odds ratio (OR) for pregnancy in affected women was 1.38 [95% confidence interval (CI): 0.73-2.60]. The number of deliveries was 22 (18%) and 16 (13%), respectively (P= 0.38). The adjusted OR was 1.45 (95% CI: 0.71-2.94). Similar results emerged when focusing exclusively on women carrying intramural lesions (n= 80 couples). There was no significant relationship between clinical outcome and either the number or size of the fibroids. CONCLUSIONS In asymptomatic patients selected for IVF, small fibroids not encroaching the endometrial cavity did not impact on the rate of success of the procedure. PMID- 21317416 TI - Immediate adverse events after second trimester medical termination of pregnancy: results of a nationwide registry study. AB - BACKGROUND Increasing gestational age is associated with an increased risk of complications in studies assessing surgical termination of pregnancy (TOP). Medical TOP is widely used during the second trimester and little is known about the frequency of complications. This epidemiological study was undertaken to assess the frequency of adverse events following the second trimester medical TOP and to compare it with that after first trimester medical TOP. METHODS This register-based cohort study covered 18 248 women who underwent medical TOP in Finland between 1 January 2003 and 31 December 2006. The women were identified from the Abortion Registry. Adverse events related to medical TOP within 6 weeks were obtained from the Hospital Discharge Registry. RESULTS When compared with first trimester medical TOP, second trimester medical TOP increased the risk of surgical evacuation [Adj. odds ratio (OR) 7.8; 95% confidence interval (CI) 6.8 8.9], especially immediately after fetal expulsion (Adj. OR 15.2; 95% CI 12.8 18.0). The risk of infection was also elevated (Adj. OR 2.1; 95% CI 1.5-2.9). Within the second trimester, increased length of gestation did not influence the risk of surgical evacuation or infection after medical TOP. CONCLUSIONS Medical TOP during the second trimester is generally safe. Surgical evacuation of the uterus is avoided in about two-thirds of cases, though it is much more common than after first trimester medical TOP. The risks of surgical evacuation and infection do not increase with gestational weeks in the second trimester TOP. PMID- 21317417 TI - Tonsillar herniation and syringomyelia caused by long-standing occlusive hydrocephalus due to aqueductal stenosis: rapid resolution after endoscopic third ventriculostomy--a case report. PMID- 21317418 TI - Bilateral renal subcapsular haematoma subsequent to vigorous exercise without direct trauma. PMID- 21317419 TI - Patterns of hospitalisation before and following initiation of haemodialysis: a 5 year single centre study. AB - BACKGROUND The utilisation of healthcare resources by prevalent haemodialysis patients has been robustly evaluated with regard to the provision of outpatient haemodialysis; however, the impact of hospitalisation among such patients is poorly defined. Minimal information is available in the UK to estimate the health and economic burden associated with the inpatient management of prevalent haemodialysis patients. The aim of this study was to assess the pattern of hospitalisation among a cohort of haemodialysis patients, before and following their initiation of haemodialysis. In addition the study sought to assess the impact of their admissions on bed occupancy in a large tertiary referral hospital in a single region in the UK. METHODS All admission episodes were reviewed and those receiving dialysis with the Belfast City Hospital Programme were identified over a 5 year period from January 2001 to December 2005. This tertiary referral centre provides dialysis services for a population of approximately 700 000 and additional specialist renal services for the remainder of Northern Ireland. The frequency and duration of hospitalisation, and contribution to bed day occupancy of haemodialysis patients, was determined and compared to other common conditions which are known to be associated with high bed occupancy. In addition, the pattern and timing of admissions in dialysis patients in relation to their dialysis initiation date was assessed. RESULTS Over the 5 year study period, 798 haemodialysis patients were admitted a total of 2882 times. These accounted for 2.5% of all admissions episodes; the median number of admissions for these patients was 3 (2-5) which compared with 1 (1-2) for non-dialysis patients. The majority of first hospitalisations (54%) were within 100 days before or after commencement of maintenance dialysis therapy. In all clinical specialties the median length of stay for haemodialysis patients was significantly longer than for patients not on haemodialysis (p=0.004). In multivariate analysis with adjustment for age, gender, and other clinically relevant diagnostic codes, maintenance haemodialysis patients stayed on average 3.75 times longer than other patient groups (ratio of geometric means 3.75, IQR 3.46-4.06). CONCLUSIONS Maintenance haemodialysis therapy is an important risk factor for prolonged hospitalisation regardless of the primary reason for admission. Such patients require admission more frequently than the general hospital population, particularly within 100 days before and after initiation of their first dialysis treatment. PMID- 21317420 TI - Diversity in oat potential immunogenicity: basis for the selection of oat varieties with no toxicity in coeliac disease. AB - BACKGROUND AND AIMS: Coeliac disease (CD) is triggered by an abnormal reaction to gluten. Peptides resulting from partially digested gluten of wheat, barley or rye cause inflammation of the small intestinal mucosa. Previous contradictory studies suggest that oats may trigger the abnormal immunological response in patients with CD. Monoclonal antibodies (moAbs) against the main immunotoxic 33-mer peptide (A1 and G12) react strongly against wheat, barley and rye but have less reactivity against oats. The stated aim of this study is to test whether this observed reactivity could be related to the potential toxicity of oats for patients with CD. METHODS: In the present study, different oat varieties, controlled for their purity and by their distinct protein pattern, were used to examine differences in moAb G12 recognition by ELISA and western blot. Immunogenicity of oat varieties was determined by 33-mer concentration, T cell proliferation and interferon gamma production. RESULTS: Three groups of oat cultivars reacting differently against moAb G12 could be distinguished: a group with considerable affinity, a group showing slight reactivity and a third with no detectable reactivity. The immunogenicity of the three types of oats as well as that of a positive and negative control was determined with isolated peripheral blood mononuclear T cells from patients with CD by measurement of cell proliferation and interferon gamma release. A direct correlation of the reactivity with G12 and the immunogenicity of the different prolamins was observed. CONCLUSIONS: The results showed that the reactivity of the moAb G12 is proportional to the potential immunotoxicity of the cereal cultivar. These differences may explain the different clinical responses observed in patients suffering from CD and open up a means to identify immunologically safe oat cultivars, which could be used to enrich a gluten-free diet. PMID- 21317421 TI - Amelioration of portal hypertension and the hyperdynamic circulatory syndrome in cirrhotic rats by neuropeptide Y via pronounced splanchnic vasoaction. AB - BACKGROUND: Splanchnic vasodilation triggers the development of the hyperdynamic circulatory syndrome in portal hypertension. Neuropeptide Y (NPY), a sympathetic co-transmitter of norepinephrine, improves contractility in mesenteric arteries of pre-hepatic portal hypertensive rats. Therefore, we investigated the effect of NPY on mesenteric arterial contractility in vitro and in vivo in cirrhotic ascitic rats, as well as the vasoactive pathways involved. METHODS: All experiments were performed in CCl4-induced cirrhotic rats with ascites and compared to controls. In vivo haemodynamic characterisation was assessed before and after cumulative application of NPY i.v. using the microspheres technique. In vitro mesenteric arterial perfusion was used to analyse the effect of NPY on the response to alpha1-adrenergic, as well as nitrergic stimulation. The NPY effects on vasoactive pathways (RhoA/Rho-kinase and NOS/NO) were analysed by western blot in mesenteric arteries. RESULTS: NPY decreased portal-venous blood flow and reduced portal pressure in cirrhotic rats, without changes in mean arterial pressure. This was accompanied by decreased cardiac output and normalised systemic vascular resistance in cirrhotic rats. By contrast, no significant splanchnic or systemic haemodynamic effect of NPY was seen in controls. NPY enhanced arterial contractility in cirrhotic but not in control rats. Furthermore, NO-mediated vasodilation was reduced to a greater extent than in controls. These findings were paralleled by an increased expression and activity of the constrictive Rho-kinase pathway and decreased activation of vasodilating NOS/NO signalling after NPY administration in mesenteric arteries. CONCLUSIONS: NPY exerts marked portal hypotensive effects and ameliorates the hyperdynamic circulation in cirrhotic ascitic rats. This is mediated mainly by a pronounced splanchnic vasoconstriction and reduction in splanchnic blood flow due to enhanced Rho-kinase expression and activity, as well as reduced NOS activation and NO effect. PMID- 21317422 TI - Notes from Batavia, the Europeans' graveyard: the nineteenth-century debate on acclimatization in the Dutch East Indies. AB - Since the advent of European colonial expansion, medical theories of acclimatization have been inextricably related to convictions about the possibility and desirability of white settlement in the colonies, and political ideas of colonial governance. Before 1800, acclimatization theories emphasized the inherent flexibility of the human constitution and its ability to adapt to new environments. During the first half of the nineteenth century, European theorists came to highlight the vulnerability of white Europeans in the tropics to disease, degeneration, and death instead. They consequently argued that white settlement in the tropics was impossible and inadvisable. European physicians in the British and French colonies presented similar views. By contrast, their colleagues in the Dutch East Indies remained optimistic. They associated themselves with the colonial European settler community and shared their grievances against autocratic colonial rule. They presented medical theories which related acclimatization to prudent behavior, morality, and proper management of the environment, thereby downplaying the significance of climate and high temperatures. During the following decades, their views on acclimatization were transferred to the Netherlands, where they were deployed as an argument against the cultivation system, the then-current approach of colonial governance, which emphasized the trade of cash crops grown by the indigenous population, severely limited European settlement, and curtailed the rights of Europeans living in the Indies. Throughout the nineteenth century, the influence of climate and the possibility of acclimatization became recurring themes in debates about colonial governance in both the Dutch East Indies and the Netherlands. PMID- 21317423 TI - The Tuskegee Syphilis Study and the scientific concept of racial nervous resistance. AB - In 1932, the U.S. Public Health Service began a study of untreated syphilis among black men in Macon County, Alabama. This project, later known as the Tuskegee Syphilis Study, became one of the most notorious ventures of twentieth-century medicine. Much has been written on it. Historians have suggested that scientific racism strongly influenced the study. But specific links between earlier racial science and the scientific conduct of the study have remained unexplored. The examination in this paper of the concept of a racially determined resistance to syphilis in the nervous system establishes such a link. Discussion of nervous resistance to syphilis appeared in the medical literature in the early twentieth century as a conjecture about the natural inferiority of blacks. White physicians used the concept to interpret racial differences in neurosyphilis as evidence of the rudimentary development of the brain. A small community of African American physicians joined other national experts in syphilis who chose to explain apparent racial differences through alternate mechanisms. But the scientific advisors to the Tuskegee Syphilis Study favored the concept of a racial resistance to neurosyphilis and steered the early design of the study to help to elucidate it. The Tuskegee Syphilis Study was an examination of untreated syphilis, but it also became a demonstration of a putative racial characteristic of syphilis long considered evidence of the natural inferiority of blacks. An examination of the concept of racial nervous resistance and its influence on the research in Macon County helps to define the influence of scientific racism on this notorious medical study. PMID- 21317424 TI - Association of high metabolic activity measured by positron emission tomography imaging with poor prognosis of choroidal melanoma. AB - AIMS: To evaluate the prognostic value of positron emission tomography (PET) imaging in patients with choroidal melanoma. METHODS: We undertook a retrospective review of 40 consecutive patients with choroidal melanoma who underwent pretreatment whole-body PET, received either brachytherapy using ruthenium-106 plaque, enucleation or gamma knife radiotherapy, and had 1 year of follow-up. Metabolic activity of choroidal melanoma measured as standardised uptake value (SUV) by PET imaging was evaluated with respect to the survival of patients. RESULTS: SUV (p=0.003) and the largest basal diameter of the tumour (p=0.003) were significantly correlated with metastatic death (Cox proportional hazards regression). There was an inverse correlation between tumour metabolic activity and time to metastasis (p=0.049; linear regression). CONCLUSION: Metabolic activity by PET imaging significantly predicted the survival of patients with choroidal melanoma. PMID- 21317425 TI - Modelling the prevalence of age-related macular degeneration (2010-2020) in the UK: expected impact of anti-vascular endothelial growth factor (VEGF) therapy. AB - AIMS: To project the number of cases with age-related macular degeneration (AMD) and the numbers with attributable sight loss in the UK in 2010-2020, taking into account the expected beneficial effect of the new anti-vascular endothelial growth factor (VEGF) therapies. METHODS: A 'system dynamics' approach was used in constructing the model to simulate the dynamics of the disease in large populations. The model computed the pool of affected cases over the simulation period, taking into account the expected demographic changes. Other determinants taken into account included: prevalence; incidence; mortality; and the expected efficacy and coverage of anti-VEGF treatment. RESULTS: In the UK, 608,213 persons in 2010 are estimated to have AMD, and this is expected to increase to 755,867 by the end of the decade. Numbers with sight loss from AMD are expected to rise from 223,224 in 2010 to 291,982 by 2020. Cases with sight loss due to neovascular AMD are expected to increase from 145,697 to 189,890 by the end of the decade. CONCLUSIONS: The model predicts that the beneficial effects of the treatment would be outweighed by the strong anticipated demographic 'ageing' effect. This reaffirms the importance of continuing efforts to develop more effective and more broadly applicable therapies for AMD. PMID- 21317426 TI - Continuous T-wave alternans monitoring to predict impending life-threatening cardiac arrhythmias during emergent coronary reperfusion therapy in patients with acute coronary syndrome. AB - AIMS: T-wave alternans (TWA) can precede onset of ventricular tachyarrhythmia (VTA). We evaluated the usefulness of continuous TWA monitoring in ultra-short term prediction of impending life-threatening VTA upon emergent reperfusion in acute coronary syndrome (ACS) patients. METHODS AND RESULTS: Twenty consecutive ACS patients undergoing emergent reperfusion therapy were studied. Continuous ambulatory electrocardiograms (ECGs) (leads V1 and V5) were recorded during emergency room visit and therapy. Peak TWA was determined before and after reperfusion by the modified moving average method. Coronary balloon angioplasty/stenting was successfully performed in 19 patients and intracoronary vasodilator was administered in 1 patient with coronary spasm. Three (15.0%) patients developed VTA requiring cardioversion soon after reperfusion. Peak TWA before reperfusion was higher in patients with VTA than in those without (33.0 +/ 4.4 vs. 15.8 +/- 4.0 uV, P < 0.001). Two patients with arrhythmia exhibited an upsurge in TWA to 75 and 105 uV before onset of VTA. In the third patient, macroscopic TWA appeared in leads V1-V4 in a 12-lead ECG prior to VTA upon pharmacological resolution of vasospasm, although the ambulatory ECG field of view could not detect the upsurge. CONCLUSION: Acute coronary syndrome patients at risk of developing VTA soon after reperfusion exhibit premonitory episodes of increased TWA. Thus, TWA monitoring may be useful for ultra-short-term prediction of life-threatening cardiac arrhythmia risk upon emergent reperfusion in ACS patients. Continuous 12-lead ECGs may be required to optimize detection of TWA, which is regionally specific. PMID- 21317427 TI - DeltaNp63, a target of DEC1 and histone deacetylase 2, modulates the efficacy of histone deacetylase inhibitors in growth suppression and keratinocyte differentiation. AB - The p63 gene, a member of the p53 family, is expressed as TA and DeltaN isoforms. DeltaNp63 is the predominant isoform expressed in cells of epithelial origin and frequently overexpressed in cancers. However, what regulates p63 expression is uncertain. Here, we showed that DeltaNp63 is regulated by the transcription factor DEC1, a p53 family target. We also showed that the ability of DEC1 to regulate DeltaNp63 is enhanced by histone deacetylase (HDAC) inhibitors or knockdown of histone deacetylase 2 (HDAC2). Consistent with this, we found that DEC1 and HDAC2 physically interact and knockdown of HDAC2 leads to increased binding of DEC1 to the DeltaNp63 promoter. Interestingly, we found that growth suppression induced by HDAC inhibitors is attenuated by ectopic expression of DEC1 in a DeltaNp63-dependent manner. In addition, we showed that ectopic expression of DEC1 inhibits, whereas knockdown of DEC1 promotes, keratinocyte differentiation via modulating DeltaNp63 expression. Finally, we showed that DEC1 cooperates with HDAC inhibitors to further decrease keratinocyte differentiation. Together, we conclude that DeltaNp63 is a novel target of DEC1 and HDAC2 and modulates the efficacy of HDAC inhibitors in growth suppression and keratinocyte differentiation. PMID- 21317428 TI - Scm3 is a centromeric nucleosome assembly factor. AB - The Cse4 nucleosome at each budding yeast centromere must be faithfully assembled each cell cycle to specify the site of kinetochore assembly and microtubule attachment for chromosome segregation. Although Scm3 is required for the localization of the centromeric H3 histone variant Cse4 to centromeres, its role in nucleosome assembly has not been tested. We demonstrate that Scm3 is able to mediate the assembly of Cse4 nucleosomes in vitro, but not H3 nucleosomes, as measured by a supercoiling assay. Localization of Cse4 to centromeres and the assembly activity depend on an evolutionarily conserved core motif in Scm3, but localization of the CBF3 subunit Ndc10 to centromeres does not depend on this motif. The centromere targeting domain of Cse4 is sufficient for Scm3 nucleosome assembly activity. Assembly does not depend on centromeric sequence. We propose that Scm3 plays an active role in centromeric nucleosome assembly. PMID- 21317429 TI - Transient-state kinetic analysis of transcriptional activator.DNA complexes interacting with a key coactivator. AB - Several lines of evidence suggest that the prototypical amphipathic transcriptional activators Gal4, Gcn4, and VP16 interact with the key coactivator Med15 (Gal11) during transcription initiation despite little sequence homology. Recent cross-linking data further reveal that at least two of the activators utilize the same binding surface within Med15 for transcriptional activation. To determine whether these three activators use a shared binding mechanism for Med15 recruitment, we characterized the thermodynamics and kinetics of Med15.activator.DNA complex formation by fluorescence titration and stopped-flow techniques. Combination of each activator.DNA complex with Med15 produced biphasic time courses. This is consistent with a minimum two-step binding mechanism composed of a bimolecular association step limited by diffusion, followed by a conformational change in the Med15.activator.DNA complex. Furthermore, the equilibrium constant for the conformational change (K(2)) correlates with the ability of an activator to stimulate transcription. VP16, the most potent of the activators, has the largest K(2) value, whereas Gcn4, the least potent, has the smallest value. This correlation is consistent with a model in which transcriptional activation is regulated at least in part by the rearrangement of the Med15.activator.DNA ternary complex. These results are the first detailed kinetic characterization of the transcriptional activation machinery and provide a framework for the future design of potent transcriptional activators. PMID- 21317430 TI - Functional cooperation between Snail1 and twist in the regulation of ZEB1 expression during epithelial to mesenchymal transition. AB - Snail1 and Zeb1 are E-cadherin-transcriptional repressors induced during epithelial mesenchymal transition (EMT). In this article we have analyzed the factors controlling Zeb1 expression during EMT. In NMuMG cells treated with TGF beta, Snail1 RNA and protein are induced 1 h after addition of the cytokine preceding Zeb1 up-regulation that requires 6-8 h. Zeb1 gene expression is caused by increased RNA levels but also by enhanced protein stability and is markedly dependent on Snail1 because depletion of this protein prevents Zeb1 protein and RNA up-regulation. In addition to Snail1, depletion of the Twist transcriptional factor retards Zeb1 stimulation by TGF-beta or decreases Zeb1 expression in other cellular models indicating that this factor is also required for Zeb1 expression. Accordingly, Snail1 and Twist cooperate in the induction of Zeb1: co-transfection of both cDNAs is required for the maximal expression of ZEB1 mRNA. Unexpectedly, the expression of Snail1 and Twist shows a mutual dependence although to a different extent; whereas Twist depletion retards Snail1 up-regulation by TGF beta, Snail1 is necessary for the rapid increase in Twist protein and later up regulation of Twist1 mRNA induced by the cytokine. Besides this effect on Twist, Snail1 also induces the nuclear translocation of Ets1, another factor required for Zeb1 expression. Both Twist and Ets1 bind to the ZEB1 promoter although to different elements: whereas Ets1 interacts with the proximal promoter, Twist does it with a 700-bp sequence upstream of the transcription start site. These results indicate that Snail1 controls Zeb1 expression at multiple levels and acts cooperatively with Twist in the ZEB1 gene transcription induction. PMID- 21317431 TI - Full, shared and hybrid paediatric care for cystic fibrosis in South and Mid Wales. AB - BACKGROUND: Although care for children with cystic fibrosis (CF) is increasingly shared between CF centres and local CF clinics, the optimal model is unclear. OBJECTIVES: The authors compared three models of care within a well established CF network: full centre care; local clinic based care with annual review by the CF centre; and hybrid care, where the child is usually reviewed at least three times a year by the specialist CF centre. RESULTS: Of 199 children and young people with CF in South and Mid Wales, 77 were receiving full care, 102 shared care and 20 hybrid care. There were no significant differences in baseline characteristics, nutritional outcomes or use of chronic therapies. There was however a statistically significant difference between full, shared and hybrid care in mean forced expiratory volume in 1 s (FEV(1)) per cent predicted (89.2% vs 74.5% vs 88.9%; p=0.001). CONCLUSIONS: These differences in pulmonary function are likely to reflect the model of care received, and may affect long term outcomes. PMID- 21317432 TI - Networking in paediatrics: the example of the Paediatric Rheumatology International Trials Organisation (PRINTO). AB - Networking is key to overcoming the logistical, methodological and ethical problems related to the implementation of paediatric studies. The adoption of legislation to encourage paediatric clinical trials by the American and European regulatory agencies has opened a new era in the assessment of drug safety and efficacy in children. Two very large international trial networks--the Pediatric Rheumatology Collaborative Study Group (PRCSG) and the Paediatric Rheumatology International Trials Organisation (PRINTO)--have played a critical role in the implementation of this legislation and have facilitated several successful controlled studies on the safety and the efficacy of new and old drugs in paediatric rheumatic diseases. The PRINTO and PRCSG networks can be seen as a model for international co-operation in other paediatric subspecialties. PMID- 21317433 TI - The pharmacokinetics of intravenous paracetamol in neonates: size matters most. AB - BACKGROUND: The aim was to describe intravenous paracetamol pharmacokinetics, determine major covariates and suggest a dosing regimen for (pre)term neonates. METHODS: A population pharmacokinetic analysis of 943 paracetamol observations from 158 neonates (27-45 weeks' postmenstrual age (PMA)) was undertaken using non linear mixed effects models. Data from three published studies were pooled with newly collected time-concentration points during repeated intravenous paracetamol administration. RESULTS: A two-compartment (central, peripheral) linear disposition model was used. Population parameter estimates (between-subject variability, %) were central volume 51.9 l/70 kg (21.6%), peripheral volume of distribution 22.7 l/70 kg, clearance 5 l/h/70 kg (40%) and intercompartment clearance 16.2 l/h/70 kg. Covariate information predicts 60.9% of clearance variance. Weight was used to predict patient size and was the major covariate contributing 57.5% of variance. Clearance expressed as mg/kg/h increases only slightly with PMA (0.138 l/kg/h at 28 weeks' PMA to 0.167 l/kg/h at 44 weeks' PMA) and contributes only 2.2% of variance. High unconjugated bilirubin levels contributed an additional 1.2%. CONCLUSIONS: Patient size (predicted by weight) is the major covariate of clearance variance in neonates. Using these estimates, a mean paracetamol serum concentration of 11 mg/l is predicted in neonates of 32 44 weeks' PMA given a standard dose of intravenous paracetamol of 10 mg/kg every 6 h. Safety data for this drug are limited in neonates. Continued surveillance therefore remains essential. PMID- 21317434 TI - Efficacy of etanercept on rheumatic signs and pulmonary function tests in advanced ankylosing spondylitis: results of a randomised double-blind placebo controlled study (SPINE). AB - OBJECTIVES: Patients with advanced ankylosing spondylitis (AS) experience disability because of reduced spinal mobility and pulmonary function impairment. This placebo-controlled study evaluated the effect of etanercept (ETN) in patients with advanced AS. METHODS: A multicentre randomised double-blind placebo controlled trial of 12 weeks' duration was performed. Patients had definite (modified New York criteria), active (Bath AS Disease Activity Index (BASDAI) >=40), severe (radiological intervertebral bridges) AS refractory to non steroidal anti-inflammatory drugs and were antitumour necrosis factor naive. They were treated with ETN 50 mg once weekly or identical placebo (PBO). RESULTS: Of the 95 patients screened, 82 were randomised to receive ETN (n=39) or PBO (n=43). At baseline the disease was active (mean BASDAI 61.0+/-13.4, C reactive protein (CRP) 20.7+/-25.5 mg/l) and severe (mean Bath AS Metrology Index (BASMI) 5.7+/ 1.3, mSASSS 36.5+/-20.5); forced pulmonary vital capacity (FVC) was 3.3+/-0.7 l. Improvement in BASDAI (normalised net incremental area under the curve between baseline and week 12, primary end point) was significantly greater in the ETN group than in the PBO group (-19.8+/-16.5 vs -11.0+/-16.4, p=0.019). Moreover, at week 12, ETN gave better results than PBO for the BASDAI (-26.4+/-19.7 vs -14.4+/ 19.7; p=0.008), total back pain (-29.2+/-24.0 vs -14.9+/-24.0; p=0.010), BASFI ( 21.7+/-17.6 vs -10.1+/-17.6; p=0.004), BASMI (-0.6+/-0.6 vs -0.2+/-0.6; p=0.011), CRP level (-15.7+/-14.2 vs -1.3+/-14.2; p<0.001) and FVC (+160+/-280 ml vs -20+/ 280 ml; p=0.006). CONCLUSIONS: ETN has short-term efficacy for patients with advanced AS, as was previously reported for less advanced disease. The efficacy is observed for the main symptoms (pain) and on markers of inflammation (CRP), as well as disease severity in terms of spinal mobility and pulmonary function. PMID- 21317435 TI - Analysis of association of DNASE2 promoter variation with rheumatoid arthritis in European Caucasians. PMID- 21317436 TI - Mortality is reduced while on opiate maintenance treatment, but there is a temporary increase in mortality immediately after starting and stopping treatment, a finding that may vary by setting. PMID- 21317440 TI - The spectrum of associated brain lesions in cerebral sinovenous thrombosis: relation to gestational age and outcome. AB - OBJECTIVE: To describe different patterns of associated brain lesions in preterm and full-term infants with cerebral sinovenous thrombosis (CSVT) and to assess whether these different patterns are related to gestational age at onset. DESIGN: Magnetic resonance scans of all neonates (six preterm, 24 full term) with suspected CSVT, collected over a 7-year period in two neonatal intensive care units, were evaluated to assess patterns of associated brain lesions. Comparisons between the two gestational age groups were made. RESULTS: CSVT was confirmed on magnetic resonance venography in 26 of 30 neonates (six preterm, 20>=36 weeks' gestational age). The straight (85%) and superior sagittal (65%) sinus were most often affected. Several sinuses were involved in 81% of infants. White matter damage affecting the entire periventricular white matter was seen in five of six preterm infants. Intraventricular haemorrhage (IVH) was common in both groups (4/6 preterm, 16/20 full term). Frontal punctate white matter lesions with restricted diffusion (15/20) and thalamic haemorrhage associated with IVH (11/20) were the most frequent lesions in full-term infants. Focal arterial infarction was present in four of 20 full-term infants. Six infants died in the neonatal period (four preterm, two full term). Follow-up MRIs at 3 months in all survivors showed evolution of the lesions with frontal atrophy in 13 of 20 (12 full term) and delayed myelination in seven of 20 (six full term). CONCLUSIONS: Preterm and full-term neonates show different patterns of associated brain lesions. Extensive white matter damage is the predominant pattern of injury in the preterm infant, while an IVH associated with a thalamic haemorrhage and punctate white matter lesions are more common in the full-term infant. PMID- 21317437 TI - Thermogenic activation induces FGF21 expression and release in brown adipose tissue. AB - FGF21 is a novel metabolic regulator involved in the control of glucose homeostasis, insulin sensitivity, and ketogenesis. The liver has been considered the main site of production and release of FGF21 into the blood. Here, we show that, after thermogenic activation, brown adipose tissue becomes a source of systemic FGF21. This is due to a powerful cAMP-mediated pathway of regulation of FGF21 gene transcription. Norepinephrine, acting via beta-adrenergic, cAMP mediated, mechanisms and subsequent activation of protein kinase A and p38 MAPK, induces FGF21 gene transcription and also FGF21 release in brown adipocytes. ATF2 binding to the FGF21 gene promoter mediates cAMP-dependent induction of FGF21 gene transcription. FGF21 release by brown fat in vivo was assessed directly by analyzing arteriovenous differences in FGF21 concentration across interscapular brown fat, in combination with blood flow to brown adipose tissue and assessment of FGF21 half-life. This analysis demonstrates that exposure of rats to cold induced a marked release of FGF21 by brown fat in vivo, in association with a reduction in systemic FGF21 half-life. The present findings lead to the recognition of a novel pathway of regulation the FGF21 gene and an endocrine role of brown fat, as a source of FGF21 that may be especially relevant in conditions of activation of thermogenic activity. PMID- 21317441 TI - A survey of Canadian medical student attitudes towards the ethics of pediatric clinical trials: are they different from Canadian and British health care professionals? AB - BACKGROUND: Due to ethical concerns and constraints inherent to research in children, the conduct of clinical trials in children has often been difficult. The views of medical professionals and trainees towards conducting clinical trials in children have been largely unexplored and are potentially important towards working to increase the number of appropriate trials conducted in children. OBJECTIVE: To explore the views of Canadian medical school trainees towards paediatric clinical trials and to compare these views with that of an earlier pilot study conducted amongst Canadian and British health care professionals. METHODS: Participants were given a questionnaire which consisted of direct questions as well as scenarios with ethical dilemmas. Responders were asked to state whether they would enter children in the trial documented in the scenario and to justify their reasons. RESULTS: 89 questionnaires were collected (74% response rate). 42% had formal teaching regarding paediatric ethical dilemmas but only 2% had formal teaching on pharmaceutical testing in children. The students were divided on whether children should only participate in trials where they receive direct benefit. Most students (85%; 95% CI: 77% to 91%) were comfortable with non-inferiority trials even with post-hoc consent. Only a third (33%; 95% CI: 24% to 43%) agreed with the use of placebo in an analgesia trial. CONCLUSION: Teaching on the ethics of paediatric clinical trials still appears to be lacking amongst medical trainees. However, there does seem to be increased willingness on the part of trainees compared to practicing medical professionals in enrolling children in clinical trials. PMID- 21317442 TI - Reporting on the prevalence of drug and alternative health product use for mental health reasons: results from a national population survey. AB - BACKGROUND: Concomitant use of alternative health products with commonly prescribed medications has been associated with elevated risks of adverse effects. OBJECTIVE: The aim of this study was to determine the prevalence and determinants of the use of alternative health products and psychotropic drugs in the same year for mental health reasons and to examine this for specific psychiatric and physical conditions. METHODS: This study used data from the Canadian Community Health Survey: Mental Health and Well-Being cycle 1.2 carried out by Statistics Canada in 2002 on 36,984 Canadians. Multivariate analyses were carried out to identify determinants of health product use. RESULTS: Overall, 13% of Canadians reported the use of alternative health products. Among respondents with a psychiatric diagnosis, heart disease, high blood pressure and diabetes the rate was 20.0%, 12.0%, 12.6% and 9.4% respectively. Use of alternative health products and psychotropic drugs within the same year was reported by 21.3%. Determinants of alternative health product use included older age, female sex, higher education, and mental disorder, the use of cardiovascular drugs, consulting a health care provider for mental health reasons and reporting an unmet mental health need. People with diabetes were less likely to be users. CONCLUSIONS: Concomitant use of alternative health products and psychotropic drugs for mental health reasons are prevalent. This increases the risk for potential drug-herb interactions. Health professionals need to be aware of patient alternative health product use, especially in the presence of co-morbid mental and physical conditions. Public health campaigns aimed towards increasing awareness and education may incite discussions between health professionals and patients on the risks and benefits of these products. PMID- 21317443 TI - A critical review of: Impact of antimicrobial stewardship program on vancomycin use in a pediatric teaching hospital. PMID- 21317444 TI - Beta-adrenergic signaling, a novel target for cancer therapy? PMID- 21317445 TI - A new therapeutic basis for treating Li-Fraumeni Syndrome breast tumors expressing mutated TP53. PMID- 21317446 TI - Refractory chronic lymphocytic leukemia--new therapeutic strategies. AB - Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy. Nevertheless, refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis. Important risk factors are 17p deletion and/or mutation of TP53. For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved. Meanwhile we have to face also refractoriness to alemtuzumab. Importantly, the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double refractory CLL. The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor. Further B-cell antigens are targeted by lumiliximab (CD23), TRU-016 (CD37) and blinatumomab (CD19). Apart from monoclonal antibody therapies, a great number of small molecules are examined for the treatment of refractory and relapsed CLL. Most of these agents aim to overcome apoptosis resistance in CLL cells or influence the microenvironment. Typical targets are regulators of the cell cycle and antiapoptotic molecules like the members of the Bcl-2 family. Up to now the most promising agents appear to be flavopiridol and lenalidomide among others. PMID- 21317447 TI - Standards and impact of hematopathology in myelodysplastic syndromes (MDS). AB - The diagnosis, classification, and prognostication of patients with myelodysplastic syndromes (MDS) are usually based on clinical parameters, analysis of peripheral blood and bone marrow smears, and cytogenetic determinants. However, a thorough histologic and immunohistochemical examination of the bone marrow is often required for a final diagnosis and exact classification in these patients. Notably, histology and immunohistology may reveal dysplasia in megakaryocytes or other bone marrow lineages and/or the presence of clusters of CD34-positive precursor cells. In other cases, histology may reveal an unrelated or co-existing hematopoietic neoplasm, or may support the conclusion the patient is suffering from acute myeloid leukemia rather than MDS. Moreover, histologic investigations and immunohistology may reveal an increase in tryptase-positive cells, a coexisting systemic mastocytosis, or bone marrow fibrosis, which is of prognostic significance. To discuss diagnostic algorithms, terminologies, parameters, and specific issues in the hematopathologic evaluation of MDS, a Working Conference involving a consortium of US and EU experts, was organized in June 2010. The outcomes of the conference and resulting recommendations provided by the faculty, are reported in this article. These guidelines should assist in the diagnosis, classification, and prognostication in MDS in daily practice as well as in clinical trials. PMID- 21317448 TI - Antiangiogenic agents in advanced gastrointestinal malignancies: past, present and a novel future. AB - Advanced gastrointestinal (GI) malignancies are varied in presentation, prognosis, and treatment options. With the exception of resectable recurrent colorectal cancer, metastatic GI malignancies are incurable. Cytotoxic chemotherapies have been the mainstay of therapy for decades but limited extension of survival or clinical benefit has been achieved in non-colorectal GI cancers. There has been great interest in the incorporation of antiangiogenic strategies to improve outcomes for these patients. Clear benefits have been identified with bevacizumab and sorafenib in colorectal cancer and hepatocellular cancer, respectively; other GI tumor sites have lacked impressive results with antiangiogenic agents. In this review, we will present the benefits, or lack thereof, of clinically tested antiangiogenic compounds in GI malignancies and explore some potential new therapeutic anti-angiogenesis options for these diseases. PMID- 21317449 TI - Targeting the PI3K/Akt/mTOR pathway--beyond rapalogs. AB - It is well established that the PI3K pathway plays a central role in various cellular processes that can contribute to the malignant phenotype. Accordingly, pharmacological inhibition of key nodes in this signaling cascade has been a focus in developmental therapeutics. To date, agents targeting upstream receptor tyrosine kinases are best studied and have achieved greatest clinical success. Further downstream, despite efficacy in certain tumor types, the rapalogs have been somewhat disappointing in the clinic. Novel inhibitors of PI3K, Akt, and mTORC1 and 2 are now passing through early phase clinical trials. It is hoped that these agents will circumvent some of the shortcomings of the rapalogs and lead to meaningful benefits for cancer patients. PMID- 21317450 TI - The pursuit of oncotargets through understanding defective cell regulation. AB - More effective anticancer agents are essential, as has too often been demonstrated by the paucity of therapeutics which preserve life. Their discovery is very difficult. Many approaches are being applied, from testing folk medicines to automated high throughput screening of large chemical libraries. Mutations in cancer cells create dysfunctional regulatory systems. This Perspective summarizes an approach to applying defective molecular control mechanisms as oncotargets on which drug discoveries against cancer can be based. PMID- 21317453 TI - Role of dual PI3/Akt and mTOR inhibition in Waldenstrom's Macroglobulinemia. AB - Tumorigenesis occurs due to synergistic interactions from a complex of signal transduction processes, including multiple onco-proteins and tumor suppressors such as Ras, Myc, PI3K/Akt/mTOR, Her-2/Neu, p53 and PTEN. Specifically, the PI3K/Akt and mTOR pathways have been shown to play a pivotal role on the initiation and progression of malignancies, enhancing cell survival by stimulating cell proliferation, and inhibiting apoptosis. Therefore, it is critical to examine therapeutic agents that explicitly target both the PI3K/Akt and mTOR signaling cascades in diseases, such as Waldenstrom Macroglobulinemia (WM), that harbor activation of the PI3K/Akt pathway. We demonstrated that dual targeting of the PI3K and mTOR pathways by the novel inhibitor NVP-BEZ235, exhibited toxicity on WM cells by directly targeting the tumor clone and indirectly through an effect on the bone marrow milieu. These findings suggest that dual targeting of the PI3K and mTOR pathways is a better modality of targeted therapy for tumors that harbor activation of the PI3K/mTOR pathways, such as in WM. PMID- 21317451 TI - Targeting metabolic remodeling in glioblastoma multiforme. AB - A key aberrant biological difference between tumor cells and normal differentiated cells is altered metabolism, whereby cancer cells acquire a number of stable genetic and epigenetic alterations to retain proliferation, survive under unfavorable microenvironments and invade into surrounding tissues. A classic biochemical adaptation is the metabolic shift to aerobic glycolysis rather than mitochondrial oxidative phosphorylation, regardless of oxygen availability, a phenomenon termed the "Warburg Effect". Aerobic glycolysis, characterized by high glucose uptake, low oxygen consumption and elevated production of lactate, is associated with a survival advantage as well as the generation of substrates such as fatty acids, amino acids and nucleotides necessary in rapidly proliferating cells. This review discusses the role of key metabolic enzymes and their association with aerobic glycolysis in Glioblastoma Multiforme (GBM), an aggressive, highly glycolytic and deadly brain tumor. Targeting key metabolic enzymes involved in modulating the "Warburg Effect" may provide a novel therapeutic approach either singularly or in combination with existing therapies in GBMs. PMID- 21317454 TI - The requirement of p53 for maintaining chromosomal stability during tetraploidization. AB - Tetraploidization is believed to promote genome instability and tumorigenesis. Whether tetraploids per se are intrinsically unstable and transforming remain incompletely understood. In this report, tetraploidization was induced with cell fusion using mouse fibroblasts. Due to the unequal segregation of chromosomes during multipolar mitosis, the majority of cells were eliminated by p53-dependent mechanisms after tetraploidization. The rare tetraploid fibroblasts that were able to undergo bipolar mitosis remained chromosomally stable and nontransformed over many generations. Suppression of p53 functions during tetraploidization, either by RNA interference or by using p53-deficient mouse fibroblasts, produced cells that were chromosomally unstable. They were fast growing and displayed anchorage-independent growth in soft agar. In contrast, impairment of p53 functions after tetraploids were established was ineffective in triggering chromosomal instability and transformation. Collectively, these results are consistent with a model that during early stages of tetraploidization, the lack of p53 promotes the survival of chromosomally unstable sub-tetraploids, leading to transformation. Once tetraploids are established, however, p53 is not essential for maintaining chromosome stability. PMID- 21317452 TI - Drug discovery approaches to target Wnt signaling in cancer stem cells. AB - Cancer stem cells (CSCs) represent a unique subset of cells within a tumor that possess self-renewal capacity and pluripotency, and can drive tumor initiation and maintenance. First identified in hematological malignancies, CSCs are now thought to play an important role in a wide variety of solid tumors such as NSCLC, breast and colorectal cancer. The role of CSCs in driving tumor formation illustrates the dysregulation of differentiation in tumorigenesis. The Wnt, Notch and Hedgehog (HH) pathways are developmental pathways that are commonly activated in many types of cancer. While substantial progress has been made in developing therapeutics targeting Notch and HH, the Wnt pathway has remained an elusive therapeutic target. This review will focus on the clinical relevance of the Wnt pathway in CSCs and tumor cell biology, as well as points of therapeutic intervention and recent advances in targeting Wnt/beta-catenin signaling. PMID- 21317455 TI - The class I HDAC inhibitor MGCD0103 induces cell cycle arrest and apoptosis in colon cancer initiating cells by upregulating Dickkopf-1 and non-canonical Wnt signaling. AB - Colorectal cancer metastatic recurrence and chemoresistance are major causes of morbidity and mortality. Colon cancer initiating cells (CCIC) are thought to contribute to both these processes. To identify drugs with anti-CCIC activity we screened a number of FDA approved and investigational compounds. We found that the class I selective histone deacetylase inhibitor (HDACi) MGCD0103 has significant activity against CCIC, and also significantly inhibits non-CCIC CRC cell xenograft formation. Both MGCD0103 and the pan-HDAC inhibitor Trichostatin impairs CCIC clonogenicity and cause cell cycle arrest and cell death. Gene expression profiling revealed that the canonical WNT ligand DKK-1 is a highly upregulated target of HDAC inhibitors. Despite the presence of APC mutations and constitutive WNT signaling in CCIC, both transfected and recombinant DKK-1 dramatically inhibit CCIC proliferation and clonogenicity. Overall, these data show that inhibition of class I HDACs is a promising novel approach to target both CCIC and non-CCIC CRC cells. Our studies also provide novel insights into roles for DKK1 in addition to canonical WNT signaling and the mechanism of CCIC tumor formation. PMID- 21317456 TI - Homologous recombination repair is essential for repair of vosaroxin-induced DNA double-strand breaks. AB - Vosaroxin (formerly voreloxin) is a first-in-class anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II, inducing site selective double-strand breaks (DSB), G2 arrest and apoptosis. Objective responses and complete remissions were observed in phase 2 studies of vosaroxin in patients with solid and hematologic malignancies, and responses were seen in patients whose cancers were resistant to anthracyclines. The quinolone-based scaffold differentiates vosaroxin from the anthracyclines and anthracenediones, broadly used DNA intercalating topoisomerase II poisons. Here we report that vosaroxin induces a cell cycle specific pattern of DNA damage and repair that is distinct from the anthracycline, doxorubicin. Both drugs stall replication and preferentially induce DNA damage in replicating cells, with damage in G2 / M > S >> G1. However, detectable replication fork collapse, as evidenced by DNA fragmentation and long tract recombination during S phase, is induced only by doxorubicin. Furthermore, vosaroxin induces less overall DNA fragmentation. Homologous recombination repair (HRR) is critical for recovery from DNA damage induced by both agents, identifying the potential to clinically exploit synthetic lethality. PMID- 21317457 TI - Sumoylation of vimentin354 is associated with PIAS3 inhibition of glioma cell migration. AB - The invasive phenotype of glioblastoma multiforme (GBM) is a hallmark of malignant process, yet the molecular mechanisms that dictate this locally invasive behavior remain poorly understood. Over-expression of PIAS3 effectively changes cell shape and inhibits GBM cell migration. We focused on the molecular target(s) of PIAS3 stimulated sumoylation, which play an important role in the inhibition of GBM cell motility. Here we report, through the immunoprecipitation with SUMO1 antibody, followed by proteomic analysis, the identification of vimentin (vimentin354), a nuclear component in GBM cells, as the main target of sumoylation promoted by PIAS3. PMID- 21317458 TI - Beta-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival. AB - Laboratory models show that the beta-blocker, propranolol, can inhibit norepinephrine-induced breast cancer cell migration. We hypothesised that breast cancer patients receiving beta-blockers for hypertension would show reduced metastasis and improved clinical outcome. Three patient subgroups were identified from the medical records of 466 consecutive female patients (median age 57, range 28-71) with operable breast cancer and follow-up (>10 years). Two subgroups comprised 43 and 49 hypertensive patients treated with beta-blockers or other antihypertensives respectively, prior to cancer diagnosis. 374 patients formed a non-hypertensive control group. Metastasis development, disease free interval, tumour recurrence and hazards risk were statistically compared between groups. Kaplan-Meier plots were used to model survival and DM. Beta-blocker treated patients showed a significant reduction in metastasis development (p=0.026), tumour recurrence (p=0.001), and longer disease free interval (p=0.01). In addition, there was a 57% reduced risk of metastasis (Hazards ratio=0.430; 95% CI=0.200-0.926, p=0.031), and a 71% reduction in breast cancer mortality after 10 years (Hazards ratio=0.291; 95% CI=0.119-0.715, p=0.007). This proof-of-principle study showed beta-blocker therapy significantly reduces distant metastases, cancer recurrence, and cancer-specific mortality in breast cancer patients suggesting a novel role for beta-blocker therapy. A larger epidemiological study leading to randomised clinical trials is needed for breast and other cancer types including colon, prostate and ovary. PMID- 21317459 TI - Evaluation of an Actinomycin D/VX-680 aurora kinase inhibitor combination in p53 based cyclotherapy. AB - p53-Based cyclotherapy is proving to be a promising approach to palliate undesired effects of chemotherapy in patients with tumours carrying p53 mutations. For example, pre-treatment of cell cultures with Nutlin-3, a highly selective inhibitor of the p53-mdm2 interaction, has been successfully used as a cytostatic agent to protect normal cells, but not p53-defective cells, from subsequent treatment with mitotic poisons or S-phase specific drugs. Here we sought to evaluate whether low doses of Actinomycin D (LDActD), a clinically approved drug and potent p53 activator, could substitute Nutlin-3 in p53-based cyclotherapy. We found that pre-treatment with LDActD before adding the aurora kinase inhibitor VX-680 protects normal fibroblasts from polyploidy and nuclear morphology abnormalities induced by VX-680. However, and although to a lower extent than normal fibroblasts, tumour cell lines bearing p53 mutations were also protected by LDActD (but not Nutlin-3) from VX-680-induced polyploidy. We also report that a difference between the response of p53 wild-type cells and p53 defective cells to the LDActD/VX-680 sequential combination is that only the former fail to enter S-phase and therefore accumulate in G1/G0. We propose that drugs that incorporate into DNA during S-phase may perform better as second drugs than mitotic poisons in cyclotherapy approaches using LDActD as a cytostatic agent. PMID- 21317460 TI - Epithelial mesenchymal transition and tumor budding in aggressive colorectal cancer: tumor budding as oncotarget. AB - Epithelial mesenchymal transition (EMT) is proposed as a critical mechanism for the acquisition of malignant phenotypes by epithelial cells. In colorectal cancer, tumor cells having undergone EMT are histologically represented by the presence of tumor buds defined as single cells or small clusters of de differentiated tumor cells at the invasive front. Tumor budding is not a static, histological feature rather it represents a snap-shot of a dynamic process undertaken by an aggressive tumor with the potential to disseminate and metastasize. Strong, consistent evidence shows that tumor budding is a predictor of lymph node metastasis, distant metastatic disease, local recurrence, worse overall and disease-free survival time and an independent prognostic factor. Moreover, the International Union against Cancer (UICC) recognizes tumor budding as a highly relevant, additional prognostic parameter. The aim of this review is to summarize the evidence supporting the implementation of tumor budding into diagnostic pathology and patient management and additionally to illustrate its worthiness as a potential therapeutic target. PMID- 21317461 TI - Targeting tumor angiogenesis with TSP-1-based compounds: rational design of antiangiogenic mimetics of endogenous inhibitors. AB - Inhibitors of angiogenesis are an important addition to conventional chemotherapy. Among different "druggable" angiogenic factors, fibroblast growth factor-2 (FGF-2) is an attractive target for novel therapies because of its intricated involvement in tumor neovascularization, tumor cell proliferation and migration, and the acquisition of resistance to antiangiogenic therapies. FGF-2 bioavailability and activity is affected by several natural ligands, including the endogenous inhibitor of angiogenesis thrombospondin-1 (TSP-1). We hypothesized that the FGF-2-binding sequence of TSP-1 might serve as a template for the development of non-peptide inhibitors of angiogenesis. Computational biology and nuclear magnetic resonance spectroscopy approaches, major investigative tools in the characterizations of protein-protein interaction (PPI), were used to map the residues at the TSP-1/FGF-2 interface. The translation of this three-dimensional information into a pharmacophore model allowed screening a small molecule databases, identifying three FGF-2-binding, antiangiogenic small molecules, mimetic of TSP-1. Pharmacophore-based approaches are thus feasible tools to exploit naturally occurring PPI, by generating a set of lead compounds mimetic of endogenous proteins, as a starting point for the development of novel therapeutic agents. PMID- 21317463 TI - Novel insights into the molecular mechanisms governing Mdm2 ubiquitination and destruction. AB - The Mdm2/p53 pathway is compromised in more than 50% of all human cancers, therefore it is an intensive area of research to understand the upstream regulatory pathways governing Mdm2/p53 activity. Mdm2 is frequently overexpressed in human cancers while the molecular mechanisms underlying the timely destruction of Mdm2 remain unclear. We recently reported that Casein Kinase I phosphorylates Mdm2 at multiple sites to trigger Mdm2 interaction with, and subsequent ubiquitination and destruction by the SCF(beta-TRCP) E3 ubiquitin ligase. We also demonstrated that the E3 ligase activity-deficient Mdm2 was still unstable in the G1 phase and could be efficiently degraded by SCF(beta-TRCP). Thus our finding expands the current knowledge on how Mdm2 is tightly regulated by both self- and SCF(beta-TRCP)-dependent ubiquitination to control p53 activity in response to stress. It further indicates that loss of beta-TRCP or Casein Kinase I function contributes to elevated Mdm2 expression that is frequently found in various types of tumors. PMID- 21317464 TI - Emerging role of sildenafil in neonatology. AB - Over the last few years, sildenafil is increasingly being used in the neonatal ICU for a variety of indications. The use is even more so in the developing world due to the limited availability of nitric oxide and extracorporeal membrane oxygenation (ECMO). There are still no clear cut guidelines for its use. At present the drug appears relatively safe and effective when other treatment options have been optimized. However, the use of sildenafil must be monitored and reported. Due to its easy availability and ease of administration we must guard against its inappropriate use. PMID- 21317465 TI - How long do you treat clinically diagnosed neonatal sepsis with negative cultures? PMID- 21317462 TI - Wnt/Beta-catenin and sex hormone signaling in endometrial homeostasis and cancer. AB - A delicate balance between estrogen and progestagen signaling underlies proper functioning of the female reproductive tract and, in particular, the monthly re- and degenerative phases characteristic of the menstrual cycle. Here, we propose that the canonical Wnt/beta-catenin signaling pathway may underlie this finely tuned hormonal equilibrium in endometrial homeostasis and, upon its constitutive activation, lead to neoplastic transformation of the endometrium. During the menstrual cycle, estradiol will enhance Wnt/beta-catenin signaling in the proliferative phase, while progesterone inhibits Wnt/beta-catenin signaling, thus restraining estrogens' proliferative actions, during the secretory phase. In case of enhanced or unopposed estrogen signaling, constitutive activation of Wnt/beta catenin signaling will trigger endometrial hyperplasia, which may develop further into endometrial cancer. PMID- 21317466 TI - Clinical screening for congenital heart disease at birth- a long way to go. PMID- 21317467 TI - Chronic and persistent diarrhea in infants and young children: status statement. AB - JUSTIFICATION: Diarrhea that lasts for more than two weeks is a common cause of mortality and morbidity in infants and children. There is a need to update the information available on this subject in Indian context. PROCESS: This review has analyzed the available published data on the subject with particular focus on developing countries. It has also outlined the current diagnostic and management practices in India based on the experience of the participants from major hospitals in different parts of the country. OBJECTIVES: Problem areas in both persistent and chronic diarrhea have been identified and remedial measures relevant to India are presented. RECOMMENDATIONS: Micronutrient supplementation, algorithm based diet regimens, and good supportive care are sufficient in most children above 6 months of age with persistent diarrhea. Paucity of diagnostic facilities limits evaluation of chronic diarrhea in most parts of the country and regional laboratories need to be set up urgently. Lack of awareness regarding cows milk protein allergy, celiac disease and immunodeficiency associated diarrhea is of particular concern. PMID- 21317468 TI - Morgagni hernia presenting as obstructive jaundice. AB - Morgagnis hernia is rare in pediatrics, representing 1%-6% of all congenital diaphragmatic hernias (CDH). We report a young boy presented with obstructive jaundice caused by compression of common bile duct (CBD) due to stretching and rotation of second part of duodenum in right-sided Morgagni hernia. Such presentation is rarely reported in literature. PMID- 21317469 TI - Giant condyloma acuminata in pediatric HIV. AB - We report a 2 year 6 months old girl suffering from HIV infection and presenting with two giant condyloma acuminata of perianal and perivulvar region along with oral candidiasis. PMID- 21317470 TI - Andersen Tawil syndrome - periodic paralysis with dysmorphism. AB - Andersen Tawil syndrome is a rare type of channelopathy characterized by the presence of periodic paralysis, cardiac arrhythmia (prolonged QT interval or ventricular arrhythmia) and distinct dysmorphic abnormalities. It is a type of potassium channelopathy that occurs sporadically or by autosomal dominant inheritance. We report a 14 year old boy with Andersen-Tawil syndrome. PMID- 21317471 TI - Snake bite envenomation in children in Kashmir. AB - A three year retrospective study was done to study snakebite envenomation among Kashmiri children. Ten children were admitted with snakebite. Snakebite was vasculotoxic in seven and mixed in two. Levantine viper bites were seen in five who had Grade 3 bites with severe local signs, severe coagulopathy and hypotension. Both environmental risk and seasonal incidence was observed. PMID- 21317472 TI - Time-lag from submission to printing in Indian biomedical journals. AB - The timeliness of publication in five Indian, clinical, biomedical journals (Indian Pediatrics, The Indian Journal of Pediatrics, Neurology India, The Indian Journal of Medical Research and Journal of Postgraduate Medicine) from January 2007 to December 2008 was compared. The time from manuscript submission to publication for the journals studied (median: 358.3 days; range: 202.9-421.3 days) was not significantly different. PMID- 21317473 TI - Age at menarche in adolescent Khasi girls, Meghalaya. AB - The mean and median age at menarche in 360 Khasi girls was found to be 13.22 +/- 0.88 and 12.13 +/- 0.79 years, respectively; socio-economic status was observed to be a strong predictor of age at menarche in this population. PMID- 21317474 TI - Cerebral perfusion abnormalities in cases of Down syndrome. AB - A SPECT (single photon emission computed tomography using Tc-99m HMPAO) study of brain with segmental quantitative analysis was conducted to access the cerebral perfusion in cases of Downs syndrome (DS). Varying level of brain hypo-perfusion was documented, probably explaining the neurophysiologic basis of cognitive and neuropsychological deficits, which are not well understood in DS. PMID- 21317475 TI - Seroprevalence of hepatitis A virus antibody in Bijapur, Karnataka. AB - We studied the seroprevalence of anti-HAV IgG in children of Bijapur a tier III city/backward district in Karnataka and its relation with sociodemographic parameters. Out of 142 children, 6 months to 15 years who were included, 63 (44.4%) were sero positive, suggesting that Bijapur is a low endemic area. PMID- 21317476 TI - Organophosphorus poisoning presenting as diabetic ketoacidosis. PMID- 21317477 TI - Dissecting aortic aneurysm with Marfan syndrome. PMID- 21317478 TI - Tobacco and non-tobacco abuse among school children in Noida, India. PMID- 21317479 TI - Superior vena cava obstruction in childhood acute lymphoblastic leukemia. PMID- 21317480 TI - Aggressive natural cell leukemia in an infant with bilateral testicular mass. PMID- 21317481 TI - Statistical analysis of target motion in gated lung stereotactic body radiation therapy. AB - An external surrogate-based respiratory gating technique is a useful method to reduce target margins for the treatment of a moving lung tumor. The success of this technique relies on a good correlation between the motion of the external markers and the internal tumor as well as the repeatability of the respiratory motion. In gated lung stereotactic body radiation therapy (SBRT), the treatment time for each fraction could exceed 30 min due to large fractional dose. Tumor motion may experience pattern changes such as baseline shift during such extended treatment time. The purpose of this study is to analyze tumor motion traces in actual treatment situations and to evaluate the effect of the target baseline shift in gated lung SBRT treatment. Real-time motion data for both the external markers and tumors from 51 lung SBRT treatments with Cyberknife Synchrony technology were analyzed in this study. The treatment time is typically greater than 30 min. The baseline shift was calculated with a rolling average window equivalent to ~20 s and subtracted from that at the beginning. The magnitude of the baseline shift and its relationship with treatment time were investigated. Phase gating simulation was retrospectively performed on 12 carefully selected treatments with respiratory amplitude larger than 5 mm and regular phases. A customized gating window was defined for each individual treatment. It was found that the baseline shifts are specific to each patient and each fraction. Statistical analysis revealed that more than 69% treatments exhibited increased baseline shifts with the lapse of treatment time. The magnitude of the baseline shift could reach 5.3 mm during a 30 min treatment. Gating simulation showed that tumor excursion was caused mainly by the uncertainties in phase gating simulation and baseline shift, the latter being the primary factor. With a 5 mm gating window, 2 out of 12 treatments in the study group showed significant tumor excursion. Baseline shifts alone could cause up to 20% of tumor excursion outside the gating window. It is concluded that baseline shifts may increase with the treatment time and are more likely to act as a time-dependent systematic error. For phase-based gated lung SBRT, a baseline shift may be one of the major sources of targeting error during treatment. PMID- 21317482 TI - Interpolation of vector fields from human cardiac DT-MRI. AB - There has recently been increased interest in developing tensor data processing methods for the new medical imaging modality referred to as diffusion tensor magnetic resonance imaging (DT-MRI). This paper proposes a method for interpolating the primary vector fields from human cardiac DT-MRI, with the particularity of achieving interpolation and denoising simultaneously. The method consists of localizing the noise-corrupted vectors using the local statistical properties of vector fields, removing the noise-corrupted vectors and reconstructing them by using the thin plate spline (TPS) model, and finally applying global TPS interpolation to increase the resolution in the spatial domain. Experiments on 17 human hearts show that the proposed method allows us to obtain higher resolution while reducing noise, preserving details and improving direction coherence (DC) of vector fields as well as fiber tracking. Moreover, the proposed method perfectly reconstructs azimuth and elevation angle maps. PMID- 21317483 TI - Iterative deconvolution of simultaneous 99mTc and 201Tl projection data measured on a CdZnTe-based cardiac SPECT scanner. AB - We present a method of correcting self-scatter and crosstalk effects in simultaneous technetium-99m/thallium-201 stress/rest myocardial perfusion (single photon emission computed tomography) SPECT scans. The method, which is in essence a hybrid between the triple energy window method and scatter modelling, is based on a model of spatial and spectral distribution of projection counts in several selected energy windows. The parameters of the model are determined from measurements of thin rod sources in air when no in-object scatter or attenuation effects are present. The model equations are solved using the iterative maximum likelihood expectation maximization algorithm in the projection space to find estimates of the primary photopeak counts of both radionuclides. The method has been developed particularly for a novel dedicated cardiac camera based on CdZnTe pixellated detectors, although it can also be adapted to a conventional scintillator camera. The method has been validated in anthropomorphic phantom experiments. Significant improvement in defect contrast has been observed with only moderate increase in image noise. The application of the method to patient data is illustrated. PMID- 21317484 TI - GPU-based fast gamma index calculation. AB - The gamma-index dose comparison tool has been widely used to compare dose distributions in cancer radiotherapy. The accurate calculation of gamma-index requires an exhaustive search of the closest Euclidean distance in the high resolution dose-distance space. This is a computational intensive task when dealing with 3D dose distributions. In this work, we combine a geometric method (Ju et al 2008 Med. Phys. 35 879-87) with a radial pre-sorting technique (Wendling et al 2007 Med. Phys. 34 1647-54) and implement them on computer graphics processing units (GPUs). The developed GPU-based gamma-index computational tool is evaluated on eight pairs of IMRT dose distributions. The gamma-index calculations can be finished within a few seconds for all 3D testing cases on one single NVIDIA Tesla C1060 card, achieving 45-75* speedup compared to CPU computations conducted on an Intel Xeon 2.27 GHz processor. We further investigated the effect of various factors on both CPU and GPU computation time. The strategy of pre-sorting voxels based on their dose difference values speeds up the GPU calculation by about 2.7-5.5 times. For n-dimensional dose distributions, gamma-index calculation time on CPU is proportional to the summation of gamma(n) over all voxels, while that on GPU is affected by gamma(n) distributions and is approximately proportional to the gamma(n) summation over all voxels. We found that increasing the resolution of dose distributions leads to a quadratic increase of computation time on CPU, while less-than-quadratic increase on GPU. The values of dose difference and distance-to-agreement criteria also have an impact on gamma-index calculation time. PMID- 21317485 TI - Enabling measurements of low-conductance single molecules using gold nanoelectrodes. AB - A high resistance nanogap platform was used to trap and electrically characterize 30 nm thiolated double-stranded DNA molecules. High resolution scanning electron microscopy was also used to image the trapped DNA strands. It was found that the surface state of the electrodes and underlying substrate could influence the measurements of trapped molecules when the measured resistances were on the order of TOmega or greater. Hydrophilic surfaces gave rise to larger leakage currents that could potentially mask the underlying signals from molecules positioned in the nanogap. Finally, the careful handling of the samples and control of the environment is essential to avoid surface charging of the oxide substrate layer as these parasitic charges affect electrical measurements of the nanogap. The presented results thus outline some important considerations when making low conductance measurements on molecules and should prove useful for the characterization of molecules in molecular electronics or sensors employing nanogap platforms. PMID- 21317486 TI - Giant room temperature electric-field-assisted magnetoresistance in La0.7Sr0.3MnO3/n-Si nanotip heterojunctions. AB - An on-chip approach for fabricating ferromagnetic/semiconductor-nanotip heterojunctions is demonstrated. The high-density array of Si nanotips (SiNTs) is employed as a template for depositing La(0.7)Sr(0.3)MnO(3) (LSMO) rods with a pulsed-laser deposition method. Compared with the planar LSMO/Si thin film, the heterojunction shows a large enhancement of room temperature magnetoresistance (MR) ratio up to 20% under 0.5 T and a bias current of 20 uA. The MR ratio is found to be tunable, which increases with increasing external bias and the aspect ratios of the nanotips. Electric-field-induced metallization, in conjunction with nanotip geometry, is proposed to be the origin for the giant MR ratio. PMID- 21317487 TI - Nucleation and growth of monodispersed cobalt nanoclusters on graphene moire on Ru(0001). AB - Monodispersed Co nanoclusters have been grown on a graphene moire on Ru(0001) at room temperature. Scanning tunneling microscopy measurements showed that the Co clusters nucleate at both the fcc and hcp regions. Co forms finely dispersed small three-dimensional (3D) clusters on graphene/Ru(0001), and a defined long range ordering of Co nanoclusters with increasing coverage is not observed. The size distribution of the clusters is narrow and the size of the clusters is tunable. The absorbed Co begins to intercalate between the graphene layer and the Ru(0001) substrate when annealing the sample at temperatures up to about 473 K. PMID- 21317488 TI - Influencing factors on the size uniformity of self-assembled SiGe quantum rings grown by molecular beam epitaxy. AB - The size uniformity of self-assembled SiGe quantum rings, which are formed by capping SiGe quantum dots with a thin Si layer, is found to be greatly influenced by the growth temperature and the areal density of SiGe quantum dots. Higher growth temperature benefits the size uniformity of quantum dots, but results in low Ge concentration as well as asymmetric Ge distribution in the dots, which induces the subsequently formed quantum rings to be asymmetric in shape or even broken somewhere in the ridge of rings. Low growth temperature degrades the size uniformity of quantum dots, and thus that of quantum rings. A high areal density results in the expansion and coalescence of neighboring quantum dots to form a chain, rather than quantum rings. Uniform quantum rings with a size dispersion of 4.6% and an areal density of 7.8*10(8) cm(-2) are obtained at the optimized growth temperature of 640 degrees C. PMID- 21317489 TI - The effect of annealing and photoactivation on the optical transitions of band band and surface trap states of colloidal quantum dots in PMMA. AB - For optoelectronic applications, colloidal CdSe quantum dots (QDs) have been integrated into solid devices by using optically transparent polymer matrices that embedded the colloidal QDs. We systematically studied the effect of annealing and photoactivation on the band-band (BB) and surface trap state (STS) transitions of colloidal CdSe QDs embedded in polymethylmethacrylate (QDs-PMMA). The QDs-PMMA composites demonstrate enhancement of the STS emissions while their annealing leads to an intensity quench of both BB and STS emissions. The annealing process also causes the red shift of the BB emission. By contrast, photoactivation of QDs-PMMA composites results in the remarkable recovery of luminescence intensity accompanied by blue shift of the emissions. Furthermore, it is found in the photoactivation process that the STS emission can be saturated earlier than the BB emission, which renders it possible to tune the light color of the emissions. The combination of annealing and photoactivation could undoubtedly provide an effective way to precisely tune the colors of light emitting devices that use colloidal CdSe QDs. PMID- 21317490 TI - Improvement of toughness and electrical properties of epoxy composites with carbon nanotubes prepared by industrially relevant processes. AB - The addition of carbon nanotubes (CNTs) to polymeric matrices or master batches has the potential to provide composites with novel properties. However, composites with a uniform dispersion of CNTs have proved to be difficult to manufacture, especially at an industrial scale. This paper reports on processing methods that overcome problems related to the control and reproducibility of dispersions. By using a high pressure homogenizer and a three-roll calendaring mill in combination, CNT reinforced epoxies were fabricated by mould casting with a well dispersed nanofiller content from 0.1 to 2 wt%. The influence of the nano carbon reinforcements on toughness and electrical properties of the CNT/epoxies was studied. A substantial increase of all mechanical properties already appeared at the lowest CNT content of 0.1 wt%, but further raising the nanofiller concentration only led to moderate further changes. The most significant enhancement was obtained for fracture toughness, reaching up to 82%. The low percolation thresholds were confirmed by electrical conductivity measurements on the same composites yielding a threshold value of only about 0.01 wt%. As corroborated by a thorough microscopic analysis of the composites, mechanical and electrical enhancement points to the formation of an interconnected network of agglomerated CNTs. PMID- 21317491 TI - Synthesis, characterization and capacitive performance of hydrous manganese dioxide nanostructures. AB - Hydrous manganese dioxide nanostructures were synthesized via a catalytic oxidation reaction mechanism at mild temperatures. It was found that the morphology of the manganese dioxide nanostructures was significantly influenced by the pH of the reaction system. With increasing pH the morphology of manganese dioxide nanostructures changed from urchin-like structures to nanobelts. The capacitive performance was investigated by using cycle voltammetry and galvanostatic charge/discharge techniques. Hydrous manganese dioxide nanostructures obtained from a basic solution exhibited a capacitance of 262 F g( 1) at a current density of 250 mA g(-1) and a capacitive retention of 75% after 1200 cycles, suggesting that this is a promising electrode material for supercapacitors. The high specific capacitance is attributed to the hydrous nature coupled with a high surface area (181 m(2) g(-1)) of the manganese dioxide nanostructure. PMID- 21317492 TI - A novel fabrication method of silicon nano-needles using MEMS TMAH etching techniques. AB - Nano-needles play important roles in nanoscale operations. However, current nano needle fabrication is usually expensive and controling the sizes and angles is complicated. We have developed a simple and low cost silicon nano-needle fabrication method using traditional microelectromechanical system (MEMS) tetramethyl ammonium hydroxide (TMAH) etching techniques. We take advantage of the fact that the decrease of the silicon etch rate in TMAH solutions exhibits an inverse fourth power dependence on the boron doping concentration in our nano needle fabrication. Silicon nano-needles, with high aspect ratio and sharp angles theta as small as 2.9 degrees , are obtained, which could be used for bio-sensors and nano-handling procedures, such as penetrating living cells. An analytic model is proposed to explain the etching evolution of the experimental results, which is used to predict the needle angle, length, and etching time. Based on our method, nano-needles with small acute angle theta can be obtained. PMID- 21317493 TI - Controllable positioning and alignment of silver nanowires by tunable hydrodynamic focusing. AB - Assembly and alignment of nanowires or nanotubes are critical steps for integrating functional nanodevices by the bottom-up strategy. However, it is still challenging to manipulate either an array of nanowires or individual nanowires in a controllable manner. Here we present a simple but versatile method of positioning and aligning nanowires by hydrodynamic focusing that functions as 'hydro-tweezers'. By adjusting the flow duration and flow rates of the sheath flows and sample flow, the density, width and position of the nanowire arrays, as building blocks of nanodevices, can be readily tuned in the hydrodynamic focusing process. This approach exhibits great potentials in the assembly of an array of functional nanodevices. With this method, multiple nanowire arrays can be positioned and aligned on predefined locations. Further focusing the sample flow, nanowires flow in single file. Thus single nanowires can also be lined up and located to desired positions. PMID- 21317494 TI - Visibility of dichalcogenide nanolayers. AB - Dichalcogenides with the common formula MX(2) are layered materials with electrical properties that range from semiconducting to superconducting. Here, we describe optimal imaging conditions for the optical detection of ultrathin, two dimensional dichalcogenide nanocrystals containing single, double and triple layers of MoS(2), WSe(2) and NbSe(2). A simple optical model is used to calculate the contrast for nanolayers deposited on wafers with varying thicknesses of SiO(2). The model is extended for imaging using the green channel of a video camera. Using AFM and optical imaging we confirm that single layers of MoS(2) and WSe(2) can be detected on 90 and 270 nm SiO(2) using optical means. By measuring contrast under broadband green illumination we are also able to distinguish between nanostructures containing single, double and triple layers of MoS(2) and WSe(2.) We observe and discuss discrepancies in the case of NbSe(2). PMID- 21317495 TI - The effect of amine protonation on the electrical properties of spin-assembled single-walled carbon nanotube networks. AB - Amine-terminated self-assembled monolayers (SAMs) have been shown to selectively adsorb semiconducting single-walled carbon nanotubes (sc-SWNTs). Previous studies have shown that when deposited by spin coating, the resulting nanotube networks (SWNTnts) can be strongly influenced by the charge state of the amine (primary, secondary, and tertiary). When the amine surfaces were exposed to varying pH solutions, the conductivity and overall quality of the resulting fabricated networks were altered. Atomic force microscopy (AFM) topography had shown that the density of the SWNTnts was reduced as the amine protonation decreased, indicating that the electrostatic attraction between the SWNTs in solution and the surface influenced the adsorption. Simultaneously, MU-Raman analysis had suggested that when exposed to more basic conditions, the resulting networks were enhanced with sc-SWNTs. To directly confirm this enhancement, Ti/Pd contacts were deposited and devices were tested in air. Key device characteristics were found to match the enhancement trends previously observed by spectroscopy. For the primary and secondary amines, on/off current ratios were commensurate with the Raman trends in metallic contribution, while no trends were observed on the tertiary amine (due to weaker interactions). Finally, differing SWNT solution volumes were used to compensate for adsorption differences and yielded identical SWNTnt densities on the various pH-treated samples to eliminate the influence of network density. These results further the understanding of the amine-SWNT interaction during the spin coating process. Overall, we provide a convenient route to provide SWNT-based TFTs with highly tunable electronic charge transport through better understanding of the influence of these specific interactions. PMID- 21317496 TI - Synthesis of single-crystal PbS nanorods via a simple hydrothermal process using PEO-PPO-PEO triblock copolymer as a structure-directing agent. AB - Single-crystal PbS nanorods were successfully synthesized through a simple hydrothermal route using PEO-PPO-PEO triblock copolymer (P123) as a structure directing agent. The XRD pattern indicates that the crystal structure of the nanorods is face-centre-cubic rocksalt. A SEM image shows that the nanorods have a diameter of 40-70 nm and a length of 200-600 nm, and both tips exhibit taper like structures. HRTEM and SAED images reveal the single-crystalline nature of the nanorods with the growth along the (111) direction. The experimental results indicated that the P123 concentration and reaction temperature played important roles in controlling the morphology of the PbS nanostructures. The optical property of PbS nanorods was investigated by UV-Vis absorption spectroscopy and the band structure was calculated by the B3LYP hybrid density functional theory. PMID- 21317497 TI - Light absorption mechanism in single c-Si (core)/a-Si (shell) coaxial nanowires. AB - We have carried out detailed investigations on the light absorption mechanism in single crystalline silicon (c-Si) (core)/amorphous Si (a-Si) (shell) coaxial nanowires (NWs). Based on the Lorenz-Mie light scattering theory, we have found that the light absorption in the coaxial NWs relies on the leaky mode resonances and that the light absorption can be optimized towards photovoltaic applications when the a-Si shell thickness is about twice the c-Si core radius. The photocurrent has been found to be enhanced up to ~ 560% compared to c-Si NWs, and to be further enhanced up to ~ 60% by coating the nonabsorbing dielectric shells. PMID- 21317498 TI - Organic vapor discrimination with chemiresistor arrays of temperature modulated tin-oxide nanowires and thiolate-monolayer-protected gold nanoparticles. AB - This paper explores the discrimination of organic vapors with arrays of chemiresistors (CRs) employing interface layers of tin-oxide nanowires (NWs) and thiolate-monolayer-protected gold nanoparticles (MPNs). The former devices use contact-printed mats of NWs on micro-hotplate membranes to bridge a pair of metal electrodes. Oxidation at the NW surface causes changes in charge transport, the temperature dependence of which differs among different vapors, permitting vapor discrimination. The latter devices use solvent cast films of MPNs on interdigital electrodes operated at room temperature. Sorption into the organic monolayers causes changes in film tunneling resistance that differ among different vapors and MPN structures, permitting vapor discrimination. Here, we compare the performance and assess the 'complementarity' of these two types of sensors. Calibrated responses from an NW CR operated at two different temperatures and from a set of four different MPN CRs were generated for three test vapors: n hexane, toluene, and nitromethane. This pooled data set was then analyzed using principal components regression classification models with varying degrees of random error superimposed on the responses via Monte Carlo simulation in order to estimate the rates of recognition/discrimination for arrays comprising different combinations of sensors. Results indicate that the diversity of most of the dual MPN-CR arrays exceeds that of the dual NW-CR array. Additionally, in assessing all possible arrays of 4-6 CR sensors, the recognition rates of the hybrid arrays (i.e. MPN + NW) were no better than that of the 4-sensor array containing only MPN CRs. PMID- 21317499 TI - Microwave reflection measurement of critical currents in a nanotube Josephson transistor with a resistive environment. AB - A scheme for measuring small intrinsic critical currents I(c) in nanoscale devices is described. Changes in Josephson inductance L(J) are converted to frequency variations that are recorded via microwave reflection measurements at 700-800 MHz. The critical current is determined from the frequency shift of the reflection magnitude at zero phase bias assuming a sinusoidal current-phase relation. The method is used to study a multiwalled carbon nanotube transistor with Pd/Nb contacts inside a resistive on-chip environment. We observe gate tunable critical currents up to I(c) ~ 8 nA corresponding to L(J) > 40 nH. The method presented is also applicable to devices shunted by closed superconducting loops. PMID- 21317500 TI - Properties of uniform diameter InN nanowires obtained under Si doping. AB - High quality, well-separated, homogeneous sizes and high aspect ratio Si-doped InN nanowires (NWs) were grown by catalyst-free molecular beam epitaxy (MBE) after optimization of the growth conditions. To this end, statistical analysis of NW density and size distribution was performed. The high crystal quality and smooth NW surfaces were observed by high resolution transmission electron microscopy. Spectral photoluminescence has shown the increase of the band filling effect with Si flux, indicating successful n-type doping. A Raman LO scattering mode appears with a pronounced low energy tail, also reported for highly doped InN films. PMID- 21317501 TI - A note from the editor. Black History Month, 2011. PMID- 21317502 TI - Street medicine: an example of reality-based health care. PMID- 21317503 TI - Publication of recruitment methods in focus group research of minority populations with chronic disease: a systematic review. AB - The relative effectiveness of strategies to recruit minority patients, populations traditionally difficult to engage in research, for focus groups is unclear. We conducted a systematic review of all peer-reviewed focus group studies targeting Black and/or Hispanic participants with diabetes, hypertension, asthma, and/or cardiovascular disease reported in Pubmed, MEDLINE, and CINAHL from January 1993 through August 2009. Reviewers extracted data on each study's characteristics, methods, and outcomes. Forty-five studies were eligible. While most described recruitment strategies, only 21 presented any metric of their success in recruiting participants. Among studies with high recruitment success rates, no discernable trends regarding effectiveness of recruitment strategies were found, largely due to variation in reporting of the use of incentives and follow-up mechanisms. Increased rigor is necessary for describing methodology of focus group research in the literature. It is incumbent upon researchers to ensure clear and detailed methodology in qualitative articles. PMID- 21317504 TI - What is the evidence for pharmaceutical patient assistance programs? A systematic review. AB - Pharmaceutical patient assistance programs (PAPs) have the potential to improve prescription drug accessibility for eligible patients, but currently there is limited information regarding their effectiveness. In an attempt to provide a systematic description of primary studies on PAPs, we reviewed 33 unique studies from commercial and grey literature (e.g., government publications, conference abstracts) sources: 15 health care outcome evaluations, seven economic evaluations, seven surveys and four miscellaneous studies. Enrollment assistance for PAPs with additional medication services (e.g., counseling) was significantly associated with improved glycemic (standardized mean difference=-0.40, 95% CI= 0.59,-0.20; k=3 one-group, pre-post-test; 1 comparison-group) and lipid (standardized mean difference=-0.52, 95% CI=0.78,-0.27; k=3 one-group, pre-post test; 1 comparison group) control. Inadequately designed economic evaluations suggest free PAP medications offset health care institutions' costs for uncompensated medications and enrollment assistance programs. More rigorous research is needed to establish the clinical and cost-effectiveness of PAPs from a patient and health care institution perspective. PMID- 21317505 TI - Faith-based organizations, science, and the pursuit of health. AB - Over the last three decades, there has been increasing interest in the role that faith-based organizations (FBOs) can play in promoting health and health care access among underserved populations. Although the research literature on church based health interventions is growing, there are relatively few rigorous evaluations of their effectiveness in addressing health and health care outcomes. Establishing a national faith-based health research network is an excellent opportunity to create an evaluative infrastructure and generate new research on health programs and their effectiveness in FBO settings. PMID- 21317506 TI - Altruism in dental students. AB - Altruistic dentists play a central role in treating minority populations, the poor, the uninsured, and those living in underserved communities. This study examines factors associated with graduating dental students' altruistic attitudes. We use a nationally representative dataset, the 2007 American Dental Education Association Survey of Dental School Seniors (n=3,841), and a comprehensive framework to investigate individual, school, and community characteristics that may influence altruism. Student characteristics were the most significant predictors: women, African Americans, Hispanics, Asian/Pacific Islanders, and students with low socioeconomic status expressed greater altruism than their counterparts. These results inform dental educators and administrators to expand efforts to recruit underrepresented racial/ethnic and low-income students into dentistry. Additionally, we found that students with altruistic personalities attend schools where the social context is more accepting and respectful of diversity. This suggests that schools can promote altruism in their students by creating a positive culture and environment for diverse populations. PMID- 21317507 TI - Family formation in the inner city: low-income men's perception of their role in unplanned conception and pregnancy prevention. AB - PURPOSE: Research documents the importance of partners in women's contraception use, pregnancy prevention/planning, and decision-making around unintended pregnancy. Little is known of men's perceptions of this crucial role. METHODS: Semi-structured, in-depth interviews (n=20) with low-income, inner-city men, aged 18-45 years, who had brought about a pregnancy. RESULTS: Responsibility framed men's understanding of their reproductive and parenting roles. Uniformly, men equated being responsible with providing financially for their families. Interpretations of being responsible evolved over men's reproductive lifetimes, influencing their perceived role in planning or preventing pregnancy, and consideration of abortion for unplanned pregnancies. The desire to take responsibility for children they fathered was limited by the structural realities of these men's lives, which were often characterized by poverty, unemployment, violence, and crime. CONCLUSIONS: Though financial responsibility is highly valued, poverty and related social factors are significant barriers to men's ability to achieve this goal. Discussions with men about family planning should reflect these realities. PMID- 21317508 TI - Eliminating disparities in cancer screening and follow-up of abnormal results: what will it take? AB - Health and health care disparities related to cancer are a major public health problem in the United States. Providing care that is truly patient-centered could address disparities in cancer screening and follow-up through better alignment between patient needs and health care resources available to address those needs. Key health care reforms offer promise for doing so. PMID- 21317509 TI - Ethnic and gender disparities in needed adolescent mental health care. AB - Psychological problems are overlooked and undertreated in adolescents, especially in low-income and ethnically-diverse youth. School-based health centers are one way to increase health care utilization, and may be particularly important for accessing hard-to-reach populations. The present study examines adolescents' psychological health and their experiences with receiving needed mental health care. Participants included 1,695 African-American (31%), Hispanic (38%), and White (31%) high-school students in southeast Texas. All students were from the same high school and all had access to a school-based mental health clinic. Twenty six percent of the sample had symptoms indicative of major depression, and 18% had scores consistent with subthreshold depression. Across all ethnicities, the prevalence of depressive symptoms was highest among females. Depressed White students were more likely than depressed minority youth to report having received a prior diagnosis of depression and to have been treated for depression. Thus, ethnic disparities in obtaining needed mental health care may persist even in settings where access to equivalent care is readily available. PMID- 21317510 TI - Racial/ethnic heterogeneity in the socioeconomic patterning of CVD risk factors: in the United States: the multi-ethnic study of atherosclerosis. AB - Many studies document racial variation, gender differences, and socioeconomic status (SES) patterning in cardiovascular disease (CVD) risk factors but few studies have investigated heterogeneity in SES differences by race/ethnicity or gender. Using data from the Multi-Ethnic Study of Atherosclerosis (N=6,814) and stratified regression models, we investigated race/ethnic differences in the SES patterning of diabetes, hypertension, smoking, and body mass index (BMI). Inverse socioeconomic gradients in hypertension, diabetes, smoking, and BMI were observed in White and Black women but associations were weaker or absent in Hispanic and Chinese women (except in the case of diabetes for Hispanic women). Even greater heterogeneity in social patterning of risk factors was observed in men. In White men all four risk factors were inversely associated with socioeconomic position, although often associations were only present or were stronger for education than for income. The inverse socioeconomic patterning was much less consistent in men of other races/ethnic groups, and higher SES was associated with higher BMI in non-White men. These findings have implications for understanding the causes of social patterning, for the analysis of SES adjusted race/ethnic differences, and for the targeting of interventions. PMID- 21317511 TI - Race and ethnicity are associated with delays in breast cancer treatment (2003 2006). AB - Access to timely treatment may be one contributing factor to survival differences by race/ethnicity among breast cancer patients. In this study, we examined the relationship between race and treatment delay among breast cancer patients diagnosed between 2003 and 2006 with Stage I-III breast cancer from the National Cancer Database (n=250,007). We evaluated factors associated with receipt of initial treatment more than 30, 60, and 90 days after biopsy using multivariable log binomial models to estimate risk ratios (RR) and 95% confidence intervals (CI). The average time to treatment was 34.30 days (+/-31.77). Independent of health insurance, stage at diagnosis, and age, Black and Hispanic patients had higher risks of 30, 60, and 90-day treatment delay compared with White patients. Further studies are needed to define the role of structural, health system, physician, clinical and patient factors in treatment delay among Black and Hispanic women and appropriate interventions. PMID- 21317512 TI - Ethnicity, nativity, and the health of American Blacks. AB - There have been few empirical studies of ethnic differences in health within the American Black population. Logistic regressions were used to examine the relationships among ethnicity, nativity, depressive symptoms, and physical health in the two largest ethnic groups of American Blacks, African Americans and Caribbean Blacks. The data were from the National Survey of American Life, a national household survey representative of the non-institutionalized U.S. Black population. We found that African Americans, U.S.-born Caribbean Blacks, and Caribbean-born Blacks had significantly different self-ratings of their health and self-reports of being diagnosed with a chronic physical health condition: Caribbean-born Blacks had the best health outcomes and U.S.-born Caribbean Blacks had the worst. This finding remained significant even after considering self reported depressive symptoms. This study highlights the importance of considering ethnic diversity, nativity and immigration as independent sources of variation in health status within the American Black population. PMID- 21317513 TI - Determinants of usual source of care disparities among African American and Caribbean Black men: findings from the National Survey of American Life. AB - PURPOSE: The Aday-Andersen model was used as a framework for investigating the contribution of immigration status (i.e., nativity and acculturation), socioeconomic factors, health care access, health status, and health insurance to usual source of health care (USOC) in a nationally representative sample of African American (n=551) and Caribbean Black men (n=1,217). METHODS: We used the 2001-2003 National Survey of American Life, a nationally representative household survey of non-institutionalized U.S. Blacks to conduct descriptive and logistic regression analyses. RESULTS: Older age, more health conditions, neighborhood medical clinic access, and health insurance were associated with higher odds of reporting a USOC. Odds were lower for men with lower-middle incomes and poorer mental health status. Having health insurance was associated with higher odds of reporting a USOC for African American men but lower odds among Caribbean Black men. Odds were higher in the presence of more health conditions for African American men than for Caribbean Black men. CONCLUSIONS: Health care reform policies aimed solely at increasing health insurance may not uniformly eliminate USOC disparities disfavoring U.S. and foreign-born non-Hispanic Black men. PMID- 21317514 TI - Predictors of cervical cancer screening for rarely or never screened rural Appalachian women. AB - BACKGROUND AND PURPOSE: Women who have not had a Papanicolaou test in five years or more have increased risk of developing invasive cervical cancer. This study compares Appalachian women whose last screening was more than one year ago but less than five years ago with those not screened for the previous five years or more. METHODS: Using PRECEDE/PROCEED as a guide, factors related to obtaining Pap tests were examined using cross-sectional data from 345 Appalachian Kentucky women. Bivariate and multivariate analyses were conducted to identify predictors of screening. RESULTS: Thirty-four percent of participants were rarely- or never screened. In multiple logistic regression analyses, several factors increased those odds, including belief that cervical cancer has symptoms, and not having a regular source of medical care. CONCLUSION: The findings from this study may lead to the development of effective intervention and policies that increase cervical cancer screening in this population. PMID- 21317515 TI - Maternal smoking in Chicago: a community-level analysis. AB - Birth certificate data were employed to determine the prevalence of maternal smoking in Chicago communities by race and ethnicity. For purposes of comparison, we present data for the U.S. and the city of Chicago as a whole. Across the city of Chicago, 5.6% of women smoked during pregnancy, a rate much lower than the national average of 13.9%. The maternal smoking rate among non-Hispanic (NH) Black women (11.8%) was more than twice that of NH White women (4.5%) and almost 10 times that of Hispanic women (1.2%). For predominantly NH White and NH Black communities, we observed a significant, negative relationship between household income and the percentage of women who smoke during pregnancy. The prevalence of smoking among NH Black women in Chicago was particularly high, demonstrating an unmet need for appropriate interventions. PMID- 21317517 TI - Successful reorganization of an interdisciplinary underserved practice. AB - Caring for underserved patients presents great challenges for community practices. This report discusses an interdisciplinary underserved practice that was reorganized in 2008 allowing for practice improvement and greater community presence. Current practice structure is discussed and a model provided that can enhance productivity, revenue, and community outreach. PMID- 21317516 TI - Correlates of patient-reported racial/ethnic health care discrimination in the Diabetes Study of Northern California (DISTANCE). AB - OBJECTIVES: We examined possible determinants of self-reported health care discrimination. METHODS: We examined survey data from the Diabetes Study of Northern California (DISTANCE), a race-stratified sample of Kaiser diabetes patients. Respondents reported perceived discrimination, and regression models examined socioeconomic, acculturative, and psychosocial correlates. RESULTS: Subjects (n=17,795) included 20% Blacks, 23% Latinos, 13% East Asians, 11% Filipinos, and 27% Whites. Three percent and 20% reported health care and general discrimination. Health care discrimination was more frequently reported by minorities (ORs ranging from 2.0 to 2.9 compared with Whites) and those with poorer health literacy (OR=1.10, 95% CI: 1.04-1.16), limited English proficiency (OR=1.91, 95% CI: 1.32-2.78), and depression (OR=1.53, 95% CI: 1.10-2.13). CONCLUSIONS: In addition to race/ethnicity, health literacy and English proficiency may be bases of discrimination. Evaluation is needed to determine whether patients are treated differently or more apt to perceive discrimination, and whether depression fosters and/or follows perceived discrimination. PMID- 21317518 TI - An opt-out influenza vaccination policy improves immunization rates in primary care. AB - PURPOSE/OBJECTIVE: During the 2007-08 influenza season 36% of outpatients seen at our urban family medicine center received an influenza immunization. We explored the expected increase in vaccinations from an opt-out policy using standing orders in a lower-income population. METHODS: A comparison of vaccination rates during the periods 10/1/2007 to 3/31/2008 (P1) versus 10/1/2008 to 3/31/2009 (P2) with adjustments for cohort non-independence. RESULTS: The overall P2 vaccination rate increased to 49% [p<.000001]. P2 rates were significantly higher for those with diabetes, both genders, African American and European American patients from 3 to 64 years old, and in all insurance groups. The vaccination rates for patients with Medicaid insurance (37% and 54%) were higher than the rates for patients with commercial insurance (31% and 43%). CONCLUSIONS: The opt-out policy is associated with a moderate (1.4 fold) increase in the vaccination rate. Primary care resource constraints may limit further improvement. PMID- 21317519 TI - A survey of Indian Health Service and tribal health providers' colorectal cancer screening knowledge, perceptions, and practices. AB - BACKGROUND: Provider recommendation is critical for colorectal cancer (CRC) screening participation, yet few data exist on practices of providers serving American Indians and Alaska Natives. We examined Indian Health Service (IHS) and tribal provider practices, beliefs about screening efficacy, and perceptions of barriers. METHODS: We developed a Web-based questionnaire and recruited respondents via electronic distribution lists. We generated descriptive statistics by region, provider type, and workplace setting. RESULTS: Most respondents (77%) recommend starting CRC screening of average-risk patients at age 50; however, 22% recommend flexible sigmoidoscopy and 43% colonoscopy at intervals inconsistent with national guidelines. Of those recommending fecal occult blood test (FOBT), 23% use a single, in-office FOBT card as their only FOBT method. Respondents reported barriers to screening to include underutilized reminder systems and inadequate resources. CONCLUSIONS: Indian Health Service/tribal providers are knowledgeable about when to begin CRC screening; however, education about the appropriate use and frequency of CRC tests is needed. PMID- 21317520 TI - Roles of community helpers in using the Medicare Part D benefit. AB - OBJECTIVES: To examine the experiences of low-income Part D beneficiaries with mental illness and their use of community helpers to access prescription medicines. METHODS: Individual semi-structured interviews were conducted with 26 Medicare beneficiaries with mental illness in community settings. The transcripts were analyzed for content related to community help-seeking and attitudes toward family and professional helpers. RESULTS: Medicare Part D beneficiaries with mental illness used the assistance of community helpers extensively. Pharmacists, nurses, community mental health case managers, and family members assisted beneficiaries with understanding their benefit plans and interpreting paperwork from plans and government agencies. Community helpers also assisted with tasks related to medication adherence. Mental health consumers appreciated the help that they received from family members and professionals. CONCLUSION: This group of Medicare beneficiaries would have experienced difficulty in using their benefits and obtaining their medication without considerable help from professionals and family members. PMID- 21317521 TI - Self-management among patients living with diabetes in the United States Virgin Islands. AB - The United States Virgin Islands (USVI) is facing a diabetes epidemic similar to the one on the U.S. mainland, yet little is known regarding the cultural context relevant to self-management in this U.S. territory. We conducted in-home interviews (n=53) supplemented by self-administered questionnaire and A1c testing with U.S. Virgin Islanders to characterize self-management knowledge, attitudes, and behaviors among patients living with diabetes. The mean glycosylated hemoglobin (A1c) was 7.63 (Range=5-13); a composite score of traditional self management behaviors was not associated with A1c. Several recurrent themes emerged from qualitative analysis including: 1) cultural nuances shaped perspectives on self-management, 2) culturally-specific challenges were barriers to effective self-management, 3) medical homes were rarely viewed as the primary source of education and support, and 4) fear largely motivated or stalled self management practices. This study highlights the need for culturally-tailored measures and interventions to address the specific needs within this population. PMID- 21317522 TI - Adaptation of the FLU-FOBT Program for a primary care clinic serving a low-income Chinese American community: new evidence of effectiveness. AB - INTRODUCTION: We sought to adapt and evaluate the FLU-FOBT Program for a primary care clinic serving a low-income Chinese American community. METHODS: We compared colorectal cancer screening (CRCS) rate changes for patients who received flu shots versus those who did not receive flu shots during the FLU-FOBT Program. Analysis of data from the year prior to the intervention was used to validate the results. RESULTS: Rates of CRCS increased by 18.0 percentage points for flu shot recipients during the FLU-FOBT Program vs. 1.7 percentage points for flu shot non recipients (p<.001 for change difference). In the year prior to the FLU-FOBT Program, flu shot recipients had only a 3.3 percentage point increase in the CRCS rate vs. a 1.9 percentage point decline for flu shot non-recipients (p=.08 for change difference). CONCLUSIONS: The FLU-FOBT Program as adapted was effective at increasing CRCS rates for primary care patients in this low-income Chinese American community. PMID- 21317523 TI - Trends in the use of complementary and alternative medicine in the United States: 2002-2007. AB - In this study we seek to assess recent trends in complementary and alternative medicine (CAM) use based on a comparative analysis of data from the 2002 and 2007 National Health Interview Survey (NHIS). The findings suggest that CAM use, in particular the use of provider-based CAM therapies such as chiropractic care, massage, and acupuncture, have grown significantly in the U.S. This growth was more pronounced among non-Hispanic Whites than among racial and ethnic minorities, increasing an already existing White-minority gap in CAM use. Findings from this study also reveal that CAM use becomes more likely when access to conventional care has been restricted. In both 2002 and 2007, having unmet needs in medical care or having delayed care due to cost were associated with a higher chance of CAM use. PMID- 21317524 TI - Creating an effective and efficient publicly sponsored health care delivery system. AB - An effective and efficient publicly sponsored health care delivery system can increase access to care, improve health care outcomes, and reduce spending. A publicly sponsored health care delivery system can be created by integrating services that are already federally subsidized: community health centers (CHCs), public and safety-net hospitals, and residency training programs. The Patient Protection and Affordable Care Act includes measures that support primary care generally and CHCs in particular. A publicly sponsored health care delivery system combining primary care based in CHCs with safety-net hospitals and the specialists that serve them could also benefit from incentives in the Patient Protection and Affordable Care Act for the creation of accountable care organizations, and reimbursement based on quality and cost control. PMID- 21317525 TI - Cost of developmental delay from prenatal exposure to airborne polycyclic aromatic hydrocarbons. AB - Early life exposure to ambient polycyclic aromatic hydrocarbons (PAHs) can result in developmental delay. The negative health effects of PAHs have been well documented but the cost of developmental delay due to PAH exposure has not been studied. The Columbia Center for Children's Environmental Health previously has reported the significant effect of prenatal exposure to ambient PAHs on delayed mental development at three years, using the Bayley Scales in a cohort of low income women and children in New York City (NYC). Here we have used the cohort results to estimate the annual costs of preschool special education services for low-income NYC children with developmental delay due to PAH exposure using the Environmentally Attributable Fraction method. The estimated cost of PAH-exposure related services is over $13.7 million per year for Medicaid births in NYC. This high cost supports policies to reduce level of PAHs in NYC air. PMID- 21317526 TI - An expenditure analysis of high-cost Medicaid recipients with HIV disease in New York State. AB - A retrospective analysis was conducted of federal fiscal year (FFY) 2007 New York State Medicaid claims and expenditure data to examine variation in expenditures among New York State Medicaid recipients with HIV disease and the extent to which this variation could be attributed to the prevalence of comorbidities and other chronic conditions unrelated to HIV disease. Median expenditures per person for the period for a high-cost group (those for whom expenditures exceeded $100,000 for the period) were over $157,000, with 40% of total expenditures for this group for treatment unrelated to their HIV disease. The prevalence of comorbidities in the high-cost population is very high, the most common being substance abuse and mental illness. PMID- 21317527 TI - Contributions of public hospitals to regional health care: a population-based analysis of the county health care system serving metropolitan Chicago. AB - To determine the proportions of countywide expenditures and service delivery for the Cook County Health and Hospitals System (CCHHS), we obtained data from the CCHHS budget; CCHHS registration, program, and pharmacy databases; public health departments and organization reports; and federal agency estimates. The annual CCHHS budget of $1.2B represents 3.4% of total Cook County health care expenditures. Eight of the nine population-based proportions of health care services delivered by the CCHHS exceeded this proportion of health expenditures by factors of 1.3-8 times. These services include diagnosis of tuberculosis, sexually transmitted diseases, and cancers; care of very low birth weight babies; primary care for HIV and diabetes; and emergency room and ambulatory visits. This county health care system is a productive contributor to overall health service delivery in Cook County, and its contributions exceed its proportionate funding in eight of nine priority health areas. PMID- 21317528 TI - Who transitions from private to public health insurance?: Lessons from expansions of the State Children's Health Insurance Program. AB - This paper examines families of children who transition from private to public health insurance. These transitions include, but are not limited to, transitions that constitute crowd-out. We pool longitudinal panels from the Survey of Income and Program Participation (SIPP) covering 1990 to 2005. The annual rate of children who transition from private to public coverage more than doubled over this period, although it remains small. Transitioning children in recent years are typically in working families with median incomes of around 200% of poverty. Children who transition from private to public coverage are more likely to belong to minority groups, to have lower incomes, and to be in poorer health than children remaining privately insured. Public coverage now provides important protections for low-income working families, especially those with children in poor health. These findings underscore the need to implement post-health-reform policies with an eye towards possible adverse selection into public programs. PMID- 21317529 TI - Gender differences in financial hardships of medical debt. AB - Women are more likely than men to forgo, delay, and ration medical care because of medical debt. Using 2003-04 Community Tracking Study Household Survey data, this study examined gender differences in five financial hardships associated with medical debt. Regression analyses accounting for predisposing, enabling, and need factors of health services use indicated women were less likely to report being contacted by a collection agency (b=-0.15, p<.05), using savings (b=-0.23, p<.005), or having any financial hardships associated with medical debt (b=-0.24, p<.05). There were no significant gender differences in putting off major purchases, borrowing money, and problems paying for necessities. Similarly, there were positive and negative relationships between medical debt financial hardships and income, insurance, and health status. Findings suggest that making health care affordable and equitable is critically important for both men and women. Research is needed to understand the differential impact of medical debt, especially among disadvantaged populations. PMID- 21317530 TI - Re: Marks SL, Wegelin JA, Bourgeois, JA, Perkins J. Anxiety disorders in rural primary care: use of the MINI to estimate prevalence in clinic patients. J Health Care Poor Underserved. 2010 May;21(2):680-90. PMID- 21317531 TI - Single cell transcriptional profiling reveals heterogeneity of human induced pluripotent stem cells. AB - Human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) are promising candidate cell sources for regenerative medicine. However, despite the common ability of hiPSCs and hESCs to differentiate into all 3 germ layers, their functional equivalence at the single cell level remains to be demonstrated. Moreover, single cell heterogeneity amongst stem cell populations may underlie important cell fate decisions. Here, we used single cell analysis to resolve the gene expression profiles of 362 hiPSCs and hESCs for an array of 42 genes that characterize the pluripotent and differentiated states. Comparison between single hESCs and single hiPSCs revealed markedly more heterogeneity in gene expression levels in the hiPSCs, suggesting that hiPSCs occupy an alternate, less stable pluripotent state. hiPSCs also displayed slower growth kinetics and impaired directed differentiation as compared with hESCs. Our results suggest that caution should be exercised before assuming that hiPSCs occupy a pluripotent state equivalent to that of hESCs, particularly when producing differentiated cells for regenerative medicine aims. PMID- 21317532 TI - Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells. AB - Nicotinic acid (niacin) is a drug used to reduce the progression of atherosclerosis. Its antiatherosclerotic activity is believed to result from lipid-modifying effects, including its ability to decrease LDL cholesterol and increase HDL cholesterol levels in plasma. Here, we report that in a mouse model of atherosclerosis, we found that nicotinic acid inhibited disease progression under conditions that left total cholesterol and HDL cholesterol plasma levels unaffected. The antiatherosclerotic effect was not seen in mice lacking the receptor for nicotinic acid GPR109A. Surprisingly, transplantation of bone marrow from GPR109A-deficient mice into atherosclerosis-prone animals also abrogated the beneficial effect of nicotinic acid. We detected expression of GPR109A in macrophages in atherosclerotic plaques. In macrophages from WT mice, but not from GPR109A-deficient animals, nicotinic acid induced expression of the cholesterol transporter ABCG1 and promoted cholesterol efflux. Furthermore, activation of GPR109A by nicotinic acid inhibited MCP-1-induced recruitment of macrophages into the peritoneal cavity and impaired macrophage recruitment to atherosclerotic plaques. In contrast with current models, our data show that nicotinic acid can reduce the progression of atherosclerosis independently of its lipid-modifying effects through the activation of GPR109A on immune cells. We conclude therefore that GPR109A mediates antiinflammatory effects, which may be useful for treating atherosclerosis and other diseases. PMID- 21317533 TI - Lack of clinical AIDS in SIV-infected sooty mangabeys with significant CD4+ T cell loss is associated with double-negative T cells. AB - SIV infection of natural host species such as sooty mangabeys results in high viral replication without clinical signs of simian AIDS. Studying such infections is useful for identifying immunologic parameters that lead to AIDS in HIV infected patients. Here we have demonstrated that acute, SIV-induced CD4(+) T cell depletion in sooty mangabeys does not result in immune dysfunction and progression to simian AIDS and that a population of CD3(+)CD4(-)CD8(-) T cells (double-negative T cells) partially compensates for CD4(+) T cell function in these animals. Passaging plasma from an SIV-infected sooty mangabey with very few CD4(+) T cells to SIV-negative animals resulted in rapid loss of CD4(+) T cells. Nonetheless, all sooty mangabeys generated SIV-specific antibody and T cell responses and maintained normal levels of plasma lipopolysaccharide. Moreover, all CD4-low sooty mangabeys elicited a de novo immune response following influenza vaccination. Such preserved immune responses as well as the low levels of immune activation observed in these animals were associated with the presence of double-negative T cells capable of producing Th1, Th2, and Th17 cytokines. These studies indicate that SIV-infected sooty mangabeys do not appear to rely entirely on CD4(+) T cells to maintain immunity and identify double-negative T cells as a potential subset of cells capable of performing CD4(+) T cell-like helper functions upon SIV-induced CD4(+) T cell depletion in this species. PMID- 21317534 TI - An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. AB - Uncontrolled macrophage activation is now considered to be a critical event in the pathogenesis of chronic inflammatory diseases such as atherosclerosis, multiple sclerosis, and chronic venous leg ulcers. However, it is still unclear which environmental cues induce persistent activation of macrophages in vivo and how macrophage-derived effector molecules maintain chronic inflammation and affect resident fibroblasts essential for tissue homeostasis and repair. We used a complementary approach studying human subjects with chronic venous leg ulcers, a model disease for macrophage-driven chronic inflammation, while establishing a mouse model closely reflecting its pathogenesis. Here, we have shown that iron overloading of macrophages--as was found to occur in human chronic venous leg ulcers and the mouse model--induced a macrophage population in situ with an unrestrained proinflammatory M1 activation state. Via enhanced TNF-alpha and hydroxyl radical release, this macrophage population perpetuated inflammation and induced a p16(INK4a)-dependent senescence program in resident fibroblasts, eventually leading to impaired wound healing. This study provides insight into the role of what we believe to be a previously undescribed iron-induced macrophage population in vivo. Targeting this population may hold promise for the development of novel therapies for chronic inflammatory diseases such as chronic venous leg ulcers. PMID- 21317535 TI - Subunit 6 of the COP9 signalosome promotes tumorigenesis in mice through stabilization of MDM2 and is upregulated in human cancers. AB - The mammalian constitutive photomorphogenesis 9 (COP9) signalosome (CSN), a protein complex involved in embryonic development, is implicated in cell cycle regulation and the DNA damage response. Its role in tumor development, however, remains unclear. Here, we have shown that the COP9 subunit 6 (CSN6) gene is amplified in human breast cancer specimens, and the CSN6 protein is upregulated in human breast and thyroid tumors. CSN6 expression positively correlated with expression of murine double minute 2 (MDM2), a potent negative regulator of the p53 tumor suppressor. Expression of CSN6 appeared to prevent MDM2 autoubiquitination at lysine 364, resulting in stabilization of MDM2 and degradation of p53. Mice in which Csn6 was deleted died early in embryogenesis (E7.5). Embryos lacking both Csn6 and p53 survived to later in embryonic development (E10.5), which suggests that loss of p53 could partially rescue the effect of loss of Csn6. Mice heterozygous for Csn6 were sensitized to gamma irradiation-induced, p53-dependent apoptosis in both the thymus and the developing CNS. These mice were also less susceptible than wild-type mice to gamma-irradiation-induced tumorigenesis. These results suggest that loss of CSN6 enhances p53-mediated tumor suppression in vivo and that CSN6 plays an important role in regulating DNA damage-associated apoptosis and tumorigenesis through control of the MDM2-p53 signaling pathway. PMID- 21317536 TI - NSR-seq transcriptional profiling enables identification of a gene signature of Plasmodium falciparum parasites infecting children. AB - Malaria caused by Plasmodium falciparum results in approximately 1 million annual deaths worldwide, with young children and pregnant mothers at highest risk. Disease severity might be related to parasite virulence factors, but expression profiling studies of parasites to test this hypothesis have been hindered by extensive sequence variation in putative virulence genes and a preponderance of host RNA in clinical samples. We report here the application of RNA sequencing to clinical isolates of P. falciparum, using not-so-random (NSR) primers to successfully exclude human ribosomal RNA and globin transcripts and enrich for parasite transcripts. Using NSR-seq, we confirmed earlier microarray studies showing upregulation of a distinct subset of genes in parasites infecting pregnant women, including that encoding the well-established pregnancy malaria vaccine candidate var2csa. We also describe a subset of parasite transcripts that distinguished parasites infecting children from those infecting pregnant women and confirmed this observation using quantitative real-time PCR and mass spectrometry proteomic analyses. Based on their putative functional properties, we propose that these proteins could have a role in childhood malaria pathogenesis. Our study provides proof of principle that NSR-seq represents an approach that can be used to study clinical isolates of parasites causing severe malaria syndromes as well other blood-borne pathogens and blood-related diseases. PMID- 21317537 TI - IRBIT governs epithelial secretion in mice by antagonizing the WNK/SPAK kinase pathway. AB - Fluid and HCO(3)(-) secretion are fundamental functions of epithelia and determine bodily fluid volume and ionic composition, among other things. Secretion of ductal fluid and HCO(3)(-) in secretory glands is fueled by Na(+)/HCO(3)(-) cotransport mediated by basolateral solute carrier family 4 member 4 (NBCe1-B) and by Cl(-)/HCO(3)(-) exchange mediated by luminal solute carrier family 26, member 6 (Slc26a6) and CFTR. However, the mechanisms governing ductal secretion are not known. Here, we have shown that pancreatic ductal secretion in mice is suppressed by silencing of the NBCe1-B/CFTR activator inositol-1,4,5-trisphosphate (IP(3)) receptor-binding protein released with IP(3) (IRBIT) and by inhibition of protein phosphatase 1 (PP1). In contrast, silencing the with-no-lysine (WNK) kinases and Ste20-related proline/alanine-rich kinase (SPAK) increased secretion. Molecular analysis revealed that the WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression, in addition to stimulating their activities. Silencing of SPAK and IRBIT in the same ducts rescued ductal secretion due to silencing of IRBIT alone. These findings stress the pivotal role of IRBIT in epithelial fluid and HCO(3)(-) secretion and provide a molecular mechanism by which IRBIT coordinates these processes. They also have implications for WNK/SPAK kinase-regulated processes involved in systemic fluid homeostasis, hypertension, and cystic fibrosis. PMID- 21317539 TI - Location of rRNA transcription to the nucleolar components: disappearance of the fibrillar centers in nucleoli of regenerating rat hepatocytes. AB - The precise location of rDNA transcription to the components of mammalian cell nucleolus is still debated. This was due to the fact that all the molecules necessary for rRNA synthesis are located in two of the three components, the fibrillar centers (FCs) and the dense fibrillar component (DFC), which together with the granular component (GC) are considered to be constantly present in mammalian cell nucleoli. In the present study we demonstrated that in nucleoli of many regenerating rat hepatocytes at 15 h after partial hepatectomy the FCs were no longer present, only the DFC and the GC being detected. At this time of regeneration the rRNA transcriptional activity was three fold that of resting hepatocytes, while the synthesis of DNA was not yet significantly increased, indicating that these nucleolar changes were due to the rRNA synthesis up regulation. The DFC appeared to be organized in numerous, small, roundish tufts of fibrils. The silver staining procedure for AgNOR proteins, which are associated with the ribosomal genes, selectively and homogeneously stained these fibrillar tufts. Immuno-gold visualization of the Upstream Binding Factor (UBF), which is associated with the promoter region and the transcribed portion of the rRNA 45S gene, demonstrated that UBF was selectively located in the fibrillar tufts. We concluded that in proliferating rat hepatocytes the increased synthesis of rRNA induced an activation of the rRNA transcription machinery located in the fibrillar centers which, by becoming associated with the ribonucleoprotein transcripts, assumed the morphological pattern of the DFC. PMID- 21317538 TI - Prolyl hydroxylase 3 (PHD3) is essential for hypoxic regulation of neutrophilic inflammation in humans and mice. AB - The regulation of neutrophil lifespan by induction of apoptosis is critical for maintaining an effective host response and preventing excessive inflammation. The hypoxia-inducible factor (HIF) oxygen-sensing pathway has a major effect on the susceptibility of neutrophils to apoptosis, with a marked delay in cell death observed under hypoxic conditions. HIF expression and transcriptional activity are regulated by the oxygen-sensitive prolyl hydroxylases (PHD1-3), but the role of PHDs in neutrophil survival is unclear. We examined PHD expression in human neutrophils and found that PHD3 was strongly induced in response to hypoxia and inflammatory stimuli in vitro and in vivo. Using neutrophils from mice deficient in Phd3, we demonstrated a unique role for Phd3 in prolonging neutrophil survival during hypoxia, distinct from other hypoxia-associated changes in neutrophil function and metabolic activity. Moreover, this selective defect in neutrophil survival occurred in the presence of preserved HIF transcriptional activity but was associated with upregulation of the proapoptotic mediator Siva1 and loss of its binding target Bcl-xL. In vivo, using an acute lung injury model, we observed increased levels of neutrophil apoptosis and clearance in Phd3-deficient mice compared with WT controls. We also observed reduced neutrophilic inflammation in an acute mouse model of colitis. These data support what we believe to be a novel function for PHD3 in regulating neutrophil survival in hypoxia and may enable the development of new therapeutics for inflammatory disease. PMID- 21317540 TI - Interpretation of the effects of protein kinase C inhibitors on human UDP glucuronosyltransferase 1A (UGT1A) proteins in cellulo. AB - UDP-glucuronosyltransferases (UGTs) catalyze the glucuronidation of a wide variety of xeno/endobiotics. Previous studies have reported that human UGT enzymes are phosphorylated and that treatment of cells with protein kinase C (PKC) inhibitors results in decreased UGT activities without affecting the UGT protein levels. In this study, we investigated the effects of PKC inhibitors on human UGT1A protein levels and activities in detail. When UGT1A-expressing HEK293 cells and LS180 cells were treated with curcumin or calphostin C, the exogenous and endogenous UGT1A protein levels in homogenates prepared with Tris-buffered saline were significantly decreased. Enzyme activity levels mirrored the changes in UGT protein levels. When the curcumin- or calphostin C-treated cells were lysed with buffer containing a detergent, the UGT protein levels did not decrease. We found that curcumin or calphostin C treatment facilitated the degradation of UGT protein after the cells were collected in the absence of a detergent. Finally, by in cellulo evaluation, we found that curcumin decreased UGT activity by the direct inhibitory effect, but calphostin C did not affect UGT activity. Thus, this study suggests that we should evaluate the data carefully when interpreting the effects of PKC inhibitors on UGT activity. PMID- 21317541 TI - Nasal delivery of P-gp substrates to the brain through the nose-brain pathway. AB - The objective of this study was to evaluate in rats the potential utility of the nasal route to enhance central nervous system (CNS) delivery of drugs recognized by P-glycoprotein (P-gp). Well-known P-gp substrates verapamil and talinolol were perfused nasally or infused intravenously, and when plasma concentrations following intravenous infusion and nasal perfusion showed similar profiles. The concentration of verapamil in the brain after nasal perfusion was twice that after intravenous infusion. Although talinolol in the brain and the cerebrospinal fluid after i.v. infusion were below the detection limit, it was detected after nasal perfusion. When rats were treated with cyclosporin A, brain concentrations of verapamil after both administration modes were increased significantly, while those of talinolol were not significantly changed. Since the permeability of talinolol is low, talinolol in the brain which was transported directly from the nasal cavity has little chance of transport by P-gp localized in the apical membrane of cerebral microvessel endothelial cells. The potential for drug delivery utilizing the nose-CNS route was confirmed for P-gp substrates. The advantage of nasal delivery over i.v. delivery of talinolol to the brain was more significant than that of verapamil, suggesting that nasal administration is more useful strategy for the brain delivery of low-permeability P-gp substrates than the use of P-gp inhibitors. PMID- 21317542 TI - Achievement of genetics in plant reproduction research: the past decade for the coming decade. AB - In the last decade, a variety of innovations of emerging technologies in science have been accomplished. Advanced research environment in plant science has made it possible to obtain whole genome sequence in plant species. But now we recognize this by itself is not sufficient to understand the overall biological significance. Since Gregor Mendel established a principle of genetics, known as Mendel's Laws of Inheritance, genetics plays a prominent role in life science, and this aspect is indispensable even in modern plant biology. In this review, we focus on achievements of genetics on plant sexual reproduction research in the last decade and discuss the role of genetics for the coming decade. It is our hope that this will shed light on the importance of genetics in plant biology and provide valuable information to plant biologists. PMID- 21317543 TI - Origin of the CMS gene locus in rapeseed cybrid mitochondria: active and inactive recombination produces the complex CMS gene region in the mitochondrial genomes of Brassicaceae. AB - CMS (cytoplasmic male sterile) rapeseed is produced by asymmetrical somatic cell fusion between the Brassica napus cv. Westar and the Raphanus sativus Kosena CMS line (Kosena radish). The CMS rapeseed contains a CMS gene, orf125, which is derived from Kosena radish. Our sequence analyses revealed that the orf125 region in CMS rapeseed originated from recombination between the orf125/orfB region and the nad1C/ccmFN1 region by way of a 63 bp repeat. A precise sequence comparison among the related sequences in CMS rapeseed, Kosena radish and normal rapeseed showed that the orf125 region in CMS rapeseed consisted of the Kosena orf125/orfB region and the rapeseed nad1C/ccmFN1 region, even though Kosena radish had both the orf125/orfB region and the nad1C/ccmFN1 region in its mitochondrial genome. We also identified three tandem repeat sequences in the regions surrounding orf125, including a 63 bp repeat, which were involved in several recombination events. Interestingly, differences in the recombination activity for each repeat sequence were observed, even though these sequences were located adjacent to each other in the mitochondrial genome. We report results indicating that recombination events within the mitochondrial genomes are regulated at the level of specific repeat sequences depending on the cellular environment. PMID- 21317544 TI - Different status of the gene for ribosomal protein S16 in the chloroplast genome during evolution of the genus Arabidopsis and closely related species. AB - The ribosomal protein S16 (RPS16), the product of the rps16, is generally encoded in the chloroplast genomes of flowering plants. However, it has been reported that chloroplast-encoded RPS16 in mono- and dicotyledonous plants has been substituted by the product of nuclear-encoded rps16, which was transferred from the mitochondria to the nucleus before the early divergence of angiosperms. Current databases show that the chloroplast-encoded rps16 has become a pseudogene in four species of the Brassicaceae (Aethionema grandiflorum, Arabis hirsuta, Draba nemorosa, and Lobularia maritima). Further analysis of Arabidopsis thaliana and its close relatives has shown that pseudogenization has also occurred via the loss of its splicing capacity (Arabidopsis thaliana and Olimarabidopsis pumila). In contrast, the spliced product of chloroplast-encoded rps16 is observed in close relatives of Arabidopsis thaliana (Arabidopsis arenosa, Arabidopsis lyrata, and Crucihimalaya lasiocarpa). In this study, we identified the different functional status of rps16 in several chloroplast genomes in the genus Arabidopsis and its close relatives. Our results strongly suggest that nuclear- and chloroplast-encoded rps16 genes coexisted for at least 126 million years. We raise the possibility of the widespread pseudogenization of rps16 in the angiosperm chloroplast genomes via the loss of its splicing capacity, even when the rps16 encoded in the chloroplast genome is transcriptionally active. PMID- 21317545 TI - The SMALL AND ROUND SEED1 (SRS1/DEP2) gene is involved in the regulation of seed size in rice. AB - The causal gene of a novel small and round seed mutant 1 (srs1) was identified in rice by map-based cloning and named SMALL AND ROUND SEED 1 (SRS1). The SRS1 gene is identical to the previously identified DENSE AND ERECT PANICLE 2 (DEP2). The SRS1/DEP2 gene encodes a novel protein of 1365 amino acids residues without known functional domains. In the longitudinal direction of the lemma, both cell length and cell number are reduced in srs1-1 compared to the wild type, whereas in the lateral cross section of the lemma, cell length in srs1-1 is greater than that in the wild type, but the cell number in srs1-1 is the same as that in wild type. These results suggest that the small and round seed phenotype of srs1-1 is due to the reduction in both cell length and cell number in the longitudinal direction, and the elongation of the cells in the lateral direction of the lemma. The SRS1 mRNA and proteins are abundant in wild type rice specifically in young organs, namely young leaves, internodes and panicles. Interestingly, the tissues expressing SRS1 are closely related to the tissues that exhibit abnormalities in the srs1 mutants. PMID- 21317547 TI - Genetic diversity in population of largemouth bronze gudgeon (Coreius guichenoti Sauvage et Dabry) from Yangtze River determined by microsatellite DNA analysis. AB - Largemouth bronze gudgeon (Coreius guichenoti Sauvage et Dabry 1874), one of the endemic fish species in the upper reaches of the Yangtze River in China, is a benthic and potamodromous fish that is typically found in rivers with torrential flow. Three dams in the Yangtze River, Ertan Dam, Three Gorges Dam and Gezhouba Dam, may have had vital impacts on the habitat and spawning behaviors of largemouth bronze gudgeon, and could ultimately threaten the survival of this fish. We studied the population genetic diversity of C. guichenoti samples collected at seven sites (JH, GLP, BX, HJ, MD, SDP and XB) within the Yangtze River and one of its tributaries, the Yalong River. Genetic diversity patterns were determined by analyzing genetic data from 11 polymorphic microsatellite loci. A high genetic diversity among these largemouth bronze gudgeon populations was indicated by the number of microsatellite alleles (A) and the expected heterozygosity (HE). No significant population variation occurred among GLP, BX, HJ and MD populations, but dramatic population differentiation was observed among JH and XB, two dam-blocked populations, versus other populations. Tests for bottlenecks did not indicate recent dramatic population declines and concurrent losses of genetic diversity in any largemouth bronze gudgeon populations. To the contrary, we found that dams accelerated the population differentiation of this fish. PMID- 21317546 TI - Analysis of three multigene families as useful tools in species characterization of two closely-related species, Dicentrarchus labrax, Dicentrarchus punctatus and their hybrids. AB - By analyzing three multigene families, two closely related and commercially important species, Dicentrarchus labrax and Dicentrarchus punctatus, were characterized by cytogenetic and molecular methods. The interspecies hybrid Dicentrarchus labrax (?) * Dicentrarchus punctatus (?) was also analyzed. The multigene families studied were the 5S rDNA, 45S rDNA and the U2 snRNA. A microsatellite GTT motif was found within the non transcribed spacers (NTS) of the 5S rDNA from the two species. However, hexanucleotide duplication next to this microsatellite was observed in the D. labrax and hybrid clones, but not in D. punctatus. The U2 snRNA appeared to be linked to the U5 gene and showed two variant sequences, in both D. labrax and D. punctatus. They differed in one insertion/deletion of 7 nucleotides. The first internal transcribed spacer (ITS 1) region showed higher nucleotide variability in D. punctatus than in D. labrax. Nucleotide polymorphism within species and also nucleotide divergence between species were determined in the different gene regions. In a FISH analysis we obtained three chromosomal markers, because the 5S rDNA, 18S rDNA and U2 snRNA probes hybridized each in three different chromosome pairs. Hence none of them was co-localized. The 5S rDNA cluster and U2 snRNA were localized in acrocentric chromosome pairs, while the 18S rRNA gene probe hybridized in a subtelocentric pair. Finally, the usefulness of the results in developing tools for phylogenetic analysis and species identification are discussed in relation to other fish species. PMID- 21317548 TI - Comparison of aryl hydrocarbon receptor gene expression in laser dissected granulosa cell layers of immature rat ovaries. AB - In order to understand ovarian toxicity of aryl hydrocarbon receptor (AhR) agonists, in situ gene expression of the AhR was examined during follicle development in immature rats. In situ hybridization on frozen sections of ovaries from 24-day-old Sprague-Dawley rats showed that the AhR mRNA was localized in the granulosa cells and occasionally in the theca cells of the follicles irrespective of the developmental stage. In situ gene quantification on granulosa cell layers collected by laser microdissection further revealed that the granulosa cells expressed less AhR mRNA according to development of belonging follicles, but more beta-subunit of inhibin A mRNA, a quality control gene. These results may help to elucidate vulnerable developmental stages of follicles to toxicities of the AhR agonists. PMID- 21317549 TI - Analyzing autophagy in Magnaporthe oryzae. AB - Magnaporthe oryzae is an important plant pathogenic fungus that greatly threatens the world's food security. Both genome-wide and individual gene studies have shown that the pathogenicity of the fungus is severely dependent on the intracellular autophagy process during appressoria development. This protocol discusses a systematic methodology to discover and monitor autophagy-related (ATG) genes in M. oryzae. PMID- 21317550 TI - DJ-1 regulation of mitochondrial function and autophagy through oxidative stress. AB - The dysregulation of mitochondrial function has been implicated in the pathogenesis of Parkinson disease. Mutations in the parkin, PINK1 and DJ-1 genes all result in recessive parkinsonism. Although the protein products of these genes have not been fully characterized, it has been established that all three contribute to the maintenance of mitochondrial function. PINK1 and parkin act in a common pathway to regulate the selective autophagic removal of depolarized mitochondria, but the relationship between DJ-1 and PINK1- and/or parkin-mediated effects on mitochondria and autophagy is less clear. We have shown that loss of DJ-1 leads to mitochondrial phenotypes including reduced membrane potential, increased fragmentation and accumulation of autophagic markers. Supplementing DJ 1-deficient cells with glutathione reverses both mitochondrial and autophagic changes suggesting that DJ-1 may act to maintain mitochondrial function during oxidative stress and thereby alter mitochondrial dynamics and autophagy indirectly. PMID- 21317551 TI - Identification of autophagy genes participating in zinc-induced necrotic cell death in Saccharomyces cerevisiae. AB - Eukaryotes use a common set of genes to perform two mechanistically similar autophagic processes. Bulk autophagy harvests proteins nonselectively and reuses their constitutents when nutrients are scarce. In contrast, different forms of selective autophagy target protein aggregates or damaged organelles that threaten to interfere with growth. Yeast uses one form of selective autophagy, called cytoplasm-to-vacuole targeting (Cvt), to engulf two vacuolar enzymes in Cvt vesicles ("CVT-somes") within which they are transported to vacuoles for maturation. While both are dispensable normally, bulk and selective autophagy help sustain life under stressful conditions. Consistent with this view, knocking out several genes participating in Cvt and specialized autophagic pathways heightened the sensitivity of Saccharomyces cerevisiae to inhibitory levels of Zn(2+). The loss of other autophagic genes, and genes responsible for apoptotic cell death, had no such effect. Unexpectedly, the loss of members of a third set of autophagy genes heightened cellular resistance to zinc as if they encoded proteins that actively contributed to zinc-induced cell death. Further studies showed that both sensitive and resistant strains accumulated similar amounts of H2O2 during zinc treatments, but that more sensitive strains showed signs of necrosis sooner. Although zinc lethality depended on autophagic proteins, studies with several reporter genes failed to reveal increased autophagic activity. In fact, microscopy analysis indicated that Zn(2+) partially inhibited fusion of Cvt vesicles with vacuoles. Further studies into how the loss of autophagic processes suppressed necrosis in yeast might reveal whether a similar process could occur in plants and animals. PMID- 21317554 TI - Elongation factor P mediates a novel post-transcriptional regulatory pathway critical for bacterial virulence. AB - Bacterial pathogens detect and integrate multiple environmental signals to coordinate appropriate changes in gene expression including the selective expression of virulence factors, changes to metabolism and the activation of stress response systems. Mutations that abolish the ability of the pathogen to respond to external cues are typically attenuating. Here we discuss our recent discovery of a novel post-transcriptional regulatory pathway critical for Salmonella virulence and stress resistance. The enzymes PoxA and YjeK coordinately attach a unique beta-amino acid onto a highly conserved lysine residue in the translation factor elongation factor P (EF-P). Strains in which EF P is unmodified due to the absence of PoxA or YjeK are attenuated for virulence and display highly pleiotropic phenotypes, including hypersusceptibility to a wide range of unrelated antimicrobial compounds. Work from our laboratory and others now suggests that EF-P, previously thought to be essential, instead plays an ancillary role in translation by regulating the synthesis of a relatively limited subset of proteins. Other observations suggest that the eukaryotic homolog of EF-P, eIF5A, may illicit similar changes in the translation machinery during stress adaptation, indicating that the role of these factors in physiology may be broadly conserved. PMID- 21317555 TI - Monitoring Shigella flexneri vacuolar escape by flow cytometry. AB - Invasive bacterial pathogens such as Shigella flexneri force their uptake into non-phagocytic host cells. Upon internalization, they rupture the endocytic vacuole and escape into the host cell cytoplasm. Recent studies applying fluorescence resonance energy transfer (FRET) based methods to track host pathogen interactions have provided insights into the process of bacterial infection at the single cell level. We have previously reported that the vacuolar escape of invasive bacteria into the host cellular cytosol can be tracked by fluorescence microscopy using a FRET CCF4/beta-Lactamase reporter assay. Here, we show that our vacuolar rupture assay can also be analyzed by flow cytometry constituting an important alternative to data acquisition by microscopy. Whereas analysis of our assay by fluorescence microscopy offers precise spatiotemporal resolution, flow cytometry analysis represents a high-throughput method that allows efficient and fast quantification of a large number of events and can further improve future research on vacuolar escape. PMID- 21317556 TI - The evolution of patient selection criteria and indications for extracorporeal life support in pediatric cardiopulmonary failure: next time, let's not eat the bones. AB - Bill James, baseball statistician and author, tells the story of hungry cavemen sitting about a campfire, waiting for tomatoes to ripen. One has the inspiration to throw an ox on the fire, and the first barbecue ensued and was endured. After eating, the conversation goes something like this. "There were some good parts." "Yeah, but there were some bad parts." And the smart one says, "This time, let's not eat the bones." The evolution of patient selection criteria for the use of extracorporeal support (ECLS) is a bit like those cavemen and their first barbecued ox. Extracorporeal life support technology and application to patient care is the unique result of a long standing history of ambitious attempt, evaluation, debate, collaboration and extension. PMID- 21317557 TI - Putting the pieces together: a crystal clear window into CLC anion channel regulation. AB - CLC anion transport proteins function as Cl (-) channels and Cl (-) /H (+) exchangers and are found in all major groups of life including archaebacteria. Early electrophysiological studies suggested that CLC anion channels have two pores that are opened and closed independently by a "fast" gating process operating on a millisecond timescale, and a "common" or "slow" gate that opens and closes both pores simultaneously with a timescale of seconds (Figure 1A). Subsequent biochemical and molecular experiments suggested that CLC channels/transporters are homodomeric proteins ( 1-3) . PMID- 21317558 TI - Ranolazine block of human Na v 1.4 sodium channels and paramyotonia congenita mutants. AB - The antianginal drug ranolazine exerts voltage- and use-dependent block (UDB) of several Na+ channel isoforms, including Na(v) 1.4. We hypothesized that ranolazine will similarly inhibit the paramyotonia congenita Na(v) 1.4 gain-of function mutations, R1448C, R1448H, and R1448P that are associated with repetitive action potential firing. Whole-cell Na+ current (I(Na)) was recorded from HEK293 cells expressing the hNa(v) 1.4 WT or R1448 mutations. At a holding potential (HP) of -140 mV, ranolazine exerted UDB (10 Hz) of WT and R1448 mutations (IC 50 = 59 - 71 uM). The potency for ranolazine UDB increased when the frequency of stimulation was raised to 30 Hz (IC 50 = 20 - 27 uM). When the HP was changed to -70 mV to mimic the resting potential of an injured skeletal muscle fibre, the potency of ranolazine to block I(Na) further increased; values of ranolazine IC 50 for block of WT, R1448C, R1448H, and R1448P were 3.8, 0.9, 6.3, and 0.9 uM, respectively. Ranolazine (30 uM) also caused a hyperpolarizing shift in the voltage-dependence of inactivation of WT and R1448 mutations. The effects of ranolazine (30 uM) to reduce I(Na) were similar (~35% I(Na) inhibition) when different conditioning pulse durations (2-20 msec) were used. Ranolazine (10 uM) suppressed the abnormal I(Na) induced by slow voltage ramps for R1448C channels. In computer simulations, 3 uM ranolazine inhibited the sustained and excessive firing of skeletal muscle action potentials that are characteristic of myotonia. Taken together, the data indicate that ranolazine interacts with the open state and stabilizes the inactivated state(s) of Na(v)1.4 channels, causes voltage- and use-dependent block of I(Na) and suppresses persistent I(Na). These data further suggest that ranolazine might be useful to reduce the sustained action potential firing seen in paramyotonia congenita. PMID- 21317559 TI - Ovarian cancer stem cells and inflammation. AB - Epithelial ovarian cancer (EOC) is the fourth leading cause of cancer-related deaths in women in the United States and the leading cause of gynecologic cancer deaths. The major limiting factor in the treatment of ovarian cancer is recurrence and chemoresistance. Individuals who succumb to advanced-stage ovarian cancer inevitably become refractory to chemotherapy, resulting in disease progression and death. The source of recurrence and lack of response to chemotherapy is unknown. The focus of this review is to evaluate the question of recurrence and chemoresistance based on the concept of the cancer stem cells and inflammation. PMID- 21317560 TI - Effect of mutations on the p53 IRES RNA structure: implications for de-regulation of the synthesis of p53 isoforms. AB - Earlier we have demonstrated the presence of internal ribosome entry site (IRES) within tumor suppressor p53 mRNA. Here we have mapped the putative secondary structure of p53- IRES RNA using information from chemical probing and nuclease mapping experiments. Additionally, the secondary structure of the IRES element of the wild-type RNA was compared with cancer-derived silent mutant p53 RNAs. These mutations might result in the conformational alterations of p53-IRES RNAs. The results also indicate decreased IRES activities of the mutants as compared to wild-type RNA. Further, it was observed that some of the cytoplasmic trans-acting factors, critical for enhancing IRES function, were unable to bind mutant RNAs as efficiently as to wild-type. Our results suggest that hnRNP C1/C2 binds to p53 IRES and siRNA mediated partial silencing of hnRNP C1/C2 showed appreciable decrease in IRES function and consequent decrease in the level of the corresponding p53 isoform. Interestingly mutant p53 IRES showed lesser binding with hnRNP C1/C2 protein. Finally, upon doxorubicin treatment, the mutant RNAs were unable to show enhanced p53 synthesis to similar extent compared to wild type. Taken together, these observations suggest that mutations occurring in the p53 IRES might have profound implications for de-regulation of its expression and activity. PMID- 21317561 TI - Challenges of ligand identification for riboswitch candidates. AB - Expanding DNA sequence databases and improving methods for comparative analysis are being exploited to identify numerous noncoding RNA elements including riboswitches. Ligands for many riboswitch classes usually can be inferred based on the genomic contexts of representative RNAs, and complex formation or genetic regulation subsequently demonstrated experimentally. However, there are several candidate riboswitches for which ligands have not been identified. In this report, we discuss three of the most compelling riboswitch candidates: the ykkC/ykkD, yybP/ykoY and pfl RNAs. Each of these RNAs is numerous, phylogenetically widespread, and carries features that are hallmarks of metabolite-binding riboswitches, such as a well-conserved aptamer-like structure and apparent interactions with gene regulation elements such as ribosome binding sites or intrinsic transcription termination stems. These RNAs likely represent only a small sampling of the challenging motifs that researchers will encounter as new noncoding RNAs are identified. PMID- 21317562 TI - RAGE regulates autophagy and apoptosis following oxidative injury. AB - The receptor for advanced glycation end products (RAGE) plays a crucial role in several disease processes including diabetes, inflammation, and cancer. Compared with apoptosis ("programmed cell death"), autophagy is a genetically programmed, evolutionarily conserved cell survival process that degrades long-lived cellular proteins and organelles ("programmed cell survival"). Recently we reported that RAGE is an important regulator of oxidative stress in pancreatic cancer cells. Upregulation of RAGE expression by the nuclear factor (NF)-kappaB pathway decreases reactive oxygen species (ROS)-induced oxidative injury. In contrast, suppression of RAGE expression increases pancreatic tumor cell sensitivity to oxidative injury. Furthermore, RAGE is a positive regulator of autophagy, and negative regulator of apoptosis during oxidative stress. These findings provide insight into how crosstalk between apoptosis and autophagy is mediated via ROS signaling with a process involving RAGE. PMID- 21317563 TI - Editorial topics in MRI: Imaging of the foot and ankle special issue. PMID- 21317564 TI - Imaging of talar dome chondral and osteochondral lesions. AB - Talar dome chondral and osteochondral lesions are a common cause of ankle pain and subjective instability. The goal of imaging these lesions is primarily their detection, demonstration of their position and extent, including status of the chondral surface, demonstration of any associated chondral delamination, assessment of the integrity of the subchondral plate, and assessment of the cancellous subchondral bone for bone marrow edema like signal, sclerosis, cystic change, and for the presence of an unstable osteochondral fragment. Although plain radiography, computerized tomography, and bone scan may be helpful in the detection and characterization of these lesions, magnetic resonance imaging is the only imaging modality that will provide a comprehensive assessment of all these issues. Technical aspects of plain radiography, computerized tomography, and magnetic resonance imaging are discussed, and imaging findings are presented. PMID- 21317565 TI - Imaging of impingement lesions in the ankle. AB - Ankle impingement and instability are well-recognized complications of ankle sprain. Ankle impingement is an important cause of chronic ankle pain in active populations, particularly in the professional athlete. Depending on anatomical location and the structures involved, impingement syndromes are classified into anterolateral, anterior, posterior, posteromedial, and anteromedial types. Clinically, impingement syndromes are characterized by painful limitation of full ankle movement. Ankle impingement results from repetitive subclinical trauma due to overuse injuries, which, in the subacute or chronic situation, lead to abnormal osseous and soft-tissue thickening within the ankle joint. Various imaging techniques can be used in the diagnosis of ankle impingement. Usually, radiography is the initial imaging technique performed to rule out bony trauma and identify potential anatomical bony abnormalities. Use of computed tomography and isotope bone scanning is largely superseded by magnetic resonance imaging, although with variable sensitivity and specificity. Arthrographic techniques, using computed tomography or magnetic resonance, are useful for exquisite demonstration of capsular recesses and synovial abnormalities. Imaging-guided injection techniques can be used in the management of impingement for pain ablation and to aid clinical diagnosis, especially in hind foot pain. PMID- 21317566 TI - Imaging of ankle tendinopathy and tears. AB - The major muscular prime movers and stabilizers of the foot and ankle originate in the mid to lower leg and send their tendons distally. Most of these tendons, with the exception of the Achilles and plantaris tendons, must negotiate a sharply curved course at the ankle and are stabilized by fibro-osseous tunnels, pulleys, or fibrous retinaculi before eventually inserting at the foot. Knowledge of specific tendon anatomy, contact points and sites of physical and vascular stress, helps to identify those regions susceptible to degeneration or tearing and to optimize the design of imaging protocols. This review covers the imaging modalities used to assess tendons about the ankle and issues related to their usage, normal tendon structure and relevant anatomy, normal imaging appearances and artifacts, and the common degenerative pathological processes which imaging can show. PMID- 21317567 TI - Imaging of tumors in the ankle and foot. AB - Common bone and soft tissue tumors in the foot and ankle are described in this article, and x-ray and magnetic resonance imaging characteristics are given. Ultrasound can be used for limited indications only, noting that ultrasound features are nonspecific. Of the bone and soft tissue tumors, approximately 7% occur in the foot and ankle. Soft tissue tumors are more common than bone tumors. Tumors of the foot and ankle are generally benign or nonneoplastic. Patients with suspected malignant lesions should be referred to a specialized bone tumor unit before biopsy. PMID- 21317568 TI - Imaging of peripheral nerve lesions in the lower limb. AB - Lower limb peripheral neuropathy may have a variety of causes. This article focuses on focal neural lesions because of neural entrapment associated with static mechanical compression or dynamic compression/stretching. Mechanical compression may relate to direct blunt trauma, surgical injury, mass effect associated with adjacent mass lesions, and frictional effects associated with fibrous bands. Stretching neural injury may be associated with abnormalities in alignment such as plano-valgus hindfoot and hindfoot pronation. Recurrent inversion ankle injuries may also cause neural injury. Neural injury may be associated with denervation of the muscles supplied by the nerve. Electromyography (EMG) remains the gold standard for diagnosis of denervation. Diagnostic imaging plays a complementary role to EMG in difficult cases, the anticoagulated patient, and in clarifying the etiology of an EMG-demonstrated neuropathy. Magnetic resonance imaging and ultrasound can be used in peripheral nerve imaging to demonstrate extrinsic compressive lesions, focal neural lesions such as neural edema and swelling, focal neural scarring (posttraumatic neuroma in continuity) and intraneural ganglia. Imaging can also demonstrate the effects of muscle denervation. Focal areas of tenderness can be highlighted using skin markers for magnetic resonance imaging and by transducer palpation on ultrasound. Ultrasound can be particularly useful in assessing for intrinsic lesions in small peripheral nerves because of the superior spatial resolution of ultrasound in assessing superficial structures. Plain x-rays (and sometimes computed tomography scanning) may show significant bone changes and should be the initial imaging modality. PMID- 21317569 TI - Confessions of a part-time hand surgeon. PMID- 21317573 TI - V-Y advancement flaps for scalp closure after acute cranial volume expansion. AB - Sometimes the surgeon who contemplates a coronal incision for craniofacial surgery, such as fronto-orbital advancement, faces a situation in which closure by primary suture becomes impossible because of acute cranial volume expansion. To avoid such a situation, the authors invented V-Y advancement flap method. This flap was found to be highly effective in 6 craniofacial patients who were treated between March 2007 and March 2008. The method consists of an incision line that starts from the highest spot on the ear and proceeds in the direction of the hairline at 45 degrees, and then runs up to the vertex in a sawtooth manner. This line is used when acute cranial volume expansion is expected after surgery. Another incision line is symmetrically drawn on the opposite side of the head. These 2 lines are conjoined at the vertex. The lengths of the 2 sides of a single sawtooth are both about 2 to 3 cm. When the scalp of an expanded cranium is closed, some V-shaped scalp margins under normal tension can simply be sutured using a traditional V-V advancement flap. However, the others under increased tension need to be in a Y-shaped pattern. During the follow-up period (6 months on average), application of this V-Y advancement flap method led to good functional and aesthetic outcomes in all 6 cases. The authors attribute these results to scalp closure using a mixture of V-V and V-Y flaps. PMID- 21317574 TI - Endorsement of the CONSORT and STROBE statements for plastic surgical clinical trials. PMID- 21317576 TI - Implications of the Henan Province report on the treatment as prevention debate. PMID- 21317578 TI - Retention among adults initiating antiretroviral therapy in South Africa: 2002 2007. PMID- 21317579 TI - The cost-effectiveness of HIV prevention interventions for HIV-infected patients seen in clinical settings. AB - BACKGROUND: The US Health Resources and Services Administration sponsored a 5 year initiative to test three types of counseling-based interventions to reduce HIV transmission among HIV-infected patients delivered in clinical settings. We assessed the cost and cost-effectiveness of the three types of interventions at 13 sites: primary care provider-based (clinical provider); social worker or peer educator-based (specialist); and a mix of primary care and specialist-based (mixed). METHODS: We developed a cost-effectiveness model to calculate average and incremental cost-effectiveness ratios and the cost-effectiveness of the 13 sites combined. RESULTS: Spending over all 3 years of the demonstration averaged $1004, $3173, and $3430 per client served for clinical provider, specialist, and mixed services, respectively. Unit costs declined with the volume of services provided for all three intervention types. The cost-effectiveness of the clinical provider sites was $107,656 per HIV case averted compared with no intervention. Clinical provider sites were less costly and more effective than the specialist or mixed sites. CONCLUSIONS: Compared with the lifetime cost of HIV/AIDS care and with other effective HIV prevention interventions, the clinical provider-led interventions in this study are cost-effective. In an incremental comparison with clinical provider sites, specialist and mixed intervention sites were not cost effective. PMID- 21317581 TI - Is tenofovir-related renal toxicity incompletely reversible? PMID- 21317582 TI - Detrimental effect of atazanavir plasma concentrations on total serum bilirubin levels in the presence of UGT1A1 polymorphisms. PMID- 21317583 TI - Clinical impact and cost of laboratory monitoring need review even in resource rich setting. PMID- 21317584 TI - Probiotics: the potential for a live microbicide to prevent HIV. PMID- 21317585 TI - Antiretroviral therapy and TB notification rates in a high HIV prevalence South African community. AB - BACKGROUND: Antiretroviral therapy (ART) has been proposed as an intervention for reducing tuberculosis (TB) burdens in areas with high HIV prevalence. However, little data is available on the impact of ART on population-level TB. METHODS: Trends in adult TB case fatality and notifications were assessed before and during increasing ART coverage in a well-defined periurban community, from 1997 to 2008. Mean changes in TB rates were measured using linear autoregression models. ART coverage increased from 1% in 2003 to 5%, 13%, and 21% of HIV infected population in 2004, 2005, and 2008, respectively. RESULTS: From 1997 to end of 2004 TB notification rates increased by an average of 187 cases/100,000/year (P < 0.001), reaching a peak of 2536/100,000 in 2005. From 2005 to 2008, TB notification rates declined by approximately 202 cases/100,000/year (P < 0.001). TB rates were initially stable in HIV-uninfected individuals, but declined moderately from 2005. TB rates declined in HIV-infected adults from 6513/100,000 in 2005 to 4741/100,000 in 2008. The predominant decline in TB notifications occurred among HIV-infected patients receiving ART (1156 cases/100,000/year) and was less marked in those not receiving ART (416 cases/100,000/year). Similarly, TB case fatality was constant for HIV-uninfected individuals, but declined in HIV-infected individuals from 23% in 2002 to 8% in 2008 (P = 0.01). CONCLUSIONS: In this community heavily affected by both HIV and TB epidemics, rapid and high ART coverage was associated with significant reductions in TB notifications and TB-associated case fatality. PMID- 21317586 TI - Sexual behaviors of adolescent emerging and young adult men who have sex with men ages 13-29 in New York City. AB - CONTENT: HIV infections among young men who have sex with men (YMSM), ages 13-29 in New York City have been steadily increasing over the last decade. OBJECTIVE: To document the sexual onset and behavior of YMSM as a means for informing the development of new HIV prevention messaging. DESIGN: Cross-sectional study. PARTICIPANTS: Five hundred fifty-eight YMSM, with more than 60% racial/ethnic minorities. RESULTS: Young adults (25-29 years) reported a greater number of lifetime sexual partners, but the adolescents (13-17 years) and emerging adults (18-24 years) reported having their first sexual encounter with another man at a younger age. Black and Latino men first engaged in various sexual behaviors, including receptive anal intercourse, at a younger age than either Asian/Pacific Islander or white men, and were more likely to report an HIV-seropositive status. Across race/ethnicity, YMSM reported an equivalent number of recent male sex partners and selected both main and casual partners who were age and race/ethnicity matches. During the most recent sexual encounter with a casual male partner, black men were more likely than white men to have had unprotected receptive anal intercourse, whereas white men were more likely to report unprotected oral sex. Black YMSM reported more recent female partners than all other groups. CONCLUSIONS: Black and Latino YMSM may be at increased risk for seroconversion because they tend to start having sex with other men at a younger age than their white and Asian/Pacific Islander peers and because they engage in unprotected sexual behaviors with men of concordant race/ethnicity and of a similar age where levels of viremia may be more elevated but not because of the sheer number of sexual partners. PMID- 21317587 TI - Scale-up and continuation of antiretroviral therapy in South African treatment programs, 2005-2009. AB - BACKGROUND: South Africa has the greatest burden of HIV-infection in the world with about 5.2 million HIV-infected adults. In 2003, the South African Government launched a comprehensive HIV and AIDS care treatment program supported by the United States in 2004 through the President's Emergency Plan for AIDS Relief (PEPFAR). METHODS: To describe the scale-up and continuation of antiretroviral therapy in South African Government and PEPFAR-supported sites in South Africa, we conducted a retrospective analysis of routinely collected program reporting data, 2005-2009. RESULTS: From 2005 through 2009, the average rate of persons initiated on antiretroviral therapy in PEPFAR-supported South African Government treatment programs increased nearly four-fold from 6,327 a month in 2005-2006 to 24,622 a month in 2008-2009 resulting in an increase from 33,543 patients on continued treatment in April-June 2005 to 631,985 patients in July-September 2009. Of those 631,985 patients receiving treatment, 65% were women. Men were more likely to be lost to follow-up (9.2% vs. 7.8%, PR 1.18, 95% CI 1.17-1.19) and more likely to die (5.6% vs. 4.1%, PR 1.36, 95% CI 1.35-1.37) than women. CONCLUSIONS: Scale-up and continuation of antiretroviral therapy in South Africa has been a remarkable medical accomplishment. Because more women receive and continue treatment, more efforts are needed to treat and retain men. PMID- 21317588 TI - Integration of buprenorphine for substance-abuse treatment by HIV care providers. PMID- 21317589 TI - Participant characteristics and HIV risk behaviors among individuals entering integrated buprenorphine/naloxone and HIV care. AB - OBJECTIVE: This study was part of a national, multisite demonstration project evaluating the impact of integrated buprenorphine/naloxone treatment and HIV care. The goals of this study were to describe the baseline demographic, clinical, and substance use characteristics of the participants and to explore HIV transmission risk behaviors in this group. METHODS: Nine sites across the United States participated. Data obtained by interview and chart review included demographic information, medical history, substance use, and risk behaviors.We performed a descriptive analysis of patient characteristics at entry and used logistic regression to evaluate factors associated with 1) unprotected anal or vaginal sex; and 2) needle-sharing within the previous 90 days. RESULTS: Three hundred eighty-six individuals were included in the study: 303 (78.5%) received buprenorphine/naloxone; 41 (10.6%) received methadone; and 42 (10.9%) received another form of treatment. The analysis of risk behaviors was limited to those in the buprenorphine group (n = 303). Among those reporting vaginal or anal sex in the previous 90 days, 24% had sex without a condom. Factors significantly associated with unprotected sex were: having a partner; female gender; and alcohol use in previous 30 days. A total of 8.9% of participants shared needles in the previous 90 days. Factors significantly associated with needle-sharing were: amphetamine use; marijuana use; homelessness; and anxiety. CONCLUSIONS: Addressing transmission risk behaviors is an important secondary HIV prevention strategy. In addition to treatment for opioid dependence, addressing other substance use, social issues, particularly housing, and mental health may have important implications for reducing HIV transmission in HIV-infected opioid dependent patients. PMID- 21317591 TI - A model federal collaborative to increase patient access to buprenorphine treatment in HIV primary care. AB - A Health Resources and Services Administration-Substance Abuse and Mental Health Services Administration collaboration was established to improve health outcomes for opiate-dependent HIV-infected patients through promotion of integrated models of HIV primary care and substance abuse treatment. The collaboration comprised 10 demonstration sites coordinated by a technical assistance/evaluation center that worked to refine planned interventions, address state-of-the-art treatment and policy issues relating to the use of buprenorphine opioid abuse treatment in HIV primary care settings, conduct local and multisite evaluations, and disseminate program findings. This article describes the goals and objectives of the collaborative as well as the interagency interactions and steps taken to establish the collaborative. PMID- 21317590 TI - HIV treatment outcomes among HIV-infected, opioid-dependent patients receiving buprenorphine/naloxone treatment within HIV clinical care settings: results from a multisite study. AB - BACKGROUND: Having opioid dependence and HIV infection are associated with poor HIV-related treatment outcomes. METHODS: HIV-infected, opioid-dependent subjects (N = 295) recruited from 10 clinical sites initiated buprenorphine/naloxone (BUP/NX) and were assessed at baseline and quarterly for 12 months. Primary outcomes included receiving antiretroviral therapy (ART), HIV-1 RNA suppression, and mean changes in CD4 lymphocyte count. Analyses were stratified for the 119 subjects not on ART at baseline. Generalized estimating equations were deployed to examine time-dependent correlates for each outcome. RESULTS: At baseline, subjects on ART (N = 176) were more likely than those not on ART (N = 119) to be older, heterosexual, have lower alcohol addiction severity scores, and lower HIV 1 RNA levels; they were less likely to be homeless and report sexual risk behaviors. Subjects initiating BUP/NX (N = 295) were significantly more likely to initiate or remain on ART and improve CD4 counts over time compared with baseline; however, these improvements were not significantly improved by longer retention on BUP/NX. Retention on BUP/NX for three or more quarters was, however, significantly associated with increased likelihood of initiating ART (beta = 1.34 [1.18, 1.53]) and achieve viral suppression (beta = 1.25 [1.10, 1.42]) for the 64 of 119 (54%) subjects not on ART at baseline compared with the 55 subjects not retained on BUP/NX. In longitudinal analyses, being on ART was positively associated with increasing time of observation from baseline and higher mental health quality of life scores (beta = 1.25 [1.06, 1.46]) and negatively associated with being homo- or bisexual (beta = 0.55 [0.35, 0.97]), homeless (beta = 0.58 [0.34, 0.98]), and increasing levels of alcohol addiction severity (beta = 0.17 [0.03, 0.88]). The strongest correlate of achieving viral suppression was being on ART (beta = 10.27 [5.79, 18.23]). Female gender (beta = 1.91 [1.07, 3.41]), Hispanic ethnicity (beta = 2.82 [1.44, 5.49]), and increased general health quality of life (beta = 1.02 [1.00,1.04]) were also independently correlated with viral suppression. Improvements in CD4 lymphocyte count were significantly associated with being on ART and increased over time. CONCLUSIONS: Initiating BUP/NX in HIV clinical care settings is feasible and correlated with initiation of ART and improved CD4 lymphocyte counts. Longer retention on BPN/NX was not associated with improved prescription of ART, viral suppression, or CD4 lymphocyte counts for the overall sample in which the majority was already prescribed ART at baseline. Among those retained on BUP/NX, HIV treatment outcomes did not worsen and were sustained. Increasing time on BUP/NX, however, was especially important for improving HIV treatment outcomes for those not on ART at baseline, the group at highest risk for clinical deterioration. Retaining subjects on BUP/NX is an important goal for sustaining HIV treatment outcomes for those on ART and improving them for those who are not. Comorbid substance use disorders (especially alcohol), mental health problems, and quality-of-life indicators independently contributed to HIV treatment outcomes among HIV-infected persons with opioid dependence, suggesting the need for multidisciplinary treatment strategies for this population. PMID- 21317592 TI - Drug treatment outcomes among HIV-infected opioid-dependent patients receiving buprenorphine/naloxone. AB - BACKGROUND: Buprenorphine/naloxone allows the integration of opioid dependence and HIV treatment. METHODS: We conducted a prospective study in HIV-infected opioid-dependent patients to investigate the impact of buprenorphine/naloxone treatment on drug use. Self-report and chart review assessments were conducted every 3 months (quarters 1-4) for 1 year. Outcomes were buprenorphine/naloxone treatment retention, drug use, and addiction treatment processes. RESULTS: Among 303 patients enrolled between July 2005 and December 2007, retention in buprenorphine/naloxone treatment was 74%, 67%, 59%, and 49% during Quarters 1, 2, 3, and 4, respectively. Past 30-day illicit opioid use decreased from 84% of patients at baseline to 42% in retained patients over the year. Patients were 52% less likely to use illicit opioids for each quarter in treatment (Odds ratio = 0.66; 95% CI: 0.61 to 0.72). Buprenorphine/naloxone doses and office visits approximated guidelines published by the United States Department of Health and Human Services. Urine toxicology monitoring was less frequent than recommended. CONCLUSIONS: Buprenorphine/naloxone provided in HIV treatment settings can decrease opioid use. Strategies are needed to improve retention and address ongoing drug use in this treatment population. PMID- 21317594 TI - Patient perspectives on buprenorphine/naloxone treatment in the context of HIV care. AB - BACKGROUND: Research has shown that buprenorphine/naloxone (bup/nx) is a safe and effective treatment for opioid dependence. Few reports, however, describe the patient perspective on bup/nx treatment and its integration into HIV care settings. METHODS: We conducted qualitative interviews with 33 patients to further investigate patient satisfaction and experience with bup/nx treatment and integrated care. Interviews focused on drug use/cessation history; attitudes toward and satisfaction with bup/nx treatment; and perspectives on integrated bup/nx treatment and HIV care. RESULTS: Patients were overwhelmingly satisfied with the pharmacologic effects and treatment outcomes of bup/nx, including effectiveness in blocking cravings and controlling opioid use; decreased fear of withdrawal and/or missing doses; and an overall improvement in quality of life. Patients also described being more engaged with both their substance abuse treatment and HIV care, including greater ability to manage their own treatment, keep, appointments, and adhere to antiretroviral medication regimes. Counseling was seen by some patients as an important component of bup/nx treatment. Nearly all were positive about their experience with integrated care, appreciative of an improved drug treatment environment, convenience, and quality of care. CONCLUSIONS: Findings suggest that patients report bup/nx to be a viable treatment and many prefer it to other opioid replacement therapies. PMID- 21317593 TI - Improved quality of life for opioid-dependent patients receiving buprenorphine treatment in HIV clinics. AB - BACKGROUND: Opioid dependence and HIV infection are associated with poor health related quality of life (HRQOL). Buprenorphine/naloxone (bup/nx) provided in HIV care settings may improve HRQOL. METHODS: We surveyed 289 HIV-infected opioid dependent persons treated with clinic-based bup/nx about HRQOL using the Short Form Health Survey (SF-12) administered at baseline, 3, 6, 9, and 12 months. We used normalized SF-12 scores, which correspond to a mean HRQOL of 50 for the general US population (SD 10, possible range 0-100). We compared mean normalized mental and physical composite and component scores in quarters 1, 2, 3, and 4 with baseline scores using generalized estimating equation models. We assessed the effect of clinic-based bup/nx prescription on HRQOL composite scores using mixed effects regression with site as random effect and time as repeated effect. RESULTS: Baseline normalized SF-12 scores were lower than the general US population for all HRQOL domains. Average composite mental HRQOL improved from 38.3 (SE 12.5) to 43.4 (SE 13.2) [beta 1.13 (95% CI: 0.72 to 1.54)] and composite physical HRQOL remained unchanged [beta 0.21 (95% CI: -0.16 to 0.57)] over 12 months follow-up. Continued bup/nx treatment across all 4 quarters was associated with improvements in both physical [beta 2.38 (95% CI: 0.63 to 4.12)] and mental [beta 2.51 (95% CI: 0.42 to 4.60)] HRQOL after adjusting for other contributors to HRQOL. CONCLUSIONS: Clinic-based bup/nx maintenance therapy is potentially effective in ameliorating some of the adverse effects of opioid dependence on HRQOL for HIV-infected populations. PMID- 21317595 TI - The impact of cocaine use on outcomes in HIV-infected patients receiving buprenorphine/naloxone. AB - BACKGROUND: Cocaine use is common in opioid-dependent HIV-infected patients, but its impact on treatment outcomes in these patients receiving buprenorphine/naloxone is not known. METHODS: We conducted a prospective study in 299 patients receiving buprenorphine/naloxone who provided baseline cocaine data and a subset of 266 patients who remained in treatment for greater than or equal to one quarter. Assessments were conducted at baseline and quarterly for 1 year. We evaluated the association between baseline and in-treatment cocaine use on buprenorphine/naloxone retention, illicit opioid use, antiretroviral adherence, CD4 counts, HIV RNA, and risk behaviors. RESULTS: Sixty-six percent (197 of 299) of patients reported baseline cocaine use and 65% (173 of 266) of patients with follow-up data reported in-treatment cocaine use. Baseline and in-treatment cocaine use did not impact buprenorphine/naloxone retention, antiretroviral adherence, CD4 lymphocytes, or HIV risk behaviors. However, baseline cocaine use was associated with a 14.8 (95% confidence interval [CI], 9.0-24.2) times greater likelihood of subsequent cocaine use (95% CI, 9.0-24.2), a 1.4 (95% CI, 1.02 2.00) times greater likelihood of subsequent opioid use, and higher log10 HIV RNA (P < 0.016) over time. In-treatment cocaine use was associated with a 1.4 (95% CI, 1.01-2.00) times greater likelihood of concurrent opioid use. CONCLUSIONS: Given cocaine use negatively impacts opioid and HIV treatment outcomes, interventions to address cocaine use in HIV-infected patients receiving buprenorphine/naloxone treatment are warranted. PMID- 21317596 TI - Hepatic safety and lack of antiretroviral interactions with buprenorphine/naloxone in HIV-infected opioid-dependent patients. AB - BACKGROUND: The safety of buprenorphine/naloxone (bup/nx) in HIV-infected patients has not been established. Prior reports raise concern about hepatotoxicity and interactions with atazanavir. METHODS: We conducted a prospective cohort study of 303 opioid-dependent HIV-infected patients initiating bup/nx treatment. We assessed changes in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) over time. We compared bup/nx doses in patients receiving the antiretroviral atazanavir to those not receiving atazanavir. We conducted surveillance for pharmacodynamic interactions. RESULTS: Median AST [37.0 vs. 37.0 units/liter (U/L) respective interquartile ranges (IQRs) 26-53 and 26-59] and ALT (33.0 vs. 33.0 U/L, respective IQRs 19-50 and 18-50) values did not change over time among 141 patients comparing pre-bup/nx exposure with post bup/nx exposure measures. During bup/nx exposure, 207 subjects demonstrated no significant change in median AST (36.0 vs. 35.0 U/L, respective IQRs 25-57 and 25 61) and ALT (29.0 vs. 31.0 U/L, respective IQRs 19-50 and 18-50) values collected a median of 6 months apart. Analyses restricted to patients with hepatitis C and HIV co-infection yielded similar results, except a small but significant decrease in first to last AST, during treatment with bup/nx (P = 0.048). Mean bup/nx dose, ranging 16.0-17.8 mg, did not differ over time or with co-administration of atazanavir. No pharmacodynamic interactions were noted. CONCLUSIONS: Buprenorphine/naloxone did not produce measurable hepatic toxicity or pharmacodynamic interaction with atazanavir in HIV-infected opioid-dependent patients. PMID- 21317597 TI - Integration of buprenorphine/naloxone treatment into HIV clinical care: lessons from the BHIVES collaborative. AB - BACKGROUND: Replication of effective practices requires detailed descriptions of implementation processes, barriers and facilitators, and lessons learned. The experiences of physicians leading the Buprenorphine HIV Evaluation and Support initiative provides valuable information for other HIV providers seeking to integrate medication-assisted treatment services into HIV clinical care. METHODS: Evaluation staff conduced site visits to the 10 funded Buprenorphine HIV Evaluation and Support programs to better understand buprenorphine/naloxone (bup/nx) integration practices; services offered; staffing; provider experiences with and perceptions of bup/nx; perceived barriers, facilitators, and sustainability; and recommendations regarding replication of integrated care program components. Interviews with site principal investigators conducted during the last year of program implementation were transcribed, coded, and analyzed according to both pre-identified and emerging themes. RESULTS: Integrated bup/nx and HIV treatment was successfully introduced to community and hospital-based clinics under the direction of infectious disease, psychiatry, and general internal medicine physicians. All but 1 of the principal investigators interviewed were highly satisfied with integrated HIV and bup/nx treatment, and all anticipated continued provision of the service. Multiple prescribers were necessary to ensure sufficient coverage and a bup/nx coordinator (eg, nurse, counselor) was seen as essential to the provision of quality care. Ongoing challenges included multisubstance use and mental health issues among patients; limited adoption of bup/nx treatment among colleagues; and the necessity of incorporating new procedures, including urine toxicology testing into established practice. CONCLUSIONS: Findings suggest that integrated bup/nx treatment and HIV care is acceptable to providers and feasible in a variety of practice settings. PMID- 21317598 TI - The BHIVES collaborative: organization and evaluation of a multisite demonstration of integrated buprenorphine/naloxone and HIV treatment. AB - Substance abuse is associated with poor medical and quality-of-life outcomes among HIV-infected individuals. Although drug treatment may reduce these negative consequences, for many patients, options are limited. Buprenorphine/naloxone, an opioid agonist treatment that can be prescribed in the United States in office based settings, can be used to expand treatment capacity and integrate substance abuse services into HIV care. Recognizing this potential, the US Health Resources and Services Administration funded the development and implementation of demonstration projects that integrated HIV care and buprenorphine/naloxone treatment at 10 sites across the country. An Evaluation and Technical Assistance Center provided programmatic and clinical support as well as oversight for an evaluation that examined the processes for and outcomes of integrated care. The evaluation included patient-level self-report and chart abstractions as well as provider and site level data collected through surveys and in-depth interviews. Although multisite demonstrations pose implementation and evaluation challenges, our experience demonstrates that these can, in part, be addressed through ongoing communication and technical assistance as well as a comprehensive evaluation design that incorporates multiple research methods and data sources. Although limitations to evaluation findings persist, they may be balanced by the scope and "real-world" context of the initiative. PMID- 21317599 TI - The cost of integrated HIV care and buprenorphine/naloxone treatment: results of a cross-site evaluation. AB - BACKGROUND: Implementing integrated HIV and buprenorphine/naloxone treatment requires cost estimates to plan and obtain funding. METHODS: We identified costs incurred at HIV clinical sites participating in a cross-site evaluation of integrated care that followed patients for 1 year. Costs include labor, overhead, and urine toxicology analyses (clinic perspective), buprenorphine/naloxone (payer perspective) and patient time and transportation (patient perspective). Sites provided resource utilization quarterly, and providers estimated time required for each activity. With site as the unit of analysis, results are reported as median (range) of average site costs in 2008 US dollars. RESULTS: The median number of monthly provider encounters for integrated care patients was 3.2 (1.5 13.3) compared with 1.7 (1.1-4.2) for similar patients not in integrated care, but integrated care patients had fewer physician encounters. Median monthly clinic costs per integrated care patient were $136 ($67-$677) for labor and overhead and $8 ($2-$23) for toxicology analyses, $22 higher than clinic costs for patients not in integrated care. Median monthly costs for buprenorphine/naloxone were $209 ($165-$272), and monthly patient costs in integrated care were $11 ($1-$54) higher. CONCLUSIONS: Integrated HIV and buprenorphine/naloxone treatment requires different resources, including costs that are not third-party reimbursed. Implementing integrated care will require funding for training and for new staff such as buprenorphine coordinators, in addition to reimbursement for buprenorphine/naloxone. Further research is needed to identify potential cost offsets outside of the clinic setting. PMID- 21317600 TI - Improving adherence to HIV quality of care indicators in persons with opioid dependence: the role of buprenorphine. AB - BACKGROUND: Opioid-dependent HIV-infected patients are less likely to receive HIV quality of care indicators (QIs) compared with nondependent patients. Buprenorphine/naloxone maintenance therapy (bup/nx) could affect the quality of HIV care for opioid-dependent patients. METHODS: We abstracted 16 QIs from medical records at nine HIV clinics 12 months before and after initiation of bup/nx versus other treatment for opioid dependence. Summary quality scores (number of QIs received/number eligible * 100) were calculated. We compared change in QIs and summary quality scores in patients receiving bup/nx versus other participants. RESULTS: One hundred ninety-four of 268 participants (72%) received bup/nx and 74 (28%) received other treatment. Mean summary quality scores increased over 12 months for participants receiving bup/nx (45.6% to 51.6%, P < 0.001) but not other treatment (48.6% to 47.8%, P = 0.788). Bup/nx participants experienced improvements in six of 16 HIV QIs versus three of 16 QIs in other participants. Improvements were mostly in preventive and monitoring care domains. In multivariable analysis, bup/nx was associated with improved summary quality score (beta 8.55; 95% confidence interval, 2.06-15.0). CONCLUSIONS: In this observational cohort study, HIV-infected patients with opioid dependence received approximately half of HIV QIs at baseline. Buprenorphine treatment was associated with improvement in HIV QIs at 12 months. Integration of bup/nx into HIV clinics may increase receipt of high-quality HIV care. Further research is required to assess the effect of improved quality of HIV care on clinical outcomes. PMID- 21317601 TI - Opioid-prescribing practices and provider confidence recognizing opioid analgesic abuse in HIV primary care settings. AB - BACKGROUND: Pain syndromes are common in HIV-infected patients, who also are commonly affected by opioid-use disorders. Although opioids can treat pain, prescribers must consider the consequences of iatrogenic or missed addiction diagnoses. METHODS: In an anonymous online survey, we asked a national sample of HIV providers about their demographics, experience, and patients, and their practices and attitudes about chronic opioid therapy, addiction, and confidence recognizing opioid analgesic abuse. RESULTS: One hundred six providers reported 28% of their patients had chronic pain; 21% received opioid analgesics; 37% were HIV infected by injecting drug use; and 12% were addicted to prescription opioids. Few providers followed recommended guidelines for chronic opioid therapy in nonmalignant pain. Mean provider confidence was 6.3 on a scale of 10. Higher confidence was associated with provider sex (P < 0.05), patient volume (P < 0.03), discussing substance use, (P < 0.05), urine toxicology (P < 0.01), prescribing longer acting opioids (P = 0.005), and prescribing buprenorphine (P = 0.009). CONCLUSIONS: HIV providers seldom follow recommended guidelines for opioid prescribing and have limited confidence in their ability to recognize opioid analgesic abuse. Clinical practices developed to reduce misuse and increase early detection and treatment of opioid dependence are associated with higher confidence. The implementation of guidelines to improve the quality of opioid prescribing in HIV clinics may aid in the diagnosis of addictive disorders and prevent their adverse outcomes. PMID- 21317602 TI - Policy implications of integrating buprenorphine/naloxone treatment and HIV care. AB - Researchers, practitioners, and policymakers have long recognized the potential benefits of providing integrated substance abuse and medical care services, particularly for special populations such as people living with HIV/AIDS. Buprenorphine, an office-based pharmacological treatment for opioid dependence, offers new opportunities for integrating drug treatment into HIV care settings. However, the historical separation between the drug treatment and medical care systems has resulted in a host of policy barriers. The Buprenorphine and HIV Care Evaluation and Support initiative, a multisite demonstration project to assess the feasibility and effectiveness of integrating buprenorphine/naloxone into HIV care settings, provided an opportunity to evaluate if and how policy barriers affect efforts to integrate HIV care and addiction treatment. We found that financing issues, workforce and training issues, and the operational consequences of some conceptual differences between HIV care and addiction treatment are barriers to the full integration of buprenorphine into HIV care. We recommend changes to financing and reimbursement policies, programs to strengthen the addiction treatment skills of physicians, and cross training between the fields of addiction, medicine, drug treatment, and HIV medicine. By addressing some of the policy barriers to integration, this promising new treatment can help the thousands of people living with HIV/AIDS who are also opioid dependent. PMID- 21317604 TI - T cell immunology for the clinician. PMID- 21317605 TI - Misperceptions about neonatal group B streptococcal sepsis in developing countries. PMID- 21317606 TI - Re-emergence of measles in young infants. PMID- 21317607 TI - Congenital mumps pneumonia and persistent pulmonary hypertension. PMID- 21317608 TI - A survey-based evaluation of dermatopathology in the United States. AB - A survey-based assessment of dermatopathologists (DPs) regarding their workload, job satisfaction, and compensation has not been previously undertaken. We e mailed approximately 1000 DPs in the United States requesting them to complete an anonymous and confidential 20-question online survey and received 110 replies. Not all answered each of the questions posed, however. Some of the responses were stratified with regard to the nature of the DPs' practice, that is, academic versus private. DPs with training in pathology, dermatology, or both comprised 64, 36, and 9 respondents, respectively. Seventy-one DPs were in private practice with 35 employed by academic institutions. DPs expressed a high degree of job satisfaction with 88% (30) of academics and 83% (59) of private practitioners stating that they were very or somewhat satisfied with their practice. Average annual compensation for DPs in private practice was $525K and $366K for those in academics. This may relate to the larger percentage of private DPs signing out 10,000 or more cases annually compared with academic DPs (59% vs. 22%). These yearly compensation figures are greater than available estimates for dermatologists or pathologists and most other medical disciplines. PMID- 21317609 TI - Disseminated eruptive clear cell acanthoma with spontaneous regression: further evidence of an inflammatory origin? AB - Clear cell acanthoma (CCA) is a benign epidermal lesion with distinctive clinicopathological features. Multiple disseminated eruptive CCA is an infrequent clinical variant that has been rarely reported. It is characterized by the presence of more than 30 lesions from 1 to 10 mm in diameter that appear progressively over the years. We report the case of a 65-year-old woman with multiple disseminated eruptive CCA affecting her lower extremities. In contrast to previous reports, most of the lesions appeared in a short period of time (less than a month) and, what is more interesting is that some of them have regressed spontaneously leaving residual hyperpigmentation. At present, the histogenesis and etiology of CCA remain unknown. Accumulating data suggest a reactive origin associated with a variety of different inflammatory conditions. The case presented in this report further substantiates that CCA is indeed a reactive epidermal reaction pattern with an inflammatory etiology. PMID- 21317610 TI - Intralymphatic granulomas as a pathogenic factor in cheilitis granulomatosa/Melkersson-Rosenthal syndrome: report of a case with immunohistochemical and molecular studies. AB - Orofacial granulomatosis, an uncommon immunologically mediated disorder, includes cheilitis granulomatosa and Melkersson-Rosenthal syndrome. It is clinically characterized by recurrent or persistent swelling of the orofacial tissues with a spectrum of other orofacial features and sometimes with neurological symptoms. The pathological findings are varied but are often characterized by the presence of noncaseating granuloma. We present a new case of orofacial granulomatosis with unusual histopathological findings, namely, intralymphatic granulomas. These may be the cause of the tissue edema. We demonstrated, by immunohistochemical studies, the lymphatic nature of the vessels affected by the granulomatous process. PMID- 21317611 TI - Psoriatic alopecia/alopecia areata-like reactions secondary to anti-tumor necrosis factor-alpha therapy: a novel cause of noncicatricial alopecia. AB - With the increasing use of anti-tumor necrosis factor alpha (anti-TNF) biologic drugs to treat autoimmune diseases, an expanding array of adverse reactions is emerging. Anti-TNF drug-induced alopecia is a less well-known side effect of this class of drugs. The aim of this study was to define the clinical and histopathological features of alopecia arising in the setting of anti-TNF therapy. Clinical and histopathological features of 3 patients who developed scalp alopecia during anti-TNF treatment were examined. Two of the 3 patients also developed psoriasiform lesions outside the scalp, and biopsies from both scalp and nonscalp sites were reviewed. Clinically, each patient had large scaly patches associated with the scalp alopecia. All scalp biopsies revealed psoriasiform epidermal features and alopecia areata-like dermal changes. Epidermal changes included acanthosis and confluent parakeratosis with neutrophils and frank pustules. Dermal changes included markedly increased catagen/telogen and miniaturized hairs and peribulbar lymphocytic inflammation. Numerous plasma cells and eosinophils were present in all cases. Biopsies from the nonscalp lesions showed psoriasiform changes and prominent eosinophils and plasma cells. Two patients showed significant improvement of the alopecia with topical treatment only. In conclusion, anti-TNF therapy-related alopecia may closely mimic psoriatic alopecia and alopecia areata but can be histologically distinguished from alopecia areata by epidermal psoriasiform changes and dermal plasma cells and from primary psoriasis by the presence of plasma cells and eosinophils. A correct diagnosis can enable effective treatment and, in some cases, allow anti-TNF therapy to continue. PMID- 21317612 TI - Circumscribed palmar hypokeratosis associated with disseminated superficial actinic porokeratosis. AB - Circumscribed palmar and plantar hypokeratosis (CPPH) is a recently described skin condition with particular clinical and histopathological findings. The etiopathogeny of CPPH is still unclear, but an abnormal clone of keratinocytes has been postulated as the possible origin. CPPH has been considered an entity with no potential malignant transformation, but recently, it has been recognized in association with signs of actinic keratosis in the same biopsy. CPPH has never been recognized in association with porokeratosis. Although these entities seem to be different, a possible relationship between them might be suggested. PMID- 21317613 TI - Lymphangiectases are common underlying warts and in normal peritumoral skin: histologic evidence of decreased immune surveillance. AB - BACKGROUND: Lymphangiectases are a histologic sign of lymphostasis, which is associated with decreased immune cell trafficking and cell-mediated immunity. OBJECTIVE: To determine if latent lymphedema is apparent underlying warts and in skin affected by cutaneous neoplasia. MATERIALS AND METHODS: The number and maximal dilation of lymphangiectases were measured in the upper half of the dermis of 51 consecutive biopsies of warts, 230 consecutive normal skin samples from primary skin tumor excisions, and 14 normal skin samples from breast reduction (11) and panniculectomy (3) specimens. RESULTS: All warts had one or more underlying lymphangiectases compared with 79% of peritumor normal skin samples and 50% of cosmetic specimens. The mean number of lymphangiectases and mean maximal dilation were significantly greater in warts than in peritumor skin, which was significantly greater than cosmetic skin samples (3.6 vs. 1.3 vs. 0.12 lymphangiectases per square millimeter and 54 vs. 23 vs. 1 MUm, respectively; P = 0.0001). Warts exhibited mild fibrosis significantly more frequently than peritumor skin (57% vs. 5%; P = 0.0001). For peritumor (normal) skin, age, solar elastosis, and adjacent malignancy correlated with greater dilation of lymphatics. Solar elastosis also correlated with increased number of lymphangiectases. CONCLUSIONS: Minor trauma and solar elastosis from chronic ultraviolet radiation exposure are likely the etiologic factors in the development of lymphostasis. By decreasing immune surveillance, latent lymphedema ostensibly facilitates human papillomavirus infection and carcinogenesis. PMID- 21317614 TI - Histochemical and immunohistochemical study in melasma: evidence of damage in the basal membrane. AB - The pathogenesis of melasma has not been clearly elucidated. Using Fontana Masson; diastase-resistant periodic acid-Schiff stains; and immunohistochemistry to stem cell factor (SCF), its receptor c-kit, anti-mast cell tryptase, and anti collagen type IV antibody, we evaluated melasma lesions and compared them with perilesional skin and photoprotected skin. Samples were taken from lesional and photoprotected nonlesional skin in 24 patients. In other 24 patients, we took biopsies of lesional and perilesional skin. With Fontana Masson, we observed many pigmented basal cells protruding into the dermis of the melasma skin. Periodic acid-Schiff stain and anti-collagen type IV showed damage on the basal membrane in 95.5% and 83%, respectively, in melasma lesion. The immunoreactivity of SCF and the prevalence of mast cells were increased in the dermis of melasma compared with perilesional dermis. The expression of c-kit was significantly increased at lesional epidermis; a frequent protrusion of c-kit-positive basal cells into the dermis was evident in 70% versus that in 29% of perilesional skin. The expression of c-kit was increased at lesional dermis of melasma compared with perilesional skin. We found a low correlation between c-kit expression and prevalence of mast cells; these were increased in melasma skin. The results may suggest a role of SCF, c-kit, and mast cells in the pathogenesis of melasma. We were surprised by the unexpected evidence of damage to basal membrane (BM), which could facilitate the fall or the migration of active melanocytes and melanin into the dermis allowing the constant hyperpigmentation in melasma. PMID- 21317615 TI - Diagnosis and management of bone cement implantation syndrome: case report and brief review. AB - Bone cement implantation syndrome (BCIS) is a rare but potentially fatal intraoperative complication that occurs in patients undergoing cemented orthopedic surgeries. Lack of a robust definition of the syndrome due to rarity of the condition has probably contributed to under reporting of cases. We report a case of a 72-year-old woman hospitalized for an elective orthopedic procedure with a postoperative course complicated by BCIS requiring supportive care in the intensive care unit setting. PMID- 21317616 TI - Hepatitis C virus treatment with pegylated interferon-alfa therapy leading to generalized interstitial granuloma annulare and review of the literature. AB - We discuss the diagnosis and management of a case of generalized granuloma annulare (GA) occurring in a 49-year-old man when being treated with pegylated interferon-alfa for hepatitis C infection. In our case, the GA lesions remained despite an undetectable hepatitis C viral load. The GA resolved only with treatment cessation. PMID- 21317617 TI - Effects of extended-release dipyridamole in vitro on thrombin indices measured by calibrated automated thrombography in poststroke survivors. AB - Randomized trials suggested superior stroke prevention with extended-release dipyridamole (ERD) in combination with low-dose aspirin than either with aspirin or dipyridamole alone. Thrombin generation (TG) is a critical step in clot formation and represents a cornerstone biomarker of atherothrombosis. We, therefore, sought to define the effect of ERD in escalating concentrations on the time course of TG using the Calibrated Automated Thrombogram (CAT) technology in patients after ischemic stroke. Serial plasma samples were obtained from 20 patients with ischemic stroke documented by neuroimaging and who were treated with aspirin for at least 30 days. The impact of 75-, 150-, 250-, and 300-nM ERD on TG was assessed using fluorogenic substrate CAT technology. The following integrated CAT indices were calculated for each ERD dose and compared with the vehicle: TGmax, start time (tstart) peak time (tpeak), and mean time (tmean). Preincubation of platelet-poor plasma with ERD resulted in a dose-dependent significant inhibition of TG. The TGmax was gradually reduced from 447 +/- 21 nM at baseline to 354 +/- 31 nM (P = 0.008) for 75-nM ERD, 298 +/- 24 nM for 150-nM ERD, 248 +/- 26 nM for 250-nM ERD, and finally to 240 +/- 23 nM for 300-nM ERD (P < 0.0001 for all). The tmean was reduced only for the highest (250-300 nM) ERD concentrations. The tstart was only slightly delayed, but not different (1.5 vs. 1.8 vs.1.9 minutes; P = 0.09), for all ERD concentrations. The tpeak was not affected by ERD. ERD in vitro affects thrombin activity indices predominantly by a dose-dependent inhibition of endogenous thrombin potential and demonstrated a trend to delayed initiation of thrombin production. These preliminary data, while intriguing, require confirmation in poststroke patients receiving orally dosed ERD to determine whether these findings are clinically relevant. PMID- 21317618 TI - Efficacy and safety of E-OA-07 in moderate to severe symptoms of osteoarthritis: a double-blind randomized placebo-controlled study. AB - The efficacy and safety of a polyherbal preparation E-OA-07 was compared against placebo in patients with moderate to severe symptoms of osteoarthritis (OA) of the knee, in a double-blind, randomized, parallel groups study. Male or female subjects with American Rheumatism Association functional class II/III and Kellgren Lawrence grade 2 or 3 OA of the knee, who had moderate to severe OA symptoms as recorded by a score of at least 60 on the modified version of the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index, and an overall pain score of at least 70 mm on a 100 mm Visual analogue (VAS) scale were studied. Subjects received 2 capsules of E-OA-07 or placebo twice daily for 12 weeks and paracetamol up to 2 gm per day as rescue medication. Efficacy outcome measures were WOMAC and VAS scores, functional tests for joint mobility and gait, consumption of rescue medication, investigator's global assessment and subjects' opinion. Safety was assessed through incidence of adverse events and subject's assessment of tolerability. After 12 weeks of treatment, there was a significant reduction of WOMAC scores in the E-OA-07 group as compared with placebo (P < 0.01). Mean (+/-SEM) reductions in WOMAC scores of pain, stiffness, and physical function for E-OA-07 versus placebo were 8.86 (1.77) versus 2.50 (0.76), 3.00 (0.65) versus 0.75 (0.45), and 30.00 (5.22) versus 10.87 (2.18). Significant between-group differences were also observed for VAS scores of pain and stiffness. The symptom alleviating effect of E-OA-07 persisted over a follow-up period of 4 and 6 weeks as VAS pain and stiffness scores continued to remain statistically lower (P < 0.01) in the E-OA-07 group than placebo. Subject's opinion was significantly greater in favor of E-OA-07 than placebo, whereas both groups received favorable responses from investigator. Consumption of rescue medication and tolerability ratings were similar between the 2 groups. One E-OA 07 subject was hospitalized due to accidental fall and withdrawn from the study. No other serious adverse event occurred. The effect of E-OA-07 in relieving moderate to severe symptoms of OA of the knee is well tolerated, superior, and more persistent than placebo. PMID- 21317619 TI - Combination use of a TandemHeart with an extracorporeal oxygenator in the treatment of five patients with refractory cardiogenic shock after acute myocardial infarction. AB - Cardiogenic shock remains the leading cause of in-hospital death for patients admitted with acute myocardial infarction. For patients with refractory cardiogenic shock, early revascularization and intra-aortic balloon pump support are often inadequate to reverse the persistent circulatory collapse. We report 5 cases in which an extracorporeal oxygenator in series with the TandemHeart system was instituted emergently in patients with refractory cardiogenic shock from acute myocardial infarction. From our experience, we showed that the device can be safely and easily inserted and that it is able to reverse circulatory collapse and provide hemodynamic stability in patients who otherwise have a high mortality rate. PMID- 21317620 TI - Clinical role of direct renin inhibition in hypertension. AB - Treatment strategies to improve blood pressure control, reduce end-organ damage, and improve cardiovascular outcomes are more important today than ever before. Most patients will require combination therapy to achieve target blood pressure; early initiation of combination therapy may help patients achieve blood pressure control more rapidly. Low-dose combinations may be more effective with fewer adverse effects than higher doses of single agents. Dysregulation of the renin angiotensin-aldosterone system (RAAS) is an important contributor in the pathogenesis of hypertension and its sequelae. Treatment with a direct renin inhibitor blocks the rate-limiting step in the RAAS, resulting in decreased angiotensin I and II production and decreased urinary aldosterone excretion. Like the angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, treatment with a direct renin inhibitor increases plasma renin concentration, but unlike the other RAAS inhibitors, treatment with a direct renin inhibitor decreases plasma renin activity. This unique combination of effects on the RAAS make a direct renin inhibitor an attractive option to combine with other antihypertensive agents for the management of hypertension and its comorbidities. Clinical studies have shown that combining the direct renin inhibitor, aliskiren, with drugs representing each of the major classes of antihypertensive agents (thiazide diuretics, beta blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, and calcium channel blockers) reduces blood pressure, improves markers for cardiovascular outcomes, or does both. Results of several ongoing randomized clinical trials should provide additional insights into the potential of therapeutic combinations that include aliskiren to improve cardiovascular morbidity and mortality in patients with hypertension and related comorbidities. PMID- 21317621 TI - Impact of an acute coronary syndrome pathway in achieving target heart rate and utilization of evidence-based doses of beta-blockers. AB - Beta-blockers remain a cornerstone of therapy in the management of acute coronary syndrome (ACS). The 2007 American College of Cardiology/American Heart Association unstable angina/non-ST elevation myocardial infarction guideline revisions recommend a target heart rate (HR) of 50-60 beats per minute (bpm). Despite improved trends toward utilization of beta-blockers therapy, beta blockers continue to be underdosed. Guideline-based tools have been shown to improve adherence to evidence-based therapy in patients with ACS. Implementation of a standardized ACS pathway would lead to titration of beta-blockers to recommended dosages with improved HRs in eligible patients. The ACS clinical protocol was implemented at the University of Toledo Medical Center in May 2007. A retrospective study of 516 patients admitted during a comparable 6-month period, before and after the institution of the protocol, was conducted. The preprotocol and protocol group included 237 and 279 patients, respectively. Patient information extracted from the medical records included age, gender, HR on admission, blood pressure on admission, duration of hospital stay, preadmission use of beta-blocker, type of beta-blocker and dosage, discharge beta blocker and dosage, peak troponin levels, and therapeutic intervention. A target HR of less than 60 bpm was achieved in 19% of the protocol group, as compared with 6% in the preprotocol group (P < 0.001). The protocol group had a significantly lower mean discharge HR than the preprotocol group (67 vs. 74 bpm; P < 0.001). The mean discharge dose of metoprolol in the protocol group was noted to be significantly higher (118 vs. 80 mg/d; P < 0.001). The institution of an ACS clinical pathway led to utilization of beta-blockers in significantly higher dosages, resulting in improved HR control and increased attainment of target HR. PMID- 21317623 TI - Fibrinolysis and thrombectomy for massive pulmonary embolus. AB - Treatment options for massive and submassive pulmonary embolus may include hemodynamic support, fibrinolysis, anticoagulation, and thrombectomy. Selection of the appropriate therapy requires scrutiny of the patient's hemodynamic status, preexisting conditions, risk of complications, and availability of services at the treatment center. This article illustrates a case of successful fibrinolysis and thrombectomy in a woman with massive pulmonary embolus. A discussion of the indications, benefits, and disadvantages of several pharmacologic, radiologic, and surgical interventions considered in pulmonary embolus will follow. PMID- 21317622 TI - Therapeutic cancer vaccines: the latest advancement in targeted therapy. AB - Therapeutic cancer vaccines represent an emerging therapeutic modality that may play a more prominent role in cancer treatment in the future. Therapeutic cancer vaccines are designed to generate a targeted, immune-mediated antitumor response. There are 2 main types of therapeutic vaccines: patient-specific (generated either from a patient's own cells or tumor) and patient- nonspecific, where a peptide- or vector-based vaccine induces an immune response in vivo against specific tumor-associated antigens. Studies are currently underway to investigate methods to enhance vaccine strategies, including combinations with standard anticancer therapies or immune-modulating agents. Cancer vaccines are usually well tolerated, with minimal toxicity compared with chemotherapy. This review summarizes selected therapeutic cancer vaccines in late clinical development. PMID- 21317624 TI - Sepsis: a review of therapeutics and considerations for anesthesiologists. AB - Sepsis and septic shock remain a major cause of morbidity and mortality. The complexity of the disease pathophysiology has resulted in a rich area of research on etiology and therapeutics. Anesthesiologists will often encounter the syndrome in their routine practice. This review summarizes some of the basic concepts of therapeutics and some novel therapeutics that are pertinent to anesthesia. PMID- 21317625 TI - Comorbidity burden, healthcare resource utilization, and costs in chronic gout patients refractory to conventional urate-lowering therapy. AB - Patients with chronic gout refractory to conventional urate-lowering therapy have high rates of flares and incidence of tophi, which impose a significant disease and potentially economic burden. This study examined healthcare resource use and costs stratified by disease burden. Adult patients diagnosed with gout (ICD-9 CM:274.xx) and having had >=3 flares defined by clinical surrogates within a 12 month period were selected for the case cohort from the Thomson MarketScan databases (2003/Q3-2008/Q3). Only patients who had received allopurinol treatment and a diagnosis of tophi (ICD-9-CM:274.8x) at any time before the first flare (index date) or within 12 months postindex were included and were matched in a 1:1 ratio with control gout-free subjects. The comorbidity burden, healthcare resource use, and annual healthcare costs (2008 US$) in the 12-month postindex period were compared between both cohorts using regression models adjusted for demographic characteristic and stratified for patients with >=6 flares. A total of 679 gout patients met the inclusion criteria for the study and had a higher prevalence of comorbidities than their matched controls. Gout cohort had a significantly higher incidence of emergency room, hospitalizations, outpatient visits, and other medical services than did their matched controls (all comparisons, uncorrected P < 0.01). After adjusting for baseline characteristics, the refractory gout cohort incurred an incremental total annual healthcare cost of $10,222 where 40% of the annual medical cost was for gout-related care compared with control cohort (P < 0.01). Patients with refractory gout have a significant economic burden compared with a gout-free population. PMID- 21317626 TI - Amiodarone-related hyponatremia: rare but potentially lethal. AB - Amiodarone is a one of the most commonly used antiarrhythmic drug with efficacy in both supraventricular and ventricular tachycardia. Hepatic, pulmonary, and thyroid adverse effect profiles of this drug are well described and mandate a close follow-up. We report a case of amiodarone-related hyponatremia, which is one of the rarest side effects associated with this medication and our case was unlike other previous case reports because severity of symptoms required hemodialysis for correction of hyponatremia despite trying dose reduction strategy. PMID- 21317627 TI - The need for novel anticoagulation therapy in acute coronary syndrome. AB - As acute coronary syndrome (ACS) becomes more common nationwide and current anticoagulation regimens used in patients with ACS continue to possess their shortcomings, the need for new anticoagulants is on the rise. Although heparin and warfarin are used effectively in patients with ACS, they both have significant side effects and delivery issues. New factor Xa inhibitors offer an oral alternative that functions early in the coagulation cascade. The role of these new drugs in ACS is explored here. Electronic search strategies were used to collect reviews, randomized controlled trials, and other studies. Databases used included Medline and Cochrane Library and hand selection. Sources selected were limited to those that discussed factor Xa inhibitors in the context of ACS. Selected studies were then assessed for quality and relevance and those deemed relevant included for analysis. Some of the factor Xa inhibitors such as rivaroxaban offer anticoagulation as effective as, if not more effective, heparin and warfarin with lower risks of bleeding and other adverse effects such as heparin-induced thrombocytopenia. Many of these new agents also come in oral form, making them easy for patients to manage and use daily. PMID- 21317628 TI - Unintentional oral beta agonist overdose: case report and review of the literature. AB - An 18-month-old male infant with oral albuterol intoxication was admitted to our pediatric emergency medicine unit with agitation, moderate hypokalemia (2.36 mEq/L), and hyperglycemia (180 mg/dL). His initial electrocardiogram showed sinus tachycardia with a low-amplitude T waves. He was admitted for observation, intravenous hydration was started with added potassium, blood glucose levels were closely monitored along with serum potassium and magnesium, and serial electrocardiography was performed. It should be stressed that as an oral bronchodilator, albuterol does not improve symptoms of asthma, and it can lead to severe complications, which can be avoided when this drug is delivered by inhalation or by a metered dose inhaler. PMID- 21317629 TI - Accidental intrathecal injection of aminophylline in spinal anesthesia. PMID- 21317630 TI - Clinician-delivered intervention to facilitate tobacco quitline use by surgical patients. AB - BACKGROUND: Telephone quitlines that provide counseling support are efficacious in helping cigarette smokers quit and have been widely disseminated; currently, they are underused. Surgery represents a teachable moment for smoking cessation, which can benefit surgical outcomes; however, few surgical patients receive smoking cessation interventions. This study developed and tested a clinician delivered intervention to facilitate quitline use by adult patients scheduled for elective surgery. METHODS: After formative work involving patients and clinicians, a brief intervention was designed to facilitate telephone quitline use. It was then evaluated in a randomized trial of 300 adults scheduled for elective surgery. A control standard brief stop-smoking intervention served as a comparator, with both interventions delivered by clinicians. The primary outcome was the use rate of a quitline accessed through a dedicated toll-free telephone number, with use defined as completing at least one full counseling session. Secondary outcomes included self-reported abstinence from cigarettes at 30 and 90 days postoperatively. RESULTS: Subject characteristics were similar between the two groups. Records from the designated quitline documented that 29 of 149 subjects (19.5%) in the quitline intervention group and 0 of 151 subjects in the control group completed the first full counseling session (P < 0.0001). There were no significant differences in the self-reported point-prevalent and continuous abstinence rates between groups at either 30 or 90 days postoperatively, although rates tended to be higher in the quitline intervention group. CONCLUSIONS: Clinicians can effectively facilitate quitline use by surgical patients. Further work is necessary to evaluate the efficacy of this approach in terms of long-term abstinence from cigarette smoking. PMID- 21317631 TI - If a troponin falls in a forest but no one measures it, does it really matter? PMID- 21317632 TI - Heat shock protein 72 overexpression prevents early postoperative memory decline after orthopedic surgery under general anesthesia in mice. AB - BACKGROUND: Problems with learning and memory are common after surgery in the elderly and are associated with high morbidity. Heat shock protein 72 (Hsp72) confers neuroprotection against acute neurologic injury. We hypothesized that overexpression of Hsp72 would prevent the development of postoperative memory loss. METHODS: C57BL/6 wild-type and Hsp72 overexpressing transgenic mice were randomly allocated to the following: control, isoflurane anesthesia alone, or tibial fracture during isoflurane anesthesia. Animals were trained 24 h before surgery using a fear conditioning protocol and assessed in their training environment and in a novel context on posttreatment days 1, 3, and 7. Microglial activation was assessed by immunostaining. RESULTS: Adult male C57BL/6 wild-type mice exhibited reduced memory evidenced by a decreased percentage freezing time on days 1 and 3 after anesthesia alone (58.8 +/- 5, 46.5 +/- 5 mean +/- SEM) and after surgery (53.4 +/- 6, 44.1 +/- 7), compared with controls (78.8 +/- 5, 63.4 +/- 6; P < 0.05 and P < 0.001, respectively). Hsp72 mice showed no difference by treatment on any day. Similarly, nonhippocampal-dependent memory was significantly impaired on days 1 and 3 after surgery and day 3 after anesthesia. The genotype effect was significant on days 1 and 7. CD68-immunopositive activated microglia in the hippocampus varied modestly with subregion and time; on day 7, there was a significant treatment effect with no genotype effect, with more activated microglia after surgery in all regions. CONCLUSION: Hsp72 overexpression is associated with prevention of postoperative hippocampal dependent and -independent memory deficit induced by anesthesia and/or surgery. Memory deficit is not correlated with numbers of activated hippocampal microglia. PMID- 21317633 TI - Case scenario: Cesarean section complicated by rheumatic mitral stenosis. PMID- 21317634 TI - Pharmacological postconditioning protects isolated rat hearts against ischemia reperfusion injury: the role of mitochondrial permeability transition pore. AB - Postconditioning has been verified to provide cardioprotection and is associated with the state of mitochondrial permeability transition pore. However, there are a few limitations with clinical use of classic postconditioning; therefore, the purpose of this investigation was to study whether inhibition of mitochondrial permeability transition pore opening with cyclosporine A also provided cardioprotection. Langendorff-perfused Sprague-Dawley rat hearts were perfused for 20 minutes with Krebs-Henseleit buffer followed by 30 minutes of crystalloid cardioplegia and 60 minutes of reperfusion. Control hearts (Con group) were reperfused with Krebs-Henseleit buffer. Postconditioning hearts (Ipo group) were with six cycles of 10 seconds reocclusion separated by 10 seconds perfusion before reperfusion. Cyclosporine A postconditioning hearts (CsA group) were reperfused with Krebs-Henseleit buffer containing 0.8 MUmol/L cyclosporine A at first 5 minutes of reperfusion. Compared with Con group, myocardial performance was better preserved in CsA group. Mitochondrial outer membrane integrity was preserved, with less cytosolic diffusion of cytochrome C (p < 0.05) and less frequency of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end labeling-positive myocytes in Ipo and CsA group (p < 0.05). Postconditioning prevented apoptosis-related mitochondrial permeabilization and dysfunction after cardioplegic arrest. Cyclosporine A postconditioning had a better effect than classic postconditioning in myocardial performance. PMID- 21317635 TI - A miniaturized extracorporeal membrane oxygenator with integrated rotary blood pump: preclinical in vivo testing. AB - Extracorporeal membrane oxygenation can achieve sufficient gas exchange in severe acute respiratory distress syndrome. A highly integrated extracorporeal membrane oxygenator (HEXMO) was developed to reduce filling volume and simplify management. Six female pigs were connected to venovenous HEXMO with a total priming volume of 125 ml for 4 hours during hypoxemia induced by a hypoxic inspired gas mixture. Animals were anticoagulated with intravenous heparin. Gas exchange, hemodynamics, hemolysis, and coagulation activation were examined. One device failed at the magnetic motor coupling of the integrated diagonal pump. In the remaining five experiments, the oxygenation increased significantly (arterial oxygen saturation [SaO2] from 79 +/- 5% before HEXMO to 92% +/- 11% after 4 hours) facilitated by a mean oxygen transfer of 66 +/- 29 ml/dl through the oxygenator. The CO2 elimination by the HEXMO reduced arterial PaCO2 only marginal. Extracorporeal blood flow was maintained at 32% +/- 6% of cardiac output. Hemodynamic instability or hemolysis was not observed. The plasmatic coagulation was only mildly activated without significant platelet consumption. The HEXMO prototype provided sufficient gas exchange to prevent hypoxemia. This proof of concept study supports further development and design modifications to increase performance and to reduce coagulation activation for potential long-term application. PMID- 21317636 TI - The effects of a novel therapeutic device on acute kidney injury outcomes in the intensive care unit: a pilot study. AB - Despite decades of improvements in the provision of renal replacement therapy, the morbidity and mortality associated with acute kidney injury (AKI) in the intensive care unit (ICU) setting remains extremely high. Much of the morbidity and mortality of this disorder is the consequence of systemic cellular damage that results from immune dysregulation. This is a prospective, single-arm, single center study designed to evaluate the safety and efficacy of treatment with a selective cytopheretic device (SCD) on clinical outcomes in AKI requiring renal replacement therapy in the ICU. The patients enrolled in the trial were compared with historical case-matched controls with respect to age and Sequential Organ Failure Assessment (SOFA) score. The mortality for the case-matched controls was 77.78%, whereas the mortality in the SCD treatment group was 22.22% (p = 0.027). Multiple regression analysis identified treatment with SCD as the only significant variable affecting mortality among age, SOFA score, average change in urine output over the first 7 days during or after treatment. Mean total urine output in the 10 subjects receiving SCD treatment increased from a baseline of approximately 500 ml/d to more than 2,000 ml/d by day 7 of treatment. The SCD represents a novel therapeutic approach to alter the acute inflammatory response seen in AKI, and further evaluation of the safety and efficacy of the device is being evaluated in a multicenter investigation in the United States under an Food and Drug Administration (FDA) approved investigational device exemption (IDE). PMID- 21317637 TI - Impact of smoking on acute phase outcomes of myocardial infarction. AB - OBJECTIVES: Previous studies have found an apparent paradox in smokers: acute phase outcomes after an acute myocardial infarction are superior to those of nonsmokers. Furthermore, it is reported that smoking has an impact on the metabolism of clopidogrel. This study aimed to examine whether this paradoxical finding exists in patients who undergo drug-eluting stent implantation and are treated with clopidogrel. METHODS: From April 2003 to June 2010, 1424 consecutive patients with acute myocardial infarction who underwent primary or rescue percutaneous coronary intervention with drug-eluting stent and clopidogrel were enrolled. They were divided into three groups: current smokers (n = 486); previous smokers (n = 349); and nonsmokers (n = 589). The primary end point was a composite of 30-day, all-cause death, nonfatal myocardial infarction, or definite stent thrombosis. RESULTS: Compared with nonsmokers, current smokers were younger (P < 0.001) and more often men (P < 0.001). They had larger myocardial infarctions than did nonsmokers [maximum troponin I, 8.9 (2.4, 38.4) vs. 6.8 (1.4, 30.1) ng/ml, P = 0.01]. Current smokers less frequently met the primary end point than did nonsmokers (2.9 vs. 6.1%, P = 0.01). However, after adjustment for baseline and angiographic characteristics, the beneficial effect of smoking was no longer seen (odds ratio 1.35, confidence interval: 0.53-3.44, P = 0.5). CONCLUSION: A beneficial effect of smoking ('smoker's paradox') in the unadjusted primary end point continues to be present; however, after adjustment for differences in baseline characteristics, no benefit was detectable. PMID- 21317638 TI - Association of matrix metalloproteinase-1, matrix metalloproteinase-9, tissue inhibitor of matrix metalloproteinase-1, and interleukin-6 with epicardial and myocardial perfusion. AB - OBJECTIVES: Matrix metalloproteinases (MMPs), which are important regulators of extracellular matrix degradation, are known to induce atherosclerotic plaque rupture because of the degradation of collagen fibers in the fibrous cap. We aimed to investigate the possible association between these enzymes and objective coronary angiographic parameters of epicardial or myocardial perfusion. METHODS: A total of 140 patients with acute coronary syndromes or stable angina pectoris, who were advised to undergo coronary angiography, were included. The correlation between the serum levels of MMP-1, MMP-9, tissue inhibitor of matrix metalloproteinase-1, interleukin-6 (IL-6), and Thrombolysis in Myocardial Infarction frame count (TFC), myocardial blush grade, and the magnitude of change in these parameters after percutaneous intervention was investigated in addition to the association between MMPs and the need for revascularization. RESULTS: TFC and corrected TFC scores were found to be higher in patients with higher MMP-1 levels (R: 0.706, P < 0.001; R: 0.867, P < 0.001). The absolute amount of decrease in TFC/corrected TFC after percutaneous intervention in the patients, who were advised to undergo revascularization, was correlated with higher MMP-1 and MMP-9 levels. MMP-1, MMP-9, and IL-6 were negatively correlated with myocardial blush grade although this association was weaker for MMP-9 and IL-6 compared with MMP-1 (R: -0.574, -0.367, and -0.496, P < 0.001). The mean serum levels of MMP-1, MMP-9, and IL-6 were higher in the patients who were advised to undergo revascularization compared with the patients who did not need revascularization. Odds ratios of MMP-1 and IL-6 for predicting revascularization need were calculated as 1.7 (95% confidence interval: 1.4-2.1; P < 0.001) and 6.5 (95% confidence interval: 2.5-16; P < 0.001), respectively. CONCLUSION: Higher levels of serum MMP-1, MMP-9, and IL-6 can be used to predict worse coronary angiographic findings and may be further targets of active investigation for wide use as risk predictors. PMID- 21317639 TI - Total cholesterol content of erythrocyte membranes in acute coronary syndrome: correlation with apolipoprotein A-I and lipoprotein (a). AB - OBJECTIVES: Recent studies reported that total cholesterol erythrocyte membrane (CEM) levels were associated with the presence of acute coronary syndrome (ACS). However, little is known about the mechanisms of CEM elevation in these patients. The aim of this study was to investigate the association between CEM and the circulating lipid profile to delineate the possible mechanisms of CEM elevation in patients with ACS. METHODS: CEM levels, serum concentrations of triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, lipoprotein (a), apolipoprotein A-I (Apo A-I), apolipoprotein B (Apo B), and high sensitive C-reactive protein levels were measured in 418 Chinese patients undergoing coronary artery angiography, including ACS (n=311) and stable angina pectoris (n=107). RESULTS: CEM levels in the ACS group were significantly higher (median, 129.82; interquartile range, 110.99-156.54 MUg/mg, P<0.001) compared with the stable angina pectoris group (median, 80.88; interquartile range, 66.69 98.57 MUg/mg). Multivariable logistic regression analyses showed a significantly independent relationship between CEM levels and the presence of ACS (odds ratio, 10.257; 95% confidence interval, 5.380-19.556, P<0.001). CEM levels were positively correlated with plasma lipoprotein (a) levels (r=0.175; P<0.001) and negatively correlated with serum Apo A-I levels (r=-0.149; P=0.002). CONCLUSION: CEM levels are closely associated with the occurrence of ACS as an independent determinant. The correlation of CEM with lipoprotein (a) and Apo A-I suggests that changes to these lipid proteins could be one possible mechanism for CEM increase in patients with ACS. PMID- 21317640 TI - Direct observation of human microcirculation during decompressive craniectomy after stroke. AB - OBJECTIVES: Most knowledge related to the pathophysiology of microcirculation in ischemic stroke comes from experimental research. Unfortunately, data on microcirculation in the human brain are limited, partially as a result of the lack of appropriate investigational techniques. The objective of our study was to test the hypothesis that cortical microcirculatory alterations in the brain, in terms of blood flow and vessel density, occur in patients with stroke who require surgical decompression compared with a control group. DESIGN: Prospective and observational study. SETTING: Third-level university hospital. PATIENTS: Six patients who had undergone decompressive surgery as a result of a space-occupying hemispheric infarction. These patients were compared with five patients who had undergone craniotomy for a disease not affecting the cortex. INTERVENTIONS: Cortical microcirculation in the brain was directly observed using sidestream dark-field imaging. All images were analyzed offline. MEASUREMENTS AND MAIN RESULTS: In patients with stroke with a space-occupying hemispheric infarction, 18 good-quality movie images were compared with 25 control group images. In the control group, cortical vessels showed a continuous flow in small, medium, and large vessels compared with patients with stroke who presented intermittent or no flow in all vessels. The proportion of perfused vessels was near 100% in control subjects and 63.44% in patients with stroke. The perfused vessel density index was also higher in control subjects (6.16 1/mm; interquartile range, 5.65-7.56) than in patients with stroke (2.77 1/mm; interquartile range, 1.75-3.86). CONCLUSION: Sidestream dark-field imaging allowed direct visualization of cerebral microcirculatory alterations in the operating room. This technique allowed the documentation of a significant blood flow reduction in the cortical microvascular and a decreased vascular density in patients with stroke compared with control subjects. PMID- 21317641 TI - Tumor necrosis factor-alpha promoter -308 G/A polymorphism and susceptibility to sepsis in very-low-birth-weight infants. AB - OBJECTIVES: To determine whether the tumor necrosis factor-alpha -308 G/A polymorphism is associated with blood culture-proven sepsis in two large cohorts of very-low-birth-weight infants. DESIGN: Genetic association studies. SETTING: Prospective, population-based, multicentered cohort of 1944 very-low-birth-weight infants born in 14 German study centers between 2003 and 2008 and 976 mothers, and a second prospective cohort of 926 very-low-birth-weight infants born in 2009 (German Neonatal Network). MEASUREMENTS AND MAIN RESULTS: In cohort I, 344 of 1944 (18.2%) very-low-birth-weight infants had at least one episode of blood culture-proven sepsis develop. The sepsis incidence stratified to genotype was 19.3% for G/G, 15.8% for G/A, 10.0% for A/A genotype (Cochrane-Armitage trend test: G/G vs. G/A: odds ratio, 1.32; 95% confidence interval, 1.03-1.71; G/G vs. A/A: odds ratio, 1.74; 95% confidence interval, 1.06-2.91; p = .03). There was a trend for association of tumor necrosis factor-alpha -308 A/G genotype with late onset sepsis episodes (incidence: 17.2% for G/G, 12.5% for G/A, 10.0% for A/A genotype; Cochrane-Armitage trend test: G/G vs. G/A: odds ratio, 1.43; 95% confidence interval, 1.09-1.9; G/G vs. A/A: odds ratio, 2.05; 95% confidence interval, 1.19-3.56; p = .009). However, after adjustment for multiple testing, no significant associations were found. Furthermore, the genotype of the investigated 976 mothers had no impact on sepsis risk for their very-low-birth weight infants. We additionally studied a second prospective cohort of 926 very low-birth-weight infants and found no associations with sepsis risk. CONCLUSIONS: No association was found between the tumor necrosis factor-alpha -308 G/A polymorphism blood culture-proven sepsis in two large cohorts of very-low-birth weight infants. A recent meta-analysis demonstrated that the tumor necrosis factor-alpha -308 A allele is associated with higher sepsis risk in adult cohorts. Thus, potential differences between adults and infants need to be incorporated in future study designs evaluating risk profiles for sepsis. PMID- 21317642 TI - Economic implications of nighttime attending intensivist coverage in a medical intensive care unit. AB - OBJECTIVE: Our objective was to assess the cost implications of changing the intensive care unit staffing model from on-demand presence to mandatory 24-hr in house critical care specialist presence. DESIGN: A pre-post comparison was undertaken among the prospectively assessed cohorts of patients admitted to our medical intensive care unit 1 yr before and 1 yr after the change. Our data were stratified by Acute Physiology and Chronic Health Evaluation III quartile and whether a patient was admitted during the day or at night. Costs were modeled using a generalized linear model with log-link and gamma-distributed errors. SETTING: A large academic center in the Midwest. PATIENTS: All patients admitted to the adult medical intensive care unit on or after January 1, 2005 and discharged on or before December 31, 2006. Patients receiving care under both staffing models were excluded. INTERVENTION: Changing the intensive care unit staffing model from on-demand presence to mandatory 24-hr in-house critical care specialist presence. MEASUREMENTS AND MAIN RESULTS: Total cost estimates of hospitalization were calculated for each patient starting from the day of intensive care unit admission to the day of hospital discharge. Adjusted mean total cost estimates were 61% lower in the post period relative to the pre period for patients admitted during night hours (7 pm to 7 am) who were in the highest Acute Physiology and Chronic Health Evaluation III quartile. No significant differences were seen at other severity levels. The unadjusted intensive care unit length of stay fell in the post period relative to the pre period (3.5 vs. 4.8) with no change in non-intensive care unit length of stay. CONCLUSIONS: We find that 24-hr intensive care unit intensivist staffing reduces lengths of stay and cost estimates for the sickest patients admitted at night. The costs of introducing such a staffing model need to be weighed against the potential total savings generated for such patients in smaller intensive care units, especially ones that predominantly care for lower-acuity patients. PMID- 21317643 TI - The Fcgamma receptor IIA-H/H131 genotype is associated with bacteremia in pneumococcal community-acquired pneumonia. AB - OBJECTIVE: To assess the potential association of the functional polymorphism rs1801274 in the receptor IIa for the Fc portion of immunoglobin G (FcgammaRIIa) gene (FCGR2A-H131R) with the susceptibility to and the severity of community acquired pneumonia (CAP). DESIGN: Multicenter prospective and observational study. SETTING: Four university hospitals in Spain. PATIENTS: FCGR2A-H131R polymorphism was determined in 1,262 patients with CAP and in 1,224 in the subject control group. MEASUREMENTS AND MAIN RESULTS: Severe sepsis was recorded in 366 patients. No significant differences in genotype or allele frequencies were seen among patients with CAP or pneumococcal CAP (PCAP) and controls. Patients with bacteremic PCAP (B-PCAP) had significantly higher frequencies of FCGR2A-H/H131 genotypes than those with nonbacteremic PCAP (p = .00016, odds ratio = 2.9, 95% confidence interval 1.58-5.3). The differences remained significant when adjusting for pneumonia severity index, hospital of origin, and intensive care unit admission (p = .0012, odds ratio = 2.83, 95% confidence interval 1.51-5.32). B-PCAP was associated with a significantly higher severity of the disease, evaluated as sepsis severity (p = .000007, odds ratio = 4.40, 95% confidence interval 2.31-8.39), multiorgan dysfunction syndrome (0.00048, odds ratio = 3.29, 95% confidence interval 1.69-6.41), intensive care unit admission, acute renal failure, and acute respiratory distress syndrome. CONCLUSIONS: Our results do not support a role of FCGR2A-H131R polymorphism in susceptibility to CAP or PCAP. However, we provide the insight that homozygosity for FCGR2A-H131 predisposes B-PCAP, which was associated with higher severity in our study. PMID- 21317644 TI - Respiratory dialysis: reduction in dependence on mechanical ventilation by venovenous extracorporeal CO2 removal. AB - OBJECTIVES: Mechanical ventilation is injurious to the lung. Use of lung protective strategies may complicate patient management, motivating a search for better lung-replacement approaches. We investigated the ability of a novel extracorporeal venovenous CO2 removal device to reduce minute ventilation while maintaining normocarbia. DESIGN: Prospective animal study. SETTING: Government laboratory animal intensive care unit. SUBJECTS: Seven sedated swine. INTERVENTIONS: Tracheostomy, volume-controlled mechanical ventilation, and 72 hrs of round-the-clock intensive care unit care. A 15-F dual-lumen catheter was inserted in the external jugular vein and connected to the Hemolung, an extracorporeal pump-driven venovenous CO2 removal device. Minute ventilation was reduced, and normocarbia (Paco2 35-45 mm Hg) maintained. Heparinization was maintained at an activated clotting time of 150-180 secs. MEASUREMENTS AND MAIN RESULTS: Minute ventilation (L/min), CO2 removal by Hemolung (mL/min), Hemolung blood flow, O2 consumption (mL/min), CO2 production by the lung (mL/min), Paco2, and plasma-free hemoglobin (g/dL) were measured at baseline (where applicable), 2 hrs after device insertion, and every 6 hrs thereafter. Minute ventilation was reduced from 5.6 L/min at baseline to 2.6 L/min 2 hrs after device insertion and was maintained at 3 L/min until the end of the study. CO2 removal by Hemolung remained steady over 72 hrs, averaging 72 +/- 1.2 mL/min at blood flows of 447 +/ 5 mL/min. After insertion, O2 consumption did not change; CO2 production by the lung decreased by 50% and stayed at that level (p < .001). As the arterial PCO2 rose or fell, so did CO2 removal by Hemolung. Plasma-free hemoglobin did not change. CONCLUSIONS: Venovenous CO2 removal enabled a 50% reduction in minute ventilation while maintaining normocarbia and may be an effective lung-protective adjunct to mechanical ventilation. PMID- 21317645 TI - Looking in the mirror: self-debriefing versus instructor debriefing for simulated crises. AB - OBJECTIVE: To examine the effectiveness of self-debriefing as compared to instructor debriefing in the change of nontechnical skills performance of anesthesiology residents. DESIGN: Prospective, randomized, controlled study. SETTING: A university hospital simulation center. SUBJECTS: : Fifty anesthesiology residents. INTERVENTIONS: Subjects were instructed in the principles of nontechnical skills for crisis management. Subsequently, each resident participated in a high-fidelity simulated anesthesia crisis scenario (pretest). Participants were randomized to either a video-assisted self debriefing or instructor debriefing. In the self-debriefing group, subjects reviewed their pretest scenario by themselves, guided by the Anesthetists' Non Technical Skills scale. The instructor debriefing group reviewed their pretest scenario guided by an expert instructor also using the Anesthetists' Non Technical Skills scale as a framework. Immediately following their respective debriefings, subjects managed a second simulated crisis (post-test). MEASUREMENTS AND MAIN RESULTS: After all data were collected, two blinded experts independently rated videos of all performances in a random order using the Anesthetists' Non-Technical Skills scale. Performance significantly improved from pretest to post-test (p < .01) regardless of the type of debriefing received. There was no significant difference in the degree of improvement between self debriefing and instructor debriefing (p = .58). CONCLUSIONS: Nontechnical skills for crisis resource management improved with training, as measured by the Anesthetists' Non-Technical Skills scale. Crisis resource management can be taught, with measurable improvements. Effective teaching of nontechnical skills can be achieved through formative self-assessment even when instructors are not available. PMID- 21317646 TI - The effect of heparin administration in animal models of sepsis: a prospective study in Escherichia coli-challenged mice and a systematic review and metaregression analysis of published studies. AB - INTRODUCTION: If thrombosis contributes to sepsis, heparin titrated using activated partial thromboplastin times may be efficacious. We investigated heparin in preclinical models. METHODS AND MAIN RESULTS: In unchallenged mice (n = 107), heparin at 100, 500, or 2500 units/kg produced activated partial thromboplastin time levels less than, within, or greater than a prespecified therapeutic range (1.5-2.5 times control), respectively. In animals (n = 142) administered intratracheal Escherichia coli challenge, compared to placebo treatment, heparin at 100, 500, or 2500 units/kg were associated with dose dependent increases in the hazard ratios of death (hazard ratio [95% confidence interval]: 1.08 [0.66, 1.76]; 1.34 [0.80, 2.24]; 3.02 [1.49, 6.10], respectively) (p = .001 for the dose effect). Compared to normal saline challenge, E. coli without heparin (i.e., with placebo) increased the activated partial thromboplastin time (p = .002) close to the therapeutic range. While heparin at 100 and 500 units/kg with E. coli further increased activated partial thromboplastin time (p < .0001 vs. placebo) within or above the therapeutic range, respectively, these did not decrease inflammatory cytokines or lung injury. In metaregression analysis of published preclinical studies, heparin improved survival with lipopolysaccharide (n = 23, p < .0001) or surgically induced infection (n = 14, p < .0001) but not monobacterial (n = 7, p = .29) challenges. CONCLUSION: Coagulopathy with sepsis or other variables, such as type of infectious source, may influence the efficacy of heparin therapy for sepsis. PMID- 21317647 TI - Is total parenteral nutrition protective against hypoglycemia during intensive insulin therapy? A hypothesis. AB - INTRODUCTION: It appears that enteral nutrition is more likely to produce hypoglycemia during intensive insulin therapy than is total parenteral nutrition. POINT OF VIEW: Although this consequence may in part be the result of frequent discontinuation of feeding or to variability of gastrointestinal absorption of nutrients, there are also distinct physiological differences between total parenteral nutrition and enteral nutrition that are more likely to be responsible, including much higher serum insulin responses to total parenteral nutrition than with enteral nutrition that approach submaximal response levels and direct appearance of administered glucose into the systemic circulation with total parenteral nutrition at rates that approximate usual postabsorptive rates and that avoid first-pass hepatic clearance. CONCLUSIONS: These factors may make total parenteral nutrition more efficacious, at least initially, with intensive insulin therapy and may justify setting a higher limit for glucose control when enteral feeding is principally used. PMID- 21317648 TI - Incidence and risk factors of recurrent acute lung injury. AB - OBJECTIVE: To determine risk factors for development of recurrent acute lung injury. DESIGN: A population-based case-control study. SETTING: The study was conducted in Olmsted County, MN, from 1999 to 2008. PATIENTS: Using a validated electronic screening protocol, investigators identified intensive care patients with acute hypoxemia and bilateral pulmonary infiltrates. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The presence of acute lung injury was independently confirmed according to American-European Consensus Conference criteria. Recurrent acute lung injury cases were subsequently matched (1:1:1) with two controls (single acute lung injury and no acute lung injury) on age, gender, duration of follow-up, and predisposing conditions. Risk factors evaluated included gastroesophageal reflux disease, alcohol consumption, smoking, chronic opioid use, and transfusions. We identified 917 patients with acute lung injury, 19 of which developed a second episode, yielding a frequency of 2.02 (95% confidence interval 1.10-2.93) per 100,000 person years. The median time to development of the second episode was 264 days (interquartile range 80-460 days), with a mortality of 47% during the episode. The history of gastroesophageal reflux disease was highly prevalent in patients who developed recurrent acute lung injury: 15 of 19 patients (79%) compared to 5 of 19 (26%) matches with a single episode of acute lung injury (p = .006) and 8 of 19 (42%) matches without acute lung injury (p = .016). Other exposures were similar between the cases and the two matched controls. CONCLUSIONS: Recurrent acute lung injury is not a rare phenomenon in the intensive care unit and may continue to increase with improvements in survival following acute lung injury. Gastroesophageal reflux disease was identified as an important risk factor for recurrent acute lung injury and may suggest an important role of gastric aspiration in the development of this syndrome. PMID- 21317649 TI - Efficacy of portable and percutaneous cardiopulmonary bypass rewarming versus that of conventional internal rewarming for patients with accidental deep hypothermia. AB - OBJECTIVE: Since 2001, at our institution, a portable and percutaneous cardiopulmonary bypass system has been used for rewarming of patients with accidental deep hypothermia. Before 2001, a conventional internal rewarming technique was used. The aim of this research is to examine the efficacy of portable and percutaneous cardiopulmonary bypass for rewarming of patients with accidental severe hypothermia and compare it with that of conventional rewarming methods. DESIGN: Historical study. SETTING: The exclusive emergency medical center and trauma center level 1 in Western Kanagawa, Japan. PATIENTS: From April 1992 to March 2009, 70 patients with accidental deep hypothermia (core temperature <28 degrees C) were transferred to our hospital. Two patients presented with intracranial hemorrhage on initial head computed tomography scans. These two patients were excluded because each required an emergency operation. Therefore, 68 patients were included in this study. We compared patients' clinical characteristics and outcomes. The parameters included the following: sex, age, vital signs on arrival to our hospital (Glasgow coma Scale scores, systolic blood pressure, heart rate, respiratory rate, core temperature), electrocardiogram on arrival to our hospital, rewarming speed, time of rewarming until 34 degrees C was reached, ventricular fibrillation occurrence rate during rewarming, cause of cold environmental exposure, Glasgow Outcome Scale scores, and mortality. In addition, we divided the conventional and portable and percutaneous cardiopulmonary bypass rewarming groups into two categories depending on whether cardiopulmonary arrest occurred on arrival to our hospital. We also compared the survival rate and average Glasgow Outcome Scale scores for each group. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients' clinical backgrounds did not differ significantly between the conventional and portable and percutaneous cardiopulmonary bypass rewarming groups. Glasgow Outcome Scale scores and survival rates of the portable and percutaneous cardiopulmonary bypass rewarming group patients, irrespective of whether cardiopulmonary arrest was experienced on arrival to our hospital, were significantly higher than those of the conventional rewarming group. CONCLUSIONS: Portable and percutaneous cardiopulmonary bypass rewarming can improve the mortality rates and Glasgow Outcome Scale scores of accidental deep hypothermia patients. PMID- 21317650 TI - Is worsening multiple organ failure the cause of death in patients with severe sepsis? AB - OBJECTIVES: Although the mortality of severe sepsis is easily quantified, the actual cause and timing of death from severe sepsis are less defined. We used the INDEPTH (International Integrated Database for the Evaluation of Severe Sepsis and Drotrecogin alfa activated) database to investigate the reported cause of death in patients with severe sepsis. DESIGN: Retrospective database analysis. PATIENTS: Data from 4459 patients with severe sepsis (drotrecogin alfa activated, n = 3228; placebo, n = 1231) included in five clinical trials conducted in tertiary care institutions in 28 countries. MEASUREMENTS AND MAIN RESULTS: We examined the cause of death and the pattern of Sequential Organ Failure Assessment scores near the time of death. We also evaluated the time course of biomarker levels at this late stage. A total of 1201 (27.0%) patients died during the 28-day study period. The main causes of death were as follows: sepsis associated multiple organ failure (43.1%), refractory septic shock (22.6%), and respiratory failure (13.0%). There were no significant differences in the distributions of cause of death between drotrecogin alfa activated and placebo patients, so that all patients were combined for analysis. The mean cardiovascular Sequential Organ Failure Assessment score increased from 2.4, 4 days before death, to 2.9, 1 day before death, and the mean respiratory Sequential Organ Failure Assessment score increased from 2.6, 4 days before death, to 2.9, 1 day before death. The increase in these individual Sequential Organ Failure Assessment scores was more prominent in patients who died early (day 0-5). Protein C levels decreased and interleukin-6 levels increased in the days before death. CONCLUSION: Patients with severe sepsis typically die of multiple organ failure, refractory shock, or respiratory failure. Persistent, more than worsening, organ failure is the more common pattern before death. PMID- 21317651 TI - Potential metabolic consequences of statins in sepsis. AB - OBJECTIVE: Statins may be important for the prevention and management of sepsis; however, through their impact on ubiquinone synthesis, they may impair mitochondrial and organ function in the septic patient. Here we provide a narrative review of the function and roles of ubiquinone in cellular metabolism, the interactions with statins, and the potential consequences in the critically ill. DATA SOURCE: Literature search using the PubMed database. Search terms included statins, mitochondria, ubiquinone, and sepsis. CONCLUSION: Statins are 3 hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and act by decreasing mevalonate levels, a precursor for cholesterol synthesis. However, mevalonate is also a precursor for ubiquinone, an integral component of the mitochondrial respiratory chain and an important antioxidant. Plasma ubiquinone is inversely related to statin levels, and impaired statin metabolism or excretion can decrease ubiquinone levels markedly. This is potentially important as critical illness markedly impairs statin metabolism. As mitochondrial dysfunction may be a major contributor to sepsis-induced organ failure, it is plausible that low ubiquinone levels may exacerbate mitochondrial and organ dysfunction. Furthermore, although the clinical relevance of low ubiquinone levels is currently unknown in the critically ill, this is often cited as a possible cause of the myopathy and rhabdomyolysis associated with statin use. PMID- 21317652 TI - Total liquid ventilation efficacy in an ovine model of severe meconium aspiration syndrome. AB - OBJECTIVE: To test the hypothesis that total liquid ventilation enables a more effective and better tolerated lavage than a bronchoalveolar lavage performed with diluted surfactant in a newborn ovine model of severe acute meconium aspiration syndrome. DESIGN: Prospective, randomized, interventional study. SETTING: Animal research laboratory at the Faculte de medecine et des sciences de la sante de l'universite de Sherbrooke, Sherbrooke, Canada. SUBJECTS: Twenty three newborn lambs, <4 days, 2.5-4.0 kg in weight. INTERVENTIONS: Animals were intubated, anesthetized, and paralyzed. Catheters were placed in the femoral artery and jugular vein. Severe meconium aspiration syndrome was obtained by instillation of a 25% dilution of human meconium in saline (1 mL/kg * 2). Lambs were then randomized in 12 total liquid ventilation-bronchoalveolar lavage (minute ventilation of 160 mL/kg/min with perfluorodecalin) vs. 11 bronchoalveolar lavage performed with diluted surfactant (conventional ventilation + 30 mL/kg in two aliquots bronchoalveolar lavage with 5 mg/mL BLES surfactant). Surviving lambs were ventilated for a total of 4 hrs and euthanized. MEASUREMENTS AND MAIN RESULTS: Arterial blood gases, systemic and pulmonary hemodynamic parameters using the thermodilution method, percentage of recovered meconium, and lung histologic scores. Total liquid ventilation bronchoalveolar lavage enabled a significantly higher PaO2 throughout the experiment. PaCO2, pH, and hemodynamic parameters were comparable for both groups except for an increase in mean pulmonary arterial pressure during total liquid ventilation. Total liquid ventilation bronchoalveolar lavage allowed for 43 +/- 14% of the instilled meconium to be removed vs. 28 +/- 10% for bronchoalveolar lavage performed with diluted surfactant (p = .022). Lung histologic analysis showed no difference between total scores. CONCLUSIONS: Total liquid ventilation bronchoalveolar lavage is well tolerated and more effective in terms of meconium washout and gas exchange than bronchoalveolar lavage performed with diluted surfactant in this experimental model of severe meconium aspiration syndrome. These positive results open the way to further experiments in our ovine model, ultimately aiming at a clinical trial with total liquid ventilation bronchoalveolar lavage to treat severe meconium aspiration syndrome. PMID- 21317653 TI - Evidence for quality indicators to evaluate adult trauma care: a systematic review. AB - OBJECTIVE: Multiple quality indicators are available to evaluate adult trauma care, but their characteristics and outcomes have not been systematically compared. We sought to systematically review the evidence about the reliability, validity, and implementation of quality indicators for evaluating trauma care. DATA SOURCES: Search of MEDLINE, EMBASE, CINAHL, and The Cochrane Library up to January 14, 2009; the Gray Literature; select journals by hand; reference lists; and articles recommended by experts in the field. STUDY SELECTION: Studies were selected that evaluated the reliability, validity, or the impact of one or more quality indicators on the quality of care delivered to patients >= 18 yrs of age with a major traumatic injury. DATA EXTRACTION: Reviewers with methodologic and content expertise conducted data extraction independently. DATA SYNTHESIS: The literature search identified 6869 citations. Review of abstracts led to the retrieval of 538 full-text articles for assessment; 40 articles were selected for review. Of these, 20 (50%) articles were cohort studies and 13 (33%) articles were case series. Five articles used control groups, including three before and after case series, a case-control study, and a nonrandomized controlled trial. A total of 115 quality indicators in adult trauma care was identified, predominantly measures of hospital processes (62%) and outcomes (17%) of care. We did not identify any posthospital or secondary injury prevention quality indicators. Reliability was described for two quality indicators, content validity for 22 quality indicators, construct validity for eight quality indicators, and criterion validity for 46 quality indicators. A total of 58 quality indicators was implemented and evaluated in three studies. Eight quality indicators had supporting evidence for more than one measurement domain. A single quality indicator, peer review for preventable death, had both reliability and validity evidence. CONCLUSIONS: Although many quality indicators are available to measure the quality of trauma care, reliability evidence, validity evidence, and description of outcomes after implementation are limited. PMID- 21317654 TI - Chemomodulatory potential of Asparagus adscendens against murine skin and forestomach papillomagenesis. AB - We have evaluated the cancer chemopreventive efficacy of the roots of Asparagus adscendens, which have been used in the Indian traditional medicine system for a long time for the treatment of various ailments. For the first time, the effect of its different doses in a test diet was examined on 7,12 dimethylbenz(a)anthracene-induced skin and benzo(a)pyrene-induced forestomach papillomagenesis in mice. The effect of these test diets was also examined on drug-metabolizing phase I and phase II enzymes, antioxidant enzymes, reduced glutathione content, and peroxidative damage in mice. Results exhibited a significant reduction in the skin and the forestomach tumor incidence with respect to all the three (2, 4, and 6%, w/w) doses as compared with control. Among all the doses tested, 4% of test diet was most effective in protecting the animals against papillomagenesis. Further, the roots of A. adscendens inhibited phase I, and activated phase II system and antioxidant enzymes in the liver especially with 4% of test diet. The content of reduced glutathione was also significantly elevated whereas the peroxidative damage along with lactate dehydrogenase activity were reduced with all the three doses of the test diet. Together, these results suggest the cancer chemopreventive potential of A. adscendens, which could be mediated through drug-metabolizing phase I and phase II enzymes as well as free radical scavenging antioxidant enzymes. PMID- 21317655 TI - Amla (Emblica officinalis Gaertn), a wonder berry in the treatment and prevention of cancer. AB - Emblica officinalis Gaertn. or Phyllanthus emblica Linn, commonly known as Indian gooseberry or amla, is arguably the most important medicinal plant in the Indian traditional system of medicine, the Ayurveda. Various parts of the plant are used to treat a range of diseases, but the most important is the fruit. The fruit is used either alone or in combination with other plants to treat many ailments such as common cold and fever; as a diuretic, laxative, liver tonic, refrigerant, stomachic, restorative, alterative, antipyretic, anti-inflammatory, hair tonic; to prevent peptic ulcer and dyspepsia, and as a digestive. Preclinical studies have shown that amla possesses antipyretic, analgesic, antitussive, antiatherogenic, adaptogenic, cardioprotective, gastroprotective, antianemia, antihypercholesterolemia, wound healing, antidiarrheal, antiatherosclerotic, hepatoprotective, nephroprotective, and neuroprotective properties. In addition, experimental studies have shown that amla and some of its phytochemicals such as gallic acid, ellagic acid, pyrogallol, some norsesquiterpenoids, corilagin, geraniin, elaeocarpusin, and prodelphinidins B1 and B2 also possess antineoplastic effects. Amla is also reported to possess radiomodulatory, chemomodulatory, chemopreventive effects, free radical scavenging, antioxidant, anti-inflammatory, antimutagenic and immunomodulatory activities, properties that are efficacious in the treatment and prevention of cancer. This review for the first time summarizes the results related to these properties and also emphasizes the aspects that warrant future research to establish its activity and utility as a cancer preventive and therapeutic drug in humans. PMID- 21317656 TI - Diagnosis and management of familial Mediterranean fever: integrating medical genetics in a dedicated interdisciplinary clinic. AB - Familial Mediterranean fever is an autosomal recessive genetic disorder characterized by recurrent febrile polyserositis, especially prevalent in individuals of Mediterranean descent. Familial Mediterranean fever can have nonspecific manifestations that mimic many common acquired disorders such as infections, acute appendicitis, cholecystitis, and arthritis, which can delay diagnosis for many years and subject patients to extensive evaluations and even unnecessary surgery. Untreated familial Mediterranean fever can result in serious complications such as end-stage renal disease and malabsorption secondary to amyloid deposition in the kidneys and digestive tract, male and female infertility, and growth retardation in children. These significant sequelae, along with the episodic acute attacks, are readily preventable by treatment with oral colchicine and underscore the necessity of early detection and treatment from a medical, psychosocial, and economic standpoint. We describe our comprehensive approach to the accurate diagnosis and effective management of this disorder by means of a dedicated familial Mediterranean fever clinic that incorporates medical genetics on equal footing with general medicine. In addition to providing the clinician with the presenting features of familial Mediterranean fever, methods of diagnosis including molecular testing, and current management based on our extensive experience with hundreds of affected individuals, we also advance this approach as a model for the incorporation of medical genetics practice into the more traditional domains of general medicine. PMID- 21317657 TI - Evaluating patient experience in online health communities: implications for health care organizations. AB - BACKGROUND: Online communities that focus on health-related matters have rapidly increased in number in the last several years or so. The increasing demand from health consumers for such forums have led several leading health care organizations (HCOs), including Kaiser Permanente and Johns Hopkins, to establish online communities/discussion forums as part of their patient-support services. Patients' interactions in such HCO-led online health communities potentially add another important dimension to the overall patient experience. However, there has been limited research focus on measuring or evaluating patients' experience in such online health communities. PURPOSES: The objective of this study was to evaluate patients' online community experience (OCE) and examine its impact on patients' attitude toward the HCO and its services. METHOD: The data collection was conducted using an online questionnaire sent to consumers/patients who participated in the online health communities of three large academic medical centers: the Johns Hopkins Pathology discussion board, run by the pathology department at Johns Hopkins University; the MD Anderson Cancer survivor board, run by MD Anderson Cancer Center at the University of Texas; and the Joslin Discussion Board, run by Joslin Diabetes Center affiliated with Harvard Medical School. Confirmatory factor analysis was done to validate the four dimensions of OCE. Linear regression technique was used to validate the impact of OCE on patient attitudes. FINDINGS: The results provide support for four dimensions of patients' OCE: pragmatic, empathic, sociability, and usability. Furthermore, all these four dimensions of OCE had a positive impact on patient's attitudes toward the HCO and its services. PRACTICE IMPLICATIONS: An understanding of the four dimensions of patient experience in online health communities and its implications on patient attitudes could help HCOs to design, deploy, and manage such online health communities more effectively. PMID- 21317658 TI - Hospital boards and hospital strategic focus: the impact of board involvement in strategic decision making. AB - BACKGROUND: Despite pressures to change the role of hospital boards, hospitals have made few changes in board composition or director selection criteria. Hospital boards have often continued to operate in their traditional roles as either "monitors" or "advisors." More attention to the direct involvement of hospital boards in the strategic decision-making process of the organizations they serve, the timing and circumstances under which board involvement occurs, and the board composition that enhances their abilities to participate fully is needed. PURPOSES: We investigated the relationship between broader expertise among hospital board members, board involvement in the stages of strategic decision making, and the hospital's strategic focus. METHODOLOGY/APPROACH: We surveyed top management team members of 72 nonacademic hospitals to explore the participation of critical stakeholder groups such as the board of directors in the strategic decision-making process. We used hierarchical regression analysis to explore our hypotheses that there is a relationship between both the nature and involvement of the board and the hospital's strategic orientation. FINDINGS: Hospitals with broader expertise on their boards reported an external focus. For some of their externally-oriented goals, hospitals also reported that their boards were involved earlier in the stages of decision making. PRACTICE IMPLICATIONS: In light of the complex and dynamic environment of hospitals today, those charged with developing hospital boards should match the variety in the external issues that the hospital faces with more variety in board makeup. By developing a board with greater breadth of expertise, the hospital responds to its complex environment by absorbing that complexity, enabling a greater potential for sensemaking and learning. Rather than acting only as monitors and advisors, boards impact their hospitals' strategic focus through their participation in the strategic decision-making process. PMID- 21317659 TI - Acute care patients discuss the patient role in patient safety. AB - BACKGROUND: Patient safety has been a highly researched topic in health care since the year 2000. One strategy for improving patient safety has been to encourage patients to take an active role in their safety during their health care experiences. However, little research has shed light on how patients view their roles. PURPOSE: This study attempted to address this deficit by inductively exploring the results of a qualitative study in which patients reported their ideas about what they believe their roles should be. METHODOLOGY: Patients with an overnight stay in the previous 90 days at one of three hospitals were surveyed using a mailing methodology. Of 1,040 respondents, 491 provided an open-ended response regarding what they believe the patient role should be. FINDINGS: Qualitative analysis found several prominent themes. The largest proportion of responses (23%) suggested that patients should follow instructions given by care providers. Other prominent themes were that patients should ask questions and become informed about their conditions and treatments, and many implied that they should expect competent care. Our results suggest that patients believe they should be able to trust that they are being provided competent care, as opposed to assuming a leadership role in their safety. PRACTICE IMPLICATIONS: Our results suggest that engaging patients in safety efforts may be complex, requiring a variety of strategies. Managers must provide environments conducive to staff and patient interactions to support patients in this effort. Different types of patients may require different engagement strategies. PMID- 21317660 TI - A case for safety leadership team training of hospital managers. AB - BACKGROUND: Delivering safe patient care remains an elusive goal. Resolving problems in complex organizations like hospitals requires managers to work together. Safety leadership training that encourages managers to exercise learning-oriented, team-based leadership behaviors could promote systemic problem solving and enhance patient safety. Despite the need for such training, few programs teach multidisciplinary groups of managers about specific behaviors that can enhance their role as leadership teams in the realm of patient safety. PURPOSE: The aims of this study were to describe a learning-oriented, team-based, safety leadership training program composed of reinforcing exercises and to provide evidence confirming the need for such training and demonstrating behavior change among management groups after training. METHODS: Twelve groups of managers from an academic medical center based in the Northeast United States were randomly selected to participate in the program and exposed to its customized, experience-based, integrated, multimodal curriculum. We extracted data from transcripts of four training sessions over 15 months with groups of managers about the need for the training in these groups and change in participants' awareness, professional behaviors, and group activity. FINDINGS: Training transcripts confirmed the need for safety leadership team training and provided evidence of the potential for training to increase targeted behaviors. The training increased awareness and use of leadership behaviors among many managers and led to new routines and coordinated effort among most management groups. Enhanced learning-oriented leadership often helped promote a learning orientation in managers' work areas. PRACTICE IMPLICATIONS: Team-based training that promotes specific learning-oriented leader behaviors can promote behavioral change among multidisciplinary groups of hospital managers. PMID- 21317661 TI - Safety culture of nursing homes: opinions of top managers. AB - BACKGROUND: Examining the perception of patient safety culture (PSC) of top managers in health care settings is important because their orientation to PSC can have a large influence on the facility. PURPOSES: In this research, the perception of PSC of nursing home administrators (NHAs) and directors of nursing (DONs) is examined. METHODOLOGY/APPROACH: Primary data were collected to examine the opinions of NHAs and DONs regarding PSC. Information was collected from a large nationally representative sample of 4,000 nursing homes. The Nursing Home Survey on Patient Safety Culture survey instrument was used as a measure of PSC. This has 12 domains and 38 items. Bias indexes, intraclass correlation coefficients, and Pearson's product-moment correlation coefficients of the differences between NHA and DON item scores were examined. FINDINGS: Using a 0 100 scale, most scores fell into the 55-80 range. Higher scores represent a higher (more favorable) PSC. Agreement between the NHAs and DONs was excellent in 10 items, good in 15 items, moderate in 4 items, and poor in 8 items. Of the four largest differences in scores, the NHA scores were higher than the DON scores for 1 item, and DON scores were higher than the NHA scores for 3 items. IMPLICATIONS: The overall perception from both NHAs and DONs appear to represent a somewhat "positive" outlook from these top managers on their institution's PSC. However, NHAs in general report higher scores than DONs do. The areas of divergence between these top managers are further discussed, with a view toward directing future patient safety investigations and initiatives in nursing homes. PMID- 21317662 TI - Performance management and goal ambiguity: managerial implications in a single payer system. AB - BACKGROUND: Goal ambiguity influences the effectiveness of performance management systems to drive organizations toward enhanced results. The literature analyzes the antecedents of goal ambiguity and shows the influence of goal ambiguity on the performance of U.S. federal agencies. However, no study has analyzed goal ambiguity in other countries or in health care systems. PURPOSE: This study has three aims: to test the validity of a measurement instrument for goal ambiguity, to investigate its main antecedents, and to explore the relationship between goal ambiguity and organizational performance in a large, public, Beveridge-type health care system. METHODOLOGY: A nationwide survey of general managers of the Italian national health system was performed. A factor analysis was used to validate the mono-dimensionality of an instrument that measured goal ambiguity. Structural equation modeling was used to test both the antecedents and the influence of goal ambiguity on organizational performance. RESULTS: Data from 135 health care organizations (53% response rate) were available for analysis. The results confirm the mono-dimensionality of the instrument, the existence of two environmental sources of ambiguity (political endorsement and governance commitment), and the negative relationship between goal ambiguity and organizational performance. PRACTICE IMPLICATIONS: Goal ambiguity matters because it may hamper organizational performance. Therefore, performance should be fostered by reducing goal ambiguity (e.g., goal-setting model, funding arrangements, and political support). Mutatis mutandis, our results may apply to public health care systems of other countries or other "public interest" sectors, such as social care and education. PMID- 21317663 TI - Successful remediation of patient safety incidents: a tale of two medication errors. AB - BACKGROUND: As patient safety acquires strategic importance for all stakeholders in the health care delivery chain, one promising mechanism centers on the proactive disclosure of medical errors to patients. Yet, disclosure and apology alone will not be effective in fully addressing patients' concerns after an adverse event unless they are paired with a remediation component. PURPOSE: The purpose of this study was to identify key features of successful remediation efforts that accompany the proactive disclosure of medical errors to patients. APPROACH: We describe and contrast two recent and very similar cases of preventable medical error involving inappropriate medication at a large tertiary care academic medical center in the Midwestern United States. FINDINGS: Despite their similarity, the two medical errors led to very different health outcomes and remediation trajectories for the injured patients. Although one error causing no permanent harm was mismanaged to the lasting dissatisfaction of the patient, the other resulted in the death of the patient but was remediated to the point of allowing the family to come to terms with the loss and even restored a modicum of trust in the providers' sincerity. PRACTICE IMPLICATIONS: To maximize the opportunities for successful remediation, as soon as possible after the incident, providers should pledge to injured patients and their relatives that they will assist and accompany them in their recovery as long as necessary and then follow through on their pledge. As the two case studies show, it takes training and vigilance to ensure adherence to these principles and reach an optimal outcome for patients and their relatives. PMID- 21317664 TI - Understanding nurse anesthetists' intention to leave their job: how burnout and job satisfaction mediate the impact of personality and workplace characteristics. AB - BACKGROUND: The retention of nurse anesthetists is of paramount importance, particularly in view of the fact that the health care workforce is shrinking. Although many health care providers find their work satisfying, they often consider leaving their jobs because of the stress. Are there ways to improve this situation? PURPOSE: This study investigated how work environment characteristics and personality dimensions relate to burnout and job satisfaction and ultimately to turnover intention among Dutch nurse anesthetists. METHODOLOGY: An online self reporting questionnaire survey was performed among Dutch nurse anesthetists. The questionnaire included scales to assess personality dimensions, work climate, work context factors, burnout, job satisfaction, and turnover intention. The research model stated that personality dimensions, work climate, and work context factors, mediated by burnout and job satisfaction, predict turnover intention. Structural equation modeling was used to test the research model. FINDINGS: Nine hundred twenty-three questionnaires were completed (46% response rate). Burnout mediated the relationship between personality dimensions and turnover intention; job satisfaction mediated the relationship of work climate and work context factors to turnover intention. PRACTICE IMPLICATIONS: To retain nursing staff and to maintain adequate staff strength, it is important to improve job satisfaction by creating a positive work climate and work context and to prevent burnout by selecting the most suitable employees through personality assessment. PMID- 21317665 TI - Hospitals' health promotion services in their communities: findings from a literature review. AB - BACKGROUND: Hospitals have long had an important role in the health of communities and the nation. Health promotion (HP) has gained attention in American health and will become more important with the 2010 health reform legislation. Many U.S. hospitals provide HP services in their communities, and hospital leaders are accountable for HP. PURPOSES: This article uses a systematic review of research literature to answer three questions about U.S. hospitals' HP services in their communities: (a) What are the characteristics of hospitals that offer HP services? (b) What are the reasons that hospitals offer HP services? And (c) what are the implementation processes hospitals use to offer HP services? METHODOLOGY/APPROACH: Authors used search criteria and found 255 articles published between 1985 and 2009. Inclusion/exclusion criteria were applied to screen and select articles, and 25 articles were kept and reviewed. Authors independently completed a standard data extraction form for each article, combined and reconciled their data, and created a database of findings. FINDINGS: Hospital size was positively associated with HP, as were participation in systems, alliances, and networks. Communities' median income, existing HP, population younger than 65 years, population above poverty, and employment levels were positively related to hospitals' HP. Relationships with hospital ownership, managed care, and competition were less clear. External norms, HP diffusion, and mimetic behavior were reasons for hospitals' HP; community benefit laws were less important. To implement HP, hospitals applied management methods, shared resources, collaborated with community organizations, and used a variety of HP methods. PRACTICE IMPLICATIONS: Collaboration and linkages with other organizations enable hospitals to expand HP. Hospitals should apply management methods (not just HP methods) to effectively offer HP services. Support for small hospitals' HP is needed. PMID- 21317666 TI - Accommodation to wavefront vergence and chromatic aberration. AB - PURPOSE: Longitudinal chromatic aberration (LCA) provides a cue to accommodation with small pupils. However, large pupils increase monochromatic aberrations, which may obscure chromatic blur. In this study, we examined the effect of pupil size and LCA on accommodation. METHODS: Accommodation was recorded by infrared optometer while observers (nine normal trichromats) viewed a sinusoidally moving Maltese cross target in a Badal stimulus system. There were two illumination conditions: white (3000 K; 20 cd/m) and monochromatic (550 nm with 10 nm bandwidth; 20 cd/m) and two artificial pupil conditions (3 and 5.7 mm). Separately, static measurements of wavefront aberration were made with the eye accommodating to targets between 0 and 4 D (COAS, Wavefront Sciences). RESULTS: Large individual differences in accommodation to wavefront vergence and to LCA are a hallmark of accommodation. LCA continues to provide a signal at large pupil sizes despite higher levels of monochromatic aberrations. CONCLUSIONS: Monochromatic aberrations may defend against chromatic blur at high spatial frequencies, but accommodation responds best to optical vergence and to LCA at 3 c/deg where blur from higher order aberrations is less. PMID- 21317667 TI - Influence of the direction of eye turn on the appearance of strabismus. AB - PURPOSE: The purpose of this study was to determine whether an equal amount of exotropia (XT) or esotropia (ET) produces a more noticeable eye turn, which gives the better impression of eye contact, and how a positive angle kappa (K) affects this judgment. METHODS: Images from a white male model were manipulated to simulate 0, 5, 10, and 15 degrees of ET and XT for both 0 and +5 degrees K. A series of image pairs was then created that juxtaposed XT and ET of equal angles for both 0 and +5 degrees K. Forty-five optometry students then judged which image in each pair appeared to have the greater tropia and which gave the greater impression of eye contact. RESULTS: When angle kappa was 0, there was no significant difference in whether XT or ET appeared to be more noticeable. However, when angle kappa was +5 degrees , an XT of 5 degrees or greater became more apparent than an equal ET (p < 0.001). However, when the criterion was eye contact, ET gave the greater impression that eye contact was being made when the deviation was 10 degrees or more, and this was true for both 0 and +5 degrees K (p < 0.001). CONCLUSIONS: When a strabismus is to be evaluated or corrected purely for cosmetic reasons, the results may differ depending on the value of angle kappa and whether the criterion for good cosmesis is ocular deviation or eye contact. PMID- 21317668 TI - Lateral pupil alignment tolerance in peripheral refractometry. AB - PURPOSE: To investigate the tolerance to lateral pupil misalignment in peripheral refraction compared with central refraction. METHODS: A Shin-Nippon NVision-K5001 open-view auto-refractor was used to measure central and peripheral refraction (30 degrees temporal and 30 degrees nasal visual field) of the right eyes of 10 emmetropic and 10 myopic participants. At each of the three fixation angles, five readings were recorded for each of the following alignment positions relative to pupil center: centrally aligned, 1 and 2 mm temporally aligned, and 1 and 2 mm nasally aligned. RESULTS: For central fixation, increasing dealignment from pupil center produced a quadratic decrease (r >= 0.98, p < 0.04) in the refractive power vectors M and J180 which, when interpolated, reached clinical significance (i.e., >= 0.25 diopter for M and >= 0.125 diopter for J180 and J45) for an alignment error of 0.79 mm or greater. M and J180 as measured in the 30 degrees temporal and 30 degrees nasal visual field led to a significant linear correlation (r >= 0.94, p < 0.02) as pupil dealignment gradually changed from temporal to nasal. As determined from regression analysis, a pupil alignment error of 0.20 mm or greater would introduce errors in M and J180 that are clinically significant. CONCLUSIONS: Tolerance to lateral pupil alignment error decreases strongly in the periphery compared with the greater tolerance in central refraction. Thus, precise alignment of the entrance pupil with the instrument axis is critical for accurate and reliable peripheral refraction. PMID- 21317669 TI - Peripheral refraction in myopic children wearing orthokeratology and gas permeable lenses. AB - PURPOSE: To investigate changes in peripheral refraction after orthokeratology (OK) and rigid gas-permeable (GP) lens wear in progressing myopic children and to compare these peripheral defocus changes with reported changes in adults wearing OK. METHODS: Sixteen myopic children subjects were fitted with an OK lens in one eye for overnight wear and a GP lens in the other eye for daily wear. Central and peripheral refraction were measured at baseline and then after 3 mo of lens wear. RESULTS: At baseline, myopic children showed relative peripheral hyperopia compared with central refraction at and beyond 20 degrees in the temporal visual field (VF) and 30 degrees in the nasal VF. Three months of OK lens wear produced hyperopic shifts in refraction between 30 degrees in the temporal VF and 20 degrees in the nasal VF. Peripheral refraction was similar to center at all positions in the temporal VF while remaining significantly myopic at all locations in the nasal VF. No change in either central or peripheral refraction was found after 3 mo in the eye assigned for GP lens wear. CONCLUSIONS: OK significantly reduced myopia in the central 20 degrees VF in myopic children, converting relative peripheral hyperopia measured at baseline to relative peripheral myopia. These changes in children are similar to changes reported in myopic adults wearing OK lenses. No change in either central or peripheral refraction was found after 3 mo of daily GP lens wear. OK lenses can be used to induce myopic defocus in the periphery in myopic children and may thus provide a potential mechanism for myopia control. PMID- 21317670 TI - Illumination system for corneal collagen crosslinking. AB - PURPOSE: We have designed and constructed an ultraviolet (UV) illumination system for use in corneal collagen crosslinking (CXL) procedures. CXL is a recently developed procedure to treat Keratectasia such as Keratoconus and Pellucid Marginal Degeneration. The role of the illumination system is to safely provide UV light at the absorption peak of the Riboflavin photosensitizer, which generates reactive oxygen species and subsequently increases the number of covalent bonds between collagen fibrils. METHODS: Raytracing simulations were used to compare various optical designs for the illumination system. Alternative layouts are presented and design compromises between competing goals are discussed in reference to safety and practical considerations for clinical use. The mechanical mounting system and the beam output power and beam diameter testing system are briefly described. RESULTS: The illumination system has several features that help provide uniform effectivity of the applied treatment over the desired treatment diameter, assuming Riboflavin has uniform absorption in the treatment zone. The optical design offers substantially greater beam control and safety than rudimentary devices relying on direct illumination. The prototype was relatively inexpensive to construct and includes a mounting system and beam testing setup. CONCLUSIONS: The UV illumination system was found to be successful in providing a balanced solution regarding clinical use and the eye safety issues relevant to CXL. PMID- 21317671 TI - Systematic review of the literature on nitinol prostheses in surgery for otosclerosis: assessment of the adequacy of statistical power. AB - OBJECTIVE: To perform a systematic review of observational studies reporting hearing outcome in primary stapes surgery where a heat-crimping prosthesis was used. DATA SOURCES: Medline, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, TRIP database, Clinical Trials Registry, ISI Web of Knowledge, and Web of Science. The search was performed on January 1, 2010, including articles published ahead of print. No language restrictions. STUDY SELECTION: Inclusion criteria for qualitative synthesis were a population of otosclerosis patients, intervention being primary stapes surgery with a nickel titanium alloy (Nitinol) heat-crimping prosthesis, and hearing outcome. Inclusion criteria for quantitative analysis: application of audiometry guidelines of the American Academy of Otolaryngology-Head and Neck Surgery Committee on Hearing and Equilibrium for evaluation of conductive hearing loss. DATA EXTRACTION: Strategy and reporting based on Cochrane, Quality of Reporting of Meta-analyses, and Meta analysis of Observational Studies in Epidemiology statements. A bias assessment tool was developed according to Cochrane guidelines. DATA SYNTHESIS: A quantitative synthesis was performed, but because of the heterogeneity in postoperative follow-up periods and outcome measures reported, we were not able to pool these data. A sample size analysis was performed to indicate the sample needed to demonstrate a statistically significant difference in hearing outcome between both interventions. Hearing outcome superiority of the Nitinol heat crimping prosthesis over manually crimping prosthesis types was not demonstrated. CONCLUSION: Superiority could probably not be demonstrated because of insufficient sample size. Research addressing technical improvements in stapes surgery should agree on a base sample size able to detect the smallest difference that is clinically important or accept the null hypothesis. With data gathered in the Common Otology Database as basis, a sample size of at least 413 patients is needed in both the intervention and the control group. Other clinical outcome measures also should be explored. PMID- 21317672 TI - Comorbid intracranial vertebral artery asymmetry as a risk factor for severe vestibular neuronitis. AB - BACKGROUND: Our previous study had demonstrated that verterbral artery hypoplasia (VAH) contribute to ipsilateral vestibular dysfunction. The aim of this study was to test if VAH contributes to prognosis of vestibular neuronitis (VN) through presumed regional malperfusion. METHODS: We performed a prospective magnetic resonance angiographic registry in patients with acute vestibular neuritis in which were then assigned to VAH (n=29) and control group (n=40). Vestibular function was determined by caloric irrigation, with the use of the vestibular paresis formula (to measure the extent of unilateral caloric paresis) within 3 days after the onset of symptoms and 12 months afterward. RESULTS: The baseline vestibular paresis was higher (56.8 +/- 15.9%) in the VAH VN subjects (n=29), than in VN subjects without VAH (n=40) (37.4 +/- 17.7%) (p=0.01). Analysis of variance showed a less percentage of the VAH group return to normal at 4th and 12th week visit. CONCLUSION: Our results suggested that comorbid VAH may predispose to severe VN at acute stage. PMID- 21317673 TI - Treatment of Meniere's disease with "on-demand" intratympanic gentamicin injections. AB - OBJECTIVE: To determine the clinical response to intratympanic administration of gentamicin in patients with Meniere's disease and to ascertain whether the pure tone average, caloric test, or disease duration might predict clinical control. DESIGN: Prospective study. Patients were followed for at least 2 years after the first injection (mean follow up time, 39 mo), and a Kaplan-Meier analysis was used to determine the survival curve that best explains the response to treatment. SETTING: Tertiary center, University hospital. PATIENTS: Individuals diagnosed with unilateral Meniere's disease that did not respond to previous medical treatment and who had not previously undergone surgery. Of the initial 83 patients recruited, 9 were lost during the follow-up, and thus, 74 subjects were included in the study. INTERVENTION: In the consultant's surgery, a myringotomy was performed with topic administration of phenol before the intratympanic administration of 2 to 3 ml of gentamicin (26.7 mg/ml). Further injections were administered if vertigo was not controlled and recurred. MAIN OUTCOME MEASURES: Absence of vertigo and the need for subsequent injections as measured in using a Kaplan-Meier time-to-event process. To test predictive variables, the log-rank test was used. RESULTS: Complete control of vertigo was obtained with a single injection of gentamicin in 53% of the patients. Subsequent injections offered a 50% chance of obtaining complete control. Better results were obtained in patients in whom disease duration was less than 3 years. CONCLUSION: On-demand administration of intratympanic gentamicin provides an alternative treatment for medically refractory Meniere's disease. Moreover, the Kaplan-Meier analysis was useful to analyze recurrent manifestations, such as vertigo attacks in Meniere's disease. PMID- 21317674 TI - Bilateral Meckel's cave arachnoid cysts with extension to the petrous apex in a patient with a vestibular schwannoma. PMID- 21317675 TI - The persistent thrombus: complications, diagnosis, and novel treatment intervention. AB - OBJECTIVE: To review the findings and discuss the implications of the topic of pharmacomechanical thrombolysis in pediatric patients with persistent thrombus. DESIGN: A pediatric case presentation with a brief literature review on treatment of venous thrombosis and pharmacomechanical thrombolysis. INTERVENTIONS: None. MAIN RESULTS: Thrombotic events refractory to standard medical and surgical care remain a life-threatening clinical challenge in the pediatric population. Research on persistent deep venous thrombosis and treatment modalities is limited. We present a pediatric patient with a history of malignant osteosarcoma who was diagnosed with deep venous thrombosis. Despite appropriate anticoagulation therapy, the thrombus remained persistent. Pharmacomechanical thrombolysis was utilized and proved to be an effective method in providing diagnosis and treatment. CONCLUSION: Pharmacomechanical thrombolysis is a valuable and effective method in providing diagnosis and treatment of persistent thrombus. PMID- 21317676 TI - Risk factors for postoperative acute kidney injury in pediatric cardiac surgery patients receiving angiotensin-converting enzyme inhibitors. AB - BACKGROUND: Angiotensin-converting enzyme inhibitor therapy is often initiated in pediatric patients who have had cardiac surgery. Acute kidney injury can occur in patients secondary to angiotensin-converting enzyme inhibitor initiation. Risk factors for acute kidney injury after angiotensin-converting enzyme inhibitor initiation have yet to be defined in postoperative pediatric cardiac patients. OBJECTIVES: To identify the frequency of acute kidney injury in patients receiving angiotensin-converting enzyme inhibitor therapy in postoperative pediatric cardiac surgical patients and to identify risk factors for acute kidney injury in this patient population. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The pharmacy and surgery databases were used to identify all patients <18 yrs of age who received angiotensin-converting enzyme inhibitor therapy after cardiac surgery at our institution from January 2006 to December 2007. Patients who did not have a baseline serum creatinine and at least one serum creatinine obtained after angiotensin-converting enzyme inhibitor initiation were excluded. Data collection included demographic information and cardiac pathophysiology/surgery, diuretic and/or nephrotoxic medication use, and angiotensin-converting enzyme inhibitor characteristics and initiation date. Baseline, daily, and maximum serum creatinine values were collected. Acute kidney injury was defined as the maximum change in pediatric-modified RIFLE (Risk, Injury, Failure, Loss, End-stage) acute kidney injury criteria within 48 hrs of initiation or increase in dose of angiotensin-converting enzyme inhibitor. Descriptive statistics were used to characterize the patient population, and a multivariate logistic regression model was developed to identify independent predictors of angiotensin-converting enzyme inhibitor-associated acute kidney injury. The study included 415 patient admissions (386 patients), 57% (n = 239) being male and infants (31 days to 2 yrs) being the most common age group. A functional single ventricle was present in 46% of the patients. Enalapril was initiated in 60% (n = 250) and captopril in 40% (n = 165) of patient admissions. Acute kidney injury occurred in 21% (n = 88) of patients initiated on an angiotensin-converting enzyme inhibitor (pediatric-modified RIFLE categories: R = 15%, I = 3%, F = 4%). Logistic regression identified cyanosis, coadministration of furosemide, and baseline estimated creatinine clearance as independent risk factors for any degree of angiotensin-converting enzyme inhibitor-associated acute kidney injury (p < .05). The hospital lengths of stay of patients with angiotensin-converting enzyme inhibitor-associated acute kidney injury (median 12 days, range 4-298 days) were greater compared to those of patients without angiotensin-converting enzyme inhibitor-associated acute kidney injury (median 10 days, range 3-199 days, p < .05). CONCLUSIONS: Initiation of angiotensin converting enzyme inhibitor after cardiac surgery in pediatric patients may result in acute kidney injury. The presence of cyanosis and coadministration of furosemide are independent risk factors for acute kidney injury in patients receiving angiotensin-converting enzyme inhibitor. PMID- 21317677 TI - Central venous catheter sampling of low molecular heparin levels: an approach to increasing result reliability. AB - BACKGROUND: The low molecular weight heparin effect in children is monitored using the anti-factor Xa level. Venipuncture is recommended; however, central venous catheter blood sampling is often necessary. Heparin infused through central venous catheters may contaminate central venous catheter blood samples, preventing reliable anti-factor Xa level measurement. Simultaneous anti-factor Xa/partial thromboplastin time measurement with central venous catheter blood sampling may predict anti-factor Xa reliability. OBJECTIVES: To determine the prevalence of heparin contamination as measured by the partial thromboplastin time/anti-factor Xa in central venous catheter blood samples and whether careful sampling could minimize heparin contamination of anti-factor Xa levels from central venous catheter blood sampling. METHODS: Simultaneous partial thromboplastin time/anti-factor Xa measurements from central venous catheter blood sampling determined the prevalence of heparin contamination of central venous catheter blood samples. In phase II, children receiving low molecular weight heparin had routine central venous catheter blood sampling to measure the peak anti-factor Xa and the simultaneous partial thromboplastin time. Anti-factor Xa levels with a partial thromboplastin time of >40 secs (pair 1) were identified; there was no low molecular weight heparin dose change, and the paired sample was repeated using a careful sampling technique (pair 2). Pairs 1 and 2 were compared to determine the efficiency of the sampling technique in removing heparin from the central venous catheter blood samples. RESULTS: In phase I, 100 children had 485 paired anti-factor Xa/partial thromboplastin time central venous catheter blood samples with 29% +/- 4.1% (95% confidence interval 25% to 33%) anti-factor Xa with partial thromboplastin times of >40 secs. In phase II, 43 children had 129 paired anti-factor Xa/partial thromboplastin time samples with partial thromboplastin times of >40 secs. The pair 1 mean partial thromboplastin times/anti-factor Xa levels were 109.8 secs (SD 53.1, range 34.0 to >200 secs) and 1.03 units/mL (SD 0.56, range 0.26-4.2 units/mL). Repeated partial thromboplastin times/anti-factor Xa levels (pair 2) were significantly decreased from those of pair 1 (p < .001) with means of 58.5 secs (SD 21.2, range 22-152 secs) vs. 109.8 secs (SD 53.1, range 34.0 to > 200 secs, p < .001) and 0.63 unit/mL (SD 0.30, range 0.02-1.77 units/mL) vs. 1.03 units/mL (SD 0.56, range 0.26-4.2 units/mL), respectively. CONCLUSIONS: Measurement of the partial thromboplastin time performed in combination with that of the anti-factor Xa level can be used to assist health practitioners to identify unfractionated heparin contamination of anti-factor Xa levels drawn from central venous catheters. A careful sampling technique may minimize heparin contamination in central venous catheter blood samples. PMID- 21317678 TI - Nutrition support and deficiencies in children with severe traumatic brain injury. AB - OBJECTIVE: Adequate nutrition support is considered important to recovery after pediatric traumatic brain injury. The 2003 Pediatric Guidelines recommend initiation of nutrition within 72 hrs after traumatic brain injury. We examined our local experience with nutritional support in severe pediatric traumatic brain injury patients (cases) and non-traumatic brain injury patients (controls). DESIGN: A retrospective review of pediatric patients with severe traumatic brain injury over an 11-yr period (1997-2009) and without traumatic brain injury over a 3-yr period (2007-2009). SETTING: Level I pediatric trauma center pediatric intensive care unit. PATIENTS: Patients with severe pediatric traumatic brain injury (age <15 yrs, Glasgow Coma Scale score of <9) and admitted to the pediatric intensive care unit for >7 days and patients without traumatic brain injury (age <15 yrs, head Abbreviated Injury Scale score of 0) and admitted to pediatric intensive care unit. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data from 101 severe traumatic brain injury and 92 non-traumatic brain injury patients were analyzed. Traumatic brain injury patients: All received enteral nutrition while 13 (12%) also received parenteral nutrition. Nutrition was started 53 +/- 20 hrs (range 12-162) after pediatric intensive care unit admission. Fifty patients (52%) received nutrition within the first 48 hrs, and 83 (82%) received nutrition support within the first 72 hrs. Caloric and protein intakes were 47% and 40% of the goals on pediatric intensive care unit day 7 and 76% and 70% of the goals on pediatric intensive care unit day 14. Caloric and protein goals were met in 26% +/- 16% and 18% +/- 19% of pediatric intensive care unit stay, respectively. Patients whose intake met nutritional goals on pediatric intensive care unit day 7 had earlier initiation of nutrition support at admission than patients who never met the goals (calorie goal met vs. unmet by day 7, 44 +/- 23 hrs vs. 67 +/- 31 hrs; p < .001; protein goal met vs. unmet by day 7, 43 +/- 17 hrs vs. 65 +/- 29 hrs; p = .001). Patients gained 0.6% +/- 11% weight by pediatric intensive care unit day 7 and lost 7% +/- 11% weight by pediatric intensive care unit day 14. Non-traumatic brain injury patients: The time to start of nutrition for the non-traumatic brain injury group was earlier only for patients with isolated orthopedic injuries (24 +/- 6 hrs; p = .02). The average caloric and protein intakes were less for the traumatic brain injury (n = 20) group (caloric 52% +/- 16% of goal and protein 42% +/- 18% of goal) than for the non-traumatic brain injury (n = 23) group (65% +/- 11% of goal and protein 51% +/- 20% of goal; both p < .01) for pediatric intensive care unit days 0-7. For pediatric intensive care unit days 8-14, there was no difference in average caloric (82% +/- 22% vs. 79% +/- 18% of goal) or protein (77% +/- 6% vs. 79% +/- 7% of goal) between the traumatic brain injury (n = 12) and non-traumatic brain injury (n = 10) groups. Addition of a nutritionist was associated with earlier time to nutrition start (p = .02). CONCLUSIONS: Nutritional support was initiated in most patients within 72 hrs of pediatric intensive care unit admission. Although daily caloric and protein goals were not achieved in the first 2 wks of pediatric intensive care unit stay and nutritional deficiencies were common, earlier start of nutritional support was associated with involvement of a nutritionist and with meeting both caloric and protein goals by pediatric intensive care unit day 7. PMID- 21317679 TI - Critical evaluation of emergency stockpile ventilators in an in vitro model of pediatric lung injury. AB - OBJECTIVE: Modern health care systems may be inadequately prepared for mass casualty respiratory failure requiring mechanical ventilation. Current health policy has focused on the "stockpiling" of emergency ventilators, though little is known about the performance of these ventilators under conditions of respiratory failure in adults and children. In this study, we seek to compare emergency ventilator performance characteristics using a test lung simulating pediatric lung injury. DESIGN: Evaluation of ventilator performance using a test lung. SETTING: Laboratory. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Six transport/emergency ventilators capable of adult/child application were chosen on the basis of manufacturer specifications, Autovent 3000, Eagle Univent 754, EPV 100, LP-10, LTV 1200, and Parapac 200D. Manufacturer specifications for each ventilator were reviewed and compared with known standards for alarms and functionality for surge capacity ventilators. The delivered tidal volume, gas flow characteristics, and airway pressure waveforms were evaluated in vitro using a mechanical test lung to model pediatric lung injury and integrated software. Test lung and flow meter recordings were analyzed over a range of ventilator settings. Of the six ventilators assessed, only two had the minimum recommended alarm capability. Four of the six ventilators tested were capable of being set to deliver a tidal volume of less than 200 mL. The delivered tidal volume for all ventilators was within 8% of the nominal setting at a positive end expiratory pressure of zero but was reduced significantly with the addition of positive end expiratory pressure (range, +/-10% to 30%; p < .01). All ventilators tested performed comparably at higher set tidal volumes; however, only three of the ventilators tested delivered a tidal volume across the range of ventilator settings that was comparable to that of a standard intensive care unit ventilator. CONCLUSIONS: Multiple ventilators are available for the provision of ventilation to children with respiratory failure in a mass casualty scenario. Few of these ventilators possess the minimum alarm functionality and consistently deliver the prescribed tidal volume that allows for safe and effective ventilation of critically ill pediatric patients. These findings will help clinicians understand the performance and limitations of available ventilators intended for use in children. PMID- 21317680 TI - A prospective study of parainfluenza virus type 4 infections in children attending daycare. AB - Studies of parainfluenza virus type 4 (PIV-4) have been limited by difficulty in culturing. We prospectively studied a cohort of 225 young children attending daycare followed for 165 child-years, using polymerase chain reaction to detect 12 viruses, including PIV-4. PIV-4 was second only to PIV-3, occurring in 9 of 87 (10%) PIV+ illnesses. PIV-4 illnesses were not more severe and not associated with a specific clinical syndrome. PMID- 21317681 TI - Single-dose pharmacokinetics and tolerability of daptomycin 8 to 10 mg/kg in children aged 2 to 6 years with suspected or proved Gram-positive infections. AB - A pharmacokinetic analysis was performed for single intravenous doses of daptomycin 8 or 10 mg/kg in subjects aged 2 to 6 years. Proportional increases in maximum plasma concentration (68.4 MUg/mL, 79.2 MUg/mL) and area under the curve (429.1 MUg . h/mL, 549.7 MUg . h/mL) were observed for each dose cohort, respectively. Half-life, clearance, and distribution volume were similar between groups. Both doses were well tolerated. PMID- 21317682 TI - Nonreplication of an association of SGIP1 SNPs with alcohol dependence and resting theta EEG power. AB - A recent study in a sample of Plains Indians showed association between eight single nucleotide polymorphisms (SNPs) located in the SGIP1 gene and resting theta electroencephalogram (EEG) power. This association appeared to generalize to alcohol use disorders, for which EEG power is a potential endophenotype. We analyzed a large, diverse sample for replication of the association of these implicated SGIP1 SNPs (genotyped on the Illumina 1M platform) with alcohol dependence (N=3988) and theta EEG power (N=1066). We found no evidence of association of the earlier implicated SGIP1 SNPs with either alcohol dependence or theta EEG power (all P>0.15) in this sample. The earlier implicated SNPs located in SGIP1 gene showed no association with alcohol dependence or theta EEG power in this sample of individuals with European and/or African ancestry. This failure to replicate may be the result of differences in ancestry between this sample and the original sample. PMID- 21317684 TI - Further study of genetic association between the TNXB locus and schizophrenia. PMID- 21317683 TI - Dual association of a TRKA polymorphism with schizophrenia. AB - OBJECTIVE: An interaction between predisposing genes and environmental stressors is thought to underlie the neurodevelopmental disorder schizophrenia. In a targeted gene screening, we previously found that the minor allele of the single nucleotide polymorphism (SNP) rs6336 in the neurotrophic tyrosine kinase receptor 1 (NTRK1/TRKA) gene is associated with schizophrenia as a risk factor. METHODS: We genotyped the TRKA SNP in a total of eight independent Caucasian schizophrenia case-control groups. RESULT: Remarkably, although in five of the groups a higher frequency of the risk allele was indeed found in the patients compared with the controls, in the three other groups the SNP acted as a protective factor. CONCLUSION: An intriguing possibility is that this dual character of the TRKA SNP is caused by its interaction with endophenotypic and/or epistatic factors. PMID- 21317685 TI - Epidemiology of syphilis among Hispanic women and associations with congenital syphilis, Maricopa county, Arizona. AB - OBJECTIVE: We investigated factors associated with high rates of congenital syphilis among Hispanic infants in Maricopa County, AZ. METHODS: Using 2004-2008 syphilis case report data from the state and county health departments, we examined characteristics of pregnant and nonpregnant women with syphilis and their male partners. RESULTS: During 2004-2008, 970 women were reported to have syphilis: 49% were Hispanic (of whom 49% were non-US citizens), 27% were white, 13% were black, and 8% were American Indian/Alaskan Native. Although 16% of Hispanic noncitizens reported drug use or high-risk sexual behaviors, 64% of these women had a male sex partner who reported drug use or anonymous sex. Hispanic women with syphilis were more likely to be pregnant (37%) than white (15%) or black women (13%) (P < 0.05), and were overrepresented among pregnant women with syphilis. Pregnant Hispanic noncitizens were treated later than pregnant Hispanic citizens (median 28 weeks gestation vs. 21 weeks, P = 0.01). CONCLUSIONS: Innovative congenital syphilis prevention strategies that are relevant to Hispanic women are warranted. Strategies should address the reproductive health and prenatal care needs of Hispanic women, and may include interventions for their male partners. PMID- 21317686 TI - The natural history of incident gonococcal infection in adolescent women. AB - BACKGROUND: The natural history of Neisseria gonorrhoeae (GC) infections is largely unknown. The objective of the current study was to use sequential weekly vaginal samples and molecular techniques to describe the natural history of incident gonorrhea infections in adolescent women. METHODS: A cohort of 387 adolescent women aged 14 to 17 were enrolled from urban, primary care clinics and followed longitudinally for a period of up to 8 years. Weekly vaginal swabs and daily diaries were provided during 12-week periods biannually, beginning and ending with a clinic visit, where all identified infections were treated. For this study, specimens and data from 16 women who became infected with GC during a weekly sampling period were analyzed. RESULTS: GC organism load was highly variable between subjects. The number of organisms did not significantly differ across the first 6 weeks of infection (P = 0.59). Organism load did not differ among women with a previously documented GC infection at week 1 (P = 0.43) or across the first 6 weeks of infection (P = 0.67). The association of concurrent chlamydial infection on gonorrhea organism load was borderline significant over the first 6 weeks of infection (P = 0.06). CONCLUSIONS: Individual shedding patterns varied widely, and GC organism load did not decline in women for at least several weeks and were not associated with genitourinary symptoms. Chlamydia coinfection is associated with higher GC organism loads, potentially increasing chances of transmission. This study utilized a standardized quantification technique to assess GC organism load. PMID- 21317687 TI - Sex worker studies: the science, semantics, and politics of targeting our HIV prevention response. PMID- 21317688 TI - Prevalence of human papillomavirus antibodies in males and females in England. AB - BACKGROUND: Most studies of human papillomavirus (HPV) epidemiology have employed DNA testing, which measures current infections. Serum antibodies offer a longer term marker of infection in individuals who seroconvert and can therefore provide additional information about the exposure of populations to HPV. METHODS: Sera from a population-based sample of males and females aged 10 to 49 years, in England, were tested for type-specific HPV antibodies using a multiplexed competitive Luminex assay and previously defined cutoffs of 20, 16, 20, and 24 mMU mL for HPV 6, 11, 16, and 18, respectively. Seropositivity and geometric mean titers of seropositives were analyzed by HPV type, gender, and age. Catalytic models were developed to explore potential effects of antibody waning over time and changing risk of infection by age-cohort. RESULTS: Seroprevalence for HPV 6, 11, 16, and 18 was 16.4%, 5.7%, 14.7%, and 6.3%, respectively, among females and 7.6%, 2.2%, 5.0%, and 2.0%, respectively, among males. Seroprevalence in females was significantly higher than males (P < 0.001 for all types) and showed a decline in older ages that was not seen in males. There was no evidence of declining antibody titers with increasing age. Model results suggest that cohort effects mediated through changes in sexual behavior better explain the observed trend in seroprevalence than waning antibodies over time. CONCLUSIONS: Preimmunization HPV seroprevalence in England shows similar trends to reports from other developed countries. We find the lower seroprevalence in older females probably reflects changes in sexual behavior over the last few decades. This study provides baseline data to monitor the impact of the immunization programme. PMID- 21317689 TI - The cost-effectiveness of herpes simplex virus-2 suppressive therapy with daily aciclovir for delaying HIV disease progression among HIV-1-infected women in South Africa. AB - BACKGROUND: The Partners in Prevention HSV/HIV transmission trial (Partners HSV/HIV Transmission Study) showed that herpes simplex virus-2 (HSV-2) suppressive therapy with daily aciclovir could decrease HIV disease progression amongst HIV-1/HSV-2 coinfected individuals. The cost-effectiveness of daily aciclovir for delaying HIV-1 disease progression in women not eligible for antiretroviral therapy (ART) is estimated. METHODS: Resource use/cost data for delivering daily aciclovir at a primary health care HIV clinic were collected in Johannesburg. Effectiveness estimates were obtained from the Partners HSV/HIV Transmission Study trial and epidemiologic data from South Africa. A Markov model simulated the cost-effectiveness of daily aciclovir on HIV-1 disease progression in ART-naive women. Therapy was given to all HIV-1-infected women. Cost effectiveness was compared against cost per life-year gained (~US $1200 per LYG) of ART provision in South Africa. RESULTS: For an ART eligibility criteria of CD4 count <200 cells/MUL and the cheapest internationally available aciclovir (US $0.026 per day for 2 * 400 mg aciclovir), the median cost per LYG is US $1023 (95% confidence interval [CI]: 537-2842), whereas it decreases to US $737 (95% CI: 373-2489) if the ART eligibility criteria is CD4 count <350 cells/MUL. Both these projections compare favorably with the estimated cost-effectiveness of ART in South Africa (~US $1200 per LYG). The cost per LYG increases dramatically for the current aciclovir cost in South Africa (US $0.14 per day), if salary costs are higher and if HSV-2 prevalence amongst HIV-1-infected women are lower. Projections suggest HSV-2 suppressive therapy could dramatically increase the proportion of women initiating ART. CONCLUSIONS: HSV-2 suppressive therapy could be an affordable strategy for reducing HIV-1 disease progression and retaining women in care before ART initiation, but cheaply available aciclovir is needed. PMID- 21317690 TI - Poor provider adherence to the Centers for Disease Control and Prevention treatment guidelines in US emergency department visits with a diagnosis of pelvic inflammatory disease. AB - BACKGROUND: Pelvic inflammatory disease (PID) is commonly diagnosed in US emergency departments (EDs). We aimed to estimate national rates of provider adherence to the Centers for Disease Control and Prevention (CDC) treatment guidelines for PID among patient visits, with a diagnosis of acute PID in US ED settings. METHODS: A multiyear cross-sectional analysis was performed on ED visits from females >12 years old, using the National Hospital Ambulatory Medical Care Survey database from 1999 to 2006. The ED diagnoses of acute PID were identified from the database. Specific antibiotics ordered or provided during ED visits diagnosed with PID were identified and compared to contemporary CDC treatment guidelines to determine provider adherence. Analyses were performed using procedures for multiple-stage survey data. RESULTS: Overall, 1,605,000 discharged ED patient visits with a diagnosis of acute PID were identified. ED provider adherence to CDC treatment guidelines was 30.5% (95% confidence intervals [CI], 24.4%-36.7%). Doxycycline was the most commonly missing medication from the recommended regimens while azithromycin was the most prescribed antibiotic that was not recommended until 2006 CDC guidelines. Additionally, among the visits without being given any CDC-recommended antibiotics, 38.4% were prescribed neither antibiotics nor pain relievers. In multivariate analysis, those without specialty consultation during ED visits and those before the announcement of 2002 guidelines were 4.95 (95% CI, 1.71-14.29) and 1.93 (95% CI, 1.14-3.27) times less likely to receive CDC-recommended antibiotic regimens versus their counterparts. CONCLUSIONS: Poor provider adherence to the CDC-recommended treatment guidelines for PID has been widespread in US EDs, especially for women who did not receive specialty consultation. PMID- 21317691 TI - The future of nursing. PMID- 21317692 TI - Does gender and ethnicity impact initial assessment and management of chest pain? AB - Review of recent evidence with translation to practice for the advanced practice nurse role is presented using a case study module for "racial and sex differences in emergency department triage assessment and test ordering for chest pain." The study results showed that there might be some differences in how triage nurses approach the management of patients with chest pain on the basis of gender and ethnicity. The implications and clinical relevance of these findings for advanced practice nurses are discussed highlighting best evidence. PMID- 21317693 TI - A case of subluxation of the radial head: nursemaids' elbow. AB - Nursemaid's elbow (subluxation of the radial head) is a common pediatric upper extremity injury encountered in the emergency and urgent care settings. Subluxation of the radial head accounts for more than 20% of upper extremity injuries in the pediatric population. A clinical case of a three-year old girl who presented to the emergency department with a nursemaids elbow requiring reduction is presented in this article. The purpose of this article is to discuss the identification and treatment of this injury and delineate the two methods of supination and pronation for reduction of the annular ligament. PMID- 21317694 TI - When snakes bite: the management of North American Crotalinae snake envenomation. AB - There are more than 120 species of snakes indigenous to the United States, 25 of which are venomous. Although snake envenomation carries a relatively low risk of mortality in the United States, it can result in significant morbidity if left untreated. The venom of Crotalinae snakes contains a complex mixture of enzymatic proteins with various clinical implications. Of these complications, the most significant are consumptive coagulopathy, compartment syndrome, and hypovolemic shock. The development of ovine Crotalidae polyvalent immune Fab antivenin (CroFab) has greatly changed the approach to snake envenomation. Nevertheless, multiple factors complicate its use and the overall management of this clinical presentation. The intent of this review is to discuss relevant management issues associated with Crotalinae envenomation in the emergency department. PMID- 21317695 TI - A 54-year-old woman with a rare case of drug-induced pancreatitis. AB - Drug-induced pancreatitis is a rare cause of acute pancreatitis. Most evidence that exists on drug-induced pancreatitis is presented in case report form. A patient with probable carbamazepine-induced pancreatitis is introduced in this article. In addition to alcoholism and biliary disease as common causes of pancreatitis, this article hopes to raise an awareness of several other differential diagnoses associated with pancreatitis, including drug-induced pancreatitis. PMID- 21317696 TI - Usefulness: forensic photo documentation after sexual assault. AB - The forensic medical legal evaluation following sexual assault establishes evidence for law enforcement's investigation and criminal prosecution by the legal system. The sexual assault nurse examiner performs the forensic evaluation and uses digital photography to document physical injuries after sexual assault. Photographs have varying degrees of usefulness, but for a photograph to be useful, it must exhibit technical elements for the viewer. There was no tool available to evaluate the usefulness of digital photographs taken during forensic evaluation of genital injuries after sexual assault. The Photo Documentation Image Quality Scoring System (PDIQSS) tool was developed to rate photographic technical elements for usefulness. Using this tool, three experts on two separate occasions evaluated a series of digital photographs taken following sexual assault. The PDIQSS tool predicted usefulness in digital photography of female genital injuries following sexual assault when measured in all dimensions. PMID- 21317697 TI - The effect of emergency department crowding on patient outcomes: a literature review. AB - The purpose of this review was to summarize the findings of published reports that investigated quality-related outcomes and emergency department (ED) crowding. Of 276 data-based articles, 23 reported associations between patient outcomes and crowding. These articles were grouped into 3 categories: delay in treatment, decreased satisfaction, and increased mortality. Although these studies suggest that crowding results in poor outcomes, it is possible that other factors such as nursing care contribute to these adverse outcomes. Nursing care has been shown to contribute to both positive and negative patient outcomes in other settings. Building an understanding of how ED crowding affects the practice of the emergency nurse is essential to examining how nursing care, surveillance, and communication impact outcomes of emergency patients. Investigation into nurse sensitive quality indicators in the ED has potential to develop strategies that deliver high quality of care, regardless of crowded conditions. PMID- 21317698 TI - Understanding the transsexual patient: culturally sensitive care in emergency nursing practice. AB - Transsexual individuals present to the emergency department for various reasons; yet, providers and nurses are often unaware of the unique needs of transsexual patients. This article provides an understanding of challenges faced by transsexual individuals in health care access and treatment. The authors explain commonly used terminology and provide an overview of the transition process including the Diagnostic and Statistical Manual, 4th edition criteria for diagnosis and the World Professional Association of Transgender Health's Standards of Care for treatment. The authors provide important details and specific recommendations for the culturally sensitive care of transsexual patients including using the correct name and pronoun, eliminating bias and discrimination, asking appropriate questions, implementing trans-inclusive policies and guidelines, and proper record keeping. PMID- 21317699 TI - Use of alteplase beyond 3 hours of ischemic stroke onset. AB - Tissue plasminogen activator, alteplase (Activase) is the U.S. Food and Drug Administration (FDA) approved thrombolytic for acute ischemic stroke and is currently FDA approved for administration up to 3 hr from stroke onset. However, new research suggests there are benefits from alteplase beyond the 3 hr window. Utilizing PubMed, a literature review was conducted between the years of 1998 and 2010 for research including the keywords "alteplase and ischemic stroke," "thrombolytics and ischemic stroke," "thrombolysis with alteplase" and "stroke protocol." New research as well as a statement from the American Heart Association and American Stroke Association, supports extending the administration of alteplase after ischemic stroke onset while continuing to acknowledge the risks alteplase poses to the patient. With the understanding that 4 out of 10 stroke victims arrive after the current 3 hr administration protocol, elongation of the allotted alteplase window has the potential to significantly improve ischemic stroke outcomes. PMID- 21317700 TI - Mild traumatic brain injury: a midwest survey about the assessment and documentation practices of emergency department nurses. AB - Research reported that mild traumatic brain injury (MTBI), the most common neurological condition in the world, is often undetected in the emergency department. Failure to properly detect and offer treatment therapies has been linked to chronic complications such as, mood disorders and postconcussion syndrome. This descriptive study used a tailored survey (25.0% response rate) to determine emergency department nurses' practices for the assessment and documentation of persons with MTBI. The primary purpose was to determine the extent to which these practices were aligned with the Centers for Disease Control and Prevention guidelines contained within the Acute Concussion Evaluation care plan. Results indicated that physical and cognitive symptoms were assessed and documented more than emotional or sleep symptoms. Still, some cognitive and physical symptoms were rarely assessed or documented. Focus seemed to be on ruling out more severe brain injury versus detection of a mild brain injury. Aligning the systematic assessment and documentation of persons with suspected concussion MTBI with recommendations from the Centers for Disease Control and Prevention is suggested. PMID- 21317701 TI - Wound care and laceration repair for nurse practitioners in emergency care: part II. AB - This is Part II of a 2-part series on wound care and laceration repair for advanced practice nurses. In Part I, the phases and categories of wound healing were outlined. The factors that affected wound healing were also discussed along with an approach for systematic wound management. Patient assessment, special circumstances involving underlying structures, and foreign bodies were also reviewed. Patient preparation, including wound cleansing, irrigation, scrubbing, and debridement were also covered along with anesthetic and analgesic tips and techniques for advanced practice nurses (APNs) in emergency care. In Part II, wound closure (e.g., sutures, staples, and adhesives) and wound closure techniques are discussed along with the pertinent aftercare instructions for patients with these wounds. Implications for APNs caring for patients with wounds in emergency care are also presented in this article. PMID- 21317704 TI - Perspectives on pure ovarian stromal neoplasms and tumor-like proliferations of the ovarian stroma. AB - In this study, we discuss the advances in our knowledge of the pathology of pure ovarian stromal neoplasms and discuss tumor-like conditions of ovarian stroma that can mimic ovarian stromal neoplasms clinically, macroscopically, or histologically. This review emphasizes recent studies and those that have significantly advanced our knowledge in the past. The neoplasms in this group occur over a wide age range and are often unilateral. In difficult cases, immunocytochemistry provides improved diagnostic accuracy. The most useful antibodies in this regard are inhibin and calretinin that are positive in most tumors and tumor-like proliferations in the ovarian stromal category. Steroidogenic factor 1 is a promising new marker that has not yet been completely validated. Recent studies of tumors in the fibroma-thecoma group suggest that nuclear atypia is more significant than mitotic activity in the assessment of the biological behavior of these neoplasms. Wherever applicable, we discuss molecular techniques that are currently diagnostically useful. PMID- 21317705 TI - Atypical tumor-stromal fibroblasts in invasive ductal carcinoma of the breast. AB - Tumor-stromal fibroblasts have recently been reported to play important roles in the tumor progression of cancer in various organs. The purpose of this study was to investigate whether any characteristic histologic features of tumor-stromal fibroblasts could accurately predict the outcome of 1042 patients with invasive ductal carcinoma of the breast. We observed a small number of tumor-stromal fibroblasts with characteristic nuclear features existing inside and outside of fibrotic foci and named them atypical tumor-stromal fibroblasts. We then classified invasive ductal carcinomas into 4 types (1, 2, 3, and 4) according to the absence or presence of fibrotic foci and the absence or presence of atypical tumor-stromal fibroblasts. We then analyzed the outcome predictive powers of these types of invasive ductal carcinomas using multivariate analyses that included well-known clinicopathologic factors. The multivariate analyses showed that type 4 invasive ductal carcinomas with fibrotic foci and atypical tumor stromal fibroblasts had significantly higher hazard ratios for tumor recurrence and tumor-related death, independent of the nodal status and histologic grade, and the type 2 invasive ductal carcinomas without fibrotic foci but with atypical tumor-stromal fibroblasts had a significant higher hazard ratio for tumor recurrence among patients with invasive ductal carcinoma with nodal metastasis and those with histologic grade 3 disease. The results of this study clearly indicated that the presence of atypical tumor-stromal fibroblasts, especially in fibrotic foci, is significantly associated with tumor recurrence and tumor related death of patients with invasive ductal carcinoma of the breast. PMID- 21317706 TI - S100P expression in ductal type of carcinoma ex pleomorphic adenoma. AB - Pleomorphic adenoma (PA) is known to occasionally progress to carcinoma, but the mechanisms of its malignant transformation have not been fully elucidated. S100P, an EF-hand calcium-binding protein, has recently been proposed as an initiator of carcinogenesis in some kinds of epithelial tumors. In this study, we aimed to elucidate the potential role of S100P in tumorigenesis and stepwise progression of carcinoma ex pleomorphic adenoma (CXPA) with ductal differentiation. In 31 ductal type CXPAs (8 in situ, 5 intracapsular, and 18 extracapsular) and 28 PAs (21 conventional and 7 atypical) of the salivary gland, we examined the protein expression of S100P, androgen receptor (AR), HER2/neu, p53, and Ki-67 by immunohistochemistry. HER2 expression, p53 expression, and the Ki-67 labeling index were higher in CXPAs than in atypical PAs and conventional PAs, whereas the AR expression level was relatively high even in atypical PAs. S100P overexpression was significantly more prevalent in CXPAs (27 cases; 87.1%) than in atypical PAs (2 cases; 28.6%) and conventional PAs (1 case; 4.8%) (P<0.05). High prevalence of S100P expression was observed in each intraductal, extraductal intracapsular, and extracapsular component of CXPAs. In addition, equivalent, high-level S100P expression was observed in all histologic subtypes of the malignant component of CXPAs. These results indicate that S100P may play an important role in malignant transformation of ductal cells of PA, and that immunohistochemical staining for S100P would be a useful diagnostic marker for identifying the early phase of CXPA, in combination with AR, HER2, p53, and Ki 67. PMID- 21317707 TI - Dedifferentiated liposarcoma with meningothelial-like whorls, metaplastic bone formation, and CDK4, MDM2, and p16 expression: a morphologic and immunohistochemical study. AB - We studied 5 cases of dedifferentiated liposarcoma with meningothelial-like whorls and metaplastic bone formation, assessing morphology and immunohistochemical expression of a panel of antigens (CDK4, MDM2, and p16 proteins, desmin, smooth muscle actin, h-caldesmon, CD34, AE1/AE3, epithelial membrane antigen, claudin-1, S100 protein, CD21, CD35, CD117, beta-catenin, vimentin, and MIB1). The specimens were from the retroperitoneum (3), pelvis (1) or paratesticular region (1), and all 5 specimens comprised exclusively or predominantly dedifferentiated liposarcoma. All 5 dedifferentiated liposarcomas showed prominent metaplastic bone, 3 produced cartilage, and 1 also had osteosarcomatous tissue. The whorls comprised concentric distributions of spindle or epithelioid cells. All cases expressed smooth muscle actin, 3 strongly, whereas 4 cases showed at least focal claudin-1 positivity. In all cases, the whorls expressed at least 2 of CDK4, MDM2, and p16. The presence of 2 morphologic subsets and the immunohistochemical findings suggest that the whorls in these dedifferentiated liposarcomas exhibit divergent myofibroblastic and possibly perineurial differentiation. The CDK4, MDM2, and p16 expression in the whorls suggests that they share a similar genetic background to well-differentiated and dedifferentiated liposarcoma, and that additional genetic events are causal to their distinct morphology. PMID- 21317708 TI - Segmental atrophy of the liver: a distinctive pseudotumor of the liver with variable histologic appearances. AB - Segmental atrophy of the liver can lead to the formation of a pseudotumor that can pose a diagnostic challenge. To better understand the full clinicopathologic spectrum of this pseudotumor, 18 cases were studied. Ages at presentation ranged from 14 to 91 years (median, 63 y) with a modest female-patient predominance (13 of 18, 72%). Upper right quadrant abdominal pain was the most common clinical presentation (14 of 18, 78%), and all the cases were mass lesions. The majority of cases were subcapsular (15 of 18, 83%) and ranged in size from 1.8 to 10.0 cm. All the cases contained abnormally thick-walled and often thrombosed vessels, with both arteries and veins affected. Biliary cysts were a common finding (7 of 18, 39%). Examination of the entire series of cases suggested a sequence of changes, with early lesions (n = 4) composed of collapsed hepatic parenchyma with preservation of portal areas, occasional islands of residual hepatocytes, and brisk bile ductular proliferation. These cases showed very mild elastosis. Other cases (n = 10) showed little or no ductular proliferation but had increased levels of elastosis. More advanced lesions (n = 3) were composed almost solely of elastosis with small scattered islands of unremarkable hepatocytes, whereas an end-stage lesion (n = 1) was a discrete nodule of fibrosis. In conclusion, segmental atrophy of the liver is typically subcapsular, and is strongly associated with vascular injury. The lesion has multiple stages ranging from parenchymal collapse, to nodular elastosis, to nodular fibrosis. Recognizing the various morphologies will aid in proper diagnosis. PMID- 21317709 TI - Spindle cell thymomas (WHO Type A) with prominent papillary and pseudopapillary features: a clinicopathologic and immunohistochemical study of 10 cases. AB - Ten cases of spindle cell thymomas with prominent papillary and pseudopapillary features were presented. The patients were 7 men and 3 women between the ages of 47 and 75 years. Clinically, 3 patients were asymptomatic, 1 patient presented with chest pain, 4 patients with shortness of breath, and 1 patient with a history of pulmonary tuberculosis. One case was found during an autopsy procedure. Nine patients underwent complete surgical resection of their mediastinal tumors, which varied in size from 4 to 9 cm in greatest diameter. Histologically, all tumors showed a spindle cell appearance (WHO type A) with elongated nuclei and inconspicuous nucleoli. Scattered lymphocytes were present admixed with the spindle cellular proliferation. In addition, all tumors showed prominent areas of papillary and pseudopapillary features, which varied in size and type. In some cases, prominent areas of hyalinization were also present, whereas in other cases the papillary-like changes were composed of edematous projections, which imparted these tumors a unique morphologic growth pattern. Three tumors were encapsulated, whereas 7 other tumors were invasive. Immunohistochemical studies for keratin CAM5.2 and keratin 5/6 showed strong positive reaction, whereas other stains including CEA, calretinin, CD-31, and thyroglobulin were negative. Follow-up information showed that 2 patients are alive and well, whereas 3 patients have died. No follow-up information was obtained in 4 patients. The current morphologic appearance has not been previously emphasized in thymomas, which is important to recognize to avoid misdiagnosis with other mediastinal neoplasms. PMID- 21317710 TI - Primary signet-ring cell/histiocytoid carcinoma of the eyelid: a clinicopathologic study of 5 cases and review of the literature. AB - Primary cutaneous signet-ring cell carcinomas are rare and aggressive neoplasms. These neoplasms have been mostly described in the eyelids, and more uncommonly, in the axillary skin. Histopathologically, the neoplasm seems to be composed of signet-ring cells or histiocytoid epithelial cells arranged in an Indian file growth pattern between collagen bundles of the dermis. Immunohistochemically, neoplastic cells expressed strong diffuse reactivity for CAM 5.2, CK7, high molecular weight CK, AE1/AE3 and MNF116 cytokeratins, carcinoembryonic antigen, epithelial membrane antigen, gross cystic disease fluid protein-15, p63, mucin-1 (MUC-1), BerEP4, and E-cadherin; moderate positivity for alpha-smooth muscle actin, tissue-specific transcription factor 1, MUC-2, Podoplanin, and N-cadherin; and weak positivity for epidermal growth factor receptor. Estrogen and progesterone receptors show positive results in some cases and negative results in others. The histopathologic and immunohistochemical features of primary signet ring cell or histiocytoid carcinoma of the eyelid are closely similar to those of histiocytoid lobular carcinoma of the breast, and there are several examples of histiocytoid mammary carcinoma metastatic to the eyelids. Therefore, histopathologic differential diagnosis between primary and metastatic signet-ring cell or histiocytoid eyelid carcinomas is mandatory. In this study, we report our experience with the clinical, histopathologic, and immunohistochemical findings in 5 cases of primary signet-ring cell or histiocytoid carcinoma of the eyelid. We investigated the usefulness of p63, epidermal growth factor receptor, MUC-1, MUC-2, mammaglobin, and E-cadherin as immunohistochemical markers for this histopathologic differential diagnosis. Primary signet-ring cell carcinoma of the eyelid is an aggressive neoplasm that may develop regional or distant metastases, and therefore, it should be excised with wide margins. PMID- 21317711 TI - The concept of hepatic artery-bile duct parallelism in the diagnosis of ductopenia in liver biopsy samples. AB - Absence of bile ducts (BDs) in >50% of portal tracts is currently the most widely accepted criterion for the diagnosis of ductopenia. In this study, we describe an alternative method for the quantitative assessment of BDs based on the percentage of portal tracts containing unpaired hepatic arteries (HAs). Diagnostic criteria for ductopenia were defined as follows: 1. presence of at least 1 unpaired HA in >10% of all portal tracts; 2. at least 2 unpaired HAs present in different portal tracts in a given sample. In liver biopsies from patients with primary biliary cirrhosis and suspected chronic allograft rejection (n = 32), loss of BD was detected in 59.4% of patients using the unpaired HA method compared with 43.7% (P = 0.31), 21.9% (P = 0.005), and 12.5% (P = 0.001) by the traditional method, depending on specific adequacy criteria used (no adequacy criteria, >10 portal tracts, or >5 complete portal tracts per biopsy, respectively). The percentage of portal tracts containing BD(s) was significantly affected by the degree of portal inflammation, fibrosis stage, percentage of complete portal tracts, and biopsy width, whereas none of these factors influenced the prevalence of unpaired arteries. The unpaired HA method showed higher sensitivity for the detection of mild degrees of loss of BD compared with the traditional method, and was not influenced by factors that affected the percentage of portal tracts containing BDs. PMID- 21317712 TI - Endocervical fibroblastic malignant peripheral nerve sheath tumor (neurofibrosarcoma): report of a novel entity possibly related to endocervical CD34 fibrocytes. AB - Primary cervical stromal sarcomas are rare neoplasms that have been poorly characterized. We report the clinical, histologic, and immunohistologic features of 3 primary endocervical S100 protein (S100p)-positive and CD34-positive sarcomas, herein designated as fibroblastic malignant peripheral nerve sheath sarcoma (endocervical neurofibrosarcoma), 2 of which occurred in women younger than 35 years of age. All tumors presented as a cervical polyp or mass lesion; 1 extended into the pelvic side wall and vaginal soft tissue. The tumors measured 2.0 to 8.0 cm, and were composed of compact fascicles of spindled cells arranged in herringbone, loose fascicular, or ill-defined storiform patterns. A focal whorled architecture was identified in all 3 tumors, but distinct Antoni A areas and Verocay bodies were absent. Ultrastructural examination in 1 case confirmed the presence of fibrocyte-like differentiation. Strong, diffuse, and in 1 case, patchy S100p expression was seen in all cases; strong and diffuse CD34 expression was also present in all tumors. Adjacent uninvolved endocervical stroma also showed CD34 positivity but expression was much less dramatic than in tumor cells. All other markers of neural, melanocytic, smooth muscle, endometrial stromal, and epithelial differentiation were negative. One of the tumors behaved extremely aggressively with extensive pelvic involvement, resulting in patient death within 16 months of diagnosis; another tumor was associated with pelvic recurrence 13 months after diagnosis; and the third tumor had an indolent course with no evidence of recurrence at 33 months after complete excision and local radiotherapy, although follow-up was limited. Review of large numbers of mesenchymal tumors in the uterus did not show similar tumors. Endocervical neurofibrosarcoma should be distinguished from solitary fibrous tumor, endometrial stromal sarcoma, leiomyosarcoma, melanoma, and other spindle cell neoplasms. The prominent fibroblastic endoneurial-like differentiation seen in this peripheral nerve sheath tumor may be related to the presence of a rich mucosal stromal fibrocyte network in the endocervix. PMID- 21317713 TI - Colorectal glandular-neuroendocrine mixed tumor: pathologic spectrum and clinical implications. AB - Colorectal glandular-neuroendocrine mixed tumor is an uncommon entity with ill defined clinicopathologic characteristics. We describe the clinicopathology of 23 new cases and review 67 previously reported cases. Clinically, patients (mean age, 61.9 y; male: female, 1.0:1.1) presented with a positive fecal occult blood test or visible rectal bleeding (44%), abdominal pain or change in bowel movement pattern (25%), bowel obstruction (19%), or weight loss (19%). Endoscopically, the tumors presented as a polypoid lesion (57%), a mass lesion (30%), or an ulcerating lesion (9%). Tumors were located in the right colon (56%), transverse colon (3%), and left colon (41%). Surgical resection was the treatment of choice in 83% of cases. After follow-up for an average of 20 months, the tumor-related death rate was 68%. Histologically, 42% were classified as composite tumors and 58% were classified as collision tumors. An adenoma to carcinoma, and then carcinoma to mixed tumor progression through the APC/beta-catenin pathway was seen in a majority of cases. Both the glandular and the neuroendocrine components of the mixed tumor can show a spectrum of differentiation, and each component can metastasize separately regardless of its percentage volume. On the basis of the combined analysis of the pathologic spectrum and the clinical behavior of our series and previously reported cases, we propose a new classification system that reflects the differentiation of each component in colorectal glandular neuroendocrine mixed tumor to facilitate uniform reporting and to better predict its clinical behavior. PMID- 21317714 TI - Histopathology of aspiration pneumonia not associated with food or other particulate matter: a clinicopathologic study of 10 cases diagnosed on biopsy. AB - Aspiration pneumonia most often presents in surgical lung biopsies as a granulomatous pneumonia with acute inflammation, microabscesses, and a granulomatous reaction to food or other particulate matter. In this study of 10 patients with clinical aspiration in whom surgical lung biopsy was performed, 3 additional patterns of lung injury were seen: organizing pneumonia (4 patients); acute diffuse alveolar damage (3 patients); and chronic bronchiolitis (3 patients), in whom 2 had evidence of extensive pleuropulmonary fibrosis and scarring. This study adds to the earlier described literature on granulomatous reactions to food and particulate matter in the lung by alerting pathologists to other histopathologic manifestations of aspiration-induced lung injury in surgical lung biopsies. PMID- 21317715 TI - ERG transcription factor as an immunohistochemical marker for vascular endothelial tumors and prostatic carcinoma. AB - ERG, an ETS family transcription factor, is known to be expressed in endothelial cells, and oncogenic ERG gene fusions occur in subsets of prostatic carcinoma, acute myeloid leukemia, and Ewing sarcoma. In this study, we immunohistochemically investigated nuclear ERG expression using a new monoclonal antibody, CPDR ERG-MAb, that is highly specific for detecting ERG protein and ERG expressing prostate carcinomas. A broad range of vascular endothelial (n = 250), other mesenchymal (n = 973), and epithelial tumors (n = 657) was examined to determine the use of ERG immunohistochemistry in surgical pathology. Only immunostains with ERG-positive normal endothelia (internal control) were considered valid, and only nuclear staining was considered to be positive. In adult tissues, ERG was restricted to endothelial cells and to a subset of bone marrow precursors, but early fetal mesenchyme and subpopulations of fetal cartilage were also positive. In vascular tumors, ERG was expressed in endothelia of all hemangiomas and lymphangiomas, and typically extensively expressed in 96 of 100 angiosarcomas, 42 of 43 epithelioid hemangioendotheliomas, and all 26 Kaposi sarcomas. Among nonvascular mesenchymal tumors, only blastic extramedullary myeloid tumors (7 of 10) and rare Ewing sarcomas (2 of 29) were positive. Among epithelial tumors, 30 of 66 prostatic adenocarcinomas showed focal-to-extensive ERG positivity, with no immunoreactivity in the normal prostate. Other carcinomas and epithelial tumors (n = 643) were ERG negative, with the exception of 1 of 42 large cell undifferentiated pulmonary carcinomas and 1 of 27 mesotheliomas, each of which showed focal nuclear ERG positivity. On the basis of the above observations, ERG is a highly specific new marker for benign and malignant vascular tumors. Among epithelial tumors, ERG shows a great promise as a marker to identify prostatic carcinoma in both primary and metastatic settings. PMID- 21317716 TI - Primary carcinoid tumors of the urinary bladder and prostatic urethra: a clinicopathologic study of 6 cases. AB - Primary carcinoid tumors of the urinary bladder are exceedingly rare. Although they have been considered to be potentially malignant neuroendocrine neoplasms, some previously reported cases were associated with a carcinoma component that might have altered the outcome. Only 8 histologically well-documented cases of pure carcinoid tumors of the bladder and 1 of the prostatic urethra have been reported in the literature. In this study, we describe 6 additional primary pure carcinoid tumors arising in the bladder (5 cases) or prostatic urethra (1 case). Patients (4 male, 2 female) ranged in age from 45 to 60 years (average, 55 y) and presented with hematuria (n = 5 of 6), obstruction (n = 1 of 6), or for concurrent genitourinary disease (n = 1 of 6). All 6 cases shared gross and microscopic findings. Cystoscopic examination showed small, smooth surfaced, or polypoid nodules. The 5 cases in the bladder were all located within or near the trigone and bladder neck region. Microscopically, these 6 tumors were subepithelial and confined within the lamina propria, associated with adjacent cystitis cystica et glandularis. The tumors were composed of uniform, cuboidal, or columnar cells with finely stippled chromatin and inconspicuous nucleoli in a prominent pseudoglandular pattern composed of acinar and cribriform structures. The cells had moderate-to-abundant cytoplasm and basally located Paneth cell-like eosinophilic granules. Although occasional atypical cells with prominent nucleoli could be seen, mitotic activity was absent or rare and cases lacked necrosis. Neuroendocrine differentiation was confirmed by immunohistochemistry in all 6 cases. All tumors were completely excised by biopsies. There was no evidence of disease recurrence or progression in all 6 patients, including 3 patients who had clinical follow-up for >4 years. Primary pure carcinoid tumors of the urinary bladder (and prostatic urethra) have distinct pathologic characteristics, with their prominent pseudoglandular features leading to difficulty in diagnosis. They are likely to have a very favorable clinical outcome, and should be distinguished from mixed carcinoid tumors or urothelial carcinomas with neuroendocrine differentiation that show focal carcinoid-like histologic features. PMID- 21317717 TI - The 2010 Fred W. Stewart award recipient: Julia A. Bridge, MD. PMID- 21317718 TI - Sequential development of histiocytic sarcoma and diffuse large b-cell lymphoma in a patient with a remote history of follicular lymphoma with genotypic evidence of a clonal relationship: a divergent (bilineal) neoplastic transformation of an indolent B-cell lymphoma in a single individual. AB - Follicular lymphoma (FL) often transforms to diffuse large B-cell lymphoma (DLBCL) during its protracted clinical course. Rarely, histiocytic sarcoma (HS) occurs secondary to or concurrent with FL, although the biological relationship between these 2 morphologically and immunophenotypically distinct entities in the same individual has not been well characterized. We report a unique case showing the sequential occurrence of first, HS and then DLBCL in a patient with a remote history of FL. In this case, HS developed 17 years after the diagnosis of FL and was shown to partly retain the immunophenotypic features characteristic of FL, while showing the morphologic and immunophenotypic profiles diagnostic of HS. DLBCL occurred 18.5 years after FL. Both HS and DLBCL harbored the IGH/BCL2 fusion gene, a hallmark of FL, per interphase fluorescence in situ hybridization analysis. Immunoglobulin gene rearrangement studies showed a clonal rearrangement of the IGH gene in both HS and DLBCL with identical amplicons, suggesting a shared origin of the neoplastic clones. These data support the hypothesis of transdifferentiation or transevolution in a mature B-cell neoplasm, and, in addition, suggest the possibility of a divergent (bilineal) neoplastic transformation of FL in a single individual. PMID- 21317719 TI - Peritoneal elastic lamina invasion in colorectal cancer: the answer to a controversial area of pathology? PMID- 21317721 TI - Blood pressure measurement in very obese patients: a challenging problem. PMID- 21317722 TI - Central and 24-h blood pressure: dwarfs standing upon the shoulders of giants? PMID- 21317723 TI - A genome-wide association study-derived candidate gene seeks replication: STK39. PMID- 21317724 TI - Run kidney, run: lifestyle interventions in the prevention of kidney disease. PMID- 21317725 TI - Blood pressure lowering therapy in older and younger hypertensive patients. PMID- 21317726 TI - Validation of the Arteriograph working principle: questions still remain. PMID- 21317728 TI - Left ventricular hypertrophy: not so much determinant of renal outcome? PMID- 21317730 TI - Leber hereditary optic neuropathy: some new observations. PMID- 21317731 TI - Neuroretinitis: review of the literature and new observations. AB - Neuroretinitis (NR) is an inflammatory disorder characterized by optic disc edema and subsequent formation of a macular star figure. The underlying pathophysiology involves increased permeability of disc vasculature, but the etiology is not fully defined. In some cases, NR is probably due to an infectious process involving the disc; in others, a postviral or autoimmune mechanism is more likely. Cases can be divided into those in which a specific infectious agent has been identified, those considered idiopathic, and those with recurrent attacks. Some reports have not distinguished among these subgroups, and it is unclear if their clinical features vary. We reviewed the literature and our own patients looking particularly at features that might better distinguish these subtypes. Features common to all 3 groups included age, absence of pain, and fundus appearance. Preceding systemic symptoms were more common in patients with cat scratch disease (CSD) and uncommon in those with recurrence. The pattern and magnitude of visual field loss differed, more commonly confined to the central field in CSD cases and more severe in recurrent cases. Recovery of visual acuity and field was less substantial in recurrent cases even after the initial episode. MRI was usually normal in all 3 groups. Enhancement confined to the optic disc was found in all 3 groups, but enhancement of the retrobulbar optic nerve was seen only in recurrent cases. Findings that are strongly suggestive of CSD include very young age, preceding systemic symptoms, and poor visual acuity but with a small or absent relative afferent pupil defect (RAPD). In contrast, the following are suggestive of idiopathic NR with a high risk of recurrence: absence of systemic symptoms, visual field defect outside the central field, preserved visual acuity with a large RAPD, and poor recovery of vision. Decisions regarding evaluation and treatment should be made with these features in mind. PMID- 21317732 TI - Recent progress in understanding congenital cranial dysinnervation disorders. AB - BACKGROUND: In 2002, the new term congenital cranial dysinnervation disorder (CCDD) was proposed as a substitute for the traditional concept of congenital fibrosis of the extraocular muscles (CFEOM) based on mounting genetic, neuropathologic, and imaging evidence, suggesting that many, if not all, of these disorders result from a primary neurologic maldevelopment rather than from a muscle abnormality. This report provides an update 8 years after that original report. EVIDENCE ACQUISITION: Review of pertinent articles published from January 2003 until June 2010 describing CCDD variants identified under PubMed MeSH terms congenital fibrosis of the extraocular muscles, congenital cranial dysinnervation disorders, individual phenotypes included under the term CCDD, and congenital ocular motility disorders. RESULTS: At present, a total of 7 disease genes and 10 phenotypes fall under the CCDD umbrella. A number of additional loci and phenotypes still await gene elucidation, with the anticipation that more syndromes and genes will be identified in the future. Identification of genes and their function, along with advances in neuroimaging, have expanded our understanding of the mechanisms underlying several anomalous eye movement patterns. CONCLUSIONS: Current evidence still supports the concept that the CCDDs are primarily due to neurogenic disturbances of brainstem or cranial nerve development. Several CCDDs are now known to have nonophthalmologic associations involving neurologic, neuroanatomic, cerebrovascular, cardiovascular, and skeletal abnormalities. PMID- 21317733 TI - Bilateral simultaneous central retinal vein occlusions in an otherwise healthy adult. PMID- 21317734 TI - Should patients with radiation-induced optic neuropathy receive any treatment? PMID- 21317736 TI - Orbital involvement in Bing-Neel syndrome. PMID- 21317737 TI - Idiopathic intracranial hypertension with Dan and beyond: the 2010 Jacobson lecture. PMID- 21317740 TI - Maintaining aim at a moving target. PMID- 21317739 TI - Finding ALK-positive lung cancer: what are we really looking for? PMID- 21317741 TI - A case series of dose-limiting peripheral edema observed in patients treated with pemetrexed. AB - INTRODUCTION: In the phase I and II trials, the dose-limiting toxicities of pemetrexed included neutropenia, thrombocytopenia, and fatigue. Grade 3 bilateral peripheral edema that resembled cellulitis was not commonly described. METHODS: Since 2009, the Thoracic Oncology Service at Memorial Sloan Kettering Cancer Center has identified 14 patients who developed bilateral peripheral edema and erythema of the lower extremities while receiving pemetrexed chemotherapy. During this time, 489 patients with thoracic malignancy have been treated with pemetrexed. RESULTS: There were seven men and seven women. Average age was 72 years. All patients had stage IV adenocarcinoma of the lung. The edema presented at a median of eight doses (range, 3-23 doses.) Other causative factors such as deep vein thrombosis, renal insufficiency, and congestive heart failure were excluded. Thirteen of the 14 patients required the drug to be stopped or dose lowered. CONCLUSION: We have collected 14 cases with lung adenocarcinoma treated with pemetrexed who developed bilateral lower extremity edema and erythema, a condition rarely described. In all cases, symptoms resolved with discontinuation or dose reduction of the drug. Patients who received corticosteroids showed improvement in their symptoms. PMID- 21317743 TI - Persistent part-solid nodule in the lung represents pulmonary adenocarcinoma. PMID- 21317742 TI - Frequency and type of epidermal growth factor receptor mutations in African Americans with non-small cell lung cancer. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) predict response to tyrosine kinase inhibitors. Mutations occur more commonly in never smokers and East Asians, but there are conflicting reports on the frequency of EGFR mutations in tumors from African Americans. METHODS: Tumors from 67 African American and 77 white participants in previous case-control studies of lung cancer were selected to determine EGFR mutational status. Mutation analysis was performed using the Sequenom mass array analyzer (Sequenom, San Diego, CA). RESULTS: Overall, 13.9% of the study population carried an EGFR mutation. EGFR mutations occurred in 11.9% of tumors from African Americans compared with 15.6% in whites (p = 0.53). All mutations found in African Americans were deletions in exon 19. The majority of mutations were found in nonsmokers among both African Americans (7/8) and whites (8/12). CONCLUSION: These results indicate that African Americans with NSCLC harbor somatic EGFR mutations at a frequency similar to whites with NSCLC. Thus, clinicians should not use race as a clinical decision parameter for the use of EGFR-tyrosine kinase inhibitors. PMID- 21317744 TI - T4 or MI? PMID- 21317745 TI - First case of A859T epidermal growth factor receptor mutation responding to erlotinib. PMID- 21317746 TI - Successful treatment with pemetrexed in a patient with mucinous bronchioloalveolar carcinoma: long-term response duration with mild toxicity. PMID- 21317747 TI - A rare case of endobronchial amelanotic melanoma. PMID- 21317749 TI - On plain language and going astray. PMID- 21317750 TI - Bevacizumab chemotherapy for pulmonary epithelioid hemangioendothelioma with severe dyspnea. PMID- 21317752 TI - Excision repair cross-complementing-1 for small cell lung cancer. PMID- 21317753 TI - High-dose erlotinib for refractory brain metastases in a patient with relapsed non-small cell lung cancer. PMID- 21317754 TI - Health, market forces, and debate in medical care: room for controversy. PMID- 21317756 TI - Response to the validity of self-reported nicotine product use in the 2001-2008 National Health and Nutrition Examination Survey. PMID- 21317757 TI - Commentary on the role of physical therapists in pediatric health promotion and obesity prevention: comparison of attitudes. PMID- 21317758 TI - Commentary on does orthotic use affect upper extremity support during upright play in infants with down syndrome? PMID- 21317759 TI - Commentary on task analyses identify coat-donning delays in preschoolers in special education. PMID- 21317760 TI - Commentry on impact of enhanced sensory input on treadmill step frequency: infants born with myelomeningocele. PMID- 21317761 TI - Commentary on reference values on the 6-minute walk test for children living in the United States. PMID- 21317762 TI - Commentary on normal values of functional reach and lateral reach tests in Indian school children. PMID- 21317763 TI - Commentary on supramaximal verification of peak oxygen uptake in adolescents with cystic fibrosis. PMID- 21317764 TI - Fuzzy modeling, a novel approach to studying pharmacodynamics. AB - Fuzzy logic can handle questions to which the answers may be "yes" at one time and "no" at the other, or may be partially true and untrue. Pharmacodynamic data deal with questions such as "Does a patient respond to a particular drug dose or not," or "Does a drug cause the same effects at the same time in the same subject or not." Such questions are typically of a fuzzy nature and might, therefore, benefit from an analysis based on fuzzy logic.The objective was to assess whether fuzzy logic can improve the precision of predictive models for pharmacodynamic data.The methods and results were as follows: (1). The quantal pharmacodynamic effects of different induction dosages of thiopental on numbers of responding subjects were used as the first example. Regression analysis of the fuzzy-modeled outcome data on the input data provided a much better fit than did the unmodeled output values with r-square values of 0.852 (F-value = 40.34) and 0.555 (F-value = 8.74), respectively. (2). The time-response effect propranolol on peripheral arterial flow was used as a second example. Regression analysis of the fuzzy modeled outcome data on the input data provided a better fit than did the unmodeled output values with r-square values of 0.990 (F-value = 416) and 0.977 (F-value = 168), respectively.Fuzzy modeling may better than conventional statistical method fit and predict pharmacodynamic data, such as, for example, quantal dose response and time response data. This may be relevant to future pharmacodynamic research. PMID- 21317765 TI - Involvement of the aldo-keto reductase, AKR1B10, in mitomycin-c resistance through reactive oxygen species-dependent mechanisms. AB - The human aldo-keto reductase (AKR) 1B10 is suggested as a tumor marker in various solid tumors. Using colon cancer cells, we found that AKR1B10 was induced with acquisition of resistance to the anticancer drug mitomycin-c (MMC). In the resistant cells, treatment with an AKR1B10 inhibitor decreased their MMC tolerance. In the nonresistant cells, overexpression and silencing of AKR1B10 decreased and increased, respectively, susceptibility to cytotoxic effects of MMC and 4-hydroxy-2-nonenal, which was formed as a product of lipid peroxidation by MMC treatment. These results suggest a role of AKR1B10 in the development of MMC resistance, which may be mediated by its ability to detoxify cytotoxic aldehydes including 4-hydroxy-2-nonenal. PMID- 21317766 TI - Does calcium contribute to the CD95 signaling pathway? AB - Death receptors play a crucial role in immune surveillance and cellular homeostasis, two processes circumvented by tumor cells. CD95 (also termed Fas or APO1) is a transmembrane receptor, which belongs to the tumor necrosis factor receptor superfamily, and induces a potent apoptotic signal. Initial steps of the CD95 signal take place through protein/protein interactions that bring zymogens such as caspase-8 and caspase-10 closer. Aggregation of these procaspases leads to their autoprocessing, to the release of activated caspases in the cytosol, which causes a caspase cascade, and to the transmission of the apoptotic signal. In parallel, CD95 engagement drives an increase in the intracellular calcium concentration (Ca(2+))i whose origin and functions remain controversial. Although Ca(2+) ions play a central role in apoptosis/necrosis induction, recent studies have highlighted a protective role of Ca(2+) in death receptor signaling. In the light of these findings, we discuss the role of Ca(2+) ions as modulators of CD95 signaling. PMID- 21317767 TI - Phase II study of S-1 monotherapy as a first-line treatment for elderly patients with advanced nonsmall-cell lung cancer: the Central Japan Lung Study Group trial 0404. AB - Although S-1 has been shown to have activity against advanced nonsmall-cell lung cancer (NSCLC), its efficacy for elderly patients remains unclear. This phase II study evaluated the efficacy and safety of S-1 as a first-line treatment for elderly patients. Chemotherapy-naive patients aged 70 years or older with stages IIIB to IV or postoperative NSCLC and performance status 1 or lower were eligible. Patients received S-1 approximately equivalent to 80 mg/m/day for 2 weeks followed by a 1-week rest period every 3 weeks. The primary end point was the response rate. Secondary end points were toxicity, disease control rate, progression-free survival, and overall survival. Twenty-nine patients were eligible. The median age was 78 years (range, 70-85 years). The overall response rate and the disease control rate were 27.6 [95% confidence interval (CI), 11.3 43.9%] and 65.5% (95% CI: 48.2-82.8%), respectively. The median progression-free survival time was 4.0 months (95% CI: 4.0-9.8 months). The median overall survival was 12.1 months (95% CI: 13.8-25.5 months) and the 1-year survival rate was 53.6%. No grade 4 toxicities were observed. The only hematological toxicity of grade 3 was anemia in 6.9% of patients. The grade 3 nonhematological toxicities included hyponatremia, anorexia, nausea, oral mucositis, and diarrhea in 3.4% of patients and infection in 6.9% of patients. S-1 monotherapy was effective and well tolerated as a first-line treatment for elderly patients with advanced NSCLC. The results of this study warrant further investigations of this regimen, including a randomized controlled trial. PMID- 21317768 TI - Antimicrobial prophylaxis and infection surveillance in extracorporeal membrane oxygenation patients: a multi-institutional survey of practice patterns. AB - The goal of this study was to characterize antimicrobial prophylaxis and infection surveillance practices at centers treating patients with extracorporeal membrane oxygenation (ECMO). A 37-question web-based survey was sent to all ECMO coordinators and directors at Extracorporeal Life Support Organization (ELSO) participating centers. Data were reported by center. The most complete response was used when multiple surveys were returned from a single center, and respondents' answers from the same center were analyzed for concordance. Responses were obtained from 76% of ELSO centers (132/173) and 41% of survey recipients (223/548). Most centers administer antibiotic prophylaxis (74%, 97/132), and almost half have a standardized protocol (49%, 64/132). Routine antibacterial but not antifungal prophylaxis is common (42%, 62/132 vs. 2/132, 2%). There is significant variation in the antibiotic choices and duration of prophylaxis, regardless of whether the center has a protocol or not. Almost half of centers (49%, 64/132) perform routine surveillance cultures but at variable intervals. There is significant heterogeneity in antibiotic prophylaxis and infection surveillance practice patterns among ELSO centers. PMID- 21317769 TI - Left ventricular mechanical support with Impella provides more ventricular unloading in heart failure than extracorporeal membrane oxygenation. AB - The Impella microaxial-flow pump can directly unload left ventricle (LV) in cases of acute heart failure. Extracorporeal membrane oxygenation (ECMO) is widely used for circulatory support. Although the clinical effectiveness of ECMO has been demonstrated, insufficient LV loading reduction may not be advantageous for myocardial recovery. The objective was to compare ventricular loading reduction and reversibility of ventricular fibrillation (VF) with either Impella or ECMO. Six dogs were used. Extracorporeal membrane oxygenation was established by the femoral artery and right atrium. The Impella LD was inserted in LV by the ascending aorta. An acute failing heart was created by sequential coronary artery ligations. Pressure-volume (PV) relationships were acquired without a device and with ECMO or Impella. When VF occurred, direct cardioversion was performed while supported by either ECMO or Impella. The PV area, which is a measure of ventricular unloading and is correlated with myocardial oxygen consumption, decreased more with Impella than with ECMO. Successful defibrillation was achieved more effectively while under Impella support. Superior ventricular unloading with the Impella device may provide higher recovery potential to damaged hearts than ECMO and may have a significant impact not only on intensive care of patients with heart failure but also on resuscitation. PMID- 21317770 TI - Anophthalmia in fronto-facial-nasal dysplasia. PMID- 21317771 TI - Patient characteristics and variation in treatment outcomes: which patients benefit most from acupuncture for chronic pain? AB - OBJECTIVES: The aim of this study was to identify patients' characteristics that increase or decrease their benefit from acupuncture treatment of chronic pain. METHODS: Patients with chronic low back pain, headache, neck pain, or pain due to osteoarthritis of the knee or hip, were included in 4 multicenter, randomized, controlled studies, all conducted in Germany. All patients received routine care; the patients randomized to the acupuncture group received additional acupuncture treatment. Data were pooled, and the main outcome was defined as the 3-month change from baseline of the SF-36 bodily pain subscale. To identify predictors for treatment effects and effect modifiers (ie, variables that interact with the form of treatment), patients' characteristics and their interaction with treatment were included in a mixed linear model to predict treatment outcome. RESULTS: A total of 9,990 patients who were treated by 2,781 physicians were analyzed. The outcome was markedly improved in the acupuncture group (P < 0.001). Age, education, duration of illness, baseline pain, and some concomitant diseases predicted treatment outcome in both groups. Patients' characteristics that enlarged the acupuncture effect (ie, acted as effect modifiers) were being female (P = 0.028), living in a multi-person household (P = 0.002), failure of other therapies before the study (P = 0.049), and former positive acupuncture experience (P = 0.005). DISCUSSION: Future research to clarify the modifying effects with special focus on patients' expectations and other psychological variables is needed. PMID- 21317772 TI - Assessing fear-avoidance beliefs in patients with whiplash-associated disorders: a comparison of 2 measures. AB - OBJECTIVES: To examine the development of fear avoidance behaviours following whiplash injury using two different measures of fear avoidance, the Pictorial Fear of Activities Scale-Cervical (PFActS-C), and the Tampa Scale of Kinesiophobia (TSK-17). Secondarily we assessed the capacity of these measures to predict recovery status at long term follow up and initial cervical range of movement (ROM). METHODS: Ninety-eight patients with acute WAD were recruited and completed measures of pain and disability (NDI), fear avoidance beliefs and cervical ROM at baseline (<4 weeks), 3 and 6 months post injury. Participants were grouped based on NDI scores at 6 months follow up as either recovered (NDI <10), mild (NDI 10-28) or moderate/severe (NDI <= 30). RESULTS: Repeated measures, linear mixed model analysis showed a significant main effect for time and group for both TSK-17 and PFActS-C scores (P <= 0.001). On both measures the moderate/severe group scored significantly higher than the mild and recovered groups. TSK-17 scores, age and initial pain intensity at baseline significantly predicted NDI scores at 6 months (P = 0.002). PFActS-C scores, age and initial pain intensity at baseline significantly predicted initial cervical extension and rotation ROM (P = 0.001). DISCUSSION: Fear avoidance beliefs and behaviours develop quickly following whiplash injury and influence both the initial physical presentation and long term outcome of patients with WAD. The PFActS-C may provide a measure of fear of movement which is more specific to the cervical spine in patients with WAD in comparison to the TSK-17. PMID- 21317773 TI - Atypical facial pain treated with upper thoracic dorsal column stimulation. AB - INTRODUCTION: Spinal cord stimulation (SCS) is the most commonly used implantable neurostimulation modality for management of pain syndromes. We present a patient with history of right facial pain successfully treated for refractory angina with SCS and had coincident near resolution of facial pain. CASE DESCRIPTION: A 45 year old male with documented coronary vasospasm presented for consideration of SCS for refractory angina. He underwent successful implantation with significant improvement in his intractable chest pain. Additionally, during trial and post implantation, the patient described almost complete resolution of his chronic facial pain. Prior to implantation, the facial pain had been thoroughly evaluated without a discernible cause. He had been symptomatically treated for atypical facial pain (AFP) with gabapentin. Post-implantation, the patient was able to discontinue gabapentin and described near complete resolution of his AFP. DISCUSSION: SCS is one of the most promising treatment options for refractory angina. Numerous randomized, controlled trials have demonstrated efficacy in increasing exercise duration and time to angina, decreasing number of angina attacks, sublingual nitrate consumption, and number of ischemic episodes. Reductions in pain, sympathetic tone, and myocardial oxygen demand as well as improvement in coronary microcirculatory blood flow have all been proposed as beneficial outcomes of stimulation. AFP is a poorly understood condition, often without etiology, and most commonly treated symptomatically. The resolution of our patient's AFP is secondary to unclear mechanism(s). We propose SCS may have altered central processing or spinal trigeminal nucleus fibers; additionally, the pain may have been sympathetically mediated and altered by SCS. PMID- 21317774 TI - Necrotic arachnidism and intractable pain from recluse spider bites treated with lumbar sympathetic block: a case report and review of literature. AB - Brown recluse (Loxosceles reclusa) spider bites mainly occur in the southern and Midwestern United States. The clinical manifestation of brown recluse spider bites varies from skin irritation, a small area of tissue damage to neuropathic pain, necrotic arachnidism and severe systemic reactions such as acute renal failure and even death. Treatment is controversial and nonspecific. We describe a case of extensive right lower extremity tissue necrosis and intractable neuropathic pain treated with lumbar sympathetic block in a patient with a documented brown recluse spider bite. Both his pain and tissue necrosis improved significantly with lumbar sympathetic block with local anesthetic. After a series of lumbar sympathetic blocks, his symptoms resolved and lower extremity wound healed rapidly. We discuss the benefit of sympathetic blockade not only for neuropathic pain but also possibly as a treatment for necrotic arachnidism from a brown recluse spider bite. PMID- 21317776 TI - Subjective well-being in patients with chronic tension-type headache: effect of acupuncture, physical training, and relaxation training. AB - BACKGROUND: Episodic tension-type headache is a common problem affecting approximately 2 of 3 of the population. The origin of tension-type headache is multifactorial, but the pathogenesis is still unclear. In some individuals episodic tension-type headache transforms into chronic tension-type headache (CTTH). Subjective symptoms related to the central nervous system might affect patients subjective well-being and quality of life. OBJECTIVE: This study compared 3 nonpharmacologic treatments; acupuncture, relaxation training, and physical training on subjective well-being in patients with CTTH. METHODS: Ninety consecutive patients with CTTH were randomly allocated to acupuncture, relaxation training, or physical training. At baseline 88 age-matched and sex-matched healthy controls were compared with the patients with CTTH. Subjective, central nervous system-related symptoms that might affect patients' subjective well-being and quality of life were assessed with the Minor Symptom Evaluation Profile, which contains 24 self-administered standardized items with visual analog scale responses. Fifteen items are categorized into 3 dimensions: contentment, vitality, and sleep. Assessments were made before treatment, immediately after, and 3 and 6 months after the last treatment. RESULTS: Baseline values of the total score of the 24 items and the 3 dimensions were generally lower in patients with tension-type headache compared with the reference group. No significant differences were found among the 3 treatment groups during the baseline period. All treatments proportionally improved the subjective, central nervous system related symptoms in patients with CTTH. The 3-month follow-up, the total score of the Minor Symptom Evaluation Profile was significantly improved in the physical training group compared with the acupuncture group (P=0.036). Total mean over period was also highest in the physical training group compared with the acupuncture group (P=0.025). The vitality and sleep dimension was significantly improved at the 6-month follow-up in the relaxation training group compared with the acupuncture group (P=0.04). CONCLUSIONS: Physical training and relaxation training seem to be preferable nonpharmacologic treatments for improvement of central nervous system-related symptoms and subjective well-being for patients with CTTH. PMID- 21317775 TI - Effectiveness of a psychoeducational treatment program implemented in general practice for fibromyalgia patients: a randomized controlled trial. AB - OBJECTIVES: A recent meta-analysis concluded that multicomponent treatments are effective for some fibromyalgia (FM) symptoms. The objective of this study was to examine whether a psychoeducational intervention implemented in primary care is more effective than usual care for improving the functional status of patients with FM. METHODS: This study was based on a randomized controlled trial. The 484 patients with FM included in a database of the Viladecans Hospital (Barcelona, Spain) were eligible for screening. Finally, 108 patients were randomly assigned to the intervention and 108 patients were assigned to usual care. The intervention comprised nine 2-hour sessions (5 sessions of education and 4 sessions of autogenic relaxation). The patients were assessed before and after the intervention with a battery of instruments (measuring sociodemographic data, medical comorbidities, functional status, trait anxiety, and social desirability). RESULTS: The posttreatment drop-out rate was 9.7% (intervention: 6.5%; control: 13%). The intention-to-treat analyses showed significant differences between the groups at posttreatment: the intervention group improved in physical impairment, days not feeling well, pain, general fatigue, morning fatigue, stiffness, anxiety, and depression (medium effect size in most cases). The patients who responded to the intervention reported less trait anxiety at baseline than nonresponders. The absolute risk reduction with the intervention was 36.1% (95% confidence interval: 23.3-48.8) and the number needed to treat was 3 (95% confidence interval: 2.0-4.3). DISCUSSION: A 2-month psychoeducational intervention improves the functional status of FM patients to a greater extent than usual care, at least in the short-term. The social desirability bias did not explain the reported outcomes. Trait anxiety was associated with response to treatment. PMID- 21317777 TI - Evaluation of the analgesic efficacy of local dexmedetomidine application. AB - OBJECTIVES: To determine the analgesic effects of locally applied dexmedetomidine in third molar surgery under general anesthesia. METHODS: Patients undergoing bilateral third molar surgery under general anesthesia were recruited into this double-blind, randomized, controlled study and were allocated to 3 study groups. Group D received preincision intravenous dexmedetomidine (1 mcg/kg) and direct infiltration of normal saline to the surgical wounds at the end of the surgery. Group P received preincision intravenous normal saline and direct infiltration of dexmedetomidine (1 MUg /kg) to the surgical wounds at the end of the surgery. A control group (group N) received normal saline at both time points. Postoperative analgesic effects, analgesic consumption, global pain satisfaction score, vital signs, adverse events, and postoperative recovery were assessed. RESULTS: Thirty three patients from each group were studied. Postoperative resting pain numerical rating scale scores were similar in all the groups. However, the areas under curves of numerical rating scale pain scores during mouth opening for 1 to 72 hours were significantly lower in group P than in group N (P=0.012). Both heart rate and systolic blood pressure in the immediate postoperative period were significantly lower in groups D and P than in group N (P<0.001). Patients from groups D and P were also more sedated than patients in group N (P=0.013 and P=0.007, respectively) but no difference in psychomotor recovery was observed. Respiratory rate, oxygen saturation, common side effects, wound infection rate, and global pain satisfaction scores were similar among the groups. CONCLUSIONS: Dexmedetomidine seems to have an antihyperalgesic effect when administered locally after bilateral third molar surgery. There is no delay in psychomotor recovery or increase in postoperative clinically significant adverse events. PMID- 21317778 TI - Measuring pain self-efficacy. AB - BACKGROUND: It is likely that people with chronic pain who have low self-efficacy have a worse prognosis. A standard, high-quality measure of self-efficacy in such populations would improve evidence, by allowing meaningful comparisons amongst subgroups and between treatments, and by facilitating pooling across studies in systematic reviews. OBJECTIVES: To identify self-administered pain-related self efficacy measures used in people with chronic pain and to evaluate the clinimetric evidence of the most commonly used scales systematically. METHODS: We searched 2 databases to identify self-efficacy questionnaires. We evaluated questionnaires identified against previously developed criteria for clinimetric assessment. RESULTS: We identified 13 relevant measurements assessing self efficacy, and clinimetrically assessed 5 of these. These questionnaires were the Arthritis Self-Efficacy Scale, the Chronic Disease Self-Efficacy Scale, the Pain Self-Efficacy Questionnaire, the Chronic Pain Self-Efficacy Scale, and the Self Efficacy Scale. None of the questionnaires showed satisfactory results for all properties. All scales were easily scored and dimensionality was assessed in 2 of 6 of the scales. Internal consistency was acceptable for all questionnaires. There was positive evidence for construct validity in 4 of 6 of the questionnaires. None of the studies used the most up-to-date method of test retest reliability or responsiveness. Information on interpretability of the scores was minimal in all questionnaires. DISCUSSION: Further research should focus on assessing responsiveness and interpretability of these questionnaires. Researchers should select questionnaires that are most appropriate for their study aims and population and contribute to further validation of these scales. Future research should measure outcome expectancy alongside self-efficacy to best predict future behavior. PMID- 21317779 TI - Bilateral cervicothoracic transforaminal blood patches for persistent headache from spontaneous intracranial hypotension: a case report and review. AB - OBJECTIVES: Spontaneous intracranial hypotension (SIH) is an uncommon cause of headache that can be challenging to treat and can have serious clinical consequences. When symptoms persist despite conservative treatment, an interlaminar epidural blood patch is often performed, but may not be effective. METHODS: Case report and review of the literature. RESULTS AND DISCUSSION: In this clinical report, we describe a case of spontaneous intracranial hypotension caused by a ventral dural tear at the cervicothoracic junction. Our patient suffered from recalcitrant postural headaches despite undergoing conventional interlaminar epidural blood patches. Bilateral transforaminal epidural blood patches were performed in order to deliver blood to the ventral epidural space at the site of the tear identified on magnetic resonance imaging. The transforaminal technique may be useful in patients who have failed conventional treatment, though a high degree of interventional experience and vigilance is required to safely perform this procedure. PMID- 21317780 TI - Is interfascial block with ultrasound-guided puncture useful in treatment of myofascial pain of the trapezius muscle? AB - OBJECTIVES: Ultrasound-guided puncture is indispensable for the injection of local anesthetic in the interfascial space, the space between 2 muscle fasciae. Interfascial infiltration or block may be useful in treating myofascial pain in the trapezius muscle. METHODS: (1) In 5 cadavers, we studied the diffusion of a physiological saline and latex solution in the interfascial space of the upper muscles of the back, and performed a histological study of the fasciae. (2) We performed an interfascial block in 25 patients with myofascial pain in the trapezius muscle. Depending on the trigger point location, the block was performed between the trapezius and the levator scapulae or between the trapezius and the rhomboideus major. RESULTS: In all cadavers, anatomical dissection showed the latex in the interfascial space. The histological study confirmed the presence of nerve structures in the fasciae and in the interfascial space itself. Pain was assessed in all patients on a visual analog scale (VAS) before and after the injection (at rest and in motion). Preinjection: mean VAS 6.4 (at rest) and 7.6 (in motion). Postinjection: mean VAS 1 (at rest) and 1.6 (in motion). DISCUSSION: The anatomical, histological, and ultrasound findings in the cadaver study confirmed the diffusion of the solution in the interfascial space. Study in patients confirms that the interfascial block in the back musculature can be as effective as in the abdominal musculature. The presence of nerve structures in this space, confirmed by the histological study, seems to explain the pain relief reported by the patients with this interfascial technique. PMID- 21317781 TI - Corneal endothelial cell changes associated with cataract surgery in patients with type 2 diabetes mellitus. AB - PURPOSE: To investigate the corneal endothelial cell density and morphology in patients with and without diabetes after phacoemulsification with intraocular lens implantation. METHODS: A clinical prospective study including 30 patients with type 2 diabetes and 30 control patients without diabetes scheduled to undergo cataract surgery. No difference in preoperative age was observed between the 2 groups (P = 0.90). Sample size was based on a power calculation (power 0.90; P = 0.05). The patients without diabetes had a casual blood glucose test performed to disclose undetected diabetes. The patients with diabetes had a serum glycosylated hemoglobin (HbA1c) test performed to reveal the glycemic control. The endothelial cell density, variation in endothelial cell size (CV), percentage of hexagonal cells, and central corneal thickness (CCT) were recorded at baseline and at 3 months postoperatively. RESULTS: The mean decrease in endothelial cell density at 3 months in the diabetic group was 154 cells per square millimeter (6.2%) and 42 cells per square millimeter (1.4%) in the control group. The difference in cell loss between the 2 groups was significant (P = 0.04). A significant decrease in the percentage of hexagonal cells was also seen in the diabetic group (P = 0.01). There was no statistically significant change in CV or CCT. Visual acuity increased significantly and equally in the 2 groups. CONCLUSIONS: The present study reveals a significantly greater loss of corneal endothelial cells in a diabetic group under good glycemic control, compared with nondiabetic group 3 months after phacoemulsification. The morphological changes in the endothelial cells in patients with well-controlled diabetes were not reflected in impaired function as judged by CCT. PMID- 21317782 TI - Morphological alterations of the cornea in the mouse model of niemann-pick disease type c1. AB - PURPOSE: Niemann-Pick disease type C1 (NPC1) is a genetic neurovisceral disorder characterized by abnormalities in intracellular sterol trafficking. A knockout mouse model (NPC1) is an important tool for the study of pathogenesis and treatment strategies. In the present study, NPC1 mice were examined for pathological changes in the cornea. METHODS: Fifteen inbred homozygous NPC1 knockout mice (NPC1, 5-10 weeks old), 5 age-matched heterozygous mice (NPC1), and 14 wild-type control mice (NPC1) were examined. In vivo confocal laser scanning microscopy (CLSM) was performed on both eyes of each animal; afterward, the eyes were processed for histology, electron microscopy, and lipid analysis. RESULTS: In vivo CLSM disclosed hyperreflective intracellular deposits in the intermediate and basal cell layers of corneal epithelium in all NPC1 mice. At the electron microscopy level, however, vacuolated cytoplasmic structures, 200-500 nm in diameter, with electron-dense material appeared in all structures investigated, including all epithelial layers and stromal keratocytes. These deposits were negative for filipin, a marker for unesterified cholesterol. Lipid analysis showed a marked increase in disialotetrahexosylganglioside 2 (GM2) level in NPC1 mice corneas, whereas no changes were detected in free cholesterol and disialotetrahexosylganglioside 3 (GM3) levels when compared with controls. CONCLUSIONS: Morphological changes characteristic for the NPC1 mouse cornea were visualized in all epithelial layers and keratocytes. In vivo CLSM findings were confirmed by other techniques. In vivo detection of ocular manifestations and analysis of ocular tissue have the potential to aid the diagnosis of NPC1 disease and to monitor the efficacy of treatment. PMID- 21317783 TI - Secondary "thin-DSEK" after long-term graft failure in DLEK: a double transplanted cornea. AB - PURPOSE: To describe a case of secondary "thin Descemet stripping endothelial keratoplasty" ("Thin-DSEK"), for borderline decompensation 6 years after an initial deep lamellar endothelial keratoplasty (DLEK). METHODS: In a 31-year-old man, who initially underwent a DLEK for bullous keratopathy in the presence of a phakic intraocular lens, a secondary Thin-DSEK was performed, while leaving the entire DLEK graft (including the donor Descemet membrane and the endothelium) in situ. RESULTS: After the initial DLEK, the best-corrected visual acuity (BCVA) improved from 20/200 (0.1) to 20/25 (0.8). Six years later, the transplanted cornea showed intermittent decompensation with a decrease in BCVA again to 20/200 (0.1). After the secondary Thin-DSEK, the BCVA improved again to 20/25 (0.8) at 1 month postoperatively and remained stable thereafter. CONCLUSIONS: Our case may show that a secondary DSEK may be a simple and effective treatment to manage secondary graft failure after DLEK. Despite the presence of a "double" stromal interface in the visual axis, secondary Thin-DSEK may provide visual rehabilitation similar to that after primary Thin-DSEK. PMID- 21317784 TI - Boiled coffee intake and subsequent risk for type 2 diabetes. AB - BACKGROUND: Many studies have found an inverse association between consumption of filtered coffee and incident type 2 diabetes. The effect of boiled coffee has been less studied. METHODS: Information on self-reported coffee consumption was available from health surveys conducted from 1985 to 1999. We estimated type 2 diabetes incidences from redeemed prescriptions of oral antidiabetic drugs in the period 1 January 2004 to 1 January 2008. RESULTS: With less than 1 cup/day as the reference, the relative risks associated with 1-4, 5-8, and 9 or more cups of boiled coffee per day were 0.87 (95% confidence interval = 0.80-0.95), 0.65 (0.59 0.72), and 0.65 (0.57-0.74), respectively, after adjusting for confounders. The corresponding relative risks associated with other types of coffee (mainly filtered) were 0.84 (0.79-0.90), 0.67 (0.62-0.71) and 0.62 (0.56-0.68). CONCLUSIONS: A moderate inverse association was found between consumption of both boiled and other types of coffee at the age of 40-45 years and the risk of being prescribed oral antidiabetic drugs 5-20 years later. PMID- 21317785 TI - Prehospital delay in patients presenting with acute ST-elevation myocardial infarction. AB - To characterize prehospital delays in patients presenting with acute ST-elevation myocardial infarction to the emergency department of a tertiary hospital in Asia. A retrospective review of 273 patients with diagnosis of ST-elevation myocardial infarction; symptom to door (S2D) time was described in two ways, time from first onset of symptoms; and time from the onset of the worst episode to presentation at emergency department. The median first onset S2D time was 173 min (interquartile range 80-350 min); and median worst episode S2D time was 131 min (interquartile range 70-261 min). Patients with prehospital delay tended to use their own transport compared with the no delay group (P=0.026, 95% confidence interval=0.02-0.24). There was no difference in S2D times for typical compared with atypical symptoms. A large proportion of patients experienced delay in seeking medical care after the onset of acute coronary symptoms. Self-transport was associated with delay. PMID- 21317786 TI - Increasing wait times predict increasing mortality for emergency medical admissions. AB - BACKGROUND: The actual impact of emergency department (ED) 'wait' time on hospital mortality in patients admitted as a medical emergency has often been debated. We have evaluated the impact of such waits on 30-day mortality, for all medical patients over a 7-year period. METHODS: All patients admitted as medical emergencies by the ED between 2002 and 2008 were studied; we looked at the impact of time to medical referral and subsequent time to a ward bed on any inhospital death within 30 days. Significant univariate predictors of outcome, including Charlson's comorbidity and acute illness severity score, were entered into a multivariate regression model, adjusting the univariate estimates of the readmission status on mortality. RESULTS: We studied 23 114 consecutive acute medical admissions between 2002 and 2008. The triage category in the ED was highly predictive of subsequent 30-day mortality ranging from 4.8 (category 5) to 46.1% (category 1). After adjustment for all outcome predictors, including comorbidity and illness severity, both door-to-team and team-to-ward times were independent predictors of death within 30 days with respective odds ratios of 1.13 (95% confidence interval 1.07-1.18), and 1.07 (95% confidence interval 1.02 1.13). CONCLUSION: Delay to admission have been shown to be independently adversely related to mortality outcome. We recommend maximal target limits of 4 and 6 h for referrals and admissions, respectively, based on these mortality observations. PMID- 21317787 TI - Risk for poor outcomes in older patients discharged from an emergency department: feasibility of four screening instruments. AB - OBJECTIVES: To compare the prognostic value of four screening instruments used to detect the risk for poor outcomes [in terms of likelihood of recurrent emergency department (ED) visits, hospitalizations, or mortality] for older patients discharged home from an ED in the Netherlands. METHODS: This is a prospective cohort study, which included all consecutive patients of at least 65 years discharged from the ED of a university teaching hospital in the Netherlands, between 1 December 2005, and 1 November 2006. Four screening instruments were tested: the identification of seniors at risk, the triage risk screening tool, and the Runciman and Rowland questionnaires. The cutoff of the Runciman questionnaire was adapted and the age cutoff was adapted for the other instruments. Recurrent ED visits, subsequent hospitalization, and mortality within 30 and 120 days after the index visit were collected from administrative data. RESULTS: In total, 381 patients were included, with a mean age of 79.1 years. Within 120 days, 14.7% of the patients returned to ED, 17.2% were hospitalized, and 2.9% died. The area under the curve was low for all instruments (between 0.43 and 0.60), indicating poor discriminatory power. CONCLUSION: Older ED patients discharged home are at higher risk of poor outcomes. None of the instruments were able to clearly discriminate between patients with and without poor outcomes. Differences in organization of the health care systems might influence the prognostic abilities of screening instruments. PMID- 21317788 TI - Surgical airway in emergency department intubation. AB - OBJECTIVES: To determine the frequency of and primary indication for surgical airway during emergency department intubation. METHODS: Prospectively collected data from all intubations performed in the emergency department from January 1999 to July 2007 were analysed to ascertain the frequency of surgical airway access. Original data were collected on a structured proforma, entered into a regional database and analysed. Patient records were then reviewed to determine the primary indication for a surgical airway. RESULTS: Emergency department intubation was undertaken in 2524 patients. Of these, only five patients (0.2%) required a surgical airway. The most common indication for a surgical airway was trauma in four of the five patients. Two patients had attempted rapid sequence induction before surgical airway. Two patients had gaseous inductions and one patient received no drugs. In all five patients, surgical airway was performed secondary to failed endotracheal intubation attempt(s) and was never the primary technique used. CONCLUSION: In our emergency department, surgical airway is an uncommon procedure. The rate of 0.2% is significantly lower than rates quoted in other studies. The most common indication for surgical airway was severe facial or neck trauma. Our emergency department has a joint protocol for emergency intubation agreed by the Departments of Emergency Medicine, Anaesthesia and Critical Care at the Edinburgh Royal Infirmary. We believe that the low surgical airway rate is secondary to this collaborative approach. The identified low rate of emergency department surgical airway has implications for training and maintenance of skills for emergency medicine trainees and physicians. PMID- 21317789 TI - Effects of a multidisciplinary rehabilitation program on pediatric obesity: the CEMHaVi program. AB - The objective of this study is to assess the effects of the unique 1-year health wellness program of exercise and health education for obese youth on body mass index (BMI) and blood pressure. The CEMHaVi program included 74 obese children. Participants, 19 girls and 18 boys, and controls, 17 girls and 20 boys, were assigned to treatment. The treatment participants were compared with a group who chose not to participate. Treatment consisted of a unique program of physical activity that emphasized playing games. Activity sessions were offered once per week, 2 h each session, for 12 months. Physical activity was complemented with health education. Controls received only the normal care of a physician in pediatrics. Physical and physiological measures were assessed before and after intervention. Findings of the study showed a significant difference in BMI between treatment and control participants (P<0.05). BMI decreased in the treatment group and increased in controls. There were no significant differences in blood pressure. In conclusion, results of the study suggest that a unique program of exercise and health education had beneficial effects on BMI in obese youth after 1 year. The feasibility of a beneficial lifestyle intervention program is encouraging. PMID- 21317790 TI - Altered cerebrovenous drainage in patients with migraine as assessed by phase contrast magnetic resonance imaging. AB - OBJECTIVE: We aimed to assess whether migraine is associated with changes in the distribution of the venous drainage through primary and secondary pathways by using phase-contrast magnetic resonance imaging (MRI). METHODS: We examined 26 patients (37.3 +/- 13.9 years) with recurring migraine headaches and 26 age- and gender-matched controls with no neurologic disease (37.3 +/- 13.7 years) on a 3 Tesla MR scanner. A 2D time-of-flight MR-venography of the upper neck region was performed to visualize the venous vasculature. Cine-phase contrast scans with high-velocity encoding were employed to quantify arterial inflow and flow in the primary venous channels (right and left jugular veins), whereas scans with low velocity encoding were employed to quantify flow in the secondary venous channels (epidural, vertebral, and deep cervical veins). RESULTS: Patients with migraine showed (i) a higher prevalence of dense secondary extracranial venous networks (15 vs. 2, P = 0.00002) and (ii) a significantly larger percentage of venous outflow through secondary channels (10.5% vs. 5.5%; of total cerebral blood flow, P = 0.02). This mainly included drainage through epidural, vertebral, and deep cervical veins. CONCLUSION: Migraine patients showed a significantly larger percentage of venous outflow through secondary channels. The mechanism of this alteration remains to be elucidated. Potential mechanisms include repeated release of vasoactive substances or growth factors. PMID- 21317791 TI - Dynamic contrast-enhanced renal MRI at 7 Tesla: preliminary results. AB - OBJECTIVE: With the successful implementation of ultra-high-field imaging in neuro- and musculoskeletal imaging, the interest of scientific research expanded toward whole-body applications. The aim of this study was to assess the feasibility of dynamic contrast-enhanced renal magnetic resonance imaging (MRI) at 7 Tesla (T), with optimization and implementation of a dedicated examination protocol. MATERIAL AND METHODS: In vivo dynamic contrast-enhanced high-field examinations were obtained in 10 healthy subjects on a 7 T whole-body MR scanner. A custom-built body transmit/receive reduced radiofrequency (RF) coil suitable for RF shimming was used for image acquisition. The examination protocol included (1) true fast imaging with steady-state precession imaging, (2) T2-weighted turbo spine echo imaging, (3) T1-weighted (T1w) in- and opposed-phase imaging, and (4) a fat-saturated 2D FLASH sequence. For dynamic imaging, gadobutrol was injected intravenously and T1w 3D FLASH images were obtained precontrast and at 20, 70, and 120 seconds delay. Qualitative image analysis was performed by 2 senior radiologists using a 3-point scale (1 = poor, 2 = moderate, 3 = good quality). Signal-to-noise ratio and contrast-to-noise ratio (CNR) of the renal cortex/medulla were measured for all sequences. For statistical analysis, a Wilcoxon Rank Test was used. RESULTS: All examinations were performed successfully and were well tolerated by all subjects without any side effects. Best overall image quality was rated for the T1w 2D FLASH sequence with an average score of 2.57, followed by the contrast-enhanced 3D FLASH sequence in the equilibrium phase (mean, 2.22). T2-weighted turbo spine echo imaging provided the weakest overall image quality score (1.30) and was most impaired by artifacts. Quantitative analysis showed highest CNR between cortex and medulla for arterial phase 3D FLASH imaging (CNR = 12.2), providing a statistically significant difference to all other sequences, except for the in- and opposed-phase and the fat-saturated 2D FLASH sequence. Conversely, equilibrium phase FLASH imaging yielded the weakest CNR score of 3.6. CONCLUSION: This feasibility study reveals the diagnostic potential and current constraints of ultra-high-field abdominal MRI. Our initial results demonstrate the potential of dedicated dynamic-contrast 7 T renal MRI and the need for further optimization of imaging sequences and RF coil concepts. PMID- 21317792 TI - Feasibility of 7 Tesla breast magnetic resonance imaging determination of intrinsic sensitivity and high-resolution magnetic resonance imaging, diffusion weighted imaging, and (1)H-magnetic resonance spectroscopy of breast cancer patients receiving neoadjuvant therapy. AB - OBJECTIVES: To evaluate the feasibility of 7T breast magnetic resonance imaging (MRI) by determining the intrinsic sensitivity gain compared with 3T in healthy volunteers and to explore clinical application of 7T MRI in breast cancer patients receiving neoadjuvant chemotherapy (NAC). MATERIALS AND METHODS: In 5 volunteers, the signal-to-noise ratio (SNR) was determined on proton density MRI at 3T using a conventional 4-channel bilateral breast coil and at 7T using a dedicated 2-channel unilateral breast coil, both obtained at identical scan parameters. Subsequently, consecutive breast cancer patients on NAC were included. The 7T breast MRI protocol consisted of diffusion-weighted imaging, 3D high-resolution (450 MUm isotropic) T1-weighted fat-suppressed gradient-echo sequences and quantified single voxel (1)H-magnetic resonance spectroscopy. Morphology was scored according to the MRI Breast Imaging-Reporting and Data System (BI-RADS)-lexicon, and the images were compared with 3T and histopathologic findings. Image quality was evaluated using a 5-point scale. RESULTS: A 5.7-fold higher SNR was measured at 7T than at 3T, which reflects the advantages of a higher field strength and the use of optimized radiofrequency coils. Three breast cancer patients were included and received a total of 13 7T MRI examinations. The image quality of the high-resolution examinations was at least satisfactory, and good to excellent in 9 of the 13 examinations performed. More anatomic detail was depicted at 7T than at 3T. In 1 case, a fat plane between the muscle and tumor was visible at 7T, but not at the clinically performed 3T examination, suggesting that there was no muscle invasion, which was confirmed by pathology. Changes in tumor apparent diffusion coefficient values could be monitored in 2 patients and were found to increase during NAC, consistent with published results from studies at lower field strengths. Apparent diffusion coefficient values increased respectively from 0.33 * 10(-3) mm(2)/s to 1.78 * 10(-3) mm(2)/s after NAC and from 1.20 * 10(-3) mm(2)/s to 1.44 * 10(-3) mm(2)/s during NAC. Choline concentrations as low as 0.77 mMol/kg(water) could be detected. In 1 patient, choline levels showed an overall decrease from 4.2 mMol/kw(water) to 2.6 mMol/kg(water) after NAC and the tumor size decreased correspondingly from 3.9 * 4.1 * 5.6 cm(3) to 2.0 * 2.7 * 2.4 cm(3). All 7T MRI findings were consistent with pathology analysis. CONCLUSION: Dedicated 7T breast MRI is technically feasible, can provide more SNR than at 3T, and has diagnostic potential. PMID- 21317793 TI - First-pass and high-resolution steady-state magnetic resonance angiography of the peripheral arteries with gadobenate dimeglumine: an assessment of feasibility and diagnostic performance. AB - PURPOSE: To assess the feasibility of combined first-pass (FP) and steady-state (SS) contrast-enhanced magnetic resonance angiography (MRA) of the peripheral arteries with gadobenate dimeglumine (MultiHance) and to evaluate diagnostic performance relative to digital subtraction angiography (DSA). MATERIALS AND METHODS: A total of 35 patients with symptomatic peripheral arterial occlusive disease (PAOD) underwent FP MRA (repetition time [TR]/echo time [TE]/flip angle [FA]/acquisition time [TA] = 3.5/1.2/30 degrees /14s) at 1.5T after intravenous injection of 10 mL of gadobenate dimeglumine. Thereafter, SS imaging of the calf (TR/TE/FA/TA = 7.5/2.3/20 degrees /40-130s) and femoropopliteal (TR/TE/FA/TA = 7.5/2.3/18 degrees /130-240s) regions was performed after a second injection of 5 mL of gadobenate dimeglumine. All patients underwent conventional DSA. Three readers reviewed separate FP and FP+SS MRA datasets for image quality and presence/absence of clinically relevant PAOD. A fourth independent observer evaluated DSA images. The diagnostic performance (sensitivity, specificity, positive and negative predictive values) achieved with each dataset was determined and compared. Inter-reader agreement was assessed using kappa statistics. RESULTS: The image quality of 134 of 140 vascular regions was optimal or adequate on SS MRA. Inter-reader agreement was good to very good for assessments of FP (kappa = 0.725) and combined FP+SS images (kappa = 0.866). SS images improved diagnostic confidence in 34 (48.6%) femoropoliteal and 46 (65.7%) crural regions and altered final diagnosis in 8 (11.4%) and 10 (14.3%) regions, respectively. Global diagnostic accuracy increased from 92.9% on FP images to 95.9% on FP+SS images, with significant (P = 0.0384) improvement in the crural region. CONCLUSION: SS MRA of the peripheral arteries is feasible with gadobenate dimeglumine and potentially improves diagnostic performance in patients with symptomatic PAOD. PMID- 21317794 TI - Safety, efficacy, and pharmacokinetics of TBR-652, a CCR5/CCR2 antagonist, in HIV 1-infected, treatment-experienced, CCR5 antagonist-naive subjects. AB - OBJECTIVES: To determine the antiviral activity, pharmacokinetics, pharmacodynamics, safety, and tolerability of several dose levels of oral TBR-652 monotherapy in HIV-1-infected, antiretroviral experienced, CCR5 antagonist-naive subjects. DESIGN: Double-blind placebo-controlled study in the United States and Argentina. METHODS: Subjects were randomized in a ratio of 4:1 per dose level to TBR-652 (25, 50, 75, 100, or 150 mg) or placebo, taken once daily for 10 days. Changes from baseline in HIV-1 RNA and CD4 cell counts were measured through day 40 and for monocyte chemotactic protein-1 (MCP-1), high-sensitivity C-reactive protein (hs-CRP), and IL-6 at day 10. Pharmacokinetic data were analyzed using noncompartmental statistics. Laboratory and clinical adverse events (AEs) and electrocardiogram changes were recorded. RESULTS: Maximum median reductions in HIV-1 RNA values for the 25, 50, 75, and 150 mg doses were -0.7, -1.6, -1.8, and 1.7 log10 copies per milliliter, respectively. All changes were significant. Median time to nadir was 10-11 days. Suppression persisted well into the posttreatment period. Mean MCP-1 increased significantly by day 10 in the 50-mg and 150-mg dose groups. Effects on CD4 cell counts, hs-CRP, and IL-6 levels were negligible. TBR-652 was generally safe and well tolerated, with no withdrawals due to AEs. CONCLUSIONS: TBR-652 caused significant reductions in HIV-1 RNA at all doses. Significant increases in MCP-1 levels suggested a strong CCR2 blockade. TBR-652 was generally well tolerated with no dose-limiting AEs. Pharmacodynamics indicate that TBR-652 warrants further investigation as an unboosted once-daily oral CCR5 antagonist with potentially important CCR2 mediated anti-inflammatory effects. PMID- 21317796 TI - Multiple sexual partnerships among poor urban dwellers in Kampala, Uganda. AB - BACKGROUND: This study examined 2 issues of current importance for AIDS prevention in Uganda: the frequency of multiple sexual partnerships and whether optimistic perceptions about the severity of AIDS are associated with riskier sexual behavior. METHODS: Four hundred five men and women aged 20-39 from 2 poor neighborhoods of Kampala were interviewed about their sexual behavior over the prior 6 months and about other partners during current relationships. They also completed a 7-item scale measuring perception of the severity of HIV/AIDS. RESULTS: About 21.2% of men and 2.9% of women reported ongoing concurrent partnerships; 28.8% and 6.8% reported more than 1 partner in the past 6 months. About 22.2% of men and 32.4% of women believed their partner had had other partners during the relationship. Overall, 56.1% of men and 57.0% of women reported potentially being involved in a multiple or concurrent partnership. Respondents rating AIDS as more severe were more likely to be monogamous. CONCLUSIONS: Multiple sexual partnerships may be more common in Uganda than generally supposed, and optimism about the severity of AIDS is associated with having multiple partners. These findings have important implications for HIV/AIDS epidemiology and prevention. PMID- 21317795 TI - Lipodystrophy and insulin resistance in combination antiretroviral treated HIV-1 infected patients: implication of resistin. AB - BACKGROUND: Little information is available with respect to the involvement of resistin in lipodystrophy and metabolic disturbances in HIV-1-infected patients treated with combination antiretroviral therapy (cART). We determined whether the resistin (rest) -420C>G single-nucleotide polymorphism and plasma resistin are associated with the development of lipodystrophy and metabolic disturbances in HIV-1-infected patients treated with cART. METHODS: The study group comprised 299 HIV-1-infected patients treated with a stable cART for at least 1 year (143 with lipodystrophy and 156 without) and 175 uninfected controls. Anthropometric, clinical, and metabolic variables were determined. Homeostasis model assessment for insulin resistance was used to evaluate insulin resistance. Plasma resistin levels were determined by enzyme-linked immunosorbent assay. The rest -420C>G was assessed using restriction fragment length polymorphism. Student t test, 1-way and 2-way analysis of variance, chi2 test, and Pearson and Spearman correlations were performed for statistical analysis. RESULTS: Genotypes containing the rest 420G variant allele were significantly more common in HIV-1-infected patients without lipodystrophy compared with those with lipodystrophy (P = 0.037). Infected patients had significantly greater plasma resistin levels than uninfected controls (P < 0.001). Among infected patients, plasma resistin levels were significantly lower in patients with lipodystrophy with respect to those without (P = 0.034). In infected patients, plasma resistin levels had a significant positive correlation with insulin and homeostasis model assessment for insulin resistance: P < 0.001 and P = 0.002 in the lipodystrophy subset and P = 0.002 and P = 0.03 in the nonlipodystrophy subset, respectively. CONCLUSIONS: In our cohort of white Spaniards, the rest -420C>G single-nucleotide polymorphism may be associated with cART-related lipodystrophy. Plasma resistin correlates with insulin resistance in infected patients with and without lipodystrophy. PMID- 21317797 TI - Puzzling observations in a trial of HIV partner notification in sub-Saharan Africa. PMID- 21317798 TI - Do cognitive and behavioral factors mediate the impact of depression on medical outcomes in people with coronary heart disease? AB - PURPOSE: Depression is common in people with coronary heart disease (CHD) and predicts worse cardiac outcomes. Cognitive and behavioral mechanisms have been proposed to explain this association, although the mediating role of these mechanisms remains unclear. We conducted a prospective cohort study to investigate whether the impact of depression on subsequent impaired health related quality of life (HRQoL) was mediated by cognitive and behavioral pathways. METHODS: Demographic and medical characteristics, depression (Hospital Anxiety and Depression Scale), illness cognitions (Brief Illness Perceptions Questionnaire and Cardiac Anxiety Questionnaire), awareness of somatic symptoms (Symptom Checklist-90, revised version), and health behaviors were recorded from 255 primary care patients with CHD. The Short Form-36 was completed by 201 participants 6 months later. RESULTS: Twenty-five participants (9.8%) were depressed at baseline. Short Form-36 Physical Component Score (PCS) was significantly lower in participants who were depressed (mean PCS score = 29.8 versus 38.0, P = .001). After controlling for demographic and medical variables, depression continued to be associated with subsequent PCS [B = -0.84 (0.20), P < .0005]. When cardiac anxiety, awareness of somatic symptoms, and negative illness perceptions were added to the regression model, depression no longer continued to make a significant independent contribution to the model [B = -0.3 (0.2), P = .16]. Maladaptive health behaviors did not fulfill criteria to mediate the relationship between depression and impaired health-related quality of life. CONCLUSIONS: Findings indicate that the impact of depression on HRQoL could be mediated by cardiac anxiety, awareness of somatic symptoms, and negative illness perceptions, but not maladaptive health behaviors. Psychological interventions targeting these mediators have potential to improve HRQoL in people with CHD. PMID- 21317799 TI - Influence of age on rehabilitation outcomes and survival in post-acute inpatient cardiac rehabilitation. AB - PURPOSE: To investigate the relationship of increasing age to clinical characteristics, rehabilitation outcomes, and long-term survival in a post-acute inpatient cardiac rehabilitation program. METHODS: The study population consisted of all 364 consecutive cardiac rehabilitation patients admitted over a 4-year period to an inpatient cardiac rehabilitation program in a long-term acute care hospital.Admission and discharge comparisons were made between 3 age cohorts: 65 years (n = 117), 65 to 74 years (n = 127), and >= 75 years (n = 120). Patients were followed through January, 2010 for survival. RESULTS: The 3 cohorts on admission differed significantly in Functional Independence Measure, estimated Glomerular Filtration Rate, smoking and hypertension histories, body mass index, and cardiac diagnoses (all P < .05) but not in Simplified Acute Physiology Score II, Cumulative Illness Rating Scale for Geriatrics, or left ventricular ejection fraction. There were no cohort differences in rehabilitation outcomes of physical function, inpatient days, and discharge disposition. Survival was longest in the youngest cohort whereas the 2 older cohorts had similar survivals (P < .01; log rank test). All 3 cohorts had at least 40% survival at 8 years. Cox regression analyses showed that the comorbidity burden as quantified by the Cumulative Illness Rating Scale for Geriatrics was the only predictor of death in all cohorts (all P <= .002). CONCLUSIONS: This study provided evidence that post acute inpatient cardiac rehabilitation programs equally benefited both elderly patients and younger patients. These programs are valuable in the continuum of care for elderly patients who are not yet ready for discharge to home following a serious cardiac event. PMID- 21317800 TI - Rates of enrollment for men and women referred to outpatient cardiac rehabilitation. AB - OBJECTIVE: Outpatient cardiac rehabilitation (CR) services are underutilized. Fewer women participate in CR than men. It is unclear whether women referred to CR enroll at the same rate as men. The purpose of this study was to compare enrollment rates of men and women who were referred to CR. METHODS: A retrospective medical record review was performed for selected variables for all adult patients who resided in Olmsted County, Minnesota, were hospitalized from January 2005 through July 2007 and were referred to a CR program. Enrollment in CR was defined as attendance at 1 or more CR sessions. RESULTS: A total of 450 patients referred to CR were identified. Of them, 286 patients (64%) enrolled in CR. Rates of enrollment for men and women were similar (65% vs 62%, P = .54). Patients of either gender who did not enroll were older, less educated, less often married, more likely to smoke, more likely to be diabetic, and less likely to have had cardiac surgery. Enrollment rates of women with or without comorbidities were similar (62% vs 61%, P = .87), while enrollment rate of men with comorbidities was lower than for men without comorbidities (52% vs 75%, P < .01). CONCLUSION: In our CR program, enrollment rates for men and women, once referred, are similar. Enrollment rates are lower for older patients of both genders and for men with comorbidities. Lower utilization of CR by women than by men does not appear to be because of a gender difference in enrollment rates after a referral is made. PMID- 21317801 TI - The association of illness uncertainty to parent and youth adjustment in juvenile rheumatic diseases: effect of youth age. AB - OBJECTIVE: : This study sought to examine the differential effect of youth age on the association between parental uncertainty and both parent distress and youth depressive symptoms within the context of juvenile rheumatic disease. METHOD: : The sample comprised 51 youth aged 9 to 17 years diagnosed with a juvenile rheumatic disease and their parents. Youth completed a measure of depressive symptoms (i.e., Children's Depression Inventory); parents completed measures of illness uncertainty (i.e., Parental Perceptions of Uncertainty Scale) and parental distress (i.e., Brief Symptom Inventory). RESULTS: : Parental uncertainty demonstrated a significant main effect on both parent distress and youth depressive symptoms. However, these main effects were qualified by significant parental uncertainty * youth age interactions. Parental uncertainty was significantly related to parent distress for both younger and older youth but was only significantly related to youth depressive symptoms in the sample of older youth. CONCLUSION: : Parental uncertainty due to illness seems to be more predictive of both parent and youth distress with increasing youth age. These findings indicate that the impact of parental illness uncertainty on adjustment outcomes is pronounced as children transition into developmental periods of increasing autonomy and independence. PMID- 21317802 TI - Relevance of the quality of partner relationships and maternal health to early child wellness. AB - OBJECTIVE: To examine the relationship between child health and maternal relationship quality with a spouse/partner, self-rated health, depressive symptoms, and social support. METHODS: In a cross-sectional study, structured interviews were completed with 595 mothers in 2002. Women were recruited from a random sample of households in low-income communities of Teresina, Piaui. Child health status was assessed with the Eisen Infant Health Rating Scale and a composite index of child fever, worms, or diarrhea in the past 2 weeks. Exposure variables included maternal relationship quality, self-rated health, depressive symptoms, and social support. Analyses included multivariable linear and logistic regression modeling, controlling for sociodemographics. RESULTS: Both a high quality partner relationship and good/excellent maternal self-rated health were significantly associated with higher scores on the Eisen Infant Health Rating Scale (a = 0.9; 95% confidence interval [CI]: 0.3-1.4 and beta = 1.1; 95% CI: 0.7 1.6, respectively). Every 5-point increase in depressive symptoms was negatively associated with infant health scores (beta = -0.3; 95% CI: -0.4 to -0.1) and with recent child wellness (lack of fever, diarrhea, or worms) (odds ratio = 0.9 95%; CI: 0.8-1.0). CONCLUSION: Maternal factors, such as partner relationship quality and health status, may be important to child health and should be considered for inclusion in confirmatory longitudinal studies. PMID- 21317804 TI - Biological and environmental factors as predictors of language skills in very preterm children at 5 years of age. AB - OBJECTIVE: Language problems are thought to occur more frequently in very preterm children compared with healthy term born children. The primary aim of this study was to examine the contributions of biological and environmental risk factors to language outcomes in very preterm children at 5 years of age. METHODS: A cohort of 227 very preterm infants (birth weight <1250 g or gestational age <30 weeks) were recruited at birth and followed up at 2 and 5 years of age (corrected for prematurity) in a prospective, longitudinal study in Melbourne, Australia. Outcomes at 5 years of age were the Expressive and Receptive Language Scales from the Kaufman Survey of Early Academic and Language Skills. A range of hypothesized biological and environmental factors identified from past research were examined as predictors of language outcomes at 5 years of age using linear regression models. RESULTS: Lower maternal education and poorer communication skills in the child at 2 years of age were predictive of poorer expressive and poorer receptive language outcomes at 5 years of age. Lower expressive language scores were also associated with the presence of moderate-severe white matter abnormalities on neonatal magnetic resonance imaging. CONCLUSIONS: Results support the role of both biological and environmental factors in the evolution of language difficulties and highlight the need to consider these factors in the follow-up of preterm infants. PMID- 21317803 TI - Patterns of disclosure of HIV status to infected children in a Sub-Saharan African setting. AB - OBJECTIVE: Adult caregivers provide children living with HIV with varying amounts and types of information about their health status that may affect their coping and health care behaviors. We aimed to describe patterns of information sharing with children and thoughts around disclosure among caregivers in the Democratic Republic of the Congo. METHODS: A total of 259 primary caregivers of children aged 5 to 17 years in an HIV pediatric care and treatment program were screened; 8 adult caregivers (3%) had informed their child of the child's HIV status. We conducted structured interviews with 201 caregivers whose children had not yet been told their HIV status. RESULTS: Nearly 50% of caregivers had provided no information to their child about their health; 15% had given partial information without mentioning HIV, and 33% provided information that deflected attention from HIV, whether deliberately so or otherwise. Almost all caregivers said that the child should be told their status some day, and three-fourths reported having ever thought about what might lead them to tell. However, nearly one-third of caregivers saw no benefits to informing the child of her/his HIV status. A majority of caregivers felt that they themselves were the best to eventually disclose to the child but some wanted support from health care providers. CONCLUSIONS: HIV-infected children are given limited information about their health. Health care providers may serve as important sources of support to caregivers as they decide when and how to talk candidly with their children about their health. PMID- 21317805 TI - Recent developments in defining microinvasive and early invasive carcinoma of the uterine cervix. AB - Although only a small proportion of invasive squamous carcinoma of the cervix present with microinvasive disease, consistent recognition of this entity is important because it carries important management implications. The objective of this review was to reassess the methods and criteria for a histopathologic diagnosis of both early invasive squamous and adenocarcinomas in light of recent pathologic and clinicopathologic studies. The diagnosis of microinvasion is primarily histopathologic. Although the concept of microinvasion initially seems obvious, there are problems in diagnostic precision. A clear understanding of both the Society of Gynaecologic Oncologists' and the International Federation of Obstetricians and Gynecologists' classifications of early invasive disease is required. Subsequently, key parameters must be assessed-measurement of depth and lateral spread, assessment of margins, and identification of lymphovascular invasion-using accepted reference points and definitions. This assessment requires properly oriented and stained histologic sections of a loop electrosurgical excision procedure or cone specimen. Immunohistochemical staining of vascular endothelium or epithelial basement membrane has only a limited/adjunctive role. Controversy continues regarding the need to appraise the extent of any lymphovascular invasion and measurement in cases with multifocal invasion. Application of criteria to invasive adenocarcinomas seems warranted but is particularly challenging because of its special morphology and different biology. PMID- 21317806 TI - Prevalence of high-risk human papillomavirus in women with abnormal and normal vaginal ThinPrep Papanicolaou cytology. AB - OBJECTIVE: The significance of high-risk HPV (hrHPV) testing in the management of women with abnormal cervical Pap tests is well known. However, the data about the hrHPV detection and its significance in abnormal vaginal specimens are very limited. The purpose of this study was to assess the prevalence of hrHPV in women with abnormal vaginal smears. METHODS: Our Copath database system was searched to retrieve all the vaginal Pap tests with adjunctive HC2 hrHPV DNA test performed between July 1, 2005, and July 30, 2009. The results of hrHPV were reviewed in different TBS 2001 categories, in different age groups, and in white and African American women. RESULTS: During the study period, there were 1,320 vaginal ThinPrep Pap tests with adjunctive HC2 hrHPV, reported as atypical squamous cells of undetermined significance (n = 1,125), atypical squamous cells cannot rule out high grade (n = 36), low-grade squamous intraepithelial lesion (n = 148), and high-grade squamous intraepithelial lesion (n = 11). A positive hrHPV DNA result was obtained in a total of 387 cases (29.3%), which included 244 atypical squamous cells of undetermined significance (21.7%), 21 atypical squamous cells cannot rule out high-grade (58.3%), 113 low-grade squamous intraepithelial lesion (76.4%), and 9 high-grade squamous intraepithelial lesions (81.8%). Mean age was 56.5 years (range = 17-93 y). High-risk HPV-positive rate was 34.5% versus 24.9% in women aged 54 years or younger compared with those aged >= 55 years or older (p < .001) and 45.1% versus 27.3% in African American women compared with white women (p < .001). High-risk HPV DNA-positive rate was 2.6% among the 1,572 women with negative vaginal Pap tests. CONCLUSIONS: Our results show that prevalence of hrHPV in abnormal vaginal smears parallels that of cervical smears with equivalent degree of abnormality. The suggestion of reflex hrHPV testing as a tool in formulating the management plan for women with abnormal vaginal smears needs further attention. PMID- 21317807 TI - Epidermoid cyst of the clitoris: a case report. AB - We report a rare case of spontaneous clitoral epidermal cyst without any declared previous female genital mutilation. This patient was successfully and surgically resected with good local and cosmetic results. PMID- 21317808 TI - Histology of loop electrosurgical excision procedures performed on women younger than 21 years and 65 years or older. AB - OBJECTIVE: To examine the prevalence and histology of loop electrosurgical excision procedures (LEEPs) done on women who are outside the age limits of the updated guidelines for cervical cytologic screening. MATERIALS AND METHODS: A database of all LEEPs performed between October 2004 and November 2009 was created. All data on age, human immunodeficiency virus status, cytology and histology before the procedure, and histology of the LEEP specimen were collected. RESULTS: There were 939 LEEPs performed during the study period, and data on 64 cases were excluded because of inadequate information. Fifty-four LEEPs were performed on women who were either younger than 21 years and those 65 years or older. All LEEPs were performed under traditionally accepted indications, except for 1 LEEP, which was excluded. None of the women gave a history of human immunodeficiency virus infection, and none of the older women had a history of abnormal cervical cytologic result before the index case. Of the procedures performed on the adolescents, 24 demonstrated high-grade lesions on LEEP (51.1%). Of the 6 procedures performed on older women, 4 LEEP specimens demonstrated high-grade lesions (66.7%). There were no cancers. CONCLUSIONS: We treated many women with LEEP excision who would not have been screened using current 2009 guidelines. Most of these women had high-grade lesions. The new guidelines may not be applicable to all population groups. PMID- 21317809 TI - Safety and utility of liver biopsy after pediatric hematopoietic stem cell transplantation. AB - Liver dysfunction is common after pediatric hematopoietic stem cell transplantation (HSCT) and liver biopsy may be necessary to diagnosis the cause of liver dysfunction and institute therapy. We report our liver biopsy experience in 356 consecutive patients. During the study period, 16 (4.5%) patients underwent 18 biopsies, all after allogeneic HSCT. The median time from HSCT to biopsy was 205.5 days. All patients had transaminase elevation and 67% had hyperbilirubinemia. The most commonly used method of biopsy was the imaging guided percutaneous approach, performed in 12 of 18 cases. Five biopsies were done transjugularly and 1 was performed during laparotomy. In all the cases a histopathologic diagnosis was made. The most common diagnosis was graft-versus host disease (GVHD) followed by iron overload. In 12 cases, management was modified based on biopsy results. Complications occurred after 5 biopsies, 4 of which were performed transjugularly. The most common complication was hemorrhage. Two patients required transfer to the intensive care unit for related complications. No complications were observed after percutaneous biopsies. In 2 cases a second procedure was required to manage the complication. We conclude that while liver biopsy yields a high-rate of diagnoses, it is accompanied by high rates of complications, particularly when the transjugular approach is used. PMID- 21317810 TI - Primary diaphragmatic yolk sac tumor and review of the literature. AB - Primary yolk sac tumor of the diaphragm in children is very rare, and diagnosis of a diaphragmatic tumor poses challenges to clinical physicians. Here, we report a primary diaphragmatic yolk sac tumor in a 9-month-old girl, together with a review of 4 earlier reported cases in the English literature. Carboplatin containing regimen successfully decreased the tumor size and a total resection of the tumor was made subsequently. The patient was disease-free 8 months after the completion of treatment. PMID- 21317811 TI - Alveolar soft part sarcoma occurring on the abdominal wall of a 2-year-old child. AB - Alveolar soft part sarcoma (ASPS) is a rare soft tissue malignant neoplasm that affects young people. It can occur in any region of the body and at any stage of development. But ASPS on the abdominal wall is rarely reported. However, a few cases were reported in children under the age of 10 years. In this study we report a case of ASPS that occurred on the abdominal wall of a 2-year-old patient. PMID- 21317812 TI - Reactive tonsillar enlargement with strong 18F-FDG uptake after chemotherapy for tonsillar diffuse large B-cell lymphoma. AB - We describe a 14-year-old boy who exhibited left palatine tonsillar enlargement after 6 cycles of aggressive chemotherapy for diffuse large B-cell lymphoma of the right palatine tonsil. The cervical computed tomography scan at 4 months after completion of chemotherapy revealed enlargement of the left palatine tonsil in addition to the thymus without any clinical symptoms. The F-fluorodeoxyglucose positron emission tomography indicated focal areas of strong F-fluorodeoxyglucose uptake in the left palatine tonsil. Histologic examination confirmed tonsillar hyperplasia with no evidence of recurrence. Reactive tonsillar hyperplasia after chemotherapy is rarely reported. PMID- 21317813 TI - Intraabdominal mass as presentation of colonic mucormycosis in a child with acute lymphoblastic leukemia. AB - Gastrointestinal mucormycosis with clinical presentation as an abdominal mass has been rarely reported in the current literature. In this observation, We report an unusual case of a child with acute lymphoblastic leukemia and neutropenic fever. During hospitalization, increasing abdominal pain and distension occurred, and initially treatments with broad-spectrum antibiotics were administered. However, the symptoms/signs progressed with the development of peritonitis and a palpated mass over the right lower quarter of the abdomen. Imaging studies showed ascending colon perforation with abscess formation. Right hemicolectomy was performed and colonic mucormycosis was confirmed on histologic examination and ascitic fluid culture. Immediately, intravenous liposomal amphotericin B was administered but the clinical condition rapidly deteriorated and the patient expired despite treatment. PMID- 21317814 TI - Can parents rate their children's quality of life? Perspectives on pediatric orthopedic outcomes. AB - The ultimate goal of treatment for children with orthopedic problems is to improve their health-related quality of life. Because children may lack the abilities to effectively interpret and answer the questions used to assess a patient's health-related quality of life, parent proxies have been used in such pediatric cases. Unfortunately, previous studies exploring the efficacy of these parent proxies have been inconsistent. It is therefore important to determine the level of agreement between child-parent dyads and whether agreement is mediated by variables such as disease type, demographics, instrument, and the domain being assessed. The purpose of this study was to examine the degree of agreement between children and their parents' ratings in the Child Health Questionnaire (CHQ) and the Pediatric Orthopaedic Data Collection Instrument (PODCI), two instruments commonly used to assess health-related quality of life in children. The CHQ, PODCI, and standard demographic and clinical data were collected from parents and children between the ages of 5 and 18 years with a wide range of musculoskeletal problems. There was a strong level of agreement between child and parent responses for most of the domains in both instruments. Exceptions included Physical Functioning (PF), General Health (GH), and Mental Health (MH) in the CHQ, and Expectations in the PODCI. All four of these domains exhibited significant differences between the two respondent groups and had medium effect sizes. Children reported a higher level of PF and lower levels of both GH and MH than their parents. Additionally, parents reported significantly higher expectations for treatment than children did. None of the regressions yielded significant beta values for child age, parent sex, match/no match between parent child sex, and scoliosis/nonscoliosis diagnosis. These significant discrepancies were not driven by specific subsamples; therefore, we concluded that these discrepancies can be generalized to the pediatric orthopedic population. Our results also indicate that the CHQ is more sensitive than the PODCI to the rating differences between children and parents. The results of this study can serve clinicians in pediatric orthopedic surgery as a guide for not only selecting the most appropriate instruments for assessment but also for interpreting treatment outcomes most meaningfully. Level of Evidence is the Level II Prognostic Study. PMID- 21317815 TI - Potential direct communication of the lung to the mediastinum: computed tomographic evaluation of pulmonary venous connections. AB - PURPOSE: We hypothesized that the remnant of the primitive pulmonary venous plexus in the embryo provides a pathway for direct communication from each lobe of the lung to the mediastinum. We assessed the presence and location of these connections by using 64-row multidetector computed tomography (CT). MATERIALS AND METHODS: This study was approved by the institutional ethics committee. First, we analyzed the multidetector row CT images of 120 normal lungs for the presence of septal structures between the pulmonary veins and the mediastinum and the extension of mediastinal fat into these septal structures. Second, we analyzed 62 patients with pneumothorax for the presence of cross-bridging structures in the pleural cavities. RESULTS: We frequently observed septal structures (36% to 77%) and the extension of mediastinal fat (8% to 56%) in the right apical segment, left apical posterior segment, both right and left anterior segments, right medial segment, and left inferior lingular segment. Cross-bridging structures were observed in 44% of right and 38% of left pneumothoraces and were noted in the right apical and posterior segments, left apical posterior segment, both anterior segments, right middle lobe, and left lingular segments. Septal and cross-bridging structures both showed a similar distribution pattern. CONCLUSIONS: Venous septal structures in normal lungs and cross-bridging structures in pneumothoraces visualized on CT images suggest the presence of direct pathways from each lobe of the lung to the mediastinum. PMID- 21317816 TI - Topical application of bleaching phenols; in-vivo studies and mechanism of action relevant to melanoma treatment. AB - Skin depigmentation represents a well-established treatment for extensive vitiligo and may likewise be suited to prevent tumor recurrences and as a prophylactic treatment of familial melanoma, as common bleaching agents are cytotoxic to melanocytes. Effective melanoma prevention requires a bleaching agent-induced loss of exposed melanocytes supported by an immune response to distant pigment cells. Studies on human explant cultures treated with depigmenting agents such as 4-tertiary butyl phenol (4-TBP) or monobenzyl ether of hydroquinone (MBEH) showed a significant increase in the migration of Langerhans cells toward the dermis only upon treatment with MBEH, thus suggesting selective elicitation of an immune response. To assess the depigmenting potential of bleaching agents in vivo, 4-TBP and MBEH were topically applied to C57BL/6 wild type as well as k14-SCF transgenic, epidermally pigmented mice. MBEH-induced significant skin depigmentation in both strains was not observed upon treatment with 4-TBP. Cytokine expression patterns in skin treated with MBEH support activation of a Th1-mediated immune response corresponding to an influx of T cells and macrophages. Importantly, despite insensitivity of tumor cells to MBEH induced cytotoxicity, significantly retarded tumor growth was observed in B16 challenged k14-SCF mice pretreated with MBEH, likely due to an abundance of cytotoxic T cells accompanied by an increased expression of Th1 and Th17 cytokines. These data support the use of MBEH as a prophylactic treatment for melanoma. PMID- 21317817 TI - Value of micromorphometric criteria of sentinel lymph node metastases in predicting further nonsentinel lymph node metastases in patients with melanoma. AB - Patients with metastases in the sentinel node (SN) are advised to undergo complete lymph node dissection, although the majority of them will have no further metastatic disease. Some of these patients undergo unnecessary surgery. In this study, we tried to predict the likelihood of further non-SN metastases on the basis of earlier published micromorphometric classifications of SN metastases. Metastases in the SN were re-evaluated on the basis of the microanatomic location of the lesions according to the Dewar's criteria, the S classification of SN, and tumor burden in accordance with the Rotterdam criteria. The results of these classifications were correlated with the presence of further non-SN metastases. Specimens of 124 positive-SN basins and subsequent complete lymph node dissection were investigated. Further metastases in non-SNs were found in 30 lymph node basins (24.2%). All of the above-mentioned classification systems were significantly correlated with non-SN tumor status. Especially, in patients with SN metastases in subcapsular location, a maximum depth of invasion of less than 0.3 mm (stage I according to the S-classification) or metastases of less than 0.1 mm in diameter had a very low probability of further non-SN metastases (0-5%). The validity of earlier published classifications of SN metastases-based on the micromorphometric criteria in predicting non-SN status was confirmed. Especially, in patients with subcapsular metastases, SI stage metastases or metastases of less than 0.1 mm had a very low risk of further non SN metastases. PMID- 21317818 TI - Restoration of tumor equilibrium after immunotherapy for advanced melanoma: three illustrative cases. AB - Metastatic melanoma runs a predictable detrimental course in the vast majority of patients. New modalities of immunotherapy, such as melanoma antigen-specific therapeutic vaccination and cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor blockade by monoclonal antibodies (mAbs), have been associated with atypical kinetics of tumor response that differ from those observed during cytotoxic treatment. Recently, new tumor response criteria have been proposed based on the tumor response characteristics observed in clinical studies with ipilimumab (the so-called 'immune-related response criteria'). We report three illustrative cases of the American Joint Committee on Cancer stage IV-M1c melanoma patients who experienced atypical kinetics of tumor response to the treatment with the CTLA-4 blocking mAb, ipilimumab (case 1), or an autologous dendritic cell vaccine in combination with interferon alpha-2b (cases 2 and 3). These cases show that atypical response patterns not only relate to the outcome of CTLA-4-blocking mAb therapy but also to the treatment with therapeutic vaccines and interferon alpha 2b. PMID- 21317819 TI - Seasonality of cutaneous melanoma diagnosis in Northern Ireland with a review. AB - In light-skinned populations, the incidence of cutaneous melanoma is highest in summer and lowest in winter. We analyzed the seasonal variation of melanoma incidence in Northern Ireland from 1984 to 2006 according to the Breslow thickness and body site. We also reviewed earlier studies on seasonal variation in the diagnosis of melanoma. Two-thirds of melanomas in women (2028 cases) and one-third of melanomas in men (1230 cases) were diagnosed on the limbs. In both sexes, pronounced seasonal variations were observed in the incidence of invasive melanomas less than 2 mm arising on the limbs. These seasonal variations were mainly noticeable in women of all ages, to a lesser degree in men aged below 50 years, and not in men aged above 50 years. No seasonal variation was observed for melanomas less than 2 mm arising on the trunk or the head and neck nor for melanomas 2 mm thickness or more, irrespective of the age, sex, and body site. Seasonal variations of thin melanomas were less noticeable in men because of the axial predominance of melanoma occurrence in this sex. The review of 15 earlier studies found by a systematic search of Medline supported the likelihood of our findings. This analysis suggests that ultraviolet radiation has a short-term promotional effect on melanocytes or nevocytes of the limbs, and is not associated with progression from thin to thick melanoma. PMID- 21317821 TI - Symptom interference with work and relationships during the menopausal transition and early postmenopause: observations from the Seattle Midlife Women's Health Study. AB - OBJECTIVE: The aim of this study was to describe the changes in symptom interference during the menopausal transition (MT) stages and early postmenopause (PM), including the effects of age, MT-related factors (estrone, follicle stimulating hormone, testosterone, MT stages), symptoms (hot flashes, depressed mood, awakening during the night, anxiety, backache, joint pain, forgetfulness, and difficulty concentrating), health-related factors (perceived health), and stress-related factors (perceived stress, cortisol). METHODS: A subset of Seattle Midlife Women's Health Study participants provided data during the late reproductive, early and late MT stages, or early PM (n = 184), including menstrual calendars for staging the MT; annual health reports completed between 1990 and 2008; morning urine samples assayed for estrone glucuronide, follicle stimulating hormone, and cortisol; and symptom diary ratings several times each year. Interference was rated in the diary along with symptoms, perceived health, and stress. Multilevel modeling with an R program was used to test the patterns of symptom interference related to age, MT-related factors, symptoms, and health- and stress-related factors, with as many as 5,656 observations. Median age was 47.4 years. RESULTS: Interference with work was significantly associated with individual covariates such as perceived health, stress, hot flashes, depressed mood, anxiety, difficulty getting to sleep, awakening during the night, early morning awakening, backache, joint pain, forgetfulness, and difficulty concentrating (for hot flashes, P = 0.01; all others, P < 0.001). A final multivariate model included perceived health, stress, depressed mood, and difficulty concentrating. Interference with relationships was significantly associated with age and individual covariates such as perceived health, estrone, perceived stress, depressed mood, anxiety, sleep symptoms, backache, joint pain, forgetfulness, and difficulty concentrating (for estrone, P = 0.03; all others, P < 0.001). A final multivariate model included perceived health, stress, depressed mood, anxiety, difficulty concentrating, and awakening during the night. CONCLUSIONS: Women's reports of how much the way they felt interfered with work and relationships were influenced by both their perceived health and stress levels. Interference was also influenced by depressed mood and difficulty concentrating, suggesting that these two symptoms may be most important to address, to enhance functioning during the MT and early PM. PMID- 21317822 TI - Adjusting for patient acuity in measurement of nurse staffing: two approaches. AB - BACKGROUND: Researchers who examine the relationship between nurse staffing and quality of care frequently rely on the Medicare case mix index to adjust for patient acuity, even though it was developed originally based on medical diagnoses and may not accurately reflect patients' needs for nursing care. OBJECTIVES: The aim of this study was to examine the differences between unadjusted measures of nurse staffing (registered nurses per 1,000 adjusted patient days) and case mix adjusted nurse staffing and nurse staffing adjusted with nursing intensity weights, which were developed to reflect patients' needs for nursing care. METHOD: Secondary data were used from 579 hospitals in 13 states from 2000 to 2006. Included were three measures of nurse staffing and hospital characteristics including ownership, geographic location, teaching status, hospital size, and percent Medicare inpatient days. RESULTS: Measures of nurse staffing differed in important ways. The differences between the measures were related systematically to ownership, geographic location, teaching status, hospital size, and percentage Medicare inpatient days. DISCUSSION: Without an accurate method to incorporate acuity into measurement of nurse staffing, research on the relationship between staffing and quality of care will not reach the full potential to inform practice. PMID- 21317823 TI - Application of a hierarchical model incorporating intrafamily correlation and cluster effects. AB - BACKGROUND: Research interventions at the family level often include individual- and group-level data that can present an analytic challenge. The study that motivated this article was an intervention study conducted with elementary school children and their parents. Randomization occurred at the school level, with families nested within schools. Repeated measurements collected from children and parents at different time points presented modeling challenges, including how to specify the covariance structure correctly among all measurements. OBJECTIVES: The aim of this study was to introduce a mixed model with random effects to model the correlations among family members, repeated measures, and the grouping effect. METHODS: A hierarchical random-effect model was used that included both fixed and random effects; time and intervention-by-time variables were included as fixed effects, the school-specific variable was included as random effect, and the intrafamily correlation was modeled through a spatial autoregression covariance matrix. Comparisons were made between the performance of the proposed modeling method and that of other parsimony models using Akaike's Information Criterion (AIC). RESULTS: The proposed modeling method produced a 3% and 9% reduction in AIC values, respectively, compared with the two other models. The likelihood ratio test further confirmed that the full model was better than the other two models (p < .0001 for both models). DISCUSSION: The data suggest that using the proposed mixed model technique will produce a significantly better model fit for intrafamily correlation with a nested study design. PMID- 21317824 TI - Examining mediators of child sexual abuse and sexually transmitted infections. AB - BACKGROUND: Interpersonal violence has increasingly been identified as a risk factor for sexually transmitted infections. Understanding the pathways between violence and sexually transmitted infections is essential to designing effective interventions. OBJECTIVE: The aim of this study was to examine dissociative symptoms, alcohol use, and intimate partner physical violence and sexual coercion as mediators of child sexual abuse and lifetime sexually transmitted infection diagnosis among a sample of women. METHODS: A convenience sample of 202 women was recruited from healthcare settings, with 189 complete cases for analysis. A multiple mediation model tested the proposed mediators of child sexual abuse and lifetime sexually transmitted infection diagnosis. Bootstrapping, a resampling method, was used to test for mediation. Key variables included child sexual abuse, dissociative symptoms, alcohol use, and intimate partner violence. RESULTS: Child sexual abuse was reported by 46% of the study participants (n = 93). Child sexual abuse was found to have an indirect effect on lifetime sexually transmitted infection diagnosis, with the effect occurring through dissociative symptoms (95% confidence interval = 0.0033-0.4714) and sexual coercion (95% confidence interval = 0.0359-0.7694). Alcohol use and physical violence were not found to be significant mediators. DISCUSSION: This study suggests that dissociation and intimate partner sexual coercion are important mediators of child sexual abuse and sexually transmitted infection diagnosis. Therefore, interventions that consider the roles of dissociative symptoms and interpersonal violence may be effective in preventing sexually transmitted infections among women. PMID- 21317825 TI - From novice to expert: confidence and activity status determine heart failure self-care performance. AB - BACKGROUND: In a previous, small, mixed-methods study, heart failure patients were described as novice, expert, or inconsistent in self-care. In that study, self-care types differed in experience, confidence, attitudes, and skill. OBJECTIVES: The aims of this study were to validate the novice-to-expert self care typology and to identify determinants of the heart failure self-care types. METHODS: A cross-sectional descriptive study was performed using data from 689 adults with heart failure (61 +/- 2.5 years; 36% female, 50% New York Heart Association class III). Two-step likelihood cluster analysis was used to classify patients into groups using all items in the maintenance and management scales of the Self-care of Heart Failure Index. Multinomial regression was used to identify the determinants of each self-care cluster, testing the influence of age, gender, left ventricular ejection fraction, body mass index, depression, anxiety, hostility, perceived control, social support, activity status (Duke Activity Status Index), and self-care confidence. RESULTS: Self-care behaviors clustered best into three types: novice (n = 185, 26.9%), expert (n = 229, 33.2%), and inconsistent (n = 275, 39.9%). The model predicting self-care cluster membership was significant (chi2 = 88.67, p < .001); Duke Activity Status Index score and Self-care of Heart Failure Index confidence score were the only significant individual factors. Higher activity status increased the odds that patients would be inconsistent (odds ratio [OR] = 1.02-1.09) or novice (OR = 1.02-1.10) in self care. Higher self-care confidence increased the odds of being an expert (OR = 1.05-1.09) or inconsistent (OR = 1.01-1.05) in self-care. DISCUSSION: The three level typology of heart failure self-care was confirmed. Patients who have fewer limitations to daily activities may not be driven adequately to engage in heart failure self-care and may need extra assistance in developing expertise. PMID- 21317826 TI - The use of "lives saved" measures in nurse staffing and patient safety research: statistical considerations. AB - BACKGROUND: Lives saved predictions are used to quantify the impact of certain remedial measures in nurse staffing and patient safety research, giving an indication of the potential gain in patient safety. Data collected in nurse staffing and patient safety are often multilevel in structure, requiring statistical techniques to account for clustering in the data. OBJECTIVE: The purpose of this study was to assess the impact of model specifications on lives saved estimates and inferences in a multilevel context. METHODS: A simulation study was carried out to assess the impact of model assumptions on lives saved predictions. Scenarios considered were omitting an important covariate, taking different link functions, neglecting the correlations coming from the multilevel data structure, and neglecting a level in a multilevel model. Finally, using a cardiac surgery data set, predicted lives saved from the random intercept logistic model and the clustered discrete time logistic model were compared. RESULTS: Omitting an important covariate, neglecting the association between patients within the same hospital, and the complexity of the model affect the prediction of lives saved estimates and the inferences thereafter. On the other hand, a change in the link function led to the same predicted lives saved estimates and standard deviations. Finally, the lives saved estimates from the two-level random intercept model were similar to those of the clustered discrete time logistic model, but the standard deviations differed greatly. CONCLUSIONS: The results stress the importance of verifying model assumptions. It is recommended that researchers use sensitivity analyses to investigate the stability of lives saved results using different statistical models or different data sets. PMID- 21317827 TI - Situational and dispositional influences on nurses' workplace well-being: the role of empowering unit leadership. AB - BACKGROUND: Unit-level leadership and structural empowerment play key roles in creating healthy work environments, yet few researchers have examined these contextual effects on nurses' well-being. OBJECTIVES: The aim of this study was to test a multilevel model of structural empowerment examining the effect of nursing unit leadership quality and structural empowerment on nurses' experiences of burnout and job satisfaction and to examine the effect of a personal dispositional variable, core self-evaluation, on these nurse experiences. METHODS: Nurses (n = 3,156) from 217 hospital units returned surveys that included measures of leader-member exchange, structural empowerment, burnout, core self-evaluation, and job satisfaction. Multilevel structural equation modeling was used to test the model. RESULTS: Nurses' shared perceptions of leader-member exchange quality on their units positively influenced their shared perceptions of unit structural empowerment (Level 2), which resulted in significantly higher levels of individual nurse job satisfaction (Level 1). Unit level leader-member exchange quality also directly influenced individual nurse job satisfaction. Unit leader-member exchange quality and structural empowerment influenced emotional exhaustion and cynicism differentially. Higher unit-level leader-member exchange quality was associated with lower cynicism; higher unit level structural empowerment was associated with lower emotional exhaustion. At Level 1, higher core self-evaluation was associated with lower levels of both emotional exhaustion and cynicism, both of which were associated with lower job satisfaction. DISCUSSION: This study provides a theoretical understanding of how unit leadership affects both unit- and individual-level outcomes. PMID- 21317828 TI - Cluster analysis of intake, output, and voiding habits collected from diary data. AB - BACKGROUND: Data that incorporate the full complexity of healthy beverage intake and voiding frequency do not exist; therefore, clinicians reviewing bladder habits or voiding diaries for continence care must rely on expert opinion recommendations. OBJECTIVE: The aims of this study were to use data-driven cluster analyses to reduce complex voiding diary variables into discrete patterns or data cluster profiles, descriptively name the clusters, and perform validity testing. METHODS: Participants were 352 community women who filled out a 3-day voiding diary. Six variables (void frequency during daytime hours, void frequency during nighttime hours, modal output, total output, total intake, and body mass index) were entered into cluster analyses. The clusters were analyzed for differences by continence status, age, race (Black women, n= 196; White women, n = 156), and, for those who were incontinent, by leakage episode severity. RESULTS: Three clusters emerged, labeled descriptively as "conventional," "benchmark," and "superplus." The conventional cluster (68% of the sample) demonstrated a mean daily intake of 1320 +/- 375 ml, a mean daily output of 1069 +/- 434 ml, mean daily voids of 5 +/- 2 times, mean modal daytime output of 290 +/- 144 ml, and mean nighttime voids of 1 +/- 1 times. The superplus cluster (7% of the sample) showed double or triple these values across the five variables, and the benchmark cluster (25%) showed values consistent with current popular recommendations on intake and output (e.g., meeting or exceeding the 8 * 8 fluid intake rule of thumb). The clusters differed significantly (p < .05) by age, race, amount of bladder irritant beverages consumed, and incontinence. DISCUSSION: Identification of three discrete clusters provides for a potential parsimonious but data-driven means of classifying individuals for additional epidemiological or clinical study. The clinical utility rests with potential for intervening to move an individual from a high-risk to low-risk cluster with regard to incontinence. PMID- 21317829 TI - The contribution of infections to neonatal deaths in England and Wales. AB - This study used anonymized death certificate data to determine the contribution of specific infections to neonatal deaths in England and Wales between 2003 and 2005. Infection was recorded in 11% of deaths, with two-thirds occurring in premature neonates. Group B Streptococcus was indicated in 32% of death certificates that specified a bacterial infection and in 11% of all infection related deaths. PMID- 21317830 TI - Association of the UGT1A1-53(TA)n polymorphism with L-thyroxine doses required for thyrotropin suppression in patients with differentiated thyroid cancer. AB - There is a considerable interindividual variation in L-thyroxine [3,5,3',5' tetraiodo-l-thyronine (T4)] dose required for thyrotropin (thyroid-stimulating hormone) suppression in patients with differentiated thyroid cancer. To investigate whether uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) mediated T4 glucuronidation in liver affects T4 dose, we genotyped 101 patients for the common UGT1A1-53(TA)n polymorphism and compared T4 doses among patients having zero (5/6 and 6/6 genotypes), one (6/7 genotype), or two (7/7 and 7/8 genotypes) copies of the low-expression (TA)7 and (TA)8 alleles. A significant trend for decreasing T4 dose with increasing number of copies of (TA)7 and (TA)8 (P=0.037) and significant difference in T4 dose across the UGT1A1-53(TA)n genotypes (P=0.048) were observed, despite considerable overlap of T4 doses among different genotypes. These results are consistent with reduced T4 glucuronidation in patients with low-expression (TA)7 and (TA)8 alleles and provide the first evidence for association between UGT1A1-53(TA)n and T4-dose requirement for thyroid-stimulating hormone suppression in a natural clinical setting. PMID- 21317832 TI - ABCC1 G2012T single nucleotide polymorphism is associated with patient outcome in primary neuroblastoma and altered stability of the ABCC1 gene transcript. AB - OBJECTIVE: Multidrug resistance is a major cause of treatment failure in neuroblastoma. Multidrug resistance protein 1 has been previously implicated in the development of drug resistance, particularly with regard to influencing clinical outcomes in neuroblastoma. Numerous single nucleotide polymorphisms (SNPs) in the gene encoding multidrug resistance protein 1, namely ATP-binding cassette sub-family C member 1 (ABCC1), have been identified, however, less is known about their potential association with patient outcome. Our aim was to determine the prognostic implications of ABCC1 polymorphisms in neuroblastoma. METHODS: We assessed the frequency of four nonsynonymous ABCC1 SNPs, namely G128C, G1299T, G2168A, and G2012T in both neuroblastoma samples and normal cord blood cells. Polymorphism rates and associations with clinicopathologic characteristics were assessed. RESULTS: The initial three examined polymorphisms were found to be present at very low levels in the Australian population. Of 195 neuroblastoma samples and 158 cord blood samples, none carried the G2012T homozygous variant allele, whereas 13% were heterozygous. The presence of the variant allele was associated with an improved outcome in patients with aggressive neuroblastoma, particularly in older children (P<0.05) and those with nonmetastatic disease (P<0.005). Tumor cell lines that were heterozygous for this SNP, expressed the variant ABCC1 gene transcript at significantly lower levels than the wild-type ABCC1 transcript, and this was associated with the reduced mRNA stability of the variant transcript. CONCLUSION: Collectively, our findings indicated a potential prognostic role of the G2012T ABCC1 polymorphism in clinically relevant subsets of patients with neuroblastoma, and provided further evidence for the ABCC1 gene being a major determinant in neuroblastoma biology. PMID- 21317831 TI - PharmGKB summary: methotrexate pathway. PMID- 21317833 TI - Longer-term outcomes of a prospective study of intravitreal ranibizumab as a treatment for decreased visual acuity secondary to central retinal vein occlusion. AB - PURPOSE: To evaluate long-term effectiveness and safety of intravitreal injection of ranibizumab as a potential treatment for decreased visual acuity secondary to central retinal vein occlusion. METHODS: In this prospective interventional case series, patients with central retinal vein occlusion were administered intravitreal ranibizumab 0.5 mg at baseline and monthly for 2 additional doses. Thereafter, the patients were given additional ranibizumab if they had macular edema by optical coherence tomography, leakage during fluorescein angiography, or any intraretinal hemorrhage. RESULTS: There were 35 eyes of 35 patients who at baseline had a mean visual acuity of 44.2 Early Treatment Diabetic Retinopathy Study letters and a mean central macular thickness of 638 MUm. At 12 months, mean visual acuity of 32 eyes improved by 16.5 letters and macular thickness decreased to 164 MUm (P < 0.001 vs. baseline for each). At 24 months, mean visual acuity of 24 eyes improved by 17.8 letters and macular thickness was 263 MUm (P < 0.001 vs. baseline for each). Patients received an average of 10.2 injections during the first year and 6.6 injections during the second year. No cases of endophthalmitis, retinal detachment, or neovascularization were observed. CONCLUSION: Intravitreal ranibizumab caused a significant improvement in visual acuity and central retinal thickness, which persisted for up to 2 years with minimal side effects. PMID- 21317834 TI - Geographic atrophy in retinal angiomatous proliferation. AB - PURPOSE: To describe the occurrence of geographic atrophy in patients with retinal angiomatous proliferation (RAP). METHODS: Demographics, visual acuity, color fundus photographs, fluorescein and indocyanine green angiograms, and fundus autofluorescence and near-infrared autofluorescence images were reviewed in 53 patients (66 eyes) with RAP. RESULTS: Of 53 treatment-naive eyes, 19 (36%) had atrophy at baseline. Of 66 eyes, 57 (86%) developed de novo atrophy or enlargement of preexisting areas of atrophy during the follow-up (median, 17 months; range, 3-53 months) after treatment. Areas of atrophy were observed at the site of the RAP (58 of 66 eyes, 88%) of a previously existing pigment epithelial detachment (18 of 44 eyes; 41%) and elsewhere (43 of 66 eyes, 65%). At presentation, RAP was found to be frequently associated with increased autofluorescence at the fovea because of cystoid macular edema (36 of 53 eyes, 68%) and reduced autofluorescence because of hard exudation (38 of 53 eyes, 72%) and intraretinal hemorrhages (32 of 53 eyes, 60%). Background reticular (39%) and homogeneous (36%) autofluorescence were most commonly observed. CONCLUSION: Geographic atrophy occurs frequently in patients with RAP after treatment. This information, if confirmed in other cohorts, would be valuable for the counseling of patients with this disease and for the understanding of the pathogenesis of this condition and its progression after treatment. PMID- 21317835 TI - Midterm results of low-dose intravitreal triamcinolone as adjunctive treatment for proliferative vitreoretinopathy. AB - PURPOSE: To evaluate the midterm anatomical and functional outcomes of intravitreal injection of low-dose triamcinolone acetonide in silicone oil-filled eyes as an adjunctive treatment for proliferative vitreoretinopathy. METHODS: This is a retrospective interventional case series. Patients with proliferative vitreoretinopathy grade C or D received pars plana vitrectomy combined with silicone oil tamponade and intravitreal injection of 2 mg of triamcinolone acetonide in the first stage and silicone oil removal in the second stage. Primary outcome measures were retinal reattachment rate and best-corrected visual acuity. RESULTS: In all, 37 eyes from 37 patients were included in this study. The mean follow-up duration was 22.9 +/- 9.6 months. Retina was reattached in 36 (97.3%) eyes at the last visit. The mean best-corrected visual acuity was 1.76 +/ 0.56 logMAR at baseline, which improved to 0.87 +/- 0.60 logMAR at the last visit (P < 0.001). Best-corrected visual acuity increased in 31 (83.8%) eyes, remained unchanged in 5 (13.5%) eyes, and decreased in 1 (2.7%) eye at last visit compared with baseline. CONCLUSION: Low-dose (2 mg) triamcinolone acetonide intravitreal injection as an adjunct to vitrectomy and silicone oil tamponade in treating proliferative vitreoretinopathy (grade C or D) appears to be effective and safe. PMID- 21317836 TI - Ocular manifestations of Takayasu arteritis: a cross-sectional study. AB - PURPOSE: To detail the spectrum of eye manifestations in Takayasu arteritis and factors predisposing to its development. METHODS: In this cross-sectional study, 61 patients with proven Takayasu arteritis who were identified during a 16-month period were evaluated for disease- and treatment-related eye manifestations. A fundus fluorescein angiography examination was performed where indicated and with the patients consent. RESULTS: The mean (+/-standard deviation) duration of illness before ophthalmic evaluation was 55 +/- 69 months. Decreased vision was the most common ocular symptom (30%). Thirty-five patients underwent fundus fluorescein angiography examination. Takayasu retinopathy was seen in 9 (15%), ocular ischemic syndrome in 4 (7%), and hypertensive retinopathy in 10 (16%) patients. The most common treatment-related ocular complication was steroid induced cataract (23%). Other manifestations included iris neovascularization (n = 3), anterior ischemic optic neuropathy (n = 2), steroid-induced glaucoma (n = 1), neovascular glaucoma (n = 1), and uveitis (n = 1). Those manifesting Takayasu retinopathy and ocular ischemic syndrome had significantly (P < 0.05) lower blood pressure in both upper limbs compared with patients not manifesting ischemic retinopathy. A significant (P < 0.03) proportion of patients with Takayasu retinopathy and ocular ischemic syndrome had a nonrecordable right upper limb blood pressure. CONCLUSION: Disease- and treatment-related ocular complications are not infrequent in Takayasu arteritis. Arteritis involving the aortic arch and its branches favors the development of ischemic ocular complications. PMID- 21317837 TI - One-year outcomes of intravitreal bevacizumab (avastin) therapy for polypoidal choroidal vasculopathy. AB - PURPOSE: To report on 1-year visual, anatomical, and angiographic responses with intravitreal bevacizumab for the treatment of polypoidal choroidal vasculopathy. METHODS: Patients with macula-involved, symptomatic polypoidal choroidal vasculopathy with initial best-corrected visual acuity of 20/400 or better and a minimal follow-up period of 12 months were retrospectively enrolled. Eyes were treated with intravitreal bevacizumab (2.5 mg) at baseline and monitored monthly for best-corrected visual acuity and central retinal thickness (by optical coherence tomography). Indocyanine green angiography was evaluated on a 6-month basis. Eyes were retreated on an "as-needed" basis according to visual and anatomical changes. RESULTS: A total of 35 eyes of 33 patients were treated with a mean of 3.3 (range, 1-8) times of injection. Best-corrected visual acuity significantly improved from a mean logarithm of the minimum angle of resolution of 0.79 +/- 0.42 at baseline (Snellen equivalent, 20/123) to 0.69 +/- 0.47 (20/94), 0.66 +/- 0.45 (20/87), 0.67 +/- 0.44 (20/87), 0.67 +/- 0.48 (20/87), and 0.67 +/- 0.51 (20/87) at 1, 3, 6, 9, and 12 months, respectively (P = 0.002, 0.0003, 0.0008, 0.017, and 0.02, respectively; paired Student's t-test). Central retinal thickness also significantly improved from a mean of 297 +/- 94 MUm at baseline to 215 +/- 58 MUm, 214 +/- 59 MUm, 218 +/- 79 MUm, 213 +/- 75 MUm, and 221 +/- 61 MUm at 1, 3, 6, 9, and 12 months, respectively (all P < 0.0001, paired Student's t-test). Indocyanine green angiography showed 3 of 32 eyes (9.4%) and 5 of 31 eyes (16.1%) with completely resolved polyps and 11 of 32 eyes (34.4%) and 10 of 31 eyes (32.3%) with reduced polyps at 6 and 12 months, respectively. No systemic complication or severe local complication, such as endophthalmitis, was found. CONCLUSION: Intravitreal bevacizumab therapy has a favorable outcome in improving visual acuity and macular exudative changes in patients with polypoidal choroidal vasculopathy. It can also moderately reduce polypoidal lesions on indocyanine green angiography. PMID- 21317838 TI - Improving long-term outcome in allograft transplantation: role of ionic composition and polyethylene glycol. AB - BACKGROUND: Ischemia reperfusion injury (IRI) is inherent to transplantation, and correlates with negative outcome. Limiting IRI requires new preservation. Fourth generation solutions are emerging, using new colloid based on polyethylene glycol (PEG) polymers and extracellular ionic composition. We evaluated their eventual benefits for optimal resistance to IRI and improved outcome. METHODS: Using primary cell culture and a preclinical pig model of low-mismatch kidney allograft transplantation, not requiring immunosuppression, we compared the following solutions: UW (University of Wisconsin), high potassium with hydroxyethyl starch, gold standard in preservation; IGL-1 (Institute George Lopez-1), low potassium solution using PEG (35 kDa, 1 g/L); and SCOT (Solution de Conservation des Organes et Tissus), plasma-like ionic composition, containing PEG 20 kDa (30 g/L). RESULTS: In vitro, SCOT-preserved cells had better viability and less necrosis. In vivo, SCOT-grafts had better function recovery, with limited histological injury compared with the other solutions. During the 3 months follow up, we found low innate and adaptative immune response in SCOT organs, whereas other groups presented high rate of invasion and antigen presentation. SCOT preserved kidneys showed low fibrosis, transforming growth factor-beta expression and apoptosis compared with the other groups. These differences impacted survival at 3 months, which was low in UW (20%) and IGL-1 (40%) groups, whereas it remained high for SCOT animals (80%, P<0.05 to UW). CONCLUSIONS: In conclusion, plasma-like ionic composition and nontoxic molecule PEG provide high resistance against IRI and optimize graft outcome. Such solutions could be invaluable for the use of fragile organs, such as from extended criteria or deceased after cardiac death donors. PMID- 21317839 TI - Recipient risk factors associated with delayed graft function: a paired kidney analysis. AB - BACKGROUND: Delayed graft function (DGF) is a common complication of deceased donor kidney transplantation that occurs because of a complex interplay between donor organ quality and the biologic milieu of the recipient. The purpose of the study is to better understand the recipient risk factors leading to DGF. METHODS: We performed a retrospective cohort study using United Network for Organ sharing data and identified pairs of primary, adult kidney-only transplants that were procured from the same adult donor with discordant occurrence of DGF (i.e., one kidney of the pair had DGF). RESULTS: A total of 5382 recipient pairs were analyzed. Recipients with DGF were more likely to be male (67% vs. 59%, P<0.01), African American (36% vs. 27%, P<0.01), obese (30% vs. 19%, P<0.01), diabetic (28% vs. 22%, P<0.01), on maintenance dialysis (92% vs. 83%, P<0.01), and to have longer wait-time (571 vs. 471 days, P<0.01), longer cold ischemia time (22 vs. 20 hr, P<0.01), and donor and recipient size mismatch (32% vs. 24%, P<0.01). Multivariable analyses confirmed these associations and identified panel reactive antibody more than 10% and low center volume as additional risk factors for DGF (odds ratio for panel reactive antibody >10%: 1.17, confidence interval 1.05 1.29, P<0.01; and odds ratio for <83 transplants/year: 1.29, confidence interval 1.17-1.44, P<0.01). CONCLUSIONS: After fully matching for donor factors, many recipient characteristics were noted to be associated with DGF. Better management of modifiable recipient and transplant risk factors such as obesity, wait time, and cold time may help to reduce the occurrence of DGF. PMID- 21317840 TI - Plant polyphenols and their anti-cariogenic properties: a review. AB - Polyphenols constitute one of the most common groups of substances in plants. Polyphenolic compounds have been reported to have a wide range of biological activities, many of which are related to their conventional antioxidant action; however, increasing scientific knowledge has highlighted their potential activity in preventing oral disease, including the prevention of tooth decay. The aim of this review is to show the emerging findings on the anti-cariogenic properties of polyphenols, which have been obtained from several in vitro studies investigating the effects of these bioactive molecules against Streptococcus mutans, as well as in vivo studies. The analysis of the literature supports the anti-bacterial role of polyphenols on cariogenic streptococci, suggesting (1) a direct effect against S. mutans; (2) an interaction with microbial membrane proteins inhibiting the adherence of bacterial cells to the tooth surface; and (3) the inhibition of glucosyl transferase and amylase. However, more studies, particularly in vivo and in situ, are necessary to establish conclusive evidence for the effectiveness and the clinical applications of these compounds in the prevention of dental caries. It is essential to better determine the nature and distribution of these compounds in our diet and to identify which of the hundreds of existing polyphenols are likely to provide the greatest effects. PMID- 21317841 TI - Polycationic glycosides. AB - Cationic lipids have long been known to serve as antibacterial and antifungal agents. Prior efforts with attachment of cationic lipids to carbohydrate-based surfaces have suggested the possibility that carbohydrate-attached cationic lipids might serve as antibacterial and antifungal pharmaceutical agents. Toward the understanding of this possibility, we have synthesized several series of cationic lipids attached to a variety of glycosides with the intent of generating antimicrobial agents that would meet the requirement for serving as a pharmaceutical agent, specifically that the agent be effective at a very low concentration as well as being biodegradable within the organism being treated. The initial results of our approach to this goal are presented. PMID- 21317842 TI - Tannin composition of cabernet-sauvignon and merlot grapes from the bordeaux area for different vintages (2006 to 2009) and comparison to tannin profile of five 2009 vintage mediterranean grapes varieties. AB - The proanthocyandin composition of skins and seeds of Bordeaux Merlot (M) and Cabernet Sauvignon (CS) grapes was evaluated by HPLC-UV-fluorescence for four consecutive vintages (2006 to 2009). The results indicated a strong vintage effect on the tannin profile of each variety. However, and in spite of the vintage effect, some tannin characteristics such as mDP, %G and %P allow discrimination of both Bordeaux varieties. The same analyses were carried out for the 2009 vintage of five Mediterranean grape varieties (Syrah, Grenache, Mourvedre, Carignan and Counoise). The results demonstrated differences among these five varieties. Syrah appeared to exhibit the highest concentrations of flavanol monomers and dimmers, especially in skins. The comparison study between Bordeaux and Mediterranean grape varieties for the same vintage (2009) revealed that mDP and %G for seed extracts were parameters specific to each vineyard area. PMID- 21317843 TI - Fast and sensitive LC-DAD-ESI/MS method for analysis of saikosaponins c, a, and d from the roots of Bupleurum Falcatum (Sandaochaihu). AB - In the present study, we developed a liquid chromatography-diode array detector electrospray ionization/mass spectrometric (LC-DAD-ESI/MS) method for analysis of saikosaponins in Bupleurum falcatum. The LC method employed a ZORBAX SB-Aq analytical column (150 x 4.6 mm i.d., 5 MUm) at a flow rate of 0.8 mL/min coupled with a diode array detector at 204 nm. A step gradient of acetonitrile-water (v/v) containing 0.5% formic acid from 30 to 70% was applied, leading to a sample analysis time of 30 min. The ESI-MS was carried out in positive and negative modes from 500 to 1,500 m/z. Saikosaponins c, a, and d gave strong sodium adducts at m/z 949.6, 803.5 and 803.6, respectively, in positive mode. The data indicate that the present LC-DAD-ESI/MS assay is an effective method for the determination of saikosaponins c, a and d from the roots of Bupleurum falcatum. PMID- 21317844 TI - Identification and characterization of three novel small interference RNAs that effectively down-regulate the isolated nucleocapsid gene expression of SARS coronavirus. AB - Nucleocapsid (N) protein of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) is a major pathological determinant in the host that may cause host cell apoptosis, upregulate the proinflammatory cytokine production, and block innate immune responses. Therefore, N gene has long been thought an ideal target for the design of small interference RNA (siRNA). siRNA is a class of small non-coding RNAs with a size of 21-25nt that functions post transcriptionally to block targeted gene expression. In this study, we analyzed the N gene coding sequences derived from 16 different isolates, and found that nucleotide deletions and substitutions are mainly located at the first 440nt sequence. Combining previous reports and the above sequence information, we create three novel siRNAs that specifically target the conserved and unexploited regions in the N gene. We show that these siRNAs could effectively and specifically block the isolated N gene expression in mammal cells. Furthermore, we provide evidence to show that N gene can effectively up-regulate M gene mediated interferon b (IFNb) production, while blocking N gene expression by specific siRNA significantly reduces IFNb gene expression. Our data indicate that the inhibitory effect of siRNA on the isolated N gene expression might be influenced by the sequence context around the targeted sites. PMID- 21317845 TI - Chronic obstructive pulmonary disease: the Disability Adjusted Life Years in northern Italy. AB - AIM: The DALY measure represents a new tool for improving the capacity of local health unit to assess population health needs and priorities. Our study aimed to increase the validity of the Disability Adjusted Life Years (DALY), by incorporating local estimates of the disease incidence and applying population specific disability weights. METHODS: This is a prospective cohort study enrolling subjects aged 45+ years, first-time admitted to the hospital with principal diagnosis of 490-492, 496 ICD IX-CM codes and followed for one year to evaluate the vital status. A subset was administered the Saint George Respiratory Questionnaire to estimate the distribution of the chronic obstructive pulmonary disease (COPD)-related disability. RESULTS: Estimates of total DALY (per 1000) for COPD varied between 2.1 to 3.4 years among men and between 1.0 to 2.3 years among women; percentages of years of life lost due to a premature mortality were between 60 and 70%. CONCLUSION: The DALY represents a new tool for improving the capacity to assess population health needs and priorities. Policy makers owning such a further element of evaluation may be better oriented in allocating resources for COPD among the different health care chapters: prevention, emergency, chronicity and rehabilitation. PMID- 21317846 TI - Imaging in osteoarthritis: what have we learned and where are we going? AB - Osteoarthritis (OA) is a widely prevalent disease of the whole joint including cartilage, bone and soft tissues. Increasing importance of imaging including assessment of all joint structures has been recognized recently. Conventional radiography is still the first and most commonly used imaging technique for evaluation of a patient with a known or suspected diagnosis of OA. However, limitations have been revealed by recent MRI-based knee OA studies. MRI plays a crucial role in understanding the natural history of the disease and in guiding future therapies due to its ability to image the knee as a whole organ and to directly and three-dimensionally assess cartilage morphology and composition. It is crucial to use the appropriate MR pulse sequences to assess various OA features, and thus support from experienced musculoskeletal radiologists should be sought for study design, image acquisition and interpretation. The aim of this article is to describe the roles and limitations of conventional radiography and MRI in imaging of OA, and also to give insight into the use of other modalities such as ultrasound, scintigraphy, computed tomography (CT) and CT arthrography in clinical practice and research in OA, particularly focusing on the assessment of knee OA in the tibiofemoral joint. PMID- 21317847 TI - Nutraceuticals for the treatment of osteoarthritis. AB - Osteoarthritis (OA) is a highly prevalent human condition which is becoming an even greater health problem in an aging global population. Existing treatments for OA provide pain relief and some anti-inflammatory effects, but no truly disease-modifying treatments are available for this disease. Furthermore, the generally advanced age and frequent comorbid conditions present in OA patients limit safety of many available drugs. Treatments with enhanced safety margins and that offer chondroprotective effects are unmet needs. Nutraceuticals derived from foods and herbs have been long used in traditional medicine, and many have wide ranging biologic effects suggesting novel mechanisms of action. Some of these have shown promise in controlled clinical trials in OA patients. Whether these approaches could offer safe symptom relief and possibly mediate beneficial joint remodeling in early OA are possibilities that merit further investigation. PMID- 21317848 TI - The management of post-traumatic osteoarthritis. AB - Posttraumatic arthritis primarily affects younger individuals, leading to reduced physical activity, chronic pain, and prolonged symptomatic treatments. The management of post-traumatic arthritis after fracture, dislocation or ligament rupture continues to be one of the most challenging clinical entities in orthopaedic and trauma surgery. Therapies to address early symptoms include anti inflammatory agents, pain killers, corticosteroid or hyaluronic acid joint injections but these offer only temporary pain relief with hardly any mid or long term benefit. There are many surgical options for the treatment of posttraumatic arthritis. For the early stages, arthroscopic debridement should be considered. At late stages, corrective osteotomies or arthrodesis are strongly recommended for the young patients. In older patients arthroplasties remain the treatment of choice. PMID- 21317849 TI - [Oxidative stress and endothelial dysfunction]. AB - Endothelial dysfunction and oxidative stress are the main pathophysiological mechanisms of several diseases such as hypertension, atherosclerosis, dyslipidemia, diabetes mellitus, cardiovascular disease, renal failure and ischemia-reperfusion injury. Reactive oxygen species (ROS) can modulate cellular function, receptor signals and immune responses in physiological conditions, but when present in excess, they mediate progressive endothelial damage through growth and migration of vascular smooth muscle and inflammatory cells, alteration of extracellular matrix, apoptosis of endothelial cells, activation of transcription factors (NFkB, AP-1), over-expression of inflammatory cytokines and adhesion molecules (ICAM-1, VCAM-1 , E-selectin). Recent evidences suggest that the major source of ROS is the NADPH-oxidase, especially activated by angiotensin II, shear stress and hyperglycemia. The unbalance between production of free radicals and the ability to neutralize them by antioxidant systems causes a condition of "oxidative stress". ROS alter vascular tone by increasing concentration of cytosolic calcium and especially causing a decreased availability of nitric oxide, the principal agent of endothelial function with vasodilating action. The data emerged from experimental and clinical studies confirm that endothelium-dependent vasodilation is altered in many diseases. PMID- 21317850 TI - [Mucositis in oncohematology]. AB - Mucositis is the result of the cytotoxic effects of many treatments given for hematological malignancies (HMs); it represents a major source of potentially devastating clinical complications and portrays negative consequences on the patient's management, such as a longer hospitalization, the need of analgesic and total parenteral nutrition use, and increased costs. The available measures for the prevention and treatment of mucositis have been substantially palliative, being limited to the control of pain, infection, bleeding and nutrition. However, in the last decade, a better insight into the complex pathogenesis of MBI has led to the development of novel therapeutic options, such as palifermin, which can provide tools potentially allowing a targeted approach to mucositis. PMID- 21317851 TI - Venous thromboembolism in patients hospitalized in internal medicine wards. AB - Venous thromboembolism (VTE) is one of the main causes of morbility and mortality in the ospedalized patients. Epidemiologist studies have also demonstrated that VTE is an important and frequent problems in medical patients. In surgical patients is done with greater frequency, but in medical patients prophylaxis is not completely codified and less often less practiced. This review shows epidemiological data, risk factors and classification of the risk of VTE in patients with medical pathologies. Then meta-analyses studies and main studies such as Medenox, Prevent and Artemis, that have examined the prophylaxis of VTE in medical patients are described and discussed, along with their results concerning morbility and mortality. The current problems of prophylaxis in medical patients are reviewed , such as duration of treatment, optimal dosage of the low molecular weight heparin (LMWH) and the correct risk assessment of VTE. EXCLAIM Study has showed the benefit of extended prophylaxis with statistically significant reduction in VTE events. PMID- 21317852 TI - An update on the diagnosis and management of psoriatic arthritis. AB - Psoriasis is a common inflammatory disease with complex genetic background affecting approximately 2-3% of the population in the Western hemisphere. Around 20% of psoriasis patients also suffer from psoriatic arthritis (PsA). The clinical spectrum comprises a wide variety of arthritic manifestations ranging from dactylitis, peripheral symmetric or asymmetric mono-, oligo-, and polyarticular arthritis, spinal disease and enthesitis. As psoriasis precedes PsA in 75-80% of affected patients, dermatologists might play a pivotal role in early diagnosis of the disease. Furthermore, magnetic resonance imaging (MRI) scanning and ultrasonography have improved the radiological diagnosis of peripheral PsA, psoriatic spondylarthropathy and enthesitis. Besides the traditional treatment of PsA the introduction of biologics has led to a significant improvement in the treatment of the disease. To further improve diagnosis, treatment and quality of life in our patients suffering from PsA an excellent interdisciplinary collaboration between dermatologists, radiologists and rheumatologists is a necessity of utmost importance. PMID- 21317853 TI - Psoriasis: comorbidities and associations. AB - Psoriasis is a chronic, genetic, inflammatory skin disease affecting approximately 2% of the population worldwide. Over the past decade, multiple studies have shown that not only is there an association between psoriasis and psoriatic arthritis, depression, and substance abuse, but psoriasis patients also have a higher incidence of obesity, diabetes, heart disease and stroke. In addition, and more concerning, young psoriatic patients particularly those with more severe disease are at an increased mortality risk even when controlling for these factors. The systemic inflammation in psoriasis generates elevation of C reactive protein, homocysteine, and inflammatory cytokines such as TNF-a, IL-6, IL-17, IL-20, IL-22, and IL-23, which may contribute to the overall morbidity and mortality in these patients. Within this article we will discuss the associations between psoriasis and multiple systemic health problems. PMID- 21317854 TI - Role of the immune system and immunological circuits in psoriasis. AB - Psoriasis vulgaris is a chronic skin disease in which our understanding of the pathogenesis has substantially grown in recent years. Our current appreciation of the role of the immune system is that it plays a necessary and driving role in the disease process. Investigations into the genetics of psoriasis has spurred further examinations into the contributions of immune mediators such as IL-23, IL 17, IL-22, and TNF as well as cellular mediators including a variety of dendritic cell populations of the skin and the growing number of T cell types, including the Th17 and Th22 subsets. Investigations into how these soluble and cellular elements interact with each other and the skin and form complex signal circuits to engender the psoriasis phenotype is starting to become elucidated. Furthermore, these recent advances have been fruitful in leading to the development of new classes of biologic therapeutics that are remarkably effective in halting the disease process. PMID- 21317855 TI - Juvenile psoriasis: rewarding endeavours in contemporary dermatology and pediatrics. AB - Childhood psoriasis is a well-known entity, which is different from adult onset psoriasis in many ways. Recent data from Germany, where a total of 33981 patients with psoriasis were identified from a database of about 1.3 million non-selected persons of a German statutory health insurance, revealed a total rate of 0.71% in children younger than 18 years. The prevalence rates increased in a linear way from 0.2% at the age of one year to 1.2% at the age of 18 years. Although the different types of psoriasis are present in both children and adults, the individual course of the disease and its distribution shows differences. The overall rate of comorbidity in psoriatic persons younger than 20 years seems to be twice as high as in persons without psoriasis. Treating children with psoriasis still remains challenging and represents one of the most rewarding endeavours in contemporary dermatology, since psoriasis can present with both joint and skin symptoms. An interdisciplinary approach with pediatricians, dermatologist and rheumatologists might be crucial. The multifactorial etiology of the disease has led to the development of a wide variety of different treatments, providing physicians with a multitude of options that must be tailored to the age of the patient and the severity of their symptoms. The provision of adequate care for juvenile psoriasis patients depends to a large extent on a precise knowledge of the range of severity and burden imposed by the disease. PMID- 21317856 TI - A global approach to psoriatic patients through PASI score and Skindex-29. AB - AIM: Psoriasis is a chronic immune-mediated inflammatory skin disorder affecting approximately 2% of the population worldwide. Because of its visible manifestations and symptoms, psoriasis has profound effects on quality of life (QoL). Our objective is to determine the clinical severity of psoriasis and its impact on QoL in patients treated with phototherapy, traditional systemic therapy and biological therapy. METHODS: Patients with plaque-type psoriasis and psoriatic arthritis were recruited at a PsoCare centre and followed up for 6 months. Psoriasis severity was assessed based on the Psoriasis Area and Severity Index (PASI) score and QoL using the SKINDEX-29 questionnaire. RESULTS: PASI score improved significantly in all patients after 6 months of therapy. The greatest improvement was observed in patients receiving biological treatments. PASI-75 was obtained by 46.9% of patients on phototherapy and 43.1% on biological therapies. Skindex-29 results did not significantly differ among the three treatment groups. CONCLUSION: Effective management of patients with psoriasis depends on the appropriate assessment of both the physical and psychosocial impact of the disease. PMID- 21317857 TI - Contact hypersensitivity to epoxy resin, methyldibromoglutaronitrile, tixocortol pivalate and budesonide in Hungary: a study in 1448 patients. AB - AIM: In order to map the frequency of contact hypersensitivity (CH) to epoxy resin, methyldibromoglutaronitrile (MDBGN), tixocortol pivalate (TP) and budesonide patch tests were carried out. METHODS: The tests were performed in 1448 patients. Most patients belong to the allergic and irritative contact dermatitis groups. The tests were administered with the allergens epoxy resin 1%, MDBGN 0.3%, TP 1% and budesonide 0.1%, applied on the back. Reactions were evaluated at 40 min, on day 2 (D2), day 3 (D3) and day 4 (D4). In the patients of the Dept. of Dermatology, Venerology and Dermatooncology of Semmelweis University (patients number =1073) reactions were evaluated on day 7 as well. RESULTS: Epoxy resin elicited immediate reactions in 1 patient at 40 min. Further evaluations showed no difference on D3, D4 and D7 with a frequency of CH of 1.03%. Patch testing for MDBGN did not provoke immediate reactions, evaluations showed an increasing hypersensitivity rate (D2: 0.93%; D7:1.77%). Patch tests with TP yielded no immediate reactions, the frequency of CH increased from 0.47% (D2) to 2.01% (D7). No immediate reactions were observed by budesonide; an increase was seen in frequency of CH (D2:0.93% to D7:3.84%). CH to the studied allergens was observed mostly in allergic contact dermatitis group, to budesonide in irritative contact dermatitis and in atopic dermatitis groups as well. CONCLUSION: The data of the present study are the first results about this four allergens in Hungary and to our knowledge from our region as well. PMID- 21317858 TI - What's new in dermatology: epidermal stem cells. AB - The study of stem cells in the epidermis is a rapidly emerging field. Great advances have been made in both basic and clinical research. Advances in basic science include the ability to assay stem cells of the epidermis in vivo, new strong evidence for the existence of an independent interfollicular epidermal stem cell, and improved ability to analyze individual stem cell divisions. Advances in the clinic include recognition of the importance of stem cells for wound repair and for gene therapy and promising results have been obtained in a patient with junctional epidermolysis bullosa over a 12 month period of observation. This article discusses these recent advances in cutaneous stem cell biology. PMID- 21317859 TI - Vitiligo: current medical and scientific understanding. AB - Vitiligo is a relatively common acquired skin depigmentary disease with a complex presentation, therapy, and etiology. Both the prognosis and therapeutic response for patients with vitiligo is unpredictable. Multiple current therapies exist however the efficacy of these are not optimal. The cause of vitiligo appears to be a combination of genetic effects in both the immune system and the melanocyte itself with a precipitating factor instigating their interaction and resulting in the melanocyte destruction. Headway is being made in understanding the etiology of vitiligo that should culminate in new and improved therapies. PMID- 21317860 TI - A new dermatoscopic pattern "vortex" in a melanoma. PMID- 21317861 TI - Combination therapy in patients with metastatic renal cell carcinoma. PMID- 21317862 TI - Galiximab in relapsed hodgkin lymphoma. PMID- 21317863 TI - Update on treatment options for newly diagnosed ovarian cancer. PMID- 21317864 TI - HPV and its effect on head and neck cancer prognosis. PMID- 21317865 TI - New intravenous iron replacement therapies. PMID- 21317866 TI - Hepatosplenic gamma-delta T-cell lymphoma presenting with disseminated intravascular coagulation and coexistent systemic mastocytosis. PMID- 21317867 TI - Hepatosplenic gamma-delta T-cell lymphoma, disseminated intravascular coagulation, and systemic mastocytosis: an unusual presentation for a rare disease. PMID- 21317868 TI - A new anticoagulant for a new era: review of recent data on dabigatran etexilate. AB - Dabigatran etexilate is an oral direct thrombin inhibitor that could be administered in fixed doses and does not require laboratory monitoring. It is currently being evaluated through the RE-VOLUTION clinical trials program, which will involve more than 38,000 patients by the time it is completed. These clinical trials will evaluate the efficacy and safety of dabigatran etexilate for several indications. This article will review the clinical development of dabigatran, the published trial data, and the potential indications for this promising oral anticoagulant. PMID- 21317869 TI - Osteosarcoma: a review of diagnosis, management, and treatment strategies. AB - Despite significant advancements in the diagnosis and treatment of osteosarcoma to date, overall survival has remained relatively constant for over 2 decades. The challenge in osteosarcoma stems from the extreme variability from one tumor to the next, making it unlikely that a single target approach would be able to address all or even a majority of patients. Awareness, education, and proper referral patterns serve to minimize avoidable errors in diagnosis and treatment. However, it is unlikely that these efforts alone will significantly improve survival outcomes. Modern multi-agent chemotherapy has resulted in the greatest improvement in overall survival to date, and it is very likely that future improvements in survival will arise from combination-targeted chemotherapy in addition to conventional treatment. PMID- 21317870 TI - Factors determining DNA double-strand break repair pathway choice in G2 phase. AB - DNA non-homologous end joining (NHEJ) and homologous recombination (HR) function to repair DNA double-strand breaks (DSBs) in G2 phase with HR preferentially repairing heterochromatin-associated DSBs (HC-DSBs). Here, we examine the regulation of repair pathway usage at two-ended DSBs in G2. We identify the speed of DSB repair as a major component influencing repair pathway usage showing that DNA damage and chromatin complexity are factors influencing DSB repair rate and pathway choice. Loss of NHEJ proteins also slows DSB repair allowing increased resection. However, expression of an autophosphorylation-defective DNA-PKcs mutant, which binds DSBs but precludes the completion of NHEJ, dramatically reduces DSB end resection at all DSBs. In contrast, loss of HR does not impair repair by NHEJ although CtIP-dependent end resection precludes NHEJ usage. We propose that NHEJ initially attempts to repair DSBs and, if rapid rejoining does not ensue, then resection occurs promoting repair by HR. Finally, we identify novel roles for ATM in regulating DSB end resection; an indirect role in promoting KAP-1-dependent chromatin relaxation and a direct role in phosphorylating and activating CtIP. PMID- 21317871 TI - Dynamics and allosteric potential of the AMPA receptor N-terminal domain. AB - Glutamate-gated ion channels (ionotropic glutamate receptors, iGluRs) sense the extracellular milieu via an extensive extracellular portion, comprised of two clamshell-shaped segments. The distal, N-terminal domain (NTD) has allosteric potential in NMDA-type iGluRs, which has not been ascribed to the analogous domain in AMPA receptors (AMPARs). In this study, we present new structural data uncovering dynamic properties of the GluA2 and GluA3 AMPAR NTDs. GluA3 features a zipped-open dimer interface with unconstrained lower clamshell lobes, reminiscent of metabotropic GluRs (mGluRs). The resulting labile interface supports interprotomer rotations, which can be transmitted to downstream receptor segments. Normal mode analysis reveals two dominant mechanisms of AMPAR NTD motion: intraprotomer clamshell motions and interprotomer counter-rotations, as well as accessible interconversion between AMPAR and mGluR conformations. In addition, we detect electron density for a potential ligand in the GluA2 interlobe cleft, which may trigger lobe motions. Together, these data support a dynamic role for the AMPAR NTDs, which widens the allosteric landscape of the receptor and could provide a novel target for ligand development. PMID- 21317872 TI - Red1 promotes the elimination of meiosis-specific mRNAs in vegetatively growing fission yeast. AB - Meiosis-specific mRNAs are transcribed in vegetative fission yeast, and these meiotic mRNAs are selectively removed from mitotic cells to suppress meiosis. This RNA elimination system requires degradation signal sequences called determinant of selective removal (DSR), an RNA-binding protein Mmi1, polyadenylation factors, and the nuclear exosome. However, the detailed mechanism by which meiotic mRNAs are selectively degraded in mitosis but not meiosis is not understood fully. Here we report that Red1, a novel protein, is essential for elimination of meiotic mRNAs from mitotic cells. A red1 deletion results in the accumulation of a large number of meiotic mRNAs in mitotic cells. Red1 interacts with Mmi1, Pla1, the canonical poly(A) polymerase, and Rrp6, a subunit of the nuclear exosome, and promotes the destabilization of DSR-containing mRNAs. Moreover, Red1 forms nuclear bodies in mitotic cells, and these foci are disassembled during meiosis. These results demonstrate that Red1 is involved in DSR-directed RNA decay to prevent ectopic expression of meiotic mRNAs in vegetative cells. PMID- 21317873 TI - Subunit-selective N-terminal domain associations organize the formation of AMPA receptor heteromers. AB - The assembly of AMPA-type glutamate receptors (AMPARs) into distinct ion channel tetramers ultimately governs the nature of information transfer at excitatory synapses. How cells regulate the formation of diverse homo- and heteromeric AMPARs is unknown. Using a sensitive biophysical approach, we show that the extracellular, membrane-distal AMPAR N-terminal domains (NTDs) orchestrate selective routes of heteromeric assembly via a surprisingly wide spectrum of subunit-specific association affinities. Heteromerization is dominant, occurs at the level of the dimer, and results in a preferential incorporation of the functionally critical GluA2 subunit. Using a combination of structure-guided mutagenesis and electrophysiology, we further map evolutionarily variable hotspots in the NTD dimer interface, which modulate heteromerization capacity. This 'flexibility' of the NTD not only explains why heteromers predominate but also how GluA2-lacking, Ca(2+)-permeable homomers could form, which are induced under specific physiological and pathological conditions. Our findings reveal that distinct NTD properties set the stage for the biogenesis of functionally diverse pools of homo- and heteromeric AMPAR tetramers. PMID- 21317874 TI - Global dissociation of HuR-mRNA complexes promotes cell survival after ionizing radiation. AB - Ionizing radiation (IR) triggers adaptive changes in gene expression. Here, we show that survival after IR strongly depends on the checkpoint kinase Chk2 acting upon its substrate HuR, an RNA-binding protein that stabilizes and/or modulates the translation of target mRNAs. Microarray analysis showed that in human HCT116 colorectal carcinoma cells (WT), IR-activated Chk2 triggered the dissociation of virtually all of HuR-bound mRNAs, since IR did not dissociate HuR target mRNAs in Chk2-null (CHK2-/-) HCT116 cells. Accordingly, several HuR-interacting mRNAs encoding apoptosis- and proliferation-related proteins (TJP1, Mdm2, TP53BP2, Bax, K-Ras) dissociated from HuR in WT cells, but remained bound and showed altered post-transcriptional regulation in CHK2-/- cells. Use of HuR mutants that were not phosphorylatable by Chk2 (HuR(3A)) and HuR mutants mimicking constitutive phosphorylation by Chk2 (HuR(3D)) revealed that dissociation of HuR target transcripts enhanced cell survival. We propose that the release of HuR-bound mRNAs via an IR-Chk2-HuR regulatory axis improves cell outcome following IR. PMID- 21317877 TI - Dual-color silver-enhanced in situ hybridization for assessing HER2 gene amplification in breast cancer. AB - Amplification of the human epidermal growth factor receptor 2 (HER2) gene occurs in 20-25% of breast cancers, and is recognized as a prognostic and predictive marker. HER2 gene amplification, evaluated as a change in protein expression or gene copy number, can be identified by a number of methods. Fluorescence in situ hybridization (FISH) is considered the gold standard for HER2 gene copy number determination; however, a number of impediments prevent its wider use in a clinical setting. The aims of our study were to compare dual-color silver enhanced in situ hybridization (SISH) with single-color SISH and FISH on formalin fixed, paraffin-embedded sections, and to validate its use as a routine method for assessing HER2 status in breast cancers. A total of 146 invasive breast carcinoma cases were assessed for HER2 gene amplification by FISH and dual-color SISH. Dual-color SISH and FISH results exhibited a concordance rate of 97% (kappa=0.912). A comparison of the single-color SISH method with dual-color SISH showed that 142 of 146 cases were in agreement (97%, kappa=0.930). Our results showed that dual-color SISH is a viable alternative to FISH that offers a number of advantages in a clinical setting. PMID- 21317876 TI - IL-10 expression by primary tumor cells correlates with melanoma progression from radial to vertical growth phase and development of metastatic competence. AB - Downregulation of the immune system facilitates tumor progression at different stages of cutaneous melanoma. Sentinel nodes, the first lymph nodes on lymphatics draining directly from a primary melanoma, are immune downregulated by tumor generated immunosuppressive cytokines, including interleukin-10 (IL-10). To better understand the kinetics of sentinel node suppression, we investigated IL 10 expression by melanoma cells and tumor-associated macrophages and lymphocytes at different stages of primary melanoma evolution. We used reverse-transcriptase in situ PCR to identify the cellular sources of IL-10 mRNA in 39 melanomas. IL-10 mRNA was identified in tumor cells of 2 of 6 melanomas in situ (33%), of 17 of 21 invasive melanomas (81%) and of 11 of 12 metastatic melanomas (92%). Higher IL-10 expression correlates with tumor progression, with differences between melanoma in situ, invasive melanoma and metastatic melanoma. In primary melanomas, the IL 10 mRNA content of tumor cells correlates with Clark's level. There was significantly more IL-10 mRNA in vertical growth-phase melanoma cells than in radial growth-phase cells. In a logistic regression model, moderate-to-high IL-10 mRNA expression by tumor cells was significantly associated with vertical growth phase melanoma. IL-10 mRNA was detected in melanoma-associated macrophages and lymphocytes. In invasive melanomas, IL-10 mRNA reactivity of macrophages decreased as Clark's level increased. Alterations of immunity by IL-10 derived from melanoma cells and melanoma-associated macrophages and lymphocytes potentially facilitate evolution of the primary melanoma and render regional lymph nodes susceptible to metastases. PMID- 21317878 TI - D2-40/p63 defined lymph vessel invasion has additional prognostic value in highly proliferating operable node negative breast cancer patients. AB - Phosphohistone H3 assessed proliferation has strong prognostic value. Lymph vessel invasion by D2-40 is also prognostic, but D2-40+ myoepithelial expression in small ducts completely filled by solid-pattern ductal carcinoma in situ can mimic lymphovascular invasion. As myoepithelial cells are also p63 positive, we have investigated whether lymph vessel invasion identified by combined D2-40/p63 is stronger prognostically than by D2-40 alone, and whether it has independent prognostic value to phosphohistone H3. In 240 operable T(1-2)N(0)M(0) node negative invasive breast cancer patients <71 years, phosphohistone H3 was determined by quantitative immunohistochemistry and lymph vessel invasion by D2 40/p63 double immunostaining. Correlation analysis between the clinico-pathologic factors and lymph vessel invasion, and univariate and multivariate prognostic survival analysis were performed. With median 117 (range: 12-192) months follow up, 36 patients (15%) developed and 28 (12%) died of distant metastases. Ten of the 61 patients (16%) with cancer cells surrounded by D2-40 were p63 positive and none of these 'false lymph vessel invasion' recurred. D2-40+/p63- lymph vessel invasion occurred in 51/239 (21%) cases and correlated with grade, mitotic activity index, phosphohistone H3, ER, cytokeratin14, and HER2. D2-40+/p63- lymph vessel invasion was strongly prognostic, but far more in women >=55 than those <55 years (P<0.0001 and 0.04). With multivariate analysis, phosphohistone H3 proliferation was the strongest single prognosticator. Lymph vessel invasion had additional prognostic value to phosphohistone H3 only in women >=55. This group of patients, without/with lymph vessel invasion, had 10-year survival rates of 83 and 50%, respectively (hazard ratio-lymph vessel invasion=3.0, P=0.04; hazard ratio-phosphohistone H3=6.9, P=0.002). Where age was <55 years, only phosphohistone H3 had independent prognostic value. Combinations of other features had no additional value. In conclusion, T(1-2)N(0)M(0) invasive breast cancer patients >=55 years with phosphohistone H3>=13, D2-40+/p63- defined lymph vessel invasion identifies a subgroup with a high risk of distant metastases. PMID- 21317875 TI - Structure of the Ire1 autophosphorylation complex and implications for the unfolded protein response. AB - Ire1 (Ern1) is an unusual transmembrane protein kinase essential for the endoplasmic reticulum (ER) unfolded protein response (UPR). Activation of Ire1 by association of its N-terminal ER luminal domains promotes autophosphorylation by its cytoplasmic kinase domain, leading to activation of the C-terminal ribonuclease domain, which splices Xbp1 mRNA generating an active Xbp1s transcriptional activator. We have determined the crystal structure of the cytoplasmic portion of dephosphorylated human Ire1alpha bound to ADP, revealing the 'phosphoryl-transfer' competent dimeric face-to-face complex, which precedes and is distinct from the back-to-back RNase 'active' conformation described for yeast Ire1. We show that the Xbp1-specific ribonuclease activity depends on autophosphorylation, and that ATP-competitive inhibitors staurosporin and sunitinib, which inhibit autophosphorylation in vitro, also inhibit Xbp1 splicing in vivo. Furthermore, we demonstrate that activated Ire1alpha is a competent protein kinase, able to phosphorylate a heterologous peptide substrate. These studies identify human Ire1alpha as a target for development of ATP-competitive inhibitors that will modulate the UPR in human cells, which has particular relevance for myeloma and other secretory malignancies. PMID- 21317879 TI - Epigenetic inactivation of calcium-sensing receptor in colorectal carcinogenesis. AB - Ca2+ is a chemopreventive agent for colon cancer. Ion transport systems are often altered in human cancer. The aim of this study was to clarify the alterations of calcium-sensing receptor (CASR), a member of the G protein-coupled receptor family, in colorectal carcinogenesis. We analyzed the expression of CASR in colorectal cancer cell lines and in cancer and adenoma tissues by RT-PCR and immunostaining. In addition, we analyzed methylation of the CASR promoter by using bisulfite sequence analysis and methylation-specific PCR. CASR mRNA and protein expression was significantly downregulated in most of the cancer cell lines. CpG islands were densely methylated in cancer cell lines with reduced CASR mRNA expression. Treatment with a demethylating agent, 5-aza-2'-deoxycytidine, and/or a histone deacetylase inhibitor, trichostatin A, restored CASR expression in the cancer cell lines. Disruption of CASR expression in CASR-unmethylated HCT 8 cells blocked the enhancing effect of Ca2+ on the cytotoxic response to 5 fluorouracil. CASR expression was observed in normal colonic epithelial cells and was retained in most adenoma tissues. CASR mRNA and protein expression was significantly downregulated in cancer tissues. There was an inverse relationship between CASR expression and degree of differentiation. Immunohistochemical CASR staining was reduced more predominantly in less-differentiated cancer tissues and/or in cancer cells at the invasive front, where nuclear/cytoplasmic beta catenin was often localized. CASR methylation was detected in 69% of colorectal cancer tissues and 90% of lymph node metastatic tissues and was significantly correlated with reduced CASR expression. CASR methylation was also detected in 32% of advanced adenoma tissues but was detected in only 9% of adenoma tissues and was not detected in hyperplastic polyp tissues. CASR methylation seems to occur at an early stage and progress in colorectal carcinogenesis. The results suggest that epigenetic inactivation of CASR has an important role in colorectal carcinogenesis. PMID- 21317880 TI - Gene expression analysis identifies two groups of ovarian high-grade serous carcinomas with different prognosis. AB - Gene expression profiling is an important tool to evaluate genetic heterogeneity in carcinomas and is useful to develop expression-based classifications for many types of cancer, as well as markers of disease outcome. In this study, we have investigated the expression profile of 22 genes involved in the PI3K-AKT pathway in 26 high-grade ovarian carcinomas (19 serous and 7 clear cell carcinomas). Unsupervised hierarchical clustering divided high-grade ovarian carcinomas into three groups. Although all clear cell carcinomas clustered in one group, high grade serous carcinomas were segregated into two separate groups with different prognosis (P=0.05). High expression of CASP3, XIAP (X-linked inhibitor of apoptosis) , NFKB1, FAS, and GSK3B mRNAs identified high-grade serous carcinomas with better prognosis. In multivariate analysis, these cluster groups were of prognostic significance independent of age, tumor size, and tumor stage (P=0.008). To validate the mRNA expression data, we studied the immunohistochemical expression of caspase-3 and XIAP on a tissue microarray. Immunoreaction for caspase-3 was concordant with the results obtained by mRNA expression analysis (Spearman r=0.762, P=0.000). Caspase-3 was exclusively expressed by the macrophages. Furthermore, co-expression of caspase-3 and XIAP identified high-grade serous carcinomas with different prognosis (P=0.03). Our results suggest that there are different biological subtypes of high-grade serous carcinomas. PMID- 21317881 TI - PAX 8 expression in non-neoplastic tissues, primary tumors, and metastatic tumors: a comprehensive immunohistochemical study. AB - PAX 8 is a transcription factor that is essential for embryonic development of the kidney, Mullerian organs, and thyroid. It may also have a role in tumor development in these organs. The diagnostic utility of PAX 8 has not been comprehensively studied. Formalin-fixed, paraffin-embedded tissue samples for non neoplastic tissues (n=1601), primary neoplasms (n=933), and metastatic neoplasms (n=496) were subjected to PAX 8 immunostain. In non-neoplastic tissues, PAX 8 was consistently noted in glomerular parietal epithelial cells, renal collecting ductal cells, atrophic renal tubular epithelial cells regardless of nephronic segments, and epithelial cells of the endocervix, endometrium, fallopian tube, seminal vesicle, epidydimis, thyroid, pancreatic islet cells, and lymphoid cells. PAX 8 was not seen in the rest of the tissue samples. In primary neoplasms, PAX 8 was expressed by 194 of 240 (89%) renal cell neoplasms, by 238 of 267 (89%) Mullerian-type neoplasms, by 65 of 65 (100%) thyroid follicular cell neoplasms, by 8 of 8 (100%) nephrogenic adenomas, and by 17 of 17 (100%) lymphomas. Weak focal staining was noted in 5 of 12 (42%) cases of parathyroid hyperplasia/adenoma and in 6 of 17 (35%) well-differentiated neuroendocrine tumors of the pancreas. PAX 8 was not seen in other neoplasms. In metastatic neoplasms, PAX 8 was expressed by 90 of 102 (88%) metastatic renal cell carcinomas, by 57 of 63 metastatic Mullerian tumors (90%), and by 6 of 6 metastatic papillary thyroid carcinomas (100%). There was also weak focal staining for 1 of 15 metastatic small cell carcinomas and for 1 of 9 metastatic well-differentiated neuroendocrine carcinomas. PAX 8 was not seen in other metastatic neoplasms. It can be successfully identified in routinely processed tissue samples, and its expression is mostly nuclear. PAX 8 expression in non neoplastic mature tissues is limited to the organs, the embryonic development of which depends on this transcription factor. This tissue/cell-specific expression is maintained during both neoplastic transformation and metastasis. PAX 8 is a sensitive and specific marker for tumors of renal, Mullerian, or thyroid origin in both primary and metastatic sites. PMID- 21317882 TI - Crystal structure of a potassium ion transporter, TrkH. AB - The TrkH/TrkG/KtrB proteins mediate K(+) uptake in bacteria and probably evolved from simple K(+) channels by multiple gene duplications or fusions. Here we present the crystal structure of a TrkH from Vibrio parahaemolyticus. TrkH is a homodimer, and each protomer contains an ion permeation pathway. A selectivity filter, similar in architecture to those of K(+) channels but significantly shorter, is lined by backbone and side-chain oxygen atoms. Functional studies showed that TrkH is selective for permeation of K(+) and Rb(+) over smaller ions such as Na(+) or Li(+). Immediately intracellular to the selectivity filter are an intramembrane loop and an arginine residue, both highly conserved, which constrict the permeation pathway. Substituting the arginine with an alanine significantly increases the rate of K(+) flux. These results reveal the molecular basis of K(+) selectivity and suggest a novel gating mechanism for this large and important family of membrane transport proteins. PMID- 21317883 TI - 53BP1 nuclear bodies form around DNA lesions generated by mitotic transmission of chromosomes under replication stress. AB - Completion of genome duplication is challenged by structural and topological barriers that impede progression of replication forks. Although this can seriously undermine genome integrity, the fate of DNA with unresolved replication intermediates is not known. Here, we show that mild replication stress increases the frequency of chromosomal lesions that are transmitted to daughter cells. Throughout G1, these lesions are sequestered in nuclear compartments marked by p53-binding protein 1 (53BP1) and other chromatin-associated genome caretakers. We show that the number of such 53BP1 nuclear bodies increases after genetic ablation of BLM, a DNA helicase associated with dissolution of entangled DNA. Conversely, 53BP1 nuclear bodies are partially suppressed by knocking down SMC2, a condensin subunit required for mechanical stability of mitotic chromosomes. Finally, we provide evidence that 53BP1 nuclear bodies shield chromosomal fragile sites sequestered in these compartments against erosion. Together, these data indicate that restoration of DNA or chromatin integrity at loci prone to replication problems requires mitotic transmission to the next cell generations. PMID- 21317884 TI - The Machado-Joseph disease deubiquitylase ATX-3 couples longevity and proteostasis. AB - Protein ubiquitylation is a key post-translational control mechanism contributing to different physiological processes, such as signal transduction and ageing. The size and linkage of a ubiquitin chain, which determines whether a substrate is efficiently targeted for proteasomal degradation, is determined by the interplay between ubiquitylation and deubiquitylation. A conserved factor that orchestrates distinct substrate-processing co-regulators in diverse species is the ubiquitin selective chaperone CDC-48 (also known as p97). Several deubiquitylation enzymes (DUBs) have been shown to interact with CDC-48/p97, but the mechanistic and physiological relevance of these interactions remained elusive. Here we report a synergistic cooperation between CDC-48 and ATX-3 (the Caenorhabditis elegans orthologue of ataxin-3) in ubiquitin-mediated proteolysis and ageing regulation. Surprisingly, worms deficient for both cdc-48.1 and atx-3 demonstrated extended lifespan by up to 50%, mediated through the insulin-insulin-like growth factor 1 (IGF-1) signalling pathway. As lifespan extension specifically depends on the deubiquitylation activity of ATX-3, our findings identify a mechanistic link between protein degradation and longevity through editing of the ubiquitylation status of substrates involved in insulin-IGF-1 signalling. PMID- 21317885 TI - UBE4B promotes Hdm2-mediated degradation of the tumor suppressor p53. AB - The TP53 gene (encoding the p53 tumor suppressor) is rarely mutated, although frequently inactivated, in medulloblastoma and ependymoma. Recent work in mouse models showed that the loss of p53 accelerated the development of medulloblastoma. The mechanism underlying p53 inactivation in human brain tumors is not completely understood. We show that ubiquitination factor E4B (UBE4B), an E3 and E4 ubiquitin ligase, physically interacts with p53 and Hdm2 (also known as Mdm2 in mice). UBE4B promotes p53 polyubiquitination and degradation and inhibits p53-dependent transactivation and apoptosis. Notably, silencing UBE4B expression impairs xenotransplanted tumor growth in a p53-dependent manner and overexpression of UBE4B correlates with decreased expression of p53 in these tumors. We also show that UBE4B overexpression is often associated with amplification of its gene in human brain tumors. Our data indicate that amplification and overexpression of UBE4B represent previously undescribed molecular mechanisms of inactivation of p53 in brain tumors. PMID- 21317886 TI - Regulation of glucose homeostasis through a XBP-1-FoxO1 interaction. AB - To date, the only known role of the spliced form of X-box-binding protein-1 (XBP 1s) in metabolic processes has been its ability to act as a transcription factor that regulates the expression of genes that increase the endoplasmic reticulum (ER) folding capacity, thereby improving insulin sensitivity. Here we show that XBP-1s interacts with the Forkhead box O1 (FoxO1) transcription factor and directs it toward proteasome-mediated degradation. Given this new insight, we tested modest hepatic overexpression of XBP-1s in vivo in mouse models of insulin deficiency or insulin resistance and found it improved serum glucose concentrations, even without improving insulin signaling or ER folding capacity. The notion that XBP-1s can act independently of its role in the ER stress response is further supported by our finding that in the severely insulin resistant ob/ob mouse strain a DNA-binding-defective mutant of XBP-1s, which does not have the ability to increase ER folding capacity, is still capable of reducing serum glucose concentrations and increasing glucose tolerance. Our results thus provide the first evidence to our knowledge that XBP-1s, through its interaction with FoxO1, can bypass hepatic insulin resistance independent of its effects on ER folding capacity, suggesting a new therapeutic approach for the treatment of type 2 diabetes. PMID- 21317887 TI - The stress kinase MKK7 couples oncogenic stress to p53 stability and tumor suppression. AB - Most preneoplastic lesions are quiescent and do not progress to form overt tumors. It has been proposed that oncogenic stress activates the DNA damage response and the key tumor suppressor p53, which prohibits tumor growth. However, the molecular pathways by which cells sense a premalignant state in vivo are largely unknown. Here we report that tissue-specific inactivation of the stress signaling kinase MKK7 in KRas(G12D)-driven lung carcinomas and NeuT-driven mammary tumors markedly accelerates tumor onset and reduces overall survival. Mechanistically, MKK7 acts through the kinases JNK1 and JNK2, and this signaling pathway directly couples oncogenic and genotoxic stress to the stability of p53, which is required for cell cycle arrest and suppression of epithelial cancers. These results show that MKK7 functions as a major tumor suppressor in lung and mammary cancer in mouse and identify MKK7 as a vital molecular sensor to set a cellular anti-cancer barrier. PMID- 21317888 TI - SUMOylation promotes de novo targeting of HP1alpha to pericentric heterochromatin. AB - HP1 enrichment at pericentric heterochromatin is considered important for centromere function. Although HP1 binding to H3K9me3 can explain its accumulation at pericentric heterochromatin, how it is initially targeted there remains unclear. Here, in mouse cells, we reveal the presence of long nuclear noncoding transcripts corresponding to major satellite repeats at the periphery of pericentric heterochromatin. Furthermore, we find that major transcripts in the forward orientation specifically associate with SUMO-modified HP1 proteins. We identified this modification as SUMO-1 and mapped it in the hinge domain of HP1alpha. Notably, the hinge domain and its SUMOylation proved critical to promote the initial targeting of HP1alpha to pericentric domains using de novo localization assays, whereas they are dispensable for maintenance of HP1 domains. We propose that SUMO-HP1, through a specific association with major forward transcript, is guided at the pericentric heterochromatin domain to seed further HP1 localization. PMID- 21317889 TI - Discovery and genotyping of genome structural polymorphism by sequencing on a population scale. AB - Accurate and complete analysis of genome variation in large populations will be required to understand the role of genome variation in complex disease. We present an analytical framework for characterizing genome deletion polymorphism in populations using sequence data that are distributed across hundreds or thousands of genomes. Our approach uses population-level concepts to reinterpret the technical features of sequence data that often reflect structural variation. In the 1000 Genomes Project pilot, this approach identified deletion polymorphism across 168 genomes (sequenced at 4 * average coverage) with sensitivity and specificity unmatched by other algorithms. We also describe a way to determine the allelic state or genotype of each deletion polymorphism in each genome; the 1000 Genomes Project used this approach to type 13,826 deletion polymorphisms (48 995,664 bp) at high accuracy in populations. These methods offer a way to relate genome structural polymorphism to complex disease in populations. PMID- 21317890 TI - Gate-controlled guiding of electrons in graphene. AB - Ballistic semiconductor structures have allowed the realization of optics-like phenomena in electronic systems, including the magnetic focusing and electrostatic lensing of electrons. An extension that appears unique to graphene is to use both n and p carrier types to create electronic analogues of optical devices with both positive and negative indices of refraction. Here, we use the gate-controlled density of both p and n carrier types in graphene to demonstrate the electronic analogue of fibre-optic guiding. Two basic effects are investigated: bipolar p-n junction guiding, based on the principle of angle selective transmission through the interface between the graphene and the p-n junction; and unipolar fibre-optic guiding, using total internal reflection controlled by carrier density. We also demonstrate modulation of the guiding efficiency through gating, and comparison of these data with numerical simulations indicates that guiding performance is limited by the roughness of the interface. The development of p-n and fibre-optic guiding in graphene may lead to electrically reconfigurable wiring in high-mobility devices. PMID- 21317891 TI - Manipulating surface states in topological insulator nanoribbons. AB - Topological insulators display unique properties, such as the quantum spin Hall effect, because time-reversal symmetry allows charges and spins to propagate along the edge or surface of the topological insulator without scattering. However, the direct manipulation of these edge/surface states is difficult because they are significantly outnumbered by bulk carriers. Here, we report experimental evidence for the modulation of these surface states by using a gate voltage to control quantum oscillations in Bi(2)Te(3) nanoribbons. Surface conduction can be significantly enhanced by the gate voltage, with the mobility and Fermi velocity reaching values as high as ~5,800 cm(2) V(-1) s(-1) and ~3.7 * 10(5) m s(-1), respectively, with up to ~51% of the total conductance being due to the surface states. We also report the first observation of h/2e periodic oscillations, suggesting the presence of time-reversed paths with the same relative zero phase at the interference point. The high surface conduction and ability to manipulate the surface states demonstrated here could lead to new applications in nanoelectronics and spintronics. PMID- 21317892 TI - Using nano-QSAR to predict the cytotoxicity of metal oxide nanoparticles. AB - It is expected that the number and variety of engineered nanoparticles will increase rapidly over the next few years, and there is a need for new methods to quickly test the potential toxicity of these materials. Because experimental evaluation of the safety of chemicals is expensive and time-consuming, computational methods have been found to be efficient alternatives for predicting the potential toxicity and environmental impact of new nanomaterials before mass production. Here, we show that the quantitative structure-activity relationship (QSAR) method commonly used to predict the physicochemical properties of chemical compounds can be applied to predict the toxicity of various metal oxides. Based on experimental testing, we have developed a model to describe the cytotoxicity of 17 different types of metal oxide nanoparticles to bacteria Escherichia coli. The model reliably predicts the toxicity of all considered compounds, and the methodology is expected to provide guidance for the future design of safe nanomaterials. PMID- 21317893 TI - Defining an allosteric circuit in the cysteine protease domain of Clostridium difficile toxins. AB - An internal cysteine protease domain (CPD) autoproteolytically regulates Clostridium difficile glucosylating toxins by releasing a cytotoxic effector domain into target cells. CPD activity is itself allosterically regulated by the eukaryote-specific molecule inositol hexakisphosphate (InsP(6)). Although allostery controls the function of most proteins, the molecular details underlying this regulatory mechanism are often difficult to characterize. Here we use chemical probes to show that apo-CPD is in dynamic equilibrium between active and inactive states. InsP(6) markedly shifts this equilibrium toward an active conformer that is further restrained upon binding a suicide substrate. Structural analyses combined with systematic mutational and disulfide bond engineering studies show that residues within a beta-hairpin region functionally couple the InsP(6)-binding site to the active site. Collectively, our results identify an allosteric circuit that allows bacterial virulence factors to sense and respond to the eukaryotic environment. PMID- 21317894 TI - Structural basis for engagement by complement factor H of C3b on a self surface. AB - Complement factor H (FH) attenuates C3b molecules tethered by their thioester domains to self surfaces and thereby protects host tissues. Factor H is a cofactor for initial C3b proteolysis that ultimately yields a surface-attached fragment (C3d) corresponding to the thioester domain. We used NMR and X-ray crystallography to study the C3d-FH19-20 complex in atomic detail and identify glycosaminoglycan-binding residues in factor H module 20 of the C3d-FH19-20 complex. Mutagenesis justified the merging of the C3d-FH19-20 structure with an existing C3b-FH1-4 crystal structure. We concatenated the merged structure with the available FH6-8 crystal structure and new SAXS-derived FH1-4, FH8-15 and FH15 19 envelopes. The combined data are consistent with a bent-back factor H molecule that binds through its termini to two sites on one C3b molecule and simultaneously to adjacent polyanionic host-surface markers. PMID- 21317895 TI - The hidden energetics of ligand binding and activation in a glutamate receptor. AB - Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate most excitatory synaptic transmission in the central nervous system. The free energy of neurotransmitter binding to the ligand-binding domains (LBDs) of iGluRs is converted into useful work to drive receptor activation. We have computed the principal thermodynamic contributions from ligand docking and ligand induced closure of LBDs for nine ligands of GluA2 using all-atom molecular dynamics free energy simulations. We have validated the results by comparison with experimentally measured apparent affinities to the isolated LBD. Features in the free energy landscapes that govern closure of LBDs are key determinants of binding free energies. An analysis of accessible LBD conformations transposed into the context of an intact GluA2 receptor revealed that the relative displacement of specific diagonal subunits in the tetrameric structure may be key to the action of partial agonists. PMID- 21317896 TI - The glmS riboswitch integrates signals from activating and inhibitory metabolites in vivo. AB - The glmS riboswitch belongs to the family of regulatory RNAs that provide feedback regulation of metabolic genes. It is also a ribozyme that self-cleaves upon binding glucosamine-6-phosphate, the product of the enzyme encoded by glmS. The ligand concentration dependence of intracellular self-cleavage kinetics was measured for the first time in a yeast model system and unexpectedly revealed that this riboswitch is subject to inhibition as well as activation by hexose metabolites. Reporter gene experiments in Bacillus subtilis confirmed that this riboswitch integrates positive and negative chemical signals in its natural biological context. Contrary to the conventional view that a riboswitch responds to just a single cognate metabolite, our new model proposes that a single riboswitch integrates information from an array of chemical signals to modulate gene expression based on the overall metabolic state of the cell. PMID- 21317897 TI - Critical nucleus size for disease-related polyglutamine aggregation is repeat length dependent. AB - Because polyglutamine (polyQ) aggregate formation has been implicated as playing an important role in expanded CAG repeat diseases, it is important to understand the biophysics underlying the initiation of aggregation. Previously, we showed that relatively long polyQ peptides aggregate by nucleated growth polymerization and a monomeric critical nucleus. We show here that over a short range of repeat lengths, from Q(23) to Q(26), the size of the critical nucleus for aggregation increases from monomeric to dimeric to tetrameric. This variation in nucleus size suggests a common duplex antiparallel beta-sheet framework for the nucleus, and it further supports the feasibility of an organized monomeric aggregation nucleus for longer polyQ repeat peptides. The data also suggest that a change in the size of aggregation nuclei may have a role in the pathogenicity of polyQ expansion in this series of familial neurodegenerative diseases. PMID- 21317898 TI - Genetic selection designed to stabilize proteins uncovers a chaperone called Spy. AB - To optimize the in vivo folding of proteins, we linked protein stability to antibiotic resistance, thereby forcing bacteria to effectively fold and stabilize proteins. When we challenged Escherichia coli to stabilize a very unstable periplasmic protein, it massively overproduced a periplasmic protein called Spy, which increases the steady-state levels of a set of unstable protein mutants up to 700-fold. In vitro studies demonstrate that the Spy protein is an effective ATP-independent chaperone that suppresses protein aggregation and aids protein refolding. Our strategy opens up new routes for chaperone discovery and the custom tailoring of the in vivo folding environment. Spy forms thin, apparently flexible cradle-shaped dimers. The structure of Spy is unlike that of any previously solved chaperone, making it the prototypical member of a new class of small chaperones that facilitate protein refolding in the absence of energy cofactors. PMID- 21317899 TI - Direct imaging of hydrogen-atom columns in a crystal by annular bright-field electron microscopy. AB - Enhancing the imaging power of microscopy to identify all chemical types of atom, from low- to high-atomic-number elements,would significantly contribute for a direct determination of material structures. Electron microscopes have successfully provided images of heavy-atom positions, particularly by the annular dark-field method, but detection of light atoms was difficult owing to their weak scattering power. Recent developments of aberration-correction electron optics have significantly advanced the microscope performance, enabling identification of individual light atoms such as oxygen, nitrogen, carbon, boron and lithium. However, the lightest hydrogen atom has not yet been observed directly, except in the specific condition of hydrogen adatoms on a graphene membrane. Here we show the first direct imaging of the hydrogen atom in a crystalline solid YH(2), based on a classic 'hollow-cone' illumination theory combined with state-of-the-art scanning transmission electronmicroscopy. The optimized hollow-cone condition derived from the aberration-corrected microscope parameters confirms that the information transfer can be extended to 22.5 nm(-1), which corresponds to a spatial resolution of about 44.4 pm. These experimental conditions can be readily realized with the annular bright-field imaging in scanning transmission electron microscopy according to reciprocity, revealing successfully the hydrogen-atom columns as dark dots, as anticipated from phase contrast of a weak-phase object. PMID- 21317900 TI - Scanning tunnelling microscopy and spectroscopy of ultra-flat graphene on hexagonal boron nitride. AB - Graphene has demonstrated great promise for future electronics technology as well as fundamental physics applications because of its linear energy-momentum dispersion relations which cross at the Dirac point. However, accessing the physics of the low-density region at the Dirac point has been difficult because of disorder that leaves the graphene with local microscopic electron and hole puddles. Efforts have been made to reduce the disorder by suspending graphene, leading to fabrication challenges and delicate devices which make local spectroscopic measurements difficult. Recently, it has been shown that placing graphene on hexagonal boron nitride (hBN) yields improved device performance. Here we use scanning tunnelling microscopy to show that graphene conforms to hBN, as evidenced by the presence of Moire patterns. However, contrary to predictions, this conformation does not lead to a sizeable band gap because of the misalignment of the lattices. Moreover, local spectroscopy measurements demonstrate that the electron-hole charge fluctuations are reduced by two orders of magnitude as compared with those on silicon oxide. This leads to charge fluctuations that are as small as in suspended graphene, opening up Dirac point physics to more diverse experiments. PMID- 21317901 TI - Mesophase behaviour of polyhedral particles. AB - Translational and orientational excluded-volume fields encoded in particles with anisotropic shapes can lead to purely entropy-driven assembly of morphologies with specific order and symmetry. To elucidate this complex correlation, we carried out detailed Monte Carlo simulations of six convex space-filling polyhedrons, namely, truncated octahedrons, rhombic dodecahedrons, hexagonal prisms, cubes, gyrobifastigiums and triangular prisms. Simulations predict the formation of various new liquid-crystalline and plastic-crystalline phases at intermediate volume fractions. By correlating these findings with particle anisotropy and rotational symmetry, simple guidelines for predicting phase behaviour of polyhedral particles are proposed: high rotational symmetry is in general conducive to mesophase formation, with low anisotropy favouring plastic solid behaviour and intermediate anisotropy (or high uniaxial anisotropy) favouring liquid-crystalline behaviour. It is also found that dynamical disorder is crucial in defining mesophase behaviour, and that the apparent kinetic barrier for the liquid-mesophase transition is much lower for liquid crystals (orientational order) than for plastic solids (translational order). PMID- 21317902 TI - Efficiency enhancement in organic solar cells with ferroelectric polymers. AB - The recombination of electrons and holes in semiconducting polymer-fullerene blends has been identified as a main cause of energy loss in organic photovoltaic devices. Generally, an external bias voltage is required to efficiently separate the electrons and holes and thus prevent their recombination. Here we show that a large, permanent, internal electric field can be ensured by incorporating a ferroelectric polymer layer into the device, which eliminates the need for an external bias. The electric field, of the order of 50 V MUm(-1), potentially induced by the ferroelectric layer is tens of times larger than that achievable by the use of electrodes with different work functions. We show that ferroelectric polymer layers enhanced the efficiency of several types of organic photovoltaic device from 1-2% without layers to 4-5% with layers. These enhanced efficiencies are 10-20% higher than those achieved by other methods, such as morphology and electrode work-function optimization. The devices show the unique characteristics of ferroelectric photovoltaic devices with switchable diode polarity and tunable efficiency. PMID- 21317903 TI - The lithium intercalation process in the low-voltage lithium battery anode Li(1+x)V(1-x)O2. AB - Lithium can be reversibly intercalated into layered Li(1+x)V(1-x)O(2) (LiCoO(2) structure) at ~0.1 V, but only if x>0. The low voltage combined with a higher density than graphite results in a higher theoretical volumetric energy density; important for future applications in portable electronics and electric vehicles. Here we investigate the crucial question, why Li cannot intercalate into LiVO(2) but Li-rich compositions switch on intercalation at an unprecedented low voltage for an oxide? We show that Li(+) intercalated into tetrahedral sites are energetically more stable for Li-rich compositions, as they share a face with Li(+) on the V site in the transition metal layers. Li incorporation triggers shearing of the oxide layers from cubic to hexagonal packing because the Li(2)VO(2) structure can accommodate two Li per formula unit in tetrahedral sites without face sharing. Such understanding is important for the future design and optimization of low-voltage intercalation anodes for lithium batteries. PMID- 21317904 TI - Structural basis for RNA trimming by RNase T in stable RNA 3'-end maturation. AB - RNA maturation relies on various exonucleases to remove nucleotides successively from the 5' or 3' end of nucleic acids. However, little is known regarding the molecular basis for substrate and cleavage preference of exonucleases. Our biochemical and structural analyses on RNase T-DNA complexes show that the RNase T dimer has an ideal architecture for binding a duplex with a short 3' overhang to produce a digestion product of a duplex with a 2-nucleotide (nt) or 1-nt 3' overhang, depending on the composition of the last base pair in the duplex. A 'C filter' in RNase T screens out the nucleic acids with 3'-terminal cytosines for hydrolysis by inducing a disruptive conformational change at the active site. Our results reveal the general principles and the working mechanism for the final trimming step made by RNase T in the maturation of stable RNA and pave the way for the understanding of other DEDD family exonucleases. PMID- 21317905 TI - Golden Goal collaborates with Flamingo in conferring synaptic-layer specificity in the visual system. AB - Neuronal connections are often organized in layers that contain synapses between neurons that have similar functions. In Drosophila, R7 and R8 photoreceptors, which detect different wavelengths, form synapses in distinct medulla layers. The mechanisms underlying the specificity of synaptic-layer selection remain unclear. We found that Golden Goal (Gogo) and Flamingo (Fmi), two cell-surface proteins involved in photoreceptor targeting, functionally interact in R8 photoreceptor axons. Our results indicate that Gogo promotes R8 photoreceptor axon adhesion to the temporary layer M1, whereas Gogo and Fmi collaborate to mediate axon targeting to the final layer M3. Structure-function analysis suggested that Gogo and Fmi interact with intracellular components through the Gogo cytoplasmic domain. Moreover, Fmi was also required in target cells for R8 photoreceptor axon targeting. We propose that Gogo acts as a functional partner of Fmi for R8 photoreceptor axon targeting and that the dynamic regulation of their interaction specifies synaptic-layer selection of photoreceptors. PMID- 21317906 TI - A reservoir of time constants for memory traces in cortical neurons. AB - According to reinforcement learning theory of decision making, reward expectation is computed by integrating past rewards with a fixed timescale. In contrast, we found that a wide range of time constants is available across cortical neurons recorded from monkeys performing a competitive game task. By recognizing that reward modulates neural activity multiplicatively, we found that one or two time constants of reward memory can be extracted for each neuron in prefrontal, cingulate and parietal cortex. These timescales ranged from hundreds of milliseconds to tens of seconds, according to a power law distribution, which is consistent across areas and reproduced by a 'reservoir' neural network model. These neuronal memory timescales were weakly, but significantly, correlated with those of monkey's decisions. Our findings suggest a flexible memory system in which neural subpopulations with distinct sets of long or short memory timescales may be selectively deployed according to the task demands. PMID- 21317907 TI - Implantable magnetic relaxation sensors measure cumulative exposure to cardiac biomarkers. AB - Molecular biomarkers can be used as objective indicators of pathologic processes. Although their levels often change over time, their measurement is often constrained to a single time point. Cumulative biomarker exposure would provide a fundamentally different kind of measurement to what is available in the clinic. Magnetic resonance relaxometry can be used to noninvasively monitor changes in the relaxation properties of antibody-coated magnetic particles when they aggregate upon exposure to a biomarker of interest. We used implantable devices containing such sensors to continuously profile changes in three clinically relevant cardiac biomarkers at physiological levels for up to 72 h. Sensor response differed between experimental and control groups in a mouse model of myocardial infarction and correlated with infarct size. Our prototype for a biomarker monitoring device also detected doxorubicin-induced cardiotoxicity and can be adapted to detect other molecular biomarkers with a sensitivity as low as the pg/ml range. PMID- 21317908 TI - A microprobe for parallel optical and electrical recordings from single neurons in vivo. AB - Recording electrical activity from identified neurons in intact tissue is key to understanding their role in information processing. Recent fluorescence labeling techniques have opened new possibilities to combine electrophysiological recording with optical detection of individual neurons deep in brain tissue. For this purpose we developed dual-core fiberoptics-based microprobes, with an optical core to locally excite and collect fluorescence, and an electrolyte filled hollow core for extracellular single unit electrophysiology. This design provides microprobes with tips < 10 MUm, enabling analyses with single-cell optical resolution. We demonstrate combined electrical and optical detection of single fluorescent neurons in rats and mice. We combined electrical recordings and optical Ca2(+) measurements from single thalamic relay neurons in rats, and achieved detection and activation of single channelrhodopsin-expressing neurons in Thy1::ChR2-YFP transgenic mice. The microprobe expands possibilities for in vivo electrophysiological recording, providing parallel access to single-cell optical monitoring and control. PMID- 21317909 TI - Confined activation and subdiffractive localization enables whole-cell PALM with genetically expressed probes. AB - We demonstrate three-dimensional (3D) super-resolution microscopy in whole fixed cells using photoactivated localization microscopy (PALM). The use of the bright, genetically expressed fluorescent marker photoactivatable monomeric (m)Cherry (PA mCherry1) in combination with near diffraction-limited confinement of photoactivation using two-photon illumination and 3D localization methods allowed us to investigate a variety of cellular structures at <50 nm lateral and <100 nm axial resolution. Compared to existing methods, we have substantially reduced excitation and bleaching of unlocalized markers, which allows us to use 3D PALM imaging with high localization density in thick structures. Our 3D localization algorithms, which are based on cross-correlation, do not rely on idealized noise models or specific optical configurations. This allows instrument design to be flexible. By generating appropriate fusion constructs and expressing them in Cos7 cells, we could image invaginations of the nuclear membrane, vimentin fibrils, the mitochondrial network and the endoplasmic reticulum at depths of greater than 8 MUm. PMID- 21317911 TI - p73 is critical for the persistence of memory. PMID- 21317912 TI - Does ethnicity matter in male hormonal contraceptive efficacy? AB - The development of male hormonal contraception has progressed significantly during the last three decades. The ultimate goal is to produce an effective, safe and reversible male method of contraception that are within reach of and can be used by all men globally. This review aims to outline the recent developments in male hormonal contraception with special emphasis on how ethnicity influences acceptability, extent of sperm suppression, and rate of recovery of spermatogenesis. Baseline differences in testicular histomorphology and testosterone metabolism between East Asian and Caucasian men have been reported, but whether this contributes significantly to varying degrees of sperm suppression in response to exogenous testosterone therapy is less known. Testosterone alone male hormonal contraceptive regimens are effective and applicable for East Asian men, and less so for Caucasians. Combinations of progestins with androgens are sufficient to optimize effectiveness of suppression and applicability to all ethnicities. New compounds such as steroidal or non steroidal selective androgen receptor modulators with dual androgenic and progestational activities are potential compounds for further development as male hormonal contraceptive methods. At the present time, combined androgen and progestin contraceptive regimens appear to be effective, safe, reversible and convenient to use for all men with ethnic, cultural and environmental differences. Further refinements on the hormonal agent, methods of delivery, and dose optimization of the androgen relative to the progestin are necessary. This goal mandates further investment and large clinical trials in multiethnic populations to better define safety and efficacy. PMID- 21317913 TI - Altered expression patterns of syndecan-1 and -2 predict biochemical recurrence in prostate cancer. AB - The clinical features of prostate cancer do not provide an accurate determination of patients undergoing biochemical relapse and are therefore not suitable as indicators of prognosis for recurrence. New molecular markers are needed for proper pre-treatment risk stratification of patients. Our aim was to assess the value of altered expression of syndecan-1 and -2 as a marker for predicting biochemical relapse in patients with clinically localized prostate cancer treated by radical prostatectomy. The expression of syndecan-1 and -2 was examined by immunohistochemical staining in a series of 60 paraffin-embedded tissue samples from patients with localized prostate cancer. Ten specimens from patients with benign prostatic hyperplasia were used as non-malignant controls. Semiquantitative analysis was performed to evaluate the staining patterns. To investigate the prognostic value, Kaplan-Meier survival curves were performed and compared by a log-rank test. In benign samples, syndecan-1 was expressed in basal and secretory epithelial cells with basolateral membrane localisation, whereas syndecan-2 was expressed preferentially in basal cells. In prostate cancer samples, the expression patterns of both syndecans shifted to granular cytoplasmic localisation. Survival analysis showed a significant difference (P < 0.05) between normal and altered expression of syndecan-1 and -2 in free prostate specific antigen recurrence survival curves. These data suggest that the expression of syndecan-1 and -2 can be used as a prognostic marker for patients with clinically localized prostate cancer, improving the prostate-specific antigen recurrence risk stratification. PMID- 21317914 TI - A good molecular target for prostate cancer chemotherapy. PMID- 21317915 TI - IFN-alpha production by human mononuclear cells infected with varicella-zoster virus through TLR9-dependent and -independent pathways. AB - Understanding the defense mechanisms of the host of an organism is important for infection control. In previous studies, we demonstrated that interferon-alpha (IFN-alpha), but not IL-12, was produced by human peripheral blood mononuclear cells infected with varicella-zoster virus (VZV). Here, we investigated what kind of cell(s) and which signal molecule(s) are involved in IFN-alpha production. Using cell isolation and ELISA, we found that plasmacytoid dendritic cells (pDCs) were responsible for IFN-alpha production during VZV infection. We also found that Toll-like receptor 9 (TLR9) was involved in VZV-induced IFN-alpha production because inhibitory CpG oligodeoxynucleotide inhibited IFN-alpha production. UV inactivated VZV-induced IFN-alpha production was lower than that of active VZV, indicating another TLR9-independent pathway. Further studies demonstrated that double-stranded RNA-dependent protein kinase, but not DNA-dependent protein kinase was involved in VZV-induced IFN-alpha production. Together, these results suggest that pDCs play an important role in IFN-alpha production during VZV infection through TLR9-dependent and -independent pathways. PMID- 21317916 TI - Thymoma and autoimmunity. AB - The thymus is a central lymphatic organ that is responsible for many immunological functions, including the production of mature, functional T cells and the induction of self-tolerance. Benign or malignant tumors may originate from the thymus gland, with thymoma being the most common and accounting for 50% of anterior mediastinal tumors. Malignancies linked to thymoma include the loss of self-tolerance and the presence of autoimmunity. In this review, we compiled the current scientific evidence detailing the various interactions between thymoma and autoimmune diseases, including myasthenia gravis, systemic lupus erythematosus, inappropriate antidiuretic hormone secretion, pure red cell aplasia, pernicious anemia, pemphigus and autoimmune thyroid diseases. In recent years, several mechanisms have been proposed to explain these interactions. Most are based on the assumption that the 'sick' thymus, like the 'normal' thymus, can generate mature T cells; however, the T cells generated by the sick thymus are impaired and thus may exert cellular autoreactivity. Here, we present several theories that may shed light on the loss of self-tolerance associated with this epithelial tumor of the thymus. PMID- 21317918 TI - Celiac disease: a model disease for gene-environment interaction. AB - Celiac sprue remains a model autoimmune disease for dissection of genetic and environmental influences on disease progression. The 2010 Congress of Autoimmunity included several key sessions devoted to genetics and environment. Several papers from these symposia were selected for in-depth discussion and publication. This issue is devoted to this theme. The goal is not to discuss genetic and environmental interactions, but rather to focus on key elements of diagnosis, the inflammatory response and the mechanisms of autoimmunity. PMID- 21317917 TI - Celiac disease in patients with type 1 diabetes: a condition with distinct changes in intestinal immunity? AB - Two common chronic childhood diseases-celiac disease (CD) and type 1 diabetes (T1D)-result from complex pathological mechanisms where genetic susceptibility, environmental exposure, alterations in intestinal permeability and immune responses play central roles. In this study, we investigated whether these characteristics were universal for CD independently of T1D association. For this purpose, we studied 36 children with normal small-bowel mucosa and 26 children with active CD, including 12 patients with T1D. In samples from the small-bowel mucosa, we detected the lowest expression of tight junction protein 1 (TJP1) mRNA in CD patients with T1D, indicating an increase in intestinal permeability. Furthermore, these samples displayed the highest expression of forkhead box P3 (FoxP3) mRNA, a marker for regulatory T cells, as compared with other patient groups. At the same time, serum levels of IgA antibodies specific for the CD related antigens deamidated gliadin and tissue transglutaminase (tTG) were the highest in CD patients with T1D. In contrast, no significant differences were found in IgA or IgG antibodies specific for bovine beta-lactoglobulin or Bifidobacterium adolescentis DSM 20083-derived proteins. There were also no differences in the transamidating activity of serum autoantibodies between patients and control individuals. Our results show that patients with T1D and newly detected CD exhibit severely altered intestinal permeability, strong local immune activation and increased immunoregulatory mechanisms in the small bowel. Further study is required to determine whether these extreme changes in this CD subgroup are due to some specific environmental factors (virus infections), unknown genetic effects or autoimmune reactions to antigenic targets in intracellular tight junctions. PMID- 21317919 TI - A new algorithm for the diagnosis of celiac disease. AB - Celiac disease (CD) affects at least 1% of the Western population but remains largely unrecognized. In our laboratory, we utilize a novel algorithm to diagnose pediatric CD that offers both high sensitivity and high specificity for diagnosis in an outpatient setting. The aim of the present study was to challenge this algorithm and to test its performance in children and adults suspected of having CD. Using a three-assay algorithm, screening with the most sensitive tissue transglutaminase (tTG) complexed with deamidated gliadin peptide neoepitope immunoglobulin A (IgA)+IgG assay and confirming with the two specific tTG IgA and tTG IgA+IgG assays, we examined the serological results from 112 children aged 0 17 years old and 60 adults in comparison to their respective biopsy results. The algorithm performance was calculated by statistical analysis. The use of the new algorithm enabled us to diagnose CD with 98% sensitivity, 93% specificity and 95% accuracy in the pediatric group and 94% sensitivity, 92% specificity and 93% accuracy in the total population studied. The false-negative cases in the adult group were attributed to previous adherence to a gluten-free diet, and the single false-negative result in a young child became a true positive after 6 months. We have also monitored three celiac patients before and after diagnosis and found that the algorithm may be suitable for disease monitoring. The newly proposed three-assay algorithm for celiac detection is very reliable in both children and adults. Due to the high performance of this assay, the further need for confirmatory intestinal biopsies will be reassessed. PMID- 21317921 TI - Cytoplasmic p27 is oncogenic and cooperates with Ras both in vivo and in vitro. AB - p27(Kip1) (p27) can have opposing roles during malignant transformation depending on cellular context: on one hand it functions as a tumor suppressor by inhibiting cyclin-cyclin-dependent kinase (CDK) activity in the nucleus and on the other it may adopt an oncogenic role that is less well understood. To gain further insight into the roles played by p27 during tumorigenesis, we compared the susceptibility with urethane-induced tumorigenesis of two p27 mouse models, p27(-/-) and p27(CK ) knockin, in which p27 cannot bind or inhibit cyclin-CDKs. In this K-Ras-driven tumorigenesis model, p27(CK-) mice had an increase in both tumor number and aggressiveness compared with p27(-/-), indicating a cooperation between p27(CK-) and activated Ras. In the lung, increased tumorigenesis was associated with cytoplasmic localization of p27(CK-) and bronchiolaveolar stem cell amplification. The ability of p27(CK-) to cooperate with other oncogenes was not universal. When c-Myc was used as a transforming agent, p27 status became irrelevant and c-Myc was equally potent in transforming p27(+/+), p27(-/-) and p27(CK-) cells. In fact, c-Myc induced the degradation of wild-type p27 via the Skp-Cullin-F-box (SCF)-Skp2 pathway. In contrast, p27(CK-) levels were not affected by c-Myc expression, as p27(CK-) is insensitive to Skp2-mediated degradation because of its inability to bind cyclin E/CDK2. However, in presence of c-Myc, p27(CK-) remained mostly nuclear, providing an explanation for its inability to cooperate with Myc during transformation. Thus, we propose that the p27(CK-) protein needs to be localized in the cytoplasm in order to function as an oncogene, otherwise it just behaves similar to a null allele. PMID- 21317920 TI - Molecular evidences for the chemosensitizing efficacy of liposomal curcumin in paclitaxel chemotherapy in mouse models of cervical cancer. AB - The microtubule-targeting antineoplastic agent, paclitaxel, is highly efficacious against a wide spectrum of human cancers. However, dose-limiting toxicity and development of drug resistance limit its clinical application. Development of novel strategies that overcome chemoresistance and sensitize cancer cells to paclitaxel can enhance the therapeutic effect of this drug. We have previously shown that curcumin, a natural polyphenol, enhances paclitaxel-induced cytotoxicity in vitro through downregulation of nuclear factor (NF)-kappaB and Akt pathways. This study was undertaken to determine whether this synergism exists in vivo and to elucidate the underlying molecular mechanisms. Mouse cervical multistage squamous cell carcinoma model using 3-methylcholanthrene (3 MC) and a xenograft model of human cervical cancer in nonobese diabetic severe combined immunodeficient (NOD-SCID) mice using HeLa cells were used to evaluate the synergism. We observed that the combined treatment of curcumin and paclitaxel induced a synergestic reduction in the tumor incidence as well as tumor volume of animals compared with the individual treatments of paclitaxel or curcumin, although curcumin alone could not induce any significant effect at the concentration used. The results suggest that a suboptimal concentration of curcumin augments the antitumor action of paclitaxel by downregulating the activation and downstream signaling of antiapoptotic factors and survival signals such as NF-kappaB, Akt and mitogen-activated protein kinases that have significant roles in proliferation, survival, angiogenesis and metastasis. This study revealed for the first time that 3-MC-induced tumorigenesis in mice is associated with a strong constitutive activation of NF-kappaB activity. Furthermore, we also observed that pre-exposure of carcinoma cells isolated from 3-MC-induced tumors to curcumin potentiates paclitaxel-induced apoptosis. Overall, the findings of this preclinical study provide a strong rationale for the validation of this combination through clinical trials. As curcumin could effectively downregulate all these survival signals induced by paclitaxel, we suggest it as a potent chemosensitizer to improve the therapeutic index of paclitaxel. PMID- 21317922 TI - Bone morphogenetic protein-7 is a MYC target with prosurvival functions in childhood medulloblastoma. AB - Medulloblastoma (MB) is the most common malignant brain tumor in children. It is known that overexpression and/or amplification of the MYC oncogene is associated with poor clinical outcome, but the molecular mechanisms and the MYC downstream effectors in MB remain still elusive. Besides contributing to elucidate how progression of MB takes place, most importantly, the identification of novel MYC target genes will suggest novel candidates for targeted therapy in MB. A group of 209 MYC-responsive genes was obtained from a complementary DNA microarray analysis of a MB-derived cell line, following MYC overexpression and silencing. Among the MYC-responsive genes, we identified the members of the bone morphogenetic protein (BMP) signaling pathway, which have a crucial role during the development of the cerebellum. In particular, the gene BMP7 was identified as a direct target of MYC. A positive correlation between MYC and BMP7 expression was documented by analyzing two distinct sets of primary MB samples. Functional studies in vitro using a small-molecule inhibitor of the BMP/SMAD signaling pathway reproduced the effect of the small interfering RNA-mediated silencing of BMP7. Both approaches led to a block of proliferation in a panel of MB cells and to inhibition of SMAD phosphorylation. Altogether, our findings indicate that high MYC levels drive BMP7 overexpression, promoting cell survival in MB cells. This observation suggests the potential relevance of targeting the BMP/SMAD pathway as a novel therapeutic approach for the treatment of childhood MB. PMID- 21317923 TI - Molecular basis of a novel oncogenic mutation in GNAO1. AB - Heterotrimeric G proteins are molecular switches that control signal transduction, and their dysregulation can promote oncogenesis. Somatic mutations in GNAS, GNAI2 and GNAQ genes induce oncogenesis by rendering Galpha subunits constitutively activated. Recently the first somatic mutation, arginine(243) -> histidine (R243H) in the GNAO1 (Galphao) gene was identified in breast carcinomas and shown to promote oncogenic transformation when introduced into cells. Here, we provide the molecular basis for the oncogenic properties of the Galphao R243H mutant. Using limited proteolysis assays, nucleotide-binding assays, and single turnover and steady-state GTPase assays, we demonstrate that the oncogenic R234H mutation renders Galphao constitutively active by accelerating the rate of nucleotide exchange; however, this mutation does not affect Galphao's ability to become deactivated by GTPase-activating proteins (GAPs) or by its intrinsic GTPase activity. This mechanism differs from that of previously reported oncogenic mutations that impair GTPase activity and GAP sensitivity without affecting nucleotide exchange. The constitutively active Galphao R243H mutant also enhances Src-STAT3 signaling in NIH-3T3 cells, a pathway previously shown to be directly triggered by active Galphao proteins to promote cellular transformation. Based on structural analyses, we propose that the enhanced rate of nucleotide exchange in Galphao R243H results from loss of the highly conserved electrostatic interaction of R243 with E43, located in the in the P-loop that represents the binding site for the alpha- and beta-phosphates of the nucleotide. We conclude that the novel R234H mutation imparts oncogenic properties to Galphao by accelerating nucleotide exchange and rendering it constitutively active, thereby enhancing signaling pathways, for example, src-STAT3, responsible for neoplastic transformation. PMID- 21317925 TI - The Hippo pathway transcriptional co-activator, YAP, is an ovarian cancer oncogene. AB - The Salvador-Warts-Hippo (SWH) pathway was first discovered in Drosophila melanogaster as a potent inhibitor of tissue growth. The SWH pathway is highly conserved between D. melanogaster and mammals, both in function and in the mechanism of signal transduction. The mammalian SWH pathway limits tissue growth by inhibiting the nuclear access and expression of the transcriptional co activator, Yes-associated protein (YAP). Mutation and altered expression of SWH pathway proteins has been observed in several types of human cancer, but the contribution of these events to tumorigenesis has been unclear. Here we show that YAP can enhance the transformed phenotype of ovarian cancer cell lines and that YAP confers resistance to chemotherapeutic agents that are commonly used to treat ovarian cancer. We find that high nuclear YAP expression correlates with poor patient prognosis in a cohort of 268 invasive epithelial ovarian cancer samples. Segregation by histotype shows that the correlation between nuclear YAP and poor survival is predominantly associated with clear cell tumors, independent of stage. Collectively our findings suggest that YAP derepression contributes to the genesis of ovarian clear cell carcinoma and that the SWH pathway is an attractive therapeutic target. PMID- 21317924 TI - Onconase mediated NFKbeta downregulation in malignant pleural mesothelioma. AB - Treatment of malignant pleural mesothelioma (MPM) with Ranpirnase (Onconase) results in disruption of protein translation and cell apoptosis. We hypothesize that Onconase exerts an effect via downregulation of nuclear factor kappa B (NFKbeta) by specific microRNAs (miRNAs) and that interference of this pathway could have implications for MPM resistance to chemotherapy. Three immortalized MPM cell lines (H2959, H2373 and H2591) were exposed to Onconase at 0-20 MUg/ml. Cell counts were measured at 48 and 72 h. Gene expression in miRNA-enriched RNA was validated by reverse transcription-PCR (RT-PCR). The functional implications of miRNA expression were evaluated by transfecting miRNA mimics or inhibitors into MPM cell lines, and performing Matrigel invasion, cell proliferation, soft agar colony formation and scratch closure assays. Effects on NFKbeta expression and downstream targets including ABC transporters, BCL-xl and IAP were assessed by RT-PCR and western blotting. Treatment with 20 MUg/ml of Onconase significantly decreased cell count and invasion. Hsa-miR-17* was significantly upregulated and hsa-miR-30c was significantly downregulated by Onconase treatment in all cell lines. Forced expression of hsa-miR-17* mimic and hsa-miR-30c inhibitor each significantly decreased functional activity of Onconase in all assays. NFKB1 (p50) expression and downstream targets were also decreased with Onconase treatment, as well as with forced expression of miRNA mimic and inhibitors. Onconase treatment caused a significant decrease in cell proliferation, invasion and in expression of certain miRNAs. Recapitulation of the resultant miRNA expression pattern with hsa-miR-17* mimic and hsa-miR-30c inhibitor resulted in downregulation of NFKB1 and reduced malignant behavior in functional assays. Thus, Onconase likely exerts its antitumor effect through these miRNAs. PMID- 21317926 TI - Functional interaction of Ugene and EBV infection mediates tumorigenic effects. AB - Epstein-Barr virus (EBV) infection is associated with many human neoplasms, in which EBV-derived latent membrane protein-1 (LMP1) appears to be critical, but its exact oncogenic mechanism remains to be defined. To this end, our initial microarray analyses identified a LMP1-inducible gene, Ugene, originally characterized as a binding partner for uracil DNA glycosylase 2, which is highly expressed in malignant colon cancer. In this report, it was found that Ugene, designated herein as LMP1-induced protein (LMPIP), was induced, in a time dependent manner, in EBV-infected peripheral blood mononuclear cells and LMP1 transfected 293 cells. Functionally, when compared with mock-transfected cells, overexpression of LMPIP in nasopharyngeal carcinoma (NPC) cell lines resulted in a decrease in reactive oxygen species production and maintained mitochondria membrane potential (Deltapsi) loss induced by H(2)O(2). The NPC cells transfected with LMPIP also showed a decrease in G1 population and an increase in the cell population in sub-G1 and multiploid phase, concomitant with increased levels of cell cycle activators, including cyclin D1 and CDK4. In contrast, silencing of LMPIP expression in the NPC tumor cell lines with short hairpin RNA interference revealed significantly decreased cell population at G1/S phase, while the number of cells in multiploid phase increased. Significantly, NPC cells with LMPIP knock down also showed a decrease in tumorigenic and transforming activity induced by ectopic LMP1 expression, as determined by analyses of soft agar foci and tumor size in nude mice. Further, elevated LMPIP expression was also noted in cytoplasm and nuclei in EBV-infected NPC tumor cell mass and non-EBV-infected tumor cell lines. These results suggested that LMPIP may have an important mediator role in EBV-mediated neoplasm and may serve as a new target for therapy of tumors induced by EBV infection. PMID- 21317927 TI - MicroRNA-21 targets tumor suppressor genes ANP32A and SMARCA4. AB - MicroRNA-21 (miR-21) is a key regulator of oncogenic processes. It is significantly elevated in the majority of human tumors and functionally linked to cellular proliferation, survival and migration. In this study, we used two experimental-based strategies to search for novel miR-21 targets. On the one hand, we performed a proteomic approach using two-dimensional differential gel electrophoresis (2D-DIGE) to identify proteins suppressed upon enhanced miR-21 expression in LNCaP human prostate carcinoma cells. The tumor suppressor acidic nuclear phosphoprotein 32 family, member A (ANP32A) (alias pp32 or LANP) emerged as the most strongly downregulated protein. On the other hand, we applied a mathematical approach to select correlated gene sets that are negatively correlated with primary-miR-21 (pri-miR-21) expression in published transcriptome data from 114 B-cell lymphoma cases. Among these candidates, we found tumor suppressor SMARCA4 (alias BRG1) together with the already validated miR-21 target, PDCD4. ANP32A and SMARCA4, which are both involved in chromatin remodeling processes, were confirmed as direct miR-21 targets by immunoblot analysis and reporter gene assays. Furthermore, knock down of ANP32A mimicked the effect of enforced miR-21 expression by enhancing LNCaP cell viability, whereas overexpression of ANP32A in the presence of high miR-21 levels abrogated the miR 21-mediated effect. In A172 glioblastoma cells, enhanced ANP32A expression compensated for the effects of anti-miR-21 treatment on cell viability and apoptosis. In addition, miR-21 expression clearly increased the invasiveness of LNCaP cells, an effect also seen in part upon downregulation of ANP32A. In conclusion, these results suggest that downregulation of ANP32A contributes to the oncogenic function of miR-21. PMID- 21317928 TI - Viral-mediated stabilization of AU-rich element containing mRNA contributes to cell transformation. AB - E4orf6 is one of the oncogene products of adenovirus, and it also has an important role for transportation of cellular and viral messenger RNA (mRNA) during the late phase of virus infection. We previously revealed that E4orf6 controls the fate of AU-rich element (ARE) containing mRNA by perturbing the chromosome maintenance region 1-dependent export mechanism. Here, we show that E4orf6 stabilizes ARE-mRNA through the region required for its oncogenic activity and ubiquitin E3 ligase assembly. Cells that failed to stabilize ARE-mRNA after HuR knockdown were unable to produce colonies in soft agar, even when E4orf6 was expressed. Furthermore, the stabilized ARE-mRNA induced the transformation of rodent immortalized cells. These findings indicate that stabilized ARE-mRNA is necessary, if not all, for the oncogenic activity of E4orf6 and has the potential to transform cells, at least under a certain condition. PMID- 21317929 TI - HEF1, a novel target of Wnt signaling, promotes colonic cell migration and cancer progression. AB - Misregulation of the canonical Wnt/beta-catenin pathway and aberrant activation of Wnt signaling target genes are common in colorectal cancer (CRC) and contribute to cancer progression. Altered expression of human enhancer of filamentation 1 (HEF1; also known as NEDD9 or Cas-L) has been implicated in progression of melanoma, breast, and CRC. However, the regulation of HEF1 and the role of HEF1 in CRC tumorigenesis are not fully understood. We here identify HEF1 as a novel Wnt signaling target. The expression of HEF1 was upregulated by Wnt 3a, beta-catenin, and Dvl2 in a dose-dependent manner, and was suppressed following beta-catenin downregulation by shRNA. In addition, elevated HEF1 mRNA and protein levels were observed in CRC cell lines and primary tumor tissues, as well as in the colon and adenoma polyps of Apc(Min/+) mice. Moreover, HEF1 levels in human colorectal tumor tissues increased with the tumor grade. Chromatin immunoprecipitation (ChIP) assays and promoter analyses revealed three functional T-cell factor (TCF)-binding sites in the promoter of HEF1 responsible for HEF1 induction by Wnt signaling. Ectopic expression of HEF1 increased cell proliferation and colony formation, while downregulation of HEF1 in SW480 cells by shRNA had the opposite effects and inhibited the xenograft tumor growth. Furthermore, overexpression of HEF1 in SW480 cells promoted cell migration and invasion. Together, our results determined a novel role of HEF1 as a mediator of the canonical Wnt/beta-catenin signaling pathway for cell proliferation, migration, and tumorigenesis, as well as an important player in colorectal tumorigenesis and progression. HEF1 may represent an attractive candidate for drug targeting in CRC. PMID- 21317930 TI - Regulation of Axl receptor tyrosine kinase expression by miR-34a and miR-199a/b in solid cancer. AB - Axl is a receptor that induces proliferation, migration and invasion in cancer. In this study, we show that specific microRNAs (miRNAs) target the 3'-UTR of Axl. Luciferase-reporter assays with wild-type and deleted miR-34 and miR-199a/b seed sequences of Axl 3'-UTR confirmed the specificity of targeting. An inverse correlation between Axl protein and miR-34a expression in a panel of non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and breast cancer (BRC) cell lines was observed, while miR-199a/b expression was completely suppressed. Pre miR transfection inhibited in vitro migration and invasion and, in vivo, reduced the number of distant lung- or liver-metastases in a chorion-allantoic-membrane (CAM) assay. Moreover, methylation-specific PCR on bisulfite-converted DNA obtained from the cell lines showed that the miR-34a promoter methylation status was inversely correlated with its expression, and that miR-199a/b promoter regions were methylated in all cells tested. In a panel of NSCLC tissues (n=44), miR-34a and miR-199a/b were found to be downregulated and significantly co expressed. A lower expression of all three miRs was significantly associated with squamous histotypes, and, in a preliminary series, NSCLC patients with miR-34a upregulation showed a positive association towards a longer survival. These results indicate that Axl receptor expression can be regulated by miR-34a and miR 199a/b, which are suppressed by promoter methylation in solid cancer cells. PMID- 21317932 TI - A new role of NUAK1: directly phosphorylating p53 and regulating cell proliferation. AB - It has been suggested that adenosine monophosphate-activated protein kinase (AMPK) and 12 AMPK-related kinases (ARK), including novel (nua) kinase family 1 (NUAK1), are activated by master kinase LKB1, a major tumor suppressor. Apart from evidence to suggest that NUAK1 participates in induction of tumor survival, invasion and p53-independent cellular senescence, its detailed biological functions remain unclear. Here we showed that in the presence of wild-type LKB1, NUAK1 directly interacts with and phosphorylates p53 in vitro and in vivo. The phosphorylation of p53 induced by LKB1 required the kinase activity of NUAK1 and phosphorylation of NUAK1 at Thr211 by LKB1 was essential for its kinase activity, which leads to the conclusion that LKB1 activates NUAK1 and regulates phosphorylation of p53 through the NUAK1 kinase, at least partially. LKB1/NUAK1 activation leads to cell cycle arrest at the G(1)/S border by inducing expression of p21/WAF1. Under the regulation of LKB1, NUAK1 interacts with p53 in the nucleus and binds to the p53-responsive element of p21/WAF1 promoter. These findings have highlighted a novel role for NUAK1 in LKB1-related signaling pathways; NUAK1 can regulate cell proliferation and exert tumor suppression through direct interaction with p53. PMID- 21317931 TI - The human DEK oncogene stimulates beta-catenin signaling, invasion and mammosphere formation in breast cancer. AB - Breast cancer is a major cause of cancer-related deaths in American women; therefore, the identification of novel breast cancer-related molecules for the discovery of new markers and drug targets remains essential. The human DEK gene, which encodes a chromatin-binding protein and DNA topology regulator, is upregulated in many types of cancer. DEK has been implicated as an oncogene in breast cancer based on mRNA expression studies, but its functional significance in breast cancer growth and progression has not yet been tested directly. We demonstrate that DEK is highly expressed in breast cancer cells compared with normal tissue, and functionally important for cellular growth, invasion and mammosphere formation. DEK overexpression in non-tumorigenic MCF10A cells resulted in increased growth and motility, with a concomitant downregulation of E cadherin. Conversely, DEK knockdown in MCF7 and MDA-MB-468 breast cancer cells resulted in decreased growth and motility with upregulation of E-cadherin. The use of DEK-proficient and -deficient breast cancer cells in orthotopic xenografts provided further in vivo evidence that DEK contributes to tumor growth. Activation of the beta-catenin signaling pathway is important for normal and cancer stem cell character, growth and metastasis. We show that DEK expression stimulated, and DEK knockdown repressed beta-catenin nuclear translocation and activity. Importantly, the expression of constitutively active beta-catenin rescued breast cancer invasion defects of DEK knockdown cells. Together, our data indicate that DEK expression stimulates the growth, stem cell character and motility of breast cancer cells, and that DEK-dependent cellular invasion occurs at least in part via beta-catenin activation. PMID- 21317933 TI - P-cadherin cooperates with insulin-like growth factor-1 receptor to promote metastatic signaling of gonadotropin-releasing hormone in ovarian cancer via p120 catenin. AB - Gonadotropin-releasing hormone (GnRH) is a potent prometastatic factor in ovarian cancer, but the intracellular signaling events are not well understood. The classical Galpha(q)-phospholipase C signal transduction pathway known to operate in the pituitary is not involved in GnRH actions at non-pituitary targets. Here we showed that GnRH treatment of ovarian cancer cells led to a rapid and remarkable tyrosine phosphorylation of p120 catenin (p120(ctn)), which was mediated by P-cadherin. The use of P-cadherin small interfering RNA or neutralizing antibodies to inhibit P-cadherin expression and function resulted in diminished p120(ctn) activation, confirming that the effect was P-cadherin specific. On exploring how P-cadherin, which lacks intrinsic kinase activity, might regulate the activation of p120(ctn), we found that P-cadherin could induce the ligand-independent activation of insulin-like growth factor-1 receptor (IGF 1R). Inhibition of IGF-1R expression or its activity significantly inhibited GnRH induced p120(ctn) activation, and the subsequent cell migration and invasion. In addition, we showed that IGF-1R regulation by P-cadherin was associated with complex formation between IGF-1R and P-cadherin, and this regulation was also observed to be in vivo correlated with metastasis. Furthermore, using a mouse model of ovarian cancer metastasis, GnRH receptor knockdown was shown to diminish peritoneal dissemination of tumors and ascites formation. These findings suggest for the first time that GnRH can initiate an outside-in p120(ctn) signal transduction through the cross-talk between P-cadherin and IGF-1R, thus providing a novel molecular mechanism by which GnRH may control the high level of aggressiveness and invasion and metastasis potential that are characteristic of ovarian cancer. PMID- 21317934 TI - Effects of azithromycin in bronchiolitis obliterans syndrome after hematopoietic SCT--a randomized double-blinded placebo-controlled study. AB - Bronchiolitis obliterans syndrome (BOS) is an important complication after hematopoietic SCT (HSCT). Recent observations suggested that azithromycin might improve lung function in BOS after HSCT. We conducted a randomized double-blinded placebo-controlled study on azithromycin in patients with BOS after HSCT. The treatment group (n=10) received oral azithromycin 250 mg daily while the control group (n=12) received placebo daily for 12 weeks. Respiratory symptoms were assessed by the St George Respiratory Questionnaires and spirometry at baseline (drug commencement), 1, 2, 3 (drug cessation) and 4 months (1 month after drug cessation). There was no significant difference in the baseline demographic characteristics between the treatment and the control groups in age, gender, time from HSCT to BOS, time since diagnosis of BOS, chronic GVHD, baseline respiratory symptom scores and baseline forced expiratory volume in 1 s (FEV(1)). Throughout and after 3 months of treatment, there were no significant changes in respiratory symptom scores and FEV(1) measurements between the treatment and the control groups. In conclusion, there was no significant benefit of 3 months of oral azithromycin on the respiratory symptoms and lung function in patients with relatively late BOS after HSCT in this randomized placebo-controlled study. PMID- 21317935 TI - Higher CD3(+) and CD34(+) cell doses in the graft increase the incidence of acute GVHD in children receiving BMT for thalassemia. AB - We evaluated the incidence of GVHD, risk factors and the impact of graft composition on acute GVHD (aGVHD) in 92 children who underwent BMT for thalassemia following busulfan/cyclophosphamide (BUCY)-based conditioning regimens and GVHD prophylaxis with CSA/short-MTX and methylprednisolone. The incidence of grade 2-4 and 3-4 aGVHD was 35% (95% confidence interval (CI) 25-44) and 9% (95% CI 4-16), respectively. We found that CD3(+) and CD34(+) cell doses above the median were associated with high incidence of grade 2-4 aGVHD (49 vs 20%, P=0.005 and 46 vs 23%, P=0.021, respectively). In multivariate analysis, high CD3(+) (hazard ratio (HR) 4.6; 95% CI 1.4-14.7; P=0.010) and CD34(+) (HR 4.3; 95% CI 1.4-12.7; P=0.011) cell doses were associated with grade 2-4 aGVHD. We further examined the effect of CD3(+) and CD34(+) cell doses on aGVHD using quartile cutoff points and found a minimum threshold for CD3(+) (38 * 10(6)/kg) and CD34(+) (4 * 10(6)/kg) cells above which the incidence of grade 2-4 aGVHD is significantly increased. This study shows for the first time a positive correlation between the number of CD3(+) and CD34(+) cells and aGVHD in children receiving sibling BMT, and indicates that using tailored and more intensive post transplant immunosuppression may permit to better control aGVHD. PMID- 21317936 TI - A case of membranous nephropathy associated with chronic GVHD successfully treated with rituximab. PMID- 21317937 TI - CsA 2-h concentration correlates best with area under the concentration-time curve after allo-SCT compared with trough CsA. AB - The relationship between CsA levels and area under the curve (AUC) in allo-SCT recipients, and the effect of age, concomitant use of steroid and MDR-1 polymorphism on this relationship remain largely unexplored. Steady-state CsA blood concentrations at time 0 (C0), 1 (C1), 1.5 (C1.5), 2 (C2), 3 (C3), 4 (C4), 6 (C6), 8 (C8) and 12 (C12) h post oral CsA dose were taken from 27 consenting allo-SCT recipients (receiving myeloablative or non-myeloablative conditioning) at D(15)-D(25) (all participants) and D(40)-D(80) (participants with myeloablative conditioning). The CsA AUC(0-4h), AUC(0-8h) and AUC(0-12h) were determined using trapezoidal rule, and the relationships between AUCs and CsA concentrations at various time points were examined. Poor correlation was observed between C0 and AUC(0-4h) (r(2)=0.15), AUC(0-8h) (r(2)=0.21) and AUC(0 12h) (r(2)=0.53). C2 was better correlated with AUC(0-4h) (r(2)=0.88), AUC(0-8h) (r(2)=0.76) and AUC(0-12h) (r(2)=0.83). The aforementioned factors did not influence the observed relationship. CsA levels taken at 2 h post oral CsA administration may represent the optimal time point for monitoring the biological effects of calcineurin inhibitors in allo-SCT recipients. PMID- 21317938 TI - [DNA mimics on the base of pyrrolidine and hydroxyproline]. AB - In order to improve physicochemical and biological properties of natural oligonucleotides in particular increasing their affinity for nucleic acids, the selectivity of action and biological sustainability, several types of DNA mimics were designed. The survey collected data on the synthesis and properties of the DNA mimics - peptide-nucleic acids analogues, which are derivatives of pyrrolidine and hydroxyproline. We examine some physicochemical and biological properties of negatively charged mimics of this type, containing phosphonate residues, and possessing a high affinity for DNA and RNA, selective binding with nucleic acids and stability in various biological systems. Examples of the use of these mimics as tools for molecular biological research, particularly in functional genomics are given. The prospects for their use in diagnostics and medicine are discussed. PMID- 21317939 TI - Biological functions of microRNAs. AB - The small regulatory non-coding RNA molecules, known as microRNAs (miRNAs), have been recognized as potential regulator of gene expression and modulate the gene function at the post-transcriptional level. It is now clear that miRNA biogenesis and function are related to the molecular mechanisms of various clinical diseases, which can potentially regulate every aspect of cellular activity, including differentiation and development, metabolism, proliferation, apoptotic cell death viral infection and tumorgenesis. Here, we review recent work and provide insight into the diverse roles of miRNAs. PMID- 21317940 TI - [The study of peptide stability during hydrolysis by rat gastroenteric tract fragments]. AB - The hydrolytic stability of therapeutic peptides such as dalargin, stemokin and some others, including cyclic tripeptides modified by ibuprofen and aspirin, was studied. Two experimental systems were used, one containing purified enzymes pepsin, trypsin and chymotrypsin and other based on fragments of rat stomach and ileum. It was found that linear peptides without D-aminoacids are hydrolyzed by fragments of stomach and ileum but resistant to hydrolysis with purified enzymes. The peptides with D-aminoacids and cyclic peptides are stable in all experimental conditions used, however, peptides modified with aspirin lost acetyl moiety of aspirin residue in acidic medium, the process is accelerated in presence of pepsin. PMID- 21317941 TI - [Purification and characterization of recombinant human alpha-fetoprotein fragment, corresponding to the C-terminal structural domain]. AB - Human alpha-fetoprotein (hAFP) is the main human oncofetal protein. Receptor of hAFP is expressed on the surface of different types of cancer cells, but not produced by normal cells of the adult organism. The hAFP interacts with the receptor via its third domain. The conjugates of native hAFP with a variety of natural cytostatic agents inhibit growth of cancer cells in vivo and in vitro. The C-terminal hAFP fragment comprising amino acids from 404 to 595 of the native hAFP was expressed in E. coli BL21 (DE3) strain. The level of the protein expression was no less than 150 mg/l. Highly efficient purification and refolding procedures were developed. The final protein yield was no less than 50% with purity of about 95%. Refolded rAFP3D bound specifically with cancer cells carrying hAFP receptor and was accumulated by them. This rAFP3D can be used as a carrier for the targeted drug delivery to cancer cells. PMID- 21317942 TI - [Chemical modification of proteins by "smart" polymers]. AB - The modification of proteinase inhibitor ovomucoid from duck eggs white by poly N,N-diethylacrylamide having a low critical solution temperature (LCST) have been studied. Modification of free amino groups of lysine and N-terminal residue of ovomucoid is resulted in a significant decrease in the activity of the inhibitor toward trypsin and small decrease in the activity toward alpha-chymotrypsin. At heating of the solution of modified ovomucoid above the LCST transformation of the antitryptic centers of ovomucoid in antichymotryptic centers was observed. It was shown that this phenomenon is due to the hydrophobization the lysine residues localized in the reactive centers of the inhibitor while maintaining the structure of the "linkage loops". Therefore the alpha-chymotrypsine molecules began to interact with these residues, mistaking them for the residues of hydrophobic amino acids of antichymotryptic centers. PMID- 21317943 TI - [An immunological study of secreted human polymeric immunoglobulins' J-peptide tissue specificity]. AB - Contents of J-peptide of secreted human polymeric immunoglobulins may vary considerably with different pathologies, reflecting the state of the adaptive immune system. In this work assessed the content of J-peptide in various tissues of healthy people to use as a baseline for studies related to the change in the content of J-peptide in pathologies. PMID- 21317944 TI - [Immunochemical characteristics of synthetic peptides incorporating T- and B-cell epitopes nonspecific porins of pathogenic Yersinia]. AB - Multiple antigenic peptides (MAPs), a sequence which include common antigenic epitopes of outer membrane porins (OM) bacteria of the genus Yersinia (Y. pseudotuberculosis, Y. enterocolitica, Y. pestis), pathogenic for humans have been synthesized. After immunization of BALB/c mice the antiserum to the peptide have been obtained. With the help of ELISA we showed that these sera interact with porins isolated from OM pathogenic Yersinia, and MAP interact with antibodies in sera from rabbits immunized with individual porins, and with antibodies in sera of patients with intestinal yersiniosis and pseudotuberculosis. PMID- 21317945 TI - [Monoclonal antibody based enzyme-linked immunosorbent assay for aminoglycoside antibiotic kanamycin in foodstuff]. AB - Monoclonal antibodies to aminoglycoside antibiotic kanamycin (KM) were raised as a result of mice complex immunization with glutaraldehyde conjugates BSA with KM, tobramycin (TM) and gentamicin. Using antibodies an indirect competitive enzyme linked immunosorbent assay was developed. This method allows to determine antibiotic up to 1.2 ng/ml in water solutions, milk and eggs and up to 2.5 ng/ml in honey. The recovery rate from these products spiked with KM was 83, 84 and 96% respectively. The assay of KM based on homologous and heterologous solid-phase conjugates were estimated. The cross-reactivity with TM could vary from 7 to 54%. The same indexes for of amikacin were more constant and reached 7-8%. The other aminoglycosides showed no inhibitory activity. PMID- 21317946 TI - [Synthesis and antiviral evaluation against Vaccinia virus of new N1-oxide analogues of 5'-noraristeromycin]. AB - New N1-benzyl esters of N1-oxide analogues of 5'-noraristeromycin were synthesized and tested as potential inhibitors of S-adenosyl-L-homocysteine hydrolase in Vaccinia virus infected cell systems. PMID- 21317947 TI - [Oligonucleotide derivatives in the nucleic acid hybridization analysis. II. Isothermal signal amplification in process of DNA analysis by minisequencing]. AB - The isothermal amplification of reporter signal via limited probe extension (minisequencing) upon hybridization of nucleic acids has been studied. The intensity of reporter signal has been shown to increase due to enzymatic labeling of multiple probes upon consecutive hybridization with one DNA template both in homophase and heterophase assays using various kinds of detection signal: radioisotope label, fluorescent label, and enzyme-linked assay. The kinetic scheme of the process has been proposed and kinetic parameters for each step have been determined. The signal intensity has been shown to correlate with physicochemical characteristics of both complexes: probe/DNA and product/DNA. The maximum intensity has been observed at minimal difference between the thermodynamic stability of these complexes, provided the reaction temperature has been adjusted near their melting temperature values; rising or lowering the reaction temperature reduces the amount of reporting product. The signal intensity has been shown to decrease significantly upon hybridization with the DNA template containing single-nucleotide mismatches. Limited probe extension assay is useful not only for detection of DNA template but also for its quantitative characterization. PMID- 21317948 TI - [Synthesis of secasterol and 24-episecasterol and their toxicity in MCF-7 cells]. AB - A convergent synthesis of biosynthetic precursors of brassinosteroids - secasterol and 24-episecasterol with Delta2-bond in cycle A is described. The key stages in the construction of the side chain of these compounds were Julia olefination of steroid 22-aldehyde followed by asymmetric Sharpless dihydroxylation of the intermediate Delta22-olefin. Toxicity of synthesized compounds against breast carcinoma MCF-7 cells was studied. PMID- 21317949 TI - [Three new polyhydroxysteroids from the tropical starfish Asteropsis carinifera]. AB - Thirteen steroidal compounds including three new polyhydroxysteroids, (24R,25S) 24-methyl-5alpha-cholestane-3beta,6alpha,8,15beta,16beta,26-hexaol, (22E,24R,25S) 24-methyl-5alpha-cholest-22-ene-3beta,6alpha,8,15beta,16beta,26-hexaol and (22E,24R,25S)-24-methyl-5alpha-cholest-22-ene 3beta,4beta,6alpha,8,15beta,16beta,26-heptaol, have been isolated along with the previously known ten polyhydroxysteroids from the tropical starfish Asteropsis carinifera collected near the coast of Vietnam. The structures of new compounds were elucidated by spectroscopic methods (mainly 2D NMR and ESI-mass spectrometry). PMID- 21317950 TI - [Synthesis and pharmacological activity of amides and ozonolysis product of maleopimaric acid]. AB - The synthesis of a new group of maleopimaric acid amides containing fragments of the methyl esters of amino acids, aliphatic amines, imidazole and N methylpiperazine was carried out. Ozonolysis of methyl maleopimarate flows through the cleavage of double bond C18(19) and the disclosure of anhydrous cycle with formation of secotriacid. As a result of screening of anti-inflammatory and antiulcer activity of maleopimaric acid derivatives new effective compounds such as methyl esters of maleopimaric acid and product of ozonolysis - diterpenic secotriacid, maleopimaric acid amide with L-leucine were revealed. An important advantage of the compounds studied is the low toxicity and the presence of bidirectional activity in the absence of adverse effects on the animal. PMID- 21317951 TI - [Synthesis of triterpenoid acylates - an effective reproduction inhibitors of influenza A (H1N1) and papilloma viruses]. AB - The synthesis of a new group of triterpenoid acylates on the basis of oleanolic, glycyrrhetic and ursolic acids and betulin is described. In studying the activity of the synthesized compounds in relation to reproduction of virus pathogens of respiratory infections 28-O-methoxycynnamoylbetulin shows high activity against influenza type A (H1N1) the selectivity index SI > 100. The high activity of 3,28 dinicotinoylbetulin against papilloma virus (strain HPV-11) was detected, the selectivity index SI was 35. PMID- 21317952 TI - [Subtyping of influenza virus A hemagglutinine with hybridization microarray]. AB - An oligonucleotide microarray for influenza A hemagglutinine subtyping was presented. The number of probes for determination of each subtype hemagglutinine (H1-H13, H15, H16, pandemic flu H1N1)varied from 13 to 28. When testing of the microarray using 40 type A influenza virus isolates the hemagglutinin subtypes were unambiguously determined for 36 specimens. PMID- 21317953 TI - [Simple synthesis of P1-(11-phenoxyundecyl)-P2-(2-acetamido-2-deoxy-alpha-D galactopyranosyl) diphosphate]. AB - A simple scheme of synthesis of P1-(11-phenoxyundecyl)-P2-(2-acetamido-2-deoxy alpha-D-galactopyranosyl) diphosphate synthetic lipid acceptor for glycosyltransferases participating in gram-negative bacteria O-antigenic polysaccharides is suggested. PMID- 21317954 TI - Managing the skin cancer surge. PMID- 21317955 TI - BCG and bladder cancer. PMID- 21317956 TI - The voice of experience: results from Cancer Control New Zealand's first national cancer care survey. AB - AIMS: The 2009 Cancer Care Survey aimed to gather information from patients about their experiences receiving outpatient cancer care. METHODS: In mid-2009, Cancer Control New Zealand sent an NRC+Picker postal survey to a stratified sample of 3251 eligible adults, who had received outpatient cancer care between October 2008 and March 2009. Eight cancer treatment facilities across New Zealand provided patient lists from which potential respondents were selected. RESULTS: The final response rate to the survey was 68%. Most of the patients surveyed responded very positively to questions related to specialist care coordination (91% positive response; 95%CI: 90-93), the level of privacy (87% positive response; 95%CI: 85-89), and the dignity and respect provided by healthcare professionals (86% positive response; 95%CI: 85-88). However, patients tended to be much less positive about the level of information they received on the effects of cancer treatment on their day-to-day life (responses ranging between 30% and 40% positive) and the level of emotional support provided (36% positive response; 95%CI: 33-39). Responses from different cancer services tended to follow similar patterns, although for twelve questions there was at least a 20% difference in response between services. CONCLUSIONS: Overall, patients rated their outpatient cancer care experiences as positive, but important gaps exist in the provision of information, emotional support, and treating patients within the context of their living situation. Cancer patient experience surveys can achieve high response rates and generate useful information on patient perceptions of their care. This data can be used to inform quality improvement efforts at both national and cancer treatment service levels. PMID- 21317957 TI - Predictors of physical activity and quality of life in New Zealand prostate cancer survivors undergoing androgen-deprivation therapy. AB - AIMS: The aims of this study were to: quantify the levels and predictors of physical activity in prostate cancer survivors on androgen-deprivation therapy (ADT); gain some insight into the effect of physical activity on the quality of life of prostate cancer survivors on ADT; and compare the quality of life of prostate cancer survivors on ADT with matched controls. METHODS: A sample of 84 prostate cancer survivors on ADT were recruited from a register held by the Auckland District Health Board. Participants were mailed a collection of self report surveys probing quality of life, physical activity and determinants of physical activity. RESULT: Less than half the prostate cancer sample were categorised as physically active, and there was no relationship between physical activity and age, PSA levels, or time on ADT. Compared to a matched control group the sample had lower scores for global quality of life, as well as on the physical and environmental quality of life domains. Results also showed that those prostate cancer survivors classified as active had higher levels of quality of life on average than those classified as insufficiently active. Attitude towards physical activity was the dominant predictor of the intention to be physically active, while perceived behavioural control was the dominant predictor of actual behaviour. CONCLUSIONS: Our findings describe a positive relationship between physical activity and quality of life in men with prostate cancer currently undergoing ADT. However, only half the sample was physically active, indicating that physical activity interventions aimed at prostate cancer survivors are of utility. Our data suggests targeting both attitudes and factors related to the ability to perform physical activity will be fruitful approaches. PMID- 21317958 TI - Robot-assisted laparoscopic prostatectomy: a 2010 update. AB - AIM: To build on the previous article and further explore the safety and efficacy of robotic-assisted laparoscopic prostatectomy (RALP) in the first 100 cases from a single institution in New Zealand. METHOD: A prospective database was created to monitor perioperative and postoperative outcomes of men undergoing RALP for clinically localised carcinoma of the prostate. RESULTS: The first 100 cases were followed prospectively with a mean follow-up of 13.9 months. There were no conversions to open surgery, or re-operations. Average blood loss was 281 ml, and there was only one blood transfusion. Mean hospital stay was 1.1 nights. Mean console time improved from 251.4 minutes over the first 10 cases to 104.6 minutes over the last 10. The overall positive margin rate was 18%. The positive margin rate from pT2 tumours was 8%. The majority of patients had well-differentiated, organ-confined disease. Postoperatively, five have a detectable PSA level. 68% use no incontinence pads at 12 months. At one year, 12% of the men who were previously fully potent have achieved full potency again without assistance CONCLUSION: The results further support RALP as a safe, effective, and well tolerated procedure for the management of carcinoma of the prostate. The early local experience compares favourably with other published early series. PMID- 21317959 TI - Immunohistochemical testing for colon cancer--what do New Zealand surgeons know? AB - AIM: 8-12% of colorectal cancers are associated with genetic syndromes. The most common of these is Lynch syndrome (also known as Hereditary Non-Polyposis Colorectal Cancer). Clinical criteria (Besthesda criteria) exist that can be used to identify colorectal cancer patients who may benefit from immunohistochemical screening of their tumour for Lynch syndrome. Treating surgeons need to know these criteria in order to request appropriate testing. The aim of this study was to assess the knowledge of New Zealand surgeons about the Bethesda criteria. METHODS: We conducted a postal survey of all New Zealand General Surgical Fellows of the Royal Australasian College of Surgeons. RESULTS: Of the surgeons returning surveys 88% knew screening using immunohistochemistry was available; 7% would not refer an abnormal result to a genetic service. Results of the practice based questions showed only 45% of respondents knew that a colorectal cancer diagnosed before the age of 50 was one of the Besthesda criteria. The correct response rates for the rest of the survey ranged from 32-96%. Questions about Lynch syndrome associated cancers returned fewest correct answers. In general, surgeons are poorly informed about cancers associated with Lynch syndrome. CONCLUSION: The study demonstrates limited awareness of the Besthesda criteria amongst New Zealand General Surgeons. Those treating colorectal cancer should be aware of the classic features of Lynch syndrome and test appropriately. PMID- 21317960 TI - A comparative analysis of cardiovascular disease risk profiles of five Pacific ethnic groups assessed in New Zealand primary care practice: PREDICT CVD-13. AB - BACKGROUND: Data on the cardiovascular disease risk profiles of Pacific peoples in New Zealand is usually aggregated and treated as a single entity. Little is known about the comparability or otherwise of cardiovascular disease (CVD) risk between different Pacific groups. AIM: To compare CVD risk profiles for the main Pacific ethnic groups assessed in New Zealand primary care practice to determine if it is reasonable to aggregate these data, or if significant differences exist. METHODS: A web-based clinical decision support system for CVD risk assessment and management (PREDICT) has been implemented in primary care practices in nine PHOs throughout Auckland and Northland since 2002, covering approximately 65% of the population of these regions. Between 2002 and January 2009, baseline CVD risk assessments were carried out on 11,642 patients aged 35-74 years identifying with one or more Pacific ethnic groups (4933 Samoans, 1724 Tongans, 1366 Cook Island Maori, 880 Niueans, 1341 Fijians and 1398 people identified as Other Pacific or Pacific Not Further Defined). Fijians were subsequently excluded from the analyses because of a probable misclassification error that appears to combine Fijian Indians with ethnic Fijians. Prevalences of smoking, diabetes and prior history of CVD, as well as mean total cholesterol/HDL ratio, systolic and diastolic blood pressures, and Framingham 5-year CVD risk were calculated for each Pacific group. Age-adjusted risk ratios and mean differences stratified by gender were calculated using Samoans as the reference group. RESULTS: Cook Island women were almost 60% more likely to smoke than Samoan women. While Tongan men had the highest proportion of smoking (29%) among Pacific men, Tongan women had the lowest smoking proportion (10%) among Pacific women. Tongan women and Niuean men and women had a higher burden of diabetes than other Pacific ethnic groups, which were 20-30% higher than their Samoan counterparts. Niuean men and women had lower blood pressure levels than all other Pacific groups while Tongan men and women had the highest total cholesterol to HDL ratios. Tongan men and women had higher absolute 5-year CVD risk scores, as estimated by the Framingham equation, than their Samoan counterparts (Age-adjusted mean differences 0.71% [95% CI 0.36% to 1.06%] for Tongan men and 0.52% [95% CI 0.17% to 0.86%] for Tongan women) although these risk differences were only about 10% higher in relative terms. CONCLUSION: The validity of the analyses depend on the assumption that the selection of participants for CVD risk assessment in primary care is similar between Pacific groups. The ethnic-specific CVD risk profiles presented do not represent estimates of population prevalence. Almost all previous Pacific data has been aggregated with Pacific peoples treated as a single entity because of small sample sizes. We have analysed data from the largest study to date measuring CVD risk factors in Pacific peoples living in New Zealand. Our findings suggest that aggregating Pacific population data appears to be reasonable in terms of assessing absolute CVD risk, however there are differences for specific CVD risk factors between Pacific ethnic groups that may be important for targeting community level interventions. PMID- 21317961 TI - Pathology referrals for skin lesions--are we giving the pathologist sufficient clinical information? AB - AIM: To assess the quality of data included in the histology request form. METHOD: We prospectively reviewed the histology request forms of 375 consecutive skin lesions. In addition, the appropriateness of the surgical specimen was determined. RESULTS: There were 196 women and 179 men with a mean age of 58.4 years. The majority of specimens (84.5%) derived from primary care. 233 lesions (62%) were removed by excision, 57 (15%) by shave, three by curettage, with 82 lesions (22%) by punch/incisional biopsy. The clinical diagnosis was either not specified in 56 cases (15%), or simply labelled as 'lesion' in 84 (22%) patients. In 140/375 cases (37%), no useful clinical information was available. The clinical diagnosis matched the histopathological diagnosis in 145 cases (39%). Sixty percent (78/131) of histologically confirmed malignant lesions had not been identified clinically as being malignant: only 2 of 12 (17%) melanomas, 33/74 (45%) BCCs and 18/45 SCCs (57%) were diagnosed clinically. The specimen type was considered inadequate to make a histopathological diagnosis in 25 cases (6.7%). CONCLUSION: In over a third of histology requests, diagnostic clinical information was absent. In addition, punch biopsy was used in 40% of lesions where a melanoma was being considered clinically. PMID- 21317962 TI - Non-melanoma skin cancers in New Zealand--a neglected problem. AB - Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the commonest types of non-melanoma skin cancer (NMSC). The incidence of NMSC has been increasing globally with Australia recording a 1.5-fold increase over the last 17 years. Given that Australia and New Zealand share similar latitude, sun exposure levels, population skin types, and other risk factors, it is conceivable that this increase has also occurred in New Zealand. However, the incidence of NMSC in New Zealand is unknown. The cost of treating NMSC in New Zealand is estimated to be more than NZ$50 million annually, based on extrapolated Australian data. In Australia, NMSC is the most costly burden to its healthcare system, and therefore the Australian Government has allocated resources to improve epidemiological research, and preventative efforts. Currently within New Zealand there is a lack of focus on the NMSC problem. The absence of New Zealand data on the incidence of NMSC has hampered the development of consistent healthcare policies (including preventative measures), that achieve an integrated and sustainable service delivery. A critical analysis of this problem based on longitudinal data is now vitally important to address this neglected problem. PMID- 21317963 TI - Changes to the eligibility to bill on Medicare in Australia: a threat to New Zealand's medical workforce? AB - Previously, New Zealand citizens and those who studied medicine in New Zealand were subject to restrictions in terms of their eligibility to bill on Medicare in Australia. As of April 2010, those restrictions have been removed, making Australia an even more attractive destination for New Zealand doctors, particularly those who have completed their specialist training. At a time when the New Zealand health system can ill afford to lose more doctors overseas, this situation is of significant concern. PMID- 21317964 TI - BCG sepsis following inadvertent intravenous BCG administration for the treatment of bladder cancer can be effectively cured with anti-tuberculosis medications. AB - AIM: To the best of our knowledge we are presenting the very first case of inadvertent intravascular administration of BCG and its successful treatment with anti-tuberculosis medications on a patient with superficial bladder cancer. METHODS: A search of the English literature (PubMed/Medline) was performed concerning inadvertent BCG administration for bladder cancer by using the key words. RESULTS: The patient was admitted to our hospital with high fever and chills a few hours after intravascular BCG administration. Chest CT showed bilateral infiltration of the lungs. Patient was placed on anti-tuberculosis treatment including isoniazid, rifampycin, ethambutol and methylprednisolone initially; and this treatment was adjusted according to his clinical course and liver function tests. By the end of the 4th week of hospitalisation patient was responded well with normalisation of his clinical status, liver function tests and a normal chest X-ray. Thereafter, he was discharged home on isoniazid, ethambutol for 6 months, streptomycin, cycloserine-C and ofloxacin for 2 months, methylprednisolone which was stopped eventually after dose reduction. On follow up at 6th month after discharge from the hospital, he was fully recovered with normal chest X-ray and blood tests. CONCLUSIONS: Development of severe sepsis is inevitable following inadvertent intravascular BCG administration. Therefore, urologists should warn and inform not only their patients and families but also healthcare workers such as nurses regarding the route of administration of the BCG treatment for bladder cancer. Our experience also proved that such a serious complication can be successfully treated if promptly acted. PMID- 21317965 TI - Isolated melanoma metastasis to stomach with possible regressed primary lesion: the importance of pursuing solitary melanoma metastases. AB - This is a case of a 60-year-old man who presented with anaemia and was subsequently diagnosed with a solitary 5 cm malignant melanoma metastasis of the gastric fundus. No primary lesion was identified. After surgical resection he is alive at 5 years follow-up, adding weight to the notion that solitary melanoma metastases should be aggressively pursued, as long-term survival is possible. PMID- 21317966 TI - A case of a testosterone-secreting oncocytic adrenocortical carcinoma. AB - Oncocytic neoplasms are most rarely found in the adrenal gland. They are usually benign and non-functioning. We present a case of a testosterone-secreting oncocytic adrenocortical carcinoma in a 19-year-old female who presented with acne, hirsutism and irregular menses. Clinical investigations revealed an elevated testosterone and DHEA-S and a 4*5 cm left adrenal mass. The tumour was successfully excised. The histology showed the tumour to be comprised of oncocytic cells with granular, eosinophilic cytoplasm, features consistent with an oncocytic carcinoma. This is the first case presented of a testosterone secreting oncocytic adrenocortical carcinoma. PMID- 21317967 TI - Medical image. Varicella-zoster virus pneumonia. PMID- 21317968 TI - Sample, send, screen, survive--simple. Rotary Club-subsidised community trial points way to simple screen for bowel cancer risk. PMID- 21317969 TI - Screening for diabetes during and after an acute myocardial infarction: when and how? PMID- 21317970 TI - Sugar consumption in New Zealand--with Thornley and McRobbie response. PMID- 21317971 TI - Ultrasound-guided nerve blocks are costly. PMID- 21317972 TI - Pelvic floor exercises. PMID- 21317973 TI - Threat-sensitive anti-intraguild predation behaviour: maternal strategies to reduce offspring predation risk in mites. AB - Predation is a major selective force for the evolution of behavioural characteristics of prey. Predation among consumers competing for food is termed intraguild predation (IGP). From the perspective of individual prey, IGP differs from classical predation in the likelihood of occurrence because IG prey is usually more rarely encountered and less profitable because it is more difficult to handle than classical prey. It is not known whether IGP is a sufficiently strong force to evolve interspecific threat sensitivity in antipredation behaviours, as is known from classical predation, and if so whether such behaviours are innate or learned. We examined interspecific threat sensitivity in antipredation in a guild of predatory mite species differing in adaptation to the shared spider mite prey (i.e. Phytoseiulus persimilis, Neoseiulus californicus and Amblyseius andersoni). We first ranked the players in this guild according to the IGP risk posed to each other: A. andersoni was the strongest IG predator; P. persimilis was the weakest. Then, we assessed the influence of relative IGP risk and experience on maternal strategies to reduce offspring IGP risk: A. andersoni was insensitive to IGP risk. Threat sensitivity in oviposition site selection was induced by experience in P. persimilis but occurred independently of experience in N. californicus. Irrespective of experience, P. persimilis laid fewer eggs in choice situations with the high- rather than low-risk IG predator. Our study suggests that, similar to classical predation, IGP may select for sophisticated innate and learned interspecific threat-sensitive antipredation responses. We argue that such responses may promote the coexistence of IG predators and prey. PMID- 21317974 TI - Holocene temperature variations at a high-altitude site in the Eastern Alps: a chironomid record from Schwarzsee ob Solden, Austria. AB - Few well-dated, quantitative Holocene temperature reconstructions exist from high altitude sites in the Central Eastern Alps. Here, we present a chironomid-based quantitative reconstruction of mean July air temperatures (T(July)) throughout the Holocene for a remote high-mountain lake, Schwarzsee ob Solden, situated above the treeline at 2796 m a.s.l. in the Austrian Alps. Applying a chironomid temperature inference model developed from lakes of the Alpine region to a high resolution chironomid record from the lake provides evidence for early Holocene (ca 10000-8600 cal yr BP) T(July) of up to 8.5 degrees C, i.e. >4 degrees C above the modern (1977-2006) mean July temperature. The reconstruction reveals the so-called '8.2-ka cold event' centered at ca 8250-8000 cal yr BP with temperatures ca 3 degrees C below the early-Holocene thermal maximum. Rather warm (ca 6 degrees C) and productive conditions prevailed during ca 7900-4500 cal yr BP. The chironomid record suggests a climate transition between ca 5200 and 4500 cal yr BP to cooler T(July). A distinct cooling trend is evident from ca 4500 until ca 2500 cal yr BP. Thereafter, the study site experienced its coldest conditions (around 4 degrees C or less) throughout the rest of the Holocene, with the exception of the warming trend during the late 20th century. Beside other factors, the Northern Hemisphere summer insolation seems to be the major driving force for the long-term trends in T(July) at high altitudes in the Eastern Alps. Due to the extreme location of the lake and the limited temperature range represented by the applied calibration data set, the chironomid-based temperature reconstruction fails to track phases of the late-Holocene climatic history with T(July) cooler than 4 degrees C. Further chironomid-based palaeoclimate model and down-core studies are required to address this problem, provide more realistic T(July) estimates from undisturbed high-altitude lakes in the Alps, and extract a reliable regional temperature signal. PMID- 21317975 TI - Detecting ingested plant DNA in soil-living insect larvae. AB - Although a significant proportion of plant tissue is located in roots and other below-ground parts of plants, little is known on the dietary choices of root feeding insects. This is caused by a lack of adequate methodology which would allow tracking below-ground trophic interactions between insects and plants. Here, we present a DNA-based approach to examine this relationship. Feeding experiments were established where either wheat (Triticum aestivum) or maize (Zea mays) was fed to Agriotes larvae (Coleoptera: Elateridae), allowing them to digest for up to 72 h. Due to the very small amount of plant tissue ingested (max = 6.76 mg), DNA extraction procedures and the sensitivity of polymerase chain reaction (PCR) had to be optimized. Whole-body DNA extracts of larvae were tested for the presence of both rbcL and trnL plastid DNA using universal primers. Moreover, based on cpDNA sequences encoding chloroplast tRNA for leucine (trnL), specific primers for maize and wheat were developed. With both, general and specific primers, plant DNA was detectable in the guts of Agriotes larvae for up to 72 h post-feeding, the maximum time of digestion in these experiments. No significant effect of time since feeding on plant DNA detection success was observed, except for the specific primers in maize-fed larvae. Here, plant DNA detection was negatively correlated with the duration of digestion. Both, meal size and initial mass of the individual larvae did not affect the rate of larvae testing positive for plant DNA. The outcomes of this study represent a first step towards a specific analysis of the dietary choices of soil-living herbivores to further increase our understanding of animal-plant feeding interactions in the soil. PMID- 21317977 TI - Substrate-induced coagulation (SIC) of nano-disperse alumina in non-aqueous media: The dispersibility and stability of alumina in N-methyl-2-pyrrolidinone. AB - This work investigated colloidal properties such as the zeta-potential, the electrophoretic mobilities and the wetting behaviour of alumina dispersed in non aqueous media. Non-aqueous dispersions of alumina were prepared in the solvent N methyl-2-pyrrolidinone (NMP). The wetting behaviour of alumina in NMP was characterized by the powder contact angle method and the Wilhemy plate method. The behaviour of the dispersion should provide information for the development of a substrate-induced coagulation (SIC) coating process of nano-sized alumina in non-aqeous media. SIC is a dip-coating process that coats pretreated but chemically different surfaces with nano-sized particles. It was found that the anionic surfactant dioctyl sulfosuccinate (AOT) had no stabilizing effect on alumina dispersed in NMP. PMID- 21317976 TI - Em algorithm for mapping quantitative trait Loci in multivalent tetraploids. AB - Multivalent tetraploids that include many plant species, such as potato, sugarcane, and rose, are of paramount importance to agricultural production and biological research. Quantitative trait locus (QTL) mapping in multivalent tetraploids is challenged by their unique cytogenetic properties, such as double reduction. We develop a statistical method for mapping multivalent tetraploid QTLs by considering these cytogenetic properties. This method is built in the mixture model-based framework and implemented with the EM algorithm. The method allows the simultaneous estimation of QTL positions, QTL effects, the chromosomal pairing factor, and the degree of double reduction as well as the assessment of the estimation precision of these parameters. We used simulated data to examine the statistical properties of the method and validate its utilization. The new method and its software will provide a useful tool for QTL mapping in multivalent tetraploids that undergo double reduction. PMID- 21317978 TI - 3D Winding Number: Theory and Application to Medical Imaging. AB - We develop a new formulation, mathematically elegant, to detect critical points of 3D scalar images. It is based on a topological number, which is the generalization to three dimensions of the 2D winding number. We illustrate our method by considering three different biomedical applications, namely, detection and counting of ovarian follicles and neuronal cells and estimation of cardiac motion from tagged MR images. Qualitative and quantitative evaluation emphasizes the reliability of the results. PMID- 21317979 TI - Palaeoenvironmental evolution of Lake Gacko (Southern Bosnia and Herzegovina): Impact of the Middle Miocene Climatic Optimum on the Dinaride Lake System. AB - In the Early to Middle Miocene, a series of lakes, collectively termed the Dinaride Lake System (DLS), spread out across the north-western part of the Dinaride-Anatolian continental block. Its deposits, preserved in numerous intra montane basins, allow a glimpse into the palaeoenvironmental, palaeobiogeographic and geodynamic evolution of the region. Lake Gacko, situated in southern Bosnia and Herzegovina, is one of the constituent lakes of the DLS, and its deposits are excellently exposed in the Gracanica open-cast coal-mine. A detailed study of the sedimentary succession that addresses facies, sediment petrography, geophysical properties, and fossil mollusc palaeoecology reveals repetitive changes in lake level. These are interpreted to reflect changes in the regional water budget. First-order chronologic constraints arise from the integration of radio-isotopic and palaeomagnetic data. (40)Ar/(39)Ar measurements on feldspar crystals from a tephra bed in the upper part of the sedimentary succession indicate a 15.31 +/- 0.16 Ma age for this level. The reversed magnetic polarity signal that characterises the larger part of the investigated section correlates to chron C5Br of the Astronomically Tuned Neogene Timescale. Guided by these chronologic data and a detailed cyclostratigraphic analysis, the observed variations in lake level, evident as two ~ 40-m and seven ~ 10-m scale transgression-regression cycles, are tuned to ~ 400-kyr and ~ 100-kyr eccentricity cycles. From the tuning, it can be inferred that the sediments in the Gacko Basin accumulated between ~ 15.8 and ~ 15.2 Ma. The economically valuable lignite accumulations in the lower part of the succession are interpreted to indicate the development of swamp forests in conjunction with lake-level falls corresponding to ~ 100-kyr eccentricity minima. Pedogenesis, rhizoliths and palustrine carbonate breccias in the upper part of the section reveal long-term aridity coinciding with a ~ 400 kyr eccentricity minimum. Eccentricity maxima are interpreted to trigger lake level high-stands. These are accompanied by eutrophication events caused by enhanced denudation of the surrounding basement and increased detrital input into the basin. The presented age model proves that Lake Gacko arose during the Middle Miocene Climatic Optimum and that the optimum climatic conditions triggered the formation of this long-lived lake. PMID- 21317980 TI - Nonmotor Symptoms in Patients with PARK2 Mutations. AB - Decreased (123)I-meta-iodobenzylguanidine (MIBG) uptake in MIBG myocardial scintigraphy, olfactory dysfunction, and rapid eye movement (REM) sleep behavior disorder (RBD) are considered useful early indicators of Parkinson disease. We investigated whether patients with PARK2 mutations exhibited myocardial sympathetic abnormalities using MIBG scintigraphy, olfactory dysfunction using the Sniffin' Sticks olfactory test, and RBD using polysomnography. None of the examined patients had RBD, and all except 1 patient exhibited an increase in the olfactory threshold. Moreover, one of the oldest patients exhibited impairment in identification and discrimination. Of 12 patients with PARK2 mutations, 4 patients, who were older than patients without abnormal uptake, exhibited decreased MIBG uptake. The results obtained in this study suggest that some patients with PARK2 mutations have increased thresholds of olfactory function and myocardial sympathetic dysfunction as nonmotor symptoms. PMID- 21317981 TI - Life-long physical activity involvement and the risk of ischemic stroke in southern china. AB - A case-control study was conducted in southern China to investigate the relationship between life-long physical activity involvement and the risk of ischemic stroke. Information on life-long physical activity exposure and other lifestyle characteristics was obtained from 374 incident stroke patients and 464 hospital-based controls using a validated and reliable questionnaire. Logistic regression analyses were performed to assess the association between life-long physical activity involvement and the ischemic stroke risk. The control subjects reported more involvement in physical activity over the life course than the stroke patients (P < .001). The risk of ischemic stroke was inversely associated with life-long physical activity exposure, with adjusted odds ratio 0.39 (95% confidence interval 0.25 to 0.59) for participants who had always been involved relative to those who have never been much involved. The dose-response relationship was also significant (P < .001). Therefore, being active life long should be encouraged to prevent this major chronic disease. PMID- 21317982 TI - Low-power, high data rate transceiver system for implantable prostheses. AB - Wireless telemetry is crucial for long-term implantable neural recording systems. RF-encoded neurological signals often require high data-rates to transmit information from multiple electrodes with a sufficient sampling frequency and resolution. In this work, we quantify the effects of interferers and tissue attenuation on a wireless link for optimal design of future systems. The wireless link consists of an external receiver capable of demodulating FSK/OOK transmission at speeds up to 8 Mbps, with <1e-5 bit-error rate (BER) without error correction, and a fully implanted transmitter consuming about 1.05 mW. The external receiver is tested with the transmitter in vivo to show demodulation efficacy of the transcutaneous link at high data-rates. Transmitter/Receiver link BER is quantified in typical and controlled RF environments for ex vivo and in vivo performance. PMID- 21317983 TI - Phenotypic heterogeneity of breast cancer stem cells. AB - Many types of tumors are organized in a hierarchy of heterogeneous cell populations, with only a small proportion of cancer stem cells (CSCs) capable of sustaining tumor formation and growth, giving rise to differentiated cells, which form the bulk of the tumor. Proof of the existence of CSC comes from clinical experience with germ-cell cancers, where the elimination of a subset of undifferentiated cells can cure patients (Horwich et al., 2006), and from the study of leukemic cells (Bonnet and Dick, 1997; Lapidot et al., 1994; and Yilmaz et al., 2006). The discovery of CSC in leukemias as well as in many solid malignancies, including breast carcinoma (Al-Hajj et al. 2003; Fang et al., 2005; Hemmati et al., 2003; Kim et al., 2005; Lawson et al., 2007; Li et al., 2007; Ricci-Vitiani et al., 2007; Singh et al., 2003; and Xin et al., 2005), has suggested a unifying CSC theory of cancer development. The reported general insensitivity of CSC to chemotherapy and radiation treatment (Bao et al., 2006) has suggested that current anticancer drugs, which inhibit bulk replicating cancer cells, may not effectively inhibit CSC. The clinical relevance of targeting CSC-associated genes is supported by several recent studies, including CD44 targeting for treatment of acute myeloid leukemia (Jin et al., 2006), CD24 targeting for treatment of colon and pancreatic cancer (Sagiv et al., 2008), and CD133 targeting for hepatocellular and gastric cancer (Smith et al., 2008). One promising approach is to target CSC survival signaling pathways, where leukemia stem cell research has already made some progress (Mikkola et al., 2010). PMID- 21317984 TI - The Role of Fas-FasL Signaling Pathway in Induction of Apoptosis in Patients with Sulfur Mustard-Induced Chronic Bronchiolitis. AB - Sulfur mustard (SM) is an alkylating agent that induces apoptosis and necrosis in cells. Fas-Fas ligand (FasL) interaction could induce apoptosis as well. In this study, it was hypothesized that apoptosis might play an important role in the pathogenesis of SM-induced lung injury via Fas-FasL signaling pathway. In a case control study, Fas and FasL levels, caspase-3 activity and percent of apoptotic cells were measured in bronchoalveolar lavage (BAL) fluid of patients 20 years after exposure to sulfur mustard and compared with the control group. Results show that Fas and FasL levels were significantly higher in BAL fluid cells in patients group compared with the control (P = .001). No significant differences were observed between mild and moderate-severe groups. BAL fluid cells caspase-3 activity was not significantly different among the mild, moderate-severe, and control groups. The data suggest that Fas-FasL-induced apoptosis was impaired in BAL fluid cells of SM-exposed patients which might be one of the initiators of pathogenesis in SM-induced lung injury in these patients. PMID- 21317985 TI - Phosphocreatine preconditioning attenuates apoptosis in ischemia-reperfusion injury of rat brain. AB - Phosphocreatine (PCr) is an endogenous compound containing high-energy phosphate bonds. It has been confirmed that PCr is effective in preventing and treating cardiac and renal ischemia-reperfusion injury. In this study, rat cerebral ischemia-reperfusion injury models were constructed. Apoptotic cells in the cortex region were measured by TUNEL method. Malondialdehyde (MDA) content was detected by chromatometry, and calmodulin (CaM) activity was detected by ELISA. Compared with sham-operated group (sham group), TUNEL-positive cells, MDA, and level of CaM activity increased in ischemia-reperfusion group (I/R group) and PCr preconditioning group (PCr group); compared with I/R group, TUNEL-positive cells, MDA content, and level of CaM activity decreased in PCr group. This study indicated that PCr can decrease the morphological damage and the neuron apoptosis of the ischemia-reperfusion injury brain through attenuating abnormalities of calcium balance and production of oxygen free radicals. PMID- 21317986 TI - Successful Treatment of a Severe Case of Fournier's Gangrene Complicating a Perianal Abscess. AB - A 67-year-old male patient with diabetes mellitus and nephritic syndrome under cortisone treatment was admitted to our hospital with fever and severe perianal pain. Upon physical examination, a perianal abscess was identified. Furthermore, the scrotum was gangrenous with extensive cellulitis of the perineum and left lower abdominal wall. Crepitations between the skin and fascia were palpable. A diagnosis of Fournier's gangrene was made. He was treated with immediate extensive surgical debridement under general anesthesia. The patient received broad-spectrum antibiotics, and repeated extensive debridements were performed until healthy granulation was present in the wound. Due to the fact that his left testicle was severely exposed, it was transpositioned into a subcutaneous pocket in the inner side of the left thigh. He was finally discharged on the 57th postoperative day. Fournier's gangrene is characterized by high mortality rates, ranging from 15% to 50% and is an acute surgical emergency. The mainstay of treatment should be open drainage and early aggressive surgical debridement of all necrotic tissue, followed by broad-spectrum antibiotics therapy. PMID- 21317987 TI - Huge interatrial septal aneurysm: a coincidental but rather fatal finding. AB - We report the case of a patient with a huge interatrial septal aneurysm as an intraoperative coincidental finding that led to a fatal outcome. The patient was admitted to our hospital in order to undergo elective coronary artery bypass grafting because he suffered from severe coronary artery disease. We intraoperatively diagnosed by transesophageal echocardiography a huge interatrial septal aneurysm mimicking a right atrial tumor. The aneurysm was initially resected and then coronary artery bypass grafting was successfully performed but the patient never achieved a successful separation from cardiopulmonary bypass probably because of massive embolic events. PMID- 21317988 TI - Isolated splenic hydatid disease. AB - Hydatid disease (HD) continues to be a significant health problem in areas where animal husbandry is common but no proper veterinary control exists. The involvement of the spleen in HD is rare, and isolated splenic involvement is even less common. In this case report, we present isolated splenic HD in a 26-year-old female with complaint of abdominal pain, and we discuss some of the clinical aspects of HD. Evaluation of the patient with ultrasonography, computed tomography, and magnetic resonance imaging revealed the presence of an isolated splenic HD as a multivesicular cystic mass located near splenic hilus, measuring 12 * 11 cm. No other organ or system involvement could be demonstrated. PMID- 21317989 TI - Thyrotoxic Dysphagia in an 82-year-old male. AB - Dysphagia is a common problem in elderly patients and a rare manifestation of Graves' disease. We report a case of an 82-year-old male who presented with a 4 week history of dysphagia and weight loss. Workup for his dysphagia with upper endoscopy, MRI brain, electromyography, acetyl-cholinesterase receptor antibodies, and voltage-gated calcium channel antibodies were negative. Modified Barium swallow test showed oropharyngeal dysphagia. Thyroid function tests that revealed hyperthyroidism and antibodies to TSH-receptor were positive. Based on the above findings, we considered Graves' disease as the most likely diagnosis. Patient was treated with methimazole and beta-blockers and subsequently his dysphagia resolved. This paper highlights the importance to clinicians of considering thyrotoxicosis as possible diagnosis in an elderly patient presenting with unexplained dysphagia. PMID- 21317990 TI - Surveillance for hepatocellular carcinoma: in whom and how? PMID- 21317991 TI - Structured management strategy versus usual care for gastroesophageal reflux disease: rationale for pooled analysis of five European cluster-randomized trials. AB - BACKGROUND: Gastroesophageal reflux disease (GERD) has a major impact at the primary care level and there is a need to evaluate whether the diagnosis and therapeutic management of GERD in Europe needs to be improved. METHODS: This project was designed to test the hypothesis that a new primary care management strategy would improve outcomes for patients with GERD, compared with usual care, in Europe. The analysis pools five separate cluster-randomized studies conducted in Austria, Italy, Norway, Spain and Sweden. These studies used a strategy based on the self-administered GerdQ questionnaire to stratify adult patients with symptoms of heartburn or regurgitation according to the frequency and impact of symptoms. A score of >=8 indicates a high probability of suffering GERD. Patients with a GerdQ impact score <=2 were treated with generic proton-pump inhibitors according to local guidance, and patients with an impact score >=3 were treated with esomeprazole 40 mg once daily. RESULTS: In total, 2400 patients were enrolled across the five studies. The protocols were modified by individual countries according to their local guidelines/requirements. In Norway, the new management strategy was compared with traditional routine endoscopy and 24-hour pH-metry, and encompassed proton-pump inhibitor reimbursement restrictions. Outcome measures differed by country, but included control of GERD symptoms, self rated health status and work productivity, treatment changes, specialist referrals and physician adherence. GERD-related use of healthcare resources was also evaluated. CONCLUSION: The pooled analysis will determine whether a locally adapted primary care management strategy for GERD, using GerdQ as a patient tailored diagnostic and therapeutic evaluation tool, is beneficial compared with usual care across five countries with different standard approaches to GERD management and control. PMID- 21317992 TI - Routine screening for eosinophilic esophagitis in patients presenting with dysphagia. AB - BACKGROUND: Eosinophilic esophagitis (EoE) is a clinicopathologic disorder first described in 1978 which has gained significant recognition over the past 10 years. Numerous prevalence studies have been performed around the globe, both in pediatric and adult populations documenting a prevalence between 0.002% and 6.5%. The aim of this study is to assess the utility of routinely screening for EoE in patients with dysphagia. METHODS: A prospective, observational study in which adult patients with a complaint of esophageal dysphagia were enrolled. RESULTS: Of the 135 patients enrolled, 122 completed the study; 100 patients had nonobstructive dysphagia, while 22 patients had a luminal finding which could explain their dysphagia. The prevalence of EoE in the nonobstructive dysphagia group was 22% (95% CI: 13.9-30.1%); 32.7% of male patients with nonobstructive dysphagia were found to have EoE compared with 8.9% of females (p = 0.004). The mean age of nonobstructive patients found to have EoE was 37.8 years. White patients with nonobstructive dysphagia were found to have a 25.9% prevalence of EoE, compared with 0% of African Americans, 0% of Asians, and 14.3% of Hispanics. When comparing Whites with non-Whites, the prevalence of EoE was noted to be 25.9% versus 5.3%, respectively (p = 0.050). CONCLUSIONS: EoE is a common cause of nonobstructive dysphagia. We believe that the high prevalence of EoE in patients with nonobstructive dysphagia supports the practice of routine biopsies to screen for the presence of abnormally high numbers of eosinophils in this subgroup. PMID- 21317993 TI - Current management strategies and therapeutic targets in chronic constipation. AB - Constipated patients who are refractory to simple lifestyle interventions will usually resort to laxatives, whether prescribed or over the counter. Clinical trial evidence is scarce for older medications such as laxatives, especially with a condition as chronic and subjective as constipation. Newer polyethylene glycol based laxatives have been investigated under rigorous clinical trial settings, but comparisons between different laxatives are not available. Newer prokinetic agents, targeting peristalsis, intestinal secretion and the colonic flora, have been developed for laxative refractory constipation. This review focuses on the evidence for each of these agents, and the relative indications for each of them. PMID- 21317994 TI - Vitamin D and gastrointestinal diseases: inflammatory bowel disease and colorectal cancer. AB - Over the past 5 years, there has been a rapid resurgence of interest in vitamin D outside of its traditional role in metabolic bone disease. Some nontraditional roles ascribed to vitamin D include anti-inflammatory and immune-modulating effects. These effects have led to possible implications in the pathophysiology of immune-mediated diseases including multiple sclerosis and inflammatory bowel disease (IBD). In addition, vitamin D insufficiency has been linked to higher rates of cancers including colon, prostate and breast cancers. Given these diverse associations of vitamin D and disease states, this review describes recent advances with regard to vitamin D and gastrointestinal diseases, in particular IBD and colorectal cancer. PMID- 21317996 TI - Development of a combined real time monitoring and integration analysis system for volatile organic compounds (VOCs). AB - A combined integration analysis and real time monitoring (Peak Capture System) system was developed for volatile organic compounds (VOCs). Individual integration analysis and real time monitoring can be used to qualitatively and quantitatively analyze VOCs in the atmosphere and in indoor environments and determine the variation in total VOC (TVOC) concentration with time, respectively. In the Peak Capture System, real time monitoring was used to predict future elevations in the TVOC concentration (peak), and this was used an indicator of when to collect (capture) ambient air samples for integration analysis. This enabled qualitative and quantitative analysis of VOCs when the TVOC concentration was high. We developed an algorithm to predict variation in the TVOC concentration, and constructed an automatic system to initiate air sampling for integration analysis. With the system, auto-sampling and analysis of VOCs in a conventional house were conducted. In comparison with background concentrations, the results of peak analysis enabled identification of compounds whose concentration rose. This also enabled an evaluation of possible VOC emission sources. PMID- 21317995 TI - Treatment of alcoholic liver disease. AB - Alcoholic liver disease (ALD) remains a major cause of liver-related mortality in the US and worldwide. The correct diagnosis of ALD can usually be made on a clinical basis in conjunction with blood tests, and a liver biopsy is not usually required. Abstinence is the hallmark of therapy for ALD, and nutritional therapy is the first line of therapeutic intervention. The role of steroids in patients with moderate to severe alcoholic hepatitis is gaining increasing acceptance, with the caveat that patients be evaluated for the effectiveness of therapy at 1 week. Pentoxifylline appears to be especially effective in ALD patients with renal dysfunction/hepatorenal syndrome. Biologics such as specific anti-TNFs have been disappointing and should probably not be used outside of the clinical trial setting. Transplantation is effective in patients with end-stage ALD who have stopped drinking (usually for >=6 months), and both long-term graft and patient survival are excellent. PMID- 21317997 TI - Pathophysiological impact of cigarette smoke exposure on the cerebrovascular system with a focus on the blood-brain barrier: expanding the awareness of smoking toxicity in an underappreciated area. AB - Recent evidence has indicated that active and passive cigarette smoking are associated, in a dose-dependent manner, with dysfunction of normal endothelial physiology. Tobacco smoke (TS) may predispose individuals to atherogenic and thrombotic problems, significantly increasing the risk for ischemic manifestations such as acute coronary syndrome and stroke. Despite the strong evidence for an association between smoking and vascular impairment, the impact of TS exposure on the blood-brain barrier (BBB) has only been marginally addressed. This is a major problem given that the BBB is crucial in the maintenance of brain homeostasis. Recent data have also shown that chronic smokers have a higher incidence of small vessel ischemic disease (SVID), a pathological condition characterized by leaky brain microvessels and loss of BBB integrity. In the brain TS increases the risk of silent cerebral infarction (SCI) and stroke owing to the pro-coagulant and atherogenic effects of smoking. In this article we provide a detailed review and analysis of current knowledge of the pathophysiology of tobacco smoke toxicity at the cerebrovascular levels. We also discuss the potential toxicity of recently marketed "potential-reduced exposure products". PMID- 21317998 TI - A novel methodology to evaluate health impacts caused by VOC exposures using real time VOC and Holter monitors. AB - While various volatile organic compounds (VOCs) are known to show neurotoxic effects, the detailed mechanisms of the action of VOCs on the autonomic nervous system are not fully understood, partially because objective and quantitative measures to indicate neural abnormalities are still under development. Nevertheless, heart rate variability (HRV) has been recently proposed as an indicative measure of the autonomic effects. In this study, we used HRV as an indicative measure of the autonomic effects to relate their values to the personal concentrations of VOCs measured by a real-time VOC monitor. The measurements were conducted for 24 hours on seven healthy subjects under usual daily life conditions. The results showed HF powers were significantly decreased for six subjects when the changes of total volatile organic compound (TVOC) concentrations were large, indicating a suppression of parasympathetic nervous activity induced by the exposure to VOCs. The present study indicated these real time monitoring was useful to characterize the trends of VOC exposures and their effects on autonomic nervous system. PMID- 21317999 TI - Dyslipidaemia and undernutrition in children from impoverished areas of Maceio, state of Alagoas, Brazil. AB - Chronic undernutrition causes reduced growth and endocrine adaptations in order to maintain basic life processes. In the present study, the biochemical profiles of chronically undernourished children were determined in order to test the hypothesis that chronic undernutrition also causes changes in lipid profile in pre-school children. The study population comprised 80 children aged between 12 and 71 months, including 60 with moderate undernutrition [height-for-age Z (HAZ) scores <= -2 and > -3] and 20 with severe undernutrition (HAZ scores <= -3). Socioeconomic, demographic and environmental data were obtained by application of a questionnaire, and anthropometric measurements and information relating to sex, age and feeding habits were collected by a trained nutritionist. Blood samples were analysed for haemoglobin, vitamin A, insulin-like growth factor 1 (IGF-1) and serum lipids, while cortisol was assayed in the saliva. Faecal samples were submitted to parasitological investigation. Analysis of variance and chi2 methods were employed in order to select the variables that participated in the multivariate logistic regression analysis. The study population was socioeconomically homogeneous, while the lack of a treated water supply was clearly associated with the degree of malnutrition. Most children were parasitised and anaemia was significantly more prevalent among the severely undernourished. Levels of IGF-1 decreased significantly with increasing severity of undernutrition. Lipid analysis revealed that almost all of the children had dyslipidemia, while low levels of high-density lipoprotein were associated with the degree of undernutrition. It is concluded that chronic malnutrition causes endocrine changes that give rise to alterations in the metabolic profile of pre school children. PMID- 21318000 TI - Racial/ethnic differences in perceived smoking prevalence: evidence from a national survey of teens. AB - Prior studies show that perceived smoking prevalence is a significant predictor of smoking initiation. In this study, we examine racial/ethnic differences in perceived smoking prevalence and racial/ethnic differences in exposure to contextual factors associated with perceived smoking prevalence. We used cross sectional time series data from the Legacy Media Tracking Surveys (LMTS), a national sample of 35,000 12- to 17-year-olds in the United States. Perceived smoking prevalence was the primary outcome variable, measured using an LMTS question: "Out of every 10 people your age, how many do you think smoke?" Multivariable models were estimated to assess the association between perceived smoking prevalence; race/ethnicity; and exposure to social contextual factors. Findings indicate that African American, Hispanic, and American Indian youth exhibit the highest rates of perceived smoking prevalence, while white and Asian youth exhibit the lowest. Minority youth are also disproportionately exposed to social contextual factors that are correlated with high perceived smoking prevalence. These findings suggest that disproportionate exposure to social contextual factors may partially explain why minority youth exhibit such high levels of perceived smoking prevalence. PMID- 21318001 TI - The impact of the 2002 Delaware smoking ordinance on heart attack and asthma. AB - In the United States, smoking is the leading cause of death - having a mortality rate of approximately 435,000 people in 2000-accounting for 8.1% of all US deaths recorded that year. Consequently, we analyzed the Delaware Hospital Discharge Database, and identified state and non-state residents discharged with AMI or asthma for the years 1999 to 2004. Statistical data analysis compared the incidence of AMI or asthma for each group before (1999-2002) and after (2003 2004) the amendment. As a result, we found that pre-ordinance and post-ordinance quarterly rates of AMI for Delaware residents were 451 (se = 21) and 430 (se = 21) respectively, representing a 4.7% reduction. Over the same time period, there was negligible change in the incidence of AMI for non-Delaware residents. After adjusting for population growth, the Risk Ratio (RR) for asthma in Delaware residents post-ordinance was 0.95 (95% CI, 0.90 to 0.999), which represented a significant reduction (P = 0.046). By comparison, non-Delaware residents had an increased RR for asthma post-ordinance of 1.62 (95% CI, 1.46 to 1.86; P < 0.0001).The results suggest that Delaware's comprehensive non-smoking ordinance effectively was associated with a statistically significant decrease in the incidence of AMI and asthma in Delaware residents when compared to non-Delaware residents. PMID- 21318002 TI - New perspectives in monitoring drinking water microbial quality. AB - The safety of drinking water is evaluated by the results obtained from faecal indicators during the stipulated controls fixed by the legislation. However, drinking-water related illness outbreaks are still occurring worldwide. The failures that lead to these outbreaks are relatively common and typically involve preceding heavy rain and inadequate disinfection processes. The role that classical faecal indicators have played in the protection of public health is reviewed and the turning points expected for the future explored. The legislation for protecting the quality of drinking water in Europe is under revision, and the planned modifications include an update of current indicators and methods as well as the introduction of Water Safety Plans (WSPs), in line with WHO recommendations. The principles of the WSP approach and the advances signified by the introduction of these preventive measures in the future improvement of drinking water quality are presented. The expected impact that climate change will have in the quality of drinking water is also critically evaluated. PMID- 21318003 TI - Pregnancy loss and maternal methemoglobin levels: an indirect explanation of the association of environmental toxics and their adverse effects on the mother and the fetus. AB - The aim of this epidemiologic study was to point out a relationship between the exposure to products of coal combustion, and complications in pregnancy where one third of causes of stillbirth are still unknown. In the town of Labin (Croatia) a coal-powered thermoelectric power plant is the single major air polluter. We compared the records of miscarriages, premature births and stillbirths in two periods: the control and the exposure period. Data on reproductive loss was based on the records of pregnant women visiting for regular monthly pregnancy checkups. At the time of the epidemiological prospective study, 260 women (n = 138 in the clean period and n = 122 in the dirty period) were considered representative. The data were processed using Chi square and correlation tests. The frequencies of miscarriages and stillbirths were significantly lower in the control than in the exposure period (p < 0.05). Methemoglobinemia and stillbirths recorded over the "exposure" period are significantly higher than in the "control" period (p = 0.0205). The level of methemoglobin in the bloodstream is an worthy biomarker, predictor and precursor of environmental toxics' adverse effects on the mother and fetus, and can indirectly explain the unrecognized level of fetal methemoglobin. Methemoglobin and heme, having prooxidant properties, also cause the early and late endothelial dysfunction of vital organs. Despite our retrospective epidemiological study findings, we emphasize that the rate of reproductive loss represents a hypothetical risk, which needs to be confirmed with further fetal clinical and anatomopatholgical researches about the effects of methemoglobin catabolism products on the fetal CNS. PMID- 21318005 TI - Estimation of uncertainty in tracer gas measurement of air change rates. AB - Simple and economical measurement of air change rates can be achieved with a passive-type tracer gas doser and sampler. However, this is made more complex by the fact many buildings are not a single fully mixed zone. This means many measurements are required to obtain information on ventilation conditions. In this study, we evaluated the uncertainty of tracer gas measurement of air change rate in n completely mixed zones. A single measurement with one tracer gas could be used to simply estimate the air change rate when n = 2. Accurate air change rates could not be obtained for n >= 2 due to a lack of information. However, the proposed method can be used to estimate an air change rate with an accuracy of <33%. Using this method, overestimation of air change rate can be avoided. The proposed estimation method will be useful in practical ventilation measurements. PMID- 21318004 TI - Sources of propylene glycol and glycol ethers in air at home. AB - Propylene glycol and glycol ether (PGE) in indoor air have recently been associated with asthma and allergies as well as sensitization in children. In this follow-up report, sources of the PGEs in indoor air were investigated in 390 homes of pre-school age children in Sweden. Professional building inspectors examined each home for water damages, mold odour, building's structural characteristics, indoor temperature, absolute humidity and air exchange rate. They also collected air and dust samples. The samples were analyzed for four groups of volatile organic compounds (VOCs) and semi-VOCs (SVOCs), including summed concentrations of 16 PGEs, 8 terpene hydrocarbons, 2 Texanols, and the phthalates n-butyl benzyl phthalate (BBzP), and di(2-ethylhexyl)phthalate (DEHP). Home cleaning with water and mop >= once/month, repainting >= one room prior to or following the child's birth, and "newest" surface material in the child's bedroom explained largest portion of total variability in PGE concentrations. High excess indoor humidity (g/m3) additionally contributed to a sustained PGE levels in indoor air far beyond several months following the paint application. No behavioral or building structural factors, except for water-based cleaning, predicted an elevated terpene level in air. No significant predictor of Texanols emerged from our analysis. Overall disparate sources and low correlations among the PGEs, terpenes, Texanols, and the phthalates further confirm the lack of confounding in the analysis reporting the associations of the PGE and the diagnoses of asthma, rhinitis, and eczema, respectively. PMID- 21318006 TI - Estimating the economic impact of climate change on cardiovascular diseases- evidence from Taiwan. AB - The main purpose of this study was to investigate how climate change affects blood vessel-related heart disease and hypertension and to estimate the associated economic damage. In this paper, both the panel data model and the contingent valuation method (CVM) approaches are applied. The empirical results indicate that the number of death from cardiovascular diseases would be increased by 0.226% as the variation in temperature increases by 1%. More importantly, the number of death from cardiovascular diseases would be increased by 1.2% to 4.1% under alternative IPCC climate change scenarios. The results from the CVM approach show that each person would be willing to pay US$51 to US$97 per year in order to avoid the increase in the mortality rate of cardiovascular diseases caused by climate change. PMID- 21318007 TI - Antimony toxicity. AB - Antimony toxicity occurs either due to occupational exposure or during therapy. Occupational exposure may cause respiratory irritation, pneumoconiosis, antimony spots on the skin and gastrointestinal symptoms. In addition antimony trioxide is possibly carcinogenic to humans. Improvements in working conditions have remarkably decreased the incidence of antimony toxicity in the workplace. As a therapeutic, antimony has been mostly used for the treatment of leishmaniasis and schistosomiasis. The major toxic side-effects of antimonials as a result of therapy are cardiotoxicity (~9% of patients) and pancreatitis, which is seen commonly in HIV and visceral leishmaniasis co-infections. Quality control of each batch of drugs produced and regular monitoring for toxicity is required when antimonials are used therapeutically. PMID- 21318008 TI - Toxicity from metals, old menaces and new threats. PMID- 21318010 TI - The impact of menthol cigarettes on smoking initiation among non-smoking young females in Japan. AB - Japan presents an excellent case-study of a nation with low female smoking rates and a negligible menthol market which changed after the cigarette market was opened to foreign competition. Internal tobacco industry documents demonstrate the intent of tobacco manufacturers to increase initiation among young females through development and marketing of menthol brands. Japanese menthol market share rose rapidly from less than 1% in 1980 to 20% in 2008. Menthol brand use was dominated by younger and female smokers, in contrast with non-menthol brands which were used primarily by male smokers. Nationally representative surveys confirm industry surveys of brand use and provide further evidence of the end results of the tobacco industry's actions-increased female smoking in Japan. These findings suggest that female populations may be encouraged to initiate into smoking, particularly in developing nations or where female smoking rates remain low, if the tobacco industry can successfully tailor brands to them. The Japanese experience provides a warning to public health officials who wish to prevent smoking initiation among young females. PMID- 21318011 TI - Blocked randomization with randomly selected block sizes. AB - When planning a randomized clinical trial, careful consideration must be given to how participants are selected for various arms of a study. Selection and accidental bias may occur when participants are not assigned to study groups with equal probability. A simple random allocation scheme is a process by which each participant has equal likelihood of being assigned to treatment versus referent groups. However, by chance an unequal number of individuals may be assigned to each arm of the study and thus decrease the power to detect statistically significant differences between groups. Block randomization is a commonly used technique in clinical trial design to reduce bias and achieve balance in the allocation of participants to treatment arms, especially when the sample size is small. This method increases the probability that each arm will contain an equal number of individuals by sequencing participant assignments by block. Yet still, the allocation process may be predictable, for example, when the investigator is not blind and the block size is fixed. This paper provides an overview of blocked randomization and illustrates how to avoid selection bias by using random block sizes. PMID- 21318009 TI - Cellular and mitochondrial effects of alcohol consumption. AB - Alcohol dependence is correlated with a wide spectrum of medical, psychological, behavioral, and social problems. Acute alcohol abuse causes damage to and functional impairment of several organs affecting protein, carbohydrate, and fat metabolism. Mitochondria participate with the conversion of acetaldehyde into acetate and the generation of increased amounts of NADH. Prenatal exposure to ethanol during fetal development induces a wide spectrum of adverse effects in offspring, such as neurologic abnormalities and pre- and post-natal growth retardation. Antioxidant effects have been described due to that alcoholic beverages contain different compounds, such as polyphenols as well as resveratrol. This review analyzes diverse topics on the alcohol consumption effects in several human organs and demonstrates the direct participation of mitochondria as potential target of compounds that can be used to prevent therapies for alcohol abusers. PMID- 21318012 TI - A murine model to study the antibacterial effect of copper on infectivity of Salmonella enterica serovar Typhimurium. AB - This study investigated the effect of copper as an antibacterial agent on the infectivity of Salmonella enterica serovar Typhimurium. Mice were infected orally with a standardized dose of unstressed Salmonella Typhimurium and copper-stressed cells of Salmonella Typhimurium. Bacterial counts in ileum, blood, liver and spleen were observed up to 168 h under normal aerobic conditions. Serum sensitivity, phagocytosis, malondialdehyde levels and histopathology were studied for both set of animals. A decreased bacterial count in the organs with mild symptoms of infection and a complete recovery by 48 h was observed in mice infected with copper-stressed bacteria. Histopathological examination of ileum tissue demonstrated regeneration of damaged tissue post-infection with copper stressed bacteria and no malondialdehyde levels were detected after 24 h in ileum, spleen and liver. Exposure to copper sensitized Salmonella Typhimurium to the lytic action of serum and intracellular killing by peritoneal macrophages. It can be concluded that copper stress confers a decrease in the infectivity of healthy Salmonella Typhimurium in normal mice. This study highlights the significance of use of copper as an antibacterial agent against Salmonella Typhimurium in reducing the risk of incidence of Salmonella infections from contaminated water. PMID- 21318013 TI - Forage as a primary source of mycotoxins in animal diets. AB - The issue of moulds and, thus, contamination with mycotoxins is very topical, particularly in connexion with forages from grass stands used at the end of the growing season. Deoxynivalenol (DON), zearalenone (ZEA), fumonisins (FUM) and aflatoxins (AFL) are among the most common mycotoxins. The aim of the paper was to determine concentrations of mycotoxins in selected grasses (Lolium perenne, Festulolium pabulare, Festulolium braunii) and their mixtures with Festuca rubra an/or Poa pratensis during the growing season as a marker of grass safety, which was assessed according to content of the aforementioned mycotoxins. During the growing season grass forage was contaminated with mycotoxins, most of all by DON and ZEA. The contents of AFL and FUM were zero or below the limit of quantification. Moreover, the level of the occurrence of mould was quantified as ergosterol content, which was higher at the specific date of cut. All results were statistically processed and significant changes were discussed. PMID- 21318014 TI - Spatio-temporal diffusion pattern and hotspot detection of dengue in Chachoengsao province, Thailand. AB - In recent years, dengue has become a major international public health concern. In Thailand it is also an important concern as several dengue outbreaks were reported in last decade. This paper presents a GIS approach to analyze the spatial and temporal dynamics of dengue epidemics. The major objective of this study was to examine spatial diffusion patterns and hotspot identification for reported dengue cases. Geospatial diffusion pattern of the 2007 dengue outbreak was investigated. Map of daily cases was generated for the 153 days of the outbreak. Epidemiological data from Chachoengsao province, Thailand (reported dengue cases for the years 1999-2007) was used for this study. To analyze the dynamic space-time pattern of dengue outbreaks, all cases were positioned in space at a village level. After a general statistical analysis (by gender and age group), data was subsequently analyzed for temporal patterns and correlation with climatic data (especially rainfall), spatial patterns and cluster analysis, and spatio-temporal patterns of hotspots during epidemics. The results revealed spatial diffusion patterns during the years 1999-2007 representing spatially clustered patterns with significant differences by village. Villages on the urban fringe reported higher incidences. The space and time of the cases showed outbreak movement and spread patterns that could be related to entomologic and epidemiologic factors. The hotspots showed the spatial trend of dengue diffusion. This study presents useful information related to the dengue outbreak patterns in space and time and may help public health departments to plan strategies to control the spread of disease. The methodology is general for space-time analysis and can be applied for other infectious diseases as well. PMID- 21318015 TI - Hotspot analysis of spatial environmental pollutants using kernel density estimation and geostatistical techniques. AB - Concentrations of four heavy metals (Cr, Cu, Ni, and Zn) were measured at 1,082 sampling sites in Changhua county of central Taiwan. A hazard zone is defined in the study as a place where the content of each heavy metal exceeds the corresponding control standard. This study examines the use of spatial analysis for identifying multiple soil pollution hotspots in the study area. In a preliminary investigation, kernel density estimation (KDE) was a technique used for hotspot analysis of soil pollution from a set of observed occurrences of hazards. In addition, the study estimates the hazardous probability of each heavy metal using geostatistical techniques such as the sequential indicator simulation (SIS) and indicator kriging (IK). Results show that there are multiple hotspots for these four heavy metals and they are strongly correlated to the locations of industrial plants and irrigation systems in the study area. Moreover, the pollution hotspots detected using the KDE are the almost same to those estimated using IK or SIS. Soil pollution hotspots and polluted sampling densities are clearly defined using the KDE approach based on contaminated point data. Furthermore, the risk of hazards is explored by these techniques such as KDE and geostatistical approaches and the hotspot areas are captured without requiring exhaustive sampling anywhere. PMID- 21318016 TI - Four polygamous families with congenital birth defects from Fallujah, Iraq. AB - Since 2003, congenital malformations have increased to account for 15% of all births in Fallujah, Iraq. Congenital heart defects have the highest incidence, followed by neural tube defects. Similar birth defects were reported in other populations exposed to war contaminants. While the causes of increased prevalence of birth defects are under investigation, we opted to release this communication to contribute to exploration of these issues. By using a questionnaire, containing residential history and activities that may have led to exposure to war contaminants, retrospective reproductive history of four polygamous Fallujah families were documented. Our findings point to sporadic, untargeted events, with different phenotypes in each family and increased recurrence. The prevalence of familial birth defects after 2003 highlights the relevance of epigenetic mechanisms and offers insights to focus research, with the aim of reducing further damage to people's health. PMID- 21318017 TI - The effect of handwashing with water or soap on bacterial contamination of hands. AB - Handwashing is thought to be effective for the prevention of transmission of diarrhoea pathogens. However it is not conclusive that handwashing with soap is more effective at reducing contamination with bacteria associated with diarrhoea than using water only. In this study 20 volunteers contaminated their hands deliberately by touching door handles and railings in public spaces. They were then allocated at random to (1) handwashing with water, (2) handwashing with non antibacterial soap and (3) no handwashing. Each volunteer underwent this procedure 24 times, yielding 480 samples overall. Bacteria of potential faecal origin (mostly Enterococcus and Enterobacter spp.) were found after no handwashing in 44% of samples. Handwashing with water alone reduced the presence of bacteria to 23% (p < 0.001). Handwashing with plain soap and water reduced the presence of bacteria to 8% (comparison of both handwashing arms: p < 0.001). The effect did not appear to depend on the bacteria species. Handwashing with non antibacterial soap and water is more effective for the removal of bacteria of potential faecal origin from hands than handwashing with water alone and should therefore be more useful for the prevention of transmission of diarrhoeal diseases. PMID- 21318018 TI - The impact of nutritional status and longitudinal recovery of motor and cognitive milestones in internationally adopted children. AB - Internationally adopted children often arrive from institutional settings where they have experienced medical, nutritional and psychosocial deprivation. This study uses a validated research assessment tool to prospectively assess the impact of baseline (immediately post adoption) nutritional status on fifty-eight children as measured by weight-for-age, height-for-age, weight-for-height and head circumference-for-age z scores, as a determinant of cognitive (MDI) and psychomotor development (PDI) scores longitudinally. A statistical model was developed to allow for different ages at time of initial assessment as well as variable intervals between follow up visits. The study results show that both acute and chronic measures of malnutrition significantly affect baseline developmental status as well as the rate of improvement in both MDI and PDI scores. This study contributes to the body of literature with its prospective nature, unique statistical model for longitudinal evaluation, and use of a validated assessment tool to assess outcomes. PMID- 21318019 TI - Constitutive, but not challenge-induced, interleukin-10 production is robust in acute pre-pubescent protein and energy deficits: new support for the tolerance hypothesis of malnutrition-associated immune depression based on cytokine production in vivo. AB - The tolerance model of acute (i.e., wasting) pre-pubescent protein and energy deficits proposes that the immune depression characteristic of these pathologies reflects an intact anti-inflammatory form of immune competence that reduces the risk of autoimmune reactions to catabolically released self antigens. A cornerstone of this proposition is the finding that constitutive (first-tier) interleukin(IL)-10 production is sustained even into the advanced stages of acute malnutrition. The IL-10 response to inflammatory challenge constitutes a second tier of anti-inflammatory regulation and was the focus of this investigation. Weanling mice consumed a complete diet ad libitum, a low-protein diet ad libitum (mimicking incipient kwashiorkor), or the complete diet in restricted daily quantities (mimicking marasmus), and their second-tier IL-10 production was determined both in vitro and in vivo using lipopolysaccharide (LPS) and anti-CD3 as stimulants of innate and adaptive defences, respectively. Both early (3 days) and advanced (14 days) stages of wasting pathology were examined and three main outcomes emerged. First, classic in vitro systems are unreliable for discerning cytokine production in vivo. Secondly, in diverse forms of acute malnutrition declining challenge-induced IL-10 production may provide an early sign that anti inflammatory control over immune competence is failing. Thirdly, and most fundamentally, the investigation provides new support for the tolerance model of malnutrition-associated inflammatory immune depression. PMID- 21318020 TI - Smoking related diseases: the central role of monoamine oxidase. AB - Smoking is a major risk factor of morbidity and mortality. It is well established that monoamine oxidase (MAO) activity is decreased in smokers. Serotonin (5-HT), a major substrate for MAO that circulates as a reserve pool stored in platelets, is a marker of platelet activation. We recently reported that smoking durably modifies the platelet 5-HT/MAO system by inducing a demethylation of the MAO gene promoter resulting in high MAO protein concentration persisting more than ten years after quitting smoking. The present data enlarges the results to another MAO substrate, norepinephrine (NE), further confirming the central role of MAO in tobacco use-induced diseases. Thus, MAO could be a readily accessible and helpful marker in the risk evaluation of smoking-related diseases, from cardiovascular and pulmonary diseases to depression, anxiety and cancer. The present review implements the new finding of epigenetic regulation of MAO and suggests that smoking-induced MAO demethylation can be considered as a hallmark of smoking related cancers similarly to other aberrant DNA methylations. PMID- 21318021 TI - Fluoride consumption and its impact on oral health. AB - OBJECTIVE: The purpose of this study was to evaluate caries and dental fluorosis among Mexican preschoolers and school-aged children in a non-endemic zone for fluorosis and to measure its biological indicators. METHODS: DMFT, DMFS, dmft, dmfs, and CDI indexes were applied. Fluoride urinary excretion and fluoride concentrations in home water, table salt, bottled water, bottled drinks, and toothpaste were determined. RESULTS: Schoolchildren presented fluorosis (CDI = 0.96) and dental caries (DMFT = 2.64 and DMFS = 3.97). Preschoolers presented dmft = 4.85 and dmfs = 8.80. DMFT and DMFS were lower in children with mild to moderate dental fluorosis (DF). Variable fluoride concentrations were found in the analyzed products (home water = 0.18-0.44 ppm F, table salt = 0-485 ppm F, bottled water = 0.18-0.47 ppm F, juices = 0.08-1.42 ppm F, nectars = 0.07-1.30 ppm F, bottled drinks = 0.10-1.70 ppm F, toothpaste = 0-2,053 ppm F). Mean daily fluoride excretion was 422 +/- 176 MUg/24 h for schoolchildren and 367 +/- 150 MUg/24 h for preschoolers. CONCLUSIONS: Data from our study show that, despite values of excretion within an optimal fluoride intake range, the prevalence of caries was significant in both groups, and 60% of the 11- to 12-year-old children presented with dental fluorosis. In addition, variable fluoride concentrations in products frequently consumed by children were found. PMID- 21318023 TI - Energy solutions, neo-liberalism, and social diversity in Toronto, Canada. AB - In response to the dominance of green capitalist discourses in Canada's environmental movement, in this paper, we argue that strategies to improve energy policy must also provide mechanisms to address social conflicts and social disparities. Environmental justice is proposed as an alternative to mainstream environmentalism, one that seeks to address systemic social and spatial exclusion encountered by many racialized immigrants in Toronto as a result of neo-liberal and green capitalist municipal policy and that seeks to position marginalized communities as valued contributors to energy solutions. We examine Toronto-based municipal state initiatives aimed at reducing energy use while concurrently stimulating growth (specifically, green economy/green jobs and 'smart growth'). By treating these as instruments of green capitalism, we illustrate the utility of environmental justice applied to energy-related problems and as a means to analyze stakeholders' positions in the context of neo-liberalism and green capitalism, and as opening possibilities for resistance. PMID- 21318022 TI - Lysyl oxidase, a critical intra- and extra-cellular target in the lung for cigarette smoke pathogenesis. AB - Cigarette smoke (CS), a complex chemical mixture, contains more than 4,800 different compounds, including oxidants, heavy metals, and carcinogens, that individually or in combination initiate or promote pathogenesis in the lung accounting for 82% of chronic obstructive pulmonary disease (COPD) deaths and 87% of lung cancer deaths. Lysyl oxidase (LO), a Cu-dependent enzyme, oxidizes peptidyl lysine residues in collagen, elastin and histone H1, essential for stabilization of the extracellular matrix and cell nucleus. Considerable evidences have shown that LO is a tumor suppressor as exemplified by inhibiting transforming activity of ras, a proto oncogene. CS condensate (CSC), 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and cadmium (Cd), major components of CS, down-regulate LO expression at such multiple levels as mRNA, protein and catalytic activity in lung cells in vitro and in vivo indicating LO as a critical intra- and extracellular target for CS pathogenesis in the lung. In view of multiple biological functions and regulation characteristics of the LO gene, molecular mechanisms for CS damage to lung LO and its role in emphysema and cancer pathogenesis are discussed in this review. PMID- 21318025 TI - Usage patterns of stop smoking medications in Australia, Canada, the United Kingdom, and the United States: findings from the 2006-2008 International Tobacco Control (ITC) Four Country Survey. AB - Varenicline is a new prescription stop smoking medication (SSM) that has been available in the United States since August 1, 2006, in the United Kingdom and other European Union countries since December 5, 2006, in Canada since April 12, 2007, and in Australia since January 1, 2008. There are few population-based studies that have examined use rates of varenicline and other stop smoking medications. We report data from the ITC Four Country survey conducted with smokers in the US, UK, Canada, and Australia who reported an attempt to quit smoking in past year in the 2006 survey (n = 4,022 participants), 2007 (n = 3,790 participants), and 2008 surveys (n = 2,735 participants) Respondents reported use of various stop smoking medications to quit smoking at each survey wave, along with demographic and smoker characteristics. The self-reported use of any stop smoking medication has increased significantly over the 3 year period in all 4 countries, with the sharpest increase occurring in the United States. Varenicline has become the second most used stop smoking medication, behind NRT, in all 4 countries since being introduced. Between 2006 and 2008, varenicline use rates increased from 0.4% to 21.7% in the US, 0.0% to 14.8% in Canada, 0.0% to 14.5% in Australia, and 0.0% to 4.4% in the UK. In contrast, use of NRT and bupropion remained constant in each country. Males and non-whites were significantly less likely to report using any SSM, while more educated smokers were significantly more likely to use any SSM, including varenicline. Our findings suggest that the introduction of varenicline led to an increase in the number of smokers who used evidence-based treatment during their quit attempts, rather than simply gaining market share at the expense of other medications. From a public health perspective, messages regarding increased success rates among medication users and the relative safety of stop smoking medications should be disseminated widely so as to reach all smokers of all socioeconomic classifications equally. PMID- 21318024 TI - Toxicity of neurons treated with herbicides and neuroprotection by mitochondria targeted antioxidant SS31. AB - The purpose of this study was to determine the neurotoxicity of two commonly used herbicides: picloram and triclopyr and the neuroprotective effects of the mitochondria-targeted antioxidant, SS31. Using mouse neuroblastoma (N2a) cells and primary neurons from C57BL/6 mice, we investigated the toxicity of these herbicides, and protective effects of SS1 peptide against picloram and triclopyr toxicity. We measured total RNA content, cell viability and mRNA expression of peroxiredoxins, neuroprotective genes, mitochondrial-encoded electron transport chain (ETC) genes in N2a cells treated with herbicides and SS31. Using primary neurons from C57BL/6 mice, neuronal survival was studied in neurons treated with herbicides, in neurons pretreated with SS31 plus treated with herbicides, neurons treated with SS31 alone, and untreated neurons. Significantly decreased total RNA content, and cell viability in N2a cells treated with picloram and triclopyr were found compared to untreated N2a cells. Decreased mRNA expression of neuroprotective genes, and ETC genes in cells treated with herbicides was found compared to untreated cells. Decreased mRNA expression of peroxiredoxins 1-6 in N2a cells treated with picloram was found, suggesting that picloram affects the antioxidant enzymes in N2a cells. Immunofluorescence analysis of primary neurons revealed that decreased neuronal branching and degenerating neurons in neurons treated with picloram and triclopyr. However, neurons pretreated with SS31 prevented degenerative process caused by herbicides. Based on these results, we propose that herbicides--picloram and triclopyr appear to damage neurons, and the SS31 peptide appears to protect neurons from herbicide toxicity. PMID- 21318026 TI - Socio-economic variation in price minimizing behaviors: findings from the International Tobacco Control (ITC) Four Country Survey. AB - This paper examines how socio-economic status (SES) modifies how smokers adjust to changes in the price of tobacco products through utilization of multiple price minimizing techniques. Data come from the International Tobacco Control Policy Evaluation (ITC) Four Country Survey, nationally representative samples of adult smokers and includes respondents from Canada, the United States, the United Kingdom and Australia. Cross-sectional analyses were completed among 8,243 respondents (7,038 current smokers) from the survey wave conducted between October 2006 and February 2007. Analyses examined predictors of purchasing from low/untaxed sources, using discount cigarettes or roll-your-own (RYO) tobacco, purchasing cigarettes in cartons, and engaging in high levels of price and tax avoidance at last purchase. All analyses tested for interactions with SES and were weighted to account for changing and under-represented demographics. Relatively high levels of price and tax avoidance behaviors were present; 8% reported buying from low or untaxed source; 36% used discount or generic brands, 13.5% used RYO tobacco, 29% reported purchasing cartons, and 63% reported using at least one of these high price avoidance behaviors. Respondents categorized as having low SES were approximately 26% less likely to report using low or untaxed sources and 43% less likely to purchase tobacco by the carton. However, respondents with low SES were 85% more likely to report using discount brands/RYO compared to participants with higher SES. Overall, lower SES smokers were 25% more likely to engage in at least one or more tax avoidance behaviors compared to their higher SES counterparts. Price and tax avoidance behaviors are relatively common among smokers of all SES strata, but strategies differed with higher SES groups more likely to report traveling to a low-tax location to avoid paying higher prices, purchase duty free tobacco, and purchase by cartons instead of packs all of which were less commonly reported by low SES smokers. Because of the strategies lower SES respondents are more likely to use, reducing price differentials between discount and premium brands may have a greater impact on them, potentially increasing the likelihood of quitting. PMID- 21318027 TI - Tobacco use among emergency department patients. AB - This is the first study to systematically track the tobacco use prevalence in an entire emergency department (ED) population and compare age-stratified rates to the general population using national, provincial, and regional comparisons. A tobacco use question was integrated into the ED electronic registration process from 2007 to 2010 in 11 northern hospitals (10 rural, 1 urban). Results showed that tobacco use documentation (85-89%) and tobacco use (26-27%) were consistent across years with the only discrepancy being higher tobacco prevalence in 2007 (32%) due to higher rates at the urban hospital. Age-stratified outcomes showed that tobacco use remained high up to 50 years old (36%); rates began to decrease for patients in their 50's (26%) and 60's (16%), and decreased substantially after age 70 (5%). The age-stratified ED tobacco rates were almost double those of the general population nationally and provincially for all but the oldest age groups but were virtually identical to regional rates. The tobacco use tracking and age-stratified general population comparisons in this study improves on previous attempts to document prevalence in the ED population, and at a more local level, provides a "big picture" overview that highlights the magnitude of the tobacco-use problem in these communities. PMID- 21318028 TI - An integrated approach for assessing aquatic ecological carrying capacity: a case study of Wujin District in the Tai Lake Basin, China. AB - Aquatic ecological carrying capacity is an effective method for analyzing sustainable development in regional water management. In this paper, an integrated approach is employed for assessing the aquatic ecological carrying capacity of Wujin District in the Tai Lake Basin, China. An indicator system is established considering social and economic development as well as ecological resilience perspectives. While calculating the ecological index, the normalized difference vegetation index (NDVI) is extracted from Moderate Resolution Imaging Spectroradiometer (MODIS) time-series images, followed by spatial and temporal analysis of vegetation cover. Finally, multi-index assessment of aquatic ecological carrying capacity is carried out for the period 2000 to 2008, including both static and dynamic variables. The results reveal that aquatic ecological carrying capacity presents a slight upward trend in the past decade and the intensity of human activities still exceeded the aquatic ecological carrying capacity in 2008. In terms of human activities, population has decreased, GDP has quadrupled, and fertilizer application and industrial wastewater discharge have declined greatly in the past decade. The indicators representing aquatic ecosystem conditions have the lowest scores, which are primarily attributed to the water eutrophication problem. Yet the terrestrial ecosystem is assessed to be in better condition since topographic backgrounds and landscape diversity are at higher levels. Based on the work carried out, it is suggested that pollutant emission be controlled to improve water quality and agricultural development around Ge Lake (the largest lake in Wujin District) be reduced. PMID- 21318029 TI - Acousticofacial-glossopharyngeal triangle: an anatomic model for rapid surgical orientation. AB - The cerebellopontine angle (CPA) poses a surgical challenge due to the complexity and variation of its associated structures. This study examined the relationship between the glossopharyngeal nerve (CN IX) and the acousticofacial complex (AFC). Retrosigmoid suboccipital dissections were preformed on 10 cadaveric specimens. A triangle formed by the AFC, CN IX, and the skull base was consistently observed. The cisternal portions of the AFC and CN IX formed two sides of the triangle. The base was formed by a line traversing the respective dural portals of these nerves at the skull base. Triangular proportions were utilized to predict distances from five points along the course of CN IX to a corresponding point along the course of the AFC. Predicted distances were not statistically different when compared with cadaveric measurements in all 10 specimens (p > 0.05). A table of predicted distances between CN IX and the AFC at all five points along CN IX was developed, revealing a quantitative model to predict the native location of the AFC in the lateral pontine cistern. The triangle and predicted location of the AFC can serve as points of reference for the identification and preservation of these structures in CPA surgery. PMID- 21318030 TI - The anterolateral approach for the transcranial resection of pituitary adenomas: technical note. AB - We sought to quantify the mean surface area of the exposed diaphragma sellae and the mean sellar volume in the subfrontal and anterolateral approaches to pituitary adenomas and to detail our expansion of the superficial and deep window in the anterolateral approach. We performed a retrospective data analysis and cadaveric study in a clinical and skull base laboratory. We studied eight patients who had anterolateral approach for transcranial resection of pituitary macroadenoma and seven cadaveric specimens. Main outcome measures were degree of tumor resection, cerebrospinal fluid (CSF) leak, cranial nerve outcome, and quantification of the exposed sella via the anterior (subfrontal) and anterolateral approach. We observed complete resection in one; visual outcome: stable in three, improved in four, worsened in one; CSF leakage in two; transient CN III palsy in three; mean surface area (mm(2)) of exposed diaphragma sellae,115.3 (subfrontal approach) versus 94.7 (anterolateral approach; p = 0.1); mean sellar volume (mm(3)) exposed, 224.8 (subfrontal approach) versus 569.3 (anterolateral approach; p < 0.0001). Our technical note supports the increased exposure of sellar volume via the anterolateral approach. Despite the relatively high complication rate, complex cranial surgeons should maintain the skills and knowledge of transcranial approaches. Indeed, the rapid expansion of transsphenoidal techniques will continue to decrease the number of cases but will also continue to increase the complexity of those adenomas that are referred for transcranial resection. PMID- 21318032 TI - A novel method of translabyrinthine cranioplasty using hydroxyapatite cement and titanium mesh: a technical report. AB - We report a novel technique for closure using titanium mesh cranioplasty in addition to hydroxyapatite cement and abdominal fat graft for acoustic neuroma. We reviewed 15 patients who underwent translabyrinthine craniectomy for resection of acoustic neuroma. Hearing loss was documented prior to surgical procedure. Over 2 years, patients underwent titanium mesh and hydroxyapatite cranioplasty with abdominal fat graft. Participants included seven men and eight women, age range 38 to 65. Main outcome measures included cosmetic outcome and incidence of cerebrospinal fluid (CSF) leak. The lesion was right-sided in seven patients and left-sided in eight. Cosmetic outcome was excellent in all. There were no cases of CSF leak. Closure used one-third the hydroxyapatite required for traditional closure. Our technique yields cosmetic results equivalent to hydroxyapatite cement alone and a comparable incidence of CSF leakage without leaving a drain in place postoperatively. The technique is easy to adopt, is more cost-effective than hydroxyapatite cement cranioplasty alone, offers greater ease of access for reoperation, and does not preclude later implantation of bone-anchored hearing aid. PMID- 21318033 TI - Our experience in the management of petrous bone cholesteatoma. AB - We present the management of a series of petrous bone cholesteatomas. We performed a retrospective analysis on 28 patients with petrous bone cholesteatoma who underwent surgery between 1991 and 2008 at Lariboisiere Hospital, Paris, France. Main outcome measures included age of patients, surgical approaches, complications, and recurrence. The mean age was 47 years. Five were congenital cholesteatomas and 23 were acquired ones. Seventeen patients had undergone previous mastoid surgery elsewhere. Ninety-six percent of patients presented with hearing loss and 37.5% with facial nerve palsy. The surgical approaches varied according to the classification. Postoperatively, four patients developed facial nerve palsy; two patients, XII nerve paresis; one patient, X nerve paresis; and eight patients, deafness. The mean follow-up was 5 years. Twenty patients had no long-term recurrence. Two cases of petrous apex cholesteatoma presenting with double vision were removed by an endoscopic transsphenoidal approach. Control of the lesion was satisfactory in both cases. However, a minor pontic stroke resulted in transient hemiparesis in the case with dehiscent dura around the petrous bone cholesteatoma. Petrous bone cholesteatoma surgery is difficult. Lateral transtemporal and middle fossa approaches are classically used to remove petrous bone cholesteatoma. Recent progresses in endoscopic surgery, using image guidance system, allow removal of the petrous apex cholesteatoma by an endoscopic transsphenoidal approach with minimal morbidity. PMID- 21318031 TI - Cranial chondrosarcoma and recurrence. AB - The literature regarding recurrences in patients with cranial chondrosarcoma is limited to small series performed at single institutions, raising the question if these data precisely reflect the true recurrence of this tumor for guiding the clinician in the management of these patients. An extensive systematic review of the English literature was performed. The patients were stratified according to treatment modality, treatment history, histological subtype, and histological grade, and the recurrence rates were analyzed. A total of 560 patients treated for cranial chondrosarcoma were included. Five-year recurrence rate among all patients was 22% with median follow-up of 60 months and median disease-free interval of 16 months. Tumor recurrence was more common in patients who only received surgery or had mesenchymal subtype tumors. Our systematic review closely reflects the actuarial recurrence rate and provides predictive factors in the recurrence of cranial chondrosarcoma. PMID- 21318034 TI - Parotid and temporal bone resection for skull base malignancies: outcome. AB - We reviewed the outcome of and determined prognostic factors for patients undergoing combined lateral skull base resection for advanced lateral skull base malignancies. We performed a retrospective, single-institution case series in an academic tertiary care hospital. Seventy-nine patients with combined temporal bone resection and parotidectomy for advanced lateral skull base malignancy were included. Main outcome measures were overall survival and disease-free survival. The mean follow-up time was 18.3 months, with an overall survival of 64.5 months and disease-free survival of 42.6 months. Disease-free survival was 36.2 months for skin tumors, 42.7 months for salivary glands tumors, and 8.5 months for tumors of mesenchymal origin. Log-rank tests for prognostic indicators demonstrated that temporal bone erosion on computed tomography (CT) scan (p = 0.009) and histology (p = 0.045) were statistically significant predictors of poor outcome. Subtotal resection of the facial nerve and positive lymph nodes were associated with poor outcome in tumors arising from skin. Advanced malignancies of the lateral skull base are best managed using a combined lateral temporal bone resection and parotidectomy, with a 50% disease-specific survival of 32 months. Malignant mesenchymal tumors as well as presence of temporal bone erosion on preoperative CT scan are associated with poor prognosis. PMID- 21318035 TI - A case of high-grade undifferentiated sarcoma after surgical resection and stereotactic radiosurgery of a vestibular schwannoma. AB - Stereotactic radiosurgery has become a more frequently used treatment modality for vestibular schwannomas; a few reports of malignant transformation and/or radiation-associated tumors have surfaced. The majority of these reported cases were in patients with underlying neurofibromatosis. The authors report a case of a 74-year-old man with rapid progression of a cerebellar-pontine angle tumor 14 years after surgical resection of a vestibular schwannoma (VS) from the same site, and 6 years after stereotactic radiosurgery. A pathological study of the recent tumor showed a high-grade spindle cell neoplasm that bore no resemblance to the initial schwannoma. The patient had no diagnosis of neurofibromatosis. Secondary malignancy occurred in a non-neurofibromatosis patient 6 years after stereotactic radiosurgery. It is our belief that documentation of such cases will provide important evidence that helps evaluate the long-term effect of radiosurgery for VS. Such observations can influence clinical decisions regarding the choice of treatment modalities. PMID- 21318036 TI - Geniculate ganglion meningioma. AB - The geniculate ganglion is an unusual location for an intratemporal/intracranial meningioma. We present a case of meningioma intrinsic to the geniculate ganglion that presented peculiar features on high-resolution computed tomography (HRCT) and magnetic resonance imaging. On HRCT, we found erosion of the geniculate ganglion with enlargement of the facial canal associated with the appearance of some calcifications within the lesion. These latter findings were confirmed at histological examination. In our patient, the T1- and T2-weighted magnetic resonance images had an intermediate signal and a mild hyperintensity, respectively. Although intracranial meningiomas can have calcifications within the mass, none of the cases of geniculate ganglion meningiomas described in the literature presented with calcifications. To our knowledge, our case is the first with this combination. The presence of calcifications led us to suspect a meningioma of the geniculate segment, which was confirmed at histological examination. PMID- 21318037 TI - Aspergillosis of the Petrous Apex and Meckel's Cave. AB - Cranial cerebral aspergillosis is a rare entity in immunocompetent patients. Invasive disease involving the petrous apex and Meckel's cave has rarely been described. We present a case of localized invasive petrous apical and Meckel's cave disease in an immunocompetent patient who presented with hemicranial neuralgic pain. PMID- 21318038 TI - Large cystic hypoglossal schwannoma with fluid-fluid level: a case report. AB - Hypoglossal schwannomas are rare skull base tumors. Furthermore, cystic hypoglossal schwannomas are extremely uncommon. We report the first case of a large cystic hypoglossal schwannoma with a fluid-fluid level. A 36-year-old woman presented with increased intracranial pressure and cerebellar signs without hypoglossal nerve palsy. Magnetic resonance imaging showed a predominantly cystic mass with a fluid-fluid level in the foramen magnum region extending into the hypoglossal canal. The intracranial tumor was largely removed via a midline suboccipital subtonsillar approach, leaving only a tiny residue in the hypoglossal canal. Histology confirmed a schwannoma with relative hypervascularity. Twenty months later, the tumor recurred and presented as a multicystic dumbbell-shaped lesion, extending intra- and extracranially through the enlarged hypoglossal canal. A complete resection of the intracranial and intracanalicular parts of the tumor was achieved with a small extracranial remnant treated by radiosurgery. Histology revealed a focal increased K(i)67 proliferative index. In this report, we discuss the possible reasons for the absence of hypoglossal nerve palsy and the potential mechanism of the formation of the fluid-fluid level, and we consider the treatment of this lesion. PMID- 21318039 TI - Endoscopic transnasal approach to the craniocervical junction. AB - Anterior access to the craniocervical junction has traditionally been through a transoral approach. With the advent of newer techniques, recent literature suggests a possible role for a transnasal endoscopic approach to the craniocervical junction. A review of the literature primarily consists of case reports and three anatomic cadaveric studies demonstrating the feasibility of an endonasal approach. In this retrospective review, we report our experience with four patients who underwent an endoscopic transnasal approach to the C1-C2 region. The surgical technique using a binasal endoscopic approach is described. The results indicate that the procedure is well tolerated with no significant deleterious sequelae. Although the use of this technique is in its early stages, the transnasal approach may offer a safe and effective alternative with minimal morbidity. Larger clinical studies are necessary to further explore the risks and benefits of this procedure. PMID- 21318040 TI - Multimodal treatment of osteogenic sarcoma of the jaw. AB - Osteosarcomas (OSs) account for 40 to 60% of primary malignant bone tumors. About 10% occur in the head and neck region, frequently in the mandibula or maxilla. We treated a 30-year-old patient with 26-month history of right-sided facial pain and paresthesia. Investigation showed high-grade OS of the right mandibular coronoid process, affecting the mandibular nerve, middle cranial fossa, internal jugular vein, and internal carotid artery (ICA). True en bloc resection was performed after upfront adjuvant chemotherapy. The ICA was trap-ligated intradurally, whereafter the floor of the middle fossa, including the mandibular nerve and the glenoid fossa, was detached from the skull base in one piece. Subsequently, a hemimandibulectomy, total parotidectomy, ICA sacrifice, and removal of the pterygoid plates and muscles were performed, and the abovementioned structures were removed as a solitary specimen, including the facial nerve branches overlying the tumor. A sural nerve graft was interposed between five major facial nerve branches to reanimate the face. The patient had an uneventful recovery, is able to eat, and has a partial facial nerve palsy. He has no tumor recurrence 26 months after surgery. OS of the jaw should be treated with radical surgery as the primary modality. PMID- 21318041 TI - Ewing's Sarcoma of the Petrous Temporal Bone: Case Report and Literature Review. AB - Ewing's sarcoma, which accounts for 6 to 9% of malignant bone neoplasms in children, typically affects the trunk and long bones and less often affects the skull (i.e., maxilla, frontal, parietal, ethmoid, temporal bones). Adding to literature of five previously reported cases, we now describe the case of the oldest child, a 16-year-old boy, with a primary Ewing's sarcoma of the petrous temporal bone. When this patient presented after 1 week of right-sided facial paralysis and new-onset headache, imaging studies showed a mass that originated in the right petrous temporal bone. During biopsy and surgical excision, the mass was found to involve the facial nerve, which then required nerve grafting. Postoperatively, he then underwent radiotherapy with both induction and adjuvant chemotherapy. Although an uncommon tumor of the temporal bone, physicians should consider Ewing's sarcoma in the differential diagnosis of children and adolescents who present with facial nerve paralysis. PMID- 21318042 TI - Chopstick injury penetrating the skull base: a case report. AB - We describe an unusual case of a foreign body penetrating the skull base and lodging in the posterior fossa. A 38-year-old woman fell onto a chopstick while eating, causing it to impact into her mouth. The chopstick penetrated the oropharynx and the occipital bone via the jugular foramen to enter the posterior fossa intracranially, piercing the tentorium cerebelli and leaving a fractured tip in the occipital lobe. Three-dimensional reconstructive computed tomographic scans were obtained to view the trajectory and position of the chopstick. Reconstructed angiography revealed the proximity of the carotid artery and the jugular vessels to the foreign object. Safe access to the chopstick was via an occipital craniotomy to retrieve the distal portion and an ipsiplateral retrosigmoid craniectomy to remove the proximal end. Provision was made to gain proximal control of all major nearby vessels in the event of any hemorrhage. Trauma causing penetration of a foreign body into the posterior fossa of the skull is rare due to its surrounding thick bone. Appropriate preoperative planning, including 3-D computed tomographic images and angiograms, are integral in the surgical approach for the safe removal of such objects. PMID- 21318043 TI - Statistical Survey of Deaths from Nonmelanoma Skin Cancer in Japan during 54 Years. AB - The author analyzed the annual trends in the number of deaths from nonmelanoma skin cancer (NMSC) from 1955 to 2008 in Japan on the basis of the data from the Vital Statistics of Japan. The general trends in the number of deaths from NMSC were downward between 1979 to 1994, but upward after 1995. The general trends in age-standardized death rates were roughly downward, although the death rates plateaued after 1995. The recent annual increased ratio of deaths from NMSC was 3.8% (95% confidence interval: 2.7 ~ 4.9%). The number and proportion of deaths from NMSC among the elderly were increasing in Japan. For females, more than 50% of the deaths occurred recently at or after 85 years of age, whereas, for males, this proportion was at or after 75 years of age, nearly reaching at or after 80 years of age. PMID- 21318044 TI - Transitional Nerve: A New and Original Classification of a Peripheral Nerve Supported by the Nature of the Accessory Nerve (CN XI). AB - Classically, the accessory nerve is described as having a cranial and a spinal root. Textbooks are inconsistent with regard to the modality of the spinal root of the accessory nerve. Some authors report the spinal root as general somatic efferent (GSE), while others list a special visceral efferent (SVE) modality. We investigated the comparative, anatomical, embryological, and molecular literature to determine which modality of the accessory nerve was accurate and why a discrepancy exists. We traced the origin of the incongruity to the writings of early comparative anatomists who believed the accessory nerve was either branchial or somatic depending on the origin of its target musculature. Both theories were supported entirely by empirical observations of anatomical and embryological dissections. We find ample evidence including very recent molecular experiments to show the cranial and spinal root are separate entities. Furthermore, we determined the modality of the spinal root is neither GSE or SVE, but a unique peripheral nerve with a distinct modality. We propose a new classification of the accessory nerve as a transitional nerve, which demonstrates characteristics of both spinal and cranial nerves. PMID- 21318046 TI - The role of imaging in the management of cardiorenal syndrome. AB - Imaging of the kidney and the heart can provide valuable information in the diagnosis and management of cardiorenal syndromes. Ultrasound- (US-) based imaging (echocardiogram and renal US) is an essential component in the initial diagnostic workup of CRS. Echocardiography provides information on the structure and function of heart, and renal ultrasound is useful in differentiating between acute and chronic kidney disease and excluding certain causes of acute kidney injury such as obstructive uropathy. In this paper we overview the basic concepts of echocardiogram and renal ultrasound and will discuss the clinical utility of these imaging techniques in the management of cardiorenal syndromes. We will also discuss the role of other imaging modalities currently in clinical use such as computerized tomography and magnetic resonance imaging as well as novel techniques such as contrast-enhanced ultrasound imaging. PMID- 21318047 TI - A Nonsecosteroidal Vitamin D Receptor Modulator Ameliorates Experimental Autoimmune Encephalomyelitis without Causing Hypercalcemia. AB - Vitamin D receptor (VDR) agonists are currently the agents of choice for the treatment of psoriasis, a skin inflammatory indication that is believed to involve an autoimmune component. 1,25-dihydroxyvitamin D3 [1,25-(OH)(2)D(3)], the biologically active metabolite of vitamin D, has shown efficacy in animal autoimmune disease models of multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and type I diabetes. However, the side effect of 1,25 (OH)(2)D(3) and its synthetic secosteroidal analogs is hypercalcemia, which is a major impediment in their clinical development for autoimmune diseases. Hypercalcemia develops as a result of the action of VDR agonists on the intestine. Here, we describe the identification of a VDR modulator (VDRM) compound A that was transcriptionally less active in intestinal cells and as a result exhibited less calcemic activity in vivo than 1,25-(OH)(2)D(3). Cytokine analysis indicated that the VDRM not only modulated the T-helper cell balance from Th1 to Th2 effector function but also inhibited Th17 differentiation. Finally, we demonstrate that the oral administration of compound A inhibited the induction and progress of experimental autoimmune encephalomyelitis in mice without causing hypercalcemia. PMID- 21318045 TI - Recent Advances in the Pathobiology of Hodgkin's Lymphoma: Potential Impact on Diagnostic, Predictive, and Therapeutic Strategies. AB - From its first description by Thomas Hodgkin in 1832, Hodgkin's disease, now called Hodgkin's lymphoma, has continued to be a fascinating neoplasm even to this day. In this review, historical aspects, epidemiology, diagnosis, tumor biology, new observations related to host-microenvironment interactions, gene copy number variation, and gene expression profiling in this complex neoplasm are described, with an exploration of chemoresistance mechanisms and potential novel therapies for refractory disease. PMID- 21318048 TI - Relationship of Physical Performance with Body Composition and Bone Mineral Density in Individuals over 60 Years of Age: A Systematic Review. AB - The purpose of this review was to examine the relationship between physical performance and body composition measurements, including fat/muscle mass and bone mineral density (BMD) in individuals >=60 years of age. Various measurements used to assess body composition, BMD, and physical performance (PP) were discussed as well. Medline/PubMed, CINAHL, and SCIE were used to identify articles. After limiting the search for age and kind of physical performance measures, 33 articles were evaluated. Higher fat mass was associated with poorer physical performance while higher muscle mass was a predictor of better physical performance, especially in the lower extremities. Additionally, evidence showed that higher muscle fat infiltration was a determinant of poorer physical performance. BMD was shown to be a good predictor of physical performance although the relationship was stronger in women than in men. Developing standardized methods for PP measurements could help in further investigation and conclusions of its relationship with body composition. PMID- 21318049 TI - Intervening on the side effects of hormone-dependent cancer treatment: the role of strength training. AB - While prostate and breast cancers are both highly prevalent and treatable using hormone suppression therapy, a constellation of side effects ensue, which mimic typical aging effects but at an accelerated pace. Because strength training is considered to be an intervention of choice for addressing the musculoskeletal and metabolic consequences of normal aging in older adults, it may be an effective intervention to attenuate or reverse the side effects of hormone-dependent cancer treatment. This paper provides an overview of the independent effects of strength training on common musculoskeletal and metabolic side effects of hormone dependent therapy used for prostate and breast cancers. Strength training appears to be an effective complementary therapy for some of the adverse effects of prostate and breast treatment. Future research needs to address potential mechanisms to explain recent findings and to explore the role of strength training in addressing specific risk factors resulting from cancer treatment. PMID- 21318050 TI - A core-shell nanomaterial with endogenous therapeutic and diagnostic functions. AB - In the present communication we report the fabrication a unique core-shell inorganic nanomaterial with potential therapeutic and diagnostic functions. It contains an iron-cobalt (FeCo) core that demonstrates MRI contrast property and a thin nanoshell of gold that inhibits the function of a pro-angiogenic growth factor, VEGF165. Au(FeCo) core-shell nanomaterials are fabricated in the gas phase and characterized using transmission electron microscopy (TEM), energy dispersive spectrum (EDS), inductively coupled plasma analysis (ICP) and magnetic resonance imaging (MRI). Inhibition of VEGF165 function by Au(FeCo) is demonstrated against VEGF165/VPF induced signaling cascades and proliferation of HUVECs. Self-contrast property of Au(FeCo) is determined in vitro by MRI after incubating HUVECs with Au(FeCo), demonstrating intrinsic contrast property of this potentially therapeutic nanomaterial. In brief, we report here the successful fabrication of an inorganic core-shell nanomaterials with potential therapeutic and diagnostic functions. It inhibits the function of VEGF165 and function as a MRI contrast agent. PMID- 21318051 TI - The Future of Cancer Survivorship Care for Veterans. AB - Veterans have unique risk factors for cancer and comorbidities that may complicate cancer survivorship care. These population-specific characteristics compel research into the needs of veteran cancer survivors to inform best practice. PMID- 21318052 TI - Maintaining Engagement in Long-term Interventions with Relational Agents. AB - We discuss issues in designing virtual humans for applications which require long term voluntary use, and the problem of maintaining engagement with users over time. Concepts and theories related to engagement from a variety of disciplines are reviewed. We describe a platform for conducting studies into long-term interactions between humans and virtual agents, and present the results of two longitudinal randomized controlled experiments in which the effect of manipulations of agent behavior on user engagement was assessed. PMID- 21318053 TI - DNA hypermethylation markers of poor outcome in laryngeal cancer. AB - This study examined molecular (DNA hypermethylation), clinical, histopathological, demographical, smoking, and alcohol variables to assess diagnosis (early versus late stage) and prognosis (survival) outcomes in a retrospective primary laryngeal squamous cell carcinoma (LSCC) cohort. The study cohort of 79 primary LSCC was drawn from a multi-ethnic (37% African American), primary care patient population, diagnosed by surgical biopsies in the Henry Ford Health System from 1991-2004, and followed from 5-18 years (through 2009). Of the 41 variables, univariate risk factors of p<0.10 were tested in multivariate models (logistic regression {diagnosis} and Cox {survival} models {p<0.05}). Aberrant methylation of ESR1 (p=0.01), race as African American (p=0.04), and tumor necrosis (extensive) (p=0.02) were independent predictors of late stage LSCC. Independent predictors of poor survival included presence of vascular invasion (p=0.0009), late stage disease (p=0.03) and methylation of the HIC1 gene (p=0.0002). Aberrant methylation of ESR1 and HIC1 signified independent markers of poorer outcome. In this multi-ethnic, primary LSCC cohort, race remained a predictor of late stage disease supporting disparate diagnosis outcomes for African American patients with LSCC. PMID- 21318054 TI - Rs9939609 variant of the fat mass and obesity-associated gene and trunk obesity in adolescents. AB - A common T/A polymorphism (rs9939609) in the fat mass and obesity associated (FTO) gene was found associated with early-onset and severe obesity in both adults and children. However, recent observations failed to find associations of FTO with obesity. To investigate the genetic background of early obesity, we analysed the single nucleotide polymorphism (SNP) rs9939609 of FTO in 371 styrian adolescents towards degree of obesity, subcutaneous adipose tissue (SAT) distribution determined by lipometry, early metabolic and preatherosclerotic symptoms. The percentage of AA homozygotes for the rs9939609 SNP of FTO was significantly increased in the obese adolescents. Compared to the TT wildtype, AA homozygotes showed significantly elevated values of SAT thickness at the trunk located lipometer measure points neck and frontal chest, body weight, body mass index, waist, and hip circumference. No associations were found with carotis communis intima media thickness, systolic, diastolic blood pressure, ultrasensitive C-reactive protein (US-CRP), homocystein, total cholesterol, triglycerides, HDL cholesterol, oxidized LDL, fasted glucose, insulin, HOMA index, liver transaminases, uric acid, and adipokines like resistin, leptin, and adiponectin. Taken together, to the best of our knowledge we are the first to report that the rs9939609 FTO SNP is associated with trunk weighted obesity as early as in adolescence. PMID- 21318057 TI - Identification of a New Splice Variant of the Human ABCC6 Transporter. AB - ABCC6 is a member of the adenosine triphosphate-binding cassette (ABC) gene subfamily C that encodes a protein (MRP6) involved in active transport of intracellular compounds to the extracellular environment. Mutations in ABCC6 cause pseudoxanthoma elasticum (PXE), an autosomal recessive disorder of the connective tissue characterized by progressive calcification of elastic structures in the skin, the eyes, and the cardiovascular system. MRP6 is codified by 31 exons and contains 1503 amino acids. In addition to a full-length transcript of ABCC6, we have identified an alternatively spliced variant of ABCC6 from a cDNA of human liver that lacks exons 19 and 24. The novel isoform was named ABCC6 Delta19Delta24. PCR analysis from cDNA of cell cultures of primary human hepatocites and embryonic kidney confirms the presence of the ABCC6Delta19Delta24 isoform. Western blot analysis of the embryonic kidney cells shows a band corresponding to the molecular weight of the truncated protein. PMID- 21318055 TI - AMPK as Target for Intervention in Childhood and Adolescent Obesity. AB - Childhood obesity is a major worldwide health problem. Intervention programs to ameliorate the rate of obesity have been designed and implemented; yet the epidemic has no end near in sight. AMP-activated protein kinase (AMPK) has become one of the most important key elements in energy control, appetite regulation, myogenesis, adipocyte differentiation, and cellular stress management. Obesity is a multifactorial disease, which has a very strong genetic component, especially epigenetic factors. The intrauterine milieu has a determinant impact on adult life, since the measures taken for survival are kept throughout life thanks to epigenetic modification. Nutrigenomics studies the influence of certain food molecules on the metabolome profile, raising the question of an individualized obesity therapy according to metabolic (and probably) genetic features. Metformin, an insulin sensitizing agent, its known to lower insulin resistance and enhance metabolic profile, with an additional weight reduction capacity, via activation of AMPK. Exercise is coadjutant for lifestyle modifications, which also activates AMPK in several ways contributing to glucose and fat oxidation. The following review examines AMPK's role in obesity, applying its use as a tool for childhood and adolescent obesity. PMID- 21318056 TI - Weight gain, obesity, and psychotropic prescribing. AB - A majority of psychiatric medications are known to generate weight gain and ultimately obesity in some patients. There is much speculation about the prevalence of weight gain and the degree of weight gain during acute and longitudinal treatment with these agents. There is newer literature looking at the etiology of this weight gain and the potential treatments being used to alleviate this side effect. The authors undertook a comprehensive literature review in order to present epidemiology, etiology, and treatment options of weight gain associated with antipsychotics, mood stabilizers, and antidepressants. PMID- 21318058 TI - The relationship between serum ghrelin levels and hair zinc concentrations in children. AB - BACKGROUND: Zinc (Zn) plays a central role in the activation of numerous enzyme systems that synthesize and degrade bioactive peptides. Some of these bioactive peptides, also called neuropeptides, are involved in the regulation of food intake. OBJECTIVE: In this study we aimed to demonstrate the relationship between serum ghrelin and hair Zn concentrations in children. METHODS: Prepubertal children brought to our outpatient clinics by their parents because of signs and symptoms of pica, poor appetite, poor growth, and other complaints were included in the study. The children were divided into two groups according to Zn hair concentrations. Group 1 consisted of children with low (< 70 MUg/g) hair Zn levels, and group 2 of children with normal ( >= 70 MUg/g) hair Zn levels. Hair Zn concentrations, serum ghrelin, insulin-like growth factor I (IGF-I) and IGF binding protein-3 (IGFBP-3) levels were measured in all children. RESULTS: There were 10 children with low hair Zn levels (group 1) and 15 with normal levels (group 2). Serum IGF-I, IGFBP-3 and ghrelin concentrations of group 1 (103.1 +/- 71.8 ng/mL, 1412.8 +/- 615.7 ng/mL and 0.96 +/- 0.22 ng/mL, respectively) were lower than in group 2(164.9 +/- 40.5 ng/mL, 2398.5 +/- 295.5 ng/mL and 1.21 +/- 0.23 ng/mL, respectively). In univariate analysis, Zn hair concentration was positively associated with serum IGF-I (r=0.424, p=0.035) and IGFBP-3 (r=0.671, p < 0.001) concentrations. The correlation between ghrelin and hair Zn concentrations was not significant (r=0.202, p=0.333). CONCLUSION: Serum ghrelin concentrations might be affected by low hair Zn concentrations in children. PMID- 21318059 TI - Puberty and pubertal growth in healthy Turkish girls: no evidence for secular trend. AB - BACKGROUND: Assessment of pubertal stages should be related to updated and reliable referance data from the same background population. OBJECTIVE: The aim of this study was to provide normative data for the onset and tempo of puberty in Turkish girls and analyze the growth parameters in puberty. METHODS: The analyses are based on data that were collected and evaluated biannually on 1020 Turkish school children aged 8-18 years and a subsample of 101 girls who had reached final height (FH). The data were analyzed cross-sectionally in the total group and longitudinally in the subsample. RESULTS: Mean age and height (Ht) at onset of puberty were 10.1 +/- 1.0 years and 141.7 +/- 7.6 cm, respectively. Peak height velocity (HtV) was 8.5 +/- 1.0 cm/year. Total pubertal height gain was 16.0 +/- 3.9 cm. The duration of puberty was 4.9 +/- 1.2 years. Age at menarche was 12.2 +/- 0.9 years. Height at onset of puberty was positively correlated with FH (p < 0.0001). Body size (weight and height) at onset of puberty and weight and height velocity before the year of onset of puberty correlated negatively with age at onset of puberty (p < 0.05). CONCLUSION: In conclusion, these results provide normative data for pubertal stages and growth parameters in girls in puberty. Height at onset of puberty is the most important determinant of FH. There is no secular trend for the onset of puberty. Weight does seem to affect the onset of puberty but not FH. PMID- 21318060 TI - A randomized clinical trial comparing breakfast and bedtime administration of insulin glargine in children and adolescents with type 1 diabetes. AB - BACKGROUND: Insulin glargine provides effective glycemic control when administered at bedtime in adults. OBJECTIVE: This study aims to investigate whether insulin glargine is equally effective if administered in the morning or at bedtime in combination with preprandial anologue insulin. METHODS: Twenty eight patients that have been treated with an intensified insulin regimen for at least one year were randomized to insulin glargine injection at breakfast (06:00 09:00) (12 patients) or bedtime (21:00-24:00) (16 patients), plus meal-time anologue insulin in the two groups. Glucose data from each day were analyzed at four different times: between 9:00 and 21:00 (t1), between 21:00 and 24:00 (t2), between 24:00 and 04:00 (t3),04:00 and 09:00 (t4) by the Minimed continuous glucose monitoring system. RESULTS: Baseline characteristics were similar in the two groups. The sensor values were lower before breakfast in the bedtime group (180.5 +/- 49.0 vs 223.8 +/- 47.3 mg/dl, p=0.03). There were 13.7 events.patient (-1).day(-1) in the bedtime group and 6.9 events.patient (-1).day(-1) in the breakfast group in which glucose levels fell below 60 mg/dl (p=0.3). There were 121.6 events.patient (-1).day(-1) in the bedtime group and 162.4 events.patient ( 1).day(-1) in the breakfast group in which glucose levels exceeded 180 mg/dl (p=0.05). Nighttime hypoglycemia only reached to a statistical significance between the two groups between 24:00 and 04:00. There were no significant correlations between the duration of nocturnal hypoglycemia, age, duration of diabetes, gender and HbA1c levels. CONCLUSION: Breakfast group is hyperglycemic during the day and hyperglycemia starts in the morning at 04:00. There is no significant difference in the frequency or duration of hypo/hyper glycemia during the day and night irrespective of the timing of glargine injection except pre breakfast levels are significantly better in the bedtime group and hypoglycemia occurs between midnight and 04:00 in the bedtime group. PMID- 21318061 TI - Food types in the diet and the nutrient intake of obese and non-obese children. AB - BACKGROUND: Childhood obesity has reached epidemic proportions world-wide. OBJECTIVE: To compare the types of food in the diet and the nutrient intake of obese children with those of non-obese children. METHODS: A total of 95 obese and 592 non-obese children aged between 6 and 10 years participated in the study. A body mass index (BMI) value exceeding the 95th percentile for age and gender was taken as the criterion for obesity. Three-day food consumption was recorded and evaluated according to standard international recommendations. RESULTS: Macronutrient intake was adequate in both obese and non-obese children. Energy intake of the obese children was significantly higher than that of the non-obese children. Micronutrient intake except fiber of both groups, calcium intake of obese children and vitamin A intake of non-obese children were higher than recommended amounts. The obese children consumed excessive fat and sugar, but less fruit and vegetables as compared to the non-obese children, and less than the recommendations of the food guide pyramid as adopted by the US Department of Food and Agriculture and the Department of Health and Human Services. CONCLUSION: The implementation of educational programs on nutrition may be important for promoting knowledge about healthy eating among obese children. PMID- 21318062 TI - Evaluation of permanent growth hormone deficiency (GHD) in young adults with childhood onset GHD: a multicenter study. AB - BACKGROUND: Reconfirming the diagnosis of childhood onset growth hormone deficiency (GHD) in young adults is necessary to demonstrate the need for continuation of GH therapy. OBJECTIVE: This nationally-based study was planned to establish GH status during adulthood in childhood-onset GH deficient patients and to evaluate factors that would predict persistency of the GHD. METHODS: In this multicenter study, 70 GH deficient patients who had reached final height were evaluated after completion of GH treatment. Fifty-two patients (74%) had isolated GHD and 18 patients (26%) had multiple pituitary hormone deficiency (MPHD). Patients who had reached final height and the pubertal Tanner stage 5 were reevaluated for GH status. After at least 6 weeks of cessation of GH treatment, patients were retested with insulin induced hypoglycemia. RESULTS: GHD was found to be transient in 64.3% of all patients. Of the isolated GH deficient patients 82.7% had transient GHD, whereas 88.9% of the MPHD patients showed persistent GHD. Comparison of isolated GH deficient and multiple hormone deficient patients indicated higher peak GH, IGF-I and IGFBP-3 levels in isolated GH deficient patients. No parameter was significantly different in the transiently and persistently GH deficient patients with respect to gender. Although specificity of IGF-I value of less than -2 SD showing persistency of GHD was lower than the specificity of IGFBP-3 value of less than -2 SD (65.7% vs 84%), negative predictive values were similar for the two parameters (85.2% and 84%, respectively). CONCLUSION: Most of the cases of childhood onset GHD are idiopathic and the GHD is transient. In patients with MPHD, GHD is generally permanent. Low IGF-I and IGFBP-3 levels are supporting findings to show persistency of the GHD. PMID- 21318063 TI - Permanent central diabetes insipidus with complete regression of pituitary stalk enlargement after 4 years of follow-up. AB - A 14 year-old patient was admitted because of a history of polyuria and polydipsia. A diagnosis of central diabetes insipidus (CDI) accompanied by growth hormone (GH) and gonadotropin deficiency was made. Hypophyseal magnetic resonance imaging (MRI) of the patient demonstrated isolated pituitary stalk enlargement. Although GH deficiency and gonadotropin deficiency were transient, CDI was persistent despite the regression of the pituitary stalk enlargement over the 4 years of follow-up. PMID- 21318064 TI - Constitutional growth delay pattern of growth in velo-cardio-facial syndrome: longitudinal follow up and final height of two cases. AB - We report two patients with velo-cardio-facial syndrome (VCFS) who were admitted to our pediatric endocrinology clinic because of short stature and followed longitudinally until attainment of final height. Both patients followed a growth pattern consistent with constitutional delay of puberty with normal and near normal final height. Case 2 also had partial growth hormone (GH) deficiency and severe short stature (height SDS -3.4 SDS), but showed spontaneous catch-up and ended up with a final height of -2 SDS. These cases suggest that short stature in children with VCFS is due to a pattern of growth similar to that observed in constitutional delay of growth and puberty. PMID- 21318065 TI - Obesity in children. AB - The prevalence of childhood obesity has increased dramatically during the past decades all over the world. The majority of obesity in adulthood has its origins in childhood which makes obesity a pediatric concern and the period when interventions should be done. Obesity is associated with increased morbidity and mortality in adult life and several adverse consequences in childhood like insulin resistance, type 2 diabetes, dyslipidemia, polycystic ovarian syndrome, pulmonary and orthopedic disorders and psychological problems. Both genetic and environmental factors play a role in the development of obesity. Prevention of obesity is critical, since effective treatment of this disease is limited. Food management and increased physical activity must be encouraged, promoted, and prioritized to protect children. PMID- 21318066 TI - Atherogenic lipid profile and systolic blood pressure are associated with carotid artery intima-media thickness in children with Turner syndrome. AB - OBJECTIVE: Women with Turner syndrome (TS) have greater carotid artery intima media thickness (cIMT) known to be a risk factor for atherosclerosis in adults. To determine whether there are risk factors for atherosclerosis in children with TS, we compared cIMT, anthropometric and metabolic parameters between children with TS and healthy controls. METHODS: Data of children with TS with XO karyotype (n=24, mean age: 11.6+/-3.6) were compared with those of healthy children (n=24, mean age: 10.5+/-3.6) with respect to anthropometric parameters, lipid levels, insulin resistance and cIMT which was measured by high resolution B-mode ultrasonography. RESULTS: Mean age and cIMT values were similar in the two groups of children. However in children with TS, fasting glucose (p=0.01), total cholesterol (p=0.006), triglyceride (p=0.04) levels and HDL-cholesterol (p=0.002) levels were higher than those of controls. In the TS group, cIMT correlated positively with LDL-cholesterol (r=0.435, p=0.034) and with systolic blood pressure (r=0.430, p=0.036) and negatively with HDL-cholesterol (r=-0.518, p=0.01). In stepwise regression analysis, HDL-cholesterol emerged as a significant predictor of cIMT (b= -0.518, p=0.01) contributing to 26.8 % of its variability. CONCLUSION: The systolic blood pressure and dyslipidaemia were shown to be risk factors for atherosclerosis in children with TS. PMID- 21318067 TI - Prevalence of cryptorchidism among Bulgarian boys. AB - BACKGROUND: Cryptorchidism is the most common congenital defect of the male urogenital system. It may be an important cause for male infertility. The data about its prevalence in South-eastern European countries and especially for the Balkan region are still incomplete. OBJECTIVE: The aim of the present study was to establish the prevalence of the abnormality in the Bulgarian population living in the different areas of the country. METHODS: In a population-based cross sectional study in Bulgaria 6200 Caucasian boys (aged under 1 year to 19 years) from five regions of the country were included. One physician examined all children in order to reduce the inter-observer error. RESULTS: The prevalence of cryptorchidism was 1.52% for the total group. It was 3.2% for boys under one year of age, 2.1% for those between one and ten years and dropped significantly in older boys (0.6%). No regional or seasonal trends were established. CONCLUSIONS: Our study suggests a relatively higher prevalence of cryptorchidism in Bulgaria for children younger than one year of age, while the overall prevalence is comparable to those reported for other countries. The prevalence of cryptorchidism did not differ significantly from the prevalence reported thirty years ago. PMID- 21318068 TI - Prevalence and correlates of obesity in schoolchildren from the city of Bursa, Turkey. AB - BACKGROUND AND OBJECTIVES: The prevalence of childhood obesity has been dramatically increasing worldwide. This study was performed to examine the prevalence and etiological factors of obesity in children aged 6-12 years and to investigate the relative contribution of exogenous factors with respect to sociodemographic data. METHODS: A total of 5368 children aged 6-12 years in eight urban elementary schools located in Bursa, the fourth largest city of Turkey, were included in this cross-sectional study. A dietary record for three days and a questionnaire for the assessment of socio-economic and demographic parameters were completed by the parents at home. The height and weight of the children were measured and relative weight and body mass index (BMI) were calculated. RESULTS: The prevalence of overweight, obesity and severe obesity according to BMI were 12.4%, 7.8% and 2.2%, respectively. The female/male ratio among obese children was 1.24. Eighty percent of obese children had one or both parents obese. Age, gender, presence of obesity in parents, higher educational level of the parents, consumption of soft beverages such as soda and juice, physical activity level and higher income of the family were found as the contributing factors to obesity. CONCLUSION: The prevalence of obesity is increasing in Turkey in parallel to the trend in many countries. There are consistent and predictable sociodemographic parameters that are associated with or may impose a risk factor for obesity. Identification of these risk factors will provide areas to target in the prevention and management of this common problem. PMID- 21318069 TI - Hypovitaminosis D in obese and overweight schoolchildren. AB - AIM: To determine the prevalence of vitamin D hypovitaminosis among obese and overweight schoolchildren. DESIGN: A cross-sectional population based sample. METHODS: In a cross-sectional study, 301 students (177 girls and 124 boys) aged 11-19 years were selected by multistage stratified sampling design. Subjects were classified according to their body mass index as obese, overweight and normal. Serum 25-hydroxyvitamin D (25-OHD), intact parathyroid hormone (iPTH) and alkaline phosphatase (ALP) were measured in late winter months. Vitamin D deficiency was defined as a 25-OHD 20 ng/ml. RESULTS: The prevalence of hypovitaminosis D was found as 65% in all students. Vitamin D deficiency was found in 12% and insufficiency in 53% of all students. Vitamin D deficiency in female students was about two times more common than in males. In obese and overweight schoolchildren with hypovitaminosis D, serum 25-OHD levels decreased as BMI increased. There were no correlations between serum 25-OHD and ALP and iPTH levels. CONCLUSION: Vitamin D deficiency and insufficiency are common in obese and overweight schoolchildren, especially in girls. Obesity could be a risk factor in terms of hypovitaminosis D in adolescents. Vitamin D supplementation should be administered particularly to adolescent girls. PMID- 21318070 TI - Severe short stature: an unusual finding in lipoid proteinosis. AB - Lipoid proteinosis (LP) is a rare disorder and it can affect every organ in the body. The clinical manifestations of LP may vary considerably between affected individuals. Short stature is reported in patients with LP however the underlying etiology is not clear. Short stature may be due to endocrine dysfunction caused by deposition of hyaline-like material in endocrine glands. We investigated a 13 year old patient with LP (507 delT mutation) who had severe short stature. He had hoarseness since the age of one year, followed by characteristic skin lesions for LP and short stature. There was no pathology with respect to endocrinological investigations in our patient including growth hormone-IGF axis. Our results show that short stature in LP can not be explained by endocrinological abnormalities. Short stature may be an intrinsic component of the syndrome. PMID- 21318071 TI - Ag(x)VOPO(4): A Demonstration of the Dependence of Battery-Related Electrochemical Properties of Silver Vanadium Phosphorous Oxides on Ag / V Ratios. AB - As a part of our on-going study on silver vanadium phosphorous oxides (Ag(x)V(y)O(z)PO(4)), we report here the first study of the electrochemical reduction of a low Ag/V ratio silver vanadium phosphorous oxide, Ag(0.48)VOPO(4).1.9H(2)O. Reminiscent of Ag(2)VO(2)PO(4) reduction, in-situ formation of silver metal nanoparticles along with an associated increase in conductivity were observed after reduction of Ag(0.48)VOPO(4).1.9H(2)O with 0.37 electron equivalents. However, in contrast to our lithium / Ag(2)VO(2)PO(4) cells, our lithium / Ag(0.48)VOPO(4).1.9H(2)O cells displayed an even higher voltage on discharge and a characteristic multi-plateau voltage profile, where vanadium reduction was the first reduction step. PMID- 21318073 TI - Experimentally approaching the ICU: monitoring outcome-based responses in the two hit mouse model of posttraumatic sepsis. AB - To simulate and monitor the evolution of posttraumatic sepsis in mice, we combined a two-hit model of trauma/hemorrhage (TH) followed by polymicrobial sepsis with repetitive blood sampling. Anesthetized mice underwent femur fracture/sublethal hemorrhage and cecal ligation and puncture (CLP) 48 h later. To monitor outcome-dependent changes in circulating cells/biomarkers, mice were sampled daily (facial vein) for 7 days and retrospectively divided into either dead (DIE) or surviving (SUR) by post-CLP day 7. Prior to CLP, AST was 3-fold higher in DIE, while all other post-TH changes were similar between groups. There was a significant post-CLP intergroup separation. In SUR, RBC and Hb were lower, platelets and neutrophils higher, and lymphocytes mixed compared to DIE. In DIE, all organ function markers except glucose (decrease) were few folds higher compared to SUR. In summary, the combination of daily monitoring with an adequate two-hit model simulates the ICU setting, allows insight into outcome-based responses, and can identify biomarkers indicative of death in the acute posttraumatic sepsis in mice. PMID- 21318074 TI - Gait disturbances in dystrophic hamsters. AB - The delta-sarcoglycan-deficient hamster is an excellent model to study muscular dystrophy. Gait disturbances, important clinically, have not been described in this animal model. We applied ventral plane videography (DigiGait) to analyze gait in BIO TO-2 dystrophic and BIO F1B control hamsters walking on a transparent treadmill belt. Stride length was ~13% shorter (P < .05) in TO-2 hamsters at 9 months of age compared to F1B hamsters. Hindlimb propulsion duration, an indicator of muscle strength, was shorter in 9-month-old TO-2 (247 +/- 8 ms) compared to F1B hamsters (272 +/- 11 ms; P < .05). Braking duration, reflecting generation of ground reaction forces, was delayed in 9-month-old TO-2 (147 +/- 6 ms) compared to F1B hamsters (126 +/- 8 ms; P < .05). Hindpaw eversion, evidence of muscle weakness, was greater in 9-month-old TO-2 than in F1B hamsters (17.7 +/ 1.2 degrees versus 8.7 +/- 1.6 degrees ; P < .05). Incline and decline walking aggravated gait disturbances in TO-2 hamsters at 3 months of age. Several gait deficits were apparent in TO-2 hamsters at 1 month of age. Quantitative gait analysis demonstrates that dystrophic TO-2 hamsters recapitulate functional aspects of human muscular dystrophy. Early detection of gait abnormalities in a convenient animal model may accelerate the development of therapies for muscular dystrophy. PMID- 21318072 TI - The small subunit processome in ribosome biogenesis-progress and prospects. AB - The small subunit (SSU) processome is a 2.2-MDa ribonucleoprotein complex involved in the processing, assembly, and maturation of the SSU of eukaryotic ribosomes. The identities of many of the factors involved in SSU biogenesis have been elucidated over the past 40 years. However, as our understanding increases, so do the number of questions about the nature of this complicated process. Cataloging the components is the first step toward understanding the molecular workings of a system. This review will focus on how identifying components of ribosome biogenesis has led to the knowledge of how these factors, protein and RNA alike, associate with one another into subcomplexes, with a concentration on the small ribosomal subunit. We will also explore how this knowledge of subcomplex assembly has informed our understanding of the workings of the ribosome synthesis system as a whole. PMID- 21318075 TI - Cadaveric renal transplantation using kidneys from donors greater than 60 years old. AB - Transplantation of kidneys from donors over the age of 60 yr is controversial. However, as the demand for cadaveric kidneys far exceeds the supply, exploration of the usefulness of kidneys outside the currently accepted donor pool is necessary. Between January 1987 and July 1989, 31 (5.5%) of the 558 cadaveric renal transplants performed at the University of Pittsburgh utilized organs from donors older than 60 yr. Median recipient age was 41 yr (range 24-71 yr); 4 recipients were diabetic and 6 had panel-reactive antibody levels greater than 20% at the time of transplant. All recipients were treated with cyclosporine, prednisone and azathioprine. The 1-yr allograft survival was 65% which was less than but not statistically different from the graft survival of 80% in a retrospective selected control group who received grafts from younger donors aged 11 to 50 yr. However, the 1-yr graft survival of older donor kidneys with cold ischemia time greater than 48 hours was 38%, which was significantly poorer than the 78% 1-yr graft survival seen with cold ischemia times less than 48 h (p=0.04 Breslow). The mean serum creatinine was significantly higher in the older donor kidneys at 1, 3, and 12 months post-transplant than in the control kidneys even when kidneys with greater than 48 h of cold ischemia time were excluded. In summary, transplantation of cadaver kidneys from donors older than 60 yr results in acceptable graft survival rates. These kidneys are more susceptible to cold ischemic injury and function with a higher serum creatinine than kidneys from younger donors. Expansion of the donor pool by the use of older donor kidneys in selected recipients could have an impact on alleviating the chronic national cadaver kidney shortage. PMID- 21318076 TI - Functional cooperation of xenoproteins after hamster-to-rat liver transplantation: With particular reference to hamster C3 and secretory component for rat IgA. AB - Long-term survival after hamster-to-rat liver xenotransplantation has provided the opportunity to study the posttransplantation source of major serum proteins and the functional consequences of several different receptor-ligand interactions, where one or the other is a xenogeneic protein. We report here that serum albumin, alpha-1-antitrypsin, complement component 3, and other acute phase reactants switch from recipient to donor origin during the first week after transplantation while serum immunoglobulins remain largely that of recipient. Despite the disparate source of complement (hamster) and immunoglobulins (rat), these two proteins were able to cooperate effectively to produce lysis of sheep red blood cells. Moreover, rat IgA was successfully processed by hamster hepatocytes and biliary epithelial cells, being present in the bile of successful liver xenograft recipients within one day after transplantation. The ability of these liver xenograft recipients to survive long-term in conventional and viral free animal facilities without grossly obvious morbidity or unusual susceptibility to stress, suggests that xenogeneic proteins are able to successfully interact with several different physiologic systems in the hamster to-rat combination. PMID- 21318078 TI - Effect of fat on measurement of bone mineral density. AB - OBJECTIVE: To determine if increasing fatness interferes with the measurement of fat and bone mineral density (BMD) by dual-energy X-ray absorptiometry (Lunar iDXA). METHODS: We performed measurements of BMD and fat on a section of a beef femur defatted by prolonged boiling in detergent, completely surrounded by increasing thicknesses of lard. Initially the bone was placed in the marked spine area, overlying a 6L plastic bottle which was placed in the marked trunk area of the iDXA. The plastic bottle was then removed and further measurements were carried out with increasing thicknesses of lard surrounding the bone. Measurements were repeated 4 times. RESULTS: The reported measurement of BMD progressively increased with each increased layer of lard surrounding the bone. All the iDXA BMD measurements were significantly (P<0.01) different from one another. When surrounded by 3 layers of lard the reported BMD was 20.5% greater than the reported BMD when the bone was not surrounded by any lard. The differences between the actual amount of fat measured by chemical analysis and weighing, and the reported measurement of fat by iDXA were significant with all 3 thicknesses of lard (P<0.01); the percentage difference between the fat measured by iDXA and that measured chemically decreased as the number of layers of lard increased. CONCLUSION: We found that iDXA overestimated fat by up to 11.1%. The percentage overestimation of fat diminished as the amount of fat increased. BMD was overestimated by 20.5% when surrounded by 3 layers of fat compared to when there was no surrounding fat. In contrast to fat, the percentage overestimation of BMD increased as increasing amounts of fat surrounding the bone Using earlier generation DXAs, others have reported that measurements were +/- 20-50% inaccurate and differed according to the configuration of the phantoms. The measurement of BMD and fat is the main clinical purpose of iDXA; the present experiment has shown that there are substantial inaccuracies in the measurement of BMD and fat. It is not known how these inaccuracies compare with those of earlier generations of DXA machines. PMID- 21318077 TI - Correction of congenital hyperbilirubinemia in homozygous Gunn rats by xenotransplantation of hamster livers. AB - The homozygous Gunn(j/j) rat is an animal model for Crigler-Najjarsyndrome in which the lack of the enzyme uridine diphosphoglucoronate-glucuronosyltransferase (UDP-GT) results in congenital unconjugated nonhemolytic hyperbilirubinemia. Because the binding of bilirubin to albumin in plasma varies from species to species, xenotransplantation (XTx) of liver afforded in this model the opportunity to study the interactions between xenoproteins of the donor and bilirubin of the recipient. For this purpose, orthotopic liver transplantation (OLTx) was performed from hamster to adult Gunn(j/j) rats. No immunosuppression (IS) was given to controls. (Group I, n=5) and to OLTx recipients of syngeneic (Gunn(j/j) rat) grafts (Group II, n=5), whereas tacrolimus (1 mg/kg/day * 15 days, IM) and cyclophosphamide (8 mg/kg/day * 7 days, IP) were administered to animals receiving hamster xenografts (Group III, n=l1). While untreated animals (Group I) died within 7 days (6.8+/-0.2 days) post-transplantation (Tx), the use however of IS resulted in prolonged (30.2+/-6.8 days) survival of xenogeneic recipients (Group III) who eventually succumbed to rejection. A precipitous decline in total serum bilirubin (TBili) from pre-operative levels of 5.3+/-1.0 mg/dL to 0.5+/-0.2 mg/dL was noted in both Group I and III animals, an observation that sustained itself only in the latter group during the course of their follow-up. The decrease in TBili was also associated with a contemporaneous increase in biliary concentration of conjugated bilirubin. No noticeable reversal of hyperbilirubinemia was however observed in OLTx recipients of syngeneic grafts (Group II). Taken together, these data suggest that hamster albumin and hepatocyte-associated xenoproteins and enzymes involved in the process of membrane transport and glucuronidation of bilirubin, functioned efficaciously after OLTx in Gunn(j/j), rats, resulting in the reversal of the inborn error of metabolism for the duration of follow-up. PMID- 21318079 TI - Chemoenzymatic Synthesis of 2-Arachidonoylglycerol, An Endogenous Ligand for Cannabinoid Receptors. AB - A simple and efficient synthesis of 2-arachidonoyl glycerol, an endogenous agonist for cannabinoid receptors was achieved using Novozym 435, immobilized lipase from Candida Antarctica. PMID- 21318080 TI - An Examination of the Mediational Effects of Cognitive and Attitudinal Factors of a Parent Intervention to Reduce College Drinking. AB - As part of a parent intervention to reduce heavy-drinking, college freshmen were assessed for their attitudes toward drinking and reasonable alternatives to drinking on the weekends, as well as cognitive variables underlying attitudinal variables. Intervention parents received a handbook the summer prior to college entrance with information about college drinking and best practices for parent teen communication. Results revealed that the association between intervention condition and drinking outcomes was mediated by attitudes favorable to drinking and reasonable alternatives to drinking, as well as beliefs about alcohol related behavior. This parent program was shown to be efficacious for changing high-risk drinking in college. Findings are discussed regarding the further development of college drinking prevention programs involving parents. PMID- 21318081 TI - A Parylene Bellows Electrochemical Actuator. AB - We present the first electrochemical actuator with Parylene bellows for large deflection operation. The bellows diaphragm was fabricated using a polyethylene glycol-based sacrificial molding technique followed by coating in Parylene C. Bellows were mechanically characterized and integrated with a pair of interdigitated electrodes to form an electrochemical actuator that is suitable for low-power pumping of fluids. Pump performance (gas generation rate and pump efficiency) was optimized through a careful examination of geometrical factors. Overall, a maximum pump efficiency of 90% was achieved in the case of electroplated electrodes, and a deflection of over 1.5 mm was demonstrated. Real time wireless operation was achieved. The complete fabrication process and the materials used in this actuator are bio-compatible, which makes it suitable for biological and medical applications. PMID- 21318082 TI - Fledgling Psychopathy in the Classroom: ADHD Subtypes Psychopathy, and Reading Comprehension in a Community Sample of Adolescents. AB - The current study explores characteristics that are associated with fledgling psychopathy and educational outcomes relating to reading comprehension performance in a community sample of 432 middle school students. Latent class analysis (LCA) produced a four-class solution. Class 1 was a large (71.5% of sample) ''control'' group of youths with no attention/hyperactivity deficits and the highest reading comprehension scores. Class 2 was 11.6% of the sample and was consistent with traits associated with attention deficit hyperactivity disorder (ADHD) predominantly inattentive type. Class 3 was 7.4% of the sample and was consistent with traits associated with ADHD predominantly hyperactive-impulsive type. Class 4 was 9.5% of the sample and was consistent with traits associated with ADHD combined type. Classes 2 and 4 were characterized by elevated levels of psychopathic and callous-unemotional (CU) traits and lower educational performance. This study extends the utility of fledgling psychopathy to educational outcomes, which has broad implications for adolescent development, delinquency, and youth violence. PMID- 21318083 TI - Religious Involvement and Physical Functioning among Older Mexican Americans. AB - BACKGROUND AND PURPOSE: Examine the association between attendance at religious services and incidence of ADL disability over a period of seven years among older Mexican Americans 65 years and older. METHODS: Using data from the Hispanic Established Population for the Epidemiological Study of the Elderly (H-EPESE), logistic generalized estimation equation (GEE) models were used to analyze the contribution of attendance at religious services to the differences in incidence of ADL disability over seven years, controlling for demographics, medical conditions, and physical mobility. RESULTS: Frequent attendees at religious services had 30% lower odds of developing ADL disability over seven years compared to the non-regular attendance group. The odds were reduced to 23%, but remained significant when physical and mental health were controlled. CONCLUSIONS: In this older Mexican American population, regular attendees at religious services were less likely to develop ADL disability over a period of seven years compared to those who attended services less often. PMID- 21318084 TI - Bayesian Models and Decision Algorithms for Complex Early Phase Clinical Trials. AB - An early phase clinical trial is the first step in evaluating the effects in humans of a potential new anti-disease agent or combination of agents. Usually called "phase I" or "phase I/II" trials, these experiments typically have the nominal scientific goal of determining an acceptable dose, most often based on adverse event probabilities. This arose from a tradition of phase I trials to evaluate cytotoxic agents for treating cancer, although some methods may be applied in other medical settings, such as treatment of stroke or immunological diseases. Most modern statistical designs for early phase trials include model based, outcome-adaptive decision rules that choose doses for successive patient cohorts based on data from previous patients in the trial. Such designs have seen limited use in clinical practice, however, due to their complexity, the requirement of intensive, computer-based data monitoring, and the medical community's resistance to change. Still, many actual applications of model-based outcome-adaptive designs have been remarkably successful in terms of both patient benefit and scientific outcome. In this paper, I will review several Bayesian early phase trial designs that were tailored to accommodate specific complexities of the treatment regime and patient outcomes in particular clinical settings. PMID- 21318085 TI - The Influence of Youth Music Television Viewership on Changes in Cigarette Use and Association with Smoking Peers: A Social Identity, Reinforcing Spirals Perspective. AB - Prior research has found strong evidence of a prospective association between R movie exposure and teen smoking. Using parallel process latent-growth modeling, the present study examines prospective associations between viewing of music video channels on television (e.g., MTV and VH-1) and changes over time in smoking and association with smoking peers. Results showed that baseline viewing of music-oriented channels such as MTV and VH-1 robustly predicted increasing trajectories of smoking and of associating with smoking peers, even after application of a variety of controls including parent reports of monitoring behavior. These results are consistent with the arguments from the reinforcing spirals model that such media use serves as a means of developing emergent adolescent social identities consistent with associating with smoking peers and acquiring smoking and other risk behaviors; evidence also suggests that media choice in reinforcing spiral processes are dynamic and evolve as social identity evolves. PMID- 21318086 TI - Changing separating distances between immune receptors as a sensitive mechanism regulating T-cell activation. PMID- 21318087 TI - The role of colorectal cancer stem cells in metastatic disease and therapeutic response. AB - Colorectal cancer is the third-leading cause of cancer related mortality in the United States. The intricate molecular mechanisms involved in the regenerative process of the normal intestine and the identity of putative somatic intestinal stem cells have become clear. In parallel with this, experiment evidence has emerged supporting the century old hypothesis that solid tumor initiation, progression, chemoresistance and recurrence is the result of a small population of cancer cells with self-renewal and pluripotency capabilities. These "cancer stem cells" (CSCs) present a unique opportunity to better understand the biology of solid tumors in general, as well as targets for future therapeutics. In this review, we will summarize the current understanding of intestinal stem cell biology and translate it to colorectal CSCs to provide a basis for understanding chemoresistance, cancer recurrence and metastasis. A more complete understanding of the biology of colorectal CSCs will translate into the development of better chemotherapeutic and biological agents for the treatment of colorectal cancer. PMID- 21318088 TI - Comparison of body composition by bioelectrical impedance analysis and dual energy X-ray absorptiometry in Hispanic diabetics. AB - OBJECTIVE: The purpose of this study was to compare Tanita tetrapolar foot-to foot bioelectrical impedance analysis (Model TBF-310, Tanita Corporation of America, Inc, Arlington Heights, IL; Tanita-BIA) and fan beam dual-energy X-ray absorptiometry (Hologic Discovery A v12.6, Waltham, MA; DXA) in diabetic patients. METHODS: Seventy Hispanic diabetic participants (23 male, 47 female; mean age: 53.03 +/- 10.32 yrs; mean weight: 81.45 +/- 17.65 kg; and mean body mass index: 31.40 +/- 6.80 kg/m(2)) were selected from the Loma Linda University En Balance culturally-sensitive Spanish diabetes education program using the baseline data. RESULTS: DXA vs Tanita-BIA fat mass (FM), percent fat mass (%FM), and fat-free mass (FFM) were compared using Pearson's (FM: 0.96, %FM: 0.91, and FFM: 0.95), and Spearman's rank (FM: 0.94, %FM: 0.91, and FFM: 0.93) correlation coefficients. Bland-Altman analyses were also used to compare the difference (DXA - BIA) vs average of DXA and BIA results and showed general agreement between the two methods. When Tanita-BIA was regressed onto DXA, the adjusted R(2) was: FM=0.91; %FM=0.83; FFM=0.90. Gender combined concordance correlations with 95% confidence intervals were calculated using a bootstrap re-sampling of the data and found high associations [FM: 0.93 (95% CI: 0.89, 0.96)], [%FM: 0.86 (95% CI: 0.79, 0.90)], and [FFM: 0.93 (95% CI: 0.89, 0.96)]. CONCLUSION: Tanita-BIA may provide valid measures of fat, percent body fat and fat-free mass in Hispanic diabetics, and could be a convenient and practical approach for assessment in community-based research. PMID- 21318089 TI - Sanguinarine suppresses prostate tumor growth and inhibits survivin expression. AB - Prostate cancer is a frequently occurring disease and is the second leading cause of cancer-related deaths of men in the United States. Current treatments have proved inadequate in curing or controlling prostate cancer, and a search for agents for the management of this disease is urgently needed. Survivin plays an important role in both progression of castration-resistant prostate cancer and resistance to chemotherapy. Altered expression of survivin in prostate cancer cells is associated with cancer progression, drug/radiation resistance, poor prognosis, and short patient survival. In the present study, the authors performed a cell-based rapid screen of the Prestwick Chemical Library consisting of 1120 Food and Drug Administration-approved compounds with known safety and bioavailability in humans to identify potential inhibitors of survivin and anticancer agents for prostate cancer. Sanguinarine, a benzophenanthridine alkaloid derived primarily from the bloodroot plant, was identified as a novel inhibitor of survivin that selectively kills prostate cancer cells over "normal" prostate epithelial cells. The authors found that sanguinarine inhibits survivin protein expression through protein degradation via the ubiquitin-proteasome system. Sanguinarine induces apoptosis and inhibits growth of human prostate cancer cells and in vivo tumor formation. Administration of sanguinarine, beginning 3 days after ectopic implantation of DU145 human prostate cancer cells, reduces both tumor weight and volume. In addition, sanguinarine sensitized paclitaxel-mediated growth inhibition and apoptosis, offering a potential therapeutic strategy for overcoming taxol resistance. These results suggest that sanguinarine may be developed as an agent either alone or in combination with taxol for treatment of prostate cancer overexpressing survivin. PMID- 21318090 TI - Impacting obesity and glycemic control using a culturally-sensitive diabetes education program in Hispanic patients with type 2 diabetes. AB - OBJECTIVES: Diabetes mellitus and obesity are prevalent in the Hispanic community. This group has not benefited greatly from diabetes interventions due to cultural, language and financial constraints. We designed a prospective cohort study to determine the clinical impact on adiposity and glycemic control in Hispanics with type 2 diabetes. RESEARCH DESIGN AND METHODS: The program conducted in Spanish by a multidisciplinary team of health care providers focused on improving glycemic control and complications through cultural lifestyle changes. Outcomes were changes in glycemic control by fasting insulin, glucose and HbA1c, body composition and selected adipokines, adiponectin, leptin and ghrelin. Body composition was measured by dual energy x-ray absorptiometry. Changes from baseline at three months were compared using paired t-tests and with Spearman's correlations. RESULTS: Glycemic control improved by HbA1c (7.9% +/- 2.0% vs 7.1% +/- 1.7%; P = <0.001), and fasting glucose (166.4 +/- 66.0 mg/dl vs 143.2 +/- 57.9 mg/dl; P = 0.003). Body weight (81.3 +/- 17.9 kg vs 80.3 +/- 18.0 kg; P = 0.002), waist circumference (101.6 +/- 13.4 cm vs 99.1 +/- 12.7 cm; P = 0.015), and truncal fat (16.5 +/- 5.7 kg vs 15.9 +/- 5.6 kg; P = 0.001) decreased. Only leptin (19.6 +/- 15.0 ng/ml vs 16.3 +/- 12.7 ng/ml; P = 0.002) was reduced and related to change in body weight (r = 0.392; P = 0.022). CONCLUSIONS: Our program significantly improved glycemic control and decreased obesity in diabetic Hispanic subjects. The early benefits on glycemic control may be related to reductions in leptin through loss of adipose tissue. Success in impacting diabetes and related complications can occur in a culturally focused and multidisciplinary context. PMID- 21318091 TI - Effect of the EnBalance, a culturally and language-sensitive diabetes education program, on dietary changes and plasma lipid profile in Hispanic diabetics. AB - OBJECTIVE: To assess the effects of a language-sensitive diabetes education program on dietary changes and plasma lipid profiles. METHOD: Hispanic participants (n=13 males and 18 females, mean age = 54.00 + 10.68 years) participated in a 3-month health education study. Spearman correlation coefficients were used to evaluate correlations between dietary intake and laboratory measurements. RESULTS: There were significant decreases in serum total cholesterol (-16.07 mg/dl, P= 0.035), HDL cholesterol (-3.23 mg/dl, P = 0.01), LDL cholesterol (-11.71 mg/dl, P = 0.013) and dietary cholesterol (-79.22 mg, P = 0.03). No significant mean change was observed in triglyceride and total cholesterol/HDL ratio. There was also a reduction in body mass index (BMI) (-0.15 kg/m(2), P = 0.40), fasting glucose (-3.90 mg/dl, P = 0.43) and dual energy X-ray absorptiometry (DXA) total fat (-0.50, P = 0.97). Although not statistically significant, saturated fatty acids (-4.90 g, P = 0.19), polyunsaturated fatty acids (-3.31g, P = 0.11), and carbohydrate (-44.82 g, P = 0.22), decreased after three months. CONCLUSION: There were significant improvements in dietary intake and serum lipids after a three-month culture-specific diabetes education program. PMID- 21318092 TI - Potential latent effects of prenatal cocaine exposure on growth and the risk of cardiovascular and metabolic disease in childhood. AB - The literature strongly suggests that prenatal exposure to certain medications and substances does not cause major malformations in early childhood. However, these exposures may have far-reaching latent health effects, such as restricted growth, hypertension, and cardiovascular events in adulthood. We reviewed the literature to identify the effects of prenatal cocaine exposure on growth and the risk of cardiovascular and metabolic disease in late adolescence and early adulthood by examining studies that were published in peer-reviewed English language journals from 1990 through 2009 and indexed in MEDLINE. We found that animal and clinical studies of the influence of prenatal cocaine exposure on child and adolescent growth and the subsequent development of myocardial and cardiometabolic disease risk factors are few and inconclusive. Studies support the hypothesis that vascular and hemodynamic functions are partially programmed in early life and thus substantially influence vascular aging and arterial stiffening in later life. Sub-optimal fetal nutrition and growth may increase blood pressure and the development of cardiovascular and metabolic disease in late life. How prenatal cocaine and other drug exposure effects this relationship is currently unknown. Despite high rates of cocaine and other drug use during pregnancy (up to 18% in some studies), little is known about the health effects of prenatal cocaine exposure in adolescence and early adulthood. The few studies of early growth deficits persisting into adolescence are inconclusive. The literature provides little information on how exposed children grow into adulthood and about their subsequent risk of cardiometabolic and vascular disease. PMID- 21318093 TI - On the Representation of Turbulent Stresses for Computing Blood Damage. AB - Computational prediction of blood damage has become a crucial tool for evaluating blood-wetted medical devices and pathological hemodynamics. A difficulty arises in predicting blood damage under turbulent flow conditions because the total stress is indeterminate. Common practice uses the Reynolds stress as an estimation of the total stress causing damage to the blood cells. This study investigates the error introduced by making this substitution, and further shows that energy dissipation is a more appropriate metric of blood trauma. PMID- 21318094 TI - [I]-Celecoxib Analogues as SPECT Tracers of Cyclooxygenase-2 in Inflammation. AB - We report the synthesis and evaluation of a series of iodinated celecoxib analogues as cyclooxygenase-2 (COX-2)-targeted single photon emission computerized tomography (SPECT) imaging agents for the detection of inflammation. The structure-activity relationship identified 5-(4-iodophenyl)-1-{4 (methylsulfonyl)phenyl}-3-(trifluoromethyl)-1H-pyrazole (8) as a promising compound with IC(50) values of 0.05 MUM against purified COX-2 and 0.03 MUM against COX-2 in activated macrophages. The arylstannane of 8 undergoes facile radio-[(123)I]-iodination upon treatment with Na(123)I/NaI and chloramine T using an EtOAc/H(2)O two-phase system. The [(123)I]-8 was produced in a radiochemical yield of 85% and a radiochemical purity of 99%. In vivo SPECT imaging demonstrated that the radiotracer was taken up by inflamed rat paws with an average 1.7-fold enrichment over contralateral noninflamed paws. This study suggests that conversion of celecoxib into its isomeric iodo-[(123)I]-analogues is a useful approach for generating novel and efficacious agents for COX-2 targeted SPECT imaging of inflammation. PMID- 21318096 TI - Large-scale Neuroanatomical Visualization Using a Manifold Embedding Approach. AB - We present a unified framework for data processing, mining and interactive visualization of large-scale neuroanatomical databases. The input data is assumed to lie in a specific atlas space, or simply exist as a separate collection. Users can specify their own atlas for comparative analyses. The original data exist as MRI images in standard formats. It is uploaded to a remote server and processed offline by a parallelized pipeline workflow. This workflow transforms the data to represent it as both volumetric and triangular mesh cortical surfaces. We use multiresolution representations to scale complexity to data storage availability as well as graphical processing performance. Our workflow implements predefined metrics for clustering and classification, and data projection schemes to aid in visualization. Additionally the system provides a visual query interface for performing selection requests based on user-defined search criteria. PMID- 21318095 TI - HPV-DNA integration and carcinogenesis: putative roles for inflammation and oxidative stress. AB - HPV-DNA integration into cellular chromatin is usually a necessary event in the pathogenesis of HPV-related cancer; however, the mechanism of integration has not been clearly defined. Breaks must be created in both the host DNA and in the circular viral episome for integration to occur, and studies have shown that viral integration is indeed increased by the induction of DNA double strand breaks. Inflammation generates reactive oxygen species, which in turn have the potential to create such DNA strand breaks. It is plausible that these breaks enable a greater frequency of HPV-DNA integration, and in this way contribute to carcinogenesis. Consistent with this idea, co-infections with certain sexually transmitted diseases cause cervical inflammation, and have also been identified as cofactors in the progression to cervical cancer. This article examines the idea that inflammation facilitates HPV-DNA integration into cellular chromatin through the generation of reactive oxygen species, thereby contributing to carcinogenesis. PMID- 21318099 TI - The Split Common Fixed Point Problem for Directed Operators. AB - We propose the split common fixed point problem that requires to find a common fixed point of a family of operators in one space whose image under a linear transformation is a common fixed point of another family of operators in the image space. We formulate and analyze a parallel algorithm for solving this split common fixed point problem for the class of directed operators and note how it unifies and generalizes previously discussed problems and algorithms. PMID- 21318098 TI - An Investigation of Compressive-sensing Image Reconstruction from Flying-focal spot CT Data. AB - Flying-focal-spot (FFS) technique has been used for improving the sampling condition in advanced clinical CT by collecting multiple cone-beam data sets with the focal-spot at different locations at each "projection view". It has been demonstrated that the increased sampling rate in FFS scans can substantially reduce aliasing artifacts in reconstructed images. However, the increase of the sampling density through multiple illuminations at each view can result in the increase of radiation dose to the imaged subject. In this work, we have applied a compressive-sensing (CS)-based algorithm to image reconstruction from data acquired in FFS scans. The results of the study demonstrate that aliasing artifacts observed images reconstructed by use of analytic algorithms can be suppressed effectively in images reconstructed with this CS-based algorithm from only data acquired at one FFS scan. PMID- 21318100 TI - Comparison of two storage methods for the analysis of cholinesterase activities in food animals. AB - Cholinesterases (ChE) are specialized carboxylic ester hydrolases that catalyse the hydrolysis of choline esters. They are classified into either acetylcholinesterase (AChE) or butyrylcholinesterase (BChE). Determination of ChE in the tissues is the appropriate tool for the diagnosis of organophosphorus and carbamate exposures. In general, a significant inhibition was seen in both AChE and BChE activities after 6 months of freezing at -80 degrees C and after 3 months of freezing at -20 degrees C. Linear regression of mean AChE and BChE was observed in all individual samples during the months of the two freezing methods. Bland and Altman plot of the ratios of the two freezing methods have showen the mean difference between the two freezing methods to be 8.8, and SD was 144.7 and 127.6 for upper and lower limits, respectively, for liver, while in muscle the mean difference was 1.5 and SD was 32.5 and -28.9 for upper and lower limits, respectively. PMID- 21318097 TI - Establishment and maintenance of HIV latency: model systems and opportunities for intervention. AB - HAART has succeeded in reducing morbidity and mortality rates in patients infected with HIV. However, a small amount of replication-competent HIV can persist during HAART, allowing the virus to re-emerge if therapy is ceased. One significant source of this persistent virus is a pool of long-lived, latently infected CD4(+) T cells. This article outlines what is known about how this reservoir is established and maintained, and describes the model systems that have provided insights into the molecular mechanisms governing HIV latency. The therapeutic approaches for eliminating latent cells that have been attempted are also discussed, including how improvements in understanding of these persistent HIV reservoirs are being used to develop enhanced methods for their depletion. PMID- 21318101 TI - Effect of honey on peridural fibrosis formation after laminectomy in rats: a novel experimental study. AB - Despite progress in surgical techniques, some patients still face postoperative recurrence of pain. Recently, more attention has been focused on peridural fibrosis (PF), which may be responsible for recurrent pain after laminectomy or discectomy. Honey has been shown to exert anti-inflammatory effects on exposed tissues besides its well-known antibacterial properties. The aim of this study were to investigate the effects of honey on the prevention of postlaminectomy fibrosis formation in a rat model. A controlled blinded study was performed in 45 male adult white Sprague-Dawley rats that underwent laminectomy at the L5-L6 levels. They were divided into 3 groups (A, B, and C) of 15 rats each. Group A (sham) underwent laminectomy and group B was treated with normal saline at the laminectomy site. Rats in group C received 0.1 mL honey at the laminectomy site. All rats were killed 4 weeks after laminectomy. PF was found in 5 rats (33%) of control groups A and B, and in 2 rats (10%) in honey-treated laminectomy group C. The difference was not statistically significant. Wound healing was not affected, and there was no cerebrospinal fluid leakage. Although honey appears to be safe, it cannot cause a significant reduction of PF formation after lumbar laminectomy in rats. PMID- 21318102 TI - Adiponectin provides cardiovascular protection in metabolic syndrome. AB - Adipose tissue plays a central role in the pathogenesis of metabolic syndrome. Adiponectin (APN) is a bioactive adipocytokine secreted from adipocytes. Low plasma APN levels (hypoadiponectinemia) are observed among obese individuals and in those with related disorders such as diabetes, hypertension, and dyslipidemia. APN ameliorates such disorders. Hypoadiponectinemia is also associated with major cardiovascular diseases including atherosclerosis and cardiac hypertrophy. Accumulating evidence indicates that APN directly interacts with cardiovascular tissue and prevents cardiovascular pathology. Increasing plasma APN or enhancing APN signal transduction may be an ideal strategy to prevent and treat the cardiovascular diseases associated with metabolic syndrome. However, further studies are required to uncover the precise biological actions of APN. PMID- 21318103 TI - Cardiac function in long-term survivors of childhood lymphoma. AB - Objectives. We studied long-term effects of therapy for childhood lymphoma on cardiac function. Design and patients. We prospectively evaluated 45 survivors of childhood lymphoma, using clinical parameters, electrocardiography and echocardiography. Further comparisons were made between lymphoma subgroups and between males and females. Results. Mean age at diagnosis was 9.1 years. Mean followup duration was 10.9 years. The NYHA functional class was I in 43 patients and II in 2 patients. A prolonged QTc interval (>0.44 msec) was found in 8 patients. Left ventricular (LV) systolic function and compliance were normal (LV shortening fraction 40 +/- 5.6%; cardiac index 2.84 +/- 1.13 L/min/m(2); E/A wave ratio 2.5 +/- 1.3; mean +/- S.D.), LV mass was normal (97 +/- 40 grams/m(2), mean +/- S.D.). Mitral regurgitation was observed in 7/45 patients (16%). Asymptomatic pericardial effusions were found in 3/45 (7%) patients. Conclusions. Long-term follow-up shows that most parameters of cardiac function are normal in survivors of childhood lymphoma. This is likely due to relatively low doses of anthracyclines in modern protocol modalities. Abnormalities in mitral valve flow, QTc prolongation and in a small proportion of survivors, and functional capacity necessitate long-term cardiac follow-up of these patients. PMID- 21318104 TI - The Role of P-Glycoprotein in Transport of Danshensu across the Blood-Brain Barrier. AB - Danshensu (3-(3, 4-dihydroxyphenyl) lactic acid), a water-soluble active component isolated from the root of Salvia miltiorrhiza Bunge, is widely used for the treatment of cerebrovascular diseases. The present study aims to investigate the role of P-glycoprotein in transport of Danshensu across the blood-brain barrier. Sprague-Dawley rats were pretreated with verapamil at a dose of 20 mg kg(-1) (verapamil group) or the same volume of normal saline (control group). Ninety minutes later, the animals were administrated with Danshensu (15 mg kg( 1)) by intravenous injection. At 15 min, 30 min, and 60 min after Danshensu administration, the levels of Danshensu in the blood and brain were detected by high-performance liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). The results showed that Danshensu concentrations in the brain of the rats pretreated with verapamil were significantly increased. In addition, the brain-plasma ratios of the group pretreated with verapamil were much higher than that of the control group. There was no difference in Danshensu level in plasma between the verapamil group and control group. The findings indicated that Danshensu can pass the blood-brain barrier, and P-glycoprotein plays an important role in Danshensu transportation in brain. PMID- 21318105 TI - Physical inactivity and mortality risk. AB - In recent years a plethora of epidemiologic evidence accumulated supports a strong, independent and inverse, association between physical activity and the fitness status of an individual and mortality in apparently healthy individuals and diseased populations. These health benefits are realized at relatively low fitness levels and increase with higher physical activity patterns or fitness status in a dose-response fashion. The risk reduction is at least in part attributed to the favorable effect of exercise or physical activity on the cardiovascular risk factors, namely, blood pressure, diabetes mellitus and obesity. In this review, we examine evidence from epidemiologic and interventional studies in support of the association between exercise and physical activity and health. In addition, we present the exercise effects on the aforementioned risk factors. Finally, we include select dietary approaches and their impact on risk factors and overall mortality risk. PMID- 21318106 TI - Different influences on tacrolimus pharmacokinetics by coadministrations of zhi ke and zhi shi in rats. AB - Tacrolimus, an immunosuppressant with narrow therapeutic window, has been used widely in transplant patients. Grapefruit juice and pomelo have been reported to increase the blood levels of tacrolimus. Zhi Ke and Zhi Shi, the ripe peels and unripe fruits of Citrus aurantium which is chemotaxonomically related to grapefruit and pomelo, are in wide use in clinical Chinese medicine. To investigate the possible interaction of these two Citrus herbs with tacrolimus, male Sprague-Dawley rats were orally given tacrolimus (1.5 mg/kg) with and without Zhi Ke and Zhi Shi decoctions in a cross-over design. Blood samples were withdrawn via cardiopuncture at specific time and quantitated by a microparticle enzyme immunoassay. In addition, to explore the mechanism of interaction, LS 180 cell line was used for the transport study of rhodamine 123, a typical substrate of P-glycoprotein (P-gp). The results showed that Zhi Shi significantly decreased the C(max) and AUC(0-t) of tacrolimus by 72.4% and 72.0%, respectively, whereas Zhi Ke did not affect tacrolimus pharmacokinetics. LS 180 cell line study indicated that Zhi Shi increased the efflux activity of P-gp, enabling us to explain the decreased oral bioavailability of tacrolimus caused by Zhi Shi. Hence, we suggest that Zhi Shi be contraindicated for transplant patients treated with tacrolimus to reduce the risk of allograft rejection. PMID- 21318108 TI - Myocardial Infarction due to Endocarditis. AB - We present a case of a 43-year-old man who sustained a myocardial infarction due to infective endocarditis. PMID- 21318109 TI - Inflammatory Process Modulation by Homeopathic Arnica montana 6CH: The Role of Individual Variation. AB - The effects of Arnica montana 6cH on the individual modulation of acute inflammation kinetics in rats were evaluated. Adult male Wistar rats were inoculated with 1% carrageenan into the footpad and treated with Arnica montana 6cH, dexamethasone (4.0 mg/kg; positive control) or 5% hydroalcoholic solution (negative control), per os, each 15 minutes, between 30 and 180 minutes after the irritant inoculation. Histopathological and immunohistochemistry procedures were done in order to get a panel of inflammatory positive cells for CD3 (T lymphocytes), CD45RA (B lymphocytes), CD18 (beta 2 integrin), CD163 (ED2 protein), CD54 (ICAM-1), and MAC 387 (monocytes and macrophages). The statistical treatment of data included a posteriori classification of animals from each group (N = 20) in two subgroups presenting spontaneous precocious or late oedema. Animals that presented precocious oedema were less responsible to Arnica montana 6cH in relation to hemodynamic changes. Instead, rats that exhibited late oedema presented less intense oedema (P = .01), lower percentage of mast cell degranulation (P = .0001), and increase in lymphatic vessels diameter (P = .05). The data suggest an individually qualitative adjustment of inflammatory vascular events by Arnica montana 6cH. PMID- 21318107 TI - Immunotherapy for lung cancers. AB - Lung cancer is the leading cause of cancer-related deaths worldwide. Although treatment methods in surgery, irradiation, and chemotherapy have improved, prognosis remains unsatisfactory and developing new therapeutic strategies is still an urgent demand. Immunotherapy is a novel therapeutic approach wherein activated immune cells can specifically kill tumor cells by recognition of tumor associated antigens without damage to normal cells. Several lung cancer vaccines have demonstrated prolonged survival time in phase II and phase III trials, and several clinical trials are under investigation. However, many clinical trials involving cancer vaccination with defined tumor antigens work in only a small number of patients. Cancer immunotherapy is not completely effective in eradicating tumor cells because tumor cells escape from host immune scrutiny. Understanding of the mechanism of immune evasion regulated by tumor cells is required for the development of more effective immunotherapeutic approaches against lung cancer. This paper discusses the identification of tumor antigens in lung cancer, tumor immune escape mechanisms, and clinical vaccine trials in lung cancer. PMID- 21318110 TI - Mortality Differentials and Religion in the U.S.: Religious Affiliation and Attendance. AB - Using data from the Health and Retirement Study, I examine the relationship between adult mortality and religious affiliation. I test whether mortality differences associated with religious affiliation can be attributed to differences in socioeconomic status (years of education and household wealth), attendance at religious services, or health behaviors, particularly cigarette and alcohol consumption. A baseline report of attendance at religious services is used to avoid confounding effects of deteriorating health. Socioeconomic status explains some but not all of the mortality difference. While Catholics, Evangelical Protestants, and Black Protestants benefit from favorable attendance patterns, attendance (or lack of) at services explains much of the higher mortality of those with no religious preference. Health behaviors do not mediate the relationship between mortality and religion, except among Evangelical Protestants. Not only does religion matter, but studies examining the effect of "religiosity" need to consider differences by religious affiliation. PMID- 21318112 TI - Glucose tolerance and left ventricular pressure-volume relationships in frequently used mouse strains. AB - We investigated glucose tolerance and left ventricular contractile performance in 4 frequently used mouse strains (Swiss, C57BL/6J, DBA2, and BalbC) at 24 weeks. Glucose tolerance was tested by measuring blood glucose levels in time after intraperitoneal glucose injection (2 mg/g body weight). Left ventricular contractility was assessed by pressure-conductance analysis. Peak glucose levels and glucose area under the curve were higher (all P < .05) in C57BL/6J (418 +/- 65 mg/dL and 813 +/- 100 mg.h/dL) versus Swiss (237 +/- 66 mg/dL and 470 +/- 126 mg.h/dL), DBA2 (113 +/- 20 mg/dL and 304 +/- 49 mg.h/dL, P < .01), and BalbC mice (174 +/- 55 mg/dL and 416 +/- 70 mg.h/dL). Cardiac output was higher (all P < .05) in Swiss (14038 +/- 4530 MUL/min) versus C57BL/6J (10405 +/- 2683 MUL/min), DBA2 (10438 +/- 3251 MUL/min), and BalbC mice (8466 +/- 3013 MUL/min). Load independent left ventricular contractility assessed as recruitable stroke work (PRSW) was comparable in all strains. In conclusion, glucose tolerance and load dependent left ventricular performance parameters were different between 4 mice background strains, but PRSW was comparable. PMID- 21318111 TI - Molecular processes leading to aberrant androgen receptor signaling and castration resistance in prostate cancer. AB - Hormone therapies targeting androgen receptor signaling are the mainstay of treatment for patients with advanced prostate cancer. The length of clinical remission induced by hormone therapies varies substantially among treated patients. Why some patients progress rapidly after treatment while others benefit with prolonged remission is a question that remains unsolved. The androgen receptor signaling pathway is the key molecular determinant of castration resistance, and a key target for prostate cancer drug design. Recent advances in characterizing molecular processes leading to the development of castration resistant prostate cancer, including the discovery of multiple androgen receptor splicing variants, offer opportunities for rational development of new clinical tools or approaches to predict, monitor or control/prevent prostate cancer progression in the castrate setting. PMID- 21318113 TI - BAC libraries from wheat chromosome 7D: efficient tool for positional cloning of aphid resistance genes. AB - Positional cloning in bread wheat is a tedious task due to its huge genome size and hexaploid character. BAC libraries represent an essential tool for positional cloning. However, wheat BAC libraries comprise more than million clones, which makes their screening very laborious. Here, we present a targeted approach based on chromosome-specific BAC libraries. Such libraries were constructed from flow sorted arms of wheat chromosome 7D. A library from the short arm (7DS) consisting of 49,152 clones with 113 kb insert size represented 12.1 arm equivalents whereas a library from the long arm (7DL) comprised 50,304 clones of 116 kb providing 14.9x arm coverage. The 7DS library was PCR screened with markers linked to Russian wheat aphid resistance gene DnCI2401, the 7DL library was screened by hybridization with a probe linked to greenbug resistance gene Gb3. The small number of clones combined with high coverage made the screening highly efficient and cost effective. PMID- 21318114 TI - Consumption of hydrogen water reduces paraquat-induced acute lung injury in rats. AB - Exposure to paraquat leads to acute lung injury and oxidative stress is widely accepted as a contributor to paraquat-induced acute lung injury. Recent studies have reported that consumption of water with dissolved molecular hydrogen to a saturated level (hydrogen water) prevents oxidative stress-induced diseases. Here, we investigated whether consumption of saturated hydrogen saline protects rats against paraquat-induced acute lung injury. Adult male Sprague-Dawley (SD) rats were randomly divided into four groups: Control group; hydrogen water-only group (HW group); paraquat-only group (PQ group); paraquat and hydrogen water group (PQ + HW group). The rats in control group and HW group drank pure water or hydrogen water; the rats in PQ group and PQ + HW group were intraperitonealy injected with paraquat (35 mg/kg) and then provided pure water or hydrogen water. Both biochemical and histological lung alterations were measured. The results showed that hydrogen water ameliorated these alterations, demonstrating that hydrogen water alleviated paraquat-induced acute lung injury possibly by inhibition of oxidative damage. PMID- 21318115 TI - Cardiovascular prevention of cognitive decline. AB - Midlife cardiovascular risk factors, including diabetes, hypertension, dyslipemia, and an unhealthy lifestyle, have been linked to subsequent incidence, delay of onset, and progression rate of Alzheimer disease and vascular dementia. Conversely, optimal treatment of cardiovascular risk factors prevents and slows down age-related cognitive disorders. The impact of antihypertensive therapy on cognitive outcome in patients with hypertension was assessed in large trials which demonstrated a reduction in progression of MRI white matter hyperintensities, in cognitive decline and in incidence of dementia. Large-scale database correlated statin use and reduction in the incidence of dementia, mainly in patients with documented atherosclerosis, but clinical trials failed to reach similar conclusions. Whether a multitargeted intervention would substantially improve protection, quality of life, and reduce medical cost expenditures in patients with lower risk profile has not been ascertained. This would require appropriately designed trials targeting large populations and focusing on cognitive decline as a primary outcome endpoint. PMID- 21318116 TI - Is there a learning curve for pancreaticoduodenectomy after fellowship training? AB - BACKGROUND: Limited data exist regarding a learning curve for pancreaticoduodenectomy (PD). This study examines whether a learning curve exists for the performance of PD after fellowship training. METHODS: Review of the outcomes of a single surgeon's first 60 PDs after completion of specialty training in pancreatic surgery. RESULTS: Sixty PDs were performed over five years, with the final 30 being done in the last 15 months. Patient age and gender did not differ between the first 30 and last 30 patients. When comparing the first 30 PDs to the second 30 PDs, significant improvements were found in operative time (463 versus 388 minutes), length of stay (10 versus 7 days), and receipt of adjuvant therapy (58% versus 91%). There were no significant differences found in mortality (7% versus 0%), complications (60% versus 50%), readmissions (18% versus 20%), or margin-positive resections (25% versus 24%). CONCLUSION: Even with extensive training in pancreatic surgery, a learning curve exists for the performance of PD. With experience, improvements were made in operative time, but more importantly in patient outcomes including length of stay and receipt of adjuvant therapy. PMID- 21318117 TI - Par genes: molecular probes to pathological assessment in breast cancer progression. AB - Taking the issue of tumor categorization a step forward and establish molecular imprints to accompany histopathological assessment is a challenging task. This is important since often patients with similar clinical and pathological tumors may respond differently to a given treatment. Protease-activated receptor-(1) (PAR(1)), a G protein-coupled receptor (GPCR), is the first member of the mammalian PAR family consisting of four genes. PAR(1) and PAR(2) play a central role in breast cancer. The release of N-terminal peptides during activation and the exposure of a cryptic internal ligand in PARs, endow these receptors with the opportunity to serve as a "mirror-image" index reflecting the level of cell surface PAR(1&2)-in body fluids. It is possible to use the levels of PAR-released peptide in patients and accordingly determine the choice of treatment. We have both identified PAR(1) C-tail as a scaffold site for the immobilization of signaling partners, and the critical minimal binding site. This binding region may be used for future therapeutic modalities in breast cancer, since abrogation of the binding inhibits PAR(1) induced breast cancer. Altogether, both PAR(1) and PAR(2) may serve as molecular probes for breast cancer diagnosis and valuable targets for therapy. PMID- 21318119 TI - CAUSAL EFFECTS OF TREATMENTS FOR INFORMATIVE MISSING DATA DUE TO PROGRESSION/DEATH. AB - In longitudinal clinical trials, when outcome variables at later time points are only defined for patients who survive to those times, the evaluation of the causal effect of treatment is complicated. In this paper, we describe an approach that can be used to obtain the causal effect of three treatment arms with ordinal outcomes in the presence of death using a principal stratification approach. We introduce a set of flexible assumptions to identify the causal effect and implement a sensitivity analysis for non-identifiable assumptions which we parameterize parsimoniously. Methods are illustrated on quality of life data from a recent colorectal cancer clinical trial. PMID- 21318118 TI - Common fragile site tumor suppressor genes and corresponding mouse models of cancer. AB - Chromosomal common fragile sites (CFSs) are specific mammalian genomic regions that show an increased frequency of gaps and breaks when cells are exposed to replication stress in vitro. CFSs are also consistently involved in chromosomal abnormalities in vivo related to cancer. Interestingly, several CFSs contain one or more tumor suppressor genes whose structure and function are often affected by chromosomal fragility. The two most active fragile sites in the human genome are FRA3B and FRA16D where the tumor suppressor genes FHIT and WWOX are located, respectively. The best approach to study tumorigenic effects of altered tumor suppressors located at CFSs in vivo is to generate mouse models in which these genes are inactivated. This paper summarizes our present knowledge on mouse models of cancer generated by knocking out tumor suppressors of CFS. PMID- 21318120 TI - Molecular breeding of advanced microorganisms for biofuel production. AB - Large amounts of fossil fuels are consumed every day in spite of increasing environmental problems. To preserve the environment and construct a sustainable society, the use of biofuels derived from different kinds of biomass is being practiced worldwide. Although bioethanol has been largely produced, it commonly requires food crops such as corn and sugar cane as substrates. To develop a sustainable energy supply, cellulosic biomass should be used for bioethanol production instead of grain biomass. For this purpose, cell surface engineering technology is a very promising method. In biobutanol and biodiesel production, engineered host fermentation has attracted much attention; however, this method has many limitations such as low productivity and low solvent tolerance of microorganisms. Despite these problems, biofuels such as bioethanol, biobutanol, and biodiesel are potential energy sources that can help establish a sustainable society. PMID- 21318121 TI - The Effect of Column and Eluent Fluorination on the Retention and Separation of non-Fluorinated Amino Acids and Proteins by HPLC. AB - The effect of column and eluent fluorination on the retention and separation of non-fluorinated amino acids and proteins in HPLC is investigated. A side-by-side comparison of fluorocarbon column and eluents (F-column and F-eluents) with their hydrocarbon counterparts (H-column and H-eluents) in the separation of a group of 33 analytes, including 30 amino acids and 3 proteins, is conducted. The H-column and the F-column contain the n-C(8)H(17) group and n-C(8)F(17) group, respectively, in their stationary phases. The H-eluents include ethanol (EtOH) and isopropanol (ISP) while the F-eluents include trifluoroethanol (TFE) and hexafluorosopropanol (HFIP). The 2 columns and 4 eluents generated 8 (column, eluent) pairs that produce 264 retention time data points for the 33 analytes. A statistical analysis of the retention time data reveals that although the H column is better than the F-column in analyte separation and H-eluents are better than F-eluents in analyte retention, the more critical factor is the proper pairing of column with eluent. Among the conditions explored in this project, optimal retention and separation is achieved when the fluorocarbon column is paired with ethanol, even though TFE is the most polar one among the 4 eluents. This result shows fluorocarbon columns have much potential in chromatographic analysis and separation of non-fluorinated amino acids and proteins. PMID- 21318122 TI - Uniform Accuracy of the Maximum Likelihood Estimates for Probabilistic Models of Biological Sequences. AB - Probabilistic models for biological sequences (DNA and proteins) have many useful applications in bioinformatics. Normally, the values of parameters of these models have to be estimated from empirical data. However, even for the most common estimates, the maximum likelihood (ML) estimates, properties have not been completely explored. Here we assess the uniform accuracy of the ML estimates for models of several types: the independence model, the Markov chain and the hidden Markov model (HMM). Particularly, we derive rates of decay of the maximum estimation error by employing the measure concentration as well as the Gaussian approximation, and compare these rates. PMID- 21318123 TI - Circulating sex hormones and mammographic breast density among postmenopausal women. AB - The use of breast density as an intermediate or predictive marker of breast cancer risk is limited by an incomplete understanding of the etiology of breast density. High blood levels of endogenous estrogens and androgens are associated with increased risk of breast cancer among postmenopausal women. We sought to examine whether these hormones are also associated with breast density. The Wisconsin Breast Density Study enrolled 257 postmenopausal women, ages 55-70 years, with no history of postmenopausal hormone use, from mammography clinics in Madison, Wisconsin. Subjects provided a blood sample for sex hormone analysis, and breast density was measured from subjects' screening mammograms using a computer-assisted thresholding method. Numerous sex hormones were associated with breast density in age-adjusted analyses. However, further adjustment for body mass index and other potentially confounding factors substantially attenuated or eliminated these associations. In the fully adjusted model, there remained a positive association between percent breast density and serum progesterone (P=0.03), with percent density rising from 11.9% (95% CI: 9.8, 14.1%) among women in the lowest quartile of serum progesterone to 15.4% (12.9, 18.2%) among women in the highest quartile. There was also a positive association between sex hormone binding globulin and percent breast density (P=0.06). In contrast, there were no independent associations between percent breast density and estradiol (total, free, or bioavailable), estrone, estrone sulfate, or testosterone (total, free, or bioavailable). These results suggest that breast density has a hormonal etiology; however, it may differ in important ways from that of breast cancer risk. PMID- 21318124 TI - A longitudinal Model for repeated interval-observed data with informative dropouts. AB - We consider repeated measures interval-observed data with informative dropouts. We model the repeated outcomes via an unobserved random intercept and it is assumed that the probability of dropout during the study period is linearly related to the random intercept in a complementary log-log scale. Assuming the random effect follows the power variance function (PVF) family suggested by Hougaard (2000), we derive the marginal likelihood in a closed form. We evaluate the performance of the maximum likelihood estimation via simulation studies and apply the proposed method to a real data set. PMID- 21318125 TI - Gender Double Standards in Parenting Attitudes. AB - This paper investigates the double standard in attitudes toward courtship and family formation behaviors of sons and daughters. We argue there are strong theoretical reasons to expect that the magnitude of this double standard varies across substantive domains, as well as amongst parents and non-parents. We also argue key methodological limitations of previous studies likely produce an under estimate of the gender double standard. We provide empirical estimates of the gender double standard that overcome these limitations, including a random assignment experiment explicitly designed to control the effects of social desirability. These estimates demonstrate variability in the double standard across domains and reveal key factors contributing to the magnitude of the double standards in parenting attitudes held by individuals. PMID- 21318126 TI - The Game of Contacts: Estimating the Social Visibility of Groups. AB - Estimating the sizes of hard-to-count populations is a challenging and important problem that occurs frequently in social science, public health, and public policy. This problem is particularly pressing in HIV/AIDS research because estimates of the sizes of the most at-risk populations-illicit drug users, men who have sex with men, and sex workers-are needed for designing, evaluating, and funding programs to curb the spread of the disease. A promising new approach in this area is the network scale-up method, which uses information about the personal networks of respondents to make population size estimates. However, if the target population has low social visibility, as is likely to be the case in HIV/AIDS research, scale-up estimates will be too low. In this paper we develop a game-like activity that we call the game of contacts in order to estimate the social visibility of groups, and report results from a study of heavy drug users in Curitiba, Brazil (n = 294). The game produced estimates of social visibility that were consistent with qualitative expectations but of surprising magnitude. Further, a number of checks suggest that the data are high-quality. While motivated by the specific problem of population size estimation, our method could be used by researchers more broadly and adds to long-standing efforts to combine the richness of social network analysis with the power and scale of sample surveys. PMID- 21318128 TI - Retroviruses: Molecular Biology, Genomics and Pathogenesis. PMID- 21318129 TI - A High-Order Immersed Boundary Method for Acoustic Wave Scattering and Low-Mach Number Flow-Induced Sound in Complex Geometries. AB - A new sharp-interface immersed boundary method based approach for the computation of low-Mach number flow-induced sound around complex geometries is described. The underlying approach is based on a hydrodynamic/acoustic splitting technique where the incompressible flow is first computed using a second-order accurate immersed boundary solver. This is followed by the computation of sound using the linearized perturbed compressible equations (LPCE). The primary contribution of the current work is the development of a versatile, high-order accurate immersed boundary method for solving the LPCE in complex domains. This new method applies the boundary condition on the immersed boundary to a high-order by combining the ghost-cell approach with a weighted least-squares error method based on a high order approximating polynomial. The method is validated for canonical acoustic wave scattering and flow-induced noise problems. Applications of this technique to relatively complex cases of practical interest are also presented. PMID- 21318127 TI - Histone modifications and chromatin organization in prostate cancer. AB - Epigenetic mechanisms, including histone modifications, nucleosomal remodeling and chromosomal looping, contribute to the onset and progression of prostate cancer. Recent technical advances significantly increase our understanding of the genome-wide epigenetic regulation of gene expression in prostate cancer. Aberrant genomic distribution and global level of histone modifications, nucleosome repositioning at the gene promoter and enhancer regions, as well as androgen receptor-mediated chromosomal looping may lead to the silencing of tumor suppressor genes and the activation of proto-oncogenes. In addition, androgen receptor-induced chromosomal looping facilitates recurrent gene fusion in prostate cancer. Studies in epigenetic regulation have translational implications in the identification of new biomarkers and the development of new therapies in prostate cancer. PMID- 21318131 TI - A solid pseudopapillary tumour arising from mesocolon without ectopic pancreas. AB - A solid pseudopapillary tumour (SPT) is an uncommon pancreatic tumour. Very rarely it has also been described outside the pancreas, usually arising from heterotopic pancreatic tissue. In this paper, we described a case arising from the transverse mesocolon without heterotopic pancreatic tissue in an 18-year-old girl. PMID- 21318130 TI - Spectroscopic Characterization of Intermolecular Interaction of Amyloid beta Promoted on GM1 Micelles. AB - Clusters of GM1 gangliosides act as platforms for conformational transition of monomeric, unstructured amyloid beta (Abeta) to its toxic beta-structured aggregates. We have previously shown that Abeta(1-40) accommodated on the hydrophobic/hydrophilic interface of lyso-GM1 or GM1 micelles assumes alpha helical structures under ganglioside-excess conditions. For better understanding of the mechanisms underlying the alpha-to-beta conformational transition of Abeta on GM1 clusters, we performed spectroscopic characterization of Abeta(1-40) titrated with GM1. It was revealed that the thioflavin T- (ThT-) reactive beta structure is more populated in Abeta(1-40) under conditions where the Abeta(1-40) density on GM1 micelles is high. Under this circumstance, the C-terminal hydrophobic anchor Val(39)-Val(40) shows two distinct conformational states that are reactive with ThT, while such Abeta species were not generated by smaller lyso-GM1 micelles. These findings suggest that GM1 clusters promote specific Abeta-Abeta interactions through their C-termini coupled with formation of the ThT-reactive beta-structure depending on sizes and curvatures of the clusters. PMID- 21318132 TI - Preparation of antioxidant enzymatic hydrolysates from honeybee-collected pollen using plant enzymes. AB - Enzymatic hydrolysates of honeybee-collected pollen were prepared using food grade proteinase and aminopeptidases entirely of plant origin. Bromelain from pineapple stem was applied (8 mAU/g substrate) in the first hydrolysis stage. Aminopeptidase (0.05 U/g substrate) and proline iminopeptidase (0.03 U/g substrate) from cabbage leaves (Brassica oleracea var. capitata), and aminopeptidase (0.2 U/g substrate) from chick-pea cotyledons (Cicer arietinum L.) were involved in the additional hydrolysis of the peptide mixtures. The degree of hydrolysis (DH), total phenolic contents, and protein contents of these hydrolysates were as follows: DH (about 20-28%), total phenolics (15.3-27.2 MUg/mg sample powder), and proteins (162.7-242.8 MUg/mg sample powder), respectively. The hydrolysates possessed high antiradical scavenging activity determined with DPPH (42-46% inhibition). The prepared hydrolysates of bee collected flower pollen may be regarded as effective natural and functional dietary food supplements due to their remarkable content of polyphenol substances and significant radical-scavenging capacity with special regard to their nutritional-physiological implications. PMID- 21318133 TI - Characteristics, risk factors, and treatment practices of known adult hypertensive patients in saudi arabia. AB - Objective. To determine the prevalence, risk factors, characteristics, and treatment practices of known adult hypertensives in Saudi Arabia. Methods. Cross sectional community-based study using the WHO stepwise approach. Saudi adults were randomly chosen from Primary Health Care Centers catchment areas. Data was collected using a questionnaire which included sociodemographic data, history of hypertension, risk factors, treatment practices, biochemical and anthropometric measurements. Collected data was cheeked, computer fed, and analysed using SPSS V17. Results. Out of 4719 subjects (99.2% response), 542 (11.5%) subjects were known hypertensives or detected by health workers in the past 12 months. Hypertension was significantly associated with age, gender, geographical location, education, employment, diabetes, physical inactivity, excess body weight, and ever smoking. Multiple logistic analysis controlling for age showed that significant predictors of hypertension were diabetes mellitus, ever smoking, obesity, and hypercholesteremia. Several treatment modalities and practices were significantly associated with gender, age, education, and occupation. About 74% were under prescribed treatment by physicians, 62% on dietary modification, 37% attempted weight reduction, 27% performed physical exercise, and less than 7% used herbs, consulted traditional healers or quitted smoking. Income was not significantly associated with any treatment modality or patient practices. Conclusion. Hypertension (known and undetected) is a major chronic health problem among adults in Saudi Arabia. Many patients' practices need changes. A comprehensive approach is needed to prevent, early detect, and control the disease targeting, the risk factors, and predictors identified. PMID- 21318134 TI - TRII: A Probabilistic Scoring of Drosophila melanogaster Translation Initiation Sites. AB - Relative individual information is a measurement that scores the quality of DNA- and RNA-binding sites for biological machines. The development of analytical approaches to increase the power of this scoring method will improve its utility in evaluating the functions of motifs. In this study, the scoring method was applied to potential translation initiation sites in Drosophila to compute Translation Relative Individual Information (TRII) scores. The weight matrix at the core of the scoring method was optimized based on high-confidence translation initiation sites identified by using a progressive partitioning approach. Comparing the distributions of TRII scores for sites of interest with those for high-confidence translation initiation sites and random sequences provides a new methodology for assessing the quality of translation initiation sites. The optimized weight matrices can also be used to describe the consensus at translation initiation sites, providing a quantitative measure of preferred and avoided nucleotides at each position. PMID- 21318135 TI - Asp295 stabilizes the active-site loop structure of pyruvate dehydrogenase, facilitating phosphorylation of ser292 by pyruvate dehydrogenase-kinase. AB - We have developed an in vitro system for detailed analysis of reversible phosphorylation of the plant mitochondrial pyruvate dehydrogenase complex, comprising recombinant Arabidopsis thalianaalpha2beta2-heterotetrameric pyruvate dehydrogenase (E1) plus A. thaliana E1-kinase (AtPDK). Upon addition of MgATP, Ser292, which is located within the active-site loop structure of E1alpha, is phosphorylated. In addition to Ser292, Asp295 and Gly297 are highly conserved in the E1alpha active-site loop sequences. Mutation of Asp295 to Ala, Asn, or Leu greatly reduced phosphorylation of Ser292, while mutation of Gly297 had relatively little effect. Quantitative two-hybrid analysis was used to show that mutation of Asp295 did not substantially affect binding of AtPDK to E1alpha. When using pyruvate as a variable substrate, the Asp295 mutant proteins had modest changes in k(cat), K(m), and k(cat)/K(m) values. Therefore, we propose that Asp295 plays an important role in stabilizing the active-site loop structure, facilitating transfer of the gamma-phosphate from ATP to the Ser residue at regulatory site one of E1alpha. PMID- 21318136 TI - Spontaneous hemopericardium leading to cardiac tamponade in a patient with essential thrombocythemia. AB - Acute cardiac tamponade requires urgent diagnosis and treatment. Spontaneous hemopericardium leading to cardiac tamponade as an initial manifestation of essential thrombocythemia (ET) has never been reported in the literature. We report a case of a 72-year-old Caucasian female who presented with spontaneous hemopericardium and tamponade requiring emergent pericardiocentesis. The patient was subsequently diagnosed to have ET. ET is characterized by elevated platelet counts that can lead to thrombosis but paradoxically it can also lead to a bleeding diathesis. Physicians should be aware of this complication so that timely life-saving measures can be taken if this complication arises. PMID- 21318137 TI - Is it antiphospholipid syndrome? AB - The diagnosis of bacterial endocarditis remains a challenge, as nearly half of cases develop in the absence of preexistent heart disease and known risk factors. Not infrequently, a blunted clinical course at onset can lead to erroneous diagnoses. We present the case of a 47-year-old previously healthy man in which a presumptive diagnosis of antiphospholipid syndrome was made based on the absence of echocardiographically detected heart involvement, a negative blood culture, normal C-reactive protein (CRP) levels, a positive lupus anticoagulant (LAC) test, and evidence of splenic infarcts. The patient eventually developed massive aortic endocarditic involvement, with blood cultures positive for Streptococcus bovis, and was referred for valvular replacement. This case not only reminds us of the diagnostic challenges of bacterial endocarditis, but also underlines the need for a critical application of antiphospholipid syndrome diagnostic criteria. PMID- 21318138 TI - Different Learning Curves for Axillary Brachial Plexus Block: Ultrasound Guidance versus Nerve Stimulation. AB - Little is known about the learning of the skills needed to perform ultrasound- or nerve stimulator-guided peripheral nerve blocks. The aim of this study was to compare the learning curves of residents trained in ultrasound guidance versus residents trained in nerve stimulation for axillary brachial plexus block. Ten residents with no previous experience with using ultrasound received ultrasound training and another ten residents with no previous experience with using nerve stimulation received nerve stimulation training. The novices' learning curves were generated by retrospective data analysis out of our electronic anaesthesia database. Individual success rates were pooled, and the institutional learning curve was calculated using a bootstrapping technique in combination with a Monte Carlo simulation procedure. The skills required to perform successful ultrasound guided axillary brachial plexus block can be learnt faster and lead to a higher final success rate compared to nerve stimulator-guided axillary brachial plexus block. PMID- 21318139 TI - Evaluation of glycemic and lipid profile of offspring of diabetic Wistar rats treated with Malpighia emarginata juice. AB - Knowing that maternal diabetes is related to hyperglycemia and fetal hyperinsulinemia, which affect the lipid metabolism, the aim of this study was to evaluate the effects of Malpighia emarginata (acerola) juice on the glycemic and lipid profile of offspring of diabetic and nondiabetic Wistar rats. The adult offspring of non-diabetic dams and of dams with severe streptozotocin-induced diabetes were divided into groups: G1, offspring (of control dams) treated with water, G2, offspring (of diabetic dams) treated with water, G3, male offspring (of control dams) treated with acerola juice, and G4, male offspring (of diabetic dams) treated with acerola juice. The offspring of diabetic dams treated with acerola juice showed significantly decreased levels of glucose, cholesterol, triglycerides, and increased HDL-c. The use of acerola juice is a potential strategy to aid in the prevention of DM and dyslipidemia and its complications or to act as an auxiliary in the treatment of these diseases. PMID- 21318140 TI - Hepatoprotective activity of dried- and fermented-processed virgin coconut oil. AB - The present study aims to determine the hepatoprotective effect of MARDI-produced virgin coconut oils, prepared by dried- or fermented-processed methods, using the paracetamol-induced liver damage in rats. Liver injury induced by 3 g/kg paracetamol increased the liver weight per 100 g bodyweight indicating liver damage. Histological observation also confirms liver damage indicated by the presence of inflammations and necrosis on the respective liver section. Interestingly, pretreatment of the rats with 10, but not 1 and 5, mL/kg of both VCOs significantly (P < .05) reduced the liver damage caused by the administration of paracetamol, which is further confirmed by the histological findings. In conclusion, VCO possessed hepatoprotective effect that requires further in-depth study. PMID- 21318142 TI - Formation of Toxic Amyloid Fibrils by Amyloid beta-Protein on Ganglioside Clusters. AB - It is widely accepted that the conversion of the soluble, nontoxic amyloid beta protein (Abeta) monomer to aggregated toxic Abeta rich in beta-sheet structures is central to the development of Alzheimer's disease. However, the mechanism of the abnormal aggregation of Abeta in vivo is not well understood. Accumulating evidence suggests that lipid rafts (microdomains) in membranes mainly composed of sphingolipids (gangliosides and sphingomyelin) and cholesterol play a pivotal role in this process. This paper summarizes the molecular mechanisms by which Abeta aggregates on membranes containing ganglioside clusters, forming amyloid fibrils. Notably, the toxicity and physicochemical properties of the fibrils are different from those of Abeta amyloids formed in solution. Furthermore, differences between Abeta-(1-40) and Abeta-(1-42) in membrane interaction and amyloidogenesis are also emphasized. PMID- 21318141 TI - Primary hyperparathyroidism in patients with multiple endocrine neoplasia type 1. AB - Primary hyperparathyroidism may occur as a part of an inherited syndrome in a combination with pancreatic endocrine tumours and/or pituitary adenoma, which is classified as Multiple Endocrine Neoplasia type 1 (MEN-1). This syndrome is caused by a germline mutation in MEN-1 gene encoding a tumour-suppressor protein, menin. Primary hyperparathyroidism is the most frequent clinical presentation of MEN-1, which usually appears in the second decade of life as an asymptomatic hypercalcemia and progresses through the next decades. The most frequent clinical presentation of MEN-1-associated primary hyperparathyroidism is bone demineralisation and recurrent kidney stones rarely followed by chronic kidney disease. The aim of this paper is to present the pathomechanism, screening procedures, diagnosis, and management of primary hyperparathyroidism in the MEN-1 syndrome. It also summarises the recent advances in the pharmacological therapy with a new group of drugs-calcimimetics. PMID- 21318143 TI - Attenuation of brain nitrostative and oxidative damage by brain cooling during experimental traumatic brain injury. AB - The aim of the present study was to ascertain whether brain cooling causes attenuation of traumatic brain injury by reducing brain nitrostative and oxidative damage. Brain cooling was accomplished by infusion of 5 mL of 4 degrees C saline over 5 minutes via the external jugular vein. Immediately after the onset of traumatic brain injury, rats were randomized into two groups and given 37 degrees C or 4 degrees C normal saline. Another group of rats were used as sham operated controls. Behavioral and biochemical assessments were conducted on 72 hours after brain injury or sham operation. As compared to those of the sham operated controls, the 37 degrees C saline-treated brain injured animals displayed motor deficits, higher cerebral contusion volume and incidence, higher oxidative damage (e.g., lower values of cerebral superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase, but higher values of cerebral malondialdehyde), and higher nitrostative damage (e.g., higher values of neuronal nitric oxide synthase and 3-nitrotyrosine). All the motor deficits and brain nitrostative and oxidative damage were significantly reduced by retrograde perfusion of 4 degrees C saline via the jugular vein. Our data suggest that brain cooling may improve the outcomes of traumatic brain injury in rats by reducing brain nitrostative and oxidative damage. PMID- 21318144 TI - Hyperthyroidism-associated insulin resistance is not mediated by adiponectin levels. AB - To evaluate the relationship between circulating adiponectin and insulin sensitivity in patients with hyperthyroid Graves' disease, we studied 19 adult patients with this disease and 19 age- and sex-matched euthyroid controls. All hyperthyroid patients were treated with antithyroid drugs and were re-evaluated after thyroid function normalized. Before antithyroid treatment, the adiponectin plasma concentrations were not different comparing with those in control group. The adiponectin levels remained unchanged after treatment. The homeostasis model assessment of insulin resistance (HOMA-IR) in hyperthyroid group was higher before treatment than after treatment. There was no significant difference in serum glucose and insulin levels between hyperthyroid and control groups and in the hyperthyroid group before and after treatment. BMI-adjusted adiponectin levels were not different among three groups. On the other hand, BMI-adjusted insulin levels and HOMA-IR values were significantly decreased after management of hyperthyroidism. Pearson's correlation revealed that insulin and HOMA-IR values positively correlated with triiodothyronine (T3) and free thyroxine (FT4) levels. However, adiponectin did not correlate with T3, FT4, insulin, HOMA-IR and thyrotropin receptor autoantibody (TRAb) levels. In conclusion, insulin resistance associated with hyperthyroidism is not mediated by the levels of plasma adiponectin. PMID- 21318145 TI - Beverage-specific alcohol sale and cardiovascular mortality in Russia. AB - OBJECTIVE: Recent research evidence suggests that the consumption of different types of alcoholic beverage may have a differential effect on cardiovascular diseases (CVD) mortality rates. The aim of this study was to examine the relation between the consumption of different beverage types and CVD mortality rates in Russia across the later-Soviet and post-Soviet periods. METHOD: Age-standardized male and female CVD mortality data for the period 1970-2005 and data on beverage specific alcohol sales were obtained Russian State Statistical Committee (Rosstat). Time-series analytical modeling techniques (ARIMA) were used to examine the relation between the sales of different alcoholic beverages and CVD mortality rates. RESULTS: Vodka consumption as measured by sales was significantly associated with both male and female CVD mortality rates: a 1 liter increase in vodka sales would result in a 5.3% increase in the male CVD mortality rate and a 3.7% increase in the female rate. The consumption of beer and wine were not associated with CVD mortality rates. CONCLUSIONS: The findings from this study suggest that public health efforts should focus on both reducing overall consumption and changing beverage preference away from distilled spirits in order to reduce cardiovascular mortality rates in Russia. PMID- 21318146 TI - Cancer stem cells and epithelial ovarian cancer. AB - The cancer stem cell hypothesis is becoming more widely accepted as a model for carcinogenesis. Tumours are heterogeneous both at the molecular and cellular level, containing a small population of cells that possess highly tumourigenic "stem-cell" properties. Cancer stem cells (CSCs), or tumour-initiating cells, have the ability to self-renew, generate xenografts reminiscent of the primary tumour that they were derived from, and are chemoresistant. The characterisation of the CSC population within a tumour that drives its growth could provide novel target therapeutics against these cells specifically, eradicating the cancer completely. There have been several reports describing the isolation of putative cancer stem cell populations in several cancers; however, no defined set of markers has been identified that conclusively characterises "stem-like" cancer cells. This paper highlights the current experimental approaches that have been used in the field and discusses their limitations, with specific emphasis on the identification and characterisation of the CSC population in epithelial ovarian cancer. PMID- 21318147 TI - The Use of HRP in Decolorization of Reactive Dyes and Toxicological Evaluation of Their Products. AB - This work studied the potential use of horseradish peroxidase (HRP) in the decolorization of the following textile dyes: Drimarene Blue X-3LR (DMBLR), Drimarene Blue X-BLN (DMBBLN), Drimarene Rubinol X-3LR (DMR), and Drimarene Blue CL-R (RBBR). Dyes were individually tested in the reaction media containing 120 mg.L(-1), considering the following parameters: temperature (20-45 degrees C), H(2)O(2) concentration (0-4.44 mmol.L(-1)), and reaction time (5 minutes, 1 and 24 h). The following conditions: 35 degrees C, 0.55 mmol.L(-1), and 1h, provided the best set of results of color removal for DMBLR (99%), DMBBLN (77%), DMR (94%), and RBBR (97%). It should be mentioned that only 5 minutes of reaction was enough to obtain 96% of decolorization for DMBLR and RBBR. After the decolorization reactions of DMBLR, DMR, and RBBR, it was possible to observe the reduction of Artemia salina mortality and the no significant increase in toxicity for the products generated from DMBBLN. PMID- 21318148 TI - Comparison between Ischemic Stroke Patients <50 Years and >=50 Years Admitted to a Single Centre: The Bergen Stroke Study. AB - Introduction. Young adults are likely to differ from old patients concerning cerebral infarction. Methods. We compared characteristics of patients aged under and above 50 years, admitted to the Department of Neurology with cerebral infarction between 2006 and 2009, based on prospective registration. Investigation followed one common protocol for both groups. Results and Discussion. One hundred patients (8.2%) were <50 years old, and the proportion of males was higher in this group (72% versus 55.8%, P = .002). Young stroke patients are more often current smokers (44.1% versus 23.6%, P < .001). Common causes for stroke in the young were cervical artery dissection (18% versus 0.6%, P < .001) and cardiac embolism due to disorders other than atrial arrhythmias (18% versus 5.5%, P < .001). Among the old, atrial fibrillation and flutter dominated (29.1% versus 5%, P < .001). Stroke severity and location did not differ. Old patients more often suffered from pneumonia (10.6% versus 2%, P < .003) and urinary tract infection (14.6% versus 2%, P = .001). Conclusions. Males dominate, and current smoking is more common in the young. Cervical artery dissection and nonarrhythmic heart disorders are frequent causes among young patients, while traditional risk factors dominate the old. Stroke severity is similar, but old patients seem more exposed for infectious complications. PMID- 21318149 TI - Effect of crumble-pellet and mash diets with different levels of dietary protein and energy on the performance of broilers at the end of the third week. AB - This experiment was conducted to investigate the effect of the form of diets with different levels of protein and energy on broilers performance at the end of the third week. A total of 2800 male broiler chicks were fed with two forms of diet (mash and crumble-pellet), two levels of protein (23% and 21% CP), and two levels of energy (3200 and 3000 Kcal/Kg ME) from 1 to 21 days of age. The bodyweight (BW) and Feed conversion rate (FCR) were affected by the form of diet with the crumble-pellet form being better (P < .001). The diet with high protein significantly increased BW and decreased FCR (P < .001). The different levels of energy did not affect FCR and BW in crumble-pellet diet but should a significant effect on them in mash diet (P < .05). There were no significant interactions for any of the parameters tested except for interactions between energy and feed form. BW and FCR were improved by energy when diets were fed in the mash form (unlike the crumble-pellet form) at all ages. It is concluded that feeding crumble-pellets from 1 to 21 days of age improved BW and FCR and that an increase in the protein (unlike energy) content of the diet increased the performance of the chickens at the end of the third week. PMID- 21318150 TI - Erratum to "the basic cardiovascular responses to postural changes, exercise, and cold pressor test: do they vary in accordance with the dual constitutional types of ayurveda?". PMID- 21318151 TI - Green tea epigallocatechin gallate exhibits anticancer effect in human pancreatic carcinoma cells via the inhibition of both focal adhesion kinase and insulin-like growth factor-I receptor. AB - The exact molecular mechanism by which epigallocatechin gallate (EGCG) suppresses human pancreatic cancer cell proliferation is unclear. We show here that EGCG treated pancreatic cancer cells AsPC-1 and BxPC-3 decrease cell adhesion ability on micro-pattern dots, accompanied by dephosphorylations of both focal adhesion kinase (FAK) and insulin-like growth factor-1 receptor (IGF-1R) whereas retained the activations of mitogen-activated protein kinase and mammalian target of rapamycin. The growth of AsPC-1 and BxPC-3 cells can be significantly suppressed by EGCG treatment alone in a dose-dependent manner. At a dose of 100 MUM which completely abolishes activations of FAK and IGF-1R, EGCG suppresses more than 50% of cell proliferation without evidence of apoptosis analyzed by PARP cleavage. Finally, the MEK1/2 inhibitor U0126 enhances growth-suppressive effect of EGCG. Our data suggests that blocking FAK and IGF-1R by EGCG could prove valuable for targeted therapy, which can be used in combination with other therapies, for pancreatic cancer. PMID- 21318152 TI - Adolescents with mild stunting show alterations in glucose and insulin metabolism. AB - Purpose. To evaluate glucose and insulin profiles in adolescents with mild stunting and overweight in order to assess the possibility of increased predisposition to diabetes. Subjects and Methods. The study population consisted of 66 pubertal adolescents classified as mildly stunted (height-for-age z scores >=-2 and <-1) or of normal stature, as well as overweight (body mass index >=85th percentile) or normal weight. Beta-cell function and insulin resistance were evaluated according to the homeostasis model assessment (HOMA). Results. In the group with mild stunting, glucose, insulin, and HOMA-IR levels were significantly higher in overweight adolescents compared with those of normal weight, whereas HOMA-B levels were significantly lower. Adolescents with mild stunting showed significantly higher accumulations of body and abdominal fat than their normal stature counterparts. Conclusions. The presence of mild stunting was associated with higher levels of glucose and insulin, diminished function of beta cells, and increased insulin resistance. These results reinforce the need for intervention in adolescents with mild stunting. PMID- 21318153 TI - AMP-activated protein kinase activation during cardioplegia-induced hypoxia/reoxygenation injury attenuates cardiomyocytic apoptosis via reduction of endoplasmic reticulum stress. AB - Cardioplegic-induced H/R injury results in cardiomyocytic apoptosis. AMPK has been shown to reduce ER stress and the unfolded protein response (UPR). Whether AMPK activation can attenuate cardiomyocytic apoptosis after cardioplegia-induced H/R injury is unknown. Cardiomyocytes were exposed to simulated ischemia by incubation in a hypoxic chamber with intermittent cold cardioplegia solution infusion at 20-minute intervals and subsequently reoxygenated in a normoxic environment. Various doses of AMPK activators (AICAR or metformin) were given 2 days before H/R injury. The cardiomyocytes were harvested after reoxygenation for subsequent examination. With both AMPK activators, the antiapoptotic genes of ER stress and UPR, the subsequent production of proapoptotic proteins was attenuated, and the antiapoptotic proteins were elevated. The activity of the apoptotic effectors of ER stress was also reduced with AMPK activation. Moreover, TUNEL staining showed that AMPK activation significantly reduced the percentage of apoptotic cardiomyocytes after cardioplegia-induced H/R injury. Our results revealed that AMPK activation during cardioplegia-induced H/R injury attenuates cardiomyocytic apoptosis, via enhancement of antiapoptotic and reduction of proapoptotic responses, resulting from lessening ER stress and the UPR. AMPK activation may serve as a future pharmacological target to reduce H/R injury in the clinical setting. PMID- 21318154 TI - Translating research into clinical scale manufacturing of mesenchymal stromal cells. AB - It sounds simple to obtain sufficient numbers of cells derived from fetal or adult human tissues, isolate and/or expand the stem cells, and then transplant an appropriate number of these cells into the patient at the correct location. However, translating basic research into routine therapies is a complex multistep process which necessitates product regulation. The challenge relates to managing the expected therapeutic benefits with the potential risks and to balance the fast move to clinical trials with time-consuming cautious risk assessment. This paper will focus on the definition of mesenchymal stromal cells (MSCs), and challenges and achievements in the manufacturing process enabling their use in clinical studies. It will allude to different cellular sources, special capacities of MSCs, but also to current regulations, with a special focus on accessory material of human or animal origin, like media supplements. As cellular integrity and purity, formulation and lot release testing of the final product, validation of all procedures, and quality assurance are of utmost necessity, these topics will be addressed. PMID- 21318155 TI - Molecular Aspects of H. pylori-Related MALT Lymphoma. AB - Helicobacter pylori-related extranodal marginal zone lymphoma of mucosa associated lymphoid tissue is a paradigm for malignancy arising in an inflammatory background. While the diagnosis of H. pylori gastritis is often straightforward, distinction between severe gastritis and early lymphoma can be difficult and requires careful assessment of clinical findings in addition to histological features and immunohistochemical results. A number of cytogenetic abnormalities have been discovered in H. pylori-related lymphomas and several have clinical importance, related to the responsiveness of lymphoma to H. pylori eradication therapy, but routine molecular studies are not widely utilized. While molecular methods may be used in equivocal cases, a trial of conservative therapy is warranted given the propensity for these lymphomas to regress with eradication of the organism. Once therapy is initiated, care must be taken to avoid a premature assignment of disease refractoriness because complete response can take several months to more than a year. Cases truly refractory to H. pylori eradication therapy may be treated with adjuvant chemoradiation with a high response rate. PMID- 21318156 TI - Impact of integrated amrita meditation technique on adrenaline and cortisol levels in healthy volunteers. AB - THE OBJECTIVE WAS TO FIND OUT THE EFFECT OF INTEGRATED AMRITA MEDITATION TECHNIQUE (IAM) ON THE STRESS HORMONES: adrenaline and cortisol. One hundred and fifty healthy subjects were randomized into three groups. Blood was collected at 0 hour, 48 hours, 2 months, and 8 months after the first visit. Adrenaline was analyzed by ELISA and cortisol by Chemiluminescent method. In the IAM, PMR and control groups 44, 44, and 36 came, respectively, for the baseline visit. Within group, cortisol and adrenaline levels reduced in the IAM 48 hours onwards and the fall sustained until 8 months (P < .05). ANCOVA (Repeated measures) on adrenaline taking the four levels of observation showed a highly significant (P = .001) drop in the IAM group. The mean cortisol values between groups were not statistically significant (P = .138). IAM Technique was effective in reducing adrenaline and cortisol levels within group comparisons. PMID- 21318158 TI - Sonographic diagnosis of arterioportal fistula. AB - AIM: We aimed to identify and describe characteristic and diagnostic ultrasonographic features of arterioportal fistula cases. PATIENTS: In this case series we describe 3 patients with arterioportal fistula. By depending on shared sonographic features of these patients we describe a "sonographic pattern" for the sonographic diagnosis of arterioportal fistula. CONCLUSION: In summary; both of the artery and vein related with fistula were wider than normal and seen as adjacent anechoic circles, there was an aneurysmatic dilation on vein which has turbulent flow within it, the communication between the artery and aneurysm can be seen sonographically, both of the vessels have arterial flow, filling of the vein was retrograde and other branches of the artery and vein unrelated with aneurysm were all normal in dimension. PMID- 21318157 TI - The consequence of immune suppressive cells in the use of therapeutic cancer vaccines and their importance in immune monitoring. AB - Evaluating the number, phenotypic characteristics, and function of immunosuppressive cells in the tumor microenvironment and peripheral blood could elucidate the antitumor immune response and provide information to evaluate the efficacy of cancer vaccines. Further studies are needed to evaluate the correlation between changes in immunosuppressive cells and clinical outcomes of patients in cancer vaccine clinical trials. This paper focuses on the role of T regulatory cells, myeloid-derived suppressor cells, and tumor-associated macrophages in cancer and cancer immunotherapy and their role in immune monitoring. PMID- 21318159 TI - Does Smoking Act as a Friend or Enemy of Blood Pressure? Let Release Pandora's Box. AB - In spite of the great number of observations which show the certainty of cardiovascular damage from smoking, the opinions on that are not yet unanimous. There is a discrepancy that could be attributed to the lack of reproducible data particularly in some epidemiological studies. On the contrary, experimental findings conducted on both animals and humans give evidence of exactly reproducible results of cardiovascular alterations and among these the course of Blood Pressure (BP). Findings identify an increase in BP of active smokers or non smokers exposed to passive smoking, while a lot of others refer a lowering of BP due to smoking. This discrepancy could be explained as follows. Initially, a vasoconstriction mediated by nicotine causes acute but transient increase in systolic BP. This phase is followed by a decrease in BP as a consequence of depressant effects played chronically by nicotine itself. Simultaneously, carbon monoxide is acting directly on the arterial wall causing, in the long run, structurally irreversible alterations. At this time, there is a change in BP that increases again, and often constantly, its levels following chronic exposure. Changes in response to antihypertensive drugs have been observed in hypertensive smokers since smoking influences metabolic steps of the drugs. PMID- 21318160 TI - Thrombopoietin receptor levels in tumor cell lines and primary tumors. AB - Thrombopoietin (TPO) receptor agonists represent a new approach for the treatment of thrombocytopenia, which may develop as a consequence of immune thrombocytopenia, chemotherapy treatment, chronic hepatitis C infection, or myelodysplastic syndromes. There are concerns that use of certain growth factors can hasten disease progression in some types of hematologic malignancies and solid tumors. In this study, expression of MPL (TPO-R) mRNA was examined in tumor cell lines, patient tumor samples (renal cell carcinoma, prostatic carcinoma, soft tissue and bony/cartilage sarcoma, colon cancer, and lymphoma), and normal tissues using microarray analysis and qRT-PCR. MPL mRNA is expressed at very low or undetectable levels compared with erythropoietin receptor (EPOR), human epidermal growth factor (ERBB2; HER2), and insulin-like growth factor-1 receptor (IGF1R) in these patient samples. These data suggest TPO-R agonists will likely preferentially stimulate proliferation and differentiation of cells of megakaryocytic lineage, potentially demonstrating their utility for correcting thrombocytopenia in clinical settings. PMID- 21318161 TI - Dosage of 2,6-bis (1.1-dimethylethyl)-4-methylphenol (BHT) in the plant extract Mesembryanthemum crystallinum. AB - A naturally occurring BHT was identified in the leaves of the halophyte plant Mesembryanthemum crystallinum. This phenol was extracted in this study by two methods at the different plant growth stages. One of the methods was better for BHT extraction; the concentration of this phenol is plant growth stage dependent. In this study, the floraison stage has the highest BHT concentration. The antioxidant activity of the plant extract was not related to BHT concentration. The higher antioxidant activity is obtained at seedlings stage. PMID- 21318162 TI - Pectinolytic and Cellulolytic Enzymes Enhance Fusarium compactum Virulence on Tubercles Infection of Egyptian Broomrape. AB - The use of enzyme could facilitate pathogen penetration into plant host. Here the combination of cellulase and pectinase was ascertained on the pathogenicity of F. compactum (1.4 * 10(6) propagules ml(-1)) on broomrape tubercles. F. compactum alone infected all the inoculated tubercles but did not kill any significant number. Infested tomato roots that were inoculated with mycelia plus pectinase (20 U ml(-1)) had over 50% tubercles dead one week after treatment. Those inoculated with mycelia plus cellulase (20 U ml(-1)) had above 60% mortality. Mixtures of mycelial plus the two enzymes (10 U ml(-1) of each enzyme) showed synergy. The activity catalyzed by an enzyme is a measure of the amount of enzyme present. It was shown that, in a 1 mg (10 U mg(-1)) cellulase used, 0.055 mg pectinase (1.1 U mg(-1)) is present. This explains why mycelial plus cellulase mix contends with mycelial plus the two enzymes. PMID- 21318164 TI - Ankle blood pressure and pulse pressure as predictors of cerebrovascular morbidity and mortality in a prospective follow-up study. AB - Background and Objective. We examined the association of elevated ankle blood pressure (ABP), together with exercise blood pressure, with incident cerebrovascular (CV) morbidity and mortality in a prospective follow-up study of 3,808 patients. The results were compared with pulse pressure, another indicator of arterial stiffness. Methods. Patients with normal ankle and exercise brachial blood pressures were taken as the reference group. Pulse pressure was considered as quartiles with the lowest quartile as the reference category. Results. A total of 170 subjects had a CV event during the follow-up. Multivariate adjusted hazard ratio of a CV event was 2.24 (95% CI 1.43-3.52, P < .0001) in patients with abnormal ABP. The pulse pressure was significant only in the model adjusted for age and sex. Conclusion. The risk of a future CV event was elevated already in those patients among whom elevated ABP was the only abnormal finding. As a risk marker, ABP is superior to the pulse pressure. PMID- 21318165 TI - Techniques for precancerous lesion diagnosis. AB - The development of the oral squamous cell carcinoma (OSCC) is a multistep process that requires the accumulation of multiple genetic alterations usually preceded by detectable mucosal changes, most often leukoplakias and erythroplakias. The clinical appearance of oral precancerous lesions and their degree of epithelium dysplasia suggests the malignization potential. Several techniques have been developed to improve the clinical and cytological diagnosis of oral precancerous lesions. The present paper reviews the main techniques used to improve premalignant lesion diagnosis. PMID- 21318163 TI - Mitochondrial Dysfunction: The Road to Alpha-Synuclein Oligomerization in PD. AB - While the etiology of Parkinson's disease remains largely elusive, there is accumulating evidence suggesting that mitochondrial dysfunction occurs prior to the onset of symptoms in Parkinson's disease. Mitochondria are remarkably primed to play a vital role in neuronal cell survival since they are key regulators of energy metabolism (as ATP producers), of intracellular calcium homeostasis, of NAD(+)/NADH ratio, and of endogenous reactive oxygen species production and programmed cell death. In this paper, we focus on mitochondrial dysfunction mediated alpha-synuclein aggregation. We highlight some of the findings that provide proof of evidence for a mitochondrial metabolism control in Parkinson's disease, namely, mitochondrial regulation of microtubule-dependent cellular traffic and autophagic lysosomal pathway. The knowledge that microtubule alterations may lead to autophagic deficiency and may compromise the cellular degradation mechanisms that culminate in the progressive accumulation of aberrant protein aggregates shields new insights to the way we address Parkinson's disease. In line with this knowledge, an innovative window for new therapeutic strategies aimed to restore microtubule network may be unlocked. PMID- 21318166 TI - Reservoir of bacterial exotoxin genes in the environment. AB - Many bacteria produce secreted virulence factors called exotoxins. Exotoxins are often encoded by mobile genetic elements, including bacteriophage (phage). Phage can transfer genetic information to the bacteria they infect. When a phage transfers virulence genes to an avirulent bacterium, the bacterium can acquire the ability to cause disease. It is important to understand the role played by the phage that carry these genes in the evolution of pathogens. This is the first report of an environmental reservoir of a bacterial exotoxin gene in an atypical host. Screening bacterial isolates from the environment via PCR identified an isolate with a DNA sequence >95% identical to the Staphylococcus aureus enterotoxin A gene (sea). 16S DNA sequence comparisons and growth studies identified the environmental isolate as a psychrophilic Pseudomonas spp. The results indicate that the sea gene is present in an alternative bacterial host, providing the first evidence for an environmental pool of exotoxin genes in bacteria. PMID- 21318167 TI - Induction of metastatic gastric cancer by peroxisome proliferator-activated receptordelta activation. AB - Peroxisome proliferator-activated receptordelta (PPARdelta) regulates a multiplicity of physiological processes associated with glucose and lipid metabolism, inflammation, and proliferation. One or more of these processes likely create risk factors associated with the ability of PPARdelta agonists to promote tumorigenesis in some organs. In the present study, we describe a new gastric tumor mouse model that is dependent on the potent and highly selective PPARdelta agonist GW501516 following carcinogen administration. The progression of gastric tumorigenesis was rapid as determined by magnetic resonance imaging and resulted in highly metastatic squamous cell carcinomas of the forestomach within two months. Tumorigenesis was associated with gene expression signatures indicative of cell adhesion, invasion, inflammation, and metabolism. Increased PPARdelta expression in tumors correlated with increased PDK1, Akt, beta-catenin, and S100A9 expression. The rapid development of metastatic gastric tumors in this model will be useful for evaluating preventive and therapeutic interventions in this disease. PMID- 21318169 TI - Regulation of Proteome Maintenance Gene Expression by Activators of Peroxisome Proliferator-Activated Receptor alpha. AB - The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) is activated by a large number of xenobiotic and hypolipidemic compounds called peroxisome proliferator chemicals (PPCs). One agonist of PPARalpha (WY-14,643) regulates responses in the mouse liver to chemical stress in part by altering expression of genes involved in proteome maintenance (PM) including protein chaperones in the heat shock protein (Hsp) family and proteasomal genes (Psm) involved in proteolysis. We hypothesized that other PPARalpha activators including diverse hypolipidemic and xenobiotic compounds also regulate PM genes in the rat and mouse liver. We examined the expression of PM genes in rat and mouse liver after exposure to 7 different PPCs (WY-14,643, clofibrate, fenofibrate, valproic acid, di-(2-ethylhexyl) phthalate, perfluorooctanoic acid, and perfluorooctane sulfonate) using Affymetrix microarrays. In rats and mice, 174 or 380 PM genes, respectively, were regulated by at least one PPC. The transcriptional changes were, for the most part, dependent on PPARalpha, as most changes were not observed in similarly treated PPARalpha-null mice and the changes were not consistently observed in rats treated with activators of the nuclear receptors CAR or PXR. In rats and mice, PM gene expression exhibited differences compared to typical direct targets of PPARalpha (e.g., Cyp4a family members). PM gene expression was usually delayed and in some cases, it was transient. Dose-response characterization of protein expression showed that Hsp86 and Hsp110 proteins were induced only at higher doses. These studies demonstrate that PPARalpha, activated by diverse PPC, regulates the expression of a large number of genes involved in protein folding and degradation and support an expanded role for PPARalpha in the regulation of genes that protect the proteome. PMID- 21318168 TI - The role of HDACs inhibitors in childhood and adolescence acute leukemias. AB - Acute leukemia is the most common type of childhood and adolescence cancer, characterized by clonal proliferation of variably differentiated myeloid or lymphoid precursors. Recent insights into the molecular pathogenesis of leukemia have shown that epigenetic modifications, such as deacetylation of histones and DNA methylation, play crucial roles in leukemogenesis, by transcriptional silencing of critical genes. Histone deacetylases (HDACs) are potential targets in the treatment of leukaemia, and, as a consequence, inhibitors of HDACs (HDIs) are being studied for therapeutic purposes. HDIs promote or enhance several different anticancer mechanisms, such as apoptosis, cell cycle arrest, and cellular differentiation and, therefore, are in evidence as promising treatment for children and adolescents with acute leukemia, in monotherapy or in association with other anticancer drugs. Here we review the main preclinical and clinical studies regarding the use of HDIs in treating childhood and adolescence leukemia. PMID- 21318170 TI - Cytogenetics of premature ovarian failure: an investigation on 269 affected women. AB - The importance of X chromosome in the aetiology of premature ovarian failure (POF) is well-known but in many cases POF still remains idiopathic. Chromosome aneuploidy increase is a physiological phenomenon related to aging, but the role of low-level sex chromosome mosaicism in ovarian function is still undiscovered. Standard cytogenetic analysis was carried out in a total of 269 patients affected by POF: 27 chromosomal abnormalities were identified, including X chromosome and autosomal structural and numerical abnormalities. In 47 patients with 46,XX karyotype we performed interphase FISH using X alpha-satellite probe in order to identify X chromosome mosaicism rate. Aneuploidy rate in the patient group was significantly higher than the general population group. These findings underline the importance of X chromosome in the aetiology of POF and highlight the potential role of low-level sex chromosome mosaicism in ovarian aging that may lead to a premature onset of menopause. PMID- 21318171 TI - In situ biodiesel production from fast-growing and high oil content Chlorella pyrenoidosa in rice straw hydrolysate. AB - Rice straw hydrolysate was used as lignocellulose-based carbon source for Chlorella pyrenoidosa cultivation and the feasibility of in situ biodiesel production was investigated. 13.7 g/L sugar was obtained by enzymatic hydrolyzation of rice straw. Chlorella pyrenoidosa showed a rapid growth in the rice straw hydrolysate medium, the maximum biomass concentration of 2.83 g/L was obtained in only 48 hours. The lipid content of the cells reached as high as 56.3%. In situ transesterification was performed for biodiesel production. The optimized condition was 1 g algal powder, 6 mL n-hexane, and 4 mL methanol with 0.5 M sulfuric acid at the temperature of 90 degrees C in 2-hour reaction time, under which over 99% methyl ester content and about 95% biodiesel yield were obtained. The results suggested that the method has great potential in the production of biofuels with lignocellulose as an alternative carbon source for microalgae cultivation. PMID- 21318172 TI - Enhancement of 2,3-butanediol production by Klebsiella oxytoca PTCC 1402. AB - Optimal operating parameters of 2,3-Butanediol production using Klebsiella oxytoca under submerged culture conditions are determined by using Taguchi method. The effect of different factors including medium composition, pH, temperature, mixing intensity, and inoculum size on 2,3-butanediol production was analyzed using the Taguchi method in three levels. Based on these analyses the optimum concentrations of glucose, acetic acid, and succinic acid were found to be 6, 0.5, and 1.0 (% w/v), respectively. Furthermore, optimum values for temperature, inoculum size, pH, and the shaking speed were determined as 37 degrees C, 8 (g/L), 6.1, and 150 rpm, respectively. The optimal combinations of factors obtained from the proposed DOE methodology was further validated by conducting fermentation experiments and the obtained results revealed an enhanced 2,3-Butanediol yield of 44%. PMID- 21318174 TI - Mix and match: heterodimers and opioid tolerance. AB - Heterodimerization of G-protein coupled receptors has become increasingly recognized as a valuable mechanism to increase receptor diversity. Heterodimers have been observed in the opioid receptor family, but one of the most intriguing is that formed between mu and delta opioid receptors. In this issue of Neuron He et al. present evidence further implicating these heterodimers in morphine tolerance. PMID- 21318175 TI - Erratum: gene-environment interaction research and transgenic mouse models of Alzheimer's disease. PMID- 21318173 TI - Glycogen storage disease type Ia in canines: a model for human metabolic and genetic liver disease. AB - A canine model of Glycogen storage disease type Ia (GSDIa) is described. Affected dogs are homozygous for a previously described M121I mutation resulting in a deficiency of glucose-6-phosphatase-alpha. Metabolic, clinicopathologic, pathologic, and clinical manifestations of GSDIa observed in this model are described and compared to those observed in humans. The canine model shows more complete recapitulation of the clinical manifestations seen in humans including "lactic acidosis", larger size, and longer lifespan compared to other animal models. Use of this model in preclinical trials of gene therapy is described and briefly compared to the murine model. Although the canine model offers a number of advantages for evaluating potential therapies for GSDIa, there are also some significant challenges involved in its use. Despite these challenges, the canine model of GSDIa should continue to provide valuable information about the potential for generating curative therapies for GSDIa as well as other genetic hepatic diseases. PMID- 21318176 TI - Who did Buzz see someone? Grammaticality judgement of wh-questions in typically developing children and children with Grammatical-SLI. AB - This paper tests claims that children with Grammatical(G)-SLI are impaired in hierarchical structural dependencies at the clause level and in whatever underlies such dependencies with respect to movement, chain formation and feature checking; that is, their impairment lies in the syntactic computational system itself (the Computational Grammatical Complexity hypothesis proposed by van der Lely in previous work). We use a grammaticality judgement task to test whether G SLI children's errors in wh-questions are due to the hypothesised impairment in syntactic dependencies at the clause level or lie in more general processes outside the syntactic system, such as working memory capacity. We compare the performance of 14 G-SLI children (aged 10-17 years) with that of 36 younger language-matched controls (aged 5-8 years). We presented matrix wh-subject and object questions balanced for wh-words (who/what/which) that were grammatical, ungrammatical, or semantically inappropriate. Ungrammatical questions contained wh-trace or T-to-C dependency violations that G-SLI children had previously produced in elicitation tasks. G-SLI children, like their language controls, correctly accepted grammatical questions, but rejected semantically inappropriate ones. However, they were significantly impaired in rejecting wh-trace and T-to-C dependency violations. The findings provide further support for the CGC hypothesis that G-SLI children have a core deficit in the computational system itself that affects syntactic dependencies at the clause level. PMID- 21318177 TI - Archaeosome adjuvant overcomes tolerance to tumor-associated melanoma antigens inducing protective CD8 T cell responses. AB - Vesicles comprised of the ether glycerolipids of the archaeon Methanobrevibacter smithii (archaeosomes) are potent adjuvants for evoking CD8(+) T cell responses. We therefore explored the ability of archaeosomes to overcome immunologic tolerance to self-antigens. Priming and boosting of mice with archaeosome-antigen evoked comparable CD8(+) T cell response and tumor protection to an alternate boosting strategy utilizing live bacterial vectors for antigen delivery. Vaccination with melanoma antigenic peptides TRP(181-189) and Gp100(25-33) delivered in archaeosomes resulted in IFN-gamma producing antigen-specific CD8(+) T cells with strong cytolytic capability and protection against subcutaneous B16 melanoma. Targeting responses against multiple antigens afforded prolonged median survival against melanoma challenge. Entrapment of multiple peptides within the same vesicle or admixed formulations were both effective at evoking CD8(+) T cells against each antigen. Melanoma-antigen archaeosome formulations also afforded therapeutic protection against established B16 tumors when combined with depletion of T-regulatory cells. Overall, we demonstrate that archaeosome adjuvants constitute an effective choice for formulating cancer vaccines. PMID- 21318179 TI - Pseudoangiomatous stromal hyperplasia: a case report. AB - Pseudoangiomatous stromal hyperplasia (PASH) is a rare benign proliferating breast condition. It was first reported in 1986 when Vuitch, Rosen, and Erlandson described nine cases of benign well-circumscribed, breast masses that simulated vascular lesions consisting of mammary stromal proliferations (Vuitch et al. (1986)). Since then there have been few reported cases of PASH in the literature (Taira et al. (2005)). We describe a large PASH, mimicking inflammatory carcinoma in a young lady that was excised with excellent cosmetic results. PMID- 21318178 TI - Aberrantly glycosylated IgA1 as a factor in the pathogenesis of IgA nephropathy. AB - Predominant or codominant immunoglobulin (Ig) A deposition in the glomerular mesangium characterizes IgA nephropathy (IgAN). Accumulated glomerular IgA is limited to the IgA1 subclass and usually galactose-deficient. This underglycosylated IgA may play an important role in the pathogenesis of IgAN. Recently, antibodies against galactose-deficient IgA1 were found to be well associated with the development of IgAN. Several therapeutic strategies based on corticosteroids or other immunosuppressive agents have been shown to at least partially suppress the progression of IgAN. On the other hand, several case reports of kidney transplantation or acquired IgA deficiency uncovered a remarkable ability of human kidney to remove mesangial IgA deposition, resulting in the long-term stabilization of kidney function. Continuous exposure to circulating immune complexes containing aberrantly glycosylated IgA1 and sequential immune response seems to be essential in the disease progression of IgAN. Removal of mesangial IgA deposition may be a challenging, but fundamental approach in the treatment of IgAN. PMID- 21318180 TI - Effect of hydrogen peroxide on the antibacterial substantivity of chlorhexidine. AB - The purpose of this in vitro study was to assess the effect of hydrogen peroxide on the antibacterial substantivity of chlorhexidine (CHX). Seventy-five dentine tubes prepared from human maxillary central and lateral incisor teeth were used. After contamination with Enterococcus faecalis for 14 days, the specimens were divided into five groups as follows: CHX, H(2)O(2), CHX + H(2)O(2), infected dentine tubes (positive control), and sterile dentine tubes (negative control). Dentine chips were collected with round burs into tryptic soy broth, and after culturing, the number of colony-forming units (CFU) was counted. The number of CFU was minimum in the first cultures in all experimental groups, and the results obtained were significantly different from each other at any time period (P < .05). At the first culture, the number of CFU in the CHX + H(2)O(2) group was lower than other two groups. At the other experimental periods, the CHX group showed the most effective antibacterial action (P < .05). Hydrogen peroxide group showed the worst result at all periods. In each group, the number of CFU increased significantly by time lapse (P < .05). In conclusion, H(2)O(2) had no additive effect on the residual antibacterial activity of CHX. PMID- 21318181 TI - Immune response in ovarian cancer: how is the immune system involved in prognosis and therapy: potential for treatment utilization. AB - Ovarian cancer is one of the leading causes of cancer-related death among women. Resistance to the disease occurs in more than 70% of the cases even after treated with chemotherapy agents such as paclitaxel- and platinum-based agents. The immune system is increasingly becoming a target for intense research in order to study the host's immune response against ovarian cancer. T cell populations, including NK T cells and Tregs, and cytokines have been associated with disease outcome, indicating their increasing clinical significance, having been associated with prognosis and as markers of disease progress, respectively. Harnessing the immune system capacity in order to induce antitumor response remains a major challenge. This paper examines the recent developments in our understanding of the mechanisms of development of the immune response in ovarian cancer as well as its prognostic significance and the existing experience in clinical studies. PMID- 21318182 TI - Mycobacterial PE/PPE proteins at the host-pathogen interface. AB - The mycobacterial PE/PPE proteins have attracted much interest since their formal identification just over a decade ago. It has been widely speculated that these proteins may play a role in evasion of host immune responses, possibly via antigenic variation. Although a cohesive understanding of their function(s) has yet to be established, emerging data increasingly supports a role for the PE/PPE proteins at multiple levels of the infectious process. This paper will delineate salient features of the families revealed by comparative genomics, bioinformatic analyses and genome-wide screening approaches and will summarise existing knowledge of subcellular localization, secretion pathways, and protein structure. These characteristics will be considered in light of findings on innate and adaptive host responses to PE/PPE proteins, and we will review the increasing body of data on B and T cell recognition of these proteins. Finally, we will consider how current knowledge and future explorations may contribute to a more comprehensive understanding of these intriguing proteins and their involvement in host pathogen interactions. Ultimately this information could underpin future intervention strategies, for example, in the area of new and improved diagnostic tools and vaccine candidates. PMID- 21318183 TI - Wound healing in mice with high-fat diet- or ob gene-induced diabetes-obesity syndromes: a comparative study. AB - In the past, the genetically diabetic-obese diabetes/diabetes (db/db) and obese/obese (ob/ob) mouse strains were used to investigate mechanisms of diabetes impaired wound healing. Here we determined patterns of skin repair in genetically normal C57Bl/6J mice that were fed using a high fat diet (HFD) to induce a diabetes-obesity syndrome. Wound closure was markedly delayed in HFD-fed mice compared to mice which had received a standard chow diet (CD). Impaired wound tissue of HFD mice showed a marked prolongation of wound inflammation. Expression of vascular endothelial growth factor (VEGF) was delayed and associated with the disturbed formation of wound margin epithelia and an impaired angiogenesis in the reduced granulation tissue. Normal wound contraction was retarded and disordered. Wound disorders in obese C57Bl/6J mice were paralleled by a prominent degradation of the inhibitor of NFkappaB (IkappaB-alpha) in the absence of an Akt activation. By contrast to impaired wound conditions in ob/ob mice, late wounds of HFD mice did not develop a chronic inflammatory state and were epithelialized after 11 days of repair. Thus, only genetically obese and diabetic ob/ob mice finally developed chronic wounds and therefore represent a better suited experimental model to investigate diabetes-induced wound healing disorders. PMID- 21318184 TI - Effect of glucose or fat challenge on aspirin resistance in diabetes. AB - Aspirin has lower antiplatelet activity in diabetic patients. Our aim is to study the roles of acute hyperglycemia and hyperlipidemia on aspirin function in diabetic subjects with and without cardiovascular disease. Using urine thromboxane (pg/mg creatinine) and VerifyNow (Aspirin Resistance Measures-ARU), we investigated diabetic subjects during a 2-hour glucose challenge (n = 49) or a 4-hour fat challenge (n = 11). All subjects were currently taking aspirin (81 or 325 mg). After fat ingestion, urine thromboxane increased in all subjects (Mean +/- SE before: after) (1209 +/- 336: 1552 +/- 371, P = .01), while we noted a trend increase in VerifyNow measures (408 +/- 8: 431 +/- 18, P = .1). The response to glucose ingestion was variable. Diabetic subjects with cardiac disease and dyslipidemia increased thromboxane (1693 +/- 364: 2799 +/- 513, P < .05) and VerifyNow (457.6 +/- 22.3: 527.1 +/- 25.8, P < .05) measures after glucose. We conclude that saturated fat ingestion increases in vivo thromboxane production despite aspirin therapy. PMID- 21318186 TI - Preliminary Characterization of the Transcriptional Response of the Porcine Intestinal Cell Line IPEC-J2 to Enterotoxigenic Escherichia coli, Escherichia coli, and E. coli Lipopolysaccharide. AB - IPEC-J2, a promising in vitro model system, is not well characterized especially on the transcriptional level, in contrast to human counterparts. The aim of this study was to characterize the gene expression in IPEC-J2 cells when coincubated with enterotoxigenic Escherichia coli (ETEC), nonpathogenic E. coli, and E. coli endotoxin. Apical infection of polarized IPEC-J2 monolayers caused a time dependent decrease in transepithelial electrical resistance (TEER). Microarray analysis showed up-regulation of interleukins when IPEC-J2 were cocultured with E. coli strains this has so far never been measured in this cell line. Highest IL8 expression was found with the ETEC strain possessing the F4 fimbrium, suggesting IPEC-J2 cells to be F4 receptor positive, confirmed in a brush border membrane adhesion assay. It is concluded that the innate immune responses to pathogens and LPS makes the IPEC-J2 cell line a suitable model for research on intestinal host pathogen interaction. PMID- 21318185 TI - Deletion of the Men1 gene prevents streptozotocin-induced hyperglycemia in mice. AB - Diabetes ultimately results from an inadequate number of functional beta cells in the islets of Langerhans. Enhancing proliferation of functional endogenous beta cells to treat diabetes remains underexplored. Here, we report that excision of the Men1 gene, whose loss-of-function mutation leads to inherited multiple endocrine neoplasia type 1 (MEN1), rendered resistant to streptozotocin-induced hyperglycemia in a tamoxifen-inducible and temporally controlled Men1 excision mouse model as well as in a tissue-specific Men1 excision mouse model. Men1 excision prevented mice from streptozotocin-induced hyperglycemia mainly through increasing the number of functional beta cells. BrdU incorporation by beta cells, islet size, and circulating insulin levels were significantly increased in Men1 excised mice. Membrane localization of glucose transporter 2 was largely preserved in Men1-excised beta cells, but not in Men1-expressing beta cells. Our findings suggest that repression of menin, a protein encoded by the Men1 gene, might be a valuable means to maintain or increase the number of functional endogenous beta cells to prevent or ameliorate diabetes. PMID- 21318187 TI - Microbiota in chronic mucosal inflammation. PMID- 21318188 TI - Assessment of bacterial antibiotic resistance transfer in the gut. AB - We assessed horizontal gene transfer between bacteria in the gastrointestinal (GI) tract. During the last decades, the emergence of antibiotic resistant strains and treatment failures of bacterial infections have increased the public awareness of antibiotic usage. The use of broad spectrum antibiotics creates a selective pressure on the bacterial flora, thus increasing the emergence of multiresistant bacteria, which results in a vicious circle of treatments and emergence of new antibiotic resistant bacteria. The human gastrointestinal tract is a massive reservoir of bacteria with a potential for both receiving and transferring antibiotic resistance genes. The increased use of fermented food products and probiotics, as food supplements and health promoting products containing massive amounts of bacteria acting as either donors and/or recipients of antibiotic resistance genes in the human GI tract, also contributes to the emergence of antibiotic resistant strains. This paper deals with the assessment of antibiotic resistance gene transfer occurring in the gut. PMID- 21318189 TI - Modulation of the cellular expression of circulating advanced glycation end product receptors in type 2 diabetic nephropathy. AB - BACKGROUND: Advanced glycation end-products (AGEs) and their receptors are prominent contributors to diabetic kidney disease. METHODS: Flow cytometry was used to measure the predictive capacity for kidney impairment of the AGE receptors RAGE, AGE-R1, and AGE-R3 on peripheral blood mononuclear cells (PBMCs) in experimental models of type 2 diabetes (T2DM) fed varied AGE containing diets and in obese type 2 diabetic and control human subjects. RESULTS: Diets high in AGE content fed to diabetic mice decreased cell surface RAGE on PBMCs and in type 2 diabetic patients with renal impairment (RI). All diabetic mice had elevated Albumin excretion rates (AERs), and high AGE fed dbdb mice had declining Glomerular filtration rate (GFR). Cell surface AGE-R1 expression was also decreased by high AGE diets and with diabetes in dbdb mice and in humans with RI. PBMC expression of AGE R3 was decreased in diabetic dbdb mice or with a low AGE diet. CONCLUSIONS: The most predictive PBMC profile for renal disease associated with T2DM was an increase in the cell surface expression of AGE-R1, in the context of a decrease in membranous RAGE expression in humans, which warrants further investigation as a biomarker for progressive DN in larger patient cohorts. PMID- 21318191 TI - Telephone-administered cognitive-behavioral therapy for clients with depressive symptoms in an employee assistance program: a pilot study. AB - BACKGROUND: To assess the clinical and work productivity effects of a brief intervention using telephone-administered cognitive-behavioral therapy (CBT) for clients with depressive symptoms attending an employee assistance program (EAP). METHODS: Self-referred clients attending the PPC Canada EAP with clinically relevant depressive symptoms at initial assessment were offered an 8-session telephone-administered CBT program. Outcomes before and after intervention were assessed with the 9-item Personal Health Questionnaire (PHQ-9), Global Assessment of Functioning (GAF), and clinician ratings of work absence and performance impairment. RESULTS: Fifty clients were referred to the pilot program; 39 participated and 31 completed the telephone CBT program. Among program participants, there was significant improvement in PHQ-9 and GAF scores. There was also a significant reduction in performance impairment but not work absence. Anecdotal reports indicated high satisfaction ratings among participants. CONCLUSIONS: The results of this pilot study, although limited by the absence of a comparison or control group, suggest that a brief telephone-administered CBT program can improve depressive symptomatology, work productivity, and general function in depressed clients attending an EAP. Further controlled studies are needed to confirm these preliminary findings. PMID- 21318190 TI - A 6-month follow-up of imaginal desensitization plus motivational interviewing in the treatment of pathological gambling. AB - BACKGROUND: Pathological gambling (PG), a disabling disorder experienced by approximately 1% of adults, has few empirically validated treatments. A recent study demonstrated that 6 sessions of imaginal desensitization plus motivational interviewing (IDMI) was effective in achieving abstinence for a majority of individuals with PG. This study sought to examine whether those benefits were maintained 6 months post-treatment. METHODS: Sixty-eight individuals who met DSM IV criteria for PG were randomly assigned to 6 sessions of IDMI or Gamblers Anonymous (GA) referral over an 8-week period. Participants who failed to respond to GA were offered IDMI after the 8-week acute treatment period. All individuals who responded to IDMI were contacted after 6 months and assessed with measures of gambling severity and psychosocial functioning. RESULTS: Forty-four participants completed 6 sessions of IDMI (25 initially assigned to IDMI and 19 to GA). Thirty five of the 44 (79.5%) responded during acute treatment, and all 35 were available for a 6-month evaluation. All gambling severity scales maintained statistically significant gains from baseline, although some measures showed significant worsening compared with post-IDMI treatment. CONCLUSIONS: Six sessions of IDMI resulted in statistically significant reductions in PG urges and behavior, which were largely maintained for 6 months. PMID- 21318193 TI - Misdiagnosis of bipolar disorder in children and adolescents: a comparison with ADHD and major depressive disorder. AB - BACKGROUND: Controversy surrounds the frequency of underdiagnosis vs overdiagnosis of bipolar disorder (BD) in children and adolescents compared with diagnoses of attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder (MDD). METHODS: Sixty-four children and adolescents (age 7 to 18) treated in a community setting were systematically assessed for diagnostic and treatment histories. Best estimate consensus diagnosis was made using DSM-IV criteria. RESULTS: ADHD was overdiagnosed (all patients with ADHD had received the diagnosis, as did 38% of patients with MDD and 29% of patients with BD, respectively), while MDD was partially underdiagnosed and partially overdiagnosed (57% of MDD patients received the diagnosis, 43% did not; 33% of patients with BD were incorrectly diagnosed with MDD). BD was underdiagnosed, not overdiagnosed (38% received the diagnosis, 62% did not; BD was not diagnosed in the ADHD sample, and in only 5% of the patients with MDD). The absence of a positive family history predicted misdiagnosis of BD (relative risk = 2.48, 95% confidence interval 1.10 to 5.56). Observational treatment response to stimulants was equally high in all groups (75% to 82%). CONCLUSIONS: In the first controlled study on this topic, BD was not over-diagnosed in children and adolescents, as it is often claimed, and ADHD was. Stimulant response was nonspecific and diagnostically uninformative. Studies with larger samples are needed to replicate or refute these results. PMID- 21318192 TI - Lamotrigine plus quetiapine combination therapy in treatment-resistant bipolar depression. AB - BACKGROUND: Lamotrigine and quetiapine are commonly used in bipolar disorder, but there are no published systematic studies of their use in combination for treatment-resistant bipolar depression. METHODS: We studied 39 trials in outpatients (15 with bipolar I disorder, 22 with bipolar II disorder, and 1 with bipolar disorder not otherwise specified; 1 patient had 2 trials) with depression resistant to quetiapine or lamotrigine who were taking a mean of 1.7 other prescription psychotropic medications. Patients were given either open-label lamotrigine or quetiapine naturalistically, for up to 12 weeks of combination therapy. RESULTS: Lamotrigine (mean dose, 204.2 mg/d) plus quetiapine (mean dose, 188.5 mg/d) increased the euthymia rate (0.0% to 46.2%), decreased syndromal (79.5% to 30.8%) and subsyndromal (20.5% to 15.4%) depression rates, and improved Clinical Global Impression-Severity (mean change, -1.0) and Global Assessment of Functioning (mean change, +5.9) scores. Approximately one-fifth of patients discontinued therapy (20.5%) or required subsequent additional pharmacotherapy (20.5%). Only 10.3% discontinued due to adverse effects, and there was no significant change in mean body weight. CONCLUSIONS: The findings of this uncontrolled open pilot study must be viewed with caution. However, randomized, double-blind, placebo-controlled studies are warranted to confirm the possibility that combination therapy with lamotrigine and quetiapine is effective and well tolerated in patients with treatment-resistant bipolar depression. PMID- 21318194 TI - Do psychiatry residents identify as psychotherapists? A multisite survey. AB - BACKGROUND: Psychiatric training was once synonymous with learning psychotherapy, but current psychiatric trainees face many options for integrating psychopharmacology and psychotherapy into their future practices, including providing primarily medication-focused visits. We examined psychiatry residents' attitudes towards learning psychotherapy, practicing psychotherapy in the future, and overall identification as psychotherapists. METHODS: We surveyed residents from 15 US residency programs during 2006-2007. The survey included 36 Likert scaled items inquiring about residents' attitudes towards their psychotherapy training and supervision, their level of psychotherapy competence, the role of psychotherapy in their psychiatric identity, and their future practice plans. Four items asked about personal psychotherapy experience. Here we describe findings related to attitudes concerning being a psychotherapist and future practice plans. RESULTS: Among 249 respondents, most (82%) viewed becoming a psychotherapist as integral to their psychiatric identity. Fifty-four percent planned to provide formal psychotherapy, whereas 62% anticipated psychopharmacology would be the foundation of treatment for most patients. Residents with personal psychotherapy experience and first-year postgraduate residents (PGY-1) were more likely to identify as psychotherapists, plan to pursue further psychotherapy training postresidency, and anticipate psychotherapy being central to their future practice. CONCLUSIONS: Despite concerns about the diminishing role of psychotherapy in the practice of psychiatry and in psychiatrists' professional identity, most psychiatric residents view psychotherapy as integral to their professional identities and future practice plans. PMID- 21318196 TI - The emerging use of technology for the treatment of depression and other neuropsychiatric disorders. AB - BACKGROUND: Our objective is to review emerging technologies intended for the treatment of depression and other neuropsychiatric disorders. METHODS: These technologies include repetitive transcranial magnetic stimulation (rTMS), magnetic seizure therapy (MST), vagus nerve stimulation (VNS), deep brain stimulation (DBS), cortical brain stimulation (CBS), and quantitative electroencephalography (QEEG). RESULTS: The rationale for these technologies, their mechanisms of action, and how they are used in clinical practice are described. rTMS and VNS are effective for treatment-resistant depression. DBS is effective for resistant obsessive-compulsive disorder. QEEG can help predict a patient's response to an antidepressant. All of these technologies continue to be investigated in treatment studies. CONCLUSIONS: As these and other emerging technologies for depression and other neuropsychiatric disorders are development and applied, psychiatrists should understand the rationale for these modalities, how they work, and how they can be used in clinical practice. PMID- 21318197 TI - Pathological guilt: a persistent yet overlooked treatment factor in obsessive compulsive disorder. AB - BACKGROUND: Guilt appears to be a factor that may increase the severity of obsessive-compulsive disorder (OCD) and negatively impact treatment outcomes. However, researchers and clinicians have paid little attention to addressing guilt in OCD treatment. Because guilt is an important perpetuating and mediating factor for OCD symptoms and the development of guilt-specific strategies may yield improved treatment outcomes, we hypothesized that a review of the relevant literature may provide important guidance for the field. METHODS: To identify existing scientific contributions across psychological, biologic, and theological disciplines, we conducted a systematic review of the literature on the topic of pathological guilt (PG) in OCD. RESULTS: Fourteen studies focusing on both PG and OCD were identified. The content of these papers consistently reflected the theme that guilt plays a significant role in OCD and obsessive-compulsive symptoms. CONCLUSIONS: The potential influence and moderating effects of guilt require more focused attention in the clinical management of OCD. Development of routine standardized measures and treatment protocols targeting the role of guilt in OCD, in addition to consultation with clergy or other appropriate community resources, would provide valuable contributions to the literature. Addressing this affective component related to OCD may lead to improved treatment outcomes and fewer relapses for this debilitating and frequently chronic illness. PMID- 21318195 TI - Cardiovascular morbidity and mortality in bipolar disorder. AB - BACKGROUND: There has been considerable interest in the elevated risk of cardiovascular disease associated with serious mental illness. Although the contemporary literature has paid much attention to major depression and schizophrenia, focus on the risk of cardiovascular mortality for patients with bipolar disorder has been more limited, despite some interest in the historical literature. METHODS: We reviewed the historical and contemporary literature related to cardiovascular morbidity and mortality in bipolar disorder. RESULTS: In studies that specifically assess cardiovascular mortality, bipolar disorder has been associated with a near doubling of risk when compared with general population estimates. This may be explained by the elevated burden of cardiovascular risk factors found in this population. These findings predate modern treatments for bipolar disorder, which may further influence cardiovascular risk. CONCLUSIONS: Given the substantial risk of cardiovascular disease, rigorous assessment of cardiovascular risk is warranted for patients with bipolar disorder. Modifiable risk factors should be treated when identified. Further research is warranted to study mechanisms by which this elevated risk for cardiovascular disease are mediated and to identify systems for effective delivery of integrated medical and psychiatric care for individuals with bipolar disorder. PMID- 21318198 TI - Hormonal replacement therapy in postpartum affective disorders. PMID- 21318199 TI - Heck reaction of arenediazonium salts with N,N-diprotected allylamines. Synthesis of cinnamylamines and indoles. AB - Novel palladium-catalyzed reactions of arenediazonium tetrafluoroborates with N,N diprotected allylamines are presented. The reaction of arenediazonium tetrafluoroborates with N,N-(Boc)(2) allylamine allows for an easy approach to cinnamylamines whereas using 2-alkynyl-N-(allyl)trifluoroacetanilides and 2-iodo N-(allyl)trifluoroacetanilide the reaction provides a useful tool for appending indole rings to aniline fragments. PMID- 21318200 TI - Alpha and beta isomers of tetrahafnium(IV) containing decatungstosilicates, [Hf4(OH)6(CH3COO)2(x-SiW10O37)2]12- (x = alpha, beta). AB - The two dimeric, Hf-containing tungstosilicates [Hf(4)(OH)(6)(CH(3)COO)(2)(alpha SiW(10)O(37))(2)](12-) (1) and [Hf(4)(OH)(6)(CH(3)COO)(2)(beta SiW(10)O(37))(2)](12-) (2) have been synthesized by reacting HfCl(4) with [gamma SiW(10)O(36)](8-) in potassium acetate solutions at pH = 3.6 and 4.8, respectively. Polyanions 1 and 2 comprise a tetrahafnium(iv) assembly {Hf(4)(OH)(6)(CH(3)COO)(2)} sandwiched between two dilacunary [alpha SiW(10)O(36)](8-) (in 1) or {beta-SiW(10)} (in 2) Keggin type decatungstosilicates. This implies that the starting precursor {gamma-SiW(10)} isomerizes in situ to [beta-SiW(10)O(37)](10-) and then to [alpha SiW(10)O(37)](10-) by controlled variation of pH and temperature. The hydrated potassium salts of 1 and 2 were investigated in the solid state by single-crystal XRD, FT-IR, thermogravimetric and elemental analyses, and in solution by UV-Vis and (183)W NMR spectroscopy, and electrochemistry. PMID- 21318201 TI - Binding and photodissociation of CO in iron(II) complexes for application in positron emission tomography (PET) radiolabelling. AB - (R-DAB)FeI(2) complexes containing bidentate diimide ligands (R-DAB = RN=CH CH=NR; R = (i)Pr, c-C(6)H(11)) have been investigated for their ability to react with carbon monoxide to form iron(II) dicarbonyl complexes, (R-DAB)FeI(2)(CO)(2). Solution IR spectroscopy revealed two nuCO stretches between 2000 and 2040 cm(-1) corresponding to a cis-arrangement of the carbonyl ligands around the iron. Photochemical decarbonylation was achieved by UV irradiation (365 nm), which occurred within 5 min as evidenced by solution IR spectroscopy. (c-C(6)H(11) DAB)FeI(2) has been characterised by X-ray crystallography. Reactions using (11)C labelled carbon monoxide were investigated and revealed that both (R-DAB)FeI(2) species were not effective as trapping complexes due to the low concentrations of [(11)C]CO used in these experiments. A Fe(TPP)(THF)(x) (TPP = tetraphenylporphyrin) complex was investigated with unlabelled CO and the monocarbonyl adduct Fe(TPP)(THF)CO was formed in situ as identified by IR spectroscopy (nuCO = 1966 cm(-1)) yet was stable to CO loss upon UV irradiation. Carbonylation reactions of in situ-generated Fe(TPP)(THF)(x) using [(11)C]CO revealed that 97% of the [(11)C]CO stream could be trapped in one pass of the gas at room temperature and at atmospheric pressure. PMID- 21318202 TI - Radial sample preconcentration. AB - In this paper we present a radial sample preconcentration strategy enabled by axisymmetric concentration polarization in a microfluidic chamber on a uniform nanoporous film. Sample analytes are focused into the centre, creating a concentrated plug that is injected vertically into the microfluidic analysis layer. No balancing pressure driven flows or tangential fields are required, and the process has essentially zero footprint on the analysis layer. An electrokinetic loading scheme enables repeat loading/concentration cycles, and a finned radial chamber geometry dampens instabilities and accommodates larger volumes. Modelling results indicate over 1800-fold concentration increases are possible in 10 s, for high mobility buffers and high applied field strength. At moderate field strength and buffer mobility, experiments demonstrate a 168-fold increase in concentration of FITC-BSA protein in 36 s. PMID- 21318203 TI - Illuminating intracellular signaling and molecules for single cell analysis. AB - Fluorescent and bioluminescent proteins are now widely used for detection of small molecules and various intracellular events ranging from protein conformational change to cell death in living cells. To analyze the dynamics of molecular processes in real time at the level of single cells, engineered protein based probes with higher sensitivity and selectivity are required. The probes can be entirely genetically encoded and can comprise fusions of different proteins or domains. This review specifically examines basic concepts of designing genetically encoded fluorescent and bioluminescent probes developed in the past decade, highlighting some potential applications for basic research and for drug discovery. PMID- 21318204 TI - Essential nanogap effects on surface-enhanced Raman scattering signals from closely spaced gold nanoparticles. AB - We have demonstrated the essential nanogap effects on surface-enhanced Raman scattering (SERS) signals obtained from two diagonally aligned gold nanoparticles with several nanometre separations, which were precisely fabricated on a glass substrate. This is the first proof of principle for extracting the light localization effects on SERS due to the formation of nanogaps from experimentally observed SERS signals. PMID- 21318205 TI - Novel methodologies for the synthesis of functionalized pyroglutamates. AB - Alkylation of amino-acid derived iminoesters with Baylis-Hillman (BH) template based allyl bromides furnished alpha-methylene-beta-substituted-pyroglutamates, while the corresponding alkylation with BH derived allylic acetates provided alpha-alkylidene-pyroglutamates. These methodologies have been applied in the synthesis of fused [3.2.0]-gamma-lactam-beta-lactones. PMID- 21318206 TI - Singlet nuclear magnetic resonance of nearly-equivalent spins. AB - Nuclear singlet states may display lifetimes that are an order of magnitude greater than conventional relaxation times. Existing methods for accessing these long-lived states require a resolved chemical shift difference between the nuclei involved. Here, we demonstrate a new method for accessing singlet states that works even when the nuclei are almost magnetically equivalent, such that the chemical shift difference is unresolved. The method involves trains of 180 degrees pulses that are synchronized with the spin-spin coupling between the nuclei. We demonstrate experiments on the terminal glycine resonances of the tripeptide alanylglycylglycine (AGG) in aqueous solution, showing that the nuclear singlet order of this system is long-lived even when no resonant locking field is applied. Variation of the pulse sequence parameters allows the estimation of small chemical shift differences that are normally obscured by larger J-couplings. PMID- 21318207 TI - Oxidation of a guanine derivative coordinated to a Pt(IV) complex initiated by intermolecular nucleophilic attacks. AB - In this study we report that fac-[Pt(IV)(dach)(9-EtG)Cl(3)](+) (dach = d,l-1,2 diaminocyclohexane, 9-EtG = 9-ethylguanine) in high pH (pH 12) or phosphate solution (pH 7.4) produces 8-oxo-9-EtG and Pt(II) species. The reaction in H(2)(18)O revealed that the oxygen atom in hydroxide or phosphate ends up at the C8 position of 8-oxo-G. The kinetics of the redox reaction was first order with respect to both Pt(IV)-G and free nucleophiles (OH(-) and phosphate). The oxidation of G initiated by hydroxide was approximately 30~50 times faster than by phosphate in 100 mM NaCl solutions. The large entropy of activation of OH(-1) (DeltaS(?) = 26.6 +/- 4.3 J mol(-1) K(-1)) due to the smaller size of OH(-) is interpreted to be responsible for the faster kinetics compared to phosphate (DeltaS(?) = -195.5 +/- 11.1 J mol(-1) K(-1)). The enthalpy of activation for phosphate reaction is more favorable relative to the OH(-) reaction (DeltaH(?) = 35.4 +/- 3.5 kJ mol(-1) for phosphate vs. 96.6 +/- 11.4 kJ mol(-1) for OH(-1)). The kinetic isotope effect of H8 was determined to be 7.2 +/- 0.2. The rate law, kinetic isotope effect, and isotopic labeling are consistent with a mechanism involving proton ionization at the C8 position as the rate determining step followed by two-electron transfer from G to Pt(IV). PMID- 21318208 TI - Charge-induced facial-selectivity in the formation of new cationic planar chiral iridacycles derived from aniline. AB - The reaction of chiral chlorido-iridacyclic 2-(4-N,N dimethylaminophenyl)pyridines with solvato-type [Cp*M(S)(3)](q+) (M = Ru, S = MeCN, q = 1; M = Ir, S = MeC(O)Me, q = 2) complexes produces new cationic racemic planar chiral iridacycles in an efficient and diastereospecific way. PMID- 21318209 TI - Dinuclear Ru(II) complexes of bis-(dipyrid-2'-yl)triazine (bis-dpt) ligands as efficient electron reservoirs. AB - A planar bis-dipyrid-2'-yltriazine (bis-dpt) bridging ligand forms dinuclear Ru(II) complexes able to store up to eight electrons upon electrochemical reduction. PMID- 21318217 TI - Hepatocyte growth factor improves the survival of rats with pulmonary arterial hypertension via the amelioration of pulmonary hemodynamics. AB - Hepatocyte growth factor (HGF) is a multifunctional growth factor with mitogenic, anti-apoptotic and anti-fibrotic activities. In this study, we investigated the effect of administration of recombinant human HGF on pulmonary arterial hypertension. Pulmonary arterial hypertension was induced in rats by a single injection of monocrotaline (MCT) and recombinant human HGF (0.12 mg/day) was administered into the right ventricle cavity using osmotic pumps, which were implanted subcutaneously 21 days after MCT injection. Continuous intravenous delivery of recombinant human HGF for 14 days led to prolonged survival of animals suffering from severe MCT-induced pulmonary arterial hypertension. Although a bolus injection of recombinant human HGF did not affect pulmonary arterial pressure, a 14-day administration of recombinant human HGF attenuated the inflammatory cell infiltrate, matrix accumulation and vascular medial thickening. As a consequence, the pulmonary lumen was enlarged and the pulmonary arterial pressure was significantly reduced. Additionally, continuous administration of recombinant human HGF suppressed lung tissue expression of platelet-derived growth factor, which plays an important role in the development of pulmonary arterial hypertension. These results indicate that recombinant human HGF possibly has a great potential for improving symptoms and altering the clinical course of pulmonary arterial hypertension. PMID- 21318218 TI - Anti-adult T-cell leukemia effects of Bidens pilosa. AB - We evaluated the effects of Bidens pilosa, a plant found in tropical and subtropical regions, and investigated the molecular pathways responsible for the anti-adult T-cell leukemia (ATL) effect. Water extracts of B. pilosa had growth suppressive effects on human T-cell leukemia virus type 1 (HTLV-1)-infected T cell lines and ATL cells. B. pilosa extracts arrested cells in G1 cell cycle and induced apoptosis of HTLV-1-infected T-cell lines. B. pilosa extracts inhibited also the phosphorylation of IkappaB kinase beta and IkappaBalpha, and NF-kappaB DNA binding, in conjunction with reduction of expression of proteins involved in G1/S cell cycle transition and suppression of apoptosis. Reactive oxygen species played a role in B. pilosa-mediated suppression of NF-kappaB activity. B. pilosa extracts also inhibited the expression of JunB and JunD, resulting in suppression of AP-1-DNA binding. In animals harboring tumors of HTLV-1-infected T-cell origin, treatment with B. pilosa extracts suppressed tumor growth. Our results suggest that B. pilosa is a potentially useful medicinal plant for treatment of ATL. PMID- 21318219 TI - Genetic variants at the miR-124 binding site on the cytoskeleton-organizing IQGAP1 gene confer differential predisposition to breast cancer. AB - IQGAP1 knockout mice develop gastric cancer, but the IQGAP1 protein is associated with some advanced-stage human cancers. IQGAP1 expression is regulated by a microRNA, miR-124, through a binding site at the 3'-untranslated region, where a single nucleotide polymorphism (SNP) exists in the core binding region. We asked whether IQGAP1 expression is associated with breast cancer development and whether genetic variants at the miR-124 binding site are important. We genotyped the IQGAP1 SNP rs1042538 A/T in 1,541 breast cancer cases and 1,598 controls and analyzed the frequency of the variant and interactions with major risk factors in these populations. We also measured the expression of IQGAP1 at both mRNA and protein levels in different IQGAP1 genotypes. The IQGAP1 TT genotype, compared with the AA genotype, was associated with a significantly lower risk of developing breast cancer [P=0.049, odds ratio (OR), 0.78; 95% confidence interval (CI), 0.61-0.99]. In case-only analyses, the TT, compared with the AA, genotype was associated with progesterone receptor-positive subjects (OR, 1.35; 95% CI, 1.00-1.83). The expression levels of IQGAP1 protein were significantly higher in the TT genotype compated to the AA genotype. The presence of SNPs at the miR-124 binding site may be a marker for predicting breast cancer risk and prognosis. PMID- 21318220 TI - In vitro transformation of MCF-10A cells by sera harvested from heifers two months post-Zeranol implantation. AB - Among many risk factors of breast cancer, estrogens and non-estrogenic endocrine disruptors are considered to play critical roles in human breast carcinogenesis. Zeranol (Z) is a non-steroidal agent with potent estrogenic activity and has been widely used as an FDA approved beef growth promoter in the US. Recently, concerns have been raised about the potential adverse health risk by consumption of products containing biologically active Z and its metabolites. By utilizing cell proliferation assay, soft agar assay, quantitative real-time PCR and Western blotting analysis, we examined the potentially tumorigenic activity of bio-active Z containing sera harvested from heifers two months post Z-implantation and the underlying mechanisms. Our results showed that the growth of MCF-10A exposed to 0.2, 1 and 5% Z-containing serum (ZS) treatment for 3 weeks was 1.3, 1.75 and 1.8 fold faster compared to that of the control sera. After further investigation, we found that ZS increased cyclin D1 and decreased p53 expression at the mRNA and protein levels in MCF-10A compared to the controls. More importantly, treatment of 1% Z-containing sera for 21 days stimulated MCF-10A cells anchorage independent colony formation in soft agar which illustrates its capability of inducing human normal breast epithelial cell neoplastic transformation. Our experimental results suggest that long-term exposure of low levels of Z and its metabolites contained in beef products might be a potential risk factor in human breast cancer initiation and development. PMID- 21318221 TI - Signalling pathways involved in endocrine resistance in breast cancer and associations with epithelial to mesenchymal transition (Review). AB - Both de novo and acquired endocrine resistance constitute a major therapeutic problem for treatment of hormone-positive breast cancer. Multiple explanatory mechanisms have been proposed through the study of cellular models which focus principally on receptor tyrosine kinase mediated signalling pathways utilizing src, PI3K, MAPK and Smads. Many of the transducing molecules, particularly nuclear transcription factors such as Snail, Twist, Snail2, ZEB, FOXC2, TCF/LEF and Goosecoid are participants in proliferation as well as invasion and metastasis, involving a process of orchestrated cellular remodeling which is being likened to the process of epithelial to mesenchymal transition that takes place during embryonic development. We review the accumulating evidence that points towards the occurrence of this phenomenon as a consequence of the loss of endocrine control, with both processes being similarly characterized by depletion of cell adhesion proteins, E-cadherin, catenins and cytokeratins, increased association with the extracellular matrix through induction of metalloproteinases, fibronectin and collagen, and a switch to a mobile vimentin based cytoskeletal structure with loss of apical basal polarity. PMID- 21318222 TI - Histone deacetylase inhibition modulates deoxyribonucleotide pools and enhances the antitumor effects of the ribonucleotide reductase inhibitor 3'-C methyladenosine in leukaemia cells. AB - Histone deacetylase (HDAC) inhibitors are a new class of epigenetic agents that were reported to enhance the cytotoxic effects of classical anticancer drugs through multiple mechanisms. However, which of the possible drug combinations would be the most effective and clinically useful are to be determined. We treated the HL60 and NB4 promyelocytic leukaemia cells with a combination of the ribonucleotide reductase (RR) inhibitor 3'-C-methyladenosine (3'-Me-Ado) and several hydroxamic acid-derived HDAC inhibitors, including two recently synthesized molecules, MC1864 and MC1879, and the reference compound trichostatin A (TSA). The results showed significant growth inhibitory and apoptotic synergistic effects with the combinations. Hence, we evaluated the effects of the combinations on cell cycle distribution and on the level of several proteins involved in the apoptotic process (p21, caspase-3, Bcl-2, Bax, AIF). Since HDAC inhibitors increased the G1-S transition block induced by 3'-Me-Ado, an effect on RR activity was hypothesized. Indeed, the HPLC evaluation of intracellular deoxyribonucleotide (dNTP) pools showed that both TSA and MC1864 induced a decrease in dNTPs, even if with a somewhat different pattern, suggesting that RR inhibition contributes to the observed synergism. Furthermore, while TSA was shown to activate the intrinsic apoptotic pathway, MC1864 induced a dose dependent increase in ROS and AIF levels. Moreover, the treatment with the radical scavenger N-acetylcysteine determined a significant inhibition of MC1864- but not TSA-mediated synergistic effects. Hence, our findings are consistent with a possible role of HDAC inhibitor mediated-ROS induction in RR inhibition and in the potentiation of RR inhibitor-mediated apoptosis. PMID- 21318223 TI - The heterogeneity of meningioma revealed by multiparameter analysis: infiltrative and non-infiltrative clinical phenotypes. AB - Tumor invasion or infiltration of adjacent tissues is the source of clinical challenges in diagnosis as well as prevention and treatment. Among brain tumors, infiltration of the adjacent tissues with diverse pleiotropic mechanisms is frequently encountered in benign meningiomas. We assessed whether a multiparametric analysis of meningiomas based on data from both clinical observations and molecular analyses could provide a consistent and accurate appraisal of invasive and infiltrative phenotypes and help determine the diagnosis of these tumors. Tissue analyses of 37 meningiomas combined enzyme linked immunosorbent assay (ELISA) and surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) assays of two different protein biomarkers (thrombospondin 1 and a phosphorylated form of vimentin) as well as gene expression analyses with oligonucleotide micro-arrays. Up to four different clinical and molecular parameters were then examined for tumor classification. From this study, we were able to cluster 36 out of the 37 tumors into two different subsets corresponding to infiltrative/invasive and non-infiltrative tumors. In addition, meningiomas that invade brain and those that infiltrate the neighboring skull bone exhibited no distinguishable molecular features. Our multi parameter analysis that combines clinical data, transcriptomic and molecular assays clearly reveals the heterogeneity of meningiomas and distinguishes the intrinsically infiltrative/invasive tumors from the non-infiltrative meningiomas. PMID- 21318224 TI - Rituximab regulates signaling pathways and alters gene expression associated with cell death and survival in diffuse large B-cell lymphoma. AB - Rituximab, a CD20-specific antibody, is used with chemotherapy as a treatment for diffuse large B cell lymphoma (DLBCL). Although many patients benefit from the addition of rituximab to chemotherapy, a favourable response is not achieved in approximately 30% of cases. This sets a prerequisite to better understand the response and resistance mechanisms of rituximab. To do so, we analyzed the gene expression profiles of one rituximab unresponsive and two responsive DLBCL cell lines. In the responsive cells, rituximab affected the expression of genes related to apoptosis, lymphocyte signaling and cytokine response. Our data show rituximab-response to be associated with gene expression in classical signaling cascades involved in cell growth and differentiation, such as previously identified MAPK and completely novel Wnt and TGF-beta pathways. Furthermore, our findings support earlier observations that rituximab can induce direct apoptosis and suggest the cell of origin to be associated with the cellular outcome. After validation of cellular results, we used a cohort of 233 R-CHOP treated DLBCL patients and found several of the most differentiating genes to have impact on survival. Together, the results provide an advanced picture of the CD20 mediated signaling of DLBCL cells and may provide new targets in future treatment protocols. PMID- 21318225 TI - Accumulation of lactosylceramide and overexpression of a PSC833-resistant P glycoprotein in multidrug-resistant human sarcoma cells. AB - The selection pressure for resistance to chemotherapy is accompanied by the enhanced expression of ABC proteins and increased cellular glycosphingolipid content. Thus, a possible connection between glycosphingolipid metabolism and ABC proteins in drug resistance has been suggested. In the present study, we established two human multidrug-resistant (MDR) cell lines derived from MESSA sarcoma cells by culturing with increasing concentrations of doxorubicin (DX5 cells) or doxorubicin together with cyclosporin A (GARF cells). Both resistant cell lines overexpressed the MDR1 gene and the wild-type P-glycoprotein at the same level. The cyclosporin derivative PSC833, a potent inhibitor of P glycoprotein, sensitized DX5 but not GARF cells to the cytotoxic effects of daunorubicin. Moreover, PSC833 increased the nuclear accumulation of daunorubicin and the cellular accumulation of [3H]vinblastine in the DX5 but not in the GARF cells. The cellular incorporation of [3H]-cyclosporin A was lower in DX5 cells compared to MESSA and GARF cells, which incorporated the same level of [3H] cyclosporin A. Sphingolipid analysis showed that the lactosylceramide level was 2.5- and 5-fold higher in DX5 and GARF cells, respectively, than in MESSA cells. Whereas the pharmacological inhibition of lactosylceramide synthesis was able to reverse only partially the resistance of GARF cells to daunorubicin without significant increase in nuclear accumulation of the drug, the same treatment before the co-treatment with PSC833 and daunorubicin increased the cytotoxic effect of daunorubicin and its nuclear accumulation. These data suggest a possible relationship between lactosylceramide levels and the resistance of P glycoprotein to modulation by MDR modulators. PMID- 21318226 TI - The cell adhesion molecule L1 promotes gallbladder carcinoma progression in vitro and in vivo. AB - Recent studies have demonstrated that the cell adhesion molecule, L1, is expressed in several malignant tumor types and its expression correlates with tumor progression and metastasis. However, the role of L1 in gallbladder carcinoma (GBC) remains unclear. Here, we demonstrate that L1 is expressed in GBC cells and plays an important role in the growth, motility, invasiveness, and adhesiveness of GBC cells. Specific depletion or overexpression of L1 in the GBC cell lines JCRB1033 and SNU-308, respectively, was achieved by lentivirus mediated transduction and expression of an L1 mRNA-specific short hairpin RNA or full-length human L1. Stable depletion of L1 led to a significant decrease in GBC cell proliferation, migration and invasion, as well as decreased intracellular signaling through AKT and FAK. Overexpression of L1 in GBC cells enhanced these cellular activities. In a GBC xenograft nude mouse model, suppression of L1 markedly reduced tumor growth and increased the survival of tumor-bearing mice whereas L1 overexpression stimulated tumorigenicity. Taken together, these results suggest that L1 plays a crucial role in GBC progression and may be a novel therapeutic target in GBC treatment. PMID- 21318227 TI - Significance of epidermal growth factor receptor gene mutations in squamous cell lung carcinoma. AB - Epidermal growth factor receptor (EGFR) gene mutations have been reported to be clinically significant in non-small cell lung cancer (NSCLC). However, because most previous studies focused only on adenocarcinomas, EGFR mutations in other histotypes are poorly investigated. We evaluated the frequency of EGFR gene mutations in squamous cell carcinoma (SCC) and its clinicopathological features. In total, 89 frozen tumor specimens that had been first diagnosed as SCCs, were examined for EGFR mutations in exons 19 and 21 using direct sequencing, PNA enriched sequencing and SmartAmp2. Additionally, pathological investigation, including immunostaining for p63 and TTF-1, alcian blue staining and EGFR mutation-specific immunohistochemistry in mutation-positive samples was also performed. The frequency of EGFR mutations was 5.6% (5/89); all mutations were deletions in EGFR exon 19. Immunohistological investigation of these samples revealed that two of five were positive for p63 and TTF-1 staining, and showed production of mucin, as evidenced by alcian blue staining. Consequently, three of the samples were considered to be true SCC at final pathological diagnosis, while the remaining two samples were revised to adenosquamous carcinoma and adenocarcinoma. The final frequency of the EGFR mutations in true SCC was 3.4% (3/87). In conclusion, EGFR mutations were found in a small, but significant, number of SCC tumor samples and thus EGFR mutational analysis was useful in the accurate diagnosis of SCC. Our data demonstrate that EGFR mutational analysis should be performed not only in adenocarcinoma, but also in SCC to allow accurate diagnosis and treatment. PMID- 21318228 TI - Occult neoplastic cells in the lymph node sinuses and recurrence/metastasis of stage III/Dukes' C colorectal cancer. AB - Lymph nodes from patients with colorectal cancer were immunohistochemically stained for cytokeratin to investigate the relationship between the presence of occult neoplastic cells (ONCs) and recurrence/metastasis. A total of 80 patients with stage III/Dukes' C colorectal cancer were divided into 16 patients who developed recurrence/metastasis (recurrence group) and 64 patients without recurrence (non-recurrence group). ONCs were compared between the two groups with respect to i) single cells (>= 3 floating ONCs), ii) clusters of cells (1 or more floating aggregates of 2-20 ONCs) and iii) single cells + clusters. When single cells were detected, the sensitivity for recurrence was 87.5% (14/16, p = 0.002), the positive predictive value (PPV) was 32.6% (14/43), the specificity was 54.7% (35/64) and the negative predictive value (NPV) was 94.6% (35/37). For clusters, the sensitivity was 87.5% (14/16, p<0.001), PPV was 41.2% (14/34), specificity was 68.8% (44/64) and NPV 95.7% (44/46). With single cells + clusters, the values were 87.5% (14/16, p<0.001), 48.3% (14/29), 76.6% (49/64) and 96.1% (49/51), respectively. These results suggest that the detection of single cells + clusters is a sensitive indicator of a high risk of recurrence/ metastasis, while ONCs are useful for identifying the low-risk group of patients with stage III colorectal cancer. PMID- 21318229 TI - Subcutaneous fat necrosis in newborn-an unusual case and review of literature. AB - Subcutaneous fat necrosis (SCFN) of the newborn is an uncommon, self-limiting panniculitis mostly occurring within the first few weeks after birth. SCFN has been described mostly in term or post-term newborn infants in literature. We report a preterm infant developing extensive subcutaneous fat necrosis within the first week of life after significant perinatal hypoxic injury. The infant was conservatively managed for subcutaneous fat necrosis but developed hypercalcaemia and required prolonged medical treatment. Hypercalcaemia is a rare but serious complication of subcutaneous fat necrosis and needs prolonged follow-up. The etiopathogenesis of both subcutaneous fat necrosis in newborn and the resultant hypercalcaemia are poorly understood. CONCLUSION: Significant subcutaneous fat necrosis can develop in both preterm and term infants, and preterm infants also develop significant complications including hypercalcaemia. PMID- 21318230 TI - The 'Motorik-Modul' (MoMo): physical fitness and physical activity in German children and adolescents. AB - OBJECTIVES: The aim of the 'Motorik-Modul' (MoMo Basiserhebung, www.motorik modul.de ) was to establish prevalence measurements on physical fitness and physical activity in German children and adolescents and to identify differences between age groups and genders. A total of 4,529 children and adolescents between the ages of 4-17 years from 167 cities across all states of the German Federation participated in this study. Sociodemographic parameters were recorded. Physical fitness was measured using endurance, strength, coordination and flexibility tests. Physical activity was assessed using a validated questionnaire, including aspects of physical activity participation (school/club/non-club), intensity of physical activity and type of activity. Chi-square tests and ANOVAS were used to compare groups and to detect age and gender effects, and data were compared with criterion-related guidelines by the WHO. For parameters describing physical fitness, age was the dominant influencing parameter. Many parameters showed increasing performance until the onset of puberty. Boys generally performed better than girls except in fine motor coordination during precision tasks and in flexibility. Physical activity was greater in older subjects with a greater intensity for adolescents who were physically active. The general activity level was similar to the data reported in the HBSC study by the WHO but lower than the recommended activity levels. CONCLUSION: With the results of this study, nationwide representative prevalence data on physical fitness and physical activity are available. These data contribute to the scientific knowledge on the prevalence and conditions of physical fitness and physical activity. PMID- 21318231 TI - Design and dynamic simulation of minimal metallo-proteins. AB - Ab initio in silico design of proteins and enzymes has emerged as a powerful tool to design application-tailored proteins and catalysts for a wide range of applications. Several enzymes exploit the unique features of metal cofactors to achieve catalytic activity otherwise unattainable through the use of only natural amino acid residues. One of the major bottlenecks in ab initio design of novel proteins relies on long-range and epistatic effects that severely limit the possibility of a rational design. Within this framework there is an ongoing effort to reduce protein length and complexity to unlock the full potential of in silico protein design. In this work we specifically address this problem designing and investigating the dynamic features of 10 in silico designed minimal metallo-proteins. In particular, in this paper we investigate whether and to what extent it is possible to design a minimal metallo-enzyme made of only residues involved in metal binding. In this research we address these questions by investigating the ability of 10 different "mini-proteins" with a length shorter than 15 residues. Molecular dynamics studies clearly show that it is possible to design a minimal protein able to bind a metal atom with the correct geometry. It is noteworthy that designed mini-proteins cannot achieve the formation of a canonical hydrophobic core, rather the metal ion provides a "metal core" around which the entire protein is organized. This opens the possibility of designing synthetic enzymes composed of only functional residues organized around a "metal core" which acts as both structural and functional determinat. PMID- 21318232 TI - Towards new green high energy materials. Computational chemistry on nitro substituted urea. AB - As part of a series of studies on new potential green high energy materials, we have calculated the structures and properties of a series of nitro-substituted urea molecules. Our results indicate that nitrated urea molecules have specific enthalpies of decomposition commensurate with current high energy materials. At the same time, they are all low in carbon, suggesting an application as a "green" high energy material. PMID- 21318233 TI - A molecular dynamics study of a miRNA:mRNA interaction. AB - In this paper we present a methodology to evaluate the binding free energy of a miRNA:mRNA complex through molecular dynamics (MD)-thermodynamic integration (TI) simulations. We applied our method to the Caenorhabditis elegans let-7 miRNA:lin 41 mRNA complex-a validated miRNA:mRNA interaction-in order to estimate the energetic stability of the structure. To make the miRNA:mRNA simulation possible and realistic, the methodology introduces specific solutions to overcome some of the general challenges of nucleic acid simulations and binding free energy computations that have been discussed widely in many previous research reports. The main features of the proposed methodology are: (1) positioning of the restraints imposed on the simulations in order to guarantee complex stability; (2) optimal sampling of the phase space to achieve satisfactory accuracy in the binding energy value; (3) determination of a suitable trade-off between computational costs and accuracy of binding free energy computation by the assessment of the scalability characteristics of the parallel simulations required for the TI. The experiments carried out demonstrate that MD simulations are a viable strategy for the study of miRNA binding characteristics, opening the way to the development of new computational target prediction methods based on three-dimensional structure information. PMID- 21318234 TI - Insight into the nature of the interactions of furan and thiophene with hydrogen halides and lithium halides: ab initio and QTAIM studies. AB - The nature of the interactions of furan and thiophene with hydrogen halides and lithium halides has been investigated using ab initio calculations and QTAIM analysis. The concept of molecule formation density difference (MFDD) is introduced to study weak hydrogen bond (HB) and lithium bond (LB) interactions. The results have shown the molecular electrostatic potentials of furan and thiophene, as well as of the hydrogen halides and lithium halides, determine the geometries of the complexes. Both the studied HB and LB interactions can be classified as "closed-shell" weak interactions. The topological properties and energy properties at the bond critical points of HB and LB have been shown to be exponentially dependent on intermolecular distances d(H-bond) and d(Li-bond), which enables interpretation of the strength of the HB and LB interactions in terms of these rho(r) properties. Electron transfer plays a more important role in the formation of HB than in that of LB, while electrostatic interaction in LB is more dominant than that in HB. PMID- 21318235 TI - Analysis of Bacillus anthracis nucleoside hydrolase via in silico docking with inhibitors and molecular dynamics simulation. AB - As the enzyme nucleoside hydrolase (NH) is widely found in nature but has not yet been detected in mammals, it is considered an ideal target in the development of chemotherapy against parasitic diseases and bacterial infections like anthrax. Considering the risk that this biological warfare agent represents nowadays, the search for new drugs and new molecular targets in the development of chemotherapy against anthrax is imperative. On this basis, we performed docking studies of six known NH inhibitors at the active site of NH from Bacillus anthracis (BaNH). Subsequently, molecular dynamics (MD) simulations of these compounds inside BaNH were carried out in order to complement the docking studies and select the most promising compounds as leads for the design of potential BaNH inhibitors. Most of the docking and MD results obtained agreed well with each other and showed good correlation with experimental data. PMID- 21318236 TI - Computational design and structure-property relationship studies on heptazines. AB - This study aimed to design novel nitrogen-rich heptazine derivatives as high energy density materials (HEDM) by exploiting systematic structure-property relationships. Molecular structures with diverse energetic substituents at varying positions in the basic heptazine ring were designed. Density functional techniques were used for prediction of gas phase heat of formation by employing an isodesmic approach, while crystal density was assessed by packing calculations. The results reveal that nitro derivatives of heptazine possess a high heat of formation and further enhancement was achieved by the substitution of nitro heterocycles. The crystal packing density of the designed compounds varied from 1.8 to 2 g cm(-3), and hence, of all the designed molecules, nitro derivatives of heptazine exhibit better energetic performance characteristics in terms of detonation velocity and pressure. The calculated band gap of the designed molecules was analyzed to establish sensitivity correlations, and the results reveal that, in general, amino derivatives possess better insensitivity characteristics. The overall performance of the designed compounds was moderate, and such compounds may find potential applications in gas generators and smoke free pyrotechnic fuels as they are rich in nitrogen content. PMID- 21318237 TI - Modeling the human intestinal mucin (MUC2) C-terminal cystine knot dimer. AB - Intestinal mucus, a viscous secretion that lines the mucosa, is believed to be a barrier to absorption of many therapeutic compounds and carriers, and is known to play an important physiological role in controlling pathogen invasion. Nevertheless, there is as yet no clear understanding of the barrier properties of mucus, such as the nature of the molecular interactions between drug molecules and mucus components as well as those that govern gel formation. Secretory mucins, large and complex glycoprotein molecules, are the principal determinants of the viscoelastic properties of intestinal mucus. Despite the important role that mucins play in controlling transport and in diseases such as cystic fibrosis, their structures remain poorly characterized. The major intestinal secretory mucin gene, MUC2, has been identified and fully sequenced. The present study was undertaken to determine a detailed structure of the cysteine-rich region within the C-terminal end of human intestinal mucin (MUC2) via homology modeling, and explore possible configurations of a dimer of this cysteine-rich region, which may play an important role in governing mucus gel formation. Based on sequence-structure alignments and three-dimensional modeling, a cystine knot tertiary structure homologous to that of human chorionic gonadotropin (HCG) is predicted at the C-terminus of MUC2. Dimers of this C-terminal cystine knot (CTCK) were modeled using sequence alignment based on HCG and TGF-beta, followed by molecular dynamics and simulated annealing. Results support the formation of a cystine knot dimer with a structure analogous to that of HCG. PMID- 21318238 TI - The complete genome analysis of two enterovirus 96 strains isolated in China in 2005 and 2009. AB - Enterovirus 96 (EV96) is a new member of species Human Enterovirus C (HEV-C). In this report, genomic characterization of two EV96 strains isolated from acute flaccid paralysis surveillance in Shandong province of China in 2005 and 2009 is described. The two strains, designated 05517 and 09228C1, had 82.7% genomic similarity with each other and 75.1-84.2% with other three strains available from GenBank in complete genome sequences. In VP1 coding region, they had 77.6-86.6% nucleotide similarity with other EV96 strains. Interestingly, deletions of 3 nucleotides in the VP3 coding region of strain 09228C1, and of 3 nucleotides in the 3A region of both Shandong strains were observed. Simplot and bootscanning analysis on HEV-C genome sequences were performed, and evidence of recombination in P3 region for Shandong EV96 strains was found. In conclusion, these strains had distant genetic relationship with each other and with other EV96 strains. PMID- 21318239 TI - Classical swine fever virus NS2 protein promotes interleukin-8 expression and inhibits MG132-induced apoptosis. AB - Classical swine fever (CSF) caused by virulent strains of classical swine fever virus (CSFV) is a hemorrhagic disease of pigs and is characterized by disseminated intravascular coagulation, thrombocytopenia, and immunosuppression. Until now, the role of the NS2 protein produced by CSFV in the pathogenesis of CSF is not well understood. In this report, we investigated the function of CSFV NS2 by examining its effects on the pro-inflammatory CXC chemokine, interleukin-8 (IL-8) expression, and cell survival. Stable swine umbilical vein endothelial cell line (SUVEC) expressing CSFV NS2 were established and showed that CSFV NS2 expressing SUVEC cells express approximately 16-fold higher levels of IL-8 as compared to control vector GFP-expressing cells, GFP-E2 expressing cells, and untransfected cells. Further studies showed that CSFV NS2 induced endoplasmic reticulum stress and activated the nuclear transcription factor kappa B (NF kappaB), which is responsible for the up-regulation of IL-8 and the anti apoptotic protein, Bcl-2, expression. In addition, the GFPNS2-expressing SUVEC cells were resistant to MG132-induced apoptosis. This study suggested that CSFV NS2 plays an important role in the inflammatory response and in persistent CSFV infection. These findings provide novel information on the function of the poorly characterized CSFV NS2. PMID- 21318240 TI - The complete nucleotide sequence and genome organization of Fig cryptic virus, a novel bipartite dsRNA virus infecting fig, widely distributed in the Mediterranean basin. AB - Two double-stranded RNA (dsRNA) segments of a virus with a bipartite genome identified in fig (Ficus carica L.) and denoted Fig cryptic virus (FCV) were cloned and sequenced. Viral dsRNAs are 1696 bp (RNA-1) and 1415 bp (RNA-2) in size. RNA-1 contains a single ORF (1419 nt) potentially encoding a 54 kDa protein and comprising the conserved amino acid motifs of the RNA-dependent RNA polymerase (RdRp) domain of species of the genus Alphacryptovirus. Its full length amino acid sequence has the highest identity with Raphanus sativus cryptic virus 2 (RsCV-2) (36%), Beet cryptic virus 3 (BCV-3) (36%) and Fragaria chiloensis cryptic virus (FCCV) (34%). RNA-2 has also a single ORF (1014 nt) coding for a polypeptide with a predicted molecular mass of 38 kDa, identified as the viral coat protein (CP). In a phylogenetic tree constructed with the amino acid sequences of the RdRp domain, FCV clusters in a clade comprising BCV-3 and a number of tentative species of the genus Alphacryptovirus. FCV is not mechanically transmissible. It was detected in fig orchards of six Mediterranean countries (Albania, Algeria, Italy, Lebanon, Syria and Tunisia) where it does not seem to induce a visible disease. PMID- 21318241 TI - Molecular characterization of a new begomovirus infecting a leguminous weed Rhynchosia minima in India. AB - A begomovirus associated with yellow mosaic disease in Rhynchosia minima, a common weed was cloned and sequenced. The virus has a bipartite genome, of which DNA-A is 2727 nucleotide length, and DNA-B 2679 nucleotides, and has a typical Old World bipartite begomovirus genome organization. Sequence comparison to all other begomovirus sequences available in the database shows the virus isolated from R. minima to be distinct. Maximum identity of 84% was seen with an isolate of Velvet bean severe mosaic virus-(India: Lucknow:2009) VBSMV-(IN:Luc:09) (GeneBank Accession No. FN543425), while less than 73% identity was observed with any other legumovirus. The molecular data show that the virus identified here is a new species in the genus Begomovirus for which the name Rhynchosia yellow mosaic India virus is proposed. PMID- 21318242 TI - Expression patterns of prion protein gene in differential genotypes sheep: quantification using molecular beacon real-time RT-PCR. AB - Determination of the transcription level of cellular prion protein (PrP(C)) is essential for understanding its role in organisms and revealing mechanism of susceptibility and resistance to scrapie. However, the expression of prion protein (PrP) mRNA in sheep has not been quantified in great detail in digestive tract which is important during scrapie spread through oral route. Herein, we report on measurement of sheep PrP mRNA using absolute quantitative real-time RT PCR. Total RNA was isolated from five different regions of the central nervous system (CNS), four regions of lymphoid system, eleven regions of digestive tract, and two reproductive organ tissues of eight sheep of two different genotypes (ARR/ARQ and ARH/ARQ) and PrP mRNA was quantified by real-time RT-PCR using molecular beacon. The results showed that highest levels of PrP mRNA were expressed in thalamus and cerebrum (P < 0.01) of CNS examined, followed by cerebellum, spinal cord, and brain stem. In peripheral organs examined, lymph tissue showed moderate level of PrP expression similar to that in digestive tract and reproduction organs. PrP expression levels in the same tissue of different genotype sheep had significant variation. Our study provided the first detail, tissue-specific and genotype-specific data of PrP mRNA expression in sheep for further studies of pathogenesis of prion diseases. PMID- 21318244 TI - Comparison of "herbal highs" composition. AB - Popularity of new psychoactive substances, known as legal highs or herbal highs, is continuously growing. These products are typically sold via internet and in so called head shops. The aim of this study was to identify active ingredients of herbal highs and to compare their chemical composition. Twenty-nine various products seized by the police in one of the "head shops" were analysed. Herbal mixtures (0.2 g) were prepared by ultrasonic-assisted extraction with 2.0 ml of ethanol for 2 h. The extracts were analysed by gas chromatography coupled to mass spectrometry (GC/MS). The main active compounds of the herbal mixtures were synthetic cannabinoids: JWH-018, JWH-073 and cannabicyclohexanol (CP-47,497-C8 homolog). Their content differed between the products; some contained only one cannabinoid whereas the others contained two or more. Cluster analysis and principal component analysis revealed that chemical composition of many products was very similar. The similarity was connected with their flavour and not the common name. This statement was true for the synthetic cannabinoids, other potential agonists of cannabinoid receptors (amides of fatty acids) and ingredients of natural origin and confirms that herbal highs are a threat to human health because the purchaser has no information on their real composition. PMID- 21318245 TI - Analytical characterization of mannosylerythritol lipid biosurfactants produced by biosynthesis based on feedstock sources from the agrofood industry. AB - Mannosylerythritol lipids (MELs) are currently one of the most promising biosurfactants because of their multifunctional applications and good biodegradability. Depending on the yeast strain and the feedstock used for the fermentation process, structural variations in the MELs obtained occur. Therefore, MELs produced by Pseudozyma aphidis DSMZ 70725 with a soybean oil feedstock were characterized by chromatography and mass spectrometry (MS). Column chromatography with silica provided fractionation of the different types of MEL. High-performance liquid chromatography combined with MS was employed for the analysis of the MEL fractions and crude mixtures. A characteristic MS pattern for the MELs was obtained and indications of the presence of new MEL homologues, showing the incorporation of longer and more unsaturated fatty acid chains than previously reported, were given. Gas chromatography-MS analysis confirmed the presence of such unsaturated fatty acid chains in the MELs, demonstrating the incorporation of fatty acids with lengths ranging from C(8) to C(14) and with up to two unsaturations per chain. The incorporation of C(16) and C(18) fatty acid chains requires further investigation. MS/MS data allowed the unambiguous identification of the fatty acids present in the MELs. The product ion spectra also revealed the presence of a new isomeric class of MELs, bearing an acetyl group on the erythritol moiety. PMID- 21318246 TI - Capillary electrophoresis-mass spectrometry using noncovalently coated capillaries for the analysis of biopharmaceuticals. AB - In this work, the usefulness of capillary electrophoresis-electrospray ionization time-of-flight-mass spectrometry for the analysis of biopharmaceuticals was studied. Noncovalently bound capillary coatings consisting of Polybrene poly(vinyl sulfonic acid) or Polybrene-dextran sulfate-Polybrene were used to minimize protein and peptide adsorption, and achieve good separation efficiencies. The potential of the capillary electrophoresis-mass spectrometry (CE-MS) system to characterize degradation products was investigated by analyzing samples of the drugs, recombinant human growth hormone (rhGH) and oxytocin, which had been subjected to prolonged storage, heat exposure, and/or different pH values. Modifications could be assigned based on accurate masses as obtained with time-of-flight-mass spectrometry (TOF-MS) and migration times with respect to the parent compound. For heat-exposed rhGH, oxidations, sulfonate formation, and deamidations were observed. Oxytocin showed strong deamidation (up to 40%) upon heat exposure at low pH, whereas at medium and high pH, mainly dimer (>10%) and trisulfide formation (6-7%) occurred. Recombinant human interferon-beta-1a (rhIFN beta) was used to evaluate the capability of the CE-MS method to assess glycan heterogeneity of pharmaceutical proteins. Analysis of this N-glycosylated protein revealed a cluster of resolved peaks which appeared to be caused by at least ten glycoforms differing merely in sialic acid and hexose N-acetylhexosamine composition. Based on the relative peak area (assuming an equimolar response per glycoform), a quantitative profile could be derived with the disialytated biantennary glycoform as most abundant (52%). Such a profile may be useful for in process and quality control of rhIFN-beta batches. It is concluded that the separation power provided by combined capillary electrophoresis and TOF-MS allows discrimination of highly related protein species. PMID- 21318247 TI - Enantioseparation by chromatographic and electromigration techniques using ligand exchange as chiral separation principle. AB - This article gives a short overview of the application of the principle of chiral ligand-exchange in HPLC, CE, and CEC. Since its introduction by Davankov, more than thousand articles have appeared in this field. Citing all these papers would extend the scope of this review-it would fill several books. Therefore only some milestones are mentioned in this article and it will focus on our own activities in this field. Some new developments are mentioned, and selected biochemical and biomedical application are presented. PMID- 21318248 TI - Application of spectroscopic techniques: ICP-OES, LA-ICP-MS and chemometric methods for studying the relationships between trace elements in clinical samples from patients with atherosclerosis obliterans. AB - The study was aimed to evaluate the influence of the vascular disease, atherosclerotic obliterans (AO), on the location and concentration of elements in the arterial wall and serum. Use of a modern method for studying element's concentration and distribution in samples of clinical material, i.e. laser ablation inductively coupled plasma mass spectrometry, is presented. Elements are not equally distributed between the inner (intima) and the outer (media + adventitia) layer of the arterial wall. Among the studied elements, calcium was found to have an unquestionable role in the calcification of the wall. Increased concentration of calcium found in the inner part of the atherosclerotic arterial wall and in the plaque, as compared to the control arterial wall samples, demonstrates the unquestionable role of this element in the calcification of the wall observed in AO. Applied chemometric methods were useful for demonstrating the differences in the element's concentration in blood serum and the arterial wall samples between AO and the control group. PMID- 21318249 TI - Proficiency testing has improved the quality of data of total vitamin B2 analysis in liquid dietary supplement. AB - A previously reported proficiency test for the analysis of vitamin B(2) in liquid dietary supplement demonstrated bimodality. The same trend has now been observed in four subsequent tests of this type. The trend would not so easily have been observed without applying a fit-for-purpose standard deviation that is more generous than that predicted by the Horwitz equation. Since originally reporting the bimodal problem and hypothesising its cause by incomplete enzymic digestion of riboflavin-5-phosphate, there has been a general improvement in the reporting of the higher mode. This is thought to correspond to free riboflavin following complete digestion of the sample. Several individual participants appear to have learned from the experience and have changed their reporting of the lower mode to the higher mode. PMID- 21318250 TI - History and current research in the field of radiochemistry at Maria Curie Sklodowska University. PMID- 21318251 TI - HPLC determination of methylphenidate and its metabolite, ritalinic acid, by high performance liquid chromatography with peroxyoxalate chemiluminescence detection. AB - An HPLC-peroxyoxalate chemiluminescence (PO-CL) method for simultaneous determination of methylphenidate (MPH) and ritalinic acid (RA) was developed. The method was used to monitor MPH and RA after administration of MPH to rats. Deproteinized plasma spiked with 1-(3-trifluoromethylphenyl)piperazine (IS) was dried and labeled with 4-(N,N-dimethylaminosulfonyl)-7-fluoro-2,1,3 benzoxadiazole (DBD-F). The labeled sample was cleaned with two kinds of solid phase extraction cartridge, and the DBD-labels were separated on an ODS column with gradient elution using a mixture of CH(3)CN and imidazole-HNO(3) buffer. Separation of MPH and RA can be achieved within 33 min. The LODs of MPH and RA at a signal-to-noise ratio of 3 were 2.2 and 0.4 ng mL(-1), respectively. Moreover, monitoring of MPH and RA after MPH administration (10 mg kg(-1)) to rat could be performed. The concentration of RA 480 min after administration was eight times higher than that of MPH. The proposed HPLC-PO-CL method was useful for determination of MPH and RA in rat plasma and was successfully used to monitor these substances after MPH administration. PMID- 21318252 TI - Highly sensitive and fast responsive fiber-optic modal interferometric pH sensor based on polyelectrolyte complex and polyelectrolyte self-assembled nanocoating. AB - A new fiber-optic pH sensor is demonstrated by coating negatively charged polyelectrolyte complex (PEC(-)) nanoparticles, made of sodium carboxymethyl cellulose and poly(diallyldimethylammonium chloride) (PDDA), and positively charged PDDA on the surface of a thin-core fiber modal interferometer (TCFMI) with a layer-by-layer (LbL) electrostatic self-assembly method. The fabricated TCFMI pH sensor has different transmission dip wavelengths under different pH values and shows high sensitivities of 0.6 nm/pH unit and -0.85 nm/pH unit for acidic and alkaline solutions, respectively, and short response time of 30-50 s. The LbL electrostatic self-assembly process of a PEC(-)/PDDA multilayer is traced by quartz crystal microbalance and shows a fast thickness growth. Atomic force microscopy shows the root mean square (RMS) surface roughness of electrostatic self-assembly nanocoating of polyelectrolyte complex/polyelectrolyte is much higher than that of polyelectrolyte/polyelectrolyte due to the larger size of PEC(-) colloidal nanoparticles. The enhanced RMS surface roughness and thickness of the nanocoating can shorten the response time and raise the sensitivity of the TCFMI pH sensor, respectively. In addition, the TCFMI pH sensor has highly reversible performance and good durability. PMID- 21318253 TI - Fractionation and characterization of nano- and microparticles in liquid media. AB - Submicron and micron particles present in liquid environmental, biological, and technological samples differ in their dimensions, shape, mass, chemical composition, and charge. Their properties cannot be reliably studied unless the particles are fractionated. Synthetic particles applied as components of analytical systems may also need preliminary fractionation and investigation. The review is focused on the methods for fractionation and characterization of nanoparticles and microparticles in liquid media, the most representative examples of their application, and the trends in developing novel approaches to the separation and investigation of particles. Among the separation techniques, the main attention is devoted to membrane filtration, field-flow fractionation, chromatographic, and capillary electrokinetic methods. Microfluidic systems employing the above-mentioned and other separation principles and providing a basis for the fabrication of lab-on-chip devices are also examined. Laser light scattering methods and other physical techniques for the characterization of particles are considered. Special attention is given to "hyphenated" techniques which enable the separation and characterization of particles to be performed in online modes. PMID- 21318254 TI - Solid-state reference electrodes based on carbon nanotubes and polyacrylate membranes. AB - A novel potentiometric solid-state reference electrode containing single-walled carbon nanotubes as the transducer layer between a polyacrylate membrane and the conductor is reported here. Single-walled carbon nanotubes act as an efficient transducer of the constant potentiometric signal originating from the reference membrane containing the Ag/AgCl/Cl(-) ions system, and they are needed to obtain a stable reference potentiometric signal. Furthermore, we have taken advantage of the light insensitivity of single-walled carbon nanotubes to improve the analytical performance characteristics of previously reported solid-state reference electrodes. Four different polyacrylate polymers have been selected in order to identify the most efficient reservoir for the Ag/AgCl system. Finally, two different arrangements have been assessed: (1) a solid-state reference electrode using photo-polymerised n-butyl acrylate polymer and (2) a thermo polymerised methyl methacrylate:n-butyl acrylate (1:10) polymer. The sensitivity to various salts, pH and light, as well as time of response and stability, has been tested: the best results were obtained using single-walled carbon nanotubes and photo-polymerised n-butyl acrylate polymer. Water transport plays an important role in the potentiometric performance of acrylate membranes, so a new screening test method has been developed to qualitatively assess the difference in water percolation between the polyacrylic membranes studied. The results presented here open the way for the true miniaturisation of potentiometric systems using the excellent properties of single-walled carbon nanotubes. PMID- 21318256 TI - Prevalence of oral soft tissue lesions in Sangli, India. AB - The purpose of this study was to determine the prevalence of oral soft tissue lesions in patients who attended the outpatient department, at Bharati Vidyapeeth Deemed University Dental College during a period of 18 months in 2009-2010. About 24,422 subjects belonging to a semi-urban district of Sangli in Western Maharastra (India) were screened. Out of these about 623 cases showed soft tissue lesions. Statistical analysis was done using the SPSS software. 2.5% of the population studied had one or more oral lesions associated with prosthetic use, trauma and tobacco consumption etc. Six hundred and twenty-three patients were found to have significant mucosal lesions. 75 had leukoplakia, 152 had oral submucous fibrosis, 14 had both both leukoplakia and oral submucous fibrosis, 82 had oral squamous cell carcinoma, 35 had oral lichen planus, 195 had apthous ulcers, 23 had denture stomatitis, 28 had fibroma and 19 cases had pyogenic granuloma. The findings in the present study reveal a high prevalence of oral soft tissue lesions and a rampant misuse of variety of addictive substances in the community. Close follow up and systematic evaluation is required in this population. There is an urgent need for awareness programs involving the community health workers, dentists and allied medical professionals. PMID- 21318257 TI - Cohort profile: the Western Australian Sleep Health Study. AB - BACKGROUND: Epidemiologic and genetic studies of obstructive sleep apnoea (OSA) are limited by a lack of large-scale, well-characterized OSA cohorts. These studies require large sample size to provide adequate power to detect differences between groups. This study describes the development of such a cohort (The Western Australian Sleep Health Study) in OSA patients of Caucasian-European origin attending the only public sleep clinic in Western Australia (WA). AIMS: The main aim of the study is to phenotype 4,000 OSA patients in order to define the genetics of OSA and its co-morbidities. METHODS: Almost all underwent laboratory-based attended polysomnography (PSG). RESULTS: Currently complete data (questionnaire, biochemistry, DNA, and PSG) has been obtained on over 3,000 individuals and will reach the target of 4,000 individuals by the end of 2010. In a separate but related study, we have developed a sleep study database containing data from all patients who have undergone PSG at the sleep laboratory since its inception in 1988 until the present day (over 30,000 PSG studies representing data from approximately 20,000 individuals). In addition, data from both cohorts have been linked prospectively to statutory health data collected by the WA Department of Health. CONCLUSION: This study will be the largest sleep clinic cohort database internationally with access to genetic and epidemiological data. It is unique among sleep clinic cohorts because of its size, the breadth of data collected and the ability to link prospectively to statutory health data. It will be a major tool to comprehensively assess genetic and epidemiologic factors determining OSA and its co-morbidities. PMID- 21318258 TI - Respiratory regulation in narcolepsy. AB - INTRODUCTION: Narcolepsy is a debilitating sleep disorder characterized by excessive daytime sleepiness, cataplexy and intrusive REM sleep. Deficits in endogenous orexins are a major pathogenic component of the disease. This disorder is also associated with the gene marker, HLADQB1*0602. An increased prevalence of sleep apnea in narcolepsy suggested interactions among ventilatory chemosensitivity, narcolepsy-cataplexy, and sleep apnea. RESULTS: Evidence from animal studies using orexin knockout mice and focal microdialysis of an orexin receptor antagonist demostrated that orexins are also contributed to respiratory regulation in a vigilance state-dependent manner, as animals with orexins dysregulation have attenuated hypercapnic ventilatory responses predominately in wakefulness, which is consistent with the notion that the activity of orexinergic neurons is higher during wake than sleep periods. Human model of hypocretin deficiency is patients with narcolepsy-cataplexy. In contrast to findings suggested by animal studies, we found significant decrease in hypoxic responsiveness but not in hypercapnic responsiveness in narcoleptics, and further analysis indicated that decreased ventilatory responses to hypoxia in human narcolepsy-cataplexy is in relation to HLA-DQB1*0602 status, not hypocretin deficiency. CONCLUSION: Unlike in mouse, hypocretin-1 is not a major factor contributing to chemoresponsiveness in human. Species differences may exist. PMID- 21318259 TI - A new coral carbonic anhydrase in Stylophora pistillata. AB - Scleractinian corals are of particular interest due to their ability to establish an intracellular mutualistic symbiosis with phototrophic dinoflagellates and to deposit high rates of calcium carbonate in their skeleton. Carbonic anhydrases have been shown to play a crucial role in both processes. In this study, we report the molecular cloning and characterization of a novel alpha-CA in the coral Stylophora pistillata. This enzyme shares homologies with the human isoform CA II and is referred to as STPCA-2. STPCA-2 is 35.2 kDa and possesses all key amino acids for catalytic activity. With a ratio between catalytic and Michaelis constants (k(cat)/K(m)) of 8.3.10(7) M(-1) s(-1) is considered as highly active. Owing to its intracellular localisation in the oral endoderm and in the aboral tissue, we propose that STPCA-2 is involved in pH regulation and/or inorganic carbon delivery to symbiont and calcification. PMID- 21318260 TI - Critical role of proteostasis-imbalance in pathogenesis of COPD and severe emphysema. AB - The environmental, genetic, and/or age-related changes in proteostasis induce inflammation, oxidative stress, and apoptosis. We quantified the correlation of protein expression of critical proteostasis mediators to severity of chronic lung disease using lung tissue samples from control and chronic obstructive pulmonary disease (COPD) subjects (GOLD stage 0-IV) and cigarette smoke (CS)-induced murine model. The human bronchial epithelial cells, HEK-293, and Beas2B cells were used for in vitro experiments to verify the mechanisms. Our data verifies the correlation of higher expression of valosin-containing protein (VCP) retrograde translocation complex (VCP-Rma1-gp78) with severity of emphysema in COPD lung tissues and over-expression of inflammatory, ER stress and apoptotic mediators like NFkappaB, GADD-153/CHOP, and p-eIF2alpha. Moreover, subjects with severe emphysema had a higher accumulation of ubiquitinated proteins and deubiquitinating enzyme, UCHL-1, indicating towards the aggregation of misfolded or damaged proteins. The modulation of both protein degradation and synthesis rates by CS-extract substantiates the pathogenetic role of proteostasis-imbalance in emphysema and COPD. We identified that VCP also mediates proteasomal degradation of HDAC2 and Nrf2, as a potential mechanism for increased oxidative stress and corticosteroid resistance in COPD subjects with emphysema. Next, we confirmed that higher VCP expression associates with increased inflammation and apoptosis using in vitro and murine models. Our data clearly shows aberrant proteostasis in COPD subjects with severe emphysema. In addition, we evaluate therapeutic efficacy of salubrinal (ER stress inhibitor) to correct the proteostasis-imbalance based on its ability to control VCP expression and ubiquitin accumulation. Overall, our data demonstrate for the first time the critical role of proteostasis-imbalance in pathogenesis of severe emphysema. PMID- 21318263 TI - The myogenic transcriptional network. AB - Myogenesis has been a leading model for elucidating the molecular mechanisms that underlie tissue differentiation and development since the discovery of MyoD. During myogenesis, the fate of myogenic precursor cells is first determined by Pax3/Pax7. This is followed by regulation of the myogenic differentiation program by muscle regulatory factors (Myf5, MyoD, Myog, and Mrf4) to form muscle tissues. Recent studies have uncovered a detailed myogenic program that involves the RP58 (Zfp238)-dependent regulatory network, which is critical for repressing the expression of inhibitor of DNA binding (Id) proteins. These novel findings contribute to a comprehensive understanding of the muscle differentiation transcriptional program. PMID- 21318261 TI - The waking brain: an update. AB - Wakefulness and consciousness depend on perturbation of the cortical soliloquy. Ascending activation of the cerebral cortex is characteristic for both waking and paradoxical (REM) sleep. These evolutionary conserved activating systems build a network in the brainstem, midbrain, and diencephalon that contains the neurotransmitters and neuromodulators glutamate, histamine, acetylcholine, the catecholamines, serotonin, and some neuropeptides orchestrating the different behavioral states. Inhibition of these waking systems by GABAergic neurons allows sleep. Over the past decades, a prominent role became evident for the histaminergic and the orexinergic neurons as a hypothalamic waking center. PMID- 21318262 TI - Stimulation of olfactory ensheathing cell motility enhances olfactory axon growth. AB - Axons of primary olfactory neurons are intimately associated with olfactory ensheathing cells (OECs) from the olfactory epithelium until the final targeting of axons within the olfactory bulb. However, little is understood about the nature and role of interactions between OECs and axons during development of the olfactory nerve pathway. We have used high resolution time-lapse microscopy to examine the growth and interactions of olfactory axons and OECs in vitro. Transgenic mice expressing fluorescent reporters in primary olfactory axons (OMP ZsGreen) and ensheathing cells (S100beta-DsRed) enabled us to selectively analyse these cell types in explants of olfactory epithelium. We reveal here that rather than providing only a permissive substrate for axon growth, OECs play an active role in modulating the growth of pioneer olfactory axons. We show that the interactions between OECs and axons were dependent on lamellipodial waves on the shaft of OEC processes. The motility of OECs was mediated by GDNF, which stimulated cell migration and increased the apparent motility of the axons, whereas loss of OECs via laser ablation of the cells inhibited olfactory axon outgrowth. These results demonstrate that the migration of OECs strongly regulates the motility of axons and that stimulation of OEC motility enhances axon extension and growth cone activity. PMID- 21318264 TI - Temporal abscess after third molar extraction in the mandible. AB - BACKGROUND: Dental infections resulting before or after third molar removal are complications in which the maxillofacial surgeon may have to initiate an earlier management. The severe dental infections resulting before or after this procedure is one of the few life-threatening complications in which the maxillofacial surgeon may have to initiate an earlier management. Infections involving the temporal space are rare and infrequently reported. Infections in this space have also been observed secondary to maxillary sinusitis, maxillary sinus fracture, temporomandibular arthroscopy, and drug injection, although more commonly associated to third molar infections. CASE REPORT: A 22-year-old man had undergone extraction of tooth 38 secondary to pericoronaritis by a general dentist. Physical examination of his face demonstrated severe trismus, pain, and swelling in temporal region. A CT scan showed an inflammatory area into the temporal space. He was started on IV cephalosporin, but the clinical course of the patient was not satisfactory. Incision and drainage were performed from an extraoral and intraoral approach. After discharged, the antibiotic was switched to clindamycin IO 600 mg. DISCUSSION: The retromaxillary and temporal infections are quite common after maxillary molar extractions but not after mandibular third molar, the spread mechanism of ascension must be involved with the virulence of microorganisms, but more studies are necessary to clarify this occurrence. PMID- 21318265 TI - Distribution and source of polycyclic aromatic hydrocarbons (PAHs) in the surface soil along main transportation routes in Jiaxing City, China. AB - Polycyclic aromatic hydrocarbons (16 EPA-PAHs) in urban surface soil from Jiaxing City were determined using HPLC. The total concentration of 16 EPA-PAHs was detected from 18.73 to 441.34 pg/g. Individual PAH occupation analysis demonstrates that four-ring PAHs comprise as much as 44.16% and were prevalent in the composition of PAH pollutants. The other components were two-ring PAHs (7.36%), three-ring PAHs (17.28%), five-ring PAHs (16.16%), and six-ring PAHs (15.04%). Source analysis on the characteristic ratios of anthracene(Ane)/[Ane+phenanthrene(Phe)], fluoranthene(Fla)/[Fla+pyrene(Pyr)], and benzo[a]pyrene(Bap)/benzo[g,h,i]perylene(Bgp) reveals that PAH pollutants originated mainly from coal combustion, but vehicular emission as a source was not negligible. All PAHs discussed in the paper have similar source in most sampling sites. The spatial distributions of pollution sources were closely related to geographic location, geographic condition, and living habit of indigenes. A linear relationship between 2-3-ring PAHs, 4-6-ring PAHs, SOM, and ?PAHs were investigated and significant correlativity were expatiated lastly. It revealed that coefficient between 2-3-ring PAHs and ?PAHs is 0.56, between 4-6 ring PAHs and ?PAHs is 0.99, between SOM and ?PAHs is 0.82. PMID- 21318266 TI - Effects of composition of labile organic matter on biogenic production of methane in the coastal sediments of the Arabian Sea. AB - Coastal regions are potential zones for production of methane which could be governed by ecological/environmental differences or even sediment properties of a niche. In order to test the hypothesis that methanogenesis in most marine sediments could be driven more by proteins than by carbohydrates and lipid content of labile organic matter (LOM), incubation experiments were carried out with sediments from different environmental niches to measure methane production. The methane production rates were examined in relationship to the sediment biochemistry, i.e., carbohydrates, proteins, and lipids. The gas production measured by head space method ranged from 216 ng g( -1) day( -1) in the mangrove sediments to 3.1 MUg g( -1) day( -1) in the shallow Arabian Sea. LOM ranged from 1.56 to 2.85 mg g( -1) in the shallow Arabian Sea, from 3.35 to 5.43 mg g( -1) in the mangrove estuary, and from 0.66 to 0.70 mg g( -1) in the sandy sediments with proteins contributing maximum to the LOM pool. Proteins influenced methane production in the clayey sediments of shallow depths of the Arabian Sea (r = 0.933, p < 0.001) and mangrove estuary (r = 0.981, p < 0.001) but in the sandy beach sediments, carbohydrates (r = 0.924, p < 0.001) governed the net methane production. The gas production was more pronounced in shallow and surface sediments and it decreased with depth apparently governed by the decrease in lability index. Thus, the lability index and protein content are important factors that determine methane production rates in these coastal ecosystems. PMID- 21318267 TI - Identification of erosional and inundation hazard zones in Ken-Betwa river linking area, India, using remote sensing and GIS. AB - Ken-Betwa river link is one of the pilot projects of the Inter Linking of Rivers program of Government of India in Bundelkhand Region. It will connect the Ken and Betwa rivers through a system of dams, reservoirs, and canals to provide storage for excess rainfall during the monsoon season and avoid floods. The main objective of this study is to identify erosional and inundation prone zones of Ken-Betwa river linking site in India using remote sensing and geographic information system tools. In this study, Landsat Thematic Mapper data of year 2005, digital elevation model from the Shuttle Radar Topographic Mission, and other ancillary data were analyzed to create various thematic maps viz. geomorphology, land use/land cover, NDVI, geology, soil, drainage density, elevation, slope, and rainfall. The integrated thematic maps were used for hazard zonation. This is based on categorizing the different hydrological and geomorphological processes influencing the inundation and erosion intensity. Result shows that the southern part of the study area which lies in Panna district of Madhya Pradesh, India, is more vulnerable than the other areas. PMID- 21318268 TI - Concentrations and bioaccessibility of metals in vegetation and dust near a mining haul road, Cape Krusenstern National Monument, Alaska. AB - Vegetation, sub-surface peat, and road dust were sampled near the Delong Mountain Transportation System (DMTS) haul road in northwest Alaska in 2005-2006 to document aluminum, barium, cadmium, lead, and zinc concentrations, and to evaluate bioaccessibility of these metals. The DMTS haul road is the transport corridor between Red Dog Mine (a large-scale, lead-zinc mine and mill) and the coastal shipping port, and it traverses National Park Service lands. Compared to reference locations, total metal concentrations in four types of vegetation (birch, cranberry, and willow leaves, and cotton grass blades/stalks) collected 25 m from the haul road were enriched on average by factors of 3.5 for zinc, 8.0 for barium, 20 for cadmium, and 150 for lead. Triple rinsing of vegetation with a water/methanol mixture reduced metals concentrations by at most 50%, and cadmium and zinc concentrations were least affected by rinsing. Cadmium and zinc bioaccessibility was greater in vegetation (50% to 100%) than in dust (15% to 20%); whereas the opposite pattern was observed for lead bioaccessibility (<30% in vegetation; 50% in dust). Barium exhibited low-to-intermediate bioaccessibility in dust and vegetation (20% to 40%), whereas aluminum bioaccessibility was relatively low (<6%) in all sample types. Our reconnaissance level study indicates that clean-up and improvements in lead/zinc concentrate transfer activities have been effective; however, as of 2006, metal dispersion from past and/or present releases of fugitive dusts along the DMTS road still may have been contributing to elevated metals in surface vegetation. Vegetation was most enriched in lead, but because bioaccessibility of cadmium was greater, any potential risks to animals that forage near the haul road might be equally important for both of these metals. PMID- 21318269 TI - Valid MR imaging predictors of prior knee arthroscopy. AB - PURPOSE: To determine whether fibrosis of the medial patellar reticulum (MPR), lateral patellar reticulum (LPR), deep medial aspect of Hoffa's fat pad (MDH), or deep lateral aspect of Hoffa's fat pad (LDH) is a valid predictor of prior knee arthroscopy. MATERIALS AND METHODS: Institutional review board approval and waiver of informed consent were obtained for this HIPPA-compliant study. Initially, fibrosis of the MPR, LPR, MDH, or LDH in MR imaging studies of 50 patients with prior knee arthroscopy and 100 patients without was recorded. Subsequently, two additional radiologists, blinded to clinical data, retrospectively and independently recorded the presence of fibrosis of the MPR in 50 patients with prior knee arthroscopy and 50 without. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for detecting the presence of fibrosis in the MPR were calculated. kappa statistics were used to analyze inter-observer agreement. RESULTS: Fibrosis of each of the regions examined during the first portion of the study showed a significant association with prior knee arthroscopy (p < 0.005 for each). A patient with fibrosis of the MPR, LDH, or LPR was 45.5, 9, or 3.7 times more likely, respectively, to have had a prior knee arthroscopy. Logistic regression analysis indicated that fibrosis of the MPR supplanted the diagnostic utility of identifying fibrosis of the LPR, LDH, or MDH, or combinations of these (p >= 0.09 for all combinations). In the second portion of the study, fibrosis of the MPR demonstrated a mean sensitivity of 82%, specificity of 72%, PPV of 75%, NPV of 81%, and accuracy of 77% for predicting prior knee arthroscopy. CONCLUSIONS: Analysis of MR images can be used to determine if a patient has had prior knee arthroscopy by identifying fibrosis of the MPR, LPR, MDH, or LDH. Fibrosis of the MPR was the strongest predictor of prior knee arthroscopy. PMID- 21318270 TI - Melanotic neuroectodermal tumor of infancy in thigh of an infant--a rare case report with diagnostic implications. AB - Melanotic neuroectodermal tumor of infancy (MNTI) is an uncommon tumor of neural crest origin, almost invariably identified in the head and neck region. It is a relatively benign tumor but can recur and rarely metastasize. Herein, a rare case of MNTI in the thigh of an infant is documented. Radiographic imaging showed a sclerotic and lytic lesion in the metadiaphyseal region of the right femur with a soft tissue component. The clinicoradiological impression was of a malignant round cell tumor and osteomyelitis. The patient's urinary vanil mandelic acid (VMA) level was elevated. FNAC smears revealed a tumor with round to polygonal cells, focally containing black melanin pigment. Biopsy and tumor excision revealed a tumor with cells in cords and nests embedded in a fibrocollagenous stroma and showed bone and soft tissue infiltration. On immunohistochemistry, tumor cells displayed immunoreactivity to vimentin, cytokeratin (CK), CK7, CK19, and MIC2, and focal reactivity for synaptophysin and HMB45. Diagnosis of an MNTI was made. The patient underwent induction chemotherapy with extracorporeal radiotherapy, followed by a soft tissue excision that revealed residual tumor. Surgically, free marrow margins were accomplished, and the patient is currently being followed-up. To the best of our knowledge this case is the fifth documented case in the English literature of MNTI in the thigh. The diagnostic and therapeutic implications are discussed. PMID- 21318271 TI - Dynamic contrast-enhanced 3-T magnetic resonance imaging: a method for quantifying disease activity in early polyarthritis. AB - OBJECTIVE: To determine whether measurement of synovial enhancement and thickness quantification parameters with 3.0-Tesla magnetic resonance imaging (3-T MRI) can reliably quantify disease activity in patients with early polyarthritis. MATERIALS AND METHODS: Eighteen patients (16 women, 2 men; mean age 46 years) with early polyarthritis with less than 12 months of symptoms were included. MRI examination using 3-T device was performed by a new approach including both wrists and hands simultaneously in the examination field-of-view. MRI scoring of disease activity included quantification of synovial enhancement with simple measurements such as rate of early enhancement (REE; REE(57) = S(57)/S(200), where S(57) and S(200) are the signal intensities 57 s and 200 s after gadolinium injection) and rate of relative enhancement (RE; RE = S(200) - S(0)). Both wrists and hands were scored according to the Rheumatoid Arthritis MRI Scoring System (RAMRIS) for synovitis. Disease activity was clinically assessed by the 28-joint Disease Activity Score (DAS28). RESULTS: DAS28 score was strongly correlated with RE (r = 0.8331, p < 0.0001), REE (r = 0.8112, p < 0.0001), and RAMRIS score for synovitis (r = 0.7659, p < 0.0002). An REE score above 0.778 accurately identified patients with clinically active disease (sensitivity 92%; specificity 67%; p < 0.05). A statistically significant difference was observed in the RE, REE, and RAMRIS scores for synovitis between patients with active and inactive disease (p < 0.05). CONCLUSIONS: Our findings support the use of 3-T dynamic contrast-enhanced MRI for precise quantification of disease activity and for discriminating active disease from inactive disease in early polyarthritis. PMID- 21318272 TI - Necrotic pseudotumor caused by a metal-on-metal total hip prosthesis: imaging characteristics on (18)F-FDG PET/CT and correlative imaging. AB - Necrotic pseudotumor is a complication of metal-on-metal arthroplasty that has been reported with increasing frequency in the last 5 years. It is believed to be the result of a hypersensitivity reaction to metal ions such as nickel, cobalt, or chromium that are released in large quantities from these prostheses. The imaging appearance of a necrotic pseudotumor caused by a metal-on-metal prosthesis, on (18)F-FDG PET/CT or (99m)Tc-MDP bone scan has not been previously described in the literature. Our case demonstrates that a necrotic pseudotumor can be detected incidentally in oncologic patients referred for an (18)F-FDG PET/CT or a (99m)Tc-MDP bone scan, and recognizing this process is vital in preventing further tissue necrosis and patient morbidity, as the offending prosthesis must be promptly removed. The imaging characteristics of a necrotic pseudotumor on PET/CT and bone scan may also mimic a malignant process such as a necrotic sarcoma, and can represent a potential pitfall leading to a false positive diagnosis in an oncologic patient. PMID- 21318273 TI - Conformational flexibility of lipase Lip1 from Candida rugosa studied by electronic spectroscopies and thermodynamic approaches. AB - We have used second-order orthogonal designs to obtain empirical models that describe the combined effect of pH and temperature on the secondary structure of a lipase (Lip1) from Candida rusosa. The equations that describe lipase conformational flexibility were derivated from the enzyme alpha helix fraction obtained from the experimental matrix. The thermal unfolding of lipase at different pH values was followed by measuring the circular dichroism signal as a function of temperature over a temperature range of 20-80 degrees C. The results showed a melting temperature of 58.9 degrees C at pH 5.5, while at pHs 7.0 and 8.6, the temperature values were 50.2 degrees C and 36.1 degrees C respectively. The optimum experimental conditions of conformations with high content of alpha helix were found at high temperature and pH, both at zero time and at one-hour incubation time of enzyme. Important variations in the enzyme secondary structure were induced for the pH and temperature. In contrast, minor changes were observed during the incubation time. This behaviour suggests that the medium pH induces a modification in the enzyme secondary structure and not due to a result of a progressive denaturation process. From the values of thermodynamic functions at different pHs, the system at initial state of unfolding process is previously disordered by the pH effect. PMID- 21318274 TI - Purification and characterization of a recombinant bacteriophytochrome of Xanthomonas oryzae pathovar oryzae. AB - Phytochrome-like proteins have been recently identified in prokaryotes but their features and functions are not clear. We cloned a gene encoding the phytochrome like protein (XoBphP) in a pathogenic bacteria, Xanthomonas oryzae pv. oryzae (Xoo) and investigated characteristics of the protein using a recombinant XoBphP. The N-terminal region of XoBphP containing the PAS/GAF/PHY domains is highly similar to most bacteriophytochromes, but Cys4, corresponding to Cys24 of DrBphP, isn't involved in chromophore attachment. Recombinant XoBphP could bind a bilin molecule and a differential spectrum from Pr/Pfr shows that XoBphP has similar characteristics of known bacteriophytochromes with shifted absorption maxima of 683 and 757 nm for the Pr and Pfr forms. Unlike other bacteriophytochromes, XoBphP has no histidine kinase domain at C-terminus. The domain was predicted from amino-acid 279 to 342 with less significance than the required threshold. This result suggests that XoBphP probably has different signal transduction mechanisms for its intracellular function. PMID- 21318275 TI - The four different types of internal hernia occurring after laparascopic Roux-en Y gastric bypass performed for morbid obesity: are there any multidetector computed tomography (MDCT) features permitting their distinction? AB - BACKGROUND: Four different types of internal hernias (IH) are known to occur after laparoscopic Roux-en-Y gastric bypass (LRYGBP) performed for morbid obesity. We evaluate multidetector row helical computed tomography (MDCT) features for their differentiation. METHODS: From a prospectively collected database including 349 patients with LRYGBP, 34 acutely symptomatic patients (28 women, mean age 32.6), operated on for IH immediately after undergoing MDCT, were selected. Surgery confirmed 4 (11.6%) patients with transmesocolic, 10 (29.4%) with Petersen's, 15 (44.2%) with mesojejunal, and 5 (14.8%) with jejunojejunal IH. In consensus, 2 radiologists analyzed 13 MDCT features to distinguish the four types of IH. Statistical significance was calculated (p<0.05, Fisher's exact test, chi-square test). RESULTS: MDCT features of small bowel obstruction (SBO) (n=25, 73.5%), volvulus (n=22, 64.7%), or a cluster of small bowel loops (SBL) (n=27, 79.4%) were inconsistently present and overlapped between the four IH. The following features allowed for IH differentiation: left upper quadrant clustered small bowel loops (p<0.0001) and a mesocolic hernial orifice (p=0.0003) suggested transmesocolic IH. SBL abutting onto the left abdominal wall (p=0.0021) and left abdominal shift of the superior mesenteric vessels (SMV) (p=0.0045) suggested Petersen's hernia. The SMV predominantly shifted towards the right anterior abdominal wall in mesojejunal hernia (p=0.0033). Location of the hernial orifice near the distal anastomosis (p=0.0431) and jejunojejunal suture widening (p=0.0005) indicated jejunojejunal hernia. CONCLUSIONS: None of the four IH seems associated with a higher risk of SBO. Certain MDCT features, such as the position of clustered SBL and hernial orifice, help distinguish between the four IH and may permit straightforward surgery. PMID- 21318276 TI - Vpr-host interactions during HIV-1 viral life cycle. AB - Human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) is a multifunctional viral protein that plays important role at multiple stages of the HIV-1 viral life cycle. Although the molecular mechanisms underlying these activities are subject of ongoing investigations, overall, these activities have been linked to promotion of viral replication and impairment of anti-HIV immunity. Importantly, functional defects of Vpr have been correlated with slow disease progression of HIV-infected patients. Vpr is required for efficient viral replication in non-dividing cells such as macrophages, and it promotes, to some extent, viral replication in proliferating CD4+ T cells. The specific activities of Vpr include modulation of fidelity of viral reverse transcription, nuclear import of the HIV-1 pre-integration complex, transactivation of the HIV-1 LTR promoter, induction of cell cycle G2 arrest and cell death via apoptosis. In this review, we focus on description of the cellular proteins that specifically interact with Vpr and discuss their significance with regard to the known Vpr activities at each step of the viral life cycle in proliferating and non proliferating cells. PMID- 21318277 TI - Detection of Rickettsia and a novel Haemaphysalis shimoga symbiont bacterium in ticks in Thailand. AB - In this study, we identified two Haemaphysalis species present at the Khao Yai National Park in Thailand and investigated the presence of rickettsia in these ticks. A total of 166 Haemaphysalis specimens were collected randomly under leaves along visitor paths at five locations in the park. Male and female adults of two different Haemaphysalis species, H. shimoga and H. lagrangei, were identified. Polymerase chain reaction (PCR) analysis revealed Rickettsia bacteria in these two Haemaphysalis species; this study represents the first time such presence has been reported in Thailand. The infection rates of Rickettsia were in both H. shimoga (7.41%) and H. lagrangei (10.17%) at these locations in addition to two pools of Haemahysalis nymphs (28.57%). Furthermore, 25.93% of H. shimoga showed positive results that matched Haemaphysalis longicornis symbionts (92% sequence identity) and the Coxeilla burnetti 16S ribosomal RNA gene (90% sequence identity). We propose that this is a novel H. shimoga symbiont bacterium in Thailand and might be a novel Coxeilla-like agent or Coxeilla sp. found in H. shimoga. In contrast, we did not observe any Wolbachia bacteria, which also belong to the order Rickettsiales, in the same group of Haemaphysalis ticks. Furthermore, PCR was used to detect three other genera of bacteria, Anaplasma, Ehrlichia and Borrelia, none of which were identified in the Haemaphysalis ticks studied. PMID- 21318278 TI - Posterior cervical fixation following laminectomy: a stress analysis of three techniques. AB - The aim of this study was to compare the following three main fixation techniques: pedicle screw (PS) technique, lateral mass screw (LS) technique, and transarticular screw (TS) technique. A detailed, geometrically accurate, nonlinear C3-C7 FE model had been successfully developed and validated. Then three finite element (FE) models were reconstructed by different fixation techniques following C4-C6 level laminectomy. A compressive preload of 74 N combined with a pure moment of 1.8 Nm in flexion, extension, left-right lateral bending, and left-right axial rotation was applied to the models. The results showed that maximum von Mises stress on the fixation devices was much higher in the FE models of TS technique, compared with the models of PS and LS techniques. Furthermore, the screws inserted by TS technique had high stress concentration at the middle part of the screws. Screw inserted by PS and LS techniques had high stress concentration at the actual cap-rod-screw interface. The highest level of maximal stress was obtained with the fixation device of the TS technique. TS technique induces noticeable differences in the stress compared to the posterior cervical fixation technique, regarding the higher stress level on fixation devices. PMID- 21318279 TI - The efficacy and complications of posterior hemivertebra resection. AB - There have been several reports on hemivertebra resection via a posterior-only procedure. However, the number of reported cases is small, and various types of instrumentation have been used. In our study, we retrospectively investigated 56 consecutive cases of congenital scoliosis that were treated by posterior hemivertebra resection with transpedicular instrumentation. Radiographs were reviewed to determine the type and location of the hemivertebra, the coronal curve magnitude and the sagittal alignment pre-operatively, post-operatively and at the latest follow-up. Radiographs were also used to assess implant failure and inter-body fusion. Surgical reports and patient charts were reviewed to record any peri-operative complications. Fifty-eight posterior hemivertebrae resections from 56 patients aged 1.5-17 years with fully segmented non-incarcerated hemivertebra were evaluated. The average age at surgery was 9.9 years (1.5-17 years). The average follow-up was 32.9 months (24-58 months). The mean fusion level was 5.0 segments (2-11 segments). There was a mean improvement of 72.9% in the segmental scoliosis, from 42.4 degrees before surgery to 12.3 degrees at the time of the latest follow-up, and there was a mean improvement of 70% in segmental kyphosis from 42.0 degrees to 14.5 degrees over the same time period. The thoracic kyphosis (T5-T12) averaged 10.8 degrees before surgery and 23.9 degrees at the latest follow-up. The lumbar lordosis (L1-S1) averaged -52.8 degrees before surgery and -51.6 degrees at the latest follow-up. Two cases with neurological claudications had complete recovery immediately after the surgery. There was one case of delayed wound healing, two fractures of the pedicle at the instrumented level, two rod breakages and one proximal junction kyphosis that required revision. There were no neurological complications. Radiolucent gaps were found in the residual space after resection on the lateral view in five cases, without any sign of implant failure or correction loss. Our results show that one-stage posterior hemivertebra resection with transpedicular instrumentation can achieve excellent correction, 360 degrees decompression and short fusion without neurological complications. Pedicle cutting still remains a challenge in younger children when using bisegmental instrumentation. In addition, the radiolucent gaps in the residual space require further investigation. PMID- 21318280 TI - The effect of food consumption on the thickness of abdominal muscles, employing ultrasound measurements. AB - Recently, the roles of transabdominal muscles particularly TrA (transverse abdominis) muscle in spinal stability leading to treatment of low back pain have been suggested. Both in clinical setting and follow up studies, abdominal muscle thickness measurements need to be repeated at a later point in time to demonstrate efficacy of a therapeutic intervention. Different issues have been suggested as source of error in the repeated measurements of abdominal muscle thickness in different days such as patient position and stability of probe location. The level of stomach fullness has not been investigated as a source of error in ultrasonic measurements of transabdominal muscles thickness. This study was performed to evaluate the effect of food consumption on thickness of lateral abdominal muscles. Lateral abdominal muscles thicknesses of 63 healthy volunteer men were measured before and after food consumption. All the measurements were performed in two transducer positions and both sides. Waist circumference and body weight of participants were also measured before and post-food consumption. The thickness measures of all three muscles layers of lateral abdominal muscles (external oblique, internal oblique and transversus abdominis) in both sides and measured positions were significantly reduced after food consumption. We found no correlation between the increase of waist circumference and reduction of muscle layer thicknesses after food consumption. In case of comparison between the values of transabdominal muscle thicknesses over the time, the effect of food consumption on muscle thickness might be assumed as a potential source of error. PMID- 21318281 TI - Vertebroplasty: benefits are more than risks in selected and evidence-based informed patients. A retrospective study of 59 cases. AB - Vertebral compression fractures represent a frequent pathology among elderly population, with potentially devastating consequences. More than 20 years have passed since percutaneous vertebroplasty was initially used in the treatment of angiomas, representing nowadays a widely used treatment for osteoporotic vertebral fractures. The authors present a retrospective review of 59 consecutive patients (in total 94 fractured levels) that underwent polymethylmethacrylate percutaneous vertebroplasty for vertebral compression fractures due to senile or secondary osteoporosis. All fractures were free from neurologic involvement and were classified as A1 type according to Magerl classification. All of patients were initially treated conservatively, by application of orthosis that allows immediate deambulation. At control, patients who complained of pain and limitation of daily activities underwent MRI. If presence of marrow signal changes, especially hypertense signal in T2-weighted images was confirmed, percutaneous vertebroplasty procedure was performed (we could call it "sub-acute" procedure). A limited group of patients that did not tolerate brace and had an insufficient pain control underwent vertebroplasty "in acute", few days after fracture. Immediate post-operative pain reduction and follow-up clinical outcome (estimating quality of life and residual back pain) were evaluated by means of Visual Analogue Scale, SF-36 and Oswestry Disability Index. In the immediate post operative course a significant pain relief was found in 39 patients (66.1%), moderate pain relief in 17 (28.8%), while 3 (5.1%) did not achieve relevant pain improvement. Pain intensity and life quality was maintained within satisfactory limits after a mean follow-up of 16 months. In conclusion, percutaneous vertebroplasty is an effective and safe procedure for treating vertebral compression fractures in the elderly. It provides immediate pain relief and allows early mobilization, thus avoiding potentially severe complications related to persistent back pain and prolonged bed rest. When performed by experienced surgeon complication rate is low, representing a safe procedure, able to provide a satisfactory outcome. PMID- 21318282 TI - Characterization of the active bacterial community involved in natural attenuation processes in arsenic-rich creek sediments. AB - Acid mine drainage of the Carnoules mine (France) is characterized by acid waters containing high concentrations of arsenic and iron. In the first 30 m along the Reigous, a small creek draining the site, more than 38% of the dissolved arsenic was removed by co-precipitation with Fe(III), in agreement with previous studies, which suggest a role of microbial activities in the co-precipitation of As(III) and As(V) with Fe(III) and sulfate. To investigate how this particular ecosystem functions, the bacterial community was characterized in water and sediments by 16S rRNA encoding gene library analysis. Based on the results obtained using a metaproteomic approach on sediments combined with high-sensitivity HPLC-chip spectrometry, several GroEL orthologs expressed by the community were characterized, and the active members of the prokaryotic community inhabiting the creek sediments were identified. Many of these bacteria are beta-proteobacteria such as Gallionella and Thiomonas, but gamma-proteobacteria such as Acidithiobacillus ferrooxidans and alpha-proteobacteria such as Acidiphilium, Actinobacteria, and Firmicutes were also detected. PMID- 21318283 TI - Sonographic subclinical entheseal involvement in dialysis patients. AB - Long-term dialysis treatment can be associated with several musculoskeletal complications. Entheseal involvement in dialysis patients remains rarely studied as its prevalence is underestimated due to its often asymptomatic presentation. The aims of the study were to determine the prevalence of subclinical enthesopathy in haemodialysis and peritoneal dialysis patients at the lower limb level, to investigate the inter-observer reliability of ultrasound assessment and to analyse the influence of biometric and biochemical parameters. Ultrasound examination was conducted at the entheses of the lower limbs level in 33 asymptomatic dialysis patients and 33 healthy adopting the Glasgow Ultrasound Enthesitis Scoring System (GUESS). The inter-observer reliability was calculated in 15 dialysis patients. Ultrasound found at least one sign of enthesopathy in 165 out of 330 (50%) entheses of dialysis patients. In healthy subjects, signs of enthesopathy were present in 54 out of 330 (16.3%) entheses (p < 0.0001). No power Doppler signal was detected in healthy controls, in contrast to four of 330 entheses of dialysis patients. No US signs of soft tissue amyloid deposits were found. The GUESS score was significantly higher in dialysis patients than in controls (p < 0.0001). There was no difference in terms of enthesopathy between haemodialysis and peritoneal dialysis. Dialysis duration resulted to be the most important predictor for enthesopathy (p = 0.0004), followed by patient age (p = 0.02) and body mass index (p = 0.035). Parathormone, calcium, phosphorus, C reactive protein, cholesterol and triglycerides apparently did not play a relevant role in favour of enthesopathy. The inter-observer reliability showed an excellent agreement between sonographers with different degree of experience. Our results demonstrated a higher prevalence of subclinical enthesopathy in both haemodialysis and peritoneal dialysis patients than in healthy subjects. Follow up will provide further information with respect to the predictive value of US findings for the development of symptomatic dialysis-related arthropathy. PMID- 21318284 TI - Reparative radiological changes of a large joint after adalimumab for rheumatoid arthritis. PMID- 21318285 TI - Mercury concentrations at a historically mercury-contaminated site in KwaZulu Natal (South Africa). AB - INTRODUCTION: A mercury (Hg) processing plant previously operating in KwaZulu Natal Province (South Africa) discharged Hg waste into a nearby river system causing widespread contamination since the 1980s. Although the processing plant ceased operation in the 1990s, Hg contamination (due to residual Hg) remains significant. Previous studies in the area since the plant's closure have found elevated Hg concentrations in fish, and that these concentrations were as a direct consequence of widespread contamination of the Hg processing plant operations conducted between the 1980s and 1990s. OBJECTIVES: This study aimed at investigating the impacts of residual Hg almost 20 years after the plant's closure. METHODS: Water, sediment and biota (invertebrates and fish) were collected in water resources in the vicinity of the processing plant to determine the Hg concentrations in these compartments, as a proxy for assessing the extent to which residual Hg that is reintroduced to the water column becomes bioavailable to biota. For water and sediment samples, higher total mercury (TotHg) and methylmercury (MeHg) concentrations were measured at sampling sites immediately downstream of the Hg processing plant when compared to the upstream sites, while concentrations decreased with distance from the plant. Fish MeHg concentrations measured just below the US EPA guideline for Hg in fish muscle tissue. RESULTS: The results show that the historically Hg-contaminated river system is a potential Hg pollution source due to the residual Hg present in sediment. Any dredging of sediment as a form of remediation in the Mngceweni River is not recommended; however, a Hg monitoring programme is recommended for assessing the bioavailability of resuspended Hg from sediment. PMID- 21318286 TI - Effects of sulfur dioxide pollution on the translocation and accumulation of heavy metals in soybean grain. AB - BACKGROUND: Open-top chambers were used to study the impact of simultaneous exposure to atmospheric SO(2) pollution and heavy metal contamination in soils on the metal contents and productivity of soybean plant. METHODS: Plants were exposed at ambient levels as control SO(2) (1.2 ppb), low SO(2) (97 ppb), and high SO(2) (490 ppb) over the whole growing season while simultaneously being exposed to either Cd (0.5 mg kg(-1)), Pb (250 mg kg(-1)), Cu (100 mg kg(-1)), or Zn (150 mg kg(-1)) in soil. RESULTS: This experimental study covering the whole growth season has shown that SO(2) has a synergistic effect in enhancing the heavy metal contents in aboveground tissues of soybean plant, and the effects of high SO(2) treatment were found to be highly significant, showing increases of 42% and 29% for Cu and Cd content of grain, respectively. CONCLUSION: The research findings are of practical significance in the environmental control for the combined pollution of air and soil to ensure the quality of agricultural products and therefore benefits for human health. PMID- 21318287 TI - The development of soil organic matter in restored biodiverse Jarrah forests of South-Western Australia as determined by ASE and GCMS. AB - BACKGROUND, AIM AND SCOPE: Soil organic matter (SOM) is known to increase with time as landscapes recover after a major disturbance; however, little is known about the evolution of the chemistry of SOM in reconstructed ecosystems. In this study, we assessed the development of SOM chemistry in a chronosequence (space for time substitution) of restored Jarrah forest sites in Western Australia. MATERIALS AND METHODS: Replicated samples were taken at the surface of the mineral soil as well as deeper in the profile at sites of 1, 3, 6, 9, 12, and 17 years of age. A molecular approach was developed to distinguish and quantify numerous individual compounds in SOM. This used accelerated solvent extraction in conjunction with gas chromatography mass spectrometry. A novel multivariate statistical approach was used to assess changes in accelerated solvent extraction (ASE)-gas chromatography-mass spectrometry (GCMS) spectra. This enabled us to track SOM developmental trajectories with restoration time. RESULTS: Results showed total carbon concentrations approached that of native forests soils by 17 years of restoration. Using the relate protocol in PRIMER, we demonstrated an overall linear relationship with site age at both depths, indicating that changes in SOM chemistry were occurring. CONCLUSIONS: The surface soils were seen to approach native molecular compositions while the deeper soil retained a more stable chemical signature, suggesting litter from the developing diverse plant community has altered SOM near the surface. Our new approach for assessing SOM development, combining ASE-GCMS with illuminating multivariate statistical analysis, holds great promise to more fully develop ASE for the characterisation of SOM. PMID- 21318288 TI - Characterization of the desiccation of wheat kernels by multivariate imaging. AB - Variations in the quality of wheat kernels can be an important problem in the cereal industry. In particular, desiccation conditions play an essential role in both the technological characteristics of the kernel and its ability to sprout. In planta desiccation constitutes a key stage in the determinism of the functional properties of seeds. The impact of desiccation on the endosperm texture of seed is presented in this work. A simple imaging system had previously been developed to acquire multivariate images to characterize the heterogeneity of food materials. A special algorithm for the use under principal component analysis (PCA) was developed to process the acquired multivariate images. Wheat grains were collected at physiological maturity, and were subjected to two types of drying conditions that induced different kinetics of water loss. A data set containing 24 images (dimensioned 702 * 524 pixels) corresponding to the different desiccation stages of wheat kernels was acquired at different wavelengths and then analyzed. A comparison of the images of kernel sections highlighted changes in kernel texture as a function of their drying conditions. Slow drying led to a floury texture, whereas fast drying caused a glassy texture. The automated imaging system thus developed is sufficiently rapid and economical to enable the characterization in large collections of grain texture as a function of time and water content. PMID- 21318289 TI - Distinct substrate specificities and unusual substrate flexibilities of two hydroxycinnamoyltransferases, rosmarinic acid synthase and hydroxycinnamoyl CoA:shikimate hydroxycinnamoyl-transferase, from Coleus blumei Benth. AB - cDNAs and genes encoding a hydroxycinnamoyl-CoA:hydroxyphenyllactate hydroxycinnamoyltransferase (CbRAS; rosmarinic acid synthase) and a hydroxycinnamoyl-CoA:shikimate hydroxycinnamoyltransferase (CbHST) were isolated from Coleus blumei Benth. (syn. Solenostemon scutellarioides (L.) Codd; Lamiaceae). The proteins were expressed in E. coli and the substrate specificity of both enzymes was tested. CbRAS accepted several CoA-activated phenylpropenoic acids as donor substrates and D-(hydroxy)phenyllactates as acceptors resulting in ester formation while shikimate and quinate were not accepted. Unexpectedly, amino acids (D-phenylalanine, D-tyrosine, D-DOPA) also yielded products, showing that RAS can putatively catalyze amide formation. CbHST was able to transfer cinnamic, 4-coumaric, caffeic, ferulic as well as sinapic acid from CoA to shikimate but not to quinate or acceptor substrates utilized by CbRAS. In addition, 3-hydroxyanthranilate, 3-hydroxybenzoate and 2,3-dihydroxybenzoate were used as acceptor substrates. The reaction product with 3-aminobenzoate putatively is an amide. For both enzymes, structural requirements for donor and acceptor substrates were deduced. The acceptance of unusual acceptor substrates by CbRAS and CbHST resulted in the formation of novel compounds. The rather relaxed substrate as well as reaction specificity of both hydroxycinnamoyltransferases opens up possibilities for the evolution of novel enzymes forming novel secondary metabolites in plants and for the in vitro formation of new compounds with putatively interesting biological activities. PMID- 21318291 TI - Epigenetic silencing of tumor suppressor genes in pancreatic cancer. AB - INTRODUCTION: Without any alteration of DNA sequence, heritable changes in gene expression, caused by epigenetic pathways, are gaining a spotlight in research of diseases, and in particular, cancer. Although the dominant paradigm in cancer research, proposed by Vogelstein, suggested that cancer progression was caused by a sequential accumulation of genetic aberrations, basic science studies in epigenetics have now advanced our knowledge enough to apply its concepts and methodology to the study of cancer. In fact, chromatin dynamics and small RNAs are altered far more prevalently in cancer than genetic alterations and most important, can be reversible, lending themselves as attractive therapeutic targets. CONCLUDING REMARKS: In the current review, the inactivation of p16 will be utilized as the most prominent example of epigenetic silencing of a tumor suppressor gene in pancreatic cancer. In addition, fundamental insight will be given into why and how epigenetics can be targeted for therapeutic purposes. This knowledge will help the reader in determining the breadth and depth of this field of study with potentially high impact to oncology. PMID- 21318290 TI - Cancer stem cells and cancer therapy. AB - Cancer stem cells (CSCs) are a subpopulation of tumour cells that possess the stem cell properties of self-renewal and differentiation. Stem cells might be the target cells responsible for malignant transformation, and tumour formation may be a disorder of stem cell self-renewal pathway. Epigenetic alterations and mutations of genes involved in signal transmissions may promote the formation of CSCs. These cells have been identified in many solid tumours including breast, brain, lung, prostate, testis, ovary, colon, skin, liver, and also in acute myeloid leukaemia. The CSC theory clarifies not only the issue of tumour initiation, development, metastasis and relapse, but also the ineffectiveness of conventional cancer therapies. Treatments directed against the bulk of the cancer cells may produce striking responses but they are unlikely to result in long-term remissions if the rare CSCs are not targeted. In this review, we consider the properties of CSCs and possible strategies for controlling the viability and tumourigenecity of these cells, including therapeutic models for selective elimination of CSCs and induction of their proper differentiation. PMID- 21318292 TI - Role of cellular mechanics in the function and life span of vascular endothelium. AB - The vascular endothelium plays a crucial role in vessel homeostasis and is implicated in the pathogenesis of cardiovascular disease. The function and life span of endothelial cells, therefore, have a large impact upon the quality and expectancy of an individual's life. Exposure to haemodynamic forces determines the phenotype of endothelial cells. Turbulent blood flow, disturbed shear stress and a rising tension of the vessel wall result in endothelial dysfunction and an enhanced endothelial cell turnover. In this scenario, the role of endothelial mechanics is yet poorly described. The streaming blood exerts shear forces transmitted to the soft cortical actin mesh immediately underneath the plasma membrane. The mechanical properties of this actin cortex seem to be an important regulator of endothelial function. Aldosterone and high plasma sodium stiffen the endothelial cell cortex which is accompanied by a decrease in NO release. If endothelial stiffening is only transient, it may be a useful mechanism to compensate for any decrease in arterial blood pressure. Long-term stiffening of the cell, however, may lead to endothelial dysfunction and may contribute to cardiovascular disorders, as observed in disturbed aldosterone/sodium homeostasis. In this case, the mineralocorticoid receptor antagonist spironolactone maintains the endothelial cell cortex soft and thereby preserves normal endothelial function and longevity. This may explain the recently observed beneficial effects of spironolactone on the cardiovascular system. Taken together, the review highlights the importance of elasticity for normal endothelial function. PMID- 21318293 TI - Family-centered care: current applications and future directions in pediatric health care. AB - Family-centered care (FCC) is a partnership approach to health care decision making between the family and health care provider. FCC is considered the standard of pediatric health care by many clinical practices, hospitals, and health care groups. Despite widespread endorsement, FCC continues to be insufficiently implemented into clinical practice. In this paper we enumerate the core principles of FCC in pediatric health care, describe recent advances applying FCC principles to clinical practice, and propose an agenda for practitioners, hospitals, and health care groups to translate FCC into improved health outcomes, health care delivery, and health care system transformation. PMID- 21318294 TI - Federal expenditures on maternal and child health in the United States. AB - The goals of this study are to estimate federal maternal and child health (MCH) expenditures and identify their sources. This analysis is intended to provide a broad view of MCH funding appropriations and a basis for discussion of whether funds could be better utilized for the benefit of the population served. Data on federal maternal and child health expenditures for fiscal year (FY) 2006 were derived from examining federal legislation, department/agency budgets, and various web-based program documents posted by federal agencies. Based on selected criteria, we identified programs targeting children under 21 or pregnant/parenting women within the United States. The funding levels of agency programs for maternal and child health activities were determined and the programs briefly summarized. The identifiable funding for maternal and child health programs in FY 2006 approached $57.5 billion dollars. Funding sources for maternal and child health were concentrated within the U.S. Department of Health and Human Services, but spread across several different agencies within the department and in the Departments of Defense, Education, Agriculture, Housing and Urban Development, and the Environmental Protection Agency. Multiple agencies and offices often funded related activities, without evidence of a common underlying strategy. Federal maternal and child health funding mechanisms may lead to a fragmentation in maternal and child health activities. The funding and service delivery apparatus would benefit from an integrative MCH infrastructure approach to pediatric research, service delivery, and data collection/access that incorporates life-course and social/environmental determinants perspectives. PMID- 21318295 TI - A high fat diet increases mitochondrial fatty acid oxidation and uncoupling to decrease efficiency in rat heart. AB - Elevated levels of cardiac mitochondrial uncoupling protein 3 (UCP3) and decreased cardiac efficiency (hydraulic power/oxygen consumption) with abnormal cardiac function occur in obese, diabetic mice. To determine whether cardiac mitochondrial uncoupling occurs in non-genetic obesity, we fed rats a high fat diet (55% kcal from fat) or standard laboratory chow (7% kcal from fat) for 3 weeks, after which we measured cardiac function in vivo using cine MRI, efficiency in isolated working hearts and respiration rates and ADP/O ratios in isolated interfibrillar mitochondria; also, measured were medium chain acyl-CoA dehydrogenase (MCAD) and citrate synthase activities plus uncoupling protein 3 (UCP3), mitochondrial thioesterase 1 (MTE-1), adenine nucleotide translocase (ANT) and ATP synthase protein levels. We found that in vivo cardiac function was the same for all rats, yet oxygen consumption was 19% higher in high fat-fed rat hearts, therefore, efficiency was 21% lower than in controls. We found that mitochondrial fatty acid oxidation rates were 25% higher, and MCAD activity was 23% higher, in hearts from rats fed the high fat diet when compared with controls. Mitochondria from high fat-fed rat hearts had lower ADP/O ratios than controls, indicating increased respiratory uncoupling, which was ameliorated by GDP, a UCP3 inhibitor. Mitochondrial UCP3 and MTE-1 levels were both increased by 20% in high fat-fed rat hearts when compared with controls, with no significant change in ATP synthase or ANT levels, or citrate synthase activity. We conclude that increased cardiac oxygen utilisation, and thereby decreased cardiac efficiency, occurs in non-genetic obesity, which is associated with increased mitochondrial uncoupling due to elevated UCP3 and MTE-1 levels. PMID- 21318296 TI - Effects of high thoracic epidural anesthesia on atrial electrophysiological characteristics and sympathetic nerve sprouting in a canine model of atrial fibrillation. AB - High thoracic epidural anesthesia (HTEA) blocks the afferent and efferent cardiac sympathetic nerve fibers and may affect atrial electrophysiological characteristics and nerve sprouting in patients with atrial fibrillation (AF). In this study, 18 dogs were randomly divided into a control group (n = 6), in which dogs were atrially paced at 400 beats/min for 6 weeks; an HTEA group (n = 6), in which dogs underwent atrial pacing and HTEA for 6 weeks; and a sham-operated group (n = 6), in which dogs underwent the operation but did not receive atrial pacing or HTEA. Electrophysiological examinations were performed in all groups. Cardiac nerves were immunocytochemically stained with anti-growth-associated protein 43 (GAP43) and anti-tyrosine hydroxylase (TH) antibodies. The protein expressions of nerve growth factor (NGF), GAP43 and TH in atrial myocardium were also studied by western blot. In addition, the plasma levels of C-reactive protein (CRP) and norepinephrine, as well as atrial production of superoxide anion (O(2)(.-)) and malondialdehyde, were measured. In the HTEA group, atrial effective refractory period increased (P < 0.05) and AF maintenance decreased (P < 0.01) significantly compared with the control group. The densities of GAP43 positive nerves and TH-positive nerves were significantly lower in the HTEA group compared with the control group. The protein levels of NGF, GAP43 and TH were also lower in the HTEA group compared with the control group. A significant positive correlation between the expressions of NGF and GAP43 (P < 0.01) was observed. A similar correlation was demonstrated for NGF and TH (P < 0.01) in our study. Furthermore, the plasma levels of CRP and norepinephrine, as well as the amount of O(2)(.-) and malondialdehyde produced from myocardium, decreased in the HTEA group compared with the control group. In conclusion, HTEA inhibited electrical and nerve remodeling and reduced the maintenance of AF in a canine AF model, in which process HTEA exhibited anti-inflammatory and antioxidant effects, indicating that, in addition to the efferent cardiac sympathetic nerve, afferent fibers also play an important role in the initiation and/or maintenance of AF. PMID- 21318297 TI - STARR and the older surgeon: what makes the difference? PMID- 21318298 TI - Impact of defunctioning loop ileostomy on outcome after restorative proctocolectomy for ulcerative colitis. AB - PURPOSE: This study analyzes the impact of a temporary loop ileostomy on postoperative outcome after restorative proctocolectomy for ulcerative colitis in terms of complications and reoperations including ileostomy closure. METHODS: The records of 122 consecutive patients undergoing restorative proctocolectomy for ulcerative colitis during a 12-year period were reviewed. In 89 patients, a defunctioning ileostomy was created, while 33 patients had no ileostomy. Statistics were done with Chi-square test and Mann-Whitney U test, p < 0.05 considered significant. RESULTS: Both study groups were comparable concerning age, colitis activity, previous diseases, previous surgery, use of steroids, and immunosuppressives. Pouch-related septic complications (anastomotic dehiscence, pouch leakage, pelvic abscess) were significantly lower in the ileostomy group (5.6% vs. 18.2%, p = 0.031), resulting in a lower rate of emergency laparotomies following restorative proctocolectomy (4.5% vs. 30.3%, p < 0.001). Including all complications associated with scheduled closure of ileostomy, the cumulative frequency of emergency laparotomies was significantly lower in the ileostomy group (13.5% vs. 30.3%, p = 0.032). The cumulative duration of hospitalization, including all hospital stays for complications or closure of the ileostomy, was significantly longer in the ileostomy group [median 22 days (11-92) vs. 14 days (9-109), p < 0.001]. During long-term follow-up, a stricture at the pouch-anal anastomosis was more common in the ileostomy group (24.7% vs. 6.1%, p = 0.021), whereas only one stricture necessitated surgical therapy. CONCLUSIONS: Creation of a defunctioning loop ileostomy reduces pouch-related septic complications and the frequency of emergency second laparotomies after restorative proctocolectomy for ulcerative colitis. PMID- 21318299 TI - Evidence-based German guidelines for surgery for obesity. AB - BACKGROUND: The young field of obesity surgery (bariatric surgery) in Germany expands as a consequence of the rapid increase of overweight and obesity. New surgical methods, minimal access techniques, and the enormous increase of scientific studies and evidence, all contribute to the success of bariatric surgery, which is the only realistic chance of permanent weight loss and regression of secondary diseases in many cases. METHODS: A systematic literature review, classification of evidence, graded recommendations, and interdisciplinary consensus. RESULTS: Obesity surgery is an integral component of the multimodal treatment of obesity, which consists of multidisciplinary evaluation and preparation, conservative and surgical treatment elements, and a life-long follow up. The guideline confirms the body mass index (BMI)-based spectrum of indications (BMI > 40 kg/m(2) or >35 kg/m(2) with secondary diseases) and extends it through elimination of all age restrictions (>18 years and <60 years) and most of the contraindications. Precondition for surgery is the failure of a structured conservative program of 6-12 months or the expected futility of it. Type II diabetes mellitus becomes an independent indication criterion for BMI < 35 kg/m(2) (metabolic surgery). The standard techniques are gastric balloon, gastric banding, gastric bypass, gastric sleeve, and biliopancreatic diversion. The choice of procedure is based on profound knowledge of results, long-term effects, complications, and patient-specific circumstances. The after-care should be structured and organized long term. CONCLUSION: The S3-guidelines contain evidence-based recommendations for the indication, selection of procedure, technique, and follow-up. Patient care should improve after implementation of these guidelines in clinical practice. Compliance by decision makers and health insurers is warranted. PMID- 21318300 TI - Assessments of inclinations of the mandibular fossa by computed tomography in an Asian population. AB - This study aims to evaluate the inclinations of right and left sides the mandibular fossa in Asian population using computed tomography (CT) images and determine its effects according to the parameters of gender, age, and asymmetry. CT images of the heads of 198 Asian subjects [95 females aged 44.2 +/- 20.7 years, range 11-88 years; and 103 males aged 44.5 +/- 19.7 years, range 15-98 years] were selected. The following eight parameters characterizing the inclinations of the mandibular fossa were measured by medical imaging software: anterior and posterior inclinations on the left and right sides on a sagittal view, and medial and lateral inclinations on the left and right sides on a coronal view. The anterior inclination was significant steeper in males than in females on both the left and right sides. A moderate positive correlation was found between age and anterior inclinations on the left and right sides. None of the other parameters were significantly affected by age or gender. None of the parameters differed significantly between the right and left sides of the mandibular fossa in males, females, or all subjects. The anterior inclination of the mandibular fossa was affected by aging and gender becoming steeper in Asians males than females. Besides, there were no asymmetry in the right and left side inclinations of the mandibular fossa. PMID- 21318301 TI - The genetic basis of resistance to downy mildew in Cucumis spp.--latest developments and prospects. AB - Downy mildew, caused by the Oomycete pathogen Pseudoperonospora cubensis, is one of the most destructive diseases of cucumber (Cucumis sativus L.) and muskmelon (C. melo L.). Although the process of pathogenesis is well understood, there are few disease control options available. The development and deployment of resistant cultivars is generally considered to be the best approach to control downy mildew. The recently completed sequencing of the cucumber genome provides a great opportunity for reliable and thorough study of the sequence and function of resistance genes in the Cucurbitaceae, which will help us to understand the resistance mechanisms and metabolic pathways activated by these genes. It can be anticipated that, in the near future, we will have more information about the genetic bases of resistance to downy mildew in Cucumis, which will facilitate efforts to breed for resistance to this pathogen. PMID- 21318302 TI - A case of femoral hemorrhage in a patient with microscopic polyangiitis with low levels of myeloperoxidase-antineutrophil cytoplasmic autoantibody. AB - We present the case of a 67-year-old female with femoral hemorrhage accompanied by microscopic polyangiitis. She was admitted to our hospital with symptoms of general fatigue, fever, and edema of the lower limbs. She was diagnosed with microscopic polyangiitis on the basis of the cardinal symptoms of the condition, including rapidly progressive glomerulonephritis and the presence of myeloperoxidase-antineutrophil cytoplasmic autoantibody (MPO-ANCA), albeit at a low titer. Renal biopsy demonstrated the presence of fibrocellular crescent shaped glomeruli with interstitial infiltration. No immune deposits were detected in immunofluorescence studies. The patient was treated with steroids and anti platelet agents; subsequently, the inflammatory reaction subsided and MPO-ANCA and C-reactive protein titers decreased. However, on day 14, the patient experienced sudden onset of swelling in the left femoral region accompanied by hypotension. Her hemoglobin level dropped from 8.8 to 4.5 g/dl in the subsequent hours. Although computed tomography of the legs revealed an extensive hematoma in the left quadriceps femoris muscle, the patient recovered after receiving a transfusion and supportive therapy with discontinuation of dipyridamole. Thereafter, her renal function improved, and she was discharged. To our knowledge, this is the first report of a case of microscopic polyangiitis accompanied by femoral hemorrhage. PMID- 21318303 TI - Aged garlic extract scavenges superoxide radicals. AB - There is increasing evidence to suggest that many degenerative or pathological processes, such as aging, cancer, and coronary heart disease, are related to reactive oxygen species and radical-mediated reactions. We examined the effectiveness of aged garlic extract (AGE), a garlic preparation rich in water soluble cysteinyl moieties, and its component for scavenging of superoxide by using the hypoxanthine-xanthine oxidase and human neutrophils. In the hypoxanthine-xanthine oxidase system, electron spin resonance showed that aged garlic extract scavenged superoxide radicals in a dose-dependent manner up to 54%. The EC(50) value of aged garlic extract for the superoxide radical scavenging effect was 0.80 mg/ml. N-alpha-(1-deoxy-D-fructos-1-yl)-L-arginine (25.9%) and (1S, 3S)-1-methyl-1,2,3,4-tetrahydro-beta-carboline-1,3-dicarboxylic acid (20.8%), water-soluble moieties of AGE, also exerted superoxide scavenging effects. Phorbol 12-myristate 13-acetate-activated human neutrophils produced superoxide radical of 56.6 +/- 9.27 nmol/min/10(7) cells. Aged garlic extract (3 mg/ml) significantly inhibited superoxide production in comparison to the control. These data suggest that aged garlic extract may be useful for preventing diseases associated with reactive oxygen species. PMID- 21318304 TI - The antioxidant and anti-proliferative activity of the Lebanese Olea europaea extract. AB - It is becoming increasingly evident that certain phytochemicals possess cancer chemopreventive properties. In this study, the anti-proliferative activity of plant extracts from olive (Olea europaea L.) leaves was tested on human leukemic cell line (Jurkat). Cytotoxicity of various concentrations of plant extracts was examined and the IC(50) was determined. Olive leaf extracts showed concentration dependent anti-proliferative effect as determined by the WST-1 proliferation kit and [(3)H]-thymidine incorporation method. To study whether cell death was due to apoptosis, cells were stained with Annexin V-FITC and PI and the expression of important regulatory proteins (Bcl-2, Bax, and p53) involved in apoptosis were examined by Western blot. The antioxidant activity of olive leaves (SC(50) = 0.1 mg dry weight) was studied using the DPPH scavenging method. Present findings suggest that olive leaves extracts exhibit anti-proliferative effect on leukemic cells by inducing apoptosis. PMID- 21318305 TI - Characterization of industrial onion wastes (Allium cepa L.): dietary fibre and bioactive compounds. AB - The food industry produces a large amount of onion wastes, making it necessary to search for possible ways for their utilization. One way could be to use these onion wastes as a natural source of high-value functional ingredients, since onion are rich in several groups of compounds, which have perceived benefits to human health. The objective of this work is to gain knowledge of any differences between the different onion wastes obtained from industry and non-commercial bulbs to use them as food ingredients rich in specific compounds. The results showed that brown skin and top-bottom could be potentially used as functional ingredient rich in dietary fibre, mainly in insoluble fraction, and in total phenolics and flavonoids, with high antioxidant activity. Moreover, brown skin showed a high concentration of quercetin aglycone and calcium, and top-bottom showed high concentration of minerals. Outer scales could be used as source of flavonols, with good antioxidant activity and content of dietary fibre. However, inner scales could be an interesting source of fructans and alk(en)yl cystein sulphoxides. In addition, discarded onions (cvs Recas and Figueres) could be used as a good source of dietary fibre, and cv Recas also as a source of phenolics compounds. PMID- 21318306 TI - Prosthetic joint infection after total hip or knee arthroplasty in rheumatoid arthritis patients treated with nonbiologic and biologic disease-modifying antirheumatic drugs. AB - The aim of this study was to identify risk factors for acute surgical-site infection (SSI) after total joint arthroplasty in rheumatoid arthritis (RA) patients treated with nonbiologic and biologic disease-modifying antirheumatic drugs (DMARDs). We performed a retrospective study of all consecutive total hip (THA) and total knee (TKA) arthroplasties performed during a 5-year period (THA 81; TKA 339). Multivariate logistic regression analysis was performed to identify SSI risk factors. Of the patients undergoing THA or TKA, 24 cases (5.7%) developed a superficial incisional SSI requiring the use of antibiotics and three cases (0.7%) developed an organ/space SSI necessitating surgical treatment to remove the artificial joint prosthesis. Multivariate logistic regression analysis revealed that the use of biologic DMARDs [P = 0.0007, odds ratio (OR) = 5.69; 95% confidence interval (CI) 2.07-15.61] and longer RA duration (P = 0.0003, OR = 1.09; 95% CI 1.04-1.14) were the only significant risk factors for acute SSI. Furthermore, an analysis that individually evaluated major agents (n > 10) adjusted for disease duration indicated that tumor necrosis factor alpha blockers increased the risk of SSI (infliximab P = 0.001, OR = 9.80, 95% CI 2.41-39.82; etanercept P = 0.0003, OR = 9.16, 95% CI 2.77-30.25). We found that the use of infliximab or etanercept and longer disease duration were associated with an increased risk of acute SSI in RA patients. Prospective studies are thus needed to determine the safety of biologic DMARDs in the perioperative period. PMID- 21318307 TI - Histopathological analysis of cerebral hemorrhage in systemic lupus erythematosus complicated with antiphospholipid syndrome. AB - A 53-year-old woman was admitted due to akinetic mutism and fever. On admission, brain computed tomography (CT) scan revealed a large hemorrhagic lesion in the left anterior lobe that required surgical operation for total removal. Her neuropsychiatric manifestation was not attenuated after the operation, and was gradually ameliorated by high doses of corticosteroid thereafter, suggesting a diagnosis of lupus psychosis. Histopathological examination revealed a necrotizing vasculature, sometimes with a disrupted lamina elastica interna, completely filled with thrombi and infiltrated with inflammatory cells and their debris. It is therefore suggested that the large frontal lobe hematoma in our patient was induced by thrombosis and arteritis in the subarachnoid space. PMID- 21318308 TI - Emergence of novel reassortant H3N2 influenza viruses among ducks in China. AB - During 2006-2009 influenza virus surveillance, three H3N2 viruses were isolated from ducks in Central China. Sequence and phylogenetic analyses revealed that most segments of these three isolates had high identity with H3N2 swine isolates in South China. However, for M, the three viruses, along with H1N1 swine isolates of North America, formed a cluster; for PB2, two of these isolates fell into the cluster of the H5N1 duck isolates, indicating a reassortment among H3N2, H1N1 swine viruses and H5N1 avian virus. The emergence of H3N2 virus with incorporation of an H5N1 virus gene raises new concerns about the generation of novel viruses that could affect humans. PMID- 21318310 TI - Smurf2 alters BPV1 trafficking and decreases infection. AB - Papillomavirus capsid proteins L1 and L2 mediate virion attachment, internalization and trafficking. In our studies of the capsid proteins, we identified an interaction of L2 with the E3 ligase Smad ubiquitin regulatory factor 2 (Smurf2). Smurf2 expression alters BPV1 virion trafficking and L2 protein levels. Using BPV1 pseudovirions (PSVs) containing a GFP or DSRed transgene encapsidated by L1 and L2 proteins, our data showed that although only BPV1 L2 interacts with Smurf2, both L1 and L2 levels decrease in a Smurf2- and ubiquitin-dependent manner. The decrease in L2 protein levels corresponded to a decrease in infection (i.e., loss of GFP or DSRed expression). We propose that Smurf2 regulates L2 protein cellular localization and therefore alters L2 protein levels. This change in trafficking and protein level decreases nuclear delivery and transcription of encapsidated pseudoviral transgenes and thus decreases BPV1 infection levels. PMID- 21318311 TI - Genomic sequence of temperate phage TEM126 isolated from wild type S. aureus. AB - Bacteriophage TEM126, a newly isolated temperate phage from a mitomycin-C-induced lysate of wild-type Staphylococcus aureus isolated from food, has an isometric head, a noncontractile tail, and a double-stranded DNA genome with a length of 33,540 bp and a G+C content of 33.94%. Bioinformatics analysis of the phage genome revealed 44 putative open reading frames (ORFs). Predicted protein products of the ORFs were determined and described. Temperate phage TEM126 can be classified as a member of the family Siphoviridae by morphology and genome structure. Temperate phage TEM126 showed 84% similarity with Staphylococcus phage phiNM1. To our knowledge, this is the first report of genomic sequencing and characterization of temperate phage TEM126 from a wild-type S. aureus isolated from foods in Korea. PMID- 21318309 TI - Ethnogeographical structure of hepatitis B virus genotype distribution in Indonesia and discovery of a new subgenotype, B9. AB - The distribution of hepatitis B virus (HBV) in the populations of island Southeast Asia is of medical and anthropological interest and is associated with an unusually high genetic diversity. This study examined the association of this HBV genetic diversity with the ethnogeography of the populations of the Indonesian archipelago. Whole genome analysis of 21 HBV isolates from East Nusa Tenggara and Papua revealed two recently reported HBV/B subgenotypes unique to the former, B7 (7 isolates) and B8 (5 isolates), and uncovered a further novel subgenotype designated B9 (4 isolates). Further isolates were collected from 419 individuals with defined ethnic backgrounds representing 40 populations. HBV/B was predominant in Austronesian-language-speaking populations, whereas HBV/C was the major genotype in Papua and Papua-influenced populations of Moluccas; HBV/B3 was the predominant subgenotype in the western half of the archipelago (speakers of the Western Malayo-Polynesian [WMP] branch of Austronesian languages), whereas B7, B8 and B9 were specific to Nusa Tenggara (Central Malayo-Polynesian (CMP)). The result provides the first direct evidence that the distribution of HBV genotypes/subgenotypes in the Indonesian archipelago is related to the ethnic origin of its populations and suggests that the HBV distribution is associated with the ancient migratory events in the peopling of the archipelago. PMID- 21318312 TI - Post-dive ultrasound detection of gas in the liver of rats and scuba divers. AB - In a previous study, we obtained histologic documentation of liver gas embolism in the rat model of rapid decompression. The aim of the study was to assess in the same model occurrence and time course of liver embolism using 2-D ultrasound imaging, and to explore by this means putative liver gas embolism in recreational scuba divers. Following 42 min compression at 7 ATA breathing air and 12 min decompression, eight surviving female rats were anesthetized and the liver imaged by ultrasound at 20 min intervals up to 120 min. A significant enhancement of echo signal was recorded from 60 to 120 min as compared to earlier post decompression times. Enzymatic markers of liver damage (AST, ALT, and GGT) increased significantly at 24 h upon decompression. Twelve healthy experienced divers were studied basally and at 15-min intervals up to 60 min following a 30 min scuba dive at 30 msw depth. At 30 min upon surfacing echo images showed significant signal enhancement that progressed and reached plateau at 45 and 60 min. Total bilirubin at 24 h increased significantly (p = 0.02) with respect to basal values although within the reference range. In conclusion, 2-D ultrasound liver imaging allowed detection of gas embolism in the rat and defined the time course of gas accumulation. Its application to scuba divers revealed liver gas accumulation in all subjects in the absence of clear-cut evidence of liver damage or of any symptom. The clinical significance of our findings remains to be investigated. PMID- 21318314 TI - Determinant of leg stiffness during hopping is frequency-dependent. AB - Identifying the major determinant of leg stiffness during hopping would be helpful in the development of more effective training methods. Despite the fact that overall leg stiffness depends on a combination of the joint stiffness, it is unclear how the major determinants of leg stiffness are influenced by hopping frequency. The purpose of this study was to identify the major determinant of leg stiffness over a wide range of hopping frequencies. Fourteen well-trained male athletes performed in a place hopping on two legs, at three frequencies (1.5, 2.2 and 3.0 Hz). We determined leg and joint stiffness of the hip, knee and ankle from kinetic and kinematic data. Multiple linear regression analysis revealed that knee stiffness could explain more of the variance of leg stiffness than could ankle or hip stiffness at 1.5 Hz hopping. Further, only ankle stiffness was significantly correlated with leg stiffness at both 2.2 and 3.0 Hz, and the standardized regression coefficient of ankle stiffness was higher than that of knee and hip stiffness. The results of the present study suggest that the major determinant of leg stiffness during hopping switches from knee stiffness to ankle stiffness when the hopping frequency is increased. PMID- 21318313 TI - Effect of isobaric breathing gas shifts from air to heliox mixtures on resolution of air bubbles in lipid and aqueous tissues of recompressed rats. AB - Deep tissue isobaric counterdiffusion that may cause unwanted bubble formation or transient bubble growth has been referred to in theoretical models and demonstrated by intravascular gas formation in animals, when changing inert breathing gas from nitrogen to helium after hyperbaric air breathing. We visually followed the in vivo resolution of extravascular air bubbles injected at 101 kPa into nitrogen supersaturated rat tissues: adipose, spinal white matter, skeletal muscle or tail tendon. Bubbles were observed during isobaric breathing-gas shifts from air to normoxic (80:20) heliox mixture while at 285 kPa or following immediate recompression to either 285 or 405 kPa, breathing 80:20 and 50:50 heliox mixtures. During the isobaric shifts, some bubbles in adipose tissue grew marginally for 10-30 min, subsequently they shrank and disappeared at a rate similar to or faster than during air breathing. No such bubble growth was observed in spinal white matter, skeletal muscle or tendon. In spinal white matter, an immediate breathing gas shift after the hyperbaric air exposure from air to both (80:20) and (50:50) heliox, coincident with recompression to either 285 or 405 kPa, caused consistent shrinkage of all air bubbles, until they disappeared from view. Deep tissue isobaric counterdiffusion may cause some air bubbles to grow transiently in adipose tissue. The effect is marginal and of no clinical consequence. Bubble disappearance rate is faster with heliox breathing mixtures as compared to air. We see no reason for reservations in the use of heliox breathing during treatment of air-diving-induced decompression sickness. PMID- 21318316 TI - Introduction to the mini-review series on bioenergetics and biomembranes authored by participants of the 39th Annual Meeting of the Brazilian Society for Biochemistry and Molecular Biology. PMID- 21318315 TI - Local heat application to the leg reduces muscle sympathetic nerve activity in human. AB - The study was designed to assess the effects of local heat (LH) application on postganglionic muscle sympathetic nerve activity (MSNA) measured by microneurography in healthy men. In the first protocol, MSNA of the left peroneal nerve, blood pressure (BP), heart rate (HR), and skin temperature of the shin (TSK) were recorded in nine men. In the second protocol, leg blood flow (LBF) was measured in the same subjects by strain-gauge plethysmography. In both protocols, after 10 min of rest in the supine position, a heated hydrocollator pack was applied to the shin and anterior foot for 15 min and recovery was monitored over a period of 20 min. TSK gradually increased from 31.7 +/- 0.1 to 41.9 +/- 0.5 degrees C (mean +/- SEM) during LH. No subject complained of pain, and BP and HR remained constant. The MSNA burst rate (16.1 +/- 2.1 beats/min) during the control period decreased significantly (P < 0.05) to 72.0 +/- 2.3% during LH. Total MSNA also decreased to 59.2 +/- 2.6% (P < 0.05) during LH, but both immediately returned to baseline at recovery. In contrast, LBF in the left leg significantly and immediately increased (P < 0.05) after LH application and remained significantly elevated until the end of the recovery period. These results suggest that: (1) LH application significantly attenuates MSNA without any changes in HR and BP. (2) Other factors in addition to MSNA seem to control regional blood flow in the lower extremity during LH. PMID- 21318317 TI - Comparison of PV signal quality using a novel circular mapping and ablation catheter versus a standard circular mapping catheter. AB - PURPOSE: Recently, new catheter technologies have been developed for atrial fibrillation (AF) ablation. We investigate the diagnostic accuracy of a circular mapping and pulmonary vein ablation catheter (PVAC) compared with a standard circular mapping catheter (Orbiter) and the influence of filter settings on signal quality. METHODS: After reconstruction of the left atrium by three dimensional atriography, baseline PV potentials (PVP) were recorded consecutively with PVAC and Orbiter in 20 patients with paroxysmal AF. PVPs were compared and attributed to predefined anatomical PV segments. Ablation was performed in 80 PVs using the PVAC. If isolation of the PVs was assumed, signal assessment of each PV was repeated with the Orbiter. If residual PV potentials could be uncovered, different filter settings were tested to improve mapping quality of the PVAC. Ablation was continued until complete PV isolation (PVI) was confirmed with the Orbiter. RESULTS: Baseline mapping demonstrated a good correlation between the Orbiter and PVAC. Mapping accuracy using the PVAC for mapping and ablation was 94% (74 of 79 PVs). Additional mapping with the Orbiter improved the PV isolation rate to 99%. Adjustment of filter settings failed to improve quality of the PV signals compared with standard filter settings. CONCLUSIONS: Using the PVAC as a stand-alone strategy for mapping and ablation, one should be aware that in some cases, different signal morphology mimics PVI isolation. Adjustment of filter settings failed to improve signal quality. The use of an additional mapping catheter is recommended to become familiar with the particular signal morphology during the first PVAC cases or whenever there is a doubt about successful isolation of the pulmonary veins. PMID- 21318318 TI - Hydroxyurea for recurrent surgery and radiation refractory meningioma: a retrospective case series. AB - Hydroxyurea (HU), an orally administered chemotherapy, has become the de facto standard therapeutic agent in patients with surgically and radiation refractory meningiomas based on a limited literature. A retrospective case series of 60 patients with recurrent WHO grade 1 meningioma treated with HU following progression after surgery and radiotherapy was conducted with primary study objective progression free survival (PFS) at 6- and 12-months. Sixty patients (45 women; 15 men: median age 61.5 years, range 26-88) with recurrent meningioma were treated with HU (1000 mg/m(2)/day orally divided twice per day; one cycle operationally defined as 4-weeks of daily HU). All patients had progressed radiographically after prior therapy with surgery (60/60) and radiotherapy (external beam radiotherapy 60/60; stereotactic radiotherapy 53/60). No patient received prior chemotherapy or targeted therapy before instituting HU. Patients received 1-12 cycles (median 2.0) of HU with modest toxicity (10% grade 3 + anemia or fatigue). There were no radiographic responses, 35% of patients had stable disease and 65% manifested progressive disease. Duration of stable disease ranged from 3 to 12 months (median 4.0 months). The overall PFS was 10% (median PFS 2.0 months). The majority of patients (80%) following progression on HU were subsequently treated on an investigational trial. In this retrospective case series, HU though generally well tolerated and convenient, appeared to have very limited activity which raises questions of what constitutes effective salvage therapy and indicates an unmet need for alternative treatments for recurrent meningiomas. PMID- 21318319 TI - Noninvasive monitoring of tumor growth in a rat glioma model: comparison between neurological assessment and animal imaging. AB - Malignant gliomas are the most common primary tumors that arise from glial cells and are characterized by extensive invasiveness and rapid progression. Limitation of the current therapeutic regimen for malignant glioma warrants the development of new therapies strategies. In order to investigate new methods of therapy, establishment of a reliable animal model is essential both in studying the tumor biology and trialing a new therapeutic strategy. Noninvasive monitoring of tumor growth in living animals may be important for new therapeutic strategy development. The development of animal imaging techniques has improved our ability to investigate animal models of malignant gliomas. In this study, both neurological examination and positron emission tomography (PET) with (18)F-FDG were used to monitor tumor growth in a rat glioma model. Visual limb placing, tactile limb placing, and beam walking tests were used to assess neurological deficits. Neurobehavioral alterations were correlated with PET findings and histopathological data. Seven days after surgery, the tumor was clearly visible on PET images. Results of behavioral tests correlated well with imaging data and histopathological findings. PET is feasible to detect experimental rat gliomas in their early stage of development. In contrast, standard neurological assessment is useful for monitoring tumor growth during the course of the disease. PMID- 21318321 TI - Framing ethical acceptability: a problem with nuclear waste in Canada. AB - Ethical frameworks are often used in professional fields as a means of providing explicit ethical guidance for individuals and institutions when confronted with ethically important decisions. The notion of an ethical framework has received little critical attention, however, and the concept subsequently lends itself easily to misuse and ambiguous application. This is the case with the 'ethical framework' offered by Canada's Nuclear Waste Management Organization (NWMO), the crown-corporation which owns and is responsible for the long-term management of Canada's high-level nuclear fuel waste. It makes a very specific claim, namely that it is managing Canada's long-lived radioactive nuclear fuel waste in an ethically responsible manner. According to this organization, what it means to behave in an ethically responsible manner is to act and develop policy in accordance with its ethical framework. What, then, is its ethical framework, and can it be satisfied? In this paper I will show that the NWMO's ethical and social framework is deeply flawed in two respects: (a) it fails to meet the minimum requirements of a code of ethic or ethical framework by offering only questions, and no principles or rules of conduct; and (b) if posed as principles or rules of conduct, some of its questions are unsatisfiable. In particular, I will show that one of its claims, namely that it seek informed consent from individuals exposed to risk of harm from nuclear waste, cannot be satisfied as formulated. The result is that the NWMO's ethical framework is not, at present, ethically acceptable. PMID- 21318320 TI - Competing for patients: an ethical framework for recruiting patients with brain tumors into clinical trials. AB - With more rapid advances in potential treatments for brain tumours, the number of clinical trials for brain tumour patients is rising. In the context of the challenges of recruitment and enrollment of patients with brain tumors, the dichotomy between the paucity of subjects and abundance of clinical trials creates a unique ethical dilemma, whereby a single patient may be eligible for several studies. Here, we identify and present three approaches for recruiting and enrolling patients who may be eligible for several trials. The ethical implications of the full disclosure, paternalistic, and random approaches are discussed. The full disclosure approach presents information to patients regarding all ongoing concurrent trials, allowing them to make an informed decision, while the paternalistic approach allows the healthcare providers to select the trial for which they believe the patient is most suitable. These introduce the biases into circumstances where equipoise is necessary and risk selection bias in study design. The random approach randomly allocates patients to each trial, which may erode patient autonomy and decrease trial enrollment. Brain tumor patients comprise a vulnerable population and it remains incumbent on healthcare providers to maintain the highest ethical standards when approaching them for clinical research. Changes in clinical trial design are required to mitigate the conflicts created by competition for patients. PMID- 21318322 TI - It's about scientific secrecy, dummy: a better equilibrium among genomics patenting, scientific research and health care. AB - This paper offers a different pragmatic and patent-based approach to concerns regarding the negative effects of genetic-based patenting on advancing scientific research and providing adequate and accessible health care services. At the basis of this approach lies an explication of a mandatory provisional patented paper procedure (PPPA), designed for genetic-based patents and administered by leading scientific journals in the field, while officially acknowledged by the USPTO, and subsequently by other patent offices as well. It is argued that the uniqueness of PPPAs lies in subsequently mitigating the negative ramifications of genetic patents on scientific research and genetic-based health care services, while basing such mitigation on a patents' advocate viewpoint that neither discards the patent system nor jeopardizes its integrity. PMID- 21318323 TI - Publication ethics from the perspective of PhD students of health sciences: a limited experience. AB - Publication ethics, an important subtopic of science ethics, deals with determination of the misconducts of science in performing research or in the dissemination of ideas, data and products. Science, the main features of which are secure, reliable and ethically obtained data, plays a major role in shaping the society. As long as science maintains its quality by being based on reliable and ethically obtained data, it will be possible to maintain its role in shaping the society. This article is devoted to the presentation of opinions of PhD candidate students in health sciences in Ankara concerning publication ethics. The data obtained from 143 PhD students from the fields of medicine, dentistry, pharmacy and veterinary reveal limited but unique experiences. It also shows that plagiarism is one of the worst issues in the publication ethics from the perspective of these young academics. PMID- 21318324 TI - ABET Criterion 3.f: how much curriculum content is enough? AB - Even after multiple cycles of ABET accreditation, many engineering programs are unsure of how much curriculum content is needed to meet the requirements of ABET's Criterion 3.f (an understanding of professional and ethical responsibility). This study represents the first scholarly attempt to assess the impact of curriculum reform following the introduction of ABET Criterion 3.f. This study sought to determine how much professional and ethical responsibility curriculum content was used between 1995 and 2005, as well as how, when, why, and to what effect changes in the amount of content occurred. Subsequently, the study sought to evaluate if different amounts of curriculum content generated differing student outcomes. The amount of curriculum content used by each of the participating programs was identified during semi-structured interviews with program administrators and a review of ABET Self-Study documents. Quantitative methods were applied to determine if a relationship existed between the curriculum content and performance on a nationally administered, engineering specific standardized examination. The findings indicate a statistical relationship, but a lack of structure between the amount of required content in the curriculum and performance on the examination. Additional findings were also generated regarding the way that programs interpret the Criterion 3.f feedback generated during accreditation visits. The primary impact of this study is that it dispels the myth that more courses or course time on professionalism and ethics will necessarily lead to positive engineering education outcomes. Much of the impetus to add more curriculum content results from a lack of conclusive feedback during ABET accreditation visits. PMID- 21318325 TI - A plea for judgment. AB - Judgment is central to engineering, medicine, the sciences and many other practical activities. For example, one who otherwise knows what engineers know but lacks "engineering judgment" may be an expert of sorts, a handy resource much like a reference book or database, but cannot be a competent engineer. Though often overlooked or at least passed over in silence, the central place of judgment in engineering, the sciences, and the like should be obvious once pointed out. It is important here because it helps to explain where ethics fits into these disciplines. There is no good engineering, no good science, and so on without good judgment and no good judgment in these disciplines without ethics. Doing even a minimally decent job of teaching one of these disciplines necessarily includes teaching its ethics; teaching the ethics is teaching the discipline (or at least a large part of it). PMID- 21318326 TI - Influenza surveillance using data from a telemedicine centre. AB - OBJECTIVES: This study aimed at investigating whether data from medical teleconsultations may contribute to influenza surveillance. METHODS: International Classification of Primary Care 2nd Edition (ICPC-2) codes were used to analyse the proportion of teleconsultations due to influenza-related symptoms. Results were compared with the weekly Swiss Sentinel reports. RESULTS: When using the ICPC-2 code for fever we could reproduce the seasonal influenza peaks of the winter seasons 07/08, 08/09 and 09/10 as depicted by the Sentinel data. For the pandemic influenza 09/10, we detected a much higher first peak in summer 2009 which correlated with a potential underreporting in the Sentinel system. CONCLUSIONS: ICPC-2 data from medical teleconsultations allows influenza surveillance in real time and correlates very well with the Swiss Sentinel system. PMID- 21318327 TI - Determinants of body weight status in Malaysia: an ethnic comparison. AB - OBJECTIVE: To investigate the roles of sociodemographic and health lifestyle factors in affecting body mass index (BMI) across ethnic groups in Malaysia. METHODS: Data are obtained from 2,436 observations from the Malaysia Non Communicable Disease Surveillance-1. The multi-ethnic sample is segmented into Malay, Chinese, and Indian/other ethnicities. Ordered probit analysis is conducted and marginal effects of sociodemographic and health lifestyle variables on BMI calculated. RESULTS: Malays between 41 and 58 years are more likely to be overweight or obese than their 31-40 years counterparts, while the opposite is true among Chinese. Retirees of Chinese and Indian/other ethnicities are less likely to be obese and more likely to have normal BMI than those between 31 and 40 years. Primary educated Chinese are more likely to be overweight or obese, while tertiary-educated Malays are less likely to suffer from similar weight issues as compared to those with only junior high school education. Affluent Malays and Chinese are more likely to be overweight than their low-middle income cohorts. Family illness history is likely to cause overweightness or obesity, irrespective of ethnicity. Malay cigarette smokers have lower overweight and obesity probabilities than non-cigarette smokers. CONCLUSIONS: There exists a need for flexible policies to address cross-ethnic differences in the sociodemographic and health-lifestyle covariates of BMI. PMID- 21318328 TI - Automated identification of exudates and optic disc based on inverse surface thresholding. AB - This paper presents a new approach to detect exudates and optic disc from color fundus images based on inverse surface thresholding. The strategy involves the applications of fuzzy c-means clustering, edge detection, otsu thresholding and inverse surface thresholding. The main advantage of the proposed approach is that it does not depend on manually selected parameters that are normally chosen to suit the tested databases. When applied to two sets of databases the proposed method outperforms a method based on watershed segmentation. PMID- 21318329 TI - MGMT immunoexpression in adamantinomatous craniopharyngiomas. AB - At present, no effective medical treatment exists for recurrent and aggressive craniopharyngiomas that are resistant to conventional therapies, including surgery and adjuvant radiotherapy. Temozolomide is an alkylating chemotherapeutic agent used routinely in the management of high grade gliomas. The response to temozolomide is suggested to be dependent on the tumoral expression of O-6 methylguanine DNA methyltransferase (MGMT). Evidence supports that low MGMT immunoexpression correlates with positive response to temozolomide. Therefore, we aimed to assess MGMT immunoexpression in adamantinomatous craniopharyngiomas, in an effort to predict the likelihood of response to temozolomide. The MGMT immunostaining was performed on 23 adamantinomatous craniofaryngiomas operated at the Sisli Etfal Training and Research Hospital and identified by histological analysis. Paraffin embedded tissue sections were immunostained for MGMT and were evaluated semi-quantitatively. Of the 23 cases evaluated, 22 (96%) demonstrated negative (<10%) and 1 (4%) demonstrated low (10%) MGMT immunoexpression. Data from this study suggest a high proportion of adamantinomatous craniopharyngiomas exhibit negative/low MGMT immunoreactivity and could be treated with temozolomide, if conventional therapy fails. PMID- 21318331 TI - Sequential stages in the age-dependent gradual formation and accumulation of tubular aggregates in fast twitch muscle fibers: SERCA and calsequestrin involvement. AB - Tubular aggregates (TAs), ordered arrays of elongated sarcoplasmic reticulum (SR) tubules, are present in skeletal muscle from patients with myopathies and are also experimentally induced by extreme anoxia. In wild-type mice TAs develop in a clear age-, sex- (male), and fiber type- (fast twitch) dependence. However, the events preceding the appearance of TAs have not been explored. We investigated the sequential stages leading to the initial appearance and maturation of TAs in EDL from male mice. TAs' formation requires two temporally distinct steps that operate via different mechanisms. Initially (before 1 year of age), the SR Ca(2+) binding protein calsequestrin (CASQ) accumulates specifically at the I band level causing swelling of free SR cisternae. In the second stage, the enlarged SR sacs at the I band level extend into multiple, longitudinally oriented tubules with a full complement of sarco(endo)plasmic reticulum Ca(2+) ATPases (SERCA) in the membrane and CASQ in the lumen. Tubules gradually acquire a regular cylindrical shape and uniform size apparently in concert with partial crystallization of SERCA. Multiple, small TAs associate to form fewer mature TAs of very large size. Interestingly, in fibers from CASQ1-knockout mice abnormal aggregates of SR tubules have different conformation and never develop into ordered aggregates of straight cylinders, possibly due to lack of CASQ accumulation. We conclude that TAs do not arise abruptly but are the final result of a gradually changing SR architecture and we suggest that the crystalline ATPase within the aggregates may be inactive. PMID- 21318330 TI - Aging affects human B cell responses. AB - Aging represents a complex remodeling in which both innate and adaptive immunities deteriorate. Age-related changes in humoral immunity are responsible for the reduced vaccine responses observed in elderly individuals. Although T cell alterations play a significant role in age-related humoral immune changes, alterations in B cells also occur. We here provide an overview of age-related changes in B cell markers and functions. Our studies have shown that intrinsic changes in B cells with age contribute to reduced antibody responses such as those to the influenza vaccine. PMID- 21318332 TI - Mechanism of Ang II involvement in activation of NF-kappaB through phosphorylation of p65 during aging. AB - Angiotensin II (Ang II), a major effector of the renin-angiotensin system, is now recognized as a pro-inflammatory mediator. This Ang II signaling, which causes transcription of pro-inflammatory genes, is regulated through nuclear factor kappaB (NF-kappaB). At present, the molecular mechanisms underlying the effect of aging on Ang II signaling and NF-kappaB activation are not fully understood. The purpose of this study was to document altered molecular events involved in age related changes in Ang II signaling and NF-kappaB activation. Experimentations were carried out using kidney tissues from Fischer 344 rats at 6, 12, 18, and 24 months of age, and the rat endothelial cell line, YPEN-1 for the detailed molecular work. Results show that increases in Ang II and Ang II type 1 receptor during aging were accompanied by the generation of reactive species. Increased Ang II activated NF-kappaB by phosphorylating IkappaBalpha and p65. Increased phosphorylation of p65 at Ser 536 was mediated by the enhanced phosphorylation of IkappaB kinase alphabeta, while phosphorylation site Ser 276 of p65 was mediated by upregulated mitogen-activated and stress-activated protein kinase-1. These altered molecular events in aged animals were partly verified by experiments using YPEN-1 cells. Collectively, our findings provide molecular insights into the pro-inflammatory actions of Ang II, actions that influence the phosphorylation of p65-mediated NF-kappaB activation during aging. Our study demonstrates the age-related pleiotropic nature of the physiologically important Ang II can change into a deleterious culprit that contributes to an increased incidence of many chronic diseases such as atherosclerosis, diabetes, and dementia. PMID- 21318333 TI - Resveratrol, but not dihydroresveratrol, induces premature senescence in primary human fibroblasts. AB - Resveratrol, trans-3,5,4'-trihydroxystilbene, is a polyphenolic compound which has been reported to mimic the gene expression patterns seen in whole animals undergoing dietary restriction. The mechanism of action of resveratrol remains poorly understood, but modulation of both cellular proliferation and apoptosis has been proposed as important routes by which the molecule may exert its effects. This study reports the effects of both resveratrol and dihydroresveratrol (a primary in vivo metabolite) on the proliferative capacity of human primary fibroblasts. No generalised reduction in the growth fraction was observed when fibroblasts derived from three different tissues were treated with resveratrol at concentrations of 10 MUm or less. However, concentrations above 25 MUm produced a dose-dependent reduction in proliferation. This loss of the growth fraction was paralleled by an increase in the senescent fraction as determined by staining for senescence associated beta galactosidase and dose recovery studies conducted over a 7-day period. Entry into senescence in response to treatment with resveratrol could be blocked by a 30-min preincubation with the p38 MAP kinase inhibitor SB203580. No effects on proliferation were observed when cells were treated with dihydroresveratrol at concentrations of up to 100 MUm. PMID- 21318334 TI - Identification of a novel CDKL5 exon and pathogenic mutations in patients with severe mental retardation, early-onset seizures and Rett-like features. PMID- 21318335 TI - Use of intravitreal triamcinolone and bevacizumab in Coats' disease with central macular edema. AB - BACKGROUND: Intravitreal application of triamcinolone and bevacizumab in Coats' disease with macular edema to improve visual outcome. METHODS: Testing of best corrected visual acuity (BCVA), ophthalmoscopy, optical coherence tomography, fluorescein angiography, 30 degrees perimetry, and full-field electroretinography were performed at initial and follow-up visits. Medical treatment consisted of intravitreal injection of 1.25 mg bevazicumab and 1.25 mg triamcinolone, followed by intravitreal injections of 1.25 mg bevazicumab at weeks 4 and 10. Follow-up was 87 weeks. RESULTS: Perimetric results, including a temporal absolute scotoma and reduced electroretinographic amplitudes (photopic and scotopic conditions), did not significantly change during the follow-up, but foveal retinal thickness decreased from 505 MUm to 212 MUm, and BCVA increased from 0.3 at baseline to 1.25 and remained stable during subsequent follow-up. CONCLUSIONS: Combined intravitreal treatment with bevacizumab and triamcinolone resulted in significant decrease of central retinal thickness and improved visual acuity in this case report. Severe local or systemic side-effects were not observed. PMID- 21318336 TI - Anticonvulsant and antioxidant actions of trimetazidine in pentylenetetrazole induced kindling model in mice. AB - The present study was carried out to investigate the effect of trimetazidine on the course of pentylenetetrazole (PTZ)-induced chemical kindling and oxidative stress markers in PTZ-kindled mice. Kindling was induced by repeated injections of a subconvulsive dose of PTZ (30 mg/kg, i.p.) on alternate days for 5 weeks or until stage 4 of the seizure score was evoked on three consecutive administrations. Trimetazidine was administered daily in three doses (5, 10 and 20 mg/kg) per orally (p.o.) along with alternate-day PTZ. Following PTZ kindling, oxidative stress parameters, i.e. levels of malondialdehyde (MDA) and reduced glutathione (GSH), were assessed in isolated homogenized whole brain tissue. The results showed that PTZ treatment progressively increased the seizure score in control mice. Biochemical analysis revealed a significant increase in MDA levels and decreased GSH levels in the brain homogenate of PTZ-kindled mice. Daily treatment with trimetazidine in doses of 10 and 20 mg/kg significantly decreased the PTZ-induced seizure score. However, a low dose of trimetazidine (5 mg/kg) failed to improve the seizure score. Pretreatment of trimetazidine in all doses showed an ameliorating effect on biochemical alteration induced by PTZ treatment. The results of the present study indicate the potential anticonvulsant activity of trimetazidine against PTZ-induced kindling in mice. PMID- 21318338 TI - Pathogenesis of dermatomyositis: role of cytokines and interferon. AB - Dermatomyositis is a systemic autoimmune disease that primarily affects skeletal muscle, skin, and the lungs. Dermatomyositis is characterized by autoantibodies, tissue inflammation, parenchymal cell damage and death, and vasculopathy. This review focuses on recent advances regarding the role of cytokines and interferon in the pathogenesis of the disease. Evidence for the role of a particular cytokine is based on data showing dysregulated levels in tissue and/or blood; correlation with histopathologic or clinical markers of disease activity; and, rarely, clinical efficacy of targeted cytokine inhibitors. Many of the recent advances pertain to elucidation of the role of interferons in both muscle and skin disease in dermatomyositis. Although a great deal of progress has been made regarding the role of interferon in the disease, many critical questions remain unanswered. PMID- 21318339 TI - Phylogenetic structure predicts capitular damage to Asteraceae better than origin or phylogenetic distance to natives. AB - Exotic species more closely related to native species may be more susceptible to attack by native natural enemies, if host use is phylogenetically conserved. Where this is the case, the use of phylogenies that include co-occurring native and exotic species may help to explain interspecific variation in damage. In this study, we measured damage caused by pre-dispersal seed predators to common native and exotic plants in the family Asteraceae. Damage was then mapped onto a community phylogeny of this family. We tested the predictions that damage is phylogenetically structured, that exotic plants experience lower damage than native species after controlling for this structure, and that phylogenetically novel exotic species would experience lower damage. Consistent with our first prediction, 63% of the variability in damage was phylogenetically structured. When this structure was accounted for, exotic plants experienced significantly lower damage than native plants, but species origin only accounted for 3% of the variability of capitular damage. Finally, there was no support for the phylogenetic novelty prediction. These results suggest that interactions between exotic plants and their seed predators may be strongly influenced by their phylogenetic position, but not by their relationship to locally co-occurring native species. In addition, the influence of a species' origin on the damage it experiences often may be small relative to phylogenetically conserved traits. PMID- 21318337 TI - Adrenergic control of cardiac gap junction function and expression. AB - Electrical intercellular communication in the heart allows the propagation of an action potential from cell to cell. This is realized by low-ohmic cell-to-cell channels, the gap junction channels, which are dodecameric proteins consisting of two hexameric hemichannels. Each of the neighbouring cell provides one hemichannel, which consists of six connexins. In the heart, the connexin isoforms Cx43, Cx40 and Cx45 are present with Cx43 being the most abundant isoform. This intercellular communication is regulated acutely by control of the gap junction conductance and chronically by control of the connexin expression. The short half life time of Cx43 indicates the permanent adaptation of cell communication to the actual requirements. beta-Adrenoceptor stimulation enhances Cx40- but reduces Cx45-conductance, while Cx43 channels in most species do not seem to be acutely affected by beta-adrenoceptor signalling. In contrast, chronic exposure to beta adrenergic stimulants activates protein kinase A and the mitogenic-activated protein kinase cascade (including protein 38 (p38), mitogenic-activated protein kinase kinase 1, extracellular signal-regulated kinase (ERK)1/2 and c-JUN NH(2) terminal kinase (JNK)), the calcineurin pathway, translocation of activator protein 1 (AP1), CRE-binding protein and nuclear factor of activated T cells, finally leading to enhanced Cx43-mRNA and Cx43-protein expression together with Cx43 phosphorylation, but does not affect Cx40. alpha-Adrenoceptors also play a role in controlling cardiac intercellular communication: alpha-adrenergic stimulation acutely uncouples the cells, while a chronic stimulation enhances Cx43 expression via protein kinase C, p38, ERK1/2, JNK, c-fos and AP1, but does not alter Cx40 expression. While general cardiac protein synthesis, e.g. of beta actin, is controlled via alpha(1A)-adrenoceptors, Cx43 expression is regulated via alpha(1D)-adrenoceptors. However, alpha-adrenoceptor density in the heart varies among species, with high abundance in rat heart and low in human heart. Acute alpha-adrenergic stimulation, e.g. during ischemia, can lead to uncoupling and facilitates re-entrant arrhythmia. Chronic adrenergic upregulation of Cx43 expression seems to be involved in cardiac hypertrophy. In maladaptive hypertrophy, the enhanced Cx43 is increasingly incorporated in the lateral membrane of the cells rather at the cell poles, which may mean a gap junction disarray. This could-together with a mismatch in cell size and coupling contribute to arrhythmogenesis. Thus, cardiac adrenoceptors are directly involved in the control of intercellular electrical communication and thus probably are a critical factor in the maintenance of regular cell-to-cell conduction and of the cardiac electrical networking. They probably are involved in the formation of an arrhythmogenic substrate in certain heart diseases. PMID- 21318340 TI - Quantifying disturbance resistance in an ecologically dominant species: a robust design analysis. AB - Disturbance is now recognized as a key ecosystem process but few studies have examined its indirect effects on individuals in a population or its relationship to ecological dominance in a community. Using an ecologically dominant small mammal population in experimentally burned habitat as a model, I empirically tested the effect of disturbance on survival, abundance and fecundity and investigated whether recently burned habitat is a population sink. I also examined the effect of fire on community diversity, particularly how fire influenced dominance by bushveld gerbils Tatera leucogaster (Peters 1852). Live trapping in the first year post-fire yielded a total of 4,774 captures of 1,076 individual bushveld gerbils in a tropical savanna in southern Africa. The robust design allowed for an investigation of the effects of fire, sex and temporal variation on survival while controlling for potential differences in detection and temporary emigration. Although there were fewer individuals in burned savanna during the first 6 months post-fire, their apparent monthly survival was not significantly lowered compared with the control, with males and females surviving equally well. Fecundity, represented by proportion of females lactating, was unaffected by fire and, overall, recently burned habitat does not appear to be sink habitat. The disturbance resistance exhibited by this species is likely a contributing factor to its ecological dominance in the area, which is subject to relatively frequent fires. Results of this study highlight the need to consider disturbance regimes when evaluating patterns of species richness and evenness in an ecosystem. PMID- 21318341 TI - Impressive results for aldosterone antagonists in mild heart failure. PMID- 21318342 TI - Exercise hemodynamics in valvular heart disease. AB - Exercise hemodynamics play an important role in the evaluation and management of patients with both severe stenotic or regurgitant valve lesions. Exercise testing in patients with valvular heart disease can help to unmask latent symptoms and define the timing of surgical intervention. Additionally, exercise-induced hemodynamics are an important tool to assess prosthetic valve function. This review summarizes both background literature and recent publications that assess the use of exercise hemodynamics in the evaluation and management of valvular heart disease. PMID- 21318343 TI - Assessment of Sarcoptes scabiei viability in vivo by reflectance confocal microscopy. PMID- 21318344 TI - Experience with non-ablative fractional photothermolysis with a dual-mode laser device (1,440/1,320 nm): no considerable clinical effect on hypertrophic/acne scars and facial wrinkles. AB - In the literature, non-ablative fractionated photothermolysis (nFP) is accredited with improvement of wrinkles and scars combined with a reduced downtime. The purpose of this work was to evaluate the impact of a combination laser (1,320/1,440 nm) for nFP on hypertrophic scars, acne scars, and facial wrinkles. Thirty-six patients suffering from hypertrophic scars (n = 7), acne scars (n = 9), and wrinkles (n = 20) were treated using a combination Nd:YAG laser [lambda(em) = 1,320 and 1,440 nm, pulse duration: 3-ms single pulse, fluence: 8.0 9.0 J/cm(2) (1,320 nm); 2.0-2.5 J/cm(2) (1,440 nm)]. The appearance of the treated condition was evaluated in a retrospective study by two blinded investigators based on follow-up photographs and by patient self-assessment. The frequency of side-effects was also assessed. Both patients and blinded observers rated the treatment results for hypertrophic scars and acne scars as slight improvement, and for wrinkles as equal as compared to baseline. No serious side effects were reported. The light device used did not lead to a considerable clinical improvement of hypertrophic scars, acne scars, or wrinkles in this study. PMID- 21318345 TI - Study of different concentric rings inside gallstones with LIBS. AB - Gallstones obtained from patients from the north-east region of India (Assam) were studied using laser-induced breakdown spectroscopy (LIBS) technique. LIBS spectra of the different layers (in cross-section) of the gallstones were recorded in the spectral region 200-900 nm. Several elements, including calcium, magnesium, manganese, copper, silicon, phosphorus, iron, sodium and potassium, were detected in the gallstones. Lighter elements, including carbon, hydrogen, nitrogen and oxygen were also detected, which demonstrates the superiority of the LIBS technique over other existing analytical techniques. The LIBS technique was applied to investigate the evolution of C(2) swan bands and CN violet bands in the LIBS spectra of the gallstones in air and an argon atmosphere. The different layers (dark and light layers) of the gallstones were discriminated on the basis of the presence and intensities of the spectral lines for carbon, hydrogen, nitrogen, oxygen and copper. An attempt was also made to correlate the presence of major and minor elements in the gallstones with the common diet of the population of Assam. PMID- 21318346 TI - The role of the occipital face area in the cortical face perception network. AB - Functional magnetic resonance imaging (fMRI) studies have identified spatially distinct face-selective regions in human cortex. These regions have been linked together to form the components of a cortical network specialized for face perception but the cognitive operations performed in each region are not well understood. In this paper, we review the evidence concerning one of these face selective regions, the occipital face area (OFA), to better understand what cognitive operations it performs in the face perception network. Neuropsychological evidence and transcranial magnetic stimulation (TMS) studies demonstrate the OFA is necessary for accurate face perception. fMRI and TMS studies investigating the functional role of the OFA suggest that it preferentially represents the parts of a face, including the eyes, nose, and mouth and that it does so at an early stage of visual perception. These studies are consistent with the hypothesis that the OFA is the first stage in a hierarchical face perception network in which the OFA represents facial components prior to subsequent processing of increasingly complex facial features in higher face-selective cortical regions. PMID- 21318347 TI - Modality-independent role of the primary auditory cortex in time estimation. AB - It has been argued that both modality-specific and supramodal mechanisms dedicated to time perception underlie the estimation of interval durations. While it is generally assumed that early sensory areas are dedicated to modality specific time estimation, we hypothesized that early sensory areas such as the primary visual cortex or the auditory cortex might be involved in time perception independently of the sensory modality of the input. To test this possibility, we examined whether disruption of the primary visual cortex or the auditory cortex would disrupt time estimation of auditory stimuli and visual stimuli using transcranial magnetic stimulation (TMS). We found that disruption of the auditory cortex impaired not only time estimation of auditory stimuli but also impaired that of visual stimuli to the same degree. This finding suggests a supramodal role of the auditory cortex in time perception. On the other hand, TMS over the primary visual cortex impaired performance only in visual time discrimination. These asymmetric contributions of the auditory and visual cortices in time perception may be explained by a superiority of the auditory cortex in temporal processing. Here, we propose that time is primarily encoded in the auditory system and that visual inputs are automatically encoded into an auditory representation in time discrimination tasks. PMID- 21318348 TI - Effects of muscarinic receptor antagonism in the basolateral amygdala on two-way active avoidance. AB - The aim of the present study was to investigate whether the blockade of muscarinic receptors (mRs) in the basolateral amygdala (BLA), which receives important cholinergic inputs related to avoidance learning, affects the consolidation of two-way active avoidance (TWAA). In Experiment 1, adult male Wistar rats were bilaterally infused with scopolamine (SCOP, 20 MUg/site) or PBS (VEH) in the BLA immediately after a single 30-trial acquisition session. Twenty four hours later, avoidance retention was tested in an identical session. Results indicated that scopolamine in the BLA did not affect TWAA performance measured by the number of avoidance responses. Experiment 2 was conducted to test whether such a negative outcome might be due to the occurrence of overtraining during acquisition, which may indeed have a protective effect against scopolamine induced memory deficits. In this experiment, rats were infused with scopolamine in the BLA immediately after a brief 10-trial acquisition session and tested 24 h later in a 30-trial retention session. The SCOP group showed significantly more avoidances and inter-trial crossings in the retention session than the VEH rats. Together, these results reveal that mRs blockade in the BLA does not disrupt TWAA consolidation and may even enhance avoidance performance when infused after a low number of acquisition trials. Performance factors, such as locomotor activity in the shuttle-box, may account, at least in part, for the facilitative effects of muscarinic antagonism in the BLA. PMID- 21318349 TI - mTOR mediates RhoA-dependent leptin-induced cardiomyocyte hypertrophy. AB - Obesity is associated with increased leptin production which may contribute to cardiac hypertrophy. However, the mechanism of leptin-induced cardiac hypertrophy remains incompletely understood. The Rho family (RhoA, Rac1, and Cdc42) and mammalian target of rapamycin (mTOR) have recently emerged as important regulators of cell growth. We therefore explored the roles and interrelationships of phosphatidylinositol 3-kinase (PI3K), mTOR, and the Rho family in the regulation of actin polymerization and leptin-induced hypertrophy in cultured neonatal rat ventricular myocytes. Five minutes treatment with leptin (3.1 nM) resulted in activation of RhoA and Rac1 (by 330 and 160%, respectively, P < 0.05) which was significantly attenuated by AG-490 (50 MUM) and LY294002 (10 MUM), specific inhibitors of JAK2 and PI3K, respectively. However, Cdc42 activity was unaffected by leptin. The hypertrophic effect of leptin was associated with an increase in phosphorylation of p70(S6K), the major target of mTOR, by 110% (P < 0.05). The specific mTOR inhibitor rapamycin (10 nM) attenuated leptin-induced RhoA and Rac1 activation. Furthermore, the leptin-induced decrease in the G/F actin ratio, a measure of actin polymerization, was blunted by rapamycin. Leptin produced activation of the transcriptional factor GATA4 which was attenuated by the RhoA inhibitor C3, the p38 MAPK inhibitor SB203580 (10 MUM) as well as rapamycin. Our results demonstrate a critical role for PI3K/mTOR/p70(S6K) in leptin-induced RhoA activation resulting in cardiomyocyte hypertrophy associated with GATA4 stimulation. PMID- 21318350 TI - Is the enzyme a powerful reactant of the biochemical reaction? AB - The mainstream explanation of enzyme catalysis relies on the assumption that enzymes can utilize the binding energy. The author suggest that (i) an enzyme with excess free energy first gives a group from its active site into the final place of the bound reactant (substrate) in order to break the first initial chemical bond; (ii) this enzyme accepts a similar group from the second bound reactant (or second group in the case of the single-substrate) into active site and finish the substrate conversion and enzyme regeneration. The detailed mechanisms of the well-studied reactions of peptide bond hydrolysis catalyzed by alpha-chymotrypsin and the glyceraldehyde-3-phosphate interconversion steps in glycolysis are in accordance with the proposed theoretical conclusions. PMID- 21318351 TI - Brain white matter abnormalities in paediatric Gaucher Type I and Type III using diffusion tensor imaging. AB - OBJECTIVE: Biomarkers to monitor neurological dysfunction in Neuronopathic Gaucher disease (NGD) are lacking. Diffusion tensor imaging (DTI) is a technique which allows us to probe the microstructure of the white-matter of the brain, in vivo. The aim of this study was to investigate the value of DTI to visualise and quantify white matter integrity in children with NGD and Type I Gaucher. DESIGN: DTI was performed and fractional anisotropy (FA), mean diffusivity (MD), axial (lambda(axial)) diffusivity and radial (lambda(radial)) diffusivity maps calculated. Tract-based spatial statistics (TBSS) was used to perform a voxel wise statistical analysis of the main white matter structures compared to age-sex matched control groups. SETTING: The study was performed at Great Ormond Street Children's Hospital NHS Trust PATIENTS: Four NGD and three Type I Gaucher paediatric patients were recruited RESULTS: The findings suggest the presence of microstructural white matter changes in NGD patients primarily in the middle cerebellar peduncles compared to an age-sex matched control group. This finding is relevant to the clinical manifestation of ataxia seen in NGD. Diffuse non specific changes were seen in the Type I patients, but without a focal point. CONCLUSIONS: This study is the first to use DTI to examine the Gaucher brain. While the numbers studied are small, the results suggest that DTI may be an attractive surrogate marker of NGD, worthy of further exploration for use in clinical studies. PMID- 21318352 TI - On the future of "omics": lipidomics. AB - Following in the wake of the genomic and proteomic revolutions new fields of "omics" research are emerging. The metabolome provides the natural complement to the genome and proteome, however, the extreme physicochemical diversity of the metabolome leads to a subdivision of metabolites into compounds soluble in aqueous solutions or those soluble in organic solvents. A complete molecular and quantitative investigation of the latter when isolated from tissue, fluid or cells constitutes lipidomics. Like proteomics, lipidomics is a subject which is both technology driven and technology driving, with the primary technologies being mass spectrometry, with or without on-line chromatography and computer assisted data analysis. In this paper we will examine the underlying fundamentals of different lipidomic experimental approaches including the "shotgun" and "top down" global approaches, and the more targeted liquid chromatography - or gas chromatography - mass spectrometry approaches. Application of these approaches to the identification of in-born errors of metabolism will be discussed. PMID- 21318354 TI - Revisiting the DNA C-values of the genome size-standards used in plant flow cytometry to choose the "best primary standards". AB - Flow cytometry (FCM) techniques have enabled characterization of the genome size for various plant species. In order to measure the nuclear genome size of a species, reference standards with well-established DNA content are necessary. However, different 2C-values have been described for the same species used as reference standard. This fact has brought about inaccurate genome measurements, making relevant the establishment of optimal DNA reference standards for plant cytometric analyses. Our work revisited the genome size of Arabidopsis thaliana and other seven plant standards, which were denominated "Dolezel's standard set" and have been widely used in plant DNA measurements. These eight plant standards were reassessed for a comparative measurement of their DNA content values, using each plant species as primary standard in a cascade-like manner, from A. thaliana to Allium cepa. The genome size values obtained here were compared to those reported in the literature by statistical analyses. As a result, Raphanus sativus and Drosophila melanogaster were considered the most inadequate primary standards, whereas A. thaliana, Solanum lycopersicum and Pisum sativum were found to be the most suitable. PMID- 21318353 TI - cDNA cloning and characterization of UDP-glucose: anthocyanidin 3-O glucosyltransferase in Freesia hybrida. AB - The enzyme that catalyzes the formation of the first stable anthocyanin in the biosynthesis of natural compounds is UDP-glucose: anthocyanidin 3-O glucosyltransferase (UF3GT). A cDNA clone (Fh3GT1) encoding UF3GT was isolated from Freesia hybrida. Phylogenetic tree analysis indicated that Fh3GT1 was a novel member of glycosyltransferase, which was classified into monocot subgroups. Semi-quantitative RT-PCR analysis detected transcripts of Fh3GT1 in different organs of F. hybrida and in petals of Freesia cultivars of different colors, and the expression level reached the maximum at the fully opened stage of petals. Characterization of the enzymatic assays indicated that Fh3GT1 had a role in anthocyanin glycoside biosyntheses in vitro. To elucidate the function of Fh3GT1, RNA interference vector (pART-Fh3GT1i) was constructed, and introduced into Petunia grandiflora by Agrobacterium-mediated transformation. Integration of the Fh3GT1 in petunia genome was confirmed by PCR and Southern blotting. SqRT-PCR revealed that the endogenous Ph3GT1 mRNA expression levels decreased in transgenic lines compared with the wild-type. The content of total anthocyanin pigments also decreased with the reduction of mRNA transcript levels, and the transgenic petunia plants had significant changes on their flower colors. In summary, this work identified a UF3GT gene from Freesia hybrida and demonstrated a method to modify plant flower color by redirecting the anthocyanin biosynthesis. PMID- 21318355 TI - Immunogenicity of nuclear-encoded LTB:ST fusion protein from Escherichia coli expressed in tobacco plants. AB - Enterotoxigenic Escherichia coli (ETEC) is one of the main causative agents of diarrhea in infants and for travelers. Inclusion of a heat-stable (ST) toxin into vaccine formulations is mandatory as most ETEC strains can produce both heat labile (LT) and ST enterotoxins. In this study, a genetic fusion gene encoding for an LTB:ST protein has been constructed and transferred into tobacco via Agrobacterium tumefaciens-mediated transformation. Transgenic tobacco plants carrying the LTB:ST gene are then subjected to GM1-ELISA revealing that the LTB:ST has assembled into pentamers and displays antigenic determinants from both LTB and ST. Protein accumulation of up to 0.05% total soluble protein is detected. Subsequently, mucosal and systemic humoral responses are elicited in mice orally dosed with transgenic tobacco leaves. This has suggested that the plant-derived LTB:ST is immunogenic via the oral route. These findings are critical for the development of a plant-based vaccine capable of eliciting broader protection against ETEC and targeting both LTB and ST. Features of this platform in comparison to transplastomic approaches are discussed. PMID- 21318356 TI - Contrast agent-induced nephrotoxicity: role of oxidative stress and apoptosis through the mitochondrial pathway. PMID- 21318357 TI - Genetic background of resistance to cadmium-induced testicular toxicity in inbred Wistar-Imamichi rats. AB - We have previously reported that inbred Wistar-Imamichi (WI) rats are highly resistant to cadmium (Cd)-induced testicular toxicity compared with inbred Fischer 344 (F344) rats. The present study was to elucidate the genetic background of resistance to Cd-induced testicular toxicity in WI rats. The genetic analysis of susceptibility to Cd-induced testicular toxicity was conducted by using Cd-resistant WI and Cd-sensitive F344 strains as the parental rats and by using the testicular hemoglobin level as the indicator. In the frequency distribution of testicular hemoglobin levels in parental, first filial (F(1)) and second filial (F(2)) rats treated with Cd at a dose of 2.0 mg/kg, F(1) rats had testicular hemoglobin levels intermediate to WI and F344 rats, and F(2) rats segregated into three groups of low, intermediate, and high phenotypes at the expected ratio. Furthermore, the backcross progeny between WI and F(1) or between F344 and F(1) segregated into two groups with the expected ratio. Based on a simple Mendelian genetic analysis, these segregation patterns lead us to conclude that two codominant alleles at a gene locus are responsible for the susceptibility to Cd-induced testicular toxicity in rats. This is the first report for the genetic analysis of susceptibility to Cd-induced testicular toxicity in inbred rat strains. PMID- 21318358 TI - Manipulation of quorum sensing regulation in Pseudomonas fluorescens NCIMB 10586 to increase mupirocin production. AB - Transcription of the 74 kb Pseudomonas fluorescens mupirocin [pseudomonic acid (PA)] biosynthesis cluster depends on quorum sensing-dependent regulation via the LuxI/LuxR homologues MupI/MupR. To facilitate analysis of novel PAs from pathway mutants, we investigated factors that affect mup gene expression. First, the signal produced by MupI was identified as N-(3-oxodecanoyl)homoserine lactone, but exogenous addition of this molecule did not activate mupirocin production prematurely nor did expression of mupI in trans increase metabolite production. Second, we confirmed that mupX, encoding an amidase/hydrolase that can degrade N acylhomoserine lactones, is also required for efficient expression, consistent with its occurrence in a regulatory module linked to unrelated genes in P. fluorescens. Third, and most significantly, mupR expression in trans to wild type and mutants can increase production of antibiotic and novel intermediates up to 17-fold. PMID- 21318359 TI - An in vitro protocol for direct isolation of potential probiotic lactobacilli from raw bovine milk and traditional fermented milks. AB - A method for isolating potential probiotic lactobacilli directly from traditional milk-based foods was developed. The novel digestion/enrichment protocol was set up taking care to minimize the protective effect of milk proteins and fats and was validated testing three commercial fermented milks containing well-known probiotic Lactobacillus strains. Only probiotic bacteria claimed in the label were isolated from two out of three commercial fermented milks. The application of the new protocol to 15 raw milk samples and 6 traditional fermented milk samples made it feasible to isolate 11 potential probiotic Lactobacillus strains belonging to Lactobacillus brevis, Lactobacillus fermentum, Lactobacillus gasseri, Lactobacillus johnsonii, Lactobacillus plantarum, Lactobacillus reuteri, and Lactobacillus vaginalis species. Even though further analyses need to ascertain functional properties of these lactobacilli, the novel protocol set-up makes it feasible to isolate quickly potential probiotic strains from traditional milk-based foods reducing the amount of time required by traditional procedures that, in addition, do not allow to isolate microorganisms occurring as sub dominant populations. PMID- 21318360 TI - Isolation and characterization of cold-active family VIII esterases from an arctic soil metagenome. AB - Functional screening for lipolytic enzymes at low temperatures resulted in the isolation of the novel cold-active esterases, EstM-N1 and EstM-N2, from a metagenomic DNA library of arctic soil samples. EstM-N1 and EstM-N2 were 395 and 407 amino acids in length, respectively, and showed the highest similarity to class C beta-lactamases. However, they shared a relatively low level of sequence similarity (30%) with each other. Phylogenetic analysis of bacterial lipolytic enzymes confirmed that EstM-N1 and EstM-N2 belonged to family VIII of bacterial esterases/lipases. The (His)(6)-tagged esterases were purified to about 99% homogeneity from the soluble fraction of recombinant Escherichia coli cultures. The purified EstM-N1 and EstM-N2 retained more than 50% of maximal activity in the temperature range of 0-35 degrees C, with optimal temperatures of 20 degrees C and 30 degrees C, respectively. Both enzymes preferred the short acyl chains of p-nitrophenyl esters and exhibited very narrow substrate specificity, indicating that they are typical esterases. The beta-lactamase activity of EstM N1 and EstM-N2 was also detected and reached about 31% and 13% of the positive control enzyme, Bacillus cereus beta-lactamase, respectively. These first cold active esterases belonging to family VIII are expected to be useful for potential biotechnological applications as interesting biocatalysts. PMID- 21318361 TI - Overexpression of an apoplastic peroxidase gene CrPrx in transgenic hairy root lines of Catharanthus roseus. AB - Peroxidases are a family of isoenzymes found in all higher plants and are known to be involved in a broad range of physiological processes. However, very little information is available concerning their role in Catharanthus roseus. The present study describes the impact of both overexpression and suppression of a peroxidase gene, CrPrx in C. roseus transgenic hairy root lines. Real-time PCR analysis in 35S-CrPrx and CrPrx-RNAi transgenic lines indicated differential transcript profile for peroxidases as well as for genes and regulators involved in MIA (monoterpenoid indole alkaloid) pathway of C. roseus. Comparative analysis revealed that MIA pathway genes showing elevated levels of expression in 35S CrPrx transgenic lines showed a significant reduction in their transcript level in CrPrx-RNAi transgenic lines. Metabolite analysis detected higher levels of ajmalicine and serpentine accumulation in overexpressed lines. It was observed that all overexpressed transgenic lines produced more amount of H(2)O(2). These results indicate a role of CrPrx gene in the regulation of MIA pathway genes and regulators, thus affecting the production of specific alkaloids. PMID- 21318362 TI - Effect of monorhamnolipid on the degradation of n-hexadecane by Candida tropicalis and the association with cell surface properties. AB - The effect of monorhamnolipid (monoRL) on the degradation of n-hexadecane by Candida tropicalis was investigated in this study. The concentration of hexadecane, cell growth, cell surface hydrophobicity (CSH), cell surface zeta potential (CSZP), and FT-IR spectra of cellular envelope were tested to determine the mechanisms. MonoRL at the initial concentrations of 11.4, 19, and 38 mg/l improved the degradation of hexadecane, and 19 mg/l was the best concentration. However, 114 mg/l monoRL suppressed the biodegradation probably because of the reduced bioavailability of hexadecane caused by the micelles. The presence of monoRL changed the cell surface properties, which was demonstrated by the increased CSH, the increased CSZP, and the changed FT-IR spectra of cellular envelope at 680 and 620 cm(-1). The changes of cell surface properties may be a reason for the enhanced biodegradation of hexadecane by the yeast. The results indicate the potential application of monoRL in the bioremediation of hydrocarbons. PMID- 21318363 TI - Comparative analysis of tertiary alcohol esterase activity in bacterial strains isolated from enrichment cultures and from screening strain libraries. AB - The preparation of enantiopure tertiary alcohols is of great contemporary interest due to the application of these versatile building blocks in organic synthesis and as precursors towards high value pharmaceutical compounds. Herein, we describe two approaches taken towards the discovery of novel biocatalysts for the synthesis of these valuable compounds. The first approach was initiated with screening of 47 bacterial strains for hydrolytic activity towards the simple tertiary alcohol ester tert-butyl acetate. In conjunction, a second method focussed on the isolation of strains competent for growth on tert-butyl acetate as the sole source of carbon and energy. From functional screening, 10 Gram positive Actinomycetes showed hydrolytic activity, whilst enrichment selection resulted in the identification of 14 active strains, of which five belong to the Gram-negative cell-wall type. Bacterial strains obtained from both approaches were viable for enantioselective hydrolysis of pyridine substituted tertiary alcohol esters in addition to bulky aliphatic and keto-derived substrates from the same class. Activity towards each of the test substrates was uncovered, with promising enantioselectivities of up to E = 71 in the hydrolysis of a para substituted pyridine tertiary alcohol ester using a strain of Rhodococcus ruber. Interestingly strains of Microbacterium and Alcaligenes sp. gave opposite enantiopreference in the hydrolysis of a meta-substituted pyridine tertiary alcohol ester with E values of 17 and 54. These approaches show that via both possibilities, screening established strain collections and performing enrichment selection, it is possible to identify novel species which show activity towards sterically challenging substrates. PMID- 21318364 TI - Co-transcription of the celC gene cluster in Clostridium thermocellum. AB - Clostridium thermocellum, an anaerobic, thermophilic, and ethanogenic bacterium produces a large cellulase complex termed the cellulosome and many free glycosyl hydrolases. Most cellulase genes scatter around the genome. We mapped the transcripts of the six-gene cluster celC-glyR3-licA-orf4-manB-celT and determined their transcription initiation sites by primer extension. Northern blot showed that celC-glyR3-licA were co-transcribed into a polycistronic messenger with the transcription initiation site at -20 bp. Furthermore, RT-PCR mapping showed that manB and celT, two cellulosomal genes immediately downstream, were co-transcribed into a bicistronic messenger with the initiation site at -233 bp. In contrast, rf4 was transcribed alone with the two initiation sites at -130 and -138 bp, respectively. Finally, quantitative RT-PCR analysis showed that celC, glyR3, and licA were coordinately induced by growing on laminarin, a beta-1,3 glucan. Gene expression peaked at the late exponential phase. Taking together with our previous report that GlyR3 binds to the celC promoter in the absence of laminaribiose, a beta-1,3 glucose dimer, these results indicate that celC, glyR3, and licA form an operon repressible by GlyR3 and inducible by laminaribiose, signaling the availability of beta-1,3 glucan. The celC operon is the first glycosyl hydrolase operon reported in this bacterium. PMID- 21318365 TI - Isolation and characterization of a chromium-resistant bacterium Serratia sp. Cr 10 from a chromate-contaminated site. AB - A novel bacterium, Cr-10, was isolated from a chromium-contaminated site and capable of removing toxic chromium species from solution by reducing hexavalent chromium to an insoluble precipitate. Sequence analysis of 16S rRNA gene of strain Cr-10 showed that it was most closely related to Serratia rubidaea JCM 1240(T) (97.68%). Physiological and chemotaxonomic data also supported that strain Cr-10 was identified as Serratia sp., a genus which was never specially reported chromate-resistant before. Serratia sp., Cr-10 was tolerant to a concentration of 1,500 mg Cr(VI) L(-1), which was the highest level reported until now. The optimum pH and temperature for reduction of Cr(VI) by Serratia sp. Cr-10 were found to be 7.0 and 37 degrees C, respectively. The Cr(VI) reduction was significantly influenced by additional carbon sources, and among them fructose and lactose offered maximum reduction, with a rate of 0.28 and 0.25 mg Cr(VI) L(-1) h(-1), respectively. The cell-free extracts and filtrate of the culture were able to reduce Cr(VI) while concentration of total chromium remained stable in the process, indicating that the enzyme-catalyzed mechanism was applied in Cr(VI) reduction by the isolate. Additionally, it was found that there was hardly any chromium on the cell surface of the strain, further supporting that reduction, rather than bioadsorption, plays a major role in the Cr(VI) removal. PMID- 21318367 TI - Pretreatment of corn stover silage with Fe(NO(3))(3) for fermentable sugar production. AB - Corn stover silage is an attractive raw material for the production of biofuels and chemicals due to its high content of carbohydrates and easy degradability. The effects of Fe(NO(3))(3) pretreatment conditions on sugar yields were investigated for corn stover silage. In addition, a combined severity factor was used to evaluate the effect of pretreatment conditions on the concentration of total sugars and inhibitors. Optimum pretreatment condition was obtained at 150 degrees C for 10 min with 0.05 M Fe(NO(3))(3), at which the yields of soluble xylose and glucose in liquid achieved 91.80% of initial xylose, 96.74% of initial arabinose and 19.09% of initial glucose, respectively, meanwhile, 91.84% of initial xylose, 98.24% of initial arabinose, and 19.91% of initial glucose were removed. In addition, a severity analysis showed that the maximum sugar concentration of 33.48 g/l was achieved at combined severity parameter value of 0.62, while the inhibitor concentration was only 0.03 g/l. Fe(NO(3))(3) is an effective catalyst to enhance hemicellulose hydrolysis in corn stover silage, the yields of monomeric xylose in the liquid fraction reached as high as 91.06% of initial xylose and 96.22% of initial arabinose, respectively. PMID- 21318368 TI - Selection of conditions for cellulase and xylanase extraction from switchgrass colonized by Acidothermus cellulolyticus. AB - Solid-state fermentation has been widely used for enzyme production. However, secreted enzymes often bind to the solid substrate preventing their detection and recovery. A series of screening studies was performed to examine the role of extraction buffer composition including NaCl, ethylene glycol, sodium acetate buffer, and Tween 80, on xylanase and cellulase recovery from switchgrass. Our results indicated that the selection of an extraction buffer is highly dependent on the nature and source of the enzyme being extracted. While a buffer containing 50 mM sodium acetate at pH 5 was found to have a positive effect on the recovery of commercial fungal-derived cellulase and xylanase amended to switchgrass, the same buffer had a significant negative effect on enzyme extraction from solid fermentation samples colonized by the bacterium Acidothermus cellulolyticus. Xylanase activity was more affected by components in the extraction buffers compared to cellulase. This study demonstrated that extraction followed by diafiltration is important for assessing enzyme recovery from solid fermentation samples. Reduction in activity due to compounds present in the switchgrass extracts is reversible when the compounds are removed via diafiltration. PMID- 21318369 TI - Expression of the rice CDPK-7 in sorghum: molecular and phenotypic analyses. AB - Sorghum (Sorghum bicolor (L.) Moench) is an important source for food, feed, and possesses many agronomic attributes attractive for a biofuels feedstock. A warm season crop originating from the semi-arid tropics, sorghum is relatively susceptible to both cold and freezing stress. Enhancing the ability of sorghum to tolerate cold and freezing offers a route to expand the acreage for production, and provides a potential drought avoidance strategy during flowering, an important parameter for protection of yield. Targeted perturbation of the signal transduction pathway, that is triggered by exposure to abiotic stress in plants, has been demonstrated in model systems as an avenue to augment tolerance. Calcium dependent protein kinases (CDPKs) are key players in a plant's response to environmental assaults. To test the impact of modulating CDPK activity in sorghum as a means to enhanced abiotic stress tolerance, we introduced a constitutively expressed rice CDPK-7 (OsCDPK-7) gene construct. Sorghum transformants carrying this cassette, were not improved in cold or salt stress under the conditions tested. However, a lesion mimic phenotype and up-regulation of a number of pathogen related proteins, along with transcripts linked to photosynthesis were observed. These results demonstrate that modulating the Ca signaling cascade in planta via unregulated enhanced CDPK activity can lead to off-type effects likely due to the broadly integrated nature of these enzymes in signaling. PMID- 21318370 TI - Retracted article: Chronical cervical infections and dysplasia (CIN I, CIN II)- vaginal vitamin D (high dose) treatment: a new effective method. PMID- 21318371 TI - Expression level of a gibberellin 20-oxidase gene is associated with multiple agronomic and quality traits in barley. AB - The use of dwarfing genes has resulted in the most significant improvements in yield and adaptation in cereal crops. The allelic dwarfing gene sdw1/denso has been used throughout the world to develop commercial barley varieties. The sdw1 gene has never been used successfully for malting barley, but only for a large number of feed varieties. One of the gibberellin 20-oxidase genes (Hv20ox2) was identified as the candidate gene for sdw1/denso. Semi-quantitative real-time RT PCR revealed that Hv20ox2 was expressed at different levels in various organs of barley. Transcriptional levels were reduced in leaf blade, sheath, stem and rachis tissue in the barley variety Baudin with the denso gene. Subsequently, the relative expression levels of Hv20ox2 were determined by quantitative real-time RT-PCR in a doubled haploid population and mapped as a quantitative trait. A single expression quantitative trait locus (eQTL) was identified and mapped to its structural gene region on chromosome 3H. The eQTL was co-located with QTLs for yield, height, development score, hectolitre weight and grain plumpness. The expression level of Hv20ox2 was reduced fourfold in the denso mutant, but around 60-fold in the sdw1 mutant, compared to the control variety. The reduced expression level of Hv20ox2 enhanced grain yield by increasing the number of effective tillers, but had negative effects on grain and malting quality. The sdw1 gene can be used only in feed barley due to its severe reduction of Hv20ox2 expression. The gene expression marker for Hv20ox2 can be used to distinguish different alleles of sdw1/denso. PMID- 21318372 TI - Fine mapping and candidate gene analysis of dense and erect panicle 3, DEP3, which confers high grain yield in rice (Oryza sativa L.). AB - Architecture of the rice inflorescence, which is determined mainly by the morphology, number and length of primary and secondary inflorescence branches, is an important agronomical trait. In the current study, we characterized a novel dense and erect panicle (EP) mutant, dep3, derived from the Oryza sativa ssp. japonica cultivar Hwacheong treated with N-methyl-N-nitrosourea. The panicle of the dep3 mutant remained erect from flowering to full maturation, whereas the panicle of the wild type plant began to droop after flowering. The dep3 mutation also regulated other panicle characteristics, including panicle length, grain shape and grain number per panicle. Anatomical observations revealed that the dep3 mutant had more small vascular bundles and a thicker culm than wild type plants, explaining the EP phenotype. Genetic analysis indicated that the phenotype with the dense and EP was controlled by a single recessive gene, termed dep3. The DEP3 gene was identified as the candidate via a map-based cloning approach and was predicted to encode a patatin-like phospholipase A2 (PLA2) superfamily domain-containing protein. The mutant allele gene carried a 408 bp genomic deletion within LOC_Os06g46350, which included the last 47 bp coding region of the third exon and the first 361 bp of the 3'-untranslated region. Taken together, our results indicated that the patatin-like PLA2 might play a significant role in the formation of vascular bundles, and that the dep3 mutant may provide another EP resource for rice breeding programs. PMID- 21318373 TI - Analysis of select members of the E26 (ETS) transcription factors family in colorectal cancer. AB - The E-twenty-six (ETS) family of transcription factors is known to act as positive or negative regulators of the expression of genes that are involved in diverse biological processes, including those that control cellular proliferation, differentiation, hematopoiesis, apoptosis, metastasis, tissue remodeling, and angiogenesis. Identification of target gene promoters of normal and oncogenic transcription factors provides new insights into the regulation of genes that are involved in the control of normal cell growth and differentiation. The aim of the present investigation was to analyze the differential expression of 11 ETS (ELF-3, ESE3, ETS1, ETV3, ETV4, ETV6, NERF, PDEF, PU1, Spi-B, and Spi C) as potential markers for prognostic of colorectal cancer. A series of paired tissue biopsies consisting of a tumor and a non-affected control sample were harvested from 28 individuals suffering from diagnosed colorectal lesions. Total RNA was isolated from the samples, and after reverse transcription, differential expression of the select ETS was carried out through real-time polymerase chain reaction. Tumor staging as determined by histopathology was carried out to correlate the degree of tumor invasiveness with the expression of the ETS genes. The results demonstrated a different quantitative profile of expression in tumors and normal tissues. ETV4 was significantly upregulated with further increase in the event of lymph node involvement. PDEF and Spi-B presented downregulation, which was more significant when lymph node involvement was present. These findings were supported by immunohistochemistry of tumoral tissues. The results suggest that select ETS may serve as potential markers of colorectal cancer invasiveness and metastasis. PMID- 21318374 TI - A musculoskeletal model for the lumbar spine. AB - A new musculoskeletal model for the lumbar spine is described in this paper. This model features a rigid pelvis and sacrum, the five lumbar vertebrae, and a rigid torso consisting of a lumped thoracic spine and ribcage. The motion of the individual lumbar vertebrae was defined as a fraction of the net lumbar movement about the three rotational degrees of freedom: flexion-extension lateral bending, and axial rotation. Additionally, the eight main muscle groups of the lumbar spine were incorporated using 238 muscle fascicles with prescriptions for the parameters in the Hill-type muscle models obtained with the help of an extensive literature survey. The features of the model include the abilities to predict joint reactions, muscle forces, and muscle activation patterns. To illustrate the capabilities of the model and validate its physiological similarity, the model's predictions for the moment arms of the muscles are shown for a range of flexion extension motions of the lower back. The model uses the OpenSim platform and is freely available on https://www.simtk.org/home/lumbarspine to other spinal researchers interested in analyzing the kinematics of the spine. The model can also be integrated with existing OpenSim models to build more comprehensive models of the human body. PMID- 21318375 TI - Surgical management of brainstem cavernous malformations. AB - Bleeding from brainstem cavernomas may cause severe deficits due to the absence of non-eloquent nervous tissue and the presence of several ascending and descending white matter tracts and nerve nuclei. Surgical removal of these lesions presents a challenge to the most surgeons. The authors present their experience with the surgical treatment of 43 patients with brainstem cavernomas. Important aspects of microsurgical anatomy are reviewed. The surgical management, with special focus on new intraoperative technologies as well as controversies on indications and timing of surgery are presented. According to several published studies the outcome of brainstem cavernomas treated conservatively is poor. In our experience, surgical resection remains the treatment of choice if there was previous hemorrhage and the lesion reaches the surface of brainstem. These procedures should be performed by experienced neurosurgeons in referral centers employing all the currently available technology. PMID- 21318376 TI - Physician knowledge and appropriate utilization of computed tomographic colonography in colorectal cancer screening. AB - GOALS: To assess physician understanding of computed tomographic colonography (CTC) in colorectal cancer (CRC) screening guidelines in a pilot study. BACKGROUND: CTC is a sensitive and specific method of detecting colorectal polyps and cancer. However, several factors have limited its clinical availability, and CRC screening guidelines have issued conflicting recommendations. STUDY: A web based survey was administered to physicians at two institutions with and without routine CTC availability. RESULTS: 398 of 1655 (24%) participants completed the survey, 59% was from the institution with routine CTC availability, 52% self identified as trainees, and 15% as gastroenterologists. 78% had no personal experience with CTC. Only 12% was aware of any current CRC screening guidelines that included CTC. In a multiple regression model, gastroenterologists had greater odds of being aware of guidelines (OR 3.49, CI 1.67-7.26), as did physicians with prior CTC experience (OR 4.81, CI 2.39-9.68), controlling for institution, level of training, sex, and practice type. Based on guidelines that recommend CTC, when given a clinical scenario, 96% of physicians was unable to select the appropriate follow-up after a CTC, which was unaffected by institution. CONCLUSIONS: Most physicians have limited experience with CTC and are unaware of recent recommendations concerning CTC in CRC screening. PMID- 21318377 TI - Multimodality imaging findings in image-guided biopsy proven splenic littoral cell angioma: series of three cases. AB - Littoral cell angioma (LCA) is a rare primary splenic vascular tumor arising from the littoral cells that line the splenic sinuses of the red pulp. Definitive diagnosis of this entity depends on histology and immunochemical studies, for which splenectomy is usually performed. We present three image-guided percutaneous core biopsy proven cases of splenic LCA and also discuss imaging features of these rare tumors on CT, MR, and US findings. PMID- 21318378 TI - Gallbladder metastasis: spectrum of imaging findings. AB - The objective of this study is to report the diagnostic features of hematogenous gallbladder metastasis using various imaging modalities. We carried out a single center retrospective analysis of 13 patients with gallbladder metastasis. The primary malignancy was cutaneous melanoma (11 cases), hepatocellular carcinoma (1 case), and non-Hodgkin lymphoma (1 case). All patients underwent sonography (US), with color-power-Doppler assessment in 11 cases. Contrast-enhanced US (CEUS) was performed in 8 patients, MDCT in 8, and MR imaging in 1. Four subjects studied by whole-body PET. The gallbladder lesions were first detected with US in 9 cases and with MDCT in 3 cases. The remaining patient was investigated because of hepatic fluorodeoxyglucose uptake at PET; CEUS failed to detect any liver metastasis in this subject but identified a gallbladder lesion. Typical findings included multiplicity of gallbladder vegetations, broad base, limited mural thickening, presence of contrast enhancement, absence of gallstones and gallbladder bed infiltration, presence of combined lesions within other organs. Only two patients presented an isolated location in the gallbladder and were successfully treated with surgery. Gallbladder metastasis is a rare but possible occurrence. Knowledge of the typical imaging features and careful evaluation of the gallbladder may avoid an incorrect or false negative diagnosis. PMID- 21318379 TI - Primary localized amyloidosis of the ureter. AB - Primary localized amyloidosis of the ureter can closely resemble those of malignancy or inflammation involving the ureters in its presentation and ureteroscopic appearance and on diagnostic imaging studies. We provide a case of ureteral amyloidosis to reveal its imaging characteristic and to distinguish localized amyloidosis from malignancy and ureteritis. PMID- 21318380 TI - Screening of 1331 Danish breast and/or ovarian cancer families identified 40 novel BRCA1 and BRCA2 mutations. AB - Germ-line mutations in the tumour suppressor genes BRCA1 and BRCA2 predispose to breast and ovarian cancer. Since 1999 we have performed mutational screening of breast and/or ovarian cancer patients in East Denmark. During this period we have identified 40 novel sequence variations in BRCA1 and BRCA2 in high risk breast and/or ovarian cancer families. The mutations were detected via pre-screening using dHPLC or high-resolution melting and direct sequencing. We identified 16 variants in BRCA1, including 9 deleterious frame-shift mutations, 2 intronic variants, 4 missense mutations, and 1 synonymous variant. The remaining 24 variants were identified in BRCA2, including 10 deleterious mutants (6 frame shift and 4 nonsense), 2 intronic variants, 10 missense mutations and 2 synonymous variants. The frequency of the variants of unknown significance was examined in control individuals. Moreover, the presumed significance of the missense mutations was predicted in silico using the align GVGD algorithm. In conclusion, the mutation screening identified 40 novel variants in the BRCA1 and BRCA2 genes and thereby extends the knowledge of the BRCA1/BRCA2 mutation spectrum. Nineteen of the mutations were interpreted as pathogenic, 3 missense mutations were suggested to be pathogenic based on in silico analysis, 6 mutations were suggested to be benign since they were identified in patients together with a well-known disease-causing BRCA1/BRCA2 mutation, while 12 were variants of unknown significance. PMID- 21318381 TI - Novel germline SDHD mutation: diagnosis and implications to the patient. AB - A 54-year-old man presented with hypertensive crisis. He was found to have bilateral pheochromocytomas and left paraaortic sympathetic paraganglioma. Although he had no family history of paragangliomas or pheochromocytomas, he had been diagnosed with bilateral head and neck paragangliomas 10 years prior. The patient had symptoms of catecholamine excess exacerbated by vanilla ice-cream consumption. Biochemical testing revealed elevated plasma-free metanephrines and chromogranin A levels. Computed tomography showed bilateral carotid body tumors and four reteroperitoneal masses (two in the right adrenal, one in the left adrenal and one in the left paraaortic area). Metaiodobenzylguanidine-SPECT scans showed functional tumors in both the adrenal gland and left paraaortic area. Fluorine 18-fluorodeoxyglucose positron emission tomography did not show any visceral or skeletal metastasis. We carried out gene mutation analysis for succinate dehydrogenase complex subunit B, and succinate dehydrogenase complex subunit D. The patient was diagnosed with hereditary paraganglioma syndrome type 1 with a previously unreported subunit D mutation in exon 3 (c.198G > A, p.W66X). He was treated with phenoxybenzamine at 10 mg/day and with metoprolol at 12.5 mg/day. His blood pressures as well as symptoms of catecholamine excess were controlled. He then underwent bilateral adrenalectomy and reteroperitoneal dissection. His blood pressure normalized and he discontinued antihypertensive medications after surgery. He is currently on replacement therapy with hydrocortisone and fludrocortisone. PMID- 21318382 TI - Genetic counseling for patients and families with hereditary breast and ovarian cancer in a developing Asian country: an observational descriptive study. AB - Genetic counseling (GC) and genetic testing are vital risk management strategies in hereditary breast and ovarian cancer (HBOC) syndromes. Hitherto, cancer genetic testing amongst Asians has been described only in developed and high income Asian countries. We studied the uptake and acceptance of GC and genetic testing services to Asian BRCA carriers in a middle-income country. A total of 363 patients were tested by full sequencing and large rearrangement analysis of both BRCA1 and BRCA2 genes in the Malaysian Breast Cancer (MyBrCa) Genetic Study. Of these, 49 index patients (13.5%) were found to carry deleterious mutations. GC pre- and post- result disclosures were provided and these groups of patients and their families were studied. GC and genetic testing were accepted by 82% of Malaysian patients at high risk for HBOC syndromes. However, risk assessment was limited by large, geographically dispersed, often polygamous or polyandrous families, and the lack of complete cancer registry. Cultural taboos about cancer diagnoses, social marginalization and lack of regulatory control of genetic discrimination were significant concerns. Only 78% of index patients informed their families of their risks and 11% of relatives came forward when offered free counseling and testing. Even when GC and genetic testing are provided at no cost, there remain significant societal and regulatory barriers to effective cancer genetic services in this underserved Asian population. Families believe there is a need for regulatory protection against genetic discrimination. Further studies are needed in the area of increasing awareness about the potential benefits of GC and genetic testing in Asians. PMID- 21318383 TI - Structure of retracted tendons after staged repair following continuous traction. AB - PURPOSE: The effect of staged repair involving continuous re-lengthening of the retracted musculotendinous unit after rotator cuff tear is not known. We quantified changes in chronically retracted tendons undergoing no repair or a staged repair involving an initial re-lengthening of the musculotendinous unit by traction in a sheep model of massive rotator cuff tear. MATERIALS AND METHODS: Infraspinatus tendons of 12 sheep were released and allowed to retract for 4 months. Repair was performed after the retracted musculotendinous unit had been progressively returned to its original length through continuous traction in 8 sheep (group I). In the other 4 sheep (group II) traction was not successful and the tendons remained retracted. Tendon structure was assessed macroscopically, by MRI, histology, and TEM. RESULTS: Normalized to their contralateral controls, at sacrifice, tendon thickness was unchanged in group I (116%, n.s) and increased in group II (129%, P < 0.05), however with substantial shortening. Increased collagen fiber crimping and disorganization was found in group II, whereas in group I the differences from normal tendon were less pronounced. CONCLUSION: Retracted musculotendinous units have deteriorated tendons, characterized by increased collagen fiber crimp, and ultrastructural collagen fibril atrophy and disorganization. Continuous traction may arrest and partially restore degenerative changes in retracted tendon. The findings of this study might contribute to new approaches for the treatment of chronic "irreparable" rotator cuff tears. PMID- 21318384 TI - Role of arthroscopic microfracture for cystic type osteochondral lesions of the talus with radiographic enhanced MRI support. AB - PURPOSE: Comparatively little literature is available on treatment evaluations of individual osteochondral lesions of the talus (OLT), such as cystic type OLT. It is also noteworthy that controversy still exists regarding the best primary treatment option for cystic type OLT. The purpose of this study was to evaluate the clinical outcomes of arthroscopic microfracture of symptomatic cystic type OLT, irrespective of lesion size, and to verify the efficacy of enhanced ankle MRI for predicting the nature of cystic osteochondral lesions. METHODS: In this study, the authors assessed 22 patients with cystic type OLTs, who all underwent arthroscopic debridement and microfracture with a minimum of 18-month follow-up. There were 16 men and 6 women. Median patient age was 40 (20-64) years. Preoperative and postoperative VAS and AOFAS scores were evaluated. RESULTS: At a median follow-up of 32 months (18-63), AOFAS scores improved from a median of 69 preoperative (29-88) to 90 postoperative (75-100) (P < 0.05); and VAS scores improved from a mean of 7.0 +/- 1.8 to a mean of 1.7 +/- 1.9, respectively (P < 0.05). The overall patient satisfaction rate was 86%. Gadolinium-enhanced MRI scans performed on 21 feet all showed enhancement of varying intensities (from low to high) for the cystic OLTs, implying a vasculogenic potential. CONCLUSIONS: The study shows that arthroscopic microfracture is a desirable first-line treatment for addressing symptomatic cystic type OLT irrespective of lesion size. Enhanced ankle MRI was also found to be a useful and important for predicting the natures of cystic osteochondral lesions. LEVEL OF EVIDENCE: Case-series, Level IV. PMID- 21318385 TI - Mosquito larvicidal, ovicidal, and repellent properties of botanical extracts against Anopheles stephensi, Aedes aegypti, and Culex quinquefasciatus (Diptera: Culicidae). AB - Mosquito-borne diseases have an economic impact, including loss in commercial and labor outputs, particularly in countries with tropical and subtropical climates; however, no part of the world is free from vector-borne diseases. In mosquito control programs, botanical origin may have the potential to be used successfully as eggs, larvae, and adult. The larvicidal, ovicidal, and repellent activities of crude benzene and ethyl acetate extracts of leaf of Ervatamia coronaria and Caesalpinia pulcherrima were assayed for their toxicity against three important vector mosquitoes, viz., Anopheles stephensi, Aedes aegypti, and Culex quinquefasciatus (Diptera: Culicidae). The larval mortality was observed after 24 h of exposure. All extracts showed moderate larvicidal effects; however, the highest larval mortality was found in benzene extract of E. coronaria against the larvae of Anopheles Stephensi, Aedes aegypti, and Culex quinquefasciatus with the LC(50) and LC(90) values were 79.08, 89.59, and 96.15 ppm and 150.47, 166.04, and 174.10 ppm, respectively. Mean percent hatchability of the ovicidal activity was observed 48 h posttreatment. The percent hatchability was inversely proportional to the concentration of extract and directly proportional to the eggs. The leaf extract of E. coronaria was found to be most effective than Caesalpinia pulcherrima against eggs/egg rafts of three vector mosquitoes. For E. coronaria, the benzene extract exerted 300, 250, and 200 ppm against Anopheles stephensi, Aedes aegypti, and Culex quinquefasciatus, respectively. The results of the repellent activity of benzene and ethyl acetate extract of E. coronaria and Caesalpinia pulcherrima plants at three different concentrations of 1.0, 2.5, and 5.0 mg/cm(2) were applied on skin of fore arm in man and exposed against adult female mosquitoes. In this observation, these two plant crude extracts gave protection against mosquito bites without any allergic reaction to the test person, and also, the repellent activity is dependent on the strength of the plant extracts. These results suggest that the leaf solvent plant extracts have the potential to be used as an ideal ecofriendly approach for the control of mosquitoes. This is the first report on the mosquito larvicidal, ovicidal, and repellent activities of the reported E. coronaria and Caesalpinia pulcherrima plants. PMID- 21318386 TI - Molecular cloning and expression of the VK247 circumsporozoite protein for serodiagnosis of variant form Plasmodium vivax. AB - Plasmodium vivax is classified into two serotypes, VK210 [the dominant form GDRA(D/A)GQPA repeats] and VK247 [the variant form-ANGA(G/D)(N/D)QPG repeats], based on sequence variation of the repeat region of the circumsporozoite (CS) protein gene. Genomic DNA for the variant CS protein gene was obtained from field isolate strains in Myanmar. The repetitive region has highly 19 immunogenic repeats flanked by non-repeat stretches of amino acids. The sequence including this region (717 bp) was subcloned into the expression vector pQE30 and expressed in Escherichia coli. The expressed recombinant protein has a molecular weight of about 50 kDa as analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis. Anti-VK247 antibodies were found in malaria patients who have been exposed to variant form of P. vivax in western blot analysis. Therefore, this recombinant protein might be a useful tool in serodiagnosis of malaria patients who have been infected with variant form of P. vivax. PMID- 21318387 TI - Adult but not juvenile Barbary macaques spontaneously recognize group members from pictures. AB - For group-living animals, it is crucial to distinguish one's own group members from those of other groups. Studies applying operant conditioning revealed that monkeys living in relatively small groups are able to recognize their own group members when tested with photographs of group members and other conspecifics. Employing a simple looking time paradigm, we here show that Barbary macaques living in two social groups comprising 46 and 57 individuals, respectively, at the enclosure 'La Foret des Singes' at Rocamadour are able to spontaneously distinguish photographs of members of their own group from those depicting animals that belong to another group. This ability appears to develop with age, as juveniles did not discriminate between members of their own group and another group, although they showed generally more interest in the pictures than did adults. Juveniles frequently displayed picture directed behaviours such as lip smacking, touching and sniffing in both conditions, indicating that the stimuli were highly salient to them. In conclusion, it appears that at least adult monkeys are able to memorize the faces of a large number of individuals. Whether the difference in behaviour is based on individual recognition of one's own group members or simply the discrimination based on familiarity remains unresolved. However, both mechanisms would be sufficient for group membership identification. PMID- 21318388 TI - Evolution of metamorphism in thymidylate synthases within the primate lineages. AB - Crystal structures of human thymidylate synthase (hTS) revealed that the protein exists in active and inactive conformations, defined by the position of a loop containing the active site nucleophile. TS is highly homologous among diverse species; however, the residue at position 163 (hTS) differs among species. Arginine at this position is predicted by structural modeling to enable conformational switching. Arginine or lysine is reported at this position in all mammals in the GenBank and Ensembl databases, with arginine reported in only primates. Sequence analysis of the TS gene of representative primates revealed that arginine occurs at this relative position in all primates except a representative of prosimians. Mutant human proteins were created with residues at position 163 that occur in TSs from prokaryotes and eukaryotes. Catalytic constants (k(cat)) of mutant enzymes were 45-149% of hTS, with the lysine mutant (R163K) exhibiting the highest k(cat). The effect of lysine substitution on solution structure and on ligand binding was investigated. R163K exhibited higher intrinsic fluorescence, a more negative molar ellipticity, and higher dissociation constants (K(d)) for ligands that modulate protein conformation than hTS. Temperature effects on intrinsic fluorescence and catalytic activity of hTS and R163K are consistent with proteins populating different conformational states. The data indicate that the enzyme with arginine at the position corresponding to 163 (hTS) evolved after the divergence of prosimians and simians and that substitution of lysine by arginine confers unique structural and functional properties to the enzyme expressed in simian primates. PMID- 21318389 TI - Effects of cadmium hyperaccumulation on the concentrations of four trace elements in Lonicera japonica Thunb. AB - Hyperaccumulators are important in the phytoremediation of cadmium (Cd) contaminated soil. In this study, Cd accumulation and the interactions between Cd and four other trace elements (Fe, Mn, Cu, and Zn) in Lonicera japonica Thunb. were investigated. As a result of exposure to soil containing 50 mg kg(-1) Cd, stem and shoot Cd concentrations reached 344.49 +/- 0.71 and 286.12 +/- 9.38 MUg g(-1) DW respectively, without showing symptoms of visible damage to the plants. This suggests that L. japonica has a strong tolerance to Cd. It is proposed that trace metal elements are involved in the Cd-detoxification mechanisms shown by hyperaccumulators. There is a synergistic interaction in accumulation and translocation between Cd and Fe and a significantly negative correlation between Cd and Cu or Zn concentrations in L. japonica plant tissues. The imbalanced trace element concentrations influences detoxification processes to Cd, therefore, L. japonica could be considered as a new Cd-hyperaccumulator model to investigate the metal tolerance strategies of plants. PMID- 21318390 TI - Ecotoxicological assessment of pesticides towards the plant growth promoting activities of Lentil (Lens esculentus)-specific Rhizobium sp. strain MRL3. AB - This study was designed to evaluate the effect of the selected pesticides [herbicides (metribuzin and glyphosate), insecticides (imidacloprid and thiamethoxam) and fungicides (hexaconazole, metalaxyl and kitazin)] at the recommended and the higher dose rates on plant growth promoting traits of Rhizobium sp. strain MRL3 isolated from lentil-nodules. Strain MRL3 was explicitly selected owing to its high pesticide-tolerance ability and substantial production of indole acetic acid, siderophores (salicylic acid and 2, 3 dihydroxy benzoic acid), exo-polysaccharides, HCN and ammonia. A trend of pesticide concentration dependent progressive-decline for plant growth promoting properties of Rhizobium sp. strain MRL3 was observed excluding exo-polysaccharides which was regularly augmented on exceeding the concentration of each tested pesticide from the recommended dose. Commonly, the maximum toxicity to plant growth promoting traits of Rhizobium was shown by glyphosate, imidacloprid and hexaconazole at three times the recommended rate among herbicides, insecticides and fungicides, respectively. PMID- 21318391 TI - Effect of Scrophularia buergeriana extract on the degranulation of mast cells and ear swelling induced by dinitrofluorobenzene in mice. AB - Scrophularia buergeriana Miquel (Scrophulariaceae, SB) is a biennial plant native to Korea, northern China, and Japan that plays an important role in traditional medicine. The dried root of SB has long been used in oriental medicine for treatment of fever, swelling, constipation, pharyngitis, neuritis, and laryngitis. In the present study, we evaluated the ethanol extract of SB (SBE) to determine if it exerted any anti-allergic effects that had not previously been demonstrated. SBE markedly inhibited beta-hexosaminidase and histamine release and suppressed the expression of tumor necrosis factor-alpha and interleukin-4 cytokines by RBL-2H3 mast cells. In addition, topical treatment with SBE effectively reduced allergic inflammation in a dinitrofluorobenzene-induced contact hypersensitivity mouse model. These results strongly suggest that SBE is a promising source of anti-allergic agents. PMID- 21318392 TI - Effects of urinary trypsin inhibitor on lipopolysaccharide-induced acute lung injury in rabbits. AB - This study was undertaken to clarify the effects of urinary trypsin inhibitor (UTI) on lipopolysaccharide (LPS)-induced acute lung injury. Rabbits were randomly assigned to one of seven groups: saline only, UTI, LPS, pre- or post-UTI high (infusion of UTI of 25,000 U/kg followed by 25,000 U/kg over 2 h), pre- or post-UTI-low (infusion of UTI of 2,500 U/kg followed by 2,500 U/kg over 2 h). UTI was administered 30 min before (pre-groups) or 15 min after (post-groups) LPS administration. Rabbits were mechanically ventilated with 40% oxygen for 6 h. LPS decreased peripheral blood leukocyte counts and increased wet/dry weight ratio of lung, lung injury score, neutrophil infiltration in lung, and IL-8 production in systemic blood and bronchoalveolar lavage fluid (BALF). Rabbits treated by UTI were protected from LPS-induced lung injury, as determined by wet/dry weight ratio, neutrophil infiltration in lung, lung injury score, and IL-8 in BALF levels. UTI attenuated LPS-induced acute lung injury in rabbits mainly by inhibiting neutrophil and IL-8 responses, which may play a central role in sepsis related lung injury. PMID- 21318393 TI - Magnitude of zinc deficiency amongst under five children in India. AB - OBJECTIVE: To estimate the prevalence of serum zinc deficiency in children of 6 months to 60 months of age. METHODS: A community based cross-sectional study was conducted to collect the data to establish the prevalence of zinc deficiency in children in 6-60 months of age in five states namely, Uttar Pradesh(Northern region), Karnataka (Southern region), Orissa (Eastern region), Gujarat (Western region) and Madhya Pradesh (Central region) of the country. In each state, all the districts with ICDS scheme were enlisted and one district was selected with the help of Random number table (RNT). In each district, all the ICDS projects were selected and one ICDS project was selected with help of RNT. In the selected ICDS project, a cluster 5 Anganwadi centres (AWC) were selected. From the selected AWCs, three hundred children in the age group of 6-60 months were selected for the detailed study. A total of 1,655 subjects (836 males and 819 females) were included. The blood samples were collected from each child. The serum zinc estimation was done by atomic absorption spectrophotometer. RESULTS: The overall prevalence of zinc deficiency in five states was 43.8% . The prevalence of zinc deficiency was highest in Orissa (51.3%), followed by Uttar Pradesh (48.1%), Gujarat (44.2%), Madhya Pradesh (38.9%) and Karnataka (36.2%). CONCLUSIONS: The present study revealed a high prevalence of zinc deficiency in children belonging to Low Socio-economic Index (LSI) in India. PMID- 21318394 TI - Follow up of children with autism spectrum disorders: stability and change in diagnosis. AB - OBJECTIVE: To assess diagnostic stability of initial autism spectrum disorder (ASD) diagnosed in children three years or less. METHODS: Participants in the study included 77 (64 boys,13 girls) children in whom a diagnosis of Autistic Disorder (AD) and Pervasive Developmental Disorder-Not Otherwise Specified (PDD NOS) was made at age 3 years or less as per the DSM IV criteria. Children were recruited from the Outpatient services of the department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh. Multi disciplinary evaluations including neurological, diagnostic, cognitive, and behavioral assessments were made. In addition, the Childhood Autism Rating Scale (CARS) was administered to assess symptom severity. Follow up was done around 4 years of age. RESULTS: At Time 1, 64 (83.11%) children were diagnosed as AD and 13 (16.88%) children with PDD-NOS. Follow up was possible in only 43 children (55.8%) at the mean age of 4 years 1 month (SD = 0.99) after a mean age interval of 1.65 years (SD = 0.95). At Time 2, 37 (86%) children were diagnosed as AD and 4 (9.3%) children were diagnosed with PDD-NOS, and 2 (4.65%) children were found to be off the ASD spectrum. The diagnosis of ASD (AD and PDD-NOS) was stable over time and 41 (95.3%) out of 43 children retained an ASD diagnosis. Looking at specific ASD diagnosis, AD diagnosis was stable for 33 out of 37 (89.18%) children and the PDD-NOS was stable for only 1 out of 6 (16.67%) children. CONCLUSIONS: An early and a stable diagnosis of ASD is possible provided there are expert clinicians available. Early detection and diagnosis of ASDs allows opportunities for children to profit more from early supports and interventions. PMID- 21318395 TI - Posterior reversible encephalopathy syndrome (PRES/RPLS) during pulse steroid therapy in macrophage activation syndrome. AB - Posterior reversible encephalopathy syndrome (PRES)or Reversible posterior leukoencephalopathy syndrome (RPLS) is a neurological complication associated with various illnesses and medications(including rheumatological illnesses and their medications). Cyclosporine is the drug which is most commonly implicated in the causation of this condition. The authors report a 6 year old patient with systemic onset juvenile idiopathic arthritis (SoJIA) with macrophage activation syndrome who developed PRES during treatment with pulse methylprednsiolone therapy. In view of persitent SoJIA disease activity, the child was subsequently treated with Cyclosporine. The child made a complete neurological recovery. This case report highlights that, in accordance with recent literature, PRES is a complication of a unique set of conditions comprising of inflammation, hypertension, immunosupression and nephropathy in different degrees and does not necessarily preclude the use of drugs implicated as inciting agents. This has important implications in rheumatology where cyclosporine is a life saving medication used in macrophage activation syndrome. PMID- 21318396 TI - Indomethacin tocolysis and neurodevelopmental outcome. AB - OBJECTIVE: To compare the neurodevelopmental outcomes, at 30-42 months adjusted age, between infants exposed to antenatal indomethacin and those unexposed to antenatal indomethacin. METHODS: This was a retrospective cohort study. The study cohort consisted of all nonanomalous infants with birth weight <= 1250 g and/or gestational age <= 28 wks born between 2000 and 2003, who completed neurodevelopmental assessments between 30-42 months adjusted age. The authors compared the neurodevelopmental outcomes of infants exposed and unexposed to antenatal indomethacin. RESULTS: Of the 321 infants, 75 infants (23%) exposed to antenatal indomethacin were lower in gestational age (26.4 vs 27.8 wks). In univariate analysis, infants exposed to antenatal indomethacin had significantly increased incidence of patent ductus arteriosus (PDA) (60% vs. 39%), surgical PDA ligation (40% vs. 18%) and bronchopulmonary dysplasia (81% vs. 60%). There was no significant difference in cerebral palsy, cognitive delay, deafness, blindness and major disability between the two groups. In multivariable logistic regression analysis, antenatal indomethacin exposure was not associated with cerebral palsy (OR, 0.70; 95% CI, 0.22-2.18), cognitive delay (OR, 0.56; 95% CI, 0.28-1.12) or neurodevelopmental disability (OR, 0.50; 95% CI, 0.21-1.19). CONCLUSIONS: Neurodevelopmental outcome of preterm infants exposed to antenatal indomethacin is equivalent to those unexposed to antenatal indomethacin, despite being born earlier. PMID- 21318397 TI - Volatiles mediating a plant-herbivore-natural enemy interaction in resistant and susceptible soybean cultivars. AB - Several studies have shown that herbivore-induced plant volatiles act directly on herbivores and indirectly on their natural enemies. However, little is known about the effect of herbivore damage on resistant and susceptible plant cultivars and its effect on their natural enemies. Thus, the aim of this study was to evaluate the attraction of the herbivorous pentatomid bug Euschistus heros and its egg parasitoid Telenomus podisi to two resistant and one susceptible soybean cultivars with different types of damage (herbivory, herbivory+oviposition, and oviposition). In a Y-tube olfactometer, the parasitoids were attracted to herbivory and herbivory+oviposition damaged soybean plants when compared to undamaged soybean plants for the resistant cultivars, but did not show preference for the susceptible cultivar Silvania in any of the damage treatments. The plant volatiles emitted by oviposition-damaged plants in the three cultivars did not attract the egg parasitoid. In four-arm-olfactometer bioassays, E. heros females did not show preference for odors of damaged or undamaged soybean plants of the three cultivars studied. The Principal Response Curves (PRC) analysis showed consistent variability over time in the chemical profile of volatiles between treatments for the resistant cultivar Dowling. The compounds that most contributed to the divergence between damaged soybean plants compared to undamaged plants were (E,E)-alpha-farnesene, methyl salicylate, (Z)-3-hexenyl acetate, and (E)-2-octen-1-ol. PMID- 21318398 TI - Alkaloids in the mite Scheloribates laevigatus: further alkaloids common to oribatid mites and poison frogs. AB - Poison frogs are chemically defended from predators by diverse alkaloids, almost all of which are sequestered unchanged from alkaloid-containing arthropods in the frog diet. Oribatid mites recently have been proposed as a major dietary source of poison frog alkaloids. Here, we report on alkaloids common to an oribatid mite and poison frogs. Gas chromatographic-mass spectrometric analysis of methanol extracts of adult Scheloribates laevigatus (Oribatida: Scheloribatidae) revealed nine alkaloids. Five of these have been detected previously in the skin glands of poison frogs: two isomers of the pumiliotoxin 291G, two isomers of the 5,6,8 trisubstituted indolizidine 209C, and the 5,6,8-trisubstituted indolizidine 195G. The other four alkaloids, a pumiliotoxin, a tricyclic (coccinelline-like), and two isomers of an izidine, were not previously known, but are similar in structure to alkaloids found in poison frogs. Alkaloids were not detected in immature S. laevigatus, suggesting that they are adult-specific and possibly the result of mite biosynthesis. Although most of the alkaloids detected in S. laevigatus are common to poison frogs, the geographic distributions of these organisms are not sympatric. The findings of this study indicate that oribatid mites, and in particular, members of the genus Scheloribates, represent a relatively unexplored arthropod repository for alkaloids and a significant dietary source of alkaloids in poison frogs. PMID- 21318399 TI - Sex pheromone and trail pheromone of the sand termite Psammotermes hybostoma. AB - Within the complex network of chemical signals used by termites, trail pheromones and sex pheromones are among the best known. Numerous recent papers map the chemical identity and glandular origin of these pheromones in nearly all major isopteran taxa. In this study, we aimed to describe the sex pheromone and the trail pheromone of a poorly known sand termite, Psammotermes hybostoma. We identified (3Z,6Z,8E)-dodeca-3,6,8-trien-1-ol (dodecatrienol) as the sex pheromone released by tergal and sternal glands of female imagos and, at the same time, as the trail pheromone secreted from the sternal gland of workers. We conclude that chemical communication in Psammotermes does not differ from that of most other Rhinotermitidae, such as Reticulitermes, despite the presence of a diterpene as a major component of the trail pheromone of Prorhinotermes to which Psammotermes is presumed to be phylogenetically close. Our findings underline once again the conservative nature of chemical communication in termites, with dodecatrienol being a frequent component of pheromonal signals in trail following and sex attraction and, at the same time, a tight evolutionary relationship between the trail following of working castes and the sex attraction of imagos. PMID- 21318400 TI - A scaffold-free multicellular three-dimensional in vitro model of osteogenesis. AB - In vitro models of osteogenesis are essential for investigating bone biology and the effects of pharmaceutical, chemical, and physical cues on bone formation. Osteogenesis takes place in a complex three-dimensional (3D) environment with cells from both mesenchymal and hematopoietic origins. Existing in vitro models of osteogenesis include two-dimensional (2D) single type cell monolayers and 3D cultures. However, an in vitro scaffold-free multicellular 3D model of osteogenesis is missing. We hypothesized that the self-inductive ossification capacity of bone marrow tissue can be harnessed in vitro and employed as a scaffold-free multicellular 3D model of osteogenesis. Therefore, rat bone marrow tissue was cultured for 28 days in three settings: 2D monolayer, 3D homogenized pellet, and 3D organotypic explant. The ossification potential of marrow in each condition was quantified by micro-computed tomography. The 3D organotypic marrow explant culture resulted in the greatest level of ossification with plate-like bone formations (up to 5 mm in diameter and 0.24 mm in thickness). To evaluate the mimicry of the organotypic marrow explants to newly forming native bone tissue, detailed compositional and morphological analyses were performed, including characterization of the ossified matrix by histochemistry, immunohistochemistry, Raman microspectroscopy, energy dispersive X-ray spectroscopy, backscattered electron microscopy, and micromechanical tests. The results indicated that the 3D organotypic marrow explant culture model mimics newly forming native bone tissue in terms of the characteristics studied. Therefore, this platform holds significant potential to be used as a model of osteogenesis, offering an alternative to in vitro monolayer cultures and in vivo animal models. PMID- 21318401 TI - Fragility fractures in men with idiopathic osteoporosis are associated with undermineralization of the bone matrix without evidence of increased bone turnover. AB - The pathogenesis of primary osteoporosis in younger individuals is still elusive. An important determinant of the biomechanical competence of bone is its material quality. In this retrospective study we evaluated bone material quality based on quantitative backscattered electron imaging to assess bone mineralization density distribution (BMDD) in bone biopsies of 25 male patients (aged 18-61 years) who sustained fragility fractures but were otherwise healthy. BMDD of cancellous bone was compared with previously established adult reference data. Complementary information was obtained by bone histomorphometry. The histomorphometric results showed a paucity of osteoblasts and osteoclasts on the bone surface in the majority of patients. BMDD revealed a significant shift to lower mineralization densities for cancellous bone values: CaMean (weighted mean Ca content, -5.9%), CaPeak (mode of the BMDD, -5.6%), and CaHigh (portion of fully mineralized bone, 76.8%) were decreased compared to normative reference; CaWidth (heterogeneity in mineralization, +18.5%) and CaLow (portion of low mineralized bone, +68.8; all P < 0.001) were significantly increased. The shift toward lower mineral content in the bone matrix in combination with reduced indices of bone formation and bone resorption suggests an inherent mineralization defect leading to undermineralized bone matrix, which might contribute to the susceptibility to fragility fractures of the patients. The alteration in bone material might be related to osteoblastic dysfunction and seems fundamentally different from that in high bone turnover osteoporosis with a negative bone balance. PMID- 21318402 TI - No alignment of cattle along geomagnetic field lines found. AB - This paper presents a study of the body orientation of domestic cattle on free pastures in several European states, based on the Google satellite photographs. In sum, 232 herds with 3,412 individuals were evaluated. Two independent groups participated in our study and came to the same conclusion that in contradiction to the recent findings of other researchers, no alignment of the animals and of their herds along geomagnetic field lines could be found. Several possible reasons for this discrepancy should be taken into consideration: poor quality of Google satellite photographs, difficulties in determining the body axis, selection of herds or animals within herds, lack of blinding in the evaluation, possible subconscious bias, and, most importantly, high sensitivity of the calculated main directions of the Rayleigh vectors to some kind of bias or to some overlooked or ignored confounder. This factor could easily have led to an unsubstantiated positive conclusion about the existence of magnetoreception. PMID- 21318403 TI - On the role of phosphatidylinositol 3-kinase, protein kinase b/Akt, and glycogen synthase kinase-3beta in photodynamic injury of crayfish neurons and glial cells. AB - Photodynamic treatment that causes intense oxidative stress and cell death is currently used in neurooncology. However, along with tumor cells, it may damage healthy neurons and glia. To study the involvement of signaling processes in photodynamic injury or protection of neurons and glia, we used crayfish mechanoreceptor consisting of a single neuron surrounded by glial cells. It was photosensitized with alumophthalocyanine Photosens. Application of specific inhibitors showed that phosphatidylinositol 3-kinase did not participate in photoinduced death of neurons and glia. Akt was involved in photoinduced necrosis but not in apoptosis of neurons and glia. Glycogen synthase kinase-3beta participated in photoinduced apoptosis of glial cells and in necrosis of neurons. Therefore, phosphatidylinositol 3-kinase/protein kinase Akt/glycogen synthase kinase-3beta pathway was not involved as a whole in photodynamic injury of crayfish neurons and glia but its components, Akt and glycogen synthase kinase 3beta, independently and cell specifically regulated death of neurons and glial cells. According to these data, necrosis in this system was a controlled but not a non-regulated cell death mode. The obtained results may be used for the search of pharmacological agents selectively modulating death and survival of normal neurons and glial cells during photodynamic therapy of brain tumors. PMID- 21318404 TI - Specific role of tight junction proteins claudin-5, occludin, and ZO-1 of the blood-brain barrier in a focal cerebral ischemic insult. AB - Blood-brain barrier (BBB) leakage plays a key role in cerebral ischemia reperfusion injury. It is quite necessary to further explore the characteristic and mechanism of BBB leakage during stroke. We induced a focal cerebral ischemia model by transient middle cerebral artery occlusion in male rats for defining the time course of BBB permeability within 120 h following reperfusion and evaluate the specific role of tight junction (TJ) associated proteins claudin-5, occludin, and ZO-1 as well as protein kinase C delta (PKCdelta) pathway in BBB leakage induced by reperfusion injury. We verified a bimodal increase in the permeability of the BBB following focal ischemia by Evans blue assay. Two peaks of BBB permeability appeared at 3 h and 72 h of reperfusion after 2 h focal ischemia, respectively. The leak at the endothelial cell was represented at the level of transmission electron microscopy. TTC staining results showed increased infarct size with time after cerebral ischemia reperfusion. The mRNA and protein expression levels of these three TJ associated proteins were significantly decreased compared with the sham-operated group within 120 h of reperfusion, corresponding to the time-dependent change of the biphasic pattern in BBB leakage. The redistribution of claudin-5, occludin, and ZO-1 in ischemia brain microvascular endothelial cells was observed at the same time points. In addition, Western blot assay revealed PKCdelta level was also significantly increased in a similar biphasic pattern to above results within 120 h after cerebral ischemia-reperfusion. This study demonstrates the timing of TJ associated proteins claudin-5, occludin, and ZO-1 in light of BBB permeability associated with cerebral ischemia reperfusion, and suggests PKCdelta pathway may participate in TJ barrier open and BBB leakage during reperfusion injury in a time-dependent manner. PMID- 21318405 TI - Kaoru Harada 1927-2010. PMID- 21318406 TI - Founder effect in the Horn of Africa for an insulin receptor mutation that may impair receptor recycling. AB - AIMS/HYPOTHESIS: Genetic insulin receptoropathies are a rare cause of severe insulin resistance. We identified the Ile119Met missense mutation in the insulin receptor INSR gene, previously reported in a Yemeni kindred, in four unrelated patients with Somali ancestry. We aimed to investigate a possible genetic founder effect, and to study the mechanism of loss of function of the mutant receptor. METHODS: Biochemical profiling and DNA haplotype analysis of affected patients were performed. Insulin receptor expression in lymphoblastoid cells from a homozygous p.Ile119Met INSR patient, and in cells heterologously expressing the mutant receptor, was examined. Insulin binding, insulin-stimulated receptor autophosphorylation, and cooperativity and pH dependency of insulin dissociation were also assessed. RESULTS: All patients had biochemical profiles pathognomonic of insulin receptoropathy, while haplotype analysis revealed the putative shared region around the INSR mutant to be no larger than 28 kb. An increased insulin proreceptor to beta subunit ratio was seen in patient-derived cells. Steady state insulin binding and insulin-stimulated autophosphorylation of the mutant receptor was normal; however it exhibited decreased insulin dissociation rates with preserved cooperativity, a difference accentuated at low pH. CONCLUSIONS/INTERPRETATION: The p.Ile119Met INSR appears to have arisen around the Horn of Africa, and should be sought first in severely insulin resistant patients with ancestry from this region. Despite collectively compelling genetic, clinical and biochemical evidence for its pathogenicity, loss of function in conventional in vitro assays is subtle, suggesting mildly impaired receptor recycling only. PMID- 21318408 TI - Lymphocytic host response to oral squamous cell carcinoma: an adaptive T-cell response at the tumor interface. AB - Lymphocytic host response (LHR) in the Risk Model is histologically quantified as the density of lymphocytes at the tumor interface (Brandwein-Gensler in Am J Surg Pathol, 34:676-688, 1; in, Am J Surg Pathol 29:167-178, 2). It is classified as strong, intermediate or weak, and is inversely associated with the risk of decreased time to disease progression. In this study, we test the hypothesis that strong LHR corresponds to a greater degree of adaptive cytotoxic T cell response as compared to moderate LHR. We studied resection specimens of primary oral squamous carcinoma classified as having either strong (n = 16), intermediate (n = 20) or weak (n = 4) LHR. CD20+, CD4+, & CD8+ cells were detected by immunohistochemistry and quantified at 40* with a grid; counting the 10 fields with the most lymphocytes at the tumor interface and within tumors. Mean counts/tumor were analyzed by the 2-sided T-test. Statistically significant differences were observed for interface CD8 cells with respect to strong versus moderate LHR, strong versus weak LHR, and moderate versus weak LHR, and tumor infiltrating CD8 cells with respect to strong versus weak LHR. Statistically significant differences were also observed for interface CD4 cells with respect to strong versus weak LHR, and moderate versus weak LHR. Statistically significant differences in interface B cell counts were seen with respect to strong versus weak LHR, and moderate versus weak LHR. Decreased CD8+ T cells were significantly associated with higher stage at presentation (P = 0.005); a direct, but nonsignificant correlation was seen between decreased CD8+ T cells and decreased survival time. Immune response at the tumor interface correlates with an adaptive T cell response; the degree of cytotoxic CD8+ cells infiltrate can distinguish between strong and intermediate LHR at the interface of oral carcinomas. PMID- 21318407 TI - Podocyte vascular endothelial growth factor (Vegf164) overexpression causes severe nodular glomerulosclerosis in a mouse model of type 1 diabetes. AB - AIMS/HYPOTHESIS: The pathogenic role of excessive vascular endothelial growth factor (VEGF)-A in diabetic nephropathy has not been defined. We sought to test whether increased podocyte VEGF-A signalling determines the severity of diabetic glomerulopathy. METHODS: Podocyte-specific, doxycycline-inducible Vegf164 (the most abundant Vegfa isoform) overexpressing adult transgenic mice were made diabetic with low doses of streptozotocin and examined 12 weeks after onset of diabetes. We studied diabetic and non-diabetic transgenic mice fed a standard or doxycycline-containing diet. VEGF-A and albuminuria were measured by ELISA, creatinine was measured by HPLC, renal morphology was examined by light and electron microscopy, and gene expression was assessed by quantitative PCR, immunoblotting and immunohistochemistry. RESULTS: Podocyte Vegf164 overexpression in our mouse model of diabetes resulted in advanced diabetic glomerulopathy, characterised by Kimmelstiel-Wilson-like nodular glomerulosclerosis, microaneurysms, mesangiolysis, glomerular basement membrane thickening, podocyte effacement and massive proteinuria associated with hyperfiltration. It also led to increased VEGF receptor 2 and semaphorin3a levels, as well as nephrin and matrix metalloproteinase-2 downregulation, whereas circulating VEGF-A levels were similar to those in control diabetic mice. CONCLUSIONS/INTERPRETATION: Collectively, these data demonstrate that increased podocyte Vegf164 signalling dramatically worsens diabetic nephropathy in a streptozotocin-induced mouse model of diabetes, resulting in nodular glomerulosclerosis and massive proteinuria. This suggests that local rather than systemic VEGF-A levels determine the severity of diabetic nephropathy and that semaphorin3a signalling and matrix metalloproteinase-2 dysregulation are mechanistically involved in severe diabetic glomerulopathy. PMID- 21318409 TI - Tolerance to anesthesia depends on synaptic proteins. AB - The hypnotic effects of anesthetics are caused by their interactions with neuronal components vital for proper signaling. An understanding of the adaptive mechanisms that lead to the development of anesthetic tolerance can offer insight into the regulation of neuroexcitability and plasticity that alter behavioral output. Here we use genetic and pharmacological manipulation of Drosophila to investigate the mechanisms of tolerance to benzyl alcohol. The mutants tested were temperature-sensitive paralytics that interfere with neuronal signaling: two mutations in dynamin that affect vesicle recycling, shi (ts1) and shi (ts2), and one that affects the voltage-activated Na(+) channel, para (ts1). We also used N ethylmaleimide (NEM) to pharmacologically interfere with synaptic function. We found that blocking the generation of action potentials using a temperature sensitive paralytic mutation does not induce nor prevent the development of functional tolerance to benzyl alcohol, but that disruption of synaptic signaling using mutations in the dynamin gene or by NEM treatment inhibits the induction of tolerance. PMID- 21318410 TI - Predictors of unsuccessful magnetic resonance imaging scanning in older generalized anxiety disorder patients and controls. AB - A thorough understanding of the neurobiology of late life anxiety is likely to depend on the use of brain imaging techniques such as magnetic resonance imaging (MRI). Generalized anxiety disorder (GAD) is one of the most prevalent anxiety disorders in older adults, and is thus a focus for neurobiological studies using MRI. This study tested 1-3 weeks predictors of unsuccessful scan outcomes (i.e., scan trials in which the participant moved excessively or prematurely terminated the scan) in older adults with GAD (n = 39) and age- and sex-matched nonanxious controls (n = 21). It was hypothesized that successful completion of a prior MRI scan, clinical status (GAD versus control), and scores on the Anxiety Sensitivity Index (ASI; Peterson et al. 1986), a measure tapping psychological aspects of medical interventions, would predict scan outcome when current diagnoses of claustrophobia were controlled. In logistic regression analyses, unsuccessful scan outcome was predicted by prior MRI completion and ASI Mental Concerns subscale scores, but not clinical status. This model correctly classified 91% of successful and 71% of unsuccessful scans. An alternative model that included a single ASI item rather than Mental Concerns subscale scores showed similar performance, and a model including categorical anxiety sensitivity groups was also effective but slightly less accurate. Implications for improving the success rates of MRI with older adults are discussed. PMID- 21318411 TI - Discrimination as a key mediator of the relationship between posttraumatic stress and HIV treatment adherence among African American men. AB - Posttraumatic stress disorder (PTSD) is relatively common among people living with HIV/AIDS (PLHA) and may be associated with antiretroviral therapy (ART) adherence. We examined the relationship between PTSD symptom severity and adherence among 214 African American males. Because PLHA may experience discrimination, potentially in the form of traumatic stress (e.g., hate crimes), we also examined whether perceived discrimination (related to race, HIV status, sexual orientation) is an explanatory variable in the relationship between PTSD and adherence. Adherence, monitored electronically over 6 months, was negatively correlated with PTSD total and re-experiencing symptom severity; all 3 discrimination types were positively correlated with PTSD symptoms and negatively correlated with adherence. Each discrimination type separately mediated the relationship between PTSD and adherence; when both PTSD and discrimination were included in the model, discrimination was the sole predictor of adherence. Findings highlight the critical role that discrimination plays in adherence among African American men experiencing posttraumatic stress. PMID- 21318412 TI - Motivational interviewing + feedback intervention to reduce alcohol-exposed pregnancy risk among college binge drinkers: determinants and patterns of response. AB - Many college women are at risk for pregnancy, and binge drinking college women are often at risk for alcohol-exposed pregnancy. Brief interventions with sustainable outcomes are needed, particularly for college women who are binge drinking, at risk for pregnancy, and at increased risk of alcohol-exposed pregnancy. Two-hundred-twenty-eight women at a Mid-Atlantic urban university at risk for alcohol-exposed pregnancy enrolled in the randomized clinical trial, and 207 completed the 4 month follow-up. The BALANCE intervention used Motivational Interviewing plus feedback to target drinking and contraception behaviors. Main outcome measures included (1) the rate of risk for alcohol-exposed pregnancy, (2) the rate of risk drinking, and (3) the rate of pregnancy risk. At 4-month follow up, the rate of alcohol-exposed pregnancy risk was significantly lower in the intervention (20.2%) than the control condition (34.9%), (P < .02). Assignment to the intervention condition halved the odds of women remaining at risk for alcohol exposed pregnancy, while not receiving the intervention doubled the odds of continued alcohol-exposed pregnancy risk (OR = 2.18; 95% CI = 1.16-4.09). A baseline history of blackouts, continued high blood alcohol drinking days at 1 month, and continued risk for pregnancy at 1 month independently contributed to a multivariate model of continued alcohol-exposed pregnancy risk at 4 month follow up. BALANCE reduced alcohol-exposed pregnancy risk, with similar outcomes to longer interventions. Because early response predicted sustained alcohol-exposed pregnancy risk reduction, those who fail to achieve initial change could be identified for further intervention. The BALANCE intervention could be adopted into existing student health or university alcohol programs. The risks of unintended pregnancy and alcohol-exposed pregnancy among binge drinking women in college merit greater prevention efforts. PMID- 21318413 TI - Microvesicles as mediators of intercellular communication in cancer--the emerging science of cellular 'debris'. AB - Cancer cells emit a heterogeneous mixture of vesicular, organelle-like structures (microvesicles, MVs) into their surroundings including blood and body fluids. MVs are generated via diverse biological mechanisms triggered by pathways involved in oncogenic transformation, microenvironmental stimulation, cellular activation, stress, or death. Vesiculation events occur either at the plasma membrane (ectosomes, shed vesicles) or within endosomal structures (exosomes). MVs are increasingly recognized as mediators of intercellular communication due to their capacity to merge with and transfer a repertoire of bioactive molecular content (cargo) to recipient cells. Such processes may occur both locally and systemically, contributing to the formation of microenvironmental fields and niches. The bioactive cargo of MVs may include growth factors and their receptors, proteases, adhesion molecules, signalling molecules, as well as DNA, mRNA, and microRNA (miRs) sequences. Tumour cells emit large quantities of MVs containing procoagulant, growth regulatory and oncogenic cargo (oncosomes), which can be transferred throughout the cancer cell population and to non-transformed stromal cells, endothelial cells and possibly to the inflammatory infiltrates (oncogenic field effect). These events likely impact tumour invasion, angiogenesis, metastasis, drug resistance, and cancer stem cell hierarchy. Ongoing studies explore the molecular mechanisms and mediators of MV-based intercellular communication (cancer vesiculome) with the hope of using this information as a possible source of therapeutic targets and disease biomarkers in cancer. PMID- 21318415 TI - A Lotka-Volterra competition model with seasonal succession. AB - A complete classification for the global dynamics of a Lotka-Volterra two species competition model with seasonal succession is obtained via the stability analysis of equilibria and the theory of monotone dynamical systems. The effects of two death rates in the bad season and the proportion of the good season on the competition outcomes are also discussed. PMID- 21318414 TI - Advances of genomic science and systems biology in renal transplantation: a review. AB - The diagnosis of rejection in kidney transplant patients is based on histologic classification of a graft biopsy. The current "gold standard" is the Banff 97 criteria; however, there are several limitations in classifying rejection based on biopsy samples. First, a biopsy involves an invasive procedure. Second, there is significant variance among blinded pathologists in the interpretation of a biopsy. And third, there is also variance between the histology and the molecular profiles of a biopsy. To increase the positive predictive value of classifiers of rejection, a Banff committee is developing criteria that integrate histologic and molecular data into a unified classifier that could diagnose and prognose rejection. To develop the most appropriate molecular criteria, there have been studies by multiple groups applying omics technologies in attempts to identify biomarkers of rejection. In this review, we discuss studies using genome-wide data sets of the transcriptome and proteome to investigate acute rejection, chronic allograft dysfunction, and tolerance. We also discuss studies which focus on genetic biomarkers in urine and peripheral blood, which will provide clinicians with minimally invasive methods for monitoring transplant patients. We also discuss emerging technologies, including whole-exome sequencing and RNA-Seq and new bioinformatic and systems biology approaches, which should increase the ability to develop both biomarkers and mechanistic understanding of the rejection process. PMID- 21318416 TI - Differential movement and movement bias models for marine protected areas. AB - Marine protected areas (MPAs) are promoted as a tool to protect overfished stocks and increase fishery yields. Previous models suggested that adult mobility modified effects of MPAs by reducing densities of fish inside reserves, but increasing yields (i.e., increasing densities outside of MPAs). Empirical studies contradicted this prediction: as mobility increased, the relative density of fishes inside MPAs (relative to outside) increased or stayed constant. We hypothesized that this disparity between theoretical and empirical results was the result of differential movement of fish inside versus outside the MPA. We, therefore, developed a model with unequal and discontinuous diffusion, and analyzed its steady state and stability. We determined the abundance in the fishing grounds, the yield, the total abundance and the log ratio at steady-state and examined their response to adult mobility (while keeping the relative inequity in the diffusion constant). Abundance in the fishing grounds and yield increased, while total abundance and log-ratio decreased, as mobility increased. These results were all qualitatively consistent with the previous models assuming uniform diffusivity. Thus, the mismatch between empirical and theoretical results must result from other processes or other forms of differential movement. Therefore, we modified our original model by assuming that species located on the boundary of the MPA will preferentially move towards the MPA. This localized movement bias model gives rise to steady state profiles that can differ radically from the profiles in the unbiased model, especially when the bias is large. Moreover, for sufficiently large bias values, the monotonicity of the four measures with increased mobility is reversed, when compared with our original model. Thus, the movement bias model reconciles empirical data and theoretical results. PMID- 21318417 TI - The effects of acute ethanol consumption on sexual response and sexual risk taking intent. AB - Two theories of sexual risk taking (disinhibition and alcohol myopia) were tested using genital measures of sexual response and computer measures of sexual risk propensity. A total of 44 men and women completed two sessions comparing responses to erotic films while consuming alcohol (breath alcohol doses were .025 g/kg and .08 g/kg) or juice alone. After consuming alcohol, more sexual arousal was reported in response to neutral films and at a breath alcohol level of .08 g/kg as compared to no alcohol. Genital responses for men and women increased during sexual films, but men did not respond as strongly when breath alcohol level was .08 g/kg. Intentions to have intercourse with a new partner at baseline predicted the level of sexual arousal reported. As self-reported sexual arousal increased in response to sexual films and higher alcohol dose, the intent to engage in intercourse with a new partner increased. Alcohol dose was not related to later sexual intercourse intentions. With no direct relationship of alcohol and intercourse intentions, results appear more consistent with a disinhibition model of sexual arousal. PMID- 21318418 TI - Granular cell tumor of the male breast. AB - A 54-year-old male presented with a painless, hard, irregular lump in his right breast, with fixation to the pectoralis muscle. Mammography and ultrasound showed a 2.5-cm mass suspicious of malignancy. The patient underwent a wide local excision. A 2.5-cm hard, stellate lump was found and sent to the pathologist, which revealed this to be a benign granular cell tumor. Granular cell tumor of the breast is a rare neoplasm, of unknown etiology, which is benign in 98% of cases, but mimics breast cancer, causing challenging diagnostic and therapeutic dilemmas. Traditional imaging techniques do not recognize any feature specific for this tumor. Only excisional biopsy allows the detection of the distinct histological and immunohistochemical profile of the lesion (granular cytoplasm and staining for the S-100 protein). Only local surgical excision is indicated. General and senologist surgeons must be aware of this entity to avoid unnecessary mastectomy or lymphadenectomy. PMID- 21318419 TI - VEGF masks BNIP3-mediated apoptosis of hypoxic endothelial cells. AB - Hypoxia results in the apoptotic death of myocytes, neurons, and epithelial cells, through the actions of Bcl-2 and Nineteen kilodalton Interacting Protein-3 (BNIP3). On the contrary, endothelial cells are especially adept at surviving conditions of oxygen deprivation via up-regulation of vascular endothelial growth factor (VEGF) the most potent endothelial survival factor. Both VEGF and BNIP3 expression are transcriptionally regulated by hypoxia inducible factor and may antagonize each other's affects in endothelial cells (ECs). Since factors that promote and inhibit apoptosis may be expressed at the same time in endothelial cells under hypoxic conditions, we decided to investigate whether VEGF and BNIP3 have opposing actions in endothelial cells. Human microvascular endothelial cells were exposed to hypoxic conditions in a Billups-Rothenburg chamber. Under hypoxic conditions BNIP3 expression by endothelial cells increased as measured by real time PCR and immunoblot. After 48 h of hypoxia, EC apoptosis was assessed by flow cytometry and was lower than in corresponding normoxia serum starved controls. The increase in EC survival under hypoxic conditions corresponded with an increase in the expression of VEGF. Under normoxic conditions adenoviral BNIP3 over-expression promoted apoptosis of ECs; however, recombinant VEGF (100 pg/ml) antagonized the BNIP3 apoptosis promoting affects. SiRNA knockdown of VEGF expression by hypoxic ECs resulted in increased apoptosis with a concomitant increase in BNIP3 expression. SiRNA knockdown of BNIP3 expression by hypoxic ECs reduced the increase in EC apoptosis as a result of VEGF knockdown. We conclude that under hypoxic conditions VEGF counteracts and masks the apoptosis promoting affects of BNIP3. PMID- 21318421 TI - Evaluation of a multi-pinhole collimator for imaging small animals with different sizes. AB - PURPOSE: Our goal was to evaluate a multi-pinhole (MPH) collimator which allows changing configurations for mouse imaging and rat imaging. PROCEDURES: The collimator length can be adjusted from 5 cm for rat imaging to a maximum of 8 cm for mouse imaging. Projections of mouse- and rat-size phantoms were simulated with collimator length of 8 cm, and the rat-size phantom was additionally simulated with collimator length of 5 cm. Bias and noise were assessed in the reconstructed images. Three physical phantoms were used to evaluate the axial sampling and resolutions for one-, four-, and five-pinhole single photon emission computed tomography (SPECT). Images of three different-sized rodents were also acquired. RESULTS: Simulations showed that for rat imaging, shorter collimator length provided an improved bias-noise trade-off compared to that of longer collimator length. Axial distortions were significantly reduced for MPH compared to single pinhole imaging. The smallest rods visible for mouse imaging and rat imaging were 1 and 1.6 mm, respectively, and their corresponding absolute sensitivities were 3.47% and 2.02% at the center field-of-view for 5-pinhole imaging. The count ratios were 1:3.78:4.42, respectively, for one-, four-, and five-pinhole for same acquisition time. Good image quality was observed in real animal studies. CONCLUSIONS: This collimator allows flexible single pinhole and MPH SPECT imaging for rodents, achieving high resolution and detection efficiency with minimal image artifacts. PMID- 21318422 TI - Impact of an antibiotic restriction program on antibiotic utilization in the treatment of community-acquired pneumonia in a Veterans Affairs Medical Center. AB - PURPOSE: The impact of an antibiotic restriction program (ARP) on the patterns of antibiotic use in the treatment of community-acquired pneumonia (CAP) was examined. We also evaluated the association between the ARP and the length of hospital stay in regard to CAP treatment and cost savings associated with the implementation of the ARP. METHODS: A retrospective cohort study of patients admitted with CAP was conducted during two 6-month periods, one prior to the ARP and one after the ARP. The health system's computerized patient record system (CPRS) was used to obtain demographics, length of hospital stays, readmission rates, blood culture results, co-morbidities, antibiotic use, and durations of therapy. A total of 130 patients met the inclusion criteria for the final analyses. Average drug costs, employee salaries, and the cost of laboratory procedures were used to assess cost savings associated with the ARP. RESULTS: From a total of 132 antibiotics that were ordered to treat CAP in the pre-ARP period, 28 were restricted (21.2%). However, the number of restricted antibiotics ordered was significantly reduced to 12 out of 114 (10.2%) antibiotics ordered in the post-ARP period (P = 0.024). In post-ARP implementation, the mean length of hospital stay was also significantly reduced from 7.6 to 5.8 days (P = 0.017), and although not statistically significant, the 30-day readmission rates declined from 16.9 to 6.2% (P = 0.097). The ARP was also associated with a saving of $943 per patient treated for CAP. CONCLUSIONS: In addition to a decrease in the antibiotic utilization and the mean length of hospital stay, the ARP may have yielded cost savings and reduced the readmission rates for those patients admitted and treated for CAP. PMID- 21318423 TI - Identification of yeasts during alcoholic fermentation of tchapalo, a traditional sorghum beer from Cote d'Ivoire. AB - This study investigated the diversity and dynamics of yeasts involved in alcoholic fermentation of a traditional sorghum beer from Cote d'Ivoire, tchapalo. A total of 240 yeast strains were isolated from fermenting sorghum wort inoculated with dry yeast from two geographic regions of Cote d'Ivoire (Abidjan and Bondoukou). Initial molecular identification to the species level was carried out using RFLP of PCR-amplified internal transcribed spacers of rDNA (ITS1-5.8S ITS2). Ten different profiles were obtained from the restriction of PCR products with the three endonucleases HaeIII, CfoI and HinfI. Sequence analysis of the D1/D2 domain of the 26S rDNA and the ACT1 gene allowed us to assign these groups to six different species: Saccharomyces cerevisiae-like, Candida tropicalis, Pichia kudriavzevii, Pichia kluyveri, Kodamaea ohmeri and Meyerozyma caribbica. The most frequent species associated with tchapalo fermentation was S. cerevisiae like (87.36%), followed by C. tropicalis (5.45%) and M. caribbica (2.71%). S. cerevisiae-like strains were diploid heterozygotes and exhibited three to four nucleotides divergence from the type strain in the D1/D2 domain and several indels in the more discriminant sequence of the intron of the ACT1 gene. During the process, the yeast species isolated and their frequencies varied according to the geographic origin of the dry yeast. The occurrence of some species was sporadic and only two non-Saccharomyces species were found in the final product. PMID- 21318424 TI - Assessing the character of the rhBMP-2- and vancomycin-loaded calcium sulphate composites in vitro and in vivo. AB - BACKGROUND: The treatment of contaminated and infected bone defects remains an intractable problem and the ideal approach is to control infection and repair the bone defect at the same time. Thus, developing an osteoconductive bone graft composite with antibiotic and growth factor release capabilities as well as osteogenesis-matched degradation properties is necessary. A new calcium sulphate composite consisting of vancomycin and rhBMP-2 was developed, and the present study assessed its efficiency in vitro and in a rabbit tibial defect model. METHODS: Firstly, we detected the bioactivity of rhBMP-2 released from the composites by ALP assay in vitro. Then, the released vancomycin in bone tissue within 1 cm from implanted site was detected by HLPC at 1, 3, 5, 7, 14, 21 and 28 days after implantation. The rhBMP-2 concentration of tissues around the defects was also detected by ELISA. Histomorphometry and histomorphometrical analysis at 5, 14 and 28 days post-implantation was done for assessing its osteoinductivity for bone defects. RESULTS: The results showed rhBMP-2 was still active in vitro at 29 days. In vivo, the composite released an initial bolus of vancomycin and rhBMP-2 to the bone followed by gradual release for more than 14 and 21 days, respectively. The histomorphometry indicated that the composite significantly augmented new bone formation in the defect compared to the control. CONCLUSIONS: This composite may be a potential therapeutic agent for contaminated or infected bone defects due to its concomitant osteoinductive and antibiotic properties. PMID- 21318425 TI - Incidence of colorectal cancer in Kashmir valley, India. AB - BACKGROUND: There is wide variation in the incidence of colorectal cancer globally and also within the same country among different racial or ethnic groups. The present population-based study was undertaken to determine the incidence of colorectal cancer in Kashmiri population which is non-migratory and ethnically homogeneous having stable food habits. METHODS: Over a period of one year, all newly diagnosed and histological proved cases of colorectal cancer in all possible areas, where such patients are diagnosed and treated were prospectively registered. RESULTS: A total of 212 cases of colorectal cancers were registered; of them 113 (53.3%) originated in the colon and other 99 (46.7%) in rectum. Male to female ratio was 1.2:1. The crude incidence rate of colorectal cancer was 3.65/100,000; it was 3.78 in males, and 3.50/100,000 in females. The incidence rates for colorectal cancer in Muslims and Hindus were different. The crude incidence rate for colorectal carcinoma was highest for district Srinagar 6.19/100,000 (urban area) and lowest for district Kupwara (rural area) 1.59/100,000. The highest numbers of cases were detected in the age group 55-59 years (n = 34). The age-specific rate for colorectal carcinoma was highest in the age group 55-59 years (17.21/100,000), followed by 65-69 years (14.86/100,000). The age standardized incidence rate was 4.52/100,000 per year. The truncated age adjusted incidence rates in age group 35-64 years was 8.31/100,000; while that for colorectal carcinoma was 8.77/100,000 in males and 7.66/100,000 in females. CONCLUSION: We conclude that the incidence of colorectal cancer in Kashmir valley is similar to that reported in the rest of India. PMID- 21318426 TI - Computed tomography in children: multicenter cohort study design for the evaluation of cancer risk. AB - Exposure to ionizing radiation is a known risk factor for cancer. Cancer risk is highest after exposure in childhood. The computed tomography is the major contributor to the average, individual radiation exposure. Until now the association has been addressed only in statistical modeling. We present the first feasible study design on childhood cancer risk after exposure to computed tomography. PMID- 21318427 TI - Local neighborhood behavior in a combinatorial library context. AB - This article revisits a particular aspect of the molecular similarity principle the Neighborhood Behavior (NB) concept. Earlier, the NB optimality criterion was introduced to select descriptor spaces, combining a given descriptor set and a similarity metric, which optimally comply with the similarity principle. Here, we focus on a "local" analysis based on the neighborhood of individual bioactive compounds. The defined NB-score measures similarity-based virtual screening success when using individual actives as queries. Systematic studies of local NB have been performed on a large combinatorial library of compounds with reported IC (50) values for five proteases, involving more than 140 descriptor/metric combinations of various fragment- and pharmacophore-based descriptors and different similarity metrics. Although, for each descriptor/metrics combination, the NB-score heavily depends on the query compound, on the average, 2D pharmacophore-based descriptors outperformed their 3D counterparts. PMID- 21318428 TI - Retraction note. Erratum to: Long-term outcome of Rives-Stoppa technique in complex ventral incisional hernia repair. PMID- 21318429 TI - Controlled tissue expansion in the initial management of the short bowel state. AB - The treatment of short gut syndrome has evolved dramatically during the past decade. The combination of surgical techniques and medical management in the context of a multidisciplinary approach has improved the outcomes of these children. The authors describe in detail their technique of controlled tissue expansion of the bowel before lengthening procedures. Monitoring of the child and troubleshooting actions during the controlled tissue expansion program also are discussed. PMID- 21318430 TI - Evaluation of current devices in single-incision laparoscopic colorectal surgery: a preliminary experience in 32 consecutive cases. AB - BACKGROUND: Single-incision laparoscopic colorectal surgery (SILS) suggests a promising alternative to conventional laparoscopic surgery. In this report we describe our initial experience with SILS for both right hemicolectomies and anterior resections. METHODS: Between June 2009 and May 2010, SILS was performed for 32 consecutive cases with benign and malignant pathology. Demographic data, intraoperative parameters, postoperative data, and pathologic data were assessed. RESULTS: Twenty-one SILS right hemicolectomies, ten ARs, and one abdominal perineal resection (APR) were performed. For SILS right hemicolectomies, one case required full "conversion" to a laparoscopic procedure. The median operating time was 85 min (range 45-150 min) and the median wound length was 5.0 cm (range 3.0 10.0 cm). Median number of lymph nodes extracted in malignant cases was 17(range 10-30) and the overall median length of stay was 6 days (range 5-11). For left sided lesions, ten cases of ARs (7 high ARs, 2 low ARs, 1 ultralow AR) and one APR were performed. Three cases were completed successfully via the SILS procedure, four cases required one additional port, and four cases required full "conversion" to a laparoscopic procedure. The median operating time was 120 min (range 65-235 min) and the median wound length was 5.0 cm (range 3.0-7.0 cm). Overall median length of stay was also 6 days (range 5-21). There was one case of anastomotic leak and one case of postoperative bleeding. CONCLUSION: In our experience, SILS for right hemicolectomies is safe and effective with reproducible oncologic results. SILS AR, however, requires greater modifications in current devices and techniques. SILS AR can be performed for both malignant and benign diseases but additional ports may be necessary for the safe completion of the procedure. PMID- 21318431 TI - Percutaneous drainage versus emergency cholecystectomy for the treatment of acute cholecystitis in critically ill patients: does it matter? AB - BACKGROUND: The aim if this study was to compare percutaneous drainage (PD) of the gallbladder to emergency cholecystectomy (EC) in a well-defined patient group with sepsis related to acute calculous/acalculous cholecystitis (ACC/AAC). METHODS: Between 2001 and 2007, all consecutive patients of our ICU treated by either PD or EC were retrospectively analyzed. Cases were collected from a prospective database. Percutaneous drainage was performed by a transhepatic route and EC by open or laparoscopic approach. Patients' general condition and organ dysfunction were assessed by two validated scoring systems (SAPS II and SOFA, respectively). Morbidity, mortality, and long-term outcome were systematically reviewed and analyzed in both groups. RESULTS: Forty-two patients [median age = 65.5 years (range = 32-94)] were included; 45% underwent EC (ten laparoscopic, nine open) and 55% PD (n = 23). Both patient groups had similar preoperative characteristics. Percutaneous drainage and EC were successful in 91 and 100% of patients, respectively. Organ dysfunctions were similarly improved by the third postoperative/postdrainage days. Despite undergoing PD, two patients required EC due to gangrenous cholecystitis. The conversion rate after laparoscopy was 20%. Overall morbidity was 8.7% after PD and 47% after EC (P = 0.011). Major morbidity was 0% after PD and 21% after EC (P = 0.034). The mortality rate was not different (13% after PD and 16% after EC, P = 1.0) and the deaths were all related to the patients' preexisting disease. Hospital and ICU stays were not different. Recurrent symptoms (17%) occurred only after ACC in the PD group. CONCLUSIONS: In high-risk patients, PD and EC are both efficient in the resolution of acute cholecystitis sepsis. However, EC is associated with a higher procedure-related morbidity and the laparoscopic approach is not always possible. Percutaneous drainage represents a valuable intervention, but secondary cholecystectomy is mandatory in cases of acute calculous cholecystitis. PMID- 21318433 TI - Relation between proteins tertiary structure, tryptophan fluorescence lifetimes and tryptophan S(o)->(1)L(b) and S(o)->(1)L(a) transitions. Studies on alpha1 acid glycoprotein and beta-lactoglobulin. AB - We measured fluorescence lifetimes and fluorescence spectra (excitation and emission) of tryptophan residues of alpha(1)-acid glycoprotein (three Trp residues) and beta-lactoglobulin (two Trp residues) in absence and presence of 450 MUM progesterone. Progesterone binds only to alpha(1)-acid glycoprotein. In absence of progesterone, each of the two proteins displays three fluorescence lifetimes. Addition of progesterone induces a partial inhibition of the S(o) -> (1)L(a) transition without affecting fluorescence lifetimes. The same experiments performed in presence of denatured proteins in 6 M guanidine show that addition of progesterone inhibits partially the S(o) -> (1)L(a) transition and its peak is 15 nm shifted to the red compared to that obtained for native proteins. However, the S(o) -> (1)L(b) transition position peak is not affected by protein denaturation. Thus, the tertiary structure of the protein plays an important role by modulating the tryptophan electronic transitions. Fluorescence emission decay recorded in absence and presence of progesterone yields three fluorescence lifetimes whether proteins are denatured or not. Thus, protein tertiary structure is not responsible for the presence of three fluorescence lifetimes. These characterize tryptophan substructures reached at the excited states and which population (pre-exponential values) depend on the tryptophan residues interaction with their microenvironment(s) and thus on the global conformation of the protein. PMID- 21318434 TI - Mechanical influences on fluid leakage past the tracheal tube cuff in a benchtop model. AB - PURPOSE: High-volume low-pressure (HVLP) cuffs on endotracheal tubes do not fully protect the lower airway from leakage of potentially contaminated secretions down the longitudinal folds within the cuff. Here, our purpose was to evaluate potential effects of positive end-expiratory pressure (PEEP), inspiratory effort intensity, and tube characteristics on fluid leakage past the cuff. METHODS: This benchtop study at a research laboratory used a tracheal tube inserted into an artificial Plexiglas trachea connected to a ventilator and lung model. Methylene blue was deposited above the tube cuff to simulate subglottic secretions. Five PEEP levels (0, 5, 10, 15, and 20 cmH2O) were tested with volume-controlled ventilation and three simulated inspiratory effort levels with pressure-support ventilation. Several cuff materials and tube sizes were tested. RESULTS: The leakage occurrence rate ranged from 91% with zero PEEP to 8% with 15 and 20 cmH2O PEEP and was indirectly proportional to the PEEP level with significant correlation (R2 = 0.39, p < 0.001), an effect not explained by higher peak inspiratory pressure. Low, moderate, and high inspiratory effort intensities were associated with 38%, 46%, and 75% leakage rates, respectively (p = 0.024). Leakage flow was considerably less with polyurethane than with polyvinylchloride tubes (mean 0.5 versus 31.8 ml/h). Leakage increased with larger tube diameters. CONCLUSION: This benchtop study shows that PEEP and a polyurethane cuff prevent leakage past the endotracheal tube cuff, whereas greater inspiratory effort and larger tube diameters for given tracheal size induce or worsen leakage. PMID- 21318435 TI - Repetitive gas embolisms after central catheter removal. PMID- 21318436 TI - Coagulation management in multiple trauma: a systematic review. AB - PURPOSE: The management of trauma patients suffering from active bleeding has improved with a better understanding of trauma-induced coagulopathy. The aim of this manuscript is to give recommendations for coagulation management. METHODS: A systematic literature search in the PubMed database was performed for articles published between January 2000 and August 2009. A total of 230 articles were included in the present systematic review. CONCLUSIONS: The "coagulopathy of trauma" is a discrete disease which has a decisive influence on survival. Diagnosis and therapy of deranged coagulation should start immediately after admission to the emergency department. A specific protocol for massive transfusion should be introduced and continued. Loss of body temperature should be prevented and treated. Acidaemia should be prevented and treated by appropriate shock therapy. If massive transfusion is performed using fresh frozen plasma (FFP), a ratio of FFP to pRBC (packed red blood cells) of 1:2-1:1 should be achieved. Fibrinogen should be substituted at levels of <1.5 g/L. For patients suffering from active bleeding, permissive hypotension (i.e. mean arterial pressure ~65 mmHg) may be aimed for until surgical cessation of bleeding. This option is contraindicated in injuries of the central nervous system and in patients with coronary heart disease, or with known hypertension. Thrombelastography or -metry may be performed to guide coagulation diagnosis and substitution. Hypocalcaemia <0.9 mmol/L should be avoided and may be treated. For actively bleeding patients, pRBC may be given at haemoglobin <10 g/L (6.2 mmol/L) and haematocrit may be targeted at 30%. PMID- 21318437 TI - Extracorporeal membrane oxygenation for severe ARDS in pregnant and postpartum women during the 2009 H1N1 pandemic. AB - PURPOSE: To describe the technical challenges, efficacy, complications and maternal and infant outcomes associated with extracorporeal membrane oxygenation (ECMO) for severe adult respiratory distress syndrome (ARDS) in pregnant or postpartum patients during the 2009 H1N1 pandemic. METHODS: Twelve critically ill pregnant and postpartum women were included in this retrospective observational study on the application of ECMO for the treatment of severe ARDS refractory to standard treatment. The study was conducted at seven tertiary hospitals in Australia and New Zealand. RESULTS: Of the 12 patients treated with ECMO, 7 (58%) were pregnant and 5 (42%) were postpartum. Their median (interquartile range [IQR]) age was 29 (26-33) years, 6 (50%) were obese. Two patients were initially treated with veno-arterial (VA) ECMO. All others received veno-venous (VV) ECMO with one or two drainage cannulae. ECMO circuit-related complications were rare, circuit change was needed in only two cases and there was no sudden circuit failure. On the other hand, bleeding was common, leading to relatively large volumes of packed red blood cell transfusion (median [IQR] volume transfused was 3,499 [1,451-4,874] ml) and was the main cause of death (three cases). Eight (66%) patients survived to discharge and seven were ambulant, with normal oxygen saturations. The survival rate of infants whose mothers received ECMO was 71% and surviving infants were discharged home with no sequelae. CONCLUSIONS: The use of ECMO for severe ARDS in pregnant and postpartum women was associated with a 66% survival rate. The most common cause of death was bleeding. Infants delivered of mothers who had received ECMO had a 71% survival rate and, like their mothers, had no permanent sequelae at hospital discharge. PMID- 21318438 TI - Social integration: an important factor for health-related quality of life after critical illness. AB - OBJECTIVES: To examine to what extent availability of social integration affects health-related quality of life (HRQoL) in former intensive care unit (ICU) patients and how it relates to corresponding findings in a general reference group. DESIGN: Controlled, multicenter, prospective, explorative study. SETTING AND PATIENTS: HRQoL data (SF-36) were collected from three combined medical and surgical ICUs in the south-east of Sweden. Social integration was assessed by the Availability of Social Integration (AVSI) instrument (seven questions related to the social interaction of the patient). As reference group, a random sample (n = 6,093) of people from the uptake area of the hospitals was used. Social integration (AVSI), HRQoL (SF-36), and comorbidity were examined also in the reference group. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: The level of social integration significantly affected HRQoL for the former ICU patients, whereas no such effect was seen for the general reference group. For the ICU patients, social integration affected HRQoL to a larger extent than age, sex, and the ICU-related factors examined, but to a lower extent than the pre-existing diseases. CONCLUSIONS: For a comprehensive assessment of HRQoL in former ICU patients, it is mandatory to include the effect of social integration. PMID- 21318439 TI - Sex steroids and bone health in older Chinese men. AB - This study examines the association between sex steroids, bone mineral density (BMD), and incident fractures in 1,489 community-living Chinese men aged 65 and over. Chinese men with low serum estradiol levels display elevated bone loss and increased risk of fractures similar to findings in Caucasians. INTRODUCTION: This study examines the association between serum total testosterone (TT), free testosterone (free T), estradiol (E(2)), bioavailable estradiol (bioE(2)), sex hormone binding globulin (SHBG), BMD, and incident fractures. METHODS: This is a cohort study with 4-year follow-up in the community in Hong Kong SAR, China. One thousand four hundred eighty-nine community-living Chinese men aged 65 and over participated. Sex steroid levels and BMD were measured at baseline; BMD was repeated after 4 years of follow-up, and fracture incidence from ascertainment from hospital databases was determined over 4 years of follow-up. RESULTS: The strongest age-adjusted positive association with total hip and femoral neck BMD was with bioE(2), followed by E(2). Greater bone loss occurred in the lowest quartile of E(2) and bioE(2). The lowest quartile of free T and bioE(2) and the two highest quartile of SHBG were associated with the highest percentage of participants with incident fractures. Those in the lowest quartile of E(2) and bioE(2) had approximately a 50% increased risk of incident fractures compared with the other three quartiles. This relationship remains significant for nonvertebral incident fractures (hip, radius, pelvis, and humerus) for E(2) only, but not bioE(2). Compared with the group with the three highest quartiles of TT and E(2), the group with the lowest quartile of both had approximately twice the risk of nonvertebral osteoporosis-related incident fractures. CONCLUSION: Chinese men with low serum estradiol levels display elevated bone loss and increased risk of fractures similar to findings in Caucasians. PMID- 21318440 TI - Maintaining femoral bone density in adults: how many steps per day are enough? AB - The amount and intensity of walking to maintain a healthy skeleton is unknown. This study examined the relationship between habitual walking activity and femoral bone mineral density (BMD) in healthy individuals using a quantitative theory for bone maintenance. Our results suggest a gender, weight, and speed sensitivity of walking interventions. INTRODUCTION: Walking has been extensively promoted for the prevention of osteoporosis. The amount and intensity of walking to maintain a healthy skeleton is unknown and evidence to support a specific target of steps per day is lacking. The goal of our study was to examine the relationship between habitual walking activity and femoral bone mineral density (BMD) in healthy individuals using a quantitative theory for bone maintenance. METHODS: Habitual walking activity and total femur BMD were measured in 105 individuals (49-64 years). An index of cumulative loading (bone density index, BDI) was examined as a predictor of BMD. The BDI-BMD relationship was used to predict the steps per day to maintain healthy BMD values for a range of body weights (BW) and walking speeds. RESULTS: For females but not for males, BDI was correlated with BMD (r (2) = 0.19, p < 0.001). The total required steps per day to maintain a T-score of -1.0 for a female with the average BW of the study cohort, walking at 1.00 m/s is 4,892 steps/day. Substantially more steps (18,568 steps/day) are required for a female with a BW 20% lighter than the average for our female cohort. For these lighter females, only at a walking speed greater than 1.32 m/s was 10,000 steps/day sufficient to maintain a T-score of -1.0. CONCLUSIONS: Our results suggest a gender, weight, and speed sensitivity of walking interventions for osteoporosis. In persons of low BW, the necessary steps per day to maintain BMD can be substantially greater than the often-quoted 10,000 steps. PMID- 21318441 TI - Patient satisfaction after retropubic and transobturator slings: first assessment using the Incontinence Outcome Questionnaire (IOQ). AB - INTRODUCTION AND HYPOTHESIS: The aim of the Incontinence Outcome Questionnaire (IOQ) is to assess quality of life and patient-reported outcome after midurethral slings. METHODS: In this retrospective study, 626 patients with a minimum follow up period of 1 year were sent the IOQ. Four hundred twenty-two of 626 (67.4%) patient responses were evaluated. RESULTS: The mean IOQ QoL extended score was 33.7 +/- 17.5 and comparable for tension-free vaginal tape (TVT), outside-in transobturator tape (TOT), and inside-out transobturator vaginal tape (TVT-O). Evaluation of IOQ question about readmission revealed a total of 32 patients (18 TVT, 12 TOT, and 2 TVT-O) who underwent a subsequent operation due to sling related complications. Freedom from reoperation for recurrent SUI at 1, 2, and 5 years was 100%, 99.7 +/- 0.3%, and 99.7 +/- 0.3% for TVT, 100% for TVT-O, and 94.2 +/- 2.5%, 91.9 +/- 2.9%, and 89.9 +/- 3.5% for TOT, respectively (p < 0.001). CONCLUSIONS: Patient satisfaction, assessed using the IOQ, is high after retropubic and transobturator slings. In our collective, relapse incontinence is higher after TOT. PMID- 21318442 TI - Bupivacaine injection during midurethral sling and postoperative pain: a randomized controlled trial. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to investigate the impact of retropubic injection of 0.125% bupivacaine during midurethral sling placement on postoperative pain. METHODS: A randomized, double-blind trial of 42 women undergoing midurethral sling for stress incontinence was conducted. The intervention group received an injection of 0.125% bupivacaine in the retropubic space prior to midurethral sling placement, while the control group received no injection. Pain scores were recorded via a 10-cm visual analog scale at 2, 6, and 24 h postoperatively. RESULTS: Pain scores were lower in the bupivacaine group compared to the control group at 2 h (1.9 versus 2.6, p = 0.05). Mean pain scores were similar at all other time points (all p > 0.45). Participants in both groups used similar amounts of pain medication in the hospital, except that patients in the bupivacaine group used more PO non-steroidal anti-inflammatory drugs (p = 0.047). CONCLUSIONS: Retropubic injection of 0.125% bupivacaine at the time of midurethral sling placement decreases short-term postoperative pain. PMID- 21318443 TI - Sigmoid diverticulitis in young patients--a more aggressive disease than in older patients? AB - INTRODUCTION: There is controversy over whether sigmoid diverticulitis (SD) is more aggressive with a higher risk of perforation in younger than in older patients. The aim of this study was to assess the clinical presentation and outcome of patients <=40 and >40 years old with acute diverticulitis. PATIENTS AND METHODS: Consecutive admissions of all patients with acute SD were prospectively recruited from January 1998 to June 2010. RESULTS: A total of 1,019 patients were included: 513 (69 <=40 years and 444 >40 years) presented with their first episode, while 506 (20 <=40 years, 486 >40 years) had a prior history of SD. The percentage of patients with severe SD did not differ between the two age groups either for the first (covered perforation, 30.4% vs. 29.5%, p = 0.875; free perforation, 26.1% vs. 23.9%, p = 0.69) or for the recurrent episode (covered perforation, 15% vs. 8.2%, p = 0.287; free perforation, 5% vs. 4.1%, p = 0.846). Furthermore, the rate of emergency surgery did not differ between both age groups either for the first (26.1% vs. 23.9%, p = 0.690) or the recurrent episode (5% vs. 4.1%, p = 0.846). No differences in the rate of Hartmann's procedure (52.6% vs. 68.3%, p = 0.180) and failure of conservative treatment (3.4% vs. 4.9%, p = 0.607) were observed between younger and older patients. CONCLUSION: Acute SD in younger patients is not more aggressive and has no higher risk of perforation or need for emergency surgery compared to older patients. PMID- 21318444 TI - Anatomic variations of intrahepatic bile ducts in a European series and meta analysis of the literature. AB - BACKGROUND: Accurate knowledge of biliary anatomy and its variants is essential to ensure successful hepatic surgery; however, data from European countries are lacking. METHODS: Two hundred cholangiograms obtained from patients submitted to whole liver transplantation were reviewed; donors' characteristics were related to the prevalence of typical biliary anatomy and its variants. A comprehensive literature search was performed with MEDLINE and EMBASE from 1980 to 2010 to investigate whether geographical origin could be related to biliary abnormalities. RESULTS: Typical biliary anatomy was observed in 64.5% of cases, but female donors more frequently presented an anatomic variation; typical anatomy was present in 55.0% of females and in 74.0% of males (P = 0.005). Twenty two reports were identified by the literature search with a total of 7,559 cases, including the present series; heterogeneity was low (Q = 14.60; I2 < 5.0%) after exclusion of three outlier reports. Prevalence of typical biliary anatomy was similar in Europeans and Americans (~60%); a slightly higher prevalence was observed in Asiatics (~65%). CONCLUSIONS: Anatomic variants seem to be more frequent in females, probably as a consequence of different embryologic development. Available data suggest that typical biliary anatomy can be more frequent in Asiatics, but an accurate means of classification is essential to making comparison realistic. PMID- 21318445 TI - The potential of osteopontin as a therapeutic target for human colorectal cancer. AB - OBJECTIVE: Osteopontin (OPN), a phosphorylated glycoprotein, is involved in tumor progression and metastasis. Previously, we have reported that high OPN mRNA expression level possessed clinicopathological or prognostic significance in human colorectal cancer (CRC). The aim of this study is to investigate whether OPN can serve as a novel molecular target for CRC therapy. MATERIAL AND METHODS: Western Blot assay was performed to detect the expression of OPN protein in 18 CRC and corresponding nontumor colon tissue samples. RNA interference (RNAi) was employed to knockdown endogenous OPN expression in CRC cell line (LoVo). MTT, colony formation, and tumorigenicity assays were performed to analyze the effect of OPN downregulation on the in vitro and in vivo proliferation of CRC cells. Wound healing and Matrigel invasion assays were performed to analyze the effect of OPN downregulation on migration and invasion of CRC cells. A clonogenic cell survival assay after radiation was performed to analyze the effect of OPN downregulation on the radiosensitivity of CRC cells. RESULTS: The relative level of OPN protein expression in CRC tissues was significantly higher than that in corresponding nontumor colon tissues (P < 0.05). We found that RNAi-mediated OPN downregulation could inhibit not only in vitro proliferation but also in vivo tumorigenicity of CRC cells. In addition, OPN downregulation could suppress in vitro invasion capacity and enhance in vitro radiosensitivity of CRC cells, which might be associated with decreased levels of MMP-2 and -9 expression. CONCLUSION: RNAi-targeting OPN could inhibit proliferation, invasion and enhance radiosensitivity of human CRC cells. Therefore, OPN could serve as a novel molecular target for gene therapy of CRC. PMID- 21318446 TI - The clinical significance of lymphovascular and perineural invasions in patients with colorectal cancer. PMID- 21318447 TI - A penrose drain to help reflect the resected "specimen side" jejunum beneath the mesenteric vessels during a pancreaticoduodenectomy. AB - INTRODUCTION: Reflecting the resected portion of the proximal jejunum behind the mesenteric vessels during a pancreaticoduodenectomy (Whipple) procedure can be a challenging maneuver. METHODS: We describe a simple technique employing a penrose drain that is sutured to the resected "specimen" portion of the jejunum and then pulling it behind the mesenteric vessels. RESULTS: Seven patients underwent this procedure over a 2-month period without difficulties. CONCLUSIONS: This simple technique helps simplify one of the key maneuvers in performing a Whipple procedure. PMID- 21318449 TI - Good outcomes despite high urinary arsenic concentrations from overdose with crabgrass killer. PMID- 21318450 TI - Fasting FDG PET compared to MPI SPECT in cardiac sarcoidosis. PMID- 21318451 TI - Experimental facts supporting a red marrow uptake due to radiometal transchelation in 90Y-DOTATOC therapy and relationship to the decrease of platelet counts. AB - PURPOSE: The aim of this study was to retrospectively evaluate whether the red marrow (RM) takes up (111)In-diethylenetriaminepentaacetic acid (DTPA)-D-Phe(1) octreotide and (86)Y-DOTATOC and to assess the correlation between the RM absorbed doses and platelet count reduction as a biological dose estimate. METHODS: Data from 12 patients who underwent at 24 h p.i. high statistics (111)In single photon emission computed tomography (SPECT) and (86)Y positron emission tomography (PET) acquisitions of the chest were analysed. Uptake was measured on >7 cm spine length and converted to total RM uptake using standard RM distribution in man. RM absorbed doses were calculated assuming specific RM uptake and using the plasma and remainder of the body models. RM doses were correlated with the platelet count reduction at 4 weeks. In vitro experiments explored the metabolism of (111)In-DTPA-D-Phe(1)-octreotide and (90)Y-DOTATOC in plasma. RESULTS: The correlation between the uptake of both tracers was excellent (R = 0.80), indicating that RM uptake of (86)Y-DOTATOC reflects a real physiological process and not reconstruction artefacts. The kinetics of (86)Y DOTATOC RM activity was different than that in blood and tumours, with no activity at 4 h p.i. indicating that the uptake is not somatostatin receptor dependent. In vitro experiments showed a transchelation of both radiometals to free transferrin that could explain the RM uptake. In patients without chemotherapy and with a normal platelet count recovery, a good correlation (R = 0.96) was found between the RM doses and the platelet count reduction at the nadir. CONCLUSION: These experimental facts support the existence of a true RM uptake likely related to transchelation of the radiometal to transferrin. RM uptake correlates well with the observed acute RM toxicity. PMID- 21318452 TI - The effect of low-dose omega 3 fatty acids on the treatment of mild to moderate depression in the elderly: a double-blind, randomized, placebo-controlled study. AB - Due to the rise in the social and economic costs of depression, new antidepressant medication with fewer side effects should be found. Several studies have shown that an association exists between omega-3 polyunsaturated fatty acids (omega-3 PUFAs) and depression. However, this association has not been clear enough in the elderly with mild to moderate depression. Sixty-six inhabitants of Kahrizak Charity Foundation participated in this double-blind, randomized, placebo-controlled study. Each participant was >= 65 years of age, had a Mini Mental State Exam of >= 22, and had scores ranging from 5 to 11 on the Geriatric Depression Scale-15 (GDS-15). During the 6 months, the drug group was treated daily with one gram of fish oil capsule containing 300 mg of both eicosapentaenoic acid and docosahexaenoic acid. No significant differences were noted between the groups in regard to level of education, use of antidepressant drugs, alcohol, tobacco use, history of chronic diseases, age, body mass index (BMI), high-sensitive C-reactive protein (hs-CRP), total cholesterol, and GDS-15 scores at baseline. After adjusting for cholesterol, BMI, and history of thyroid dysfunctions, a statistically significant difference was seen in GDS-15 scores between both groups. Furthermore, treatment with omega-3 PUFAs was clinically more effective in treating depression in comparison with the placebo. In this study, low-dose omega-3 PUFAs had some efficacy in the treatment of mild to moderate depression in elderly participants. PMID- 21318453 TI - Effect of temperature difference between manikin and wet fabric skin surfaces on clothing evaporative resistance: how much error is there? AB - Clothing evaporative resistance is one of the inherent factors that impede heat exchange by sweating evaporation. It is widely used as a basic input in physiological heat strain models. Previous studies showed a large variability in clothing evaporative resistance both at intra-laboratory and inter-laboratory testing. The errors in evaporative resistance may cause severe problems in the determination of heat stress level of the wearers. In this paper, the effect of temperature difference between the manikin nude surface and wet textile skin surface on clothing evaporative resistance was investigated by both theoretical analysis and thermal manikin measurements. It was found that the temperature difference between the skin surface and the manikin nude surface could lead to an error of up to 35.9% in evaporative resistance of the boundary air layer. Similarly, this temperature difference could also introduce an error of up to 23.7% in the real clothing total evaporative resistance (R ( et_real ) < 0.1287 kPa m(2)/W). Finally, it is evident that one major error in the calculation of evaporative resistance comes from the use of the manikin surface temperature instead of the wet textile fabric skin temperature. PMID- 21318454 TI - Response of two mustard (Brassica juncea L.) cultivars differing in photosynthetic capacity subjected to proline. AB - The present paper deals with the effect of exogenous application of proline as a shotgun approach on growth, photosynthesis, and antioxidative system in 25-day old plants of two different cultivars of Brassica juncea L. (Varuna and RH-30) under natural conditions. Exogenous application of proline significantly increased plant growth, photosynthetic rate, and the activities of antioxidant enzymes, compared with untreated seedlings. Pre-sowing seed soaking in 20 mM proline, for 8 h, proved best among all the other concentrations used. PMID- 21318455 TI - Paternal incarceration and support for children in fragile families. AB - High U.S. incarceration rates have motivated recent research on the negative effects of imprisonment on later employment, earnings, and family relationships. Because most men in jail and prison are fathers, a large number of children may be placed at considerable risk by policies of incarceration. This article examines one dimension of the economic risk faced by children of incarcerated fathers: the reduction in the financial support that they receive. We use a population-based sample of urban children to examine the effects of incarceration on this support. Both cross-sectional and longitudinal regressions indicate that formerly incarcerated men are less likely to contribute to their families, and those who do contribute provide significantly less. The negative effects of incarceration on fathers' financial support are due not only to the low earnings of formerly incarcerated men but also to their increased likelihood to live apart from their children. Men contribute far less through child support (formal or informal) than they do when they share their earnings within their household, suggesting that the destabilizing effects of incarceration on family relationships place children at significant economic disadvantage. PMID- 21318456 TI - Abstracts of the Sylvester O'Halloran Meeting. March 4-5, 2011. Limerick, Ireland. PMID- 21318457 TI - A case of psoriasis with ANCA-negative pauci-immune crescentic glomerulonephritis in children. PMID- 21318458 TI - Nutcracker syndrome manifesting with severe proteinuria: a challenging scenario in a single-kidney patient. AB - Nutcracker syndrome (NS) refers to compression of the left renal vein between the aorta and the superior mesenteric artery which results in left renal venous hypertension. The typical clinical presenting feature is hematuria. In this report we describe the case of patient with a single kidney who developed severe proteinuria due to NS. She was successfully treated with left renal vein transposition. This case clearly shows the relation between NS and severe proteinuria based on normal biopsy findings and the complete disappearance of proteinuria following surgery. PMID- 21318460 TI - Impaired autonomic function in normotensive obese children. AB - PURPOSE: To evaluate baroreflex sensitivity and autonomic control in a cohort of normotensive obese (OB) children. METHOD: A cross-sectional investigation, in which, baroreflex sensitivity and autonomic control were evaluated using transfer function and power spectral density analysis (PSDA) of the electrocardiogram and beat-to-beat blood pressures in normotensive OB children and normal weight normotensive controls. All methods used were noninvasive and data were captured while seated and at rest. RESULTS: The OB and control subjects non-obese (NO) were of similar age (OB 9.1+/-1.9 years vs. NO 9.2+/-1.4 years). The OB group was classified as having a BMI greater than the 95th percentile adjusted for age and gender, and a NO group with a BMI at or less than the 95th percentile (BMI percentile OB. 97.5+/-1.3 vs. NO 58.5+/-24.1). Both groups had similar normotensive blood pressures. T tests revealed that baroreflex sensitivity and HFRR were significantly reduced in the OB 9.2+/-2.7 vs. 15.2+/-4.7 (ms/mmHg) and 6.7+/-1.1 vs. 8.2+/-1.1 ms2, respectively, while LFSBP and LF/HF ratio were significantly increased in the OB 11.9+/-5.6 vs. 8.2+/-4.7 mmHg2 and 1.2+/-0.7 vs. 0.54+/-0.3, respectively. CONCLUSIONS: Normotensive OB children exhibited significantly reduced baroreflex sensitivity, parasympathetic control as well as increased sympathetic control when compared with healthy, NO controls. Findings in this investigation raise the awareness that autonomic dysfunction is present in young OB normotensive children. PMID- 21318459 TI - The potential of the immunological markers of sarcoidosis in exhaled breath and peripheral blood as future diagnostic and monitoring techniques. AB - Sarcoidosis is characterised by non-caseating granulomatous inflammation, with exaggerated immune responses at sites of disease and derangements of normal tissue architecture. The lungs are most commonly involved and progressive inflammation may result in pulmonary fibrosis. The immunopathogenesis and aetiology remain uncertain, which has made it difficult to identify a single sufficiently sensitive or specific diagnostic marker. Further investigation is needed to identify sensitive and specific markers of disease, such as in peripheral blood and exhaled breath condensate (EBC). Identification of disease markers may also be useful for investigating disease activity and predicting progression to fibrosis. This review explores the literature on the cytokine profiles of blood and bronchoalveolar lavage lymphocytes following ex vivo stimulation, as well as disease markers measured using the medium of EBC. PMID- 21318461 TI - Link between heart rate and blood pressure Mayer wave during general anesthesia. AB - OBJECTIVE: Mayer wave (~10 s) blood pressure (BP) oscillations may represent rhythmic vasomotor activity. However, it remains unclear if volatile anesthetics disturb the coherence between heart rate (HR) and BP rhythms in this region, which may result in improperly affecting BP-HR modulation by the baroreflex, especially when sympathetic stimulation is evoked during general anesthesia using sevoflurane-nitrous oxide (Sev-N2O). METHODS: Twenty-seven patients were anesthetized with Sev-N2O, followed by surgical incision which induces Mayer wave augmentation. Baseline status before surgical incision was compared with that of 19 awake volunteers, and with status after surgical incision. Baroreflex function was assessed by gain and coherence by transfer function analysis, and the baroreflex effectiveness index (BEI). BP Mayer waves were measured by BP variability at a low frequency (LF) of ~0.1 Hz, and spontaneous baroreflex sensitivity (BRS) was obtained by assessing transfer function gain at LF (BRSLF), and the sequence technique (BRSSEQ). RESULTS: Sev-N2O anesthesia markedly reduced Mayer waves by 93%, BRSLF by 42%, BRSSEQ by 81%, BEI by 37%, coherence by 42%, and the number of coherent segments by 73%, compared with awake controls. During sympathetic stimulation by surgical incision, however, augmentation of Mayer waves (-1.57+/-0.72 vs. -0.60+/-1.00, ln mmHg2 P<0.001) did not improve depressed coherence above 0.5 (0.37+/-0.09 vs. 0.43+/-0.11) or BEI (0.17+/-0.13 vs. 0.13+/ 0.05). CONCLUSIONS: Sev-N2O anesthesia alters the link between HR and BP Mayer wave oscillation even during sympathetic stimulation, indicating weak spontaneous baroreceptor-HR modulation during general anesthesia. PMID- 21318462 TI - A new dawn for industrial photosynthesis. AB - Several emerging technologies are aiming to meet renewable fuel standards, mitigate greenhouse gas emissions, and provide viable alternatives to fossil fuels. Direct conversion of solar energy into fungible liquid fuel is a particularly attractive option, though conversion of that energy on an industrial scale depends on the efficiency of its capture and conversion. Large-scale programs have been undertaken in the recent past that used solar energy to grow innately oil-producing algae for biomass processing to biodiesel fuel. These efforts were ultimately deemed to be uneconomical because the costs of culturing, harvesting, and processing of algal biomass were not balanced by the process efficiencies for solar photon capture and conversion. This analysis addresses solar capture and conversion efficiencies and introduces a unique systems approach, enabled by advances in strain engineering, photobioreactor design, and a process that contradicts prejudicial opinions about the viability of industrial photosynthesis. We calculate efficiencies for this direct, continuous solar process based on common boundary conditions, empirical measurements and validated assumptions wherein genetically engineered cyanobacteria convert industrially sourced, high-concentration CO(2) into secreted, fungible hydrocarbon products in a continuous process. These innovations are projected to operate at areal productivities far exceeding those based on accumulation and refining of plant or algal biomass or on prior assumptions of photosynthetic productivity. This concept, currently enabled for production of ethanol and alkane diesel fuel molecules, and operating at pilot scale, establishes a new paradigm for high productivity manufacturing of nonfossil-derived fuels and chemicals. PMID- 21318463 TI - Measurement of cardiac output in children by bioreactance. AB - The objective of this study was to evaluate a new bioreactance method for noninvasive cardiac output (CO) measurement (NICOM) in children. Ten patients between 1 and 144 months of age and with no hemodynamic disturbances were studied. Using bioreactance, heart rate (HR), mean arterial pressure (MAP), and cardiac index (CI) measurements were made every 6-8 h. CI was 2.4 +/- 1.03 l/min/1.73 m(2) (range 1-4.9 l/min/1.73 m(2)); There were significant correlations between CI and age (r = 0.50, P = 0.003), weight (r = 0.66, P < 0.001), and MAP (r = 0.369, P = 0.037). Significant differences in CI (P < 0.001) were detected between children weighing <10 kg (1.9 +/- 0.73 l/min/1.73 m(2); range 1-3.2), 10-20 kg (2.07 +/- 0.7 l/min/1.73 m(2); range 1-3.6), and >20 kg (3.7 +/- 0.8 l/min/1.73 m(2); range 2.4-4.9). We conclude that the CI measured by bioreactance in children varies with the age and weight of the patients and is lower than the normal range in a large percentage of measurements. These data suggest that this method is not useful for evaluating CI in small children. PMID- 21318464 TI - Limb ischemic preconditioning for open heart surgery in infants. PMID- 21318465 TI - Cardiac arrhythmias induced by chloral hydrate in rhesus monkeys. AB - Chloral hydrate has been long used as a safe sedative and hypnotic drug in humans. However, reports on its cardiovascular adverse effects have been published from time to time. The present study was undertaken to use Rhesus monkeys as a model to define the dose regiment of chloral hydrate at which cardiac arrhythmias can be induced and the consequences of the cardiac events. Male Rhesus monkeys of 2-3 years old were intravenously infused with chloral hydrate starting at 50 mg/kg with an increasing increment of 25 mg/kg until the occurrence of cardiac arrhythmias. In addition, a traditional up-and-down dosing procedure was applied to define a single dose level at which cardiac arrhythmias can be induced. The data obtained showed that when the sequentially escaladed dose reached 125 mg/kg, cardiac arrhythmias occurred in all monkeys tested. The single effective dose to cause cardiac arrhythmias calculated from the crossover analysis was 143 +/- 4 mg/kg. This value would be equivalent to 68.6 +/- 1.9 mg/kg for children and 46.4 +/- 1.3 mg/kg for adults in humans. Under either multiple or single dose condition, cardiac arrhythmias did not occur before 40 min after the onset of anesthesia induced by chloral hydrate. Cardiac arrhythmias were recovered without help at the end of the anesthesia in most cases, but also continued after the regain of consciousness in some cases. The cardiac arrhythmias were accompanied with compromised cardiac function including suppressed fractional shortening and ejection fraction. This study thus suggests that cautions need to be taken when chloral hydrate is used above certain levels and beyond a certain period of anesthesia, and cardiac arrhythmias induced by chloral hydrate need to be closely monitored because compromised cardiac function may occur simultaneously. In addition, patients with cardiac arrhythmias induced by chloral hydrate should be monitored even after they are recovered from the anesthesia. PMID- 21318466 TI - Health equity or iniquity? PMID- 21318467 TI - Glucokinase regulatory protein (GCKR) gene rs4425043 polymorphism is associated with overweight and obesity in Chinese women. AB - The aim of this study was to investigate the effects of GCKR polymorphism on the prevalence of overweight and obesity in Chinese female subjects using a gene-wide tagging- single nucleotide polymorphism (tSNP) strategy. We conducted a genetic association study in the Taizhou Retiree Women Cohort, a sub-cohort of the Taizhou longitudinal study. We genotyped four tSNPs (rs4425043, rs780094, rs814295, and rs8179206) of the GCKR gene using the Taqman assay in 2,851 female subjects and investigated their associations with overweight and obesity. Odds ratios and their 95% confidence intervals (CIs) were derived from ordered logistic regression model. We observed significant association between rs4425043 and body-mass-index-defined overweight and obesity. The frequencies of A allele of the rs4425043 exhibited a significant increasing trend from normal weight (13.20%), overweight (15.08%), to obese subjects (17.10%) (P = 0.006). Individuals with the GA or AA genotypes showed a 31% excessive risk to develop overweight or obesity (95% CI: 1.12-1.52, P = 0.001). In addition, we observed significantly increased levels of fasting plasma glucose associated with variations of both rs780094 and rs814295 (5.03, 5.09, and 5.15 mmol/L for rs780094 AA, GA and GG genotypes, respectively, and 5.03, 5.11, and 5.20 mmol/L for rs814295 AA, GA and GG genotypes, respectively). In conclusion, a novel polymorphism (rs4425043) in the GCKR gene increases the risk of overweight and obesity in Chinese women. Previous report that other polymorphisms in the GCKR gene are associated with glucose levels have also been confirmed. PMID- 21318468 TI - Mild testicular hyperthermia transiently increases lipid droplet accumulation and modifies sphingolipid and glycerophospholipid acyl chains in the rat testis. AB - Spermatogenesis is known to be vulnerable to temperature. The aim of this study was to investigate the effects on testicular lipids of the transient germ cell loss that is induced by mild testicular hyperthermia. Adult rat testes were exposed once a day to 43 degrees C for 15 min for 5 days and the effects were followed for several weeks. Two week after the last heat exposure, spermatocytes and early spermatids had virtually disappeared and the seminiferous tubules were populated mostly by mature spermatids and spermatozoa. One week later, the latter were also absent and mostly Sertoli cells populated the tubules. During these 3 weeks, glycerophospholipids (Gpl) and triacylglycerols with long-chain polyunsaturated fatty acids (PUFA) (e.g., 22:5n-6) and species of sphingomyelin and ceramide with nonhydroxy and 2-hydroxy very long-chain (VLC) PUFA (e.g., 28:4n-6, 2-OH 30:5n-6) decreased alongside the germ cells. Concomitantly, the amounts of cholesteryl esters and ether-linked triglycerides increased, both lipids accumulating long-chain and very-long-chain polyenes. This concurred with a considerable buildup of lipid droplets in Sertoli cells, evidently containing these neutral lipids, apparently formed during germ cell-derived membrane lipid catabolism. Between week 4 and week 6, new cohorts of spermatocytes appeared, and by week 12 most cell changes were reversed. Accordingly, as germ cell differentiation proceeded, 22:5n-6-rich Gpl augmented and spermatocyte-associated sphingolipids with nonhydroxy VLCPUFA appeared before their 2-hydroxy counterparts. The unique fatty acids of rat testicular lipids after mild hyperthermia reveal lipid catabolic and biosynthetic reactions that occur in normal spermatogenesis. PMID- 21318469 TI - The development of flow-through bio-catalyst microreactors from silica micro structured fibers for lipid transformations. AB - This study demonstrates the utility of a flow-through enzyme immobilized silica microreactor for lipid transformations. A silica micro structured fiber (MSF) consisting of 168 channels of internal diameter 4-5 MUm provided a large surface area for the covalent immobilization of Candida antartica lipase. The specific activity of the immobilized lipase was determined by hydrolysis of p-nitrophenyl butyrate and calculated to be 0.81 U/mg. The catalytic performance of the lipase microreactor was demonstrated by the efficient ethanolysis of canola oil. The parameters affecting the performance of the MSF microreactor, including temperature and reaction flow rate, were investigated. Characterization of the lipid products exiting the microreactor was performed by non-aqueous reversed phased liquid chromatography (NARP-LC) with evaporative light scattering detector (ELSD) and by comprehensive two-dimensional gas chromatography (GC x GC). Under optimized conditions of 1 MUL/min flow rate of 5 mg/mL trioleoylglycerol (TO) in ethanol and 50 degrees C reaction temperature, 2-monooleoylglycerol was the main product at > 90% reaction yield. The regioselectivity of the Candida antartica lipase immobilized MSF microreactor in the presence of ethanol was found to be comparable to that obtained under conventional conditions. The ability of these reusable flow-through microreactors to regioselectively form monoacylglycerides in high yield from triacylglycerides demonstrate their potential use in small scale lipid transformations or analytical lipids profiling. PMID- 21318470 TI - Injury pattern after a fatal feet-first fall from a building. PMID- 21318471 TI - "Broken heart" syndrome in an elder abuse case: forensic considerations from the case. AB - "Takotsubo" cardiomyopathy (also known as stress cardiomyopathy or "broken heart syndrome") is a recently recognised transient condition that frequently mimics acute coronary syndrome. It is typically precipitated by acute emotional stress. Elder abuse is the infliction of physical, emotional or psychological harm on an older adult. As in other forms of abuse, elder abuse is a complex problem, easily prone to misconceptions and, therefore, to under-reporting. Herein, the authors present a case of a 76-year-old Caucasian woman, living in a dysfunctional family environment, who presented to her local Emergency Department with acute chest pain following an altercation with her daughter. Diagnostic criteria for "takotsubo" cardiomyopathy were met, namely, ST-segment elevation and T-wave changes, a mild increase of cardiac enzymes, an akinesia of the mid-portion and apex of the left ventricle and no significant epicardial coronary artery disease. The victim was admitted to the Cardiac Department on the second day and her condition improved over the following week. She was discharged and sent home after the situation was reported to competent authorities and subsequently to medico-legal services, who assessed the situation while still in-hospital. The case implications are discussed, as well as the impact that such cases may have when addressing elder abuse management and prevention, with a view to improving the forensic examination of these patients. PMID- 21318472 TI - Ultrasound assessment of the lateral collateral ligamentous complex of the elbow: imaging aspects in cadavers and normal volunteers. AB - OBJECTIVE: The Lateral Collateral Ligamentous complex (LCL) is an important stabiliser of the elbow. It has a Y-shaped structure with three components. In this study, we sought to describe the ultrasound aspect of the individual components of this ligamentous complex and to evaluate the performance of ultrasound in both cadavers and in normal subjects. METHODS: Ten cadaveric elbow specimens underwent high-frequency ultrasound. Two specimens were sliced and two were dissected for anatomical correlation. Ten elbows of normal subjects were also evaluated by ultrasound. The findings were compared. RESULTS: The three components of the LCL could be visualised in all specimens and normal subjects with the exception of the proximal portion of one specimen. In 80% of the specimens and 100% of the healthy volunteers the proximal portion of the LCL could be separated from the extensor tendons. CONCLUSION: High-resolution ultrasound can assess all components of the LCL of the elbow and can distinguish them from surrounding structures. PMID- 21318473 TI - CT of the hips in the investigation of protrusio acetabuli in Marfan syndrome. A case control study. AB - OBJECTIVES: To establish the prevalence of protrusio acetabuli (PA) in adults fulfilling the Ghent criteria for Marfan syndrome (MFS), and in a normal adult population. METHODS: 105 adults with probable MFS and 107 controls were included. CT of the hips was obtained. A qualitative assessment of PA was performed. A new method for estimating the degree of PA was introduced with measurement of the parameter CWD (circle-wall distance). Results were compared to an alternative method based on MRI [1]. RESULTS: 87 of the study group fulfilled the Ghent criteria of MFS (Ghent positives), and 18 did not (Ghent negatives). PA was diagnosed qualitatively in 74.7% of Ghent positive persons, in 27.8% of Ghent negative persons, and in 3.7% of the controls. CWD was significantly different between the three groups (p < 0.001). A slight but significant gender difference was found in Ghent positive persons only. The alternative method did not differentiate between the groups with respect to PA, but showed a significant difference between genders. CONCLUSIONS: PA was found significantly more often in MFS persons than in controls. Our method was found to be robust and highly reproducible, giving a direct measurement of pelvic protrusion irrespective of pelvic shape. PMID- 21318474 TI - Influence of carbon sources and electron shuttles on ferric iron reduction by Cellulomonas sp. strain ES6. AB - Microbially reduced iron minerals can reductively transform a variety of contaminants including heavy metals, radionuclides, chlorinated aliphatics, and nitroaromatics. A number of Cellulomonas spp. strains, including strain ES6, isolated from aquifer samples obtained at the U.S. Department of Energy's Hanford site in Washington, have been shown to be capable of reducing Cr(VI), TNT, natural organic matter, and soluble ferric iron [Fe(III)]. This research investigated the ability of Cellulomonas sp. strain ES6 to reduce solid phase and dissolved Fe(III) utilizing different carbon sources and various electron shuttling compounds. Results suggest that Fe(III) reduction by and growth of strain ES6 was dependent upon the type of electron donor, the form of iron present, and the presence of synthetic or natural organic matter, such as anthraquinone-2,6-disulfonate (AQDS) or humic substances. This research suggests that Cellulomonas sp. strain ES6 could play a significant role in metal reduction in the Hanford subsurface and that the choice of carbon source and organic matter addition can allow for independent control of growth and iron reduction activity. PMID- 21318475 TI - Detection of monochlorobenzene metabolizing bacteria under anoxic conditions by DNA-stable isotope probing. AB - Cultivation-independent analyses were applied to study the structural diversity of the bacterial community which developed in groundwater inoculated microcosms actively metabolizing monochlorobenzene (MCB) under anaerobic conditions. Addition of (13)C-labelled MCB demonstrated that the community produced (13)CO(2) as a metabolite at slightly increasing rates over a period of 1,051 days while no (13)C-methane evolved. Genetic profiles of partial 16S rRNA genes generated with the single-strand conformation polymorphism (SSCP) technique by PCR from directly extracted total DNA revealed that, despite the long incubation period, six replicate microcosms were characterized by almost the same microbial members. Nine distinguishable contributors to the SSCP-profiles were characterized by DNA sequencing, revealing the presence of different members from the phyla Proteobacteria, Fibrobacteres and from the candidate division OD1. DNA-stable isotope probing (SIP) was applied to distinguish the actual MCB metabolizing bacteria from the other community members. This study reveals for the first time the structural diversity of an anaerobic MCB metabolizing bacterial community. However, it also demonstrates the limitations of SIP to detect bacteria slowly metabolizing carbon sources under anaerobic conditions. PMID- 21318476 TI - Relationships between hippocampal microstructure, metabolism, and function in early Alzheimer's disease. AB - Abnormal microstructural integrity and glucose metabolism of the hippocampus are common in subjects with Alzheimer's disease (AD) that typically manifest as episodic memory impairment. The above-tissue alterations can be captured in vivo using diffusion tensor imaging (DTI) and positron emission tomography with [18F]fluorodeoxyglucose (FDG-PET). Here, we explored relationships between the above neuroimaging and cognitive markers of early AD-specific hippocampal damage. Twenty patients with early AD (MMSE 25.7 +/- 1.7) were studied using DTI and FDG PET. Episodic memory performance was assessed using the free delayed verbal recall task (DVR). In the between-modality correlation analysis, FDG uptake was strongly associated with diffusivity in the left anterior hippocampus only (r = 0.81, p < 0.05 Bonferroni's corrected for multiple tests). Performance on DVR significantly correlated with left anterior (r = -0.80, p < 0.05) and left mean (r = -0.72, p < 0.05) hippocampal diffusivity, while the correlation with left anterior FDG uptake did not reach statistical significance (r = 0.52, n.s.). DTI derived diffusivity of the anterior hippocampus might be a sensitive early marker of hippocampal dysfunction as reflected at the synaptic and cognitive levels. This neurobiological distinction of the anterior hippocampus might be related to the disruption of the perforant pathway that is known to occur early in the course of AD. PMID- 21318477 TI - Copper accelerates glycolytic flux in cultured astrocytes. AB - Astrocyte-rich primary cultures were used to investigate the consequences of a copper exposure on the glucose metabolism of astrocytes. After application of CuCl(2) (30 MUM) the specific cellular copper content increased from initial 1.5 +/- 0.2 nmol/mg to a steady state level of 7.9 +/- 0.9 nmol/mg within about 12 h. The copper accumulation was accompanied by a significant increase in the extracellular lactate concentration. The stimulating effect of copper on the lactate production remained after removal of extracellular copper. Copper treatment accelerated the rates of both glucose consumption and lactate production by about 60%. The copper induced acceleration of glycolytic flux was prevented by inhibition of protein synthesis, and additive to the stimulation of glycolysis observed for inhibitors of respiration or prolyl hydroxylases. A copper induced stimulation of glycolytic flux in astrocytes could have severe consequences for the glucose metabolism of the brain in conditions of copper overload. PMID- 21318478 TI - Fine mapping the KLK3 locus on chromosome 19q13.33 associated with prostate cancer susceptibility and PSA levels. AB - Measurements of serum prostate-specific antigen (PSA) protein levels form the basis for a widely used test to screen men for prostate cancer. Germline variants in the gene that encodes the PSA protein (KLK3) have been shown to be associated with both serum PSA levels and prostate cancer. Based on a resequencing analysis of a 56 kb region on chromosome 19q13.33, centered on the KLK3 gene, we fine mapped this locus by genotyping tag SNPs in 3,522 prostate cancer cases and 3,338 controls from five case-control studies. We did not observe a strong association with the KLK3 variant, reported in previous studies to confer risk for prostate cancer (rs2735839; P = 0.20) but did observe three highly correlated SNPs (rs17632542, rs62113212 and rs62113214) associated with prostate cancer [P = 3.41 * 10(-4), per-allele trend odds ratio (OR) = 0.77, 95% CI = 0.67-0.89]. The signal was apparent only for nonaggressive prostate cancer cases with Gleason score <7 and disease stage 8 or stage >=III (P = 0.31, per-allele trend OR = 1.12, 95% CI = 0.90-1.40). One of the three highly correlated SNPs, rs17632542, introduces a non-synonymous amino acid change in the KLK3 protein with a predicted benign or neutral functional impact. Baseline PSA levels were 43.7% higher in control subjects with no minor alleles (1.61 ng/ml, 95% CI = 1.49-1.72) than in those with one or more minor alleles at any one of the three SNPs (1.12 ng/ml, 95% CI = 0.96-1.28) (P = 9.70 * 10(-5)). Together our results suggest that germline KLK3 variants could influence the diagnosis of nonaggressive prostate cancer by influencing the likelihood of biopsy. PMID- 21318479 TI - Combination of NMR spectroscopy and X-ray crystallography offers unique advantages for elucidation of the structural basis of protein complex assembly. AB - NMR spectroscopy and X-ray crystallography are two premium methods for determining the atomic structures of macro-biomolecular complexes. Each method has unique strengths and weaknesses. While the two techniques are highly complementary, they have generally been used separately to address the structure and functions of biomolecular complexes. In this review, we emphasize that the combination of NMR spectroscopy and X-ray crystallography offers unique power for elucidating the structures of complicated protein assemblies. We demonstrate, using several recent examples from our own laboratory, that the exquisite sensitivity of NMR spectroscopy in detecting the conformational properties of individual atoms in proteins and their complexes, without any prior knowledge of conformation, is highly valuable for obtaining the high quality crystals necessary for structure determination by X-ray crystallography. Thus NMR spectroscopy, in addition to answering many unique structural biology questions that can be addressed specifically by that technique, can be exceedingly powerful in modern structural biology when combined with other techniques including X-ray crystallography and cryo-electron microscopy. PMID- 21318480 TI - Proteomic analysis of human epithelial ovarian cancer xenografts in immunodeficient mice exposed to chronic psychological stress. AB - This work aims at comparing alterations in the proteomes of human epithelial ovarian cancer xenografts between stressed and non-stressed immunodeficient mice as well as exploring the molecular mechanisms linking chronic psychological stress to ovarian cancer oncogenesis and progression. SK-OV-3 cells were injected subcutaneously into nude mice. The stress group was subjected to a chronic physical restraint protocol for 6 h on 35 consecutive days, while the control group was unrestrained. All mice were sacrificed on day 36 after SK-OV-3 cell injection, and tumors were excised. Tumor tissues were processed for 2D gel electrophoresis, mass spectrometry (nanoUPLC-ESI-MS/MS) and Western blotting. The expression of 20 proteins was found to be significantly altered between the stress and control groups, of which 14 were up-regulated, five were down regulated, and one protein was found only in the stress group. All proteins were identified by UPLC-ESI-MS/MS, and Western blotting results were consistent with those of proteomic methods. The present results provide new evidence relating to the molecular mechanism underlying the relationship between psychological stress and tumor progression. PMID- 21318481 TI - Up-regulation of prohibitin 1 is involved in the proliferation and migration of liver cancer cells. AB - Although prohibitin 1 (PHB) is known to be associated with tumors, there are few studies regarding the role of PHB in hepatocellular carcinoma. An earlier glycoproteomics study of ours showed that PHB is over-expressed in MHCC97-H cells, a highly metastatic liver cancer cell line, and can be captured by wheat germ agglutinin. In the present study, western blotting and reverse transcription PCR experiments showed an approximately 2-fold up-regulation in the expression of PHB in MHCC97-H cells. However, PHB was not significantly up-regulated in MHCC97 L cells, a low-metastatic liver cancer cell line. When PHB was over-expressed in MHCC97-L cells, cell proliferation was inhibited by 35% and migration increased about 2-fold. The results of this study show that PHB is up-regulated in MHCC97-H cells and is associated with both proliferation and migration of liver cancer cells. PMID- 21318482 TI - Linkage with cathepsin B-sensitive dipeptide promotes the in vitro and in vivo anticancer activity of PEGylated tumor necrosis factor-alpha (TNF-alpha) against murine fibrosarcoma. AB - To improve the pharmacological profile of tumor necrosis factor alpha (TNF alpha), we have synthesized a new PEGylated prodrug, PEG-vcTNF-alpha, using a cathepsin B-sensitive dipeptide (valine-citrulline, vc) to link branched PEG and TNF-alpha. PEG-modified TNF-alpha without the dipeptide linker (PEG-TNF-alpha) and unconjugated TNF-alpha were also tested as controls. It was found for the first time that TNF-alpha released from PEG-vcTNF-alpha was specifically dependent on the presence of cathepsin B. PEG-vcTNF-alpha induced higher cytotoxicity and greater apoptosis against L929 murine fibrosarcoma cells than PEG-TNF-alpha. Reversal of these effects by a cathepsin-B inhibitor confirmed that these effects were mediated by cathepsin B-specific release of TNF-alpha. In vivo pharmacokinetics studies demonstrated that the plasma stability of PEG-vcTNF alpha was significantly increased compared to TNF-alpha. Finally, the improved anticancer efficacy of PEG-vcTNF-alpha and the distinct activities among the three formulations confirmed the positive contribution of both PEGylation and the dipeptide linkage to the improved drug-like properties of PEG-vcTNF-alpha. The results here indicate that linking proteins and PEG via the cathepsin B-sensitive dipeptide may be a promising strategy for developing protein therapeutics. PMID- 21318483 TI - Identification of a combination of SNPs associated with Graves' disease using swarm intelligence. AB - Graves' disease, the production of thyroid-stimulating hormone receptor stimulating antibodies leading to hyperthyroidism, is one of the most common forms of human autoimmune disease. It is widely agreed that complex diseases are not controlled simply by an individual gene or DNA variation but by their combination. Single nucleotide polymorphisms (SNPs), which are the most common form of DNA variation, have great potential as a medical diagnostic tool. In this paper, the P-value is used as a SNP pre-selection criterion, and a wrapper algorithm with binary particle swarm optimization is used to find the rule for discriminating between affected and control subjects. We analyzed the association between combinations of SNPs and Graves' disease by investigating 108 SNPs in 384 cases and 652 controls. We evaluated our method by differentiating between cases and controls in a five-fold cross validation test, and it achieved a 72.9% prediction accuracy with a combination of 17 SNPs. The experimental results showed that SNPs, even those with a high P-value, have a greater effect on Graves' disease when acting in a combination. PMID- 21318484 TI - Expression of hunchback during oogenesis and embryogenesis in Locusta migratoria manilensis (Meyen). AB - hb (hunchback) is a contributing factor in anteroposterior axial patterning of insects. Although the hb function in Locusta migratoria manilensis has been investigated, its expression pattern remains unknown. Here, the mouse polyclonal antibody was produced against Hb fusion protein, and then its expression pattern during oogenesis and embryogenesis of L. migratoria manilensis was examined by immunohistochemical staining. Hb protein was detected in the oocyte nucleus which was positioned centrally within the developing oocyte. The oocyte nucleus gradually moved to the posterior end of the egg along with the oocyte maturing. In freshly laid eggs, Hb formed gradient at the posterior end of the egg, and then hb was expressed as a band in the middle of the blastodisc. As the blastodisc differentiated into the head and trunk, the expression region became wide, which would develop into spatial gnathal and thoracic segments. With abdominal segmentation, the expression domain in the gnathal and thoracic region became faint and eventually faded out, while the Hb expression domain appeared at the posterior growth zone in a discontinuous expression manner. The hb expression pattern of L. migratoria manilensis is greatly similar to that of other locusts, such as Schistocerca americana and another L. migratoria. Compared with other insects, hb expression is conserved in the gnathal and thoracic domains, while divergent in oogenesis and abdomen. PMID- 21318485 TI - Temporal allocation of metabolic tolerance to transgenic Bt cotton in beet armyworm, Spodoptera exigua (Hubner). AB - Digestive and detoxification enzyme activity and nutrient composition were examined in the body of fourth instar beet armyworms, Spodoptera exigua (Hubner), fed on transgenic Bacillus thuringiensis (Bt) and non-Bt cotton for different time periods. Nutrient composition and specific enzyme activities differed significantly between the S. exigua fed Bt vs. non-Bt cotton. At 1, 6 and 24 h, free fatty acid and glucose levels were significantly lower in S. exigua fed on Bt cotton than those fed on non-Bt cotton. S. exigua fed on Bt cotton had significantly higher trypsin and total superoxide dismutase (T-SOD) activities and significantly lower lipase, carboxylesterase and acetylcholinesterase activities than non-Bt fed worms for all feeding time periods. Differences were also observed among feeding times within each cotton variety group. Significantly lower free fatty acid and total amino acid were observed in S. exigua fed on Bt cotton for 24 h than in those fed for 1 h. Significantly lower activities of lipase and trypsin were detected in S. exigua fed on Bt cotton for 24 h than those for 1 and 4 h. However, carboxylesterase and acetylcholinesterase activities in S. exigua fed on Bt cotton for 24 h were significantly higher than those for 1, 4 and 6 h. The interaction between cotton variety and feeding time significantly affected the activities of lipase, trypsin, acetylcholinesterase and T-SOD enzymes in S. exigua. Measuring the temporal allocation of protection and detoxification enzyme activities in the body of S. exigua in response to B. thuringiensis can provide a meaningful evaluation on the metabolic tolerance of herbivorous insects under the continuous selection pressure of a toxic protein. PMID- 21318486 TI - Enhanced hyperplasia in muscles of transgenic zebrafish expressing Follistatin1. AB - Myostatin is a member of the transforming growth factor-beta (TGF-beta) super family and functions as a negative regulator of muscle growth. Binding of the specific receptor, Activin receptor IIB (Act RIIB), with myostatin or other related TGF-beta members, could be inhibited by the activin-binding protein follistatin (Fst) in mammals. Overexpressing Fst in mouse skeletal muscle leads to muscle hypertrophy and hyperplasia. To determine if Fst has similar roles in fish, we generated transgenic zebrafish expressing high levels of zebrafish Fst1 using the promoter of the zebrafish skeletal muscle-specific gene, myosin, light polypeptide 2, skeletal muscle (Mylz2). Independent transgenic zebrafish lines exhibited elevated expression levels of myogenic regulatory genes MyoD and Pax7 in muscle cells. Adult Fst1 overexpressing transgenic zebrafish exhibited a slight body weight increase. The high level of Fst1 expression dramatically increased myofiber numbers in skeletal muscle, without significantly changing the fiber size. Our findings suggest that Fst1 overexpression can promote zebrafish muscle growth by enhancing myofiber hyperplasia. PMID- 21318487 TI - Ultrastructural observation on sterilization of melittin. AB - ABSTACT: The effects of melittin on growth and bacteriostasis of four pathogens were extensively investigated using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The results indicated that the melittin had a marked bacteriostatic effect on the four pathogenic bacteria. Among these, E. cacotowora was influenced most powerfully and quickly, the yeast and F. fulva were the second, and the S. aureus was inhibited by a low concentration but was killed by a high concentration. It was observed in the experiments that melittin killed pathogenic bacteria in three ways. One was by pore formation. After integrating melittin into the plasma membrane, a vacuole was formed then penetrated, resulting in bacterial content leakage. The vacuole also experienced plasmolysis and the growing cavity destroyed the membrane. A third effect was the formation of vacuoles in the cells which induced the pycnosis of the cytoplasm resulting in a cell death. The mechanism of melittin bacteriostasis was the result of integrating melittin with phospholipid double layers of the plasmalemma and the endomembranes. PMID- 21318488 TI - A possible mechanism for the formation of annual growth lines in bivalve shells. AB - We report a unique shell margin that differed from the usual shell structure of Pinctada fucata. We observed empty organic envelopes in the prismatic layer and the formation of the nacreous layer in the shell margin. All the characteristics of the growing margin indicated that the shell was growing rapidly. To explain this anomaly, we propose the concept of "jumping development". During jumping development, the center of growth in the bivalve shell jumps forward over a short time interval when the position of the mantle changes. Jumping development explains the unusual structure of the anomalous shell and the development of annual growth lines in typical shells. Annual growth lines are the result of a discontinuity in the shell microstructure induced by jumping development. PMID- 21318489 TI - The role of tocopherol cyclase in salt stress tolerance of rice (Oryza sativa). AB - Tocopherols synthesized exclusively by photosynthetic organisms are major antioxidants in biomembranes. In plants, tocopherol cyclase (TC/VTE1) catalyzes the conversion of 2,3-dimethyl-5-phytyl-1,4-benzoquinone (DMPBQ) to gamma tocopherol. In the present study, OsVTE1, which encodes a rice tocopherol cyclase ortholog, was cloned and characterized. OsVTE1 was induced significantly by abiotic stresses such as high salt, H(2)O(2), drought, cold and by the plant hormones ABA and salicylic acid. The tissue-specific expression pattern and OsVTE1-promoter GUS activity assay showed that OsVTE1 was mainly expressed in the leaf, and also could be detected in the root, stem and panicle. Compared with control plants, transgenic plants with Os-VTE1 RNA interference (OsVTE1-RNAi) were more sensitive to salt stress whereas, in contrast, transgenic plants overexpressing OsVTE1 (OsVTE1-OX) showed higher tolerance to salt stress. The DAB in vivo staining showed that OsVTE1-OX plants accumulated less H(2)O(2) than did control plants. PMID- 21318490 TI - Functional modules with disease discrimination abilities for various cancers. AB - Selecting differentially expressed genes (DEGs) is one of the most important tasks in microarray applications for studying multi-factor diseases including cancers. However, the small samples typically used in current microarray studies may only partially reflect the widely altered gene expressions in complex diseases, which would introduce low reproducibility of gene lists selected by statistical methods. Here, by analyzing seven cancer datasets, we showed that, in each cancer, a wide range of functional modules have altered gene expressions and thus have high disease classification abilities. The results also showed that seven modules are shared across diverse cancers, suggesting hints about the common mechanisms of cancers. Therefore, instead of relying on a few individual genes whose selection is hardly reproducible in current microarray experiments, we may use functional modules as functional signatures to study core mechanisms of cancers and build robust diagnostic classifiers. PMID- 21318491 TI - Neural correlates of audio-visual modal interference inhibition investigated in children by ERP. AB - In order to detect cross-sectional age characteristics of cognitive neural mechanisms in audio-visual modal interference inhibition, event-related potentials (ERP) of 14 10-year-old children were recorded while performing the words interference task. In incongruent conditions, the participants were required to inhibit the audio interference words of the same category. The present findings provided the preliminary evidence of brain mechanism for the children's inhibition development in the specific childhood stage. PMID- 21318492 TI - In reply. PMID- 21318493 TI - Design and performance of an acidic precipitation delivery system for field investigations with plants. AB - An acidic precipitation delivery system is described that was designed and constructed for use in a field investigation of the response of red spruce saplings (Picea rubens Sarg.) to the interactive stresses of ozone and acid rain. The system utilizes hydraulic, solid-cone spray nozzles to produce simulated rainfall with droplet size distributions approximating natural rain events, which are of low intensity, i.e., about 1-1.5 cm hr(-1), and are relatively uniform in distribution of volume over a 2.4 m diameter plot. Three different pH treatments (3.1, 4.1, 5.1) were dispensed randomly to each of three treatment subplots located in twelve open-top field chambers and three ambient control chambers. Storage capacity of the system permitted a 2.3 hr rain event. Construction materials used were chosen for resistance to the corrosive nature of the rain simulant, stability to ambient UV radiation, and resistance to penetration by sunlight. Simulated events were not synchronized to ambient events, but were scheduled to prevent moisture deficits. PMID- 21318494 TI - Protection afforded citrus pesticide applicators by coveralls. AB - Four airblast applicators of the pesticides dicofol and ethion to Florida citrus were monitored for pesticide exposure with pads placed inside and outside two types of protective coveralls. Hand exposure was not assessed. Pesticide accumulated uniformly over the coveralls' outer surface at a mean rate of 55 +/-6 mg/hr. The penetration of ethion through a reusable treated twill suit was 8 +/ 2% and through a disposable synthetic suit was 6 +/-4%; corresponding values for dicofol were 4 +/-1% and 1 +/-0%, respectively. While these four penetration values could not be separated statistically at p<0.05, it isprobable (p<0.20) that ethion was the better penetrator, and the disposable synthetic suit the better protector against dicofol. PMID- 21318495 TI - Fate of mutagenic activity during conventional treatment of municipal wastewater sludge. AB - The mutagenic activity of wastewater was followed during conventional activated sludge treatment at a municipal plant. Raw wastewater was initially screened for mutagenic potential, using the AmesSalmonella/mammalian microsomal test and employer tester strains. The combined raw wastewater produced dose-related mutagenic responses in the presence of S9 metabolic activation. Raw wastewater from domestic sources alone was not mutagenic. Mutagenic activity was observed throughout the treatment process. Activated sludge prior to chlorination contained the highest specific mutagenic activity. Chlorination decreased the specific mutagenic activity at pH 11. Mutagenic activity in municipal wastewater containing industrial discharges is not removed by conventional treatment processes and can be enhanced by activated sludge treatment. PMID- 21318496 TI - Organic toxicants and mutagens in ashes from eighteen municipal refuse incinerators. AB - Ashes, obtained from about one-fourth of the operating municipal refuse incinerators in the United States, were analyzed for a range of organic toxicants and mutagens. Thirty percent of the ash samples, which consisted of bottom ash or bottom ash-fly ash mixtures, contained 20-74% organic matter. Thirty percent of the ashes contained direct-acting and/or promutagens which revertedSalmonella typhimurium TA98 or TA100. Sixty percent of the ashes contained more than 5 ng/g of polychlorinated biphenyls. The concentration of tetra- and pentachlorinated biphenyls were higher than the mono-, di-, hepta- and octachlorinated biphenyls. A similar distribution of congeners was seen in polychlorinated dibenzodioxins found in the ashes. The major volatileN-nitroso compounds found in the ashes wereN-nitrosodimethylamine andN-nitrosomorpholine. Other classes of compounds which were found in the ashes included chlorinated benzenes, phthalates, and substituted benzothiophenes. PMID- 21318497 TI - Exposure assessment of sewage treatment plant effluent by a selected chemical marker method. AB - Organic chemicals unique to sewage effluent can be useful as markers of an effluent plume. Samples were collected at a domestic wastewater outfall near Cocoa, Florida, and chemically characterized. Receiving waters were analyzed to determine the chemical components in the effluent most suitable for the assessment. The saturated hydrocarbon fraction and sterol fraction appeared to be of greatest utility for such purposes, and the concentrations of these fractions were determined for water, particulate matter, and sediment. Concentrations of the marker compounds decreased rapidly with increasing distance from the outfall. PMID- 21318498 TI - Toxicity of zinc and bleached kraft mill effluent to larval english sole (Parophrys vetulus) and topsmelt (Atherinops affinis). AB - Toxicity test protocols were developed for larvae of two species of marine fishes of the Pacific coast of the United States. During winter months, larvae were obtained from adult English sole (Parophrys vetulus) spawned in the laboratory. Newly-hatched, nonfeeding larvae were used in 96-hr experiments to determine their acute sensitivity to inorganic and organic toxicants. Exposure to ZnSO(4) produced a 96-hr LC(50) of 14.5 mg Zn/L. A complex and variable organic effluent (untreated bleached kraft mill effluent; BKME) yielded 96-hr LC(50)s ranging from 1.2-9.3% BKME.Larvae were obtained from eggs collected from wild and laboratory populations of the spring and summer-spawning topsmelt (Atherinops affinis). Both acute (96-hr) mortality and longer-term (7-14 days) growth responses of topsmelt larvae to BKME were determined. Acute toxicity levels (96-hr LC(50)s) ranged from 6.2-9.7% BKME. No Observed Effect Levels (NOELs) for 7 and 14 day exposures ranged from 1.0-3.0% BKME. PMID- 21318499 TI - Effects of cadmium in freshwater clams. I. Interaction with essential elements inAnodonta cygnea. AB - The elemental composition of the freshwater clam,Anodonta cygnea, was investigated in response to exposure to cadmium at 50 ppb (MUg/L) Cd during 12 weeks. Accumulation of cadmium affected the composition in various tissues and hemolymph. From 2 to 8 weeks of exposure considerable loss of sodium occurred, to about half the levels in control animals. During the last four weeks of exposure, sodium concentrations stabilized at the decreased level while those of potassium started to decline. Minor changes were noticeable for other elements. Calcium and iron tended to increase in all organs examined while magnesium levels remained constant. Zinc increased slightly during exposure to cadmium. For some elements, especially zinc and sulphur, hemolymph concentrations showed a response opposite to those in tissues. Concentrations of Al, B, Ba, Be, Ce, Co, Cr, Cu, Li, Mn, Mo, Ni, P, Pb, Sn, Sr, Ti, V, Y, and Zr did not change during Cd exposure. Possible sites of cadmium interaction with ionic regulation are discussed. PMID- 21318500 TI - Effects of cadmium in freshwater clams. II. Ultrastructural changes in the renal system ofAnodonta cygnea. AB - An ultrastructural study was made of the renal system of freshwater clams,Anodonta cygnea, that had been exposed to cadmium chloride (50 MUg Cd/L) for 12 weeks. By stereological analysis an extended lysosomal system and a decreased number of mitochondria was apparent in the epithelial cells lining the proximal compartment of the kidney. The increase of the lysosomal system was mainly accountable to the appearance of a distinct type of lysosome, that accumulated in the apical cell region. The decrease of the mitochondrial population was accompanied by a considerable swelling of the individual mitochondria. Finally, a severe reduction of the glycogen stores was noticed. Similar, but less obvious, changes occurred in the distal kidney compartment. The results suggest that long-term exposure ofAnodonta cygnea to cadmium stimulates the lysosomal system and disturbs the function of organelles involved in the energy metabolism of resorptive kidney cells. PMID- 21318501 TI - Effects of cadmium in freshwater clams. III. Interaction with energy metabolism inAnodonta cygnea. AB - Freshwater clams,Anodonta cygnea, were exposed to cadmium, at 50 ppb (MUg/L), to investigate the effects of semi-chronic exposure on energy metabolism. Parameters examined included: adenylate energy charge (AEC), glycogen content, blood glucose and protein concentration, the accumulation of anaerobic metabolic end products,viz. lactate and succinate, and mitochondrial NADH-oxidase activity. In all tissues, AEC was significantly lowered after 12 weeks. Glycogen contents of the separate organs, except for the gills, were diminished to one half those of control animals. Hemolymph glucose increased between 4 and 8 weeks, whereas protein in hemolymph steadily decreased, to about one half the concentration of controls at 12 weeks. Lactate increased in mantle and midgut gland, whereas in gill only an initial accumulation was found after 2 weeks of exposure. Succinate concentrations increased in all organs between 4 and 8 weeks of Cd exposure. Thereafter, no further accumulation occurred. From the onset of exposure to cadmium there was a gradual reduction of NADH-oxidase activity of gill mitochondria, down to 60% of the control value after 12 weeks. The data indicate an impairment of oxidative carbohydrate metabolism that is brought about by a metabolic blockade, rather than by (partial) anaerobiosis as a consequence of shell closure. PMID- 21318502 TI - Metal concentrations in pelagic seabirds from the North Pacific Ocean. AB - Concentrations of four essential elements (Fe, Mn, Zn, and Cu) and two toxic metals (Cd and Hg) were measured in selected tissues of 19 pelagic seabird species collected in the North Pacific and neighboring waters. Essential metal concentrations were generally highest in the liver and less variable than toxic metals among species and also within each species. Fe concentrations in the muscle were higher in Alcidae than in the other families, whereas the opposite trend was found for Fe and Mn in the liver. Zn concentrations varied among species, depending on the Cd concentrations. On the other hand, toxic metal concentrations were highest in the liver or kidney and varied widely among species, greatly depending on differences in the diet among species. Extraordinarily high Hg concentrations were found in Black-footed Albatrosses,Diomedea nigripes, exceeding 300 MUg/g wet weight in some, and seemed to be due to constraints on the elimination of Hg. Also, some geographical differences in Cd and Hg concentrations of the seabirds were observed. The concentrations of Cd and Hg reported here, however, seem to be natural rather than due to environmental pollution. PMID- 21318503 TI - Recent influxes of metals into Lake Pepin, a natural lake on the Upper Mississippi River. AB - The recent chronology of metal deposition was examined in Lake Pepin, a large natural lake on the Upper Mississippi River about 75 km downstream from the Minneapolis-St. Paul, Minnesota, metropolitan area. The lake, which has a high trapping efficiency for suspended sediments, serves as a sink for metals from industrial and domestic effluents discharged into the river. Sediment cores collected in 1981 from seven locations in the lake were analyzed for Cd, Cr, Cu, Ni, Pb, Zn, and Al (a reference element). Dating of a core with(137)Cs indicated that inputs of these metals increased markedly in the late 1950s, peaked in the early 1970s, and decreased in the late 1970s to 1981. Sediment enrichment factors decreased in the order Pb>Cd>Cu[Symbol: see text]Cr>Zn>Ni. The depth of the most highly contaminated strata in the core profiles decreased longitudinally from upstream to downstream-paralleling the upstreamto-downstream decrease in sedimentation rates. Changes in metal inputs to the lake would be most readily detected by analysis of sediments from the uppermost reaches, but the potential for release of sediment-associated metals to the water column is probably greatest in downstream reaches. PMID- 21318504 TI - Selenium and other elements in juvenile striped bass from the San Joaquin Valley and San Francisco Estuary, California. AB - Concentrations of selenium and other trace elements were determined in 55 whole body samples of juvenile anadromous striped bass (Morone saxatilis) from the San Joaquin Valley and San Francisco Estuary, California. The fish (<=1 yr old-the predominant life stage in the San Joaquin Valley) were collected in September December 1986 from 19 sites in the Valley and 3 sites in the Estuary, and analyzed for the following elements: aluminum (Al), arsenic (As), boron (B), barium (Ba), beryllium (Be), cadmium (Cd), chromium (Cr), copper (Cu), iron (Fe), mercury (Hg), magnesium (Mg), molybdenum (Mo), nickel (Ni), lead (Pb), selenium (Se), strontium (Sr), vanadium (V), and zinc (Zn). When compared to concentrations in whole freshwater fish measured by surveys from other waters, a few samples contained higher levels, of As, Cd, Cu, Pb, and Se. The median concentrations of Al, As, Cu, Fe, Mg, Se, and Sr also differed significantly (P[Symbol: see text]0.05) among sites. However, only Se concentrations were highest (up to 7.9 MUg/g dry weight) in samples from Valley sites exposed to agricultural subsurface (tile) drainwater; concentrations were lower in samples collected elsewhere. Water quality variables-especially those strongly influenced by tile drainwater (conductivity, total dissolved solids, total alkalinity, and total hardness)-were also significantly correlated (P[Symbol: see text]0.05) with Se concentrations in fish. Selenium concentrations in striped bass from the Estuary were only one-fourth to one-half the concentrations measured in the most contaminated fish from the San Joaquin River. PMID- 21318505 TI - National contaminant biomonitoring program: Concentrations of arsenic, cadmium, copper, lead, mercury, selenium, and zinc in U.S. Freshwater Fish, 1976-1984. AB - From late 1984 to early 1985, the U.S. Fish and Wildlife Service collected a total of 315 composite samples of whole fish from 109 stations nationwide, which were analyzed for arsenic, cadmium, copper, lead, mercury, selenium, and zinc. Geometric mean, maximum, and 85th percentile concentrations (MUg/g wet weight) for 1984 samples were as follows: arsenic-0.14, 1.5, 0.27; cadmium-0.03, 0.22, 0.05; copper-0.65, 23.1, 1.0; mercury-0.10, 0.37, 0.17; lead-0.11, 4.88, 0.22; selenium-0.42, 2.30, 0.73; and zinc-21.7, 118.4, 34.2. The mean concentrations of selenium and lead were significantly lower than in the previous NCBP collection (1980-81). Mean concentrations of arsenic and cadmium also declined significantly between 1976, when elemental contaminants in fish were first measured in the NCBP, and 1984. Of greatest significance, lead concentrations declined steadily from 1976 to 1984, suggesting that regulatory measures have successfully reduced the influx of lead to the aquatic environment. PMID- 21318506 TI - National contaminant biomonitoring program: Residues of organochlorine chemicals in U.S. Freshwater Fish, 1976-1984. AB - The U.S. Fish and Wildlife Service periodically determines concentrations of organochlorine chemicals in freshwater fish collected from a nationwide network of stations as part of the National Contaminant Biomonitoring Program (NCBP, formerly a part of the National Pesticide Monitoring Program). From late 1984 to early 1985, a total of 321 composite fish samples were collected from 112 stations and analyzed for organochlorine chemical residues. The mean concentrations of total DDT did not change from 1980-81 to 1984, following a period of steady decline through the 1970's; however, the mean concentrations ofp,p'-DDT declined significantly. The most persistent DDT homolog (p,p'-DDE) was detected at 98% of the stations sampled in 1984, and constituted 73% of total DDT residues, up from 70% in 1974-79. Collectively, these findings indicate a low rate of influx and continued weathering of DDT in the environment. Residues of polychlorinated biphenyls (PCBs) also remained widespread, but a significant downward trend in total PCBs was evident, and early eluting PCB components were present at fewer stations than in the past. Mean concentrations of dieldrin have not changed since 1978-79; concentrations remained highest in Hawaii and in the Great Lakes. Toxaphene concentrations declined from 1980-81 to 1984, especially in the Great Lakes, and the incidence of toxaphene declined from 88% of the stations sampled in 1980-81 to 69% in 1984. Mean chordane concentrations did not change from 1980-81 to 1984, following a period of decline; however,trans nonachlor replacedcis-chlordane as the most abundant component, suggesting a lower influx of chlordane to the aquatic environment. Residues of other organochlorines-mirex, pentachloroanisole (PCA), benzene hexachloride (BHC) isomers, endrin, heptachlor, hexachlorobenzene (HCB), and Dacthal((r)) (DCPA) were either found at relatively few (<25%) of the stations sampled in 1984 or were characterized by relatively low concentrations. In general, organochlorine concentrations were lower in 1984 than at any time reported previously. PMID- 21318507 TI - Preliminary studies on the development of a microbiological treatment for polychlorinated biphenyls. AB - A series of experiments comprising microbiological testing, surfactant screening and microcosm systems are described for the preliminary development of a treatment for polychlorinated biphenyls (PCBs). Microbial isolates from contaminated soil and sludge and culture collections, were screened for degradation of a defined mixture of PCB congeners in liquid culture. Initially, one group of bacteria substantially degraded the dichloro-to pentachlorobiphenyls except where chlorinated at the 4,4' position, but not hexachlorobiphenyl; whereas other microorganisms, includingPhanerochaete chrysosporium, showed greater degradation of the apparently more recalcitrant congeners. Repeated subculturing of the most promising bacteria on biphenyl supplemented media apparently increased their ability to degrade both the range and extent of congeners tested. The non-ionic Triton((r)) X-100 and Tensoxid((r)) S50 were the most effective surfactants at desorbing PCB from sand but had varying degrees of inhibition either to the growth, or alternatively to the PCB metabolism of the isolates tested. The greatest degree of PCB metabolism in the presence of Triton((r)) X-100 was towards 2,3-dichlorobiphenyl, with a general reduction in the degree of degradation of trichlorinated to hexachlorinated congeners. The most effective reduction of Aroclor((r)) 1242 in sand systems spiked with 1,000 mg/kg was achieved through a combination of inoculating biphenyl-degrading bacterial isolates together withPh. chrysosporium. This resulted in a reduction of approximately 40% in a 20-week period, although this was attributable largely to the removal of the less chlorinated rather than the more chlorinated congeners. PMID- 21318508 TI - Introduction to Alzheimer's disease. AB - In 1907, Alois Alzheimer published an account (1) of a 51-year-old female patient, Auguste D., who suffered from strong feelings of jealousy towards her husband, increased memory impairment, disorientation, hallucinations, and often loud and aggressive behavior. After four and a half years of rapidly deteriorating mental illness, Auguste D died in a completely demented state. Postmortem histological analysis of her brain using the Bielschowsky silver technique revealed dense bundles of unusual fibrils within nerve cells (neurofibrillary tangles or NFTs) and numerous focal lesions within the cerebral cortex, subsequently named "senile plaques" by Simchowicz (2) Fig. 1). This combination of progressive presenile dementia with senile plaques and neurofibrillary tangles came to be known as Alzheimer's disease (AD), a term that was later broadened to include senile forms of dementia with similar neuropathological findings. It was Divry (3) who first demonstrated the presence of amyloid at the center of the senile plaque, by means of Congo red staining. All amyloid deposits were originally thought to be starch-like in nature (hence the name), but it is now apparent that they are formed from a variety of different peptides and proteins (the latest count being 18). All amyloid share the property of a characteristic birefringence under polarized light after staining with Congo red dye, which is due to the presence of well-ordered 10 nm fibrils. The underlying protein component of these fibrils invariably adopts predominantly an antiparallel beta-pleated sheet configuration. Ultrastructural observations have confirmed that the core of the senile plaque consists of large numbers of closely-packed, radiating fibrils, similar in appearance to those seen in other forms of amyloidosis (4,5), and have also revealed the presence of paired helical filaments (PHFs) within the NFTs (6). However, it took more than 50 yr from Divry's original observation to determine the precise chemical nature of the senile plaque amyloid. Many neuropathologists have regarded this amyloid as a "tombstone" (an inert bystander) of AD. However, the advent of molecular genetics has finally and firmly established the central role of amyloid in the pathogenesis of the disease, although this is still disputed by some workers in the field. This introductory chapter is written in support of what has become known as the "amyloid cascade" hypothesis. PMID- 21318509 TI - The genetics of Alzheimer's disease. AB - Since the first description of Alzheimer's disease (AD) at the beginning of the century until relatively recently, it was customary to define Alzheimer's disease as occurring in the presenium. The same neuropathological changes occurring in brains over the age of 65 were called "senile dementia." Because there have been no clinical or pathological features to separate the two groups, this somewhat arbitrary distinction has been abandoned. Although AD is currently considered to be a heterogeneous disease, the most consistent risk factor to be implicated other than advancing age is the presence of a positive family history. This potential genetic vulnerability to AD has been recognized for some time. Some of the earliest evidence suggestive of a genetic contribution to AD came from Kallmann's 1956 study (1) demonstrating a higher concordance rate in monozygotic twins for "parenchymatous senile dementia" compared with dizygotic twins and siblings. This monozygotic excess has been confirmed in studies applying more rigorous diagnostic criteria although there may be widely disparate ages of onset between twins (2). The most convincing evidence for a genetic contribution to AD has come form the study of pedigrees in which the pattern of disease segregation can be clearly defined. Thus, the abandonment of the early and late-onset dichotomy has occurred at a time when, at the genetic level, important differences have been identified through the discovery of specific gene defects in early onset cases. PMID- 21318510 TI - Advances in methodology and current prospects for primary drug therapies for Alzheimer's disease. AB - There has been gratifying progress in the development of drugs for Alzheimer's disease (AD). Even though the current generation of medications, the cholinesterase inhibitors (CEIs), has produced only modest benefits, our concept of an "effective" therapy has matured considerably over this time. A less visible but equally important advance has been a quantum leap in expertise in clinical trial methodology. This chapter reviews the methodological underpinnings of clinical trials in AD: patient selection issues, key design issues, and an overview of currently available agents and the prospects for drugs of the future. PMID- 21318511 TI - Production and Functional Assays of Recombinant Secreted Amyloid Precursor Protein (APP) (sAPPalpha). AB - The beta-amyloid precursor protein (APP) is connected to Alzheimer's disease by both biochemistry and genetics. As the source of the major constituent of amyloid plaques, APP has been the subject of many studies of its expression and metabolism. The accumulation of amyloid beta-peptide (Abeta) in these plaques was the first evidence that APP might be processed abnormally in Alzheimer's, and this idea was strengthened by the discovery of mutations in APP that segregate with the disease with high penetrance. Aberrant processing of APP was incorporated into the Amyloid Hypothesis, which supposes that the clinical symptoms, neuropathology, and ultimate fatality of Alzheimer's result from the actions of Abeta. But to the extent that the Amyloid Hypothesis remains hypothetical, it would be irresponsible to ignore other theories that might explain the links between APP and Alzheimer's. APP can be proteolytically processed in a way that does not produce (and, in fact, precludes) Abeta. This "alpha-secretase" event cleaves within the Abeta sequence and liberates most of the extracellular portion (sAPPalpha) of APP from the cell surface Fig. 1). Because the "beta-secretase" event required for the generation of Abeta creates a different soluble derivative (sAPPbeta), disease-related increases in beta secretase processing -such as demonstrated with the "Swedish" mutation of APP have the potential to affect events dependent on the normal function(s) of sAPPalpha. Furthermore, the increases in APP expression that occur as a result of injury or trisomy 21 may elevate the total levels of all sAPP species. To understand the implications of these events, it is critical to elucidate the biological activities of sAPPalpha and related moieties. PMID- 21318512 TI - Quantifying Abeta(1-40) and Abeta (1-42) Using Sandwich-ELISA. AB - The role of Abeta accumulation in the pathogenesis of Alzheimer's disease (AD) is supported by genetic studies showing that mutations in the amyloid-beta precursor protein (APP) that alter Abeta production are linked to a subset of familial AD (FAD) cases with autosomal penetrance (reviewed in ref. 1). Several of these FAD associated APP mutations, as well as FAD-associated mutations in the presenilin 1 (PS1) and presenilin 2 (PS2) genes, lead to an increase in the production of Abeta(1)-(42) relative to Abeta(1)_(40). This, combined with the observation that these peptides are differentially deposited in senile plaques (SPs) in vivo, suggests that differential production of Abeta(1)-(40) and Abeta(1)_(42) may be crucially important in the pathogenesis of AD. Thus, it is important to use techniques that not only quantitate Abeta production, but also specifically differentiate between these two peptides in a variety of experimental paradigms. Here we describe the use of a highly sensitive sandwich-ELISA (enzyme-linked immunosorbent assay) to quantitate both Abeta(1)-(40) and Abeta(1)-(42) in soluble pools, after secretion by cultured cells into the medium or in human cerebrospinal fluid (CSF) samples, as well as in insoluble pools, as found intracellularly in cultured cells, or deposited in the brain parenchyma. PMID- 21318513 TI - Electrophoretic separation and immunoblotting of abeta(1-40) and abeta (1-42). AB - The main protein component of the plaques found in the brains of Alzheimer's disease patients is Abeta, a peptide of 39 to 43 amino acids (reviewed in refs. 1 and 2). Two major Abeta isoforms have been identified in the brains of affected individuals ending at amino acids 40 and 42, respectively (3). The longer form, Abeta42, aggregates more rapidly in vitro (4) and is preferentially deposited in vivo (3 ,5,6). Normally, Abeta is secreted as an apparently soluble molecule (7 9). It is generated by all cultured cells expressing its precursor protein, APP, and can be detected in vivo in the cerebrospinal fluid (10) and in plasma (11). Mutations linked to familial forms of Alzheimer's disease have been found in the APP gene as well as two other genes encoding presenilin 1 and presenilin 2. They were shown to alter APP metabolism and, in particular, to either increase total Abeta or the relative abundance of the longer Abeta42 isoform (12-17). These observations have led to the hypothesis that Abeta42 may play a critical role in amyloid plaque formation and the development of Alzheimer's disease. Obviously methods discriminating between the two major Abeta species are important in order to study this notion. PMID- 21318514 TI - Abeta-Induced Proinflammatory Cytokine Release from Differentiated Human THP-1 Monocytes. AB - As noted in the introductory chapters of this book, neuritic plaques composed of accumulated amyloid beta (Abeta) peptide are a hallmark pathological feature of the Alzheimer's disease (AD) brain. Compelling genetic data now implicate these plaques as key causative agents in AD onset, as all known mutations that lead to early onset familial AD (1-6) result in an increased production of the amyloidogenic Abeta1-42 isoform (7-11). Although it appears likely that the deposition of multimeric Abeta fibrils into plaques is a necessary step in AD onset, there is still uncertainty as to how Abeta and neuritic plaques might cause the neuropathology that leads to the dementia that is characteristic of this disease. PMID- 21318515 TI - Effects of the beta-Amyloid Peptide on Membrane Ion Permeability. AB - Several lines of evidence suggest a role for membrane ion channels in the neurotoxic effects of the beta-amyloid peptide (Abeta). This chapter describes the electrophysiological techniques that can be employed to isolate and record specific membrane conductances that may be altered by Abeta. In general, an increase in conductances that cause depolarization of the cell membrane may be considered excitotoxic since they will: (1) increase Ca(2+)influx through voltage gated Ca(2+)channels and (2) reduce Mg(2+)-dependent block of ionotropic glutamate receptors, thereby increasing Ca(2+)influx through N-methyl-D-aspartate (NMDA) receptor channels. Conversely, an increase in conductances that cause membrane hyperpolarization might be considered to have a protective effect. This is a simplistic view, as it has been shown that for certain forms of apoptosis an increase in hyperpolarizing K(+)currents may be involved (1). It is, therefore, important to consider the functional effects of any changes in membrane conductances or ion channel currents induced by Abeta in the light of neurotoxic effects of the peptide. PMID- 21318516 TI - Analysis of beta-Amyloid Peptide Degradation In Vitro. AB - The accumulation of insoluble Abeta peptide aggregates in the brain is the diagnostic feature of Alzheimer's disease. Identical deposits are seen in the elderly who are at risk for this disease. The formation of the approx 4 kDa Abeta peptide is implicated as a key component in the development of Alzheimer's disease pathology. Genetic evidence strongly supports this contention (1,2), as well as a number of demonstrated relevant biological activities of the Abeta peptide such as its neurotoxicity (3) and proinflammatory properties (4). A great deal of attention has been focused on the processes involved in the generation of Abeta peptide. In contrast, the fate of this peptide once it has been released from the cell is less well understood. Recently, this situation has been changing as studies on the clearance of Abeta peptide are being published. The identification of Abeta-degrading enzymes produced in the brain, their class, and selectivity, as well as their cellular origin, are important unresolved questions. One key issue of Abeta peptide clearance is whether the brain may be limited in its capacity to degrade this protein, as all cells produce Abeta, yet it is seen to accumulate only in brain tissue. Because alterations in Abeta peptide clearance may potentially contribute to increased levels and to the development of insoluble Abeta deposits in the brains of afflicted individuals, this chapter focuses on specific approaches to clarifying Abeta peptide-clearance mechanisms. PMID- 21318517 TI - Posttranslational modifications of amyloid precursor protein : ectodomain phosphorylation and sulfation. AB - The amyloid precursor protein (APP) is a type I transmembrane protein with a large ectodomain, a single transmembrane domain and a small cytoplasmic tail (1). Translation of APP occurs at the endoplasmic reticulum (ER) and the protein is translocated into the ER lumen. The N-terminal domain of APP is directed towards the luminal compartment of the ER, whereas the C-terminal domain faces the cytoplasm. After synthesis, APP passes from the ER to the Golgi compartment. APP can then be transported in secretory vesicles to the cell surface, where the large ectodomain faces the extracellular milieu. Cell surface APP can be reinternalized into endosomes and lysosomes (for review see refs. 2 and 3). During its passage through the secretory pathway, APP is subjected to a variety of posttranslational modifications, including proteolytic processing, glycosylation, sulfation, and phosphorylation. Immediately on translocation into the ER, the signal peptide of APP is removed from the N-terminus by signal peptidase. APP is then modified cotranslationally by N-glycosylation on NH(2) groups of asparagine residues. After passage into the Golgi compartment, the ectodomain of APP is subjected to O-glycosylation. In late Golgi compartments, e.g., the trans Golgi network, APP is subjected to sulfation on tyrosine residues within its ectodomain (4). PMID- 21318518 TI - Posttranslational modifications of the amyloid precursor protein : glycosylation. AB - Many studies have demonstrated the importance of amyloid precurser protein (APP) in the pathogenesis of Alzheimer's disease. Nonetheless, the exact mechanism by which APP contributes to the pathogenesis of Alzheimer's disease is still not clear. Because APP is a glycoprotein, and because glycosylation can be important in the cell biology of individual glycoproteins (for review, see refs. 1 and 2), it is possible that changes in APP glycosylation during development and aging are important in APP biosynthesis, proteolysis, and degradation. However, few studies have addressed this issue (3 -8). This chapter provides methods for analyzing the glycosylation of APP that is actively synthesized by living cells in tissue culture. These methods can be applied to primary cultures, continuous cell lines, and transfected cell lines expressing recombinant APP. PMID- 21318519 TI - Using an Amyloid Precursor Protein (APP) Reporter to Characterize alpha Secretase. AB - Human genetic studies suggest decreasing amyloid peptide (Abeta) levels in the brain could alter the course of Alzheimer's disease (AD) (1 -4). Proteolytic cleavages govern the level of Abeta generated from the amyloid precursor protein (APP). beta- and gamma-cleavages at the amino and carboxyl termini of Abeta produce amyloidogenic peptides; in contrast, alpha-cleavage within the Abeta domain destroys the amyloidogenic potential of APP. The proteases responsible for these cleavages have not been identified. PMID- 21318520 TI - Inhibition of alpha-Secretase by Zinc Metalloproteinase Inhibitors. AB - The amyloid precursor protein (APP) is cleaved by at least three proteinases termed the alpha-, beta-, and gamma-secretases. Cleavage of APP at the N-terminus of the beta-amyloid (Abeta) peptide by beta-secretase and at the C-terminus by one or more gamma-secretases constitutes the amyloidogenic pathway. In the nonamyloidogenic pathway, alpha-secretase cleaves APP within the Abeta peptide between Lys16 and Leu17 (numbering from the N-terminus of the Abeta peptide) (1), thereby preventing deposition of intact Abeta peptide. The alpha-secretase cleavage site lies some 12 amino acid residues on the extracellular side of the membrane, releasing the large ectodomain of APP (sAPPalpha), which has neuroprotective properties (2 ,3). The identification and characterization of the APP secretases is important for the development of therapeutic strategies to control the buildup of Abeta in the brain and the subsequent pathological effects of Alzheimer's disease. Regulation of the balance of APP processing by the amyloidogenic and nonamyloidogenic pathways through either selective inhibition of beta- and gamma-secretases or activation of alpha-secretase can all be considered as potential therapeutic approaches. As a first step towards isolating the APP secretases, we have investigated the effect of protease inhibitors on the activities of alpha- and beta-secretase. From these studies we have identified low molecular weight inhibitors of alpha-secretase. PMID- 21318521 TI - Development of Neoepitope Antibodies Against the beta-Secretase Cleavage Site in the Amyloid Precursor Protein. AB - A detailed understanding of the biochemical events leading to the proteolytic excision of the beta-amyloid peptide (A beta) from the amyloid precursor protein (APP) has eluded many researchers. This is largely because the measurement of the various APP processing products is technically challenging owing to their low levels of production in in vitro and in vivo test systems. Sequence analysis of products in cell cultures, cerebrospinal fluid (CSF), and amyloid plaques has been used to predict the major cleavage sites resulting from the beta- and gamma secretase proteolytic activities that release the Abeta peptide from APP (1 -3). More routine identification of the secretase activities has relied on the specificity and sensitivity of antibodies raised to the predicted cleavage products and has been impeded by the difficulties associated with the generation of such reagents. PMID- 21318522 TI - beta-Secretase : Tissue Culture Studies of Sequence Specificity, Inhibitors, and Candidate Enzymes. AB - When the amyloid precursor protein (APP) was cloned, Abeta was found to be part of the large APP molecule and it became obvious that at least two endoproteolytic cleavage events are required to release Abeta from its large precursor (1). More than 10 yr later nobody has published definitive identification of either of the proteases, although they are prime therapeutic targets for an antiamyloid therapy for Alzheimer's disease. PMID- 21318523 TI - Using beta-Secretase Inhibitors to Distiguish the Generation of the Abeta Peptides Terminating at Val-40 and Ala-42. AB - A large body of evidence suggests a causative role of beta-amyloid (Abeta) in the pathogenesis of Alzheimer's disease (reviewed in refs. 1 and 2). Abeta is neurotoxic and toxicity requires the formation of amyloid fibrils similar to those found in senile plaques (3). Autosomal dominant mutations linked to Alzheimer's disease were identified in three different genes (4 ,5). All mutations apparently alter amyloid precursor protein (APP) metabolism to increase the generation of Abeta peptides terminating at amino acid Ala-42. Due to the tendency of the longer Abeta peptides to more readily form fibrils (7), these may accelerate Abeta deposition, which ultimately leads to more aggressive, early onset forms of Alzheimer's disease (8). With the transgenic expression of APP in mice this was explored further (9). Whereas a twofold overexpression of APP did not lead to Abeta deposition, the same quantitative expression of APP with a mutation at codon 717 known to increase the formation of Abeta42 led to the appearance of Abeta deposits at the age of 18 mo. These data suggest that the Abeta load in the brain as well as the amyloidogenic properties of the Abeta isoforms directly regulate deposition and senile plaque formation. PMID- 21318524 TI - Designing Animal Models of Alzheimer's Disease with Amyloid Precursor Protein (APP) Transgenes. AB - Amyloid precursor protein (APP) and Alzheimer's disease are irrevocably linked, as APP is cleaved to form the Abeta peptides that are the major components of amyloid plaques. One of the most resilient hypotheses about the cause of AD centers on the Abeta peptide; all genetic causes and risk factors can be fitted into a general "amyloid cascade hypothesis," which maintains that all pathology is initiated by an abnormal accumulation of Abeta amyloid (1). PMID- 21318525 TI - Phosphorylation of Amyloid Precursor Protein (APP) Family Proteins. AB - It has been well established that beta-amyloid peptide is the principal protein component of extracellular cerebral amyloid deposits in patients with Alzheimer's disease (1,2). beta-Amyloid is derived from a large precursor protein, amyloid precursor protein (APP), which is an integral membrane protein, with a receptor like structure (3). APP is a member of a gene family which encodes extremely well conserved membrane proteins. APP/APP-like genes have been isolated from various species including fly (4), nematode (5), and fish (6). In mammals, two APP-like genes, amyloid precursor-like protein 1 (APLP1) and 2 (APLP2), have been isolated (7,8). The amino acid sequences of these APP family proteins are highly conserved, especially in the cytoplasmic domain, except that unlike APP, APP-like proteins lack the beta-amyloid sequence. It has been thought that APP and APLP2 have a similar physiological function (9). In contrast, APLP1 is believed to differ functionally from APP and APLP2, although the physiological functions of these APP family proteins have not yet been well analyzed. PMID- 21318526 TI - Determining the transmembrane topology of the presenilins. AB - Mutations in two related genes, PS1 (1) and PS2 (2,3) located on chromosomes 14 and 1, respectively, account for the majority of early onset cases of familial Alzheimer's disease (FAD). PS1 and PS2 are predominantly localized in the endoplasmic reticulum and Golgi (4-7). PS1 is a 467 amino acid peptide predicted to contain between seven and nine transmembrane helices based on hydrophobicity profiles (1,8). The protein topology of PS1 and its C. elegans homologues, SEL-12 and HOP-1, have been examined by several investigators (7,9-13). This chapter describes two approaches we utilized to determine the topological orientation of the PS1 N-terminal, and C-terminal domains, and a hydrophilic "loop" region encompassing amino acids 263-407. The first approach is based on the proteolytic sensitivity of amyloid precursor protein (APP) protein chimeras to endoproteolytic cleavage by beta-secretase in the lumen of the Golgi. The second approach is based on selective permeabilization of the plasma membrane using a bacterial pore-forming toxin, streptolysin-O (SLO), and subsequent immunocytochemical probing for cytosolic epitopes using specific antibodies. Both of these methods can be easily adapted to determine the topology of other membrane proteins. PMID- 21318527 TI - Normal proteolytic processing of the presenilins. AB - The majority of familial Alzheimer's disease (AD) cases are linked to mutations of the presenilin 1 and 2 (PS1, PS2) genes on chromosomes 14 and 1, respectively (1-3). PS1 and PS2 are about 67% identical in amino acid sequence. Based on hydrophobicity analysis, the presenilins are predicted to have multiple transmembrane domains. Structural analysis (see Chapter 19 }) suggest that presenilins are 6-8 transmembrane proteins which are located in the endoplasmic reticulum (ER) and Golgi. The N- and C-termini and the large hydrophilic loop region are oriented to the cytoplasm (4,5). More than 40 AD-causing mutations have been identified in PS1, whereas only two mutations have been identified in PS2. The disease-causing mutations span most domains of the protein, with clusters of mutations in the second transmembrane domain and the large hydrophilic loop region Fig. 1). PMID- 21318528 TI - Apoptotic proteolytic cleavage of the presenilins by caspases. AB - Familial Alzheimer's disease (FAD) is a genetically heterogeneous disorder that is caused by defects in at least three early onset genes (age of onset:<60 yr.): presenilin 2 (PS2) on chromosome 1 (1), presenilin 1 (PS1) on chromosome 14 (2), and amyloid protein precursor (APP) on chromosome 21 (3,4). Mutations within the APP gene are responsible for only a small portion (<2%) of reported cases of FAD (5), whereas up to half of all early onset FAD cases are caused by mutations in the PSEN1 and PSEN2 genes (6,7). PMID- 21318529 TI - The phosphorylation of presenilin proteins. AB - The phosphorylation of presenilin (PS) proteins was initially analyzed in cultured cells overexpressing the respective proteins. These studies revealed that the homologous PS proteins are differentially phosphorylated in vivo. Fulllength PS2 was found to be constitutively phosphorylated on serine residues (1,2). In contrast, very little if any (1) or a variable phosphorylation (2) was observed for PS1. The familial Alzheimer's disease (FAD) mutations tested, the A246E mutation of PS1 and the N141I mutation (volga german) of PS2, apparently have no effect on the differential phosphorylation of PS1 and PS2 (1). Because both PS proteins appeared to reside predominantly within the endoplasmic reticulum (1-4) differential phosphorylation is not due to distinct subcellular localizations of these proteins. Instead, the differential phosphorylation seems to be determined by structural differences between PS1 and PS2. The phosphorylation of full-length PS2 was localized to its N-terminal domain preceding the first transmembrane region (1). Although both PS proteins are highly homologous (5-7), their N-terminal domains differ in the primary structure. PS2 contains a stretch of acidic residues (amino acids 1-20), which is lacking in PS1 Fig. 1). This acidic domain of PS2 contains three consensus sites for casein kinases (CK), one site for CK-1 (serine 19) and two for CK-2 (serines 7 and 9; Fig. 1). Mutagenesis analyzes demonstrated that all three serine residues (serines 7, 9, and 19) are phosphorylated in cultured cells overexpressing PS2 (1). Moreover, in vitro phosphorylation demonstrated that the N-terminal domain of PS2 can be phosphorylated by both CK-1 and CK-2 (1). Thus, it is likely that full-length PS2 is phosphorylated by CK-1 and CK-2 in vivo within its N-terminal domain. The phosphorylated residues within the acidic region of PS2 precedes a PEST motif (8,9), which is lacking in PS1. PEST sequences have been shown to be implicated in the regulation of protein turnover, e.g., the degradation of proteins containing a PEST motif is enhanced (9). It will be of great interest to test whether the phosphorylation of PS2 influences its turnover. PMID- 21318530 TI - Interaction of the Presenilins with the Amyloid Precursor Protein (APP). AB - The genes encoding presenilin-1 (PS1) and presenilin-2 (PS2) were identified as the genes that harbour mutations that cause more than 60% of early onset familial Alzheimer's disease cases (FAD) (1-3). So far, more than 40 missense mutations have been described for presenilin-1 and two have been found in the gene coding for presenilin-2 (reviewed in refs. 4 and 5). Carriers of mutated presenilin genes develop in their brain neuropathological changes characteristic of Alzheimer's disease including the deposition of amyloid Abeta peptide. The latter is released from its cognate amyloid precursor protein (APP) by a two-step proteolytic conversion: first, proteolysis of APP by beta-secretase, which releases the N-terminus of Abeta, and second, conversion of the remaining fragment by gamma-secretase, which cleaves within the predicted transmembrane region of APP. This releases the C-terminus of Abeta, which may end either at position 40 or, to a lesser extent, at position 42 (reviewed in ref. 6). The latter species, Abeta(1-42), is more prone to aggregation and deposition than Abeta(1-40) and is produced at higher levels in the brains and primary fibroblasts of FAD patients carrying PS missense mutations (7). The same result was obtained when cultured cells transfected with mutated PS1 orPS2, or transgenic mice harboring missense PS1 were analyzed for the production of Abeta(1-42): in every case increased amounts of the longer Abeta(1-42) species were observed (8-10). The mechanisms by which mutations in the PS genes affect the proteolytic processing of APP by gamma-secretase have not been resolved in detail. There are two possibilities by which the normal processing of APP may be disturbed: either mutations in the presenilins affect APP metabolism in an indirect way by modulation of proteases or interaction with proteins involved in APP intracellular routing, or presenilins may modulate APP processing directly through physical interactions with APP. Such a direct interaction between presenilins and APP was first demonstrated by us for PS2 (11). Later on, formation of stable complexes with APP was reported not only for PS2 but also for PS1 (12,13,13a). PMID- 21318531 TI - Distribution of Presenilins and Amyloid Precursor Protein (APP) in Detergent Insoluble Membrane Domains. AB - Until recently, the detergent insolubility of certain membrane-associated proteins was singularly attributed to an association with the cytoskeleton. However, in 1988 we observed that a number of glycosyl-phosphatidylinositol (GPI) anchored proteins were resistant to solubilization by nonionic detergents such as Triton X-100 (1). This detergent insolubility is acquired as the proteins pass through the endoplasmic reticulum and on to the Golgi apparatus (2), and arises not from a direct interaction of the GPI-anchored proteins with cytoskeletal elements but as a result of the specific lipid composition of the membrane domains with which these proteins associate (3,4). Mammalian cell membranes contain hundreds of individual lipid species which can be grouped under several major headings (e.g., glycerophospholipids, sphingomyelins, ceramides, glycosphingolipids, and cholesterol) (2,5,6). Glycerophospholipids, such as phosphatidylcholine and phosphatidylethanolamine, predominate in the membrane milieu. Consequently, the bulk of the cell membrane is fluid and in a continual state of flux. However, the membrane domains with which GPI-anchored proteins associate are enriched with sphingolipids and cholesterol, making them less fluid than the membrane milieu (2,4). Such membrane domains have been referred to as "lipid rafts" (7) and there has been some controversy as to whether they exist in vivo or whether they form as an artefact of the procedures employed in their isolation (8). However, recent studies in both artificial lipid bilayers and living cell membranes using such techniques. PMID- 21318532 TI - Characterization and use of monoclonal antibodies to tau and paired helical filament tau. AB - Antibodies to the microtubule-associated protein tau have been used for more than a decade, both in studies of the role of tau neuronal function, and in examination of the neurofibrillary pathology of Alzheimer's disease (AD). The vast majority of the available antibodies have been produced with preparations obtained from the brains of patients with AD, although a few antibodies have been generated with tau purified from bovine brain. This chapter restricts discussion to the production and characterization of monoclonal antibodies, although some investigators continue to use affinity-purified polyclonal antibodies. The opinions expressed in this chapter are based on the author's experience in the production of several series of monoclonal antibodies to tau and paired helical filaments (PHF-tau) over the last 10 yr. There is no doubt that modifications in the procedures described can be developed for specific purposes, but the discussion is confined to those methods that we have found to be reliable and informative. PMID- 21318533 TI - Tau phosphorylation both in vitro and in cells. AB - Tau was originally isolated from brain microtubules and shown to be a microtubule associated protein (MAP) that promoted tubulin polymerization (1). It is largely confined to axons, where it is the major MAP. It promotes microtubule nucleation, elongation, and bundling, and stabilizes microtubules by inhibiting depolymerization. PMID- 21318534 TI - Transglutaminase-catalyzed formation of Alzheimer-like insoluble complexes from recombinant tau. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease in which abnormal filamentous inclusions accumulate in dystrophic and dying nerve cells. These inclusions have been described as neurofibrillary tangles (NFTs) of which paired helical filaments (PHFs) are the primary constituents (1-3). The PHFs primarily are composed of the microtubule-associated protein tau, which has undergone posttranslational modification such as phosphorylation (4,5), glycation (6-9), and crosslinking by transglutaminase (TGase) (10-16). Crosslinking of proteins catalyzed by TGase results in the deposition of these proteins into insoluble matrices that are resistant to proteolytic digestion and chaotropic denaturation (for review see ref. 17). In this regard, TGase has been demonstrated to be associated with NFTs from the Alzheimer brain (13,14) and to exhibit elevated activity in the AD brain as compared with normal aged-matched control subjects (16). Here we discuss important aspects of TGase and in vitro experimental approaches that address its ability to catalyze the tau protein into insoluble complexes exhibiting biophysical and immuno-logical properties similar to those of the Alzheimer PHFs and NFTs. PMID- 21318535 TI - An intervention to assist men who have sex with men disclose their serostatus to family members: results from a pilot study. AB - The purpose of this study was to evaluate the efficacy of an intervention to assist HIV positive men who have sex with men (MSM) in forming and executing strategies for the disclosure of their serostatus to their families of origin. Results indicate that the intervention was successful in assisting men with the primary outcome of disclosure. Participants reported no regret with disclosures occurring during the intervention and follow-up period. Effects on secondary outcomes including family functioning, depression, loneliness, and perceived social support were inconclusive. Implications, refinements of this intervention, and suggestions for future disclosure research are provided. PMID- 21318536 TI - Statistical challenges in studying complex and changing families. AB - This paper describes challenges of studying complex and changing families and provides suggestions for methods of analyses to study these family systems. Five common problems that NIMH-funded investigators have encountered in analyzing family based studies are addressed and analytic solutions for addressing these problems are illustrated using data from Family HIV/AIDS projects. The problems discussed in the paper are (1) differences in subgroup responses to interventions; (2) longitudinal changes in family relationships and covariates that vary by group in nested designs; (3) dealing with missing data over time from attrition and planned missing data due to death; (4) dealing with multiple reports from different family members; and (5) developing concordance measures among family members. The use of multi-level and growth curve modeling techniques to address these problems is illustrated with some of the studies. PMID- 21318555 TI - Attention biases to threat link behavioral inhibition to social withdrawal over time in very young children. AB - Behaviorally inhibited children display a temperamental profile characterized by social withdrawal and anxious behaviors. Previous research, focused largely on adolescents, suggests that attention biases to threat may sustain high levels of behavioral inhibition (BI) over time, helping link early temperament to social outcomes. However, no prior studies examine the association between attention bias and BI before adolescence. The current study examined the interrelations among BI, attention biases to threat, and social withdrawal already manifest in early childhood. Children (N=187, 83 Male, M (age)=61.96 months) were characterized for BI in toddlerhood (24 & 36 months). At 5 years, they completed an attention bias task and concurrent social withdrawal was measured. As expected, BI in toddlerhood predicted high levels of social withdrawal in early childhood. However, this relation was moderated by attention bias. The BI withdrawal association was only evident for children who displayed an attention bias toward threat. The data provide further support for models associating attention with socioemotional development and the later emergence of clinical anxiety. PMID- 21318556 TI - Carotid artery disease and stenting: insights from recent clinical trials. AB - OPINION STATEMENT: Cerebrovascular disease remains a leading cause of morbidity, mortality, and health care expenditure in the United States. Approximately 80% of strokes are ischemic in origin, with 20% to 25% due to atherosclerotic disease of the carotid artery. It is well established that untreated, symptomatic carotid stenosis confers a 25% risk of stroke within 2 years, and that asymptomatic carotid stenosis > 60% is associated with an 11% stroke risk at 5 years. Over the past six decades, surgical revascularization with carotid endarterectomy, when performed by experienced surgeons, has been demonstrated to be effective in reducing stroke risk in patients with severe stenosis. During the same time, medical therapy has improved considerably, and endovascular therapy with carotid angioplasty and stenting has emerged as an important alternative strategy that may play a significant role in reducing the risk of stroke in patients with carotid disease. In this review, we examine the current evidence regarding optimal medical therapy, endarterectomy, and stenting for the management of patients with carotid stenosis. Armed with these data, we may tailor our approach to optimize care based on patient- and lesion-specific considerations. PMID- 21318557 TI - Incisional hernia in patients at risk: can it be prevented? AB - INTRODUCTION: Incisional hernia is a long-term complication of laparotomy. Its exact frequency varies according to different authors, but is always around 10 15%. There are patients who present with systemic associated diseases [chronic obstructive pulmonary disease (COPD), obesity, severe cardiopathies, immunodeficiencies, etc.] that favour or increase the risk of appearance of an incisional hernia. The aim of the present study was to assess whether the prophylactic placement of a polypropylene mesh in patients at risk can reduce or avoid the appearance of an incisional hernia. MATERIALS AND METHODS: Seventy-two selected patients with clear risk factors and colon pathology underwent surgical intervention through median infraumbilical laparotomy. During laparotomy the preperitoneal space was dissected at a point where a low-molecular weight polypropylene mesh was to be placed when closing the peritoneum. Meshes were about 7-8 cm wide and had a variable length that depended on the length of the surgical incision. Of the 72 patients, 41 were obese (BMI > 30 kg/m(2)), 45 presented with COPD, and 42 with colorectal neoplasia; 29 patients had two risk factors, and 15 had three risk factors. The mesh was held in place with polypropylene stitches in 28% of cases, and with fibrin glue in 72% of cases. RESULTS: All patients were assessed by a protocol that included interview, examination of the surgical wound, and abdominal CT scan. Follow-up was between 3 and 5 years. There were no noteworthy complications or operative mortality. No mesh had to be removed in any patient. Two patients developed liver metastasis, and in a second surgery the good condition of the abdominal wall and the absence of hernia were confirmed. Twenty patients required postoperative chemotherapy. Two patients died at 37 and 43 months after surgery because of progression of the neoplastic disease. Fourteen patients were monitored for more than 5 years after surgery, and 46 patients were monitored for 48 months. None of the 72 patients developed an incisional hernia. CONCLUSION: Prophylactic use of a low-molecular weight polypropylene mesh in abdominal surgery may be useful for the prevention of incisional hernia. PMID- 21318558 TI - Isolated right ventricular stress-induced ("Tako-Tsubo") cardiomyopathy. PMID- 21318559 TI - Comparison of inhaled nitric oxide with aerosolized iloprost for treatment of pulmonary hypertension in children after cardiopulmonary bypass surgery. AB - OBJECTIVES: Pilot study to compare the effect of inhaled nitric oxide (iNO) and aerosolized iloprost in preventing perioperative pulmonary hypertensive crises (PHTCs). BACKGROUND: Guidelines recommend the use of iNO to treat PHTCs, but treatment with iNO is not an ideal vasodilator. Aerosolized iloprost may be a possible alternative to iNO in this setting. METHODS: Investigator-initiated, open-label, randomized clinical trial in 15 infants (age range 77-257 days) with left-to-right shunt (11 out of 15 with additional trisomy 21), and pulmonary hypertension (i.e. mean pulmonary artery pressure [PAP] >25 mmHg) after weaning from cardiopulmonary bypass. Patients were randomized to treatment with iNO at 10 ppm or aerosolized iloprost at 0.5 ug/kg (every 2 h). The observation period was 72 h after weaning from cardiopulmonary bypass. The primary endpoint was the occurrence of PHTCs; the secondary endpoints were mean PAP, duration of mechanical ventilation, safety of administration, and in-hospital mortality. RESULTS: Seven patients received iNO and eight patients received iloprost. During the observation period, 13 of the 15 patients had at least one major or minor PHTC. There was no difference between the groups with regard to the frequency of PHTCs, mean PAP and duration of mechanical ventilation (p > 0.05). CONCLUSIONS: In this pilot study, aerosolized iloprost had a favorable safety profile. Larger trials are needed to compare its efficacy to iNO for the treatment of perioperative pulmonary hypertension. However, neither treatment alone abolished the occurrence of PHTCs. PMID- 21318560 TI - Heterologous expression and characterization of a recombinant thermostable alkylsulfatase (sdsAP). AB - A novel alkylsulfatase gene, sdsAP, was cloned from a newly isolated bacterium Pseudomonas sp. S9. It encoded a protein of 675 amino acids with a calculated molecular mass of 74.9 kDa. The protein contained a typical N-terminal signal peptide of 41 amino acid residues, followed by a metallo-beta-lactamase like domain at the N-terminus and a SCP-2-like domain at the C-terminus. This domain organization mode suggested that it belonged to the type III sulfatase. The mature alkylsulfatase was overexpressed in Escherichia coli. The optimal temperature and pH of the recombinant SdsAP were 70 degrees C and 9.0, respectively. Notably, at optimal conditions, the purified recombinant SdsAP had a high specific activity of 23.25 MUmol min(-1) mg(-1), a K(m (app)) of 264.3 MUmol, and a V(max (app)) of 33.8 MUmol min(-1) mg(-1) for SDS. Additionally, it still retained more than 90% activity after incubation at 65 degrees C for 1 h, which was much different from other alkylsulfatases reported. The recombinant enzyme hydrolyzed the primary alkyl sulfate such as sodium octyl sulfate and sodium dodecyl sulfate (SDS). It was a Zn(2+)-containing and Ca(2+) activated alkylsulfatase. This is the first report to explore the various characteristics of the heterologous recombinant alkylsulfatase in details. These favorable properties could make SdsAP attractive to be useful in the degradation of SDS containing waste. PMID- 21318561 TI - Functional evaluation of four putative DNA-binding regions in Thermoanaerobacter tengcongensis reverse gyrase. AB - Reverse gyrase (RG) is an ATP-dependent type I DNA topoisomerase that introduces positive supercoils into DNA in thermophiles. Four regions of RG, i.e., the N terminal zinc-finger motif, the beta-hairpin in subdomain H1, the "latch", and the C-terminal zinc-finger motif, were predicted to be involved in DNA binding previously. In this paper, the functions of these regions in the enzymatic activity were evaluated by mutational analysis of the Thermoanaerobacter tengcongensis reverse gyrase (TtRG). We demonstrated that TtRG exhibited positive supercoiling activity only at high temperature (>50 degrees C) and low salt concentration (~30 mM NaCl), and three of these four regions (except for the "latch") were involved in DNA binding. Notably, mutations in the "latch" and beta hairpin regions of TtRG strongly impaired the ATPase activity, while mutations in the two zinc-finger motifs dramatically affected its thermal stability besides significant impairment of the DNA-binding ability. Accordingly, all of these four regions were found to be indispensable for the positive-supercoiling activity of TtRG. Taken together, we revealed that these putative DNA-contact regions affect the enzymatic activity of RG in different ways, and provided new insights into the structure and function of RG. PMID- 21318562 TI - Effects of systemic or nucleus accumbens-directed dopamine D1 receptor antagonism on sucrose seeking in rats. AB - RATIONALE: Conditioned cues can elicit relapse to drug- and food-seeking behavior over prolonged periods of abstinence. If seeking behavior depends on mesolimbic dopamine D1 receptors, blocking these receptors should reduce seeking behavior. OBJECTIVES: We examined the effects of either systemic or intra-nucleus accumbens administration of the D1 antagonist SCH 23390 on extinction responding (sucrose seeking) by rats either 1 or 30 days into forced abstinence. MATERIALS AND METHODS: Rats self-administered 10% sucrose paired with a tone + light cue for 10 days. After either 1 or 30 days of forced abstinence, rats received systemic (0, 1, 5, or 25 MUg/kg IP) or bilateral nucleus accumbens core or shell (0.3 or 0.6 MUg/site) injections of SCH 23390 prior to extinction testing. RESULTS: Saline treated rats responded more during extinction following 30 vs. 1 day of forced abstinence ("incubation of craving"). Systemic SCH 23390 reduced sucrose seeking after 1 day of forced abstinence, significantly reducing responding following pretreatment with 1, 5, and 25 MUg/kg SCH 23390, but only 25 MUg/kg significantly reduced sucrose seeking after 30 days of forced abstinence. SCH 23390 (0.3 or 0.6 MUg/site) in the core or shell of the nucleus accumbens reduced sucrose seeking in all groups. CONCLUSION: Nucleus accumbens D1 receptors are involved in sucrose seeking, but it is not clear if they are involved in the incubation of craving. The fact that D1 antagonism reduced sucrose seeking across an extended period of abstinence may be of use for development of treatment strategies for relapse. PMID- 21318563 TI - Acceptability and effectiveness for withdrawal symptom relief of a novel oral nicotine delivery device: a randomised crossover trial. AB - RATIONALE: Existing nicotine replacement therapies (NRT) improve the chances of smoking cessation but are limited by either relatively slow nicotine absorption rates or unpleasant side effects, leaving scope for the development of more effective and acceptable products. OBJECTIVES: This study aimed to test the acceptability and effectiveness for withdrawal symptom relief of a novel nicotine delivery device, the 'Nicotine Cannon' (NC), compared with three existing, equivalent products: the nicotine lozenge, mini-lozenge and nicotine inhalator. METHODS: A repeated-measures crossover trial where participants were randomised to one of two conditions (1- or 10-h abstinence) and in each condition to one of 24 possible sequence permutations to test each product for 10 min was carried out. Standard sociodemographic and smoking characteristics were assessed as well as withdrawal and NRT use symptoms before, during and after NRT use and product satisfaction after use. RESULTS: The results were similar across both durations of abstinence. The NC was significantly more effective than the inhalator in reducing withdrawal symptoms (F(3, 196)=3.5, p=0.015) and together with the mini lozenge performed better than other NRT in alleviating urges to smoke (F(3, 563)=9.6, p<0.001) and desire for cigarettes within 10 min of use (F(3, 727)=26.1, p<0.001). The NC induced fewer adverse side effects than other NRT and was judged to be more enjoyable (F(3, 87)=13.56, p<0.001) and satisfying to use (F(3, 92)=12.35, p<0.001). CONCLUSIONS: The 'Nicotine Cannon' is at least as effective as equivalent NRT in reducing withdrawal symptoms and more acceptable to users, suggesting that it would be a useful addition to existing NRT. The acceptability profile could make it particularly useful as a 'harm reduction' tool. PMID- 21318564 TI - A pilot study of the effectiveness of D-cycloserine during cue-exposure therapy in abstinent alcohol-dependent subjects. AB - RATIONALE: Cue-exposure therapy (CET) has been advocated as a potentially effective treatment of addictive behaviours. Strategies that enhance learning may improve the outcome of CET. D-cycloserine (DCS), a partial N-methyl-D-aspartate receptor agonist, has been shown to facilitate extinction of learned fear in rats and augment exposure-based treatment in some anxiety disorders in man. OBJECTIVE: This double-blind placebo-controlled pilot study used a cue-exposure paradigm, salient for an individual's alcohol drinking, to see if DCS would reduce cue reactivity compared with placebo. METHODS: Sixteen abstinent, alcohol-dependent individuals were randomised to receive either a single-dose (250 mg) DCS or placebo before CET sessions, separated by at least 1 week. Subjective responses were assessed using the Alcohol Urge Questionnaire (AUQ) and visual analogue scales. Cardiovascular responses were assessed using Finapres(c). RESULTS: The cue-exposure paradigm significantly increased craving assessed with the AUQ during the first session. In subsequent sessions, the degree of craving was reduced. However, no significant difference was seen between the DCS and placebo groups in any outcome measure. The variability of responses between individuals was great with more than half the groups reporting no or very small changes in AUQ scores. CONCLUSION: This is the first human study to our knowledge to assess the efficacy of DCS in facilitating CET in alcohol dependence. The high proportion of subjects with little or no response to cue-exposure would make any effect of DCS very difficult to detect. It is important that future studies carefully consider the criteria for inclusion. PMID- 21318565 TI - A prospective open-label study of aripiprazole in fragile X syndrome. AB - RATIONALE: Fragile X syndrome (FXS) is the most common inherited form of developmental disability and most common single gene cause of autism. Persons with FXS frequently exhibit irritable behavior marked by aggression, self-injury, and severe tantrums. Despite frequent clinical use of atypical antipsychotic drugs to target this behavioral cluster, no systematic trials to date have assessed the efficacy and safety of these drugs in persons with FXS. METHODS: We conducted a prospective open-label 12-week trial of aripiprazole in 12 persons aged 6-25 years (mean age, 14.3 years) with FXS who were free of concomitant psychoactive drugs. RESULTS: Aripiprazole use (mean dose, 9.8 mg/day) was associated with treatment response (defined by a Clinical Global Impressions Improvement scale score of much improved or very much improved and a >= 25% improvement on the Aberrant Behavior Checklist-Irritability subscale) in 10 of 12 (87%) persons. Two individuals (13%) discontinued aripiprazole prior to study completion due to adverse events. One discontinuation was due to akathisia, mild drooling, and mild tiredness and the other due to moderate tiredness and moderate drooling. No significant changes in vital signs including weight or laboratory measures occurred during treatment with aripiprazole. CONCLUSIONS: Aripiprazole was generally safe and well tolerated and was associated with significant improvement in irritable behavior. Given these findings, a double-blind, placebo controlled study of aripiprazole in FXS is warranted. PMID- 21318566 TI - MDMA and methamphetamine: some paradoxical negative and positive mood changes in an acute dose laboratory study. AB - RATIONALE: This study investigated the acute mood effects of oral MDMA, methamphetamine, and placebo in a double-blind laboratory study. METHODS: Fifty two healthy participants comprised abstinent recreational users of stimulant drugs, 27 female and 25 male, mean age 24.8 years. Three test sessions involved acute 100 mg oral 3.4-methylendioxymethamphetamine (MDMA), 0.42 mg/kg oral methamphetamine, and matching placebo. Drug administration was counterbalanced, testing was double-blind, and medical supervision was present throughout. Car driving performance on a laboratory simulator was assessed after 3 and 24 h, with the findings being presented elsewhere. Positive and negative moods (PANAS self ratings) were completed before drug administration, 3, 4.5, and 24 h later. Blood samples were taken to monitor drug plasma levels. RESULTS: Following MDMA, there were no significant increases in positive moods, whereas negative moods were significantly higher than under placebo. Methamphetamine led to significant increases in both positive and negative moods. The MDMA findings contrast with the elated moods, typically noted by dance clubbers on Ecstasy. However, they are consistent with some previous laboratory findings, since a wide array of positive and negative mood changes have been demonstrated. One possible explanatory factor was the neutral environmental situation, particularly if a primary action of MDMA is to intensify ongoing psychological states. Other explanatory factors, such as dosage, gender, post-drug timing, neurohormonal aspects, and social factors, are also discussed. CONCLUSIONS: In the laboratory, acute methamphetamine led to significantly higher positive moods. However, against expectations, MDMA did not generate a significant increase in positive moods. PMID- 21318567 TI - Effect of prazosin and guanfacine on stress-induced reinstatement of alcohol and food seeking in rats. AB - RATIONALE AND OBJECTIVES: Relapse to alcohol use during abstinence or maladaptive eating habits during dieting is often provoked by stress. The anxiogenic drug yohimbine, which causes stress-like responses in humans and non-humans, reliably reinstates alcohol and food seeking in a rat relapse model. Yohimibine is a prototypical alpha-2 adrenoceptor antagonist, but results from studies on noradrenaline's role in yohimbine-induced reinstatement of drug and food seeking are inconclusive. Here, we further addressed this issue by studying the effect of the alpha-1 adrenoceptor antagonist prazosin and the alpha-2 adrenoceptor agonist guanfacine on yohimbine-induced reinstatement. METHODS: In exp. 1, we trained rats to self-administer alcohol (12% w/v, 1 h/day), and after extinction of alcohol-reinforced lever pressing, we tested prazosin's (0.5, 1.0, and 2.0 mg/kg, i.p.) or guanfacine's (0.125, 0.25, and 0.5 mg/kg, i.p.) effect on yohimbine (1.25 mg/kg, i.p.)-induced reinstatement; we also examined prazosin's effect on intermittent-footshock-stress-induced reinstatement. In exp. 2, we trained food restricted rats to self-administer 45 mg food pellets and first examined prazosin's or guanfacine's effects on food-reinforced responding, and then, after extinction of lever presses, on yohimbine-induced reinstatement. RESULTS: Prazosin (0.5-2.0 mg/kg) blocked yohimbine-induced reinstatement of food and alcohol seeking, as well as footshock-induced reinstatement of alcohol seeking. Guanfacine attenuated yohimbine-induced reinstatement of alcohol seeking at the highest dose (0.5 mg/kg), but its effect on yohimbine-induced reinstatement of food seeking was not significant. Neither prazosin nor guanfacine affected high rate food-reinforced responding. CONCLUSIONS: Results demonstrate an important role of postsynaptic alpha-1 adrenoceptors in stress-induced reinstatement of alcohol and food seeking. PMID- 21318568 TI - Duration of post-surgical antibiotic therapy for adult chronic osteomyelitis: a single-centre experience. AB - PURPOSE: The optimal duration of concomitant antibiotic therapy after surgical intervention for implant-free chronic osteomyelitis is unknown. No randomized data exist. Available recommendations are based on expert's opinion. We evaluated the duration of post-surgical antibiotic treatment related to remission of chronic osteomyelitis. METHODS: This was a retrospective single-centre study at Geneva University Hospitals with a minimal follow-up of two years after treatment. We used multivariate logistic regression analysis with exclusion of pediatric cases and of implant-related chronic osteomyelitis. RESULTS: A total of 49 episodes of implant-free chronic osteomyelitis in 49 adult patients were studied. The median number of surgical interventions was two (range, 1-10). The median duration of post-debridement antibiotic treatment was eight weeks (range, 4-14 weeks). Thirty-nine patients (80%) were in remission after a minimal follow up of two years. In multivariate logistic regression analysis, one week of intravenous therapy had the same remission as two to three weeks (0.2, 0.1-1.9) or >= 3 weeks (0.3, 0.1-2.4). More than six weeks of total antibiotic treatment equalled <= six weeks (0.8, 0.1-5.2). CONCLUSIONS: In chronic osteomyelitis in adults, a post-debridement antibiotic therapy beyond six weeks, or an IV treatment longer than one week, did not show enhanced remission incidences. Prospective randomized trials are required to confirm this observation. PMID- 21318569 TI - Total hip replacement with an uncemented Wagner cone stem for patients with congenital hip dysplasia. AB - PURPOSE: The purpose of this study was to review retrospectively the cases operated upon in our department in recent years with a Wagner stem and a small socket in cases of Crowe I or II dysplastic hips. METHODS: We conducted a retrospective clinical radiological review of 30 hips diagnosed with hip dysplasia Crowe I or II treated in our centre between 2002 and 2008. All of them were treated with a Wagner cone stem and a small Trilogy acetabulum (Zimmer (r)). RESULTS: There were 15 men and 11 women with 13 left and 17 right femurs. Mean follow-up was 43.44 months (range 14-87). Eight patients were Crowe I type and 22 were Crowe II type. Merle d'Aubigne score pre-operatively was 12.23 and at the last follow-up was 15.54. Mean leg length inequality was 1.79 and after surgery it was 0.69 cm. Complications included three infection and three dislocations (two of them in the same patient). CONCLUSIONS: The use of a Wagner stem is a good option to correct the different deformities in the proximal femur in these cases. A small socket allows a correct relocation of the acetabulum in a dysplastic socket with good bone coverage. PMID- 21318570 TI - Fibula-pro-tibia in plating tibial non-unions. AB - PURPOSE: Plating non-unions of the tibial diaphysis often presents the technical problem of poor purchase of screws due to osteoporosis. To improve the stabilization, insertion of one or more screws through the plate across the tibio fibular space to the fibula (fibula-pro-tibia plating) has been practiced. The aim of this study is to evaluate the effectiveness of the fibula-pro-tibia plating technique in managing difficult diaphyseal tibial non-unions. METHODS: Between 2000 and 2008, 30 patients with diaphyseal non-union of tibia were managed with this technique. The time between injury and index operation ranged between six and 24 months (average, 11 months). Sixteen patients had three surgical procedures before the index operation, ten had two procedures and four patients had one. RESULTS: The duration of follow-up ranged between ten and 38 months (average 26 months). The mean healing time was 3.5 months. Complications were minimal and included two cases of delayed union which required regrafting after four months and two cases, which had infected nonunion, had reactivation of the infection, which resolved completely after achieving union and removing the plates. There was no negative effect from this fixation technique on the ankle joint motion. CONCLUSION: The fibula-pro-tibia plating technique is an effective variation in plating diaphyseal tibial non-unions. PMID- 21318571 TI - Synoviorthesis induced by rifampicin in hemophilic arthropathy: a report of 24 treated joints. AB - Intra-articular hemorrhage is the clinical hallmark of hemophilia. Synoviorthesis, the intra-articular injection of chemical or radioactive substances in order to produce fibrosis of the hypertrophied synovium, has proved effective in the treatment of chronic hemophilic synovitis. Between December 2006 and July 2007, we treated 21 patients with hemophilic arthropathy by synoviorthesis with rifampicin once a week. The procedures were performed on 14 knees, five elbows, four ankles, and one shoulder (24 joints and 113 injections). The mean age was 16.7 years (range, 7-49 years). According to the Fernandez Palazzi classification, synoviorthesis was considered satisfactory (excellent or good) in 21 (87.5%) joints and unsatisfactory (fair or poor) in three (12.5%). A mean reduction of 6.3 bleeding episodes per month was obtained (P < 0.0001). The mean pain score was reduced from 2.62 (range, 2-3; SD, 0.49) before treatment to 0.79 (range, 0-2; SD, 0.65) after treatment. The mean World Federation of Hemophilia (WFH) score was 5.45 (range, 2-8) before synoviorthesis and 3.5 (range, 1-7) after treatment. This method effectively reduced hemarthrosis and pain and also improved the range of motion in patients with hemophilic arthropathy. Chemical synoviorthesis with rifampicin appears to be efficient, inexpensive, and simple and also especially practical in developing countries where radioactive agents are not easily available. PMID- 21318572 TI - Romiplostim in children with chronic refractory ITP: randomized placebo controlled study. AB - Romiplostim stimulates thrombopoietin receptor to increase platelet production of megakaryocytes in idiopathic thrombocytopenic purpura (ITP). This study aimed to evaluate the safety and efficacy of romiplostim in children with chronic ITP. Eighteen patients with chronic ITP, either none responsive or failed to maintain response on two or more therapeutic modalities, were enrolled. Patients were randomized (2:1) to receive romiplostim or placebo for 12 weeks, initiated at 1 MUg/kg/week, escalated to 5 MUg/kg/week, and then tapered. Median patients' age was 8.5 years, and the median baseline platelet count (PC) was 10.5 * 10(9)/L. The median weekly dose of romiplostim was 2 MUg/kg. Fifty percent of patients in both romiplostim and placebo arms had at least one adverse event (AE); none was serious. Ten patients on romiplostim (83.3%) maintained the efficacy endpoint (PC > 50,000). Romiplostim was well-tolerated and efficient in treating the children with chronic refractory ITP with no unexpected AEs. PMID- 21318573 TI - Intrathecal application of donor lymphocytes in leukemic meningeosis after allogeneic stem cell transplantation. AB - Extramedullary relapses after allogeneic stem cell transplantation, especially within the central nervous system (CNS), are not only difficult to treat but also associated with poor outcome. Although the graft-versus-leukemia (GvL) effect is nowadays accepted and well documented, it remains controversial whether one can make use of GvL effects in immunological-restricted areas ("sanctuary sites") like the central nervous system. Here, we present data of three hematological patients suffering from isolated CNS relapse of CML or AML after allogeneic stem cell transplantation. Patients received in addition to chemotherapy intrathecal infusions of donor lymphocytes by CD14 depletion of peripheral blood mononuclear cells from the correspondent allogeneic donor. Referring to an observation period of maximum 17 months no immediate or delayed side effects could be detected. PMID- 21318574 TI - Iron status and treatment modalities in transfusion-dependent patients with myelodysplastic syndromes. AB - Transfusion dependency and iron overload are common among patients with myelodysplastic syndromes (MDS) treated with red blood cell (RBC) transfusions. Transfusion dependency is associated with leukemic progression and shorter survival. Guidelines recommend iron chelation therapy to manage iron overload, however little is known about the chelation patterns in daily clinical practice. The objective of this multicenter, retrospective, cross-sectional, observational study was to evaluate iron status and its management in transfusion-dependent MDS patients. A total of 193 patient records from 29 centers were eligible for inclusion. Median patient age was 76, and median age at diagnosis of MDS was 74. Patients had received an average of 13.4 +/- 7.6 RBC units in the past 4 months; 44% had received more than 50 units since their MDS diagnosis. Medium serum ferritin was 1,550 MUg/L. Ninety patients (46.6%) received iron chelation therapy with either deferoxamine (41%), deferasirox (36%), and deferoxamine followed by deferasirox (23%). There were no statistically significant differences between chelated and nonchelated patients in terms of International Prognostic Scoring System (IPSS), French-American-British (FAB), and/or World Health Organization (WHO) status, though chelated patients had received more RBC transfusions (p = 0.014). Iron chelation therapy may be underutilized in transfusion-dependent patients. Undertreatment can be reduced by complementing sound clinical judgment with the generally accepted guidelines of a serum ferritin level >1,000 MUg/L and/or two or more RBC transfusions per month for the past year; considering patients on the basis of their IPSS, FAB, and/or WHO status; and individually tailored treatment regimens. Prospective randomized trials are necessary to establish causally the efficacy of iron chelation therapy in MDS. PMID- 21318575 TI - Impact of CT-based diagnostic imaging on management and outcome of nonfunctioning pancreatic tumors. AB - BACKGROUND: Sporadic malignant non-functioning pancreatic endocrine tumors (NF PETs) are an important subset of pancreatic neoplasms. The aim of this study was to assess the impact of improved imaging on these features in a tertiary referral centre within a 20-year follow-up. PATIENTS AND METHODS: From 1988 to 2009, 51 patients were treated for sporadic malignant NF-PETs. Forty-one patients who underwent tumor resection were retrospectively attributed according to the date of the initial diagnosis, group 1: 1988-1999 vs. group 2: 2000-2009. RESULTS: Cross-sectional imaging led to positive prediction of NF-PETs in all patients. Curative resection was achieved in 76%. Synchronous metastases were present in 56% with a positive prediction of 43%. In group 1, the mean reported CT determined tumor size was 56 vs. 54 mm in group 2 (p = 0.89). Synchronous metastases were present in 61% in group 1 vs. 57% (p = 0.99) in group 2. Metachronous metastases were recorded in 39% in group 1 vs. 43% (p = 0.84) in group 2. The mean interval from initial resection to diagnosis of metastatic disease was significantly shorter (p = 0.01) in patients from group 1 (14 vs. 61 months). Cumulative 5- and 10-year survival rates were 77% and 72% in group 1 vs. a 5-year survival rate of 66% in group 2. CONCLUSION: So far, improved CT-based imaging has no impact on earlier detection of initial synchronous metastases in sporadic malignant NF-PETs, while metachronous metastases are detected earlier. PMID- 21318576 TI - Clinical features and outcomes of Staphylococcus aureus infections in non neutropenic cancer patients. AB - GOAL OF WORK: This study was performed to evaluate the clinical features and outcomes of Staphylococcus aureus infection in non-neutropenic cancer patients. MATERIALS AND METHODS: From the database of a surveillance study for S. aureus infections, the data regarding S. aureus infections in non-neutropenic cancer patients were analyzed. MAIN RESULTS: Of 649 non-neutropenic cancer patients with S. aureus infections, 156 (24.0%) had a central venous catheter and 176 (27.1%) had an indwelling urinary catheter. The prevalence of methicillin-resistant S. aureus (MRSA) infections was 54.7% (355 out of 649). As for types of infection, skin and soft tissue infections were the most common (n = 173, 26.7%), followed by pneumonia (n = 165, 25.4%) and primary bacteremia (n = 91; 14.0%). Overall, the 30-day mortality rate was 28.2% (124 out of 440), 34.1% (73 out of 214) in MRSA group, and 22.6% (51 out of 226) in methicillin-sensitive S. aureus group (P = 0.007). When outcomes according to the types of infection were evaluated, the mortality rates were 49.5% (53 out of 107) for pneumonia and 41.2% (49 out of 119) for bacteremia. Multivariate analysis showed that pneumonia, concomitant bacteremia, comorbid liver disease, and intubated state with ICU care were independent risk factors associated with 30-day mortality. CONCLUSION: Our study demonstrated that S. aureus infections in cancer patients are serious clinical conditions with high mortality rates, even in non-neutropenic patients. PMID- 21318577 TI - Perceptions about complementary and alternative medicine use among Chinese immigrant parents of children with cancer. AB - PURPOSE: Research indicates complementary and alternative medicine (CAM) use among children with cancer is common and widespread. CAM use, particularly traditional Chinese medicine (TCM), is prevalent in the country of origin of Chinese immigrant families, yet little is known about its use after immigrating to Canada. This paper describes 25 Chinese immigrant parents' perception about the use of CAM in their child with cancer in Canada. METHODS: This qualitative grounded theory study is part of a larger study of the caregiving experiences of first generation Chinese and South Asian parents of children with cancer. Chinese parents of children at least 6 months post-diagnosis were recruited from four Canadian pediatric oncology centers. Interviews were conducted in English, Cantonese, or Mandarin and transcribed into English. Analysis involved coding and the use of the constant comparison method to identify important themes. RESULTS: In discussing their caregiving experiences, CAM emerged as an important theme. The following sub-themes were identified: (1) trust in conventional medicine to cure cancer; (2) use of dietary modifications and restrictions; (3) extent of communication with healthcare providers about TCM use; and (4) limited availability of culturally relevant information. CONCLUSIONS: While Chinese immigrant parents in this study placed their trust in conventional medicine to treat their child, the use of food as therapy is part of their daily cultural practice. To ensure safe cancer treatment and more culturally sensitive care, it is essential for health providers to offer reliable information and encourage open discussions about CAM use with Chinese immigrant parents. PMID- 21318578 TI - Diffusion tensor imaging of peripheral nerve in patients with chronic inflammatory demyelinating polyradiculoneuropathy: a feasibility study. AB - INTRODUCTION: The purpose of this study was to assess the clinical feasibility of diffusion tensor imaging (DTI) for the evaluation of peripheral nerves in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: Using a 3-T magnetic resonance imaging scanner, we obtained DTI scans of the tibial nerves of 10 CIDP patients and 10 sex- and age-matched healthy volunteers. We prepared fractional anisotropy (FA) maps, measured the FA values of tibial nerves, and compared these values in the two study groups. In nine patients, we also performed tibial nerve conduction studies and analyzed the correlation between the FA values and parameters of the nerve conduction study. RESULTS: The tibial nerve FA values in CIDP patients (median 0.401, range 0.312 0.510) were significantly lower than those in healthy volunteers (median 0.530, range 0.469-0.647) (Mann-Whitney test, p < 0.01). They were significantly correlated with the amplitude of action potential (Spearman correlation coefficient, p = 0.04, r = 0.86) but not with nerve conduction velocity (p = 0.79, r = 0.11). CONCLUSION: Our preliminary data suggest that the noninvasive DTI assessment of peripheral nerves may provide useful information in patients with CIDP. PMID- 21318579 TI - Suppression of isotope scrambling in cell-free protein synthesis by broadband inhibition of PLP enymes for selective 15N-labelling and production of perdeuterated proteins in H2O. AB - Selectively isotope labelled protein samples can be prepared in vivo or in vitro from selectively labelled amino acids but, in many cases, metabolic conversions between different amino acids result in isotope scrambling. The best results are obtained by cell-free protein synthesis, where metabolic enzymes are generally less active, but isotope scrambling can never be suppressed completely. We show that reduction of E. coli S30 extracts with NaBH(4) presents a simple and inexpensive way to achieve cleaner selective isotope labelling in cell-free protein synthesis reactions. The purpose of the NaBH(4) is to inactivate all pyridoxal-phosphate (PLP) dependent enzymes by irreversible reduction of the Schiff bases formed between PLP and lysine side chains of the enzymes or amino groups of free amino acids. The reduced S30 extracts retain their activity of protein synthesis, can be stored as well as conventional S30 extracts and effectively suppress conversions between different amino acids. In addition, inactivation of PLP-dependent enzymes greatly stabilizes hydrogens bound to alpha carbons against exchange with water, minimizing the loss of alpha-deuterons during cell-free production of proteins from perdeuterated amino acids in H(2)O solution. This allows the production of highly perdeuterated proteins that contain protons at all exchangeable positions, without having to back-exchange labile deuterons for protons as required for proteins that have been synthesized in D(2)O. PMID- 21318580 TI - Colorectal Congress in St. Gallen, Switzerland. PMID- 21318581 TI - Prospective evaluation of stapled haemorrhoidopexy versus transanal haemorrhoidal dearterialisation for stage II and III haemorrhoids: three-year outcomes. AB - INTRODUCTION: The aim of the study was to compare short- and medium-term outcomes of transanal haemorrhoidal dearterialisation (THD) versus stapled haemorrhoidopexy (SH) for the treatment of second- and third-degree haemorrhoids. METHODS: Patients with second- or third-degree haemorrhoids who failed conservative treatment were randomly allocated to THD or SH. Preoperative and postoperative symptoms, postoperative pain, time until return to normal activities, complications, patient satisfaction and recurrence rates were all assessed prospectively. Patients were followed up at 2, 8 months and when the study was completed. RESULTS: Twenty-eight patients (43% third degree) underwent THD and 24 (38% third degree) underwent SH. There were no significant differences in terms of postoperative pain, expected pain and analgesia requirements, but more THD patients returned to work within 4 days (P < 0.05). One THD patient developed a sub-mucosal haematoma after surgery, one SH patient occlusion of the rectal lumen and two rectal bleeding. At 8-month follow-up, two SH patients complained of faecal urgency. At 38-month follow-up (range 33-48 months), all short-term complications resolved. Patient satisfaction ("excellent/good outcome", THD 89 vs. SH 87%) and recurrence rate (THD 14 vs. SH 13%) were similar in the two groups. CONCLUSIONS: Short-term results although similar seem to suggest SH may result in increased morbidity while return to work is quicker after THD. Medium-term results demonstrate that THD and SH have similar effectiveness. PMID- 21318582 TI - Impact of reduced glomerular filtration rate on outcomes in patients with ST segment elevation myocardial infarction undergoing fibrinolysis: a CLARITY-TIMI 28 analysis. AB - Reduced glomerular filtration rate (GFR) is associated with adverse outcomes in patients with cardiovascular disease. We explored the relationship between GFR and angiographic and clinical outcomes in ST-segment elevation myocardial infarction (STEMI) patients receiving pharamacologic reperfusion, with or without clopidogrel. Data were available to estimate GFR in 3,252 STEMI patients undergoing fibrinolysis, randomized to clopidogrel versus placebo in the CLARITY TIMI 28 trial. Patients with a creatinine > 2.5 mg/dl were excluded from the trial. We compared outcomes between patients with no, mild or moderate reductions in baseline estimated GFR (ml/min/1.73 m2) of >= 90, 60-89, and <60, respectively. Compared to patients with no (n = 841) or mildly reduced GFR (n = 1897), those with moderately reduced GFR (n = 514) were older, more often female, and were more likely to have diabetes and hypertension (P <= 0.001 for all). The risk of the primary endpoint (an occluded infarct-related artery on angiography or death/myocardial infarction by day 8), 30 day cardiovascular events (death, myocardial infarction, or urgent revascularization for recurrent ischemia) and 30 day Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding increased as GFR declined (P for trend 0.003, <0.0001, and 0.0008 respectively). The adjusted risk of 30 day ischemic complications remained higher in patients with moderately reduced versus normal GFR (OR 1.5, 95% CI 1.0-2.1, P = 0.04). Treatment with clopidogrel tended to yield greater benefit in patients with normal or mildly reduced GFR versus in patients with moderately reduced GFR. In conclusion, STEMI patients with reduced GFR treated with medical reperfusion, including dual antiplatelet therapy, have higher rates of adverse clinical outcome. Further research on optimal STEMI therapy in this high-risk group is warranted. PMID- 21318583 TI - Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor. AB - Apixaban (BMS-562247; 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl) 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide), a direct inhibitor of activated factor X (FXa), is in development for the prevention and treatment of various thromboembolic diseases. With an inhibitory constant of 0.08 nM for human FXa, apixaban has greater than 30,000-fold selectivity for FXa over other human coagulation proteases. It produces a rapid onset of inhibition of FXa with association rate constant of 20 MUM-1/s approximately and inhibits free as well as prothrombinase- and clot-bound FXa activity in vitro. Apixaban also inhibits FXa from rabbits, rats and dogs, an activity which parallels its antithrombotic potency in these species. Although apixaban has no direct effects on platelet aggregation, it indirectly inhibits this process by reducing thrombin generation. Pre-clinical studies of apixaban in animal models have demonstrated dose dependent antithrombotic efficacy at doses that preserved hemostasis. Apixaban improves pre-clinical antithrombotic activity, without excessive increases in bleeding times, when added on top of aspirin or aspirin plus clopidogrel at their clinically relevant doses. Apixaban has good bioavailability, low clearance and a small volume of distribution in animals and humans, and a low potential for drug drug interactions. Elimination pathways for apixaban include renal excretion, metabolism and biliary/intestinal excretion. Although a sulfate conjugate of Omicron-demethyl apixaban (O-demethyl apixaban sulfate) has been identified as the major circulating metabolite of apixaban in humans, it is inactive against human FXa. Together, these non-clinical findings have established the favorable pharmacological profile of apixaban, and support the potential use of apixaban in the clinic for the prevention and treatment of various thromboembolic diseases. PMID- 21318585 TI - Non-contrasted computed tomography for the accurate measurement of liver steatosis in obese patients. AB - BACKGROUND: Hepatic macrosteatosis (HMS) is prevalent among high BMI patients, but a lack of validation of non-invasive measures of liver fat hampers non alcoholic liver disease (NAFLD) investigation in general. Recent work suggests BMI adjusted, non-contrasted computed tomography (nc-CT) attenuation data (Hounsfield units) reflects liver fat accumulation in a normal weight population. However, this and other CT-based HMS studies have only approximated macrosteatosis (%) histologically, but have not validated findings with chemical liver triglyceride (TG) concentrations (mg/gram protein). Also, all previous CT based steatosis studies excluded high BMI subjects, whose habitus may affect properties of the scan. We hypothesized that in high BMI patients nc-CT attenuation measurements expressed in Hounsfield units (HU) accurately estimate liver triglyceride concentrations as well as histological macrosteatosis. METHODS: With informed consent, 15 patients underwent nc-CT scan of the abdomen prior to weight loss surgery with intraoperative wedge and core needle liver biopsy. Mean left lobe nc-CT Hounsfield units (CT(L)), liver TG (mg/g Pr), HMS (%), BMI (kg/m(2)), liver-spleen index (CT(L/S) = hepatic HU/splenic HU), and liver-spleen difference (CT(L-S) = hepatic HU - splenic HU) were a priori outcomes. RESULTS: In 15 patients (11 female) with a BMI of 44.4 +/- 1.1 (mean +/ SEM), CT(L/S), CT(L-S), and CT(L) measures were significantly associated with liver TG concentrations (r = -0.80, P < 0.001; r = -0.80, P < 0.001; and r = 0.71, P < 0.01, respectively; Table 1). Macrosteatosis (%) and liver triglyceride concentration were positively associated (r = 0.83; P < 0.0001). BMI did not correlate strongly to liver triglyceride (r = 0.44, P = NS). CONCLUSION: Estimates of liver fat obtained by nc- CT scans (esp. CT(L/S), CT(L-S)) correlate to chemical measurement of liver triglyceride concentrations, suggesting non contrasted CT may be a suitable non-invasive "gold standard" for hepatic steatosis quantification in these patients. PMID- 21318584 TI - The California Neighborhoods Data System: a new resource for examining the impact of neighborhood characteristics on cancer incidence and outcomes in populations. AB - Research on neighborhoods and health has been growing. However, studies have not investigated the association of specific neighborhood measures, including socioeconomic and built environments, with cancer incidence or outcomes. We developed the California Neighborhoods Data System (CNDS), an integrated system of small area-level measures of socioeconomic and built environments for California, which can be readily linked to individual-level geocoded records. The CNDS includes measures such as socioeconomic status, population density, racial residential segregation, ethnic enclaves, distance to hospitals, walkable destinations, and street connectivity. Linking the CNDS to geocoded cancer patient information from the California Cancer Registry, we demonstrate the variability of CNDS measures by neighborhood socioeconomic status and predominant race/ethnicity for the 7,049 California census tracts, as well as by patient race/ethnicity. The CNDS represents an efficient and cost-effective resource for cancer epidemiology and control. It expands our ability to understand the role of neighborhoods with regard to cancer incidence and outcomes. Used in conjunction with cancer registry data, these additional contextual measures enable the type of transdisciplinary, "cells-to-society" research that is now being recognized as necessary for addressing population disparities in cancer incidence and outcomes. PMID- 21318586 TI - Differentiation-inducing activity of hydroxycamptothecin on cancer stem-like cells derived from hepatocellular carcinoma. AB - BACKGROUND: Hydroxycamptothecin (HCPT) is an anti-tumor agent that can induce differentiation in human cancer cells. Recent evidence indicates that side population (SP) cells possess characteristics of stem-like cells, and may be capable of initiating tumor growth. AIMS: The present study investigated the differentiation of cancer stem-like cells derived from hepatocellular carcinoma. METHODS AND RESULTS: Flow cytometry was used to isolated SP cells from HCC cell line (MHCC97 cells). These SP cells exhibit several stem-like cell characteristics that are distinct from the main population (MP) cells in vitro. After 3 days of induction with a low concentration of HCPT, the SP cells lost their capacity to proliferate and invade, and their tumorigenicity declined. Based on real-time quantitative RT-PCR, we also found that the expression of hepatocyte-specific markers such as alpha-fetoprotein, albumin, hepatocyte nuclear factor-4 and miR-122 gradually changed during the differentiation of SP cells. CONCLUSIONS: Our data suggest that a low concentration of HCPT can induce hepatocyte-specific differentiation of cancer stem-like cells from MHCC97 cells, offering a possible therapeutic strategy for the treatment of human malignancies. PMID- 21318587 TI - Prevalence of advanced adenomas in small and diminutive colon polyps using direct measurement of size. AB - BACKGROUND AND AIMS: Most studies reporting polyp size use visual estimates. Determining the prevalence of advanced histology based on direct measurement of polyp size may help guide the management of polyps found at optical colonoscopy (OC) and CT colonography (CTC). METHODS: We designed a large, prospective study to assess the prevalence of advanced adenomas based on direct measurement of polyp size by a certified pathologists' assistant as reported in the pathology report. Patients between 40 and 89 years of age who presented for screening colonoscopy were included in our study. Advanced adenomas were defined as >=10 mm or >=25% villous features, high grade dysplasia or cancer. Polyps were divided by size into three groups: diminutive (<=5 mm), small (6-9 mm) and large (>=10 mm). If more than one adenoma was present, the most advanced was used for analysis. RESULTS: We evaluated 6,905 consecutive patients referred for colonoscopy between January 2005 and December 2006. Of the 4,967 who met the inclusion criteria, the mean age was 58.8 and consisted of 59% women. Overall, 930 (18.7%) had an adenoma; 248 (5%) were advanced adenomas including 8 (0.16%) cancers. Of 89 polyps>=10 mm, 76 (85%) had advanced histology; of 247 polyps 6-9 mm, 67 (27%) were advanced; of 1,025 polyps <=5 mm, 105 (10%) were advanced. Thus, 172 of 248 (69%) patients with advanced adenomas had small or diminutive adenomas. CONCLUSIONS: Our data indicate the majority (69%) of advanced adenomas are <10 mm. Even among polyps<=5 mm, there was an appreciable prevalence of advanced adenomas (10%). These findings may help guide the management of sub-centimeter colon polyps found by OC or CTC. PMID- 21318588 TI - Defining virologic relapse in chronic hepatitis B. AB - BACKGROUND AND AIMS: Different definitions of virologic relapse (VR) are being used. One way of defining VR is "reappearance of HBV DNA in the serum," while another definition is an "increase in HBV DNA level greater than 1 log in two determinations at least 4 weeks apart." The aim of this study was to see the effectiveness of these two definitions METHODS: Forty-five HBeAg-positive chronic hepatitis B patients with a virologic response [negative PCR (<12 IU/ml)] who had discontinued therapy were analyzed retrospectively for VR, HBeAg reversion and biochemical flare. RESULTS: HBV DNA reappeared in the serum (>=12 IU/ml) of all 45 patients (100%). An increase in HBV DNA level greater than 1 log in two determinations at least 4 weeks apart was identified in 20 of 25 patients (80%). Biochemical flare and HBeAg reversion were observed in 18 (40%) and 14 (31%) patients, respectively. Peak off-therapy HBV DNA level was significantly associated with biochemical flare (r=0.758, P<0.001) and HBeAg reversion (r=0.645, P<0.001). Two patients with high initial off-therapy HBV DNA levels (>=4.0 log(10) IU/ml) were reassessed at 4 weeks, and both experienced a biochemical flare and HBeAg reversion. Two patients had an increase in HBV DNA level greater than 1 log at a very low level (1 log to 2 or 3 log), but did not experience biochemical flare or HBeAg reversion during follow-up. CONCLUSIONS: Reappearance of HBV DNA was universal when sensitive HBV DNA assay was used. Waiting 4 weeks to confirm VR may be harmful for patients with a high HBV DNA level, and was ineffective to indicate re-therapy for patients with increase in HBV DNA at a very low level. There is a need for improved and standardized definitions of VR. PMID- 21318589 TI - Management of common bile duct stones in cirrhotic patients with coagulopathy: a comparison of supra-papillary puncture and standard cannulation technique. AB - BACKGROUND AND STUDY AIMS: Bleeding is not uncommon following endoscopic sphincterotomy. Supra-papillary puncture (SPP) might be safer than standard cannulation (SC) techniques in patients with coagulopathy. The aim of the study was to compare the safety and effectiveness of SPP and SC. PATIENT AND METHODS: This was a prospective case control intervention study. Decompensated cirrhotic patients with coagulopathy and choledocolithiasis underwent SC and SPP methods for biliary access. RESULTS: One hundred five patients (56 [53.3%] men, mean [SD] age 56 [15.8]) underwent ERCP. SC and SPP were performed in 63 and 42 patients, respectively. Biliary access was achieved in 56/63 (89%) and 40/42 (95%) of patients undergoing SC and SPP, respectively (P = 0.13; 95% CI [-0.16; 0.03]). Complications occurred in 10/63 (15.8%) patients undergoing SC and 5/42 (11.9%) SPP (P = 0.28; 95% CI [-0.17, 0.16]). Five (7.9%) and two (3.2%) episodes of post sphincterotomy bleeding was seen in the SC and SPP groups, respectively (P = 0.36; 95% CI [-0.16, 0.05]). In contrast, three (4.8%) episodes of pancreatitis were seen in the SC and none in the SPP group (P = 0.05; 95% CI [0.001; 0.004]). A cost-effectiveness analysis demonstrated that SPP is an acceptable alternative at an ICER of US$ 5,974.92 per additional successful procedure. CONCLUSION: SPP is a safe and effective technique for the management of common bile duct stones in decompensated cirrhotic patients. Conditional to the willingness-to-pay and to the local ERCP-related costs, SPP is also a cost-effective alternative to the SC methods. SPP is associated with a lower rate of complications but larger studies to validate these findings are necessary. PMID- 21318590 TI - Association between proton pump inhibitor use and anemia: a retrospective cohort study. AB - BACKGROUND: Proton pump inhibitors (PPIs) are widely prescribed to treat gastrointestinal diseases. However, concerns have been raised regarding their long-term use. Gastric acid suppression may decrease iron absorption, and it remains uncertain whether iron-deficiency anemia may result from chronic PPI therapy. AIMS: We aimed to explore the association between chronic PPI use and iron-deficiency anemia. METHODS: We conducted a retrospective cohort study of adult patients in an academic outpatient setting who received PPI therapy for at least 1 year between January 1, 2004 and January 1, 2006. We compared the change in hematologic indices among patients receiving PPI therapy for at least 1 year with matched controls. RESULTS: Of the 98 patients on chronic PPI therapy who met inclusion criteria, 35% had no documented indication for such therapy. At baseline, demographics and hematologic indices were similar between PPI-users and controls. Among patients on PPI therapy, all hematologic indices decreased from baseline, including hemoglobin (-0.19 g/dL, P=0.03), hematocrit (-0.63%, P=0.02), and mean corpuscular volume (-0.49 fL, P=0.05). PPI users had significant decreases in mean hemoglobin and hematocrit (P<0.01 for both) compared with matched controls. After adjustment for confounders, including rates of esophagogastroduodenoscopy, colonoscopy and remote cancer status, the odds ratio of decreasing hemoglobin by 1.0 g/dL while on chronic PPI therapy was 5.03 (95% CI, 1.71-14.78, P<0.01), while the odds ratio of decreasing hematocrit by 3% was 5.46 (95% CI, 1.67-17.85, P<0.01). CONCLUSIONS: Among adult patients receiving chronic PPI therapy, there is a significant decrease in hematologic indices from baseline. PMID- 21318591 TI - The regulation of thymic stromal lymphopoietin in gut immune homeostasis. AB - Thymic stromal lymphopoietin is a novel IL-7-like cytokine that exerts immunomodulatory effects and is constitutively expressed by intestinal epithelial cells in response to commensal bacteria colonization. Thymic stromal lymphopoietin can directly or indirectly promote Th2 and Treg responses, and is believed to inhibit Th1 and Th17 responses and limit the expression of proinflammatory cytokines such as IL-17 and IFN-gamma. In response to infection by enteric pathogens, intestinal epithelial cells upregulate thymic stromal lymphopoietin expression in order to generate balance between inflammation and immune clearance. Recently, however, aberrant expression of thymic stromal lymphopoietin has been associated with inflammatory bowel disease. Thus, we sought to examine the relationship between the TLSP-TSLPR pathway and inflammation in hopes of contributing to the search for a novel therapeutic target to treat a variety of inflammatory diseases, including inflammatory bowel disease. PMID- 21318592 TI - Sertoli cell-conditioned medium induces germ cell differentiation in human embryonic stem cells. AB - PURPOSE: To investigate the spontaneous germ cell differentiation capacity of VUB hESC lines, develop a protocol for the induction of germ cell differentiation using conditioned medium from Sertoli cells (SCCM) and compare it to existing protocols. METHODS: hESC were allowed to differentiate spontaneously or after the addition of bone morphogenetic proteins (BMPs) and/or SCCM. VASA transcripts were measured by relative quantification real-time RT-PCR to determine the efficiency of germ cell differentiation. RESULTS: VUB hESC lines can differentiate spontaneously towards the germ cell lineage, however, more consistently in an embryoid body approach than in monolayer cultures. BMPs and SCCM significantly improve VASA expression, but do not have a synergistic effect. Direct contact of differentiating hESC with Sertoli cells does not improve VASA expression. CONCLUSIONS: SCCM contains inductive factors for germ cell differentiation and could represent an element for in-vitro differentiation to germ cells. PMID- 21318593 TI - The influence of genetic polymorphisms and interacting drugs on initial response to warfarin in Chinese patients with heart valve replacement. AB - PURPOSE: Compared with genetic factors, drug interactions were largely unexplored in warfarin pharmacogenetic studies. This study sought to systematically investigate the effects of genetic polymorphisms of VKORC1, STX4A, CYP2C9, CYP3A4, and GGCX and interacting drugs on the initial responses to warfarin in Chinese patients with heart valve replacement (HVR). METHODS: A retrospective study was conducted in 809 patients starting warfarin therapy after HVR. The relationships between 12 polymorphisms plus 47 drugs and primary outcomes of the time to the first international normalized ratio (INR) >= 1.8 and the time to the first INR > 3.5 and the secondary outcomes of the proportion of time INR < 1.8, the proportion of time INR > 3.5, and the daily warfarin dose in the first 28 days after the initiation of warfarin treatment were analyzed. RESULTS: Genetic polymorphisms and interacting drugs could significantly affect the primary and secondary outcomes. The time to the first INR >= 1.8 was significantly influenced by the body surface area (BSA), VKORC1 g.3588G > A allele, and CYP2C9*3 allele, with hazard ratio (HR; 95% confidence interval [CI]) of 0.34 (0.17-0.66), 2.71 (2.2-3.35) and 1.43 (1.07-1.93) respectively. The time to the first INR > 3.5 was affected not only by BSA, VKORC1 g.3588G > A allele, and CYP2C9*3 allele with HR (95%CI) of 0.26 (0.07-0.99), 2.76 (1.61-4.72), and 3.09 (2.02-4.74) respectively, but also by age and interacting drugs, including fluconazole, amiodarone, and simvastatin with HR (95%CI) of 1.02 (1.01-1.04), 2.66 (1.16-6.08), 1.78 (1.17 2.73), and 5.33 (1.67-16.96) respectively. CONCLUSIONS: Not only VKORC1 and CYP2C9 genotypes, but also interacting drugs, had a significant impact on the variability of the initial response to warfarin. PMID- 21318594 TI - Bioavailability of dexmedetomidine after intranasal administration. AB - PURPOSE: The aim of this proof-of-concept study was to characterize the pharmacokinetics and pharmacodynamics of intranasal dexmedetomidine compared with its intravenous administration in a small number of healthy volunteers. METHODS: Single doses of 84 MUg of dexmedetomidine were given once intravenously and once intranasally to seven healthy men. Plasma dexmedetomidine concentrations were measured for 10 h, and pharmacokinetic variables were calculated with standard noncompartmental methods. Heart rate, blood pressure, concentrations of adrenaline and noradrenaline in plasma, and central nervous system drug effects (with the Maddox wing, Bispectral Index, and three visual analog scales) were monitored to assess the pharmacological effects of dexmedetomidine. RESULTS: Six individuals were included in the analyses. Following intranasal administration, peak plasma concentrations of dexmedetomidine were reached in 38 (15-60) min and its absolute bioavailability was 65% (35-93%) (medians and ranges). Pharmacological effects were similar with both routes of administration, but their onset was more rapid after intravenous administration. CONCLUSIONS: Dexmedetomidine is rather rapidly and efficiently absorbed after intranasal administration. Compared with intravenous administration, intranasal administration may be a feasible alternative in patients requiring light sedation. PMID- 21318595 TI - Impact of the Lund Integrated Medicines Management (LIMM) model on medication appropriateness and drug-related hospital revisits. AB - PURPOSE: To examine the impact of systematic medication reconciliations upon hospital admission and of a medication review while in hospital on the number of inappropriate medications and unscheduled drug-related hospital revisits in elderly patients. METHODS: This was a prospective, controlled study in 210 patients, aged 65 years or older, who were admitted to one of three internal medicine wards at a University Hospital in Sweden. Intervention patients received the complete Lund Integrated Medicines Management model (medication reconciliation upon admission and discharge, and medication review and monitoring) provided by a multi-professional team, including a clinical pharmacist. Control patients received standard care and medication reconciliation upon discharge. Blinded reviewers evaluated the appropriateness of the prescribing (using the Medication Appropriateness Index) on admission and discharge, and assessed the probability that a drug-related problem was the reason for any patient readmitted to hospital or visiting the emergency department within 3 months of discharge (using World Health Organisation causality criteria). RESULTS: There was a greater decrease in the number of inappropriate drugs in the intervention group than in the control group for both the intention-to-treat population {51% [95% confidence interval (CI) 43-58%] vs. 39% (95% CI 30-48%); p = 0.0446} and the per-protocol population [60% (95% CI 51 67%) vs. 44% (95% CI 34-52%); p = 0.0106)]. There were six revisits to hospital in the intervention group which were judged as 'possibly, probably or certainly drug-related', compared with 12 in the control group (p = 0.0469). CONCLUSIONS: In this study, medication reconciliation and review provided by a clinical pharmacist in a multi-professional team significantly reduced the number of inappropriate drugs and unscheduled drug-related hospital revisits among elderly patients. PMID- 21318596 TI - Application of iPS in assisted reproductive technology: sperm from somatic cells? AB - Infertility is an emotionally charged problem, and it is a condition of increasing incidence. In addition, in 40% to 60% of all infertile couples, it was the male who had a problem that led to infertility. Among the male fertility problems, non-obstructive azoospermia (NOA) (caused by testis failure or impaired spermatogenesis) is the most prevalent. Despite enormous clinical and experimental efforts, treatment of this disorder--assistant reproduction technique (ART) with donor spermatozoa remains controversial. We present the hypothesis that induced pluripotent stem (iPS) cell derived spermatozoa can be a potential source for male gametes for patients with NOA; we support this with the following three evidence: the first is the generation of viable, live-born, fertile mature organism from iPS cells; the second is the successful induced differentiation of male gametes from pluripotent cells in vitro; and the last is the wide use of intracytoplasmic sperm injection (ICSI) in human assisted reproduction. If the hiPS derived spermatozoa prove practical in the generation offspring with ICSI, this method might be able to grant a new chance for NOA patients to have their genetic children with fewer emotional, ethical and legislative problems. To ensure the safety of the technology itself and the production of healthy offspring, further investigations are needed. We also suggest several laboratory and clinical approaches for testing our hypothesis. PMID- 21318597 TI - Methods for the identification, characterization and banking of human DPSCs: current strategies and perspectives. AB - Dental pulp stem cells (DPSCs), originating from neural crests, can be found within dental pulp. Up to now, it has been demonstrated that these cells are capable of producing bone tissue, both in vitro and in vivo and differentiate into adipocytes, endotheliocytes, melanocytes, neurons, glial cells, and can be easily cryopreserved and stored. Moreover, recent attention has been focused on tissue engineering and on the properties of these cells. In addition, adult bone tissue with good vascularisation has been obtained in grafts. The latest use in clinical trials for bone repair enforces the notion that DPSCs can be used successfully in patients. Therefore, their isolation, selection, differentiation and banking is of great importance. The isolation and detection techniques used in most laboratories are based on the use of antibodies revealed by flow cytometers with cell sorter termed FACS (fluorescent activated cell sorter). In this report, we focus our attention on the main procedures used in the selection of DPSCs by flow cytometry, cell culture, freezing/thawing, cell cycle evaluation, histochemistry/immunofluorescence and differentiation of DPSCs. In addition, new methods/protocols to select and isolate stem cells without staining by fluorescent markers for implementation in biomedical/clinical laboratories are discuss. We emphasize that the new methods must address simplicity and short times of preparation and use of samples, complete sterility of cells, the potential disposable, low cost and complete maintenance of the viability and integrity of the cells with real-time response for subsequent applications in the biomedical/clinical/surgical fields. PMID- 21318598 TI - Transient extremity ischemia augments CD34+ progenitor cell availability. AB - Peripheral blood is an easily accessed source for stem cell production; however, the number of cells produced is relatively low. We hypothesized that ischemic preconditioning may serve as a safe method to increase the number of CD34+ cells that can be harvested and cultured in a short period. This study was conducted to test this hypothesis by examining the safety and efficacy of brief, transient ischemia of the lower limbs to augment the number of cells that can be produced from blood of healthy volunteers. Following induction of ischemia, blood samples were withdrawn at baseline, 30 min, 12 h and 24 h. The number of progenitor cells was determined by flow cytometry after the harvested cells were cultured for 5 days. We also analyzed the blood samples to determine IL-8 and VEGF concentrations. No serious adverse events were observed. The total number of cells increased from 0.46 +/- 0.1 * 10(6) cells/ml in the pretreatment blood samples to 0.7 +/- 0.1 * 10(6) cells/ml in blood taken 12 h after the conclusion of transient ischemia, p = 0.0029. The number of CD34+ cells increased from 4.23 +/- 0.8 * 10(4) cells/ml in the pretreatment samples to 7.17 +/- 1.34 * 10(4) cells/ml in blood taken 12 h after ischemia, p = 0.0001. The harvested stem cells maintained their ability to construct tubular structures. The augmentation in the number of CD34+ cells was positively correlated with the increase of IL-8, but not with VEGF concentrations. Ischemic preconditioning is a safe and effective technique to increase the availability of stem cells for therapeutic purposes. PMID- 21318599 TI - Combining accurate genetic and clinical information in breast cancer risk model. PMID- 21318600 TI - Alcohol consumption and breast cancer risk in Japanese women: the Miyagi Cohort study. AB - Alcohol consumption is known to be a risk factor for breast cancer in Western countries, but few epidemiologic data have been available in Japan. This population-based prospective cohort study evaluated the associations of alcohol consumption with breast cancer risk in a Japanese population. A total of 19,227 women aged 40-64 years were followed from 1990 to 2003. During 246,703 person years of follow-up, 241 breast cancer cases were identified. Hazard ratios (HRs) were estimated by the Cox proportional-hazard regression model. After adjustment for potential risk factors of breast cancer and nutritional factors, the HR and 95% confidence interval (CI) for current drinkers was 1.00 (0.74-1.34) compared with never drinkers. According to the amount of alcohol intake per day, a higher amount (>=15.0 g/day) had no significant relation to breast cancer risk (HR = 0.87, 95% CI: 0.40-1.91; P for trend = 0.85). Age upon starting to drink, and the frequency of drinking, were not associated with breast cancer risk. In analysis stratified according to exogenous female hormone use, a higher alcohol intake (>=15.0 g/day) was associated with an increased risk of breast cancer among hormone users (HR = 1.67, 95% CI: 0.17-16.73); however, this was not statistically significant. Stratification according to folate intake with energy adjustment (<219, >= 219 MUg/day) found that breast cancer risk tended to increase with increasing alcohol consumption among women with a low intake of folate (P for trend = 0.09). Our findings suggest that alcohol consumption has no overall effect on breast cancer risk among Japanese women, whereas nutritional factors such as folate intake may modify the alcohol-breast cancer risk relationship. PMID- 21318601 TI - Tumor angiogenesis as prognostic and predictive marker for chemotherapy dose intensification efficacy in high-risk breast cancer patients within the WSG AM-01 trial. AB - The goal of this analysis was to characterize the survival impact of angiogenesis in the patients with high-risk breast cancer, particularly the predictive impact on benefit from dose intensification of adjuvant chemotherapy. Formalin-fixed tissue sample of 152 patients treated as part of the WSG AM-01 trial by either high-dose or conventional dose-dense chemotherapy were analyzed. Angiogenic activity was measured using microvessel count and vascular surface area (VSA) determined by the expression of vascular markers CD31 (n = 128) and CD105/endoglin (n = 130). Protein molecular breast cancer subclasses were analyzed by k-means clustering (k = 5). The univariate impact of factors on event free (EFS) and overall survival (OS) was tested by log-rank statistics and quantified by univariate Cox analysis. Multivariate survival analysis included factors significant in univariate analysis, as well as interactions was performed for EFS. Both VSA/CD31 (P = 0.004) and VSA/CD105 (P = 0.003) were significantly higher among cases with increased Ki-67. A significant association with molecular subtypes was also found for VSA/CD105: in patients with basal-like/Her-2 subtypes, mean was 1.72 versus 1.24 in patients with other subtypes (P < 0.001). Elevated VSA/CD105 was associated with both significantly decreased EFS (P = 0.01) and OS (P = 0.02). Increased tumor size and positive Her-2 status were also prognostic for poorer EFS. The benefit of dose intensification for EFS was seen in those low-VSA/CD105 patients. The result was evident both in univariate and in multivariate survival analysis including all factors that were significant at the univariate level. Expression of angiogenesis markers may mirror or confer resistance to chemotherapy in the patients with breast cancer, particularly within the context of dose intensified chemotherapy. Highly angiogenic tumors may not derive sufficient benefit from dose intensification of chemotherapy alone. Our findings may serve as a rationale for further exploring anti-angiogenic treatment options in the patients with such highly angiogenic tumor subtypes. PMID- 21318603 TI - Current evidences on XPC polymorphisms and breast cancer susceptibility: a meta analysis. AB - Published data on the association between three polymorphisms (Lys939Gln, Ala499Val, and PAT+/-) of Xeroderma Pigmentosum group C (XPC) and breast cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Crude ORs with 95% CIs were used to assess the strength of association between them. A total of 11 studies including 5,090 cases and 5,214 controls were involved in this meta-analysis. For XPC Lys939Gln polymorphism, no obvious associations were found for all genetic models when all studies were pooled into the meta-analysis (Lys/Gln vs. Lys/Lys: OR = 1.00, 95% CI 0.92-1.10; Gln/Gln vs. Lys/Lys: OR = 0.96, 95% CI 0.84-1.09; dominant model: OR = 0.99, 95% CI 0.91-1.08; and recessive model: OR = 0.97, 95% CI 0.86-1.09). In the subgroup analysis by ethnicity or study design, still no obvious associations were found. For XPC Ala499Val polymorphism, also no obvious associations were found for all genetic models when all studies were pooled into the meta-analysis (Val/Ala vs. Ala/Ala: OR = 0.91, 95% CI 0.79-1.05; Val/Val vs. Ala/Ala: OR = 1.07, 95% CI 0.80-1.44; dominant model: OR = 0.93, 95% CI 0.81 1.06; and recessive model: OR = 1.11, 95% CI 0.84-1.48). For XPC PAT+/- polymorphism, obvious associations were found for recessive model when all studies were pooled into the meta-analysis (OR = 1.41, 95% CI 1.05-1.89). In conclusion, this meta-analysis suggests that the XPC PAT+/- polymorphism allele may be a low-penetrant risk factor for developing breast cancer. PMID- 21318602 TI - Differential expression of arrestins is a predictor of breast cancer progression and survival. AB - Emerging evidence has implicated G protein-coupled receptors, such as CXCR4 and PAR2, in breast cancer progression and the development of metastatic breast cancer. However, the role of proteins that regulate the function of these receptors, such as arrestins, in breast cancer has yet to be determined. Examination of the expression of the two nonvisual arrestins, arrestin2 and 3, in various breast cancer cell lines revealed comparable expression of arrestin3 in basal and luminal lines while arrestin2 expression was much higher in the luminal lines compared to the more aggressive basal lines. Analysis of normal human breast tissue revealed that arrestin2 and 3 were expressed in both luminal and myoepithelial cells of mammary epithelia with arrestin2 highest in myoepithelial cells and arrestin3 comparable in both cell types. Quantitative immunofluorescence-based examination of primary breast tumors revealed that arrestin2 expression significantly decreased with cancer progression from ductal carcinoma in situ to invasive carcinoma and further to lymph node metastasis (P < 0.001). Moreover, decreased arrestin2 expression was associated with decreased survival (P = 0.0007) as well as positive lymph node status and increased tumor size and nuclear grade. In contrast, arrestin3 expression significantly increased during breast cancer progression (P < 0.001) and increased expression was associated with decreased survival (P = 0.014). Arrestin3 was also an independent prognostic marker of breast cancer with a hazard ratio of 1.65. Overall, these studies demonstrate that arrestin2 levels decrease while arrestin3 levels increase during breast cancer progression and these changes correlate with a poor clinical outcome. PMID- 21318604 TI - Efficacy and safety of mometasone furoate nasal spray in the treatment of chronic rhinosinusitis. AB - INTRODUCTION: This study evaluated the efficacy and safety of mometasone furoate nasal spray (MFNS) in patients with chronic sinusitis. METHODS: In this double blind, placebocontrolled, multicenter, parallel-group study, 60 patients with persistent sinusitis symptoms were randomized to receive either MFNS 200 MUg twice daily or placebo, for 16 weeks (112 days). Eventually, 53 patients terminated the study in regular course. RESULTS: Total Symptom Scores (TSS) in patients receiving MFNS changed by a mean of -7.27 (95% CI -9.71, -4.84), versus 5.35 (95% CI -6.73, -3.96) in the placebo group (P=0.51). MFNS reduced nasal congestion and discharge scores, and improved patients' olfactory function. There were few side effects. Considerably more patients in the MFNS group were satisfied with the treatment than those who had received placebo (P<0.05). Also, more patients would take the medication again in the event of symptoms, compared with those who had taken placebo (P<0.05). Furthermore, the MFNS patients would recommend it to others. CONCLUSION: The positive patient assessment and few side effects are reflected in the efficacy evaluation performed by the physicians. The endoscopic results under MFNS were always numerically more favorable than those under placebo, and the overall difference reached statistical significance (P<0.01). MFNS offers an effective and safe treatment for chronic rhinosinusitis. PMID- 21318605 TI - Prevention of serious respiratory syncytial virus-related illness. II: Immunoprophylaxis. AB - Respiratory syncytial virus (RSV) causes significant morbidity in very young children, preterm infants with and without chronic lung disease, and children with hemodynamically significant congenital heart disease. In the absence of a safe and effective vaccine, alternative means of protecting high-risk infants and young children from serious RSV illness have been studied. Clinical observations and animal model data over the past 30 years suggested that RSV immunoglobulin G (IgG) neutralizing antibodies might offer protection from severe RSV lower respiratory tract disease. Transfer of adequate amounts of IgG to the fetus does not occur efficiently until the third trimester of pregnancy, which helps to explain why premature infants are at high risk of serious RSV illness. Efforts shifted toward the prophylactic monthly administration of standard immunoglobulins and, later, of RSV-enriched immunoglobulin in selected high-risk infants and young children. Although this approach proved effective, RSV-enriched immune globulin was not suitable for all patients and administration was labor intensive. The development of palivizumab, a monoclonal antibody that can bind to a specific antigenic site on the virus and prevent cell-to-cell spread of infection has since become the mainstay of RSV illness prevention in preterm infants and those with significant congenital heart disease. Palivizumab, the only monoclonal antibody approved for the prevention of RSV lower respiratory tract disease must be administered monthly throughout the RSV season and does not always prevent serious RSV illness. Further research to develop more effective and less labor-intensive immunoprophylactic agents is ongoing. PMID- 21318606 TI - Prevention of serious respiratory syncytial virus-related illness. I: Disease pathogenesis and early attempts at prevention. AB - Respiratory syncytial virus (RSV) was first described 160 years ago but was not officially recognized as a cause of serious illness in children until the late 1950s. It has been estimated that virtually all children have had at least one RSV infection by their second birthday. RSV is responsible for annual disease outbreaks, usually during a defined winter seasonal period that can vary by community and year. RSV is recognized as the leading cause of hospitalization among young children worldwide. Infants of young chronologic age and children with predisposing factors, such as premature birth, pulmonary disease, or congenital heart disease, are most susceptible to serious illness. Unlike other viruses, immunity to RSV infection is incomplete and short lived, and reinfection is common throughout life. Initial attempts to develop a vaccine in the 1960s met with unexpected and tragic results; many children vaccinated with a formalin inactivated wild-type virus developed serious pulmonary disease upon subsequent natural infection. Numerous other vaccine technologies have since been studied, including vectored approaches, virus-like particles, DNA vaccines, and live attenuated virus vaccine. As of early 2010, only two companies or institutions had RSV vaccine candidates in early clinical trials, and no vaccine is likely to be licensed for marketing in the immediate future. PMID- 21318607 TI - Previous sick leaves as predictor of subsequent ones. AB - PURPOSE: There is evidence that a history of sick leave (SL) increases the risk of suffering a new episode. However, little is known about the effect of the number of previous SL on subsequent ones. The aim of this paper was to quantify the effect of prior episodes on the risk of experiencing a new one and the effect on the duration of episodes, by diagnosis. METHODS: Prospective study. Sample comprises 1,542 workers from a university hospital, whose first contract started during 2000-2007. RESULTS: The studied workers accumulated 5,138 episodes, 21,250 days of absence and 45,324.2 months of follow-up. For all the causes, recurrence density was higher than incidence density. The higher the number of prior SL, the greater is the hazard of presenting a new episode. This is particularly true for episodes due to mental and behavioral disorders, diseases of the skin and subcutaneous tissue, and diseases related to nervous system. The adjusted hazard of suffering an SL episode due to mood disorders was increased 21.44 times when the worker had previously had one SL. The corresponding figures were 14.58 and 13.92 for SL due to skin and mucous membrane diseases and due to neurotic or stress-related disorders, respectively. CONCLUSIONS: The results obtained provide evidence that having suffered previous SL episodes implies a significant increase in the risk of experiencing a new one. High recurrence density of certain diagnoses should be interpreted as a general indication that something is wrong in the occupational setting. PMID- 21318608 TI - A systematic review of job-specific workers' health surveillance activities for fire-fighting, ambulance, police and military personnel. AB - PURPOSE: Some occupations have tasks and activities that require monitoring safety and health aspects of the job; examples of such occupations are emergency services personnel and military personnel. The two objectives of this systematic review were to describe (1) the existing job-specific workers' health surveillance (WHS) activities and (2) the effectiveness of job-specific WHS interventions with respect to work functioning, for selected jobs. METHODS: The search strategy systematically searched the PubMed, PsycINFO and OSH-update databases. The search strategy consisted of several synonyms of the job titles of interest, combined with synonyms for workers' health surveillance. The methodological quality was checked. RESULTS: At least one study was found for each of the following occupations fire fighters, ambulance personnel, police personnel and military personnel. For the first objective, 24 studies described several job-specific WHS activities aimed at aspects of psychological, 'physical' (energetic, biomechanical and balance), sense-related, environmental exposure or cardiovascular requirements. The seven studies found for the second objective measured different outcomes related to work functioning. The methodological quality of the interventions varied, but with the exception of one study, all scored over 55% of the maximum score. Six studies showed effectiveness on at least some of the defined outcomes. The studies described several job-specific interventions: a trauma resilience training, healthy lifestyle promotion, physical readiness training, respiratory muscle training, endurance and resistance training, a physical exercise programme and comparing vaccines. CONCLUSIONS: Several examples of job-specific WHS activities were found for the four occupations. Compared to studies focusing on physical tasks, a few studies were found that focus on psychological tasks. Effectiveness studies for job specific WHS interventions were scarce, although their results were promising. We recommend studying job-specific WHS in effectiveness studies. PMID- 21318609 TI - Disparities in management of new-onset atrial fibrillation in the emergency department despite adherence to the current guidelines: data from a large metropolitan area. AB - Atrial Fibrillation management is still a matter for debate. Past research has largely been based on the outpatient setting in which patients are followed during ambulatory visits. Very little data exist on the optimal management of AF in the Emergency Department (ED). This study investigated which factors drive different AF treatments in the ED, describing their use in different hospitals. Finally, the efficacy of different strategies in terms of cardioversion in the ED was analyzed. Charts of patients treated for atrial fibrillation (AF) were collected in 6 EDs in a large metropolitan area over a 24-consecutive month period and were reviewed and analysed. Demographics, comorbidities, treatment strategy and ED outcome were collected. Inclusion criteria were symptom onset <3 weeks and stable hemodynamic conditions at presentation. A propensity score was used to adjust for baseline clinical characteristics and to compare the efficacy of different treatments. 3,085 patients were included in the analysis. Variables associated with a rhythm control strategy were onset of symptoms <48 h, age, dyspnea, palpitations, renal failure and the presence of a mechanical valve. Different EDs applied different strategies in terms of drugs used and the electrocardioversion rate, showing heterogeneity in AF management. Adjusting for the propensity score, electrocardioversion and antidysrhythmic drugs of class Ic were more effective than a wait-and-watch strategy in the ED. Despite international guidelines being respected, AF management is heterogeneous in different ED settings. A rhythm control strategy with electrocardioversion and Class Ic drugs is more effective than a wait-and watch approach during the ED visit. Further research, toward an evidence-based approach to the emergent management of AF in the ED, is still needed. PMID- 21318610 TI - Mollaret's meningitis: 65 years of history. PMID- 21318611 TI - Hyperparathyroidism in celiac disease: always secondary? PMID- 21318612 TI - Cough syncope and multiple pulmonary nodules. PMID- 21318613 TI - Combination antibiotic treatment of severe community-acquired pneumonia. PMID- 21318614 TI - Pediatric traumatic carotid, vertebral and cerebral artery dissections: a review. AB - Traumatic cerebral dissections are rare but potentially dangerous conditions that through improved diagnostics have recently gained increased interest. However, there is still a significant lack of knowledge on the natural history, as well as on the best treatment options. Most of the literature on this topic consists of case reports and retrospective studies with no prospective randomized controlled studies. In our review, we highlight the fact that there is no level 1 evidence for the natural history of cerebral dissections or for the best treatment. We present 26 case studies derived from 70 pediatric patients affected by dissections, occlusions, and pseudoaneurysms. PMID- 21318615 TI - Subarachnoid hemorrhage secondary to ruptured posterior communicating artery aneurysm in a child. AB - Intracranial arterial aneurysms in children are very rare. The authors present the clinical and neuroradiological findings in a 12-year-old child with subarachnoid and intraventricular hemorrhage related to posterior communicating artery aneurysm. The aneurysm was successfully treated with endovascular coiling. The literature regarding this topic is reviewed and the management of subarachnoid hemorrhage in children is discussed. PMID- 21318616 TI - Cerebellar mutism: incidence, risk factors and prognosis. PMID- 21318617 TI - Microcephaly in ancient Greece--the Minoan Microcephalus of Zakros. PMID- 21318618 TI - Development of second-generation VEGFR tyrosine kinase inhibitors: current status. AB - The vascular endothelial growth factor (VEGF) signaling pathway appears to be the dominant pathway involved in tumor angiogenesis, providing a rationale for targeting the VEGF receptors (VEGFR-1, -2, and -3) in the treatment of cancers. In particular, VEGF signaling is thought to be important in renal cell carcinoma (RCC) because of the deregulation of the pathway through nearly uniform loss of the von Hippel Lindau protein. The tyrosine kinase inhibitors (TKIs) sorafenib, sunitinib, and pazopanib are approved by the US Food and Drug Administration for the treatment of advanced RCC; however, these multitargeted agents inhibit a wide range of kinase targets in addition to the VEGFRs, resulting in a range of adverse effects unrelated to efficient VEGF blockade. This article reviews recent advances in the development of the second-generation VEGFR TKIs, including the more selective VEGFR TKIs tivozanib and axitinib, and focuses on the potential benefits of novel inhibitors with improved potency and selectivity. PMID- 21318619 TI - Mortality rates among Arab Americans in Michigan. AB - The objectives of this study were to: (1) calculate age-specific and age-adjusted cause-specific mortality rates for Arab Americans; and (2) compare these rates with those for blacks and whites. Mortality rates were estimated using Michigan death certificate data, an Arab surname and first name list, and 2000 U.S. Census data. Age-specific rates, age-adjusted all-cause and cause-specific rates were calculated. Arab Americans (75+) had higher mortality rates than whites and blacks. Among men, all-cause and cause-specific mortality rates for Arab Americans were in the range of whites and blacks. However, Arab American men had lower mortality rates from cancer and chronic lower respiratory disease compared to both whites and blacks. Among women, Arab Americans had lower mortality rates from heart disease, cancer, stroke, and diabetes than whites and blacks. Arab Americans are growing in number. Future study should focus on designing rigorous separate analyses for this population. PMID- 21318620 TI - Evaluation of association between biomarkers of lead exposure in Sardinian children (Italy). AB - The aim of this work is to verify whether there are statistically significant correlations between the concentrations of lead in blood, urine, and hair in children. The sample collected in 2007 consists of 163 children of both sexes from 11-14-year-olds, living in three municipalities of Sardinia (Italy). Inductively coupled plasma atomic mass spectrometry has been used in the determination of lead concentration in biological material. For the overall sample, there is a non-significant partial correlation among the three matrices. However, for subjects with blood lead levels >=5 MUg/dL, there is a significant positive partial correlation between the lead levels in blood and hair, but not between blood and urine or between urine and hair. The results suggest that blood is the preferred biomarker to ascertain lead exposure in human populations, whereas hair can be used as a tool screening when an area is exposed to medium or high lead pollution. PMID- 21318621 TI - Development of a new pollution index for heavy metals in sediments. AB - This study aims to investigate the pollution rate of heavy metals on the western seaboard of Bandarabbas in southeast Iran using a new pollution index. The bulk of the analysis was conducted on sediments, followed by selection of a few samples to perform experiments on chemical partitioning studies as well as biological accessibility. On this basis, the proportions of natural and anthropogenic elements were calculated. Finally, with regard to chemical separation results, the pollution rate was calculated based on Muller's geo chemical index, enrichment factor, pollution index, and a new "Risk" index. Chemical separation showed the anthropogenic origin of elements are as follows: Ni(27.5%) > Zn(6.5%) > Pb(2%) > Al (0.2%). The newly developed pollution index is indicative of "low environmental pollution "for Ni. PMID- 21318622 TI - Review: micronutrient selenium deficiency influences evolution of some viral infectious diseases. AB - Recently emerged viral infectious diseases (VIDs) include HIV/AIDS, influenzas H5N1 and 2009 H1N1, SARS, and Ebola hemorrhagic fevers. Earlier research determined metabolic oxidative stress in hosts deficient in antioxidant selenium (Se) (<1 MUMol Se/L of blood) induces both impaired human host immunocompetence and rapidly mutated benign variants of RNA viruses to virulence. These viral mutations are consistent, rather than stochastic, and long-lived. When Se deficient virus-infected hosts were supplemented with dietary Se, viral mutation rates diminished and immunocompetence improved. Herein is described the role of micronutrient Se deficiency on the evolution of some contemporary RNA viruses and their subsequent VIDs. Distinguishing cellular and biomolecular evidence for several VIDs suggests that environmental conditions conducive to chronic dietary Se deprivation could be monitored for bioindicators of incipient viral virulence and subsequent pathogenesis. PMID- 21318623 TI - A novel membrane-integrated fermentation reactor system: application to pyruvic acid production in continuous culture by Torulopsis glabrata. AB - This paper describes the performance of a novel bio-reactor system, the membrane integrated fermentation reactor (MFR), for efficient continuous fermentation. The MFR, equipped with an autoclavable polyvinylidene difluoride membrane, has normally been used for biological wastewater treatment. The productivity of the MFR system, applied to the continuous production of pyruvic acid by the yeast Torulopsis glabrata, was remarkably high. The volumetric productivity of pyruvic acid increased up to 4.2 g/l/h, about four times higher than that of batch fermentation. Moreover, the membrane was able to filter fermentation broth for more than 300 h without fouling even though the cell density of the fermentation broth reached 600 as OD(660). Transmembrane pressure, used as an indicator of membrane fouling, remained below 5 kPa throughout the continuous fermentation. These results clearly indicate that the MFR system is a simple and highly efficient system that is applicable to the fermentative production of a range of biochemicals. PMID- 21318624 TI - Immobilizing Pt nanoparticles and chitosan hybrid film on polyaniline naofibers membrane for an amperometric hydrogen peroxide biosensor. AB - A convenient and effective way for fabricating amperometric hydrogen peroxide (H2O2) biosensor was designed in this paper. First, the polyaniline (PANI) nanofibers membrane with good conductance and high surface area was electropolymerized on a gold electrode surface. Then, Pt nanoparticle (PtNP) was electrochemically deposited on the PANI nanofibers membrane. Finally, the hybrid film of gold nanoparticle, chitosan, and horseradish peroxidase (HRP) was cast onto the modified electrode to form a stable biofunctional film, which was also employed as a protective layer to PtNP. The proposed biosensor exhibited a rapid response to H2O2 with the linear range from 7.0 * 10(-6) to 1.4 * 10(-2) M and a detection limit of 2.8 * 10(-6) M (S/N = 3). The sensitivity of 558 MUA mM(-1) cm(-2) was obtained. The Michaelis-Menten constant, K(app)M value was 1.90 mM suggesting a high affinity. Moreover, it displayed a good reproducibility and long-term stability. PMID- 21318625 TI - Latent class analysis: an alternative perspective on subgroup analysis in prevention and treatment. AB - The overall goal of this study is to introduce latent class analysis (LCA) as an alternative approach to latent subgroup analysis. Traditionally, subgroup analysis aims to determine whether individuals respond differently to a treatment based on one or more measured characteristics. LCA provides a way to identify a small set of underlying subgroups characterized by multiple dimensions which could, in turn, be used to examine differential treatment effects. This approach can help to address methodological challenges that arise in subgroup analysis, including a high Type I error rate, low statistical power, and limitations in examining higher-order interactions. An empirical example draws on N = 1,900 adolescents from the National Longitudinal Survey of Adolescent Health. Six characteristics (household poverty, single-parent status, peer cigarette use, peer alcohol use, neighborhood unemployment, and neighborhood poverty) are used to identify five latent subgroups: Low Risk, Peer Risk, Economic Risk, Household & Peer Risk, and Multi-Contextual Risk. Two approaches for examining differential treatment effects are demonstrated using a simulated outcome: 1) a classify analyze approach and, 2) a model-based approach based on a reparameterization of the LCA with covariates model. Such approaches can facilitate targeting future intervention resources to subgroups that promise to show the maximum treatment response. PMID- 21318626 TI - [Health services research: the example of hand eczema]. AB - Hand eczema is one of the most frequent skin diseases with a lifetime prevalence of up to 15% and a median incidence rate of 6 cases per 1000 person-years. Female gender, contact allergy, atopic eczema and wet work have been identified as the most important associated risk factors. Hand eczema has a high public health and socio-economic significance, since the vast majority of occupational skin disease is hand eczema. Hand eczema is often chronic, chronically relapsing or persisting. It entails substantial impairment of health-related quality of life for the affected individual. The cost-of-illness of hand eczema is estimated to be in the range of moderate to severe psoriasis and even higher than that of atopic eczema. Although various therapeutic options to treat hand eczema exist, an assessment of these options in randomized, controlled clinical trials to build up an evidence base is mostly lacking. The investigation of the treatment of chronic hand eczema under everyday conditions in dermatological clinics and private practices has only just begun. The first register of patients with chronic hand eczema (acronym: carpe) is expected to yield substantial insights in the effectiveness and safety of different therapeutic measures. A related task is the assessment of the quality of care in the light of the guidelines for the management of chronic hand eczema. PMID- 21318627 TI - Synthesis, characterization and osteoconductivity properties of bone fillers based on alendronate-loaded poly(epsilon-caprolactone)/hydroxyapatite microspheres. AB - A superior drug controlled release system capable of achieving efficient osteogenesis is in imperative demand because of limited bone substitute tissue for the treatment of bone defect. In the present study, we investigated the potential of using poly(epsilon-caprolactone)-hydroxyapatite (PCL-HA) composite microspheres as an injectable bone repair vehicle by controlled release of alendronate (AL), a medicine that belongs to the bisphosphonates family. The PCL/HA-AL microspheres were prepared with solid/oil/water emulsion technique, which included two processes: (1) AL was loaded on the hydroxyapatite nanoparticles; (2) the HA-AL complex was built in the PCL matrix. The spherical PCL/HA-AL microspheres were characterized with its significantly improved encapsulation efficiency of hydrophilic AL and better sustained release. Human bone mesenchymal stem cells (hMSCs) were cultured on the surface of these microspheres and exhibited high proliferative profile. Specifically, in osteogenic medium, hMSCs on the surface of PCL/HA-AL microspheres displayed superior osteogenic differentiation which was verified by alkaline phosphatase activity assay. In conclusion, by presenting strong osteogenic commitment of hMSCs in vitro, the PCL/HA-AL microspheres have the potential to be used as an injectable vehicle for local therapy of bone defect. PMID- 21318628 TI - Is noncontact ACL injury associated with the posterior tibial and meniscal slope? AB - BACKGROUND: The risk of noncontact ACL injury reportedly is increased in patients with a greater posterior tibial slope (PTS), but clinical data are inconsistent. It is unclear whether the medial and lateral PTSs have a different impact on this connection. It also is unknown whether the meniscal slope (MS) is associated with ACL injury. PATIENTS/METHODS: Using MRI, we compared the medial and lateral PTSs and MSs separately in 55 matched pairs of patients with isolated noncontact ACL injuries and a control group. RESULTS: Neither the PTS nor the relative difference between the medial and lateral PTSs differed between groups. In contrast, the lateral MS was greater with ACL injuries: 2.0 degrees versus -2.7 degrees in males with and without ACL injury and 1.7 degrees versus -0.9 in females. Uninjured females had a greater PTS than males: 4.9 degrees versus 3.0 degrees in females and males medially, respectively; 5.7 degrees versus 4.0 degrees lateral. CONCLUSIONS: There is no obvious link between the medial or lateral PTSs and ACL injury, and there is no obvious link between the relative difference in the medial and lateral PTSs and noncontact ACL injury. However, a greater lateral MS may indicate a greater risk of injury. The PTS can differ between the genders but the average difference is small. LEVEL OF EVIDENCE: Level II, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 21318629 TI - Pelvic rotation and tilt can cause misinterpretation of the acetabular index measured on radiographs. AB - BACKGROUND: Radiographic diagnosis and followup studies of developmental dysplasia of the hip are commonly performed by measuring the acetabular index on radiographs using Hilgenreiner's method. The outcome of the measurement, however, depends on the orientation of the subject's pelvis relative to the xray source. The influence of pelvic rotation and tilt on the measurement error has been evaluated separately but not in combination. QUESTIONS/PURPOSES: We asked whether (1) combinations of pelvic rotation and tilt introduced systematic error in acetabular index measurement in a reproducible way, and (2) ratios proposed to evaluate either pelvic rotation (R(rotation)) or pelvic tilt (R(tilt)) are influenced by pelvic tilt and rotation, respectively. METHODS: Radiographic measurements of the acetabular index, R(rotation), and R(tilt) were performed on digitally reconstructed radiographs of one high-resolution three-dimensional CT dataset with various combinations of pelvic rotation and tilt. RESULTS: For rotations and tilt up to 12 degrees , the average systematic errors in the acetabular index varied from -8.8 degrees to 4.5 degrees . Negative and positive error values can be interpreted as underestimations and overestimations of the acetabular index, respectively. Errors in acetabular index measurements were acceptable for R(rotation) values between 1.0 and 2.0 and R(tilt) values between 1.1 and 1.8. CONCLUSIONS: To limit the systematic error in assessing the acetabular index caused by pelvic misalignment, we recommend only radiographs acquired with +/- 4 degrees rotation and +/- 4 degrees tilt be considered acceptable. PMID- 21318631 TI - Functional characterization of a delta 6-desaturase gene from the black seabream (Acanthopagrus schlegeli). AB - Delta 6-fatty acid desaturase (D6DES) is used in the synthesis of polyunsaturated fatty acids (PUFAs) from microorganisms to higher animals, including arachidonic acid (ARA) and eicosapentaenoic acid (EPA). A 1,338 bp full-length cDNA encoding D6DES was cloned from Acanthopagrus schlegeli (AsD6DES) through degenerate- and RACE-PCR methods. A recombinant vector expressing AsD6DES (pYES-AsD6DES) was subsequently constructed and transformed into Saccharomyces cerevisiae to test the enzymatic activity of AsD6DES towards the production of n-6 and n-3 fatty acids. The exogenously expressed AsD6DES produced gamma-linolenic acid (18:3 n-6) and stearidonic acid (18:4n-3) at 26 and 36% from exogenous linoleic acid (18:2n 6) and alpha-linolenic acid (18:3n-3), respectively, indicating that it is essentially a delta 6-fatty acid desaturase. PMID- 21318630 TI - Expression of the human cancer/testis antigen NY-SAR-35 is activated by CpG island hypomethylation. AB - The novel cancer/testis antigen gene, NY-SAR-35, is expressed exclusively in normal testis and in various histological types of tumor. However, the NY-SAR-35 gene expression is observed to be aberrant in several cancer cell lines and tissues. The analysis of methylation status of the NY-SAR-35 gene promoter in various cancer cell lines showed that its expression was related to methylation of the promoter region. Treatment of human cancer cell lines with the demethylating agent 5-aza-2'-deoxycytidine activated the expression of the NY-SAR 35 gene. In addition, transfection experiments on various fragments of the CpG rich gene promoter indicate that in vitro methylation of the NY-SAR-35 gene promoter results in the loss of promoter activity. The expression of NY-SAR-35 is therefore activated by hypomethylation of the CpG island in the gene promoter. PMID- 21318632 TI - Exploiting the interactions between poly-histidine fusion tags and immobilized metal ions. AB - Immobilized metal affinity chromatography (IMAC) of proteins containing poly histidine fusion tags is an efficient research tool for purifying recombinant proteins from crude cellular feedstocks at laboratory scale. Nevertheless, to achieve successful purification of large amounts of the target protein for critical therapeutic applications that demand the precise removal of fusion tags, it is important to also take into consideration issues such as protein quality, efficiency, cost effectiveness, and optimal affinity tag choice and design. Despite the many considerations described in this article, it is expected that enhanced selectivity, the primary consideration in the field of protein separation, will continue to see the use of IMAC in solving new purification challenges. In addition, the platform nature of this technology makes it an ideal choice in purifying proteins with unknown properties. Finally, the unique interaction between immobilized metal ions and poly-histidine fusion tag has enabled new developments in the areas of biosensor, immunoassay, and other analytical technologies. PMID- 21318633 TI - Selection and validation of reference genes for gene expression studies by reverse transcription quantitative PCR in Xanthomonas citri subsp. citri during infection of Citrus sinensis. AB - Xanthomonas citri subsp. citri (Xcc) causes citrus canker, a worldwide disease found mainly in sweet oranges (Citrus sinensis (L.) Osbeck). The expression of nine candidate internal reference genes was analyzed in Xcc grown alone and during C. sinensis infection to identify genes most suitable for comparative expression studies in Xcc using reverse transcription quantitative PCR (qRT-PCR). The stability of these genes was determined using the programs geNorm, NormFinder and BestKeeper. The genes most suitable for data normalization during C. sinensis infection were atpD, rpoB, gyrA and gyrB. The use of at least three reference genes is essential for accurate data normalization in Xcc. PMID- 21318634 TI - The deep brain stimulation of the pedunculopontine tegmental nucleus: towards a new stereotactic neurosurgery. AB - The application of deep brain stimulation (DBS) to the pedunculopontine tegmental nucleus (PPTg) has required profound modifications of classic neurosurgical techniques and of the criteria for evaluation of clinical results. This review analyzes a novel method of targeting the PPTg, based on angio-computerized tomography (angio-CT) scans and the tridimensional reconstruction of nuclei and cerebral vessels, and considers the advantages of applying these methods in comparison to the more traditional approach based on reference points obtained through the evaluation of the bicommessural line. Validation of the results obtained following unilateral PPTg DBS through neurophysiological recordings and objective measurements of functional parameters suggests that the PPTg may be considered as an initial target for the treatment of motor symptoms in selected patients affected by idiopathic Parkinson's disease (PD), which, if required, could be followed by DBS of other target areas. Moreover, on the basis of the observations derived from stimulating the PPTg, the potential utility attributed up to date to intraoperative neurophysiological recordings for identifying neurosurgical targets should be revisited, and the need for changes in the intraoperative management of patients has arisen from the body of evidence accumulated over recent years. The results obtained by different groups following PPTg DBS in parkinsonian patients are not uniform, most likely due to a cautious acceptance of this methodology, the experience progressively acquired, the criteria for patient selection and to subtle differences in target location. Although the role of PPTg in PD and/or in other pathologies remains to be clarified, pursuing the traditional approach on classical basal ganglia targets may limit the perspective of DBS based on multiple implantations. PMID- 21318635 TI - Ultrastructural aspects of iron storage, transport and metabolism. AB - The iron storage proteins, ferritin and hemosiderin, enable electron microscopic visualization thanks to their electron-dense iron content, which is not present in other compounds involved in transport or metabolism of iron such as transferrin, lactoferrin, or hemoglobin. It is this electron density which contributed to the unraveling of stages in absorption, transport, deposition, storage, and release of iron. In recent years, additional methods of investigation have further supported the information achieved by the ultrastructural studies. Even while using new analytical methods, the seminal morphological observations remain valid for understanding the role of iron in health and disease. In this review, we will illustrate a few basic findings of electron microscopy in humans, experimental animals, and cell cultures. The importance of H chain ferritin as a transporter across the blood-brain barrier is just an example of a new role revealed for an "old" storage protein, explaining some controversial observations on the presence of iron in the brain. PMID- 21318636 TI - Regulation of the immediate-early genes arc and zif268 in a mouse operant model of cocaine seeking reinstatement. AB - Reinstatement of extinguished operant responding for drug is an appropriate model of relapse to drug abuse. Due to the difficulty of implementing in mice the procedure of instrumental intravenous self-administration, mechanisms of reinstatement have so far been studied almost exclusively in rats. A mouse model of reinstatement of cocaine seeking has recently been characterized (Soria et al. 2008). The aim of the present study was to assess regional brain activation, as measured by induction of the immediate early genes (IEG) arc and zif268, during priming- or cue-elicited reinstatement of cocaine seeking using this new mouse model and the in situ hybridization technique. We have demonstrated that cue elicited reinstatement of cocaine seeking was associated with induction of the IEG in the medial prefrontal cortex (prelimbic and infralimbic) and basolateral amygdala. Priming-induced reinstatement produced a more widespread up-regulation of those genes in forebrain regions including medial prefrontal, orbitofrontal and motor cortex, dorsal striatum and basolateral amygdala. These patterns of IEG expression are in agreement with previous results obtained in rats and thus indicate that the new mouse model of reinstatement is functionally equivalent to rat models. That comparability adds to the usefulness of the mouse model as a tool for addressing neurobiological mechanisms of addiction. PMID- 21318637 TI - Pulmonary function and abdominal and thoracic kinematic changes following aerobic and inspiratory resistive diaphragmatic breathing training in asthmatics. AB - This study investigated the effect of 8 weeks, three times weekly, of aerobic exercise (AE), diaphragmatic inspiratory resistive breathing (DR), and aerobic exercise combined with diaphragmatic inspiratory resistive breathing (CE) on pulmonary function and abdominal and thoracic dimensions and kinematics in asthmatics. Eighty-eight inactive, moderate-persistent asthmatics were matched and randomly assigned to AE, DR, CE, or nonexercise control (NE) groups (n = 22 each). AE subjects walked and/or jogged at 60% of age-predicted maximum heart rate. DR subjects performed diaphragmatic breathing combined with inspiratory resistive breathing at varying inspiration, expiration ratios. CE subjects utilized a combination of the AE and DR programs. AE, DR, and CE significantly (p <= 0.05) improved chest dimensions and kinematics during inspiration at the height of the second intercostal space, during inspiration and expiration at the height of the xiphoid process, and during inspiration and expiration at the height of the midpoint between the xiphoid process and umbilicus. All exercise interventions significantly improved FVC, FEV(1), PEF, and IVC, while MVV improved following AE and CE. However, CE proved superior to AE at improving FVC (p = 0.001), FEV(1) (p = 0.001), and IVC (p = 0.009). There were no significant changes (p > 0.05) in any of the measured parameters in the NE group. CE produces adaptations greater than those for single-mode training in moderate-persistent asthmatics. The results suggest synergy rather than interference between aerobic exercise and diaphragmatic inspiratory resistive breathing and that this mode of training might be useful as an adjunct therapy in asthmatic patients. PMID- 21318638 TI - CpG-conjugated apoptotic tumor cells elicit potent tumor-specific immunity. AB - The primary goal of cancer immunotherapy is to elicit an immune response capable of eradicating established tumors and preventing tumor metastasis. One strategy to achieve this goal utilizes whole killed tumor cells as the primary immunogen. Killed tumor cells provide a comprehensive source of tumor-associated antigens (TAAs), thereby eliminating the need to identify individual antigens. Unfortunately, killed tumor cells tend to be poorly immunogenic. To overcome this limitation, we covalently conjugated immunostimulatory CpG oligodeoxynucleotides (ODN) to apoptotic tumor cells and examined their ability to induce TAA-specific immune responses. Results indicate that CpG conjugation enhances the uptake of cell-based vaccines by dendritic cells (DCs), up-regulates co-stimulatory molecule expression, and promotes the production of immunostimulatory cytokines. Vaccination with CpG-conjugated tumor cells triggers the expansion of tumor specific cytotoxic T lymphocytes (CTL) that reduce the growth of established tumors and prevents their metastatic spread. Thus, conjugating CpG ODN to cell based tumor vaccines is an important step toward improving cancer immunotherapy. PMID- 21318639 TI - Protecting the public: is it time for a paradigm shift in expected practice standards? PMID- 21318640 TI - Anti-NMDA-receptor encephalitis: case report and literature review of an under recognized condition. AB - Anti-N-methyl-D-aspartate receptor (anti-NMDA-R) encephalitis is an immune mediated syndrome that remains under-recognized despite a growing body of literature. This syndrome has been predominantly described in young females with a constellation of symptoms, including personality changes, autonomic dysfunction and neurologic decompensation. It is commonly associated with mature ovarian teratomas. We describe the classic presentation of anti-NMDA-R encephalitis in three dramatically different patients: Case A, a young woman with ovarian teratoma; Case B, the eldest case reported to date; and Case C, a young male with no identifiable tumor. We review the literature summarizing the differential diagnosis, investigative approach, treatment options and challenges inherent to this disorder. We advocate good supportive care, involvement of multiple health disciplines and use of immune-modulating therapies in patient management. These cases underscore the need for increased awareness and high diagnostic suspicion when approaching the patient with suspected viral encephalitis. PMID- 21318641 TI - Can individuals with autism abstract prototypes of natural faces? AB - There is a growing amount of evidence suggesting that individuals with autism have difficulty with face processing. One basic cognitive ability that may underlie face processing difficulties is the ability to abstract a prototype. The current study examined prototype formation with natural faces using eye-tracking in high-functioning adults with autism and matched controls. Individuals with autism were found to have significant difficulty forming prototypes of natural faces. The eye-tracking data did not reveal any between group differences in the general pattern of attention to the faces, indicating that these difficulties were not due to attentional factors. Results are consistent with previous studies that have found a deficit in prototype formation and extend these deficits to natural faces. PMID- 21318642 TI - College students' openness toward autism spectrum disorders: improving peer acceptance. AB - One probable consequence of rising rates of autism spectrum disorder diagnosis in individuals without co-occurring intellectual disability is that more young adults with diagnoses or traits of ASD will attend college and require appropriate supports. This study sought to explore college students' openness to peers who demonstrate ASD-characteristic behaviors. Results showed a significant difference in openness between students who had a first-degree relative with an ASD (n = 18) and a gender-matched comparison group of students without such experience (F = 4.85, p = .035). Engineering and physical science majors did not demonstrate more overall openness. Universities should make efforts to prevent social isolation of students with ASD, such as programs to educate students about ASD and supports to ease college transition. PMID- 21318643 TI - Characteristics and dental experiences of autistic children in Saudi Arabia: cross-sectional study. AB - The purpose of this study is to report base line information about characteristics, and dental experiences of a group of autistic children in three major cities of Saudi Arabia. Most of the children (76.2%) included in the study were diagnosed with autism before the age of 5 years. More than half of the children (53.7%) had no previous dental experience while 33% were treated under general anesthesia. The American Academy of Pediatrics' recommendations should be applied in Saudi Arabia to help improve the average age of diagnosis and make a positive effect on children with autism and their families. Regular visits to dental clinics should be recommended to all families with autistic children to reduce dental disease. PMID- 21318645 TI - Paediatric interventional uroradiology. AB - Paediatric interventional uroradiology lies at the intersection of the disciplines of paediatric interventional radiology and paediatric endourology. Interdisciplinary collaboration has led to the development of new techniques and refinement of procedures adopted from adult practice. This article reviews the major procedures used in paediatric interventional uroradiology, with emphasis on nephrostomy, percutaneous nephrolithotomy, balloon-burst pyeloplasty, and antegrade ureteric stenting. PMID- 21318644 TI - Progress in understanding autism: 2007-2010. AB - Scientific progress is discussed in relation to clinical issues; genetic issues; environmental issues; and the state of play on psychological treatments. It is concluded that substantial gains in knowledge have been achieved during the last 3 years, and there have been some unexpected findings, but major puzzles remain. We should be hopeful of ever greater gains in the years ahead, but both prevention and cure remain elusive. PMID- 21318646 TI - Examining the SF-36 in an older population: analysis of data and presentation of Australian adult reference scores from the Dynamic Analyses to Optimise Ageing (DYNOPTA) project. AB - PURPOSE: To examine the psychometric properties of, and present reference scores for the SF-36 using data from a large community sample of older adults. METHODS: Data are from the DYNOPTA project. We focus on data from five studies that included the SF-36, providing a sample of 41,338 participants aged 45-97 years. We examine the factor structure of the SF-36 and item-internal consistency. RESULTS: The psychometric properties of the eight scales of the SF-36 were largely consistent with previous research based on younger and/or smaller samples. However, the assumption of orthogonality between the second-order factors was not supported. In terms of age-related effects, most scales demonstrated a nonlinear effect with markedly poorer health evident for the oldest respondents. In addition, the scales measuring aspects of physical health (PH, BP, RP, GH) showed an overall linear decline in health with increasing age. There were, however, no consistent linear age-related differences in health evident for those scales most strongly associated with mental health (MH, RE, SF, VT). CONCLUSIONS: The results confirm the structural validity and internal consistency of the eight scales from the SF-36 with an older population and support its use to assess the health of older Australian adults. PMID- 21318647 TI - Concordance in the measurement of quality of life and health indicators between two methods of computer-assisted interviews: self-administered and by telephone. AB - PURPOSE: The aim of this study was to establish the concordance for quality of life (QOL), disability, and use of health service indicators between two modes of computer-assisted interviews: audio-computer-assisted self-interview (A-CASI) and computer-assisted telephone interview (CATI). High concordance between these modes of data collection would allow comparisons and interchangeable use in cross sectional or longitudinal assessments. METHODS: Adult English-speaking women (n = 126) were enrolled from women's health clinics at a public hospital. QOL using the short form 12 version 2, disability (days missed from work, inability to do household activities), and utilization of health services (number of emergency room visits and hospitalizations) were assessed first with A-CASI at the time of enrollment and again (n = 102) with CATI 1 week later. Participants assessed with both modes were 38 years old on average, predominantly African-American, 41% had a high school education or less, and 61% were uninsured. Lin's concordance correlation coefficient or Cohen's kappa was calculated to establish concordance between paired A-CASI and CATI assessments. RESULTS: Concordance between the two interview methods ranged from fair to substantial for the QOL components, (concordance correlation coefficient [CCC] of .76 and .87, respectively), the QOL subscales, and disability indices (CCC range; .53-.91). For health services utilization, there was moderate concordance for emergency room visits (CCC = .70) but only slight concordance for the number of hospitalizations in the past year (CCC = .37). CONCLUSIONS: Administering surveys through a telephone or self administered computer-assisted interview resulted in moderate to substantial agreement for the short form QOL components and fair to substantial for the QOL subscales and disability measures. These findings suggest A-CASI and CATI can be used interchangeably for some QOL scales. PMID- 21318661 TI - On the age-sex composition of the population that would result from given fertility and mortality conditions. AB - This article presents new formulas for calculating the eventual sex-ratio and the eventual age-sea composition of the population that would result from given fertility and mortality conditions. These formulas provide more accurate methods and are more widely applicable than earlier methods. The application of the formulas is illustrated through the use of available data on fertility and mortality conditions in the United States in 1964. PMID- 21318662 TI - New household projections for the united states. AB - This paper reviews the methods used to prepare the new household projections for the United States that were recently issued by the Bureau of the Census and examines the effect on the resulting number of households of the assumptions made about future marriages and future proportions of household heads in the population.One population projection series was used, since all series are identical for the adult population. Marriage assumptions were generated by assuming various outcomes of the marriage squeeze (defined as the excess of females relative to the number of males in the main ages at marriage in the next few years). Assumptions about proportions of household heads were generated by assuming, in varying degrees, continuation of recent trends in these proportions.Projected changes in marriage and in the proportions of household heads in the population account for one-fourth to one-third of the projected increase in the number of households; the remaining increase is attributable to projected changes in the size and structure of the adult population. Varying the assumed proportions of household heads produces greater differences in the projected total number of households than does varying the marriage assumptions used here. Nevertheless, the various possible outcomes of the marriage squeeze, as represented by the assumptions used, produce significantly different projections of increases in the number of young husband-wife households.The most striking finding is that by 1985, proportions of household heads among the population not "married, spouse present" may well rise to such a level that over the long term, the smaller the number of persons who marry, the larger will be the number of households. PMID- 21318663 TI - Some notes on fertility problems in a colombian semi-urban community. AB - Significant efforts in the field of study and control of reproductive habits of the Colombian population have been made in the last few years by local medical groups. This article attempts to illustrate how the data obtained in this program can be meaningfully exploited from the demographic point of view. Although data available at the time of writing did not comply with the principles of scientific sampling procedures, it is thought that such studies can throw some light on particular issues, such as the patterns of mating, the effect of contraception on birth spacing among married couples, and the relation of fecundity to frequency of coitus. This article deals with some methodological issues which center around these problems. PMID- 21318664 TI - The vital statistics method of estimating net migration by age cohorts. AB - The focus of this paper is the development and testing of a method of estimating deaths which occur during a decade to aging birth and death cohorts, so that it may be possible to estimate net migration by the vital statistics (VS) method for age cohorts. Until now the VS method has been used only in making estimates of total net migration.The results obtained by using the VS method for age cohorts show that (1) the average census survival rate (CSR) method generally yields algebraically lower estimates of net migration than does the VS method; but (2) there are some striking exceptions which are apparently associated with errors in census enumeration by age, sex, and color. Comparisons between the average CSR and the VS methods are shown, by age, for both the North Carolina and the coterminous United States populations.A cursory examination of these comparisons suggests that the exclusive use of the VS method in estimating net migration for age cohorts may lead to substantial error. Finally, the magnitude of these errors in estimating net migration, as well as in census enumeration, can be roughly approximated if it is assumed that the use of the CSR method yields reasonably accurate estimates of net migration. PMID- 21318665 TI - Internal migration in the USSR: 1897-1926. AB - The purpose of this study is to describe and to analyze internal migration in the USSR primarily by the use of data from the 1926 census of the USSR. The article is divided into two parts. The first is devoted to a description of the aggregate and regional migration patterns based on place-of-birth data. The second is an analysis of these migration patterns, primarily in terms of economic differentials by guberniya. Because only limited income data are available for the period around1926 and because other economic data are scarce or unusable owing to boundary changes, census data on labor force distribution, literacy, and urbanization are used as substitute variables to approximate income differences.Migrationis a complex phenomenon related to a host of factors. The present study does not presume fully to explain migration in the USSR, but it does attempt to isolate differences in income and to relate these to the internal migration that occurred during this period. As a result of processing and analyzing an extensive array of data, we have shown that differences in income, derived indirectly from a variety of data, are closely related to internal migration in the USSR in the period prior to the 1926 census. There were striking similarities in respect to internal migration between the period prior to the 1897 census and the period prior to the1926 census. The chief areas of out migration and in-migration were roughly the same,and migrants in both periods moved primarily to areas of higher income. PMID- 21318666 TI - Future trends in world population growth. AB - Because world population growth is marked by differing trends in the more developed and developing regions, the successful solution of future social and demographic problems will depend, in all likelihood, on whether population growth is considered in isolation or as a problem which is inextricably interwoven with other leading features of social and economic development.Both total population growth and changing age structure produce new economic and social problems, and within both the more developed and the developing regions, there are sub-areas in various stages of development. First, together with the total estimated increase in working-age population, there will be substantial differences in age structure. Although the proportion of world population of dependent age is expected to go down, up to 1980its level will be higher than in 1960, owingto an upward tendency in developing regions, where the "heavy youth dependency" is so extraordinarily high that even in 1980 there will be about ten children to every old person, and at the end of the century, more than seven. It is estimated that in the more developed regions there will be twenty-five to every one-hundred old persons in 1980, and twenty-two in the year 2000. This shows that heavy old-age dependency will have arisen in these regions. Second, the dependency ratio will probably grow, moreover, as a consequence of the degree of economic activity and variation. Although there will bea decrease in the proportion of dependent children, these will still constitute over one-half of the dependents in all areas. These forecasts seem to indicate that the changing structure of dependency and the increase in its total volume may be expected to create problems, particularly in the developing regions. Third, working life tends to become longer as a result of declining mortality, and this, combined with rising labor force replacement levels, will result in an increased total labor supply.While such an expansion of world population obviously emphasizes the quantitative aspect of population problems, structural and qualitative aspects seem to be of equal importance. But these aspects are largely overshadowed by the growth problem, for growing numbers of people have more and more needs: the inflow of people into schools, into the labor market, and into towns and cities will be apparently unprecedented.In recent years circumstances have not favored the development of conditions needed for rapid change in reproductive behavior in the developing regions. The mobilization of resources and the adaption of different types of society in view of the future growth of total population-with emphasis on the less-developed regions-will be one of the most important challenges to mankind's ability to meet its own needs.The main value of the calculations of various characteristics of future population growth discussed in this paper is to show "in the light of contemporary information" future trends and some relationships of world population of world population growth to economic and social development. PMID- 21318667 TI - Estimating interregional population and migration operators from interregional population distributions. AB - A common constraint in analyses of interregional population systems is the absence of reliable data for describing the behavior of the fundamental components of population change. As a result, demographers frequently have had to rely on crudely constructed measures of natural increase and net migration.Recent efforts to express interregional population growth in matrix form, however, suggest a method for estimating the regime of growth of a multiregional system solely on the basis of historical data on interregional population distributions. This paper describes and illustrates such a method. Since the results are largely unsatisfactory, a large portion of the paper is devoted to an analysis of the conditions leading to the poor performance of the method, by evaluating, in particular, alternative estimators and by considering the possibility of "data smoothing." PMID- 21318668 TI - Migration in the southeast. AB - Between 1940 and 1960 the Southeast experienced both economic and demographic revolutions. They were interrelated in many ways. Agriculture was mechanized and reorganized making millions of farmers and farm laborers surplus. The natural assets of the region were developed and industry grew more rapidly than in other regions. There were marked changes in the labor force, a rapid increase in the proportion of women employed and a decrease in the proportion of Negroes. The level of family income rose faster than in other regions.Five and three quarter million persons were transferred from the farm population. A net of 2.7 million left the region and 3 million were absorbed in nonfarm areas within the region. In 1960 52 percent of the population was in cities. Increase was especially fast in metropolitan urban areas, mostly in suburbs. There were also substantial increases in the rural nonfarm areas. Small cities as a group showed no net in migration. Among the net migrants out of the region the ratio was 4 colored to1 white.The age and sex distribution was warped, especially below age 30, slowing down the early marriage rate and the crude birth rate.The projection of the trend which was being followed in the early 1960s indicates that the regional rate of increase may overtake that of the rest of the country, being particularly rapid in the young adult and adolescent ages.For the purposes of this study the Southeast includes: South Carolina, Georgia, Alabama, Mississippi, and Louisiana. These were originally the heaviest cotton producing states and the heart of the sharecropping area where the reorganization of the economy was particularly disruptive. PMID- 21318669 TI - Duration of residence and prospective migration: the evaluation of a stochastic model. AB - The objective of this paper is to evaluate the empirical accuracy of the Cornell mobility model. Migration is formulated as a stochastic process governed by non stationary probabilities: during a given interval of time, an individual is presumed to undergo a risk of migrating that decreases as he continues to reside in the same community. The major hypothesis, then, is that a person's propensity to move declines as his duration of residence increases.A secondary hypothesis proposes that age interacts with this relationship. Longitudinal data (5,000 residential histories from the Netherlands system of population registers) were analyzed and translated into prospective probabilities that are age- and duration specific.Both hypotheses were substantiated. Specifically, the relationship is negative, curvilinear, and varies significantly by age. To facilitate simulation analysis of the model, the relationships found in the data are summarized in a set of logarithmic prediction equations.The findings of this paper underscore the fundamental limitation of stationary probability models in portraying migration and suggest that the non-stationary alternative is a more accurate formulation. More generally, processes of change which bear only a formal resemblance to migration (for example, brand switching or attitudinal change) may be governed by a principle of cumulative stability too. The evidence warrants further inquiry into the applicability of the model to other social processes where inertialike factors operate. PMID- 21318670 TI - Residential segregation in the mid-sixties. AB - Special censuses conducted by the Bureau of the Census at the request and expense of local governments provide current statistics for many large cities which are compared with corresponding data from the1960 Census. An analysis was made of the changes in the racial composition of the cities, and of the areas within the cities (defined by census tracts) which had a high concentration of Negro population in 1960 for ten cities of 100,000 or more population at mid-decade.As in the 1950-60 period, Negroes continue to move into the central cities of metropolitan areas while white persons continue to move out to the suburbs at a faster rate, and this results in net declines in the populations of the cities. The proportion of nonwhite persons living in areas of high Negro concentration has remained about the same or increased slightly in a majority of the cities, while in a few (such as Cleveland, Rochester, and Raleigh) this proportion has declined; that is, relatively more Negroes in these cities now live outside the ghetto neighborhoods. When the racial composition of the ghettos is examined, however, a higher proportion of the residents are now Negro when compared to 1960 in each of the ten cities.Thus, the concentration of Negroes in ghetto areas has shown little change, but the trend of white persons moving away from the Negro neighborhoods, either to other parts of the cities or to the suburbs, has increased sharply, and this has tended to polarize the Negro and white populations within large cities. PMID- 21318671 TI - The impact of family planning on fertility in a rural area of East pakistan. AB - This pape revaluates a family planning pilot project conducted by the Pakistan Academy for Rural Development in Comilla, East Pakistan. The evaluation is based upon an analysis of the extent to which adoption of conventional contraceptives (condoms and foam tablets) has reduced fertility in selected villages of the Comilla-Kotwali precinct, during the years 1962-66.The study was carried out by comparing adopter and non-adopter rates of pregnancy and analyzing the trends in pregnancy reduction that resulted from adoption. The findings indicate that (1) although the pregnancy rate of adopters has increased steadily throughout the time period, in 1966 the rate is still less than half of what was expected had adoption not occurred; (2) contraceptive use-effectiveness decreases with length of time of use; and (3) pregnancy reduction has been declining since 1964. PMID- 21318672 TI - Knowledge and use of birth control in barbados. AB - Based on material collected in Barbados in 1964, this paper examines knowledge and use of birth control in terms of three types of family union-married, common law, and visiting. Analysis of knowledge of birth control is dealt with for the sample at large, for educational attainment, and for the average number of methods known by each woman. The relative importance of the different methods known is also treated by family type and education.The extent to which women in the sample make use of birth control is discussed from four aspects. First, the growing use of the different methods among younger-age cohorts is made evident from tabulations of methods-last-used. Second, information on the agencies and individuals recommending the use of different contraceptives emphasizes the degree to which the partner's influence is responsible for resort to birth control. Third, the proportions of users in religious groups show that religion is not a barrier to the use of any method. Fourth, the material is treated from the standpoint of age cohorts, since there is, in many cases, a vagueness as to the age at which use began, although women are able to identify the inter pregnancy period when use began. PMID- 21318673 TI - Communication and diffusion of the iucd: a case study in urban india. AB - In this study the diffusion and adoption framework is used to investigate a family planning innovation. The study indicates the utility of this framework from an analytical point of view both for the researcher to the process by which family planning comes to be adopted, and for the administrator to understand the working of the communications elements of his program.The data indicate that different communications media and informal communications networks are used at different stages of the adoption process. At the awareness stage, messages emanating from the family planning administration make their biggest impact. At the later stages of interest and evaluation, local sources of information become important, and interaction with the clinic staff takes place at high rates.Both husbands and wives are involved in the communications processes, but they have different communication patterns. Both are also involved in the final adoption decision-making processes. PMID- 21318674 TI - Interaction and family planning in the french urban family. AB - During the last two years, a survey about interaction in the couple has been conducted among 550 urban families in France by the National Center for Scientific Research, with the assistance of the United States Public Health Service. The data given here are relative to the importance of the couple's interaction in the realization of family planning goals.These data are used to answer the question, are socioeconomic variables (husband's level of education, occupation, and income, for example) more closely correlated with the success of the couple's family planning than are the variables of positive interaction (agreement, communication, and equality in decision-making, for example)?While the Indianapolis study has not answered this question, the Puerto Rican study has shown that freedom of the wife and communication between spouses were more closely connected with the success of family planning than were the husband's level of education or income. But, one might think that this result was linked to the Puerto Rican sample, in which the levels of income and education were generally low.The French survey, undertaken with a random sample stratified according to the socioeconomic level of the husband, shows that this last hypothesis is not true. Just as in the Puerto Rican study, the factors of positive interaction in the couple are more closely associated with the success of family planning-particularly with the eradication of excessive fertility-than with socioeconomic variables. These results show the importance of the couple's education as a determining factor in a successful family planning program. PMID- 21318675 TI - A study of differential fertility in bombay. AB - This study is based on special tabulations of the "order of pregnancy," as reported on the birth certificate, according to mother's age, locality, and religion and father's state of birth and duration of stay in Bombay, India. The sample consists of 50 percent of the births registered in 1960 in Bombay (where birth registration has a fairly high degree of completeness).Despite the limitations of statistical information on the complex of factors influencing fertility, it wasfound that three indicators derived from the 1961 census could numerically account for 51 percent of the total variance of the parity averages in the sections of Bombay. Overcrowding (which is an indicator of the level of living) had the strongest influence and accounted alone for 44 percent of the variance. Knowledge of thereligious patternraised thepercentage to49, whileinclusionof theilliteracy measure added only another two to this percentage.An assessment of fertility differences by religious groups, as well as by place of origin of the father, is then carried out. The data show significant differences among religious groups, with Moslems and Buddhists having the highest parity averages, followed by Hindus and Jains. A considerably lower level is shown by Christians, but the lowest parity level is that of the small Parsi community. Mothers whose husbands were born in the south and east were found to show the lowest parity level, while those who have north-born husbands showed the highest level.Finally, the data show consistent increase in age-standardized parity averages with increase of the duration of stay in Bombay. This pattern is observed for each of the three main geographic regions of origin. While this increase is difficult to explain on the basis of the available data, the fact that the pattern of parity differences among regions persists from one duration group to the next lends support to the conclusion that little assimilation seems to have been taking place. PMID- 21318676 TI - Fertility differentials in early postwar malaya. AB - During theearlypostwar years up to1957, the three main races in Malaya-Malays, Chinese, and Indians-experienced some differences in their levels of fertility. The lowest fertility was recorded among the Malays, with Chinese and Indian fertility about 5 percent and 10 percent higher, respectively. The comparatively low fertility of the Malays was owing to the exceptionally high rate of divorce, which meant unstable marriages and shorter periods of exposure to the risk of childbearing.A fairly well-defined pattern of state differences in fertility levels is found to exist in Malaya. Briefly, fertility was on the high side in the northern states of Johore, Malacca, and Negri Sembilan, and on the low side in the northern states of Penanq, Kelantan, Perlis, Kedah, and Trengganu, with the central states of Perak, Selangor, and Pahang in the intermediate position.The usual rural-urban fertility differentials are seen to prevail in Malaya as a whole and in the smaller units at state levels. Finally, the three main races registered higher fertility in rural areas, and the greatest gap between rural and urban rates prevailed among the Chinese. PMID- 21318677 TI - Modernization and tradition in the recent history of italian fertility. AB - The secular decline of Italian fertility, started in the last decade of the nineteenth century, came to an end in the early 1950'sand has recovered slightly in the last fifteen years. Italian experience seems to follow, with a twenty-year lag, the experience of the more advanced western European populations. At present, with an average of 2.5 children per marriage, Italian fertility is very close to the French and to the average European level.At the regional level, two contrasting patterns can be detected. On one side stands the very low fertility of the North and of the Center, mostly below replacement in the last thirty years;on the other, the still high fertility of the South.In the North and in the Center, where the decline started earlier, fertility has fallen well below replacement level in the last thirty years. In the South, where the decline started in the late 1920's and early 1930's, a large family system still prevails, and the spreading of voluntary control faces barriers setup by a long historyof cultural isolation,attachment to tradition and religion. In the last 15 years, however, the gap has narrowed slowly, more because of an upturn of fertility in the North and in the Center than because of the decline in the South.Another interesting feature of Italian fertility is low class differentials: the fertility of the most prolific segment (farmers, farm laborers) is only 20 percent higher than the fertility of the less prolific professional groups. Finally, Italian experience provides an interesting example of the changing relationship linking the economic level of the population and fertility changes; in 1931-51 a negative correlation linked the changes in fertility to the economic level of the region, while in 1951-61 and 1961-66 a very high and positive correlation can be observed.As for the future trends in fertility, two factors may have an important role. In the first place, on the one hand, the economic policy of the government, aiming at reducing the economic gap between the South and the rest of the country, may accelerate the leveling of regional fertility differentials. The same effect, on the other hand, may be reached by more liberal legislation, now under way, for birth control and family planning propaganda. PMID- 21318678 TI - Seasonality of coitus and seasonality of birth. AB - Seasonal variation of birth rates has been observed in every population in which it has been studied. Many hypotheses have been advanced to account for the variation, including seasonal variation in frequency of coitus. This relationship is known to be true for other primates, but seasonal variation in coital rate has not been previously documented in man.This paper presents over one hundred woman years of data on coital rates from about .fifty white, mostly well-educated, premenopausal, married, husband-present volunteers. Seasonal fluctuations were seen in coital rates, of about the same magnitude as seasonal variations in the white birth rates reported for New York City, 1962-64; for the United States, 1963; and for the highest socioeconomic quintile census tracts, Baltimore, 1952 56. However, shifting the birth rates back forty weeks to approximate conception dates revealed no association with the observed coital rates.If the pattern presented has great generality, seasonal variations in births cannot be explained by seasonality of coitus. PMID- 21318679 TI - Asymptotic properties of a human age distribution under a continuous net maternity function. AB - A useful and intuitively appealing proposition in theoretical demography asserts that the age distribution of a closed human populationis asymptotically independent of this shapein thedistant past, and is therefore exclusively determined by the historyof fertility and mortalitythat has prevailed during a reasonably long period of time. The mathematical foundations of this ergodic principle arelaid out in this article and thedetailsof its proofareworked out afteremphasizing an intuitive understanding of the process through which an age distribution tends to "forget" its past. The tendency for an unchanging schedule of vital ratesto produce a fixed agestructure in a closed population, is presented as a corollary of the main proposition dealt with in this article. PMID- 21318680 TI - Estimation of the birth rate for the congo through nonconventional techniques. AB - This paper attempts to produce a set of alternative estimates of birth rates for the Congo and for its main regions through nonconventional techniques. The main body of data used for this purpose is supplied by the demographic survey undertaken during 1955-57. Two types of information on fertility are produced by this survey: (1) births to women by age during the 12 months preceding the survey and (2) children-ever-born to women by age. The available data, while reliable in certain respects, are deficient in others. Thus, the reports on children born during the year preceding the survey are acceptably accurate for the children who have survived but are insufficient for the children who have died.The task was to make the best possible use of various reliable pieces of information directly or indirectly related to fertility, in order to produce some reasonably acceptable estimate of birth rate. One procedure consisted of correcting the reported birth rate for the omission of infant deaths; another procedure involved the adjustment of the reported birth rate with reference to the mean parity of women. In addition to these, an estimate of birth rate was derived by means of stable population technique from the proportion of children under 5 years of age.Three sets of estimates of birth rate, then, have been produced. They yielded a high agreement for the country as a whole, as well as for the provincial and district levels. These estimates were then compared with the proportion of childless women and the proportion of children-the latter having been derived from the records of "continuous registration of inhabitants," a source of information which is completely independent of the demographic survey of 1955-57. Again, a reasonable agreement has been found among all these estimates.Statistical evidence examined in this paper supports a birth rate of about 45 per 1,000 for the Congo. The analysis reveals a high regional variation in birth rate: from 20 per 1,000 (Bas Uele) to 60 per 1,000 (Kivu). This variation is consistent with the variation in sterility level as evidenced by the proportion of women never having had a live birth. The proportion of childlessness varies from 5 percent (Kivu) to about 40 percent (Bas Uele) for women past child-bearing age. PMID- 21318681 TI - Survivorship of sons under conditions of improving mortality. AB - The strong desire of fathers to be assured that at least one son will outlive them, coupled with the traditional belief in a high probability of sons predeceasing their father, is often a deterrent to restriction of family size. A calculation of the probabilities of survivorship of sons on the basis of the United Nations Model Life Tables, however, shows that the probabilities of a father being outlived by even one son are remarkably high, particularly after that son has survived the first two years of life. When cohort tables are used, reflecting expected mortality improvements, the probabilities are even higher. In general, it is found that the probability that a two-year-old son will outlive his father is 80% or better, subject to the current mortality level and the age of the father.Finally, this paper examines (1) probabilities of a father being outlived by at least one of two or three sons, (2) probabilities of a mother or of both parents being outlived by a son, and (3) the probability that at least one of two sons will outlive a father when allowance is made for the fact that mortality probabilities of the sons are not independent of one another. PMID- 21318682 TI - A size-function typology of cities. AB - In this article the characteristics of an ideal system of classification are presented, and a new system for the classification of urban areas is developed which has these characteristics. Both economic function and size are used as criterion variables for classifying urban areas under this new system. The paper demonstrates the superiority of the size-function system over the purely functional systems and presents a size-functional classification of all urban areas in the United States with over 10,000 population in 1960. PMID- 21318683 TI - An empirical examination of megalopolitan structure. AB - Recently, the emergence of a new community form has attracted considerable attention. Gottmann has written of the "megalopolis," and others have written of the development of "urban fields" which will replace the traditional concepts of "city" and "metropolis." The belief underlying these efforts is that an increasing intermetropolitan division of labor is bringing about a new type of community. Now, if we are to understand the process of urbanization in an industrialized society which is characterized by constantly shrinking spatio temporal barriers, it seems necessary to determine if a new community form actually is present.This study of the metropolitan northeastern portion of the United States utilizes Census data on the industrial composition of the labor force in 1950 and 1960, and compares the variance of location quotients in various industries with that in retail food in an effort to determine whether there has been increasing economic differentiation. The author finds scant evidence of an increasing intermetropolitan division of labor and questions the validity of "megalopolis" as a community form. PMID- 21318684 TI - Considerations in determining the content of the 1970 census. AB - This paper describes some of the factors that are being considered in planning the content of the 1970 Census. The key factor, is the conclusion by the top Bureau officials that the major needs for data in 1970 can be met by a schedule whose content is similar to that used in 1960. Although there will be some disagreement with this conclusion, it is based on a widespread sampling of opinion in which all interested parties were invited-indeed urged-to present their views.This framework places serious limitations on the opportunity to introduce innovations in schedule content. Since there appears to be no good reason-technical or otherwise-to drop items that were included in 1960, it is not likely that new items will be traded off for old ones. There also does not appear to be any good prospect that it will be possible for new items to be financed by savings in field procedures such as the mail-out mail-back approach. According to the best current estimates, this procedure may produce better coverage and a substantial capital improvement in the form of an address reqister; but it is not likely to result in any major savings in cost.The major innovation in the results produced by the 1970 Census will probably be in the greater availability of data for more small areas. It does not seem likely at present that there will be significant changes in content. PMID- 21318685 TI - Projected innovations in the data delivery system for the 1970 census. AB - One of the critical pieces in the data-access puzzle is knowledge of the user's needs, for with this knowledge, creating data access would be relatively simple. But this knowledge can never be fully developed because unpublished census data are used for unanticipated problems.Many needs are known, however, and with a flexible definition of census results, there is some chance of meeting unanticipated needs. Now, a flexible definition would be: "a collection of basic data, edited summaries of these data, and a set of techniques for using the collection and summaries." This definition emphasizes software and organizational arrangements that permit flexibility in fulfilling the user's ever-changing analytic requirements. The results will represent a rudimentary information system.Using this definition, the Bureau is engaged in many activities. Pertinent developments are (1) a laboratory for the development of data-access and use problem solutions; (2) a census-data files-documentation center; (3) a dictionary of universe definitions and of a universe index-code system for concepts; (4) analytic computer programs for comparing characteristics of many small areas; (5) computer-prepared demographic maps and charts; (6) evaluation of social indicators based on census data; (7) data-processing capability at non-Bureau sites; (8) data-access descriptions of new techniques; and (9) a data-needs clearinghouse designed to eliminate duplication. PMID- 21318686 TI - A comparison of different survey techniques for obtaining vital data in A developing country. AB - This article presents estimates of the sources and the extent of observation errors in different questionnaires and methods used to collect birth and death data in the 1961-63 multi-purpose sample survey of Morocco.The questionnaires used in the analysis of the three survey rounds were a list of household members (Rounds1 and 2) and a roll-call (Round3); retrospective death (Rounds1, 2, and 3) and birth (Round 3) queries; a date-of-birth tabulation (Round 2); and a household check-sheet to explain differences between Rounds 1 and 2. All available questionnaires for a given household were brought together and collated to provide several sources of information on births and deaths and a basis for assessing errors.From this analysis, the survey attempted to define the nature and to estimate the frequency of the errors which would have occurred if more restricted types of survey design had been used. Results, based on the period between Rounds 1 and 2, led to three major conclusions.First, if vital data had been collected with a single-round retrospective procedure, gross error (over enumeration plus underenumeration) would have been 17 percent for births and 36 percent for deaths. There is a net error of overenumeration of 3 percent for births (1.4 per1,000population) and 9 percent for deaths (2.3 per1,000population).Second, if two rounds were available to permit a combination of household composition follow-up and a retrospective mortality questionnaire, overenumeration would be almost entirely eliminated and underenumeration would be noticeably reduced. Third, most of the remaining errors of underestimation may be attributed to (1) an estimated number of infants born and deceased between two rounds and missed by all questionnaires, (2) matching failures caused by the absence of adults at Round 1, and (3) matching errors. PMID- 21318687 TI - Demographic and economic correlates of development as measured by energy consumption. AB - Per capita consumption of energy in 112 world areas was related to a series of economic and demographic variables. Linear associations were found for four economic variables, and a curvilinear association in the form of a J curve for four demographic variables. It was found that the exponential distribution y = e( X) for the curves for the demographic variables (crude birth rate, infant mortality rate, percent of deaths from contagious and infectious diseases, and life expectancy). By using a table of exponential functions, one can determine values for the distribution of these variables and the crude death rate for any desired level of energy consumption. PMID- 21318688 TI - Attitudes toward family size and family planning in nairobi. AB - In Nairobi, 352 married African adults, 152 men and 200 women, were interviewed on their attitudes toward family size and family planning. The respondents had, on the average, slightly less than three children at the time of interview and hoped to add slightly more than three children to this total. There was little difference in desired family size by sex.About one-half of both men and women had some knowledge of family planning methods, and there was a general interest (75 percent of the men and 90 percent of the women) in learning more. In addition, two out of every three men, and nine out of every ten women, approved of family planning, and even greater majorities of both sexes were willing to have the government of Kenya provide such services.In spite of their approval, however, only 13 percent of the men, and 2 percent of the women, had ever practiced family planning. These findings are broadly comparable to those found in other emerging nations and suggest that knowledge, interest, and approval generally precede use. PMID- 21318689 TI - Recent immigration and studies of ethnic assimilation. AB - Studies of ethnic assimilation are frequently based upon status comparisons between the foreign born and their "children," the second generation. The assumption that recent immigration has been negligible and that the foreign born represent a closed population is implicit in that procedure. However, analysis of official statistics indicates that immigrants who arrived since World War II now comprise a substantial share of the foreign-born population, while the foreign born who arrived before quota restrictions are rapidly being depleted by mortality. Recent immigrants, as intended by quota legislation, are of much higher socioeconomic status than immigrants who arrived before World War 1. Hence, characteristics of both recent immigrants and earlier arrivals are confounded in data for the foreign-born population. Existing data do not permit rigorous assessment of this confusion or adequate control for it. This paper suggests that tabulations of the foreign born by "year of arrival" would improve the sociological utility of data for ethnic groups. PMID- 21318690 TI - The japanese americans: Comparative occupational status, 1960 and 1950. AB - This paper uses 1950 and 1960 census data on the demographic, educational, and occupational distributions of Japanese Americans, after the enforced migrations of the Second World War, in order to compare the achievement of the urban Japanese Americans to that of their white counterparts.First, the data show that the Japanese-American population has increased in all regions of the nation, especially in the representative West (from 71 percent in 1950 to 82 percent in 1960). Second, educational attainment, which was about equal to that of whites in 1950, was better for males, and increasing at a faster rate or better for females, in 1960. Third, while in 1950 the differences in the occupational distributions of Japanese Americans and whites showed concentrations unfavorable to overall Japanese-American occupational structure, by 1960 the Japanese Americans had approached the levels of the white majority.The data, then, permit the author to conclude that if "minority" means full exclusion from participation in the life of society, the Japanese Americans cannot be called a minority. In conclusion, the author suggests that it would be useful to investigate the migration patterns of the Japanese Americans, for if redistribution has resulted in integration, will integration promote greater mobility to attain better integration? PMID- 21318691 TI - A reconsideration of negro-white mortality differentials in the united states. AB - This paper summarizes the results of an investigation of the validity of Negro white mortality differentials as reflected in the series of official United States life tables since the turn of the century. Pertinent excerpts from these often-quoted tables are reproduced in Appendix Table A-1 for convenient reference. The paper divides into two main parts.First, mortality levels and differentials beyond early childhood are derived, without use of the existing vital records, by interpreting the series of ten-year cumulative survival rates implicit in the census records for native whites and for Negroes. The results are in general agreement with the official figures, particularly for males.Second, mortality levels and differentials in early childhood are estimated by extrapolating the official 1)5 values via model life tables; that is, by the analytical procedure that would be followed in the absence of direct information on early childhood mortality. Unless it is assumed that age patterns of death for United States Negroes were extremely deviant from those found in populations with reliable census and vital statistics, one must conclude that the official figures grossly underestimate early childhood mortality for Negroes, at least for the period, 1910-40. It follows that, during those decades, Negro-white mortality differentials in terms of expectation of life at birth were also substantially higher than is suggested by the official estimates. PMID- 21318692 TI - Computer models of social processes: the case of migration. AB - The demographic model is a program for representing births, deaths, migration, and social mobility as social processes in a non-stationary stochastic process (Markovian). Transition probabilities for each age group are stored and then retrieved at the next appearance of that age cohort. In this way new transition probabilities can be calculated as a function of the old transition probabilities and of two successive distribution vectors.Transition probabilities can be calculated to represent effects of the whole age-by-state distribution at any given time period, too. Such effects as saturation or queuing may be represented by a market mechanism; for example, migration between metropolitan areas can be represented as depending upon job supplies and labor markets. Within metropolitan areas, migration can be represented as invasion and succession processes with tipping points (acceleration curves), and the market device has been extended to represent this phenomenon.Thus, the demographic model makes possible the representation of alternative classes of models of demographic processes. With each class of model one can deduce implied time series (varying parame-terswithin the class) and the output of the several classes can be compared to each other and to outside criteria, such as empirical time series. PMID- 21318693 TI - Occupational classification. AB - The need for a common occupational classification system has begun to outweigh the importance of the precision of a multipurpose classification system. Recent multiplication, in government, of sources of occupational statistics, the variety of uses to which occupationally classified data are now put, and the theoretical dissatisfaction shown in recent literature make it desirable that a single, standard classification system be developed for all agencies.Work is now starting on a standard classification system (presently in the major group of professional, technical, and related workers). Although final results will not be available for use in the1970 Census, there is detailed effort to reduce the large residual census categories and to develop a more detailed list of classifications for that Census. The statistician should beaware that work is in progress on one of the classifications of growing importance to him. PMID- 21318694 TI - A note on the accuracy of male responses to questions on fertility. AB - There seems to be little doubt that reliablefertility information can be obtained from Latin A merican women. The question remains, however, whether such information can be obtained from males. This paper presents evidence on the accuracy of reports of the number of live births collected in a survey of 1,640 male residents of the Monterrey, Mexico metropolitan area. The accuracy of the number of live births recorded in this survey is evaluated on the basis of (1) internal consistency, (2) the Mexican census, and (3) previous investigation. The present analysis indicates that the information collected is of good quality and potentially useful for several types of fertility analysis. No evidence was found of underreporting. PMID- 21318695 TI - The distribution of sums of rounded percentages. AB - When percentages are computed for counts in several categories or for several positive measurements0 each taken as a fraction of their sum, the rounded percentages often fail to add to 100 percent. We investigate how frequently this failure occurs and what the distributions of sums of rounded percentages are for (1) an empirical set of data, (2) the multinomial distribution in small samples, (3) spacings between points dropped on an interval-the broken-stick model-; and (4) for simulation for several categories. The several methods produce similar distributions.We find that the probability that the sum of rounded percentages adds to exactly 100 percent is certain for two categories, about three-fourths for three categories, about two-thirds for four categories, and about [Formula: see text] for larger numbers of categories, c, on the average when categories are not improbable. PMID- 21318696 TI - Errors in chinese age statistics. AB - The first section of this paper is devoted to an analysis of some theoretical aspects of the Chinese system of reckoning ages, and the second section offers a method of collecting the age statistics of a Chinese population: A discussion of the errors found in the age returns and the unsuccessful measures taken to eradicate these errors in the Malayan censuses conducted prior to1957 leads to an appraisal of the method of collecting Chinese age data in the 1957 census. PMID- 21318697 TI - A Standardized dependency ratio. AB - The dependency ratio is a measure of the effect which demographic factors exert on standards of living. It is usually defined either as the ratio of the young and the aged population to the working age population, or as the ratio of the population which does not participate in the labor force to that which does. But the consumption requirements of dependents may vary with their age. Therefore, variations in the real burden of maintaining a dependent population need not be positively associated with variations in its relative size; for example, when a decrease in the relative number of all dependents is accompanied by an increase in that of the aged.Furthermore, under the labor-force participation definition of dependency, inter-temperal and international variations are complicated because the population's average participation rate does not vary only with changes in its age distribution, but with changes in the social norms which regulate working habits.In this paper, adult-equivalence scales derived from family budget studies were used to make dependents of various ages comparable in terms of the maintenance burden they create. Similarly, constant labor-force participation rates were used to obtain estimates of the size of the population carrying this burden. When thus estimated, international differences in the dependency load are shown to be much smaller than is suggested by the normally used unweighted index. PMID- 21318698 TI - The Pattern of Age-Specific fertility rates. AB - A study of the pattern of age-specific fertility rates by five-year age-groups has revealed the possibility of using the Pearsonian type I curve as a graduating equation. Such distinctions have been examined for fifty countries having high, medium, and low fertility rates. Results have been found to be quite satisfactory, even when, for purposes of simplicity, the parameters have been restricted to depend on the first two moments, instead of the first four. The number of independent parameters has thus been reduced to only three, and method shave been suggested for their estimates, using ancillary information which is usually provided in the census reports. The findings seem to be particularly useful for countries lacking effective registration systems of vital events such as births related, as they are, to the age of the mother.In short, the determination of a series of age-specific fertility rates depends primarily on the modal fertile age (a1) and on one of the two exponents (m, or m2) of the type I distribution. It has been shown that the proportions of women married in the age groups 20-24 years and 25-29 years can be used for approximate evaluations of both of these parameters. While estimates of a, and m, are sufficient to generate a relative distribution of age-specific fertility rates, actual values can be obtained if, in addition, the annual number of births is either known or can be estimated from census age distributions of children.Modal distributions of relative values of age-specific fertility rates (such that the sum of these rates adds up to 100.0) have also been obtained for different combinations of al and m1, but are not shown here for lack of space. Once the estimates of al and m, have been made, the modal tables can always be referred to for the corresponding distributions of age-specific fertility rates. PMID- 21318699 TI - On measuring the marriage squeeze. AB - During the 1960's, single men have been marrying at an increasing rate, and single women at a decreasing rate. These trends can be explained almost entirely by disproportions between the sexes at the prime ages of marriage-that is, by what is commonly called the "marriage squeeze." The disproportions arose from the increase in births during the period 1939-47, coupled with the fact that women marry earlier than men.These changes in marriage patterns must certainly have some effect on the birth rate and on household formation, although perhaps a secondary one. The consequences of these changes are a project for further inquiry. PMID- 21318700 TI - Premarital pregnancies and out-of-wedlock births in denmark, 1950-65. AB - Although comprehensive investigation of child spacing patterns requires consideration of those births that were conceived before marriage, detailed data on such births often are not available, especially in the United States. Danish statistics on first births by duration of marriage and on out-of-wedlock births permit evaluation of trends in premarital pregnancies. For the period 1950-65, they point to (1) a rise in the percentage of all brides who are pregnant at marriage; (2) an increase in the proportion of first births occurring within both six and nine months of marriage; and (3) a rise in out-of-wedlock births.The trend for the country as a whole also characterizes Copenhagen, but at a higher level, and this reflects the capital's more urban character, greater permissiveness, and attraction to young migrants. Age differentials indicate that as high as 90 percent of all first births among married women aged under 20 years and over 50 percent of those to women aged 20-24 years are premaritally conceived. The rise in the number of first births among young women largely accounts for the overall rise in the level of premarital conceptions. Compared to its suburbs, Copenhagen in 1965 had higher levels of premarital conceptions. The overall residential differential stems both from higher proportions of such births in all age groups in Copenhagen (but especially those aged 20 years and over) and from the fact that Copenhagen has proportionally more first births occurrinq to women aged under 20 years, the age group in which the rates of premarital conceptions are especially high. PMID- 21318701 TI - The study of urbanization. AB - Seven years' work of the Committee on Urbanization of the Social Science Research Council has produced The Study of Urbanization. Although the book is an excellent series of documentations of trends in specific fields, it lacks any attempt to unify the contributions to a concise definition of urbanization.Most contributors view urbanization as a process of aggregation, but this is no more than a rough indicator of the fundamental processes at work, and each discipline explores only the matter confined to its assigned segment of the process. Thus, for example, the city is viewed as a sub-division of localized space; as a complex of markets for land, labor, housing, and goods and services; or as a set of market-social units. From what is offered in this volume, then, one is led to think that sociology cannot find a comprehensive approach to fashioning a general model of urbanization.While three papers come close to defining urbanization as substance and process and are an orderly account of at least the salient features of urbanization through early, transitional, and late phases, urbanization as a process in different areas and cultures is a subject which is treated casually. While the very concept of urbanization implies the recurrence of common features, a set of criteria for avoiding preoccupation with the exotic and inconsequential in different cultures is still needed. We need to study the significance of the fact that peoples of various parts of the world have entered urbanization at different points in industrial, institutional, and administrative technology. Here, organization, the most commonly agreed upon variable in this book, is not a sufficient explanation.In sum, the subject is too broad for close agreement, but the failure of the book to achieve its objective is counterbalanced by the individual quality of the contributions. PMID- 21318703 TI - Communications from readers. PMID- 21318704 TI - Application of life table techniques to measurement of contraceptive effectiveness. AB - Two problems are associated with the analysis of use-effectiveness of contraception. First, couples belonging to a sample of contraceptors typically vary in their monthly chances of contraceptive failure. Second, one does not observe for many, and perhaps a majority of the couples, how long they can remain protected with the contraceptive, because either they are stopping contraception to plan a pregnancy or else observation of them is being interrrupted by lost contact, by discontinuation of contraception for other reasons, or by the end of the study. It is argued that because of these two problems-namely, sample heterogeneity and incomplete histories-the Pearl pregnancy rate, which has been traditionally used to measure contraceptive effectiveness, is inadequate.A life table method is described that permits one to combine incomplete histories with complete ones for purposes of estimating the proportions of the sample that might have remained protected for specified periods if all members had remained under observation for these periods. The versatility of the techniques is illustrated in relation toa retrospective survey. A detailed account of procedure is given. Finally, it is shown that only under specialized conditions that are rarely met in practice is it possible to estimate the results of the new technique from knowledge of Pearl pregnancy rates alone. PMID- 21318705 TI - Recent developments in seasonally adjusting vital statistics. AB - Birth rates, marriage rates, and death rates computed on a monthly basis have exhibited relatively stable seasonal patterns over a period of years. Elimination of these seasonal fluctuations facilitates the description and interpretation of month-to-month changes in the underlying trend of the rates. Several methods have recently been developed, using an electronic computer, to identify and remove the seasonal component from time series of monthly data. The methods are basically adaptations of a standard technique-the ratio-to-moving average method-for seasonally adjusting time series.The application of seasonal adjustment programs by electronic computer to vital statistics yields useful information about their seasonal component and provides a means to estimate the trend of current as well as retrospective data. Seasonally adjusted birth, marriage, and death rates for recent years are shown.Continuing research should yield better approximations of the trend for birth and marriages and improved methods for isolating the epidemic component of mortality time series. PMID- 21318706 TI - Family growth and family planning: Responses to a family-planning action program in a rural district of Thailand. AB - A resurvey of a rural district in Thailand, of about 70,000 population, was conducted after a family-planning program had been in operation for eight months in order to ascertain indications of effectiveness of the program. Both the "before" and "after" surveys employed a 25 percent simple random, though non overlapping, sample of married women 20-44 years of age whose husbands were living. The only difference in design and execution was the inclusion in the resurvey of questions about the action program. Barring one or two exceptions, the characteristics of the two population samples were so similar that differences in knowledge, attitudes, and practices could be regarded as effects of the program.The action program not only made itself widely known in the district, it also evoked a highly favorable appraisal, to such an extent that nine of every ten women thought the program should be extended over the entire kingdom. Motivation to engage in family planning increased perceptibly. A substantial proportion (23 percent) of the women who formerly disapproved of the practice changed their attitudes to approval, mainly because they had become convinced of the harmlessness and the utility of fertility control. Less than 3 percent of the former approvers had become negative.The proportion of women who claimed some kind of knowledge about contraceptive methods more than doubled during the eight months of the program's operation. More impressive, however, was the change in actual use of methods, which rose from 1 to 21 percent of the eligible women (women who were not pregnant, subfecund, or sterilized). Another 16 percent, in the resurvey, planned to begin use of contraceptives in the near future, in most instances after a current pregnancy. The frequency of acceptance of family planning practice exceeded the expected frequency among women who were approaching or had attained the "ideal" number of children (4.0 children). High parity women 40 or more years of age seldom accepted clinical assistance. PMID- 21318707 TI - Use of the intra-uterine contraceptive device in rural West Pakistan. AB - This paper presents selected aspects of experience with the intra-uterine contraceptive device (IUD) in rural West Pakistan. There were 1,162 IUD cases analyzed with respect to retention or non-retention. Retention rates were estimated, using life table methods, to be between 55 and 75 percent at one year; the smaller figure was obtained when theIUD was considered to be in situ only until the last examination, when it was observed to be in place. The latter or larger figure was obtained when the IUD was considered to be in situ unless known to be out.The extent of follow-up greatly affects estimates of the length of time the IUD remains in situ. Retention also varies with the type of I UD employed; exclusive use of Loop 3, which has the best retention record of those used,may be expected to yield higher retention rates by as much as 5 to 10 percent for one year. A number of other factors were examined that might explain non-retention. The objective variables that were examined in this experience, such as age, previous contraception, and husband's illiteracy, were on the whole rather poor predictors of IUD retention. Expulsion and other medical complications appear to account for most discontinuance of use of the IUD. PMID- 21318708 TI - A study in family planning communication-Direct mailing. AB - It is sometimes stated that direct mailing to individuals in developing countries like India may be wasteful due to the low literacy rate among village people. Direct mailing is a relatively new development in India and comparatively a newer channel of communication. An exploratory study was carried out by the Central Family Planning Institute to test this hypothesis. The observations made showed that direct mailing is practical, controllable, inexpensive, and useful.The information provided by direct mailing seems to cross the barriers of illiteracy. Based on this experience, the Central Family Planning Institute has initiated a large-scale communication action research project in Meerut district in North India where the impact of direct mailing on specific groups is being studied further. It is hoped that such studies would help in developing prototype information material and would provide a methodology to supplement the available channels of communication in a nation-wide family planning program. PMID- 21318709 TI - A study of migration to Greater Santiago (Chile). AB - The most significant results of a survey in Greater Santiago in 1962 by the Latin American Demographic Center are presented in this paper. The population studied had slightly more than 2 million inhabitants at the time the survey was taken. A probability sample was drawn and interviews were taken without regard to the migration status of the household. The interview schedules were designed to obtain data on the demographic and social aspects of the migrant as contrasted with the non-migrant population. Migration history, the objective and subjective factors that appear to have "motivated" movement to Santiago, and other aspects oj the migratory move itself were also topics of inquiry.Tabulations of this survey portray Santiago as a city of great in-migration. The flow is estimated to be between 1.5 and 1.7 percent per year. Among the population 15 years of age or over, about 50 percent were found to be migrants from outside the metropolitan area. A high level of flow has been sustained for several decades, for only 60 percent of the total in-migrants have arrived during the last twenty years.Migration to Santiago was found to be selective by sex. For each two male in-migrants there were three female migrants. Migration was also selective by age. During the decade preceding the survey, two-thirds had arrived before attaining their twenty-fifth birthday. Forty-four percent of the men and 51 percent of the women had been between 15 and 29 years of age at time of arrival. The migrants had moved very little before their journey to Santiago. Among those who were 15 years of age or older at the time of migration, more than half had moved directly from their place of birth to Santiago. Prior mobility was slightly higher among persons coming from rural or semiurban origins than among those coming from urban origins.Two-thirds of the in-migrants arrived from urban places (places of 5,000 or more inhabitants in 1952). Despite the fact that in 1952 almost 50 percent of Chile's population outside Santiago was genuinely rural, only 13 percent of the in-migrants came from such origins. The balance came from areas classed as semiurban.The principal motive given for making the move to Santiago was work in 60 percent of the cases. Education was the second most commonly cited principal motive, given by 10 percent. Among those coming from rural and semiurban origins, an even greater proportion claimed work to be the principal motive, while those coming from urban settings were more inclined to report education.The spatial distribution of migrants within the territory of Greater Santiago was studied in four sectors, each with different socioeconomic characteristics. The present distribution, as well as the distribution of first places of residence, indicates that the distribution was more or less proportionate among the sectors and follows the expansion of the metropolitan area. However, a high concentration of migrant women was found in the middle- and upper-class residential sectors. This is probably due to the existence of housemaids in those sectors.Migrants were found to be living in poorer housing than non-migrants-especially for families whose heads were recent migrants(from 1952 to 1962). Among the migrants who had arrived within the last ten years, 30 percent lived in dwellings that lacked the basic services, such as running water, electricity, or sewer. Migrants who had arrived more than ten years before the survey tended to live in houses lacking these facilities only with about the same frequency as the non-migrants-23 percent.The educational attainment of migrants was lower than that of natives. This differential was especially great among women.The recent migrants have a greater rate of labor-force participation than the other groups. Among males, the rate for migrants was 84 percent and for natives 78 percent. The differential is even greater in the group 15-29 years of age, where the rates were 73 percent for migrants and 61 percent for natives. A similar differential was found for women.An income differential unfavorable toward migrants was found for both male and female workers. Among male workers there were no major occupational differences between migrants and non-migrants; among both migrants and natives two-thirds of the labor-force participants were classified as laborers. Among women there was a large differential; 80 percent of female migrants were laborers as contrasted with 56 percent for natives.It is interesting to mention that the proportion of manual workers, in the group "personal services," is higher among migrants than among natives. And, at the same time, the proportion of non-manual workers, in the group of "professionals and techniques," is higher among migrants than among natives.Finally, fertility of the native married women, whose husbands were present, is high. The average number of living children of women from 20 to 49 years old was 3.38 for native women and 3.19 for migrant women. PMID- 21318710 TI - Bombay migration study: A pilot analysis of migration to an Asian metropolis. AB - This paper reports on a pilot study of migration to Greater Bombay, initiated on the recommendation of the Population Commission of United Nations, and utilizes both published tables from the 1961 Census of India and a set of specially prepared tables from the same census. Migrants were defined by birthplace and cross-classified by age and duration of residence in Bombay.Data (1901-61) on net migration (obtained from successive age-sex distributions) are analyzed in terms of underlying trends to give historical perspective to the analysis of recent data with special emphasis on changes in industrial and occupotiona structure.For the 1951-61 decade, the extensiveness of out-migration of former in-migrants, its age-sex selectivity, and its high incidence among recent migrants are demonstrated. As is true elsewhere, migration to Bombay is shown to be highly selective for ages of maximum economic activity. Migration streams to Bombay were preponderantly male, and, among males, the married segment predominated. The propensity to migrate was unusually high among minority religious groups. As to educational level, migrants were superior to the general population at origin but inferior to nonmigrants residing in Bombay. The work participation rates of migrants were higher for every age group than for resident nonmigrants; the proportion of employees was higher; and there was evidence of migrant concentration in industries and occupations requiring less skill, less education, and less capital than was true of nonmigrants. There were significant tendencies toward "division of labor" among various migration streams on the basis of skills and abilities acquired not only by formal education but also through tradition and precept. From the standpoint of the promotion of social change, the large volume (and selectivity) of reverse or return migration is especially note worthy.The paper concludes with a methodological evaluation of the reliability and validity of duration-of-residence data and indicates that the relatively simple techniques of enumeration and tabulation utilized in this pilot study may have wide applicability in other developing countries. PMID- 21318711 TI - Effect of census errors on the measurement of net migration. AB - This paper traces the history of the use of vital statistics, survival rates, and ratios in the estimation of net migration from one decade to another. Net migration studies by Hart (1921); Baker (1933) ; Hamilton (1934); Thornthwaite (1934); Lively and Taeuber (1939) ; Henderson (1943); Hamilton and Henderson (1943); Hamilton (1951); Siegel and Hamilton (1952); Lee and Bowles (1954); Price (1955); Lee, Miller, and others (1957); Hamilton (1959); Zachariah (1962); Tarver (1962); Shryock (1964); Eldridge (1965); Hamilton (1965); and the United States Census Bureau are cited as the principal users of various residual methods of estimating net migration. All these demographers have either implicitly or explicitly recognized that errors in census enumeration and in the registration of births and deaths have been reflected in errors of estimated net migration.The underlying characteristic of all the methods used by these demographers has been the estimation of net migration as a residual obtained by subtracting natural increase in an area during a decade from the population change during the same decade. This method has been most generally stated in the classic formula {fx394 1} This formula has been used both with total populations and with aging cohorts. The principal variations of the basic formula have involved the use of life table and census survival ratios as a means of measuring natural increase (B - D), or of estimating "expected" populations assuming no migration. The main points of controversy have involved life table v. censm survival ratios, assumptions regarding the similarity in national and state census enumeration errors, and ways and means of estimating the errors involved in estimates of migration and of migration rates by the various methods.Daniel O. Price (1955) and Zachariah (1962) made important mathematical contributions and attempted to evaluate the errors involved in the me of census survival rates. Eldridge (1965) discovered that, in the United States between 1950 and 1960, the use of the census survival rate method usually gave much lower estimates of net migration than did the classic vital statistic method. Hamilton (1965), using some suggestions by Hope T. Eldridge, developed a mathematical theory or explanation of not only why the CSR estimates were usually lower than the VS estimates but also why the CSR estimates would usually give closer estimates on the true net migration than would the EVS method, which itself is subject to errors of census enumeration and of underregistration of births and deaths. The author also discusses the effect of improvement in census enumeration between 1950 and 1960 on estimates of net migration and derives a generalized formula which takes the timing of migration into consideration.The author acknowledges with sincere appreciation important constructive suggestions made by Dr. Hope T. Eldridge, Population Studies Center, University of Pennsylvania, and the authors of the many papers used as original material. This paper is a revision of a paper read before the annual meeting ot the Population Association of America, Hotel Roosevelt, New York, New York, April 29-30, 1966. Contribution from the Departments of Sociology and Experimental Statistics, North Carolina Agricultural Experiment Station, North Carolina State University. Published with the approval of the Director of Research as Paper No. 2227 of the Journal series. PMID- 21318712 TI - Cohort migration. AB - Most migration analyses focus on net migration and are concerned with areal redistributions of population. Migration may also be studied as an event in the life-cycle of an individual, and migration rates may be defined as properties of cohorts. A number of efforts to examine migration as a cohort process has been hampered by the character of available data [or the United States. Rather than await the development of a registration system-either directly or via social security and tax records-the collection of residence histories is suggested as the most feasible approach to obtaining suitable data. A schematic representation of residence histories clarifies their relation to other types of migration data and illustrates the need to design such surveys with specific research purposes in mind. Exploratory work with the 1958 Residence History Supplement to the Current Population Survey (by Beale, Shryock, myself, and various colleagues) demonstrates the utility of this approach.Local studies have made fruitful use of residence histories but typically are unable to delineate birth cohorts or other appropriate base populations exposed to risk. Development of cohort migration techniques analogous to the life table approach to mortality or cohort Jertility analysis requires national data. But migration, unlike Jertility and mortality, involves events that are reversible and repeatable. Hence the demographer's stock of analytic tools requires expansion. To the sociologist-demographer, experimentation with cohort migration models seems to be getting at one of the crucial methodological problems of sociology, the analysis of social mobility. A mutually profitable interchange with students of social mobility is envisaged. PMID- 21318713 TI - Economic development and fertility. AB - Two schools of theorists have been concerned with the effect of economic development on fertility. One school has contended that economic development has an inhibiting effect on fertility. The demographic transition which has occurred among the non-developed countries confirms their viewpoint. Another school of thought, including in its members Thomas Malthus, has believed that economic development promoted fertility. Much empirical evidence may also be brought to bear to support this viewpoint.The present paper attempts to reconcile these viewpoints. It is hypothesized that the direct effect of economic development is to increase fertility. However, various factors which usually accompany the process of economic development serve to reduce fertility. These include an increase in the level of education and a reduction in infant and childhood mortality. Making use of data for 41 nations pertaining to the decade of the 1950's, it is found that fertility is directly associated with per capita net national product when controls for other relevant variables are in8tituted. On the other hand, per capita newspaper circulation is inversely related to fertility, and infant mortality is directly related.If the hypothesis advanced in this paper is correct, relatively large governmental expenditures on health and education will enhance the reduction in fertility obtainable from an increase in national economic level alone. PMID- 21318714 TI - Contributions of natality models to program planning and evaluation. AB - This paper is an attempt to describe and assess the contributions made by the newer quantitative models of natality to program planning and development. Considerable interest in models of natality is being reflected in reports of a large variety of ideas, suggestions, and proposed models. In view of this current activity, any assessment made now of the contributions of these models can be only tentative and should consider also prospects for the future.The present approach to assessment will be made in three parts: a description of recent developments in natality models, a discussion of the contributions of newer models, and a consideration of prospects for the future. The discussion applies not only to models whose primary focus is on natality but also to more general models that investigate natality among other processes. PMID- 21318715 TI - A computer model of family building based on expected values. AB - A computerized probability model of family building is described. Called FERMOD, the model is designed to follow the changing distribution of children ever born and birth intervals of a large homogeneous population as it moves through the reproductive period. Use of the model presupposes assumptions about such factors as risks of fetal wastage, lengths of pregnancy, and postdelivery amenorrhea conditional to outcome of pregnancy, length of reproductive period, fecundability, desired family size, preferred birth spacing!, and effectiveness of contraception. Use of FERMOD is illustrated in a limited application to United States fertility. Relations to other models are briefly discussed. PMID- 21318716 TI - A further look at catholic fertility. AB - The purpose of this paper is to determine the extent to which suburbanization has influenced the traditional fertility differences observed between Catholics and Protestants. It is hypothesized that suburbanization has served to decrease religious differences in fertility, since in the more advanced stages of urbanism, that is, suburbanization, the Catholic population is likely to adopt the fertility patterns of the larger and more secularized society. Attention is focused on two objectives: (1) to examine selected aspects of fertility for Catholic8 and Protestants living in metropolitan areas and (2) to analyze religious differentials in fertility among residents in different parts of the metropolitan community.The data, consisting of a sample of households in six metropolitan areas in three population size classes, supported the general findings pertaining to religious differences in fertility that have been reported in the literature. Catholics had larger families, shorter average spacing between children, and longer fertility spans when compared to Protestants, even when a number of control variables were employed. Examining fertility differences between Catholics and Protestants in central city and suburban segments of large and small metropolitan areas, we found that the data indicated that marked Catholic-Protestant differences are still found in central cities. However, fertility differences between the two religious groups tended largely to disappear among suburban residents. The convergence in the fertility patterns of suburbanites is due to combined effects of higher fertility among Protestant suburban residents when compared to central city Protestants and the tendency of suburban Catholics to have fewer children than those who live in the city. The net result is convergence in suburban fertility. PMID- 21318717 TI - Validity of centenarian data in the 1960 Census. AB - This paper examines the question of how many genuine centenarians there actually are in the United States as compared with those reported in the census. It is concluded that the numbers of centenarians shown in various United States censuses are definite overstatements of the number of true centenarians. It seems likely that instead of the 10,326 centenarians reported in the 1960 census there were at most only about 3,700. Overstatement of ages seems to be particularly the case among those who claim to be aged 110 or over, and it is believed that there probably are no persons who are actually this old.The analysis has been made by projecting, through the me of population life table survival factors, the populations reported cit carious advanced age groups in one census to the next census and then comparing the results with the corresponding number reported in the latter census for the same age cohort. In general, the enumerated populations at ages below 95 are reasonably close to the projected populations, especially for white persons. On the other hand, at ages 95 and over-especially for centenarians-the enumerated populations significantly exceed the projected ones.As a subsidiary part of the analysis, the paper points out the significant differences at the older ages between the "full count" age distribution in the 1960 census and the corresponding "inflated 25 per cent sample" one. This is a subject that bears further investigation and explanation.The paper also discusses centenarians on the social security benefit rolls and concludes that the present data cannot be considered of substantial accuracy with regard to genuine centenarians, particularly the oldest ones. In a number of years, however, this program will provide excellent data, became the individuals involved will have been on the benefit rolls for many years and will have had their ages proved with reasonable accuracy. PMID- 21318718 TI - Study of age misstatement among young children in Ghana. AB - In the 1960 Population Census of Ghana, the first attempt to enumerate the population by single years of age was made. The use of these data to estimate fertility levels was rendered somewhat difficult by the pattern assumed by the age statement of children. This pattern was similar to others found widely in developing countries. There appeared to be unexpectedly few children under two years of age and more children aged three years than any other single age. In order to investigate such age reporting, and in the hope of being able to provide some kind of correction to the census data, an attempt was made to trace one thousand children 0-99 months of age in ten different centers, with knoum dates of registered birth. If found, they were approached, as if by census enumerators, to obtain statements of age from the families. The investigation had to be confined to the compulsory registration areas where an eighth of the population of the country lives.It was found that age misstatement occurs partly because of digital preference but even more commonly because of a tendency to approximate age to the nearest birthday. Thus, when age misstatement occurs through the latter cause, it always takes the form of age advancement. Errors in age statement of more than one year fell evenly and randomly above and below the correct age. The age data in years were not appreciably affected by seeking further information on age in years and months. However, it was shown that the standard deviation of stated from real age was approximately proportional to real age and was equal to about one-eighth of it.The findings were then applied to the 1960 enumeration, where some problems such as the small number of one-year-olds, were solved. More work is needed to explain satisfactorily the peaking at three years of age. It was shown that age advancement may have reduced the size of the 0-4 age group by about 5 percent relative to adult female age groups, and this would result in an understatement of fertility as measured by the child/woman age ratio of the same amount.The research described in this paper was program of that post. With the exception of a carried out when the writer held the Population part of the analysis which has been carried out at Council demography post attached to the University of Ghana and formed part of the research program of that post. With the exception of a carried out when the writer held the Population part of the analysis which has been carried out at the Australian National University, the project was financed entirely by the Population Council. PMID- 21318719 TI - Residential redistribution of socioeconomic strata in metropolitan areas. AB - This paper is a preliminary report on an ecological analysis of recent changes in the spatial distribution of socioeconomic strata within 363 Standard Metropolitan Statistical Areas (or substituted units) in the United States. The central hypothesis guiding the study is that certain population subgroups in and around the larger urban areas are shifting their residential locations in predictable directions. Changes in the distribution of educational classes between the central city (or cities) and their surrounding rings from 1950 to 1960 are traced by using census data. A special feature of the analysis is the inclusion of 163 "lquasi-metropolitan areas" centered on cities that had 25,000-50,000 inhabitants in 1960.The initial results indicate that residential redistribution according to "social class" is occurring in all these metropolitan areas and that the pattern of change varies systematically. Regional differences are pronounced, and, as prior research has suggested, age of the city and population size appear to be important factors. The percent of adults in the high school and college categories in the rings of older and larger metropolitan areas generally increased disproportionately compared to the central cities. A variety of patterns of change, however, occurred among the younger and smaller metropolitan areas.Subsequent analyses will include (a) alternative methods of controlling color and regional location, (b) other measures of the independent and dependent variables used here, and (c) a multivariate approach to the problem of identifying and assessing the explanatory power of additional independent variables (including population growth, the over-all rate of decentralization, annexation history, economic base, and the character of the ring). The extent as well as the direction of change will also be investigated. Finally, the feasibility of quantifying an "evolutionary sequence" in the distribution of social classes will also receive attention. PMID- 21318720 TI - Late-thirteenth-century Ireland as a region. AB - The population distribution of late-thirteenth-century Irish cities is used to determine the status of culture (the term used anthropologically) of the island as a region. The evidence derives largely from areas of the cities and from numbers of city lots (burgages) in the descriptions (extents) of city taxation. Around A.D. 1275-85, Ireland had a population of about 650,000. Its largest city, Dublin, had about 10,000 inhabitants, thus nearly the expected 1 1/2 percent of the region. The other large cities or clusters of cities seem to fall into the expected pattern of size. So, although sharp social and economic differences existed between the urban and feudal English and the pastoral Irish, the possibility of a normal political and economic region was present. Although Edward I granted common law rights to the Welsh, he refused them to the Irish, thus preventing integration with the English and prolonging the Anglo-Irish rift at the one most favorable time to have ended it. PMID- 21318721 TI - Small town growth in the United States: An analysis by size class and by place. AB - Small town population change is an important factor in the urbanization process. We analyzed changes in incorporated places under 10,000 in the United States during the 1940-60 period, making a distinction between changes in population size classes and changes in places grouped by initial size. We made balance sheets for size classes under 1,000, 1,000-2,500, and 2,500-10,000 in order to divide the percent increase by size class into five additive components: (1)growth of places staying in the class, (2) net shifts of growing towns into and out of the class, (8) net shifts of declining towns into and out of the class, (4) addition of new places, and (5) disappearance of places during the time period. Separate tabulations were made by metropolitan location, region, and decade. p ]Places under 10,000 population the initial year grew during both census decades considered. Growth differentials paralleled those generally found for the total population, with the most rapid growth near large cities in the West and (except for non-metropolitan places) over the 1940-60 decade.We found results to be different for population changes of particular size classes. Except in some Urbanized Area locations, the two larger size classes increased in population over both decades. In contrast, the under-1,000 size class declined in almost every case. This decline was not due to decreasing population of places within the class or to the disappearance of places between censuses but rather to the growth of places into larger classes not compensated for by decline of other places into the class or new incorporations. PMID- 21318722 TI - A unified approach to interpolation and graduation. AB - The subject of interpolation and graduation is customarily treated by finite difference formulas of great variety and complexity, these having been developed with the convenience of hand calculation in mind. The cheapening of computation which has occurred in the past few years permits a simplification and unification of the subject. This is accomplished by linear equations which express conditions it is desired to impose on the interpolating curve and the elimination of the constants resulting in a determinantal equation. A computer program which evaluates a determinant then suffices for nearly any problem of graduation, interpolation, numerical differentiation and integration, as well as for the calculation of the remainder term or error of any of these. PMID- 21318723 TI - The multiregional matrix growth operator and the stable interregional age structure. AB - Current population-forecasting efforts generally adopt minor variants of the cohort-survival projection method. This technique focuses on a population disaggregated into cohorts, a group of people having one or more common characteristics at a point in time and, by subjecting each cohort to class specific rates of fertility, mortality, and net migration, generates a distribution of survivors and descendants of the original population, at successive intervals of time.Although cohort-survival methods take on a large number of variations, they all are essentially trend-based, dynamic, aspatial models of growth. The temporal element is introduced by a recursive structure which operates over a sequence of unit time intervals. The spatial dimension, when it is included at all, typically is accommodated by replicating the analysis over as many areal units as comprise the study area. Realistically, however, time and space need to be considered jointly in population-forecasting models. The need for interregional models which systematically introduce place-to-place movements and simultaneously consider the spatial as well as the temporal character of interrelated population processes is becoming increasingly apparent.Recently several demographers have taken advantage of the conceptual elegance and computational simplicity of matrix methods of population analysis. Their models, however, assume a "closed" population which is subject only to the processes of fertility and mortality. These, therefore, are not directly applicable to interregional "open" systems in which migration is frequently a much more variable and important contributor to population change than births or deaths. However, a natural extension of the demographer's matrix model allows one to incorporate place-to-place migration and provides an integrated interregional population-forecasting model which easily may be programmed for any of the current generation of digital computers. Such a model is outlined in this paper. PMID- 21318724 TI - The impact of Medicare on demography. AB - The so-called Medicare program enacted by the 1965 Amendments to the Social Security Act will have a significant impact on demographic studies, in view of the vast amount of previously unobtainable data that will be made available. Not only will there be extensive information in regard to hospitalization and other medical-care costs for persons aged 65 and over (with adequate subdivisions by age and sex) but also reliable data in regard to the true size of the population aged 65 and over will be produced.The reason for this latter result is that virtually all pereons aged 65 and over in the country will become eligible for hospital insurance, even though they may not have been previously covered, or have been survivors of persons covered, under the Old-Age, Survivors, and Disability Insurance System. As a result, not only will there be an accurate count (unlike the census, where the enumeration necessarily is not complete), but also there will be a verification of age, since this is necessary under the claims process. PMID- 21318725 TI - White-nonwhite differentials: Overview and implications. AB - This paper reviews the arguments for maintaining a separate series of statistics for the white and nonwhite populations of the United States; only by maintaining factual data will it be possible to document inequality and discrimination. It then summarizes some white-nonwhite differentials: fertility, life expectancy, health, school attendance, educational attainment, and income. The human, social, and political implications are then reviewed. PMID- 21318726 TI - Demographic implications of the New United States certificates. AB - To assist in developing uniform reporting of vital events among the fifty states, Puerto Rico, and the Virgin Islands, the United States government prepares standard certificates of birth, fetal death, death, marriage, and divorce. These model forms are revised, with the assistance of the states, approximately every ten years. Revisions are now being prepared by the National Center for Health Statistics which will become effective beginning January 1, 1968. Important new source material for demography will be introduced.Most changes will appear in the Standard Certificate of Live Birth and in the Standard Certificate of Fetal Death. An item on education of father and mother will provide detailed national data on education and fertility. The date of the last live birth to the mother and the date of the last fetal death will provide information on previous pregnancy outcome and on child-spacing. The recording of state file numbers for mates born alive and dead in the same delivery will make it easier to match live birth and fetal death certificates for the preparation of detailed tabulations on multiple births. Several new items related to maternal and child health have also been added. No significent changes were planned for the Standard Certificate of Death.The Standard Certificate of Marriage will include as new items the education of the bride and groom, the date on which the last marriage, if any, ended, and specification of the officiant as a religious or civil official. The Standard Certificate of Divorce or Annulment will obtain information on the education of husband and wife, the approximate date on which the couple separated, the mode of dissolution of the previous marriage, and the total number of living children. It is anticipated that most of the new items will be included in the certificates of all the states. The National Center for Health Statistics will provide detailed tabulations related to these items, beginning with data year 1968.Demographers are making an increased use of vital records and at the same time are extending their contacts with state health departments; in some states collaborative projects have been undertaken. Because of the importance of the source documents, which in some cases have not been exploited fully, demographers should increase their contact with the state vital statistics offices which develop, collect, and process the records. By indicating an interest in vital registration and by making their research needs known, demographers can encourage the acceptance of new concepts and collaborate in the improvement of vital records for demographic research purposes. PMID- 21318727 TI - The demographic viewpoint in the vital and health statistics monographs of The American Public Health Association. AB - The plan calls for monographs on 16 specific topics and a review volume. The specific topics include a monograph on fertility, another on marriage and divorce, and one on social and economic factors in mortality, all of which are of obvious demographic interest. The core of the development of the monographs dealing with the disease topics, and accidents, homicide, and suicide, is a tabulation program involving specific and age-adjusted death rates based upon the deaths in the United States for the three year period 1959-61 and the 1960 census of population. The program called for a set of standard tabulations common to each monograph and also a set of special tabulations tailored to meet the particular needs for each topic as specified by its authors. This wealth of demographic detail regarding mortality in the United States during 1959-61 fills only one aspect of its health picture. To fill out the health picture, use is being made of the great volume of morbidity data out of the National Health Interview and Examination Surveys and a wide variety of other specialized surveys. In all of these, the findings are invariably described in terms of the demographic characteristics of age and sex, and frequently in terms of such social-economic variables as education, income, work status, and occupational class.A large part of the content of the monograph on social and economic factors in mortality will come out of available results of the 1960 census-death certificate matching study at the University of Chicago. One important feature of this monograph, not contained in the Chicago study, is a regression and correlation analysis of total mortality in 202 Standard Metropolitan Statistical Areas in relation to a large number of social, economic, and climatic factors. Among the features in the monograph on fertility are chapters on the medical and biological characteristics of births, fecundity and family planning, and an analysis of cohort fertility trends. The monograph on marriage and divorce will make use of the detailed tabulations from the 1960 census on marital status in relation to education, race, parentage, earnings and other classifications of individuals and of husband and wife in married couples. It will also contain a matching study of divorce records in certain states for a short period before the census of 1960 with the returns in the census. The project is supported by a grant from the United States Public Health Service (CH 00075; formerly RG 08262). Publication will be by the Harvard University Press. PMID- 21318728 TI - CharacteriStics and utilization of midwives in a selected rural area of East Pakistan. AB - The purpose of this study was to obtain information about the utilization of midwives (dais) by village women and to learn more about the characteristics and practices of those dais. Two interview schedules were prepared. The first was used to interview 632 village women to determine who performed or assisted with their last two deliveries. The second was used to obtain information from 21 dais.The results of the first phase may be summarized as follows: (a) 38 per cent of the women were delivered by relatives; (b) 33 per cent of the women delivered their own children; (c) 14 per cent were delivered by neighbors; (d) 6 per cent were delivered by dais; (e) 2 percent were delivered in hospitals; and (f) the remaining 7 per cent were accounted for by several minor categories.The results of the interviews with dais are summarized as follows: (a) they are mainly widows and older women; (b) they have no formal training; (c) they work for friends, neighbors, and relatives and receive a sari as compensation; (d) they cannot handle complicated deliveries; (e) they deliver 3-4 children a year; (f) their sterilizing procedures depend upon soap, water, and folk beliefs; (g) most think midwifery is a worthwhile service; (h) about one-half have a general understanding of the reproduction process; (i) most do not know how to prevent conception; and (j) about half think that it is a good idea to participate actively in a family planning program. PMID- 21318729 TI - How many people have lived on the earth? AB - A simple formula is proposed for estimating the number of people who have ever lived. Using assumptions that seem reasonable, an estimate of 69 billion (1960) is obtained. The present world population is about 4 percent of this number. PMID- 21318730 TI - Abridged life tables for Pakistan and Provinces: 1962. PMID- 21318731 TI - Identification of immunogenic regions within the alternative reading frame protein of hepatitis C virus (genotype 3). AB - Hepatitis C virus (HCV) encodes ten classic proteins as well as a newly discovered alternative reading frame protein (ARFP) whose synthesis originates from the core region by a +1 frameshift. ARFP is produced by all HCV genotypes, but its function remains unknown. Although the immunogenicity of genotype 1- and 2-derived ARFP in infected hosts has been reported, no information is available for genotype 3-encoded ARFP. HCV genotype 3 core/ARFP region was PCR amplified, cloned, and sequenced. Recombinant ARFP and peptides were employed in ELISAs with patient serum samples. The effect of peptides on peripheral blood mononucleocytes (PBMCs) was also studied. DNA cloning and sequencing of HCV genotype 3 strain (PKHCV3) revealed it to encode 160 aa ARFP, which harbors a C-terminal extension of 36 aa. Serum from 74 of 88 patients (84%) contained rARFP-reactive antibodies. Peptide ELISAs showed that all regions of rARFP were immunogenic, with peptide F7 (DSLSPRRAGAKAGPGLSPGT) being the most immunodominant. When incubated with PBMCs from HCV-infected individuals, F7 stimulated the production of TNFalpha and IL10. PKHCV3-derived ARFP encodes a 160 aa protein and antibodies against its entire length are found in 84% of all genotype 3-infected subjects. Peptide ELISAs revealed F7 to be highly immunogenic and capable of eliciting impressive T-cell responses. PMID- 21318732 TI - Specific detection of Salmonella enterica and Escherichia coli strains by using ELISA with bacteriophages as recognition agents. AB - The use of bacteriophages, instead of antibodies, in the ELISA-based detection of bacterial strains was tested. This procedure appeared to be efficient, and specific strains of Salmonella enterica and Escherichia coli could be detected. The sensitivity of the assay was about 10(5) bacterial cells/well (10(6)/ml), which is comparable with or outperforms other ELISA tests detecting intact bacterial cells without an enrichment step. The specificity of the assay depends on the kind of bacteriophage used. We conclude that the use of bacteriophages in the detection and identification of bacteria by an ELISA-based method can be an alternative to the use of specific antibodies. The advantages of the use of bacteriophages are their environmental abundance (and, thus, a possibility to isolate various phages with different specificities) and the availability of methods for obtaining large amounts of phage lysates, which are simple, rapid, cheap, and easy. PMID- 21318733 TI - Reactive oxygen species and NADPH oxidase 4 induced by transforming growth factor beta1 are the therapeutic targets of polyenylphosphatidylcholine in the suppression of human hepatic stellate cell activation. AB - OBJECTIVE AND DESIGN: To clarify the molecular mechanism of polyenylphosphatidylcholine (PPC), we examined the involvement of reactive oxygen species (ROS) and NADPH oxidase 4 (Nox4) in human hepatic stellate cells (HSCs). MATERIAL: Using human LX-2 HSC cells, we examined the effects of PPC on expression of alpha-smooth muscle actin (alpha-SMA) and collagen 1, generation of ROS, Nox4 expression, p38 activation and cell proliferation, induced by transforming growth factor beta1 (TGFbeta1). RESULTS: PPC suppressed ROS which are induced by TGFbeta1, phosphorylation of p38MAPK, and expression levels of alpha-SMA and collagen 1 in a dose-dependent manner. Higher concentrations of PPC also suppressed Nox4 levels. CONCLUSION: These results suggest that ROS and Nox4 induced by TGFbeta1 are the therapeutic targets of PPC in the suppression of human hepatic stellate cell activation. PMID- 21318734 TI - Quiet-eye training for soccer penalty kicks. AB - Anxiety has been shown to disrupt visual attention, visuomotor control and subsequent shot location in soccer penalty kicks. However, optimal visual attention has been trained in other far aiming skills, improving performance and resistance to pressure. We therefore asked a team of ten university soccer players to follow a quiet eye (QE; Vickers 1996) training program, designed to align gaze with aiming intention to optimal scoring zones, over a 7-week period. Performance and gaze parameters were compared to a placebo group (ten players) who received no instruction, but practiced the same number of penalty kicks over the same time frame. Results from a retention test indicated that the QE-trained group had more effective visual attentional control, were significantly more accurate, and had 50% fewer shots saved by the goalkeeper than the placebo group. Both groups then competed in a penalty shootout to explore the influence of anxiety on attentional control and shooting accuracy. Under the pressure of the shootout, the QE-trained group failed to maintain their accuracy advantage, despite maintaining more distal aiming fixations of longer duration. The results therefore provide only partial support for the effectiveness of brief QE training interventions for experienced performers. PMID- 21318735 TI - Levels of total mercury in different fish species and sediments from the Upper Volta Basin at Yeji in Ghana. AB - In this study, total mercury concentrations were determined in sediments and seven different fish species from the Upper Volta Basin area of Yeji in Ghana. Mercury concentrations found ranged from 44.17 to 85.88 ng/g wet weight for Synodontis gambiesis, from 11.25 to 79.73 ng/g wet weight for Synodontis membranaceus, from 13.11 to 38.64 ng/g wet weight for Synodontis ocellifer, from 16.39 to 25.82 ng/g wet weight for Distishodus rotratus, from 40.80 to 90.30 ng/g wet weight for Bagrus docmac, from 10.48 to 61.90 ng/g wet weight for Chrysichthys nigrodigitatus and from 12.33 to 24.18 ng/g wet weight for Gnathoneus senegalensis. These values are below the 500 ng/g guideline recommended by the WHO/FAO, implying that fish from the Upper Volta Basin area of Yeji are safe for human consumption. Good correlation was observed between mercury concentration and fresh weight (R(2) = 0.6067) and total length (R(2) = 0.8754) for Gnathonemus senegalensis. However, poor correlations were observed between mercury concentration and fresh weight and total length for the other six species. Mercury in sediments ranged from 11.87 to 70.25 ng/g dry weights with a mean of 41.60 ng/g dry weight being below the IAEA threshold of 810 ng/g.. These values show that sections of the Upper Volta River remain relatively clean in spite of substantial loadings of mercury into the river's basin from gold mining activities. PMID- 21318736 TI - Analysis of HER2 gene amplification and protein expression in esophageal squamous cell carcinoma. AB - The HER2 gene, which is located on chromosomes 17, is a therapeutic target for cancer. Amplification of HER2 has been described in several tumor types. However, few studies of HER2 gene amplification and protein expression in esophageal carcinoma have been conducted. This study was to investigate the relationship between the expression of HER2/neu and the clinical characteristics, including survival rate, of esophageal squamous carcinoma. The clinical data of 145 patients admitted in Renmin Hospital of Wuhan University, from 2000 to 2005, were reviewed. The HER2 protein expression and gene status in 145 esophageal carcinomas were evaluated using immunohistochemistry and fluorescence in situ hybridization. The survival rate was calculated by the Kaplan-Meier method and the log-rank test using SPSS13.0 software. Compared to normal esophageal epithelium (23/95, 24.2%), HER2 protein was overexpressed in most esophageal squamous carcinoma tissues (60/145, 41.4%), of which 45 (31.0%) were 2+ and 15 (10.4%) were 3+, HER2 overexpression associated significantly with HER2 gene amplification. There is a correlation between the overexpression of HER2 and the differentiation of the carcinoma, the HER2 gene amplification and the differentiation of the carcinoma and the tumor stage. According to univariate analysis, there was a significant difference in survival rates when cases with and without HER-2/neu overexpression or amplification were compared. HER-2/neu amplification/overexpression may be used as an independent prognostic factor in patients with esophageal squamous cancer, and patients with HER-2/neu amplification/overexpression might be potential candidates for new adjuvant therapies that involve the use of humanized monoclonal antibodies. PMID- 21318738 TI - Comparative genetics of the central nervous system in epigean and hypogean Astyanax mexicanus. AB - The extreme environment of subterranean caves presents an adaptive challenge to troglobitic organisms. The mechanisms by which natural selection modify an ancestral surface neural circuit to produce a novel subterranean behavior remain a mystery. To address this question, we performed cross species microarray experiments to compare differences in gene expression levels in the adult brain of the teleost Astyanax mexicanus. This species provides a unique opportunity for comparative genetic studies as it consists of extant epigean (surface) and hypogean (cave) conspecifics. Microarray experiments herein revealed significant changes in transcription levels of seventeen genes, several of which are important for behaviors involved in metabolic management. We focused on genes central to three neurotransmission and neuromodulation networks: the endocannabinoid system (Cannabinoid receptor CB1), the dopaminergic system (Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein) and the glutamatergic system (glutamate receptor AMPA 2a). All three genes were upregulated in the hypogean form of A. mexicanus compared to the epigean form, indicating that behavioral differences in the hypogean form of the species could be due to alterations in expression levels of several key genes. This information provides insights into the complex relationships among environmental factors, genetics, nervous systems and adaptive behavior, and can subsequently help us understand how these interactions affect behavior in other biological systems. PMID- 21318737 TI - The role of human papillomavirus infection in breast cancer. AB - Breast cancer is the leading female cancer and the third most common cause of cancer deaths worldwide. Many studies have suggested a possible link between breast cancer pathogenesis and viral infection, particularly mouse mammary tumour virus, simian virus 40, Epstein-Barr virus, and human papillomavirus (HPV). A significant number of recent studies have reported that approximately 29% of human breast cancer tissues were positive for high-risk HPV subtypes, especially HPV subtypes 16, 18, or 33. In contrast, several other investigations did not detect any HPV subtypes in either breast cancer tissue or normal breast tissue from patients diagnosed with breast cancer. Given these conflicting data and the established complexity of the association between HPV with other cancers, a definitive relationship between human breast cancer and HPV infection has not been determined. Recent advances in laboratory methodologies aim to overcome the inherent challenges in detecting HPV in breast cancer tissue. There is an urgent need to obtain additional evidence in order to assess the possibility of breast cancer prevention using HPV vaccines. PMID- 21318739 TI - Pneumonia in patients with novel influenza A (H1N1) virus in Southeastern Turkey. AB - The objective of this study was to describe the clinical characteristics and the radiological and laboratory findings of the hospitalised patients who had novel, laboratory-confirmed, swine-origin influenza A virus (S-OIV) infection with pneumonia. Between October and December 2009, 56 patients hospitalised for pneumonia who were tested for S-OIV infection were retrospectively evaluated. Thirty-three patients had positive S-OIV infections. In addition, 23 of the 56 patients who had negative test results for S-OIV infection were compared with the positive group. The mortality rate amongst the patients with S-OIV infection was 24.2%. Of the 33 patients, 42.4% had at least one underlying medical condition and 4 (12%) patients were pregnant or postpartum. Fourteen patients (42.4%) with S-OIV infection were followed up in an intensive care unit. The most common symptom was dyspnea. The mean peak body temperature during hospital stay (39.42 +/- 0.70) was higher in this group than in the negative group (38.51 +/- 1.05) (p = 0.001). Thrombocytopenia, increased creatine kinase and elevated lactate dehydrogenase levels were statistically significant. Bilateral infiltration was more common in the patients with S-OIV infection. Although some laboratory, radiological and clinical data show a significant difference between the patients with S-OIV pneumonia and the negative group, each patient presenting with signs of pneumonia during pandemia should be tested for Influenza A. PMID- 21318740 TI - [Respiratory system at high altitude: pathophysiology and novel therapy options]. AB - This mini-review conveys information on lung function in hypoxia. Included are presentations of shape and layering of the atmosphere, physiologic basics of lung function at high altitude, pathophysiology of high altitude pulmonary edema (HAPE) and of current and potential therapy approaches for HAPE. PMID- 21318741 TI - Synthesis of Polyampholyte Comb-Type Copolymers Consisting of a Poly(L-lysine) Backbone and Hyaluronic Acid Side Chains for DNA Carrier. AB - Polycations have been used as nonviral gene carriers because the polycations and DNAs form stable complexes in a noncovalent manner (1-3). The polycations, e.g., poly(L-lysine) (PLL), are reported to be conjugated with several ligands for targeted gene delivery (4-8). The physicochemical properties of the DNA complexes have been described as factors that influence transfection activity (9-11). PMID- 21318742 TI - Cationic alpha-Helical Peptides for Gene Delivery into Cells. AB - Development of nonviral gene transfer techniques has progressed, particularly the use of several kinds of cationic lipids and cationic polymers such as polylysine derivatives, polyethyleneimines, polyamidoamine dendrimers, and so on, which electrostatically form a complex with the negatively charged DNA, which can be taken up by the cells. Furthermore, targeted gene transfer has also been realized by modification of the gene carriers using cell-targeting ligands such as asialoorosomucoid, transferrin, insulin, or galactose. PMID- 21318743 TI - Supramolecular Self-Assembly of Poly(ethylene glycol)-Block-Poly (L-lysine) Dendrimer with Plasmid DNA. AB - Research and development related to nonviral gene carriers comprising chemically synthesized molecules has increased enormously during the past decade. Polycationic polymers and cationic lipids have constituted the main themes of the studies. Various polymers from synthetic to naturally occurring ones have been introduced and tested for their suitability in the field of gene therapy. Several cationic polymers were found to be promising but their intrinsic drawbacks, such as solubility, cytotoxicity, and low transfection efficiency, limited their use as in vivo gene carriers (1). Among them, however, dendrimers are still very attractive to many scientists for the design of gene carriers because of their well-defined structure and ease of control of surface functionality. Already, both polyamidoamine dendrimer and polyethylenimine dendrimer have been tested for their potential utility and have exhibited high transfection efficiency in vitro and in vivo (2,3). However, these dendrimers have not yet overcome the problems of solubility of the complex with DNA and cytotoxicity. PMID- 21318744 TI - Water-soluble cationic methacrylate polymers for nonviral gene delivery. AB - The aim of gene therapy is to treat inherited or acquired genetic deficiencies (e.g., cystic fibrosis) or viral diseases (e.g., hepatitis B, HIV) by introduction of DNA encoding a therapeutic protein or a specific virus antigen, respectively, into the nucleus of the target cell. Because naked DNA will barely pass cellular membranes, a carrier system is required for transfection (1-4). Cationic polymers, which condense DNA by ionic interaction, form a promising class of nonviral transfection agents. Well-known examples of these polymers are DEAE dextran, poly(L-lysine), poly(ethylenimine), and poly(2- [dimethylamino]ethyl methacrylate) (pDMAEMA) (5-10). In order to achieve transfection, aplasmid must be delivered into the nucleus, which requires cellular uptake of polymerDNA complexes, generally referred to as "polyplexes" (11), which most likely occurs via endocytosis, followed by endosomal escape and transport to the nucleus. The polyplex must dissociate, either in the cytosol or in the nucleus, which may be a critical step in the transfection process. PMID- 21318745 TI - Stabilization of Polycation-DNA Complexes by Surface Modification with Hydrophilic Polymers. AB - Polycation-DNA complexes represent promising synthetic vectors for gene delivery, showing good transfection activities in vitro and safety in vivo. However, simple polycation-DNA complexes suffer from several disadvantages that limit their potential usefulness in vivo. Advances in this field thus rely on better control of the structure, colloidal, and surface properties of condensed DNA particles. PMID- 21318746 TI - Use of disulfide cationic lipids in plasmid DNA delivery. AB - Gene therapy provides a paradigm of the treatment of human diseases. The ultimate goal of gene therapy is to cure both inherited and acquired disorders by removing the original causes, i.e., adding, blocking, correcting, or replacing genes. Although gene therapy trials have been initiated worldwide for more than two decades, little has been achieved in clinically curing diseases. One of the major hurdles for gene therapy is the lack of an efficient gene delivery system. An ideal gene delivery system should be specifically targeting, biodegradable, nontoxic, nonimmunogenic, and stable for storage. Cationic lipo-somes are the most extensively investigated nonviral vectors. It is generally believed that DNA liposome complexes enter cells via endocytosis, although other pathways such as membrane fusion may exist (1,2). The barriers involved in the transfection process in vitro generally include the following aspects (3): 1. Formation of the liposome-DNA complexes. 2. Entry of complexes into cell. 3. Escape of DNA from the endosomes. 4. Dissociation of DNA from liposomes. 5. Entry of DNA into nucleus. 6. DNA transcription. PMID- 21318747 TI - Interactions of lipid-oligonucleotide conjugates with low-density lipoprotein. AB - The ability of antisense oligonucleotides to interdict, sequence-specifically, the expression of pathogenic genes affords an exciting new strategy for therapeutic intervention (1-3). Oligonucleotides with physiological phosphodiester internucleotide bonds are rapidly degraded, predominantly by exonucleases. Numerous oligonucleotide analogs have therefore been synthesized to confer resistance toward nuclease activity (3). The phosphorothioate analog is the most extensively studied, and phosphorothioate oligodeoxynucleotides have been shown to be potent inhibitors of the expression of their target genes in vitro and in vivo (1,3). However, phosphorothioate oligodeoxynucleotides also bind avidly and nonspecifically to proteins, thus provoking a variety of non antisense effects (4). Oligonucleotide analogs that do not bind to proteins are therefore expected to display less nonantisense side effects. However, protein binding also affects the in vivo disposition of oligonucleotides. Nonphosphorothioate oligonucelotide analogs generally do not bind to serum proteins, and are therefore rapidly cleared from the circulation, protein-bound phosphorothioate oligodeoxynucelotides circulate much longer (5,6). PMID- 21318748 TI - Coupling of nuclear localization signals to plasmid DNA. AB - This chapter focuses on a methodology for covalently associating nuclear localization signal (NLS) peptides to DNA, in which cationic NLS peptides are covalently bound to plasmid DNA by photoactivation. Described here are the synthesis and characterization of these conjugates. PMID- 21318749 TI - Progress toward a synthetic virus : a multicomponent system for liver-directed DNA delivery. AB - Vectors for gene transfer can be categorized as viral and nonviral. The advantages of nonviral carriers are their ease of preparation and scale-up, flexibility regarding the size of DNA to be transferred, and safety in vivo. Despite these advantages, nonviral vectors need to be further optimized for their efficiency is generally low. Thus, the future of non-viral vectors will be dependent on the possibility of creating synthetic efficient systems. A possible and reasonable approach is to develop artificial nucleic acid carriers that incorporate functional elements mimicking viruses. PMID- 21318750 TI - Characterization of polyampholyte comb-type copolymer DNA carriers. AB - The authors have reported several comb-type copolymers, consisting of a polycation backbone such as poly-L-lysine (PLL) and hydrophilic side chains of polysaccharides, for controling the assembling structure of DNA-copolymer complexes (1-3). The DNA-copolymer system consists of two phases: compacted DNA polycation complex and highly hydrated glycocalyx. The latter plays multiple roles in reducing the aggregation of the resulting complexes and increasing the solubility of the complexes (2-3). Furthermore, the grafting degree of the copolymer affects the DNA conformation in the complex, permitting regulation of DNA compaction. The comb-type copolymers with a higher degree of grafting induce little compaction of DNA and stabilize DNA duplexes and triplexes by shielding the repulsion between phosphate anions of DNA. The grafting chains also reduce the nonspecific interaction of the PLL backbone with proteins. PMID- 21318751 TI - Methods for Studying the Formation of Polycation-DNA Complexes and Properties Useful for Gene Delivery. AB - There is an urgent requirement in the field of gene therapy for gene transfer vectors that are both safe to use and able to efficiently deliver therapeutic genes to target cells in vivo. Viral vectors, such as retrovirus, adenovirus, and herpes simplex virus, are efficient in transducing a broad range of cells, but they often lead to an inflammatory response against successfully transduced tissues, along with a strong immunogenicity of the virus itself (1). A further problem is the often expensive and laborious procedure required to produce the virus in sufficient quantities. In the past decade, several nonviral gene transfer vectors based on polycations (2) and liposomes (3,4), have been developed in order to overcome such problems. These vectors are becoming increasingly popular for use in delivering DNA to target cells both in vitro and in vivo because they are generally nonimmunogenic and easier to manufacture in bulk quantities. This chapter focuses on the use of polycations in gene delivery vectors. PMID- 21318752 TI - Characterization of DNA condensates by atomic force microscopy. AB - In recent years, interest in in vitro DNA condensation has been revived by efforts to develop vectors for nonviral gene therapy (1,2). One of the critical elements for successful and versatile delivery of specific genes into targeted cells is that DNA vectors of several kilobase pairs must be compressed and packaged into small particles. Ideally, the size of these particles should be similar to that of viruses, typically less than 100 nm in diameter (3,4). It is well known that several classes of multivalent cations can be used to condense DNA in vitro to form well-defined structures, particularly toroids and rods (5,6). Because of its simplicity, this type of in vitro condensation of DNA has become a widely studied system for investigating mechanisms of DNA condensation. PMID- 21318753 TI - Rapid and Systematic Transfer and Recovery of Large BACs/PACs into Mammalian Cells by HAEC Retrofitting. AB - Studies of the human genome have prompted the development of several cloning systems that can manipulate large fragments of human DNA as functional units. The discoveries in yeast of the sequences for replication (autonomously replicating sequence [ARS]), centromeres, and telomeres have allowed the creation of large linear molecules (yeast artificial chromosome [YAC]), which can replicate and segregate as chromosomes (1). YACs have been used to generate genomic libraries from different organisms with megabase insert size and have become an essential tool for physical and genetic mapping of various mammalian genomes (2). Nevertheless, the instabilities associated with YAC libraries (chimerism and deletions) have led to the development of alternative cloning systems (3). PMID- 21318754 TI - Systemic delivery of therapeutic proteins by intramuscular injection of plasmid DNA. AB - In vivo delivery of a cytokine gene to treat a tumor has usually involved either injection of ex vivo transfected cells around the tumor site or direct intratumoral injection of a virus or plasmid DNA (pDNA) vector encoding the cytokine gene (1,2). In this manner, transfected cells in or around the tumor site may secrete cytokine locally and stimulate an antitumor immune response (3,4). Recently, a new method of cytokine gene delivery for treating tumors was described. In this method, a naked pDNA encoding a cytokine, in this case, interferon-alpha (IFN-alpha), was injected intramuscularly (im) into C57BL/6 mice bearing solid or metastatic B16F10 melanoma tumors (5). The mice treated in this manner had a striking inhibition of tumor growth. PMID- 21318755 TI - Local Delivery of Therapeutic Proteins by Intratumoral Injection of Plasmid DNA Lipid Complexes. AB - There are several strategies by which one may deliver a plasmid DNA (pDNA) encoding a therapeutic gene to a tumor. One may transfect cells ex vivo, single cell clone, expand the clone in vitro, and reinject the cells at the tumor site. This is a labor-intensive process and is especially impractical for human tumor therapy. Another method is intramuscular (im) injection of the therapeutic pDNA to achieve circulating levels of the protein (discussed in Chapter 14 by Horton and Parker). A third method is to directly inject the therapeutic pDNA into the tumor. For accessible neoplasms, this is a simple procedure, and can be useful for delivery of a therapeutic gene, such as a cytokine gene, to the tumor site. Using this technique, one may achieve high local levels of a therapeutic protein, yet have low systemic levels, thereby reducing side effects (1,2). In addition, producing a cytokine locally may attract immune cells to the tumor site and promote an antitumor immune response (1-3). Furthermore, certain cytokines may be more effective when delivered locally, rather than systemically (Horton, unpublished results). PMID- 21318756 TI - Nonviral DNA delivery from polymeric systems. AB - Gene therapy holds great promise for the treatment of disease by delivering genes encoding for therapeutic proteins. Although it was originally devised for the treatment of inherited genetic disorders, such as cystic fibrosis, recent work has expanded the applications of gene therapy to develop strategies for HIV, cancer (1), and wound healing applications (2). The challenge of gene therapy is to develop safe and efficient gene delivery systems (1). Most studies have focused on the use of viral vectors because of their potentially high efficiencies; however, the safety and ease of manufacturing of nonviral vectors may make them the preferred choice in the future. PMID- 21318757 TI - Promotion of duplex and triplex DNA formation by polycation comb-type copolymers. AB - Triplex DNA has attracted considerable interest recently because of its possible biological functions in vivo and its wide variety of potential applications, such as regulation of gene expression, site-specific cleavage of duplex DNA, mapping of genomic DNA, and gene-targeted mutagenesis (1-3). A triplex is usually formed through the sequence-specific interaction of a single-stranded homopyrimidine or homopurine triplex-forming oligonucleotide (TFO) with the major groove of the homopurine-homopyrimidine stretch in duplex DNA (1-5). In the pyrimidine motif triplex, a homopyrimidine TFO binds parallel to the homopurine strand of the target duplex by Hoogsteen hydrogen bonding to form T[Symbol: see text]A:T and C(+[Symbol: see text])G:C triplets ([Symbol: see text] and : represent Hoogsteen hydrogen bonding and Watson Crick base pairing, respectively). (1-5). Because the cytosine bases in a homopyrimidine TFO are to be protonated to bind with the guanine bases of the G:C duplex, the formation of the pyrimidine motif triplex needs an acidic pH condition, and is thus unstable at physiological pH (6-8). On the other hand, in the purine motif triplex, a homopurine TFO binds antiparallel to the homopurine strand of the target duplex by reverse Hoogsteen hydrogen bonding to form A[Symbol: see text]A:T (or T[Symbol: see text]A:T) and G[Symbol: see text]G:C triplets (1-5). Although the purine motif triplex is pH-independent, triplexes involving guanine-rich TFOs are inhibited by physiological concentrations of certain monovalent cations (M(+)), especially K(+) (9,10). PMID- 21318758 TI - Lyophilization of nonviral gene delivery systems. AB - This chapter presents a qualitative description of the freeze-drying process as it pertains to the development of stable, dry polycation-DNA complex formulations. It is not intended to be a comprehensive treatise on freeze-drying. Readers are referred to a series of excellent papers by Pikal (1-5) for more detailed, quantitative explanations of the freeze-drying process. PMID- 21318759 TI - Ultraviolet absorption and circular dichroism spectroscopy of nonviral gene delivery complexes. AB - A powerful, yet often underutilized tool available to probe the structure of macromolecules is absorption spectroscopy. The first of the various spectroscopic techniques to be widely developed, data from absorption spectroscopy is commonly viewed as low in overall information content compared to modern forms of X-ray diffraction, nuclear magnetic resonance, fourier-transformed infrared, and circular dichroism (CD) spectroscopies. With the development of diode array spectrophotometers and analysis software capable of quickly and simply producing high-definition derivative spectra, however, ultraviolet-visible spectroscopy remains a useful analytical technique, especially when applied to nucleic acids. This approach offers significant advantages in terms of flexibility, accuracy, speed, low expense, and instrumental availability. Thus, the technique can be productively applied to the analysis of nonviral gene delivery vectors, focusing primarily on the oligonucleotide component. Here are presented applications of derivative absorbance spectroscopy to the analysis of nucleic acid-cationic polymer complexes. Additionally, a brief overview of the theory, instrumentation, and general applications of zero and second-derivative absorption spectroscopy is presented, followed by a discussion of the complementary absorptive technique of circular dichroism in the same context. PMID- 21318760 TI - Characterization of synthetic gene delivery vectors by infrared spectroscopy. AB - For many decades, infrared (IR) spectroscopy has been used to characterize the structure of molecules. In IR spectroscopy, absorption of light, corresponding to vibrational and rotational transitions of a molecule, is measured. For a transition to be IR-active, a change in the dipole moment of a particular bond must occur upon excitation. This vibrational energy is not only dependent on the chemical nature of the particular covalent bonds, but also on the environment of these coupled atoms and bonds. IR spectroscopy has been previously employed in the study of the structure of nucleic acids, producing not only information about the individual bases, sugars, and phosphate backbone, but also providing information about the helical conformation of polynucleotides (1-3). IR spectroscopy has also been successfully applied to the analysis of lipids, as well as to numerous other polymers (4). Thus, IR spectroscopy potentially possesses the ability to obtain structural information about all of the components of most synthetic gene delivery complexes, as well as changes in the structure of polymeric or lipid components upon complex formation. In addition to the ability to gather detailed structural information, there are also some practical advantages to the use of IR spectroscopy for the study of plas-mid DNA and DNA complexes compared to other techniques, including the availability of a variety of sampling techniques, permitting the analysis of samples in a wide variety of physical states including solutions, solids, and gels. There is also no upper limit to the size of the sample molecule examined, allowing both short oligonucleotides and higher molecular weight DNA to be studied. IR spectroscopy is not a destructive technique, and requires only small amounts of material, making it ideal for the analysis of valuable samples. PMID- 21318761 TI - Characterization of cationic vector-based gene delivery vehicles using isothermal titration and differential scanning calorimetry. AB - Within the past 10 years, major advances in the design and development of differential scanning calorimeters (DSC) (1) and isothermal titration calorimeters (ITC) (2) have resulted in an unparalleled level of sensitivity, stability, and reproducibility in calorimetric measurements of large molecules. These improvements have allowed the thermal stability and ligand binding processes of biological macromolecules to be thermodynamically characterized with speed, accuracy, and convenience. With their increasing commercial availability, experiments that were previously limited to specialist calorimetry laboratories can now be routinely performed by most investigators. PMID- 21318762 TI - Light-scattering techniques for characterization of synthetic gene therapy vectors. AB - The colloidal properties of delivery systems currently being developed for nonviral gene therapy are extremely important. The physical stability of these systems on the shelf, as well as in the biological milieu, is mostly based on their size and interfacial properties. The size and surface charge of these systems can also have dramatic effects on their biological activity (1-4). With these facts in mind, it is apparent that adequate characterization of these properties is necessary for the development of any synthetic gene delivery system. PMID- 21318763 TI - Renal gene therapy. AB - Until now there is no renal gene therapy available for clinical use, however, gene therapy for several experimental renal diseases has been tested with promising results. The kidney is a well-differentiated organ with a variety of specialized compartments, i.e., vascular, glomerular, tubular, and interstitial. Many physiological factors such as cell turnover rate, blood flow, and urine flow, as well as anatomical factors such as glomerular basement membrane and nephron segment arrangement, may affect the specificity and efficacy of gene therapy in the kidney. On the other hand, the kidney has a major advantage over other solid organs, since it is accessible by many routes, including intrarenal artery infusion, retrograde delivery through the urinary tract, direct injection into renal parenchyma, and perfusion into the donor graft prior to transplantation (1). This chapter reviews nonviral gene transfer in the different compartments of the kidney (for review of viral vectormediated renal gene transfer, see refs. 2-5), and in skeletal muscle, for renal gene therapy, and potential applications and safety concerns for renal gene therapy. PMID- 21318764 TI - Point Mutations in the alpha-Synuclein Gene. AB - Idiopathic Parkinson's disease (PD) is an age-dependent, neurodegenerative disorder and is predominantly sporadic. Only 20-30% of patients have a positive family history for PD with a complex mode of inheritance. In a few extended families, the disease is inherited as an autosomal dominant trait. Linkage to chromosome 4 was reported in a large Italian kindred multiply affected by an early-onset form of PD (1). However, this finding was not replicated in a sample of 94 Caucasian families by Scott et al. (2), or in 13 multigenerational families by Gasser et al. (3). It has recently been demonstrated that a mutation within the a-synuclein gene on chromosome 4 segregates with disease in the Italian family (4). It was further demonstrated that the same missense mutation was also present in three Greek families with early onset PD. Sequence analysis of exon 4 of the gene revealed a single base pair change at position 209 from G to A (G209A). This mutation results in an Ala to Thr substitution at position 53 of the protein (Ala53Thr) and creates a Tsp45I restriction site (4). This is the first report of a mutation causing clinically and pathologically defined idiopathic PD associated with the critical pathologic finding, the intraneuronal inclusions called Lewy bodies in brainstem nuclei including the substantia nigra. However, KrUger et al. (5) reported a G->C transversion at position 88 of the coding sequence in two sibs and the deceased mother in a German family. It was concluded that this mutation is the cause of PD in this family. PMID- 21318765 TI - Autosomal Recessive Juvenile Parkinsonism (AR-JP): Genetic Diagnosis. AB - Autosomal recessive juvenile parkinsonism (AR-JP) is a familial levodoparesponsive parkinsonism resulting from Lewy body negative degeneration of nigral neurons in the zona compacta of the substantia nigra (1-4). The first proposal for a distinct clinical entity with recessively inherited parkinsonism was made in Japan and was termed "paralysis agitans with marked diurnal fluctuations of symptoms" (1). This syndrome was later designated as autosomal recessive form of juvenile parkinsonism (2). It was subsequently found to be linked to the 17-cM region on chromosome 6q25.2-27, and the locus was recently designated Park2 (3,5). Through the study of a patient who had homozygous microdeletion of the marker D6S305 (5), the responsible gene was identified by positional cloning and was designated parkin (6). Linkage and mutation analysis to date have shown that founders of mutations in this gene are multiple and widely distributed in the world (7-13). Abnormalities in this gene, which are specific for AR-JP, include homozygous exonic deletions, small deletions, and point mutations. The presence of homozygous exonic deletions strengthens the notion that nigral neurodegeneration in AR-JP is caused by loss of function of the parkin protein. PMID- 21318766 TI - Parkinson's Disease, Dementia with Lewy Bodies, and Multiple System Atrophy as alpha-Synucleinopathies. AB - Parkinson's disease (PD) is the most common neurodegenerative movement disorder (1). Neuropathologically, it is defined by nerve cell loss in the substantia nigra and the presence of Lewy bodies and Lewy neurites (2,3). In many cases, Lewy bodies are also found in the dorsal motor nucleus of the vagus, the nucleus basalis of Meynert, the locus coeruleus, the raphe nuclei, the midbrain Edinger Westphal nucleus, the cerebral cortex, the olfactory bulb, and some autonomic ganglia (4). PMID- 21318767 TI - alpha-Synuclein/Amyloid Interactions. AB - Human alpha-synuclein was originally identified as the precursor of a peptide named non-Abeta component of Alzheimer's disease (NAC) that was tightly associated to purified Alzheimer's disease amyloid (1). Senile amyloid plaques consist predominantly of the 39-42 amino acid residue peptide Abeta arranged in beta-pleated sheets. Abeta is generated by hydrolysis from the transmembrane amyloid precursor protein APP. The mechanism by which the intracellular presynaptic alpha-synuclein or its NAC fragment becomes integrated in extracellular senile plaques is still unclear. However, in vitro studies have shown that NAC and alpha-synuclein have the potential to participate actively in the biology of senile plaques since NAC can (1) interact with Abeta (2), (2) form amyloid fibrils (3), and (3) stimulate the aggregation of Abeta (4). alpha synuclein can also stimulate Abeta aggregation and interact with senile plaques in situ (5). The techniques described in this chapter allow the study of interactions of alpha-synuclein with senile plaques in brain sections and with Abeta peptides in solution. Information on the following points are found in Jensen et al. (5) and references therein: (1) Expression and purification of recombinant human alpha-synuclein; (2) methodology for performing sodium dodecyl sulfate (SDS) gel electrophoresis and fluorography; and (3) standard histologic techniques for fixing, sectioning, and handling of human brain tissue. PMID- 21318768 TI - Functional Defect Conferred by the Parkinson's Disease-Causing alpha-Synuclein (Ala30Pro) Mutation. AB - The association of missense mutations in the alpha-synuclein gene to heritable Parkinson's diesease (PD) indicates that dysfunction of normal alpha-synuclein metabolism, or novel gain-of-functions by the mutant peptides, can elicit early onset PD (1,2). The accumulation of alpha-synuclein in nerve cell Lewy bodies of the common sporadic PD suggests a wider role for alpha-synuclein in the development of PD (3). However, investigations into the loss and gain of functions caused by the specific mutations have been sparse, although an increased fibrillogenic potential have been reported (4,5). We have shown that a fraction of alpha-synuclein is moved by fast axonal transport to the synaptic terminus (6,7). Fast axonal transport is mediated by the motor-driven movement of vesicular structures along microtubules. By studying the interaction between alpha-synuclein and brain vesicles we discovered that the Ala30Pro mutation inhibits the interaction between mutant a-synuclein and brain vesicles (6). Hypothetically, this inhibitory effect could perturb the fast axonal transport of alpha-synuclein thus increasing its concentration in the cell body where it may aggregate into Lewy bodies. The technique described in this chapter is modified from Brown & Rose (8) and allows the study of interactions between alpha synuclein and brain vesicles and therefore the functional effects of pathogenic point mutations or deletions of specific domains. Information on the following points can be found in Jensen et al. (6,9) and references therein: (1) Mutagenesis, expression, and purification of recombinant human alpha-synucleins and (2) methodology for performing sodium dodecyl sulfate (SDS) gel electrophoresis and electroblotting. PMID- 21318769 TI - Molecular biology of dopamine-induced apoptosis : possible implications for Parkinson's disease. AB - The causes for the highly selective loss of dopaminergic neurons in the substantia nigra pars compacta in Parkinson's disease (PD) are still unknown. However, a major advance has been recently made with the introduction of the concept of apoptosis as the route leading this specific neuronal population to degeneration. Apoptosis, or programmed cell death (PCD), is an active, controlled program inherent in every living cell. Upon receiving certain signals, cells that are destined to die undergo a highly characteristic process of "suicide." This process consists of massive biochemical and morphological alterations, including cell shrinkage, loss of cell-to-cell contacts, blebbing of cell membranes, cytoskeletal rearrangements, and DNA condensation and fragmentation. It culminates in cell conversion to membrane-bound particles (apoptotic bodies) that are ready to be digested by neighboring macrophages (1-3). PMID- 21318770 TI - Animal models of induced apoptotic death in the substantia nigra. AB - Apoptosis is a form of cell death in which genetically regulated programs intrinsic to the cell bring about its own demise. In recent years, there has been a tremendous growth of interest in apoptosis as a mechanism of disease in a wide range of human disorders including the neurodegenerative diseases, such as Parkinson's disease (PD) (1). This growth of interest has spawned an extraordinary number of recent discoveries about the molecular basis of apoptosis. It is important to emphasize, however, that much of this new knowledge has been attained in the study of relatively simple systems, such as invertebrate models or mammalian nonneural cell culture systems. Less is known about these mechanisms in neural cells, and much of what is known is based on studies of peripheral neural cells (such as sympathetic ganglia and PC 12 cells) in tissue culture. Much less is known about central neurons; in particular, we know little about the regulation of apoptotic death in central neurons in living animals. It is especially important to try to identify the mechanisms of cell death in central neurons of known phenotype, particularly those implicated in human neurodegenerative disease, such as the dopamine neurons in PD. The purpose of the models we have developed of induced apoptosis in dopamine neurons of the substantia nigra (SN) is to try to translate what is being learned about the molecular mechanisms of apoptosis in simpler systems to these neurons. PMID- 21318771 TI - Apoptotic morphology in phenotypically defined dopaminergic neurons of the substantia nigra. AB - In the preceding chapter we described three paradigms by which we have studied programmed cell death in the substantia nigra (SN) of living animals: natural cell death and death induced either by developmental injury to the target striatum or by dopamine terminal destruction with the neurotoxin 6 hydroxydopamine (6-OHDA). In each of these paradigms, in order to relate experimental investigations specifically to dopamine neurons, the dopaminergic phenotype must be identified in conjunction with the demonstration of apoptotic morphology. This identification is essential, because apoptosis has been recognized in diverse neuronal populations and in glia (1). PMID- 21318772 TI - The role of nitric oxide in Parkinson's disease. AB - Neurodegenerative disorders are adult-onset disabling neurologic conditions such as Parkinson's disease (PD) in which specific subsets of brain neurons are dying. Without exception, the frequency of these disorders is increasing dramatically as the proportion of elderly in our society grows. The search for efficacious therapies, if not to prevent, at least to slow down or halt the progression of these diseases, is of major public health importance. However, this goal can only be achieved through a better understanding of the causes and mechanisms by which neurons die in these degenerative disorders. We review here the question of nitric oxide (NO), a small and ubiquitous molecule believed to be a pivotal element in the cascade of deleterious events underlying neurodegeneration in PD. Since NO synthases (NOS) are the only known enzymes that produce NO, in this chapter particular attention is paid to the anatomic distribution and catalytic activity of these enzymes in the brain. We also provide several experimental protocols commonly used for quantitative and qualitative studies of NOS. PMID- 21318773 TI - Oxidative stress indices in Parkinson's disease : biochemical determination. AB - ABSTRUCT: Parkinson's disease (PD) is associated with progressive degeneration of melanin-containing dopamine neuron cell bodies arising in the substantia nigra pars compacta (SNpc) and projecting terminals to the striatum. The disease is best characterized biochemically as a deficiency of striatal dopamine. The mechanism of neurodegeneration remains an enigma despite a large body of investigation and several hypotheses (1-5). In the past decade much has been learned about the chemical pathology of the disease. This progress has been helped by elucidation of the mechanism of the neurotoxic actions of 6 hydroxydopamine (6-OHDA) and N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which are used to induce animal models of this disease. Thus, the most valid current hypothesis concerning the pathogenesis of idiopathic PD is progressive oxidative stress (OS), which can generate excessive reactive oxygen species (ROS) selectively in the SNpc (1-9), and subsequent biochemical abnormalities (Table 1). In addition, the ROS scavenging system may also diminish, which would exaggerate the condition leading to accumulation of ROS. In PD, it is thought that both these events occur; Table 1 gives a summary of the biochemical changes identified to date in the SNpc of PD patients. Iron, monoamine oxidase B (MAO-B), copper/zinc superoxide dismutase (Cu/Zn-SOD), and heme oxygenase (radical producing) are increased; reduced glutathione (GSH) and vitamin C (radical scavenging) are decreased. Whether OS is a primary or secondary event in PD has not been established, but when it does occur, OS can lead to a cascade of events resulting in the demise of the nigrostriatal dopaminergic neurons. One approach toward protection of such neurons is the use of radical scavengers or iron chelators as neuroprotective drugs (10). Table 1 Biochemical Alterations in Substantia Nigra of Parkinson's Disease Indicating Oxidative Stress Elevated Decreased Iron (in microglia, astrocytes, oligodendrocytes, and melanized dopamine neurons and mitochondria) GSH (GSSG unchanged); GSH/GSSG ratio decreased Mitochondrial complex I Ferritin Calcium binding protein (calbindin 28) Mitochondrial monoamine oxidase B Transferrin and transferrin receptor Lipofuscin Vitamins E and C Ubiquitin Copper Cu/Zn-superoxide dismutase Cytotoxic cytokines (TNF-a, IL-1, IL-6) Inflammatory transcription factor NFKB Heme oxygenase-1 Ratio of oxidized to reduced glutathione (GSSG/GSH) Nitric oxide Neuromelanin. PMID- 21318774 TI - Quantification of tyrosine hydroxylase mRNA. AB - The main biochemical characteristic of Parkinson's disease (PD) is reduction of the neurotransmitter dopamine and the dopamine-synthesizing enzyme system, including tyrosine hydroxylase (TH, tyrosine 3-monooxygenase, EC 1.14.16.2) and tetrahydrobiopterin (BH(4) co-factor, in nigrostriatal neurons (1). The deficiency in dopamine-synthesizing enzymes is accompanied by cell loss, which is thought to be caused by unknown exogenous environmental factors as well as endogenous genetic factors. PMID- 21318775 TI - Immunochemical analysis of dopamine transporters in Parkinson's disease. AB - The identification of specific and selective markers of the dopamine-producing neurons that are lost in Parkinson's disease has been a major research focus since Hornykiewicz first reported a dopamine deficiency in the disease (1). Antibodies to dopamine or tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, have been used to identify these neurons. Recently, considerable attention has been given to the plasma membrane dopamine tranporter (DAT) and the vesicular monoamine transporter (VMAT2), which are responsible for the transport, packaging, and release of dopamine (2). DAT acts to terminate dopamine transmission by rapid reuptake of dopamine from the synapse, and VMAT2 packages cytoplasmic dopamine into vesicles for storage and subsequent release. We have developed specific antibodies to these transporters and used them to characterize the distribution and expression of DAT and VMAT2 in brain from human idiopathic Parkinson's disease and animal models of the disease. The purpose of this chapter is to describe the immunochemical techniques involved in assessing damage to dopamine neurons in Parkinson's disease and experimental models of the disease. PMID- 21318776 TI - Dopamine transporter and vesicular monoamine transporter knockout mice : implications for Parkinson's disease. AB - One of the most valuable methods for understanding the function of a particular protein is the generation of animals that have had the gene encoding for the protein of interest disrupted, commonly known as a "quo;knockout"quo; or null mutant. By incorporating a sequence of DNA (typically encoding antibiotic resistance to aid in the selection of the mutant gene) into embryonic stem cells by homologous recombination, the normal transcription of the gene is effectively blocked (Fig. 1). Since a particular protein is encoded by two copies of a gene, it is necessary to have the gene on both alleles "quo;knocked out."quo; This is performed by cross-breeding animals with one affected allele (heterozygote) to generate offspring that have inherited two mutant alleles (homozygote). This procedure has been used to generate animals lacking either the plasma membrane dopamine transporter (DAT; Fig. 2) or the vesicular monoamine transporter (VMAT2; Fig. 3). Both DAT and VMAT2 are essential for dopamine homeostasis and are thought to participate in the pathogenesis of Parkinson's disease (1-5). Fig. 1. Maps of the targeting vector and the mock construct. The mouse genomic fragment (clone 11) was isolated from a Stratagene 129 SvJ library by standard colony hybridization using a PCR probe from the 5' end of rat cDNA. The restriction site abbreviations are as follows: H, HindIII; N, NotI; Sc, SacI; Sn, SnaI; X, XbaI; and Xh, XhoI. The region between HindIII and SnaI on clone 11 containing the coding sequence from transmembrane domains 3 and 4 of VMAT2 was deleted and replaced with PGK-neo. The 3' fragment of clone 11 was reserved as an external probe for Southern analysis. To facilitate PCR screening of embryonic stem cell clones, a mock construct containing the SnaI/XbaI fragment and part of the Neo cassette was generated as a positive control. pPNT and pGEM4Z were used to construct knockout and mock vectors, respectively. (Reproduced with permission from ref. 1). Fig. 2. DAT and VMAT2 expression in wild-type and DAT knockout midbrain. DAT immunoreactivity in wild-type (A) and DAT knockout midbrain (B). VMAT2 immunoreactivity in wild-type (C) and DAT knockout midbrain (D). Robust immunoreactivity was observed in the ventral tegmental area and substantia nigra pars compacta and reticulata in the wild-type brain. Note absence of DAT immunoreactivity and modest reduction of VMAT2 immunoreactivity in the DAT knockout. Fig. 3. Characterization of VMAT2 gene disruption. (A) Southern blot analysis of mouse genomic DNA. The Southern blot was prepared with 15 MUg of genomic DNA per lane and probed with a 1.4-kb 3' external genomic fragment. +/+, wild type littermates; +/-, heterozygote; -/-, homozygote. (B) RT-PCR analysis of mouse brain poly(A)+ RNA. For each reverse transcription assay, 0.5 MUg of poly(A)+ RNA was used. Equal volumes of cDNA templates were used for each PCR assay. The PCR primers used flank the neomycin cassette for the purpose of detecting potential readthrough of the neomycin DNA. The heterozygote has a reduced amount of transcripts compared with the wild-type littermate; the homozygote is devoid of VMAT2 transcripts. G3PDH was used as internal control. (C) Western blot analysis of wholebrain synaptic vesicles. Samples (25 MUg) of vesicles were solubilized and separated by SDS-PAGE, transferred to nitrocellulose, subjected to Western blot analysis with anti-VMAT2-Ct (top) or anti-a-tubulin (bottom) antibodies, and developed with chemiluminescence. Molecular mass markers (kDa) are shown to the left. To confirm equal loading and transfer of proteins, the blots were stripped and reprobed with an antibody to alpha-tubulin. (Reproduced with permission from ref. 1). The importance of DAT in neuronal function is highlighted in animals in which DAT has been genetically deleted (DAT KO) (3). In the homozygote DAT KO mice, released dopamine remains in the extracellular space up to 300 times longer than normal. As expected, these animals display behaviors consistent with persistent activation of dopamine receptors, such as hyperlocomotion. Genetic deletion of VMAT2 reveals the essential role of vesicular storage and release of monoamines. Homozygote VMAT2 knockout mice survive for only a few days, whereas heterozygotes appear normal. Studies performed in homozygote pups and heterozygote adults clearly show that the level of VMAT2 expression calibrates the level of vesicular filling (1,2,bi4). With only 50% of normal VMAT2, heterozygote animals have reduced vesicular filling and release. These alterations in presynaptic monoamine function in the heterozygotes are thought to be responsible for the observed sensitization to the psychostimulants cocaine and amphetamine and to ethanol (1). Knockout animals also appear to parallel the changes that occur in reserpinized animals, suggesting that the adverse actions of this drug are mediated by VMAT2. PMID- 21318777 TI - Transcription mechanisms for dopamine receptor genes. AB - Transcription regulation is a complex but key control mechanism that underlies differential gene expression during development and in the adult organism. Like all protein coding genes, those encoding dopamine receptors are subject to this form of regulation as well. Modifications in dopamine receptors have been implicated in a number of neurobehavioral disorders, including Parkinson's disease and schizophrenia, as well as in the complications of their long-term therapy (1-5). Based on clinical pharmacologic observations in parkinsonian and schizophrenic patients, the D(2) dopamine receptor has traditionally been thought to be the main mediator of the motor and behavioral effects of dopamine (1,6). More recent molecular and neurophysiologic advances, in addition to the availability of receptor-selective pharmacologic agents, have clarified the importance of the D(1) class of dopamine receptors as well (7,8). The D(1A) dopamine receptor is one of two dopamine receptors abundantly expressed in the striatum (9), suggesting that it has a critical role in transmitting the nigrostriatal dopaminergic signal resulting in normal motor function. In the prefrontal cortex, the D(1A) receptor is more abundantly expressed than the D(2) receptor (10) and has been shown to modulate memory (11). PMID- 21318778 TI - Detection of DNA/Protein Interactions in Dopamine Receptor Genes. AB - ABSTRUCT: In the previous chapter, we discussed practical methods to study transcription control mechanisms for the D(1A) dopamine receptor gene. Since these processes are mediated by a complex set of nuclear regulatory proteins that interact with specific DNA sequences, methods to delineate these interactions are paramount in understanding transcription control. In the case of the D(1A) gene, we found several consensus binding sites for known transcription factors on the 5'-noncoding region and examined their binding to the nuclear proteins and known transcription factors (1). PMID- 21318779 TI - In situ hybridization on brain tissue. AB - ABSTRUCT: In situ hybridization (ISH) is an important method for determining the distribution of mRNA within cells or tissue preparations by hybridization of a nucleic acid probe (either DNA or RNA) with a specific target nucleic acid (usually mRNA) (1,2). Thus, ISH enables the localization of transcripts within cells, tissues, and whole body and allows a neuroanatomic comparison of specific mRNA expression with the respective protein expression. Furthermore, ISH can serve as a tool to detect quantitative changes in gene expression in distinct neuroanatomic areas under various experimental conditions. PMID- 21318780 TI - Regulation of Striatal N-Methyl-D-Aspartate Receptor (NMDAR) Function by Phosphorylation of its Subunits in Parkinsonian Rats. AB - The cardinal signs of Parkinson's disease (PD) reflect striatal dopamine depletion due to the progressive degeneration of neurons arising from the substantia nigra. Initially, treatment with the dopamine precursor levodopa ordinarily confers substantial clinical benefit. Later, however, increasing difficulties arise mainly due to the appearance of motor response fluctuations and dyskinesias complicating the treatment of late-stage PD (1-6). Available evidence suggests that standard dopaminomimetic treatment regimens promote the intermittent activation of striatal dopaminergic receptors, which under normal conditions operate mainly tonically (7), and that this nonphysiologic stimulation favors the appearance of the motor fluctuations and dyskinesias (8). PMID- 21318781 TI - Chronic Intracerebral Delivery of Trophic Factors via a Programmable Pump as a Treatment for Parkinsonism. AB - The most common treatment for Parkinson's disease (PD) aims at pharmacologically augmenting striatal dopamine (DA) using the DA precursor levodopa. Such treatment provides symptomatic relief, but does not slow or halt continued degeneration of nigral dopaminergic neurons. Considerable effort has been devoted to the search for neurotrophic factors with survival-promoting activities on dopaminergic neurons that could potentially be of therapeutic value in the treatment of PD. One such candidate is glial cell line-derived neurotrophic factor (GDNF). PMID- 21318782 TI - Grafting genetically engineered cells into the striatum of nonhuman primates. AB - An emerging new technology based on genetic engineering of viral vectors that can insert genes into the cells of living organisms may play a significant role in treating disorders of the central nervous system (CNS). Most neurodegenerative disorders affect focal regions of the brain. Preventive and/ or palliative treatment strategies need to be targeted only to the diseased parts of the brain without affecting other regions. Administration of therapeutic genes specifically to the disease-affected regions of the brain may be more beneficial than current treatment strategies, which are largely based on systemically administering small molecules. The latter can result not only in peripheral side effects but also CNS side effects since the drugs can affect both targeted and nontargeted brain sites. In addition, many therapeutic agents are prevented from entering the brain by the blood-brain barrier (BBB). For these reasons, many otherwise potentially useful proteins, such as trophic factors, cannot be administered systemically (1). PMID- 21318783 TI - Encapsulated cell implants as a novel treatment for Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive degeneration of the dopaminergic cells of the substantia nigra pars compacta (SNPc). Systemic levodopa therapy has proved to be an effective initial treatment for this disorder. However, resistance to this therapy inevitably develops with time, necessitating other approaches including surgery. Current experimental surgical treatments for this disorder include pallidal stimulation, pallidal lesion, subthalamic stimulation, and dopaminergic cell transplants. The current limitation of these approaches is that they all treat the symptoms but not the cause, that is, the progressive degeneration of the SNPc goes unabated. PMID- 21318784 TI - Neural stem cell technology as a novel treatment for Parkinson's disease. AB - The transplantation of human fetal ventral mesencephalic (VM) tissue for patients with advanced Parkinson's disease (PD) has now proved to be of benefit in early clinical trials (1-3). This has been clearly seen in terms of improved motor function, which has been correlated with increased fluorodopa signal on positron emission tomographic scanning at the site of the implant and the presence of abundant tyrosine hydroxylase (TH)-positive neurons in those patients who have come to postmortem analysis (4,5). However, although the concept of restoration of function through neural transplantation is promising, there are major practical as well as ethical problems with the use of aborted human fetal tissue. In particular, aborted fetal tissue is not available in many countries, and even where it can be obtained, isolation of the VM from the large numbers of fetuses the procedure requires presents major logistical difficulties. For example, in PD the best results have been obtained using an average of six to eight fetuses per patient. Therefore, the search for alternative sources of tissue for transplantation is imperative if the procedure is to be widely adopted in the clinical domain. A number of possibilities are currently being explored experimentally (see Table 1), although all of them present difficulties that must be overcome before they can be adopted clinically (reviewed in ref. 6). Table 1 Alternatives to Primary Human Neuronal Cells for Transplantation in PD Dopamine containing polymers that release dopamine slowly over months/years. Catecholamine producing cells found naturally within the adult, which may thus be suitable for autotransplantation, e.g., adrenal medulla, carotid body, superior cervical ganglion. Catecholamine-producing cell lines that may be encapsulated to prevent rejection and spread of the tumour cells out into the host brain, e.g., PC12 cells. Cells transfected with tyrosine hydroxylase, which potentially allows for the possibility of autotransplantation, e.g., skin fibroblasts. Xenografts of dopamine-rich tissue, e.g., embryonic porcine ventral mesencephalic tissue. Neural stem cells. Embryonic stem (ES) cells. PMID- 21318785 TI - Renal cell carcinoma : clinical features and management. AB - In 1999 it was estimated that renal cell carcinoma (RCC) would account for 29,990 new cancer cases diagnosed in the United States (61% in men and 39% in women), and lead to 11,600 deaths. RCC accounts for 2-3% of all malignancies in adults and causes 2.3% of all cancer deaths in the United States annually (1). Approx 4% of all RCC cases are bilateral at some point in the life of the patient. Data from over 10,000 cases of renal cancer entered in the Connecticut Tumor Registry suggests an increase in the incidence of renal cancer from 1935-1989; in women the incidence increased from 0.7 to 4.2 in 100,000, and in men from 1.6 to 9.6 in 100,000 (2). Factors implicated in the development of RCC include cigarette smoking, exposure to petroleum products, obesity, diuretic use, cadmium exposure, and ionizing radiation (3-9). PMID- 21318786 TI - Pathology of kidney tumors. AB - The classification of epithelial tumors of the kidney has undergone considerable change in the last two decades. Systems based on cytoplasmic characteristics and cytogenetic analysis have expanded our understanding of this group of tumors. These new, nontraditional systems have led to the development of a more clinically significant pathological classification (1,2). Although many questions remain unanswered and debate continues concerning the validity of these proposals, research studies on epithelial neoplasms of the kidney must take these advances into consideration. Scientific studies of any type should incorporate information regarding the type of tumor(s) included in the study group. This chapter briefly reviews the accepted subtypes of renal epithelial neoplasms, with a focus on the morphological features that distinguish them. PMID- 21318787 TI - Telomerase assay in renal cancer. AB - Telomeres are repeating sequences located at each end of eukaryotic chromosomes. These sequences function to protect chromosome positioning and replication (1-3). In vertebrates, telomere DNA consists of tandem repeats of TTAGGG, 10-15 kb pairs long (4). In most normal cells, DNA replication during mitosis results in the loss of telomere sequences 50-100 bp at the 5' ends of DNA termini (1,5). This sequence loss is mandated by the end-replication-splicing problem (Fig. 1). Thus, telomeres progressively shorten with age in somatic cells in culture and in vivo. In contrast, cancer cells and malignant cell lines retain telomere length despite repeated mitosis (6). This is believed to be an essential component of immortalization for most cells. Fig. 1. End-replication problem. As the replication fork proceeds from left to right, the leading strand proceeds to replicate one strand of original DNA (see B). The direction of the lagging strand is opposite to the direction of the replication fork and relies on the ligation of Okazaki fragments, which are primed with short stretches. Most RNA primer is never replaced with DNA (see C). Consequently, each round of replication produced a daughter chromosome. These are deficient in the sequences corresponding to the original 3' ends. PMID- 21318788 TI - Comparative genomic hybridization. AB - Comparative genomic hybridization (CGH) allows a genome-wide survey of the relative copy number of tumor DNA in a single hybridization. The tumor-cell DNA (Test DNA) is hybridized together with a sex-matched normal DNA (Reference DNA) onto normal metaphase spreads. Test DNA and Reference DNA are labeled with fluorochrome-conjugated reagents of different color, thereby allowing the detection of genetic imbalance in the abnormal cells. PMID- 21318789 TI - Analyzing the FHIT Gene by RT-PCR, Western Blotting, and Immunohistochemistry. AB - FHIT (fragile histidine triad) is a tumor-suppressor gene located at chromosome band 3p14.2. The genomic locus, which is greater than 1 Mb, contains 10 small exons that make up the 1.1-kb FHIT cDNA. The coding region starts in exon 5 and stops in exon 9, producing a 16.8-kDa cytoplasmic protein. The FHIT locus contains the hereditary renal cell carcinoma (RCC) t(3;8) translocation, and also encompasses the FRA3B common fragile region (for review, 1). Numerous studies have proven that the FHIT gene is inactivated by deletions in both primary tumors and cell lines derived from head and neck, stomach, lung, and kidney cancers (2 6). Since FHIT is inactivated in so many cancers, it is essential to learn its normal function and analyze how the loss of its function contributes to the progression and development of cancer. For example, an early event in the lungs of a smoker is breakage at the FHIT locus, causing a reduced or absent FHIT protein expression in the preneoplastic lesions. Compensation for the functional loss of FHIT via a recombinant, nonfragile FHITgene may prove therapeutically useful (7,8). Our studies have also shown that the FHIT gene is altered or absent in the majority of transitional-cell carcinoma (TCC) cases of the bladder examined (9). Through the utilization of molecular techniques such as those described here, FHIT alterations may be detected in an early stage of cancer, and thus prove to be a useful diagnostic tool to prevent cancer progression. PMID- 21318790 TI - Detection of apoptosis in renal cell carcinoma. AB - Apoptosis is a selective process of programmed cell death that plays an important role in both physiologic and malignant states. In neoplastic disease, the rate at which a tumor grows depends on cell deletion as well as cell proliferation. It has been shown in several types of tumors that more aggressive tumors usually have a higher proliferative activity as well as an increased rate of apoptosis. The same characteristics seem true of renal neoplasms, as the frequency of apoptosis has been positively correlated with tumor grade, stage, and size in renal cell carcinoma (RCC) (1). Apoptosis is closely related to proliferative activity, tumor differentiation, and depth of invasion in transitional-cell carcinoma of the renal pelvis and ureter (2). The mechanisms of cell-cycle control, proliferation, and apoptosis are key issues in the biology and prognosis of RCCs. The expression of bcl-2 and p53 has been implicated in the control of apoptosis in tumorigenesis, and as a possible pathway to which cancer treatments could be directed. A reciprocal correlation was found between apoptosis and p53 positivity in RCC suggesting that the presence of mutant p53 is a negative regulator of apoptosis (3). PMID- 21318791 TI - Fluorescence In Situ Hybridization (FISH) to Metaphase and Interphase Chromosomes. AB - The unambiguous identification of human chromosomes became possible with the discovery and implementation of G-banding techniques (1). Almost immediately, investigators developed various methods to physically map specific DNA sequences to banded chromosomes. A commonly used early technique involved the hybridization in situ of radioactively labeled probes to heat-denatured human metaphase chromosomes (reviewed in 2). These techniques were efficient, yet costly, time consuming, and technically difficult. Isotopic hybridization in situ was rapidly superseded by nonisotopic techniques-especially those utilizing fluorescently labeled probes (3-6). This chapter describes basic methodology for the accomplishment of metaphase and interphase fluorescence in situ hybridization (FISH). PMID- 21318792 TI - Polymerase chain reaction detection of DNA sequence deletions. AB - Allelic loss of human chromosome sequences contributes to tumorigenesis through the inactivation of putative tumor-suppressor genes. The Knudson hypothesis proposes that deletion or mutation must affect both alleles of the gene in order to disable tumor suppression (1). As might be expected, the effect of "two hits" on tumor-suppressor gene integrity-e.g., deletion of one allele and mutation of the remaining allele-would disable the gene from encoding gene product. The von Hippel-Lindau (VHL) gene is an example of a tumorsuppressor gene that fulfills the Knudson hypothesis-e.g., one mutant allele is inherited in the germline, and the other is mutated or deleted somatically in many clear-cell renal cell carcinomas (recently reviewed in ref. 2). PMID- 21318793 TI - Matrix metalloproteinases and their inhibitors. AB - Matrix metalloproteinases (MMPs) are a group of 16 enzymes that are capable of degrading extracellular matrix components. Their catalytic function is dependent on a zinc ion in the active center. MMPs are separated in three groups: gelatinases (type IV-collagenases), stromelysins, and interstitial collagenases. Their physiological and pathological significance is to modulate the extracellular matrix-e. g., in embryogenesis, in the ovarian cycles, or in inflammatory diseases such as rheumatoid arthritis or fibrosis of the liver or kidney (1,2). PMID- 21318794 TI - Purification of Growth Factor mRNA in Renal Tissues:bFGF-2, FGF-2, TGFalpha, and EGFR. AB - Growth factors are polypeptides that induce cell mitogenicity, and thus play an important role in the etiology and progression of tumors (1). Fibroblast growth factors (FGF) constitute a family of structurally related polypeptides of 146 amino acids, which exhibit a wide spectrum of biologic activities, including angiogenesis or the formation of a vascular network. FGFs are mitogenic towards many mesodermal and ectodermal cell types, and can also induce and/or inhibit differentiation of cells (2). These heparin-binding factors are categorized as FGF-1 through FGF-10. Acidic FGF, or FGF-1, is found mostly in brain and other neural tissues. Basic FGF, or FGF- 2, a protein of 18 kDa mw, is one of the most ubiqitous growth factors. It is found in numerous benign and cancerous human and animal tissues, including kidney, prostate, and bladder (3-6). In some cases it has also been demonstrated to have potential as a tumor marker (7-11). One group reported greater recovery of both FGF-2 protein and FGF-2 mRNA from renal-cancer tissue compared to equal amounts of normal renal tissue (5). Furthermore, when purified FGF-2 from renal cell carcinoma (RCC) is added exogenously to other established renal tumorcell lines and endothelial cell lines, it demonstrates significant mitogenic activity (6). Thus, renal tumors may use FGF-2 in an autocrine manner to sustain themselves. PMID- 21318795 TI - Laser-capture microdissection. AB - Laser-capture microdissection is a recently discovered state-of-the-art method to obtain cells for genetic analysis. It is a one-step procedure that allows capture of selected cells under direct microscopic visualization. PMID- 21318796 TI - Expression of c-met and WT-1. AB - Protooncogenes and tumor-suppressor genes are two types of genes associated with cancer development. PMID- 21318797 TI - Molecular analysis of the von hippel-lindau disease gene. AB - Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder that predisposes the affected individual to develop characteristic tumors. These include CNS hemangioblastoma, retinal angiomas, endolymphatic sac tumors, pancreatic cysts and tumors, epididymal cystadenomas, pheochromocytomas, renal cysts, and clear-cell renal carcinoma. The VHL gene was localized to 3p25 and then isolated by Latif et al. (1). The gene contains three exons with an open reading frame of 852 nucleotides, which encode a predicted protein of 284 amino acids. The VHL protein is believed to have several functions. It is involved in transcription regulation through its inhibition of elongation by binding to the B and C subunits of elongin. Mutations of VHL allow the B and C subunits to bind with the A subunit. This complex then overcomes "pausing" of RNA polymerase during mRNA transcription (2,3). Several studies suggest that the VHL protein is also involved in regulation of hypoxia-inducible transcripts, particularly vascular endothelial growth factor (VEGF), by altering mRNA stability (4,5). Therefore, VHL gene mutations permit the overexpression of VEGF under normoxic conditions, which leads to the angiogenesis believed to be required for tumor growth. The VHL-elongin BC complex (VBC) also binds two other proteins-CUL2 and Rbx1-in a complex that has structural similarity to other E3 ubiquitin ligase complexes (6). Such complexes mediate the degradation of cell-cycle regulatory proteins. PMID- 21318798 TI - Experimental models and methods in antibody targeting of renal cell carcinoma. AB - Metastatic renal cell carcinoma (RCC) is incurable and there are few treatment options that assure even a short prolongation in survival. It is the most common malignancy of the adult kidney and accounts for approximately 12,000 deaths per year (1). Due to a lack of diagnostic markers for early detection and the infrequency of notable symptoms early in the disease process, about one third of patients present with known metastatic disease. However, the staging of RCC is an inaccurate science and in 40% of those patients where a nephrectomy is the treatment choice for presumed organ-confined disease, metastases become evident within about 1 yr (2). For reasons that are poorly understood, metastatic RCC has remained relatively resistant to chemotherapy, biological response modifiers and cellular immunotherapy-although, glimpses of encouragement have appeared in numerous studies. These are discussed in great depth throughout the accompanying chapters. PMID- 21318799 TI - Orthotopic model of renal cell carcinoma. AB - A human renal cancer was first established in continuous culture in 1962. Currently, there are well over 100 different characterized renal cancer cell lines derived from both primary and metastatic renal cell carcinomas (RCCs) (1 3). The biological phenotype of cultured renal cancer cells typically includes a sustained and essentially unlimited growth capacity, a lack of contact inhibition and anchorage dependence, a capacity to form tumors in athymic mice, and an aneuploid karyotype including nonrandom chromosomal abnormalities (1,2). The antigenic phenotype of RCCs as determined by monoclonal antibodies (mAbs) generated against cell-surface glycoproteins, glycolipids, and blood-group antigens of renal cancers provide a series of phenotypic markers which characterize these tumors (4-6). Many of these mAbs also react with the proximal tubule portion of the human nephron, confirming earlier studies indicating that >90% of renal cancers derive from epithelial cells of the proximal tubule (7,8). While established RCC cell lines have frequently been analyzed for molecular defects, their greatest utility has been to screen combinations of chemotherapeutic and biologic agents for antiproliferative activity (9-12). Short term cultures of renal cancer cells derived from fresh tumor specimens have similarly been used to screen drugs (13), but inhibitory effects in vitro have not been shown to predict a response in vivo (i.e., in human patients). PMID- 21318800 TI - Murine animal model. AB - Experimental animal models are available for the development of new treatment. Murine animal models have particular advantages for comparative study to evaluate the efficacy and safety of different treatment modalities because many mice can be treated at the same time with easy handling. Among several experimental models, murine renal carcinoma (Renca), which arises spontaneously in Balb/c mice, is the most frequently used for the assessment of chemotherapy, immunotherapy, and radiotherapy. Renca cells readily establish tumors in isogenic mice, producing histologically proven adenocarcinoma with a predictable growth rate to mimic the clinical situation for orthotopic growth and metastasis in a reasonable time frame. Because of its poor immunogenicity and its responsiveness to immunotherapy, the number of studies using cytokine gene-modified tumor vaccines-such as interferon-alpha or interleukin-2-in the Renca system is growing. Therefore, Renca experiments greatly contribute to the analysis of the mechanisms of antitumor immune response. In this chapter, we describe several experimental systems using this Renca model. PMID- 21318801 TI - Angiogenesis assays. AB - Angiogenesis-the formation of a vascular network-is essential for the support of a developing tumor when simple diffusion of nutrients is impossible. The ability of a solid tumor to achieve metabolic needs beyond simple diffusion is dependent on the development of this neovascular network. The process of angiogenesis lets the tumor become self-sufficient to grow, and also gives it the ability to metastasize. Growth factors added to human-vein endothelial cells in culture may demonstrate tubularization of cells, but this does not necessarily imply angiogenesis. True in vivo angiogenesis means not only the mobilization of endothelial cells, but the degradation of the matrix and the formation of vessel sprouts in a network that can transport red blood cells (RBCs). PMID- 21318802 TI - Antiangiogenic approaches to renal cell carcinoma : assays for inhibitors and clinical trials. AB - Angiogenesis-the formation of new blood vessels from preexisting ones-is a complex process regulated by a number of soluble factors as well as important interactions between endothelial cells, extracellular matrix components, and adjacent cells (1-5). Activation of the endothelial cell, which occurs when the balance between proangiogenic and antiangiogenic signals within a given microenvironment tilts in a positive direction, leads initially to increased expression of proteases, allowing the endothelial cell to mobilize itself and release inducers sequestered within the matrix (1,6,7). This is followed by endothelial-cell proliferation and migration and culminates in reorganization of the endothelial cell plexus to form tubules and eventually capillary structures that can conduct blood. Most proangiogenic factors-such as VEGF and basic fibroblast growth factor (bFGF)-are peptide growth factors that bind to transmembrane-receptor tyrosine kinases on the surface of the endothelial cell, initiating intracellular transduction pathways resulting in cellular activation (8,9). Other important angiogenic factors-the angiopoietins-further modulate this process by stabilizing or destabilizing interactions between small blood vessels and adjacent pericytes (10 ). Expression of angiopoietin 2 results in dissociation of pericytes, which can lead to endothelial-cell activation or vascular regression, depending on whether angioinductive or angioinhibitory signals predominate (10,11). In contrast, angiopoietin 1 stabilizes interactions with pericytes and promotes vascular quiescence (10,12). PMID- 21318803 TI - Interferon Alpha, GM-CSF-Activated T Cells, and IL-6 in Renal Cell Carcinoma. AB - Treatment of renal cell carcinoma (RCC) has historically involved surgical removal of the primary tumor when localized, but when presented with metastatic disease the options have been limited. Approximately 30% of patients present with metastatic disease implicating a generally poor prognosis. The most significant advances have occurred in the area of immunotherapy as treatment for metastatic disease. This is because RCC is generally resistant to chemotherapy and radiation. One of the major successes of immunotherapy has been with interleukin 2 (IL-2). Initial IL-2 therapy proved difficult due to the significant administrative and side effect problems that occurred. This led to numerous variations in dose scheduling and delivery to identify an optimal beneficial way of administering IL-2. In addition, investigation also led to other immunotherapy agents such as interferon and cellular therapy. PMID- 21318804 TI - Immunotherapeutic approach to cancer with cutaneous DNA vaccination. AB - Innovations for the development of cancer vaccines are emerging from advances in molecular immunology and cancer biology (1). Of these, DNA-based vaccination has become a powerful and potentially versatile method for eliciting an immune response against cancer. One method for DNA immunization involves the delivery of plasmid DNA by particle bombardment. Originally developed for plant hybridization, this approach has proven to be readily transferable to mammalian applications (2-3). Otherwise known as the gene gun, this method allows for the introduction of exogenous "naked" DNA into skin (4) (Fig. 1). Fig. 1. Photograph of the helium-driven gene gun. This is a hand-held device attached to a high pressure helium line and electrical source which operates the trigger. As shown, plastic bullets containing gold particles coated with plasmid DNA are measured and cut to fit within a cartridge. The cartridge, filled with 12 bullets, is easily placed within the barrel of the gun. PMID- 21318805 TI - Monoclonal antibodies : generation and clinical use. AB - Originally, the term "antibody" referred to an unknown entity in serum, which had the capacity to neutralize pathogenic bacteria. Ehrlich discovered that the socalled antibody had to be a discrete substance, and was the first to propose a theory on antibody formation (1). A few years later, he hypothesized that antibodies might be applied for selective treatment of cancer, provided that the antibody showed specificity for the tumor tissue (2 ). Later studies showed that antibodies could be produced against a wide variety of substances, including tumors. PMID- 21318806 TI - Treatment strategies in metastatic renal cell carcinoma : cytokines, vaccines, and gene therapy. AB - In recent years, the incidence of renal cell carcinoma (RCC) has increased dramatically (54% from 1975 to 1990), and in 1996, approx 30,000 new cases were diagnosed in the United States (1). In the same year, an estimated 12,000 RCC related deaths occurred in the United States. The increased incidence of RCC in recent years may be linked to certain risk factors such as smoking, obesity, high protein diets, and hypertension (2). PMID- 21318807 TI - 23 assessment of T-cell immune dysfunction in patients with renal cell carcinoma. AB - Functional T cells are the central component of an effective antitumor immune response. However, in patients with renal cell carcinoma (RCC), the growth of antigenic tumors proceeds in the absence of significant T-cell responses, posing a distinct obstacle to the development of effective immunotherapy strategies and cancer vaccines. The minimum required elements of a functional antitumor immune T cell response have been identified, including T cells that can preferentially recognize tumor-associated antigens (1). However, despite increasing evidence that T-cells recognize discrete tumor antigen, transformed cells continue to evade immune destruction, and tumors thereby progress. There is now little doubt that the immune response to tumor antigens is altered in patients with cancer (2). This rarely manifests clinically as generalized immune suppression, which may reflect the antigen specificity of the immune dysfunction in the initial stages of the disease. PMID- 21318808 TI - Transforming Growth Factor-beta1 as a Novel Marker of Response to Therapy for Renal Cell Carcinoma. AB - Renal cell carcinoma is expected to account for 30,000 new cancer cases and 11,900 cancer deaths in the United States in 1999 (1). At the time of initial presentation, up to one-third of patients with renal cell carcinoma (RCC) have metastatic disease; furthermore, almost half of the patients resected for cure will relapse (2). Due to the poor results of cytotoxic chemotherapy in the management of metastatic RCC (3), physicians have explored the use of new therapies including immunotherapy and gene therapy. Some of these therapies are discussed in other chapters of this textbook. The use of these new therapies allows for the identification and utilization of new tumor markers that may allow investigators to identify patients at risk for advanced disease as well as establish new definitions of tumor response. PMID- 21318809 TI - Static and flow cytometry. AB - It has been known for over 50 years that the amount of nuclear chromatin (DNA) in malignant neoplasms differs from that of homologous normal cells (1). More recently, it has been shown that nuclear DNA content correlates with the clinical outcome of various human neoplasms including urologic malignancies (2-10). An important problem in the care of patients with renal cell carcinoma (RCC) is the prediction of the neoplasms malignant potential, and in turn the patient's prognosis. Various parameters have been used to assess the malignant potential of renal cell carcinoma, including clinical and pathologic stage, histologic grade, tumor size, nuclear morphology, immunohistochemistry, age, elevated erythrocyte sedimentation rate, and hypercalcemia. To date, the most important predictors of prognosis in patients with RCC have been tumor pathologic stage, histologic grade and type (11,12). However, it has been shown that patients within a specified stage and grade may differ in their disease progression and survival (13,14). Furthermore, none of these variables alone or in combination has shown to provide total reliable prognostic information for the individual patient. These reasons led several groups to evaluate the prognostic value of nuclear DNA content in patients with renal cell carcinoma. PMID- 21318810 TI - Microdissection of histologic sections : manual and laser capture microdissection techniques. AB - The molecular analysis of human cancer is complicated by the difficulty in obtaining pure populations of tumor cells to study. One traditional method of obtaining a pure representation has been establishing cancer cell lines from primary tumors. However, this technique is time consuming and of low yield. Artifacts of cell culture include the selection of genetic alterations not present in primary tumors (1,1) and the alteration of gene expression as compared to primary tumors (3). When molecular techniques move from experimental to diagnostic settings, the need for robust, reproducible and "real time" testing will probably therefore require the direct analysis of tissue samples. PMID- 21318811 TI - Isolation of a purified epithelial cell population from human colon. AB - While in situ techniques have been valuable in identifying the presence and localization of cytoplasmic and membrane components in tissue (1), there is often a need to study directly one or more cell types, free from its own microenvironment. For the human colon, isolation techniques to allow direct study have been described for mononuclear cells in the lamina propria, smooth muscle cells at or below the muscularis mucosae, and cells of the enteric nervous system, located between the subserosa and the lamina propria (2-4). More recently, interest has risen to isolate populations of intestinal epithelial cells, for investigations of human colonic adenocarcinoma-which originates from colonic epithelia; as well as for study of the epithelial response to infection and inflammation. The technique for isolating epithelial cells from the human colon involves mechanical dissection to separate mucosa from the muscle layers which are discarded; and enzymatic digestion of collagen, followed by discontinuous gradient centrifugation in Percoll. The goal is to isolate>90% pure epithelial cells. Although the cells appear intact under the microscope, viability is variable from 50-80%. The yield depends on the size of the available tissue. PMID- 21318812 TI - Xenografting human colon cancers. AB - Xenografting of human tumors has been used to produce samples which are enriched for neoplasia and optimal for subsequent molecular analyses. Molecular studies of xenograft tumors generated from both human colon and pancreatic adenocarcinomas have led to the discovery of important genetic alterations underlying these malignancies (e.g., Smad4, Smad2) (1,2). Moreover, analysis of pancreatic xenografts helped facilitate the discovery of BCRA2 through identification of homozygous deletions ( 3 ). Furthermore, xenografted tumors have facilitated the discovery of distinctive allelic loss patterns in pancreatic and stomach adenocarcinomas (4,5). Comparative genomic hybridization analysis of xenografted human gastric cancers has demonstrated consistent DNA copy number changes, including both gains and losses of chromosomal regions (6). PMID- 21318813 TI - Comparative genomic hybridization technique. AB - Screening for chromosomal changes in solid tumors was long hindered by methodological problems encountered in standard cytogenetic analysis. Comparative genomic hybridization (CGH), a technique that emerged in 1992 (1) has proved to be a powerful tool for molecular cytogenetic analysis of neoplasms. The main prerequisite of the technique is DNA isolated from tumor samples. As no cell culture of tumor material is required, the technique has been successfully used to study fresh and frozen tissue samples, as well as archival formalin-fixed paraffin-embedded tissue samples. CGH allows to screen entire tumor genomes for gains and losses of DNA copy number, enabling consequent mapping of aberrations to chromosomal subregions. The technique is based on fluorescence in situ hybridization. Tumor and reference DNA are differentially labeled with fluorochromes (green and red, respectively) and mixed in equal amounts. The mixture is cohybridized competitively to a normal metaphase slide prepared from a lymphocyte cell culture of a normal healthy individual. After hybridization and washes, the chromosomes are counterstained with DAPI (blue) and slides are mounted with an antifading medium. PMID- 21318814 TI - Fluorescence in situ hybridization : application in cancer research and clinical diagnostics. AB - An opportunity to look inside of the individual cell for the direct visualization in situ of "what happened?" is the most wonderful feature offered by fluorescence in situ hybridization (FISH). DNA in situ hybridization is a technique that allows the visualization of defined sequences of nucleic acids within the individual cells. The method is based on the site specific annealing (hybridization) of single-stranded labeled DNA fragments (probes) to denatured, homologous sequences (targets) on cytological preparations, like metaphase chromosomes, interphase nuclei, or naked chromatin fibers. Visualization of hybridization sites becomes possible after detection steps by using a wide spectrum of the fluorescent dyes available. PMID- 21318815 TI - Microsatellite analysis to assess chromosome 18q status in colorectal cancer. AB - Loss of the long arm of chromosome 18 (18q) is one of the most common genetic changes in colorectal cancer. This chapter describes the method to determine chromosome 18q status using microsatellite markers. Specifically, tumor and normal tissue are separated by microdissection of routine formalinfixed paraffin embedded tissues obtained from surgical resection. Total genomic DNA are isolated and subjected to polymerase chain reaction (PCR) using polymorphic microsatellite markers located on the long arm of chromosome 18 (1). PMID- 21318816 TI - The SURF Technique : Selective Genetic Analysis of Microscopic Tissue Heterogeneity. AB - Selective ultraviolet radiation fractionation (SURF) is a simple technique for the isolation of histologically defined microscopic tissue regions (1,2). Very small numbers (100-400) of cells can be rapidly isolated with relatively crude equipment. The isolated cells can be analyzed genetically by PCR, thereby allowing a direct comparison between microscopic phenotype with genotype. The ability to compare genotype between different tissue areas provides opportunities to analyze many disease processes, including the heterogeneity expected of multistep tumor progression. PMID- 21318817 TI - Microsatellite instability testing. AB - Microsatellites are tandem repeats of simple sequences that occur abundantly and are randomly interspersed throughout the human genome. They typically consist of 10-50 copies of 1-6 bp motifs, and are characterized by a high degree of polymorphism. Despite the variability observed among individuals, microsatellite are replicated faithfully at each cell division in normal germline and somatic cells (1). PMID- 21318818 TI - Immunohistochemical Analysis for hMLH1 and hMSH2 Expression in Colorectal Cancer. AB - Defective DNA mismatch repair (MMR) occurs in the majority of tumors from patients with hereditary non-polyposis colorectal cancer (HNPCC) and approx 15% of sporadic colorectal cancer (CRC) (1,2). In HNPCC-associated tumors, defective MMR is most often due to inactivating mutations of the DNA MMR genes hMLH1 and hMSH2 (3,4). Defective MMR in sporadic CRC, on the other hand, is generally due to hypermethylation of the hMLH1 promoter (5-7). As might be expected, inactivating mutations of hMSH2 and hMLH1 lead to a loss of hMSH2 or hMLH1 expression respectively and hypermethylation of the hMLH1 promoter to a loss of hMLH1 expression (5-8). One of the hallmarks of defective DNA MMR is a type of genetic instability known as microsatellite instability (MSI). Tumors with defective DNA MMR generally exhibit MSI at the majority of the loci examined (MSI H phenotype) (8,9). PMID- 21318819 TI - Mutation detection in colorectal cancers : direct sequencing of DNA mismatch repair genes. AB - The detection of unknown mutations has proved complex and time consuming, and this is certainly the case for HNPCC. Germline mutations have been detected in five of the six human DNA mismatch repair genes (in hMLH1, hMSH2, hMSH6, hPMS1, hPMS2, but not hMSH3) in HNPCC patients (1-7) with hMLH1 and hMSH2 being the most frequently affected (8-9). Point mutations resulting in missense, nonsense and frameshift alterations are found in HNPCC, as well as mutations leading to splicing alterations (9). The detection of mutations in these genes has relied upon direct sequencing of genomic DNA. Scanning or prescreening methods have been investigated (12-15), but at this stage direct sequencing is the gold standard by which these methods are generally judged. One caveat however, is that this method does not detect deletions that span exons or entire genes, the frequency of which may be up to 6.5% of HNPCC cases (16). To be rigorous, it would be prudent to include direct sequencing along with Southern analysis. This chapter will focus on the direct sequencing of hMLH1 and hMSH2, although the overall strategy may also be used for the analysis of the other mismatch repair genes. PMID- 21318820 TI - Mutation Detection inTGF-beta Receptors. AB - The transforming growth factor beta (TGF-beta) receptors are an important class of tumor suppressor gene. TGF-beta markedly inhibits the growth of many epithelial cell types; whereas in contrast, cancers of many different tissue types are commonly TGF-beta resistant (10). Many cancer cell lines are resistant to the growth suppressive effects of TGF-beta and display evidence of disruption of TGF-beta signal transduction (10,4,10). To date, this resistance appears to often result from mutations in the TGF-beta receptors or the smad family of TGF beta signaling proteins (5,11,12,14,16). PMID- 21318821 TI - Direct analysis for familial adenomatous polyposis mutations. AB - Over the past decade, the genes that underlie the development of many human diseases have been identified and the diseases causing mutations within these genes have been unveiled. Many genetic alterations responsible for a variety of human disorders have been characterized. These alterations range from simple Mendelian inherited syndromes to more complex traits such as cancers that involve multiple genetic and environmental factors. Identification and characterization of disease-causing mutations has practical as well as biological implications. As our understanding of these alterations advances, the potential for developing molecular genetic markers with clinical applications increases. This improved understanding also opens new avenues for advances in diagnostic testing, prognostication, and design of preventative strategies or therapeutic interventions. Indeed, direct genetic testing for an inherited colorectal cancer predisposition syndromes, Familial Adenomatous Polyposis (FAP) is currently available to the medical community with appropriate genetic counseling (1). PMID- 21318822 TI - I1307K Mutation Detection by Allele-Specific PCR in Familial Colorectal Cancer. AB - Familial colorectal cancer (FCC) is a hereditary form of colorectal cancer that accounts for 15-50% of all colorectal cancers (1,2). FCC patients generally have one or two family members affected with colon polyps or cancer. A mutation (I1307K) in the APC gene has been associated with colorectal cancer in Ashkenazi Jews (3). This specific mutation is detected in approx 6% of the Ashkenazic Jewish population. The frequency increases to about 28% in Ashkenazim with a family history of colorectal cancer. A person carrying this mutation will have a twofold increased risk, over the general Ashkenazic Jewish population, of developing colorectal cancer in his or her lifetime (3). This risk is estimated to be approx 18-30% (3). Screening for this mutation is therefore important preventative care in this high-risk population. PMID- 21318823 TI - Microsatellite Analysis of the Insulin-Like Growth Factor II Receptor in Colorectal Carcinomas. AB - The insulin-like growth factor II (IGFII) growth control pathway is comprised of three major components: IGFII ligand, insulin-like growth factor I receptor (IGFIR), and insulin-like growth factor II receptor (IGFIIR). IGFIR and IGFIIR work together to maintain constant circulating levels of IGFII. IGFII is a potent mitogen, produced by epithelial cells, which stimulates cell growth and prevents apoptosis by binding to IGFIR (1,2). IGFIR is a member of the receptor tyrosine kinase family (3) Upon binding IGFII, IGFIR autophosphorylates tyrosine residues, thereby initiating signaling Fig. 1 ) (3). Both mitogenic and anti-apoptotic signaling pathways are initiated by the binding of IGFII to IGFIR (3). Fig. 1. The Insulin-Like Growth Factor II pathway. IGFII ligand binds IGFIR thereby initiating a signaling cascade which is both mitogenic and anti-apoptotic. IGFIIR counterbalances these mitogenic and anti-apoptotic effects by binding, internalizing, and degrading IGFII thus making IGFII unavailable to activate IGFIR. IGFIR and IGFIIR work together to maintain constant circulating leveles of IGFII. PMID- 21318824 TI - Molecular detection of smad2/smad4 alterations in colorectal tumors. AB - The signaling pathways mediated by the transforming growth factor-beta (TGF-beta) family of factors are implicated in a wide array of biological processes including cell differentiation and proliferation, determination of cell fate during embryogenesis, cell adhesion and cell death. The recent discovery of the SMAD family of signal transducer proteins as mediators of TGF-beta relaying signals from cell membrane to nucleus has revolutionized the understanding of the molecular basis of these processes (1,2). To date, at least eight homologues of the Smad genes have been identified and shown to be downstream of the serine/threonine kinase receptors Table 1 ). SMADs are molecules of relative mass 42K-60K composed of two regions of homology at the amino and carboxy terminals of the protein. The activation of SMADs by receptors upon TGF-beta binding results in the formation of hetero-oligomeric complexes and translocation to the nucleus where transcription of target genes is effected. However, some of the SMADs apparently inhibit rather than mediate, TGF-beta signaling. These inhibitory SMADs are also induced by TGF-beta stimulation suggesting that there is an intracellular negative-feedback loop. Table 1 Human SMAD Genes and Cancers Gene Map position Affected cancers Reference(s) SMAD1 4q28-31 None 24 SMAD2 18q21 Colon 24 , 26 , 32 SMAD3 15q21-22 None 24 , 33 SMAD4 18q21 Lung, pancreatic,and colon 22-25 , 33 SMAD5 5q31 None 24 , 33 SMAD6 15q21-22 None 24 , 33 SMAD7 18q21 None 24 , 33 , 34 SMAD8/MADH6 13q12-14 None 35. PMID- 21318825 TI - Direct Sequencing for Juvenile Polyposis Gene SMAD4/DPC4 Mutations. AB - Juvenile polyposis (JP) is a rare dominantly inherited tumor predisposition syndrome, the typical lesion being a benign hamartomatous intestinal polyp with dilated crypts. Solitary juvenile polyps are relatively common in childhood, and appear not to be associated with neoplasia (1,2). There is no consensus of how many polyps in one patient would justify the diagnosis for the condition. The number of polyps usually present is low compared to familial adenomatous polyposis where typically hundreds of lesions are found in the fully developed disease. Five histologically confirmed juvenile polyps in one patient have been proposed as a sufficient number to establish juvenile polyposis diagnosis (3). Juvenile polyposis usually presents in childhood, most often with rectal bleeding. In some cases associated congenital defects such as malform ations of the heart and the cranium occur (4,5). PMID- 21318826 TI - 17 Direct Sequencing for Peutz-Jeghers Gene LKB1 (STK11) Mutations. AB - While Peutz-Jeghers syndrome (PJS) has been acknowledged as a clinical entity for decades (1,2), the molecular background for the disease has been unraveled only very recently. PJS has two cardinal features: First, many but not all patients display mucocutaneous melanin pigmentation that is most prominently seen around the mouth, but can also be present for example in the buccal mucosa, lips, palms, feet, and in the anal region. Second, the patients have a predisposition to hamartomatous intestinal polyps. These lesions can occur anywhere in the gastrointestinal tract, but are most commonly seen in the small intestine (3). Tumor predisposition is not limited to intestinal hamartomas. The patients have a relatively unfocused increased risk of cancer, which has been reported to be 10- to 18-fold of that of the general population. Especially the relative risk for breast and gynecologic cancers is high (4,5). Other sites possibly involved include at least small and large intestine, and pancreas (3). Benign testicular tumors also occur commonly in the syndrome (6). Some of the malignant tumors may arise from the benign hamartomatous lesions, which appear to have some malignant potential at least in the context of PJS (7-10). PMID- 21318827 TI - 18 Direct Sequencing for Cowden Syndrome Gene PTEN (MMAC1) Mutations. AB - Cowden syndrome is a rare dominantly inherited condition with predisposition to benign hamartomatous polyposis of the intestine, as well as malignant tumors of the breast and thyroid, and possibly some other cancer types. Other features include macrocephaly and dysplastic cerebellar gangliocytomatosis with ataxia, as well as predisposition to formation of trichilemmomas of the skin (1). The latter are tumors of the hair root sheath. PMID- 21318828 TI - Genetic analysis using microarrays. AB - A vast amount of genome sequencing data has become available over the past few years and methods to facilitate high-throughput analysis of large sets of genes and samples have been developed to localize novel genes related to human cancer. As advanced robotic applications have made it possible to manufacture high precision microarrays on glass or membranes, pioneering scientists have introduced several variants of the "array" technology: oligonucleotide arrays (1), DNA microarrays (CGH arrays) (2), tissue microarrays (3), and cDNA microarrays (4,5). The array technology is based on fluorescently (glass-based arrays, chips) or radioactively (filter-based array) labeled nucleic acids that are hybridized to the microarray and imaged with a laser scanner or a phosphor imager, respectively. The images are then processed using microarray analysis software. These techniques have recently been reviewed in detail in Nature Genetics (vol. 21, Suppl. 1, 1999). PMID- 21318829 TI - Cclooxygenase-2 (COX-2) Protein Expression by Western Blotting. AB - Most epidemiological studies (1-7) support a protective role of aspirin and nonsteroidal antiinflammatory drugs (NSAIDs) against colorectal cancer. People who (by their report) take aspirin regularly have about a 50% decrease in the incidence (3,4) and mortality (1,2) from colorectal cancer compared to those who reported no aspirin use. In addition, hospital-based case control studies suggest a protective effect of aspirin use on the development of large-bowel adenomas (5 7). On the other hand, the Physician's Health Study failed to detect any protective effect for aspirin against the subsequent development of colorectal cancer over 12 years of follow up, although this may be due to the short period of follow up (8,9). PMID- 21318830 TI - The immunohistochemical method. AB - Immunohistochemistry involves the binding of an antibody to a cellular or tissue antigen of interest and then visualization of the bound product by a detection system. With the ever-increasing number of antibodies against cellular epitopes, immunohistochemistry is an extremely useful diagnostic tool as well as a means to guide specific therapies that target a particular antigen on neoplastic cells. As many antibodies are effective in fixed paraffin-embedded tissues, large retrospective studies of protein expression in a variety of human cancers can easily be performed. PMID- 21318831 TI - Immunohistochemical detection and quantitation of cell surface receptors for prostanoids. AB - The mucosa of the colon occupies 25% of the intestinal wall, from the muscularis mucosa to the lumen-lining epithelium, and contains a variety of cell types, predominantly B and T lymphocytes, but also monocytes, mast cells, and macrophages (1,2). These cells secrete a variety of cytokines, including interleukins, leakotrienes, and prostaglandins. Most of these are locally active, diffuse throughout the mucosa, and do not substantially contribute to the concentration of cytokines in the blood. PMID- 21318832 TI - Adhesion signaling through integrins. AB - Tumor cell interactions with the local microenvironment influence a range of cellular activities. A ubiquitous and important ";signal"; for tumor cells is the surrounding protein stroma, the extracellular matrix (ECM). This protein network varies in composition and structure throughout the body and within tissues, having a profound effect on the cells interacting with it. Input from these proteins regulates normal and tumor cell functions including adhesion, motility, proliferation, apoptosis, and differentiation. PMID- 21318833 TI - Electrophoretic Mobility Shift Assay (EMSA). AB - Transcriptional regulation of gene expression is controlled through the binding of sequence-specific DNA-binding proteins (transcription factors) to the regulatory regions of genes. The exact gene expression program of a cell is determined by the spectrum of transcription factors present with the nucleus of a cell. The presence of these factors is dependent upon the cell type being examined and the stimulus to which the cell has been subjected. A knowledge of the transcription factors present during any given time can be important in generating a more thorough understanding of how a cell or tissue responds to its environment. Additionally, identifying the transcription factors required for the expression of a specific gene can provide a better understanding of the molecular mechanisms involved and suggest new therapies which may specifically target an individual gene or set of genes. PMID- 21318834 TI - Transfection assays for transformation of model colonic cell lines. AB - The recognition of cancer as a genetic disease has changed the approach investigators take to understanding the mechanisms of carcinogenesis. The discovery of oncogenes, and the recognition of the inactivation of tumor suppressor genes, DNA repair enzymes, and of apoptotic pathways have provided a clearer picture of the dysregulation which is required for a cell to become a cancer. PMID- 21318835 TI - Assessment of intestinal stem cell survival using the microcolony formation assay. AB - The microcolony assay originally described by Withers and Elkind in 1970 (1) has been a useful method for investigating the effects of radiation and various other genotoxic and cytotoxic damaging agents on the intestinal epithelial stem cell population and to assess the ability of a variety of compounds to protect the epithelial stem cell population from the lethal effects of chemical and physical agents (e.g., 2-7). Epithelial stem cells are located near the base of each intestinal crypt and play an important role in normal epithelial renewal and differentiation, epithelial injury-repair, and in neoplastic transformation (8 11). In the adult mouse small intestine these functionally anchored clonogenic stem cells divide rarely to produce a daughter stem cell (self renewal) as well as a more rapidly replicating transit cell. Transit cells, in turn, undergo a number of rapid cell divisions in the proliferative zone located in the lower half of each crypt. Their progeny subsequently differentiate into the mature epithelial cell types found in the small intestine as they migrate away from the proliferative zone in each intestinal crypt (8-11). Following intestinal injury and disruption of the epithelium, epithelial cells adjacent to the wound first migrate over the injured area to reestablish continuity of the epithelium. Stem cells subsequently proliferate to increase their numbers and to give rise to the more rapidly proliferating transit cell population. The transit cell population then expands rapidly to form a regenerative crypt. If the injury has completely destroyed some crypts, the surviving regenerative crypts can subsequently branch and divide to restore near normal numbers of viable crypts (3). PMID- 21318836 TI - Gene transfer into the colonic mucosa. AB - Somatic gene therapy is based on the principle of transferring recombinant genes efficiently into somatic tissues and achieving expression of the gene product in order to replace genetically defective gene functions or alter pathological disease processes. The development of a gene therapy model system that can stably produce and deliver bioactive target proteins into the intestinal microenvironment may represent an important advance in the treatment of several gut-related diseases including inflammatory bowel disease (IBD) and colon cancer. Ideally, transfection of the gut epithelia and their progenitor stem cells (i.e., epithelial crypt cells), would enable the local and targeted production of the desired gene product into the intestinal milieu. Furthermore, such genetically altered cells would have the ability to replicate the transfected gene and continue to produce and secrete its specifically encoded protein without interfering with the function of the tissue in which they reside. PMID- 21318837 TI - Chemical construction of immunotoxins. AB - Immunotoxins (ITs) are chimeric proteins consisting of an antibody linked to a toxin. The antibody confers specificity (ability to recognize and react with the target), whereas the toxin confers cytotoxicity (ability to kill the target) (1 3). ITs have been used in both mice and humans to eliminate tumor cells, autoimmune cells, and virus-infected cells (4-6. PMID- 21318838 TI - Construction of ribonuclease-antibody conjugates for selective cytotoxicity. AB - Immunotoxins based on human and humanized ribonuclease may have potential for cancer therapy while exhibiting less toxic side effects and stimulating less of an immune response in humans than immunotoxins based on plant and bacterial toxins (1). Both recombinant RNase fusion proteins (2-4 see also Chapter 6 , this volume) and chemical RNase conjugates have been made and characterized. The cytotoxic potential of targeted ribonuclease was first demonstrated with bovine RNase conjugated to transferrin or an antibody directed against the human transferrin receptor (5). Antibody RNase conjugates have also been shown to have potent anti-tumor activity against human glioma cells in athymic mice (6) and to enhance the activity of vincristine in mdr1 multidrug-resistant colon cancer cells in vitro and in vivo (7). Recently, RNase chemically conjugated to an antibody against CD22 was found to specifically kill Daudi lymphoma cells in cell culture at picomolar concentrations (IC(50), 10-50 pM) and to exhibit potent antitumor activity in SCID mice with disseminated Daudi lymphoma (unpublished data). Methods for linking RNase to specific cell binding ligands are described. PMID- 21318839 TI - Intracellular targeting using bispecific antibodies. AB - The technological development and application of bispecific antibodies for biological research have advanced steadily since the idea of creating hybrid reagents with dual specificity was first promulgated by Nisonoff and Rivers (1). It was realized that appropriately designed bispecific antibodies could provide a unique means for selectively delivering biologically active agents onto the surface of target cells so that they could ultimately be internalized (2-7). Hybrid constructs developed in my laboratory used a specific antibody to reversibly bind the effector molecule within its combining site, whereas the second antibody or ligand component accurately targeted the complex to selected sites on the cell membrane Fig. 1). Those target receptor sites, along with the attached hybrid antibody complex, are subsequently taken inside the cell via receptor-mediated endocytosis. Cytotoxic drugs and toxins were chosen for delivery via the bispecific reagent because the entry of these potent molecules into target cells is signaled by an easily measured intracellular activity (2-7). Fig. 1. Intracellular delivery of effector molecules using bispecific antibodies. A bifunctional carrier is constructed by linking a monoclonal anti-effector antibody to a monoclonal cell-targeting antibody. A noncovalent complex forms when the effector is added and binds to its specific antibody-combining sites. The targeting antibody directs this preformed complex to a distinct receptor site on the cell membrane. Alternatively, cells can be pretreated with the bispecific antibody, allowing the empty combining sites of the cell-bound reagent to be filled by subsequently added effector molecules. Surface-localized complexes quickly enter cells via a receptor-mediated endocytosis pathway. Escape of the effector from the cell vesicle system and passage into the cytosol is achieved but occurs slowly (~24 h). PMID- 21318841 TI - Folate as a targeting device for proteins utilizing folate receptor-mediated endocytosis. AB - Folic acid (M (r) = 441, Fig. 1 ) is a vitamin essential for de novo nucleotide synthesis and one-carbon metabolism. The ability to acquire folate, therefore, is important to the viability of proliferating cells. Fig. 1. Folic acid. PMID- 21318840 TI - Antibody conjugation methods for active targeting of liposomes. AB - Liposomes are useful drug delivery vehicles since they may protect encapsulated drugs from enzymatic degradation and rapid clearance in vivo, or alter biodistribution, potentially leading to reduced toxicities (1,2). A major limitation to the development of many specialized applications is the problem of directing liposomes to tissues where they would not normally accumulate. Consequently, a great deal of effort has been made over the years to develop liposomes that have targeting vectors attached to the bilayer surface. These vectors have included ligands such as oligosaccharides (3,4), peptides (5,6), proteins (7,8) and vitamins (9). Most studies have focused on antibody conjugates since procedures for producing highly specific monoclonal antibodies (MAbs) are well established. In principle it should be possible to deliver liposomes to any cell type as long as the cells are accessible to the carrier. In practice it is usually not this simple since access to tissue, competition, and rapid clearance are formidable obstacles. It has also been shown that antibodies become immunogenic when coupled to liposomes (10,11), although in similar experiments with ovalbumin we have demonstrated that immunogenicity can be suppressed by formulating the liposomes with the cytotoxic drug doxorubi-cin (12). Such issues as these suggest that the development of antibody-targeted liposomes for in vivo applications will present difficult challenges. PMID- 21318842 TI - Preparation of Recombinant RNase Single-Chain Antibody Fusion Proteins. AB - Selective cytotoxicity is an important goal of specific drug targeting. Toward this end, toxins isolated primarily from higher plants and bacteria have been coupled to monoclonal antibodies (MAbs) and evaluated for their clinical efficacy in cancer, AIDS, and immunological diseases (1,2). Immune responses against murine monoclonal antibodies MAbs (3,4) and antitoxin antibodies have been detected in both animals and humans treated with immunotoxins (ITs) (5-7) and present a major obstacle to the successful application of this technology. Although development of humanized antibodies have alleviated some of these effects (8, and references therein), the toxins themselves remain a problem. Consequently, the identification of human proteins to be used as components of immunoconjugates is highly desirable. PMID- 21318843 TI - Practical considerations in the exploitation of passive tumor targeting. AB - Specific targeting of radioisotopes or toxic drugs to tumors for cancer detection and treatment is an enticing but elusive goal. It has proved difficult to achieve adequate concentration ratios between tumor and normal tissues to improve on standard diagnostic and therapeutic methods. PMID- 21318844 TI - Effect of dose, molecular size, and binding affinity on uptake of antibodies. AB - The huge molecular radius of immunoglobulins would seem to be a major drawback for the targeting of solid tumors, because of slow extravasation into tumor interstitium and along plasma half-life. The permeability of normal continuous capillary endothelia to intravascular solutes of different molecular sizes has been determined in animals, mainly for macromolecules, and different sources give data consistent with the graph in Fig. 1 (1-3). The position of whole antibodies (IgG, mol wt 150 kDa and effective molecular radius 5.5 nm) is well to the right of albumen (66 kDa and 3.5 nm), and they are therefore very slowly extravasated in normal tissues. A F(ab')2 fragment (100 kDa, 5.06 nm) should not extravasate much faster than the intact molecule on this basis and a monomeric Fab' fragment (50 kDa, 3.48 nm) still has quite a high molecular radius (4), so a much smaller molecule would be necessary to equilibrate very quickly with extracellular fluid (ECF). Fig. 1. Relationship between molecular radius and permeability/surface area product for intact capillaries. PMID- 21318845 TI - Inhibition of tumor blood flow. AB - Research into the treatment of cancer has often been driven by the idea that a common biochemical pathway might exist in all tumors, providing an ideal target for therapy. However, it is now clear that a great variety of genetic changes contributes to the development of individual cancers, and that no two cancers are identical. Nevertheless, a common feature in solid tumors is the disorganized way in which the blood vessels develop. Networks of tumor capillaries, linked to the blood supply by arterioles and venules, are necessary for tumors to grow but, in contrast to capillaries supplying normal tissue, are haphazard in both their structure and their dynamics. It may be possible to use this common feature as a basis for selective therapy. In this chapter we provide a short review of the vasculature of solid tumors, then describe methods by which drugs might be used to inhibit tumor blood flow. Finally, we review some of the methods available for measurement of tumor blood flow. PMID- 21318846 TI - 10 targeting in myocardial infarction. AB - Targeting pharmaceuticals to the infarcted myocardium has two primary objectives: the diagnostic imaging of the infarcted myocardium and the delivery of therapeutic agents to compromised myocardial areas. Various diagnostic and therapeutic agents (such as radiolabeled compounds, thrombolytic enzymes, proteolytic drugs, and antioxidants) have been proposed for visualization or treatment of the infarcted myocardium. However, none of these reagents has the specificity for targeting the compromised myocardium. Therefore, the availability of a target-specific delivery system should increase the efficacy of diagnosis and therapy. Furthermore, the existence of such a targeted delivery system may pave the way for the use of new pharmaceuticals that by themselves can be harmful to normal tissues. PMID- 21318847 TI - 11 Targeting HIV-Infected Cells. AB - This chapter will describe methods that may be used to deliver agents to HIV infected cells. These materials may be used for therapeutic or experimental purposes. There are several general approaches to delivering compounds to human immunodeficiency cells (HIV)-infected cells. All cells may be exposed to materials that only have an effect or become activated in HIV-infected cells. Examples include drugs that are specific for HIV-encoded enzymes, such as reverse transcriptase or protease, or genes that are expressed under the control of the HIV-LTR. Lack of specificity is a major limitation to this approach; for example, reverse transcriptase inhibitors also inhibit cellular DNA polymerases and cellular transcription factors clan initiate low-level-transcription off the HIV LTR, even in the absence of tat. The alternative approach, which is the subject of this chapter, is to target the materials specifically to the infected cells. We have used monoclonal antibodies (MAbs) to deliver toxins to HIV-infected cells, but others have used this approach to deliver antiviral agents, liposomes, and even genes. PMID- 21318848 TI - 12 making fusion toxins to target leukemia and lymphoma. AB - Recombinant toxins are cytotoxic proteins that are encoded by DNA sequences that can be expressed in prokaryotic or eukaryotic cells. The proteins contain both a ligand, for binding to cells, and a toxin, for killing the cells. In recombinant toxins the connection between the toxin and ligand is encoded by the DNA and not produced by chemical conjugation. Since recombinant toxins must bind specifically to cell surface molecules to kill cells, the number of possible recombinant toxin molecules that can bind to a cell is in the hundreds or thousands; hence, the toxins must be very potent. PMID- 21318849 TI - Antibody-bearing liposomes as chloroquine vehicles in treatment of murine malaria. AB - Malaria is a serious public health problem that affects about 300-500 million people and claims 1.5-2.7 million deaths every year. One-third of all humans live in zones where they risk catching it (1). The situation is aggravated because the malarial parasites are rapidly developing resistance to the existing antimalarial drugs, like chloroquine (2), when given in classical pharmaceutical forms. Studies on the molecular basis of chloroquine resistance suggest that enhanced active efflux of the drug from the cells infected with resistant parasite strain prevents drug accumulation to toxic levels within the cytosol of the infected erythrocytes (3-5). It has been shown that erythrocytes infected with chloroquine resistant parasite accumulate less chloroquine than those with sensitive parasites (6,7). Furthermore, inhibiting the chloroquine efflux by Ca(2+)-channel blockers render the resistant cells fully sensitive to chloroquine (8), indicating that the antimalarial activity of the chloroquine is directly related to its concentration within the parasite food vacuole (9). The mechanism by which this concentration effect is achieved is unclear, but it is believed to involve binding to a putative chloroquine receptor (10). PMID- 21318850 TI - 14 immunotargeting of catalase to the pulmonary vascular endothelium. AB - Hydrogen peroxide formed in the lung tissue in ischemia/reperfusion or released from activated leukocytes causes oxidative injury of the vascular endothelial cells (1-3). H(2)O(2)-degrading enzyme, catalase, has been extensively explored in order to protect cells and tissues against H(2)O(2)-mediated injury (4). Catalase, however, has short lifetime in the bloodstream and provides only marginal protective effect after intravascular administration in animals (5). Catalase modification (conjugation with polyethylene glycol (6) or encapsulation in liposomes [7]), prolongs catalase lifetime in the circulation and facilitate its cellular uptake. These modifications, however, do not provide it with an affinity to the endothelial cells. In order to provide catalase with such an affinity, catalase could be chemically conjugated with a carrier antibodies recognizing the surface endothelial antigens (8). A monoclonal antibody (MAb) against such an antigen, angiotensin-converting enzyme (anti-ACE MAb 9B9, produced by Dr. Sergei M. Danilov [9]), accumulates in the pulmonary endothelium after systemic injection (10). Therefore, MAb 9B9 may serve as an affinity carrier for targeting of catalase to the pulmonary endothelial cells, for specific augmentation of their antioxidative defense. PMID- 21318851 TI - 15 targeted gene transfer : a practical guide based on experience with lipid based plasmid delivery systems. AB - The overall goal of gene therapy is to cure or stabilize a disease process that results from the production of a mutant protein (for example, the chloride channel protein important in cystic fibrosis) or overproduction of a normal protein (such as the products of certain oncogenes). We can achieve this goal by replacing the defective gene or by reducing the overexpression of the target gene using an antisense strategy, thus reducing the production of the diseasepromoting protein (1,2). For either method, it is critical to transfer DNA into target cells in a concentration high enough to be effective in modifying the disease. DNA must be delivered to the desired cell population in an intact state, whereby it can be efficiently transcribed and ultimately translated. The method of gene transfer must be highly efficient and nontoxic, and the delivery system must be relatively easy to prepare and administer (3). There is a great deal of optimism surrounding the development of gene therapy as an effective strategy for management of many different human diseases. The active agent used to procure gene therapy is likely to consist of oligonucleotides, ribozymes, or a DNA sequence that can be transcribed into a message capable of eliciting a therapeutic response. Unlike conventional small-molecule therapeutics however, gene therapy requires the use of a carrier system to deliver the active agent directly into the target cell population. PMID- 21318852 TI - Rotaviruses: basic facts. AB - Rotaviruses (RVs) are the chief etiologic agent of viral gastroenteritis in infants and young children, and in the young of a large variety of animal species. Since the discovery of RVs in man 25 yr ago, much has been learned about their genome and protein composition; their three-dimensional structure; their replication, pathogenesis and clinical pattern; the host's immune response; and the epidemiology. Measures of individual treatment have recently been complemented by the licensure in the United States of a tetravalent (TV), live attenuated rhesus rotaviruses (RRV)-based, human reassortant vaccine which may to be universally applied. PMID- 21318853 TI - Electron cryomicroscopy and computer image processing techniques : use in structure-function studies of rotavirus. AB - Rotavirus (RV), a double-stranded (ds)RNA virus in the family Reoviridae, is a complex, relatively large (diameter, including spikes = 1000 A), nonenveloped icosahedral virus. Once RV was recognized as a major human pathogen, it was extensively studied using modern molecular genetic and biological techniques, as discussed elsewhere in this book. These studies provided basic information about gene-coding assignments, protein processing, genome expression and replication, viral morphogenesis, and pathogenesis (1). In addition, molecular epidemiological studies, coupled with the characterization of neutralizing monoclonal antibodies (MAbs) and sequencing of the genes that encode the neutralizing antigens, provided an understanding at the molecular level of the antigenic and genetic variability of the RVs. PMID- 21318854 TI - Virus replication. AB - The effort to understand the molecular biology of rotaviruses (RVs) has led to the development of procedures that can be used to study the replication and transcription of the RV genome, the assembly and structure of the rotavirion, and the structure and function of RV proteins. Because it is not possible to provide a detailed description of all the techniques developed, this chapter stresses only those that have broad application, or which represent important new technical advances. In particular, this chapter emphasizes procedures used to prepare large amounts of purified triple-(TLP), double-(DLP), and single-layered (core) RV particles; to synthesize viral RNAs in vitro, through the transcriptase and replicase activities associated with RV particles; to evaluate the RNA binding activity of RV proteins; and to assemble core-like and virus-like particles (CLPs and VLPs, respectively) via the expression of RV recombinant proteins. PMID- 21318855 TI - Rotavirus entry into tissue culture cells. AB - Rotavirus (RV) is a triple-protein-layered icosahedral virus, for which studies have established that the two outer-layer proteins, viral protein 4 (VP4) and viral protein 7 (VP7), are required for viral infectivity (1,2). VP7, a glycoprotein, is the major component of the outer-layer, but its role in viral entry is unclear. VP4 forms dimers extending out from the VP7-coated viral surface (3,4) and have been shown to be a determinant of host range and virulence, and is directly involved in cell attachment and RV entry into cells (5 8). Proteolytic cleavage of VP4 into two noncovalently associated subunits, VP8* and VP5* (2,9,10), significantly enhances viral infectivity (11-13). PMID- 21318856 TI - Mixed infections with rotaviruses : protocols for reassortment, complementation, and other assays. AB - Mixed infection of tissue culture cells is the primary means of studying genetic and nongenetic interactions between viral mutants. The purpose of the mixed infection is to place two different viral genomes into the same cell, where interactions between the genomes and their encoded gene products can take place. In some cases, interactions are observed in the context of the mixed infected cell, but generally the yield of progeny virus from the mixed infected cells is assayed to reveal the result of the interactions. Here, methods for mixed infections between conditional-lethal mutants of the temperature-sensitive (ts) phenotype will be presented and considered. (Mutants with ts phenotype are designated according to the following nomenclature: tsA [778], in which ts indicates the phenotype, A indicates the mutant belongs to recombination group A, and [778] indicates the number of the specific mutant in group A.) Temperature sensitive mutants are particularly useful for genetic studies, because they can be propagated at the permissive temperature (PT; 31 degrees C in the case of rotavirus [RV] ts mutants), but the mutant phenotype is expressed at the nonpermissive temperature (NPT; 39 degrees C in the case of RV ts mutants). The conditional-lethality of the ts mutations allows the use of selective conditions in the analysis of the progeny of the mixed infections, so that the results of genetic and nongenetic interactions can be easily revealed. PMID- 21318857 TI - Pathogenesis and animal models. AB - Because of the limitations in studying human rotavirus (HRV) pathogenesis and mucosal immunity in the natural host (infants and children), various animal models have been utilized to investigate rotavirus (RV) disease pathogenesis and immunity. Mice and rabbits serve as useful models to evaluate and dissect immune responses to RV (see Chapter 9 ). However, because older mice (>14 d) and rabbits are not susceptible to diarrhea after inoculation with either homologous (murine or lapine, respectively) or heterologous (human) RVs, assessment of protective immunity is restricted to prevention of virus shedding only (1-3). PMID- 21318858 TI - Immunologic methods and correlates of protection. AB - Studies of natural rotavirus (RV) infection in children have shown that protection against subsequent RV disease occurs (1). Assessment of humoral immune responses has included study of the importance of circulating vs intestinal antibodies (Abs), serotype-specific vs group-specific Abs, and RV-specific immunoglobulins IgA, IgM, and IgG (1). Following natural RV infection, RV specific IgM, followed by IgA and IgG, appear in serum and duodenal fluid or stool of young children (2). Protection against subsequent RV infection is predicted by the quantity of virus-specific IgA in the feces and serum (3, 4). In addition, virus-specific antibody-secreting cells (ASC) of the IgA, IgM, and IgG isotypes have been detected in the blood of infants following RV infection (5), although correlation between the presence of ASCs and protection against subsequent disease has not been studied. Serum neutralizing antibodies (nAbs) occur after natural RV infection in children, and are serotype-specific (4,6). Overall, protection against subsequent RV infection is correlated with higher titers of nAb (4). Protection against infection has been correlated with homotypic nAb to the G1 serotype (4); however, other studies suggest that protection is not dependent on serotype-specific nAb (7). PMID- 21318859 TI - In vivo study of immunity to rotaviruses : selected methods in mice. AB - Rotaviruses (RVs) are important human pathogens. The murine model of RV infection has been very useful in clarifying the mechanisms that mediate clearance of primary RV infection, and the mechanisms that mediate immunity to reinfection. The use of immunodeficient strains of mice, immunodepletion studies with specific monoclonal antibodies (MAbs), and passive transfer of purified cells are three basic, complementary experimental approaches that have been used for this purpose, and are the subject of this chapter. These experimental approaches analyze the outcome of RV infection under artificial conditions; thus, the relevance of the results obtained, to the physiological immune response of immunocompetent mice or humans, is at times difficult to establish. For example, immunodeficient strains of mice frequently develop compensatory immune mechanisms that are potentially absent or nonfunctional in immunocompetent mice. Immunodepletion experiments introduce into the experimental animal high (nonphysiological) levels of antibodies (Abs) that potentially have other immunomodulatory effects different from the desired one, and, many times, depletion strategies fail to completely eliminate the target cell population. Passive cell transfer experiments analyze the antiviral capacity of a specific cell population (many times abnormal in number), independent of other cells with which it may normally interact, and in an environment to which it is at least partially alien. Because of these and other limitations of such experimental approaches, one should be very careful in selecting adequate controls, and cautious in the interpretation of the results, by taking into account results obtained with two or three of the approaches and analysis of the characteristics of the immune response in normal animals. The combination of two or three strategies (for example, passive cell transfer into immunodeficient hosts and immunodepletion of selected cell populations in immunocompetent hosts) have proven particularly useful in the study of immunity to RV. PMID- 21318860 TI - Evaluation of rotavirus vaccines in small animal models. AB - The high morbidity and mortality of rotavirus (RV) infections has spurred the development of RV vaccines (1-13). Although children naturally infected with RV commonly undergo multiple infections, primary infections in children generally induce disease, and children are normally protected against severe disease during subsequent infections (1,2,6-8,14). For RV, the immunologic mechanisms responsible for protection are poorly understood, but antibody (Ab) in the intestine appears to be the primary mechanism of protection (2,15,16). Because RV is a localized enteric infection, and induction of intestinal mucosal immune responses was expected to be required for protection, live orally administered vaccines were pursued first. Vaccine development of the live attenuated vaccines proceeded to clinical trials in humans without prior animal testing. In August 1998, RotashieldTM, a three dose, live attenuated tetravalent (TV), rhesus rotavirus (RRV) vaccine produced by Wyeth Lederle Vaccines and Pediatrics (West Henrietta, NY), was licensed. This vaccine shows promise, eliciting ~80% protection against severe disease (6,7,12,17-19). The recent detection or emergence of new RV serotypes in humans suggests that incorporation of additional P-and G-serotypes into this vaccine may be necessary in the future (20-22). Additional concerns with the use of live attenuated vaccines include interference of vaccine replication by other enteric pathogens (common in children from the underdeveloped world); neutralization by maternal Ab; limited replication competence of animal strains, because of the host range restriction observed with RVs; and safety, because of the possibility of producing new virulent virus, emerging by reassortment of circulating wild-type (WT) virus with the vaccine virus.Development and testing of nonreplicating RV vaccines have also been pursued, and will be the focus of this chapter. The use of nonreplicating immunogens presents additional challenges beyond that of developing RV vaccines effective in young children against potential infection by multiple serotypes of RV. The nonreplicating immunogen must be able to induce protective immune responses against the target virus. Traditionally, nonreplicating vaccines have been thought to be poor inducers of mucosal immune responses and protection of the mucosa. Without amplification of the vaccine virus by replication, a high dose of nonreplicating immunogen may be required. To enhance the immune response to nonreplicating immunogens, development and testing of new adjuvants and/or delivery systems, and alternative routes of immunization to boost immunogenicity and protective efficacy, are needed. If administered orally, the nonreplicating immunogens must be stable in the digestive environments of the stomach and intestine. PMID- 21318861 TI - Methods of rotavirus detection, sero- and genotyping, sequencing, and phylogenetic analysis. AB - The clinical symptoms associated with rotavirus (RV) gastroenteritis are not sufficiently characteristic to distinguish between RV infection and other causes of gastroenteritis. Therefore, laboratory procedures, including electron microscopy (EM) (1), enzyme-linked immunosorbent assays (ELISA) (2), passive particle agglutination tests (PPAT) (3,4), polyacrylamide gel electrophoresis (PAGE) (5), or reverse transcription-polymerase chain reaction (RT-PCR) (6-8), are necessary to confirm a clinical diagnosis of RV gastroenteritis. Virus shedding in the feces of RV-infected individuals, with up to 10(11) virus particles/mL feces at the peak of diarrhea, coincides with the duration of the diarrhea. However, virus-shedding can continue once symptoms have ceased (9). Laboratory diagnosis is relatively easy, either through the visualization of virus particles by EM, the detection of virus antigen (Ag) by ELISA or PPAT, or the detection of the virus genome by PAGE or RT-PCR. PMID- 21318862 TI - Epidemiology of group a rotaviruses surveillance and burden of disease studies. AB - Human infection has been reported with groups A, B, and C rotaviruses (RVs). Of these, Group A RVs are the most important, being a major cause of severe gastroenteritis (GE). Each year, Group A RVs are estimated to cause approx 870,000 deaths worldwide in children less than 5 years (yr) of age, mostly in developing countries (1). This chapter will describe the epidemiological features of Group A RV infections, and will critically review the current surveillance strategies used to define the burden of disease. PMID- 21318863 TI - Future rotavirus research. AB - Since the discovery of animal rotaviruses (RVs) in the 1960s (1,2), and of human rotaviruses (HRVs) 25 yr ago (3,4), much has been learned about virus structure, classification, evolution, replication, pathogenesis, and specific immune responses, and their correlation with protection and epidemiology. As pathogens that infect the gastrointestinal tract, these viruses continue to serve as useful models to understand mucosal virus-cell interactions. Recently, a RV vaccine to prevent disease in children has been licensed in the United States (US); this vaccine is expected to be applied worldwide. The chapters of this book have reviewed some of the research on RVs, with an emphasis on molecular methodological approaches. This summary chapter draws attention to some topics on which ongoing research is likely to produce significant results in the years to come, but also on which more research is needed. PMID- 21318865 TI - Exploring polyamine biosynthetic diversity through comparative and functional genomics. AB - The existence of multiple, alternative pathways for polyamine biosynthesis, and the presence of alternative polyamine structural analogs, is an indication of the physiological importance of polyamines and their long evolutionary history. Polyamine biosynthesis is modular: diamines are synthesized directly or indirectly from amino acids, and triamines are synthesized from diamines by transfer of aminopropyl, carboxyaminopropyl, or aminobutyl groups to the diamine. Diversification of polyamine biosynthesis has depended on gene duplication and functional divergence, on gene fusion, and on horizontal gene transfer. Four examples of polyamine biosynthetic diversification are presented here with a discussion of methodological and conceptual approaches for identification of new pathways. PMID- 21318866 TI - Characterization of genes for polyamine modulon. AB - Polyamines are essential for normal cell growth and exist mainly as RNA-polyamine complexes in cells. Thus, effects of polyamines on protein synthesis have been studied. It was found that several kinds of protein synthesis, which are important for cell growth, were enhanced by polyamines at the level of translation. We proposed that a group of genes whose expression is enhanced by polyamines at the level of translation be referred to as a "polyamine modulon." In Escherichia coli, most members of the polyamine modulon thus far identified were transcription factors. These transcription factors enhanced the synthesis of several kinds of mRNA and tRNA, and also rRNA. In this way, polyamines enhanced growth of E. coli. We also succeeded in identifying three kinds of "polyamine modulon" in mammalian cells. One of the mechanisms of polyamine stimulation at the molecular level was due to the stabilization of the bulged-out region of double-stranded RNA in mRNA. The procedures used to identify components of the polyamine modulon are described in this chapter. PMID- 21318867 TI - Posttranscriptional regulation of gene expression in epithelial cells by polyamines. AB - In addition to regulating gene transcription, polyamines also potently modulate gene expression posttranscriptionally. Posttranscriptional gene regulation, which includes processes such as mRNA transport, turnover, and translation, involves specific mRNA sequences (cis-element) that interact with transacting factors such as RNA-binding proteins (RBPs) and microRNAs. U- or AU-rich elements (ARE) are the best characterized cis-acting sequences located in the 3'-untranslated regions of many labile mRNAs. Several RBPs, including AUF1, BRF1, TTP, and KSRP, promote ARE-mRNA decay through the recruitment of the ARE-bearing mRNA to sites of mRNA degradation, whereas RBPs such as HuR, HuB, HuC, and HuD stabilize target mRNAs and stimulate their translation. HuR is one of the best-studied RBPs and has emerged as a key regulator of posttranscriptional control of gene expression and its activity is tightly regulated by cellular polyamines. Ribonucleoprotein immunoprecipitation assays and biotin pull-down assays are two major methods used extensively in experiments investigating the roles and mechanisms of cellular polyamines in the posttranscriptional regulation and are described in detail in this chapter. PMID- 21318868 TI - Identification, chemical synthesis, and biological functions of unusual polyamines produced by extreme thermophiles. AB - Unusual long polyamines such as caldopentamine and caldohexamine, and branched polyamines such as tetrakis(3-aminopropyl)ammonium and N (4) aminopropylspermidine were often found in cells of extreme thermophiles and hyperthermophiles belonging to both Bacteria and Archaea domains. Some of these unusual polyamines are essential for life at extreme temperatures. In some cases, the unusual polyamines also exist in cells of nonthermophilic organisms and play important physiological roles under normal conditions. Methods for chromatographic analysis, isolation, and chemical syntheses of unusual polyamines as well as experimental methods for measuring their physiological roles are discussed. Especially, many newly improved methods for chemical syntheses are presented in this article. PMID- 21318869 TI - Polyamine block of inwardly rectifying potassium channels. AB - Polyamine blockade of inwardly rectifying potassium (Kir) channels underlies their steep voltage--dependence observed in native cells. The structural determinants of polyamine blockade and the structure-activity profile of endogenous polyamines requires specialized methodology for characterizing polyamine interactions with Kir channels. Recent identification and growing interest in the structure and function of prokaryotic Kir channels (KirBacs) has driven the development of new techniques for measuring ion channel activity. Several methods for measuring polyamine interactions with prokaryotic and eukaryotic Kir channels are discussed. PMID- 21318864 TI - Current status of the polyamine research field. AB - This chapter provides an overview of the polyamine field and introduces the 32 other chapters that make up this volume. These chapters provide a wide range of methods, advice, and background relevant to studies of the function of polyamines, the regulation of their content, their role in disease, and the therapeutic potential of drugs targeting polyamine content and function. The methodology provided in this new volume will enable laboratories already working in this area to expand their experimental techniques and facilitate the entry of additional workers into this rapidly expanding field. PMID- 21318870 TI - Carcinogenesis studies in mice with genetically engineered alterations in polyamine metabolism. AB - Polyamines are intimately linked to essential cellular processes that are required for cell growth and -proliferation, and abundant evidence links polyamine metabolism to tumor susceptibility and progression. Intensive efforts over the past 2 decades have yielded numerous mouse models of cancer that utilize genetic manipulations to recapitulate the molecular alterations and cellular interactions that characterize human cancers. These models provide the ideal genetic context to examine the impact of altered polyamine content on tumor biology, with the goal of applying the knowledge acquired in mice to the prevention and treatment of human cancer. Transgenic and knockout mouse technologies allow the investigator to enhance or delete, respectively, the expression of a given polyamine metabolic enzyme or regulatory protein, and advanced models facilitate both temporal and spatial control of gene expression in the mouse. These methods can be utilized to modulate total polyamine content or relative polyamine ratios in specific cell populations in vivo and evaluate the impact of this manipulation on tumor appearance and progression. This chapter provides resources to identify existing mouse strains that exhibit increased susceptibility to tumor development as well as strains that were engineered for increased or decreased expression of polyamine regulatory proteins. A conceptual framework is then presented to combine these resources in order to successfully complete a carcinogenesis study in mice with altered polyamine metabolism. PMID- 21318871 TI - Transgenic rodents with altered SSAT expression as models of pancreatitis and altered glucose and lipid metabolism. AB - Depletion of pancreatic acinar cell polyamines in response to activation of polyamine catabolism is associated with the development of acute pancreatitis in experimental rodent models. The disease is characterized by general hallmarks seen also in human pancreatitis, such as accumulation of intraperitoneal ascites, acinar cell necrosis, and pancreatic as well as remote organ edema and inflammation. Thus, these animals make useful models for the human disease. Determination of these hallmarks can be used to assess the severity of the disease and to evaluate the efficacy of any therapy applied. The metabolic changes seen in genetically modified mice with either accelerated or inactivated polyamine catabolism have revealed that polyamine catabolism is involved in the regulation of glucose and lipid metabolism. The simplest method to determine the metabolic phenotype of the animal is to assess the concentrations of blood metabolites. Fasting blood glucose level is an indicator of overall glucose homeostasis, whereas fasting insulin level is a useful marker of insulin sensitivity. A more detailed analysis of glucose homeostasis and insulin sensitivity can be obtained by intraperitoneal glucose and insulin tolerance tests. Blood lipid levels mainly reflect triglyceride, free fatty acid, and cholesterol metabolism. Altered blood glucose and/or lipid levels are associated with several diseases, e.g., diabetes, Cushing's syndrome, hyperthyroidism, atherosclerosis, pancreatitis, and dysfunction of the liver and kidneys. PMID- 21318872 TI - Use of (Gyro) Gy and spermine synthase transgenic mice to study functions of spermine. AB - The polyamines putrescine, spermidine, and spermine are essential for mammalian cell growth, -differentiation, and cell death and have important physiological roles in all tissues. Many of the properties of polyamines that can be demonstrated in vitro are common to all three molecules with differences only in potency. Loss of any of the enzymes needed to make either putrescine or spermidine (which also -prevent the production of spermine) is lethal, but male mice lacking spermine synthase (SpmS) due to a deletion of part of the X chromosome are viable on the B6C3H background. These mice are termed Gyro (Gy) due to their circling behavior. They have a variety of abnormalities including deafness, neurological problems, small size, and a tendency to early death. They can therefore be used to evaluate the physiological function(s) uniquely provided by spermine. They also provide a potential animal model for Snyder-Robinson syndrome (SRS), a rare human inherited disease due to a loss of SpmS activity. An essential control in experiments using Gy mice is to demonstrate that the abnormal phenotypes exhibited by these mice are abolished by providing replacement spermine and this can be accomplished by breeding with CAG-SMS mice that express SpmS from a ubiquitous promoter. Techniques for identifying, characterizing, and using these mouse strains and limitations of this approach are described in this chapter. PMID- 21318873 TI - A simple assay for mammalian spermine oxidase: a polyamine catabolic enzyme implicated in drug response and disease. AB - Spermine oxidase (SMO), the most recently characterized polyamine metabolic enzyme, catalyzes the direct back-conversion of spermine to spermidine in an FAD dependent reaction that also yields the byproducts hydrogen peroxide (H(2)O(2)) and 3-aminopropanal. These metabolites, particularly H(2)O(2), have been implicated in cytotoxic cellular responses to specific antitumor polyamine analogs, as well as in the inflammation-associated generation of DNA damage. This chapter describes a rapid, sensitive, and inexpensive method for the chemiluminescent measurement of SMO (or alternatively, N (1)-acetyl polyamine oxidase, APAO) enzyme activity in cultured cell lysates, without the need for radioactive reagents or the use of high performance liquid chromatography (HPLC). Specifically, H(2)O(2) production by SMO is coupled to chemiluminescence generated by the horseradish peroxidase-catalyzed oxidation of luminol. Detailed protocols for preparation of reagents, harvesting cell lysates, generation of a standard curve, assaying of samples, and calculation of SMO enzyme activity are presented. PMID- 21318874 TI - Characterization, assay, and substrate specificity of plant polyamine oxidases. AB - Polyamine oxidation is the main catabolic process of polyamines. This process is crucial because not only it participates in the regulation of the endogenous titers of polyamines but also it generates hydrogen peroxide, which can act as a signaling molecule. The recent identification of polyamine oxidases that differ in substrate specificity and mode of action in plants necessitates the use of additional techniques for their characterization based on the determination of the end-product. Herein, we describe the most widely used techniques as well as new techniques that can be used for analysis of the newly identified polyamine oxidases. PMID- 21318875 TI - Assay of deoxyhypusine synthase activity. AB - Deoxyhypusine synthase catalyzes an unusual protein modification reaction. A portion of spermidine is covalently added to one specific lysine residue of one eukaryotic protein, eIF5A (eukaryotic initiation factor 5A) to form a deoxyhypusine residue. The assay measures the incorporation of radioactivity from [1,8-(3)H]spermidine into the eIF5A protein. The enzyme is specific for the eIF5A precursor protein and does not work on short peptides (<50 amino acids). Optimum conditions for the reaction and four detection methods for the product, deoxyhypusine-containing eIF5A, are described in this chapter. The first, and most specific, method is the measurement of the amount of [(3)H]deoxyhypusine in the protein hydrolysate after its separation by ion exchange chromatography. However, this method requires some specialized equipment. The second method is counting the radioactivity in TCA-precipitated protein after thorough washing. The third method involves determining the radioactivity in the band of [(3)H]deoxyhypusine-containing eIF5A after separation by SDS-PAGE. The fourth method is a filter-binding assay. It is important to minimize nonspecific binding of [(3)H]spermidine to proteins in the assay mixture, especially for methods 2 and 4, as illustrated in a comparison figure in the chapter. PMID- 21318876 TI - Assay of deoxyhypusine hydroxylase activity. AB - The eukaryotic translation initiation factor 5A (eIF5A) is the only cellular protein that contains an unusual amino acid, hypusine [N (epsilon)-(4-amino-2 hydroxybutyl)-lysine]. eIF5A and its hypusine/deoxyhypusine modification are vital for eukaryotic cell proliferation. Hypusine is formed posttranslationally by two enzymatic steps catalyzed by deoxyhypusine synthase and deoxyhypusine hydroxylase. Deoxyhypusine hydroxylase catalyzes a stereo-specific hydroxylation of the deoxyhypusine residue in the eIF5A intermediate protein, eIF5A(Dhp). The enzyme is totally specific for this protein and does not act on short peptides (<50 amino acids). The assay measures the conversion of the radiolabeled deoxyhypusine residue to a hypusine residue in eIF5A. Optimum conditions for the reaction and two detection methods for the product, hypusine-containing eIF5A, are described in this chapter. The first, and most reliable, method is the measurement of the amount of [(3)H]hypusine in the protein hydrolysate after its separation from [(3)H]deoxyhypusine, by ion exchange chromatography. This method does require specialized equipment. The second method is based on counting the total TCA soluble radioactivity after sodium periodate oxidation of the reaction mixture, since the radiolabeled 4-amino-2-hydroxy butyl moiety of the hypusine residue is cleaved and is released from protein as radiolabeled beta propionaldehyde and formaldehyde by periodate oxidation. PMID- 21318877 TI - Identification and assay of allosteric regulators of S-adenosylmethionine decarboxylase. AB - Polyamine biosynthesis is extensively regulated in cells by multiple mechanisms, including regulation of enzyme activity posttranslationally. The identified regulatory factors include both small molecules and regulatory proteins, and the mechanisms vary in different species across the evolutionary tree. Based on this diversity of mechanism, it is likely that regulatory factors of the pathway remain unidentified in many species. This article focuses on methods for identifying novel regulatory factors of polyamine biosynthesis as illustrated by the discovery of a novel protein activator of the key biosynthetic enzyme S adenosylmethionine decarboxylase in the protozoan trypanosomatid parasites. PMID- 21318878 TI - Protocols for studying antizyme expression and function. AB - Antizyme (AZ) is a key molecule in feedback regulation of cellular polyamines. It is induced by polyamines through stimulation of ribosomal frameshifting during its translation. In mammals, AZ is diverged into three paralogs, AZ1-3. Tissue and subcellular distribution are different among the paralogs, as determined by immunochemical methods or expression of fluorescent-tagged proteins. Only AZ2 is known to be phosphorylated. AZ regulates cellular polyamine levels through multiple mechanisms. It binds to ornithine decarboxylase (ODC) to form an inactive complex and to trigger degradation of ODC by 26S proteasomes. The AZ activity to promote ODC degradation can be measured both in vitro and in cells. AZ also inhibits cellular uptake of polyamines. This chapter comprises seven subchapters describing methods for studying expression and function of AZ. PMID- 21318879 TI - Identification, assay, and functional analysis of the antizyme inhibitor family. AB - Polyamines are small aliphatic polycations present in all living cells. Polyamines are involved in regulating fundamental cellular functions and are absolutely essential for the process of cellular proliferation. Because they fulfill essential cellular functions, their intracellular concentration is tightly regulated via a unique autoregulatory circuit that responds to the intracellular concentration of polyamines. In the heart of this circuit is a small protein called antizyme (Az), whose synthesis is stimulated by polyamines. Az inactivates Ornithine decarboxylase [(ODC), the first key enzyme in the polyamine biosynthetic pathway] and marks it for ubiquitin-independent degradation by the 26S proteasome. In addition, Az inhibits uptake of polyamines via a yet unresolved mechanism. Az itself is subjected to regulation by an ODC related protein termed antizyme inhibitor (AzI). AzI is highly homologous to ODC, but it lacks ornithine decarboxylating activity. Since its affinity to Az is greater than the affinity Az has for ODC, it rescues ODC from degradation and enables polyamines uptake into the cell. PMID- 21318880 TI - Posttranscriptional regulation of ornithine decarboxylase. AB - Activity of the polyamine biosynthetic enzyme ornithine decarboxylase (ODC) and intracellular levels of ODC protein are controlled very tightly. Numerous studies have described ODC regulation at the levels of transcription, translation, and protein degradation in normal cells and dysregulation of these processes in response to oncogenic stimuli. Although posttranscriptional regulation of ODC has been well documented, the RNA binding proteins (RBPs) that interact with ODC mRNA and control synthesis of the ODC protein have not been defined. Using Ras transformed rat intestinal epithelial cells (Ras12V cells) as a model, we have begun identifying the RBPs that associate with the ODC transcript. Binding of RBPs could potentially regulate ODC synthesis by either changing mRNA stability or rate of mRNA translation. Techniques for measuring RBP binding and translation initiation are described here. Targeting control of ODC translation or mRNA decay could be a valuable method of limiting polyamine accumulation and subsequent tumor development in a variety of cancers. PMID- 21318881 TI - Identification and assays of polyamine transport systems in Escherichia coli and Saccharomyces cerevisiae. AB - Polyamine content in cells is regulated by biosynthesis, degradation, and transport. With regard to transport, uptake and excretion proteins exist in Escherichia coli and Saccharomyces cerevisiae. In E. coli, the uptake systems comprise a spermidine-preferential uptake system consisting of the PotA, B, C, and D proteins, and a putrescine-specific uptake system consisting of the PotF, G, H, and I proteins. Two other proteins, PotE and CadB, each containing 12 transmembrane segments, function as antiporters (putrescine-ornithine and cadaverine-lysine) and are important for cell growth at acidic pH. MdtJI was identified as a spermidine excretion system. When putrescine was used as energy source, PuuP functioned as a putrescine transporter. In S. cerevisiae, DUR3 and SAM3, containing 16 or 12 transmembrane segments, are the major polyamine uptake proteins, whereas TPO1 and TPO5, containing 12 transmembrane segments, are the major polyamine excretion proteins, and UGA4 is a putrescine transporter on the vacuolar membrane. The activities of DUR3 and TPO1 are regulated by phosphorylation of serine/threonine residues. The identification and assay procedures of these transporters are described in this chapter. PMID- 21318882 TI - Genetic and biochemical analysis of protozoal polyamine transporters. AB - Polyamines are aliphatic polycations that function in key cellular processes such as growth, differentiation, and macromolecular biosynthesis. Intracellular polyamines pools are maintained from de novo synthesis and from transport of polyamines from the extracellular milieu. This acquisition of exogenous polyamines is mediated by cell surface transporter proteins. Protozoan parasites are the etiologic agents of a plethora of devastating and often fatal diseases in humans and their domestic animals. These pathogens accommodate de novo and/or salvage mechanisms for polyamine acquisition. Because of its therapeutic relevance, the polyamine biosynthetic pathway has been thoroughly investigated in many genera of protozoan parasites, but the polyamine permeation pathways have generally been ignored. Our group has now identified at the molecular level polyamine transporters from two species of protozoan parasites, Leishmania major and Trypanosoma cruzi, characterized these polytopic proteins with respect to ligand specificities and affinities, and determined the subcellular environments in which these transporters reside. PMID- 21318883 TI - Heparan sulfate proteoglycan-mediated polyamine uptake. AB - The polyamines are polycationic compounds essential for cellular proliferation and transformation. In addition to a well-defined biosynthesis pathway, polyamines are internalized into cells by as yet incompletely defined mechanisms. Numerous reports have shown that efficient polyamine uptake depends on the presence of polyanionic, cell surface-associated heparan sulfate proteoglycans (HSPGs). In this chapter, we provide protocols for studying HSPG-mediated uptake of polyamines in various cell lines, and provide instructions for the use of two different genetic models of HSPG deficiency. We describe the enzymatic reduction of cell surface HSPG through Heparinase III lyase treatment as well as the use of phage display-derived single chain variable fragment (scFv) anti-HS antibodies to block HSPGs at the cell surface. Finally, we provide a protocol for the quantitative verification of loss or reduction of cell surface HSPGs and a detailed description of polyamine uptake measurement. PMID- 21318884 TI - Polyamine transport systems in mammalian cells and tissues. AB - Polyamine transport plays an important role in the homeostatic regulation of the polyamine levels. In animals, dietary polyamines are absorbed efficiently in the intestinal tract. In the colon, luminal bacterial derived polyamines are important contributors to cellular polyamine contents. Polyamine transport involves unique uptake and export mechanisms. The amino acid transporter SLC3A2 acts as a polyamine exporter in colon cancer-derived cells. Polyamine uptake is mediated by caveolin-1 dependent -endocytosis. The K-RAS oncogene signals increased polyamine uptake and decreased polyamine export. Here, we describe the methods of polyamine transport analysis in the colon and the small intestine using -membrane vesicles, culture cells, and mouse models. PMID- 21318885 TI - Procedures to evaluate the importance of dietary polyamines. AB - Polyamines not only play vital physiological functions including modulating transcription and translation of genetic material, cell proliferation and growth, ion channel regulation and cell signaling, but have also been cited in the pathogenesis of diseases. Many plant and animal sources used as food contain high amounts of polyamines. Knowledge of the content of polyamines in food as a source of these growth factors is therefore critical. A 2-step perchloric acid precipitation method to obtain acid soluble extracts from food that are subsequently taken through a dansylation process to produce dansyl polyamine derivatives for HPLC measurement is described. Examples are provided to illustrate mathematical correction factors. PMID- 21318886 TI - Determination of N1,N12-diacetylspermine in urine: a novel tumor marker. AB - N1,N12-diacetylspermine (DiAcSpm) is a minor component of human urine that constitutes less than 0.5% of total polyamine species in human urine. Structurally related polyamines and acetylpolyamines were separated and analyzed by HPLC and gas chromatography, and refinement of these procedures led to the identification of this minor component. Subsequent analyses of urines from cancer patients as well as healthy persons revealed that DiAcSpm is a promising candidate for a novel tumor marker. It is much more sensitive than established tumor markers in detecting colorectal and other cancers, and most importantly, is able to detect 60% of early colorectal cancers confined to mucous membranes. Serum CEA is able to detect only about 10% of colorectal cancers at this stage. Collection of urine is easy and does not give any pain to patients, which adds another merit to urinary DiAcSpm as a tumor marker. DiAcSpm-specific antibodies were then developed for simpler determination of DiAcSpm in urine, and the antibodies were used to construct an ELISA system. More recently, a reagent kit for DiAcSpm determination based on colloidal gold aggregation that can be used with automatic biochemical analyzers was also developed. PMID- 21318887 TI - Spermidine/spermine-N1-acetyltransferase in kidney ischemia reperfusion injury. AB - Ischemic reperfusion injuries such as acute renal failure, acute liver failure, stroke, and myocardial infarction are prevalent causes of morbidity and mortality. Kidney ischemic reperfusion injury is the leading cause of acute renal failure and dysfunction of transplanted kidneys. Although significant progress has been made in deciphering the factors that contribute to ischemic reperfusion injury, treatment options for these injuries remain scant. Identifying the molecules that contribute to ischemic reperfusion injury and can be therapeutically targeted will lead to development of new approaches for the treatment of such injuries. The expression of spermidine/spermine-N1 acetyltransferase increases in the kidneys subjected to ischemic reperfusion injury. Furthermore, inactivation of the spermidine/spermine-N1-acetyltransferase gene reduces the severity of kidney damage after ischemic reperfusion injury. Enhanced expression of spermidine/spermine-N1-acetyltransferase in cultured cells leads to DNA damage, cell cycle arrest, and disruption of cell matrix interactions. The aforementioned observations strongly suggest that enhanced polyamine back conversion plays an important role in the mediation of tissue damage in renal Ischemic reperfusion injury. PMID- 21318888 TI - Use of polyamine metabolites as markers for stroke and renal failure. AB - Acrolein and H(2)O(2) are among the metabolic products of spermine and spermidine, and it was found that acrolein was more toxic than H(2)O(2). It was determined whether acrolein can serve as a biochemical marker for stroke (brain infarction) and chronic renal failure. Since acrolein rapidly reacts with lysine residues in protein, protein-conjugated acrolein (PC-Acro) was measured. PC-Acro was increased at the locus of brain infarction and in plasma in a mouse model of stroke involving photochemically induced thrombosis. An increase in PC-Acro in plasma was found to be a good biochemical marker in patients with stroke or with chronic renal failure. Using a receiver operating characteristic curve, the combined measurement of PC-Acro, IL-6 and CRP together with age indicated silent brain infarction (SBI) with 89% sensitivity and 91% specificity. The procedures to measure PC-Acro and polyamine oxidases [spermine oxidase (SMO) and acetylpolyamine oxidase (ACPAD)], and its application as markers in stroke and chronic renal failure are described in this chapter. PMID- 21318889 TI - Methods to evaluate alterations in polyamine metabolism caused by Helicobacter pylori infection. AB - Helicobacter pylori is a Gram-negative bacteria that infects the human stomach of half of the world's -population. Colonization is followed by infiltration of the gastric mucosa by lymphocytes and myeloid cells. These cells are activated by various bacterial factors, causing them to produce immune/inflammatory mediators, including reactive nitrogen species and polyamines that contribute to cellular damage and the pathogenesis of H. pylori-associated gastric cancer. In vitro experiments have revealed that H. pylori induces macrophage polyamine production by upregulation of the arginase 2/ornithine decarboxylase (ODC) metabolic pathway and enhances hydrogen peroxide synthesis through the activity of spermidine oxidase (SMO). In this chapter, we present a survey of the methods used to analyze the induction and the role of the enzymes related to polyamine metabolism, i.e., arginase, ODC, and SMO in H. pylori-infected macrophages. PMID- 21318891 TI - Spermine synthase deficiency resulting in X-linked intellectual disability (Snyder-Robinson syndrome). AB - Polyamines, small positively charged molecules, are vital for cell proliferation and differentiation. They are found ubiquitously in eukaryotic cells. Additionally, they interact with a wide range of other molecules and some membrane associated receptors. Polyamines, spermidine and spermine, are synthesized by two aminopropyltransferases, spermidine synthase and spermine synthase. Recently, mutations in the latter enzyme have been shown to be responsible for an X-linked intellectual disability condition known as Snyder Robinson syndrome. Spermine synthase deficiency is thus far the only known polyamine deficiency syndrome in humans. PMID- 21318890 TI - High-resolution capillary gas chromatography in combination with mass spectrometry for quantification of three major polyamines in postmortem brain cortex. AB - There is considerable evidence supporting a role of the polyamine system in the etiology and pathology of mental disorders. Changes in the expression and activity of polyamine anabolic/catabolic enzymes, as well as in the levels of individual polyamines, have been found in many psychiatric conditions, including schizophrenia, mood disorders, anxiety, and suicidal behavior. Recent microarray studies have found that spermidine/spermine-N1-acetyltransferase (SAT1, SSAT), the key enzyme in charge of the polyamine catabolic pathway, is downregulated in brain tissue of individuals who were depressed and died by suicide. To provide further insight into the downstream effects of altered SAT1 expression, we developed a quantitative gas chromatography-mass spectrometry method for measurement of polyamine concentrations in postmortem human brain tissues. This protocol employs a conventional electron ionization method with total ion and selected ion monitoring. This method can accurately measure the levels of the polyamines putrescine, spermidine, and spermine from very small quantities (1-50 mg) of postmortem brain tissues, with quantitation limits down to 10 ng/g of wet tissue for putrescine and 100 ng/g for spermidine and spermine. PMID- 21318892 TI - Methylated polyamines as research tools. AB - Earlier unknown racemic beta-methylspermidine (beta-MeSpd) and gamma methylspermidine (gamma-MeSpd) were -synthesized starting from crotononitrile or methacrylonitrile and putrescine. Lithium aluminum hydride reduction of the intermediate di-Boc-nitriles resulted in corresponding di-Boc-amines, which after deprotection gave target beta- and gamma-MeSpd's. To prepare alpha-MeSpd, the starting compound, 3-amino-1-butanol, was converted into N-Cbz-3-amino-1-butyl methanesulfonate, which alkylated putrescine to give (after deprotection of amino group) the required alpha-MeSpd. Novel beta- and gamma-MeSpd's in combination with earlier alpha-MeSpd are useful tools for studying enzymology and cell biology of polyamines. PMID- 21318893 TI - Fluorescent substrates for polyamine catabolic enzymes and transport. AB - The most widely used methods for measuring polyamine enzyme activities are radioisotope methods that measure the radioactivity of compounds produced from radiolabeled substrate by the enzyme reaction. Several fluorescent polyamines have been developed for the measurement of the polyamine transport system (PTS) or transglutaminase. Although fluorophores in the fluorescent polyamines may affect the affinity of the polyamine moiety to the enzyme protein, the assays that use fluorescent substrate are sensitive and simple for common laboratory usage.In this chapter, the uses of dansyl polyamines with a simple high performance liquid chromatography system for the measurement of the PTS and polyamine catabolic enzymes including spermidine/spermine N1-acetyltransferase and N1-acetylpolyamine oxidase are described. PMID- 21318895 TI - Measurement of polyamine pKa values. AB - The extent of ionization of the polyamines is an important factor in their interactions with cellular components. The pK(a) is the pH at which a functional group is 50% ionized. For compounds such as polyamines with more than one ionizable center (atom or functional group), there is a pK(a) value for each center of ionization. This chapter describes the pK(a) values for each amine group in many important polyamines, the factors influencing these values and methods for their determination using potentiometric titration and nuclear magnetic resonance spectroscopy. PMID- 21318894 TI - Use of polyamine derivatives as selective histone deacetylase inhibitors. AB - Histone acetylation and deacetylation, mediated by histone acetyltransferase and the 11 isoforms of histone deacetylase, play an important role in gene expression. Histone deacetylase inhibitors have found utility in the treatment of cancer by promoting the reexpression of aberrantly silenced genes that code for tumor suppressor factors. It is unclear which of the 11 histone deacetylase isoforms are important in human cancer. We have designed a series of polyaminohydroxamic acid (PAHA) and polyaminobenzamide (PABA) histone deacetylase inhibitors that exhibit selectivity among four histone deacetylase isoforms. Although all of the active inhibitors promote reexpression of tumor suppressor factors, they produce variable cellular effects ranging from stimulation of growth to cytostasis and cytotoxicity. This chapter describes the procedures used to quantify the global and isoform-specific inhibition caused by these inhibitors, and techniques used to measure cellular effects such as reexpression of tumor suppressor proteins and hyperacetylation of histones H3 and H4. Procedures are also described to examine the ability of PAHAs and PABAs to utilize the polyamine transport system and to induce overexpression of the early apoptotic factor annexin A1. PMID- 21318896 TI - Polyamine analysis by LC-MS. AB - This chapter describes a protocol to analyze polyamines without any derivatization steps utilizing LC-MS/MS. Polyamines are separated by reversed phase LC prior MS analysis using heptafluorobutyric acid as MS compatible volatile ion-pairing agent, and selective and sensitive MS detection is performed using MS/MS in selected reaction monitoring mode. PMID- 21318897 TI - Virtual screening for lead discovery. AB - The identification of small drug-like compounds that selectively inhibit the function of biological targets has historically been a major focus in the pharmaceutical industry, and in recent years, has generated much interest in academia as well. Drug-like compounds are valuable as chemical genetics tools to probe biological pathways in a reversible, dose- and time-dependent manner for drug target identification. In addition, small molecule compounds can be used to characterize the shape and charge preferences of macromolecular binding sites, for both structure-based and ligand-based drug design. High-throughput screening is the most common experimental method used to identify lead compounds. Because of the cost, time, and resources required for performing high-throughput screening for compound libraries, the use of alternative strategies is necessary for facilitating lead discovery. Virtual screening has been successful in prioritizing large chemical libraries to identify experimentally active compounds, serving as a practical and effective alternative to high-throughput screening. Methodologies used in virtual screening such as molecular docking and scoring have advanced to the point where they can rapidly and accurately identify lead compounds in addition to predicting native binding conformations. This chapter provides instructions on how to perform a virtual screen using freely available tools for structure-based lead discovery. PMID- 21318898 TI - Computer-aided drug discovery and development. AB - Computer-aided approaches have been widely used in pharmaceutical research to improve the efficiency of the drug discovery and development pipeline. To identify and design small molecules as clinically effective therapeutics, various computational methods have been evaluated as promising strategies, depending on the purpose and systems of interest. Both ligand and structure-based drug design approaches are powerful technologies, which can be applied to virtual screening for lead identification and optimization. Here, we review the progress in this field and summarize the application of some new technologies we developed. These state-of-the-art tools have been used for the discovery and development of active agents for various diseases, in particular for cancer therapies. The described protocols are appropriate for all drug discovery stages, but expertise is still needed to perform the studies based on the targets of interest. PMID- 21318899 TI - Using active site mapping and receptor-based pharmacophore tools: prelude to docking and de novo/fragment-based ligand design. AB - Understanding the three-dimensional aspects of drug-receptor interactions and their specificity at the molecular level has become a focal point in modern drug discovery. Herein, we describe a set of methods by which the binding site on a protein can be located and mapped and the protein-ligand intermolecular interactions can be studied in the context of drug discovery. The methodology we describe is based on the empirical Hydropathic INTeraction (HINT) force field. Applications of the novel cavity detection algorithm, VICE, are demonstrated in delineating the binding pockets. The binding site environment is mapped using hydropathic "complementary map." The two binding sites are compared by calculating their 3D differences and the intermolecular interactions between a bound ligand and protein was further studied by HINT intermolecular maps. We illustrate the applications of these different types of HINT maps through an example from the development of selective COX-2 inhibitors. PMID- 21318900 TI - Methods for evaluation of structural and biological properties of antiinvasive natural products. AB - Prostate cancer is considered the most common cancer form among males in Western countries. Very limited options are available for the treatment of advanced metastatic prostate cancer. More than 50% of today's anticancer drugs are natural products or derived from a natural origin. To discover new entities with potential to treat prostate cancer at androgen-refractory stages, 36 structurally diverse natural products were screened using functional-based assays. The tested compounds were selected broadly from major secondary metabolites of plants, marine invertebrates, and fungi. These diverse entities were prescreened for their antiinvasive ability against prostate cancer cells, PC-3M, using spheroid disaggregation assay. Active representatives including three selected structural classes, a macrolide, a beta-carboline alkaloid, and a phenylmethylene hydantoin (PMH), were then tested for their ability to stabilize junctional complexes and enhance cell-cell adhesion of androgen independent prostate cancer cells. Transepithelial resistance (TER) and paracellular permeability assays were used to elicit the aforementioned properties. These studies led to the emergence of PMHs as a small molecule class from the marine sponge Hemimycale arabica with a unique potential to attenuate CT-stimulated prostate cancer growth, metastasis, paracellular permeability, and enhance TER and cell-cell adhesion of prostate cancer cells. The unique activities of PMHs were validated using several in vitro assays followed by in vivo testing in two mice models. A 3D QSAR was established using SYBYL 8.1-Comparative Molecular Field Analysis (CoMFA) model. This chapter includes the methodology for evaluation of structural and biological properties of new antiinvasive molecules with an exceptional potential to stabilize junctional complexes from diverse natural product sources. PMID- 21318901 TI - Solid-phase peptide synthesis using microwave irradiation. AB - Since the advent of solid-phase peptide synthesis (SPPS) in the late 1950s, numerous advancements in the underlying chemistry (i.e., orthogonal protection strategy, coupling reagents, and solid support matrices) have greatly improved the efficiency of the technique. More recently, application of microwave radiation to SPPS has been found to reduce reaction time and/or increase the initial purity of synthetic peptide products. In this protocol, conditions are described to accomplish rapid peptide coupling and 9-fluorenylmethoxycarbonyl (Fmoc) removal reactions under temperature-controlled conditions in either a manual or automated synthesis format using a microwave reactor. These microwave assisted peptide synthesis procedures have been used to rapidly prepare a "difficult" peptide sequence from the acyl carrier protein, ACP(65-74), in less than 3 h and the reduced, linear precursor to human hepcidin, in high initial purity. PMID- 21318903 TI - DNA-directed assembly microarray for protein and small molecule inhibitor screening. AB - A robust high-throughput and high-fidelity screening platform for identifying and validating potential target molecules is the key for drug development. During the past decade, microarray platforms have demonstrated enormous potential for developing robust tools for small molecules as well as protein-based drug discovery and analysis. Recently, we developed a DNA-directed assembly microarray platform with improved screening and immobilization strategies. In contrast to conventional microarray platforms, our technique allows the solution phase interaction of the probes and analytes in a biological environment and further the detection through the directed assembly of specific DNA probes on a dendrimer modified glass surface. Herein, we describe the detailed experimental protocols in performing the DNA-directed assembly platform for antibody microarray, a RNA polymerase-DNA binding microarray, and a drug-screening microarray. PMID- 21318902 TI - Fluorescent and lanthanide labeling for ligand screens, assays, and imaging. AB - The use of fluorescent (or luminescent) and metal contrast agents in high throughput screens, in vitro assays, and molecular imaging procedures has rapidly expanded in recent years. Here we describe the development and utility of high affinity ligands for cancer theranostics and other in vitro screening -studies. In this context, we also illustrate the syntheses and use of heteromultivalent ligands as targeted imaging agents. PMID- 21318904 TI - Selection of peptide ligands for human placental transcytosis systems using in vitro phage display. AB - Fetal pharmacotherapy generally relies on nonspecific biodistribution of therapeutic agents to the unborn child following drug administration into the maternal circulation system. Physiologically, transfer of polar, high-molecular weight solutes across the placenta is facilitated by a specialized, vesicular transport mechanism termed transcytosis. To develop biotechnology-based drugs such as proteins, DNA, and siRNA as clinically effective therapeutics, transcytosis systems have been evaluated as a promising strategy to augment drug transfer across endothelial and epithelial barriers. Screening of random peptide libraries using phage display is a powerful technology to identify peptide sequences with high affinity for surface proteins on desired target cells. Here, we describe assembly of a diverse, cyclic heptapeptide library on the icosahedral T7 bacteriophage platform. This phage-displayed library of random peptides was used for functional in vitro screens across BeWo cell monolayers to identify peptide ligands that facilitate placental transcytosis of viral particles across this cell culture model of the human trophoblast barrier. PMID- 21318905 TI - Optimization of the tetrazolium dye (MTT) colorimetric assay for cellular growth and viability. AB - The MTT colorimetric assay is an established method of determining viable cell number in proliferation and cytotoxicity studies. This assay is based on the cleavage of the yellow tetrazolium salt, MTT, to form a soluble blue formazan product by mitochondrial enzymes, and the amount of formazan produced is directly proportional to the number of living, not dead cells, present during MTT exposure. Since the MTT assay is rapid, convenient, and economical, it has become a very popular technique for quantification of viable cells in culture. However, various parameters have been identified that can affect cellular metabolism and other factors, which significantly modify MTT-specific activity and can result in calculated false high or false low cell counts. Therefore, it is essential to establish assay parameters with the proper controls for each cell line and/or drug treatment in order to optimize assay conditions and minimize confounding effects. These parameters should include determining appropriate cell densities, culture medium, optimal concentrations and exposure times for MTT, fresh culture medium at the time of assay to avoid nutrient depletion, and controlling for drug treatment effects that may influence cellular metabolism. By controlling these important parameters, the MTT colorimetric assay provides accurate and reliable quantification of viable cell number. PMID- 21318906 TI - Imaging NF-kappaB signaling in mice for screening anticancer drugs. AB - The activation of NF-kappaB has been implicated in various forms of cancer. Thereafter, targeting NF-kappaB has been suggested for cancer therapy. Instant and accurate tools to monitor NF-kappaB activation are necessary for such drug screening. Currently, there are various assays available to study NF-kappaB activation in vitro, however, techniques involving the imaging of NF-kappaB in vivo models remains limited. Male NF-kappaB-RE-luc (Oslo) mice from Xenogen Corporation (Alameda, California) provide a great model for studying and imaging anticancer drugs that target NF-kappaB signaling. In addition, the bioluminescent (LPTA) animal model DBA/1, BALB/C-Tg (NF-kappaB-RE-luc (Oslo)), carries a transgene containing three NF-kappaB response element sites from the Igk light chain promoter and modified firefly luciferase cDNA (Promega pGL-3). The reporter is inducible during inflammatory processes triggered by LPS and TNF-alpha. This model provides for the rapid study of transcriptional regulation of the NF-kappaB gene and the treatment of inflammatory diseases and cancer. Therefore, in this chapter, we will provide step-by-step methods on utilizing the NF-kappaB-RE-luc animal model. In addition, we will provide notes on effective compound administration and imaging strategies that have been proven effective in previous studies. PMID- 21318907 TI - Evaluation of anticancer agents using flow cytometry analysis of cancer stem cells. AB - Flow cytometry can sensitively detect and efficiently sort cells based on fluorescent signals integrated into cellular markers of proteins or DNA. It has been broadly applied to assess cell division, apoptosis and to isolate cells including stem cells. As the seeds for tumorigenesis and metastasis, cancer stem cells (CSCs) are often more resistant to cytotoxins and anticancer agents than other heterogeneous cells in tumors. Analyzing CSCs under treatments is an effective way to evaluate new therapeutic agents for cancers. We introduce a method using flow cytometry to assess breast CSCs (CD44(+)/CD24(-)/(low)) in human MCF-7/Dox breast cancer cells, after the treatment of mixed-backbone oligonucleotide against glucosylceramide synthase. Flow cytometry analysis of CSCs is a reliable, effective, and easy-handling approach to screen agents targeting CSCs. PMID- 21318908 TI - Chemical screening with zebrafish embryos. AB - Functional chemicals are very useful tools for molecular biology studies. Due to its small size, large progeny clutch, and embryonic transparency, zebrafish serves as a superb in vivo animal model for chemical compound screens and characterization. During zebrafish embryogenesis, multiple developmental phenotypes can be easily examined under the microscope, therefore allowing a more comprehensive evaluation for identifying novel functional chemicals than cell based assays. Ever since the first zebrafish-based chemical screen was conducted in the year 2000, many functional chemicals have been discovered using this strategy. In this chapter, we describe how to perform a typical zebrafish-based chemical screen and discuss the details of the protocol by using the example of the identification and characterization of two new Smo inhibitors with a Gli:GFP transgenic line. PMID- 21318909 TI - iTRAQTM labeling coupled with LC-MALDI mass spectrometry for monitoring temporal response of colorectal cancer cells to butyrate treatment. AB - Mass spectrometry (MS)-based quantitative proteomics plays important roles in drug discovery. In this chapter, we describe a stable isotope labeling technique which employs 4-plex iTRAQ(TM) isobaric reagents coupled with two-dimensional (2 D) liquid chromatography (LC) and MALDI-TOF/TOF MS, for a temporal study of HCT 116 colon carcinoma cells treated with butyrate. Butyrate is a short-chain fatty acid fermentation by-product of fiber that can induce temporal cell maturation, from the early phase of growth arrest, to differentiation, and to the activation of apoptotic cascades. Our quantitative proteomics study uncovered several integrated cellular processes and pathways involved in growth arrest, apoptosis, and metastasis. Selected protein targets are validated by real-time PCR and western blotting. PMID- 21318910 TI - Heterotypic cell adhesion assay for the study of cell adhesion inhibition. AB - CD2 is a cell adhesion molecule that mediates T-cell activation by binding to its ligand CD58 on antigen-presenting cells. Interaction between CD2 and CD58 or leukocyte function-associated antigen-3 (LFA-3) helps to optimize immune recognition facilitating contact between T lymphocytes and antigen-presenting cells. Modulation or inhibition of this interaction has been shown to be therapeutically useful in the treatment of autoimmune diseases. Antibodies and small molecules including peptides have been designed to modulate or disrupt the cell adhesion interactions due to CD2 and CD58. E-rosetting assay is a widely used method applied in the study of the modulation of CD2-CD58 interaction, which is either labor-intensive or radio-hazardous. In this chapter, we describe two methods that are used to study cell adhesion inhibition: (a) E-rosetting Assay and (b) Lymphocyte-epithelial assay. The second method, lymphocyte-epithelial assay, is a rapid and sensitive heterotypic cell adhesion assay for studying cell adhesion inhibition. The method relies on the CD2 expression on the surface of Jurkat cells and the CD58 expression on the surface of Caco-2 cells, which were confirmed by flow cytometry and ELISA studies respectively. This heterotypic cell adhesion assay described typically takes less than 4 h to perform, allows the evaluation of inhibitory activity of peptides/small molecules to modulate CD2 CD58 interaction in real cell system. PMID- 21318911 TI - Evaluation of antibacterial activity of proteins and peptides using a specific animal model for wound healing. AB - Wound healing is a complex process involving the integrated actions of numerous cell types, soluble mediators, and extracellular matrix (ECM). In this study, phospholipase A(2) (PLA(2)) purified from crotalid snake venom was found to express in vitro bactericidal activity against a group of clinical human pathogens. Based on the sequence homology of PLA(2), a series of peptides were derived from the C-terminal region of crotalid PLA(2). These short synthetic peptides were found to reproduce the bactericidal activity of its parent molecule. In vitro assays for bactericidal and cytolytic activities of these peptides showed very high microbicidal potency against Gram-negative and Gram positive (Staphylococcus aureus) bacteria. Variants of the peptides showed reduced toxicity toward normal human cells, while retaining high bactericidal potency. Here we describe the protocol for evaluating the wound healing process by antibacterial peptides. We evaluated the biological roles of the candidate peptides in skin wound healing, using a specific BALB/c mice model. Peptide treated animals showed accelerated healing of full-thickness skin wounds, with increased reepithelialization, collagen synthesis, and angiogenesis observed during the healing process. Healing wounds in protein/peptide-treated mice had higher densities of neutrophils, macrophages, and fibrocytes. Along with increased leukocyte infiltration, levels of macrophage-derived chemokine expression were also upregulated. These results demonstrate that the protein/peptide derived from snake venoms promotes healing of skin wounds. The primary mechanism seems to be an increase in leukocyte infiltration, leading to locally elevated synthesis and release of collagen and growth factors. PMID- 21318912 TI - In vitro immunogenicity risk assessment of therapeutic proteins in preclinical setting. AB - Immunogenicity against therapeutic proteins is a clinical problem in the successful treatment of many diseases and, as such, immunogenicity risk assessment in preclinical setting would be useful to improve safety and efficacy of protein-based therapeutics in the product development stages. Here, we attempted a mechanism-based in vitro study as screening tool to capture clinically observed antibody-based immune response against two representative therapeutic proteins: recombinant human Erythropoietin-alpha (rHuEPO)and recombinant Factor VIII (rFVIII). Flow-cytometry was used to determine the maturation level of dendritic cells (DCs), a primary initiator of T-cell responses. Studies to capture T-lymphocyte proliferation upon challenge with free rFVIII were performed and secretion of immunomodulatory cytokines was analyzed by ELISA assay. These in vitro techniques could be used as risk assessment tool to determine the immunogenic potential of formulations of recombinant proteins in preclinical setting. PMID- 21318913 TI - Caries risks and appropriate intervals between bitewing x-ray examinations in schoolchildren. AB - Short intervals between bitewing examinations favor the timely detection of lesions on approximal surfaces. Long intervals reduce the exposure to radiation. Thus, the question arises which intervals between bite-wing examinations are appropriate. The length of intervals between bitewing examinations should be adapted to the caries risk on approximal surfaces of molars and premolars. In order to estimate the caries risk in the Swiss school population, longitudinal data of 591 schoolchildren from the Canton (County) of Zurich were analyzed. These schoolchildren had been examined at 4-year intervals. The proportion of 7 year-olds with caries increment on approximal surfaces within 4 years was 7.1%, i.e., the caries risk in the population was 7.1%. In the 11-year-olds, the caries risk was 17.60%. Seven-year-olds without caries experience on selected approximal surfaces had a low caries risk of 2.2%. However, 7-year-olds with caries experience on selected approximal surfaces had a high risk of 24.2%. The same applied to 11-year-olds: those without caries experience had a low risk (7.5%), and those with caries experience had a high risk (38.5%). For the 7-year-old schoolchildren without any caries experience, an x-ray interval of 8 years is proposed. For the 7-year-old schoolchildren with caries experience, an x-ray interval of 1 year is proposed. PMID- 21318914 TI - Racial disparity in access to cardiac intensive care over 20 years. AB - OBJECTIVES: The purposes of this article are: (1) to systematically examine racial disparities in access to and use of cardiac care units (CCUs) in acute care hospitals; and (2) to assess racial differences in post-hospital mortality following CCU stays. DESIGN: Data from the National Health and Nutrition Examination Survey I: Epidemiologic Follow-up Study of adults aged 25 and older at baseline are analyzed to track CCU use and survival after hospitalization over 20 years (N=4227). Estimates are derived from Cox proportional-hazards models with time-dependent covariates and from negative binomial and tobit regression analyses. All analyses adjust for disease severity, hospitalization history, and resources. RESULTS: Black adults were less likely than White adults to be admitted to a CCU, even after adjusting for morbidities, health behaviors, previous hospitalization experience, and socioeconomic status. Comparing Black and White adults admitted to CCUs, Black adults spent fewer days and a smaller proportion of their hospital stay in CCUs. Black adults also had fewer CCU stays over the 20-year period and were more likely to die post-discharge, although the latter result was mediated by disease severity. CONCLUSIONS: Higher morbidity, lower admission rates, fewer stays, and shorter stays reveal that racial inequality is far-reaching and exists even in such highly-specialized units as CCUs. The fact that Black individuals' greater post-discharge mortality was mediated by disease severity illustrated that even among high-risk individuals, the accumulation of morbidity factors (beyond cardiac problems) is a salient concern. Overall findings demonstrate that the accumulation of disadvantage for Black adults is not confined to discretionary medical measures, but also exists in critical care for serious health problems. PMID- 21318915 TI - Quantification of lead and cadmium in poultry and bird game meat by square-wave anodic-stripping voltammetry. AB - A square-wave anodic-stripping voltammetric method for the analysis of lead and cadmium in chicken muscle and liver was developed and validated, and the results of a monitoring study relative to chicken and pigeon meat are reported. The voltammetric method allows the analysis of lead and cadmium at the same time in samples after acid digestion. The use of perchloric acid for digestion and of acetate buffer in the supporting electrolyte are suitable to reduce matrix interferences and obtain limits of quantification which were below 10 ng g-1 for meat and liver samples. The regression between the analytical signal and the concentration of the target analytes in spiked samples and Certified Reference Materials proved to be linear within the 10-100 ng g-1 range for meat and within the 50-500 ng g-1 range for liver. The analytical method was verified using available Certified Reference Materials BCR-184 (cattle meat) and BCR-185R (cattle liver) as well as with spiked chicken samples. Precision (i.e. repeatability and intermediate precision) and accuracy (percentage recovery and bias) were of the order of 0.3-4.5% for both lead and cadmium The level of lead in muscle was in the range between 6.4 and 59.8 ng g-1 in chickens and between 7.9 and 63.6 ng g-1 in farmed pigeons, whereas it was between 8.0 and 84.4 ng g-1 in chicken liver. The cadmium concentration was 0.4-10.4 ng g-1 in chicken muscle, 10.4-90.6 ng g-1 in chicken liver and 2.2-8.0 ng g-1 in farmed pigeons. PMID- 21318916 TI - Fate of three insect growth regulators (IGR) insecticides (flufenoxuron, lufenuron and tebufenozide) in grapes following field application and through the wine-making process. AB - The dissipation of three insecticide flufenoxuron, lufenuron and tebufenozide residues in grapes after field treatments and during the wine-making process was assessed. Residues were determined in grape, must, centrifuged must and wine samples by HPLC-UV after cyclohexane extraction and clean-up on silica-phase cartridges. Vines in vineyards with white and red grapes located in Central Greece were sprayed once with commercial formulations of each insecticide at the recommended doses in experiments carried out in 2004 and repeated in 2006. The insecticide residues in grapes showed slow reduction for a period of 42 days after application following first-order kinetics with dissipation rates ranged from 0.011 to 0.018 mg kg-1 day-1. However, at the recommended pre-harvest interval (PHI) residues did not exceed 0.27 +/- 0.03 mg kg-1 for flufenoxuron and lufenuron and 0.68 +/- 0.07 mg kg-1 for tebufenozide, and they were clearly lower than the maximum residue limits (MRLs) set by the European Union for grape (2 mg kg-1 for flufenoxuron, 1 mg kg-1 for lufenuron and 3 mg kg-1 for tebufenozide). Grape processing into wine caused an almost complete reduction for flufenoxuron and lufenuron as their residues in wine were below the method LOQs (<0.01 mg l 1), but only a moderate reduction for tebufenozide with concentrations from 0.13 to 0.26 mg l-1 measured in the produced wines. Mean transfer factors for tebufenozide of 0.45 for white 'Roditis' and 0.34 for red 'Cabernet Sauvignon' were found from grapes into wine for the wines processed without maceration. The wine-making technique (with or without maceration) had the same influence on tebufenozide residues in wine. Of the various clarifying agents studied, charcoal was found to be the only one effective in removing tebufenozide residues from wine. PMID- 21318917 TI - Empathic exchanges in online cancer support groups: distinguishing message expression and reception effects. AB - Past studies on the efficacy of participation in online cancer support groups have primarily focused on the role of expression in the accrual of health benefits for participants. Unfortunately, few steps have been taken to determine whether this observed effect arises solely from the internal mental processes underlying the act of expressing or, perhaps, owes something to a nuanced, multidimensional understanding of expression that includes reception of responses to what is expressed. To test for the multilayered effect, we attend to one of the key concepts in the online support community scholarship: empathy. Our findings suggest that it is a combination of empathy expression and reception that is crucial to attaining optimal benefits for cancer patients. Further, our finding supports the buffering hypothesis that empathic expression provides a salutary effect for patients who experienced a higher degree of concern associated with their cancer diagnosis and follow-up treatments. PMID- 21318918 TI - Social support, loneliness, recuperative processes, and their direct and indirect effects on health. AB - This study tested predictions that potentially explain why social support is associated with better health and loneliness is associated with poorer health. Social support was predicted to be associated with better health because it minimizes loneliness, which itself is associated with poor health. In particular, this study evaluated the role of recuperative processes, namely, sleep and leisure, in the association between loneliness and poor health. Participants were 224 adults aged 18-81 years who completed measures of social support, loneliness, health, sleep quality, and leisure. Results indicated that social support had an indirect association with better health, through lower loneliness. There was also evidence supporting or at least partially supporting the assumption that one mechanism by which loneliness is associated with poorer health is through less functional recuperative processes, specifically sleep and leisure. Finally, social support moderated the association between age and health such that among those with relatively high levels of social support, age and health were positively associated. PMID- 21318920 TI - Anxiety during respirator use: comparison of two respirator types. AB - Anxiety may interfere with proper respirator use. This study directly compares the effect of two types of respirators--elastomeric half-face mask with dual cartridges (HFM) and N95 filtering facepiece--on anxiety levels. Twelve volunteers with normal or mildly impaired respiratory conditions performed a series of simulated work tasks using the HFM and N95 on different days. The State Trait Anxiety Inventory (STAI) measured state anxiety (SA) before and during respirator use. STAI also measured trait anxiety (TA), a stable personal characteristic. The effect of the respirator was measured as the difference between SA pre-use and during use. Work with HFM was associated with an increase in SA (2.92 units, p < .01), whereas work with the N95 had no observed effect. Anxiety should be considered in the selection of the best respirator for a user. Impact on anxiety should be considered for respirator design and certification purposes, particularly if the device is to be widely used in workplace and community settings. PMID- 21318921 TI - Unknown exposures: gaps in basic characterization addressed with person-portable gas chromatography-mass spectrometry instrumentation. AB - A newly developed person-portable gas chromatography-mass spectrometry (GC-MS) system was used to analyze several solvent standards, contact cement, paint thinner, and polychlorinated biphenyl samples. Passive solid phase microextraction sampling and fast chromatography with a resistively heated low thermal mass GC column were used. Results (combined sampling and analysis) were obtained in <2 min for solvent, contact cement, and paint thinner samples, and in <13 min for the polychlorinated biphenyl sample. Mass spectra produced by the small toroidal ion trap detector used were similar to those produced with heavily used transmission quadrupole mass spectrometers for polychlorinated biphenyl compounds, simple alkanes, and cycloalknes, while mass spectra for benzene and the ketone compounds analyzed showed evidence for ion/molecule reactions in the ion trap. For one of the contact cement samples analyzed, no evidence was found to indicate the presence of n-hexane, although the relevant material safety data sheet listed this ingredient. Specific chemical constituents corresponding to a potentially wide range of petroleum distillate compounds were identifiable from GC-MS analyses. The possibility for an improved basic characterization step in the exposure assessment process exists with the availability of fast, person portable GC-MS, although work is needed to further refine this tool and understand the best ways it may be used. PMID- 21318922 TI - Women's autonomy and timing of most recent sexual intercourse in Sub-Saharan Africa: a multi-country analysis. AB - Since the 1994 Cairo International Conference on Population and Development, there has been increasing interest in promoting women's empowerment, particularly for sexual and reproductive health. Women's ability to negotiate the timing of intercourse with an intimate partner has not been extensively studied. This study explored the relationships between married women's autonomy and the time since most recent sexual intercourse in Ghana, Malawi, Mali, Rwanda, Uganda, and Zimbabwe using the Demographic and Health Surveys. Significant variation both within and between countries in the timing of most recent sex was found. A strong relationship between women's decision-making autonomy and time since last sexual intercourse in all six settings, even after controlling for factors such as the husband living elsewhere, age, marital duration, and other sociodemographic variables, was found. Men's decision-making autonomy was not associated with the time since last intercourse. Understanding how women's position in the household influences their sexual activity may be an essential piece in protecting the sexual rights of women and helping them to achieve a sexual life that is both safe and pleasurable. PMID- 21318925 TI - Editors' introduction to the special issue on health promotion interventions. PMID- 21318926 TI - Changing exercise through targeting affective or cognitive attitudes. AB - Two studies investigated the impact of affective and cognitive messages compared to a no-message control on self-reported exercise. Students (Study 1, N = 383 and Study 2, N = 197) were randomly allocated to one of the three conditions (control - no message, affective message or cognitive message). Participants completed questionnaire measures tapping components of the theory of planned behaviour in relation to exercise and reported their level of exercise (3 weeks later). In Study 2, measures of need for affect (NFA) and need for cognition (NFC) were also completed. Results showed that affective messages consistently produced greater increases in self-reported level of exercise than the other conditions. In both studies, this effect was partly mediated by affective attitude change. Study 2 indicated these effects to be significantly stronger among those high in NFA or low in NFC. These findings indicate the value of affective messages that target affective attitudes in changing exercise behaviour. PMID- 21318927 TI - Self-efficacy as a moderator of the planning-behaviour relationship in interventions designed to promote physical activity. AB - Individuals who lack perceived self-efficacy may benefit less from planning interventions because they fail to apply their plans when encountering situations that appear challenging. Thus, self-efficacy may operate as a moderator in relation to the effects of planning interventions on behaviour. This article reports from two experimental studies using cluster randomisation. Study 1 included 58 patients with diabetes who received a face-to-face action planning intervention to improve their physical activity levels. Study 2 targeted the roles of planning and self-efficacy for the maintenance of regular running and for relapse prevention in 187 active individuals over a 2-year period. The email delivered intervention prompted specific goal setting and facilitated planning to mobilise social support to secure relapse prevention. Results of the two studies were consistent with a moderating effect of self-efficacy in relation to the planning-behaviour relationship. Individuals with high self-efficacy benefited from planning interventions. If a person lacks self-efficacy, planning may not effectively promote physical activity. PMID- 21318928 TI - Cognitive-behavioural health-promotion intervention increases fruit and vegetable consumption and physical activity among South African adolescents: a cluster randomised controlled trial. AB - Rates of chronic diseases are high among Black South Africans but few studies have tested cognitive-behavioural health-promotion interventions to reduce this problem. We tested the efficacy of such an intervention among adolescents in a cluster-randomised controlled trial. We randomly selected 9 of 17 matched pairs of schools and randomised one school in each pair to the cognitive-behavioural health-promotion intervention designed to encourage health-related behaviours and the other to a human immunodeficiency virus (HIV)/sexually transmitted disease (STD) risk-reduction intervention that served as the control. Interventions were based on social cognitive theory, the theory of planned behaviour and qualitative data from the target population. Data collectors, blind to participants' intervention, administered confidential assessments at baseline and 3, 6 and 12 months post-intervention. Primary outcomes were fruit and vegetable consumption and physical activity. Participants were 1057 grade 6 learners (mean age = 12.4 years), with 96.7% retained at 12-month follow-up. Generalised estimating equations revealed that averaged over the follow-ups, a greater percentage of health-promotion intervention participants than HIV/STD control participants met 5-a-Day fruit and vegetable and physical activity guidelines. The intervention also increased health-promotion knowledge, attitude and intention, but did not decrease substance use or substance-use attitude and intention. The findings suggest that theory based and contextually appropriate interventions may increase health behaviours among young adolescents in sub-Saharan Africa. PMID- 21318929 TI - Effects of the Positive Action programme on problem behaviours in elementary school students: a matched-pair randomised control trial in Chicago. AB - This study examined the effects of the Positive Action (PA) programme in Chicago Public Schools on problem behaviours among a cohort of elementary school students from grade three through grade five. Using a matched-pair, randomised control design with 14 elementary schools, approximately 510 fifth-graders self-reported lifetime substance use, serious violence-related behaviour, and current bullying and disruptive behaviours. Three-level (i.e. students nested within schools within school pairs) overdispersed Poisson models were used to examine programme effects on the number of items endorsed for each of the four outcomes. Findings indicated that students in the intervention endorsed 31% fewer substance use behaviours (incidence rate ratio [IRR] = 0.69), 37% fewer violence-related behaviours (IRR = 0.63) and 41% fewer bullying behaviours (IRR = 0.59), respectively, compared to students in the control schools. Reduction in reported disruptive behaviours was of a similar magnitude (27%, IRR = 0.73), but was not statistically significant. These results replicate findings of an earlier randomised trial of the PA programme and extend evidence of its effectiveness to youth attending large urban school systems. PMID- 21318930 TI - Justify your love: testing an online STI-risk communication intervention designed to promote condom use and STI-testing. AB - The efficacy of a tailored, web-based intervention communicating the risks of sexually transmitted infections (STI) for heterosexual young adults was examined in a randomised, controlled trial. The main aims of the relationship-oriented intervention were to influence risk perceptions and to promote (maintenance of) condom use and STI-testing among young adults who reported being recently engaged in a heterosexual relationship. The intervention addressed risk perceptions, attitudes, normative beliefs, self-efficacy and skills related to condom use and STI-testing. Outcomes were compared immediately after the intervention (N = 171) and 3 months later (N = 115) to a non-tailored intervention group and to a control group. Cognitive and behavioural outcomes showed that the tailored intervention was efficacious in influencing perceived susceptibility to STI and STI-testing intentions immediately after the intervention, and in reducing rates of unprotected sex at 3 months. PMID- 21318931 TI - Preliminary efficacy of a computer-based HIV intervention for African-American women. AB - This study evaluated the preliminary efficacy of a computer-based HIV intervention to enhance HIV-protective sexual behaviours, based on a randomised controlled trial among 135 African-American women, 21-29 years of age, seeking services at Planned Parenthood in Atlanta, GA. Participants were randomised either to a control session two, 60-minute computer-based HIV intervention sessions administered on a laptop computer that each concluded with a 15-minute small group session or to a control session of general health information including discussion on HIV prevention. Relative to controls, participants in the computer-based HIV intervention were more knowledgeable about HIV/STD prevention and reported higher scores on the measure of condom use self-efficacy at 3 months post-intervention; they also reported a higher percentage of condom-protected sex and were more likely to use condoms consistently for vaginal sex (odds ratio, OR = 5.9; p < 0.039) and were more likely to use condoms consistently for oral sex (OR = 13.83; p < 0.037). This relatively brief intervention provides preliminary support that an evidence-based group-based HIV prevention intervention for young African-American women can be adapted to a computer-based HIV intervention. PMID- 21318932 TI - Effects of group prenatal care on psychosocial risk in pregnancy: results from a randomised controlled trial. AB - Few interventions have succeeded in reducing psychosocial risk among pregnant women. The objective of this study was to determine whether an integrated group prenatal care intervention already shown to improve perinatal and sexual risk outcomes can also improve psychosocial outcomes compared to standard individual care. This randomised controlled trial included pregnant women ages 14-25 from two public hospitals (N = 1047) who were randomly assigned to standard individual care, group prenatal care or integrated group prenatal care intervention (CenteringPregnancy Plus, CP+). Timing and content of visits followed obstetrical guidelines, from 18-week gestation through birth. Each 2-h group prenatal care session included physical assessment, education/skills building and support via facilitated discussion. Using intention-to-treat models, there were no significant differences in psychosocial function; yet, women in the top tertile of psychosocial stress at study entry did benefit from integrated group care. High-stress women randomly assigned to CP+ reported significantly increased self esteem, decreased stress and social conflict in the third trimester of pregnancy; social conflict and depression were significantly lower 1-year postpartum (all p values < 0.02). CP+ improved psychosocial outcomes for high-stress women. This 'bundled' intervention has promise for improving psychosocial outcomes, especially for young pregnant women who are traditionally more vulnerable and underserved. PMID- 21318934 TI - [Radiofrequency of the liver - an update]. AB - The impact of radiofrequency ablation (RFA) as a local ablative tumor therapy is increasing. Randomized trials justify RFA for small hepatocellular carcinoma (HCC) (single tumor <= 5 cm or three or less tumors <= 3 cm). Surgical resection still remains the gold standard for resectable colorectal liver metastases (CRLM). Several single center trials demonstrate improved patient survival by RFA and justify RFA for non-resectable CRLM. Local recurrence increases significantly with tumor diameters > 3 cm. There is insufficient evidence at this time to resolve the issue of optimal approach for treatment of CRLM. Technical development of the electrode design, improved ablation algorithms, and simplification of the exact electrode placement by new real-time fusion techniques of pre-interventional CT or MRT images with intra-interventional ultrasound have the potential to reduce the variable and sometimes high rate of local tumor recurrence. The clinical impact of immunological aspects following RFA with regard to patient survival and local tumor recurrence remains unclear. PMID- 21318935 TI - Clinical MR mammography: impact of hormonal status on background enhancement and diagnostic accuracy. AB - PURPOSE: Hormonal stimulation can induce background enhancement (BE) in MR mammography (MRM). This fact has been assumed to decrease the accuracy of MRM. Consequently, this report investigates: 1. The prevalence of BE in postmenopausal vs. premenopausal women in correlation to hormonal cycle phase (CP). 2. The impact of hormonal status (HS) and BE on diagnostic accuracy. MATERIALS AND METHODS: Consecutive patients over 22 months with complete HS information (week of CP or postmenopausal) were included in this prospective investigation. Exclusion criteria were any hormonal therapy, hysterectomy as well as cancer proven by biopsy. The standard of reference was histopathology. All MRM scans were acquired using the same protocol (1.5 T, dynamic T 1w GRE after 0.1 mmol/kg bw Gd-DTPA i. v.). Two radiologists rated all examinations in consensus according to BI-RADS. BE was defined as: 0 = missing, 1 = moderate, 2 = distinct. RESULTS: 224 patients (150 postmenopausal, 74 premenopausal, 45 in the second week of CP) were included in this study (83 benign and 141 malignant findings). BE was more frequent in premenopausal women (p = 0.006), but did not differ between CP (p = 0.460). Neither HS nor BE had a significant impact on the diagnostic parameters of MRM (p >= 0.375). However, regarding BE, the relative number of false positive (FP) findings was highest (5 / 10; 50 %) in the distinct BE group. Regarding HS, 17 % more FP findings were observed in premenopausal women examined outside the second week of CP. CONCLUSION: In premenopausal women, HS leads to increased BE of breast tissue, independent of CP. Distinct BE and less pronounced, non-optimal CP may lead to an increased number of false positive findings. PMID- 21318937 TI - [1st diagnosis of a true "hepar mobilis" in childhood]. PMID- 21318936 TI - Emergency and elective implantation of covered stent systems in iatrogenic arterial injuries. AB - PURPOSE: To evaluate the effectiveness and safety of covered stents for the management of iatrogenic arterial injury. MATERIALS AND METHODS: Between 03 / 1998 and 12 / 2009, 31 patients underwent selective covered stent implantation after iatrogenic arterial injury. 12 / 31 of these patients (38.7 %) were hemodynamically unstable. Six different endovascular covered stent types were utilized. The primary endpoints of this study were technical and clinical success and rates of minor and major complications. RESULTS: Initial angiograms demonstrated active extravasation in 19 (61.3 %) patients and pseudoaneurysms in 12 (38.7 %) patients. The following sites of bleeding origin were detected: axillary artery, subclavian artery, common iliac artery, external iliac artery, internal iliac artery, common femoral artery, superficial femoral artery, popliteal and fibular artery, femoro-popliteal and popliteo-crural bypasses, common hepatic artery, aberrant hepatic artery, cystic and gastroduodenal artery. In all patients bleeding was effectively controlled by covered stent implantation resulting in an immediate technical success of 100 %. Clinical success attributed to covered stent implantation was documented in 30 of the 31 patients (96.8 %). Major complications included death in four patients (11.1 %), acute thrombosis with arm ischemia in one patient (2.8 %) and stent fracture with associated pseudoaneurysm in another patient (2.8 %). In 2 / 31 patients (6.5 %) covered stent failure was detected and successfully treated by implantation of a second covered stent. CONCLUSION: Emergency and elective implantation of covered stents may be used for minimally invasive and effective management of iatrogenic arterial injury. PMID- 21318938 TI - Quetiapine in adolescents with non-affective psychotic disorders: an open-label trial. AB - INTRODUCTION: There is a need for more studies on the clinical effectiveness, tolerability and pharmacokinetics of atypical antipsychotics in adolescents with psychotic disorders, as this represents a vulnerable and difficult population to treat. According to recent concerns regarding disabling side effects of antipsychotics, particularly weight gain, further monitoring of their safety profiles is needed. This situation prompted the authors to carry out an investigation on the clinical effectiveness of quetiapine in psychotic adolescents. METHODS: 23 adolescents (13-18 years old) with psychotic disorders participated in a 12-week open label trial, including 6 visits assessing clinical efficacy, tolerability and safety of quetiapine (50-750 mg daily). RESULTS: Adolescents were treated with lower doses compared to adults. Significant decreases in CGI and PANSS total scores were observed after both 4 and 12 weeks of quetiapine treatment compared to baseline. Sedation was the main adverse effect, but medication was generally well tolerated. Irregular compliance, (as assessed by pill counts, a questionnaire and by plasma quetiapine concentration monitoring), and alcohol and/or cannabis consumption were factors identified in this study which add to the difficulty in treating this population. DISCUSSION: The results of the present study help to consolidate evidence of the usefulness of quetiapine as a treatment for adolescents with psychotic disorders. However, this study also highlights the issues encountered in treating this group, including the presence of comorbidities such as drug abuse. PMID- 21318939 TI - Pregabalin-induced suicidal ideations. PMID- 21318940 TI - A case of deep pulmonary laceration associated with blunt chest trauma treated by emergency room thoracotomy. AB - A 30-year-old man fell from the fourth floor of a building and suffered a chest injury. He was transported to our hospital within 50 minutes. Chest roentgenography showed left hemopneumothorax and a shift of the mediastinal shadow to the right. Furthermore, most of the left upper lobe did not appear collapsed, and an infiltrative shadow and light macular shadows were noted. These findings led to a diagnosis of deep pulmonary laceration. The volume of blood in the left drainage tube reached about 1,000 mL within 1 hour. Therefore, we performed emergency room thoracotomy (ERT) and clamped the pulmonary hilum manually. We then moved him to an operating room. Upon surgery, we found extensive laceration of the whole lung, and left pneumonectomy was necessary. He was discharged on hospital day 58. ERT and pulmonary hilum clamping may improve the survival of patients with deep pulmonary laceration and uncontrollable pleural hemorrhage. PMID- 21318941 TI - Usefulness of the Eating Disorder Inventory-2 Japanese version in patients with eating disorders. AB - OBJECTIVE: We produced a Japanese version of the Eating Disorder Inventory-2 (EDI 2) and investigated its reliability and validity. METHODS: EDI-2 Japanese version was administered to 246 patients with eating disorders and 100 control subjects. The internal consistency as well as discriminant validity were examined. RESULTS: The alpha reliability coefficients were high (0.71 to 0.92) in all subscales except the asceticism subscale which was rated 0.61. The anorexia nervosa binge purging type and bulimia nervosa showed significantly higher scores in all the EDI-2 subscales when compared to the controls, and also significantly higher scores in seven EDI-2 subscales compared to anorexia nervosa restricting type (AN R). AN-R showed significantly lower scores in the body dissatisfaction subscale. Lower scores in Japanese than Western patients for drive for thinness as well as marked difference in perfectionism and maturity fears suggested cross-cultural issues between Japan and western countries. CONCLUSION: Japanese version of EDI-2 is a measure instrument that can be expected to have a satisfactory level of internal consistency except the asceticism subscale as well as high validity as a tool for the evaluation of the psychopathology of eating disorder. PMID- 21318942 TI - Spontaneous expectoration of bronchial foreign body: a case report. AB - A nine-year-old girl with mental retardation accidentally swallowed an axle of a toy car and was urgently hospitalized with the diagnosis of left bronchial foreign body. While various monitors were installed and removal of the foreign body by a ventilating rigid bronchoscope was in preparation, the patient suddenly coughed and vomited, with the foreign body found in the vomit. When examining infant cases of air way foreign body, attention tends to be focused on the diagnosis and treatment. However, patients are at risk of aggravating difficulty in breathing or suffocation as long as foreign bodies are present in the air way. It is important to monitor carefully for changes in the breathing and to prepare for unexpected events. PMID- 21318943 TI - Bladder tumor associated with phenacetin abuse: a case report and a review of the literature. AB - We herein report the case of a bladder tumor in an 85-year-old man who had been engaged in phenacetin abuse. He had been taking phenacetin owing to migraine headaches since he was 45 year of age. His total intake of phenacetin was approximately 7.3 to 11.5 kg over a period of years. He visited the Department of Urology in our hospital due to gross hematuria and pain on urination. IVP and a pelvic CT scan revealed a tumor mass on the right lateral wall of the urinary bladder. TUR-BT was performed. A histopathological examination of the resected specimen was diagnosed as urotherial carcinoma, grade 2~3, pT2N0M0. To our acknowledge, only 24 cases of urotherial tumors owing to phenacetin abuse have been previously reported in the Japanese literature, making this the 25 th such case to be reported in Japan. PMID- 21318944 TI - A case of traumatic cardiac tamponade showing sudden spontaneous disappearance of the pericardial fluid. AB - Traumatic cardiac tamponade must be treated by pericardial drainage as soon as possible. We recently encountered a rare case of traumatic cardiac tamponade in which the pericardial fluid disappeared spontaneously immediately before the planned drainage. This case is reported in this paper. The patient was a 22-year old male who was transported to our hospital after he sustained injuries in a traffic accident. The patient was diagnosed to have a facial bone fracture, bilateral lung contusions, myocardial contusion (suspected), injury to the spinal cord at the L3-L4 level, injury to the left kidney and pelvic fracture. After TAE was performed to deal with the bleeding from the injured pelvis, the patient was immediately hospitalized. About 6 hours after the injury, pericardial fluid accumulation began to be noted, and about 18 hours after the injury, the patient went into shock, responding poorly to fluid resuscitation and treatment with pressor agents. At this time, a diagnosis of cardiac tamponade was made and emergency operation was arranged for. However, just before this could be executed, the patient's blood pressure showed a sharp rise, accompanied by disappearance of the pericardial fluid. He continued to show steady improvement and could eventually be discharged from the hospital. PMID- 21318945 TI - C1q nephropathy in a 2-year-old boy presenting with steroid resistant nephrotic syndrome. AB - We experienced a case of a 2-year-old boy, who presented with steroid resistant nephrotic syndrome, which developed insidiously. Renal biopsy revealed that he had focal and segmental glomerulosclerosis on light microscopy, dominant mesangial deposition of C1q by immunofluorescent staining, and electron dense deposits on electron microscopy, which are all compatible with C1q nephropathy. He had no clinical sign of any collagen diseases, including systemic lupus erythematodes. So, the diagnosis of C1q nephropathy was made. An intensive treatment by a combination of cyclosporine, prednisolone and methylprednisolone pulse therapy was successful in achieving remission and disappearance of proteinuria in this patient. Although he developed hypertension requiring calcium blocker and angiotensin converting enzyme inhibitor, his renal function stayed within normal limit for 3 years after the initiation of the treatment. The growth was well preserved during the 3 years of treatment with almost unchanged SD scores for height. He has delay in speech, which may not be associated with the etiology of his nephropathy, based on the absence of such association in the previous reports. C1q nephropathy is still a controversial clinical entity, so accumulation of the cases may help further understand the pathogenesis and clinical manifestation of C1q nephropathy. PMID- 21318946 TI - A case of bilateral medial medullary infarction presenting with "heart appearance" sign. AB - Bilateral medial medullary infarction (bilateral MMI) is an extremely rare cerebrovascular accident presenting with quadriplegia as the initial symptom and resulting in poor functional prognosis. Diagnosis of bilateral MMI has become possible based on brain MRI findings in recent years, but is still very difficult to diagnose. In the present case, brain MRI was performed 9 hours after the onset, and the infarcted area was detected only by diffusion-weighted MRI. However, changes over time were clearly detected by FLAIR-MRI on days 3, 5 and 7, but it is essential to confirm the disease by DW-MRI in the early stage.The infarct observed on horizontal MRI sections showed the characteristic "heart appearance" sign. For an early diagnosis of bilateral MMI, it is essential to bear in mind that characteristic findings may be obtained by diffusion-weighted MRI. PMID- 21318947 TI - Effect of dermal fibroblasts on long-term maintenance of regenerating xenotransplanted human esophageal epithelial cells in immunodeficient mice. AB - OBJECTIVE: Artificial esophagus of various materials has been tried without satisfactory results. Effects of fibroblasts derived from human dermis on cultured human esophageal epithelial cells were investigated regarding their preservation over time. METHODS: Human esophageal epithelial cells (EE) were subcutaneously injected either alone or with human esophageal fibroblasts (EF) or human dermal fibroblasts (DF) into the flank of the BALB/cA-nu, scid mice of 8 to 12 weeks of age. At 10 days, 3, 6 and 48 weeks after transplantation, randomly chosen mice were sacrificed and the rates of nodule formation at the injected sites were compared. Nodules were examined histologically by hematoxylin and eosin staining and immunohistochemically with anti- Ki-67 and anti-p63 antibodies. RESULTS: The rate of subcutaneous epidermoid cyst formation at 10 days was 33% for EE, and 67% for EE with EF, and 100% for EE with DF transplantation. At 6 weeks after transplantation, subcutaneous cysts were not found for EE alone or EE with EF, but were detected in 100% of the mice transplanted EE with DF and still preserved at 12 months. CONCLUSIONS: Long-term preservation of regenerated esophageal epithelium in vivo after transplantation of cultured esophageal epithelial cells is possible by co-transplantation of human dermal fibroblasts. PMID- 21318948 TI - Laparoscopic function-preserving surgery for early gastric cancer in the upper third of the stomach: vagus-sparing proximal gastrectomy with side-to-side esophagogastric-tube anastomosis. AB - OBJECTIVE: Proximal gastrectomy with an anti-reflux procedure has been a treatment option for gastric cancer in the upper third of the stomach. For early gastric cancer, laparoscopic function-preserving gastrectomy with limited lymphadenectomy can be performed. Objective of this study was to develop a new surgical technique for gastric cancer in the upper third of the stomach. METHODS: We present here our totally laparoscopic proximal gastrectomy with vagus-sparing lymphadenectomy and gastric-tube reconstruction. Six patients (five males and one female; mean age 74 years) with gastric cancer in the upper third of the stomach underwent the procedure. Detailed operative procedure and preliminary results were presented. RESULTS: We have successfully performed the procedure with no conversion to open surgery. The mean operative time and blood loss were 413 minutes and 85 mL. No intraoperative and postoperative complications occurred except for reflux esophagitis in one patient. At the mean follow up of 25 months, all patients were alive without any sign of recurrence. CONCLUSION: Although long term follow up and a larger number of patients are required to evaluate functional outcomes and oncological adequacy, our new technique provides a minimally invasive surgical option for early gastric cancer in the cardiac area. PMID- 21318949 TI - Acceleration of the proliferative activity of esophageal carcinoma with invasion beyond the muscularis mucosae; immunohistochemical analysis using MIB-1 for the Ki-67 antigen. AB - Squamous cell carcinoma of the esophagus with cancer invasion beyond the muscularis mucosae is known to have lymph node metastasis and lymphatic or blood vessel invasion compared with intramucosal carcinoma. In submucosal and T2-3 carcinoma, lymph node and lymphatic/vascular involvement are shown more frequently, leading to a poor prognosis. Therefore, we examined proliferative activity of esophageal squamous cell carcinoma including early carcinoma in relation to clinicopathological findings. 77 cases of esophageal squamous cell carcinoma, including 23 cases of mucosal carcinoma (Tis+T1a), 35 cases of submucosal carcinoma (T1b) and 19 cases of advanced invasive carcinoma (T2+T3) undergoing surgical resection without preoperative treatment were studied using monoclonal antibody MIB-1 for Ki-67 antigen immunohistochemically, and the labeling index (LI) was calculated. The LI of MIB-1 positive nuclei correlated with the depth of cancer invasion was significantly increased in the cancer invading beyond the musculais mucosae. The LI at the invasive tip was significantly higher than that at the core of differentiated carcinoma. The LI values at both invasive tip and core of poorly differentiated carcinoma were higher than those of differentiated carcinoma with significant difference. The LI at the invasive tip of the carcinoma with lymph node metastasis or lymphatic invasion was significantly higher than that without them. Proliferative activities of esophageal cancer cell, immunostaining with MIB-1, had correlations to depth of tumor invasion, differentiation, lymph node metastasis and lymphatic invasion with significant difference. But if invading deeper than m3, the proliferative activity did not increase anymore. PMID- 21318950 TI - Effect of low-intensity pulsed ultrasound treatment for delayed and non-union stress fractures of the anterior mid-tibia in five athletes. AB - Effects of optional use of low-intensity pulsed ultrasound (LIPUS) treatments for delayed and non-union stress fractures at the anterior mid-tibia in athletes were examined. The subjects were 5 competitive athletes (4 males and 1 female) with the anterior mid-tibia stress fracture, which was confirmed by radiography and bone scintigraphy (Technetium-99m). All patients consistently received daily 20 minute LIPUS treatment, until radiographic recovery was achieved. Recovery was evaluated using clinical symptoms, radiographic examination, bone scintigraphy and functional outcome. Patients returned to full sports activity at an average of 3 months after the onset of treatment (range, 2 to 4 months). Absence of pain was achieved at an average of 3.8 months (range, 2 to 5 months), and disappearance of bone umbauzone was achieved at an average of 11 months (range, 8 to 14 months). These results were clearly faster than that of other previously reported conservative treatments. Thus, the LIPUS treatment is useful for early alleviation of focal pain in anterior mid-tibia stress fracture (delayed and nonunion stress fracture), resulting in early return to sports activity. However, achievement of pain-free status did not coincide with radiological indications of bone healing, thus careful follow-up should be necessary. PMID- 21318951 TI - Treatment with internal pneumatic stabilization for anterior flail chest. AB - OBJECTIVE: Advantages and disadvantages have been reported for both internal pneumatic stabilization and surgical stabilization as treatments for anterior flail chest. We retrospectively investigated therapeutic outcomes and problems associated with pneumatic stabilization for anterior flail chest patients. METHODS: Subjects were 43 patients admitted to Tokai University Hospital with anterior flail chest, 1988-1999. Pneumatic stabilization was performed with continuous positive pressure ventilation and a positive end-expiratory pressure of 10 cm H20 or higher. We analyzed mean times required for pneumatic stabilization, weaning, and mechanical ventilation; sternal fracture (presence vs. absence); survival, and other clinical variables. RESULTS: Continuous positive pressure ventilation was needed for 12.5 days and mechanical ventilation for 15.6 days. Flail chest was relieved by pneumatic stabilization alone in 42 patients; 1 patient with a displaced sternal fracture required sternal fixation. Four cases were complicated by pneumonia. Pneumatic stabilization allowed physicians to treat severe combined nonthoracic organ injuries during the acute phase. Forty patients survived, and 3 died from nonthoracic injuries (survival rate 93%). CONCLUSIONS: Anterior flail chest unaccompanied by sternal fracture can be relieved by pneumatic stabilization alone. We hope to combine pneumatic stabilization with simple surgical stabilization in anterior flail chest patients to shorten the mechanical ventilation period. PMID- 21318952 TI - Infrequent hypermethylation of WIF-1 promoter in BCR/ABL-negative myeloproliferative disorders. AB - OBJECTIVE: The Wnt/beta;-catenin signaling pathway is important in the pathogenesis of hematological malignancies. Wnt inhibitory factor-1 (WIF-1) is a negative regulator of Wnt signaling that is frequently downregulated by hypermethylation of the WIF-1 promoter in acute promyelocytic leukemia (APL) and other malignancies. On the other hand, an acquired mutation in JAK2 tyrosine kinase involving a V617F amino-acid substitution shows a strong association with the pathogenesis of BCR/ABL-negative MPD. This is the first study to examine the relationship between WIF-1 methylation and the existence of JAK2V617F mutation in the pathogenesis of BCR/ABL-negative myeloproliferative disorders (MPD) including polycythemia vera, essential thrombocythemia, idiopathic myelofibrosis, and chronic myeloproliferative disease, unclassifiable. METHODS: We evaluated 49 newly diagnosed and previously treated patients with MPD in chronic phase. Bone marrow (BM) mononuclear cells, when available, or PB mononuclear cells of patients were used for the analysis. The mutation status of JAK2 was analyzed using sequencing analysis. The methylation status of the WIF-1 promoter was analyzed by methylation-specific polymerase chain reaction (MSP). RESULTS: The JAK2V617F mutation was found in 23/49 patients (46.9%) with BCR/ABL-negative MPD, while WIF-1 methylation was detected in 1/49 patients (2.0%). CONCLUSION: WIF-1 is infrequently methylated in BCR/ABL-negative MPD. PMID- 21318953 TI - A case of the primary small intestinal cancer which performed operation under laparoscopy after ileus decompression. AB - The patient was a 66-year-old man with repeated episodes of abdominal pain resulting in a diagnosis of ileus, and he was admitted to this hospital. During hospitalization, the pain symptoms improved after the insertion of an ileus tube, but there was a recurrence of ileus after the patient was started on a liquid diet. An adhesive intestinal obstruction was thus suspected, and laparoscopy was performed. A diagnosis of small intestinal carcinoma was made based on the intraoperative findings. A partial resection of the small bowel and a regional lymphadenectomy were performed through a minor laparotomy. The incidence of primary small intestinal cancer has been relatively rare, and it is difficult to differentiate the disease in most cases. A laparoscopy is considered useful to diagnose and treat ileus after decompression of the intestinal tract, and this article describes the case with some discussion. PMID- 21318954 TI - Laparoscopy-assisted resection of an appendiceal mucinous cystadenoma. AB - We present a 48-year-old man with a complaint of dull right-lower abdominal pain who was diagnosed with mucocele of the appendix. He underwent laparoscopy assisted resection of the tumor. In the procedure, the entire right colon was freed from the retroperitoneal structures without rupturing the tumor; and ileocecal resection and anastomosis were performed extracorporeally. The pathological diagnosis of the tumor was mucinous cystadenoma of the appendix, measuring 9.0 cm * 8.0 cm * 4.0 cm. The postoperative course was uneventful, and he had no recurrent disease at a 2-year follow up. When resecting an appendiceal mucinous tumor laparoscopically, it is essential (1) to keep the tumor intact during manipulation, and to use a wound-protecting device when delivering the lesion; (2) to consider the extent of tumor resection with a negative surgical margin as well as prophylactic lymph node dissection in cases of suspected adenocarcinoma, even though the oncological adequacy of the laparoscopic procedure for carcinoma remains to be elucidated; and (3) to check whether any mucinous fluid has accumulated in the abdominal cavity, which represents an indication for open surgery. PMID- 21318955 TI - Radiological reporting that combine continuous speech recognition with error correction by transcriptionists. AB - OBJECTIVE: We evaluated the usefulness of radiological reporting that combines continuous speech recognition (CSR) and error correction by transcriptionists. MATERIALS AND METHODS: Four transcriptionists (two with more than 10 years' and two with less than 3 months' transcription experience) listened to the same 100 dictation files and created radiological reports using conventional transcription and a method that combined CSR with manual error correction by the transcriptionists. We compared the 2 groups using the 2 methods for accuracy and report creation time and evaluated the transcriptionists' inter-personal dependence on accuracy rate and report creation time. We used a CSR system that did not require the training of the system to recognize the user's voice. RESULTS: We observed no significant difference in accuracy between the 2 groups and 2 methods that we tested, though transcriptionists with greater experience transcribed faster than those with less experience using conventional transcription. Using the combined method, error correction speed was not significantly different between two groups of transcriptionists with different levels of experience. CONCLUSION: Combining CSR and manual error correction by transcriptionists enabled convenient and accurate radiological reporting. PMID- 21318956 TI - Estimation of aortic-to-radial artery distribution of arterial wall elasticity. AB - OBJECTS: The purpose of this paper is to clarify the cause of the peaking/steepening phenomenon and pressure gradient after cardiopulmonary bypass by measuring the distribution of intra-arterial pressures and that of pulse wave velocities and estimating the vascular wall elasticity's from the aorta to radial artery. METHODS: We measured the intra-arterial pressures and pulse wave velocities simultaneously from aorta to radial artery using a guide-wire tipped with a pressure transducer before and after cardio-pulmonary bypass (CPB), and calculated the distribution of the stiffness parameters (called beta) of aorta-to radial artery wall. Thereafter, we converted beta's into the wall elasticity's. RESULTS: We found that before CPB the intra-vascular pressures increased gradually from aorta to radial artery, and that corresponding beta and wall elasticity increased simultaneously. After CPB, the intra-arterial pressure and beta or wall elasticity showed the gradual decrease from aorta to radial artery. These results suggest that aortic-to-radial artery pressure change is attributed to gradual change in beta, that is, in the wall elasticity. CONCLUSIONS: The findings indicate that the gradual rise and fall in beta, namely, the increase and decrease in vascular elasticity may account for the peaking, steepening and pressure gradient. PMID- 21318957 TI - Whole body protection to lethally irradiated mice by oral administration of semipurified fraction of Podophyllum hexandrum and post irradiation treatment of Picrorhiza kurroa. AB - OBJECTIVE: to evaluate the radioprotective potential of alcoholic fraction of Podophyllum hexandrum rhizomes (REC-2001) individually as well as in combination with Picrorhiza kurroa administered orally in lethally irradiated Swiss albino mice. METHODS: The study was divided into different treatment groups. Whole body survival was observed upto 30 days in all the treatment groups. Besides survival, toxicity of REC-2001 was also evaluated. All the groups were studied for spleen endogenous colony forming units (CFUs), plasma antioxidant potential and hematological variables, using standard techniques. RESULTS: Animals in radiation alone group died with in 12 days of exposure. Single dose of REC-2001 which did not bring any toxic manifestation/mortality (MTD) was found to be 155 mg/kg b.w. On administration of 250 mg/kg b.w. (single dose) 50% of the animals died (LD50), while a dose of 350 mg/kg b.w. of REC-2001 brought 100% death. Oral administration of single dose of REC-2001 (25 mg /kg b.w. -1h) prior to irradiation (10 Gy) was observed rendering up to 48% protection. Survival enhanced to the level of 55% when the animals had pre- treatment of REC-2001 (25 mg /kg b.w. -1h) followed by irradiation (10 Gy) and post treatment with a single dose of Picrorhiza kurroa rhizome extract (pkre, 8 mg/kg b.w.+1h). Radiation induced plasma antioxidant status was significantly (P < 0.02) countered by REC 2001 administration. Post treatment of pkre elevated CFU counts (P < 0.05). Total leukocytes count and hemoglobin content in REC-2001 pretreated and pkre post treated group approached normal limits within 30 days of the study. CONCLUSION: REC-2001 in combination with pkre holds promise for further studies to achieve radioprotection against lethal radiation by oral administration. PMID- 21318958 TI - Early carcinoma of the esophagus associated with achalasia treated by endoscopic mucosal resection: report of a case. AB - A case of endoscopically resected early esophageal carcinoma associated with achalasia is reported. A 63-year-old woman was made diagnosis of esophageal achalasia, sigmoid type and grade III. The patient was operated by Tokai University method, Heller's long esophagomyectomy, Hill's posterior cardiopexy, fundoplication and selective proximal vagotomy using a laparotomy. Two years and six months after the operation, an early carcinoma of type 0-IIb, 1cm in size, was detected in the upper thoracic esophagus, and treated by endoscopic mucosal resection using EEMR-tube method. Pathological examination revealed proliferation of squamous cell carcinoma in situ (Tis: m1). The entire esophageal mucosa around the carcinoma demonstrated hyperplastic changes of stratified squamous epithelium and foci of dysplastic changes. In the patient of achalasia, food stasis in esophagus is thought to induce chronic hyperplastic esophagitis, converting eventually to malignant transformation. Achalasia is known as a risk factor of esophageal carcinoma. Early operation or good drainage of the esophageal lumen might reduce the risk. Long-term follow-up for patients of achalasia by endoscopic screening is recommended. PMID- 21318959 TI - Clinical experience of bone anchored hearing aid: a case report. AB - To improve conventional bone conduction hearing aids, Tjellstrom, Branemark, developed an implant system consisting of a maxillofacial implant that derived from dental implants and a bone conduction hearing aid that was attached directly to the implant. This system has been commercially available as a bone anchored hearing aid (BAHA). More than 10,000 patients have benefited from BAHA in Scandinavia, North America, and many other regions. BAHA first became available in 1977 in Sweden but has not been used in Japan as widely as expected. This paper reports a case of a 8-year use of BAHA for hearing loss caused by microtia and external auditory canal atresia, with a review of literature. The patient has been followed up for 9 years after implant placement. Play audiometry with a loudspeaker showed a hearing loss of 25 dB. The patient says that BAHA is superior to conventional transcutaneous bone conduction hearing aids in easiness of attachment, esthetics, and speech recognition and music recognition. The skin and the bone around the implants remain in favorable condition. She has been free from the use of a headband for a conventional hearing aid. PMID- 21318960 TI - A new device for fixing the premaxilla with osteotomy in a child with complete bilateral cleft lip and palate in the mixed dentition period--a preliminary case report. AB - In the treatment of a protruded premaxilla associated with complete bilateral cleft lip and palate, some patients require surgical setback of the premaxilla with osteotomy as functional and aesthetic treatment. No satisfactory surgical approaches have been established for the setback because it is usually difficult to fix the premaxilla after osteotomy in the mixed dentition period. This paper reports the new method for fixing the premaxilla with osteotomy in a child with a severely protruded premaxilla in the mixed dentition period. To fix the segment, we fabricated a device consisting of a palatal bite plate and an anterior tray before surgery. The space between the tray and the premaxilla was filled with soft resin during surgery so that the reposition of the premaxilla could be adjusted. This approach produced a favorable result. Our device has several advantages. It allows the adjustment of repositioning of the premaxilla during surgery. It can change the range of the adjustment according to the intended position of the premaxilla. It allows secure fixation of the segment. It is removable for tooth brushing and observation of bone union. Our device can be applied to many children similar to our patient reported in this paper. PMID- 21318961 TI - Activation of inducible nitric oxide synthase increases MMP-2 and MMP-9 levels in ApoE-knockout mice. AB - OBJECTIVES: Atheroma with reduced collagen content becomes fragile, but the underlying mechanisms have not been established. We investigated the influence of inducible nitric oxide synthase (iNOS) induction upon matrix metalloproteinases (MMP)s and collagen content in atheroma. METHODS AND RESULTS: ApoE-/- x iNOS-/- double knockout and ApoE-/- x iNOS+/+ mice were fed a high-cholesterol diet for 15 weeks. Large atheromatous lesions of comparable size appeared in the roof of the aorta in both strains. Induction of iNOS mRNA was observed only in the atheroma of the ApoE-/-/iNOS+/+ mice. Collagen content was sparse and fat droplets were increased. Gelatin zymography and in situ zymography showed that pro- and active forms of MMP-2 and MMP-9 were more strongly expressed in ApoE-/ /iNOS+/+ than in ApoE-/-/iNOS-/- mice, nitrotyrosine and MMP-9 were co-expressed in the atheroma. CONCLUSION: We conclude that induction of iNOS in atheroma of high-cholesterol-fed ApoE-/-/iNOS+/+ mice leads to increased production and activation of MMPs, with a subsequent decrease in collagen content, affording fragile plaque. PMID- 21318962 TI - A case of chronic infection 28 years after silicone orbital implant. AB - Silicone was one of the most common biocompatible materials used for orbital floor reconstruction about twenty to thirty years ago. Recently, surgeons hardly use silicone due to numerous reports of complications such as infection, extrusion and implant displacement. We present a case of chronic infection seen after 28 years of silicone implant used in orbital floor repair. Although it is reported that infection due to silicone implant may decrease after long years of follow up, our case demonstrated the possible case of unexpected infection after more than twenty years with orbital silicone implant. PMID- 21318963 TI - Ultrasonographic diagnosis of adult intussusception caused by pedunculated colon carcinoma. AB - Adult intussusception is clinically rare. We report a case with colon intussusception caused by a pedunculated polyp of the sigmoid colon in a 54-year old male. Abdominal ultrasonographic screening for hematochezia showed intussusception in the sigmoid colon, demonstrating a multiple concentric ring sign and a mobile leading colon polyp. Histological examination of a biopsy specimen of the polyp revealed adenoma. This report suggests that ultrasound imaging is a modality of choice for differential diagnosis of intestinal intussusception with hematochezia in adults. PMID- 21318964 TI - A case of primary jejunal cancer diagnosed by preoperative small intestinal endoscopy. AB - The patient was a 37-year-old female. She was brought to our hospital by ambulance with nausea and vomiting. Abdominal ultra sound and abdominal enhanced CT scan showed a tumor in left side of the abdominal aorta 6 cm in size, and it showed an expanded stomach and duodenum. Upper gastrointestinal series revealed an apple core sign in upper jejunum near the Treitz' ligament. Small intestinal endoscopy (XSIF-240 endoscope, Olympus Inc.) revealed stenosis related to an epithelially protruding lesion with an irregular surface in the jejunum on the anal side of the horizontal duodenal peduncle. Biopsy suggested a well differentiated adenocarcinoma. Scintigraphy showed hot spot in left middle abdomen. Under a diagnosis of primary jejunum cancer, Partial resection of the jejunum and partial resection of the transverse colon was performed. Histopathologically, the tumor was well differentiated adenocarcinoma exposed serosal surface. Postoperatively, the stage was evaluated as III (T3, N1, M0). Preoperative diagnosis to use small intestinal endoscopy was effectiveness. We report a patient with primary jejunum cancer in whom a definitive diagnosis was made before surgery. PMID- 21318965 TI - Chronic administration of methamphetamine increases the mRNA expression of diazepam binding inhibitor in rat brain. AB - Anxiety is one of the common features of withdrawal syndrome caused by abuse inducing drugs such as methamphetamine (MAP). The neural pathways associated with anxiety are established within the network sustained by diencephalon, cerebral cortex, cerebellum and hippocampus. Diazepam binding inhibitor (DBI), a peptide consisting of 87 amino acids, serves as an inverse agonist for the type A receptor of the gamma-aminobutyric acid (GABAA receptor) with endogenous anxiogenic potential. We examined the effect of chronic administration of MAP on the mRNA expression of DBI and DBI-related proteins, such as alpha 2 subunit of GABAA receptor (GABA-alpha2), peripheral-type benzodiazepine receptor (PBR), and pituitary adenylate cyclase-activating polypeptide (PACAP) in seven regions (diencephalon, cerebral cortex, cerebellum, striatum, hippocampus, midbrain, and pons-medulla) of the rat brain. The mRNA expression of DBI increased significantly in all areas of the brain, especially diencephalon, after chronic administration of MAP. The mRNA expression of PBR, GABA-alpha2 and PACAP increased significantly in all areas of the brain, especially cerebral cortex, after chronic administration of MAP. These results suggest that anxiety is associated with the mRNA expression of DBI as well as DBI-related genes. PMID- 21318966 TI - Acute administration of methamphetamine decreases the mRNA expression of diazepam binding inhibitor in rat brain. AB - Chronic administration of methamphetamine (MAP) up-regulated the mRNA expression of diazepam binding inhibitor (DBI) in rat brain, possibly leading to anxiety. Acute effects of MAP on anxiety associated with DBI, however, are not clear. In this study, we examined the effects of acute administration of MAP on behavior related to anxiety and the expression level of DBI mRNA and pituitary adenylate cyclase-activating polypeptide (PACAP) mRNA, calibrated with the glyceraldehydes 3-phosphate dehydrogenase mRNA as the internal control in rat brain. The elevated plus-maze test was applied to the analysis of the possible anxiety-related profile of MAP. Acute administration of MAP (5 mg/kg, intraperitoneal administration) significantly increased spent time in the open-space arms at 4 h after the administration compared with a saline-treated group. The expression of DBI mRNA in a large number of regions of rat brain significantly decreased 2, 4, 8 and 16 h after acute administration of MAP. In contrast, the expression of PACAP mRNA in a large number of regions of rat brain significantly increased 4 and 8 h after the administration of MAP. These results suggest that MAP, at this dose, has an anxiolytic effect, based on the reduction of the putative anxiogenic peptides, DBI. PMID- 21318967 TI - Fully functional MR-compatible flexible operating table resolves the neurosurgeon's dilemma over use of intraoperative MRI. AB - In February 2006, our hospital officially opened the Magnetic Resonance / X-ray / operation (MRXO) suite, which is the first hybrid neurosurgical procedure suite to combine magnetic resonance imaging (MRI), computed tomography and angiography with a neurosurgical operating room. For this suite, we have developed a specially designed fully functional magnetic resonance (MR)-compatible flexible operating table. Here, we describe the details of this operating table and discuss its advantages. Its MR-compatible tabletop can be bent during surgery. The specially designed MR-compatible flexible operating table for the MRXO suite reduces limitations on neurosurgeons during standard neurosurgical procedures. Also, it does not give rise to imaging artifacts on MRI. The specially designed MR-compatible flexible operating table resolves the neurosurgeon's dilemma over use of intraoperative MRI. PMID- 21318968 TI - A case of colon lymphangioma treated with laparoscopy-assisted ileocecal resection. AB - We encountered a patient with colon lymphangioma and performed laparoscopy assisted ileocecal resection. The patient was a 68-year-old male who visited our hospital for weight loss in May 1999. Since fecal occult blood was positive on close examination, colonoscopy was performed. A light-permeable, transparent, and pedunculated polyp was found in the ascending colon and diagnosed as submucosal tumor. The patient was admitted for close examination and treatment. Abdominal CT detected a tumor in the ascending colon accompanied by disturbed surrounding adipose tissue, suggesting extramural invasion of the tumor. Based on the diagnosis of extramural submucosal tumor of the ascending colon, ileocecal resection was performed with laparoscopic assistance. The laparoscopic findings were as follows: 1) Lymph vascular dilatation filled with lymph expanding on the serosal surface, 2) light-permeability/translucency, 3) laparoscopic cushion sign, and 4) lymph vascular dilatation in the surrounding adipose tissue. Laparoscopy-assisted surgery was useful for the diagnosis and treatment of colon lymphangioma, and characteristic laparoscopic findings were noted. Laparoscopic surgery is a useful for a diagnosis and the treatment of large lymphangioma of colon. PMID- 21318969 TI - Successful treatment of a case with acute hepatic failure following hot bath immersion. AB - Heat stroke is often complicated by hepatic dysfunction as a manifestation of multiple organ dysfunctions, but acute hepatic failure rarely progresses to become the major morbid condition of heat stroke. We encountered a case who survived life-threatening classic heat stroke; the patient developed this condition, subsequently associated with acute hepatic failure, while bathing at home. A 73-year-old man was found in the bath in his home with unconsciousness, and was transferred to a nearby hospital. At the time he was in a coma, but no remarkable abnormalities were detected on blood examination. Rubor of his entire body beneath the cervical region was recognized. Under the diagnosis of a burn with consciousness disturbance, he was referred and transferred to our hospital. He was comatose and his axillary body temperature was 39.7 degrees C. His consciousness improved after admission, but blood examination revealed rhabdomyolysis, DIC and hepato-renal dysfunction. Subsequent blood examination findings showed rapid exacerbation. On the 2nd hospital day, PT% was 12, INR was 4.8. On the 3rd hospital day, serum ALT was elevated to 3,873 U/L, and the patient had hyperammonemia. On the 13th hospital day, serum total bilirubin was elevated to 33 mg/dl. Thereafter, additional conservative treatment produced gradual recovery of hepatic function. PMID- 21318970 TI - Inflammatory pseudotumor of the liver: case report and review of literature. AB - Inflammatory pseudotumor (IPT) is a benign tumorous lesion of unknown cause, which is composed of fibrous tissue with infiltration of plasma cells and lymphocytes. A 57-year-old male with gastritis was indicated to have hepatic dysfunction during observation of the course of gastritis at a nearby hospital. He was referred to our facility to undergo detailed examinations. When he visited our hospital for the initial examination, he had no subjective symptoms. His past medical history was unremarkable. There were no distinct abnormalities on the medical examination. Blood tests revealed a white blood cell count of 10400 / L, CRP of 0.29 mg/dl, AST of 31 IU/L, ALT of 46 IU/L, ALP of 583 IU/L and -GTP of 408 IU/L, showing a mild inflammatory reaction and elevated hepatobiliary enzymes. Abdominal ultrasonographic examination revealed a tumor mass approximately 4 cm in diameter in a lateral hepatic segment. The margin and center of the mass were hypoechoic and iso- to hyperechoic, respectively, and the inside of the mass was non-homogeneous. Needle biopsy revealed only inflammatory findings with no indications of malignancy. Since computed tomography (CT) of the abdomen, done 4 months after detection of the tumor mass, revealed the mass to have increased to approximately 6 cm in diameter, excision biopsy was considered. The CT taken 2 months later revealed the mass to have regressed to approximately 2 cm in diameter, but excision of the lateral hepatic segment was undertaken at the patient's request. As a result, the diagnosis of IPT of the liver was confirmed. Imaging findings of hepatic IPT are variable and specific findings are lacking. Since the rate of correct diagnosis with needle biopsy is also low, IPT of the liver is often very difficult to differentiate from malignant tumors. On the other hand, since it may show spontaneous regression, indications for surgery must be assessed very carefully. PMID- 21318971 TI - Lentigo maligna occurring in a patient with the past history of laser therapy. AB - A 70-year-old Japanese woman visited our clinic with a pigmented patch on her face from her upper lip to under her nose following laser therapy 15 years ago. Physical examination revealed an asymmetrical dark brown macule with a clear border along with irregular black dots measuring 20 mm. A biopsy specimen showed some irregular-sized atypical melanocytes with deep-colored nuclei on staining. There were observed on the basal layer and a few of them in the prickle-cell layer only in the epidermis. We diagnosed this case as lentigo maligna (LM). Total resection and reconstruction with the Abbe flap were carried out. We searched previous literature for reports on laser therapies resulting in LM and determined the following: (1) there were no reports indicating that laser therapy is one of the causes of LM, (2) judging from invalidity of treatment or recurrence of the condition, laser therapies were considered ineffective for LM treatment, and (3) the numbers of patients undergoing laser therapies, who were not diagnosed with LM, were increasing. PMID- 21318972 TI - Renovascular hypertension due to bilateral renal artery stenosis treated with stent implantation in a 12-year old girl. AB - Renovascular hypertension (RVH) in children is a relatively rare disease, but it is important in that it is a treatable condition when properly diagnosed. Percutaneous transluminal renal angioplasty (PTRA) with or without stenting is widely applied to adult patients with RVH. However, limited information is available as to PTRA with stenting in pediatric patients. We experienced a case of RVH in a 12-year-old girl, who had severe hypertension (180/110 mmHg). Bilateral renal artery stenosis was demonstrated by 3D-CT, MR angiography and selective renal arteriography. Renal function and plasma renin activity were normal. Angiotensin blockade was refrained for fear of functional deterioration of the kidney. Medical treatment with amlodipine insufficiently lowered the pressure to 140-160/80-100 mmHg, so we performed PTRA. Stenotic lesion and pressure gradient was still present after balloon angioplasty on both sides, prompting us to place LUMINEXX(r) stents on both renal arteries. Blood pressure dropped dramatically after the intervention. Amlodipine was discontinued, and then, enalapril and warfarin were administered to prevent neointima and thrombus formation. Her blood pressure and renal function was stable 18 months after PTRA. Oversized self-expanding stent such as LUMINEXX(r) stent could be used for renal artery stenting even in pediatric patients with RVH. PMID- 21318973 TI - Visualization of azygos arch valves using computed tomography: comparison of scanning delay times. AB - OBJECTIVE: To evaluate the frequency and appearance of azygos arch valves after short and long scanning delays and high injection rates of contrast material (CM) using a 64-slice multi-detector-row computed tomography (MDCT). METHODS: We retrospectively reviewed the findings from 264 contrast-enhanced MDCT chest examinations. The rate of injection for 300 mg I/ml CM was 3.0 ml/sec; the short and long scanning delays were 20 and 180 sec, respectively. The presence of residual CM in the azygos arch valves and reflux of CM into the azygos arch were recorded. A chi-square test was used to compare the frequency of residual CM in azygos arch valves and reflux of CM into the azygos arch in both groups. RESULTS: Of the 132 examinations with short scanning delays, 91 (68.9%) demonstrated residual CM in azygos arch valves and 103 (78.0%) demonstrated reflux of CM into the azygos arch. A significantly higher frequency of reflux of CM into the azygos arch and residual CM in azygos arch valves was seen with short scanning delays than with long scanning delays (P<0.05). However, no reflux of CM into azygos arch was seen with long scanning delays. CONCLUSIONS: Both reflux of CM into azygos arch valve and residual CM in the azygos arch were frequently seen using short scanning delays. PMID- 21318974 TI - CT features of juxtapapillary duodenal diverticula with complications. AB - OBJECTIVE: We evaluated the computed tomography (CT) features of juxtapapillary duodenal diverticula (JPDD) with complications in patients who had acute abdomen. MATERIALS AND METHODS: Nineteen JPDD were evaluated in 14 patients (mean age: 50 years), who had acute abdomen on contrast-enhanced helical CT with a diagnosis of complicated JPDD by endoscopic retrograde cholangiopancreatography (ERCP). The size, number, and contents of the JPDD, pacreticobiliary ductal dilation, biliary stones, and other associated findings were evaluated on CT scans. RESULTS: Eighteen of the 19 JPDD (94.4%) containing air were demonstrated by CT. Their diameter ranged from 20 to 40 mm (mean: 30 mm). Common bile duct dilation was visualized in 12 patients and biliary stones were found in 8 patients. The other findings were cholecystitis, cholangitis, pancreatitis, and liver abscess. The most serious complication was perforation into the retroperitoneal space caused by diverticulitis associated with an enterolith. CONCLUSION: Complicated JPDD were well depicted on CT scans, and various findings were revealed. CT evaluation of complicated JPDD was useful for management of these patients. PMID- 21318975 TI - Intensive insulin therapy for Japanese patients with type 2 diabetes mellitus- results in the patients from single hospital. AB - OBJECTIVE: We investigated the clinical characteristics of intensive insulin therapy in Japanese type 2 diabetes patients who commenced intensive insulin therapy during the in-hospital diabetes education program at Tokai university hospital. METHODS: 81 type 2 diabetes patients who received intensive insulin therapy and in-hospital diabetes education program were examined their clinical features. RESULTS: Intensive insulin therapy maintained HbA(1C) below 7% at all time points during the 2-year follow-up, though it was not necessary to increase the insulin dose, thus highlighting the clinical utility of the therapy in preventing diabetic complications. Insulin therapy could be withdrawn from more than 25% of patients. The diabetic morbid period was shorter and urinary C peptide level at admission was higher in patients of the withdrawal group than those of the non-withdrawal group, suggesting that patients with well maintained pancreatic beta cell reserve could be withdrawn from insulin therapy. CONCLUSIONS: Based on our results of the efficacy of strict glycemic control for preventing the development and progression of diabetic complications, we recommend early introduction of intensive insulin therapy to achieve better glycemic control. PMID- 21318976 TI - Endoscopy-assisted totally laparoscopic resection of a submucosal tumor of the duodenum. AB - Although, endoscopic polypectomy is one of the first options for diagnosis and treatment of submucosal tumors of the duodenum, it is sometimes difficult for large or sessile tumors. Therefore, local excision or more extended surgery is performed under open laparotomy. In this paper, we present a laparoscopic resection of Brunner's gland hyperplasia of the duodenum which demonstrated rapid interval size change. A 73-year-old male with a histologically unproven submucosal tumor underwent endoscopy-assisted laparoscopic resection of the tumor and intracorporeal suturing of the defect. Simultaneous duodenoscopy and laparoscopy were performed to identify the line of resection. A duodenotomy was performed and the tumor was excised after everting the tumor toward the abdominal cavity. The defect was handsewn with the greater curvature side rolled caudally with an exteriorized stay suture. Postoperative pain was minimal and the patient quickly returned to normal activity. Our new technique provides a minimal invasive treatment for tumors of the duodenum. PMID- 21318977 TI - Statistical analysis of post-operative complications after head and neck surgery. AB - The risk factors for wound complications after surgery for head and neck cancers at Tokai University Hospital were evaluated. The medical records of 71 head and neck cancer patients who underwent surgery between January 2000 and December 2002 were reviewed. The overall incidence of postoperative complications was 39.4%. Uni- and multivariate analyses of the risk factors leading to complications demonstrated that free flap use was significant. Further, we analyzed the relationship between radiotherapy and postoperative complications. There was no significant correlation between them.The prevention and treatment of postoperative complications were discussed. PMID- 21318978 TI - Spontaneous rupture of pheochromocytoma and its clinical features: a case report. AB - Rupture of adrenal pheochromocytoma is extremely rare and can be lethal because of dramatic changes in the circulation. We describe a 58-year-old Japanese man who suffered rupture of a pheochromocytoma. The patient was referred to our hospital because of severe hypertension (256/127 mmHg) and a left adrenal tumor. T2-weighted magnetic resonance imaging showed high signal intensity in the 50-mm left adrenal tumor. Endocrinological examinations showed elevated plasma and urinary catecholamine levels. These findings suggested that the left adrenal tumor was a pheochromocytoma. Phentolamine mesilate was administered intravenously. This resulted in a decrease of the systolic blood pressure to 100 mmHg. On the third hospital day, the patient complained of left back pain, and abdominal computed tomography showed rupture of the pheochromocytoma. Pulmonary congestion and effusion, and paralytic small-intestinal ileus occurred. Blood pressure was controlled, small-intestinal decompression was done with a Miller Abbot tube, and body water was controlled by fluid replacement. After the general condition of the patient had became stable, laparoscopic adrenalectomy was performed. Phentolamine mesilate is a useful alpha-adrenergic blocker. However, care is needed with its administration, because rupture of pheochromocytoma may be related to a decrease in blood pressure induced by phentolamine mesilate. PMID- 21318979 TI - Late diaphragmatic laceration detected as a result of spontaneous pneumothorax. AB - Injury to the right diaphragm is sometimes missed in the acute stage and is detected only when the rupture becomes more extensive, a diaphragmatic hernia develops, and dyspnea ensues. We report a case in which spontaneous right pneumothorax developed 46 months after blunt trauma due to a fall. Air had leaked into the right pleural cavity, passed through the injured right diaphragm, and entered the abdominal cavity; the patient presented with intraperitoneal emphysema. PMID- 21318980 TI - Intracordal injection technique: materials and injection site. AB - OBJECTIVE: Various materials have been used for intracordal injection to treat deficiencies in glottal closure. However, specific injection sites and materials are desirable for various conditions. Here, we reviewed injection sites and materials. METHODS: By considering the characteristics of injection materials used in Japan to date as well as the normal structure of the vocal cord, we have determined injection materials and sites suitable for different type of disease. RESULTS: Collagen obtained commercially for injection consists mainly of type I collagen, as does autologous fascia. When this material is injected into the superficial layer of the lamina propria mucosae of the vocal cord, the wave motion of the mucosa during phonation is disturbed. This material therefore should be injected deeper into the lamina propria. Indications for collagen injection include unilateral recurrent laryngeal nerve paralysis. Even when injected into the lamina propria, fat tissue does not disturb mucosal wave motion, and is useful for treating vocal cord atrophy or sulcus vocalis. CONCLUSION: When intracordal injection is used in vocal rehabilitation, material and site should be selected, based on the cause of glottal dysfunction. PMID- 21318981 TI - New method of blood purification (Recycle Filtration System). AB - OBJECT: We have developed a new blood purification system, the Recycle Filtration System (RFS), because back contamination of endotoxin (ET) from the dialysate in on-line hemodiafiltration (HDF) is a potential problem when a highly permeable membrane is used. METHODS: When the RFS is used for HDF, some of the purified fluid is pumped by a purified fluid pump to the venous side of the blood circuit, and the remainder is returned to the filtrate side of the hemofilter to be used for diffusion. This circuit enables simultaneous diffusion and filtration through the hemofilter. RESULTS: 1. The rate of removal of urea nitrogen (UN) increased with either decreased or increased quantity of recycled filtration flow (QRF). The rate of removal of beta-2-microglobulin (beta2-MG) decreased as QRF increased, but its clearance and removal rate increased as the quantity of drainage flow increased. 2. No significant change in beta2-MG clearance was observed in the filtration unit, even when recycling was continued for 24 h. 3. ET was not detected in the filtration unit, even though its level in the dialysate, which was reconstituted with tap water, was 806.2+/-105.4 EU/L. CONCLUSION: It is possible to regulate filtration using the RFS by giving importance to the elimination of either small molecules or low-molecular-weight proteins. PMID- 21318982 TI - Concurrent chemoradiotherapy with docetaxel for T2 laryngeal carcinoma. AB - OBJECTIVE: To evaluate the efficacy and safety of concurrent chemoradiotherapy with docetaxel (DOC) for T2 laryngeal carcinoma. METHOD: Twelve patients with T2 laryngeal cancer received concurrent chemoradiotherapy (60-70Gy) with weekly DOC (10 mg/m2) (CCRT group). The clinical files of the patients were retrospectively reviewed and survival rates and laryngeal preservation rates were analyzed compared with the group treated with conventional radiation therapy alone (RT group). RESULTS: Complete response was observed in 11 of 12 patients (91.7%) in the CCRT group. Overall 5-year survival rates by Kaplan-Meier's method were 90% for the CCRT group and 78% for the RT group. The disease free survival with anterior commisure involvement was 90% in CCRT group and 53% in RT group, respectively. Toxicity over grade III was noticed in 3 patients. CONCLUSION: Concurrent chemoradiotherapy with DOC is a feasible and effective treatment modality for organ preservation in T2 laryngeal cancer in the outpatient setting. Efficacy and safety of this treatment modality in an outpatient setting were discussed. PMID- 21318983 TI - A case of essential thrombocythemia presenting with aortic thrombosis. AB - Essential thrombocythemia (ET) is a chronic myeloproliferative disorder characterized by thrombo-hemorrhagic complications. But aortic thrombus formation is not so common in the patients with ET at the initial diagnosis. We describe a 65-year-old woman with ET found to have a thoraco-abdominal aortic thrombosis and have splenic infarction, which were successfully treated with medical therapy alone. To our knowledge, only two cases were published with presenting large aortic thrombosis at the onset. PMID- 21318984 TI - Preliminary study comparing diffuse gastric FDG uptake and gastritis. AB - Diffuse high FDG uptake in the stomach is occasionally observed on positron emission tomography (PET) images. Some PET oncologists believe this to be physiologic uptake, but the exact cause is undetermined. We retrospectively compared PET images and endoscopic findings to examine the relation between diffuse gastric FDG uptake and gastritis. From September to December 2005, 113 individuals (68 men and 45 women), aged 52 +/- 12 years, underwent both gastrofiberscopy and PET/computed tomography on the same day as part of a cancer screening program. Gastric FDG uptake was visually evaluated on PET images and classified as low, moderate, or high. Gastritis was classified as mild, moderate, or severe. For each screenee, the degree of FDG uptake was compared with the severity of gastritis. FDG uptake was low, moderate, and high in 64, 31, and 18 screenees, respectively. Gastritis was mild, moderate, and severe in 59, 44, and 10 screenees, respectively. A significant relation was observed between the degree of FDG uptake and the degree of gastritis (p<0.0001). High FDG uptake was observed significantly more often in the upper half of the stomach than in the lower half (p<0.0001). Similarly, gastritis was observed significantly more often in the upper half of the stomach (p=0.005). A significant relation was observed between the degree of FDG uptake and the severity of gastritis in both the upper (p<0.0001) and lower (p=0.01) portions. In conclusion, the significant relation we found between the degree of FDG uptake and the severity of gastritis suggests that gastritis is a major cause of diffuse FDG uptake in the stomach. PMID- 21318985 TI - An adult case of hand, foot, and mouth disease caused by enterovirus 71 accompanied by opsoclonus myoclonica. AB - We reported a 23-year-old female who was treated for rash due to hand, foot, and mouth disease (HFMD). On day 4 of hospitalization, the patient showed opsoclonus (jerky eye movements in all directions), myoclonus of the neck, trunk, and extremities, and cerebellar ataxia. Based on the changes in serum viral antibody titer, the patient was diagnosed as enterovirus 71 infection. No obvious abnormal findings were noted in head MRI. Immunoglobulin 5 g/day was administered for 3 days in the early stages of infection, and administration of methylprednisolone 500 mg/day for 3 days was repeated twice. Afterwards, oral corticosteroids were given, resulting in neurological improvements a month. Including our case, there are only 2 cases within opsoclonus myoclonica associated with enterovirus 71 infection. Our case suggests, based on the course of treatment, possible involvement of direct viral action or autoimmune response in opsoclonus myoclonica. PMID- 21318986 TI - Secondary pulmonary alveolar proteinosis in a patient with chronic myeloid leukemia in the accelerated phase. AB - Pulmonary alveolar proteinosis (PAP) is a rare respiratory disease the character of which is accumulation of protein consisting of surfactant in alveolar spaces. PAP sometimes complicates with hematological malignancies, especially myeloid leukemia. As one of the cause of PAP, impairment of alveolar macrophage is considered. We experienced a case of PAP with chronic myeloid leukemia (CML). 41 years old woman having CML for nine years developed PAP, and was treated by bronchoalveolar lavage and imatinib. She died of respiratory failure in the end, but BAL fluid had been becoming gradually crystalline after induction of imatinib. We consider that we should try to treat to improve respiratory status not only PAP but also hematological disease. PMID- 21318987 TI - HLA alleles are associated with postherpetic neuralgia but not with herpes zoster. AB - OBJECTIVE: In some herpes zoster (HZ) patients, one symptom is problematic; postherpetic neuralgia (PHN), a persistence of pain such as spontaneous pain and stimulus-evoked pain, allodynia or hyperpathia, for more than 6 months after healing of the vesicular eruptions. In our previous study, we reported the association between HLA alleles, HLA-A*33 and B*44, and PHN patients. In this study, we aim to refine the association of these alleles with PHN or HZ using higher-resolution HLA typing technique with an increased sample size. METHODS: HLA allele frequencies were compared in 70 PHN patients, 80 HZ patients, 52 HZ(-) patients, and 140 Japanese controls using HLA typing kits of SSOP protocols. RESULT AND CONCLUSION: The allele frequencies of HLA-A*3303, B*4403, and DRB1*1302 in PHN(+) patients were significantly higher than those in Japanese controls (P=0.00007, P=0.000002, and P=0.0003, respectively). The frequencies of above alleles in PHN(+) patients were also significantly higher than those in PHN(-) patients (P=0.03, P=0.006 and P=0.03, respectively). However, no association was found in comparison of HZ(+) patients and HZ(-). And the frequency of HLA-B*5101 in HZ(-) patients was significantly higher than those in HZ(+) and PHN(+) patients (P=0.003 and P=0.009, respectively) indicating that HLA B*5101 functions as a protective allele to HZ. PMID- 21318988 TI - Histopathological study of specimens obtained by left ventricular biopsy during ventriculoplasty for idiopathic dilated cardiomyopathy. AB - OBJECTIVE: Pathological changes in the myocardium in idiopathic dilated cardiomyopathy (DCM) are usually studied using endomyocardial biopsy specimens, but the relationship between pathological changes in the myocardium and clinical findings is unclear. The goal of the study was to examine correlations between clinical findings and histopathological findings in specimens of the left ventricular myocardium collected during left ventriculoplasty in DCM patients. METHODS: The subjects were 20 DCM patients (17 males and 3 females; mean age: 59 +/- 14 years old) who underwent left ventriculoplasty, including 16 cases of overlapping ventriculoplasty (OLVP) and 4 of papillary muscle approximation (PMA) with left ventricular incision. Preoperative age, sex, The New York Heart Association (NYHA) classification, the brain natriuretic peptide (BNP) level, cardiothoracic ratio (CTR), echocardiographic data, history of diabetes mellitus, drug history of spironolactone, ACE inhibitor, ARB, and beta-blocker were used as clinical findings. Histopathological scores were determined for each patient and semi-quantitative data for hypertrophy, attenuation, vacuolation and fibrosis were obtained. RESULTS: A significant correlation was found between age and interstitial fibrosis. A significant inverse correlation was found between left ventricular diastolic diameter (LVDd) in echocardiographic data and interstitial fibrosis. There were no other significant relation between histopathological scores and clinical findings. CONCLUSION: From this study, we found that interstitial fibrous increased with aging and more dilated LVDd had less interstitial fibrosis. It is concluded that the kinetics of myocardial fibrosis with remodeling might be variable and histopathological findings does not reflect the clinical and hemodynamic changes in DCM patients. Further morphological data are needed to verify this result. PMID- 21318989 TI - New method of laparoscopic incisional hernia repair with double circumferential transfascial sutures. AB - BACKGROUND: Although, laparoscopic incisional hernia repair (LIHR) provides an alternative method for managing incisional hernias, the ideal procedure for reducing the incidence of postoperative complications remains unclear. PATIENTS AND METHODS: We have developed a new method of LIHR that involves a double transfascial suture and does not require the use of spiral tackers. We performed this procedure consecutively in five patients (four males and one female with a mean age of 65.6 years). We describe our new method of LIHR, and present preliminary clinical results. RESULTS: The mean defect size was 26.2 +/- 15.8 cm(2), and the mesh size that was used was 121.7 cm(2) in all cases. An occult hernia was found in one patient during laparoscopic observation. The mean operative time was 198.4 +/- 49.3 minutes with a blood loss of 12.2 +/- 24.6 mL. Postoperative courses were uneventful with a median postoperative hospitalization period of 8 days. No patient required mesh removal and none developed a recurrent hernia during the median follow-up period of 13 months. CONCLUSION: Although, larger number of patients and longer follow-up will be required to prove the operative adequacy of our new procedure, it appears to represent a feasible option for LIHR. PMID- 21318990 TI - Uretero-aortic fistula: a case report. AB - We report a case of uretero-aortic fistula following prolonged ureteral stenting in the left ureter which crossed over the aorta toward the cutaneous ureterostomy stoma. A 59 year-old woman presented massive bleeding from the left cutaneous ureterostomy of the single stoma for bilateral ureters. The patient underwent radical hysterectomy and total cystectomy with a single stoma cutaneous ureterostomy for advanced cervical and bladder cancers. The postoperative course was uneventful except for pyelonephritis due to bilateral ureteral stenosis, which were treated by bilateral ureteral stenting. The patient had intermittent hematuria from the left cutaneous ureterostomy for 4 years after ureteral stenting. Massive bleeding from the left cutaneous ureterostomy requiring a big amount of blood transfusion followed intermittent hematuria, finally. A Computed tomography (CT) suggested both severe adhesion of the left ureter to the aorta and left renal pelvic hematoma. Massive bleeding seemed to be caused by uretero aortic fistula. A fistula, about 5 mm in diameter, from the left ureter to the aorta was detected at exploration. The defect of aortic wall was closed primarily and then left nephroureterectomy underwent for nonfunctioning kidney. Her postoperative course was uneventful at the 18-month follow-up. PMID- 21318991 TI - Fasting plasma glucose reference values among young Japanese women requiring 75g oral glucose tolerance tests. AB - OBJECTIVE: Currently there are various discussions on the upper limit of FPG (Fasting Plasma Glucose) levels. In Japan, when abnormal levels of FPG are detected at general health checkups or complete physical examinations, 75g Oral Glucose Tolerance Tests (75g OGTT) are often conducted in follow-up examinations. Therefore we investigated the appropriate upper limit of FPG levels to decide whether 75g OGTT are actually necessary. RESEARCH DESIGN AND METHODS: Based on the FPG levels of 256,309 women with an age range of 20 to 79, we established the upper limits of FPG levels by 5-year intervals, using a method equivalent to the National Committee for Clinical Laboratory Standards (NCCLS) used in the U. S. [4]. We also obtained the ROC curve from the 75g OGTT results from 160 women aged 20 to 39. We then divided those 160 women into four categories based on their 75g OGTT results, and compared the abnormal rates of their 2-hour post-75g OGTT glucose levels, HOMA-R and Insulin Index using the Kruskal-Wallis test. RESULTS: The upper limits of FPG levels were 99 mg/dl in the 20-29 age range, 101 mg/dl in the 30-34 age range, and 104 mg/dl in the 35-39 age range. The upper limits of the FPG reference intervals increased almost proportionally up to the age 50, and showed little difference thereafter. The point on the ROC curve where the total value of sensitivity plus specificity reached the highest had an FPG level of 99.5 mg/dl. For 2-hour post-75g OGTT glucose levels and HOMA-R, there was a significant difference in abnormal rates between the categories of FPG <= 99 mg/dl and 100 <= FPG <= 109 mg/dl, but not in Insulin Index. CONCLUSIONS: We believe that 75g OGTT are necessary for Japanese women aged 20 to 39 with FPG levels of 100 mg/dl or above. PMID- 21318992 TI - Re-evaluation of body weight as an indicator for contrast material dosage for indirect CT venography. AB - OBJECTIVE: We evaluated body weight as an accurate indicator for determining contrast load using nonionic monomeric contrast material in indirect CT venography. MATERIALS AND METHODS: One hundred and thirty-two patients (mean age 51 years) underwent indirect CT venography to exclude the possibility of DVT. We used 150 ml of isohexol (iodine, 300 mgI/ml) administered at a rate of 3.0 ml/s. Scanning delay was 180 s from the time of initiation of contrast injection. Scans were obtained in a caudal-to-cranial direction starting from the ankle. Hounsfield unit (HU) measurements were recorded at the common femoral and popliteal veins. Using linear regression analysis, we calculated the correlation the coefficient between the CT attenuation and the iodine dose per body weight of each patient. We also recorded the presence of DVT and measured the CT attenuation of the clots. RESULTS: Average contrast dosage per weight was 765.3 mgI (from 420.5 -1184.2 mgI). Average measurements of HU at the common femoral and popliteal veins were 114.4 +/- 17.8 HU and 109.9 +/- 21.4 HU, respectively. The regression coefficients were 0.62 and 0.41 for the common femoral and popliteal veins, respectively. DVT was detected in 33 of 132 patients. The average HU of the thrombus was 47.7 +/- 13.3 HU. CONCLUSION: Indirect CT venography for detecting DVT initiated 180 s after the start of infusion of contrast material (150 ml) and a contrast injection at a rate of 3 ml/s produced high mean levels of venous enhancement. However, correlation between dose of contrast material per patient weight and CT attenuation of veins was fairly low. PMID- 21318993 TI - Telangiectatic focal nodular hyperplasia of the liver in an infant with spontaneous regression: a case report. AB - A distinctive mass in the liver in a two-month-old girl with elevated serum alpha fetoprotein (AFP) level was diagnosed as telangiectatic focal nodular hyperplasia (FNH) after biopsy. The tumor spontaneously regressed and finally became no longer detectable by any imaging study within normal range of AFP. The nature of this novel entity and its management are discussed based on literature review. PMID- 21318994 TI - Effect of the herbal medicine dai-kenchu-to on gastrointestinal motility in patients with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) and chronic idiopathic intestinal pseudo-obstruction (CIIP): report of two cases. AB - Dai-kenchu-to (DKT), a traditional Japanese herbal medicine (Kampo medicine), composed of zanthoxylum fruit, ginseng root, dried ginger rhizome and malt sugar, is clinically effective for postoperative ileus and chronic constipation. MMIHS and CIIP are severe motility disorder associated with high morbidity. The aim of this study was to evaluate the effect of DKT on functional intestinal obstruction. DKT was clinically effective for gastrointestinal motility in a case with MMIHS, but not effective in one with CIIP. MMIHS and CIIP are speculated to have different pathogenesis regarding gastrointestinal pseudo-obstruction based upon the effect of this drug. PMID- 21318995 TI - Improved response of growth hormone to growth hormone-releasing hormone and reversible chronic thyroiditis after hydrocortisone replacement in isolated adrenocorticotropic hormone deficiency. AB - We report a 44-year-old Japanese man who showed a reversible blunted response of growth hormone (GH) to GH-releasing hormone (GRH) stimulation test and reversible chronic thyroiditis accompanied by isolated ACTH deficiency. He was admitted to our hospital because of severe general malaise, hypotension, and hypoglycemia. He showed repeated attacks of hypoglycemia, and his serum sodium level gradually decreased. Finally, he was referred to the endocrinology division, where his adrenocorticotropic hormone (ACTH) and cortisol values were found to be low, and his GH level was slightly elevated. An increased value of thyroid stimulating hormone (TSH) and decreased values of free triidothyronine and free thyroxine were observed along with anti-thyroglobulin antibody, suggesting chronic thyroiditis. Pituitary stimulation tests revealed a blunted response of ACTH and cortisol to corticotropin-releasing hormone, and a blunted response of GH to GRH. Hydrocortisone replacement was then started, and this improved the patient's general condition. His hypothyroid state gradually ameliorated and his titer of anti-thyroglobulin antibody decreased to the normal range. Pituitary function was re-evaluated with GRH stimulation test under a maintenance dose of 20 mg/day hydrocortisone and showed a normal response of GH to GRH. It is suggested that re evaluation of pituitary and thyroid function is useful for diagnosing isolated ACTH deficiency after starting a maintenance dose of hydrocortisone in order to avoid unnecessary replacement of thyroid hormone. PMID- 21318996 TI - Cervical myelopathy with retroodontoid pseudotumor caused by atlantoaxial rotatory fixation and senile tremor. AB - OBJECTIVE: A rare case of retroodontoid pseudotumor caused by the combination of atlantoaxial rotatory fixation and senile tremor is reported. METHOD: A 63-year old man was treated for cervical myelopathy with retroodontoid pseudotumor caused by atlantoaxial rotatory fixation and senile tremor. He had an 18-year history of torticollis and a 7-year history of tremor. Magnetic resonance imaging revealed a retroodontoid pseudotumor compressing the spinal cord. Computed tomography showed an atlantoaxial rotatory fixation and osteoarthritis of the lateral facets. Resection of the posterior arch of the atlas and a posterior occiput-to-axis arthrodesis were performed with an autologous bone graft. His neurological condition improved, and the retroodontoid pseudotumor disappeared at 3-year follow up. CONCLUSIONS: Frequent rotation of the head by the senile tremor caused friction of the lateral atlantoaxial facet with the development of osteoarthritis. This long-term mechanical stress was thought to cause the soft tissue hypertrophy around the lateral facet. Although spontaneous resolution of the pseudotumor after fixation of the unstable segment has been reported as the treatment of choice, decompression with occipitoaxial fusion was selected in the current case because the patient's neurological deficit was severe and progressive because of a remarkable canal stenosis at level C1/2. PMID- 21318997 TI - An in vitro method to measure permeability of gases through a cuff membrane of tracheal tube in conditions relevant to its clinical uses. AB - The cuff pressure on a tracheal tube while being used in a clinical setting is affected by various physiological conditions. Hence, it is difficult to accurately assess the tracheal tube cuff membrane permeability for gases. We developed an experimental system that enabled accurate assessment of the transition and permeability of gases through a cuff membrane. To simulate nitrous oxide anesthesia, the partial pressure about a cuff membrane was considered separately in oral side, pulmonary side, and intracuff. The cuff pressure of a newly developed tracheal tube with gas barrier materials was assessed, and the permeability through the cuff membrane was evaluated. As a result, the study condition of Experiment II (the cuff was inflated with a gas mixture of 50% nitrous oxide and 50% oxygen) was the most appropriate in which the intracuff was inflated with the same gas mixure because of no concentration gradient between intra- and extra-cuff space. In the schematic diagram of the intracuff pressure changes during anesthesia with nitrous oxide, because of concentration gradient of the gas mixture, gases flow from pulmonary side into the cuff and in the latter phase gases pass through the cuff membrane. Our in vitro experimental system was revealed to be useful in accurately assessing the gas permeability through the cuff membrane of a tracheal tube in conditions relevant to clinical uses. PMID- 21318998 TI - Gastroesophageal reflux disease in hemodialysis patients. AB - BACKGROUND: The association between gastroesophageal reflux disease (GERD) and chronic renal failure (CRF) remains unclear. The aim of the present study is to assess the prevalence of GERD and also attempt to identify possible pathogenic factors in the development of reflux in hemodialysis (HD) patients. PATIENTS AND METHODS: This study consisted of 418 stable CRF patients who underwent HD and did not necessarily undergo gastroendoscopy. Instead of gastroendoscopy, QUEST, a structured questionnaire for the assessment of symptomatic GERD, was used to diagnose GERD. We checked the age, sex, body mass index, etiology of renal disease, QUEST score, medication, alcohol consumption, smoking and laboratory data, and compared GERD group with non-GERD group. RESULTS: In the 418 stable CRF patients who did not undergo gastroendoscopy, the prevalence of GERD was 24.2%. There were no statistically significant differences in age, sex, BMI, alcohol consumption, smoking, etiology of CRF, laboratory data and medication between GERD group and non-GERD group. CONCLUSIONS: Compared to the reported prevalence of GERD in Japan (16.3%), the prevalence of GERD in CRF patients who underwent HD (24.2%), was increased. The risk factor for this increased GERD in CRF patients was not clear in the present study. PMID- 21318999 TI - Curative surgical treatment after preoperative chemotherapy for primarily inoperable locally advanced pancreatic carcinoma: report of a case. AB - Pancreatic cancer is considered resectable only when there are no distant metastases or infiltration of surrounding organs or arteries. We describe a patient with primarily inoperable locally advanced pancreatic adenocarcinoma who underwent curative surgical treatment after preoperative chemotherapy. A 61-year old woman was admitted for further evaluation of a pancreatic head mass discovered fortuitously on a health screening. Examination revealed locally advanced pancreatic cancer with infiltration of the superior mesenteric artery. After a partial response was obtained by chemotherapy with gemcitabine (GEM) and S-1, we performed pancreaticoduodenectomy. Microscopically, the main tumor was replaced with fibrotic tissue, and there were only a few residual adenocarcinoma cells in the pancreatic head. The radicality of the surgery was R0, according to the TNM classification. Our results suggest that neoadjuvant treatment with GEM/S 1 on a sustainable regimen offers the possibility of a multimodal treatment concept for all patients and a higher radical-resection rate in patients with otherwise unresectable pancreatic cancers. PMID- 21319000 TI - A case of acquired aplastic anemia with repeated cerebral infarctions at the beginning of immunosuppressive therapy. AB - Acquired aplastic anemia is a rare hematopoietic stem-cell disorder that results in pancytopenia and hypocellular bone marrow. The pathophysiology is immune mediated in most cases, with activated type 1 cytotoxic T cells implicated. Acquired aplastic anemia can now be cured or ameliorated by stem-cell transplantation or immunosuppressive drug therapy such as antithymocyte globulin or cyclosporine. We present a rare case report of a 68-year old patient with acquired severe aplastic anemia with repeated cerebral infarctions at the beginning of immunosuppressive therapy. He started immunosuppressive drug therapy with antithymocyte globulin and cyclosporine. During follow-up, magnetic resonance imaging revealed high signals at right thalamus and right pons by diffusion-weighted image. He was diagnosed with repeated cerebral infarctions of right thalamus and right pons. We successfully managed cerebral infarctions by frequent transfusions, edaravone administration, keeping the trough of serum cyclosporine (CsA) concentration around lower limit. This is the first report of successful management of acquired aplastic anemia with repeated cerebral infarctions. PMID- 21319001 TI - Effects of low-frequency repetitive transcranial magnetic stimulation in Parkinson's disease. AB - OBJECTIVE: The therapeutic effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) were investigated in Parkinson's disease with cognitive dysfunction known as impaired set switching. METHODS: Six patients with Parkinson's disease exhibiting impaired performances on the Wisconsin card sorting test (WCST) were enrolled. Under electroencephalogram (EEG) monitoring, rTMS was performed using a concave circular coil once a week for three months. A 0.2-Hz rTMS was applied over the frontal region (Fz) at an intensity of 1.2 x the motor threshold of the abductor pollicis brevis (APB) for a total of 100 stimuli per session. The Trail Making Test part B (TMT-B), WCST, Wechsler Adult Intelligence Scale Revised (WAIS-R), Self-rating Depression Scale (SDS), Functional Independence Measure (FIM), and 20 m Walk time were evaluated before and after rTMS. Subjective symptoms and objective findings were also evaluated. RESULTS: Significant improvements in the TMT-B and WCST scores after rTMS were observed for all six patients. In addition, the subjective symptoms and objective findings also improved. The 20 m walk time decreased significantly in all four subjects after rTMS. The SDS scores improved in four of the five subjects, although the differences between the baseline and follow-up scores were not significant. No significant improvements in the WAIS-R, FIM scores were observed. CONCLUSIONS: Low-frequency suprathreshold rTMS applied over bilateral prefrontal areas alleviated impaired set switching in Parkinson's disease. These results suggest that rTMS can affect the functional recovery of the frontostriatal circuit. PMID- 21319002 TI - The efficacy of supraglottic swallow as an indirect swallowing exercise by analysis of hyoid bone movement. AB - Supraglottic swallow (SGS) is one of the swallowing maneuvers used to enhance safe bolus passage into the esophagus and to avoid aspiration into the trachea. We examined the efficacy of SGS as an indirect swallowing exercise by quantifying hyoid bone movements during SGS. Videofluorography was used to analyze SGS in 10 healthy volunteers. SGS increased the hyoid bone posterior and superior excursion, and maintained these displacements longer, suggesting the effectiveness of the SGS as an indirect swallowing exercise. Thus SGS could be used not only as air way protection but also as an indirect swallowing exercise to strengthen the muscles adhering to the hyoid bone, and to expand the range of motion of the hyoid bone. PMID- 21319003 TI - A case of accidental ingestion of a salbutamol sulfate inhalant, Venetlin(r). AB - Pediatricians examine increasing numbers of children with bronchial asthma every year. In Japan, medical institutions can provide standardized therapies according to the Japanese Pediatric Guideline for the Treatment and Management of Asthma 2005. Inhalation therapy is highly beneficial, and a substantial proportion of patients choose to purchase inhalators and practice inhalation therapy at home. Recently, we experienced a case of accidental ingestion of a salbutamol sulfate inhalant by a non-asthmatic child, which reminded us anew of the importance of managing the medicines for asthma. We also recognized the need to educate patients and their families on the knowledge of these medicines. In this report, we analyze the case and discuss measures that pediatricians can implement to avoid accidental inhalant ingestion by children. PMID- 21319004 TI - Gastroesophageal reflux disease in chronic renal failure patients: evaluation by endoscopic examination. AB - BACKGROUND: The association between gastroesophageal reflux disease (GERD) and chronic renal failure (CRF) remains unclear. The aim of the present study is to assess the gastroendoscopic findings and the prevalence of GERD in CRF patients by endoscopic examination. PATIENTS AND METHODS: This study consisted of 156 CRF patients (97 men and 59 women, mean age: 64.2 years) whose creatinine level was more than 2 mg/dl and who underwent endoscopic examination. We checked their renal function, gastrointestinal symptoms and gastroendoscopical findings, and examined the relationship between renal function and gastroendoscopic findings, and the prevalence of GERD. RESULTS: In the gastroendoscopic findings of the 156 CRF patients who underwent endoscopic examination, the prevalence of GERD was 34.0%. Especially, in symptomatic cases, the prevalence of GERD was 44.0%. In hemodialysis patients, the prevalence of GERD was 50.0%. The prevalence of GERD tended to increase as renal function become worse. There were statistically significant differences between the patients on hemodialysis and pre-dialysis in the prevalence of GERD (P < 0.01). The severity of GERD tended to be mild. CONCLUSIONS: Compared to the reported prevalence of GERD in 6010 Japanese adults (16.3%), the prevalence of GERD in CRF patients, especially who underwent hemodialysis (50.0%), was increased. PMID- 21319005 TI - Ultrastructural effects of tamoxifen on uterus in rats. AB - Tamoxifen is a triphenylethylene derivative commonly used in the treatment of breast cancer The Wistar rats (9 weeks old, 180-200 g body weight) used in these trials were divided into two groups of 20 animals each (control and experimental group). Animals of the experimental group were given drinking water containing 200 MUg/kg tamoxifen citrate for a period of 30 day. At the end of exposure, body and uterus weights were measured. There was no statistical difference in the uterus weights between the control and treated groups (p < 0,05). Squamous metaplasia, characterized by the presence of stratified squamous epithelium on the lumenal surface of the uterus and the lining of the luminal surface of uterine glands was seen in some animals that had received tamoxifen. Ultrastructural changes were revealed in the form of vacularization of cell cytoplasm and The cytoplasm contained areas of low electron density. Not only was the cytoplasm full with intense crystalized and degeneration in mitochondria. PMID- 21319006 TI - A case of mushroom shape temporal bone osteoma. AB - A cranial vault Osteoma is relatively common benign tumor. Mushroom shaped skull osteoma is, however, extremely rare. Twenty seven years old female developed slow growing hard mass posterior to the ear. CT scan revealed a mushroom shaped osseous mass approximately 2.5 cm in diameter protruding from the temporal bone at the site of asterion. And the tumor was located over the right sigmoid sinus. The sigmoid sinus engraved approximately 4mm to the tumor and had a branching to one emissaries' vein. Operation was performed under general anesthesia. The tumor was excised first by cutting the base of the tumor, and then residual tumor was grinded using a round head cutting bar. A chisel dissection was not recommended because of underlining sinus. Histological findings were consistent with a benign osteoma. The postoperative course was uneventful. CT examination immediately done after operation revealed no evidence of intracranial hemorrhage, or injury of vessels. Osetoma was excised, and the surface of cranial bone at the operation site was smooth and cosmetically acceptable. At 6-months follow up, patient remains asymptomatic and recurrence free. CT examination with Multi Planer Reconstruction imaging or 3D reconstruction is highly recommended for the operational planning of cranial osteoma. PMID- 21319007 TI - Beneficial aspect of oral estriol as hormone replacement therapy: consideration on bone and lipid metabolism. AB - To improve the quality of life of elderly people in Japanese society where women have the longest life expectancy in the world, osteoporosis, and hyperlipidemia are among the major targets of medical treatment. To differentiate two types of regimens for hormone replacement therapy (HRT), we tried to evaluate the efficacy on lipid and bone metabolism. With informed consent, 34 postmenopausal women of more than 2 years were assigned to receive 1 of 2 types of HRT (the HRT group) for 12 months observation: one with a combination of conjugated equine estrogen (CEE) 0.625 mg/day and medroxyprogesterone acetate (MPA) 2.5 mg/day (the CEE group), and the other with oral estriol (E3) 2 mg/day (the E3 group). Parameters of serum lipid were measured, as well as those of bone metabolism with bone mineral density (BMD) by dual-energy X-ray absorptiometry (DEXA) using QDR-2000. In HRT groups, lipid and bone metabolism were confirmed to be improved. Whereas, an increase of triglycerides (TG) observed in the CEE group was not observed in the E3 group. Thus, in the clinical management of postmenopausal women, oral E3 preparation as an alternative regimen for HRT for CEE might be efficacious. PMID- 21319008 TI - Liposome-encapsulated hemoglobin accelerates gastric wound healing in the rat. AB - BACKGROUND: Liposome-encapsulated hemoglobin, a nanometer-sized artificial O2 carrier with a high O2 affinity (h-LEH), may facilitate O2 delivery to surgical wounds and thereby accelerate healing after gastrointestinal surgery. METHODS: Ten mL/kg of h-LEH (n = 25), empty liposome (n = 21) or homologous washed red blood cells (RBC, n = 22) was intravenously infused prior to the creation of a 10 mm incision and interrupted suture closure of the gastric wall in rats. After two and four days, the stomach was excised and the bursting pressure was determined by gradually inflating the stomach with air. This procedure was followed by histological examinations. RESULTS: The bursting pressure of the surgical wound was significantly higher two days after surgery in the h-LEH-treated rats in comparison to the control rats that received either empty liposome or RBC transfusion (P < 0.05). The three groups displayed similar bursting pressures four days after surgery. Histological examinations revealed less neutrophil infiltration, better granulation, and more macrophage infiltration in the h-LEH treated rats after two days; however, these differences were no longer significant four days after surgery. CONCLUSION: The results suggest that h-LEH, but not a homologous transfusion or empty liposome, may accelerate early wound healing after a gastric incision and anastomosis in a rat model. PMID- 21319009 TI - Combination therapy by trastuzumab with 5'-deoxy-5-fluorouridine and cyclophosphamide in patients with metastatic breast cancer. AB - BACKGROUND: Trastuzumab (Herceptin(r)) was clinically introduced in Japan in 2001 to treat metastatic breast cancer patients who show an over-expression of human epidermal growth factor receptor 2 (HER2). Since that time, this anticancer drug has played an important role in the treatment of cancer. In the present retrospective study, trastuzumab was administered in combination with 5'-deoxy-5 fluorouridine (5'-DFUR) and cyclophosphamide (CPM) as the third- to sixth- line therapy in 25 patients whose HER2-positive metastatic breast cancers did not respond but showed recurrence after treatment with several chemotherapeutic regimens, namely, trastuzumab alone, and trastuzumab combined with taxane or other anticancer drugs. METHODS: Trastuzumab was administered at a dose of 2 mg/kg (at a loading dose of 4 mg/kg) once weekly; 5'-DFUR, at an oral daily dose of 800-1200 mg/body; and CPM, at an oral daily dose of 100 mg/body for 2 weeks followed by one week discontinuation of the drug. RESULTS: The response rate to the combination therapy was 32% (95% confidence interval, 17-52%). Grade 3 adverse effects, according to National Cancer Institute-Clinical Therapeutic Conference version 2.0. (NCI-CTC ver. 2.0), included: neutropenia in 7 patients, anemia in one, and elevation of alkaline phosphatase (ALP) in one. Other adverse events of grade 1 or 2 in accordance with NCI-CTC included general fatigue, nausea, vomiting, thrombocytopenia, increased transaminase, and decreased serum albumin. All adverse events were easily controllable and reversible after discontinuation of the drug. CONCLUSIONS: Combination therapy with trastuzumab, 5'-DFUR and CPM is effective and well tolerated as the third- to six line treatment option for patients with HER2-overexpressing metastatic breast cancer. MINI-ABSTRACT: Combination therapy by trastuzumab with 5'-DFUR and cyclophosphamide can be safely administered on an outpatient basis and is useful to treat patients with HER2-overexpressing metastatic breast cancer. PMID- 21319010 TI - Persistent ectopic pregnancy after laparoscopic salpingotomy: a manageable complication to preserve reproductive tubal function. AB - OBJECTIVE: We evaluated whether or not persistent ectopic pregnancy (PEP) is a preventable complication after conservative laparoscopic surgery (salpingotomy) for tubal pregnancy. METHODS: We reviewed the medical records of 139 patients who underwent salpingotomy between December 1992 and December 2008. RESULTS: Out of 139 patients, 23 (16.5%) were diagnosed with a PEP after salpingotomy. When compared with 114 (82.5%) successfully treated patients, there were no differences in preoperative features (gestational age, serum human chorionic gonadotropin [hCG] levels, and ultrasonography findings ) and postoperative reproductive potentials (ipsilateral tubal patency and pregnancy outcomes). CONCLUSIONS: PEP, when appropriately treated, does not adversely affect tubal functions and postoperative fertility. We should uniformly perform an exact surgery paying careful attention to preserving the tubal function regardless of preoperative features. PMID- 21319011 TI - Reconstruction of wide cleft lip scar by Abbe flap and advancement flap from lateral upper lip. AB - Primary surgery of cleft lip and palate has dramatically improved with technical and material advances. Some adults who previously underwent surgery still have upper lip deformities or extensive scar, and they are occasionally seen for secondary treatment. We reported a case of unilateral cleft lip patient who had extensive scar involving the central 1/4 of the upper lip, with gross lip and nasal deformity. In this patient, we reconstructed the entire affected upper lip using an Abbe flap and an advancement flap from the lateral lip. This not only improved the upper lip contracture, but also moved the scar to the margin of the aesthetic unit. This removal of the visible scar from central portion of the lip provided a satisfactory aesthetic result. A large V-Y advancement flap from lateral upper lip has several advantages. These are sufficient soft tissue volume, inconspicuous scar in accordance with margin of aesthetic unit, and texture and color match. There is no previous report describes the application of V-Y advancement flap for secondary lip reconstruction of unilateral cleft lip deformity in the literature. PMID- 21319012 TI - Changes in sensory functions after low-frequency repetitive transcranial magnetic stimulation over the motor cortex. AB - OBJECTIVE: To investigate changes in various sensory functions after low frequency repetitive transcranial magnetic stimulation (rTMS) in healthy subjects. METHODS: A Neurometer(r) CPT/C was used to measure current perception threshold (CPT) values at frequencies of 2000, 250, and 5 Hz in the left index finger to assess the tactile sense, fast pain, and slow pain, respectively. Somatosensory evoked potentials (SEPs) elicited by left median nerve stimulation at the wrist were used to assess excitability in the primary sensory cortex (S1). These were investigated before and after rTMS (0.9 Hz, 0.9 AEresting motor threshold, 500 pulses) or sham rTMS over the right primary motor cortex (M1). RESULTS: All CPT values increased significantly and the P25-N33 of SEP amplitude decreased significantly after real rTMS, but not after sham rTMS; however, no correlations between the changes were observed. CONCLUSIONS: Low-frequency rTMS over the M1 provides global anesthetic effects and inhibits excitability in S1. The lack of correlation between these changes suggests that the anesthetic effects may not always relate to the excitability of S1; thus, the mechanisms responsible for the changes remain unclear. Nevertheless, these findings suggest that rTMS may be a useful strategy for treating intractable pain in rehabilitation medicine. PMID- 21319013 TI - A case of neonatal mature teratoma transformed to malignancy in the neck extending to the mouth floor. AB - A case with neonatal teratoma originating from the cervicofacial region which transformed to be malignant during treatment is reported. The case is a full-term baby girl with swallowing difficulty and has a mass at the floor of her mouth with the right neck swelling. The mass was revealed to be multi-cystic and extending deep into the sublingual space and protruding outside. Puncture and marsupialisation of the cyst could not relieve her symptom and the tumor was resected in three occasions and was diagnosed as mature teratoma without malignant component. However, three months after the last resection, the solid right neck mass enlarged rapidly and the serum alpha-fetoprotein level was elevated. Biopsied specimen demonstrated the mass to be germ cell tumor with embryonal carcinoma and yolk sac tumor component. Eight courses of JEB regimen with recurrent mass resection successfully lead to complete regression without compromising patient growth as well as cosmetics. Head and neck teratomas in children are mostly benign amenable to curative excision but its rarity and site and size of the tumor make its treatment challenging. It is important to have multi-disciplinary management for the disease from neonatal period until growth has finished. There exists a relationship between the age at diagnosis and outcome of a patient with teratoma and head and neck teratomas in neonate are mostly benign but should be removed completely as soon as the patient condition is stabilized to reduce the risk of malignant change. PMID- 21319014 TI - Analysis of posture and eye movement responses to Coriolis stimulation under 1 G and microgravity conditions. AB - To detect the effect of microgravity on vestibular responses, we conducted Coriolis stimulation experiments at 1 G and MU G. Five men with vision occluded were asked to tilt their head forward while rotating at 100 degrees/sec. Postural changes were recorded by a 3D linear accelerometer, and the distance of upper body movement was derived from recordings of linear acceleration. Eye movements were recorded by a CCD camera. For a second period after commencing head tilt, the upper body moved 10 cm in the direction of inertia input at 1 G, but it moved to the opposite direction at MU G, i.e., 4 cm in the direction of inertia force. Nystagmus peak slow-phase velocity immediately after head tilt and its attenuation process did not differ between 1 G and MU G. The strength of movement sensation and the severity of motion sickness were far weaker at MU G than at 1 G. It was concluded that inertia input is valid to induce postural and sensation responses only when the external reference is given Z axis by gravity. Vestibular ocular response may be maintained at MU G because the head reference is valid even after the external reference becomes arbitrary. PMID- 21319015 TI - Beneficial effects of medical advice provided to elderly persons under the anti aging health check-up system at Tokai University Tokyo Hospital. AB - OBJECTIVE: Tokai University Tokyo Hospital implemented its holistic anti-aging health check-up system in June 2006. This system is characterized by more than 70 check items and the provision of individual post-diagnostic advice of far greater detail than an ordinary health check-up. We analyzed aging-related changes in subjects who had completed their second check-up in order to determine the difference before and after coaching type of medical advice. SUBJECTS AND METHODS: Twenty-five recipients of the anti-aging health check-up at Tokai University Tokyo Hospital between June 2006 and April 2008 were included (15 males 10 females, mean age 65.1 +/- 9.6 years, average check-up interval 12.5 +/- 1.6 months). Based on the results of the first check-up, written advice on issues including diet, exercise, rest (sleep), smoking, alcohol intake, and supplements was provided by nutritionists, supplement advisers, and trainers specializing in Sports Medical Science in Tokai University. Besides this, doctors specializing in anti-aging medicine provided comprehensive coaching. Changes in BMI, abdominal girth at navel level, pressure wave velocity (PWV) and serum levels of total cholesterol (TC), HDL cholesterol (HDL-C), adiponectin (Adi) and free testosterone (in males) were expressed as % basal change and compared in the first and second check-ups. RESULTS: A year after the coaching, Adi and HDL-C both increased significantly while PWV tended to decrease. However, BMI and abdominal girth were unchanged. DHEA-S showed a rising trend while free testosterone also increased significantly. CONCLUSIONS: These results indicate that the coaching type of medical advice provided in the anti-aging health check up potentially mitigates aging-related detrimental changes, bringing some benefits to elderly persons. PMID- 21319016 TI - One case of Candidemia developed after surgery for tongue cancer in a young adult. AB - Candidemia is an opportunistic infection caused primarily by Candida albicans. We experienced a case of severe Candidemia that developed after surgical treatment for tongue cancer and required considerable labor to diagnose and to treat, though no particular immunodeficiency was seen before. The case was resistant to an antifungal agent, fluconazole, but was successfully treated with amphotericin B. Positive blood cultures, local wound culture, and increased beta;-D-glucan were useful to diagnose the infection. In particular, gallium-67 scintigraphy was remarkably useful for the diagnosis and the evaluation of therapeutic effects in this case. Development of Candidemia following an oral and maxillofacial surgery is extremely rare among young adults, thus this case report serves to draw attention to the risk in oral and maxillofacial surgery. PMID- 21319017 TI - Endoscopic examination for duodenal ulcer bleeding during transcatheter arterial embolization: analysis of two cases. AB - Endoscopy is usually effective in treating duodenal ulcer bleeding, but depending on the lesion site and overall patient condition, hemostasis may be difficult to achieve with endoscopy alone. We described two patients with duodenal ulcer bleeding in whom endoscopic hemostasis was difficult. Immediately after transcatheter arterial embolization, endoscopic examination was used to confirm hemostasis and completing of the angiographic procedures. PMID- 21319018 TI - Atrial fibrillation induced by applying acetylcholine to subadventitial layer of pulmonary vein in normal canine heart. AB - OBJECTIVES: We determined whether acetylcholine (Ach) application to the pulmonary vein (PV) wall could induce AF and clarified its mechanisms, and determined whether circumferential PV radiofrequency ablation (CPVA) could prevent Ach-induced AF in canine hearts. METHODS: Thirty seven beagle dogs were used for the study. Ach was injected into the subadventitial layer of the left superior PV (LSPV), at different distance from the LSPV-left atrium junction (LSPV-LA-J) to locate AF initiation. When AF was not induced by Ach alone, programmed electrical stimulation (S1-S2 method) was added to elicit AF. Atropine was injected at the same site of Ach injection to determine whether muscarine receptor blockade suppressed AF, and CPVA at the LSPV-LA-J was performed using a newly devised basket electrode-catheter. RESULTS: AF was reproducibly induced by Ach injection in 19 of the 26 dogs (73%). S1-S2 method after Ach initiated AF in 5 of the remaining 7 dogs. Ach into the subadventitial layer of the LSPV, especially the distal portion, could elicit AF, which was preceded by pause (sinus arrest) >= 2.0 sec (37%) (pause-AF group), sinus bradycardia (32%) (brady AF group) and sinus tachycardia (32%) (tachy-AF group). The time from Ach injection to AF initiation and AF duration were not significantly different between pause-AF, brady-AF and tachy-AF groups. AF was not initiated by injecting Ach after atropine pretreatment. To eliminate AF, 1-6 (average 4.1 ?? 1.2) CPVAs at the LSPV-LA-J were required. CONCLUSIONS: Our observations suggest that local Ach application can initiate AF in PVs, preceded by a variety of modes such as pause, bradycardia or tachycardia, and an increase in vagal tone at the LSPV plays a critical role in eliciting AF in structurally normal heart. PMID- 21319019 TI - Breast conserving surgery for male noninvasive intracystic papillary carcinoma: a case report. AB - We report an exceedingly rare case of male breast cancer on two brothers. The patient has family history that his younger brother had breast cancer 5 years ago. The patient was 70-years old man who presented with chief complaint of an indolent tumor mass of the left breast. Mammography demonstrated a well defined mass with microcalcifications. Noninvasive intracystic papillary carcinoma was diagnosed by excisional biopsy. We performed breast conserving surgery (BCS) with sentinel lymph node biopsy for this patient. The histological diagnosis was same as above, with no metastasis of sentinel lymph node. Immunohistochemical study showed estrogen receptor (ER) and progesterone receptor (PgR) were positive respectively, and human epidermal growth factor receptor type 2 (HER2/c-erbB-2) was negative. After surgery, he underwent radiation therapy of 60 Gy for left chest wall include nipple and areolar area. We report the case of BCS for male breast cancer. The preservation of the nipple areolar complex in male patients may also have a positive psychological impact as is the case in women treated for breast cancer. Our patients report an outstanding cosmetic result. As for the man, breast conserving therapy should be enforced without overt nipple and areolar involvement like a woman. PMID- 21319020 TI - Three cases of bortezomib-resistant multiple myeloma with extramedullary masses. AB - In some patients with multiple myeloma, extramedullary masses may be present at diagnosis or may develop during treatment. Recently, multiple myeloma has been treated using newer therapeutic regimens based on thalidomide and bortezomib. Using these drugs, positive responses to treatment, not found with conventional antineoplastic agents, have been reported along with an improvement in patient outcome. In the present study, we report on three patients with extramedullary masses associated with multiple myeloma. Although all three patients were treated with bortezomib, it was ineffective against the extramedullary masses and the clinical course of the disease differed between the three patients. We propose that the effects of bortezomib on extramedullary masses may differ from case to case and may not be evident in cases of severe disease. Also, the effects of bortezomib may not be evident in the case of myeloma cells that have left the bone marrow microenvironment, similar to thalidomide. In addition, resistance to bortezomib may manifest as extramedullary masses. (160 words in the body of abstract). PMID- 21319021 TI - Syndrome of inappropriate antidiuretic hormone secretion in patients with adult Still's disease. AB - Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a rare complication of adult Still's disease (ASD). We experienced a male ASD patient who complained of arthralgia and intermittent fever. Chest radiograph and pleural fluid analysis revealed pleurisy with effusion. We diagnosed this patient with SIADH and confirmed the disappearance of hyponatremia and pleurisy after starting treatment with nonsteroidal anti-inflammatory drugs. In this study, we reviewed previous literature and the case of our ASD patient with hyponatremia. This reported case is the fourth case of SIADH in an ASD patient. Further, we found that hyponatremia is a relatively common complication of ASD, and pleurisy has a possibility to develop SIADH in patients with ASD. PMID- 21319022 TI - A prognostic value of neuron-specific enolase in cerebrospinal fluid of acute cerebellar ataxia. AB - We examined 16 patients with acute cerebellar ataxia (ACA) to determine whether clinical manifestations or laboratory findings could predict the prognosis of ACA. We divided the patients into two groups: a benign group of patients whose cerebellar symptoms completely disappeared within 21 days (9 patients), and a prolonged group of patients whose cerebellar symptoms persisted for more than 22 days (7 patients). The two groups were compared on the basis of demographic and clinical characteristics, and laboratory variables. The cerebellar symptoms did not differ significantly between the two groups, except in duration. The level of neuron-specific enolase (NSE) in the cerebrospinal fluid (CSF) of the prolonged group was significantly higher than that of the benign group (p < 0.01); other parameters, including protein and cell count in the CSF, were not significantly different. The results suggest that the NSE level in CSF is of prognostic value in ACA. PMID- 21319023 TI - Suprathreshold 0.2 Hz repetitive transcranial magnetic stimulation (rTMS) over the prefrontal area. AB - OBJECTIVE: This study was designed to evaluate the effects of suprathreshold 0.2 Hz repetitive transcranial magnetic stimulation (rTMS) to the prefrontal area and motor cortex on the cerebral cortex excitability. METHODS: The study involved 15 healthy volunteers. With a concave circular coil, rTMS to Fz (bilateral dorsolateral prefrontal areas) was carried out for 100 sessions at a frequency of 0.2 Hz and an intensity 1.2 times the resting motor threshold. In addition, rTMS to M1 (primary motor cortex) (Lt motor hand area) was performed in a similar manner. Before and after rTMS, resting motor threshold, motor evoked potential, cortical silent period (CSP) and F wave were recorded, and their changes after rTMS as compared to the pre-rTMS were analyzed. RESULTS: Neither Fz stimulation nor M1 stimulation caused any significant change in the resting motor threshold, motor evoked potential latency, amplitude or area as compared to the values measured before rTMS. No significant changes were seen in the amplitude and persistence of the F wave. However, while Fz stimulation produced significant prolongation of the CSP duration (p < 0.01), M1 stimulation produced no such prolongation. The sham stimulation (control) showed no significant prolongation of the CSP duration following either M1 or Fz stimulation. CONCLUSION: These results suggest that suprathreshold 0.2 Hz rTMS of Fz induces a significant suppression of excitability in the primary motor cortex. PMID- 21319024 TI - Protective effect of Brewer's yeast on methimazole-induced-adrenal atrophy (a stereological study). AB - Induction of hypothyroidism by thioamide drugs will cause adrenal gland atrophy and decrease in its hormones. To prevent side effect on the adrenal gland, brewer's yeast, a natural product rich in vitamins and minerals was used. Serological techniques were applied to measure the volume of adrenal gland. For this purpose, 48 Sprague-Dawley rats were randomly divided into one control and three experimental groups. In group 1, methimazole was administered at the dose of 30 mg/kg/day days, in group 2, 120 mg/kg/day of, brewer's yeast, in group 3, 30 mg/kg/day of methimazole plus 120 mg/kg/day of brewer yeast, and for the control group, an equal volume of saline (0.5 ml/rat/day) was orally given. After 30 days, all the animals were anesthetized and their adrenal glands were removed, fixed, embedded and stained. The volume of different zones of the adrenal glands was estimated by Cavalieri principle and point counting methods. statistical analysis was performed using Mann-Withney test and p < 0.05 was considered as statistically significant. The results indicated that methimazole decreased the volume of fasciculata zone in the cortex of the adrenal gland and also decreased the blood cortisol level. Brewer's yeast reduced the methimazole side effects on this zone. In conclusion, it seems that the use of brewer's yeast could prevent methimazole-induced atrophy of the adrenal gland. PMID- 21319025 TI - Vanadium supplementation effect on vanadium metabolism during hypokinesia in rats. AB - OBJECTIVES: Microelement supplementation during Hypokinesia (HK; diminished movement) affects differently microelement metabolism from that of normal muscular activity. In view of the effect of trace element supplementation and HK upon microelement metabolism we investigated the effect of vanadium (V) supplements on tissue V content and V loss during HK. METHODS: Studies were performed on 240 male Wistar rats during a pre-experimental period of 9 days and an experimental period of 98 days. Rats were equally divided into four groups: unsupplemented control rats (UCR), unsupplemented experimental rats (UER), supplemented control rats (SCR) and supplemented experimental rats (SER). A daily supplementation of 0.8 MUmol vanadium sulfate was given to the rats in the SCR and SER groups. Muscle V content, plasma V level and V loss was measured in the experimental and control groups of rats. RESULTS: The gastrocnemius muscle and right femur bone V content decreased (p < 0.05), and plasma V level and urinary and fecal V loss increased (p < 0.05) in the SER and UER groups compared to their pre-experimental values and their respective control groups (SCR) and UCR). However, the tissue V content decreased more (p < 0.05) and plasma V level and V loss increased more (p < 0.05) in the SER group than in the UER group. The tissue V content and plasma V level and V loss did not change in the control groups of rats compared to the pre-experimental values. CONCLUSIONS: It is concluded that during HK V supplementation decreases more tissue V content and increases more V loss and plasma V level in V deficient tissue indicating lower V utilization. PMID- 21319026 TI - A case of submucosal hematoma of the esophagus and stomach, possibly caused by fish bone ingestion. AB - Submucosal hematoma of the esophagus is a rare disorder. We encountered a 70-year old woman with an extremely large submucosal hematoma of the esophagus that extended from the cervical esophagus to the gastric angle. It was likely that her hematoma was caused by accidental ingestion of a fish bone, and her condition improved with conservative treatment alone. In this article, we summarize the reported cases of submucosal hematoma of the esophagus in Japan, and discuss the case with a review of the literature. PMID- 21319027 TI - Black adrenal adenoma causing preclinical Cushing's syndrome. AB - Functioning black adrenal adenoma (BAA) rarely causes preclinical Cushing's syndrome (CS). In the present case, a 46-year-old Japanese Peruvian woman presented with left flank pain and hypertension. Abdominal computed tomography showed that she had a 15-mm in diameter, round, left adrenal adenoma. She had no physical features of CS, such as moon face, buffalo hump, truncal obesity, or purple striae. Endocrinological examination showed that the plasma adrenocorticotropic hormone (ACTH) level was below the detectable level, despite a serum cortisol level within the normal range. A normal cortisol circadian rhythm was not present. Dexamethasone (1 mg and 8 mg) suppression testing did not decrease serum cortisol levels to the reference levels. These findings were compatible with preclinical CS. The left adrenal adenoma was laparoscopically removed. Examination of the surgical specimen revealed unilateral double adrenal adenomas of the left adrenal gland, one of which was a BAA. The BAA measured 20 * 11 * 10 mm. Microscopically, the BAA showed proliferation of compact cells containing numerous brown-pigmented granules. There were also foci of myelolipomatous degenerative changes in the tumor. The compact cell zones remained in the adrenal cortex adjacent to the BAA showed atrophic change. These findings indicated that BAA appeared to have caused preclinical CS in this patient. PMID- 21319028 TI - Gene expression of lymphocyte prolactin receptor was suppressed in lactating mothers. AB - Prolactin (PRL) receptor (PRL-R) was proven to be ubiquitously expressed by cells in the immune system, while the physiological role of PRL was established in milk production in mammary glands. We analyzed the mRNA content of PRL-R in human lymphocytes in normo- and hyperprolactinemic conditions to document the presence of functioning PRL-R of human lymphocytes. Blood samples were obtained prior to treatment, and with written informed consent, from outpatients with ovarian dysfunction and hyperprolactinemia (n = 8; 19 ~ 41 y/o), from breast-feeding mothers after normal delivery (n = 12; 27 ~ 36 y/o), and from healthy volunteers: men (n = 9; 33 ~ 40 y/o) and women (n = 9; 26 ~ 36 y/o). Subsequently, total RNA was prepared from the lymphocytes separated. The quantity of PRL-R mRNA was examined by reverse transcription and polymerase chain reaction and normalized with a simultaneously measured amount of b actin. The resultant mRNA level of PRL R was analyzed for its correlation with serum concentration of PRL measured by immunoassay. PRL-R mRNA levels of lymphocytes were significantly suppressed in lactating mothers, while there was a statistically significant negative correlation between PRL-R mRNA and serum PRL levels. However, there was no significant difference of PRL-R mRNA in the pathological condition of outpatients with ovarian dysfunction and/or hyperprolactinemia. While a few investigators reported the extra-mammary regulation on PRL-R by PRL, our data suggest that the PRL-R levels of circulating lymphocytes could be down-regulated by the elevated serum levels of PRL and that pituitary PRL may participate in regulating the expression of PRL-R genes on cells of the human immune system, especially in physiological circumstances such as in the postpartum period. PMID- 21319029 TI - A case of fat injection for treating subcutaneous atrophy caused by local administration of corticosteroid. AB - A 42 year old female received intramuscular injection of 40 mg triamcinolone acetonide on the right upper arm for the treatment of pollen allergy at another clinic. Subcutaneous atrophy appeared at the injection site a few days after. Since there were no signs of improvement, the patient visited our clinic for further examination. The subcutaneous atrophy after local injection of corticosteroids is generally considered to be reversible and it improves within about 1 year after the injection. After one year since local injection, subcutaneous atrophy did not improve and we performed fat injection using autologous fat. As a treatment, we thought that the fat injection method is a superior method since it is less invasive from a cosmetic standpoint. PMID- 21319030 TI - Suprahyoid muscles motor evoked potentials in response to transcranial magnetic stimulation. AB - OBJECTIVE: The objective of this study was to reveal whether corticobulbar projection to the suprahyoid muscles (SHM) is contralateral or bilateral. METHODS: Thirty-nine healthy subjects between 27 and 77 years of age participated. All subjects underwent transcranial magnetic stimulation (TMS) in both cerebral hemispheres using surface EMG recording in bilateral SHM. One subject underwent TMS in cerebral hemisphere at the same time using needle and surface EMG recording in the contralateral and ipsilateral SHM. Eight subjects underwent TMS in both cerebral hemispheres using surface EMG recording in bilateral SHM, within 6 months of the first day. RESULTS: We obtained larger response in contralateral SHM than in ipsilateral SHM in the surface EMG recording. However, in the needle EMG recording, only contralateral SHM responses were evoked. TMS of either hemisphere evoked contralateral SHM motor-evoked potentials (MEPs) in all subjects [SHM latency: (left) 8.5 +/- 0.9 ms, (right) 8.6 +/- 1.1 ms]. There was no significant difference in latency between the first and second tests. In a case of right medullary infarction with left cortical stimulation, MEPs of right SMH were absent. CONCLUSION: Corticobulbar projections to the SHM appear to be dominated by contralateral projections in healthy adults. PMID- 21319031 TI - Atypical thymic carcinoid associated with Cushing's syndrome. AB - A 56-year-old Japanese woman with adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS) was admitted to hospital, where she was diagnosed as having a mediastinal tumor with ectopic ACTH production. The tumor and associated lymph node metastases were resected endoscopically, and the pathological diagnosis was atypical thymic carcinoid. Radiation therapy and administration of metyrapone, an inhibitor of 11b-hydroxylase to decrease the cortisol level, were attempted, but the levels of ACTH and cortisol were unresponsive. Bilateral adrenalectomy and hydrocortisone replacement were performed to ameliorate the patient's hypercortisolism. She subsequently developed multiple vertebral metastases, but was unwilling to undergo chemotherapy. Her condition deteriorated progressively, and she died of heart and respiratory failure 3 years and 6 months after the first admission. Immunostaining for ACTH, chromogranin A, synaptophysin, and neuron-specific enolase was positive in the carcinoid cells. Since somatostatin (SS) and SS analogues inhibit the growth of carcinoid via the SS receptor (SSTR) 2, we evaluated the expression of SSTR2 in the carcinoid cells using reverse transcription-polymerase chain reaction, and this confirmed the expression of SSTR2 in the carcinoid cells. Our experience of this patient with CS due to an ectopic ACTH-producing atypical thymic carcinoid suggests that SS analogues may be useful for treatment of carcinoid showing expression of SSTR2. PMID- 21319032 TI - Organized chronic subdural haematoma with a thick calcified inner membrane successfully treated by surgery: a case report. AB - The optimal surgical procedure for patients with calcified and organized chronic subdural haematoma (CSDH), or "armoured brain", has not been established because it is difficult to obtain good re-expansion of the brain after surgery. We present herein the case of a 32-year-old woman with huge calcified CSDH manifesting as refractory headache, periods of unconsciousness, and unsteady gait who obtained favourable results after craniotomy. Thinning of the thick calcified inner membrane using high-speed air drilling was performed after removal of the organized CSDH. The patient obtained good re-expansion after surgery. This observation illustrates that it is possible to perform such a surgery even on a huge calcified CSDH. PMID- 21319033 TI - A case of pure agraphia due to left thalamic hemorrhage. AB - Pure agraphia is an isolated writing disturbance without intellectual impairment, aphasia, alexia, or apraxia. The authors report a case of pure agraphia following left thalamic hemorrhage. The patient showed impairment in the writing of both kanji and kana. The most frequent error in the writing of kanji was substitution (46%) followed by no reaction (23%) and partial omission or addition of characters (21%). The copying of kanji by hand was normal. Even when the patient was unable to write a kanji character, he understood the meaning and correctly recited the other readings. He complained that he could not recall the graphic image of the kanji. When we cued the patient by writing a part of a kanji he initially failed to recall, he correctly completed the character. The kanji and kana he was unable to write were inconsistent over time: in some cases he was unable to write words he had successfully written a week before, and vice versa. These findings suggested that the patient's pure agraphia resulted from combined impairments in recalling and selecting letters. While the thalamic lesion might have influenced the manifestation of pure agraphia, the dysfunction seemed to originate from the secondary negative effect of the lesion on the function of the left cerebral cortex. PMID- 21319034 TI - A questionnaire survey on operability of syringe pumps for prefilled syringes. AB - Some types of syringe pumps currently available for use of prefilled syringes (PFS) require setting for syringe size which varies from manufacturer to manufacturer. We conducted a questionnaire survey for 10 nurses at the emergency critical care center of this hospital on the operating procedures of two different types of syringe pump (i.e., from turning on the power to PFS setting, PFS mounting, flow rate setting, and start of drug infusion), in terms of (1) manipulation time, (2) accuracy of task performance, and (3) operability. The syringe pumps used were: type A, TE-331S0N (Terumo Corporation), and type B, CSP 100S (Daiken Medical Co., Ltd.). The PFS product used was Inovan Injection 0.3% Syringe (dopamine hydrochloride injection; Kyowa Hakko Kirin Co., Ltd.). Type A required no mode setting for exclusive use of PFS, while mode setting for exclusive use of PFS is mandatory for type B. The task process from turning on the power to drug infusion start comprised 5 and 13 steps for type A and B, respectively. Manipulation time was significantly shorter with type A, compared to type B. As for accuracy of task performance, 90% of nurses performed manipulations accurately with type A; whereas with type B, 90% of nurses were close to failing or actually failed to follow the procedures appropriately, and only 10% followed accurately. Thus, type A proved superior in 4 of the 5 points of issue except "easy to set flow rate". In conclusion, the results indicate the importance of standardizing the syringe size and other specifications through the cooperation of pharmaceutical companies and medical device manufacturers to cope with the future spread of PFS. PMID- 21319035 TI - Ten cases of palliation of cancer pain with morphine. AB - OBJECTIVE: With the discovery of novel opioids in recent years, it has become feasible to alleviate various forms of cancer pain. If the characteristics of individual opioids are exploited depending on pain-related factors in cancer patients may yield satisfactory pain relief with a low incidence of adverse reactions. METHODS: This study involved 10 patients (5 male and 5 female) with cancerous abdominal pain, for whom the original opioid regimen was switched to morphine alone or continued in combination with morphine. The primary disease was gastric cancer in 5 patients, and uterine cervix, ovary cancer, leukemia, malignant pleuroperitoneal mesothelioma, and colon cancer in 1 patient each. Pain assessment was carried out using the Numerical Rating Scale. RESULTS: In all the 10 cases, the opioid administered first was fentanyl; the pain relief was inadequate. Satisfactory pain relief was achieved in all patients by switchover to morphine alone or by concomitant administration of morphine with fentanyl. CONCLUSION: Enhanced gastrointestinal motility accounts, at least in part, for cancerous abdominal pain. Further, this kind of pain can be relieved by suppression of gastrointestinal motility with morphine. PMID- 21319036 TI - Non-response to previous interferon therapy and cirrhosis are risk factors for predicting breakthrough during lamivudine therapy in patients with chronic hepatitis B. AB - AIMS: Lamivudine is a potent oral anti-viral medicine for the treatment of hepatitis B virus (HBV) infection. However, one of the major problems is the breakthrough (BT) followed by flare-up of hepatitis. We examined the influences of clinical background, progression of liver fibrosis, presence or absence of HBeAg and previous interferon (IFN) therapy on the occurrence of breakthrough. SUBJECTS AND METHODS: This study comprised 51 patients with HBV related chronic hepatitis (CH) or cirrhosis (LC) who were treated with lamivudine for the mean period of 33.8 +/- 13.1 months (range 3-63 months). Thirty-six patients were CH, 25 were HBeAg- positive, and 25 had a previous history of IFN therapy. Patients were divided into two groups according to the occurrence of BT, either BT(+) or BT(-). Age, gender, alanine aminotransferase (ALT) and HBV titer before treatment, normalization of ALT (<= 40 IU/L) and flare-up of hepatitis (ALT > 80 IU/L) rates, degree of hepatic fibrosis (CH/LC), presence or absence of HBeAg (HBeAg(+)/(-), and previous IFN therapy (IFN(+)/(-) were analyzed using Cox's proportional hazards analysis. RESULTS: Twenty-five patients showed BT. Background data were not different between the patients with and without BT. Flare-up of hepatitis occurred more frequently in BT. Rates of BT were markedly higher in LC (P = 0.025) and IFN(+) (P = 0.036), but HBeAg was not associated with BT. In multivariate analysis, progression of liver fibrosis (P = 0.006) and previous IFN therapy were independent risk factors for BT (P = 0.023). CONCLUSIONS: BT significantly occurred in patients with LC and the history of previous IFN therapy. Multivariate analysis showed that progression of hepatic fibrosis and previous interferon therapy are independent risk factors for BT. PMID- 21319037 TI - A patient with obstructive jaundice due to bleeding in the common bile duct after ultrasound-guided liver biopsy. AB - A-63-year-old man was referred to our hospital for interferon therapy to treat chronic hepatitis C. The patient complained of right upper abdominal pain 1 hour after the ultrasound-guided liver biopsy. Bleeding in the gallbladder and the common bile duct were found on emergency CT. Obstructive jaundice due to the common bile duct hematoma was diagnosed, and endoscopic retrograde cholangiopancreatography(ERCP) was performed, and a filling defect thought to be a hematoma was seen in the bile duct on cholangiography. The hematoma in the bile duct was extracted after endoscopic sphincteroyomy. PMID- 21319038 TI - Multiple giant cell tumors in maxilla and skull complicating Paget's disease of bone. AB - Paget's disease of bone (PDB) is a very rare disease in the Asian countries including Japan, although as a bone metabolism disease it is relatively common in Europeans and Americans. An infrequent complication of PDB is the giant cell tumor (GCT). We encountered a case of GCT in the maxilla complicating PDB in a 57 year-old Japanese woman. She developed her first GCT in the right occipital bone 14 years ago, which was resected. At the same time, she was given a diagnosis of polyostotic PDB. Four years ago, she developed two GCTs in the parietal bone, which were resected. Recently, she was found to have a GCT in the maxilla and maxillotomy was performed. The sporadic form of GCT associated with PDB almost always arises in pagetic bone. The clinicopathologic features of this rare lesion are described and correlated with a review of the literature. PMID- 21319039 TI - Long-distance relay transportation of a patient with twin-twin transfusion syndrome requiring early delivery by Doctor-Helicopters. AB - In Japan, there has recently been a severe shortage of physicians in regional core hospitals, limiting the acceptance of emergency patients. Searching for available medical institutions over an extended area beyond the regular regional medical area should increase the possibility of finding medical institutions capable of accepting patients. Physician staffed helicopter ambulance system, so called the Doctor-Helicopter service is highly effective in saving patients life, since emergency doctors start to treat patients at the scene. It may be also useful to transport the critically ill patients for a long distance. A 29 year old female diagnosed twin fetus with twin-twin transfusion syndrome needs urgent delivery at about 29 weeks of gestation. The patients had to be transported to the perinatal care center which is 160 km from the hospital to where the patient was admitted because of a lack of NICU. During transportation, the maternal vital signs were stable without cervical dilatation. After arrived at the perinatal center, the patient underwent Caesarian section. Both babies had respiratory distress syndrome and admitted to NICU. With increasing cases in which medical institutions cannot accept peripartum emergency patients, it needs to search for medical institutions over an extended area and transport patients by Doctor Helicopter. PMID- 21319040 TI - A case of recurrence of congenital ocular toxoplasmosis with frosted branch angiitis (ocular toxoplasmosis with frosted branch angiitis). AB - PURPOSE: To describe a case of recurrence of congenital ocular toxoplasmosis with frosted branch angiitis. CASE REPORT: A 24-year-old woman presented with hyperemia in her right eye. Medical history included epilepsy at age 14 and mild mental retardation. Iridocyclitis and vitreous opacity were observed in the right eye, and furthermore widespread retinal vessel sheathing due to frosted branch angiitis was seen. Acyclovir was initiated for acute retinal necrosis with frosted branch angiitis. One week later, serologic tests showed elevated toxoplasma antibody level and toxoplasma antibody IgG level, and a white retinal exudative lesion with unclear margins was noted. Therefore, acetylspiramycin and prednisolone were initiated for a recurrence of congenital ocular toxoplasmosis. After treatment, inflammation subsided, the exudative lesion shrank, and the frosted branch angiitis improved. CONCLUSION: We encountered a case of ocular toxoplasmosis due to recurrence of congenital toxoplasmosis with frosted branch angiitis. The clinical symptoms of ocular toxoplasmosis can be varied and the diagnosis should be kept in mind. PMID- 21319041 TI - Vertebral osteomyelitis associated with Granulicatella adiacens. AB - Granulicatella adiacens is a nutritionally variant streptococci. Only 3 cases of vertebral osteomyelitis due to these microorganisms have been reported. We experienced a 73-year-old male who consulted us due to fever and back pain of about 1-month duration. On examination, a presystolic murmur was heard in the apical region. Echocardiography showed prolapse of the mitral valve, but no vegetation was observed. MRI revealed osteomyelitis of lumbar vertebrae. As G. adiacens was detected in blood culture, it was determined as the cause of vertebral osteomyelitis, and combination antibiotics therapy was started. The condition improved, the patient underwent valvoplasty, and no trace of infective endocarditis was noted in the resected valve. All the previous cases had infection caused by G. adiacens and complicated with infective endocarditis. This is the first case without infective endocarditis. Vertebral osteomyelitis due to NVS is very rare. Since nutritionally variant streptococci do not grow in common culture media, and since the sensitivity of isolation by standard conventional biochemical methods is low, the condition may be misdiagnosed as blood-culture negative vertebral osteomyelitis. Therefore, the possibility of nutritionally variant streptococci infection should be considered if a patient with vertebral osteomyelitis shows a positive Gram stain but negative blood cultures. PMID- 21319042 TI - A case of juvenile primary pulmonary malignant fibrous histiocytoma. AB - An 18-year-old female presented with an abnormal shadow of a 22-mm nodule in the left anterior segment of the upper lung lobe (S3) on chest X-ray and computed tomography (CT). Thoracoscopic partial lobectomy was performed, when a frozen section suggested spindle cell sarcoma of extrapulmonary origin, including malignant fibrous histiocytoma (MFH). A histologic diagnosis of the MFH was rendered postoperatively on permanent sections. As no other primary focus was detected in spite of intensive investigation, including 18F-fluorodeoxyglucose positron emission tomography - CT scans, a definitive diagnosis was made of primary pulmonary MFH. Primary pulmonary MFH is usually treated by total resection, however, in the current case we performed a partial lobectomy with clear margins and a watchful follow-up without any additional aggressive treatment. No relapse has been observed for 3 years after the surgery. PMID- 21319043 TI - Possible mechanism of preventive effects of coffee intake on the formation of arterial occlusive thrombosis. AB - BACKGROUND: Prevalence and incidence of arterial occlusive thrombosis are influenced by life-style. Coffee consumption was shown with a lower incidence of myocardial infarction by Framingham Study. Yet, the mechanism is to be elucidated. METHODS: We examined the effects of coffee intake on the progression of occlusive thrombus formation in mouse cremasteric arteries. After 7 days of free intake of pure water, coffee containing water (5 mg/ml), or caffeine containing water (0.1 mg/ml), endothelial cell function was locally damaged by FeCl3. Circulating platelet and leukocytes were rendered fluorescently by rhodamine 6G. Process of occlusive thrombus growth was continuously visualized by 3-D imaging system equipped with ultra-fast confocal microscopy, and time to vascular occlusion was measured in each mouse. RESULTS: Platelet accumulation started immediately after FeCl3 exposure in all tested groups. However, arterial occlusion time in taking coffee containing water was significantly longer than those taking pure water. (46.0 +/- 17.4 min (n = 5) vs. 12.3 +/- 2.6 min (n = 31), p < 0.05) Arterial occlusion time in mice taking caffeine (13.8 +/- 5.9 min (n = 4)) was not different from those taking pure water. CONCLUSION: Coffee, but not caffeine intake, may have preventive effect on arterial occlusive thrombus formation initiated by functional injury of arterial endothelium. PMID- 21319044 TI - Subchronic administration of ketamine decreases the mRNA expression of serine racemase in rat brain. AB - The behavioral impairment produced by ketamine represents a pharmacological model for some aspects of schizophrenia such as positive, negative, and cognitive symptoms. Despite the multiple properties of ketamine, the main mechanism for its psychomimetic and anesthetic effect involves NMDA receptor system. Present study examined whether subchronic administration of ketamine at the subanesthetic doses (50 mg/kg) induces changes of behavior analogous to those observed in schizophrenia and the gene expressions of the enzymes for D-serine, an endogenous co-agonist for the NMDA-glycine site, in rat brain. Administration of ketamine daily for 14 consecutive days increased stereotyped behavior, ataxia and locomotion. The levels of serine racemase mRNAs in forebrain areas significantly decreased after subchronic administration of ketamine. In contrast, subchronic ketamine administration produced a significant increase in the mRNA expression of D-amino acid oxidase in the midbrain. These findings suggest that there is a relationship between the gene expression of the D-serine-related enzymes and the blockade of the NMDA receptors. PMID- 21319045 TI - The efficacy of an oxygen mask with reservoir bag in patients with respiratory failure. AB - BACKGROUND: Oxygen masks with reservoir bags (OMR) are widely used for oxygen therapy in patients with severe respiratory failure. The purpose of the present study was to determine whether OMRs are effectively used in clinical practice. METHODS AND RESULTS: In the first phase of the study on the patients with severe respiratory failure, no apparent respiratory motions of the reservoir bag were noted, and the oxygen saturation level as determined by pulseoximetry (SpO2) did not decrease even after shrinkage of the reservoir bag. In the second phase, when a healthy female volunteer wore an OMR, pressure swings in the reservoir bag were less than 0.1 cmH2O, even when she was breathing with her maximal respiratory efforts (tidal volume, 1.14 L and respiratory frequency, 19.2 bpm). These pressure swings provoke a less than 50 mL oxygen supply from the reservoir bag. The decreased efficacy of OMR in oxygen therapy may be primarily due to the large space between the OMR and the nose but this space is inevitable in sitting or orthopneic subjects. CONCLUSIONS: Fixing an OMR very tightly to the face is mandatory for its effective use. It should also be kept in mind that there are limitations to the efficacy of OMR, even when they are used with such careful management. PMID- 21319046 TI - Trastuzumab and chemotherapy after the treatment failure of lapatinib for HER2 positive metastatic breast cancer. AB - We describe a patient with human epidermal growth factor receptor type 2 (HER2/c erbB-2)-positive metastatic breast cancer who survived for approximately 6 years after the initiation of combination therapy with trastuzumab and varying types of chemotherapeutic agents. The patient was a 48-year-old postmenopausal female who underwent partial mastectomy with axillary node dissection for cancer of the right breast in March 1994. She developed lung metastases 2 years thereafter, but survived free of relapse for 8 years following chemotherapy and pulmonary lobectomy. The patient failed to respond to lapatinib, a HER1 (EGFR)/HER2 tyrosine kinase inhibitor, received during the course of her treatment but then again responded to subsequently administered trastuzumab. Primary treatment with trastuzumab and paclitaxel was initiated in April 2004 when the patient developed hepatic metastases 8 years after undergoing surgery for lung metastases. Long term combination therapy with continued trastuzumab and a variety of chemotherapeutic agents was administered for 6 years without any significant adverse events. We discuss the treatment strategies for HER2-positive breast cancer and the role of lapatinib, a recently approved anticancer drug. PMID- 21319047 TI - Protein oxidative damage and heme oxygenase in sunlight-exposed human skin: roles of MAPK responses to oxidative stress. AB - Oxidative stress derived from ultraviolet (UV) light in sunlight induces different hazardous effects in the skin, including sunburn, photo-aging and DNA mutagenesis. In this study, the protein-bound lipid peroxidation products 4 hydroxy-2-nonenal (HNE) and the oxidative DNA damage marker 8-hydroxy-2' deoxyguanosine (8OHdG) were investigated in chronically sun-exposed and sun protected human skins using immunohistochemistry. The levels of antioxidative enzymes, such as heme oxygenase 1 and 2, Cu/Zn-SOD, Mn-SOD and catalase, were also examined. Oxidative stress is also implicated in the activation of signal transduction pathways, such as mitogen-activated protein kinase (MAPK). Therefore, the expression and distribution of phosphorylated p38 MAPK, phosphorylated Jun N-terminal kinase (JNK) and phosphorylated extracellular signal-regulated kinase (ERK) were observed. Skin specimens were obtained from the surgical margins. Chronically sunlight-exposed skin samples were taken from the ante-auricular (n = 10) and sunlight-protected skin samples were taken from the post-auricular (n = 10). HNE was increased in the chronically sunlight exposed skin but not in the sunlight-protected skin. The expression of heme oxygenase-2 was markedly increased in the sunlight-exposed skin compared with the sun-protected skin. In contrast, the intensity of immunostaining of Cu/Zn-SOD, Mn SOD and catalase was not different between the two areas. Phosphorylated p38 MAPK and phosphorylated JNK accumulated in the ante-auricular dermis and epidermis, respectively. These data show that particular anti-oxidative enzymes function as protective factors in chronically sunlight-exposed human skin. Taken together, our results suggest (1) antioxidative effects of heme oxygenase-2 in chronically sunlight-exposed human skin, and that (2) activation of p38 MAPK may be responsible for oxidative stress. PMID- 21319048 TI - Bilateral brachial plexus palsies due to malpositioning after burn injury. AB - We reported a case of a 62-year-old man who sustained bilateral brachial plexus palsies resulting from malpositioning while being restrained due to agitation after burn injury. According to the clinical and EMG findings, we selected conservative treatment with rehabilitative intervention. Approximately 1 year after the injury, the patient became able to eat meals, dress himself, and use the toilet independently. To prevent brachial plexus injury in the supine position, the arms should be abducted and flexed to less than 90 degrees . Clinicians should be vigilant regarding positioning when patients must be restrained. PMID- 21319049 TI - Fine mapping of a psoriasis-susceptibility locus within the HLA class II region by using microsatellite markers in an association study of Japanese cases and controls. AB - BACKGROUND: The association between psoriasis and the HLA antigens encoded by the Major Histocompatibility Complex (MHC) genomic region is well known, but the role of the HLA class II region in susceptibility to psoriasis is unclear. OBJECTIVE: The purpose of this study is to map the psoriasis-susceptibility locus within the HLA class II region. METHODS: Three hundred seventy five unrelated Japanese patients with psoriasis vulgaris and 375 unrelated Japanese healthy controls were studied by an association analysis using 15 polymorphic microsatellite markers. RESULTS: Statistically significant differences were found at three microsatellite loci. The most significant association of psoriasis vulgaris with the microsatellite markers was found with DRA_CA (pc=0.0000135), the second with DQCARII (pc=0.0000840) and the third with G5_11525 (pc=0.0240). These significant microsatellite markers are in close vicinity to the DQA2, DQB1, DRB1, DRA and BTNL2 genes. CONCLUSION: The results suggest that there are psoriasis susceptibility genes located within the HLA class II region and therefore strongly support previous findings of a positive association between psoriasis and certain alleles of the DQB1 and DRB1 genes. PMID- 21319050 TI - Primary cardiac lymphoma. AB - OBJECTIVE: To report a rare autopsy case of primary cardiac lymphoma with microscopical involvements of extracardiac organs in an immunocompetent man. METHODS: An autopsy case of primary cardiac lymphoma in a 70-year-old man was examined grossly, microscopically and immunohistochemically. In addition, in situ hybridization for Epstain-Barr virus was performed. RESULTS: Clinically, a tumor was at first found only in the heart by various imaging techniques but tumor involvements were noted in chest and abdominal organs as the disease progressed. He died of cardiac failure six months after the first presentation. An autopsy revealed a tumor formation only in the right atrium and right ventricle of the heart. Histological and immunohistochemical studies showed that the cardiac tumor was diffuse large B cell lymphoma of non-germinal center B-cell like type. In addition to the heart, the tumor cells were found to microscopically involve lungs and peritoneal and retroperitoneal fat tissue of several organs. Epstein Barr virus protein and DNA were negative by immunohistochemistry and in situ hybridization. CONCLUSIONS: It was suggested that primary cardiac lymphoma may involve extracardiac organs as the disease progresses and that it may occur in immunocompetent persons. PMID- 21319051 TI - Hyperaldosteronemia and hypogammaglobulinemia secondary to atopic dermatitis induced exudation in an infant presenting with growth failure. AB - The present case is a 5-month-old female with atopic dermatitis who was brought to hospital for growth failure noted upon regular health examination. Laboratory examinations revealed hyponatremia, hyperkalemia, hypoproteinemia, hypogammaglobulinemia, elevated plasma renin activity and hyperaldosteronemia. Immune function was normal. Composition of the exudate collected from the skin lesions of atopic dermatitis was similar to that of plasma. Application of a steroid ointment improved the lesions as well as all laboratory values. These findings indicate that voluminous exudation caused by extensive atopic dermatitis can lead to hypotonic dehydration, electrolyte abnormalities, hypoproteinemia, hypogammaglobulinemia and, finally, to growth failure in infants. We conclude that intensive treatment is important for severe atopic dermatitis in infants to prevent serious complications. PMID- 21319052 TI - Usefulness of combined PET/CT for patient with epithelial ovarian cancer showing recurrence based on tumor marker CA125. AB - We report the case of a 41-year-old patient with epithelial ovarian cancer of stage IIIc. One year and nine months after completion of chemotherapy performed after surgery, the level of the tumor marker CA125 began to increase gradually. Conventional computed tomography (CT) and magnetic resonance imaging (MRI) were performed, but the recurrence site could not be determined clearly. However, combined positron emission tomography/computed tomography (PET/CT) revealed a metastasis in the right external iliac lymph node. This allowed commencement of chemotherapy at an early recurrent stage and subsequently the level of CA125 showed a significant decrease. PMID- 21319053 TI - 11-year-old boy with panic disorder responding to paroxetine. AB - We experienced an 11-year-old boy with panic disorder responding remarkably to paroxetine. Only a few studies have reported the clinical application of selective serotonin reuptake inhibitors (SSRIs) on children with panic disorder. In Japan, there are reports of child depression, autism, and school phobia; no study has focused on paroxetine treatment for children with panic disorder. Therefore, the case is discussed in this study. PMID- 21319054 TI - P-F study can predict the psychiatric symptoms of patients confined to the germ free unit. AB - Psychological symptoms are often seen in pediatric patients who are confined to a germ-free unit while undergoing bone marrow transplants. The Picture-Frustration Study( P-F study) was performed at the outpatient clinic before admission to the germ-free unit. After admission to the germ-free unit, the patients were interviewed once a week in the germ-free unit, and their mental symptoms were recorded in their clinical records. Condition of anxiety, unresponsiveness, resistance to treatment, and aggression have been noted in pediatric patients below the age of 18 in the Tokai University Hospital. Insomnia, appetite loss, anxiety, unresponsiveness showed a significant correlation with the patient's age. Forty-seven children were given the P-F study before entering the germ free unit. Anxiety, depression, and unresponsiveness correlated significantly with several items in the P-F study. The results of P-F study are useful in predicting the appearance of psychological or physical symptoms of patients confined to the germ-free unit. PMID- 21319055 TI - Altered cell motility behaviour and reorganization of contractile proteins after primary monolayer cultures of isolated hepatocytes. AB - OBJECTIVE: The aim of this study is to elucidate the temporal changes of the cell motility and the localization of contractile proteins in isolated hepatocytes after primary monolayer cultures. METHODS: Cultured hepatocyte couplets and triplets were observed at 4 hr and 24 hr with time-lapse video recording using video-enhanced contrast, differential interference contact (VEC-DIC) microscopy. The distribution of actin and myosin was examined by immunofluorescence, transmission electron microscopy, and electron microscopy using a whole cell mount. RESULTS: In 4 hr-cultured hepatocyte couplets, bile canalicular contractions, mediated by the surrounding actin and myosin, were spontaneous and forceful. At 24 hr, the cells spread and flattened out, and VECDIC microscopy revealed rope-like fibers, possibly stress fibers in the flattened cytoplasm. Stress fiber motilities were active and independent of other cell movements. The saltatory movement of the vesicles in the cytoplasm was clearly visualized with time-lapse recording. However, the bile canaliculi between two hepatocytes were closed at 24 hr, and the canalicular contractions were no longer seen. Actin and myosin were found in the same area as stress fibers were observed by VEC-DIC microscopy. CONCLUSIONS: It was possible to visualize high-resolution images of the dynamic cell function in the living hepatocytes, using VEC-DIC microscopy with time-lapse recording. The changes in the cell motility pattern may be ascribed to the reorganization of the contractile proteins in isolated hepatocytes after monolayer cultures. Four hr-cultured hepatocyte couplets are considered to be similar to the liver in a living state in terms of the cell morphology and the physiological motility function of the canaliculi. PMID- 21319056 TI - The incidence of internal malignancies in autoimmune bullous diseases. AB - Autoimmune bullous diseases are classified into pemphigus and pemphigoid. Pemphigus is designated as incurable disease by the Ministry of Health, Labor and Welfare, and it is said that pemphigus is difficult to care and can be fatal. The clinical course of bullous pemphigoid (BP) is better than that of pemphigus. However, as to the incidence of internal malignancies, it is well known that there is a significant difference between the two diseases. As the incidence of internal malignancies is high in BP, it is described in textbooks that patients with BP should be followed by a detailed screening for internal malignancies. We investigated the incidence of internal malignancies in 204 Japanese patients with autoimmune bullous disease who visited Tokai University Hospital in Kanagawa, Japan. We found that the incidence of internal malignancies was 11.2% in patients with pemphigus and 10.4% in patients with BP. Among pemphigus variants, the incidence was as high as 20% for pemphigus erythematosus. No relationship was found between malignancies and the severity of the autoimmune bullous diseases. Therefore it is clinically important to carry out a detailed screening for internal malignancies in patients with pemphigus as well as in patients with BP. PMID- 21319057 TI - Clinical outcome of proximal gastrectomy in patients with early gastric cancer in the upper third of the stomach. AB - OBJECTIVE: To determine whether clinical outcomes after proximal gastrectomy are better than those after total gastrectomy with Roux-en Y reconstruction. METHODS: We studied 10 consecutive patients with early gastric cancer who underwent esophagogastrostomy after proximal gastrectomy (PG group). Nutritional variables in these patients were compared with those in 10 consecutive patients who underwent Roux-en Y reconstruction after total gastrectomy (TG group). Patients were followed up for 5 years after operation. RESULTS: There was no anastomotic leakage. The total cholesterol level 1 year after operation was higher in the PG group than in the TG group (p< 0.05). Body mass index was significantly lower than the preoperative value between 1 month and 2 years postoperation in the PG group, whereas the TG group showed decreases between 3 months to 5 years postoperation. The percent decreases in body weight at 3 and 4 years in the PG group were lower than those in the TG group (both p< 0.05). Postoperative weight loss was thus milder in the PG group than in the TG group. CONCLUSION: Esophagogastrostomy after PG may produce better clinical outcomes than Roux-en Y reconstruction after TG in patients with early gastric cancer arising in the upper third of the stomach. PMID- 21319058 TI - Impact of a clinical pathway in cases of transurethral resection of the prostate. AB - Due to the recent dramatic increase in health care costs, costs containment for medical care has been recognized as an important issue. We evaluated the effects of a clinical pathway on hospital charges and the clinical outcome. The subjects consisted of 48 patients who underwent transurethral resection of the prostate (TUR-P) at the Department of Urology, Nerima General Hospital via its own clinical pathway during the two-year period from April 1998 to March 2000. The mean length of hospital stay, clinical outcome and the medical insurance charges for these patients were compared with those of 68 patients who had undergone TUR P before the implementation of the clinical pathway. As a result of the clinical pathway implementation for TUR-P, the length of hospital stay decreased from 17.2 days to 3.8 days and the total medical insurance charges (insurance points) also decreased from 37,484.6 to 31,278.9 yen. The postoperative complications did not substantially differ before and after the implementation of the clinical pathway. These results demonstrate that the establishment of clinical pathway can improve the treatment efficiency for almost all patients. It is, however, important to take into account the individuality of patients. PMID- 21319059 TI - Three-dimensional CT and histopathological findings of airway malacia in Hunter syndrome. AB - A 19-year-old man with known Hunter syndrome presented with dyspnea, and was admitted to our hospital. Bronchoscopy revealed tracheal narrowing with excessive granulation tissue formation in the trachea. Three-dimensional CT clearly demonstrated severe stenosis in the trachea and both main bronchi. Autopsy showed granulomatous tissue proliferation and deposition of mucopolysaccharide in the tracheal wall. We demonstrated the clinico-radiological-pathological correlation of bronchial lesions in Hunter syndrome, and emphasized that three-dimensional CT is helpful in deciding upon therapeutic strategy to treat stenosis in the large airway. PMID- 21319060 TI - A survey of head and neck malignancy at Tokai University Hospital. AB - Patients with head and neck malignancy who visited Tokai University Hospital over seven years were statistically surveyed. Six hundred and eighty-three patients were newly registered in this period. The most frequent primary lesion was the larynx (29.3%), followed by the hypopharynx (20.6%), oral cavity (11.9%), oropharynx (11.9%), and nose and paranasal sinus (8.6%). About two-thirds of the patients had advanced cancers. The patients were referred from adjacent regions, most frequently from the Shonan area. Referred patients with malignancy were increasing each year. The trends in head and neck cancers and the treatment modality were discussed. After the opening of a new hospital building in 2006, a further increase in the number of referred patients and operations is expected. PMID- 21319061 TI - Utility of virtual bronchoscopy in congenital tracheomalacia. AB - Utility of virtual bronchoscopy was evaluated in a case of congenital tracheomalacia by comparing virtual bronchoscopic images with those of fiberoptic bronchoscopy. Results indicate that virtual bronchoscopy is useful in diagnosing stationary lesions. However, its diagnostic value is inferior to that of fiberoptic bronchoscopy for mobile lesions, in that virtual bronchoscopy does not permit dynamic images. We recommend that the institutions, where fiberoptic bronchoscopy is available, should perform virtual bronchoscopy in parallel to explore its utility. PMID- 21319062 TI - Efficacy of balloon-occluded retrograde transvenous obliteration (B-RTO) performed in a patient with primary biliary cirrhosis with severe recurrent hepatic encephalopathy due to splenorenal shunt. AB - CASE: A 73 year old female had been diagnosed as primary biliary cirrhosis and Sjogren's syndrome since the age of 50. With persisting hyperammonemia, the patient was admitted on several occasions for the management of hepatic encephalopathy. Computed tomography (CT) scan and magnetic resonance imaging (MRI) of the abdomen showed varices in the splenic hilar region and a splenorenal shunt. A balloon-occluded retrograde transvenous obliteration (B-RTO) using 5% ethanolamine oleate plus iopamidol (EOI) was performed for treatment of recurrent hepatic encephalopathy. Celiac and superior mesenteric angiograms prior to B-RTO demonstrated a hepatofugal portal circulation through the splenic varices, splenorenal shunt, left renal vein and inferior vena cava. Immediately following the B-RTO, the portal circulation became restored to a hepatopetal blood flow and no visualization of the splenic varices and splenorenal shunt was verified. On day 2 post-B-RTO, blood NH3 level was noted to have decreased from 134 to 61 MUg/dL, indicating an improvement of hyperammonemia. The liver parenchymal blood flow using the dynamic CT time-concentration curve showed a decrease in hepatic artery blood flow and a marked increase in portal flow following the B-RTO. The patient has since been free from any signs of hepatic encephalopathy due to hyperammonemia for over 5 years following the B-RTO. CONCLUSIONS: B-RTO may be considered useful for the treatment of severe recurrent hepatic encephalopathy due to the collateral shunt in portal hypertension. PMID- 21319063 TI - [Frailty: the heart of elderly psychiatry]. PMID- 21319064 TI - [Flanders versus The Netherlands: focus on differences between depressive symptoms in men and women measured on the basis of CES-D8]. AB - BACKGROUND: A consistent finding in international research is the higher prevalence of depression in women than in men, but it is not known to what extent this gender difference is robust in population research. AIM: In this study we focus on gender differences in depressive symptoms of the population of Flanders and the Netherlands. method We made use of the European Social Survey organised in 2006 and 2007 (n = 3014); depression being measured by means of an 8-item version of the Center of Epidemiological Studies Depression Scale, CES-D. First we studied the psychometric properties of the depression inventory, looking closely at both the reliability and factional validity of the scale. Next we compared the gender and regional differences in the prevalence of depressive symptoms as measured by the CES-D8 scale. Finally, using regression analysis, we examined to what extent the gender differences between Flanders and the Netherlands were family-related and linked to socio-economic factors. RESULTS: Our study pointed to the reliability and factional validity of the CES-D8. Our results confirmed a higher prevalence of depressive symptoms among women than among men. On average, Flemish respondents reported fewer depressive symptoms than Dutch respondents, but their scores showed greater dispersion. CONCLUSIONS: These differences can be explained partly by different family and socioeconomic circumstances. PMID- 21319065 TI - [Risk assessment with intellectual disabled forensic psychiatric patients: how useful are risk assessment instruments?]. AB - BACKGROUND: Instruments for assessing the risk of violent behaviour have proved their worth in the field of forensic psychiatry. However, it is not certain whether such instruments provide an accurate assessment of recidivism when used with psychiatric patients who have an intellectual disability. AIM: To find out whether these instruments - or which of these instruments - can provide a reliable assessment of the risk of violent sexual recidivism if used with forensic psychiatric patients who have an intellectual disability. method We searched PubMed, PsycINFO and Google Scholar for studies in English or Dutch, published between 1980 and 2010, concerning the reliability of instruments for assessing the risk of recidivism in forensic psychiatric patients with an intellectual disability. RESULTS: The studies show that several of the risk assessment instruments currently in use provide reliable predictions concerning patients with an intellectual disability. CONCLUSIONS: The HCR-20 and HKT-30 are recommended for assessing the risk of violent recidivism in patients with an intellectual disability. The Static-99 is the preferred instrument for assessing the risk of sexual recidivism. Further research is needed for assessing to what extent SVR-20, ARMIDILO, DROS, and PCL-R are applicable to forensic psychiatric patients in the Netherlands who have an intellectual disability. PMID- 21319066 TI - [Depot antipsychotics in the year 2011]. AB - BACKGROUND: People suffering from a psychotic disorder show limited compliance with the prescribed regimen of antipsychotics. Insufficient compliance and insufficient insight into their illness are important contributing factors predicting recurrence of psychotic symptoms. AIM: To discuss what contribution long-acting, mainly intramuscular (depot) antipsychotics can make in reducing the chance of a psychotic relapse. Also, we suggest procedures for switching from oral to depot antipsychotics. METHOD: The currently available depot antipsychotics in the Netherlands are compared with each other, desired and undesired treatment effects are discussed. Also, the possible role of depot antipsychotics in limiting compliance problems is discussed. Expected developments in depot antipsychotics in the near future are presented. RESULTS: A review of the literature shows that there are insufficient studies supporting an evidence-based choice for oral versus depot antipsychotics in different clinical situations. A choice for depot antipsychotics does not solve all compliance problems, but it does make them manifest. CONCLUSION: The choice for oral or depot administration of an antipsychotic will have to be based on the patient's particular circumstances, including the medical history and insight in his/ her illness, risks to patients and others and the personal preferences of both patient and clinician. The choice for switching to depot antipsychotics in order to reduce compliance problems needs to be part of an overall treatment plan that includes psychosocial support. PMID- 21319067 TI - [Typical and atypical antipsychotics: Is there a difference in their influence on neurocognition?]. AB - BACKGROUND: Neurocognitive dysfunction is a core feature of schizophrenia and is related to the functional outcome of the illness. It has been suggested that the so-called atypical antipsychotics may have a more favourable influence on neurocognition than the older, typical antipsychotics and thus also on the functional outcome. AIM: To review the recent scientific literature concerning the effects of antipsychotics on neurocognition. METHOD: The literature was reviewed systematically via the most important databases. RESULTS: Meta-analyses suggest that atypical antipsychotics have moderate, positive effects on neurocognition and in that respect are more beneficial than typical antipsychotics. Recent studies, however, challenge this finding. CONCLUSION: The reported positive, cognitive effects of atypical antipsychotics are slight, particularly compared to the severity of neurocognitive dysfunction found in schizophrenia. In clinical practice there seem to be no convincing reason for attaching much weight to any differential effects that typical or atypical antipsychotics may have on neurocognition. PMID- 21319068 TI - [Development of a fidelity scale for function assertive community treatment (FACT)]. AB - BACKGROUND: Assertive community treatment (ACT) is one of the most important models for the care and treatment, in the community, of people with severe mental illness (SMI). ACT is concerned primarily with smi-patients who have the most complex problems and it provides care by means of intensive assertive outreach. Function act (FACT) provides care for the entire group of SMI - patients and combines the principles of case management and ACT. For a long time it has been possible to measure the degree of ACT model reliability using the facts reliability scale. Throughout this time, however, a reliability scale for FACT was not available. AIM: To develop a reliability scale for fact teams. METHOD: Using the knowledge of experts and feedback from fact teams it has been possible to develop a reliability scale for fact teams. The scale was tested and subsequently adapted as a result of 10 pilot trials performed by 10 fact teams. RESULTS: The definitive version of the scale was confirmed in 2008 and is currently used in the field. CONCLUSION: With the ACT and FACT reliability scales the research field now have two instruments with which teams working with SMI - patients can measure model reliability. The DACTS and FACTS provide opportunities for quality improvement and transparency. PMID- 21319069 TI - [Neurosyphilis: unexpected reunion with an old acquaintance]. AB - A 45-year-old man was admitted to a psychiatric hospital with confusion and disorientation; he was suspected of having Korsakoff syndrome. He was known to have a history of alcohol abuse, complicated by epileptic fits, and to have had a recent ischaemic cerebrovascular attack. Unexpectedly, screening for syphilis turned out to be positive. Examination of the cerebrospinal fluid led to the diagnosis of neurosyphilis. Most neurological and psychiatric symptoms disappeared after treatment with antibiotics. PMID- 21319070 TI - [Reaction on 'Awareness of illness in patients with schizophrenia: theoretical insights and a proposal for treatment']. PMID- 21319071 TI - Moist wound healing: current concepts and applications. AB - The search for the optimal environment that enhances tissue healing is well under way. Since Winter's landmark study over 30 years ago, moist wound healing has become the subject of intensive scientific and clinical research. Numerous studies of molecular and cell biology have demonstrated the benefits of wound healing in a moist environment. The use of occlusive dressings that retain moisture is now accepted as a first line of treatment in the management of a variety of wound types. Clinicians have a myriad of dressing alternatives at their disposal that enable more active control over the healing process. This article reviews the beneficial effects of moist wound healing and the occlusive dressings available to achieve such an environment. PMID- 21319072 TI - Selected applications of balloon dissection. AB - Historically, balloons have been used in surgery for a variety of applications. Over the past decades, balloons have been used by surgeons for retaining means (Foley catheter), extraction and occlusion (Fogarty catheter), tamponade (Sengstaken-Blakemore tube) as well as other uses such as dilation and calibration. The pioneering efforts of Gauer and Kieturakis have broadened the use of balloons for a new surgical application - dissection. An important feature of balloon dissection is that it allows the surgeon to create a new operative working space in which a surgical procedure can be performed. Currently, a particularly useful working space is the region immediately outside the peritoneum, frequently termed the extraperitoneal space. A variety of procedures can be performed laparoscopically in the extraperitoneal space such as herniorrhaphy, bladder neck suspension, lymph node dissection, and varicocelectomy. PMID- 21319073 TI - Surgical simulation using virtual reality technology: design, implementation, and implications. AB - Atremendous demand exists for enhancing the way by which physicians learn new invasive procedures. Appropriate education in new medical and surgical procedures is often outpaced by the desire of physicians to incorporate a procedure in their practice. Computerized surgical simulations have the potential for improving surgical morbidy and mortality. Studies have shown that, for a wide range of diagnostic and therapeutic procedures, doctors doing their first few to several dozen cases are much more likely to make a greater number of errors. This phenomenon has been referred to as 'the learning curve'. Adequate proctoring of learners by experienced surgeons is cumbersome, as there are few surgeons experienced to proctor their colleagues. It is difficult for physicians, particularly those in rural areas, to travel to larger medical centers for training. The requirement also places a burden on experts who could become overwhelmed with proctoring requests, in addition to leaving their clinical responsibilities. PMID- 21319074 TI - Cryodestruction of hepatic tumors. AB - Cryodestruction of hepatic tumors is done by freezing the tumor and an appropriate amount of surrounding normal tissue in situ. The goal is complete destruction of malignant tissue. Local and systemic host mechanisms activated by the cold injury complete the process. Resorption of devitalized tissue and stabilization of the residual scar occurs during the ensuing months. Immune factors may contribute to the long-term process of cryodestruction although such effects are inconstant and ill defined. The purpose of this overview is to delineate the mechanisms of cryodestruction, briefly summarize clinical results and discuss the technique for treatment of hepatic tumors. PMID- 21319075 TI - Antibiotic update for the surgeon. AB - All too often, it seems that the utilization of antibiotics by surgeons for either prophylaxis or the treatment of established infections is shrouded in a combination of mysticism and marketing. What should be straight forward, frequently becomes confused by factors such as superstition, habit, recent interaction with an industry representative, and faulty information. The rational use of antibiotics is surprising simply, and is based on the fact that these agents are, quite simply, systemic chemotherapy against bacteria. Once delivered to the patient these agents act not only locally, but, more importantly, sistemically against susceptible microorganisms. This demands that the practitioner make an educated guess as to which bacteria are likely to be present, as well as use an agent that both safe and effective in that specific patient. The types and variety of bacteria present in a surgical infection, or likely to be present, can usually be deduced by the location and / or organ system involved. The safest and most effective agent to be used against those organisms is primarily a function of the specific hospital that the patient in, and whether the infection is hospital-acquired (nosocomial) or community acquired. The susceptibility patterns for bacteria vary from community to community (as noted by local hospitals), as well as from hospital to hospital dependent on whether it is a community hospital or a tertiary referral center. It is illogical to assume that the same drug or drugs will be just as effective in one setting as in another, regardless of whether they are used for prophylaxis or an established infection. PMID- 21319076 TI - Anesthetic considerations for patients undergoing laparoscopic surgery. AB - Once a technique used primarily for gynecologic surgery, laparoscopy is becoming increasingly popular for the performance of abdominal procedures such as cholecystectomy, bowel resection, splenectomy, adrenalectomy, nephrectomy and inguinal hernia repair. Laparoscopy results in a shorter postoperative hospital stay, less time between surgery and the resumption of full activity, reduced hospital costs, and an earlier return to the work force. By avoiding a large abdominal incision, laparoscopic surgery results in improved cosmetic results and a reduced incidence of postoperative intraabdominal adhesions. Compared to open procedures, postoperative pain is generally considered less after laparoscopic surgery. Finally, respiratory function is less compromising following Iaparoscopic compared to open surgical procedures. PMID- 21319077 TI - Embryo manipulation after mid-gestation stages in mice. AB - The system for directly manipulating mammalian embryos is an advantage not only to revealing the various developmental evidences but also in evaluating the availability of possible techniques for fetal surgery. "Exo utero development in mice" was reported by Muneoka et. al. and has been one of the most useful techniques in experimental embryology ? including developmental neurobiology and prenatal plastic surgery for malformations. We have applied this method to establish experimental animal models with congenital disorders and examined the mechanisms of normal and abnormal morphogenesis. In this paper, we would like to introduce the technique of exo utero development in combination with a microinjection system in mice embryos. PMID- 21319078 TI - Microsurgical techniques in the genetic engineering of Mammalian embryos at the preimplantation stage. AB - The genetic engineering of mammalian whole embryos has become one of the most popular and fruitful techniques in modern developmental biology, not only to investigate the normal development and pathogenesis of diseases but also to develop future gene-therapy applications for human genetic diseases. Although the rapid advancement of molecular biological techniques has created a theoretical basis for genetically engineering mammalian embryos, it has become practical only after the establishment of the culture system for mammalian embryos, which normally develop (hidden from the human eye) in the oviduct and the uterus, the improvement of optic instruments, and finally, the development and establishment of microsurgical techniques. PMID- 21319079 TI - Endoscopic surgery - a fascinating idea requires responsibility in evaluation and handling. AB - When we think of the pioneers of endoscopic surgery, we think of people like Wittmoser, Semm, Muhe, Wickham, Mouret, Perissat and Buess as well as industrialists like Karl Storz and Leon C. Hirsch (Figure 1). Despite differences in personalities, these pioneers had an impact on endoscopic surgery because of important, common denominators they shared, such as curiosity, eccentricity, and, according to De Bono and Bocher, "lateral thinking." Of course, these pioneers were ignored at the beginning and even called crazy. They saw controlled clinical trials as irrelevant to their work. They were open minded, innovative and recognized the revolutionary potential of seeing their ideas come to fruition. And it was from these risk-takers that endoscopic surgery - this fascinating alternative in general surgery - was born. PMID- 21319080 TI - Credentialing, privileging, proctoring in the era of laparoscopic surgery, history of credentialing problems originating with laparoscopic surgery. AB - Laparoscopic surgery in the United States was revolutionized in 1989. Even though Semm had popularized laparoscopic surgery in the early nineteen eighties in Germany, it was the advent of Laparoscopic Cholecystectomy in 1989 that triggered the explosive training and eredentialing issues in laparoscopic surgery. In a letter to the editor of the American Journal of Surgery, in June 1990, the author had recommended the following for training courses: 1) the operators should have extensive hands-on experience in diagnostic laparoscopy prior to embarking on laparoscopic surgery; 2) hands-on training to develop hand-eye coordination using Berci-Sackier trainers; 3) extensive explanation on the use and abuse of video laparoscope and accessory instrumentation; 4) a minimum experience as prime operator in at least 3 pigs, each weighing 90-100 lbs., with experience as an assistant operator and camera operator in 6 more pigs, making a total of 9 pigs per participant. This letter was written with an intent that proper training of surgeons would take place. We advocated a surgeon/co-surgeon team approach, to avoid adverse outcomes. In those days, weekend courses proliferated and surgeons came back and started doing procedures with minimal experience. This explosive growth was driven by patient demands for this procedure. As anticipated, untoward outcomes were reported. PMID- 21319081 TI - Training for advanced laparoscopic surgical skills: suturing, knotting, and anastomosis techniques. AB - If surgical art can be defined as the operative relationship between the surgeon and the living tissue then it is easy to conclude that this relationship has changed. On the one hand, changed for the better as far as the end result is concerned, but on the other hand, for the worse, as far as it relates to the surgeon's effort, that is, the method by which this improved result is obtained. In essence, the surgeon will have to work a great deal harder to provide the added benefit for the patient. PMID- 21319082 TI - Advanced endoscopic imaging: 3-d laparoscopic endoscopy. AB - Video imaging technology has significantly enhanced the performance of minimally invasive surgical procedures. However, a major limiting factor for the endoscopic surgeon is to work in a 3-dimensional field while viewing a two-dimensional video image. Advances in electronic video imaging have resulted in satisfactory image quality yet the lack of depth perception with standard 2-dimensional video system results in the surgeon having to rely on indirect evidence to assess the third dimension. To gauge depth, one may have to rely on touching the tissues with endoscopic instruments or estimate the relative movement of the instruments in relation to the intra-abdominal organs. These maneuvers result in a reduction in the speed of surgery and may cause unnecessary tissue trauma. Recently a number of manufacturers have developed three-dimensional (3-D) video systems which significantly improve visualization and enhance the ability of the surgeon to perform delicate endoscopic dissection and suturing. These 3-D video systems may also improve the education of surgeons-in-training as they would have a better understanding of 3-dimensional anatomy during laparoscopic surgery. PMID- 21319083 TI - Laparoscopic fixation and guiding devices. AB - Since the new advances in video technology in the mid 1980's and the couplmg of the video camera to the laparoscope the surgeon no longer needs to control the laparoscope with his own hands. The advantage of this new development in laparoscopic surgery is that (1) it is not as tiring to perform (i.e., he no longer had to bend over the patient to look through the laparoscope's ocular), (2) the whole operating team could follow the progress of the surgery (for better or worse), and (3) that the surgeon is then enabled to operate with two hands, a new skill which must be learned since it is one of the keys to being more effective and efficient under the laparoscope. One of these advanced skills, intracorporeal suturing, is an especially demanding skill and requires a well centered, and steady camera support for the technique to be performed efficiently. The disadvantage is that he must give oral commands to the individual who is now charged with guiding the laparoscope within the operative field and this disadvantage alone is sometimes thought the tip the balance in the wrong direction. PMID- 21319084 TI - Ultrasonic energy in laparoscopic surgery. AB - The ideal energy form for use in laparoscopic surgery should provide controlled, hemostatic cutting. A good dissection technique should be further characterized by minimal thermal injury to surrounding tissue, no smoke obscuring the visual field, cutting ability equal to or superior to a conventional scalpel, coagulative ability equal to or greater than electrosurgery, lack of danger to the patient such as from stray energy, no toxins from exposure to smoke in the pneumoperitoneum elevating patient levels of methemoglobin or carboxyhemoglobin, no need for special preparation of the patient (grounding pad) or surgeon (glasses), and no need for special training. For a technology to replace that which is the current standard, this should all be provided at a cost similar to the cost associated with electrosurgery. PMID- 21319085 TI - Complications of Trocar Wounds and their Prophylaxis. AB - Laparotomy is vision of the abdominal content by direct eyesight through an abdominal incision. Laparoscopy achieves the same or better result with an optic device placed into the abdomen through special introducers. Exploration, part or complete procedures, can be performed with much less postoperative morbidity; thishas instilled a new sense of optimism in both the community and surgical ranks. Suddenly it appeared that the old "sacred" rules of traditional surgery had been buried under a thick layer of dust. PMID- 21319086 TI - Laparoscopic surgery of the liver. AB - The liver, with its multiple metabolic, detoxifying, and filtering functions plays a key role in the field of oncology, as it is the site of both metastatic and primary cancers. This phenomenon occurs because of two factors, namely the proximity of the liver to other intra-abdominal organs as well as the extensive portal vein and lymphatic drainage systems. The lobular structure of the liver represents a barrier to cancer cells which ultimately flourish by producing either synchronous or metachronous hepatic lesions. The size of these metastasizes varies greatly and obeys the laws of expediential tumor growth, thus implying that some lesions will be too small to be detected by conventional methods. PMID- 21319087 TI - Transcystic C-tube Drainage Following Laparoscopic Common Bile Duct Exploration. AB - At the beginning of laparoscopic surgery, common bile duct (CBD) stones were thought to be a contraindication for laparoscopic cholecystectomy (LC) in the treatment of gallstones. At present, well-trained surgeons remove these stones in relation to LC. CBD stones are often present during laparoscopic cholecystectomy and when these stones are removed choledochoscopically a T-tube has to be inserted. This approach to remove the CBD stones has been documented. Insertion of a T-tube into the CBD is a subject open to discussion, because of one disadvantage when the T-tube is inserted into the CBD, patients stay in the hospital for more than 2 to 3 weeks postoperatively. PMID- 21319088 TI - Laparoscopic common bile duct exploration and hand sutured closure of the choledochotomy. AB - In the years since 1987, when Mouret introduced laparoscopic cholecystectomy in France, this approach has become the preferred method for management of symptomatic gallbladder disease. However, the treatment of calculous disease other than the gallbladder is not generally practiced by the laparoscopic approach. The treatment of common duct stones is largely managed by preoperative Endoscopic Retrograde Cholangio Pancreatography (ERCP) or choledochotomy and exploration through a laparotomy incision. The authors believe that this lack of acceptance of laparoscopic treatment of common duct stones is because of the ready availability of ERCP and sphincterotomy in most centers countenanced by the difficulty of laparoscopic treatment. PMID- 21319089 TI - Laparoscopic treatment of bastro-esophageal reflux disease. AB - Gastro-esophageal reflux disease (GERD), with or without hiatal hernia, is the consequence of a functional disturbance of the lower sphincter of the esophagus. This dysfunction is more and more often seen in populations with Western eating habits. According to recent reports, 10 percent of the patients suffer from constant heartburn, 30 percent from discontinuous heartburn demanding active treatment. Finally, a great number of non-digestive symptoms, either pulmonary, E.N.T., or cardiac, are also connected with GERD. In the early 1970s, medical treatment was not very effective, hence the popularity of open surgery. Although the results were satisfactory, postoperative sequelae, in particular parietal ones, could not be avoided. The reason is that a large laparotomy is necessary to gain access to the esophageal hiatus, which always involves potential risks of postoperative incisional hernia. PMID- 21319090 TI - Laparoscopic Billroth II Gastrectomy. AB - The first successful totally intra-abdominal laparoscopic Billroth II gastrectomy was performed on February 10, 1992, by our group in Singapore. The patient was a 76-year-old Chinese man with a 2-year history of gastric ulcer, which presented with bleeding. The operation took 4 hours and consumed 17 ENDO GIA (Auto Suture, USSC, Norwalk, CT) staplers. The benefits of this minimally invasive approach were clearly evident. The patient was walking on the first postoperative day, taking liquids on the third, solids on the fourth, and was discharged on the fourth postoperative day. The operation was subsequently emulated by surgeons in about a dozen countries. The description in this chapter is a modification of the original technique, using the improved instrumentation that is now available. PMID- 21319091 TI - Extraperitoneal laparoscopic hernia repair: experience in 178 patients. AB - The evolution of a preferred technique for laparoscopic inguinal hernia repair has been occurring over the past several years. The early work of Ger involved a stapled closure of the dilated internal ring using a specialized 12-mm. instrument, which combined the functions of tissue approximation and stapling. This was followed by a prosthetic mesh plug technique of Schultz and Corbitt, which consisted of a free mesh plug occlusion of the inguinal canal, combined with prosthetic patch coverage of the hernia defect. PMID- 21319092 TI - Laparoscopic colon resection and intracorporeal hand-sewn anastomosis. AB - The application of laparoscopic surgical techniques to colonic surgery is restricted to selected cases and to rather few surgical centers. On the one hand, the disadvantages of the open approach involves the sizable laparotomy incision for mobilization of the viscera, especially if the colonic flexures are to be mobilized. On the other hand, in the minimally invasive approach the extent of dissection requires additional skills and a well honed endoscopic surgical team is needed especially if laparoscopic reconstruction of the large colon is to be accomplished. The teamwork is more critical for colon procedures than for laparoscopic gallbladder surgery. PMID- 21319093 TI - An innovative thoracoscopic surgery for patent ductus arteriosus: a Japanese first case report. AB - A 5-year-old girl with patent ductus arteriosus (PDA) was successfully treated by thoracoscopic surgery, which was the first successful case in Japan. The operation was carried out under general anesthesia with the usual endotracheal intubation. Short trocars were inserted through the left intercostal spaces to introduce a flexible video thoracoscope and adequate surgical instruments. After the ductus was carefully dissected and exposed, two titanium clips, 11 mm in length, were applied to interrupt the ductus completely. The continuous heart murmur of PDA disappeared, as confirmed by an esophageal stethoscope. Postoperative course was uneventful and the patient was discharged on the 6 postoperative day. Eighteen months after surgery, no residual PDA shunt was revealed by doppler echocardiogram. The advantages of thoracoscopic surgery for PDA are less postoperative pain and discomfort, early recovery and short hospital stay, and cosmetic preservation. Availability of smaller sized surgical instruments should allow smaller children or newborns with PDA to be treated with this method. PMID- 21319094 TI - Use of endoluminal illuminated bougie during laparoscopic and thoracoscopic surgery of the esophagus. AB - Newly developed endoscopic instruments and devices, along with advanced endoscopic surgical techniques, have made it possible to perform an increasing variety of endoscopic procedures. These procedures consist of the same steps employed in the open procedure that preceded them but avoid their large incisions. This in turn eliminates many of the disadvantages associated with laparotomy and thoracotomy incisions. Postoperative pain is greatly decreased, postoperative hospital stay is shortened, and return to normal activities is expedited. Postoperative complications as well as early and late morbidity related to the surgical wound (e.g. wound infection, incisional hernia, wound dehiscence) are minimized. The incidence of intraabdominal adhesions and both early and late postoperative intestinal obstruction are decreased. Cosmesis is dramatically enhanced. PMID- 21319095 TI - Endoscopic surgery in rhinology and ophthalmology. AB - The rapid development of endoscopic methods in many fields of surgery has been possible by the fiberoptic technique in connection with high-quality video representation and computer-tomograhic imaging. In rhinology, there has been a worldwide adoption of the technique in diagnostics and treatment. In the beginning, the technique was founded on concepts developed after many years of endoscopic investigation and clinical observations by W. Messerklinger and coworkers in Graz, Austria, with later contributions from other European ENT clinicians, and it was subsequently made popular by Kennedy and colleagues in the United States. Nasal and paranasal sinus endoscopy proved to be a valuable diagnostic contribution to rhinology. Endoscopic sinus surgery (ESS) has also proved suitable for treatment, not only of rhinologic disorders but also for some ophthalmologic and neurosurgical conditions. When properly used, ESS causes much less morbidity than does treatment with older "conventional" surgical methods. In the following discussion, I will briefly cover the pathophysiology of some of the disorders, the surgical indications and technique, as well as the results and complications of this kind of surgery. PMID- 21319096 TI - Suprapubic needle cystoscopy: a new technique to detect iatrogenic injuries to the lower urinary tract. AB - Latrogenic injury to the lower urinary tract, specifically the ureter and bladder, is a potential risk of any pelvic surgery. According to the available literature, the incidence of injury to the ureter ranges from 0.5-2.5% for routine pelvic operarions. In actuality, the incidence of ureteral injury during pelvic surgery may even be higher, as many cases are not reported, not detected or are asymptomatic. Injury to the bladder during pelvic surgery most commonly occurs in the form of inadverant laceration or placement of sutures through the bladder wall. Previous pelvic surgery, including Cesearean section, hysterectomy and bladder suspension procedures, and gynecologic conditions such as malignancy, endometriosis and pelvic inflammatory disease increase the risk for bladder trauma. PMID- 21319097 TI - Laser treatment of benign prostatic hyperplasia. AB - With the increasing longevity of the population, the incidence of symptomatic bladder outlet obstruction due to benign prostatic hyperplasia (BPH) is expected to increase. Transurethral resection of the prostate (TURP) is currently considered the standard surgical treatment for this disease. However, TURP is an invasive procedure associated with some morbidity and, rarely, mortality. During the past several years, several alternative treatments for BPH have emerged. Visual laser ablation of the prostate (VLAP) is one of the more attractive choices among these alternatives. The use of laser energy to treat BPH has several advantages over TURP. Laser energy causes coagulation of the blood vessels, thus minimizing blood loss and fluid absorption. VLAP is an outpatient procedure performed under direct vision utilizing a standard or continuous-flow cystoscope. The technique of VLAP is relatively easily learned and has a much shorter learning curve than that of TURP. To date, clinical trials have confirmed the efficacy and safety of VLAP and the minimal associated morbidity. In the short-term follow-up, improvement in both subjective (symptom score) and objective (urinary flow rate) factors is similar to that after TURP. Although the results obtained with this laser technology are exciting and encouraging, further study and long-term follow-up are needed to confirm the durability of these results. PMID- 21319098 TI - Pharmaceutical Treatment Of BPH And Its Effect On Indications For Prostate Surgery. AB - Benign Prostatic Hyperplasia (BPH) is a pathological description of an aging process that affects a great majority of men. Classically, obstructive and irritative symptoms such as frequency, nocturia and weak urinary stream are described as "prostatism". Microscopically, BPH can be described as hyperplasia of stromal and epithilial cellular element which can macroscopically present as a gross adenomatous enlargement of the prostate gland. Thus, treatment of BPH is aimed at alleviating symptoms of prostatism and associated morbidities of prostatic obstruction. PMID- 21319099 TI - Recent advances in laparoscopic hysterectomy and pelvic floor reconstruction. AB - What role could laparoscopy possibly play in treatment of uterine disorders and pelvic floor relaxation? The basic principle that laparoscopy is a mode of access, not a mode of treatment, must be emphasized. Statements such as "laparoscopic treatment of genuine stress urinary incontinence" are misleading because they imply that laparoscopy is a treatment modality, which it isn't. Laparoscopy provides only access to the anatomical area. Theoretically any procedure classically done at laparotomy, can be done under laparoscopic control. Is executing such procedures self gratification for the surgeon or a benefit for the patient? No doubt, procedures performed under laparoscopic control require more surgical skill. The benefits for the patient are reduced need for analgesia, which means that the procedure is significantly less painful, less postoperative ileus, reduced length of hospital stay, and finally, reduced cost to society through both direct and indirect savings. The fact that the procedure is less painful is reason enough to eliminate laparotomy in favor of laparoscopy: "Dolor per primam" is part of Hippocrates' oath. PMID- 21319100 TI - Laparoscopic tubotubal anastomosis: laparoscopic microsurgery in gynecology. AB - Tubotubal anastomosis technique dates back to the 1920's when large sutures were used to approximate proximal and distal ends of the fallopian tube. Direct vision, aided by overhead illumination, was used and stitches were placed superficially to avoid inclusion of the posterior wall. Delicate tissue handling was not stressed. No major breakthroughs in this area developed over the next half century. The 21% success rate for the conventional technique was disappointingly low although a clear explanation has never been established. Presumably it was caused either by the failure to reconstruct a patent lumenal channel or by causing extensive postoperative adhesion formation. PMID- 21319102 TI - Laparoscopic presacral neurectomy. AB - Presacral neurectomy (PSN) has been successfully used to treat women experiencing midline premenstrual and menstrual dysmenorrhea along with mid line pelvic pain for almost 100 years. Recent developments in minimally-invasive surgical technique have allowed the gynecologic surgeon to perform laparoscopic presacral neurectomy (LPSN) as an isolated procedure or in conjunction with other conservative procedures for the treatment of pelvic pain and dysmenorrhea. PMID- 21319101 TI - Endometriosis of the intestine and genitourinary tract. AB - As with other organs, the etiology of bowel endometriosis is unknown. Its occurrence was reported as early as 1922 by Sampson. Following his investigation of nineteen cases, he proposed that "implantation adenoma of endometrial type of some portion of the intestinal tract may be present in at least one half of the cases of perforated ovarian hematoma of endometrial type with peritoneal implantations." PMID- 21319103 TI - Recent developments in renal transplantation - FK506 and bone marrow augmentation. AB - In the past 40 years, clinical renal transplantation has evolved from a risky, highly speculative endeavor to a fairly mature, well-established service. There are hundreds of programs around the world, transplanting thousands of patients annually, and reasonably good suecess rates have been achieved. Current expectations are of one year patient survival of 90 - 98%, and one year graft survival of 75 - 90%. In addition, patients who have been successfully transplanted have a markedly improved quality oflife compared with patients on dialysis. However, in spite of these encouraging results, there remain significant problems. Among them are acute rejection, which still occurs in 40 - 75% of cases, and graft loss secondary to rejection, acute or chronic, which limits the half-life of cadaveric kidneys to 8 years. As part of an effort to address these issues, there have been a number of new immunosuppressive agents and therapeutic modalities that have been investigated over the past several years. This chapter will focus on 2 areas of ongoing research in our institution, the use of FK506 in renal transplant patients, and the program of combined kidney/bone marrow transplantation. PMID- 21319104 TI - Preservation of intra-abdominal organs for transplantation. AB - The history of clinical organ transplantation and its development in routine surgical practice has been packed into the last 40 years and is encompassed by the careers of many of the pioneers of transplantation. Improved immunosuppression, surgical, anesthetic, and postoperative management have transformed results and allowed many new organs to be transplanted. Progress in preserving organs for transplantation has lagged behind the other advances in transplantation. Until the introduction of UW solution, no major progress was made after the introduction of machine perfusion preservation by Dr. Belzer in 1967 and that of simple cold storage by Dr Collins in 1969. This solution was developed at the University of Wisconsin and has allowed extended simple cold storage of the pancreas, liver, kidney, and more recently, the small bowel prior to transplantation. The UW solution represents a good answer to the problem of short-term storage of organs for transportation and early reimplantation, but equally important, it has also stimulated renewed research interest in this area. A more profound understanding of the events occurring during hypothermic storage and subsequent reperfusion is needed if further advances are to be made. It is anticipated that if long-term organ storage is to be achieved this will require a perfusion preservation system that allows the maintenance of essential metabolic processes. PMID- 21319105 TI - The latest advances in liver transplantation at the pittsburgh transplantation institute: evolution of FK506, liver-intestinal transplantation, clinical xenotransplantation, and the induction of graft acceptance. AB - During the past 30 years orthotopic liver transplantation (OLTx) has become a highly successful form of therapy, and as of this writing it is being performed at more than 100 institutions in the U.S., and a similar number in Europe. This is testimony to the great advances achieved in this field since the 1960s and 1970s, when there were essentially only two places actively engaged in liver transplantation. Essential to its success have been the technical refinements introduced during the last three decades, which have allowed many surgeons around the world to be able to do the procedure safely. Liver transplantation is still considered as one of the most complex operations, and therefore the margin of error is small and attention to technical detail is crucial to a satisfactory outcome. This is magnified in importance since OLTx, unlike kidney, heart, pancreas and intestinal transplantation, lacks a back-up system, such as dialysis, ventricular assist device, insulin or total parenteral nutrition. Thus, the smallest mistake in the surgical management of the patient may prove fatal. PMID- 21319106 TI - Incidence and pathogenesis of aneurysmal disease of the abdominal aorla. AB - Abdominal aortic aneurysms (AAAs) are a major cause of illness and death in the United States and abroad. Along with progress in the surgical management of this condition, numerous advances have been made in understanding the pathogenesis of AAAs. Since the time of Scarpa (1804), AAA disease has been associated with, and attributed to, atherosclerotic vessel changes. Excluding patients with Marfan's Syndrome and Ehlers-Danlos type IV diseases, virtually all human AAA specimens contain some degree of atherosclerosis. However, atherosclerotic changes are associated with diverse arteriopathies (ie, aorto-occlusive disease versus AAAs). Over the last 25 years, considerable research has been performed comparing aneurysmal, occlusive, and normal aortae. AAA disease is a unique process with pathogenic mechanisms that may operate independently of atherosclerosis. In this chapter we discuss the incidence of AAA as well as its pathogenesis concerning genetics, molecular biology, biochemistry, and immunology. PMID- 21319107 TI - Cardiac transplantation and mechanical assistance. AB - The era of human heart transplantation began in 1967 by Dr. Christian Barnard in South Africa. Unfortunately, most patients died within the first year after transplantation from rejection or opportunistic infection, and the procedure was abandoned in all but a few centers. With the dedicated work of Dr. Norman Shumway from Stanford University, advances in immunosuppression and improved detection and management of rejection allowed heart transplantation to evolve from a laboratory curiosity into a clinical reality. Finally, with the introduction of the immunosuppressant, Cyclosporin A (CyA), in the 1980s the number of cardiac transplants being performed increased exponentially. Heart transplantation has entered the mainstream of surgical management of congestive heart failure and approximately 2000 procedures are performed annually in the United States and 3000 worldwide. PMID- 21319108 TI - Cardiac valve replacement surgery: prostheses and technological considerations. AB - Cardiac valve replacement surgery has advanced considerably over the past 20 years with suitable choices of mechanical prostheses and bioprostheses as valvular substitutes. The extensive developments over the past three decades have been introduced to reduce or eliminate valve related complications, namely thromboembolism, anticoagulant related hemorrhage, and structural failure as well as to optimize hemodynamic performance. The mechanical prostheses have been developed to eliminate structural failure, to facilitate prevention of blood status and thrombus formation, to facilitate intraoperative leaflet positioning and to facilitate radiopacity for evaluation of prosthesis function. The biological valvular prostheses, namely porcine aortic or bovine pericardium, have been developed with tissue preservation, together with stent designs, that contribute to preservation of anatomical characteristics and biomechanical properties of the leaflets. The implantation of the various present generation bioprostheses and mechanical prostheses requires special considerations to support ventricular performance and avoid technical complications. PMID- 21319109 TI - Stented drafts for the treatment of arterial vascular disease. AB - Vascular surgery has evolved considerably over the past 100 years from a specialty that offered patients only palliative procedures to treat significant vascular diseases to a field centered on the diagnosis and correction of vascular disorders. Aortic and peripheral artery aneurysms were once medical problems rarely diagnosed and frequently fatal. Diffuse, occlusive arterial disease secondary to atherosclerosis frequently resulted in limb gangrene or specific end organ ischemia. Modern vascular therapy has dramatically reduced the incidence of primary limb amputations and significantly decreased the risk of fatal complication of arterial aneurysm rupture. PMID- 21319110 TI - Endovascular repair of abdominal aortic aneurysms and other arterial lesions. AB - The diagnosis of abdominal aortic aneurysm (AAA) has been established with increasing frequency during the past two decades. Although AAA may cause distal embolization, rupture remains the most common and deadly complication. For nearly 40 years, elective replacement with a synthetic graft has proved to be the most appropriate method to prevent AAA rupture, and it has been associated with a postoperative mortality rate of less than 5% at most medical centers. Nonfatal complications occur with some regularity, irrespective of the setting in which the operation is performed. Increasingly, vascular surgeons are encountering older patients with severe comorbid medical conditions that can increase operative morbidity and may significantly elevate mortality. This, in turn, can increase operative morbidity and may significantly elevate mortality for aortic surgery. An alternative form of treatment such as induction of aneurysm thrombosis generally has been abandoned despite preliminary reports ofinitial success. PMID- 21319111 TI - Angioscopy. AB - Angiography currently is the principle diagnostic test for evaluation of the vasculature. Though this invasive radiologic procedure demonstrates vascular anatomy and areas of narrowing and blockage, it does not define the specific cause of the occlusion. This limitation may inhibit the appropriate treatment of vascular disease. Recently, a variety of endovascular tools designed for the treatment of specific disorders have been developed, such as lytic therapy for thrombotic occlusions, lasers for fibrotic occlusions, and atherectomy catheters for calcific atherosclerotic occlusions. For effective use of these tools, the specific cause of a vascular lesion must be determined. Angioscopy can enhance the use of these innovative therapies by providing a real-time panoramic view of the lumen, which permits both the diagnosis of luminal irregularities and visual guidance of specific luminal therapy. PMID- 21319112 TI - Administration of the vascular laboratory: headaches for the 1990s. AB - As has been the case in many fields in medicine, noninvasive vascular testing techniques originated in research projects to provide more exact definition of normal and abnormal physiology. Early tests were cumbersome to perform, due in part to the lack of dedicated equipment. The introduction of Doppler ultrasound technology in the late 1960s expanded the horizon for vascular testing. By the early 1970s, vascular testing had moved out of the research laboratory into the clinical arena. Dedicated noninvasive laboratories were established within hospital settings as well as part of office practices. The addition of duplex scanning greatly enhanced the capability of noninvasive laboratories and contributed further to growth of noninvasive testing. By the end of the decade, the vascular laboratories were well established across the country. The 1980s saw a great increase in the number of vascular laboratories, as well as the number of tests performed. There appeared to be unrestricted potential for growth and, unfortunately, increasing examples of abuse were encountered. As could be expected, excesses did not remain unchallenged and increasing restrictions were placed on the vascular laboratories, primarily in the areas of payment policy and levels of reimbursement. PMID- 21319113 TI - Carotid Endarterectomy without Angiography. AB - Each new technique for achieving and clarifying the diagnosis of arterial disease has stimulated an effort to establish its value as a tool for guiding surgical intervention. Noninvasive studies such as oculoplethysmography (OPG), phonoangiography, Doppler ultrasound spectral analysis, B-scan ultrasound, duplex ultrasound, computed tomographic (CT) scanning, magnetic resonance imaging (MRI), and transcranial Doppler have been seductive because these tools require no invasion of the. body or the artery of interest and are, therefore, eminently safe. PMID- 21319114 TI - Chronic venous insufficiency. AB - Chronic venous insufficiency has been known as a distinct pathologic entity at least since the time of Hippocrates, yet many pathologic features of this common ailment remain obscure. A recent resurgence of investigative effort in chronic venous insufficiency has occurred, spurred by the development of valve reconstruction surgery. The advent of newer diagnostic devices and techniques such as duplex scan and air plethysmography allow for a more detailed examination of the venous system than was possible previously. PMID- 21319115 TI - Inferior vena cava filters for prevention of pulmonary embolism. AB - Thromboembolism from a venous source continues to be of clinical significance with an annual incidence of 300,000 to 600,000 cases. These episodes of pulmonary embolism result in at least 50,000 deaths per year despite the use of effective prophylaxis and availability of noninvasive techniques to establish early diagnosis and treatment of thrombotic events. The main treatment modality continues to be effective anticoagulation, but this treatment may fail to control thromboembolism in 5% to 10% of patients, and anticoagulants have been associated with a mortality rate of up to 15%. PMID- 21319116 TI - Elective vascular surgery without transfusion. AB - Although blood transfusion has helped make major vascular surgery possible, it has done so at a potential cost to our patients. Allogeneic red cell transfusions subject patients to the risks of transfusion reactions, disease transmission, and immunomodulation. These risks can be avoided in the majority of our patients through a better understanding of transfusion practices and the use of multiple alternatives to allogeneic blood. PMID- 21319117 TI - No access surgery: the gamma knife. AB - Swedish neurosurgeon Lars Leksell, frustrated by the invasiveness of existing surgical tools and the morbidity some neurosurgical patients endured, created the field of stereotactic radiosurgery in 1951. He subsequently pioneered the development of the dedicated multi-source Cobalt 60 Gamma Knife. During the 27 year interval from its first clinical use in 1967 to its latest application in 1994, single fraction, closed skull irradiation of deep intracranial targets has been performed in more than 20,000 patients worldwide. The goals of radiosurgery are obliteration or prevention of further growth of the target coupled with reduced patient risk in comparison to more invasive procedures. PMID- 21319118 TI - Human brain drafting: an approach to the treatment of neurodegenerative diseases. AB - The aim of human brain grafting is to deliver adequate amounts of endocrine or neural tissue to neurodegenerated areas of the diseased or lesioned brain for functional recovery. The many options available make brain grafting and other neural grafting procedures potentially applicable for the treatment of varied alterations of the central nervous system, such as Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease, epilepsy, amyotrophic lateral sclerosis, spinal cord lesions, assorted traumatic lesions to the central nervous system, stroke, etc. PMID- 21319119 TI - Minimal invasive procedures in neurosurgery. AB - Ever since surgery was introduced for the treatment of neurological diseases, miniaturized approaches have been considered and developed in order to limit trauma of vital and delicate structures of the central nervous system. Thus, the application of stereotactic techniques and endoscopy date back to the beginning of this century. Stereotactic neurosurgery started with the goal of reaching target areas in the brain through a burrhole and then to guide (by the aid of landmarks on the bony skull and its radiographic image) small instruments such as needles and biopsy forceps. Moreover, ventriculograms with contrast material were used as guides to calculate coordinates for a 3-dimensional guiding-system within the brain. Coordinates for the brain's interior structures had to be taken from a theoretical average human brain as shown in a stereotactic brain atlas. PMID- 21319120 TI - Videoscopic plastic surgery. AB - Efforts to explore the cavities of the human body date back to Hippocrates, who pioneered "endoscopic" procedures by performing rectoscopy. The following 2400 years brought tremendous technical advances and an understanding of normal and abnormal human anatomy and physiology. In this century, organ transplantation, microsurgery, and most recently fetal surgery have stepped out of the realm of science fiction and into reality. PMID- 21319121 TI - Reconstruction of Severe Breast Deformities following Conservative Cancer Surgery and Radiation Therapy with a Latissimus Dorsi Myocutaneous Flap. AB - Conservative surgery of selected breast-cancer tumors up to 4 cm in size gives rise to equivalent overall survival rates in both retrospective and randomized chmcal trials. Although 90 percent of patients display satisfactory functional and cosmetic results when surgery is performed by highly competent teams, the remaining 10 percent end up with severe breast deformities due to factors such as inappropriate selection of patients, poor surgical techniques, postradiation fibrosis and scar contractures. These patients also suffer from painful, hard, edematous breasts. Severe breast deformities are always associated with malpositioning and distortion of the nipple-areola complex. Significant contour abnormalities, characterized by retraction and depression, may hinder reconstruction by the plastic surgeon if the patient wishes to retain the residual breast. PMID- 21319122 TI - Twenty years in brachial plexus surgery. AB - Brachial plexus surgery has been performed since the first half of our century, but initially the procedure was a rudimentary technique. Results were very poor, in fact, because of insufficient knowledge of the anatomy of the brachial plexus, of the pathophysiology of nerve regeneration and because of inadequate means of diagnosis and lack of modern sophisticated surgical equipment. Because of the poor results, a group of outstanding orthopedic surgeons wrote, in the sixties, an official agreement stating that brachial plexus surgery was useless and should be abandoned. Nevertheless, even though obstetrical palsies were on the decline due to the increase in Cesarean sections, the need for brachial plexus surgery was on the rise with the dramatic increase in the number of car and motorcycle accidents. PMID- 21319123 TI - The role of constraint in contemporary modular knee designs. AB - The current success of total knee arthroplasty (TKA) as a solution for arthritic problems about the knee is reflected in the increasing number of these procedures. The 1992 annual hospital discharge summaries indicate approximately 160,000 TKAs were performed in the United States for both primary and revision indications. Clinical success of TKA is rooted in a refined appreciation of patient habitus, technical proficiency and implant design. The understanding of this integrated triad has evolved over the past two decades. The evolution of knee implant design reflects recognition of the principle that implant geometry, acting in concert with surrounding soft tissues, determines the joint stability, range of motion and implant/bone interface forces. Interchangeable plateau geometries associated with modular designs, represent a recent development which permit an optimization of these interactions for a specific patient pathology. This paper describes a comparative evaluation of the geometrical constraint offered by six primary modular knee systems and describes their clinical applicability. PMID- 21319124 TI - Technical considerations in difficult primary total hip arthroplasty. AB - Total joint replacement has become one of the more common orthopaedic operations, with approximately 240,000 major joint arthroplasties performed annually in the United States, a large percentage of these being of the hip. The vast majority of hip replacements are for the diagnosis of degenerative arthritis and are performed in patients greater than 60 years of age. Less commonly the procedure is performed for other diagnoses (eg, developmental disorders of the hip, inflammatory arthritis, and post-traumatic arthritis) and in younger patients. Each of these diagnoses are associated with unique characteristics posing an array of technical challenges for the surgeon. The purpose of this manuscript is to highlight the more common of these processes with emphasis on the technical difficulties encountered when reconstructing these hips. PMID- 21319125 TI - Anatomical reconstruction of the anterior cruciate ligament with a patellar tendon autograft using a miniarthrotomy technique. AB - Looking at the drawings in Hey Groves pioneering (1920) description of cruciate ligament reconstruction, it is obvious that what the author had in mind was insertion of the anterior cruciate ligament (ACL) at the anatomical attachment sites, even though he did not make that point in so many words. Palmer was the first to stress the importance of precise drill-hole placement in 1938, and to design his own drill guide to obtain this precision. And only in the last 10 years have the biomechanical principles of accurate cruciate reconstruction been established. The term "isometry" was coined to express the need for a near constant distance between the femoral and tibial attachments of the substitute ligament throughout the range of knee movement. In practice, however, ideal isometry is impossible to achieve, and length variations of up to 2mm are often acceptable. Both the anterior and the posterior cruciate ligament are made up of several bundles, with each bundle consisting of a large number of fibrils (Figure 1a, b). There is no point in the range of movement, including full extension, at which all the ACL fibers would be taut; throughout the range, some fibers will be tense, while others will be slack. The greater part of the stress is taken by the anteromedial bundle; these are the fibers that are tense in full extension. This is why Friederich. et al. recommend ACL reconstruction with drill holes within the proximal and distal attachments of the native anteromedial bundle. Hefzy, et al. tried to determine the factors that affect the region of most isometric femoral attachments of the ACL. They noted that there is no completely isometric attachment. Kentsch and Muller described for the first time a technique for replacing both the anteromedial and the posterolateral bundle using a split patellar tendon graft. One strip would be positioned over the top, the other through a transcondylar tunnel. However, this technique is very difficult and time-consuming. PMID- 21319126 TI - Endoscopic ACL Reconstruction - Mitek Anchor Surgical Technique. AB - Techniques for the repair and reconstruction of the anterior cruciate ligament (ACL) have advanced rapidly in the last decade. The procedure for ACL reconstruction and its equipment have become progressively sophisticated from what was once an open surgery requiring dislocation of the patella to the point where ACL reconstruction surgery can now be performed endoscopically through one small incision. By avoiding a superior / lateral incision through the quadriceps muscle, the endoscopic technique provides the advantages of reduced soft tissue morbidity, reduced pain and improved cosmetic appearance for the patient, and reduced costs due to the fact that the procedure can be performed on an outpatient basis. However, the success of the procedure in restoring normal stability and function to the knee is still based on the variables of graft type, placement, tension, and fixation, as well as postoperative rehabilitation. Numerous studies have provided valuable information regarding advancements in the surgical technique and rehabilitation for ACL reconstruction surgery. Regardless, variable success rates continue to be reported. For failures occurring within the first six months after surgery, graft fixation failure has been shown to be the major cause. PMID- 21319127 TI - Lumbar spinal fusion: advantages of posterior lumbar interbody fusion. AB - From its inception in 1911, the topic of spinal fusion has seemingly been shrouded in controversy. In that year, Dr. Russell Hibbs performed the first human spinal fusion on a patient with spinal tuberculosis. This spawned a debate over the procedure that led to the denial of Hibbs' membership to the American Orthopedic Association. The procedure (and Hibbs' appointment to the AOA) was validated by the Association after ten years of debate. The debate over spinal fusions is manifold to this date. The literature is replete with differing opinions regarding the indications, techniques and outcomes of spinal fusions. The topic is further compounded by the fact that the specifics of a spinal fusion are often distinct to the area of the spine fused. PMID- 21319128 TI - A new bone anchor for re-attachment of soft tissue and management of fractures and dislocations. AB - The attachment of soft tissue to bone is a problem in orthopedic surgery. Over the last one hundred years several methods have been used. The earliest method involved drilling a hole in the bone, pulling the tendon through the hole and sewing the tendon onto itself. While this worked on tendon transfers, it did not work particularly well around the knee, shoulder and the ankle where there are large areas of cancellous bone and the tissue to be reattached is ligamentous and is less well-defined than a tendon. The second method was to split the periosteum, prepare a trough in the bone, and sew the tendon or the soft tissue directly into the periosteum. This method requires long immobilization of the joint, and while it does work, the immobilization often leads to arthrofibrosis. Staples, nails, tacks, and other devices have been used to attach soft tissue with various degrees of success. PMID- 21319129 TI - Early cannulation prosthetic graft (FlixeneTM) for arteriovenous access. AB - PURPOSE: Preferred hemodialysis (HD) access is an autologous fistula. Vascular grafts are used in patients with vessels unsuitable to accomplish an arteriovenous fistula (AVF). It is recommended that most current grafts mature in situ for 2-3 weeks before being accessed. Graft complications occur because the structure was not designed for the trauma of repeated cannulation. This study graft has a different structure that enables early use. Its design minimizes weeping through the graft walls and is meant to endure repeated access, thus minimizing the use of HD catheters. The purpose of this study was to show that the FlixeneTM graft can be safely placed in patients where fistulas have failed and can be cannulated in 24-72 hr, while maintaining patency rates similar to other polytetrafluoroethylene (PTFE) grafts on the market. FlixeneTM configuration should also reduce the incidence of pseudoaneurysms and seromas. METHODS: A prospective two-center study placed 33 grafts in 33 patients; graft efficacy, post-operative complications, and patency were evaluated. Ease of cannulation and dialysis center complications related to early cannulation were documented. Six month follow-up data was analyzed. RESULTS: Successful access was achieved in all 33 patients within 72 hr (29 patients within 24 hr). Overall primary patency at 6 months was 49%; primary-assisted patency at 6 months was 80%. No pseudoaneurysms or seromas were documented at 6 months. Complications were typical of graft access. CONCLUSION: Early cannulation was successful in all patients. Primary and secondary patency rates at 6-months were equivalent to other data reported on PTFE grafts. FlixeneTM successfully prevented pseudoaneurysm and seroma formation at 6 months of prospective follow-up. This graft is a better last-resort option for patients who cannot receive a fistula, compared to double-lumen cuffed catheters. PMID- 21319130 TI - Mycophenolate mofetil in treatment of childhood steroid-resistant nephrotic syndrome. AB - INTRODUCTION: The literature on the clinical effectiveness of treatments for steroid-resistant nephrotic syndrome (SRNS) is very limited. The available evidence suggests a beneficial effect of cyclosporine on remission rates. Mycophenolate mofetil (MMF) represents a promising therapeutic alternative without nephrotoxicity. The purpose of the present study was to evaluate the efficacy and tolerance of MMF therapy in children with SRNS. METHODS: Six patients with SRNS were treated with MMF combined with oral prednisolone at a dosage of 1 mg/kg per day. The initial dosage of MMF was 600 mg/m2 per 12 hours, adjusted to maintain levels of mycophenolic acid at 2.5-5 ug/mL. The planned duration of study to assess treatment efficacy was 12 weeks. All patients had a pathological renal study. RESULTS: The treatment with MMF was started at a median age of 11 years (range 9-13). Pathological patterns were 4 patients with focal segmental glomerulosclerosis (FSGS), 1 patient with minimal change disease (MCD) and 1 patient with diffuse mesangial proliferation glomerulonephritis (DMP). Only 1 patient, who had MCD, achieved complete remission. One patient went into partial remission. However, the subgroup with no response to MMF appeared to have a reduction in proteinuria and an increase of serum albumin. There were no significant beneficial effects on the level of glomerular filtration. CONCLUSIONS: In this small, single-center study, a therapeutic response to MMF was obtained only in one third of patients. This response rate, though it is low, encourages us to use MMF in some patients who are resistant to conventional therapy for SRNS. PMID- 21319131 TI - The role of bone morphogenetic protein-5 (BMP-5) in human nephrosclerosis. AB - BACKGROUND: Bone morphogenetic protein-5 (BMP-5) has been shown to be essential for nephrogenesis. Its role in adult kidney and in patients with hypertensive nephrosclerosis is still unknown. METHODS: BMP-5 expression was evaluated by immunostaining and real-time PCR in tissue samples from normal and nephrosclerotic human kidneys. The impact of transforming growth factor-beta (TGF beta), tumor necrosis factor-alpha (TNF-alpha) and angiotensin-II (AT-II) on expression of BMP-5 and its receptors was quantified in proximal tubular cells (HK-2). Functional characteristics of BMP-5 were evaluated by testing its influence on TGF-beta-induced epithelial-to-mesenchymal transition (EMT), TNF alpha-induced apoptosis of HK-2 cells and inflammatory cell infiltration. RESULTS: BMP-5 expression was localized in tubular epithelial cells and significantly decreased in nephrosclerotic kidneys. Stimulation of HK-2 cells with TGF-beta, TNF-alpha and AT-II resulted in a significant decreased expression of BMP-5 and its receptors. BMP-5 attenuated TGF-beta-induced EMT, TNF-alpha induced apoptosis and migration of mononuclear cells. CONCLUSIONS: BMP-5 is expressed in the tubuli of adult kidneys. Its decreased expression in nephrosclerosis along with its regenerative capabilities in HK-2 cells may point to a protective role in hypertensive nephrosclerosis. PMID- 21319132 TI - Emerging strategies to preserve renal function. AB - Although there has been tremendous improvement in managing chronic kidney disease (CKD) with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in the last 15 years, CKD still progresses. Therefore, new emerging strategies are needed. The gold standard still lies with optimum renin angiotensin-aldosterone system blockade, although many questions remain about how this is best achieved, such as regarding the efficacy of combinations of ACE inhibitor and ARBs, supramaximal doses of ARBs alone and combinations of either ACE inhibitor or ARBs with direct renin inhibitors, antialdosterone agents. Other promising molecules currently being tested are endothelin receptor antagonists and glitazones. Also, the role of other current therapies being used during CKD, including statins, vitamin D and erythropoiesis-stimulating agents, will be discussed, as these may also exert nephroprotective effects. PMID- 21319133 TI - Hypertension management in chronic kidney disease: translating guidelines into daily practice. AB - BACKGROUND: Whether nephrology management improves over time achievement of blood pressure (BP) goal (<130/<80 mm Hg) in nondialysis CKD is still ill-defined. This historical cohort analysis evaluated the relationship between 1-year nephrology management and BP control in 275 incident CKD patients in an academic renal clinic. METHODS: Comparative analysis between referral and month-12 visit. RESULTS: Estimated glomerular filtration rate (GFR) was 42.1 +/- 15.5 ml/min per 1.73 m2 and median proteinuria 0.20 g/24 hours. From baseline to month-12 visit, BP decreased from 148 +/- 23 / 81 +/- 12 mm Hg to 136 +/- 18 / 76 +/- 11 mm Hg, with BP goal prevalence increasing from 13.8% to 33.8%. We stratified patients into at-goal and not-at-goal on the basis of month-12 BP levels. Regression analysis identified diabetes (odds ratio [OR] = 1.96; 95% confidence interval [95% CI], 1.07-3.56) and basal systolic BP (OR=1.12; 95% CI, 1.03-1.21) as independent predictors of not-at-goal BP. The decrease in systolic/diastolic BP was smaller in not-at-goal versus at-goal patients (-7/3 mm Hg vs. -21/9 mm Hg); in not-at-goal reduction was, however, significant versus baseline (p<0.001) and coupled with a similar decline in proteinuria (p<0.001). CONCLUSIONS: Sustained nephrology management improves hypertension control in CKD, but achievement of BP goals remains suboptimal, with high systolic BP and diabetes being the main problems. Further studies are needed to verify the clinical significance of BP and proteinuria changes in patients whose BP remains above target levels. PMID- 21319134 TI - Evaluation of serum human telomerase reverse transcriptase as a novel marker for cervical cancer. AB - Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of human telomerase and its rate-limiting component. The purpose of the present study was to investigate the diagnostic value of hTERT in serum of cervical cancer patients. Preoperative values of hTERT, squamous cell carcinoma antigen (SCC-ag) and cancer antigen 125 (CA 125) were measured by enzyme-linked immunosorbent assay (ELISA) in 192 patients with squamous cell carcinoma or adenocarcinoma of the uterine cervix and 38 healthy controls. Elevated pretreatment levels of hTERT were identified in 80.2% of squamous cell carcinoma and 73.8% of adenocarcinoma patients. The expression of serum hTERT was correlated with telomerase activity in cancer tissues of both histological types. Pretreatment serum hTERT levels showed a significant correlation with clinical stage, tumor size and lymph node metastasis, but not with age. Serum hTERT measurement was found to be useful in the diagnosis and assessment of clinical stage of cervical cancer, and to be superior to the conventional tumor markers. Therefore, serum hTERT is a novel and readily available marker for cervical malignancies. PMID- 21319135 TI - Agreement in detecting glaucomatous visual field progression by using guided progression analysis ?and Humphrey overview printout. AB - PURPOSE: To examine the level of agreement among 3 clinicians in assessing glaucoma visual field progression by using 2 different methods. METHODS: Each visual field was assessed by Humphrey Field Analyzer (HFA), program SITA standard 30-2 or 24-2. In each printout the first 3 fields were excluded to minimize learning effect: the fourth and fifth full-threshold or SITA Standard examinations were used as baseline. Three clinicians assessed the progression status of each series using both HFA overview printouts and the guided progression analysis (GPA). The level of agreement among the clinicians was evaluated using a weighted kappa statistic (k). RESULTS: A total of 510 tests, comprising 83 eyes with an average of 6.1 tests each, was assessed by the 3 specialists. The mean follow-up time was 5.8 +/- 1.75 years (mean +/- standard deviation). When the intraobserver intermethod agreement was evaluated, k ranged from 0.5 to 0.7. When the interobserver agreement was analyzed, if HFA overview printouts were used, k ranged from 0.4 to 0.7. But when GPA was used, k ranged from 0.2 to 0.6. The level of agreement on progression status between the clinicians was always higher when they used HFA overview printouts (median k = 0.54) than when they used GPA (median k = 0.37). CONCLUSIONS: Agreement among expert clinicians about visual field progression status was moderate when GPA printouts were used. Clinicians' agreement about patients' visual field progression status was better when HFA overview printouts were used than with GPA printouts. PMID- 21319136 TI - Macular function in prediabetic and diabetic Omani adults: a microperimetric evaluation. AB - PURPOSE: To assess if functional visual loss preceded structural changes or vice versa in diabetic patients by evaluating the macular function in prediabetic patients and in diabetic patients with varying grades of retinopathy and comparing the findings with those of age-matched healthy controls by means of microperimetry. METHODS: Retinal sensitivity, fixation pattern, and test response were evaluated in 25 prediabetic patients (50 eyes), 25 diabetic patients (50 eyes), and 25 age-related normal nondiabetic patients (50 eyes) using Nidek microperimetry. The diabetic patients were classified into 3 groups on the basis of clinical and fundus fluorescein angiographic evidence: group 1 = no clinical or angiographic evidence of retinopathy, group 2 = background retinopathy only, group 3 = with macular edema. Classification of retinopathy was based on Early Treatment Diabetic Retinopathy Study standards. Statistical analysis was conducted by Fisher exact test. RESULTS: In diabetic patients, 20 eyes (40%) had no clinical or angiographic evidence of retinopathy, 13 eyes (26 %) had background changes, and 17 eyes (34%) had macular edema. Statistically significant difference in the fixation pattern, test response, and retinal sensitivity was noted in the diabetic and the prediabetic patients when compared to the controls. CONCLUSIONS: Significant loss of macular function in the eyes of prediabetic subjects was noted. These preliminary findings probably support the hypothesis that neurodegeneration precedes microangiopathy. PMID- 21319137 TI - Extensive submacular hemorrhage following intravitreal ranibizumab for small occult choroidal neovascular membrane. AB - PURPOSE: Although intravitreal ranibizumab represents an established therapeutic approach for exudative age-related macular degeneration (AMD), the possible occurrence of adverse events remains under ongoing research. The purpose of this report is to present an incidence of an extensive submacular hemorrhage after intravitreal ranibizumab administration. METHODS: Interventional case report. RESULTS: A 72-year-old woman was referred to our retinal department for sudden visual loss in the right eye (RE). She had undergone an intravitreal ranibizumab injection 48 hours prior to her presentation. She had known AMD with a confirmed occult choroidal neovascularization (CNV) for which she had been subjected to a total of 24 intravitreal injections in the RE (with monthly intervals) over the last 2 years. Clinical examination revealed an extensive submacular hemorrhage in the RE. CONCLUSIONS: To our knowledge, this is the first report of a submacular hemorrhage soon after ranibizumab administration in a patient with a small occult CNV. Although such a correlation cannot be established, the authors underline the possibility of such an adverse event in patients with small CNVs following a long therapeutic course involving high injection volume. PMID- 21319138 TI - Improvement in S-cone-mediated visual fields and rod function after correction of vitamin A deficiency. AB - PURPOSE: To evaluate S-cone-mediated visual fields and full-field electroretinograms (ERGs) in a patient with vitamin A deficiency. METHODS: A 65 year-old woman diagnosed with primary sclerosing cholangitis reported experiencing night blindness. The patient underwent comprehensive ophthalmic examination, including funduscopy, ERGs, Humphrey standard automated perimetry (SAP), and short-wavelength automated perimetry (SWAP). Serum vitamin A concentrations were measured. RESULTS: The patient's best-corrected visual acuity was 1.2 in both eyes. The ERG results showed no rod b-waves, reduced combined rod plus-cone responses (negative type), and normal cone and 30-Hz flicker responses. Serum vitamin A concentration was 18 IU/dL (normal range 97-316 IU/dL). The SAP mean deviation (MD) values were -1.09 dB (OD) and -0.97 dB (OS), whereas the SWAP MD values were -10.10 dB (OD) and -10.50 dB (OS). The rate of sensitivity decreased with increasing eccentricity in SWAP. Four months after starting oral administration of vitamin A, all ERG values were normalized, and SWAP MD values were greatly improved (OD -3.47 dB, OS -4.10 dB) compared with changes in SAP MD values (OD +0.67 dB, OS +0.41 dB). Rod dysfunction and impaired S-cone-mediated pathways were preferentially observed and found to be reversed after the treatment. CONCLUSIONS: The findings in this patient suggest that rods and S cones are more susceptible to vitamin A deficiency than L and M cones. Vitamin A deficiency visual impairment may therefore be reversible with appropriate therapy. PMID- 21319139 TI - Lack of effect of intraocular lens asphericity on visual performance with acrylic intraocular lenses. AB - PURPOSE: To determine whether implantation of acrylic intraocular lens (IOL) with aspheric design (Tecnis Z9003, AMO) results in improved visual acuity or contrast sensitivity compared with conventional spherical acrylic IOL (AR40e, AMO). METHODS: In an intraindividual randomized prospective study of 60 patients with bilateral cataract, the Tecnis Z9003 IOL was compared with the AR40e IOL. Ocular aberrations for a 4.0-mm pupil and 6.0-mm pupil were measured with a Hartmann Shack aberrometer. Quality of vision was measured using visual acuity and contrast sensitivity under mesopic and photopic conditions. RESULTS: Eyes with the Tecnis Z9003 IOL had significantly less spherical aberration and greater Strehl ratio after surgery, showing a better optical quality in comparison with the standard spherical IOL. However, visual acuity and both mesopic and photopic contrast sensitivity were not significantly different between the groups. CONCLUSIONS: The significantly better optical quality achieved with the aspheric acrylic IOL design did not result in improved visual acuity or contrast sensitivity in comparison with a conventional spherical acrylic IOL. PMID- 21319140 TI - Technique for autologous nasal mucosa transplantation in severe ocular surface disease. AB - PURPOSE: To describe the detailed surgical technique used for harvesting and transplantation of autologous nasal mucosa grafts for ocular surface reconstruction, to evaluate the clinical results and utility of autologous nasal mucosa grafts in ocular surface diseases. METHODS: Autologous nasal mucosa was harvested from either the middle or inferior turbinate. It was transplanted on 11 eyes with severe ocular surface diseases including 4 eyes with chemical burns, 2 eyes with thermal burns, 1 eye with Stevens-Johnson syndrome, 1 eye with erythema multiforme major, and 3 eyes with extensively recurred pterygiums. Clinical outcomes were assessed based on ocular manifestation, epithelization, and visual acuity. RESULTS: The mean follow-up period was 19.9 months (range 13-32 months). Nasal mucosal tissues were safely excised, and their mucosal harvest sites were completely healed in 2 weeks without postoperative complications. All nasal mucosa autograft survived successfully with rapid epithelization, well-developed horizontal vascularization, and abundant mucin secretion. Clinical success, intact ocular surface epithelium without epithelial erosion more than 4 weeks, was achieved in all eyes. There was no recurrence of significant ulceration, conjunctivalization, fibrovascularization, symblepharon, or pterygium. CONCLUSIONS: Goblet cell transplantation using autologous turbinate nasal mucosa presents a promising treatment method in patients with severe ocular surface disorders. PMID- 21319141 TI - Identification of a gene-expression signature for predicting lymph node metastasis in patients with early stage cervical carcinoma. AB - BACKGROUND: Pelvic lymph node metastasis (PLNM) is an important prognostic factor for patients with cervical carcinoma. The objective of this study was to identify a gene-expression signature that could predict PLNM in cervical carcinoma. METHODS: Eighty-eight women with cervical carcinoma with PLNM (n = 23) and without PLNM (n = 65) were divided randomly into a training group and a test group. An oligonucleotide microarray that contained probes for 1440 human cancer related genes was fabricated in-house and was used to detect the gene expression profile of cervical carcinoma. The gene expression levels detected in the microarray were verified by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). RESULTS: A gene-expression signature for predicting PLNM was developed in patients from the training group, including 11 genes: ribosomal protein L35 (RPL35); thymosin beta 10 (TMSB10); tyrosine 3-mono oxytenase/tryptophan 5-mono-oxygenase activation protein, zeta polypeptide (YWHAZ); biotinidase (BTD); lactate dehydrogenase A (LDHA); glucuronidase beta (GUSB); superoxide dismutase 2 (SOD2); nuclear receptor subfamily 3, group C, member 2 (NR3C2); fructosamine 3 kinase (FN3K); x-ray repair cross-complementing 4 (XRCC4); and wingless-type mouse mammary tumor virus integration site family member 2 (WNT2). In the test group, the signature's accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 91%, 90.9%, 93.9%, 83.3%, and 96.9%, respectively, for predicting PLNM. The expression levels of 5 genes in the signature were confirmed by qRT-PCR. A multivariate analysis demonstrated that patients with 11-gene high-risk scores were had a 33 fold increased risk for PLNM compared with patients who had low-risk scores. The 5-year overall and disease-free survival rates for patients who had 11-gene high risk scores were marginally significantly lower than the rates for patients who had 11-gene low-risk scores (P = .087 and P = .174, respectively). CONCLUSIONS: In this study, 11-gene signature for predicting PLNM in cervical carcinoma was identified that may help clinicians in planning therapy for patients with cervical carcinoma. PMID- 21319142 TI - FLT3 inhibitors in the treatment of acute myeloid leukemia: the start of an era? AB - Despite recent modest improvements in the chemotherapy regimens used to treat acute myeloid leukemia (AML), many patients diagnosed with AML ultimately die of the disease. Commonly occurring genetic alterations have been identified that strongly affect the prognosis for patients with AML. These alterations represent possible targets for investigational therapies that could act to specifically halt the aberrant growth of AML cells while limiting damage to normal cells. One such gene is the Fms-like tyrosine kinase 3 (FLT3) gene, which is mutated in approximately 30% of adult patients with AML and has a significant impact on prognosis. In particular, internal tandem duplications in FLT3 confer a poor prognosis to this large subgroup of patients with AML. Agents that target FLT3 are in development for the treatment of patients who have AML and offer a potential paradigm change in the current standard treatment of AML. For this report, the authors reviewed the prognostic significance of genetic alterations observed in AML with a focus on the therapeutic implications of targeting FLT3. The introduction of such agents may be the next major step toward the era of personalized therapy in AML. PMID- 21319143 TI - Prospective evaluation of spinal reirradiation by using stereotactic body radiation therapy: The University of Texas MD Anderson Cancer Center experience. AB - BACKGROUND: Stereotactic body radiotherapy for previously irradiated, progressive spinal metastases may be a viable option in selected patients. The authors review a prospective series of spinal metastasis patients reirradiated with stereotactic body radiotherapy. METHODS: A total of 59 patients with 63 tumors of the spine were reirradiated with stereotactic body radiotherapy between 2003 and 2009. Spinal magnetic resonance imaging was performed both before treatment initiation and at regular follow-up intervals. Stereotactic body radiotherapy was delivered to a peripheral dose of 30 grays (Gy) in 5 fractions (6 Gy per fraction), or 27 Gy in 3 fractions (9 Gy per fraction). The National Cancer Institute Common Toxicity Criteria 2.0 and McCormick neurological function system were used to evaluate toxicity and neurologic status, respectively. RESULTS: Mean follow-up was 17.6 months. Actuarial 1-year radiographic local control and overall survival for all patients were both 76%. Of the tumors that progressed after stereotactic body radiotherapy, 13 (81%) of 16 patients had tumors that were within 5 mm of the spinal cord, and 6 of them eventually developed spinal cord compression. Toxicity was most commonly grade 1 or 2 fatigue. Two patients experienced mild to moderate radiation injury (lumbar plexopathy) while remaining independently ambulatory and pain free. Freedom from neurologic deterioration from any cause was 92% at 1 year. CONCLUSIONS: Reirradiation for progressive spinal metastases with stereotactic body radiotherapy results in good local control and limited toxicity. Initial surgery should be considered for tumors within 5 mm of the spinal cord. Radiation dose should be tailored for tumors near or invading the psoas muscle secondary to observed risk of lumbar plexopathy. PMID- 21319145 TI - Technology impacting on biology: spine radiosurgery. PMID- 21319146 TI - Balancing the harms and benefits of early detection of prostate cancer. PMID- 21319147 TI - Effectiveness of a patient and practice-level colorectal cancer screening intervention in health plan members: the CHOICE trial. AB - BACKGROUND: Colorectal cancer (CRC) screening reduces CRC incidence and mortality but is underused. Effective interventions to increase screening that can be implemented broadly are needed. METHODS: A controlled trial was conducted to evaluate a patient-level and practice-level intervention to increase the use of recommended CRC screening tests among health plan members. The patient-level intervention was a patient decision aid and included stage-targeted brochures that were mailed to health plan members. Intervention practices received academic detailing to prepare practices to facilitate CRC testing once patients were activated by the decision aid. We used patient surveys and claims data to assess CRC test completion. RESULTS: Among 443 active participants, 75.8% were ages 52 to 59 years, 80.9% were white, 62.1% were women, and 46.4% had college degrees or greater education. Among 380 active participants with known screening status at 12 months based on survey results, 39% in the intervention group reported receiving CRC screening compared with 32.2% in the usual care group (unadjusted odds ratio [OR], 1.34; 95% confidence interval; [CI], 0.88-2.05; P = .17). After adjusting for baseline differences and accounting for clustering, the effect was somewhat larger (OR, 1.64; 95% CI, 0.98-2.73; P = .06). Claims analysis produced similar effects for active participants. The intervention was more effective in those who had incomes >$50,000 (OR, 2.16; 95% CI, 1.07-4.35) than in those who had lower incomes (OR, 1.25; 95% CI, 0.53-2.94; P = .03 for interaction). CONCLUSIONS: Interventions combining a patient-directed decision aid and practice directed academic detailing had a modest but statistically nonsignificant effect on CRC screening rates among active participants. PMID- 21319148 TI - Clinicodemographic factors influencing outcomes in patients with low-grade serous ovarian carcinoma. AB - BACKGROUND: Low-grade serous carcinoma (LGSC) of the ovary is a rare tumor that is distinct from its high-grade counterpart. The objective of this study was to determine whether patient demographic factors and clinical treatment histories affected survival in a population of women with LGSC. METHODS: A review of patients who had pathologically confirmed LGSC of the ovary diagnosed between 1977 and 2009 was performed. Abstracted data included medical and social histories, anthropometric measurements, and details about diagnosis, treatment, and follow-up. Statistical analyses included Fisher exact tests, Cox proportional hazards models, and the Kaplan-Meier method. RESULTS: The study sample included 194 patients who had a median follow-up of 60.9 months (range, 1-383 months). In multivariate analyses, smoking had a negative association with both overall survival (OS) (hazard ratio [HR], 1.73; 95% confidence interval [CI], 1.03-2.92; P = .04) and progression-free survival (PFS) (HR, 1.72; 95% CI, 1.00-2.96; P = .05). The median OS was shorter in current smokers than in former/never smokers (48.0 months vs 79.9 months; P = .002). PFS also was predicted by year of diagnosis >1994 (HR, 1.74; P = .01). Although the difference was not statistically significant, hormone consolidation appeared to be associated with better OS (HR, 0.15; P = .06) and better PFS (HR, 0.44; P = .07). A smaller proportion of the patients who received hormone consolidation experienced disease recurrence compared with the patients who did not receive hormone consolidation (66.7% vs 87.6%; P = .07). CONCLUSIONS: Smoking was associated negatively with survival outcomes in women with LGSC of the ovary, whereas consolidation treatment with hormone antagonists demonstrated a protective associative trend with survival. Both lifestyle modification and innovative treatment plans should be considered in this group of patients. PMID- 21319149 TI - Plasma Epstein-Barr virus DNA level strongly predicts survival in metastatic/recurrent nasopharyngeal carcinoma treated with palliative chemotherapy. AB - BACKGROUND: Plasma Epstein-Barr virus (EBV) DNA is widely used in screening, monitoring, and prediction of relapse in nonmetastatic nasopharyngeal carcinoma (NPC). However, data regarding utility of plasma EBV DNA in metastatic NPC are rare. The current study was to test the prognostic implication of plasma EBV DNA level in metastatic/recurrent NPC patients treated with palliative chemotherapy. METHODS: Plasma EBV DNA level was measured at baseline and thereafter at the start of each treatment cycle in 127 histologically proven metastatic/recurrent NPC patients treated with palliative chemotherapy. Correlations of pre-treatment and post-treatment plasma EBV DNA levels to survival and response were analyzed. RESULTS: Patients with a low pre-treatment plasma EBV DNA level (=median). Patients with a post-treatment plasma EBV DNA decline to an undetectable level had better survival and better tumor response compared with those with a sustained detectable post-treatment plasma EBV DNA level. The early decrease of post-treatment plasma EBV DNA to an undetectable level after 1 cycle of chemotherapy was associated with significantly increased survival. Patients with low pre-treatment plasma EBV DNA level and undetectable post-treatment plasma EBV DNA showed a favorable prognosis (5-year overall and progression-free survival of 50.6% and 21.7%, respectively). CONCLUSIONS: Plasma EBV DNA is of predictive value for prognosis in metastatic/recurrent NPC patients undergoing palliative chemotherapy. The pre-treatment plasma EBV DNA level as well as the early decrease of plasma EBV DNA after chemotherapy enabled easy and early discrimination between patients who will and those who will not benefit from continued treatment. PMID- 21319150 TI - Hypoxic regulation and prognostic value of LAMP3 expression in breast cancer. AB - BACKGROUND: LAMP3 is a newly described hypoxia regulated gene of potential interest in hypoxia-induced therapy resistance and metastasis. The prognostic value of LAMP3 in breast cancer was investigated. METHODS: Expression levels of LAMP3 in breast cancer cell lines and patient tissues were determined by real time polymerase chain reaction and in a tissue microarray by immunohistochemistry. Immunofluorescent staining was used to evaluate the distribution of LAMP3 in tumor xenografts relative to pimonidazole. Kaplan-Meier analysis as well as multivariate Cox regression survival analyses were performed. RESULTS: LAMP3 was variably expressed in breast cancer cell lines and induced in an oxygen concentration-dependent manner. LAMP3 protein expression colocalized with hypoxic areas in breast cancer xenografts. LAMP3 mRNA was higher in breast tumors from patients with node-positive (P = .019) and/or steroid hormone receptor-negative tumors (P < .001). Breast cancer patients with high LAMP3 mRNA levels had more locoregional recurrences (P = .032 log-rank). This was limited to patients treated with lumpectomy and radiotherapy as primary treatment (n = 53, P = .009). No association with metastasis-free survival was found. In multivariate Cox regression analysis, LAMP3 remained as a statistically independent prognostic factor for locoregional recurrence (hazard ratio, 2.76; 95% confidence interval, 1.01-7.5; P = .048) after correction for menopausal status, histologic grade, tumor size, nodal status, therapy, and steroid hormone receptor status. LAMP3 protein in breast cancer tissue proved also to be of prognostic relevance. CONCLUSIONS: Evidence was provided for an association of LAMP3 with tumor cell hypoxia in breast cancer xenografts. In the current breast cancer cohorts, LAMP3 had independent prognostic value. PMID- 21319151 TI - Aromatase (CYP19) promoter gene polymorphism and risk of nonviral hepatitis related hepatocellular carcinoma. AB - BACKGROUND: Experimental studies suggest that sex hormones may induce or promote the development of hepatocellular carcinoma (HCC). Androgens are converted to estrogens by the CYP19 gene product, aromatase. Hepatic aromatase level and activity have been shown to be markedly elevated in HCC. Aromatase expression in liver tumors is driven by a promoter upstream of CYP19 exon I.6. METHODS: First, the authors identified an A/C polymorphism in the exon I.6 promoter of the CYP19 gene. To determine whether allelic variants in the CYP19 I.6 promoter differ in their ability to drive gene expression, we carried out an in vitro reporter gene assay. Then, the authors studied the association between this polymorphism and HCC risk in 2 complementary case-control studies: 1 in high-risk southern Guangxi, China, and another in low-risk US non-Asians of Los Angeles County. RESULTS: Transcriptional activity was 60% higher for promoter vectors carrying the rs10459592 C allele compared with those carrying an A allele (P = .007). In both study populations, among subjects negative for at-risk serologic markers of hepatitis B or C, there was a dose-dependent association between number of high activity C allele and risk of HCC (P(trend) = .014). Risk of HCC was significantly higher (odds ratio [OR], 2.25; 95% confidence interval (CI), 1.18 4.31) in subjects homozygous for the C allele compared with those homozygous for the A allele. CONCLUSIONS: This study provides epidemiologic evidence for the role of hepatic aromatization of androgen into estrogen in the development of nonviral hepatitis-related HCC. PMID- 21319152 TI - Gastrointestinal cancer and brain metastasis: a rare and ominous sign. AB - Metastatic brain tumors represent 20% to 40% of all intracranial neoplasms and are found most frequently in association with lung cancer (50%) and breast cancer (12%). Although brain metastases occur in <4% of all tumors of the gastrointestinal (GI) tract, the incidence of GI brain metastasis is rising in part due to more effective systemic treatments and prolonged survival of patients with GI cancer. Data were collected from 25 studies (11 colorectal, 7 esophageal, 2 gastric, 1 pancreatic, 1 intestinal, 3 all-inclusive GI tract cancer) and 13 case reports (4 pancreatic, 4 gallbladder, and 5 small bowel cancer). Brain metastases are found in 1% of colorectal cancer, 1.2% of esophageal cancer, 0.62% of gastric cancer, and 0.33% of pancreatic cancer cases. Surgical resection with whole brain radiation therapy (WBRT) has been associated with the longest median survival (38.4-262 weeks) compared with surgery alone (16.4-70.8 weeks), stereotactic radiosurgery (20-38 weeks), WBRT alone (7.2-16 weeks), or steroids (4-7 weeks). Survival in patients with brain metastasis from GI cancer was found to be diminished compared with metastases arising from the breast, lung, or kidney. Prolonged survival and improvement in clinical symptoms has been found to be best achieved with surgical resection and WBRT. Although early treatment has been linked to prolonged survival and improved quality of life, brain metastases represent a late manifestation of GI cancers and remain an ominous sign. PMID- 21319153 TI - Incidence of pulmonary embolism in oncologic outpatients at a tertiary cancer center. AB - BACKGROUND: Incidence of pulmonary embolism (PE) for different cancer types in oncology outpatients is unknown. The purposes of the current study is to determine the incidence of PE in oncology outpatients and to investigate whether the incidence for PE is higher in certain cancers. METHODS: A cohort of oncology outpatients who had imaging studies at Dana-Farber Cancer Institute, a tertiary outpatient cancer institute, from January 2004 through December 2009 was identified using research patient data registry. Radiology reports were reviewed to identify patients who developed PE. Incidences of PE in the total population and in each of 16 predefined cancer groups were calculated. Risk of PE for each cancer was compared using Fisher exact test. RESULTS: A total of 13,783 patients was identified, of which 395 (2.87%; 95% confidence interval [CI], 2.59-3.16) developed PE. The incidence of PE was highest in the central nervous system ([CNS] 12.90%; 95% CI, 8.45-18.59), hepatobiliary (6.85%; 95% CI, 3.33-12.24), pancreatic (5.81%; 95% CI, 3.59-8.84), and upper gastrointestinal (5.81%; 95% CI, 3.96-8.20) malignancies. The risk of PE was significantly higher for CNS (P < .0001; odds ratio [OR], 5.28), pancreatic (P = .0027; OR, 2.15), upper gastrointestinal (P = .0002; OR, 2.18), and lung/pleural malignancies (P = .0028; OR, 1.45). There was significantly lower risk of PE for hematologic (incidence, 1.16%; 95% CI, 0.79-1.64; P < .0001; OR, 0.35) and breast malignancies (incidence, 1.50%; 95% CI, 1.02-2.11; P < .0001; OR, 0.47). CONCLUSIONS: The incidence of PE in oncology outpatients in a tertiary cancer center during a 6 year period was 2.87%. CNS, pancreatic, upper gastrointestinal, and lung/pleural malignancies had a significantly higher risk for PE than other malignancies, whereas hematologic and breast malignancies had a significantly lower risk. PMID- 21319154 TI - Prognostic markers and long-term outcomes in ductal carcinoma in situ of the breast treated with excision alone. AB - BACKGROUND: Increased use of breast cancer screening has led to an increase in the number of diagnosed cases of ductal carcinoma in situ (DCIS). However, there is no definite way to predict progression or recurrence of DCIS. We analyzed the significance of biological markers and tumor characteristics in predicting recurrence in a large series of DCIS patients with long-term follow-up treated with breast conservation surgery (BCS) alone. METHODS: Clinical and pathological data were analyzed for 141 patients who underwent BCS for DCIS. All had negative surgical margins. Using local disease recurrence as an endpoint, we sought to determine the prognostic significance of several histopathological characteristics (tumor size, presence of necrosis, and subtype) and biological markers (estrogen receptor, progesterone receptor, and Her-2/neu.) RESULTS: At a median follow-up of 122 months (maximum follow-up, 294 months), 60 recurrences occurred, with a median time to recurrence of 191 months. On multivariate analysis, Her-2 positivity (3+) was found to be significantly associated with reduced time to tumor recurrence (P = .028). Tumor size and higher grade were marginally statistically significant (P = .099, P = .070). Neither necrosis nor tumor pathological characteristics were found to be significantly related to time to disease recurrence. CONCLUSIONS: Our results suggested that status of Her 2/neu, larger tumor size, and higher nuclear grade were significantly correlated with time to tumor recurrence in patients treated with BCS alone. Using logistical analyses, no significant correlation was found between tumor pathological characteristics and disease recurrence. PMID- 21319155 TI - Knowledge, attitudes, risk perception, and cancer screening behaviors among cancer survivors. AB - BACKGROUND: Knowledge, attitudes, and risk perception in relation to second primary cancer (SPC) screening and their impact on screening practices in cancer survivors are largely unknown. METHODS: A total of 326 cancer survivors who had completed primary treatment for cancer >1 year previously were recruited from 6 oncology care outpatient clinics in the Republic of Korea. Survivors' knowledge, attitudes, perceived risk, and screening practices were assessed along with sociodemographic, behavioral, and clinical characteristics. Multivariate logistic regression was used to examine behavioral factors associated with the completion of all appropriate SPC screening according to national guidelines. RESULTS: Approximately 37.7% of survivors had undergone all appropriate SPC screening tests. Survivors were found to have a high perceived risk of SPC, high perceived benefits of screening, and positive attitudes toward cancer screening. However, they had limited knowledge regarding SPC screening tests and few had received a recommendation from a physician to undergo SPC screening. Although there was no association found between perceived risk and positive attitudes with screening behavior, higher knowledge was noted to be significantly associated with the completion of all appropriate SPC screening (adjusted odds ratio, 1.81; 95% confidence interval, 1.03-3.33). CONCLUSIONS: In the current study, cancer survivors were found to have limited knowledge regarding second cancer screening tests, which may have resulted in lower rates of completion of screening practices in this population. PMID- 21319156 TI - Association between receipt and timing of adjuvant chemotherapy and survival for patients with stage III colon cancer in Alberta, Canada. AB - BACKGROUND: Surgery followed by adjuvant chemotherapy has been standard treatment for stage III colon cancer since 1990. However, to date, clinical trials have not been conducted to determine the definitive outer time limit by which adjuvant chemotherapy should be received for optimal survival benefit. The objective of the current study was to assess the association between the receipt/timing of adjuvant chemotherapy and patient survival in clinical practice. METHODS: Residents of Alberta who were diagnosed with stage III colon adenocarcinoma in years 2000 to 2005 who underwent surgery were included in the study. Patients were identified from the Alberta Cancer Registry and were linked to hospital data and neighborhood-level socioeconomic data from the 2001 Canadian Census. Cox proportional hazards models were used to estimate hazard ratios of death according to the timing of chemotherapy. RESULTS: There were 1053 patients in the study; 648 (61%) initiated adjuvant chemotherapy within 16 weeks of surgery. There was no difference in overall survival or colon cancer-specific survival between those who received adjuvant chemotherapy from 8 to 12 weeks postsurgery compared with those who received it within 8 weeks. However, those who received chemotherapy 12 to 16 weeks after surgery and those who either received it >16 weeks after surgery or received no treatment had a 43% and 107% greater risk of dying, respectively, than those who received chemotherapy within 8 weeks of surgery (hazard ratio, 1.43 [95% confidence interval, 0.96-2.13] and hazard ratio, 2.07 [95% confidence interval, 1.56-2.76], respectively). Analyses were controlled for age, year, and region of residence at diagnosis; sex; neighborhood level socioeconomic factors; and number of comorbidities. CONCLUSIONS: The results from this study were consistent with current guideline recommendations in Alberta that patients with stage III adenocarcinoma should receive chemotherapy within 12 weeks of surgery. PMID- 21319158 TI - Local progression after radiofrequency ablation for pulmonary metastases. AB - BACKGROUND: Local treatment for pulmonary metastases is considered to be a reasonable treatment option in patients with oligometastatic disease. Percutaneous radio frequency ablation (RFA) has been reported as an alternative to surgery. Results of RFA for local control of pulmonary metastases were evaluated. METHODS: All consecutive patients treated with RFA for pulmonary metastases (2004-2009) were included. RFA was performed percutaneously under computed tomographic guidance. Follow-up was scheduled at 1, 3, and 6 months after treatment and every 6 months thereafter. Major outcome parameters were local and any-site progression, complications, and survival. RESULTS: Ninety pulmonary metastases were treated, in 46 patients at 65 sessions. Many patients had recurrent metastases after previous surgery (n = 36 of 46). Pneumothorax occurred in 34% (chest drain in 25%) and major complications in 6%. After median follow-up of 22 months (range, 2-65 months), 25 local progressions occurred after RFA; the 2-year local progression rate per lesion was 35%. Overall survival at 3 years was 69%. CONCLUSIONS: Notwithstanding its relatively low morbidity, follow up after RFA for pulmonary metastases shows a considerable rate of local progression. The role of local ablation techniques for long-term disease control in oligometastatic disease is discussed. PMID- 21319157 TI - Was race a factor in the outcomes of the Women's Health Eating and Living Study? AB - BACKGROUND: The objective of this study was to determine whether women who were participating in the Women's Healthy Eating and Living (WHEL) Study exhibited similar dietary changes, second breast cancer events, and overall survival regardless of race/ethnicity. METHODS: For this secondary analysis, the authors used data from 3013 women who were self-identified as Asian American, African American, Hispanic, or white and who were assigned randomly to a dietary intervention or a comparison group. Changes in dietary intake over time by race/ethnicity and intervention status were examined using linear mixed-effects models. Cox proportional hazards models were used to examine the effects of the intervention on the occurrence of second breast cancer events and overall survival. Statistical tests were 2-sided. RESULTS: African Americans and Hispanics consumed significantly more calories from fat (+3.2%) and less fruit ( 0.7 servings daily) than Asians and whites at baseline (all P < .01). Overall, intervention participants significantly improved their dietary pattern from baseline to the end of Year 1, reducing calories from fat by 4.9% and increasing intake of fiber (+6.6 grams daily), fruit (+1.1 servings daily), and vegetables (+1.6 servings daily; all P < .05). Despite improvements in the overall dietary pattern of these survivors, the intervention did not significantly influence second breast cancer events or overall survival. CONCLUSIONS: Overall, all racial groups significantly improved their dietary pattern over time, but the maintenance of these behaviors were lower among African-American women. More research and larger minority samples are needed to determine the specific factors that improve breast cancer-specific outcomes in diverse populations of survivors. PMID- 21319161 TI - Examining the impact of excipient material property variation on drug product quality attributes: a quality-by-design study for a roller compacted, immediate release tablet. AB - A quality-by-design study examining the impact of variability in excipient material properties on the quality attributes of an immediate release tablet was performed. A literature review and risk analysis identified particle size of microcrystalline cellulose (MCC), spray-dried lactose (SDL), and magnesium stearate (MgSt), and polymorph and specific surface area of MgSt as potential high-risk material properties. The following results were obtained with laboratory-scale processing equipment: (1) a 32-um increase in d(50) (mean particle diameter) of MCC and SDL led to a ~ 30-um increase in blend and granulation d(50) and a statistically significant increase in the blend and granulation flow function coefficients, and (2) a 32-um increase in d(50) of MCC and SDL, a 4.4 m(2)/g increase in the surface area, and a 19-um decrease in the particle size of MgSt yielded an 18%-28% increase in ribbon tensile strength and tablet hardness. Confirmatory experiments with kilo-scale equipment showed impact of excipient variability on granulation particle size and tablet hardness was ~ 50% smaller. Although the impact of these differences on overall manufacturability and performance of the tablets examined here were deemed low, the presence of statistically significant effects supports examining excipient variability as part of the design and control strategy of new drug products. PMID- 21319162 TI - Transdermal evaporation delivery system of praziquantel for schistosomiasis japonicum chemotherapy. AB - A transdermal evaporation delivery system (TEDS) of praziquantel (PZQ) was developed by selecting ethylene glycol monophenyl ether as a nonvolatile component solvent and ethanol as a volatile component solvent to control efficiently the transmission and morbidity of the global schistosomiasis, providing a convenient administration system of PZQ for both humans and domestic animals. The solubility of PZQ in TEDS was more than 400 mg/mL when the ethanol concentration was 50% (w/w) in the solvent mixture at 32 degrees C, enabling to adapt requirements for the treatment of schistosomiasis. The highest serum drug concentration reached 35.93 ug/mL after transdermal administration of TEDS of PZQ in rabbits, being 6.3-fold higher than that after oral administration at the same dose. The TEDS of PZQ achieved treatment efficacy with the worm reduction of 100% when it was applied in the experimental treatment of Schistosoma japonicum in rabbits. The TEDS of PZQ that provides passive and nonocclusive delivery, having the inexpensive cost, low skin irritation rates, and precise dose of administration, should find application in the transmission control and chemotherapy of global schistosomiasis. PMID- 21319163 TI - Decrease of liposomal size and retarding effect on fluconazole skin permeation by lysine derivatives. AB - Liposomes are ideal dermal drug delivery systems because of their ability to alter the biodistribution profile of incorporated drugs. In a novel approach to optimize the liposomal microstructure, lysine derivatives were employed. The effect of the oligopeptides Lys-5 and Lys-7 on the structure as well as on the skin permeation of the antimycotic drug fluconazole in 1,2-dipalmitoyl-sn-glycero 3-phosphocholine vesicles was studied using a variety of techniques. It was demonstrated by addition of the shift reagent praseodymium(III)chloride and subsequent (31)P NMR measurements that the liposomes produced consisted mainly of unilamellar vesicles. This was confirmed by cryo-transmission electron microscopy. The addition of Lys-5 and Lys-7 induced a structural change resulting in a decrease in particle size between 10% and 40% and a retarding effect on fluconazole skin permeation. PMID- 21319164 TI - Evaluation of the effect of syringe surfaces on protein formulations. AB - Packaging of drugs in prefillable syringes offers considerable advantages over conventional vials. Almost all major biotech molecules are available on the market today in prefilled syringes, and are safe and efficacious. Newer high concentration liquid formulations, especially fusion proteins, however, can suffer from instability in prefilled syringes due to syringe components like silicone oil. To assess the effect of siliconized and modified syringe surfaces on protein formulations, the stability of the recombinant protective antigen (rPA) for anthrax, abatacept, a fusion protein formulation with known silicone oil sensitivity, and an antistaphylococcal enterotoxin B (anti-SEB) monoclonal antibody (mAb) was assessed in siliconized, uncoated, and BD-42-coated (a proprietary coating developed by BD Technologies) prefilled syringes under different conditions. Both the soluble protein content and the number of subvisible particles were followed over time. When filled in siliconized syringes, all three protein solutions showed increased number of subvisible particles relative to uncoated or BD-42-coated syringes; the abatacept formulation with known silicone sensitivity also developed visible particles. Although rPA and anti-SEB mAb formulations mainly showed individual droplets, presumably of silicone, the abatacept formulation also showed droplets entangled in a fibrous structure. Uncoated glass and BD-42-coated syringes considerably reduced the formation of both visible and subvisible particles after immediate contact and after agitation. The anti-SEB mAb also adhered as a thin layer to the siliconized surface after agitation, irrespective of storage temperature. The development of visible particles could not be correlated with the loss of soluble protein fraction at protein concentrations above 4 mg/mL. It appears that protein formulations interact differently with different surfaces. The BD-42 coating appears to be a promising solution for packaging silicone-sensitive proteins in prefillable syringes and needs to be investigated further. It is demonstrated that BD-42 provides an inert surface with adequate lubrication while limiting the formation of visible and subvisible particles. It is hypothesized that these particles are formed due to the release of silicone droplets in the solution and result in the formation of silicone-induced visible aggregates. PMID- 21319165 TI - Short-term unilateral resistance training affects the agonist-antagonist but not the force-agonist activation relationship. AB - In this study we investigated the contribution of neural adaptations to strength changes after 4 weeks of unilateral isometric resistance training. Maximal and submaximal isometric knee extension contractions were assessed before and after training. Surface electromyography (EMG) data were collected from the agonist and antagonist muscles and normalized to evoked maximal M-wave and maximal knee flexor EMG, respectively. The interpolated twitch technique (ITT) was also used to determine activation at maximum voluntary force (MVF). MVF increased in the trained (+20%) and untrained (+8%) legs. Agonist EMG at MVF increased in the trained leg (+26%), although activation determined via the ITT was unchanged. In both legs the position of the force-agonist EMG relationship was unchanged, but antagonist coactivation was lower for all levels of agonist activation. Strength gains in the trained leg were due to enhanced agonist activation, whereas decreased coactivation may have affected strength changes in both legs. PMID- 21319166 TI - Upper leg conduction time distinguishes demyelinating neuropathies. AB - BACKGROUND: The objective of this study was to determine whether differentiation between demyelinating and axonal neuropathies could be enhanced by comparing conduction time changes in defined segments of the total peripheral nerve pathway. METHODS: Compound muscle action potentials (CMAPs) were elicited by cathodal stimulation of the tibial nerve at the ankle and popliteal fossa, and by paravertebral neuromagnetic stimulation at proximal and distal cauda equina while recording from muscles of the foot, shin, and thigh. Segmental conduction times were calculated in normal subjects; in patients with lumbosacral radiculopathy, distal symmetric diabetic neuropathy, amyotrophic lateral sclerosis, acute and chronic inflammatory demyelinating polyneuropathy; and in patients with anti myelin-associated glycoprotein, myelomatous, and Charcot-Marie-Tooth type 1a polyneuropathies. RESULTS: Distal cauda equina latency and CMAP duration and segmental conduction times in upper leg and cauda equina facilitated differentiation of demyelinating from axonal neuropathies, even in the presence of a range of reduced amplitude CMAPs. CONCLUSIONS: Within the demyelinating neuropathy spectrum, it was further possible to distinguish subtypes. PMID- 21319167 TI - Evaluation of muscles affected by myositis using magnetic resonance elastography. AB - INTRODUCTION: Idiopathic inflammatory myopathies (IIMs, or myositis) represent a group of autoimmune diseases that result in decreased muscle strength and/or endurance. Non-invasive tools to assess muscle may improve our understanding of the clinical and functional consequences of myopathies and their response to treatment. In this study we examine magnetic resonance elastography (MRE), a non invasive technique that assesses the shear modulus (stiffness) of muscle, in IIM subjects. METHODS: Nine subjects with active myositis completed the MRE protocol. Participants lay in a positioning device, and scans of the vastus medialis (VM) were taken in the relaxed state and at two contraction levels. Manual inversion was used to estimate the stiffness. RESULTS: A significant reduction in muscle stiffness was seen in myositis subjects compared with healthy controls during the "relaxed" condition. DISCUSSION: The use of non-invasive technologies such as MRE may provide greater understanding of the pathophysiology of IIM and improve assessment of treatment efficacy. PMID- 21319168 TI - Prognostic indicators from electrodiagnostic studies for ulnar neuropathy at the elbow. AB - INTRODUCTION: We examined the prognostic value of electrodiagnostic (EDX) studies for ulnar neuropathy at the elbow (UNE). METHODS: In this retrospective study, EDX results were compared with subjective recovery (resolution of symptoms) and surgery in patients diagnosed with UNE. RESULTS: Of the 193 patients, 59 with "definite" UNE were included in the analysis. The combination of conduction block across the elbow to the first dorsal interosseous (FDI) and normal distal compound muscle action potential (CMAP) amplitude from the abductor digiti minimi (ADM) was strongly associated with recovery: 86% of these subjects achieved full subjective recovery compared to only 7% without conduction block and with an abnormal CMAP. There were no EDX predictors of surgery. CONCLUSION: EDX results contain useful prognostic information in UNE. PMID- 21319169 TI - Amyloid neuropathy in a younger domino liver transplanted recipient. PMID- 21319170 TI - The dissertation manuscript option, internet posting, and publication. PMID- 21319171 TI - Prevalence and spectrum of coronary artery anomalies in patients with an isolated congenital left ventricular aneurysm or diverticulum. AB - BACKGROUND: Congenital left ventricular aneurysm (LVA) and diverticulum (LVD) are rare cardiac anomalies and frequently associated with other cardiac anomalies. The objective of our study was to investigate the prevalence and the spectrum of coronary anomalies in such patients. HYPOTHESIS: The incidence of coronary anomalies is increased in patients with LVA or LVD. METHODS: We assessed 117 patients with isolated LVA or LVD for the prevalence of coronary anomalies and compared the findings with an age- and sex-matched control group (n = 117) without the diagnosis of LVA or LVD. RESULTS: Coronary anomalies were present in 58.1% of the study population (68 of 117). The median age of affected patients was 64 years, and 45 (38.5%) were male. Coronary anomalies were more prevalent in patients with LVA or LVD (58.1% vs 6.8%, P < 0.001), male patients (89% vs 57%, P = 0.0002), and in patients with nonapical location of LVA or LVD (24% vs 45%, P = 0.02) compared with control, whereas age and type (LVA vs LVD) had no influence (57% vs 57.6%, P = 0.4; and 58.8% vs 57.6%, P = 0.87, respectively). The number of adverse cardiac events was similar in both groups during a 4.2-year follow-up period (29% vs 19%, P = 0.09). None of the patients in our series had major coronary anomalies with potential lethal consequences. CONCLUSIONS: This large single-center study suggests that the prevalence of abnormal coronary-artery anatomy in patients with isolated LVA or LVD is as high as 58.1%. However, we did not identify major coronary anomalies with potential lethal consequences, and the clinical course during follow-up was not influenced by the presence or absence of coronary anomalies. PMID- 21319172 TI - Mental health and sleep in permanent atrial fibrillation patients from the general population. AB - BACKGROUND: Anxiety and depression has been found in atrial fibrillation (AF) patients referred to secondary care. Little is known about the level of such distress in AF patients from the general population. HYPOTHESIS: Permanent AF patients from the general population might have more anxiety, depression, and sleep impairment than subjects in sinus rhythm. METHODS: Patients with permanent AF and controls in sinus rhythm were recruited from a 75-year-old cohort from 2 Norwegian municipalities. The main outcome variables were anxiety and depression, measured by the Hospital Anxiety and Depression Scale (HADS) and sleep quality measured by Pittsburgh Sleep Quality Index (PSQI) score. Short Form 36 (SF-36) was also completed. RESULTS: Twenty-seven patients with permanent AF and 71 subjects in sinus rhythm participated. No significant score differences were found between AF patients and controls for HADS anxiety (median, inter quartile range, 3 [1, 5] vs 4 [1, 6]; HADS depression, 3 [1,6] vs 2 [1,4]; and PSQI 6 [3, 11] vs 5 [4, 8]). AF patients had significantly poorer scores for SF-36 physical functioning, physical role, general health, vitality, and social functioning compared to subjects in sinus rhythm. CONCLUSIONS: Elderly permanent AF patients from the general population had similar levels of anxiety, depression, and sleep quality, despite poorer physical health-related quality of life compared to controls in sinus rhythm. Copyright (c) 2011 Wiley Periodicals, Inc. This work was supported by unrestricted grants from the governmental Health Region South East, Norway, and from the Stein Erik Hagen Foundation for Clinical Heart Research, Norway. The authors have no other funding, financial relationships, or conflicts of interest to disclose. PMID- 21319173 TI - Cellular analysis by open-source software for affordable cytometry. AB - Image cytometry is an important technique in affordable healthcare and cellular research. Some efforts toward establishing a personal, low-cost cytometer have been described in the literature. However, a self-assembled fluorescence microscope requires software for cytometric analysis. There are some open-source image-based software analysis applications available. However, for a quantitative analysis of images, software that can generate data comparable to those of previously evaluated cytometric analyses programs is required. Hence, the aim of this study is to compare results of a commercially available image cytometry program to data obtained using the open-source software CellProfiler (CP). Leukocytes and fluorescent bead images obtained using a Laser Scanning Cytometer were analyzed by CP and the results compared with those of conventional cytometric analyses' programs. Algorithms were developed enabling the analysis of leukocytes and beads by CP. CP provided similar results to those obtained by the cytometer software. Hallmark parameters, including cell count and fluorescence intensity, revealed a high correlation in the analysis of both programs. Therefore, CP is appropriate for cellular analysis on a self-assembled microscope, thereby enabling affordable cytometry. PMID- 21319174 TI - The extract of the jellyfish Phyllorhiza punctata promotes neurotoxic effects. AB - Phyllorhiza punctata (P. punctata) is a jellyfish native to the southwestern Pacific. Herewith we present the biochemical and pharmacological characterization of an extract of the tentacles of P. punctata. The tentacles were subjected to three freeze-thaw cycles, homogenized, ultrafiltered, precipitated, centrifuged and lyophilized to obtain a crude extract (PHY-N). Paralytic shellfish poisoning compounds such as saxitoxin, gonyautoxin-4, tetrodotoxin and brevetoxin-2, as well as several secretory phospholipase A(2) were identified. PHY-N was tested on autonomic and somatic neuromuscular preparations. In mouse vas deferens, PHY-N induced phasic contractions that reached a peak of 234 +/- 34.7% of control twitch height, which were blocked with either 100 MU m of phentolamine or 1 m m of lidocaine. In mouse corpora cavernosa, PHY-N evoked a relaxation response, which was blocked with either L-N(G) -Nitroarginine methyl ester (0.5 m m) or 1 m m of lidocaine. PHY-N (1, 3 and 10 MUg ml(-1) ) induced an increase in tonus of the biventer-cervicis neuromuscular preparation that was blocked with pre treatment of galamine (10 MU m). Administration of 6 mg kg(-1) PHY-N intramuscularly produced death in broilers by spastic paralysis. In conclusion, PHY-N induces nerve depolarization and nonspecifically increases neurotransmitter release. PMID- 21319175 TI - Malformation spectrum induced by ketoconazole after single administration to pregnant rats during the critical period - comparison with vitamin A-induced malformation spectrum. AB - Azole derivatives have teratogenic effects in rodents. In the present study, malformations and their sensitive windows induced by high-dose ketoconazole (KCZ), an azole derivative, without maternal toxicity were investigated. In addition, the malformation spectrum determined was compared with that induced by vitamin A palmitate (VAP). Pregnant rats were administered a single dose of KCZ by oral gavage on specific individual days from gestational days 8 to 15 (GDs 8 15). Maternal animals were subjected to necropsy on GD 20, and the obtained fetuses were examined for external, visceral and skeletal malformations. The malformation spectrum of VAP was identified from available published data (Noda, Sato, and Udaka, 1982) and a complementary study (single administration of VAP at 1 200 000 IU kg(-1) ). Embryonic lethality was observed in dams given KCZ on GDs 9-12 with peak incidence on GDs 10 and 11 with complete resorption. KCZ induced major malformations included cleft palate, digital anomalies, misshapen limbs and unique discontinuous ribs, and the sensitive window for each was identified. Compared with the malformations induced by VAP, unique malformations (e.g. discontinuous ribs by KCZ, neural tube defects by VAP), similar malformations with similar sensitive windows (e.g. digital and limb malformations) and similar malformations with different sensitive windows (e.g. embryonic lethality and cleft palate) were distinguished, suggesting that the mechanisms of several of the types of KCZ-induced malformation are related to excessive vitamin A. PMID- 21319176 TI - Toxicological effect of emodin in mouse testicular gene expression profile. AB - Emodin (1,3,8-trihydroxy-6-methyl-anthraquinone) is a herbal medicine extracted from the rhizomes of Rheum palmatum, and is known as an inhibitor of casein kinase II (CK2). The CK2alpha' knockout mice are known to be male-infertile; however, there have been no reports on the toxicity of emodin in male reproductive organs/tissues. To evaluate the toxicological effects of emodin on differential gene expression profiles of the testis as compared with acrylamide, mice were orally administered emodin and acrylamide for 5 days at a dose of 1000 and 50 mg kg(-1) per day, respectively, and euthanized 24 h after the final administration. Both chemicals induced hypospermatogenesis, eosinophilic change and apoptosis of germ cell. A DNA microarray analysis showed that the IGF-1 receptor signaling was most closely related to the above testicular toxicity induced by emodin, and the RhoA regulation, TGF/WNT and cytoskeletal remodeling, TNFR1 signaling and adenosine A2A receptor signaling were commonly associated with the two chemicals. We selected 36 genes associated with CK2, apoptosis and spermatogenesis and determined their expression by quantitative reverse transcription-polymerase chain reaction (qPCR). Both chemicals perturbed the expression of genes associated with CK2. Genes related to spermatogenesis were also affected, as evidenced by hypospermatogenesis, and eosinophilic change and apoptosis of germ cell. The results suggest that emodin causes testicular toxicity, including apoptosis with related the IGF-1 receptor signaling pathway, and the two chemicals commonly affect CK2, spermatogenesis and sperm motility via four pathways, such as TNFR1 signaling. PMID- 21319177 TI - Investigation of anticholinergic and non-steroidal anti-inflammatory prodrugs which reduce chemically induced skin inflammation. AB - As part of a continuous effort to develop efficient counter measures against sulfur mustard injuries, several unique NSAID prodrugs have been developed and screened for anti-inflammatory properties. Presented herein are three classes of prodrugs which dually target inflammation and cholinergic dysfunction. Compounds 1-28 contain common NSAIDs linked either to choline bioisosteres or to structural analogs of acetylcholinesterase (AChE) inhibitors. These agents have shown utility as anti-vesicants and anti-inflammatory agents when screened in a mouse ear vesicant model (MEVM) against both 2-chloroethyl ethyl sulfide (CEES), a blistering agent, and 12-O-tetradecanoylphorbol-13-acetate (TPA), a common topical irritant. Many of the prodrugs have activity against CEES, with 5, 18, 22 and 27 reducing inflammation by more than 75% compared with a control. Compounds 12, 13, 15 and 22 show comparable activity against TPA. Promising activity in the MEVM is related to half-lives of NSAID release in plasma, moderate to high lipophilicity, and some degree of inhibition of AChE, a potential contributor to sulfur mustard-mediated tissue damage. PMID- 21319180 TI - A battle over brains: neonatal maturity hypothesis or grey ceiling for explaining brain size in mammals? PMID- 21319183 TI - Neonatal maturity as the key to understanding brain size evolution in homeothermic vertebrates. PMID- 21319184 TI - Molecular mechanisms of interspecies transmission and pathogenicity of influenza viruses: Lessons from the 2009 pandemic. AB - The emergence of the 2009 H1N1 virus pandemic was unexpected, since it had been predicted that the next pandemic would be caused by subtype H5N1. We also had to learn that a pandemic does not necessarily require the introduction of a new virus subtype into the human population, but that it may result from antigenic shift within the same subtype. The new variant was derived from human and animal viruses by genetic reassortment in the pig, supporting the concept that this animal is the mixing vessel for the generation of new human influenza viruses. Although it is generally believed that the 2009 outbreak was mild, there have been severe cases particularly among the young and the middle-aged. Pathogenicity and host range are determined to a large extent by the polymerase, the haemagglutinin and the NS1 protein of influenza A viruses. There is evidence that mutations of these proteins may change the pathogenicity of the new virus. PMID- 21319185 TI - Transcription factors regulating the progression of monocot and dicot seed development. AB - Seed development in this paper has been classified into the three landmark stages of cell division, organ initiation and maturation, based on morphological changes, and the available literature. The entire process proceeds at the behest of an interplay of various specific and general transcription factors (TFs). Monocots and dicots utilize overlapping, as well as distinct, TF networks during the process of seed development. The known TFs in rice and Arabidopsis have been chronologically categorized into the three stages. The main regulators of seed development contain B3 or HAP3 domains. These interact with bZIP and AP2 TFs. Other TFs that play an indispensable role during the process contain homeobox-, NAC-, MYB-, or ARF-domains. This paper is a comprehensive analysis of the TFs essential for seed development and their interactions. An understanding of this interplay will not only help unravel an integrated developmental process, but will also pave the way for biotechnological applications. PMID- 21319186 TI - Up-regulation of the fibroblast growth factor 8 subfamily in human hepatocellular carcinoma for cell survival and neoangiogenesis. AB - Fibroblast growth factors (FGFs) and their high-affinity receptors [fibroblast growth factor receptors (FGFRs)] contribute to autocrine and paracrine growth stimulation in several non-liver cancer entities. Here we report that at least one member of the FGF8 subfamily (FGF8, FGF17, and FGF18) was up-regulated in 59% of 34 human hepatocellular carcinoma (HCC) samples that we investigated. The levels of the corresponding receptors (FGFR2, FGFR3, and FGFR4) were also elevated in the great majority of the HCC cases. Overall, 82% of the HCC cases showed overexpression of at least one FGF and/or FGFR. The functional implications of the deregulated FGF/FGFR system were investigated by the simulation of an insufficient blood supply. When HCC-1.2, HepG2, or Hep3B cells were subjected to serum withdrawal or the hypoxia-mimetic drug deferoxamine mesylate, the expression of FGF8 subfamily members increased dramatically. In the serum-starved cells, the incidence of apoptosis was elevated, whereas the addition of FGF8, FGF17, or FGF18 impaired apoptosis, which was associated with phosphorylation of extracellular signal-regulated kinase 1/2 and ribosomal protein S6. In contrast, down-modulation of FGF18 by small interfering RNA (siRNA) significantly reduced the viability of the hepatocarcinoma cells. siRNA targeting FGF18 also impaired the cells' potential to form clones at a low cell density or in soft agar. With respect to the tumor microenvironment, FGF17 and FGF18 stimulated the growth of HCC-derived myofibroblasts, and FGF8, FGF17, and FGF18 induced the proliferation and tube formation of hepatic endothelial cells. CONCLUSION: FGF8, FGF17, and FGF18 are involved in autocrine and paracrine signaling in HCC and enhance the survival of tumor cells under stress conditions, malignant behavior, and neoangiogenesis. Thus, the FGF8 subfamily supports the development and progression of hepatocellular malignancy. PMID- 21319187 TI - Enrichment of Nur77 mediated by retinoic acid receptor beta leads to apoptosis of human hepatocellular carcinoma cells induced by fenretinide and histone deacetylase inhibitors. AB - The synthetic retinoid fenretinide is one of the most promising clinically tested retinoids. Previously, we have shown that fenretinide induces apoptosis of Huh7 cells, but HepG2 cells are relatively resistant to fenretinide-induced apoptosis. This study examines the interactive role of fenretinide and histone deacetylase inhibitors (HDACi) in inducing apoptosis of human hepatocellular carcinoma (HCC) cells and the underlying mechanism. Trichostatin A and scriptaid can either enhance fenretinide-induced apoptosis in the fenretinide sensitive HCC cells (Huh7 and Hep3B) or sensitize the fenretinide resistant cells (HepG2) to become sensitive to the apoptotic effect of fenretinide in a cancer cell-specific manner. The sensitivity of cells to fenretinide-induced apoptosis was not associated with reactive oxygen species production nor with antioxidant gene expression. However, the level of retinoic acid receptor beta (RARbeta) and Nur77 (NR4A1) was important for inducing apoptosis. Upon fenretinide and HDACi treatment, the expression of RARbeta and Nur77 were induced and colocalized in the cytosol. The induction of Nur77 protein level, but not the messenger RNA level, was RARbeta-dependent. In addition, RARbeta interacted with Nur77. Nur77 was essential for fenretinide-induced and HDACi-induced apoptosis of Huh7 cells. Induction of the expression, the interaction, and the nuclear export of RARbeta and Nur77 mediate fenretinide-induced and HDACi-induced apoptosis. CONCLUSION: Our findings suggest that targeting Nur77 and RARbeta simultaneously provides an effective way to induce HCC cell death. PMID- 21319188 TI - Concerted action of sulfiredoxin and peroxiredoxin I protects against alcohol induced oxidative injury in mouse liver. AB - Peroxiredoxins (Prxs) are peroxidases that catalyze the reduction of reactive oxygen species (ROS). The active site cysteine residue of members of the 2-Cys Prx subgroup (Prx I to IV) of Prxs is hyperoxidized to cysteine sulfinic acid (Cys-SO(2) ) during catalysis with concomitant loss of peroxidase activity. Reactivation of the hyperoxidized Prx is catalyzed by sulfiredoxin (Srx). Ethanol consumption induces the accumulation of cytochrome P450 2E1 (CYP2E1), a major contributor to ethanol-induced ROS production in the liver. We now show that chronic ethanol feeding markedly increased the expression of Srx in the liver of mice in a largely Nrf2-dependent manner. Among Prx I to IV, only Prx I was found to be hyperoxidized in the liver of ethanol-fed wildtype mice, and the level of Prx I-SO(2) increased to ~30% to 50% of total Prx I in the liver of ethanol-fed Srx(-/-) mice. This result suggests that Prx I is the most active 2-Cys Prx in elimination of ROS from the liver of ethanol-fed mice and that, despite the up regulation of Srx expression by ethanol, the capacity of Srx is not sufficient to counteract the hyperoxidation of Prx I that occurs during ROS reduction. A protease protection assay revealed that a large fraction of Prx I is located together with CYP2E1 at the cytosolic side of the endoplasmic reticulum membrane. The selective role of Prx I in ROS removal is thus likely attributable to the proximity of Prx I and CYP2E1. CONCLUSION: The pivotal functions of Srx and Prx I in protection of the liver in ethanol-fed mice was evident from the severe oxidative damage observed in mice lacking either Srx or Prx I. PMID- 21319189 TI - Performance of the aspartate aminotransferase-to-platelet ratio index for the staging of hepatitis C-related fibrosis: an updated meta-analysis. AB - The aspartate aminotransferase-to-platelet ratio index (APRI), a tool with limited expense and widespread availability, is a promising noninvasive alternative to liver biopsy for detecting hepatic fibrosis. The objective of this study was to update the 2007 meta-analysis to systematically assess the accuracy of APRI in predicting significant fibrosis, severe fibrosis, and cirrhosis stage in hepatitis C virus (HCV) monoinfected and HCV / human immunodeficiency virus (HIV) coinfected individuals. Studies comparing APRI versus biopsy in HCV patients were identified via a thorough literature search. Areas under summary receiver operating characteristic curves (AUROC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were used to examine the APRI accuracy for the diagnosis of significant fibrosis, severe fibrosis, and cirrhosis. Heterogeneity was explored using meta-regression. Twenty one additional studies were eligible for the update and, in total, 40 studies were included in this review (n = 8,739). The summary AUROC of the APRI for the diagnosis of significant fibrosis, severe fibrosis, and cirrhosis were 0.77, 0.80, and 0.83, respectively. For significant fibrosis, an APRI threshold of 0.7 was 77% sensitive and 72% specific. For severe fibrosis, a threshold of 1.0 was 61% sensitive and 64% specific. For cirrhosis, a threshold of 1.0 was 76% sensitive and 72% specific. Moreover, we found that the APRI was less accurate for the identification of significant fibrosis, severe fibrosis, and cirrhosis in HIV/HCV coinfected patients. CONCLUSION: Our large meta-analysis suggests that APRI can identify hepatitis C-related fibrosis with a moderate degree of accuracy. Application of this index may decrease the need for staging liver biopsy specimens among chronic hepatitis C patients. PMID- 21319190 TI - DNA hypomethylation causes bile duct defects in zebrafish and is a distinguishing feature of infantile biliary atresia. AB - Infantile cholestatic disorders arise in the context of progressively developing intrahepatic bile ducts. Biliary atresia (BA), a progressive fibroinflammatory disorder of extra- and intrahepatic bile ducts, is the most common identifiable cause of infantile cholestasis and the leading indication for liver transplantation in children. The etiology of BA is unclear, and although there is some evidence for viral, toxic, and complex genetic causes, the exclusive occurrence of BA during a period of biliary growth and remodeling suggests an importance of developmental factors. Interestingly, interferon-gamma (IFN-gamma) signaling is activated in patients and in the frequently utilized rhesus rotavirus mouse model of BA, and is thought to play a key mechanistic role. Here we demonstrate intrahepatic biliary defects and up-regulated hepatic expression of IFN-gamma pathway genes caused by genetic or pharmacological inhibition of DNA methylation in zebrafish larvae. Biliary defects elicited by inhibition of DNA methylation were reversed by treatment with glucocorticoid, suggesting that the activation of inflammatory pathways was critical. DNA methylation was significantly reduced in bile duct cells from BA patients compared to patients with other infantile cholestatic disorders, thereby establishing a possible etiologic link between decreased DNA methylation, activation of IFN-gamma signaling, and biliary defects in patients. CONCLUSION: Inhibition of DNA methylation leads to biliary defects and activation of IFN-gamma-responsive genes, thus sharing features with BA, which we determine to be associated with DNA hypomethylation. We propose epigenetic activation of IFN-gamma signaling as a common etiologic mechanism of intrahepatic bile duct defects in BA. PMID- 21319192 TI - Loss of histone acetyltransferase cofactor transformation/transcription domain associated protein impairs liver regeneration after toxic injury. AB - Organ regeneration after toxin challenge or physical injury requires a prompt and balanced cell-proliferative response; a well-orchestrated cascade of gene expression is needed to regulate transcription factors and proteins involved in cell cycle progression and cell proliferation. After liver injury, cell cycle entry and progression of hepatocytes are believed to require concerted efforts of transcription factors and histone-modifying activities; however, the actual underlying mechanisms remain largely unknown. The purpose of our study was to investigate the role of the histone acetyltransferase (HAT) cofactor transformation/transcription domain-associated protein (TRRAP) and histone acetylation in the regulation of cell cycle and liver regeneration. To accomplish our purpose, we used a TRRAP conditional knockout mouse model combined with toxin induced hepatic injury. After we treated the mice with a carbon tetrachloride toxin, conditional ablation of the TRRAP gene in those mice severely impaired liver regeneration and compromised cell cycle entry and progression of hepatocytes. Furthermore, loss of TRRAP impaired the induction of early and late cyclins in regenerating livers by compromising histone acetylation and transcription factor binding at the promoters of the cyclin genes. Our results demonstrate that TRRAP and TRRAP/HAT-mediated acetylation play an important role in liver regeneration after toxic injury and provide insight into the mechanism by which TRRAP/HATs orchestrate the expression of the cyclin genes during cell cycle entry and progression. PMID- 21319191 TI - Overexpression of cholesterol 7alpha-hydroxylase promotes hepatic bile acid synthesis and secretion and maintains cholesterol homeostasis. AB - We reported previously that mice overexpressing cytochrome P450 7a1 (Cyp7a1; Cyp7a1-tg mice) are protected against high fat diet-induced hypercholesterolemia, obesity, and insulin resistance. Here, we investigated the underlying mechanism of bile acid signaling in maintaining cholesterol homeostasis in Cyp7a1-tg mice. Cyp7a1-tg mice had two-fold higher Cyp7a1 activity and bile acid pool than did wild-type mice. Gallbladder bile acid composition changed from predominantly cholic acid (57%) in wild-type to chenodeoxycholic acid (54%) in Cyp7a1-tg mice. Cyp7a1-tg mice had higher biliary and fecal cholesterol and bile acid secretion rates than did wild-type mice. Surprisingly, hepatic de novo cholesterol synthesis was markedly induced in Cyp7a1-tg mice but intestine fractional cholesterol absorption in Cyp7a1-tg mice remained the same as wild-type mice despite the presence of increased intestine bile acids. Interestingly, hepatic but not intestinal expression of several cholesterol (adenosine triphosphate binding cassette G5/G8 [ABCG5/G8], scavenger receptor class B, member 1) and bile acid (ABCB11) transporters were significantly induced in Cyp7a1-tg mice. Treatment of mouse or human hepatocytes with a farnesoid X receptor (FXR) agonist GW4064 or bile acids induced hepatic Abcg5/g8 expression. A functional FXR binding site was identified in the Abcg5 gene promoter. Study of tissue-specific Fxr knockout mice demonstrated that loss of the Fxr gene in the liver attenuated bile acid induction of hepatic Abcg5/g8 and gallbladder cholesterol content, suggesting a role of FXR in the regulation of cholesterol transport. CONCLUSION: This study revealed a new mechanism by which increased Cyp7a1 activity expands the hydrophobic bile acid pool, stimulating hepatic cholesterol synthesis and biliary cholesterol secretion without increasing intestinal cholesterol absorption. This study demonstrated that Cyp7a1 plays a critical role in maintaining cholesterol homeostasis and underscores the importance of bile acid signaling in regulating overall cholesterol homeostasis. PMID- 21319193 TI - Risk assessment of hepatitis B virus-related hepatocellular carcinoma development using liver stiffness measurement (FibroScan). AB - Liver stiffness measurement (LSM) using FibroScan accurately assesses the degree of liver fibrosis and the risk of hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C. This study investigated the usefulness of LSM as a predictor of HCC development in patients with chronic hepatitis B (CHB). A total of 1,130 patients with non-biopsy-proven CHB who underwent LSM between May 2005 and December 2007 were enrolled in this prospective study. After LSM was performed, patients attended regular follow-up as part of a surveillance program for the detection of HCC. The mean age of the patients (767 men, 363 women) was 50.2 years, and the median LSM was 7.7 kPa. Six hundred seventy-two (59.5%) patients received antiviral treatment before or after enrollment. During the follow-up period (median, 30.7 months; range, 24.0-50.9 months), HCC developed in 57 patients (2.0% per 1 person-year). The 1-, 2-, and 3-year cumulative incidence rates of HCC were 0.80%, 3.26%, and 5.98%, respectively. On multivariate analysis, together with old age, male sex, heavy alcohol consumption (>80 g/day), serum albumin, and hepatitis B e antigen positivity, patients with a higher LSM (>8 kPa) were at a significantly greater risk of HCC development, with the following hazard ratios: 3.07 (95% confidence interval [CI], 1.01-9.31; P = 0.047) for LSM 8.1-13 kPa; 4.68 (95% CI, 1.40-15.64; P = 0.012) for LSM 13.1-18 kPa; 5.55 (95% CI, 1.53-20.04; P = 0.009) for LSM 18.1-23 kPa; and 6.60 (95% CI, 1.83-23.84; P = 0.004) for LSM >23 kPa. CONCLUSION: Our data suggest that LSM could be a useful predictor of HCC development in patients with CHB. PMID- 21319194 TI - Epithelial cell adhesion molecule (EpCAM) marks hepatocytes newly derived from stem/progenitor cells in humans. AB - Epithelial cell adhesion molecule (EpCAM) is a surface marker on human hepatic stem/progenitor cells that is reported as absent on mature hepatocytes. However, it has also been noted that in cirrhotic livers of diverse causes, many hepatocytes have EpCAM surface expression; this may represent aberrant EpCAM expression in injured hepatocytes or, as we now hypothesize, persistence of EpCAM in hepatocytes that have recently derived from hepatobiliary progenitors. To evaluate this concept, we investigated patterns of EpCAM expression in hepatobiliary cell compartments of liver biopsy specimens from patients with all stages of chronic hepatitis B and C, studying proliferation, senescence and telomere lengths. We found that EpCAM(+) hepatocytes were rare in early stages of disease, became increasingly prominent in later stages in parallel with the emergence of ductular reactions, and were consistently arrayed around the periphery of cords of keratin 19(+) hepatobiliary cells of the ductular reaction, with which they shared EpCAM expression. Proliferating cell nuclear antigen (proliferation marker) and p21 (senescence marker) were both higher in hepatocytes in cirrhosis than in normal livers, but ductular reaction hepatobiliary cells had the highest proliferation rate, in keeping with being stem/progenitor cell-derived transit amplifying cells. Telomere lengths in EpCAM(+) hepatocytes in cirrhosis were higher than EpCAM(-) hepatocytes (P < 0.046), and relatively shorter than those in the corresponding ductular reaction hepatobiliary cells (P = 0.057). CONCLUSION: These morphologic, topographic, immunophenotypic, and molecular data support the concept that EpCAM(+) hepatocytes in chronic viral hepatitis are recent progeny of the hepatobiliary stem/progenitor cell compartment through intermediates of the transit amplifying, ductular reaction hepatobiliary cells. PMID- 21319195 TI - Patatin-like phospholipase domain-containing 3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C. AB - Steatosis has been reported to negatively influence the natural history of chronic hepatitis C (CHC), but controversy remains over its causal role due to the confounding effect of adiposity, insulin resistance, and diabetes. The rs738409 C>G patatin-like phospholipase domain-containing 3 (PNPLA3) single nucleotide polymorphism (SNP), encoding for the I148M protein variant, influences liver fat without affecting insulin resistance and body composition. The aim of this study was to evaluate the effect of the rs738409 CG genotype on liver fat and fibrosis in CHC patients. We also explored the possible effect of PNPLA3 genotype on other steatosis-related complications, namely, treatment failure and hepatocellular carcinoma (HCC) development. To this end we considered two independent series of 325 and 494 CHC patients with available DNA and liver biopsy followed at tertiary referral centers in northern Italy. The rs738409 genotype was determined by a Taqman assay. The rs738409 GG genotype, observed in 10% of patients, was associated with steatosis independently of age, sex, body mass index (BMI), diabetes, alcohol intake, and viral genotype (odds ratio [OR] 1.90, 95% confidence interval [CI] 1.4-2.7; P < 0.001). The association with rs738409 genotype was confirmed for severe steatosis, was independent of alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) values, and was observed in all viral genotypes but the 3. The rs738409 GG genotype was associated with fibrosis stage and cirrhosis (OR 1.47, 95% CI 1.2-1.9; P = 0.002), treatment response (n = 470; OR 0.63, 95% CI 0.4-0.8; P = 0.006), and HCC occurrence (n = 325; OR 2.16, 95% CI 1.3-3.6; P = 0.002), independently of confounders. CONCLUSION: The rs738409 PNPLA3 genotype influences steatosis development in CHC and is independently associated with cirrhosis and other steatosis-related clinical outcomes, such as lack of response to antiviral treatment and possibly HCC. PMID- 21319196 TI - Paired box gene 5 is a novel tumor suppressor in hepatocellular carcinoma through interaction with p53 signaling pathway. AB - The paired box 5 (PAX5) is a member of PAX transcription factors family involved in the regulation of embryonic development. However, the role of PAX5 in carcinogenesis is largely unclear. We identified that PAX5 is involved in human cancer by methylation-sensitive representational difference analysis. We examined the biological functions and related molecular mechanisms of PAX5 in hepatocellular carcinoma (HCC). Promoter methylation of PAX5 was evaluated by methylation-specific polymerase chain reaction (PCR) and bisulfite genomic sequencing (BGS). The functions of ectopic PAX5 expression were determined by viability assay, colony formation, and cell cycle analyses, along with in vivo tumorigenicity assays. The PAX5 target signal pathway was identified by promoter luciferase assay, chromosome immunoprecipitation (ChIP), and pathway PCR array. PAX5 is expressed in normal human liver tissue, but silenced or down-regulated in 83% (10/12) of HCC cell lines. The mean expression level of PAX5 was significantly lower in primary HCCs as compared to their adjacent normal tissues (P < 0.0001). The promoter methylation contributes to the inactivation of PAX5. Restoring PAX5 expression in silenced HCC cell lines suppressed cell proliferation, induced apoptosis in vitro, and inhibited tumor growth in nude mice (P < 0.0001). The pathway luciferase reporter assay indicated that PAX5 activated p53 and p21 signaling. ChIP analysis demonstrated that PAX5 directly bound to the p53 promoter. The antitumorigenic function of PAX5 was at least up regulated by p53 and its downstream targets including tumor necrosis factor, Fas ligand, leucine-rich repeats, and death domain-containing, poly(rC) binding protein 4, p21, and growth arrest and DNA-damage-inducible alpha. CONCLUSION: PAX5 is frequently inactivated by promoter methylation in HCC. PAX5 appears to be a functional tumor suppressor involved in liver carcinogenesis through direct regulation of the p53 signaling pathway. PMID- 21319197 TI - MicroRNA-492 is processed from the keratin 19 gene and up-regulated in metastatic hepatoblastoma. AB - MicroRNAs (miRNAs) are well-known regulators of proliferation, apoptosis, and differentiation and are recognized to play an important role in the development of cancers. Here we aimed to identify the functional contribution of miRNAs to the biology of hepatoblastoma (HB), the most common malignant liver tumor in childhood. As overexpression of the oncogene PLAG1 (pleomorphic adenoma gene 1) is a characteristic phenomenon in HB, we used RNA interference and subsequent miRNA array analysis to identify miR-492 as most strongly influenced by PLAG1. We provide novel experimental evidence that miR-492 can originate from the coding sequence of the HB marker gene keratin 19 (KRT19). In agreement with these in vitro observations, significantly elevated levels of coexpressed KRT19 and miR 492 were particularly found in metastatic HB tumor samples. Stable overexpression of miR-492 in HB cell clones served to identify a broad range of differentially expressed transcripts, including several candidate targets of miR-492 predicted by computational algorithms. Among those the liver enzyme BAAT showed significant association with miR-492 expression in HB tumor samples. CONCLUSION: A close functional relationship between KRT19 and miR-492 was identified that may play an important role in the progression of malignant embryonal liver tumors. Additionally, miR-492 and its associated targets might serve as new HB biomarkers of clinical utility and could assist to explore targeted therapies, especially in metastatic HB with a poor prognosis. PMID- 21319199 TI - Insurance status and treatment candidacy of hepatitis C patients: analysis of population-based data from the United States. AB - Successful treatment with antiviral therapy could potentially reduce morbidity and mortality in patients with hepatitis C virus (HCV) infection. However, at the population level, these benefits may be offset by a limited number of patients who have access to antiviral treatment. Using data from the National Health and Nutrition Examination Survey conducted in 2005-2008, we analyzed the health insurance status and treatment candidacy of HCV-positive (HCV+) individuals. A total of 10,582 subjects were examined; of those, 1.16% had detectable HCV RNA and were defined as HCV+. The HCV+ patients were less likely to be insured than HCV-negative individuals (61.2% versus 81.2%; P = 0.004). Among those with health insurance, HCV+ patients were less likely to have private insurance, whereas the coverage by Medicare/Medicaid and other government-sponsored plans was similar to the rest of the population. In multivariate analysis, HCV infection was an independent predictor of being uninsured even after adjustment for demographic disparity of the HCV+ cohort (odds ratio, 0.43; 95% confidence interval, 0.24 0.78). Of all HCV+ patients, 66.7% were eligible for anti-HCV treatment. However, only 54.3% of HCV+ treatment candidates had any type of insurance coverage. Finally, only 36.3% of HCV+ patients were potentially eligible for treatment and had health insurance. CONCLUSION: A high proportion of HCV+ patients are currently uninsured, and many have publicly funded health insurance. Among those who could be candidates for treatment, the rate of insurance coverage is even lower. These findings can have important implications for health insurance coverage of these patients under the new health care reform legislation in the United States. PMID- 21319198 TI - Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings. AB - The diagnosis of nonalcoholic steatohepatitis (NASH) is defined by the presence and pattern of specific histological abnormalities on liver biopsy. A separate system of scoring the features of nonalcoholic fatty liver disease (NAFLD) called the NAFLD Activity Score (NAS) was developed as a tool to measure changes in NAFLD during therapeutic trials. However, some studies have used threshold values of the NAS, specifically NAS >=5, as a surrogate for the histologic diagnosis of NASH. To evaluate whether this unintended use of the NAS is valid, biopsy and clinical data from the 976 adults in NASH Clinical Research Network (CRN) studies were reviewed. Biopsies were evaluated centrally by the NASH CRN Pathology Committee. Definite steatohepatitis (SH) was diagnosed in 58.1%, borderline SH in 19.5% and "not SH" in 22%. The NAS was >=5 in 50% and <=4 in 49%; in this cohort only 75% of biopsies with definite SH had an NAS >=5, whereas 28% of borderline SH and 7% of "not SH" biopsies had NAS >=5. Of biopsies with an NAS >=5, 86% had SH and 3% "not SH". NAS <=4 did not indicate benign histology; 29% had SH and only 42% had "not SH." Higher values of the NAS were associated with higher levels of alanine aminotransferase and aspartate aminotransferase, whereas the diagnosis of SH was associated with features of the metabolic syndrome. CONCLUSION: The diagnosis of definite SH or the absence of SH based on evaluation of patterns as well as individual lesions on liver biopsies does not always correlate with threshold values of the semiquantitative NAS. Clinical trials and observational studies should take these different performance characteristics into account. PMID- 21319200 TI - HepaRG cells: a human model to study mechanisms of acetaminophen hepatotoxicity. AB - Acetaminophen (APAP) overdose is the leading cause of acute liver failure in Western countries. In the last four decades much progress has been made in our understanding of APAP-induced liver injury through rodent studies. However, some differences exist in the time course of injury between rodents and humans. To study the mechanism of APAP hepatotoxicity in humans, a human-relevant in vitro system is needed. Here we present evidence that the cell line HepaRG is a useful human model for the study of APAP-induced liver injury. Exposure of HepaRG cells to APAP at several concentrations resulted in glutathione depletion, APAP-protein adduct formation, mitochondrial oxidant stress and peroxynitrite formation, mitochondrial dysfunction (assessed by JC-1 fluorescence), and lactate dehydrogenase (LDH) release. Importantly, the time course of LDH release resembled the increase in plasma aminotransferase activity seen in humans following APAP overdose. Based on propidium iodide uptake and cell morphology, the majority of the injury occurred within clusters of hepatocyte-like cells. The progression of injury in these cells involved mitochondrial reactive oxygen and reactive nitrogen formation. APAP did not increase caspase activity above untreated control values and a pancaspase inhibitor did not protect against APAP induced cell injury. CONCLUSION: These data suggest that key mechanistic features of APAP-induced cell death are the same in human HepaRG cells, rodent in vivo models, and primary cultured mouse hepatocytes. Thus, HepaRG cells are a useful model to study mechanisms of APAP hepatotoxicity in humans. PMID- 21319201 TI - Molecular therapy for obesity and diabetes based on a long-term increase in hepatic fatty-acid oxidation. AB - Obesity-induced insulin resistance is associated with both ectopic lipid deposition and chronic, low-grade adipose tissue inflammation. Despite their excess fat, obese individuals show lower fatty-acid oxidation (FAO) rates. This has raised the question of whether burning off the excess fat could improve the obese metabolic phenotype. Here we used human-safe nonimmunoreactive adeno associated viruses (AAV) to mediate long-term hepatic gene transfer of carnitine palmitoyltransferase 1A (CPT1A), the key enzyme in fatty-acid beta-oxidation, or its permanently active mutant form CPT1AM, to high-fat diet-treated and genetically obese mice. High-fat diet CPT1A- and, to a greater extent, CPT1AM expressing mice showed an enhanced hepatic FAO which resulted in increased production of CO(2) , adenosine triphosphate, and ketone bodies. Notably, the increase in hepatic FAO not only reduced liver triacylglyceride content, inflammation, and reactive oxygen species levels but also systemically affected a decrease in epididymal adipose tissue weight and inflammation and improved insulin signaling in liver, adipose tissue, and muscle. Obesity-induced weight gain, increase in fasting blood glucose and insulin levels, and augmented expression of gluconeogenic genes were restored to normal only 3 months after AAV treatment. Thus, CPT1A- and, to a greater extent, CPT1AM-expressing mice were protected against obesity-induced weight gain, hepatic steatosis, diabetes, and obesity-induced insulin resistance. In addition, genetically obese db/db mice that expressed CPT1AM showed reduced glucose and insulin levels and liver steatosis. CONCLUSION: A chronic increase in liver FAO improves the obese metabolic phenotype, which indicates that AAV-mediated CPT1A expression could be a potential molecular therapy for obesity and diabetes. PMID- 21319202 TI - Nuclear receptors in liver disease. AB - Nuclear receptors are ligand-activated transcriptional regulators of several key aspects of hepatic physiology and pathophysiology. As such, nuclear receptors control a large variety of metabolic processes including hepatic lipid metabolism, drug disposition, bile acid homeostasis, as well as liver regeneration, inflammation, fibrosis, cell differentiation, and tumor formation. Derangements of nuclear receptor regulation and genetic variants may contribute to the pathogenesis and progression of liver diseases. This places nuclear receptors into the frontline for novel therapeutic approaches for a broad range of hepatic disorders and diseases including cholestatic and fatty liver disease, drug hepatotoxicity, viral hepatitis, liver fibrosis, and cancer. PMID- 21319203 TI - In vivo evaluation of the cross-genotype neutralizing activity of polyclonal antibodies against hepatitis C virus. AB - Control of hepatitis C virus (HCV) infection remains a huge challenge of global medical importance. Using a variety of in vitro approaches, neutralizing antibodies (nAbs) have been identified in patients with acute and chronic hepatitis C. The exact role these nAbs play in the resolution of acute HCV infection still remains elusive. We have previously shown that purified polyclonal antibodies isolated from plasma obtained in 2003 from a chronic HCV patient (Patient H) can protect human liver chimeric mice from a subsequent challenge with the autologous HCV strain isolated from Patient H in 1977 (H77). In this study we investigated whether polyclonal antibodies isolated from Patient H in 2006 (H06), which display high cross-genotype neutralizing activity in both the HCV pseudoparticle (HCVpp) and HCV cell culture (HCVcc) systems, were also able to prevent HCV infection of different genotypes (gt) in vivo. Following passive immunization with H06-antibodies, chimeric mice were challenged with the consensus strains H77C (gt1a), ED43 (gt4a), or HK6a (gt6a). In accordance with previous results, H06-antibodies prevented infection of chimeric mice with the autologous virus. However, the outcome of a homologous challenge is highly influenced by the amount of challenge virus injected. Depending on the viral genotype used, H06-antibodies were able to protect up to 50% of chimeric mice from a heterologous challenge. Animals in which the antibody pretreatment failed displayed a clear delay in the kinetics of viral infection. Sequence analysis of the recovered viruses did not suggest antibody-induced viral escape. CONCLUSION: Polyclonal anti-HCV antibodies isolated from a chronic HCV patient can protect against an in vivo challenge with different HCV genotypes. However, the in vivo protective efficacy of cross-genotype neutralizing antibodies was less than predicted by cell culture experiments. PMID- 21319204 TI - Eye-tracking with nonhuman primates is now more accessible than ever before. AB - Human and nonhuman primates rely almost exclusively on vision for social communication. Therefore, tracking eye movements and examining visual scan paths can provide a wealth of information about many aspects of primate social information processing. Although eye-tracking techniques have been utilized with humans for some time, similar studies in nonhuman primates have been less frequent over recent decades. This has largely been owing to the need for invasive manipulations, such as the surgical implantation of devices to limit head movement, which may not be possible in some laboratories or at some universities, or may not be congruent with some experimental aims (i.e., longitudinal studies). It is important for all nonhuman primate researchers interested in visual information processing or operant behavior to realize that such invasive procedures are no longer necessary. Here, we briefly describe new methods for fully noninvasive video eye-tracking with adult rhesus monkeys (Macaca mulatta). We also describe training protocols that require only ~30 days to accomplish and quality control measures that promote reliable data collection. It is our hope that this brief overview will reacquaint nonhuman primate researchers with the benefits of eye-tracking and promote expanded use of this powerful methodology. PMID- 21319205 TI - Toward a cross-species neuroscientific understanding of the affective mind: do animals have emotional feelings? AB - Do we need to consider mental processes in our analysis of brain functions in other animals? Obviously we do, if such BrainMind functions exist in the animals we wish to understand. If so, how do we proceed, while still retaining materialistic-mechanistic perspectives? This essay outlines the historical forces that led to emotional feelings in animals being marginalized in behavioristic scientific discussions of why animals behave the way they do, and why mental constructs are generally disregarded in modern neuroscientific analyses. The roots of this problem go back to Cartesian dualism and the attempt of 19th century physician-scientists to ground a new type of medical curriculum on a completely materialistic approach to body functions. Thereby all vitalistic principles were discarded from the lexicon of science, and subjective experience in animals was put in that category and discarded as an invalid approach to animal behavior. This led to forms of rigid operationalism during the era of behaviorism and subsequently ruthless reductionism in brain research, leaving little room for mentalistic concepts such as emotional feelings in animal research. However, modern studies of the brain clearly indicate that artificially induced arousals of emotional networks, as with localized electrical and chemical brain stimulation, can serve as "rewards" and "punishments" in various learning tasks. This strongly indicates that animal brains elaborate various experienced states, with those having affective contents being easiest to study rigorously. However, in approaching emotional feelings empirically we must pay special attention to the difficulties and vagaries of human language and evolutionary levels of control in the brain. We need distinct nomenclatures from primary (unconditioned phenomenal experiences) to tertiary (reflective) levels of mind. The scientific pursuit of affective brain processes in other mammals can now reveal general BrainMind principles that also apply to human feelings, as with neurochemical predictions from preclinical animal models to self-reports of corresponding human experiences. In short, brain research has now repeatedly verified the existence of affective experience-various reward and punishment functions-during artificial arousal of emotional networks in our fellow animals. The implications for new conceptual schema for understanding human/primate affective feelings and how such knowledge can impact scientific advances in biological psychiatry are also addressed. PMID- 21319206 TI - The design and cytotoxic evaluation of some 1-aryl-3-isopropylamino-1-propanone hydrochlorides towards human Huh-7 hepatoma cells. AB - A series of 1-aryl-3-isopropylamino-1-propanone hydrochlorides 1 and a related heterocyclic analog 2 as candidate antineoplastic agents were prepared and the rationale for designing these compounds is presented. A specific objective in this study is the discovery of novel compounds possessing growth-inhibiting properties of hepatoma cells. The compounds in series 1 and 2 were prepared and their structures established unequivocally. X-ray crystallography of two representative compounds 1d and 1g were achieved. Over half of the compounds are more potent than 5-fluorouracil which is an established drug used in treating liver cancers. QSAR evaluations and molecular modeling studies were undertaken with a view to detecting some physicochemical parameters which govern cytotoxic potencies. A number of guidelines for amplification of the project have been formulated. PMID- 21319207 TI - Synthesis and biological evaluation of 2'-oxo-2,3-dihydro-3'H- spiro[chromene 4,5'-[1,3]oxazolidin]-3'yl]acetic acid derivatives as aldose reductase inhibitors. AB - Aldose reductase (ARL2) is the first enzyme in the polyol pathway which catalyzes the NADPH-dependent reduction of glucose to sorbitol. Its involvement on diabetic complications makes this enzyme a challenge therapeutic target widely investigated to limit and/or prevent them. On this basis, a limited series of 4 spiro-oxazolidinone-benzopyran derivatives (1-7) were synthesized to evaluate them as potential ARL2 inhibitors. The activity was determined spectrophotometrically by monitoring the oxidation of NADPH catalyzed by ALR2. Within the series of compounds, the 4-methoxy derivative 1b showed to be the most active compound, exhibiting inhibitory levels in the submicromolar range. In addition, the activity against the aldehyde reductase isoform (ARL1) was also evaluated. Unlike sorbinil (reference drug) that lack of selectivity towards the two enzyme all the tested compounds resulted to be devoid of ARL1 inhibitory activity (IC(50) > 10 uM), thus proving to be selective. PMID- 21319208 TI - Effects of diet on the chemical composition of migratory locusts (Locusta migratoria). AB - An experiment was conducted to determine the effects of diet on the chemical composition of migratory locusts (Locusta migratoria L.). Fresh and dry weight and the contents of dry matter, ash, lipid, protein, Ca, K, Mg, Na, P, Cu, Fe, Zn, retinol, lutein, zeaxanthine, cryptoxanthin, carotenes, lycopene and gross energy were determined in penultimate instar and adult locusts, that had been fed three different diets. The locusts received a diet of grass or grass+wheat bran or grass+wheat bran+carrots. Adding wheat bran decreased the protein content and increased fat content (633 vs. 583 and 182 vs. 231 g/kg DM, respectively). Addition of carrots to the diet increased fat content further from 231 to 271 g/kg DM. Mineral concentrations of Ca, K, Mg, and Na, were significantly affected by diet. P, K, Cu, and Fe concentrations were significantly different in penultimate migratory locusts compared with adults. Wheat bran decreased the alpha-carotene content, which did not change by incorporating carrots in the diet. However, carrots did result in higher beta-carotene concentrations. Retinol concentrations were increased by incorporating both wheat bran and carrots in the diet compared with the diet containing only grass. This study shows that the chemical composition of migratory locusts can be manipulated through the diet. As such, it enables nutritionists to adapt the chemical composition of live feeder insects to better meet the nutritional demands of predators. PMID- 21319209 TI - Evaluation of an alternative to feeding whole frozen fish in belugas (Delphinapterus leucas). AB - Feeding fish to captive piscivores can be challenging owing to cost, availability, variability in nutrient, and caloric composition, as well as handling and storage concerns. This trial evaluated the response of three belugas to being fed Fish Analog, an alternative to frozen fish. Body condition, gut transit time, serum chemistry and metabolic hormone analytes, immune function, and behavioral motivation were the dependent variables. Belugas (n=3) were fed various levels of Fish Analog (0-50%) over a 6-month period, and follow-up studies were conducted to further examine several dependent variables. When provided in gradually increasing amounts, belugas consumed the Fish Analog, with only minor fecal consistency changes and without behavioral responses indicative of gastric discomfort. Axillary girth and blubber thickness were positively correlated, and did not differ significantly with changes in the percentage of Fish Analog fed. Individual animal variation in initial passage time, some serum chemistry analytes, and immune function differences were noted following feeding of Fish Analog. Feeding Fish Analog reduced blood n9 fatty acids compared with captive belugas fed no Fish Analog. Feeding a DHA-enriched Fish Analog increased several n3 fatty acids, including eicosapentaenoic acid, but not DHA, compared with whales fed no Fish Analog or non-DHA-enriched Fish Analog. Fish Analog was shown to be a viable alternative to feeding fish at up to 50% of the dietary caloric density. PMID- 21319210 TI - An assessment of gum-based environmental enrichment for captive gummivorous primates. AB - In the wild, many primates consume gums exuded from trees, and many species are gum specialists. In spite of this, few data exist concerning gum feeding in captivity. Using a web-based survey of 46 zoos in 12 countries, we evaluated the extent to which zoos feed gum to primates. We found that although callitrichids and galagos receive gum-based enrichment, cercopithecines generally do not. Environmental enrichment is important for stimulating naturalistic behavior to promote the psychological wellbeing of animals. Thus, gum-based enrichment is important for captive gummivores. Our study highlights the need to improve environmental enrichment for captive gummivores, in particular that of cercopithecines. This is most striking for the patas monkey (Erythrocebus patas), an obligate gummivore. The exchange of ecological data between field research and captive settings is crucial, and is just one way primate caretakers can contribute to the conservation and welfare of some of our closest living relatives. PMID- 21319211 TI - The captive husbandry and reproduction of the pink-eared turtle (Emydura victoriae) at Perth Zoo. AB - In 1997, Perth Zoo acquired six pink-eared turtles (Emydura victoriae) from the wild for display in the reptile facility. There is very little documented information on pink-eared turtles in captivity. This article looks at the reproductive biology, ecology, behavior, diet, and captive husbandry of the species. Eight clutches of eggs were documented over a 2-year period with an average clutch size of 10 eggs. Egg size was recorded with three clutches incubated to hatching. Ten hatchlings were maintained for a growth and development study. Measurements of weight, carapace length, width, height, and plastron length were recorded weekly for about 12 months, and then monthly for approximately 2 years. The data were analyzed and showed positive growth curves in all animals. Sexual dimorphism was observed after 20 weeks and sexual maturity in males observed after 2 years. PMID- 21319212 TI - Noninvasive analysis of fecal reproductive hormone metabolites in female veiled chameleons (Chamaeleo calyptratus) by enzyme immunoassay. AB - The noninvasive technique of gonadal steroid metabolite measurement in feces for evaluation of reproductive activity has proven an effective and important tool for population management in various captive species, but has not yet been validated and used in reptile species. In this study, enzyme immunoassays (EIAs) were validated for the analysis of fecal samples from female veiled chameleons (Chamaeleo calyptratus) for estrogen (E2), testosterone (T), and progesterone (P) and their metabolites. High performance liquid chromatography and physiological methods (GnRH stimulation) were used for the validation of the assays. Biological events, such as skin color changes indicative of ovarian activity and oviposition, correlated with the cyclical pattern of E2, T and P metabolites in feces over a period of two reproductive cycles. This is the first study to report frequent longitudinal measurements of fecal hormone levels by EIA in a reptile species. PMID- 21319213 TI - Results of the third reproductive assessment survey of North American Asian (Elephas maximus) and African (Loxodonta africana) female elephants. AB - A written survey assessed reproductive status of female Asian and African elephants in AZA/SSP facilities in 2008, and data were compared to surveys conducted in 2002 and 2005. Results showed that ovarian acyclicity rates across the surveys remained unchanged for Asian (13.3, 10.9 and 11.1%) and African (22.1, 31.2 and 30.5%) elephants, respectively (P > 0.05), but were higher overall for African compared to Asian elephants (P < 0.05). In 2008, the percentages of Asian and African elephants with irregular cycles (14.3 and 15.8%) and irregular + no cycles (25.4 and 46.4%) was similar to 2005 (7.6 and 11.8%; 18.5 and 43.0%), but were increased compared to 2002 (2.6 and 5.2%; 16.0 and 27.3%), respectively (P < 0.05). For both species, ovarian acyclicity increased with age (P < 0.05). Reproductive tract pathologies did not account for the majority of acyclicity, although rates were higher in noncycling females (P < 0.05). Bull presence was associated with increased cyclicity rates (P < 0.05) for Asian (92.5 vs. 58.3%) and African (64.9 vs. 57.8%) elephants compared to females at facilities with no male, respectively. Cyclicity rates were higher for Asian (86.8 vs. 65.2%) and African (67.9 vs. 56.7%) elephants managed in free compared to protected contact programs (P < 0.05), respectively. Geographical facility location had no effect on cyclicity (P > 0.05). In summary, incidence of ovarian cycle problems continues to predominantly affect African elephants. Although percentages of acyclicity did not increase between 2005 and 2008, 42.2% Asian and 30.2% African females were no longer being hormonally monitored; thus, reproductive cycle abnormalities could be worse than current data suggest. PMID- 21319214 TI - Technology at the zoo: the influence of a touchscreen computer on orangutans and zoo visitors. AB - A computer-controlled touchscreen apparatus (hereafter referred to as "touchscreen") in the orangutan exhibit at Zoo Atlanta provides enrichment to the animals and allows cognitive research to take place on exhibit. This study investigated the impact of the touchscreen on orangutan behavior and visibility, as well as its impact on zoo visitors. Despite previous research suggesting that providing a single computer system may negatively affect orangutan behavior, there was not a significant increase in aggression, stereotypic, or distress related behaviors following the activation of the on-exhibit touchscreen. We also investigated the possibility that zoo visitors may be negatively affected by technology because it deviates from naturalism. However, we did not find a change in stay time or overall experience rating when the computer was turned on. This research was the first to assess visitor attitudes toward technology at the zoo, and we found that visitors report highly positive attitudes about technology for both animals and visitors. If subjects visited the exhibit when the computer was turned on, they more strongly agreed that orangutans benefit from interacting with computerized enrichment. This study is the first investigation of an on exhibit touchscreen in group-housed apes; our findings of no negative effects on the animals or zoo visitors and positive attitudes toward technology suggest a significant value of this practice. PMID- 21319215 TI - The role of TLE1 in synovial sarcoma. AB - The treatment outcome of synovial sarcoma is poor owing to its resistance to radiation and chemotherapy. The transducin-like enhancer of split 1 (TLE1) is a co-repressor that involves many signaling pathways like cell survival, hematopoiesis and differentiation. Although TLE1 is uniquely expressed in synovial sarcomas, the biological role of TLE1 is not completely understood. This study evaluated the function of TLE1 in synovial sarcomas using knock-down of TLE1, and examined whether the inhibition of TLE1 suppresses the proliferation of synovial sarcomas and enhances the cytotoxicity caused by doxorubicin (doxo). The over-expression of TLE1 was first confirmed in synovial sarcoma cells (HS-SYII). When the HS-SYII cells and normal fibroblast were transiently transfected with TLE1 siRNA, the MTT assay revealed growth inhibition in the HS-SY-11 cells but not in the normal fibroblast. TLE1 silencing also potentiated the cytotoxic effects of doxo against HS-SYII cells. This effect of TLE1 silencing was attributed mainly to the induction of apoptosis. Subsequent analysis revealed that Bcl-2 is a possible downstream target of TLE1 signaling. This study demonstrated that TLE1 is a critical factor for the survival of synovial sarcomas. Overall, the inhibition of TLE1 affects cell proliferation and the apoptosis pathway by suppressing the expression of Bcl-2. PMID- 21319216 TI - Autologous chondrocyte implantation drives early chondrogenesis and organized repair in extensive full- and partial-thickness cartilage defects in an equine model. AB - Autologous chondrocyte implantation (ACI) has been used clinically for over 15 years and yet definitive evidence of chondrocyte persistence and direct impact on cartilage repair in full-thickness lesions is scant and no data are available on ACI in partial-thickness defects in any animal model. This study assessed the effect of chondrocytes secured using periosteal overlay in partial- and full thickness cartilage defects in the equine model. Paired cartilage defects 15 mm in diameter were made in the patellofemoral joint of 16 horse and repaired with ACI or periosteal flap alone. Response was assessed at 8 weeks by clinical, microradiographic, and histologic appearance, and by collagen type II immunohistochemistry, and proteoglycan and DNA quantification. ACI improved histologic scores in partial- and full-thickness cartilage defects, including defect filling, attachment to the underlying subchondral bone, and presence of residual chondrocyte accumulations. For partial-thickness defects chondrocyte predominance, collagen type II content, and toluidine stained matrix were enhanced, and attachment to the surrounding cartilage improved. DNA and PG content of grafted partial-thickness defects was improved by chondrocyte implantation. Periosteal patches alone did not induce cartilage repair. This study indicated implantation of chondrocytes to cartilage defects improved healing with a combination of persisting chondrocyte regions, enhanced collagen type II formation, and better overall cartilage healing scores. Use of ACI in the more challenging partial-thickness defects also improved histologic indices and biochemical content. The equine model of cartilage healing closely resembles cartilage repair in man, and results of this study confirm cell persistence and improved early cartilage healing events after ACI. PMID- 21319217 TI - Effects of medicinal herb salvia miltiorrhiza on osteoblastic cells in vitro. AB - Sufficient osteoinduction is essential for the success and effectiveness of bone grafting. It was previously found that Salvia Miltiorrhiza (SM), a commonly used Chinese herb increased osteogenesis in vivo. The aim of this study is to investigate the effects of SM on bone cells in vitro, in an attempt to get a better understanding on how SM can promote bone remodeling. MC3T3-E1, an osteoblastic cell line, was cultured with SM for different time intervals (24, 48, and 72 h), whereas the control group consisted of cells cultured without any intervention. The mRNA expression of alkaline phosphatase (ALP), osteocalcin (OCN), osteoprotegerin (OPG), and the receptor activator of nuclear factor kappa B ligand (RANKL) were examined by real-time polymerase chain reaction (qPCR). The expression of ALP showed an early increase at 24 h by 50% (p < 0.001) and at 48 h by 13% (p < 0.001). OCN was decreased by 22% at 24 h (p < 0.001) but increased by 50% and 88% at 48 and 72 h, respectively (p < 0.001). RANKL showed an early increase at the first two time points of 24 and 48 h by 45% (p < 0.001) and 36% (p < 0.01), respectively, while OPG was up-regulated at the latter two time points by 10% at 48 h (p < 0.01) and 68% at 72 h (p < 0.001). Thus, OPG/RANKL was down-regulated first, and then up-regulated. SM enhances bone remodeling by regulating the gene expression of ALP, OCN, OPG, and RANKL. It is a potential medicinal herb to be utilized in the application that requires stimulation in bone cell activities. PMID- 21319218 TI - Effects of surgical correction for the treatment of adult acquired flatfoot deformity: a computational investigation. AB - Computational models of the foot/ankle complex were developed to predict the biomechanical consequences of surgical procedures that correct for stage II adult acquired flatfoot deformity. Cadaveric leg and foot bony anatomy was captured by CT imaging in neutral flexion and imported to the modeling software. Ligaments were approximated as tension only springs attached at insertion sites. Muscle contraction of the gastrocnemius/soleus complex was simulated through force vectors and desired external loads applied to the model. Ligament stiffnesses were modified to reflect stage II flatfoot damage, followed by integration of corrective osteotomies-medializing calcaneal osteotomy (MCO) and Evans and calcaneocuboid distraction arthrodesis (CCDA)--to treat flatfoot. Joint angles, tissue strains, calcaneocuboid contact force, and plantar loads were analyzed. The flatfoot simulation demonstrated clinical signs of disease evidenced by degradation of joint alignment. Repair states corrected these joint misalignments with MCO having greatest impact in the hindfoot, and Evans/CCDA having greatest effect in the mid- and forefoot. The lateral procedures unevenly strained plantar structures, while offloading the medial forefoot, and increased loading on the lateral forefoot, which was amplified by combining with MCO. The Evans procedure raised calcaneocuboid joint contact force to twice intact levels. Computational results are in agreement with clinical and experimental findings. The model demonstrated potential precursors to such complications as lateral tightness and arthritic development and may thus be useful as a predictor of surgical outcomes. PMID- 21319219 TI - Reduction of flow artifacts by using partial saturation in RF-spoiled gradient echo imaging. AB - Radiofrequency (RF)-spoiled gradient-echo imaging provides a signal intensity close to pure T(1) contrast by using spoiler gradients and RF phase cycling to eliminate net transverse magnetization. Generally, spins require many RF excitations to reach a steady-state magnetization level; therefore, when unsaturated flowing spins enter the imaging slab, they can cause undesirable signal enhancement and generate image artifacts. These artifacts can be reduced by partially saturating an outer slab upstream to drive the longitudinal magnetization close to the steady state, while the partially saturated spins generate no signal until they enter the imaging slab. In this work, magnetization evolution of flowing spins in RF-spoiled gradient-echo sequences with and without partial saturation was simulated using the Bloch equations. Next, the simulations were validated by phantom and in vivo experiments. For phantom experiments, a pulsatile flow phantom was used to test partial saturation for a range of flip angles and relaxation times. For in vivo experiments, the technique was used to image the carotid arteries, abdominal aorta, and femoral arteries of normal volunteers. All experiments demonstrated that partial saturation can provide consistent T(1) contrast across the slab while reducing inflow artifacts. PMID- 21319220 TI - Expression of N-methyl D-aspartate receptor subunits in amoeboid microglia mediates production of nitric oxide via NF-kappaB signaling pathway and oligodendrocyte cell death in hypoxic postnatal rats. AB - The present study was focused on identifying the expression of N-methyl D aspartate receptor (NMDAR) subunits on activated microglia and to determine their role in the pathogenesis of periventricular white matter damage (PWMD) in neonatal rats following hypoxia. One day old wistar rats were subjected to hypoxia (5% O(2) ; 95% N(2) ) and the mRNA and protein expression of NMDAR subunits (NR1, NR2A-D, and NR3A) in the periventricular white matter (PWM) was determined at different time points (3,24 h, 3, 7, and 14 days) following hypoxic exposure. Immunoexpression of NR1 and NR2A-D was localized in amoeboid microglial cells (AMC) suggesting the presence of functional NMDARs in them. The expression of NMDAR in primary microglial cultures was ascertained by RT-PCR analysis and double immunofluorescence studies. The functionality of the microglial NMDAR in cultured microglial cells was examined by monitoring calcium movements in cells with fura-2. In primary microglial cultures, hypoxia induced the nuclear translocation of NF-kappaB which was suppressed by administration of MK801, an NMDAR antagonist. MK801 also down regulated the hypoxia-induced expression of tumor necrosis factor-alpha, interleukin-1beta, inducible nitric oxide synthase (iNOS), and nitric oxide (NO) production by microglia which may be mediated by the NF-kappaB signaling pathway. NO produced by microglia is known to cause death of oligodendrocytes in the developing PWM. In this connection, pharmacological agents such as MK801, BAY (NF-kappaB inhibitor), and 1400w (iNOS inhibitor) proved to be beneficial since they reduced the hypoxia-induced iNOS expression, NO production, and a corresponding reduction in the death of oligodendrocytes following hypoxia. PMID- 21319221 TI - GSK3beta negatively regulates oligodendrocyte differentiation and myelination in vivo. AB - Glycogen synthase kinase 3beta (GSK3beta) is an essential integrating molecule for multiple proliferation and differentiation signals that regulate cell fate. Here, we have examined the effects of inhibiting GSK3beta on the development of oligodendrocytes (OLs) from their oligodendrocyte precursors (OP) in vivo by injection into the lateral ventricle of postnatal mice and ex vivo in organotypic cultures of isolated intact rodent optic nerve. Our results show that a range of GSK3beta inhibitors (ARA-014418, lithium, indirubin, and L803-mt) increase OPs and OLs and promote myelination. Inhibition of GSK3beta stimulates OP proliferation and is prosurvival and antiapoptotic. The effects of GSK3beta inhibition in OPs is via the canonical Wnt signaling pathway by stimulating nuclear translocation of beta-catenin. However, direct comparison of the effects of Wnt3a and GSK3beta inhibition in optic nerves shows that they have opposing actions on OLs, whereby GSK3beta inhibition strikingly increases OL differentiation, whereas Wnt3a inhibits OL differentiation. Notably, GSK3beta inhibition overrides the negative effects of Wnt3a on OLs, indicating novel GSK3beta signaling mechanisms that negatively regulate OL differentiation. We identify that two mechanisms of GSK3beta inhibition are to stimulate cAMP response element binding (CREB) and decrease Notch1 signaling, which positively and negatively regulate OL differentiation and myelination, respectively. A key finding is that GSK3beta inhibition has equivalent effects in the adult and stimulates the regeneration of OLs and remyelination following chemically induced demyelination. This study identifies GSK3beta as a profound negative regulator of OL differentiation that contributes to inefficient regeneration of OLs and myelin repair in demyelination. PMID- 21319222 TI - Following nerve injury neuregulin-1 drives microglial proliferation and neuropathic pain via the MEK/ERK pathway. AB - Following peripheral nerve injury microglia accumulate within the spinal cord and adopt a proinflammatory phenotype a process which contributes to the development of neuropathic pain. We have recently shown that neuregulin-1, a growth factor released following nerve injury, activates erbB 2, 3, and 4 receptors on microglia and stimulates proliferation, survival and chemotaxis of these cells. Here we studied the intracellular signaling pathways downstream of neuregulin-1 erbB activation in microglial cells. We found that neuregulin-1 in vitro induced phosphorylation of ERK1/2 and Akt without activating p38MAPK. Using specific kinase inhibitors we found that the mitogenic effect of neuregulin-1 on microglia was dependant on MEK/ERK1/2 pathway, the chemotactic effect was dependant on PI3K/Akt signaling and survival was dependant on both pathways. Intrathecal treatment with neuregulin-1 was associated with microgliosis and development of mechanical and cold pain related hypersensitivity which was dependant on ERK1/2 phosphorylation in microglia. Spinal nerve ligation results in a robust microgliosis and sustained ERK1/2 phosphorylation within these cells. This pathway is downstream of neuregulin-1/erbB signaling since its blockade resulted in a significant reduction in microglial ERK1/2 phosphorylation. Inhibition of the MEK/ERK1/2 pathway resulted in decreased spinal microgliosis and in reduced mechanical and cold hypersensitivity after peripheral nerve damage. We conclude that neuregulin-1 released after nerve injury activates microglial erbB receptors which consequently stimulates the MEK/ERK1/2 pathway that drives microglial proliferation and contributes to the development of neuropathic pain. PMID- 21319223 TI - Suppressed microglial E prostanoid receptor 1 signaling selectively reduces tumor necrosis factor alpha and interleukin 6 secretion from toll-like receptor 3 activation. AB - Activation of innate immunity via toll-like receptors (TLRs) is associated with neurodegenerative diseases, and some effectors, like tumor necrosis factor alpha (TNFalpha) and interleukin 6 (IL-6), directly contribute to neurodegeneration. We tested the hypothesis that prostaglandin (PG) E(2) receptor subtype 1 (EP1) was necessary for the induction of microglial cytokines following the activation of innate immunity. Primary murine microglia had cytokine secretion by activators of TLR3 > TLR9 > TLR4 > TLR2. TLR3 activation induced early expression of cyclooxygenase 2 (COX2) and delayed expression of membranous PGE synthase and secretion of PGE(2) . Nonselective and COX2-selective inhibitors blocked TLR3 induction of TNFalpha and IL-6. Moreover, of the nine of twenty cytokines and chemokines induced by TLR3 activation, only TNFalpha and IL-6 were significantly dependent on EP1 signaling as determined using microglia from mice homozygous deficient for EP1 gene or wild-type microglia coincubated with an EP1 antagonist. These results were confirmed by blocking intracellular Ca(2+) release with 2 aminoethoxy-diphenyl borate or Xestospongin C, inhibitors of IP3 receptors. Our results show that suppression of microglial EP1 signaling achieves much of the desired effect of COX inhibitors by selectively blocking TLR3-induced microglial secretion of two major effectors of paracrine neuron damage. In combination with the ability of EP1 suppression to ameliorate excitotoxicity, these data point to blockade of EP1 as an attractive candidate therapeutic for neurodegenerative diseases. PMID- 21319225 TI - Common genetic polymorphisms in pre-microRNAs and risk of cervical squamous cell carcinoma. AB - MicroRNAs (miRNAs) function as gene regulator and they participate in diverse biological pathways. Common single nucleotide polymorphisms (SNPs) in pre microRNAs may change their property through altering miRNAs expression and/or maturation. We conducted a pilot study to test whether SNPs in pre-microRNAs were associated with cervical squamous cell carcinoma (CSCC). Genotypes of three SNPs in pre-miRNAs (hsa-miR-196a2 rs11614913 C/T, hsa-miR-499 rs3746444 A/G, and hsa miR-146a rs2910164 G/C) in 226 CSCC patients and 309 control subjects were determined with the use of PCR-restriction fragment length polymorphism (RFLP) assay. Significantly increased CSCC risks were found to be associated with G allele of rs3746444 and G allele of rs2910164 (P = 0.017, OR = 1.454, and P = 0.016, OR = 1.355, respectively). Increased CSCC risks were associated with them in different genetic model (P = 0.0004, OR = 1.98 for rs3746444 in an overdominant model, and P = 0.024, OR = 2.10 for rs2910164 in a codominant model, respectively). Results of stratified analyses revealed that rs2910164 is associated with tumor differentiation and lymph node status (P = 0.043, OR = 2.08, and a borderline P = 0.057, OR = 0.41, respectively). No association between rs11614913 and CSCC risk was observed. The present study provides evidence that rs3746444 and rs2910164 are associated with CSCC, indicating that common genetic polymorphisms in pre-microRNAs contribute to the pathogenesis of CSCC. PMID- 21319224 TI - Expression of LPP3 in Bergmann glia is required for proper cerebellar sphingosine 1-phosphate metabolism/signaling and development. AB - Bioactive lipids serve as intracellular and extracellular mediators in cell signaling in normal and pathological conditions. Here we describe that an important regulator of some of these lipids, the lipid phosphate phosphatase-3 (LPP3), is abundantly expressed in specific plasma membrane domains of Bergmann glia (BG), a specialized type of astrocyte with key roles in cerebellum development and physiology. Mice selectively lacking expression of LPP3/Ppap2b in the nervous system are viable and fertile but exhibit defects in postnatal cerebellum development and modifications in the cytoarchitecture and arrangement of BG with a mild non-progressive motor coordination defect. Lipid and gene profiling studies in combination with pharmacological treatments suggest that most of these effects are associated with alterations in sphingosine-1-phosphate (S1P) metabolism and signaling. Altogether our data indicate that LPP3 participates in several aspects of neuron-glia communication required for proper cerebellum development. PMID- 21319226 TI - Critical roles of cellular glutathione homeostasis and jnk activation in andrographolide-mediated apoptotic cell death in human hepatoma cells. AB - Andrographolide (ANDRO), isolated from the traditional herbal medicine Andrographis paniculata, is reported to have the potential therapeutic effects for hepatocellular carcinoma (HCC) in our previous reports. Here, we investigated the mechanism of ANDRO-mediated apoptotic cell death, focusing on the involvement of cellular reduced glutathione (GSH) homeostasis and c-Jun NH(2) -Terminal kinase (JNK). Buthionine sulfoximine (BSO), an inhibitor of cellular GSH biosynthesis, significantly augmented ANDRO-induced cytotoxicity in hepatoma Hep3B and HepG2 cells. BSO depleted cellular GSH, and augmented ANDRO-induced apoptosis, inhibition of colony formation and JNK activation in Hep3B cells. All these effects could be reversed by GSH monoethyl ester (GSH.EE), whose deacetylation replenishes cellular GSH. BSO also augmented ANDRO-induced activation of apoptosis signal-regulating kinase 1 (ASK1), mitogen-activated protein kinase kinase-4 (MKK4) and c-Jun, which are all up-stream or down-stream signals of JNK. Further results showed that JNK inhibitor SP600125 and 420116 both reversed ANDRO-induced cytotoxicity, and SP600125 also decreased ANDRO increased intracellular GSH and GCL activity. Finally, we showed that in nude mice bearing xenografted Hep3B tumors, BSO improved the inhibition of tumor growth by ANDRO. Taken together, our results suggest that there is a crosstalk between JNK activation and cellular GSH homeostasis, and ANDRO targets this to induce cytotoxicity in hepatoma cells. PMID- 21319227 TI - Penta-1,2,3,4,6-O-galloyl-beta-D-glucose induces senescence-like terminal S-phase arrest in human hepatoma and breast cancer cells. AB - Senescence is a permanent growth arrest and has been implicated as an efficient anti-carcinogenesis mechanism. The purpose of this study was designed to test the hypothesis that penta-1,2,3,4,6-O-galloyl-beta-D-glucose (PGG), a naturally occurring polyphonolic gallotannin compound, might induce this type of permanent growth arrest in cancer cells. Our results show, for the first time, that PGG induced senescence-like S-phase arrest in HepG2, Huh-7 human hepatoma cells, and SKBr3 human breast cancer cells at sublethal doses, judged by cellular morphological changes, increased senescence-associated beta-galactosidase (SA beta-gal) activity, together with loss of proliferative capacity after being released from the treatment. This senescence-like response was mediated by intracellular ROS generation, but was not attributed to p53 Ser15 phosphorylative activation and was uncoupled from the p21cip1 axis, which has been shown to mediate Pten loss-induced cellular senescence or oncogene-driven senescence. The findings of the present study implicate a novel mechanism of PGG action to induce an atypical cellular senescence, adding to its promise as a potential chemopreventive agent. PMID- 21319228 TI - Crk and CrkL present with different expression and significance in epithelial ovarian carcinoma. AB - Adaptor protein Crk and CrkL were thought to be closely related because both consist of one SH2 and two SH3 domains and share 60% homology with the highest identity within their functional domains. Their functions were most presumed to be in part, if not all, redundant. And both were suggested to be implicated in carcinogenesis. In this study, both Crk and CrkL presented with much higher expression in ovarian cancer tissues than those in normal and benign ovarian tissues. However, in contrast with CrkL, high Crk expression displayed close association with advanced stages and high-grade diseases. Furthermore, the differential binding selectivity of Crk and CrkL to their downstream partners Dock 180 and C3G was demonstrated in ovarian cancer cell line SKOV3 through coimmunoprecipitation. Additionally, Crk-knockdown cells presented with changed morphology, reduced growth, and cell invasion but remained viable. In contrast, all CrkL-knockdown cells could not survive over time, gradually detaching from the bottom of plastic dish. In conclusion, these two highly homologous proteins hold features that allow for the differential association with each binding molecules, thereby activating different signaling pathways and being involved in diverse roles in ovarian cancer. PMID- 21319230 TI - Self-sorting of water-soluble cucurbituril pseudorotaxanes. PMID- 21319231 TI - Alkynylcyclopropanes from terminal alkynes through consecutive coupling to Fischer carbene complexes and selective propargylene transfer. PMID- 21319232 TI - Direct asymmetric Michael addition of cyclic N-sulfonylimines to alpha,beta unsaturated aldehydes. PMID- 21319233 TI - Asymmetric crossed-conjugate addition of nitroalkenes to enones by a chiral bifunctional diamine organocatalyst. PMID- 21319234 TI - Heterometallic coordination polymer gels based on a rigid, bifunctional ligand. PMID- 21319235 TI - Exceptionally large second-order nonlinear optical response in donor-graphene nanoribbon-acceptor systems. AB - Graphene nanoribbon (GNR) has been used, for the first time, as an excellent conjugated bridge in a donor-conjugated bridge-acceptor (D-B-A) framework to design high-performance second-order nonlinear optical materials. Owing to the unique diradical planar conjugated bridge of GNR, D(NH(2))-GNR-A(NO(2)) exhibits exceptionally large static first hyperpolarizability (beta(0)) up to 2.5*10(6) a.u. (22000*10(-30) esu) for H(2)N-(7,3)ZGNR-NO(2) (ZGNR=zigzag-edged GNR), which is about 15 times larger than the recorded value of beta(0) (1470*10(-30) esu) for the D-A polyene reported by Blanchard-Desce et al. [Chem. Eur. J. 1997, 3, 1091]. Interestingly, we have found that the size effect of GNR plays a key role in increasing beta(0) for the H(2)N-GNR-NO(2) system, in which the width effect of GNR perpendicular to the D-A direction is superior to the length effect along the D-A direction. PMID- 21319236 TI - Visible-light-induced dye degradation over copper-modified reduced graphene oxide. AB - Previously, it was found that reduced graphene oxide (RGO) can degrade rhodamine B (RhB) under visible-light irradiation, but with an extraordinarily slow rate. It was also found that modification of RGO with gold nanoparticles can dramatically accelerate the photoreaction rate. Herein, we describe the preparation and photocatalytic properties of copper-ion-modified RGO composite materials, which display a faster photocatalytic reaction rate and better mineralization under visible-light irradiation than gold-modified RGO. The copper ion-modified RGO composites were prepared by an immersion method. The characterization results of X-ray diffraction, transmission electron microscopy, field-emission scanning electron microscopy, and X-ray photoelectron spectroscopy show the presence of crystalline copper species Cu(2)(OH)(3)NO(3) and Cu(2)(OH)(3)Cl on the surface of RGO. Modification of RGO with the copper species greatly enhances the degradation of RhB--after 3 hours of reaction under visible light irradiation, the total organic carbon is decreased by about 31%. The copper species act as an electron relay, passing the excited electrons from the RGO sheets to adsorbed oxygen, thus leading to continuous generation of reactive oxygen species for the degradation of RhB. PMID- 21319237 TI - Assembly of a self-complementary monomer: formation of supramolecular polymer networks and responsive gels. AB - Self-complementary monomer 1, which combines a macrotricyclic polyether and two dibenzylammonium ions together, was synthesized, and its self-assembly into supramolecular polymer networks by host-guest interactions was studied. For the purpose of comparative study, two model molecules 2 and 3 were also prepared. It was found that model molecule 2 and dibenzylammonium ion 4 form a 1:2 complex in solution and in the solid state, which afforded a model system for the investigation of the assembly behavior of monomer 1. Consequently, the (1)H NMR spectrum of 1 in CD(3)CN showed characteristic proton signals similar to the model system, which suggested that 1 self-assembles into a supramolecular polymer network. Formation of the supramolecular polymer was further evidenced by the MALDI-TOF MS spectrum, viscometry, and dynamic light-scattering (DLS) experiments. Moreover, it was found that the decomposition and re-formation of the supramolecular polymer could be chemically controlled by the use of triethylamine and trifluoroacetic acid. Interestingly, the supramolecular polymer forms an organogel both in CD(3)CN and in 1:1 (v/v) CDCl(3)/CD(3)CN, and reversible thermo- and pH-induced gel-sol transitions were also found. The presented work will provide a new strategy for the construction of supramolecular polymers with specific structures and properties. PMID- 21319238 TI - Pure trinuclear 4f single-molecule magnets: synthesis, structures, magnetism and ab initio investigation. AB - A family of linear Dy(3) and Tb(3) clusters have been facilely synthesized from the reactions of DyCl(3), the polydentate 3-methyloxysalicylaldoxime (MeOsaloxH(2) ) ligand with auxiliary monoanionic ligands, such as trichloroacetate, NO(3)(-), OH(-), and Cl(-). Complexes 1-5 contain a nearly linear Ln(3) core, with similar Ln...Ln distances (3.6901(4)-3.7304(3) A for the Dy(3) species, and 3.7273(3)-3.7485(5) A for the Tb(3) species) and Ln...Ln...Ln angles of 157.036(8)-159.026(15) degrees for the Dy(3) species and 157.156(8) 160.926(15) degrees for the Tb(3) species. All three Ln centers are bridged by the two doubly-deprotonated [MeOsalox](2-) ligands and two of the four [MeOsaloxH](-) ligands through the N,O-eta(2)-oximato groups and the phenoxo oxygen atoms (Dy-O-Dy angles=102.28(16)-106.85(13) degrees ; Tb-O-Tb angles=102.00(11)-106.62(11) degrees ). The remaining two [MeOsaloxH](-) ligands each chelate an outer Ln(III) center through their phenoxo oxygen and oxime nitrogen atoms. Magnetic studies reveal that both Dy(3) and Tb(3) clusters exhibit significant ferromagnetic interactions and that the Dy(3) species behave as single-molecule magnets, expanding upon the recent reports of the pure 4f type SMMs. PMID- 21319239 TI - Stereoselective single (copper) or double (platinum) boronation of alkynes catalyzed by magnesia-supported copper oxide or platinum nanoparticles. AB - Copper(II) oxide nanoparticles supported on magnesia have been prepared from Cu(II) supported on magnesia by hydrogen reduction at 400 degrees C followed by storage under ambient conditions. X-ray photoelectron spectroscopy of the material clearly shows that immediately after the reduction copper(0)-metal nanoparticles are present on the magnesia support, but they undergo fast oxidation to copper oxide upon contact with the ambient for a short time. TEM images show that the catalytically active CuO/MgO material is formed of well dispersed copper oxide nanoparticles supported on fibrous MgO. CuO/MgO exhibits a remarkable catalytic activity for the monoborylation of aromatic, aliphatic, terminal, and internal alkynes, the products being formed with high regio- (borylation at the less substituted carbon) and stereoselectivity (trans configured). CuO/MgO exhibits complete chemoselectivity towards the monoborylation of alkynes in the presence of alkenes. Other metal nanoparticles such as gold or palladium are inactive towards borylation, but undergo undesirable oligomerization or partial hydrogenation of the C=C triple bond. In contrast, platinum, either supported on magnesia or on nanoparticulate ceria, efficiently promotes the stereoselective diborylation of alkynes to yield a cis configured diboronate alkene. By using platinum as the catalyst we have developed a tandem diborylation/hydrogenation reaction that gives vic-diboronated alkanes from alkynes in one pot. PMID- 21319240 TI - Kinetic data for the transmetalation/reductive elimination in palladium-catalyzed Suzuki-Miyaura reactions: unexpected triple role of hydroxide ions used as base. AB - The mechanism of the reaction of trans-[ArPdX(PPh(3))(2)] (Ar=p-Z-C(6)H(4); Z=CN, F, H; X=I, Br, Cl) with Ar'B(OH)(2) (Ar'=p-Z'-C(6)H(4); Z'=CN, H, OMe) has been established in DMF in the presence of the base OH(-) in the context of real palladium-catalyzed Suzuki-Miyaura reactions. The formation of the cross-coupling product ArAr' and [Pd(0)(PPh(3))(3)] has been followed through the application of electrochemical techniques. Kinetic data have been obtained for the first time, with determination of the observed rate constant, k(obs), of the overall reaction. trans-[ArPdX(PPh(3))(2)] is not reactive in the absence of the base. The base OH(-) plays three roles. It favors the reaction: 1) by formation of trans-[ArPd(OH)(PPh(3))(2)], a key complex which, in contrast to trans [ArPdX(PPh(3))(2)], reacts with Ar'B(OH)(2) (rate-determining transmetalation), and 2) by unexpected promotion of the reductive elimination from the intermediate trans-[ArPdAr'(PPh(3))(2)], which generates ArAr' and a Pd(0) species. Conversely, the base OH(-) disfavors the reaction by formation of the unreactive anionic Ar'B(OH)(3)(-). As a consequence of these antagonistic effects of OH(-), the overall reactivity is controlled by the concentration of OH(-) and passes through a maximum as the concentration of OH(-) is increased. Therefore, the base favors the rate-determining transmetalation and unexpectedly also the reductive elimination. PMID- 21319241 TI - pH-responsive poly(methacrylic acid)-grafted hollow silica vesicles. AB - Poly(methacrylic acid)-grafted hollow silica vesicles (PMAA-g-hollow silica vesicles) were obtained through a grafting-from approach. PMAA brushes were formed by performing atom-transfer radical polymerisation of sodium methacrylate with an initiator attached to the hollow silica spheres. PMAA-g-hollow silica vesicles were characterised by using TEM, thermogravimetric analysis (TGA) and FTIR spectroscopy. pH-dependent xi potential and (1)H NMR spectra of PMAA-g hollow silica vesicles were measured, and the results indicated that MAA brushes in PMAA-g-hollow silica vesicles had a lower ionisation degree and low solubility in acidic aqueous solution, for example, pH 3.4, but a higher ionisation degree and high solubility when the pH was higher than 7. Also it was demonstrated that calcein blue and fluorescein isothiocyanate (FITC) labelled dextran (M(n):10 kDa) could be encapsulated in the interiors of the PMAA-g-hollow silica vesicles with a negligible amount in PMAA brushes at pH 2, and pH-triggered release of calcein blue and FITC-labelled dextran from PMAA-g-hollow silica vesicles was observed at pH 7.4. PMID- 21319242 TI - Pd(II) and Pt(II) complexes of 2-(2'-pyridyl)-4,6-diphenylphosphinine: synthesis, structure, and reactivity. AB - The coordination chemistry of the bidentate P,N hybrid ligand 2-(2'-pyridyl)-4,6 diphenylphosphinine (1) towards Pd(II) and Pt(II) has been investigated. The molecular structures of the complexes [PdCl(2)(1)] and [PtCl(2)(1)] were determined by X-ray diffraction, representing the first crystallographically characterized lambda(3)-phosphinine-Pd(II) and -Pt(II) complexes. Both complexes reacted with methanol at the P=C double bond at an elevated temperature, leading to the corresponding products [MCl(2)(1H.OCH(3))]. The molecular structure of [PdCl(2)(1H.OCH(3))] was determined crystallographically and revealed that the reaction with methanol proceeds selectively by syn addition and exclusively to one of the P=C double bonds. Strikingly, the reaction of [PdCl(2)(1H.OCH(3))] with the chelating diphosphine DPEphos at room temperature in CH(2)Cl(2) led quantitatively to [PdCl(2)(DPEphos)] and phosphinine 1 by elimination of CH(3)OH and rearomatization of the phosphorus heterocycle. PMID- 21319244 TI - An evolutionary review of human telomere biology: the thrifty telomere hypothesis and notes on potential adaptive paternal effects. AB - Telomeres, repetitive DNA sequences found at the ends of linear chromosomes, play a role in regulating cellular proliferation, and shorten with increasing age in proliferating human tissues. The rate of age-related shortening of telomeres is highest early in life and decreases with age. Shortened telomeres are thought to limit the proliferation of cells and are associated with increased morbidity and mortality. Although natural selection is widely assumed to operate against long telomeres because they entail increased cancer risk, the evidence for this is mixed. Instead, here it is proposed that telomere length is primarily limited by energetic constraints. Cell proliferation is energetically expensive, so shorter telomeres should lead to a thrifty phenotype. Shorter telomeres are proposed to restrain adaptive immunity as an energy saving mechanism. Such a limited immune system, however, might also result in chronic infections, inflammatory stress, premature aging, and death--a more "disposable soma." With an increased reproductive lifespan, the fitness costs of premature aging are higher and longer telomeres will be favored by selection. Telomeres exhibit a paternal effect whereby the offspring of older fathers have longer telomeres due to increased telomere lengths of sperm with age. This paternal effect is proposed to be an adaptive signal of the expected age of male reproduction in the environment offspring are born into. The offspring of lineages of older fathers will tend to have longer, and thereby less thrifty, telomeres, better preparing them for an environment with higher expected ages at reproduction. PMID- 21319246 TI - Microevolutionary processes due to landscape features in the province of Jujuy (Argentina). AB - OBJECTIVES: We seek to evaluate the influence of a diverse and rugged physical environment on the genetic background of human populations. METHODS: We analyzed eight polymorphic Alu insertions in 226 individuals from Jujuy province (Argentina), which is composed of several regions with well-defined geographical features and marked contrasts between them associated with differences in altitude (range: 700-3300 m). This regional division was used to assess the spatial variation of the Alu diversity. RESULTS: Deviations from Hardy-Weinberg Equilibrium expectations resulting from heterozygous deficit were found for FXIIIB and PV92 in the highest subpopulations. Several Alu elements showed genetic heterogeneity between the highest region (La Puna) and the lowest regions (Valle and Selva). Similarly, a decreasing trend of the average heterozygosity according to altitude was found. Both the centroid method and the admixture analysis unveiled a gene flow above the average in lowland populations, indicating a higher proportion of foreign genes introduced by immigrants of European and African ancestry. Furthermore, several Alu frequency clines fitting the orientation of the altitude gradient were detected. CONCLUSIONS: Our study reveals a spatial patterning of the Alu diversity in Jujuy, most likely determined by disparities in landscape and environmental features between the different subregions. Differences in the physical environment would have drastically reduced the homogenizing effects of the gene flow and would have promoted genetic drift episodes in the highest subpopulations. Microevolutionary processes detected in Jujuy have played an important role in the shaping of the gene pool of the populations from this sub-Andean zone from Argentina. PMID- 21319245 TI - Elevated pulmonary artery pressure among Amhara highlanders in Ethiopia. AB - OBJECTIVE: Pulmonary arterioles respond to hypoxia with constriction that raises vascular resistance and pulmonary artery blood pressure. The response is sustained indefinitely by the chronic hypoxia of high-altitude residence among highlanders of European and Andean descent, but not Tibetans. The objective of this study was to identify the consequences of lifelong hypoxia exposure for the pulmonary vasculature among Amhara high-altitude natives from Ethiopia. METHODS: A three-way static group comparison tested for the effect of Amhara ancestry and high residence altitude on pulmonary hemodynamics measured using echocardiography in samples of 76 healthy adult Amhara lifelong residents at 3700 m, 54 Amhara lifelong residents at 1200 m, and 46 U.S. low-altitude residents at 282 m. RESULTS: Amhara at 3700 m had average Doppler-estimated pulmonary artery systolic pressure (tricuspid regurgitant gradient) of 27.9 +/- 8.4 (SD) mm Hg as compared with 21.9 +/- 4.0 among Amhara at low altitude and 16.5 +/- 3.6 in the U.S. low altitude reference sample. However, there was no residence altitude effect on pulmonary blood flow or vascular resistance. Amhara ancestry was associated with greater pulmonary artery systolic pressure and pulmonary blood flow, yet lower pulmonary vascular resistance. CONCLUSIONS: The Amhara at 3700 m had elevated pulmonary artery pressure, but without the elevated pulmonary vascular resistance characteristic of the classic model of the response to long-term hypoxia by the pulmonary vasculature. The elevated pressure among Amhara may be a consequence of high pulmonary blood flow regardless of altitude and represent a newly identified pattern of response. PMID- 21319247 TI - Birth weight and early socio-economic disadvantage as predictors of sex hormones and sex hormone binding globulin in men at age 49-51 years. AB - OBJECTIVES: A number of associations have been shown between early growth and later sex hormone levels in women, but less is known about this relationship in men. This study investigated life-course predictors of sex hormones in men in the Newcastle Thousand Families birth cohort. METHODS: The Newcastle Thousand Families Study is a prospective study initiated in 1947. At age 49-51 years, 574 study members returned detailed self-completion questionnaires and 412 attended for clinical examination, including 172 men in whom blood samples were taken. Estradiol, follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and sex hormone binding globulin (SHBG) were measured. Free testosterone concentrations were also calculated. RESULTS: Social class at birth independently predicted FSH and LH, with higher levels with increasing socioeconomic disadvantage. SHBG was higher with increasing standardized birth weight and lower with increasing contemporary body mass index (BMI). BMI also predicted LH, SHBG, and testosterone. None of the variables included within this analysis were significant predictors of estradiol. No other associations were seen with any of the variables included from across the life-course. CONCLUSIONS: Our findings suggest that birth weight may be positively associated with SHBG and early socioeconomic status may be related to FSH and LH in men. These novel findings are independent of contemporary BMI. Given the links between sex hormones, SHBG and disease outcomes such as type II diabetes and osteoporosis, it is possible that sex hormones may play a mediating role in the associations between circumstances in early life and later risk of chronic disease. PMID- 21319248 TI - Season of birth and subsequent body size: the potential role of prenatal vitamin D. AB - OBJECTIVES: The relationship between season of birth and various physical and psychological outcomes was reported in many studies, although the underlying mechanism still remains unrecognized. The aim of this study was to explore the season-of-birth effect on body size in the sample of 1,148 eight-year-old Polish urban children and propose the mechanism responsible for this effect. METHODS: The children were examined three times at their birthdays and at two cross sectional surveys. Effects of the season of birth were checked by fitting the cosine function to empirical values and by comparison between two groups born in different periods of the year. RESULTS: Data gathered at three examinations led to the same results: season-of-birth effect occurred only in boys and only in those relatively shortly breastfed and/or descended from the families of low socioeconomic status. Specifically, the individuals born in October-April were taller (by 2-3 cm), heavier (by 2-3 kg), and fatter than those born in May September. CONCLUSIONS: The following explanatory mechanism has been formulated: insolation in Poland is minimal in November-February (winter period), and so ultraviolet absorption and vitamin D production is then the lowest. Vitamin D regulates embryo's cellular differentiation, and its deficiency triggers permanent developmental changes. Therefore, individuals conceived in autumn (i) are at the greatest risk of early vitamin D deficiency, (ii) are born in summer, and (iii) are relatively small in their further lives. The contribution of low socioeconomic status, short breastfeeding, and being a male to the occurrence of the season-of-birth effect is also discussed. PMID- 21319249 TI - Sex differences in the consequences of early-life exposure to epidemiological stress--a life-history approach. AB - OBJECTIVES: Exposure to infectious disease in early life has been suggested to have a negative effect on later-life survival,possibly through the induction of inflammatory responses. Although a life-course perspective emphasizes the importance of both survival and reproduction for individual fitness, to date, no studies have investigated whether early-life exposure to infectious disease has an impact on reproduction as it has been suggested for later survival. METHODS: To address this question, I have used family reconstitution data from a historical (18th and 19th century) human population in the Krummhorn (Germany) comparing survival and reproduction between an exposed and a non-exposed group. The exposed group comprised those exposed to a high-infectious disease load during prenatal and early postnatal development. RESULTS: The results show a marked sex difference in the impact of early-life exposure to infectious disease. Exposed females show no effect on their life expectancy but significantly reduced fertility (number of children). For exposed males, however, the effect on survival is opponent over time: mortality is increased during childhood but decreased in late adulthood. Above that, exposed males reproduce earlier and have a smaller proportion of surviving children. CONCLUSIONS: This study does not support former studies indicating a negative association between early-life disease load and later survival. I argue that due to differences in male and female life strategies, males in general are more vulnerable especially early in life. Hence, adverse environmental conditions may have a stronger effect on male survivability and reproductive performance. PMID- 21319250 TI - Secular trends in height and weight for healthy Han children aged 0-7 years in China, 1975-2005. AB - OBJECTIVES: To report the secular growth changes of Chinese children aged 0-7 years between 1975 and 2005. METHODS: Height and weight measurements obtained from four consecutive national surveys were used to analyze the secular trends. Urban-rural difference and regional difference in growth were compared, respectively. RESULTS: A rapid positive secular trend was observed in China over the last three decades, increased by 5.3 and 5.0 cm in height for urban boys and girls at age 6-7 years, respectively. Urban-rural height difference has continuously reduced, but weight difference has gradually widened after 3-years old which results from the excessive weight increase of urban children, 2.68 kg for rural boys aged 6-7 years but 3.26 kg for urban during the 30 years. Clear regional differences in growth are not narrowing over time. Generally, the growth level in eastern China is higher than central-western, successively higher than southern. CONCLUSIONS: The rapid positive secular trends will still continue with the rapid socio-economic development in China. Urban-rural height difference will further narrow. Currently no sufficient evidence indicates that growth difference in inter-city has reduced. Weight increases rapidly for urban children, which does not match with height. PMID- 21319251 TI - Body composition trajectories into adolescence according to age at pubertal growth spurt. AB - OBJECTIVE: To investigate whether the development of body composition into adolescence differs among children with an early, average, or late pubertal growth spurt (age at take-off [ATO]). METHODS: Mixed-effect polynomial models were applied to serial anthropometric measurements spanning from 4 years before to 4 years after ATO in 215 DONALD participants. Sex-specific trajectories of fat mass index (FMI, FM/m(2) ), fat-free mass index (FFMI, FFM/m(2) ), and their z scores were compared among those with an early, average, or late ATO. RESULTS: Compared with girls with a late ATO (reference group), those with an early or average ATO experienced a significant increase in FFMI z-scores [beta (standard error) for linear trends in early and average ATO group: +0.15 (0.05) FFMI z scores/year (P = 0.001) and +0.11 (0.04) FFMI z-scores/year (P = 0.005), respectively, adjusted for early life factors]. Similar differences were observed in boys [adjusted beta (standard error): +0.20 (0.06) FFMI z-scores/year (P = 0.0004) and +0.07 (0.05) FFMI z-scores/year (P = 0.1), respectively]. Graphical illustration of the predicted trajectories revealed that differences in relative FFMI emerged from ATO onward. For FMI, comparison with late maturers showed a more pronounced quadratic trend (kg/m(2) /years(2) ) (P = 0.01) among early maturing girls and a reduced linear trend in FMI z-scores/year (P = 0.04) among early-maturing boys. CONCLUSIONS: This longitudinal study suggests that children who experience an early pubertal growth spurt accrue progressively more fat-free mass during the first years of puberty than late-maturing peers of the same age. Higher levels of adiposity commonly observed in adults with early puberty onset are, thus, likely to develop subsequently in later adolescence. PMID- 21319252 TI - Mitochondrial polymorphisms associated with differential longevity do not impact lifetime-reproductive success. AB - OBJECTIVE: To determine if individuals who carry mitochondrial markers which have been previously shown to affect longevity also have differential lifetime reproductive success (LRS). METHODS: We extracted the mtDNA from living subjects residing in Atenas, Costa Rica. Since mtDNA does not recombine, and its probability of mutation is low, we assume that all maternal ancestors of the living subjects have the same mtDNA. We reconstructed the maternal genealogy of the living subjects, so that we have information on the LRS and longevity of the maternal ancestors of the living subjects. We compared the LRS of women who carried the 5178A marker in haplogroup D (associated with decreased longevity) and who carried the 150T polymorphism (associated with increased longevity) with the LRS of controls born in the same half century time period from 1750 to 1939. RESULTS: We found that the LRS of neither group of women with a longevity associated polymorphism (LAP) differed from the LRS of controls, even if these women differed significantly from the controls in their longevity. CONCLUSIONS: Although LAPS significantly affect longevity, such differential longevity does not result in differential lifetime reproductive success. From an evolutionary perspective, these longevity-associated polymorphisms do not affect the carriers' Darwinian fitness. PMID- 21319253 TI - Substantial variation in qPCR measured mean blood telomere lengths in young men from eleven European countries. AB - OBJECTIVES: Telomeres, repetitive DNA sequences found at the ends of chromosomes, shorten with age in proliferating human tissues and are implicated in senescence. Previous studies suggest that shorter telomeres impair immune and cardiovascular function and result in increased mortality. Although few, prior studies have documented ethnic/population differences in human telomere lengths. The nature and cause(s) of these population differences remain poorly understood. METHODS: Here, we extend the work of Salpea et al. (2008) by reporting variation in mean blood telomere lengths (BTL) from 765 individuals from 14 study centers across 11 European countries. Subjects are male students (ages 18-28), half of whom had fathers with myocardial infarction before 55 and the remainder age-matched controls. Controlling for age and case-control status, telomere lengths averaged 10.20 kilobases (interpolated from qPCR measures) across study centers and ranged from 5.10 kilobases in Naples, Italy to 18.64 kilobases in Ghent, Belgium--a greater than threefold difference across populations. These population level differences in BTLs were neither explained by national level measures of population genetic structure nor by national level ecological analysis of indices of infection/economic status. CONCLUSIONS: These findings suggest considerable population variation in BTL in Europe that is not obviously a result of broad measures of population structure or infection/economic exposure measured in early life or in adulthood.Studying telomere dynamics in a wider variety of populations, and with greater attention to life-cycle dynamics, will be important to help elucidate the causes and possible consequences of human population variation in telomere length. PMID- 21319256 TI - Proposal for a rational classification of neck dissections. PMID- 21319257 TI - Identification of IGHCdelta-BACH2 fusion transcripts resulting from cryptic chromosomal rearrangements of 14q32 with 6q15 in aggressive B-cell lymphoma/leukemia. AB - In B-cell malignancies, genes implicated in B-cell differentiation, germinal center formation, apoptosis, and cell cycle regulation are juxtaposed to immunoglobulin loci through chromosomal translocations. In this study, we identified the BTB and CNC homology 2 (BACH2) gene as a novel translocation partner of the immunoglobulin heavy chain (IGH) locus in a patient with IGH-MYC positive, highly aggressive B-cell lymphoma/leukemia carrying der(14)t(8;14) and del(6)(q15). Fluorescence in situ hybridization analysis using an IGH/MYC probe detected an IGH-MYC fusion signal on der(14) and IGH signal on del(6). Genome copy number analysis showed a deletion in the 6q15-25 region and a centromeric breakpoint within the BACH2 gene. cDNA bubble polymerase chain reaction using BACH2 primers revealed that the first exon of Cdelta was fused to the 5' untranslated region of BACH2 exon 2. The Cdelta-BACH2 fusion transcript consisted of exon 1 of Cdelta and exons 2 to 9 of BACH2, encompassing the entire BACH2 coding region, and the BACH2 was highly expressed in this patient. These results indicate that Cdelta-BACH2 fusion may cause constitutive activation of BACH2. Although additional screening of 47 samples of B-cell non-Hodgkin's lymphoma (B NHL) patients and 29 cell lines derived from B-cell malignancies by double-color fluorescence in situ hybridization analysis detected a split signal with deletion of centromeric region of BACH2 only in a patient with follicular lymphoma, BACH2 was highly expressed in lymphoma cells of the patient and B-NHL cell lines with IGH-MYC translocation. These findings suggest that BACH2 plays a critical role in B-cell lymphomagenesis, especially related to IGH-MYC translocation in some way. PMID- 21319258 TI - Chromosome-specific segmentation revealed by structural analysis of individually isolated chromosomes. AB - Analysis of structural rearrangements at the individual chromosomal level is still technologically challenging. Here we optimized a chromosome isolation method using fluorescent marker-assisted laser-capture and laser-beam microdissection and applied it to structural analysis of two aberrant chromosomes found in a lung cancer cell line. A high-density array-comparative genomic hybridization (array-CGH) analysis of DNA samples prepared from each of the chromosomes revealed that these two chromosomes contained 296 and 263 segments, respectively, ranging from 1.5 kb to 784.3 kb in size, derived from different portions of chromosome 8. Among these segments, 242 were common in both aberrant chromosomes, but 75 were found to be chromosome-specific. Sequences of 263 junction sites connecting the ends of segments were determined using a PCR/Sanger sequencing procedure. Overlapping microhomologies were found at 169 junction sites. Junction partners came from various portions of chromosome 8 and no biased pattern in the positional distribution of junction partners was detected. These structural characteristics suggested the occurrence of random fragmentation of the entire chromosome 8 followed by random rejoining of these fragments. Based on that, we proposed a model to explain how these aberrant chromosomes are formed. Through these structural analyses, it was demonstrated that the optimized chromosome isolation method described here can provide high-quality chromosomal DNA for high resolution array-CGH analysis and probably for massively parallel sequencing analysis. PMID- 21319259 TI - Microhomologies and topoisomerase II consensus sequences identified near the breakpoint junctions of the recurrent t(7;21)(p22;q22) translocation in acute myeloid leukemia. AB - RUNX1 rearrangements are common genetic abnormalities in acute leukemia. The t(7;21)(p22;q22) translocation, recently described in three cases of myeloid neoplasias, fuses the ubiquitin specific peptidase 42 gene, USP42, a member of the deubiquitinating enzyme family, to RUNX1. In this study, we characterized the semicryptic t(7;21)(p22;q22) translocation, identified by fluorescent in situ hybridization and spectral karyotyping, in a novel case of acute myeloid leukemia. Sequence analysis of the reverse transcription-polymerase chain reaction products confirmed the presence of two in-frame RUNX1-USP42 and one reciprocal in-frame USP42-RUNX1 fusion transcripts. Bioinformatic analysis of the genomic translocation breakpoints revealed microhomologies and insertion of shared nucleotides at the junctions. A topoisomerase II sequence was also detected near the break site. Additionally, we demonstrated a significant overexpression of the rearranged USP42 gene in t(7;21) positive cells using quantitative real-time PCR. Our results provide the first evidence of the possible involvement of the nonhomologous end-joining mechanism in the origin of the recurrent t(7;21) translocation. Moreover, presence of the complete catalytic USP site in the putative chimeric proteins and the upregulated expression of USP42 suggest a role of the deubiquitinating enzyme in the pathogenesis of this leukemia. PMID- 21319260 TI - Alternative lengthening of telomeres--an enhanced chromosomal instability in aggressive non-MYCN amplified and telomere elongated neuroblastomas. AB - Telomere length alterations are known to cause genomic instability and influence clinical course in several tumor types, but have been little investigated in neuroblastoma (NB), one of the most common childhood tumors. In the present study, telomere-dependent chromosomal instability and telomere length were determined in six NB cell lines and fifty tumor biopsies. The alternative lengthening of telomeres (ALT) pathway was assayed by scoring ALT-associated promyelocytic leukemia (PML) bodies (APBs). We found a reduced probability of overall survival for tumors with increased telomere length compared to cases with reduced or unchanged telomere length. In non-MYCN amplified tumors, a reduced or unchanged telomere length was associated with 100% overall survival. Tumor cells with increased telomere length had an elevated frequency of APBs, consistent with activation of the ALT pathway. The vast majority of tumor biopsies and cell lines exhibited an elevated rate of anaphase bridges, suggesting telomere-dependent chromosomal instability. This was more pronounced in tumors with increased telomere length. In cell lines, there was a close correlation between lack of telomere-protective TTAGGG-repeats, anaphase bridging, and remodeling of oncogene sequences. Thus, telomere-dependent chromosomal instability is highly prevalent in NB, and may contribute to the complexity of genomic alterations as well as therapy resistance in the absence of MYCN amplification and in this tumor type. PMID- 21319261 TI - Evaluation of TP53 mutations with the AmpliChip p53 research test in chronic lymphocytic leukemia: correlation with clinical outcome and gene expression profiling. AB - Given that TP53 alterations predict prognosis and response to therapy in chronic lymphocytic leukemia (CLL), screening for TP53 mutations has an increasing role in patient management. TP53 direct sequencing is a time-consuming method, while the AmpliChip p53 Research Test is a novel non time-consuming microarray-based resequencing assay and queries Exons 2-11. We evaluated the impact of TP53 mutations on clinical outcome by analyzing 98 untreated CLL using the AmpliChip p53 Research Test and direct sequencing and performed microarrays analysis on TP53 mutated and/or deleted cases. The AmpliChip p53 Research Test detected 17 mutations in 14 patients (17.3%); a significant association between TP53 mutations and del(17p) was recorded. From a clinical standpoint, a higher percentage of mutation was found in CLL with unfavorable outcome (17.2% vs. 7.1% in progressive vs. stable cases). Detection of TP53 mutations by the AmpliChip p53 Research Test was associated with a significantly worse survival (P = 0.0002). Comparison of the array and direct sequencing tests showed that the p53 Research Test detected more mutations, although it failed to identify two microdeletions. Finally, microarrays analysis showed a more distinctive signature associated with del(17p) than with TP53 mutations, likely due to a concomitant gene dosage effect. The AmpliChip p53 Research Test is a straightforward method that bears prognostic value. This study confirms a high percentage of TP53 mutations in CLL with unfavorable outcome and a significant association between TP53 aberrations and del(17p). Finally, specific gene expression profiles are recognized for TP53 alterations. PMID- 21319262 TI - Sporadic breast cancer patients' germline DNA exhibit an AT-rich microsatellite signature. AB - Using a custom CGH-like oligonucleotide array to measure the global microsatellite content in the genomes of 72 cancer, cancer-free, and high risk patient and cell line samples (56 germline DNA and 16 in tumor or tumor cell line DNA) we found a unique, reproducible, and statistically significant pattern of 18 motif-specific microsatellite families (out of 962 possible 1-6 mer repeats) in breast cancer patient germline and tumor DNA, but not in germline DNA of cancer free volunteer controls or in breast cancer patients with BRCA1/2 mutations. These high-similarity A/T rich repetitive motifs were also more pronounced in the germlines and tumors of colon cancer tumor patients (3/6 samples) and microsatellite unstable colon cancer cell lines; however, germline DNA of sporadic breast cancer patients exhibited the largest global content shift for those motifs with extreme AT/GC ratios. These results indicate that global microsatellite variability is complex, suggest the existence of a previously unknown genomic destabilization mechanism in breast cancer patients' germline DNA, and warrant further testing of such microsatellite variability as a predictor of future breast cancer development. PMID- 21319263 TI - Expression status of the autophagy-regulatory gene ATG6/BECN1 in ERBB2-positive breast carcinomas: bypassing ERBB2-induced oncogenic senescence to regulate the efficacy of ERBB2-targeted therapies. PMID- 21319264 TI - Double dissociation between syntactic gender and picture naming processing: a brain stimulation mapping study. AB - Neural foundations of syntactic gender processing remain poorly understood. We used electrostimulation mapping in nine right-handed awake patients during surgery for a glioma within the left hemisphere, to study whether the cortico subcortical structures involved in naming versus syntactic gender processing are common or distinct. In French, the article determines the grammatical gender. Thus, the patient was asked to perform a picture naming task and to give the appropriate article for each picture, with and without stimulation. Cortical stimulation elicited reproducible syntactic gender disturbances in six patients, in the inferior frontal gyrus (three cases), and in the posterior middle temporal gyrus (three cases). Interestingly, no naming disorders were generated during stimulation of the syntactic sites, while cortical areas inducing naming disturbances never elicited grammatical gender errors when stimulated. Moreover, at the subcortical level, stimulation of the white matter lateral to the caudate nucleus induced gender errors in three patients, with no naming disorders. Using cortico-subcortical electrical mapping in awake patients, we demonstrate for the first time (1) a double dissociation between syntactic gender and naming processing, supporting independent network model rather than serial theory, (2) the involvement of the left inferior frontal gyrus, especially the pars triangularis, and the posterior left middle temporal gyrus in grammatical gender processing, (3) the existence of white matter pathways, likely a sub-part of the left superior longitudinal fasciculus, underlying a large-scale distributed cortico-subcortical circuit which might selectively sub-serve syntactic gender processing, even if interconnected with parallel sub-networks involved in naming (semantic and phonological) processing. PMID- 21319265 TI - Early event-related cortical activity originating in the frontal eye fields and inferior parietal lobe predicts the occurrence of correct and error saccades. AB - Although the cortical circuitry underlying saccade execution has well been specified by neurophysiological and functional imaging studies, the temporal dynamics of cortical activity predicting the occurrence of voluntary or reflexive saccades in humans are largely unknown. Here, we examined electrophysiological activity preceding the onset of correct (i.e., voluntary) or error (i.e., reflexive) saccades in an oculomotor capture task. Participants executed saccades to lateralized visual targets while attempting to inhibit reflexive glances to abruptly appearing distracters. Since the visual display was identical for both types of saccades, different electrophysiological patterns preceding correct and error saccades could not be explained by low-level perceptual differences. Compared to correct saccades electrophysiological activity preceding error saccades showed significant differences of the scalp electric field and of voltage amplitudes at posterior electrodes. In addition, though error saccades had significantly shorter latency than correct saccades a prolonged topographic configuration of electric potentials prior to error saccades was found ~120-140 ms following target onset. In agreement with the known asymmetry in hemispheric dominance for spatial attention, distinct electrophysiological patterns were only found for leftward saccades. While error saccades were associated with stronger activity in the right Frontal Eye Field, correct saccades were preceded by stronger activity in the inferior parietal lobule. These findings suggest that selection of the saccade target in a conflicting situation is determined by early top-down biases originating in frontal and parietal cortical regions critical for spatial attention and saccade programming. PMID- 21319266 TI - Exploring the detection of associatively novel events using fMRI. AB - Identifying and evaluating events which are novel in a particular environment is crucially important for adaptive behavior. These events are often not just novel, as they typically violate expectations which may be formulated based on numerous features of our surroundings, one of which includes the ordinal structure (temporal order) of relevant stimuli. Events which violate such expectations, namely sequential deviants, constitute one category of associatively novel stimuli. The present event-related fMRI study investigated the detection of sequential deviants presented within three types of equivalently organized, attended visual sequences which differed in stimulus dimensions relevant for defining the sequential structure (position, rhythm, and object identity). Presenting deviants within perceptual sequences defined by position and rhythm stimulus properties triggered comparable patterns of activations within the lateral parietal, premotor, and prefrontal regions. However, the activations identified in the context of position sequences showed a more dorsal distribution when compared to those in rhythm sequences. In contrast, detection of deviants within object sequences was supported by right-lateralized parietal and temporal cortices. Thus, although the obtained results indicate similarities and partial overlap in activations triggered by specific pairs of deviants, differences in their processing were also revealed. This suggests that the general task context and specific stimulus features which define the deviant itself influence which brain regions within a widespread network incorporating lateral prefrontal, anterior premotor, and posterior (mainly lateral parietal) areas will become engaged in its processing. PMID- 21319267 TI - Neural processes for intentional control of perceptual switching: a magnetoencephalography study. AB - This article reports an interesting link between the psychophysical property of intentional control of perceptual switching and the underlying neural activities. First, we revealed that the timing of perceptual switching for a dynamical dot quartet can be controlled by the observers' intention, without eye movement. However, there is a clear limitation to this control, such that each animation frame of the stimulus must be presented for a sufficiently long time length; in other words, the frequency of the stimulus alternation must be sufficiently slow for the control. The typical stimulus onset asynchrony for a 50% level of success was about 275 ms for an average of 10 observers. On the basis of psychophysical property, we designed three experiments for investigating the neural process with a magnetoencephalography. They revealed that: (1) a peak component occurring about 300 ms after a reversal was stronger when the direction of perceived motion was switched intentionally than when it was not switched, and (2) neural components about 30-40 ms and 240-250 ms after the reversal of the stimulus animation were stronger when perception was altered intentionally than when it was switched unintentionally. The 300 ms component is consistent with a previous study about passive perceptual switching (Struber and Herrmann [ 2002]: Cogn Brain Res 14:370-382), but the intentional effect was seemed to be a different component from the well-known P300 component. PMID- 21319268 TI - Improving the interpretability of all-to-all pairwise source connectivity analysis in MEG with nonhomogeneous smoothing. AB - Studying the interaction between brain regions is important to increase our understanding of brain function. Magnetoencephalography (MEG) is well suited to investigate brain connectivity, because it provides measurements of activity of the whole brain at very high temporal resolution. Typically, brain activity is reconstructed from the sensor recordings with an inverse method such as a beamformer, and subsequently a connectivity metric is estimated between predefined reference regions-of-interest (ROIs) and the rest of the source space. Unfortunately, this approach relies on a robust estimate of the relevant reference regions and on a robust estimate of the activity in those reference regions, and is not generally applicable to a wide variety of cognitive paradigms. Here, we investigate the possibility to perform all-to-all pairwise connectivity analysis, thus removing the need to define ROIs. Particularly, we evaluate the effect of nonhomogeneous spatial smoothing of differential connectivity maps. This approach is inspired by the fact that the spatial resolution of source reconstructions is typically spatially nonhomogeneous. We use this property to reduce the spatial noise in the cerebro-cerebral connectivity map, thus improving interpretability. Using extensive data simulations we show a superior detection rate and a substantial reduction in the number of spurious connections. We conclude that nonhomogeneous spatial smoothing of cerebro-cerebral connectivity maps could be an important improvement of the existing analysis tools to study neuronal interactions noninvasively. PMID- 21319269 TI - Altered functional connectivity in default mode network in absence epilepsy: a resting-state fMRI study. AB - Dysfunctional default mode network (DMN) has been observed in various mental disorders, including epilepsy (see review Broyd et al. [2009]: Neurosci Biobehav Rev 33:279-296). Because interictal epileptic discharges may affect DMN, resting state fMRI was used in this study to determine DMN functional connectivity in 14 healthy controls and 12 absence epilepsy patients. To avoid interictal epileptic discharge effects, testing was performed within interictal durations when there were no interictal epileptic discharges. Cross-correlation functional connectivity analysis with seed at posterior cingulate cortex, as well as region wise calculation in DMN, revealed decreased integration within DMN in the absence epilepsy patients. Region-wise functional connectivity among the frontal, parietal, and temporal lobe was significantly decreased in the patient group. Moreover, functional connectivity between the frontal and parietal lobe revealed a significant negative correlation with epilepsy duration. These findings indicated DMN abnormalities in patients with absence epilepsy, even during resting interictal durations without interictal epileptic discharges. Abnormal functional connectivity in absence epilepsy may reflect abnormal anatomo functional architectural integration in DMN, as a result of cognitive mental impairment and unconsciousness during absence seizure. PMID- 21319270 TI - Probabilistic fiber tracking using the residual bootstrap with constrained spherical deconvolution. AB - Constrained spherical deconvolution (CSD) is a new technique that, based on high angular resolution diffusion imaging (HARDI) MR data, estimates the orientation of multiple intravoxel fiber populations within regions of complex white matter architecture, thereby overcoming the limitations of the widely used diffusion tensor imaging (DTI) technique. One of its main applications is fiber tractography. The noisy nature of diffusion-weighted (DW) images, however, affects the estimated orientations and the resulting fiber trajectories will be subject to uncertainty. The impact of noise can be large, especially for HARDI measurements, which employ relatively high b-values. To quantify the effects of noise on fiber trajectories, probabilistic tractography was introduced, which considers multiple possible pathways emanating from one seed point, taking into account the uncertainty of local fiber orientations. In this work, a probabilistic tractography algorithm is presented based on CSD and the residual bootstrap. CSD, which provides accurate and precise estimates of multiple fiber orientations, is used to extract the local fiber orientations. The residual bootstrap is used to estimate fiber tract probability within a clinical time frame, without prior assumptions about the form of uncertainty in the data. By means of Monte Carlo simulations, the performance of the CSD fiber pathway uncertainty estimator is measured in terms of accuracy and precision. In addition, the performance of the proposed method is compared to state-of-the-art DTI residual bootstrap tractography and to an existing probabilistic CSD tractography algorithm using clinical DW data. PMID- 21319271 TI - Cdk6-dependent regulation of G(1) length controls adult neurogenesis. AB - The presence of neurogenic precursors in the adult mammalian brain is now widely accepted, but the mechanisms coupling their proliferation with the onset of neuronal differentiation remain unknown. Here, we unravel the major contribution of the G(1) regulator cyclin-dependent kinase 6 (Cdk6) to adult neurogenesis. We found that Cdk6 was essential for cell proliferation within the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. Specifically, Cdk6 deficiency prevents the expansion of neuronally committed precursors by lengthening G(1) phase duration, reducing concomitantly the production of newborn neurons. Altogether, our data support G(1) length as an essential regulator of the switch between proliferation and neuronal differentiation in the adult brain and Cdk6 as one intrinsic key molecular regulator of this process. PMID- 21319272 TI - Concise review: stem cells for the treatment of cerebellar-related disorders. AB - Embryonic neural transplants have become clinically relevant over the past 25 years for their possible application in the treatment of cerebellum-related neurodegenerative diseases. While highlighting the important role that fetal neural progenitors have in meeting these challenges, we define rationales for all types of cell therapy involving adult stem cells as well as human embryonic stem cells (hESC) and human induced pluripotent stem (iPS) cells. The recent advances in the field of hESC and iPS cells, including their capacity for differentiation toward regional specific neural lineages, could open a new era of transplantation in cell-based therapy for cerebellar ataxias. PMID- 21319274 TI - Genetics of ulcerative colitis. AB - Ulcerative colitis (UC) and Crohn's disease (CD) are related polygenic inflammatory bowel diseases (IBDs), with distinct and overlapping susceptibility loci. Recently, hypothesis-free genome-wide association (GWA) studies have revolutionized the field of complex disease genetics. Substantial advances have been achieved in defining the genetic architecture of IBD. To date, over 60 published IBD susceptibility loci have been discovered and replicated, of which approximately a third are associated with both UC and CD, although 21 are specific to UC and 23 to CD. In CD, the breakthrough identification of NOD2 as a susceptibility gene was followed by a rapid phase of gene discovery from GWA studies between 2006 and 2008. Progress in UC was slower; however, by initially testing hits for CD in UC, and later scanning larger UC cohorts, significant new loci for UC have been discovered, with exciting novel insights into disease pathogenesis. Notably, genes implicated in mucosal barrier function (ECM1, CDH1, HNF4alpha, and laminin B1) confer risk of UC; furthermore, E-cadherin is the first genetic correlation between colorectal cancer and UC. Impaired IL10 signaling has reemerged as a key pathway in intestinal inflammation, and is perhaps the most amenable to therapeutic intervention in UC. Collaborative international efforts with large meta-analyses of GWA studies and replication will yield many new UC genes. Furthermore, a large effort is required to characterize the loci found. Fine-mapping, deep resequencing, and functional studies will be critical to translating these gene discoveries into pathogenic insights, and ultimately into clinical insights and novel therapeutics. PMID- 21319273 TI - An important role for CDK2 in G1 to S checkpoint activation and DNA damage response in human embryonic stem cells. AB - A precise understanding of mechanisms used by human embryonic stem cells (hESCs) to maintain genomic integrity is very important for their potential clinical applications. The G1 checkpoint serves to protect genomic integrity and prevents cells with damaged DNA from entering S-phase. Previously, we have shown that downregulation of cyclin-dependent kinase 2 (CDK2) in hESC causes G1 arrest, loss of pluripotency, upregulation of cell cycle inhibitors p21 and p27 and differentiation toward extraembryonic lineages. In this study, we investigate in detail the role of CDK2 in cellular processes, which are crucial to the maintenance of genomic stability in hESC such as G1 checkpoint activation, DNA repair, and apoptosis. Our results suggest that downregulation of CDK2 triggers the G1 checkpoint through the activation of the ATM-CHK2-p53-p21 pathway. Downregulation of CDK2 is able to induce sustained DNA damage and to elicit the DNA damage response (DDR) as evidenced by the formation of distinct gamma-H2.AX and RAD52-BRCA1 foci in hESC nuclei. CDK2 downregulation causes high apoptosis at the early time points; however, this is gradually decreased overtime as the DDR is initiated. Our mass spectrometry analysis suggest that CDK2 does interact with a large number of proteins that are involved in key cellular processes such as DNA replication, cell cycle progression, DNA repair, chromatin modeling, thus, suggesting a crucial role for CDK2 in orchestrating a fine balance between cellular proliferation, cell death, and DNA repair in hESC. PMID- 21319275 TI - Prednisolone treatment affects the performance of the QuantiFERON gold in-tube test and the tuberculin skin test in patients with autoimmune disorders screened for latent tuberculosis infection. AB - BACKGROUND: During screening for latent tuberculosis infection (LTBI), before anti-tumor-necrosis-factor-alpha treatment, most patients are already receiving immunosuppressive therapy. The objective was to evaluate the performance of the QuantiFERON Gold In-Tube (QFT-IT) and the Tuberculin Skin Test (TST). METHODS: A prospective multicenter study included 248 patients with ulcerative colitis (39), Crohn's disease (54), rheumatoid arthritis (111), and spondylo-arthropathy (44). RESULTS: QFT-IT was positive in 7/248 (3%), negative in 229 (92%), and indeterminate in 12 (5%). TST was positive in 54/238 (23%) patients. Chest x-ray was suspect for tuberculosis in 5/236 (2%), and 35/167 (21%) had >=1 risk-factors for infection with Mycobacterium tuberculosis. The main finding was a pronounced negative effect on QFT-IT and TST performance associated with prednisolone treatment. During prednisolone treatment interferon gamma (IFN-gamma) response to mitogen stimulation was impaired (median IFN-gamma response 4.9 IU/mL; interquartile range [IQR] 0.8 to >=10.0) compared to patients 1) not receiving corticosteroids (median >=10.0; IQR 5.0 to >=10.0; P = 0.0015) or 2) receiving long-acting corticosteroids (median >10.0; IQR 9.7 to >10.0; P = 0.0058). Prednisolone treatment was strongly associated with negative TST, adjusted odds ratio (AOR) 0.22 (0.1-0.8; P = 0.018), and with an increased risk of indeterminate QFT-IT results AOR 16.1 (4.1-63.2; P < 0.001), whereas no negative effect was found for long-acting corticosteroids. Doses of >=10 mg prednisolone were associated with a 27% risk of indeterminate results. Single use of azathioprine, methotrexate, or 5-aminosalicylate (5-ASA) did not affect the test results. CONCLUSIONS: Oral prednisolone severely suppressed QFT-IT and TST performance, whereas the long-acting corticosteroids methotrexate, azathioprine, and 5-ASA did not have a similar detrimental effect. Patients should be screened for LTBI with QFT-IT or TST prior to initiation of prednisolone therapy and negative QFT-IT or TST results interpreted with caution in patients treated with any corticosteroid until further data are available. PMID- 21319276 TI - Splenic granulomas in a patient with severe Crohn's disease associated with multiple extraintestinal manifestations. PMID- 21319277 TI - Fetal genetic risk of isolated cleft lip only versus isolated cleft lip and palate: a subphenotype analysis using two population-based studies of orofacial clefts in Scandinavia. PMID- 21319278 TI - Maternal self-reported genital tract infections during pregnancy and the risk of selected birth defects. AB - BACKGROUND: Genital tract infections are common during pregnancy and can result in adverse outcomes including preterm birth and neonatal infection. This hypothesis-generating study examined whether these infections are associated with selected birth defects. METHODS: We conducted a case-control study of 5913 children identified as controls and 12,158 cases with birth defects from the National Birth Defects Prevention Study (1997-2004). Maternal interviews provided data on genital tract infections that occurred from one month before pregnancy through the end of the first trimester. Infections were either grouped together as a single overall exposure or were considered as a subgroup that included chlamydia/gonorrhea/pelvic inflammatory disease. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression with adjustment for potential confounders. RESULTS: Genital tract infections were associated with bilateral renal agenesis/hypoplasia (OR, 2.89; 95% CI, 1.11 7.50), cleft lip with or without cleft palate (OR, 1.46; 95% CI, 1.03-2.06), and transverse limb deficiency (OR, 1.84; 95% CI, 1.04-3.26). Chlamydia/gonorrhea/pelvic inflammatory disease was associated with cleft lip only (OR, 2.81; 95% CI, 1.39-5.69). These findings were not statistically significant after adjustment for multiple comparisons. CONCLUSIONS: Caution is needed in interpreting these findings due to the possible misclassification of infection, the limited sample size that constrained consideration of the effects of treatment, and the possibility of chance associations. Although these data do not provide strong evidence for an association between genital tract infections and birth defects, additional research on the possible effects of these relatively common infections is needed. PMID- 21319279 TI - Health outcomes among infants born to women deployed to United States military operations during pregnancy. AB - BACKGROUND: Military professionals who deploy to combat operations may encounter hazards that could adversely affect reproductive health. Pregnant women are generally exempt from deployment to military operations; however, exposures to such environments may inadvertently occur. We investigated whether maternal deployment during pregnancy was associated with adverse health outcomes in infants. METHODS: The United States Department of Defense Birth and Infant Health Registry identified infants born to military service women between 2002 and 2005, and defined their health outcomes at birth and in the first year of life. Multivariable modeling was applied to investigate preterm birth and birth defects among infants, based on maternal deployment experience during pregnancy. RESULTS: Among 63,056 infants born to military women from 2002 to 2005, 22,596 were born to women with deployment experience in support of the current military operations before, during, or after their pregnancy. These included 2941 infants born to women who appeared to have been deployed some time during their first trimester of pregnancy. Compared to infants born to women who deployed at other times, or never deployed, exposed infants were not more likely to be born preterm, diagnosed with a major birth defect, or diagnosed with a malignancy. CONCLUSIONS: In this exploratory analysis, infants born to women who inadvertently deployed to military operations during their pregnancy were not at increased risk of adverse birth or infant health outcomes. Future analyses should examine outcomes related to specific maternal exposures during deployment, and outcomes among the growing number of infants conceived after deployment. PMID- 21319280 TI - Tele-practice guidelines for the symptom management of children undergoing cancer treatment. AB - The provision of tele-practice symptom management is often without the provision of evidence-based guidelines. Under the auspices of the Pediatric Oncology Group of Ontario, a nursing task force was established to appraise the evidence and develop guidelines. Promising new efforts to enhance symptom management through tele-practice are emerging. Seven guidelines and one documentation tool were created from evidence compiled from case reports, clinical examples, and nonexperimental studies. The symptom management guidelines contribute to the paucity of literature and may serve as a useful resource for health professionals providing telephone advice and conducting tele-practice symptom management assessments. PMID- 21319281 TI - Invasive fungal infections in pediatric oncology. AB - BACKGROUND: Data on the epidemiology and outcome of invasive fungal infections in children with cancer are limited. The aim of the study was to delineate the epidemiologic, clinical features, risk factors, and outcome of invasive fungal infections in this population. PROCEDURE: The medical records of all children with malignancies diagnosed with an invasive fungal infection in 1998-2006 at a tertiary pediatric medical center were reviewed for demographic, clinical, and laboratory data. Invasive fungal infection was diagnosed according to the latest EORTC/MSG criteria. RESULTS: Of the 1,047 children hospitalized in the hematology/oncology department during the study period, 75 (7.2%) were diagnosed with a proven (n = 16, 21.3%), probable (n = 18, 24%), or possible (n= 41, 54.7%) invasive fungal infection. Fifteen (20%) had candidemia (non-albicans in 60%), and 60 (80%) had a mold infection (non-Aspergillus in 55%). Crude mortality was 21.7%. The most common underlying diseases were myeloid leukemia (n = 26, 34.7%) and acute lymphoblastic leukemia (n = 24, 32%). Compared to other malignancies, acute myeloid leukemia was significantly associated with the development of invasive fungal infections. Profound neutropenia and high treatment intensity were present in 89% and 73% of patients with IFI respectively. CONCLUSIONS: The current mortality rates of invasive fungal infection in children with cancer are lower than previously reported in children and adults. However, the proportion of non-albicans candidemia is increasing, and non-Aspergillus molds are emerging as important pathogens, which may have important implications for prophylaxis and empiric therapy. Improved prevention, early detection, and advanced treatment strategies are needed to improve the outcome. PMID- 21319282 TI - Impact of chemotherapy on disseminated low-grade glioma in children and adolescents: report from the HIT-LGG 1996 trial. AB - BACKGROUND: We describe demographic data of disseminated childhood low-grade glioma (DLGG) prospectively recruited in the HIT-LGG 1996 study and evaluate the impact of primary chemotherapy (CT) on the outcome of these tumors, which have previously only been described in small and retrospective series. PATIENTS AND METHODS: The multicenter study HIT-LGG 1996 accrued 1181 children and adolescents with low-grade glioma. 61 patients (5.2%) had tumor dissemination, with 2.8% being present at diagnosis. Frequencies of dissemination for different subgroups were calculated. Efficiency of first-line CT with vincristine/carboplatin was defined in 24 children with dissemination prior to first-line non-surgical treatment. RESULTS: Incidence of dissemination was high among infants (16%) with hypothalamic-chiasmatic-glioma (HCG) and diencephalic syndrome. A relevant percentage of HCG showed isolated spinal dissemination. CT achieved objective and overall response rates of 25% and 79% of the primary tumor and a similar response of disseminated lesions. Clinical stabilization or improvement could be achieved in the majority of patients during treatment. However, 20 of 24 patients experienced further progression and 5-year PFS was 6%. Dissemination prior to CT was a negative prognostic factor for PFS within the study (P = 0.005). Overall survival of primary DLGG was inferior compared to LGG without dissemination at diagnosis (P < 0.001). CONCLUSION: Complete MRI scan should be a standard diagnostic procedure in young children with hypothalamic-chiasmatic tumors especially if presenting with diencephalic syndrome. Dissemination in childhood LGG relates to impaired PFS. CT delays progression for responders. Multicenter studies have to evaluate the efficacy of extended treatment strategies in DLGG to improve outcome. PMID- 21319283 TI - Decision rules in childhood febrile neutropenia. PMID- 21319284 TI - A cross-sectional study of overweight in pediatric survivors of acute lymphoblastic leukemia (ALL). AB - BACKGROUND: Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for overweight, predisposing them to long-term morbidity. We examined the relationship between body mass index (BMI) and demographic and lifestyle factors in a cohort of ALL survivors. PROCEDURE: We enrolled consecutive ALL survivors who attended the institutional AfterCare Clinic over a 1-year period. BMI (kg/m(2) ) at diagnosis, end-therapy, and current time were calculated. Survivors were classified as overweight/obese (overweight group; BMI for age >= 85th percentile) or normal/underweight (normal weight group; BMI for age <85th percentile). We assessed the relationship between current BMI and self-reported current caloric intake, physical activity, and sedentary behavior. RESULTS: 102/157 (65%) eligible survivors consented to enrollment. Median age was 14.3 years (range 8.4-18.6) and time from end of treatment 7 years (2.5-15.6). The proportion of overweight survivors was 21%, 45%, and 35% at diagnosis, end therapy, and current time, respectively. The overweight group reported less calories (Delta324 kcal, P = 0.018), fat (Delta14.5 g, P = 0.02), and carbohydrates (Delta39 g, P = 0.02) than the normal weight group. These differences disappeared after excluding patients classified as under-reporting their calorie intake according to the Goldberg cut-off method. There were no differences in sedentary behavior or activity between groups. CONCLUSIONS: Many children with ALL gain weight during therapy and fail to return to normal weight after treatment concludes. Subsequent diet, physical activity, and sedentary behavior do not appear to differ between overweight and normal weight survivors. Clinicians should focus on ways to minimize weight gain during therapy rather than waiting for treatment to conclude. PMID- 21319285 TI - FondaKIDS: a prospective pharmacokinetic and safety study of fondaparinux in children between 1 and 18 years of age. AB - BACKGROUND: The incidence of thromboembolic disease is increasing in children. New anticoagulants have been licensed in adults and need to be studied in children. This report describes the first prospective study of fondaparinux in children. PROCEDURE: The purpose of the study was to determine the dosing, pharmacokinetics, and safety of fondaparinux in children with deep vein thrombosis (DVT) or heparin-induced thrombocytopenia (HIT). Hospitalized children between 1 and 18 years of age with DVT or HIT received fondaparinux 0.1 mg/kg once daily. Fondaparinux-based anti-factor Xa levels were assessed at 2, 4, 12, and 24 hr following the first dose, and peak levels were measured twice weekly thereafter. Detailed pharmacokinetic analyses were performed. RESULTS: Twenty four subjects in 3 age cohorts were enrolled and completed the study. Pharmacokinetic modeling demonstrated that a once-daily dose of fondaparinux at 0.1 mg/kg resulted in similar concentrations known to be efficacious in adults. Safety was demonstrated with only two bleeding events: one which may have pre dated study drug administration and one which led only to temporary discontinuation of study drug. CONCLUSION: Dosing of fondaparinux at 0.1 mg/kg once daily in children resulted in PK profiles comparable to those in adults receiving standard dosing. Fondaparinux can be considered an attractive alternative to LMWH given its once-daily dosing, acceptable safety data, and other favorable properties. PMID- 21319286 TI - Thiopurine S-methyltransferase (TPMT) polymorphisms in children with acute lymphoblastic leukemia, and the need for reduction or cessation of 6 mercaptopurine doses during maintenance therapy: the Polish multicenter analysis. AB - BACKGROUND: 6-Mercaptopurine (6-MP) is used for the treatment of pediatric acute lymphoblastic leukemia (ALL). Mutations in the TPMT gene may influence the efficacy and safety of 6-MP treatment. This multicenter study investigated the association between TPMT genotype, 6-MP dose adjustments, and the incidence of adverse effects in patients. PROCEDURE: A total of 203 ALL children were genotyped using PCR/allele-specific amplification and PCR/RFLP. The control group consisted of 394 healthy volunteers. RESULTS: The TPMT*3A variant allele was found in 16 patients (15 TPMT*1/*3A, 1 TPMT*3A/*3A) and the TPMT*3C (A719G) allele in 1 patient. No TPMT*2 (G238C) or TPMT*3B (G460A) alleles were detected in the study group. TPMT*3A, TPMT*1 (wild-type), and TPMT*3C alleles were detected at frequencies of 3.94%, 95.81%, and 0.25%, respectively. The genotype and allele distributions were similar in the ALL and control groups. The 6-MP dose was reduced more frequently in patients with TPMT*3A and TPMT*3C alleles, compared with wild-type alleles (P = 0.042). Reductions because of leucopenia with respiratory tract infection, or because of leucopenia, anemia and/or thrombocytopenia were four (P = 0.007) and five (P = 0.03) times more common, respectively. The groups differed with regard to the rates of 6-MP dose reduction (P = 0.028). 6-MP was discontinued more often in patients with TPMT*3A and TPMT*3C alleles (14-fold) as a result of leucopenia, anemia, and/or thrombocytopenia (P = 0.004). CONCLUSIONS: The results indicate that TPMT genotype influences the safety and efficacy of ALL treatment and genotype information may therefore be useful for optimizing 6-MP therapy. PMID- 21319288 TI - Health related quality of life in adolescent and young adult survivors of lower extremity bone tumors. AB - BACKGROUND: Dramatic increases in survival rates have led to increased interest regarding the health related quality of life (HRQOL) of adolescent and young adult survivors of bone tumors. This study investigated HRQOL and physical disability in adolescent and young adult survivors of lower extremity bone tumors as a function of type of surgical intervention, gender, and age at assessment. PROCEDURE: Twenty-eight participants (age range 18-32 years) completed three generic and one disease-specific measures of HRQOL and a measure of physical disability. For analysis, surgical intervention was grouped into limb sparing surgeries (LS; allograft fusion and endoprosthesis) and ablative surgeries (AMP; amputation or Van Nes rotationplasty). Age at study was grouped into <= 25 years of age and >= 26 years of age. The MOS-SF-36, HUI2, HUI3, and EORTC-QLQ-C30 were used to measure HRQOL and the TESS was used to assess physical disability. RESULTS: Survivors reported HRQOL equivalent to the general population, with the exception of physical functioning. LS reported poorer HRQOL than AMP participants for emotional functioning and fatigue. Males reported better HRQOL compared with females for overall HRQOL, general health, physical functioning, and social functioning. Finally, younger participants generally reported better HRQOL than older participants for overall HRQOL and physical functioning. CONCLUSIONS: This study identifies LS surgical intervention, female gender and older age as risk factors for reduced HRQOL in adolescent and young adult survivors of lower extremity bone tumors. This study also provides information about what instrument may be most useful in identifying these specific difficulties and subgroups. PMID- 21319287 TI - Preclincial testing of sorafenib and RAD001 in the Nf(flox/flox) ;DhhCre mouse model of plexiform neurofibroma using magnetic resonance imaging. AB - BACKGROUND: Neurofibromatosis type 1 (NF1) is an inherited disease predisposing affected patients to variable numbers of benign neurofibromas. To date there are no effective chemotherapeutic drugs available for this slow growing tumor. Molecularly targeted agents that aim to slow neurofibroma growth are being tested in clinical trials. So preclinical models for testing potential therapies are urgently needed to prioritize drugs for clinical trials of neurofibromas. PROCEDURE: We used magnetic resonance imaging (MRI) to monitor neurofibroma development in the Nf1(flox/flox) ;DhhCre mouse model of GEM grade I neurofibroma. Based on studies implicating mTOR and Raf signaling in NF1 mutant cells, we tested the therapeutic effect of RAD001 and Sorafenib in this model. Mice were scanned to establish growth rate followed by 8 weeks of drug treatment, then re-imaged after the last dose of drug treatment. Tumor volumes were determined by volumetric measurement. RESULTS: We found that rate of tumor growth varied among mice, as it does in human patients. RAD001 inhibited its predicted target pS6K, yet there was no significant decrease in the tumor volume in RAD001 treated mice compared to the vehicle control group. Sorafenib inhibited cyclinD1 expression and cell proliferation in tumors, and volumetric measurements identified significant decreases in tumor volume in some mice. CONCLUSION: The data demonstrate that volumetric MRI analysis can be used to monitor the therapeutic effect in the preclinical neurofibroma drug screening, and suggest that Sorafenib might have clinical activity in some neurofibromas. PMID- 21319289 TI - Survival and late effects in children with stage 4 neuroblastoma. AB - BACKGROUND: Treatment of metastatic neuroblastoma (NB) demands aggressive oncological therapy, which may cause long-term sequelae in survivors. The aim of this retrospective single center study is to give an overview of survival in children with stage 4 NB and to describe the spectrum of late effects seen in survivors. PROCEDURE: Medical records of 31 patients with stage 4 NB treated between 1984 and 2009, who were included in a follow-up programme, were reviewed for information on tumor, treatment and late effects. RESULTS: Five-year overall survival was 54.3 +/- 9% and 5-year event-free survival was 44.9 +/- 9%. Patients diagnosed after 1996 had a significantly better survival rate than those diagnosed before (74 +/- 11.2% vs. 33.3 +/- 12.2%, P = 0.011). In 15 of the 16 survivors (93.8%), numerous late effects were detected. The most common long-term sequelae were renal changes in 10 patients (62.5%) and endocrine disturbances in 9 patients (56.3%), including hypothyroidism with need of substitution in 50%, GH deficiency in 37.5% and hypogonadism in 12.5%. Sensorineural hearing loss occurred in 37.5% of survivors. Further observed late effects were hepatobiliary changes (31.3%), musculoskeletal problems, and pulmonary abnormalities (each 25%), as well as neurologic changes (18.8%), dental defects (12.5%), and unilateral blindness (6.3%). Second neoplasms appeared in 3 patients, 1 of whom died of hepatocellular carcinoma following infection with hepatitis B. CONCLUSIONS: More than 50% of children with stage 4 NB may survive. The high incidence of severe long-term sequelae underlines the importance of careful follow-up in order to detect and treat late effects early enough. PMID- 21319290 TI - Religious coping and the use of prayer in children with sickle cell disease. AB - BACKGROUND: While adolescents and adults with sickle cell disease (SCD) have reported using religion to cope with SCD, there is no data examining religious coping in young children with SCD. The purpose of this qualitative study was to: (1) describe the types of religious coping used by children with SCD; (2) describe the content and frequency of prayer used in relation to SCD; and (3) examine how children viewed God/Higher Power in relation to their SCD. PROCEDURE: Children with SCD participated in a semi-structured interview and an art drawing exercise focused on the use of general coping and religious coping. Interviews were coded, organized, and analyzed using a template organizational style of interpretation and NVivo 8.0 qualitative software. RESULTS: Of the 19 participants, the average age was 8.05 years (SD +/-1.81); 11 were female (58%); all (100%) were African-American and 9 (47%) were Protestant. Children used religion to gain control, make meaning, and find comfort. Most children reported praying to get well, to keep from getting sick, and to get out of the hospital. Children described a functional God who made them take their medicine or took them to the hospital and an emotional God who made them happy and comforted them when they were sad or scared. CONCLUSIONS: These children with SCD reported using religion to help cope with the illness. Providers should be aware of the importance of religion to many of these children and integrate religion, as appropriate, into discussions about coping with SCD. PMID- 21319291 TI - Neuropathic pain during treatment for childhood acute lymphoblastic leukemia. AB - BACKGROUND: Improved cure rates for childhood acute lymphoblastic leukemia (ALL) over the past 2 decades have allowed greater attention to patients' quality of life. Neuropathic pain (NP) is an unpleasant side effect of chemotherapeutic agents for leukemia, especially vincristine. PROCEDURE: We retrospectively reviewed the records of 498 patients treated on a single protocol for ALL to investigate the risk factors, the incidence, and the use of therapeutic and prophylactic gabapentin treatment for NP. RESULTS: White non-Hispanic race was the only patient variable predictive of NP. One hundred and seventy-four of 498 patients (34.9%) experienced 207 episodes of NP; 16% (28 of 174) patients experienced at least one recurrence of pain after the initial episode. No statistical significance was found in the relation between the severity (grade) of the NP episode and the cumulative dose of vincristine (P = 0.45) or the vincristine dose that immediately preceded the diagnosis (1.5 mg/m(2) versus 2.0 mg/m(2) [correction made here after initial online publication], P = 0.59). Of 180 episodes with treatment data, 62.2% (112) and 37.8% (68) were treated with gabapentin or opioids, respectively. The selection of treatment with gabapentin or opioids was not influenced by the pain intensity score at the time of diagnosis of NP (P = 0.91). The mean gabapentin dose used for 112 episodes was 15.5 mg/kg/day (SD 7.9). We found no evidence that gabapentin prevented recurrence of NP. CONCLUSIONS: Our results highlight the need for prospective randomized studies to elucidate the value of gabapentin regimen for prevention or treatment of vincristine-related pain during treatment of childhood leukemia. PMID- 21319293 TI - Nanostructured titanium promotes keratinocyte density. AB - Infection of a transcutaneous orthopedic prosthesis is undesirable and decreases the success rate of an implant. Critical to reducing this infection is to develop materials that can decrease bacteria colonization and/or increase skin growth. Since previous studies have demonstrated significantly less bacteria colonization (yet promoted osteoblast, bone forming cell, functions) on titanium (Ti) with select nanofeatures, the objective of this in vitro study was to determine keratinocyte (skin forming cells) functions on Ti modified to have nanoscale surface features. To further promote keratinocyte functions, some Ti surfaces were functionalized with fibroblast growth factor-2 (FGF-2). Nanometer-sized topographical surface features were created on traditional Ti implants by anodization (termed nanotubular) and electron beam evaporation (termed nanorough). This study found that compared to conventional (nanosmooth) Ti, the nanotubular and nanorough Ti surfaces promoted keratinocyte density. Moreover, when functionalized with FGF-2, keratinocyte density increased on all surfaces, resulting in the greatest keratinocyte density on nanorough and nanotubular Ti functionalized with FGF-2 after 5 days of culture. Interestingly, keratinocyte densities on nanorough and nanotubular Ti were similar to that achieved on conventional Ti functionalized with FGF-2. Therefore, when considered in the context of other studies, the results of this in vitro study demonstrated that certain nanometer-sized Ti topographies may be useful for increasing keratinocyte density while reducing bacteria adhesion and promoting bone tissue formation and, thus, should be further studied for improving the efficacy of various transcutaneous Ti-based orthopedic implants. PMID- 21319292 TI - Circulating endothelial cells and circulating endothelial precursor cells in patients with osteosarcoma. AB - BACKGROUND: Circulating endothelial cells (CECs) have been detected at increased numbers in patients with solid cancers. CECs have not been systematically evaluated in patients with osteosarcoma. PROCEDURE: Patients 12 months to 30 years of age with newly diagnosed high-grade osteosarcoma were eligible for this prospective cohort study. Patients provided a single blood sample at study entry for CEC quantification by flow cytometry at a single reference laboratory. CECs were defined as CD146+, CD31+, CD45-, and CD133-. CEC progenitor cells (CEPs) were defined as CD146+, CD31+, CD45-, and CD133+. RESULTS: Eighteen patients enrolled (11 males; median age 16 years; range 5-21 years). CEC counts did not differ between patients with osteosarcoma compared to seven pediatric healthy controls (median 645 cells/ml, range 60-5,320 cells/ml vs. 1,670 cells/ml, range 330-4,700 cells/ml, respectively; P = 0.12). CEP counts did not differ between patients compared to controls (median 126 cells/ml, range 0-5,320 cells/ml vs. median 260 cells/ml, range 0-10,670 cells/ml, respectively; P = 0.69). CEC and CEP counts did not correlate with metastatic status, tumor size, or histologic response to neoadjuvant chemotherapy. CONCLUSIONS: CEC and CEP levels are not increased in patients with osteosarcoma compared to healthy controls. CECs and CEPs do not correlate with clinical features of osteosarcoma. Alternative novel markers of disease burden and response are needed in this disease. PMID- 21319294 TI - Effect of molecular weight of chitosan degraded by microwave irradiation on lyophilized scaffold for bone tissue engineering applications. AB - Chitosan (CTS) is biocompatible, biodegradable, and can be formed into 3D porous structures for bone tissue engineering applications. Although studies have reported on the effects of molecular weight (MW) on CTS physicochemical properties, studies evaluating CTS biological property relationships often do not account for MW that confounds interpretation of study results. The aim of this study was to evaluate the effect of MW on CTS physicochemical and biological properties. CTS materials were treated for 6, 18, and 30 min by microwave irradiation to decrease MW without affecting deacetylation (DDA). Materials were evaluated for crystallinity using X-ray diffraction, thermal degradation using differential scanning calorimetry, water content, swelling ratio, and in vitro compatibility using Saos-2. Results showed that microwave treatments did not affect DDA but decreased MW and swelling ratio by 45.78% and 36.75%, respectively, after 30 min of microwave treatment. Microwave-treated CTS showed reduced or no crystalline peaks. Initial increase in exothermic peak temperatures with short (6 min) microwave treatment times were followed by a decrease with longer (18 and 30 min) treatment times. Cell growth over 7 days on samples was proportional to MW with the number of cells being 62% higher on CTS with the highest MW (3.71 +/- 0.25 * 10(5) g/mol) when compared with the lower MW CTS (2.38 +/- 0.12 * 10(5) g/mol). These results demonstrate the importance of MW of CTS to both its physicochemical characteristics and biological properties, providing researchers with another tool for the modulation and optimization of CTS for different biomedical applications. PMID- 21319295 TI - Blood protein-polymer adsorption: implications for understanding complement mediated hemoincompatibility. AB - The aim of this study was to create polymeric materials with known properties to study the preconditions for complement activation. Initially, 22 polymers were screened for complement activating capacity. Based on these results, six polymers (P1-P6) were characterized regarding physico-chemical parameters, for example, composition, surface area, pore size, and protein adsorption from human EDTA plasma. P2, P4, and reference particles of polystyrene and polyvinyl chloride, were hydrophobic, bound low levels of protein and were poor complement activators. Their accessible surface was limited to protein adsorption in that they had pore diameters smaller than most plasma proteins. P1 and P3 were negatively charged and adsorbed IgG and C1q. A 10-fold difference in complement activation was attributed to the fact that P3 but not P1 bound high amounts of C1 inhibitor. The hydrophobic P5 and P6 were low complement activators. They selectively bound apolipoproteins AI and AIV (and vitronectin), which probably limited the binding of complement activators to the surface. We demonstrate the usefulness of the modus operandi to use a high-throughput procedure to synthesize a great number of novel substances, assay their physico-chemical properties with the aim to study the relationship between the initial protein coat on a surface and subsequent biological events. Data obtained from the six polymers characterized here, suggest that a complement-resistant surface should be hydrophobic, uncharged, and have a small available surface, accomplished by nanostructured topography. Additional attenuation of complement can be achieved by selective enrichment of inert proteins and inhibitors. PMID- 21319296 TI - Biomaterials coated by dental pulp cells as substrate for neural stem cell differentiation. AB - This study is focused on the development of an in vitro hybrid system, consisting in a polymeric biomaterial covered by a dental pulp cellular stroma that acts as a scaffold offering a neurotrophic support for the subsequent survival and differentiation of neural stem cells. In the first place, the behavior of dental pulp stroma on the polymeric biomaterial based on ethyl acrylate and hydroxy ethyl acrylate copolymer was studied. For this purpose, cells from normal human third molars were grown onto 0.5-mm-diameter biomaterial discs. After cell culture, quantification of neurotrophic factors generated by the stromal cells was performed by means of an ELISA assay. In the second place, survival and differentiation of adult murine neural stem cells on the polymeric biomaterials covered by dental pulp stromal cells was studied. The results show the capacity of dental pulp cells to uniformly coat the majority of the material's surface and to secrete neurotrophic factors that become crucial for a subsequent differentiation of neural stem cells. The use of stromal cells cultured on scaffolding biomaterials provides neurotrophic pumps that may suggest new criteria for the design of cell therapy experiments in animal models to assist the repair of lesions in Central Nervous System. PMID- 21319297 TI - Directed assembly of cell-laden microgels for building porous three-dimensional tissue constructs. AB - The organization of cells within a well-defined microenvironment is important in generating the resulting tissue function. However, the cellular organization within biodegradable scaffolds often does not resemble those of native tissues. In this study, we present directed assembly of microgels to organize cells for building porous 3D tissue constructs. Cell-laden microgels were generated by molding photocrosslinkable polyethylene glycol diacrylate within a poly(dimethyl siloxane) stencil. The resulting microgels were subsequently packed as individual layers (1 mm in height) on a glass substrate by removing the excess prepolymer solution around the microgels. These clusters were crosslinked and stacked on one another to fabricate thick 3D constructs that were greater than 1 cm in width and 3 mm in thickness. To generate pores within the engineered structures, sodium alginate microgels were integrated in the engineered constructs and used as a sacrificial template. These pores may be potentially useful for fabricating a vascular network to supply oxygen and nutrients to the engineered tissue constructs. This simple and versatile building approach may be a useful tool for various 3D tissue culture and engineering applications. PMID- 21319298 TI - Potential role of cathepsin B in the embryonic and larval development of clam Meretrix meretrix. AB - This study was designed to investigate the possible role of Meretrix meretrix cathepsin B (MmeCB) in embryonic and larval development. MmeCB mRNA expression profile was revealed by semi-quantitative RT-PCR. The level of MmeCB mRNA expression was low in trochophore stage but high in pedveliger stage. MmeCB protein expression was detected in the digestive gland, velum, and epidermis along the edges of the shell in D-larvae and pedveligers by immunocytochemistry. In post larvae, MmeCB protein expression was noticed abundant in the digestive gland, whereas a modest expression was identified in the gill filament. The average shell length of larvae hatched from embryos treated with 0.01, 1, and 10 umol/L Ca074Me (a cathepsin B inhibitor) was significantly shorter than that of control groups. The metamorphosis rates of larvae treated with 0.01 and 1 umol/L Ca074Me were significantly lower than that of control groups in 4-day larvae, but not in 5-day larvae. Taken together, these results indicated that MmeCB may have stimulatory effects on embryonic development, metamorphosis, and larval growth during M. meretrix larval development. PMID- 21319299 TI - Standardization of models and methods used to assess nanoparticles in cardiovascular applications. AB - Nanotechnology has the potential to revolutionize the management and treatment of cardiovascular disease. Controlled drug delivery and nanoparticle-based molecular imaging agents have advanced cardiovascular disease therapy and diagnosis. However, the delivery vehicles (dendrimers, nanocrystals, nanotubes, nanoparticles, nanoshells, etc.), as well as the model systems that are used to mimic human cardiac disease, should be questioned in relation to their suitability. This review focuses on the variations of the biological assays and preclinical models that are currently being used to study the biocompatibility and suitability of nanomaterials in cardiovascular applications. There is a need to standardize appropriate models and methods that will promote the development of novel nanomaterial-based cardiovascular therapies. PMID- 21319300 TI - Simple and automatic determination of aldehydes and acetone in water by headspace solid-phase microextraction and gas chromatography-mass spectrometry. AB - We describe a simple and automatic method to determine nine aldehydes and acetone simultaneously in water. This method is based on derivatization with 2,2,2 trifluoroethylhydrazine (TFEH) and consecutive headspace-solid-phase microextraction and gas chromatography-mass spectrometry. Acetone-d(6) was used as the internal standard. Aldehydes and acetone in water reacted for 30 min at 40 degrees C with TFEH in a headspace vial and the formed TFEH derivatives were simultaneously vaporized and adsorbed on polydimethylsiloxane-divinylbenzene. Under the established condition, the method detection limit was 0.1-0.5 MUg/L in 4 mL water and the relative standard deviation was less than 13% at concentrations of 0.25 and 0.05 mg/L. This method was applied to determine aldehydes and acetone in 5 mineral water and 114 surface water samples. All mineral water samples had detectable levels of methanal (24.0-61.8 MUg/L), ethanal (57.7-110.9 MUg/L), propanal (11.5-11.7 MUg/L), butanal, pentanal (3.3 3.4 MUg/L) and nonanal (0.3-0.4 MUg/L). Methanal and ethanal were also detected in concentration range of 2.7-117.2 and 1.2-11.9 MUg/L, respectively, in surface water of 114 monitoring sites in Korea. PMID- 21319301 TI - Solid-Phase Cross-Linking (SPCL): a new tool for protein structure studies. AB - A wide range of chemical reagents are available to study the protein-protein interactions or protein structures. After reaction with such chemicals, covalently modified proteins are digested, resulting in shorter peptides that are analyzed by mass spectrometry (MS). Used especially when NMR of X-ray data are lacking, this methodology requires the identification of modified species carrying relevant information, among the unmodified peptides. To overcome the drawbacks of existing methods, we propose a more direct strategy relying on the synthesis of solid-supported cleavable monofunctional reagents and cross-linkers that react with proteins and that selectively release, after protein digestion and washings, the modified peptide fragments ready for MS analysis. Using this Solid-Phase Cross-Linking (SPCL) strategy, only modified sequences are analyzed and consistent data can be easily obtained since the signals of interest are not masked or suppressed by over-represented unmodified materials. PMID- 21319302 TI - Proteomic identification of radiation response markers in mouse intestine and brain. AB - Increasing efforts are being made to develop more sensitive and faster molecular methodologies at the genomic and proteomic levels for the identification of protein markers after exposure to ionizing radiation (IR). However, few specific protein markers, especially organ-specific markers, have been identified. In this study, we analyzed altered protein expressions in various tissues, namely, brain, lung, spleen, and intestine, from 1 Gy-irradiated mice by employing 2-DE analysis. MALDI-TOF MS and peptide mapping identified 25 proteins that showed greater than twofold expressional changes. In order to confirm significant differences between control and IR-treated samples, ten identified proteins with available commercial antibodies were selected for immunoblotting. Of these, only five showed protein expression patterns that were similar to 2-DE data. These were heat shock protein 5 (HSP 5), HSP 90 kDa beta, HSP 1, transaldolase 1 (TA1), and phosphoglycerate kinase 1 (PGK1). In particular, PGK1 was specifically upregulated in mouse intestine, and TA1 was specifically downregulated in brain by irradiation. TA1 expression was unaltered in other tissues. Based on these data, we suggest that TA1 and PGK1 can be considered as candidate tissue-specific protein markers of IR exposure. PMID- 21319303 TI - Neuropeptide profiling of the bovine hypothalamus: thermal stabilization is an effective tool in inhibiting post-mortem degradation. AB - The hypothalamus is the central regulatory region of the brain that links the nervous system to the endocrine system via the pituitary gland. It synthesizes and secretes neuropeptide hormones, which in turn act to stimulate or inhibit the secretion of pituitary hormones. We have undertaken a detailed MS investigation of the peptides present in the bovine hypothalamus by adapting a novel heat stabilization methodology, which improved peptide discovery to direct our studies into the molecular mechanisms involved in bovine reproduction. The untreated samples contained large numbers of protein degradation products that interfered with the analysis of the neuropeptides. In the thermally stabilized samples, we were able to identify many more neuropeptides that are known to be expressed in the bovine hypothalamus. Furthermore, we have characterized a range of post translational modifications that indicate the presence of processed intact mature neuropeptides in the stabilized tissue samples, whereas we detected many trimmed or truncated peptides resulting from post-mortem degradation in the untreated tissue samples. Altogether, using an optimized workflow, we were able to identify 140 candidate neuropeptides. We also nominate six new candidate neuropeptides derived from proSAAS, secretogranin-2 and proTRH. PMID- 21319304 TI - Proteome profiling suggests a pro-inflammatory role for plasma cells through release of high-mobility group box 1 protein. AB - The final step of B-cell maturation is to differentiate into plasma cells, a process that is accompanied by gross changes in subcellular organization to enable antibody secretion. To better understand this critical step in mounting a humoral immune response, we analyzed proteome dynamics during plasma cell differentiation with combined 2-DE/MS. Thirty-two identified protein spots changed in relative abundance when lipopolysaccharide (LPS)-stimulated primary B cells differentiated into antibody-secreting plasma cells. A correlative analysis of protein and transcript abundance suggested that one third of these proteins are post-transcriptionally regulated. Apart from ER-resident chaperones, lipid metabolic enzymes, and translation initiation factors, we identified several proteins that had not been previously studied in plasma cells. Among them is the transiently upregulated proteasome activator (PA) 28gamma, a component of the putative nuclear proteasome. Additionally, we discovered that the non-canonical inflammatory cytokine high-mobility group box 1 (HMG1) was released from plasma cells into the extracellular milieu. This suggests a novel role for plasma cells as pro-inflammatory mediators, which has important implications for various autoimmune diseases and chronic inflammation. PMID- 21319305 TI - From EosFP to mIrisFP: structure-based development of advanced photoactivatable marker proteins of the GFP-family. AB - Fluorescent proteins from the GFP family have become indispensable imaging tools in life sciences research. In recent years, a wide variety of these proteins were discovered in non-bioluminescent anthozoa. Some of them feature exciting new properties, including the possibility to change their fluorescence quantum yield and/or color by irradiating with light of specific wavelengths. These photoactivatable fluorescent proteins enable many interesting applications including pulse-chase experiments and super-resolution imaging. In this review, we discuss the development of advanced variants, using a structure-function based, molecular biophysics approach, of the photoactivatable fluorescent protein EosFP, which can be photoconverted from green to red fluorescence by ~400 nm light. A variety of applications are presented that demonstrate the versatility of these marker proteins in live-cell imaging. PMID- 21319306 TI - Does gestational temperature or prenatal sex ratio influence development of sexual dimorphism in a viviparous skink? AB - Prenatal sex ratio (through exposure to hormones from siblings in utero) can influence sexually dimorphic traits of many mammals; but research on viviparous reptiles has contrasting outcomes, which have yet to be resolved. The thermal environment experienced during gestation has a strong effect on the phenotype of reptiles, but whether this thermal effect overrides that of prenatal sex ratio has yet to be explored. We experimentally investigated whether the gestation temperature, or litter sex ratio, influences sexually dimorphic traits (head width and axilla-groin length) in a viviparous skink (Oligosoma maccanni). We found that gestation temperature had a significant influence on sexually dimorphic traits of neonates, and at 3 months of age still influenced head width. We found no evidence that traits in either sex were masculinized or feminized in response to litter sex ratio. The development of external sexual dimorphisms increased gradually (all thermal regimes pooled), with neonates showing no sexual dimorphism, 3-month-old juveniles showing some sexual dimorphism in head width, and adults having stronger, but incompletely separated, sexual dimorphism for both traits. We suggest that the overlap in sexually dimorphic traits of adult O. maccanni (and perhaps other reptiles) may be better explained by natural variation in temperatures experienced during embryonic development, rather than hormonal effects arising from litter sex ratio. The interaction of hormones and temperature during gestation and the effect of these factors on sexual dimorphism within reptiles deserve further exploration. PMID- 21319307 TI - Small lesions, big dilemmas: earlier detection creates ethical questions. PMID- 21319308 TI - Wrestling over robotic surgery. PMID- 21319309 TI - Neoplastic pulmonary cytology: why all the fuss over "NSCLC"? PMID- 21319310 TI - Anal cancer and cervical cancer screening: key differences. AB - Cervical cancer and anal cancer share many similarities including causation by oncogenic human papillomaviruses; however, significant differences exist in their epidemiology, risk factors, biologic behavior, management, and treatment. Although rare, the incidence of anal cancer is alarmingly high and continues to increase in high-risk populations, particularly men who have sex with men regardless of their human immunodeficiency virus (HIV) status. There are no national screening guidelines for anal cancer. Using the success of cervical cancer screening as a model, anal cancer screening approaches apply anal cytology, high-resolution anoscopy, and directed biopsy to guide treatment and management strategies. Although much has been learned about the natural history and epidemiology of anal intraepithelial neoplasia (AIN), the rate of progression of high-grade anal intraepithelial neoplasia (HGAIN) to invasive squamous cell carcinomas is not known. The impact of screening and treatment of HGAIN on morbidity and mortality from anal cancer are also unknown. Because the incidence of HGAIN and anal squamous cell carcinoma continue to increase, it is imperative to find pathways for effective screening, early detection, and therapeutic intervention. This article provides an overview of anal cancer screening while highlighting its differences from cervical cancer screening and the remaining obstacles and controversies to implementation of a successful anal cancer screening program. PMID- 21319312 TI - Fine-needle aspiration of renal and extrarenal rhabdoid tumors: the experience of the Institut Curie regarding 20 tumors in 13 patients. AB - BACKGROUND: Rhabdoid tumors (RT) are rare, renal or extrarenal, high-grade malignancies. The cytologic diagnosis may be confirmed if combined with genomic results. In the current study, the authors present the cytologic and ancillary techniques used to diagnose RT in their series of 20 tumors in 13 patients. METHODS: Clinical charts as well as cytologic, histologic, karyotypic, and molecular biology results were reviewed. RESULTS: Twelve fine-needle aspirations (FNAs) were performed for primary diagnosis, 7 were to confirm a metastasis, and 1 was to confirm local recurrence. Primary tumors were in the kidney in 7 cases and 13 were extrarenal. Patient age ranged from 5 months to 26 years. There were 7 females and 6 males. FNAs were cell-rich in 16 cases and cell-poor in 4 cases and revealed a mix of atypical spindle-shaped, round, rhabdoid, or epithelioid cells, singly or in clusters. Mitosis and necrosis occasionally were present. The original cytologic diagnosis was malignant in all cases. There were no unsatisfactory or false-negative samples. In the 12 primary tumors, the preliminary FNA diagnosis was RT in 7 cases (58%), rhabdomyosarcoma in 4 cases (33%), and malignant peripheral nerve sheath tumor in 1 case (8%). Karyotypes were available in 6 cases, 3 of which demonstrated chromosome 22 changes. Fluorescence in situ hybridization revealed loss of probe signals for the SMARCB1 gene locus in 5 cases; DNA sequence analysis performed in 9 cases revealed deletions in codons of the SMARCB1 gene in 7 cases and a mutation in 2 cases. CONCLUSIONS: The primary diagnosis of RT is possible on FNA. In the current study, 12 of 13 cases were diagnosed by FNA with a combination of clinical information, immunocytochemistry, and molecular analysis. PMID- 21319315 TI - Diagnostic issues with cytopathologic interpretation of lung neoplasms displaying high-grade basaloid or neuroendocrine morphology. AB - Basaloid squamous cell carcinoma (BSQCC) and high-grade neuroendocrine carcinomas (HGNEC) including small cell carcinoma (SMCC) and large cell neuroendocrine carcinoma (LCNEC) can be difficult to differentiate on lung cytology. This problem is particularly true in scant specimens where immunoperoxidase stains cannot be adequately performed. Sixty-six cases of BSQCC, LCNEC, and SMCC (22 cases of each) on lung or mediastinal cytology were retrospectively reviewed from the cytopathology archives of two hospitals. Common cytomorphologic characteristics were; hypercellularity, small to intermediate round blue (hyperchromatic) cells, lack of prominent nucleoli, lack of three dimensional architecture, karyorrhexis/necrosis, mitoses, naked nuclei, nuclear crush artifact, and nuclear molding. Distinctive features included: larger cell size with pleomorphism, more cohesive architecture, syncytial aggregation, slightly coarser chromatin texture, rare keratinized malignant cells, and a granular smear background seen more often in BSQCC as opposed to HGNEC. Larger cells with prominent nucleoli and more cytoplasm with focal rosette formation were helpful in distinguishing LCNEC from SMCC and BSQCC. Finally, SMCC displayed uniform small cells with extensive necrosis, and higher mitotic rate. Immunoperoxidase (IPOX) staining using p63, CK5, 6, neuroendocrine markers (chromogranin, synaptophysin and CD56) and TTF-1 were helpful. BSQCC showed p63 expression and was mostly negative for neuroendocrine markers and TTF-1. HGNEC showed immunoreactivity for neuroendocrine markers with variable immunoreactivity for TTF-1. BSQCC, SMCC, and LCNEC share overlapping cytomorphologic features and can be difficult to differentiate on limited cytology specimens. Careful consideration to subtle but definite cytomorphologic clues and attention to selective IPOX stains can lead to a definitive diagnosis. PMID- 21319316 TI - Fine-needle aspiration of renal cell carcinoma: is accurate Fuhrman grading possible on cytologic material? AB - The Fuhrman grading system of renal cell carcinoma (RCC) consists of four grades based on nuclear size/contour and nucleolar conspicuousness. Fuhrman grading of histpathologic material is an independent prognostic parameter for RCC. Although widely used in surgical pathology, Fuhrman grading is not routinely performed on cytologic material. Thirty-three cases of renal fine needle aspirations (FNAs) with histologically proven RCC were retrieved from the cytopathology archives at Johns Hopkins Hospital. Fuhrman grade was determined independently and blindly by three faculty cytopathologists and compared with the Fuhrman grade of the subsequent surgical pathology specimen. The 33 resection specimens had the following Fuhrman grades: 0/33, grade I; 24/33 (73%), grade II; 9/33 (27%), grade III; and 0/33, grade IV. After Fuhrman grading was applied to the FNA material, diagnostic sensitivity was 83% for grade II versus 44% for grade III. The specificity and accuracy were 50 and 75%, respectively, for grade II versus 100% and 84% for grade III. Diagnostic sensitivity for grade II tumors ranged from 38 to 83%, grade III 44-62%. Diagnostic specificity for grade II tumors ranged from 50 to 78%, grade III 80-100%. Accuracy ranged from 48 to 75% for grade II and 75 87% for grade III. Using a two-tier grading model, accuracy improved to 84.2%. In our experience, Fuhrman grading of FNA specimens yielded variable results. There was only moderate agreement between cytopathologists, with an overall tendency to undergrade the tumor when compared with the resection specimen. Averaging the participants' grading and using a two-tier instead of four-tier system improved overall performance. PMID- 21319317 TI - Morphometric analysis and p63 improve the identification of myoepithelial cells in breast lesion cytology. AB - Nuclear findings, including size, shape, chromatin, or nucleoli, affect the cytological diagnosis and were found to have prognostic significance in several studies based on morphometric analysis. In this study, we investigated whether the nucleus area relates to the appearance of p63-positive myoepithelial cells. The nucleus area was analyzed in 101 breast cancers and 14 benign breast lesions using morphometric analysis and immunohistochemistry for p63. Breast cancer patients were classified into two groups; small nucleus group (n = 19) and large nucleus group (n = 82) based on the average nucleus area of ductal cells. The nucleus area was significantly negative correlating with p63-positive myoepithelial cells (P = 0.031), and there was a significant positive correlation with small cells with hyperchromatic nuclei (P = 0.002). Although small cells with hyperchromatic nuclei were similar to myoepithelial cells, there was no significant correlation with the appearance of small cells with hyperchromatic nuclei and p63-positive myoepithelial cells in breast cancer patients (P = 0.189). Although the identification of normal myoepithelial cells is mainly performed by immunostaining for p63, morphometric analysis of the nucleus area also suggests the existence of p63-positive myoepithelial cells. PMID- 21319318 TI - Cytologic appearance of myospherulosis of the breast diagnosed by fine-needle aspirates: a clinical, cytological and immunocytochemical study of 23 cases. AB - The objective of this study was to introduce the clinical and cytological aspects of myospherulosis. A total of 5,174 consecutive breast fine needle aspiration (FNA) cytology cases were reviewed, among which 23 cases of myospherulosis of the breast were found, all in female patients. The main findings of myospherulosis, best seen with the Papanicolaou stain, consisted in the observation of spherules that were homogeneously smooth or contained one or more internal dense bodies. Routine Papanicolaou-stained slides with or without Romanowsky staining were analyzed. Immunocytochemistry was conducted for carbonic anhydrase 1 (CA1), glycophorin C, KP1, and PGM1. The patients' ages ranged from 41 to 79 years (mean age: 56 years). Of the 23 patients, 21 had a previous history of breast surgery. Cytologically malignant or suspicious diagnoses were made in four of the 23 cases. The size of parent bodies varied from 18.2 to 151 MUm (mean, 52 MUm). The size of spherules ranged from 2.1 to 16.4 MUm (mean, 6.6 MUm). Immunocytochemistry showed that the myospherules reacted with anti-CA1 and anti glycophorin C antibodies. Most breast myospheruloses occur in patients with a history of breast surgery. Immunocytochemistry for CA1 and glycophorin C can enhance the diagnosis of myospherulosis. PMID- 21319319 TI - Fine-needle aspiration cytology of mammary fibroadenoma: a comparison of ThinPrep(r) and cytospin preparations. AB - Mammary fibroadenoma (FA) is a lesion frequently sampled and diagnosed by fine needle aspiration (FNA). Accurate cytologic diagnosis of this common benign lesion is important as this can lead to non-surgical, conservative management when breast imaging and clinical examination are concordant. In most instances, a confident diagnosis of FA is possible because of a characteristic cytologic appearance that includes hypercellularity, large epithelial cell groups, staghorn epithelial configurations, stromal fragments, and numerous background stripped nuclei. Nevertheless, FAs can be diagnostically challenging because of shared cytomorphologic features with other benign lesions and low-grade carcinoma. As such, FA is a well-recognized source of false results on FNA cytology. Furthermore, there are reports that newer thin layer cytopreparatory techniques, including the ThinPrep(r) (TP) system (Hologic Corp., Bedford, MA), alter the appearance of FA on FNA compared to conventional preparations and may compromise accurate cytologic diagnosis. PMID- 21319320 TI - Cyclooxygenase-2 expression in lung cancer cells evaluated by immunocytochemistry. AB - Cyclooxygenase-2 (COX-2) expression may be a prognostic factor in lung cancer. In previous studies, COX-2 expression has almost exclusively been evaluated with immunohistochemical methods performed on histology sections of tissue biopsies. However, in clinical practice, lung cancer is often diagnosed with cytological techniques only. We present methodology and results from analysis of COX-2 expression with immunochemistry on cytological material in 53 patients with lung cancer. Preparation and staining with the method established at our laboratory were easy to perform and resulted in good quality slides. The percentage COX-2 stained cells and the intensity of staining varied widely between and within the different cases. The proportion of positively stained tumor cells was as follows: <1% in 20 patients, 1-10% in 7 patients, 11-50% in 17 patients, and more than 50% in 9 patients. In 17 cases, groups of cells with different intensity of COX-2 staining were found in the same slide. In conclusion, immunocytochemical analysis of COX-2 expression is technically easy to perform with routine diagnostic procedures. There is a great variation in the proportion of COX-2-positive cells among patients and in the intensity of staining among individual cells in many single cases. PMID- 21319321 TI - Spindle shaped pigmented cells in a vitreous fluid cytology. PMID- 21319322 TI - Cytological features of the native pineal gland in intraoperative squash preparations. PMID- 21319323 TI - Endometrial clear cell adenocarcinoma diagnosed by endometrial cytological examination: two cases report. AB - In contrast to endometrioid endometrial adenocarcinoma (EA), endometrial clear cell adenocarcinoma (ECCA) is rare and shows a clinically aggressive potential, resulting in a poor prognosis. Therefore, the early diagnosis of ECCA is crucial for the treatment of patients bearing the tumor. Here, we report two cases of ECCA diagnosed by cytological examination. Case 1 was a 67-year-old female, while case 2 was a 68-year-old female. In both cases, tumors of the corpus uteri were identified, and they were diagnosed as ECCA on cytological examination with specimens derived from endometrial brushing. The diagnosis was confirmed by the histological examination of the surgical specimens. PMID- 21319324 TI - Combining cytomorphology and serology for the diagnosis of cat scratch disease. AB - Cat scratch disease (CSD) is a self limited zoonotic disease that presents most commonly as a regional lymphadenopathy. We are reporting a case of a 25-year-old male patient who presented with fever and large right inguinal lymphadenopathy. The diagnosis of cat scratch disease was confirmed based on the characteristic cytopathological features on aspirate smears from the lymph node and the serological titers for Bartonella henselae. This case report emphasizes the importance of combining Bartonella serology, and cytopathology in the diagnostic work-up of febrile lymphadenopathy and suspected CSD since the culture of this organism is arduous. PMID- 21319325 TI - Pleomorphic hyalinizing angiectatic tumor: cytomorphologic features on fine needle aspiration. AB - Pleomorphic hyalinizing angiectatic tumor (PHAT) is a rare low-grade neoplasm occurring predominantly in the subcutaneous tissue of the lower extremity, which is characterized histologically by intermixed bland spindle cells and larger pleomorphic cells, ectatic blood vessels with fibrin, and prominent hyalinization. Here we describe the cytologic features of PHAT seen on fine needle aspiration of a right calf mass in a 46-year-old man. The smears were cellular, composed predominantly of bland spindle cells dispersed singly as well as in tissue fragments and characterized by open chromatin and small nucleoli. A second population of pleomorphic spindle cells with coarse chromatin, prominent nucleoli, and occasional intranuclear pseudoinclusions was also present. Many of the pleomorphic cells surrounded hyalizined vessels. No mitotic figures were identified. The cytologic diagnosis was a "spindle cell lesion, NOS" with the differential diagnosis including benign lesions and low-grade neoplasms, including PHAT and schwannoma. PMID- 21319326 TI - Fine-needle aspiration biopsy of low-grade cribriform cystadenocarcinoma of the salivary gland. AB - Low-grade cribriform cystadenocarcinoma (LGCCC) is a rare tumor, defined in the 2005 WHO classification as a primary salivary duct tumor. Previously, the neoplasm had been recognized as a variant of salivary duct carcinomas. A 56-year old Japanese woman noticed a mass in the left subaural region. On radiological examinations, a multicystic tumor was seen in the left parotid gland. Fine-needle aspiration biopsy was performed. The smears revealed several characteristic cytologic features. The tumor cells were arranged in irregular overlapping and showed inconspicuous nuclear atypia with variable-sized and irregularly shaped cytoplasmic vacuoles. Based on these findings, a cystic tumor with uncertain malignancy was diagnosed. A parotidectomy was performed, because the tumor was slowly growing and contained solid components on the radiological images. Based on the histologic findings, along with immunohistochemistry, LGCCC was diagnosed based on resemblance to breast low-grade ductal carcinoma in situ and intraductal proliferation of tumor cells. This is the first report of the cytomorphological findings of LGCCC. PMID- 21319327 TI - Cell cannibalism and cancer. AB - Cellular cannibalism, defined as a large cell enclosing a slightly smaller one within its cytoplasm. In this review, we discussed the morphology, possible mechanism, and the cytological significance of cannibalism in relation to malignancy. Cannibalism is a completely different entity than phagocytosis, entosis, and emeriopoliosis. It is an important morphologic feature to distinguish benign from malignant lesions. Cannibalism has been described in various cancers such as, bladder cancer, breast cancer, lung cancer, etc, and this is related with the aggressiveness of the malignancy. PMID- 21319328 TI - Bronchoscopic and transthoracic cytology and biopsy for pulmonary nonsmall cell carcinomas: performance characteristics by procedure and tumor type. AB - Recent advances have increased the demand for the accurate diagnosis of pulmonary nonsmall cell carcinoma (NSCLC) rendered by biopsy or cytology. However, precise classification is not possible in all cases. In this study, we investigated the performance characteristics of preresection bronchoscopic and transthoracic procedures for the diagnosis of NSCLC. The pathology files were searched for resected NSCLCs and carcinoid tumors with corresponding preresection cytology and/or biopsy cases. The preresection diagnoses were correlated with the resection diagnosis and the type of bronchoscopic or transthoracic procedure. Among the bronchoscopic procedures, endobronchial/transbronchial biopsy (ETBX) had the highest yield for obtaining a positive (malignant) diagnosis and was the best procedure for obtaining precise classification. For transthoracic procedures, fine-needle aspiration (FNA) and needle core biopsy (NCB) were similar in providing a positive (malignant) diagnosis; however, NCB was better than FNA in obtaining precise classification. From the perspective of the neoplasms, carcinoid tumors yielded a positive (malignant) specimen with accurate classification most often (e.g., 100% by ETBX). This was followed by squamous cell carcinoma and adenocarcinoma. In contrast, precise classification was not possible for adenosquamous carcinoma, large cell carcinoma, and large cell neuroendocrine carcinoma. Bronchoscopic and transthoracic procedures have different performance characteristics. Furthermore, the diagnostic yield is dependent on the histologic type of the neoplasm. While carcinoid tumors are accurately classified in most cases, some other neoplasms are difficult to diagnose and subclassify due to histologic complexity, poor differentiation, or sampling limitations. PMID- 21319329 TI - Expression of Epstein-Barr virus and granzyme B in cytologic smears of histiocytic necrotizing lymphadenitis. AB - Histiocytic necrotizing lymphadenitis (HNL) is a non-neoplastic disease of the lymph nodes that is self-limiting in its clinical course. In this study, the expression of Epstein-Barr virus (EBV), granzyme B, and other phenotypic markers of HNL was investigated in fine needle-aspirated (FNA) cytologic smears obtained from 38 patients with HNL. The smear were subjected to immunohistochemical staining for granzyme B, CD3, CD4, CD8, CD20, and CD68 in addition to in-situ hybridization for EBV to determine whether marker expression could be correlated with disease pathogenesis. The mean age of 28 female and 10 male patients was 22.8 years. CD8-positive cytotoxic T cells were noted in 65.0% of the smears (13/20 cases), whereas CD4 and CD68 were rarely observed. Granzyme B reactivity was seen in lymphocytes, especially in apoptotic areas, and in histiocytes, with positive rates of 25.0% (9/36) and 11.1% (4/36), respectively. Most FNA smears showed immunoreactivity to both CD3 and CD20, with a predominance of CD3-positive cells. In-situ hybridization for EBV was positive in 22.9% (8/35) of the cases. The immunohistochemical staining and EBV in-situ hybridization results obtained in bleached FNA smears were similar to those in histologic sections. Overall, our results implicate that even though EBV positivity and granzyme B immunoreactivity are noted in HNL, they do not appear to have any apoptosis-associated role. PMID- 21319330 TI - Cytomorphology of giant cell glioblastoma: Report of a case and brief review of literature. AB - Giant cell glioblastoma is a histological variant of glioblastoma that accounts for less than 1% of intracranial tumors and to 5% of glioblastoma. They occur at any age and are likely to affect the younger as well the older age group unlike the conventional glioblastoma multiforme (GBM). They are often located subcortically in the temporal and parietal lobes. Cytological descriptions of giant cell glioblastoma are extremely rare. We describe squash cytomorphology of giant cell glioblastoma of left posterior frontal region in 35-year-old male. The squash smears were moderately cellular displaying malignant astrocytic tumor cells disposed in cohesive clusters and dispersed population on a necrotic background. Most striking feature was numerous multinucleated giant cells. We also discuss the differential diagnosis in light of relevant literature. PMID- 21319333 TI - Journal of Basic Microbiology. Editorial. PMID- 21319335 TI - Cardio-vascular safety of acetyl cholinesterase inhibitors in patients suffering from Alzheimer's disease; factors that predict poor tolerability. PMID- 21319334 TI - Cognitive functioning in individuals with severe compulsive hoarding behaviors and late life depression. AB - OBJECTIVES: The cognitive characteristics of individuals with severe compulsive hoarding behaviors (SCH) are not well understood and existing studies have largely focused on individuals with SCH and concurrent anxiety disorders. The present study was conducted to evaluate the frequency with which SCH co-occurs with LLD and to compare the cognitive characteristics of individuals with late life depression and concurrent SCH (LLD+SCH) to that of LLD individuals without SCH (LLD). METHODS: Participants included 52 LLD individuals who received psychiatric and neuropsychological evaluations as part of a larger study. Cognitive performance on measures of memory, attention, language, information processing speed, and categorization/problem solving ability was evaluated for each participant using standard neuropsychological measures. Measures of depression and anxiety symptom severity were also obtained. RESULTS: Seven (13%) of the 52 LLD participants reported significant SCH behaviors. The two groups (LLD+SCH; LLD) did not differ with respect to demographic characteristics or severity of depression or anxiety. Individuals with LLD+SCH demonstrated significantly poorer performance on two measures of categorization/problem solving ability relative to individuals with isolated LLD. Clinically significant impairments on measures of categorization ability, information processing speed, and verbal memory were more common for SCH+LLD than LLD participants. CONCLUSIONS: Our preliminary results suggest that SCH behaviors in LLD are associated with specific aspects of executive dysfunction characterized by categorization deficits and to a lesser extent information processing speed and verbal memory deficits. Further study of cognitive functioning in older adults with LLD and SCH may clarify the underlying cognitive characteristics of the SCH syndrome. PMID- 21319336 TI - Risk for dementia and age at measurement. PMID- 21319337 TI - The role of the calcium and the voltage clocks in sinoatrial node dysfunction. AB - Recent evidence indicates that the voltage clock (cyclic activation and deactivation of membrane ion channels) and Ca(2+) clocks (rhythmic spontaneous sarcoplasmic reticulum Ca(2+) release) jointly regulate sinoatrial node (SAN) automaticity. However, the relative importance of the voltage clock and Ca(2+) clock for pacemaking was not revealed in sick sinus syndrome. Previously, we mapped the intracellular calcium (Ca(i)) and membrane potentials of the normal intact SAN simultaneously using optical mapping in Langendorff-perfused canine right atrium. We demonstrated that the sinus rate increased and the leading pacemaker shifted to the superior SAN with robust late diastolic Ca(i) elevation (LDCAE) during beta-adrenergic stimulation. We also showed that the LDCAE was caused by spontaneous diastolic sarcoplasmic reticulum (SR) Ca(2+) release and was closely related to heart rate changes. In contrast, in pacing induced canine atrial fibrillation and SAN dysfunction models, Ca(2+) clock of SAN was unresponsiveness to beta-adrenergic stimulation and caffeine. Ryanodine receptor 2 (RyR2) in SAN was down-regulated. Using the prolonged low dose isoproterenol together with funny current block, we produced a tachybradycardia model. In this model, chronically elevated sympathetic tone results in abnormal pacemaking hierarchy in the right atrium, including suppression of the superior SAN and enhanced pacemaking from ectopic sites. Finally, if the LDCAE was too small to trigger an action potential, then it induced only delayed afterdepolarization (DAD)-like diastolic depolarization (DD). The failure of DAD-like DD to consistently trigger a sinus beat is a novel mechanism of atrial arrhythmogenesis. We conclude that dysfunction of both the Ca(2+) clock and the voltage clock are important in sick sinus syndrome. PMID- 21319338 TI - A comparison of predictability of cardiovascular events between each metabolic component in patients with metabolic syndrome based on the revised National Cholesterol Education Program criteria. AB - PURPOSE: The prevalence of metabolic syndrome (MetS) generally varies depending on its diagnostic definition, and many different definitions inevitably lead to substantial confusion and lack of comparability between studies. Despite extensive research, there is still no gold standard for the definition of MetS, which continues to be a matter of debate. In this study, we investigate whether and to what extent its individual components are related to the risk of cardiovascular disease (CVD) in Korean population. MATERIALS AND METHODS: We used data from the 2005 Korea National Health and Nutrition Examination Survey, which is a nationally representative survey of the noninstitutionalized civilian population. The study sample consisted of 1,406 Korean adults (587 men, 819 women) who were diagnosed with MetS based on the revised National Cholesterol Education Program (NCEP) criteria. Central obesity is defined as a waist circumference cutoff point reported in Asia-Pacific criteria for obesity based on waist circumference by the World Health Organization. CVD was defined as presence of stroke, myocardial infarction, or angina pectoris on a medical history questionnaire. RESULTS: The CVD prevalence among the subjects was 6.8% for men and 8.6% for women. Besides age, the components of MetS showing a significant difference in the number of CVD events were high fasting glucose (FG) in men and high blood pressure (BP) and high FG in women. After adjusting for gender and age, high FG was shown to yield a significant difference (odds ratio: unadjusted 2.08, adjusted 1.81), alone among all MetS components. However, after adjusting for only age, no significant difference was found. CONCLUSION: Fasting glucose level is the highest predicting factor for CVD in Korean patients with MetS based on the revised NECP definition. PMID- 21319339 TI - The decellularized vascular allograft as an experimental platform for developing a biocompatible small-diameter graft conduit in a rat surgical model. AB - PURPOSE: The present study was aimed to assess the feasibility of using decellularized aortic allograft in a rat small animal surgical model for conducting small diameter vascular tissue engineering research. MATERIALS AND METHODS: Decellularized aortic allografts were infra-renally implanted in 12 Sprague-Dawley (SD) adult rats. The conduits were harvested at 2 (n = 6) and 8 weeks (n = 6), and assessed by hematoxylin and eosin (H&E), van Gieson, Masson Trichrome staining, and immunohistochemistry for von Willebrand factor, CD 31(+), and actin. RESULTS: Consistent, predictable, and reproducible results were produced by means of a standardized surgical procedure. All animals survived without major complications. Inflammatory immune reaction was minimal, and there was no evidence of aneurysmal degeneration or rupture of the decellularized vascular implants. However, the aortic wall appeared thinner and the elastic fibers in the medial layer showed decreased undulation compared to the normal aorta. There was also minimal cellular repopulation of the vascular media. The remodeling appeared progressive from 2 to 8 weeks with increased intimal thickening and accumulation of both collagen and cells staining for actin. Although the endothelial like cells appeared largely confluent at 8 weeks, they were not as concentrated in appearance as in the normal aorta. CONCLUSION: The results showed the present rat animal model using decellularized vascular allograft implants to be a potentially durable and effective experimental platform for conducting further research on small diameter vascular tissue engineering. PMID- 21319340 TI - Relationships between serum adiponectin with metabolic syndrome and components of metabolic syndrome in non-diabetic Koreans: ARIRANG study. AB - PURPOSE: Growing evidence suggests that hypoadiponectinemia may play a significant role in the development of metabolic syndrome (MetS). Therefore, the relationships between serum adiponectin with MetS and components of MetS were investigated in non-diabetic samples of drawn from the Koreans general population. MATERIALS AND METHODS: We performed a cross-sectional study in samples of older Koreans (age > 40 years) including 2,471 men and 3,463 women. MetS was defined according to the Asian modified criteria of the National Cholesterol Education Program Adult Treatment Panel III report. Serum adiponectin concentrations were measured by radioimmunoassay. RESULTS: The median adiponectin level in MetS was significantly lower than that in non-MetS subjects in men (6.00 vs. 8.00 MUg/mL, p < 0.001) and women (10.12 vs. 11.74 MUg/mL, p < 0.001). Adiponectin concentration was negatively correlated with waist circumference and levels of triglyceride, C-reactive protein (CRP), fasting glucose, and insulin, and positively correlated with high-density lipoprotein and age in both genders (p < 0.001). In a multivariate regression model after adjustment for age, body mass index, smoking, CRP, and lipid profiles, the odds ratio of MetS comparing extreme quartiles of adiponectin distribution was 0.32 [95% confidence interval (CI), 0.20 to 0.50] in men and 0.57 (95% CI, 0.43 to 0.76) in women. CONCLUSION: Adiponectin levels are independently associated with the phenotype of MetS, as well as components of MetS in the non-diabetic Korean general population. PMID- 21319341 TI - Changes of body weight and inflammatory markers after 12-week intervention trial: results of a double-blind, placebo-control pilot study. AB - PURPOSE: Low grade inflammation is a well-known characteristic in obese subjects. We investigated body weight changes and inflammatory markers after 12-week intervention trial. MATERIALS AND METHODS: Twenty-six obese subjects were enrolled and 19 (13 men and 6 women) completed the study. Sibutramine is an FDA approved drug for body weight control; therefore, we chose this drug as the standard treatment medication in this study. Patients were randomly allocated to receive an anti-inflammatory agent (Diacerein treatment group; n = 12) or placebo (n = 7) for 12 weeks. Anthropometry, body proportion by dual-energy X-ray absorptiometry, and metabolic parameters at the beginning and end of study were measured and compared. RESULTS: The treatment group had a tendency towards more reduction in anthropometry as compared to the placebo group, in body weight reduction (-7.0 kg vs. -4.6 kg), body mass index (-2.51 kg/m2 vs. -1.59 kg/m2), and waist circumference (-7.3 cm vs. -4.4 cm). These reductions were not statistically significant. Changes in levels of high-sensitivity C-reactive protein and adiponectin in the treatment group were more favorable than in the placebo group. CONCLUSION: This small pilot study showed no statistical difference for changes in anthropometry, and inflammatory markers between the two groups. Therefore, we could not find any additional effects of Diacerein on weight loss and inflammatory variables in this study. PMID- 21319342 TI - Application of Protein-Rich Oriental Diet in a community-based obesity control program. AB - PURPOSE: To evaluate the efficacy, safety and availability of a 12-week, community-based obesity control program called the Protein-Rich Oriental Diet (PRO Diet) and to compare it to a conventional diet. MATERIALS AND METHODS: A total of 515 overweight people (55 men and 460 women; mean age 41.9 +/- 9.8 years; body mass index (BMI) 28.1 +/- 3.6 kg/m2) participated in the program at two public health centers. PRO Diet was offered as the main diet recommendation for 12 weeks. As a control group, we selected a population who had followed a conventional diet program conducted at a public health center in 2006. RESULTS: 177 subjects (34.3%) completed the 12-week PRO Diet program. In a per protocol (PP) analysis, the mean changes in anthropometry were (conventional program vs. PRO Diet; weight, -2.3 kg vs. -4.7 kg, p < 0.001; BMI, -1.1 kg/m2 vs. -1.9 kg/m2, p < 0.001; waist circumference, -3.3 cm vs. -6.8 cm, p < 0.001; fat mass, -2.0 kg vs. -4.2 kg, p < 0.001; fat % mass, -1.8% vs. -3.9%, p < 0.001). The triglyceride reduction was significantly greater (-30.16 mg/dL, p < 0.001) in the PRO Diet group after intervention compared to the conventional group. CONCLUSION: The PRO Diet was an effective tool for weight loss in a community-based weight control program and well-tolerated. PMID- 21319343 TI - Delayed response of amylin levels after an oral glucose challenge in children with Prader-Willi syndrome. AB - PURPOSE: Amylin secretion is increased parallel to insulin in obese subjects. Despite their marked obesity, a state of relative hypoinsulinemia occurs in children with Prader-Willi syndrome (PWS). Based on the hypothesis that amylin levels may be relatively low in PWS children, contributing to their excessive appetite, we studied amylin levels after oral glucose loading in children with PWS and overweight controls. MATERIALS AND METHODS: Plasma levels of amylin, glucagon, insulin, and glucose were measured at 0, 30, 60, 90, and 120 min after a glucose challenge in children with PWS (n = 18) and overweight controls (n = 25); the relationships among the variables were investigated in these two groups. RESULTS: Amylin levels were significantly correlated with insulin during fasting and during the oral glucose tolerance test in both groups. Amylin levels between 0 and 60 min after glucose loading were statistically different between the two groups. They were lower in children with PWS than in the controls between 0 and 30 min after glucose loading. CONCLUSION: The relatively low levels of amylin, compared to those in overweight controls, during the early phase of glucose loading in patients with PWS, may contribute, in part, to the excessive appetite of PWS patients as compared to the overweight controls. PMID- 21319344 TI - Changes in glycogen and glycosaminoglycan levels in hepatocytes of iduronate-2 sulfatase knockout mice before and after recombinant iduronate-2-sulfatase supplementation. AB - PURPOSE: Mucopolysaccharidosis II (MPS II) is a lysosomal storage disorder caused by a deficiency of iduronate-2 sulfatase (IdS), which is involved in the degradation of glycosaminoglycan (GAG). In this study, the frequency of fasting hypoglycemia in patients with MPS II was investigated and changes in accumulation of glycogen and GAG in the hepatocytes of IdS-knockout (KO) mice were evaluated before and after recombinant IdS enzyme replacement therapy (ERT). MATERIALS AND METHODS: Plasma glucose levels were evaluated after an 8-hour fast in 50 patients with MPS II. The IdS-KO mice were divided into three groups (group 2; saline, group 3; 0.15 mg/kg of IdS, and group 4; 0.5 mg/kg of IdS); wild-type mice were included as controls (group 1). ERT was initiated intravenously at four weeks of age, and continued every week until 20 weeks of age. RESULTS: The mean glucose level after an 8-hour fast was 94.1 +/- 23.7 mg/dL in the patients with MPS II. Two (4%) out of 50 patients had fasting hypoglycemia. For the mice, GAG in the lysosomes nearly disappeared and glycogen particles in the cytoplasm were restored to the normal range in group 4. CONCLUSION: Glucose metabolism in patients with MPS II appeared to function well despite hepatocytic GAG accumulation and hypothetical glycogen depletion. A higher dose of IdS infusion in MPS II mice led to disappearance of lysosomal GAG and restoration of glycogen to the cytoplasm of hepatocytes. PMID- 21319345 TI - Addition of theophylline or increasing the dose of inhaled corticosteroid in symptomatic asthma: a meta-analysis of randomized controlled trials. AB - PURPOSE: Low-dose theophylline has anti-inflammatory effects. The aim of this study was to evaluate the effects of adding theophylline compared with increasing the dose of inhaled corticosteroid (ICS) on symptomatic asthma. MATERIALS AND METHODS: The associated literature was acquired through deliberate searching and selected based on the established inclusion criteria for publications. The extracted data were further analyzed by a meta-analysis. RESULTS: Four randomized, controlled, parallel studies were selected. Addition of theophylline produced a greater increase of forced expiratory volume in one second as %predicted (FEV1pred) by 2.49% [95% confidence interval (CI) 1.99-3.00; z = 9.70; p < 0.001], compared with increasing the dose of ICS. There was no difference between the two treatments in terms of peak expiratory flow (PEF). CONCLUSION: Addition of theophylline to ICS has similar therapeutic effects on improving lung function as increasing the dose of ICS in the treatment of symptomatic asthma. PMID- 21319346 TI - Utility of procalcitonin as an early diagnostic marker of bacteremia in patients with acute fever. AB - PURPOSE: Procalcitonin (PCT) is a current, frequently used marker for severe bacterial infection. The aim of this study was to assess the ability of PCT levels to differentiate bacteremic from nonbacteremic patients with fever. We assessed whether PCT level could be used to accurately rule out a diagnosis of bacteremia. MATERIALS AND METHODS: Serum samples and blood culture were obtained from patients with fever between August 2008 and April 2009. PCT was analyzed using a VIDAS(r) B.R.A.H.M.S PCT assay. We reviewed the final diagnosis and patient histories, including clinical presentation and antibiotic treatment. RESULTS: A total of 300 patients with fevers were enrolled in this study: 58 with bacteremia (positive blood culture) (group I); 137 with local infection (group II); 90 with other diseases (group III); and 15 with fevers of unknown origin (group IV). PCT levels were significantly higher in patients with bacteremia than in those with non-bacteremia (11.9 +/- 25.1 and 2.5 +/- 14.7 ng/mL, respectively, p < 0.001). The sensitivity and specificity were 74.2% and 70.1%, respectively, at a cut-off value of 0.5 ng/mL. A serum PCT level of < 0.4 ng/mL accurately rules out diagnosis of bacteremia. CONCLUSION: In febrile patients, elevated PCT may help predict bacteremia; furthermore, low PCT levels were helpful for ruling out bacteremia as a diagnosis. Therefore, PCT assessment could help physicians limit the number of prescriptions for antibiotics. PMID- 21319347 TI - The difference in clinical presentations between healthcare-associated and community-acquired pneumonia in university-affiliated hospital in Korea. AB - PURPOSE: Healthcare-associated pneumonia (HCAP) has been proposed as a new category of pneumonia. However, epidemiological studies for HCAP in South Korea are limited. This study aimed to reveal the differences between HCAP and community-acquired pneumonia (CAP), especially in elderly patients, in university affiliated hospital in South Korea. MATERIALS AND METHODS: We conducted a retrospective observational study of patients with HCAP and CAP (older than 60 years old) who were hospitalized between January 2007 and December 2008. We compared the baseline characteristics, comorbidities, severity, pathogen distribution, antibiotics, and clinical outcomes. RESULTS: A total of 210 patients were evaluated, including 35 patients with HCAP (17%) and 175 with CAP (83%). The most common causative organism was Streptococcus pneumoniae in CAP (33.3%), whereas, Staphylococcus aureus was most common pathogen in HCAP (40.0%). Initial inappropriate antibiotics (6.3% vs. 22.9%; p < 0.005) and initial treatment failure (15.4% vs. 31.4%; p = 0.018) were more frequent in HCAP than CAP. However, mortality (11.4% vs. 5.7%; p = 0.369) was not different between the two groups. CONCLUSION: The present study provides additional evidence that HCAP should be distinguished from CAP, even in elderly patients, in South Korea. Physicians should consider S. aureus and MDR pathogens in selecting initial empirical antibiotics of HCAP in South Korea. PMID- 21319348 TI - Splenic abscess: a single institution study and review of the literature. AB - PURPOSE: The aim of this study was to review our experience with splenic abscesses, with respect to the relevant aspects of splenic abscesses and treatment outcomes. MATERIALS AND METHODS: We reviewed the cases of 18 patients who had splenic abscesses and who were treated at our hospital from November 1993 to December 2008. RESULTS: The most common symptom at presentation was abdominal pain in 12 patients (66.7%). The median duration from symptom onset until establishment of a diagnosis was 22 days. Streptococcus viridans was the most common pathogen (27.8%), follow by Klebsiella pneumoniae (22.2%). The mortality rate during the inpatient period and the previous 90 days was 16.6%. Three of four patients with Klebsiella pneumoniae showed a single abscess pocket. Four patients (22.2%) underwent percutaneous drainage, eight (44.5%) received antibiotic treatment only and six (33.3%) underwent splenectomy. CONCLUSION: There is no gold standard for treating splenic abscesses. Treatment should be customized for each patient. PMID- 21319349 TI - Efficacy of itraconazole prophylaxis for autologous stem cell transplantation in children with high-risk solid tumors: a prospective double-blind randomized study. AB - PURPOSE: The risk of invasive fungal infection is greater for allogeneic hematopoietic stem cell transplantation (HSCT) than for autologous transplantation. Therefore, many transplantation centers use antifungal prophylaxis for allogeneic HSCT, however, there exists no standard guidelines or consensus regarding autologous HSCT. MATERIALS AND METHODS: A prospective double blind randomized study was conducted in autologous HSCT recipients who were divided into prophylaxis and empirical treatment groups, and we investigated the efficacy of itraconazole prophylaxis in pediatric autologous HSCT. RESULTS: Total 87 autologous HSCT episodes in 55 children with high-risk solid tumors were studied. No invasive fungal infections occurred in either group. However, patients in the prophylaxis group had a significantly shorter duration of fever (p < 0.05) and received antibacterial treatment of shorter duration (p < 0.05) with fewer numbers of antibiotics (p < 0.05 for the use of second line antibiotics) than those in the empirical group. No significant additional adverse events were found with itraconazole prophylaxis. CONCLUSION: Although beneficial effects such as a shorter duration of fever and reduced need for antibiotic use were observed in the prophylaxis group, the results were not sufficient to draw a definite recommendation about the routine use of antifungal prophylaxis in pediatric autologous HSCT recipients with high-risk solid tumors (Trial registration: NCT00336531). PMID- 21319350 TI - Comparison of diagnostic performance of three real-time PCR kits for detecting Mycobacterium species. AB - PURPOSE: PCR is widely used for rapidly and accurately detecting Mycobacterium species. The purpose of this study was to assess the diagnostic performance of three real-time PCR kits and evaluate the concordance with two older PCR methods. MATERIALS AND METHODS: Using 128 samples, the five PCR methods were assessed, including an in-house PCR protocol, the COBAS Amplicor MTB, the COBAS TaqMan MTB, the AdvanSure TB/NTM real-time PCR, and the Real-Q M. tuberculosis kit. The discrepant results were further examined by DNA sequencing and using the AdvanSure Mycobacteria Genotyping Chip for complete analysis. RESULTS: For Mycobacterium tuberculosis (MTB) detection, all five kits showed 100% matching results (positive; N = 11 and negative; N = 80). In non-tuberculous mycobacterium (NTM) discrimination, the AdvanSure yielded two true-positive outcomes from M. intracellulare and one false positive outcome, while the Real-Q resulted in one true-positive outcome and one false negative outcome for each case and another false negative result using the provided DNA samples. CONCLUSION: Real-time PCR, yielded results that were comparable to those of the older PCR methods for detecting MTB. However, there were disagreements among the applied kits in regard to the sample test results for detecting NTM. Therefore, we recommend that additional confirmatory measures such as DNA sequencing should be implemented in such cases, and further research with using a larger numbers of samples is warranted to improve the detection of NTM. PMID- 21319351 TI - Laparoendoscopic single-site nephrectomy using a modified umbilical incision and a home-made transumbilical port. AB - PURPOSE: To assess the clinical utility of laparoendoscopic single-site surgery (LESS) nephrectomy using a modified umbilical incision and home-made transumbilical port in cases requiring extirpative surgery. MATERIALS AND METHODS: Initial consecutive 18 patients underwent LESS nephrectomies that were performed by a single surgeon. A home-made port was placed through a modified umbilical incision, the length of which had preoperatively been determined. The laparoscopic transperitoneal nephrectomy procedures were performed with various combinations of standard and articulating laparoscopic instruments. Patient characteristics and perioperative outcomes, including pathologic results, were recorded prospectively. RESULTS: All 18 extirpative surgeries, including simple nephrectomy (eight cases), radical nephrectomy (nine cases), and nephroureterectomy (one case), were completed successfully. The median operation time was 167 min (range 82-220), and the median blood loss was 250 mL (range 0 1050). All specimens were extracted intact through a modified umbilical incision (median length 2.5 cm, range 1.5-6.0). Final pathological analysis revealed a nonfunctioning kidney in five cases, a dysplastic kidney in three cases, a mixed epithelial and stromal tumor in one case, renal cell carcinoma in eight cases (T1: five cases, T3: three cases), and Ta ureter transitional cell carcinoma in one case. CONCLUSION: LESS nephrectomy using a home-made port and modified umbilical incision is feasible with both minimal incision and cost-effective. Our technique may be more useful for extirpative procedures in which a specimen needs to be removed intact, because incision length can be freely adjusted. Prospective comparisons are warranted to more clearly elucidate the utility of this surgical technique. PMID- 21319352 TI - Cantilever transforaminal lumbar interbody fusion for upper lumbar degenerative diseases (minimum 2 years follow up). AB - PURPOSE: To evaluate the clinical outcomes of cantilever transforaminal lumbar interbody fusion (c-TLIF) for upper lumbar diseases. MATERIALS AND METHODS: Seventeen patients (11 males, 6 females; mean +/- SD age: 62 +/- 14 years) who underwent c-TLIF using kidney type spacers between 2002 and 2008 were retrospectively evaluated, at a mean follow-up of 44.1 +/- 12.3 months (2 year minimum). The primary diseases studied were disc herniation, ossification of posterior longitudinal ligament (OPLL), degenerative scoliosis, lumbar spinal canal stenosis, spondylolisthesis, and degeneration of adjacent disc after operation. Fusion areas were L1-L2 (5 patients), L2-L3 (9 patients), L1-L3 (1 patient), and L2-L4 (2 patients). Operation time, blood loss, complications, Japanese Orthopaedic Association (JOA) score for back pain, bone union, sagittal alignment change of fusion level, and degeneration of adjacent disc were evaluated. RESULTS: JOA score improved significantly after surgery, from 12 +/- 2 to 23 +/- 3 points (p < 0.01). We also observed significant improvement in sagittal alignment of the fusion levels, from - 1.0 +/- 7.4 to 5.2 +/- 6.1 degrees (p < 0.01). Bony fusion was obtained in all cases. One patient experienced a subcutaneous infection, which was cured by irrigation. At the final follow-up, three patients showed degenerative changes in adjacent discs, and one showed corrective loss of fusion level. CONCLUSION: c-TLIF is a safe procedure, providing satisfactory results for patients with upper lumbar degenerative diseases. PMID- 21319353 TI - Central corneal thickness and corneal endothelial cell changes caused by contact lens use in diabetic patients. AB - PURPOSE: To analyze the effects of soft contact lenses on central corneal thickness and morphologic characteristics of the corneal endothelium in diabetic patients. MATERIALS AND METHODS: Ultrasound pachymetry and noncontact specular microscopy were performed on 26 diabetic patients who regularly use soft contact lenses (group 1), 27 diabetic patients who do not use soft contact lenses (group 2) and 30 normal subjects (group 3). We compared the values in each group using the Mann-Whitney test. RESULTS: The central cornea was found to be thicker in diabetic patients, both those who use and do not use contact lenses, than in the normal control group. The central corneal thickness was significantly higher in group 1 (564.73 +/- 35.41 MUm) and group 2 (555.76 +/- 45.96 MUm) than in the control group (534.05 +/- 27.02 MUm), but there was no statistically significant difference between groups 1 and 2. Endothelial cell density was significantly different between the groups, and was smallest in the group of diabetic patients using contact lenses. The coefficient of variation of cell size was significantly higher and the percentage of hexagonal cells was significantly lower in contact lens using diabetic patients than in non-contact lens using diabetic patients and in the control group. CONCLUSION: Central corneal thickness and endothelial cell density is more affected by diabetes mellitus, and corneal endothelial cell morphology is more affected by contact lens use, when compared with normal subjects. PMID- 21319354 TI - Comparison of the effects of propofol and midazolam on inflammation and oxidase stress in children with congenital heart disease undergoing cardiac surgery. AB - PURPOSE: To investigate and compare the effects of propofol and midazolam on inflammation and oxidase stress in children with congenital heart disease undergoing cardiac surgery. MATERIALS AND METHODS: Thirty-two ASA class I-II children with congenital heart disease undergoing cardiac surgery were randomly divided into two groups: propofol combined with low dose fentanyl (PF group, n = 16) and midazolam combined with low dose fentanyl (MF group, n = 16). Tracheal extubation time and length of Intensive Care Unit (ICU) stay were recorded. Blood samples were taken before operation (T0), at 2 h after release of the aorta cross clamp (T3) and at 24 h after operation (T4) to measure interleukin 6 (IL-6), IL 8, superoxide dismutase (SOD) and malondialdehyde (MDA) levels. Myocardium samples were collected at 10-20 min after aorta cross-clamp (T1) and at 10-20 min after the release of the aorta cross-clamp (T2) to detect heme oxygenase-1 (HO-1) expression. RESULTS: Tracheal extubation time and length of ICU stay in PF group were significantly shorter than those of the MF group (p < 0.05, respectively). After cardiopulmonary bypass, IL-6, IL-8 and MDA levels were significantly increased, and the SOD level was significantly reduced in both two groups, but PF group exhibited lower IL-6, IL-8 and MDA levels and higher SOD levels than the MF group (p < 0.05, respectively). The HO-1 expression in the PF group was significantly higher than that in MF group at the corresponding time points (p < 0.05, respectively). CONCLUSION: Propofol is superior to midazolam in reducing inflammation and oxidase stress and in improving post-operation recovery in children with congenital heart disease undergoing cardiac surgery. PMID- 21319355 TI - The effects of a single bolus of remifentanil on corrected QT interval change during sevoflurane induction. AB - PURPOSE: Opioids may affect changes in the corrected QT interval (QTc) during anesthetic induction. This study examine whether a single bolus of remifentanil would prolong QTc after laryngeal mask airway (LMA) insertion during sevoflurane induction. MATERIALS AND METHODS: Forty women of American Society of Anesthesiologists physical status 1 (ASA PS1) undergoing gynecological surgery were studied. All patients were induced using three vital capacity inhalation inductions with 5% sevoflurane. Two minutes after induction, the inspiratory concentration of sevoflurane was reduced to 2%. Using double-blinded randomization, patients were allocated into one of two groups, receiving either saline (placebo group, n = 20) or 0.25 MUg.kg-1 remifentanil (remifentanil group, n = 20) over a period of thirty seconds. Sixty seconds later, LMA insertion was performed. Recordings were taken with a 12-lead electrocardiogram at baseline, 2 min after induction and 1 and 3 min after LMA insertion. QTc was calculated by Bazett's formula. The mean arterial pressure (MAP) and heart rate (HR) were also measured at each time point. RESULTS: The QTc interval was significantly prolonged in the placebo group as compared to the remifentanil group at 1 min after LMA insertion (467.8 +/- 16.5 vs. 442.7 +/- 21.3 ms, p < 0.001). However, there was no significant difference in QTc at 3 min after LMA insertion between the two groups. MAP and HR were significantly higher in the placebo group (p < 0.001). CONCLUSION: A single bolus of remifentanil is safe method to attenuate prolonged QTc associated with insertion of LMA. PMID- 21319356 TI - Risk factors for postoperative complications after open infrarenal abdominal aortic aneurysm repair in Koreans. AB - PURPOSE: Open infrarenal abdominal aortic aneurysm (AAA) repair is performed without event in most cases. However, some patients suffer major morbidities such as renal failure, myocardial infarction, paraplegia, acute respiratory distress syndrome, or hepatic dysfunction. Predicting what kinds of patient populations are more prone to develop such complications may keep the clinicians more attentive to the patients, possibly leading to better prognoses. In this retrospective study, we searched the incidence of and risk factors for postoperative complications and their predictive equations in 162 patients who underwent open infrarenal AAA repair. MATERIALS AND METHODS: Postoperative complications were observed within 30 days. Patient characteristics, types of aneurysm and surgery, and hemodynamic and metabolic variables during the periclamp period were analyzed in relation to postoperative complications using multiple logistic regression analysis. RESULTS: Postoperative complications involved the cardiac (20%), pulmonary (14%), renal (13%), gastrointestinal (6%), hepatic (3.1%), and neurologic (2.5%) systems, and bleeding occurred in 1.2% of cases. The mortality rate was 5.6%. The risk factors were age [> 67 yrs, odds ratio (OR) 2.6], clamp duration (> 110 min, OR 4.7), volume of blood transfusion (> 1,280 mL, OR 4.4), emergency operation (OR 1.4), and vasopressor infusion during clamp (OR 1.4). The prediction model was: P(x) = exp(a)/[1 + exp(a)] a; 2.2 + 0.9 * age + 1.5 * clamp duration + 1.5 * transfusion + 0.3 * emergency + 0.4 * vasopressor infusion [insert 1 if risk factors exist, otherwise, insert 0 to each variable]. CONCLUSION: A significant number of complications occurred after infrarenal AAA repair. Therefore, creating a protocol to identify and monitor high risk patients would improve postoperative care. PMID- 21319357 TI - Serum anti-Saccharomyces cerevisiae antibodies in Greek patients with Behcet's disease. AB - We tested 59 Greek patients with Behcet's Disease (BD) for serum anti Saccharomyces cerevisiae antibodies. No increase of these antibodies was detected in the cases compared to 55 healthy unrelated blood donors from the same population. This finding is in contrast with the correlation between Saccharomyces cerevisiae antibodies and BD as reported in other populations. It seems that environmental factors may contribute to disease expression in different populations, producing different effects according to the individual's genetic predisposition. Saccharomyces cerevisiae antibodies do not seem to be of any significance in the Greek population. PMID- 21319358 TI - The characteristics of metallo-beta-lactamase-producing gram-negative bacilli isolated from sputum and urine: a single center experience in Korea. AB - Metallo-beta-lactamase (MBL) production usually results in high-level resistance to most beta-lactams, and a rapid spread of MBL producing major gram-negative pathogens is a matter of particular concern worldwide. However, clinical data are scarce and most studies compared MBL producer (MP) with MBL non-producer (MNP) strains which included carbapenem susceptible isolates. Therefore, we collected clinical data of patients in whom imipenem-nonsusceptible Pseudomonas aeruginosa (PA) and Acinetobacter baumannii (AB) were isolated from sputum or urine, and investigated MBL production and the risk factors related with MBL acquisition. The antimicrobial susceptibility patterns were also compared between MPs and imipenem-nonsusceptible MNPs (INMNP). Among the 176 imipenem-nonsusceptible isolates, 12 MPs (6.8%) were identified. There was no identifiable risk factor that contributed to the acquisition of MPs when compared to INMNPs, and case fatalities were not different between the two groups. The percentage of susceptible isolates was higher among MPs for piperacilin/tazobactam and fluoroquinolones while that of ceftazidime was higher in INMNPs (p < 0.05). As regards to aztreonam, which has been known to be a uniquely stable beta-lactam against MBLs, susceptibility was preserved in only two isolates (16.7%) among MPs, and was not higher than that of INMNPs (23.2%). In conclusion, the contribution of MBLs to imipenem non-susceptibility in PA/ABs isolated from sputum and urine was relatively limited, and there was no significant risk factor associated with acquisition of MPs compared with INMNPs. However, limited susceptibility to aztreonam implies that MPs may hold additional resistance mechanisms, such as extended spectrum beta-lactamases, AmpC beta-lactamases, or other non-enzymatic mechanisms. PMID- 21319359 TI - Abdominal compartment syndrome due to spontaneous retroperitoneal hemorrhage in a patient undergoing anticoagulation. AB - Spontaneous retroperitoneal hemorrhage is one of the most serious and often lethal complications of anticoagulation therapy. The clinical symptoms vary from femoral neuropathy to abdominal compartment syndrome or fatal hypovolemic shock. Of these symptoms, abdominal compartment syndrome is the most serious of all, because it leads to anuria, worsening of renal failure, a decrease in cardiac output, respiratory failure, and intestinal ischemia. We report a case of a spontaneous retroperitoneal hemorrhage in a 48-year-old female who had been receiving warfarin and aspirin for her artificial aortic valve. She presented with a sudden onset of lower abdominal pain, dizziness and a palpable abdominal mass after prolonged straining to defecate. Computed tomography demonstrated a huge retroperitoneal hematoma and active bleeding from the right internal iliac artery. After achieving successful bleeding control with transcatheter arterial embolization, surgical decompression of the hematoma was performed for management of the femoral neuropathy and the abdominal compartment syndrome. She recovered without any complications. We suggest that initial hemostasis by transcatheter arterial embolization followed by surgical decompression of hematoma is a safe, effective treatment method for a spontaneous retroperitoneal hemorrhage complicated with intractable pain, femoral neuropathy, or abdominal compartment syndrome. PMID- 21319360 TI - Prostate cancer with solitary metastases to the bilateral testis. AB - We present the case of an 81-year-old patient with testicular metastasis from prostate carcinoma. After the initial diagnosis of prostate cancer, he had an 8 year course of hormonal therapy and showed no clinical evidence of metastasis to other organs. Asymptomatic metastasis of prostate carcinoma to the testis is a rare clinical condition. We diagnosed his condition, based on histopathology following a subcapsular orchiectomy and transurethral resection of the prostate. PMID- 21319361 TI - Iliac vein injury due to a damaged Hot ShearsTM tip cover during robot assisted radical prostatectomy. AB - We report a rare case of vascular injury secondary to a damaged Hot ShearsTM tip cover. Two 1 mm holes in the tip cover resulted in perforations in the obturator and external iliac veins during pelvic node dissection. Bleeding was controlled with bipolar coagulation and a 5 mm metal clip in the obturator and iliac vein, respectively. The rest of the procedure was completed uneventfully. Frequent integrity assessment of this accessory is necessary. Its function is important in order to carry out safe dissection in proximity to delicate structures. When injuries arise from areas not directly involved in the dissection, immediate inspection of the instruments should be mandatory. PMID- 21319362 TI - Hereditary spherocytosis coexisting with UDP-glucuronosyltransferase deficiency highly suggestive of Crigler-Najjar syndrome type II. AB - Patients with co-existing hereditary spherocytosis (HS) and UDP glucuronosyltransferase 1A1 (UGT1A1) deficiency as Gilbert's syndrome (GS) have been reported, and previous studies have demonstrated an increased risk for developing gallstones in patients with co-inheritance of GS and HS. We experienced an interesting case of HS showing persistent jaundice after splenectomy, and upon further evaluation, the 25-year-old female patient was found to have HS combined with UGT1A1 deficiency. Sequence analysis of the UGT1A1 gene revealed that she was a compound heterozygote with p.[G71R; Y486D] + [Y486D] mutations, which suggests Crigler-Najjar syndrome type II rather than GS. Careful evaluation of inappropriately elevated bilirubin level compared with the degree of hemolysis is important, reflecting the therapeutic implication of splenectomy and cholecystectomy. PMID- 21319363 TI - Lipogranuloma with osseous metaplasia in the breast that developed after "Bu Hwang" oriental medicine treatment. AB - A lipogranuloma is an inflammatory reactive process associated with exogenous or endogenous lipids, and it's occurrence in the breast has rarely been reported. Osseous metaplasia, which is used to describe bone formation in abnormal locations, can develop from several conditions such as trauma or a tumor. However, few studies have reported benign breast lesions that have been seen as osseous metaplasia. We present a case of a benign calcified breast lesion that developed after a traumatic treatment process called "Bu-Hwang", and it was confirmed as a lipogranuloma with osseous metaplasia. To the best of our knowledge, this is the first reported case of a lipogranuloma with osseous metaplasia in the breast. PMID- 21319364 TI - Re: Hemopericardium following acupuncture? PMID- 21319365 TI - [Progress in study and application of several new technologies applied in pharmaceutical analysis]. PMID- 21319366 TI - [Determination of quercetin metabolism in UGT1A3 cDNA-expressing cells by RP HPLC]. AB - OBJECTIVE: To develop a RP-HPLC method for the determination of quercetin in UGT1A3 cDNA-transfected cells. METHODS: The lysate of cells transfected with human recombinant uridine 5-diphosphate glucuronosyltransferases UGT1A3 cDNA was co-incubated with quercetin, the reaction was terminated with acetonitrile, and luteolin was used as internal standard. The determination was performed on a C(1) reversed phase column with a mobile phase of methanol-0.1% formic acid (V/V) at a flow rate of 1.0 ml/min. The gradient elution was as follows: 0 - 25 min (30:70 80:20, methanol:0.1% formic acid), > 25-25.5 min (80:20), >25.5-27 min (80:20 30:70), > 27-30 min (30:70). A UV-VIS detector was operated at 368 nm. RESULT: The standard curve was linear over the concentration range of 5-200 MUmol/L (r = 0.9999). The limit of detection was 1.25 MUmol/L(S/N >= 3), and the limit of quantification was 5 MUmol/L (S/N >10, RSD = 6.99%). The method afforded recoveries of 99.1%-103.5%, and precisions for inter- and intra-assay were < 2.5% and < 8%, respectively. In addition, kinetic analysis indicated that the K(m), V(max) and CL(int) (V(max)/K(m)) values for quercetin glucuronide were (62.95 +/- 13.16) MU mol/L, (284.50 +/- 24.35)nmol*min-1*g-1 and 4.52 ml*min-1*g-1, respectively. CONCLUSION: The method established is accurate and simple and suitable for the determination of quercetin in UGT1A3 cDNA-expressed cells. PMID- 21319367 TI - [Chiral separation of fluvastatin enantiomers with in vitro cellular method]. AB - OBJECTIVE: To establish a chiral separation method for determination of fluvastatin enantiomer with in vitro cellular model. METHODS: The determination was performed on Chiralpak AD column (4.6 mm * 250 mm); and the phase consisted of hexane-isopropanol-trifluoroacetic acid (90:10:0.1) at a flow rate of 0.5 ml/min with UV detection of 239 nm. RESULT: The standard curve was linear over the concentration range of 20 MUmol/L-300 MUmol/L (r2 = 0.9993, r2 = 0.9997). The recovery for this assay was (99.4 +/- 0.8)%, precision for inter-assay and intra assay was <10 %. CONCLUSION: The normal-phase HPLC chiral separation method was accurate and suitable for study on the stereoselectivity of fluvastatin with in vitro cellular model. PMID- 21319368 TI - [Comprehensive quality control method for total flavonoid of Fructus Aurantii]. AB - OBJECTIVE: To establish a comprehensive quality control method for total flavonoid of Fructus Aurantii. METHODS: RP-HPLC and spectrophotometry were applied for the quantitative and fingerprint analysis of total flavonoid of Fructus Aurantii. The contents of naringin and neohesperidin were determined on an Agilent SB-C18column (4.6 mm * 250 mm, 5 MUm). The mobile phase was composed of 0.02 % H3PO4 and CH3CN (80:20). The flow rate was 1 ml/min with DAD detected at 280 nm. The column temperature was maintained at 35 degrees C. The fingerprints were developed on an Agilent SB-C18 column (4.6 mm * 250 mm, 5 MUm). The mobile phase was composed of 0.5 % HAc and CH3OH with a linear gradient elution. The ratio of 0.5 % HAc and CH3OH was: 0 min, 80:20; 10 min, 60:40; 35 min, 30:70; 50 min, 0:100. The flow rate was 1 ml/min with DAD detected at 320 nm. The column temperature was maintained at 30 degree. Meanwhile, the contents of total flavonoid were determined at 283 nm. RESULT: The contents range of naringin, neohesperidin and total flavonoid were 38.3 %- 47.2%, 21.0 %- 28.5% and 79.9%-88.6 %, respectively. The fingerprints of the effective fractions showed 12 common peaks and the fingerprint similarity was all above 98.0 % compared with the standard chromatogram. CONCLUSION: The method reported in this paper can be used effectively for the quality control of total flavonoid of Fructus Aurantii. PMID- 21319369 TI - [Determination of four effective components from total flavonoids of Scutellaria barbata by high performance liquid chromatography]. AB - OBJECTIVE: To establish a HPLC method for simultaneous determination of 4 effective components from total flavonoids of Scutellaria barbata (FSB). METHODS: The HPLC method was developed on an Agilent Zorbax C18 column (4.6 mm * 250 mm, 5 MUm). The mobile phase was composed of 1% HAc and CH3OH:CH3CN (80:20) with a linear gradient elution. The flow rate was 1.0 ml/min, and UV detection wave length was set at 280 nm. The column temperature was maintained at 30 degrees C. RESULT: The linear range of 4 effective components (scutellarin, isoscutellarein 8-O-glucuronide, isoscutellarein and luteolin) was 0.14-11.20 MUg, 0.03-2.40 MUg, 0.007-0.560 MUg and 0.027-2.160 MUg, respectively. The average recovery for 4 effective components was (101.9 +/- 1.4)%, (103.5 +/- 0.6)%, (98.1 +/- 2.9)% and (100.5 +/- 2.3)%, respectively. The contents of 4 flavonoids were determined, with scutellarin 7.3%-14.3%, isoscutellarein-8-O-glucuronide 2.4%-9.3%, isoscutellarein 0.3%-0.5%, and luteolin 0.2%-0.6%, respectively. CONCLUSION: The method can be used effectively to evaluate the quality of FSB. PMID- 21319370 TI - [Optimization of alcohol precipitation process for extract of Carthamus tinctorius by multiple guidelines grading method]. AB - OBJECTIVE: To investigate the optimal alcohol precipitation parameters for extract of Carthamus tinctorius. METHODS: The effects of different factors on the transfer rate of hydroxy safflower yellow A (HSYA) was studied via single factor experiments, including the final alcohol concentration of the liquor, the speed of stirring, the initial density of the extract, the temperature and the pH of the liquor. Based on the results of single factor experiments, the final alcohol concentration of the liquor, the speed of stirring, the initial density of the extract and the pH of the liquor were studied by an orthogonal test and a multiple guidelines grading method, and the transfer rate of HSYA, the yield and the purity of extract in the supernatant were used as comprehensive evaluation index. RESULT: The optimal alcohol precipitation process of Carthamus tinctorius extract was as follows: the final alcohol concentration of the liquor 50%, the speed of stirring 500 r/min, the initial density of the extract 1.15 g/ml and the pH of the liquor 5.0. CONCLUSION: The proposed alcohol precipitation process is convenient and steady with high transfer rate of HSYA, high yield and purity of extract in the supernatant. PMID- 21319371 TI - [Inhibitory and inductive effects of (-)- and (+)-tetrahydropalmatine on CYP450 in mice]. AB - OBJECTIVE: To investigate the inhibitive and inductive effect of (-) tetrahydropalmatine (THP) and (+)-THP on main CYP450 isoforms in mouse liver microsomes. METHODS: The in vitro inhibitory effect was evaluated by incubating ( )-THP or(+)-THP with the probe substrates of main phase I metabolic enzymes in mouse liver microsomes, and the remaining substrates were determined by HPLC or LC-MS/MS method. Mice were administered with (-)-THP or(+)-THP at dosage of 240 mg/kg or 60 mg/kg by gastric lavage for successive 7 days, then the cocktail-LC MS method was applied to assess the activities of main CYP450 isoforms in mouse liver microsomes. RESULT: The IC(50) values of both (-)-THP and (+)-THP on isoforms studied were higher than 100 MUmol/L except that IC(50) value of (+)-THP on CYP2C was 43.89 MUmol/L, indicating weak inhibition of (-)-THP and (+)-THP on CYP1A2, CYP2D22, CYP2E1 and CYP3A11 in vitro. Compared with the vehicle group, the activities of CYP2D22, CYP2E1 and CYP3A11 were not increased significantly in (-)-THP and (+)-THP treatment groups, while the activities of CYP1A2 in 60 mg/kg and 240 mg/kg (-)-THP groups were 68.7% and 73.0% higher, than that of the vehicle group (P < 0.05, P < 0.01, respectively), the activity of CYP2C37 in 240 mg/kg (-)-THP treatment group was 80.4%, higher than that of the vehicle group (P < 0.05). CONCLUSION: There is negligible or weak inhibition on main CYP450 in mouse liver microsomes by (-)-THP and (+)-THP in vitro. (+)-THP does not induce main CYP450 in mouse liver microsomes while (-)-THP weakly induces CYP1A2 and CYP2C37. PMID- 21319372 TI - [Determination of residual solvents in 7-amino-3-chloro cephalosporanic acid by gas chromatography]. AB - OBJECTIVE: To develop a gas chromatography method for determination of residual solvents in 7-amino-3-chloro cephalosporanic acid (7-ACCA). METHODS: The residual levels of acetone, methanol, dichloromethane, ethyl acetate, isobutanol, pyridine and toluene in 7-ACCA were measured by gas chromatography using Agilent INNOWAX capillary column (30 m * 0.32 mm,0.5 MUm). The initial column temperature was 70 degrees maintained for 6 min and then raised (10 degrees C/min) to 160 degrees C for 1 min. Nitrogen gas was used as carrier and FID as detector. The flow of carrier was 1.0 ml/min, the temperature of injection port and detector was 200 degrees C and 250 degrees C, respectively. RESULT: The limits of detection for acetone, methanol, dichloromethane, ethyl acetate, isobutanol, pyridine, toluene in 7-ACCA were 2.5 MUg/ml, 1.5 MUg/ml, 15 MUg/ml, 2.5 MUg/ml, 2.5 MUg/ml, 2.5 MUg/ml and 11 MUg/ml, respectively. Only acetone was detected in the sample, and was less than the limits of Ch.P. CONCLUSION: The method can effectively detect the residual solvents in 7-ACCA. PMID- 21319373 TI - [Preparation method of polystyrene core-poly (acrylamide-acrylic acid) shell fluorescent microspheres]. AB - OBJECTIVE: To investigate the preparation method of polystyrene core-poly (acrylamide-acrylic acid) shell fluorescent microspheres. METHODS: The polystyrene core-poly (acrylamide-acrylic acid) shell (P-(St-co-AAM)) fluorescent microspheres were prepared using fluorescent microspheres as the core and acrylamide/acrylic as polymerization monomer. Reaction conditions affecting the morphology of core-shell structure including feeding mode, initiator, cross linker, pH, concentration and swelling were studied. RESULT: Fluorescent microscopy showed that the relatively uniform particle sizes were distributed in a range of 7-8 MUm. Fourier transform infra-red spectroscopy (FT-IR) proved the existence of poly (acrylamide-acrylic acid) shell and amide group on the surface. The optimal conditions for seeding polymerization: azobisisobutyronitrile was used as the initiator in the absence of cross linker, after a 40 h swelling treatment by using alcohol with the appropriate reaction temperature (70 degree), reaction time (3 h) and pH(6-7). The average dispersion and stability were 25.14 % and 90.21%, respectively. The fluorescein release percentage was kept stable at approximately 30% after 40 h. CONCLUSION: The fluorescent microspheres prepared by this method have core-shell structure and satisfactory fluorescence properties with good dispersion and stability. PMID- 21319374 TI - [Effect of benzo(a)pyrene on platelet aggregation and expression of P-selectin]. AB - OBJECTIVE: To investigate the effect of benzo(a)pyrene (BaP) on platelet aggregation and expression of P-selectin. METHODS: Blood samples were collected from healthy volunteers and the platelets was washed. Platelet aggregation was monitored by aggregometer and the expression of P-seletin was detected by whole blood flow cytometry. RESULT: BaP (10 MUmol/L, 1 MUmol/L and 0.1 MUmol/L) did not induce platelet aggregation; however, preincubation with BaP (10 MUmol/L) significantly enhanced ADP-induced platelet aggregation (P < 0.01) and platelet aggregation was (80 +/- 10)%, while BaP-preincubation failed to enhance platelet aggregation under collagen and thrombin stimulation. Flow cytometry showed that preincubation with BaP increased ADP-induced, but not thrombin-induced P-selectin expression (P < 0.01). CONCLUSION: BaP can stimulate ADP-induced platelet aggregation and P-selectin expression, probably through the interaction with ADP mediated signal pathway. PMID- 21319375 TI - [Small interfering RNA inhibits cell proliferation in gastric cancer cell lines highly expressing RegIalpha]. AB - OBJECTIVE: To investigate the effect of small interfering RNA on cell proliferation and apoptosis in gastric cancer cell lines with high expression of RegIalpha. METHODS: Total RNA was isolated from six gastric cancer cell lines,and the expression of RegI alpha mRNA was detected by RT-PCR. RegI alpha RNAi expression vector was constructed and stably transfected into MKN45 and AGS cells with high RegI alpha expression, empty-vector was used as control. RegI alpha mRNA and protein expression was measured by RT-PCR and Western blot respectively in stable transfected cell lines. Cell proliferation and apoptosis were detected with MTT assay and flow cytometry. RESULT: RT-PCR results indicated that RegI alpha mRNA expression was significantly inhibited by RNAi in both cell lines compared with empty-vector. Western blot results showed that RegIalpha protein was down-regulated to (44 +/- 4)% and (25 +/- 4)% respectively in MKN45 and AGS cells compared to empty-vector. MTT results showed that cell growth was significantly inhibited in MKN45 and AGS cells. The apoptosis rate in MKN45 and AGS cells was remarkable increased compared to that of empty-vector (12.96 +/- 0.50)% compared with (3.99 +/- 0.30)% and (11.59 +/- 1.10)% compared with (4.22 +/- 0.40)% (P < 0.05). CONCLUSION: Small interfering RNA of RegI alpha gene can efficiently down-regulate RegI alpha expression in MKN45 and AGS cell lines, and further inhibit cell growth and induce cell apoptosis. PMID- 21319376 TI - [Effect of atorvastatin on MMP-9 and TIMP-1 levels in bronchoalveolar lavage fluid and serum of rats with bleomycin-induced pulmonary fibrosis]. AB - OBJECTIVE: To investigate the effects of atorvastatin on matrix metalloproteinase 9 (MMP-9) and the tissue inhibitor-1 of matrix metalloproteinase (TIMP-1) levels in bronchoalveolar lavage fluid (BALF) and serum of rats with experimental pulmonary fibrosis. METHODS: Pulmonary fibrosis was induced by intratracheal administration of bleomycin in 30 female rats, which were further divided into two groups: Group M (without treatment) and Group A (treated with atorvastatin 10 mg/kg); control group (n = 5, Group C) was intratracheally administrated with same volume of saline. Five animals were sacrificed at 2 weeks (M2 and A2), 4 weeks (M4 and A4) and 6 weeks (M6 and A6) after model establishment, respectively. Lung tissue samples were harvested and prepared for HE and Masson's trichrome staining. Concentrations of MMP-9 and TIMP-1 in BALF and serum were measured by ELISA. RESULT: The severity of inflammation and pulmonary fibrosis was significantly reduced in Group A than that in Group M, especially at week 6. No significant difference was noted in the serum concentrations of MMP-9 and TIMP 1 among the Group M, A and Group C. The BALF concentrations of MMP-9 in Group M2 and M6 were significantly higher than those in Group C (P < 0.01 and 0.05), whereas those in the atorvastatin groups (A2, A4 and A6) were lower than those in M2, M4 and M6. Although the MMP-9 was still higher in Groups A2 and A4 than in the Group C, there was no significant difference in MMP-9 between Group A6 and Group C. TIMP-1 levels in BALF were significantly higher in M4 and M6 than Group C (P < 0.01 and 0.05), there were no significant differences between Group M2 and Group C. The TIMP-1 levels in BALF of atorvastatin groups were significantly lower than those of model groups and control group (P < 0.01 and 0.05), which resulted in a significantly increased ratio of MMP-9 to TIMP-1 in the atorvastatin groups. CONCLUSION: Atorvastatin inhibits the synthesis and release of MMP-9 and TIMP-1 in the lung tissue of rats with bleomycin-induced pulmonary fibrosis, and has no significant effect on circulating MMP-9 and TIMP-1, which may be associated with the attenuation of experimental pulmonary fibrosis in rats. PMID- 21319377 TI - [Effect of AT1 receptor on changes of tyrosine hydroxylase-immunoreactivity in rostral ventrolateral medulla induced by brain cholinergic stimuli in rats]. AB - OBJECTIVE: To investigate the effect of AT1 receptor on the changes of tyrosine hydroxylase-immunoreactivity (TH-IR) in rostral ventrolateral medulla (RVLM) induced by brain cholinergic stimuli in rats. METHODS: Male SD rats were randomly divided into 4 groups: NS + CBC group, Los + CBC group, Los + NS group and NS + NS group. AT1 was blocked by pretreatment of 20 MUg losartan in Los + CBC and Los + NS groups; intracerebroventricular injection of 0.5 MUg carbachol was used for cholinergic stimuli in NS + CBC and Los + CBC groups; normal saline (NS) was used for control. The output amount of natrium in kidney, glomerular filtration rate (GFR) and renal plasma flow (PRF) were observed. The changes of TH-IR in the RVLM were observed by immunohistochemistry. RESULT: In NS + CBC group carbachol induced potent natriuresis, after pretreatment of losartan the natriuretic effect was partially inhibited in Los + CBC group. Both the number and optical density of TH-IR positive neurons in NS + CBC group were markedly increased than those in NS + NS group (P < 0.05); while those in Los + CBC group were significantly lower than those in NS+CBC group (P < 0.05). Intracerebroventricular injection of carbachol and losartan had no effect on GFR and RPF(P > 0.05). CONCLUSION: The results suggest that cholinergic stimuli can induce potent natriuresis and increase the activity of adrenergic neurons in the RVLM; the above effects can be down regulated by blockade of brain AT1 receptor. PMID- 21319378 TI - [Clinical evaluation of laser in situ keratomileusis operation with three different ablative patterns]. AB - OBJECTIVE: To evaluate the clinical outcome among three different laser in situ keratomileusis (LASIK) ablations: Q-factor customized ablation (aberration smart ablation, ASA), wave-front guided ablation (WASCA) and ablation under wave-front guiding plus iris recognition system (IR+WASCA). METHODS: This prospective study comprised 96 eyes of 96 patients, and they were randomly divided into three groups: 30 patients in ASA group, 32 in WASCA group, and 34 in IR+WASCA group. There were no any statistical differences in spherical equivalent (SE), age, sex, pupil diameter, higher-order aberrations (HOA) among three groups preoperatively. Wave-front analysis was performed before and 1, 3 months after operation. RESULT: All patients got an uncorrected visual acuity (UCVA) >= 0.8 1 and 3 months after operation. The residual SE was in +/- 0.50D both at 1 and 3 months after surgery. There was no statistical difference in SE value, HOA, change of HOA, and coma aberration postoperatively among three groups. Horizontal coma (Z31) aberration took the majority of coma. HOA, total coma aberrations and spherical aberration increased postoperatively (P = 0.000), but without significant difference between 1 month and 3 months after surgery. CONCLUSION: That three customized LASIK are all effective, safe, accurate and stable; meanwhile WASCA may have better UCVA than the other two groups postoperatively. PMID- 21319379 TI - [Sleep quality and influencing factors of perimenopausal women in Ningbo region]. AB - OBJECTIVE: To investigate the sleep quality and influencing factors of perimenopausal women in Ningbo region. METHODS: A total of 527 perimenopausal women who lived in Ningbo for more than 5 years were enrolled in the study. The subjects were surveyed by self-designed questionnaire and Pittsburgh sleep quality index (PSQI); PSQI > 7 was defined as the cut-off value for sleep quality. Data were analyzed by software SPSS 11.0. RESULT: The mean PSQI score was 5.79 +/- 3.08 and 23.6 % of perimenopausal women in the study showed poor sleep quality. The proportion of poor sleep in 55-60 age group was 40.2%, significantly higher than that of 40-44, 45-49 and 50-54 age groups (P < 0.05). The sleep quality was associated with physical exercise, social activity, sleep circumstance, anxiety and family income in perimenopausal women. CONCLUSION: The sleep quality of perimenopausal women and the influencing factors are associated with mental health, life style and social environment, which suggests that some interventions should be undertaken to improve the sleep quality of perimenopausal women. PMID- 21319380 TI - [Combination of canales sacralis drop with acupotomy dissolution in treatment of discogenic lumbocrural pain]. AB - OBJECTIVE: To evaluate the combination of drop in canales sacralis with acupotomy dissolution in the treatment of lumbocrural pain caused by slipped discs. METHODS: One hundred and thirty-nine patients with lumbocrural pain caused by slipped discs were randomly divided into 3 groups: cases in Group A were treated by the drop in canales sacralis, in Group B by acupotomy dissolution and in Group C by the combination of canales sacralis drop with acupotomy dissolution. MacNab score and VAS score were assayed before treatment and 1 week, 3 and 6 months after treatment. RESULT: The effective rates in Groups A, B and C at 1 week, 3 and 6 months after treatment were 71.4%, 75.5%, 79.6%; 75.0%, 79.6%, 81.8% and 89.1%, 91.3%, 93.5%, respectively (P < 0.01). The pain intensity in Group C was reduced more markedly at different time points after treatment than that in Group A and Group B (P < 0.01). CONCLUSION: The combination of canales sacralis drop with acupotomy dissolution is superior to each method used alone in treatment of lumbocrural pain caused by slipped discs in the short-and long-term. PMID- 21319381 TI - [Research progress on proliferative property and capacity of human corneal endothelium]. AB - Primary and secondary corneal endothelial decompensation leads to stromal edema, corneal opacity and loss of visual acuity. The pathogenesis of corneal endothelial decompensation is that adult corneal endothelium in vivo lacks of a robust proliferative response to injury, does not divide sufficiently to replace the lost cells. Previous studies indicate that cell-cell contact inhibition and transforming growth factor-beta2 (TGF-beta2) in aqueous humor may be responsible for maintaining human endothelial cells in a non-replicative state in vivo. The results of the experimental investigation by using immunofluorescent staining of the cell cycle-associated proteins and cell proliferation marker Ki67 in corneal endothelium indicate that human corneal endothelial cells in vivo are arrested in the G1-phase and have not exited from the cell cycle. Successful outgrowth in culture of human corneal endothelial cells in vitro and the establishment of the immortalized human endothelial cell line, provide strong evidence that corneal endothelial cells retain proliferative capacity. Experiments with cell culture ex vivo demonstrate that corneal endothelial cells cultured from young donors grow more robustly than those from older donors, and cells cultured from peripheral area of corneas show greater cell density than central regions. Studies have demonstrated that in vitro human corneal endothelia undergo mitotic changes in response to stimulation of growth promoting agents, such as growth factors, EDTA and extracellular matrix. Identification of corneal endothelial stem cells and isolation and culture of human endothelial precursor cells in vitro will be beneficial for further investigation regarding the mechanism of corneal endothelial regeneration as well as corneal endothelial cells in vitro culture. PMID- 21319382 TI - [Advances in research on neuroprotective effects of inert gas]. AB - Inert gas is a group of rare gases with very low activity, their application in medical field has increasingly drawn attentions. It is known that inert gases helium, xenon and argon have protective effects on nervous system and the mechanisms are related to eradicating free radicals, anti-inflammation, suppressing apoptosis, influencing ion channels and so on. Further study on the neuroprotective effect of inert gas will shed light on a new approach to treat neurological diseases. PMID- 21319383 TI - [Involvement of LMO4 in tumorigenesis associated epithelial-mesenchymal transition]. AB - LMO4 is a novel member of the LIM-only (LMO) subfamily of LIM domain-containing transcription factors, so named because they are composed almost entirely of two tandem LIM domains. This subgroup of LIM proteins has 4 members: LMO-1, LMO-2, LMO-3 and LMO-4. They all play important roles in the normal mammalian development, functioning as an important regulator of cell proliferation. LMO4 is highly expressed in the epithelial compartments at locations of active epithelial mesenchymal interactions, and can interact with some signaling pathways involved in epithelial-mesenchymal signaling. Thus the disregulation of LMO4 expression may be involved in tumorigenesis. In this paper, we will at first expound LMO4 in detail, based on which the possible mechanisms for its interaction with TGF-beta signaling and the roles of this cross-talk between them in the vital process of cell will be introduced. All of those will add to our understanding of tumorigenesis and contribute to the search of new targets for the treatment of cancer. PMID- 21319384 TI - [Mandibular plasmacytoma: a case report]. PMID- 21319385 TI - I am facing the possibility of bypass surgery and would like to know the benefits of the heart-lung machine, and if I should have any concerns. PMID- 21319386 TI - What's the best way to reduce risk of hypothermia and frostbite during these cold winter months? PMID- 21319387 TI - I've been told to avoid "purines" because I have gout. What are purines, and what foods contain them? PMID- 21319388 TI - [A comparative study of the efficiency of trapeziform, rectilinear, and quasi sinusoidal Gurvich-Venin bipolar defibrillation pulses based on high-resistivity experimental animal simulations]. PMID- 21319389 TI - [Laboratory diagnosis of infected pancreonecrosis]. AB - The results of treatment and examination were analyzed in 175 patients admitted to a clinic for sterile pancreonecrosis (PN). The significance of routinely available (clinical, biochemical, and microbiological) laboratory tests in the diagnosis of purulent complications was analyzed in patients with varying severity of pancreatic autolysis. Complex laboratory monitoring was found to be of importance in predicting and detecting infected PN with obligatory fine-needle punctures under ultrasound guidance and further microscopic studies of puncture specimens. PMID- 21319390 TI - [Current approaches to laboratory diagnosis of syphilis]. AB - The efficiency of chemiluminescence immunoassay (CIA) used as a treponemal test in the serological diagnosis of syphilis was evaluated, by applying the serum samples of 219 patients screened for syphilitic infection. The efficiency of CIA was evaluated in two steps: (1) comparison of the results of tests using the IMMULITE 2000 Syphilis Screen and LIAISON Syphilis screen reagent kits; (2) that of the results of tests applying the IMMULITE 2000 Syphilis Screen and Recombi Best antipallidum-summary antibodies kits. A 100% correlation was found when comparing the results of tests employing the IMMULITE 2000 Syphilis Screen and DiaSorin LIAISON Syphilis Screen kits (n=66). Comparison of CIA using the IMMULITE 2000 Syphilis Screen kits versus that applying the Recombi Best antipallidum-summary antibodies kits (n=153) revealed 3 discordant samples, which amounted to 1.96% of the number of results. Evaluation of the impact of related microorganisms on the detection of T. pallidum antibodies (n= 140) with the IMMULITE 2000 Syphilis Screen kit indicated no interference or cross-reactivity. PMID- 21319391 TI - [Complex procedure for diagnosis of manifestations in intestinal dysbacteriosis]. AB - The procedure for diagnosing the degree of intestinal dysbacteriosis comprises a study of changes in the species-specific and quantitative composition of the intestinal microflora and additional determination via enzyme immunoassay of the levels of various classes of gram-negative endobacterial lipopolysacharide immunoglobulins in human coprofiltrates. Antiendotoxic antibody titers were in the range between 1:100 to 1:150; 1:200 to 1:400, and above 1:400 in the examinees with grades 1, 2, and 3 dysbacteriosis, respectively. The complex procedure for diagnosing the degree of intestinal dysbacteriosis is easy-to-use, has no expensive components, and enables a judgment of the degree of local antiendotoxin immunity in the intestine throughout the working day, which may be used for timely and individual correction. PMID- 21319392 TI - [Species-specific sera against surface antigens of Bacillus anthracis strains]. AB - The species-related specificity of sera against 94-KD proteins isolated from culture filtrates of B. anthracis strains with different levels of virulence plasmids was studied to determine whether they might be used to identify the pathogen of anthrax. Sera against fractions 1 of culture filtrates of B. anthracis strains CTI (pXO1+ pXO2-), 81/1TR (pXO1- pXO2-), Davies (pXO1- pXO) separated by gel chromatography on Sephacryl S-300 were examined. In the gel immunodiffusion test with growing cultures, the sera exhibited non-identical antigens and differed in the presence of antibodies to antigens of related bacilli. The sera against fractions 1 of culture filtrates of toxin-producing and plasmidless strains displayed antigens produced only by B. anthracis strains into nutrient agar. Electroimmunotransblotting revealed that they contained antibodies mainly to 94-kD proteins and failed to react with B. cereus proteins with a molecular weight of 94 kD and with B. thuringiensis proteins with a molecular weight of 97 kD, which were extracted from autonomous cells. In the immunofluorescence test, immunoglobulins of sera against fractions 1 of culture filtrates of three strains stained autonomous cells and spores of 23 B. anthracis strains with different levels of virulence plasmids. In working dilutions, they did not react with antigens of 18 strains of related bacilli, which presents a possibility of using them for species identification of B. anthracis. PMID- 21319393 TI - Retraction of article. Synthesis and pharmacological activity of potential cocaine antagonists. 2. Structure-activity relationship studies of piperidine ring-substituted methylphenidate analogs. PMID- 21319394 TI - Back pain. A look at causes, treatment and prevention. PMID- 21319395 TI - Emotional cues and concerns in medical consultations. PMID- 21319397 TI - Microbicide breakthroughs may signal new era in HIV prevention. 'Researchers actually got a standing ovation, which is unheard of'. PMID- 21319396 TI - Policy implications of early onset breast cancer among Mexican-origin women. AB - BACKGROUND: Overall, Latinas are more likely to be diagnosed with a more advanced stage of breast cancer and are 20% more likely to die of breast cancer than non Hispanic white women. It is estimated that from 2003 to 2006, $82.0 billion in direct medical care expenditures, in addition to 100,000 lives annually, could be saved by eliminating health disparities experienced by Latinos and increasing the use of up to 5 preventive services in the United States. An additional 3700 lives could be saved if 90% of women aged >=40 years were recently screened for breast cancer. METHODS: The authors examined the risk for breast cancer in a case control, population-based sample of Mexican-origin women in Harris County, Texas (n=714), where the rates of breast cancer mortality for Latina women have doubled since 1990. RESULTS: Half of breast cancer cases (n=119) were diagnosed in women aged <50 years. In a multivariate model, women who had a family history of breast cancer (odds ratio [OR], 4.3), who were born in Mexico and had high levels of language acculturation (OR, 2.5), and who did not have health insurance (OR, 1.6) had the highest risk for breast cancer. CONCLUSIONS: Because the current results indicated that Mexican-origin women are at high-risk for early onset, premenopausal breast cancer, the authors recommended policies that target screening, education, and treatment to prevent increased disparities in mortality. The authors concluded that the inclusion of community members and policymakers as partners in these endeavors would further safeguard against an increase in cancer health disparities and aid in formulating a policy agenda congruent with scientifically based, community-driven policy efforts that address breast cancer screening, education, and treatment in this vulnerable population. PMID- 21319398 TI - ["Varicose vein" following clavicular fracture]. PMID- 21319399 TI - [Reimbursement distribution. What happens with extra-budgetary services?]. PMID- 21319400 TI - [Cannabis medicinal drugs. "Psychedelics" by prescription?]. PMID- 21319401 TI - [Soft tissue infections from folliculitis to necrotizing fasciitis. When is it dangerous?]. PMID- 21319402 TI - [Management of food allergies. No dietary prescriptions without provocation]. PMID- 21319403 TI - [Difficult decision at bedside. Withholding treatment due to costs?]. PMID- 21319404 TI - [Erythema migrans successfully treated. What are the options when antibodies persist?]. PMID- 21319405 TI - [Naturopathy consultation. Hemorrhoids]. PMID- 21319406 TI - [Current recommendations for the treatment of community-acquired pneumonia. How to put the guidelines into practice]. PMID- 21319407 TI - [Diagnostic work-up in community-acquired pneumonia]. PMID- 21319408 TI - [Treatment of community-acquired pneumonia]. PMID- 21319409 TI - [Surgical treatment of incisional hernias]. PMID- 21319410 TI - [Sleep apnea and hypertension]. PMID- 21319411 TI - [Clean tasks for 2011]. PMID- 21319412 TI - [The time of ceramic restorations have made metal crowns unnecessary. Yes]. PMID- 21319413 TI - [The time of ceramic restorations have made metal crowns unnecessary. No]. PMID- 21319414 TI - [Treatment of removable partial dentures. 1. Legislation, rules of conduct, care plan and treatment plan]. AB - An invasive treatment, such as the treatment involving a removable partial denture, requires a well-structured approach. Regulations governing the communication between a healthcare professional and a patient in the Netherlands can be found in the Dutch Medical Treatment Act and the Rules of Conduct for Dentists of the Dutch Society for the Advancement of Dentistry (NMT). According to the regulations in these sources, a healthcare provider needs a patient's informed consent for any medical treatment and he is required to maintain a file of medical records. Consent should be based on efficacious communication and explanation of treatment options, risks and costs. With regard to the duty to maintain records, a care plan and a treatment plan are required for an invasive treatment. A standard structure and sequence of points for the care plan and the treatment plan will reduce the risk of overlooking essential issues. PMID- 21319415 TI - [Treatment of removable partial dentures. 2. Causes and consequences of a reduced occlusal system]. AB - The occlusal system is part of the orofacial system and consists of the maxillary and mandibular alveolar ridge and teeth which are occluding or not or the removable denture teeth. The most prevalent causes of loss of teeth are insufficient oral self care or inadequate professional oral healthcare service. A reduced dentition can be described in terms of diastemas in the anterior region and number of occluding pairs of (pre)molars, differentiated as interrupted or shortened dental arches. Characteristic of a healthy functional occlusal system are the absence of pathology and the possibility to practice all oral functions without inconvenience. The consequences of a reduced occlusal system may be overload and/or migration of teeth, mandibular instability, and impaired esthetics and chewing function. Morphological and functional alterations can be considered to be adaptations to changed situations or to be pathological. The distinction between adaptation and pathology cannot be sharply defined. If prosthetic replacement of teeth is needed, the trend is to avoid removable partial dentures. PMID- 21319416 TI - [Acrylic resin removable partial dentures]. AB - An acrylic resin removable partial denture is distinguished from other types of removable partial dentures by an all-acrylic resin base which is, in principle, solely supported by the edentulous regions of the tooth arch and in the maxilla also by the hard palate. When compared to the other types of removable partial dentures, the acrylic resin removable partial denture has 3 favourable aspects: the economic aspect, its aesthetic quality and the ease with which it can be extended and adjusted. Disadvantages are an increased risk of caries developing, gingivitis, periodontal disease, denture stomatitis, alveolar bone reduction, tooth migration, triggering of the gag reflex and damage to the acrylic resin base. Present-day indications are ofa temporary or palliative nature or are motivated by economic factors. Special varieties of the acrylic resin removable partial denture are the spoon denture, the flexible denture fabricated of non rigid acrylic resin, and the two-piece sectional denture. Furthermore, acrylic resin removable partial dentures can be supplied with clasps or reinforced by fibers or metal wires. PMID- 21319417 TI - [Routine oral examinations and specific after-care for removable partial dentures]. AB - Following treatment with a removable partial denture, routine oral examinations are required to stabilize the existing condition in a sustainable way and to make possible the timely treatment of anomalies which have appeared. In cases of problems assessed during a routine oral examination in relation to the removable partial dentures, maintenance, restorative and prosthetic treatment may be indicated. Maintenance treatments are indicated for small and easily retrievable alterations. In removable partial denture treatment, adequate space between prepared tooth and denture is essential. Possible prosthetic treatments of a removable partial denture are relining, rebasing, improving or renewing the maxillomandibular relation, repairment, and extension. PMID- 21319418 TI - [The Virtual Hospital, a European project in nursing education]. PMID- 21319419 TI - [An information circuit optimized for a medical-surgical ambulatory unit]. PMID- 21319420 TI - [Telemedicine, an opening for new nursing practices]. PMID- 21319421 TI - [Nurse bloggers speak out. Interview by Jerome Jean]. PMID- 21319422 TI - [Nurse on Molene Island. Interview by Jerome Jean]. PMID- 21319423 TI - [Supporting the practice of nursing from a shared humanity perspective]. PMID- 21319424 TI - [The clinical examination has an ancient history in nursing practice]. PMID- 21319425 TI - [Complemental nurses in a health service for patients with chronic obstructive lung disease]. PMID- 21319426 TI - [Interdisciplinary individualized patient-centered care plan]. PMID- 21319427 TI - [Nursing assistant in gerontology, a new function]. PMID- 21319428 TI - [Collaborative thinking between future professional nurses and nurse's aides on the theme of caring]. PMID- 21319429 TI - [Central venous catheters]. PMID- 21319430 TI - [Personality disorders 3/4]. PMID- 21319431 TI - [Alice Clamageran (1906-1998)]. PMID- 21319432 TI - [Please, take me to the movies!]. PMID- 21319434 TI - [Antiretroviral management of HIV infection in Mali]. PMID- 21319433 TI - [AIDS related Kaposi's disease in Hospital area in Bamako]. AB - The goal of this prospective work were to describe the clinical, therapeutic and evolutionary aspects of Kaposi's disease occurring during AIDS in the infectious diseases service from October 1, 2004 to September 30, 2005. The diagnosis of the infection by the HIV was based on the positivity of serology with 2 fast tests. That of the Kaposi's disease was based on the clinical aspect and /or histological of the lesions. On these 2189 patients, 37 presented the Kaposi's disease that means a prevalence of 1.6%. They were 17 men and 20 women average age 39.5 years and heterosexuals in 97.30 % of the cases. Kaposi's disease limited on the skin and mucous were most represented within (48.65 %), followed by the skin limited (43.24 %) and mucous localization (8.11%). Papulo-nodulare feature was the major clinical founded to the physical examination in 54.05 %. The rate of average CD4 was 76 cellules/mm3 with the extreme one going from 1 to 512 cellules/mm3. It was favorable at 14 (43.75%) of the 32 patients having profited from antiretroviral treatment. The Kaposi's disease during the AIDS is relatively frequent with the service of the infectious diseases and the prognosis remains severe. However the antiretroviral therapy can improve the prognosis of the skin limited forms. PMID- 21319435 TI - Shenzhen: city of suspended possibility. AB - This essay on Shenzhen, China, presents three vignettes addressing the question of home in a city of migrants. The first section explores the ubiquitous narratives of success forming the city's foundational myth. The second follows this myth into the world of a Shenzhen filmmaker and his characters, as they navigate the tension between the idea of home and the urge to start anew, resulting in the suspended possibility of the title. The last section looks at young architects who hope to preserve the city's heterotopic sites of migrants and original villagers through architectural innovations. The cases show how an economy of desire supplements the political economy of this export-driven city. The city appears as an urban desiring machine that produces itself as an object of desire for the migrants of all classes who flock to its factories, "urban villages", white-collar jobs, luxury villas and underground economy. The essay is an encounter with the mythology of success and failure, the intertwining of home as an end and home as the beginning, and with the manipulation of space that allows residents to control their own subjectivity. PMID- 21319436 TI - Physician workforce. PMID- 21319437 TI - Education in authorship ethics: should it be compulsory? PMID- 21319438 TI - "We were all trespassers": George Edward Lemmon, Anglo-American cattle ranching, and the Great Sioux Reservation. AB - With the opening of the Black Hills to white settlement in the mid-1870s, thousands of fortune-seekers made their way into Dakota Territory. George Edward Lemmon, a man later renowned as one of the world's most accomplished cowboys, was among them. During the 1880s his employer, the Sheidley Cattle Company, grazed thousands of cattle in western Dakota Territory, many of them on Sioux Indian land. Indeed, the company owed a great deal of its success to illegal grazing on the Great Sioux Reservation. Opportunists such as Lemmon supported Indian reservations because they could use those lands to make a profit. The interaction between large-scale white ranchers and the Indians of the Great Sioux Reservation provides insight into the development of the range cattle industry in the northern Great Plains and illuminates the motivations that led many ranchers to support, rather than oppose, the reservation system. PMID- 21319439 TI - Under the trees: the Georgia peach and the quest for labor in the twentieth century. AB - The Georgia peach boom around the turn of the twentieth century was often hailed as a successful experiment in diversification. Peach growers, the story went, threw off the tyranny of King Cotton by pledging their allegiance to the "Queen of Fruits." This portrayal is partly true; unlike other proposed alternatives to cotton, peaches flourished in many places. But the history of the "labor problem" in the Georgia peach belt makes it clear that peach production depended on the cotton economy. Peaches required large amounts of labor only at harvest time, which came during a lull in the cotton season. Thus, for many years, growers found a ready labor supply in a rural population otherwise at loose ends. As this population relocated to cities, and as cotton farmers mechanized their operations, peach growers turned increasingly to the federal government to help shore up their workforces. PMID- 21319440 TI - [Studies on the killing effect of gamma ray irradiated peripheral blood mononuclear cells combined with (-)-gossypol on human prostate cancer LNCaP cells]. AB - AIM: To observe the killing effect of irradiated peripheral blood mononuclear cells (PBMCs) at low dose combined with (-)-gossypol on cultured human prostate cancer LNCaP cells. METHODS: Human PBMCs were irradiated by gamma ray at 1 gray, the irradiation dose rate was 17 Gy/min. The experiments were divided into control group (LNCaP cells only), LNCaP cells with irradiated and non-irradiated PBMCs co-culture groups, (-)-gossypol treatment group, irradiated PBMCs and (-) gossypol co-treatment group. Acridine orange/ethidium bromide (AO/EB) staining and MTT method were used to observe the killing effect of PBMCs and/or (-) gossypol. RESULTS: The killing activity of irradiated PBMCs group and (-) gossypol treatment group were obviously increased and were higher than that of non-irradiated group (P < 0.05). The killing activity of combined group was much higher than that of irradiated group and ApoG2 treatment group (P < 0.01). CONCLUSION: Irradiated PBMCs at low dose combined with (-)-gossypol can enhance the anti-tumor effects obviously. PMID- 21319441 TI - The first rite of passage: baptism in medieval memory. AB - This article is part of a wider study that examines over 10,000 jurors' testimonies in proof-of-age hearings from 1246 to 1432, which were conducted to determine the legal majority of heirs-in-chief of the crown. It looks specifically at more than 1,500 references to the ceremony of baptism and tries to build up a picture of what the service was like in the memories of the participants. It reveals the haste and sometimes confusion of the preparations beforehand, the naming of infants, the role of godparents, the use of writing and the giving of gifts to record the birth, the celebrations that accompanied it, and details of the ceremonial itself, including the processions with lit torches and the crowds that often gathered. Despite the stereotypical nature of much testimony, it attempts to capture the atmosphere of what went on and what stuck in the minds of jurors. PMID- 21319442 TI - Fertility decline in rural China: a comparative analysis. AB - Many models have been proposed to explain both the rapidity of China's fertility decline after the 1960s and the differential timing of the decline in different places. In particular, scholars argue over whether deliberate policies of fertility control, institutional changes, or general modernization factors contribute most to changes in fertility behavior. Here the authors adopt an ethnographically grounded behavioral-institutional approach to analyze qualitative and quantitative data from three different rural settings: Xiaoshan County in Zhejiang (East China), Ci County in Hebei, (North China), and Yingde County in Guangdong (South China). The authors show that no one set of factors explain differential timing by a combination of differences in social-cultural environments (e.g. spread of education, reproductive ideologies, and gender relations) and politico-economic conditions (e.g. economic development, birth planning campaigns, and collective systems of labor organization) during the early phases of the fertility decline. PMID- 21319443 TI - Marriage and the family in a Maltese parish: St. Mary's (Qrendi) in the eighteenth century. AB - This article addresses the Maltese traditional family, taking St. Mary's (Qrendi) as a test case. It results that couples married in their early twenties, while a high proportion of men and women never married at all. Marriage was not popular so that one-fifth of all marriages were remarriages. Very few widows remarried and it was only for some economic reason that they sought another man. There is no evidence though that a high rate of celibacy resulted in flagrant promiscuity even if there is evidence that the Qrendin were not so particular about their sex life. No birth control was practiced within marriage and children followed one another regularly. This brings into relief the parents' unconcern for their offspring's future as well as the inferior status of women because husbands made their wives several offspring. Relations between the spouses were poor so that dissatisfied couples went their own ways. PMID- 21319444 TI - [Changes of IL-8 and TNF-alpha in gingival crevicular fluid before and after treatment from chronic periodontitis]. AB - AIM: To investigate the changes of IL-8 and TNF-alpha in gingival crevicular fluid (GCF) before and after treatment from chronic periodontitis. METHODS: 96 patients with chronic periodontitis were selected as study group and experienced initial periodontal therapy. 50 healthy people were selected as control group. Gingival crevicular fluid was collected before and after treatment. At the same time, the clinical parameters, including PLI, PD, SBI and AL were recorded, and the levels of IL-8 and TNF-alpha in GCF were measured by ELISA in two groups. RESULTS: The levels of IL-8 and TNF-alpha in GCF after treatment were significantly lowered in study group as compared with those before treatment (P < 0.05), while PLI, PD, SBI and AL showed significant reduction (P < 0.05). The levels of IL-8 and TNF-alpha in GCF before and after treatment were significantly highered in study group as compared with those in control group (P < 0.05). There was significant correlation between PD and IL-8 in GCF (r = 0.486, P < 0.05) and between SBI, PD and TNF-alpha in GCF (r = 0.495, 0.648, P < 0.05). CONCLUSION: IL 8 and TNF-alpha may be associated with the development and the severity of periodontitis. PMID- 21319445 TI - PAs, NPs and defensive medicine in the ED. PMID- 21319446 TI - All roads lead to the healthcare home. PMID- 21319447 TI - Reimbursement coding for specialty services. PMID- 21319448 TI - Coming into focus. Pharmacologic treatment for ADHD. PMID- 21319449 TI - Treatment of viral croup. No humidity needed. PMID- 21319450 TI - Cervical cancer in lesbians. A call to action. PMID- 21319451 TI - Actinic keratosis. Patient-based approaches to adverse event management. PMID- 21319452 TI - Triglycerides & omega-3s. Prescription omega-3 fatty acids are now among the hypertriglyceridemia therapies. PMID- 21319453 TI - NP Entrepreneur of the Year. Marcia Upson, president of Naturally Slim. PMID- 21319454 TI - Laura M.Gunder. The 2010 Family Practice PA of the Year. PMID- 21319455 TI - Efficacy of echinacea on the action of cyproterone acetate in male rats. AB - The study aimed to evaluate the effect Echinacea extract (E) on the testicular antioxidants function in normal rats or that subjected to anti-androgenic compound, cyproterone acetate (CA). Rats were divided into 5 groups treated daily via an oral tube for two intervals 2 and 4 weeks, 1st control, 2nd E (Echinacea treated group in dose 63 mg kg(-1)), 3rd CA (cyproterone acetate treated group in dose 25 mg kg(-1)), 4th E+CA and 5th E as prophylactic one week before E+CA treatment with the same aforementioned E or CA doses. The body, testes, epididymis and vas deferens weights were recorded. Sperm count, Nitric Oxide (NO), calcium ion (Ca2+) and malondialdhyde (MDA) contents in addition to superoxide dismutase (SOD), glutathione S-transferase (GST) activities were determined in testicular tissues. CA exhibited direct negative effect on reproductive organs weight and significant reducing effect on sperm count and Ca2+ contents. SOD and GST activities significantly decreased in addition to significant increase in NO, MDA contents reflecting the oxidative status of testis in CA treated rats. The prophylactic effect of E treatment, in time related manner, showed significant improvement in the antioxidant status of the testicular tissue which is more pronounced as compared to E+CA treatment. PMID- 21319456 TI - Effect of inhaled corticosteroids on growth and puberty in Egyptian asthmatic children and adolescents. AB - Growth suppression and delayed puberty may be major concerns for Inhaled Corticosteroids (ICS) treatment in children. Thus, we aimed to assess the effect of long-term ICS on growth and pubertal status in 30 asthmatic children and adolescents in comparison to 20-matched healthy subjects. Auxological measurements, Tanner staging and bone age assessment were performed. Measurements of basal and Lutenizing hormone releasing hormone (LHRH) stimulated follicle stimulating hormone (FSH) and Lutenizing hormone (LH) were done for patients only. In addition, pelvic ultrasound for measurements of uterine length and right ovarian volume was done for females aged > 11 years. Patients' height, bone age and their Standard Deviation Scores (SDSs) were significantly lower, while weight SDSs were significantly higher than controls. ICS at doses > 400 microg/day negatively affected height and its SDS (OR: 8.5, 95% CI: 2.15-33.8), whereas the use of ICS for > 1 year significantly affected all auxological parameters with a particular risk on height SDS (OR: 9, 95% CI = 3.10-10.64) and weight for height SDS (OR: 6.82, 95% CI: 1.36-34.27). Significantly lower stimulated gonadotropins were encountered at doses > 400 microg/day, while a duration > 1 year was associated with significantly lower basal and stimulated gonadotropins. Logistic analysis revealed that the use of ICS for > 1 year carried the highest risk of association with low stimulated FSH (OR: 5.80, 95%, CI: 1.54-33.70) and LH (OR: 8.31, 95% CI: 1.83-50.47). In conclusion, ICS at doses > 400 microg/day carry a significant risk of retarding height of asthmatic children while their continuous use for > 1 year carries significant risks of short stature, weight gain and delayed puberty. PMID- 21319457 TI - Chemical, physical and microbiological changes during composting of the water hyacinth. AB - An investigation of the physical, chemical and microbial population changes that occurred during the composting of water hyacinth was carried out. After 11 weeks of composting, the compost turned black, had decomposed and had no smell. The pH was 7 and the highest temperature reached, of 40 degrees C occurred in the first week. The initial carbon/nitrogen ratio was 17.61 and this increased to 18.12 by the end of the composting. The coliform population declined greatly from 8.11 to 5.85 MPN (log)/g and fecal coliforms and Escherichia coli were not detected in the final product. Bacteria were the dominant microbes in the compost followed by actinomycetes and fungi. Mesophillic microorganisms were present in higher numbers than thermophillic microorganisms throughout the composting. The highest cellulase and xylanase activities in the compost of 6.67 and 10.24 U/kg DW, respectively were detected in the second week which was related to the temperature. Bacillus sp. strain B4 was isolated and investigated for cellulase and xylanase using agro-industrial residues as substrates during Solid-State Fermentation (SSF) processes. Corncob and rice straw were good substrates for the production of the enzymes with a maximum cellulase of 1.19 U/gDW and xylanase activity of 2.54 U/g DW, respectively. The activities of both enzymes were stable and maximum at 50 degrees C. This study indicated that agro-industrial residues should be mixed with water hyacinth for composting to facilitate the development of a thermophilic phase during the composting process and to improve the product. Bacillus sp. strain B4 can be used as a starter strain. PMID- 21319458 TI - Assessment of survival, mortality and recovery of coral reefs of East Kish Island, Persian Gulf. AB - Coral reefs are specialized communities that develop clear, well-lit tropical and subtropical water; they provide shelter and canopy for great variety of organisms, living in mean temperature of 20 degrees C. Coral Bleaching and mortality have been associated with elevated seawater temperature. The aim of the study was to investigate coral bleaching and evaluate health condition of the corals. Distribution of coral reefs around Kish Island was determined by the Timed Swim (TS) technique. This survey carried out in 2 times (May and October, 2009) in 2 depths of 3-5 m and 6-10 m. Two Divers swam in constant speed for a set amount of time in three dive sites. The timed swim survey around the Kish Island showed that the most healthy live hard coral assemblages were found in the site called Persian Gulf seaport, whereas the greatest percentage of bleached corals were located in Jurassic Park station, located at the southeast of the Island. Branching corals (Acropora sp.) were bleached among all 3 stations and no sign of recovery could be detected. In Big coral site suitable substrate for accumulation of living organisms including Echinometra mathaie (sea urchin) existed due to presence of great amount of algae on dead corals and rocks. Based on the observation, it seems that the cause of reef destruction in Kish Island fall in to two categories, natural and human impacts. PMID- 21319459 TI - Isolation and characterization of chalcone synthase gene isolated from Dendrobium Sonia Earsakul. AB - To isolate and characterize chalcone synthase gene in anthocyanin biosynthetic pathway during flower development of Dendrobium Sonia Earsakul. The gene was isolated from floral tissues of the orchid by reverse transcriptase polymerase chain reaction. Characterization of the gene considered to its relatedness to chalcone synthase gene in other orchid plants elucidated by construction of a neighbor-joining phylogenetic tree. Gene expression pattern related to flower development and pigmentation was investigated by relative quantification real time polymerase chain reaction. A complete coding sequence was obtained and sequence analysis revealed that the gene of Dendrobium Sonia Earsakul consisted of 1,188 bp. Blast analysis and multiple alignments showed that the chalcone synthase gene of Dendrobium Sonia Earsakul shares high homology to chalcone synthase gene of Dendrobium genus particularly Dendrobium hybrid Uniwai prince. Phylogenetic tree revealed that chalcone synthase of Dendrobium genus are highly conserved. The chalcone synthase gene of Dendrobium Sonia Earsakul was highly expressed in young flower bud with no pigmentation and the expression was sharply decreased when young flower bud started accumulation of pigments. Expression of chalcone synthase gene was then maintained at the same level until young bud developed into fully opened flowers. PMID- 21319460 TI - Comparison of chest compression to ventilation outcome ratio during basic life support and CPR in 2009. AB - The aim of this study was to compare the effect of a 40:2, 15:2 versus 30:2 Compression: Ventilation (C:V) ratio on rate of Chest Compression (CC), rescuer fatigue and satisfaction. We measured the BP and pulse. Fifty three persons performed BLS and CPR using C:V of 15:2, 30:2 and 40:2 on an adult resuscitation lardal manikin for 2 min. Two researchers measured the above mentioned variables. Data were analyzed by ANOVA, student's t-test or Mann-Whitney U test between groups. The value of p < 0.05 was considered as significant. The results revealed fatigue after 2 min and satisfaction from the performed technique in the groups differed (p< 0.05). Number of breathing in two minutes was 8.8 +/- 4.7(1-24). Total cardiac massage in 2 min. in the study groups was 131.7 +/- 40.6 (20-265), of this number in 130.6 +/- 40.5 was done correctly. The number of compression per 2 min increased with C:V ratio of 40:2 than to other C:V ratio. Most of participants (71.7%) prefer using 30:2 ratios to achieve the primary goal of Cardiopulmonary Resuscitation (CPR). The PR and systolic, diastolic BP of rescuers before and 2 min after resuscitation had insignificant difference (p < 0.001) and SBP differed between groups (p < 0.04). Although the rescuers prefer to perform the C:V ratio 30:2, but number of CC is less than standard recommended by AHA. Alternative C:V ratio of 40:2 methods, is equal to the AHA recommended 80 compressions/minute and also highest number of CC is done in 2 min, while, in the other methods is less than the recommended number. PMID- 21319461 TI - Nutrient changes and antinutrient contents of beniseed and beniseed soup during cooking using a Nigerian traditional method. AB - Evaluations of the effect of prolong cooking on the nutrient and antinutrient composition ofbeniseed and beniseed soup were carried out in this study. Proximate, mineral, vitamin A and C and antinutrient compositions of raw beniseed (BS-R), beniseed boiled (BSB) for 15, 30, 45 and 60 min and beniseed soup (BSS) cooked for the same intervals of time were assessed. Results of the proximate composition analyses showed that raw and boiled beniseed had lower moisture content (5.39-5.51%) than beniseed soups (10.06-15.20%). Nitrogen-free extract (total carbohydrates), fats and phosphorus contents were improved in both the boiled beniseed and beniseed soup while calcium and potassium were increased in the boiled seeds and soup samples respectively. Moisture (in the raw and boiled beniseed), ash, magnesium, zinc, iron contents in both the seed and soup were unchanged in all the samples. Vitamins A and C levels of both boiled beniseed and beniseed soup samples were reduced with increase in cooking time. Beniseed soup had higher protein contents than both the raw and boiled beniseed which decreased with increase in cooking time. Beniseed samples provided good sources of energy (572.97-666.05 kcal/100 g). Except for phytate, the levels of antinutrients tested were lower in the raw and boiled beniseed than in the soup samples which decreased with increase in cooking time. The results are discussed with reference to the effect of prolonged cooking on the nutrient requirements of consumers. PMID- 21319462 TI - Climate change, health and the need to increase resilience and capacity. PMID- 21319463 TI - Black Saturday and the Victorian bushfires of February 2009: a descriptive survey of nurses who assisted in the pre-hospital setting. AB - BACKGROUND: In February 2009, bushfires devastated the state of Victoria, Australia, resulting in the loss of property and life--this event was named 'Black Saturday'. Pre, during and post the impact of this event, health care professionals, such as nursing members of St John Ambulance Australia, provided clinical care in the pre-hospital environment. There is a paucity of literature regarding the clinical and disaster background, education and preparedness of those health care professionals who assist in similar emergencies, as such the characteristics of responders are not well understood. METHOD: This research used a retrospective descriptive postal survey design, to survey nursing members of St John Ambulance Australia regarding their nursing experience; pre-hospital experience; disaster education, training and experience; and their role during the response to the 2009 Victorian bushfires. RESULTS: A total of 53 nurses were approached for inclusion in this research, of which 24 (45%) voluntarily participated. Males represented 46% and females represented 54% of participants. Participants had more combined years of nursing experience in the medical and surgical environments, then other areas of practice. Post-graduate critical care nursing was the primary area of completed post-graduate education. The previous disaster experience of participants was principally related to bushfire emergency response. Most participants had undertaken disaster related education, however this varied in type and duration. Similarly, most had participated in training or mock disasters; however this was commonly not related to bushfire emergencies. During the response to the Victorian bushfires, those nurses who undertook a clinical role did so at a staging area, caring for fire fighters and working with other members of their organisation. Half of the participants undertook an administrative role. CONCLUSIONS: This research has provided insight into the characteristics and level of preparedness, of nurses who responded to the 2009 Victorian bushfires. Previously, such information has not been available in the literature. In this research, males were overrepresented when compared to the national average of nurses. The most amount of nursing experience was in the medical and surgical environment, this is consistent with national nursing workforce trends. Whilst most had clinical experience in bushfires, no training or mock scenarios focused specifically to bushfires. There is a need to explore further, the various roles undertaken by nurses during response, as this research has focused on one event--the 2009 Victorian bushfires. PMID- 21319464 TI - A literature review of disaster nursing competencies in Japanese nursing journals. AB - INTRODUCTION: Competencies is an important concept used for assessing health professionals' capability to perform their role. By means of a literature review of Japanese professional journals this paper will investigate the competencies concept, particularly with relation to disaster nursing. METHODS: The literature research was conducted using the database ichu-shi (ver. 4). All literature is written and published in Japanese and was published between 2001 and 2008. Due to an unfamiliarity of the term 'competencies' in Japanese, the key words were sought while deconstructing the meaning and concepts of 'competencies' into terms more recognisable in the Japanese context. Twelve key words: disaster, capability, education, practice, licensure, ability, function, prevention, response, planning, emergency, and disaster nursing were chosen as being most likely to find literature relevant to the English Language concept of competencies. The searched articles were then written into the disaster nursing competencies review worksheet for analysis. RESULT: One hundred and twenty articles were found by searching a combination of these key words. Of these articles, those that were not in the context of disaster nursing were eliminated. As a result, 43 articles were chosen as being suitable for analysis of the context. These articles are classified into four themes. CONCLUSION: These theme groups indicated a foundation for competencies in disaster nursing. The definition of competencies in Japanese nursing journals was quite varied and cannot be easily defined as common disaster nursing competencies. Given the variety of areas and the distinct phases in disaster nursing, as well as the 'what for' and 'who governs', disaster nursing competencies will need its own discussion in order to establish the common competencies internationally. PMID- 21319465 TI - Emergency department patient presentations during the 2009 heatwaves in Adelaide. AB - While the full impact of climate change is uncertain, it has been widely documented to be responsible for the extreme weather conditions which are experienced in many places around the world. High temperatures during summer are the expected norm for the population living in Adelaide South Australia (SA) and if temperatures reach and remain in the upper thirties centigrade they can be expected to meet the Australian Government Bureau of Meteorology definition of a "heatwave". A number of studies have shown that there is a direct link between the increase in mortality and morbidity among emergency department (ED) patient presentations and periods of extreme heat. Heatwave conditions affect individuals with particular health problems such as cardiovascular, renal or mental health which results in an increase in the patient presentations to the emergency department (ED). This paper describes the findings from the initial phase of a long-term research project investigating the effects of heatwave exposure on particular health conditions with respect to patient presentations (ICD-10 categories) to ED's in metropolitan Adelaide, South Australia. The initial results from one public hospital during two heatwave periods experienced in 2009 are presented in this paper. The heat wave events were compared to non-heat wave periods before and after each heat wave. Demographic information as well as diagnostic descriptors are also presented. PMID- 21319466 TI - Piloting a mass gathering conceptual framework at an Adelaide schoolies festival. AB - During the summer months in Australia, school leavers celebrate their end of school life at schoolies festivals around the nation. These events are typically described as a mass gathering as they are an organised event taking place within a defined space, attended by a large number of people. A project was undertaken to analyse the usefulness of Arbon's (2004) conceptual model of mass gatherings in order to develop a process to better understand the Adelaide Schoolies Festival. METHOD: Arbon's conceptual framework describes the inter-relationship between the psychosocial, environmental and bio-medical domains of a mass gathering. Each domain has set characteristics which help to understand the impact on the mass gathering event. The characteristics within three domains were collected using field work and bio-medical data to examine the relationship between injury and illness rates. RESULTS: Using the conceptual framework to evaluate this schoolies event helped create an understanding of the physiology, environment and behaviour contributing to patient presentations. Results showed that the schoolies crowd was active and energetic, and the main crowd behaviour observed was dancing and socialising with friends. The environmental domain was characterised by a grassy outdoor venue that was bounded and dry. Due to the overall health of the crowd, activities undertaken and the supportive environment, the majority of injuries to schoolies were minor (68%). However, twenty-four percent of schoolies who presented with alcohol related illness were found to have consumed alcohol at risky levels; half of this cohort was transported to hospital. CONCLUSION: The conceptual framework successfully guided a higher level of examination of the mass gathering event. In particular, the framework facilitated a greater understanding of the inter-relationships of the various characteristics of a mass gathering event, in this case the Adelaide Schoolies Festival. PMID- 21319467 TI - What is the role of nursing students and schools of nursing during disaster? a discussion paper. AB - During times of disaster, the front-line nursing workforce and the health services in which they work may be overwhelmed by a surge in patient demand. As a result, assistance will be required to bolster the nursing workforce. Commonly, discussions regarding workforce supply and sustainability during disasters are isolated within particular health service institutions. The aims of this discussion paper are to; firstly, consider the potential contribution of nursing students and schools of nursing within Australian universities to increase the health workforce during a disaster, and secondly, to present a number of recommendations that universities and schools of nursing could consider in developing their own emergency and disaster plans. PMID- 21319468 TI - Communicating information regarding human H1N1-09 virus to high-risk consumers: knowledge and understanding of COPD patients in Melbourne, Australia. AB - BACKGROUND: One of the public health challenges during an influenza pandemic is how to rapidly access groups of high-risk individuals to ensure that they have accurate information regarding prevention and management of infection. The aim of this survey was to evaluate the level of understanding of the H1N1-09 (Swine Flu) pandemic, amongst a high-risk group of individuals with chronic lung disease. This study was conducted in Melbourne, Australia towards the end of the 2009 pandemic. METHODS: Questions included in the survey were based on the consumer information sheets available from the Department of Health (Victoria) website (frequently asked questions for the general public). Participants were recruited from patients attending community-based programs for chronic lung disease. RESULTS: Eighty participants were interviewed in August-September 2009, the majority 70/80 were aware of the H1N1-09 pandemic in Melbourne. Most participants gained their information from media reports rather than health care providers. Although they were aware of some ways to decrease the spread of infection, only 20/80 (25%) knew that there were antiviral treatments available if they did contract the infection. It is noteworthy that in a substantial minority (25%), information reported in the media caused some confusion or anxiety and it appears that there was a gap in the provision of evidence-based information to this high risk group. CONCLUSION: In the context of future pandemics, respiratory-outreach nurses and educators could be used to promote pertinent information regarding infection prevention and management to high-risk individuals. Currently this appeared to be an under-utilised means of imparting pandemic information to consumers. PMID- 21319469 TI - Changes to Australian nursing and midwifery registration: implications for interstate disaster response. PMID- 21319470 TI - The current status of nurses' emergency preparedness: a commentary on the development of emergency preparedness and response competency. PMID- 21319471 TI - Trinities, innovations, and solutions. PMID- 21319472 TI - Adaptation of a community-based participatory research model to gain community input on identifying indicators of successful parenting. AB - Parenting models are generally based on families in stable homes, rather than in transitional situations such as in foster care, homeless shelters, and other temporary, at-risk residences. Consequently, these models do not recognize the unique challenges of families in transition. This study explored the domains of the Circumplex Model and examined its fit for transitional families using tenets from community-based participatory research. Findings suggest that in addition to the Circumplex Model's components, caregivers with children living in transition believe that managing the scrutiny of external authority systems and countering the negative influences of poverty and racism are two indicators that contribute to parenting success. Obtaining consumer-informed views of parenting not only is an important contributor to standards of practice, but also a promising avenue for future research. PMID- 21319473 TI - A qualitative study of exodus graduates: family-focused residential substance abuse treatment as an option for mothers to retain or regain custody and sobriety in Los Angeles, California. AB - In this article, 21 long-term, poly-substance abusing mothers describe how they successfully completed an 18-month family-focused residential substance abuse treatment program in southern California that helped them retain or regain custody of their children. Their stories and experiences with specific program characteristics and approaches of this rare treatment option are described, in their own voices. Policy implications for child welfare and parental substance abuse treatment are examined in light of these success stories. PMID- 21319474 TI - Dimensions of child neglect: an exploration of parental neglect and its relationship with delinquency. AB - While neglect is generally associated with poor developmental outcomes, it remains poorly defined. Factor analysis was applied to 39 parental behavior variables on data from the Cambridge Study in Delinquent Development (CSDD) to explore underlying dimensions of parental behavior that were consistent with the concept of neglect. Logistic regression assessed associations between the dimensions of neglect recovered from the CSDD and future adult delinquency. Factor analysis revealed four dimensions; logistic regression revealed significant associations between two of these dimensions--poor supervision and a disorganized, chaotic home environment--and future adult delinquency. Neglect is a viable construct that can summarize aspects of parental behavior and predict future adult delinquency. PMID- 21319475 TI - Animal-human relationships in child protective services: getting a baseline. AB - Inclusion of certain aspects of animal-human relationships (AHR), such as animal abuse and animal-assisted interventions, can enhance child welfare practice and there are resources available to promote such inclusion. However, there is little knowledge of whether this is being accomplished. This study sought to fill this gap by conducting a national survey of state public child welfare agencies to examine AHR in child protective services practice, their assessment tools, and cross-reporting policies. PMID- 21319476 TI - Research evidence utilization in policy development by child welfare administrators. AB - An exploratory qualitative study was conducted to explore how child welfare administrators use research evidence in decision-making. Content analysis revealed that a cultural shift toward evidence-based practice (EBP) is occurring in Canadian child welfare organizations and multiple types of evidence inform policy decisions. Barriers to using evidence include individual, organizational, and environmental factors. Facilitating factors include the development of internal champions and organizational cultures that value EBP. Integrating research into practice and policy decisions requires a multifaceted approach of creating organizational cultures that support research utilization and supporting senior bureaucrats to use research evidence in policy development. PMID- 21319477 TI - An asset-based approach to facilitating positive youth development and adoption. AB - The present study examined outcomes for youth in foster care who participated in an asset-based camp designed to build youth assets and facilitate adoption. The study addresses youth perceptions of their assets and the relationship between assets and adoption status. Youth perceived that their assets increased over time and adopted youth reported having more assets than youth who were not adopted. An asset-based approach may lead to positive outcomes for youth in foster care. PMID- 21319478 TI - Flexibility is key to review. PMID- 21319479 TI - Process of conducting qualitative research. PMID- 21319480 TI - Phenomenological approaches: challenges and choices. AB - Phenomenology is a recognised approach for investigating experiences in health research. Difficulties regarding the approach, however, have been documented with even the definitions and terminology sometimes being unclear. In addition to this, there have been claims that many nurse researchers have failed to report how the gap between philosophically related theory and research practice is managed. While legitimacy can be increased by claims regarding theoretical location, there have also been suggestions that engaging too intensely in methodological awareness can hinder the practice and progress of a research project. A balance is therefore required. This article concentrates on the dilemmas and challenges facing a researcher looking for an appropriate method and approach for a study investigating the experiences of stroke survivors. The challenges of using phenomenology as a research method and the approach of interpretative phenomenological analysis are further considered. PMID- 21319481 TI - Hermeneutic inquiry: insights into the process of interviewing. AB - Interviewing is a popular research method, closely associated with hermeneutic inquiry as a means of obtaining lived experience material from the viewpoint of the experiencing person. This article provides personal and theoretical insights into the use of the research interview to explore the meaning of witnessed resuscitation from the perspectives of emergency department registered nurses and ambulance staff who have experienced this situation. The discussion focuses on the decisions and actions taken by the researcher to enhance the nature and quality of interviews and offers a step-by-step guide to the practicalities of interviewing. The interview process is theorised and discussed in the tradition of hermeneutic enquiry. PMID- 21319482 TI - Member checking and Heideggerian phenomenology: a redundant component. AB - Although member-checking has long been accepted as the gold standard in quantitative research, it is not the pinnacle for expressing rigour in Heideggerian phenomenology because it contradicts many o the underpinning philosophies. Similarly, employing 'experts' to confirm findings conflicts with the values of interpretivism. In this paper, th authors argue that member checking is frequently used to cover poor interview technique or a lack of understanding of the methodology chosen to underpin the study. They debate why member-checking is incongruent with Heideggerian philosophy and suggest strategies that enhance the generation of data and render the follow-u interview redundant. PMID- 21319483 TI - Theoretical versus pragmatic design in qualitative research. AB - For many years, discussions of the relative merits of generic and theoretical approaches to qualitative research have divided researchers while overshadowing the need to focus on addressing clinical questions. Drawing on the challenges of designing a study that explored parents' experiences of living with children with hydrocephalus, the authors of this paper argue that over-adherence to, and deliberations about, the philosophical origins of qualitative methods is undermining the contributions qualitative research could make to evidence-based health care and suggest qualitative methods should stand alone. PMID- 21319484 TI - Qualitative data analysis: the framework approach. AB - Qualitative methods are invaluable for exploring the complexities of health care and patient experiences in particular. Diverse qualitative methods are available that incorporate different ontological and epistemological perspectives. One method of data management that is gaining in popularity among healthcare researchers is the framework approach. We will outline this approach, discuss its relative merits and provide a working example of its application to data management and analysis. PMID- 21319485 TI - Development and validation of the Child-to-Mother Violence Scale. AB - This article describes the development and tests the reliability and validity of a new survey instrument, the Child-to-Mother Violence Scale (CMVS). This instrument was devised specifically to measure data regarding the incidence, perpetrators, targets, experiences and influences on child-to-mother violence as the first phase of a larger study that investigated child-to-mother violence in the western suburbs of Sydney, Australia. PMID- 21319486 TI - Planning and conducting focus group research with nurses. AB - Focus groups are increasingly popular in nursing research. However, proper care and attention are critical to their planning and conduct, particularly those involving nursing staff. This article uses data gleaned from prior research to address the complexities present in clinical settings when conducting focus groups with nurses. Applying their combined experiences of conducting studies with nursing staff, the authors present a data-derived approach to thorough preparation and successful implementation of focus group research, offering a unique contribution to the literature regarding this research strategy. PMID- 21319487 TI - Are we being true to the peer-review process? PMID- 21319488 TI - Neurocircuitry of cognition emotion, and behavior. PMID- 21319489 TI - Emergent processes in cognitive-emotional interactions. AB - Emotion and cognition have been viewed as largely separate entities in the brain. Within this framework, significant progress has been made in understanding specific aspects of behavior. Research in the past two decades, however, has started to paint a different picture of brain organization, one in which network interactions are key to understanding complex behaviors. From both basic and clinical perspectives, the characterization of cognitive-emotional interactions constitutes a fundamental issue in the investigation of the mind and brain. This review will highlight the interactive and integrative potential that exists in the brain to bring together the cognitive and emotional domains. First, anatomical evidence will be provided, focusing on structures such as hypothalamus, basal forebrain, amygdala, cingulate cortex, orbitofrontal cortex, and insula. Data on functional interactions will then be discussed, followed by a discussion of a dual competition framework, which describes cognitive-emotional interactions in terms of perceptual and cognitive competition mechanisms. PMID- 21319490 TI - Imaging genetics of schizophrenia. AB - Recent years have seen an explosive growth of interest in the application of imaging genetics to understand neurogenetic mechanisms of schizophrenia. Imaging genetics applies structural and functional neuroimaging to study subjects carrying genetic risk variants that relate to a psychiatric disorder. We review selected aspects of this literature, starting with a widely studied candidate gene--the catechol-O-methyltransferase gene (COMT)--discussing other candidate genes in the dopaminergic system, and then discussing variants with genome-wide support. In future perspectives, approaches to characterize epistatic effects, the identification of new risk genes through forward-genetic approaches using imaging phenotypes, and the study of rare structural variants are considered. PMID- 21319491 TI - Evolution of the nervous system: a critical evaluation of how genetic changes translate into morphological changes. AB - Living creatures evolve, and this evolution allows them to adapt to an ever changing milieu. Two main adaptive strategies coexist. The first involves genetic mutations taking place at the species level. The second strategy occurs at the individual level, and primarily involves changes in chromatin organization and brain circuits. We shall illustrate how the two modes of adaptation are interdependent, and will show the difference in their respective importance depending on the species. It will be proposed that changes in developmental strategies, genetically selected, can lead to more or less epigenetic freedom, sometimes with dramatic consequences. In particular it will be shown, taking chimpanzees and humans as examples, how minor genetic modifications can translate into nonlinear changes in brain structure and cultural practices, placing the two types of primates at a much greater distance than had been anticipated. PMID- 21319492 TI - Neurocircuitry of the nicotinic cholinergic system. AB - Continuing to discover how the brain works is one of the great challenges ahead of us. Although understanding the brain anatomy and its functional organization provided a first and indispensable foundation, it became clear that a static view was insufficient. To understand the complexity of neuronal communication, it is necessary to examine the chemical nature of the neurotransmission and, using the example of the acetylcholine receptors, follow the different layers of networks that can be distinguished. The natural alkaloid nicotine contained in tobacco leaves acts as an agonist with a subclass of acetylcholine receptors, and provides an interesting tool to approach brain functions. Analysis of the nicotinic acetylcholine receptors, which are ligand gated channels, revealed that these receptors are expressed at different critical locations on the neurons including the synaptic boutons, neurites, cell bodies, and even on the axons. These receptors can modulate the activity at the microcircuit synaptic level, in the cell processing of information, and, by acting on the velocity of action potential, the synchrony of communication between brain areas. These actions at multiple levels of brain organization provide an example of the complexity of brain neurocircuitry and an illustration of the relevance of this knowledge for psychiatry. PMID- 21319494 TI - Human intelligence and brain networks. AB - Intelligence can be defined as a general mental ability for reasoning, problem solving, and learning. Because of its general nature, intelligence integrates cognitive functions such as perception, attention, memory, language, or planning. On the basis of this definition, intelligence can be reliably measured by standardized tests with obtained scores predicting several broad social outcomes such as educational achievement, job performance, health, and longevity. A detailed understanding of the brain mechanisms underlying this general mental ability could provide significant individual and societal benefits. Structural and functional neuroimaging studies have generally supported a frontoparietal network relevant for intelligence. This same network has also been found to underlie cognitive functions related to perception, short-term memory storage, and language. The distributed nature of this network and its involvement in a wide range of cognitive functions fits well with the integrative nature of intelligence. A new key phase of research is beginning to investigate how functional networks relate to structural networks, with emphasis on how distributed brain areas communicate with each other. PMID- 21319493 TI - Brain serotonergic circuitries. AB - Brain serotonergic circuitries interact with other neurotransmitter systems on a multitude of different molecular levels. In humans, as in other mammalian species, serotonin (5-HT) plays a modulatory role in almost every physiological function. Furthermore, serotonergic dysfunction is thought to be implicated in several psychiatric and neurodegenerative disorders. We describe the neuroanatomy and neurochemistry of brain serotonergic circuitries. The contribution of emergent in vivo imaging methods to the regional localization of binding site receptors and certain aspects of their functional connectivity in correlation to behavior is also discussed. 5-HT cell bodies, mainly localized in the raphe nuclei, send axons to almost every brain region. It is argued that the specificity of the local chemocommunication between 5-HT and other neuronal elements mainly depends on mechanisms regulating the extracellular concentration of 5-HT the diversity of high-affinity membrane receptors, and their specific transduction modalities. PMID- 21319495 TI - Reciprocal organization of the cerebral hemispheres. AB - The cerebral hemispheres are anatomically and neurophysiologically asymmetrical. The evolutionary basis for these differences remains uncertain. There are, however, highly consistent differences between the hemispheres, evident in reptiles, birds, and mammals, as well as in humans, in the nature of the attention each applies to the environment. This permits the simultaneous application of precisely focused, but narrow, attention, needed for grasping food or prey, with broad, open, and uncommitted attention, needed to watch out for predators and to interpret the intentions of conspecifics. These different modes of attention can account for a very wide range of repeated observations relating to hemisphere specialization, and suggest that hemisphere differences lie not in discrete functional domains as such, but distinct modes of functioning within any one domain. These modes of attention are mutually incompatible, and their application depends on inhibitory transmission in the corpus callosum. There is also an asymmetry of interaction between the hemispheres at the phenomenological level. PMID- 21319497 TI - Affective neuroscience of the emotional BrainMind: evolutionary perspectives and implications for understanding depression. AB - Cross-species affective neuroscience studies confirm that primary-process emotional feelings are organized within primitive subcortical regions of the brain that are anatomically, neurochemically, and functionally homologous in all mammals that have been studied. Emotional feelings (affects) are intrinsic values that inform animals how they are faring in the quest to survive. The various positive affects indicate that animals are returning to "comfort zones" that support survival, and negative affects reflect "discomfort zones" that indicate that animals are in situations that may impair survival. They are ancestral tools for living--evolutionary memories of such importance that they were coded into the genome in rough form (as primary brain processes), which are refined by basic learning mechanisms (secondary processes) as well as by higher-order cognitions/thoughts (tertiary processes). To understand why depression feels horrible, we must fathom the affective infrastructure of the mammalian brain. Advances in our understanding of the nature of primary-process emotional affects can promote the development of better preclinical models of psychiatric disorders and thereby also allow clinicians new and useful ways to understand the foundational aspects of their clients' problems. These networks are of clear importance for understanding psychiatric disorders and advancing psychiatric practice. PMID- 21319496 TI - Neural systems underlying approach and avoidance in anxiety disorders. AB - Approach-avoidance conflict is an important psychological concept that has been used extensively to better understand cognition and emotion. This review focuses on neural systems involved in approach, avoidance, and conflict decision making, and how these systems overlap with implicated neural substrates of anxiety disorders. In particular, the role of amygdala, insula, ventral striatal, and prefrontal regions are discussed with respect to approach and avoidance behaviors. Three specific hypotheses underlying the dysfunction in anxiety disorders are proposed, including: (i) over-representation of avoidance valuation related to limbic overactivation; (ii) under- or over-representation of approach valuation related to attenuated or exaggerated striatal activation respectively; and (iii) insufficient integration and arbitration of approach and avoidance valuations related to attenuated orbitofrontal cortex activation. These dysfunctions can be examined experimentally using versions of existing decision making paradigms, but may also require new translational and innovative approaches to probe approach-avoidance conflict and related neural systems in anxiety disorders. PMID- 21319498 TI - Empathy: shared circuits and their dysfunctions. AB - Observing another individual acting upon an object triggers cerebral activity well beyond the visual cortex of the observer in areas directly involved in planning and executing actions. This we will call action simulation. Importantly, the brain does not solely simulate the actions of others but also the sensations they feel, and their emotional responses. These simulation mechanisms are most active in individuals who report being very empathic. Simulation may indeed be instrumental for our understanding of the emotional and mental state of people in our sight, and may contribute heavily to the social interactions with our peers by providing a first-person perspective on their inner feelings. Simulation mechanisms are at work at an early stage of social development and might be defective in young individuals with autism spectrum disorders (ASD). However, the results to date regarding ASD are not clearcut, and an equal number of studies report positive and negative findings. PMID- 21319499 TI - Neurocircuitry of emotion and cognition in alcoholism: contributions from white matter fiber tractography. AB - Chronic alcoholism is characterized by impaired control over emotionally motivated actions towards alcohol use. Neuropathologically, it is associated with widespread brain structural compromise marked by gray matter shrinkage, ventricular enlargement, and white matter degradation. The extent to which cortical damage itself or cortical disconnection by white matter fiber pathway disruption contribute to deficits in emotion, cognition, and behavior can be investigated with in vivo structural neuroimaging and diffusion tensor imaging (DTI)-based quantitative fiber tracking. Tractography in alcoholism has revealed abnormalities in selective white matter fiber bundles involving limbic fiber tracts (fornix and cingulum) that connect cortico-limbic-striatal nodes of emotion and reward circuits. Studies documenting brain-behavior relationships support the role of alcoholism-related white matter fiber degradation as a substrate of clinical impairment. An understanding of the role of cortico-limbic fiber degradation in emotional dysregulation in alcoholism is now emerging. PMID- 21319500 TI - Tissue-based classification of HPV infections of the uterine cervix and vagina (mucosal HPV infections). AB - Terminology of HPV infections of the uterine cervix and vagina is somewhat confusing, with various terms having different meanings to different authors. This prompted us to revise the current terminology and propose a "tissue-based" classification of HPV infections of the cervix and vagina (mucosal HPV infections), which is based on histological appearance of the lesions and should be clear-cut in everyday practice of managing these patients. We hope the proposed nomenclature may overcome some of the confusion and controversy that exist in the current terminologies describing these lesions. PMID- 21319501 TI - Peroxisome proliferator-activated receptor and epithelial ovarian cancer. PMID- 21319502 TI - Ovarian tumours in childhood and adolescence. AB - Malignant ovarian tumors are very rare during childhood and adolescence where their incidence is approximately 0.71 per 100,000. We reviewed the symptoms, histologic subtypes, diagnostic evaluation and management of ovarian tumours in children and adolescents with emphasis on malignant tumours. The histology of these tumours is complex and their diagnosis frequently poses problems. Surgery and chemotherapy yield high cure rates in patients with malignant germ cell tumours whereas prognosis is poorer in ovarian carcinomas. Elucidation of the mechanisms underlying the pathogenesis of ovarian tumors might further improve the management of these patients. PMID- 21319503 TI - Reliability of oupatient endometrial brush cytology vs biopsy in postmenopausal symptomatic women. AB - OBJECTIVE: To compare outpatient endometrial sampling cytology with conventional biopsy in postmenopausal women with abnormal uterine bleeding and/or abnormal endometrial thickness at ultrasound. METHOD: Between December 2003 and December 2009 a group of 1,056 postmenopausal women was referred to the Department of Gynecological Sciences, Perinatology an Child Health II Faculty of Medicine, University of Rome, S.Andrea Hospital. Four hundred and eighty-two patients (45.6%) had abnormal uterine bleeding and 602 (57.0%) showed an endometrial thickness > 5 mm at ultrasound. Patients on hormonal therapy (n = 194) including hormonal replacement therapy (HRT) or tamoxifen (TMX), were enrolled in the study. Endometrial cytologic sampling was performed using a brush device (EBC) while endometrial histological sampling was retrieved using a Novak curette. Histologic evaluation showed: a) malignant neoplasia b) atypical hyperplasia c) benign pathology d) normal or atrophic endometrium. The following points were investigated: a) failure in performing a procedure for cervical stenosis or pelvic pain; b) nondiagnostic specimens; c) diagnostic accuracy. RESULTS: Evidence in score pain differences between brush and curette endometrial samples were observed: 50% of patients undergoing brush cytology had lower pain scores (chi-square = 288.33; p = .001), whereas 60% of patients undergoing endometrial biopsy had higher pain scores (chi-square = 264.84; p = .001). The failure rate in performing procedures was 8.0% vs 4.1%, and the results were statistically significant on the McNemar test, respectively p = .01 and p = .001. A nondiagnostic specimen was obtained in 3.9% of cases by EBC, and 10.3% of cases by the Novak curette (p = .001). Cytological evaluation had a sensitivity of 100%, specificity of 99%, positive and negative predictive value of 97% and 100% for diagnosing malignant neoplasia. Cytology had high diagnostic accuracy for atypical hyperplasia: sensitivity 100%, specificity 99%, positive and negative predictive value 83% and 100%, respectively. CONCLUSIONS: EBC is a reliable, well tolerated outpatient diagnostic tool for endometrial sampling in detecting early stage cancer in postmenopausal patients at high risk for endometrial cancer. PMID- 21319504 TI - Immunohistochemical expressions of p16 and p53 proteins in cervical intraepithelial neoplasia and in benign cervical tissue. AB - PURPOSE OF INVESTIGATION: To evaluate the immunohistochemical expressions of p16 and p53 in cervical intraepithelial neoplasia (CIN) and do a comparison with non neoplastic cervical lesions. METHODS: Sixty cases diagnosed as CIN after histopathological examination and 25 controls diagnosed as chronic cervicitis were included in the study. Immunohistochemical expressions for p16 and p53 were evaluated and compared in all cases. The cases in the study were defined according to the Bethesda system. Of these, 31.8% (n = 27) had a low-grade squamous intraepithelial lesion (LGSIL), and 38.8% (n = 33) had a high-grade squamous intraepithelial lesion (HGSIL). RESULTS: There was a statistically significant difference between chronic cervicitis and CIN in terms of p53 and p16 expression levels (p = 0.001). On the other hand, the level of p16 expression was statistically different between LGSIL and HGSIL (p = 0.001), while there was no significant difference in terms of p53 expression. Among the HGSIL cases (n = 33), 91% had p16 expression, while 66.7% (n = 27) of the LGSIL patients had no p16 expression. In the chronic cervicitis group, 84% (n = 21) did not reveal any p16 expression, while 96% (n = 24) did not reveal any p53 expression. Various levels of p53 expressions were detected in 59.2% (n = 16) of CIN1 cases, 69.3% (n = 9) of CIN2 cases, and 90% (n = 18) of CIN3 cases. CONCLUSION: While p16 is useful in detecting high-grade cervical lesions, p53 is not a good biomarker for distinguishing high-grade lesions from low grade ones. PMID- 21319506 TI - Granular cell tumour of the breast: case series and review of the literature. AB - Granular cell tumours (GCTs) are uncommon rare neoplasms that may occur in any part of the body. Approximately 5-8% of granular cell tumours occur within the breast. Although nearly always benign in behaviour, granular cell tumours of the breast can often mimic breast malignancies both clinically and on the basis of imaging techniques. This article reports five cases of benign granular cell tumours appearing in the breast, mimicking a malignant breast lesion. In addition to reporting the cases, the relevant literature was reviewed. PMID- 21319505 TI - Repeat low-grade squamous intraepithelial cytology with unsatisfactory colposcopy treated by the loop electrosurgical excision procedure: a retrospective study. AB - INVESTIGATION: To evaluate the value of the loop electrosurgical excision procedure (LEEP) for repeat low-grade squamous intraepithelial lesions (LSIL) with unsatisfactory colposcopy and the outcomes of postconization. METHODS: We performed LEEP in 136 patients and followed them up with colposcopy, cytology, and high-risk HPV (HR-HPV) detection using Hybrid Capture II (HCII). RESULTS: 55.1% of women had CIN 1 in the specimen, 17.6% had CIN 2-3, and 27.2% had no lesion. The sensitivity of detecting persistent/recurrent disease can reach 90.9% when positive post-treatment HR-HPV or first abnormal cervical cytology after LEEP are found, and the specificity is 95.3% when positive post-treatment HR-HPV coexisting with first abnormal cervical cytology after LEEP are detected. CONCLUSION: Repeat LSIL with unsatisfactory colposcopy implies a significant risk of CIN 2-3. LEEP is a rational option to those patients with high-risk HPV infection or dysplastic endocervical curettage. Post-treatment follow-up of patients should include both cytology and HR-HPV testing. PMID- 21319507 TI - Comparison of histopathologic classification and surgical stage by cytokeratin 8 and cytokeratin 18 in endometrial cancer. AB - PURPOSE OF INVESTIGATION: The aim of the study was to show the role of the cytoskeletal proteins CK8 and CK18 in endometrial cancer invasion and to histopathologically classify endometrial cancer patients. METHODS: This study was a prospective analysis of 49 histologic samples of consecutively surgically operated endometrial cancer patients. After histopathologic classification the most invasive tumor area was selected for immunohistochemistry. Monoclonal antihuman keratin Ab-4 and keratin Ab-1 were applied. RESULTS: CK8 and CK18 stained tumoral tissue and tumoral cell debris in the lymphovascular space were significantly correlated with stage (p < or = 0.005). CONCLUSIONS: To understand the causes of early treatment failure in endometrial cancer patients, further studies are needed to show the role of enhancing factors of endometrial cancer invasion. PMID- 21319508 TI - Percutaneous nephrostomy in the management of advanced and terminal-stage gynecologic malignancies: outcome and complications. AB - PURPOSE: The goal of the study was to evaluate the outcome and complications after percutaneous nephrostomy (PCN) insertion in advanced and terminal-stage gynecological malignancies with ureteral obstruction (UO). MATERIALS AND METHODS: We analyzed data of 117 patients with UO due to gynecological malignancies, who had undergone PCN between 1996 and 2006. Cervical cancer was evidenced in 108 patients, uterine carcinoma in six and ovarian cancer in three patients. Eighty nine had UO at the initial manifestation of the disease, 22 had persistent or recurrent cancer, and six were disease-free after initial therapy. Oliguria was observed in 22.2% and creatine elevation in 79.5%. Mean follow-up was 11.43 months (range 0-112). RESULTS: The median age was 51 years (range 28-85). Bilateral nephrostomy was performed in 36.7% and unilateral in 63.3%. Renal function normalization occurred in 24.8%. Overall two-year survival (OS) was 16.8%. Higher OS occurred in patients without initial azotemia versus those with azotemia (26.8% vs 13.9%). Median survival time for all the patients was seven months, eight in primary cases versus six in recurrent ones, and eight months in patients after initial therapy. Complications appeared in 53.85%. Most frequent were the loss of the nephrostomy catheter in 37.61% and urinary tract infections in 19.6%. CONCLUSION: Improvement of renal function after PCN can be of clinical benefit in patients who might be cured or for prolonged palliative care. Azotemia seems to be poor prognostic sign. PMID- 21319509 TI - Gynecological malignant neoplasias diagnosed after hysterectomy performed for leiomyoma in a university hospital. AB - PURPOSE: To analyze the findings of malignant neoplasms after hysterectomy for benign conditions. METHODS: A retrospective study from January 1987 to December 2008 was conducted. We analyzed all simple hysterectomies with or without salpingo-oophorectomy for benign conditions (leiomyoma). Incomplete dossiers of patients or cases with uncertain clinical diagnostics were excluded. We analyzed histopathological results, age, parity, indications for hysterectomies with or without salpingo-oophorectomy, stage (if malignant) and therapy. RESULTS: 2,016 hysterectomies with or without salpingo-oophorectomy were performed. Of 2,016, 652 (32.3%) had had a previous diagnosis of malignancy and 1,364 (67.7%) had had a clinical diagnosis of benignancy (leiomyoma). From the total of 1,364, three (0.22%) cases of cancer were diagnosed after anatomopathological study of the uterine specimen, two sarcomas and one endometrial cancer. No cases of incidental ovarian or uterine cervical cancer were diagnosed. CONCLUSIONS: Gynecological malignances in surgical specimens of patients submitted to surgery (hysterectomy and/or salpingo-oophorectomy) for benign conditions are rarely found. PMID- 21319510 TI - The spread pattern of right and left epithelial ovarian cancers. AB - OBJECTIVE: No attention has been paid in the past to the spread pattern of right and left epithelial carcinomas of the ovaries. We aimed to investigate the incidence, spread pattern and distribution of lymph node metastasis in epithelial ovarian cancer (EOC), comparing right versus left EOC of any stage, where the contralateral ovary is apparently and histologically tumor-free. METHODS: Out of a total of 442 patients with EOC, 318 (72%) patients in the study had bilateral and 124 (28%) patients had unilateral ovarian cancer. The study enrolled 60 (48%) patients with right and 64 patients with left ovarian involvement (52%) where the contralateral ovary was tumor-free. Groups Right and Left were compared in terms of age, the tumor status of the lymph nodes, surgical stage, histology, grade, tumor extension out of the ovaries, omental tumor involvement and also omental and nodal involvement together. RESULTS: The comparisons of the variables between Groups Right and Left did not show significant differences except for metastasis patterns in the left iliac lymph nodes and omentum (p < 0.05). Independent of age and histological type of the tumor, women with left-side EOC showed a significantly higher incidence of metastasis in the left iliac lymph nodes (OR: 7.04, 95% CI, 1.36-36.44) and omentum (OR: 2.87, 95% CI, 1.03-8.01), when compared to right-side EOC (p < 0.05). CONCLUSION: In this cohort of patients, we found that left-side unilateral EOC was more likely to metastasize to the left iliac lymph nodes and omentum than the right side where the contralateral ovary was tumor-free. This might be due to the difference in lymphatic drainage on the right and left side and/or the influence of peritoneal fluid movements. This suggestion needs to be supported by further studies. PMID- 21319511 TI - Overall survival in BRCA-associated ovarian cancer: case-control study of an Italian series. AB - About 10% of all ovarian cancers are due to BRCA 1 and/or BRCA 2 mutations. Some studies have shown that patients belonging to this group have a better survival compared to sporadic groups but data are still inconclusive. The aim of this study was to investigate overall survival in patients with ovarian cancer and germ-line mutations in the BRCA1/2 genes in comparison to high-risk patients, defined as patients with ovarian cancer and a strong family history of breast and ovarian cancer, but who tested negative for the BRCA mutation. We collected all the clinical features and did follow-up. The two groups showed similar characteristics concerning age at diagnosis, histological type and stage. Grade 3 was more frequent in the BRCA group. Survival data did not show any advantage for the BRCA mutated group. PMID- 21319512 TI - Expression of survivin, caspase-3 and p53 in cervical cancer assessed by tissue microarray: correlation with clinicopathology and prognosis. AB - OBJECTIVE: The aim of this study was to determine the role of survivin, caspase-3 and p53 expression in cervical cancer, and their correlation with clinicopathological features and prognosis. METHODS: Two hundred and twenty-eight cases of cervical disease were analyzed retrospectively between February 2003 and May 2007 at Taizhou Hospital of Taizhou Enze Medical Center. The expressions of survivin, caspase-3 and p53 were detected by immunohistochemistry (EnVision), assessed by tissue microarray. The correlation of the three genes and clinicopathological factors as well as prognosis were statistically analyzed. RESULTS: The results showed that the positive expression rate of survivin, caspase-3 and p53 in cervical cancer was significantly higher than in the CIN group and cervicitis group (p < 0.05). The expression of survivin was related with clinical staging, stromal involvement and lymph node metastasis (p < 0.05). The positive ratio of caspase-3 was significantly different from histological grading (p < 0.05). The positive expression of p53 was correlated with histological type and grading (p < 0.05). The expression of survivin in cervical cancer was negatively associated with that of caspase-3 (p < 0.01). The positive expression of survivin in the survival group and non-survival group was significantly statistically difference (p < 0.01). There was a significant difference between survivin expression and survival duration by the log-rank method. Whereas no association with survival was seen for caspase-3 and p53 positivity. CONCLUSION: Survivin, caspase-3 and p53 may play an important role in the occurrence and development of cervix carcinoma. It has been suggested that the high expression of survivin or p53 and low expression of caspase-3 are closely correlated with cervical cancer. They could be used as markers for malignant degree and invasiveness of cervix cancer. Survivin can also be used in the estimation of prognosis and survival time of cervix carcinoma. PMID- 21319513 TI - Factors affecting recurrence and disease-free survival in granulosa cell tumors of the ovary. AB - PURPOSE OF INVESTIGATION: To determine risk factors for prognosis and recurrence in ovarian adult-type granulosa cell tumor (GCT). METHODS: A retrospective review of GCT cases treated at our university hospital between 1991-2006. RESULTS: Of 39 patients with GCT, 82% had Stage I disease. The median follow-up period was 71 months. There were 12 cases of recurrence (30.8%) and seven of them had died of disease. The pelvis and liver were the most common sites of recurrence (8 and 3 patients, respectively). Interestingly lymph node recurrence was encountered in two patients. Estimated disease-free survival for five years was 82%. Stage and presence of residual tumor were calculated to be the only associated risk factors for recurrence and prognosis (p < 0.05). CONCLUSION: Recurrences in GCT might be associated with stage and presence of residual tumor during primary surgery. Although rarely present during diagnosis, lymph node metastasis might be more common in recurrent disease. PMID- 21319514 TI - Ovarian carcinoma patients--life quality analysis in the postoperative period- how to improve it? AB - PURPOSE OF INVESTIGATION: The objective of this research was to analyze the quality of life of patients with advanced ovarian carcinoma in the period following radical surgery and application of chemotherapy. METHODS: A random selection method was used to choose 30 patients who had previously filled out the QLQ-C30 health questionnaire. Data obtained from questionnaires were statistically analyzed. RESULTS: The percentage of the general health scores were the highest in the bottom third of the scale, where 21.9% of the patients self scored at 0. Financial difficulties were scored the lowest at 65.6%. The impairment of physical functioning was reported by 21.9% of patients, where the score for impact of this physical impairment was reported at 0 by 18.8%, and the impact of cognitive impairment was scored at 0 by 56.3%. Nausea, vomiting and loss of appetite were completely affecting normal daily functioning of 40.6% patients, constipation was present in 59.4% cases and diarrhea in as many as 71.9% patients; 15.6% patients reported being in continuous pain. CONCLUSION: Health questionnaires should be used because they can help identify patients prone to develop psychological problems and symptoms. Early recognition of patients prone to psychosomatic problems would allow doctors to help maintain and/or improve on patients' quality of life. PMID- 21319515 TI - Internal jugular vein thrombosis as paraneoplastic syndrome of primary ovarian non-Hodgkin's lymphoma. AB - Primary malignant lymphoma involving the ovaries is extremely rare. We present a unique case of a primary Non-Hodgkin's lymphoma (NHL) of both ovaries, preceded by an internal jugular vein trombosis (IJVT) as paraneoplastic syndrome. Currently, 36 months after surgical treatment of this FIGO Stage Ib, Ann Arbor Stage 2E NHL, the patient is clinically free of disease. Based on this case and a review of the literature it is concluded that paraneoplastic syndromes like spontaneous IJVT should prompt the clinician to make a thorough diagnostic work up in search of an underlying malignancy, including the female genital tract. PMID- 21319516 TI - Primary mucinous adenocarcinoma of the vagina. AB - PURPOSE: Primary mucinous adenocarcinoma of the vagina is a rare disease which is characterized by aggressiveness and poor prognosis because of its rapid growth and recurrence, its frequent distant metastases, and its relative resistance to conventional treatment modalities including surgery, radiotherapy, and chemotherapy. We report a case of advanced stage primary mucinous adenocarcinoma of the vagina that showed a highly aggressive course and resistance to combination chemotherapy with paclitaxel and carboplatin. CASE: A 46-year-old multigravid Japanese woman was admitted to our hospital to be treated for Stage IVb primary mucinous adenocarcinoma of the vagina. She had no history of in utero exposure to diethylstilbestrol. She was treated by two courses of neoadjuvant chemotherapy with tri-weekly paclitaxel and carboplatin, which were not effective. Subsequently, total pelvic exenteration with pelvic lymphadenectomy was performed. However, the disease progressed rapidly and the patient died five months after the initial treatment. CONCLUSION: Because of its rarity, little is known about the behavior of primary mucinous adenocarcinoma of the vagina. Additional data about patients with this rare tumor should be collected and analyzed in an attempt to elucidate its prognostic factors, characteristics, optimal treatment, and outcome. PMID- 21319517 TI - Primary yolk sac tumor of the omentum: a case report and literature review. AB - BACKGROUND: Yolk sac tumor (YST) is the second most common malignant ovarian germ cell tumor, while a YST arising in the omentum is an exceedingly rare malignancy. CASE: A 44-year-old woman was admitted with a history of abdominal distension of a month's duration. The alpha-fetoprotein (AFP) serum level was elevated to 27,612 ng/ml, and CT scanning reported an obviously thickened omentum. Explorative findings revealed a large omental mass with a small implantation on the surface of the left ovary. Histological evaluation of the specimen after surgery exhibited typical patterns of YST, and the specimen was stained for AFP, cytokeratin, and placental alkaline phosphatase. The patient was treated with total abdominal hysterectomy with bilateral salpingo-oophorectomy and infracolic omentectomy followed by four cycles of bleomycin, etoposide, and cisplatin combination chemotherapy. She has remained free of the disease for seven months after completion of therapy. The subject of YST arising in the omentum is reviewed. CONCLUSION: This is the fourth case of primary omental YST in females. The case of omental YST must be seriously considered once the tumor shows omentum thickening with elevated AFP serum levels. PMID- 21319518 TI - Dermatofibrosarcoma protuberans with areas of giant cell fibroblastoma in the vulva: a case report. AB - OBJECTIVE: To review the clinical, morphologic, immunohistochemical, and histogenetic characteristics of dermatofibrosarcoma protuberans with areas of giant cell fibroblastoma and explore current treatment options. METHODS: We describe the case of a 38-year-old patient with a tumor measuring 5.7 cm on the right labium majus of the vulva. Serial sections stained with hematoxylin-eosin were examined and immunohistochemical staining was performed for CD34 and PDGF receptor alpha and beta (PDFGRA and PDGFRB). RESULTS: The histologic study showed spindle-cell proliferation typical of dermatofibrosarcoma protuberans and other areas containing fibrosis and giant cells lining pseudovascular spaces. Both tumor areas expressed CD34, PDGFRA, and PDGFRB. CONCLUSIONS: Only two cases of dermatofibrosarcoma protuberans with areas of giant cell fibroblastoma in the vulva have been reported to date. Both dermatofibrosarcoma protuberans and giant cell fibroblastoma are characterized by the translocation t (17;22) (q22;q13). The fact that PDGFRA and PDGFRB are overexpressed in these tumors opens new treatment options with imatinib. Surgical excision with wide margins or Mohs micrographic surgery continues to be the treatment of choice. PMID- 21319519 TI - A case of recurrent yolk sac tumor as spindle cell sarcoma of the abdominal wall. AB - Few studies report on tissue morphology in recurrence of yolk sac tumor. The case of the recurrence of a yolk sac tumor as a spindle cell sarcoma of the abdominal wall is presented. A 27-year-old woman was referred to our hospital due to suspicion of an ovarian tumor. Right salpingo-oophorectomy, partial omentectomy, and extirpation of disseminated foci as fertility-preserving surgery was done since the intraoperative pathological diagnosis was yolk sac tumor. Final pathological examination showed a germ cell tumor of which yolk sac tumor formed the major component including a small area that appeared to be immature nerve tissue. Although residual tumor was not less than 1 cm, clinical complete remission was reached after the sixth course of BEP regimen. However, the recurrence of a yolk sac tumor as an unclassified spindle cell sarcoma of the abdominal wall was found about two years after the initial surgery. Thereafter, the patient expired due to progression of the intraperitoneal disseminated lesions. The mesenchyme-like component of the yolk sac tumor is characterized by spindle cells originating from epithelial elements, and is likely to give rise to a chemoresistant, diversely differentiated sarcoma. This report suggests that the sarcoma reported in the case here also arose when spindle cells of the mesenchyme like component underwent sarcomatous change during or after chemotherapy, subsequently relapsed as a chemoresistant tumor, and metastasized. PMID- 21319520 TI - Contralateral axillary involvement in breast cancer recurrence: locoregional disease or metastasis? AB - We describe a case of right mammary homolateral recurrence with controlateral axillary invasion. The absence of occult involvement of the left breast was confirmed by MRI. A subsequent thoraco-abdomino-pelvic scan and bone scintigraphy did not reveal any metastases. Lymphoscintigraphy of the right breast, after periareolar injection, revealed lymphatic drainage from the right breast into the left contralateral axillary lymph node. Because of the changes in axillary drainage after mammary and axillary surgery observed by lymphoscintigraphy, contralateral axillary involvement could be considered as locoregional disease in the same way as homolateral lymph node involvement. PMID- 21319521 TI - Cervical granulocytic sarcoma: report of one case and review of the literature. AB - Granulocytic sarcoma in the female genital tract generally has a poor prognosis. We report the case of a 52-year-old nonleukemic patient with relapsed granulocytic sarcoma at the vaginal stump after an 11-year complete remission from the uterine cervix. Magnetic resonance imaging of the pelvis showed a pear shaped mass arising from the vagina mimicking a normal uterus. The unusual clinical presentation and the difficulties encountered in evaluation are presented. A review of the literature indicates that survival is better with multimodality management and in patients without leukemia. PMID- 21319522 TI - Primary ovarian malignant lymphoma presenting as ovarian carcinomatosis: a case report and literature review. AB - INTRODUCTION: Primary ovarian lymphoma may present with a clinical scenario consistent with advanced epithelial ovarian carcinoma. Although ovarian lymphoma is a rare entity, accounting for 0.5% of all non-Hodgkin's lymphoma and 1.5% of all ovarian neoplasms, it should be included in the differential diagnosis of an ovarian mass. CASE: We report a case of a 78-year-old woman who presented with an ovarian neoplasm suggestive of advanced ovarian carcinoma. During diagnostic laparoscopy, biopsies were obtained with frozen section analysis revealing malignant lymphoma. Further histopathologic analysis revealed a diffuse large B cell lymphoma (DLBCL). The treatment plan was for six cycles of R-CHOP chemotherapy. A drammatic response was noted after only three cycles of R-CHOP. CONCLUSION: Primary ovarian lymphoma presenting as an ovarian tumor is exceedingly rare. Since the prognosis and treatment of lymphoma differs significantly from ovarian carcinoma, a representative tissue sample of the adnexal tumor should be obtained and sent for frozen section analysis to establish the diagnosis. Principal treatment for non-Hodgkin's lymphoma is chemotherapy without surgical cytoreductive efforts. PMID- 21319523 TI - Severe vaginal chronic graft-versus-host disease (GVHD): two cases with late onset and literature review. AB - Female genital graft-versus-host disease (GVHD) occurs after allogenic stem cell transplantation (SCT) in 25% of long-term survivors. To date, 28 severe cases with hematocolpos requiring surgery have been documented. We report two cases of severe gynecological GVHD. Although most of the vaginal GVH disease cases occurred within two years after oncologic treatment, our two cases highlight the possibility of a very long onset. We also confirmed that hormonal replacement therapy does not protect against synechia and that corticoid treatment has a good therapeutic value in recurrence after surgery. In conclusion, women with SCT experience a high risk of vaginal GVHD that could impair quality of life and sexual function. These cases pinpointed the importance of very long-term gynecological follow-up in order to diagnose early symptoms. To date, only early therapy with local corticoid application might reduce symptoms and development of severe genital GVHD. We support systematic use of topical corticoid therapy in severe cases even after surgery because of the high incidence of recurrence. PMID- 21319524 TI - Giant pelvic retroperitoneal liposarcoma: case report. AB - BACKGROUND: Pelvic retroperitoneal liposarcomas are rare tumors of mesenchymal origin. We present a case of a giant pelvic well-differentiated liposarcoma of the retroperitoneum in a woman, presenting with a large abdominal mass. CASE: A 62-year-old woman presented with a rapid abdominal enlargement. Pelvic examination revealed a huge mass occupying the whole pelvis and part of the right abdomen. At surgery, the pelvic organs were displaced to the right side by a retroperitoneal mass that marginally involved the part of the posterior abdominal wall, left parietal peritoneum of the diaphragm, left colic flexure and the left adnexa. The huge mass, uterus, and both adnexa were removed; hemicolectomy and latero-lateral anastomosis were carried out. No adjuvant irradiation was given. The patient is alive and free of disease five years after the operation. CONCLUSION: The gynecologist should consider retroperitoneal liposarcoma in the differential diagnosis of large pelvic or abdominal masses. PMID- 21319525 TI - Retroperitoneal mass with ischiorectal fossa extension: diagnosis, clinical features and surgical approach. A literature review starting from a rare clinical case of primary retroperitoneal dermoid cyst. AB - BACKGROUND: Primary retroperitoneal teratomas are rare and occur mostly in the sacrococcygeal area of children. They constitute less than 4% of all extragonadal teratomas with less than 120 cases having been reported, and only partly described in the retroperitoneum of adults. We describe an unusual case of a paravescical teratoma with ischio-rectal extension and its successful surgical management. CLINICAL CASE: A 24-year-old female was referred to our hospital with a history of pelvic pain, pressure and evidence of a pelvic-perineal tumor. Serial work-up disclosed a mass in the left paravesical fossa that bulged out through the levator-ani muscle, in the left ischial-rectal fossa, altering the symmetry of the gluteal/perineal region. At surgery a cystic tumor, consistent with a dermoid, was completely excised from the left paravesical fossa by means of a laparotomic approach. Pathological examination revealed a mature cystic teratoma. The postoperative course was smooth and the patient was doing well at two-year followup. CONCLUSION: This is the second reported case of paravesical dermoid cyst with ischio-rectal extension through the levator-ani muscle. Retroperitoneal teratomas are rare and difficult to early diagnose because of non specific signs and symptoms and should be considered in the differential diagnosis of a pelvic mass in adults. Solid and cystic morphology, fat signal and areas of calcification are some of the helpful features in diagnosing this neoplasia. Once the diagnosis is made, surgical removal is indispensable because of the indeterminate course of the disease. Prognosis depends on the histologic nature of teratoma. Patients with complete resection of benign teratoma have an excellent prognosis. Malignant teratomas, either with germ cell elements or with somatic elements, have a poor outcome. PMID- 21319526 TI - Mullerian adenosarcoma of the uterus: a rare neoplasm with a need for onco fertility. AB - A 23-year-old nulliparous woman re-presented with menorrhagia and intermenstrual bleeding two years after her first presentation with a similar history. Her initial symptoms were thought to be due to a removed fibroid polyp with histological confirmation. However at the second presentation, following a polypectomy, a diagnosis of low-grade mullerian adenocarcinoma of the uterine body was made. She had total abdominal hysterectomy and pelvic lymph node dissection, peritoneal fluid for cytology with conservation of ovaries to conserve her fertility. No residual tumour was found and lymph nodes were negative. She remains well under clinical surveillance in a multidisciplinary team setting. Different management options that have been used in past reports have been examined and also fertility sparing surgical techniques available for use in successful management of gynaecological cancer are also being explored to shed more light on potential surgical techniques that may be used in treating such rare tumours, particularly in women wishing to retain their fertility. PMID- 21319527 TI - Primary mixed epithelial and germ cell tumors of the ovary. Two case reports and literature review. AB - Two cases of mixed germ cell and epithelial primary ovarian tumors which developed in women 47 and 57 years of age are reported. In both cases, large teratomas measuring 20 and 21 cm were observed in combination with carcinoids and malignant mucinous neoplasms. A possible common oncogenic mechanism is discussed and a literature review is presented. PMID- 21319528 TI - Grade 2 endometrioid adenocarcinoma arising from adenomyosis of the uterus: report of a case. AB - Adenomyosis is defined by the presence of endometrial tissue (glands and stroma) within the myometrium and malignant transformation of adenomyosis in premenopausal women with normal endometrium is extremely rare. Adenocarcinomas arising within adenomyosis need to be distinguished from endometrial carcinomas which arise from the eutopic endometrium, then extend into preexisting adenomyosis of the uterine wall. We report a case of grade 2 endometrioid adenocarcinoma arising from an adenomyotic focus in the uterus. PMID- 21319529 TI - Fear and its consequences. PMID- 21319530 TI - The bright side of gridlock. How to move the science agenda forward in the next two years. PMID- 21319531 TI - Which pills work? PMID- 21319532 TI - They like your guts. PMID- 21319533 TI - Forces to reckon with. PMID- 21319534 TI - Charging against the flu. PMID- 21319536 TI - When earth was a snowball. PMID- 21319535 TI - Particles that flock. PMID- 21319537 TI - Why you're probably less popular than your friends. PMID- 21319538 TI - The YouTube cure. PMID- 21319539 TI - An open question. PMID- 21319540 TI - How to fix the obesity crisis. PMID- 21319541 TI - Citizen satellites. PMID- 21319542 TI - The blue food revolution. PMID- 21319543 TI - How language shapes thought. PMID- 21319544 TI - The inner life of the genome. PMID- 21319545 TI - A friend to aliens. Interview by Brendan Borrell. PMID- 21319546 TI - X-ray vision. PMID- 21319547 TI - Mind out of body. PMID- 21319549 TI - Houdini's skeptical advice. PMID- 21319548 TI - Jefferson's moose. PMID- 21319550 TI - Your brain in love. PMID- 21319551 TI - A comprehensive disaster training program to improve emergency physicians' preparedness: a 1-year pilot study. AB - OBJECTIVES: The main objective of this pilot study was to measure the effectiveness of a 1-year comprehensive training program on the long-term cognitive competence in disaster preparedness among attending emergency physicians (EPs). DESIGN: Ten attending EPs participated in a year-long training program in disaster preparedness and management. A baseline pretraining test and self-evaluation questionnaire were administered to the participants. Post training written test and self-evaluation questionnaire were repeated at 12 months after the completion of the program. SETTING: The study took place at an urban tertiary care medical center from July 2007 to June 2008. INTERVENTIONS: The training program was divided into three main categories: didactic core topics, formally recognized courses, and a practicum (drill). MAIN OUTCOME MEASURES: Pretraining and posttraining test scores in addition to pretraining and posttraining self-assessments were compared for disaster preparedness in various areas. RESULTS: There was a statistically significant increase in the overall post-test versus pretest scores on the written examination for the entire group (44.4 vs. 29.8, p < 0.005). In addition, statistically significant increases in each area of disaster preparedness were noted for the self-assessments (2.7 +/- 0.82 vs. 3.9 +/- 0.56, p = 0.01), where 1 means not prepared at all and 5 means extremely well prepared. CONCLUSIONS: Disaster preparedness is an essential area of clinical competence for EPs. Participation in a yearlong pilot training program demonstrated a statistically significant increase in cognitive competence among a pilot sample of EPs. More research is needed to validate the content of the training program and its instruments of evaluation. PMID- 21319552 TI - Preparedness for the evaluation and management of mass casualty incidents involving anticholinesterase compounds: a survey of emergency department directors in the 12 largest cities in the United States. AB - OBJECTIVES: Anticholinesterases include carbamate and organophosphorus (OP) insecticides and nerve agents. Release of these compounds can flood emergency departments (EDs) with large numbers of poisoned victims and worried individuals. It was hypothesized that despite the focus of disaster preparedness on large metropolitan areas, EDs in these cities would still report self-perceptions of deficiencies in preparedness for mass casualty incidents (MCIs) involving these chemicals. DESIGN AND SETTING: A secure and anonymous online survey was prepared and piloted, and E-mail invitations were sent to the physician directors of the 220 continuously staffed EDs in the 12 most populous incorporated cities in the United States. RESULTS: Forty-six ED directors could not be contacted despite repeated attempts. Of the remaining 174 directors, eight declined and 89 took the survey, for a response rate of 51.1 percent. Fewer than 20 percent were very confident in the effectiveness of their training, and only 4.9 percent were very confident that drills had given them the preparation that they needed. Only 45. 7 percent of reporting hospitals had a board-certified medical toxicologist to help in such an emergency. Almost two-thirds (73.6 percent) of those familiar with the online Radiation Event Medical Management (REMM) module from the National Library of Medicine and the National Institutes of Health thought that a chemical counterpart to REMM would be either moderately or very helpful for MCIs involving anticholinesterases. CONCLUSIONS: This study demonstrates that physician ED directors perceived marked deficiencies in their abilities to respond to this kind of toxicological emergency and suggests critical directions for remediation of these deficiencies. PMID- 21319553 TI - Hospital-based special needs patient decontamination: lessons from the shower. AB - OBJECTIVES: A hospital-based decontamination team tested whether it could (1) perform effective technical decontamination while maintaining safety of staff and patients; (2) safely accommodate unique needs in the showers, including guide dogs and motorized wheelchairs; (3) identify needs of special needs populations by patient type, including blindness, hearing loss, and cognitive learning disabilities; (4) outline effective use of federal preparedness funds to support planning and execution of tabletop and mock victim drills; and (5) demonstrate the ability of a community hospital to act as a catalyst for community-wide disaster response improvements. DESIGN: A series of five disaster exercises were used to test hypotheses and to generate quality improvement results. SETTING: Fixed emergency department decontamination facilities. PATIENTS/PARTICIPANTS: A total of 39 hospital-based decontamination team members, 40 other drill staff and 35 mock victims were included. MAIN OUTCOME MEASURES: Three priority decontamination operations changes resulted from each of the five completed drills. RESULTS: Formulated prioritized list of decontamination team procedural changes to improve patient safety and technical decontamination and to generate a table of best practices to share. CONCLUSIONS: With enhanced training, disaster drills participation of community response agencies and special needs patients, community hospitals can improve safety while accommodating unique patient needs. PMID- 21319554 TI - Suicidality following a natural disaster. AB - OBJECTIVES: It was intended to study the suicidal cognitions and behaviors following a super-cyclone. DESIGN: Cross-sectional evaluation study. SETTING: Community. PARTICIPANTS: Using simple random procedure, 12 months after a super cyclone, 540 victims were selected. MAIN OUTCOME MEASURES: Suicidal cognitions and behaviors through the Suicidality Screening Questionnaire. This included items on whether life was worth living, death wishes, suicidal idea, plan, and attempt, and history of a suicide attempt. Self-Reporting Questionnaire was used to screen for possible psychiatric morbidity. The influence of various sociodemographic factors, degree of exposure, and clinical variables on suicidal cognitions and attempt was studied. RESULTS: A considerable number of victims had suicidal cognitions: death wishes (66.4 percent), suicidal ideas (38.0 percent), and suicidal plans (18.3 percent). Sixty-eight persons (12.6 percent) of the sample had made suicide attempts after the cyclone. The risk of a suicide attempt was high in persons with current psychiatric morbidity, past history of psychiatric illness, postcyclone thoughts of life not worth living, suicidal ideation and plans, and living with inadequate support. CONCLUSIONS: There was a reported increase of suicidal cognitions and attempts within 12 months following a natural disaster. Awareness of increased suicidality, attention to associated risk factors, and support regarding these may help in the prevention of suicide following disasters. PMID- 21319555 TI - Mechanical ventilation in disaster situations: a new paradigm using the AGILITIES Score System. AB - BACKGROUND: The failure of life-critical systems such as mechanical ventilators in the wake of a pandemic or a disaster may result in death, and therefore, state and federal government agencies must have precautions in place to ensure availability, reliability, and predictability through comprehensive preparedness and response plans. METHODS: All 50 state emergency preparedness response plans were extensively examined for the attention given to the critically injured and ill patient population during a pandemic or mass casualty event. Public health authorities of each state were contacted as well. RESULTS: Nine of 51 state plans (17.6 percent) included a plan or committee for mechanical ventilation triage and management in a pandemic influenza event. All 51 state plans relied on the Centers for Disease Control and Prevention Flu Surge 2.0 spreadsheet to provide estimates for their influenza planning. In the absence of more specific guidance, the authors have developed and provided guidelines recommended for ventilator triage and the implementation of the AGILITIES Score in the event of a pandemic, mass casualty event, or other catastrophic disaster. CONCLUSIONS: The authors present and describe the AGILITIES Score Ventilator Triage System and provide related guidelines to be adopted uniformly by government agencies and hospitals. This scoring system and the set ofguidelines are to be used iA disaster settings, such as Hurricane Katrina, and are based on three key factors: relative health, duration of time on mechanical ventilation, and patients' use of resources during a disaster. For any event requiring large numbers of ventilators for patients, the United States is woefully unprepared. The deficiencies in this aspect of preparedness include (1) lack of accountability for physical ventilators, (2) lack of understanding with which healthcare professionals can safely operate these ventilators, (3) lack of understanding from where additional ventilator resources exist, and (4) a triage strategy to provide ventilator support to those patients with the greatest chances of survival. PMID- 21319556 TI - Dilemmas and controversies within civilian and military organizations in the execution of humanitarian aid in Iraq: a review. AB - Civilian humanitarian assistance organizations and military forces are working in a similar direction in many humanitarian operations around the world. However, tensions exist over the role of the military in such operations. The purpose of this article is to review cultural perspectives of civilian and military actors and to discuss recent developments in civil-military humanitarian collaboration in the provision of health services in Iraq for guiding such collaborative efforts in postconflict and other settings in future. Optimal collaborative efforts are most likely to be achieved through the following tenets: defining appropriate roles for military forces at the beginning of humanitarian operations (optimally the provision of transportation, logistical coordination, and security), promoting development of ongoing relationships between civilian and military agencies, establishment of humanitarian aid training programs for Department of Defense personnel, and the need for the military to develop and use quantitative aid impact indicators for assuring quality and effectiveness of humanitarian aid. PMID- 21319557 TI - Another side to CT, MRI data? PMID- 21319558 TI - Patient care: New standards of care urged to reduce incidences of delirium. PMID- 21319559 TI - Governance: Trustees take on a larger role as health system transforms. PMID- 21319561 TI - The ride of a lifetime, a family's mission. PMID- 21319560 TI - Emergency department: Emergency departments for seniors tackle future challenges of geriatric care. PMID- 21319562 TI - Mapping out care delivery with an assist from GIS. PMID- 21319563 TI - Patient satisfaction: Hospitals go mobile to keep pace with patients. PMID- 21319564 TI - Medicaid: Providers brace for another RAC attack. PMID- 21319565 TI - Beyond the fame and glory. PMID- 21319566 TI - ACOs: Forging the links. AB - Hospital executives see building accountable care organizations as the key to better managing patient care across the continuum and preparing for bundled payments. This ACO primer looks at the big issues hospitals face, from regulatory concerns to governance. The No. 1 step to success is building stronger relationships with physicians. PMID- 21319567 TI - Violence in hospitals: prevent and protect. PMID- 21319568 TI - Health reform in-depth: small + rural hospitals. PMID- 21319569 TI - Why board diversity matters. AB - Ideally, membership on your board of trustees should mirror the community your hospital serves. Here is some practical advice to help. PMID- 21319570 TI - 'Most improved' take similar steps to reach new heights. PMID- 21319571 TI - The legislative learning curve. PMID- 21319572 TI - Findings from the 2010 EBRI/MGA Consumer Engagement in Health Care Survey. PMID- 21319573 TI - Funding savings needed for health expenses for persons eligible for Medicare. AB - UPDATED MODELING: This report updates earlier modeling by EBRI on the level of savings needed for health care expenses in retirement. Some prior estimates have been significantly revised down as a result of changes to Medicare Part D cost sharing that will be phased in by 2020 due to recently enacted health reform. However, the research indicates that retirees will continue to need a substantial amount of savings to cover their health care expenses in retirement, and that uncertainty related to health care use, prescription drug use, and longevity will still play a major role in planning for retiree health care. As before, EBRI's research shows that women will need significantly higher levels of savings than men, due to their greater longevity. Results are shown by the desired level of probability (50, 75, and 90 percent) of having enough savings to cover health costs in retirement. SAVINGS TO SUPPLEMENT MEDICARE WITH MEDIGAP AND PART D: EBRI finds that a man with median drug expenditures would need $65,000 in savings and a woman would need $93,000 if they want an average (50 percent) chance of having enough money to cover health care expenses in retirement. For a higher (90 percent) chance of having enough, a man would need $124,000 and a woman $152,000. A couple both with median drug expenses would need $158,000 for a 50 percent chance of having enough money, and $271,000 for a 90 percent chance. At the highest (90th percentile) level of drug spending, a man would need $187,000 and a woman $213,000 to have a 90 percent chance of having enough money to cover health care expenses in retirement. SAVINGS TO SUPPLEMENT MEDICARE WITH SUBSIDIZED EMPLOYMENT-BASED COVERAGE: A 65-year-old man retiring in 2010 with retiree health benefits from a former employer will need $66,000 to have a 50 percent chance of having enough savings to cover health care expenses in retirement; for a 90 percent chance, he would need $125,000. Women would need $88,000 and $143,000, respectively. Few employers continue to provide subsidized retiree health coverage. SAVINGS TO SUPPLEMENT MEDICARE WITH EMPLOYMENT-BASED COVERAGE WITHOUT SUBSIDY: Retirees who have employment-based retiree health benefits to supplement Medicare and whose former employer does not subsidize premiums will need to save more money than retirees whose premiums are subsidized. A man without subsidized premiums would need $109,000 in savings to cover health care costs in retirement if he wants a 50 percent chance of having enough money to cover health care expenses in retirement, while a woman would need $146,000. To have a 90 chance of having enough savings to cover health care costs in retirement, a man would need $211,000 and a woman would need $242,000 if the benefit is through a former employer and not subsidized. WIDE VARIATION IN MEDIGAP PREMIUMS AFFECTS SAVINGS TARGETS: There is wide variation in Medigap premiums. The average premium was $1479 for Plan F in 2010, but Connecticut had the highest average premium for Plan F at $2493. Indiana has the higher premium variation, with at least one plan offering Plan F at a premium of $14,604. PMID- 21319574 TI - Improving the health of our nation. PMID- 21319575 TI - Nurses at work in Texas. PMID- 21319576 TI - A year of challenges and opportunities. PMID- 21319577 TI - W(h)ither primary care with regards to hospital medicine? PMID- 21319579 TI - Occupational burnout, retention and health outcomes in nephrology nurses. AB - Occupational burnout can have serious implications on productivity, nurses'health, service usage, and health care costs. This study examined the effect of burnout on nurses' mental and physical health outcomes and job retention. Randomly selected Canadian nephrology nurses completed surveys consisting of the Maslach Burnout Inventory and the Pressure Management Indicator. The nurses also completed questions related to job retention. After controlling for age and years of nephrology nursing experience, the multivariate results demonstrated that almost 40% of mental health symptoms experienced by nephrology nurses could be explained by burnout and 27.5% of physical symptoms could be explained by burnout. Twenty-three per cent of the sample had plans to leave their current position and retention was significantly associated with burnout, mental, and physical symptoms. Organizational strategies aimed at reducing perceptions of burnout are important, as a means to keep nurses healthy and working to their fullest potential. PMID- 21319580 TI - Smoking cessation in patients with chronic kidney disease. PMID- 21319581 TI - Detoxifying a tech room. PMID- 21319582 TI - Witness. PMID- 21319583 TI - Corticosteroids. PMID- 21319584 TI - Practicing it forward... PMID- 21319585 TI - Report of AMA interim meeting. PMID- 21319586 TI - Is physician supervision required, or not? Recent OPPS changes provide clarification. PMID- 21319587 TI - Smokeless tobacco and prevalence of cardiovascular disease. AB - INTRODUCTION: Few studies have examined the possible increased risk of cardiovascular disease with smokeless tobacco. Existing studies have yielded inconsistent results and have been based on limited populations. The purpose of this study was to assess whether the use of smokeless tobacco increases the risk of cardiovascular disease and to identify higher risk groups. METHODS: Data from the Behavioral Risk Factor Surveillance System (BRFSS) from 1999 to 2001 for the state of Oklahoma were analyzed. We analyzed 10332 complete records to assess association of any use of smokeless tobacco (over the respondent's life time) with cardiovascular disease. Similarly, the association between cardiovascular disease and individual socio-demographic covariates such as age, gender, smoking, and BMI was checked. As a secondary analysis we explored associations among three categories for smokeless tobacco users, current, former, and never users, with cardiovascular disease. RESULTS: Logistic regression models, which controlled for age, sex, race-ethnicity, obesity, and smoking, estimated the odds of having cardiovascular disease were 1.18 (95% CI: 0.96, 1.45) times higher among smokeless tobacco users. This odds ratio was more than two fold in the Non White/Hispanic group (O.R. 2.31, 95% CI: 1.42, 3.73). Similarly the odds of cardiovascular disease were higher among female ST users than among females who were non-users of ST (O.R. 1.72 95% CI: 1.12, 2.65). CONCLUSION: A modest increase in the odds of cardiovascular disease was associated with smokeless tobacco. Two risk groups were identified, females and Non-Whites/Hispanics, whose odds of cardiovascular disease increased with the use of smokeless tobacco. PMID- 21319588 TI - Question: Should patients who have a significant increase in BUN or creatinine (more than 30% above baseline) in response to an ACEI or ARB be tested for renal stenosis? PMID- 21319589 TI - OHCA continues move toward electronic communication. PMID- 21319590 TI - Predicting prognosis in idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a parenchymal lung disease characterized by progressive interstitial fibrosis. In 2002, the ATS/ERS published new criteria that significantly changed the definition of IPF, resulting in a more homogeneous group of patients. IPF has a poor prognosis with a median of 2.5-3.5 years, but varying from a few months to a decade. In order to predict survival at diagnosis or during follow-up, a considerable number of studies were conducted identifying promising prognostic biomarkers. However, many had been performed before the new ATS/ERS consensus and included patients who would not meet current IPF criteria. This review provides an overview of prognostic markers of survival in IPF after the ATS/ERS consensus statement in 2002. Molecular biomarkers in serum, especially so-called pneumoproteins are relatively easy to obtain and have been independently replicated as predictors of prognosis. Cellular constituents of bronchoalveolar lavage (BAL) have been investigated as predictors of survival, but results remain contradictory. Further, a robust marker of prognosis is the change in lung function over time. However, calculating change in lung function is usually only possible over a 6-12 months period, and is therefore not useful at first presentation. The extent of fibrosis on HRCT scan and the number of fibroblast foci on lung biopsy can be measured at presentation and correlate with prognosis, but the applicability of these markers is being hampered by the lack of user- and patient friendliness. In conclusion, a number of biomarkers are potential candidates for an individualised prognosis of IPF, of which so-called pneumoproteins appear most promising and should be a major focus of fu- PMID- 21319591 TI - Effect of gender on health related quality of life in sarcoidosis. AB - BACKGROUND: Sarcoidosis has different phenotypic manifestations which may have a diverse effect on functional status and quality of life. There are few studies in sarcoidosis addressing gender disparity and its effect on Health-Related Quality of Life (HRQL) and functional status. OBJECTIVE: The purpose of this study was to investigate the effects of gender on HRQL and to identify associations between poor HRQL and the results of common clinical tests. DESIGN: We assessed HRQL for 221 patients with sarcoidosis in a prospective, cross-sectional study using the Short Form-36 Health Survey and Sarcoidosis Health Questionnaire. We evaluated the association between the scores of these measures with patient characteristics, pulmonary function test (PFT) and 6-minute walk test (6MWT) data. RESULTS: Women had lower scores than men on every measure of HRQL and weaker associations to findings from PFT and 6MWT. Multivariate linear regression analyses demonstrated that reduced 6MWT distance and DLCO were significantly associated with poor HRQL in both genders but the sensation of dyspnea played a significant role in women only. CONCLUSIONS: Our results indicate that women with sarcoidosis have a lower HRQL score and a greater degree of functional impairment than men. The factors that are associated with poor HRQL differ by gender. Predictors of poor HRQL include reduction in DLCO and 6MWT distance and an increased sensation of dyspnea. PMID- 21319592 TI - Risk factors of acute exacerbation of idiopathic pulmonary fibrosis. AB - BACKGROUND: Although acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is a well known clinical condition, predicting risk factors remain unknown. We evaluated the frequency, risk factors and impact on survival of AE-IPF. METHODS: We retrospectively studied patients diagnosed with IPF based on the criteria of the ATS/ERS consensus statement and followed them for periods of more than 3 years except in dead cases. Initial characteristics including the level of dyspnoea, which was assessed with the modified Medical Research Council (MRC) scale, and decline of forced vital capacity (FVC) defined by at least 10% decline at 6 months, were evaluated as possible risk factors for AE. RESULTS: Seventy four patients with IPF were studied. One-year, two-year, and three-year incidence of AE were 8.6%, 12.6%, and 23.9%, respectively. Multivariate analysis revealed that higher body mass index (BMI) [hazard ratio (HR), 1.20; 95% confidence interval (CI), 1.03-1.40], higher modified MRC scale [HR, 2.93; 95% CI, 1.46 5.85], and a decline in FVC at 6 mounths [HR, 0.97-2.60 (per mo); 95% CI, 1.01 7.45] were independent risk factors for AE-IPF. The causes of death were assessed to be AE in 20 of 57 expired patients. A stepwise multivariate Cox regression model evaluating AE-IPF, adjusted for %FVC and decline in FVC, demonstrated a statistically significant impact on overall survival [HR, 2.79; 95% CI, 1.59 4.88; p < 0.001]. CONCLUSION: These data suggest that initial high modified MRC scale, high BMI, and decline in FVC at 6 months were significant independent risk factors for AE-IPF. AE was an independent prognostic factor in IPF. PMID- 21319593 TI - Sarcoidosis in Ireland: regional differences in prevalence and mortality from 1996-2005. AB - BACKGROUND: Sarcoidosis is a common multisystem disease of unknown cause and Ireland is among the countries with the highest reported prevalence of disease worldwide. Despite this, reports on the geographical distribution of disease and differences in mortality due to sarcoidosis within Northern Ireland (NI) and the Republic of Ireland (ROI) are currently lacking. OBJECTIVE: This study was performed to examine sarcoidosis prevalence and mortality in Ireland (NI and ROI) to specifically determine if geographical or temporal clusters of disease are present and if any differences in mortality exist between NI and ROI. DESIGN: A retrospective study, examining hospital discharge data for NI and ROI and data on deaths due to sarcoidosis, obtained from the relevant official government agencies. RESULTS: For 1996-2005, the prevalence of sarcoidosis was 28.13 per 100,000 for ROI compared with 11.16 per 100,000 for NI (p = 0.002). Two significant spatial clusters of disease were detected in the Northwest (Prevalence = 44.9 per 100,000) and also the Midlands region (32.1 per 100,000). Two lower-prevalence spatial clusters were also detected in the South and Southeast of ROI. Temporal clustering was also present throughout ROI and NI for the years 2000 to 2004, while space-time clustering was found in three regions, the West (ROI), the East (ROI) and Northeast (ROI and NI). The case fatality rate for ROI was 0.84%, and for NI was 1.44% (p = 0.03). CONCLUSION: Considerable heterogeneity in disease prevalence is evident in Ireland as significant spatial, temporal and space-time clusters of sarcoidosis are demonstrated in this study. Prevalence rates are also higher than that previously reported for Ireland and are comparable to those of Scandinavian countries. Although case-fatality is low in both ROI and NI, it is significantly lower in ROI. Further study is needed to investigate these findings and the creation of an all-island sarcoidosis registry would provide a mutually beneficial means of capturing this data more effectively. PMID- 21319594 TI - A haplotype of cyclooxygenase-2 gene is associated with idiopathic pulmonary fibrosis. AB - BACKGROUND: Cyclooxygenase-2, a key regulatory enzyme in the synthesis of the antifibrotic agent prostaglandin E2, is downregulated in lung tissue from patients with idiopathic pulmonary fibrosis. OBJECTIVE: To investigate the association between COX2.3050 (G --> C), COX2.8473 (C --> T) and COX2.926 (G --> C) single nucleotide polymorphisms (SNP) and the susceptibility to idiopathic pulmonary fibrosis and the progression of the disease. DESIGN: Genetic polymorphisms were analyzed in 121 out of 225 available control subjects and in all of 174 patients with idiopathic pulmonary fibrosis by real time polymerase chain reaction. Logistic regression analysis of covariance and chi-squares test were used for statistical analysis. RESULTS: While analysis of disease development did not find any significant association with single SNP genotype, a haplotype analysis revealed a strong association between the disease development and one haplotype [GC] at loci COX2.3050 and COX2.8473, and suggested a recessive genetic effect of this haplotype. Further analysis concluded that subjects having two copies of [GC] haplotype, or equivalently (GG/CC) genotype at the two SNPs, had an increased risk after adjusting for age and sex. Due to the interaction, this elevated risk increased slowly with age, and the estimated odds ratio (OR) decreased with age from OR = 1.4 at age 30 to OR = 1 at age 74 and OR = 0.96 at age SO. The OR was significantly greater than 1 up to age 66, and not significant for age older than 66. Therefore, the recessive effect of [GC] haplotype increased the risk of IPF of subjects younger than 66 years, but its effect diminished for seniors older than 66. One hundred and forty-nine patients with idiopathic pulmonary fibrosis were followed up for 33.7 +/- 2.1 months. Further analysis of disease progressions, defined by the changes in pulmonary function tests, did not reveal any association with either SNP genotypes or haplotypes. CONCLUSIONS: The carriage of double homozygote (GG/CC) at the SNP loci of COX2.3050 and COX2.8473 polymorphisms may increase the susceptibility to idiopathic pulmonary fibrosis, by approximately 1.4 folds at age 30 and by a smaller fold greater than 1 up to age 66 years, but not the progression of the disease. These findings may help to improve our understanding of idiopathic pulmonary fibrosis pathogenesis and may lead to the development of new therapeutic strategies. PMID- 21319595 TI - TNF-alpha and TNF-beta gene polymorphisms in Polish patients with sarcoidosis. Connection with the susceptibility and prognosis. AB - BACKGROUND: Sarcoidosis is a systemic granulomatous disease of unknown aetiology, in which genetic factors, especially the genes of the highly polymorphic MHC region, seem to play an important role in the disease predisposition and course. The aim of this study was to evaluate the role of TNF genes polymorphism in sarcoidosis and to estimate possible association between these polymorphisms and susceptibility and prognosis of sarcoidosis. The analysis of -308G > A TNF-alpha gene (TNFA*1 and TNFA*2 alleles) and 252A > G TNF-beta gene polymorphisms (TNFB*1 and TNFB*2 alleles) were performed. METHODS: The study comprised of 130 sarcoidosis patients (75 subjects in the radiological stage I, and 55 in the stages II/III). Lofgren syndrome (LS) was manifested in 38 patients. After at least 3-years observation, 69 patients had remission, 24 subjects manifested persistent disease and 25 patients had progression. The control group consisted of 84 healthy subjects. The genotypes were determined using PCR-RFLP assay. RESULTS: The variant allele TNFA*2 was observed significantly more frequent in patients with Lofgren syndrome when compared to control group (OR = 2.301, C.I. = [1.23-4.32], chi2 = 6.91, p > 0.01), as well as to non-LS patients (OR = 2.167, C.I. = [1.17-4.01], chi2 = 6.22, p < 0.05). Moreover, the variant allele TNFA*2 was also observed significantly more frequent in patients with disease resolution than in patients with persistent disease and progression (OR = 3.53, C.I. = [1.66 7.50], chi2 = 11.65, p < 0.001). The variant allele TNF*2 was also overrepresented in patients with disease resolution after exclusion the patients with Lofgren syndrome (OR = 2.4, C.I. = [1-5.772], chi2 = 3.98, p < 0.05). There was no significant difference in TNF-A allele distribution between the control group and whole sarcoidosis group. The variant allele TNFB*1 was observed significantly more frequent in patients with disease resolution than in patients with persistent disease and progression. This difference was caused only by overrepresentation of TNFB*1 variant allele in Lofgren group. The significant differences in the distribution of TNFB*1 allele between the sarcoidosis an the control group was also noted (OR = 1,607, C.I. = [1,033-2,5], chi2 = 4.46, p < 0.05), but it was limited only to patients displaying Lofgren syndrome. CONCLUSION: Two alleles TNFB*1 and TNFA*2 of TNF gene are overrepresented in polish patients with Lofgren syndrome. The TNFA*2 allele is related with mild course of sarcoidosis in patients without LS. PMID- 21319596 TI - CA 15-3 as an alternative marker for KL-6 in fibrotic lung diseases. AB - BACKGROUND: KL-6 is a mucin that is increased in interstitial lung diseases (ILD), and in some malignancies. CA 15-3, a tumor marker for breast cancer, refers to the same mucin but utilizes antibodies against different epitopes. OBJECTIVE: The aim of our study was to evaluate CA 15-3 as a viable alternative to KL-6 as a for ILDs with and without fibrosis. DESIGN: Serum from 242 patients with ILDs and from 327 healthy controls were included and KL-6 and CA 15-3 were measured in all subjects. Regression analyses and ROC curves were used to compare the performances of both markers. RESULTS: KL-6 and CA 15-3 levels were both significantly higher in the ILD patients compared to the controls (p < 0.0001). A weak yet significant correlation was found between serum KL-6 and CA 15-3 levels in the controls (R = 0.39, p < 0.0001), but showed a much higher correlation in the patient group (R = 0.85, p < 0.0001). CA 15-3 correlated best with KL-6 in patients with fibrotic ILDs (R = 0.83, p < 0.0001). KL-6 performed better as a marker compared to CA 15-3 in most ILDs. Both markers performed best in identifying idiopathic pulmonary fibrosis (IPF) and were equally able to differentiate between ILDs with and without fibrosis: (sensitivity and specificity %): 100/97, 95/92, and 90/72, respectively. CONCLUSION: CA 15-3 and KL-6 are equally sensitive and specific in terms of differentiating between ILDs with and without fibrosis. The wide availability, ease of use, and cost effectiveness, make CA 15-3 a viable alternative for KL-6 as a possible marker for pulmonary fibrosis. PMID- 21319597 TI - Angiotensin II receptor type 1 1166 A/C and angiotensin converting enzyme I/D gene polymorphisms in a Dutch sarcoidosis cohort. AB - BACKGROUND: The angiotensin II type 1 receptor (AT2R1) is the receptor for angiotensin II, a potent vasoconstrictor produced by ACE from angiotensin I. A recent study by Biller and colleagues revealed a gender-specific association between the AT2R1 1166 A/C gene polymorphism and disease susceptibility as well as a co-dependent association between AT2R1 1166 A/C and the angiotensin converting enzyme (ACE) insertion/deletion polymorphism on ACE levels in a group of German sarcoidosis patients. OBJECTIVE: . The aim of our study was to compare our results from Dutch Caucasian sarcoidosis patients with the results of Biller et al. DESIGN: Serum and DNA from 99 patients with sarcoidosis and from 327 healthy controls were included. The AT2R1 1166 A/C and ACE I/D polymorphisms and serum ACE levels were analyzed in all subjects. RESULTS: No significant differences were found between the genotype distributions between the sarcoidosis patients and controls. The genotype distributions for either polymorphism between genders and between patients with progressive/chronic disease and those with acute/remission type disease were not different. The ACE D allele contributed significantly to higher ACE levels. This was true for both sarcoidosis patients and controls. There was no association between the AT2R1 1166 A/C genotype and ACE levels, nor did AT2R1 modify the ACE D/I effects on ACE levels. No significant differences were observed in co-incidence of ACE and AT2R1 genotypes between patients and controls. CONCLUSION: Our study could not confirm the findings by Biller and colleagues other than the influence of the ACE I/D polymorphism on serum ACE levels in both sarcoidosis patients and controls. PMID- 21319598 TI - Sarcoidal granulomas in the spleen associated with multiple carcinomas. AB - Sarcoid reactions are relatively rare manifestations of epithelioid cell granulomas associated with malignancy; they are especially found in the lymph nodes draining malignant tumors, but rarely found in other organs. We present a case of a 60-year-old female with sarcoid reactions in the spleen identified during the consecutive diagnosis and management of ovarian, breast, and thyroid carcinomas during a period of about 2 years. The symptoms and laboratory data suggestive of systemic sarcoidosis were absent except for a slight mediastinal lymphadenopathy detected only by a computed tomographic scan. The splenic granulomas were accompanied by dendritic cells of mature and immature types, the latter being different from the reported nodal counterparts. To our knowledge, this is the first reported case of splenic sarcoid reactions associated with multiple cancers, and the first reported immunohistochemical detection of dendritic cells in splenic granuloma. PMID- 21319599 TI - Atypical sarcoidosis masquerading as neutropenia. AB - Sarcoidosis is a systemic granulomatous disease of unknown etiology. Gastrointestinal involvement in sarcoidosis is rare and so are its hematological manifestations. We report an unusual case of sarcoidosis with isolated gastric involvement and concomitant B12 and iron deficiency, leucopenia and severe neutropenia. The diagnosis of GI tract sarcoidosis is difficult and other causes of GI tract granulomas should be excluded. Patients can have unusual manifestations like B12 deficiency and one should be aware of this possibility. Careful follow-up and frequent reevaluation of the patient may be a sound strategy in equivocal cases with unusual presentation. PMID- 21319600 TI - A case of systemic polyarteritis nodosa involving bronchial artery. AB - Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis involving predominantly medium-sized muscular arteries. It commonly involves skin, kidney, cardiovascular system, gastrointestinal system, and neurological system. But bronchial artery involvement of PAN is rarely identified. We report a case of PAN with initial presentation of hemoptysis. On admission, chest radiograph and chest CT angiography revealed no focus of bleeding. Angiography showed a bronchial artery aneurysm and multiple arterial aneurysms in both renal, hepatic, mesenteric and branches of small bowel arteries. These findings were compatible with the diagnosis of PAN. The patient was started on steroid and cyclophosphamide. PMID- 21319601 TI - Quality of randomized controlled trials in acupuncture treatment of hepatitis B virus infection--a systematic review. AB - The purpose of this work was to evaluate the quality of randomized controlled trials (RCTs) with acupuncture treatment for hepatitis B virus (HBV) infection. A systematic review of the literature for clinical trials was performed up to September 2008. RCTs assessing acupuncture point stimulation for patients with HBV infection were considered for inclusion. The search identified 70 relevant trials meeting the inclusion. The quality of each trial was assessed using the revised Consolidated Standards for Reporting of Trials (CONSORT) statement, facilitating critical appraisal and interpretation of RCTs by providing guidance to authors; the Standards for Reporting Interventions in Controlled Trials of Acupuncture (STRICTA) recommendations, acting as an extension of the CONSORT guidelines for the specific requirements of acupuncture studies; and the Jadad scale, widely used in different settings to assess methodological quality. All trials were reported "randomization", but only 2 mentioned the methods. None reported allocation concealment, a method used to keep clinicians and participants unaware of upcoming assignments. None reported blinding. 3 studies described the number of withdrawals/dropouts, while none used the analysis of "intention to treat". The reported items of the STRICTA recommendations were assigned for 65% (13 out of 20). Only 2 studies had a high quality Jadad score. The results from our work show that the quality was low caused by their methodological flaws and inadequate reports. Further rigorous clinical trials for HBV infection would be necessary to evaluate the efficacy of acupuncture. PMID- 21319602 TI - A comparison between pulsed radiofrequency and electro-acupuncture for relieving pain in patients with chronic low back pain. AB - Many treatment options for chronic low back pain are available, including varied forms of electric stimulation. But little is known about the electricity effect between electro-acupuncture and pulsed radiofrequency. The objective of this study is to assess the difference in effectiveness of pain relief between pulsed radiofrequency and electro-acupuncture. Visual analog score (VAS) pain score, the Oswestry disability index (ODI) to measure a patient's permanent functional disability, and Short form 36 (SF-36) which is a survey used in health assessment to determine the cost-effectiveness of a health treatment, were used as rating systems to measure the pain relief and functional improvement effect of pulsed radiofrequency and electro-acupuncture, based on the methodological quality of the randomized controlled trials, the relevance between the study groups, and the consistency of the outcome evaluation. First, the baseline status before therapy shows no age and gender influence in the SF-36 and VAS score but it is significant in the ODI questionnaire. From ANOVA analyses, it is apparent that radiofrequency therapy is a significant improvement over electro-acupuncture therapy after one month. But electro-acupuncture also showed functional improvement in the lumbar spine from the ODI. This study provides sufficient evidence of the superiority of pulsed radiofrequency (PRF) therapy for low back pain relief compared with both electro-acupuncture (EA) therapy and the control group. But the functional improvement of the lumbar spine was proved under EA therapy only. Both therapies are related to electricity effects. PMID- 21319603 TI - Effects of transcutaneous electrical stimulation (1 pulse/sec) through custom made disposable surface electrodes covering Omura's ST36 area of both legs on normal cell telomeres, oncogen C-fosAb2, integrin alpha5beta1, chlamydia trachomatis, etc. in breast cancer & alzheimer patients. AB - Our previous study indicated that when extremely reduced normal cell (NC) telomeres in various cancer patients are increased over 500 ng BDORT units, abnormally high cancer cell telomeres and cancer-related markers such as Oncogen C-fosAb2 (Onco.)& Integrin alpha5beta1 (Integ.), & 8-OH-dG as well as bacterial & viral infections, mercury, asbestos, chromium, & beta-amyloid (1-42) markedly reduced due to improved circulation & excretion of these substances in urine. Since 1995, we have been using press-needle stimulation of Omura's ST36 with 200x press-release procedure 4x a day, with significant improvements in various cancer patients. In this study, Transcutaneous Electrical Stimulation (TES) at 60 pulses/min, which is close to patient's heart rate, was given between Omura's ST36 of both legs of the breast cancer & Alzheimer's patients. After about 10 minutes of TES, NC telomeres increased from 1 yg (= 10-24 g) to 500-525 ng; Integ. reduced from 85-75 ng to 0.5 ng & Chlamydia trachomatis (CT) reduced from 4500-3500 ng to 0.5 ng. An additional 10 minutes TES increased NC telomeres to 800-875 ng, while Integ. reduced to 0.5 yg & CT became less than 0.1 yg. After a total 30 minutes of TES, NC telomeres increased to 1000-1200ng BDORT units, with decreases in Integ. and Onco. to less than 0.1 yg. CT reduced to << 0.1 yg. About 24 hours later, NC telomeres were still 300 ng & both Integ. and Onco. were 2.5 ng. CT was approximately 20 ng. In Alzheimer patient, abnormally high beta Amyloid (1-42) of 7-12 ng markedly reduced to within normal value of less than 1.5 ng by 20-30 min TES. Stimulation beyond 30 minutes gradually reduced NC telomeres. TES pulse rate of 4 pulses/sec for the same patient initially increased NC telomere up to 750-950 ng BDORT units within 20 minutes, but when stimulation continued more than 20 min, NC telomeres rapidly reduced to -150 ng in less than 10 min of TES with reduced beneficial effects. PMID- 21319604 TI - Clinical effectiveness of acupuncture for mandibular subluxation and dislocation. AB - Dislocation or subluxation of mandible could occur suddenly without Patient's awareness of its forthcoming. Patient may discover suddenly during yawning, laughing, or when the mouth is wide open that he or she could not close the jaw. It may cause serve anxiety and apprehension, that may put the patient in such a nervous state that may worsen the condition, and also may spastically tense the muscles associated with dislocation. We treated 37 patients in the past and found that, although five patients could be manipulated to have their dislocated jaw reduced to the normal state, we found that a majority of the cases could not be manipulated without supplementing with other adjunctive methods such as acupuncture at the pertinent acupoints, or injections of local anesthetic around the temporomandibular joint area. Twenty-seven patients were successful to have the dislocation or subluxation reduced, five patients required local anesthetic for reduction and 1 patient had to have the reduction done in the operating room under deep sedation. We found acupuncture is valuable in reducing the mandibular subluxation and dislocation. Three acupoints in calming down the patients were a valuable aid during treatment. LI 4 which is known to reduce pain in head and neck region could increase pain threshold and decrease anxiety associated with discomfort encountered during reduction treatment. Additional acupoints such as P 6 (Neikuan), Ext 1 (Yintang), and H 7 (Shenmen) are valuable for the patients who are tense and nervous. Those acupoints are also could be utilizied as additional aid to ease the spasm of the muscles associated with subluxation and dislocation. Post-operative care includes stabilization at the head and neck region. PMID- 21319605 TI - Effect of bandwidth knowledge of results on the learning of a grip force control task. AB - An experiment was conducted to investigate the persistence of the effect of "bandwidth knowledge of results (KR)" manipulated during the learning phase of performing a manual force-control task. The experiment consisted of two phases, an acquisition phase with the goal of maintaining 60% maximum force in 30 trials, and a second phase with the objective of maintaining 40% of maximum force in 20 further trials. There were four bandwidths of KR: when performance error exceeded 5, 10, or 15% of the target, and a control group (0% bandwidth). Analysis showed that 5, 10, and 15% bandwidth led to better performance than 0% bandwidth KR at the beginning of the second phase and persisted during the extended trials. PMID- 21319606 TI - Sex differences in association of race performance, skin-fold thicknesses, and training variables for recreational half-marathon runners. AB - The purpose of this study was to investigate the association between selected skin-fold thicknesses and training variables with a half-marathon race time, for both male and female recreational runners, using bi- and multivariate analysis. In 52 men, two skin-fold thicknesses (abdominal and calf) were significantly and positively correlated with race time; whereas in 15 women, five (pectoral, mid axilla, subscapular, abdominal, and suprailiac) showed positive and significant relations with total race time. In men, the mean weekly running distance, minimum distance run per week, maximum distance run per week, mean weekly hours of running, number of running training sessions per week, and mean speed of the training sessions were significantly and negatively related to total race time, but not in women. Interaction analyses suggested that race time was more strongly associated with anthropometry in women than men. Race time for the women was independently associated with the sum of eight skin-folds; but for the men, only the mean speed during training sessions was independently associated. Skin-fold thicknesses and training variables in these groups were differently related to race time according to their sex. PMID- 21319607 TI - Early sport involvement in young Portuguese basketball players. AB - The purpose of this study was to examine the quantity and type of sporting activities undertaken by young Portuguese basketball players in early stages of athletic development. 750 basketball players aged between 12 and 16 years served as participants, grouped by sex and competitive level. The Skilled group comprised players representing the 9 highly ranked regional teams (n=378) while the Less-skilled group comprised the players representing the remaining 9 regional teams (n=372). All the participants filled out a previously validated questionnaire based on retrospective information linked to the training activities experienced throughout their involvement in sport. Results suggest that the majority of the players started practicing sports preferentially between 6 and 10 years. However, a significant number of players reported a later start, between 11 and 14 years of age. The pattern of sport involvement confirmed important divergences in the path reported by the players by the team's competitive level. The major findings of this study confirmed that players representing the highly ranked teams demonstrated a tendency to extend their training activities during longer periods during the week and throughout each season. PMID- 21319608 TI - Predictor variables for a 100-km race time in male ultra-marathoners. AB - In 169 male 100-km ultra-marathoners, the variables of anthropometry, training, and prerace experience, in order to predict race time, were investigated. In the bivariate analysis, age (r = .24), body mass (r = .20), Body Mass Index (r = .29), circumference of upper arm (r = .26), percent body fat (r = .45), mean weekly running hours (r = -.21), mean weekly running kilometers (r = -.43), mean speed in training (r=-.56), personal best time in a marathon (r = .65), the number of finished 100-km ultra-runs (r = .24), and the personal best time in a 100-km ultra-run (r = .72) were associated with race time. Stepwise multiple regression showed that training speed (p < .0001), mean weekly running kilometers (p < .0001), and age (p < .0001) were the best correlations for a 100-km race time. Performance may be predicted (n=169, r2 = .43) by the following equation: 100-km race time (min) = 1085.60 - 36.26 x (training speed, km/hr.) - 1.43 x (training volume, km/wk.) + 2.50 x (age, yr.). Overall, intensity of training might be more important for a successful outcome in a 100-km race than anthropometric attributes. Motivation to train intensely for such an ultra endurance run should be explored as this might be the key for a successful finish. PMID- 21319609 TI - Appearance (ethnic origin) of requester affects the foot-in-the-door technique. AB - A study was designed to examine the effect of the appearance of the requester within one of the variants of the foot-in-the-door paradigm, that is, the foot-in the-door with implicit demand described by Uranowitz in 1975. A confederate (Black vs. Blanc vs. Beur2) approached the participant in a park and presented a small request. Three steps further, the confederate "accidentally" dropped 30 sheets of paper. Whether or not the participant helped the confederate in retrieving the dropped pamphlets was recorded as the implicit dependent variable. The foot-in-the-door effect was observed solely when the requester was Blanc. This result shows that the foot-in-the-door effect is not as strong as the literature suggests and undermines the usual interpretations of the foot-in-the door effect in terms of self-perception and commitment. PMID- 21319610 TI - A follow-up study on utilization of a chopsticks training device. AB - Retention of a skill was estimated after using a training device to assist in correcting the use of chopsticks. Simulated food-serving tasks (pulling, pinching, and moving tasks) were administered twice with a 1-mo. interval. The current work was based on 22 of 30 persons who had practiced the use of the scissor-pinching technique with chopsticks. A control group of 22 who typically used the pincers-pinching technique was also recruited for comparison. Analysis showed 1-mo. retention of skill at the pincers-pinching technique using three measures, since no difference in performance between the groups was noted. PMID- 21319611 TI - Testing the factor structure of the beliefs about language learning inventory. AB - This preliminary study examined the factor structure of the Beliefs About Language Learning Inventory in two samples of about 750 college students of English as a foreign language in Taiwan. Results of confirmatory factor analysis lend partial support to Horwitz's theoretical five-factor belief model. Subsequent exploratory and confirmatory factor analyses of data show that a four factor model represented by only 12 items performed better than other models both theoretically and empirically. This model consists of two dimensions already theorized in the inventory: Difficulty of Language Learning and Foreign Language Aptitude, and two newly interpreted dimensions, Importance of Spoken Language and Analytical Approaches to Language Learning. Although this four-factor model could be replicated in an independent sample, the factors are not reliable, suggesting the need to search for a more representative set of beliefs to tap specific aspects of language learning. PMID- 21319612 TI - Electromechanical delay in ballistic movement of superior limb: comparison between karate athletes and nonathletes. AB - The aim of the study was to analyze electromechanical delay in a ballistic movement of the superior limb. 10 male karate athletes and 9 nonathletes (without karate experience) performed a motor skill as fast and powerfully as possible, with impact on a makiwara (karate training instrument). For each participant, 10 choku-zuki performances were analyzed. Kinematics and surface electromyographic (EMG) activity of the anterior and posterior portions of deltoid, pectoralis major, latissimus dorsi, triceps brachii, and biceps brachii were recorded. Athletes had significantly shorter delay in arm flexion agonist muscles and significantly higher delay in arm flexion antagonist muscles and in forearm extension agonists. Results suggest that enhanced performance in athletes was mainly due to motor learning. PMID- 21319613 TI - A validation study of goal orientations and self-efficacy scales. AB - The aim of the current study was to investigate the validity and reliability of goal orientation and self-efficacy scales. The scales were administered to 264 university students (154 from engineering departments, 110 from business administration). Two samples were used. In the first sample, the original factor model was tested with confirmatory factor analysis. In the second sample, the Turkish versions of the scales were factor analyzed. Principal components analysis resulted in three components for the Goal Orientation scale: Learning goal orientation, Performance-prove goal orientation, and Performance-avoid goal orientation. The Self-efficacy scale had one factor as expected. Cronbach's alpha coefficients were satisfactory. The results did not fully support the use of current Turkish versions of the scales. Results of the studies are discussed along with the strengths and limitations of the study and suggestions for further development of the scales. PMID- 21319614 TI - Effects of providing advance cues during a soccer penalty kick on the kicker's rate of success. AB - The effect of explicitly providing goalkeeper's movement advanced cue to the kicker during a real penalty kick task was assessed. 32 expert soccer players (M age= 23.2 yr.), who were divided into four groups: an experimental group, a discovery group, a placebo group, and a control group, participated. Rate of success in the task was assessed, as well as goals, decision times, and ball flight times. Providing an advance cue significantly improved the players' rate of success relative to players without the advance cue; this difference was still present after 1 and 7 days without training. The experimental group adapted better to the time range within which the response could be effective, while the discovery group showed adaptations. Explicit instructions about the advance cues available from goalkeepers' actions before the dive during practice can improve penalty kick performance. PMID- 21319615 TI - Grip strength impairments among older adults receiving physical therapy in a home care setting. AB - A hand-grip dynamometer was used to assess the magnitude and prevalence of grip strength impairments among 41 home-care patients with diverse diagnoses (e.g., stroke, cancer, fracture, osteoarthritis). Based on published reference values, patients (as a whole) were weaker than normal for age and sex. The prevalence of weakness was 85.4% on one or the other side and 70.7% on both sides. Considering the prognostic importance of grip strength, this study emphasized the potential value of its measurement in a home-care population. PMID- 21319616 TI - Early maturation of frequency-following responses to voice pitch in infants with normal hearing. AB - Neural plasticity of pitch processing mechanisms at the human brainstem, as reflected by the scalp-recorded frequency-following response (FFR) to voice pitch, has been reported for normal-hearing adults. Characteristics and maturation of such a response during the first year of life have remained unclear. The purpose of this study was to examine the characteristics of FFR to voice pitch in normal-hearing infants and to make a direct comparison with adults using the same stimulus and recording parameters. 9 infants and 9 adults were recruited. A Chinese monosyllable that mimics the English vowel /i/ with a rising pitch was used to elicit the FFR to voice pitch. The results demonstrated that infant FFRs showed slightly larger Pitch Strength but comparable Frequency Error, Slope Error, and Tracking Accuracy to those obtained from adults. Early maturation of FFRs was also observed in the infants starting from 1 to 3 mo. of age. PMID- 21319617 TI - Examination of the passive facial feedback hypothesis using an implicit measure: with a furrowed brow, neutral objects with pleasant primes look less appealing. AB - 98 undergraduates (54 men, 44 women) participated in an experiment to examine whether having an artificially furrowed brow would have an effect on participants' subjective impression of perceived targets. An elastic adhesive bandage was either stretched to create furrows on the brow when it retracted, or not stretched so as to avoid creating wrinkles. While wearing the bandages, the participants rated their impressions of neutral targets preceded by agreeable, disagreeable, or neutral primes in a modified Affect Misattribution Procedure. The results showed that participants with artificially furrowed brows tended to rate the neutral targets preceded by agreeable primes less favorably than did the control participants, while both groups rated similarly the targets preceded by disagreeable primes. PMID- 21319618 TI - Burnout and self-perceptions of physical fitness in a sample of Italian physical education teachers. AB - This study examined the relations of physical education teachers' burnout with some individual variables, including teachers' self-perceived physical fitness and the perceived influence of personal fitness on teaching. Participants were 219 Italian physical education teachers in secondary school. Demographic and professional information, ratings of self-perception of physical condition, and the Italian version of the Maslach Burnout Inventory were recorded. Compared to the data of a normative sample, average scores on the three dimensions of the Maslach Burnout Inventory (Emotional Exhaustion, Depersonalisation, and Reduced Personal Accomplishment) were found. There were statistically significant associations among Reduced Personal Accomplishment, the self-perception of physical fitness, and the perception of the influence of personal fitness on teaching. Women reported scores on Emotional Exhaustion and Reduced Personal Accomplishment indicative of greater severity than men. No significant differences appeared to be related to the years of teaching. Recommendations for further studies are discussed. PMID- 21319619 TI - Illusory lightness in the Delboeuf figure. AB - A white disk presented inside a small concentric circle (a display like the Delboeuf figure) looks lighter than when inside a larger one. The magnitude of the effect was measured with 20 observers (10 women, 10 men; ages 19 to 26 years). The decrements in luminance of the disk inside the smaller circle, in order to match the lightness of the disk inside the larger circle, are reported for three different grey backgrounds and correspond to 9.13, 10.33, and 10.46%. PMID- 21319620 TI - Similarity of anthropometric measures for male ultra-triathletes and ultra runners. AB - Previous research concluded that Triple Iron ultra-triathletes were close to runners in anthropometry. We assessed similarities in anthropometry between 64 Triple Iron triathletes who competed over 11.4 km swimming, 540 km cycling, and 126 km running versus 95 100-km ultra-marathoners. Variables of anthropometry such as body mass, body height, length and circumferences of limbs, skin-folds and body fat, and training such as volume and speed were compared between ultra triathletes and ultra-runners. The Triple Iron triathletes completed their race distance within 2811 min. (SD=379) and the 100-km ultra-marathoners within 691 min. (SD=117). Triathletes were younger, had higher body mass, shorter legs, higher circumference of upper arm and thigh, lower sum of skin-folds, and lower percent body fat compared to runners. Weekly training volume was higher for triathletes, and weekly hours in running and weekly kilometres in running were higher for runners. In the Triple Iron ultra-triathletes, the sum of eight skin folds correlated to total race time. The circumference of upper arm, the sum of eight skin-folds, and percent body fat correlated with time in the running section .42, .47, and .43, respectively. In the 100-km ultra-marathoners, the sum of eight skin-folds, the skin-fold thickness of thigh, percent body fat, weekly running hours, and weekly running kilometres correlated with race time .55, .40, .56, -.50, and -.51, respectively. However, in the triathletes, none of these training variables was significantly correlated with race time. In the ultra marathoners, the sum of eight skin-folds, the skin-fold thickness of thigh, percent body fat, weekly running kilometres, and speed in running during training were related to race time (correlations of .55, .40, -.28, and -.51, respectively). Overall, the ultra-triathletes were not similar to ultra-runners in their anthropometric measures and training variables. PMID- 21319621 TI - The simplest chronoscope II: reaction time measured by meterstick versus machine. AB - Visual simple reaction time (SRT) scores measured in 31 college students of both sexes by use of the simplest chronoscope methodology (meterstick SRT) were compared to scores obtained by use of an electromechanical multi-choice reaction timer (machine SRT). Four hypotheses were tested. Results indicated that the previous mean value of meterstick SRT was replicated; meterstick SRT was significantly faster than long-standing population estimates of mean SRT; and machine SRT was significantly slower than the same long-standing mean SRT estimates for the population. Also, the mean meterstick SRT of 181 msec. was significantly faster than the mean machine SRT of 294 msec. It was theorized that differential visual information processing occurred such that the dorsal visual stream subserved meterstick SRT; whereas the ventral visual stream subserved machine SRT. PMID- 21319622 TI - Wayfinding through an unfamiliar environment. AB - Strategies for finding one's way through an unfamiliar environment may be helped by 2D maps, 3D virtual environments, or other navigation aids. The relative effectiveness of aids was investigated. Experiments were conducted in a large, park-like environment. 24 participants (12 men, 12 women; age range = 22-50 years; M=32, SD = 7.4) were divided into three groups of four individuals, who explored a 2D map of a given route prior to navigation, received a silent guided tour by means of an interactive virtual representation, or acquired direct experience of the real route through a silent guided tour. Participants then had to find the same route again on their own. 12 observers were given a "simple" route with only one critical turn, and the other 12 a "complex" route with six critical turns. Compared to three people familiar with the routes, among the naive participants, those who had a direct experience prior to navigation all found their way again on the simple and complex routes. Those who had explored the interactive virtual environment were unable to find their way on the complex route. The relative scale representation in the virtual environment may have given incorrect impressions of relative distances between objects along the itinerary, rendering important landmark information useless. PMID- 21319623 TI - Validation of adult omni perceived exertion scales for elliptical ergometry. AB - This investigation examined the validity of newly developed Adult OMNI Elliptical Ergometer Ratings of Perceived Exertion Scales. 60 men and women performed a graded exercise test on an elliptical ergometer. Oxygen consumption (VO2), heart rate (HR), and ratings of perceived exertion were recorded at each stage from the Borg 15 Category scale and two different OMNI scales. One scale employed an elliptical ergometer format of the OMNI Picture System of Perceived Exertion. The second scale modified verbal, numerical, and pictorial descriptors at the low end of the response range. Concurrent and construct validity were established by the positive relation between ratings of perceived exertion from each OMNI scale with VO2, HR, and Borg scale ratings of perceived exertion (men, r = .94-.97; women, r = .93-.98). Validity was established for both OMNI scales, indicating either metric can be used to estimate ratings of perceived exertion during partial weight-bearing exercise. PMID- 21319624 TI - Verbal working memory and planning: learning to compare movement durations of objects. AB - Relations between duration judgments and verbal or visual working memory, between duration judgments and effect of learning to plan the processing of information about such judgments were investigated. A computer monitor was used to present images of two cars traveling in the same direction for various durations and distances. Participants (N=30) were asked to identify the car that had traveled for the longer duration. Then, participants learned how to solve Piagetian tasks logically. After the learning, they tried to solve the duration judgments task again. Finally, their verbal and visual working memory capacities were assessed. Results indicated the following: (a) numbers of correct answers on the Piagetian tasks were correlated with verbal and visual working memory capacity; (b) the correlations did not significantly decrease after the participants learned how to solve the Piagetian tasks. PMID- 21319625 TI - Visual biasing of auditory localization in azimuth and depth. AB - Correctly integrating sensory information across different modalities is a vital task, yet there are illusions which cause the incorrect localization of multisensory stimuli. A common example of these phenomena is the "ventriloquism effect". In this illusion, the localization of auditory signals is biased by the presence of visual stimuli. For instance, when a light and sound are simultaneously presented, observers may erroneously locate the sound closer to the light than its actual position. While this phenomenon has been studied extensively in azimuth at a single depth, little is known about the interactions of stimuli at different depth planes. In the current experiment, virtual acoustics and stereo-image displays were used to test the integration of visual and auditory signals across azimuth and depth. The results suggest that greater variability in the localization of sounds in depth may lead to a greater bias from visual stimuli in depth than in azimuth. These results offer interesting implications for understanding multisensory integration. PMID- 21319626 TI - Sex differences in discriminative power of volleyball game-related statistics. AB - To identify sex differences in volleyball game-related statistics, the game related statistics of several World Championships in 2007 (N=132) were analyzed using the software VIS from the International Volleyball Federation. Discriminant analysis was used to identify the game-related statistics which better discriminated performances by sex. Analysis yielded an emphasis on fault serves (SC = -.40), shot spikes (SC = .40), and reception digs (SC = .31). Specific robust numbers represent that considerable variability was evident in the game related statistics profile, as men's volleyball games were better associated with terminal actions (errors of service), and women's volleyball games were characterized by continuous actions (in defense and attack). These differences may be related to the anthropometric and physiological differences between women and men and their influence on performance profiles. PMID- 21319627 TI - Parameter value switching in discrete and continuous aiming movements. AB - The effect of practice variations on spatial and temporal accuracy was investigated in both discrete and continuous aiming movements in the preferred hand of college-aged participants (N=25). In a completely within-subject design, participants made rapid reversal movements with a lightweight lever in the sagittal plane, practicing 20 degrees and 60 degrees movements in repeated (same distance) and alternating (switching between 20 degrees and 60 degrees) conditions. Movements were also made one at a time (discretely) or in sequences of 20 movements (continuously). Spatial constant error, spatial variable error, spatial overall error, the coefficient of variation, movement time, and the relative timing were calculated for each set of 20 movements and analyzed by within-subject analyses of variance. Movements in the repeated conditions for both discrete and continuous movements were more accurate and consistent compared to the alternating condition where the short movements were overshot and the long movements were undershot. Discrete movements were more spatially and temporally variable than continuous movements. The discrete and continuous movements showed different relative timing patterns, suggesting that the temporal structure of the motor program is affected by task characteristics. PMID- 21319628 TI - Meditation and attention: a comment on a recent article. AB - Meditation and attention are considered associated in different ways. For example, contemporary concepts state that to meditate, a practitioner has either to (i) focus attention on the object of meditation (FA) or (ii) maintain vigilance and disengage their attention consciously from all distracters (OM). The Indian sage Patanjali (circa 900 B.C.), mentioned that there are two stages of meditation, which differ subtly from the descriptions of FA and OM. One stage is called dharana, or focusing attention on the object of meditation. Another stage is called dhyana, during which all thoughts remain effortlessly directed to the object of meditation, excluding all other thoughts. Vigilance and attention are not required during dhyana, which is the actual phase of meditation. In a previous study, participants who practiced dharana performed better in a task for selective attention than those who practiced dhyana. Brainstem auditory evoked potential changes during the two states differed. Descriptions of yoga practices from ancient texts can give added insights about meditation and attention, supported by objective assessments. PMID- 21319629 TI - Accuracy of stereomotion speed perception with persisting and dynamic textures. AB - It has been established that the motion in depth of stimuli visible to both eyes may be signalled binocularly either by a change of disparity over time or by the difference in the velocity of the images projected on each retina, known as an interocular velocity difference. A two-interval forced-choice stereomotion speed discrimination experiment was performed on four participants to ascertain the relative speed of a persistent random dot stereogram (RDS) and a dynamic RDS undergoing directly approaching or receding motion in depth. While the persistent RDS pattern involved identical dot patterns translating in opposite directions in each eye, and hence included both changing disparity and interocular velocity difference cues, the dynamic RDS pattern (which contains no coherent monocular motion signals) specified motion in depth through changing disparity, but no motion through interocular velocity difference. Despite an interocular velocity difference speed signal of zero motion in depth, the dynamic RDS stimulus appeared to move more rapidly. These observations are consistent with a scheme in which cues that rely on coherent monocular motion signals (such as looming and the interocular velocity difference cue) are less influential in dynamic stimuli due to their lack of reliability (i.e., increased noise). While dynamic RDS stimuli may be relatively unaffected by the contributions of such cues when they signal that the stimulus did not move in depth, the persistent RDS stimulus may retain a significant and conflicting contribution from the looming cue, resulting in a lower perceived speed. PMID- 21319630 TI - Validation of the DynaPort MiniMod during sleep: a pilot study. AB - To measure activity during sleep, polysomnography and actigraphy are often used. The DynaPort MiniMod measures movement intensity and body position day and night. The goal was to examine the validity of the DynaPort MiniMod in assessing physical activity and body posture during sleep. In Study A, 10 healthy participants slept with the DynaPort MiniMod and the Actiwatch for one night. In Study B, 8 participants suspected of having Obstructive Sleep Apnoea Syndrome slept for one night with the DynaPort MiniMod and underwent complete polysomnography as part of the typical care protocol. In Study A, there was a significant moderate correlation (r = .70) between the movement scores of the Actiwatch and the DynaPort MiniMod. In Study B, a high intraclass correlation (r = .84) between body posture scores of the DynaPort MiniMod and the polysomnography position sensor was observed. The DynaPort MiniMod is a valid measurement device for physical activity during sleep. PMID- 21319631 TI - Tactical skills and ball speed during a field simulation of penalty kick strategies in soccer. AB - This study investigates the efficacy of intermediate penalty kickers by comparing the effect of applying an automated WiFi system on the field of play to simulate a strategy that takes account of goalkeeper action (dependent) with another for which goalkeeper strategy is irrelevant (independent). Intermediate penalty kickers (n=12) took a pretreatment test of 32 kicks in a "real-play" situation with intermediate goalkeepers (n=3). Two groups of kickers underwent 11 treatment sessions using different strategies and then were administered a posttreatment test. The variables measured were the number of goals scored, whether the direction of the shot was the same or different from the direction of the goalkeeper's move (DDG), ball speed, and the duration of the kicking movement. Data suggested the goalkeepers had a greater capacity to identify advance cues when faced with independent strategy kickers and that dependent strategy kickers achieved lower ball speeds. PMID- 21319632 TI - Age and physiological, perceptual, and affective responses during walking at a self-selected pace. AB - The aim of this study was to examine physiological, perceptual, and affective responses during self-paced walking for three age groups. 66 adult women were assigned into three groups by age: 20-25 yr. (n=22), 30-35 yr. (n=22), and 40-45 yr. (n=22). Each participant completed a maximal exercise test and a 20-min. bout of walking at a self-selected pace. The preferred walking speed was similar for all age groups, whereas physiological responses relative to maximal and ventilatory threshold values were greater in the 40-45 yr. group than the other two groups. Nevertheless, perceptual and affective responses were similar for all age groups. These findings suggest that physiological responses, but not perceptual and affective responses, of sedentary women are associated with age during walking at a self-selected pace. PMID- 21319633 TI - Researchers and productivity metrics: the tail that wags the dog? PMID- 21319634 TI - The challenge is before us: nursing health systems research. PMID- 21319635 TI - Reflections on nursing health services research: where the idealism of research meets the realities of practice. PMID- 21319636 TI - Missed nursing care: the impact on intention to leave and turnover. AB - The purpose of the study was to examine the relationship between missed nursing care, nurse turnover, and intention to leave. A cross-sectional study using the MISSCARE Survey was conducted. The sample comprised 110 patient-care units in 10 acute-care hospitals. Staffing data, turnover rates, and unit-level Case Mix Index were collected from the participating hospitals. Higher percentages of females on the unit were associated with lower turnover rates (beta = -.235, p = .010). Units with higher rates of missed care (beta = .302, p < .0001) and absenteeism (beta = .247, p = .034) had more staff with intention to leave. Units with nursing staffwho worked overtime (beta = -.283, p = .001) and who were over 35 years of age (beta = -.270, p = .050) were less likely to have staff with intention to leave. By minimizing missed nursing care, organizations may be able to improve satisfaction and reduce intention to leave (and subsequent turnover). PMID- 21319637 TI - Role transition in rural and remote primary health care nursing: a scoping literature review. AB - In order to align health services with population health needs, health authorities in sparsely populated rural and northern Canada are exploring how to better organize and deliver primary health care (PHC) services. A significant component of PHC innovation involves changes to the roles, work settings, and practice modes of registered nurses.While many studies have identified the need to revise nursing roles, few have examined the transition itself. The authors present the findings of a scoping literature review examining the transition of nursing roles in PHC, with a focus on rural and remote settings. Their review of 69 articles provides clear examples of the process of role transition and key professional and organizational issues, while also identifying the supports needed to change and sustain nurses' roles and responsibilities in PHC. PMID- 21319638 TI - Nurses' perceptions of and satisfaction with the medication administration system in long-term-care homes. AB - The purpose of this study was to explore nurses' perceptions of and level of satisfaction with the medication administration system in long-term care (LTC). The cross-sectional survey design included both quantitative and open-ended questions. Data were collected from licensed registered nurses (RNs) and registered practical nurses (RPNs) at 9 LTC residences in southwestern Ontario, Canada. Using independent sample t tests, the researchers found that RNs were significantly less satisfied than RPNs with their medication administration system, particularly with respect to safety issues. RNs identified a number of related barriers, including time constraints, poor packaging, insufficient drug information, prescription changes, lack of staff competency, and unwieldy medication carts. Implications for practice and policy are discussed, including recommendations for improving medication administration practices and for addressing the workload demands of LTC nurses. PMID- 21319639 TI - Dalhousie University/WHO Collaborating Centre on Health Workforce Planning and Research: planning for HHR around the world. PMID- 21319640 TI - Ontario's Nursing Health Services Research Unit marks the 20th anniversary of its founding. PMID- 21319641 TI - Evaluation of a patient care delivery model: system outcomes in acute cardiac care. AB - Hierarchical linear modelling was used to evaluate the influence of nurse staffing, work environment, and nurse and patient variables on system outcomes based on data collected in Canadian cardiac and cardiovascular inpatient units. Staffing utilization levels below 80% at the unit level and less overtime optimized perceived care quality and the completion of therapeutic interventions. Fewer patients per nurse improved perceived care quality and reduced longer-than expected length of stay. Nurse reports of greater resource adequacy were associated with less absenteeism and fewer uncompleted or delayed nursing interventions. System outcomes were also influenced by patient characteristics (health, pre-operative education, nursing diagnoses); nurse characteristics (experience, expertise, health, effort-reward imbalance); and work-environment factors (autonomy, unit instability). PMID- 21319642 TI - Self-harm intentions: can they be distinguished based upon a history of childhood physical and sexual abuse? AB - A non-experimental, comparative design is used to measures self-harm intention in clients with and without a history of childhood physical and sexual abuse (CP/SA) presenting to an emergency department with an episode of self-harm behaviour. The traditional suicide literature identifies the key intention concepts of wish-to die, lethality, hopelessness, and depression. However, the trauma literature understands self-harm behaviour to be an adaptive response to CP/SA and as such possibly helpful for managing intense affect and dissociation. The findings of this study demonstrate that a CP/SA history is not a distinguishing factor in self-harm intention. Almost all participants, regardless of abuse history, gave multiple reasons for their self-harm behaviour, in addition to or other than the wish-to-die. The striking similarity between the non-abused and abused groups with regard to self-harm intention challenges clinicians to assess for the full range of intentions of people who engage in self-harm and suicidal behaviour. PMID- 21319643 TI - Disappointed by editorial. PMID- 21319644 TI - CDHCs: addressing barriers to care. PMID- 21319645 TI - Scope-of-practice issues. PMID- 21319646 TI - 'Underemployment' pay for a part-time employee. PMID- 21319647 TI - Why won't the MDA approve my practice advertisement? PMID- 21319648 TI - Understanding the new 'patient's Bill of Rights' regulations. PMID- 21319649 TI - The value of virtual assistants. PMID- 21319650 TI - A sampling of health and medical apps. PMID- 21319651 TI - Pediatric oral health: our shared responsibility. PMID- 21319652 TI - Meeting the oral needs of Michigan's children. PMID- 21319653 TI - Guiding the behavior of children in the dental setting. Opportunities for success. AB - Through use of communication-based strategies, effective local anesthesia, and judicious use of nitrous oxide, the vast majority of children can be cooperative at the dentist's office. Proper communication with children helps to ensure that dental care is completed in a compassionate, safe manner, helping to make children's dentistry a very rewarding part of a dental practice. PMID- 21319654 TI - The stainless steel crown debate: friend or foe? AB - In this article, we will explore the use of the stainless steel crown (SSC) in dentistry today. For the pediatric population, many factors can affect the choice of restoration, such as the variations between primary and permanent tooth morphology, oral environment, and patient selection. The current literature and dentistry guidelines encourage dentists to make an informed decision when determining the restoration recommended for a carious primary molar. To further help educate dental providers on the topic of SSCs the following items will be reviewed: the indications; techniques for placement; advantages; and drawbacks when compared to alternative restorative materials. Regardless of personal opinion, the SSC should continue to be recognized for its efficiency, cost effectiveness, and successful treatment modality. PMID- 21319655 TI - Business as usual just isn't good enough. PMID- 21319656 TI - The linchpin. PMID- 21319657 TI - Finding our voice. PMID- 21319658 TI - MAG to concentrate on issues that matter most to members in 2011. PMID- 21319659 TI - Palliative and hospice care in metro Atlanta today. PMID- 21319660 TI - Physicians reap $2 billion in benefits from MDL settlement. PMID- 21319661 TI - Funding trauma care in Georgia. PMID- 21319662 TI - A CME approach to smoking cessation. AB - Overall, both project participants and project coordinators were very positive about their experiences and the outcomes of the projects. Several projects went beyond expectations, utilizing patient audits to determine outcomes and indicated changes in processes and behaviors to improve patient outcomes in smoking cessation. Many grantees indicated that their project was a catalyst for future programs and other policy changes. Finally, local CME coordinators acknowledged that this type of project with supporting evaluation and content assisted them in providing higher quality CME and meeting the new Accreditation Council for Continuing Medical Education requirements. PMID- 21319663 TI - Cyanosis in an eight-week-old infant. PMID- 21319664 TI - Physician, heal thyself? The ethics behind self-prescribing and curb-siding. PMID- 21319665 TI - Constitutional challenges to the patient protection and affordable care act. PMID- 21319666 TI - Health care reform and accountable care organizations: are they really relevant? PMID- 21319667 TI - Simple prescription mistake leads to tragic outcome. PMID- 21319668 TI - The art of communication. PMID- 21319669 TI - At last--support for the early years. PMID- 21319670 TI - Raising the standards in sexually transmitted infection services. AB - Services dealing with sexually transmitted infections (STIs) have been transformed in recent years with many Primary Care Trusts (PCTs) now commissioning a variety of STI services from different providers based on local needs. In recognition of these changes, and to ensure that quality is maintained throughout the NHS, the British Association for Sexual Health and HIV (BASHH), together with the Medical Foundation for AIDS and Sexual Health (MedFASH), have produced Standards for the Management of STIs. The nine standards cover all aspects of STI management, from diagnosis and treatment to the wider public health role of infection control. The standards apply to all those involved in providing STI care. For public health nurses the management of infection, as well as advice to help prevent unwanted pregnancy, are particularly relevant. Of the nine standards in the document, Standard 1: Principles of STI care is the core standard and is the most pertinent for advising clients on how to access care. It also contains background knowledge about sexual health services and what clients may expect from them. Through raising awareness of the standards among all those involved in providing STI care, it is hoped that universal implementation will bring about significant public health benefits through preventing reinfection, reducing transmission and making the utmost of the resources available. PMID- 21319671 TI - Help with your research? Sources of information and support. AB - High quality research is essential to the provision of excellent health care in both primary and hospital settings. Midwives, health visitors, other community practitioners and allied health professionals should be encouraged to initiate and participate in research. No one should undertake research in isolation. Those who are novices should make sure that they are part of a team of more experienced researchers from whom they can learn and develop their own research skills. The National Institute for Health Research provides research training programmes, research funding and infrastructure to support researchers. The latter includes RDInfo, a free resource for all health and social care researchers in the UK. It provides comprehensive information on available research funding and training as well as individualised referrals for research advice. PMID- 21319672 TI - An evaluation of midwives' knowledge of formula feeding and their role in supporting mothers who formula feed their infants. AB - OBJECTIVE: To explore midwives' knowledge of and support for formula feeding and to identify barriers that may prevent midwives giving information to mothers who formula feed their infants. METHOD: The study was designed in two phases using both qualitative and quantitative approaches. The total sample was 132 midwives. Guidance on ethical approval was obtained from the National Research Ethics Service. RESULTS: The study identified that many midwives had a lack of knowledge of formula milks and that limited support is available for mothers who formula feed. This was compounded by a lack of unbiased literature for both mothers and midwives and a lack of understanding and/or a misinterpretation of policies. CONCLUSIONS: National guidelines support a policy of health professionals giving mothers who formula feed the information they require. Mothers who have chosen to formula feed need this information to ensure their infants receive nourishment that is appropriate and is safely and correctly reconstituted. Recommendations are made for clinical practice that should have potential health benefits for infants who are formula fed while not undermining breast-feeding. PMID- 21319673 TI - Foreign body ingestion in children: case series, review of the literature and guidelines on minimising accidental ingestions. AB - Foreign body ingestion in young children is one of the commonest presentations in the Accident and Emergency Department. It has been estimated that 40% of such ingestions may go unnoticed and the child may remain asymptomatic. However, complications can arise which may need urgent medical attention. Unwitnessed cases can delay the diagnosis as foreign bodies may remain in the oesophagus or stomach for a significant period of time causing non-specific symptoms. An index of suspicion is needed amongst primary and secondary health care practitioners to manage these cases early. Prevention of ingestion in the first place is the key to avoiding such accidents in children. Health visitors and the primary health team can play a significant role in advising parents or carers on how to make the home a safe environment for their child. Adult supervision is of the utmost importance in preschool children while playing with toys and other household objects. We present four cases of accidental ingestion of a foreign body, two of which were reportedly unwitnessed by the carers. Each case carries a lesson for prevention. We discuss clinical aspects of foreign body ingestion in children and provide some guidelines to minimise the risk of accidental ingestions that primary health care professionals can discuss with parents and carers during home visits. Health educational resources for parents and clinics are suggested. PMID- 21319674 TI - Infantile colic: practicalities of management, including dietary aspects. AB - The incidence of infantile colic is between 5-20%. It occurs equally in breast- and bottle-fed infants, and in both sexes. The aetiology is unknown. The elimination of cow's milk protein and using extensively hydrolysed protein formula have been shown to be effective treatments for infantile colic. Partially hydrolysed milk has also been shown to be helpful and can be a useful option in the community when a cow's milk allergy is not considered to be an underlining cause of the colic. If symptoms persist the situation should be reassessed, as further investigations and treatment may be necessary. Certain behavioural interventions, such as reassurance, making changes to the parents' responsiveness to the infant, using motion/sound to calm the infant and reducing stimuli to the infant have also been shown to be effective treatments for infantile colic. There is some evidence to suggest that the use of prebiotic oligosaccharides, to restore normal healthy gut flora, can be beneficial. Soya milk is not recommended as a treatment. PMID- 21319675 TI - Healthy family, healthy child. PMID- 21319676 TI - DIGO: drug-induced gingival overgrowth. Part II: molecular mechanism. PMID- 21319677 TI - Making the right investments in 2011--Stocks? Bonds? Gold? T-bills? Mutual funds? Pork bellies? PMID- 21319678 TI - The 2011 General Assembly--looking ahead. PMID- 21319679 TI - Health care reform & accountable care organizations top agenda at AMA Interim Meeting. PMID- 21319680 TI - What's next for medicine now? PMID- 21319681 TI - How to reduce your risk of sexual harassment claims & litigation. PMID- 21319682 TI - Neckties for physicians: Yes? No? Maybe? AB - Nosocomial infections, especially those involving resistant microorganisms, represent one of the challenging problems of modern medicine. Health care providers play an important role in the transmission of these infections. White coats and neckties are among the culprits implicated as vectors for transmission of infections by health care providers. Both pathogenic and non-pathogenic bacteria commonly colonize neckties and avoiding neckties is a simple measure that may prove helpful in our fight against nosocomial infections. PMID- 21319683 TI - The necktie in medicine...professional or a double Windsor fomite? PMID- 21319684 TI - Whether or "knot": breaking the tie. PMID- 21319685 TI - On the front lines: What's new in botox and facial fillers. PMID- 21319686 TI - Upper blepharoplasty and brow lift: state of the art. AB - This paper will review the effects of upper facial aging and emphasize patient evaluation, surgical techniques and complications of upper blepharoplasty. The philosophy for brow lifting and brief overview of current brow lift techniques will also be presented. Asian blepharoplasty will not be covered. PMID- 21319687 TI - Lower eyelid blepharoplasty: a procedure in evolution. AB - The commonly perceived aging changes in the lower eyelid are a natural consequence of the anatomic attachments and age-related changes in the periorbital tissues. A variety of techniques have evolved to address cosmetic concerns in the lower eyelid including subtractive blepharoplasty techniques, elevation of ptotic eyelid and midface tissues, and the injection or implantation of autogenous or alloplastic materials to diminish lower eyelid "bags." Greater anatomic understanding of the pathogenesis of aging changes in the lower eyelid has led to more anatomically conservative and appropriate cosmetic surgical treatments. The decline in purely subtractive surgical techniques in blepharoplasty surgery and the advent of fat repositioning and other volume enhancement techniques has improved surgical outcomes. PMID- 21319688 TI - Ischemic stroke: prevention of complications and secondary prevention. AB - In stroke cases where there has been acute interventional therapy and in those where no intervention was possible, attention to prevention of complications and secondary stroke prevention can substantially improve outcomes. Standardized clinical tools such as clinical pathways and standing order sets as well as collaboration among highly trained nurses and physicians are essential in implementing best practices. This article summarizes the current evidence in relation to these very important aspects of stroke care. PMID- 21319689 TI - Geriatric psychiatry--an emerging specialty. AB - This paper reviews the emergence of geriatric psychiatry in the United States and Missouri. It discusses current and future needs for geriatric psychiatrists. Lastly, it focuses on recent developments in key psycho-geriatric syndromes with an emphasis on current and emerging treatments. PMID- 21319690 TI - Dietary strategies for the prevention & treatment of metabolic syndrome. AB - Obesity and the metabolic syndrome are epidemic health problems that are the root of many of the chronic diseases in our society. The increase in obesity in western societies can be largely attributed to changes in diet associated with modern civilization. Dietary strategies to reduce postprandial glucose and triglyceride spikes, and to increase the intake of dietary antioxidants, potassium, and omega-3 fatty acids will be helpful for improving health and reducing metabolic syndrome and obesity. PMID- 21319691 TI - The consequence of the trend of decline: the life of the St. Louis Insane Asylum, ca. 1900. AB - Insane asylums began to decline around the turn of the 20th century. As patients with incurable illnesses filled them, asylums became warehouses for people who could not be maintained elsewhere. The St. Louis Insane Asylum exemplifies this trend of decline. Overcrowding and lack of funding led to placement of patients in the St. Louis Poorhouse and to unhealthy conditions at the asylum. Dr. Edward Runge, the superintendent, tried to counteract this trend of decline, but the asylum was able to offer little more than custodial care. PMID- 21319692 TI - 2010 Medical Student Lobby Day: assessment of outcomes and future directions. AB - In April 2010, the Missouri State Medical Association (MSMA) sponsored the Second Annual Medical Student Lobby Day to increase student understanding of the relationship between state politics and medicine, further MSMA policy positions, remove barriers to political action, and improve future Lobby Day events. A detailed description is provided, which could be used as a reproducible model for creating similar events in other states. Participant surveys were administered and outcome data was collected and analyzed. PMID- 21319693 TI - Current tobacco use trends among Mississippi public high school students: 1993 2009. AB - This study investigates trends in tobacco use based on gender, race, and grade level among Mississippi public high school students during 1993-2009. Data were obtained by combining eight weighted Mississippi Youth Risk Behavior Surveys (YRBS). Current tobacco use (cigarette, smokeless, and cigar) was selected for investigation. During 1993-2009, the prevalence of current cigarette and cigar use among Mississippi public high school students showed a significant linear decrease (p < 0.0001). A quadratic trend was also detected for current cigarette use (p = 0.0038) indicating that it increased during 1993-1995 and then decreased over the remaining period of the study. Neither linear nor quadratic trends were observed for current smokeless tobacco use. Male students were more likely to be current tobacco users. White students were more likely to use cigarettes and smokeless tobacco. Programs that target male and white students on certain products such as smokeless tobacco are needed to further decrease overall tobacco use in the state. PMID- 21319694 TI - About obstructive sleep apnea. PMID- 21319695 TI - Mental health is everyone's business. PMID- 21319696 TI - Send in the clowns. PMID- 21319697 TI - How to avoid legal liability for online activities. PMID- 21319698 TI - A pox upon ye! PMID- 21319699 TI - Study on oxidation of pyrite by in situ absorption spectroscopy. AB - Pyrite is one of the common natural mineral. It is easily oxidized and brings heavy metal contaminations, therefore it is the main source of acidity mine drainage. The study on the dynamics of pyrite is helpful to comprehending the mechanism of its pollution. In the present paper, an experimental method was designed that phenanthroline reacts with Fe2+ that is released from pyrite in solution, and produces stable orange-red complex compound. It can be detected by absorption spectroscopy. In-situ characterization of oxidation of pyrite can be achieved by this method. The results showed that the method is reliable and accurate, and it has high sensitivity and little interference; the reaction rate of oxidation increased linearly with time, corresponding to the characterization of zero-order reaction; oxidation of pyrite belongs to the surface reaction and the process of surface reaction is rate determining step. PMID- 21319700 TI - Symposium: "The treatment of cancer of the subperitoneal rectum". PMID- 21319701 TI - Current role of surgery in the treatment of digestive fistulas. AB - Surgery is the main treatment of digestive fistulas (DF) but its role has changed over the last 40 years. The aim of this review is to analyze the surgical management of DF paying attention to timing and type of surgery. METHODS: We performed a review considering the following electronic databases: Medline, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, EMBASE and the reference lists of the key papers. Literature searches were carried out using the following medical subject headings: "digestive fistula"; "gastrointestinal fistula"; "enterocutaneous fistula"; 'AND surgery"; "AND surgical treatment". Because the absence of randomized studies, we have considered the larger series or original techniques. RESULTS: Surgical treatment of DF has two indications: to treat complications due to DF juice action such as peritonitis, abscesses, gangrene, bleeding; and when a fistula fails to heal. In this case the surgical indication is often difficult to establish, because of the risk of making an inconclusive act. CONCLUSIONS: Indications to surgery, timing and choice of operation cannot often be standardized because they depend on a mixture of DF and patient characteristics. In specific cases, involvement of nutritionist and plastic surgeon is required. PMID- 21319702 TI - Post-thyroidectomy hypocalcemic syndrome: predictive value of early PTH. Preliminary results. AB - AIM: The aim of this study is to determine an early measured serous PTH cut-off value below which it's possible to predict post-thyroidectomy hypocalcaemia outbrake. MATERIALS OF STUDY: Ninety-three consecutive patients having a benign thyroid pathology were submitted to total thyroidectomy. In all the patients serous post-surgery intact PTH and total calcium were measured within an hour from weaning. 65 patients were measured a second time 18 hours from surgery. We searched for a correlation between the post-surgery PTH values at 1 and 18 hours from surgery with the calcemia at 1 and 18 hours from surgery. We carried out a one-year follow-up for each patient. Hypocalcemia developed in 26 patients (27.95%). It was transitory in twenty-two patients (23.65%) and permanent in 4 patients (4.3%). No correlation was found between PTH1 and Cal (p = 0.8). Statistically relevant correlation (p = 0.008) was found between PTH1 and Ca2. The correlation between PTH2 and Ca2 (p = 0.001) turns out to be even more relevant. We also calculated a found that 9.5 pg/dl was PTH1 cut-off value below which it is possible to predict hypocalcemia onset (p = 0.001). DISCUSSION AND CONCLUSIONS: Early post-surgery PTH measuring is a highly predictive test of post surgery hypocalcemia. We identified a PTH1 cut-off value of 9.5 pg/dl, below which hypocalcemia onset is extremely frequent. This assessment permits us to establish an adequate drug prophylaxis, thus avoiding the related symptoms. We can also perform one-day surgery thyroidectomy in patients showing normal PTH values. PMID- 21319703 TI - Structure and biosynthesis of lecanopyrone, a naphtho[1,8-cd]pyran-3-one derivative from cultured lichen mycobionts of Lecanora leprosa. AB - From the cultures of spore-derived mycobionts of the lichen Lecanora leprosa a novel naphtho[1,8-cd]pyran-3-one derivative, lecanopyrone, was isolated. Its structure was determined by spectroscopic methods. The assembly pattern of acetate units in its biosynthesis was verified using sodium [1-13C]-acetate and sodium [1,2-13C2]-acetate. PMID- 21319704 TI - In vitro antiproliferative and antifungal activity of essential oils from Erigeron acris L. and Erigeron annuus (L.) Pers. AB - Antiproliferative and antifungal activities of essential oils from Erigeron acris root and herb and from Erigeron annuus herb were investigated. The cell viability assay was performed in cultured fibroblasts, cancer cell lines (MCF-7 and MDA-MBA 231), and endometrial adenocarcinoma (Ishikawa) cells as well as colon adenocarcinoma (DLD-1) cells using 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT). The essential oil from E. acris root showed the highest antiproliferative activity in the MCF-7 cell line with an IC50 value of 14.5 microg/mL. No effect of the essential oil on normal cells at that concentration was found. Antifungal activity against various strains of five Candida species, i.e. C. albicans, C. glabrata, C. tropicalis, C. krusei, and C. parapsilosis, was tested by the microdilution method. It was found that all examined oils can be useful as antifungal agents against the above-mentioned species, but the essential oil of E. acris herb was the most active. Their minimum inhibitory concentrations (MIC) ranged from 30 to 0.4 microL/mL. The data presented suggest that essential oils from E. acris and E. annuus possess antifungal activity against Candida spp. and antiproliferative activity against breast cancer MCF-7 cells. PMID- 21319705 TI - Biological activity of 1-aryl-3-phenethylamino-1-propanone hydrochlorides and 3 aroyl-4-aryl-1-phenethyl-4-piperidinols on PC-3 cells and DNA topoisomerase I enzyme. AB - A number of studies reported Mannich bases to manifest antimicrobial, cytotoxic, anticancer, anti-inflammatory, and anticonvulsant activities. A considerable number of therapeutically important cytotoxic compounds are active on DNA topoisomerases that regulate the DNA topology. In the present study we evaluated the biological activity of mono-Mannich bases, 1-aryl-3-phenethylamino-1 propanone hydrochlorides (1a-10a), and semicyclic mono-Mannich bases, 3-aroyl-4 aryl-1-phenethyl-4-piperidinols (1b-9b), synthesized in our laboratory. We employed androgen-independent human prostate cancer cells (PC-3) to assess the cytotoxicity of the compounds and extended the biological activity evaluation to cover supercoil relaxation assays of mammalian type I topoisomerases. Our results showed that the compounds had cytotoxicity within the 8.2-32.1 microM range, while two compounds gave rise to a comparable average value in topo I interference of 42% and 40% for 10a (with a hydroxy substituent on the phenyl ring from mono-Mannich bases) and 5b (with a fluoro substituent on the phenyl ring from the semicyclic mono-Mannich base series, piperidinols), respectively. PMID- 21319706 TI - Radical scavenging activities of Heracleum aquilegifolium Wight (Apiaceae) fruit oils in vitro. AB - The fruits of Heracleum aquilegifolium Wight (Apiaceae) were collected from Western Ghats of the Indian Peninsula. The essential oils were extracted by hydrodistillation. The chemical composition of the essential oils was analysed by gas chromatography and gas chromatography-mass spectrometry (GC-MS). Beta-Pinene (22.3%), 1,8-cineole (20.3%), and beta-phellandrene (12.4%) were the main components of H. aquilegifolium fruit oils. The antioxidant properties of essential oils of H. aquilegifolium were examined by different procedures namely reducing power ability, 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, nitric oxide radical scavenging activity, hydrogen peroxide scavenging activity, hydroxyl radical scavenging activity, superoxide anion scavenging activity, and metal chelating activity. The antioxidant activities were compared with those of synthetic antioxidants and standard drugs such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, alpha tocopherol, curcumin, and quercetin. The study confirmed the possible antioxidant potential of essential oils tested with various in vitro antioxidant methods. The presence of monoterpenes in combination with other components in the oils could be responsible for the activity. PMID- 21319707 TI - Chemical composition and antimicrobial activity of the essential oils from Chloranthus japonicus Sieb. and Chloranthus multistachys Pei. AB - We examined the composition and antimicrobial activity of two essential oils from Chloranthus japonicus Sieb. and Chloranthus multistachys Pei. GC-FID and GC-MS analyses identified 48 and 39 compounds, which represented 95.56% and 94.58%, respectively, of all components in these oils. Of these, 28 compounds were common to both, with a relatively high amount of oxygenated monoterpenes (50.95% and 39.97%). Antimicrobial properties were evaluated in vitro via disc diffusion and microbroth dilution assays. Activities were strong against most tested microorganisms, with inhibition zones ranging from 8.1 to 22.2 mm. For both species, minimum values for inhibitory and bactericidal concentrations were 0.39 to 12.50 mg/mL and 0.78 to 50.00 mg/mL, respectively. These results suggest that these essential oils are potent natural sources of antimicrobial agents for the medicinal and pharmaceutical industries. PMID- 21319708 TI - Cholinesterase inhibitory and antioxidant properties of Verbascum mucronatum Lam. and its secondary metabolites. AB - The aqueous extract of Verbascum mucronatum Lam. along with its fractions and secondary metabolites were assessed for their antioxidant, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) inhibitory activities. The antioxidant activity was evaluated by three methods: as 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, ferrous ion-chelating effect, and ferric-reducing antioxidant power (FRAP) tests. The AChE activity was determined by the Ellman method using an ELISA microplate reader. Phytochemical investigations revealed the presence of four iridoid glucosides, ajugol (1), aucubin (2), lasianthoside I (3) and catalpol (4), two saponins, ilwensisaponin A (5) and C (6), and a phenylethanoid glycoside, verbascoside (7), in Verbascum mucronatum. Their structures were elucidated by spectral techniques. The aqueous extract and fractions including the phenylethanoid glycoside 7 showed DPPH scavenger effect and had the best FRAP. Besides these results, one of the phenylethanoid fractions displayed the highest ferrous ion-chelating effect. While only 7 was found to possess moderate AChE inhibition, the extract, fractions, and all other tested compounds did not inhibit AChE and BChE. PMID- 21319709 TI - Exogenous salicylate application affects the lead and copper accumulation characteristics of Lemna gibba L. AB - Previous studies have shown that salicylates can change the ion permeability of root cells. Therefore the possible effects of exogenous salicylate application on lead (Pb) and copper (Cu) accumulation and its protective role against DNA damage due to metal exposure in Lemna gibba were studied. L. gibba was exposed to 5, 10, and 25 microM Pb and Cu for six days in the presence and absence of sodium salicylate (SA) (0.1, 0.5, and 1 mM). At all concentrations tested, SA application decreased Pb accumulation. On the other hand, application of 0.5 mM SA increased Cu accumulation. SA did not reduce DNA damage resulting from Pb and Cu toxicity. In summary, SA may be useful for reducing Pb accumulation, and application of SA at 0.5 mM may be useful for the phytoextraction of Cu. PMID- 21319710 TI - A green Paramecium strain with abnormal growth of symbiotic algae. AB - Some hundred cells of Chlorella-like green algae are naturally enclosed within the cytoplasm of a single cell of green paramecia (Paramecium bursaria). Therefore, P. bursaria serves as an experimental model for studying the nature of endo-symbiosis made up through chemical communication between the symbiotic partners. For studying the mechanism of symbiotic regulations, the materials showing successful symbiosis are widely used. Apart from such successful model materials, some models for symbiotic distortion would be of great interest in order to understand the nature of successful symbiosis. Here, we describe a case of unsuccessful symbiosis causing unregulated growth of algae inside the hosting ciliates. Recently, we have screened some cell lines, from the mass of P. bursaria cells survived after paraquat treatment. The resultant cell lines (designated as KMZ series) show novel and unusual morphological features with heavily darker green colour distinguishable from the original pale green-coloured paramecia. In this type of isolates, endo-symbiotic algae are restricted within one or two dense spherical structures located at the center of the host cells' cytoplasm. Interestingly, this isolate maintains the host cells' circadian mating response which is known as an alga-dependent behaviour in the host cells. In contrast, we discuss that KMZ lacks the host-dependent regulation of algal growth, thus the algal complex often over-grows obviously exceeding the original size of the normal hosting ciliates. Additionally, possible use of this isolate as a novel model for symbiotic cell-to-cell communication is discussed. PMID- 21319711 TI - Biotransformation of some steroids by Aspergillus wentii. AB - First steroid biotransformations performed by Aspergillus wentii MRC 200316 are reported. Testosterone (1) yields 6beta-hydroxytestosterone (3) and 14alpha hydroxytestosterone (4) while progesterone (2) yields 11alpha-hydroxyprogesterone (5). PMID- 21319712 TI - Characterization of a novel long-chain n-alkane-degrading strain, Dietzia sp. E1. AB - The newly isolated strain E1, identified as a Dietzia sp., proved to have an excellent ability to degrade n-C12 to n-C38 alkane components of crude oil. The preferred substrate was the very long-chain alkane n-eicosane at an optimal temperature of 37 degrees C and an optimal pH of 8 under aerobic conditions. The growth and substrate uptake kinetics were monitored during the n-alkane fermentation process, and Dietzia sp. E1 cells were found to possess three distinct levels of cell-surface hydrophobicity. Gas chromatographic/mass spectrometric analysis revealed that intracellular substrate mineralization occurred through the conversion of n-alkane to the corresponding n-alkanal. The monoterminal oxidation pathway was presumably initiated by AlkB and CYP153 terminal alkane hydroxylases, both of their partial coding sequences were successfully detected in the genome of strain E1, a novel member of the Dietzia genus. PMID- 21319713 TI - Effect of the number of rol genes integrations on phenotypic variation in hairy root-derived Hypericum perforatum L. plants. AB - The extent of phenotypic variation of St. John's wort (Hypericum perforatum L.) plants transformed with wild agropine ATCC 15834 Agrobacterium rhizogenes plasmid was evaluated with respect to the number of rol genes integrations. The transfer of T(L)-DNA to plant explants during each transformation event was incomplete with different rolA, rolB, and rolC copy numbers. Along with typical features representing the hairy root syndrome, an altered size, number and density of dark and translucent glands, changes in ability to synthesize secondary metabolites, and reduced fertility were observed. The highest copy number of transferred rol genes resulted in weak expression of transgenic character and comparable quantitative parameters with the controls. Only 1 out of 11 transgenic clones was able to produce seed progeny and not more than 4 out of its 35 offsprings were positive for rolC gene integration. Sterility of the clones was due to retarded development of both gametophytes. PMID- 21319714 TI - Proteomic analysis of differentially expressed proteins involved in BmNPV resistance in the fat body of silkworm, Bombyx mori. AB - To investigate the mechanism of nucleopolyhedrovirus resistance of silkworm, we bred a near-isogenic silkworm line, designated BC9, from the parental resistant strain NB and the susceptible strain 306, that is resistant to infection by nucleopolyhedrovirus. Proteomic techniques were employed to search for candidate genes playing a role in the antivirus response, based on differential protein expression profiles in the fat bodies of these strains. Four proteins were identified, two of which are possibly related to energy metabolism, the third one may have a function similar to integrase, and the fourth one is completely novel. Thus, our strategy of the combined use of near-isogenic silkworm line and proteomic techniques is effective for discovering new genes in the antivirus response of insects. PMID- 21319715 TI - Characterization and induction of two cytochrome P450 genes, CYP6AE28 and CYP6AE30, in Cnaphalocrocis medinalis: possible involvement in metabolism of rice allelochemicals. AB - Two cDNAs specific for P450 genes, CYP6AE28 and CYP6AE30, have been isolated from the rice leaf folder Cnaphalocrocis medinalis Guenee (Lepidoptera: Pyralidae). Both cDNA-predicted proteins have 504 amino acid residues in length, but with molecular masses of 60177 Dalton for CYP6AE28 and 60020 Dalton for CYP6AE30, and theoretical pI values of 8.49 for CYP6AE28 and 8.56 for CYP6AE30, respectively. Both putative proteins contain the conserved structural and functional domains characteristic of all CYP6 members. CYP6AE28 and CYP6AE30 show 52% amino acid identity to each other; both of them have 49-56% identities with CYP6AE1, Cyp6ae12, and CYP6AE14. Phylogenetic analysis showed that the two P450s are grouped in the lineage containing some of the CYP6AE members, CYP6B P450s and CYP321A1. The transcripts of CYP6AE28 and CYP6AE30 were found to be induced in response to TKM-6, a rice variety with high resistance to C. medinalis. The results suggest that the two P450s may play important roles in adaptation to the host plant rice. This is the first report of P450 genes cloned in C. medinalis. PMID- 21319716 TI - Expression, purification, and characterization of functional recombinant human daintain/AIF-1 in Escherichia coli. AB - Daintain/AIF-1 was identified from injured rat carotid arteries and porcine intestine in the mid 1990s. It is involved in autoimmune disorders, chronic rejection of allografts, gliomas, and breast cancer. Since it is convenient and economical to obtain such a peptide biologically, in this study, we describe the expression, purification, and characterization of recombinant human daintain/AIF 1 (rhdaintain/AIF-1). The backbone of vector pET32a, a high-level expression plasmid, was used to construct the pET32a-daintain/AIF-1 plasmid for daintain/AIF 1 expression in Escherichia coli. The recombinant daintain/AIF-1 protein was solubly expressed in the BL21 (DE3) strain and was purified by Ni2+ affinity chromatography. After purification, the recombinant protein showed the expected size of 18 kDa on Tricine-SDS-PAGE gels which was further confirmed by Western blotting. A total of 34.0 mg of high purity (over 98%) rhdaintain/AIF-1 was obtained from 1 L culture. The recombinant peptide was able to increase blood glucose elimination rates and enhance the proliferation of human MCF-7 cells. These results suggest that biological activity of the recombinant peptide was preserved after purification. PMID- 21319717 TI - Beyond Rose's strategies: a typology of scenarios of policy impact on population health and health inequalities. AB - There is growing interest and debate in the area of policy strategies to tackle health inequalities, as well as the impact of health policies and non-health sector policies on the health of populations. Geoffrey Rose's milestone idea of a population strategy to "shift the curve" has provided key insights for both research and policy on social determinants of health. However, changes that occur both in the overall shift and in the shape of the curve (i.e., in inequality) should also be considered. This article presents a classification of policies and interventions based on all possible outcome scenarios of changes in population health and health inequalities, with examples of real policies. PMID- 21319718 TI - Health care access and utilization among children of single working and nonworking mothers in the United States. AB - To examine indicators of health care access and utilization among children of working and nonworking single mothers in the United States, the authors used data on unmarried women participating in the 1997-2008 National Health Interview Survey who financially supported children under 18 years of age (n = 21,842). Stratified by maternal employment, the analyses assessed health care access and utilization for all children. Outcome variables included delayed care, unmet care, lack of prescription medication, no usual place of care, no well-child visit, and no doctor's visit. The analyses reveal that maternal employment status was not associated with health care access and utilization. The strongest predictors of low access/utilization included no health insurance and intermittent health insurance in the previous 12 months, relative to those with continuous private health insurance coverage (odds ratio ranges 3.2-13.5 and 1.3 10.3, respectively). Children with continuous public health insurance compared favorably with those having continuous private health insurance on three of six access/utilization indicators (odds ratio range 0.63-0.85). As these results show, health care access and utilization for the children of single mothers are not optimal. Passage of the U.S. Healthcare Reform Bill (HR 3590) will probably increase the number of children with health insurance and improve these indicators. PMID- 21319719 TI - Work or place? Assessing the concurrent effects of workplace exploitation and area-of-residence economic inequality on individual health. AB - Building on previous multilevel studies in social epidemiology, this cross sectional study examines, simultaneously, the contextual effects of workplace exploitation and area-of-residence economic inequality on social inequalities in health among low-income nursing assistants. A total of 868 nursing assistants recruited from 55 nursing homes in Kentucky, Ohio, and West Virginia were surveyed between 1999 and 2001. Using a cross-classified multilevel design, the authors tested the effects of area-of-residence (income inequality and racial segregation), workplace (type of nursing home ownership and managerial pressure), and individual-level (age, gender, race/ethnicity, health insurance, length of employment, social support, type of nursing unit, preexisting psychopathology, physical health, education, and income) variables on health (self-reported health and activity limitations) and behavioral outcomes (alcohol use and caffeine consumption). Findings reveal that overall health was associated with both workplace exploitation and area-of-residence income inequality; area of residence was associated with activity limitations and binge drinking; and workplace exploitation was associated with caffeine consumption. This study explicitly accounts for the multiple contextual structure and effects of economic inequality on health. More work is necessary to replicate the current findings and establish robust conclusions on workplace and area of residence that might help inform interventions. PMID- 21319720 TI - Inequalities in medical care utilization by South Korean cancer patients according to income: a retrospective cohort study. AB - This study explores income inequalities in the utilization of medical care by cancer patients in South Korea, according to type of medical facilities and survival duration. The five-year retrospective cohort study used data drawn from the Korean Cancer Registry, the National Health Insurance database, and the death database of the Korean National Statistical Office. The sample consisted of 43,433 patients diagnosed with cancer in 1999. The authors found significant quantitative inequalities as a function of income in the patients' utilization of medical care. Cancer patients from the highest income class used inpatient and outpatient care more frequently than did patients from the lowest income class. Those with higher incomes tended to use more inpatient and outpatient services at major tertiary hospitals, which were known as providing better medical care than other types of hospitals and clinics. Moreover, horizontal inequality in cancer care expenditures favoring those with higher incomes was observed during earlier periods of treatment. In conclusion, income substantially affects the utilization of inpatient and outpatient services, amount of medical expenditures, and type of medical facilities. PMID- 21319721 TI - International Monetary Fund and aid displacement. AB - Several recent papers find evidence that global health aid is being diverted to reserves, education, military, or other sectors, and is displacing government spending. This is suggested to occur because ministers of finance have competing, possibly corrupt, priorities and deprive the health sector of resources. Studies have found that development assistance for health routed to governments has a negative impact on health spending and that similar assistance routed to private nongovernmental organizations has a positive impact. An alternative hypothesis is that World Bank and IMF macro-economic policies, which specifically advise governments to divert aid to reserves to cope with aid volatility and keep government spending low, could be causing the displacement of health aid. This article evaluates whether aid displacement was greater when countries undertook a new borrowing program from the IMF between 1996 and 2006. As found in existing studies, for each $1 of development assistance for health, about $0.37 is added to the health system. However, evaluating IMF-borrowing versus non-IMF-borrowing countries reveals that non-borrowers add about $0.45 whereas borrowers add less than $0.01 to the health system. On average, health system spending grew at about half the speed when countries were exposed to the IMF than when they were not. It is important to take account of the political economy of global health finance when interpreting data on financial flows. PMID- 21319722 TI - In search of the less hazardous cigarette. AB - Since the 1950s, despite considerable and long-term tobacco industry and government efforts, attempts to develop a less risky cigarette that reduces harmful ingredients, generally or specifically, have failed. Moreover, even under ideal conditions with adequate scientific testing, the efficacy of purportedly reducing the severe health effects cannot be scientifically verified for up to 20 years after introduction of a product on the market. A key and central provision in the 2009 U.S. Food and Drug Administration (FDA) legislation is to reduce the risk or harm of cigarettes. Because creating a less risky cigarette is not currently possible, this renders the efficacy of the 2009 FDA legislation highly uncertain, with a large risk that the proposed program may not reduce harm. PMID- 21319723 TI - Disease mongering and the fear of pandemic influenza. AB - The catastrophic H1N1 pandemic of 1918, which killed tens of millions, is now legendary, and influenza policy has centered on preventing another such disaster. There is reason for concern about influenza A. It can rapidly alter its genetic makeup to increase virulence and can jump from other species to humans. Nonetheless, ignorance about influenza in 1918, the lack of effective vaccines or antibacterial and antiviral drugs, and the social disruption caused by World War I also contributed heavily to the lethality, and it is unlikely that influenza of similar destructiveness will recur. The stupefying publicity over the threat of influenza has been generated partly by those, such as the pharmaceutical industry and influenza researchers, who benefit from the increased expenditures the publicity provokes. It is, in effect, disease mongering, the promotion of disease or dread of disease for one's own gain. Huge expenditures on influenza preparedness have produced little demonstrable benefit and some harm, independent of the wasted resources. Disease mongering, including spreading fear of influenza, is widespread and unhealthy and should be vigorously opposed. PMID- 21319724 TI - Why we don't spend enough on public health: an alternative view. AB - The primary determinants of public health are political. Comparisons among countries have shown that the importance of public health within public institutions and the priorities given by those institutions depend on the power relations in existence in that society. Authors who attribute the limited influence of public health in the United States to the public's limited understanding of the issues and/or to the supposed anti-government position of the American population miss the roots of the problem. PMID- 21319725 TI - A camel through the eye of a needle: expertise and the late recognition of asbestos-related diseases. AB - The aim of this study is to provide new insights into the late recognition of asbestos-related diseases in contemporary societies. It addresses the role of expert culture in the identification, management, and control of asbestos risks, and examines the contribution of these processes to the late recognition and minimization of risks. After focusing first on Spain, the article presents three historical case studies to illustrate some shortcomings of the expert explanatory model. First, the narrow definition of asbestosis forged by medical experts in interwar Britain helped shape a public perception of the asbestos issue as finite and controllable. Second, the alternative approach to asbestos hazard management proposed by the Spanish trade union Comisiones Obreras in the early 1980s, inspired by the so-called Italian workers' model, prioritized locally produced knowledge. Finally, in the changing public view of asbestos risks in France during the last third of the 20th century, cultural and social factors played a crucial role in broadening the issue beyond its conception as just an occupational health problem. The author argues that expertise itself becomes a deproblematizing agent for industrial health issues, paving the way for their social invisibility. PMID- 21319726 TI - Elevated in vivo strontium-90 from nuclear weapons test fallout among cancer decedents: a case-control study of deciduous teeth. AB - Risks to health from large-scale atmospheric nuclear weapons testing are still relatively unknown. A sample of 85,000 deciduous teeth collected from Americans born during the bomb-testing years assessed risk by in vivo measurement of residual strontium-90 (Sr-90) concentrations, using liquid scintillation spectrometry. The authors' analysis included 97 deciduous teeth from persons born between 1959 and 1961 who were diagrosed with cancer, and 194 teeth of matched controls. Average Sr-90 in teeth of persons who died of cancer was significantly greater than for controls (OR = 2.22; p < 0.04). This discovery suggests that many thousands have died or will die of cancer due to exposure to fallout, far more than previously believed. PMID- 21319727 TI - Change of government: one more big bang health care reform in England's National Health Service. AB - Once again the National Health Service (NHS) in England is undergoing major reform, following the election of a new coalition government keen to reduce the role of the state and cut back on big government. The NHS has been undergoing continuous reform since the 1980s. Yet, despite the significant transaction costs incurred, there is no evidence that the claimed benefits have been achieved. Many of the same problems endure. The reforms follow the direction of change laid down by the last Conservative government in the early 1990s, which the recent Labour government did not overturn despite a commitment to do so. Indeed, under Labour, the NHS was subjected to further market-style changes that have paved the way for the latest round of reform. The article considers the appeal of big bang reform, questions its purpose and value, and critically appraises the nature and extent of the proposed changes in this latest round of reform. It warns that the NHS in its current form may not survive the changes, as they open the way to privatization and a weakening of its public service ethos. PMID- 21319728 TI - Is the Bamako Initiative still relevant for West African health systems? AB - Faced with the difficulty of implementing primary health care services as proposed at Alma-Ata, UNICEF and the World Health Organization launched a new public health policy in 1987, the Bamako Initiative, to improve access to health care by revitalizing primary health care. The key principle was to decentralize retention of user fees to the local level in health centers managed by a committee of community representatives. Initially, measures were envisioned to exempt the worst-off who were unable to pay; however, these measures were never applied. Today, with most funding agencies in favor of abolishing user fees and some African countries already starting to do so, the relevance of this public policy is being reconsidered for West African countries. PMID- 21319729 TI - Isolation of the silicatein-alpha interactor silintaphin-2 by a novel solid-phase pull-down assay. AB - The skeleton of siliceous sponges consists of amorphous biogenous silica (biosilica). Biosilica formation is driven enzymatically by means of silicatein(s). During this unique process of enzymatic polycondensation, skeletal elements (spicules) that enfold a central proteinaceous structure (axial filament), mainly comprising silicatein, are formed. However, only the concerted action of silicatein and other proteins can explain the genetically controlled diversity of spicular morphotypes, from simple rods with pointed ends to intricate structures with up to six rays. With the scaffold protein silintaphin 1, a first silicatein interactor that facilitates the formation of the axial filament and, consequently, of the growing spicule was discovered. In this study, a new interactor has been identified by both a conventional yeast two-hybrid library screening and a newly established pull-down assay. For the latter approach, silicatein-alpha has been bioengineered to carry a Glu tag, which confers binding affinity to hydroxyapatite. After immobilization on a solid-phase matrix (hydroxyapatite), the Glu-tagged silicatein was used as bait for the identification of interactors. Both approaches revealed a 15 kDa polypeptide, and its identity was confirmed by matrix-assisted laser desorption ionization time-of flight mass spectrometry. Colocalization of silintaphin-2 and silicatein-alpha within the axial filament and on the spicule surface was shown by immunohistological analyses. Subsequent autoradiography demonstrated the Ca(2+) binding affinity of this silicatein interactor. These findings indicate that both proteins operate in concert during spiculogenesis. Besides binding of calcium, silintaphin-2 shares several structural features with certain acidic, secreted extracellular matrix proteins that facilitate tissue mineralization in Metazoa. Hence, silintaphin-2 might mediate signal transduction during spiculogenesis or may play a more direct role during biosilica formation, in concert with silicatein. PMID- 21319730 TI - N-Linked glycosylation of antibody fragments in Escherichia coli. AB - Glycosylation is the predominant protein modification to diversify the functionality of proteins. In particular, N-linked protein glycosylation can increase the biophysical and pharmacokinetic properties of therapeutic proteins. However, the major challenges in studying the consequences of protein glycosylation on a molecular level are caused by glycan heterogeneities of currently used eukaryotic expression systems, but the discovery of the N-linked protein glycosylation system in the epsilon-proteobacterium Campylobacter jejuni and its functional transfer to Escherichia coli opened up the possibility to produce glycoproteins in bacteria. Toward this goal, we elucidated whether antibody fragments, a potential class of therapeutic proteins, are amenable to bacterial N-linked glycosylation, thereby improving their biophysical properties. We describe a new strategy for glycoengineering and production of quantitative amounts of glycosylated scFv 3D5 at high purity. The analysis revealed the presence of a homogeneous N-glycan that significantly increased the stability and the solubility of the 3D5 antibody fragment. The process of bacterial N-linked glycosylation offers the possibility to specifically address and alter the biophysical properties of proteins. PMID- 21319731 TI - Synthesis and biodistribution of a novel (99m)TcN complex of norfloxacin dithiocarbamate as a potential agent for bacterial infection imaging. AB - Achieving a (99m)Tc-labeled fluoroquinolone derivative as a single photon emission computed tomography (SPECT) tracer is considered to be of great interest. The norfloxacin dithiocarbamate (NFXDTC) was synthesized and radiolabeled with a [(99m)TcN]2(+) intermediate to form the (99m)TcN-NFXDTC complex in high yield. The radiochemical purity of (99m)TcN-NFXDTC was over 90%, as measured by thin layer chromatography (TLC) and high performance liquid chromatography (HPLC), without any notable decomposition at room temperature over a period of 6 h. The partition coefficient and electrophoresis results indicated that (99m)TcN-NFXDTC was lipophilic and neutral. The bacterial binding assay studies showed tht (99m)TcN-NFXDTC had a good binding affinity. Biodistribution results in bacterial infected mice showed that (99m)TcN-NFXDTC had a higher uptake at the sites of infection and better abscess/blood and abscess/muscle ratios than those of (99m)Tc-ciprofloxacin and (99m)TcN-CPFXDTC (CPFXDTC = ciprofloxacin dithiocarbamate). The biodistribution results of (99m)TcN-NFXDTC in bacterially infected mice and in mice with turpentine-induced abscesses indicated that (99m)TcN-NFXDTC was suited to be a bacteria-specific infection imaging agent. Single photon emission computed tomography (SPECT) image studies showed there was a visible accumulation in infection sites, suggesting that it would be a promising candidate for bacterial infection imaging. PMID- 21319732 TI - CyLoP-1: a novel cysteine-rich cell-penetrating peptide for cytosolic delivery of cargoes. AB - Cell-penetrating peptides (CPPs) may have impli-cations in biomedical sciences by improving the delivery of a wide variety of drugs through the membrane barrier. CPPs are generally taken up by endocytotic pathways, and vesicular encapsulation is a limiting factor in the area of intracellular targeting. A novel, cationic cysteine-rich CPP, CyLoP-1, has been developed exhibiting distinguished diffused cytosolic distribution along with endosomal uptake at low micromolar concentrations. Comparative uptake analysis with known CPPs showed CyLoP-1 as a promising delivery vector to access the cytosol in a variety of cell types. In addition to the positively charged residues, the presence of cysteines and tryptophans proved to be essential to maintain its functionality. Also, the oxidation status of the cysteines played an important role for the uptake efficiency of CyLoP-1, with the disulfide-containing form being more effective. The distinct feature of CyLoP-1 to enter the cytosol was further explored by the covalent attachment of cargoes of different nature and sizes. In particular, induction of caspase-3 activity (indicating apoptosis) by a CyLoP-1-SmacN7 conjugate proved successful delivery of the pro-apoptotic cargo to its site of action in the cytosol. Efficient intracellular delivery into the entire cytosol already at low micromolar concentrations makes CyLoP-1 a promising candidate for cytosolic delivery of cargoes of small sizes. Thus, this peptide might prove to be useful for efficient transmembrane delivery of agents directed to cytosolic targets. PMID- 21319733 TI - Chromium(VI) bioremoval by Pseudomonas bacteria: role of microbial exudates for natural attenuation and biotreatment of Cr(VI) contamination. AB - Laboratory batch and column experiments were conducted to investigate the role of microbial exudates, e.g., exopolymeric substance (EPS) and alginic acid, on microbial Cr(VI) reduction by two different Pseudomonas strains (P. putida P18 and P. aeuroginosa P16) as a method for treating subsurface environment contaminated with Cr(VI). Our results indicate that microbial exudates significantly enhanced microbial Cr(VI) reduction rates by forming less toxic and highly soluble organo-Cr(III) complexes despite the fact Cr(III) has a very low solubility under the experimental conditions studied (e.g., pH 7). The formation of soluble organo-Cr(III) complexes led to the protection of the cells and chromate reductases from inactivation. In systems with no organic ligands, soluble organo-Cr(III) end products were formed between Cr(III) and the EPS directly released by bacteria due to cell lysis. Our results also provide evidence that cell lysis played an important role in microbial Cr(VI) reduction by Pseudomonas bacteria due to the release of constitutive reductases that intracellularly and/or extracellularly catalyzed the reduction of Cr(VI) to Cr(III). The overall results highlight the need for incorporation of the release and formation of organo-Cr(III) complexes into reactive transport models to more accurately design and monitor in situ microbial remediation techniques for the treatment of subsurface systems contaminated with Cr(VI). PMID- 21319734 TI - Diurnal variation of diazinon volatilization: soil moisture effects. AB - Diurnal variations in diazinon volatilization were monitored in three field experiments conducted with differing soil moisture contents. The highest flux rates in all experiments were recorded just after diazinon application, but the magnitudes of those initial rates differed according to the soil moisture content, with wetter soil producing a higher rate: 5.6 * 10(-4) MUg cm(-2) min( 1) for initial soil moisture above field capacity, 8.3 * 10(-5) MUg cm(-2) min( 1) for initial soil moisture at field capacity, and 2.5 * 10(-5) MUg cm(-2) min( 1) for initially very dry soil. Volatilization decreased during the first day in the two experiments with initially wet soils but remained relatively constant in the experiment with initially dry soil. The volatilization rate during the first night for the wettest soil remained about an order-of-magnitude higher than that observed for driest soil. When the surface dried in the experiment conducted at the intermediate water content, the volatilization rate and temporal pattern transitioned and became similar to that observed for the initially dry soil. Around noon of the second day, a daily maximum value was observed in the volatilization rate for wet soil, whereas a minimum value was observed for the dry soil, resulting in an order-of magnitude difference. This study demonstrates the importance of soil moisture on emissions of pesticides to the atmosphere. PMID- 21319735 TI - Spatial and vertical distribution of short chain chlorinated paraffins in soils from wastewater irrigated farmlands. AB - Chlorinated paraffins (CPs) are one of the most complex groups of halogenated contaminants in the environment. However, studies of short chain CPs (SCCPs) in China are very scarce. In this study, the concentrations and distribution of SCCPs in farm soils from a wastewater irrigated area in China were investigated. SCCPs were detected in all topsoil samples, with the sum of the concentrations (SigmaSCCPs) in the range of 159.9-1450 ng/g (dry weight, dw). A noticeable spatial trend and specific congener distribution were observed in the wastewater irrigated farmland. Soil vertical profiles showed that SigmaSCCP concentrations below the plowed layer decreased exponentially and had a significant positive relationship (R(2) > 0.83) with total organic carbon in soil cores. Furthermore, soil vertical distributions indicated that lower chlorinated (Cl(5-6)) and shorter chain (C(10-12)) congeners are more prone to migrate to deeper soil layers compared to highly chlorinated and longer chain congeners. This work demonstrated that effluents from sewage treatment plants (STPs) could be a significant source of SCCPs to the ambient environment and wastewater irrigation can lead to higher accumulation of SCCPs in farm soils. PMID- 21319737 TI - Method to attenuate U(VI) mobility in acidic waste plumes using humic acids. AB - Acidic uranium (U) groundwater plumes have resulted from acid-extraction of plutonium during the Cold War and from U mining and milling operations. A sustainable method for in situ immobilization of U under acidic conditions is not yet available. Here, we propose to use humic acids (HAs) for in situ U immobilization in acidic waste plumes. Our laboratory batch experiments show that HA can adsorb onto aquifer sediments rapidly, strongly and practically irreversibly. Adding HA greatly enhanced U adsorption capacity to sediments at pH below 5.0. Our column experiments using historically contaminated sediments from the Savannah River Site under slow flow rates (120 and 12 m/year) show that desorption of U and HA were nondetectable over 100 pore-volumes of leaching with simulated acidic groundwaters. Upon HA-treatment, 99% of the contaminant [U] was immobilized at pH <= 4.5, compared to 5% and 58% immobilized in the control columns at pH 3.5 and 4.5, respectively. These results indicate that HA-treatment is a promising in situ remediation method for acidic U waste plumes. As a remediation reagent, HAs are resistant to biodegradation, cost-effective, nontoxic, and easily introducible to the subsurface. PMID- 21319738 TI - Transport and bacterial interactions of three bacterial strains in saturated column experiments. AB - The impact of bacteria-solid and bacteria-bacteria interactions on the transport of Klebsiella oxytoca, Burkholderia cepacia G4PR1, and Pseudomonas sp. #5 was investigated in saturated sand column experiments (L = 114 mm; o = 33 mm) under constant water velocities (~ 5 cm . h(-1)). Bacterial strains were injected into the columns as pulses either individually, simultaneously, or successively. A one dimensional mathematical model for advective-dispersive transport and for irreversible and reversible bacterial kinetic sorption was used to analyze the bacterial breakthrough curves. Different sorption parameters were obtained for each strain in each of the three experimental setups. In the presence of other bacteria, sorption parameters for B. cepacia G4PR1 remained similar to results from individual experiments, indicating the presence of other bacteria generally had a lesser influence on its migration than for the other bacteria. K. oxytoca is more competitive for the sorption sites when simultaneously injected with the other bacteria. Ps. sp. #5 generally yielded the greatest detachment rates and the least affinity to attach to the sand, indicative of its mobility in groundwater systems. The results of this study clearly indicate both bacteria solid and bacteria-bacteria interactions influence the migration of bacteria. A more complete understanding of such interactions is necessary to determine potential migration in groundwater systems. PMID- 21319739 TI - Electrostriction in electrolyte solutions. PMID- 21319740 TI - Interfacing capillary-based separations to mass spectrometry using desorption electrospray ionization. AB - The powerful hybrid analysis method of capillary-based separations followed by mass spectrometric analysis gives substantial chemical identity and structural information. It is usually carried out using electrospray ionization. However, the salts and detergents used in the mobile phase for electrokinetic separations suppress ionization efficiencies and contaminate the inlet of the mass spectrometer. This report describes a new method that uses desorption electrospray ionization (DESI) to overcome these limitations. Effluent from capillary columns is deposited on a rotating Teflon disk that is covered with paper. As the surface rotates, the temporal separation of the eluting analytes (i.e., the electropherogram) is spatially encoded on the surface. Then, using DESI, surface-deposited analytes are preferentially ionized, reducing the effects of ion suppression and inlet contamination on signal. With the use of this novel approach, two capillary-based separations were performed: a mixture of the rhodamine dyes at milligram/milliliter levels in a 10 mM sodium borate solution was separated by capillary electrophoresis, and a mixture of three cardiac drugs at milligram/milliliter levels in a 12.5 mM sodium borate and 12.5 mM sodium dodecyl sulfate solution was separated by micellar electrokinetic chromatography. In both experiments, the negative effects of detergents and salts on the MS analyses were minimized. PMID- 21319741 TI - Glutamic acid 181 is negatively charged in the bathorhodopsin photointermediate of visual rhodopsin. AB - Assignment of the protonation state of the residue Glu-181 is important to our understanding of the primary event, activation processes and wavelength selection in rhodopsin. Despite extensive study, there is no general agreement on the protonation state of this residue in the literature. Electronic assignment is complicated by the location of Glu-181 near the nodal point in the electrostatic charge shift that accompanies excitation of the chromophore into the low-lying, strongly allowed pipi* state. Thus, the charge on this residue is effectively hidden from electronic spectroscopy. This situation is resolved in bathorhodopsin, because photoisomerization of the chromophore places Glu-181 well within the region of negative charge shift following excitation. We demonstrate that Glu-181 is negatively charged in bathorhodopsin on the basis of the shift in the batho absorption maxima at 10 K [lambda(max) band (native) = 544 +/- 2 nm, lambda(max) band (E181Q) = 556 +/- 3 nm] and the decrease in the lambda(max) band oscillator strength (0.069 +/- 0.004) of E181Q relative to that of the native protein. Because the primary event in rhodopsin does not include a proton translocation or disruption of the hydrogen-bonding network within the binding pocket, we may conclude that the Glu-181 residue in rhodopsin is also charged. PMID- 21319742 TI - Comparison of fluorescence, laser-induced fluorescence, and ultraviolet absorbance detection for measuring HPLC fractionated protein/peptide mixtures. AB - Proteomics is the study of all proteins in a biological sample. High-pressure liquid chromatography coupled online with mass spectrometry (HPLC/MS) is currently the method of choice for proteomic analysis. Proteins are extracted, separated at the protein or peptide level (after enzymatic digestion), and fractions are analyzed by HPLC/MS. Detection during off-line fractionation is generally conducted using UV-vis, which is not sensitive enough to distinguish fractions having the largest concentration of proteins/peptides and should not be combined prior to HPLC/MS. To overcome this deficiency, we utilize fluorescence or UV-laser induced fluorescence (UV-LIF) detection for measuring proteins/peptides during the off-line fractionation. Fluorescence detection allows low-abundance proteins/peptides that contain aromatic amino acids to be measured. In this study, peptide/protein samples fractionated using ion-exchange chromatography were detected using UV absorbance, fluorescence, and UV-LIF. The results indicated that fluorescence and UV-LIF were able to detect the lower abundance proteins/peptides to give a more representative chromatogram, allowing the analyst to decide which fractions should be combined prior to HPLC/tandem mass spectrometry (MS/MS) analysis. PMID- 21319743 TI - Supported bilayer electrophoresis under controlled buffer conditions. AB - A pH controlled flow cell device was constructed to allow electrophoretic movement of charged lipids and membrane associated proteins in supported phospholipid bilayers. The device isolated electrolysis products near the electrodes from the electrophoresis process within the bilayer. This allowed the pH over the bilayer region to remain within +/-0.2 pH units or better over many hours at salt concentrations up to 10 mM. Using this setup, it was found that the electrophoretic mobility of a dye conjugated lipid (Texas Red 1,2-dihexadecanoyl sn-glycero-3-phosphoethanolamine (TR-DHPE)) was essentially constant between pH 3.3 and 9.3. In contrast, streptavidin, which was bound to biotinylated lipids, shifted from migrating cathodically at acidic pH values to migrating anodically under basic conditions. This shift was due to the modulation of the net charge on the protein, which changed the electrophoretic forces experienced by the macromolecule. The addition of a polyethylene glycol (PEG) cushion beneath the bilayer or the increase in the ionic strength of the buffer solution resulted in a decrease of the electroosmotic force experienced by the streptavidin with little effect on the Texas Red-DHPE. As such, it was possible in part to control the electrophoretic and electroosmotic contributions to streptavidin independently of one another. PMID- 21319745 TI - Thermally induced transformations of amorphous carbon nanostructures fabricated by electron beam induced deposition. AB - We studied the thermally induced phase transformations of electron-beam-induced deposited (EBID) amorphous carbon nanostructures by correlating the changes in its morphology with internal microstructure by using combined atomic force microscopy (AFM) and high resolution confocal Raman microscopy. These carbon deposits can be used to create heterogeneous junctions in electronic devices commonly known as carbon-metal interconnects. We compared two basic shapes of EBID deposits: dots/pillars with widths from 50 to 600 nm and heights from 50 to 500 nm and lines with variable heights from 10 to 150 nm but having a constant length of 6 MUm. We observed that during thermal annealing, the nanoscale amorphous deposits go through multistage transformation including dehydration and stress-relaxation around 150 degrees C, dehydrogenation within 150-300 degrees C, followed by graphitization (>350 degrees C) and formation of nanocrystalline, highly densified graphitic deposits around 450 degrees C. The later stage of transformation occurs well below commonly observed graphitization for bulk carbon (600-800 degrees C). It was observed that the shape of the deposits contribute significantly to the phase transformations. We suggested that this difference is controlled by different contributions from interfacial footprints area. Moreover, the rate of graphitization was different for deposits of different shapes with the lines showing a much stronger dependence of its structure on the density than the dots. PMID- 21319744 TI - Macrocyclic beta-sheet peptides that inhibit the aggregation of a tau-protein derived hexapeptide. AB - This paper describes studies of a series of macrocyclic beta-sheet peptides 1 that inhibit the aggregation of a tau-protein-derived peptide. The macrocyclic beta-sheet peptides comprise a pentapeptide "upper" strand, two delta-linked ornithine turn units, and a "lower" strand comprising two additional residues and the beta-sheet peptidomimetic template "Hao". The tau-derived peptide Ac-VQIVYK NH(2) (AcPHF6) aggregates in solution through beta-sheet interactions to form straight and twisted filaments similar to those formed by tau protein in Alzheimer's neurofibrillary tangles. Macrocycles 1 containing the pentapeptide VQIVY in the "upper" strand delay and suppress the onset of aggregation of the AcPHF6 peptide. Inhibition is particularly pronounced in macrocycles 1a, 1d, and 1f, in which the two residues in the "lower" strand provide a pattern of hydrophobicity and hydrophilicity that matches that of the pentapeptide "upper" strand. Inhibition varies strongly with the concentration of these macrocycles, suggesting that it is cooperative. Macrocycle 1b containing the pentapeptide QIVYK shows little inhibition, suggesting the possibility of a preferred direction of growth of AcPHF6 beta-sheets. On the basis of these studies, a model is proposed in which the AcPHF6 amyloid grows as a layered pair of beta-sheets and in which growth is blocked by a pair of macrocycles that cap the growing paired hydrogen-bonding edges. This model provides a provocative and appealing target for future inhibitor design. PMID- 21319746 TI - Fluorescence determination of DNA using the gatifloxacin-europium(III) complex. AB - A method for the determination of DNA based on the fluorescence intensity of the gatifloxacin-europium(III) (GFLX-Eu(3+)) complex that could be enhanced by DNA was developed. The GFLX-Eu(3+) complex showed an up to 6-fold enhancement of luminescence intensity after adding DNA. Under the optimized experimental conditions, the system exhibited a linear relationship between the enhanced fluorescence intensity and the concentration of calf thymus DNA (ctDNA) over the range from 1.0 * 10(-8) to 1.5 * 10(-6) g mL(-1), with a correlation coefficient (R) of 0.997, and the detection limit (3sigma) of the method was determined as 6.0 * 10(-9) g mL(-1). The mechanism of the fluorescence enhancement effect was also discussed. PMID- 21319747 TI - Hypersensitive luminescence of Eu3+ in dimethyl sulfoxide as a new probing for water measurement. AB - Dimethyl sulfoxide (DMSO) is a well-known organic solvent that can be used for biological applications. DMSO is miscible with water, and it is very common that the two solvents are mixed for some applications. It is important to detect water in DMSO, and this has been done using the luminescence decay lifetimes from Eu(3+) ions. We observed that the emissions of Eu(3+) in DMSO are very strong and very sensitive to water. The emission band from the (5)D(0) -> (7)F(2) transition has two peaks at 613 and 617 nm, respectively, and these two peaks change in the opposite ways when water is added into DMSO. The intensity ratio of the two peaks follows nearly perfect linear dependence on the water concentration added in DMSO. This linear relationship provides a new and convenient method for water measurement in DMSO. PMID- 21319748 TI - Plasticity of the nickel(II) coordination environment in complexes with hemilabile phosphino thioether ligands. AB - A series of homoligated Ni(II) complexes formed from two phosphino thioether (P,S) chelating ligands has been synthesized and characterized. Interestingly, this included octahedral Ni(II) complexes which, unlike previously characterized d(8) Rh(I), Pt(II), and Pd(II) analogues, exhibit in situ exchange processes centered around chloride ligand dissociation. This was verified and studied through the controlled abstraction from and introduction of chloride ions to this system, which showed that these processes proceed through complexes with square pyramidal, tetrahedral, and square planar geometries. These complexes were studied with a variety of characterization methods, including single-crystal X ray diffraction studies, solution (31)P{(1)H} NMR spectroscopy, UV-vis spectroscopy, and DFT calculations. A general set of synthetic procedures that involve the use of coordinating and noncoordinating counteranions, as well as different hemilabile ligands, to mediate geometry transformations are presented. PMID- 21319749 TI - Structure-activity relationship, conformational and biological studies of temporin L analogues. AB - Temporins are naturally occurring peptides with promising features, which could lead to the development of new drugs. Temporin-1Tl (TL) is the strongest antimicrobial peptide, but it is toxic on human erythrocytes and this fact makes the design of synthetic analogues with a higher therapeutic index vital.We studied the structure-activity relationships of a library of TL derivatives focusing on the correlation between the alpha-helix content of the peptides, the nature of their cationic residues, and their antibacterial/antiyeast/hemolytic activities. We found that the percentage of helicity of TL analogues is directly correlated to their hemolytic activity but not to their antimicrobial activity. In addition, we found that the nature of positively charged residues can affect the biological properties of TL without changing the peptide's helicity. It is noteworthy that a single amino acid substitution can prevent the antimicrobial activity of TL, making it a lytic peptide presumably due to its self-association. Last, we identified a novel analogue with properties that make it an attractive topic for future research. PMID- 21319750 TI - Bridging the gap between physicochemistry and interpretation prevalent in cell surface interactions. PMID- 21319751 TI - Design, synthesis, and biological activity of potent and orally available G protein-coupled receptor 40 agonists. AB - G protein-coupled receptor 40 (GPR40) is being recently considered to be a new potential drug target for the treatment of type 2 diabetes because of its role in the enhancement of free fatty acid-regulated glucose-stimulated insulin secretion in pancreatic beta-cells. We initially identified benzyloxyphenylpropanoic acid (1b) (EC(50) = 510 nM), which was designed based on the structure of free fatty acids, as a promising lead compound with GPR40 agonist activity. Chemical modification of compound 1b led to the discovery of 3-{4-[(2',6'-dimethylbiphenyl 3-yl)methoxy]-2-fluorophenyl}propanoic acid (4p) as a potent GPR40 agonist (EC(50) = 5.7 nM). Compound 4p exhibited acceptable pharmacokinetic profiles and significant glucose-lowering effects during an oral glucose tolerance test in diabetic rats. Moreover, no hypoglycemic event was observed even after administration of a high dose of compound 4p to normal fasted rats. These pharmacological results suggest that GPR40 agonists might be novel glucose dependent insulin secretagogues with little or no risk of hypoglycemia. PMID- 21319752 TI - Self-assembled G4-DNA-silver nanoparticle structures. AB - Here, we describe the preparation and properties of discrete conjugates between silver nanoparticles and G-quadruplex DNA. The 20 nm silver nanoparticles (AgNPs) were connected by G-quadruplexes containing phosphorothioate anchor residues at both ends of the DNA, and the resulting conjugates were separated on the basis of the number of nanoparticles by gel electrophoresis. The molecular morphology of discrete conjugates was confirmed by TEM analysis. We have shown that the absorption spectrum of the conjugates is broader than that of AgNPs not connected to each other, indicating the presence of plasmon-mediated interparticle interactions. We discuss possible application of the conjugates in nanoelectronics. PMID- 21319753 TI - Poly(ethylene glycol-co-allyl glycidyl ether)s: a PEG-based modular synthetic platform for multiple bioconjugation. AB - A series of random copolymers comprising ethylene oxide (EO) and 0-100% allyl glycidyl ether (AGE) has been prepared by anionic ring-opening polymerization with molecular weights between 5000 and 13,600 g/mol and polydispersity indices in the range of 1.04-1.19. As key for the homogeneity of the PEG conjugates, real time 1H NMR polymerization kinetics, 13C NMR analysis of triad sequence distribution, and analysis of the thermal behavior by differential scanning calorimetry (DSC) revealed a distinctive random copolymer structure. Via thiol ene coupling (TEC), showing mainly "click" characteristics and nearly quantitative yields, PEG derivatives with multiple amino, carboxy, or hydroxy functionalities have been prepared, providing suitable reactivities for further attachment. Without further modification, P(EO-co-AGE)s were conjugated with cysteine or the tripeptide glutathione (GSH) via TEC, resulting in well-defined hybrid materials with multiple peptide units conjugated to the PEG backbone. The results demonstrate superior loading capacity of the copolymers in comparison to the PEG homopolymer. PMID- 21319754 TI - Synthesis and characterization of Au102(p-MBA)44 nanoparticles. AB - The synthesis of Au(102)(p-MBA)(44) nanoparticles on a preparative scale in high yield is described. Various analytical methods are shown to give results consistent with the composition and known structure of the particles, showing the preparation is essentially homogeneous, and attesting to the validity of the methods as well. Derivatization of the particles with proteins and DNA is demonstrated, and conditions are described for imaging individual particles by cryo-EM at low electron dose, close to focus, conditions optimal for recording high-resolution details. PMID- 21319755 TI - Protein folding with implicit crowders: a study of conformational states using the Wang-Landau method. AB - In this paper we introduce the idea of the implicit crowding method to study the statistical mechanical behaviors of folding of beta-sheet peptides. Using a simple bead-lattice model, we are able to consider, separately, the conformational entropy involving the bond angles along the backbone and the orientational entropy associated with the dihedral angles. We use a Ising-like model to partially account for the dihedral angle entropy and, implicitly, the hydrogen-bond formations. We also compare our results to recent experiments and find good quantitative agreement on the predicted folded fraction. On the basis of the predictions from the scaled particle theory, we investigate changes in the melting temperature of the protein, suggesting crowding enhanced stability for a variant of trpzip hairpin and a slight instability for the larger beta-sheet designed proteins. PMID- 21319756 TI - Dynamics of ethylene-propylene random copolymers by (1)H and (13)C solid-state NMR. AB - The dynamic behavior of three completely amorphous ethylene-propylene random copolymers with slightly different structural properties was investigated by means of a multifrequency global fitting approach, presented in a previous paper. To this end, the trends of NMR (1)H and (13)C spin-lattice relaxation times with temperature, obtained at different frequencies, were analyzed by means of unified motional models for the segmental main-chain motion and rotation of methyl groups about their ternary symmetry axis. To evaluate the reliability of both the models and the method used with respect to the dimensionality of the data set, as well as to identify the minimal data set to be used for getting reliable dynamic information on similar systems, the fitting results obtained from the analysis of three different experimental data sets collected on the same polymer were compared. The data collected on the three polymers using the minimal data set were analyzed and the results discussed to evaluate the degree of sensitivity of the method to differences in the dynamic behavior of structurally similar systems. The results demonstrated that the method shows good sensitivity to the use of different dynamic models depending on the number and/or type of relaxation curves included in the analysis and that variations in the dynamic features of the same motions on different systems can be revealed even in the presence of polymeric systems characterized by very similar structural properties. PMID- 21319757 TI - Dynamics of mixed surfactants in aqueous solutions. AB - The dynamics of mixed surfactants in aqueous solution has been studied at a molecular level by nuclear magnetic resonance (NMR) spectroscopy. The line widths and line shapes of the resonance peaks of two types of binary mixed surfactant systems, ionic/nonionic mixed solutions (12-2-12/TX-100, 14-2-14/TX-100, 14-2 14/Brij-35, and SDS/TX-100) and ionic/ionic mixed solutions (12-2-12/TTAB and 14 2-14/TTAB), in the (1)H NMR spectra offered semiquantitative results about the influence of mixing on the surfactant exchange dynamics between monomers in aqueous solution and those in the micelles. The results showed that the exchange rates of the mixed surfactants were enhanced by each other for the three cationic/nonionic mixed solutions, while the exchange rates were lowered by each other for the two cationic/cationic mixed solutions. As for SDS/TX-100 mixed systems, the addition of SDS made the exchange rate of TX-100 in solution faster, while TX-100 made the exchange rate of SDS slower. These results provide some information about surfactant interaction in mixed solutions. PMID- 21319758 TI - Calculations of bond dissociation energies. New select applications of an old method. AB - Application of Sanderson's definition of electronegativity as stability ratios (SRs), which BE = [E(i) + E(DA)] (IC) + E(cov) had been applied in the past to a wide variety of organic and nontransitional metal inorganic compounds with very good success, has been revived, modified so as to be applied to any types of molecules, including those containing transition metals, lanthanides, and actinides. This paper is limited to a demonstration of the method which is applied to a few metal cyclopentadienyl compounds, plus specific emphasis on the U(III) metallocene (CpSiMe(3))(3)U-AlCp* recently prepared by Arnold and co workers having no experimental bond energies available. It is shown that computed bond energies of pertinent metallocyclopentadieneyls are in excellent agreement with the available experimental data. Calculated bond energies for all essential bonds in the uranium metallocene cited above are provided together with a further analysis of the bonding and magnetic properties of this unique compound. PMID- 21319759 TI - Photooxidation of n-octanal in air: experimental and theoretical study. AB - Dilute mixtures of n-octanal in synthetic air (up to 100 ppm) were photolyzed with fluorescent UV lamps (275-380 nm) at 298 K. The main photooxidation products were 1-hexene, CO, vinyl alcohol, and acetaldehyde. The photolysis rates and the absolute quantum yields were found to be slightly dependent on the total pressure. At 100 Torr, Phi(100) = 0.41 +/- 0.06, whereas at 700 Torr the total quantum yield was Phi(700) = 0.32 +/- 0.02. Two decomposition channels were identified: the radical channel C(7)H(15)CHO -> C(7)H(15) + HCO and the molecular channel C(7)H(15)CHO -> C(6)H(12) + CH(2)?CHOH, having absolute quantum yields of 0.022 and 0.108 at 700 Torr. The product CH(2)?CHOH tautomerizes to acetaldehyde. Carbon balance data lower than unities suggest the existence of unidentified decomposition channel(s) which substantially contributes to the photolysis. On the basis of experimental and theoretical evidence, n-octanal photolysis predominantly proceeds to form Norrish type II products as the major ones. PMID- 21319760 TI - Effect of ultrasonic frequency on the mechanism of formic acid sonolysis. AB - The kinetics and mechanism of formic acid sonochemical degradation were studied at ultrasonic frequencies of 20, 200, and 607 kHz under argon atmosphere. Total yield of HCOOH sonochemical degradation increases approximately 6-8-fold when the frequency increased from 20 to 200 or to 607 kHz. At low ultrasonic frequencies, HCOOH degradation has been attributed to oxidation with OH(*) radicals from water sonolysis and to the HCOOH decarboxylation occurring at the cavitation bubble liquid interface. With high-frequency ultrasound, the sonochemical reaction is also influenced by HCOOH dehydration. Whatever the ultrasonic frequency, the sonolysis of HCOOH yielded H(2) and CO(2) in the gas phase as well as trace amounts of oxalic acid and formaldehyde in the liquid phase. However, CO and CH(4) formations were only detected under high-frequency ultrasound. The most striking difference between low-frequency and high-frequency ultrasound is that the sonolysis of HCOOH at high ultrasonic frequencies initiates Fischer-Tropsch hydrogenation of carbon monoxide. PMID- 21319761 TI - Influence of surfactant concentration and background salt on forced dynamic wetting and dewetting. AB - Forced wetting and dewetting of polymer surfaces in aqueous solutions containing cationic surfactant cetyltrimethylammonium bromide (CTAB) has been studied with a rotating cylinder half immersed in the solution. The receding contact angle decreases with faster withdrawing speeds. This decrease is enhanced when adding CTAB. The addition of salt to the CTAB solution further enhances the effect but does not have a significant effect alone. We interpret this change in the dynamic contact angle with a surfactant-induced Marangoni effect. PMID- 21319762 TI - Probing protein-membrane interactions using solid supported membranes. AB - Tethered bilayer lipid membranes have been used as a model system to mimic the interactions between the whey protein beta-lactoglobulin and a lipid interface. The approach allowed for a detailed study of the lipid-protein interactions, the results being of possible importance in food and cosmetic applications. For such applications, lipid-protein interactions and the interfacial behavior are vital factors in controlling and manipulating process conditions such as emulsion stabilization and gelification. Lipid composition as well as the structural properties of the protein governed their interactions, which were probed by a combination of surface plasmon spectroscopy, neutron reflectivity, and electrochemical impedance spectroscopy. Comparison of results obtained using native and a partially unfolded protein indicated that the protein preferentially forms loosely packed layers at the lipid interface. PMID- 21319763 TI - The binding of an amphipathic peptide to lipid monolayers at the air/water interface is modulated by the lipid headgroup structure. AB - We used monolayer techniques combined with infrared reflection absorption spectroscopy (IRRAS) to study the behavior of the 18-mer cationic peptide KLA1 (KLAL KLAL KAW KAAL KLA-NH2) at the air/water interface as well as its interaction with lipid films of different composition. The adsorption of the peptide from the subphase to the air/water interface was observed measuring the increase in surface pressure (pi) at constant surface area. The binding of the peptide to lipid monolayers was followed by recording the change in lipid area at a constant surface pressure (pi = 30 mN m(-1)). At the air/water interface, the peptide initially adopted an alpha-helix at large surface area per molecule, that is, low surface pressure, but further accumulation of the peptide at the interface induced a conformational change from alpha-helix to intermolecular beta sheet, driven by intermolecular aggregation. When the peptide was injected into the subphase underneath lipid monolayers, it adsorbed pronouncedly to anionic monolayers containing phosphatidylglycerol forming an alpha-helix, but not to zwitterionic lipid monolayers. The large change in area observed upon peptide binding suggests that the peptide helix was incorporated into the apolar chain region of the lipids. An apparent partition coefficient of (0.3-1) * 10(6) M(-1) could be calculated for binding to pure POPG monolayers. Significant differences in binding affinity were observed comparing PG/PC with PG/PE monolayers, with the latter showing a higher binding constant. This shows that not only electrostatic and hydrophobic effects but also specific interactions between the headgroups of the lipids and the peptide side chains modulate the binding affinity. PMID- 21319764 TI - Hydration effects on membrane structure probed by single molecule orientations. AB - Single molecule fluorescence measurements are used to probe the structural changes in glass-supported DPPC bilayers as a function of relative humidity (RH). Defocused polarized total internal reflection fluorescence microscopy is employed to determine the three-dimensional orientation of the fluorescent lipid analogue BODIPY-PC, doped into DPPC membranes in trace amounts. Supported DPPC bilayers formed using vesicle fusion and Langmuir-Blodgett/Langmuir-Schafer (LB/LS) transfer are compared and show similar trends as a function of relative humidity. Population histograms of the emission dipole tilt angle reveal bimodal distributions as observed previously for BODIPY-PC in DPPC. These distributions are dominated by large populations of BODIPY-PC molecules with emission dipoles oriented parallel (>=81 degrees ) and normal (<=10 degrees ) to the membrane plane, with less than 25% oriented at intermediate tilts. As the relative humidity is increased from 13% to 95%, the population of molecules oriented normal to the surface decreases with a concomitant increase in those oriented parallel to the surface. The close agreement in trends observed for bilayers formed from vesicle fusion and LB/LS transfer supports the assignment of an equivalent surface pressure of 23 mN/m for bilayers formed from vesicle fusion. At each RH condition, a small population of BODIPY-PC dye molecules are laterally mobile in both bilayer preparations. This population exponentially increases with RH but never exceeds 6% of the total population. Interestingly, even under conditions where there is little lateral diffusion, fluctuations in the single molecule orientations can be observed which suggests there is appreciable freedom in the acyl chain region. Dynamic measurements of single molecule orientation changes, therefore, provide a new view into membrane properties at the single molecule level. PMID- 21319765 TI - Precision polysaccharide synthesis catalyzed by enzymes. PMID- 21319766 TI - The origin of cholesterol's condensing effect. AB - The condensing effect of cholesterol on fluid bilayers of 1,2-dipalmitoyl-sn glycero-3-phosphocholine has been compared with that of dihydrocholesterol and coprostanol by means of nearest-neighbor recognition measurements. Whereas dihydrocholesterol exhibits a condensing power that is equivalent to that of cholesterol, the action of coprostanol is significantly weaker. These results provide strong support for a template mechanism of condensation and argue against an umbrella mechanism. PMID- 21319768 TI - Fabrication of size-controllable hexagonal non-close-packed colloidal crystals and binary colloidal crystals by pyrolysis combined with plasma-electron coirradiation of polystyrene colloidal monolayer. AB - We present an unprecedented and systematic route to controllably fabricate hexagonal non-close-packed (hncp) monolayer colloidal crystals and binary colloidal crystals (BCCs) based on plasma-electron coirradiation of polystyrene colloidal monolayers followed by thermal decomposition. Hncp colloidal crystals with tunable particle sizes and periods could be fabricated by changing the pristine colloidal particle size and the thermal decomposition time. In addition, BCCs and trimodal colloidal crystals that are composed of different-sized colloidal particles can also be fabricated by adding small particles on the prepared hncp colloidal crystals. Both the particle size ratio and the volume fraction of the BCCs can be widely tuned. These hncp colloidal crystals and BCCs have various potential applications as optical and photonic materials as well as in catalysis and sensors. PMID- 21319767 TI - Gold nanoparticle layer: a promising platform for ultra-sensitive cancer detection. AB - Developing new technologies applicable to the sensitive detection of cancer in its early stages has always been attractive in diagnosis. A stable gold nanoparticle layer (GNPL)-modified high-binding ELISA plate was obtained via chemical plating and was proven to be more efficient in binding proteins while maintaining their activity. GNPL-based ELISA for the representative biomarker carcinoembryonic antigen (CEA) demonstrated that GNPL markedly amplified the ELISA signal and significantly improved the limit of detection (LOD). Antithrombin detection further confirms the effectiveness and universality of this GNPL-based platform. The entire assay procedure is simple and low in cost and does not require special facilities. All these virtues indicate that this GNPL platform holds great promise in clinical applications for the early diagnosis of cancer. PMID- 21319770 TI - Composition driven monolayer to bilayer transformation in a surfactant intercalated Mg-Al layered double hydroxide. AB - The structure and organization of dodecyl sulfate (DDS) surfactant chains intercalated in an Mg-Al layered double hydroxide (LDH), Mg(1-x)Alx(OH)2, with differing Al/Mg ratios has been investigated. The Mg-Al LDHs can be prepared over a range of compositions with x varying from 0.167 to 0.37 and therefore provides a simple system to study how the organization of the alkyl chains of the intercalated DDS anions change with packing density; the Al/Mg ratio or x providing a convenient handle to do so. Powder X-ray diffraction measurements showed that at high packing densities (x >= 0.3) the alkyl chains of the intercalated dodecyl sulfate ions are anchored on opposing LDH sheets and arranged as bilayers with an interlayer spacing of ~27 A. At lower packing densities (x < 0.2) the surfactant chains form a monolayer with the alkyl chains oriented flat in the galleries with an interlayer spacing of ~8 A. For the in between compositions, 0.2 <= x < 0.3, the material is biphasic. MD simulations were performed to understand how the anchoring density of the intercalated surfactant chains in the Mg-Al LDH-DDS affects the organization of the chains and the interlayer spacing. The simulations are able to reproduce the composition driven monolayer to bilayer transformation in the arrangement of the intercalated surfactant chains and in addition provide insights into the factors that decide the arrangement of the surfactant chains in the two situations. In the bilayer arrangement, it is the dispersive van der Waals interactions between chains in opposing layers of the anchored bilayer that is responsible for the cohesive energy of the solid whereas at lower packing densities, where a monolayer arrangement is favored, Coulomb interactions between the positively charged Mg-Al LDH sheets and the negatively charged headgroup of the DDS anion dominate. PMID- 21319769 TI - Dinuclear Zn(II) complex catalyzed phosphodiester cleavage proceeds via a concerted mechanism: a density functional theory study. AB - Density functional theory (DFT) calculations were used to study the mechanism for the cleavage reaction of the RNA analogue HpPNP (HpPNP = 2-hydroxypropyl-4 nitrophenyl phosphate) catalyzed by the dinuclear Zn(II) complex of 1,3-bis(1,4,7 triazacyclonon-1-yl)-2-hydroxypropane (Zn(2)(L(2)O)). We present a binding mode in which each terminal phosphoryl oxygen atom binds to one zinc center, respectively, and the nucleophilic 2-hydroxypropyl group coordinates to one of the zinc ions, while the hydroxide from deprotonation of a water molecule coordinates to the other zinc ion. Our calculations found a concerted mechanism for the HpPNP cleavage with a 16.5 kcal/mol reaction barrier. An alternative proposed stepwise mechanism through a pentavalent oxyphosphorane dianion reaction intermediate for the HpPNP cleavage was found to be less feasible with a significantly higher energy barrier. In this stepwise mechanism, the deprotonation of the nucleophilic 2-hydroxypropyl group is accompanied with nucleophilic attack in the rate-determining step. Calculations of the nucleophile (18)O kinetic isotope effect (KIE) and leaving (18)O KIE for the concerted mechanism are in reasonably good agreement with the experimental values. Our results indicate a specific-base catalysis mechanism takes place in which the deprotonation of the nucleophilic 2-hydroxypropyl group occurs in a pre equilibrium step followed by a nucleophilic attack on the phosphorus center. Detailed comparison of the geometric and electronic structure for the HpPNP cleavage reaction mechanisms in the presence/absence of catalyst revealed that the catalyst significantly altered the determining-step transition state to become far more associative or tight, that is, bond formation to the nucleophile was remarkably more advanced than leaving group bond fission in the catalyzed mechanism. Our results are consistent with and provide a reliable interpretation for the experimental observations that suggest the reaction occurs by a concerted mechanism (see Humphry, T.; Iyer, S.; Iranzo, O.; Morrow, J. R.; Richard, J. P.; Paneth, P.; Hengge, A. C. J. Am. Chem. Soc. 2008, 130, 17858-17866) and has a specific-base catalysis character (see Yang, M.-Y.; Iranzo, O.; Richard, J. P.; Morrow, J. R. J. Am. Chem. Soc. 2005, 127, 1064-1065). PMID- 21319771 TI - Synthesis, composition, and structure of sillenite-type solid solutions in the Bi2O3-SiO2-MnO2 system. AB - Individual compounds and solid solutions are obtained under hydrothermal conditions in the Bi(2)O(3)-SiO(2)-MnO(2) system in the form of faceted crystals and epitaxial films on the Bi(24)Si(2)O(40) substrate. The crystals have the shape of a cube (for the molar ratio of the starting components Na(2)SiO(3).9H(2)O:Mn(NO(3))(2).6H(2)O > 1), a tetrahedron (for Na(2)SiO(3).9H(2)O:Mn(NO(3))(2).6H(2)O < 1), or a tetrahedron-cube combination (for Na(2)SiO(3).9H(2)O:Mn(NO(3))(2).6H(2)O = 1). Crystal-chemical analysis based on the data of single-crystal and powder X-ray diffraction, IR spectra, and the results of calculation of the local balance by the bond-valence method reveals formation of the Bi(24)(Si(4+),Mn(4+))(2)O(40) phases, which probably include Mn(5+) ions (epitaxial films), as well as the Bi(24)(Si(4+),Bi(3+),Mn(4+))(2)O(40) and Bi(24)(Si(4+),Mn(4+))(2)O(40) phases in the (1 - x)Bi(3+)(24)Si(4+)(2)O(40) - x(Bi(3+)(24)Mn(4+)(2)O(40)) system and the Bi(24)(Bi(3+),Mn(4+))(2)O(40) phase in the (1 - x)Bi(3+)(24)Bi(3+)(2)(O(39)i(1)) x(Bi(3+)(24)Mn(4+)(2)O(40)) system. Precision X-ray diffraction studies of single crystals of the Bi(24)(Bi,Si,Mn)(2)O(40) general composition show that these sillenites crystallize in space group P23 and not I23 as the Bi(24)Si(2)O(40) phase. The dissymmetrization of sillenite phases is observed for the first time. It is explained by a kinetic (growth) phase transition of the order-disorder type due to population of a crystallographic site by atoms with different crystal-chemical properties and quasi-equilibrium conditions of crystal growth in the course of a hydrothermal synthesis below 400 degrees C at unequal molar amounts of the starting components in the batch. PMID- 21319772 TI - Synthesis of boroxine-linked aluminum complexes. AB - The reaction of LAlH(2) (L = HC(CMeNAr)(2), Ar = 2,6-iPr(2)C(6)H(3)) (1) with 3 methylphenylboronic acid and 3-fluorophenylboronic acid resulted in the boroxine linked aluminum compounds LAl[OB(3-CH(3)C(6)H(4))](2)(MU-O) (2) and LAl[OB(3 FC(6)H(4))](2)(MU-O) (3), respectively. LAl[OB(2-PhC(6)H(4))(OH)](2) (4) was synthesized by the reaction of 1 with 2-biphenylboronic acid. Compound 4 is the intermediate analogue to those, which we postulated for the formation of 2 and 3. The reaction of 1 with 3-hydroxyphenylboronic acid resulted in the first metal benzoboroxole oxide LAl[OB(o-CH(2)O)C(6)H(4)](2) (5), which is formed from a compound with B-(OH)(2) and C-OH functionalities. PMID- 21319773 TI - Natural compound cudraflavone B shows promising anti-inflammatory properties in vitro. AB - Cudraflavone B (1) is a prenylated flavonoid found in large amounts in the roots of Morus alba, a plant used as a herbal remedy for its reputed anti-inflammatory properties. The present study shows that this compound causes a significant inhibition of inflammatory mediators in selected in vitro models. Thus, 1 was identified as a potent inhibitor of tumor necrosis factor alpha (TNFalpha) gene expression and secretion by blocking the translocation of nuclear factor kappaB (NF-kappaB) from the cytoplasm to the nucleus in macrophages derived from a THP-1 human monocyte cell line. The NF-kappaB activity reduction resulted in the inhibition of cyclooxygenase 2 (COX-2) gene expression. Compound 1 acts as a COX 2 and COX-1 inhibitor with higher selectivity toward COX-2 than indomethacin. Pretreatment of cells by 1 shifted the peak in an regulatory gene zinc-finger protein 36 (ZFP36) expression assay. This natural product has noticeable anti inflammatory properties, suggesting that 1 potentially could be used for development as a nonsteroidal anti-inflammatory drug lead. PMID- 21319774 TI - Unusual tigliane diterpenes from Euphorbia grandicornis. AB - Phytochemical study of the aerial parts of Euphorbia grandicornis led to the isolation of two new tigliane diterpenes, 16-angeloyloxy-13alpha-isobutanoyloxy 4beta,9alpha,20-trihydroxytiglia-1,5-diene-3,7-dione (1) and 16-angeloyloxy 13alpha-isobutanoyloxy-4beta,9alpha,7beta-trihydroxytiglia-1,5-dien-3-one (2). The structures and relative configuration of the new compounds were elucidated on the basis of extensive spectroscopic analysis, including 1D and 2D NMR experiments ((1)H NMR, JMOD, (1)H-(1)H COSY, NOESY, HSQC, and HMBC), mass spectrometry, and comparison with literature data. The biogenesis of 1 and 2 with respect to the unusual 5-en-7-one and 5-en-7-ol moieties is also discussed. PMID- 21319775 TI - From quantum motifs to assemble nanoaggregates: the preparation of organo molybdenum hybrid nanostructures. AB - Nanoaggregates such as nanowires, nanoparticles, nanotubules, and nanoribbons were prepared from bulk crystals, which are shaped as needles (1), blocks (2), tubules (3alpha), and plates (3beta), respectively, by grinding and ultrasonication. Nanowires have diameters of approximately 2 nm, lengths of thousands of nanmeters, and the distance between adjacent nanowires is approximately 2 nm. The diameters of nanoparticles range from 3 to 5 nm. Nanotubules display diameters of 70 nm and lengths of thousands of nanometers, and nanoribbons exhibit widths of approximately 50 nm and lengths of hundreds of nanometers. All of the bulk crystals have been synthesized by the wet chemical method. Single-crystal X-ray diffraction reveals that crystal 1 is constituted by infinite one-dimensional {[NH(3)CH(2)CH(NH(2))CH(3)](C(6)H(4)O(2))[MU(2) OC(6)H(4)O](Mo(VI)-O-Na-O)[NH(2)CH(2)CH(NH(2))CH(3)]}(n) (1), which acts as a parallel aligned quantum wire forming lamellas that assemble themselves into multilayered architecture. Crystal 2 consists of discrete [NH(3)CH(2)CH(NH(2))CH(3)](2)[Mo(VI)O(2)(O(2)C(6)H(4))(2)] (2), which presents as quantum particles and repeats itself along a three-dimensional crystal lattice. Crystal 3alpha, formed under 5 degrees C, and 3beta, crystallized above 10 degrees C, are both composed of (NH(3)CH(2)CH(2)NH(2))(2)[Mo(VI)O(2)(O(2)C(6)H(4))(2)](NH(2)CH(2)CH(2)NH(2))(0.5) (3) but are packed in different ways. In crystal 3alpha, four [Mo(VI)O(2)(O(2)C(6)H(4))(2)](2-) circle into a quantum tube that is further assembled into multitubular architecture. However, in crystal 3beta, two [Mo(VI)O(2)(O(2)C(6)H(4))(2)](2-) form a bilayered quantum lamellar motif that is piled into multilayered architecture. TEM reveals that all of the morphologies of the nanoaggregates are associated with the structures of the quantum motifs in their crystal lattices, which provide successful and effective access to assemble controlled nanostructures from quantum motifs of fine-desired and well-ordered bulk crystals. The technology of grinding and ultrasonication to prepare nanoaggregates is simple and available. PMID- 21319776 TI - Addition of N-heterocyclic carbenes to a ruthenium(VI) nitrido polyoxometalate: a new route to cyclic guanidines. AB - The scope of N-atom transfer from the electrophilic ruthenium(VI) nitrido containing polyoxometalate [PW(11)O(39)Ru(VI)N](4-) has been extended to the N heterocyclic carbene {CH(2)(Mes)N}(2)C and the coupling product {CH(2)(Mes)N}(2)CNH(2)(+) characterized by (1)H NMR and high-resolution mass spectrometry. Because guanidines display many fields of applications ranging from biology to supramolecular chemistry, this could afford an original route to the synthesis of cyclic guanidines. This also enlarges the potential of nitrido complexes in the synthesis of heterocycles, mainly illustrated in the literature through the formation of aziridines through N-atom transfer to alkenes. In the course of the reaction, the ruthenium(III)-containing polyoxometallic intermediate [PW(11)O(39)Ru(III){NC{N(Mes)CH(2)}(2)}](5-) has been thoroughly characterized by continuous-wave and pulsed electron paramagnetic resonance, which nicely confirms the presence of the organic moiety on the polyoxometallic framework, Ru K-edge X-ray absorption near-edge structure, and electrochemistry. PMID- 21319777 TI - pB(2) intermediate of the photoactive yellow protein: structure and excitation energies. AB - pB(2) is the last electronically excited intermediate of the photoactive yellow protein (PYP) before it thermally reverts to the dark state. We investigate the structure of pB(2) by quantum refinement and QM/MM methods and compare our results with a previously published crystal structure ( 1TS6 ). We find differences in the chromophore geometries, mostly with regard to torsion angles, that lead to a somewhat higher degree of planarity than in 1TS6 . Quantum chemical calculations at the DFT/MRCI level show that these geometry changes affect the excitation energies and oscillator strengths for transitions into the two lowest singlet excited states. The DFT/MRCI results for the presently determined structures agree well with the experimental spectrum. A classical molecular dynamics simulation of free water molecules surrounding the fixed-in space PYP indicates hydrogen bonding between water and the solvent-exposed pB(2) chromophore, since one water molecule is constantly found around the phenolic OH group. Including this additional water molecule in the quantum refinement yields improved electron density maps with a good fit of previously unresolved densities. On the other hand, this extra water molecule has little influence on the chromophore structure and the calculated excitation energies. The overall best pB(2) structure from the present work comes from quantum refinement with electrostatics and with an additional water molecule near the phenolic OH group of the chromophore (model 4). PMID- 21319778 TI - Are superhydrophobic surfaces best for icephobicity? AB - Ice formation can have catastrophic consequences for human activity on the ground and in the air. Here we investigate water freezing delays on untreated and coated surfaces ranging from hydrophilic to superhydrophobic and use these delays to evaluate icephobicity. Supercooled water microdroplets are inkjet-deposited and coalesce until spontaneous freezing of the accumulated mass occurs. Surfaces with nanometer-scale roughness and higher wettability display unexpectedly long freezing delays, at least 1 order of magnitude longer than typical superhydrophobic surfaces with larger hierarchical roughness and low wettability. Directly related to the main focus on heterogeneous nucleation and freezing delay of supercooled water droplets, the observed ensuing crystallization process consisted of two distinct phases: one very rapid recalescent partial solidification phase and a subsequent slower phase. Observations of the droplet collision process employed for the continuous liquid mass accumulation up to the point of ice formation reveal a previously unseen atmospheric-pressure, subfreezing-temperature regime for liquid-on-liquid bounce. On the basis of the entropy reduction of water near a solid surface, we formulate a modification to the classical heterogeneous nucleation theory, which predicts the observed freezing delay trends. Our results bring to question recent emphasis on super water-repellent surface formulations for ice formation retardation and suggest that anti-icing design must optimize the competing influences of both wettability and roughness. PMID- 21319779 TI - Unique properties of bubbles and foam films stabilized by HFBII hydrophobin. AB - The HFBII hydrophobin is an amphiphilic protein that can irreversibly adsorb at the air/water interface. The formed protein monolayers can reach a state of two dimensional elastic solid that exhibits a high mechanical strength as compared to adsorption layers of typical amphiphilic proteins. Bubbles formed in HFBII solutions preserve the nonspherical shape they had at the moment of solidification of their surfaces. The stirring of HFBII solutions leads to the formation of many bubbles of micrometer size. Measuring the electrophoretic mobility of such bubbles, the zeta-potential was determined. Upon compression, the HFBII monolayers form periodic wrinkles of wavelength 11.5 MUm, which corresponds to bending elasticity k(c) = 1.1 * 10(-19) J. The wrinkled hydrophobin monolayers are close to a tension-free state, which prevents the Ostwald ripening and provides bubble longevity in HFBII stabilized foams. Films formed between two bubbles are studied by experiments in a capillary cell. In the absence of added electrolyte, the films are electrostatically stabilized. The appearance of protein aggregates is enhanced with the increase of the HFBII and electrolyte concentrations and at pH close to the isoelectric point. When the aggregate concentration is not too high (to block the film thinning), the films reach a state with 12 nm uniform thickness, which corresponds to two surface monolayers plus HFBII tetramers sandwiched between them. In water, the HFBII molecules can stick to each other not only by their hydrophobic moieties but also by their hydrophilic parts. The latter leads to the attachment of HFBII aggregates such as dimers, tetramers, and bigger ones to the interfacial adsorption monolayers, which provides additional stabilization of the liquid films. PMID- 21319780 TI - Influence of Schiff base and lanthanide metals on the synthesis, stability, and reactivity of monoamido lanthanide complexes bearing two Schiff bases. AB - The monoamido lanthanide complexes stabilized by Schiff base ligand L(2)LnN(TMS)(2) (L = 3,5-Bu(t)(2)-2-(O)-C(6)H(2)CH?N-8-C(9)H(6)N, Ln = Yb (1), Y (2), Eu (3), Nd (4), and La (5)) were synthesized in good yields by the reactions of Ln[N(TMS)(2)](3) with 1.8 equiv of HL in hexane at room temperature. It was found that the stability of 1-5 depends greatly on the size of the lanthanide metals with the increasing trend of Yb ~ Y < Nd < La. The amine elimination of Ln[N(TMS)(2)](3) with the bulky bidentate Schiff base HL' (L' = 3,5-Bu(t)(2)-2 (O)-C(6)H(2)CH?N-2,6-Pr(i)(2)-C(6)H(3)) afforded the monoamido lanthanide complexes L'(2)LnN(TMS)(2) (Ln = Yb (9), Y (10), Nd (11), and La (12)). While the amine elimination with the less bulky Schiff base HL'' (L'' = 3,5-Bu(t)(2)-2-(O) C(6)H(2)CH?N-2,6-Me(2)-C(6)H(3)) yielded the desired monoamido complexes with the small metals of Y and Yb, L''(2)LnN(TMS)(2) (Ln = Yb (13) and Y (14)), and the more stable tris-Schiff base complexes with the large metals of La and Nd, yielded L''(3)Ln as the only product. Complexes 1-14 were fully characterized including X-ray crystal structural analysis. Complexes 1-5, 10, and 14 can serve as the efficient catalysts for addition of amines to carbodiimides, and the catalytic activity is greatly affected by the lanthanide metals with the active sequence of Yb < Y < Eu ~ Nd ~ La. PMID- 21319781 TI - Layer-by-layer polypeptide macromolecular assemblies-mediated synthesis of mesoporous silica and gold nanoparticle/mesoporous silica tubular nanostructures. AB - A simple and versatile approach is proposed to use the LbL-assembled polypeptide macromolecular assemblies as mediating agents and templates for directed growth of gold nanoparticles and biomimetic silica mineralization, allowing the synthesis of polypeptide/silica and polypeptide/gold nanoparticle/silica composite materials, as well as mesoporous silica (meso-SiO2) and gold nanoparticle/mesoporous silica (Au NP/meso-SiO2). The formation of tubular nanostructures was demonstrated by silicification and growth of gold nanoparticles within macromolecular assemblies formed by poly(L-lysine) (PLL) and poly(L-glutamic acid) (PLGA) using polycarbonate membranes as templates. The experimental data revealed that the silicified macromolecular assemblies adopted mainly sheet/turn conformation. The as-prepared mesoporous silica materials possessed well-defined tubular structures with pore size and porosity depending on the size of sheet/turn aggregates, which is a function of the molecular weight of polypeptides. The directed growth of Au NP and subsequent silica mineralization in the macromolecular assembly resulted in Au NP/meso-SiO2 tubes with uniform nanoparticle size and the as-prepared materials exhibited promising catalytic activity toward the reduction of p-nitrophenol. This approach provides a facile and general method to synthesize organic-inorganic composite materials, oxide and metal-oxide nanomaterials with different compositions and structures. PMID- 21319782 TI - Facile formation of biomimetic color-tuned superhydrophobic magnesium alloy with corrosion resistance. AB - The design of color-tuned magnesium alloy with anticorrosive properties and damping capacity was created by means of a simple and inexpensive method. The vertically self-aligned nano- and microsheets were formed on magnesium alloy AZ31 by a chemical-free immersion process in ultrapure water at a temperature of 120 degrees C, resulting in the color expression. The color changed from silver with metallic luster to some specific colors such as orange, green, and orchid, depending on the immersion time. The color-tuned magnesium alloy showed anticorrosive performance and damping capacity. In addition, the colored surface with minute surface textures was modified with n-octadecyltrimethoxysilane (ODS), leading to the formation of color-tuned superhydrophobic surfaces. The corrosion resistance of the color-tuned superhydrophobic magnesium alloy was also investigated using electrochemical potentiodynamic measurements. Moreover, the color-tuned superhydrophobic magnesium alloy showed high hydrophobicity not just for pure water but also for corrosive liquids, such as acidic, basic, and some aqueous salt solutions. In addition, the American Society for Testing and Materials (ASTM) standard D 3359-02 cross cut tape test was performed to investigate the adhesion of the color-tuned superhydrophobic film to the magnesium alloy surface. PMID- 21319783 TI - Unprecedented 1,3-diaza[3]ferrocenophane scaffold as molecular probe for anions. AB - The guanidine unit in the guise of 2-aminoimidazole in the new structural motif 2 arylamino-1,3-diaza[3]ferrocenophane 4 acts as a binding site for anions. The electrochemical behavior of this compound has been studied by cyclic voltammetry (CV) and differential pulse voltammetry (DPV) and was found to exhibit a quasi reversible oxidation peak, associated to the Fe(II)/Fe(III) redox couple (Ep = 440 mV), and a non-reversible oxidation wave (Ep = 817 mV), probably associated to the oxidation of the C?N unit present in the guanidine bridge. Recognition of AcO(-), PhCO(2)(-), F(-), Cl(-), and Br(-) anions by the free receptor and the less basic anions Br(-), Cl(-), and NO(3)(-) by its monoprotonated form takes place by unusual redox-ratiometric measurements and spectroscopic ((1)H NMR and UV-vis) changes. PMID- 21319784 TI - Isostructural Pd(II) and Pt(II) pyrophosphato complexes: polymorphism and unusual bond character in d8-d8 systems. AB - Isostructural, "clamshell"-like, neutral dimeric pyrophosphato complexes of general formula {[M(bipy)](2)(MU-P(2)O(7))} [M = Pd(II) (1) or Pt(II) (2)] were synthesized and studied through single-crystal X-ray diffraction, IR, (31)P NMR spectroscopy, and MALDI-TOF mass spectrometry. Compound 1 was synthesized through the reaction of palladium(II) acetate, 2,2'-bipyridine (bipy), and sodium pyrophosphate (Na(4)P(2)O(7)) in water. Compound 2 was prepared through two different routes. The first involved the reaction of the Pt(IV) precursor Na(2)PtCl(6), bipy, and Na(4)P(2)O(7) in water, followed by reduction in DMF. The second involved the reaction of the Pt(II) precursor K(2)PtCl(4), bipy, and Na(4)P(2)O(7) in water. Both complexes crystallize in the monoclinic chiral space group Cc as hexahydrates, 1.6H(2)O (1a, yellow crystals) and 2.6H(2)O (2a, orange crystals), and exhibit a zigzag chain-like supramolecular packing arrangement with short and long intra/intermolecular metal-metal distances [3.0366(3)/4.5401(3) A in 1a; 3.0522(3)/4.5609(3) A in 2a]. A second crystalline phase of the Pt species was also isolated, with formula 2.3.5H(2)O (2b, deep green crystals), characterized by a dimer-of-dimers (pseudo-tetramer) structural submotif. Green crystals of 2b could be irreversibly converted to the orange form 2a by exposure to air or water, without retention of crystallinity, while a partial, reversible crystal-to-crystal transformation occurred when 2a was dried in vacuo. (31)P NMR spectra recorded for both 1 and 2 at various pHs revealed the occurrence of a fluxional protonated/deprotonated system in solution, which was interpreted as being composed, in the protonated form, of [HO=PO(3)](+) (P(alpha)) and O=PO(3) (P(beta)) pyrophosphate subunits. Compounds 1 and 2 exhibited two successive one-electron oxidations, mostly irreversible in nature; however, a dependence upon pH was observed for 1, with oxidation only occurring in strongly basic conditions. Density functional theory and atoms in molecules analyses showed that a d(8)-d(8) interaction was present in 1 and 2. PMID- 21319785 TI - Mechanistic and computational studies of the atom transfer radical addition of CCl4 to styrene catalyzed by copper homoscorpionate complexes. AB - Experimental as well as theoretical studies have been carried out with the aim of elucidating the mechanism of the atom transfer radical addition (ATRA) of styrene and carbon tetrachloride with a Tp(x)Cu(NCMe) complex as the catalyst precursor (Tp(x) = hydrotrispyrazolyl-borate ligand). The studies shown herein demonstrate the effect of different variables in the kinetic behavior. A mechanistic proposal consistent with theoretical and experimental data is presented. PMID- 21319787 TI - Comparison of multistandard and TMS-standard calculated NMR shifts for coniferyl alcohol and application of the multistandard method to lignin dimers. AB - Coniferyl alcohol is a monomeric building block of lignin, the second most abundant biopolymer. During lignification, the monomer forms a variety of linkages through free radical additions. A large NMR database has been constructed that reports the (1)H and (13)C chemical shifts for thousands of lignin oligomers. Herein, Boltzmann averaged (1)H and (13)C GIAO NMR calculations were performed on coniferyl alcohol and four of its dimers, beta-O-4, beta-beta, beta-5, and 5-5, to compare the calculated chemical shifts with experiment. Six B3LYP/6-311++G(d,p) energy-minimized conformational isomers of coniferyl alcohol were subjected to single-point GIAO NMR calculations. Initially, four NMR shift calculation methods were compared: three were performed using the TMS-standard method at the HF/6-311+G(2d,p), B3LYP/6-311+G(2d,p), and mPW1PW91/6-31G(d) theory levels, and the fourth was performed with a multistandard approach using a mPW1PW91/6-31G(d) theory level. For the multistandard method, benzene was used as the standard for aromatic C and H atoms and methanol was used for aliphatic C and H atoms. The hydroxyl-H of methanol was used as the standard for hydroxyl-H atoms. The Boltzmann averaged results for six conformers showed that the multistandard method is more accurate for coniferyl alcohol and its dimers than the often used TMS-standard method, based on the mean unsigned, root-mean squared, and maximum errors, as well as linear correlations between observed and calculated values. The (13)C results were more accurate than the (1)H results, due to poorer agreement between calculated hydroxyl-H results and observed data. Further Boltzmann-averaged, multistandard NMR calculations compared the (13)C and (1)H chemical shifts with experiment for the four stereoisomers of the beta-O-4 dimer, as well as the 5-5, beta-5, and beta-beta dimers of coniferyl alcohol. The (13)C results correlated well with experiment (r(2)>0.99) for all dimers and showed small statistical errors, compared with experiment. The correlation with experiment for (1)H NMR was generally inferior to the (13)C NMR results for the dimers. PMID- 21319786 TI - Profiling impaired hepatic endoplasmic reticulum glycosylation as a consequence of ethanol ingestion. AB - Alcoholic liver disease (ALD) is a prominent cause of morbidity and mortality in the United States. Alterations in protein folding occur in numerous disease states, including ALD. The endoplasmic reticulum (ER) is the primary site of post translational modifications (PTM) within the cell. Glycosylation, the most abundant PTM, affects protein stability, structure, localization, and activity. Decreases in hepatic glycosylation machinery have been observed in rodent models of ALD, but specific protein targets have not been identified. Utilizing two dimensional gel electrophoresis and liquid chromatography-tandem mass spectrometry, glycoproteins were identified in hepatic microsomal fractions from control and ethanol-fed mice. This study reports for the first time a global decrease in ER glycosylation. Additionally, the identification of 30 glycoproteins within this fraction elucidates pathway-specific alterations in ALD impaired glycosylation. Among the identified proteins, triacylglycerol hydrolase (TGH) is positively affected by glycosylation, showing increased activity following the addition of sugar moieties. Impaired TGH activity is associated with increased cellular storage of lipids and provides a potential mechanism for the observed pathologies associated with ALD. PMID- 21319788 TI - Study on the phase transition behavior of poly(butylene adipate) in its blends with poly(vinyl phenol). AB - The phase transition behavior of poly(butylene adipate) (PBA) crystals in its blends with poly(vinyl phenol) (PVPh) was investigated by infrared (IR) spectroscopy and X-ray diffraction (XRD). The IR and XRD studies indicate that the hydrogen bonding between the C?O group of PBA and the OH group of PVPh developed in the PBA/PVPh blends with the ratios of 80/20 and 50/50 does not influence the solution crystallization behavior of PBA. The phase transition behavior of PBA in the blends is, however, significantly altered by the blending. In the neat PBA, linear changes of the intensities of IR bands at 1077, 930, and 910 cm(-1) are observed in the temperature range of 25-47.5 degrees C followed by an abrupt change corresponding to the occurrence of beta-to-alpha phase transition. In the blends, the accelerated intensity changes of the those IR bands occur before the beta-to-alpha phase transition, which is contributed to the melting of imperfect beta-PBA crystals at relatively lower temperature. In addition, the significantly depressed beta-to-alpha phase transition temperature is also identified. PMID- 21319789 TI - Controlled photophysical behaviors between dibenzo-24-crown-8 bearing terpyridine moiety and fullerene-containing ammonium salt. AB - A novel [2]pseudorotaxane was successfully constructed by the complexation of dibenzo[24]-crown-8 (DB24C8) derivative bearing terpyridine moiety (1) with lanthanide ion (Tb(3+)) and fullerene-containing ammonium salt (2), exhibiting the controlled photophysical behaviors as a reversible luminescent lanthanide switch in the presence of K(+) or 18-crown-6 (18C6). PMID- 21319790 TI - Coordination chemistry of N-heterocyclic stannylenes: a combined synthetic and Mossbauer spectroscopy study. AB - The N-heterocyclic stannylenes (NHSns), [(Dipp) N(CH(2))(n)N(Dipp)S n] (Dipp = 2,6- (i)Pr(2)C(6)H(3); n = 2, 1; n = 3, 5) and [((t)Bu) N(CHMe)(2)N((t)Bu)S n] (10) are competent ligands toward a variety of transition metal centers, as seen in the complexes [W(CO)(5).1] (2), [(OC)(4)Fe(MU-1)(2)Fe(CO)(4)] (3), [(OC)(4)Fe(MU-1)Fe(CO)(4)] (4), [Fe(CO)(4).5](n) (6, n = 1 or 2), [(OC)(4)Fe(MU 5)Fe(CO)(4)] (7), [Ph(3)PPt(MU-1)(2)PtPPh(3)] (8), [Fe(CO)(4).10] (11), and [(eta(5)-C(5)H(5))(OC)(2)Mn.10] (12). X-ray crystallographic studies show that the NHSns are structurally largely unperturbed binding to the metal, but in contrast to the parent NHCs, NHSns often adopt a bridging position across dinuclear metal units. The balance between terminal and bridging positions for the stannylene is evidently closely balanced as shown by the observation of both monomers and dimers for 6 in the solid state and in solution. (119)Sn and (57)Fe Mossbauer spectroscopy of the complexes shows the tin atoms in such complexes to be consistent with electron deficient Sn(II) centers. PMID- 21319791 TI - LRET-based biodetection of DNA release in live cells using surface-modified upconverting fluorescent nanoparticles. AB - In this work, we demonstrate near-infrared-to-visible upconverting fluorescent nanoparticles as a promising platform for lanthanide-based or luminescence resonance energy transfer (LRET)-based biodetection of DNA release in live cells. Highly monodispersed, stable aqueous suspension of nanoparticles, surface functionalized with amino groups for binding to DNA, were prepared and characterized. These amino-functionalized nanoparticles were able to electrostatically bind to DNA and protect it from DNaseI degradation as shown by gel electrophoresis. Attachment of DNA to the nanoparticles was also confirmed by LRET, which was observed to occur between the donor nanoparticle and acceptor POPO-3 dye intercalating the DNA. The intrinsic fluorescence property of upconverting fluorescent nanoparticles makes them useful for tracking their cellular localization without the use of any additional fluorescent tag. We were able to track the movement of these DNA-loaded nanoparticles into the cell cytoplasm where they successfully released their genetic cargo. Successful transfection of the loaded DNA material in vitro and in vivo was confirmed by expression of its encoded green fluorescent protein (GFP) in Hela cells and induction of specific antibody in mice, respectively. PMID- 21319792 TI - Comparative proteomic analysis of lung tissue from patients with idiopathic pulmonary fibrosis (IPF) and lung transplant donor lungs. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease for which no effective therapy exists to date. To identify the molecular mechanisms underlying IPF, we performed comparative proteome analysis of lung tissue from patients with sporadic IPF (n = 14) and human donor lungs (controls, n = 10) using two-dimensional gel electrophoresis and MALDI-TOF-MS. Eighty-nine differentially expressed proteins were identified, from which 51 were up regulated and 38 down-regulated in IPF. Increased expression of markers for the unfolded protein response (UPR), heat-shock proteins, and DNA damage stress markers indicated a chronic cell stress-response in IPF lungs. By means of immunohistochemistry, induction of UPR markers was encountered in type-II alveolar epithelial cells of IPF but not of control lungs. In contrast, up regulation of heat-shock protein 27 (Hsp27) was exclusively observed in proliferating bronchiolar basal cells and associated with aberrant re epithelialization at the bronchiolo-alveolar junctions. Among the down-regulated proteins in IPF were antioxidants, members of the annexin family, and structural epithelial proteins. In summary, our results indicate that IPF is characterized by epithelial cell injury, apoptosis, and aberrant epithelial proliferation. PMID- 21319793 TI - Nox5 forms a functional oligomer mediated by self-association of its dehydrogenase domain. AB - Nox5 belongs to the calcium-regulated subfamily of NADPH oxidases (Nox). Like other calcium-regulated Noxes, Nox5 has an EF-hand-containing calcium-binding domain at its N-terminus, a transmembrane heme-containing region, and a C terminal dehydrogenase (DH) domain that binds FAD and NADPH. While Nox1-4 require regulatory subunits, including p22phox, Nox5 activity does not depend on any subunits. We found that inactive point mutants and truncated forms of Nox5 (including the naturally expressed splice form, Nox5S) inhibit full-length Nox5, consistent with formation of a dominant negative complex. Oligomerization of full length Nox5 was demonstrated using co-immunoprecipitation of coexpressed, differentially tagged forms of Nox5 and occurred in a manner independent of calcium ion. Several approaches were used to show that the DH domain mediates oligomerization: Nox5 could be isolated as a multimer when the calcium-binding domain and/or the N-terminal polybasic region (PBR-N) was deleted, but deletion of the DH domain eliminated oligomerization. Further, a chimera containing the transmembrane domain of Ciona intestinalis voltage sensor-containing phosphatase (CiVSP) fused to the Nox5 DH domain formed a co-immunoprecipitating complex with, and functioned as a dominant inhibitor of, full-length Nox5. Radiation inactivation of Nox5 overexpressed in HEK293 cells and endogenously expressed in human aortic smooth muscle cells indicated molecular masses of ~350 and ~300 kDa, respectively, consistent with a tetramer being the functionally active unit. Thus, Nox5 forms a catalytically active oligomer in the membrane that is mediated by its dehydrogenase domain. As a result of oligomerization, the short, calcium independent splice form, Nox5S, may function as an endogenous inhibitor of calcium-stimulated ROS generation by full-length Nox5. PMID- 21319794 TI - Redox-cycling and H2O2 generation by fabricated catecholic films in the absence of enzymes. AB - Phenolic matrices are ubiquitous in nature (e.g., lignin, melanin, and humics) but remain largely intractable to characterize. We examined an abiotic phenol polysaccharide matrix fabricated by the anodic grafting of catechol to chitosan films. Previous studies have shown that catechol-modified chitosan films are redox-active and can be repeatedly interconverted between oxidized and reduced states. Here we developed quantitative electrochemical methods to characterize biorelevant redox properties of the catechol-modified chitosan films. Our analysis demonstrates that these films can (i) accept electrons from biological reductants (e.g., ascorbate and nicotinamide adenine dinucleotide phosphate, NADPH) and (ii) donate electrons in a model biological oxidation process. Furthermore, these films can donate electrons to O(2) to generate H(2)O(2). The demonstration that abiotic catechol-chitosan films possess catalytic activities in the absence of enzymes suggests the possibility that phenolic matrices may play an important role in redox cycling and reactive oxygen species (ROS) signaling in biology and the environment. PMID- 21319795 TI - Helical hairpin structure of influenza hemagglutinin fusion peptide stabilized by charge-dipole interactions between the N-terminal amino group and the second helix. AB - The fusion domain of the influenza coat protein hemagglutinin HA2, bound to dodecyl phosphocholine micelles, was recently shown to adopt a structure consisting of two antiparallel alpha-helices, packed in an exceptionally tight hairpin configuration. Four interhelical H(alpha) to C?O aliphatic H-bonds were identified as factors stabilizing this fold. Here, we report evidence for an additional stabilizing force: a strong charge-dipole interaction between the N terminal Gly(1) amino group and the dipole moment of helix 2. pH titration of the amino-terminal (15)N resonance, using a methylene-TROSY-based 3D NMR experiment, and observation of Gly(1 13)C' show a strongly elevated pK = 8.8, considerably higher than expected for an N-terminal amino group in a lipophilic environment. Chemical shifts of three C-terminal carbonyl carbons of helix 2 titrate with the protonation state of Gly(1)-N, indicative of a close proximity between the N terminal amino group and the axis of helix 2, providing an optimal charge-dipole stabilization of the antiparallel hairpin fold. pK values of the side-chain carboxylate groups of Glu(11) and Asp(19) are higher by about 1 and 0.5 unit, respectively, than commonly seen for solvent-exposed side chains in water-soluble proteins, indicative of dielectric constants of epsilon = ~30 (Glu(11)) and ~60 (Asp(19)), placing these groups in the headgroup region of the phospholipid micelle. PMID- 21319797 TI - Metadynamics study of a beta-hairpin stability in mixed solvents. AB - Understanding the molecular mechanisms that allow some organisms to survive in extremely harsh conditions is an important achievement that might disclose a wide range of applications and that is constantly drawing the attention of many research fields. The high adaptability of these living creatures is related to the presence in their tissues of a high concentration of osmoprotectants, small organic, highly soluble molecules. Despite osmoprotectants having been known for a long time, a full disclosure of the machinery behind their activity is still lacking. Here we describe a computational approach that, taking advantage of the recently developed metadynamics technique, allows one to fully describe the free energy surface of a small beta-hairpin peptide and how it is affected by an osmoprotectant, glycine betaine (GB) and for comparison by urea, a common denaturant. Simulations led to relevant thermodynamic information, including how the free energy difference of denaturation is affected by the two cosolvents; unlike urea, GB caused a considerable increase of the folded basin stability, which transposes into a higher melting temperature. NMR experiments confirmed the picture derived from the theoretical study. Further molecular dynamics simulations of selected conformations allowed investigation into deeper detail the role of GB in folded state protection. Simulations of the protein in GB solutions clearly showed an excess of osmoprotectant in the solvent bulk, rather than in the protein domain, confirming the exclusion from the protein surface, but also highlighted interesting features on its interactions, opening to new scenarios besides the classic "indirect mechanism" hypothesis. PMID- 21319796 TI - Conformationally constrained macrocyclic diporphyrin-fullerene artificial photosynthetic reaction center. AB - Photosynthetic reaction centers convert excitation energy from absorbed sunlight into chemical potential energy in the form of a charge-separated state. The rates of the electron transfer reactions necessary to achieve long-lived, high-energy charge-separated states with high quantum yields are determined in part by precise control of the electronic coupling among the chromophores, donors, and acceptors and of the reaction energetics. Successful artificial photosynthetic reaction centers for solar energy conversion have similar requirements. Control of electronic coupling in particular necessitates chemical linkages between active component moieties that both mediate coupling and restrict conformational mobility so that only spatial arrangements that promote favorable coupling are populated. Toward this end, we report the synthesis, structure, and photochemical properties of an artificial reaction center containing two porphyrin electron donor moieties and a fullerene electron acceptor in a macrocyclic arrangement involving a ring of 42 atoms. The two porphyrins are closely spaced, in an arrangement reminiscent of that of the special pair in bacterial reaction centers. The molecule is produced by an unusual cyclization reaction that yields mainly a product with C(2) symmetry and trans-2 disubstitution at the fullerene. The macrocycle maintains a rigid, highly constrained structure that was determined by UV-vis spectroscopy, NMR, mass spectrometry, and molecular modeling at the semiempirical PM6 and DFT (B3LYP/6-31G**) levels. Transient absorption results for the macrocycle in 2-methyltetrahydrofuran reveal photoinduced electron transfer from the porphyrin first excited singlet state to the fullerene to form a P(*+)-C(60)(*-)-P charge separated state with a time constant of 1.1 ps. Photoinduced electron transfer to the fullerene excited singlet state to form the same charge-separated state has a time constant of 15 ps. The charge separated state is formed with a quantum yield of essentially unity and has a lifetime of 2.7 ns. The ultrafast charge separation coupled with charge recombination that is over 2000 times slower is consistent with a very rigid molecular structure having a small reorganization energy for electron transfer, relative to related porphyrin-fullerene molecules. PMID- 21319798 TI - Temperature dependence of spin-selective charge transfer pathways in donor-bridge acceptor molecules with oligomeric fluorenone and p-phenylethynylene bridges. AB - The temperature dependence of spin-selective intramolecular charge recombination (CR) in a series of 2,7-fluorenone (FN(1-2)) and p-phenylethynylene (PE(1-2)P) linked donor-bridge-acceptor molecules with a 3,5-dimethyl-4-(9-anthracenyl) julolidine (DMJ-An) electron donor and a naphthalene-1,8:4,5-bis(dicarboximide) (NI) acceptor was studied using nanosecond transient absorption spectroscopy in the presence of a static magnetic field. Photoexcitation of DMJ-An into its charge transfer band and subsequent electron transfer to NI results in a nearly quantitative yield of (1)(DMJ(+*)-An-FN(n)-NI(-*)) and (1)(DMJ(+*)-An-PE(n)P-NI( *)), which undergo rapid radical pair intersystem crossing (RP-ISC) to produce the triplet RPs, (3)(DMJ(+*)-An-FN(n)-NI(-*)) and (3)(DMJ(+*)-An-PE(n)P-NI(-*)), respectively. The CR rate constants, k(CR), in toluene were measured over a temperature range from 270 to 350 K, and a kinetic analysis of k(CR) in the presence of an applied static magnetic field was used to extract the singlet and triplet charge recombination rate constants, k(CRS) and k(CRT), respectively, as well as the intersystem crossing rate constant, k(ST). Plots of ln (kT(1/2)) versus 1/T for PE(1)P show a distinct crossover at 300 K from a temperature independent singlet CR pathway to a triplet CR pathway that is positively activated with a barrier of 1047 +/- 170 cm(-1). The singlet CR pathway via the FN(1) bridge displays a negative activation energy that results from donor-bridge and bridge-acceptor torsional motions about the single bonds joining them. In contrast, the triplet CR pathway via the FN(1-2) and PE(1-2)P bridges exhibits positive activation energies. The activation barriers to these torsional motions range from 1100 to 4500 cm(-1) and can be modeled by semiclassical electron transfer theory. PMID- 21319799 TI - Macrocyclic hosts for fullerenes: extreme changes in binding abilities with small structural variations. AB - Exploiting the shape and electronic complementarity of C(60) and C(70) with pi extended derivatives of tetrathiafulvalene (exTTF), we have very recently reported a macrocyclic receptor featuring two exTTF recognizing units which forms 1:1 complexes with C(60) with log K(a) = 6.5 +/- 0.5 in chlorobenzene at 298 K. This represents one of the highest binding constants toward C(60) reported to date and a world-record for all-organic receptors. Here, we describe our efforts to fine-tune our macrocyclic bis-exTTF hosts to bind C(60) and/or C(70), through structural variations. On the basis of preliminary molecular modeling, we have explored p-xylene, m-xylene, and 2,6-dimethylnaphthalene as aromatic spacers between the two exTTF fragments and three alkene-terminated chains of different length to achieve macrocycles of different size through ring closing metathesis. Owing to the structural simplicity of our design, all nine receptors could be accessed in a synthetically straightforward manner. A thorough investigation of the binding abilities of these nine receptors toward C(60) and C(70) has been carried out by means of UV-vis titrations. We have found that relatively small variations in the structure of the host lead to very significant changes in affinity toward the fullerene, and in some cases even in the stoichiometry of the associates. Our results highlight the peculiarities of fullerenes as guests in molecular recognition. The extreme stability of these associates in solution and the unique combination of electronic and geometrical reciprocity of exTTF and fullerenes are the main features of this new family of macrocyclic hosts for fullerenes. PMID- 21319800 TI - Synthesis and biological evaluation of analogues of AKT (protein kinase B) inhibitor-IV. AB - Inhibitors of the PI3-kinase/AKT (protein kinase B) pathway are under investigation as anticancer and antiviral agents. The benzimidazole derivative AKT inhibitor-IV (ChemBridge 5233705) affects this pathway and exhibits potent anticancer and antiviral activity. To probe its biological activity, we synthesized AKT inhibitor-IV and 21 analogues using a novel six-step route based on ZrCl(4)-catalyzed cyclization of 1,2-arylenediamines with alpha,beta unsaturated aldehydes. We examined effects on viability of HeLa carcinoma cells, viability of normal human cells (NHBE), replication of recombinant parainfluenza virus 5 (PIV5) in HeLa cells, and replication of the intracellular bacterium Mycobacterium fortuitum in HeLa cells. Replacement of the benzimidazole N-ethyl substitutent of AKT inhibitor-IV with N-hexyl and N-dodecyl groups enhanced antiviral activity and cytotoxicity against the cancer cell line, but these compounds showed substantially lower toxicity (from 6-fold to >20-fold) against NHBE cells and no effect on M. fortuitum, suggesting inhibition of one or more host protein(s) required for proliferation of cancer cells and PIV5. The key structural elements identified here may facilitate identification of targets of this highly biologically active scaffold. PMID- 21319801 TI - Synthesis of 2-(substituted phenyl)-3,5,5-trimethylmorpholine analogues and their effects on monoamine uptake, nicotinic acetylcholine receptor function, and behavioral effects of nicotine. AB - Toward development of smoking cessation aids superior to bupropion (2), we describe synthesis of 2-(substituted phenyl)-3,5,5-trimethylmorpholine analogues 5a-5h and their effects on inhibition of dopamine, norepinephrine, and serotonin uptake, nicotinic acetylcholine receptor (nAChR) function, acute actions of nicotine, and nicotine-conditioned place preference (CPP). Several analogues encompassing aryl substitutions, N-alkylation, and alkyl extensions of the morpholine ring 3-methyl group provided analogues more potent in vitro than (S,S) hydroxybupropion (4a) as inhibitors of dopamine or norepinephrine uptake and antagonists of nAChR function. All of the new (S,S)-5 analogues had better potency than (S,S)-4a as blockers of acute nicotine analgesia in the tail-flick test. Two analogues with highest potency at alpha3beta4*-nAChR and among the most potent transporter inhibitors have better potency than (S,S)-4a in blocking nicotine-CPP. Collectively, these findings illuminate mechanisms of action of 2 analogues and identify deshydroxybupropion analogues 5a-5h as possibly superior candidates as aids to smoking cessation. PMID- 21319802 TI - Non-nucleoside inhibitors of human adenosine kinase: synthesis, molecular modeling, and biological studies. AB - Adenosine kinase (AK) catalyzes the phosphorylation of adenosine (Ado) to AMP by means of a kinetic mechanism in which the two substrates Ado and ATP bind the enzyme in a binary and/or ternary complex, with distinct protein conformations. Most of the described inhibitors have Ado-like structural motifs and are nonselective, and some of them (e.g., the tubercidine-like ligands) are characterized by a toxic profile. We have cloned and expressed human AK (hAK) and searched for novel non-substrate-like inhibitors. Our efforts to widen the structural diversity of AK inhibitors led to the identification of novel non nucleoside, noncompetitive allosteric modulators characterized by a unique molecular scaffold. Among the pyrrolobenzoxa(thia)zepinones (4a-qq) developed, 4a was identified as a non-nucleoside prototype hAK inhibitor. 4a has proapoptotic efficacy, slight inhibition of short-term RNA synthesis, and cytostatic activity on tumor cell lines while showing low cytotoxicity and no significant adverse effects on short-term DNA synthesis in cells. PMID- 21319803 TI - Increased bioavailability of tricin-amino acid derivatives via a prodrug approach. AB - Tricin (4',5,7-trihydroxy-3',5'-dimethoxyflavone) has demonstrated diverse biological activities. This compound has a high anti-human cytomegalovirus (HCMV) activity; however, its oral availability is low. To improve its bioavailability, we synthesized tricin-amino acid derivatives as prodrugs and investigated their cell permeability, stability in vitro, and oral availability in vivo. The results demonstrated that the tricin-alanine-glutamic acid conjugate exhibited enhanced permeability, stability in MDCK cells, and excellent bioavailability after oral administration in Crl:CD (SD) male rats. Tricin-alanine-glutamic acid conjugate is a potential new anti-HCMV drug. PMID- 21319804 TI - Characterization of unusual proanthocyanidins in leaves of bayberry ( Myrica rubra Sieb. et Zucc.). AB - Extractable and unextractable proanthocyanidins (EPAs and UEPAs) from leaves of bayberry were characterized. Both EPAs and UEPAs were analyzed by acid catalysis in the presence of excess phloroglucinol. The main cleavage product, epigallocatechin-3-O-gallate-(4beta->2)-phloroglucinol, was successfully identified. The EPAs were of the prodelphinidin type. In fact, epigallocatechin-3 O-gallate (EGCG) and traces of epigallocatechin (EGC) were detected as the extension units, but only EGCG was present in the terminal units. All of the compounds exhibited a 2,3-cis configuration, and >98% of them were galloylated. The mean degree of polymerization (mDP) of bayberry leaf EPAs was 6.5, and the most abundant EPAs were the polymers, with mDP values of 9.5-26.7. The UEPAs were highly polymerized prodelphinidins consisting of EGCG and traces of EGC. In addition, EGCG, three EPA dimers, and two trimers were identified. The EPAs and UEPAs consisted mostly of EGCG, which is unusual in the plant kingdom. PMID- 21319805 TI - Analysis of the effect of temperature changes combined with different alkaline pH on the beta-lactoglobulin trypsin hydrolysis pattern using MALDI-TOF-MS/MS. AB - Temperature and pH influence the conformation of the whey protein beta lactoglobulin (beta-Lg) monomer, dimer, and octamer formation, its denaturation, and solubility. Most hydrolyses have been reported at trypsin (EC 3.4.21.4) optimum conditions (pH 7.8 and 37 degrees C), while the hydrolysate mass spectrometry was largely limited to peptides with <4 kDa. There are few reports on trypsin peptide release patterns away from optimum. This work investigated the influence of alkaline (8.65 and 9.5) and optimum (7.8) pH at different temperatures (25, 37.5, and 50 degrees C) on beta-Lg (7.5%, w/v) hydrolysis. Sample aliquots were drawn out before the addition of trypsin (blank sample) and at various time intervals (15 s to 10 min) thereafter. Matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry (MALDI-TOF-MS/MS) was used to monitor peptide evolution over time with the use of two matrixes: alpha-cyano-4-hydroxycinnamic acid (HCCA) and 2.5-dihydroxyacetophenone (DHAP). Mass analysis showed that the N- and C-terminals (Lys(8)-Gly(9), Lys(100) Lys(101), Arg(124)-Thr(125), Lys(141)-Ala(142), and Arg(148)-Leu(149)) of beta-Lg were cleaved early (15 s) implying the ease of trypsinolysis at the exposed terminals. Hydrolyses at 25 degrees C and pH 7.8 as well as at 50 degrees C and pH 9.5 were slowed down and ordered. Nonspecific chymotrypsin-like behavior occurred more at higher temperatures (50 degrees C) than at lower ones (25 and 37.5 degrees C). In addition to our earlier work in the acid pH region, it can be concluded that there is potential for controlled hydrolysis outside the trypsin optimum, where different target peptides with predictable biofunctionalities could be produced. PMID- 21319806 TI - Pigment metabolism of 'Sikitita' olive ( Olea europaea L.): a new cultivar obtained by cross-breeding. AB - The new olive cultivar 'Sikitita' was obtained from a cross between the 'Picual' and 'Arbequina' varieties. 'Sikitita' was selected for its features, making it particularly suited to high-density olive hedgerow orchards. From the standpoint of chloroplast pigment metabolism, the fruits of the 'Picual' and 'Arbequina' varieties have significant differences. It is therefore extremely interesting to analyze the descendants of both cultivars. With regard to chlorophyll catabolism, 'Sikitita' has proven to be a cultivar with low pigmentation and low levels of chlorophyllase activity. This is contrary to the findings obtained to date, where varieties with low pigmentation are a consequence of high chlorophyllase activity ('Arbequina') and highly pigmented fruits are due to low chlorophyllase activity ('Picual'). 'Arbequina' was, until recently, the only cultivar described that had developed a carotenogenic process, despite its anthocyanic ripening. However, from its father ('Arbequina'), the 'Sikitita' cultivar has inherited the pool of enzymes necessary to esterify xanthophylls at the chromoplast level. This makes 'Sikitita' a very interesting cultivar, with potential chemotaxonomic differences (such as esterified xanthophylls in the olive oils), and demonstrates the interest in genetic improvement programs for olive cultivars with different organoleptic characteristics. PMID- 21319807 TI - Changes in hydrophilic and lipophilic antioxidant activity in relation to their phenolic composition during the chamber drying of red grapes at a controlled temperature. AB - The purpose of this work was to study the variation of phenol compounds, as measured by HPLC, during the chamber drying under controlled temperature conditions of red grapes of the Merlot and Tempranillo varieties in relation to antioxidant activity. Both lipophilic and hydrophilic antioxidant activities in these grapes increased during the drying process; the former was measured via proton transfer in the coupled oxidation reaction between linoleic acid and beta carotene, and the second via electron transfer in the DPPH assay. The hydrophilic component was invariably greater in Tempranillo grapes, and so was the lipophilic component in Merlot grapes. Only the increase in hydrophilic antioxidant activity obtained a significant correlation with the phenolic compounds during the drying process. However, based on the phenolic fraction analysis, this result was primarily due to phenolic polymers and, to a lesser extent, also to phenolic acids, flavans, and some flavonols and anthocyans. PMID- 21319808 TI - High-throughput selection, enumeration, electrokinetic manipulation, and molecular profiling of low-abundance circulating tumor cells using a microfluidic system. AB - A circulating tumor cell (CTC) selection microfluidic device was integrated to an electrokinetic enrichment device for preconcentrating CTCs directly from whole blood to allow for the detection of mutations contained within the genomic DNA of the CTCs. Molecular profiling of CTCs can provide important clinical information that cannot be garnered simply by enumerating the selected CTCs. We evaluated our approach using SW620 and HT29 cells (colorectal cancer cell lines) seeded into whole blood as a model system. Because SW620 and HT29 cells overexpress the integral membrane protein EpCAM, they could be immunospecifically selected using a microfluidic device containing anti-EpCAM antibodies immobilized to the walls of a selection bed. The microfluidic device was operated at an optimized flow rate of 2 mm s(-1), which allowed for the ability to process 1 mL of whole blood in <40 min. The selected CTCs were then enzymatically released from the antibody selection surface and hydrodynamically transported through a pair of Pt electrodes for conductivity-based enumeration. The efficiency of CTC selection was found to be 96% +/- 4%. Following enumeration, the CTCs were hydrodynamically transported at a flow rate of 1 MUL min(-1) to an on-chip electromanipulation unit, where they were electrophoretically withdrawn from the bulk hydrodynamic flow and directed into a receiving reservoir. Using an electric field of 100 V cm(-1), the negatively charged CTCs were enriched into an anodic receiving reservoir to a final volume of 2 MUL, providing an enrichment factor of 500. The collected CTCs could then be searched for point mutations using a PCR/LDR/capillary electrophoresis assay. The DNA extracted from the CTCs was subjected to a primary polymerase chain reaction (PCR) with the amplicons used for a ligase detection reaction (LDR) to probe for KRAS oncogenic point mutations. Point mutations in codon 12 of the KRAS gene were successfully detected in the SW620 CTCs for samples containing <10 CTCs in 1 mL of whole blood. However, the HT29 cells did not contain these mutations, consistent with their known genotype. PMID- 21319809 TI - Bioinspired polymerization of dopamine to generate melanin-like nanoparticles having an excellent free-radical-scavenging property. AB - Melanin-like nanoparticles were synthesized with size control through neutralization of dopamine hydrochloride with NaOH, followed by spontaneous air oxidation of dopamine. Although the particle characteristic of natural melanins was understood to be significantly affected by the biological and structural environment, melanin-lke nanoparticles can be realized through the chemical reactions only. Melanin-like nanoparticles that are <100 nm showed excellent dispersion stability in water as well as biological media and good biocompatibility to HeLa cells after the appropriate surface modification with thiol-terminated methoxy-poly(ethylene glycol) (mPEG-SH). Furthermore, the demonstrated ability of melanin-like nanoparticles to reduce 2,2-diphenyl-1 picrylhydrazyl (DPPH) suggests free radical scavenging activity of the material. PMID- 21319810 TI - Direct analysis in real time coupled to multiplexed drift tube ion mobility spectrometry for detecting toxic chemicals. AB - Current and future chemical threats to homeland security motivate the need for new chemical detection systems to provide border, transportation, and workplace security. We present the first successful coupling of a commercial direct analysis in real time (DART) ion source to a resistive glass monolithic drift tube ion mobility spectrometer (DTIMS) as the basis for a low maintenance, versatile, and robust chemical monitoring system. in situ ionization within the electric field gradient of the instrument enhances sensitivity and provides a safe sampling strategy. The instrument uses nitrogen as both the DART discharge and DTIMS drift gases, allowing for a high electric field to be used for ion separation while keeping cost-of-use low. With the use of a traditional signal averaging acquisition mode, the 95% probability of detection (POD) for analytes sampled from melting point capillary tubes was 11.81% v/v for DMMP, 1.13% v/v for 2-CEES, and 10.61 mM for methamidophos. Sensitivity was improved via a prototype transmission-mode geometry interface, resulting in an almost 2 orders of magnitude decrease in the POD level for DMMP (0.28% v/v). As an alternative to transmission mode operation, digital multiplexing of the DTIMS ion injection step was also implemented, finding a 3-fold improvement in signal-to-noise ratios for 200 MUs gate injections and a 4.5-fold for 400 MUs gate injections. PMID- 21319811 TI - Coordination features and affinity of the Cu2+ site in the alpha-synuclein protein of Parkinson's disease. AB - Parkinson's disease (PD) is the second most prevalent age-related, neurodegenerative disorder, affecting >1% of the population over the age of 60. PD pathology is marked by intracellular inclusions composed primarily of the protein alpha-synuclein (alpha-syn). These inclusions also contain copper, and the interaction of Cu(2+) with alpha-syn may play an important role in PD fibrillogenesis. Here we report the stoichiometry, affinity, and coordination structure of the Cu(2+)-alpha-syn complex. Electron paramagnetic resonance (EPR) titrations show that monomeric alpha-syn binds 1.0 equiv of Cu(2+) at the protein N-terminus. Next, an EPR competition technique demonstrates that alpha-syn binds Cu(2+) with a K(d) of ~0.10 nM. Finally, EPR and electron spin echo modulation (ESEEM) applied to a suite of mutant and truncated alpha-syn constructs reveal a coordination sphere arising from the N-terminal amine, the Asp2 amide backbone and side chain carboxyl group, and the His50 imidazole. The high binding affinity identified here, in accord with previous measurements, suggests that copper uptake and sequestration may be a part of alpha-syn's natural function, perhaps modulating copper's redox properties. The findings further suggest that the long range interaction between the N-terminus and His50 may have a weakening effect on the interaction of alpha-syn with lipid membranes, thereby mobilizing monomeric alpha-syn and hastening fibrillogenesis. PMID- 21319812 TI - Layer-by-layer films made from extracellular matrix macromolecules on silicone substrates. AB - The layer-by-layer (LbL) technique has been widely used to produce nanofilms for biomedical applications. Naturally occurring polymers such as ECM macromolecules are attractive candidates for LbL film preparation. In this study, we assessed the build-up of type I collagen (Col1)/chondroitin sulfate (CS) or Col1/Heparin (HN) on polydimethylsiloxane (PDMS) substrates. The build-up was assessed by quartz crystal microbalance with dissipation (QCM-D) and atomic force microscopy (AFM). Integrin-mediated cell adhesion was assessed by studying the cytoskeletal organization of mammalian primary cells (chondrocytes) seeded on different end layers and number of layers. Data generated from the QCM-D observations showed a consistent build-up of films with more adsorption in the case of Col1/HN. Col1/CS films were stable in media, whereas Col1/HN films were not. AFM analysis showed that the layers were fibrillar in structure for both systems and between 20 and 30 nm thick. The films promoted cell adhesion when compared with tissue culture plastic in serum-free media with cycloheximide. Crosslinking of the films resulted in constrained cell spreading and a ruffled morphology. Finally, beta1 integrin blocking antibodies prevented cell spreading, suggesting that cell adhesion and spreading were mediated mainly by interaction with the collagen fibrils. The ability to construct stable ECM-based films on PDMS has particular relevance in mechanobiology, microfluidics, and other biomedical applications. PMID- 21319813 TI - Copolymers from unsaturated macrolactones: toward the design of cross-linked biodegradable polyesters. AB - The enzymatic synthesis of a series of random copolyesters by ring-opening polymerization of unsaturated macrolactones like globalide and ambrettolide with 1,5-dioxepan-2-one (DXO) and 4-methyl caprolactone (4MeCL) was investigated. (13)C NMR diad analysis confirmed the randomness of all copolymers irrespective of the comonomer ratios. Thermal investigation showed that incorporating the comonomers lowered the melting points of the polymers as compared with the macrolactone homopolymers. The decrease was dependent on the comonomer ratio. The unsaturated copolymers were thermally cross-linked using dicumyl peroxide, which resulted in completely amorphous insoluble networks. It was found that 10% incorporation of the unsaturated macolactone was sufficient to obtain a gel content of 95 wt %. Preliminary degradation tests confirm that the cross-linked copolymers are enzymatically degradable and that the incorporation of hydrophilic comonomers like DXO enhances degradation. PMID- 21319814 TI - Identification of 'carbon hot-spots' and quantification of GHG intensities in the biodiesel supply chain using hybrid LCA and structural path analysis. AB - It is expected that biodiesel production in the EU will remain the dominant contributor as part of a 10% minimum binding target for biofuel in transportation fuel by 2020 within the 20% renewable energy target in the overall EU energy mix. Life cycle assessments (LCA) of biodiesel to evaluate its environmental impacts have, however, remained questionable, mainly because of the adoption of a traditional process analysis approach resulting in system boundary truncation and because of issues regarding the impacts of land use change and N(2)O emissions from fertilizer application. In this study, a hybrid LCA methodology is used to evaluate the life cycle CO(2) equivalent emissions of rape methyl ester (RME) biodiesel. The methodology uses input-output analysis to estimate upstream indirect emissions in order to complement traditional process LCA in a hybrid framework. It was estimated that traditional LCA accounted for 2.7 kg CO(2)-eq per kg of RME or 36.6% of total life cycle emissions of the RME supply chin. Further to the inclusion of upstream indirect impacts in the LCA system (which accounted for 23% of the total life cycle emissions), emissions due to direct land use change (6%) and indirect land use change (16.5%) and N(2)O emissions from fertilizer applications (17.9%) were also calculated. Structural path analysis is used to decompose upstream indirect emissions paths of the biodiesel supply chain in order to identify, quantify, and rank high carbon emissions paths or 'hot-spots' in the biodiesel supply chain. It was shown, for instance, that inputs from the 'Other Chemical Products' sector (identified as phosphoric acid, H(3)PO(4)) into the biodiesel production process represented the highest carbon emission path (or hot-spot) with 5.35% of total upstream indirect emissions of the RME biodiesel supply chain. PMID- 21319815 TI - Effects of ionizing radiation and temperature on uranyl silicates: soddyite (UO2)2(SiO4)(H2O)2 and Uranophane Ca(UO2)2(SiO3OH)2.5H2O. AB - The stability of soddyite under electron irradiation has been studied over the temperature range of 25-300 degrees C. At room temperature, soddyite undergoes a crystalline-to-amorphous transformation (amorphization) at a total dose of 6.38 * 10(8) Gy. The electron beam irradiation results suggest that the soddyite structure is susceptible to radiation-induced nanocrystallization of UO(2). The temperature dependence of amorphization dose increases linearly up to 300 degrees C. A thermogravimetric and calorimetric analysis (TGA-DSC) combined with X-ray diffraction (XRD) indicates that soddyite retains its water groups up to 400 degrees C, followed by the collapse of the structure. Based on thermal analysis of uranophane, the removal of some water groups at relatively low temperatures provokes the collapse of the uranophane structure. This structural change appears to be the reason for the increase of amorphization dose at 140 degrees C. According to the results obtained, radiation field of a nuclear waste repository, rather than temperature effects, may cause changes in the crystallinity of soddyite and affect its stability during long-term storage. PMID- 21319816 TI - Dynamics of unfolded protein transport through an aerolysin pore. AB - Protein export is an essential mechanism in living cells and exported proteins are usually translocated through a protein-conducting channel in an unfolded state. Here we analyze, by electrical detection, the entry and transport of unfolded proteins, at the single molecule level, with different stabilities through an aerolysin pore, as a function of the applied voltage and protein concentration. The frequency of ionic current blockades varies exponentially as a function of the applied voltage and linearly as a function of protein concentration. The transport time of unfolded proteins decreases exponentially when the applied voltage increases. We prove that the ionic current blockade duration of a double-sized protein is longer than that assessed for a single protein supporting the transport phenomenon. Our results fit with the theory of confined polyelectrolyte and with some experimental results about DNA or synthetic polyelectrolyte translocation through protein channels as a function of applied voltage. We discuss the potential of the aerolysin nanopore as a tool for protein folding studies as it has already been done for alpha-hemolysin. PMID- 21319817 TI - The nature of surface barriers on nanoporous solids explored by microimaging of transient guest distributions. AB - Nanoporous solids are attractive materials for energetically efficient and environmentally friendly catalytic and adsorption separation processes. Although the performance of such materials is largely dependent on their molecular transport properties, our fundamental understanding of these phenomena is far from complete. This is particularly true for the mechanisms that control the penetration rate through the outer surface of these materials (commonly referred to as surface barriers). Recent detailed sorption rate measurements with Zn(tbip) crystals have greatly enhanced our basic understanding of such processes. Surface resistance in this material has been shown to arise from the complete blockage of most of the pore entrances on the outer surface, while the transport resistance of the remaining open pores is negligibly small. More generally, the revealed correlation between intracrystalline diffusion and surface permeation provides a new view of the nature of transport resistances in nanoporous materials acting in addition to the diffusion resistance of the regular pore network, leading to a rational explanation of the discrepancy which is often observed between microscopic and macroscopic diffusion measurements. PMID- 21319818 TI - Tuning the morphology of gold clusters by substrate doping. AB - The morphology of small metal clusters can have a big impact on their electronic, magnetic, and chemical properties. This has been shown earlier, for example, for Au(20) clusters on MgO(001), where planar and tetrahedral geometries are possible for the gold atoms. While the planar geometry is more desirable for catalytic applications, it is disfavored in the usual situation. While earlier suggestions that have been made for tilting this balance in favor of the planar isomer are of considerable fundamental interest, they do not easily lend themselves to practical applications. Here, we suggest a conceptually simple but practicable way of achieving the same goal: viz., by doping the MgO substrate with Al atoms. We show, by performing density functional theory calculations, that this stabilizes the planar over the tetrahedral arrangement by an energy difference that is linearly proportional to the dopant concentration and is insensitive to the position of the dopant atom. The charge transferred to the Au cluster also depends monotonically on the doping concentration. This work is of interest for possible applications in the field of gold nanocatalysis. PMID- 21319819 TI - On the origins of core-electron chemical shifts of small biomolecules in aqueous solution: insights from photoemission and ab initio calculations of glycine(aq). AB - The local electronic structure of glycine in neutral, basic, and acidic aqueous solution is studied experimentally by X-ray photoelectron spectroscopy and theoretically by molecular dynamics simulations accompanied by first-principle electronic structure and spectrum calculations. Measured and computed nitrogen and carbon 1s binding energies are assigned to different local atomic environments, which are shown to be sensitive to the protonation/deprotonation of the amino and carboxyl functional groups at different pH values. We report the first accurate computation of core-level chemical shifts of an aqueous solute in various protonation states and explicitly show how the distributions of photoelectron binding energies (core-level peak widths) are related to the details of the hydrogen bond configurations, i.e. the geometries of the water solvation shell and the associated electronic screening. The comparison between the experiments and calculations further enables the separation of protonation induced (covalent) and solvent-induced (electrostatic) screening contributions to the chemical shifts in the aqueous phase. The present core-level line shape analysis facilitates an accurate interpretation of photoelectron spectra from larger biomolecular solutes than glycine. PMID- 21319820 TI - Biomimetic crystallization of Ag2S nanoclusters in nanopore assemblies. AB - Self-organized nanocrystal architectures with subnanometric spatial resolution were obtained by mimicking the biological crystal growth. The key step of this facile, one-pot, biomimetic route is to induce the self-assembly of the artificial nanopore cucurbit[7]uril with metal ions, which generates supramolecular aggregates that recreate the physicochemical environment of biomineralization processes. The approach holds great promise for the fabrication of nanocrystal superstructures of functional materials, useful in optics, electronics, and catalysis. PMID- 21319821 TI - Manipulating photogenerated radical ion pair lifetimes in wirelike molecules using microwave pulses: molecular spintronic gates. AB - We have studied spin-dependent charge transfer dynamics in wirelike donor-bridge acceptor (D-B-A) molecules comprising a phenothiazine (PTZ) donor, an oligo(2,7 fluorene) (FL(n)) bridge, and a perylene-3,4:9,10-bis(dicarboximide) (PDI) acceptor, PTZ-FL(3)-PDI (1) and PTZ-FL(4)-PDI (2), dissolved in the magnetic field-aligned nematic phase of 4-cyano-4'-n-pentylbiphenyl (5CB) at 295 K. Time resolved EPR spectroscopy using both continuous wave and pulsed microwaves shows that the photogenerated radical pairs (RPs), PTZ(+*)-FL(3)-PDI(-*) and PTZ(+*) FL(4)-PDI(-*), recombine much faster from the singlet RP manifold than the triplet RP manifold. When a strong resonant microwave pi pulse is applied following RP photogeneration in 1 and 2, the RP lifetimes increase about 50-fold as indicated by electron spin-echo detection. This result shows that the RP lifetime can be greatly extended by rapidly switching off fast triplet RP recombination. PMID- 21319822 TI - Supramolecular control on chemo- and regioselectivity via encapsulation of (NHC) Au catalyst within a hexameric self-assembled host. AB - The encapsulation of a Au(I) catalyst within a self-assembled, hydrogen bonded, hexameric capsule dramatically changes its catalytic activity, leading to unusual products due to the steric requirements of the host's cavity. PMID- 21319823 TI - Sodium or lithium ion-binding-induced structural changes in the K-ring of V ATPase from Enterococcus hirae revealed by ATR-FTIR spectroscopy. AB - V-ATPase from Enterococcus hirae forms a large supramolecular protein complex (total molecular weight ~700,000) and physiologically transports Na(+) and Li(+) across a hydrophobic lipid bilayer. Stabilization of these cations in the binding site has been discussed on the basis of X-ray crystal structures of a membrane embedded domain, the K-ring (Na(+)- and Li(+)-bound forms). Here, sodium or lithium ion-binding-induced difference IR spectra of the intact V-ATPase have for the first time been measured at physiological temperature under a sufficient amount of hydration. The results suggest that sodium or lithium ion binding induces the deprotonation of Glu139, a hydrogen-bonding change in the tyrosine residue, and a small conformational change in the K-ring. These structural changes, especially the deprotonation of Glu139, are considered to be important for reducing energetic barriers to the transport of cations through the membrane. PMID- 21319824 TI - Chemically reversible four-electron oxidation and reduction utilizing two inorganic functional groups. AB - Four-electron oxidation of the quadruply bonded W(2)(II,II) compound W(2)(2,2' dipyridylamide)(4), 1, results in the formation of a novel, diamagnetic ditungsten terminal oxo compound [W(2)O(2,2'-dipyridylamide)(4)](2+), 2. In contrast to the chemical inertness of mononuclear tungsten oxo species, 2 undergoes a four-electron reduction including oxygen-atom transfer in reactions with excess tri-tert-butylphosphine in acetonitrile to recover 1. This unusual chemically reversible multielectron reactivity is ascribed to the cooperation of W-O and W-W multiple bonding. PMID- 21319825 TI - Unraveling the correlated dynamics of the double hydrogen bonds of nucleic acid base pairs in solution. AB - Quantum mechanics/molecular mechanics hybrid simulations (CPMD/GROMOS) of nonlinear infrared spectra are performed for a modified adenine-uracil base pair in CDCl(3) solution. Employing a mapping between hydrogen bond distances and fundamental as well as overtone transition frequencies on the basis of on-the-fly snapshot potential energy curves, energy gap correlation functions are established. These correlation functions are utilized to determine pump-probe and two-dimensional photon echo spectra. Analysis of the latter yields off-diagonal peaks signifying correlated fluctuations of the N-H...N and N-H...O hydrogen bonds. PMID- 21319826 TI - Evidence for the role of tetramethylethylenediamine in aqueous Negishi cross coupling: synthesis of nonproteinogenic phenylalanine derivatives on water. AB - The structure of the alkylzinc-tetramethylethyl-enediamine (TMEDA) cluster cation 3 has been determined in the gas phase by a combination of tandem mass spectrometry, infrared multiphoton dissociation (IRMPD) spectroscopy, and DFT calculations. Both sets of experimental results establish the existence of a strongly stabilizing interaction of TMEDA with the zinc cation. High-level DFT calculations on the alkylzinc-TMEDA cluster cation 3 allowed the identification of two low energy conformers, each featuring a four-coordinate zinc atom with a bidentate TMEDA ligand, and internal coordination from the carbonyl group of the Boc group to zinc. The experimental IRMPD spectrum is reproduced with an appropriately weighted combination of the IR spectra of the two conformers identified by theory. DFT calculations on the structure of the alkylzinc halide 2 with coordinated TMEDA using the PCM model of water solvent suggest that TMEDA can promote ionization of the zinc-iodine bond in organozinc iodides under aqueous conditions, providing a credible explanation for the role of TMEDA in stabilizing the carbon-zinc bond. Reaction of the serine-derived iodide 1 with aryl iodides "on water", promoted by nano zinc in the presence of PdCl(2)(Amphos)(2) (5 mol %) and TMEDA, leads to the formation of protected phenylalanine derivatives 4 in reasonable yields. In the case of ortho substituted aryl iodides and aryl iodides that are solids at room temperature, conducting the reaction at 65 degrees C gives improved results. In all cases, the product 5 of reductive dimerization of the iodide 1 is also isolated. PMID- 21319827 TI - Ions redistribution and meniscus relaxation during Langmuir wetting process. AB - Nonstationary kinetics of the ion redistribution within the meniscus region during deposition of a charged Langmuir monolayer after beginning or stopping of the substrate motion is analyzed on the basis of the results of numerical simulations. The time evolution of the ions concentration profiles forming at the contact line and propagating toward the bulk solution is considered. It is shown that the diffusion front propagates much slower within the region of overlapping diffuse layers than outside of this region. At the beginning of the deposition process a region characterized by quasi-stationary behavior of the ion concentration and electric potential distributions is formed in close vicinity to the contact line. A stationary deposition regime is established when the region of quasi-stationary distributions reaches the external boundary of the Nernst layer provided that the substrate motion is not very fast. For the substrate velocities higher than the critical one the concentration near the contact line can decrease to such small values which do not allow a stable deposition process. The developed mathematical model allows addressing to transient regimes of the monolayer deposition which are very important for understanding the mechanisms leading to meniscus instability. PMID- 21319828 TI - Nanostructured protic ionic liquids retain nanoscale features in aqueous solution while precursor Bronsted acids and bases exhibit different behavior. AB - Small- and wide-angle X-ray scattering (SWAXS) has been used to investigate the effect that water has on the nanoscale structure of protic ionic liquids (PILs) along with their precursor Bronsted acids and bases. The series of PILs consisted of primary, secondary, and tertiary alkylammonium cations in conjunction with formate, nitrate, or glycolate anions. Significant differences were observed for these systems. The nanoscale aggregates present in neat protic ionic liquids were shown to be stable in size on dilution to high concentrations of water, indicating that the water is localized in the ionic region and has little effect on the nonpolar domains. The Bronsted acid-water solutions did not display nanostructure at any water concentration. Primary amine Bronsted bases formed aggregates in water, which generally displayed characteristics of poorly structured microemulsions or a form of bicontinuous phase. Exceptions were butyl- and pentylamine with high water concentrations, for which the SWAXS patterns fitted well to the Teubner-Strey model for microemulsions. Bronsted base amines containing multiple alkyl chains or hydroxyl groups did not display nanostructure at any water concentration. IR spectroscopy was used to investigate the nature of water in the various solutions. For low PIL concentrations, the water was predominately present as bulk water for PIL molar fractions less than 0.4-0.5. At high PIL concentrations, in addition to the bulk water, there was a significant proportion of perturbed water, which is water influenced in some way by the cations and anions. The molecular state of the water in the studied amines was predominately present as bulk water, with smaller contributions from perturbed water than was seen in the PILs. PMID- 21319829 TI - Reducing lambda repressor to the core. AB - Lambda repressor fragment lambda(*)(6-85) is one of the fastest folding small protein fragments known to date. We hypothesized that removal of three out of five helices of lambda(*)(6-85) would further reduce this protein to its smallest folding core. Molecular dynamics simulations singled out two energetically stable reduced structures consisting of only helices 1 and 4 connected by a short glycine/serine linker, as well as a less stable control. We investigated these three polypeptides and their fragments experimentally by using circular dichroism, fluorescence spectroscopy, and temperature jump relaxation spectroscopy to gain insight into their thermodynamic and kinetic properties. Based on the thermal melts, the order of peptide stability was in correspondence with theoretical predictions. The most stable two-helix bundle, lambda(blue1), is a cooperatively folding miniprotein with the same melting temperature and folding rate as the full-length lambda(*)(6-85) pseudo wild type and a well-defined computed structure. PMID- 21319830 TI - Isolation and structural characterization of acrylamide-pyridoxamine adducts. AB - Pyridoxamine (PM) is an effective inhibitor of the formation of the carcinogen acrylamide (AA) from its precursors in low-moisture model systems. Although AA is widely assumed to act by scavenging carbonyl compounds, no alternative pathways have to date been explored. In this work, we found AA to directly react with PM in a low-moisture acrylamide-pyridoxamine model system heated at 140 degrees C for up to 40 min. The reaction products gave four major chromatographic peaks that were assigned to acrylamide-pyridoxamine adducts. Two of the adducts (AA-PM 1 and AA-PM-3) were selected for isolation and structural characterization with various spectroscopic (UV, fluorescence, IR, and NMR) and mass spectrometric techniques (MS, MS/MS). As shown by the proposed reaction scheme, PM can directly react with AA via Michael addition. The reaction involves a nucleophilic attack of the PM amine group on AA (an alpha,beta-unsaturated carbonyl compound) to give adduct AA-PM-3, which was identified as 3-(((3-hydroxy-5-(hydroxymethyl)-2 methylpyridin-4-yl)methyl)amino)propanamide. However, AA-PM-3 further reacts with any additional AA present in the medium to give adduct AA-PM-1 identified as 3,3' (((3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4 yl)methyl)azanediyl)dipropanamide. The time courses of these adduct formation reactions were studied in cookies supplemented with PM, where AA-PM-3 was found to be the predominant structure. PMID- 21319831 TI - Kinetics of 3-chlorotyrosine formation and loss due to hypochlorous acid and chloramines. AB - The persistent activation of innate immune cells in chronic inflammation is gaining recognition as a contributing factor in a number of human diseases. A distinguishing feature of activated leukocytes at sites of inflammation is their production of reactive species such as hypochlorous acid (HOCl). Investigating the role of reactive molecules such as HOCl in inflammation and human disease requires appropriate biomarkers. The preferred biomarker for HOCl, and by extension its synthesizing enzyme myeloperoxidase, is 3-chlorotyrosine. 3 Chlorotyrosine is a chemically stable product formed when HOCl, or an HOCl generated chloramine, reacts with the tyrosine side chain and is readily measured by sensitive mass spectrometry methods. However, Whiteman and Spencer ((2008) Biochem. Biophys. Res. Commun., 371, 50 - 53.) noted that 3-chlorotyrosine is degraded by HOCl, calling into question its use as a biomarker. The kinetic rate constants for the reaction of 3-chlorotyrosine with HOCl, histidine chloramine, or lysine chloramine to form 3,5-dichlorotyrosine are reported. The kinetics of tyrosine chlorination in the context of a peptide with a nearby lysine residue was also determined and further supports the role of chloramines in the chlorination of protein-bound tyrosine residues. The likelihood of free and protein-bound 3,5-dichlorotyrosine occurring in vivo, given the reported rate constants, is discussed. PMID- 21319832 TI - Palladium-catalyzed denitrogenation reaction of 1,2,3-benzotriazin-4(3H)-ones incorporating isocyanides. AB - 1,2,3-Benzotriazin-4(3H)-ones and 1,2,3,4-benzothiatriazine 1,1(2H)-dioxide reacted with isocyanides in the presence of a palladium catalyst to give 3 (imino)isoindolin-1-ones and 3-(imino)thiaisoindoline 1,1-dioxides, respectively, in high yield. An intermediate azapalladacycle was generated through denitrogenation of the triazine moiety, and an isocyanide was incorporated therein. PMID- 21319833 TI - Novel aerobic oxidation of primary sulfones to carboxylic acids. AB - Primary alkyl aryl sulfones are converted to the corresponding carboxylic acids in fair to excellent yield through double deprotonation and exposure to atmospheric oxygen. The methodology allows for the convenient synthesis of (13)C labeled carboxylic acids. PMID- 21319834 TI - Highly enantioselective direct vinylogous Michael addition of gamma-butenolide to enals. AB - An unprecedented and simple direct vinylogous addition of deconjugated butenolide to enals has been developed in excellent stereoselectivities (>95% ee), with Aminal-PYrrolidine (APY) catalyst. This methodology allows for the efficient preparation of complex gamma-butenolide from readily available renewable resources. Furthermore, preliminary mechanistic investigations have allowed for the better understanding of the origin of both stereoselectivities and of the observed high reactivities. PMID- 21319835 TI - Room temperature, metal-free synthesis of diaryl ethers with use of diaryliodonium salts. AB - A fast, high-yielding synthesis of diaryl ethers with use of mild and metal-free conditions has been developed. The scope includes bulky ortho-substituted diaryl ethers, which are difficult to obtain by metal-catalyzed protocols. Halo substituents, racemization-prone amino acid derivatives, and heteroaromatics are also tolerated. The methodology is expected to be of high utility in the synthesis of complex molecules and in the pharmaceutical industry. PMID- 21319836 TI - Efficient monophosphorus ligands for palladium-catalyzed Miyaura borylation. AB - In combination with the Bedford Pd precursor, the new biaryl monophosphorus ligand 5 was efficient for palladium-catalyzed Miyaura borylation of sterically hindered aryl bromides at low catalyst loadings. PMID- 21319837 TI - Diabolo nanoantenna for enhancing and confining the magnetic optical field. AB - In this Letter, we introduce a new nanoantenna concept aimed at generating a single magnetic hot spot in the optical frequency range, thus confining and enhancing the magnetic optical field on the background of a much lower electric field. This nanoantenna, designed by applying Babinet's principle to the bowtie nanoaperture, takes the shape of a diabolo. It differs from the well-known bowtie nanoantenna in that the opposing pair of metal triangles are electrically connected through their facing tips. Thus instead of a large charge density accumulating at the air gap of the bowtie nanoantenna, leading to a large electric field, a high optical current density develops within the central "metal gap" of the diabolo nanoantenna, leading to a large magnetic field. Numerical simulation results on the first nanodiabolo geometries show a 2900-fold enhancement of the magnetic field at a wavelength of 2540 nm, confined to a 40-by 40 nm region near the center of the nanoantenna. PMID- 21319838 TI - Suitability of Au- and self-assisted GaAs nanowires for optoelectronic applications. AB - The incorporation of Au during vapor-liquid-solid nanowire growth might inherently limit the performance of nanowire-based devices. Here, we assess the material quality of Au-assisted and Au-free grown GaAs/(Al,Ga)As core-shell nanowires using photoluminescence spectroscopy. We show that at room temperature, the internal quantum efficiency is systematically much lower for the Au-assisted nanowires than for the Au-free ones. In contrast, the optoelectronic material quality of the latter is comparable to that of state-of-the-art planar double heterostructures. PMID- 21319840 TI - Plasmon resonant enhancement of photocatalytic water splitting under visible illumination. AB - We demonstrate plasmonic enhancement of photocatalytic water splitting under visible illumination by integrating strongly plasmonic Au nanoparticles with strongly catalytic TiO2. Under visible illumination, we observe enhancements of up to 66* in the photocatalytic splitting of water in TiO2 with the addition of Au nanoparticles. Above the plasmon resonance, under ultraviolet radiation we observe a 4-fold reduction in the photocatalytic activity. Electromagnetic simulations indicate that the improvement of photocatalytic activity in the visible range is caused by the local electric field enhancement near the TiO2 surface, rather than by the direct transfer of charge between the two materials. Here, the near-field optical enhancement increases the electron-hole pair generation rate at the surface of the TiO2, thus increasing the amount of photogenerated charge contributing to catalysis. This mechanism of enhancement is particularly effective because of the relatively short exciton diffusion length (or minority carrier diffusion length), which otherwise limits the photocatalytic performance. Our results suggest that enhancement factors many times larger than this are possible if this mechanism can be optimized. PMID- 21319839 TI - Biomimetic high density lipoprotein nanoparticles for nucleic acid delivery. AB - We report a gold nanoparticle-templated high density lipoprotein (HDL AuNP) platform for gene therapy that combines lipid-based nucleic acid transfection strategies with HDL biomimicry. For proof-of-concept, HDL AuNPs are shown to adsorb antisense cholesterylated DNA. The conjugates are internalized by human cells, can be tracked within cells using transmission electron microscopy, and regulate target gene expression. Overall, the ability to directly image the AuNP core within cells, the chemical tailorability of the HDL AuNP platform, and the potential for cell-specific targeting afforded by HDL biomimicry make this platform appealing for nucleic acid delivery. PMID- 21319841 TI - On the energy shift between near-field and far-field peak intensities in localized plasmon systems. AB - The localized plasmons of metallic nanoparticles and nanostructures are known to display an interesting and apparently universal phenomenon: upon optical excitation, the maximum near-field enhancements occur at lower energies than the maximum of the corresponding far-field spectrum. Here we present an explanation for this behavior, showing that it results directly from the physics of a driven and damped harmonic oscillator. We show that the magnitude of the shift between the near- and far-field peak intensities depends directly on the total damping of the system, whether it is intrinsic damping within the metal of the nanoparticle or radiative damping of the localized plasmon. PMID- 21319842 TI - Nanolithographic control of the spatial organization of cellular adhesion receptors at the single-molecule level. AB - The ability to control the placement of individual molecules promises to enable a wide range of applications and is a key challenge in nanoscience and nanotechnology. Many biological interactions, in particular, are sensitive to the precise geometric arrangement of proteins. We have developed a technique which combines molecular-scale nanolithography with site-selective biochemistry to create biomimetic arrays of individual protein binding sites. The binding sites can be arranged in heterogeneous patterns of virtually any possible geometry with a nearly unlimited number of degrees of freedom. We have used these arrays to explore how the geometric organization of the extracellular matrix (ECM) binding ligand RGD (Arg-Gly-Asp) affects cell adhesion and spreading. Systematic variation of spacing, density, and cluster size of individual integrin binding sites was used to elicit different cell behavior. Cell spreading assays on arrays of different geometric arrangements revealed a dramatic increase in spreading efficiency when at least four liganded sites were spaced within 60 nm or less, with no dependence on global density. This points to the existence of a minimal matrix adhesion unit for fibronectin defined in space and stoichiometry. Developing an understanding of the ECM geometries that activate specific cellular functional complexes is a critical step toward controlling cell behavior. Potential practical applications range from new therapeutic treatments to the rational design of tissue scaffolds that can optimize healing without scarring. More broadly, spatial control at the single-molecule level can elucidate factors controlling individual molecular interactions and can enable synthesis of new systems based on molecular-scale architectures. PMID- 21319843 TI - Plasmonics and enhanced magneto-optics in core-shell co-ag nanoparticles. AB - We present theoretical and experimental studies that explain the observed strong enhancement of the magneto-optical (MO) Faraday rotation in all-metal core-shell Co-Ag nanoparticles (NPs) attributed to localized surface plasmon resonance (LSPR). We also explain why the optical absorption and MO spectra peaks appear blue-shifted with increased Co core size while keeping the NP size constant. Further, we demonstrate direct correlation between the strong LSPR induced electromagnetic fields and the enhanced MO activity of the NPs. PMID- 21319844 TI - Atomic layer deposition of lead sulfide quantum dots on nanowire surfaces. AB - Quantum dots provide unique advantages in the design of novel optoelectronic devices owing to the ability to tune their properties as a function of size. Here we demonstrate a new technique for fabrication of quantum dots during the nucleation stage of atomic layer deposition (ALD) of PbS. Islands with sub-10 nm diameters were observed during the initial ALD cycles by transmission electron microscopy, and in situ observations of the coalescence and sublimation behavior of these islands show the possibility of further modifying the size and density of dots by annealing. The ALD process can be used to cover high-aspect-ratio nanostructures, as demonstrated by the uniform coating of a Si nanowire array with a single layer of PbS quantum dots. Photoluminescence measurements on the quantum dot/nanowire composites show a blue shift when the number of ALD cycles is decreased, suggesting a route to fabricate unique three-dimensional nanostructured devices such as solar cells. PMID- 21319845 TI - Probe-independent image correlation spectroscopy. AB - Conventional image correlation spectroscopy (ICS) analysis assumes point-like probe particles whose sizes are much smaller than the beam focus. This assumption yields erroneous results when the particle size is larger than a certain threshold. Here, a formalism is presented to study image correlation spectroscopy for particles of arbitrary geometries, sizes, and fluorophore distributions. We demonstrate the usefulness of this method by analyzing simulated image sequences of diffusing fluorescent point sources, disks, and randomly oriented rigid rods of various sizes. In addition, we also perform ICS analysis on confocal images of fluorescent microspheres of different diameters diffusing in a medium of known viscosity to experimentally validate the method. The new method, which we call template analysis, yields excellent agreement with theoretical predictions, thus extending the capability of ICS for studying dynamic processes in a probe independent manner. PMID- 21319846 TI - Microtopographic patterns affect Escherichia coli biofilm formation on poly(dimethylsiloxane) surfaces. AB - Biofilms are involved in 80% of human bacterial infections and are up to 1000 times more tolerant to antibiotics than their planktonic counterparts. To better understand the mechanism of bacteria-surface interactions, polydimethylsiloxane (PDMS) surfaces with microtopographic patterns were tested to study the effects of surface topography on bacterial adhesion and biofilm formation. The patterned PDMS surfaces were prepared by transferring complementary surface topography from a silicon wafer etched via photolithography to introduce 10 MUm tall square-shape features. The dimension of protruding square features and the distance between adjacent features were systematically varied. Escherichia coli RP437/pRSH103 (with constitutive expression of red fluorescent protein) was found to preferentially attach and form biofilms in valleys between protruding features even when the dimension of plateaus (top of the square features) is considerably larger than valleys. In addition, significant adhesion of E. coli on plateaus was only observed when the plateaus were bigger than 20 MUm * 20 MUm for face-up patterns and 40 MUm * 40 MUm for face-down patterns. This finding suggests that a threshold dimension may be essential for biofilm formation on flat surfaces without physical confinement. PMID- 21319847 TI - Effect of brush thickness and solvent composition on the friction force response of poly(2-(methacryloyloxy)ethylphosphorylcholine) brushes. AB - The frictional properties of poly(2-(methacryloyloxy)ethylphosphorylcholine) (PMPC) brushes grown from planar silicon surfaces by atom transfer radical polymerization (ATRP) have been characterized using in situ friction force microscopy (FFM). The dry thicknesses of the PMPC brushes ranged from 20 to 421 nm. For brush layers with dry thicknesses greater than ca. 100 nm, the coefficient of friction decreased with increasing film thickness. For shorter brushes, the coefficient of friction varied little with brush thickness. We hypothesize that the amount of bound solvent increases as the brush length increases, causing the osmotic pressure to increase and yielding a reduced tendency for the brush layer to deform under applied load. A comparison of the force-displacement plots acquired for various PMPC brushes under water supports this hypothesis, since a greater repulsive force is measured for thicker brushes. FFM was also used to investigate the well-known co-nonsolvency behavior exhibited by PMPC chains. For a PMPC brush layer of 307 nm dry thickness, the friction force was determined as a function of the volume fraction of alcohol in alcohol/water mixtures. Unlike a previous macroscopic study, a significant increase in the coefficient of friction was observed for ethanol/water mixtures at a volume fraction of 90%. This is attributed to brush collapse due to co nonsolvency, leading to loss of hydration of the brush chains and hence substantially reduced lubrication. Force measurements normal to the surface indicate much greater hysteresis between approaching and retraction curves under co-nonsolvency conditions. However, no such effect was observed for 2 propanol/water and methanol/water mixtures over a wide range of volume fractions, in agreement with recent ellipsometric studies of PMPC brushes. PMID- 21319848 TI - Sesquiterpenes from Blumea balsamifera. AB - Five new guaiane sesquiterpenes, blumeaenes E1 (1), E2 (2), K (3), L (4), and M (5), and one new eudesmane sesquiterpene, samboginone (6), along with three known compounds, cryptomeridiol, 3,3',5,7-tetrahydroxy-4'-methoxyflavanone, and austroinulin, were isolated from the leaves of the Philippine medicinal herb sambong, Blumea balsamifera. The absolute configuration of the new guaiane core was determined as 1S,7S,9S,10R by employing the modified Mosher's method. In the structure of 1, the absolute configuration of the epoxyangelic acid moiety was identified as 2S,3S using (R)-PGME as a chiral anisotropic auxiliary. PMID- 21319849 TI - Raman 2D-band splitting in graphene: theory and experiment. AB - We present a systematic experimental and theoretical study of the two-phonon (2D) Raman scattering in graphene under uniaxial tension. The external perturbation unveils that the 2D mode excited with 785 nm has a complex line-shape mainly due to the contribution of two distinct double resonance scattering processes (inner and outer) in the Raman signal. The splitting depends on the direction of the applied strain and the polarization of the incident light. The results give new insight into the nature of the 2D band and have significant implications for the use of graphene as reinforcement in composites since the 2D mode is crucial to assess how effectively graphene uptakes an applied stress or strain. PMID- 21319850 TI - Highly ordered assembly of single-domain dichloropentacene over large areas on vicinal gold surfaces. AB - Defining pathways to assemble long-range-ordered 2D nanostructures of specifically designed organic molecules is required in order to optimize the performance of organic thin-film electronic devices. We report on the rapid fabrication of a nearly perfect self-assembled monolayer (SAM) composed of a single-domain 6,13-dichloropentacene (DCP) brick-wall pattern on Au(788). Scanning tunneling microscopy (STM) results show the well-ordered DCP SAM extends over hundreds of nanometers. Combining STM results with insights from density functional theory, we propose that a combination of unique intermolecular and molecule-step interactions drives the DCP SAM formation. PMID- 21319851 TI - Organogels based on J- and H-type aggregates of amphiphilic perylenetetracarboxylic diimides. AB - Three new perylenetetracarboxylic diimide (PDI) compounds substituted with hydrophobic and/or hydrophilic groups at the two imide nitrogen positions, namely N,N'-di[N-(4-aminophenyl)-3,4,5-tris(2-(2-(2 methoxyethoxy)ethoxy)ethoxy)benzamide]-1,7-di(4-tert-butylphenoxy)perylene 3,4;9,10-tetracarboxylic diimide (1), N,N'-di[N-amido-3,4,5-tris(2-(2-(2 methoxyethoxy)ethoxy)ethoxy)benzamide]-1,7-di(4-tert-butylphenoxy)perylene 3,4;9,10-tetracarboxylic diimide (2), and N-amido-3,4,5-tris(2-(2-(2 methoxyethoxy)ethoxy)ethoxy)benzamide-N'-amido-3,4,5-tris(dodecyloxy)benzamide 1,7-di(4-tert-butylphenoxy)perylene-3,4;9,10-tetracarboxylate diimide (3), have been designed and prepared. The gelating abilities of them in different solvents have been investigated, and the results indicated that compounds 1 and 3 can form fluorescent gels whereas compound 2 cannot. The properties of the gels of compounds 1 and 3 have been investigated by UV-vis absorption and emission spectra. The results indicate that the gel of compound 1 is composed of H aggregates, whereas the gel of compound 3 is composed of J-aggregates. The reversible transformation between gel and solution states induced by temperature change is observed. The structure of dried gel has been investigated by X-ray diffraction (XRD) experiments, and the morphology has been measured by atomic force microscopy (AFM). This research revealed successfully the crucial roles of amphiphilic properties and the side-chain conformations in controlling the gelating properties of PDI molecules. This information may be useful for the design of novel organogels based on perylenetetracarboxylic diimides. PMID- 21319852 TI - Development of Expressed Sequence Tag (EST)-based Cleaved Amplified Polymorphic Sequence (CAPS) markers of tea plant and their application to cultivar identification. AB - To develop cleaved amplified polymorphic sequence (CAPS) markers for cultivar identification of the tea leaf, 5 primer pairs designed on the basis of genes that encode proteins related to nitrogen assimilation and 26 primer pairs based on expressed sequence tag (EST) sequences of the root of tea plant were screened. From combinations of primer pair and restriction enzyme that showed polymorphism among tea plants, 16 markers were selected and applied to DNA fingerprinting of Japanese tea cultivars. Sixty-three cultivars, except for a bud sport (Kiraka) and its original cultivar (Yabukita) and a pair that was the progeny of the same crossing parent (Harumoegi and Sakimidori), were distinguished from one another. By combining the 16 markers with previously developed CAPS markers and observing the physical appearance, 67 cultivars were distinguishable. The cultivars involve approximately 95% of total tea cultivating area in Japan; therefore, about 95% of tea leaves produced in Japan can be authenticated by labeling their cultivars. PMID- 21319853 TI - MALDI-TOF MS characterization of glycation products of whey proteins in a glucose/galactose model system and lactose-free milk. AB - The major modifications induced by thermal treatment of whey proteins alpha lactalbumin (alpha-La) and beta-lactoglobulin (beta-Lg) in a model system mimicking lactose-free milk (L(-) sugar mix) were investigated by matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS). The analysis of the intact alpha-La revealed species with up to 7 and 14 adducts from lactose and sugar mix, respectively, whereas for beta-Lg 3 and up to 5 sugar moieties were observed in the case of lactose and sugar mix experiments, respectively. A partial enzymatic hydrolysis with endoproteinase AspN prior to mass spectrometric analysis allowed the detection of further modifications and their localization in the amino acid sequence. Using alpha-cyano-4-chlorocinnamic acid as MALDI matrix, it could be shown that heating alpha-La and beta-Lg with glucose or galactose led to the modification of lysine residues that are not glycated by lactose. The higher glycation degree of whey proteins in a lactose free milk system relative to normal milk with lactose reflects the higher reactivity of monosaccharides compared to the parent disaccharide. Finally, the analysis of the whey extract of a commercial lactose-free milk sample revealed that the two whey proteins were present as three main forms (native, single, and double hexose adducts). PMID- 21319854 TI - Apple polyphenols extend the mean lifespan of Drosophila melanogaster. AB - Apple polyphenols (AP) are an excellent source of dietary antioxidants. The present study investigated the effect of AP on the lifespan of fruit flies and their interaction with gene expressions of superoxide dismutase (SOD), catalase (CAT), methuselah (MTH), Rpn11, and cytochrome c oxidase (CcO) subunits III and VIb. Results showed the mean lifespan was significantly extended by 10% in fruit flies fed the AP diet. This was accompanied by up-regulation of genes SOD1, SOD2, and CAT and down-regulation of MTH in the aged fruit flies. Paraquat and H(2)O(2) challenge tests demonstrated that AP prolonged the survival time only for Oregon R wild type flies but not for SOD(n108) or Cat(n1) mutants, in which either SOD or CAT was knocked out. Chronic paraquat exposure could shorten the maximum lifespan from 68 to 31 days and reduce the climbing ability by 60%, whereas AP could partially reverse the paraquat-induced mortality and decline in climbing ability. AP could up-regulate Rpn11 at day 30, whereas it appeared to have no significant effect on gene expression of ubiquitinated protein, CcO subunits III and VIb. These AP-induced changes were unlikely associated with caloric restriction as the gustatory assay found no difference in average body weight and stomach redness index between the control and AP fruit flies. It was therefore concluded that the antiaging activity of AP was, at least in part, mediated by its interaction with genes SOD, CAT, MTH, and Rpn11. PMID- 21319855 TI - Clusters in colloidal systems. AB - We study the dynamical properties of a model for charged colloidal particles, performing molecular dynamics simulations and observing the behavior of bond persistence functions, self-intermediate scattering functions at different wave vectors, and mean-square displacements of the particles, in three different regimes of the volume fraction. At the lowest volume fraction the system displays properties very similar to those of a gelling system, which can be interpreted in terms of the distribution of cluster sizes, with a peak in the dynamical susceptibility at the lowest wave vector. At the highest volume fraction, a percolating network of bonds is always present, and the system is strongly reminiscent of strong glasses, with the maximum in the dynamical susceptibility increasing when the temperature is lowered, and an Arrhenius dependence of the relaxation times. At intermediate volume fractions, a complex behavior is found, where both the distribution of cluster sizes and the intercluster correlations due to crowding are important. PMID- 21319856 TI - Peptide synthesis of gold nanoparticles: the early steps of gold reduction investigated by density functional theory. AB - Gold nanoparticles can be synthesized by reducing chloroaurate(III) ions in the presence of peptides. Here, such reduction for serine and tyrosine is studied by density functional theory including solvent effects. We find that the formation of chloroaurate complexes of these amino acids is thermodynamically viable and facilitates the reduction of Au(III), to a greater degree for tyrosine as found in experiments. Our results also suggest a rationale for the behavior of tyrosine intercalated peptides. PMID- 21319857 TI - Halide affinity for the water-air interface in aqueous solutions of mixtures of sodium salts. AB - The water-air interface plays a critical role in many physical and chemical processes of the Earth's atmosphere. In particular, heavy halide ions are strongly involved in processes of fundamental importance in determining the prevalence of many atmospheric components through heterogeneous reactions at the water-air interface. In this work, molecular dynamics simulations are used to study the halide enhancements at the water-air interface in the case of mixtures of Cl(-), Br(-), and I(-) ions. The results show a pattern of enhancement directly correlated to the anion polarizability. This effect is explained in terms of the charge distribution across the slab resembling an electrical double layer. As a result, the anions with higher polarizability lower the system's potential energy by enhancing their presence at the interface. PMID- 21319858 TI - Catalytic dehydrative S-allylation of cysteine-containing peptides in aqueous media toward lipopeptide chemistry. AB - Thiol-containing peptides and cysteine have been successfully S-allylated with various allyl alcohols in aqueous medium containing a catalytic amount of [CpRu(eta(3)-C(3)H(5))(2-quinolinecarboxylato)]PF(6). Quick and easy install of 2 propen-l-ol having a long-chain alkyl group at C(2) facilitates the synthesis of a new series of artificial lipopeptides, indicating a potential application to synthetic biology. PMID- 21319859 TI - The effects of photochemical and mechanical damage on the excited state dynamics of charge-transfer molecular crystals composed of tetracyanobenzene and aromatic donor molecules. AB - Charge-transfer molecular crystals are structurally well-defined systems whose electron transfer dynamics can be studied using time-resolved spectroscopy. In this paper, five 1:1 complexes, consisting of 1,2,4,5-tetracyanobenzene as the electron acceptor and durene, 9-methylanthracene, naphthalene, phenanthrene, and pyrene as electron donors, are studied using time-resolved fluorescence and transient absorption in the diffuse reflectance geometry. Two different sample morphologies were studied: single crystals and powders prepared by pulverizing the crystals and diluting them with barium sulfate microparticles. Fluorescence lifetime and transient absorption measurements performed on the crystals and the powders yielded different results. The crystals typically exhibited long-lived monoexponential fluorescence decays, while the powders had shorter multiexponential decays. Exposure of both types of samples to high laser fluence was also shown to induce faster excited state decay dynamics as observed using fluorescence and diffuse reflectance. In addition to the more rapid decays, these molecular crystals exhibited relatively high photobleaching quantum yields on the order of 10(-4). Previous work that interpreted picosecond decays in the transient absorption as evidence for rapid recombination and charge dissociation should be re-evaluated based on the susceptibility of this class of compounds to mechanical and photochemical damage. PMID- 21319860 TI - Asymmetric synthesis of ethoxydienamines in superbasic medium mediated by chiral sulfinyl group. AB - The direct addition of metalated alkoxydiene 2, obtained from alpha,beta unsaturated acetal 1 through a LIC-KOR-promoted conjugated elimination reaction, to enantiopure sulfinimines 3 (both R and SN-sulfinyl imines) afforded N-sulfinyl alkoxydienyl amines 4 with high diastereoselectivity. Functionalized enantiopure alkoxydienyl amines 5 were then easily obtained upon the selective removal of the chiral auxiliary under mild conditions. Moreover, the further hydrolysis of the alkoxydienyl moiety gave access to protected enantiopure beta-keto amines 7. PMID- 21319861 TI - Impact of water on the OH + HOCl reaction. AB - The effect of a single water molecule on the OH + HOCl reaction has been investigated. The naked reaction, the reaction without water, has two elementary reaction paths, depending on how the hydroxyl radical approaches the HOCl molecule. In both cases, the reaction begins with the formation of prereactive hydrogen bond complexes before the abstraction of the hydrogen by the hydroxyl radical. When water is added, the products of the reaction do not change, and the reaction becomes quite complex yielding six different reaction paths. Interestingly, a geometrical rearrangement occurs in the prereactive hydrogen bonded region, which prepares the HOCl moiety to react with the hydroxyl radical. The rate constant for the reaction without water is computed to be 2.2 * 10(-13) cm(3) molecule(-1) s(-1) at room temperature, which is in good agreement with experimental values. The reaction between ClOH...H(2)O and OH is estimated to be slower than the naked reaction by 4-5 orders of magnitude. Although, the reaction between ClOH and the H(2)O...HO complex is also predicted to be slower, it is up to 2.2 times faster than the naked reaction at altitudes below 6 km. Another intriguing finding of this work is an interesting three-body interchange reaction that can occur, that is HOCl + HO...H(2)O -> HOCl...H(2)O + OH. PMID- 21319863 TI - Altered liver secretion of vascular regulatory proteins in hypoxic pregnancies stimulate angiogenesis in vitro. AB - Placental vascular malformations result in fetal hypoxia, a serious pregnancy complication. Recent studies have linked liver-secreted and hemostatic proteins with angiogenesis. We therefore evaluated liver protein secretion changes following hypoxia, and their effect on angiogenesis, to identify potential angiogenic protein changes in the plasma of hypoxic newborns. Human vascular endothelial cells exhibited 10-fold increased tube formation with secretions from HepG2 cells cultured in 1% O(2) and 3-fold in 4% O(2) (p < 0.0001, p < 0.05) compared to 20% O(2). 2-DGE profiling of the secretions revealed significant density changes (p < 0.05) in spots identified as angiogenic proteins by LC MS/MS. Clusterin decreased (-1.6-fold), whereas two spots of plasminogen activator inhibitor-1 (PAI-1) (2.4, and 3.6-fold), and three spots of transferrin (1.3, 1.5, and 2.6-fold) increased with 1% O(2). The levels of these proteins, subsequently determined in fetal plasma by immunoassays, strongly correlate with the fetal blood oxygen level at birth; PAI-1 and transferrin increase with low venous pO(2) (r = -0.70, p = 0.02, and r = -0.66, p = 0.04), clusterin and fibrinogen decrease (r = 0.82, p = 0.002, and r = 0.70, p = 0.02). These findings demonstrate that low oxygen levels in utero lead to pro-angiogenic changes in liver secreted plasma proteins. The pro-vascular plasma environment in hypoxic pregnancies may be acting to mitigate the compromised vasculature. PMID- 21319862 TI - Advances in transition metal (Pd, Ni, Fe)-catalyzed cross-coupling reactions using alkyl-organometallics as reaction partners. PMID- 21319865 TI - Drugs in development for viral hepatitis: care and caution. PMID- 21319864 TI - Gonadotropin-releasing hormone agonists and the risks of type 2 diabetes and cardiovascular disease in men with prostate cancer. PMID- 21319866 TI - The role of dopamine agonists in the treatment of depression in patients with Parkinson's disease: a systematic review. AB - Depressive disorders as well as depressive symptoms are common in Parkinson's disease (PD) and an important factor affecting quality of life. Treatment of depressive symptoms not only improves mood but is also associated with improvement of motor symptoms, disability and cognitive symptoms. Currently, dopamine agonists are being suggested as an alternative to antidepressants for the treatment of depression in PD. The aim of this article is to systematically review the efficacy of dopamine agonists in the treatment of depression in PD. Since 1983, 19 studies have reported on the effects of dopamine agonists on depressive disorder, depressive symptoms or mood in PD. To date, no double-blind, placebo-controlled, randomized controlled trial of the treatment of major depressive disorder in PD with a dopamine agonist has been conducted. Studies of the effects of treatment with dopamine agonists on depressive symptoms in PD, or on mood in non-depressed PD patients, have yielded inconclusive results. Most studies are not designed to test effects on mood and are limited by methodological flaws. It can be concluded that, although the preliminary evidence of the effects on mood and depression in PD is interesting and in need of further study, there is as yet insufficient evidence to recommend dopamine agonists in the treatment of either depressive disorder or depressive symptoms in patients with PD. Treatment of depressive disorder and clinically relevant depressive symptoms should be based on pharmacological or non-pharmacological interventions with known efficacy in this population, such as citalopram, nortriptyline, desipramine or cognitive behavioural therapy. This strategy has the additional advantage of enabling the clinician to treat depressive symptoms independently of motor symptoms, thus avoiding potential complications of dopaminergic therapy. PMID- 21319867 TI - Non-hormonal treatment strategies for vasomotor symptoms: a critical review. AB - Hot flashes (or flushes) are the most commonly reported symptoms during the menopause transition and early postmenopausal years, particularly in Western societies; they affect 60-90% of women and can lead to significant physical discomfort and functional impairment. The emergence of hot flashes and night sweats (also known as vasomotor symptoms [VMS]) coincide with a period in life that is also marked by dynamic changes in hormone and reproductive function that interconnect with the aging process, changes in metabolism, lifestyle behaviours and overall health. Estrogen-based therapies have long been the treatment of choice for women suffering from VMS. More recent concerns over long-term safety of menopausal hormone treatments, however, have led physicians and patients to pursue non-hormonal strategies to alleviate their symptoms. In this article, we review most of the efficacy and safety data on non-hormonal treatments for VMS published over the past 20 years. We discuss the evidence for treating symptomatic women in different clinical scenarios, e.g. VMS with and without concomitant depression or VMS following the use of anti-estrogen therapies. Overall, efficacy data support the use of some psychotropic medications, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors and gabapentin. Complementary and alternative methods for VMS also showed limited but promising results, although more definitive studies are warranted. Clinicians should therefore be able to tailor treatment strategies for those who are unable or unwilling to use hormones to alleviate VMS and improve overall functioning and quality of life. PMID- 21319868 TI - Current options and new developments in the treatment of haemophilia. AB - Haemophilia A and B are X-linked bleeding disorders due to the inherited deficiency of factor VIII or factor IX, respectively. Of the approximately 1 per 5000-10000 male births affected by haemophilia, 80% are deficient in factor VIII and 20% are deficient in factor IX. Haemophilia is characterized by spontaneous and provoked joint, muscle, gastrointestinal and CNS bleeding leading to major morbidity and even mortality if left untreated or under-treated. The evolution of haemophilia management has been marked by tragedy and triumph over recent decades. Clotting factors and replacement strategies continue to evolve for patients without inhibitors. For patients with an inhibitor, factor replacement for acute bleeding episodes and immune tolerance, immune modulation and extracorporeal methods for inhibitor reduction are the cornerstone of care. In addition, adjuvant therapies such as desmopressin, antifibrinolytics and topical agents also contribute to improved outcomes for patients with and without inhibitors. The future direction of haemophilia care is promising with new longer acting clotting factors and genetic therapies, including gene transfer and premature termination codon suppressors. With these current and future treatment modalities, the morbidity and mortality rates in patients with haemophilia certainly will continue to improve. PMID- 21319869 TI - Current and emerging pharmacological treatments for gastrointestinal stromal tumour. AB - Gastrointestinal stromal tumours (GIST) are the most common mesenchymal tumours of the gastrointestinal tract, previously classified as leiomyosarcomas. Most GIST express KIT and the majority have mutations in the KIT gene. The most common KIT mutation occurs in the juxtamembrane domain of exon 11. These mutations lead to cellular proliferation and survival. GIST with exon 11 mutations respond better to tyrosine kinase inhibitors (TKIs) than those with exon 9 mutations. Most KIT-negative GIST express platelet-derived growth factor receptor (PDGFR) alpha; however, a small percentage of GIST are negative for both KIT and PDGFRalpha. Imatinib and other TKIs have dramatically improved the outcome of patients with metastatic GIST. Newer and more advanced TKIs are under intense investigation as eventually all GIST patients develop resistant tumours. In addition, these drugs can be utilized in the preoperative setting for patients with unresectable localized tumours or those at high risk for surgical morbidity. TKIs have been given in the adjuvant setting for patients with resected tumours at high risk for recurrence. The duration of adjuvant therapy is currently under evaluation; however, it is possible that these patients would need to continue therapy indefinitely. PMID- 21319870 TI - Treatment of viral conjunctivitis with antiviral drugs. AB - Viral conjunctivitis is one of the most common disorders observed in ophthalmic emergency departments, yet no established treatment exists. Lately, antiviral medications have been introduced into clinical practice; however, a systematic review focusing on their use and effectiveness in the treatment of viral conjunctivitis has not been previously reported. We systemically reviewed the literature to identify studies where antiviral drugs were used to treat viral conjunctivitis. Currently, aciclovir, trifluridine and valaciclovir are commonly used as antiviral agents to treat herpesvirus infections. Cidofovir has been used successfully to treat some cases of adenoviral conjunctivitis, although toxicity has also been reported. The use of other medications, such as idoxuridine, has been minimized in clinical practice due to their high toxicity. Interestingly, most of the antiviral drugs developed are used to treat herpesvirus infections, while less progress has been made in the field of adenoviral infections. For other viral causes of conjunctivitis, no effective remedy is currently available, and treatment focuses on the relief of symptoms. Caution should be exercised when coadministering other pharmacological agents, such as corticosteroids, because of emerging adverse effects. PMID- 21319871 TI - Sitagliptin/metformin fixed-dose combination: in patients with type 2 diabetes mellitus. AB - Sitagliptin/metformin is a single-tablet, fixed-dose combination of the dipeptidyl peptidase-4 inhibitor sitagliptin and the biguanide antihyperglycaemic metformin that achieves greater improvements in glycaemic control than either component alone in patients with type 2 diabetes mellitus. Recommended dosages of sitagliptin plus metformin, either as the fixed-dose tablet or a combination of the individual agents, significantly reduced glycosylated haemoglobin (HbA(1c)) levels in two well designed clinical trials in treatment-naive patients with type 2 diabetes. The improvements in glycaemic control seen with sitagliptin plus metformin therapy after 18 or 24 weeks were greater than those observed with the individual components alone and/or placebo, and sustained over treatment durations of up to 2 years. As add-on therapy in treatment-experienced patients with inadequate glycaemic control, the HbA(1c)-lowering efficacy of sitagliptin plus metformin was noninferior to that of glimepiride plus metformin in a 30 week, double-blind trial. Sitagliptin plus metformin and glipizide plus metformin lowered HbA(1c) levels by generally similar magnitudes, with the noninferiority of sitagliptin plus metformin to glipizide plus metformin being established in one 52-week study. As part of triple combination therapy, also in treatment experienced patients with inadequate glycaemic control, sitagliptin added to ongoing glimepiride with or without metformin or ongoing insulin with or without metformin significantly improved glycaemic control over 24 weeks. Sitagliptin plus metformin, as the fixed-dose tablet or a combination of the individual agents, was generally well tolerated in patients with type 2 diabetes, and was associated with a low risk of hypoglycaemia. PMID- 21319872 TI - Fulvestrant: a review of its use in the management of hormone receptor-positive metastatic breast cancer in postmenopausal women. AB - Fulvestrant (Faslodex(r)) is an intramuscularly administered steroidal estrogen receptor antagonist that is devoid of any known estrogen agonist effects. It is indicated as second-line therapy for the treatment of postmenopausal women with hormone receptor-positive advanced breast cancer who have progressed following prior endocrine therapy. In well designed, randomized clinical trials, regimens of fulvestrant 250 and 500 mg provided effective second-line therapy for postmenopausal women with advanced breast cancer who had progressed following prior endocrine therapy. Moreover, fulvestrant 250 mg monthly (with or without a loading dose) was as effective as aromatase inhibitor therapy. However, fulvestrant is absorbed slowly, and greater steady-state concentrations are achieved more rapidly when using a higher dosage with a loading dose regimen. Consequently, a regimen of fulvestrant 500 mg monthly with a loading dose was significantly more effective than a regimen of 250 mg monthly in postmenopausal women with disease progression. Limited data also indicate a potential role for the fulvestrant 500 mg regimen as first-line therapy. Fulvestrant is generally well tolerated with no additional adverse events noted with the high-dose regimen compared with the 250 mg regimens. Furthermore, the incidence of joint disorders was shown to be significantly lower with fulvestrant 250 mg monthly than with anastrozole. Treatment with fulvestrant is not associated with any clinically significant effects on endometrial thickening, bone-specific turnover markers or sex hormone levels. In conclusion, a monthly regimen of intramuscular fulvestrant 500 mg with a loading dose provides effective and well tolerated second-line therapy for postmenopausal women with advanced breast cancer who have progressed following prior endocrine therapy and is now the approved optimal dose. PMID- 21319874 TI - Alcohol use trajectories and the ubiquitous cat's cradle: cause for concern? AB - In recent years, trajectory approaches to characterizing individual differences in the onset and course of substance involvement have gained popularity. Previous studies have sometimes reported 4 prototypic courses: (a) a consistently "low" group, (b) an "increase" group, (c) a "decrease" group, and (d) a consistently "high" group. Although not always recovered, these trajectories are often found, despite these studies varying in the ages of the samples studied and the duration of the observation periods employed. Here, the authors examined the consistency with which these longitudinal patterns of heavy drinking were recovered in a series of latent class growth analyses that systematically varied the age of the sample at baseline, the duration of observation, and the number and frequency of measurement occasions. Data were drawn from a 4-year, 8-wave panel study of college student drinking (N = 3,720). Despite some variability across analyses, there was a strong tendency for these prototypes to emerge regardless of the participants' age at baseline and the duration of observation. These findings highlight potential problems with commonly employed trajectory-based approaches and the need to not over-reify these constructs. PMID- 21319875 TI - Externalizing psychopathology and gain-loss feedback in a simulated gambling task: dissociable components of brain response revealed by time-frequency analysis. AB - Externalizing is a broad construct that reflects propensity toward a variety of impulse control problems, including antisocial personality disorder and substance use disorders. Two event-related potential responses known to be reduced among individuals high in externalizing proneness are the P300, which reflects postperceptual processing of a stimulus, and the error-related negativity (ERN), which indexes performance monitoring based on endogenous representations. In the current study, the authors used a simulated gambling task to examine the relation between externalizing proneness and the feedback-related negativity (FRN), a brain response that indexes performance monitoring related to exogenous cues, which is thought to be highly related to the ERN. Time-frequency (TF) analysis was used to disentangle the FRN from the accompanying P300 response to feedback cues by parsing the overall feedback-locked potential into distinctive theta (4-7 Hz) and delta (<3 Hz) TF components. Whereas delta-P300 amplitude was reduced among individuals high in externalizing proneness, theta-FRN response was unrelated to externalizing. These findings suggest that in contrast with previously reported deficits in endogenously based performance monitoring (as indexed by the ERN), individuals prone to externalizing problems show intact monitoring of exogenous cues (as indexed by the FRN). The results also contribute to a growing body of evidence indicating that the P300 is attenuated across a broad range of task conditions in high-externalizing individuals. PMID- 21319876 TI - Building team adaptive capacity: the roles of sensegiving and team composition. AB - The current study draws on motivated information processing in groups theory to propose that leadership functions and composition characteristics provide teams with the epistemic and social motivation needed for collective information processing and strategy adaptation. Three-person teams performed a city management decision-making simulation (N=74 teams; 222 individuals). Teams first managed a simulated city that was newly formed and required growth strategies and were then abruptly switched to a second simulated city that was established and required revitalization strategies. Consistent with hypotheses, external sensegiving and team composition enabled distinct aspects of collective information processing. Sensegiving prompted the emergence of team strategy mental models (i.e., cognitive information processing); psychological collectivism facilitated information sharing (i.e., behavioral information processing); and cognitive ability provided the capacity for both the cognitive and behavioral aspects of collective information processing. In turn, team mental models and information sharing enabled reactive strategy adaptation. PMID- 21319877 TI - Antecedents of team potency and team effectiveness: an examination of goal and process clarity and servant leadership. AB - Integrating theories of self-regulation with team and leadership literatures, this study investigated goal and process clarity and servant leadership as 3 antecedents of team potency and subsequent team effectiveness, operationalized as team performance and organizational citizenship behavior. Our sample of 304 employees represented 71 teams in 5 banks. Results showed that team-level goal and process clarity as well as team servant leadership served as 3 antecedents of team potency and subsequent team performance and team organizational citizenship behavior. Furthermore, we found that servant leadership moderated the relationships between both goal and process clarity and team potency, such that the positive relationships between both goal and process clarity and team potency were stronger in the presence of servant leadership. PMID- 21319878 TI - Taking the reins: the effects of new leader status and leadership style on team performance. AB - New leaders face a challenging task when they take charge of their teams. They have to determine how best to guide the work process, and they must understand how their behaviors will affect the members of their team. This research examines how a newly assigned team leader's status moderates subordinates' reactions to different leadership styles to affect assessments of the leader's self-confidence and effectiveness, and how this impacts team performance. Across 2 experimental studies, results demonstrate that low-status leaders are rated as more effective when they use a directive style, whereas high-status leaders are viewed as more effective when they use a participative style, and this relationship is mediated by perceptions of self-confidence. In addition, teams whose leaders are viewed more favorably perform better on a complex group task. These findings imply that low-status individuals are able to enhance their level of personal power by drawing on whatever positional power they hold, whereas high-status individuals are better off relying solely on their personal power to influence others. This research also provides a clear demonstration that assessments of new leaders' behaviors are subject to an appraisal that is clouded by observers' status perceptions and attributions. PMID- 21319879 TI - Factors for radical creativity, incremental creativity, and routine, noncreative performance. AB - This study extends theory and research by differentiating between routine, noncreative performance and 2 distinct types of creativity: radical and incremental. We also use a sensemaking perspective to examine the interplay of social and personal factors that may influence a person's engagement in a certain level of creative action versus routine, noncreative work. Results demonstrate that willingness to take risks, resources for creativity, and career commitment are associated primarily with radical creativity; that the presence of creative coworkers and organizational identification are associated with incremental creativity; and that conformity and organizational identification are linked with routine performance. Theoretical and managerial implications are discussed. PMID- 21319880 TI - The criterion-related validity of integrity tests: an updated meta-analysis. AB - Integrity tests have become a prominent predictor within the selection literature over the past few decades. However, some researchers have expressed concerns about the criterion-related validity evidence for such tests because of a perceived lack of methodological rigor within this literature, as well as a heavy reliance on unpublished data from test publishers. In response to these concerns, we meta-analyzed 104 studies (representing 134 independent samples), which were authored by a similar proportion of test publishers and non-publishers, whose conduct was consistent with professional standards for test validation, and whose results were relevant to the validity of integrity-specific scales for predicting individual work behavior. Overall mean observed validity estimates and validity estimates corrected for unreliability in the criterion (respectively) were .12 and .15 for job performance, .13 and .16 for training performance, .26 and .32 for counterproductive work behavior, and .07 and .09 for turnover. Although data on restriction of range were sparse, illustrative corrections for indirect range restriction did increase validities slightly (e.g., from .15 to .18 for job performance). Several variables appeared to moderate relations between integrity tests and the criteria. For example, corrected validities for job performance criteria were larger when based on studies authored by integrity test publishers (.27) than when based on studies from non-publishers (.12). In addition, corrected validities for counterproductive work behavior criteria were larger when based on self-reports (.42) than when based on other-reports (.11) or employee records (.15). PMID- 21319881 TI - Rapid cellular genesis and apoptosis: effects of exercise in the adult rat. AB - Long-term aerobic exercise improves cognition in both human and nonhuman animals and induces plastic changes in the central nervous system (CNS), including neurogenesis and angiogenesis. However, the early and immediate effects of exercise on the CNS have not been adequately explored. There is some evidence to suggest that exercise is initially challenging to the nervous system and that the plastic changes commonly associated with chronic exercise may result as adaptations to this challenge. The current experiment assessed levels of apoptosis, angiogenesis, and neurogenesis during the first week of an exercise regimen in the adult rat. The results indicate that exercise rapidly induces these processes in the hippocampus and cerebellum. The temporal pattern of these events suggests that voluntary exercise in the adult rat rapidly and transiently induces apoptosis, followed by angiogenesis. Neurogenesis is an immediate and independent consequence of exercise in the hippocampus that may require the additional metabolic support supplied by angiogenesis. This is the first report of CNS neuronal apoptosis as a consequence of exercise in the adult rat and suggests that this process is a potential mediator of rapid exercise-induced plasticity. PMID- 21319883 TI - Maternal separation results in early emergence of adult-like fear and extinction learning in infant rats. AB - Recent studies in rats have shown that extinction occurring early in life is resistant to relapse and may represent the erasure of fear memories. In the present study we examined the effects of early life stress on extinction in the developing rat, which could have important implications for the treatment of anxiety disorders in those who have experienced early life stress. In the present study, we used maternal-separation on postnatal days (P) 2-14 as an early life stressor. On P17, maternally separated and standard-reared animals were trained to fear a noise associated with a footshock. The fear of this noise was then extinguished (through repeated nonreinforced noise presentations) on P18. Animals were tested for contextually mediated, stress-mediated, and GABA-mediated fear relapse the day after extinction. We found that young animals exposed to maternal separation were more likely to exhibit context- and stress-mediated relapse after extinction than standard-reared animals (Experiments 1 and 2). Further, unlike standard-reared animals, maternally separated rats exhibited a return of fear when the inhibitory neurotransmitter GABA was blocked at test (Experiment 3). These effects were not the result of maternal separation increasing rats' sensitivity to footshock (Experiment 5) and may in part be related to superior long-term memory for contexts in P17 maternally separated rats (Experiment 4). Taken together, these results suggest that early life adversity may prepare young animals to respond more cautiously toward fear signals in their environment. PMID- 21319882 TI - mGluR5 positive allosteric modulation enhances extinction learning following cocaine self-administration. AB - Extinction of classically and instrumentally conditioned behaviors, such as conditioned fear and drug-seeking behavior, is a process of active learning, and recent studies indicate that potentiation of glutamatergic transmission facilitates extinction learning. In this study, the authors investigated the effects of the Type-5 metabotropic glutamate receptors (mGluR5) positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) on the extinction of cocaine-seeking behavior in rats with a history of intravenous cocaine self-administration. To assess its effects on acquisition and consolidation of extinction learning, CDPPB (60 mg/kg) or vehicle was administered either 20 min prior to, or immediately following, each of 10 extinction sessions, respectively. When administered prior to each extinction session, CDPPB produced a significant reduction in the number of active lever presses on all 10 days of extinction training as compared to vehicle-treated animals. When administered following each extinction session, a significant reduction in the number of active lever presses was observed on the 2nd through 10th day of extinction. Both treatment regimens also reduced the number of extinction-training sessions required to meet extinction criteria. Pre- or postextinction-training administration of CDPPB did not alter responding on the inactive lever and had no effects on open field locomotor activity. These data indicate that positive allosteric modulation of mGluR5 receptors facilitates the acquisition and consolidation of extinction learning following cocaine self administration and may provide a novel pharmacological approach to enhancing extinction learning when combined with cue exposure therapy for the treatment of cocaine addiction. PMID- 21319884 TI - Strain-specific cognitive deficits in adult mice exposed to early life stress. AB - Early life stress is a prominent risk factor for the development of adult psychopathology. Numerous studies have shown that early life stress leads to persistent changes in behavioral and endocrine responses to stress. However, despite recent findings of gene expression changes and structural abnormalities in neurons of the forebrain neocortex, little is known about specific cognitive deficits that can result from early life stress. Here we examined five cognitive functions in two inbred strains of mice, the stress-resilient strain C57Bl/6 and the stress-susceptible strain Balb/c, which were exposed to an infant maternal separation paradigm and raised to adulthood. Between postnatal ages P60 to P90, mice underwent a series of tests examining five cognitive functions: Recognition memory, spatial working memory, associative learning, shifts of attentional sets, and reversal learning. None of these functions were impaired in IMS C57Bl/6 mice. In contrast, IMS Balb/c mice exhibited deficits in spatial working memory and extradimensional shifts of attention, that is, functions governed primarily by the medial prefrontal cortex. Thus, like recently discovered changes in frontocortical gene expression, the emergence of specific cognitive deficits associated with the medial prefrontal cortex is also strain-specific. These findings illustrate that early life stress can indeed affect specific cognitive functions in adulthood, and they support the hypothesis that the genetic background and environmental factors are critical determinants in the development of adult cognitive deficits in subjects with a history of early life stress. PMID- 21319887 TI - Effects of reward timing information on cue associability are mediated by amygdala central nucleus. AB - The central nucleus of the amygdala (CeA) has been implicated in a range of associative learning phenomena often attributed to changes in attentional processing of events. Experiments using a number of behavioral tasks have shown that rats with lesions of CeA fail to show the enhancements of stimulus associability that are normally induced by the surprising omission of expected events. By contrast, in other tasks, rats with lesions of CeA show normal enhancements of associability when events are presented unexpectedly. In this experiment, we examined the effects of CeA lesions on changes in cue associability in a reward timing task. In sham-lesioned rats, the associability of cues that were followed by stimuli that provided reward timing information was maintained at higher levels than that of cues that were followed by uninformative stimuli. Rats with lesions of CeA failed to show this advantage. These results indicate that the role of CeA in the modulation of associability is not limited to cases of event omission. (PsycINFO Database Record (c) 2011 APA, all rights reserved). PMID- 21319886 TI - Timing in the absence of supraspinal input III: regularly spaced cutaneous stimulation prevents and reverses the spinal learning deficit produced by peripheral inflammation. AB - In the absence of brain input, spinal systems can adapt to new environmental relations. For example, spinally transected rats given a legshock each time the leg is extended exhibit a progressive increase in flexion duration that minimizes net shock exposure, a simple form of instrumental learning. This capacity for learning is modulated by prior stimulation; both variable shock and inflammation produce a lasting inhibition of learning. An extended exposure to fixed spaced shock has no adverse effect on learning and opposes the consequences of variable shock. The present studies expand on these findings and demonstrate that fixed stimulation ameliorates the impact of peripheral inflammation. Spinally transected rats were administered 900 fixed spaced legshocks before (Experiment 1) or 1,800 legshocks after (Experiment 2) a subcutaneous hindpaw injection of capsaicin. Learning was assessed 24 hr later. Treatment with fixed shock attenuated the capsaicin-induced inhibition of learning. These findings suggest that fixed stimulation promotes adaptive plasticity and may foster recovery after injury. PMID- 21319889 TI - Thermogenic and vocalization responses to cold in the chicken hatchling during normoxia and hypoxia. AB - We investigated the vocalization and the thermogenic responses to cold during hypoxia in chicken hatchlings during the first postnatal day. Calls were quantified in number and sound characteristics (amplitude and frequency); the change in oxygen (O2) consumption, measured by an open-flow methodology, represented thermogenesis. The cold challenge consisted of a decrease in ambient temperature (Ta) from ~39 to 28 degrees C, in steps of 2 degrees C, or an acute exposure to ~28 degrees C, either in normoxia or hypoxia (10% O2). Hypoxia lowered thermogenesis and the critical Ta, suggesting a decrease in the set point for thermoregulation. The vocalization response to cold was rapid; did not progress with the duration or intensity of the cold stimulus; was similar in very young (<8 hr old) and older (12-24 hr) hatchlings despite their differences in thermogenic capacity; and was essentially unaffected by hypoxia. We conclude that the hatchling's vocalization in the cold follows a stereotyped pattern not related to the thermogenic regulation of body temperature. The dissociation between vocalization and thermogenesis might carry some advantage in conditions of cold and hypoxia. PMID- 21319890 TI - Lesions of basolateral and central amygdala differentiate conditioned cue preference learning with and without unreinforced preexposure. AB - In the separated arms conditioned cue preference (CCP) task rats are trained by confining them in one arm of an eight-arm radial maze with food and in another arm on the opposite side of the maze with no food on alternate days. After two such trials, rats prefer the food-paired arm when allowed to move freely between the two arms, neither of which contains food. However, if the rats are preexposed to the maze by exploring it without food before training, no preference is observed and at least 4 training trials are required to produce a CCP, suggesting that unreinforced preexposure to the maze latently inhibits acquisition. If this interpretation is correct, preexposure should reduce the size of the preference acquired with both 2 and 4 training trials. In Experiment 1, this prediction was replicated for 2 training trials; however, with 4 training trials, eliminating preexposure also eliminated the CCP. A previous finding that basolateral amygdala lesions impair the CCP with preexposure and 4 training trials was replicated in Experiment 2, but similar lesions had no effect on the CCP in non-preexposed rats given 2 training trials. In contrast, lesions of the central nucleus impaired the 2 training trial CCP but had no effect on the 4 training trial CCP. This double dissociation suggests that the BLA-mediated 4 training trial CCP may be due to learning about the reward features of the maze space, while the central-nucleus mediated 2 training trial CCP may be due to a conditioned approach response. PMID- 21319888 TI - A heterogeneous population code for elapsed time in rat medial agranular cortex. AB - The neural mechanisms underlying the temporal control of behavior are largely unknown. Here we recorded from medial agranular cortex neurons in rats while they freely behaved in a temporal production task, the peak-interval procedure. Due to variability in estimating the time of food availability, robust responding typically bracketed the expected duration, starting some time before and ending some time after the signaled delay. These response periods provided analytic "steady state" windows during which subjects actively indicated their temporal expectation of food availability. Remarkably, during these response periods, a variety of firing patterns were seen that could be broadly described as ramps, peaks, and dips, with different slopes, directions, and times at which maxima or minima occur. Regularized linear discriminant analysis indicated that these patterns provided sufficiently reliable information to discriminate the elapsed duration of responding within these response periods. Modeling this across neuron variability showed that the utilization of ramps, dips, and peaks, with different slopes and minimal/maximal rates at different times, led to a substantial improvement in temporal prediction errors, suggesting that heterogeneity in the neural representation of elapsed time may facilitate temporally controlled behavior. PMID- 21319891 TI - A comparison of adult and adolescent rat behavior in operant learning, extinction, and behavioral inhibition paradigms. AB - Poor self-control, lack of inhibition, and impulsivity contribute to the propensity of adolescents to engage in risky or dangerous behaviors. Brain regions (e.g., prefrontal cortex) involved in impulse-control, reward-processing, and decision-making continue to develop during adolescence, raising the possibility that an immature brain contributes to dangerous behavior during adolescence. However, very few validated animal behavioral models are available for behavioral neuroscientists to explore the relationship between brain development and behavior. To that end, a valid model must be conducted in the relatively brief window of adolescence and not use manipulations that potentially compromise development. The present experiments used three operant arrangements to assess whether adolescent rats differ from adults in measures of learning, behavioral inhibition, and impulsivity, within the aforementioned time frame without substantial food restriction. In Experiment 1, separate squads of rats were trained to lever-press and then transitioned to two types of extinction. Relative to their baselines, adolescent rats responded more during extinction than adults, suggesting that they were less sensitive to the abolishment of the reinforcement contingency. Experiment 2 demonstrated similar age-related differences during exposure to a differential reinforcement of low rates schedule, a test of behavioral inhibition. Lastly, in Experiment 3, adolescent's responding decreased more slowly than adults during exposure to a resetting delay of reinforcement schedule, suggesting impaired self-control. Results from these experiments suggest that adolescents exhibit impaired learning, behavioral inhibition and self-control, and in concert with recent reports, provide researchers with three behavioral models to more fully explore neurobiology of risk-taking behavior in adolescence. PMID- 21319892 TI - D-cycloserine enhances memory consolidation in the plus-maze retest paradigm. AB - Prior undrugged exposure to the elevated plus-maze (EPM) alters future behavioral strategy as well as responsivity to conventional anxiolytic agents. This EPM retest phenomenon appears to be dependent upon learning the spatial configuration of the maze on initial exposure and, in particular, the location of the relatively safe enclosed arms. As posttraining administration of the glycineB receptor partial agonist, D-cycloserine (DCS), has been shown to enhance the consolidation of many forms of memory, we have examined the effects of this compound on the EPM retest effect in male mice. The results of Experiment 1 confirmed that 5 min undrugged exposure to the EPM completed abolishes the anxiolytic efficacy of chlordiazepoxide (CDP; 15 mg/kg) on 24 hr retest. In Experiment 2, posttraining administration of DCS (7.5 and 15 mg/kg), but not CDP (15 mg/kg) or DCS (30 mg/kg), significantly and selectively increased time spent in the enclosed arms (and reciprocally decreased open arm exploration) on 24 hr retest, a finding consistent with an enhancement of consolidation. Experiment 3 used a modified EPM retest protocol to assess the effects of posttraining DCS (15 mg/kg) on behavioral responses to CDP (15 mg/kg) challenge on 24 hr retest. Using a 1-min prior exposure regimen that did not compromise the anxiolytic efficacy of CDP in control mice, the results showed that posttraining administration of DCS abolished the anxiolytic response to CDP challenge. These data strongly suggest that the EPM retest effect involves glycineB/NMDA receptor-dependent neuroplasticity. Further studies will be required to identify the neural circuitry involved. PMID- 21319893 TI - c-Fos, Arc, and stargazin expression in rat eyeblink conditioning. AB - Neuronal plasticity induced by behavioral experience, as in memory formation, has been considered to involve transcriptional or translational changes in subsets of neurons involved in different forms of learning. Here, alteration in protein expression during cerebellar learning was investigated using rat eyeblink conditioning. After a single training session of delay conditioning, c-Fos was insignificantly increased when compared to naive or pseudoconditioned rats. In contrast, the number of Purkinje cells with positive expression of activity regulated cytoskeletal-associated protein was significantly increased in the cerebellar cortex. A significant increase in Stargazin expression was also identified in the whole cerebellum. These preliminary findings document possible molecular mechanisms underlying the establishment of memory in the mammalian cerebellum. PMID- 21319894 TI - Synthetic versus natural cat odorant effects on rodent behavior and medial amygdala plasticity. AB - Fear and anxiety behaviors are underpinned by neuronal changes within the amygdala. Here, the effects of exposure to natural and synthetic cat odor on behavior and amygdala plasticity were determined. Exposure to natural odor elicited typical and persistent anxiety-related behaviors, such as avoidance, freezing, and flat-back approach; however, synthetic odorant evoked no significant alteration in behavior. Furthermore, ex vivo induction of long-term potentiation within the medial nucleus of the amygdala, a principal area involved in olfactory perception, was significantly reduced after exposure to natural, but not synthetic, odor. Data presented here suggests that the synthetic odorant utilized may lack the constituents that are required to indicate predator presence in rodents and also the capacity to modulate neuronal plasticity within the medial nucleus of the amygdala. PMID- 21319895 TI - Sexual risk among African American girls: psychopathology and mother-daughter relationships. AB - OBJECTIVE: To examine the associations among mental health problems, maternal monitoring and permissiveness, mother-daughter communication and attachment, and sexual behaviors among African American girls receiving outpatient psychiatric care. Youths with mental health problems report higher rates of HIV-risk behavior than do their peers, and African American girls have higher rates of sexually transmitted infections than do girls of all other racial groups. METHOD: A sample of 12- to 16-year-old African American girls (N = 266, mean age = 14.46 years) and their female caregivers (73% biological mothers) completed computerized assessments of girls' mental health symptoms, maternal monitoring and permissiveness, and mother-daughter communication and attachment. Girls indicated their sexual risk behaviors (vaginal/anal sex, consistent condom use, number of partners). RESULTS: African American girls who reported clinically significant externalizing problems, more permissive parenting, less open mother-daughter sexual communication, and more frequent mother-daughter communication were more likely to report having had vaginal and/or anal sex. Sexually active girls with greater maternal attachment were less likely to report inconsistent condom use. CONCLUSIONS: Findings revealed important risk and protective factors for African American girls in psychiatric care. HIV-prevention programs may be strengthened by improving mother-daughter relationships and communication and by reducing girls' mental health problems. PMID- 21319896 TI - ModerateDrinking.Com and moderation management: outcomes of a randomized clinical trial with non-dependent problem drinkers. AB - OBJECTIVE: To evaluate the effectiveness of a web-based protocol, ModerateDrinking.com (MD; www.moderatedrinking.com) combined with use of the online resources of Moderation Management (MM; www.moderation.org) as opposed to the use of the online resources of MM alone. METHOD: We randomly assigned 80 problem drinkers to either the experimental or control group with follow-ups at 3, 6, and 12 months. RESULTS: Seventy-five participants (94%) had outcome data at 1 or more follow-up points, and 59 participants (73%) were assessed at all 3 follow-ups. Comparing baseline measures to the average outcomes at follow-ups indicated a significant overall reduction in both groups in alcohol-related problems and consumption variables. Compared with the control group, the experimental group had better outcomes on percent days abstinent. There was an interaction between intensity of drinking at baseline and treatment in determining outcomes assessing drinking. Less heavy drinkers in the experimental group had better outcomes on log mean blood alcohol content (BAC) per drinking day compared with the control group. Heavier drinkers did not differentially benefit from the MD program on this measure. Mixed model analyses in general corroborated these outcomes. CONCLUSION: The outcome data provide partial evidence for the effectiveness of the MD web application combined with MM, compared with the effectiveness of the resources available online at MM by themselves. PMID- 21319897 TI - Randomized controlled trial of a preventive intervention for perinatal depression in high-risk Latinas. AB - OBJECTIVE: A randomized controlled trial was conducted to evaluate the efficacy of a cognitive-behavioral (CBT) intervention to prevent perinatal depression in high-risk Latinas. METHOD: A sample of 217 participants, predominantly low-income Central American immigrants who met demographic and depression risk criteria, were randomized into usual care (UC; n = 105) or an 8-week CBT group intervention during pregnancy and 3 individual booster sessions during postpartum (n = 112). Participants completed measures assessing depressive symptoms (Center for Epidemiological Studies Depression Scale at baseline; Beck Depression Inventory, Second Edition [BDI-II]) and major depressive episodes (Mood Screener) at 5 time points throughout the perinatal period. RESULTS: Intent-to-treat analyses indicated that intervention participants had significantly lower depressive symptoms and fewer cases of moderate depression (BDI-II >= 20) at Time 2 than UC participants. These effects were stronger for women who fully participated in the intervention (>= 4 classes). The cumulative incidence of major depressive episodes was not significantly different between the intervention (7.8%) and UC (9.6%) groups. CONCLUSIONS: A CBT intervention for low-income, high-risk Latinas reduced depressive symptoms during pregnancy but not during the postpartum period. Low levels of depressive symptoms and lower than expected rates of clinical depression in both groups may partially be due to methodological issues. As perinatal depression is a significant public health problem, more work is needed to prevent perinatal depression in low-income, ethnically diverse women. PMID- 21319898 TI - Predictors of the change in self-stigma following a single session of group counseling. AB - One of the major obstacles to seeking psychological help is the stigma associated with counseling and therapy. Self-stigma, the fear of losing self-respect or self esteem as a result of seeking help, is an important factor in the help-seeking process. In the present study, college students meeting a clinical cutoff for psychological symptoms participated in 1 session of group counseling that either contained therapist self-disclosure or did not. In general, participants reported significantly less self-stigma following the session. Working alliance-bond and session depth significantly predicted the change in self-stigma. Furthermore, self-stigma (as well as bond, depth, psychological symptoms, and being female) predicted the intention to seek help following the session. Self-stigma and session depth also predicted interest in continuing with counseling. The therapist self-disclosure condition, however, had no effect on the change in self stigma, intentions to seek help, or interest in continuing with group counseling. PMID- 21319899 TI - Revision and extension of a multidimensional measure of sexual minority identity: the Lesbian, Gay, and Bisexual Identity Scale. AB - Two studies were conducted to investigate a revised and extended version of the Lesbian and Gay Identity Scale (Mohr & Fassinger, 2000): the 27-item Lesbian, Gay, and Bisexual Identity Scale (LGBIS). This revision features more inclusive and less stigmatizing language than the previous version and includes 2 new subscales assessing identity affirmation and centrality. In Study 1, an exploratory factor analysis (n = 297) and a confirmatory factor analysis (n = 357) supported an 8-factor solution assessing acceptance concerns, concealment motivation, identity uncertainty, internalized homonegativity, difficulty with the identity development process, identity superiority, identity affirmation, and identity centrality. Predicted associations with measures of identity-related constructs and psychosocial functioning provided preliminary validity evidence for LGBIS scores in a college student population. Study 2 (N = 51) provided evidence of the test-retest and internal consistency reliability of LGBIS scores. These studies suggest that the LGBIS may offer researchers an efficient means of assessing multiple dimensions of sexual orientation minority identity. PMID- 21319900 TI - Evaluating mixture modeling for clustering: recommendations and cautions. AB - This article provides a large-scale investigation into several of the properties of mixture-model clustering techniques (also referred to as latent class cluster analysis, latent profile analysis, model-based clustering, probabilistic clustering, Bayesian classification, unsupervised learning, and finite mixture models; see Vermunt & Magdison, 2002). Focus is given to the multivariate normal distribution, and 9 separate decompositions (i.e., class structures) of the covariance matrix are investigated. To provide a link to the current literature, comparisons are made with K-means clustering in 3 detailed Monte Carlo studies. The findings have implications for applied researchers in that mixture-model clustering techniques performed best when the covariance structure and number of clusters were known. However, as the information about the shape and number of clusters became unknown, degraded performance was observed for both K-means clustering and mixture-model clustering. PMID- 21319901 TI - Establishing the next generation at work: leader generativity as a moderator of the relationships between leader age, leader-member exchange, and leadership success. AB - In this study, the authors investigated leader generativity as a moderator of the relationships between leader age, leader-member exchange, and three criteria of leadership success (follower perceptions of leader effectiveness, follower satisfaction with leader, and follower extra effort). Data came from 128 university professors paired with one research assistant each. Results showed positive relationships between leader age and leader generativity, and negative relationships between leader age and follower perceptions of leader effectiveness and follower extra effort. Consistent with expectations based on leadership categorization theory, leader generativity moderated the relationships between leader age and all three criteria of leadership success, such that leaders high in generativity were better able to maintain high levels of leadership success at higher ages than leaders low in generativity. Finally, results of mediated moderation analyses showed that leader-member exchange quality mediated these moderating effects. The findings suggest that, in combination, leader age and the age-related construct of generativity importantly influence leadership processes and outcomes. PMID- 21319902 TI - Skills of Cognitive Therapy (SoCT): a new measure of patients' comprehension and use. AB - The authors describe the development and psychometric properties of a new measure called the Skills of Cognitive Therapy (SoCT) in depressed adults and their cognitive therapists. The 8-item SoCT assesses patients' understanding and use of basic cognitive therapy (CT) skills rated from the perspectives of both observers (SoCT-O; therapists in this report) and patients (SoCT-P). Ratings of patients' skill usage are made on 5-point Likert-type scales ranging from 1 (never) to 5 (always or when needed). Higher scores reflect greater patient skill in applying cognitive therapy principles and coping strategies. To develop this scale, a 33 item pool was used, rated by both patients and their therapists at the middle and end of CT (Ns = 359-416), and evaluated the reliability and concurrent and predictive validity of both versions of the scale. The SoCT has excellent internal consistency reliability and moderate correlations between the observer and patient versions. It is important to note that the SoCT showed good predictive validity for response when collected at the midpoint of acute phase CT. Considering both patients' self-ratings and clinicians' SoCT ratings, the odds ratio for responding to CT was 2.6. The practical utility of the SoCT is discussed, as well as its theoretical importance in research of patient CT skills (e.g., acquisition, comprehension, and generalization) as putative moderators or mechanisms of symptom change in the therapy. PMID- 21319903 TI - Classifying adolescent perfectionists. AB - A large school-based sample of 9th-grade adolescents (N = 875) completed the Almost Perfect Scale-Revised (APS-R; Slaney, Mobley, Trippi, Ashby, & Johnson, 1996). Decision rules and cut-scores were developed and replicated that classify adolescents as one of two kinds of perfectionists (adaptive or maladaptive) or as nonperfectionists. A four-cluster solution further differentiating nonperfectionists was also evaluated. Criterion-related validity of the cluster solutions was supported by perfectionist and nonperfectionist group differences on select subscales of the Multidimensional Students' Life Satisfaction Scale (MSLSS; Huebner, 1994) and the Behavior Assessment System for Children, Second Edition: Self-Report-Adolescent (BASC-2: SRP-A; Reynolds & Kamphaus, 2004). Adaptive and maladaptive perfectionists were supported in both cluster solutions and validity analyses. In addition to the two types of perfectionists, the four cluster solution differentiated two types of nonperfectionists from one that seemed similar to maladaptive perfectionists in terms of BASC-2: SRP-A scores. Although the four-cluster solution may have potential value, the three-cluster solution was recommended as more parsimonious for studies attempting to differentiate perfectionists. The findings and straightforward decision rules were generally consistent in principle with other studies attempting to classify perfectionists, although the final APS-R cut-scores differed from those of other studies of adults. The results provided additional descriptive inferences for perfectionistic and nonperfectionistic adolescents. Among other issues, the findings raised the question of whether the label of maladaptive for a subgroup of perfectionists was too broad given that the criterion-related validity scores revealed that the group's problems in adjustment were conspicuous only in the areas of anxiety and social stress. PMID- 21319904 TI - Validating an indirect measure of clarity of feelings: evidence from laboratory and naturalistic settings. AB - This study analyzed the reliability and validity of an indirect measure of clarity of feelings that is based on response latencies (RTs) of mood ratings. Fifty-two participants completed a laboratory session and an experience-sampling week with 6 measurement occasions per day. Shorter RT of mood ratings measured in the laboratory (but not self-reported dispositional clarity) predicted higher overall mood regulation success during the experience-sampling week. As a new indirect ambulatory measure of clarity, RTs of mood ratings were measured on handheld devices during the experience-sampling week. The new ambulatory RT measure of clarity demonstrated good psychometric properties. Within-occasions reliability (internal consistency) was satisfactory, and between-occasions reliability (consistency of aggregated scores) was high. Ambulatory RT of mood ratings demonstrated moderate to high convergence with RT of mood ratings measured in the laboratory session. Both RT measures were unrelated to self reported dispositional clarity of feelings. However, momentary RT converged with a self-report measure of momentary clarity on the within-persons level: Participants were faster to rate those mood items that they were more certain about. Evidence for the predictive validity of the new ambulatory RT measure was provided by the finding that on the within-persons level, shorter RT (but not self-reported momentary clarity) predicted higher mood regulation success and better mood at subsequent measurement occasions. The results suggest that RT of mood ratings can be used as a reliable and valid indicator of an individual's clarity of feelings in laboratory and experience-sampling studies. PMID- 21319905 TI - The equivalence of regression models using difference scores and models using separate scores for each informant: implications for the study of informant discrepancies. AB - Research on informant discrepancies has increasingly utilized difference scores. This article demonstrates the statistical equivalence of regression models using difference scores (raw or standardized) and regression models using separate scores for each informant to show that interpretations should be consistent with both models. First, regression equations were used to demonstrate that difference score models are equivalent to models using separate scores for each informant. Second, a hypothesis-driven empirical example (218 mother-child dyads, mean age = 11.5 years, 49% female participants, 49% White, 47% African American) was used to provide an illustration of the equivalence of the 2 models. Implications of the equivalence of models using difference scores and models using separate scores for each informant are discussed in terms of the growing prevalence of an interpretation in the literature of difference score analyses that is inconsistent with results from equivalent separate informant analyses. Differences in the separate predictive ability of informants should be acknowledged as an alternative interpretation of the difference score regression coefficient. PMID- 21319906 TI - Psychometric properties of reverse-scored items on the CES-D in a sample of ethnically diverse older adults. AB - Reverse-scored items on assessment scales increase cognitive processing demands and may therefore lead to measurement problems for older adult respondents. In this study, the objective was to examine possible psychometric inadequacies of reverse-scored items on the Center for Epidemiologic Studies Depression Scale (CES-D) when used to assess ethnically diverse older adults. Using baseline data from a gerontologic clinical trial (n = 460), we tested the hypotheses that the reversed items on the CES-D (a) are less reliable than nonreversed items, (b) disproportionately lead to intraindividually atypical responses that are psychometrically problematic, and (c) evidence improved measurement properties when an imputation procedure based on the scale mean is used to replace atypical responses. In general, the results supported the hypotheses. Relative to nonreversed CES-D items, the 4 reversed items were less internally consistent, were associated with lower item-scale correlations, and were more often answered atypically at an intraindividual level. Further, the atypical responses were negatively correlated with responses to psychometrically sound nonreversed items that had similar content. The use of imputation to replace atypical responses enhanced the predictive validity of the set of reverse-scored items. Among older adult respondents, reverse-scored items are associated with measurement difficulties. It is recommended that appropriate correction procedures such as item readministration or statistical imputation be applied to reduce the difficulties. PMID- 21319907 TI - The psychometric properties and utility of the Short Sadistic Impulse Scale (SSIS). AB - Sadistic personality disorder (SPD) has been underresearched and often misunderstood in forensic settings. Furthermore, personality disorders in general are the subject of much controversy in terms of their classification (i.e., whether they should be categorical or dimensional). The Sadistic Attitudes and Behaviors Scale (SABS; Davies & Hand, 2003; O'Meara, Davies, & Barnes-Holmes, 2004) is a recently developed scale for measuring sadistic inclinations. Derived from this is the Short Sadistic Impulse Scale (SSIS), which has proved to be a strong unidimensional measure of sadistic inclination. Through cumulative scaling, it was investigated whether the SSIS could measure sadism on a continuum of interest, thus providing a dimensional view of the construct. Further, the SSIS was administered along with a number of other measures related to sadism in order to assess the validity of the scale. Results showed that the SSIS has strong construct and discriminant validity and may be useful as a screening measure for sadistic impulse. PMID- 21319908 TI - Assessing adolescent mindfulness: validation of an adapted Mindful Attention Awareness Scale in adolescent normative and psychiatric populations. AB - Interest in mindfulness-based interventions for children and adolescents is burgeoning, bringing with it the need for validated instruments to assess mindfulness in youths. The present studies were designed to validate among adolescents a measure of mindfulness previously validated for adults (e.g., Brown & Ryan, 2003), which we herein call the Mindful Attention Awareness Scale Adolescent (MAAS-A). In 2 large samples of healthy 14- to 18-year-olds (N = 595), Study 1 supported a single-factor MAAS-A structure, along with acceptably high internal consistency, test-retest reliability, and both concurrent and incremental validity. In Study 2, with a sample of 102 psychiatric outpatient adolescents age 14-18 years, participants randomized to a mindfulness-based stress reduction intervention showed significant increases in MAAS-A scores from baseline to 3-month follow-up, relative to nonsignificant score changes among treatment-as-usual participants. Increases in MAAS-A scores among mindfulness based stress reduction participants were significantly related to beneficial changes in numerous mental health indicators. The findings support the reliability and validity of the MAAS-A in normative and mixed psychiatric adolescent populations and suggest that the MAAS-A has utility in mindfulness intervention research. PMID- 21319909 TI - Personality Assessment Inventory profiles of deployed combat troops: an empirical investigation of normative performance. AB - The present study examined the normative scores and psychometric properties of the Personality Assessment Inventory (PAI; Morey, 1991) within a non-treatment seeking sample of soldiers deployed to combat zones in Iraq, compared with a sample of community adults matched with respect to age and gender. Results indicate the scores and properties of the PAI scales were generally quite similar in the Iraq and community samples, with modest differences emerging on only 3 subscales addressing antisocial behavior, issues with close relationships, and interpersonal vigilance. These results suggest that standard normative interpretation of PAI scales is appropriate even when the instrument is administered in a combat zone. In comparison with prior research, the results may suggest that documented mental health issues among combat veterans, when present, may be particularly likely to emerge postdeployment. PMID- 21319910 TI - Let's get serious: communicating commitment in romantic relationships. AB - Are men or women more likely to confess love first in romantic relationships? And how do men and women feel when their partners say "I love you"? An evolutionary economics perspective contends that women and men incur different potential costs and gain different potential benefits from confessing love. Across 6 studies testing current and former romantic relationships, we found that although people think that women are the first to confess love and feel happier when they receive such confessions, it is actually men who confess love first and feel happier when receiving confessions. Consistent with predictions from our model, additional studies have shown that men's and women's reactions to love confessions differ in important ways depending on whether the couple has engaged in sexual activity. These studies have demonstrated that saying and hearing "I love you" has different meanings depending on who is doing the confessing and when the confession is being made. Beyond romantic relationships, an evolutionary economics perspective suggests that displays of commitment in other types of relationships--and reactions to these displays--will be influenced by specific, functional biases. PMID- 21319911 TI - Essentialism goes social: belief in social determinism as a component of psychological essentialism. AB - Individuals tend to explain the characteristics of others with reference to an underlying essence, a tendency that has been termed psychological essentialism. Drawing on current conceptualizations of essentialism as a fundamental mode of social thinking, and on prior studies investigating belief in genetic determinism (BGD) as a component of essentialism, we argue that BGD cannot constitute the sole basis of individuals' essentialist reasoning. Accordingly, we propose belief in social determinism (BSD) as a complementary component of essentialism, which relies on the belief that a person's essential character is shaped by social factors (e.g., upbringing, social background). We developed a scale to measure this social component of essentialism. Results of five correlational studies indicate that (a) BGD and BSD are largely independent, (b) BGD and BSD are related to important correlates of essentialist thinking (e.g., dispositionism, perceived group homogeneity), (c) BGD and BSD are associated with indicators of fundamental epistemic and ideological motives, and (d) the endorsement of each lay theory is associated with vital social-cognitive consequences (particularly stereotyping and prejudice). Two experimental studies examined the idea that the relationship between BSD and prejudice is bidirectional in nature. Study 6 reveals that rendering social-deterministic explanations salient results in increased levels of ingroup favoritism in individuals who chronically endorse BSD. Results of Study 7 show that priming of prejudice enhances endorsement of social-deterministic explanations particularly in persons habitually endorsing prejudiced attitudes. PMID- 21319912 TI - If you are able to control yourself, I will trust you: the role of perceived self control in interpersonal trust. AB - The present research tested the hypothesis that perception of others' self control is an indicator of their trustworthiness. The authors investigated whether, in interactions between strangers as well as in established relationships, people detect another person's self-control, and whether this perception of self-control, in turn, affects trust. Results of 4 experiments supported these hypotheses. The first 2 experiments revealed that participants detected another person's trait of self-control. Experiments 3 and 4 revealed that participants also detected the temporary depletion of another person's self control. Confirming the authors' predictions, perceived trait and state self control, in turn, influenced people's judgment of the other person's trustworthiness. In line with previous research, these findings support the positive value of self-control for relationships and highlight the role of perceived self-control for the development of a fundamental relationship factor: trust. PMID- 21319913 TI - Simultaneous backward conditioned inhibition and mediated conditioning. AB - Demonstrations of retrospective revaluation suggest that remembered stimuli undergo a reduction in association with the unconditioned stimulus (US) present during learning. Conversely, demonstrations of mediated conditioning in flavor conditioning experiments with rats suggest that remembered stimuli undergo an increase in association with the US present during learning. In a food allergy prediction task with 23 undergraduates, we demonstrated simultaneous backward conditioned inhibition and mediated conditioning effects. These results are compatible with the hypothesis that the direction of change (decrease or increase) in associative strength depends on whether the remembered stimulus was of a different category (conditioned stimulus/antecedent) or the same category (US/outcome) as the presented US. PMID- 21319914 TI - The hide-and-seek of retrospective revaluation: recovery from blocking is context dependent in human causal learning. AB - In a typical blocking procedure, pairings of a compound consisting of 2 stimuli, A and X, with the outcome are preceded by pairings of only A with the outcome (i.e., A+ then AX+). This procedure is known to diminish responding to the target cue (X) relative to a control group that does not receive the preceding training with blocking cue A. We report 2 experiments that investigated the effect of extinguishing a blocking cue on responding to the target cue in a human causal learning paradigm (i.e., A+ and AX+ training followed by A- training). The results indicate that extinguishing a blocking cue increases conditioned responding to the target cue. Moreover, this increase appears to be context dependent, such that increased responding to the target is limited to the context in which extinction of the blocking cue took place. We discuss these findings in the light of associative and propositional learning theories. PMID- 21319915 TI - Overt attention and predictiveness in human contingency learning. AB - Two experiments used eye-tracking procedures to investigate the relationship between attention and associative learning in human participants. These experiments found greater overt attention to cues experienced as predictive of the outcomes with which they were paired, than to cues experienced as nonpredictive. Moreover, this attentional bias persisted into a second training phase when all cues were equally predictive of the outcomes with which they were paired, and it was accompanied by a related bias in the rate of learning about these cues. These findings are consistent with the attentional model of associative learning proposed by Mackintosh (1975), but not with that proposed by Pearce and Hall (1980). PMID- 21319916 TI - Numerical judgments by chimpanzees (Pan troglodytes) in a token economy. AB - We presented four chimpanzees with a series of tasks that involved comparing two token sets or comparing a token set to a quantity of food. Selected tokens could be exchanged for food items on a one-to-one basis. Chimpanzees successfully selected the larger numerical set for comparisons of 1 to 5 items when both sets were visible and when sets were presented through one-by-one addition of tokens into two opaque containers. Two of four chimpanzees used the number of tokens and food items to guide responding in all conditions, rather than relying on token color, size, total amount, or duration of set presentation. These results demonstrate that judgments of simultaneous and sequential sets of stimuli are made by some chimpanzees on the basis of the numerousness of sets rather than other non-numerical dimensions. The tokens were treated as equivalent to food items on the basis of their numerousness, and the chimpanzees maximized reward by choosing the larger number of items in all situations. PMID- 21319917 TI - Competitive short-term and long-term memory processes in spatial habituation. AB - Exposure to a spatial location leads to habituation of exploration such that, in a novelty preference test, rodents subsequently prefer exploring a novel location to the familiar location. According to Wagner's (1981) theory of memory, short term and long-term habituation are caused by separate and sometimes opponent processes. In the present study, this dual-process account of memory was tested. Mice received a series of exposure training trials to a location before receiving a novelty preference test. The novelty preference was greater when tested after a short, rather than a long, interval. In contrast, the novelty preference was weaker when exposure training trials were separated by a short, rather than a long interval. Furthermore, it was found that long-term habituation was determined by the independent effects of the amount of exposure training and the number of exposure training trials when factors such as the intertrial interval and the cumulative intertrial interval were controlled. A final experiment demonstrated that a long-term reduction of exploration could be caused by a negative priming effect due to associations formed during exploration. These results provide evidence against a single-process account of habituation and suggest that spatial habituation is determined by both short-term, recency-based memory and long-term, incrementally strengthened memory. PMID- 21319918 TI - Orientation in trapezoid-shaped enclosures: implications for theoretical accounts of geometry learning. AB - Human participants learned to select 1 of 4 distinctively marked corners in a rectangular virtual enclosure. After training, control and test trials were interspersed with training trials. On control and test trials, all markers were equivalent in color, but only during test trials was the shape of the enclosure manipulated. Specifically, for each test trial, a single long wall or short wall of the enclosure increased twice as long as or decreased half as long as that present in the training enclosure. These manipulations produced 8 unique trapezoid-shaped enclosures. Participants were allowed to select 1 corner during control and test trials. Performance during control trials revealed that participants selected the correct and rotationally equivalent locations. Performance during test trials revealed that participants selected locations in trapezoid-shaped enclosures that were consistent with those predicted by global geometry (i.e., principal axis of space) but were inconsistent with those predicted by local geometry (i.e., proportion of rewarded training features present at a location). Results have implications for theoretical accounts of geometry learning. PMID- 21319919 TI - How does processing affect storage in working memory tasks? Evidence for both domain-general and domain-specific effects. AB - Two studies that examine whether the forgetting caused by the processing demands of working memory tasks is domain-general or domain-specific are presented. In each, separate groups of adult participants were asked to carry out either verbal or nonverbal operations on exactly the same processing materials while maintaining verbal storage items. The imposition of verbal processing tended to produce greater forgetting even though verbal processing operations took no longer to complete than did nonverbal processing operations. However, nonverbal processing did cause forgetting relative to baseline control conditions, and evidence from the timing of individuals' processing responses suggests that individuals in both processing groups slowed their responses in order to "refresh" the memoranda. Taken together the data suggest that processing has a domain-general effect on working memory performance by impeding refreshment of memoranda but can also cause effects that appear domain-specific and that result from either blocking of rehearsal or interference. PMID- 21319920 TI - Prediction and uncertainty in human Pavlovian to instrumental transfer. AB - Attentional capture and behavioral control by conditioned stimuli have been dissociated in animals. The current study assessed this dissociation in humans. Participants were trained on a Pavlovian schedule in which 3 visual stimuli, A, B, and C, predicted the occurrence of an aversive noise with 90%, 50%, or 10% probability, respectively. Participants then went on to separate instrumental training in which a key-press response canceled the aversive noise with a .5 probability on a variable interval schedule. Finally, in the transfer phase, the 3 Pavlovian stimuli were presented in this instrumental schedule and were no longer differentially predictive of the outcome. Observing times and gaze dwell time indexed attention to these stimuli in both training and transfer. Aware participants acquired veridical outcome expectancies in training--that is, A > B > C, and these expectancies persisted into transfer. Most important, the transfer effect accorded with these expectancies, A > B > C. By contrast, observing times accorded with uncertainty--that is, they showed B > A = C during training, and B < A = C in the transfer phase. Dwell time bias supported this association between attention and uncertainty, although these data showed a slightly more complicated pattern. Overall, the study suggests that transfer is linked to outcome prediction and is dissociated from attention to conditioned stimuli, which is linked to outcome uncertainty. PMID- 21319921 TI - The effects of concurrent verbal and visual tasks on category learning. AB - Current theories of category learning posit separate verbal and nonverbal learning systems. Past research suggests that the verbal system relies on verbal working memory and executive functioning and learns rule-defined categories; the nonverbal system does not rely on verbal working memory and learns non-rule defined categories (E. M. Waldron & F. G. Ashby, 2001; D. Zeithamova & W. T. Maddox, 2006). However, relatively little research has explored the importance of visual working memory or visual processing for either system. The authors investigated the role of working memory (Experiment 1a and 1b), visual processing (Experiment 2), and executive functioning for each system, using a concurrent task methodology. It was found that visual tasks with high executive functioning demands and verbal tasks with high or low executive demands disrupted rule defined learning, whereas any visual task, regardless of executive functioning demand, disrupted non-rule-defined learning. Taken together, these results confirm the importance of verbal working memory and executive functioning for the verbal system and provide new evidence for the importance of visual processing for the nonverbal system. These results help to clarify understanding of the nonverbal system and have implications for multiple systems theories of category learning (F. G. Ashby, L. A. Alfonso-Reese, A. U. Turken, & E. M. Waldron, 1998). PMID- 21319922 TI - Did lifetime rates of alcohol use disorders increase by 67% in 10 years? A comparison of NLAES and NESARC. AB - Two nationally representative epidemiological samples (the National Longitudinal Alcohol Epidemiological Survey and the National Epidemiological Survey of Alcohol and Related Conditions) have been used to track changes in the prevalence of alcohol use disorders (AUDs) between 1992 and 2002 in the United States. Strikingly, estimates from these two data sets suggest that the lifetime prevalence of AUD increased by approximately 67% (from 18.2% to 30.3%) during this time frame. This article explores potential reasons for these discrepant estimates. Analyses indicated that a vast majority of change in lifetime AUD occurred with respect to alcohol abuse and not alcohol dependence. Most of this increase in abuse was attributable to self-reported changes in hazardous use that did not track with other archival measures of outcomes related to hazardous use in the population. Key methodological differences regarding the frequency requirements for prior-to-past-year alcohol abuse appeared to explain most of the discrepancy in lifetime AUD estimates. These findings, in conjunction with the relative lack of differences in the 12-month prevalence of AUDs, suggest that the discrepant lifetime estimates are likely due to methodological differences between the two surveys. These findings have important implications for substance use and other psychiatric surveillance and epidemiology where meaningful cross temporal comparisons are desired. PMID- 21319923 TI - Sex differences in the genetic and environmental influences on childhood conduct disorder and adult antisocial behavior. AB - Sex differences in the genetic and environmental influences on childhood conduct disorder and adult antisocial behavior were examined in a large community sample of 6,383 adult male, female, and opposite-sex twins. Retrospective reports of childhood conduct disorder (prior to 18 years of age) were obtained when participants were approximately 30 years old, and lifetime reports of adult antisocial behavior (antisocial behavior after 17 years of age) were obtained 8 years later. Results revealed that either the genetic or the shared environmental factors influencing childhood conduct disorder differed for males and females (i.e., a qualitative sex difference), but by adulthood, these sex-specific influences on antisocial behavior were no longer apparent. Further, genetic and environmental influences accounted for proportionally the same amount of variance in antisocial behavior for males and females in childhood and adulthood (i.e., there were no quantitative sex differences). Additionally, the stability of antisocial behavior from childhood to adulthood was slightly greater for males than females. Though familial factors accounted for more of the stability of antisocial behavior for males than females, genetic factors accounted for the majority of the covariation between childhood conduct disorder and adult antisocial behavior for both sexes. The genetic influences on adult antisocial behavior overlapped completely with the genetic influences on childhood conduct disorder for both males and females. Implications for future twin and molecular genetic studies are discussed. PMID- 21319924 TI - Risk factors for disordered eating during early and middle adolescence: prospective evidence from mainland Chinese boys and girls. AB - Despite evidence that sociocultural and psychological factors contribute to disordered eating, researchers have yet to examine the extent to which putative risk factors influence vulnerability for girls versus boys within and across phases of adolescence, particularly in non-Western cultures. In this study, early and middle adolescent samples from China (N = 2,909) completed measures of eating disorder pathology and putative risk factors at baseline and were reassessed 12 months later. Among both younger and older girls, elevations in appearance focused interactions with friends, negative affect, and body dissatisfaction predicted increases in symptomatology at follow-up. In contrast, there was more discontinuity in risk factors relevant to samples of boys. Although media and friendship influences contributed to later disturbances among early adolescent boys, psychological factors, including body dissatisfaction and negative affect, had stronger effects in the multivariate model for older boys. Implications of finding are discussed in relation to adolescent development and a Chinese cultural context. PMID- 21319925 TI - Change in maternal criticism and behavior problems in adolescents and adults with autism across a 7-year period. AB - In a previous study, high levels of maternal criticism predicted increased behavior problems in adolescents and adults with autism spectrum disorders (ASD) over an 18-month period (Greenberg, Seltzer, Hong, & Orsmond, 2006). The current investigation followed these families over a period of 7 years to examine the longitudinal course of criticism and behavior problems, to assess the association between their trajectories, and to determine the degree to which change in each of these factors predicted levels of criticism and behavior problems at the end of the study period. A sample of 118 mothers coresiding with their adolescent and adult children with ASD provided open-ended narratives about their children and reported on the children's behavior problems at 4 waves. Maternal criticism was derived from expressed emotion ratings of the narratives. Criticism exhibited low but significant stability over the 7-year period, and behavior problems exhibited high stability. Through latent growth curve modeling, (a) criticism was found to have increased over time, but only for the group of families in which the sons or daughters transitioned from high school services during the study period; (b) individual changes in criticism and behavior problems were positively correlated over the 7-year period; and (c) changes in criticism predicted levels of behavior problems at the conclusion of the study. Changes in behavior problems were not predictive of end levels of criticism. Implications for intervention and prevention efforts are discussed. PMID- 21319926 TI - Heterogeneity of auditory verbal working memory in schizophrenia. AB - The heterogeneity of schizophrenia remains an obstacle for understanding its pathophysiology. Studies using a tone discrimination screening test to classify patients have found evidence for 2 subgroups having either a specific deficit in verbal working memory (WM) or deficits in both verbal and nonverbal memory. This study aimed to (a) replicate in larger samples differences between these subgroups in auditory verbal WM; (b) evaluate their performance on tests of explicit memory and sustained attention; (c) determine the relation of verbal WM deficits to auditory hallucinations and other symptoms; and (d) examine medication effects. The verbal WM and tone discrimination performance did not differ between medicated (n = 45) and unmedicated (n = 38) patients. Patients with schizophrenia who passed the tone screening test (discriminators; n = 60) were compared with those who did not (nondiscriminators; n = 23) and healthy controls (n = 47). The discriminator subgroup showed poorer verbal WM than did controls and a deficit in verbal but not visual memory on the Wechsler Memory Scale-Revised (Wechsler, 1987), whereas the nondiscriminator subgroup showed overall poorer performance on both verbal and nonverbal tests and a marked deficit in sustained attention. Verbal WM deficits in discriminators were correlated with auditory hallucinations but not with negative symptoms. The results are consistent with a verbal memory deficit in a subgroup of schizophrenia having intact auditory perception, which may stem from dysfunction of language-related cortical regions, and a more generalized cognitive deficit in a subgroup having auditory perceptual and attentional dysfunction. PMID- 21319927 TI - To see ourselves as others see us: an experimental integration of the intra and interpersonal consequences of self-protection in social anxiety disorder. AB - The current study investigated the mechanism through which safety behaviors perpetuate perceived and actual negative social outcomes hypothesized to maintain social anxiety disorder (SAD). Eighty individuals diagnosed with generalized SAD took part in a "getting acquainted" conversation with a trained experimental confederate. Participants were then randomly assigned to either a safety behavior reduction plus exposure condition (SB + EXP) or a graduated exposure (EXP) control condition and completed a 2nd conversation with the same interaction partner. Mediation analyses revealed that participants instructed to reduce their idiosyncratic safety behaviors displayed significantly greater increases in both perceived and actual positive interpersonal outcomes relative to the EXP group. However, whereas the safety behavior manipulation influenced participants' appraisals of their partner's reaction to them through reducing self-judgments about the visibility of anxiety-related behaviors, in reality, the SB + EXP group elicited more positive partner reactions because they displayed a greater increase in social approach behavior. Thus, although both parties recognized positive changes in the social exchange following the safety behavior manipulation, different sources of social information accounted for participant versus partner interpersonal judgments. The current findings point to the potential value of considering both the intra and interpersonal consequences of safety behaviors in SAD. PMID- 21319928 TI - Emotional reactivity to daily events in major and minor depression. AB - Although emotional dysfunction is an important aspect of major depressive disorder (MDD), it has rarely been studied in daily life. Peeters, Nicolson, Berkhof, Delespaul, and deVries (2003) observed a surprising mood-brightening effect when individuals with MDD reported greater reactivity to positive events. To better understand this phenomenon, we conducted a multimethod assessment of emotional reactivity to daily life events, obtaining detailed reports of appraisals and event characteristics using the experience-sampling method and the Day Reconstruction Method (Kahneman, Krueger, Schkade, Schwarz, & Stone, 2004) in 35 individuals currently experiencing a major depressive episode, 26 in a minor depressive (mD) episode, and 38 never-depressed healthy controls. Relative to healthy controls, both mood-disordered groups reported greater daily negative affect and lower positive affect and reported events as less pleasant, more unpleasant, and more stressful. Importantly, MDD and mD individuals reported greater reductions in negative affect following positive events, an effect that converged across assessment methods and was not explained by differences in prevailing affect, event appraisals, or medications. Implications of this curious mood-brightening effect are discussed. PMID- 21319929 TI - Experimental modification of attribution processes. AB - Attributional style is hypothesized to be a causative factor in depression vulnerability; however, no studies to date have examined whether manipulation of attributional style influences depressed mood. The purpose of this study was to determine whether computer-based cognitive bias modification (CBM) procedures could modify attributional style and influence stress vulnerability. Participants were provided with multiple training trials that were intended to promote the use of either a positive or a negative attributional style. Compared with individuals in the negative attributional style condition, individuals in the positive attributional style condition showed decreased tendency to make self-deficient causal attributions for poor performance on a difficult anagram test. Furthermore, individuals in the positive attributional style condition reported less depressed mood in response to this academic stressor. These results suggest that attributional style is not invariable and can potentially be modified with CBM approaches. PMID- 21319930 TI - Associations between serotonin transporter gene promoter region (5-HTTLPR) polymorphism and gaze bias for emotional information. AB - The serotonin transporter promoter region polymorphism (5-HTTLPR) is associated with neural response to negative images in brain regions involved in the experience of emotion. However, the behavioral implications of this sensitivity have been studied far less extensively. The current study used eye-tracking methodology to examine how individuals genotyped for the 5-HTTLPR, including the single nucleotide polymorphism (SNP) rs25531, allocated attention during prolonged (30-s) exposure to face stimuli depicting positive and negative emotion. Short 5-HTTLPR allele carriers and carriers of the long allele with guanine at the sixth nucleotide (S/LG) displayed a stronger gaze bias (total fixation time, number of fixations, mean fixation length) for positive than for sad, threat, or neutral stimuli. In contrast, those homozygous for the long 5 HTTLPR allele with adenine at the sixth nucleotide (LA) viewed the emotion stimuli in an unbiased fashion. Time course analyses indicated no initial 5 HTTLPR group differences; however, S/LG 5-HTTLPR allele carriers were more likely than LA 5-HTTLPR homozygotes to direct gaze toward happy than toward sad stimuli over time. This bias toward positive stimuli during the later stages of information processing likely reflects a strategic effort to downregulate heightened reactivity to negative stimuli among 5-HTTLPR S/LG allele carriers. PMID- 21319931 TI - The joint structure of DSM-IV Axis I and Axis II disorders. AB - The Diagnostic and Statistical Manual (4th ed. [DSM-IV]; American Psychiatric Association, 1994) distinction between clinical disorders on Axis I and personality disorders on Axis II has become increasingly controversial. Although substantial comorbidity between axes has been demonstrated, the structure of the liability factors underlying these two groups of disorders is poorly understood. The aim of this study was to determine the latent factor structure of a broad set of common Axis I disorders and all Axis II personality disorders and thereby to identify clusters of disorders and account for comorbidity within and between axes. Data were collected in Norway, through a population-based interview study (N = 2,794 young adult twins). Axis I and Axis II disorders were assessed with the Composite International Diagnostic Interview (CIDI) and the Structured Interview for DSM-IV Personality (SIDP-IV), respectively. Exploratory and confirmatory factor analyses were used to investigate the underlying structure of 25 disorders. A four-factor model fit the data well, suggesting a distinction between clinical and personality disorders as well as a distinction between broad groups of internalizing and externalizing disorders. The location of some disorders was not consistent with the DSM-IV classification; antisocial personality disorder belonged primarily to the Axis I externalizing spectrum, dysthymia appeared as a personality disorder, and borderline personality disorder appeared in an interspectral position. The findings have implications for a meta structure for the DSM. PMID- 21319932 TI - Trauma reactivity, avoidant coping, and PTSD symptoms: a moderating relationship? AB - In the immediate aftermath of a traumatic event, many individuals experience physiological reactivity in response to reminders of the traumatic event that typically lessens over time. However, an overreliance on avoidant coping strategies may interfere with the natural recovery process, particularly for those who are highly reactive to trauma reminders. In the current investigation, we examined avoidant coping as a moderator of the association between heart rate reactivity to a trauma monologue measured shortly after a traumatic event and severity of posttraumatic stress disorder (PTSD) symptoms measured several months later. Fifty-five female survivors of assault completed PTSD diagnostic interviews and a self-report coping measure and participated in a trauma monologue procedure that included continuous heart rate measurement. These procedures were completed within 1 month of the assault and again 3 months postassault. After we controlled for the effect of initial symptom levels, the interaction of heart rate reactivity to the trauma monologue and avoidant coping measured at Time 1 was associated with PTSD symptom severity at Time 2. Individuals who are relatively highly reliant on avoidant coping strategies and relatively highly reactive to trauma reminders may be at greatest risk of maintaining or potentially increasing their PTSD symptoms within the first few months following the trauma. These findings may help inform early intervention efforts for survivors of traumatic events. PMID- 21319933 TI - Short-term memory in autism spectrum disorder. AB - Three experiments examined verbal short-term memory in comparison and autism spectrum disorder (ASD) participants. Experiment 1 involved forward and backward digit recall. Experiment 2 used a standard immediate serial recall task where, contrary to the digit-span task, items (words) were not repeated from list to list. Hence, this task called more heavily on item memory. Experiment 3 tested short-term order memory with an order recognition test: Each word list was repeated with or without the position of 2 adjacent items swapped. The ASD group showed poorer performance in all 3 experiments. Experiments 1 and 2 showed that group differences were due to memory for the order of the items, not to memory for the items themselves. Confirming these findings, the results of Experiment 3 showed that the ASD group had more difficulty detecting a change in the temporal sequence of the items. PMID- 21319934 TI - Preferences and intention of rural adolescents toward seeking help for mental health problems. AB - INTRODUCTION In Australia, rural adolescents still face barriers to obtaining professional psychological help due to poor availability and accessibility of services in rural areas when delay in seeking help for mental health problems can lead to poorer treatment outcomes. The aims of this study were to: investigate the preferences and intentions of rural Australian youth towards seeking help for mental health problems; determine predictors of help-seeking intention among rural adolescents; and verify results from previous qualitative research on the barriers to help-seeking in a rural context. METHOD: Participants were 201 adolescents recruited from 8 rural schools in the state of Victoria, Australia. Participants ranged in age from 11 to 18 years. Using the Accessibility and Remoteness Index of Australia (ARIA+), approximately 149 participants were classified as currently living in an inner regional area of Victoria, whereas 52 participants lived in an outer regional area. Participants completed an open ended survey of help-seeking intention. RESULTS: Overall, 55.7% of the sample indicated that they would seek help for a mental health problem. The majority of participants, regardless of subgroup, indicated that they would seek help for a mental health problem from a school counsellor as their first choice. Gender differences were observed such that males had a higher preference for seeking help from a psychologist than females. Furthermore, older adolescents were more likely to prefer seeking help from a GP than younger participants. A multivariate analysis of help-seeking intentions revealed that ARIA was the only predictor of help-seeking intention; however, when extreme scores of depression and anxiety were also taken into account, these also predicted help-seeking intention. A content analysis of the barriers to help-seeking nominated by participants revealed that perceived limited availability of professional services in towns, perceived social proximity and fear of rural gossip, and difficulties associated with travelling to obtain help were the most significant concerns for these youth. CONCLUSIONS: These findings verify previous research on help-seeking among rural youth and reinforce that these young people face additional barriers to help-seeking by virtue of living in a rural environment. The availability of services for rural youth needs to be improved, as do young people's knowledge of service availability and access (especially travel options). It must be taken into account that rural adolescents of different ages and sex may differ in their help-seeking preferences. Finally, mental health promotion work with rural youth should consider the influence of rural culture on help-seeking intentions. PMID- 21319935 TI - Effects of noise, nonlinear processing, and linear filtering on perceived music quality. AB - OBJECTIVE: The purpose of this study was to determine the relative impact of different forms of hearing aid signal processing on quality ratings of music. DESIGN: Music quality was assessed using a rating scale for three types of music: orchestral classical music, jazz instrumental, and a female vocalist. The music stimuli were subjected to a wide range of simulated hearing aid processing conditions including, (1) noise and nonlinear processing, (2) linear filtering, and (3) combinations of noise, nonlinear, and linear filtering. STUDY SAMPLE: Quality ratings were measured in a group of 19 listeners with normal hearing and a group of 15 listeners with sensorineural hearing impairment. RESULTS: Quality ratings in both groups were generally comparable, were reliable across test sessions, were impacted more by noise and nonlinear signal processing than by linear filtering, and were significantly affected by the genre of music. CONCLUSIONS: The average quality ratings for music were reasonably well predicted by the hearing aid speech quality index (HASQI), but additional work is needed to optimize the index to the wide range of music genres and processing conditions included in this study. PMID- 21319936 TI - The development of psychometrically equivalent Cantonese speech audiometry materials. AB - OBJECTIVE: The aim of this study was to develop and psychometrically evaluate speech audiometry materials that can be used to measure word recognition (WR) and speech recognition testing (SRT) in quiet for native speakers of Cantonese. STUDY SAMPLE: Commonly used bisyllabic and trisyllabic Cantonese words were digitally recorded by native male and female talkers and then evaluated by twenty normal hearing Cantonese listeners. DESIGN: The recorded bisyllabic words were psychometrically evaluated and arranged into four WR lists and eight half-lists that are relatively homogeneous in audibility. Using logistic regression, SRT materials were developed by selecting 28 trisyllabic words with relatively steep psychometric functions and digitally adjusting their intensity to match the listeners' mean pure-tone average. RESULT: The mean psychometric slopes for the WR materials were 7.5%/dB for the male talker and 7.6%/dB for the female talker, with no statistically significant differences between the lists or half-lists. At intensity levels required for 50% intelligibility, the mean psychometric slopes of the male and female talker SRT materials were 14.5%/dB and 14.9 %/dB, respectively. CONCLUSION: High-quality digital recordings of Cantonese speech audiometric WR and SRT materials were developed and validated in this study. These materials are available on compact disc, indexed by talker gender. PMID- 21319937 TI - The Danish hearing in noise test. AB - OBJECTIVE: A Danish version of the hearing in noise test (HINT) has been developed and evaluated in normal-hearing (NH) and hearing-impaired (HI) listeners. The speech material originated from Nielsen & Dau (2009) where a sentence-based intelligibility equalization method was presented. DESIGN: In the present study, the speech material was evaluated for naturalness and a subset of sentences selected. The new sentence lists were validated, and after three weeks retested. An additional experiment investigated how recollection of sentences affected the listeners' performance. STUDY SAMPLE: 16 NH and 16 HI listeners participated in the validation and retest. Twelve HI listeners participated in the experiment on recollection. RESULTS: The average speech recognition threshold in noise (SRT(N)) for the NH listeners was -2.52 dB, with an overall standard deviation of 0.87 dB. The within-subject standard deviation was similar for the NH and the HI listeners. In the retest, the SRT(N) decreased by 0.4 dB in both groups. CONCLUSIONS: The Danish HINT consists of 10 test lists and three practice lists each containing 20 sentences. The validation results are comparable to those of other versions of HINT. The test seems equally reliable for NH and HI listeners. After three weeks, reliable results can be obtained when sentence lists are reused with the same listeners. PMID- 21319938 TI - Is impact a factor? PMID- 21319939 TI - Editorial comment. PMID- 21319941 TI - Application of laser technology for removal of caries: a systematic review of controlled clinical trials. AB - OBJECTIVE: To evaluate the scientific evidence regarding laser technology for removal of carious tissue. MATERIAL AND METHODS: A search for literature on the effect of treatment and on economic aspects of laser technology identified 23 papers. No relevant studies on economic aspects were found. Regarding the effect of treatment, 16 papers were selected for assessment according to established criteria. RESULTS: Cavity preparation and caries excavation by erbium laser were evaluated in three studies of medium quality. The time required to remove carious tissue was evaluated in five studies assessed as being of medium quality for this outcome. In four studies the effect of laser treatment on the dental pulp was included as an outcome but, due to the short follow-up time, the quality was assessed as low. Two studies that included the longevity of the restoration as an outcome were also assessed as being of low quality because the follow-up time was inadequate. Patient response was evaluated in three studies, which were assessed as being of medium quality with respect to this outcome. CONCLUSIONS: There is limited scientific evidence that laser treatment is as effective as a rotary bur for removing carious tissue. Treatment time is prolonged. There is limited scientific evidence that adults prefer laser treatment. No conclusions can be drawn regarding biological or technical complications, children's perception of laser treatment or the cost-effectiveness of the method. PMID- 21319942 TI - Different scanning electron microscopic evaluation methods of cement interface homogeneity of adhesively luted glass fiber posts. AB - OBJECTIVE: To compare two methods used to examine the cement interface homogeneity of adhesively luted glass fiber posts (GFPs). MATERIAL AND METHODS: GFPs were divided into four groups (n = 5 in each) and inserted into artificial root canals under standardized conditions: Group I = RelyX Unicem, application with application aid; Group II = RelyX Unicem; Group III = Panavia F 2.0; and Group IV = Variolink II. Posts in Groups II-IV were cemented without using an appliance. All specimens were sectioned at three levels (cervical, middle and apical) perpendicularly to the post's long axis and examined and photographed (n = 60) using scanning electron microscopy (SEM). Cement interface inhomogeneities were (A) measured by means of SEM software and (B) estimated using a graphics program with SEM images being divided into 72 equal circle segments to calculate a percentage value of inhomogeneities of the 360 degrees circumference. RESULTS: Median values of inhomogeneities (A/B; %) within the cement interface for the cervical, middle and apical levels of analysis, respectively were 1.4/2.1, 2.2/4.2 and 1.9/2.1 for Group I; 21.0/20.1, 24.8/23.6 and 27.0/24.3 for Group II; 1.5/1.7, 5.5/6.3 and 19.4/20.8 for Group III; and 18.1/16.7, 16.1/15.3 and 27.2/25.7 for Group IV. The two methods correlated very well (0.994), with a value of one indicating a 100% correlation. CONCLUSION: Both evaluation methods were found to be equally appropriate for quantifying the cement interface homogeneity of SEM cross-sections of adhesively luted GFPs. PMID- 21319943 TI - Saccular sensitivity function measured by vestibular evoked myogenic potential. AB - CONCLUSIONS: Vestibular myogenic potential responses were present when evoked by tone burst stimuli of 250, 500, 1000, and 2000 Hz; however, they were more effective for low-frequency stimuli. OBJECTIVES: Few studies refer to specific frequency sensitivities of the saccular afferents. Accordingly, the aim of the present study was to analyze p13 and n23 latency and amplitude parameters of vestibular evoked myogenic potential (VEMP) captured with tone bursts at frequencies of 250, 500, 1000, and 2000 Hz. METHODS: VEMP was captured in 156 ears (78 subjects), recorded in the sternocleidomastoid muscle, averaging 200 stimuli, stimulus rate of 5 Hz, duration 10 ms (rise, 4 ms; plateau, 2 ms; fall, 4 ms), at intensity of 95 dB nHL. The recordings were performed in 50 ms windows. RESULTS: We found lower p13 latencies in women compared with men, except for the frequency of 250 Hz. We found higher mean absolute latency values for p13 and n13 and lower p13-n13 amplitude and p13-n13 inter-peak values for a frequency of 2000 Hz. Higher amplitudes were observed at frequencies of 250 and 500 Hz. When frequencies of 250, 500, 1000, and 2000 Hz were compared using ANOVA, we found statistically significant differences for all the VEMP parameters (p <= 0.005). PMID- 21319944 TI - Long-term safety of naproxen and esomeprazole magnesium fixed-dose combination: phase III study in patients at risk for NSAID-associated gastric ulcers. AB - OBJECTIVE: To evaluate long-term safety of enteric-coated naproxen 500 mg and immediate-release esomeprazole magnesium 20 mg fixed-dose combination (FDC) in patients at risk of NSAID-associated upper gastrointestinal (UGI) ulcers. RESEARCH DESIGN AND METHODS: In this open-label, multicenter, phase III study, Helicobacter pylori-negative patients aged >=50 years or 18-49 years with history of uncomplicated ulcer within the past 5 years, who had osteoarthritis, rheumatoid arthritis, or other condition requiring daily NSAIDs for >=12 months received naproxen/esomeprazole twice daily for 12 months. CLINICAL TRIAL REGISTRATION: NCT00527904. MAIN OUTCOME MEASURES: Adverse events (AEs), vital signs, physical examination, and laboratory tests. Subgroup analyses included age and low-dose aspirin (LDA) use. Predefined NSAID-associated UGI and cardiovascular AEs were analyzed. RESULTS: Of 239 patients treated (safety population), 135 completed >=348 treatment days (12-month completers). AE incidence was approximately 70%; dyspepsia, constipation, upper respiratory tract infection, nausea, back pain, and contusion were most frequent (>=5% patients, either population). Treatment-related AEs occurred in 28.0% and 23.7% of patients in the safety and 12-month completer populations, respectively; 18.8% of patients withdrew due to AEs (safety population). Few serious AEs and no deaths occurred. In the safety population, AE incidence was 71.4% and 76.9% in patients aged <65 years (n = 161) and >=65 years (n = 78), respectively, and 67.6% and 75.8% in LDA users (n = 74) and non-users (n = 165), respectively. Predefined UGI and cardiovascular AEs were observed in 18.8% and 6.3% of patients, respectively, in the safety population, and 16.3% and 5.2%, respectively, in 12-month completers. Dyspepsia and hypertension were most common. Additional assessments showed no unexpected findings. CONCLUSIONS: Based on these outcome measures, long-term treatment with FDC naproxen/esomeprazole is not associated with any new safety issues, including predefined UGI and cardiovascular AEs, in patients requiring NSAID therapy who are at risk of UGI complications. PMID- 21319945 TI - Blockage of longitudinal flow in Meniere's disease: A human temporal bone study. AB - CONCLUSION: Blockage of the endolymphatic duct is a significant finding in Meniere's disease. The position of the utriculo-endolymphatic valve (UEV) and blockage of the ductus reuniens in the temporal bones were not found to be directly indicative of Meniere's disease. OBJECTIVE: Comparison of blockage of the longitudinal flow of endolymph between ears affected by Meniere's disease and normal ears. METHODS: We examined 21 temporal bones from 13 subjects who had Meniere's disease and 21 normal temporal bones from 12 controls. RESULTS: The endolymphatic duct was blocked in five (23%) ears affected by Meniere's disease (p = 0.016). The utricular duct was blocked in 16 (76%) ears affected by Meniere's disease and 11 (52%) normal ears (p = 0.112). The saccular duct was blocked in 6 (28%) of ears affected by Meniere's disease and 16 (76%) normal ears (p = 0.001). The ductus reuniens was blocked in 10 (47%) ears affected by Meniere's disease and 10 (47%) normal ears (p = 1.000). PMID- 21319946 TI - Finite element model of human ear reconstruction through micro-computer tomography. AB - CONCLUSIONS: The validated finite element model of human middle ear can be used as a tool in hearing loss research. OBJECTIVE: To establish an accurate finite element model of the external ear canal and middle ear through micro-computer tomography and test its feasibility in the human. METHODS: A fresh specimen of human temporal bone was scanned by micro-computer tomography. The finite element model was established based on the images, and then the simulation results were compared with published experimental data. RESULTS: After a series of simulations were conducted, the simulated results were compatible with the published experimental data and this confirms the validation of the finite element model. PMID- 21319947 TI - Long-term effects of the Meniett device in Japanese patients with Meniere's disease and delayed endolymphatic hydrops reported by the Middle Ear Pressure Treatment Research Group of Japan. AB - CONCLUSION: The Meniett device is a minimally invasive and safe treatment that may be used to provide longer-term reduction of vestibular symptoms in patients with delayed endolymphatic hydrops (DEH) as well as those with Meniere's disease (MD). OBJECTIVE: The effects of the Meniett device were evaluated in patients with a diagnosis of definite MD or DEH according to the 1995 AAO-HNS criteria. METHODS: Twenty-nine ears of 28 patients with MD and 5 ears of 5 patients with DEH (ipsilateral type 4, contralateral type 1) were treated with the Meniett device by the Middle Ear Pressure Treatment Research Group of Japan. All of the patients had failed to respond to medical treatment including diuretics before the pressure treatment. RESULTS: Sixteen (57%) patients with MD and all five (100%) patients with DEH remained entirely free from vertigo spells; nine (32%) patients with MD responded with a significant decrease in the frequency of vertigo spells. In regard to hearing, 25 ears (74%: MD, n = 21; ipsilateral DEH, n = 4) had stable hearing levels; only 4 ears (12%: MD, n = 3; contralateral DEH, n = 1) showed a significant hearing improvement. No complications were attributable to the Meniett device. PMID- 21319948 TI - A comparison of mortality and costs associated with FOLFOX versus FOLFIRI in stage IV colorectal cancer. AB - OBJECTIVE: To examine cost and mortality among stage IV colorectal cancer (CRC) patients treated with 5-fluorouracil (5FU)/leucovorin/oxaliplatin (FOLFOX) or 5FU/leucovorin/irinotecan (FOLFIRI). METHODS: Adult CRC patients newly treated with FOLFOX or FOLFIRI were identified from a large database using medical and pharmacy claims for services delivered January 1, 2002 through December 31, 2005. Cancer stage for a subset of patients was abstracted from medical records. Outcomes were annualized costs calculated for 4 years of observation, and deaths as recorded by the National Death Index. Cost was analyzed using generalized linear modeling; mortality was modeled using Cox proportional hazards analysis. RESULTS: Unadjusted annualized median and mean costs were $134,401 and $152,213, respectively, for the FOLFOX cohort (n = 41) and $103,150 and $107,994 for the FOLFIRI cohort (n = 86). Death occurred among five (12%) FOLFOX and 42 (53%) FOLFIRI patients. Adjusted analysis revealed no significant difference in cost between cohorts, even after adjusting for reduced irinotecan costs due to generic availability. Incremental costs associated with one additional life saved per year were only $1,236 higher for patients treated with FOLFOX compared with FOLFIRI. Cox analysis revealed a significant survival advantage for FOLFOX over FOLFIRI (HR = 5.2; 95% CI: 1.7-15.8). CONCLUSIONS: A significant survival benefit was seen for CRC patients receiving FOLFOX versus FOLFIRI; multivariate analysis revealed no significant cost differences. However, the small sample size may have resulted in lack of adequate power to detect a difference between cohorts. There may be factors influencing mortality that were not included in the multivariate modeling. PMID- 21319951 TI - Serum vascular endothelial growth factor-D levels correlate with cervical lymph node metastases in papillary thyroid carcinoma. AB - The aim of this multicenter study was to evaluate the clinical relevance of serum vascular endothelial growth factor-D (VEGF-D) in papillary thyroid carcinoma (PTC). This prospective study consisted of 74 patients with primary PTC and 15 patients with benign thyroid nodules treated from 2008 to 2009. VEGF-D concentration was compared with patient clinicopathologic features and lymph node metastases. There was no significant difference in mean serum VEGF-D levels between the PTC and benign thyroid nodule groups. Within the PTC group, serum VEGF-D levels were significantly higher in patients with lymph node metastases than in patients without metastases (241.92 vs. 213.89 pg/ml, respectively; P = 0.035). Receiver operating characteristic curve analysis revealed that preoperative serum VEGF-D levels were predictive of lymph node metastases in the patients >45 years. Serum VEGF-D level that was correlated with the presence of cervical lymph node metastases in PTC patients might be a useful prognostic indicator. PMID- 21319953 TI - Contribution of nano-copper particles to in vivo liver dysfunction and cellular damage: role of IkappaBalpha/NF-kappaB, MAPKs and mitochondrial signal. AB - The present study investigated the oxidative stress responsive cell signaling in nano-copper-induced hepatic dysfunction and cell death. Exposure to nano-copper (18 nm) dose-dependently (200-600 mg/kg bw) reduced the hepatic index, caused oxidative stress and led to hepatic dysfunction. Nano-copper burden also increased the transcriptional activity of NF-kappaB, up-regulated the expression of phosphorylated p38, ERK1/2 and caused the reciprocal regulation of Bcl-2 family proteins, disruption of mitochondrial membrane potential, release of cytochrome C, formation of apoptosome and activation of caspase 3. DAPI staining, immunofluorescence study, FACS analysis and histological findings also support this observation. Soluble copper (Cu(+2), 110 mg/kg bw)-exposed animals were used as a positive control. Different doses of particulate and soluble forms were used in the study because of different LD(50) values. The results suggest that nano copper induces hepatic dysfunction and cell death via the oxidative stress dependent signaling cascades and mitochondrial event. PMID- 21319954 TI - Human skin penetration of gold nanoparticles through intact and damaged skin. AB - Gold nanoparticles (AuNPs) are produced for many applications but there is a lack of available data on their skin absorption. Experiments were performed using the Franz diffusion cell method with intact and damaged human skin. A physiological solution was used as receiving phase and 0.5 mL (1st exp) and 1.5 mL (2nd exp) of a solution containing 100 mg L-1 of AuNPs (15 and 45 MUg cm-2, respectively) was applied as donor phase to the outer surface of the skin for 24 h. Skin absorption was dose dependent. Mean gold content of 214.0 +/- 43.7 ng cm-2 and 187.7 +/- 50.2 ng cm-2 were found in the receiving solutions of cells where the AuNPs solution was applied in higher concentration on intact skin (8 Franz cells) and on damaged skin (8 Franz cells), respectively. Twenty-four hours gold flux permeation was 7.8 +/- 2.0 ng cm-2 h-1 and 7.1 +/- 2.5 ng cm-2 h-1 in intact and damaged skin, respectively, with a lag time less than 1 hour. Transmission Electron Microscope analysis on skin samples and chemical analysis using Inductively Coupled Plasma-Mass Spectrometry demonstrated the presence of AuNPs into epidermis and dermis. This study showed that AuNPs are able to penetrate the human skin in an in vitro diffusion cell system. PMID- 21319957 TI - Changes in the pharmacokinetics of digoxin in polyuria in streptozotocin-induced diabetic mice and lithium carbonate-treated mice. AB - In humans, digoxin is mainly eliminated through the kidneys unchanged, and renal clearance represents approximately 70% of the total clearance. In this study, we used the mouse models to examine digoxin pharmacokinetics in polyuria induced by diabetes mellitus and lithium carbonate (Li(2)CO(3)) administration, including mechanistic evaluation of the contribution of glomerular filtration, tubular secretion, and tubular reabsorption. After digoxin administration to streptozotocin (STZ)-induced diabetic mice, digoxin CL/F increased to approximately 2.2 times that in normal mice. After treatment with Li(2)CO(3) (0.2%) for 10 days, the CL/F increased approximately 1.1 times for normal mice and 1.6 times for STZ mice. Creatinine clearance (CLcr) and the renal mRNA expression levels of mdr1a did not differ significantly between the normal, STZ, and Li(2)CO(3)-treated mice. The urine volume of STZ mice was approximately 26 mL/day, 22 times that of normal mice. The urine volume of Li(2)CO(3)-treated mice increased approximately 7.3 times for normal mice and 2.3 times for STZ mice. These results suggest that the therapeutic effect of digoxin may be significantly reduced in the presence of polyuria either induced by diabetes mellitus or manifested as an adverse effect of Li(2)CO(3) in diabetic patients, along with increased urine volume. PMID- 21319958 TI - Identification of human UGT isoforms responsible for glucuronidation of efavirenz and its three hydroxy metabolites. AB - Uridine 5'-diphosphate-glucuronosyltransferases (UGTs) involved in the glucuronide formation of efavirenz (EFV) and its three hydroxy metabolites, 8 hydroxyefavirenz (8-OH EFV), 7-hydroxyefavirenz (7-OH EFV), and 8,14 dihydroxyefavirenz (8,14-diOH EFV), were assessed. Among 12 recombinant UGT isoforms tested, only UGT2B7 showed catalytic activity in the formation of EFV-N glucuronide (EFV-G) as previously reported. On the other hand, almost all UGT isoforms were involved in the glucuronidation of the three hydroxy metabolites, although their relative contribution is unclear. The catalytic activities in the formation of EFV-G by 17 different human liver microsomes exhibit a more than 40 fold inter-individual variability, whereas those of glucuronidation of the three hydroxy metabolites showed almost identical activity. The formation of EFV-G showed a significant correlation (r = 0.920; p < 0.0001) with UGT2B7-catalysed azidothymidine glucuronidation in 17 different human liver microsomes. Furthermore, fluconazole, a known UGT2B7 inhibitor, potently inhibited the formation of EFV-G up to 80%. This suggests that EFV might be a specific UGT2B7 substrate in vitro. This is the first study identifying specific UGT isozymes that glucuronidate EFV and its three hydroxy metabolites. Continued identification and characterisation of these pathways may help reduce adverse effects such as CNS toxicity in EFV therapy. PMID- 21319959 TI - Intestinal absorption mechanisms of berberine, palmatine, jateorhizine, and coptisine: involvement of P-glycoprotein. AB - The absorption and transport mechanisms of berberine, palmatine, jateorhizine, and coptisine were studied using a Caco-2 cells uptake and transport model, with the addition of cyclosporin A and verapamil as P-glycoprotein (P-gp) inhibitors and MK-571 as a multidrug resistance-associated protein 2 (MRP(2)) inhibitor. In the uptake experiment, berberine, palmatine, jateorhizine, and coptisine were all taken into Caco-2 cells, and their uptakes were increased in the presence of cyclosporin A or verapamil. In the transport experiment, P(app) (AP-BL) was between 0.1 and 1.0 * 10(6) cm/sec for berberine, palmatine, jateorhizine, and coptisine and was lower than P(app) (BL-AB). ER values were all >2. Cyclosporin A and verapamil both increased P(app) (AP-BL) but decreased P(app) (BL-AB) for berberine, palmatine, jateorhizine, and coptisine; ER values were decreased by >50%. MK-571 had no influence on the transmembrane transport of berberine, palmatine, jateorhizine, and coptisine. At a concentration of 1-100 MUM, berberine, palmatine, jateorhizine, and coptisine had no significant effects on the bidirection transport of Rho123. Berberine, palmatine, jateorhizine, and coptisine were all P-gp substrates; and at the range of 1-100 MUM, berberine, palmatine, jateorhizine, and coptisine had no inhibitory effects on P-gp. PMID- 21319960 TI - Aspirin, P2Y12 blockers, cilostazol, PAR-1 blockers and emerging antiplatelet therapies: can biomarkers guide clinical development and practice? PMID- 21319961 TI - Beyond platelet functional testing: value in the aggregate. PMID- 21319962 TI - Clinical value of antiplatelet therapy in patients with acute coronary syndromes and in percutaneous coronary intervention. AB - Dual antiplatelet therapy with aspirin and clopidogrel is recommended in all patients who have had an acute coronary syndrome or who undergo percutaneous coronary intervention to prevent further ischemic events. Resistance or reduced responsiveness to aspirin and/or clopidogrel has been associated with adverse cardiovascular outcomes, including stent thrombosis. There have been significant advances in this field, which aim to overcome antiplatelet resistance, including the development of new antiplatelet agents. The rationale for dual antiplatelet therapy, the impact of suboptimal efficacy and the potential ways of overcoming resistance or variability in response to antiplatelet agents will be reviewed in this article. PMID- 21319963 TI - Functional testing methods for the antiplatelet effects of aspirin. AB - At antiplatelet doses of 75-325 mg/day, aspirin irreversibly inhibits the platelet cyclooxygenase (COX)-1-dependent thromboxane A(2) (TXA(2)) formation. This is the pharmacological mode of action of aspirin, and it can be predicted that if aspirin does not inhibit COX-1 sufficiently, patients will not benefit from its antiplatelet effects. A pharmacodynamic failure of aspirin occurs in 1 2% of patients. The vast majority of atherothrombotic events in patients treated with aspirin result from mechanisms that are dependent on residual (non-COX-1 dependent) platelet reactivity. Global tests of platelet activation in vitro may identify patients with high residual platelet reactivity but are not sufficiently specific to test the pharmacological effect of aspirin. A further problem is the absence of standardized normal ranges for many assays and the fact that different equipment measures different signals, which are also influenced by the agonist and the anticoagulant used. Similar considerations apply for the determination of platelet-derived biomarkers such as circulating P-selectin, soluble CD40 ligand and others. The direct measurement of inhibition of thromboxane-forming capacity is the most specific pharmacological assay for aspirin. However, there is no linear correlation between inhibition of TXA(2) formation and inhibition of platelet function. Measurement of urinary levels of the TXB(2) metabolite, 11 dehydro-thromboxane B(2), represents an index of TXA(2) biosynthesis in vivo, but is also sensitive to other cellular sources of TXA(2). One general problem of all assays is the relationship with clinical outcome, which is still unclear. Monitoring aspirin treatment by testing platelet function or measuring biomarkers in clinical practice should not be recommended until a clear relationship for the predictive value of these assays for clinical outcome has been established. PMID- 21319964 TI - Functional testing methods for the antiplatelet effect of P2Y12 receptor antagonists. AB - Dual antiplatelet therapy with aspirin and a P2Y(12) receptor antagonist is the cornerstone of management in patients with acute coronary syndrome and those with coronary artery disease who have undergone coronary stent implantation. Clopidogrel is the most commonly used P2Y(12) antagonist. Despite clopidogrel's clinical effectiveness in reducing recurrent cardiovascular events in patients with coronary artery disease, the pharmacodynamic effect of clopidogrel is heterogeneous. Various platelet function tests that provide a quantitative measure of the downstream effects of clopidogrel on the P2Y(12) receptor are available. The consistent observation that a lack of clopidogrel effect based on these tests is associated with poor clinical outcome has led to the promise of an individualized, patient-centered approach to antiplatelet therapy. Over the past few years, a wealth of data have helped bring this promise closer to reality, and upcoming clinical trials of platelet function testing could at last bring personalized medicine into routine clinical practice. PMID- 21319965 TI - Ticagrelor: from concept to clinical evaluation. AB - Dual antiplatelet therapy with aspirin and a platelet adenosine diphosphate P2Y(12) receptor blocker reduces the risk of major adverse cardiovascular events following percutaneous coronary intervention or an acute coronary syndrome. Clopidogrel is the most widely used P2Y(12) receptor blocker, but has suboptimal speed of onset of action and maximal platelet inhibition, as well as variability in the inhibition of platelet aggregation achieved. Therefore, novel P2Y(12) receptor blockers have been developed to address these limitations, including prasugrel and ticagrelor. This article describes the pharmacokinetic and pharmacodynamic evaluation of ticagrelor, which has been demonstrated to have significantly faster onset, faster offset, greater maximal inhibition of platelet aggregation and less variability in response compared with clopidogrel. These detailed Phase II data helped guide the design of the large landmark clinical trial Platelet Inhibition and Patient Outcomes (PLATO; n = 18,624 patients with acute coronary syndrome) in which ticagrelor was associated with a 16% relative risk reduction in the primary composite end point of cardiovascular death, myocardial infarction or stroke at 12 months (9.8 vs 11.7%; hazard ratio: 0.84; 95% CI: 0.77-0.92; p < 0.001). Ongoing trials are evaluating the clinical value of individualizing therapy according to on-treatment residual platelet activity, genetic polymorphism (loss-of-function allele status) and by improved safety/efficacy risk stratification. PMID- 21319966 TI - Glycoprotein IIb/IIIa inhibitors: an update on the mechanism of action and use of functional testing methods to assess antiplatelet efficacy. AB - The human glycoprotein (GP)IIb/IIIa belongs to a large family of cation-dependent adhesion molecules known as integrins, which share a common heterodimeric structure. The primary function of GPIIb/IIIa is to aid platelet aggregation by transmitting bidirectional signals across the plasma membrane. Since the GPIIb/IIIa receptor is among the key integrins involved in platelet aggregation and, therefore, thrombus formation, the development of GPIIb/IIIa antagonists (e.g., abciximab, eptifibatide and tirofiban) has become an attractive strategy for antiplatelet therapy with an expected strong and specific effect. All three drugs are administered intravenously, and large-scale clinical trials have demonstrated a clear clinical benefit and good safety profile in high-risk patients, especially those undergoing percutaneous coronary intervention. However, the adverse events related to thrombosis or bleeding are still reported in patients undergoing therapy with GPIIb/IIIa antagonists and reflect a variable interindividual responsiveness. Therefore, some form of laboratory monitoring is required to optimize the effects of a drug or to indicate that it needs replacing with other antithrombotic agents, as well as for identifying and enhancing the platelet inhibition in this subgroup of patients to improve the clinical outcome and reduce bleeding complications. As such, the aim of this article is to provide an update on the mechanism of action and use of functional testing methods to assess antiplatelet efficacy in patients undergoing therapy with GPIIb/IIIa antagonists. PMID- 21319967 TI - Innovative biomarker development for personalized medicine in breast cancer care. PMID- 21319968 TI - MRI as a frontrunner in the search for amyotrophic lateral sclerosis biomarkers? PMID- 21319970 TI - Circulating tumor cells and plasma DNA analysis in patients with indeterminate early or metastatic breast cancer. AB - BACKGROUND: Circulating tumor cells (CTCs) and tumor-specific alterations in cell free plasma DNA can both be used as markers of prognosis in breast cancer. To date, there have been no studies that have compared these as markers for subclinical metastases in the follow-up of early breast cancer. In this study, we measured CTCs and plasma DNA in a published group of patients with multiple pulmonary nodules and indeterminate metastatic disease. PATIENTS & METHODS: A single blood sample for CTC and plasma DNA measurement was taken approximately 1.5 years after surgery from 19 women with histologically confirmed primary breast cancer and small pulmonary nodules. The CellSearch system was used to enrich and enumerate CTCs from peripheral blood. DNA was isolated from plasma and was analyzed by quantitative real-time PCR for DNA concentration, integrity and evidence of HER2 amplification. RESULTS: Of the 19 individuals with 'indeterminate' early or metastatic breast cancer, 17 demonstrated no evidence of CTCs, one had one CTC and one had three CTCs. The mean plasma DNA concentration was low and within the range detected in healthy female controls, as were the values for DNA integrity. HER2 amplification was detected in the plasma DNA in four of the eight patients with HER2 immunohistochemistry 3+ tumors, but there was no overlap with the two CTC-positive patients. None of the patients have relapsed thus far (median follow-up: 3.5 years). CONCLUSION: Both CTC and plasma DNA analyses together suggested that these patients had little evidence of metastatic disease. Future studies will be designed to assess the utility of these biomarkers in the follow-up of a larger number of women with breast cancer. PMID- 21319971 TI - Applied strategies towards EEG/MEG biomarker identification in clinical and cognitive research. AB - As the underlying causes of several neuronal disorders and neurodegenerative diseases still remain, to some extent, unknown and no accurate diagnostic tests are available, the identification of prognostic and predictive neurophysiological biomarkers has attracted tremendous interest. The continuous advancement of neuroscience methods applied in EEG and magnetoencephalography has been successful in capturing brain processes and identifying persistent cognitive deficits. In this article, the most promising approaches of this rapidly evolving field, along with some indicative clinical applications in major neuropathophysiological disorders, are reviewed. Such strategies for biomarker identification will lead the way to future clinical applications even if, currently, EEG biomarkers are in a premature state. PMID- 21319974 TI - Chicken anemia virus: an understanding of the in-vitro host response over time. AB - Chicken anemia virus (CAV) is an economically important virus affecting the chicken meat and egg industry. CAV is characterized by anemia, lymphoid depletion, and immunosuppression. Microarrays were used to investigate the response of MDCC-MSB1 cells (MSB1) to infection with CAV at 24 and 48 h post infection (hpi). The major genes responding to CAV infection include genes involved in inflammation, apoptosis, and antiviral activity. Several cytokines were differentially regulated at either 24 or 48 hpi, including interleukin 2 (IL 2), interleukin receptors IL-1R, IL-22R, IL-18R, and IL-7R, and interferon-alpha (IFN-alpha). While there were many genes differentially regulated in this experiment, only two genes were common to both time points, suggesting a dramatic change in gene expression over the two time points studied. The present study is the first microarray experiment to investigate CAV, and we identified a number of key pathways involved in viral infection. Overall, there were more genes upregulated at 24 hpi than at 48 hpi, including genes involved in cytokine signaling, apoptosis, and antiviral activity. The two time points were vastly different in their gene expression patterns, in that at 24 hpi there were many genes involved in the response to infection, whereas at 48 hpi there were many genes associated with apoptosis and immunosuppression. PMID- 21319975 TI - Herpes simplex virus type 1-induced FasL expression in human monocytic cells and its implications for cell death, viral replication, and immune evasion. AB - Herpes simplex virus type 1 (HSV-1) is a ubiquitously occurring pathogen that infects humans early in childhood. The virus persists as a latent infection in dorsal root ganglia, especially of the trigeminal nerve, and frequently becomes reactivated in humans under conditions of stress. Monocytic cells constitute an important component of the innate and adaptive immune responses. We show here for the first time that HSV-1 stimulates human FasL promoter and induces de novo expression of FasL on the surface of human monocytic cells, including monocytes and macrophages. This virus-induced FasL expression causes death of monocytic cells growing in suspension, but not in monolayers (e.g., macrophages). The addition of a broad-spectrum caspase inhibitor, as well as anti-FasL antibodies, reduced cell death but increased viral replication in the virus-infected cell cultures. We also show here for the first time that the virus-induced de novo expression of FasL on the cell surface acts as an immune evasion mechanism by causing the death of interacting human CD4+ T cells, CD8+ T cells, and natural killer (NK) cells. Our study provides novel insights on FasL expression and cell death in HSV-infected human monocytic cells and their impact on interacting immune cells. PMID- 21319976 TI - Reciprocal changes of naive and effector/memory CD8+ T lymphocytes in chronic hepatitis B virus infection. AB - Persistent viruses, such as cytomegalovirus or human immunodeficiency virus, cause major perturbations of CD8+ T-lymphocyte subpopulations. To test whether chronic infection with hepatitis B virus (HBV) could also be responsible for such modifications, we analyzed the expression of CD27, CD28, CCR7, and perforin in blood CD8+ T lymphocytes. In comparison to healthy subjects and patients recovering from acute hepatitis B, chronic hepatitis B patients showed higher percentages of naive CD8+ T lymphocytes (CD45RA+CD27+CD28+), and lower percentages of intermediately-differentiated CD27+CD28-CD8+ T cells. The late differentiated CD45RA+CD27-CD28- subset was also present in a large percentage in some patients, but no statistically significant difference with healthy controls was observed. Removal from the circulation of intermediately-differentiated CD8+ T lymphocytes may occur during chronic HBV infection, favoring the recruitment of naive cells. This may result in impairment of the generation of functionally competent memory cells, and an inability to achieve control of HBV replication. PMID- 21319977 TI - Chinese human immunodeficiency virus-1 patients with different routes of transmission exhibit altered expression levels of blood dendritic cell subpopulations. AB - Dendritic cells (DCs) play a pivotal role in the pathogenesis of human immunodeficiency virus-1 (HIV-1). Reduced numbers of blood DCs have been observed in individuals with chronic HIV-1 infection. In the present study, we analyzed the expression levels of monocytes, myeloid dendritic cell (mDC) precursors, mDCs, and plasmacytoid dendritic cells (pDCs), in HIV-1-infected patients in China who were infected via different routes of transmission, including heterosexual and homosexual sexual contact, and blood transmission through importation of blood or blood products, to further elucidate their role in HIV. Compared with HIV-negative individuals (n = 40), relative levels of CD11c+CD14 mDCs, CD11c++CD123(low) mDCs, and CD11c-CD123+ pDCs in total peripheral blood mononuclear cells (PBMCs) were significantly lower in all HIV patients (n = 93), and in those with blood transmission (n = 26) and heterosexual transmission (n = 43), while relative levels of CD11c+CD14-mDCs were significantly lower in HIV patients infected via homosexual transmission (n = 24). The results of correlation analysis demonstrated a significant negative correlation between CD4+ T-cell counts and the relative levels of CD11c++CD123(low) mDCs in HIV-I patients infected via blood transmission. There was no significant correlation between CD4+ T-cell counts and the expression level of other DC subpopulations in PBMCs from HIV patients. The results of this study suggest that HIV-1 patients with different routes of transmission exhibit altered expression levels of blood DC subpopulations, which contributes to dysregulated immune responses and pathogenesis of HIV-1. PMID- 21319978 TI - Broad humoral and cellular immunity elicited by a bivalent DNA vaccine encoding HA and NP genes from an H5N1 virus. AB - Influenza A virus is highly variable and a major viral respiratory pathogen that can cause severe illness in humans. Therefore it is important to induce a sufficient immune response specific to current strains and to heterosubtypic viruses with vaccines. In this study, we developed a dual-promoter-based bivalent DNA vaccine that encodes both hemagglutinin (HA) and nucleoprotein (NP) proteins from a highly pathogenic A/Chicken/Henan/12/2004 (H5N1) virus. Our results show that the expression levels of HA and NP genes from the dual-promoter plasmid are similar to those seen when they are expressed individually in independent plasmids. When the bivalent DNA vaccine was inoculated via intramuscular injection and in vivo electroporation, high levels of both humoral and cellular immune responses were elicited against homologous H5N1 virus and heterosubtypic H9N2 virus. Furthermore, no obvious antigenic competition was observed between HA and NP proteins in the dual-promoter-based bivalent vaccine compared to monovalent vaccines. Our data suggest that a combination of influenza surface and internal viral genes in a dual-promoter-expressing plasmid may provide a new approach for developing a DNA vaccine that may protect not only specifically against a currently circulating strain, but also may cross-protect broadly against new heterosubtypic viruses. PMID- 21319981 TI - Amino acid mutations in the env gp90 protein that modify N-linked glycosylation of the Chinese EIAV vaccine strain enhance resistance to neutralizing antibodies. PMID- 21319979 TI - Analysis of CD4+CD25+Foxp3+ regulatory T cells in HIV-exposed seronegative persons and HIV-infected persons with different disease progressions. AB - Regulatory T cells (Tregs) are a subset of T cells that play an important role in the regulation of T-cell function. In a previous study, CD25 was used as a marker of Tregs; however, FoxP3 was recently discovered to be a valuable phenotype of Tregs. In this study, we compared the frequency of Tregs in HIV-1-infected long term nonprogressors (LTNP), AIDS patients (AP), HIV-exposed seronegative (ES) persons, and healthy controls (HC), by using CD4+CD25+FoxP3+ as a marker of Tregs. The results showed that the frequency of Tregs in AP was significantly higher than in the LTNP, ES, and HC, which suggests that Tregs may play a role in disease progression. Another unique finding in this study is that we found a decrease of Tregs in ES. PMID- 21319983 TI - Re: Rapid maxillary expansion compared to surgery for assistance in maxillary face mask protraction. By Nazan Kucukkeles, Sirin Nevzatoglu, and Tamer Koldas. Angle Orthod. 2011:81;44-51. PMID- 21319985 TI - Satellite cells say NO to radiation. AB - Skeletal muscles are commonly exposed to radiation for diagnostic procedures and the treatment of cancers and heterotopic bone formation. Few studies have considered the impact of clinical doses of radiation on the ability of satellite cells (myogenic stem cells) to proliferate, differentiate and contribute to recovering/maintaining muscle mass. The primary objective of this study was to determine whether the proliferation of irradiated satellite cells could be rescued by manipulating NO levels via pharmacological approaches and mechanical stretch (which is known to increase NO levels). We used both SNP (NO donor) and PTIO (NO scavenger) to manipulate NO levels in satellite cells. We observed that SNP was highly effective in rescuing the proliferation of irradiated satellite cells, especially at doses less than 5 Gy. The potential importance of NO was further illustrated by the effects of PTIO, which completely inhibited the rescue effect of SNP. Mechanical cyclic stretch was found to produce significant increases in NO levels of irradiated satellite cells, and this was associated with a robust increase in satellite cell proliferation. The effects of both radiation and NO on two key myogenic regulatory factors (MyoD and myogenin) were also explored. Irradiation of satellite cells produced a significant increase in both MyoD and myogenin, effects that were mitigated by manipulating NO levels via SNP. Given the central role of myogenic regulatory factors in the proliferation and differentiation of satellite cells, the findings of the current study underscore the need to more fully understand the relationship between radiation, NO and the functionality of satellite cells. PMID- 21319988 TI - Information: the key to improved quality in health care. PMID- 21319989 TI - Low-cost reusable instrumentation for laparoendoscopic single-site nephrectomy: assessment in a porcine model. AB - PURPOSE: To test different sets of prebent instruments and a new reusable access device for laparoendoscopic single-site (LESS) surgery. MATERIALS AND METHODS: Three surgeons with previous experience in LESS performed 12 nephrectomies in six pigs. In all procedures, a multichannel access device (X-CONE) and a 5-mm extra long telescope were used. Four sets of prebent instruments with different profiles (S-portal) were tested: Standard (one straight scissors and one curved grasper), Cuschieri, Carus, and Leroy set (each of them consisting of two curved instruments with different configurations). Assessment was performed based on both objective (procedure time; time to manage the pedicle; time to free kidney) and subjective parameters (entry/exit of instruments; triangulation; dissection up/down; dissection lateral; retraction; interdependence). The subjective assessment tool used was a Likert type scale (1 = easy to 5 = prohibitive). The access device was assessed by using objective (time to complete insertion of device after skin incision) and subjective (significant air leakage, movement constraint) parameters. RESULTS: Time to insertion of the X-CONE was <1 minute in all the cases. Surgeons reported significant insufflant leakage in 58% of cases. The procedure was completed in 10/12 (83%) cases. Mean operative time was 8.3 +/- 4.2 minutes, being lower for the Carus group (4.5 min) and higher for the standard group (13 min). Among the different sets, the standard one obtained the best mean scores for all subjective parameters. CONCLUSIONS: X-CONE allows easy abdominal access, and its reusable properties represent cost savings for LESS compared with disposable devices. Prebent instruments might also represent attractive low-cost tools for LESS. PMID- 21319986 TI - Long-term consequences of radiation-induced bystander effects depend on radiation quality and dose and correlate with oxidative stress. AB - Widespread evidence indicates that exposure of cell populations to ionizing radiation results in significant biological changes in both the irradiated and nonirradiated bystander cells in the population. We investigated the role of radiation quality, or linear energy transfer (LET), and radiation dose in the propagation of stressful effects in the progeny of bystander cells. Confluent normal human cell cultures were exposed to low or high doses of 1GeV/u iron ions (LET ~ 151 keV/um), 600 MeV/u silicon ions (LET ~ 51 keV/um), or 1 GeV protons (LET ~ 0.2 keV/um). Within minutes after irradiation, the cells were trypsinized and co-cultured with nonirradiated cells for 5 h. During this time, irradiated and nonirradiated cells were grown on either side of an insert with 3-um pores. Nonirradiated cells were then harvested and allowed to grow for 20 generations. Relative to controls, the progeny of bystander cells that were co-cultured with cells irradiated with iron or silicon ions, but not protons, exhibited reduced cloning efficiency and harbored higher levels of chromosomal damage, protein oxidation and lipid peroxidation. This correlated with decreased activity of antioxidant enzymes, inactivation of the redox-sensitive metabolic enzyme aconitase, and altered translation of proteins encoded by mitochondrial DNA. Together, the results demonstrate that the long-term consequences of the induced nontargeted effects greatly depend on the quality and dose of the radiation and involve persistent oxidative stress due to induced perturbations in oxidative metabolism. They are relevant to estimates of health risks from exposures to space radiation and the emergence of second malignancies after radiotherapy. PMID- 21319990 TI - Prostate cancer proteomics. AB - Proteomics has offered the hope of biomarker discovery to improve the management of prostate cancer. Markers are needed for screening and diagnosis, distinguishing latent from aggressive disease, defining the men who will benefit from therapy, differentiating localized from metastatic disease, predicting outcome and identifying new targets for therapy. There are many potential sources of proteins derived from the prostate, including urine, prostatic fluid (expressed or ejaculate), serum, and plasma or tissue, each with distinct advantages and limitations. Equally, there are many methodological platforms for proteomic studies of the prostate. Despite the promise, protoemics has yielded little of relevance to the management of prostate cancer, and most of the work that has been published is either irreproducible or of no clinical value. PMID- 21319992 TI - Determining and interpreting new predictive rules for breast cancer familial inheritance. AB - DNA copy number alterations have been discovered to be key genetic events in development and progression of cancer. No clear data of familial and sporadic breast cancer are available. We focused on looking for an independent platform as a tool to identify the chromosomal profile in familial versus sporadic breast cancer patients. A total of 124 breast cancer patients were studied utilizing aCGH. The dataset was analyzed using Gaussian Mixture Models to determine the thresholds in order to assess gene copy number changes and to minimize the impact of noise on further data analyses. The identification of regions of consistent aberration across samples was carried out with statistical approaches and machine learning tools to draw profiles for familial and sporadic groups. Familial and sporadic cases resulted with a chromosome imbalance of 15% [false discovery rate (FDR): q=718E-5] and 18% (FDR: q=632E-13), respectively. The differential map evidenced two cytogenetic bands (8p23 and 11q13-11q14) significantly altered in familial versus sporadic cases (FDR: q=7E-4). The application of a new bioinformatics tool that discovers fuzzy classification rules (IFRAIS) let to individualize association of genes alterations that identify familial or sporadic cases. These results are comparable to those of the other systems used and are consistent from the biological point of view. PMID- 21319991 TI - Biomarkers in the age of omics: time for a systems biology approach. AB - Limitations to biomarker discovery are not only technical or bioinformatic but conceptual as well. In our attempt to offer a solution, we are highlighting three issues that we think are limiting progress in biomarkers discovery. First, the confusion stemming from the imposition of a pathology-type immunohistochemical marker (IHCM) concept on omics data without fully understanding the characteristics and limitations of IHCMs as applied in clinical pathology. Second, the lack of serious consideration for the scope of disease heterogeneity. Third, the refusal of the biomedical community to borrow from other biological disciplines their well established methods for dealing with heterogeneity. Therefore, real progress in biomarker discovery will be attained when we recognize that an omics biomarker cannot be assigned and validated without a priori data modeling and subtyping of the disease itself to reveal the extent of its heterogeneity, and its omics' clonal aberrations (drivers) underlying its subtypes and pathways' diversity. To further support our viewpoints, we are contributing a novel a systems biology method such as parsimony phylogenetic approach for disease modeling prior to biomarker circumscription. As an analytical approach that has been successfully used for a half of a century in other biological disciplines, parsimony phylogenetics simultaneously achieves several objectives: it provides disease modeling in a hierarchical phylogenetic classification, identifies biomarkers as the shared derived expressions or mutations--synapomorphies, constructs the omics profiles of specimens based on the most parsimonious arrangement of their heterogeneous data, and permits network profiling of affected signaling pathways as the biosignature of disease classes. PMID- 21319993 TI - Identification of novel prognostic markers in relapsing localized resectable neuroblastoma. AB - Patients with localized resectable neuroblastoma (NB) generally have an excellent prognosis and can be treated by surgery alone, but approximately 10% of them develop local recurrences or metastatic progression. The known predictive risk factors are important for the identification of localized resectable NB patients at risk of relapse and/or progression, who may benefit from early and aggressive treatment. These factors, however, identify only a subset of patients at risk, and the search for novel prognostic markers is warranted. This review focuses on the recent advances in the identification of new prognostic markers. Recently we addressed the search of novel genetic prognostic markers in a selected cohort of patients with stroma-poor localized resectable NB who underwent disease relapse or progression (group 1) or complete remission (group 2). High-resolution array comparative genomic hybridization (CGH) DNA copy-number analysis technology was used. Chromosome 1p36.22p36.32 loss and 1q22qter gain, detected almost exclusively in group 1 patients, were significantly associated with poor event free survival (EFS). Increasing evidence points to anaplastic lymphoma kinase (ALK) as a fundamental oncogene associated with NB. The immunohistochemical analysis of sporadic NB localized resectable primary tumors (stage 1-2) showed a correlation between aberrant ALK level of expression and tumor progression and clinical outcome. Moreover, other factors that might influence the clinical behavior of these tumors will be reviewed. PMID- 21319994 TI - A systems biology approach to cancer: fractals, attractors, and nonlinear dynamics. AB - Cancer begins to be recognized as a highly complex disease, and advanced knowledge of the carcinogenic process claims to be acquired by means of supragenomic strategies. Experimental data evidence that tumor emerges from disruption of tissue architecture, and it is therefore consequential that the tissue level should be considered the proper level of observation for carcinogenic studies. This paradigm shift imposes to move from a reductionistic to a systems biology approach. Indeed, cell phenotypes are emergent modes arising through collective nonlinear interactions among different cellular and microenvironmental components, generally described by a phase space diagram, where stable states (attractors) are embedded into a landscape model. Within this framework cell states and cell transitions are generally conceived as mainly specified by the gene-regulatory network. However, the system's dynamics cannot be reduced to only the integrated functioning of the genome-proteome network, and the cell-stroma interacting system must be taken into consideration in order to give a more reliable picture. As cell form represents the spatial geometric configuration shaped by an integrated set of cellular and environmental cues participating in biological functions control, it is conceivable that fractal shape parameters could be considered as "omics" descriptors of the cell-stroma system. Within this framework it seems that function follows form, and not the other way around. PMID- 21319995 TI - Association between single nucleotide polymorphisms in the cyclooxygenase-2, tumor necrosis factor-alpha, and vascular endothelial growth factor-A genes, and susceptibility to hepatocellular carcinoma. AB - Cyclooxygenase-2 (COX-2), vascular endothelial growth factor-A (VEGF-A), and tumor necrosis factor-alpha (TNF-alpha) are mediators of inflammation and angiogenesis; all of them are produced in liver cirrhosis (LC) and in hepatocellular carcinoma (HCC). It was proposed that there is an association between single nucleotide polymorphisms (SNPs) and HCC. These allelic variants influence the transcriptional activity of these genes, and therefore the proteins levels. The VEGF-A pathway is a potential therapeutic target in HCC, and several antiangiogenic agents have entered clinical trials in HCC. We evaluated the frequency of SNPs of COX-2, TNF-alpha, and VEGF-A genes in patients with HCC versus LC patients and a control group. The aim of this article was to verify the correlation between the allelic variations and the risk of developing HCC. The study included 96 HCC, 79 LC patients, and 162 healthy subjects. The evaluation of SNPs was performed by the restriction fragment length polymorphism (RFLP-PCR) method. The SNPs analyzed were: -1195 G>A of the COX-2 gene, -308 G>A of the TNF alpha gene, and +936 C>T of the VEGF-A gene. Chi-square and Fisher exact tests were used for statistical analysis. Our results confirm that carriers with the C allele in the VEGF-A gene are more frequent in HCC versus LC (p=0.039), suggesting that this SNP may predispose to the development of HCC. PMID- 21319996 TI - Global regulation on microRNA in hepatitis B virus-associated hepatocellular carcinoma. AB - Recent work has revealed the causative links between deregulation of microRNAs (miRNAs) and cancer development. In hepatocellular carcinoma (HCC), aberrant expression of miRNAs has been observed, but the molecular mechanisms that contribute to such changes remains to be elucidated. Here, we reported the analysis of miRNA expression in 94 pairs of tumor and adjacent nontumor tissues from HBV-associated HCC in Chinese patients. We found miRNAs were aberrantly expressed in HCC tissues. To investigate the cause of such deregulation, we detected changes in DNA copy number by measuring locus-specific hybridization intensity, and found changes in expression of several miRNAs are correlated with genomic amplification or deletion. For example, the genomic regions of miR-30d and miR-151 were amplified in ~50% of HCC tumor tissues, and the expressions of these miRNAs are significantly correlated with DNA copy number. We also employed cDNA microarray data, and provide evidence that key regulators of the miRNA biosynthetic pathway, including DROSHA, DGCR8, AGO1, and AGO2, are frequently overexpressed in HCC. This study provides molecular clues that may contribute to the global changes of miRNA expression in HCC. PMID- 21319997 TI - Adeno-associated viral vectors for mapping, monitoring, and manipulating neural circuits. AB - Understanding the structure and function of neural circuits is central is neuroscience research. To address the associated questions, new genetically encoded tools have been developed for mapping, monitoring, and manipulating neurons. Essential to implementation of these tools is their selective delivery to defined neuronal populations in the brain. This has been facilitated by recent improvements in cell type-specific transgene expression using recombinant adeno associated viral vectors. Here, we highlight these developments and discuss areas for improvement that could further expand capabilities for neural circuit analysis. PMID- 21319998 TI - Clonal inventory screens uncover monoclonality following serial transplantation of MGMT P140K-transduced stem cells and dose-intense chemotherapy. AB - Gene transfer of mutant O(6)-methylguanine-DNA-methyltransferase (MGMT(P140K)) into hematopoietic stem cells (HSCs) protects hematopoiesis from alkylating agents and allows efficient in vivo selection of transduced HSCs. However, insertional mutagenesis, high regenerative stress associated with selection, and the genotoxic potential of alkylating drugs represent considerable risk factors for clinical applications of this approach. Therefore, we investigated the long term effect of MGMT(P140K) gene transfer followed by repetitive, dose-intensive treatment with alkylating agents in a murine serial bone marrow transplant model and assessed clonality of hematopoiesis up to tertiary recipients. The substantial selection pressure resulted in almost completely transduced hematopoiesis in all cohorts. Ligation-mediated PCR and next-generation sequencing identified several repopulating clones carrying vector insertions in distinct genomic regions that were ~ 9 kb of size (common integration sites). Beside polyclonal reconstitution in the majority of the mice, we also detected monoclonal or oligoclonal repopulation patterns with HSC clones showing vector insertions in the Usp10 or Tubb3 gene. Interestingly, neither Usp10, Tubb3, nor any of the genes located in common integration sites have been linked to clonal expansion in previous preclinical or clinical gene therapy trials. However, a considerable number of these genes are involved in DNA damage response and cell fate decision pathways following cytostatic drug application. Thus, in summary, our study advocates ligation-mediated PCR and next generation sequencing as an effective and reliable method to identify gene products associated with clonal survival in specific experimental settings such as chemoselection using alkylating agents. PMID- 21319999 TI - Leisure participation for school-aged children with Down syndrome. AB - PURPOSE: To describe leisure participation for school-aged children with Down syndrome and to investigate how factors, classified by the World Health Organisation's International Classification of Functioning, Disability and Health, influence their leisure participation. METHOD: Families in Western Australia with a child aged 5-18 years with Down syndrome were surveyed in a population-based study (n = 208) in 2004. RESULTS: One-third of parents reported that their child with Down syndrome had no friends although half reported two or more friends. Factors affecting number of friendships included the child's functional ability, behavioural issues and parent's availability of time. Those children with higher functional independence scores in daily tasks were more likely to have two or more friends than those with lower functional independence scores (OR: 1.02, 95% CI 1.01-1.04 for a single point increase in WeeFIM score). All children participated in predominantly solitary and sedentary leisure activities. CONCLUSIONS: Leisure participation was affected by complex factors both within and external to the child with Down syndrome. Further investigation of the relevance of these factors to leisure may enable more satisfying and meaningful participation in leisure for school-aged children with Down syndrome. PMID- 21320000 TI - Unusual presentation of carpal tunnel syndrome with cutaneous signs: a case report and review of the literature. AB - Carpal tunnel syndrome (CTS) is a neurological impairment caused by compression of the median nerve throughout the carpal tunnel, which consequently induces ischemia and mechanical disruption, dysfunctional axonal transport, and epidural blood flow. Most common symptoms include numbness, rather than pain, with a typical night exacerbation, weakness, paresthesia, and loss of sensitive discrimination. In rare cases, such syndrome may present with cutaneous manifestations localized on the distal phalanges of the hands, even without the above mentioned neurological symptoms. We describe a case of a woman who came to our attention complaining of the appearance of recurrent bullous eruptions involving the distal phalanges innervated by the median nerve. She did not report any neurological signs whatsoever. After excluding a bullous disease, we further investigated through additional analysis that revealed a CTS. Hence, physicians should consider CTS as a differential diagnosis when assessing cutaneous lesions of the first three fingers of the hands. PMID- 21320001 TI - Does the antiviral therapy of patients with chronic hepatitis exert nephrotoxic effects? AB - INTRODUCTION: HBV and HCV chronic hepatitis can be accompanied by secondary renal disease. In addition, these patients receive antiviral drugs with potential nephrotoxicity. It is known that interferon (IFN) therapy in HCV-infected kidney transplant recipients is followed by rejection of the transplant in 50% of the cases. Ribavirin is contraindicated in hemodialyzed patients and in patients with a GFR <50 ml/min/1.73 m(2). IFN therapy requires dosage reduction and close monitoring in patients with a GFR <50 ml/min/1.73 m(2) and in patients with end stage renal disease. The aim of our study was to assess the nephrotoxicity of antiviral drugs in patients with chronic hepatitis by measuring three renal biomarkers: urinary albumin, N-acetyl-beta-D-glucosaminidase (NAG) and alpha 1 microglobulin, as well as glomerular filtration rate (GFR-MDRD4) before and at 6 months of therapy. METHODS: Fifty-five patients (28 male and 27 female, with a mean age of 47.85 +/- 12.03 years) with chronic hepatitis (40 patients with HCV, 13 patients with HBV, 1 patient with HBV+HCV, and 1 patient with HBV+HDV) were enrolled into the study. Different antiviral drug associations were used on a case-by-case basis. The 40 patients with HCV chronic hepatitis received either Peg-IFN-alpha 2a+Ribavirin (37 patients) or Peg-IFN-alpha 2b+Ribavirin (3 patients). The 13 patients with HBV chronic hepatitis received Peg-IFN-alpha 2a (9 patients), Lamivudine (2 patients), Entecavir (1 patient), or Adefovir (1 patient). The patient with HBV+HCV chronic hepatitis received Peg-IFN-alpha 2a+Ribavirin. The patient with HBV+HDV chronic hepatitis received IFN-alpha 2a. Urinary albumin (ELISA), NAG (colorimetrical method), alpha 1-microglobulin (ELISA), and serum creatinine were measured before and at 6 months of antiviral therapy. Urinary markers were expressed as either mg/gCr (for albumin and alpha 1 microglobulin) or U/gCr (for NAG). Statistical analysis (Pearson's correlation coefficient, paired t-test and chi(2)-test) was performed. RESULTS: At 6 months of therapy urinary albumin/gCr did not increase significantly: 16.58 +/- 23.39 vs. 15.85 +/- 24.96 mg/gCr before therapy, p = 0.87. Urinary NAG/gCr did not increase significantly: 4.21 +/- 3.37 vs. 3.83 +/- 3.2 U/gCr before therapy, p = 0.53. Urinary alpha 1-microglobulin/gCr was almost unchanged: 4.38 +/- 4.47 vs. 4.38 +/- 3.57 mg/gCr before therapy, p = 0.99. The GFR did not decline significantly: 92.41 +/- 22.21 vs. 94.59 +/- 36.1 ml/min/1.73 m(2) before therapy, p = 0.7. Ten patients (18.18%) were albuminuric before therapy, and 14 patients (25.45%) were albuminuric at 6 months of therapy, a non-significant increase (p = 0.35). We found a correlation between urinary albumin/gCr and NAG/gCr and between urinary albumin/gCr and alpha 1-microglobulin/gCr both at baseline and at 6 months of therapy: r = 0.54, p = 0.0005; r = 0.29, p = 0.03; r = 0.51, p = 0.0005; and r = 0.4, p = 0.002, respectively. In the patient receiving Adefovir, a known nephrotoxic drug, two of the three biomarkers (urinary albumin/gCr and NAG/gCr) increased, most notably NAG/gCr. Both HCV and HBV chronic hepatitis therapy were associated with non-significant changes in renal biomarker excretion and GFR. CONCLUSIONS: With the exception of Adefovir, all of the drug associations used in this study were safe. PMID- 21320002 TI - New nucleoside analogs for patients with hematological malignancies. AB - INTRODUCTION: In the last few years, several new purine and pyrimidine nucleoside analogs have been synthesized and made available for both preclinical studies and clinical trials. AREAS COVERED: This article summarizes recent achievements in the mechanism of action, pharmacological properties and clinical activity and toxicity as well as the emerging role of newer purine and pyrimidine nucleoside analogs potentially active in lymphoid and myeloid malignancies. A literature review was conducted from the MEDLINE database PubMed for articles in English. Publications from 2000 to October 2010 were scrutinized. The search terms used were clofarabine, nelarabine, forodesine, 8-chloroadenosine, LMP-420, azacitidine, decitabine, sapacitabine, troxacitabine, thiarabine and zebularine in conjunction with hematologic malignancies, leukemia and lymphoma. Conference proceedings from the previous 5 years of the American Society of Hematology, European Hematology Association, and American Society of Clinical Oncology were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles. EXPERT OPINION: Several new nucleoside analogs are currently under investigation in preclinical and clinical studies concerning hematological malignancies. Clofarabine, nelarabine, azacitidine and decitabine have been recently approved for the treatment of leukemias and/or myelodysplastic syndromes. Other agents including forodesine, 8-chloroadenosine, LMP-420, sapacitabine, troxacitabine, thiarabine and zebularine seem to be promising for the treatment of lymphoid and myeloid malignancies. However, definitive data from ongoing and future clinical trials will aid in better defining their status in the treatment of hematological disorders. PMID- 21320003 TI - The use of vasopressin receptor antagonists in hyponatremia. AB - INTRODUCTION: Considerable data have recently characterized hyponatremia as fairly common in the intensive care and general hospital settings. Moreover, mounting evidence suggests the association of mild degrees of hyponatremia with untoward neurocognitive and musculoskeletal outcomes. A key development in our ability to treat hyponatremia was the introduction and approval of aquaretics (vaptans). These vasopressin receptor antagonists work by increasing electrolyte free water excretion and thus raising serum sodium concentration. AREAS COVERED: This review presents a diagnostic approach for hyponatremia and discusses some therapeutic considerations. It displays new evidence linking mild chronic hyponatremia with unfavorable outcomes and examines the available treatment options and their limitations and strengths. New data on vaptans and their potential role to treat hyponatremia in different clinical settings are reviewed. EXPERT OPINION: Vaptans are likely to play an important role in treating hyponatremia, given their clinical efficacy and tolerability. High cost remains an impediment for vaptans, and more studies are needed to further define their best use in hyponatremic patients. PMID- 21320004 TI - BIBW 2992 in non-small cell lung cancer. AB - INTRODUCTION: EGFR targeting is a valid and vital approach in the treatment of patients with lung cancer. However, all patients treated with reversible inhibitors develop acquired resistance over time. It is of paramount importance that novel agents are designed and developed to overcome such acquired resistance. AREAS COVERED: The role of EGFR targeting in NSCLC, mechanisms of primary and acquired resistance to reversible inhibitors, and strategies to overcome resistance are examined. Preclinical and clinical data pertaining to BIBW 2992 in advanced solid tumors, and particularly in NSCLC, are also thoroughly reviewed. We hope that the reader will gain a comprehensive knowledge of the emerging field of resistance to EGFR inhibition, specifically relating to drugs being developed for lung cancer patients. EXPERT OPINION: Irreversible dual inhibitors of EGFR-HER2 such as BIBW 2992 provide a promising approach to overcoming acquired resistance to erlotinib and gefitinib in lung cancer. It is yet to be seen whether the drug can overcome primary drug resistance or delay time to development of acquired resistance to EGFR-targeted agents in NSCLC. PMID- 21320006 TI - Stem cells: in theory and practice: veterinarians treating horses, dogs, cats with stem cells as research continues. PMID- 21320007 TI - Questions conclusion in study on managing urethral obstructions in cats. PMID- 21320008 TI - What is your diagnosis? Retrobulbar abscess. PMID- 21320009 TI - What is your diagnosis? Complete comminuted sagittal fracture of the medial aspect of the humeral head and lesser tubercle. PMID- 21320010 TI - Diagnostic imaging in veterinary dental practice. Dentigerous cyst with secondary infection. PMID- 21320011 TI - What is the evidence? Surgical treatment of large dogs with hip joint osteoarthritis. PMID- 21320012 TI - Pathology in practice. Superficial necrolytic dermatitis and nodular hepatopathy (lesions consistent with hepatocutaneous syndrome). PMID- 21320013 TI - Pathology in practice. Severe, chronic, pyogranulomatous rhinosinusitis with necrosis and fungal septate hyphae consistent with Fusarium spp infection. PMID- 21320014 TI - Relationships among common measures of student performance and scores on the North American Veterinary Licensing Examination. AB - OBJECTIVE: To determine relationships among several common measures of performance prior to and during veterinary school (ie, Graduate Record Examination [GRE] scores, undergraduate grade point average [UGPA], Qualifying Examination [QE] scores, overall grade point average during veterinary school [VGPA], and scores for the North American Veterinary Licensing Examination [NAVLE]). DESIGN: Longitudinal retrospective study. SAMPLE POPULATION: 192 students from the Iowa State University College of Veterinary Medicine and 152 students from the University of Minnesota College of Veterinary Medicine. PROCEDURES: Student UGPA, VGPA, and GRE score data were gathered during the normal admissions and academic processes. The QE was administered as a low-stakes examination at both institutions for the purposes of curricular assessment. Scores on the NAVLE were provided with student permission by the National Board of Veterinary Medical Examiners. Path analysis was used to explore hypothesized relationships among variables. RESULTS: GRE scores and UGPA predicted NAVLE scores indirectly through QE scores and VGPA, whereas QE scores and VGPA directly predicted NAVLE scores. The resulting models explained 58% to 62% of the variance in NAVLE scores, with QE score being the strongest predictor. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that for veterinary school students, GRE scores, UGPA, VGPA, and QE scores could be used to predict scores on the NAVLE. This suggests that these measures could prove useful to veterinary schools when admitting students or preparing them for the NAVLE. PMID- 21320015 TI - Identification of hypercoagulability in dogs with primary immune-mediated hemolytic anemia by means of thromboelastography. AB - OBJECTIVE: To evaluate whole blood hemostasis by means of thromboelastography in dogs with primary immune-mediated hemolytic anemia (IMHA) to determine whether these dogs had evidence of hypercoagulability prior to the administration of immunosuppressant medications, blood transfusion products, or anticoagulant agents. DESIGN: Evaluation study. ANIMALS: 11 client-owned dogs admitted to a teaching hospital for management of primary IMHA and 20 clinically normal dogs. PROCEDURES: Citrated whole blood samples were obtained from all dogs for performance of kaolin-activated thromboelastography. Citrated plasma was harvested from blood samples of dogs with IMHA for plasma-based coagulation testing, including activated partial thromboplastin time, prothrombin time, D dimer concentration, fibrinogen concentration, and antithrombin activity. RESULTS: Compared with control dogs, dogs with primary IMHA had evidence of hypercoagulability as indicated by a significantly lower median (range) clot formation time (0.8 seconds [0.8 to 2.0 seconds] vs 1.9 seconds [1.3 to 3.8 seconds]), higher median angle (76.1 degrees [59.2 degrees to 84.6 degrees ] vs 64.0 degrees [45.4 degrees to 71.0 degrees ]), higher median maximum amplitude (75.9 mm [66.3 to 86.3 mm] vs 55.7 mm [49.9 to 63.6 mm]), and higher median clot strength (15,000 dyne/cm(2) [9,900 to 31,400 dyne/cm(2)] vs 6,100 dyne/cm(2) [4,900 to 8,700 dyne/cm(2)]). CONCLUSIONS AND CLINICAL RELEVANCE: Dogs with primary IMHA had hypercoagulability as demonstrated by thromboelastography at the time of initial diagnosis and prior to treatment. Such hypercoagulability may be a precursor to clinically evident thrombosis as a complication of the disease process. PMID- 21320016 TI - Detection of innocent systolic murmurs by auscultation and their relation to hematologic and echocardiographic findings in clinically normal Whippets. AB - OBJECTIVE: To determine murmur prevalence by auscultation of 105 apparently healthy Whippets without signs of cardiac disease, to determine the origin of these murmurs, and to evaluate the influence of sex, type of pedigree (ie, bred for showing or racing), and training on these murmurs. DESIGN: Cross-sectional study. ANIMALS: 105 client-owned Whippets. PROCEDURES: All dogs were auscultated by the first author and underwent a complete physical and cardiological examination, together with a hematologic assessment. Several RBC variables and echocardiographic variables were compared between dogs with or without a murmur at the level of the aortic valve. RESULTS: 44 of 105 (41.9%) dogs had no murmur. A soft systolic murmur was present with point of maximal intensity at the level of the aortic valve in 50 (47.6%) dogs, at the level of the pulmonic valve in 8 (7.6%) dogs, and at the level of the mitral valve in 3 (2.9%) dogs. No significant differences were found in heart rate, rhythm, murmur presence, point of maximal intensity, and murmur grade between males and females, between dogs with race- and show-type pedigrees, or between dogs in training and not in training. Dogs with a murmur at the level of the aortic valve had a significantly higher aortic and pulmonic blood flow velocity and cardiac output, compared with dogs without a murmur. CONCLUSIONS AND CLINICAL RELEVANCE: Whippets have a high prevalence of soft systolic murmurs in the absence of any structural abnormalities, which fit the description of innocent murmurs. No influence of sex, pedigree type, or training was found on the occurrence of these murmurs in Whippets. PMID- 21320017 TI - Predictors of outcome in dogs with subcutaneous or intramuscular hemangiosarcoma. AB - OBJECTIVE: To identify prognostic factors in a large group of dogs with subcutaneous or intramuscular hemangiosarcoma (HSA) or both. Design-Multi institutional retrospective cohort study. Animals-71 dogs with subcutaneous or intramuscular HSA. PROCEDURES: Medical records of affected dogs were reviewed. The following factors were evaluated for an association with outcome: dog age and sex, clinical signs, anemia, thrombocytopenia, neutrophilia, tumor stage at diagnosis, achievement of complete excision, intramuscular involvement, presence of gross disease, tumor recurrence, and treatment. RESULTS: Of the 71 cases identified, 16 (29%) had intramuscular tumor involvement. For all dogs, median time to tumor progression and overall survival time (OST) were 116 and 172 days, respectively; 25% survived to 1 year. Univariate analysis identified presence of clinical signs or metastasis at diagnosis, dog age, tumor size, use of any surgery, and presence of gross disease as predictors of time to tumor progression and OST. There was no significant difference in survival time between dogs with respect to type of HSA. Multivariate analysis confirmed that adequate local tumor control, tumor diameter <= 4 cm, presence of metastasis at diagnosis, and presence of gross disease were significantly associated with OST. CONCLUSIONS AND CLINICAL RELEVANCE: Subcutaneous and intramuscular HSA remains a heterogeneous group of tumors that generally carries a poor prognosis. Adequate local control of smaller tumors with no associated clinical signs or metastasis may provide the best chance of long-term survival. PMID- 21320018 TI - Predictors of long-term survival in dogs with high-grade multicentric lymphoma. AB - OBJECTIVE: To determine factors predicting survival in dogs with high-grade multicentric lymphoma. Design-Retrospective cohort study. Animals-127 dogs with high-grade multicentric lymphoma evaluated at 4 veterinary hospitals from 2000 to 2009. PROCEDURES: Records were reviewed to identify dogs with completely staged high-grade multicentric lymphoma treated with chemotherapy. Data collected included signalment, history, hematologic findings, tumor characteristics, treatment, and outcome. Long-term survival was defined as surviving > 2 years after diagnosis. Variables were analyzed for associations with dogs living > 2 years. RESULTS: Among the 127 enrolled dogs, 13 (10%) survived > 2 years with a median survival time of 914 days (range, 740 to 2,058 days). Survival rates at 3, 4, and 5 years were 4%, 3%, and 1 %, respectively. At diagnosis, 11 of the 13 long-term survivors had a body weight >= 10 kg, PCV >= 35%, absence of ionized hypercalcemia, centroblastic lymphoma, immunophenotype B, absence of bone marrow involvement, and lymphoma stages I through IV and were not previously treated with corticosteroids. The same combination of factors was present in 26 of 114 (23%) dogs surviving <= 2 years, yielding a negative predictive value of 97.8% for long-term survivors. Four of the 6 long-term survivors that died during the study died of another cancer; 3 of them had osteosarcoma. CONCLUSIONS AND CLINICAL RELEVANCE: Absence of the aforementioned combination of variables at diagnosis may help identify dogs with lymphoma that will not survive > 2 years. Other types of neoplasia, in particular osteosarcoma, may develop in long-term surviving dogs. PMID- 21320019 TI - Identification of risk factors for septic peritonitis and failure to survive following gastrointestinal surgery in dogs. AB - OBJECTIVE: To identify risk factors for failure to survive and development of septic peritonitis following full-thickness gastrointestinal incision in dogs. Design-Retrospective cohort study. ANIMALS: Dogs that underwent gastrointestinal surgery from 1998 through 2007 at the University of Georgia Veterinary Teaching Hospital. Procedures-Medical records of dogs undergoing a full-thickness gastrointestinal incision were reviewed, and information regarding dog history, clinicopathologic findings, surgery characteristics, and outcome was collected. RESULTS: Records for 197 dogs (225 surgeries) were evaluated. In 35 (16%) surgeries, the dogs died prior to hospital discharge. After 28 (12%) surgeries, dogs developed septic peritonitis. For 45 (20%) surgeries, dogs had preoperative septic peritonitis; of those, approximately a third resulted in continued septic peritonitis (17/45; 38%) or death (15/45; 33%). Of the 180 surgeries performed in dogs lacking preoperative septic peritonitis, 11 (6%) resulted in development of septic peritonitis and 20 (11 %) resulted in death. When all surgeries were considered, common risk factors for development of septic peritonitis included preoperative septic peritonitis, low preoperative serum albumin and plasma protein concentrations, and intraoperative hypotension. Presence of a foreign body was a protective factor. CONCLUSIONS AND CLINICAL RELEVANCE: Multiple factors were associated with failure to survive and development of septic peritonitis after gastrointestinal surgery in dogs. Aggressive perioperative attempts to increase protein concentrations and intraoperative surgical strategies to decrease the chance of a poor outcome may be indicated in dogs with risk factors identified in this study. PMID- 21320020 TI - Clinicopathologic characterization of odontogenic tumors and focal fibrous hyperplasia in dogs: 152 cases (1995-2005). AB - OBJECTIVE: To characterize clinicopathologic features of the most common odontogenic tumors and focal fibrous hyperplasia (FFH) in dogs. DESIGN: Retrospective case series. ANIMALS: 152 dogs evaluated for oral tumors of possible odontogenic origin at the William R. Pritchard Veterinary Medical Teaching Hospital of the University of California-Davis between 1995 and 2005. PROCEDURES: Information was collected from records, including dog breed, age, reproductive status, and location of lesion in the oral cavity. Histologic slides pertaining to each dog were reviewed by 3 investigators. Data regarding clinicopathologic features of the 3 most common lesions (canine acanthomatous ameloblastoma [CAA], peripheral odontogenic fibroma [POF], and FFH) were summarized. RESULTS: 152 dogs with odontogenic tumors or FFH were identified. Sixty-eight (45%) dogs had CAA, 47 (31 %) had POF, 24 (16%) had FFH, and 13 (9%) had other odontogenic tumors. Canine acanthomatous ameloblastoma was present most commonly in the rostral aspect of the mandible, with POF and FFH more common in the rostral aspect of the maxilla. Males and females were equally represented among dogs with CAA and FFH. Castrated males were overrepresented among dogs with POF. Golden Retrievers, Akitas, Cocker Spaniels, and Shetland Sheepdogs were overrepresented among dogs with CAA. No breed predisposition was detected for FFH or POF. Dogs with FFH had a greater mean age at initial evaluation than did dogs with CAA or POF. CONCLUSIONS AND CLINICAL RELEVANCE: CAA, POF, and FFH have distinct clinical patterns that may help clinicians and pathologists identify such lesions more readily. PMID- 21320021 TI - Evaluation of factors associated with second remission in dogs with lymphoma undergoing retreatment with a cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy protocol: 95 cases (2000-2007). AB - OBJECTIVE: To evaluate factors associated with second remission in dogs with lymphoma retreated with a cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) protocol after relapse following initial treatment with a first line 6-month CHOP protocol. DESIGN: Retrospective case series. ANIMALS: 95 dogs with lymphoma. PROCEDURES: Medical records were reviewed. Remission duration was estimated by use of the Kaplan-Meier method. Factors potentially associated with prognosis were examined. RESULTS: Median remission duration after the first-line CHOP protocol was 289 days (range, 150 to 1,457 days). Overall, 78% (95% confidence interval [CI], 69% to 86%) of dogs achieved a complete remission following retreatment, with a median second remission duration of 159 days (95% CI, 126 to 212 days). Duration of time off chemotherapy was associated with likelihood of response to retreatment; median time off chemotherapy was 140 days for dogs that achieved a complete remission after retreatment and 84 days for dogs that failed to respond to retreatment. Second remission duration was associated with remission duration after initial chemotherapy; median second remission duration for dogs with initial remission duration >= 289 days was 214 days (95% CI, 168 to 491 days), compared with 98 days (95% CI, 70 to 144 days) for dogs with initial remission duration < 289 days. CONCLUSIONS AND CLINICAL RELEVANCE: Findings suggested that retreatment with the CHOP protocol can be effective in dogs with lymphoma that successfully complete an initial 6-month CHOP protocol. PMID- 21320022 TI - Adverse effects associated with inadvertent intravenous penicillin G procaine penicillin G benzathine administration in two dogs and a cat. AB - CASE DESCRIPTION: 2 dogs and a cat were inadvertently given penicillin G procaine penicillin G benzathine IV instead of propofol during induction of anesthesia for routine dental prophylaxis. One dog and the cat required hospitalization because of severe neurologic impairment and cardiopulmonary arrest (cat); the remaining dog did not develop any clinical signs. CLINICAL FINDINGS: In the 2 animals that developed signs consistent with an immediate adverse reaction, clinical signs included muscle tremors, seizures, blindness, vocalization, agitation, and transient loss of vision. Hypothermia, pruritus, hypotension, and cardiac arrest were also documented. TREATMENT AND OUTCOME: The 2 affected patients responded to treatment with anticonvulsant medications, centrally acting muscle relaxants, sedation, and intensive supportive care including IV fluid administration and oxygen supplementation as needed. Cardiopulmonary cerebral resuscitation was performed successfully in the cat. The dog that did not develop any clinical signs was not treated. The 2 affected patients recovered fully and were discharged from the hospital after 3 to 4 days with no apparent sequelae. CLINICAL RELEVANCE: Penicillin G procaine-penicillin G benzathine and propofol are common drugs in veterinary practice and may both be administered to patients undergoing elective procedures. Because of their similar milky white appearance, veterinarians should label syringes and take care to avoid this medication error. There is no specific antidote for penicillin orprocaine toxicosis. Aggressive and immediate treatment is required in patients that develop an adverse reaction to ensure a successful outcome. PMID- 21320023 TI - The pharmacokinetic evaluation of artemisinin drugs for the treatment of malaria in paediatric populations. AB - INTRODUCTION: The use of artemisinin combination therapies to treat uncomplicated malaria is growing and, therefore, so is the number of children exposed to these agents. As a result, there is a huge drive to develop paediatric formulations. However, relatively limited data exist regarding the pharmacokinetic properties of these drugs in this vulnerable population. AREAS COVERED: The article reviews the pharmacokinetic data for artemisinin drugs used for the treatment of malaria in paediatric populations. The authors discuss how developmental and environmental factors can produce significant variation in the pharmacokinetic properties of artemisinin drugs. The authors also discuss how this variation may lead to suboptimal therapeutic drug concentrations with implications on efficacy, safety and the development of parasite resistance to these drugs. EXPERT OPINION: There is currently a lack of published studies on the pharmacokinetics of artemisinin drugs in children and this subject is complicated by several interdependent variables. Therefore, the construction of a systems-based model of this subject should be a priority area in order to identify gaps in current knowledge to ensure their continued effective and safe use. PMID- 21320024 TI - Methylation-mediated regulation of E2F1 in DNA damage-induced cell death. AB - E2F1 promotes DNA damage-induced apoptosis and the post-translational modifications of E2F1 play an important role in the regulation of E2F1-mediated cell death. Here, we found that Set9 and LSD1 regulate E2F1-mediated apoptosis upon DNA damage. Set9 methylates E2F1 at lysine 185, a conserved residue in the DNA-binding domain of E2F family proteins. The methylation of E2F1 by Set9 leads to the stabilization of E2F1 and up-regulation of its proapoptotic target genes p73 and Bim, and thereby induces E2F1-mediated apoptosis in response to genotoxic agents. We also found that LSD1 demethylates E2F1 at lysine 185 and reduces E2F1 mediated cell death. The identification of the methylation/demethylation of E2F1 by Set9/LSD1 suggests that E2F1 is dynamically regulated by epigenetic enzymes in response to DNA damage. PMID- 21320025 TI - Insights into the physiomodulatory role of histaminergic receptors in vertebrate skin pigmentation. AB - All organisms, from simple invertebrates to complex human beings, exist in different colors and patterns, which arise from unique distribution of pigments throughout the body. Being the largest organ of the body, skin is always under the influence of internal and external factors that often react to certain intrinsic agents in an unorthodox manner, modifying the integral pigmentation patterns and resulting into complex physiological aberrancies. One of these intrinsic agents involved in numerous immunological and non-immunological processes within the body is histamine. Histamine mediates its multifarious biological activities stimulated by various immunological and non-immunological stimuli via differential expression of its four classes of receptors (H1, H2, H3, and H4) on effector cells. Interestingly, recent studies have described the expression of functional histamine receptors in vertebrate pigment cells melanocytes, emphasizing the potential physiomodulatory effects of this molecule in the phenomenon of skin pigmentation. This noteworthy finding has opened numerous perspectives to elucidate several contentions regarding skin-related conditions. The focus of this review is to provide an updated overview of the involvement and role of histamine and its receptors together with the physiological and pharmacological aspects of their agonists and antagonists impinging the phenomenon of pigmentation and the mechanisms by which they do so. PMID- 21320026 TI - Inhibitory effects of chelidonic acid on IL-6 production by blocking NF-kappaB and caspase-1 in HMC-1 cells. AB - Chelidonic acid (CA) is a gamma-pyrone which is contained in the rhizome of Chelidonium majus L. It has multiple pharmacological effects including those of a mild analgesic, an antimicrobial, an oncostatic and a central nervous system sedative, but the anti-inflammatory effect of CA and its molecular mechanisms are poorly understood. In this study, we investigated the regulatory mechanism of CA in mast cell-mediated inflammatory response by phorbol 12-myristate 13-acetate and calcium ionophore A23187. The results indicate that CA inhibits the production of interleukin-6 (IL-6) and the expression of IL-6 mRNA through the regulation of nuclear factor-kappaB. In addition, CA suppresses the activation and expression of caspase-1. These results provide new insights into the pharmacological actions of CA as a potential molecule for use in therapy in mast cell-mediated inflammatory diseases. PMID- 21320027 TI - "Triage" of lymphoid malignancies in the peripheral blood using the Extended Immunofluorescent Application of the CELL-DYN Sapphire automated hematology analyzer. PMID- 21320028 TI - Evaluation of the accuracy of serum human epididymis protein 4 in combination with CA125 for detecting ovarian cancer: a prospective case-control study in a Korean population. AB - BACKGROUND: This study aimed to determine the serum concentrations of CA125 and human epididymis protein 4 (HE4) in patients with ovarian cancer, and to evaluate the sensitivity and specificity of these biomarkers for differentiating between patients with benign gynecological disease and those with ovarian cancer, when used alone and in combination in a Korean population. METHODS: We consecutively recruited 159 women with an adnexal mass, including 78 women with ovarian cancer. A total of 224 healthy women served as controls. The serum concentrations of HE4 and CA125 were analyzed using immunochemiluminescence assays. The concentrations of the markers were compared among the different subgroups, and the diagnostic accuracy of each marker and the combination of the two markers was assessed by plotting receiver operating characteristic (ROC) curves. In addition, the Risk of Ovarian Malignancy Algorithm (ROMA) was utilized to categorize patients into low- and high-risk groups for epithelial ovarian cancer. RESULTS: Serum HE4 and CA125 concentrations were significantly higher in the ovarian cancer patients compared with those seen in patients with benign disease or in the healthy controls (p<0.0001 in both). In patients with an adnexal mass, the area under the ROC curve was higher when the combination of the markers was used compared with use of CA125 only. Using ROMA, patients could be successfully classified into high- and low-risk group, with 87.5% sensitivity at a specificity of 93.8%. CONCLUSIONS: These findings suggest that measuring serum HE4 concentrations along with CA125 concentrations may provide higher accuracy for detecting ovarian cancer. PMID- 21320029 TI - Quantification of HER2 autoantibodies in the amplification phenomenon of HER2 in breast cancer. AB - BACKGROUND: Gene amplification of HER2 (human epidermal growth factor receptor 2) is a well-known phenomenon in various cancers. However, little is known about the mechanism of the gene amplification phenomenon itself. Autoantibodies to cellular receptors have been described in several cancer types. We hypothesised that autoantibodies against HER2 might have a stimulatory capacity and could be the cause of the HER2 gene amplification phenomenon. To investigate this, we developed a test for the detection of autoantibodies against HER2 in serum (S HER2Ab). METHODS: Blood and tissue samples were collected from 311 women consecutively admitted for surgical treatment of primary breast cancer. Paraffin embedded tissue sections were analysed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). HER2 protein concentrations in tissue were determined in 115 patients. Circulating extracellular domain of HER2 (S HER2) was measured using the Advia Centaur (Siemens AG, Munich, Germany). Analysis for autoantibodies was developed on an ImmunoCAP 100 (Phadia AB, Uppsala, Sweden) with an automated Fluorescent Enzyme Immuno Assay. RESULTS: Of 311 women, 55 (17.7%) had HER2Ab and 51 (16.4%) showed amplification of the HER2 gene determined by IHC/FISH. Eleven women had detectable S-HER2Ab as well as HER2 gene amplification, but no statistically significant correlation was found between the two phenomena. A significantly higher level of S-HER2Ab was found both in HER2 gene-amplified and non-amplified breast cancer patients compared to an age-matched healthy control group. No statistically significant difference in presence or concentration of S-HER2Ab was found in HER2 gene-amplified vs. non amplified breast cancer. CONCLUSIONS: S-HER2Ab can be measured accurately with the ImmunoCAP 100. There is an increased prevalence and concentration of S-HER2Ab in breast cancer patients but no correlation with HER2 gene amplification. We conclude that autoantibodies against HER2 do not seem to be the cause of HER2 gene amplification. PMID- 21320030 TI - Biomarkers of neurodegenerative diseases. PMID- 21320031 TI - Chemical-biological ocular injury from turkey bile. AB - A 43-year-old male who worked in the food processing industry presented with a painful, red eye following an accidental exposure to turkey bile. A large epithelial defect was noted which healed slowly over a week. The possible mechanism of injury is discussed. PMID- 21320033 TI - Longitudinal studies of cognition in first episode psychosis: a systematic review of the literature. AB - Although cognitive deficits are recognized as a core feature in schizophrenia, their evolution over the course of the illness is still debated. Longitudinal studies of cognition in patients after a first episode of psychosis (FEP) provide extremely useful information, in that they include an adequate and realistic baseline measure of cognitive performance, while at the same time minimizing the effect of confounding variables associated with chronicity. The aim of this systematic review was to summarize findings of studies assessing the longitudinal course of neuropsychological deficits in patients with FEP for durations of at least one year. Overall, the neuropsychological deficits that are present following a first episode of psychosis appeared to remain stable over time for periods of up to ten years, the only possible exception being verbal memory deficits, where there is some evidence of further deterioration over the long term. However, further studies are needed to confirm this conclusion, especially in the (somewhat inconsistently defined) domain of executive function. Improvements in psychopathology appear to positively influence the course of cognitive deficits, although the effects of antipsychotic medication are not as clear. PMID- 21320034 TI - Is borderline personality a particularly right hemispheric disorder? A study of P3a using single trial analysis. AB - OBJECTIVE: To test the hypothesis that borderline personality disorder is a manifestation of a particularly right hemispheric disturbance, involving deficient higher order inhibition, and to consider the therapeutic implications of the findings. METHODS: A cohort of 17 medication free borderline patients were compared with 17 age and sex matched controls by means of a study of p3a, which reflects the activity of one of the two main generators of the P300 (P3) of the event-related-potential. P3b reflects the output of the other generator. P3a, an aspect of the attentional system, depends upon prefrontally connected neurocircuitry. P3b is underpinned by a particularly parietally connected neural system. Using an oddball paradigm, P3a was extracted from the responses to targets using a novel single trial analysis. RESULTS: In borderline patients, over homologous electrode sites, p3a amplitudes, but not latencies, were significantly larger in the right hemisphere compared with the left. The differences were most marked fronto-centrally. No such difference was shown in the control subjects. P3a at right hemisphere sites was significantly larger in borderline compared with control patients. There was no significant difference between the groups for the left hemisphere sites. CONCLUSIONS: The abnormally large amplitudes of P3a at right hemisphere sites in borderline patients together with the failure of habituation of P3a, are consistent with deficient inhibitory activity. Discussion of the findings suggest that they may reflect impeded maturation of the fronto-medial processing systems which, it is argued, may be a consequence of the typical early environment of those with the borderline condition. This suggestion leads to a consideration of optimal therapeutic behaviour in this condition, in particular for 'matching' or 'analogical' responsiveness. PMID- 21320035 TI - Adeno-associated virus liver transduction efficiency measured by in vivo [18F]FHBG positron emission tomography imaging in rodents and nonhuman primates. AB - Recombinant adeno-associated virus 5 (rAAV5) represents a candidate vector with unique advantages for the treatment of hepatic disorders because of its narrow hepatic tropism. Noninvasive in vivo imaging of transgene expression provides an important tool with which to quantify the transduction efficiency, and duration and location, of transgene expression. In this study, we used positron emission tomography (PET) and positron emission tomography-computed tomography (PET-CT) imaging to monitor liver transduction efficacy in rodents and nonhuman primates that received rAAV5 vector encoding herpes simplex virus thymidine kinase (HSV TK). HSV-TK expression in liver was also measured by immunohistochemistry. Notable differences in liver transduction efficiency were found, dependent on the animal species and sex. Male rodents were better transduced than females, as previously described. Moreover, male nonhuman primates also displayed increased hepatic expression of the rAAV5-delivered transgene, indicating that differences in rAAV-mediated liver transduction can be anticipated in humans. Our results demonstrate the high sensitivity and reproducibility of PET, using HSV-TK and [(18)F]FHBG, to detect gene expression after rAAV vector administration into living animals, confirming the utility of this technology in the quantification of transgene expression, even at low expression levels. However, we also describe how an immune response against HSV-TK hampered analysis of long-term expression in nonhuman primates. PMID- 21320036 TI - The impact of cholesterol and its metabolites on drug metabolism. AB - INTRODUCTION: Global prevalence of Western-type diet has increased in the last decades resulting in occurrence of certain chronic diseases. This type of diet is also linked to high-cholesterol intake and increase in blood cholesterol. Many of the molecular mechanisms of dealing with increased levels of cholesterol and its metabolites have been elucidated in animal models and humans. It is also evident that cholesterol metabolism is closely connected to drug metabolism. Cholesterol/bile acids and drugs share many transporters, enzymes and regulatory proteins which are key points in the crosstalk. AREAS COVERED: This review presents an overview of the effect of cholesterol and its metabolites on drug metabolism with special emphasis on species-specific differences. The article focuses on the role of nuclear receptors farnesoid X receptor, vitamin D receptor and liver X receptor in the regulation of drug metabolism genes and the role of cholesterol biosynthesis intermediates, oxysterols and bile acids in the induction of drug metabolism through pregnane X receptor. EXPERT OPINION: Studies show that the regulation of drug metabolism by sterols is multileveled. Many species-dependent differences were observed which hinder the transfer of findings from model animals to humans. As of now, there is little evidence available for cholesterol impact on drug metabolism in vivo in humans. There is also the need to confirm the results obtained in animal models and in vitro analyses in human cells but this is very difficult given the current lack of tools. PMID- 21320037 TI - Undiagnosis: an important new role for psychiatry. AB - OBJECTIVE: This paper discusses an activity, hitherto inadequately identified, which is an increasingly important part of contemporary practice. CONCLUSION: Iatrogenesis presents today in new guises but can be satisfying and productive to address. PMID- 21320038 TI - Elevated serum level of circulating syndecan-1 (CD138) in active systemic lupus erythematosus. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) is characterized by loss of B cell tolerance and by the presence of polyclonal B cell activation. Syndecan-1 (CD138) is expressed on plasma cells derived from B cells, and is suspected to play a role in SLE. We evaluated the level of soluble CD138 (sCD138) and cell surface expression of CD138 in patients with active SLE, and also examined correlations among the serum levels of BAFF, a proliferation-inducing ligand (APRIL), and CD138 in these patients. METHODS: Peripheral blood samples were obtained from 22 SLE patients in an active disease state and 14 normal controls. The levels of serum sCD138, sBAFF, and sAPRIL were measured using ELISA, and cell surface CD138 was analyzed by flow cytometry. The levels of CD138 mRNA were analyzed by RT-PCR. Blood samples were obtained longitudinally when the patients were in an inactive disease state. RESULTS: The levels of circulating CD138, CD138 mRNA in PBMC, and the numbers of CD20(- )CD38(+)CD138(+) plasma cells were increased in patients with active SLE in comparison with normal controls. Furthermore, the serum sCD138 level in SLE patients was found to correlate with the proportion of CD20(- )CD38(+)CD138(+) plasma cells. On the other hand, patients with active SLE showed a reduced level of sCD138, and this was inversely correlated with the serum level of sAPRIL. CONCLUSIONS: These results suggest that sCD138 may be applicable as a surrogate marker of disease activity, and that syndecan-1/APRIL signaling may be a potential therapeutic target for patients with active SLE. PMID- 21320040 TI - Genetic variations of bile salt transporters as predisposing factors for drug induced cholestasis, intrahepatic cholestasis of pregnancy and therapeutic response of viral hepatitis. AB - INTRODUCTION: Drug-induced cholestasis, intrahepatic cholestasis of pregnancy and viral hepatitis are acquired forms of liver disease. Cholestasis is a pathophysiologic state with impaired bile formation and subsequent accumulation of bile salts in hepatocytes. The bile salt export pump (BSEP) (ABCB11) is the key export system for bile salts from hepatocytes. AREAS COVERED: This article provides an introduction into the physiology of bile formation followed by a summary of the current knowledge on the key bile salt transporters, namely, the sodium-taurocholate co-transporting polypeptide NTCP, the organic anion transporting polypeptides (OATPs), BSEP and the multi-drug resistance protein 3. The pathophysiologic consequences of altered functions of these transporters, with an emphasis on molecular and genetic aspects, are then discussed. EXPERT OPINION: Knowledge of the role of hepatocellullar transporters, especially BSEP, in acquired cholestasis is continuously increasing. A common variant of BSEP (p.V444A) is now a well-established susceptibility factor for acquired cholestasis and recent evidence suggests that the same variant also influences the therapeutic response and disease progression of viral hepatitis C. Studies in large independent cohorts are now needed to confirm the relevance of p.V444A. Genome-wide association studies should lead to the identification of additional genetic factors underlying cholestatic liver disease. PMID- 21320039 TI - Neonatal exposure to herbicide acetochlor alters pubertal development in female wistar rats. AB - OBJECTIVES: The purpose of this study was to evaluate the effects of neonatal exposure to the herbicide acetochlor (ACT) on pubertal development and reproductive functions in female Wistar rats and to investigate capability of ACT to interfere with estradiol binding to rat uterine estrogen receptors (ERs) ex vivo. METHODS: Acetochlor (7.68 and 15.36 mg/kg/day) was administered by subcutaneous injection from postnatal day (PND) 4-7, and vaginal opening, and estrous cyclicity were evaluated from PND 8-159. A second group of adult ovariectomized female rats was dosed for 6 days with ACT (153.6 mg/kg/day, oral gavage). The interference of ACT with the binding of [3H]Estradiol -17beta to uterine nuclear and cytoplasmic estrogen receptors was analyzed ex vivo in receptor binding assay. RESULTS: Both doses of ACT caused acceleration of the age at eye opening and vaginal patency that were significantly different from the control. In addition, altered estrous cyclicity was observed in the ACT (15.36 mg/kg/day) group with 54% of the female rats displaying irregular cycles at PND 159. While uterine weights were not altered, a significant accumulation of uterine nuclear estrogen receptors was observed in the ACT group. CONCLUSION: These results indicate that acetochlor can act as the endocrine disruptor and that endpoints related to pubertal development and reproductive functions sensitive sites are targeted with this persistent pollutant. PMID- 21320041 TI - The strengths of mass spectrometry are not just sensitivity and selectivity. PMID- 21320042 TI - Cat and mouse: the analytical toxicology of designer drugs. PMID- 21320043 TI - Implications of differences in bioanalytical regulations between Canada, USA and South America. AB - To complete globally, pharmaceutical companies desire to use bioanalytical data and reports as a single version for all filings; not revising for specific countries or regions. Historically, this meant following the US FDA and International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guidance/guidelines; finding them sufficient to achieve global acceptance. However, a growing challenge of the past decade has been additional country-specific and regional regulations that have been released. The differences between the bioanalytical regulations among countries have been recognized as a challenge to the pharmaceutical industry and its CRO partners. Harmonization of the regulations at a global level has been the subject of a number of recent articles and editorials, and the topic has been vigorously discussed at several conferences over the past year. Since all have been in agreement about the need to harmonize regulations, this article will not focus on harmonization but rather it will provide a comparison of the USA/Canadian regulations versus those of South America, in particular Brazil, noting the additional work needed to achieve compliance with country-specific regulations. All countries discussed have specific guidance or regulations on clinical bioequivalence studies, and due to the higher standards for these studies, the regulations for bioequivalence studies will be used as the basis for comparison in the article. PMID- 21320045 TI - Conference report: the conference on small molecule science. AB - The Conference on Small Molecule Science (CoSMoS), organized by the Society for Small Molecule Science (a 501(c)(3) nonprofit chartered organization), was held in Portland, Oregon, USA, on the 27-29 September 2010. The meeting is focused on analytical scientists, from varied scientific and industrial backgrounds, to foster practical 'how to' discussions. CoSMoS organizes highly interactive workshop environments, where in addition to presentations of a unique topical value, a discussion of what has been tried and didn't work, including reasons why, is an instructive part of the proceedings. The conference included six plenary sessions and five workshop sessions. This year CoSMoS was jointly hosted with the 'small molecule' NMR spectroscopy meeting, SMASH, and the program for the final day represented a combination of topics spanning the two interdisciplinary groups. PMID- 21320046 TI - Conference report: 9th International Symposium on Drug Analysis. AB - The successful International Symposium series on Drug Analysis started in Brussels in 1983. So far it has been followed by a further eight editions. Presently, this meeting series is organized on a once every 4-years basis. The 9th edition was held in Antwerp (Belgium) from 21 to 24 September 2010. PMID- 21320048 TI - Reliable procedures to evaluate and repair crosstalk for bioanalytical MS/MS assays. AB - Louis-Philippe Morin is a senior instrument application specialist at Algorithme Pharma, a CRO located in Laval, Canada. He has been working in the bioanalysis industry for the past 10 years where he became a subject matter expert in analytical instrumentation, especially in the MS field. His responsibilities in his current position are to optimize the workflow of the laboratory and to find new procedures, or approaches, to fix complex analytical problems. Louis Philippe's expertise acquired over the years has led him to multiple publications regarding instrumentation. LC-MS/MS is the analytical technique of choice for the quantification of drugs in biological fluids. In recent years, MS/MS detection has been impacted by the rapid evolution of bioanalysis industry requirements. The availability of fast chromatographic systems, the demand for wider dynamic ranges and the extensive use of stable isotope-labeled internal standards in bioanalysis has pushed some triple quadrupole detectors to their limits of operation. Consequently, this situation has led to a re-evaluation of the problem of crosstalk as a potential cause of issues in bioanalysis. In this article, the importance of crosstalk verification on the MS/MS instrument will be demonstrated. Additionally, procedures to identify, evaluate and fix possible crosstalk issues during bioanalytical assays on MS/MS instruments are proposed. PMID- 21320049 TI - Rapid and sensitive method for determination of withaferin-A in human plasma by HPLC. AB - BACKGROUND: To develop and validate a rapid and sensitive high-performance liquid chromatographic method for determination of withaferin-A in human plasma. Withaferin-A, the active molecule of a traditional Indian herb, has demonstrated several biological activities in preclinical models. A validated bioassay is not available for its pharmacokinetic evaluation. RESULTS: The chromatographic system used a reverse-phase C18 column with UV-visible detection at 225 nm. The mobile phase consisted of water and acetonitrile applied in a gradient flow. Withaferin A was extracted by simple protein-precipitation technique. The calibration curve was linear in the concentration range of 0.05-1.6 ug/ml. The method has the desired sensitivity to detect the plasma concentration range of withaferin-A that is likely to show biological activity based on in vitro data. CONCLUSION: This is the first HPLC method ever described for the estimation of withaferin-A in human plasma which could be applied for pharmacokinetic studies. PMID- 21320050 TI - Evaluation of acetone as organic modifier in SPE for bioanalytical quantitative LC-MS/MS. AB - BACKGROUND: To assess the suitability of acetone as an alternative to acetonitrile in SPE under otherwise commonly used conditions, with a focus on selectivity with regard to the most abundant phospholipid class. Two representative analytes were included, leuprolide and tramadol, a peptide and a small molecule, respectively. RESULTS: The use of acetone resulted in analogous elution profiles of all monitored compounds in the majority of conditions. The only significant difference was on silica-based C18, where acetone effected markedly enhanced elution of lysophosphatidylcholines than did acetonitrile. Unmodified silica was shown to operate in per aqueous LC mode in highly aqueous conditions. CONCLUSION: Acetone was established as a selectively similar and slightly more eluotropic alternative to acetonitrile in bioanalytical SPE. PMID- 21320051 TI - The determination of urinary free and conjugated cortisol using UPLC-MS/MS. AB - BACKGROUND: To develop an UPLC-MS/MS method to replace the in-house immunoassay for the analysis of urinary cortisol. RESULTS: Cortisol was extracted from human urine by ethyl acetate and analyzed on a Waters ACQUITY TQD system using a BEH C18 column. Linear calibration curves were generated over the range of 27.6 to 1380 nmol/l and exhibited consistent linearity and reproducibility with a correlation coefficient greater than 0.9950. Intra-day coefficients of variation were between 3.74 and 5.10% and inter-day coefficients of variations were between 4.22 and 6.73%. The extraction recovery of cortisol was greater than 83%. CONCLUSION: An accurate, rapid and robust UPLC-MS/MS method for the determination of urinary cortisol has been developed and validated. With a lower flow rate (0.4 ml/min), a shorter running time per sample and a simple and cost-effective sample preparation, this method is a desirable option for clinical laboratories. PMID- 21320053 TI - In vitro and in vivo characterizations of PEGylated liposomal doxorubicin. AB - One challenge in developing a nanoparticle drug-delivery system is understanding the critical physicochemical properties that may impact its in vivo performance and establishing analytical techniques that can adequately characterize in vitro and in vivo properties. Doxil(r)/Caelyx(r), a PEGylated liposomal doxorubincin (PLD), is one of the leading approved nanoparticle product used in cancer therapy. In this review, we use PLD as an example to illustrate identification of key in vitro and in vivo characteristics. The following characteristics, including liposome composition, state of encapsulated drug, internal environment of liposome, liposome size distribution, lamellarity, grafted polyethylene glycol at the liposome surface, electrical surface potential or charge, and in vitro leakage, are considered critical to demonstrate the supramolecular structure of PLD and ensure consistent drug delivery to cancer tissues. Corresponding analytical techniques are discussed to determine these liposome characteristics. Furthermore, in vivo stability of the PLD can be determined by plasma pharmacokinetics of both free and liposome-encapsulated drug. A better understanding of the critical in vitro and in vivo liposome characteristics together with improvements in analytical technology will enable generic liposome product development and ensure liposome product quality. PMID- 21320052 TI - From pixel to voxel: a deeper view of biological tissue by 3D mass spectral imaging. AB - Three dimensional mass spectral imaging (3D MSI) is an exciting field that grants the ability to study a broad mass range of molecular species ranging from small molecules to large proteins by creating lateral and vertical distribution maps of select compounds. Although the general premise behind 3D MSI is simple, factors such as choice of ionization method, sample handling, software considerations and many others must be taken into account for the successful design of a 3D MSI experiment. This review provides a brief overview of ionization methods, sample preparation, software types and technological advancements driving 3D MSI research of a wide range of low- to high-mass analytes. Future perspectives in this field are also provided to conclude that the outlook for 3D MSI is positive and promises ever-growing applications in the biomedical field with continuous developments of this powerful analytical tool. PMID- 21320055 TI - The protein-protein interactions as a target in medicinal chemistry and drug discovery. PMID- 21320056 TI - Discovery of modulators of protein-protein interactions: current approaches and limitations. AB - Protein-protein interactions are involved in most of the essential processes that occur in living organisms from cell motility to DNA replication, which makes them interesting targets for drug discovery. However, due to the lack of deep pockets, and the large contact surfaces involved in these interactions, they are considered challenging targets and have been often times dismissed as "undruggable". Nonetheless, significant efforts in pharmaceutical and academic laboratories have been devoted to finding ways to exploit protein-protein interactions as drug targets. This article provides an overview of the principles underlying the main general strategies for discovering small-molecule modulators of protein-protein interactions, namely: high-throughput screening, fragment based drug discovery, peptide-based drug discovery, protein secondary structure mimetics, and computer-aided drug discovery. In addition, examples of successful discovery of modulators of protein-protein interactions are discussed for each of those strategies. PMID- 21320057 TI - Protein-protein interactions and cancer: targeting the central dogma. AB - Between 40,000 and 200,000 protein-protein interactions have been predicted to exist within the human interactome. As these interactions are of a critical nature in many important cellular functions and their dysregulation is causal of disease, the modulation of these binding events has emerged as a leading, yet difficult therapeutic arena. In particular, the targeting of protein-protein interactions relevant to cancer is of fundamental importance as the tumor promoting function of several aberrantly expressed proteins in the cancerous state is directly resultant of its ability to interact with a protein-binding partner. Of significance, these protein complexes play a crucial role in each of the steps of the central dogma of molecular biology, the fundamental processes of genetic transmission. With the many important discoveries being made regarding the mechanisms of these genetic process, the identification of new chemical probes are needed to better understand and validate the druggability of protein protein interactions related to the central dogma. In this review, we provide an overview of current small molecule-based protein-protein interaction inhibitors for each stage of the central dogma: transcription, mRNA splicing and translation. Importantly, through our analysis we have uncovered a lack of necessary probes targeting mRNA splicing and translation, thus, opening up the possibility for expansion of these fields. PMID- 21320059 TI - Targeting IAPs as an approach to anti-cancer therapy. AB - Apoptosis is an essential process for embryonic and lymphocyte development, immune system modulation and tissue homeostasis. Defects in apoptotic signaling often lead to diseases of immune deficiency, neurodegeneration and cancer [1, 2]. In the cancer arena, these defects may contribute to the establishment and growth of tumors. Moreover, many cytotoxic chemotherapies act in part by activating these apoptotic networks. Occasionally apoptotic pathways are activated, however key players downstream of initiation are inhibited by negative regulators that have been dysregulated by the diseased state of the cell. Removal of these barriers to apoptosis signaling, it has been rationalized, could restore cell death in diseased cells while sparing those that are not primed for programmed cell death. Additionally, the subversion of these death evading mechanisms may re sensitize cells that have developed resistance to chemotherapies in this manner. The importance of apoptosis as a maintenance process, and the promise that restoring this signaling could mean in treating cancer has placed many targets on the front line of oncology research. Approaches are being developed that will activate death receptor pathways, synthetically activate caspases, restore the activity of tumor suppressor genes such as p53, and counteract the effects of anti-apoptotic factors. Among these approaches, small molecules are in clinical trials against several anti-apoptotic players, namely the Bcl-2 and IAP proteins. This review will focus on the efforts being advanced against the Inhibitor of Apoptosis Proteins (IAP), the chemical matter of the inhibitors and the biology emerging from this research. PMID- 21320058 TI - Development of small-molecule PUMA inhibitors for mitigating radiation-induced cell death. AB - PUMA (p53 upregulated modulator of apoptosis) is a Bcl-2 homology 3 (BH3)-only Bcl-2 family member and a key mediator of apoptosis induced by a wide variety of stimuli. PUMA is particularly important in initiating radiation-induced apoptosis and damage in the gastrointestinal and hematopoietic systems. Unlike most BH3 only proteins, PUMA neutralizes all five known antiapoptotic Bcl-2 members though high affinity interactions with its BH3 domain to initiate mitochondria-dependent cell death. Using structural data on the conserved interactions of PUMA with Bcl 2-like proteins, we developed a pharmacophore model that mimics these interactions. In silico screening of the ZINC 8.0 database with this pharmacophore model yielded 142 compounds that could potentially disrupt these interactions. Thirteen structurally diverse compounds with favorable in silico ADME/Toxicity profiles have been retrieved from this set. Extensive testing of these compounds using cell-based and cell-free systems identified lead compounds that confer considerable protection against PUMA-dependent and radiation-induced apoptosis, and inhibit the interaction between PUMA and Bcl-xL. PMID- 21320061 TI - Drug design from the ADME/PK perspective: does chemical intuition suffice in multifaceted drug discovery? PMID- 21320062 TI - Predicting clearance in humans from in vitro data. AB - The use of in vitro metabolism in scaling to predict human clearance of new chemical entities has become a commonplace activity in the research and development of new drugs. The measurement of in vitro lability in human liver microsomes, a rich source of drug metabolizing cytochrome P450 enzymes, has become a high throughput screen in many research organizations which is a testament to its usefulness in drug design. In this chapter, the methods used to scale in vitro clearance data to predict in vivo clearance are described. Importantly, the numerous assumptions that are required in order to use in vitro data in this manner are laid out. These include assumptions regarding the scaling process as well as technical aspects of the generation of the in vitro data. Finally, some other drug clearance processes that have been emerging as important are described with regard to ongoing research efforts to develop clearance prediction methods. PMID- 21320060 TI - Modulation of protein-protein interactions as a therapeutic strategy for the treatment of neurodegenerative tauopathies. AB - The recognition that malfunction of the microtubule (MT) associated protein tau is likely to play a defining role in the onset and/or progression of a number of neurodegenerative diseases, including Alzheimer's disease, has resulted in the initiation of drug discovery programs that target this protein. Tau is an endogenous MT-stabilizing agent that is highly expressed in the axons of neurons. The MT-stabilizing function of tau is essential for the axonal transport of proteins, neurotransmitters and other cellular constituents. Under pathological conditions, tau misfolding and aggregation results in axonal transport deficits that appear to have deleterious consequences for the affected neurons, leading to synapse dysfunction and, ultimately, neuronal loss. This review focuses on both progress and unresolved issues surrounding the development of novel therapeutics for the treatment of neurodegenerative tauopathies, which are based on (A) MT stabilizing agents to compensate for the loss of normal tau function, and (B) small molecule inhibitors of tau aggregation. PMID- 21320063 TI - Controversies in allometric scaling for predicting human drug clearance: an historical problem and reflections on what works and what does not. AB - This review focuses on a discussion of the controversies in allometric scaling (AS) for predicting human clearance from a mathematical and statistical perspective. First, a history of allometric scaling in comparative biology and its use in pharmacokinetics are reviewed. It is shown that the application of AS in predicting human clearance values based on a limited number of animal species (typically, 3 or 4) contains fundamental statistical errors when AS was first introduced from comparative biology. Second, the mathematical nature of various allometrically-based methods is revealed and the soundness of these methods is assessed. It is demonstrated that any of these methods, which incorporate a correction factor in a traditional allometric approach (varying-exponent allometry), not only reduces the statistical power of the allometric analysis, but are also incorrect with regard to aspects of biology. Finally, it is concluded that allometry remains a valuable tool for predicting human clearance, and should be applied in the context of a fixed exponent. However, fixed-exponent allometry does not provide satisfactory accuracy in predicting human clearance, since it is not able to capture the biological differences among species. Therefore, it is recommended that the overall effort in predicting human pharmacokinetics should be directed to the collection and generation of reliable data (both in vitro and in vivo) along with a better understanding of the DMPK properties of the chemical entity. PMID- 21320064 TI - Drug design tools--in silico, in vitro and in vivo ADME/PK prediction and interpretation: is PK in monkey an essential part of a good human PK prediction? AB - Quantitative human pharmacokinetic (PK) predictions play a critical role in assessing the quality of potential drug candidates and in selecting a human starting dose for clinical evaluation, where the parameters of clearance, volume of distribution, and bioavailability as well as the plasma concentration time profiles are the desired endpoints. While there are numerous reports validating the use of different methods for predictions, it still remains an open question as to what animal species to include when extrapolating the animal PK to human. Given toxicological assessment is generally conducted in two species, a rodent and a non-rodent species, prior to evaluation in human subjects, rat, dog and/or monkey are typically the species ADME scientists employ to evaluate PK. However, the question is, can we achieve an adequate prediction without the use of larger species such as monkey? In the end, the data and tools utilized for human PK predictions will depend on a number of factors such as information from observed human PK for structurally related compounds; the primary mechanism of clearance, and the availability of in silico and in vitro tools applicable to the respective clearance mechanism. Despite these dependencies, for most situations, adequate predictions can be achieved without the use of monkey PK for predicting human. PMID- 21320065 TI - In-silico ADME models: a general assessment of their utility in drug discovery applications. AB - ADME prediction is an extremely challenging area as many of the properties we try to predict are a result of multiple physiological processes. In this review we consider how in-silico predictions of ADME processes can be used to help bias medicinal chemistry into more ideal areas of property space, minimizing the number of compounds needed to be synthesized to obtain the required biochemical/physico-chemical profile. While such models are not sufficiently accurate to act as a replacement for in-vivo or in-vitro methods, in-silico methods nevertheless can help us to understand the underlying physico-chemical dependencies of the different ADME properties, and thus can give us inspiration on how to optimize them. Many global in-silico ADME models (i.e generated on large, diverse datasets) have been reported in the literature. In this paper we selectively review representatives from each distinct class and discuss their relative utility in drug discovery. For each ADME parameter, we limit our discussion to the most recent, most predictive or most insightful examples in the literature to highlight the current state of the art. In each case we briefly summarize the different types of models available for each parameter (i.e simple rules, physico-chemical and 3D based QSAR predictions), their overall accuracy and the underlying SAR. We also discuss the utility of the models as related to lead generation and optimization phases of discovery research. PMID- 21320066 TI - Assessment of cytochrome p450 enzyme inhibition and inactivation in drug discovery and development. AB - Evaluation of the potential of a drug candidate to inhibit or inactivate cytochrome P450 (CYP) enzymes remains an important part of pharmaceutical drug Discovery and Development programs. CYP enzymes are considered to be one of the most important enzyme families involved in the metabolic clearance of the vast majority of prescribed drugs. Clinical drug-drug interactions (DDI) involving inhibition or time-dependent inactivation of these enzymes can result in dangerous side effects resulting from reduced clearance/increased exposure of the drug being affected (the 'victim' drug). In this regard, pharmaceutical companies have become quite vigilant in mitigating CYP inhibition/inactivation liabilities of drug candidates early in Discovery including continued risk assessment throughout Development. In this review, common strategies and decision making processes for the assessment of DDI risk in the different stages of pharmaceutical development are discussed. In addition, in vitro study designs, analysis, and interpretation of CYP inhibition and inactivation data are described in stage appropriate context. The in vitro tools and knowledge available now enable the Discovery Chemist to place the potential CYP DDI liability of a drug candidate into perspective and to aid in the optimization of chemical drug design to further mitigate this risk. PMID- 21320067 TI - Pharmacodynamic-pharmacokinetic integration as a guide to medicinal chemistry. AB - A primary objective of pharmacokinetic-pharmacodynamic (PKPD) reasoning is to identify key in vivo drug and system proper!ties, enabling prediction of the magnitude and time course of drug responses under physiological and pathological conditions in animals and man. Since the pharmacological response generated by a drug is highly dependent on the actual system used to study its action, knowledge about its potency and efficacy at a given concentration or dose is insufficient to obtain a proper understanding of its pharmacodynamic profile. Hence, the output of PKPD activities extends beyond the provision of quantitative measures (models) of results, to the design of future protocols. Furthermore, because PKPD integrates DMPK (e.g. clearance) and pharmacology (e.g. potency),it provides an anchor point for compound selection, and, as such, should be viewed as an important weapon in medicinal chemistry. Here we outline key PK concepts relevant to PD, and then consider real-life experiments to illustrate the importance to the medicinal chemist of data obtained by PKPD. Useful assumptions and potential pitfalls are described, providing a holistic view of the plethora of determinants behind in vitro-in vivo correlations. By condensing complexity to simplicity, there are not only consequences for experimental design, and for the ranking and design of compounds, but it is also possible to make important predictions such as the impact of changes in drug potency and kinetics. In short, by using quantitative methods to tease apart pharmacodynamic complexities such as temporal differences and changes in plasma protein binding, it is possible to target the changes necessary for improving a compound's profile. PMID- 21320068 TI - Strategies and chemical design approaches to reduce the potential for formation of reactive metabolic species. AB - Metabolic activation of new chemical entities to reactive intermediates is routinely monitored in drug discovery and development. Reactive intermediates may bind to cellular macromolecules such as proteins, DNA and may eventually lead to cell death via necrosis, apoptosis or oxidative stress. The evidence that the ultimate outcome of metabolic activation is an adverse drug reaction manifested as in vivo toxicity, is at best circumstantial. However, understanding the process of bioactivation of structural alerts by trapping the reactive intermediates is critical to guide medicinal chemistry efforts in quest for safer and potent molecules. This commentary provides a brief introduction to adverse drug reactions and mechanisms of reactive intermediate formation for various functional groups, followed by a review of chemical design approaches, examples of such strategies, possible isosteric replacements for structural alerts and rationalization of laboratory approaches to determine reactive intermediates, as a guide to today's medicinal chemist. PMID- 21320069 TI - Do we need to optimize plasma protein and tissue binding in drug discovery? AB - It is a commonly accepted assumption that only unbound drug molecules are available to interact with their targets. In order to achieve high unbound plasma drug concentration, it seems obvious to design compounds with low plasma protein binding. Similarly to achieve high unbound tissue concentration, we apparently need compounds with low tissue binding. Our theoretical analysis and experimental data demonstrate that unbound plasma concentration is not determined by plasma protein binding but by hepatic intrinsic clearance after oral dose, and unbound tissue concentration is not determined by tissue binding but determined by unbound plasma concentration and transport properties at the blood-tissue barrier. Reduction of plasma and tissue protein binding for a compound will increase the unbound concentration in vitro but may not increase its unbound plasma or tissue concentration in vivo after oral administration. We conclude that plasma protein and tissue binding are essential parameters to understand pharmacokinetics and pharmacodynamics but they should not be optimized independently in drug discovery. Instead we should focus on reducing clearance and efflux at the blood-tissue barrier to increase in vivo plasma and tissue unbound concentration. PMID- 21320070 TI - Discovery and ADMET: Where are we now. AB - The gradual alignment with all of drug metabolism with all aspects of drug discovery and development has led to a complete realignment of the way the work is conducted. From a background of conducting bespoke in vivo studies much of the work is now in a high throughput screening mode. Large technological advances have been made, but the nature of drug metabolism processes, being multi-system and promiscuous means that much of the help provided to the medicinal chemistry is reactive rather than based on fundamental disposition structure-activity relationships. Lessons learned around the chemical and physicochemical properties more often associated with successfull discovery and development projects are only moderately helpful when the high value pharmacological targets of today only yield potent ligands outside of the boundaries these properties describe. Pivotal to the impact of these properties is the intrinsic permeability of a molecule, something not as widely recognised as perhaps it should be. Metabolic lability is still a problem and the tactics employed are unchanged in 20 years: attempt to lower lipophilicity, if it is too high overall or introduce blocking groups, particularly halogens, after identifying the sites of metabolism Perhaps the greatest success drug metabolism science has had over the last fifteen years is it's pivotal role in characterising drug-drug interactions and providing screening systems and computational models to investigate them. It still has many undeveloped areas of the science such as the role of metabolites in drug activity and why compounds vary in their extent of biliary excretion. PMID- 21320071 TI - Comparing the potential renal protective activity of desferrioxamine B and the novel chelator desferrioxamine B-N-(3-hydroxyadamant-1-yl)carboxamide in a cell model of myoglobinuria. AB - Accumulating Mb (myoglobin) in the kidney following severe burns promotes oxidative damage and inflammation, which leads to acute renal failure. The potential for haem-iron to induce oxidative damage has prompted testing of iron chelators [e.g. DFOB (desferrioxamine B)] as renal protective agents. We compared the ability of DFOB and a DFOB-derivative {DFOB-AdAOH [DFOB-N-(3-hydroxyadamant-1 yl)carboxamide]} to protect renal epithelial cells from Mb insult. Loading kidney tubule epithelial cells with dihydrorhodamine-123 before exposure to 100 MUM Mb increased rhodamine-123 fluorescence relative to controls (absence of Mb), indicating increased oxidative stress. Extracellular Mb elicited a reorganization of the transferrin receptor as assessed by monitoring labelled transferrin uptake with flow cytometry and inverted fluorescence microscopy. Mb stimulated HO-1 (haem oxygenase-1), TNFalpha (tumour necrosis factor alpha), and both ICAM (intercellular adhesion molecule) and VCAM (vascular cell adhesion molecule) gene expression and inhibited epithelial monolayer permeability. Pre-treatment with DFOB or DFOB-AdAOH decreased Mb-mediated rhodamine-123 fluorescence, HO-1, ICAM and TNFalpha gene expression and restored monolayer permeability. MCP-1 (monocyte chemotactic protein 1) secretion increased in cells exposed to Mb-insult and this was abrogated by DFOB or DFOB-AdAOH. Cells treated with DFOB or DFOB-AdAOH alone showed no change in permeability, MCP-1 secretion or HO-1, TNFalpha, ICAM or VCAM gene expression. Similarly to DFOB, incubation of DFOB-AdAOH with Mb plus H2O2 yielded nitroxide radicals as detected by EPR spectroscopy, indicating a potential antioxidant activity in addition to metal chelation; Fe(III)-loaded DFOB-AdAOH showed no nitroxide radical formation. Overall, the chelators inhibited Mb-induced oxidative stress and inflammation and improved epithelial cell function. DFOB-AdAOH showed similar activity to DFOB, indicating that this novel low-toxicity chelator may protect the kidney after severe burns. PMID- 21320073 TI - alpha-Tocopherol attenuates NF-kappaB activation and pro-inflammatory cytokine IL 6 secretion in cancer-bearing mice. AB - Cancer development and progression are closely associated with inflammation. NF kappaB (nuclear factor kappaB) provides a mechanistic link between inflammation and cancer, and is a major factor controlling the ability of malignant cells to resist tumour surveillance mechanisms. NF-kappaB might also regulate tumour angiogenesis and invasiveness and the signalling pathways that mediate its activation provide attractive targets for new chemopreventive and chemotherapeutic approaches. ROS (reactive oxygen species) initiate inflammation by up-regulation of pro-inflammatory cytokines and therefore antioxidants provide a major defence against inflammation. alpha-Tocopherol is a lipid-soluble antioxidant. In addition to decreasing lipid peroxidation, alpha-tocopherol may exert intracellular effects. Hence, the aim of this study was to test the effect of alpha-tocopherol supplementation in cancer prevention via suppression of NF kappaB-mediated pro-inflammatory cytokines. alpha-Tocopherol treatment significantly down-regulates expression, synthesis as well as secretion of pro inflammatory cytokine IL-6 (interleukin-6) in cancerous mice. It also suppresses NF-kappaB binding to IL-6 promoter in liver leading to decreased secretion of IL 6 in serum. The regulation of the signalling pathway by alpha-tocopherol is found apart from its antioxidant capacity to reduce lipid peroxidation. Thus, the present study provides evidence for the hypothesis that besides the powerful free radical scavenging effects, alpha-tocopherol has genomic effects in down regulation of pro-inflammatory cytokine and cancer prevention via the NF-kappaB dependent pathway. PMID- 21320072 TI - Molecular interaction and functional regulation of connexin50 gap junctions by calmodulin. AB - Cx50 (connexin50), a member of the alpha-family of gap junction proteins expressed in the lens of the eye, has been shown to be essential for normal lens development. In the present study, we identified a CaMBD [CaM (calmodulin) binding domain] (residues 141-166) in the intracellular loop of Cx50. Elevations in intracellular Ca2+ concentration effected a 95% decline in gj (junctional conductance) of Cx50 in N2a cells that is likely to be mediated by CaM, because inclusion of the CaM inhibitor calmidazolium prevented this Ca2+-dependent decrease in gj. The direct involvement of the Cx50 CaMBD in this Ca2+/CaM dependent regulation was demonstrated further by the inclusion of a synthetic peptide encompassing the CaMBD in both whole-cell patch pipettes, which effectively prevented the intracellular Ca2+-dependent decline in gj. Biophysical studies using NMR and fluorescence spectroscopy reveal further that the peptide stoichiometrically binds to Ca2+/CaM with an affinity of ~5 nM. The binding of the peptide expanded the Ca2+-sensing range of CaM by increasing the Ca2+ affinity of the C-lobe of CaM, while decreasing the Ca2+ affinity of the N-lobe of CaM. Overall, these results demonstrate that the binding of Ca2+/CaM to the intracellular loop of Cx50 is critical for mediating the Ca2+-dependent inhibition of Cx50 gap junctions in the lens of the eye. PMID- 21320074 TI - Peroxisomal multifunctional enzyme type 2 from the fruitfly: dehydrogenase and hydratase act as separate entities, as revealed by structure and kinetics. AB - All of the peroxisomal beta-oxidation pathways characterized thus far house at least one MFE (multifunctional enzyme) catalysing two out of four reactions of the spiral. MFE type 2 proteins from various species display great variation in domain composition and predicted substrate preference. The gene CG3415 encodes for Drosophila melanogaster MFE-2 (DmMFE-2), complements the Saccharomyces cerevisiae MFE-2 deletion strain, and the recombinant protein displays both MFE-2 enzymatic activities in vitro. The resolved crystal structure is the first one for a full-length MFE-2 revealing the assembly of domains, and the data can also be transferred to structure-function studies for other MFE-2 proteins. The structure explains the necessity of dimerization. The lack of substrate channelling is proposed based on both the structural features, as well as by the fact that hydration and dehydrogenation activities of MFE-2, if produced as separate enzymes, are equally efficient in catalysis as the full-length MFE-2. PMID- 21320075 TI - Lysophosphatidic acid (LPA) stimulates mouse mammary epithelial cell growth. AB - LPA (lysophosphatidic acid) is a bioactive phospholipid having diverse effects on various types of tissues. When NMuMG (normal murine mammary gland) cells were cultured in the presence of 0-10 MUM LPA, cell numbers were increased by dose dependency for the 6-day culture periods (P<0.05). In DNA synthesis assay, 10 MUM LPA induced 4.5-fold more DNA synthesis compared with control (P<0.05). In addition, the cultured cell density in the given area was increased by LPA treatment. MMP (matrix metalloproteinase) inhibitor GM6001 and EGFR [EGF (epidermal growth factor) receptor] tyrosine kinase inhibitor AG1478 [tyrphostin AG1478, 4-(3-chloroanilino)-6,7-dimethoxyquinazoline] significantly decreased LPA induced DNA synthesis and cell growth without cell death (P<0.05). To test the hypothesis that LPA-induced cell growth is mediated through LPA subtype receptors, LPA subtype receptor gene expressions were amplified by PCR. NMuMG cells expressed LPA1 and LPA2 receptor genes in the presence of 10% FBS (fetal bovine serum). LPA treatments increased ERK1/2 (extracellular-signal-regulated kinase) phosphorylation at 30 min and then dephosphorylated at 2 h after treatment. LPA treatment phosphorylated at tyrosine residues on a variety of Gi and PI3-dependent signal transducers in NMuMG cells. These results suggest that LPA subtype receptors play a role as the active transactivator of EGFR-associated kinases as well as direct growth regulator in mammary tissues. PMID- 21320076 TI - Mast cells in health and disease. AB - Although MCs (mast cells) were discovered over 100 years ago, for the majority of this time their function was linked almost exclusively to allergy and allergic disease with few other roles in health and disease. The engineering of MC deficient mice and engraftment of these mice with MCs deficient in receptors or mediators has advanced our knowledge of the role of MCs in vivo. It is now known that MCs have very broad and varied roles in both physiology and disease which will be reviewed here with a focus on some of the most recent discoveries over the last year. MCs can aid in maintaining a healthy physiology by secreting mediators that promote wound healing and homoeostasis as well as interacting with neurons. Major developments have been made in understanding MC function in defence against pathogens, in recognition of pathogens as well as direct effector functions. Probably the most quickly developing area of understanding is the involvement and contribution MCs make in the progression of a variety of diseases from some of the most common diseases to the more obscure. PMID- 21320077 TI - CXCL13 chemokine in pediatric and adult neuroborreliosis. AB - OBJECTIVES: Diagnosis of Lyme neuroborreliosis (NB) depends on the proof of intrathecal antibody production against Borrelia burgdorferi. CXCL13 has been seen to be elevated early in NB, before antibody production has started. In this study, we determined the diagnostic role of the CXCL13 chemokine in cerebrospinal fluid (CSF) and serum for the first time in pediatric NB patients as well as in adults, compared to controls and blood donors (BD). MATERIAL AND METHODS: CXCL13 levels were measured in CSF and serum of 33 children and 42 adult patients. Serum CXCL13 was measured in 300 BD. RESULTS: CSF CXCL13 levels were significantly elevated in definite and probable acute NB in children and adults compared to seropositive and seronegative neurological controls (P < 0.001). Serum CXCL13 levels showed great fluctuations and were not significantly elevated in NB patients. CONCLUSIONS: Our study suggests that CSF CXCL13 can be used as a diagnostic marker for NB in children as well. In contrast, CXCL13 serum levels show great variance even in the healthy population and are not indicative of active NB. PMID- 21320078 TI - Classifying clinical depression: an operational proposal. PMID- 21320080 TI - Translating assessments of the film of daily life into person-tailored feedback interventions in depression. PMID- 21320082 TI - Anesthesia & Analgesia policy on Institutional Review Board approval and informed consent for research. PMID- 21320081 TI - Research, audit and journal policies. PMID- 21320083 TI - Never events. PMID- 21320084 TI - Incidence of unintentional intraneural injection and postoperative neurological complications with ultrasound-guided interscalene and supraclavicular nerve blocks. AB - It is proposed that ultrasound guidance decreases the risk of intraneural injection and associated postoperative neurological complications. However, the incidence of unintentional intraneural injection with ultrasound is unknown. Two hundred and fifty-seven patients were enrolled in a prospective, single-blind observational study. All patients underwent a pre-operative neurological examination before ambulatory shoulder arthroscopy with sedation and ultrasound guided interscalene or supraclavicular block. Patients were followed up at 1 week and at 4-6 weeks postoperatively. Two blinded anaesthesiologists viewed the same video of the ultrasound image during the block offline to determine intraneural trespass. Intraneural injection occurred in 42 patients (17%; 95% CI 12-22%). No patient suffered from postoperative neurological complications (0%; 95% CI 0 1.6%) at follow-up. PMID- 21320085 TI - Critical phase distractions in anaesthesia and the sterile cockpit concept. AB - In aviation, the sterile cockpit rule prohibits non-essential activities during critical phases of flight, takeoff and landing, phases analogous to induction of, and emergence from, anaesthesia. We studied distraction during 30 anaesthetic inductions, maintenances and emergences. Mean (SD) noise during emergence (58.3 (6.2) dB) was higher than during induction (46.4 (4.3) dB) and maintenance (52 (4.5) dB; p<0.001). Sudden loud noises, greater than 70 dB, occurred more frequently at emergence (occurring 34 times) than at induction (occurring nine times) or maintenance (occurring 13 times). The median (IQR [range]) of staff entrances or exits were 0 (0-2 [0-7]), 6 (3-10 [1-18]) and 10 (5-12 [1-20]) for induction, maintenance and emergence, respectively (p<0.001). Conversations unrelated to the procedure occurred in 28/30 (93%) emergences. These data demonstrate increased distraction during emergence compared with other phases of anaesthesia. Recognising and minimising distraction should improve patient safety. Applying aviation's sterile cockpit rule may be a useful addition to our clinical practice. PMID- 21320086 TI - Nasotracheal fibreoptic intubation: a randomised controlled trial comparing the GlideRite(r) (Parker-Flex(r) Tip) nasal tracheal tube with a standard pre-rotated nasal RAETM tracheal tube. AB - In a randomised controlled study, we compared the ease of railroading a GlideRite(r) nasal tracheal tube over a fibrescope with that of a pre-rotated RAETM nasal tracheal tube. We studied 110 anaesthetised patients with no known airway difficulties undergoing elective dental or maxillofacial surgery. Impingement was more common with the GlideRite tubes (11/55 (20%)) compared with the pre-rotated RAE tubes (3/55 (5%); p=0.02). The median (IQR [range]) time to intubation (GlideRite 7.6 (4.7-10.8 [3.0-46.2]) s; RAE 8.0 (6.2-10.7 [2.4-30.0]) s) and postoperative sore throat numerical ratings (GlideRite 2 (0-3 [0-10]); RAE 2 (0-5 [0-8])) were similar. A 90 degrees anticlockwise pre-rotation of a standard nasal RAE tube has a higher initial rate of successful railroading at first attempt and is therefore superior to a GlideRite nasotracheal tube during nasal fibreoptic intubation. PMID- 21320087 TI - Comparison of blind tracheal intubation through the intubating laryngeal mask airway (LMA FastrachTM) and the Air-QTM. AB - This study assessed two disposable devices, the LMA FastrachTM and the newly developed supraglottic airway device, the Air-QTM, as a conduit for tracheal intubation in 154 healthy adults undergoing elective surgery. Using a non inferiority approach, the primary outcome measure was successful tracheal intubation within two blind insertion attempts. Successful blind intubation after two attempts was achieved in 75/76 (99%) of the patients in the LMA Fastrach group vs 60/78 (77%) in the Air-Q group (95% CI for the difference 12-32%, p<0.0001). Fibreoptic intubation was used to assist the third attempt. The rate of successful intubation after three attempts was 100% in the LMA Fastrach group and 95% in Air-Q group. The single-use LMA Fastrach appears superior compared with the Air-Q, as a conduit to facilitate blind tracheal intubation. PMID- 21320088 TI - Update on modern neuraxial analgesia in labour: a review of the literature of the last 5 years. AB - Several strategies and alternative therapies have been used to provide analgesia for labour pain. Over the last few years, a number of improvements have enhanced the efficacy and safety of neuraxial analgesia and ultimately have improved mothers' satisfaction with their birth experience. As labour analgesia is a field of obstetric anaesthesia that is rapidly evolving, this review is an update, from a clinical point of view, of developments over the last 5-7 years. We discuss advantages and controversies related to combined spinal-epidural analgesia, patient controlled epidural analgesia and the integration of computer systems into analgesic modalities. We also review the recent literature on future clinical and research perspectives including ultrasound guided neuraxial block placement, epidural adjuvants and pharmacogenetics. We finally look at the latest work with regards to epidural analgesia and breastfeeding. PMID- 21320089 TI - Allergy to low dose sugammadex. AB - We describe the case of a fit 17-year-old man who developed a severe allergic reaction to a low clinical dose of sugammadex (3.2 mg kg(-1) , 200 mg intravenously), 1 min after its administration. This was manifest by an intense erythema over the anterior part of the thorax, severe lip and palpebral oedema and bilateral wheeze. On later investigation, the patient had a positive skin prick test to sugammadex (5-mm diameter response, with a negative saline control and positive histamine control of 5 mm) and no response to any other drug tested. Other diagnostic tests supported a diagnosis of allergic reaction to sugammadex. PMID- 21320090 TI - Self-plagiarism. PMID- 21320091 TI - Logging the potential for intravenous lipid emulsion in propranolol and other lipophilic drug overdoses. PMID- 21320092 TI - Comparing ultrasound and nerve stimulation: time to ask the question? PMID- 21320093 TI - Can sugammadex save a patient in a simulated 'cannot intubate, cannot ventilate' situation? PMID- 21320094 TI - Sugammadex following rocuronium rapid sequence induction. PMID- 21320095 TI - Sugammadex for rocuronium rapid sequence induction. PMID- 21320097 TI - Basic training in anaesthesia: the effect of a run-through programme in one school of anaesthesia. PMID- 21320098 TI - Lingual nerve injury following the use of an i-gel laryngeal mask. PMID- 21320099 TI - Rapid sequence spinal anaesthesia: another perspective. PMID- 21320100 TI - Minimum local analgesic concentration of ropivacaine for intra-operative caudal analgesia in pre-school and school age children--analysis using the Dixon method. PMID- 21320102 TI - Another case of a McCoy blade problem! PMID- 21320103 TI - Potency and recovery characteristics of rocuronium mixed with sodium bicarbonate. PMID- 21320105 TI - Visiting hours impact on medical care. PMID- 21320106 TI - Air embolism caused by a laceration to central venous catheter during shaving. PMID- 21320107 TI - Canine visit! In ICU? PMID- 21320108 TI - Cesare Lombroso and epilepsy 100 years later: an unabridged report of his original transactions. AB - Cesare Lombroso (1835-1909) still represents one of the most famous and, at the same time, controversial figures of neuropsychiatry. His idea of the "atavist" criminal, prisoner of his/her biologic inheritance, became extremely popular in Western countries. Unfortunately, Lombroso's theory of a strict connection between epilepsy and the criminal personality exerted a long-lasting negative influence on both medical and public opinion, and strongly contributed to the stigmatization of patients with epilepsy. In this report, we aim to present the complete and unabridged series of passages of Cesare Lombroso's works, published only in the Italian language, discussing the issue of epilepsy and crime. All original Italian quotations are offered and an English translation is provided. Although we believe that the medical profession must be well aware of the "evil" distortions generated by Lombrosian theories, which clearly emerge from his original transactions, any comment is deliberately avoided because, in our opinion, people and their ideas must be judged in accordance with the historical period to which they belonged. PMID- 21320109 TI - A randomized, double-blind, placebo-controlled study of the efficacy, safety, and tolerability of adjunctive carisbamate treatment in patients with partial-onset seizures. AB - PURPOSE: To assess the efficacy, safety, and tolerability of adjunctive carisbamate treatment at 800 mg/day and 1,200 mg/day in patients with partial onset seizures (POS). METHODS: Patients >= 16 years of age with an established diagnosis of POS for >= 1 year and uncontrolled on one to three antiepileptic drugs were enrolled. Eligible patients remained on stable doses of prescribed antiepileptic drugs for an 8-week pretreatment baseline phase and were then randomized (1:1:1) to receive carisbamate (800 mg/day or 1,200 mg/day), or placebo, for a 14-week double-blind phase. Primary efficacy endpoints were percentage reduction in POS frequency and responder rate (patients with >= 50% reduction in POS frequency) during the double-blind versus baseline phase. KEY FINDINGS: Five hundred forty-seven patients were randomized; 540 composed the intent-to-treat (ITT) analysis. Four hundred thirty-four patients (79%) completed the study. The median percent reduction from baseline to treatment phase in POS frequency was: 21% (placebo); 30% (carisbamate 800 mg); 36% (carisbamate 1,200 mg), and 32% (combined carisbamate doses). The combined carisbamate dose group was not significantly different from placebo for the median percent reduction of POS frequency (p = 0.20) or responder rate (p = 0.18). Therefore, the difference from placebo for the individual carisbamate dose groups was also considered nonsignificant, based on a prespecified step-down analysis. Dizziness was the most common treatment-emergent adverse event, with a higher incidence (>= 5% difference) in the combined carisbamate group (31%) than placebo (9%); the incidence was higher with carisbamate 1,200 mg (32%, n = 58) than with carisbamate 800 mg (30%, n = 53). SIGNIFICANCE: Adjunctive carisbamate therapy in patients with POS did not demonstrate efficacy across the dose range assessed versus placebo. No new safety findings were observed. PMID- 21320110 TI - Management and long-term outcome in patients presenting with ictal asystole or bradycardia. AB - PURPOSE: Ictal asystole (IA) and ictal bradycardia (IB) are rare autonomic symptoms during epileptic seizures and may be potentially life-threatening. Guidelines for the care of these patients are missing. The aim of this multicenter study was to evaluate the management and long-term outcome in patients with IA and IB. PATIENTS AND METHODS: All patients with IA and IB were included from four epilepsy centers (Bielefeld, Kork, Marburg, and Zurich) from 2002 until 2009. Using a standardized assessment form, clinical data, treatment decisions, and outcomes were extracted from patient charts and simultaneous electroencephalography/electrocardiography (EEG/ECG) recordings. KEY FINDINGS: Seizures with IA or IB were identified in 16 patients. In all patients an associated temporal seizure pattern was recorded and in 15 patients, sudden falls, fainting, or trauma was previously reported or recorded during the monitoring. In three patients (18.8%) diagnosis of focal epilepsy was newly established and anticonvulsive treatment was initiated. Two patients with refractory epilepsy underwent epilepsy surgery. In seven patients (43.8%) a cardiac pacemaker was implanted. In 14 of 16 treated patients, seizure freedom (n = 5) or absence of sudden falls, fainting, or trauma (n = 9) could be achieved. Two patients denied epilepsy surgery as well as a pacemaker and continue to have frequent falls and trauma. SIGNIFICANCE: Our study demonstrates that epilepsy surgery and antiepileptic drugs may lead to sustained freedom of seizures as well as ictal syncope. In drug-resistant patients not suitable for epilepsy surgery, implantation of a cardiac pacemaker may prevent sudden falls as well as trauma. Based on our results and previously reported cases we propose a treatment algorithm. PMID- 21320111 TI - Seizure outcome in infantile spasms--a retrospective study. AB - PURPOSE: Prior to the United Kingdom Infantile Spasms Study (UKISS), our practice was to initiate vigabatrin for infantile spasms. However, since then we tend to use steroids as first-line agent for infantile spasms. Herein we compare seizure free outcomes in children with infantile spasms on steroid therapy or vigabatrin therapy. METHODS: This was a retrospective case study over 8 years of children with infantile spasms who were treated at our center. A positive response to therapy was defined as a two-week spasm-free interval. KEY FINDINGS: Of the 98 children presenting to us, 75 were included for this study. The ratio of cryptogenic to symptomatic spasms was 24:51. The response rate for steroid therapy was 61.1% and 42.5% for vigabatrin. Cessation of spasms was achieved faster in the group receiving steroids. Both groups had similar relapse rates. Steroids had significantly better response in the cryptogenic group, whereas in the symptomatic group both the medications were equally effective. Cryptogenic spasms have a better neurodevelopmental outcome. Early introduction of therapy for spasms did not predict a good neurodevelopmental outcome. Seventy-eight percent of children with spasms had seizures of other types at 12 months follow up. SIGNIFICANCE: At our center, steroids are now the preferred choice for initial therapy of infantile spasms. This is likely to have been a beneficial change, particularly for children with cryptogenic spasms. Spasms in 25% of the patients tend to be refractory, and the majority of patients from the cohort continue to have epilepsy with motor and cognitive disabilities. PMID- 21320112 TI - The adverse event profile of pregabalin: a systematic review and meta-analysis of randomized controlled trials. AB - PURPOSE: Despite the widespread use of antiepileptic drugs (AEDs) across different neurologic and psychiatric disorders, no study has systematically reviewed all available randomized controlled trials (RCTs) of a given AED to fully uncover its tolerability profile. We aimed at identifying treatment emergent adverse events (AEs) associated with pregabalin through a systematic review and meta-analysis of all available RCTs. We also assessed the association between serious AEs and pregabalin, and investigated whether pregabalin AEs display a dose-response relationship. METHODS: We searched MEDLINE, EMBASE, and Cochrane CENTRAL to February 2010 for RCTs. Additional studies were identified from reference lists of retrieved papers and from online clinical databases. We selected placebo-controlled, double-blind RCTs investigating the therapeutic effects of pregabalin in adults with any condition. Studies had to include at least 20 subjects per arm and have a duration of at least 4 weeks. AEs were assessed for their association with pregabalin after identification/exclusion of synonyms, rare AEs, and nonassessable AEs due to methodologic limitations. We used relative risks (RRs) to assess the association of any [99% confidence intervals (CIs)] or serious AEs (95% CIs) with pregabalin, and risk differences (RDs, 95% CIs) to investigate dose-response relationships of pregabalin AEs. KEY FINDINGS: Thirty-eight RCTs were included in our study. Of 39 AEs, 20 (51%) were significantly associated with pregabalin (dizziness, vertigo, incoordination, balance disorder, ataxia, diplopia, blurred vision, amblyopia, tremor, somnolence, confusional state, disturbance in attention, thinking abnormal, euphoria, asthenia, fatigue, edema, peripheral edema, dry mouth, constipation). The highest RRs were found for cognition/coordination AEs. There was no significant association between serious AEs and pregabalin. There was a selective dose-response pattern in the onset of pregabalin AEs, with certain AEs appearing at lower doses than others. SIGNIFICANCE: Individuals starting treatment with pregabalin are at increased risk for several AEs, particularly those affecting cognition/coordination. Pregabalin AEs appear according to a selective dose response pattern, possibly reflecting the severity of dysfunction of distinct anatomic structures. These findings may aid clinicians in providing better patient management, and support the value of including in meta-analyses of AED tolerability profiles RCTs performed in different conditions. PMID- 21320113 TI - Socioeconomic status, health care use, and outcomes: persistence of disparities over time. AB - PURPOSE: To determine the persistence of disparities in health care use and outcomes in socioeconomically diverse populations of epilepsy patients. METHODS: We followed patients for a year at one clinic in Houston and two in New York City that serve predominantly low-income, minority, Medicaid-insured, or uninsured patients, and a fourth clinic in Houston that serves a more balanced racial/ethnic and higher socioeconomic status (SES) population. We interviewed the patients several times regarding health care use, seizures, side effects, and outcomes, and examined differences between the patients at the three low-SES clinics and the patients at the high-SES clinic. KEY FINDINGS: After controlling for patients' age, gender, race/ethnicity, marital status, seizures, and side effects we found that low SES patients had consistently higher use of the hospital emergency room and more visits to a general practitioner. Hospitalizations were also consistently higher but the differences were not significant in most periods. Neurologist visits were relatively similar. Patients at the low SES sites also had a greater likelihood of having uncontrolled seizures, drug-related side effects, to be stigmatized, and have a lower overall quality of life throughout the study period. SIGNIFICANCE: These findings suggest the persistence of SES-related disparities in health care use and outcomes among patients with epilepsy who are receiving regular care. PMID- 21320114 TI - A population-based study of long-term outcomes of cryptogenic focal epilepsy in childhood: cryptogenic epilepsy is probably not symptomatic epilepsy. AB - PURPOSE: To compare long-term outcome in a population-based group of children with cryptogenic versus symptomatic focal epilepsy diagnosed from 1980 to 2004 and to define the course of epilepsy in the cryptogenic group. METHODS: We identified all children residing in Olmsted County, MN, 1 month through 17 years, with newly diagnosed, nonidiopathic focal epilepsy from 1980 to 2004. Children with idiopathic partial epilepsy syndromes were excluded. Medical records were reviewed to determine etiology, results of imaging and EEG studies, treatments used, and long-term outcome. Children were defined as having symptomatic epilepsy if they had a known genetic or structural/metabolic etiology, and as cryptogenic if they did not. KEY FINDINGS: Of 359 children with newly diagnosed epilepsy, 215 (60%) had nonidiopathic focal epilepsy. Of these, 206 (96%) were followed for > 12 months. Ninety-five children (46%) were classified as symptomatic. Median follow-up from diagnosis was similar in both groups, being 157 months (25%, 75%: 89, 233) in the cryptogenic group versus 134 months (25%, 75%: 78, 220) in the symptomatic group (p = 0.26). Of 111 cryptogenic cases, 66% had normal cognition. Long-term outcome was significantly better in those with cryptogenic versus symptomatic etiology (intractable epilepsy at last follow-up, 7% vs. 40%, p < 0.001; seizure freedom at last follow-up, 81% vs. 55%, p < 0.001). Of those who achieved seizure freedom at final follow-up, 68% of the cryptogenic group versus only 46% of the symptomatic group were off antiepileptic medications (p = 0.01). One-third of the cryptogenic group had a remarkably benign disorder, with no seizures seen after initiation of medication, or in those who were untreated, after the second afebrile seizure. A further 5% had seizures within the first year but remained seizure-free thereafter. With the exception of perinatal complications, which predicted against seizure remission, no other factors were found to significantly predict outcome in the cryptogenic group. SIGNIFICANCE: More than half of childhood nonidiopathic localization-related epilepsy is cryptogenic. This group has a significantly better long-term outcome than those with a symptomatic etiology, and should be distinguished from it. PMID- 21320115 TI - An association analysis at 2q36 reveals a new candidate susceptibility gene for juvenile absence epilepsy and/or absence seizures associated with generalized tonic-clonic seizures. AB - PURPOSE: To further evaluate the previously shown linkage of absence epilepsy (AE) to 2q36, both in human and WAG/Rij absence rat models, a 160-kb region at 2q36 containing eight genes with expressions in the brain was targeted in a case control association study involving 205 Turkish patients with AE and 219 controls. METHODS: Haplotype block and case-control association analysis was carried out using HAPLOVIEW 4.0 and inhibin alpha subunit (INHA) gene analysis by DNA sequencing. KEY FINDINGS: An association was found between the G allele of rs7588807 located in the INHA gene and juvenile absence epilepsy (JAE) syndrome and patients having generalized tonic-clonic seizures (GTCS) with p-values of 0.003 and 0.0002, respectively (uncorrected for multiple comparisons). DNA sequence analysis of the INHA gene in 110 JAE/GTCS patients revealed three point mutations with possible damaging effects on inhibin function in three patients and the presence of a common ACTC haplotype (H1) with a possible dominant protective role conferred by the T allele of rs7588807 with respective p-values of 0.0005 and 0.0014. SIGNIFICANCE: The preceding findings suggest that INHA could be a novel candidate susceptibility gene involved in the pathogenesis of JAE or AE associated with GTCS. PMID- 21320116 TI - Relationship of clinical and quality of life trajectories following the onset of seizures: findings from the UK MESS Study. AB - PURPOSE: We defined a series of clinical trajectories represented among adult patients with new-onset seizures across a 4-year follow-up period; and linked these clinical trajectories to the quality of life (QOL) profiles and trajectories of those experiencing them. We examined both between- and within group differences. METHODS: Analyses were based on 253 individuals completing QOL questionnaires at baseline and 2 and 4 years subsequently. Based on patient self report, we defined five "clinical trajectory" groups: individuals experiencing a single seizure only; individuals entering early remission; individuals experiencing late remission; individuals initially becoming seizure-free but subsequently relapsing; individuals with seizures persisting throughout follow up. QOL profiles at each time point were compared using a validated QOL battery, NEWQOL. KEY FINDINGS: Even at baseline, there were significant between-group differences, with patients experiencing a single seizure only reporting the best QOL profile and those with seizures subsequently persisting across all time points reporting the worst. By 2 years, the QOL profiles of individuals experiencing early remission were similar to those of single seizure patients, as were those for late remission and relapse patients. SIGNIFICANCE: A consistent pattern was seen, with "single seizure" individuals doing best and individuals with persistent seizures doing worst. Of particular concern is that even at baseline, individuals whose seizures persisted were doing poorly for QOL, suggesting the possibility that underlying neurobiologic mechanisms were operating. In contrast, our findings support previous reports of only short-lived and small QOL decrements for individuals experiencing a single or few seizures. PMID- 21320117 TI - Clinical course and variability of non-Rasmussen, nonstroke motor and sensory epilepsia partialis continua: a European survey and analysis of 65 cases. AB - PURPOSE: To gain new insights into the clinical presentation, causes, treatment and prognosis of epilepsia partialis continua (EPC), and to develop hypotheses to be tested in a prospective investigation. METHODS: In this retrospective multicenter study, all cases were included that fulfilled these criteria: constantly repeated fragments of epileptic seizures, with preserved consciousness, lasting >= 1 h and representing locally restricted motor or sensory epileptic activity. Single episodes were included when they lasted for a minimum of 1 day. EPC with Rasmussen syndrome and acute stroke were excluded. KEY FINDINGS: Three time courses with two subtypes each were distinguished, that is, EPC as a solitary event (de novo or in preexistent epilepsy); chronic repetitive nonprogressive EPC (with frequent or rare episodes); and chronic persistent nonprogressive EPC (primarily or evolving out of an episodic course). These were unrelated to etiologies (morphologic lesions 34%, inflammatory 29%, systemic disorders 9%, idiopathic 5%, unknown 23%). Precipitation and inhibition of seizures is a frequent feature of EPC. Levetiracetam and topiramate have improved the possibilities for pharmacotherapy. Topiramate seems to be particularly effective with dysontogenetic etiologies. SIGNIFICANCE: The existence of several clearly distinct courses of nonprogressive EPC is a new finding. These distinctions will be further investigated in a prospective study with precise protocols for electroencephalography (EEG), imaging, and other studies. This should better establish the relation of motor and somatosensory EPC; further clarify the relations, pathogenesis, and significance of the different types and their etiologies; and possibly identify more semiologic variants. It should also provide more precise knowledge about therapy and modification of ictogenesis by external stimuli. PMID- 21320118 TI - The clinical spectrum of nodular heterotopias in children: report of 31 patients. AB - PURPOSE: The phenotypic and etiologic spectrum in adults with nodular heterotopias (NHs) has been well characterized. However, there are no large pediatric case series. We, therefore, wanted to review the clinical features of NHs in our population. METHODS: Hospital records of 31 patients with pathology or imaging-confirmed NHs were reviewed. Two-sided Fisher's exact t-test was used to assess associations between distribution of NHs and specific clinical features. KEY FINDINGS: NHs were distributed as follows: 8 (26%) unilateral focal subependymal, 3 (10%) unilateral diffuse subependymal, 5 (16%) bilateral focal subependymal, 12 (39%) bilateral diffuse subependymal, and 3 (10%) isolated subcortical. The phenotypic spectrum in our population differs from that described in adults. Significant morbidity and mortality are associated with presentation in childhood. Twenty-two of 31 patients (71%) died in the neonatal period or in childhood. Additional cerebral malformations were found in 80% and systemic malformations in 74%. The majority of patients had developmental delay, intellectual deficit, and intractable epilepsy. Patients with unilateral focal NHs were more likely to have ventriculomegaly (p = 0.027), and those with bilateral diffuse NHs more likely to have cerebellar abnormalities (p = 0.007). Isolated subcortical NHs were associated with multiple malformations (p = 0.049) and cardiac abnormalities (p = 0.027). Underlying etiology was heterogeneous and determined in only six cases (19%): del chr 1p36, del chr 15q11, pyruvate dehydrogenase deficiency, sialic acidosis type 1, Aicardi syndrome, and FLNA mutation. SIGNIFICANCE: NHs are present in childhood as part of multiple cerebral and systemic malformations; developmental delay and refractory seizures are the rule rather than the exception. Milder forms go unrecognized until seizure onset in adulthood. PMID- 21320119 TI - A multicenter, randomized, placebo-controlled trial of levetiracetam in children and adolescents with newly diagnosed absence epilepsy. AB - PURPOSE: To evaluate the potential efficacy of levetiracetam as an antiabsence agent in children and adolescents with newly diagnosed childhood or juvenile absence epilepsy. METHODS: Patients were randomized in a 2:1 ratio to receive de novo monotherapy with levetiracetam (up to 30 mg/kg/day) or placebo for 2 weeks under double-blind conditions. Responder status (primary end point) was defined as freedom from clinical seizures on days 13 and 14 and from electroencephalographic (EEG) seizures during a standard EEG recording with hyperventilation and intermittent photic stimulation on day 14. The double-blind phase was followed by an open-label follow-up. KEY FINDINGS: Nine of 38 patients (23.7%) were responders in the levetiracetam group, compared with one of 21 (4.8%) in the placebo group (p = 0.08). Seven of 38 patients (18.4%) were free from clinical and EEG seizures during the last 4 days of the trial (including 24 h EEG monitoring on day 14) compared with none of the patients treated with placebo (p = 0.04). Seventeen patients remained seizure-free on levetiracetam after 1 year follow-up. Of the 41 patients who discontinued levetiracetam due to lack of efficacy (n = 39) or adverse events (n = 2), 34 became seizure-free on other treatments. SIGNIFICANCE: Although superiority to placebo just failed to reach statistical significance for the primary end point, the overall findings are consistent with levetiracetam having modest efficacy against absence seizures. Further controlled trials exploring larger doses and an active comparator are required to determine the role of levetiracetam in the treatment of absence epilepsy. PMID- 21320120 TI - Lipopolysaccharide-induced miR-1224 negatively regulates tumour necrosis factor alpha gene expression by modulating Sp1. AB - The innate immune response provides the initial defence mechanism against infection by other organisms. However, an excessive immune response will cause damage to host tissues. In an attempt to identify microRNAs (miRNAs) that regulate the innate immune response in inflammation and homeostasis, we examined the differential expression of miRNAs using microarray analysis in the spleens of mice injected intraperitoneally with lipopolysaccharide (LPS) and saline, respectively. Following challenge, we observed 19 miRNAs up-regulated (1.5-fold) in response to LPS. Among these miRNAs, miR-1224, whose expression level increased 5.7-fold 6 hr after LPS injection and 2.3-fold after 24 hr, was selected for further study. Tissue expression patterns showed that mouse miR-1224 is highly expressed in mouse spleen, kidney and lung. Transfection of miR-1224 mimics resulted in a decrease in basal tumour necrosis factor-alpha (TNF-alpha) promoter reporter gene activity and a down-regulation of LPS-induced TNF-alpha mRNA in RAW264.7 cells. With public databases of miRNA target prediction, miR 1224 was shown to bind to the 3' untranslated region (UTR) of Sp1 mRNA, whose coding product controls TNF-alpha expression at the transcriptional level. Furthermore, we found that in HEK-293 cells, the activity of the luciferase reporter bearing Sp1 mRNA 3' UTR was down-regulated significantly when transfected with miR-1224 mimics. After transfection of miR-1224 in RAW264.7 cells, nucleus Sp1 protein level decreased, and when endogenous miR-1224 was blocked, the decrease was abolished. Therefore, we initially speculated that miR 1224 was a negative regulator of TNF-alpha in an Sp1-dependent manner, which was confirmed in vivo by chromatin immunoprecipitation assay, and might be involved in regulating the LPS-mediated inflammatory responses. PMID- 21320121 TI - Coincidence of autoantibody production with the activation of natural killer T cells in alpha-galactosylceramide-mediated hepatic injury. AB - Natural killer T (NKT) cells are known to be specifically activated by alpha galactosylceramide (alpha-GalCer) via their interaction with CD1d. At that time, NKT cells mediate autoreactivity and eventually induce hepatic injury. As these immune responses resemble acute autoimmune hepatitis, it was examined whether autoantibody production and the activation of autoantibody-producing B-1 cells were accompanied by this phenomenon. Autoantibodies against Hep-2 cells and double-stranded DNA were detected in sera as early as day 3 (showing a peak at day 14) when mice were treated with alpha-GalCer. On day 3, B220(low) cells appeared in the liver. These B220(low) cells were CD5(-) (i.e. B-1b cells) and CD69(+) (an activation marker). Primarily, such B220(low) cells were present in the peritoneal cavity, but the proportion of B220(low) cells increased with the administration of alpha-GalCer even at this site. In parallel with the appearance of B220(low) cells in the liver, hepatic lymphocytes acquired the potential to produce autoantibodies in in vitro cell culture in the presence of lipopolysaccharide. These results suggested that hepatic injury induced by alpha GalCer administration resembled acute autoimmune hepatitis and that the major effector lymphocytes were NKT cells with autoreactivity and autoantibody producing B-1 cells. PMID- 21320122 TI - Cytoadherence-dependent induction of inflammatory responses by Mycoplasma pneumoniae. AB - Pathogenesis of Mycoplasma pneumoniae infection is considered to be in part attributed to excessive immune responses. Mycoplasma pneumoniae shows strong cytoadherence to host cells and this cytoadherence is thought to be involved in the progression of pneumonia. However, the interaction between the cytoadherence and the immune responses is not known in detail. In this study, we demonstrated that the induction of pro-inflammatory cytokines in the human monocyte cell line THP-1 is dependent on the property of cytoadherence of M. pneumoniae. A wild-type strain of M. pneumoniae with cytoadherence ability induced pro-inflammatory cytokines such as tumour necrosis factor-alpha and interleukin-1beta (IL-1beta). Whereas, heat-killed M. pneumoniae and cytoadherence-deficient mutants of M. pneumoniae caused significantly less production of pro-inflammatory cytokines than the wild-type strain. The wild-type strain induced pro-inflammatory cytokines in an endocytosis-independent manners, but the induction by heat-killed M. pneumoniae and cytoadherence-deficient mutants was dependent on endocytosis. Moreover, the wild-type strain induced caspase-1 production and ATP efflux, promoting the maturation of IL-1beta and release of the pro-IL-1beta precursor, whereas heat-killed M. pneumoniae and the cytoadherence-deficient mutants failed to induce them. These data suggest that the cytoadherence ability of M. pneumoniae activates immune responses and is involved in the pathogenesis of M. pneumoniae infection. PMID- 21320123 TI - Analyses of phenotypic and functional characteristics of CX3CR1-expressing natural killer cells. AB - We previously demonstrated a correlation between the frequency of CX3CR1 expressing human natural killer (NK) cells and disease activity in multiple sclerosis and showed that CX3CR1(high) NK cells were more cytotoxic than their CX3CR1(neg/low) counterparts. Here we aimed to determine whether human NK cell fractions defined by CX3CR1 represent distinct subtypes. Phenotypic and functional NK cell analyses revealed that, distinct from CX3CR1(high), CX3CR1(neg/low) NK cells expressed high amounts of type 2 cytokines, proliferated robustly in response to interleukin-2 and promoted a strong up-regulation of the key co-stimulatory molecule CD40 on monocytes. Co-expression analyses of CX3CR1 and CD56 demonstrated the existence of different NK cell fractions based on the surface expression of these two surface markers, the CX3CR1(neg) CD56(bright), CX3CR1(neg) CD56(dim) and CX3CR1(high) CD56(dim) fractions. Additional investigations on the expression of NK cell receptors (KIR, NKG2A, NKp30 and NKp46) and the maturation markers CD27, CD62L and CD57 indicated that CX3CR1 expression of CD56(dim) discriminated between an intermediary CX3CR1(neg) CD56(dim) and fully mature CX3CR1(high) CD56(dim) NK cell fractions. Hence, CX3CR1 emerges as an additional differentiation marker that may link NK cell maturation with the ability to migrate to different organs including the central nervous system. PMID- 21320124 TI - Regulation of effector and memory T-cell functions by type I interferon. AB - Type I interferon (IFN-alpha/beta) is comprised of a family of highly related molecules that exert potent antiviral activity by interfering with virus replication and spread. IFN-alpha/beta secretion is tightly regulated through pathogen sensing pathways that are operative in most somatic cells. However, specialized antigen-presenting plasmacytoid dendritic cells are uniquely equipped with the capacity to secrete extremely high levels of IFN-alpha/beta, suggesting a key role for this cytokine in priming adaptive T-cell responses. Recent studies in both mice and humans have demonstrated a role for IFN-alpha/beta in directly influencing the fate of both CD4(+) and CD8(+) T cells during the initial phases of antigen recognition. As such, IFN-alpha/beta, among other innate cytokines, is considered an important 'third signal' that shapes the effector and memory T-cell pool. Moreover, IFN-alpha/beta also serves as a counter-regulator of T helper type 2 and type 17 responses, which may be important in the treatment of atopy and autoimmunity, and in the development of novel vaccine adjuvants. PMID- 21320125 TI - Identification of four functional NR3B isoforms in developing white matter reveals unexpected diversity among glutamate receptors. AB - Functional neurotransmitter receptors are expressed in central white matter, where they mediate ischemic damage to glia and may be involved in cell-cell signalling. In this study, we analysed NMDA receptor NR1, NR2B-C and NR3A-B subunit expression in the brain and optic nerve by molecular cloning. In addition to the canonical forms of NR1 and NR2, four previously unknown NR3B variants, generated by alternative splicing, were identified. The variants encoded for isoforms with deletions of 8/15 amino acids in the N-terminal domain or 200/375 amino acids removing one or three transmembrane domains and part of the C terminal domain, as compared with the previously characterized NR3B isoform. Co expression of NR3B isoforms with NR1/NR2A-C modulated the amplitude and Mg(2+) sensitivity of glutamate responses in a NR2 subunit-dependent fashion, with significant variations in the effects produced by different isoforms. These effects were not the result of reduced surface expression of the receptor complex since all NR3B isoforms reduced surface expression by a similar degree. These data reveal previously uncharacterized regulation of NMDA receptor function by alternative splicing of the NR3B subunit. PMID- 21320127 TI - Fusicoccin-induced catalase inhibitor is produced independently of H+-ATPase activation and behaves as an organic acid. AB - The phytotoxin fusicoccin (FC) was found to induce an increase in apoplastic H2O2 content in Arabidopsis thaliana cells, apparently linked to the presence of an as yet unidentified catalase inhibitor detectable even in the external medium of FC treated cells. This study, aimed to further characterize the inhibitor's features, shows that (1) FC-induced H2O2 accumulation increases as a function of FC concentration and correlates to the amount of inhibitor released at apoplastic level. The pattern of H+ efflux, conversely, does not fit with that of these two parameters, suggesting that neither the production nor the release of the catalase inhibitor is linked to the main role of FC in activating the plasma membrane (PM) H+-ATPase; (2) treatment with 10 uM erythrosine B (EB) early and totally inhibits net H+ and K+ fluxes across the PM, indicative of the H+ pump activity; nevertheless, also in these conditions a huge FC-induced H2O2 accumulation occurs, confirming that this effect is not related to the FC-induced PM H+-ATPase activation; (3) the inhibitor's release increases with time in all conditions tested and is markedly affected by extracellular pH (a higher pH value being associated to a larger efflux), in agreement with a weak acid release; and (4) the inhibitor can be almost completely recovered in a CH2C2-soluble fraction extracted from the incubation medium by sequential acid-base partitioning which contains nearly all of the organic acids released. These final results strongly suggest that the metabolite responsible for the FC-induced catalase inhibition belongs to the organic acid class. PMID- 21320128 TI - Photosynthetic acclimation in relation to nitrogen allocation in cucumber leaves in response to changes in irradiance. AB - Leaves deep in canopies can suddenly be exposed to increased irradiances following e.g. gap formation in forests or pruning in crops. Studies on the acclimation of photosynthesis to increased irradiance have mainly focused on the changes in photosynthetic capacity (A(max)), although actual irradiance often remains below saturating level. We investigated the effect of changes in irradiance on the photosynthesis irradiance response and on nitrogen allocation in fully grown leaves of Cucumis sativus. Leaves that fully developed under low (50 umol m-2 s-1) or moderate (200 umol m-2 s-1) irradiance were subsequently exposed to, respectively, moderate (LM-leaves) or low (ML-leaves) irradiance or kept at constant irradiance level (LL- and MM-leaves). Acclimation of photosynthesis occurred within 7 days with final A(max) highest in MM-leaves, lowest in LL-leaves and intermediate in ML- and LM-leaves, whereas full acclimation of thylakoid processes underlying photosystem II (PSII) efficiency and non-photochemical quenching occurred in ML- and LM-leaves. Dark respiration correlated with irradiance level, but not with A(max). Light-limited quantum efficiency was similar in all leaves. The increase in photosynthesis at moderate irradiance in LM-leaves was primarily driven by nitrogen import, and nitrogen remained allocated in a similar ratio to Rubisco and bioenergetics, while allocation to light harvesting relatively decreased. A contrary response of nitrogen was associated with the decrease in photosynthesis in ML-leaves. Net assimilation of LM-leaves under moderate irradiance remained lower than in MM leaves, revealing the importance of photosynthetic acclimation during the leaf developmental phase for crop productivity in scenarios with realistic, moderate fluctuations in irradiance that leaves can be exposed to. PMID- 21320126 TI - Targets for AD treatment: conflicting messages from gamma-secretase inhibitors. AB - Current evidence suggests that Alzheimer's disease (AD) is a multi-factorial disease that starts with accumulation of multiple proteins. We have previously proposed that inhibition of gamma-secretase may impair membrane recycling causing neurodegeneration starting at synapses (Sambamurti K., Suram A., Venugopal C., Prakasam A., Zhou Y., Lahiri D. K. and Greig N. H. A partial failure of membrane protein turnover may cause Alzheimer's disease: a new hypothesis. Curr. Alzheimer Res., 3, 2006, 81). We also proposed familal AD mutations increase Abeta42 by inhibiting gamma-secretase. Herein, we discuss the failure of Eli Lilly's gamma secretase inhibitor, semagacestat, in clinical trials in the light of our hypothesis, which extends the problem beyond toxicity of Abeta aggregates. We elaborate that gamma-secretase inhibitors lead to accumulation of amyloid precursor protein C-terminal fragments that can later be processed by gamma secretase to yields bursts of Abeta to facilitate aggregation. Although we do not exclude a role for toxic Abeta aggregates, inhibition of gamma-secretase can affect numerous substrates other than amyloid precursor protein to affect multiple pathways and the combined accumulation of multiple peptides in the membrane may impair its function and turnover. Taken together, protein processing and turnover pathways play an important role in maintaining cellular homeostasis and unless we clearly see consistent disease-related increase in their levels or activity, we need to focus on preserving their function rather than inhibiting them for treatment of AD and similar diseases. PMID- 21320129 TI - Protein synthesis is the primary target of reactive oxygen species in the photoinhibition of photosystem II. AB - Photoinhibition of photosystem II (PSII) occurs when the rate of photodamage to PSII exceeds the rate of the repair of photodamaged PSII. Recent examination of photoinhibition by separate determinations of photodamage and repair has revealed that the rate of photodamage to PSII is directly proportional to the intensity of incident light and that the repair of PSII is particularly sensitive to the inactivation by reactive oxygen species (ROS). The ROS-induced inactivation of repair is attributable to the suppression of the synthesis de novo of proteins, such as the D1 protein, that are required for the repair of PSII at the level of translational elongation. Furthermore, molecular analysis has revealed that the ROS-induced suppression of protein synthesis is associated with the specific inactivation of elongation factor G via the formation of an intramolecular disulfide bond. Impairment of various mechanisms that protect PSII against photoinhibition, including photorespiration, thermal dissipation of excitation energy, and the cyclic transport of electrons, decreases the rate of repair of PSII via the suppression of protein synthesis. In this review, we present a newly established model of the mechanism and the physiological significance of repair in the regulation of the photoinhibition of PSII. PMID- 21320130 TI - Preparation of granulocyte concentrates by apheresis: collection modalities in the USA. PMID- 21320131 TI - Relationship between gastrointestinal transit time and anesthetic fasting protocols in the captive chimpanzee, Pan troglodytes. AB - BACKGROUND: Lengthy social separation and prolonged fasting time contribute to increased risks associated with anesthesia in captive primates. This study is an initial attempt to identify a safe pre-anesthetic fasting procedure by identifying gastric emptying time (GET) and gastrointestinal transit time (GTT) of captive chimpanzees, Pan troglodytes. METHODS: Seven adult chimpanzees at the North Carolina Zoo immobilized for annual physical examinations were fed barium impregnated polyethylene spheres to measure GET. Eleven animals were individually fed a color dye marker and fecal passage was observed to determine GTT. RESULTS: Gastric emptying time (GET) was approximated to be >3 hours but <16 hours. The mean GTT was 16.5 hours. CONCLUSIONS: This study indicates that a fasting time of 3 hours would allow for complete gastric emptying and could potentially replace the current overnight fast (>=16 hour) to help minimize complications associated with pre-anesthetic fasting in captive primates. PMID- 21320132 TI - Systemic herpesvirus infection in an Azara's Night Monkey (Aotus azarae). AB - BACKGROUND: Intra- and inter-species transmission of Human herpesvirus type 1 were noticed. In the present study, the herpesviral infection of a 1-year-old Azara's Night Monkey (Aotus azarae) was investigated. METHODS: Immunohistochemistry and electron microscopy investigations were done. RESULTS: A fatal systemic herpesviral infection was demonstrated. CONCLUSION: The results reveal the susceptibility of Azara's Night Monkey to the Human herpesvirus type 1. Moreover, humans shedding herpes viral particles during the reactivation phase of the infection directly infect the Azara's Night Monkeys. PMID- 21320133 TI - 100 years of hyposensitization: history of allergen-specific immunotherapy (ASIT). AB - Hundred years ago, Leonhard Noon and John Freeman published their pioneering works on allergen-specific immunotherapy (ASIT) using grass pollen extracts. To honor their contribution to the development of ASIT as the only causal treatment of IgE-mediated allergies, we review the history of ASIT that started with the anecdotal descriptions of ASIT performed by the ancient king Mithridates (132-63 B.C.) and Jenner's development of a cowpox vaccine. Following Noon's and Freeman's first controlled human trials, ASIT was performed by a large number of modalities and with a myriad of pharmacologic preparations. These developments range from early aqueous pollen extracts and whole bee extracts to chemically modified allergens (allergoids) and various recombinant allergens. In addition to allergen-specific immunotherapy, non-specific immune response modifiers have been used in the past or are in the developmental stage. Also, currently many innovative experimental approaches of ASIT are studied in animal models and human in vitro systems and will hopefully further broaden the range of allergies that can be treated by ASIT, with enhanced efficacy and further reduced side-effects. PMID- 21320134 TI - How do peanut and nut-allergic consumers use information on the packaging to avoid allergens? AB - BACKGROUND: Recent legislation has sought to improve the information printed on packaged foods relevant to the safety of food allergic consumers. We aimed to understand the complex risk assessment decisions made by peanut and nut-allergic adults when purchasing food, with particular reference to use of printed package information. METHODS: The behaviour and 'thinking aloud' of 32 participants were recorded during their normal food shop, followed by a semi-structured interview. During the interview they were given 13 potentially problematic packaged foods, and asked if they would purchase the product and what their reasons were. Transcribed data from the shop, interview and 13-product task were analysed to explore use of allergy advice boxes, ingredients lists and other packaging information. RESULTS: Some participants used the ingredients list as their primary check for allergens, but most used the allergy advice box. Package-based information was generally considered reliable, but some supermarket and brand labels were trusted more than others. Images and product names were used to draw inferences about the presence of nuts. A number of improvements were suggested by participants, particularly a request for more 'nut free' labelling. CONCLUSIONS: Food labels were used in conjunction with nonpacket-based strategies (e.g. previous experience) to make choices. External factors (e.g. trust of manufacturer) informed interpretation of and confidence in labels. Images and product names, not intended by manufacturers as an allergen risk assessment aid, were also used to inform choices. PMID- 21320135 TI - Novel non-motile phenotypes of Yersinia ruckeri suggest expansion of the current clonal complex theory. AB - The biochemical and cell surface characteristics of 63 non-motile isolates of Yersinia ruckeri from various sources were compared using the API 20E rapid identification system and conventional phenotypic methods. Eight individual phenotypic groups from a variety of fish species were observed from the data set. Non-motile isolates were not exclusively observed from serogroup O1; membership of biotype 2 was recorded for representatives from serogroups O2-O7. Variations in phenotypes highlights that new clonal groups are arising and that the current typing scheme requires expansion. Previously, it was hypothesized that disease was caused by a few virulent clones; data in this paper suggests that this assumption is not the case. The lipopolysaccharide (O antigen) type in the non motile biotype was different from other isolates of Y. ruckeri. PMID- 21320136 TI - Gastric histology in children treated with proton pump inhibitors long term, with emphasis on enterochromaffin cell-like hyperplasia. AB - BACKGROUND: There are longstanding concerns that carcinoid tumours or atrophic gastritis might develop in children receiving proton pump inhibitors (PPIs) long term. In children, this has not been studied using stains sensitive and specific for enterochromaffin-like (ECL) cells. AIM: To evaluate gastric biopsies for ECL hyperplasia or gastric atrophy, in children treated long-term with PPIs. METHODS: Synaptophysin and chromogranin immunostaining, biopsies read anonymised, blinded. Endocrine cell numbers graded according to Rindi and Solcia. RESULTS: Of 130 children with gastro-oesophageal reflux disease (GERD), 65 had sequential gastric biopsies, starting at median 8.2 years (<1 to 17). Of the 65, 83% had GERD predisposing conditions, mostly neurological impairment or repaired oesophageal atresia. Four hundred and fifty-eight tissue blocks (208 antrum, 250 body) were available from a mean of 5.8 endoscopies (2-14). Of 82 gastric body biopsies in 40 patients with ECL hyperplasia, 67 had grade 1 hyperplasia, 15 grade 2. Of the 40, nine had ECL hyperplasia before PPI use; all nine had received H2-receptor antagonists. Median duration of PPI use was 3.17 years in patients with ECL hyperplasia, 2.20 years in those without (P=0.16). Helicobacter pylori was present in four patients; two had ECL hyperplasia. PPI duration was >3 years in 24 patients. In nine patients who received H2-receptor antagonists, changes were present before PPI use. No patient had atrophic gastritis. CONCLUSIONS: A high percentage of children (61%) receiving long-term PPI continuously for up to 10.8 years (median 2.84 years) develop minor degrees of ECL hyperplasia. This has no known clinical significance. Children on PPIs for this duration do not appear to develop atrophic gastritis or carcinoid tumours. PMID- 21320137 TI - Review article: oesophageal dilation in adults with eosinophilic oesophagitis. AB - BACKGROUND: Eosinophilic oesophagitis is a chronic inflammatory disorder of the oesophagus, characterised by the proton pump inhibitor-refractory accumulation of eosinophils in the oesophageal epithelium (>15 intraepithelial eosinophils/high powered field). Adults present with solid food dysphagia and recurrent food impactions. Oesophageal remodelling produces the characteristic endoscopic feature of adult eosinophilic oesophagitis including strictures, rings and a narrow calibre oesophagus. AIM: To evaluate the safety and efficacy of oesophageal dilation as the initial therapy for adults with eosinophilic oesophagitis. METHODS: Medline search from 1975 to November 2010 for all reports of the treatment of patients with eosinophilic oesophagitis using search words: eosinophilic oesophagitis treatment, dilation and eosinophilic oesophagitis, steroids and eosinophilic oesophagitis. RESULTS: Our systematic review found that 92% of patients treated with oesophageal dilation had improvement in their dysphagia symptoms for up to 1-2 years. Three case series clearly showed clinical resolution of dysphagia symptoms, independent of the degree of eosinophil infiltration, which was unchanged after dilation. Postprocedure pain for several days is common, due to some degree of mucosal tear, but true perforation very rare (<0.1%). CONCLUSIONS: Oesophageal dilation is an acceptable option for healthy adult eosinophilic oesophagitis patients with anatomic narrowing, possibly followed by a course of topical steroids to reduce inflammation and retard remodelling. Future studies should include a head-to-head comparison of topical steroids and oesophageal dilation, bougie vs through-the-scope balloon dilation and maintenance topical steroids compared with on-demand treatment. PMID- 21320138 TI - Randomised clinical trial: effects of monotherapy with ADX10059, a mGluR5 inhibitor, on symptoms and reflux events in patients with gastro-oesophageal reflux disease. AB - BACKGROUND: ADX10059, a metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator, has been shown to reduce gastro-oesophageal reflux events and oesophageal acid exposure in patients with gastro-oesophageal reflux disease (GERD) and healthy subjects. AIM: To evaluate the effects of ADX10059 monotherapy for 2 weeks on symptom control in patients with GERD. METHODS: This was a double-blind, placebo-controlled, multi-centre trial in GERD patients who were responders to proton pump inhibitors (PPIs). Following PPIs withdrawal, a 2 week baseline washout period was followed by 2-week treatment with either ADX10059 120 mg or placebo b.d. The primary clinical efficacy endpoint was the number of GERD symptom-free days in treatment week 2 compared with the last 7 days of baseline. The effect on reflux events using 24-h impedance-pH monitoring was also determined in a subset of 24 patients. RESULTS: The full analysis set comprised 103 patients ADX10059 (N= 50), Placebo (N=53). In treatment week 2, ADX10059 significantly increased GERD symptom-free days (P=0.045) and heartburn free days (P=0.037), reduced antacid use (P=0.017), improved total symptom score (P=0.048) including subscale heartburn/regurgitation (P=0.007) and sleep disturbance because of GERD (P= 0.022). ADX10059 significantly reduced total (P=0.034) and acidic reflux events (P=0.003). ADX10059 was well tolerated. Most common adverse events for ADX10059 were mild to moderate dizziness 16% and vertigo 12% (placebo 4% and 2%). CONCLUSIONS: Inhibition of mGluR5 with ADX10059 monotherapy reduces reflux events and improves symptoms in GERD patients. This mechanism has promise for the management of GERD. PMID- 21320139 TI - Review article: infliximab for Crohn's disease treatment--shifting therapeutic strategies after 10 years of clinical experience. AB - BACKGROUND: Crohn's disease is a progressive condition, with most patients developing a penetrating or stricturing complication over time. A decade ago, treatment goals consisted of immediate symptomatic control. The introduction of anti-tumour necrosis factor (anti-TNF) therapies, however, has changed the way patients with Crohn's disease are treated. Over 10 years of clinical data and experience have demonstrated these therapies to be highly effective in Crohn's disease. AIM: To provide clinicians guidance on optimising treatment with anti TNF therapies in Crohn's disease by introducing an evidence- and personal opinion based treatment algorithm using infliximab initial anti-TNF therapy. METHODS: Scientific literature was reviewed using MEDLINE to evaluate data on clinical trials with infliximab in luminal and fistulising Crohn's disease. RESULTS: The data from several landmark infliximab trials have changed clinical practice and led to a readjustment of treatment goals in Crohn's disease, allowing patients to achieve more than just symptomatic relief including sustained steroid-free remission. Infliximab induces complete mucosal healing and reduces the rates of hospitalisation and surgery. Based on disease-related risk factors, a treatment algorithm for infliximab is delineated in favour of a rapid step-up approach in patients at high risk for a disabling course of disease. CONCLUSION: Adopting the suggested treatment algorithm for infliximab into clinical routine is aimed to optimise outcomes for patients with Crohn's disease. PMID- 21320140 TI - Wrongs, preferences, and the selection of children: a critique of Rebecca Bennett's argument against the principle of procreative beneficence. AB - Rebecca Bennett, in a recent paper dismissing Julian Savulescu's principle of procreative beneficence, advances both a negative and a positive thesis. The negative thesis holds that the principle's theoretical foundation - the notion of impersonal harm or non-person-affecting wrong - is indefensible. Therefore, there can be no obligations of the sort that the principle asserts. The positive thesis, on the other hand, attempts to plug an explanatory gap that arises once the principle has been rejected. That is, it holds that the intuitions of those who adhere to the principle are not genuine moral intuitions, but instead simply give voice to mere (non-moral) preferences. This paper, while agreeing that Savulescu's principle does not express a genuine moral obligation, takes issue with both of Bennett's theses. It is suggested that the argument for the negative thesis is either weak or question-begging, while there is insufficient reason to suppose the positive thesis true. PMID- 21320141 TI - Can familism be justified? AB - This paper argues against the continued practice of Confucian familism, even in its moderate form, in East Asian hospitals. According to moderate familism, a physician acting in concert with the patient's family may withhold diagnostic information from the patient, and may give it to the patient's family members without her prior approval. There are two main approaches to defend moderate familism: one argues that it can uphold patient's autonomy and protect her best interests; the other appeals to cultural relativism by construing the principle of 'family autonomy' to be incommensurable with that of individual autonomy. We respond to the first approach by explaining how the familist arguments either depend on some unreasonable assumptions or simply fail to articulate. The critique of the second approach is based on our recent survey showing that there is no dichotomy of relevant values between the East and the West: we believe that the result can effectively block the familist's reliance on certain traditional or cultural values to explain their resistance to the incorporation of pluralist values. Despite our disagreement with familism, we consider the Eastern emphasis on the family to be conducive to the communication between patient, family members and medical personnel, which is indispensible to the patient's well being and autonomy. We conclude that respect for patient autonomy is perfectly consistent with the involvement of the family in making medical decision as long as the family plays a merely consultant role. PMID- 21320142 TI - Genetic enhancement, social justice, and welfare-oriented patterns of distribution. AB - The debate over the host of moral issues that genetic enhancement technology (GET) raises has been significant. One argument that has been advanced to impugn its moral legitimacy is the 'unfair advantage argument' (UAA), which states: allowing access to GET to be determined by socio-economic status would lead to unjust outcomes, namely, create a genetic caste system, and with it the exacerbation and perpetuation of existing socio-economic inequalities. Fritz Allhoff has recently objected to the argument, the kernel of which is that it conflates the use of the technology with its distribution. GET, he argues, would generate unjust outcomes only if it is distributed according to principles of an unjust pattern of distribution; for if we can determine what constitutes a 'just' distributive scheme, then the technology can be allocated according to the principles of that scheme. In this paper I argue the following cluster of related claims: (1) both UAA and Allhoff's proposed distributive schemes ignore the importance of non-genetic factors in the development of an individual's characteristics and capacities; (2) if we accept the view that it is good to prevent unjust outcomes that arise because some have exclusive access to GET, then we have to accept wide-ranging distributive schemes; (3) by tracking genetic and non-genetic factors wide-ranging schemes do violate in some sense the widely shared value of neutrality in liberal democracies. PMID- 21320143 TI - Children as means and ends in large-scale medical research. AB - This paper considers the often-expressed fear that medical research may use children merely as means, and not respect them as ends in themselves - especially insofar as they are deemed less able to consent than adults. The main focus is on large-scale genetic, socio-medical and epidemiological research. The theoretical starting point of the paper is that to be treated as an end in oneself is to be regarded as - and to act as - a participant in cooperative endeavours. This participatory status is certainly connected with individual authority to consent and dissent; and there is no doubt that consent plays an important role when adults participate in many research projects. However, insofar as consent is located within structures of human cooperation, the authority to consent is not a straightforward privilege. Rather, consent is bound up with responsibility for one's choices and commitment to shared terms of cooperation. Given this understanding, it is argued that consent should not be our principal concern when we involve children in research. This is not because of children's (possible) incompetence to consent as such, but rather because children are still learning how to respect and assess the cooperative terms involved in our institutional lives. Instead, our leading concern should be with the terms regulating their involvement in research. Given suitable safeguards, research is one way in which children may learn what it is to bear responsibilities and to act as an end in oneself - that is, to cooperate with others on reasonable terms and for worthy ends. PMID- 21320144 TI - Cluster randomization and political philosophy. AB - In this paper, I will argue that, while the ethical issues raised by cluster randomization can be challenging, they are not new. My thesis divides neatly into two parts. In the first, easier part I argue that many of the ethical challenges posed by cluster randomized human subjects research are clearly present in other types of human subjects research, and so are not novel. In the second, more difficult part I discuss the thorniest ethical challenge for cluster randomized research--cases where consent is genuinely impractical to obtain. I argue that once again these cases require no new analytic insight; instead, we should look to political philosophy for guidance. In other words, the most serious ethical problem that arises in cluster randomized research also arises in political philosophy. PMID- 21320145 TI - 'Because we see them naked' - nurses' experiences in caring for hospitalized patients with dementia: considering artificial nutrition or hydration (ANH). AB - The aim of this study was to explore and describe how Flemish nurses experience their involvement in the care of hospitalized patients with dementia, particularly in relation to artificial nutrition or hydration (ANH). We interviewed 21 hospital nurses who were carefully selected from nine hospitals in different regions of Flanders. 'Being touched by the vulnerability of the demented patient' was the central experience of the nurses, having great impact on them professionally as well as personally. This feeling can be described as encompassing the various stages of the care process: the nurses' initial meeting with the vulnerable patient; the intense decision-making process, during which the nurses experienced several intense emotions influenced by supporting or hindering contextual factors; and the final coping process, a time when nurses came to terms with this challenging experience. From our examination of this care process, it is obvious that nurses' involvement in ANH decision-making processes that concern patients with dementia is a difficult and ethically sensitive experience. On the one hand, the feeling of 'being touched' can imply strength, as it demonstrates that nurses are willing to provide good care. On the other hand, the feeling of 'being touched' can also imply weakness, as it makes nurses vulnerable to moral distress stemming from contextual influences. Therefore, nurses have to be supported as they carry out this ethically sensitive assignment. Practical implications are given. PMID- 21320146 TI - Against homeopathy--a utilitarian perspective. AB - I examine the positive and negative features of homeopathy from an ethical perspective. I consider: (a) several potentially beneficial features of homeopathy, including non-invasiveness, cost-effectiveness, holism, placebo benefits and agent autonomy; and (b) several potentially negative features of homeopathy, including failure to seek effective healthcare, wastage of resources, promulgation of false beliefs and a weakening of commitment to scientific medicine. A utilitarian analysis of the utilities and disutilities leads to the conclusion that homeopathy is ethically unacceptable and ought to be actively rejected by healthcare professionals. PMID- 21320147 TI - Risk perception. PMID- 21320148 TI - The risk of sustainability and the sustainability of risk (analysis). PMID- 21320150 TI - Caring for health in a globalized world. PMID- 21320151 TI - Endotoxemia and the host systemic response during experimental gingivitis. AB - AIM: To assess endotoxemia episodes and subsequent changes in serum inflammatory biomarkers using the experimental gingivitis model. MATERIALS AND METHODS: Data from 50 healthy black and white adult males and females were compared for serum concentrations of endotoxin, and serum biomarkers [neutrophil oxidative activity, interleukin (IL)-1beta, IL-6, IL-8, C-reactive protein (CRP), and fibrinogen] at baseline, at 3 weeks of experimental gingivitis, and after 2 weeks of recovery. Means were compared using repeated measures analysis of variance. RESULTS: Endotoxemia was reported in 56% of the serum samples at 3 weeks of induced gingivitis. At 2 weeks of recovery, endotoxin levels decreased to levels similar to those reported at baseline. Neutrophil oxidative activity increased significantly following 3 weeks of gingivitis versus baseline (p<0.05). In the endotoxin-negative group this increase was associated with the black subjects whereas in the endotoxin-positive group change in neutrophil activity was driven by the female subpopulation. Serum cytokines, CRP, and fibrinogen levels did not change during the study. CONCLUSIONS: Experimental gingivitis was associated with endotoxemia and hyperactivity of circulating neutrophils, but not with changes in systemic levels of cytokines and acute-phase proteins. This may be attributed to the mild nature and the short duration of the induced gingivitis. PMID- 21320152 TI - Variability in the population pharmacokinetics of isoniazid in South African tuberculosis patients. AB - AIM: This study was designed to characterize the population pharmacokinetics of isoniazid in South African pulmonary tuberculosis patients. METHODS: Concentration-time measurements obtained from 235 patients receiving oral doses of isoniazid as part of routine tuberculosis chemotherapy in two clinical studies were pooled and subjected to nonlinear mixed-effects analysis. RESULTS: A two compartmental model, including first-order absorption and elimination with allometric scaling, was found to describe the observed dose-exposure relationship for oral isoniazid adequately. A mixture model was used to characterize dual rates of isoniazid elimination. Estimates of apparent clearance in slow and fast eliminators were 9.70 and 21.6 l h(-1) , respectively. The proportion of fast eliminators in the population was estimated to be 13.2%. Central volume of distribution was estimated to be 10% smaller in female patients and clearance was found to be 17% lower in patients with HIV. Variability in absorption rate (90%) was completely interoccasional in nature, whereas in relative bioavailability, interoccasional variability (8.4%) was lower than interindividual variability (26%). Oral doses, given once daily according to dosing policies at the time, were sufficient to reach therapeutic concentrations in the majority of the studied population, regardless of eliminator phenotype. Simulations suggested that current treatment guidelines (5 mg kg(-1) ) may be suboptimal in fast eliminators with low body weight. CONCLUSIONS: A population pharmacokinetic model was developed to characterize the highly variable pharmacokinetics of isoniazid in a South African pulmonary tuberculosis patient population. Current treatment guidelines may lead to underexposure in rapid isoniazid eliminators. PMID- 21320155 TI - Evidence-based nursing interventions warrant rigorous development methods. PMID- 21320153 TI - Influence of genetic, biological and pharmacological factors on warfarin dose in a Southern Brazilian population of European ancestry. AB - AIMS: To investigate the influence of polymorphisms in CYP2C9, VKORC1, CYP4F2 and F2 genes on warfarin dose-response and develop a model including genetic and non genetic factors for warfarin dose prediction needed for each patient. METHODS: A total of 279 patients of European ancestry on warfarin medication were investigated. Genotypes for -1639G>A, 1173C>T, and 3730G>A SNPs in the VKORC1 gene, CYP2C9*2 and CYP2C9*3, 1347C>T in the CYP4F2 gene and 494C>T in the F2 gene were determined by allelic discrimination with Taqman 5'-nuclease assays. RESULTS: The CYP2C9*2 and CYP2C9*3 polymorphisms in the CYP2C9 gene, -1639G>A and 1173C>T in the VKORC1 gene and 494C>T in the F2 gene are responsible for lower anticoagulant doses. In contrast, 1347C>T in the CYP4F2 gene and 3730G>A in the VKORC1 gene are responsible for higher doses of warfarin. An algorithm including genetic, biological and pharmacological factors that explains 63.3% of warfarin dose variation was developed. CONCLUSION: The model suggested has one of the highest coefficients of determination among those described in the literature. PMID- 21320158 TI - Chromosome diversity and similarity within the Actinomycetales. AB - Many chromosomes from Actinomycetales, an order within the Actinobacteria, have been sequenced over the last 10 years and the pace is increasing. This group of Gram-positive and high G+C% bacteria is economically and medically important. However, this group of organisms also is just about the only order in the kingdom Bacteria to have a relatively high proportion of linear chromosomes. Chromosome topology varies within the order according to the genera. Streptomyces, Kitasatospora and Rhodococcus, at least as chromosome sequencing stands at present, have a very high proportion of linear chromosomes, whereas most other genera seem to have circular chromosomes. This review examines chromosome topology across the Actinomycetales and how this affects our concepts of chromosome evolution. PMID- 21320157 TI - Hepatitis C virus in primary care: survey of nurses' attitudes to caring. AB - AIM: This paper is a report of a study measuring attitudes of primary care nurses towards caring for people with hepatitis C. BACKGROUND: Hepatitis C is a major public health problem. Attitudes to caring for people with hepatitis C vary and can have an impact on nursing care practices. International literature has identified discriminating practices amongst healthcare professionals including nurses. There is limited research examining primary care nurses' attitudes to caring for people with hepatitis C. METHODS: A cross-sectional postal census survey of 981 nurses working in one health board region in the Republic of Ireland was conducted during the period March 2006 to June 2006. RESULTS: A response rate of 57.1% (n=560) was achieved. Exploratory factor analysis of an attitude scale identified three latent variables: 'infection control behaviour', 'caring' and 'fear'. Attitudes were generally positive towards caring for persons with hepatitis C; however, 51.7% of respondents would use additional infection control precautions if caring for someone with known hepatitis C. Younger nurses and those educated to degree level and above held significantly more positive attitudes to caring. Nurses agreed that they have a central role in managing and treating people with hepatitis C; however, many agreed that they lack the knowledge and skills to care for persons with hepatitis C. CONCLUSIONS: Negative attitudes can result in discriminatory experiences for persons with hepatitis C or at risk. Nurses require ongoing education on hepatitis C to improve knowledge, to limit concerns and ensure adherence to infection control guidelines. PMID- 21320154 TI - Anti-platelet therapy: cyclo-oxygenase inhibition and the use of aspirin with particular regard to dual anti-platelet therapy. AB - Aspirin and P2Y(12) antagonists are commonly used anti-platelet agents. Aspirin produces its effects through inhibition of thromboxane A(2) (TXA(2)) production, while P2Y(12) antagonists attenuate the secondary responses to ADP released by activated platelets. The anti-platelet effects of aspirin and a P2Y(12) antagonist are often considered to be separately additive. However, there is evidence of an overlap in effects, in that a high level of P2Y(12) receptor inhibition can blunt TXA(2) receptor signalling in platelets and reduce platelet production of TXA(2). Against this background, the addition of aspirin, particularly at higher doses, could cause significant reductions in the production of prostanoids in other tissues, e.g. prostaglandin I(2) from the blood vessel wall. This review summarizes the data from clinical studies in which dose-dependent effects of aspirin on prostanoid production have been evaluated by both plasma and urinary measures. It also addresses the biology underlying the cardiovascular effects of aspirin and its influences upon prostanoid production throughout the body. The review then considers whether, in the presence of newer, more refined P2Y(12) receptor antagonists, aspirin may offer less benefit than might have been predicted from earlier clinical trials using more variable P2Y(12) antagonists. The possibility is reflected upon, that when combined with a high level of P2Y(12) blockade the net effect of higher doses of aspirin could be removal of anti-thrombotic and vasodilating prostanoids and so a lessening of the anti-thrombotic effectiveness of the treatment. PMID- 21320159 TI - Hungry mouths, now and in the future--how will our elders fare? PMID- 21320160 TI - General health, dental status and perceived dental treatment needs of an elderly population in Istanbul. AB - BACKGROUND: Comprehensive data on the oral health status and dental treatment needs of the elderly population in Turkey are deficient. OBJECTIVES: This pilot study determined the general and dental health status, perceived medical and dental treatment needs of an elderly population dwelling in residential homes in Istanbul. METHOD: Subjects at three different residential homes, namely one belonging to the state and two supported by foundations in Istanbul (N=121, female: 63 and male: 58) were involved in this study. A detailed questionnaire was prepared and dental examinations were conducted. Information was collected related to age, education levels, financial status, current physical functional status, general health, mental health, previous dental history, current dental status, oral hygiene practices and denture hygiene of these elderly people. The prevalence of edentulism, the presence and type of dental prostheses, dental and denture status and denture cleanliness were further evaluated. RESULTS: The three most prevalent reported general health problems were associated with genito urinary problems (24%) followed by cardiovascular (18%) and respiratory problems (14%) varying significantly between genders, with males suffering more from cardiovascular problems than females (p < 0.05). Females showed significantly higher gastrointestinal and orthopaedic problems than males (p < 0.05). Females were more frequently edentulous than males but denture hygiene was significantly better in females than in males (p < 0.05). Brushing frequency did not significantly increase denture hygiene (p = 0.6). More than one-third of the subjects had not been to the dentist within the previous 5-10 years, mainly due to lack of demand, followed by the cost of the dental care and fear. More than two-thirds of denture-wearing subjects wore their dentures only during eating. CONCLUSIONS: There was significant perceived dental treatment and care need for the sample population of elderly studied. PMID- 21320162 TI - Antimicrobial activity of disinfectant agents incorporated into type IV dental stone. AB - PURPOSE: This study evaluated the antimicrobial activity of two disinfectant agents, 2% chlorhexidine digluconate solution (CHX) and 98% chlorhexidine hydrochloride powder (HYD), incorporated into type IV dental stone at the time of mixing. MATERIAL AND METHODS: Agar diffusion test was used for the following microorganisms: Escherichia coli, Staphylococcus aureus, Bacillus subtilis and Candida albicans. The specimens were grouped in: (1) dental stone mixed with sterile distilled water; (2) paper disc soaked with CHX; (3) dental stone mixed with CHX; and (4) dental stone with incorporation of HYD, in 1% proportion of the dental stone mass and mixed with sterile distilled water. The culture medium was inoculated with microbial suspensions 1 and 24 h after pouring of the dental stone. The antimicrobial activity was evaluated by the average diameter of microbial growth inhibition zones. The data were analysed with a nested anova (p < 0.05) and Tukey test for specific comparisons. RESULTS: The disinfectant agents demonstrated antimicrobial activity against all microorganisms, with the exception of C. albicans, against which the CHX was ineffective in two periods of analysis. Significant differences between disinfectants were found with all microorganisms. CONCLUSION: The disinfectant agents analysed were effective against most of the microorganisms tested, except C. albicans. PMID- 21320163 TI - Pulmonary embolism following coronary artery bypass grafting. AB - BACKGROUND: Pulmonary embolism (PE) is a life-threatening complication, with a deceptive clinical presentation following coronary artery bypass grafting (CABG). METHODS: We identified 13 studies on PE in post-CABG patients, spanning a period of 34 years. RESULTS: The overall cumulative incidence of PE following CABG was 1.3% (111 PEs in 8553 CABGs). CONCLUSION: We suggest further prospective randomized studies to examine the effect of saphenous system vein grafting, and choice of low molecular weight heparin prophylaxis on the incidence of post-CABG PE. PMID- 21320164 TI - Adult living-related liver donation for acute liver failure: is it ethically appropriate? AB - Acute liver failure (ALF) results in the annual death of approximately 3.5 per million people in the United States. Unfortunately, given the marked shortage of cadaveric liver donations and the ethical questions that plague utilization of living donor liver transplantation (LDLT) for ALF, many patients with ALF die before a liver is allocated to them. In this review, we discuss how the consistent utilization of LDLT for ALF could decrease the mortality rate of ALF. Additionally, we examine a key underlying issue: is LDLT for ALF ethically appropriate? PMID- 21320165 TI - Inhibitory effects of albuterol and fenoterol on RANTES and IP-10 expression in bronchial epithelial cells. AB - Short-acting beta2-adrenoreceptor agonist (SABA) is the major asthma reliever as indicated in the GINA guidelines. Regulated on activation, normal T expressed and secreted (RANTES) is a chemokine that attracts eosinophils, mast cells, and basophils toward site of allergic inflammation. Interferon gamma-inducible protein (IP)-10 is a Th1-related chemokine that is also important in asthmatic inflammation and also involved in our immune defense against pathogens. Bronchial epithelial cells are first-line barrier against invasive pathogen and also have immunomodulatory function. However, whether albuterol and fenoterol (two SABAs) have modulatory effects on RANTES and IP-10 expression in bronchial epithelial cells is unknown. The human bronchial epithelial cell lines, BEAS-2B cells, were pre-treated with different concentrations of albuterol, fenoterol or dibutyryl cAMP (a cyclic AMP analog) before polyinosinic-polycytidylic acid (poly I:C) stimulation. In some condition, BEAS-2B cells were pre-treated with ICI-118551, a selective beta2-adrenoreceptor antagonist, 30 min before albuterol or fenoterol treatment. The levels of RANTES and IP-10 were measured by ELISA. Intracellular signaling was investigated using cAMP assay, mitogen-activated protein kinase (MAPK) inhibitor, nuclear factor (NF)-kappaB inhibitor, and western blot. Albuterol and fenoterol suppressed poly I:C-induced RANTES and IP-10 expression of BEAS-2B cells. ICI-118551 could partly reverse the suppressive effects of albuterol and fenoterol on RANTES and IP-10 expression. Albuterol and fenoterol increased intracellular cAMP levels. Dibutyryl-cAMP conferred the similar effects of albuterol and fenoterol. Western blot revealed that albuterol suppressed p ERK, p-JNK and pp38, and also their associated kinase expression. Albuterol had no effect on pp65 expression. Albuterol and fenoterol could suppress poly I:C induced RANTES and IP-10 expression in human bronchial epithelial cells via at least partly the beta2-adrenoreceptor-cAMP and the MAPK pathways, implicating that albuterol and fenoterol could exert anti-inflammatory effect and benefit asthmatic patients by suppressing RANTES and IP-10 expression. However, these suppressive effects of albuterol and fenoterol may inhibit the defense against viral infection. PMID- 21320166 TI - The effects of cyclic loading and preparation on the fracture strength of zirconium-dioxide implants: an in vitro investigation. AB - OBJECTIVES: Zirconia is a potential material for the fabrication of oral implants. The aim of this study was to evaluate the effects of cyclic loading and preparation on the fracture strength of a zirconia implant system. MATERIALS AND METHODS: Forty-eight one-piece implants were divided into two groups of 24 implants: group A (without modification) and group B (1 mm chamfer preparation). Groups A and B were divided into three subgroups of eight implants each (1 = no artificial load, 2 = artificial load [98 N; 1.2 million loading cycles], and 3 = artificial load [98 N; 5 million loading cycles]). After completion of the loading, the fracture strength of each implant was determined in a universal testing machine. A two-way analysis of variance was used, the continuous response variable (fracture strength in Newtons) is modeled as a function of preparation, cycles, and the corresponding interaction as explanatory variables. RESULTS: The mean fracture strength values obtained for the groups were: A1 (no preparation, no load) = 1928.73 N, A2 (no preparation, 1.2 million cycles) = 2044.84 N, A3 (no preparation, 5 million cycles) = 1364.50 N, B1 (preparation, no load) = 1221.66 N, B2 (preparation, 1.2 million cycles) = 967.11 N, and B3 (preparation, 5 million cycles) = 884.89 N. Fracture values were significantly different between subgroups A1 vs. A3 and B1 vs. B3. There was no significant difference between subgroups A1 vs. A2 and B1 vs. B2. CONCLUSIONS: Preparation as well as cyclic loading can decrease the fracture strength resistance of zirconia implants. Nevertheless, even the lowest values of mean fracture strength of the implants used in our study seem to withstand average occlusal forces even after an extended interval of artificial loading. PMID- 21320167 TI - The effect of chemotherapeutic agents on titanium-adherent biofilms. AB - OBJECTIVE: To assess the effectiveness of different chemotherapeutic agents on biofilm-contaminated titanium surfaces. MATERIAL AND METHODS: This study used a recently described biofilm model. In experiment 1, Streptococcus mutans biofilms grown on titanium discs were treated with (1) EDTA, (2) citric acid (CA), (3) cetylpyridium chloride, (4) Ardox-X, (5) hydrogen peroxide (H(2) O(2) ), (6) chlorhexidine (CHX) and (7) water. In experiment 2, polymicrobial biofilms were treated with (1) CA, (2) Ardox-X, (3) H(2) O(2) , (4) Ardox-X followed by CA, (5) H(2) O(2) followed by CA, (6) CHX and (7) water. Aliquots of the suspended biofilms were plated and incubated anaerobically to enable counts of the total remaining viable bacteria, which were expressed as CFUs. Following incubation, the amount of protein remaining in the treated S. mutans biofilms was quantified to assess the removal potency of each treatment agent. RESULTS: H(2) O(2) , Ardox X and CA killed significantly more S. mutans compared with the other treatments. H(2) O(2) and CA removed significantly more protein than water. CA and the combination treatments were significantly more effective against the polymicrobial biofilms than CHX, H(2) O(2) and Ardox-X. The difference in the killing efficacy between CA alone and the combination treatments was not statistically significant. CONCLUSION: Among the chemicals tested, CA demonstrated the greatest decontamination capacity with respect to both the killing and the removal of biofilm cells. This combination of effects is clinically desirable because it promotes biocompatibility and healing around a previously contaminated implant surface. These results should, however, be validated in in vivo studies. PMID- 21320168 TI - Dimension of the facial bone wall in the anterior maxilla: a cone-beam computed tomography study. AB - OBJECTIVE: To determine the thickness of the facial bone wall in the anterior dentition of the maxilla and at different locations apical to the cemento-enamel junction (CEJ). MATERIAL AND METHODS: Two-hundred and fifty subjects, aged between 17 and 66 years, with all maxillary front teeth present were included. Written informed consents were obtained. Cone-beam computed tomography scans were performed with the iCAT unit. This examination included all tooth and edentulous sites in the dentition. The images were acquired by means of the iCAT software and processed by a computer. Measurements of the (i) distance between the CEJ and the facial bone crest and (ii) the thickness of the facial bone wall were performed. The bone wall dimensions were assessed at three different positions in relation to the facial bone crest, i.e., at distances of 1, 3, and 5 mm apical to the crest. RESULTS: The measurements demonstrated that (i) the distance between the CEJ and the facial bone crest varied between 1.6 and 3 mm and (ii) the facial bone wall in most locations in all tooth sites examined was <=1 mm thick and that close to 50% of sites had a bone wall thickness that was <=0.5 mm. CONCLUSION: Most tooth sites in the anterior maxilla have a thin facial bone wall. Such a thin bone wall may undergo marked dimensional diminution following tooth extraction. This fact must be considered before tooth removal and the planning of rehabilitation in the anterior segment of the dentition in the maxilla. PMID- 21320169 TI - Alveolar ridge dimensions in maxillary posterior sextants: a retrospective comparative study of dentate and edentulous sites using computerized tomography data. AB - AIM: To compare the alveolar ridge dimensions between edentulous sites and contralateral dentate sites of maxillary posterior sextants in the same individuals. MATERIALS AND METHODS: Computerized tomography scans of 32 patients with one fully edentulous and one fully dentate maxillary posterior sextants were analyzed. RESULTS: When compared with dentate sextants, edentulous sextants showed (i) a lower bone height (BH) at second premolar, first molar and second molar sites, which was associated with a more coronal position of the maxillary sinus floor at second premolar site; (ii) a more apical position of the ridge at second premolar and second molar sites; (iii) a lower bone width (BW)(1 mm) at first and second premolar sites, and a lower BW(3 mm) at all sites, (iv) a lower, although not significant, prevalence of premolar and molar sites with BH >=8 mm and BW(1 mm) >=6 mm. CONCLUSIONS: The edentulous sextants in the posterior maxilla showed a reduced height and width of the ridge when compared with contralateral dentate sextants. The reduced vertical dimensions observed in edentulous sextants were variably associated with ridge resorption as well as sinus pneumatization. PMID- 21320170 TI - Primary stability and self-tapping blades: biomechanical assessment of dental implants in medium-density bone. AB - AIM: The aim of this biomechanical study was to assess the influence of self tapping blades in terms of primary implant stability between implants with self tapping blades and implants without self-tapping blades using five different analytic methods, especially in medium-density bone. MATERIALS AND METHODS: Two different types of dental implants (4 * 10 mm) were tested: self-tapping and non self-tapping. The fixture design including thread profiles was exactly the same between the two groups; the only difference was the presence of cutting blades on one half of the apical portion of the implant body. Solid rigid polyurethane blocks with corresponding densities were selected to simulate medium-density bone. Five mechanical assessments (insertion torque, resonance frequency analysis [RFA], reverse torque, pull-out and push in test) were performed for primary stability. RESULTS: Implants without self-tapping blades showed significantly higher values (P<0.001) in four biomechanical assessments, except RFA (P=0.684). However, a statistically significant correlation could not be detected between insertion torque values with the four different outcome variables (P>0.05). CONCLUSIONS: The outcomes of the present study indicate that the implant body design without self-tapping blades has a good primary stability compared with that with self-tapping blades in medium-density bone. Considering the RFA, a distinct layer of cortical bone on marginal bone will yield implant stability quotient values similar to those in medium-bone density when implants have the same diameter. PMID- 21320171 TI - Effect of platform switching on peri-implant bone levels: a randomized clinical trial. AB - OBJECTIVE: The concept of platform switching has been introduced to implant dentistry based on observations of reduced peri-implant bone loss. However, randomized clinical trials are still lacking. This study aimed to test the hypothesis that platform switching has a positive impact on crestal bone-level changes. MATERIAL AND METHODS: Two implants with diameters of 4 mm were inserted epicrestally into one side of the posterior mandibles of 25 subjects. After 3 months of submerged healing, the reentry surgery was performed. On the randomly placed test implant, an abutment 3.3 mm in diameter was mounted, resulting in a horizontal circular step of 0.35 mm (platform switching). The control implant was straight, with an abutment 4 mm in diameter. Single-tooth crowns were cemented provisionally. All patients were monitored at short intervals over the course of 1 year. Standardized radiographs and microbiological samples from the implants' inner spaces were obtained at baseline (implant surgery), and after 3, 4, and 12 months. RESULTS: After 1 year, the mean radiographic vertical bone loss at the test implants was 0.53+/-0.35 mm and at the control implants, it was 0.58+/-0.55 mm. The mean intraindividual difference was 0.05+/-0.56 mm, which is significantly <0.35 mm (P=0.0093, post hoc power 79.9%). The crestal bone-level changes depended on time (P<0.001), but not on platform switching (P=0.4). The implants' internal spaces were contaminated by bacteria, with no significant differences in the total counts between the test and the control at any time point (P=0.98). CONCLUSIONS: The present randomized clinical trial could not confirm the hypothesis of a reduced peri-implant bone loss at implants restored according to the concept of platform switching. PMID- 21320172 TI - Campylobacter ureolyticus: an emerging gastrointestinal pathogen? AB - A total of 7194 faecal samples collected over a 1-year period from patients presenting with diarrhoea were screened for Campylobacter spp. using EntericBio((r)) , a multiplex-PCR system. Of 349 Campylobacter-positive samples, 23.8% were shown to be Campylobacter ureolyticus, using a combination of 16S rRNA gene analysis and highly specific primers targeting the HSP60 gene of this organism. This is, to the best of our knowledge, the first report of C. ureolyticus in the faeces of patients presenting with gastroenteritis and may suggest a role for this organism as an emerging enteric pathogen. PMID- 21320173 TI - Transcriptional regulation and activation of the mitogen-activated protein kinase pathway after Japanese encephalitis virus infection in neuroblastoma cells. AB - Japanese encephalitis virus (JEV), the most frequent and the single most important cause of encephalitis worldwide, has spread throughout most of Asia. For the development of appropriate and effective therapy, there is an immediate requirement to understand the role of host factors in JEV-induced neuropathogenesis. In the present study, we investigated the role of mitogen activated protein kinases (MAPKs) in JEV infection of mouse neuroblastoma (N2A) cells. The MAPK pathway was studied at the transcriptional level to access the gene expression profile at different time points after JEV infection. The effector MAPK genes were also analyzed for protein expression and activation. Gene expression analysis showed a significant regulation of extracellular signal regulated kinases (ERK)1, ERK2 and c-Jun N-terminal kinase (JNK)3 genes along with their downstream transcription factors such as Mef2c, c-Jun and Sfn. Experiments with the JNK inhibitor, SP600125, and the ERK inhibitor, PD98059, showed the involvement of JNK in JEV-induced caspase-3 activation and apoptosis, but ERK1/2 had no effect. Overall, our results show the transcriptional regulation of the MAPK pathway and the essential role of JNK in JEV-induced apoptosis in neuroblastoma cells. These findings provide a new insight into the role of the mitogen- and stress-activated kinases in JEV pathogenesis and opens up new avenues of therapeutics. PMID- 21320174 TI - Effect of short-term feeding duration of diets containing commercial whole-cell yeast or yeast subcomponents on immune function and disease resistance in channel catfish, Ictalurus punctatus. AB - Juvenile channel catfish, Ictalurus punctatus, were fed diets supplemented with yeast or yeast subcomponents (YYS) as commercial preparations of beta-glucan (MacroGard((r)) and Betagard A((r))), mannan oligosaccharide (Bio-Mos((r)) Aqua Grade), or whole-cell Saccharomyces cerevisiae (Levucell SB20((r))) at the manufacturers' recommended levels. Fish were fed experimental diets for 1 or 2 weeks prior to disease challenge (pre-challenge feeding periods) and sampled at the end of each feeding period to measure haematological and immune parameters and to determine the effects of dietary YYS on resistance to Edwardsiella ictaluri, the causative agent of enteric septicaemia disease (ESC). Feeding of experimental diets continued for 3 weeks post-challenge. In channel catfish fed diets supplemented with MacroGard((r)), Betagard A((r)), or Levucell SB20((r)), survival in the 1 week pre-challenge feeding group and antibody titres in the 2 week feeding group were significantly higher post-E. ictaluri challenge in relation to catfish fed with the control diet. In fish fed these same three diets, survival to ESC was significantly higher after 1 week vs. 2 weeks feeding, while the antibody response was significantly higher after 2 weeks vs. 1 week. Lysozyme activity was also higher in the 1 week feeding group, but the increased activity was unrelated to diet. Feeding YYS-supplemented diets for a shorter duration of 1 week prior to challenge may prove beneficial in increasing resistance to ESC in channel catfish. However, we cannot discount that feeding YYS diets during the recovery period may have contributed to 'glucan overload' and reduced survival in the 2 week feeding group. PMID- 21320175 TI - Terpenes transfer to milk and cheese after oral administration to sheep fed indoors. AB - Terpenes have been proposed as potential biomarkers in verifying the diets of grazing animals. A study of the relationships between the intake of terpenes and their presence in animal tissues (blood and milk) as well as in the final product (cheese) was conducted. Eight dairy sheep were divided into two equal groups, representing control (C) and treatment group (T). In T group oral administration of a mixture of terpenes, alpha-pinene, limonene and beta-caryophyllene, was applied over a period of 18 days. Blood and milk samples were collected regularly and terpenes were identified by extraction using petroleum ether and the solid phase micro-extraction (SPME) method, respectively, followed by GC-MS analysis. Cheese was produced, from C and T animals separately, twice during the period of terpenes oral administration. Terpenes contents and chemical properties of the produced cheeses were investigated. Limonene and alpha-pinene were found in all blood and milk samples of the T group after a lag-phase of 2 days, while beta caryophyllene was detected in few plasma samples and in all milk samples. None of the terpenes was traced in blood and milk of C animals. The contents of cheese, in dosed terpenes, presented a more complicated pattern suggesting terpenes non credible as biomarkers. We conclude terpenes can be used as biomarkers for authentification of ewes' milk, but further research is required on factors affecting their transfer to dairy products from grazing diets. PMID- 21320176 TI - Coordinated gene expression in adipose tissue and liver differs between cows with high or low NEFA concentrations in early lactation. AB - Dairy cows with high and low plasma non-esterified fatty acid (NEFA) concentrations in early lactation were compared for plasma parameters and mRNA expression of genes in liver and subcutaneous adipose tissue. The study involved 16 multiparous dairy cows with a plasma NEFA concentration of >500 MUmol/l [n = 8, high NEFA (HNEFA)] and <140 MUmol/l [n = 8, low NEFA (LNEFA)] in the first week post-partum (pp). Blood samples, adipose and liver tissues were collected on day 1 (+1d) and at week 3 pp (+3wk). Blood plasma was assayed for concentrations of metabolites and hormones. Subcutaneous adipose and liver tissues were analysed for mRNA abundance by real-time qRT-PCR encoding parameters related to lipid metabolism. Results showed that mean daily milk yield and milk fat quantity were higher in HNEFA than in LNEFA cows (p < 0.01), and the NEB was more negative in HNEFA than in LNEFA in +3wk too (p < 0.05). HNEFA cows had slightly lower (p < 0.1) insulin concentrations than LNEFA cows across the study period, and the body condition score decreased more from +1d to +3wk in HNEFA than in LNEFA (p = 0.09). The mRNA abundance of genes in the liver related to fatty acid oxidation (carnitine palmitoyltransferase 2 and very long chain acyl-coenzyme A dehydrogenase) and ketogenesis (3-hydroxy-3-methylglutaryl-coenzyme A synthase 2) were lower in HNEFA than in LNEFA cows. No differences between the two groups were observed for mRNA expression of genes in adipose tissue. The number of calculated significant correlation coefficients (moderately strong) between parameters in the liver and in adipose tissue was nearly similar on +1d, and higher for HNEFA compared with LNEFA cows in +3wk. In conclusion, dairy cows with high compared with low plasma NEFA concentrations in early lactation show differentially synchronized mRNA expression of genes in adipose tissue and liver in +3wk that suggests a different orchestrated homeorhetic regulation of lipid metabolism. PMID- 21320177 TI - Chemical composition, in vitro digestibility and gas production of straws from different varieties and accessions of chickpea. AB - Chemical composition, in vitro digestibility and gas production of straw from four different varieties of Kabuli chickpea (Cicer arietinum) were studied. Kinetics of fermentation of straws from 19 different accessions of chickpea was also evaluated using gas production technique. Significant difference (p < 0.05) was observed in the yield of straw [from 1041 to 1174 kg dry matter (DM)/ha] from different varieties. The proportion of seed/straw from different varieties varied from 0.61 to 0.93. Crude protein, neutral detergent fibre and acid detergent fibre content of straw ranged from 28.1 to 35.8, 598.6 to 645.4 and 459.2 to 473.4 g/kg DM respectively. Organic matter digestibility was different (p < 0.05) among varieties and varied from 471.4 to 535.5 g/kg DM. Potential gas production (A), the rate constants (c and d) and lag times of straws from different chickpea varieties were not different (p > 0.05). However, the rate constants (c and d) and lag times were different (p < 0.05) among accessions. Potential gas production (A) differed (p < 0.05) approximately twofold among different accessions. The results emphasized that in any evaluation of chickpea varieties or accessions, where straw of this legume seed is used as an animal feed, not only seed yield but also yield and quality of straw should be taken into consideration. PMID- 21320178 TI - Selenium balance in the adult cat in relation to intake of dietary sodium selenite and organically bound selenium. AB - The response of cats to dietary sodium selenite (Na(2) SeO(3)) and organically bound selenium was studied in two separate studies with four cats per treatment and three levels of selenium supplementation (targets 1.0, 1.5 and 2.0 MUg/g DM) for each Se source. Whole blood and plasma selenium concentrations and glutathione peroxidase (GPx) activity were determined at 7-time points across the 32-day study. Faeces were quantitatively collected during the last 8 days and urine was collected daily during both studies. The basal diet used had a low apparent faecal selenium absorption of 25.3 +/- 3.0%. Daily faecal and urinary selenium excretion increased linearly with increasing selenium intake for both Se sources. Urinary selenium concentration of the cats fed the supplemented diets increased rapidly (~2 days) and remained constant throughout the remainder of the study. Apparent faecal selenium absorption was high for both selenium sources (73.2% and 80.0%). Plasma, and to a lesser extent, whole blood selenium concentrations increased in a dose-dependent manner with supplementation. Whole blood and plasma GPx activity were highly variable and showed a variable response to dietary selenium intake. Cats closely regulate selenium homeostasis through increasing urinary excretion whilst faecal absorption remains unaffected. PMID- 21320179 TI - Induction of parturition with aglepristone in the Majorera goat. AB - This study assessed the efficacy of aglepristone at inducing parturition in pregnant goats. Six experimental groups were defined: group A-5 (n = 12), group A 3.3 (n = 12), group A-2.5 (n = 12) and group A-1.5 (n = 12) in which goats were injected SC once with 5.0, 3.3, 2.5 and 1.5 mg of aglepristone per kg body weight of goat, respectively, group L (n = 11), which was treated IM with 3.75 mg of luprostiol; and group Ct (n = 11), which was injected SC with 1 ml of saline solution. Different parameters associated with parturition were thereafter investigated. In addition, plasma progesterone concentrations were defined after treatments till parturition. Aglepristone effectively induced parturition in all of the goats. In the A-5, A-3.3 and A-2.5 groups, the time to parturition was around 30-34 h, and the majority of goats (97.2%, 35/36) started kidding between 25 and 40 h after the aglepristone injection. However, the goats in group A-1.5 showed a significantly (p < 0.01) higher time to parturition (mean: 46.8 h). Overall, the incidence of dystocia registered in aglepristone-induced goats (20.8%, 10/48) and luprostiol-induced goats was not different from that observed after a spontaneous parturition. The percentage of live kids was very similar between A-5, A-3.3, A.2.5 and L groups (95.7, 95.3, 95.0 and 96.3%, respectively) but was higher that observed in the control (83.4%) and A-1.5 (81.2%) groups. In addition, no maternal mortality was registered in any groups. No changes in plasma progesterone were observed during the first 24 h after treatment, and high plasma progesterone concentrations were present at kidding (6.7, 5.5, 4.5 and 3.6 ng/ml for groups A-5, A-3.3, A-2.5 and A-1.5, respectively), confirming that aglepristone does not induce parturition via luteolysis. This study demonstrates that aglepristone can be used to induce parturition in goats with satisfactory efficacy, inducing pregnancy termination without direct or immediate modifications of luteal function. PMID- 21320180 TI - Antibiotic-induced ribosomal assembly defects result from changes in the synthesis of ribosomal proteins. AB - Inhibitors of protein synthesis cause defects in the assembly of ribosomal subunits. In response to treatment with the antibiotics erythromycin or chloramphenicol, precursors of both large and small ribosomal subunits accumulate. We have used a pulse-labelling approach to demonstrate that the accumulating subribosomal particles maturate into functional 70S ribosomes. The protein content of the precursor particles is heterogeneous and does not correspond with known assembly intermediates. Mass spectrometry indicates that production of ribosomal proteins in the presence of the antibiotics correlates with the amounts of the individual ribosomal proteins within the precursor particles. Thus, treatment of cells with chloramphenicol or erythromycin leads to an unbalanced synthesis of ribosomal proteins, providing the explanation for formation of assembly-defective particles. The operons for ribosomal proteins show a characteristic pattern of antibiotic inhibition where synthesis of the first proteins is inhibited weakly but gradually increases for the subsequent proteins in the operon. This phenomenon most likely reflects translational coupling and allows us to identify other putative coupled non-ribosomal operons in the Escherichia coli chromosome. PMID- 21320181 TI - Functional analysis of epigenetic regulation of tandem RhopH1/clag genes reveals a role in Plasmodium falciparum growth. AB - The Plasmodium RhopH complex is a high molecular weight antigenic complex consisting of three subunits - RhopH1/clag, RhopH2 and RhopH3 - located in the rhoptry secretory organelles of the invasive merozoite. In Plasmodium falciparum RhopH1/clag is encoded by one of five clag genes. Two highly similar paralogous genes, clag 3.1 and clag 3.2, are mutually exclusively expressed. Here we show clonal switching from the clag 3.2 to the clag 3.1 paralogue in vitro. Chromatin immunoprecitation studies suggest that silencing of either clag 3 paralogue is associated with the enrichment of specific histone modifications associated with heterochromatin. We were able to disrupt the clag 3.2 gene, with a drug cassette inserted into the clag 3.2 locus being readily silenced in a position-dependent and sequence-independent manner. Activation of this drug cassette by drug selection results in parasites with the clag 3.1 locus silenced and lack full length clag 3.1 or 3.2 transcripts. These clag 3-null parasites demonstrate a significant growth inhibition compared with wild-type parasites, providing the first genetic evidence for a role for these proteins in efficient parasite proliferation. Epigenetic regulation of these chromosomally proximal members of a multigene family provides a mechanism for both immune evasion and functional diversification. PMID- 21320182 TI - Aspergillus nidulans transcription factor AtfA interacts with the MAPK SakA to regulate general stress responses, development and spore functions. AB - Fungi utilize a phosphorelay system coupled to a MAP kinase module for sensing and processing environmental signals. In Aspergillus nidulans, response regulator SskA transmits osmotic and oxidative stress signals to the stress MAPK (SAPK) SakA. Using a genetic approach together with GFP tagging and molecular bifluorescence we show that SakA and ATF/CREB transcription factor AtfA define a general stress-signalling pathway that plays differential roles in oxidative stress responses during growth and development. AtfA is permanently localized in the nucleus, while SakA accumulates in the nucleus in response to oxidative or osmotic stress signals or during normal spore development, where it physically interacts with AtfA. AtfA is required for expression of several genes, the conidial accumulation of SakA and the viability of conidia. Furthermore, SakA is active (phosphorylated) in asexual spores, remaining phosphorylated in dormant conidia and becoming dephosphorylated during germination. SakA phosphorylation in spores depends on certain (SskA) but not other (SrrA and NikA) components of the phosphorelay system. Constitutive phosphorylation of SakA induced by the fungicide fludioxonil prevents both, germ tube formation and nuclear division. Similarly, Neurospora crassa SakA orthologue OS-2 is phosphorylated in intact conidia and gets dephosphorylated during germination. We propose that SakA-AtfA interaction regulates gene expression during stress and conidiophore development and that SAPK phosphorylation is a conserved mechanism to regulate transitions between non-growing (spore) and growing (mycelia) states. PMID- 21320183 TI - Calcineurin is required for Leishmania major stress response pathways and for virulence in the mammalian host. AB - Leishmania parasites must adapt to elevated temperatures and other environmental stresses during infection of their mammalian hosts. How these environmental cues are sensed is poorly understood. In this study we show that calcium uptake is required for parasite thermotolerance at 34-37 degrees C. To identify potential downstream targets of calcium influx, a Leishmania major mutant lacking the essential regulatory subunit (CnB) of the Ca(2+) /calmodulin-dependent serine/threonine-specific phosphatase, calcineurin, was generated. The Deltacnb mutant grew as well as wild-type parasites at 27 degrees C and differentiated normally to infective metacyclic promastigotes. However, Deltacnb parasites lost viability when exposed to increased temperature (34 degrees C) and were hypersensitive to endoplasmic reticulum and membrane stress, induced by tunicamycin and inhibitors of sterol and sphingolipid biosynthesis respectively. Deltacnb promastigotes were internalized by macrophages, but their differentiation to the heat adapted amastigote stage was delayed and the resulting parasites failed to proliferate. Strikingly, the Deltacnb parasites were completely cleared by susceptible BALB/c mice. Complementation of Deltacnb parasites with CnB restored thermotolerance and infectivity in both macrophages and animal models. Our results suggest that Ca(2+) influx and calcineurin signalling are required for both early and long-term adaptive parasite responses to environmental stresses encountered in the mammalian host. PMID- 21320184 TI - The YvcK protein is required for morphogenesis via localization of PBP1 under gluconeogenic growth conditions in Bacillus subtilis. AB - The YvcK protein was previously shown to be dispensable when B. subtilis cells are grown on glycolytic carbon sources but essential for growth and normal shape on gluconeogenic carbon sources. Here, we report that YvcK is localized as a helical-like pattern in the cell. This localization seems independent of the actin-like protein, MreB. A YvcK overproduction restores a normal morphology in an mreB mutant strain when bacteria are grown on PAB medium. Reciprocally, an additional copy of mreB restores a normal growth and morphology in a yvcK mutant strain when bacteria are grown on a gluconeogenic carbon source like gluconate. Furthermore, as already observed for the mreB mutant, the deletion of the gene encoding the penicillin-binding protein PBP1 restores growth and normal shape of a yvcK mutant on gluconeogenic carbon sources. The PBP1 is delocalized in an mreB mutant grown in the absence of magnesium and in a yvcK mutant grown on gluconate medium. Interestingly, its proper localization can be rescued by YvcK overproduction. Therefore, in gluconeogenic growth conditions, YvcK is required for the correct localization of PBP1 and hence for displaying a normal rod shape. PMID- 21320185 TI - Small RNA-mediated control of the Agrobacterium tumefaciens GABA binding protein. AB - Wounded plants activate a complex defence programme in response to Agrobacterium tumefaciens. They synthesize the non-proteinogenic amino acid gamma-aminobutyric acid (GABA), which stimulates degradation of the quorum sensing signal N-(3-oxo octanoyl) homoserine lactone. GABA is transported into A. tumefaciens via an ABC transporter dependent on the periplasmic binding protein Atu2422. We demonstrate that expression of atu2422 and two other ABC transporter genes is downregulated by the conserved small RNA (sRNA) AbcR1 (for ABC regulator). AbcR1 is encoded in tandem with another sRNA, which is similar in sequence and structure. Both sRNAs accumulate during stationary phase but only the absence of AbcR1 resulted in significant accumulation of Atu2422 and increased GABA import. AbcR1 inhibits initiation of atu2422 translation by masking its Shine-Dalgarno sequence and thereby reduces stability of the atu2422 transcript. It is the first described bacterial sRNA that controls uptake of a plant-generated signalling molecule. Given that similar sRNAs and ABC transporter genes are present in various Rhizobiaceae and in Brucella, it is likely that such sRNA-mediated control impacts a number of host-microbe interactions. PMID- 21320186 TI - Escherichia coli Rep DNA helicase and error-prone DNA polymerase IV interact physically and functionally. AB - Escherichia coli DNA polymerase IV, encoded by the dinB gene, is a member of the Y family of specialized DNA polymerases. Pol IV is capable of synthesizing past DNA lesions and may help to restart stalled replication forks. However, Pol IV is error-prone, contributing to both DNA damage-induced and stress-induced (adaptive) mutations. Here we demonstrate that Pol IV interacts in vitro with Rep DNA helicase and that this interaction enhances Rep's helicase activity. In addition, Pol IV polymerase activity is stimulated by interacting with Rep, and Pol IV beta clamp-binding motif appears to be required for this stimulation. However, neither Rep's helicase activity nor its ability to bind DNA is required for it to stimulate Pol IV's polymerase activity. The interaction between Rep and Pol IV is biologically significant in vivo as Rep enhances Pol IV's mutagenic activity in stationary-phase cells. These data indicate a new role for Rep in contributing to Pol IV-dependent adaptive mutation. This functional interaction also provides new insight into how the cell might control or target Pol IV's mutagenic activity. PMID- 21320188 TI - Editorial: Roles in midwifery. PMID- 21320189 TI - A systematic review of variability and reliability of manual and automated blood pressure readings. AB - AIMS AND OBJECTIVES: To compare the accuracy and appropriateness of auscultatory (manual) and oscillometric (automated) devices for measuring blood pressure in clinical settings. BACKGROUND: Accurate measurement of blood pressure is integral to early recognition of deterioration in the condition of a patient. Despite recommendations regarding the use of auscultatory devices in situations where treatment decisions are made dependent on blood readings, the use of automated machines is becoming common practice. DESIGN: Systematic review. METHODS: A search of the Medline, CINAHLPlus and The Cochrane Library databases was undertaken for papers published in English between January 1997-May 2009. Sixteen studies were identified that fulfilled the inclusion criteria. After quality assessment, all were included in the review. Results are presented in tabular and narrative form. RESULTS: In 10 of the studies reviewed, the authors came to the conclusion that oscillometric devices were less accurate than auscultatory devices. However, in most cases the oscillometric device appears sufficiently accurate for clinical use, the exceptions being use with hypertensive patients, patients with arrhythmia and after trauma. Only two studies assessed the comparative accuracy of aneroid devices, and these indicated that they were more accurate than oscillometric devices, but the differences were not clinically important. CONCLUSIONS: There are situations where the substitution of oscillometric for auscultatory devices could have particularly serious repercussions for the patient, such as when the patient is either hypertensive or hypotensive. However, further research is required on the use of aneroid sphygmomanometers as a replacement for mercury devices. RELEVANCE TO CLINICAL PRACTICE: Practitioners should be made aware of the need to use auscultatory devices in specific circumstances, such as in management of hypertension, after the patient has experienced trauma or where there is significant potential for deterioration in the patient's condition. PMID- 21320187 TI - Investigation of the significance of Oil Red O-positive macrophage excess in bronchoalveolar lavage fluid during HIV infection. AB - OBJECTIVE: To assess the significance of increased levels of Oil Red O-positive macrophages (ORO-PM) in bronchoalveolar lavage fluids (BALFs) from HIV-positive patients. METHODS: Cytological data for seventy BALF samples from 66 consecutive HIV-infected patients were analysed according to antiretroviral therapy regimen, presence of Pneumocystis jiroveci infection, blood CD4(+) T cell count, HIV-1 viral load and plasma lipid levels. Non-parametric tests were used to compare the values between groups. RESULTS: The percentages of ORO-PM were high in this group: 40% [6-80] (median [interquartile range]). They were positively correlated with the BALF total cell count, 21% [5-48.5] for <300 cells/mm(3) and 60% [26.5 80] for >300 cells/mm(3) (P<0.01) but inversely correlated with the percentage of BALF lymphocytes, 50% [20-80] for <15% lymphocytes and 11.5% [2-47] for >=15% lymphocytes (P<0.01). Antiretroviral therapy with or without protease inhibitors, plasma lipid levels, HIV-1 viral load, blood CD4(+) T cell count or presence of a Pneumocystis jiroveci infection were not correlated with the ORO-PM status. CONCLUSION: Significantly increased numbers of ORO-PM were correlated with high total cell counts and low lymphocyte counts in BALF, irrespective of disease activity or treatment. Extended work on a larger series of patients needs to be conducted. PMID- 21320190 TI - A review of pain management interventions in bone marrow biopsy. AB - AIMS: This review was designed to evaluate the evidence relating to pain management interventions for patients having bone marrow biopsy. BACKGROUND: Bone marrow biopsy is an invasive procedure causing considerable pain and anxiety for adult patients, yet there are no guidelines to inform effective nursing care. Although this is an under-researched area, a range of pain interventions have been tested on this patient group, but this evidence has not been synthesised. DESIGN: Structured evidence review. METHOD: The Cochrane Library and databases Medline, Scopus and Cinahl were searched for original research reports. Reference lists of retrieved papers were hand-searched and researchers in the field were contacted. Retrieved papers were analysed using the CASP framework. A narrative data synthesis considered the strengths and limitations of included studies and findings were collated and interpreted. RESULTS: No systematic reviews of evidence have been undertaken and the search strategy identified twelve research studies eligible for inclusion in the review. Hand-searching did not identify any additional studies, and emails to researchers confirmed this is an under researched field. Analysis shows three main interventions, intravenous midazolam, premedication with analgesia and/or anxiolysis and the use of EntonoxTM are used to manage the pain experience for patients undergoing a bone marrow biopsy. CONCLUSIONS: Evidence is inconclusive and provides little guidance for practice. There is an urgent need for research into effective interventions for pain management in bone marrow biopsy and in understanding the patient experience. RELEVANCE TO CLINICAL PRACTICE: Nurses have a central role to play in the assessment and management of the pain and anxiety associated with bone marrow biopsy. There is little evidence to guide this aspect of care, but it is important that nurses involved with bone marrow biopsy are aware of the best evidence to facilitate the most effective management of their patients' pain. PMID- 21320191 TI - Why is pain still not being assessed adequately? Results of a pain prevalence study in a university hospital in Sweden. AB - AIM: The aim of this study was to investigate the prevalence of pain and pain assessment among inpatients in a university hospital. BACKGROUND: Pain management could be considered an indicator of quality of care. Few studies report on prevalence measures including all inpatients. DESIGN: Quantitative and explorative. METHOD: Survey. RESULTS: Of the inpatients at the hospital who answered the survey, 494 (65%) reported having experienced pain during the preceding 24 hours. Of the patients who reported having experienced pain during the preceding 24 hours, 81% rated their pain >3 and 42.1% rated their pain >7. Of the patients who reported having experienced pain during the preceding 24 hours, 38.7% had been asked to self-assess their pain using a Numeric Rating Scale (NRS); 29.6% of the patients were completely satisfied, and 11.5% were not at all satisfied with their participation in pain management. CONCLUSIONS: The result showed that too many patients are still suffering from pain and that the NRS is not used to the extent it should be. Efforts to overcome under-implementation of pain assessment are required, particularly on wards where pain is not obvious, e.g., wards that do not deal with surgery patients. Work to improve pain management must be carried out through collaboration across professional groups. RELEVANCE TO CLINICAL PRACTICE: Using a pain assessment tool such as the NRS could help patients express their pain and improve communication between nurses and patients in relation to pain as well as allow patients to participate in their own care. Carrying out prevalence pain measures similar to those used here could be helpful in performing quality improvement work in the area of pain management. PMID- 21320193 TI - A comparison of postnatal depression and related factors between Chinese new mothers and fathers. AB - AIMS: This study aims to examine the differences in the prevalence of depression and related factors between new mothers and fathers during the postnatal period. BACKGROUND: Although the transition to motherhood and postnatal depression has been extensively studied, few studies compared maternal and paternal psychological health during the postnatal period. DESIGN: A cross-sectional design was used. METHODS: A total of 376 pairs of new parents participated in this study. The Edinburgh Postnatal Depression Scale, the Perceived Stress Scale and the Social Support Rating Scale were used to measure depression, perceived stress and social support, respectively. We performed paired t-test and multiple regression to analyse the data. RESULTS: No significant difference in the prevalence of postnatal depression was found between the new mothers and fathers (14.9 vs. 12.5%). Fathers experienced similar stress levels as mothers did, while they received lower level of social support than mothers. Perceived stress, social support and partner's Edinburgh Postnatal Depression Scale score were significantly associated with depression for both mothers and fathers. Less sleeping time of infant and a tense relationship between mothers and mother-in law were related to mothers' depression. The preference for a male baby was associated with fathers' depression. CONCLUSION: Both new mothers and fathers experienced postnatal depression in China. RELEVANCE TO CLINICAL PRACTICE: Clinical nurses should pay attention to psychological health among new parents during postnatal period. Perinatal services, such as antenatal and postnatal education and counselling, should also be provided for fathers. PMID- 21320192 TI - Physical exercise: does it help in relieving pain and increasing mobility among older adults with chronic pain? AB - AIM: To provide a physical exercise programme for older adults living in nursing homes. BACKGROUND: Pain is common among older persons and for those already in long-term care and having difficulty in coping with pain will be at risk of further reducing their optimal independent function. DESIGN: A quasi-experimental single group pretest-posttest design. METHOD: Older persons from a nursing home were invited to join an eight-week physical exercise programme. Each session lasted an hour and sessions were conducted once a week by physiotherapist and nurses. Physical exercise programme consisted of stretching, strengthening, balancing, towel dancing and self-administered massage to various acupressure points. On completion of each session, older persons were given a pamphlet with pictures to illustrate the exercise of the day and they were encouraged to practise these exercises by themselves. Outcome measures including pain intensity, range of movement, activities of daily living and mobility were collected before and after the physical exercise programme. RESULTS: There were 75 older adult participants (57 female and 18 male, mean age 85.14 SD 5.30). Seventy-three percent (n = 55) of them had pain in the previous three months and were referred as pain group, while 25% (n = 20) were no pain group. Pain scores of 4.89 (on a 10-point scale) indicated medium pain intensity before the intervention for the pain group; the location of pain was mainly in the knee, back and shoulder. On completion of the physical exercise programme, there was a significant decrease in pain intensity to 2.89 (SD 2.14) (p < 0.01). There was a significant increase in range of movement in the neck, shoulder, back, hip and knee rotation, flex and abduction (p < 0.01). Mobility level was significantly increased post intervention, yet activities of daily living remained unchanged. CONCLUSIONS: The present study demonstrated the effectiveness of a physical exercise programme in relieving pain and enhancing functional mobility for older persons. Relevance to clinical practice. It is important to educate older persons, especially those living in nursing homes, on the importance of engaging in regular physical exercise and maintaining mobility. PMID- 21320194 TI - Biopsychosocial risk factors for preterm birth and postpartum emotional well being: a case-control study on Turkish women without chronic illnesses. AB - AIMS AND OBJECTIVES: The study aimed to determine bio-psycho-social risk factors for preterm birth in a sample of Turkish women without chronic illnesses and evaluate their anxiety and depression in early postpartum period. BACKGROUND: Preterm birth is a devastating event with long-term health and social implications. Studies have identified several risk factors; however, the contribution of these causes differs by ethnic groups. DESIGN: This case-control study was conducted in a tertiary hospital in Istanbul over one year. In total, 149 preterm mothers were included in the case group and 150 term mothers who delivered in the same day with a case group woman were included in the control group. Chronic illnesses and anomalies were excluded. METHOD: Data were gathered using a form that addressed risk factors for preterm birth. Multidimensional Scale of Perceived Social Support, Beck Depression Inventory and Spielberger's State-Trait Anxiety Inventory were administered within 24-72 hours after birth. RESULTS: Logistic regression analysis revealed that partner's lower education (<= 8 years), history of preterm birth, antenatal hospitalisation, genitourinary infection and irregular prenatal care were significant risk factors. Perceived social support from family and friends were significantly lower in preterm group. Preterm mothers experienced significantly more anxiety and depressive symptoms in early postpartum. CONCLUSION: Many of the socio-economical and obstetric causes of preterm births were similar to other countries with higher preterm birth rates. Preterm births were associated with lower social support along with more anxiety and depressive symptoms in early postpartum. RELEVANCE TO CLINICAL PRACTICE: Women who have established risk factors can be targeted for more intensive antenatal care for the prevention of preterm birth. Increased maternal anxiety and depression reveal the necessity of emotional support immediately after birth. PMID- 21320195 TI - Predictors of postpartum stress. AB - AIM: To predict important factors in women's postpartum stress. BACKGROUND: The transition to motherhood is often accompanied by stress, but research on predictors of postpartum stress is scant. DESIGN: A cross-sectional survey was used in the study. METHODS: Proportional stratified quota sampling based on births at 11 registered general hospitals and seven specialty clinics in the Kaohsiung area of southern Taiwan was used to obtain a high degree of representation. Eight hundred and fifty-nine women participated in the study within six weeks postpartum. The Hung postpartum stress scale, the social support scale and the 12-item Chinese Health Questionnaire were used in this study. RESULTS: Women with minor psychiatric morbidity, one or two children, junior college educational level, formula feeding for their infants, preference for an infant boy and a low level of social support were important predictors for women's postpartum stress. CONCLUSION: Our findings provide information and data for service planning and community care for the prevention and amelioration of postpartum stress. RELEVANCE TO CLINICAL PRACTICE: Postpartum women face a constellation of factors that could put them at risk for high levels of postpartum stress. Postpartum stress could significantly negatively impact women's health status. Nursing interventions should be tailored to decrease women's postpartum stress as a means of promoting postpartum women's pursuit of well-being. PMID- 21320196 TI - Use of polyurethane foam inside plaster casts to prevent the onset of heel sores in the population at risk. A controlled clinical study. AB - AIM: The aim of this study was to test the effectiveness of polyurethane foam in contact with the heel inside a plaster cast to decrease the rate of pressure sores in the population at most risk. BACKGROUND: The rate of pressure sores caused by the plaster cast is reported to be 14-15% in the paediatric population, 33.3% in patients having undergone chemotherapy for bone tumours and 43% in orthopaedic patients who already have sore skin when the cast is applied (grade 1 lesion) to the heel. DESIGN: Controlled clinical trial. METHODS: From November 2007-January 2009, all consecutive subjects requiring lower limb casts having undergone chemotherapy and/or presenting heel soreness received polyurethane foam in contact with the skin of the heel before applying the cast. The results were compared with those of patients with the same risk factors but were not administered the foam and were enrolled from May 2005-August 2006. RESULTS: In total, 156 patients were enrolled, 85 in the control group and 71 in the experimental group. In the experimental group, 2 of the 56 patients (3.6%) with sore skin developed a pressure sore compared with 21 of 49 (42.9%) in the control group without polyurethane foam (p < 0.0005). In the experimental group, one of the 24 patients (4.2%) patients undergoing chemotherapy developed a pressure sore compared with 18 of 54 (33.3%) in the control group (p = 0.005). CONCLUSIONS: Placing polyurethane foam in contact with the skin of the heel inside a plaster cast prevents the formation of pressure sores. RELEVANCE TO CLINICAL PRACTICE: This study provides evidence that using polyurethane foam to prevent sores even inside plaster casts in populations at most risk is a simple and cost-effective strategy and decreases the discomfort, pain and risks in these patients. PMID- 21320197 TI - Effects of a home-based aerobic exercise programme in children with type 1 diabetes mellitus. AB - AIMS: To explore the effects of exercise programme on glycosylated haemoglobin and peak oxygen uptake in children and adolescents with type 1 diabetes mellitus. BACKGROUND: Regular exercise has been shown to be effective in blood glucose control, which includes improving glucose tolerance and insulin sensitivity, decreasing glycosylated haemoglobin levels and improving cardiorespiratory fitness. DESIGN: Quasi-experimental design with a twelve-week home-based aerobic exercise programme. METHOD: Twenty-eight participants completed the study: 12 in the home-based exercise group, 11 in the non-exercise control group and five in the self-directed exercise group. A mixed model was used to capture longitudinal change in glycosylated haemoglobin levels. RESULTS: The home-based aerobic exercise group showed no significant effect on glycemic control and peak oxygen uptake in this study across assessment times. However, a group difference in glycosylated haemoglobin levels at the nine-month follow-up was significant (general linear model: F = 4.06, p = 0.03). A Bonferroni test indicated that glycosylated haemoglobin levels in the home-based exercise group were higher than in the self-directed exercise group (p < 0.05) and higher in the control group than in the self-directed exercise group (p < 0.05) at the nine-month follow-up. Home-based aerobic exercise showed no significant effect on peak oxygen uptake in this study. CONCLUSIONS: A three-month home-based aerobic exercise programme has no significant effect on glycosylated haemoglobin and peak oxygen uptake levels in children with type 1 diabetes mellitus. RELEVANCE TO CLINICAL PRACTICE: Our exercise programme has designed that children can practice exercise at home and is a viable component of self-care intervention to improve patient's self-care skill and diabetes care control. However, how to encourage patients to adhere the exercise programme is a challenge for health care providers. PMID- 21320198 TI - The effect of patient education and home monitoring on medication compliance, hypertension management, healthy lifestyle behaviours and BMI in a primary health care setting. AB - AIM: The aim of this study was to determine the effect of anti-hypertensive patient-oriented education and in-home monitoring for medication adherence and management of hypertension in a primary care setting, by providing education on healthy lifestyle behaviours and medication adherence. BACKGROUND: Hypertension is the third most common cause of death worldwide. Prevalence of hypertension in Turkey is approximately 30% in the general population and 45-50% in population over 50. DESIGN: Randomised controlled study. METHODS: This study conducted in Turkey used a study group comprised of 120 subjects (40 Group A, 40 Group B, 40 controls), all previously diagnosed with hypertension and who started medication therapy at least one year prior to start of study. The study was conducted between February-November 2006 at public primary health care facilities and homes of the study participants. Participants in Group A and B received a total of six monthly education sessions, four times during clinic visits and two home visits. Medication adherence education for Groups A and B and education about healthy lifestyle behaviours for Group B were administered in a structured and individualised format. The control group was routinely monitored in health care facilities. RESULTS: Healthy lifestyle behaviours and perception of self-efficacy regarding medication adherence showed improvement after education sessions in Groups A and B. Systolic and diastolic blood pressures of subjects in Group A and B showed a significant decrease compared with those of the control group; the blood pressure decrease in Group B was greater than in Group A. CONCLUSION: Nurses play an important role in uncontrolled hypertension detection and can improve medication adherence and healthy lifestyle behaviours. RELEVANCE TO CLINICAL PRACTICE: Patient education medication adherence alone and in combination with healthy lifestyle behaviour teaching is an effective tool for blood pressure reduction in the hypertensive population in primary health care settings. PMID- 21320199 TI - The profile of absconding psychiatric inpatients in Australia. AB - AIMS AND OBJECTIVES: The purpose of this study was to examine absconding behaviour (a patient leaving the hospital without permission) in acute and rehabilitation wards of one Australian psychiatric institution to describe the characteristics of the absconding patient and these events. BACKGROUND: Absconding is a significant issue in psychiatric inpatient settings, with risks that include patient harm, aggression and violence. In spite of this, limited research has been conducted in Australia on patients who abscond while receiving psychiatric care. DESIGN: The study was a retrospective descriptive analysis. METHOD: Absconding events from three acute and seven rehabilitation wards over a 12-month period were studied. RESULTS: The rate of absconding events by detained patients was 20.82%. Gender was not significantly associated with absconding, although 61.19% of those who absconded were men diagnosed with schizophrenic disorders. Over half of acute care patients who absconded left during their first 21-day detention order. More than half of absconding events were by patients that absconded more than once. There was limited support for the efficacy of locking ward doors. Age and diagnosis emerged as particularly important factors to consider. DISCUSSION: The study revealed that men are not more likely to abscond than women, that locking ward doors does not deter the determined absconders and that once a person has absconded, they are more likely to do so again. Younger patients and those with a schizophrenic disorder may be particularly likely to abscond. There also appears to be a link between continuing detention orders and an absconding event. CONCLUSIONS: Findings provide new data about the profile of absconding patients in Australia. Exploration of the reasons why patients abscond and why many do so repeatedly warrants further investigation. RELEVANCE TO CLINICAL PRACTICE: Risk management approaches taking into account factors associated with absconding could be trialled to reduce the incidence of absconding in psychiatric inpatient settings. PMID- 21320200 TI - A Taiwanese version of the International Consultation on Incontinence Questionnaire--Urinary Incontinence Short Form for pregnant women: instrument validation. AB - AIM: To translate the International Consultation on Incontinence Questionnaire- Urinary Incontinence Short Form (ICIQ-UI SF) from English to Taiwanese and to evaluate its reliability and validity for pregnant Taiwanese women. BACKGROUND: Urinary incontinence in pregnant women has been little investigated in Taiwan. A validated assessment instrument for urinary incontinence is needed for pregnant Taiwanese women. DESIGN: A non-experimental design was used to test the psychometric properties of the Taiwanese version of the ICIQ-UI SF. METHOD: The internal consistency reliability and construct validity of the Taiwanese version of the ICIQ-UI SF for pregnant women were evaluated in a random sample of 121 pregnant women at a medical center in Taiwan. Test-retest reliability was assessed for a sample of 55 pregnant women who completed this version at two time points in four weeks. Construct validity was verified with three questions and seven urinary-leakage situations by factor analysis. RESULTS: The Taiwanese version of the ICIQ-UI SF showed adequate test-retest reliability in pregnant Taiwanese women. The Pearson's correlation coefficient of the total score was 0.75, kappa statistics showed excellent or good reproducibility for most items and McNemar's test confirmed that there was no significant difference in the test retest pair for each item of the scale. The internal consistency reliability of the scale was good, with Cronbach's alpha = 0.80. Three factors were extracted and identified with an eigenvalue >= 1.04, explaining 65.64% the total variance. The first, second and third factors were 'symptom and quality of life', 'stress incontinence or other types' and 'urge or overflow incontinence'. CONCLUSIONS: The results provide evidence of the validity and reliability of the psychometric properties of the Taiwanese version of the ICIQ-UI SF for pregnant women. RELEVANCE TO CLINICAL PRACTICE: This questionnaire is a suitable instrument for evaluating urinary incontinence in pregnant Taiwanese women. PMID- 21320201 TI - Indicators of acute deterioration in adult patients nursed in acute wards: a factorial survey. AB - OBJECTIVES: The primary objective of the study was to determine which professional, situational and patient characteristics predict nurses' judgements of patient acuity and likelihood of referral for further review. A secondary aim was to test the feasibility of the factorial survey method in an acute area. BACKGROUND: There is increasing recognition that indicators of deterioration in acutely unwell adults are being missed and referrals delayed. The reasons for this are unclear and require exploration. Assessing nurses' clinical decision making or judgements in a 'real-world' situation is problematic. DESIGN: The study used a factorial survey design where participants completed randomly generated paper-based vignettes on one occasion. METHODS: The dependent variables were assessment of patient acuity and likelihood of referral. Independent variables consisted of a number of patient characteristics, i.e. heart rate, blood pressure, nurse characteristics, i.e. clinical experience, and situational characteristics i.e. staffing. SETTING AND PARTICIPANTS: Participants were registered nurses working in acute areas excluding intensive care and theatre. Ninety-nine participants responded resulting in 1940 completed vignettes. RESULTS: An early warning score was the single most significant predictor of referral behaviour accounting for 9.6% of the variance. When this was not included in the vignette, nurses used physiological characteristics e.g. respiratory rate, urine output, neurological status. These explained 12% of the variance in the model predicting assessment of patient acuity and 9.4% or the variance predicting likelihood of referral. CONCLUSIONS: When given a series of vignettes, nurses appear to use appropriate physiological parameters to make decisions about patient acuity and need for referral. Our results support the use of early warning scoring systems. Education and professional development should focus more on developing and maximising clinical experience and expertise rather than knowledge acquisition alone. A factorial survey method is feasible to explore decision-making in this area. RELEVANCE TO PRACTICE: This study has several implications for practice. The emergence of an early warning scoring system as a significant individual predictor supports the use of such systems. However, the small amount of explained variance suggests that there are other influences on nurses' assessment of patient acuity and referral decisions that were not measured by the factorial survey approach. Educational provision might focus not just on knowledge acquisition but include educational delivery methods that incorporate or mimic real-ward settings. PMID- 21320202 TI - A cross-sectional study on nurses' oral care practice for mechanically ventilated patients in Malaysia. AB - AIMS AND OBJECTIVES: This study sought to determine the strategies, methods and frequency of oral care provided for mechanically ventilated patients in Malaysian intensive care units. The study also described nurses' attitudes to providing oral care and their knowledge of the mode of transmission of ventilator associated pneumonia. BACKGROUND: Oral care is an important nursing intervention in the intensive care unit to reduce dental plaque. Dental plaque provides a repository for respiratory pathogens contributing to ventilator-associated pneumonia in the critically ill. DESIGN: Cross-sectional study. METHODS: This study used both survey and observational methods. The observational study was conducted by a nurse, trained in the study protocol. The observation period a selected shift over three weeks in 2007. FINDINGS: Intensive care unit nurses (n = 284) participated in the survey. Respondents had a positive attitude towards providing oral care. On a 10-point Likert scale, aspiration of contaminated secretions from the oropharynx was identified by nurses as the highest risk factor for ventilator-associated pneumonia (mean response 6.8, SD 2.0). The majority of nurses used cotton and forceps for oral care. Toothbrushes were not used in any of the study sites. CONCLUSIONS: Although nurses had a positive attitude to oral hygiene, this study found no intensive care units incorporated a soft toothbrush in oral care protocols which is recommended in best practice guidelines. A review of strategies to implement evidence-based practice in the intensive care unit is warranted. RELEVANCE TO CLINICAL PRACTICE: This study has identified a failure to adhere with evidence-based practice. Implementing and evaluating protocols for oral hygiene in the intensive care unit has the potential to improve patient outcomes. PMID- 21320203 TI - Difficulties in the daily life of patients with osteoarthritis of the knee: scale development and descriptive study. AB - AIM: The aim of this study was to develop an instrument to assess difficulties in daily life experienced by patients with osteoarthritis of the knee and to investigate factors influencing difficulties in daily life. BACKGROUND: Osteoarthritis of the knee is commonly associated with clinical symptoms and disabilities. No scale has been available to assess the comprehensive and subjective difficulties felt in daily life by patients affected in social and cultural lifestyle. Therefore, little is known about difficulties in osteoarthritis of the knee patients and supportive care necessary for them. DESIGN: A scale development and descriptive study. METHODS: The participants consisted of 362 patients with osteoarthritis of the knee. The scale development involved several phases including item development, reliability testing, criterion-related validity testing and construct validity testing. RESULTS: The exploratory factor analysis included three domains: 'suffering in social life', 'hardship in activities in daily life' and 'apprehension about the future life'. A confirmatory factor analysis confirmed validity of the construct, with a demonstrated good fit between the factor structure of the new scale and the observed data. Difficulties in daily life scores were significantly influenced by pain, loss of balance, muscle weakness, stiffness and swelling. CONCLUSION: We developed a reliable and valid scale for the measurement of difficulties in daily life experienced by patients with osteoarthritis of the knee. It is important for healthcare professionals to understand these difficulties in daily life experienced by patients with osteoarthritis of the knee and to educate patients with practical information and self-management strategies. RELEVANCE TO CLINICAL PRACTICE: This new scale could provide useful information to guide clinical practice in assessing and managing difficulties in daily life experienced by patients with osteoarthritis of the knee. PMID- 21320204 TI - Dignity in care in the hospital setting from patients' perspectives in Taiwan: a descriptive qualitative study. AB - AIM: The aim of this study was to explore dignity in care from patients' perspectives in Taiwan. BACKGROUND: Dignity is a core element of nursing care. In nurses' clinical practice, maintaining the dignity of patients is an important issue because a lack of dignity in care can affect the health and recovery of patients. In Western countries, patient dignity has been well researched, but only one study has examined this topic in an Asian country. DESIGN: Descriptive qualitative methods were used in this study. METHODS: Interviews were conducted with 40 patients purposively sampled at a teaching hospital in eastern Taiwan from May-August 2009. Audiotaped interviews were transcribed verbatim, and data in transcripts were coded and analysed by content analysis. RESULTS: The major findings revealed that many hospitalised patients were satisfied with the maintenance of their dignity. Six themes that contribute to the preservation of their dignity were identified: sense of control and autonomy, being respected as a person, avoidance of body exposure, caring from the nursing staff, confidentiality of disease information and prompt response to needs. CONCLUSIONS: The findings can help nurses better understand dignity in care because it is described from the patient viewpoint. RELEVANCE TO CLINICAL PRACTICE: By identifying the most important factors from patients' perspectives that contribute to dignity, nursing interventions in clinical practice can be further developed and improved. PMID- 21320205 TI - A survey of the reasons patients do not chose percutaneous endoscopic gastrostomy/jejunostomy (PEG/PEJ) as a route for long-term feeding. AB - AIMS: To investigate why patients do not choose percutaneous endoscopic gastrostomy or percutaneous endoscopic jejunostomy as a route for long-term feeding. BACKGROUND: Home enteral tube feeding is well recognised as a valuable therapeutic option for patients requiring nutritional support following discharge from hospital. The number of patients discharged from hospital and receiving home enteral tube feeding increases annually in Taiwan. DESIGN: A cross-sectional study. METHOD: Participants (n = 607) were chosen from one free-standing home care agency and three hospital-based home care departments in Taipei. A review of the patients' records to gather demographic data, medical diagnosis, length of home care and length of intubation prior to the home visit was conducted. A face to-face interview was conducted at the time of the home visit. FINDINGS: The prevalence rate of home enteral tube feeding was 70.3% (n = 427). Of the 427 tube fed subjects, 93.4% were fed with a nasogastric tube. The most common reasons for refusing to use percutaneous endoscopic gastrostomy or percutaneous endoscopic jejunostomy were 'too old to suffer from an operation', 'worried about wound infection or leakage after performing percutaneous endoscopic gastrostomy' and 'to keep subjects' body integrity'. Stroke, no dementia, poor activities of daily living and poor cognitive status were significant predictors of being tube-fed, while higher education and better cognitive status were significant predictors of percutaneous endoscopic gastrostomy or percutaneous endoscopic jejunostomy use. CONCLUSION: The reasons patients refused to use percutaneous endoscopic gastrostomy or percutaneous endoscopic jejunostomy reflect the influence of cultural values and the level of patients' education, which home health care nurses need to discuss with patients in detail. RELEVANCE TO CLINICAL PRACTICE: Investigating patients' perspective on the meaning of 'body' in Taiwanese culture and the decision-making processes related to home enteral tube feeding is recommended for nurses to provide better care and support when home enteral tube feeding in an option. PMID- 21320206 TI - A quasi-experimental investigation into the efficacy of a suicide education programme for second-year student nurses in Taiwan. AB - AIM: This study was designed to investigate the learning outcomes of a suicide education programme for second-year student nurses in Taiwan. BACKGROUND: Research demonstrates that nurses' attitudes impact on the care provided to suicidal patients. However, evidence is sparse on promoting positive caring attitudes in nurses towards suicidal patients. DESIGN: A quasi-experiment. METHOD: The total sample group (n = 174) comprised second-year student nurses. Some (n = 95) were randomly allocated to an experimental group who attended a four-hour suicidal education programme and others (n = 79) comprised a control group who did not attend the programme. All participants were given a questionnaire before and after the programme in 2008. The questionnaire contained 30 items and was divided into five categories. They were (1) the acceptability of suicidal behaviours, (2) morality and mental illness, (3) professional role and care, (4) communication and attention and (5) beliefs. RESULTS: Results demonstrated that the experimental group had higher scores on all five categories of the questionnaire than the control group did. Participants in the experimental group held more positive attitudes towards the acceptance of suicidal behaviours and were non-judgmental in their morality. Further, they showed more positive attitudes towards the provision of professional care and believed that people who attempt suicide are communicating their psychic pain. Moreover, participants in the experimental group held more positive beliefs about people who attempt suicide than the control group did. CONCLUSION: This suicide education programme raised student nurses' awareness about the phenomenon of suicide and promoted positive caring attitudes towards people who attempt suicide and hence their nursing care. RELEVANCE TO CLINICAL PRACTICE: A four-hour suicide education programme can promote positive caring attitudes towards people who attempt suicide and may have an affirmative influence on the nursing care provided to suicidal patients. PMID- 21320207 TI - Experiences of supernumerary status and the hidden curriculum in nursing: a new twist in the theory-practice gap? AB - AIMS AND OBJECTIVES: This paper aims to increase our understanding about how student nurses' experiences of supernumerary status are embedded in the hidden curriculum in clinical practice and contribute to the theory-practice gap in nursing. BACKGROUND: Current literature suggests that the hidden curriculum exists in many professional curricula and that it functions to socialise students into professional behaviours and practice. However, in nursing, there is a gap in our understanding of how these socialisation processes have been influenced by supernumerary status and what forms the hidden curriculum might take currently in clinical practice. DESIGN: An ethnographic case study design. METHOD: Data were collected in four sites using fieldwork in clinical practice as well as interviews with students, mentors and key stakeholders, an online survey of student bodies and curriculum analysis in four universities. The findings in this paper are drawn from the qualitative fieldwork and interviews and were analysed thematically. RESULTS: The findings suggest that supernumerary status is an important aspect of the hidden curriculum in clinical learning for nursing students; that students are expected by trained staff to work while they learn and that on registration, they are expected to be competent to work immediately as registered nurses. These expectations are at odds with those of academic nurses and contribute to a theory-practice gap for student nurses. These expectations form part of the hidden curriculum that shapes the clinical context, and students have to learn to negotiate their status as supernumerary students in practice to meet these expectations. CONCLUSION: Consequently, students have to learn in a disintegrated learning context where opposing values of learning exist. RELEVANCE TO CLINICAL PRACTICE: To reintegrate student nurses' learning, educators in universities and clinical practice have to understand how the hidden curriculum and expectations around supernumerary status among trained staff affect learning for students. PMID- 21320208 TI - Facing death, facing self: nursing students' emotional reactions during an experiential workshop on life-and-death issues. AB - AIM AND OBJECTIVES: This study presents the findings of a qualitative study exploring the experiences of undergraduate nursing students imagining the possibility of their own death during a workshop on life-and-death issues. BACKGROUND: Didactic instruction in end-of-life care is a critical element of nursing education and for most health professions training in general. Properly implementing this often-overlooked educational process requires providing students with opportunities to reflect on death and dying along with guidance during nursing practice in coping with emotional reactions to caring for dying patients. DESIGN: An interpretive descriptive design was adopted. METHOD: Data were gathered from the text of 20 students' reflective journals and workshop evaluations and researchers' field notes on observations during the workshop at a Taiwan university in August 2007. RESULTS: Students experienced a process of dying, death and rebirth. Students not only expressed emotional responses that included surprise, reluctance to let go and gratitude but also realised the importance of cherishing the present, committing to the nursing profession and valuing their own lives. CONCLUSIONS: Students can learn their fear of death and possible emotional reactions towards dying patients through self-reflection during a workshop on life-and-death issues. The foundation for facilitating students' self-awareness is a safe environment for them to gain experiential knowledge of the dying process and end-of-life care. Experiential education not only helps students grow personally but also increases their motivation to learn. RELEVANCE TO CLINICAL PRACTICE: Students' ability to recognise and manage their own emotional reactions towards death and dying patients should be included as part of end-of-life education. A workshop on life-and-death issues can help students discover that they are not alone and that they can support each other and learn how to manage their own emotions. PMID- 21320209 TI - Advancing nursing practice: redefining the theoretical and practical integration of knowledge. AB - AIM: The aim of this paper is to offer an alternative knowing-how knowing-that framework of nursing knowledge, which in the past has been accepted as the provenance of advanced practice. BACKGROUND: The concept of advancing practice is central to the development of nursing practice and has been seen to take on many different forms depending on its use in context. To many it has become synonymous with the work of the advanced or expert practitioner; others have viewed it as a process of continuing professional development and skills acquisition. Moreover, it is becoming closely linked with practice development. However, there is much discussion as to what constitutes the knowledge necessary for advancing and advanced practice, and it has been suggested that theoretical and practical knowledge form the cornerstone of advanced knowledge. DESIGN: The design of this article takes a discursive approach as to the meaning and integration of knowledge within the context of advancing nursing practice. METHOD: A thematic analysis of the current discourse relating to knowledge integration models in an advancing and advanced practice arena was used to identify concurrent themes relating to the knowing-how knowing-that framework which commonly used to classify the knowledge necessary for advanced nursing practice. CONCLUSION: There is a dichotomy as to what constitutes knowledge for advanced and advancing practice. Several authors have offered a variety of differing models, yet it is the application and integration of theoretical and practical knowledge that defines and develops the advancement of nursing practice. An alternative framework offered here may allow differences in the way that nursing knowledge important for advancing practice is perceived, developed and coordinated. RELEVANCE TO CLINICAL PRACTICE: What has inevitably been neglected is that there are various other variables which when transposed into the existing knowing-how knowing-that framework allows for advanced knowledge to be better defined. One of the more notable variables is pattern recognition, which became the focus of Benner's work on expert practice. Therefore, if this is included into the knowing how knowing-that framework, the knowing-how becomes the knowledge that contributes to advancing and advanced practice and the knowing-that becomes the governing action based on a deeper understanding of the problem or issue. PMID- 21320210 TI - Intent to stay in nursing: internal and external migration in Hungary. AB - AIMS: To estimate the proportion of nurses in Hungary who intend to change their profession or want to migrate abroad; to compare the proportion of nurses who intend to leave nursing in Hungary and in selected European countries; and to describe factors that predict nurses' intent to work in their current job another year. DESIGN: An exploratory research design with subsequent comparison was used, and a cross-sectional mail survey was implemented. METHODS: Measures of intent to leave, to work another year as well as indicators of push and pull factors were identified and adopted from a literature review. One thousand nurses were randomly selected and mailed a questionnaire. Comparison was made with the results from the NEXT study. For statistical analyses, linear and logistic regression was used to predict nurses' intention to leave and proportional z-test for making comparisons. RESULTS: Nurses (n = 754) responded the questionnaire. Approximately half of the sample did not consider changing to another health care job or leaving the profession. Compared with Hungary, the proportion of nurses who intended to leave nursing was significantly lower in Belgium and the Netherlands but was greater or the same in the rest of the European countries. Speaking a foreign language was the most significant predictor of working abroad for Hungarian nurses. Number of shifts, satisfaction with flexible scheduling and managerial support were all relevant predictors of working another year as a nurse. CONCLUSIONS: Both the intent to leave nursing and migrating abroad were prevalent issues in Hungary. Working conditions and social/managerial support were key factors identified as strong predictors of stay in the same job for another year. Compared with other European countries, Hungary was not in a worse position in the proportion of nurses wanting to leave nursing. RELEVANCE TO CLINICAL PRACTICE: All hospital managers and head nurses should be aware of their role in keeping nurses in the clinical practice and avoid staff nurses migration from the Hungarian health care system. PMID- 21320211 TI - Self-preservation in abortion care: a grounded theory study. AB - AIM: To seek an explanation as to why nurses concede and conceal their judgements towards women having an abortion. BACKGROUND: Recent advances in abortion techniques and pharmacology have resulted in a greater proportion of medical abortions occurring at a lower gestation than previously. As this technique demands more of nurses, it becomes important to ask whether they are equipped to deal with this greater involvement. DESIGN: A grounded theory approach using a recognised framework was used. Theoretical sampling was used in this study to increase the depth of focus from a previous study of nurses who were found to concede and conceal their judgement in abortion care. FINDINGS: Several important aspects of abortion care were elucidated as to why nurses concealed and conceded their judgements. Lower gestation of abortions was central in determining greater involvement of nurses in the abortion process. It was found that some nurses treated women the same and some treated women differently, but all strived for equitable care. Self-preservation in the form of 'switching off' or 'getting on with it' was employed by nurses when they encountered the foetus or women who were blase. Self-preservation was found to be a key phenomenon and a major reason why nurses conceded and then concealed their judgement. CONCLUSIONS: In rapidly advancing abortion care, there needs to be positive ways of ensuring self preservation in nurses without compromising care. RELEVANCE TO CLINICAL PRACTICE: Abortion care demands specific skills of nurses, and this is likely to increase in the near future. Self-preservation needs to be embedded into nurses' professional development by the use of positive strategies such as guided reflection in providing a productive woman-centred service. PMID- 21320212 TI - The Mental Health Nurse Incentive Program: desirable knowledge, skills and attitudes from the perspective of nurses. AB - AIM: To enhance the understanding of the skills and attitudes of mental health nurses working in the Australian Mental Health Nurse Incentive Program. BACKGROUND: The Mental Health Nurse Incentive Program places qualified mental health nurses alongside community-based general practitioners, private psychiatric practices and other appropriate organisations to provide clients with mental health conditions with a more integrated treatment plan. DESIGN: An exploratory, qualitative approach was undertaken, given the paucity of relevant research in this area. METHODS: Exploratory individual interviews were conducted with ten mental health nurses working in this scheme. Data analysis was organised and managed using QSR NVivo qualitative analysis software. RESULTS: Respondents identified specific skills and attitudes required for practice under the Mental Health Nurse Incentive Program. Eight areas of skill and attitude were identified as essential for mental health nurses working in this field. This study highlights that many of these skills and attitudes are specific to the setting where mental health nurses are working. CONCLUSION: Mental health nurses working under this programme have a role to play in the dissemination of knowledge about their practice. More needs to be done by governments and other institutions to ensure that general practitioners and other health professionals understand the role played by mental health nurses in the provision of care. RELEVANCE TO CLINICAL PRACTICE: The extent to which the Mental Health Nurse Incentive Program becomes a sustainable strategy to promote quality and accessible mental health care will depend to some degree on the capacity to identify the skills and attitudes necessary for practice. The findings presented in this paper provide a significant contribution to articulating the essential characteristics required for this area of practice. PMID- 21320213 TI - Commentary on Lopez R, Amella E, Mitchell S & Strumpf N (2010) Nurses' perspectives on feeding decisions for nursing home residents with advanced dementia. Journal of Clinical Nursing 19, 632-638. PMID- 21320214 TI - Commentary on Kowalski C, Ommen O, Driller E, Ernstmann N, Wirtz M, Kohler T & Pfaff H (2010) Burnout in nurses--the relationship between social capital in hospitals and emotional exhaustion. Journal of Clinical Nursing 19, 1654-1663. PMID- 21320215 TI - Commentary on Chan MF (2009) Factors affecting nursing staff in practising spiritual care. Journal of Clinical Nursing 19, 2128-2136. PMID- 21320216 TI - Editorial: online health communication in improving outcomes. PMID- 21320218 TI - The adoption, local implementation and assimilation into routine nursing practice of a national quality improvement programme: the Productive Ward in England. AB - AIM AND OBJECTIVE: To explore why innovations in service and delivery are adopted and how they are then successfully implemented and eventually assimilated into routine nursing practice. BACKGROUND: The 'Productive Ward' is a national quality improvement programme that aims to engage nursing staff in the implementation of change at ward level. DESIGN: Mixed methods (analysis of routine data, online survey, interviews) to apply an evidence-based diffusion of innovations framework. METHOD: (1) Broad and narrow indicators of the timing of 'decisions to adopt' the Productive Ward were applied. (2) An online survey explored the perceptions of 150 respondents involved with local implementation. (3) Fifty eight interviews in five organisational case studies to explore the process of assimilation in each context. RESULTS: Since the launch of the programme in May 2008 staff in approximately 85% of NHS acute hospitals had either downloaded Productive Ward materials or formally purchased a support package (as of March 2009). On a narrower measure, 40% (140) of all NHS hospitals had adopted the programme (i.e. purchased a support package) with large variation between geographical regions. Four key interactions in the diffusion of innovations framework appeared central to the rapid adoption of the programme. Despite widespread perception of significant benefits, frontline nursing staff report that more needs to be carried out to ensure that impact can be demonstrated in quantifiable terms and include patient perspectives. CONCLUSIONS: The programme has been rapidly adopted by NHS hospitals in England. A variety of implementation approaches are being employed, which are likely to have implications for the successful assimilation of the programme into routine nursing practice. RELEVANCE TO CLINICAL PRACTICE: This paper summarises the perceived benefits of the Productive Ward programme and highlights important lessons for nurse leaders who are designing (or adapting) and then implementing quality improvement programmes locally, particularly in terms of how to frame such initiatives - and provide support to - ward-level staff. PMID- 21320217 TI - Music therapy for patients receiving spine surgery. AB - AIMS AND OBJECTIVES: The aim of this study was to evaluate the effects of music therapy on anxiety, postoperative pain and physiological reactions to emotional and physical distress in patients undergoing spinal surgery. BACKGROUND: Surgery related anxiety and pain are the greatest concern of surgical patients, especially for those undergoing major procedures. DESIGN: A quasi-experimental study design was conducted in a medical centre in Taiwan from April-July 2006. METHODS: Sixty patients were recruited. The study group listened to selected music from the evening before surgery to the second day after surgery. The control group did not listen to music. Patients' levels of anxiety and pain were measured with visual analogue scales (VAS). Physiological measures, including heart rate, blood pressure and 24-hour urinalysis, were performed. RESULTS: The average age of the 60 patients was 62.18 (SD 18.76) years. The mean VAS score for degree of anxiety in the study group was 0.8-2.0, compared with 2.1-5.1 in the control group. The mean VAS score for degree of pain in the study group was 1.7 3.0, compared with 4.4-6.0 in the control group. The differences between the two groups in VAS scores for both anxiety (p = 0.018-0.001) and pain (p = 0.001) were statistically significant. One hour after surgery, the mean blood pressure was significantly lower in the study group than in the control group (p = 0.014), but no significant differences were found between the two groups in urine cortisol (p = 0.145-0.495), norepinephrine (p = 0.228-0.626) or epinephrine values (p = 0.074 0.619). CONCLUSIONS: Music therapy has some positive effects on levels of anxiety and pain in patients undergoing spinal surgery. RELEVANCE TO CLINICAL PRACTICE: Complementary music therapy can alleviate pain and anxiety in patients before and after spinal surgery. PMID- 21320219 TI - The use of complementary and alternative medicine among chronic renal failure patients. AB - AIMS AND OBJECTIVES: The aim of this study is to evaluate the factors affecting the use and frequency of use of complementary and alternative medicine among chronic renal failure patients. BACKGROUND: The use of complementary and alternative medicine in the general population and patients with chronic renal failure has increased significantly. Despite this, there is limited information concerning the use of complementary and alternative medicine among chronic renal failure patients. DESIGN: Cross-sectional survey. METHOD: The research was carried out at the nephrology and internal medicine outpatient clinics. Two hundred and six chronic renal failure patients admitted to the outpatient clinics were included in the study. Mean outcomes measures were the frequency and type of complementary and alternative medicine use, demographic and disease-related characteristics affecting complementary and alternative medicine use and the reasons for using complementary and alternative medicine. The data were evaluated by Pearson's chi-square test and Fisher's exact test. RESULTS: While 2.9% of the patients had been using complementary and alternative medicine before the renal disease occurred, 25.2% of the patients reported that they had at least once used complementary and alternative medicine methods after the renal disease occurred. A significant difference was found between complementary and alternative medicine usage and age, gender, place of living, occupational status and educational background (p < 0.05). While most of the patients using complementary and alternative medicine (78.3%) stated that they used such methods as a cure for their disease, 46.1% used body-mind techniques. CONCLUSIONS: The results of our study showed that one-fourth of the chronic renal failure patients were using complementary and alternative medicine, mainly body-mind techniques. In addition, the study proved that most of the patients do not discuss their complementary and alternative medicine usage with their doctors and nurses. RELEVANCE TO CLINICAL PRACTICE: It is essential that nephrology doctors and nurses should ask specific questions about complementary and alternative medicine usage while taking anamnesis on the patients' disease and nutritional status and that the nephrology team should expand their knowledge on complementary and alternative medicine methods to ensure patient and treatment safety. PMID- 21320220 TI - The role of health care assistants in supporting district nurses and family carers to deliver palliative care at home: findings from an evaluation project. AB - AIMS AND OBJECTIVES: To examine the role of trained health and personal care assistants in supporting district nurses and family carers in providing palliative and end of life care in the community. BACKGROUND: In the UK, there is a policy directive to improve end of life care and to enable greater numbers of people to die at home. This places considerable demands on community nursing services and family carers. In response to this, the Complex and Palliative Continuing Care Service employing generic health and personal care assistants was developed as part of the Marie Curie Delivering Choice Programme in one city in the UK. This paper draws on findings from an independent evaluation of the scheme. DESIGN: The wider evaluation used a formative evaluation methodology. METHOD: This paper draws on in-depth interviews with a range of stakeholders (n = 17), in-depth interviews with bereaved carers (n = 6) and an analysis of documentation. RESULTS: Stakeholders and bereaved carers perceived that the health and personal care assistants made a vital contribution to community palliative care. Careful recruitment, specific training, case management by district nursing with allocation of specific tasks and close ongoing communication were key features which stakeholders indentified. Family carers welcomed the way assistants developed relationships and became familiar and able to meet the care needs of patients. There were some problems reported which related to capacity, work flow and the need for extensive written care plans. CONCLUSION: Employing health care assistants under the supervision of district nurses appears to support patients and family at home during end of life care and contribute to good quality nursing care. RELEVANCE TO CLINICAL PRACTICE: The needs for community-based palliative and end of life care will increase rapidly over the course of the next 20 years, placing pressure on community nursing services and family carers. PMID- 21320221 TI - Predictors of health-related quality of life in a sample of children and adolescents: a school survey. AB - AIM: The aim is to study the health-related quality of life in a school sample of children and adolescents aged 8-18 years and to examine the relationship between health-related quality of life and the following variables; age, gender, perceived pain, body image, body mass index and bullying. BACKGROUND: The study of health-related quality of life in children and adolescents have received little attention compared with adults in health care research and still little is known about the associations between health-related quality of life and other variables. DESIGN: A cross-sectional design was chosen. METHOD: We measured the health-related quality of life using the generic questionnaire KIDSCREEN-10. We administered the KIDSCREEN 52-item, and the 10 items were selected from this according to the KIDSCREEN manual. Multilevel regression models were used to evaluate the associations between health-related quality of life and the independent variables. RESULTS: The sample included 1066 children and adolescents, 576 girls and 490 boys, with a response rate of 74%. The results show that body mass index was not significant associated with health-related quality of life in full model. However, in addition to age, being bullied, pain and body image were significant associated with health-related quality of life. Of these predictors, body image has the strongest impact in terms of explained variance in health-related quality of life. CONCLUSION: The subjective sense of satisfaction or dissatisfaction with one's body, perceived body image, is a powerful predictor of health-related quality of life. RELEVANCE TO CLINICAL PRACTICE: Knowledge about predictors of health-related quality of life is especially important for public health nurses. Health promotion and intervention programmes that aim to strengthen psychosocial well-being, especially those that strengthen body image, should be developed for both genders. PMID- 21320222 TI - Memory consolidation in insomnia patients: first steps towards understanding a complex issue. PMID- 21320223 TI - Neuropsychological effects of second language exposure in Down syndrome. AB - BACKGROUND: While it has been common practice to discourage second language learning in neurodevelopmental disorders involving language impairment, little is known about the effects of second language exposure (SLE) on broader cognitive function in these children. Past studies have not found differences on language tasks in children with Down syndrome (DS) and SLE. We expand on this work to determine the effects on the broader cognitive profile, including tests tapping deficits on neuropsychological measures of prefrontal and hippocampal function. METHOD: This study examined the specific cognitive effects of SLE in children with DS (aged 7-18 years). Children with SLE (n = 13: SLE predominantly Spanish) and children from monolingual homes (n = 28) were assessed on a standardised battery of neuropsychological tests developed for DS, the Arizona Cognitive Test Battery. The current exposure level to a language other than English in the SLE group was greater than 4 h per day on average. RESULTS: No group differences were observed for any outcome, and level of exposure was also not linearly related to neuropsychological outcomes, several of which have been shown to be impaired in past work. CONCLUSION: There were no measurable effects of SLE on neuropsychological function in this sample of children with DS. Potential clinical implications of these findings are discussed. PMID- 21320224 TI - Alcohol control policy: evidence-based medicine versus evidence-based marketing. PMID- 21320225 TI - Agonist substitution for high-dose benzodiazepine-dependent patients: let us not forget the importance of flumazenil. PMID- 21320226 TI - Pill content, dose and resulting plasma concentrations of 3,4 methylendioxymethamphetamine (MDMA) in recreational 'ecstasy' users. AB - AIMS: To improve our understanding of the pharmacology of 'ecstasy' in recreational environments; in particular, to describe the composition of ecstasy pills, patterns of ecstasy use and the relationship between dose of 3,4 methylendioxymethamphetamine (MDMA) and resulting plasma concentrations. DESIGN, SETTING AND PARTICIPANTS: A naturalistic observational study of 56 experienced 'ecstasy' users in recreational settings in Australia. MEASUREMENTS: Drug use patterns (number of pills consumed, other drugs consumed). drug content of pills and resultant plasma concentrations of MDMA and related drugs were assessed by gas chromatography/mass spectrometry (GC/MS). FINDINGS: Ecstasy pills generally contained MDMA, but this was often combined with other drugs such as 3,4 ethylendioxyethylamphetamine (MDEA) and methamphetamine. The dose of MDMA per pill ranged from 0 to 245 mg and users consumed from one-half to five pills, with the total dose consumed ranging up to 280 mg. Plasma concentrations of MDMA increased with number of pills consumed and cumulative MDMA dose. Use of larger numbers of pills was associated with extended exposure to the drug. CONCLUSIONS: MDMA is the major active drug in ecstasy pills, but there is a high degree of variation in doses. Use of multiple pills over the course of one session is common and results in a sustained increase in MDMA plasma concentrations over a number of hours. This is likely to lead to a much greater exposure of the brain to MDMA than would be predicted from controlled single-dose pharmacokinetic studies. PMID- 21320227 TI - Employment-based reinforcement of adherence to depot naltrexone in unemployed opioid-dependent adults: a randomized controlled trial. AB - AIMS: Naltrexone can be used to treat opioid dependence, but patients refuse to take it. Extended-release depot formulations may improve adherence, but long-term adherence rates to depot naltrexone are not known. This study determined long term rates of adherence to depot naltrexone and whether employment-based reinforcement can improve adherence. DESIGN: Participants who were inducted onto oral naltrexone were assigned randomly to contingency (n = 18) or prescription (n = 17) groups. Participants were offered six depot naltrexone injections and invited to work at the therapeutic workplace on week days for 26 weeks, where they earned stipends for participating in job skills training. Contingency participants were required to accept naltrexone injections to maintain workplace access and to maintain maximum pay. Prescription participants could work independently of whether they accepted injections. SETTING: The therapeutic workplace, a model employment-based intervention for drug addiction and unemployment. PARTICIPANTS: Opioid-dependent unemployed adults. MEASUREMENTS: Depot naltrexone injections accepted and opiate-negative urine samples. FINDINGS: Contingency participants accepted significantly more naltrexone injections than prescription participants (81% versus 42%), and were more likely to accept all injections (66% versus 35%). At monthly assessments (with missing urine samples imputed as positive), the groups provided similar percentages of samples negative for opiates (74% versus 62%) and for cocaine (56% versus 54%). Opiate-positive samples were more likely when samples were also positive for cocaine. CONCLUSIONS: Employment-based reinforcement can maintain adherence to depot naltrexone. Future research should determine whether persistent cocaine use compromises naltrexone's effect on opiate use. Workplaces may be useful for promoting sustained adherence to depot naltrexone. PMID- 21320228 TI - Deviant socialization mediates transmissible and contextual risk on cannabis use disorder development: a prospective study. AB - AIMS: This study examined the contribution of transmissible risk, in conjunction with family and peer contextual factors during childhood and adolescence, on the development of cannabis use disorder in adulthood. DESIGN: The family high-risk design was used to recruit proband fathers with and without substance use disorder and track their sons longitudinally from late childhood to adulthood. SETTING: The families were recruited under the aegis of the Center for Education and Drug Abuse Research in Pittsburgh, Pennsylvania. PARTICIPANTS: The oldest son in the family was studied at ages 10-12, 16, 19 and 22 years. MEASUREMENTS: The transmissible liability index (TLI), along with measures of quality of the parent child relationship, cooperative behavior at home, social attitudes and peer milieu were administered to model the developmental pathway to cannabis use disorder. FINDINGS: Affiliation with socially deviant peers and harboring non normative attitudes (age 16) mediate the association between transmissible risk for substance use disorder (SUD) (age 10-12) and use of illegal drugs (age 19), leading to cannabis use disorder (age 22). CONCLUSIONS: Deviant socialization resulting from transmissible risk and poor parent-child relationship is integral to development of cannabis use disorder in young adulthood. PMID- 21320229 TI - Comorbid psychiatric disorders and nicotine dependence in adolescence. AB - AIMS: To examine bidirectional influences of onset of psychiatric disorders and nicotine dependence among adolescent smokers. DESIGN: A prospective longitudinal cohort of adolescents and mothers drawn from a large city school system. Adolescents were interviewed five times and mothers three times over 2 years. SETTING: Chicago, Illinois. PARTICIPANTS: Subsample of adolescent smokers (n = 814). MEASUREMENTS: Selected DSM-IV psychiatric disorders, nicotine dependence and selected risk factors were ascertained. FINDINGS: Among lifetime smokers, 53.7% experienced at least one nicotine dependence criterion; 26.1% full dependence; 14.1% experienced an anxiety disorder, 18.8% a mood disorder and 29.5% a disruptive disorder. Nicotine dependence and psychiatric disorders were comorbid: nicotine-dependent youths had higher rates of individual and multiple disorders than those not dependent. Controlling for other covariates, mood disorder and nicotine dependence did not predict each other; anxiety disorder predicted nicotine dependence. Bidirectional influences were observed for disruptive disorder and nicotine dependence. Predictors of onset of full nicotine dependence included earlier onset age of tobacco use, high initial pleasant sensitivity to tobacco, alcohol and illicit drug use, abuse and dependence and parental nicotine dependence. Predictors of psychiatric disorder onset included gender, race/ethnicity, other psychiatric disorders, illicit drug abuse or dependence and parental depression and delinquency. CONCLUSIONS: Initial pleasant experiences of smoking are predictive of later development of nicotine dependence. There may be reciprocal influences between disruptive disorder and development of nicotine dependence in adolescence, and intergenerational transmission of parental nicotine dependence and psychopathology. PMID- 21320230 TI - Staff regard towards working with substance users: a European multi-centre study. AB - AIMS: To compare regard for working with different patient groups (including substance users) among different professional groups in different health-care settings in eight European countries. DESIGN: A multi-centre, cross-sectional comparative study. SETTING: Primary care, general psychiatry and specialist addiction services in Bulgaria, Greece, Italy, Poland, Scotland, Slovakia, Slovenia and Spain. PARTICIPANTS: A multi-disciplinary convenience sample of 866 professionals (physicians, psychiatrists, psychologists, nurses and social workers) from 253 services. MEASUREMENTS: The Medical Condition Regard Scale measured regard for working with different patient groups. Multi-factor between subjects analysis of variance determined the factors associated with regard for each condition by country and all countries. FINDINGS: Regard for working with alcohol (mean score alcohol: 45.35, 95% CI 44.76, 45.95) and drug users (mean score drugs: 43.67, 95% CI 42.98, 44.36) was consistently lower than for other patient groups (mean score diabetes: 50.19, 95% CI 49.71, 50.66; mean score depression: 51.34, 95% CI 50.89, 51.79) across all countries participating in the study, particularly among staff from primary care compared to general psychiatry or specialist addiction services (P<0.001). After controlling for sex of staff, profession and duration of time working in profession, treatment entry point and country remained the only statistically significant variables associated with regard for working with alcohol and drug users. CONCLUSIONS: Health professionals appear to ascribe lower status to working with substance users than helping other patient groups, particularly in primary care; the effect is larger in some countries than others. PMID- 21320231 TI - Developmental pharmacology; filling one knowledge gap in pediatric anesthesiology. PMID- 21320232 TI - Microassay of drugs and modern measurement techniques. AB - Details of the development of conventional analytical methods for the determination of drugs in pediatric plasma/serum samples via microassays are presented. Examples of the development of small-volume sampling and the use of the newer detection systems such as LC/MS/MS for enhanced detection are presented. Dried blood spot sampling has conventionally been used for the study of inborn errors of metabolism using Guthrie cards. Limited applications in the area of drug-level determination, for example, in therapeutic drug monitoring had been reported but the methodology had not been widely used up until relatively recently. In the last few years, there has been a resurgence of interest in this methodology for drug-level determinations, and examples of drug analysis in pediatric and neonatal patients where the small-volume samples are particularly useful are presented. The application of the methodology in pharmacokinetic/pharmacodynamic studies is discussed. The utilization of solid phase microextraction and stir bar sorptive extraction in drug analysis is presented. Clinical applications of these methodologies are reported including the development of in vivo solid-phase microextraction. PMID- 21320233 TI - Tips and traps analyzing pediatric PK data. AB - Pharmacokinetic (PK) and pharmacodynamic (PD) modeling has elucidated aspects of developmental pharmacology of value to the anesthetic community. The increasing sophistication of modeling techniques is associated with pitfalls that may not be readily apparent to readers or investigators. While size and age are considered primary covariates for PK models, the impact of birth on clearance maturation is poorly documented, dose in obese children is poorly investigated, pharmacologic implications of physiologic changes poorly portrayed, disease progression on drug response poorly depicted and the impact of metabolites on effect poorly illustrated. This review identifies some of these pitfalls and suggests ideas to circumvent or investigate these hazards. PMID- 21320234 TI - Developmental pharmacogenomics. AB - Interindividual variability in the disposition and action associated with similar doses of a given medication is an inherent characteristic of both adult and pediatric populations. Genotype-phenotype relationships in infants and children must take into account the role that ontogeny plays in producing variability in both pharmacokinetics and pharmacodynamics. This review explores pharmacogenomics in the context of ontogeny and relates these to the expression of drug metabolizing enzymes and transporters and the consequent effect on the exposure response relationship in the early years of life. PMID- 21320235 TI - Predicting weight using postmenstrual age--neonates to adults. AB - OBJECTIVES: To describe the pattern and variability of body weight with postmenstrual age (PMA) using nonlinear mixed effect modeling and to create a single mathematical function that can be used from prematurity to adulthood. BACKGROUND: PMA has been shown to predict functional properties of humans such as glomerular filtration rate and drug clearance. Widely used growth charts use postnatal age to predict weight in an idealized population and are not available as a mathematical function. METHODS: We modeled 7164 body weight and PMA observations from a pooled database of 5031 premature neonates, infants, children, and adults. All subjects were participants in pharmacokinetic or renal function studies. PMA ranged from 23 weeks to 82 years. A mixed effect model was used to describe fixed (PMA, sex) and random between-subject variability. RESULTS: A model based on the sum of three sigmoid hyperbolic and one exponential functions described the data. Females were typically 12% lighter in weight. Part of the between-subject variability in weight decreased exponentially with a half life of 3.5 PMA years, while the remainder stayed a constant fraction of the weight asymptote for each of the four functions. CONCLUSIONS: The change of weight with PMA and sex can be described with a simple equation. This is suitable for simulation of typical weight-age distributions and may be useful for evaluation of appropriate weight for age in children requiring medical treatment. PMID- 21320237 TI - Marathon of eponyms: 16 Paget disease of bone. AB - The use of eponyms has long been contentious, but many remain in common use, as discussed elsewhere (Editorial: Oral Diseases. 2009: 15; 185). The use of eponyms in diseases of the head and neck is found mainly in specialties dealing with medically compromised individuals (paediatric dentistry, special care dentistry, oral and maxillofacial medicine, oral and maxillofacial pathology, oral and maxillofacial radiology and oral and maxillofacial surgery) and particularly by hospital-centred practitioners. This series has selected some of the more recognised relevant eponymous conditions and presents them alphabetically. The information is based largely on data available from MEDLINE and a number of internet websites as noted below: the authors would welcome any corrections. This document summarises data about Paget disease of bone. PMID- 21320238 TI - Effects of octreotide on jejunal hypersensitivity triggered by Cryptosporidium parvum intestinal infection in an immunocompetent suckling rat model. AB - BACKGROUND: Similar to other bacterial or protozoan infections, human cryptosporidiosis may trigger postinfectious irritable bowel syndrome (IBS)-like symptoms, a condition in which enhanced visceral perception of pain during intestinal distension plays a pivotal role. In an immunocompetent suckling rat model which mimicks features of postinfectious IBS, Cryptosporidium parvum infection induces long-lasting jejunal hypersensitivity to distension in association with intestinal activated mast cell accumulation. The aim of the present study was to explore in this model whether octreotide, a somatostatin agonist analog, could prevent the development of jejunal hypersensitivity and intestinal mast cell/nerve fiber accumulation. METHODS: Five-day-old Sprague Dawley rats were infected with C. parvum and treated 10 days later with octreotide (50 g kg(-1) day(-1), i.p.) for 7 days. KEY RESULTS: Compared with untreated infected rats, octreotide treatment of infected rats resulted in increased weight gain [day 23 postinfection (PI)], decreased food intake (day 16 PI), and a reduction in jejunal villus alterations (day 14 PI), CD3(+) IEL (day 37 PI) and mast cell (days 37 and 50 PI) accumulations, nerve fiber densities (day 50 PI), and hypersensitivity to distension (day 120 PI). In uninfected rats, the effects of octreotide treatment were limited to higher weight gain (days 16 and 23 PI) and decreased food intake (day 23 PI) compared with uninfected untreated rats. CONCLUSIONS & INFERENCES: Data confirms the relevance of the present rat model to postinfectious IBS studies and prompt further investigation of somatostatin-dependent regulatory interactions in cryptosporidiosis. PMID- 21320236 TI - Aging and gastrointestinal neuromuscular function: insights from within and outside the gut. PMID- 21320239 TI - Development and psychometric evaluation of the German version of the Medication Regimen Complexity Index (MRCI-D). AB - BACKGROUND: Several factors contribute to the complexity of pharmacotherapeutic regimens, like the total number of medications to be taken, the number of dosage units to take at a time, dosage frequency, as well as specific directions concerning the administration. The Medication Regimen Complexity Index (MRCI) is a validated instrument developed in English for the measurement of the complexity of a given pharmacotherapeutic regimen. OBJECTIVES: Translation of the MRCI into German and evaluation of the translated instrument (MRCI-D) in order to make it more easily accessible for use in German practice and research. METHODS: The process of validation included the translation of the English version to German, back-translation into English, comparison of the back-translated and the original versions, pre-tests, and pilot-testing of the German version by three raters using 20 medication regimens for inpatients. The subsequent psychometric evaluation included the calculation of inter-rater and test-retest reliability, as well as the assessment of convergent validity. RESULTS: The number of medications correlated highly and statistically significantly with the MRCI-D score (0.91, P < 0.001), indicating sufficient convergent validity of the instrument. Both inter-rater and test-retest reliability were very high (intraclass correlation coefficients above 0.80 in all cases). CONCLUSION: Our results demonstrate that the German version of the MRCI reflects the complexity of therapeutic regimens with similar validity and reliability as the established English version. Thus, it may be a valuable tool to analyse therapeutic regimens in both clinical practice and science. PMID- 21320240 TI - Factors associated with patient and health care system delay in diagnosis and treatment for TB in sub-Saharan African countries with high burdens of TB and HIV. AB - OBJECTIVE: To identify factors causing delayed diagnosis and treatment for tuberculosis in high tuberculosis (TB)/HIV burden African countries. METHODS: We searched Ovid Medline, CINAHL, PsychInfo, Scopus and Sabinet-South African journals and reference lists, Google, Google Scholar and Google SA for reports in English, >=1992, of original data from sub-Saharan countries on patient or system delay in TB diagnosis or treatment with populations >=15 years old. Two reviewers extracted data independently for each study. We categorized independent variables as predisposing, enabling or reinforcing (PRECEDE model). Meta-analysis was conducted for factors associated with delay in >=2 studies. RESULTS: Of 20 eligible studies, 12 assessed both sources of delay; 1, system delay; and 7, patient delay only. Most were cross-sectional surveys (k = 13) with samples of consecutive patients (k = 13) and bivariate analyses (k = 11). Starting and endpoints for patient delay were consistent, but not system delay. Patient characteristics were studied frequently; HIV stigma and enabling factors were studied infrequently, although the last were most often associated with delay. Consulting traditional healers first--usually by rural residents--consistently led to patient delay; OR = 3.45 (1.91-6.21). Travel time for the return visit was consistently associated with system delay OR = 1.87 (1.378-2.531). CONCLUSIONS: We recommend partnerships with traditional healers and research emphasizing HIV and system factors, standard definitions of delay and qualitative and cohort studies to identify enabling and reinforcing factors related to delay. PMID- 21320241 TI - Dengue transmission in the Asia-Pacific region: impact of climate change and socio-environmental factors. AB - OBJECTIVE: To review the scientific evidence about the impact of climate change and socio-environmental factors on dengue transmission, particularly in the Asia Pacific region. METHODS: Search of the published literature on PubMed, ISI web of Knowledge and Google Scholar. Articles were included if an association between climate or socio-environmental factors and dengue transmission was assessed in any country of the Asia-Pacific region. RESULTS: Twenty-two studies met the inclusion criteria. The weight of the evidence indicates that global climate change is likely to affect the seasonal and geographical distribution of dengue fever (DF) in the Asia-Pacific region. However, empirical evidence linking DF to climate change is inconsistent across geographical locations and absent in some countries where dengue is endemic. CONCLUSION: Even though climate change may play an increasing role in the transmission of DF, no clear evidence shows that such impact has already occurred. More research is needed across countries to better understand the relationship between climate change and dengue transmission. Future research should also consider and adjust for the influence of important socio-environmental factors in the assessment of the climate change related effects on dengue transmission. PMID- 21320242 TI - Millennium development goals and the water target: details, definitions and debate. AB - One of the primary targets of MDG 7, dealing with issues of environmental sustainability, is to halve by 2015 (from 1990 levels) the proportion of the population without sustainable access to safe drinking water and basic sanitation. It is undoubtedly difficult to summarise a complex target such as access to water or safety of water source in a single quantifiable indicator. However, in our opinion, the indicators used to estimate how much of the population has 'access' to 'safe' drinking water leave out some important elements that should be taken into account when determining whether the goals have been met. In addition, the authors propose a modification to Bradley's classification of water-related illness to include a category for waterborne diseases of a non-infectious aetiology. PMID- 21320243 TI - Use of an HRP2-based rapid diagnostic test to guide treatment of children admitted to hospital in a malaria-endemic area of north-east Tanzania. AB - OBJECTIVE: To compare the performance of the ParacheckTM rapid diagnostic test (RDT) with microscopy for diagnosing malaria in hospitalised children. METHODS: Children aged between 2 months and 13 years with fever were enrolled in the study over 1 year. A standard clinical history and examination were recorded and blood drawn for culture, complete blood count, ParacheckTM RDT and double-read blood slide. RESULTS: Of 3639 children enrolled, 2195 (60.3%) were slide positive. The sensitivity and specificity of Paracheck were 97.5% (95% CI 96.9-98.0) and 65.3% (95% CI 63.8-66.9), respectively. There was an inverse relationship between age specific prevalence of parasitaemia and Paracheck specificity. In logistic regression model, false-positive Paracheck results were significantly associated with pre-admission use of antimalarial drug (OR 1.44, 95% CI 1.16-1.78), absence of current fever (OR 0.64, 95% CI 0.52-0.79) and non-typhi Salmonella bacteraemia (OR 3.89. 95% CI 2.27-6.63). In spite of high sensitivity, 56/2195 (2.6%) of true infections were Paracheck negative and 8/56 (14.3%) were in patients with >50,000 parasites/MUl. CONCLUSIONS: Paracheck had poor specificity in diagnosing malaria in severely ill children; this was likely to be due to HRP2 persistence following recent parasite clearance. The combination of positive Paracheck and negative blood slide results identified a group of children at high risk of non-typhi Salmonella infection. While Paracheck was highly sensitive, some high-density infections were missed. For children with severe febrile illness, at least two reliable negative parasitological test results should be available to justify withholding antimalarial treatment; the optimal choice of these has yet to be identified. PMID- 21320244 TI - Risk factors for non-communicable diseases among older adults in rural Africa. AB - OBJECTIVE: To expand the evidence base on the prevalence of non-communicable disease (NCD) risk factors in rural Africa, in particular among older adults aged 50 and older. METHODS: Cross-sectional study in three rural sites in Malawi, Rwanda and Tanzania. One person was interviewed from each of 665 households selected through a stratified random sampling procedure across the three sites. The questionnaire included socio-demographic characteristics, smoking and alcohol intake as well as a food frequency questionnaire. RESULTS: Smoking rates among older men and women were higher than among adults under 50. While only 2.3% of women under 50 were current smokers, 21.0% of older women smoked (P<0.0001). Among men, 19.0% of men under 50 smoked versus 36.6% of older men (P=0.001). Alcohol consumption among older women aged 50 and older (45.0%) was more common (P=0.005) than among women under 50 (27.6%). Examining a set of five risk factors, more men aged 50 and older (49.5%) had two or more risk factors than men under 50 (25.5%) (P<0.0001). Similarly, 52.0% of women aged 50 and older had two or more risk factors, versus 24.1% of women under 50 (P<0.0001). CONCLUSION: Contrary to what is seen in developed country settings, this study reveals high rates of smoking and alcohol consumption among men and women aged 50 years and older in rural Africa that puts them at risk of NCDs. The health of older adults in rural Africa has been neglected, and these findings highlight the importance of reaching out to older adults with messaging regarding diet, smoking, alcohol use and general health. PMID- 21320245 TI - Tracking progress towards safe motherhood: meeting the benchmark yet missing the goal? An appeal for better use of health-system output indicators with evidence from Zambia and Sri Lanka. AB - OBJECTIVES: Indicators of health-system outputs, such as Emergency Obstetric Care (EmOC) density, have been proposed for monitoring progress towards reducing maternal mortality, but are currently underused. We seek to promote them by demonstrating their use at subnational level, evaluating whether they differentiate between a high-maternal-mortality country (Zambia) and a low maternal-mortality country (Sri Lanka) and assessing whether benchmarks are set at the right level. METHODS: We compared national and subnational density of health facilities, EmOC facilities and health professionals against current benchmarks for Zambia and Sri Lanka. For Zambia, we also examined geographical accessibility by linking health facility data to population data. RESULTS: Both countries performed similarly in terms of EmOC facility density, implying this indicator, as currently used, fails to discriminate between high- and low maternal-mortality settings. In Zambia, the WHO benchmarks for doctors/midwives were met overall, but distribution between provinces was highly unequal. Sri Lanka overshot the suggested benchmarks by three times for midwives and over 30 times for doctors. Geographical access in Zambia--which is much less densely populated than Sri Lanka--was poor, less than half the population lived within 15 km of an EmOC facility. CONCLUSIONS: Current health-system output indicators and benchmarks on EmOC need revision to enhance discriminatory power and should be adapted for different population densities. Subnational disaggregation and assessing geographical access can identify gaps in EmOC provision and should be routinely considered. Increased use of an improved set of output indicators is crucial for guiding international efforts towards reducing maternal mortality. PMID- 21320246 TI - Cryptosporidiosis: a rare and severe infection in a pediatric renal transplant recipient. AB - Cryptosporidium is an intracellular protozoan parasite that causes gastroenteritis in human. In immunocompromised individuals, cryptosporidium causes far more serious disease. There is no effective specific therapy for cryptosporidiosis, and spontaneous recovery is the rule in healthy individuals. However, immunocompromised patients need effective and prolonged therapy. Here, we present our clinical experience in a six-yr-old boy who underwent living related donor renal transplantation and who was infected with Cryptosporidium spp. Our patient was successfully treated with antimicrobial agents consisting of spiramycin, nitazoxanide, and paromomycin. At the end of second week of therapy, his stool became negative for Cryptosporidium spp. antigen and spiramycin was discontinued. Nitazoxanide and paromomycin treatment was extended to four wk. With this case, we want to emphasize that cryptosporidiosis should be considered in the differential diagnosis of severe or persistent diarrhea in solid organ transplant recipients where rigorous antimicrobial therapy is needed. PMID- 21320247 TI - Extraperitoneal renal transplantation in small children results in a transient improvement in early graft function. AB - Renal transplantation is considered more technically challenging in small children compared to adults, especially when live donor adult kidneys are used. Transplanted kidneys have traditionally been placed intraperitoneally, although over the last decade extraperitoneal positioning has been attempted. The aim of this study was to establish whether there is a difference in kidney function and outcome dependent on the surgical approach to transplantation. The medical notes of all children under the age of six who received a renal transplant at our unit between January 1998 and October 2009 were reviewed. Demographic data, operation details, HLA mismatch, immunosuppression regime, complications, and function of the graft were analyzed. A total of 30 transplants were performed in children under six yr of age. The one-yr patient and graft survival were 97% and 93%, respectively. Eighteen were undertaken via an intraperitoneal approach, with the remaining being placed extraperitoneally. There were no significant differences in the number of complications observed between the two groups, and median length of stay was comparable (extraperitoneal 19.5 days vs. intraperitoneal 20.5 days). The plasma creatinine values for the two groups were compared using multivariate linear regression analysis and adjusted for age, weight, gender and baseline plasma creatinine. Between days 2 and 14 post-operatively, there was a significant difference in absolute plasma creatinine between the two surgical approaches. However, the trend of change in mean plasma creatinine values over time did not differ significantly between the two groups. Extraperitoneal kidney transplantation in small children is safe and technically feasible. From our series, there appears to be early improved function, although there is no long term difference in function between approaches. PMID- 21320248 TI - A quantitative meta-analysis of fMRI studies in bipolar disorder. AB - OBJECTIVES: Functional magnetic resonance imaging (fMRI) has been widely used to identify state and trait markers of brain abnormalities associated with bipolar disorder (BD). However, the primary literature is composed of small-to-medium sized studies, using diverse activation paradigms on variously characterized patient groups, which can be difficult to synthesize into a coherent account. This review aimed to synthesize current evidence from fMRI studies in midlife adults with BD and to investigate whether there is support for the theoretical models of the disorder. METHODS: We used voxel-based quantitative meta-analytic methods to combine primary data on anatomical coordinates of activation from 65 fMRI studies comparing normal volunteers (n = 1,074) and patients with BD (n = 1,040). RESULTS: Compared to normal volunteers, patients with BD underactivated the inferior frontal cortex (IFG) and putamen and overactivated limbic areas, including medial temporal structures (parahippocampal gyrus, hippocampus, and amygdala) and basal ganglia. Dividing studies into those using emotional and cognitive paradigms demonstrated that the IFG abnormalities were manifest during both cognitive and emotional processing, while increased limbic activation was mainly related to emotional processing. In further separate comparisons between healthy volunteers and patient subgroups in each clinical state, the IFG was underactive in manic but not in euthymic and depressed states. Limbic structures were not overactive in association with mood states, with the exception of increased amygdala activation in euthymic states when including region-of interest studies. CONCLUSIONS: In summary, our results showed abnormal frontal limbic activation in BD. There was attenuated activation of the IFG or ventrolateral prefrontal cortex, which was consistent across emotional and cognitive tasks and particularly related to the state of mania, and enhanced limbic activation, which was elicited by emotional and not cognitive tasks, and not clearly related to mood states. PMID- 21320249 TI - Structural brain and neuropsychometric changes associated with pediatric bipolar disorder with psychosis. AB - OBJECTIVES: To identify neuropsychological and structural brain changes using a combination of high-resolution structural and diffusion tensor imaging in pediatric bipolar disorder (PBD) with psychosis (presence of delusions and or hallucinations). METHODS: We recruited 15 patients and 20 euthymic age- and gender-matched healthy controls. All subjects underwent high-resolution structural and diffusion tensor imaging. Voxel-based morphometry (VBM), tract based spatial statistics (TBSS), and probabilistic tractography were used to analyse magnetic resonance imaging data. RESULTS: The PBD subjects had normal overall intelligence with specific impairments in working memory, executive function, language function, and verbal memory. Reduced gray matter (GM) density was found in the left orbitofrontal cortex, left pars triangularis, right premotor cortex, occipital cortex, right occipital fusiform gyrus, and right crus of the cerebellum. TBSS analysis showed reduced fractional anisotropy (FA) in the anterior corpus callosum. Probabilistic tractography from this cluster showed that this region of the corpus callosum is connected with the prefrontal cortices, including those regions whose density is decreased in PBD. In addition, FA change was correlated with verbal memory and working memory, while more widespread reductions in GM density correlated with working memory, executive function, language function, and verbal memory. CONCLUSIONS: The findings suggest widespread cortical changes as well as specific involvement of interhemispheric prefrontal tracts in PBD, which may reflect delayed myelination in these tracts. PMID- 21320250 TI - A population-based morphometric MRI study in patients with first-episode psychotic bipolar disorder: comparison with geographically matched healthy controls and major depressive disorder subjects. AB - OBJECTIVES: Many morphometric magnetic resonance imaging (MRI) studies that have investigated the presence of gray matter (GM) volume abnormalities associated with the diagnosis of bipolar disorder (BD) have reported conflicting findings. None of these studies has compared patients with recent-onset psychotic BD with asymptomatic controls selected from exactly the same environment using epidemiological methods, or has directly contrasted BD patients against subjects with first-onset psychotic major depressive disorder (MDD). We examined structural brain differences between (i) BD (type I) subjects and MDD subjects with psychotic features in their first contact with the healthcare system in Brazil, and (ii) these two mood disorder groups relative to a sample of geographically matched asymptomatic controls. METHODS: A total of 26 BD subjects, 20 subjects with MDD, and 94 healthy controls were examined using either of two identical MRI scanners and acquisition protocols. Diagnoses were based on DSM-IV criteria and confirmed one year after brain scanning. Image processing was conducted using voxel-based morphometry. RESULTS: The BD group showed increased volume of the right dorsal anterior cingulate cortex relative to controls, while the MDD subjects exhibited bilateral foci GM deficits in the dorsolateral prefrontal cortex (p < 0.05, corrected for multiple comparisons). Direct comparison between BD and MDD patients showed a focus of GM reduction in the right-sided dorsolateral prefrontal cortex (p < 0.05, corrected for multiple comparisons) and a trend (p < 0.10, corrected) toward left-sided GM deficits in the dorsolateral prefrontal cortex of MDD patients. When analyses were repeated with scanner site as a confounding covariate the finding of increased right anterior cingulate volumes in BD patients relative to controls remained statistically significant (p=0.01, corrected for multiple comparisons). CONCLUSIONS: These findings reinforce the view that there are important pathophysiological distinctions between BD and MDD, and indicate that subtle dorsal anterior cingulate abnormalities may be relevant to the pathophysiology of BD. PMID- 21320251 TI - Bcl-2 SNP rs956572 associates with disrupted intracellular calcium homeostasis in bipolar I disorder. AB - OBJECTIVES: Disrupted intracellular calcium (Ca(2+) ) homeostasis (ICH) related to mitochondrial and/or endoplasmic reticulum (ER) dysfunction has been implicated in bipolar disorder (BD). The anti-apoptotic protein B-cell CLL/lymphoma 2 (Bcl-2), encoded in a putative BD susceptibility locus, modulates ER-Ca(2+) dynamics. Recently, an intronic single-nucleotide polymorphism (SNP) in the Bcl-2 gene, rs956572, was suggested as a functionally active SNP that influences its messenger RNA (mRNA) and protein level as well as human gray matter volume. We sought to evaluate the impact of this variant on ICH in BD. METHODS: Basal intracellular Ca(2+) concentrations ([Ca(2+) ](B) ) and rs956572 genotypes were determined in B lymphoblast cell lines (BLCLs) from bipolar I disorder (BD-I) (n=150), bipolar II disorder (BD-II) (n=65), and major depressive disorder (n=30) patients, and from healthy subjects (n=70). Bcl-2 mRNA and protein levels were determined by quantitative reverse transcriptase polymerase chain reaction and immunoblotting, respectively. Functional interactions of rs956572 with ICH were assessed by thapsigargin- and lysophosphatidic acid (LPA) stimulated Ca(2+) responses. RESULTS: Although rs956572 variation was not significantly associated with BD, BD-I, or BD-II, BLCL [Ca(2+) ](B) was significantly higher in BD-I G/G patients compared with other genotypes and with healthy subjects. Bcl-2 mRNA and protein levels were lowest in BD-I G/G patients. Compared with A carriers, BD-I patients with G/G variants showed a modest enhancing effect on thapsigargin- and LPA-stimulated Ca(2+) responses. CONCLUSIONS: These findings support the notion that genetic variation in Bcl-2 affecting its expression impacts ICH in BD. Moreover, we show here for the first time that this interactive effect is diagnostically specific to BD-I. PMID- 21320252 TI - Markers of gluten sensitivity and celiac disease in bipolar disorder. AB - OBJECTIVES: Increased immune sensitivity to dietary gluten proteins has been reported in schizophrenia but has not been studied in bipolar disorder. In this study, we examine the levels of antibody reactivity to gliadin, deamidated gliadin, and tissue transglutaminase (tTG) in individuals with bipolar disorder and compare these levels to those in individuals who do not have any history of psychiatric disorder. METHODS: The sample of 275 individuals included 102 with bipolar disorder and 173 controls without a psychiatric disorder. Immunoglobulin G (IgG) and immunoglobulin A (IgA) antibodies to gliadin and tTG and IgG antibodies to deamidated gliadin were measured by enzyme immunoassay. Participants' levels of antibodies to deamidated gliadin and tTG were classified based on the cutoffs for positivity that are predictive of celiac disease. Quantitative levels of antibodies were compared between groups employing regression models which were controlled for demographic variables. RESULTS: Individuals with bipolar disorder had increased levels of IgG antibodies to gliadin compared with controls in multivariate analyses. We also found evidence of increased levels of antibodies to deamidated gliadin in the bipolar disorder population. The levels of IgA class antigliadin antibodies and antibodies to tTG did not differ significantly between groups. There was also not a significant difference between groups in the number of persons who were classified as having levels of antibodies to deamidated gliadin or tTG that are predictive of celiac disease. CONCLUSIONS: Individuals with bipolar disorder have increased levels of IgG antibodies to gliadin. However, such antibody increase is not accompanied by an elevation in IgA antibodies to gliadin or the celiac disease-associated antibodies against deamidated gliadin and tTG. These results warrant further detailed examination of the molecular specificity and pattern of reactivity of the antibody response to gluten antigens in bipolar disorder. PMID- 21320253 TI - Pain and rejection sensitivity in bipolar depression. AB - OBJECTIVES: Little is known regarding the correlates of pain in bipolar disorder. Recent neuroimaging studies support the contention that depression, as well as pain distress and rejection distress, share the same neurobiological circuits. In a recently published study, we confirmed the hypothesis that perception of increased pain during treatment-refractory depression, predominantly unipolar, was related to increased rejection sensitivity. In the present study, we aimed to test this same hypothesis for bipolar depression. METHODS: The present study analysed data from 67 patients presenting to the Black Dog Institute Bipolar Disorders Clinic in Sydney, Australia. The patients all met DSM-IV criteria for bipolar disorder and had completed a self-report questionnaire regarding perceived pain and rejection sensitivity during depression. RESULTS: A significant increase in the experience of headaches (p=0.003) as well as chest pain (p=0.004) during bipolar depression was predicted by a major increase in rejection sensitivity when depressed, i.e., state rejection sensitivity. Being rejection sensitive in general, i.e., trait rejection sensitivity, did not predict pain during depression. CONCLUSIONS: The experience of increased headaches and chest pain during bipolar depression is related to increased rejection sensitivity during depression. Research to further elucidate this relationship is required. PMID- 21320254 TI - Early psychosocial intervention for youth at risk for bipolar I or II disorder: a one-year treatment development trial. AB - OBJECTIVES: Previous studies have identified behavioral phenotypes that predispose genetically vulnerable youth to a later onset of bipolar I or II disorder, but few studies have examined whether early psychosocial intervention can reduce risk of syndromal conversion. In a one-year open trial, we tested a version of family-focused treatment adapted for youth at high risk for bipolar disorder (FFT-HR). METHODS: A referred sample of 13 children (mean 13.4+/-2.69 years; 4 boys, 9 girls) who had a parent with bipolar I or II disorder participated at one of two outpatient specialty clinics. Youth met DSM-IV criteria for major depressive disorder (n=8), cyclothymic disorder (n=1), or bipolar disorder not otherwise specified (n=4), with active mood symptoms in the past month. Participants were offered FFT-HR (12 sessions in four months) with their parents, plus psychotropic medications as needed. Independent evaluators assessed depressive symptoms, hypomanic symptoms, and global functioning at baseline and then every four months for one year, with retrospective severity and impairment ratings made for each week of the follow-up interval. RESULTS: Families were mostly adherent to the treatment protocol (85% retention), and therapists administered the FFT-HR manual with high levels of fidelity. Youth showed significant improvements in depression, hypomania, and psychosocial functioning scores on the Adolescent Longitudinal Interval Follow-up Evaluation. They also showed significant improvements in Young Mania Rating Scale and Children's Depression Rating Scale scores. CONCLUSIONS: FFT-HR is a promising intervention for youth at high risk for BD. Larger-scale randomized trials that follow youth into young adulthood will be necessary to determine whether early psychosocial intervention can reduce the probability of developing bipolar I or II disorder among genetically vulnerable youth. PMID- 21320255 TI - Suicidality in pediatric bipolar disorder: predictor or outcome of family processes and mixed mood presentation? AB - OBJECTIVE: Pediatric bipolar disorder (PBD) involves a potent combination of mood dysregulation and interpersonal processes, placing these youth at significantly greater risk of suicide. We examined the relationship between suicidal behavior, mood symptom presentation, family functioning, and quality of life (QoL) in youth with PBD. METHODS: Participants were 138 youths aged 5-18 years presenting to outpatient clinics with DSM-IV diagnoses of bipolar I disorder (n=27), bipolar II disorder (n=18), cyclothymic disorder (n=48), and bipolar disorder not otherwise specified (n=45). RESULTS: Twenty PBD patients had lifetime suicide attempts, 63 had past or current suicide ideation, and 55 were free of suicide ideation and attempts. Attempters were older than nonattempters. Suicide ideation and attempts were linked to higher depressive symptoms, and rates were even higher in youths meeting criteria for the mixed specifier proposed for DSM-5. Both suicide ideation and attempts were associated with lower youth QoL and poorer family functioning. Parent effects (with suicidality treated as outcome) and child effects (where suicide was the predictor of poor family functioning) showed equally strong evidence in regression models, even after adjusting for demographics. CONCLUSIONS: These findings underscore the strong association between mixed features and suicidality in PBD, as well as the association between QoL, family functioning, and suicidality. It is possible that youths are not just a passive recipient of family processes, and their illness may play an active role in disrupting family functioning. Replication with longitudinal data and qualitative methods should investigate both child and parent effect models. PMID- 21320256 TI - Does stage of illness impact treatment response in bipolar disorder? Empirical treatment data and their implication for the staging model and early intervention. AB - OBJECTIVE: The staging model suggests that early stages of bipolar disorder respond better to treatments and have a more favourable prognosis. This study aims to provide empirical support for the model, and the allied construct of early intervention. METHODS: Pooled data from mania, depression, and maintenance studies of olanzapine were analyzed. Individuals were categorized as having had 0, 1-5, 6-10, or >10 prior episodes of illness, and data were analyzed across these groups. RESULTS: Response rates for the mania and maintenance studies ranged from 52-69% and 10-50%, respectively, for individuals with 1-5 previous episodes, and from 29-59% and 11-40% for individuals with >5 previous episodes. These rates were significantly higher for the 1-5 group on most measures of response with up to a twofold increase in the chance of responding for those with fewer previous episodes. For the depression studies, response rates were significantly higher for the 1-5 group for two measures only. In the maintenance studies, the chance of relapse to either mania or depression was reduced by 40 60% for those who had experienced 1-5 episodes or 6-10 episodes compared to the >10 episode group, respectively. This trend was statistically significant only for relapse into mania for the 1-5 episode group (p=0.005). CONCLUSION: Those individuals at the earliest stages of illness consistently had a more favourable response to treatment. This is consistent with the staging model and underscores the need to support a policy of early intervention. PMID- 21320257 TI - Paced finger-tapping abnormalities in bipolar disorder indicate timing dysfunction. AB - OBJECTIVES: Theoretical and empirical evidence suggests that impaired time perception and the neural circuitry contributing to internal timing mechanisms may contribute to severe psychiatric disorders, including mood disorders. The structures that are involved in subsecond timing, i.e., cerebellum and basal ganglia, have also been implicated in the pathophysiology of bipolar disorder. However, the timing of subsecond intervals has infrequently been studied in this population. METHODS: Paced finger-tapping tasks have been used to characterize internal timing processes in neuropsychiatric disorders. A total of 42 bipolar disorder patients (25 euthymic, 17 manic) and 42 age-matched healthy controls completed a finger-tapping task in which they tapped in time with a paced (500-ms intertap interval) auditory stimulus (synchronization), then continued tapping without auditory input while attempting to maintain the same pace (continuation). This procedure was followed using the dominant index finger, then with alternating thumbs. RESULTS: Bipolar disorder participants showed greater timing variability relative to controls regardless of pacing stimulus (synchronization versus continuation) or condition (dominant index finger versus alternating thumbs). Decomposition of timing variance into internal clock versus motor implementation components using the Wing-Kristofferson model showed higher clock variability in the bipolar disorder groups compared to controls, with no differences between groups on motor implementation variability. CONCLUSIONS: These findings suggest that internal timing mechanisms are disrupted in bipolar disorder patients, independent of symptom status. Increased clock variability in bipolar disorder may be related to abnormalities in cerebellar function. PMID- 21320258 TI - Long-term outcome of bipolar depressed patients receiving lamotrigine as add-on to lithium with the possibility of the addition of paroxetine in nonresponders: a randomized, placebo-controlled trial with a novel design. AB - OBJECTIVE: In two previous manuscripts, we described the efficacy of lamotrigine versus placebo as add-on to lithium (followed by the addition of paroxetine in nonresponders) in the short-term treatment of bipolar depression. In this paper we describe the long-term (68 weeks) outcome of that study. METHODS: A total of 124 bipolar depressed patients receiving lithium were randomized to addition of lamotrigine or placebo. After eight weeks, paroxetine was added to nonresponders for another eight weeks. Responders continued medication and were followed for up to 68 weeks or until a relapse or recurrence of a depressive or manic episode. RESULTS: After eight weeks, the addition of lamotrigine to lithium was significantly more efficacious than addition of placebo, while after addition of paroxetine in nonresponders both groups further improved with no significant difference between groups at week 16. During follow-up the efficacy of lamotrigine was maintained: time to relapse or recurrence was longer for the lamotrigine group [median time 10.0 months (confidence interval: 1.1-18.8)] versus the placebo group [3.5 months (confidence interval: 0.7-7.0)]. CONCLUSION: In patients with bipolar depression, despite continued use of lithium, addition of lamotrigine revealed a continued benefit compared to placebo throughout the entire study. PMID- 21320259 TI - Association of clinical symptoms and neurocognitive performance in bipolar disorder: a longitudinal study. AB - OBJECTIVE: Despite evidence that individuals with bipolar disorder have neurocognitive impairment that persists during euthymia, the impact of changes in affective symptoms on cognitive function has not been well established. Here, we sought to determine whether specific neurocognitive functions are sensitive to mood changes in individuals with bipolar disorder assessed three months apart without changes in treatment regimen. METHODS: A total of 29 individuals with DSM IV bipolar disorder and 30 healthy controls participated in the study. All participants received a comprehensive neuropsychological assessment and ratings of depressive [Hamilton Depression Rating Scale (HAMD)] and manic [Young Mania Rating Scale (YMRS)] symptoms at baseline and follow-up. Changes in symptoms over time were calculated and were examined in relation to changes in neurocognitive performance. RESULTS: At baseline, clinically stable but symptomatic patients were impaired on measures of speed of processing and attention. Over the three month follow-up period, HAMD scores changed by 6 points on average [range: -10 to +18] and YMRS scores changed by 5.31 points on average [range -11 to +15]. Changes in depressive symptoms were correlated with poorer verbal fluency, while no relationship between manic symptoms and neuropsychological performance was detected. CONCLUSIONS: Individuals with bipolar disorder showed consistent impairment on speed of processing and attention over time, despite significant changes in mood. PMID- 21320260 TI - Extinction vulnerability of coral reef fishes. AB - With rapidly increasing rates of contemporary extinction, predicting extinction vulnerability and identifying how multiple stressors drive non-random species loss have become key challenges in ecology. These assessments are crucial for avoiding the loss of key functional groups that sustain ecosystem processes and services. We developed a novel predictive framework of species extinction vulnerability and applied it to coral reef fishes. Although relatively few coral reef fishes are at risk of global extinction from climate disturbances, a negative convex relationship between fish species locally vulnerable to climate change vs. fisheries exploitation indicates that the entire community is vulnerable on the many reefs where both stressors co-occur. Fishes involved in maintaining key ecosystem functions are more at risk from fishing than climate disturbances. This finding is encouraging as local and regional commitment to fisheries management action can maintain reef ecosystem functions pending progress towards the more complex global problem of stabilizing the climate. PMID- 21320261 TI - Predator-driven component Allee effects in a wild ungulate. AB - Negative density dependence is an important driver of population dynamics of large vertebrates. Allee effects (positive density dependence), however, can affect small populations. Allee effects can be generated by predation and recent research has revealed potentially important indirect effects of predation on population dynamics. For wild populations, however, quantification of both Allee effects and indirect effects of predation remains scarce. We monitored for 27 years a bighorn sheep (Ovis canadensis) population that declined dramatically as episodes of cougar (Puma concolor) predation depressed survival. Predation led to a positive relationship between lamb survival and population size below a threshold, and to an overall positive relationship between yearling and adult ewe survival and population size. During years of high predation, lambs also suffer mortality through reduced growth, contributing a third of the total impact of predation on lamb survival. There was no positive association between population growth and population size, probably because growth was affected by several factors other than predation, including disease. Our results support the contention that predator-driven component Allee effects may exacerbate the effects of other environmental drivers and increase the risk of extinction of small populations. PMID- 21320262 TI - Testing Darwin's naturalization hypothesis in the Azores. AB - Invasive species are a threat for ecosystems worldwide, especially oceanic islands. Predicting the invasive potential of introduced species remains difficult, and only a few studies have found traits correlated to invasiveness. We produced a molecular phylogenetic dataset and an ecological trait database for the entire Azorean flora and find that the phylogenetic nearest neighbour distance (PNND), a measure of evolutionary relatedness, is significantly correlated with invasiveness. We show that introduced plant species are more likely to become invasive in the absence of closely related species in the native flora of the Azores, verifying Darwin's 'naturalization hypothesis'. In addition, we find that some ecological traits (especially life form and seed size) also have predictive power on invasive success in the Azores. Therefore, we suggest a combination of PNND with ecological trait values as a universal predictor of invasiveness that takes into account characteristics of both introduced species and receiving ecosystem. PMID- 21320263 TI - A cohort study of acute pancreatitis in relation to exenatide use. AB - AIM: Reports of acute pancreatitis associated with exenatide treatment prompted this study to estimate the association between acute pancreatitis and exenatide use relative to other antihyperglycaemic drugs. METHODS: This cohort study included patients without claims for prior pancreatic disease who initiated exenatide or other antihyperglycaemic drugs between June 2005 and December 2007. Acute pancreatitis was identified with diagnosis codes and confirmed through review of blinded medical records. Poisson regression models provided estimates of rate ratios (RRs) and 95% confidence intervals (CIs) comparing the rate of acute pancreatitis during periods of current (days supplied + 31 days), recent (current definition + 31 days) and past use (>=32 days beyond current definition) of exenatide relative to other antihyperglycaemic drugs, adjusted for propensity scores. A prespecified nested case-control analysis provided RR estimates adjusted for patient characteristics abstracted from medical records. RESULTS: Initiators of exenatide (N = 25719) had more baseline claims for obesity and concomitant diabetes drugs than comparators (N = 234536). There were 40 confirmed cases of acute pancreatitis in the exenatide cohort and 254 among other antihyperglycaemic drug initiators. Compared to other antihyperglycaemic drugs, the propensity score-adjusted RR for exenatide was 0.5 (95% CI 0.2-0.9) for current use, 1.1 (95% CI 0.4-3.2) for recent use and 2.8 (95% CI 1.6-4.7) for past use. The case-control analysis resulted in a RR of 0.2 for current use (95% CI 0.0-1.4) and 0.1 for recent use (95% CI 0.0-1.3), but an attenuated RR in the past use association (RR 1.1; 95% CI 0.1-11.0). CONCLUSIONS: Exenatide use was not associated with an increased risk of acute pancreatitis. PMID- 21320264 TI - Telmisartan, a dual ARB/partial PPAR-gamma agonist, protects myocardium from ischaemic reperfusion injury in experimental diabetes. AB - AIM: Apart from its angiotensin receptor blocker (ARB) activity, telmisartan is also a partial agonist of peroxisome proliferator-activated receptor gamma (PPAR gamma). Therefore, we assessed whether telmisartan treatment attenuates myocardial ischaemia/reperfusion (I/R) injury in diabetic rats through PPAR-gamma pathway. METHODS: Diabetic rats were randomized to receive vehicle (sham and I/R), telmisartan (10 mg/kg/day, orally), PPAR-gamma antagonist GW9662 (1 mg/kg/day, intraperitoneally) or both for 14 days. On 15th day, excluding sham group, left anterior descending coronary artery occlusion was performed for 45 min followed by 1 h of reperfusion. Haemodynamic, biochemical, histopathological, ultrastructural, immunohistochemical (Bax and Bcl-2 protein), TUNEL positivity, infarct size and western blot studies were performed. RESULTS: Telmisartan treatment significantly improved cardiac function by normalizing mean arterial pressure, left ventricular pressure (+/-LVdP/dt(max) , a marker of myocardial contraction and relaxation), by decreasing left ventricular end-diastolic pressure (a marker of preload, 3.7 +/- 0.41 vs. 7.3 +/- 0.89, p < 0.001) and percent infarct area (37.52 +/- 5.83 vs. 46.27 +/- 3.20, p < 0.01) as compared to diabetic I/R group. Interestingly, GW9662 worsens the I/R injury (percent infarct area, 54.38 +/- 6.48 vs. 46.27 +/- 3.20, p < 0.01), whereas telmisartan with GW9662 (percent infarct area, 41.16 +/- 8.23 vs. 46.27 +/- 3.20, p < 0.05) showed lesser significant results as compared to telmisartan alone. Additionally, telmisartan significantly ameliorates activities of endogenous antioxidants, creatine kinase-MB isoenzyme, lactate dehydrogenase and prevented the increase of tumour necrosis factor-alpha and malondialdehyde in myocardium. Furthermore, telmisartan also decreased Bax expression (4.45 +/- 1.24% vs. 10.25 +/- 0.96%, p < 0.01), number of TUNEL-positive cells (6.2 +/- 0.98% vs. 13.0 +/- 1.6, p < 0.01), inflammation, myonecrosis and increased Bcl-2 expression (5.45 +/- 0.15% vs. 1.24 +/- 0.3%, p < 0.01). On the other hand, GW9662 treatment alone increased the Bax expression, TUNEL positivity and decreased Bcl-2 expression. Telmisartan protective effects were partially attenuated by a co-administration with GW9662. Western blot analysis showed that telmisartan treatment enhanced PPAR-gamma expression, whereas GW9662 decreased it in myocardium. CONCLUSIONS: In addition to the class effect of ARBs, telmisartan has a beneficial effect in I/R injury in diabetic rats in part because of activation of PPAR-gamma. PMID- 21320265 TI - Adipocytes express a functional system for serotonin synthesis, reuptake and receptor activation. AB - AIMS: Serotonergic pathways in the central nervous system (CNS) are activated in the regulation of food intake and body weight. We hypothesized that adipocytes, like other cells of mesenchymal origin, possess serotonin receptors and thus could be regulated by peripherally circulating serotonin. METHODS: In vivo studies: four Sprague-Dawley rats were given daily serotonin (5HT) injections subcutaneously (s.c., 25 mg/kg) for 5 days; four controls received saline. In a long-term study, 12 rats were given serotonin s.c. for 4 months, 10 controls received saline. Body weight was registered throughout the studies, and visceral adipose tissue and plasma were collected and analysed. Adipocytes were isolated from normal rat visceral abdominal adipose tissue and analysed for the expression of serotonin receptors, the serotonin transporter (5HTT/SERT), activation of serotonin synthesis (tryptophan hydroxylase 1, Tph1) and secretion and serotonin induced leptin regulation by RT-PCR and protein analyses. RESULTS: Hyperserotoninergic rats had significantly lower body weight (-7.4 and -6.8%) and plasma leptin levels (-44 and -38%) than controls, after both short- and long term serotonin treatment, respectively, whereas plasma ghrelin levels were unaffected. Compared to controls, serotonin induced a 40-fold upregulation of 5HTT mRNA in visceral adipose tissue after 5 days of treatment. In vitro experiments showed that adipocytes express serotonin receptors, Tph1 and 5HTT, synthesize and secrete serotonin and that serotonin regulates leptin in mature adipocytes. CONCLUSIONS: These findings show that serotonin may regulate adipocyte function in a direct manner via the blood circulation and/or paracrine and autocrine mechanisms, and not only indirectly via the CNS as previously assumed. PMID- 21320266 TI - Therapeutic potential of panduratin A, LKB1-dependent AMP-activated protein kinase stimulator, with activation of PPARalpha/delta for the treatment of obesity. AB - AIM: AMP-activated protein kinase (AMPK) activators have shown potential as therapeutic agents for metabolic disorders. This study was conducted to evaluate therapeutic potential of panduratin (PAN) A, a natural AMPK stimulator, with activation of PPARalpha/delta for the treatment of obesity. METHODS: We used the novel AMPK activator PAN A, a natural compound isolated from Boesenbergia pandurata rhizomes, to investigate the regulation of LKB1-dependent AMPK PPARalpha/delta signalling by western blot, reporter gene assay and small interfering RNA knockdown analysis. In addition, the antiobesity effects of PAN A were evaluated in C57BL/6J mice with high-fat diet (HFD)-induced obesity. RESULTS: PAN A stimulated AMPK signalling, induced nuclear translocation of the AMPKalpha2 subunit and activated PPARalpha/delta; LKB1, a kinase that lies upstream of AMPK, mediated these effects. PAN A stimulated the direct binding of the AMPKalpha2 subunit to PPARalpha/delta, but PPARdelta activation required direct interaction with PPARgamma coactivator 1alpha (PGC-1alpha). Further, PAN A (50 mg/kg/day) reduced weight gain, fat mass, fatty liver and improved serum lipid profiles in obese mice. Additionally, PAN A reduced ectopic fat accumulation and increased the proportion of slow-twitch myofibres and mitochondria content in skeletal muscle, thereby increasing running endurance. CONCLUSIONS: PAN A, an LKB1-dependent AMPK stimulator, activated PPARalpha/delta and attenuated HFD-induced obesity and dysregulation of lipid metabolism. Our findings suggest that PAN A is a potent AMPK activator and show a novel molecular mechanism for the treatment of metabolic disorders. PMID- 21320267 TI - Dipeptidyl peptidase-4 inhibitors and HbA1c target of <7% in type 2 diabetes: meta-analysis of randomized controlled trials. AB - AIM: We assessed the efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors vildagliptin, sitagliptin, saxagliptin and alogliptin to reach the haemoglobin HbA1c target of <7% in people with type 2 diabetes. METHODS: We conducted an electronic search for randomized controlled trials (RCTs) involving DPP-4 inhibitors through September 2010. RCTs were included if they lasted at least 12 weeks, included 30 patients or more and reported the proportion of patients reaching the HbA1c target of <7%. RESULTS: A total of 43 RCTs reporting 52 comparisons met the selection criteria, which included 19 101 study participants evaluated for the primary endpoint, 10 467 treated with a DPP-4 inhibitor and 8634 treated with placebo or a comparator drug. DPP-4 inhibitors showed a statistically significant reduction in HbA1c compared to placebo and approximately 40% of participants achieved the HbA1c goal of <7%: this was associated with weight neutrality and no greater hypoglycaemia. The reduction of the HbA1c level and the rate of HbA1c goal attainment was not different from comparator drugs, with similar hypoglycaemia, and different effect on weight owing to the nature of comparator (metformin, sulfonylurea or glitazones). Baseline HbA1c was the best predictor for achievement of A1C target (overall weighted r(2) value = 0.410, p < 0.001). CONCLUSIONS: A greater proportion of type 2 diabetic patients can achieve the HbA1c goal <7% with DPP-4 inhibitors compared to placebo, with no weight gain, and no hypoglycaemic risk when used alone; DPP-4 inhibitors were not different from comparator drugs. PMID- 21320268 TI - Novel use of an air-filled breast prosthesis to allow radiotherapy to recurrent colonic cancer. AB - AIM: The authors present the novel and successful use of an air-filled breast prosthesis for extra pelvic exclusion of small bowel to facilitate adjuvant radiotherapy following resection of recurrent adenocarcinoma of the ascending bowel. The therapeutic use of radiotherapy in colon cancer can cause acute or chronic radiation enteropathy. Mobile small bowel can be sequestered in 'dead space' or by adhesions exposing it to adjuvant radiotherapy. A variety of pelvic partitioning methods have been described to exclude bowel from radiation fields using both native and prosthetic materials. METHOD: In this case a 68 year old presented with ascending colon adenocarcinoma invading the peritoneum and underwent en bloc peritoneal resection. Thirty-seven months later surveillance CT identified a local recurrence. Subsequent resection resulted in a large iliacus muscle defect which would sequester small bowel loops thus exposing the patient to radiation enteropathy. The lateral position of the defect precluded the use of traditional pelvic partitioning methods which would be unlikely to remain in place long enough to allow radiotherapy. A lightweight air-filled breast prosthesis (Allergan 133 FV 750 cms) secured in place with an omentoplasty was used to fill the defect. RESULTS: Following well tolerated radiotherapy the prosthesis was deflated under ultrasound guidance and removed via a 7-cm transverse incision above the right iliac crest. The patient is disease free 18 months later with no evidence of treatment related morbidity. CONCLUSION: The use of a malleable air-filled prosthesis for pelvic partitioning allows specific tailoring of the prosthesis size and shape for individual patient defects. It is also lightweight enough to be secured in place using an omentoplasty to prevent movement related prosthesis migration. In the absence of adequate omentum a mesh sling may be considered to allow fixation. In this case the anatomy of the prosthesis position allowed for its removal without the need for repeat laparotomy. Pre-operative deflation of the air-filled prosthesis under ultrasound guidance also reduces the size of the incision required for removal. This technique may be valuable to prevent collateral small bowel irradiation following resection of renal or retroperitoneal malignancy. PMID- 21320269 TI - Anastomotic leakage: a disaster or a challenge with an impact on survival after rectal cancer surgery? PMID- 21320272 TI - Mid-term oncological control after laparoscopic radical cystectomy in men: a single-centre experience. AB - OBJECTIVE: * To assess the mid-term (3 years of follow-up) oncological control of laparoscopic radical cystectomy (LRC) for high-grade muscle-invasive bladder cancer in a well studied male population. PATIENTS AND METHODS: * We assessed 40 men with bladder cancer (mean [range] age 66.5 [50-75] years) who underwent LRC and extended pelvic lymphadenectomy at our institution between April 2004 and September 2008. * Of the 40 patients, 13 (32.5%) had a complete laparoscopic procedure (ileal conduit: seven patients; neobladder: five patients; bilateral ureterostomy: one patient) and 27 (67.5%) had an LRC procedure only (ileal conduit: 15 patients; neobladder: 12 patients). RESULTS: * No major complications were observed intraoperatively. * The mean operating time was 407 min and the mean blood loss was 720 mL. Four patients (10%) required conversion to open surgery. The mean (range) hospital stay was 10.2 (7-25) days. One patient died of myocardial infarction in the postoperative period. * Pathological analysis showed organ-confined tumours (stage pT0/pT1/pT2/pT3a) in 22 patients (55%) and extravesical disease (pT3/pT4) in 18 (45%). Of the 40 patients, six (15%) had lymph node involvement. The mean (range) number of nodes removed was 19.9 (5-40). * At a mean (range) follow-up period of 36 (0-72) months, 26 patients were alive with no evidence of disease (disease-free survival rate 67%). CONCLUSION: * Laparoscopic radical cystectomy is a safe, feasible, and effective alternative to open radical cystectomy (ORC). The 3-year oncological efficacy was comparable with that of ORC. PMID- 21320273 TI - Population-based analyses of radical cystectomy and urinary diversion for bladder cancer in northern Italy. AB - OBJECTIVE: *To provide updated figures on urinary diversion, length of stay and mortality after cystectomy in two regions of northern Italy. PATIENTS AND METHODS: *Discharge records of patients undergoing cystectomy for bladder cancer in 2000-2008 were extracted from the regional archives of hospital discharges. *Data on partial vs radical cystectomy and type of urinary diversion were obtained from intervention codes. *The influence of demographic characteristics, year of intervention, presence of comorbidities and hospital cystectomy volume on the adoption of a continent diversion and on in-hospital mortality was assessed through multilevel models. RESULTS: *The crude cystectomy rate was close to 10 per 100,000. *The share of partial cystectomies declined from 5.5% in 2000-2002 to 3.0% in 2006-2008. *A continent diversion was adopted in 35% of radical cystectomies, with higher rates in young male patients treated in high-volume hospitals. *Median length of stay declined from 20 days in 2000-2002 to 18 in 2006-2008; in-hospital mortality decreased from 3.2% to 2.2%. CONCLUSION: *This first population-based report on cystectomies for bladder cancer from continental Europe evidences a limited role of partial cystectomy, a high proportion of continent diversion and a decreasing trend of length of stay and in-hospital mortality. PMID- 21320274 TI - Addition of gemcitabine at the time of sunitinib resistance in metastatic renal cell cancer. AB - OBJECTIVE: *To investigate the role of adding gemcitabine at the time of sunitinib failure in patients with metastatic renal cell cancer (mRCC). PATIENTS AND METHODS: *A retrospective chart review of 13 patients with mRCC who experienced disease progression on sunitinib and received gemcitabine 750 mg/m(2) i.v. on days 1 and 8 and sunitinib 37.5 mg/day on days 2-15 every 21 days from September 2006-2009 was carried out. *Responses were assessed using the Response Evaluation Criteria in Solid Tumors. *The median age was 59, male to female ratio 10:3, Eastern Cooperative Oncology Group performance status 1-3; the number of prior regimens ranged from one to five, and duration on sunitinib alone ranged from 3 months to >1 year. RESULTS: *Twelve out of 13 patients received more than two cycles with one documented partial response, five stable disease and seven progressive disease. *The median time to progression was 21 weeks. *We documented grade 4 pulmonary emboli (n= 1), grade 3 neutropenia (n= 2), anaemia (n= 2) and thrombocytopenia (n= 1). CONCLUSION: *The combination of sunitinib and gemcitabine in patients with mRCC may delay disease progression in some patients exhibiting resistance to sunitinib. This regimen merits further prospective investigation in this patient population. PMID- 21320275 TI - Urinary cytology has a poor performance for predicting invasive or high-grade upper-tract urothelial carcinoma. AB - OBJECTIVE: * To evaluate the diagnostic accuracy of urine cytology for detecting aggressive disease in a multi-institutional cohort of patients undergoing extirpative surgery for upper-tract urothelial carcinoma (UTUC). METHODS: * We reviewed the records of 326 patients with urinary cytology data who underwent a radical nephroureterectomy or distal ureterectomy without concurrent or previous bladder cancer. * We assessed the association of cytology (positive, negative and atypical) with final pathology. Sensitivity and positive predictive value (PPV) of a positive (+/- atypical) cytology for high-grade and muscle-invasive UTUC was calculated. RESULTS: * On final pathology, 53% of patients had non-muscle invasive disease (pTa, pTis, pT1) and 47% had invasive disease (>= pT2). Low grade and high-grade cancers were present in 33% and 67% of patients, respectively. * Positive, atypical and negative urine cytology was noted in 40%, 40% and 20% of cases. Positive urinary cytology had sensitivity and PPV of 56% and 54% for high-grade and 62% and 44% for muscle-invasive UTUC. * Inclusion of atypical cytology with positive cytology improved the sensitivity and PPV for high-grade (74% and 63%) and muscle-invasive (77% and 45%) UTUC. Restricting analysis to patients with selective ureteral cytologies further improved the diagnostic accuracy when compared with bladder specimens (PPV > 85% for high grade and muscle-invasive UTUC). CONCLUSIONS: * In this cohort of patients with UTUC treated with radical surgery, urine cytology in isolation lacked performance characteristics to accurately predict muscle-invasive or high-grade disease. * Improved surrogate markers for pathological grade and stage are necessary, particularly when considering endoscopic modalities for UTUC. PMID- 21320276 TI - Epstein criteria for insignificant prostate cancer. AB - Study Type - Prognosis (systematic review). LEVEL OF EVIDENCE: 2b. What's known on the subject? and What does the study add? Overtreatment of prostate cancer is a major problem in contemporary urological practice. The Epstein Criteria reduces overtreatment by identifying insignificant prostate cancers that may be amenable to surveillance therapy. This systematic review of the Epstein Criteria validation studies provides a collective insight into the application and accuracy of the Epstein Criteria to predict for insignificant prostate cancer across different institutions and geographies. OBJECTIVE: * To review the accuracy of the Epstein Criteria for insignificant prostate cancer and to explore the effect of the modified Gleason classification system on this system. METHODS: * We searched PubMed, EMBASE and the Cochrane Database using search terms 'Epstein Criteria', 'Prostate Cancer', 'Validation' and 'Insignificant Cancer' between 1994 to 2010 for validation articles. * These were divided into pre-2005 and post-2005 and concordances for organ-confined status, Gleason score <= 6 and insignificant cancer were analysed. RESULTS: * A pre-2005 study showed concordance for insignificant prostate cancer, Gleason score <= 6 and organ confined status at 84%, 90.3% and 91.6%, respectively. * Five post-2005 validation studies were concordant for insignificant cancer, Gleason score <= 6 and organ-confined status at 37-76%, 54.3-75.9% and 80.0-96.9%, respectively. CONCLUSIONS: * The Epstein Criteria has a suboptimal accuracy for predicting for insignificant prostate cancer. * The modification to Gleason scoring may be responsible for a reduced accuracy over time. * However, significant heterogeneity in the validation studies means better quality validation studies are required. PMID- 21320277 TI - Regional lymph node status in patients with bladder cancer found to be pathological stage T0 at radical cystectomy following systemic chemotherapy. AB - OBJECTIVE: *To evaluate the effect of preoperative cisplatin-based chemotherapy on the regional lymph nodes of patients with bladder cancer who attain pathological T0 status in the bladder after chemotherapy followed by radical cystectomy. PATIENTS AND METHODS: *Patients who underwent radical cystectomy at MSKCC for urothelial carcinoma of the bladder were retrospectively reviewed. *Those patients achieving pT0 status after preoperative chemotherapy were identified and classified into two groups, those rendered pT0: (i) after receiving neoadjuvant chemotherapy and (ii) after receiving definitive chemotherapy (defined in this case as chemotherapy given for unresectable or regionally metastatic disease). *These two groups were analyzed separately for lymph node status at cystectomy and regional lymph node recurrence. RESULTS: *Of 169 pT0 patients, 24 patients (14%) had received neoadjuvant chemotherapy, whereas 17 patients (10%) had received definitive chemotherapy for unresectable or regionally metastatic disease. *No patient rendered pT0 after neoadjuvant chemotherapy had lymph node involvement at radical cystectomy or recurrence within the regional lymph node template. *Among patients with advanced disease rendered pT0 by definitive chemotherapy, 35% had lymph node involvement at radical cystectomy or subsequent recurrence within the dissection template. CONCLUSIONS: *Patients achieving pT0 status after receiving neoadjuvant chemotherapy had no evidence of lymph node involvement at cystectomy. *Patients undergoing definitive chemotherapy for advanced disease followed by cystectomy experienced reduced rates of nodal involvement compared to the lymph node positive rates predicted by preoperative clinical staging. However, there remains a risk of regional lymph node involvement in this group. PMID- 21320279 TI - Soluble thrombomodulin in coronary heart disease: lack of an association in the MONICA/KORA case-cohort study. PMID- 21320278 TI - Age at first joint bleed and bleeding severity in boys with severe hemophilia A: Canadian Hemophilia Primary Prophylaxis Study. PMID- 21320280 TI - External quality assurance for the PFA-100(r). PMID- 21320281 TI - The chemotherapy metabolite acrolein upregulates thrombin generation and impairs the protein C anticoagulant pathway in animal-based and cell-based models. AB - BACKGROUND: Thrombosis is a common complication in cancer patients receiving chemotherapy regimens that include cyclophosphamide. However, the mechanisms by which these agents increase this risk are largely uncharacterized. OBJECTIVES: To examine the effects of cyclophosphamide and its metabolite acrolein on procoagulant and anticoagulant pathways in both cell-based and animal-based models. METHODS: Thrombin and activated protein C (APC) generation were measured in defibrinated plasma exposed to acrolein-treated endothelial and smooth muscle cells. Tissue factor (TF) activity was measured on acrolein-treated cells. Cell surface levels of phosphatidylserine, TF, endothelial protein C receptor and thrombomodulin were measured. Healthy BALB/c mice received injections of saline (control), acrolein, or cyclophosphamide; blood was collected, and plasma thrombin-antithrombin (TAT) complex, protein C and APC levels were analyzed. RESULTS: Exposure of acrolein-treated endothelial and smooth muscle cells to defibrinated plasma increased thrombin generation in the plasma. This was associated with enhanced phosphatidylserine exposure and/or increased TF activity on acrolein-treated cells. Despite elevated levels of thrombin generation, plasma APC levels were not elevated. In vivo, treatment of mice with cyclophosphamide and acrolein resulted in elevations of plasma TAT complex levels, whereas APC levels remained low. CONCLUSIONS: This is the first study to examine thrombin generation and the APC pathway in chemotherapy-treated mice. Cyclophosphamide and acrolein appear to upregulate procoagulant pathways, while impairing endogenous anticoagulant pathways. This may explain, in part, the increased risk of thrombosis observed in cancer patients receiving cyclophosphamide-containing chemotherapy. PMID- 21320282 TI - Effects of in vitro adult platelet transfusions on neonatal hemostasis. AB - BACKGROUND: Thrombocytopenia is frequent among neonates, and 20-25% of affected infants are treated with platelet transfusions. These are frequently given for mild thrombocytopenia (platelets: 50-100 * 10(9) L(-1)), largely because of the known hyporeactivity of neonatal platelets. In tests of primary hemostasis, however, neonates have shorter bleeding and closure times (CTs) than adults. This has been attributed to their higher hematocrits, higher von Willebrand factor (VWF) concentrations, and predominance of longer VWF polymers. OBJECTIVE: To determine whether the 'transfusion' of adult (relatively hyperreactive) platelets into neonatal blood results in a hypercoagulable profile. METHODS: Cord blood (CB) and adult peripheral blood (PB) were separated (with a modified buffy coat method) to generate miniaturized platelet concentrates (PCs) and thrombocytopenic blood. PB-derived and CB-derived PCs (n = 7 per group) were then 'transfused'in vitro into thrombocytopenic CB and PB. The effects of autologous vs. allogeneic (developmentally mismatched) 'transfusions' were evaluated with whole blood aggregometry, a platelet function analyzer (PFA-100), and thromboelastography (TEG). RESULTS: Adult platelets aggregated significantly better than neonatal platelets in response to thrombin receptor-activating peptide, ADP, and collagen, regardless of the blood into which they were transfused. The 'transfusion' of adult platelets into thrombocytopenic CB resulted in shorter CTs-EPI (PFA-100) and higher clot strength and firmness (TEG) than 'transfusion' of neonatal autologous platelets. CONCLUSIONS: In vitro'transfusion' of adult platelets into neonatal blood results in shorter CTs than 'transfusion' with neonatal platelets. Our findings should raise awareness of the differences between the neonatal and adult hemostatic system and the potential 'developmental mismatch' associated with platelet transfusions for neonatal hemostasis. PMID- 21320283 TI - Factor XIII supports platelet activation and enhances thrombus formation by matrix proteins under flow conditions. AB - BACKGROUND: Activated coagulation factor XIII (FXIIIa) is a transglutaminase that crosslinks fibrin at sites of vascular injury. FXIIIa also associates with blood platelets, although its role in platelet function is unclear and requires clarification. OBJECTIVES: To evaluate the ability of FXIIIa to support platelet adhesion and spreading under conditions of physiologic flow, and to identify the underpinning receptors and signaling events. METHODS AND RESULTS: Platelet adhesion to immobilized FXIIIa was measured by fluorescence microscopy, and signaling events were characterized by immunoblotting. Immobilized FXIIIa supported platelet adhesion and spreading under static conditions through mechanisms that were dually and differentially dependent on integrins alpha(IIb)beta(3) and alpha(v)beta(3). Platelet adhesion was independent of FXIIIa transglutaminase or protein disulfide isomerase activity. Moreover, adhesion was abolished by antibodies that prevented interaction with FXIIIa, but maintained when potential interactions with fibrinogen were blocked. Platelet adhesion to FXIIIa was reduced significantly by either the specific alpha(IIb)beta(3) antagonist tirofiban or the selective alpha(v)beta(3)-blocking antibody LM609, and abolished when they were used in combination. Importantly, platelet adhesion was preserved under venous and arterial flow conditions in which both integrins played essential roles. In contrast, FXIIIa stimulated the formation of filopodia and lamellipodia in adherent platelets that was mediated exclusively by alpha(IIb)beta(3) and eliminated by the Src-family inhibitor 4 amino-5-(4-methylphenyl-7-(t-butyl)pyrazolo(3,4-d)pyrimidine, indicating a tyrosine kinase-dependent mechanism. Crucially, under conditions of arterial shear, FXIIIa accentuated platelet recruitment by von Willebrand factor and collagen. CONCLUSIONS: Our data demonstrate a potential role for FXIIIa in supporting platelet adhesion at sites of vascular damage, particularly in association with other thrombogenic matrix proteins. PMID- 21320284 TI - EMMPRIN (CD147/basigin) mediates platelet-monocyte interactions in vivo and augments monocyte recruitment to the vascular wall. AB - BACKGROUND: Platelets play a central role in hemostasis, in inflammatory diseases such as atherosclerosis, and during thrombus formation following vascular injury. Thereby, platelets interact intensively with monocytes and enhance their recruitment to the vascular wall. OBJECTIVES: To investigate the role of the extracellular matrix metalloproteinase inducer (EMMPRIN) in platelet-monocyte interactions. METHODS AND RESULTS: Isolated human monocytes were perfused in vitro over firmly adherent platelets to allow investigation of the role of EMMPRIN in platelet-monocyte interactions under flow conditions. Monocytes readily bound to surface-adherent platelets. Both antibody blockade and gene silencing of monocyte EMMPRIN substantially attenuated firm adhesion of monocytes to platelets at arterial and venous shear rates. In vivo, platelet interactions with the murine monocyte cell line ANA-1 were significantly decreased when ANA-1 cells were pretreated with EMMPRIN-silencing small interfering RNA prior to injection into wild-type mice. Using intravital microscopy, we showed that recruitment of EMMPRIN-silenced ANA-1 to the injured carotid artery was significantly reduced as compared with control cells. Further silencing of EMMPRIN resulted in significantly fewer ANA-1-platelet aggregates in the mouse circulation as determined by flow cytometry. Finally, we identified glycoprotein (GP)VI as a critical corresponding receptor on platelets that mediates interaction with monocyte EMMPRIN. Thus, blocking of GPVI inhibited the effect of EMMPRIN on firm monocyte adhesion to platelets under arterial flow conditions in vitro, and abrogated EMMPRIN-mediated platelet-monocyte aggregate formation in vivo. CONCLUSIONS: EMMPRIN supports platelet-monocyte interactions and promotes monocyte recruitment to the arterial wall. Therefore, EMMPRIN might represent a novel target to reduce vascular inflammation and atherosclerotic lesion development. PMID- 21320286 TI - Homozygous F5 deep-intronic splicing mutation resulting in severe factor V deficiency and undetectable thrombin generation in platelet-rich plasma. AB - BACKGROUND: Coagulation factor (F) V deficiency is associated with a bleeding tendency of variable severity, but phenotype determinants are largely unknown. Recently, we have shown that three patients with undetectable plasma FV and mild bleeding symptoms had sufficient residual platelet FV to support thrombin generation in platelet-rich plasma (PRP). Therefore, we hypothesized that FV deficient patients with severe bleeding manifestations may lack platelet FV. OBJECTIVES: To characterize a FV-deficient patient with a severe bleeding diathesis. PATIENTS/METHODS: We performed FV mutation screening and functional studies in a 31-year-old male (FV:C < 1%) with umbilical bleeding at birth, recurrent hemarthrosis and muscle hematomas, and a recent intracranial hemorrhage. RESULTS: The proband was homozygous for a deep-intronic mutation (F5 IVS8 +268A->G) causing the inclusion of a pseudo-exon with an in-frame stop codon in the mature F5 mRNA. Although platelet FV antigen was detectable by immunoprecipitation followed by Western blotting, no FV activity could be demonstrated in the proband's plasma or platelets with a prothrombinase-based assay. Moreover, no thrombin generation was observed in PRP triggered with 1-50 pm tissue factor (even in the presence of platelet agonists), whereas an acquired FV inhibitor was excluded. Clot formation in the proband's whole blood, as assessed by thromboelastometry, was markedly delayed but not abolished. CONCLUSIONS: This is the first report of a pathogenic deep-intronic mutation in the F5 gene. Our findings indicate that the minimal FV requirement for viability is extremely low and suggest that thrombin generation in PRP may predict bleeding tendency in patients with undetectable plasma FV. PMID- 21320285 TI - Glycogen synthase kinase-3 negatively regulates tissue factor expression in monocytes interacting with activated platelets. AB - BACKGROUND: At the site of vascular injury, monocytes (MN) interacting with activated platelets (PLT) synthesize tissue factor (TF) and promote thrombus formation. Intracellular signals necessary for the expression of TF in MN, in the context of a developing thrombus, remain unknown. OBJECTIVE: The study was designed to investigate the role of the glycogen synthase kinase 3 (GSK3, a serine-threonine kinase) downstream insulin receptor pathway, in PLT-induced TF expression in MN. METHODS: To this purpose we used a well-characterized in vitro model of human MN-PLT interactions that allows detailed analysis of TF activity, TF protein and gene expression. RESULTS: The results demonstrated that, in MN interacting with activated PLT: (i) TF activity, antigen and mRNA were low until 8-10 h and dramatically increased thereafter, up to 24 h; (ii) according to the kinetics of TF expression in MN, GSK3beta undergoes phosphorylation on serine 9, a process associated with down-regulation of enzyme activity; (iii) pharmacological blockade of GSK3 further increased TF expression and was accompanied by increased accumulation of NF-kB, in the nucleus; (iv) blockade of phosphoinositide-3 kinase (PI(3)K) by wortmannin inhibited PLT-induced TF expression; and (v) according to the established role of the GSK3 downstream insulin receptor, insulin increased PLT-induced TF expression in a PI(3)K dependent manner. CONCLUSION: GSK3 acts as a molecular brake on the signaling pathway, leading to TF expression in MN interacting with activated PLT. PI(3)K, through Akt-dependent phosphorylation of GSK3, relieves this brake and allows TF gene expression. This study identifies a novel molecular link between thrombotic risk and metabolic disorders. PMID- 21320287 TI - The association between platelet activation and FcgammaRIIa proteolysis. PMID- 21320288 TI - Artemisinins act through at least two targets in a yeast model. AB - Artemisinin and related compounds are potent and widely used antimalarial drugs but their biochemical mode of action is not clear. There is strong evidence that ATP-dependent calcium transporters are a key target in the malarial parasite. However, work using Saccharomyces cerevisiae suggests that disruption of mitochondrial function is critical in the cell killing activity of these compounds. Here it is shown that, in the absence of reducing agents, artemisinin and artesunate targeted the S. cerevisiae calcium channels Pmr1p and Pmc1p. Both compounds affected the growth of yeast on fermentable and nonfermentable media. This growth inhibition was not seen in a yeast strain in which the genes encoding both calcium channels were deleted. In the presence of reducing agents, which break the endoperoxide bridge in the drugs, growth inhibition was only observed in nonfermentable media. This inhibition could be partially relieved by the addition of a free radical scavenger. These results suggest that the drugs have two biochemical modes of action - one acting by specific binding to calcium channels and one involving free radical production in the mitochondria. PMID- 21320289 TI - Dopamine D4 receptor oligomerization--contribution to receptor biogenesis. AB - Dopamine D(4) receptors (D(4) Rs) are G protein-coupled receptors that play a role in attention and cognition. In the present study, we investigated the dimerization properties of this receptor. Western blot analysis of the human D(4.2)R, D(4.4)R and D(4.7)R revealed the presence of higher molecular weight immunoreactive bands, which might indicate the formation of receptor dimers and multimers. Homo- and heterodimerization of the receptors was confirmed by co immunoprecipitation and bioluminescence resonance energy transfer studies. Although dimerization of a large number of G protein-coupled receptors has been described, the functional importance often remains to be elucidated. Folding efficiency is rate-limiting for D(4)R biogenesis and quality control in the endoplasmic reticulum plays an important role for D(4)R maturation. Co immunoprecipitation and immunofluorescence microscopy studies using wild-type and a nonfunctional D(4.4)R folding mutant show that oligomerization occurs in the endoplasmic reticulum and that this plays a role in the biogenesis and cell surface targeting of the D(4)R. The different polymorphic repeat variants of the D(4)R display differential sensitivity to the chaperone effect. In the present study, we show that this is also reflected by bioluminescence resonance energy transfer saturation assays, suggesting that the polymorphic repeat variants have different relative affinities to form homo- and heterodimers. In summary, we conclude that D(4)Rs form oligomers with different affinities and that dimerization plays a role in receptor biogenesis. PMID- 21320290 TI - Immunophenotyping in peripheral blood mononuclear cells, aqueous humour and vitreous in a Blau syndrome patient caused by a novel NOD2 mutation. AB - The genetic and immunophenotypic characteristics of a 3-year-old patient with Blau syndrome (BS), an early onset sarcoidosis caused by mutations in NOD2, were investigated. Molecular analysis of NOD2 gene was achieved by PCR and direct nucleotide sequencing. Immunophenotyping included cytometric analysis of memory effector markers on T-cells, and cytokine in serum, aqueous humour and vitreous. A novel M513R mutation in NOD2 was demonstrated. Immunophenotyping revealed higher frequency of CCR4+ cells and CCR9+ cells on CD4+ cells; most CD8+ cells were CCR7- and CCR9+. IL6 and IL-8 were detected in a gradient manner: vitreous humour>aqueous humour>serum. The immunophenotype in this patient was characterized by a differential expression of chemokine receptors on T cells and by a particular ocular microenvironment enriched in IL-6 and IL-8. To our knowledge, this is the first study analysing the immunological features of BS at aqueous humour, vitreous and blood levels. Our results expand the knowledge of the genetic and immunopathological basis of BS. PMID- 21320291 TI - Artificial neural network weights of residues for the serological specificities of HLA. AB - New human leucocyte antigen (HLA) alleles are assigned largely based on their sequence homologies due to lack of information on the serological reactivities. Artificial neural networks (ANNs) have been tested as a possible tool for helping to predict the serology of new alleles in the absence of serological information. However, an ANN analysis per se imparts no information regarding which residues are important in determining serological specificity. To address this issue, we extracted ANN weights of HLA residues. The ANN was trained using 139 HLA-A, 302 HLA-B and 136 HLA-DRB1 alleles, for which serological specificities were assigned in the 2004 Nomenclature Report. When the trained ANN was evaluated using alleles that were contained in the HLA Dictionary 2008 but had not been employed in the training set, the accuracy was 91% (29/32) for HLA-A, 91% (40/44) for HLA-B and 90% (9/10) for HLA-DR. Finally, ANN residue weights were extracted by summing the weights of directly connected ANN nodes. When we assessed the significance of the ANN residue weights by comparing our data with the results of epitope studies conducted by El-Awar and colleagues, we found that the ANN weights tended to be high at the epitopes described by El-Awar et al. Furthermore, the ANN weights extracted in this work could be used to explain ambiguous characteristics of serological specificities to some extent. Our data are thus considered to support the results of the epitope studies conducted by El-Awar and advance our understanding of the ambiguous serological specificities of some alleles. PMID- 21320293 TI - Receptor tyrosine kinases and their activation in melanoma. AB - Receptor tyrosine kinases (RTKs) and their downstream signalling pathways have long been hypothesized to play key roles in melanoma development. A decade ago, evidence was derived largely from animal models, RTK expression studies and detection of activated RAS isoforms in a small fraction of melanomas. Predictions that overexpression of specific RTKs implied increased kinase activity and that some RTKs would show activating mutations in melanoma were largely untested. However, technological advances including rapid gene sequencing, siRNA methods and phospho-RTK arrays now give a more complete picture. Mutated forms of RTK genes including KIT, ERBB4, the EPH and FGFR families and others are known in melanoma. Additional over- or underexpressed RTKs and also protein tyrosine phosphatases (PTPs) have been reported, and activities measured. Complex interactions between RTKs and PTPs are implicated in the abnormal signalling driving aberrant growth and survival in malignant melanocytes, and indeed in normal melanocytic signalling including the response to ultraviolet radiation. Kinases are considered druggable targets, so characterization of global RTK activity in melanoma should assist the rational development of tyrosine kinase inhibitors for clinical use. PMID- 21320292 TI - In vitro studies of dasatinib, its targets and predictors of sensitivity. PMID- 21320294 TI - Molecular characterization of foot-and-mouth disease virus: implications for disease control in Bangladesh. AB - Foot-and-mouth disease (FMD) is endemic in Bangladesh, and to implement an effective FMD control programme, it is essential to understand the complex epidemiology of the disease. Here, we report on the characterization of FMD virus (FMDV) recovered from FMD outbreaks in Bangladesh in late 2009. All isolated viruses belonged to the FMDV serotype O. The phylogenetic reconstruction showed that all isolates belonged to the Middle East-South Asia (ME-SA) topotype, but fell into two distinct sublineages, one named Ind-2001 (the other has not been named). Within both sublineages, the 2009 Bangladesh isolates were most closely related to viruses from Nepal collected during 2008 and 2009. Additionally, both sublineages contained older viruses from India collected in 2000 and 2001. In South Asia, there is extensive cross-border cattle movement from Nepal and India to Bangladesh. Both these findings have implications for the control of FMD in Bangladesh. Because of the porous borders, a regional FMD control strategy should be developed. Further, animal identification and monitoring animal movements are necessary to identify the cross-border movements and market chain interactions of ruminants, leading to improved border and movement controls. Additionally, a vaccination strategy should be developed with the initial objective of protecting small-scale dairy herds from disease. For any successful FMD control programme, long-term Government commitment and adequate resources are necessary. A sustainable programme will also need farmer education, commitment and financial contributions. PMID- 21320295 TI - Assessment of interactions between African swine fever virus, bushpigs (Potamochoerus larvatus), Ornithodoros ticks and domestic pigs in north-western Madagascar. AB - Since its introduction in Madagascar in 1998, African swine fever (ASF) has severely affected national pig production and persists as a common disease in that country. Two of its natural hosts in the African continent, the bushpig (Potamochoerus larvatus) and tick vectors of the Ornithodoros moubata complex, are reported in west and central regions of the island. However, their role in the maintenance and transmission of the virus has been insufficiently studied. In this work, we tried to assess their potential role in the epidemiology of the disease in Madagascar, by assessing the levels of interaction between (i) ASF virus (ASFV) and bushpigs and (ii) between soft ticks and domestic and wild suids in north-western Madagascar. Twenty-seven sera and 35 tissue samples from bushpigs were collected and analysed for the presence of anti-ASF antibodies and viral DNA. In addition, the sera from 27 bushpigs and 126 domestic pigs were analysed with an ELISA test for the detection of antibodies against salivary antigens from Ornithodoros ticks. No circulation of ASFV or anti-ASFV antibodies nor anti-tick antibodies were detected in bushpigs. However, seven of the domestic pig sera (5.6% of the total sample population) were antibody positive for O. moubata antigens. The probability of freedom from ASFV in the bushpig population using Bayesian statistical methods ranged between 73% and 84%. The probabilities of absence of anti-tick antibodies in domestic and wild pigs were estimated at 63% and 71%, respectively. These preliminary results suggest that bushpigs are unlikely to play a significant role in the maintenance and transmission of ASFV in Madagascar. Nevertheless, further ASFV surveys are needed on that species to confirm this assumption. In addition, the presence of antibodies against O. moubata in domestic pigs suggests that soft ticks may be able to maintain ASFV within a domestic pig cycle in areas of Madagascar where they remain present. PMID- 21320296 TI - Detection of disease-associated prion protein in the posterior portion of the small intestine involving the continuous Peyer's patch in cattle orally infected with bovine spongiform encephalopathy agent. AB - Twenty-eight calves were exposed to 5 g of homogenized brainstems confirmed as bovine spongiform encephalopathy (BSE) agents. Two to five animals were sequentially killed for post-mortem analyses 20 months post-inoculation (MPI) at intervals of 6 or 12 months. Samples from animals challenged orally with BSE agents were examined by Western blot and immunohistochemical analyses. Immunolabelled, disease-associated prion protein (PrPsc) was detected in a small portion of follicles in the continuous Peyer's patch from the posterior portion of the small intestine involving the entire ileum and the posterior jejunum but not in the discrete Peyer's patches in the remaining jejunum in preclinical animals at 20, 36, and 48 MPI. The PrPsc-positive cells corresponded to tingible body macrophages on double immunofluorescence labelling. In addition, PrPsc accumulated in 7 of 14 animals in the central nervous system (CNS) after 34 MPI, and five of them developed clinical signs and were killed at 34, 46, 58, and 66 MPI. Two preclinical animals killed at 36 and 48 MPI presented the earliest detectable and smallest deposition of immunolabelled PrPsc in the dorsal motor nucleus of the vagus nerve, the spinal trigeminal nucleus of the medulla oblongata at the obex region, and/or the intermediolateral nucleus of the 13th thoracic segment of the spinal cord. Based on serial killing, no PrPsc was detectable in the CNS, including the medulla oblongata at the obex level, before 30 MPI, by Western blot and immunohistochemical analyses. These results are important for understanding the pathogenesis of BSE. PMID- 21320298 TI - Considerations for the inclusion of 2x mammalian genomes in phylogenetic analyses. PMID- 21320297 TI - A Drosophila model for the role of epigenetics in brain function and development. AB - A genetic study in Drosophila gives important insights into the epigenetic control of gene expression implicated in a human mental retardation syndrome. PMID- 21320299 TI - Immunization with different PfAMA1 alleles in sequence induces clonal imprint humoral responses that are similar to responses induced by the same alleles as a vaccine cocktail in rabbits. AB - BACKGROUND: Antibodies to key Plasmodium falciparum surface antigens have been shown to be important effectors that mediate clinical immunity to malaria. The cross-strain fraction of anti-malarial antibodies may however be required to achieve strain-transcending immunity. Such antibody responses against Plasmodium falciparum apical membrane antigen 1 (PfAMA1), a vaccine target molecule that is expressed in both liver and blood stages of the parasite, can be elicited through immunization with a mixture of allelic variants of the parasite molecule. Cross strain antibodies are most likely elicited against epitopes that are shared by the allelic antigens in the vaccine cocktail. METHODS: A standard competition ELISA was used to address whether the antibody response can be further focused on shared epitopes by exclusively boosting these common determinants through immunization of rabbits with different PfAMA1 alleles in sequence. The in vitro parasite growth inhibition assay was used to further evaluate the functional effects of the broadened antibody response that is characteristic of multi-allele vaccine strategies. RESULTS: A mixed antigen immunization protocol elicited humoral responses that were functionally similar to those elicited by a sequential immunization protocol (p > 0.05). Sequential exposure to the different PfAMA1 allelic variants induced immunological recall of responses to previous alleles and yielded functional cross-strain antibodies that would be capable of optimal growth inhibition of variant parasites at high enough concentrations. CONCLUSIONS: These findings may have implications for the current understanding of the natural acquisition of clinical immunity to malaria as well as for rational vaccine design. PMID- 21320300 TI - Efficacy and safety of a multifactor intervention to improve therapeutic adherence in patients with chronic obstructive pulmonary disease (COPD): protocol for the ICEPOC study. AB - BACKGROUND: Low therapeutic adherence to medication is very common. Clinical effectiveness is related to dose rate and route of administration and so poor therapeutic adherence can reduce the clinical benefit of treatment. The therapeutic adherence of patients with chronic obstructive pulmonary disease (COPD) is extremely poor according to most studies. The research about COPD adherence has mainly focussed on quantifying its effect, and few studies have researched factors that affect non-adherence. Our study will evaluate the effectiveness of a multifactor intervention to improve the therapeutic adherence of COPD patients. METHODS/DESIGN: A randomized controlled clinical trial with 140 COPD diagnosed patients selected by a non-probabilistic method of sampling. Subjects will be randomly allocated into two groups, using the block randomization technique. Every patient in each group will be visited four times during the year of the study. INTERVENTION: Motivational aspects related to adherence (beliefs and behaviour): group and individual interviews; cognitive aspects: information about illness; skills: inhaled technique training. Reinforcement of the cognitive-emotional aspects and inhaled technique training will be carried out in all visits of the intervention group. DISCUSSION: Adherence to a prescribed treatment involves a behavioural change. Cognitive, emotional and motivational aspects influence this change and so we consider the best intervention procedure to improve adherence would be a cognitive and emotional strategy which could be applied in daily clinical practice. Our hypothesis is that the application of a multifactor intervention (COPD information, dose reminders and reinforcing audiovisual material, motivational aspects and inhalation technique training) to COPD patients taking inhaled treatment will give a 25% increase in the number of patients showing therapeutic adherence in this group compared to the control group.We will evaluate the effectiveness of this multifactor intervention on patient adherence to inhaled drugs considering that it will be right and feasible to the clinical practice context. TRIAL REGISTRATION: Current Controlled Trials ISRCTN18841601. PMID- 21320301 TI - Temporal stability of Glossina fuscipes fuscipes populations in Uganda. AB - BACKGROUND: Glossina fuscipes, a riverine species of tsetse, is the major vector of human African trypanosomiasis (HAT) in sub-Saharan Africa. Understanding the population dynamics, and specifically the temporal stability, of G. fuscipes will be important for informing vector control activities. We evaluated genetic changes over time in seven populations of the subspecies G. f. fuscipes distributed across southeastern Uganda, including a zone of contact between two historically isolated lineages. A total of 667 tsetse flies were genotyped at 16 microsatellite loci and at one mitochondrial locus. RESULTS: Results of an AMOVA indicated that time of sampling did not explain a significant proportion of the variance in allele frequencies observed across all samples. Estimates of differentiation between samples from a single population ranged from approximately 0 to 0.019, using Jost's DEST. Effective population size estimates using momentum-based and likelihood methods were generally large. We observed significant change in mitochondrial haplotype frequencies in just one population, located along the zone of contact. The change in haplotypes was not accompanied by changes in microsatellite frequencies, raising the possibility of asymmetric mating compatibility in this zone. CONCLUSION: Our results suggest that populations of G. f. fuscipes were stable over the 8-12 generations studied. Future studies should aim to reconcile these data with observed seasonal fluctuations in the apparent density of tsetse. PMID- 21320303 TI - Effectiveness of a structured education reminiscence-based programme for staff on the quality of life of residents with dementia in long-stay units: a study protocol for a cluster randomised trial. AB - BACKGROUND: Current projections indicate that there will be a significant increase in the number of people with dementia in Ireland, from approximately 40,000 at present to 100,000 by 2036. Psychosocial interventions, such as reminiscence, have the potential to improve the quality of life of people with dementia. However, while reminiscence is used widely in dementia care, its impact on the quality of life of people with dementia remains largely undocumented and there is a need for a robust and fair assessment of its overall effectiveness. The DementiA education programme incorporating REminiscence for Staff study will evaluate the effectiveness of a structured reminiscence-based education programme for care staff on the quality of life of residents with dementia in long-stay units. METHODS/DESIGN: The study is a two-group, single-blind cluster randomised trial conducted in public and private long-stay residential settings in Ireland. Randomisation to control and intervention is at the level of the long-stay residential unit. Sample size calculations suggest that 18 residential units each containing 17 people with dementia are required for randomisation to control and intervention groups to achieve power of at least 80% with alpha levels of 0.05. Each resident in the intervention group is linked with a nurse and care assistant who have taken the structured reminiscence-based education programme. Participants in the control group will receive usual care. The primary outcome is quality of life of residents as measured by the Quality of Life-AD instrument. Secondary outcomes include agitation, depression and carer burden. Blinded outcome assessment is undertaken at baseline and at 18-22 weeks post randomisation. DISCUSSION: Trials on reminiscence-based interventions for people with dementia have been scarce and the quality of the information arising from those that have been done has been undermined by methodological problems, particularly in relation to scale and scope. This trial is powered to deliver more credible and durable results. The trial may also convey process utility to a long-stay system in Ireland that has not been geared for education and training, especially in relation to dementia. The results of this trial are applicable to long-stay residential units in Ireland and internationally. TRIAL REGISTRATION: Current Controlled Trials ISRCTN99651465. PMID- 21320302 TI - Reduced antioxidant defense in early onset first-episode psychosis: a case control study. AB - BACKGROUND: Our objective is to determine the activity of the antioxidant defense system at admission in patients with early onset first psychotic episodes compared with a control group. METHODS: Total antioxidant status (TAS) and lipid peroxidation (LOOH) were determined in plasma. Enzyme activities and total glutathione levels were determined in erythrocytes in 102 children and adolescents with a first psychotic episode and 98 healthy controls. RESULTS: A decrease in antioxidant defense was found in patients, measured as decreased TAS and glutathione levels. Lipid damage (LOOH) and glutathione peroxidase activity was higher in patients than controls. Our study shows a decrease in the antioxidant defense system in early onset first episode psychotic patients. CONCLUSIONS: Glutathione deficit seems to be implicated in psychosis, and may be an important indirect biomarker of oxidative stress in early-onset schizophrenia. Oxidative damage is present in these patients, and may contribute to its pathophysiology. PMID- 21320304 TI - Response to mTOR inhibition: activity of eIF4E predicts sensitivity in cell lines and acquired changes in eIF4E regulation in breast cancer. AB - BACKGROUND: Inhibitors of the kinase mTOR, such as rapamycin and everolimus, have been used as cancer therapeutics with limited success since some tumours are resistant. Efforts to establish predictive markers to allow selection of patients with tumours likely to respond have centred on determining phosphorylation states of mTOR or its targets 4E-BP1 and S6K in cancer cells. In an alternative approach we estimated eIF4E activity, a key effector of mTOR function, and tested the hypothesis that eIF4E activity predicts sensitivity to mTOR inhibition in cell lines and in breast tumours. RESULTS: We found a greater than three fold difference in sensitivity of representative colon, lung and breast cell lines to rapamycin. Using an assay to quantify influences of eIF4E on the translational efficiency specified by structured 5'UTRs, we showed that this estimate of eIF4E activity was a significant predictor of rapamycin sensitivity, with higher eIF4E activities indicative of enhanced sensitivity. Surprisingly, non-transformed cell lines were not less sensitive to rapamycin and did not have lower eIF4E activities than cancer lines, suggesting the mTOR/4E-BP1/eIF4E axis is deregulated in these non-transformed cells. In the context of clinical breast cancers, we estimated eIF4E activity by analysing expression of eIF4E and its functional regulators within tumour cells and combining these scores to reflect inhibitory and activating influences on eIF4E. Estimates of eIF4E activity in cancer biopsies taken at diagnosis did not predict sensitivity to 11-14 days of pre-operative everolimus treatment, as assessed by change in tumour cell proliferation from diagnosis to surgical excision. However, higher pre-treatment eIF4E activity was significantly associated with dramatic post-treatment changes in expression of eIF4E and 4E-binding proteins, suggesting that eIF4E is further deregulated in these tumours in response to mTOR inhibition. CONCLUSIONS: Estimates of eIF4E activity predict sensitivity to mTOR inhibition in cell lines but breast tumours with high estimated eIF4E activity gain changes in eIF4E regulation in order to enhance resistance. PMID- 21320305 TI - Anti-inflammatory and anti-infectious effects of Evodia rutaecarpa (Wuzhuyu) and its major bioactive components. AB - This article reviews the anti-inflammatory relative and anti-infectious effects of Evodia rutaecarpa and its major bioactive components and the involvement of the nitric oxide synthases, cyclooxygenase, NADPH oxidase, nuclear factor kappa B, hypoxia-inducible factor 1 alpha, reactive oxygen species, prostaglandins, tumor necrosis factor, LIGHT, amyloid protein and orexigenic neuropeptides. Their potential applications for the treatment of endotoxaemia, obesity, diabetes, Alzheimer's disease and their uses as cardiovascular and gastrointestinal protective agents, analgesics, anti-oxidant, anti-atherosclerosis agents, dermatological agents and anti-infectious agents are highlighted. Stimulation of calcitonin gene-related peptide release may partially explain the analgesic, cardiovascular and gastrointestinal protective, anti-obese activities of Evodia rutaecarpa and its major bioactive components. PMID- 21320307 TI - Characterization of a synthetic human LINE-1 retrotransposon ORFeus-Hs. AB - Long interspersed elements, type 1(LINE-1, L1) are the most abundant and only active autonomous retrotransposons in the human genome. Native L1 elements are inefficiently expressed because of a transcription elongation defect thought to be caused by high adenosine content in L1 sequences. Previously, we constructed a highly active synthetic mouse L1 element (ORFeus-Mm), partially by reducing the nucleotide composition bias. As a result, the transcript abundance of ORFeus-Mm was greatly increased, and its retrotransposition frequency was > 200-fold higher than its native counterpart. In this paper, we report a synthetic human L1 element (ORFeus-Hs) synthesized using a similar strategy. The adenosine content of the L1 open reading frames (ORFs) was reduced from 40% to 27% by changing 25% of the bases in the ORFs, without altering the amino acid sequence. By studying a series of native/synthetic chimeric elements, we observed increased levels of full-length L1 RNA and ORF1 protein and retrotransposition frequency, mostly proportional to increased fraction of synthetic sequence. Overall, the fully synthetic ORFeus-Hs has > 40-fold more RNA but is at most only ~threefold more active than its native counterpart (L1RP); however, its absolute retrotransposition activity is similar to ORFeus-Mm. Owing to the elevated expression of the L1 RNA/protein and its high retrotransposition ability, ORFeus Hs and its chimeric derivatives will be useful tools for mechanistic L1 studies and mammalian genome manipulation. PMID- 21320306 TI - Female house sparrows "count on" male genes: experimental evidence for MHC dependent mate preference in birds. AB - BACKGROUND: Females can potentially assess the quality of potential mates using their secondary sexual traits, and obtain "good genes" that increase offspring fitness. Another potential indirect benefit from mating preferences is genetic compatibility, which does not require extravagant or viability indicator traits. Several studies with mammals and fish indicate that the genes of the major histocompatibility complex (MHC) influence olfactory cues and mating preferences, and such preferences confer genetic benefits to offspring. We investigated whether individual MHC diversity (class I) influences mating preferences in house sparrows (Passer domesticus). RESULTS: Overall, we found no evidence that females preferred males with high individual MHC diversity. Yet, when we considered individual MHC allelic diversity of the females, we found that females with a low number of alleles were most attracted to males carrying a high number of MHC alleles, which might reflect a mating-up preference by allele counting. CONCLUSIONS: This is the first experimental evidence for MHC-dependent mating preferences in an avian species to our knowledge. Our findings raise questions about the underlying mechanisms through which birds discriminate individual MHC diversity among conspecifics, and they suggest a novel mechanism through which mating preferences might promote the evolution of MHC polymorphisms and generate positive selection for duplicated MHC loci. PMID- 21320308 TI - Developing and implementing mental health policy in Zanzibar, a low income country off the coast of East Africa. AB - BACKGROUND: The Zanzibar Ministry of Health and Social Welfare, concerned about mental health in the country, requested technical assistance from WHO in 1997. AIMS: This article describes the facilitation over many years by a WHO Collaborating Centre, of sustainable mental health developments in Zanzibar, one of the poorest countries in the world, using systematic approaches to policy design and implementation. METHODS: Based on intensive prior situation appraisal and consultation, a multi-faceted set of interventions combining situation appraisal to inform planning; sustained policy dialogue at Union and state levels; development of policy and legislation, development of strategic action plans, establishment of intersectoral national mental health implementation committee, establishment of national mental health coordination system, integration of mental health into primary care, strengthening of primary secondary care liaison, rationalisation and strengthening of secondary care system, ensuring adequate supply of medicines, use of good practice guidelines and health information systems, development of services for people with intellectual disability, establishment of formal mechanism for close liaison between the mental health services and other governmental, non-governmental and traditional sectors, mental health promotion, suicide prevention, and research and development. RESULTS: The policy and legislation introduced in 1999 have resulted in enhanced mental health activities over the ensuing decade, within a setting of extreme low resource. However, advances ebb and flow and continued efforts are required to maintain progress and continue mental health developments. Lessons learnt have informed the development of mental health policies in neighbouring countries. CONCLUSIONS: A multi-faceted and comprehensive programme can be effective in achieving considerable strengthening of mental health programmes and services even in extremely low resource settings, but requires sustained input and advocacy if gains are to be maintained and enhanced. PMID- 21320309 TI - Viral-mediated oncolysis is the most critical factor in the late-phase of the tumor regression process upon vaccinia virus infection. AB - BACKGROUND: In principle, the elimination of malignancies by oncolytic virotherapy could proceed by different mechanisms--e.g. tumor cell specific oncolysis, destruction of the tumor vasculature or an anti-tumoral immunological response. In this study, we analyzed the contribution of these factors to elucidate the responsible mechanism for regression of human breast tumor xenografts upon colonization with an attenuated vaccinia virus (VACV). METHODS: Breast tumor xenografts were analyzed 6 weeks post VACV infection (p.i.; regression phase) by immunohistochemistry and mouse-specific expression arrays. Viral-mediated oncolysis was determined by tumor growth analysis combined with microscopic studies of intratumoral virus distribution. The tumor vasculature was morphologically characterized by diameter and density measurements and vessel functionality was analyzed by lectin perfusion and extravasation studies. Immunological aspects of viral-mediated tumor regression were studied in either immune-deficient mouse strains (T-, B-, NK-cell-deficient) or upon cyclophosphamide-induced immunosuppression (MHCII+-cell depletion) in nude mice. RESULTS: Late stage VACV-infected breast tumors showed extensive necrosis, which was highly specific to cancer cells. The tumor vasculature in infected tumor areas remained functional and the endothelial cells were not infected. However, viral colonization triggers hyperpermeability and dilatation of the tumor vessels, which resembled the activated endothelium in wounded tissue. Moreover, we demonstrated an increased expression of genes involved in leukocyte endothelial cell interaction in VACV-infected tumors, which orchestrate perivascular inflammatory cell infiltration. The immunohistochemical analysis of infected tumors displayed intense infiltration of MHCII-positive cells and colocalization of tumor vessels with MHCII+/CD31+ vascular leukocytes. However, GI-101A tumor growth analysis upon VACV-infection in either immunosuppressed nude mice (MHCII+-cell depleted) or in immune-deficient mouse strains (T-, B-, NK-cell deficient) revealed that neither MHCII-positive immune cells nor T-, B-, or NK cells contributed significantly to VACV-mediated tumor regression. In contrast, tumors of immunosuppressed mice showed enhanced viral spreading and tumor necrosis. CONCLUSIONS: Taken together, these results indicate that VACV-mediated oncolysis is the primary mechanism of tumor shrinkage in the late regression phase. Neither the destruction of the tumor vasculature nor the massive VACV mediated intratumoral inflammation was a prerequisite for tumor regression. We propose that approaches to enhance viral replication and spread within the tumor microenvironment should improve therapeutical outcome. PMID- 21320310 TI - Developing a method to derive alcohol-attributable fractions for HIV/AIDS mortality based on alcohol's impact on adherence to antiretroviral medication. AB - BACKGROUND: Alcohol consumption is causally linked to nonadherence to antiretroviral treatment that in turn causes an increase in HIV/AIDS mortality. This article presents a method to calculate the percentage of HIV/AIDS deaths attributable to alcohol consumption and the associated uncertainty. METHODS: By combining information on risk relations from a number of published sources, we estimated alcohol-attributable fractions (AAFs) of HIV/AIDS in a stepwise procedure. First, we estimated the effect of alcohol consumption on adherence to antiretroviral treatment, and then we combined this estimate with the impact of nonadherence on death. The 95% uncertainty intervals were computed by estimating the variance of the AAFs using Taylor series expansions of one and multiple variables. AAFs were determined for each of the five Global Burden of Disease regions of Africa, based on country-specific treatment and alcohol consumption data from 2005. RESULTS: The effects of alcohol on HIV/AIDS in the African Global Burden of Disease regions range from 0.03% to 0.34% for men and from 0% to 0.17% for women, depending on region and age category. The detrimental effect of alcohol consumption was statistically significant in every region and age category except for the North Africa/Middle East region. CONCLUSIONS: Although the method has its limitations, it was shown to be feasible and provided estimates of the impact of alcohol use on the mortality outcome of HIV/AIDS. PMID- 21320311 TI - Role of hypoxia and glycolysis in the development of multi-drug resistance in human tumor cells and the establishment of an orthotopic multi-drug resistant tumor model in nude mice using hypoxic pre-conditioning. AB - BACKGROUND: The development of multi-drug resistant (MDR) cancer is a significant challenge in the clinical treatment of recurrent disease. Hypoxia is an environmental selection pressure that contributes to the development of MDR. Many cancer cells, including MDR cells, resort to glycolysis for energy acquisition. This study aimed to explore the relationship between hypoxia, glycolysis, and MDR in a panel of human breast and ovarian cancer cells. A second aim of this study was to develop an orthotopic animal model of MDR breast cancer. METHODS: Nucleic and basal protein was extracted from a panel of human breast and ovarian cancer cells; MDR cells and cells pre-exposed to either normoxic or hypoxic conditions. Western blotting was used to assess the expression of MDR markers, hypoxia inducible factors, and glycolytic proteins. Tumor xenografts were established in the mammary fat pad of nu/nu mice using human breast cancer cells that were pre exposed to either hypoxic or normoxic conditions. Immunohistochemistry was used to assess the MDR character of excised tumors. RESULTS: Hypoxia induces MDR and glycolysis in vitro, but the cellular response is cell-line specific and duration dependent. Using hypoxic, triple-negative breast cancer cells to establish 100 mm3 tumor xenografts in nude mice is a relevant model for MDR breast cancer. CONCLUSION: Hypoxic pre-conditiong and xenografting may be used to develop a multitude of orthotopic models for MDR cancer aiding in the study and treatment of the disease. PMID- 21320312 TI - Enhancing implementation of tobacco use prevention and cessation counselling guideline among dental providers: a cluster randomised controlled trial. AB - BACKGROUND: Tobacco use adversely affects oral health. Tobacco use prevention and cessation (TUPAC) counselling guidelines recommend that healthcare providers ask about each patient's tobacco use, assess the patient's readiness and willingness to stop, document tobacco use habits, advise the patient to stop, assist and help in quitting, and arrange monitoring of progress at follow-up appointments. Adherence to such guidelines, especially among dental providers, is poor. To improve guideline implementation, it is essential to understand factors influencing it and find effective ways to influence those factors. The aim of the present study protocol is to introduce a theory-based approach to diagnose implementation difficulties of TUPAC counselling guidelines among dental providers. METHODS: Theories of behaviour change have been used to identify key theoretical domains relevant to the behaviours of healthcare providers involved in implementing clinical guidelines. These theoretical domains will inform the development of a questionnaire aimed at assessing the implementation of the TUPAC counselling guidelines among Finnish municipal dental providers. Specific items will be drawn from the guidelines and the literature on TUPAC studies. After identifying potential implementation difficulties, we will design two interventions using theories of behaviour change to link them with relevant behaviour change techniques aiming to improve guideline adherence. For assessing the implementation of TUPAC guidelines, the electronic dental record audit and self-reported questionnaires will be used. DISCUSSION: To improve guideline adherence, the theoretical-domains approach could provide a comprehensive basis for assessing implementation difficulties, as well as designing and evaluating interventions. After having identified implementation difficulties, we will design and test two interventions to enhance TUPAC guideline adherence. Using the cluster randomised controlled design, we aim to provide further evidence on intervention effects, as well as on the validity and feasibility of the theoretical-domain approach. The empirical data collected within this trial will be useful in testing whether this theoretical-domain approach can improve our understanding of the implementation of TUPAC guidelines among dental providers. TRIAL REGISTRATION: Current Controlled Trials ISRCTN15427433. PMID- 21320313 TI - Closing-wedge high tibial osteotomy: survival and risk factor analysis at long term follow up. AB - BACKGROUND: Closing-wedge high tibial osteotomy (HTO) is successful for the treatment of medial osteoarthritis with varus malalignment. Preoperative risk factors for HTO failure are still controversial. The aim of this study was to elucidate the outcome and assess the influence of risk factors on long term HTO survival. METHODS: 199 patients were retrospectively studied with a mean follow up period of 9.6 years after HTO. HTO failure was defined as the need for conversion to TKA. Survival was analyzed with the Kaplan-Meier method. Knee function was evaluated by the Hospital for Special Surgery (HSS) score. HTO associated complications were also assessed. Univariate, multivariate, and logistic regression analysis were performed to evaluate the influence of age, gender, BMI, preoperative Kellgren-Lawrence osteoarthritis grade, and varus angle on HTO failure. RESULTS: 39 complications were recorded. Thus far, 36 HTOs were converted to TKA. The survival of HTO was 84% after 9.6 years. Knee function was considered excellent or good in 64% of patients. A significant preoperative risk factor for HTO failure was osteoarthritis, Kellgren-Lawrence grade >2. CONCLUSION: HTO provides good clinical results in long-term follow-up. Preoperative osteoarthritis Kellgren-Lawrence grade >2 is a significant predictive risk factor for HTO failure. Results of HTO may be improved by careful patient selection. Complications associated with HTO should not be underestimated. PMID- 21320314 TI - Upper gastrointestinal endoscopy for dyspepsia: exploratory study of factors influencing patient compliance in Greece. AB - BACKGROUND: Upper gastrointestinal endoscopy is the most preferable diagnostic examination for patients over fifty when upper gastrointestinal symptoms appear. However, limited knowledge exists in concerns to the compliance of primary care patients' to the doctors' recommendations for endoscopy. METHODS: Patients who visited primary care practices in Greece and experienced upper gastrointestinal symptoms within a 10 days screening study, were referred for an upper endoscopy exam. The patients which refused to complete the endoscopy exam, were interviewed by the use of an open- ended translated and validated questionnaire, the Identification of Dyspepsia in General Population (IDGP) questionnaire. A qualitative thematic analysis grounded on the theory of planned behavior was performed to reveal the reasons for patients' refusal, while socio-demographic predictors were also assessed. RESULTS: Nine hundred and ninety two patients were recorded, 159 of them (16%) were found positive for dyspepsia and gastro esophageal reflux disease according to the IDGP questionnaire. Out of the above, 131 (83.6%) patients refused further investigation with endoscopy. Patients who refused upper endoscopy were predominantly female (87.8%) (p = 0.036) and over the age of 50. The lack of severe symptoms, fear of pain, concerns of sedation, comorbidity and competing life demands were reported by patients as barriers to performing an endoscopic investigation. CONCLUSIONS: Patients with dyspepsia in rural Greece tend to avoid upper gastrointestinal endoscopy, with two major axons considered to be the causes of patients' refusal: their beliefs towards endoscopy and their personal capability to cope with it. Future research examining reasons of low compliance should be carried out in combination with modern behavioral theories so as to investigate into the above. PMID- 21320315 TI - Effect of terminal accuracy requirements on temporal gaze-hand coordination during fast discrete and reciprocal pointings. AB - BACKGROUND: Rapid discrete goal-directed movements are characterized by a well known coordination pattern between the gaze and the hand displacements. The gaze always starts prior to the hand movement and reaches the target before hand velocity peak. Surprisingly, the effect of the target size on the temporal gaze hand coordination has not been directly investigated. Moreover, goal-directed movements are often produced in a reciprocal rather than in a discrete manner. The objectives of this work were to assess the effect of the target size on temporal gaze-hand coordination during fast 1) discrete and 2) reciprocal pointings. METHODS: Subjects performed fast discrete (experiment 1) and reciprocal (experiment 2) pointings with an amplitude of 50 cm and four target diameters (7.6, 3.8, 1.9 and 0.95 cm) leading to indexes of difficulty (ID = log2[2A/D]) of 3.7, 4.7, 5.7 and 6.7 bits. Gaze and hand displacements were synchronously recorded. Temporal gaze-hand coordination parameters were compared between experiments (discrete and reciprocal pointings) and IDs using analyses of variance (ANOVAs). RESULTS: Data showed that the magnitude of the gaze-hand lead pattern was much higher for discrete than for reciprocal pointings. Moreover, while it was constant for discrete pointings, it decreased systematically with an increasing ID for reciprocal pointings because of the longer duration of gaze anchoring on target. CONCLUSION: Overall, the temporal gaze-hand coordination analysis revealed that even for high IDs, fast reciprocal pointings could not be considered as a concatenation of discrete units. Moreover, our data clearly illustrate the smooth adaptation of temporal gaze-hand coordination to terminal accuracy requirements during fast reciprocal pointings. It will be interesting for further researches to investigate if the methodology used in the experiment 2 allows assessing the effect of sensori-motor deficits on gaze-hand coordination. PMID- 21320316 TI - Effects of Study Design and Allocation on participant behaviour--ESDA: study protocol for a randomized controlled trial. AB - BACKGROUND: What study participants think about the nature of a study has been hypothesised to affect subsequent behaviour and to potentially bias study findings. In this trial we examine the impact of awareness of study design and allocation on participant drinking behaviour. METHODS/DESIGN: A three-arm parallel group randomised controlled trial design will be used. All recruitment, screening, randomisation, and follow-up will be conducted on-line among university students. Participants who indicate a hazardous level of alcohol consumption will be randomly assigned to one of three groups. Group A will be informed their drinking will be assessed at baseline and again in one month (as in a cohort study design). Group B will be told the study is an intervention trial and they are in the control group. Group C will be told the study is an intervention trial and they are in the intervention group. All will receive exactly the same brief educational material to read. After one month, alcohol intake for the past 4 weeks will be assessed. DISCUSSION: The experimental manipulations address subtle and previously unexplored ways in which participant behaviour may be unwittingly influenced by standard practice in trials. Given the necessity of relying on self-reported outcome, it will not be possible to distinguish true behaviour change from reporting artefact. This does not matter in the present study, as any effects of awareness of study design or allocation involve bias that is not well understood. There has been little research on awareness effects, and our outcomes will provide an indication of the possible value of further studies of this type and inform hypothesis generation. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12610000846022. PMID- 21320317 TI - The salt-responsive transcriptome of chickpea roots and nodules via deepSuperSAGE. AB - BACKGROUND: The combination of high-throughput transcript profiling and next generation sequencing technologies is a prerequisite for genome-wide comprehensive transcriptome analysis. Our recent innovation of deepSuperSAGE is based on an advanced SuperSAGE protocol and its combination with massively parallel pyrosequencing on Roche's 454 sequencing platform. As a demonstration of the power of this combination, we have chosen the salt stress transcriptomes of roots and nodules of the third most important legume crop chickpea (Cicer arietinum L.). While our report is more technology-oriented, it nevertheless addresses a major world-wide problem for crops generally: high salinity. Together with low temperatures and water stress, high salinity is responsible for crop losses of millions of tons of various legume (and other) crops. Continuously deteriorating environmental conditions will combine with salinity stress to further compromise crop yields. As a good example for such stress-exposed crop plants, we started to characterize salt stress responses of chickpeas on the transcriptome level. RESULTS: We used deepSuperSAGE to detect early global transcriptome changes in salt-stressed chickpea. The salt stress responses of 86,919 transcripts representing 17,918 unique 26 bp deepSuperSAGE tags (UniTags) from roots of the salt-tolerant variety INRAT-93 two hours after treatment with 25 mM NaCl were characterized. Additionally, the expression of 57,281 transcripts representing 13,115 UniTags was monitored in nodules of the same plants. From a total of 144,200 analyzed 26 bp tags in roots and nodules together, 21,401 unique transcripts were identified. Of these, only 363 and 106 specific transcripts, respectively, were commonly up- or down-regulated (>3.0-fold) under salt stress in both organs, witnessing a differential organ-specific response to stress.Profiting from recent pioneer works on massive cDNA sequencing in chickpea, more than 9,400 UniTags were able to be linked to UniProt entries. Additionally, gene ontology (GO) categories over-representation analysis enabled to filter out enriched biological processes among the differentially expressed UniTags. Subsequently, the gathered information was further cross-checked with stress-related pathways. From several filtered pathways, here we focus exemplarily on transcripts associated with the generation and scavenging of reactive oxygen species (ROS), as well as on transcripts involved in Na+ homeostasis. Although both processes are already very well characterized in other plants, the information generated in the present work is of high value. Information on expression profiles and sequence similarity for several hundreds of transcripts of potential interest is now available. CONCLUSIONS: This report demonstrates, that the combination of the high-throughput transcriptome profiling technology SuperSAGE with one of the next-generation sequencing platforms allows deep insights into the first molecular reactions of a plant exposed to salinity. Cross validation with recent reports enriched the information about the salt stress dynamics of more than 9,000 chickpea ESTs, and enlarged their pool of alternative transcripts isoforms. As an example for the high resolution of the employed technology that we coin deepSuperSAGE, we demonstrate that ROS scavenging and -generating pathways undergo strong global transcriptome changes in chickpea roots and nodules already 2 hours after onset of moderate salt stress (25 mM NaCl). Additionally, a set of more than 15 candidate transcripts are proposed to be potential components of the salt overly sensitive (SOS) pathway in chickpea. Newly identified transcript isoforms are potential targets for breeding novel cultivars with high salinity tolerance. We demonstrate that these targets can be integrated into breeding schemes by micro-arrays and RT-PCR assays downstream of the generation of 26 bp tags by SuperSAGE. PMID- 21320318 TI - A case report of vibration-induced hand comorbidities in a postwoman. AB - BACKGROUND: Prolonged exposure to hand-transmitted vibration is associated with an increased occurrence of symptoms and signs of disorders in the vascular, neurological and osteoarticular systems of the upper limbs. However, the available epidemiological evidence is derived from studies on high vibration levels caused by vibratory tools, whereas little is known about possible upper limb disorders caused by chronic exposure to low vibration levels emitted by fixed sources. CASE PRESENTATION: We present the case of a postwoman who delivered mail for 15 years using a low-powered motorcycle. The woman was in good health until 2002, when she was diagnosed with bilateral Raynaud's phenomenon. In March 2003 a bilateral carpal tunnel syndrome was electromyographically diagnosed; surgical treatment was ineffective. Further examinations in 2005 highlighted the presence of chronic tendonitis (right middle finger flexor). RISK ASSESSMENT: From 1987, for 15 years, our patient rode her motorcycle for 4 h/day, carrying a load of 20-30 kg. For about a quarter of the time she drove over country roads. Using the information collected about the tasks carried out every day by the postwoman and some measurements performed on both handles of the motorcycle, as well as on both iron parts of the handlebars, we reconstructed the woman's previous exposure to hand-arm vibration. 8-hour energy-equivalent frequency weighted acceleration was about 2.4 m/s2. The lifetime dose was 1.5 * 109(m2/s4)hd. CONCLUSIONS: The particular set of comorbidities presented by our patient suggests a common pathophysiological basis for all the diseases. Considering the level of exposure to vibrations and the lack of specific knowledge on the effects of vibration in women, we hypothesize an association between the work exposure and the onset of the diseases. PMID- 21320319 TI - Assessing the information desire of patients with advanced cancer by providing information with a decision aid, which is evaluated in a randomized trial: a study protocol. AB - BACKGROUND: There is a continuing debate on the desirability of informing patients with cancer and thereby involving them in treatment decisions. On the one hand, information uptake may be hampered, and additional stress could be inflicted by involving these patients. On the other hand, even patients with advanced cancer desire information on risks and prognosis. To settle the debate, a decision aid will be developed and presented to patients with advanced disease at the point of decision making. The aid is used to assess the amount of information desired. Factors related to information desire are explored, as well as the ability of the medical oncologist to judge the patient's information desire. The effects of the information on patient well-being are assessed by comparing the decision aid group with a usual care group. METHODS/DESIGN: This study is a randomized controlled trial of patients with advanced colorectal, breast, or ovarian cancer who have started treatment with first-line palliative chemotherapy. The trial will consist of 100 patients in the decision aid group and 70 patients in the usual care group. To collect complete data of 170 patients, 246 patients will be approached for the study. Patients will complete a baseline questionnaire on sociodemographic data, well-being measures, and psychological measures, believed to predict information desire. The medical oncologist will judge the patient's information desire. After disease progression is diagnosed, the medical oncologist offers the choice between second-line palliative chemotherapy plus best supportive care (BSC) and BSC alone. Randomization will take place to determine whether patients will receive usual care (n = 70) or usual care and the decision aid (n = 100). The aid offers information about the potential risks and benefits of both treatment options, in terms of adverse events, tumour response, and survival. Patients decide for each item whether they desire the information or not. Two follow-up questionnaires will evaluate the effect of the decision aid. DISCUSSION: This study attempts to settle the debate on the desirability of informing patients with cancer. In contrast to several earlier studies, we will actually deliver information on treatment options to patients at the point of decision making. PMID- 21320320 TI - The origin of multicellularity in cyanobacteria. AB - BACKGROUND: Cyanobacteria are one of the oldest and morphologically most diverse prokaryotic phyla on our planet. The early development of an oxygen-containing atmosphere approximately 2.45-2.22 billion years ago is attributed to the photosynthetic activity of cyanobacteria. Furthermore, they are one of the few prokaryotic phyla where multicellularity has evolved. Understanding when and how multicellularity evolved in these ancient organisms would provide fundamental information on the early history of life and further our knowledge of complex life forms. RESULTS: We conducted and compared phylogenetic analyses of 16S rDNA sequences from a large sample of taxa representing the morphological and genetic diversity of cyanobacteria. We reconstructed ancestral character states on 10,000 phylogenetic trees. The results suggest that the majority of extant cyanobacteria descend from multicellular ancestors. Reversals to unicellularity occurred at least 5 times. Multicellularity was established again at least once within a single-celled clade. Comparison to the fossil record supports an early origin of multicellularity, possibly as early as the "Great Oxygenation Event" that occurred 2.45-2.22 billion years ago. CONCLUSIONS: The results indicate that a multicellular morphotype evolved early in the cyanobacterial lineage and was regained at least once after a previous loss. Most of the morphological diversity exhibited in cyanobacteria today--including the majority of single-celled species -arose from ancient multicellular lineages. Multicellularity could have conferred a considerable advantage for exploring new niches and hence facilitated the diversification of new lineages. PMID- 21320321 TI - Relationships between biomarkers of cartilage, bone, synovial metabolism and knee pain provide insights into the origins of pain in early knee osteoarthritis. AB - INTRODUCTION: We tested the hypothesis that there exist relationships between the onset of early stage radiographically defined knee osteoarthritis (OA), pain and changes in biomarkers of joint metabolism. METHODS: Using Kellgren-Lawrence (K/L) grading early radiographic knee OA (K/L 2) was detected in 16 of 46 patients. These grades (K/L 1 is no OA and K/L 2 is early OA) were divided into two groups according to the presence or absence of persistent knee pain. Sera (s) and urines (u) were analysed with biomarkers for cartilage collagen cleavage (sC2C and uCTX II) and synthesis (sCPII), bone resorption (uNTx) and synovitis (hyaluronic acid: sHA). RESULTS: sCPII decreased and sC2C/sCPII, uCTX-II/sCPII and sHA increased with onset of OA (K/L 2 versus K/L 1) irrespective of joint pain. In contrast, sC2C and uCTX-II remained unchanged in early OA patients. Of the patients with K/L grades 1 and 2 sC2C, sCPII, sHA, uNTX and uCTX-II were all significantly increased in patients with knee pain independent of grade. Among the K/L grade 2 subjects, only uCTX-II and uCTX-II/sCPII were increased in those with knee pain. In grade 1 patients both sC2C and sCPII were increased in those with knee pain. No such grade specific changes were seen for the other biomarkers including sHA. CONCLUSIONS: These results suggest that changes in cartilage matrix turnover detected by molecular biomarkers may reflect early changes in cartilage structure that account directly or indirectly for knee pain. Also K/L grade 1 patients with knee pain exhibit biomarker features of early OA. PMID- 21320322 TI - A systematic review of interventions for promoting active transportation to school. AB - BACKGROUND: Active transportation to school is an important contributor to the total physical activity of children and adolescents. However, active school travel has declined over time, and interventions are needed to reverse this trend. The purpose of this paper is to review intervention studies related to active school transportation to guide future intervention research. METHODS: A systematic review was conducted to identify intervention studies of active transportation to school published in the scientific literature through January 2010. Five electronic databases and a manual search were conducted. Detailed information was extracted, including a quantitative assessment comparing the effect sizes, and a qualitative assessment using an established evaluation tool. RESULTS: We identified 14 interventions that focused on active transportation to school. These interventions mainly focused on primary school children in the United States, Australia, and the United Kingdom. Almost all the interventions used quasi-experimental designs (10/14), and most of the interventions reported a small effect size on active transportation (6/14). CONCLUSION: More research with higher quality study designs and measures should be conducted to further evaluate interventions and to determine the most successful strategies for increasing active transportation to school. PMID- 21320323 TI - The genetic interaction network of CCW12, a Saccharomyces cerevisiae gene required for cell wall integrity during budding and formation of mating projections. AB - BACKGROUND: Mannoproteins construct the outer cover of the fungal cell wall. The covalently linked cell wall protein Ccw12p is an abundant mannoprotein. It is considered as crucial structural cell wall component since in baker's yeast the lack of CCW12 results in severe cell wall damage and reduced mating efficiency. RESULTS: In order to explore the function of CCW12, we performed a Synthetic Genetic Analysis (SGA) and identified genes that are essential in the absence of CCW12. The resulting interaction network identified 21 genes involved in cell wall integrity, chitin synthesis, cell polarity, vesicular transport and endocytosis. Among those are PFD1, WHI3, SRN2, PAC10, FEN1 and YDR417C, which have not been related to cell wall integrity before. We correlated our results with genetic interaction networks of genes involved in glucan and chitin synthesis. A core of genes essential to maintain cell integrity in response to cell wall stress was identified. In addition, we performed a large-scale transcriptional analysis and compared the transcriptional changes observed in mutant ccw12Delta with transcriptomes from studies investigating responses to constitutive or acute cell wall damage. We identified a set of genes that are highly induced in the majority of the mutants/conditions and are directly related to the cell wall integrity pathway and cell wall compensatory responses. Among those are BCK1, CHS3, EDE1, PFD1, SLT2 and SLA1 that were also identified in the SGA. In contrast, a specific feature of mutant ccw12Delta is the transcriptional repression of genes involved in mating. Physiological experiments substantiate this finding. Further, we demonstrate that Ccw12p is present at the cell periphery and highly concentrated at the presumptive budding site, around the bud, at the septum and at the tip of the mating projection. CONCLUSIONS: The combination of high throughput screenings, phenotypic analyses and localization studies provides new insight into the function of Ccw12p. A compensatory response, culminating in cell wall remodelling and transport/recycling pathways is required to buffer the loss of CCW12. Moreover, the enrichment of Ccw12p in bud, septum and mating projection is consistent with a role of Ccw12p in preserving cell wall integrity at sites of active growth.The microarray data produced in this analysis have been submitted to NCBI GEO database and GSE22649 record was assigned. PMID- 21320324 TI - The role of IREB2 and transforming growth factor beta-1 genetic variants in COPD: a replication case-control study. AB - BACKGROUND: Genetic factors are known to contribute to COPD susceptibility and these factors are not fully understood. Conflicting results have been reported for many genetic studies of candidate genes based on their role in the disease. Genome-wide association studies in combination with expression profiling have identified a number of new candidates including IREB2. A meta-analysis has implicated transforming growth factor beta-1 (TGFbeta1) as a contributor to disease susceptibility. METHODS: We have examined previously reported associations in both genes in a collection of 1017 white COPD patients and 912 non-diseased smoking controls. Genotype information was obtained for seven SNPs in the IREB2 gene, and for four SNPs in the TGFbeta1 gene. Allele and genotype frequencies were compared between COPD cases and controls, and odds ratios were calculated. The analysis was adjusted for age, sex, smoking and centre, including interactions of age, sex and smoking with centre. RESULTS: Our data replicate the association of IREB2 SNPs in association with COPD for SNP rs2568494, rs2656069 and rs12593229 with respective adjusted p-values of 0.0018, 0.0039 and 0.0053. No significant associations were identified for TGFbeta1. CONCLUSIONS: These studies have therefore confirmed that the IREB2 locus is a contributor to COPD susceptibility and suggests a new pathway in COPD pathogenesis invoking iron homeostasis. PMID- 21320325 TI - Two novel types of hexokinases in the moss Physcomitrella patens. AB - BACKGROUND: Hexokinase catalyzes the phosphorylation of glucose and fructose, but it is also involved in sugar sensing in both fungi and plants. We have previously described two types of hexokinases in the moss Physcomitrella. Type A, exemplified by PpHxk1, the major hexokinase in Physcomitrella, is a soluble protein that localizes to the chloroplast stroma. Type B, exemplified by PpHxk2, has an N-terminal membrane anchor. Both types are found also in vascular plants, and localize to the chloroplast stroma and mitochondrial membranes, respectively. RESULTS: We have now characterized all 11 hexokinase encoding genes in Physcomitrella. Based on their N-terminal sequences and intracellular localizations, three of the encoded proteins are type A hexokinases and four are type B hexokinases. One of the type B hexokinases has a splice variant without a membrane anchor, that localizes to the cytosol and the nucleus. However, we also found two new types of hexokinases with no obvious orthologs in vascular plants. Type C, encoded by a single gene, has neither transit peptide nor membrane anchor, and is found in the cytosol and in the nucleus. Type D hexokinases, encoded by three genes, have membrane anchors and localize to mitochondrial membranes, but their sequences differ from those of the type B hexokinases. Interestingly, all moss hexokinases are more similar to each other in overall sequence than to hexokinases from other plants, even though characteristic sequence motifs such as the membrane anchor of the type B hexokinases are highly conserved between moss and vascular plants, indicating a common origin for hexokinases of the same type. CONCLUSIONS: We conclude that the hexokinase gene family is more diverse in Physcomitrella, encoding two additional types of hexokinases that are absent in vascular plants. In particular, the presence of a cytosolic and nuclear hexokinase (type C) sets Physcomitrella apart from vascular plants, and instead resembles yeast, where all hexokinases localize to the cytosol. The fact that all moss hexokinases are more similar to each other than to hexokinases from vascular plants, even though both type A and type B hexokinases are present in all plants, further suggests that the hexokinase gene family in Physcomitrella has undergone concerted evolution. PMID- 21320326 TI - Primary effusion lymphoma associated with Human Herpes Virus-8 and Epstein Barr virus in an HIV-infected woman from Kampala, Uganda: a case report. AB - INTRODUCTION: Primary effusion lymphoma is a recently recognized entity of AIDS related non-Hodgkin lymphomas. Despite Africa being greatly affected by the HIV/AIDS pandemic, an extensive MEDLINE/PubMed search failed to find any report of primary effusion lymphoma in sub-Saharan Africa. To our knowledge this is the first report of primary effusion lymphoma in sub-Saharan Africa. We report the clinical, cytomorphologic and immunohistochemical findings of a patient with primary effusion lymphoma. CASE PRESENTATION: A 70-year-old newly diagnosed HIV positive Ugandan African woman presented with a three-month history of cough, fever, weight loss and drenching night sweats. Three weeks prior to admission she developed right sided chest pain and difficulty in breathing. On examination she had bilateral pleural effusions.Haematoxylin and eosin stained cytologic sections of the formalin-fixed paraffin-embedded cell block made from the pleural fluid were processed in the Department of Pathology, Makerere University, College of Health Sciences, Kampala, Uganda. Immunohistochemistry was done at the Institute of Haematology and Oncology "L and A Seragnoli", Bologna University School of Medicine, Bologna, Italy, using alkaline phosphatase anti-alkaline phosphatase method. In situ hybridization was used for detection of Epstein-Barr virus.The tumor cells were CD45+, CD30+, CD38+, HHV-8 LANA-1+; but were negative for CD3-, CD20-, CD19-, and CD79a- and EBV RNA+ on in situ hybridization. CD138 and Ki-67 were not evaluable. Our patient tested HIV positive and her CD4 cell count was 127/MUL. CONCLUSIONS: A definitive diagnosis of primary effusion lymphoma rests on finding a proliferation of large immunoblastic, plasmacytoid and anaplastic cells; HHV-8 in the tumor cells, an immunophenotype that is CD45+, pan B-cell marker negative and lymphocyte activated marker positive. It is essential for clinicians and pathologists to have a high index of suspicion of primary effusion lymphoma when handling HIV positive patients who have effusions without palpable tumor masses. Basic immunohistochemistry is essential for definitive diagnosis. PMID- 21320327 TI - Benign giant mediastinal schwannoma presenting as cardiac tamponade in a woman: a case report. AB - INTRODUCTION: Mediastinal schwannomas are typically benign and asymptomatic, and generally present no immediate risks. We encountered a rare case of a giant benign posterior mediastinal schwannoma, complicated by life-threatening cardiac tamponade. CASE PRESENTATION: We report the case of a 72-year-old Japanese woman, who presented with cardiogenic shock. Computed tomography of the chest revealed a posterior mediastinal mass 150 cm in diameter, with pericardial effusion. The cardiac tamponade was treated with prompt pericardial fluid drainage. A biopsy was taken from the mass, and after histological examination, it was diagnosed as a benign schwannoma, a well-encapsulated non-infiltrating tumor, originating from the intrathoracic vagus nerve. It was successfully excised, restoring normal cardiac function. CONCLUSION: Our case suggests that giant mediastinal schwannomas, although generally benign and asymptomatic, should be excised upon discovery to prevent the development of life-threatening cardiopulmonary complications. PMID- 21320328 TI - Isolated angioedema of the bowel due to C1 esterase inhibitor deficiency: a case report and review of literature. AB - INTRODUCTION: We report a rare, classic case of isolated angioedema of the bowel due to C1-esterase inhibitor deficiency. It is a rare presentation and very few cases have been reported worldwide. Angioedema has been classified into three categories. CASE PRESENTATION: A 66-year-old Caucasian man presented with a ten month history of episodic severe cramping abdominal pain, associated with loose stools. A colonoscopy performed during an acute attack revealed nonspecific colitis. Computed tomography of the abdomen performed at the same time showed a thickened small bowel and ascending colon with a moderate amount of free fluid in the abdomen. Levels of C4 (< 8 mg/dL; reference range 15 to 50 mg/dL), CH50 (< 10 U/mL; reference range 29 to 45 U/ml) and C1 inhibitor (< 4 mg/dL; reference range 14 to 30 mg/dL) were all low, supporting a diagnosis of acquired angioedema with isolated bowel involvement. Our patient's symptoms improved with antihistamine and supportive treatment. CONCLUSION: In addition to a detailed comprehensive medical history, laboratory data and imaging studies are required to confirm a diagnosis of angioedema due to C1 esterase inhibitor deficiency. PMID- 21320329 TI - Human Nek6 is a monomeric mostly globular kinase with an unfolded short N terminal domain. AB - BACKGROUND: The NIMA-related kinases (Neks) are widespread among eukaryotes. In mammalians they represent an evolutionarily conserved family of 11 serine/threonine kinases, with 40-45% amino acid sequence identity to the Aspergillus nidulans mitotic regulator NIMA within their catalytic domains. Neks have cell cycle-related functions and were recently described as related to pathologies, particularly cancer, consisting in potential chemotherapeutic targets. Human Nek6, -7 and -9 are involved in the control of mitotic spindle formation, acting together in a mitotic kinase cascade, but their mechanism of regulation remain elusive. RESULTS: In this study we performed a biophysical and structural characterization of human Nek6 with the aim of obtaining its low resolution and homology models. SAXS experiments showed that hNek6 is a monomer of a mostly globular, though slightly elongated shape. Comparative molecular modeling together with disorder prediction analysis also revealed a flexible disordered N-terminal domain for hNek6, which we found to be important to mediate interactions with diverse partners. SEC-MALS experiments showed that hNek6 conformation is dependent on its activation/phosphorylation status, a higher phosphorylation degree corresponding to a bigger Stokes radius. Circular dichroism spectroscopy confirmed our in silico predictions of secondary structure content and thermal stability shift assays revealed a slightly higher stability of wild-type hNek6 compared to the activation loop mutant hNek6(S206A). CONCLUSIONS: Our data present the first low resolution 3D structure of hNek6 protein in solution. SAXS, comparative modeling and SEC-MALS analysis revealed that hNek6 is a monomeric kinase of slightly elongated shape and a short unfolded N-terminal domain. PMID- 21320330 TI - Sizing the lung of mechanically ventilated patients. AB - INTRODUCTION: This small observational study was motivated by our belief that scaling the tidal volume in mechanically ventilated patients to the size of the injured lung is safer and more 'physiologic' than scaling it to predicted body weight, i.e. its size before it was injured. We defined Total Lung Capacity (TLC) as the thoracic gas volume at an airway pressure of 40 cm H2O and tested if TLC could be inferred from the volume of gas that enters the lungs during a brief 'recruitment' maneuver. METHODS: Lung volume at relaxed end expiration (Vrel) as well as inspiratory capacity (IC), defined as the volume of gas that enters the lung during a 5 second inflation to 40 cm H2O, were measured in 14 patients with respiratory failure. TLC was defined as the sum of IC and Vrel. The dependence of IC and Vrel on body mass index (BMI), respiratory system elastance and plateau airway pressure was assessed. RESULTS: TLC was reduced to 59 +/- 23% of that predicted. Vrel/TLC, which averaged 0.45 +/- 0.11, was no different than the 0.47 +/- 0.04 predicted during health in the supine posture. The greater than expected variability in observed Vrel/TLC was largely accounted for by BMI. Vrel and IC were correlated (r = 0.76). Taking BMI into account strengthened the correlation (r = 0.92). CONCLUSIONS: We conclude that body mass is a powerful determinant of lung volume and plateau airway pressure. Effective lung size can be easily estimated from a recruitment maneuver derived inspiratory capacity measurement and body mass index. PMID- 21320332 TI - Metronidazole-induced encephalopathy in a patient with infectious colitis: a case report. AB - INTRODUCTION: Encephalopathy is a rare disease caused by adverse effects of antibiotic drugs such as metronidazole. The incidence of metronidazole-induced encephalopathy is unknown, although several previous studies have addressed metronidazole neurotoxicity. Here, we report the case of a patient with reversible cerebellar dysfunction on magnetic resonance imaging, induced by prolonged administration of metronidazole for the treatment of infectious colitis. CASE PRESENTATION: A 71-year-old Asian man, admitted to our hospital with hematochezia, underwent Hartmann's operation for the treatment of colorectal cancer three years ago. He was diagnosed with an infectious colitis by colonoscopy. After taking metronidazole, he showed drowsiness and slow response to verbal commands. Brain magnetic resonance imaging showed obvious bilateral symmetric hyperintensities within his dentate nucleus, tectal region of the cerebellum, and splenium of corpus callosum in T2-weighted images and fluid attenuated inversion recovery images. Our patient's clinical presentation and magnetic resonance images were thought to be most consistent with metronidazole toxicity. Therefore, we discontinued metronidazole, and his cerebellar syndrome resolved. Follow-up magnetic resonance imaging examinations showed complete resolution of previously noted signal changes. CONCLUSION: Metronidazole may produce neurologic side effects such as cerebellar syndrome, and encephalopathy in rare cases. We show that metronidazole-induced encephalopathy can be reversed after cessation of the drug. Consequently, careful consideration should be given to patients presenting with complaints of neurologic disorder after the initiation of metronidazole therapy. PMID- 21320331 TI - Evaluating clinic and community-based lifestyle interventions for obesity reduction in a low-income Latino neighborhood: Vivamos Activos Fair Oaks Program. AB - BACKGROUND: Obesity exerts an enormous health impact through its effect on coronary heart disease and its risk factors. Primary care-based and community based intensive lifestyle counseling may effectively promote weight loss. There has been limited implementation and evaluation of these strategies, particularly the added benefit of community-based intervention, in low-income Latino populations. DESIGN: The Vivamos Activos Fair Oaks project is a randomized clinical trial designed to evaluate the clinical and cost-effectiveness of two obesity reduction lifestyle interventions: clinic-based intensive lifestyle counseling, either alone (n = 80) or combined with community health worker support (n = 80), in comparison to usual primary care (n = 40). Clinic-based counseling consists of 15 group and four individual lifestyle counseling sessions provided by health educators targeting behavior change in physical activity and dietary practices. Community health worker support includes seven home visits aimed at practical implementation of weight loss strategies within the person's home and neighborhood. The interventions use a framework based on Social Cognitive Theory, the Transtheoretical Model of behavior change, and techniques from previously tested lifestyle interventions. Application of the framework was culturally tailored based on past interventions in the same community and elsewhere, as well as a community needs and assets assessment. The interventions include a 12-month intensive phase followed by a 12-month maintenance phase. Participants are obese Spanish-speaking adults with at least one cardiovascular risk factor recruited from a community health center in a low-income neighborhood of San Mateo County, California. Follow-up assessments occur at 6, 12, and 24 months for the primary outcome of percent change in body mass index at 24 months. Secondary outcomes include specific cardiovascular risk factors, particularly blood pressure and fasting glucose levels. DISCUSSION AND CONCLUSIONS: If successful, this study will provide evidence for broad implementation of obesity interventions in minority populations and guidance about the selection of strategies involving clinic-based case management and community-based community health worker support. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT01242683. PMID- 21320333 TI - The dimensional structure of the functional abilities in cases of long-term sickness absence. AB - BACKGROUND: The health problems that working people suffer can affect their functional abilities and, consequently, can cause a mismatch between those abilities and the demands of the work, leading to sickness absence. A lasting decrease in functional abilities can lead to long-term sickness absence and work disability, with negative consequences for both the worker and the larger society. The objective of this study was to identify common disability characteristics among large groups of long-term sick-listed and disabled employees. METHODS: As part of the disability benefit entitlement procedure in the Netherlands, an insurance physician assesses the functional abilities of the claimant in a standardised form, known as the List of Functional Abilities (LFA), which consists of six sections containing a total of 106 items. For the purposes of this study, we compiled data from 50,931 assessments. These data were used in an exploratory factor analyses, and the results were then used to construct scales. The stability of dimensional structure of the LFA and of the internal consistency of the scales was studied using data from 80,968 assessments carried out earlier, under a slightly different legislation. RESULTS: Three separate factor analyses carried out on the functional abilities of five sections of the LFA resulted in 14 scale variables, and one extra scale variable was based on the items from the sixth section. The resulting scale variables showed Cronbach's Alphas ranging from 0.59 to 0.97, with the exception of one of 0.54. The dimensional structure of the LFA in the verification population differed in some aspects. The Cronbach's Alphas of the verification population ranged from 0.58 to 0.97, again with the exception of the same scale: Alpha = 0.49. CONCLUSION: The differences between the dimensional structures of the primary data and the earlier data we found in this study restrict the possibilities to generalise the results. The scales we constructed can be utilised to produce a compact description of the functional abilities of groups of claimants in the Netherlands. Moreover, the matching work demands can be used to identify jobs low on those demands as being the most accessible for the specific type of disabled employees, particularly severely disabled individuals. PMID- 21320334 TI - Spindle cell oncocytoma of the adenohypophysis in a woman: a case report and review of the literature. AB - INTRODUCTION: Spindle cell oncocytoma of the adenohypophysis is a rare tumour recently reported by Roncaroli et al. in 2002. This tumour is considered a grade I tumour by the World Health Organization. CASE PRESENTATION: We describe what is, to the best of our knowledge, the 14th case of its kind in the literature. A 45-year-old African woman presented clinical and radiological findings related to a nonfunctioning pituitary adenoma. The diagnosis was made on the basis of histological and immunohistochemical findings. CONCLUSION: The purpose of this work is to report a rare pituitary tumour and to describe its histological and immunohistochemical features, which were characterized by the expression of thyroid transcription factor 1 antigen by tumour cells. This fact could support the theory of a possible common origin of these tumours in pituicytomas. In fact, thyroid transcription factor 1 is considered to be a specific marker of pituicytes. PMID- 21320335 TI - Late capsular bag contraction and intraocular lens subluxation in retinitis pigmentosa: a case report. AB - INTRODUCTION: Retinitis pigmentosa is clinically characterized by loss of predominantly rod photoreceptor function as well as loss of peripheral vision. The classic clinical triad is considered to be the presence of bone spicule pigmentation in the peripheral retina, arteriolar attenuation, and waxy disc pallor. Cataracts, most commonly of the posterior subcapsular type, are often found in all forms of retinitis pigmentosa. Ectopia lentis and lens dislocation are known risk factors for those with retinitis pigmentosa, presumably secondary to zonular fiber weakness and vitreous degeneration. The post-operative complication of lens dislocation following cataract extraction in patients with retinitis pigmentosa has also been documented. CASE PRESENTATION: We report a case of severe capsular bag contraction with intraocular lens subluxation following cataract extraction in a 58-year-old Hispanic woman with retinitis pigmentosa. CONCLUSION: Patients with retinitis pigmentosa undergoing cataract surgery should be notified of this potentially late complication of surgery. PMID- 21320336 TI - Molecular characteristics of Polish field strains of Marek's disease herpesvirus isolated from vaccinated chickens. AB - BACKGROUND: Twenty-nine Marek's disease virus (MDV) strains were isolated during a 3 year period (2007-2010) from vaccinated and infected chicken flocks in Poland. These strains had caused severe clinical symptoms and lesions. In spite of proper vaccination with mono- or bivalent vaccines against Marek's disease (MD), the chickens developed symptoms of MD with paralysis.Because of this we decided to investigate possible changes and mutations in the field strains that could potentially increase their virulence. We supposed that such mutations may have been caused by recombination with retroviruses of poultry - especially reticuloendotheliosis virus (REV). METHODS: In order to detect the possible reasons of recent changes in virulence of MDV strains, polymerase chain reaction (PCR) analyses for meq oncogene and for long-terminal repeat (LTR) region of REV were conducted. The obtained PCR products were sequenced and compared with other MDV and REV strains isolated worldwide and accessible in the GeneBank database. RESULTS: Sequencing of the meq oncogene showed a 68 basepair insertion and frame shift within 12 of 24 field strains. Interestingly, the analyses also showed 0.78, 0.8, 0.82, 1.6 kb and other random LTR-REV insertions into the MDV genome in 28 of 29 of strains. These genetic inserts were present after passage in chicken embryo kidney cells suggesting LTR integration into a non-functional region of the MDV genome. CONCLUSION: The results indicate the presence of a recombination between MDV and REV under field conditions in Polish chicken farms. The genetic changes within the MDV genome may influence the virus replication and its features in vivo. However, there is no evidence that meq alteration and REV insertions are related to the strains' virulence. PMID- 21320337 TI - Cellular immune responses in patients with hepatitis B surface antigen seroclearance induced by antiviral therapy. AB - BACKGROUND: The mechanisms by which chronic hepatitis B is completely resolved through antiviral therapy are unknown, and the contribution of acquired T cell immunity to hepatitis B surface antigen (HBsAg) seroclearance has not been investigated. Therefore, we measured the T-cell responses to core and envelope antigens in patients with HBsAg seroclearance. METHODS: Fourteen subjects with HBsAg seroclearance following antiviral treatment for chronic hepatitis B, 7 HBeAg-positive immunotolerant HBV carriers and 9 HBeAg-negative inactive HBsAg carriers were recruited. HBV-specific T-cell responses to recombinant HBV core (rHBcAg) and envelope (rHBsAg) proteins and pools of core and envelope peptides were measured using an ELISPOT assay detecting interferon-gamma and intracellular cytokine staining (ICS) assays detecting interferon-gamma or interleukin 2. RESULTS: Interferon-gamma ELISPOT assays showed a low frequency of weak responses to the rHBsAg and S peptide pool in the HBsAg seroclearance group, and the response frequency to the rHBcAg and the C peptide pool was higher than to the rHBsAg (P < 0.001) and S peptide pool (P = 0.001) respectively. A higher response frequency to C than S peptide pools was confirmed in the interferon-gamma ICS assays for both CD4+ (P = 0.033) and CD8+ (P = 0.040) T cells in the HBsAg seroclearance group. The responses to C and S antigens in the inactive carriers were similar. CONCLUSIONS: There was a low frequency of CD4+ and CD8+ T cell immune responses to envelope antigens in Chinese subjects with HBsAg seroclearance following antiviral therapy. It is unlikely that these immune responses are responsible for HBsAg seroclearance in these subjects. PMID- 21320338 TI - Homeopathy for depression--DEP-HOM: study protocol for a randomized, partially double-blind, placebo controlled, four armed study. AB - BACKGROUND: Homeopathy is often sought by patients with depression. In classical homeopathy, the treatment consists of two main elements: the case history and the prescription of an individually selected homeopathic remedy. Previous data suggest that individualized homeopathic Q-potencies were not inferior to the antidepressant fluoxetine in a sample of patients with moderate to severe depression. However, the question remains whether individualized homeopathic Q potencies and/or the type of the homeopathic case history have a specific therapeutical effect in acute depression as this has not yet been investigated. The study aims to assess the two components of individualized homeopathic treatment for acute depression, i.e., to investigate the specific effect of individualized Q-potencies versus placebo and to investigate the effect of different approaches to the homeopathic case history. METHODS/DESIGN: A randomized, partially double-blind, placebo-controlled, four-armed trial using a 2 x 2 factorial design with a six-week study duration per patient will be performed. 228 patients diagnosed with major depression (moderate episode) by a psychiatrist will be included. The primary endpoint is the total score on the 17 item Hamilton Depression Rating Scale after six weeks. Secondary end points are: Hamilton Depression Rating Scale total score after two and four weeks; response and remission rates, Beck Depression inventory total score, quality of life and safety at two, four and six weeks. Statistical analyses will be by intention-to treat. The main endpoint will be analysed by a two-factorial analysis of covariance. Within this model generalized estimation equations will be used to estimate differences between verum and placebo, and between both types of case history. DISCUSSION: For the first time this study evaluates both the specific effect of homeopathic medicines and of a homeopathic case taking in patients with depression. It is an attempt to deal with the challenges of homeopathic research and the results might be useful information in the current discussion about the evidence on homeopathy TRIAL REGISTRATION: ClinicalTrials.gov: NCT01178255. PMID- 21320339 TI - Impact of biodiversity-climate futures on primary production and metabolism in a model benthic estuarine system. AB - BACKGROUND: Understanding the effects of anthropogenically-driven changes in global temperature, atmospheric carbon dioxide and biodiversity on the functionality of marine ecosystems is crucial for predicting and managing the associated impacts. Coastal ecosystems are important sources of carbon (primary production) to shelf waters and play a vital role in global nutrient cycling. These systems are especially vulnerable to the effects of human activities and will be the first areas impacted by rising sea levels. Within these coastal ecosystems, microalgal assemblages (microphytobenthos: MPB) are vital for autochthonous carbon fixation. The level of in situ production by MPB mediates the net carbon cycling of transitional ecosystems between net heterotrophic or autotrophic metabolism. In this study, we examine the interactive effects of elevated atmospheric CO(2) concentrations (370, 600, and 1000 ppmv), temperature (6 degrees C, 12 degrees C, and 18 degrees C) and invertebrate biodiversity on MPB biomass in experimental systems. We assembled communities of three common grazing invertebrates (Hydrobia ulvae, Corophium volutator and Hediste diversicolor) in monoculture and in all possible multispecies combinations. This experimental design specifically addresses interactions between the selected climate change variables and any ecological consequences caused by changes in species composition or richness. RESULTS: The effects of elevated CO(2) concentration, temperature and invertebrate diversity were not additive, rather they interacted to determine MPB biomass, and overall this effect was negative. Diversity effects were underpinned by strong species composition effects, illustrating the importance of individual species identity. CONCLUSIONS: Overall, our findings suggest that in natural systems, the complex interactions between changing environmental conditions and any associated changes in invertebrate assemblage structure are likely to reduce MPB biomass. Furthermore, these effects would be sufficient to affect the net metabolic balance of the coastal ecosystem, with important implications for system ecology and sustainable exploitation. PMID- 21320340 TI - Protein secretion in human mammary epithelial cells following HER1 receptor activation: influence of HER2 and HER3 expression. AB - BACKGROUND: Protein secretion by mammary cells results in autocrine and paracrine signaling that defines cell growth, migration and the extracellular environment. Even so, we have a limited understanding of the cellular processes that regulate protein secretion. METHODS: In this study, we utilize human epithelial mammary cell (HMEC) lines that were engineered to express different levels of HER1, HER2 and HER3. Using an ELISA microarray platform, we evaluate the effects of epidermal growth factor family receptor (HER) expression on protein secretion in the HMEC lines upon initiation of HER1 receptor activation. The secreted proteins include three HER1 ligands, interleukins 1alpha and 18, RANTES, vascular endothelial and platelet-derived growth factors, matrix metalloproteases 1, 2 and 9, and the extracellular portion of the HER1 and HER2 proteins. In addition, we investigate whether MAPK/Erk and PI3K/Akt signaling regulate protein secretion in these cell lines and if so, whether the involvement of HER2 or HER3 receptor alters their response to MAPK/Erk and PI3K/Akt signal pathway inhibition in terms of protein secretion. RESULTS: Differential expression of HER2 and HER3 receptors alters the secretion of a variety of growth factors, cytokines, and proteases. Some alterations in protein secretion are still observed when MAPK/Erk or PI3K/Akt signaling is inhibited. CONCLUSION: This study suggests that HER overexpression orchestrates broad changes in the tumor microenvironment by altering the secretion of a diverse variety of biologically active proteins. PMID- 21320341 TI - Successful radiation treatment of anaplastic thyroid carcinoma metastatic to the right cardiac atrium and ventricle in a pacemaker-dependent patient. AB - Anaplastic thyroid carcinoma (ATC) is a rare, aggressive malignancy, which is known to metastasize to the heart. We report a case of a patient with ATC with metastatic involvement of the pacemaker leads within the right atrium and right ventricle. The patient survived external beam radiation treatment to his heart, with a radiographic response to treatment. Cardiac metastases are usually reported on autopsy; to our knowledge, this is the first report of the successful treatment of cardiac metastases encasing the leads of a pacemaker, and of cardiac metastases from ATCs, with a review of the pertinent literature. PMID- 21320342 TI - Postresuscitation care with mild therapeutic hypothermia and coronary intervention after out-of-hospital cardiopulmonary resuscitation: a prospective registry analysis. AB - INTRODUCTION: Mild therapeutic hypothermia (MTH) has been shown to result in better neurological outcome after cardiopulmonary resuscitation. Percutaneous coronary intervention (PCI) may also be beneficial in patients after out-of hospital cardiac arrest (OHCA). METHODS: A selected cohort study of 2,973 prospectively documented adult OHCA patients within the German Resuscitation Registry between 2004 and 2010. Data were analyzed by backwards stepwise binary logistic regression to identify the impact of MTH and PCI on both 24-hour survival and neurological outcome that was based on cerebral performance category (CPC) at hospital discharge. Odds ratios (95% confidence intervals) were calculated adjusted for the following confounding factors: age, location of cardiac arrest, presumed etiology, bystander cardiopulmonary resuscitation, witnessing, first electrocardiogram rhythm, and thrombolysis. RESULTS: The Preclinical care dataset included 2,973 OHCA patients with 44% initial return of spontaneous circulation (n = 1,302) and 35% hospital admissions (n = 1,040). Seven hundred and eleven out of these 1,040 OHCA patients (68%) were also registered within the Postresuscitation care dataset. Checking for completeness of datasets required the exclusion of 127 Postresuscitation care cases, leaving 584 patients with complete data for final analysis. In patients without PCI (n = 430), MTH was associated with increased 24-hour survival (8.24 (4.24 to 16.0), P < 0.001) and the proportion of patients with CPC 1 or CPC 2 at hospital discharge (2.13 (1.17 to 3.90), P < 0.05) as an independent factor. In normothermic patients (n = 405), PCI was independently associated with increased 24-hour survival (4.46 (2.26 to 8.81), P < 0.001) and CPC 1 or CPC 2 (10.81 (5.86 to 19.93), P < 0.001). Additional analysis of all patients (n = 584) revealed that 24-hour survival was increased by MTH (7.50 (4.12 to 13.65), P < 0.001) and PCI (3.88 (2.11 to 7.13), P < 0.001), while the proportion of patients with CPC 1 or CPC 2 was significantly increased by PCI (5.66 (3.54 to 9.03), P < 0.001) but not by MTH (1.27 (0.79 to 2.03), P = 0.33), although an unadjusted Fisher exact test suggested a significant effect of MTH (unadjusted odds ratio 1.83 (1.23 to 2.74), P < 0.05). CONCLUSIONS: PCI may be an independent predictor for good neurological outcome (CPC 1 or CPC 2) at hospital discharge. MTH was associated with better neurological outcome, although subsequent logistic regression analysis did not show statistical significance for MTH as an independent predictor for good neurological outcome. Thus, postresuscitation care on the basis of standardized protocols including coronary intervention and hypothermia may be beneficial after successful resuscitation. One of the main limitations may be a selection bias for patients subjected to PCI and MTH. PMID- 21320343 TI - Prevalence of sealants in relation to dental caries on the permanent molars of 12 and 15-year-old Greek adolescents. A national pathfinder survey. AB - BACKGROUND: The use of sealants as an effective measure for the prevention of pit and fissure caries in children has been well documented by several studies; either they are used on an individual or on a public health basis. In order to plan and establish a national preventive program with sealants in a community, it is mandatory to know the epidemiological pattern of caries along with other variables influencing their use and effectiveness. AIMS: To assess the utilization and distribution pattern of pit and fissure sealants on the first and second permanent molars of Greek adolescents and to evaluate whether the existing usage of sealants and some socio-demographic factors are correlated to caries prevalence on the population examined METHODS: A stratified cluster sample of 2481 Greek adolescents was selected according to WHO guidelines (1224 twelve and 1,257 fifteen-year-old), living in urban and rural areas in 11 districts within the country. Five calibrated examiners carried out clinical examinations, recording caries experience at the dentine threshold (BASCD criteria) and presence or absence of sealants along with Socio-demographic indicators associated with oral health. Mann Whitney and Pearson's chi-square non parametric tests were utilized for assessing the data. The level of significance was p < 0.05. RESULTS: Sealants utilization varied considerably within the different districts, with 8,3% of the 12 and 8,0% of the 15-year-old adolescents having at least one sealed molar. Sealants reduced DMFS scores by 11% in the 12-year-olds and by 24% in the 15-year-olds, while 15-year-old adolescents from rural areas had a statistically significant (p = 0.002) less chance of having sealants (71%) compared to children from urban areas. Girls had higher chance to receive sealants in both age groups (26% for the 12 and 19% for the 15-year-old) as well as patients that visited the dentist for prevention compared to those visiting the dentist because they thought they needed a restoration or because they were in pain. CONCLUSIONS: The finding that sealants reduced DMFS scores despite their very low utilization, along with the high prevalence of dental caries found on the occlusal surfaces of the posterior teeth of Greek adolescents, is calling for a national preventive program with sealants which could eliminate caries to a larger extent. PMID- 21320345 TI - Which chronic diseases and disease combinations are specific to multimorbidity in the elderly? Results of a claims data based cross-sectional study in Germany. AB - BACKGROUND: Growing interest in multimorbidity is observable in industrialized countries. For Germany, the increasing attention still goes still hand in hand with a small number of studies on multimorbidity. The authors report the first results of a cross-sectional study on a large sample of policy holders (n = 123,224) of a statutory health insurance company operating nationwide. This is the first comprehensive study addressing multimorbidity on the basis of German claims data. The main research question was to find out which chronic diseases and disease combinations are specific to multimorbidity in the elderly. METHODS: The study is based on the claims data of all insured policy holders aged 65 and older (n = 123,224). Adjustment for age and gender was performed for the German population in 2004. A person was defined as multimorbid if she/he had at least 3 diagnoses out of a list of 46 chronic conditions in three or more quarters within the one-year observation period. Prevalences and risk-ratios were calculated for the multimorbid and non-multimorbid samples in order to identify diagnoses more specific to multimorbidity and to detect excess prevalences of multimorbidity patterns. RESULTS: 62% of the sample was multimorbid. Women in general and patients receiving statutory nursing care due to disability are overrepresented in the multimorbid sample. Out of the possible 15,180 combinations of three chronic conditions, 15,024 (99%) were found in the database. Regardless of this wide variety of combinations, the most prevalent individual chronic conditions do also dominate the combinations: Triads of the six most prevalent individual chronic conditions (hypertension, lipid metabolism disorders, chronic low back pain, diabetes mellitus, osteoarthritis and chronic ischemic heart disease) span the disease spectrum of 42% of the multimorbid sample. Gender differences were minor. Observed-to-expected ratios were highest when purine/pyrimidine metabolism disorders/gout and osteoarthritis were part of the multimorbidity patterns. CONCLUSIONS: The above list of dominating chronic conditions and their combinations could present a pragmatic start for the development of needed guidelines related to multimorbidity. PMID- 21320344 TI - Evaluation of genetic susceptibility to childhood allergy and asthma in an African American urban population. AB - BACKGROUND: Asthma and allergy represent complex phenotypes, which disproportionately burden ethnic minorities in the United States. Strong evidence for genomic factors predisposing subjects to asthma/allergy is available. However, methods to utilize this information to identify high risk groups are variable and replication of genetic associations in African Americans is warranted. METHODS: We evaluated 41 single nucleotide polymorphisms (SNP) and a deletion corresponding to 11 genes demonstrating association with asthma in the literature, for association with asthma, atopy, testing positive for food allergens, eosinophilia, and total serum IgE among 141 African American children living in Detroit, Michigan. Independent SNP and haplotype associations were investigated for association with each trait, and subsequently assessed in concert using a genetic risk score (GRS). RESULTS: Statistically significant associations with asthma were observed for SNPs in GSTM1, MS4A2, and GSTP1 genes, after correction for multiple testing. Chromosome 11 haplotype CTACGAGGCC (corresponding to MS4A2 rs574700, rs1441586, rs556917, rs502581, rs502419 and GSTP1 rs6591256, rs17593068, rs1695, rs1871042, rs947895) was associated with a nearly five-fold increase in the odds of asthma (Odds Ratio (OR) = 4.8, p = 0.007). The GRS was significantly associated with a higher odds of asthma (OR = 1.61, 95% Confidence Interval = 1.21, 2.13; p = 0.001). CONCLUSIONS: Variation in genes associated with asthma in predominantly non-African ethnic groups contributed to increased odds of asthma in this African American study population. Evaluating all significant variants in concert helped to identify the highest risk subset of this group. PMID- 21320346 TI - Evaluating the effectiveness of IPTi on malaria using routine health information from sentinel health centres in southern Tanzania. AB - BACKGROUND: Intermittent preventive treatment of malaria in infants (IPTi) consists of the administration of a treatment dose of sulphadoxine-pyrimethamine (SP) at the time of routine vaccinations. The use of routine Health Management and Information Services (HMIS) data to investigate the effect of IPTi on malaria, anaemia, and all-cause attendance in children aged 2-11 months presenting to 11 health centres in southern Tanzania is described. METHODS: Clinical diagnosis of malaria was confirmed with a positive blood slide reading from a quality assurance laboratory. Anaemia was defined using two thresholds (mild [Hb<11 g/dL], severe [Hb<8 g/dL]). Incidence rates between IPTi and non implementing health centres were calculated using Poisson regression, and all statistical testing was based on the t test due to the clustered nature of the data. RESULTS: Seventy two per cent of infants presenting in intervention areas received at least one dose of IPTi--22% received all three. During March 2006 April 2007, the incidence of all cause attendance was two attendances per person, per year (pppy), including 0.2 episodes pppy of malaria, 0.7 episodes of mild and 0.13 episodes of severe anaemia. Point estimates for the effect of IPTi on malaria varied between 18% and 52%, depending on the scope of the analysis, although adjustment for clustering rendered these not statistically significant. CONCLUSIONS: The point estimate of the effect of IPTi on malaria is consistent with that from a large pooled analysis of randomized control trials. As such, it is plausible that the difference seen in health centre data is due to IPTi, even thought the effect did not reach statistical significance. Findings draw attention to the challenges of robust inference of effects of interventions based on routine health centre data. Analysis of routine health information can reassure that interventions are being made available and having desired effects, but unanticipated effects should trigger data collection from representative samples of the target population. PMID- 21320347 TI - Treatment utilization and barriers to treatment: results of a survey of dependent methamphetamine users. AB - BACKGROUND: Australia has one of the highest rates of methamphetamine use in the world; however, treatment access for methamphetamine is comparatively low. This descriptive study aimed to identify patterns of treatment utilization and perceived barriers to accessing treatment among dependent methamphetamine users in the hope that such information will enable services to more appropriately respond to this group. METHODS: One hundred and twenty-six methamphetamine users who had a current or past history of methamphetamine dependence were interviewed about their experiences of, and perceived barriers to, treatment. RESULTS: Treatment utilization among methamphetamine users was reportedly low. One of the main reasons cited for not accessing treatment was that methamphetamine users did not perceive their drug use to be a problem (despite apparent levels of dependence). Self-detoxification with the use of other licit and illicit drugs was high among this group. Participants identified a lack of confidence in the ability of treatment services to address methamphetamine dependence and the 'opiate-centric' nature of treatment services as significant blocks to treatment entry. Suggestions for improvement by participants included operating specialist services for methamphetamine users, placing an emphasis on responsiveness and routinely involving case management services for this group. DISCUSSION AND CONCLUSIONS: To improve service delivery, treatment services should reorient their services to better address the needs of methamphetamine users by making small changes such as specific opening times for methamphetamine users or using a dedicated space for methamphetamine treatment. Alternative options such as online treatments and specialist methamphetamine clinics should be considered for methamphetamine users. PMID- 21320348 TI - Religious subgroups influencing vaccination coverage in the Dutch Bible belt: an ecological study. AB - BACKGROUND: The Netherlands has experienced epidemics of vaccine preventable diseases largely confined to the Bible belt, an area where -among others- orthodox protestant groups are living. Lacking information on the vaccination coverage in this minority, and its various subgroups, control of vaccine preventable diseases is focused on the geographical area of the Bible belt. However, the adequacy of this strategy is questionable. This study assesses the influence of presence of various orthodox protestant subgroups (orthodox protestant denominations, OPDs) on municipal vaccination coverage in the Bible belt. METHODS: We performed an ecological study at municipality level. Data on number of inhabitants, urbanization level, socio-economical status, immigration and vaccination coverage were obtained from national databases. As religion is not registered in the Netherlands, membership numbers of the OPDs had to be obtained from church year books and via church offices. For all municipalities in the Netherlands, the effect of presence or absence of OPDs on vaccination coverage was assessed by comparing mean vaccination coverage. For municipalities where OPDs were present, the effect of each of them (measured as membership ratio, the number of members proportional to total number of inhabitants) on vaccination coverage was assessed by bivariate correlation and multiple regression analysis in a model containing the determinants immigration, socio economical status and urbanization as well. RESULTS: Mean vaccination coverage (93.5% +/- 4.7) in municipalities with OPDs (n = 135) was significantly lower (p < 0.001) than in 297 municipalities without OPDs (96.9% +/- 2.1). Multiple regression analyses showed that in municipalities with OPDs 84% of the variance in vaccination coverage was explained by the presence of these OPDs. Immigration had a significant, but small explanatory effect as well. Membership ratios of all OPDs were negatively related to vaccination coverage; this relationship was strongest for two very conservative OPDs. CONCLUSION: As variance in municipal vaccination coverage in the Bible belt is largely explained by membership ratios of the various OPDs, control of vaccine preventable diseases should be focused on these specific risk groups. In current policy part of the orthodox protestant risk group is missed. PMID- 21320349 TI - Myocardial post-conditioning with Danshen-Gegen decoction protects against isoproterenol-induced myocardial injury via a PKCepsilon/mKATP-mediated pathway in rats. AB - BACKGROUND: Danshen-Gegen decoction (DG), a Chinese herbal formula, has been demonstrated to be effective for the treatment of coronary heart disease such as myocardial infarction. In the present study, we investigated the effect of DG post-conditioning on isoproterenol (ISO)-induced myocardial injury in rats. METHODS: ISO was injected intraperitoneally (200 mg/kg) to induce acute (2-6 hours) myocardial injury in adult female rats. DG (4 g/kg) was administered per oral immediately after the injection of ISO in the rats. Extent of myocardial injury was assessed by measurements of plasma enzyme activities. Myocardial mitochondrial glutathione antioxidant status, lipid peroxidation and mitochondrial calcium ion loading and cytochrome c release were also measured. Effects of inhibitors of protein kinase C-epsilon (PKCepsilon) ranslocation and mitochondrial ATP-sensitive potassium channel (mKATP) on myocardial post conditioning by DG were investigated. RESULTS: ISO inflicted acute myocardial injury in the rats as evidenced by increased plasma enzyme activities. DG post treatment alleviated the ISO-induced acute myocardial injury. CONCLUSION: DG post treatment protected the myocardium against ISO-induced acute injury in rats. The myocardial post-conditioning by DG is likely mediated by PKCepsilon/mKATP signaling pathway. PMID- 21320350 TI - Active protein aggregates induced by terminally attached self-assembling peptide ELK16 in Escherichia coli. AB - BACKGROUND: In recent years, it has been gradually realized that bacterial inclusion bodies (IBs) could be biologically active. In particular, several proteins including green fluorescent protein, beta-galactosidase, beta-lactamase, alkaline phosphatase, D-amino acid oxidase, polyphosphate kinase 3, maltodextrin phosphorylase, and sialic acid aldolase have been successfully produced as active IBs when fused to an appropriate partner such as the foot-and-mouth disease virus capsid protein VP1, or the human beta-amyloid peptide Abeta42(F19D). As active IBs may have many attractive advantages in enzyme production and industrial applications, it is of considerable interest to explore them further. RESULTS: In this paper, we report that an ionic self-assembling peptide ELK16 (LELELKLK)2 was able to effectively induce the formation of cytoplasmic inclusion bodies in Escherichia coli (E. coli) when attached to the carboxyl termini of four model proteins including lipase A, amadoriase II, beta-xylosidase, and green fluorescent protein. These aggregates had a general appearance similar to the usually reported cytoplasmic inclusion bodies (IBs) under transmission electron microscopy or fluorescence confocal microscopy. Except for lipase A-ELK16 fusion, the three other fusion protein aggregates retained comparable specific activities with the native counterparts. Conformational analyses by Fourier transform infrared spectroscopy revealed the existence of newly formed antiparallel beta sheet structures in these ELK16 peptide-induced inclusion bodies, which is consistent with the reported assembly of the ELK16 peptide. CONCLUSIONS: This has been the first report where a terminally attached self-assembling beta peptide ELK16 can promote the formation of active inclusion bodies or active protein aggregates in E. coli. It has the potential to render E. coli and other recombinant hosts more efficient as microbial cell factories for protein production. Our observation might also provide hints for protein aggregation related diseases. PMID- 21320351 TI - Murine model for congenital CMV infection and hearing impairment. AB - BACKGROUND: Congenital cytomegalovirus (CMV) infection is the leading cause of sensorineural hearing loss (SNHL), and SNHL is the most frequent sequela of congenital CMV infection. But the pathogenic mechanism remains unknown, and there is no ideal CMV intrauterine infection animal model to study the mechanisms by which SNHL develops. METHODS: We established the congenital murine cytomegalovirus (MCMV) infection model by directly injecting the virus into the placenta on day 12.5 of gestation. Then, we observed the development and the MCMV congenital infection rate of the fetuses on the day they were born. Furthermore, we detected the auditory functions, the conditions of the MCMV infection, and the histological change of the inner ears of 28-day-old and 70-day-old offspring. RESULTS: Both the fetal loss rate and the teratism rate of offspring whose placentas were inoculated with MCMV increased, and their body length, head circumference, and weight decreased. The hearing level of offspring both decreased at both 28- and 70-days post birth; the 70-day-old mice developed lower hearing levels than did the 28-day old mice. No significant inflammatory changes in the cochleae of the mice were observed. MCMV DNA signals were mainly detected in the spiral ganglion neurons and the endolymph area, but not in the perilymph area. The number of neurons decreased, and their ultrastructures changed. Moreover, with age, the number of neurons dramatically decreased, and the ultrastructural lesions of neurons became much more severe. CONCLUSIONS: The results suggest that the direct injection of MCMV into the placenta may efficiently cause fetal infection and disturb the intrauterine development of the fetus, and placental inoculation itself has no obvious adverse effects on offspring. The reduction in the number of spiral ganglion neurons and the ultrastructural lesions of the neurons may be the major cause of congenital CMV infection-induced progressive SNHL. PMID- 21320352 TI - Envelope 2 protein phosphorylation sites S75 & 277 of hepatitis C virus genotype 1a and interferon resistance: a sequence alignment approach. AB - BACKGROUND: Hepatitis C is a major health problem affecting more than 200 million individuals in world including Pakistan. Current treatment regimen consisting of interferon alpha and ribavirin does not always succeed to eliminate virus completely from the patient's body. RESULTS: Interferon induced antiviral protein kinase R (PKR) has a role in the hepatitis C virus (HCV) treatment as dsRNA activated PKR has the capacity to phosphorylate the serine and threonine of E2 protein and dimerization viral RNA. E2 gene of hepatitis C virus (HCV) genotype 1 has an active role in IFN resistance. E2 protein inhibits and terminates the kinase activity of PKR by blocking it in protein synthesis and cell growth. This brings forward a possible relation of E2 and PKR through a mechanism via which HCV evades the antiviral effect of IFN. CONCLUSION: A hybrid in-silico and wet laboratory approach of motif prediction, evolutionary and structural anlysis has pointed out serine 75 and 277 of the HCV E2 gene as a promising candidate for the serine phosphorylation. It is proposed that serine phosphorylation of HCV E2 gene has a significant role in interferon resistance. PMID- 21320353 TI - Sequence and gene expression of chloroquine resistance transporter (pfcrt) in the association of in vitro drugs resistance of Plasmodium falciparum. AB - BACKGROUND: Plasmodium falciparum chloroquine resistance (CQR) transporter protein (PfCRT) is known to be the important key of CQR. Recent studies have definitively demonstrated a link between mutations in the gene pfcrt and resistance to chloroquine in P. falciparum. Although these mutations are predictive of chloroquine resistance, they are not quantitatively predictive of the degree of resistance. METHODS: In this study, a total of 95 recently adapted P. falciparum isolates from Thailand were included in the analysis. Parasites were characterized for their drug susceptibility phenotypes and genotypes with respect to pfcrt. From the original 95 isolates, 20 were selected for complete pfcrt sequence analysis. RESULTS: Almost all of the parasites characterized carried the previously reported mutations K76T, A220S, Q271E, N326S, I356T and R371I. On complete sequencing, isolates were identified with novel mutations at K76A and E198K. There was a suggestion that parasites carrying E198K were less resistant than those that did not. In addition, pfcrt and pfmdr1 gene expression were investigated by real-time PCR. No relationship between the expression level of either of these genes and response to drug was observed. CONCLUSION: Data from the present study suggest that other genes must contribute to the degree of resistance once the resistance phenotype is established through mutations in pfcrt. PMID- 21320354 TI - Amyloidosis cutis dyschromica in two female siblings: cases report. AB - BACKGROUND: Cutaneous amyloidosis has been classified into primary cutaneous amyloidosis (PCA, OMIM #105250), secondary cutaneous amyloidosis and systemic cutaneous amyloidosis. PCA is the deposition of amyloid in previously apparent normal skin without systemic involvement. Amyloidosis cutis dyschromica (ACD) is a rare distinct type of PCA. Here, the unique clinical and histological findings of two Chinese female siblings with ACD were described. CASES PRESENTATIONS: Patient 1 was a 34-year-old female, presented with mildly pruritic, diffuse mottled hyperpigmentation and hypopigmentation. The lesions involved all over the body since she was 10 years old. There were a few itchy blisters appearing on her arms, lower legs and truck, especially on the sun-exposed areas in summer. Some hypopigmented macules presented with slight atrophy. Patient 2 was 39-year-old, the elder sister of patient 1. She had similar skin lesions since the same age as the former. The atrophy and blisters on the skin of the patient with amyloidosis cutis dyschromica have not been described in previous literature. Histological examinations of the skin biopsies taken from both patients revealed amyloid deposits in the whole papillary dermis. Depending on the histological assessment, the two cases were diagnosed as amyloidosis cutis dyschromica. CONCLUSION: The two cases suggest that the atrophy and blisters may be the uncommon manifestations of amyloidosis cutis dyschromica. It alerts clinicians to consider the possibility of ACD when meeting patients with cutaneous dyschromia. Skin biopsy is essential and family consultation of genetic investigation is very important in such cases. PMID- 21320355 TI - Combined treatment of adenoid cystic carcinoma with cetuximab and IMRT plus C12 heavy ion boost: ACCEPT [ACC, Erbitux(r) and particle therapy]. AB - BACKGROUND: Local control in adjuvant/definitive RT of adenoid cystic carcinoma (ACC) is largely dose-dependent leading to the establishment of particle therapy in this indication. However, even modern techniques leave space for improvement of local control by intensification of local treatment. Radiation sensitization by exploitation of high EGFR-expression in ACC with the EGFR receptor antibody cetuximab seems promising. METHODS/DESIGN: The ACCEPT trial is a prospective, mono-centric, phase I/II trial evaluating toxicity (primary endpoint: acute and late effects) and efficacy (secondary endpoint: local control, distant control, disease-free survival, overall survival) of the combined treatment with IMRT/carbon ion boost and weekly cetuximab in 49 patients with histologically proven (>=R1-resected, inoperable or Pn+) ACC. Patients receive 18 GyE carbon ions (6 fractions) and 54 Gy IMRT (2.0 Gy/fraction) in combination with weekly cetuximab throughout radiotherapy. DISCUSSION: The primary objective of ACCEPT is to evaluate toxicity and feasibility of cetuximab and particle therapy in adenoid cystic carcinoma. TRIAL REGISTRATION: Clinical Trial Identifier: NCT 01192087. EudraCT number: 2010 - 022425 - 15. PMID- 21320356 TI - Antibiotic prescriptions in primary health care in a rural population in Crete, Greece. AB - BACKGROUND: Antibiotic over-prescribing has generally been considered to be common in Greece, however not much is known about current antibiotic use. FINDINGS: The aim of this study was to investigate antibiotic prescribing in a well-defined rural population of 159 adults and 99 children over a 12-month period in Crete, Greece. The daily-defined doses (DDD) for 1000 people/day (DID) were 22.1 and 24.2 for children and adults respectively. The overall DID was 23.4, markedly lower than that previously reported for Greece. The use of penicillins was 49.5% of DDD in children and 31.7% in adults. Quinolones represented 2.2% of the total antibiotics (0% in children). Prescriptions of antibiotics were more common during the 3-month period from January to March for both children and adults. CONCLUSIONS: The findings of this study confirm the seasonal distribution of antibiotics used and the predominance of prescribing for respiratory tract infections. In the area of the study, antibiotic use seems to be lower than that previously reported for Greece, probably as a result of the recently established net of well-trained primary health physicians. PMID- 21320357 TI - Expression and shedding of endothelial protein C receptor in prostate cancer cells. AB - BACKGROUND: Increasing evidences show that beyond its role in coagulation, endothelial protein C receptor (EPCR) interferes with carcinogenesis. Pro carcinogenic effects of EPCR were linked with a raised generation of activated protein C (aPC) and anti-apoptotic signalling. This study was carried out to analyze the expression, cell surface exposition, and shedding of EPCR in normal and malignant prostate cell lines. RESULTS: EPCR expression is up-regulated both at the mRNA and protein levels in invasive prostate DU-145 and PC-3 cells in comparison to normal prostate epithelial cells (PrEC) and less-invasive LNCaP cells. Release of soluble EPCR (sEPCR) is induced by 12-myristate 13-acetate, ionomycin, H2O2, and disruptor of lipid rafts in PrEC, DU-145, and PC-3 cells. Furthermore, interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF alpha), but not interleukin-6 or interferon-gamma increase sEPCR release. In LNCaP cells, neither pharmacological agents nor IL-1beta or TNF-alpha result in a significant increase of sEPCR release. The effects of IL-1beta and TNF-alpha on EPCR shedding in DU-145 cells are mediated by MEK/ERK 1/2, JNK, and p38 MAPK signalling cascades. In PC-3 cells, however, the MEK/ERK 1/2 pathway is down regulated and incubation with cytokines did not elevate the phosphorylated ERK 1/2 fraction as in the case of DU-145 cells. Treatment with 4-aminophenylmercuric acetate (APMA), an activator of metalloproteases, causes a disproportionately large increase of sEPCR release in DU-145 and PC-3 cells, compared to PrEC and LNCaP cells. Finally, an increased release of sEPCR mediated by APMA treatment is shown to be connected with reduced generation of activated protein C indicating the functionality of EPCR in these cells. CONCLUSIONS: The study demonstrates a number of substantial differences in expression and shedding of EPCR in prostate cancer cell lines in comparison with normal cells that may be relevant for understanding the role of this receptor in carcinogenesis. PMID- 21320358 TI - A clinical trial alert tool to recruit large patient samples and assess selection bias in general practice research. AB - BACKGROUND: Many research projects in general practice face problems when recruiting patients, often resulting in low recruitment rates and an unknown selection bias, thus limiting their value for health services research. The objective of the study is to evaluate the recruitment performance of the practice staff in 25 participating general practices when using a clinical trial alert (CTA) tool. METHODS: The CTA tool was developed for an osteoporosis survey of patients at risk for osteoporosis and fractures. The tool used data from electronic patient records (EPRs) to automatically identify the population at risk (net sample), to apply eligibility criteria, to contact eligible patients, to enroll and survey at least 200 patients per practice. The effects of the CTA intervention were evaluated on the basis of recruitment efficiency and selection bias. RESULTS: The CTA tool identified a net sample of 16,067 patients (range 162 to 1,316 per practice), of which the practice staff reviewed 5,161 (32%) cases for eligibility. They excluded 3,248 patients and contacted 1,913 patients. Of these, 1,526 patients (range 4 to 202 per practice) were successfully enrolled and surveyed. This made up 9% of the net sample and 80% of the patients contacted. Men and older patients were underrepresented in the study population. CONCLUSION: Although the recruitment target was unreachable for most practices, the practice staff in the participating practices used the CTA tool successfully to identify, document and survey a large patient sample. The tool also helped the research team to precisely determine a slight selection bias. PMID- 21320359 TI - Cognitive bias modification in the treatment of social anxiety in early psychosis: a single case series. AB - BACKGROUND: Social anxiety is a common problem among people who are recovering from psychosis. At present there is no evidence based psychological treatment targeting social anxiety in this population. Cognitive Bias Modification for Interpretation (CBM-I) has been shown to be effective in reducing social anxiety in people who do not have a history of psychosis. AIMS: To assess the feasibility and acceptability of the CBM-I methodology for use in a clinical setting with people who are experiencing social anxiety following an episode of psychosis. METHOD: Eight participants with social anxiety were recruited from an early intervention service. A single session of computerized CBM-I was conducted, with mood and cognitive interpretation bias being assessed before and after the session. RESULTS: All participants reported an improvement in mood immediately following the CBM-I session (n=8). For those participants who had a negative interpretation bias, none became more negative following the CBM-I session, with three out of six participants showing a beneficial change. CONCLUSION: These results suggest that CBM-I is acceptable for use with people who are experiencing social anxiety following a psychotic episode. Further research looking at how CBM I could be made more interactive and producing more applicable scenarios for use in a clinical setting is recommended. PMID- 21320360 TI - Pilot study of group cognitive behaviour therapy for heterogeneous acute psychiatric inpatients: treatment in a sole-standalone session allowing patients to choose the therapeutic target. AB - BACKGROUND: Group CBT (G-CBT) for heterogeneous acute psychiatric inpatients (HAPIs), which allows patients to choose the group therapeutic target, might have clinical utility but is empirically untested. AIMS: To test the feasibility, acceptability and patient-rated effectiveness of G-CBT for HAPIs in which patients' themselves choose the group therapeutic targets, within a previously rarely used sole-standalone session format. METHOD: Weekly G-CBT was run for two HAPI wards. The G-CBT was evaluated in terms of attendances/re-attendances, and patient feedback on 5-point scales of how strongly patients agreed/disagreed that the group was useful, enjoyable, worth re-attending, and had led to them learning something they could use to reduce their distress. RESULTS: One hundred and thirty-seven separate patients attended a total of 291 times across 31 groups. Being female or having a diagnosis of bipolar disorder significantly predicted re attendance. Sixty-three percent of patient feedback questionnaires were obtained from groups 10-31 and over 75% of respondents agreed positively with each of the evaluation dimensions. CONCLUSIONS: Practise-based evidence from this pilot study suggests that G-CBT for HAPIs, allowing patients to choose therapeutic targets in a sole-session format, is feasible, acceptable and patients find it effective. This supports more widespread deployment of this CBT treatment format. Future research might now test the format's clinical effectiveness with standardized and objective clinical outcome measures. PMID- 21320361 TI - Improving the quality of cognitive behaviour therapy case conceptualization: the role of self-practice/self-reflection. AB - BACKGROUND: CBT case conceptualization is considered to be a key competency. Prior to the publication in 2009 of Kuyken, Padesky and Dudley's book, little has been documented concerning methods for training conceptualization skills and the conceptualization process is usually perceived as predominantly an intellectual process. In this paper, the Declarative-Procedural-Reflective model of therapist skill acquisition provides a route to understanding how different kinds of knowledge systems can be integrated to enhance therapist skill acquisition. METHOD: Sixteen recent graduates of a postgraduate diploma in cognitive behaviour therapy worked independently through a self-practice/self-reflection workbook designed to lead them through a series of CBT interventions commonly used to elicit the information required for a CBT conceptualization. RESULTS: The participants' self-reflections were thematically analyzed and uncovered the following inter-related themes: increased theoretical understanding of the CBT model, self-awareness, empathy, conceptualization of the therapeutic relationship, and adaptation of clinical interventions and practice. CONCLUSIONS: A tentative conclusion reached, based on the self-reflections of the participants, was that targeted self-practice/self-reflection enhanced case conceptualization skill by consolidating the Declarative, Procedural and Reflective systems important in therapist skill acquisition. PMID- 21320362 TI - Insecticide use and competition shape the genetic diversity of the aphid Aphis gossypii in a cotton-growing landscape. AB - Field populations of the cotton aphid, Aphis gossypii Glover, are structured into geographically widespread host races. In the cotton-producing regions of West and Central Africa (WCA), two genotypes have been repeatedly detected within the cotton host race, one of which (Burk1) is prevalent (>90%) and resistant to several insecticides, as opposed to the second one (Ivo). Here, we conducted whole plant and field cage experiments to test hypotheses for such low genetic diversity, including selection from insecticide treatments, interclonal competition and adaptation to host plant, or climatic conditions. To assess the genetic diversity of immigrant aphids, alatae were trapped and collected on cotton and relay host plants (okra and roselle) in the early cropping season. Individuals were genotyped at eight specific microsatellite loci and characterized by a multilocus genotype (MLG). When independently transferred from cotton (Gossypium hirustum L.) leaf discs to whole plants (G. hirsutum and G. arboreum, roselle and okra), Ivo and Burk1 performed equally well. When concurrently transferred from cotton leaf discs to the same plant species, Ivo performed better than Burk1, indicating that competition favoured Ivo. This was also the case on G. hirsutum growing outdoors. Conversely, Burk1 prevailed when cotton plants were sprayed with insecticides. In experiments where aphids were allowed to move to neighbouring plants, Burk1 was better represented than Ivo on low-populated plants, suggesting that dispersal may be a way to avoid competition on crowded plants. Most cotton aphids collected on cotton or relay host plants in the early cropping season were Burk1 (>90%), indicating high dispersal ability and, probably reflecting high frequency on host plants from which they dispersed. In the agricultural landscape of WCA, the use of broad-range insecticides on both cotton and relay host plants has led to the prevalence of one genotype of A. gossypii resistant to different classes of insecticides. Deployment of widespread and integrated pest management strategies are needed to restore cotton aphid control. PMID- 21320363 TI - Is the alpine divide becoming more permeable to biological invasions? - Insights on the invasion and establishment of the Walnut Husk Fly, Rhagoletis completa (Diptera: Tephritidae) in Switzerland. AB - The Walnut Husk Fly, Rhagoletis completa Cresson (Diptera: Tephritidae), is native to North America (Midwestern US and north-eastern Mexico) and has invaded several European countries in the past decades by likely crossing the alpine divide separating most parts of Switzerland from Italy. Here, we determined its current distribution in Switzerland by sampling walnuts (Juglans regia L.) in ecologically and climatically distinct regions along potential invasion corridors. R. completa was found to be firmly established in most low altitude areas of Switzerland where walnuts thrive, but notably not a single parasitoid was recovered from any of the samples. Infested fruit was recovered in 42 of the 71 localities that were surveyed, with mean fruit infestation rate varying greatly among sites. The incidence of R. completa in Switzerland is closely related to meteorological mean spring temperature patterns influencing growing season length, but not to winter temperatures, reflecting survival potential during hibernation. Importantly, areas in which the fly is absent correspond with localities where the mean spring temperatures fall below 7 degrees C. Historical data records show that the natural cold barrier around the Alpine divide in the central Swiss Alps corresponding to such minimal temperatures has shrunk significantly from a width of more than 40 km before 1990 to around 20 km after 2000. We hypothesize on possible invasion/expansion routes along alpine valleys, dwell on distribution patterns in relation to climate, and outline future research needs as the incursion of R. completa into Switzerland; and, more recently, other European countries, such as Germany, Austria, France and Slovenia, represent an example of alien species that settle first in the Mediterranean Basin and from there become invasive by crossing the Alps. PMID- 21320364 TI - Investigation of the genetic diversity of an invasive whitefly (Bemisia tabaci) in China using both mitochondrial and nuclear DNA markers. AB - It is often considered that reduced genetic variation due to bottlenecks and founder effects limits the capacity for species to establish in new environments and subsequently spread. The recent invasion (during the past five years) of an alien whitefly, one member of Bemisia tabaci cryptic species complex, referred to as Mediterranean (herein referred to as Q-type) in Shandong Province, China, provides an ideal opportunity to study the changes in genetic variation between its home range in the Mediterranean region and its invasion range. Using both the mitochondrial cytochrome oxidase I (mtCOI) and nuclear (microsatellite) DNA, we show that Q in Shandong likely originated in the western Mediterranean. We also found that the haplotype diversity was low compared with its presumed geographic origin, whereas microsatellite allele diversity showed no such decline. A key factor in invasions is the establishment of females and so bottleneck and founder events can lead to a very rapid and considerable loss of mitochondrial diversity. The lack of haplotype diversity in Shandong supports the interpretation that, at one or more points between the western Mediterranean and China, the invading Q lost haplotype diversity, most probably through the serial process of establishment and redistribution through trade in ornamental plants. However, the loss in haplotype diversity does not necessarily mean that nuclear allelic diversity should also decline. Provided females can mate freely with whichever males are available, allelic diversity can be maintained or even increased relative to the origin of the invader. Our findings may offer some explanation to the apparent paradox between the concept of reduced genetic variation limiting adaptation to new environments and the observed low diversity in successful invaders. PMID- 21320365 TI - Consumption of a plant sterol-based spread derived from rice bran oil is effective at reducing plasma lipid levels in mildly hypercholesterolaemic individuals. AB - To establish the effectiveness of a new phytosterol-containing spread derived from rice bran oil (RBO), a randomised, double-blind, cross-over human clinical trial was conducted over 12 weeks. A total of eighty mildly hypercholesterolaemic (total blood cholesterol level >= 5 and <= 7.5 mmol/l with a serum TAG level of <= 4.5 mmol/l) individuals were randomised into two groups (n 40). Group 1 consumed spread only daily for 4 weeks. They were randomised to consume 20 g RBO spread (RBOS), 20 g standard spread (SS) or 20 g phytosterol-enriched spread (PS). After a 4-week period, individuals changed to the next randomised treatment until all three treatments had been consumed. Group 2 consumed spread plus oil daily for 4 weeks. They consumed 20 g RBOS plus 30 ml RBO, 20 g SS plus 30 ml sunflower oil or 20 g RBOS. Blood samples were collected for the analysis of lipid parameters, and 3 d diet records were collected. Compared with SS, RBOS significantly reduced total cholesterol by 2.2 % (P = 0.045), total cholesterol:HDL by 4.1 % (P = 0.005) and LDL-cholesterol by 3.5 % (P = 0.016), but was not as effective overall as PS, which reduced total cholesterol by 4.4 % (P = 0.001), total cholesterol:HDL by 3.4 % (P = 0.014) and LDL-cholesterol by 5.6 % (P = 0.001). In group 2, the addition of RBO to the RBOS produced no differences in cholesterol levels. These results confirm that RBOS is effective in lowering serum cholesterol when consumed as part of a normal diet. PMID- 21320366 TI - Effects on markers of inflammation and endothelial cell function of three ad libitum diets differing in type and amount of fat and carbohydrate: a 6-month randomised study in obese individuals. AB - Diet is important for the prevention of CVD, and diets high in MUFA might be more cardioprotective than low-fat diets. We hypothesise that inflammation and endothelial cell function will be improved most favourably by a high-MUFA diet compared with a low-fat diet. This was tested in a parallel randomised intervention trial on overweight individuals (aged 28.2 (SD 4.6) years) assigned to a diet moderate in the amount of fat (35-45% of energy; >20% of fat as MUFA; MUFA diet, n 39), a low-fat (20-30% of energy) diet (LF diet, n 43) or a control diet (35 % of energy as fat, n 24) for 6 months after weight loss. Protein constituted 10-20 % of energy in all diets. Food was provided free of charge. Fasting blood samples were collected before and after the intervention and analysed for C-reactive protein (CRP), IL-6, intercellular adhesion molecule, von Willebrand factor (vWF) and tissue factor pathway inhibitor. vWF concentrations tended to fall on the LF diet (4.78 (SD 16.44) %; P = 0.07). Concentrations of IL 6 were reduced by the MUFA (0.37 (SD 0.74) pg/ml; P < 0.01) and LF (0.47 (SD 0.69) pg/ml; P < 0.001) diets, and CRP was reduced on all diets (MUFA: 0.48 (SD 1.93) mg/l (P < 0.01); LF: 1.46 (SD 2.89) mg/l (P < 0.001); control: 1.20 (SD 1.97) mg/l (P < 0.01)). No significant differences were observed between changes induced by the different diets. Our findings suggest that in overweight subjects after weight loss, the MUFA and LF diets have similar long-term effects on inflammation and endothelial cell function. PMID- 21320367 TI - Geographical distribution of drinking-water with high iodine level and association between high iodine level in drinking-water and goitre: a Chinese national investigation. AB - Excessive iodine intake can cause thyroid function disorders as can be caused by iodine deficiency. There are many people residing in areas with high iodine levels in drinking-water in China. The main aim of the present study was to map the geographical distribution of drinking-water with high iodine level in China and to determine the relationship between high iodine level in drinking-water and goitre prevalence. Iodine in drinking-water was measured in 1978 towns of eleven provinces in China, with a total of 28,857 water samples. We randomly selected children of 8-10 years old, examined the presence of goitre and measured their urinary iodine in 299 towns of nine provinces. Of the 1978 towns studied, 488 had iodine levels between 150 and 300 MUg/l in drinking-water, and in 246 towns, the iodine level was >300 MUg/l. These towns are mainly distributed along the original Yellow River flood areas, the second largest river in China. Of the 56 751 children examined, goitre prevalence was 6.3 % in the areas with drinking water iodine levels of 150-300 MUg/l and 11.0 % in the areas with drinking-water iodine >300 MUg/l. Goitre prevalence increased with water and urinary iodine levels. For children with urinary iodine >1500 MUg/l, goitre prevalence was 3.69 times higher than that for those with urinary iodine levels of 100-199 MUg/l. The present study suggests that drinking-water with high iodine levels is distributed in eleven provinces of China. Goitre becomes more prevalent with the increase in iodine level in drinking-water. Therefore, it becomes important to prevent goitre through stopping the provision of iodised salt and providing normal drinking water iodine through pipelines in these areas in China. PMID- 21320368 TI - A protein-rich beverage consumed as a breakfast meal leads to weaker appetitive and dietary responses v. a protein-rich solid breakfast meal in adolescents. AB - The purpose of the present study was to determine whether a protein-rich beverage leads to a differential response in appetite, satiety and subsequent energy intake compared with an energy- and macronutrient-matched solid version in young people. A total of fifteen adolescents (eight girls and seven boys; age 14 (SEM 1) years, BMI percentile 79 (SEM 4) %) randomly completed two testing days that included protein-rich (PR) breakfast meals (38 % of energy as protein, 48 (SEM 2) g/meal) provided as a solid (S) or beverage (B). Breakfast was 24 % of estimated daily energy needs (2146 (SEM 96) kJ/meal). Perceived appetite and satiety responses were collected over 5 h followed by an ad libitum lunch buffet. The PR S meal led to greater reductions in 4 h postprandial appetite (- 6221 (SEM 1171) mm * 240 min) v. the PR-B meal (- 3570 (SEM 957) mm * 240 min; P < 0.05). When examining the data according to hourly responses, the PR-S meal led to greater reductions in appetite during postprandial hours 2, 3 and 4 v. the PR-B meal (all comparisons, P < 0.05). No differences in postprandial hourly or total (4 h) fullness were observed following the PR-S v. PR-B meals. The PR-S meal led to approximately 480 kJ less energy consumed at the ad libitum lunch buffet (1418 (SEM 222) kJ) v. the PR-B meal (1900 (SEM 326) kJ; P < 0.05). These data indicate that, although the food form of the PR breakfast meals had little, if any, effect on satiety, the appetitive responses were diminished and the subsequent food intake was greater when protein was consumed as a beverage v. a solid meal. PMID- 21320369 TI - Estimation of total antioxidant capacity from diet and supplements in US adults. AB - Given the importance of dietary antioxidants in reducing the risks of chronic diseases, the present study aimed to estimate the intake of total antioxidant capacity (TAC) from diet and dietary supplements of US adults. We utilised the US Department of Agriculture flavonoid and proanthocyanidin databases, dietary supplement data and food consumption data of 4391 US adults aged 19+ years in the National Health and Nutrition Examination Survey 2001-2. In order to convert the intake data of individual antioxidant compounds to TAC values, the vitamin C equivalent (VCE) of forty-three antioxidant nutrients measured previously was also applied. Daily TAC averaged 503.3 mg VCE/d (approximately 75 % from diet and 25 % from supplements). The energy-adjusted daily TAC level from diet and supplements was higher in women (except for carotenoids), older adults, Caucasian (except for carotenoids), non-alcohol consumers (for vitamin E and proanthocyanidins), subjects with higher income (except for carotenoids) and higher exercise levels than their counterparts (P < 0.05). TAC was positively associated with daily consumption of fruits and fruit juices, vegetables and vegetable products, beverages, wines and teas (P < 0.001). Teas, dietary supplements, and fruits and fruit juices were the major sources of dietary TAC of the US population (28, 25 and 17 %, respectively), while the contribution of vegetables and vegetable products to TAC was minimal ( < 2 %). The present study indicates that antioxidant intake from various diet and supplements contributes to TAC status. TAC levels are different in sociodemographic subgroups of the US population. The relationship between TAC intake and risks of chronic disease warrants further investigation. PMID- 21320370 TI - Is the function of all cardiac valves after the arterial switch operation influenced by an associated ventricular septal defect? AB - A ventricular septal defect in transposition of the great arteries is frequently closely related to the cardiac valves. The valvar function after arterial switch operation of patients with transposition of the great arteries and ventricular septal defect or intact ventricular septum was compared. We analysed the function of all cardiac valves in patients who underwent the arterial switch operations pre- and post-operatively, 1 year after the procedure and on follow-up. The study included 92 patients - 64 with transposition of the great arteries/intact ventricular septum and 28 with transposition of the great arteries/ventricular septal defect. The median age at surgery was 5.5 days in transposition of the great arteries/intact ventricular septum (0-73 days) and 7.0 days in transposition of the great arteries/ventricular septal defect (4-41 days). Follow up was 51.7 months in transposition of the great arteries/intact ventricular septum (3.3-177.3 months) and 55 months in transposition of the great arteries/ventricular septal defect (14.6-164.7 months). Neo-aortic, neo pulmonary, and mitral valvar function did not differ. Tricuspid regurgitation was more frequent 1 year post-operatively in transposition of the great arteries/ventricular septal defect (n = 4) than in transposition of the great arteries/intact ventricular septum. The prevalence of neo-aortic regurgitation and pulmonary stenosis increased over time, especially in patients with transposition of the great arteries/intact ventricular septum. The presence of a ventricular septal defect in patients undergoing arterial switch operation for transposition of the great arteries only has a minor bearing for the development of valvar dysfunction on the longer follow-up. PMID- 21320371 TI - The application of an enzyme-linked immunosorbent assay or an immunofluorescent assay test leads to different estimates of seroprevalence of Coxiella burnetii in the population. AB - The diagnosis and epidemiological studies of Q fever depend on serology. Among the main methods employed are the enzyme-linked immunosorbent assay (ELISA) and the immunofluorescent assay test (IFAT). We show that two commercial assays representing the two methods with two different cut-off titres can lead to significant differences in diagnostic and seroprevalence estimates. This in turn emphasizes the need for a standardized gold method to compare the various assays; whether this standard is 'in-house' or commercially obtained. PMID- 21320372 TI - A long-term serological survey on Aujeszky's disease virus infections in wild boar in East Germany. AB - Between 1985 and 2008, a total of 102,387 wild boar sera originating from Eastern Germany covering an area of 108 589 km2 were tested for the presence of Aujeszky's disease virus (ADV)-specific antibodies. From 1985 until 1991 and from 1992 until 2008, wild boar sera were exclusively investigated using either conventional seroneutralization assays (n=39 621) or commercial gB and full antigen ELISAs (n=62,766), respectively. Spatial-temporal analysis revealed an increasing ADV seroprevalence from 0.4% to 15.9%, on average, during the 24-year observation period that went along with a continuous spread of the infection in a western direction. During 2006 and 2008, 18% of the 66 affected districts had ADV seroprevalences >30%. There was a significant correlation between ADV seroprevalence and the hunting index of population density (HIPD) of wild boar in the entire study area, although this did not hold true for some regions. Seroprevalences did not differ between sexes but were age-dependent. East Germany has been officially free of Aujeszky's disease (pseudorabies) in domestic pigs since 1985. Although a risk for domestic pigs cannot be completely ruled out, experience has shown that ADV in domestic pigs could be eliminated although the virus was present in the wild boar population. Despite increasing ADV seroprevalence in the East German wild boar population no spillover infections from wild boar to domestic pigs have been reported. To further trace ADV infections in the wild boar population in Germany, a nationwide serological monitoring programme should be implemented. PMID- 21320373 TI - A novel field-based approach to validate the use of network models for disease spread between dairy herds. AB - The introduction of a centralized system for recording cattle movements in the UK has provided a framework for network-based models for disease spread. However, there are many types of non-reportable contacts between farms which may play a role in disease spread. The lack of real pathogen data with which to test network models makes it difficult to assess whether reported data adequately captures the risk-potential network between farms and improves the accuracy of disease forecasts. A novel multi-disciplinary approach is described whereby network-based models, built upon reported cattle movements and non-reportable local contacts between study farms, are parameterized using field data on bovine Staphylococcus aureus strains. Reported cattle movements were found to play a role in strain spread between farms, but other contacts via farm visitors were also correlated with strain distribution, suggesting that parameterizing contact networks using cattle-tracing data alone may not adequately capture the disease dynamics. PMID- 21320375 TI - Syphilis with HIV in Florence, 2003-2009: a 7-year epidemiological study. AB - The aims of this study were to describe the trend of acquired syphilis in the city of Florence and its province over a 7-year period, to investigate sexual behaviours in the syphilis-infected population and to analyse syphilis/HIV co infection. A total of 259 patients were classified according to age, sex and HIV infection. We estimated that from 2004 to 2008 cases increased by 248%. Most patients with concurrent HIV infection were male (31-45 years), but 40- to 60 year-old men who had sex with men predominated in both male and HIV-positive patients. Oral sex was identified as the most significant route of transmission, although most patients did not consider it so. Late-presenters with HIV accounted for 33% of HIV-positive patients: they were unaware of their HIV status and showed syphilis lesions only. In these cases, syphilis heralded the presence of HIV infection and allowed earlier diagnosis. PMID- 21320376 TI - Hospital-acquired infections in Belgian acute-care hospitals: an estimation of their global impact on mortality, length of stay and healthcare costs. AB - Assessing the overall burden of disease which can be attributed to hospital acquired infections (HAIs) remains a challenge. A matched cohort study was performed to estimate excess mortality, length of stay and costs attributable to HAIs in Belgian acute-care hospitals, using six matching factors (hospital, diagnosis-related group, age, ward, Charlson score, estimated length of stay prior to infection). Information was combined from different sources on the epidemiology and burden of HAIs to estimate the impact at national level. The total number of patients affected by a HAI each year was 125 000 (per 10.9 million inhabitants). The excess mortality was 2.8% and excess length of stay was 7.3 days, corresponding to a public healthcare cost of ?290 million. A large burden was observed outside the intensive-care unit setting (87% of patients infected and extra costs, 73% of excess deaths). PMID- 21320377 TI - Stroop effects in persons with traumatic brain injury: selective attention, speed of processing, or color-naming? A meta-analysis. AB - The color word Stroop test is the most common tool used to assess selective attention in persons with traumatic brain injury (TBI). A larger Stroop effect for TBI patients, as compared to controls, is generally interpreted as reflecting a decrease in selective attention. Alternatively, it has been suggested that this increase in Stroop effects is influenced by group differences in generalized speed of processing (SOP). The current study describes an overview and meta analysis of 10 studies, where persons with TBI (N = 324) were compared to matched controls (N = 501) on the Stroop task. The findings confirmed that Stroop interference was significantly larger for TBI groups (p = .008). However, these differences may be strongly biased by TBI-related slowdown in generalized SOP (r2 = .81 in a Brinley analysis). We also found that TBI-related changes in sensory processing may affect group differences. Mainly, a TBI-related increase in the latency difference between reading and naming the font color of a color-neutral word (r2 = .96) was linked to Stroop effects. Our results suggest that, in using Stroop, it seems prudent to control for both sensory factors and SOP to differentiate potential changes in selective attention from other changes following TBI. PMID- 21320374 TI - Time-dependent analysis of extra length of stay and mortality due to ventilator associated pneumonia in intensive-care units of ten limited-resources countries: findings of the International Nosocomial Infection Control Consortium (INICC). AB - Ventilator-associated pneumonias (VAPs) are a worldwide problem that significantly increases patient morbidity, mortality, and length of stay (LoS), and their effects should be estimated to account for the timing of infection. The purpose of the study was to estimate extra LoS and mortality in an intensive-care unit (ICU) due to a VAP in a cohort of 69,248 admissions followed for 283,069 days in ICUs from 10 countries. Data were arranged according to the multi-state format. Extra LoS and increased risk of death were estimated independently in each country, and their results were combined using a random-effects meta analysis. VAP prolonged LoS by an average of 2.03 days (95% CI 1.52-2.54 days), and increased the risk of death by 14% (95% CI 2-27). The increased risk of death due to VAP was explained by confounding with patient morbidity. PMID- 21320379 TI - Job satisfaction amongst aged care staff: exploring the influence of person centered care provision. AB - BACKGROUND: There are challenges in attracting and sustaining a competent and stable workforce in aged care, and key issues of concern such as low staff job satisfaction and feelings of not being able to provide high quality care have been described. This study aimed to explore the association between person centered care provision and job satisfaction in aged care staff. METHODS: Residential aged care staff (n = 297) in Australia completed the measure of job satisfaction and the person-centered care assessment tool. Univariate analyses examined relationships between variables, and multiple linear regression analysis explored the extent to whichperceived person-centredness could predict job satisfaction of staff. RESULTS: Perceived person-centred care provision was significantly associated with job satisfaction, and person-centred care provision could explain nearly half of the variation in job satisfaction. The regression model with the three person-centered care subscales as predictor variables accounted for 40% of the variance in job satisfaction. Personalizing care had the largest independent influence on job satisfaction, followed by amount of organizational support and degree of environmental accessibility. Personalizing care and amount of organizational support had a statistically significant unique influence. CONCLUSIONS: As person-centered care positively correlated with staff job satisfaction, supporting staff in providing person-centered care can enhance job satisfaction and might facilitate attracting and retaining staff in residential aged care. The findings reiterate a need to shift focus from merely completing care tasks and following organizational routines to providing high quality person-centered care that promotes the good life of residents in aged care. PMID- 21320378 TI - Spatial bias and right hemisphere function: sex-specific changes with aging. AB - Patterns of cerebral asymmetry related to visuospatial functions may change with age. The typical leftward bias on a line bisection task may reflect cerebral asymmetry. With age, such leftward bias decreases. This study demonstrated that the age-related decrease of leftward bias may actually be sex-specific. In addition, previous research suggests that young adults' deviation in line bisection may reflect asymmetric hemispheric activation of perceptual-attentional "where" spatial systems, rather than motor-intentional "aiming" spatial systems; thus, we specifically fractionated "where" and "aiming" bias of men and women ranging in age from 22 to 93 years old. We observed that older men produced greater rightward line bisection errors, of primarily "where" spatial character. However, women's errors remained leftward biased, and did not significantly change with age. "Where" spatial systems may be linked to cortico-cortical processing networks involving the posterior part of the dorsal visuospatial processing stream. Thus, the current results are consistent with the conclusion that reduced right dorsal spatial activity in aging may occur in the male, but not female, adult spatial system development. PMID- 21320380 TI - Intratympanic gentamicin in Meniere's disease: our experience. AB - AIMS: To analyse intratympanic gentamicin injection as a treatment option in patients with monolateral Meniere's disease resistant to medical treatment. MATERIAL AND METHODS: Longitudinal, prospective, descriptive study of response to gentamicin treatment in 71 patients diagnosed with Meniere's disease and treated medically for more than a year, unsuccessfully. American Academy of Otolaryngology-Head and Neck Surgery criteria were used for diagnosis and follow up. RESULTS: Complete vertigo control was obtained in 65.6 per cent of patients, and complete or substantial control in 84.37 per cent. Thirteen patients (18.3 per cent) suffered significant hearing loss. CONCLUSION: This intratympanic gentamicin injection protocol enabled effective vertigo control in most patients, and represents a good alternative to more aggressive techniques for the treatment of Meniere's disease which does not respond to medical treatment. PMID- 21320381 TI - Associations between dairy consumption and body weight: a review of the evidence and underlying mechanisms. AB - As the incidence of obesity is reaching 'epidemic' proportions, there is currently widespread interest in the impact of dietary components on body-weight and food intake regulation. The majority of data available from both epidemiological and intervention studies provide evidence of a negative but modest association between milk and dairy product consumption and BMI and other measures of adiposity, with indications that higher intakes result in increased weight loss and lean tissue maintenance during energy restriction. The purported physiological and molecular mechanisms underlying the impact of dairy constituents on adiposity are incompletely understood but may include effects on lipolysis, lipogeneis and fatty acid absorption. Furthermore, accumulating evidence indicates an impact of dairy constituents, in particular whey protein derivatives, on appetite regulation and food intake. The present review summarises available data and provides an insight into the likely contribution of dairy foods to strategies aimed at appetite regulation, weight loss or the prevention of weight gain. PMID- 21320382 TI - Ruminant and industrial sources of trans-fat and cardiovascular and diabetic diseases. AB - The various positional isomers of oleic acid (18 : 1Delta9c or 9c-18 : 1) may have distinct biological effects. Detrimental effects of consumption of industrial trans-fatty acids (TFA) (elaidic acid; 18 : 1Delta9t) from partially hydrogenated vegetable oils on CVD risk factors are well documented. In addition, epidemiological data suggest that chronic consumption of industrial sources of TFA could alter insulin sensitivity and predispose for type 2 diabetes. However, intervention studies on this issue have remained inconclusive. Moreover, very little information is available on the effect of natural sources of TFA (vaccenic acid; 18 : 1Delta11t) coming from dairy products and ruminant meat on the development of CVD and type 2 diabetes. The review focuses on the impact of the consumption of ruminant TFA in relation to cardiovascular risk factors, inflammation and type 2 diabetes. PMID- 21320384 TI - Eukaryotic systematics: a user's guide for cell biologists and parasitologists. AB - Single-celled parasites like Entamoeba, Trypanosoma, Phytophthora and Plasmodium wreak untold havoc on human habitat and health. Understanding the position of the various protistan pathogens in the larger context of eukaryotic diversity informs our study of how these parasites operate on a cellular level, as well as how they have evolved. Here, we review the literature that has brought our understanding of eukaryotic relationships from an idea of parasites as primitive cells to a crystallized view of diversity that encompasses 6 major divisions, or supergroups, of eukaryotes. We provide an updated taxonomic scheme (for 2011), based on extensive genomic, ultrastructural and phylogenetic evidence, with three differing levels of taxonomic detail for ease of referencing and accessibility (see supplementary material at Cambridge Journals On-line). Two of the most pressing issues in cellular evolution, the root of the eukaryotic tree and the evolution of photosynthesis in complex algae, are also discussed along with ideas about what the new generation of genome sequencing technologies may contribute to the field of eukaryotic systematics. We hope that, armed with this user's guide, cell biologists and parasitologists will be encouraged about taking an increasingly evolutionary point of view in the battle against parasites representing real dangers to our livelihoods and lives. PMID- 21320383 TI - Health benefits of cereal fibre: a review of clinical trials. AB - Cereal fibre and whole-grain intakes have been consistently associated in the epidemiological literature with reduced mortality and risk of chronic disease including obesity, CVD and type 2 diabetes. The present review focuses on intervention trials with three primary aims: (1) understanding the mechanisms through which fibre consumption improves health (for example, examination of intermediate endpoints reflecting improved lipid, glucose and energy metabolism); (2) close evaluation of qualitative factors which modify fibre's effectiveness including physiochemical properties (for example, solubility, fermentability and viscosity), fibre extract molecular weight, fibre particle size and botanical structure of the fibre source grain; and (3) identification of areas in which additional research is needed. The first two aims typify the goals of nutrition research, in that improved understanding of the specific factors which determine fibre's health benefits has critical implications for dietary recommendations as well as improving understanding of physiological mechanisms. The third aim acknowledges the substantial gap between recommended and actual fibre intakes in many developed countries including the USA and the UK. In recognition of this deficit in total fibre intake, food manufacturing processes increasingly utilise fibre extracts and concentrates as food additives. However, whether fibre extracts provide similar health benefits to the fibre supplied in the constituents of whole grain is largely unexplored. The relative benefits of fibre extracts compared with whole-grain fibre sources therefore represent a critical area in which additional research is needed. PMID- 21320385 TI - Parasite diversity as an indicator of environmental change? An example from tropical grouper (Epinephelus fuscoguttatus) mariculture in Indonesia. AB - Fish parasites are used to monitor long-term change in finfish grouper mariculture in Indonesia. A total of 210 Epinephelus fuscoguttatus were sampled in six consecutive years between 2003/04 and 2008/09 and examined for parasites. The fish were obtained from floating net cages of a commercially run mariculture facility that opened in 2001. The fauna was species rich, consisting of ten ecto- and 18 endoparasite species. The ectoparasite diversity and composition was relatively stable, with the monogeneans Pseudorhabdosynochus spp. (83-100% prevalence, Berger-Parker Index of 0.82-0.97) being the predominant taxon. Tetraphyllidean larvae Scolex pleuronectis and the nematodes Terranova sp. and Raphidascaris sp. 1 were highly abundant in 2003/04-2005/06 (max. prevalence S. pleuronectis 40%, Terranova sp. 57%, Raphidascaris sp. 1 100%), and drastically reduced until 2008/09. These parasites together with the prevalence of Trichodina spp., ecto-/endoparasite ratio and endoparasite diversity illustrate a significant change in holding conditions over the years. This can be either referred to a definite change in management methods such as feed use and fish treatment, or a possible transition of a relatively undisturbed marine environment into a more affected habitat. By visualizing all parameters within a single diagram, we demonstrate that fish parasites are useful bioindicators to monitor long-term change in Indonesian grouper mariculture. This also indicates that groupers can be used to monitor environmental change in the wild. Further taxonomic and systematic efforts in less sampled regions significantly contributes to this new application, supporting fish culture and environmental impact monitoring also in other tropical marine habitats. PMID- 21320386 TI - Impact of community-directed treatment on soil transmitted helminth infections in children aged 12 to 59 months in Mazabuka District, Zambia. AB - This study assessed the impact of adding community-directed treatment (ComDT) to the routine health facility (HF)-based treatment on prevalence and intensity of soil transmitted helminth (STH) infections among children aged 12 to 59 months. Repeated cross-sectional surveys were conducted among randomly selected children of this age group from the intervention area (HF+ComDT area) and the comparison area (HF area) at baseline (n=986), 12 months (n=796) and 18 months (n=788) follow-up. The prevalence of Ascaris lumbricoides was significantly higher in the HF+ComDT as compared to the HF area at baseline (P=0.048), but not at 12 and 18 months follow-up. At baseline the HF+ComDT area had significantly higher intensities of A. lumbricoides compared to the HF area (P<0.001), but not at 12 and 18 months follow-ups. Prevalence and intensity of hookworm did not differ significantly between treatment arms at any time. Analysis of trends showed a significant decrease in prevalence of A. lumbricoides and hookworm in the HF+ComDT area (P<0.001), of hookworm in the HF area (P<0.05), but not of A. lumbricoides in the HF area. It is concluded that the ComDT approach generally enhanced the treatment effect among under-five year children and that this alternative approach may also have advantages in other geographical settings. PMID- 21320387 TI - Treatment and prevention of cryptosporidiosis: what options are there for a country like Zambia? AB - Cryptosporidiosis is a major infection of humans, leading to diarrhoea and growth failure in children, diarrhoea and malnutrition in immunocompromised adults, and is associated with increased mortality in all age groups. Using the country of Zambia as an example, I review the possible approaches to treatment and prevention in a tropical setting. The current optimal therapy for cryptosporidiosis is nitazoxanide which works well in HIV uninfected children, but treatment in patients with HIV infection remains remarkably difficult. No single drug has demonstrated efficacy in a randomised trial. No vaccine is available, so the best option for prevention for the moment is filtration and clean storage of drinking water. This would be expected to reduce cryptosporidiosis dramatically, but this needs to be demonstrated directly. Water filtration would have the added benefit of protection against many other pathogens, but the paucity of alternative approaches highlights the need for a better understanding of this important human pathogen. PMID- 21320388 TI - An attempt to use ectoparasites as tags for habitat occupancy by small mammalian hosts in central Europe: effects of host gender, parasite taxon and season. AB - OBJECTIVE: We used data on fleas and gamasid mites parasitic on 8 species of small mammals to test whether (a) species composition of ectoparasite infracommunities may be used to predict host habitat occupancy and (b) the accuracy of this prediction differs between ectoparasite taxa, host genders and seasons. METHODS: We used a Random Forests algorithm that is based on the methodology of classification trees. RESULTS: The accuracy of prediction of habitat occupancy was relatively low and varied substantially among host species. The combined rate of the correct prediction of host habitat occupancy from data on ectoparasites was significantly higher than 50%, albeit being relatively low. The accuracy of prediction (a) did not differ between male and female hosts when it was based on species composition of fleas in summer or of mites in summer and winter, (b) was significantly higher in male hosts than in female hosts when the winter data on fleas were used and (c) was significantly higher for flea than mite assemblages. The effect of season was found in mites but not in fleas with the accuracy of prediction being significantly higher in summer than in winter assemblages. CONCLUSIONS: Ectoparasites appeared to be not especially useful as biological markers for distinguishing host populations in different habitats in temperate zones. PMID- 21320389 TI - A systematic review on reporting and assessment of adverse effects associated with transcranial direct current stimulation. AB - Transcranial direct current stimulation (tDCS) is a non-invasive method of brain stimulation that has been intensively investigated in clinical and cognitive neuroscience. Although the general impression is that tDCS is a safe technique with mild and transient adverse effects (AEs), human data on safety and tolerability are largely provided from single-session studies in healthy volunteers. In addition the frequency of AEs and its relationship with clinical variables is unknown. With the aim of assessing tDCS safety in different conditions and study designs, we performed a systematic review and meta-analysis of tDCS clinical trials. We assessed Medline and other databases and reference lists from retrieved articles, searching for articles from 1998 (first trial with contemporary tDCS parameters) to August 2010. Animal studies, review articles and studies assessing other neuromodulatory techniques were excluded. According to our eligibility criteria, 209 studies (from 172 articles) were identified. One hundred and seventeen studies (56%) mentioned AEs in the report. Of these studies, 74 (63%) reported at least one AE and only eight studies quantified AEs systematically. In the subsample reporting AEs, the most common were, for active vs. sham tDCS group, itching (39.3% vs. 32.9%, p>0.05), tingling (22.2% vs. 18.3%, p>0.05), headache (14.8% vs. 16.2%, p>0.05), burning sensation (8.7% vs. 10%, p>0.05) and discomfort (10.4% vs. 13.4%, p>0.05). Meta-analytical techniques could be applied in only eight studies for itching, but no definite results could be obtained due to between-study heterogeneity and low number of studies. Our results suggested that some AEs such as itching and tingling were more frequent in the tDCS active group, although this was not statistically significant. Although results suggest that tDCS is associated with mild AEs only, we identified a selective reporting bias for reporting, assessing and publishing AEs of tDCS that hinders further conclusions. Based on our findings, we propose a revised adverse effects questionnaire to be applied in tDCS studies in order to improve systematic reporting of tDCS-related AEs. PMID- 21320390 TI - Evidence-based pharmacotherapy for personality disorders. AB - Patients with personality disorders are prescribed psychotropic medications with greater frequency than almost any other diagnostic group. Prescribing practices in these populations are often based on anecdotal evidence rather than rigorous data. Although evidence-based psychotherapy remains an integral part of treatment, Axis II psychopathology is increasingly conceptualized according to neurobiological substrates that correspond to specific psychopharmacological strategies. We summarize the best available evidence regarding medication treatment of personality disordered patients and provide optimal strategies for evidence-based practice. Most available evidence is concentrated around borderline and schizotypal personality disorders, with some additional evidence concerning the treatment of avoidant and antisocial personality disorders. Although maladaptive personality symptoms respond to antidepressants, antipsychotics, mood stabilizers, and other medications, evidence-based pharmacotherapy is most useful in treating circumscribed symptom domains and induces only partial improvement. Most available evidence supports use of medication in reducing impulsivity and aggression, characteristic of borderline and antisocial psychopathology. Efforts have also begun to reduce psychotic-like symptoms and improve cognitive deficits characteristic of schizotypy. Indirect evidence is also provided for psychopharmacological reduction of social anxiety central to avoidant personality disorder. Evidence-based practice requires attention to domains of expected clinical improvement associated with a medication, relative to the potential risks. The development of future rational pharmacotherapy will require increased understanding of the neurobiological underpinnings of personality disorders and their component dimensions. Increasing efforts to translate personality theory and social cognitive neuroscience into increasingly specific neurobiological substrates may provide more effective targets for pharmacotherapy. PMID- 21320391 TI - The place of implementation science in the translational medicine continuum. AB - There is a growing consensus that the transfer of knowledge from biomedical discoveries into patient and public benefit should be accelerated. At the same time there is a persistent lack of conceptual clarity about the precise nature of the phases of the translational continuum necessary to implement this. In this paper, we: (i) propose an integrated schema to understand the five sequential phases that link basic biomedical research with clinical science and implementation; (ii) discuss the nature of three blocks along this translational pathway; (iii) outline key issues that need to be addressed in removing such barriers. The five research phases described are: (0) basic science discovery; (1) early human studies; (2) early clinical trials; (3) late clinical trials; (4) implementation (which includes adoption in principle, early implementation and persistence of implementation). This schema also sets out three points at which communication blocks can occur. The application of 'implementation science' is in its early stages within mental health and psychiatric research. This paper therefore aims to develop a consistent terminology to understand the discovery, development, dissemination and implementation of new interventions. By better understanding the factors that promote or delay knowledge to flow across these blocks, we can accelerate progression along translational medicine pathways and so realize earlier patient benefit. PMID- 21320393 TI - [Prophylaxis of lung cancer-perplexity and hopes in the new era]. PMID- 21320392 TI - A mouse model of high trait anxiety shows reduced heart rate variability that can be reversed by anxiolytic drug treatment. AB - Increasing evidence suggests that specific physiological measures may serve as biomarkers for successful treatment to alleviate symptoms of pathological anxiety. Studies of autonomic function investigating parameters such as heart rate (HR), HR variability and blood pressure (BP) indicated that HR variability is consistently reduced in anxious patients, whereas HR and BP data show inconsistent results. Therefore, HR and HR variability were measured under various emotionally challenging conditions in a mouse model of high innate anxiety (high anxiety behaviour; HAB) vs. control normal anxiety-like behaviour (NAB) mice. Baseline HR, HR variability and activity did not differ between mouse lines. However, after cued Pavlovian fear conditioning, both elevated tachycardia and increased fear responses were observed in HAB mice compared to NAB mice upon re-exposure to the conditioning stimulus serving as the emotional stressor. When retention of conditioned fear was tested in the home cage, HAB mice again displayed higher fear responses than NAB mice, while the HR responses were similar. Conversely, in both experimental settings HAB mice consistently exhibited reduced HR variability. Repeated administration of the anxiolytic NK1 receptor antagonist L-822429 lowered the conditioned fear response and shifted HR dynamics in HAB mice to a more regular pattern, similar to that in NAB mice. Additional receiver-operating characteristic (ROC) analysis demonstrated the high specificity and sensitivity of HR variability to distinguish between normal and high anxiety trait. These findings indicate that assessment of autonomic response in addition to freezing might be a useful indicator of the efficacy of novel anxiolytic treatments. PMID- 21320394 TI - [Analysis of the familial risk factors on lung cancer]. AB - BACKGROUND: To study the familial risk factors on lung cancer and the effect of genetic factors on lung cancer. METHODS: With methods of genetic epidemiology, 370 probands of lung cancer and 370 spouses of the probands (control) were studied. RESULTS: The risk of the probands' relatives was 1.85 times higher than that of their spouses' relatives (P < 0.01). Compared with the spouses' parents and female relatives, the OR of the probands' parents and female relatives was 2.66 and 2.64 (P < 0.01), respectively. Compard with the female controls' parents, the OR of female probands' parents was 2.27 (P < 0.01). CONCLUSIONS: The susceptibility of the probands' relatives with lung cancer is higher than that of their spouses' relatives. The genetic factor is one of risk factors on lung cancer. PMID- 21320395 TI - [Establishment of cohort to study lung cancer in Yunnan tin miners]. AB - BACKGROUND: To establish a cohort for the study of risk factors of lung cancer, and to support the study of early biomarkers and prevention of lung cancer. METHODS: Designed a special population-based prospectively dynamic cohort among radon- and arsenic-exposed tin miners aged 40 or more years old with at least 10 years of occupational exposure in Yunnan Province, P.R.China. The mass screenings with sputum cytology and chest X-ray were conducted annually. The baseline information was collected for assessing demographic characteristics and risk factors. The multiple sputum specimens, chest radiographs and numerous biologic specimens have been collected and stored. RESULTS: From 1992-1999, 9143 miners have been enrolled and 460 new cases of lung cancer have been found. There had 47655 person-time chest radiographs and 46625 person-time sputum cytology among the cohort in 8 years. The relative risks of age-adjusted exposure to chronic bronchitis, silicosis, and tobacco were 1.73, 1.46, and 1.32 respectively. CONCLUSIONS: A cohort of unique occupationally-exposed tin miners with an extensive biologic specimen repository and data bank has been successfully established. Although occupational exposures are the predominant risk factors among the high risk miners, lung cancer risk is also associated with chronic obstructive lung disease (chronic bronchitis and silicosis) and a number of measures of exposure to tobacco smoke, including early age of first use, duration, and cumulative exposure. PMID- 21320396 TI - [Psychosocial factors and lung cancer development]. AB - BACKGROUND: To study the association between psychosocial factors and the development of lung cancer. METHODS: Case-control matched study was employed in the study. A standardized life event, social support and defense mechanisms interview was administered respectively. Total 118 lung cancer patients who were diagnosed pathologically were chosen as case group, and 118 matched healthy people were as control group. The pair had the same gender, the same race, and the same occupation, and lived in the same area, and the age difference between the two groups was +/-3 years. RESULTS: Univariate analysis showed that smoking, defect of sleeping, alcohol consuming, smoking and drinking during meal, preserved food consuming, irregularity of life increased the risk of lung cancer development (P < 0.05). The scores of life events, social support had no significant difference between two groups (P > 0.05), but the scores of stress life events was higher in cancer group than that in control group. The immature factors of defense mechanisms in cancer group were higher than those in control group (P < 0.05). Multiple qualified logistic regression showed that smoking and defect of sleeping were the main risk factors of lung cancer genesis. CONCLUSIONS: There is certain association between psychosocial factors and lung cancer development. The immature defensive factor is the psychosocial factor of lung cancer genesis, and smoking, defect of sleeping, alcohol consuming, smoking and drinking during meal, preserved food consuming, irregularity of life are the risk factors of lung cancer. PMID- 21320397 TI - [A study on mortality rates of lung cancer patients in Yanting County from 1969 to 1997]. AB - BACKGROUND: To study the mortality rate and its trend in lung cancer patients in Yanting County, Sichuan, P.R.China, during 1969-1997. METHODS: According to the surveillance death data of the residents in Yanting County, the time series of mortality rates of lung cancer, the average changing speed of mortality rate every year and the proportion of death from lung cancer among all malignant diseases were analyzed. The relationship between the age and the death of lung cancer was explored by birth cohort analysis. RESULTS: The mortality rate of lung cancer increased year by year (Chi-square=457.51, P=0.000). The proportion of death from lung cancer among all malignant diseases remarkably increased year by year (Chi-square=273.29, P=0.000). Both in male and female lung cancer patients, the mortality rate increased with age. And in the later birth group, the mortality rate increased more quickly. CONCLUSIONS: The mortality rate of lung cancer patients in Yanting County has significantly gone up during the past 28 years. The prevention and treatment of malignant tumor should be focused on lung cancer. PMID- 21320398 TI - [A case-control study on risk factor of lung cancer in female nonsmokers]. AB - BACKGROUND: To investigate the risk factors of lung cancer in female nonsmokers. METHODS: An 1:1 matched case-control study was carried out in Shenyang, P.R.China. A questionnaire covering demographics, family history of cancer, previous disease history, living conditions, passive smoking history, occupational exposure, diet/nutritional preferences and cooking habits, sources of indoor pollution and so on was used to ask each subject. A total of 126 new cases diagnozed as primary lung cancer and 126 controls matched for age and sex were randomly selected from the female nonsmokers. RESULTS: Adenocarcinoma was the main type of female lung cancer, accounting for 62.7%. The higher number of deliveries was, the more risk of lung cancer was (OR=1.466, 95%CI=1.06-2.01). The lower the body mass index (BMI), the higher the risk of lung cancer (OR=2.082, 95%CI=1.2-3.60). With the increase of BMI, the risk of lung cancer decreased. Eating too much viscera (OR=1.891, 95%CI=1.45-2.46), maize and sorghum (OR=1.538, 95%CI= 1.22 -1.93) could increase the risk of lung cancer. Using petroleum gas as fuel (OR=1.741, 95%CI=1.29-2.34) and indoor coal burning (OR=1.785, 95%CI=1.33 2.38) were lung cancer's risk factors, too. The OR value of family cancer history of first-class relatives was 3.18 (95%CI=2.43-4.15). CONCLUSIONS: The results suggest that low value of BMI, high number of child deliveries, eating too much viscera, maize and sorghum, indoor coal burning and using petroleum gas as fuel can increase the risk of lung cancer in female nonsmokers. PMID- 21320399 TI - [A case-control study on the relationship among indoor air pollution,depression and oncogenesis of lung cancer]. AB - BACKGROUND: To evaluate the relationship among indoor air pollution, depression and oncogenesis of lung cancer. METHODS: An 1:3 matched case-control study was carried out. Conditional logistic regression was applied to process the data. RESULTS: After some confounding factors were adjusted, the ORs increased 122% and 113% for the amount of coal using >=46kg/m2 and heating by coal stove respectively. The ORs elevated more than five-folds for disharmony and rupture of marriage, difference of accommodation and acclimation by oneself and human relationship respectively. The risk of lung caner obviously increased for frequent exposure to indoor cooking smoke combinated with depressed mood or mental scar respectively. CONCLUSIONS: The indoor air pollution, depression and mental scar are important factors of oncogenesis of lung cancer. PMID- 21320400 TI - [Cyclooxygenase-2 expression in female pulmonary adenocarcinoma]. AB - BACKGROUND: To explore the relationship between the expression of COX-2 and pathophysiological features in female pulmonary adenocarcinoma patients. METHODS: Expression of COX-2 protein was detected in 50 cases of female pulmonary adenocarcinoma tissues and 50 cases of paracancerous tissues by streptavidin biotin immunoperoxidase method. RESULTS: The positive rates of COX-2 expression were 78% and 26% in tumor tissues and paracancerous tissues respectively, and there was a highly significant difference between the two groups (Chi square=27.08, P < 0.01). No significant difference was found among COX-2 expression level, age (P=0.50), smoking history (P=1.0), differentiation grade of tumor cells (P=0.712), TNM stage (P=0.591), size of primary tumor (P=0.63) and lymph nodes metastasis (P=0.88). CONCLUSIONS: Overexpression of COX-2 may play an important role in oncogenesis of female lung adenocarcinoma. PMID- 21320401 TI - [An experimental study on the association of cyclin D1 oncoprotein with mutated p53 in progressive development of pulmonary tumors]. AB - BACKGROUND: To study the correlation of cyclin D1 oncoprotein with a mutated p53 in pulmonary tumors progression. METHODS: Thirty-one male A/J strain mice were treated intraperitoneally with a single injection of 20-methylcholanthrene and sacirificed at various ages. A total of 292 lesions in various histological type were obtained. Immunohistochemical methods were employed to detect the expression of cyclin D1 and p53 in paraffin-embeded tissues. RESULTS: Expression of cyclin D1 oncoprotein was seen in 6 out of 7 (86%) in hyperplasias, 89 out of 102 (87%) in alveolar adenomas, 41 out of 56 (73%) in papillary adenomas, and 17 of 25 (68%) in papillary carcinomas. Cyclin D1 expression did not correlate with the progression of the lung neoplasms, and tended to decrease in papillary carcinomas than in papillary adenomas, in alveolar adenomas and hyperplasias (Chi square=5.531, P=0.033). Expressions of p53 gene were obviously stronger in malignant lesions than in benign lesions (Chi-square=41.77, P=0.000). The p53 showed positive staining in carcinoma and severe atypical cell population. Expression of p53 was seen in 16 out of 40 (40%) in papillary carcinomas, 6 out of 69 (9%) in papillary adenomas, and 4 out of 121 (3%) in alveolar adenoma. No positive p53 stain was observed in hyperplasias. Co-expressive rate of cyclin D1 and p53 was highest in papillary carcinomas (26%), but did not show in alveolar adenomas and hyperplasias. CONCLUSIONS: Cyclin D1 oncoprotein may play an important role in the oncogenesis of lung neoplasms, especially in the early stage. p53 expression increases significantly as the histological grade advances, and may correlate with the progression of pulmonary tumors and the malignant potential of tumor. PMID- 21320402 TI - [Study on the relationship between the dendritic cell infiltration in cancer tissues and prognosis in patients with lung cancer]. AB - BACKGROUND: To study the correlation among the number of tumor-infiltrating dendritic cells (TIDC) in cancer tissues and biological behavior and prognosis in lung cancer patients. METHODS: S-100 protein expression level was determined in 39 patients with lung cancer by immunohistochemistry technique. The number of S 100 + TIDC and DNA ploidy were measured by means of flow cytometry. RESULTS: The rate of positive S-100 protein expression was 100% in 39 patients, S-100 + cells showed typical morphology of dendritic cells. The percentage of S-100 +TIDC in patients with heteroploid (21.81%+/-8.18%) was significantly higher than those with diploid (16.03%+/-4.75%) (P=0.006). There was no statistical difference between lymph node metastasis group (20.43%+/-7.74%) and no lymph node metastasis group ( 19.41% +/-7.76%), between tumor size greater than 3cm group ( 20.90% +/ 8.65%) and less than 3cm group ( 19.70% +/-7.61%), between non-small cell lung cancer group (19.48%+/-7.98%) and small cell lung cancer group (21.74%+/-6.17%). No correlation was found between survival time ( 1 year , 1-3 years, greater than 3 years, respectively) and percentage of S-100 +TIDC (21.96%+/-8.05%, 19.47%+/ 6.18%, 19.14%+/-8.76%, respectively). CONCLUSIONS: The number of TIDC should not be chosen as an independent prognostic criterion in human lung cancer. PMID- 21320403 TI - [The effect of radio-frequency ablation in the treatment of the VX2 tumor in rabbit lung]. AB - BACKGROUND: To observe the CT appearance and pathological changes of VX2 tumor in rabbit lung after radio-frequency ablation. METHODS: After VX2 tumor tissue suspension was injected into the lungs, the transplanted lung cancer models were established in 36 New Zealand white rabbits. Twenty-eight rabbits were treated with radio-frequency ablation, and another 8 rabbits without any treatment as control. The CT appearances and pathological changes were observed in different time intervals after the treatment in 14 rabbits out of experimental group. The survival periods of the rabbits were recorded in the rest 14 rabbits of experimental group and the control group respectively. RESULTS: Coagulative necrosis and cell apoptosis appeared in the tumor tissues after the ablation, and inflammatory cells were found in the lung tissues around the areas of ablation. Wadding shadows appeared in CT images after the treatment and disappeared with the inflammation vanished, but the tumor shadows ceased to increase. In the experimental group, tumor tissues were almost necrosed in the target areas of 21 rabbits, however, peripheral residual nests of histologically viable tumor were found in the target areas of the other 7 rabbits. The survival periods of rabbits in the experimental group and the control group were 38 days+/-3.4 days days and 26 days+/-2.8 days respectively (P < 0.05). CONCLUSIONS: Radio-frequency ablation may be an effective method in the treatment of lung cancer. PMID- 21320404 TI - [The construction and expression of phage display library of anti human lung adenocarcinoma monoclonal antibody 5F-11]. AB - BACKGROUND: To construct and express a phage display library of anti human lung cancer monoclonal antibody 5F-11. METHODS: Immunoglobulin variable regions (VH,VL) were amplified from 5F-11 hybridrom by RT-PCR. ScFv genes consisting of VH DNA and VL DNA joined together by a linker DNA were cloned into a phage vector pCANTAB5E. After 4 rounds of screening with lung adenocarcinoma cell line A2 as antigen, an enriched secondary phage display library was obtained. RESULTS: A recombinant phage display library with total of 8*107 pfu/ml was established. Randomized clones from unselected library digested with BstNI showed different patterns, however, those from selected library showed that phages with special pattern were enriched. Twenty-three out of 30 clones were found to respond strongly to A2 cell lines. CONCLUSIONS: The ScFv of anti-lung adenocarcinoma monoclonal antibody 5F-11 can be successfully produced, which may be useful to widen the application of the antibody. PMID- 21320405 TI - [The growth-inhibiting effect and its molecular mechanism of Tanshinone on human lung cancer cell line in vitro]. AB - BACKGROUND: To study the growth-inhibiting effect and its molecular mechanism of Tanshinone on human lung carcinoma cell line. METHODS: Human lung adenocarcinoma cell line (SPC-A-1) was treated in vitro with 0.5MUg/ml Tanshinone IIA for five days, and the cells treated with all trans retinoic acid (RA) and DDP as control. Changes in cell morphology, proliferation dynamics, cell cycle distribution and tumor-related gene expression were detected. RESULTS: The cell growth and rate of clone formation of SPC-A-1 cells were markedly inhibited in Tanshinone group than RA group. Flow cytometry demonstrated that S phase cells decreased and G0/G1 phase cells increased in Tanshinone group. Expression of p53, p21 was up regulated obviously but CDKN2 was down-regulated markedly by Tanshinone IIA. CONCLUSIONS: Tanshinone IIA can inhibit cell growth and clone formation in human lung cancer cell line (SPC-A-1) and its possible molecular mechanism may be inhibiting DNA synthesis by up-regulating p53, p21 and down-regulating CDKN2. PMID- 21320406 TI - [Detection of circulating lung cancer cells with cytokeratin and 2F7/S5A monoclonal antibody in patients with lung cancer]. AB - BACKGROUND: To investigate the clinical possibility of detection of lung cancer cells in the peripheral blood with cytokeratin and 2F7/S5A monoclonal antibody by flow cytometry (FCM) in patients with lung cancer. METHODS: Five mililiter peripheral blood was collected. The mononuclear cells were isolated by Ficoll Hypaquegradient centrifugation. Then the cells were labeled with lung specific antibody (2F7/S5A) and antibodies against CD45, cytokeratin (CK). The quantitation of CD45 -CK +2F7/S5A + cells were performed by FCM. RESULTS: A total of 151 people were studied, including 20 healthy controls, 116 patients with lung cancer and 15 patients with benign pulmonary diseases. The phenotype of monocytes of peripheral blood was CD45 +CK -2F7/S5A -, while the phenotype of lung cancer cells was CD45 -CK +2F7/S5A +. No cancer cell was found in peripheral blood of all the healthy controls. One out of 15 cases of benign pulmonary diseases was found to have CD45 +CK -2F7/S5A - cells in peripheral blood. And 39 out of 116 patients with lung cancer were found to have circulating lung cancer cells. The sensitivity, specificity, positive predictive value and negative predictive value of detection was 33.62% , 93.33%, 97.50% and 15.38%, respectively. The average quantitation of circulating cancer cell detected was 0.12*106/L. CONCLUSIONS: There is high specificity and positive predictive value of the examination of circulating cancer cells in patients with lung cancer by FCM, which could detect trace cancer cell in peripheral blood of lung cancer. It may be valuable in diagnosis and treatment of lung cancer. PMID- 21320407 TI - [Value of right ventricular ejection fraction in the preoperative risk evaluation for pulmonary resection]. AB - BACKGROUND: To evaluate the preoperative right ventricular ejection fraction (RVEF) as a predictor of postoperative complications after lung resection. METHODS: RVEF was consecutively assessed in 254 patients before pulmonary resection by echocardiography. According to preoperative right ventricular function, the patients were divided into: group Ia (n=82, RVEF>=45%), group Ib (n=92,RVEF < 45%), group Ic (n=42, RVEF < 40%),and group Id (n=38, RVEF<=35%). Postoperative RVEF was detected again in 122 patients 3 weeks later after lung resection. RESULTS: Preoperative RVEF of patients with postoperative complications was significantly higher than that of patitents without postoperative complications (P < 0.001). Among group Ia, Ib, Ic, and Id, there were significant differences in postoperative morbidities (P < 0.005). Patients with a preoperative RVEF less than 40% had a higher incidence of complications than those with RVEF over 40% (P < 0.005). Of the 122 patients, postoperative RVEF was remarkably lower than preoperative RVEF (P < 0.01). CONCLUSIONS: The preoperative RVEF may be a predictor of postoperative complications for lung resection. RVEF higher than 40% is considered as a safe range for pneumonectomy. PMID- 21320408 TI - [A clinical research on immuno-function of erythrocytes in the patients with pulmonary carcinoma]. AB - BACKGROUND: To study the immuno-function of erythrocytes and the influence of surgical treatment on it in the patients with lung cancer. METHODS: A total of 61 patients with lung cancer were studied, consisting of 35 non-operative patients and 26 post-operative patients. Their immuno-function of erythrocytes was analyzed and compared with 30 normal controls. RESULTS: In the post-operative group, the values of RBC C3BRRT and NTER were significantly higher than those of non-operative group (P < 0.01), but still lower than those of normal control group (P < 0.05); RFER, DTER, ETER and ATER higher than those of non-operative group (P < 0.01), and not significantly different from normal control group (P > 0.05); RBC ICR lower than that of non-operative group (P < 0.01), and not remarkably different from normal control group (P > 0.05); and RFIR lower than that of non-operative group (P < 0.01), however, still higher than that of normal control group (P < 0.01). CONCLUSIONS: The immuno-function of erythrocytes may be related to body tumor load of the patients with lung cancer, and it may gradually recover after the primary tumor is resected. PMID- 21320409 TI - [CT-guided radio-frequency ablation in the treatment of lung cancer]. AB - BACKGROUND: To investigate the clinical results of radio-frequency ablation in the treatment of locally advanced lung cancer. METHODS: Twenty-two patients with locally advanced lung cancer were treated with radio-frequency ablation guided by CT. RESULTS: CT scan after radio-frequency ablation showed that there was cavity in the parenchyma of cancer. Most lung cancer patients felt remittent in chest pain in some extend. Follow-up CT scan in 20 patients revealed retraction of the treated region 3 months later after radio-frequency ablation. Out of the 20 patients, 1 had complete response, 12 had partial response, 4 had minor response, and 3 had stable diseases. CONCLUSIONS: Radio-frequency ablation guided by CT is a promising minimally invasive technique in the treatment of locally advanced lung cancer. PMID- 21320410 TI - Fluoxetine affects GluK2 editing, glutamate-evoked Ca(2+) influx and extracellular signal-regulated kinase phosphorylation in mouse astrocytes. AB - BACKGROUND: We sought to study the effects of chronic exposure to fluoxetine - a selective serotonin reuptake inhibitor (SSRI) and specific 5-HT(2B) receptor agonist in astrocytes - on the expression of kainate receptors (GluK1-5) in cultured astrocytes and in intact brains in mice and on GluK2 editing by adenosine deaminase acting on RNA (ADAR), as well as the ensuing effects of fluoxetine on glutamate-mediated Ca(2+) influx and extracellular signal-regulated kinase (ERK)(1/2) phosphorylation in astrocytes. METHODS: We performed reverse transcription-polymerase chain reaction (PCR) to assess mRNA expression. We analyzed RNA editing with amplification refractory mutation system PCR and complementary DNA sequencing. Protein expression and ERK phosphorylation were assessed using Western blots. We studied gene silencing with specific small interfering RNAs (siRNA), and we studied intracellular Ca(2+) using fluorometry. RESULTS: All GluK subunits were present in the brain in vivo, and GluK2-5 subunits were present in cultured astrocytes. Fluoxetine upregulated GluK2 and ADAR2. Enhanced GluK2 editing by fluoxetine abolished glutamate-mediated increases in intra cellular Ca(2+) and ERK(1/2) phosphorylation. Enhanced editing of GluK2 was prevented by siRNA against the 5-HT(2B) receptor or ADAR2. LIMITATIONS: Limitations of our study include the use of an in vitro system, but our cultured cells in many respects behave like in vivo astrocytes. CONCLUSION: Fluoxetine alters astrocytic glutamatergic function. PMID- 21320411 TI - [Patients with first-episode psychosis should be thoroughly examined]. PMID- 21320412 TI - [Patients with first-episode psychosis should not be scanned routinely]. AB - In this systematic review of the literature, we reviewed the evidence for maintaining the current recommendation that a routine CT scan should be performed in first-episode psychotic patients (Danish National Board of Health). We identified eight papers comprising 625 CT and 214 MRI scans. The share of potentially causal brain abnormalities was 0.8% with CT and 3.3% with MRI, but the findings had limited clinical consequences. We concluded that there is no evidence in support of performing routine CT scans of first-episode psychotic patients. If intracranial pathology is suspected clinically, an MRI scan should be performed. PMID- 21320413 TI - [Diagnosis and treatment of morbus Osler]. AB - Morbus Osler or hereditary haemorrhagic telangiectasia (HHT) is a genetic disorder resulting in development of arteriovenous malformations in the mucosa and in visceral organs. The most common symptom is epistaxis. The disease may, however, cause a variety of other serious manifestations such as pulmonary arteriovenous malformations (PAVM), cerebral arteriovenous malformations (CAVM) and gastrointestinal bleeding. Collaboration between various medical specialties is essential in order to provide an up-to-date treatment and thorough work-up in the individual patient. Disregard of symptoms may result in substantial morbidity and may have serious consequences. This overview presents our current understanding of HHT. PMID- 21320414 TI - [Coccygectomy can be a treatment option in chronic coccygodynia]. AB - Coccygodynia is pain in the region of the coccyx. Treatment is primarily conservative, but some patients have persistent pain and may require surgical treatment. This study was performed to investigate if patients benefit from coccygectomy where conservative treatment has failed. Via a search on MedLine, we found 24 studies including a total of 702 patients who had undergone coccygectomy. Overall, 83% had an excellent or good result. We recommend coccygectomy for selected patients with intractable coccygodynia. PMID- 21320415 TI - [Flank pain in renal and ureteral calculus]. AB - Flank pain is common and often associated with stone colics. Similar pain characteristics can, however, be observed in other diseases. Stone colics have all the characteristics of visceral pain. The pain is diffuse, often referred to the body wall and accompanied by autonomic reflexes. In patients with recurrent stones, the colics may be more intense due to sensitisation of the nervous system. Furthermore, painful diseases in the reproductive organs can enhance stone colics. Non-steroidal anti-inflammatory drugs are the first choice for stone colics because they act by reducing the renal pelvic pressure. PMID- 21320416 TI - [Malignant degeneration in laryngeal papillomatosis]. AB - Recurrent respiratory papillomatosis (RRP) is considered a benign disease although malignant transformation is well-described. The involvement of human papilloma virus (HPV) in malignant transformation is still being discussed. We present a case of rapid malignant transformation of RRP in a 29-year-old male. The tumour as well as biopsies from his previous laryngeal papillomas tested positive for HPV 16. Introduction of a quadrivalent HPV vaccine with a view to preventing cervical cancer may also reduce RRP, and subsequently possibly also the incidence of head-and-neck cancers. PMID- 21320417 TI - [Mutations in the gene encoding filaggrin cause ichthyosis vulgaris]. AB - Ichthyosis vulgaris is a common genetic skin disorder with an estimated prevalence of 1:250 caused by mutations in the gene encoding filaggrin. This disorder manifests itself within the first year of life and is clinically characterized by dry, scaly skin, keratosis pilaris, palmar hyperlinearity and atopic manifestations. Patients with a severe phenotype are homozygous or compound heterozygous for the mutations, whereas heterozygous patients show mild disease, suggesting semidominant inheritance with incomplete penetrance. We present a patient with classic severe ichthyosis vulgaris, atopic eczema and two loss-of-function mutations. PMID- 21320418 TI - [Colonic malacoplakia treated with sulfamethizole and trimethoprim]. AB - We report a case of colonic malacoplakia in a 78-year-old woman, developed following short-term treatment with prednisolone. Clinically, the patient presented with diarrhoea (up to ten times a day) and malaise. Laboratory tests revealed severe anaemia and elevated inflammatory parameters. Colonoscopy showed macroscopic yellowish nodular changes throughout the colon. Biopsies were diagnostic for malacoplakia and exhibited moderate growth of Escherichia faecium and ciprofloxacin-resistant Escherichia coli. The condition resolved during three months of antibiotic treatment with sulfamethizole and trimethoprim. PMID- 21320419 TI - Microsecond single-molecule tracking (MUsSMT). AB - Here we report on a method to track individual molecules on nanometer length and microsecond timescales using an optical microscope. Our method is based on double labeling of a molecule with two spectrally distinct fluorophores and illuminating it with laser pulses of different wavelengths that partially overlap temporally. We demonstrate our method by using it to resolve the motion of short DNA oligomers in solution down to a timescale of 100 MUs. PMID- 21320420 TI - Improved resolution of tertiary structure elasticity in muscle protein. AB - Rearrangement of tertiary structure in response to mechanical force (termed tertiary structure elasticity) in the tandem Ig chain is the first mode of elastic response for muscle protein titin. Tertiary structure elasticity occurs at low stretching forces (few tens of pN), and was described at atomic resolution in a recent molecular dynamics study, in which an originally crescent-shaped six Ig chain was stretched into a linear chain. However, the force-extension profile that resulted from this explicit solvent simulation was dominated by the hydrodynamic drag force, and effects of tertiary structure elasticity only manifested for stretching forces above 20 pN. Here we report a slow pulling 100 ns simulation (along with other auxiliary simulations), in which hydrodynamic drag force is seen to reduce to near 0 pN, such that tertiary structure elasticity could be characterized over a 0-200 pN range. Statistical mechanical analysis showed that the stretching velocity was sufficiently low such that the protein remained significantly relaxed during the major part of its extension. PMID- 21320421 TI - Tropomyosin: the gatekeeper's view of the actin filament revealed. PMID- 21320422 TI - Platelet adhesion from shear blood flow is controlled by near-wall rebounding collisions with erythrocytes. AB - The efficacy of platelet adhesion in shear flow is known to be substantially modulated by the physical presence of red blood cells (RBCs). The mechanisms of this regulation remain obscure due to the complicated character of platelet interactions with RBCs and vascular walls. To investigate this problem, we have created a mathematical model that takes into account shear-induced transport of platelets across the flow, platelet expulsion by the RBCs from the near-wall layer of the flow onto the wall, and reversible capture of platelets by the wall and their firm adhesion to it. This model analysis allowed us to obtain, for the first time to our knowledge, an analytical determination of the platelet adhesion rate constant as a function of the wall shear rate, hematocrit, and average sizes of platelets and RBCs. This formula provided a quantitative description of the results of previous in vitro adhesion experiments in perfusion chambers. The results of the simulations suggest that under a wide range of shear rates and hematocrit values, the rate of platelet adhesion from the blood flow is mainly limited by the frequency of their near-wall rebounding collisions with RBCs. This finding reveals the mechanism by which erythrocytes physically control platelet hemostasis. PMID- 21320423 TI - Metabolic synchronization by traveling waves in yeast cell layers. AB - The coordination of cellular behavior is a prerequisite of functionality of tissues and organs. Generally, this coordination occurs by signal transduction, neuronal control, or exchange of messenger molecules. The extent to which metabolic processes are involved in intercellular communication is less understood. Here, we address this question in layers of resting yeast cells and report for the first time the observation of intercellular glycolytic waves. We use a combined experimental and theoretical approach and explain the radial velocity of the waves to arise from the substrate gradient due to local substrate addition. Our results show that metabolic processes introduce an additional level of local intercellular coordination. PMID- 21320424 TI - A matter of life or death: modeling DNA damage and repair in bacteria. AB - DNA damage is a hazard all cells must face, and evolution has created a number of mechanisms to repair damaged bases in the chromosome. Paradoxically, many of these repair mechanisms can create double-strand breaks in the DNA molecule which are fatal to the cell. This indicates that the connection between DNA repair and death is far from straightforward, and suggests that the repair mechanisms can be a double-edged sword. In this report, we formulate a mathematical model of the dynamics of DNA damage and repair, and we obtain analytical expressions for the death rate. We predict a counterintuitive relationship between survival and repair. We can discriminate between two phases: below a critical threshold in the number of repair enzymes, the half-life decreases with the number of repair enzymes, but becomes independent of the number of repair enzymes above the threshold. We are able to predict quantitatively the dependence of the death rate on the damage rate and other relevant parameters. We verify our analytical results by simulating the stochastic dynamics of DNA damage and repair. Finally, we also perform an experiment with Escherichia coli cells to test one of the predictions of our model. PMID- 21320425 TI - Inositol (1,4,5)-trisphosphate receptor microarchitecture shapes Ca2+ puff kinetics. AB - Inositol (1,4,5)-trisphosphate receptors (IP(3)Rs) release intracellular Ca(2+) as localized Ca(2+) signals (Ca(2+) puffs) that represent the activity of small numbers of clustered IP(3)Rs spaced throughout the endoplasmic reticulum. Although much emphasis has been placed on estimating the number of active Ca(2+) release channels supporting Ca(2+) puffs, less attention has been placed on understanding the role of cluster microarchitecture. This is important as recent data underscores the dynamic nature of IP(3)R transitions between heterogeneous cellular architectures and the differential behavior of IP(3)Rs socialized into clusters. Here, we applied a high-resolution model incorporating stochastically gating IP(3)Rs within a three-dimensional cytoplasmic space to demonstrate: 1), Ca(2+) puffs are supported by a broad range of clustered IP(3)R microarchitectures; 2), cluster ultrastructure shapes Ca(2+) puff characteristics; and 3), loosely corralled IP(3)R clusters (>200 nm interchannel separation) fail to coordinate Ca(2+) puffs, owing to inefficient triggering and impaired coupling due to reduced Ca(2+)-induced Ca(2+) release microwave velocity (<10 nm/s) throughout the channel array. Dynamic microarchitectural considerations may therefore influence Ca(2+) puff occurrence/properties in intact cells, contrasting with a more minimal role for channel number over the same simulated conditions in shaping local Ca(2+) dynamics. PMID- 21320426 TI - Theoretical modeling of aging effects in microtubule dynamics. AB - The microtubule (MT) network, an important part of the cytoskeleton, is constantly remodeled by alternating phases of growth and shrinkage of individual filaments. Plus-end tracking proteins (+TIPs) interact with the MT and in many cases alter its dynamics. Although it is established that some +TIPs modify MT dynamics by increasing rescues, the plus-end tracking mechanism is still under debate. We present a model for MT dynamics in which a rescue factor is dynamically added to the filament during growth. As a consequence, the filament shows aging behavior that should be experimentally accessible and thus allow one to exclude some hypothesized models regarding the inclusion of rescue factors at the MT plus end. This result is not limited to +TIPs and can be extended to any kind of mechanism shifting the parameters of dynamic instability. Additionally, we show that the cell geometry has a strong influence on the quantitative results. PMID- 21320427 TI - Structural dynamics of an actin spring. AB - Actin-based motility in cells is usually associated with either polymerization/depolymerization in the presence of cross-linkers or contractility in the presence of myosin motors. Here, we focus on a third distinct mechanism involving actin in motility, seen in the dynamics of an active actin spring that powers the acrosomal reaction of the horseshoe crab (Limulus polyphemus) sperm. During this process, a 60-MUm bent and twisted bundle of cross-linked actin uncoils and becomes straight in a few seconds in the presence of Ca(2+). This straightening, which occurs at a constant velocity, allows the acrosome to forcefully penetrate the egg. Synthesizing ultrastructural information with the kinetics, energetics, and imaging of calcium binding allows us to construct a dynamical theory for this mechanochemical engine consistent with our experimental observations. It also illuminates the general mechanism by which energy may be stored in conformational changes and released cooperatively in ordered macromolecular assemblies. PMID- 21320428 TI - Signaling network triggers and membrane physical properties control the actin cytoskeleton-driven isotropic phase of cell spreading. AB - Cell spreading is regulated by signaling from the integrin receptors that activate intracellular signaling pathways to control actin filament regulatory proteins. We developed a hybrid model of whole-cell spreading in which we modeled the integrin signaling network as ordinary differential equations in multiple compartments, and cell spreading as a three-dimensional stochastic model. The computed activity of the signaling network, represented as time-dependent activity levels of the actin filament regulatory proteins, is used to drive the filament dynamics. We analyzed the hybrid model to understand the role of signaling during the isotropic phase of fibroblasts spreading on fibronectin coated surfaces. Simulations showed that the isotropic phase of spreading depends on integrin signaling to initiate spreading but not to maintain the spreading dynamics. Simulations predicted that signal flow in the absence of Cdc42 or WASP would reduce the spreading rate but would not affect the shape evolution of the spreading cell. These predictions were verified experimentally. Computational analyses showed that the rate of spreading and the evolution of cell shape are largely controlled by the membrane surface load and membrane bending rigidity, and changing information flow through the integrin signaling network has little effect. Overall, the plasma membrane acts as a damper such that only ~5% of the actin dynamics capability is needed for isotropic spreading. Thus, the biophysical properties of the plasma membrane can condense varying levels of signaling network activities into a single cohesive macroscopic cellular behavior. PMID- 21320429 TI - Basilar membrane velocity in a cochlea with a modified organ of Corti. AB - Many cochlear models assign zero longitudinal coupling in the cochlea. Although this is consistent with the transverse basilar membrane (BM) fibers, the cochlear partition contains cellular longitudinal coupling. In cochlear models, longitudinal coupling diminishes passive BM tuning; however, it has recently been employed in theories of active mechanics to enhance tuning. Our goal in this study was to probe passive longitudinal coupling by comparing BM responses in damaged cochleae with passive responses in normal cochleae. The cochleae of gerbils were damaged with intratympanic neomycin followed by a waiting period to ensure that all of the cells of the partition were missing or severely disrupted. We then measured BM motion and examined the cochleae histologically. In comparison with passive responses in normal cochleae, we observed a downward shift in characteristic frequency, an expected consequence of reduced stiffness from cellular damage. However, we did not observe enhanced passive tuning in the damaged cochleae, as would be expected if longitudinal coupling were substantially greater in the normal cochleae. Thus, we conclude that cell-based longitudinal coupling is not large enough to influence passive cochlear mechanics. This finding constrains theories of active mechanics. PMID- 21320430 TI - Toward prediction of the local onset of alternans in the heart. AB - A beat-to-beat variation in the cardiac action potential duration is a phenomenon known as alternans. Alternans has been linked to ventricular fibrillation, and thus the ability to predict the onset of alternans could be clinically beneficial. Theoretically, it has been proposed that the slope of a restitution curve, which relates the duration of the action potential to the preceding diastolic interval, can predict the onset of alternans. Experimentally, however, this hypothesis has not been consistently proven, mainly because of the intrinsic complexity of the dynamics of cardiac tissue. It was recently shown that the restitution portrait, which combines several restitution curves simultaneously, is associated with the onset of alternans in isolated myocytes. Our main purpose in this study was to determine whether the restitution portrait is correlated with the onset of alternans in the heart, where the dynamics include a spatial complexity. We performed optical mapping experiments in isolated Langendorff perfused rabbit hearts in which alternans was induced by periodic pacing at different frequencies, and identified the local onset of alternans, B(onset). We identified two regions of the heart: the area that exhibited alternans at B(onset) (1:1(alt)) and the area that did not (1:1). We constructed two dimensional restitution portraits for the epicardial surface of the heart and measured the spatial distribution of three different slopes (the dynamic restitution slope, S(dyn)(RP), and two local S1-S2 slopes, S(12) and S(12)(max)) separately for these two regions. We found that the S(12) and S(12)(max) slopes differed significantly between the 1:1(alt) and 1:1 regions just before the onset of alternans, and S(dyn)(RP) slopes were statistically similar. In addition, we found that the slopes of the dynamic restitution curve S(dyn) were also statistically similar between these two regions. On the other hand, the quantitative values of all slopes were significantly different from the theoretically predicted value of one. These results demonstrate that the slopes measured in the restitution portrait correlate with the onset of alternans in the heart. PMID- 21320431 TI - Interaction of diverse voltage sensor homologs with lipid bilayers revealed by self-assembly simulations. AB - Voltage sensors (VS) domains couple the activation of ion channels/enzymes to changes in membrane voltage. We used molecular dynamics simulations to examine interactions with lipids of several VS homologs. VSs in intact channels in the activated state are exposed to phospholipids, leading to a characteristic local distortion of the lipid bilayer which decreases its thickness by ~10 A. This effect is mediated by a conserved hydrophilic stretch in the S4-S5 segment linking the VS and the pore domains, and may favor gating charges crossing the membrane. In cationic lipid bilayers lacking phosphate groups, VSs form fewer contacts with lipid headgroups. The S3-S4 paddle motifs show persistent interactions of individual lipid molecules, influenced by the hairpin loop. In conclusion, our results suggest common interactions with phospholipids for various VS homologs, providing insights into the molecular basis of their stabilization in the membrane and how they are altered by lipid modification. PMID- 21320432 TI - Allosteric features of KCNQ1 gating revealed by alanine scanning mutagenesis. AB - Controlled opening and closing of an ion-selective pathway in response to changes of membrane potential is a fundamental feature of voltage-gated ion channels. In recent decades, various details of this process have been revealed with unprecedented precision based on studies of prototypic potassium channels. Though current scientific efforts are focused more on a thorough description of voltage sensor movement, much less is known about the similarities and differences of the gating mechanisms among potassium channels. Here, we describe the peculiarities of the KCNQ1 gating process in parallel comparison to Shaker. We applied alanine scanning mutagenesis to the S4-S5 linker and pore region and followed the regularities of gating perturbations in KCNQ1. We found a fractional constitutive conductance for wild-type KCNQ1. This component increased significantly in mutants with considerably leftward-shifted steady-state activation curves. In contrast to Shaker, no correlation between V(1/2) and Z parameters was observed for the voltage-dependent fraction of KCNQ1. Our experimental findings are explained by a simple allosteric gating scheme with voltage-driven and voltage independent transitions. Allosteric features are discussed in the context of extreme gating adaptability of KCNQ1 upon interaction with KCNE beta-subunits. PMID- 21320433 TI - Temperature dependence of acetylcholine receptor channels activated by different agonists. AB - The temperature dependence of agonist binding and channel gating were measured for wild-type adult neuromuscular acetylcholine receptors activated by acetylcholine, carbamylcholine, or choline. With acetylcholine, temperature changed the gating rate constants (Q(10) ~ 3.2) but had almost no effect on the equilibrium constant. The enthalpy change associated with gating was agonist dependent, but for all three ligands it was approximately equal to the corresponding free-energy change. The equilibrium dissociation constant of the resting conformation (K(d)), the slope of the rate-equilibrium free-energy relationship (Phi), and the acetylcholine association and dissociation rate constants were approximately temperature-independent. In the mutant alphaG153S, the choline association and dissociation rate constants were temperature dependent (Q(10) ~ 7.4) but K(d) was not. By combining two independent mutations, we were able to compensate for the catalytic effect of temperature on the decay time constant of a synaptic current. At mouse body temperature, the channel opening and -closing rate constants are ~400 and 16 ms(-1). We hypothesize that the agonist dependence of the gating enthalpy change is associated with differences in ligand binding, specifically to the open-channel conformation of the protein. PMID- 21320434 TI - Mapping heat exchange in an allosteric protein. AB - Nicotinic acetylcholine receptors (AChRs) are synaptic ion channels that spontaneously isomerize (i.e., gate) between resting and active conformations. We used single-molecule electrophysiology to measure the temperature dependencies of mouse neuromuscular AChR gating rate and equilibrium constants. From these we estimated free energy, enthalpy, and entropy changes caused by mutations of amino acids located between the transmitter binding sites and the middle of the membrane domain. The range of equilibrium enthalpy change (13.4 kcal/mol) was larger than for free energy change (5.5 kcal/mol at 25 degrees C). For two residues, the slope of the rate-equilibrium free energy relationship (Phi) was approximately constant with temperature. Mutant cycle analysis showed that both free energies and enthalpies are additive for energetically independent mutations. We hypothesize that changes in energy associated with changes in structure mainly occur close to the site of the mutation, and, hence, that it is possible to make a residue-by-residue map of heat exchange in the AChR gating isomerization. The structural correlates of enthalpy changes are discussed for 12 different mutations in the protein. PMID- 21320435 TI - A theory for the proton transport of the influenza virus M2 protein: extensive test against conductance data. AB - A theory for calculating the proton flux through the influenza virus M2 channel is tested here against an extensive set of conductance data. The flux is determined by the rate constants for binding to the His(37) tetrad from the two sides of the membrane and the corresponding unbinding rate constants. The rate constants are calculated by explicitly treating the structure and dynamics of the protein. Important features revealed by previous studies, such as a gating role for Val(27) at the entrance to the channel pore, and channel activation by viral exterior pH, are incorporated in this theory. This study demonstrates that the conductance function of the M2 proton channel can now be quantitatively rationalized by the structure and dynamics of the protein. PMID- 21320436 TI - The beta(1a) subunit of the skeletal DHPR binds to skeletal RyR1 and activates the channel via its 35-residue C-terminal tail. AB - Although it has been suggested that the C-terminal tail of the beta(1a) subunit of the skeletal dihyropyridine receptor (DHPR) may contribute to voltage activated Ca(2+) release in skeletal muscle by interacting with the skeletal ryanodine receptor (RyR1), a direct functional interaction between the two proteins has not been demonstrated previously. Such an interaction is reported here. A peptide with the sequence of the C-terminal 35 residues of beta(1a) bound to RyR1 in affinity chromatography. The full-length beta(1a) subunit and the C terminal peptide increased [(3)H]ryanodine binding and RyR1 channel activity with an AC(50) of 450-600 pM under optimal conditions. The effect of the peptide was dependent on cytoplasmic Ca(2+), ATP, and Mg(2+) concentrations. There was no effect of the peptide when channel activity was very low as a result of Mg(2+) inhibition or addition of 100 nM Ca(2+) (without ATP). Maximum increases were seen with 1-10 MUM Ca(2+), in the absence of Mg(2+) inhibition. A control peptide with the C-terminal 35 residues in a scrambled sequence did not bind to RyR1 or alter [(3)H]ryanodine binding or channel activity. This high-affinity in vitro functional interaction between the C-terminal 35 residues of the DHPR beta(1a) subunit and RyR1 may support an in vivo function of beta(1a) during voltage activated Ca(2+) release. PMID- 21320438 TI - Oscillations in the lateral pressure of lipid monolayers induced by nonlinear chemical dynamics of the second messengers MARCKS and protein kinase C. AB - The binding of the MARCKS peptide to the lipid monolayer containing PIP(2) increases the lateral pressure of the monolayer. The unbinding dynamics modulated by protein kinase C leads to oscillations in lateral pressure of lipid monolayers. These periodic dynamics can be attributed to changes in the crystalline lipid domain size. We have developed a mathematical model to explain these observations based on the changes in the physical structure of the monolayer by the translocation of MARCKS peptide. The model indicates that changes in lipid domain size drives these oscillations. The model is extended to an open system that sustains chemical oscillations. PMID- 21320437 TI - Single ryanodine receptor channel basis of caffeine's action on Ca2+ sparks. AB - Caffeine (1, 3, 7-trimethylxanthine) is a widely used pharmacological agonist of the cardiac ryanodine receptor (RyR2) Ca(2+) release channel. It is also a well known stimulant that can produce adverse side effects, including arrhythmias. Here, the action of caffeine on single RyR2 channels in bilayers and Ca(2+) sparks in permeabilized ventricular cardiomyocytes is defined. Single RyR2 caffeine activation depended on the free Ca(2+) level on both sides of the channel. Cytosolic Ca(2+) enhanced RyR2 caffeine affinity, whereas luminal Ca(2+) essentially scaled maximal caffeine activation. Caffeine activated single RyR2 channels in diastolic quasi-cell-like solutions (cytosolic MgATP, pCa 7) with an EC(50) of 9.0 +/- 0.4 mM. Low-dose caffeine (0.15 mM) increased Ca(2+) spark frequency ~75% and single RyR2 opening frequency ~150%. This implies that not all spontaneous RyR2 openings during diastole are associated with Ca(2+) sparks. Assuming that only the longest openings evoke sparks, our data suggest that a spark may result only when a spontaneous single RyR2 opening lasts >6 ms. PMID- 21320439 TI - 25-Hydroxycholesterol increases the availability of cholesterol in phospholipid membranes. AB - Side-chain oxysterols are enzymatically generated oxidation products of cholesterol that serve a central role in mediating cholesterol homeostasis. Recent work has shown that side-chain oxysterols, such as 25-hydroxycholesterol (25-HC), alter membrane structure in very different ways from cholesterol, suggesting a possible mechanism for how these oxysterols regulate cholesterol homeostasis. Here we extend our previous work by using molecular-dynamics simulations of 25-HC and cholesterol mixtures in 1-palmitoyl-2-oleoyl phosphatidylcholine bilayers to examine the combined effects of 25-HC and cholesterol in the same bilayer. 25-HC causes larger changes in membrane structure when added to cholesterol-containing membranes than when added to cholesterol-free membranes. We also find that the presence of 25-HC changes the position, orientation, and solvent accessibility of cholesterol, shifting it into the water interface and thus increasing its availability to external acceptors. This is consistent with experimental results showing that oxysterols can trigger cholesterol trafficking from the plasma membrane to the endoplasmic reticulum. These effects provide a potential mechanism for 25-HC-mediated regulation of cholesterol trafficking and homeostasis through modulation of cholesterol availability. PMID- 21320440 TI - Single vesicle assaying of SNARE-synaptotagmin-driven fusion reveals fast and slow modes of both docking and fusion and intrasample heterogeneity. AB - Lipid mixing between vesicles functionalized with SNAREs and the cytosolic C2AB domain of synaptotagmin-1 recapitulates the basic Ca(2+) dependence of neuronal exocytosis. However, in the conventional ensemble lipid mixing assays it is not possible to discriminate whether Ca(2+) accelerates the docking or the fusion of vesicles. Here we report a fluorescence microscopy-based assay to monitor SNARE mediated docking and fusion of individual vesicle pairs. In situ measurement of the concentration of diffusing particles allowed us to quantify docking rates by a maximum-likelihood approach. This analysis showed that C2AB and Ca(2+) accelerate vesicle-vesicle docking with more than two orders of magnitude. Comparison of the measured docking rates with ensemble lipid mixing kinetics, however, suggests that in most cases bilayer fusion remains the rate-limiting step. Our single vesicle results show that only ~60% of the vesicles dock and only ~6% of docked vesicles fuse. Lipid mixing on single vesicles was fast (t(mix) < 1 s) while an ensemble assay revealed two slow mixing processes with t(mix) ~ 1 min and t(mix) ~ 20 min. The presence of several distinct docking and fusion pathways cannot be rationalized at this stage but may be related to intrasample heterogeneities, presumably in the form of lipid and/or protein composition. PMID- 21320441 TI - Three distinct modes of exocytosis revealed by amperometry in neuroendocrine cells. AB - Neurotransmission requires Ca(2+)-dependent release of secretory products through fusion pores that open and reclose (partial membrane distention) or open irreversibly (complete membrane distention). It has been challenging to distinguish between these release modes; however, in the work presented here, we were able to deduce different modes of depolarization-evoked exocytosis in neuroendocrine chromaffin and PC12 cells solely by analyzing amperometric recordings. After we determined the quantal size (Q), event half-width (t(50)), event amplitude (I(peak)), and event decay time constant (tau(decay)), we fitted scatter plots of log-transformed data with a mixture of one- and two-dimensional Gaussian distributions. Our analysis revealed three distinct and differently shaped clusters of secretory events, likely corresponding to different modes of exocytosis. Complete membrane distention, through fusion pores of widely varying conductances, accounted for 70% of the total amount of released catecholamine. Two different kinds of partial membrane distention (kiss-and-run and kiss-and stay exocytosis), characterized by mode-specific fusion pores with unitary conductances, accounted for 20% and 10%, respectively. These results show that our novel one- and two-dimensional analysis of amperometric data reveals new release properties and enables one to distinguish at least three different modes of exocytosis solely by analyzing amperometric recordings. PMID- 21320442 TI - Lipid lateral organization on giant unilamellar vesicles containing lipopolysaccharides. AB - We developed a new (to our knowledge) protocol to generate giant unilamellar vesicles (GUVs) composed of mixtures of single lipopolysaccharide (LPS) species and Escherichia coli polar lipid extracts. Four different LPSs that differed in the size of the polar headgroup (i.e., LPS smooth > LPS-Ra > LPS-Rc > LPS-Rd) were selected to generate GUVs composed of different LPS/E. coli polar lipid mixtures. Our procedure consists of two main steps: 1), generation and purification of oligolamellar liposomes containing LPSs; and 2), electroformation of GUVs using the LPS-containing oligolamellar vesicles at physiological salt and pH conditions. Analysis of LPS incorporation into the membrane models (both oligolamellar vesicles and GUVs) shows that the final concentration of LPS is lower than that expected from the initial E. coli lipids/LPS mixture. In particular, our protocol allows incorporation of no more than 15 mol % for LPS smooth and LPS-Ra, and up to 25 mol % for LPS-Rc and LPS-Rd (with respect to total lipids). We used the GUVs to evaluate the impact of different LPS species on the lateral structure of the host membrane (i.e., E. coli polar lipid extract). Rhodamine-DPPE-labeled GUVs show the presence of elongated micrometer sized lipid domains for GUVs containing either LPS-Rc or LPS-Rd above 10 mol %. Laurdan GP images confirm this finding and show that this particular lateral scenario corresponds to the coexistence of fluid disordered and gel (LPS enriched)-like micron-sized domains, in similarity to what is observed when LPS is replaced with lipid A. For LPSs containing the more bulky polar headgroup (i.e., LPS-smooth and LPS-Ra), an absence of micrometer-sized domains is observed for all LPS concentrations explored in the GUVs (up to ~15 mol %). However, fluorescence correlation spectroscopy (using fluorescently labeled LPS) and Laurdan GP experiments in these microscopically homogeneous membranes suggests the presence of LPS clusters with dimensions below our microscope's resolution (~380 nm radial). Our results indicate that LPSs can cluster into gel-like domains in these bacterial model membranes, and that the size of these domains depends on the chemical structure and concentration of the LPSs. PMID- 21320443 TI - Adhesion and merging of lipid bilayers: a method for measuring the free energy of adhesion and hemifusion. AB - Lipid bilayers can be induced to adhere to each other by molecular mediators, and, depending on the lipid composition, such adhesion can lead to merging of the contacting monolayers in a process known as hemifusion. Such bilayer-bilayer reactions have never been systematically studied. In the course of our studies of membrane-active molecules, we encountered such reactions. We believe that they need to be understood whenever bilayer-bilayer interactions take place, such as during membrane fusion. For illustration, we discuss three examples: spontaneous adhesion between phospholipid bilayers induced by low pH, polymer-induced osmotic depletion attraction between lipid bilayers, and anionic lipid bilayers cross bridged by multicationic peptides. Our purpose here is to describe a general method for studying such interactions. We used giant unilamellar vesicles, each of which was aspirated in a micropipette so that we could monitor the tension of the membrane and the membrane area changes during the bilayer-bilayer interaction. We devised a general method for measuring the free energy of adhesion or hemifusion. The results show that the energies of adhesion or hemifusion of lipid bilayers could vary over 2 orders of magnitude from -1 to -50 * 10(-5) J/m(2) in these examples alone. Our method can be used to measure the energy of transition in each step of lipid transformation during membrane fusion. This is relevant for current research on membrane fusion, which focuses on how fusion proteins induce lipid transformations. PMID- 21320444 TI - Interleaflet coupling and domain registry in phase-separated lipid bilayers. AB - There is clear evidence of an interleaflet coupling in model lipid/cholesterol membranes exhibiting liquid-liquid phase separation. The strength of this coupling is quantified by the mismatch free energy, gamma. We calculate it using a molecular mean-field model of a phase-separated lipid/cholesterol bilayer and obtain values that increase as the concentration of saturated lipids in the coexisting phases is increased. These values lie in the range 0.01-0.03 k(B)T/nm(2). We clarify the relationship between the interleaflet coupling and the extent of interleaflet alignment of liquid domains by analyzing a statistical mechanical model of coupled fluctuating domain interfaces. The model is solved exactly using the correspondence between statistical mechanics and quantum mechanics, yielding an expression for the characteristic size of fluctuations out of domain registry. This length scale depends only weakly on the strength of the interleaflet coupling and inevitably is only of the order of nanometers, which explains the experimental result that fluctuations out of domain registry have not been observed by optical microscopy. PMID- 21320445 TI - Tropomyosin position on F-actin revealed by EM reconstruction and computational chemistry. AB - Electron microscopy and fiber diffraction studies of reconstituted F-actin tropomyosin filaments reveal the azimuthal position of end-to-end linked tropomyosin molecules on the surface of actin. However, the longitudinal z position of tropomyosin along F-actin is still uncertain. Without this information, atomic models of F-actin-tropomyosin filaments, free of constraints imposed by troponin or other actin-binding proteins, cannot be formulated, and thus optimal interfacial contacts between actin and tropomyosin remain unknown. Here, a computational search assessing electrostatic interactions for multiple azimuthal locations, z-positions, and pseudo-rotations of tropomyosin on F-actin was performed. The information gleaned was used to localize tropomyosin on F actin, yielding an atomic model characterized by protein-protein contacts that primarily involve clusters of basic amino acids on actin subdomains 1 and 3 juxtaposed against acidic residues on the successive quasi-repeating units of tropomyosin. A virtually identical model generated by docking F-actin and tropomyosin atomic structures into electron microscopy reconstructions of F-actin tropomyosin validated the above solution. Here, the z-position of tropomyosin alongside F-actin was defined by matching the seven broad and narrow motifs that typify tropomyosin's twisting superhelical coiled-coil to the wide and tapering tropomyosin densities seen in surface views of F-actin-tropomyosin reconstructions. The functional implications of the F-actin-tropomyosin models determined in this work are discussed. PMID- 21320446 TI - Enhanced active cross-bridges during diastole: molecular pathogenesis of tropomyosin's HCM mutations. AB - Three HCM-causing tropomyosin (Tm) mutants (V95A, D175N, and E180G) were examined using the thin-filament extraction and reconstitution technique. The effects of Ca(2+), ATP, phosphate, and ADP concentrations on cross-bridge kinetics in myocardium reconstituted with each of these mutants were studied at 25 degrees C, and compared to wild-type (WT) Tm at physiological ionic strength (200 mM). All three mutants showed significantly higher (2-3.5 fold) low Ca(2+) tension (T(LC)) and stiffness than WT at pCa 8.0. High Ca(2+) tension (T(HC)) was significantly higher for E180G than that for WT, whereas T(HC) of V95A and D175N was similar to WT; high Ca(2+) stiffness (Y(HC)) had the same trend. The Ca(2+) sensitivity of isometric force was significantly greater for V95A and E180G than for WT, whereas that of D175N remained the same as for WT; for all mutants, cooperativity was lower than for WT. Nine kinetic constants and the cross-bridge distribution were deduced using sinusoidal analysis. The number of force-generating cross bridges was similar among the D175N, E180G, and WT Tm forms, but it was significantly larger in the case of V95A than WT. We conclude that the increased number of actively cycling cross bridges at pCa 8 is the major cause of Tm mutation-related HCM pathogenesis, which may result in diastolic dysfunction. Decreased contractility (T(act)) in V95A and D175N may further contribute to the severity of myocyte hypertrophy and related prognosis of the disease. PMID- 21320447 TI - Evidence for pre- and post-power stroke of cross-bridges of contracting skeletal myofibrils. AB - We examined the orientational fluctuations of a small number of myosin molecules (approximately three) in working skeletal muscle myofibrils. Myosin light chain 1 (LC1) was labeled with a fluorescent dye and exchanged with the native LC1 of skeletal muscle myofibrils cross-linked with 1-ethyl-3-[3(dimethylamino) propyl] carbodiimide to prevent shortening. We observed a small volume within the A-band (~10(-15) L) by confocal microscopy, and measured cyclic fluctuations in the orientation of the myosin neck (containing LC1) by recording the parallel and perpendicular components of fluorescent light emitted by the fluorescently labeled myosin LC1. Histograms of orientational fluctuations from fluorescent molecules in rigor were represented by a single Gaussian distribution. In contrast, histograms from contracting muscles were best fit by at least two Gaussians. These results provide direct evidence that cross-bridges in working skeletal muscle assume two distinct conformations, presumably corresponding to the pre- and post-power-stroke states. PMID- 21320448 TI - Downstream DNA tension regulates the stability of the T7 RNA polymerase initiation complex. AB - Gene transcription by the enzyme RNA polymerase is tightly regulated. In many cases, such as in the lac operon in Escherichia coli, this regulation is achieved through the action of protein factors on DNA. Because DNA is an elastic polymer, its response to enzymatic processing can lead to mechanical perturbations (e.g., linear stretching and supercoiling) that can affect the operation of other DNA processing complexes acting elsewhere on the same substrate molecule. Using an optical-tweezers assay, we measured the binding kinetics between single molecules of bacteriophage T7 RNA polymerase and DNA, as a function of tension. We found that increasing DNA tension under conditions that favor formation of the open complex results in destabilization of the preinitiation complex. Furthermore, with zero ribonucleotides present, when the closed complex is favored, we find reduced tension sensitivity, implying that it is predominantly the open complex that is sensitive. This result strongly supports the "scrunching" model for T7 transcription initiation, as the applied tension acts against the movement of the DNA into the scrunched state, and introduces linear DNA tension as a potential regulatory quantity for transcription initiation. PMID- 21320449 TI - Ni2+-enhanced charge transport via pi-pi stacking corridor in metallic DNA. AB - The mechanism underlying DNA charge transport is intriguing. However, poor conductivity of DNA makes it difficult to detect DNA charge transport. Metallic DNA (M-DNA) has better conducting properties than native DNA. Ni(2+) may chelate in DNA and thus enhance DNA conductivity. On the basis of this finding, it is possible to reveal the mechanisms underlying DNA charge transport. The conductivity of various Ni-DNA species such as single-stranded, full complement, or mismatched sequence molecules was systematically tested with ultraviolet absorption and electrical or chemical methods. The results showed that the conductivity of single-stranded Ni-DNA (Ni-ssDNA) was similar to that of a native DNA duplex. Moreover, the resistance of Ni-DNA with a single basepair mismatch was significantly higher than that of fully complementary Ni-DNA duplexes. The resistance also increased exponentially as the number of mismatched basepairs increased linearly after the tunneling current behavior predicted by the Simmons model. In conclusion, the charges in Ni(2+)-doped DNA are transported through the Ni(2+)-mediated pi-pi stacking corridor. Furthermore, Ni-DNA acts as a conducting wire and exhibits a tunneling barrier when basepair mismatches occur. This property may be useful in detecting single basepair mismatches. PMID- 21320450 TI - Cy3-DNA stacking interactions strongly depend on the identity of the terminal basepair. AB - We characterized the effect of the first basepair on the conformational dynamics of the fluorescent dye Cy3 attached to the 5' end of double-stranded DNA using gaussian-mixture adaptive umbrella sampling simulations. In the simulations, the sampling of all five dihedral angles along the linker was enhanced, so that both stacked and unstacked states were sampled. The affinity of Cy3 for a T.A basepair (with the dye attached to T) was found to be significantly less than for the other basepairs. This was verified experimentally by measuring the activation energies for cis-trans isomerization of the dye. The simulation and experimental results indicate the existence of partially unstacked conformations amenable to photoisomerization. The simulations also showed that stacking of Cy3 straightens the DNA while stabilizing the first basepair. Our findings indicate that fluorescence is modulated by Cy3-DNA interactions in a sequence-dependent manner. PMID- 21320451 TI - Evidence of protein collective motions on the picosecond timescale. AB - We investigate the presence of structural collective motions on a picosecond timescale for the heme protein, cytochrome c, as a function of oxidation and hydration, using terahertz (THz) time domain spectroscopy and molecular dynamics simulations. The THz response dramatically increases with oxidation, with the largest increase for lowest hydrations, and highest frequencies. For both oxidation states the THz response rapidly increases with hydration saturating above ~25% (g H(2)O/g protein). Quasiharmonic vibrational modes and dipole-dipole correlation functions were calculated from molecular dynamics trajectories. The collective mode density of states alone reproduces the measured hydration dependence, providing strong evidence of the existence of these motions. The large oxidation dependence is reproduced only by the dipole-dipole correlation function, indicating the contrast arises from diffusive motions consistent with structural changes occurring in the vicinity of buried internal water molecules. This source for the observed oxidation dependence is consistent with the lack of an oxidation dependence in nuclear resonant vibrational spectroscopy measurements. PMID- 21320452 TI - Enantiospecificity of chloroperoxidase-catalyzed epoxidation: biased molecular dynamics study of a cis-beta-methylstyrene/chloroperoxidase-compound I complex. AB - Molecular dynamics simulations of an explicitly solvated cis-beta methylstyrene/chloroperoxidase-Compound I complex are performed to determine the cause of the high enantiospecificity of epoxidation. From the simulations, a two dimensional free energy potential is calculated to distinguish binding potential wells from which reaction to 1S2R and 1R2S epoxide products may occur. Convergence of the free energy potential is accelerated with an adaptive biasing potential. Analysis of binding is followed by analysis of 1S2R and 1R2S reaction precursor structures in which the substrate, having left the binding wells, places its reactive double bond in steric proximity to the oxyferryl heme center. Structural analysis of binding and reaction precursor conformations is presented. We find that 1), a distortion of Glu(183) is important for CPO-catalyzed epoxidation as was postulated previously based on experimental results; 2), the free energy of binding does not provide significant differentiation between structures leading to the respective epoxide enantiomers; and 3), CPO's enantiospecificity toward cis-beta-methylstyrene is likely to be caused by a specific group of residues which form a hydrophobic core surrounding the oxyferryl heme center. PMID- 21320453 TI - Alzheimer's disease drug candidates stabilize A-beta protein native structure by interacting with the hydrophobic core. AB - Deposition of amyloid fibrils, consisting primarily of Abeta(40) and Abeta(42) peptides, in the extracellular space in the brain is a major characteristic of Alzheimer's disease (AD). We recently developed new (to our knowledge) drug candidates for AD that inhibit the fibril formation of Abeta peptides and eliminate their neurotoxicity. We performed all-atom molecular-dynamics simulations on the Abeta(42) monomer at its alpha-helical conformation and a pentamer fibril fragment of Abeta(42) peptide with or without LRL and fluorene series compounds to investigate the mechanism of inhibition. The results show that the active drug candidates, LRL22 (EC(50) = 0.734 MUM) and K162 (EC(50) = 0.080 MUM), stabilize hydrophobic core I of Abeta(42) peptide (residues 17-21) to its alpha-helical conformation by interacting specifically in this region. The nonactive drug candidates, LRL27 (EC(50) > 10 MUM) and K182 (EC(50) > 5 MUM), have little to no similar effect. This explains the different behavior of the drug candidates in experiments. Of more importance, this phenomenon indicates that hydrophobic core I of the Abeta(42) peptide plays a major mechanistic role in the formation of amyloid fibrils, and paves the way for the development of new drugs against AD. PMID- 21320454 TI - A statistical analysis of the PPII propensity of amino acid guests in proline rich peptides. AB - There has been considerable debate about the intrinsic PPII propensity of amino acid residues in denatured polypeptides. Experimentally, the propensity scale is based on the behavior of guest amino-acid residues placed in the middle of polyproline hosts. We have used classical molecular dynamics simulations, with state-of-the-art force fields to carry out a comprehensive analysis of the conformational equilibria of the proline-based host oligopeptides with single guests. The tracked structural characteristics include the PPII content, the cis/trans isomerization of the prolyl bonds, the puckering of the pyrrolidine rings of the proline residues, and the secondary structural motifs. We find no evidence for an intrinsic PPII propensity in any of the guest amino acids other than proline. Instead, the PPII content as derived from experiments may be explained in terms of: 1), a local correlation between the dihedral angles of the guest amino acid and the proline residue immediately preceding it; and 2), a nonlocal correlation between the cis/trans states of the peptide bonds. In terms of the latter, we find that the presence of a guest (other than proline, tyrosine, or tryptophan) increases the trans content of most of the prolyl bonds, which results in an effective increase of the peptide PPII content. With respect to the local dihedral correlations, we find that these are well described in terms of the so-called odds-ratio statistic. Expressed in terms of free energy language, the PPII content based on the odds-ratio of the relevant residues correlate well with the experimentally measured PPII content. PMID- 21320455 TI - Inhibitor binding increases the mechanical stability of staphylococcal nuclease. AB - Staphylococcal nuclease (SNase) catalyzes the hydrolysis of DNA and RNA in a calcium-dependent fashion. We used AFM-based single-molecule force spectroscopy to investigate the mechanical stability of SNase alone and in its complex with an SNase inhibitor, deoxythymidine 3',5'-bisphosphate. We found that the enzyme unfolds in an all-or-none fashion at ~26 pN. Upon binding to the inhibitor, the mechanical unfolding forces of the enzyme-inhibitor complex increase to ~50 pN. This inhibitor-induced increase in the mechanical stability of the enzyme is consistent with the increased thermodynamical stability of the complex over that of SNase. Because of its strong mechanical response to inhibitor binding, SNase, a model protein folding system, offers a unique opportunity for studying the relationship between enzyme mechanics and catalysis. PMID- 21320456 TI - Built-in mechanical stress in viral shells. AB - Mechanical properties of biological molecular aggregates are essential to their function. A remarkable example are double-stranded DNA viruses such as the phi29 bacteriophage, that not only has to withstand pressures of tens of atmospheres exerted by the confined DNA, but also uses this stored elastic energy during DNA translocation into the host. Here we show that empty prolated phi29 bacteriophage proheads exhibit an intriguing anisotropic stiffness which behaves counterintuitively different from standard continuum elasticity predictions. By using atomic force microscopy, we find that the phi29 shells are approximately two-times stiffer along the short than along the long axis. This result can be attributed to the existence of a residual stress, a hypothesis that we confirm by coarse-grained simulations. This built-in stress of the virus prohead could be a strategy to provide extra mechanical strength to withstand the DNA compaction during and after packing and a variety of extracellular conditions, such as osmotic shocks or dehydration. PMID- 21320457 TI - Velocity-dependent mechanical unfolding of bacteriorhodopsin is governed by a dynamic interaction network. AB - Bacteriorhodopsin is a model system for membrane proteins. This seven transmembrane helical protein is embedded within a membrane structure called purple membrane. Its structural stability against mechanical stress was recently investigated by atomic force microscopy experiments, in which single proteins were extracted from the purple membrane. Here, we study this process by all-atom molecular dynamics simulations, in which single bacteriorhodopsin molecules were extracted and unfolded from an atomistic purple membrane model. In our simulations, key features from the experiments like force profiles and location of key residues that resist mechanical unfolding were reproduced. These key residues were seen to be stabilized by a dynamic network of intramolecular interactions. Further, the unfolding pathway was found to be velocity-dependent. Simulations in which the mechanical stress was released during unfolding revealed relaxation motions that allowed characterization of the nonequilibrium processes during fast extraction. PMID- 21320458 TI - Effects of macromolecular crowding on an intrinsically disordered protein characterized by small-angle neutron scattering with contrast matching. AB - Small-angle neutron scattering was used to examine the effects of molecular crowding on an intrinsically disordered protein, the N protein of bacteriophage lambda, in the presence of high concentrations of a small globular protein, bovine pancreatic trypsin inhibitor (BPTI). The N protein was labeled with deuterium, and the D(2)O concentration of the solvent was adjusted to eliminate the scattering contrast between the solvent and unlabeled BPTI, leaving only the scattering signal from the unfolded protein. The scattering profile observed in the absence of BPTI closely matched that predicted for an ensemble of random conformations. With BPTI added to a concentration of 65 mg/mL, there was a clear change in the scattering profile representing an increase in the mass fractal dimension of the unfolded protein, from 1.7 to 1.9, as expected if crowding favors more compact conformations. The crowding protein also inhibited aggregation of the unfolded protein. At 130 mg/mL BPTI, however, the fractal dimension was not significantly different from that measured at the lower concentration, contrary to the predictions of models that treat the unfolded conformations as convex particles. These results are reminiscent of the behavior of polymers in concentrated melts, suggesting that these synthetic mixtures may provide useful insights into the properties of unfolded proteins under crowding conditions. PMID- 21320459 TI - Nonadditivity in conformational entropy upon molecular rigidification reveals a universal mechanism affecting folding cooperativity. AB - Previously, we employed a Maxwell counting distance constraint model (McDCM) to describe alpha-helix formation in polypeptides. Unlike classical helix-coil transition theories, the folding mechanism derives from nonadditivity in conformational entropy caused by rigidification of molecular structure as intramolecular cross-linking interactions form along the backbone. For example, when a hydrogen bond forms within a flexible region, both energy and conformational entropy decrease. However, no conformational entropy is lost when the region is already rigid because atomic motions are not constrained further. Unlike classical zipper models, the same mechanism also describes a coil-to-beta hairpin transition. Special topological features of the helix and hairpin structures allow the McDCM to be solved exactly. Taking full advantage of the fact that Maxwell constraint counting is a mean field approximation applied to the distribution of cross-linking interactions, we present an exact transfer matrix method that does not require any special topological feature. Upon application of the model to proteins, cooperativity within the folding transition is yet again appropriately described. Notwithstanding other contributing factors such as the hydrophobic effect, this simple model identifies a universal mechanism for cooperativity within polypeptide and protein-folding transitions, and it elucidates scaling laws describing hydrogen-bond patterns observed in secondary structure. In particular, the native state should have roughly twice as many constraints as there are degrees of freedom in the coil state to ensure high fidelity in two-state folding cooperativity, which is empirically observed. PMID- 21320460 TI - Rotational diffusion of the alpha(2a) adrenergic receptor revealed by FlAsH labeling in living cells. AB - The fluorescein arsenical hairpin binder (FlAsH) shows much promise to determine the relative orientations of protein regions and structures even in living cells and in the plasma membrane. In this study, we characterized FlAsH's photophysical properties by steady-state anisotropy and time-resolved single photon counting for further applications with G-protein coupled receptors. We find that FlAsH has a relatively high initial anisotropy of 0.31 +/- 0.01 and a three-component fluorescence lifetime with an average of 4.1 +/- 0.1 ns. We characterized the FlAsH fluorophore orientation in the alpha(2A) adrenergic receptor revealing rigid orientations of FlAsH in the membrane plane for rotational correlation times of ~50 ns in living cells. To elucidate the fluorophore-membrane orientation and rotational correlation time, an anisotropy treatment similar to that of another researcher (Axelrod, D. 1979. Biophys. J. 26:557-573) was developed. The rotational correlation times were observed to increase by up to 16 ns after agonist addition. The rotational correlation time also allowed for a comparison to the theoretical relationship between translational and rotational diffusion (originally proposed by Saffman, P. G., and M. Delbruck. 1975. Proc. Natl. Acad. Sci. USA. 72:3111-3113) and revealed a discrepancy of a factor between 10 and 100. PMID- 21320461 TI - A dual layer hair array of the brown lacewing: repelling water at different length scales. AB - Additional weight due to contamination (water and/or contaminating particles) can potentially have a detrimental effect on the flight capabilities of large winged insects such as butterflies and dragonflies. Insects where the wing surface area body mass ratio is very high will be even more susceptible to these effects. Water droplets tend to move spontaneously off the wing surface of these insects. In the case of the brown lacewing, the drops effectively encounter a dual bed of hair springs with a topographical structure which aids in the hairs resisting penetration into water bodies. In this article, we demonstrate experimentally how this protective defense system employed by the brown lacewing (Micromus tasmaniae) aids in resisting contamination from water and how the micro- and nanostructures found on these hairs are responsible for quickly shedding water from the wing which demonstrates an active liquid-repelling surface. PMID- 21320462 TI - Optimization of the enzyme-linked lectin assay for enhanced glycoprotein and glycoconjugate analysis. AB - Lectins are proteins capable of recognizing and binding to specific oligosaccharide structures found on glycoproteins and other biomolecules. As such, they have utility for glycoanalytical applications. One common difficulty encountered in the application of these proteins, particularly in multiwell plate assay formats known as enzyme-linked lectin assays (ELLAs), is finding appropriate blocking solutions to prevent nonspecific binding with plate surfaces. Many commonly used blocking agents contain carbohydrates and generate significant background signals in ELLAs, limiting the utility of the assays. In this study, we examined the suitability of a range of blocking reagents, including protein-based, synthetic, and commercially available carbohydrate-free blocking reagents, for ELLA applications. Each blocking reagent was assessed against a panel of 19 commercially available biotinylated lectins exhibiting diverse structures and carbohydrate specificities. We identified the synthetic polymer polyvinyl alcohol (PVA) as the best global blocking agent for performing ELLAs. We ultimately present an ELLA methodology facilitating broad spectrum lectin analysis of glycoconjugates and extending the utility of ELLAs. PMID- 21320463 TI - Small-scale, high-throughput method for plant N-glycan preparation for matrix assisted laser desorption/ionization time-of-flight mass spectrometry analysis. AB - A simple, small-scale, and high-throughput method for preparation of plant N glycans for matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is described. This method entailed the extraction of soluble proteins, pepsin digestion, release of N-glycans by glycopeptidase A, and a three-step chromatographic purification process using cation exchange, anion exchange, and graphitized carbon. Homemade minicolumns using commercially available filter unit devices were used for N-glycan purification steps. All purification steps were designed to be easy. Using this method, N-glycans from 10 mg leaf samples of different plant species and only 2 MUg of pure horseradish peroxidase were successfully purified. PMID- 21320464 TI - Redox Bohr effects and the role of heme a in the proton pump of bovine heart cytochrome c oxidase. AB - Structural and functional observations are reviewed which provide evidence for a central role of redox Bohr effect linked to the low-spin heme a in the proton pump of bovine heart cytochrome c oxidase. Data on the membrane sidedness of Bohr protons linked to anaerobic oxido-reduction of the individual metal centers in the liposome reconstituted oxidase are analysed. Redox Bohr protons coupled to anaerobic oxido-reduction of heme a (and Cu(A)) and Cu(B) exhibit membrane vectoriality, i.e. protons are taken up from the inner space upon reduction of these centers and released in the outer space upon their oxidation. Redox Bohr protons coupled to anaerobic oxido-reduction of heme a(3) do not, on the contrary, exhibit vectorial nature: protons are exchanged only with the outer space. A model of the proton pump of the oxidase, in which redox Bohr protons linked to the low-spin heme a play a central role, is described. This article is part of a Special Issue entitled: Allosteric cooperativity in respiratory proteins. PMID- 21320465 TI - Cardiac mitochondria in heart failure: normal cardiolipin profile and increased threonine phosphorylation of complex IV. AB - Mitochondrial dysfunction is a major contributor in heart failure (HF). We investigated whether the decrease in respirasome organization reported by us previously in cardiac mitochondria in HF is due to changes in the phospholipids of the mitochondrial inner membrane or modifications of the subunits of the electron transport chain (ETC) complexes. The contents of the main phospholipid species, including cardiolipin, as well as the molecular species of cardiolipin were unchanged in cardiac mitochondria in HF. Oxidized cardiolipin molecular species were not observed. In heart mitochondria isolated from HF, complex IV not incorporated into respirasomes exhibits increased threonine phosphorylation. Since HF is associated with increased adrenergic drive to cardiomyocytes, this increased protein phosphorylation might be explained by the involvement of cAMP activated protein kinase. Does the preservation of cAMP-induced phosphorylation changes of mitochondrial proteins or the addition of exogenous cAMP have similar effects on oxidative phosphorylation? The usage of phosphatase inhibitors revealed a specific decrease in complex I-supported respiration with glutamate. In saponin-permeabilized cardiac fibers, pre-incubation with cAMP decreases oxidative phosphorylation due to a defect localized at complex IV of the ETC inter alia. We propose that phosphorylation of specific complex IV subunits decreases oxidative phosphorylation either by limiting the incorporation of complex IV in supercomplexes or by decreasing supercomplex stability. PMID- 21320466 TI - hERG channel blockade by externally applied quaternary ammonium derivatives. AB - The human ether-a-go-go related gene potassium channel is a key player in cardiac rhythm regulation, thus being an important subject for a cardiac toxicity test. Ever since human ether-a-go-go related gene channel inhibition-related cardiac arrest was proven to be fatal, numerous numbers of data on human ether-a-go-go related gene channel inhibition have been piled up. However, there has been no quantitative study on human ether-a-go-go related gene channel inhibition by quaternary ammonium derivatives, well-known potassium channel blockers. Here, we present human ether-a-go-go related gene channel blockade by externally applied quaternary ammonium derivatives using automated whole-cell patch-clamp recordings as well as ab initio quantum calculations. The inhibitory constants and the relative binding energies for human ether-a-go-go related gene channel inhibition were obtained from quaternary ammoniums with systematically varied head and tail groups, indicating that more hydrophobic quaternary ammoniums have higher affinity blockade while cation-pi interactions or size effects are not a deterministic factor for human ether-a-go-go related gene channel inhibition by quaternary ammoniums. Further studies on the effect of quaternary ammoniums on human ether-a-go-go related gene channel inactivation implied that hydrophobic quaternary ammoniums either with a longer tail group or with a bigger head group than tetraethylammonium permeate the cell membrane to easily access the high affinity internal binding site in human ether-a-go-go related gene channel and exert stronger blockade. These results may be informative for the rational drug design to avoid cardiac toxicity. PMID- 21320467 TI - Effects of phenylpropanolamine (PPA) on in vitro human erythrocyte membranes and molecular models. AB - Norephedrine, also called phenylpropanolamine (PPA), is a synthetic form of the ephedrine alkaloid. After reports of the occurrence of intracranial hemorrhage and other adverse effects, including several deaths, PPA is no longer sold in USA and Canada. Despite the extensive information about PPA toxicity, reports on its effects on cell membranes are scarce. With the aim to better understand the molecular mechanisms of the interaction of PPA with cell membranes, ranges of concentrations were incubated with intact human erythrocytes, isolated unsealed human erythrocyte membranes (IUM), and molecular models of cell membranes. The latter consisted in bilayers built-up of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE), phospholipid classes present in the outer and inner monolayers of most plasmatic cell membranes, respectively. The capacity of PPA to perturb the bilayer structures of DMPC and DMPE was assessed by X-ray diffraction, DMPC large unilamellar vesicles (LUV) and IUM were studied by fluorescence spectroscopy, and intact human erythrocytes were observed by scanning electron microscopy (SEM). This study presents evidence that PPA affects human red cell membranes as follows: (a) in SEM studies on human erythrocytes it was observed that 0.5 mM PPA induced shape changes; (b) in IUM PPA induced a sharp decrease in the fluorescence anisotropy in the lipid bilayer acyl chains in a concentration range lower than 100 MUM; (c) X-ray diffraction studies showed that PPA in the 0.1-0.5 mM range induced increasing structural perturbation to DMPC, but no effects on DMPE multibilayers were detected. PMID- 21320468 TI - Induction of ER stress protects gastric cancer cells against apoptosis induced by cisplatin and doxorubicin through activation of p38 MAPK. AB - We investigated the role of endoplasmic reticulum (ER) stress response and p38 MAPK pathways in the resistance of gastric cancer cells to chemotherapy. Pretreatment of the gastric cancer cells with the ER stress inducer drastically decreased the apoptotic rate induced by cisplatin or doxorubicin. Induction of ER stress also led to the activation of p38. Inhibition of p38 activity abrogated the effects of ER stress-induced resistance to apoptosis induced by cisplatin- and doxorubicin treatment. Thus, ER-stress response in gastric cancer cells causes resistance to cisplatin- and doxorubicin-induced apoptosis, and ER-stress induced chemo-resistance can be overcome by blocking p38 activity. PMID- 21320469 TI - The essential role of FKBP38 in regulating phosphatase of regenerating liver 3 (PRL-3) protein stability. AB - The phosphatase of regenerating liver-3 (PRL-3) is a member of protein tyrosine phosphatases and whose deregulation is implicated in tumorigenesis and metastasis of many cancers. However, the underlying mechanism by which PRL-3 is regulated is not known. In this study, we identified the peptidyl prolyl cis/trans isomerase FK506-binding protein 38 (FKBP38) as an interacting protein of PRL-3 using a yeast two-hybrid system. FKBP38 specifically binds to PRL-3 in vivo, and that the N-terminal region of FKBP38 is crucial for binding with PRL-3. FKBP38 overexpression reduces endogenous PRL-3 expression levels, whereas the depletion of FKBP38 by siRNA increases the level of PRL-3 protein. Moreover, FKBP38 promotes degradation of endogenous PRL-3 protein via protein-proteasome pathway. Furthermore, FKBP38 suppresses PRL-3-mediated p53 activity and cell proliferation. These results demonstrate that FKBP38 is a novel regulator of the oncogenic protein PRL-3 abundance and that alteration in the stability of PRL-3 can have a dramatic impact on cell proliferation. Thus, FKBP38 may play a critical role in tumorigenesis. PMID- 21320470 TI - Effects of divalent cations on bovine testicular hyaluronidase catalyzed transglycosylation of chondroitin sulfates. AB - Glycosaminoglycans were prepared as salts of different divalent cations and tested as donors in bovine testicular hyaluronidase catalyzed transglycosylation reactions. All of the metal cations examined had similar binding efficiency of divalent cations to hyaluronan. However, cations bound with different efficiencies to chondroitin sulfate species and the differences were marked in the case of chondroitin 6-sulfate; the numbers of cations bound per disaccharide unit were estimated to be 0.075 for Mn, 1.231 for Ba, 0.144 for Zn, and 0.395 for Cu. While barium salt of chondroitin sulfates enhanced transglycosylation, the zinc salt of chondroitin sulfates inhibited transglycosylation. Therefore, by selecting the proper divalent cation salt of chondroitin sulfates as a donor in the transglycosylation reaction it is possible to improve the yields of the products. PMID- 21320471 TI - Decreased histone deacetylase 2 impairs Nrf2 activation by oxidative stress. AB - Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a crucial role in cellular defence against oxidative stress by inducing the expression of multiple anti-oxidant genes. However, where high levels of oxidative stress are observed, such as chronic obstructive pulmonary disease (COPD), Nrf2 activity is reduced, although the molecular mechanism for this defect is uncertain. Here, we show that down-regulation of histone deacetylase (HDAC) 2 causes Nrf2 instability, resulting in reduced anti-oxidant gene expression and increase sensitivity to oxidative stress. Although Nrf2 protein was clearly stabilized after hydrogen peroxide (H(2)O(2)) stimulation in a bronchial epithelial cell line (BEAS2B), Nrf2 stability was decreased and Nrf2 acetylation increased in the presence of an HDAC inhibitor, trichostatin A (TSA). TSA also reduced Nrf2-regulated heme oxygenase-1 (HO-1) expression in these cells, and this was confirmed in acute cigarette-smoke exposed mice in vivo. HDAC2 knock-down by RNA interference resulted in reduced H(2)O(2)-induced Nrf2 protein stability and activity in BEAS2B cells, whereas HDAC1 knockdown had no effect. Furthermore, monocyte derived macrophages obtained from healthy volunteers (non-smokers and smokers) and COPD patients showed a significant correlation between HDAC2 expression and Nrf2 expression (r=0.92, p<0.0001). Thus, reduced HDAC2 activity in COPD may account for increased Nrf2 acetylation, reduced Nrf2 stability and impaired anti oxidant defences. PMID- 21320472 TI - The novel synthetic ether lipid inositol-C2-PAF inhibits phosphorylation of the tyrosine kinases Src and FAK independent of integrin activation in transformed skin cells. AB - New alkyl-phospholipids that are structurally derived from platelet-activating factor are promising candidates for anticancer treatment. The mechanism of action of derivatives of the platelet-activating factor is distinctly different from that of known DNA- or tubulin-targeting anticancer agents because they are incorporated into cell membranes, where they accumulate and interfere with a wide variety of key enzymes. We recently presented evidence of a novel group of alkyl phospholipids, glycosidated phospholipids that efficiently inhibit cell proliferation. One member of this group, inositol-C2-PAF (Ino-C2-PAF), displays high efficacy and low cytotoxicity in HaCaT-cells, an immortalized non tumorigenic skin keratinocyte cell line. Here, we show that Ino-C2-PAF also inhibits the motility of the skin-derived transformed cell lines HaCaT and squamous cell carcinoma (SCC)-25. This decrease in motility is accompanied by an altered F-actin cytoskeleton, increased clustering of integrins, and increased cell-matrix adhesion. Despite enhanced integrin clustering and matrix adhesion, we observed less phosphorylation of the cytoplasmic tyrosine kinases focal adhesion kinase (FAK) and Src, key regulators of cellular motility, at focal adhesion sites. Transient transfection of constitutively active variants of FAK and Src could at least in part bybass this inhibitory effect of Ino-C2-PAF. This fact indicates that Ino-C2-PAF interferes with the fine-tuned balance between adhesion and migration. Ino-C2-PAF at least partially uncouples integrin-mediated attachment from subsequent integrin-dependent signaling steps, which inhibits migration in transformed keratinocyte cell lines. PMID- 21320473 TI - Deprivation of anticipated food under scheduled feeding induces c-Fos expression in the caudal part of the arcuate nucleus of hypothalamus through histamine H1 receptors in rats: potential involvement of E3 subgroup of histaminergic neurons in tuberomammillary nucleus. AB - It is well established that histaminergic neurons densely innervate the anterior hypothalamus and regulate several functions through histamine H(1) receptor (H1R). However, functional innervations of histaminergic neurons in the caudal hypothalamus have been poorly investigated. Recently, we have demonstrated that c Fos, a marker of neuronal activation, was significantly induced by food deprivation under scheduled feeding in H1R-expressing cells in the caudal part of the arcuate nucleus of hypothalamus (cARC) of rats and histaminergic neurons innervating this area. In this study, we have examined the functional involvement of histaminergic neurons in the food deprivation-induced c-Fos expression in the cARC under scheduled feeding. The c-Fos expression in the cARC by food deprivation was significantly suppressed by pretreatment with antihistamines. After food deprivation, the number of c-Fos-histidine decarboxylase (HDC) double positive neurons was mostly increased in the E3 subdivision of the tuberomammillary nucleus (TM). Under the restricted feeding schedule, significant expressions of c-Fos were detected in the TM and cARC only when rats strongly anticipated feeding, compared with a slight c-Fos induction in both nuclei when they were satiated. These findings suggest that the histaminergic neurons in the E3 subdivision of the TM are selectively activated by deprivation of an anticipated food under scheduled feeding and functionally innervate the H1R expressing neurons in the cARC. PMID- 21320474 TI - Zonisamide-induced long-lasting recovery of dopaminergic neurons from MPTP toxicity. AB - Zonisamide is an antiepileptic drug that also improves the cardinal symptoms of Parkinson's disease. This study investigated the effects of zonisamide on dopaminergic neuronal degeneration in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-treated mice. Six groups of mice were treated as follows: 1) normal saline; 2) MPTP, 15 mg/kg*4 every 2h; 3) MPTP and zonisamide, 40 mg/kg*1, 1h after the last MPTP dose; 4) MPTP and zonisamide, 1 day after the last dose of MPTP; 5) MPTP and zonisamide, 1h before the first MPTP dose; and 6) zonisamide, 40 mg/kg. MPTP-treatment decreased the contents of dopamine as well as the number and area of tyrosine hydroxylase (TH)-positive neurons. Concurrent treatment of mice with zonisamide and MPTP did not show any inhibition of the toxic effect of MPTP towards dopamine contents at 1 week after treatment but it increased the number and area of TH-positive neurons compared to the MPTP-treated group. Surviving TH-positive neurons had recovery of dopamine production after several weeks. Moreover, zonisamide increased the number of S100beta-positive and glial fibrillary acidic protein (GFAP)-positive astrocytes and dopamine turnover. These results suggest that zonisamide acts as a neuro-protectant against MPTP induced dopaminergic neuronal degeneration as shown by an increase of TH-positive neurons and this may be mediated by increased S100beta secretion. PMID- 21320475 TI - Conjugated double bonds in lipid bilayers: a molecular dynamics simulation study. AB - Conjugated linoleic acids (CLA) are found naturally in dairy products. Two isomers of CLA, that differ only in the location of cis and trans double bonds, are found to have distinct and different biological effects. The cis 9 trans 11 (C9T11) isomer is attributed to have the anti-carcinogenic effects, while the trans 10 cis 12 (T10C12) isomer is believed to be responsible for the anti obesity effects. Since dietary CLA are incorporated into membrane phospholipids, we have used Molecular Dynamics (MD) simulations to investigate the comparative effects of the two isomers on lipid bilayer structure. Specifically, simulations of phosphatidylcholine lipid bilayers in which the sn-2 chains contained one of the two isomers of CLA were performed. Force field parameters for the torsional potential of double bonds were obtained from ab initio calculations. From the MD trajectories we calculated and compared structural properties of the two lipid bilayers, including areas per molecule, density profiles, thickness of bilayers, tilt angle of tail chains, order parameters profiles, radial distribution function (RDF) and lateral pressure profiles. The main differences found between bilayers of the two CLA isomers, are (1) the order parameter profile for C9T11 has a dip in the middle of sn-2 chain while the profile for T10C12 has a deeper dip close to terminal of sn-2 chain, and (2) the lateral pressure profiles show differences between the two isomers. Our simulation results reveal localized physical structural differences between bilayers of the two CLA isomers that may contribute to different biological effects through differential interactions with membrane proteins or cholesterol. PMID- 21320476 TI - Insulin resistance is associated with the metabolic syndrome and is not directly linked to coronary artery disease. AB - BACKGROUND: Insulin resistance (IR) is the key feature of the metabolic syndrome (MetS). Its association with directly visualized coronary atherosclerosis is unclear. We hypothesised that insulin resistance is associated with both angiographically determined coronary artery disease (CAD) and with the MetS. METHODS: In 986 consecutive patients undergoing coronary angiography for the evaluation CAD, IR was determined by the HOMA index; the MetS was defined according to NCEP-ATPIII criteria; and significant CAD was diagnosed when coronary stenoses >=50% were present. RESULTS: HOMA IR scores were higher in MetS patients than in subjects without the MetS (4.9+/-6.4 vs. 2.2+/-2.0; p<0.001). HOMA IR did not differ significantly between patients with significant CAD and those who did not have significant CAD. When both, the presence of MetS and of significant CAD were considered, HOMA IR was significantly higher in patients with the MetS both among those who had significant CAD (4.9+/-6.8 vs. 2.2+/-1.8; p<0.001) and among those who did not have significant CAD (5.0+/-5.8 vs. 2.1+/ 2.3; p<0.001), it did not differ significantly between patients with significant CAD and subjects without significant CAD among patients with the MetS nor among those without MetS. Similar results were obtained with the IDF definition of the MetS. CONCLUSION: IR is significantly associated with the MetS but not with angiographically determined CAD. IR may play a greater role in the eventual precipitation of thrombosis than in the gradual progression of atherosclerosis. PMID- 21320477 TI - A novel frame-shift mutation of GLI3 causes non-syndromic and complex digital anomalies in a Chinese family. AB - A three-generation Han Chinese family was found with complex digital anomalies including various types of polydactyly and syndactyly of fingers and toes. Some extra digits are composed only of soft tissues while others are complete fingers or toes, making this complex case different from previously reported pedigrees. The digital disease shows an autosomal dominant inheritance model. To locate the causative gene, whole-genome SNP analysis was performed using Illumina 370 K CNV Quad chips followed by linkage analysis with a self-developed algorithm Haplo2Ped (http://bighapmap.big.ac.cn/software.html). Three candidate regions with the highest signals (LOD scores 2.1070) were identified. In one region from 33,904,914 bp to 45,529,271 bp in chromosome 7, GLI3 was selected for further analysis. PCR sequencing and subsequent clone sequencing revealed a single nucleotide deletion (c.2884delG) in exon 14. This frame shift mutation generated a truncated protein with 40 non-endogenous amino acids in its C-terminal (p.Asp962MetfsX41). GLI3 was previously reported to associate with Greig Cephalopolysyndactyly Syndrome, Pallister-Hall Syndrome, and a few cases of preaxial and postaxial polydactylies. We report for the first time a novel mutation of GLI3 causing various digital abnormalities, including multi symptoms as both polydactyly and syndactyly among affected members but no other body maldevelopments (non-syndromic). PMID- 21320478 TI - Oxidative stress and antioxidant status in Saudi asthmatic patients. AB - OBJECTIVES: Asthma is a chronic inflammatory airway disorder associated with recruitment of inflammatory cells. This study aims to clarify the role of oxidative stress and antioxidant status in the deterioration accompanied asthma. DESIGN AND METHODS: Vitamin E, Vitamin C, superoxide dismutase (SOD), glutathione peroxidase (GPx), reduced glutathione (GSH), total antioxidant status together with the concentrations of lipid peroxides, total nitrates and oxidative DNA damage (8-oxodeoxyguanine) were determined in plasma or whole blood of 47 Saudi asthmatic patients and compared to age-matching control samples. RESULTS: The present study showed that asthmatic patients have significantly decreased levels of GSH, alpha-tocopherol, GPx, total antioxidant status and higher levels of SOD, lipid peroxides, total nitrate and 8-oxo-dG. Vitamin C recorded more or less similar levels in both groups. CONCLUSION: Alteration of the selected measured parameters confirms that oxidative stress and defective antioxidant status could represent the primary causative factor in the pathogenesis of asthma. PMID- 21320479 TI - Day-to-day variation of late-night salivary cortisol in healthy voluntaries. AB - OBJECTIVES: The study examines the components of biological variation of nocturnal salivary cortisol in healthy subjects. DESIGN AND METHODS: Eight repetitive measurements were performed in seven subjects during a 25-day time period (study A), and then, for comparison, two salivary specimens were taken during two consecutive days from 20 subjects (study B). Salivary cortisol was measured with the Salimetrics HS-Cortisol assay. RESULTS: Mean salivary cortisol (1.27 nmol/L), analytical variation (CVa=15.4%), within-subject variation (CVi=34.1%), between-subject variation (CVg=35.3%), index of individuality (II=1.06) and reference change value (RCV=104%) were obtained for study A. Similar results were obtained from the set of samples of study B. CONCLUSION: The study results show a medium degree of individuality for salivary cortisol. Both conventional reference values and comparison of serial results may be equally used for clinical interpretation. A change greater of 104% between two successive measurements should be considered significant. PMID- 21320480 TI - Cox proportional hazard model analysis of survival in end-stage renal disease patients with small-sized high-density lipoprotein particles. AB - OBJECTIVE: Dyslipidemia is commonly seen in patients with end-stage renal disease (ESRD). This prospective study investigates whether small-sized high-density lipoprotein (HDL) particles alone or in combination with high sensitivity C reactive protein (hsCRP) are independent determinants of ESRD mortality. DESIGN AND METHODS: We performed 36 months follow-up study in 122 haemodialysis (HD) patients. HDL size and subclass distribution were determined by gradient gel electrophoresis. Baseline characteristics of the patients were evaluated for the prediction of mortality. RESULTS: Cox regressions analysis showed that patients with small-sized HDL particles had 2.8-fold higher risk of lethal outcome (P<0.05). Concomitant presence of small-sized HDL particles and increased hsCRP concentration were significantly associated with reduced survival rate (HR=3.907; P<0.05). Observed relationships persisted after adjustment for serum lipid and lipoprotein concentrations. CONCLUSIONS: Our results indicate that small-sized HDL particles alone and combined with elevated hsCRP concentrations are independent predictors of reduced survival in HD patients. PMID- 21320481 TI - Hoxb3 negatively regulates Hoxb1 expression in mouse hindbrain patterning. AB - The spatial regulation of combinatorial expression of Hox genes is critical for determining hindbrain rhombomere (r) identities. To address the cross-regulatory relationship between Hox genes in hindbrain neuronal specification, we have generated a gain-of-function transgenic mouse mutant Hoxb3(Tg) using the Hoxb2 r4 specific enhancer element. Interestingly, in r4 of the Hoxb3(Tg) mutant where Hoxb3 was ectopically expressed, the expression of Hoxb1 was specifically abolished. The hindbrain neuronal defects of the Hoxb3(Tg) mutant mice were similar to those of Hoxb1(-/-) mutants. Therefore, we hypothesized that Hoxb3 could directly suppress Hoxb1 expression. We first identified a novel Hoxb3 binding site S3 on the Hoxb1 locus and confirmed protein binding to this site by EMSA, and by in vivo ChIP analysis using P19 cells and hindbrain tissues from the Hoxb3(Tg) mutant. We further showed that Hoxb3 could suppress Hoxb1 transcriptional activity by chick in ovo luciferase reporter assay. Moreover, in E10.5 wildtype caudal hindbrain, where Hoxb1 is not expressed, we showed by in vivo ChIP that Hoxb3 was consistently bound to the S3 site on the Hoxb1 gene. This study reveals a novel negative regulatory mechanism by which Hoxb3 as a posterior gene serves to restrict Hoxb1 expression in r4 by direct transcriptional repression to maintain the rhombomere identity. PMID- 21320482 TI - Control of Distal-less expression in the Drosophila appendages by functional 3' enhancers. AB - The expression of the Hox gene Distal-less (Dll) directs the development of appendages in a wide variety of animals. In Drosophila, its expression is subjected to a complex developmental control. In the present work we have studied a 17kb genomic region in the Dll locus which lies downstream of the coding sequence and found control elements of primary functional importance for the expression of Dll in the leg and in other tissues. Of particular interest is a control element, which we have called LP, which drives expression of Dll in the leg primordium from early embryonic development, and whose deletion causes severe truncation and malformation of the adult leg. This is the first Dll enhancer for which, in addition to the ability to drive expression of a reporter, a role can be demonstrated in the expression of the endogenous Dll gene and in the development of the leg. In addition, our results suggest that some enhancers, contrary to the widely accepted notion, may require a specific 5' or 3' position with respect to the transcribed region. PMID- 21320484 TI - A microarray based expression profiling of paclitaxel and vincristine resistant MCF-7 cells. AB - Resistance to the broad spectrum of chemotherapeutic agents in cancer cell lines and tumors has been called multiple drug resistance (MDR). In this study, the molecular mechanisms of resistance to two anticancer agents (paclitaxel and vincristine) in mammary carcinoma cell line MCF-7 were investigated. Drug resistant sublines to paclitaxel (MCF-7/Pac) and vincristine (MCF-7/Vinc) that were developed from sensitive MCF-7 cells (MCF-7/S) were used. cDNA microarray analysis was performed for the RNA samples of sensitive and resistant cells in duplicate experiments. GeneSpring GX 7.3.1 Software was used in data analysis. The results indicated that the upregulation of MDR1 gene is the dominating mechanism of the paclitaxel and vincristine drug resistance. Additionally the upregulation of the genes encoding the detoxifying enzymes (i.e. GSTP1) was observed. Significant downregulation of apoptotic genes (i.e. PDCD2/4/6/8) and upregulation of some cell cycle regulatory genes (CDKN2A, CCNA2 etc.) was seen which may be in close relation to MDR in breast cancer. Drug resistant cancer cells exhibit different gene expression patterns depending on drug treatment, and each drug resistance phenotype is probably genetically different. Further functional studies are needed to demonstrate the complete set of genes contributing to the drug resistance phenotype in breast cancer cells. PMID- 21320483 TI - Evolutionary bioscience as regulatory systems biology. AB - At present several entirely different explanatory approaches compete to illuminate the mechanisms by which animal body plans have evolved. Their respective relevance is briefly considered here in the light of modern knowledge of genomes and the regulatory processes by which development is controlled. Just as development is a system property of the regulatory genome, causal explanation of evolutionary change in developmental process must be considered at a system level. Here I enumerate some mechanistic consequences that follow from the conclusion that evolution of the body plan has occurred by alteration of the structure of developmental gene regulatory networks. The hierarchy and multiple additional design features of these networks act to produce Boolean regulatory state specification functions at upstream phases of development of the body plan. These are created by the logic outputs of network subcircuits, and in modern animals these outputs are impervious to continuous adaptive variation unlike genes operating more peripherally in the network. PMID- 21320485 TI - PTEN ameliorates high glucose-induced lipid deposits through regulating SREBP 1/FASN/ACC pathway in renal proximal tubular cells. AB - Phosphatase and tensin homology deleted on chromosome ten (PTEN) is a negative regulator of PI3K/Akt pathway, and here we investigated the effect of PTEN on lipogenesis in diabetic rats and high glucose-stimulated human renal proximal tubular cell line (HKC). Decreased PTEN and increased phospho-Akt were found in kidney of diabetic rats, and in vitro research revealed that high glucose attenuated PTEN expression in a time-dependent manner, concomitant with activation of Akt. Again, expression of PTEN significantly inhibited high glucose caused increased phospho-Akt and lipogenic genes including SREBP-1, fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC). Furthermore, we confirmed inhibition of TGF-beta1 pathway with SB431542 blocked the effect of high glucose on PTEN down-regulation, an increase in phospho-Akt and lipogenesis. These above data suggest that decreased PTEN mediates high glucose-induced lipogenesis in renal proximal tubular cells and TGF-beta1 might be involved in PTEN down regulation. PMID- 21320486 TI - Recruitment of APPL1 to ubiquitin-rich aggresomes in response to proteasomal impairment. AB - Inhibitors of proteasomes have been shown to affect endocytosis of multiple membrane receptors, in particular at the step of cargo sorting for lysosomal degradation. Here we demonstrate that the inhibition of proteasomes causes specific redistribution of an endosomal adaptor APPL1, which undergoes initial solubilization from APPL endosomes followed by clustering in the perinuclear region. MG132 treatment decreases APPL1 labeling of endosomes while the staining of the canonical early endosomes with EEA1 remains unaffected. Upon prolonged treatment with proteasome inhibitors, endogenous APPL1 localizes to the site of aggresome formation, with perinuclear APPL1 clusters encapsulated within a vimentin cage and co-localizing with aggregates positive for ubiquitin. The clustering of APPL1 is concomitant with increased ubiquitination and decreased solubility of this protein. We determined that the ubiquitin ligase Nedd4 enhances polyubiquitination of APPL1, and the ubiquitin molecules attached to APPL1 are linked through lysine-63. Taken together, these results add APPL1 to only a handful of endogenous cellular proteins known to be recruited to aggresomes induced by proteasomal stress. Moreover, our studies suggest that the proteasome inhibitors that are already in clinical use affect the localization, ubiquitination and solubility of APPL1. PMID- 21320487 TI - Changes in Musashi-1 subcellular localization correlate with cell cycle exit during postnatal retinal development. AB - RNA-binding proteins, and in particular, the Musashi genes, function as essential regulators of progenitor functioning in both the developing and adult organism. In this report, we characterize the differential subcellular distribution of Musashi-1 in cells engaged in either proliferating or differentiating contexts in the developing mouse retina, and in cultured Muller glia. During retinal cell differentiation, Musashi-1 immunoreactivity shifts from exclusively cytoplasmic in retinal progenitor cells, to predominantly nuclear localization in differentiating neurons. This nuclear shift is transient, with localization in the adult retina becoming predominantly perinuclear and cytoplasmic in Muller glia and photoreceptors. A correlation between cell cycle progression and subcellular distribution of Musashi-1 is observed in passageable, adult Muller glial cells in vitro. Furthermore, treatment of Muller cultures with neuron promoting differentiation media induces asymmetric cytoplasmic Musashi-1 immunoreactivity in dividing daughter cells. The observed shifts in subcellular Musashi-1 localization are consistent with contrasting roles for Musashi-1 during cell proliferation and differentiation. These data provide evidence that nuclear, and cytoplasmic sequestering of Musashi-1 in retinal cells is context-specific, and may contribute to downstream functioning of Musashi-1. PMID- 21320488 TI - Treatment with connexin 46 siRNA suppresses the growth of human Y79 retinoblastoma cell xenografts in vivo. AB - Tumors with a hypoxic component, including human Y79 retinoblastoma cells, express a specific gap junction protein, Connexin 46 (Cx46), which is usually only found in naturally hypoxic tissues such as the differentiated lens. The aim of this study was to investigate if Cx46 downregulation would suppress Y79 tumor formation in vivo. Five-week old nude mice were subcutaneously implanted with human Y79 retinoblastoma cells and treated with intratumor siRNA injections of 30 MUg Cx46 siRNA (n = 6), 30 MUg non-silencing siRNA (n = 6), or no siRNA treatment (n = 6) every 2 days for a maximum of 10 treatments. Tumor volume (TV) was calculated from the recorded caliper measurements of length and width. Excised tumors were measured and weighed. Western blot analyses were performed to evaluate Cx46 and Cx43 expression in tumors which received Cx46 siRNA, non silencing siRNA, or no siRNA treatment. Tumor histopathology was used to assess tumor features. Cx46 siRNA treated Y79 tumors had a reduced TV (287 mm(3) +/- 77 mm(3)) when compared to the tumors of mice receiving the negative control siRNA (894 mm(3) +/- 218 mm(3); P <= 0.03) or no siRNA (1068 mm(3) +/- 192 mm(3); P <= 0.002). A 6-fold knockdown of Cx46 and a 3-fold rise in Cx43 protein expression was observed from western blots of tumors treated with Cx46 siRNA compared to mice treated with non-silencing siRNA. Knockdown of Cx46 with siRNA had an antitumor effect on human Y79 retinoblastoma tumors in the nude mouse model. The results suggest that anti-Cx46 therapy may be a potential target in the future treatment of retinoblastoma. PMID- 21320490 TI - Trypanosoma evansi: a comparative study of four diagnostic techniques for trypanosomosis using rabbit as an experimental model. AB - The goal of this study was to compare two parasitological diagnostic techniques, such as by Micro-Haematocrit Centrifugation Technique (MHCT) and Direct Microscopic Examination (DME) with a serological method (iELISA), and a molecular procedure PCR, in rabbits experimentally infected with Trypanosoma evansi, in order to determine their sensitivity throughout the course of disease. The parasitological methods were not able of detecting the presence of the parasite during the phases of low parasitemia, the prepatency period and the chronic phase. In contrast, PCR detected T. evansi in the prepatency and chronic phase, when increase the amount of DNA from 100 to 300ng. 100% detection was observed with iELISA only in the chronic stage of the disease. In the acute phase, all samples were positively diagnosed using either MHCT or PCR, whereas only few samples were diagnosed by DME. Samples obtained from day 15 post infection were also detected by iELISA. The highest diagnostic register during the course of infection was achieved by the PCR technique (93.8%), followed by iELISA (71.1%), MHCT (59%) and DME (13.6%). Therefore, we recommend the use of PCR in epidemiological studies in order to implement sanitary control plans for the improvement of livestock productivity in the country. PMID- 21320491 TI - Entamoeba histolytica: biochemical characterization of a protein disulfide isomerase. AB - Protein disulfide isomerase (PDI) enzymes are eukaryotic oxidoreductases that catalyze oxidation, reduction and isomerization of disulfide bonds in polypeptide substrates. Here, we report the biochemical characterization of a PDI enzyme from the protozoan parasite Entamoeba histolytica (EhPDI). Our results show that EhPDI behaves mainly as an oxidase/isomerase and can be inhibited by bacitracin, a known PDI inhibitor; moreover, it exhibits chaperone-like activity. Albeit its physiological role in the life style of the parasite (including virulence and survival) remains to be studied, EhPDI could represent a potential drug target for anti-amebic therapy. PMID- 21320492 TI - The tricarboxylic acid cycle in L3 Teladorsagia circumcincta: metabolism of acetyl CoA to succinyl CoA. AB - Nematodes, like other species, derive much of the energy for cellular processes from mitochondrial pathways including the TCA cycle. Previously, we have shown L3 Teladorsagia circumcincta consume oxygen and so may utilise a full TCA cycle for aerobic energy metabolism. We have assessed the relative activity levels and substrate affinities of citrate synthase, aconitase, isocitrate dehydrogenase (both NAD+ and NADP+ specific) and alpha-ketoglutarate dehydrogenase in homogenates of L3 T. circumcincta. All of these enzymes were present in homogenates. Compared with citrate synthase, low levels of enzyme activity and low catalytic efficiency was observed for NAD+ isocitrate dehydrogenase and especially alpha-ketoglutarate dehydrogenase. Therefore, it is likely that the activity of these to enzymes regulate overall metabolite flow through the TCA cycle, especially when [NAD+] limits enzyme activity. Of the enzymes tested, only citrate synthase had substrate affinities which were markedly different from values obtained from mammalian species. Overall, the results are consistent with the suggestion that a full TCA cycle exists withinL3 T. circumcincta. While there may subtle variations in enzyme properties, particularly for citrate synthase, the control points for the TCA cycle inL3 T. circumcincta are probably similar to those in the tissues of their host species. PMID- 21320489 TI - Diabetes as a chronic metabolic stressor: causes, consequences and clinical complications. AB - Diabetes mellitus is an endocrine disorder resulting from inadequate insulin release and/or reduced insulin sensitivity. The complications of diabetes are well characterized in peripheral tissues, but there is a growing appreciation that the complications of diabetes extend to the central nervous system (CNS). One of the potential neurological complications of diabetes is cognitive deficits. Interestingly, the structural, electrophysiological, neurochemical and anatomical underpinnings responsible for cognitive deficits in diabetes are strikingly similar to those observed in animals subjected to chronic stress, as well as in patients with stress-related psychiatric illnesses such as major depressive disorder. Since diabetes is a chronic metabolic stressor, this has led to the suggestion that common mechanistic mediators are responsible for neuroplasticity deficits in both diabetes and depression. Moreover, these common mechanistic mediators may be responsible for the increase in the risk of depressive illness in diabetes patients. In view of these observations, the aims of this review are (1) to describe the neuroplasticity deficits observed in diabetic rodents and patients; (2) to summarize the similarities in the clinical and preclinical studies of depression and diabetes; and (3) to highlight the diabetes-induced neuroplasticity deficits in those brain regions that have been implicated as important pathological centers in depressive illness, namely, the hippocampus, the amygdala and the prefrontal cortex. PMID- 21320493 TI - Effect of the Synadenium carinatum latex lectin (ScLL) on Leishmania (Leishmania) amazonensis infection in murine macrophages. AB - Antiparasitic effect of a lectin isolated from Synadenium carinatum latex (ScLL) was evaluated against Leishmania (Leishmania) amazonensis promastigotes/amastigotes. Pretreatment of murine inflammatory peritoneal macrophages with ScLL reduced by 65.5% the association index of macrophages and L. (L) amazonensis promastigotes. Expression of cytokines (IL-12, IL-1 and TNF alpha) was detected in infected macrophages pretreated with ScLL (10MUg/mL). ScLL also reduced the growth of L. (L) amazonensis amastigote intracellular forms, showing no in vitro cytotoxic effects in mammalian host cells. ScLL treatment in infected murine inflammatory peritoneal macrophages did not induce nitric oxide production, suggesting that a nitric oxide independent pathway is activated to decrease the number of intracellular Leishmania. PMID- 21320494 TI - Lipid matrix plays a role in Abeta fibril kinetics and morphology. AB - While neuronal membranes are proposed to be the primary target of amyloid plaques, the effect of phospholipids on fibril formation kinetics and morphology has not yet been resolved. We report that interaction of various compositions with neuronal mimics promoted different processes of fibril formation: negatively charged surfaces increased the lag time and elongation rate in thioflavin T assays, while brain total lipid extract had an opposite effect compared to that in the absence of lipid. Electron microscopy showed thin and elongated fibrils when the peptide was incubated with anionic lipids, while neutral surfaces promoted coarse and small fibrils. Circular dichroism and thioflavin T assays confirmed an initially unstructured peptide, and measured its transition to an aggregated beta-sheet conformation. PMID- 21320495 TI - Cytotoxicity of red fluorescent protein DsRed is associated with the suppression of Bcl-xL translation. AB - Red fluorescent protein (RFP) DsRed and its variants are widely applied in live cell imaging experiments. However, a major factor that restricts the application of DsRed is its cytotoxicity. Here, we report that DsRed and its variant DsRed Express2 inhibit the expression of B-cell lymphoma-extra large (Bcl-xL) in HeLa cells by translational regulation. Over-expression of Bcl-xL can reduce the cytotoxicity of DsRed. Meanwhile, Turbo RFP, a mutant RFP from Entacmaea quadricolor, does not affect Bcl-xL expression, suggesting that cytotoxic mechanisms of RFP from different species may be varied. Our results reveal a possible mechanism for the cytotoxicity of DsRed, providing a potential strategy to improve the application of DsRed and its variants. PMID- 21320496 TI - Identification and functional analysis of a new phosphorylation site (Y398) in the SH3 domain of Abi-1. AB - Abi-1 is an adaptor protein for Abelson kinase (c-Abl), and Abi-1 promotes the Abl-mediated phosphorylation of Mammalian Enabled (Mena) by binding both c-Abl and Mena. Here, we identified a new phosphorylation site (Y398) in the SH3 domain of Abi-1, and disruption of Y398, combined with the previously identified phosphorylation site Y213, significantly weakens the binding of Abi-1 to c-Abl. The SH3 domain of Abi-1 and the proline-rich domain of c-Abl are involved in this interaction. Abi-1 phosphorylation at both sites stimulates the phosphorylation of Mena through the activation of c-Abl kinase. The phosphorylation of Abi-1 also plays a role in enhancing the adhesion of Bcr-Abl-transformed leukemic cells. PMID- 21320497 TI - Green tea polyphenol epigallocatechin-3-gallate inhibits TLR2 signaling induced by peptidoglycan through the polyphenol sensing molecule 67-kDa laminin receptor. AB - Here we show the molecular basis for the inhibition of peptidoglycan (PGN) induced TLR2 signaling by a major green tea polyphenol epigallocatechin-3-gallate (EGCG). Recently, we identified the 67-kDa laminin receptor (67LR) as the cell surface EGCG receptor. Anti-67LR antibody treatment or silencing of 67LR resulted in abrogation of the inhibitory action of EGCG on PGN-induced production of pro inflammatory mediators and activation of mitogen-activated protein kinases. Silencing of Toll-interacting protein (Tollip), a negative regulator of TLR signaling impaired the TLR2 signaling inhibitory activity of EGCG, suggesting that TLR2 response could be inhibited by EGCG via 67LR and Tollip. PMID- 21320498 TI - Modification of mouse A2M B (620-792) and A2M N (168-230) by malondialdehyde and acetaldehyde attenuates the proteinase and TGF-beta1 binding ability of A2MB. AB - Acetaldehyde and malondialdehyde react covalently with cellular proteins forming protein-malondialdehyde-acetaldehyde adducts thus modulating their biochemical functions. Alpha-2 macroglobulin, an acute phase protein produced by liver binds to cytokines, growth factors and neutralizes proteinases. In this study we examined the formation of MAA adducts of N-terminal and bait region of mouse A2M and their effect on modulating its proteinase and TGF-beta1 binding activities. Adduct formation abrogated the binding of bait region with TGF-beta1, trypsin, and elastase. TGF-beta1 induced NO production was also suppressed. Acetaldehyde and MDA adduction of A2M may have physiological consequences in alcoholic patients. PMID- 21320499 TI - Combining clinical, pathology, and gene expression data to predict recurrence of hepatocellular carcinoma. AB - BACKGROUND & AIMS: In approximately 70% of patients with hepatocellular carcinoma (HCC) treated by resection or ablation, disease recurs within 5 years. Although gene expression signatures have been associated with outcome, there is no method to predict recurrence based on combined clinical, pathology, and genomic data (from tumor and cirrhotic tissue). We evaluated gene expression signatures associated with outcome in a large cohort of patients with early stage (Barcelona Clinic Liver Cancer 0/A), single-nodule HCC and heterogeneity of signatures within tumor tissues. METHODS: We assessed 287 HCC patients undergoing resection and tested genome-wide expression platforms using tumor (n = 287) and adjacent nontumor, cirrhotic tissue (n = 226). We evaluated gene expression signatures with reported prognostic ability generated from tumor or cirrhotic tissue in 18 and 4 reports, respectively. In 15 additional patients, we profiled samples from the center and periphery of the tumor, to determine stability of signatures. Data analysis included Cox modeling and random survival forests to identify independent predictors of tumor recurrence. RESULTS: Gene expression signatures that were associated with aggressive HCC were clustered, as well as those associated with tumors of progenitor cell origin and those from nontumor, adjacent, cirrhotic tissues. On multivariate analysis, the tumor-associated signature G3-proliferation (hazard ratio [HR], 1.75; P = .003) and an adjacent poor-survival signature (HR, 1.74; P = .004) were independent predictors of HCC recurrence, along with satellites (HR, 1.66; P = .04). Samples from different sites in the same tumor nodule were reproducibly classified. CONCLUSIONS: We developed a composite prognostic model for HCC recurrence, based on gene expression patterns in tumor and adjacent tissues. These signatures predict early and overall recurrence in patients with HCC, and complement findings from clinical and pathology analyses. PMID- 21320500 TI - Use of aspirin or nonsteroidal anti-inflammatory drugs increases risk for diverticulitis and diverticular bleeding. AB - BACKGROUND & AIMS: Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, have been implicated in diverticular complications. We examined the influence of aspirin and NSAID use on risk of diverticulitis and diverticular bleeding in a large prospective cohort. METHODS: We studied 47,210 US men in the Health Professionals Follow-up Study cohort who were 40-75 years old at baseline in 1986. We assessed use of aspirin, nonaspirin NSAIDs, and other risk factors biennially. We identified men with diverticulitis or diverticular bleeding based on responses to biennial and supplementary questionnaires. RESULTS: We documented 939 cases of diverticulitis and 256 cases of diverticular bleeding during a 22 year period of follow-up evaluation. After adjustment for risk factors, men who used aspirin regularly (>=2 times/wk) had a multivariable hazard ratio (HR) of 1.25 (95% confidence interval [CI], 1.05-1.47) for diverticulitis and a HR of 1.70 (95% CI, 1.21-2.39) for diverticular bleeding, compared with nonusers of aspirin and NSAIDs. Use of aspirin at intermediate doses (2-5.9 standard, 325-mg tablets/wk) and frequency (4-6 days/wk) were associated with the highest risk of bleeding (multivariable HR, 2.32; 95% CI, 1.34-4.02, and multivariable HR, 3.13; 95% CI, 1.82-5.38, respectively). Regular users of nonaspirin NSAIDs also had an increased risk of diverticulitis (multivariable HR, 1.72; 95% CI, 1.40-2.11) and diverticular bleeding (multivariable HR, 1.74; 95% CI, 1.15-2.64), compared with men who denied use of these medications. CONCLUSIONS: Regular use of aspirin or NSAIDs is associated with an increased risk of diverticulitis and diverticular bleeding. Patients at risk of diverticular complications should carefully consider the potential risks and benefits of using these medications. PMID- 21320501 TI - JNK signaling promotes intestinal tumorigenesis through activation of mTOR complex 1 in Apc(Delta716) mice. AB - BACKGROUND & AIMS: Signaling by the mammalian target of rapamycin complex 1 (mTORC1) has been implicated in various human cancers. mTORC1 signaling is activated in intestinal tumors of adenomatous polyposis coli (Apc(Delta716)) mice, a model of familial adenomatous polyposis; in these mice, the mTORC1 inhibitor RAD001 can block tumor formation. However, the precise mechanism of mTORC1 signaling in intestinal tumors is not clear. We investigated whether c-Jun NH(2) terminal kinase (JNK) is involved in the mTORC1 activation. METHODS: We investigated the effects of an inhibitor and an activator of JNK, as well as small interfering RNA against JNK, on mTORC1 in Apc(Delta716) mice and colon cancer cell lines. We also determined the role of JNK in mTORC1 signaling using in vitro kinase assays. RESULTS: JNK was activated in intestinal polyps of Apc((Delta716) mice); the JNK inhibitor SP600125 significantly suppressed tumor formation. In colorectal cancer cell lines, the JNK activator anisomycin activated mTORC1, whereas SP600125 or small interfering RNAs against JNK suppressed signaling. Importantly, JNK stimulated the mTORC1 kinase activity in vitro, through direct phosphorylation of Raptor at serine 863. CONCLUSIONS: JNK is required for activation of mTORC1 in intestinal tumor cells. JNK inhibitors might be developed as therapeutics or to prevent development of intestinal tumors. PMID- 21320502 TI - A fibronectin-independent mechanism of collagen fibrillogenesis in adult liver remodeling. AB - BACKGROUND & AIMS: Fibrosis is an abnormal extension of the wound healing process that follows tissue damage; it is involved in pathogenesis in a variety of chronic diseases. The formation of extracellular matrix is an essential response in wound healing. Although it has been proposed that collagen organization and assembly depend on the fibronectin matrix in culture, the contribution of fibronectin to these processes remains to be defined in vivo. METHODS: We generated a conditional, fibronectin-deficient mouse model of liver injury and explored whether fibronectin would be a suitable target for preventing extensive collagen deposits and scar formation that could lead to liver fibrosis. RESULTS: The lack of fibronectin did not interfere with reconstruction of collagen fibril organization in response to liver injury. Signaling by transforming growth factor beta and type V collagen were required for collagen fibrillogenesis during remodeling of adult liver tissue. CONCLUSIONS: Transforming growth factor-beta and type V collagen are targets for regulating the initial fibrogenic response to liver damage. PMID- 21320503 TI - CD151 amplifies signaling by integrin alpha6beta1 to PI3K and induces the epithelial-mesenchymal transition in HCC cells. AB - BACKGROUND & AIMS: Overexpression of CD151 is associated with poor prognosis for hepatocellular carcinoma (HCC), yet its role in pathogenesis is not known. METHODS: We analyzed the expression of the integrin subunit alpha6 by quantitative, real-time polymerase chain reaction and immunoblot analyses of 120 HCC tissue samples; its clinical significance was investigated using tissue microarray (TMAs) analysis of samples from 335 patients with HCC. Immunoprecipitation was used to assess the relationship between alpha6 and CD151. The molecular effects of high expression levels of alpha6 and CD151 in HCC cells were determined using RNA interference and pharmacologic approaches. RESULTS: Overexpression of alpha6 correlated with poor prognosis of patients with HCC; alpha6 formed a complex with endogenous CD151 in HCC cells. In cells that expressed high levels of alpha6 and CD151, laminin-5 promoted cell spreading by inducing the epithelial-mesenchymal transition (EMT); this effect was not observed in cells that expressed high levels of only alpha6 or CD151. Cells that expressed high levels of alpha6 and CD151 underwent the EMT in response to laminin-5, through hyperactivation of phosphatidylinositol-3-kinase (PI3K), primarily induced via the PI3K-protein kinase B (Akt)-Snail-phosphatase and tensin homolog feedback pathway. The EMT was reversed by PI3K inhibitors and antibodies against CD151 or alpha6 in vitro, and was delayed by specific interference with CD151 and alpha6 in vivo. CONCLUSIONS: High expression levels of CD151 and alpha6 promote invasiveness of HCC cells. Either of these proteins, or PI3K signaling, might be targets for therapeutics for subgroups of patients with HCC. PMID- 21320504 TI - Central pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) decrease the baroreflex sensitivity in trout. AB - Although PACAP and VIP exert diverse actions on heart and blood vessels along the vertebrate phylum, no information is currently available concerning the potential role of these peptides on the regulation of the baroreflex response, a major mechanism for blood pressure homeostasis. Consequently, the goal of this study was to examine in our experimental model, the unanesthetized rainbow trout Oncorhynchus mykiss, whether PACAP and VIP are involved in the regulation of the cardiac baroreflex sensitivity (BRS). Cross-spectral analysis techniques using a fast Fourier transform algorithm were employed to calculate the coherence, phase and gain of the transfer function between spontaneous fluctuations of systolic arterial blood pressure and R-R intervals of the electrocardiogram. The BRS was estimated as the mean of the gain of the transfer function when the coherence between the two signals was high and the phase negative. Compared with vehicle, intracerebroventricular (i.c.v.) injections of trout PACAP-27 and trout VIP (25 100 pmol) dose-dependently reduced the cardiac BRS to the same extent with a threshold dose of 50 pmol for a significant effect. When injected intra arterially at the same doses as for i.c.v. injections, only the highest dose of VIP (100 pmol) significantly attenuated the BRS. These results suggest that the endogenous peptides PACAP and VIP might be implicated in the central control of cardiac baroreflex functions in trout. PMID- 21320505 TI - Genetic analyses of atypical Toxoplasma gondii strains reveal a fourth clonal lineage in North America. AB - Toxoplasma gondii is a widespread parasite of animals that causes zoonotic infections in humans. Previous studies have revealed a strongly clonal population structure in North America and Europe, while strains from South America are genetically separate and more diverse. However, the composition within North America has been questioned by recent descriptions of genetically more variable strains from this region. Here, we examined an expanded set of isolates using sequenced-based phylogenetic and population analyses to re-evaluate the population structure of T. gondii in North America. Our findings reveal that isolates previously defined by atypical restriction fragment length polymorphism patterns fall into two discrete groups. In one case, these new isolates represent variants of an existing lineage, from which they differ only by minor mutational drift. However, in the second case, it is evident that these isolates define a completely new lineage that is common in North America. Support for this new lineage was based on phylogeny, principle components analysis, STRUCTURE analyses, and statistical analysis of gene flow between groups. This new group, referred to as haplogroup 12, contains divergent genotypes previously referred to as A and X, isolated from sea otters. Consistent with this, group 12 was found primarily in wild animals, as well as occasionally in humans. This new lineage also has a highly clonal population structure. Analysis of the inheritance of multilocus genotypes revealed that different strains within group 12 are the products of a single recombination event between type 2 and a unique parental lineage. Collectively, the archetypal type 2 has been associated with clonal expansion of a small number of lineages in the North, as a consequence of separate but infrequent genetic crosses with several different parental lines. PMID- 21320506 TI - Phenotypic plasticity in the reproductive traits of a parasitoid. AB - Organisms show phenotypic plasticity--the capacity for a given genotype to express different phenotypes--in response to changes in the environment. Among the several factors that can cause phenotypic plasticity, nutritional constraints during development can affect the size of organisms and, consequently, affect most life-history traits, including reproductive traits. As their larvae are restricted by the amount of food contained in their host, parasitoids are a good model to study phenotypic plasticity related to size. The phenotypic plasticity of reproductive traits was investigated in the egg parasitoid Trichogramma euproctidis (Hymenoptera: Trichogrammatidae) by using host species of different sizes. Adult size, sperm storage organs (seminal vesicles and spermatheca), number of sperm stored and gamete size (sperm and oocyte) are all influenced by the host species; larger individuals have larger organs which contain more sperm, and both sperm and oocytes are correlated with adult size. However, while females become larger than males and mature larger oocytes in larger hosts, increase in sperm length stops after a given threshold. PMID- 21320508 TI - Role of reactive oxygen species in the regulation of cardiac contractility. AB - Increased production of reactive oxygen species (ROS) has been linked to the pathogenesis of contractile dysfunction in heart failure. However, it is unclear whether ROS can regulate physiological cellular processes in the myocardium. Here, we characterized the role of endogenous ROS production in the acute regulation of cardiac contractility in the intact rat heart. In isolated perfused rat hearts, endothelin-1 (ET-1, 1nmol/L) stimulated ROS formation in the left ventricle, which was prevented by the antioxidant N-acetylcysteine and the NAD(P)H oxidase inhibitor apocynin. N-acetylcysteine, the superoxide dismutase mimetic MnTMPyP, and apocynin significantly attenuated ET-1-mediated inotropic effect, which was accompanied by inhibition of extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation. Moreover, the mitochondrial K(ATP) channel blocker 5-HD, and the mitochondrial large conductance calcium activated potassium channel blocker paxilline, but not the sarcolemmal K(ATP) channel blocker HMR 1098 attenuated the inotropic response to ET-1. However, ET-1-induced ROS generation was not abolished by inhibiting mitochondrial K(ATP) channel opening. In contrast to ET-1 stimulation, the positive inotropic effect of beta(1) adrenergic receptor agonist dobutamine (250nmol/L) was significantly augmented by N-acetylcysteine and apocynin. Moreover, dobutamine-induced phospholamban phosphorylation was markedly enhanced by apocynin. In conclusion, NAD(P)H oxidase derived ROS play a physiological role in the acute regulation of cardiac contractility in the intact rat heart. Our results reveal that ET-1-induced increase in cardiac contractility is partially dependent on enhanced ROS generation, which in turn, activates the ERK1/2 pathway. On the other hand, beta adrenergic receptor-induced positive inotropic effect and phospholamban phosphorylation is enhanced by NAD(P)H oxidase inhibition. PMID- 21320507 TI - Three 4-letter words of hypertension-related cardiac hypertrophy: TRPC, mTOR, and HDAC. AB - Left ventricular hypertrophy due to hypertension represents a major risk factor for adverse cardiovascular events and death. In recent years, the prevalence of cardiac hypertrophy has increased due to obesity and an aging population. Notably, a significant number of individuals have persistent cardiac hypertrophy in the face of blood pressure that is normalized by drug treatment. Thus, a better understanding of the processes underlying the cardiac remodeling events that are set into play by hypertension is needed. At the level of the cardiac myocytes, hypertrophic growth is often described as physiological, as occurs with exercise, or pathological, as seen with hypertension. Here we discuss recent developments in three areas that are fundamental to pathological hypertrophic growth of cardiac myocytes. These areas are the transient receptor potential canonical (TRPC) channels, mammalian target of rapamycin (mTOR) complexes, and histone deacetylase (HDAC) enzymes. In the last several years, studies in each of these areas have yielded new and exciting discoveries into the genesis of pathological growth of cardiac myocytes. The phosphoinositide 3-kinase-Akt signaling network may be the common denominator that links these areas together. Defining the interrelationship among TRPC channels, mTOR signaling, and HDAC enzymes is a promising, but challenging area of research. Such knowledge will undoubtedly lead to new drugs that better prevent or reverse left ventricular hypertension. PMID- 21320509 TI - Cyclic di-GMP activation of polynucleotide phosphorylase signal-dependent RNA processing. AB - The second messenger cyclic diguanylic acid (c-di-GMP) is implicated in key lifestyle decisions of bacteria, including biofilm formation and changes in motility and virulence. Some challenges in deciphering the physiological roles of c-di-GMP are the limited knowledge about the cellular targets of c-di-GMP, the signals that control its levels, and the proportion of free cellular c-di-GMP, if any. Here, we identify the target and the regulatory signal for a c-di-GMP responsive Escherichia coli ribonucleoprotein complex. We show that a direct c-di GMP target in E. coli is polynucleotide phosphorylase (PNPase), an important enzyme in RNA metabolism that serves as a 3' polyribonucleotide polymerase or a 3'-to-5' exoribonuclease. We further show that a complex of polynucleotide phosphorylase with the direct oxygen sensors DosC and DosP can perform oxygen dependent RNA processing. We conclude that c-di-GMP can mediate signal-dependent RNA processing and that macromolecular complexes can compartmentalize c-di-GMP signaling. PMID- 21320511 TI - Theoretical approach to the functional optimisation of spiriferide brachiopod shell: Optimum morphology of sulcus. AB - Evidence suggests that biological forms that provide physiological and autecological functions have evolved to adapt to environmental conditions and to optimise requisite morpho-functions. We examined whether shell morphology is functionally optimised to generate passive feeding flow in the Devonian spiriferide brachiopod Paraspirifer bownockeri. This study was based on quantitative results from a computational fluid dynamics simulation and the Lagrangian multiplier method. We estimated the optimum development of the ventral median shell depression, which is called the sulcus, by minimising the pressure difference along the gape. This estimation was made under the constraint that the number of spiral flow rotations must be greater than one, which is effective for spiriferide feeding because of its alignment with the spiral lophophore. During mathematical optimisation, the equation resulted in a suitable flow velocity of approximately 0.1m/s. At this velocity, the pressure difference was minimised, regardless of sulcus development. The constraint equation showed that the number of spiral flow rotations increased with sulcus development. The optimal solution was similar to the original sulcus form of Paraspirifer under an ambient flow of approximately 0.1m/s. This result suggests that the variation of shell outline in spiriferids could provide a variety of preferential conditions for ambient flow and that the flow intensity could be adjusted by sulcus development to generate a robust passive feeding flow along the spiral feeding organs. PMID- 21320510 TI - The reverse transcriptase encoded by the non-LTR retrotransposon R2 is as error prone as that encoded by HIV-1. AB - Reverse transcriptases (RTs) encoded by a wide range of mobile retroelements have had a major impact on the structure and function of genomes. Among the most abundant elements in eukaryotes are the non long terminal repeat (LTR) retrotransposons. Here we compare the dNTP concentration requirements and error rates of the RT encoded by the non-LTR retrotransposon R2 of Bombyx mori with the well-characterized RTs of retroviruses. Surprisingly, R2 was found to have properties more similar to those of lentiviral RTs, such as human immunodeficiency virus type 1 (HIV-1), than to those of oncoretroviral RTs, such as murine leukemia virus. Like HIV-1 RT, R2 RT was able to synthesize DNA at low dNTP concentrations, suggesting that R2 is able to retrotranspose in nondividing cells. R2 RT also showed levels of misincorporation in biased dNTP pools and replication error rates in M13 lacZalpha forward mutation assays, similar to HIV 1 RT. Most of the R2 base substitutions in the forward mutation assay were caused by the misincorporation of dTMP. Analogous to HIV-1, the high error rate of R2 RT appears to be a result of its ability to extend mismatches once generated. We suggest that the low fidelity of R2 RT is a by-product of the flexibility of its active site/dNTP binding pocket required for the target-primed reverse transcription reaction used by R2 for retrotransposition. Finally, we discuss that in spite of the high R2 RT error rate, the long-term nucleotide substitution rate for R2 is not significantly above that associated with cellular DNA replication, based on the frequency of R2 retrotranspositions determined in natural populations. PMID- 21320512 TI - Evolution of virulence driven by predator-prey interaction: Possible consequences for population dynamics. AB - The evolution of pathogen virulence in natural populations has conventionally been considered as a result of selection caused by the interactions of the host with its pathogen(s). The host population, however, is generally embedded in complex trophic interactions with other populations in the community, in particular, intensive predation on the infected host can increase its mortality, and this can affect the course of virulence evolution. Reciprocally, in the long run, the evolution of virulence within an infected host can affect the patterns of population dynamics of a predator consuming the host (e.g. resulting in large amplitude oscillations, causing a severe drop in the population size, etc.). Surprisingly, neither the effect of predation on the evolution of virulence within a host, nor the influence of the evolution of virulence upon the consumer's dynamics has been addressed in the literature yet. In this paper, we consider a classical S-I ecoepidemiological model in which the infected host is consumed by a predator. We are particularly interested in the evolutionarily stable virulence of the pathogen in the model and its dependence upon ecologically relevant parameters. We show that predation can prominently shift the evolutionarily stable virulence towards more severe strains as compared to the same system without predation. We demonstrate that the evolution of virulence can result in a succession of dynamical regimes and can even lead to the extinction of the predator in the long run. The presence of a predator can indirectly affect the evolution within its prey since the evolutionarily stable virulence becomes a function of the prey growth rate, which would not be the case in a predator-free system. We find that the evolutionarily stable virulence largely depends on the carrying capacity K of the prey in a non-monotonous way. The model also predicts that in an eutrophic environment the shift of virulence towards evolutionarily stable benign strains can cause demographically stochastic evolutionary suicide, resulting in the extinction of both species, thus artificially maintaining severe strains of pathogen can enhance the persistence of both species. PMID- 21320513 TI - Structural pattern and functional correlations of the long bone diaphyses intracortical vascular system: investigation carried out with China ink perfusion and multiplanar analysis in the rabbit femur. AB - The intracortical vessel system of the rabbit femur has been studied after perfusion of the vascular tree with a water solution of dye (China ink) with multiplanar analysis. This method utilizes the full depth of field of the microscope objectives focusing different planes of the thick cortex. The microscopic observation even if restricted to a limited volume of cortex allowed to differentiate true 3-D nodes (54.5%) from the superimposition of vessels lying on different planes. The network model with elongated meshes preferentially oriented along the longitudinal axis of the diaphysis in his static configuration is not very different from the vascular anatomy depicted in the 2-D traditional models; however, the semi-quantitative morphometric analysis applied to the former supported the notion of a multidirectional microvascular network allowing change of flow according to the functional requirements. Other peculiar aspects not previously reported were cutting cone loops, blind-end and short-radius-bent vessels, and button-holes figures. The network design and node distribution were consistent with the straight trajectory of the secondary remodeling, with the proximal-to-distal and distal-to-proximal advancement directions of the cutting cones and with two main modes of node formation, namely bifurcation of the cutting cone and interception with pre-existing canals. The general organization of the network and its uninterrupted transformation during bone modeling and remodeling suggested a substantial plasticity of the intracortical vascular system capable to adapt itself to the changeable haemodynamic conditions. PMID- 21320514 TI - Viewing and feeling touch modulates hand position for reaching. AB - Action requires knowledge of our body location in space. Here we asked if interactions with the external world prior to a reaching action influence how visual location information is used. We investigated if the temporal synchrony between viewing and feeling touch modulates the integration of visual and proprioceptive body location information for action. We manipulated the synchrony between viewing and feeling touch in the Rubber Hand Illusion paradigm prior to participants performing a ballistic reaching task to a visually specified target. When synchronous touch was given, reaching trajectories were significantly shifted compared to asynchronous touch. The direction of this shift suggests that touch influences the encoding of hand position for action. On the basis of this data and previous findings, we propose that the brain uses correlated cues from passive touch and vision to update its own position for action and experience of self-location. PMID- 21320515 TI - Are the basal ganglia critical in producing redundancy gain effects on simple sensorimotor responses? An investigation on the effects of Parkinson's disease. AB - Redundancy gain (RG) is a well-known effect in the experimental psychology literature which is thought to reflect integration of sensory information. RG is a facilitation in speed of responding on a detection task when two stimuli are presented at once compared to when one stimulus is presented alone. Even though sensorimotor tasks involving integration of sensory information form the basis of a large repertoire of human skilled actions, the neural basis of reliable effects such as RG remains elusive. The present study examines whether the integrity of the basal ganglia system is likely to be critical for RG effects to occur. Based on a thorough analysis of performance on a standard paradigm of RG (and on the related paradigm of crossed-uncrossed differences: CUDs) in patients with mild to moderate Parkinson's disease and matched controls, we found virtually no differences between groups. We conclude that normal RG and CUD effects are not likely to rely critically on the BG. PMID- 21320516 TI - Gender differences in the neural correlates of humor processing: implications for different processing modes. AB - Humor is a complex phenomenon of human social cognition with large inter individual variability. Gender differences in emotion processing are a common finding in functional neuroimaging studies, and have been documented in behavioral studies of humor, but have received limited attention in functional neuroimaging studies on humor. Using blood oxygenation level dependent (BOLD) contrasts with high-field (3T) functional magnetic resonance imaging (fMR) we investigated 29 healthy subjects (14 female, 15 male) during the processing of humorous cartoons. In women, the ventral system implicated in detection and appraisal of emotion was activated, including amygdala, insula, and Anterior Cingulate Cortex (ACC). Men showed activation in both the ventral and dorsal processing systems. The results indicate that women process humor though limbic reactivity, involving appraisal of its emotional features, while men apply more evaluative, executive resources to humor processing. PMID- 21320517 TI - The neuroprotective action of pyrroloquinoline quinone against glutamate-induced apoptosis in hippocampal neurons is mediated through the activation of PI3K/Akt pathway. AB - Pyrroloquinoline quinone (PQQ), a cofactor in several enzyme-catalyzed redox reactions, possesses a potential capability of scavenging reactive oxygen species (ROS) and inhibiting cell apoptosis. In this study, we investigated the effects of PQQ on glutamate-induced cell death in primary cultured hippocampal neurons and the possible underlying mechanisms. We found that glutamate-induced apoptosis in cultured hippocampal neurons was significantly attenuated by the ensuing PQQ treatment, which also inhibited the glutamate-induced increase in Ca2+ influx, caspase-3 activity, and ROS production, and reversed the glutamate-induced decrease in Bcl-2/Bax ratio. The examination of signaling pathways revealed that PQQ treatment activated the phosphorylation of Akt and suppressed the glutamate induced phosphorylation of c-Jun N-terminal protein kinase (JNK). And inhibition of phosphatidylinositol-3-kinase (PI3K)/Akt cascade by LY294002 and wortmannin significantly blocked the protective effects of PQQ, and alleviated the increase in Bcl-2/Bax ratio. Taken together, our results indicated that PQQ could protect primary cultured hippocampal neurons against glutamate-induced cell damage by scavenging ROS, reducing Ca2+ influx, and caspase-3 activity, and suggested that PQQ-activated PI3K/Akt signaling might be responsible for its neuroprotective action through modulation of glutamate-induced imbalance between Bcl-2 and Bax. PMID- 21320518 TI - Characterization of protoberberine analogs employed as novel human P2X7 receptor antagonists. AB - The P2X(7) receptor (P2X(7)R), a member of the ATP-gated ion channel family, is regarded as a promising target for therapy of immune-related diseases including rheumatoid arthritis and chronic pain. A group of novel protoberberine analogs (compounds 3-5), discovered by screening of chemical libraries, was here investigated with respect to their function as P2X(7)R antagonists. Compounds 3-5 non-competitively inhibited BzATP-induced ethidium ion influx into hP2X(7) expressing HEK293 cells, with IC(50) values of 100-300nM. This antagonistic action on the channel further confirmed that both BzATP-induced inward currents and Ca(2+) influx were strongly inhibited by compounds 3-5 in patch-clamp and Ca(2+) influx assays. The antagonists also effectively suppressed downstream signaling of P2X(7) receptors including IL-1beta release and phosphorylation of ERK1/2 and p38 proteins in hP2X(7)-expressing HEK293 cells or in differentiated human monocytes (THP-1 cells). Moreover, IL-2 secretion from CD3/CD28-stimulated Jurkat T cell was also dramatically inhibited by the antagonist. These results imply that novel protoberberine analogs may modulate P2X(7) receptor-mediated immune responses by allosteric inhibition of the receptor. PMID- 21320520 TI - Metabolic profiling using HPLC allows classification of drugs according to their mechanisms of action in HL-1 cardiomyocytes. AB - Along with hepatotoxicity, cardiotoxic side effects remain one of the major reasons for drug withdrawals and boxed warnings. Prediction methods for cardiotoxicity are insufficient. High content screening comprising of not only electrophysiological characterization but also cellular molecular alterations are expected to improve the cardiotoxicity prediction potential. Metabolomic approaches recently have become an important focus of research in pharmacological testing and prediction. In this study, the culture medium supernatants from HL-1 cardiomyocytes after exposure to drugs from different classes (analgesics, antimetabolites, anthracyclines, antihistamines, channel blockers) were analyzed to determine specific metabolic footprints in response to the tested drugs. Since most drugs influence energy metabolism in cardiac cells, the metabolite "sub profile" consisting of glucose, lactate, pyruvate and amino acids was considered. These metabolites were quantified using HPLC in samples after exposure of cells to test compounds of the respective drug groups. The studied drug concentrations were selected from concentration response curves for each drug. The metabolite profiles were randomly split into training/validation and test set; and then analysed using multivariate statistics (principal component analysis and discriminant analysis). Discriminant analysis resulted in clustering of drugs according to their modes of action. After cross validation and cross model validation, the underlying training data were able to predict 50%-80% of conditions to the correct classification group. We show that HPLC based characterisation of known cell culture medium components is sufficient to predict a drug's potential classification according to its mode of action. PMID- 21320519 TI - Association between body mass index and arsenic methylation efficiency in adult women from southwest U.S. and northwest Mexico. AB - Human arsenic methylation efficiency has been consistently associated with arsenic-induced disease risk. Interindividual variation in arsenic methylation profiles is commonly observed in exposed populations, and great effort has been put into the study of potential determinants of this variability. Among the factors that have been evaluated, body mass index (BMI) has not been consistently associated with arsenic methylation efficiency; however, an underrepresentation of the upper BMI distribution was commonly observed in these studies. This study investigated potential factors contributing to variations in the metabolism of arsenic, with specific interest in the effect of BMI where more than half of the population was overweight or obese. We studied 624 adult women exposed to arsenic in drinking water from three independent populations. Multivariate regression models showed that higher BMI, arsenic (+3 oxidation state) methyltransferase (AS3MT) genetic variant 7388, and higher total urinary arsenic were significantly associated with low percentage of urinary arsenic excreted as monomethylarsonic acid (%uMMA) or high ratio between urinary dimethylarsinic acid and uMMA (uDMA/uMMA), while AS3MT genetic variant M287T was associated with high %uMMA and low uDMA/uMMA. The association between BMI and arsenic methylation efficiency was also evident in each of the three populations when studied separately. This strong association observed between high BMI and low %uMMA and high uDMA/uMMA underscores the importance of BMI as a potential arsenic-associated disease risk factor, and should be carefully considered in future studies associating human arsenic metabolism and toxicity. PMID- 21320521 TI - The role of independent motion in object segmentation in the ventral visual stream: Learning to recognise the separate parts of the body. AB - This paper investigates how the visual areas of the brain may learn to segment the bodies of humans and other animals into separate parts. A neural network model of the ventral visual pathway, VisNet, was used to study this problem. In particular, the current work investigates whether independent motion of body parts can be sufficient to enable the visual system to learn separate representations of them even when the body parts are never seen in isolation. The network was shown to be able to separate out the independently moving body parts because the independent motion created statistical decoupling between them. PMID- 21320522 TI - Effects of object shape on the visual guidance of action. AB - Little is known of how visual coding of the shape of an object affects grasping movements. We addressed this issue by investigating the influence of shape perturbations on grasping. Twenty-six participants grasped a disc or a bar that were chosen such that they could in principle be grasped with identical movements (i.e., relevant sizes were identical such that the final grips consisted of identical separations of the fingers and no parts of the objects constituted obstacles for the movement). Nevertheless, participants took object shape into account and grasped the bar with a larger maximum grip aperture and a different hand angle than the disc. In 20% of the trials, the object changed its shape from bar to disc or vice versa early or late during the movement. If there was enough time (early perturbations), grasps were often adapted in flight to the new shape. These results show that the motor system takes into account even small and seemingly irrelevant changes of object shape and adapts the movement in a fine grained manner. Although this adaptation might seem computationally expensive, we presume that its benefits (e.g., a more comfortable and more accurate movement) outweigh the costs. PMID- 21320523 TI - Telomere elongation followed by telomere length reduction, in leukocytes from divers exposed to intense oxidative stress--implications for tissue and organismal aging. AB - Many cross-sectional studies have tried to assess the in vivo effect of oxidative stress on organismal aging in general and on telomere length dynamics specifically. Here we followed telomere length dynamics over a 12-month interval, in divers exposed to intense hyperbaric oxygen in comparison with an age-matched control group. Both groups were exposed to extreme physical activity, as well. Among the divers following the oxidative stress, significant telomere elongation was observed in granulocytes and naive T cells, but not in memory T cells and B cells. Telomere length in granulocytes was mildly elongated in the control group as well, a finding that may relate to the extreme physical activity to which they were exposed. While telomere elongation in naive T cells may be attributed to telomerase activation, we suggest that in granulocytes the elongation results from undifferentiated hematopoietic cells carrying longer telomeres that repopulate the peripheral hematopoietic compartment. This event might be accompanied by enhanced cell division within the repopulating pool. Since the aging of mammalian tissues can be attributed in part to the reduction in the replicative potential of self renewing cells, enhanced cell turnover under conditions of hyperbaric oxidative stress might be directly relevant to tissue and organismal aging. PMID- 21320524 TI - Defining community capacity building: is it possible? AB - OBJECTIVE: Community capacity building has emerged as an important element in effective health promotion practice. The literature highlights many interpretations of community capacity building. Like other broad concepts such as community and social capital, the term 'community capacity building' is not easily captured. The context in which capacity is built is important and possibly contributes to the array of definitions. METHOD: This paper reviews the definitions of community capacity building in health promotion beginning with early definitions in the 1990s to the latest offered by the WHO's Health Promotion Glossary in 2006. RESULTS: The definitions have a common formula with three features: (1) community capacity building is a process/an approach; (2) capacity building is a collection of domains often referred to as characteristics, aspects, capabilities or dimensions; and (3) definitions incorporate an outcome or the rationale for building capacity. CONCLUSION: The commonality in definition challenges the idea that the term 'capacity building' is fraught with a plethora of meanings. The formula can be utilised by communities needing to define capacity building for their own purposes, in their own contexts. PMID- 21320525 TI - Agreement of accelerometer and a physical activity questionnaire in adults with intellectual disabilities. AB - PURPOSE: To assess the level of agreement between accelerometer and proxy respondent questionnaire measurement of the physical activity levels of adults with intellectual disabilities. METHODS: In Glasgow, U.K., from May to September 2009, the main carer of participants with intellectual disabilities was asked to complete the International Physical Activity Questionnaire-Short Version, detailing the participants' regular physical activity levels. Participants were also invited to wear an ActiGraph GT1M accelerometer for seven consecutive days, during all waking hours. The level of agreement from the two measurements was compared using the Bland-Altman method. RESULTS: There is limited agreement between physical activity and sedentary behavior measured with accelerometer and proxy-respondent questionnaire. The 95% limits of agreement for both moderate activity and sedentary activity were -44.48 to 34.20 min per day and -8.41 to 6.79 h per day, respectively. As physical activity increased above 10 min per day, the agreement between the accelerometer and International Physical Activity Questionnaire-Short Version data decreased further. CONCLUSION: It remains uncertain whether questionnaire methods have sufficient reliability for use in surveillance of physical activity levels of adults with intellectual disabilities. PMID- 21320526 TI - Energy expenditure comparison: a pilot study of standing instead of sitting at work for obesity prevention. PMID- 21320527 TI - Characterization of a rat hypoxia-ischemia model where duration of hypoxia is determined by seizure activity. AB - Perinatal and early childhood asphyxia is common, debilitating and has few efficacious treatments. A hypoxia ischemia (HI) rat model that involves a unilateral ligation of the common carotid artery followed by a 60 min period of 8% oxygen hypoxia is often used to test proposed treatments. However, this HI protocol produces inconsistent infarction volumes due to the variability of individual rats to compensate for the ligated artery and hypoxia. Therefore, this HI model is problematic for experiments that prevent measurement of infarction volume, such as those that require analysis of homogenised brain tissue. We therefore aimed to find a simple and non-invasive predictor of infarction volume. Observations made prior, during and following HI in p26 rats showed that weight change 24 h following surgery was a strong predictor of infarction volume. The occurrence of a tonic clonic seizure during hypoxia was highly correlated with success of inducing an infarction, and for this reason we assessed whether ceasing the hypoxia for each rat following a tonic clonic seizure would produce a more consistent infarction volume. Using this procedure, infarction volumes measured at 3 and 15 days after surgery were significantly less variable, resulting in considerable improvements in statistical power compared with the original model. PMID- 21320528 TI - The effect of intraperitoneally administered dimethyl sulfoxide on absence-like epileptic activity of freely moving WAG/Rij rats. AB - Dimethyl sulfoxide (DMSO) is a widely used solvent for water-insoluble molecules and it has antioxidant, neuroprotective and cryopreservative effects. While DMSO is a regularly used solvent in research and a therapeutic agent, several cases of DMSO evoked seizures were reported in the literature. Therefore, we investigated the effect of different doses of DMSO on the absence-like epileptic activity of Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. We revealed that low doses of DMSO decreased whereas high doses of DMSO increased the absence-like epileptic activity of WAG/Rij rats. PMID- 21320529 TI - Ipsilateral, cabled sural nerve for a sciatic nerve defect: an experimental model in the rat. AB - The 10 mm rat sciatic nerve defect model is commonly used to investigate new strategies to improve functional recovery with segmental nerve defects. However, a lack of standardization makes comparisons between studies difficult. The present study aims to evaluate a standardized experimental model that can minimize the number of animals required for obtaining valid results and simulates a current treatment for human peripheral nerve injury defects. Eighteen cadaveric Sprague-Dawley rats were utilized in the anatomic arm of the study and 18 living Sprague-Dawley rats were used in the experimental arm. The results from the cadaveric study allowed us to create an ipsilateral, three-cable autologous sural nerve graft technique in the rat. This repair construct was evaluated with functional and histomorphometric analysis of nerve regeneration. The results support functional recovery of the sciatic nerve in all grafted animals. The use of an ipsilateral cabled sural nerve graft technique in the rat sciatic nerve defect model is a viable control group that utilizes a single incision, incurs minimal morbidity, and maintains muscle attachments. We conclude that this rat model can be used in various experimental trials in the field of peripheral nerve regeneration. PMID- 21320530 TI - A low-cost, portable, micro-controlled device for multi-channel LED visual stimulation. AB - Light emitting diodes (LEDs) are extensively used as light sources to investigate visual and visually related function and dysfunction. Here, we describe the design of a compact, low-cost, stand-alone LED-based system that enables the configuration, storage and presentation of elaborate visual stimulation paradigms. The core functionality of this system is provided by a microcontroller whose ultra-low power consumption makes it well suited for long lasting battery applications. The effective use of hardware resources is managed by multi-layered architecture software that provides an intuitive and user-friendly interface. In the configuration mode, different stimulation sequences can be created and memorized for ten channels, independently. LED-driving current output can be set either as continuous or pulse modulated, up to 500 Hz, by duty cycle adjustments. In run mode, multiple-channel stimulus sequences are automatically applied according to the pre-programmed protocol. Steady state visual evoked potentials were successfully recorded in five subjects with no visible electromagnetic interferences from the stimulator, demonstrating the efficacy of combining our prototyped equipment with electrophysiological techniques. Finally, we discuss a number of possible improvements for future development of our project. PMID- 21320531 TI - Design and assessment of a real time reverse transcription-PCR method to genotype single-stranded RNA male-specific coliphages (Family Leviviridae). AB - A real-time, reverse transcription-PCR (RT-qPCR) assay was developed to differentiate the four genogroups of male-specific ssRNA coliphages (FRNA) (family Leviviridae). As FRNA display a trend of source-specificity (human sewage or animal waste) at the genogroup level, this assay provides a tool to help identify the origin of fecal contamination. Primers and probes were designed using complete genomic sequences from 29 FRNA phages. The final selection of primer/probe sets were based on (i) ability to amplify a single, specific product, (ii) genogroup specificity, (iii) lack of cross-reactivity, and (iv) experimental reproducibility and sensitivity over a range of target concentrations. Assay time was reduced by using heat-released viral RNA rather than purified RNA. For quality assurance, a custom RNA molecule was employed as an internal, non-competitive control. The usefulness of this method to identify sources of fecal contamination was tested on a total of 49 FRNA phages isolated from various warm-blooded animals, sewage and combined sewage overflow. FRNA phages from animal wastes were genotyped as 86% I, 4% III Q-like and 9% IV. Two sewage isolates typed to genogroup I and combined sewage overflow isolates genotyped as 40% II and 52% III. Primer specificity designed from this comprehensive sequence database may better discriminate FRNA from different sources. PMID- 21320532 TI - Detecting protein-protein interactions in vesicular stomatitis virus using a cytoplasmic yeast two hybrid system. AB - Protein-protein interactions play an important role in many virus-encoded functions and in virus-host interactions. While a "classical" yeast two-hybrid system (Y2H) is one of the most common techniques to detect such interactions, it has a number of limitations, including a requirement for the proteins of interest to be relocated to the nucleus. Modified Y2H, such as the Sos recruitment system (SRS), which detect interactions occurring in the cytoplasm rather than the nucleus, allow proteins from viruses replicating in the cytoplasm to be tested in a more natural context. In this study, a SRS was used to detect interactions involving proteins from vesicular stomatitis virus (VSV), a prototypic non segmented negative strand RNA (NNS) virus. All five full-length VSV proteins, as well as several truncated proteins, were screened against each other. Using the SRS, most interactions demonstrated previously involving VSV phosphoprotein, nucleocapsid (N) and large polymerase proteins were confirmed independently, while difficulties were encountered using the membrane associated matrix and glycoproteins. A human cDNA library was also screened against VSV N protein and one cellular protein, SFRS18, was identified which interacted with N in this context. The system presented can be redesigned easily for studies in other less tractable NNS viruses. PMID- 21320533 TI - GABAA receptors in the posterior, but not anterior, ventral tegmental area mediate Ro15-4513-induced attenuation of binge-like ethanol consumption in C57BL/6J female mice. AB - GABA(A) receptors have been shown to modulate dopaminergic output from the ventral tegmental area (VTA) in studies of both natural and drug rewards, including alcohol. Ro15-4513, the imidazobenzodiazepine derivative and allosteric modulator at the GABA(A) receptor, reliably antagonizes the behavioral effects of alcohol. Various models of alcohol consumption show a decrease in consummatory behaviors, specific to ethanol, following acute administration of the drug. In the present study, Ro15-4513 was systemically administered, or microinjected into the anterior or posterior VTA, to explore the role of GABA(A) receptors at this region in modulating the high pattern of alcohol consumption by C57BL/6J inbred mice in the Drinking in the Dark (DID) model. Animals had 2h access to ethanol for 6 days prior to drug manipulations. Immediately before the seventh day of access, mice were systemically (I.P.) or site-specifically administered Ro15 4513. Systemic Ro15-4513 (at 10mg/kg) decreased binge-like ethanol intake in the DID paradigm. Additionally, there was a stepwise decrease in consumption following Ro15-4513 microinjection into the posterior VTA, with the highest dose significantly decreasing ethanol intake. There was no effect found following microinjection into the anterior VTA, nor was there an effect of systemic or intra-posterior VTA Ro15-4513 on consumption of a 5% sucrose solution or water. The present findings support a role for Ro15-4513 sensitive VTA-GABA(A) receptors in modulating binge-like ethanol consumption. Moreover, the work here adds to the growing body of literature suggesting regional heterogeneity in the VTA. PMID- 21320534 TI - Investigation of the Bcl-2 multimerisation process: structural and functional implications. AB - Bcl-2 plays a prominent role in regulating the function of mitochondria during respiration and in determining the threshold of apoptotic sensitivity. Despite its relevance, the mechanism through which these processes are achieved is still unknown. Using surface plasmon resonance technology to monitor Bcl-2 multimerisation we discovered that a simple dimeric model does not fit with experimental data. A molecular model of the experimentally observed Bcl-2 homomeric complex has been developed. Accordingly, using a panel of mutants we identified in the loop a critical region for the process of Bcl-2 multimerisation. Our results indicate that the Bcl-2 loop posttranscriptional changes can modulate its ability to make homo and hetero-complexes, ultimately leading to functional modulation, suggesting an intriguing relationship between the ability of Bcl-2 to form multimeric complexes and its multi-functional role as a membrane channel. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. PMID- 21320536 TI - CNK1 and other scaffolds for Akt/FoxO signaling. AB - FoxO transcription factors mediate anti-proliferative and pro-apoptotic signals and act as tumor suppressors in cancer. Posttranslational modifications including phosphorylation and acetylation regulate FoxO activity by a cytoplasmic-nuclear shuttle mechanism. Scaffold proteins coordinating signaling pathways in time and space play a critical role in this process. CNK1 acts as a scaffold protein in several signaling pathways controlling the function of FoxO proteins. An understanding of CNK1 and other scaffolds in the FoxO signaling network will provide insights how to release the tumor suppressor function of FoxO as a possibility to block oncogenic pathways. This article is part of a Special Issue entitled: P13K-AKT-FoxO axis in cancer and aging. PMID- 21320535 TI - Gastrins, iron homeostasis and colorectal cancer. AB - The peptide hormone gastrin has been identified as a major regulator of acid secretion and a potent mitogen for normal and malignant gastrointestinal cells. The importance of gastric acid in the absorption of dietary iron first became evident 50 years ago when iron deficiency anemia was recognized as a long-term consequence of partial gastrectomy. This review summarizes the connections between circulating gastrins, iron status and colorectal cancer. Gastrins bind two ferric ions with micromolar affinity and, in the case of non-amidated forms of the hormone, iron binding is essential for biological activity in vitro and in vivo. The demonstration of an interaction between gastrin and transferrin by biochemical techniques led to the proposal that gastrins catalyze the loading of transferrin with iron. Several lines of evidence, including the facts that the concentrations of circulating gastrins are increased in mice and humans with the iron overload disease hemochromatosis and that transferrin saturation positively correlates with circulating gastrin concentration, suggest the potential involvement of gastrins in iron homeostasis. Conversely, recognition that ferric ions play an unexpected role in the biological activity of gastrins may assist in the development of useful therapies for colorectal carcinoma and other disorders of mucosal proliferation in the gastrointestinal tract. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. PMID- 21320538 TI - Coxiella burnetii DNA in goat milk after vaccination with Coxevac((r)). AB - Q fever is a zoonotic disease caused by Coxiella burnetii, a species of bacteria that is distributed globally. A large Q fever epidemic is currently spreading throughout the Netherlands with more than 3500 human cases notified from 2007 to 2009. Governmental measures to prevent further spread of the disease imposed in December 2009 included vaccination of all dairy goats and sheep and, in parallel, bulk tank milk testing to identify contaminated goat and sheep farms. When bulk tank milk was found to contain C. burnetii DNA, pregnant ruminants were culled. An important, but unsolved issue in this policy was whether vaccine-derived C. burnetii DNA is excreted in milk after vaccination. Using real time PCR and single nucleotide polymorphism (SNP) genotyping techniques, we show here that within hours and up to 9 days after vaccination with Coxevac((r)), vaccine derived C. burnetii DNA can be detected in the milk of dairy goats. This is the first report describing DNAlactia of vaccine-derived DNA after vaccination with a completely inactivated vaccine. This finding had implications for the Dutch policy to combat the Q fever epidemic. A 2-week interval was introduced between vaccination and bulk tank milk testing to identify infected farms. PMID- 21320537 TI - Immunization of knock-out alpha/beta interferon receptor mice against lethal bluetongue infection with a BoHV-4-based vector expressing BTV-8 VP2 antigen. AB - New effective tools for vaccine strategies are necessary to limit the spread of bluetongue, an insect-transmitted viral disease of domestic and wild ruminants. In the present study, BoHV-4-based vector cloned as a bacterial artificial chromosome (BAC) was engineered to express the bluetongue virus (BTV) immune dominant glycoprotein VP2 provided of a heterologous signal peptide to its amino terminal and a trans-membrane domain to its carboxyl terminal (IgK-VP2gDtm), to allow the VP2 expression targeting to the cell membrane fraction. Based on adult alpha/beta interferon receptor knockout (IFNAR(-/-)) mice, a newly generated bluetongue laboratory animal model, a pre-challenge experiment was performed to test BoHV-4 safety on such immune-compromised animal. BoHV-4 infected IFNAR(-/-) mice did not show clinical signs even following the inoculation of BoHV-4 intra cerebrally, although many areas of the brain got transduced. IFNAR(-/-) mice intraperitoneally inoculated twice with BoHV-4-A-IgK-VP2gDtm at different time points developed serum neutralizing antibodies against BTV and showed a strongly reduced viremia and a longer survival time when challenged with a lethal dose of BTV-8. The data acquired in this pilot study validate BoHV-4-based vector as a safe and effective heterologous antigen carrier/producer for the formulation of enhanced recombinant immunogens for the vaccination against lethal bluetongue. PMID- 21320539 TI - Herd immunity after two years of the universal mass vaccination program against rotavirus gastroenteritis in Austria. AB - Austria was the first country in Europe implementing a universal mass vaccination program against rotavirus gastroenteritis (RV-GE) for all infants nationwide. Epidemiological data from a hospital based surveillance system show that incidence rates of children hospitalized with RV-GE decreased in 2009 compared to 2008 and compared to the prevaccination period 2001-2005. Decreasing hospitalization-rates from RV-GE were observed in children of all age groups, even in those not eligible for vaccination according to their age, suggesting herd immunity induced by universal mass vaccination against RV-GE. In 2009 the disease burden was highest in children below three months of age stressing the importance of the early start of the immunization course. PMID- 21320540 TI - A computationally optimized broadly reactive antigen (COBRA) based H5N1 VLP vaccine elicits broadly reactive antibodies in mice and ferrets. AB - Pandemic outbreaks of influenza are caused by the emergence of a pathogenic and transmissible virus to which the human population is immunologically naive. Recent outbreaks of highly pathogenic avian influenza (HPAI) of the H5N1 subtype are of particular concern because of the high mortality rate (60% case fatality rate) and novel subtype. In order to develop a vaccine that elicits broadly reactive antibody responses against emerging H5N1 isolates, we utilized a novel antigen design technique termed computationally optimized broadly reactive antigen (COBRA). The COBRA HA sequence was based upon HA amino acid sequences from clade 2 H5N1 human infections and the expressed protein retained the ability to bind the receptor, as well as mediate particle fusion. Non-infectious recombinant VLP vaccines using the COBRA HA were purified from a mammalian expression system. Mice and ferrets vaccinated with COBRA HA H5N1 VLPs had protective levels of HAI antibodies to a representative isolates from each subclade of clade 2. Furthermore, VLP vaccinated animals were completely protected from a lethal challenge of the clade 2.2 H5N1 virus A/Whooper Swan/Mongolia/244/2005. This is the first report describing the use of COBRA based antigen design. The COBRA HA H5N1 VLP vaccine elicited broadly reactive antibodies and is an effective influenza vaccine against HPAI virus. PMID- 21320542 TI - Novel gene isolated from Caligus rogercresseyi: a promising target for vaccine development against sea lice. AB - Sea lice (Copepoda, Caligidae) are the most widely distributed marine pathogens in the salmon industry in the last 30 years. Caligus rogercresseyi is the most important species affecting Chile's salmon industry. Vaccines against caligid copepods have the potential to be a cost-effective means of controlling the infestation and avoid many of the disadvantages of medicine treatments. However, research in the development of such vaccines has begun only recently and approaches used thus far have met with little or no success. In the present study, we characterized a novel gene (denoted as my32) from C. rogercresseyi which has the highest identity with the Lepeophtheirus salmonis gene akirin-2. To assess the function of the gene an RNA interference experiment was developed and a reduction in the number of ectoparasites on fish in the my32-dsRNA treated group was observed. The recombinant my32 protein was used in a vaccination challenge trial to evaluate its ability to protect against sea lice infestations. A significant reduction in the number of parasites per fish was observed at 24 days post-challenge. These results, together with the delay observed in the development of parasites from the vaccinated group suggest that the major effect of immunization was on the second parasite generation. The results of these experiments suggest that the my32 protein may be a promising target for vaccine development to control sea lice infestations in fish. PMID- 21320541 TI - A complex adenovirus vaccine against chikungunya virus provides complete protection against viraemia and arthritis. AB - Chikungunya virus, a mosquito-borne alphavirus, recently caused the largest epidemic ever seen for this virus. Chikungunya disease primarily manifests as a painful and debilitating arthralgia/arthritis, and no effective drug or vaccine is currently available. Here we describe a recombinant chikungunya virus vaccine comprising a non-replicating complex adenovirus vector encoding the structural polyprotein cassette of chikungunya virus. A single immunisation with this vaccine consistently induced high titres of anti-chikungunya virus antibodies that neutralised both an old Asian isolate and a Reunion Island isolate from the recent epidemic. The vaccine also completely protected mice against viraemia and arthritic disease caused by both virus isolates. PMID- 21320543 TI - Altered or impaired immune response upon vaccination in WNIN/Ob rats. AB - The present study was aimed to study the immune response in three months old male and female naive obese animals and upon hepatitis B vaccination in three months old female WNIN/Ob obese mutant rats, established at our institute in comparison with its lean litter mates. Altered immune profile was seen in naive obese mutant rats in terms of percentage of splenic CD8(+) cytotoxic cells in males and percentages of splenic CD3(+) T lymphocytes and CD4(+) T helper cells in females respectively. Furthermore these obese mutant rats also exhibited impaired immune response to hepatitis B vaccine with low specific Hepatitis B surface antigen (HBsAg) specific IgG response and splenic lymphocyte proliferative response to HBsAg compared to the lean counterpart. The loss of immunological memory following vaccination could be attributed to the metabolic and hormonal changes associated with obesity. This observation has implication in public health policies related to vaccination in developed as well as developing countries. PMID- 21320544 TI - A live attenuated strain of Yersinia pestis KIM as a vaccine against plague. AB - Yersinia pestis, the causative agent of plague, is a potential weapon of bioterrorism. Y. pestis evades the innate immune system by synthesizing tetra acylated lipid A with poor Toll-like receptor 4 (TLR4)-stimulating activity at 37 degrees C, whereas hexa-acylated lipid A, a potent TLR4 agonist, is made at lower temperatures. Synthesis of Escherichia coli LpxL, which transfers the secondary laurate chain to the 2'-position of lipid A, in Y. pestis results in production of hexa-acylated lipid A at 37 degrees C, leading to significant attenuation of virulence. Previously, we described a Y. pestis vaccine strain in which crp expression is under the control of the arabinose-regulated araC P(BAD) promoter, resulting in a 4-5 log reduction in virulence. To reduce the virulence of the crp promoter mutant further, we introduced E. coli lpxL into the Y. pestis chromosome. The chi10030(pCD1Ap) (DeltalpxP32::P(lpxL)lpxL DeltaP(crp21)::TT araC P(BAD)crp) construct likewise produced hexa-acylated lipid A at 37 degrees C and was significantly more attenuated than strains harboring each individual mutation. The LD(50) of the mutant in mice, when administered subcutaneously or intranasally was >10(7)-times and >10(4)-times greater than wild type, respectively. Mice immunized subcutaneously with a single dose of the mutant were completely protected against a subcutaneous challenge of 3.6*10(7) wild-type Y. pestis and significantly protected (80% survival) against a pulmonary challenge of 1.2*10(4) live cells. Intranasal immunization also provided significant protection against challenges by both routes. This mutant is an immunogenic, highly attenuated live Y. pestis construct that merits further development as a vaccine candidate. PMID- 21320545 TI - A novel broad-spectrum treatment for respiratory virus infections: influenza based defective interfering virus provides protection against pneumovirus infection in vivo. AB - Respiratory viruses represent a major clinical burden. Few vaccines and antivirals are available, and the rapid appearance of resistant viruses is a cause for concern. We have developed a novel approach which exploits defective viruses (defective interfering (DI) or protecting viruses). These are naturally occurring deletion mutants which are replication-deficient and multiply only when coinfection with a genetically compatible infectious virus provides missing function(s) in trans. Interference/protection is believed to result primarily from genome competition and is therefore usually confined to the virus from which the DI genome originated. Using intranasally administered protecting influenza A virus we have successfully protected mice from lethal in vivo infection with influenza A viruses from several different subtypes [1]. Here we report, contrary to expectation, that protecting influenza A virus also protects in vivo against a genetically unrelated respiratory virus, pneumonia virus of mice, a pneumovirus from the family Paramyxoviridae. A single dose that contains 1MUg of protecting virus protected against lethal infection. This protection is achieved by stimulating type I interferon and possibly other elements of innate immunity. Protecting virus thus has the potential to protect against all interferon sensitive respiratory viruses and all influenza A viruses. PMID- 21320546 TI - A comparative review on European-farmed finfish RNA viruses and their vaccines. AB - The diseases causing the highest ecological and socio-economical impacts in European farmed finfish are produced by RNA viruses. Salmon, trout, sea bream, sea bass, carp and turbot, suffer viral nervous necrosis produced by betanodaviruses (VNNV), infectious pancreatic necrosis produced by aquabirnaviruses (IPNV), viral haemorrhagic septicemia (VHSV) and infectious haematopoietic necrosis (IHNV) produced by novirhabdoviruses, spring viremia of carp produced by vesicular-like rhabdoviruses (SVCV), salmon pancreas disease and trout sleeping disease produced by alphaviruses (SAV) and infectious salmon anaemia produced by isaviruses (ISAV). There are not yet any effective treatments other than destroying all fish in infected farms, avoiding fish movements to and from infected areas and, in some particular cases, vaccination. The comparative study of the molecular characteristics of those RNA viruses and the state of knowledge of their vaccines, point to the development of new DNA vaccines for some RNA viruses, design of new mass delivery methods, maternal transfer of immunity, more extensive crossprotection studies between genotypes, use of safer all-fish plasmid control elements and study of DNA plasmid distribution after vaccination, as some of the major gaps that need urgent filling. In addition, to obtain similar protection levels to those produced by viral infections in survivors, live attenuated and/or some oil-adjuvanted inactivated virus vaccines, molecular adjuvants and/or other viral components (dsRNA or viral proteins interfering with fish defences), might have to be included in new DNA vaccine formulations. Furthermore, to be approved by the corresponding European authorities, fish viral DNA vaccines would also require the study of the persistence in fish of the introduced DNA, their possible impact to the aquatic environment and the acceptance of potential consumers. PMID- 21320547 TI - Immunogenicity and protection against Haemophilus parasuis infection after vaccination with recombinant virulence associated trimeric autotransporters (VtaA). AB - Haemophilus parasuis is the etiological agent of Glasser's disease in swine, characterized by fibrinous polyserositis, polyarthritis and meningitis. The lack of a vaccine against a broad spectrum of strains has limited the control of the disease. Recently, virulence associated trimeric autotransporters (VtaA) were described as antigenic proteins of H. parasuis. In this study 6 VtaA were produced as recombinant proteins and used to immunize snatch-farrowed, colostrum deprived piglets. Immunized animals developed specific systemic and mucosal antibodies. The protective capacity of the anti-VtaA antibodies was evaluated by the inoculation of 3 * 10(8) or 6 * 10(6) colony forming units (CFU) of the highly virulent strain Nagasaki. Vaccinated animals had a delayed course of disease and 33 or 57%, respectively, of the animals survived the lethal challenge. The partial protection achieved with the recombinant VtaA supports their potential as candidates to be included in future vaccine formulations against H. parasuis. PMID- 21320548 TI - Altered decamer and nonamer from an HLA-A0201-restricted epitope of Survivin differentially stimulate T-cell responses in different individuals. AB - Survivin is a universal tumor antigen that is being currently targeted in vaccine approaches against cancer. Our study here examined the immunogenicity of a novel variant of an HLA-A0201-binding decamer peptide from region 95 to 104 of Survivin (ELMLGEFLKL) with a T->M modification at position 3 in the peptide. We found that this new modified 10-mer peptide had enhanced HLA-A0201 binding and induced a stronger T-cell response over its wild type counterpart peptide (ELTLGEFLKL) in select HLA-A0201(+) normal donors. In addition, when compared to the previously characterized altered 96-104 peptide (LMLGEFLKL) from the same region of Survivin currently used in vaccine trials, we found that both peptides had similar immunogenicity, but donor T cells preferentially reacted strongly to either one or the other, but not strongly to both. These results suggest that these two closely related Survivin peptides yield distinct T-cell responses and that most individuals dominantly respond to one or the other altered peptide. We also found a novel association between positive reactivity to the new altered decamer Survivin peptide in some individuals and their expression of the HLA-C0701 allele along with HLA-A0201. Thus, vaccinating with both the 10-mer and 9-mer peptides would be required to immunize a maximum number of individuals in the HLA-A0201(+) population and could lead to more consistent T-cell responses against this region of Survivin. PMID- 21320549 TI - The immunogenicity and impact on nasopharyngeal carriage of fewer doses of conjugate pneumococcal vaccine immunization schedule. AB - The immunogenicity and impact on carriage of fewer doses of pneumococcal conjugate vaccine (PCV7) followed by booster with pneumococcal polysaccharide vaccine (PPV) were investigated. 684 infants were assigned randomly to one of the three groups that received one (A), two (B) or three (C) doses of PCV7 between 2 and 4 months of age, plus PPV at 10 months. Following primary vaccination protective antibody titers of >0.35 MUg/ml against the PCV7 serotypes combined increased significantly with the number of PCV7 doses, 44% vs. 77% vs. 94% (p<0.001), and correlated positively with the opsonophagocytic indices, but negatively with nasopharyngeal carriage of pneumococcus. The differences in antibody responses and pneumococcal carriage between the groups diminished following booster with PPV, implying that administration of one or two doses of PCV7, with a booster dose of PPV might lower the cost of protection against IPD in young children in resource poor countries. PMID- 21320550 TI - Sub-optimal prevalence of mumps antibodies in a population based study of young adults in Israel after 20 years of two dose universal vaccination policy. AB - BACKGROUND: A recent mumps outbreak in Israel despite an ongoing national program of a 2-dose universal childhood vaccination policy since 1988, raised questions regarding population immunity among young adults. OBJECTIVE: To assess the seroprevalence of mumps antibodies among young Israeli adults born after 1987 in order to determine evidence based vaccination policy. METHODS: We conducted a seroprevalence study of mumps IgG antibodies among 441 Israeli adults born in 1988-9, based on a representative sample of sera collected upon recruitment to mandatory military service in 2007. RESULTS: The overall seroprevalence of IgG antibody to mumps virus among 1988-9 born was 83.7%, 82.1% among males and 85.7% among females. Seroprevalence among 2007 recruits was similar to 1999 recruits (83.3%, P=0.89) and significantly lower than 1987 recruits (94.1%, P<0.0001). The absolute decrease between 2007 and 1987 for males was 13.1% (P<0.0001) and for females 7.0% (P=0.02). Seroprevalence was not significantly higher among native Israelis (84.9%) than among young adults born in the Commonwealth of Independent States (81.1%, P=0.46) and significantly higher compared to young adults born in Western Europe or North America (68.2%, P=0.045). CONCLUSIONS: Our findings indicate sub-optimal population seroprevalence despite a 2-dose universal childhood vaccination policy. This study allows better understanding of current mumps outbreaks in Israel and elsewhere following periods of low circulation of wild virus. These findings support mumps vaccination, even for populations and individuals that received two doses during childhood, as means for outbreak containment among young adults, especially in crowded settings, and serve as a reminder to the need for dynamic vaccination policy, supported by health promotion activities. PMID- 21320551 TI - Methodological considerations in ambulatory skin conductance monitoring. AB - Little is known how much skin conductance (SC) recordings from the fingers are affected by factors such as electrode site deterioration, ambient temperature (TMP), or physical activity (ACT), or by age, sex, race, or body mass index. We recorded SC, TMP, and ACT in 48 healthy control subjects for a 24-hour period, and calculated SC level (SCL), its standard deviation, the coefficient of SC variation, and frequency and amplitude of non-specific SC fluctuations. One method of assessing electrode site deterioration showed an average decline of 20%, while a second method found no significant change. All SC measures were higher during waking than sleep. Other factors influenced different measures in different ways. Thus, 24-hour SC recording outside the laboratory is feasible, but some measures need to be corrected for the influence of confounding variables. PMID- 21320552 TI - A novel approach to the physiological measurement of mental workload. AB - While performing a visuo-motor task under incrementally-varied levels of difficulty, individuals were probed with a variety of novel, task-irrelevant, auditory stimuli. To determine the effect of task load on cerebral-cortical processing of these stimuli, event-related potentials were recorded while participants performed the task. We found that N1, P2, P3 and late positive potential (LPP) component amplitudes were inversely related to task-difficulty. This suggests that a variant of the oddball paradigm - in which the stimulus stream comprises novel sounds - is capable of providing a reliable index of mental workload. PMID- 21320553 TI - Prenatal stress induces anxiety-like behavior together with the disruption of central serotonin neurons in mice. AB - Most pregnant women are at risk of showing some emotional abnormality, since some biological functions such as hormonal systems may dramatically change in pregnancy. Some of them may be exposed to strong stress as hesitation of positive drug therapies because of worries regarding adverse effects on the embryo. A growing body of evidence suggests that prenatal stress increases the vulnerability to neuropsychiatric disorders, including depression and anxiety. However, the mechanisms involved are still unknown. To clarify the influence of exposure to prenatal stress on emotional development, we examined behavioral responses in offspring exposed to weak- or strong-prenatal restraint stress. We found that offspring that had been exposed to strong stress displayed anxiety like behavior as determined by the elevated plus-maze test. It has been widely accepted that central serotonin (5-hydroxytryptamine; 5-HT) neurons play a critical role in emotional behaviors. Immunohistochemical studies showed that exposure to strong-prenatal restraint stress increased the expression of 5-HT positive cells in the dorsal raphe nuclei in mice. Moreover, under these conditions, tryptophan hydroxylase-like immunoreactivities were also dramatically increased. In contrast, these behavioral and neurochemical abnormalities were not observed in offspring that had been exposed to weak-prenatal restraint stress. These findings indicate that exposure to excessive prenatal stress induces anxiety-like behavior together with disruption of the development of 5-HT neurons in mice. PMID- 21320554 TI - A novel vector for a rapid generation of fiber-mutant adenovirus based on one step ligation and quick screening of positive clones. AB - The generation of fiber-modified adenoviral vector has proven difficult. In the paper, we developed a new system for rapid construction of fiber-modified adenoviral vector containing foreign peptides in the HI loop or C-terminal of the fiber knob. The new system was established through the following processes. First, a unique BamHI mutation was made in the genome of Ad5 without causing amino acid change. Second, two unique restriction enzymes BamHI and SfuI, both with sticky end, were introduced in the HI loop or C-terminal of Ad5 fiber knob. Third, a lacza expression cassette was placed between BamHI and SfuI sites for a quick identification of positive cloning based on white-blue color screening. This system allows generation of recombinant adenoviral vector by a single step, in vitro ligation followed by quick white-color positive clone screening. To prove the principle of the method, Ad5HI-RGD by modifying HI-loop of the fiber knob with RGD motif and Ad5Cter-PK7 by modifying C-terminal of the knob with poly lysine (pK7) were successfully generated in vitro. Ad5 with a knob modified in the HI loop of the fiber with Tat-PTD, NGR or SIKVAV peptide were also successfully developed. The transduction of the modified viruses for Hela, U87 MG and MDA-MB-231 cells was investigated in vitro compared with unmodified Ad5. In conclusion, the new vector system allows for a rapid generation of fiber-mutant adenovirus and provides useful tool for gene function analysis and cancer gene therapy. PMID- 21320555 TI - Control of adhA and sucR expression by the SucR regulator in Corynebacterium glutamicum. AB - The alcohol dehydrogenase gene adhA in Corynebacterium glutamicum is subject to a complex carbon source-dependent regulation mediated by RamA, RamB and GlxR. In this study we identified SucR as the fourth transcriptional regulator involved in expression control of the adhA gene. SucR specifically binds to the adhA promoter and acts as transcriptional repressor independent of the carbon source used. Furthermore, we found that SucR negatively controls the expression of its own gene. This negative autoregulation is mediated by binding of SucR to at least one of four identified binding sites located in the promoter region of sucR. EMSA experiments and subsequent sequence analysis led to the identification of the SucR consensus binding sequence YYAACAWMAW. This binding motif is different from the binding site (ACTCTAGGGG) recently described for SucR in the promoter region of the sucCD operon. However, we were not able to detect a specific interaction of purified SucR protein with this motif present in the sucCD promoter region. PMID- 21320556 TI - Mechanism of action of ribavirin in a novel hepatitis C virus replication cell system. AB - Ribavirin (RBV) is a potential partner of interferon (IFN)-based therapy for patients with chronic hepatitis C. However, to date, its anti-hepatitis C virus (HCV) mechanism remains ambiguous due to the marginal activity of RBV on HCV RNA replication in HuH-7-derived cells, which are currently used as the only cell culture system for robust HCV replication. We investigated the anti-HCV activity of RBV using novel cell assay systems. The recently discovered human hepatoma cell line, Li23, which enables robust HCV replication, and the recently developed Li23-derived drug assay systems (ORL8 and ORL11), in which the genome-length HCV RNA (O strain of genotype 1b) encoding renilla luciferase efficiently replicates, were used for this study. At clinically achievable concentrations, RBV unexpectedly inhibited HCV RNA replication in ORL8 and ORL11 systems, but not in OR6 (an HuH-7-derived assay system). The anti-HCV activity of RBV was almost cancelled by an inhibitor of equilibrative nucleoside transporters. The evaluation of the anti-HCV mechanisms of RBV proposed to date using ORL8 ruled out the possibility that RBV induces error catastrophe, the IFN-signaling pathway or oxidative stress. However, we found that the anti-HCV activity of RBV was efficiently cancelled with guanosine, and demonstrated that HCV RNA replication was notably suppressed in inosine monophosphate dehydrogenase (IMPDH)-knockdown cells, suggesting that the antiviral activity of RBV is mediated through the inhibition of IMPDH. In conclusion, we demonstrated for the first time that inhibition of IMPDH is a major antiviral target by which RBV at clinically achievable concentrations inhibits HCV RNA replication. PMID- 21320558 TI - Discovery of hepatitis E: the epidemic non-A, non-B hepatitis 30 years down the memory lane. AB - Hepatitis E was first recognised during an epidemic of hepatitis, which occurred in Kashmir Valley in 1978. The epidemic involved an estimated 52,000 cases of icteric hepatitis with 1700 deaths. The disease had unique clinical and epidemiological features. The epidemic was water-borne with highly compressed epidemic curve. Following the epidemic, secondary waves of hepatitis did not occur. Clinical profile was characterized by cholestasis in around 20% of patients. The disease predominantly occurred in young adults. There was increased incidence and severity of the disease in pregnant women. A subset of patients had distinctive liver histology with bile plugs in the canaliculi and formation of pseudo-ductules by hepatocytes around the bile plugs. All surviving patients had self limiting disease. Sera lacked serological markers of acute hepatitis A and hepatitis B. Based on these data, the possibility of another human hepatitis virus distinct from post-transfusion non-A, non-B hepatitis was postulated. Balayan et al. (1983) successfully transmitted the disease into himself by oral administration of pooled stool extracts of 9 patients from a non-A, non-B hepatitis outbreak which had occurred in a Soviet military camp located in Afghanistan. Reyes et al. (1990) cloned and sequenced hepatitis E virus genome. Over the years, hepatitis E was identified as a major health problem in developing countries with unsafe water supplies and poor sanitary disposal. Data from sero-surveys forced re-evaluation of the epidemiology of hepatitis E and gave an indirect indication to vocationally acquired HEV infections in industrialized countries. Soon, autochthonous hepatitis E was recognised as a clinical problem in such countries. Several animal species especially domestic swine, wild boar and wild deer were found to be reservoirs of hepatitis E virus genotype 3 & 4 in these countries. Human infections occur through intake of uncooked or undercooked meat of the infected animals and pig livers or sausages made from these livers and sold in supermarkets. Chronic hepatitis E resulting in rapidly progressive liver cirrhosis and end stage liver disease was described in organ transplant patients and those with other immunodeficiency states from many European countries. Two recombinant hepatitis E virus vaccines have successfully undergone phase 3 trials. PMID- 21320557 TI - Host genetic variation in susceptibility to Punta Toro virus. AB - Infection of small laboratory animals by Punta Toro virus (PTV), family Bunyaviridae, genus Phlebovirus, is a model for the study of the human pathogen Rift Valley fever virus (RVFV). We have identified inbred mouse strains with significant differences in host response to the Adames strain of PTV. Nine inbred strains of mice representing major branches in the Mus musculus phylogeny were inoculated subcutaneously with a high dose of PTV in survival experiments. Two inbred strains of mice, NZW/LacJ and 129S1/SvImJ, died ~4 days after PTV infection, whereas 7 other strains survived the challenge and showed no clinical signs of disease. Histologically, 129S1/SvImJ mice showed massive hepatocellular necrosis and had additional lesions in lung, brain, and spleen, whereas NZW/LacJ mice had mild piecemeal hepatocellular necrosis. PTV viral loads in the livers of infected mice were determined by reverse transcriptase quantitative PCR. Inbred mice from strains that showed clinical signs and succumbed to PTV infection had higher liver viral loads than did mice of resistant strains. Hybrid F1 mice were generated by crossing susceptible 129S1 and resistant FVB/N mice and tested for susceptibility. The hybrid F1 mice showed significantly higher viral loads in the liver than the resistant parental FVB/N mice, suggesting that susceptibility is dominant. These findings will enable an unbiased genetic approach to identify host genes mediating susceptibility to PTV. PMID- 21320559 TI - Epithelial-mesenchymal transition in chronic liver disease: fibrogenesis or escape from death? AB - The possibility that epithelial-mesenchymal transition (EMT) could contribute to hepatic fibrogenesis in chronic liver diseases as reported in other organs, particularly the kidney, reinforced the concept that activated hepatic stellate cells were not the only key players in the hepatic fibrogenic process and that other cell types, either hepatic (i.e. portal fibroblast) or extrahepatic (bone marrow-derived cells and circulating fibrocytes) could contribute to this process. The possibility of the rapid mobilization of a large amount of fibrogenic cells by EMT after liver tissue injury made this phenomenon a relevant and suitable target for anti-fibrogenic strategies. Following an initial enthusiasm for the discovery of this novel pathway in fibrogenesis and the publication of a several highly quoted papers, more recent research has started to cast serious doubts upon the real relevance of this phenomenon in human fibrogenetic disorders. The debate on the authenticity of EMT or at least on its real contribution to the fibrogenic process has become very animated, sometimes reaching levels of "religious" integralism. The overall result is a general confusion on the meaning and on the definition of several key aspects. The aim of this article is to analyze and discuss the evidence supporting or confuting this possibility in order to reach reasonable and useful conclusions. PMID- 21320560 TI - SLC40A1-R178G mutation and ferroportin disease. PMID- 21320561 TI - Effect of human beta-defensin-3 on the proliferation of fibroblasts on periodontally involved root surfaces. AB - Human beta-defensin-3 (HBD-3) has versatile antibacterial activity against oral bacteria and can promote the proliferation of fibroblasts. The goal of the present study was to investigate the effect of HBD-3 on attachment and proliferation of periodontal ligament cells (PDL) onto the periodontitis affected root surfaces. PDL cells were seeded onto healthy and diseased root specimens with scaling and root planing (SRP), SRP & HBD-3 (100 ng/ml), or SRP & HBD-3 (200 ng/ml) treatment for 1, 3, and 7 days incubation. The results showed that HBD-3, especially in the 200 ng/ml group, significantly promoted fibroblast attachment and proliferation onto the diseased root surfaces. The cell number in the HBD-3 group was much greater than in the group treated with SRP alone. On day 7, the cells in the HBD-3 were well-spread and formed a network similar to those on the surfaces of the healthy root specimens. These results suggest that HBD-3 could play an important role in antibacterial activity and fibroblast proliferation, thus promoting periodontal regeneration. Meanwhile, HBD-3 might act as a potent regeneration-promoter in infectious diseases. PMID- 21320562 TI - Donor human leukocyte antigen specific antibodies predict development and define prognosis in transplant glomerulopathy. AB - The pathogenesis of transplant glomerulopathy (TG) remains unclear, with evidence of human leukocyte antigen (HLA) antibodies as important contributors to the disease. We studied the risk factors and the associations of HLA antibodies in the development of TG. Sixty-one cases with morphologic features of TG were identified and compared with contemporaneous matched patients (without TG) from a 17-year period, all undergoing renal biopsy in a single center. Univariate risk factors for TG were previous glomerulitis [odds ratio (OR) 3.3, 95% confidence interval (95% CI) [1.2-9.4], p = 0.025), delayed graft function (OR 2.3 [1.0 5.1], p = 0.042), HLA class I presensitization defined by Luminex solid-phase immunoassays (OR 5.0 [2.3-11.0]. p < 0.001), and de novo posttransplant development of donor HLA specific antibody (DSA) (OR 4.7 [1.7-13.2], p = 0.002). Only DSA remained significantly associated with TG after adjustment (OR 3.8 [1.1 12.9], p = 0.032). DSA was detected in >50% of TG patients, suggesting HLA antibodies play a critical role in TG pathogenesis. TG patients with DSA had increased risk of graft loss (median graft survival 4.4-5.2 years), whereas patients with morphologic features of TG without DSA had similar graft survival compared with the non-TG group (median graft survival 15 years). Thus, DSA is a useful predictor for graft failure in TG patients. PMID- 21320563 TI - Arg753Gln polymorphism of the human Toll-like receptor 2 gene from infection to disease in pediatric tuberculosis. AB - The aim of this study is to examine the occurrence of the Arg753Gln polymorphism of the Toll-like receptor 2 (TLR2) gene in Turkish children with pulmonary and/or extrapulmonary tuberculosis (TB) disease compared with that in healthy children with latent TB infection (LTBI) and to assess the risk of progression from LTBI to active TB disease in children. The Arg753Gln polymorphism of the TLR2 gene was studied in 198 TB patients compared with 200 ethnically and age-matched children with LTBI. The culture confirmed TB patients were more frequently Arg753Gln heterozygous [odds ratio (OR) 5.05, 95% confidence interval (95% CI) 2.61-9.76, p = 0.00], and Gln allele frequency was significantly higher in the patient group (13.86% vs 3.5%, OR 4.40, 95% CI 2.34-8.30, p = 0.00). We also showed that the frequencies of the heterozygous Arg753Gln genotype and the Gln allele were significantly higher in patients with pulmonary TB alone and in patients with definitive pulmonary plus extrapulmonary TB than in children with LTBI. Our data suggest that the Arg753Gln polymorphism of the TLR-2 gene influences the speed of progression from infection to TB disease in children. Further investigations are needed to clarify whether this polymorphism has a strong impact on susceptibility to TB in children. PMID- 21320564 TI - Bioinformatics and the allergy assessment of agricultural biotechnology products: industry practices and recommendations. AB - Bioinformatic tools are being increasingly utilized to evaluate the degree of similarity between a novel protein and known allergens within the context of a larger allergy safety assessment process. Importantly, bioinformatics is not a predictive analysis that can determine if a novel protein will ''become" an allergen, but rather a tool to assess whether the protein is a known allergen or is potentially cross-reactive with an existing allergen. Bioinformatic tools are key components of the 2009 CodexAlimentarius Commission's weight-of-evidence approach, which encompasses a variety of experimental approaches for an overall assessment of the allergenic potential of a novel protein. Bioinformatic search comparisons between novel protein sequences, as well as potential novel fusion sequences derived from the genome and transgene, and known allergens are required by all regulatory agencies that assess the safety of genetically modified (GM) products. The objective of this paper is to identify opportunities for consensus in the methods of applying bioinformatics and to outline differences that impact a consistent and reliable allergy safety assessment. The bioinformatic comparison process has some critical features, which are outlined in this paper. One of them is a curated, publicly available and well-managed database with known allergenic sequences. In this paper, the best practices, scientific value, and food safety implications of bioinformatic analyses, as they are applied to GM food crops are discussed. Recommendations for conducting bioinformatic analysis on novel food proteins for potential cross-reactivity to known allergens are also put forth. PMID- 21320565 TI - Assessing attention in the zebrafish: Are we there yet? AB - Traditionally, rodent sustained attention models are used for studying the neurobiological underpinnings of attention, for assessing the disruptive and interactive effects of drugs and environmental toxins and for predicting the efficacy of pharmacotherapies for attention disorders. Virtually all-major psychiatric disorders are characterized by disturbances in attention or concentration. Additionally, many psychoactive drugs produce simultaneous effects on a variety of psychological processes. Behavioral measures in tasks designed to assess cognitive processes in rodents characterize and dissociate these multiple influences. While the zebrafish (Danio rerio) has been at the vanguard of neurobiological research and is increasing in popularity as a model organism for behavioral applications, their attentional capacity has not been fully assessed. Here we review some of the more popular animal models and discuss the utility of a choice discrimination zebrafish model. PMID- 21320566 TI - Identification of JAK2 mutations in canine primary polycythemia. AB - OBJECTIVE: Primary polycythemia in dogs is classified as a myeloproliferative syndrome with a chronic progressive course and unspecific symptoms. Diagnosis is based on exclusion criteria. In humans, the presence of an acquired recurrent mutation within the JAK2 gene has recently been identified in 90% of the patients with polycythemia vera. This mutation (V617F) is located in the pseudokinase domain of JAK2, leading to constitutive activation of the kinase responsible for the polycythemia. Detection of the mutation has now become a major diagnostic tool in humans for polycythemia vera diagnosis. As the canine JAK2 gene shares strong homology with its human counterpart, we looked for the presence of JAK2 mutations in dogs with an elevated hematocrit. MATERIALS AND METHODS: Direct sequencing of the JAK2 exon 14 was performed on DNA extracted from the peripheral blood of five dogs suspected of primary polycythemia. Mutant subclones were expressed in interleukin-3-dependent BaF3 cells and tested for cytokine independency. RESULTS: One dog presented with a three-base change in codons 617 and 618 of JAK2 giving rise to V617F and C618L mutations. By polymerase chain reaction product subcloning, we demonstrated the coexistence of the wild-type sequence and a triple mutant sequence, while DNA from buccal swab contained the wild-type sequence only. Transfection of BaF3 cells with the triple mutant cDNA, but not with the wild-type complementary DNA, resulted in cytokine-independent growth and constitutive signal transducer and activation of transcription 5 phosphorylation. CONCLUSIONS: Identical mutations of the JAK2 gene occur in humans and dogs, giving rise to a constitutively active JAK2 kinase, suggesting a common mechanism for human and canine diseases. Thus, common diagnostic tools and therapeutic approaches may be relevant. PMID- 21320567 TI - Regulation of MMP-9 expression by the A2b adenosine receptor and its dependency on TNF-alpha signaling. AB - OBJECTIVE: Macrophage- and vascular-derived matrix metalloproteinase (MMP)-9 plays an important role in neointima formation after vascular injury. The A2b adenosine receptor (A2bAR) elevates cyclic adenosine monophosphate and suppresses tumor necrosis factor-alpha (TNF-alpha) levels at baseline and after vascular injury. Considering the influences of TNF-alpha on MMP-9 expression and activity, here we examined the effect of the A2bAR on the expression of MMP-9 and its potential dependency on TNF-alpha. MATERIALS AND METHODS: We applied protein activity and mRNA analyses of MMP-9 in macrophages derived from A2bAR knockout (KO) and TNF-alpha receptor KO mice. We employed guidewire-induced femoral artery injuries on A2bAR KO and control mice and analyzed by immunohistochemistry MMP-9 expression in the neointima area. RESULTS: MMP-9 activity is somewhat less in resident A2bAR KO macrophages compared with wild-type cells. However, MMP-9 is increased in activated macrophages from A2bAR KO when TNF-alpha is further elevated, or in wild-type cells after TNF-alpha treatment. In accordance, A2bAR activation downregulates MMP-9 expression in wild-type macrophages, which is ablated in TNF-alpha receptor KO cells. A greater vascular lesion after femoral artery injury in A2bAR KO mice is associated with elevated TNF-alpha levels and augmented MMP-9, compared to control mice. CONCLUSIONS: Ablation of the A2bAR in activated macrophages increases MMP-9. A2bAR activation reduces MMP-9 expression, which depends on TNF-alpha and could contribute to the protective role of A2bAR in a vascular injury model. PMID- 21320568 TI - Chronic central leptin infusion differently modulates brain and liver insulin signaling. AB - Recent studies reported the impact of leptin on peripheral insulin sensitivity and glucose utilization. However, little is known concerning the effect of central leptin on hypothalamic and hepatic insulin efficiency. This study aimed to determine the consequence of chronic intra-cerebroventricular (ICV) leptin or murine leptin antagonist (MLA) infusion on hypothalamic and hepatic insulin signaling pathways, in rats. A 2-week central leptin infusion enhanced insulin dependent Akt phosphorylation in the liver without changing PTP-1B protein expression, associated to insulin receptor (IR) upregulation and reduced IRS-1 phosphorylation on Ser302 residue. In the hypothalamus, a chronic ICV leptin infusion induced PTP-1B associated with a specific decrease in insulin-dependent Akt phosphorylation. In contrast, a chronic MLA infusion did not alter IR and PTP 1B expressions in hypothalamus and liver. Our results underline a brain leptin dependent increase in hepatic insulin efficiency as mirrored by IR up-regulation, increased insulin-dependent Akt phosphorylation and reduced IRS-1 phosphorylation on Ser302 residue. PMID- 21320569 TI - Contralateral neuropathology in dorsal root ganglia in a rat model of noncompressive disc herniation. AB - Some cases of lumbar disc herniation with contralateral radiculopathy have been reported. Many investigators explained this clinical syndrome from several aspects. However, to our best knowledge, there is no explanation on the basis of molecular changes in the contralateral dorsal root ganglia (DRG) until now. We firstly explored the expression of activating transcription factor 3 (ATF3, a marker of nerve injury), glial fibrillary acidic protein (GFAP, a marker of satellite cells activation) in bilateral L5 DRG and spinal cord using immunohistochemistry after nucleus pulposus (NP) application onto the left L5 DRG exposed by unilateral facetectomy. Immunoblotting was used to detect the expression of tumor necrosis factor-alpha (TNF-alpha) in bilateral L5 DRG. We tested that ATF3-immunoreactive (IR) neurons, GFAP-IR satellite cells and TNF alpha expression in the contralateral DRG increased significantly after NP application. In the spinal cord, ATF3-IR motor neurons increased significantly after surgery, but GFAP-IR astrocytes were not significant. These results suggested that NP application on the unilateral DRG could induce nerve injury, satellite cells activation and upregulation of TNF-alpha expression in the contralateral DRG. In addition, our results indicated that motor neurons injury might play a significant role in contralateral changes. PMID- 21320570 TI - Differential gene expression of multiple chondroitin sulfate modification enzymes among neural stem cells, neurons and astrocytes. AB - Chondroitin sulfate/dermatan sulfate (CS/DS) polysaccharides have been reported to play a crucial role in the proliferation and maintenance of neural stem cells (NSCs). However, little is known about the structural changes and functional role of CS/DS chains in the differentiation of NSCs. Western blots of NSCs, neurons and astrocytes in culture, with three CS-polysaccharide antibodies of different specificities, revealed marked differences in CS structure among the three cell types. To confirm this finding, we measured gene expression levels of CS sulfotransferases and C5-epimerase in these cell types, as these are responsible for producing the high structural diversity of CS/DS. Expressions of chondroitin 4-O-sulfotransferase, chondroitin 6-O-sulfotransferase, and N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase mRNAs were low in cultures of differentiated neural cells, such as neurons and astrocytes, in comparison to NSCs. In contrast, expressions of uronyl 2-O-sulfotransferase and C5-epimerase mRNAs were higher in the differentiated neural cells than NSCs. Thus, we first provide evidence to support the hypothesis that CS/DS undergoes structural changes during NSC differentiation. The structural changes in CS/DS may be implicated in the regulation of NSC differentiation through interactions with growth/neurotrophic factors and cytokines. PMID- 21320571 TI - Analysis of mutations and the association between polymorphisms in the cerebral dopamine neurotrophic factor (CDNF) gene and Parkinson disease. AB - Neurotrophic factors support the survival of dopaminergic neurons. The cerebral dopamine neurotrophic factor (CDNF) is a novel neurotrophic factor with strong trophic activity on dopaminergic neurons comparable to that of glial cell line derived neurotrophic factor (GDNF). To investigate whether rare or common variants in CDNF are associated with Parkinson disease (PD), we performed mutation analysis of CDNF and a genetic association study between CDNF polymorphisms and PD. We screened 110 early-onset Parkinson disease (EOPD) patients for CDNF mutations. Allelic and genotype frequencies of 3 CDNF single nucleotide polymorphisms (SNPs) (rs1901650, rs7094179, and rs11259365) were compared in 215 PD patients and age- and sex-matched controls. We failed to identify any mutations in CDNF among the EOPD patient sample population. We observed a trend towards increased risk for PD in patients carrying the C allele of SNP rs7094179 (odds ratio (OR)=1.27, 95% confidence interval (CI) 0.96-1.67). Patients carrying the C allele were susceptible to PD in both dominant (CC+CA vs. AA; OR=7.20, 95% CI 0.88-59.1) and recessive (CA+AA vs. CC; OR=0.64, 95% CI 0.41 0.99) models. Genotype and allele frequencies of SNPs rs1901650 and rs11259365 did not differ between PD patients and controls. Our study suggests that the C allele of an intronic CDNF SNP (rs7094179) might be an allele for susceptibility to PD. Further studies with larger sample size are required to confirm our results. PMID- 21320573 TI - Retigeric acid B exerts antifungal effect through enhanced reactive oxygen species and decreased cAMP. AB - BACKGROUND: Retigeric acid B (RAB), a triterpene acid isolated from Lobaria kurokawae exerts antifungal effect. The present study was designed to elucidate the underlying mechanisms by which RAB regulates the proliferation and cell death of Candida albicans. METHODS: We measured the metabolic activity of C. albicans with WST1 Cell Proliferation and Cytotoxicity Assay Kit, analyzed the cell cycle by flow cytometry, visualized the ultrastructure by transmission electron microscopy (TEM) and investigated the apoptosis and necrosis induced by RAB using confocal microscopy. The reactive oxygen species (ROS) accumulation was determined by spectrophotometry, flow cytometry and fluorescent microscopy. The mtDeltapsi was detected using flow cytometry. And the levels of intracellular cAMP and ATP were measured with cAMP ELISA and ATP Assay Kits, respectively. RESULTS: The proliferation of the yeasts was blocked in G(2)/M phase by a low dose of RAB treatment and in G(1) phase at high concentration. When cultured in phosphate buffered saline (PBS) deprived of energy source, yeasts displayed the phenotype of death caused by accumulated ROS, mtDeltapsi hyperpolarization and dramatic decrease in ATP level in the presence of high dose of RAB. GENERAL SIGNIFICANCE: RAB inhibits the growth of C. albicans by stimulating ROS production and reducing intracellular cAMP. The ROS accumulation, mtDeltapsi hyperpolarization, ATP depletion and damaged plasma membrane integrity together mediate cell death of C. albicans induced by RAB. Our findings provide a novel molecular mechanism for exploring possible applications of lichen derived metabolites in fighting fungal infection in humans. PMID- 21320572 TI - From sequence to function: Insights from natural variation in budding yeasts. AB - BACKGROUND: Natural variation offers a powerful approach for assigning function to DNA sequence-a pressing challenge in the age of high throughput sequencing technologies. SCOPE OF REVIEW: Here we review comparative genomic approaches that are bridging the sequence-function and genotype-phenotype gaps. Reverse genomic approaches aim to analyse sequence to assign function, whereas forward genomic approaches start from a phenotype and aim to identify the underlying genotype responsible. MAJOR CONCLUSIONS: Comparative genomic approaches, pioneered in budding yeasts, have resulted in dramatic improvements in our understanding of the function of both genes and regulatory sequences. Analogous studies in other systems, including humans, demonstrate the ubiquity of comparative genomic approaches. Recently, forward genomic approaches, exploiting natural variation within yeast populations, have started to offer powerful insights into how genotype influences phenotype and even the ability to predict phenotypes. GENERAL SIGNIFICANCE: Comparative genomic experiments are defining the fundamental rules that govern complex traits in natural populations from yeast to humans. This article is part of a Special Issue entitled Systems Biology of Microorganisms. PMID- 21320575 TI - Development of gap junctional intercellular communication within the lateral wall of the rat cochlea. AB - Auditory function depends on gap junctional intercellular communication (GJIC) between fibrocytes within the cochlear spiral ligament, and basal cells and intermediate cells within stria vascularis. This communication within the lateral wall is hypothesized to support recirculation of K+ from perilymph to the intra strial space, and thus is essential for the high [K+] measured within endolymph, and the generation of the endocochlear potential. In rats, the [K+] within endolymph reaches adult levels by postnatal day 7 (P7), several days before hearing onset, suggesting that GJIC matures before auditory responses are detectable. In this study we have mapped the postnatal development of GJIC within the cochlear lateral wall, to determine the stage at which direct communication first exists between the spiral ligament and stria vascularis. Connexin 30 immunofluorescence revealed a progressive increase of gap junction plaque numbers from P0 onwards, initially in the condensing mesenchyme behind strial marginal cells, and spreading throughout the lateral wall by P7-P8. Whole-cell patch clamp experiments revealed compartmentalized intercellular dye-coupling in the lateral wall between P2 and P5. There was extensive dye-coupling throughout the fibrocyte syncytium by P7. Also, by P7 dye introduced to fibrocytes could also be detected within strial basal cells and intermediate cells. These data suggest that lateral wall function matures several days in advance of hearing onset, and provide anatomical evidence of the existence of a putative K+ recirculation pathway within the cochlear lateral wall. PMID- 21320574 TI - Time dependent changes in aortic tissue during cold storage in physiological solution. AB - BACKGROUND: Stored vascular tissues are employed in biomedical research for studies in imaging, in biomechanics, and/or in assessing vessel diseases. In the present study, the stability of aortic tissue in phosphate buffer saline (PBS) at 4 degrees C was monitored over a course of 10 days as determined by the rate of glucose permeation measured by optical coherence tomography (OCT) and validated by histology. METHODS AND RESULTS: The initial mean permeability through fresh porcine aorta was (2.32 +/- 0.46)* 10(-5)cm/s (n=5); after maintaining the tissue at 4 degrees C for 10 days, the mean rate was (7.37 +/- 0.41)* 10(-5)cm/s (n=4), an increase of nearly 300%. A z-test verified that a significant change in the permeability rate (p<0.05) had occurred after 4 days of 4 degrees C storage. Histology was used to quantify changes in tissue pore area. The increase in average pore area paralleled the increase in permeability rate over 10 days. CONCLUSIONS: These results suggest that (1) the structural integrity of aortic tissue at 4 degrees C is retained for at least the first three days after resection and (2) OCT is a powerful technology well suited for evaluating tissue structural integrity over time. GENERAL SIGNIFICANCE: Functional OCT imaging provides for a noninvasive and quantitative technique in determining the structural integrity of aortic tissue stored at 4 degrees C. This modality may be used for assessing the efficacy of other preservation techniques. PMID- 21320576 TI - Estradiol synthesis within the human brain. AB - Estradiol biosynthesis is catalyzed by the enzyme aromatase, the product of the CYP19A1 gene. Aromatase is expressed in the brain, where it is involved not only in the control of neuroendocrine events and reproduction, but also in the regulation of neural development, synaptic plasticity and cell survival. In this review we summarize the existing data related with the detection of aromatase in human brain, with particular emphasis in the so-called "non-primary reproductive" areas. Besides hypothalamus, amygdala and preoptic/septal areas, aromatase is expressed in certain regions of basal forebrain, cerebral cortex, hippocampus, thalamus, cerebellum and brainstem of the human brain. Aromatase in human brain is produced by neurons, but there is also an astrocyte subpopulation that constitutively expresses the enzyme. The use of different methodological approaches, including the in vivo analysis by positron emission tomography of human subjects, has permitted to draw a general map of human brain aromatase, but the detailed distribution map is still far to be completed. On the other hand, despite the fact that there is only one aromatase protein, there are multiple mRNA transcripts that differ in the 5'-untranslated region, where regulatory elements reside. To date, some of the aromatase transcripts characteristic of cerebral cortex, as well as of human cell lines of neural origin, have been identified. This characteristic may confer tissue or even region-specific regulation of the expression and therefore it is conceivable to develop selective aromatase modulators to regulate the expression of the enzyme in the human brain. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain. PMID- 21320577 TI - Regional and laminar differences in antigen profiles and spatial distributions of astrocytes in the mouse hippocampus, with reference to aging. AB - The heterogeneity of astrocytes is of growing interest, because this information is now considered to be crucial for understanding the diverse roles of astrocytes, for example, support and nutrition for neurons, and modulation of synaptic plasticity. In this study, we stereologically estimated the regional and laminar differences in antigen profiles and spatial distributions of astrocytes in the young adult (2-month-old) and middle-aged (10-month-old) mouse hippocampus. Here we used two established astrocyte markers, that is, glial fibrillary acidic protein (GFAP) and S100beta, to identify the astrocyte population. In addition, we examined the patterns of expression of sex determining region Y-box 2 (Sox2) in the hippocampus. The majority of astrocytes expressed Sox2, and few regional and laminar differences were observed in the expression ratios of Sox2 in astrocytes. GFAP-negative astrocytes were specifically seen in the strata pyramidale and lucidum of the ventral CA3 region. S100beta-negative astrocytes were mainly found in the hilus of the dorsal and ventral dentate gyrus. Antigen profiles of astrocytes defined by Sox2, GFAP, and S100beta were rather constant until middle age. We then estimated the heterogeneity in spatial distributions of astrocytes. The numbers of astrocytes in the stratum lacunosum-molecular of the dorsal part of Ammon's horn were significantly larger in the middle-aged mice than in young adult mice. On the contrary, the astrocyte numbers in the stratum oriens of Ammon's horn showed significant age-dependent decline. Despite such changes, the total number of astrocytes in the whole area of the hippocampus showed no differences between young adult and middle-aged mice. The present data may work as an essential anatomical reference to understand the heterogeneity of astrocytes in the hippocampus. PMID- 21320578 TI - BL-1023 improves behavior and neuronal survival in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-intoxicated mice. AB - The therapeutic potential of BL-1023, a chemical combination of L-3,4 dihydroxyphenylalanine (L-DOPA) and gamma-aminobutyric acid (GABA), was investigated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxicated mice. Such animals exhibit nigrostriatal degeneration, characteristic of human Parkinson's disease. Drug was administered during and after the development of MPTP-induced nigrostriatal lesions followed by measures of motor function and behavior, surviving nigrostriatal dopaminergic neurons and termini, and striatal dopamine levels. When administered after lesion development, BL-1023 improved motor function of MPTP-mice as measured by rotarod, total floor and vertical plane movements, and stereotypic movements in open field activity tests compared to MPTP-mice without treatment. This also paralleled modest nigral dopaminergic neuronal protection. Such significant improvements in motor function, behaviors, and dopaminergic neuronal numbers were not seen when BL-1023 was administered during MPTP-induced lesion development. The data demonstrate select abilities of BL-1023 to increase dopaminergic neuronal survival and improve motor function in MPTP-mice. PMID- 21320579 TI - Multiple origins of cholinergic innervation of the cochlear nucleus. AB - Acetylcholine (Ach) affects a variety of cell types in the cochlear nucleus (CN) and is likely to play a role in numerous functions. Previous work in rats suggested that the acetylcholine arises from cells in the superior olivary complex, including cells that have axonal branches that innervate both the CN and the cochlea (i.e. olivocochlear cells) as well as cells that innervate only the CN. We combined retrograde tracing with immunohistochemistry for choline acetyltransferase to identify the source of ACh in the CN of guinea pigs. The results confirm a projection from cholinergic cells in the superior olivary complex to the CN. In addition, we identified a substantial number of cholinergic cells in the pedunculopontine tegmental nucleus (PPT) and the laterodorsal tegmental nucleus (LDT) that project to the CN. On average, the PPT and LDT together contained about 26% of the cholinergic cells that project to CN, whereas the superior olivary complex contained about 74%. A small number of additional cholinergic cells were located in other areas, including the parabrachial nuclei.The results highlight a substantial cholinergic projection from the pontomesencephalic tegmentum (PPT and LDT) in addition to a larger projection from the superior olivary complex. These different sources of cholinergic projections to the CN are likely to serve different functions. Projections from the superior olivary complex are likely to serve a feedback role, and may be closely tied to olivocochlear functions. Projections from the pontomesencephalic tegmentum may play a role in such things as arousal and sensory gating. Projections from each of these areas, and perhaps even the smaller sources of cholinergic inputs, may be important in conditions such as tinnitus as well as in normal acoustic processing. PMID- 21320581 TI - 'Personalised medicine' through 'personalised medicines': time to integrate advanced, non-invasive imaging approaches and smart drug delivery systems. AB - In this Commentary, the authors briefly discuss the status of efforts to individualize therapeutic interventions. They differentiate between the widely discussed idea of further shaping 'personalized medicine' approaches by using (new) biomarkers and (molecular) imaging techniques and the much less debated topic of 'personalized medicines': medicines, often carrier based, specifically geared to treat the individual patient optimally. An example where 'personalized medicine' is achieved by 'personalized medicines' is described: a smart drug delivery system is activated at the target site by non-invasive radiation (focused ultrasonic radiation, FU) while this spatial and temporal release process is guided and monitored by MRI (Magnetic Resonance Imaging guided High Intensity Focused Ultrasonic, MRIgHIFU). PMID- 21320580 TI - Complex repeat structures and novel features in the mitochondrial genomes of the diatoms Phaeodactylum tricornutum and Thalassiosira pseudonana. AB - The mitochondrial genome of the raphid pennate diatom Phaeodactylum tricornutum has several novel features compared with the mitochondrial genomes of the centric diatom Thalassiosira pseudonana and the araphid pennate diatom Synedra acus. It is almost double the size (77,356 bp) due to a 35,454 bp sequence block consisting of an elaborate combination of direct repeats, making it the largest stramenopile (heterokont) mitochondrial genome known. In addition, the cox1 gene has a +1 translational frameshift involving Pro codons CCC and CCT, the first translational frameshift to be detected in an algal mitochondrial genome. The nad9 and rps14 genes are fused by the insertion of an in-frame sequence and cotranscribed. The nad11 gene is split into two parts corresponding to the FeS and molybdate-binding domains, but both parts are still on the mitochondrial genome, in contrast to the brown algae where the second domain appears to have been transferred to the nucleus. In contrast to P. tricornutum, the repeat region of T. pseudonana consists of a much smaller 4790 bp string of almost identical double-hairpin elements, evidence of slipped-strand mispairing and active gene conversion. The diatom mitochondrial genomes have undergone considerable gene rearrangement since the three lineages of diatoms diverged, but all three have kept their repeat regions segregated from their relatively compact coding regions. PMID- 21320582 TI - SiRNA delivery with functionalized carbon nanotubes. AB - Carbon nanotubes (CNTs) have been studied for drug, antigen and nucleic acid delivery both in vitro and in vivo. Due to their nano-needle structure, they are supposed to cross the plasma membrane and enter directly into the cytoplasm likely upon an endocytosis-independent mechanism without inducing cell death. In this study, two cationically functionalized CNTs (CNT-PEI and CNT-pyridinium) were investigated for siRNA delivery. Both functionalized CNTs complexed siRNA and showed 10-30% silencing activity and a cytotoxicity of 10-60%. However, in terms of reduced toxicity or increased silencing activity, CNT-PEI and CNT pyridinium did not show an added value over PEI and other standard transfection systems. Probably, the type of functionalization of carbon nanotubes might be a key parameter to obtain an efficient and non-cytotoxic CNT-based delivery system. Nevertheless, in view of the present results and importantly also of the non degradability of CNTs, preference should currently be given to designing biodegradable carriers which mimic the needle structure of CNTs. PMID- 21320583 TI - Analysis on Actinobacillus pleuropneumoniae LuxS regulated genes reveals pleiotropic roles of LuxS/AI-2 on biofilm formation, adhesion ability and iron metabolism. AB - LuxS is an enzyme involved in the activated methyl cycle and the by-product autoinducer-2 (AI-2) was a quorum sensing signal in some species. In our previous study, the functional LuxS in AI-2 production was verified in the porcine respiratory pathogen Actinobacillus pleuropneumoniae. Enhanced biofilm formation and reduced virulence were observed in the luxS mutant. To comprehensively understand the luxS function, in this study, the transcriptional profiles were compared between the A. pleuropneumoniae luxS mutant and its parental strain in four different growth phases using microarray. Many genes associated with infection were differentially expressed. The biofilm formation genes pgaABC in the luxS mutant were up-regulated in early exponential phase, while 9 genes associated with adhesion were down-regulated in late exponential phase. A group of genes involved in iron acquisition and metabolism were regulated in four growth phases. Phenotypic investigations using luxS mutant and both genetic and chemical (AI-2) complementation on these virulence traits were performed. The results demonstrated that the luxS mutant showed enhanced biofilm formation and reduced adhesion ability and these effects were not due to lack of AI-2. But AI-2 could increase biofilm formation and adhesion of A. pleuropneumoniae independent of LuxS. Growth under iron restricted condition could be controlled by LuxS through AI-2 production. These results revealed pleiotropic roles of LuxS and AI 2 on A. pleuropneumoniae virulence traits. PMID- 21320584 TI - The role of the phoPQ operon in the pathogenesis of the fully virulent CO92 strain of Yersinia pestis and the IP32953 strain of Yersinia pseudotuberculosis. AB - At the genomic level, Yersinia pestis and Yersinia pseudotuberculosis are nearly identical but cause very different diseases. Y. pestis is the etiologic agent of plague; whereas Y. pseudotuberculosis causes a gastrointestinal infection primarily after the consumption of contaminated food. In many gram-negative pathogenic bacteria, PhoP is part of a two-component global regulatory system in which PhoQ serves as the sensor kinase, and PhoP is the response regulator. PhoP is known to activate a number of genes in many bacteria related to virulence. To determine the role of the PhoPQ proteins in Yersinia infections, primarily using aerosol challenge models, the phoP gene was deleted from the chromosome of the CO92 strain of Y. pestis and the IP32953 strain of Y. pseudotuberculosis, leading to a polar mutation of the phoPQ operon. We demonstrated that loss of phoPQ from both strains leads to a defect in intracellular growth and/or survival within macrophages. These in vitro data would suggest that the phoPQ mutants would be attenuated in vivo. However, the LD(50) for the Y. pestis mutant did not differ from the calculated LD(50) for the wild-type CO92 strain for either the bubonic or pneumonic murine models of infection. In contrast, mice challenged by aerosol with the Y. pseudotuberculosis mutant had a LD(50) value 40* higher than the wild type strain. These results demonstrate that phoPQ are necessary for full virulence by aerosol infection with the IP32953 strain of Y. pseudotuberculosis. However, the PhoPQ proteins do not play a significant role in infection with a fully virulent strain of Y. pestis. PMID- 21320585 TI - Biological and virulence characteristics of Salmonella enterica serovar Typhimurium following deletion of glucose-inhibited division (gidA) gene. AB - Salmonella enterica serovar Typhimurium is a frequent cause of enteric disease due to the consumption of contaminated food. Identification and characterization of bacterial factors involved in Salmonella pathogenesis would help develop effective strategies for controlling salmonellosis. To investigate the role of glucose-inhibited division gene (gidA) in Salmonella virulence, we constructed a Salmonella mutant strain in which gidA was deleted. Deletion of gidA rendered Salmonella deficient in the invasion of intestinal epithelial cells, bacterial motility, intracellular survival, and induction of cytotoxicity in host cells. Deletion of gidA rendered the organism to display a filamentous morphology compared to the normal rod-shaped nature of Salmonella. Furthermore, a significant attenuation in the induction of inflammatory cytokines and chemokines, histopathological lesions, and systemic infection was observed in mice infected with the gidA mutant. Most importantly, a significant increase in LD(50) was observed in mice infected with the gidA mutant, and mice immunized with the gidA mutant were able to survive a lethal dose of wild-type Salmonella. Additionally, deletion of gidA significantly altered the expression of several bacterial factors associated with pathogenesis as indicated by global transcriptional and proteomic profiling. Taken together, our data indicate GidA as a potential regulator of Salmonella virulence genes. PMID- 21320586 TI - Pregnancy reduces the genetic resistance of C57BL/6 mice to Listeria monocytogenes infection by intragastric inoculation. AB - In this study, we compared genetically resistant C57BL/6 and susceptible A/J mice for their resistance to Listeria monocytogenes infection during pregnancy. Intragastric infection with modest numbers of bacterial cells (10(5) CFU) caused reproducible fetal infection and abortion in both mouse strains. Bioluminescence imaging demonstrated dissemination of L. monocytogenes cells from maternal to fetal organs within 3 days of intragastric infection. Although non-pregnant C57BL/6 mice were significantly more resistant to infection than non-pregnant A/J mice, C57BL/6 and A/J mice had similar microbial loads (CFU) in maternal and fetal tissues during pregnancy. Inflammation and necrosis, however, were more severe in A/J mice as evaluated by semi-quantitative histopathology. Although the microbial load in fetal tissues was similar for all fetuses within a single uterus, inflammation and necrosis varied among individual fetuses and placentas. We also noted that the uterus is a target for L. monocytogenes infection in non pregnant mice. PMID- 21320588 TI - Glucose-induced endoplasmic reticulum stress is independent of oxidative stress: A mechanistic explanation for the failure of antioxidant therapy in diabetes. AB - Oxidative stress contributes to the pathogenesis of diabetes and its complications. However, a large number of interventional studies have failed to show any health benefits of antioxidants. The overwhelming failure of antioxidant therapy to prevent disease can be explained by inadequacy of the doses of antioxidants used, short duration of therapy, or poor timing of initiation of the supplementation. A more likely reason for failure of antioxidants to reduce diabetes-related complications is the multiplicity of mechanisms of glucotoxicity that are independent of oxidative stress. Recently, endoplasmic reticulum (ER) stress has emerged as an important contributor to diabetes-related complications. Multiple lines of experimental evidence indicate that ER stress in endothelial cells can be uncoupled from oxidative stress induced by hyperglycemia, and antioxidants can ameliorate the latter without altering the ER stress. These observations provide a novel mechanistic explanation for the failure of antioxidant therapy in interventional clinical trials. PMID- 21320587 TI - Neuroinflammation and the plasticity-related immediate-early gene Arc. AB - Neurons exist within a microenvironment that significantly influences their function and survival. While there are many environmental factors that can potentially impact neuronal function, activation of the innate immune system (microglia) is an important element common to many neurological and pathological conditions associated with memory loss. Learning and memory processes rely on the ability of neurons to alter their transcriptional programs in response to synaptic input. Recent advances in cell-based imaging of plasticity-related immediate-early gene (IEG) expression have provided a tool to investigate plasticity-related changes across multiple brain regions. The activity-regulated, cytoskeleton-associated IEG Arc is a regulator of protein synthesis-dependent forms of synaptic plasticity, which are essential for memory formation. Visualisation of Arc provides cellular level resolution for the mapping of neuronal networks. Chronic activation of the innate immune system alters Arc activity patterns, and this may be a mechanism by which it induces the cognitive dysfunction frequently associated with neuroinflammatory conditions. This review discusses the use of Arc expression during activation of the innate immune system as a valid marker of altered plasticity and a predictor of cognitive dysfunction. PMID- 21320589 TI - Redox activity of alpha-synuclein-Cu is silenced by Zn7-metallothionein-3. AB - The aggregation of alpha-synuclein (alpha-Syn), the major component of intracellular Lewy body inclusions in dopaminergic neurons of the substantia nigra, plays a critical role in the etiology of Parkinson disease (PD). Long-term effects of redox-active transition metals (Cu, Fe) and oxidative chemical imbalance underlie the disease progression and neuronal death. In this work, we provide evidence that a brain metalloprotein, Zn7-metallothionein-3 (Zn7MT-3), possesses a dynamic role in controlling aberrant protein-copper interactions in PD. We examined the properties of the alpha-Syn-Cu(II) complex with regard to molecular oxygen, the biological reducing agent ascorbate, and the neurotransmitter dopamine. The results revealed that under aerobic conditions alpha-Syn-Cu(II) possesses catalytic oxidase activity. The observed metal centered redox chemistry significantly promotes the production of hydroxyl radicals and alpha-Syn oxidation and oligomerization, processes considered critical for cellular toxicity. Moreover, we show that Zn7MT-3, through Cu(II) removal from the alpha-Syn-Cu(II) complex, efficiently prevents its deleterious redox activity. We demonstrate that the Cu(II) reduction by thiolate ligands of Zn7MT-3 and the formation of Cu(I)4Zn4MT-3, in which an unusual oxygen-stable Cu(I)4-thiolate cluster is present, comprise the underlying molecular mechanism by which alpha-Syn and dopamine oxidation, alpha-Syn oligomerization, and ROS production are abolished. These studies provide new insights into the bioinorganic chemistry of PD. PMID- 21320591 TI - Effects of S-(3,4-dichlorobenzyl) isothiourea on different cellular events in the cyanobacterium Anabaena sp. strain PCC 7120. AB - S-(3, 4-dichlorobenzyl) isothiourea (A22) has been reported to specifically inhibit the function of MreB, an actin-like protein in rod-shaped bacteria. This study investigated the role of A22 in cyanobacterium Anabaena sp. strain PCC 7120, which can form nitrogen-fixing heterocysts under combined-nitrogen deprivation. Results indicated that A22 could inhibit cell growth, cause abnormal cellular morphology and bring about asymmetric cell division and irregular DNA distribution. However, A22 has little effect on heterocyst formation. An A22 resistant mutant named C23 was isolated by growing cells on A22-containing plates. It had normal appearance of cell shape, division and DNA content when treated by A22. However, this mutant retained a wild-type allele of mreB. PMID- 21320590 TI - Prenatal nicotine exposure in rhesus monkeys compromises development of brainstem and cardiac monoamine pathways involved in perinatal adaptation and sudden infant death syndrome: amelioration by vitamin C. AB - Maternal smoking during pregnancy greatly enhances perinatal morbidity/mortality and is the major risk factor for Sudden Infant Death Syndrome (SIDS). Studies in developing rodents indicate that nicotine is a neuroteratogen that targets monoamine pathways involved in the responses to hypoxia that are in turn, hypothesized to contribute to these adverse events. We administered nicotine to pregnant Rhesus monkeys from gestational day 30 through 160 by continuous infusion, achieving maternal plasma levels comparable to those in smokers; we examined neurochemical parameters immediately after Cesarean delivery at the end of the exposure period. Nicotine evoked elevations in brainstem serotonin levels and serotonin turnover, indicating hyperactivity of these pathways. The same treatment evoked a deficit in cardiac norepinephrine levels. Both effects were offset by coadministration of the antioxidant, Vitamin C. Brainstem serotonin hyperinnervation is a hallmark of SIDS, and the hyperactivity seen here can also account for the downregulation of serotonin receptors noted in this disorder. Deficient cardiac sympathetic innervation is also consistent with increased vulnerability to hypoxia during delivery or in the agonal event in SIDS. Our results thus indicate that nicotine exposure in a primate model produces brainstem and autonomic abnormalities of the key monoamine systems that govern the response to hypoxia, indicate an important role of oxidative stress in the adverse effects, and point to potential amelioration strategies that could offset these particular effects of nicotine. PMID- 21320592 TI - Profound differences in the transcriptome of Campylobacter jejuni grown in two different, widely used, microaerobic atmospheres. AB - It was noted that quantitative and qualitative differences occurred between the growth of Campylobacter in microaerobic atmospheres provided by a gas replacement jar and that in a modular atmosphere controlled system cabinet, despite the fact that oxygen levels were comparable. Hydrogen was, however, only present in the replacement mixture (3%). Investigations were therefore carried out to examine any accompanying physiological or transcriptional differences. Growth curves and motility studies using Campylobacter jejuni HPC5 showed that cultures growing in the cabinet were impaired, but only in the early stages of growth compared to growth in the jar. However, transcriptome studies highlighted profound changes in the transcript profiles of exponential cultures grown in the cabinet compared to the jar, including genes indicative of oxidative stress. Genes involved in detoxification, synthesis and modification of macromolecules, probable prophage genes and genes associated with inhibition of natural transformation showed relative increases in expression in the cabinet. Conversely, genes that function in energy metabolism, chaperones, heat shock and motility were increased in the jar, which was indicative of balanced growth. This work highlights the need to carefully annotate the different methods of atmosphere generation in the description of experiments in microarray databases; the assessment of these experimental details is crucial to overcome difficulties in comparing transcriptomic studies of campylobacter cultures between different laboratories. PMID- 21320593 TI - Natural roles of antimicrobial peptides in microbes, plants and animals. AB - Antimicrobial peptides (AMPs) are ribosomally synthesized natural antibiotics that are crucial effectors of innate immune systems in all living organisms. AMPs are diverse peptides, differing in their amino acid composition and structure, that generally display rapid killing and broad-spectrum antimicrobial activities. Therefore, AMPs have high potential for therapeutic use in healthcare and agriculture. This review focuses on in vivo studies relating how organisms - bacteria, plants, insects and mammals - employ AMPs in their interactions with microbial competitors, pathogens and symbionts. PMID- 21320594 TI - Differential functional properties of chromosomal- and plasmid-encoded H-NS proteins. AB - The nucleoid-associated protein H-NS can be either chromosomal- or plasmid encoded. We provide in this report evidence indicating that chromosomal- and plasmid-encoded H-NS proteins may differ in their functional properties. The modulatory function of chromosomal H-NS is antagonized by the H-NST(EPEC) protein. We show that the H-NS protein encoded by the IncHI plasmid R27 (H NS(R27)) is less sensitive to H-NST(EPEC) antagonism than its chromosomal counterpart. H-NS(R27) plays a relevant role by modulating R27 conjugation in response to temperature. Hence, we suggest that this modulator has evolved to avoid the deregulation of R27 conjugation by H-NST(EPEC)-like proteins. PMID- 21320595 TI - Rapid genotyping of Achromobacter xylosoxidans, Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa and Stenotrophomonas maltophilia isolates using melting curve analysis of RAPD-generated DNA fragments (McRAPD). AB - Typing of bacteria is important for monitoring newly emerging pathogens and for examining local outbreaks. We evaluated the randomly amplified polymorphic DNA technique in combination with melting curve analysis (McRAPD) of the amplified DNA fragments to genotype isolates from five Gram-negative species, i.e. Achromobacter xylosoxidans, Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa and Stenotrophomonas maltophilia. By determining the melting temperature peaks of the amplified DNA fragments, we were able to distinguish the different genotypes of isolates, as they had been assessed by other genotyping techniques, i.e. agarose gel electrophoresis of RAPD fragments, multilocus sequence typing and/or AFLPTM. According to our results, McRAPD may offer the possibility of genotyping a limited number of bacterial isolates, e.g. in case of suspicion of hospital outbreak, via a less costly, more rapid, less laborious and more user-friendly technique than RAPD followed by electrophoresis. PMID- 21320596 TI - Genotypic and phenotypic characterization of the Acinetobacter calcoaceticus Acinetobacter baumannii complex with the proposal of Acinetobacter pittii sp. nov. (formerly Acinetobacter genomic species 3) and Acinetobacter nosocomialis sp. nov. (formerly Acinetobacter genomic species 13TU). AB - Acinetobacter genomic species (gen. sp.) 3 and gen. sp. 13TU are increasingly recognized as clinically important taxa within the Acinetobacter calcoaceticus Acinetobacter baumannii (ACB) complex. To define the taxonomic position of these genomic species, we investigated 80 strains representing the known diversity of the ACB complex. All strains were characterized by AFLP analysis, amplified rDNA restriction analysis and nutritional or physiological testing, while selected strains were studied by 16S rRNA and rpoB gene sequence analysis, multilocus sequence analysis and whole-genome comparison. Results supported the genomic distinctness and monophyly of the individual species of the ACB complex. Despite the high phenotypic similarity among these species, some degree of differentiation between them could be made on the basis of growth at different temperatures and of assimilation of malonate, l-tartrate levulinate or citraconate. Considering the medical relevance of gen. sp. 3 and gen. sp. 13TU, we propose the formal names Acinetobacter pittii sp. nov. and Acinetobacter nosocomialis sp. nov. for these taxa, respectively. The type strain of A. pittii sp. nov. is LMG 1035(T) (=CIP 70.29(T)) and that of A. nosocomialis sp. nov. is LMG 10619(T) (=CCM 7791(T)). PMID- 21320597 TI - Circadian rhythm of adrenal glucocorticoid: its regulation and clinical implications. AB - Glucocorticoid (GC) is an adrenal steroid hormone that controls a variety of physiological processes such as metabolism, immune response, cardiovascular activity, and brain function. In addition to GC induction in response to stress, even in relatively undisturbed states its circulating level is subjected to a robust daily variation with a peak around the onset of the active period of the day. It has long been believed that the synthesis and secretion of GC are primarily regulated by the hypothalamus-pituitary-adrenal (HPA) neuroendocrine axis. However, recent chronobiological research strongly supports the idea that multiple regulatory mechanisms along with the classical HPA neuroendocrine axis underlie the diurnal rhythm of circulating GC. Most notably, recent studies demonstrate that the molecular circadian clockwork is heavily involved in the daily GC rhythm at multiple levels. The daily GC rhythm is implicated in various human diseases accompanied by abnormal GC levels. Patients with such diseases frequently show a blunted GC rhythmicity and, more importantly, circadian rhythm related symptoms. In this review, we focus on recent advances in the understanding of the circadian regulation of adrenal GC and its implications in human health and disease. PMID- 21320598 TI - Energy metabolism affects susceptibility of Anopheles gambiae mosquitoes to Plasmodium infection. AB - Previous studies showed that Anopheles gambiae L3-5 females, which are refractory (R) to Plasmodium infection, express higher levels of genes involved in redox metabolism and mitochondrial respiration than susceptible (S) G3 females. Our studies revealed that R females have reduced longevity, faster utilization of lipid reserves, impaired mitochondrial state-3 respiration, increased rate of mitochondrial electron leak and higher expression levels of several glycolytic enzyme genes. Furthermore, when state-3 respiration was reduced in S females by silencing expression of the adenine nucleotide translocator (ANT), hydrogen peroxide generation was higher and the mRNA levels of lactate dehydrogenase increased in the midgut, while the prevalence and intensity of Plasmodium berghei infection were significantly reduced. We conclude that there are broad metabolic differences between R and S An. gambiae mosquitoes that influence their susceptibility to Plasmodium infection. PMID- 21320599 TI - Vildagliptin blocks vascular injury in thoracic aorta of diabetic rats by suppressing advanced glycation end product-receptor axis. AB - Vildagliptin is a stable inhibitor of dipeptidyl peptidase-IV, a responsible enzyme that mainly inactivates glucagon-like peptide-1, and now one of the widely used agents for the treatment of diabetes. However, effects of vildagliptin on vascular injury in diabetes are largely unknown. Since advanced glycation end products (AGEs) and their receptor RAGE axis are reported to contribute to vascular complications in diabetes, we investigated here whether vildagliptin inhibits vascular damage in thoracic aorta of Otsuka Long-Evans Tokushima Fatty rats (OLETF rats), an animal model of type 2 diabetes with obesity, by blocking the AGEs-RAGE axis. OLETF and control LETO rats at 22 weeks old were given vehicle or 3 mg/kg of vildagliptin for another 12 weeks. Vildagliptin treatment decreased fasting plasma glucose and heart rate in OLETF rats. Compared with control LETO rats, levels of AGEs, RAGE mRNA and protein, an oxidative stress marker, 8-hydroxydeoxyguanosine, two membrane components of NADPH oxidase, p22 and gp91phox mRNAs, and phospho-NF-kappaB p65 in thoracic aorta were significantly enhanced in OLETF rats, all of which were inhibited by the treatment with vildagliptin. Vildagliptin significantly reduced both mRNA and protein levels of monocyte chemoattractant protein-1, vascular cell adhesion molecule-1 and plasminogen activator inhibitor-1 in thoracic aorta of OLETF rats. Enhanced expression of transforming growth factor-beta in the aorta of diabetic rats was also suppressed by vildagliptin. Our present data suggest that vildagliptin could play a protective role against vascular injury in diabetes partly by attenuating the deleterious effects of AGEs-RAGE-oxidative stress axis. PMID- 21320600 TI - Conformation parameters of linear macromolecules from velocity sedimentation and other hydrodynamic methods. AB - Linear macromolecules constitute a broad class of synthetic and natural polymers which are highly useful in various technologies and represent the key molecular systems in living nature. The study of the molecular characteristics of these polymers represents an important problem in fundamental and applied science. The methods of molecular hydrodynamics have been and remain an important way of studying the molar mass, molar mass distribution, size and conformation of linear polymers. This paper discusses the approaches to the problems of hydrodynamic methods, in particular analytical velocity ultracentrifugation, in the study of various types of linear macromolecule. The velocity sedimentation data were processed with three different methods: Sedanal and Sedfit software, and the classical approach of evaluating the rate at which the sedimentation boundary moves. The Sedfit program also allows an evaluation of the frictional ratio values, i.e., the coefficient of translational diffusion. It will be discussed for which systems the estimation of the frictional ratio obtained by Sedfit is adequate and for which it is not. The applications of other hydrodynamic methods (intrinsic viscosity, translational diffusion) are also discussed with a view to obtaining the conformational characteristics of linear macromolecules. PMID- 21320602 TI - Large scale expression and purification of recombinant RNA in Escherichia coli. AB - Stable, folded RNA are involved in many key cellular processes and can be used as tools for biological, pharmacological and/or molecular design studies. However, their widespread use has been somewhat limited by their fragile nature and by the difficulties associated with their production on a large scale, which were limited to in vitro methods. This work reviews the novel techniques recently developed that allow efficient expression of recombinant RNA in vivo in Escherichia coli. Based on the extensive data available on the genetic and metabolic mechanisms of this model organism, conditions for optimal production can be derived. Combined with a large repertoire of RNA motifs which can be assembled by recombinant DNA techniques, this opens the way to the modular design of RNA molecules with novel properties. PMID- 21320601 TI - Assembly of multifunctional phi29 pRNA nanoparticles for specific delivery of siRNA and other therapeutics to targeted cells. AB - Recent advances in RNA nanotechnology have led to the emergence of a new field and brought vitality to the area of therapeutics [P. Guo, The emerging field of RNA nanotechnology, Nat. Nanotechnol., 2010]. Due to the complementary nature of the four nucleotides and its special catalytic activity, RNA can be manipulated with simplicity characteristic of DNA, while possessing versatile structure and diverse function similar to proteins. Loops and tertiary architecture serve as mounting dovetails or wedges to eliminate external linking dowels. Unique features in transcription, termination, self-assembly, self-processing, and acid resistance enable in vivo production of nanoparticles harboring aptamer, siRNA, ribozyme, riboswitch, or other regulators for therapy, detection, regulation, and intracellular computation. The unique property of noncanonical base-pairing and stacking enables RNA to fold into well-defined structures for constructing nanoparticles with special functionalities. Bacteriophage phi29 DNA packaging motor is geared by a ring consisting of six packaging RNA (pRNA) molecules. pRNA is able to form a multimeric complex via the interaction of two reengineered interlocking loops. This unique feature makes it an ideal polyvalent vehicle for nanomachine fabrication, pathogen detection, and delivery of siRNA or other therapeutics. This review describes methods in using pRNA as a building block for the construction of RNA dimers, trimers, and hexamers as nanoparticles in medical applications. Methods for industrial-scale production of large and stable RNA nanoparticles will be introduced. The unique favorable PK (pharmacokinetics) profile with a half life (T(1/2)) of 5-10h comparing to 0.25 of conventional 2'-F siRNA, and advantageous in vivo features such as non-toxicity, non-induction of interferons or non-stimulating of cytokine response in animals will also be reviewed. PMID- 21320603 TI - Bacterial expression, purification, and model membrane reconstitution of the transmembrane and cytoplasmic domains of the human APP binding protein LR11/SorLA for NMR studies. AB - LR11 (SorLA) is a recently identified neuronal protein that interacts with amyloid precursor protein (APP), a central player in the pathology of the Alzheimer's disease (AD). AD is a neurodegenerative disease and the most common cause of dementia in the elderly. Current estimates suggest that as many as 5.3 million Americans are living with AD. Recent investigations have uncovered the pathophysiological relevance of APP intracellular trafficking in AD. LR11 is of particular importance due to its role in regulating APP transport and processing. LR11 is a type I transmembrane protein and belongs to a novel family of Vps10p receptors. Using a new expression vector, pMTTH (MBP-MCS1 (multiple cloning site) Thrombin protease cleavage site-MCS2-TEV protease cleavage site-MCS3-His(6)), we successfully expressed, purified and reconstituted the LR11 transmembrane (TM) and cytoplasmic (CT) domains into bicelles and detergent micelles for NMR structural studies. This new construct allowed us to overcome several obstacles during sample preparation. MBP fused LR11TM and LR11TMCT proteins are preferably expressed at high levels in Escherichia coli membrane, making a refolding of the protein unnecessary. The C-terminal His-tag allows for easy separation of the target protein from the truncated products from the C-terminus, and provides a convenient route for screening detergents to produce high quality 2D (1)H-(15)N TROSY spectra. Thrombin protease cleavage is compatible with most of the commonly used detergents, including a direct cleavage at the E. coli membrane surface. This new MBP construct may provide an effective route for the preparation of small proteins with TM domains. PMID- 21320604 TI - Deciphering correct strategies for multiprotein complex assembly by co expression: application to complexes as large as the histone octamer. AB - Macromolecular complexes are responsible for most of the essential mechanisms in cells, leading to a broad interest in their purification and characterization. Co expression is now widely recognized as a major technique for assembling multiprotein complexes and many co-expression systems are currently available for performing co-expression experiments in different hosts. However, comparative knowledge on co-expression strategies is still crucially lacking. Using versatile co-expression systems for Escherichia coli, the pET-MCN and pET-MCP series, and ternary protein complexes as examples, we demonstrate how to successfully delineate correct co-expression strategies. Specifically, an appropriate, complex dependent approach alleviates stoichiometry imbalance and yield problems, and even failure in producing complexes. Importantly, some of the parameters influencing co-expression strategies appear independent of the expression host, thus having implications for co-expression in eukaryotic hosts. By further using these strategies, we show that co-expression in E. coli enables reconstitution of protein complexes as large as the deubiquitination module of the SAGA transcription factor and the histone octamer. PMID- 21320605 TI - Molecular cloning of rock bream's (Oplegnathus fasciatus) tumor necrosis factor receptor-associated factor 2 and its role in NF-kappaB activiation. AB - Tumor necrosis factor receptor-associated factor 2 (TRAF2) acts as a transducer of tumor necrosis factor-alpha (TNF-alpha)-triggered cell signals which results in inflammation, cell proliferation and antiapoptotic response. In this study, we have cloned cDNA of rock bream (Oplegnathus fasciatus) TRAF2, and analyzed its function in activation of NF-kappaB. The full length cDNA of rock bream TRAF2 consisted of 95 bp 5' UTR, 335 bp 3' UTR, and 1563 bp ORF encoding 520 amino acids that contained N-terminal RING-type and TRAF-type zinc finger domains and a C-terminal TRAF domain. The deduced amino acid sequence of rock bream TRAF2 showed more than 75% identity with other fish TRAF2s, and even as high as 56% identity with mouse and human TRAF2 proteins. To know whether the rock bream TRAF2 involves in NF-kappaB activation, Epithelioma papulosum cyprini (EPC) cells harboring an NF-kappaB reporting vector were transfected with a vector expressing rock bream TRAF2 or a control empty vector. NF-kappaB activity of EPC cells was significantly increased by exposure to the rock bream recombinant TNF-alpha. EPC cells transfected with the vector expressing rock bream TRAF2 showed significantly higher NF-kappaB activity by stimulation with the recombinant TNF alpha than cells transfected with a control empty vector, suggesting the present rock bream TRAF2 acts as a transducer of TNF-alpha-mediated cell signals that enhance NF-kappaB activation. PMID- 21320606 TI - High-field (9.4 T) MRI of brain dysmyelination by quantitative mapping of magnetic susceptibility. AB - The multilayered myelin sheath wrapping around nerve axons is essential for proper functioning of the central nervous system. Abnormal myelination leads to a wide range of neurological diseases and developmental disorders. Non-invasive imaging of myelin content is of great clinical importance. The present work demonstrated that loss of myelin in the central nervous system of the shiverer mouse results in a dramatic reduction of magnetic susceptibility in white matter axons. The reduction resulted in a near extinction of susceptibility contrast between gray and white matter. Quantitative magnetic susceptibility imaging and diffusion tensor imaging were conducted on a group of control and shiverer mice at 9.4 T. We measured the resonance frequency distribution of the whole brain for each mouse. Magnetic susceptibility maps were computed and compared between the two groups. It was shown that the susceptibility contrast between gray and white matter was reduced by 96% in the shiverer compared to the controls. Diffusion measurements further confirmed intact fiber pathways in the shiverer mice, ruling out the possibility of axonal injury and its potential contribution to the altered susceptibility. As an autosomal recessive mutation, shiverer is characterized by an almost total lack of central nervous system myelin. Our data provide new evidences indicating that myelin is the predominant source of susceptibility differences between deep gray and white matter observed in magnetic resonance imaging. More importantly, the present study suggests that quantitative magnetic susceptibility is a potential endogenous biomarker for myelination. PMID- 21320607 TI - The role of GABAergic modulation in motor function related neuronal network activity. AB - At rest, the primary motor cortex (M1) exhibits spontaneous neuronal network oscillations in the beta (15-30 Hz) frequency range, mediated by inhibitory interneuron drive via GABA-A receptors. However, questions remain regarding the neuropharmacological basis of movement related oscillatory phenomena, such as movement related beta desynchronisation (MRBD), post-movement beta rebound (PMBR) and movement related gamma synchronisation (MRGS). To address this, we used magnetoencephalography (MEG) to study the movement related oscillatory changes in M1 cortex of eight healthy participants, following administration of the GABA-A modulator diazepam. Results demonstrate that, contrary to initial hypotheses, neither MRGS nor PMBR appear to be GABA-A dependent, whilst the MRBD is facilitated by increased GABAergic drive. These data demonstrate that while movement-related beta changes appear to be dependent upon spontaneous beta oscillations, they occur independently of one other. Crucially, MRBD is a GABA-A mediated process, offering a possible mechanism by which motor function may be modulated. However, in contrast, the transient increase in synchronous power observed in PMBR and MRGS appears to be generated by a non-GABA-A receptor mediated process; the elucidation of which may offer important insights into motor processes. PMID- 21320608 TI - Structural MRI detects progressive regional brain atrophy and neuroprotective effects in N171-82Q Huntington's disease mouse model. AB - Huntington's disease (HD) displays progressive striatal atrophy that occurs long before the onset of clinical motor symptoms. As there is no treatment for the disease once overt symptoms appear, it has been suggested that neuroprotective therapy given during this presymptomatic period might slow progression of the disease. This requires biomarkers that can reliably detect early changes and are sensitive to treatment response. In mouse models of HD, structural MRI measures have been shown to detect disease onset. To determine whether such measures could also be suitable biomarkers for following responses to treatment, we used T2 weighted MR imaging combined with automated morphological analyses and characterized changes in regional brain volumes longitudinally in the N171-82Q HD mouse model in a preclinical trial. We report here that N171-82Q HD mice exhibit adult-onset and progressive brain atrophy in the striatum and neocortex as well as in whole brain; the progressive atrophy in striatum and neocortex is positively correlated with motor deficits. Most notably, MRI also detected neuroprotective effects of sertraline treatment, a neuroprotective agent confirmed in our previous studies. Our present studies provide the first evidence that longitudinal structural MRI measures can detect the therapeutic effect in HD mice, suggesting that such measures in brain could be valuable biomarkers in HD clinical trials. PMID- 21320609 TI - Age and disease related changes in the translocator protein (TSPO) system in the human brain: positron emission tomography measurements with [11C]vinpocetine. AB - BACKGROUNDS AND PURPOSE: The main objectives of the present study were (i) to measure density changes of activated microglia and the peripheral benzodiazepine receptor/translocator protein (TSPO) system during normal ageing in the human brain with positron emission tomography (PET) using the TSPO molecular imaging biomarker [(11)C]vinpocetine and (ii) to compare the level and pattern of TSPO in Alzheimer (AD) patients with age matched healthy subjects, in order to assess the biomarker's usefulness as a diagnostic imaging marker in normal (ageing) and pathological (AD) up-regulation of microglia. METHODS AND SUBJECTS: PET measurements were made in healthy volunteers, aged between 25 and 78 years, and AD patients, aged between 67 and 82 years, using [(11)C]vinpocetine as the tracer. Global and regional quantitative parameters of tracer uptake and binding, including time activity curves (TAC) of standard uptake values (%SUV), binding affinity parameters, intensity spectrum and homogeneity of the uptake distribution were measured and analysed. RESULTS: Both %SUV and binding values increased with age linearly in the whole brain and in all brain regions. There were no significant differences between the %SUV values of the AD patients and age matched control subjects. There were, however, significant differences in %SUV values in a large number of brain regions between young subjects and old subjects, as well as young subjects and AD patients. The intensity spectrum analysis and homogeneity analysis of the voxel data show that the homogeneity of the %SUV values decreases with ageing and during the disease, whereas the centre of the intensity spectrum is shifted to higher %SUV values. These data indicate an inhomogeneous up-regulation of the TSPO system during ageing and AD. These changes were significant between the group of young subjects and old subjects, as well as young subjects and AD patients, but not between old subjects and AD patients. CONCLUSIONS: The present data indicate that [(11)C]vinpocetine may serve as a molecular imaging biomarker of the activity of the TSPO system and, consequently, of the up-regulation of microglia during ageing and in neuroinflammatory diseases. However, the global and regional brain %SUV values between AD patients and age matched controls are not different from each other. The disease specific changes, measured with [(11)C]vinpocetine in AD, are significantly different from those measured in age matched controls only if the inhomogeneities in the uptake pattern are explored with advanced mathematical techniques. For this reason, PET studies using [(11)C]vinpocetine, as molecular imaging biomarker, can efficiently visualise the activation of microglia and the up-regulation of TSPO during ageing and in diseased brains with the help of an appropriate inhomogeneity analysis of the radioligand's brain uptake pattern. PMID- 21320610 TI - Processing of facial expressions and their significance for the observer in subregions of the human amygdala. AB - Amygdala responses to emotional faces can be influenced by concomitant gaze direction. As an explanation it has been suggested that the observer uses eye gaze as a cue to decipher the source of a potential threat in order to evaluate the significance of the situation. To test this assumption, we kept gaze direction ambiguous and replaced the information possibly provided by gaze direction with explicit, contextual information about intentions of angry and fearful faces. Using fMRI we show that this manipulation evokes a similar pattern of amygdala activation as prior gaze-related accounts: angry faces targeting at the observer elicited stronger amygdala responses than angry faces targeting at another person, whereas the opposite pattern was observed for fearful faces. We further combined our paradigm with high-resolution fMRI which enabled us to localize clusters of activation in amygdala subregions: purely facial-expression evoked signal changes were observed in the accessory basal nucleus, whereas our data suggest a critical role of the corticomedial amygdala in linking contextual information to emotional faces and in deciphering the significance of the faces for the observer. PMID- 21320611 TI - Functional MRI response and correlated electrophysiological changes during posterior hypothalamic nucleus deep brain stimulation. AB - Identification of active networks involved in behavior is central to understanding brain function as an emergent property. Functional magnetic resonance imaging (fMRI) allows the identification of areas with increased or decreased activity, but the cellular correlates to changes in fMRI response is still controversial. Deep brain stimulation of the posterior hypothalamic nucleus (PH) is known to facilitate locomotor behaviors and rescue locomotion in rodent models of parkinsonian akinesia by an unknown mechanism. Here, we performed 9.4 T fMRI during deep brain stimulation of PH in the anesthetized rat as a model system to explore the network substrates for its behavioral consequences. In addition, multi-unit and field potential recordings were made to examine the physiological correlates to changes in fMRI response. The most robust and reliable MR signal increases were observed in the somatosensory and motor cortices, with minor limbic and sparse thalamic activation. Electrophysiological experiments demonstrated that increased fMRI response in the neocortex corresponds to general increases in spiking activity, decreased slow oscillations and increased delta band activity. Forelimb movements evoked by intracortical microstimulation had reduced thresholds and larger representational (motor map) areas during and following PH stimulation. These findings identify the sensorimotor cortices as major contributors for behavioral effects of PH stimulation, and that coincident increase in spiking, synaptic activity and MR signal reflect functional facilitation of neocortical output. PMID- 21320612 TI - Accurate measurement of brain changes in longitudinal MRI scans using tensor based morphometry. AB - This paper responds to Thompson and Holland (2011), who challenged our tensor based morphometry (TBM) method for estimating rates of brain changes in serial MRI from 431 subjects scanned every 6 months, for 2 years. Thompson and Holland noted an unexplained jump in our atrophy rate estimates: an offset between 0 and 6 months that may bias clinical trial power calculations. We identified why this jump occurs and propose a solution. By enforcing inverse-consistency in our TBM method, the offset dropped from 1.4% to 0.28%, giving plausible anatomical trajectories. Transitivity error accounted for the minimal remaining offset. Drug trial sample size estimates with the revised TBM-derived metrics are highly competitive with other methods, though higher than previously reported sample size estimates by a factor of 1.6 to 2.4. Importantly, estimates are far below those given in the critique. To demonstrate a 25% slowing of atrophic rates with 80% power, 62 AD and 129 MCI subjects would be required for a 2-year trial, and 91 AD and 192 MCI subjects for a 1-year trial. PMID- 21320613 TI - A distance-based least-square method for dating speciation events. AB - Distance-based phylogenetic methods are widely used in biomedical research. However, there has been little development of rigorous statistical methods and software for dating speciation and gene duplication events by using evolutionary distances. Here we present a simple, fast and accurate dating method based on the least-squares (LS) method that has already been widely used in molecular phylogenetic reconstruction. Dating methods with a global clock or two different local clocks are presented. Single or multiple fossil calibration points can be used, and multiple data sets can be integrated in a combined analysis. Variation of the estimated divergence time is estimated by resampling methods such as bootstrapping or jackknifing. Application of the method to dating the divergence time among seven ape species or among 35 mammalian species including major mammalian orders shows that the estimated divergence time with the LS criterion is nearly identical to those obtained by the likelihood method or Bayesian inference. PMID- 21320614 TI - Osteoarthritis year 2010 in review: biochemical markers. AB - At the 2010 Osteoarthritis Research Society International (OARSI) congress in Brussels I was asked to present on "Biochemical Markers" in the "Year in Review" session. This provided an opportunity to summarize ongoing work and consensus building in the osteoarthritis research community related to osteoarthritis biomarkers, and second, and an opportunity to briefly overview a subset of studies from the previous 12 months related to soluble biomarkers that provided novel insights in the field. This review therefore briefly summarizes the progress in 2010 of the OARSI OA Biomarkers Global Initiative and the OARSI FDA Biomarkers Working Group, and provides a summary of selected osteoarthritis biomarker studies reported over the previous 12 months based on a review of articles from seven musculoskeletal journals and a PubMed search using the terms biomarkers and osteoarthritis. PMID- 21320615 TI - Osteoarthritis year 2010 in review: pharmacological therapies. AB - This review highlights a selection of original studies related to the treatment of osteoarthritis in 2010. PMID- 21320616 TI - Osteoarthritis year 2010 in review: imaging. AB - Osteoarthritis (OA) is no longer viewed as a passive, degenerative disorder, but rather an active disease process driven primarily by mechanical factors. OA should also be conceptualized as a disease of a whole joint organ, and therefore imaging of OA requires techniques which enable us to visualize the whole joint organ. Although clinical decision making based on imaging findings remains controversial the importance of imaging-derived data in OA research cannot be overemphasized. Since mid-2009, numerous publications reporting on imaging oriented studies on OA have been reported. These include magnetic resonance (MR) imaging of numerous features of the whole joint such as synovitis, subchondral bone, meniscus, cartilage and cyst-like lesions. Active research is also ongoing using conventional radiography with a focus on measurements of joint space width and alignment of the knee joint. Ultrasound is emerging as a useful imaging technique, particularly in the field of hand OA research. As the importance of imaging-derived data increases, all potential authors are advised that they should seek opinions from expert musculoskeletal radiologist to ascertain the application of correct imaging techniques, especially the MR pulse sequences and image interpretation. The peer-review process of OA imaging in any journal, therefore, should involve musculoskeletal radiologists experienced in OA research to ensure the publication of papers with scientifically sound contents. PMID- 21320617 TI - Osteoarthritis year 2010 in review: genetics. AB - At the 2010 Osteoarthritis Research Society International (OARSI) congress in Brussels I was asked to present on "Genetics" in the "Year in Review" session. This gave me an opportunity to reflect on the talk that I gave on the same topic at the 2007 OARSI congress in Ft Lauderdale, Florida. My 2007 talk was very upbeat and ended with the hostage to fortune statement "The next few years will provide tremendous clarity in our genetic understanding of osteoarthritis". PMID- 21320618 TI - The path to epigenetic treatment of memory disorders. AB - A new line of neuroscience research suggests that epigenetics may be the site of nature and nurture integration by providing the environment with a mechanism to directly influence the read-out of our genome. Epigenetic mechanisms in the brain are a series of post-translational chromatin and DNA modifications driven by external input. Given the critical hub that epigenetics appears to be, neuroscientists have come to suspect its fundamental influence on how our minds change in response to our unique environment and, in turn, how these changes can then impact our future interactions with the environment. The field of learning and memory is becoming particularly interested in understanding the cognitive influence of epigenetics. With the majority of us working with an eye toward therapeutics, the question naturally arises: "Has neuroepigenetics gotten us closer to treating memory disorders and if so, where do we go from here?" This review will begin with a brief exploration of recent advances in our understanding of how epigenetic mechanisms contribute to learning and memory processes that are susceptible to failure. Next the implications for disorders of cognition, such as Alzheimer's disease, will be discussed. Finally, we will use parallels from the field of cancer to speculate on where we should consider heading from here in the pursuit of therapeutics. PMID- 21320619 TI - Low risk of chronic graft-versus-host disease and relapse associated with T cell depleted peripheral blood stem cell transplantation for acute myelogenous leukemia in first remission: results of the blood and marrow transplant clinical trials network protocol 0303. AB - Graft-versus-host disease (GVHD) is most effectively prevented by ex vivo T cell depletion (TCD) of the allograft, but its role in the treatment of patients undergoing allogeneic hematopoietic cell transplantation (HCT) for acute myelogenous leukemia (AML) in complete remission (CR) remains unclear. We performed a phase 2 single-arm multicenter study to evaluate the role of TCD in AML patients in CR1 or CR2 up to age 65 years. The primary objective was to achieve a disease-free survival (DFS) rate of >75% at 6 months posttransplantation. A total of 44 patients with AML in CR1 (n = 37) or CR2 (n = 7) with a median age of 48.5 years (range, 21-59 years) received myeloablative chemotherapy and fractionated total body irradiation (1375 cGy) followed by immunomagnetically selected CD34-enriched, T cell-depleted allografts from HLA identical siblings. No pharmacologic GVHD prophylaxis was given. All patients engrafted. The incidence of acute GVHD grade II-IV was 22.7%, and the incidence of extensive chronic GVHD was 6.8% at 24 months. The relapse rate for patients in CR1 was 17.4% at 36 months. With a median follow-up of 34 months, DFS for all patients was 82% at 6 months, and DFS for patients in CR1 was 72.8% at 12 months and 58% at 36 months. HCT after myeloablative chemoradiotherapy can be performed in a multicenter setting using a uniform method of TCD, resulting in a low risk of extensive chronic GVHD and relapse for patients with AML in CR1. PMID- 21320620 TI - Glyoxalase in ageing. AB - The glyoxalase system has been studied since 1913. The biochemical function of this enzymatic system is the metabolism of reactive dicarbonyl metabolites, glyoxal and methylglyoxal, to less reactive products. In the last decade research has shown that methylglyoxal is the precursor of quantitatively important damage to the proteome and genome, forming mainly hydroimidazolone and imidazopurinone adducts in protein and DNA respectively. The aim of this article is to review the evidence of the involvement of the glyoxalase system in ageing and role of glyoxalase in future research into healthy ageing-mainly in mammalian systems for insights into consequences and interventions in human health. Protein and DNA damage by glyoxalase system substrates is linked to dysfunction of proteins susceptible to dicarbonyl modification-the dicarbonyl proteome, and DNA instability and mutation. A component of the glyoxalase system, glyoxalase 1, is a gene with expression influential on lifespan-increasing longevity being associated with increased expression of glyoxalase 1. The glyoxalase 1 gene is also a site of copy number variation in both transcribed and non-transcribed regions giving rise to population variation of expression. The glyoxalase system and Glo1 expression particularly is therefore likely linked to healthy ageing. PMID- 21320621 TI - Purinergic signaling in neural development. AB - Extracellular purine and pyrimidine compounds induce a multiplicity of cellular signal pathways that can induce multiple trophic functions. They interact with other low molecular weight messengers, growth factors, and extracellular matrix components. An increasing number of studies now provide evidence for a role of purinergic signaling in neural development, including progenitor cell proliferation, cell migration, neuronal and glial maturation and differentiation, and cell death and survival. This brief overview highlights recent developments supporting a contribution of purinergic signaling to embryonic and adult neurogenesis. PMID- 21320622 TI - Neuroglial interactions mediated by purinergic signalling in the pathophysiology of CNS disorders. AB - Purinergic signalling in neurons and glia is relevant to acute and chronic neurological diseases. In particular, emerging evidence indicates that adenosine can play a neuromodulatory role in balancing GABA and glutamate neurotransmission and thus, have a tremendous therapeutic potential for the treatment of epilepsy. On the other hand, signalling via P2 purinergic receptors contributes to post ischemic injury to grey and white matter as well as endogenous neurogenesis in response to tissue damage. Likewise, P2 receptors mediate demyelinating damage in animal models of multiple sclerosis, and recent evidences suggest that P2X receptor function is altered in this disorder. In all instances, complex interactions between neurons and glia via purine signals are relevant to disease and its prevention or attenuation. Here, we review current knowledge on how purinergic signalling is involved in the pathophysiology of CNS diseases, with an emphasis in epilepsy, ischemia and multiple sclerosis. Understanding in depth the primary and secondary mechanisms relevant to the control of excitation and/or damage by purines will undoubtedly lead to the development of novel therapies based on the use of drugs acting at the purinergic system. PMID- 21320623 TI - Ionotropic ATP receptors in neuronal-glial communication. AB - In the central nervous system ATP is released from both neurones and astroglial cells acting as a homo- and heterocellular neurotransmitter. Glial cells express numerous purinoceptors of both ionotropic (P2X) and metabotropic (P2Y) varieties. Astroglial P2X receptors can be activated by ongoing synaptic transmission and can mediate fast local signalling through elevation in cytoplasmic Ca(2+) and Na(+) concentrations. These ionic signals can be translated into various physiological messages by numerous pathways, including release of gliotransmitters, metabolic support of neurones and regulation of activity of postsynaptic glutamate and GABA receptors. Ionotropic purinoceptors represent a novel pathway of glia-driven modulation of synaptic signalling that involves the release of ATP from neurones and astrocytes followed by activation of P2X receptors which can regulate synaptic activity by variety of mechanisms expressed in both neuronal and glial compartments. PMID- 21320625 TI - Mechanisms of unisexual mating in Cryptococcus neoformans. AB - Sex serves a pivotal role in genetic exchange and it contributes to the fitness and genetic diversity for eukaryotic populations. Although the importance of the canonical bisexual mating has been widely accepted, the significance of the evolution and maintenance of unisexual mating observed in some eukaryotes is unclear. The recent discovery of same-sex mating in the human fungal pathogen Cryptococcus neoformans and the revelation of its impact on the Cryptococcus global population structure provide a platform to elucidate the molecular mechanisms and significance of unisexual mating. Here, we review the evidence of unisexual mating in Cryptococcus and provide some perspective on the biological significance of this life style on the survival of this important fungal pathogen in the environment and in animal hosts. We also summarize our current understanding of the molecular mechanisms governing this unconventional mode of reproduction. PMID- 21320624 TI - Nonsynaptic and nonvesicular ATP release from neurons and relevance to neuron glia signaling. AB - Studies on the release of ATP from neurons began with the earliest investigations of quantal neurotransmitter release in the 1950s, but in contrast to ATP release from other cells, studies of ATP release from neurons have been narrowly constrained to one mechanism, vesicular release. This is a consequence of the prominence of synaptic transmission in neuronal communication, but nonvesicular mechanisms for ATP release from neurons are likely to have a broader range of functions than synaptic release. Investigations of activity-dependent communication between axons and myelinating glia have stimulated a search for mechanisms that could release ATP from axons and other nonsynaptic regions in response to action potential firing. This has identified volume-activated anion channels as an important mechanism in activity-dependent ATP release from axons, and renewed interest in micromechanical changes in axons that accompany action potential firing. PMID- 21320626 TI - Fiber type and metabolic characteristics of lion (Panthera leo), caracal (Caracal caracal) and human skeletal muscle. AB - Lion (Panthera leo) and caracal (Caracal caracal) skeletal muscle samples from Vastus lateralis, Longissimus dorsi and Gluteus medius were analyzed for fiber type and citrate synthase (CS; EC 2.3.3.1), 3-hydroxyacyl Co A dehydrogenase (3HAD; EC 1.1.1.35), phosphofructokinase-1 (PFK; EC 2.7.1.11), creatine kinase (CK; EC 2.7.3.2), phosphorylase (PHOS; EC 2.4.1.1) and lactate dehydrogenase (LDH; EC 1.1.1.27) activities and compared to human runners, the latter also serving as validation of methodology. Both felids had predominantly type IIx fibers (range 50-80%), whereas human muscle had more types I and IIa. Oxidative capacity of both felids (CS: 5-9 MUmol/min/g ww and 3HAD: 1.4-2.6 MUmol/min/g ww) was lower than humans, whereas the glycolytic capacity was elevated. LDH activity of caracal (346 +/- 81) was higher than lion (227 +/- 62 MUmol/min/g ww), with human being the lowest (55 +/- 17). CK and PHOS activities were also higher in caracal and lion compared to human, but PFK was lower in both felid species. The current data and past research are illustrated graphically showing a strong relationship between type II fibers and sprinting ability in various species. These data on caracal and lion muscles confirm their sprinting behavior. PMID- 21320627 TI - Live prey enrichment, with particular emphasis on HUFAs, as limiting factor in false percula clownfish (Amphiprion ocellaris, Pomacentridae) larval development and metamorphosis: molecular and biochemical implications. AB - In fast growing organisms, like fish larvae, fatty acids provided through live prey are essential to satisfy high energy demand and are required to promote growth. Therefore, in recent decades, a great amount of research has been directed towards the development of lipid enrichment in order to improve larval fish survival and growth. However, in fish, the biochemical and molecular processes related to highly unsaturated fatty acid (HUFA) administration are still poorly understood. In the current study, the false percula clownfish, a short larval phase marine species, was used as an experimental model and the effects of a standard and a HUFAs-enriched diet were tested through a molecular, biochemical, ultrastructural and morphometric approach. Our results support the hypothesis that HUFA administration may improve larval development through the presence of better structured mitochondria, a higher synthesis of energy compounds and coenzymes with a central position in the metabolism, with respect to controls. This higher energy status was confirmed by better growth performance and a shorter larval phase in larvae fed with an enriched diet with respect to the control. This strategy of rapid growth and early energy storage may be considered positively adaptive and beneficial to the survival of this species. PMID- 21320628 TI - Stage-dependent differences in RNA composition and content affect the outcome of expression profiling in roach (Rutilus rutilus) ovary. AB - The influence of changing composition and content of RNA on the results of expression profiling was studied in the group-synchronous ovaries of roach (Rutilus rutilus) over the course of their maturation. The highest yield of total RNA was detected in the primary growth and early cortical alveolus stages. The total RNA yield gradually decreased through the late cortical alveolus and late vitellogenic stages. In the primary growth and early cortical alveolus stages, total RNA was characterized by a low percentage of 18S and 28S rRNA and a high percentage of smaller-sized RNAs (tRNA, 5S and 5.8S rRNA), whereas 18S and 28S rRNA had increased by the late cortical alveolus stage and dominated by the late vitellogenic stage. The ratio of mRNA to total RNA was highest at the primary growth stage but decreased significantly in later ovarian stages. When total RNA was used for reverse transcription (RT), the shift in the mRNA/total RNA ratio influenced the results of qPCR expression profiling of several commonly used reference genes (ribosomal protein L8, elongation factor-1alpha, RNA polymerase subunit B5, and beta2-microglobulin) and of two target genes, gonad-type aromatase (cyp19a1a) and follistatin (fst). We conclude that the expression of target genes should be related to the mRNA pool using the same input of either mRNA to RT or cDNA to qPCR. Furthermore, gene expression was related to tissue specific RNA yield per body mass (RNA yield x ovary mass x body mass-1) thereby reflecting the massive increase in the size and cellular composition of the ovary during the reproductive cycle. PMID- 21320629 TI - Physiological flexibility and climate change: The case of digestive function regulation in lizards. AB - Our planet is undergoing fast environmental changes, which are referred as global change. In this new scenario, it is of paramount relevance to understand the mechanistic basis of animal responses to environmental change. Here we analyze to what extent seasonal changes in the digestive function of the lizard Liolaemus moradoensis is under endogenous (i.e., hard wired) or exogenous (i.e., environmentally determined) control. For this purpose we compared animals collected in the field during autumn, winter and summer, against (experimental) specimens collected in the field at the beginning of autumn and reared in the laboratory under simulated summer conditions until winter. We found that different aspects of the digestive function are under different types of control: small intestine length appears to be under endogenous control (i.e., experimental animals were similar to winter animals), small intestine mass appears to be under exogenous control (i.e., experimental animals were similar to summer animals), and specific enzyme activities did not change throughout the year. Thus, we suspect that processes related with gut length, such as cell division, may be under endogenous control, while others related with gut mass, such as enterocyte size and content, may be determined by exogenous factors, such as the presence of food in the intestinal lumen. Faced with accelerated changing conditions, the ability of vertebrates to cope will be closely related with their plasticity in fitness-associated traits. More studies aimed at determining the levels and limits of physiological flexibility will be necessary to understand this phenomenon. PMID- 21320630 TI - Reproductive phase dependent daily variation in melatonin receptors (Mel(1a) and Mel(1b)), androgen receptor (AR) and lung associated immunity of Perdicula asiatica. AB - Our knowledge about the involvement of melatonin in the regulation of lung associated immune system (LAIS) is still poor though the melatonin receptor types (Mel(1a) and Mel(1b)) have been localized in lungs of some wild birds. We thought to explore the correlation between daily variation (within a 24h time scale) in peripheral melatonin and testosterone along with expression of melatonin receptors (Mel(1a) and Mel(1b)) and androgen receptor (AR) in lungs during reproductively active and inactive phases. Receptor expression of Mel(1b) was more prominent than Mel(1a) at all the time points during both the reproductive phases. The expression of AR was inversely related to both the melatonin and its receptor expression at the 24h time scale during both the reproductive phases. Results also reflected a parallel relationship of melatonin, melatonin receptors and all the immune parameters (total leukocyte count, lymphocyte count, % stimulation ratio) suggesting that peripheral melatonin might be responsible for daily periodicity of LAIS. The presence of androgen receptors in lung led us to propose that gonadal steroid does influence the LAIS. Therefore melatonin along with testosterone might be acting as a temporal synchronizer for daily rhythms in lung associated immunity in Perdicula asiatica during different reproductive phases. PMID- 21320631 TI - Optimization of a heterologous pathway for the production of flavonoids from glucose. AB - The development of efficient microbial processes for the production of flavonoids has been a metabolic engineering goal for the past several years, primarily due to the purported health-promoting effects of these compounds. Although significant strides have been made recently in improving strain titers and yields, current fermentation strategies suffer from two major drawbacks-(1) the requirement for expensive phenylpropanoic precursors supplemented into the media and (2) the need for two separate media formulations for biomass/protein generation and flavonoid production. In this study, we detail the construction of a series of strains capable of bypassing both of these problems. A four-step heterologous pathway consisting of the enzymes tyrosine ammonia lyase (TAL), 4 coumarate:CoA ligase (4CL), chalcone synthase (CHS), and chalcone isomerase (CHI) was assembled within two engineered l-tyrosine Escherichia coli overproducers in order to enable the production of the main flavonoid precursor naringenin directly from glucose. During the course of this investigation, we discovered that extensive optimization of both enzyme sources and relative gene expression levels was required to achieve high quantities of both p-coumaric acid and naringenin accumulation. Once this metabolic balance was achieved, however, such strains were found to be capable of producing 29 mg/l naringenin from glucose and up to 84 mg/l naringenin with the addition of the fatty acid enzyme inhibitor, cerulenin. These results were obtained through cultivation of E. coli in a single minimal medium formulation without additional precursor supplementation, thus paving the way for the development of a simple and economical process for the microbial production of flavonoids directly from glucose. PMID- 21320632 TI - A physiologically-based kinetic model for the prediction of plasma cholesterol concentrations in the mouse. AB - The LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C) concentrations are determined by the activity of a complex network of reactions in several organs. Physiologically-based kinetic (PBK) computational models can be used to describe these different reactions in an integrated, quantitative manner. A PBK model to predict plasma cholesterol levels in the mouse was developed, validated, and analyzed. Kinetic parameters required for defining the model were obtained using data from published experiments. To construct the model, a set of appropriate submodels was selected from a set of 65,536 submodels differing in the kinetic expressions of the reactions. A submodel was considered appropriate if it had the ability to correctly predict an increased or decreased plasma cholesterol level for a training set of 5 knockout mouse strains. The model thus defined consisted of 8 appropriate submodels and was validated using data from an independent set of 9 knockout mouse strains. The model prediction is the average prediction of 8 appropriate submodels. Remarkably, these submodels had in common that the rate of cholesterol transport from the liver to HDL was not dependent on hepatic cholesterol concentrations. The model appeared able to accurately predict in a quantitative way the plasma cholesterol concentrations of all 14 knockout strains considered, including the frequently used Ldlr-/- and Apoe-/- mouse strains. The model presented is a useful tool to predict the effect of knocking out genes that act in important steps in cholesterol metabolism on total plasma cholesterol, HDL C and LDL-C in the mouse. PMID- 21320634 TI - Antioxidant response and oxidative stress levels in Macrobrachium borellii (Crustacea: Palaemonidae) exposed to the water-soluble fraction of petroleum. AB - The aim of the present work was to evaluate the effect of the water soluble fraction of hydrocarbons (WSF) on the antioxidant status of the freshwater prawn Macrobrachium borellii. First, seasonal variations were studied in a non-polluted area. Hepatopancreas and gills showed season-related fluctuations in catalase (CAT), glutathione-S-transferase (GST) activities and in lipid peroxidation levels (LPO), but not in superoxide dismutase (SOD). Then, adults were exposed semi-statically to sublethal doses for 7days. CAT, SOD, GST, and glutathione peroxidase (GPx) activities and LPO, reduced glutathione (GSH) and protein oxidation (PO) levels were determined. Exposed individuals showed significant increases in CAT, SOD, and GST activities in hepatopancreas and CAT activity in gills. GPx activity did not vary in either tissues. While LPO levels increased, GSH levels decreased significantly in hepatopancreas of exposed animals, but PO levels showed no variation. Induction of SOD was also assessed by Real-time PCR mRNA expression in hepatopancreas. The non-enzymatic antioxidant activity was also tested; ABTS 2,2'-azino-bis(3-ethyl-benzothiazoline-6-sulfonic acid) was higher in hemolymph of treated-prawns compared to controls, but ferric reducing activity of plasma assay (FRAP) values did not change. Taken together, the present results indicated that the antioxidant defenses of M. borellii, mainly in hepatopancreas, were significantly affected by aquatic hydrocarbon contamination, regardless of the season. PMID- 21320633 TI - Exploring the inhibitory activity of short-chain phospholipids against amyloid fibrillogenesis of hen egg-white lysozyme. AB - Amyloid fibrillogenesis is an important pathological feature of a group of degenerative human diseases. The 129-residue enzyme hen egg-white lysozyme has been shown to form fibrils in vitro at pH 2.0 and 55 degrees C. In this research, using various spectroscopic techniques, light scattering, and transmission electron microscopy, we first examined the influence of short-chain phospholipids on the amyloid fibrillogenesis and the structural changes derived from hen lysozyme in vitro. Both model short-chain phospholipids were observed to mitigate the fibrillogenesis of hen lysozyme. Also, urea-induced unfolding results suggested that the susceptibility of hen lysozyme to conformational changes elicited by the denaturant was observed to decrease upon addition of short-chain phospholipids. Moreover, our molecular dynamics simulations results demonstrated that the observed inhibitory action of short-chain phosoholipids against hen lysozyme fibrillogenesis might be attributable to the interference of beta-strand extension by the binding of phospholipids to lysozyme's beta-sheet-rich region. We believe that the outcome from this study may contribute to a better understanding the molecular factors affecting amyloid fibrillogenesis and the molecular mechanism(s) of the interactions between phospholipids/lipids and amyloid-forming proteins. PMID- 21320635 TI - Effects of hypoxia and petroleum on the genotoxic and morphological parameters of Hippocampus reidi. AB - Hypoxia events are common in many aquatic systems, which may be a natural event or provoked by anthropogenic actions, as well as accidents involving oil occurring throughout the world are frequent. Thus, through the possibility of occurrence of these two situations in same place the purpose of this study was to evaluate if damage caused by crude oil on genotoxic and morphological parameters in the marine fish species Hippocampus reidi will be aggravated by events of severe hypoxia. Sea horses were exposed during 8h to the following conditions: crude oil (OIL), severe hypoxia (HYP), association of severe hypoxia and crude oil (HYP+OIL) and normoxia without contaminant (CONT). An increase in micronuclei observed in OIL and HYP+OIL groups indicates that the crude oil exposure was a determining factor in the micronuclei induction and hypoxia did not intensify this result. In comet assays, both petroleum and hypoxia provoke DNA damage. The most frequent histopathology in the control groups and in those exposed to OIL and HYP+OIL groups were: hypertrophy and capillary dilation; hypertrophy and hyperplasia; hypertrophy, epithelial "lifting" and epithelial hyperplasia. An elongation of the lamellae was observed in fish from the two groups exposed to hypoxia, probably due to the fact that these groups required a greater flow of blood in the gills to increase the efficiency of gas exchange, since they were in a hypoxic environment. In summary, the micronuclei test and comet assay can be used as a good biomarker of contamination by petroleum. The association of hypoxia with crude oil in some aspects may exacerbate the responses of fish, in the light of the increase in DNA damage and the alterations in thickness of the gill epithelium. PMID- 21320636 TI - Anti-inflammatory effect of genistein on non-alcoholic steatohepatitis rats induced by high fat diet and its potential mechanisms. AB - Genistein is a naturally occurring plant-derived phytoestrogen present in the human diet, and is known to possess anti-cancer, anti-oxidant and anti osteoporosis effects. Anti-inflammatory activity of genistein has been revealed in animal studies. In this paper, we investigated the anti-inflammatory effect of genistein on non-alcoholic steatohepatitis (NASH) rats induced by high fat diet (HFD), and explored its potential mechanisms. Rats were fed with normal chow diet or HFD for 12 weeks with or without low (4 mg/kg/day body weight) or high (8 mg/kg/day body weight) dose of genistein. Serum levels of aminotransferases, thiobarbituric acid-reactive substances (TBARS), tumor necrosis factor alpha (TNF alpha), interleukin-6 (IL-6) and transforming growth factor beta (TGF-beta(1)) were measured, hepatic inflammation, liver TBARS, IL-6, TNF-alpha and TGF-beta(1) levels were determined, and proteins involved in mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-kappaB) pathways were assayed. The results showed that the NASH model rats reproduced typical pathogenetic and histopathological features of NASH in human, and genistein administration improved liver function, slowed down NASH progression, decreased the levels of TBARS, TNF-alpha and IL-6 in serum and liver, as well as inhibited IkappaB-alpha phosphorylation, nuclear translocation of NF-kappaB p65 subunit, and activation of c-Jun N-terminal kinase (JNK). In conclusion, genistein may be a promising drug to inhibit the inflammatory process and prevent liver damage in patients with NASH. PMID- 21320637 TI - LPS-induced CD11b+Gr1(int)F4/80+ regulatory myeloid cells suppress allergen induced airway inflammation. AB - In humans, the bacterial product lipopolysaccharide (LPS) has been associated with protection from allergic diseases such us asthma. However, in mouse models of allergic asthma, differential effects of LPS have been noted based on the dose. A low dose of LPS promotes Th2 responses and allergic disease but a high dose has been associated with suppression of allergic airway inflammation. Our recent work has described the ability of LPS to increase the frequency of CD11b+Gr1(int)F4/80+(abbreviated as Gr1(int) cells) cells in the lung tissue of mice in a dose-dependent fashion that is dependent on TLR4 and the TLR adaptor protein, MyD88. Both phenotypically and morphologically, the cells were found to have similarities with mycloid-derived suppressor cells. Adoptive transfer of LPS induced Gr1(int) cells suppressed allergen-induced airway inflammation suggesting regulatory functions of the cells in allergic asthma. Although the Gr1(int) cells are detectable in the lung tissue of LPS-treated mice, they are barely detectable in the lung-draining lymph nodes (Lns) or in the airway lumen. This causes selective enrichment of these cells over dendritic cells (Dcs) in the tissue which upon LPS stimulation migrate to lung-draining LNs. The Gr1(int) cells were found to blunt the ability of the lung DCs to upregulate GATA-3 or to promote STAT5 activation in primed Th2 cells, both transcription factors having critical roles in TH2 effector function. Thus, a complete understanding of the generation and regulation of the Gr1(int) cells would provide new avenues to either promote or delete these cells for disease-specific immunoregulation. PMID- 21320638 TI - WITHDRAWN: Dual targeting of glioma U251 cells and neovasculature with a nanoparticle encoding vasohibin and RGD peptides prevents tumor angiogenesis and inhibits tumor growth. AB - This article has been withdrawn at the request of the author(s) and editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 21320639 TI - Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. AB - BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) can progress to hepatocellular carcinoma (HCC). We aimed to characterize the clinical features of NASH patients with HCC. METHODS: In a cross-sectional multicenter study in Japan, we examined 87 patients (median age, 72 years; 62% male) with histologically proven NASH who developed HCC. The clinical data were collected at the time HCC was diagnosed. RESULTS: Obesity (body mass index >=25 kg/m(2)), diabetes, dyslipidemia, and hypertension were present in 54 (62%), 51 (59%), 24 (28%), and 47 (55%) patients, respectively. In nontumor liver tissues, the degree of fibrosis was stage 1 in 10 patients (11%), stage 2 in 15 (17%), stage 3 in 18 (21%), and stage 4 (ie, liver cirrhosis) in 44 (51%). The prevalence of cirrhosis was significantly lower among male patients (21 of 54, 39%) compared with female patients (23 of 33, 70%) (P = .008). CONCLUSIONS: Most patients with NASH who develop HCC are men; the patients have high rates of obesity, diabetes, and hypertension. Male patients appear to develop HCC at a less advanced stage of liver fibrosis than female patients. PMID- 21320640 TI - Factors that contribute to blood loss in patients with colonic angiodysplasia from a population-based study. AB - BACKGROUND & AIMS: Most studies of angiodysplasia are small and performed at a single center. We investigated the epidemiology and management of colonic angiodysplasia by using a national endoscopy database. METHODS: Colonoscopy reports (n = 229,727; generated from January 2000 to December 2002) from patients with documented angiodysplasia (n = 4159) were retrieved from the Clinical Outcomes Research Initiative. Predictors of occult or overt blood loss and endoscopic treatment were identified by using multivariate logistic regression. RESULTS: Most patients with documented angiodysplasia were older than 60 years (73%) or had right-sided lesions (62%). There was evidence of blood loss in 56% of patients with angiodysplasia. Predictors of blood loss included inpatient status (odds ratio [OR], 8.74; 95% confidence interval [CI], 5.42-14.10), 2-10 angiodysplasias (OR, 1.50; 95% CI, 1.29-1.75), more than 10 lesions (OR, 2.18; 95% CI, 1.69-2.80), black race (OR, 1.95; 95% CI, 1.46-2.62), severe illness (OR, 1.97; 95% CI, 1.62-2.41), Hispanic ethnicity (OR, 1.71; 95% CI, 1.32-2.22), and age older than 80 years (OR, 1.32; 95% CI, 1.06-1.63). Endoscopic therapy was given to 28% of patients with evidence of blood loss and in 68% with active bleeding. Endoscopic treatment increased among patients in a university practice setting (vs community setting, OR, 2.53; 95% CI, 1.96-3.27) and decreased in Northwest geographic locations (vs Southwest, OR, 0.60; 95% CI, 0.43-0.84). CONCLUSIONS: Predictors of blood loss in patients with colonic angiodysplasia include inpatient status, comorbidities, age, race/ethnicity, and lesion number. Endoscopic therapy for angiodysplasia varied according to practice setting and region. PMID- 21320641 TI - Risk factors for unfavorable outcomes after endoscopic removal of submucosal invasive colorectal tumors. AB - BACKGROUND & AIMS: Oncologic surgery is recommended after endoscopic resection of submucosal invasive T1 colorectal carcinomas if patients are considered to be at high risk for tumor recurrence or metastasis. However, there are sparse data on the outcome of high-risk patients treated only by endoscopy. METHODS: Data were collected from 474 patients who underwent endoscopic resection for T1 colorectal cancers from 1974-2002 at Neuperlach Hospital in Munich, Germany. Patient files were reviewed, and patients or referring physicians were contacted to assess outcomes during a follow-up period of at least 24 months (n = 390). Histopathology and endoscopy factors associated with an unfavorable outcome (local recurrence of tumors, metastasis, or death from colorectal cancer) were assessed. RESULTS: Of the 390 patients followed, 141 received oncologic surgery, and 249 did not; overall, 10% had an unfavorable outcome (39/390). Multivariate regression analysis revealed that lymphatic vessel infiltration, poor grading of tumor stage, and incomplete endoscopic resection were risk factors for unfavorable outcomes (odds ratios, 7.8, 3.4, and 2.6, respectively). If these risk factors were applied to patients who did not receive oncologic surgery, negative predictive values for an unfavorable outcome were 94.6% for lymphatic vessel infiltration, 94.2% for poor grading of tumor stage, and 96.5% for incomplete endoscopic resection; positive predictive values were 44.4%, 42.9%, and 19.6%, respectively. CONCLUSIONS: Tumor infiltration of lymphatic vessels is the greatest risk factor for an unfavorable outcome after endoscopic resection for colorectal carcinoma. However, its positive predictive value is low. The decision to perform surgery after endoscopic resection of T1 colorectal cancers should be made on the basis of specific features of each patient. PMID- 21320642 TI - A 78-year-old man with difficulty swallowing. AB - CP bar is an uncommon but important cause of dysphagia in elderly people. A CP bar is often undetected during upper endoscopy and might be missed with barium radiography if adequate attention is not focused on the hypopharynx. In suspected cases, evaluation for alternative etiologies of dysphagia is important because the CP bar might be an incidental finding. Secondary causes of CP dysfunction resulting from underlying primary myopathic or neuropathic disorders should be considered before therapy. The effectiveness of dilation and surgical myotomy in alleviating dysphagia associated with CP bars has been reported in small series. PMID- 21320643 TI - Phylogeography and epidemiological history of West Nile virus genotype 1a in Europe and the Mediterranean basin. AB - Aim of this study was to reconstruct the temporal and spatial phylodynamics of WNV-1a, the genotype to which the majority of European/Mediterranean viral strains belongs, by using sequences retrieved from public databases. WNV-1a isolates segregated into two major clades: the recent West Mediterranean sequences formed a single monophyletic group within clade A. Clade B included sequences from East Mediterranean and America. Phylogeographic analysis suggested that WNV-1a probably originated in sub-Saharan Africa in the early XXth century, and then spread northwards since the late 1970s, via two routes: one crossing Eastern Mediterranean and the other the Western Mediterranean countries. Our data suggest that the circulation of the virus in a given geographical area usually precedes the onset of the outbreak by one year or more, and underline the importance of the spatial-temporal phylodynamics reconstruction in clarifying the recent epidemiology and in setting up an efficient surveillance system for emerging/reemerging zoonosis. PMID- 21320644 TI - The pathogenesis of oligoarticular/polyarticular vs systemic juvenile idiopathic arthritis. AB - Juvenile idiopathic arthritis (JIA) has had a long and difficult problem with classification. It is clearly a heterogeneous and multi-factorial autoimmune disease but all too often the distinctions among subtypes were unclear. In fact, there is now increasing evidence of a distinct pathogenesis of oligo/polyarticular JIA compared to systemic JIA. Oligo/polyarticular JIA is an antigen-driven lymphocyte-mediated autoimmune disease with abnormality in the adaptive immune system. Cartilage-derived auto-antigens activate autoreactive T cells including Th1 and Th17 cells with production of pro-inflammatory cytokines IFN-gamma and IL-17. On the other hand, the inhibition of regulatory T (Treg) cells including natural Foxp3(+) Treg and self-heat shock protein-induced Treg cells with decreased anti-inflammatory cytokine IL-10 results in the loss of immune tolerance. Imbalance between autoreactive Th1/Th17 and Treg cells leads to the failure of T cell tolerance to self-antigens, which contributes to the synovial inflammation of oligo/polyarticular JIA. By contrast, systemic JIA is an autoinflammatory disease with abnormality in the innate immune system. A loss of control of the alternative secretory pathway leading to aberrant activation of phagocytes including monocytes, macrophages and neutrophils seems to be involved in the release of pro-inflammatory cytokines IL-1, IL-6, IL-18 and pro inflammatory S100-proteins, which contribute to the multisystem inflammation of systemic JIA. Markedly distinct pathogenesis of oligo/polyarticular JIA and systemic JIA implies that they might need different treatment strategies. PMID- 21320645 TI - Serum 25-OH vitamin D concentrations are linked with various clinical aspects in patients with systemic sclerosis: a retrospective cohort study and review of the literature. AB - Low vitamin D serum concentrations have been reported in several autoimmune conditions. The study's aim was to explore such a relationship in a large multinational population of patients with systemic sclerosis (SSc) and to pursue possible clinical and laboratory correlates with vitamin D concentrations. 327 sera samples of European patients with SSc and 141 samples of compatible healthy controls were studied for vitamin D concentrations using the commercial kit LIAISON 25-OH vitamin D assay (Diasorin). Additionally, clinical parameters including the Rodnan skin score, diffusing lung capacity for carbon monoxide (DLCO), systolic pulmonary artery pressure (sPAP), forced vital capacity (FVC), and nailfold video capillaroscopic, erythrocyte sedimentation rate (ESR), anti nuclear antibodies (ANA and scl70), rheumatoid factor (RF) were investigated. Vitamin D serum concentration was 13.5 +/- 9.0 ng/ml (mean +/- standard deviation) in patients with SSc compared to 21.6 +/- 9.7 ng/ml in a control group (p<0.001). A negative correlation between patients' age and vitamin D concentration (r = -0.2, p<0.05, n = 96) was observed. An inverse relationship was found between skin involvement and vitamin D serum concentrations; Patients with a Rodnan skin score of 10 or lower (n = 11) had a mean vitamin D concentration of 17.7 +/- 10.4 ng/ml compared to patients with a score above 10 (n = 28) 8 +/- 10.1 ng/ml (p=0.02, by the Mann-Whitney test). In conclusion, Patients with SSc have significantly lower serum vitamin D concentrations compared to healthy controls; moreover fibrosis of the cutaneous tissue is inversely related to the vitamin D concentration. PMID- 21320646 TI - Procedures to improve the repeatability of forced oscillation measurements in school-aged children. AB - Forced oscillation technique (FOT) parameters are less repeatable than spirometry, and the impact of technical factors, such as data acquisition and data filtering, are unknown. FOT was performed, in triplicate, on 48 children (8 11 years) and repeated two weeks later. We examined the separate effects of monitoring tidal volume (V(T)) prior to measurement and length of data acquisition on measurement repeatability. We compared the effects on repeatability of a filtering technique in which complete breaths containing respiratory artefact were rejected and statistical filters in which outlying data points were rejected. Within- and between-session repeatability of respiratory system resistance (Rrs) and reactance (Xrs) were assessed using coefficient of variation (CV) and intra-class correlation coefficient (ICC). Longer data acquisition reduced CV of Rrs and Xrs (60s vs. shorter durations, p <= 0.001). Monitoring V(T) reduced CV of Rrs (p = 0.05). Complete breath filtering improved CV and ICC for both Rrs and Xrs. The repeatability of FOT measurements can be improved by optimising data acquisition and filtering. PMID- 21320647 TI - Effect of the pore structure of bioactive glass balls on biocompatibility in vitro and in vivo. AB - We prepared porous bioactive glass (BG) balls with various pore architectures using a modified version of a polymer templating technique which is generally used for the synthesis of mesoporous BG. Sol-gel derived porous BG is an excellent candidate as a graft material for bone tissue regeneration due to its good bone forming bioactivity and biodegradability. The biodegradability is largely related to the pore architecture and affects its biocompatibility. The pore architecture of the BG balls was controllable by changing the reaction time in chloroform. The relationship between the pore architecture of the BG balls and biocompatibility were studied using MC3T3-E1 pre-osteoblast cells in vitro and the rabbit calvarial model in vivo 8 weeks after implantation. The mesoporous BG balls (BG0) and porous BG beads with a hierarchical pore structure on the nano- to microscale (BG0.5 and BG2) showed a good cell proliferation response and differentiation behavior in vitro and in vivo without serious toxicity. These hierarchically porous structures also enhanced osteoconductivity. However, the existence of too many microscale pores in the BG balls (BG24) led to their rapid biodegradation and, consequently, to serious negative effects in vitro and in vivo. The pore architecture of the BG balls greatly influenced their biocompatibility, as well as bone formation, and should be carefully controlled when designing new materials for use in bioapplications. The porous BG balls with hierarchical pores on the nano- to microscale exhibit favorable biocompatibility in vitro and promise excellent potential applications in the field of biomaterials, such as tissue regeneration and drug storage. PMID- 21320648 TI - Biocatalytic synthesis and antitumor activities of novel silybin acylated derivatives with dicarboxylic acids. AB - Novel silybin acylated derivatives with dicarboxylic acids were prepared in various organic solvents using immobilized Candida antarctica lipase B (Novozym 435((r))). The reaction parameters affecting the silybin conversion, such as the nature of the organic solvent and the acyl donor used were investigated. The antiproliferative effects of silybin monoesters, and their ability to modulate the secretion of vascular endothelial growth factor (VEGF) were estimated using K562 human lymphoblastoma cells and compared to the parental compound. The synthesized esters retained the biological function of silybin and in some cases were more effective, indicating that target biotransformation may generate novel compounds with improved antitumor and antiangiogenic activities. PMID- 21320649 TI - Proteins associated with cork formation in Quercus suber L. stem tissues. AB - Cork (phellem) formation in Quercus suber stem was studied by proteomic analysis of young shoots of increasing age (Y0, Y1 and Y4) and recently-formed phellem (Y8Ph) and xylem (Y8X) from an 8-year-old branch. In this study 99 proteins were identified, 45 excised from Y8X and 54 from Y8Ph. These ones, specifically associated with phellem, are of "carbohydrate metabolism" (28%), "defence" (22%), "protein folding, stability and degradation" (19%), "regulation/signalling" (11%), "secondary metabolism" (9%), "energy metabolism" (6%), and "membrane transport" (2%). The identification in phellem of galactosidases, xylosidases, apiose/xylose synthase, laccases and diphenol oxidases suggests intense cell wall reorganization, possibly with participation of hemicellulose/pectin biosynthesis and phenol oxidation. The identification of proteasome subunits, heat shock proteins, cyclophylin, subtilisin-like proteases, 14-3-3 proteins, Rab2 protein and enzymes interacting with nucleosides/nucleic acids gives additional evidence for cellular reorganization, involving cellular secretion, protein turnover regulation and active control processes. The high involvement in phellem of defence proteins (thioredoxin-dependent peroxidase, glutathione-S-transferase, SGT1 protein, cystatin, and chitinases) suggests a strong need for cell protection from the intense stressful events occurring in active phellem, namely, desiccation, pests/disease protection, detoxification and cell death. Identically, highly enhanced defence functions were previously reported for potato periderm formation. PMID- 21320650 TI - The influence of temperature on plant development in a vernalization-requiring winter wheat: A 2-DE based proteomic investigation. AB - In this work, proteomics was used to study the influence of both optimal and low temperatures on growth and development in a vernalization-requiring winter wheat (Triticum aestivum L. cv Cheyenne) after prolonged times of treatment. For this purpose, plants were grown at optimal temperature (20 degrees C) for 14 days (zero point) after which half were transferred to conditioned chambers kept at 4 degrees C for a period of 63 days. Cold tolerance, as estimated from lethal temperatures (LT(50)), and phenological development, as measured by final leaf number (FLN) and shoot apex dissection, were determined. Proteomic analysis indicated a down-accumulation of several photosynthesis-related proteins and a concomitant increase in abundance of some Calvin cycle enzymes. A cold-induced accretion of soluble sugars and proline was observed as well. In parallel, an increase of proteolysis accomplished by an up-modulation of TCA cycle enzymes was also noticed, probably suggesting an efficient recycling of amino acids as energy source. Proteomic analysis of plants grown at optimal temperature allowed to specifically discriminate cold-induced proteins and highlight molecular processes driven by vernalization. Among identified proteins typically involved in vernalization responses and floral transition we observed a marked increase of wrab17, wcor18 and glycine-rich RNA-binding proteins. PMID- 21320651 TI - Advanced imaging assessment of bone fragility in glucocorticoid-induced osteoporosis. AB - Advanced bone imaging techniques provide structural information, beyond bone mineral density (BMD), and growing evidence indicates that BMD only partially explains bone strength and fracture resistance. Assessing glucocorticoid-induced osteoporosis (GIO) is important, especially the documentation of glucocorticoid (GC) impact on trabecular and cortical bone and on macro and microstructural features. Advanced methods for assessing macrostructure of bone include volumetric quantitative computed tomography (vQCT), high-resolution computed tomography (hrCT), and high-resolution magnetic resonance imaging (hrMRI). The methods for assessing bone microstructure include micro computed tomography (MUCT) and micro magnetic resonance imaging (MUMRI). Many advanced imaging techniques have been used in vitro and in vivo to examine structural effects of GIO in animals and in humans, and these applications are explored in this review. In human in vitro studies, investigators have used standard bone histomorphometry and MUCT to compare trabecular microarchitecture and bone remodeling in postmenopausal women and in males with GIO, and have found that high-dose GC produces dramatic bone loss, accompanied by major reduction in trabecular connectivity and increases in trabecular perforations. In animal studies, investigators have used standard histomorphometry along with pQCT, vQCT, hrMRI or MUCT to examine GIO in a variety of animal models including rats, minipigs and sheep. They generally have found excellent relationships between treatment induced structural changes assessed by these advanced imaging techniques and changes in BMD and biomechanical properties. They also have examined various therapeutic interventions in animals and monitored their efficacy using quantitative imaging methods. In human in vivo studies, investigators have serially examined postmenopausal women and males with GIO in order to assess the extent of skeletal deterioration and to determine the best advanced measures of BMD and structure, with which to monitor disease activity and therapeutic response, and to predict fracture risk. They generally have found that bone density and structural measures obtained by pQCT, vQCT and hrMRI contributed substantially to understanding the skeletal effects of glucocorticoids and to predicting the risk of fracture in human GIO. These animal and human applications, illustrating advanced imaging in GIO, are still in early stages of development. However, as discussed in this review, the novelty and power of the imaging approaches are compelling, and their utility is promising. PMID- 21320652 TI - Bisphosphonates in oncology. AB - Bone metastases result in considerable morbidity, often affecting quality of life and independence over years, and may place complex demands on health care resources. The bisphosphonates have been shown to reduce skeletal morbidity in multiple myeloma and solid tumours affecting bone by 30-50%. Quite appropriately, these agents are increasingly used alongside anticancer treatments to prevent skeletal complications and relieve bone pain. The use of bisphosphonates in early cancer has become increasingly important to prevent adverse effects of cancer treatments on bone health. These include chemotherapy induced ovarian failure and the use of aromatase inhibitors in breast cancer and androgen deprivation therapy in prostate cancer. Bisphosphonate strategies, similar to those used to treat post-menopausal osteoporosis, are the intervention of choice for patients with low bone mineral density or rapid bone loss, along with adequate calcium and vitamin D intake and a healthy lifestyle. There is a strong preclinical rationale for bisphosphonates to prevent metastasis, primarily through inhibition of the vicious cycle of metastasis within the microenvironment. Recent data suggest that adjuvant bisphosphonates, at least in some patient subgroups, may modify the course of the disease and disrupt the metastatic process, reducing the risks of disease recurrence. In comparison to most other cancer treatments, adverse events related to bisphosphonate therapy are generally mild and infrequent; thus, the benefits of treatment within licensed indications will almost always outweigh the risks. PMID- 21320655 TI - Magnet hospitals: recruiting and retaining nurses. PMID- 21320653 TI - Correlations of nursing home characteristics with prescription of osteoporosis medications. AB - BACKGROUND: Osteoporosis is highly prevalent in the nursing home (NH) populations but medications that increase bone mineral density are used infrequently. Prior research finds few patient characteristics predict treatment. NH characteristics have been associated with prescription of some medications. We examined associations of NH-level characteristics with osteoporosis treatment in elderly patients admitted to a NH after a fracture. METHOD: We conducted a cohort study of patients with hip, wrist and humeral fractures admitted to a NH in NJ. They were followed for 12 months from 1999 to 2004. Possible NH-level predictors of receiving osteoporosis treatment were assessed in mixed multivariable models to account for clustering within individual NHs. RESULTS: Of the 2838 post-fracture patients identified from 180 NHs, 156 (5.5%) were prescribed an osteoporosis medication. There was wide variation in treatment between individual NHs (0-40%), which was substantially reduced after adjusting for patient case mix. Several patient characteristics did associate with osteoporosis treatment-female gender (odds ratio (OR) 2.56, 95% confidence interval (CI) 1.42, 4.61), younger age per year (OR 0.98, 95%CI 0.96, 0.99), white race (OR 2.37, 95%CI 1.23, 4.56) and prior history of fracture (OR 4.41, 95%CI 1.04, 18.73). However no NH characteristics significantly associate with treatment (profit status, NH chain member, occupancy rate, and bed size). CONCLUSION: NH characteristics did not predict pharmacological treatment of osteoporosis. Further studies of osteoporosis prescribing in NHs need to consider other types of variables as possible correlates of prescribing. PMID- 21320656 TI - Nursing and the aging workforce: myths and reality, what do we really know? AB - Not unlike the general population, the population of nurses is aging. This trend is problematic for the nursing workforce in the light of a predicted shortage yet the extent of the effect of the aging population is unknown. What should individuals older than 45 years know to mitigate the effects of aging both physically and professionally? This article describes the magnitude of the aging nursing workforce issue, explores the myths and realities related to the aging process, discusses evidence-based strategies supporting healthy aging and retention of experienced nurses in one Magnet hospital, and introduces recommendations for further study. PMID- 21320657 TI - Creating a nursing strategic planning framework based on evidence. AB - This article describes an evidence-informed strategic planning process and framework used by a Magnet-recognized public health system in California. This article includes (1) an overview of the organization and its strategic planning process, (2) the structure created within nursing for collaborative strategic planning and decision making, (3) the strategic planning framework developed based on the organization's balanced scorecard domains and the new Magnet model, and (4) the process undertaken to develop the nursing strategic priorities. Outcomes associated with the structure, process, and key initiatives are discussed throughout the article. PMID- 21320658 TI - The implementation of the UHC/AACN new graduate nurse residency program in a community hospital. AB - Transition into the workforce for the new graduate nurse is affected by many factors. New graduate nurses can benefit from support provided through participation in the UHC/AACN Residency Program. The retention of even one graduate nurse saves the employing institution up to an estimated $80,000 annually. St Joseph's Hospital has improved the retention of new graduate nurses from approximately 40% to 100% with the addition of the UHC/AACN Residency Program alongside other system changes. Data are being monitored at St Joseph's and on a national level through this multisite collaborative aimed at improving patient care and increasing nurse retention. PMID- 21320659 TI - Professional practice model: strategies for translating models into practice. AB - In the current health care climate, economic and cultural conditions have created an optimal opportunity to envision a new direction for nursing as a profession. Nurses find themselves at the formative stages of charting this new direction. The articulation of a professional practice model provides a framework for setting this new direction and thus the achievement of exemplary clinical outcomes. In this article, the authors describe the evolution of the professional practice model at the Massachusetts General Hospital and how the model continues to be evaluated and modified over time by the nurses within the system. PMID- 21320660 TI - Transforming organizational culture through nursing shared governance. AB - Nursing shared governance (NSG) provides a framework for the professionalization of nursing, provides a broader distribution of decision making across the profession, and allocates decisions based on accountability and role expectations. Shared governance defines staff-based decisions, accountability, roles, and ownership of staff in those activities that directly affect nurses' lives and practice. Although NSG is a somewhat ambiguous concept with a vast application, examining it from the perspective of structure, process, and outcomes can more clearly outline a successful strategy for implementation and growth. PMID- 21320661 TI - Empowering nurses through an innovative scheduling model. AB - In 1980, Froedtert Hospital opened its doors using an innovative registered nurse scheduling model. The hospital has grown to 500 beds, with over 1,600 registered nurses, and continues to use the 7/70 staffing pattern as a core scheduling model. Registered nurses work a straight seven, 10-hour days, and then have 1 week off, or 26 weeks off a year. For professional registered nurses in acute care, the schedule is predictable and consistent for years. This scheduling pattern has resulted in excellent registered nurse satisfaction, increased retention, and consistency in care delivery teams since 1980. PMID- 21320662 TI - Promoting professional nursing practice: linking a professional practice model to performance expectations. AB - Professional practice models (PPMs) provide the conceptual framework for establishing professional nursing practice. Integrating a PPM requires complex organizational change. One strategy for integrating a PPM is to directly link the PPM with performance expectations to ensure that underlying beliefs are integrated into everyday practice. This article describes the development, implementation, and successful outcomes of a clinical advancement system that was aligned with a PPM. PMID- 21320663 TI - Building an engaged and certified nursing workforce. AB - Professional certification has been linked to positive patient, system, and nurse outcomes. However, certification rates among nurses remain low. Using tenets from employee engagement theory, we designed strategies to fully engage nurses within our nursing division to pursue certification. After 1 year, certification rates more than doubled in our cardiac departments. PMID- 21320664 TI - The outcomes of Magnet environments and nursing staff engagement: a case study. AB - To ensure that nursing as a profession is recognized for the value we provide to our organizations, communities, and the world, a consistent level of practice and professionalism will be necessary. Consistency across the profession can be achieved through support of the framework and structures required for the process of attaining Magnet designation. This article is a case study of an organization that on all levels from economic, manpower, quality, and safety has benefited from the Magnet journey. PMID- 21320665 TI - The rural pipeline: building a strong nursing workforce through academic and service partnerships. AB - Nurse recruitment and the retention of a high-quality workforce are challenging issues facing rural hospitals and health centers. The Bassett Healthcare Network has met these challenges by building a supportive framework to develop and support nurses at every level of their professional careers. The organization has partnered with local colleges to help staff nurses further their education. These and other partnership endeavors, such as the organization's clinical ladder and collaborative continuing nursing education opportunities, are helping Bassett sustain and grow the nursing workforce across 8 counties in rural upstate New York and develop stronger ties with academic partners. PMID- 21320666 TI - Collaborative research partnerships in support of nursing excellence. AB - Nursing leadership is committed to advancing the profession of nursing through research and evidence-based practice. Partnerships between the hospital and area academic institutions were formed to develop a comprehensive research program that supported active involvement for frontline staff and provide clinical research opportunities for area faculty. Through this collaborative model, the research program has continually expanded and provided clinical research that is making a difference for patients and families. The commitment of this service/academic research partnership is shown by the close involvement of each in future planning for studies and program development. A collaborative partnership is an excellent means to promote clinical research and support nursing excellence. PMID- 21320667 TI - Shaping future nurse leaders through shared governance. AB - The progression of five professional nurses from shared governance council chairs to unit director positions and the progression of three nurses from shared governance council chairs to clinical nurse specialist roles in an 18-year period provide compelling evidence of the impact shared governance has provided in the development of future nurse leaders in our organization. The collective wisdom of those who have lived this experience suggests that the opportunities inherent in these clinical nurse leadership roles make this a logical progression, including getting noticed and nudged, developing an understanding of the big picture, developing a results orientation, and substantial skill acquisition. PMID- 21320668 TI - Novel diagnostic and therapeutic approaches in Gynecologic Oncology: considerations for a new decade. PMID- 21320669 TI - Supporting gynecologic cancer research: the last 20 years and beyond. PMID- 21320670 TI - Conservative management of early stage cervical cancer: is there a role for less radical surgery? AB - OBJECTIVES: The utility of parametrial resection in women with early stage cervical cancer is controversial. In patients with favorable pathologic characteristics such as tumor size <2cm and the absence of lymphovascular space invasion, the rate of parametrial involvement is very low. More conservative surgical approaches have therefore been suggested. The objective of this report is to review the existing literature in this area and to describe an ongoing prospective study evaluating the safety and efficacy of conservative surgery in women with early stage cervical cancer. METHODS: We performed a search of PubMed for English language articles published between 1970 and 2010 using the MeSH terms "cervical cancer", "conservative surgery", and "cone biopsy". RESULTS: Several retrospective studies have shown that <1% of patients with early stage cervical cancer with favorable pathologic characteristics have parametrial involvement. In addition, approximately 60% of patients undergoing radical trachelectomy have no residual disease in the final pathologic specimen. Recent studies have reported on the feasibility and safety of performing less radical surgery consisting of pelvic lymphadenectomy with cone biopsy, simple trachelectomy or simple hysterectomy in women with stage IA1 to IB1 cervical carcinoma. In addition, a prospective, multi-center, international trial is currently being performed to evaluate the outcomes of performing pelvic lymphadenectomy with conservative surgery (simple hysterectomy or cervical conization) in patients with favorable pathologic characteristics. Neoadjuvant chemotherapy followed by conservative surgery is also being explored as an option for patients with larger tumors and other pathologic characteristics that do not meet the criteria to perform conservative surgery alone. CONCLUSIONS: The rate of parametrial involvement in women with early stage cervical cancer with favorable pathologic characteristics is low. Should the results of ongoing studies be favorable, conservative surgery could become the standard of care for certain women with early stage cervical cancer. PMID- 21320672 TI - Heart failure self-management instruction: Impact on heart failure outcomes. PMID- 21320673 TI - Improved bed use with creation of a short-stay unit in a cardiac catheterization recovery room. AB - OBJECTIVE: To solve a capacity problem in a pediatric cardiovascular program, a 5 bed short-stay unit was created in the cardiac catheterization recovery room area within a 6-week timeframe. We describe the problem, solution, and early results in hospital performance and patient outcomes. METHODS: Data were reviewed for 183 patients who underwent various cardiac catheterization procedures and recovered overnight in the cardiac short-stay unit during the first 4 months of operation. The effect on bed use throughout the cardiac program and impact on the usual recovery room operations were assessed. RESULTS: The cardiovascular inpatient bed shortage was relieved with the creation of a 5-bed short-stay unit, and no cardiac procedures were canceled because of lack of beds during the study period. CONCLUSION: There was no negative impact on clinical operations in the catheterization laboratory recovery room, and the short-stay unit was cost effective. According to the rate of admission after recovery in the short-stay unit (5/183), patient selection was appropriate. PMID- 21320674 TI - Left spontaneous pneumothorax presenting with ST-segment elevations: a case report and review of the literature. AB - Common electrocardiogram (ECG) changes associated with left-sided pneumothorax include right axis deviation, reduced R-wave amplitude in precordial leads, QRS alterations (amplitude changes), and T-wave inversions. Few reports exist of ST segment elevations or changes suggestive of acute myocardial infarction (AMI), and these involve older patients with tension pneumothorax and previous coronary heart disease. We report on a young man with no significant medical history, presenting with left-sided spontaneous pneumothorax and ECG changes that included ST-segment elevations and T-wave inversions in the precordial leads, reminiscent of AMI. All changes resolved after decompression of the pneumothorax. On the basis of the patient's presenting symptoms, response to therapy, and our review of the literature, we propose a number of possible mechanisms explaining his electrocardiographic findings. PMID- 21320675 TI - HER-2/neu expression is consistent in primary and metastatic lung adenocarcinoma. PMID- 21320676 TI - Health Web sites for teens. PMID- 21320677 TI - NAPNAP position statement on immunizations. PMID- 21320678 TI - Recipe sharing at the macro level. PMID- 21320679 TI - Early intervention in pediatrics offices for emerging disruptive behavior in toddlers. AB - BACKGROUND: This study provides preliminary data about a parenting intervention for families of preschoolers with early attention deficit hyperactivity disorder/oppositional defiant disorder symptoms carried out in two diverse primary care pediatric offices. METHOD: Parents of toddlers completed behavioral screening questionnaires at well-child visits. Eligible parents participated in a 10-week parenting education group using the Incredible Years program. Mothers completed several outcome measures at three time points: before participating in the group, immediately after the group ended, and 6 months thereafter. These measures assessed changes in parenting practices, parenting stress, and child symptoms. Parent and provider satisfaction also were assessed. RESULTS: Mothers reported improvements in parenting skills and a decrease in stress. They also reported a decrease in child aggression and an increase in compliance. Mothers and providers reported high levels of satisfaction. CONCLUSIONS: Results support the benefits and feasibility of providing parenting education groups to parents of toddlers in pediatric practice settings. PMID- 21320680 TI - Perceptions of parenting children with type 1 diabetes diagnosed in early childhood. AB - INTRODUCTION: The purpose of this study was to explore perceptions of psychosocial adaptations in parenting young children with type 1 diabetes (T1DM) from diagnosis through childhood. METHOD: Fourteen parents of 11 children with T1DM who were diagnosed at age five years or younger participated in semi structured interviews. Data were analyzed using content analysis. RESULTS: Three significant themes were identified. In the theme "Diagnostic Experiences: Frustrations, Fears, and Doubts," parents described inadequate diagnostic experiences with pediatricians where concerns were minimized and diagnosis was sometimes delayed. Although hospitalization occurred abruptly, communication with specialists was more satisfactory. In the theme "Adapting to Diabetes," parents described isolation in caring for their child's T1DM. Family and friends had minimal understanding of T1DM care. Support groups lessened mothers' isolation, but fathers were less positive about this experience. Parental adaptation was more effective when responsibility for diabetes decision making was shared. All parents reported never mastering diabetes management. The theme "Negotiating Developmental Transitions" revealed that normative childhood events were stressful, requiring that parents balance concerns to foster their child's participation. CONCLUSIONS: Pediatric providers can improve diagnostic and treatment experiences for parents of children with T1DM by recognizing feelings of isolation and lack of mastery, providing attentive communication, encouraging parental teamwork, and offering ongoing anticipatory guidance. PMID- 21320681 TI - Fathers' coping mechanisms related to parenting a chronically ill child: implications for advanced practice nurses. AB - INTRODUCTION: The presence of a father has been positively associated with outcomes in several aspects of a child's life. This descriptive study investigated coping methods used by fathers of chronically ill children, fathers' perceived severity of the child's illness, and demographic differences related to coping mechanisms. METHOD: A sample of 54 fathers of chronically ill children completed measurements of demographics, coping processes, and severity levels of their child's chronic condition. Data were analyzed with SPSS 14.0 using parametric and nonparametric tests to examine relationships and coping behaviors used by fathers in northwest Florida. RESULTS: A majority of fathers used an emotion-focused coping process with a religious dimension. No association was found between perceived level of severity of their child's illness and eight subscales used to measure coping methods; however, statistical significance was found between the age and marital status of fathers with seven of the subscales. Married and older fathers more often used "positive" coping mechanisms than did younger, unmarried fathers. DISCUSSION: The findings emphasize the need for practitioners, clinicians, and educators to assess, support, and provide appropriate resources to fathers in order to promote positive effective coping and increase the level of involvement in the child's life. PMID- 21320682 TI - Adolescents' perception of asthma symptoms and health care utilization. AB - INTRODUCTION: Pediatric asthma is accountable for a substantial use of health care services. The purpose of this study was to systemically examine the extent to which inaccurate perception of asthma symptoms is associated with the use of health care services. METHODS: This exploratory study included 126 adolescents with asthma who were between 13 and 20 years of age. Subjects were classified as having inaccurate symptom perception (IG); well-controlled accurate symptom perception (WCA); and poorly controlled accurate symptom perception (PCA). These groups were compared with respect to health care utilization, including emergency department (ED) visits, hospitalization, and office visits and school absenteeism in the past 3 months. RESULTS: More adolescents in the IG group had at least one hospitalization compared with adolescents in the PCA or WCA groups (23.1% vs. 11.1% vs. 2.6%, respectively). A similar trend was seen for ED visits. Compared with the WCA group, adolescents in the IG group were nearly nine times more likely to have been hospitalized, 3.4 times more likely to have visited an ED, and four times more likely to have missed school days. DISCUSSION: Adolescents with inaccurate symptom perception are more likely to have hospitalizations, ED visits, and missed days from school compared with those who have accurate perceptions. The findings underscore the importance of screening for perceptual accuracy of asthma symptoms and call for interventions promoting accurate symptom assessment in adolescents with asthma to ensure appropriate care. PMID- 21320683 TI - A review of attachment theory in the context of adolescent parenting. AB - The purpose of this article is to review attachment theory and relate the attachment perspective to adolescent mothers and their children. Attachment theory explains positive maternal-infant attachment as a dyadic relationship between the infant and mother that provides the infant with a secure base from which to explore the world. With respect to cognitive, social, and behavioral domains, securely attached infants tend to have more favorable long-term outcomes, while insecurely attached infants are more likely to have adverse outcomes. Adolescent parenthood can disrupt normal adolescent development, and this disruption influences development of the emotional and cognitive capacities necessary for maternal behaviors that foster secure attachment. However, it appears that if specialized supports are in place to facilitate the process of developing attachment, infants of adolescent mothers can obtain higher rates of secure attachment than normative samples in this population. PMID- 21320684 TI - Chronic wet cough. PMID- 21320685 TI - Heat-related illness risk with methylphenidate use. PMID- 21320686 TI - Assessment of Children's Public Health Insurance Program enrollment applications: a health literacy perspective. AB - INTRODUCTION: More than half of uninsured children in the United States qualify for Medicaid or the Children's Health Insurance Program (CHIP). Application readability and other complex features may be barriers to enrollment for some of these families. The purpose of this study was to conduct a literary assessment of state-issued English- and Spanish-language Medicaid/CHIP Internet-based enrollment applications, including an evaluation of reading demands, layout characteristics, and document complexity. METHOD: In May 2010, we downloaded all currently available English-language (n = 50) and Spanish-language (n = 39) Internet-based, state-issued Medicaid/CHIP enrollment applications. We estimated the reading demands of each CHIP enrollment application "Signature" page using the Lexile Analyzer. We assessed layout characteristics using the User Friendliness Tool and we evaluated document complexity using the PMOSE/IKIRSCH scale. RESULTS: On average, Medicaid/CHIP enrollment application "Signature" pages were written at a high school reading level (English language = 12th- to 13th-grade reading level; Spanish language = 10th- to 11th-grade reading level). Five Medicaid/CHIP enrollment applications (5.6%) consistently used a 12-point or larger font size throughout. Most Medicaid/CHIP enrollment applications (n = 83; 93.3%) needed "some" or "much" improvement in the amount of white space. Document complexity ranged from level 3 (moderate) to level 5 (very high), with the majority of Medicaid/CHIP enrollment applications ranked at level 4 (high). DISCUSSION: Revisions are required in almost all state Medicaid/CHIP enrollment applications to achieve consistency and to meet standard low-literacy guidelines (e.g., written at a 6th grade or lower reading level and using a font of 12 points or larger). Additionally, to increase access to Medicaid/CHIP for eligible Hispanic children, all states should provide an online Spanish-language version of the Medicaid/CHIP enrollment application. PMID- 21320688 TI - Peaceful mutualism in the gut: revealing key commensal bacteria for the creation and maintenance of immunological homeostasis. AB - Quantitative and qualitative aspects of commensal bacteria determine the active and quiescent status of host immunity. In a recent Science paper, Atarashi et al. (2011) identify Clostridium clusters IV and XIVa as indigenous commensal bacteria that induce regulatory T cells for the creation and maintenance of immunological homeostasis. PMID- 21320689 TI - HATs on for drug resistance. AB - Mutations in the human cytomegalovirus UL27 gene confer resistance to an inhibitor of the viral protein kinase UL97. Reitsma and colleagues (2011) demonstrate that UL27 destabilizes the Tip60 histone acetyltransferase, setting forth intriguing new mechanisms for antiviral drug resistance and for viral regulation of the cell cycle. PMID- 21320690 TI - Activation of plant nod-like receptors: how indirect can it be? AB - Pioneering plant research has shown that many Nod-like receptors (NLRs) detect pathogens indirectly via recognizing modifications of other host proteins. In this issue, two groups show that the RPM1 NLR is activated by phosphorylation of the host protein RIN4, probably resulting from activation of a host kinase by pathogen effectors. PMID- 21320691 TI - Evicting the pneumococcus from its nasopharyngeal lodgings. AB - Nasopharyngeal colonization by Streptococcus pneumoniae precedes invasive disease and mediates community transmission of the pathogen. In this issue, Moffitt et al. (2011) used proteomic analysis to identify conserved pneumococcal protein vaccine antigens that elicit T(H)17-dependent responses capable of preventing such colonization. PMID- 21320692 TI - An identical miRNA of the human JC and BK polyoma viruses targets the stress induced ligand ULBP3 to escape immune elimination. AB - The human polyoma viruses JCV and BKV establish asymptomatic persistent infection in 65%-90% of humans but can cause severe illness under immunosuppressive conditions. The mechanisms by which these viruses evade immune recognition are unknown. Here we show that a viral miRNA identical in sequence between JCV and BKV targets the stress-induced ligand ULBP3, which is a protein recognized by the killer receptor NKG2D. Consequently, viral miRNA-mediated ULBP3 downregulation results in reduced NKG2D-mediated killing of virus-infected cells by natural killer (NK) cells. Importantly, when the activity of the viral miRNA was inhibited during infection, NK cells killed the infected cells more efficiently. Because NKG2D is also expressed by various T cell subsets, we propose that JCV and BKV use an identical miRNA that targets ULBP3 to escape detection by both the innate and adaptive immune systems, explaining how these viruses remain latent without being eliminated by the immune system. PMID- 21320693 TI - Antiviral inhibition targeting the HCMV kinase pUL97 requires pUL27-dependent degradation of Tip60 acetyltransferase and cell-cycle arrest. AB - Infection with the beta-herpesvirus human cytomegalovirus (HCMV) is lifelong, causing limited disease in healthy adults, but life threatening in immunocompromised individuals. The viral kinase pUL97, a functional ortholog of cellular cyclin-dependent kinases (CDKs), is critical for HCMV replication and a target for antiviral drug development. Upon kinase inhibition, drug-resistant strains emerge with mutations in UL27, an HCMV gene of unknown function. Using a proteomics approach, we discovered that pUL27 is necessary and sufficient to degrade Tip60, a host acetyltransferase and interacting partner of HIV Tat. Consistent with this, the expression of Tat restored antiviral inhibition of an otherwise resistant HCMV strain. The functional consequence of Tip60 degradation was the induction of the CDK inhibitor p21(Waf1/Cip1) and cell-cycle arrest, representing changes necessary for the antiviral effects of pUL97 inhibition. Consequently, either increasing p21(Waf1/Cip1) expression or decreasing Tip60 levels improved the antiviral activity of the HCMV kinase inhibitor maribavir. PMID- 21320694 TI - DNA repair proteins are directly involved in regulation of gene expression during plant immune response. AB - Systemic acquired resistance (SAR), an inducible plant-defense response to local infection, requires the signaling molecule salicylic acid (SA) and the transcriptional coactivator NPR1, with concerted activation of pathogenesis related (PR) genes. Arabidopsis sni1 is an npr1 suppressor and derepression of defense genes in sni1 causes reduced growth and fertility and increased homologous recombination. Characterizing suppressors of sni1, we identify the DNA damage repair proteins SSN2 and RAD51D as genetic and physical interactors with SNI1. During plant defense, SSN2 and possibly RAD51D replace the transcription repressor SNI1 at pathogenesis-related gene promoters. In the presence of SNI1, NPR1 is also required for SSN2 binding. Thus, coordinated action of SNI1, SSN2 RAD51D, and NPR1 ensures the tight control of plant immune gene expression. Given that the SSN2-RAD51D complex is conserved in eukaryotes, their dual function in homologous recombination and transcription regulation of plant-defense genes suggests a general link between these two stress responses. PMID- 21320695 TI - Specific threonine phosphorylation of a host target by two unrelated type III effectors activates a host innate immune receptor in plants. AB - The Arabidopsis NB-LRR immune receptor RPM1 recognizes the Pseudomonas syringae type III effectors AvrB or AvrRpm1 to mount an immune response. Although neither effector is itself a kinase, AvrRpm1 and AvrB are known to target Arabidopsis RIN4, a negative regulator of basal plant defense, for phosphorylation. We show that RIN4 phosphorylation activates RPM1. RIN4(142-176) is necessary and, with appropriate localization sequences, sufficient to support effector-triggered RPM1 activation, with the threonine residue at position 166 being critical. Phosphomimic substitutions at T166 cause effector-independent RPM1 activation. RIN4 T166 is phosphorylated in vivo in the presence of AvrB or AvrRpm1. RIN4 mutants that lose interaction with AvrB cannot be coimmunoprecipitated with RPM1. This defines a common interaction platform required for RPM1 activation by phosphorylated RIN4 in response to pathogenic effectors. Conservation of an analogous threonine across all RIN4-like proteins suggests a key function for this residue beyond the regulation of RPM1. PMID- 21320696 TI - A receptor-like cytoplasmic kinase phosphorylates the host target RIN4, leading to the activation of a plant innate immune receptor. AB - Plants have evolved sophisticated surveillance systems to recognize pathogen effectors delivered into host cells. RPM1 is an NB-LRR immune receptor that recognizes the Pseudomonas syringae effectors AvrB and AvrRpm1. Both effectors associate with and affect the phosphorylation of RIN4, an immune regulator. Although the kinase and the specific mechanisms involved are unclear, it has been hypothesized that RPM1 recognizes phosphorylated RIN4. Here, we identify RIPK as a RIN4-interacting receptor-like protein kinase that phosphorylates RIN4. In response to bacterial effectors, RIPK phosphorylates RIN4 at amino acid residues T21, S160, and T166. RIN4 phosphomimetic mutants display constitutive activation of RPM1-mediated defense responses and RIN4 phosphorylation is induced by AvrB and AvrRpm1 during P. syringae infection. RIPK knockout lines exhibit reduced RIN4 phosphorylation and blunted RPM1-mediated defense responses. Taken together, our results demonstrate that the RIPK kinase associates with and modifies an effector-targeted protein complex to initiate host immunity. PMID- 21320697 TI - RAB-5- and RAB-11-dependent vesicle-trafficking pathways are required for plasma membrane repair after attack by bacterial pore-forming toxin. AB - Pore-forming toxins (PFTs) secreted by pathogenic bacteria are the most common bacterial protein toxins and are important virulence factors for infection. PFTs punch holes in host cell plasma membranes, and although cells can counteract the resulting membrane damage, the underlying mechanisms at play remain unclear. Using Caenorhabditis elegans as a model, we demonstrate in vivo and in an intact epithelium that intestinal cells respond to PFTs by increasing levels of endocytosis, dependent upon RAB-5 and RAB-11, which are master regulators of endocytic and exocytic events. Furthermore, we find that RAB-5 and RAB-11 are required for protection against PFT and to restore integrity to the plasma membrane. One physical mechanism involved is the RAB-11-dependent expulsion of microvilli from the apical side of the intestinal epithelial cells. Specific vesicle-trafficking pathways thus protect cells against an attack by PFTs on plasma membrane integrity, via altered plasma membrane dynamics. PMID- 21320699 TI - Adherence and persistence with taking medication to control high blood pressure. AB - Nonadherence and poor or no persistence with taking antihypertensive medications results in uncontrolled high blood pressure, poor clinical outcomes and preventable health care costs. Factors associated with nonadherence are multilevel and relate not only to the patient, but also to the provider, health care system, health care organization, and community. National guideline committees have called for more aggressive approaches to implement strategies known to improve adherence and technologies known to enable changes at the systems level including improved communication among providers and patients. Improvements in adherence and persistence are likely to be achieved by supporting patient self-management, a team approach to patient care, technology-supported office practice systems, better methods to measure adherence, and less clinical inertia. Integrating high blood pressure control into health care policies that emphasize and improve prevention and management of chronic illness remains a challenge. Four strategies are proposed: focusing on clinical outcomes; empowering informed, activated patients; developing prepared proactive practice teams; and advocating for health care policy reform. With hypertension remaining the most common reason for office visits, the time is now. PMID- 21320698 TI - T(H)17-based vaccine design for prevention of Streptococcus pneumoniae colonization. AB - Streptococcus pneumoniae is a leading cause of mortality in young children. While successful conjugate polysaccharide vaccines exist, a less expensive serotype independent protein-based pneumococcal vaccine offers a major advancement for preventing life-threatening pneumococcal infections, particularly in developing nations. IL-17A-secreting CD4+ T cells (T(H)17) mediate resistance to mucosal colonization by multiple pathogens including S. pneumoniae. Screening an expression library containing >96% of predicted pneumococcal proteins, we identified antigens recognized by T(H)17 cells from mice immune to pneumococcal colonization. The identified antigens also elicited IL-17A secretion from colonized mouse splenocytes and human PBMCs suggesting that similar responses are primed during natural exposure. Immunization of two mouse strains with identified antigens provided protection from pneumococcal colonization that was significantly diminished in animals treated with blocking CD4 or IL-17A antibodies. This work demonstrates the potential of proteomic screening approaches to identify specific antigens for the design of subunit vaccines against mucosal pathogens via harnessing T(H)17-mediated immunity. PMID- 21320700 TI - Mindfulness-based stress reduction for patients with anxiety disorders: evaluation in a randomized controlled trial. AB - The aim of this study was to investigate the effect of mindfulness-based stress reduction (MBSR) for patients with heterogeneous anxiety disorders. Seventy-six self-referred patients were randomized to MBSR or a waiting-list control condition. Eight participants did not complete the eight-week MBSR intervention. Treatment completers improved significantly on all outcome measures compared to controls. The completer sample showed medium to large effect sizes on measures of anxiety (Cohen's d = 0.55-0.97), and a large effect size for symptoms of depression (Cohen's d = 0.97). Intention-to-treat analyses yielded effect sizes in the small to moderate range (Cohen's d = 0.32-0.76). Gains were maintained at six months follow-up. The percentage of participants reaching recovered status was highest for symptom measures of depression and anxiety, and lower for worry and trait anxiety. Mediation analyses indicated that mindfulness fully mediated changes in acute anxiety symptoms, and partially mediated changes in worry and trait anxiety. However, the present study did not find evidence of temporal precedence for the proposed mediator. In the absence of true mediation and an active control condition, it cannot be ruled out that results are due to non specific aspects of treatment. Despite these and other limitations, we conclude that MBSR is an effective treatment for anxiety disorders and related symptomatology. PMID- 21320701 TI - A comparative study of the O-3 reactivity of isomeric N-dimethylmaleoyl-protected D-glucosamine and D-allosamine acceptors. AB - Four isomeric N-dimethylmaleoyl 4,6-O-benzylidene-protected d-hexosamine acceptors (2, 3, 4, and 5) with all possible configurations at C-1 and C-3 (e.g., derived from d-glucosamine and D-allosamine) were prepared, and the assessment of their O-3 relative reactivity through competition experiments using the known per O-acetylated D-galactopyranosyl trichloroacetimidate donor (15) was then carried out. The reactivities are in the order 4?2>5>3. The analysis of the NMR spectra of 2-5 at different temperature and modeling experiments carried out on analogs of 2-5 (DFT) and on the acceptors themselves (MM) are coincident, and have helped to establish the stability of the different hydrogen bonds, and of the conformers which carry them. The whole results suggest that the electronic effects (hydrogen bonds) are required to explain the observed trend, in spite of the axial conformation of the most reactive hydroxyl group. The steric effects appear only when hydrogen bonds are weak. PMID- 21320702 TI - Synthesis of 1,2-cis- and 1,2-trans-glycosides of 2-acetamido-4,6-O-benzylidene-2 deoxy-D-glucopyranose by anomeric O-alkylation. AB - The reaction of a partially protected 1-hydroxy derivative of N-acetyl-D glucosamine with benzyl bromide under conditions of anomeric O-alkylation was studied. It was found that the stereoselectivity of the reaction depended on the nature of the alkali metal cation constituent of a transient ion pair. The substitution of the Li(+) cation for K(+) or complexation with a crown ether allowed the steric outcome to be shifted from beta- to alpha-selectivity. PMID- 21320703 TI - The importance of infiltrating neutrophils in SDF-1 production leading to regeneration of the thymus after whole-body X-irradiation. AB - Our previous study demonstrated that neutrophils transiently infiltrated into a site where apoptosis had been induced. However, the role of infiltrating neutrophils has not been fully elucidated. In this study, we examined their role in regeneration of the thymus after whole-body X-irradiation by focusing on SDF-1 production. After X-irradiation, the thymus became severely atrophied presumably due to phagocytosis of apoptotic thymocytes. At that time, a significant number of neutrophils were detected in the thymus. The thymus was then partially regenerated on day 7, whereas the level of SDF-1 in it was significantly increased on days 3 and 5. Depletion of neutrophils greatly impaired SDF-1 production and the thymus regeneration. Moreover, administration of a CXCR4 antagonist also greatly suppressed the thymus regeneration. Furthermore, coculturing of a stromal cell line with infiltrating neutrophils increased SDF-1 production. These results suggest that infiltrating neutrophils play an auxiliary role in regeneration of the thymus after whole-body X-irradiation through augmentation of SDF-1 production. PMID- 21320704 TI - Over the limit: use of peripheral venous cannulae above the manufacturer's recommended flow rates. PMID- 21320705 TI - WO3/BiOCl, a novel heterojunction as visible light photocatalyst. AB - A bismuth oxychloride (BiOCl) nanostructure is prepared by a new low temperature route using sodium dodecyl sulfate as template and urea as hydrolytic agent. A novel heterojunction is developed between BiOCl and tungsten oxide (WO(3)) to make it an efficient visible light photocatalyst. The catalysts were characterized by X-ray diffraction analysis, Raman spectroscopy, thermogravimetric analysis, energy-dispersive X-ray spectroscopy, scanning electron microscopy, transmission electron microscopy, and N(2) sorption isotherms. The WO(3)/BiOCl heterojunction system extends the absorption edge to the visible region efficiently. BiOCl works as a main photocatalyst while WO(3) acts as the photosensitizer absorbing visible light in the WO(3)/BiOCl composite. The individual BiOCl and WO(3) show very low photocatalytic efficiency under visible light irradiation but their heterojunction provides unexpectedly high efficiency in decomposing rhodamine B as compared to Degussa P25, pure BiOCl, and WO(3). PMID- 21320706 TI - The development of automatic and controlled inhibitory retrieval processes in true and false recall. AB - In three experiments, we investigated the role of automatic and controlled inhibitory retrieval processes in true and false memory development in children and adults. Experiment 1 incorporated a directed forgetting task to examine controlled retrieval inhibition. Experiments 2 and 3 used a part-set cue and retrieval practice task to examine automatic retrieval inhibition. In the first experiment, the forget cue had no effect on false recall for adults but reduced false recall for children. In Experiments 2 and 3, both tasks caused retrieval impairments for true and false recall, and this occurred for all age groups. Implicit inhibition, which occurs outside of our conscious control, appears early in childhood. However, because young children do not process false memories as automatically as adults, explicit inhibition can reduce false memory output. PMID- 21320707 TI - Two frequent polymorphisms of angiotensinogen and their association with multiple sclerosis progression rate. AB - A total of 195 patients with multiple sclerosis (MS) and 126 controls were investigated for angiotensinogen/(-6)A/G, M235T/and angiotensin converting enzyme I/D gene polymorphisms to test their association with MS susceptibility and/or disease progression using Global Multiple Sclerosis Severity Score (MSSS). We demonstrated a significant association of M235T polymorphism with MSSS. The MM homozygotes had the lowest (3.8), heterozygotes MT higher (5.2) and homozygotes TT the highest (5.4) mean MSSS values (P=0.02). For polymorphisms (-6)A/G of ATG, only a trend was observed (P=0.06), where the homozygotes GG carried lower MSSS values than heterozygotes and homozygotes AA. No significant association with susceptibility was observed. For ACE I/D polymorphism, neither significant differences in the genotype-phenotype study nor in the case-control study were observed. PMID- 21320708 TI - Transapical miniaturized ventricular assist device: design and initial testing. AB - BACKGROUND: Left ventricular assist devices are increasingly used to treat patients with advanced and otherwise refractory heart failure as bridge to transplant or destination therapy. We evaluated a new miniaturized left ventricular assist device that requires minimal surgery for implantation, potentially allowing implantation in earlier stage heart failure. METHODS: HeartWare (Miami Lakes, Fla) developed transapical miniaturized ventricular assist device. Acute (n = 4), 1-week (n = 2), and 30-day (n = 4) bovine model experiments evaluated hemodynamic efficacy and biocompatibility of the device, which was implanted through small left thoracotomy with single insertion at apex of left ventricle without cardiopulmonary bypass. The device outflow cannula was positioned across the aortic valve. The international normalized ratio was maintained between 2.0 and 2.5 with warfarin. Hemodynamic, echocardiographic, fluoroscopic, hematologic, and blood chemistry measurements were evaluated. RESULTS: The device was successfully implanted through the left ventricular apex in all 10 animals. The device was operated at 15,000 +/- 1000 rpm (power consumption, 3.5-6.0 W). The device maintained normal end-organ perfusion with no significant hemolysis (0-30 mg/dL). There were no pump failures or device-related complications. At autopsy, no abnormalities were seen in endocardium, aortic valve leaflets, or aortic root. There was no evidence of thromboembolism or abnormalities in any peripheral end organs. CONCLUSIONS: We successfully demonstrated feasibility of a novel intraventricular assist device that can be completely implanted through left ventricular apex. This transapical surgical approach eliminates needs for sternotomy, device pocket, cardiopulmonary bypass, ventricular coring, and construction of an outflow graft anastomosis. PMID- 21320709 TI - Prognostic implications of pulmonary hypertension in patients with severe aortic stenosis. AB - OBJECTIVE: We sought to determine the clinical outcomes of patients undergoing surgical aortic valve replacement with hemodynamically confirmed severe pulmonary hypertension and aortic stenosis and compare them with the outcomes of patients not undergoing aortic valve replacement and patients undergoing aortic valve replacement with mild-to-moderate pulmonary hypertension. METHODS: A total of 317 patients with severe aortic stenosis (aortic valve area < 1 cm(2)) underwent right heart catheterization along with left heart catheterization between 2004 and 2009. Severe pulmonary hypertension (mean pulmonary artery pressure > 35 mm Hg) was present in 81 patients, of whom 35 (43.2%) underwent surgical aortic valve replacement. We compared the clinical outcomes of these 35 patients with the 46 patients with severe pulmonary hypertension who did not undergo surgical aortic valve replacement. RESULTS: Thirty-day mortality after aortic valve replacement was 2.85% in patients with severe pulmonary hypertension and 10.86% in patients not undergoing aortic valve replacement (P = .001). During a mean follow-up of 339.0 +/- 343.7 days, overall mortality in patients undergoing aortic valve replacement was 14.2% in patients with severe pulmonary hypertension and 50% in patients with severe pulmonary hypertension who did not undergo aortic valve replacement (P < .0001). On the other hand, among patients who underwent surgery, overall mortality was similar in both the mild-to-moderate pulmonary hypertension group (23 patients [20.3%]) and the severe pulmonary hypertension group at the end of the follow-up period (P = .4). In a multivariate analysis, the presence of chronic obstructive pulmonary disease and the lack of reduction in mean pulmonary artery pressure were independent predictors of mortality in these high-risk patients undergoing aortic valve replacement, whereas baseline mean pulmonary artery pressure was not a predictor. Preoperative pulmonary capillary wedge pressure was a significant predictor of postoperative reduction in mean pulmonary artery pressure. CONCLUSIONS: In patients with severe aortic stenosis and severe pulmonary hypertension who undergo aortic valve replacement, baseline pulmonary artery pressure does not unfavorably affect survival. Aortic valve replacement should be considered for patients with aortic stenosis with severe pulmonary hypertension, especially with higher pulmonary capillary wedge pressure. PMID- 21320711 TI - Bronchiolitis obliterans syndrome occurs earlier in the post-lung allocation score era. AB - OBJECTIVES: In 2005, the time-based waiting list for lung transplantation was replaced by an illness/benefit lung allocation score (LAS). Although short-term outcomes after transplantation have been reported to be similar before and after the new system, little is known about long-term results. The objective of this study was to evaluate the impact of LAS on the development of bronchiolitis obliterans syndrome as well as on overall 3-year and bronchiolitis obliterans syndrome-related survival. METHODS: Data obtained from the United Network for Organ Sharing were used to review 8091 patients who underwent lung transplantation from 2002 to 2008. Patients were stratified according to time of transplantation into those treated before initiation of the LAS (pre-LAS group, January 2002-April 2005, n = 3729) and those treated after implementation of the score (post-LAS group, May 2005-May 2008, n = 4362). Overall, 3-year survivals for patient groups were compared using a univariate analysis, Cox proportional hazards model to generate a relative risk, and Kaplan-Meier curve analyses. RESULTS: During the 3-year follow-up period, bronchiolitis obliterans syndrome developed in 22% of lung transplant recipients (n = 1801). Although the incidence of postoperative bronchiolitis obliterans syndrome development was similar between groups, post-LAS patients incurred fewer bronchiolitis obliterans syndrome-free days (609 +/- 7.5 vs 682 +/- 9; P <.0001; log-rank test P = .0108) than did pre-LAS patients. Overall 3-year survival was lower in post-LAS patients and approached statistical significance (P = .05). Similarly, bronchiolitis obliterans syndrome-related survival was worse for patients in the post-LAS group (log-rank test P = .01). CONCLUSIONS: In the current LAS era, lung transplant recipients have significantly fewer bronchiolitis obliterans syndrome-free days after 3-year follow-up. Compared with the pre-LAS population, overall and bronchiolitis obliterans syndrome-related survival appears worse in the post-LAS era. Limitation of known risk factors for development of bronchiolitis obliterans syndrome-may prove even more important in this patient population. PMID- 21320712 TI - Cone reconstruction of the tricuspid valve in Ebstein anomaly with or without one and a half ventricle repair. AB - OBJECTIVE: We sought to review our institutional experience and midterm results with cone reconstruction in Ebstein anomaly with or without one and a half ventricle repair to evaluate these 2 important surgical methods for the treatment of Ebstein anomaly. METHODS: From January 1, 2004, to October 1, 2009, 30 consecutive patients with Ebstein anomaly underwent cone reconstruction. All patients underwent cone reconstruction, and 20 patients with severe Ebstein anomaly had a bidirectional cavopulmonary shunt constructed. The median age was 60 months (range, 2-192 months). Our criteria to define severe Ebstein anomaly include a severely enlarged right-sided chamber, significant abnormality of the septal leaflet of the tricuspid valve, and hemodynamic instability after cardiopulmonary bypass. Clinical or echocardiographic characteristics were studied both preoperatively and postoperatively. RESULTS: There was 1 (3.3%) hospital death. Before the operation, tricuspid incompetence was moderate in 8 and severe in 22 patients. Postoperative early echocardiographic analysis showed that tricuspid incompetence was mild in 26 patients, moderate in 3 patients, and severe in 1 patient. After a median follow-up time of 22 months, tricuspid incompetence of 20 patients with bidirectional cavopulmonary shunt was mild in 15 and moderate in 4. Tricuspid incompetence of 10 patients without a bidirectional cavopulmonary shunt from the latest echocardiogram (median follow-up time, 32 months) was mild in 4, moderate in 4, and severe in 2 patients. For patients whose postoperative tricuspid incompetence was beyond mild among the 10 patients without a bidirectional cavopulmonary shunt, preoperative echocardiographic analysis shows a severely dilated right ventricle. CONCLUSIONS: Addition of a bidirectional cavopulmonary shunt to cone reconstruction of the tricuspid valve should be considered for young patients with severe Ebstein anomaly who are at high risk of right ventricular failure after the operation. PMID- 21320713 TI - The destructive date-mussel fishery and the persistence of barrens in Mediterranean rocky reefs. AB - The illegal and destructive fishery of date mussels (i.e. the endolithic mollusc Lithophaga lithophaga) reduces the bio-physical complexity of Mediterranean rocky reefs and dramatically impacts biodiversity. Although date-mussel fishermen do not directly impact sea urchins, these echinoids dramatically increase in abundance on rocky reefs impacted by date-mussel fishery (DMF). The recovery of rocky reefs affected by DMF is hampered by the intense unselective grazing of sea urchins on benthic organisms. No evidence is available, however, about the mechanisms that cause the increase in the population density of sea urchins. I demonstrated here that DMF creates a new microhabitat, i.e. the holes left empty after date mussels are extracted, where small-sized sea urchins take refuge and escape predation. This study thus sheds light on a mechanism through which DMF may locally increase sea urchin population density, contributing to maintain the rocks bare on the long term. PMID- 21320714 TI - Faecal excretion of intestinal spirochaetes by urban dogs, and their pathogenicity in a chick model of intestinal spirochaetosis. AB - This study aimed to obtain information about the types of spirochaetes colonising urban dogs in Thailand, and to investigate their pathogenic potential in a day old chick model of intestinal spirochaetosis. Spirochaetes were isolated from the faeces of six of 47 (12.8%) healthy dogs and 11 of 104 (10.6%) dogs with diarrhoea. Their biochemical properties and 16S ribosomal DNA sequences were analysed. Four isolates were identified as Brachyspira pilosicoli, three resembled "Brachyspira pulli", nine clustered with "Brachyspira canis" and one was similar to Brachyspira intermedia. Canine isolates of B. pilosicoli, "B. canis" and "B. pulli", and control strains of Brachyspira hyodysenteriae, B. pilosicoli and Brachyspira innocens colonised experimentally infected day-old chicks. The chicks did not develop diarrhoea, but were significantly lighter than the non-infected group and those infected with B. innocens after 21 days (P<0.05). Using immunohistochemistry, spirochaetes were observed covering the surface epithelium and in the crypts of chicks in all three groups challenged with the canine isolates. Variable histopathological changes were seen, with the greatest inflammatory cell infiltration into the lamina propria occurring in the group infected with "B. pulli". Canine "B. canis", "B. pulli" and B. pilosicoli isolates may have pathogenic potential. PMID- 21320715 TI - Adenosine deaminase activity in serum, erythrocytes and lymphocytes of rats infected with Leptospira icterohaemorrhagiae. AB - Leptospirosis is a systemic disease of humans and domestic animals, mainly dogs, cattle and swine. The course of human leptospirosis varies from mild to severe fatal forms and the most severe form of human leptospirosis is principally caused by Leptospira interrogans serovar icterohaemorrhagiae (L. icterohaemorrhagiae). The enzyme adenosine deaminase (ADA) plays an important role in the production and differentiation of blood cells. The aim of this study was to evaluate the activity of ADA in serum, erythrocytes and lymphocytes of rats infected with L. icterohaemorrhagiae, as compared with non-infected rats. Twenty-four adult rats, divided into two uniform groups (A and B) were used for the enzymatic assays. The animals in Group B were inoculated intraperitoneally with 2*10(8) leptospires/rat, and the rodents in Group A (control) were not-inoculated. Blood collection was performed on days 5 and 15 post-infection (PI) and the blood used to assess the ADA activity. The infection by L.icterohaemorrhagiae altered erythrocyte count, hemoglobin concentration and hematocrit, causing a decrease in all these parameters on day 15 PI. Lymphocytes decreased significantly on day 15 PI, and ADA activity in serum was inhibited in infected rats on days 5 and 15 PI and its activity in erythrocytes were increased on day 5 PI. On day 5 PI, we found an increase in ADA activity in erythrocytes of infected rats. No correlation was observed between hematocrit and erythrocyte ADA activity on days 5 and 15 PI. The ADA activity was inhibited in rats infected on day 15 PI. A positive correlation (r(2)=60) was also observed between the number of lymphocytes and ADA activity in lymphocytes on day 15 PI (P<0.05). In conclusion, our results showed that the ADA activity is altered in serum, lymphocytes and erythrocytes in experimental infection by L.icterohaemorrhagiae in rats, concomitantly with hematological parameters. PMID- 21320716 TI - Association of the 894G>T polymorphism in the endothelial nitric oxide synthase gene with risk of venous thromboembolism in Chinese population. AB - INTRODUCTION: Endothelium derived nitric oxide (NO) is a key mediator of vascular homeostasis. Endothelial nitric oxide synthase (eNOS) gene, by affecting the expression and functional activity of the eNOS enzyme, thereby reducing NO availability, may be implicated in venous thromboembolism (VTE). We investigated the eNOS G894T polymorphism in VTE patients in the Chinese population. MATERIALS AND METHODS: A case-control study was conducted in a general hospital. Blood samples, collected from 462 consecutive patients with VTE and 462 healthy controls, were used for DNA extraction. Single nucleotide polymorphisms (SNP) of eNOS (894G/T) were determined by allele specific-polymerase chain reaction (ARMS PCR) analysis. RESULTS: The eNOS 894G/T polymorphism alleles distribution was in agreement with the principle of Hardy-Weinberg equilibrium. The prevalence of homozygote, heterozygote and pathological homozygote for the eNOS G894T polymorphism in VTE patients was 79.7%, 18.1% and 2.2%, respectively (controls: 86.6%,12.3% and 1.1%). T allele distribution in the VTE (11.3%) and especially the male VTE patients (12.5%) was more common than in healthy controls (7.3%). The frequency of GT+TT genotype was significantly higher among the age<=55years patients in VTE group than in controls (20.1% vs. 12.2%, P=0.033). CONCLUSION: Our result demonstrates that the 894G/T polymorphism variant of eNOS is a risk factor for VTE in Chinese population. PMID- 21320717 TI - Decreased T-cell receptor signaling through CARD11 differentially compromises forkhead box protein 3-positive regulatory versus T(H)2 effector cells to cause allergy. AB - BACKGROUND: Allergy, the most common disease of immune dysregulation, has a substantial genetic component that is poorly understood. Although complete disruption of T-cell receptor (TCR) signaling causes profound immunodeficiency, little is known about the consequences of inherited genetic variants that cause partial quantitative decreases in particular TCR-signaling pathways, despite their potential to dysregulate immune responses and cause immunopathology. OBJECTIVE: We sought to elucidate how an inherited decrease in TCR signaling through CARD11, a critical scaffold protein that signals to nuclear factor kappaB (NF-kappaB) transcription factors, results in spontaneous selective accumulation of large numbers of T(H)2 cells. METHODS: "Unmodulated" mice carry a Card11 single nucleotide variant that decreases but does not abolish TCR/CD28 signaling to induce targets of NF-kappaB. The consequences of this mutation on T-cell subset formation in vivo were examined, and its effects within effector versus regulatory T-cell subsets were dissected by the adoptive transfer of wild-type cells and by the examination of forkhead box protein 3 (Foxp3)-deficient unmodulated mice. RESULTS: Unlike the pathology-free boundary points of complete Card11 sufficiency or deficiency, unmodulated mice have a specific allergic condition characterized by increased IgE levels and dermatitis. The single nucleotide variant partially decreases both the frequency of Foxp3(+) regulatory T cells and the efficiency of effector T-cell formation in vivo. These intermediate effects combine to cause a gradual and selective expansion of T(H)2 cells. CONCLUSIONS: Inherited reduction in the efficiency of TCR-NF-kappaB signaling has graded effects on T-cell activation and Foxp3(+) regulatory T-cell suppression that result in selective T(H)2 dysregulation and allergic disease. PMID- 21320718 TI - Allele-specific transcription of the asthma-associated PHD finger protein 11 gene (PHF11) modulated by octamer-binding transcription factor 1 (Oct-1). AB - BACKGROUND: Asthma is a common, chronic inflammatory airway disease of major public health importance with multiple genetic determinants. Previously, we found by positional cloning that PHD finger protein 11 (PHF11) on chromosome 13q14 modifies serum immunoglobulin E (IgE) concentrations and asthma susceptibility. No coding variants in PHF11 were identified. OBJECTIVE: Here we investigate the 3 single nucleotide polymorphisms (SNPs) in this gene most significantly associated with total serum IgE levels--rs3765526, rs9526569, and rs1046295--for a role in transcription factor binding. METHODS: We used electrophoretic mobility shift assays to examine the effect of the 3 SNPs on transcription factor binding in 3 cell lines relevant to asthma pathogenesis. Relative preferential expression of alleles was investigated by using the allelotyping method. RESULTS: Electrophoretic mobility shift assays show that rs1046295 modulates allele specific binding by the octamer-binding transcription factor 1 (Oct-1). Analysis of the relative expression levels of the 2 alleles of this SNP in heterozygous individuals showed a modest, but highly significant (P = 6.5 * 10(-16)), preferential expression of the A allele consistent with a functional role for rs1046295. CONCLUSION: These results suggest a mechanism by which rs1046295 may act as a regulatory variant modulating transcription at this locus and altering asthma susceptibility. PMID- 21320719 TI - Further validation and definition of the psychometric properties of the Asthma Impact Survey. AB - BACKGROUND: The Asthma Impact Survey (AIS-6) is a brief disease-specific quality of-life instrument with limited published validation data. OBJECTIVE: To obtain additional validation data and psychometric properties of the AIS-6. METHODS: In November, 2007, patients with persistent asthma were mailed a survey that included the AIS-6, the mini-Asthma Quality of Life Questionnaire (mAQLQ), and the Asthma Control Test (ACT). Follow-up surveys were sent in April, July, and October 2008. Year 2008 exacerbations and short-acting beta-agonist (SABA) dispensings were captured from administrative data. RESULTS: A total of 2680 patients had complete baseline survey data. Criterion validity was demonstrated by the strong correlations of the AIS-6 with the mAQLQ (r = -0.84 to -0.86); construct validity by significant relationships (P < .0001) of the AIS-6 with mAQLQ domain scores, ACT score, and history of exacerbations; and predictive validity by significant relationships (P < .0001) between AIS-6 scores at the end of 2007 and year 2008 exacerbations and high SABA dispensings. Responsiveness was demonstrated by significant (P < .0001) correlations (r = -0.39 to -0.58) between changes in AIS-6 scores and changes in mAQLQ and ACT scores over time. A preliminary minimally important difference (MID) in AIS-6 was estimated to be 4 by using the mAQLQ MID as an anchor. Excellent internal consistency (alpha = 0.94) and test-retest reliability (intraclass correlation coefficient = 0.86 0.91) were also demonstrated. CONCLUSION: The AIS-6 demonstrated good psychometric properties in a large independent sample and could be used to assess asthma-specific quality of life in clinical practice and clinical research. PMID- 21320720 TI - Allergy-related outcomes in relation to serum IgE: results from the National Health and Nutrition Examination Survey 2005-2006. AB - BACKGROUND: The National Health and Nutrition Examination Survey (NHANES) 2005 2006 was the first population-based study to investigate levels of serum total and allergen-specific IgE in the general US population. OBJECTIVE: We estimated the prevalence of allergy-related outcomes and examined relationships between serum IgE levels and these outcomes in a representative sample of the US population. METHODS: Data for this cross-sectional analysis were obtained from NHANES 2005-2006. Study subjects aged 6 years and older (n = 8086) had blood taken for measurement of total IgE and 19 specific IgE levels against common aeroallergens, including Alternaria alternata, Aspergillus fumigatus, Bermuda grass, birch, oak, ragweed, Russian thistle, rye grass, cat dander, cockroach, dog dander, dust mite (Dermatophagoides farinae and Dermatophagoides pteronyssinus), mouse and rat urine proteins, and selected foods (egg white, cow's milk, peanut, and shrimp). Serum samples were analyzed for total and allergen-specific IgE by using the Pharmacia CAP System. Information on allergy related outcomes and demographics was collected by questionnaire. RESULTS: In NHANES 2005-2006, 6.6% reported current hay fever, and 23.5% had current allergies. Allergy-related outcomes increased with increasing total IgE levels (adjusted odds ratios for a 10-fold increase in total IgE level of 1.86 [95% CI, 1.44-2.41] for hay fever and 1.64 [95% CI, 1.41-1.91] for allergies). Increased levels of plant-, pet-, and mold-specific IgE contributed independently to allergy-related symptoms. The greatest increase in odds was observed for hay fever and plant-specific IgE (adjusted odds ratio, 4.75; 95% CI, 3.83-5.88). CONCLUSION: In the US population self-reported allergy symptoms are most consistently associated with increased levels of plant-, pet-, and mold-specific IgE. PMID- 21320721 TI - Effects of one versus two doses of prostaglandin F2alpha on AI pregnancy rates in a 5-day, progesterone-based, CO-Synch protocol in crossbred beef heifers. AB - The present study determined whether a 5-d progesterone-based CO-Synch protocol with a single dose of prostaglandin F(2alpha) (PGF) at progesterone withdrawal on Day 5, would yield a timed AI pregnancy rate similar to two doses of PGF given 6 h apart on Day 5. Angus cross beef heifers (N = 562) at six locations were used. All heifers received 100 ug of gonadorelin hydrochloride (GnRH) and a controlled internal drug release (CIDR) insert on Day 0. Within farm, heifers were randomly allocated to receive one dose of 25 mg dinoprost (PGF) at CIDR removal on Day 5 (1 PGF; N = 264), or two doses of 25 mg PGF, with the first dose given on Day 5 at CIDR removal, and the second dose 6 h later (2 PGF; N = 298). Most heifers (N = 415) received a heat detector patch at CIDR removal. After CIDR removal, heifers were observed twice daily through Day 7 for estrus and heat detector aid status was recorded. On Day 8, heifers were given 100 ug of GnRH, heat detector aid status was recorded, and heifers were inseminated approximately 72 h after CIDR removal. Accounting for significant variables such as location (P < 0.01), heifers in estrus at or prior to AI (P < 0.001), and a treatment by location interaction (P < 0.01), two doses of PGF on Day 5 tended to have higher pregnancy rates to timed AI compared to those that received one dose of PGF (P = 0.06). In conclusion, heifers given two doses of PGF at CIDR removal on Day 5, in a 5-d CIDR-CO-Synch protocol, tended to have a higher pregnancy rate than those that received only one dose of PGF. PMID- 21320722 TI - Effect of roscovitine treated donor cells and different activation methods on development of handmade cloned goat (Capra hircus) embryos. AB - The aim of the present investigation was to find out the effects of roscovitine treatment of donor cells and different activation methods on development of HMC goat embryos. Goat fetal fibroblast cells were cultured and divided into three treatment groups-contact inhibition group, roscovitine treatment group and serum starvation group. There was a significant decrease in blastocyst yield in serum starvation group (6.82%) compared to roscovitine treatment group (19.31%) and contact inhibition group (18.52%), however, no significant difference was found between roscovitine treatment group and contact inhibition group. To see the effect of different methods of activation, the reconstructed embryos were randomly divided into two groups and activated by two methods-one half by 2 MUM Ca ionophore and another half by 2.31 kV/cm for 15 MUSec electrical pulse. Subsequently, cloned embryos were cultured in TCM-199 based embryo development medium supplemented with 10 mg/mL bovine serum albumin in WOW culture system. There was a significant increase in the rate of cleavage and blastocyst production in electric pulse activation of 78.57% and 21.43% than Ca ionophore activation of 62.63% and 10.61% respectively. In conclusion, treatment of donor cells with roscovitine yields a significantly increased blastocyst than serum starved donor cells but equivalent blastocyst to contact inhibition group and electrical pulse activation (EPA) improves the production of HMC goat embryos. PMID- 21320723 TI - The effect of melatonin on the quality of extended boar semen after long-term storage at 17 degrees C. AB - Melatonin (MLT) is an efficient antioxidant that protects cells and tissues and initiates a host of receptor-mediated effects. In order to enhance the life span of refrigerated boar semen, our aim was to evaluate the effects of addition of 1 MUM MLT to commercially produced pig semen (33 seminal doses from 14 boars) that had been preserved at 17 degrees C for 7 days. Samples without MLT served as controls. On Days 1, 4 and 7, we evaluated motility parameters and the percentage of total motile and progressively motile spermatozoa by a computer-aided sperm analysis system. Viability (SYBR-14/PI), acrosomal status (FITC-PNA/PI), membrane fluidity (M-540/YoPro-1) and mitochondrial membrane potential status (JC-1) were evaluated by flow cytometry. MLT treatment significantly enhanced the percentage of static spermatozoa after 7 days of storage and significantly reduced the percentage of progressively motile spermatozoa on Day 7. The velocity characteristics (VCL, VSL and VAP) were significantly higher for MLT-treated samples on Day 1 and were their lowest on Day 7. With regard to flow cytometry results, the percentage of viable spermatozoa with an intact acrosome was higher in MLT samples throughout the entire storage period. In addition, there was a significantly higher proportion of live spermatozoa on Day 7 in the samples that had not been treated with MLT. The proportion of spermatozoa showing a high mitochondrial membrane potential remained at similar levels (P > 0.05) throughout the trial. Although the findings of the present study revealed that 1 MUM MLT increased the proportion of live sperm with an intact acrosome, this treatment did not enhance the spermatic quality of refrigerated boar semen. PMID- 21320724 TI - The effects of cross-linked thermo-responsive PNIPAAm-based hydrogel injection on retinal function. AB - There is significant interest in biomaterials that provide sustained release of therapeutic molecules to the retina. Poly(N-isopropylacrylamide) (PNIPAAm)-based materials have received significant attention as injectable drug delivery platforms due to PNIPAAm's thermo-responsive properties at approximately 32 degrees C. While the drug delivery properties of PNIPAAm materials have been studied extensively, there is a need to evaluate the safety effects of hydrogel injection on retinal function. The purpose of this study was to examine the effect of poly(ethylene glycol) diacrylate (PEG-DA) crosslinked PNIPAAm hydrogel injection on retinal function. Utilizing scanning laser ophthalmoscopy (SLO), optical coherent tomography (OCT), and electroretinography (ERG), retinal function was assessed following hydrogel injection. In region near the hydrogel, there was a significant decrease in arterial and venous diameters (~4%) and an increase in venous blood velocity (~8%) 1 week post-injection. Retinal thickness decreased (~6%) at 1 week and the maximum a- and b-wave amplitudes of ERG decreased (~15%). All data returned to baseline values after week 1. These data suggest that the injection of PEG-DA crosslinked PNIPAAm hydrogel results in a small transient effect on retinal function without any long-term effects. These results further support the potential of PNIPAAm-based materials as an ocular drug delivery platform. PMID- 21320725 TI - Pathway of programmed cell death in HeLa cells induced by polymeric anti-cancer drugs. AB - Synthesis of anticancer polymeric materials plus their biological applications is one of the most charming and active research areas in biological functional materials. However, the predominant mechanisms for controlling cancer cell viability are not yet clear. In this work, cell culture polymeric materials co immobilized with death signal proteins interferon-gamma (IFN-gamma)/tumor necrosis factor-alpha (TNF-alpha) on the surface were prepared by photochemical method to develop an anticancer polymeric drug model. Various characterizations on the microstructures and compositions, including the Fourier transform infrared spectroscopy, UV absorption spectroscopy, fluorescence measurement, atomic force microscopy, and electron spectroscopy for chemical analysis, were performed. For addressing the biological applications, we investigated systematically the death pathways of HeLa cells attached onto the drug model by means of a series of cell biology techniques. It was demonstrated that the IFN-gamma plus TNF-alpha co immobilized on the polymeric material surface exhibited more notable inhibitive effects than the free IFN-gamma plus TNF-alpha, and the induced HeLa cells were mainly along apoptosis-like PCD with the translocation of EndoG from the cytoplasm to the nucleus. These findings indicate that the polymeric drugs with the co-immobilized IFN-gamma plus TNF-alpha may offer significant potentials for therapeutic manipulation of human cervical cancer. PMID- 21320726 TI - Effects of antipsychotics on the serum BDNF levels in schizophrenia. AB - Brain-derived neurotrophic factor (BDNF) is active during a critical developmental period and likely influences the neuroplasticity of schizophrenia. This study longitudinally examined the effects of atypical antipsychotics on serum BDNF levels in schizophrenic patients. Specifically, this study measured serum BDNF levels in 53 patients with paranoid schizophrenia during a relapse and again 4 weeks following the administration of antipsychotic treatment (with risperidone in 32 cases, and clozapine in 21 cases). BDNF levels remained unchanged relative to study entry after 4 weeks of atypical antipsychotic treatment. However, serum BDNF was significantly increased in the subgroup receiving risperidone compared to that receiving clozapine, albeit only in the 15 male subjects and not in the 17 females. These results suggest that gender might significantly influence the antipsychotic treatment of schizophrenia from the perspective of BDNF. These findings may also indicate that the treatment with atypical antipsychotic agents differentially affects BDNF levels. PMID- 21320727 TI - The association between verbal memory, processing speed, negative symptoms and functional capacity in schizophrenia. AB - The aim of this paper is to explore the links among verbal memory, processing speed, negative symptoms, and functional capacity, using structural equation modeling techniques. Model A is a multiple regression model with cognitive and symptom variables as predictors and functional capacity as the latent outcome variable. Model B consists of three two mediator models that assess the ability of each variable to mediate the effect of the other variable on outcome conditional on the inclusion of the other mediator in the model. Ninety-eight community-dwelling patients with schizophrenia (mean age=35.8years, S.D.=10.1) participated in the study. Results indicate that verbal memory, processing speed and negative symptoms significantly contributed to functional status. Verbal memory was at least partially mediated by processing speed in its effect on outcome, while the impact of processing speed on outcome was mediated by both verbal memory and negative symptoms. The influence of negative symptoms on functional capacity was partially mediated by processing speed. These findings enrich our understanding of the direct and indirect effects of these three interrelated variables and provide a basis for the development of intervention strategies. PMID- 21320728 TI - Epstein-Barr virus infection as a cause of cervical lymphadenopathy in children. AB - OBJECTIVE: Cervical lymphadenopathy is a common pediatric problem; reactive hyperplasia, specific infective agents, and malignancy are mainly the differential diagnosis. The aim of our study was to detect the prevalence of Epstein-Barr virus infection among children who complained of cervical lymphadenopathy and also to evaluate the clinical manifestations of the disease in pediatric patients. METHODS: One hundred and sixty children presented with cervical lymphadenopathy were subjected to Epstein-Barr Virus (EBV) serology testing. Cases that showed positivity to heterophile antibody test, and/or EBV specific antibodies; IgM against viral capsid antigen (VCA-IgM) and IgG against viral capsid antigen (VCA-IgG) were evaluated clinically for manifestations of the disease. RESULTS: Twenty-four cases (15%) showed positivity to EBV serology, all of them had posterior cervical lymph nodes enlargement, 70.8% had fever, 66.6% had tonsillo-pharyngitis, 58.3% had splenomegaly, 25% had hepatomegaly, 41.6% had generalized lymphadenopathy, while skin rash was detected in 12.5%, and both palatal petechiae and palpebral edema were detected in 8.3%. CONCLUSIONS: EBV infection is not a rare cause of cervical lymphadenopathy in children. Posterior cervical lymphadenopathy in pediatric age group may represent a password for suspicion of EBV infection, while other clinical manifestations of the disease may include hepato-splenomegaly, skin rash, palpebral edema and palatal petechiae. PMID- 21320729 TI - Trichothecene genotypes and chemotypes in Fusarium graminearum strains isolated from wheat in Argentina. AB - Argentina is the fourth largest exporter of wheat in the world. The main pathogen associated with Fusarium Head Blight (FHB) of wheat in Argentina is Fusarium graminearum lineage 7 also termed F. graminearum sensu stricto in the F. graminearum species complex, which can produce the Type B trichothecenes, usually deoxynivalenol (DON) and its acetylated forms (3-ADON and 15-ADON) or nivalenol (NIV). We used a multiplex PCR assay of Tri3, Tri7, and Tri13 to determine the trichothecene genotype of 116 strains F. graminearum collected from three locations in Argentina and then verified the chemotype by chemical analysis. PCR assays and chemical analyses gave the same results for all strains that produced trichothecenes. Most strains (> 92%) had the 15-ADON genotype, with the remaining strains having the DON/NIV genotype. We observed neither the NIV nor the 3-ADON genotypes amongst the strains evaluated. The nine strains with the DON/NIV genotype produced DON when analyzed chemically. Thus, the Argentinean populations of F. graminearum are similar to those from wheat elsewhere in the world, in that all the strains produced DON/15-ADON and belong to lineage 7. However approximately 8% of the strains tested were incorrectly diagnosed as DON/NIV producers with the current multiplex PCR and were only DON producers by chemical analysis. PMID- 21320730 TI - Chemical composition and antifungal activity of essential oil from Cicuta virosa L. var. latisecta Celak. AB - The essential oil extracted from the fruits of Cicuta virosa L. var. latisecta Celak was tested in vitro and in vivo against four foodborne fungi, Aspergillus flavus, Aspergillus oryzae, Aspergillus niger, and Alternaria alternata. Forty five different components accounting for 98.4% of the total oil composition were identified by gas chromatography-mass spectrometry. The major components were gamma-terpinene (40.92%), p-cymene (27.93%), and cumin aldehyde (21.20%). Antifungal activity was tested by the poisoned food technique against the four fungi. Minimum inhibitory concentration against the fungi was 5 MUL/mL and percentage inhibition of mycelial growth was determined at day 9. The essential oil had a strong inhibitory effect on spore production and germination in all tested fungi proportional to concentration. The oil exhibited noticeable inhibition on dry mycelium weight and synthesis of aflatoxin B1 (AFB1) by A. flavus, completely inhibiting AFB(1) production at 4 MUL/mL. The effect of the essential oil on inhibition of decay development in cherry tomatoes was tested in vivo by exposing inoculated and control fruit to essential oil vapor at a concentration of 200 MUL/mL. Results indicated that the essential oil from C. virosa var. latisecta (CVEO) has potential as a preservative to control food spoilage. PMID- 21320731 TI - Progress in genomics, metabolism and biotechnology of bifidobacteria. AB - Members of the genus Bifidobacterium were first described over a century ago and were quickly associated with a healthy intestinal tract due to their numerical dominance in breast-fed babies as compared to bottle-fed infants. Health benefits elicited by bifidobacteria to its host, as supported by clinical trials, have led to their wide application as probiotic components of health-promoting foods, especially in fermented dairy products. However, the relative paucity of genetic tools available for bifidobacteria has impeded development of a comprehensive molecular understanding of this genus. In this review we present a summary of current knowledge on bifidobacterial metabolism, classification, physiology and genetics and outline the currently available methods for genetically accessing and manipulating the genus. PMID- 21320732 TI - Detection of low numbers of healthy and sub-lethally injured Salmonella enterica in chocolate. AB - The capacity to detect low levels of healthy and sub-lethally injured Salmonella enterica cells in chocolate by two alternative rapid detection methods iQ Check(TM)Salmonella II real-time PCR (Bio-Rad) and VIDAS(r) Easy SLM (BioMerieux) was assessed and compared with ISO 6579:2005. Chocolate, a low moisture food known to support the survival of Salmonella, was challenged as food matrix. Buffered peptone water (BPW) did not support the recovery of low levels of sub lethally injured S. enterica independent of the detection method, while BPW supplemented with milk powder enabled detection by the three examined methods. However, inhibition of real-time PCR was observed since for one out of three repetitions of chocolate inoculated with a low number of sub-lethally injured S. enterica cells, no PCR signal was obtained. Therefore, attention should be paid to the enrichment step to avoid false negative results due to the presence of especially sub-lethally injured Salmonella cells in chocolate. An appropriate sample preparation (such as enrichment media and conditions for incubation) remains the key factor for reliable detection including sub-lethally injured cells and should be evaluated, if necessary optimized, for each detection assay. PMID- 21320733 TI - Serum asymmetric dimethylarginine levels in diabetic patients with neuropathy. AB - OBJECTIVE: The goal of our study was to evaluate the role of asymmetric dimethylarginine (ADMA) in patients with diabetic neuropathy. MATERIALS AND METHODS: In this study, 58 diabetic patients and 26 healthy volunteers were included. In both groups ADMA measurements were performed together with other biochemical examinations. Nerve conduction studies and Neuropathy Symptom Score (NSS) were administered to the diabetic patients. RESULTS: ADMA levels were found significantly higher in diabetic patients compared to the control group (p = 0.0001). However, ADMA levels were not statistically significant between diabetic patients with neuropathy and without neuropathy (p = 0.86 and p = 0.47). CONCLUSION: These results demonstrate that there is not any significant relationship between ADMA and diabetic neuropathy. PMID- 21320734 TI - Renal outcomes in patients with type 2 diabetes with or without coexisting non diabetic renal disease. AB - AIMS: We sought not only to determine the independent predictors of non-diabetic renal disease (NDRD) but also to investigate the impact of NDRD on renal outcomes in patients with type 2 diabetes who underwent renal biopsy and were followed-up longitudinally. METHODS: The present study was conducted by reviewing the medical records of 119 type 2 diabetic patients who underwent renal biopsy at Yonsei University Health System from January 1988 to December 2008. RESULTS: Renal biopsy findings declared that 43 patients (36.1%) had diabetic nephropathy alone, 12 (10.1%) had NDRD superimposed on diabetic nephropathy, and 64 (53.8%) had only NDRD. On multivariate analysis, the absence of diabetic retinopathy, higher hemoglobin levels, and shorter duration of diabetes were independent predictors of NDRD in these patients. During the follow-up period, end-stage renal disease (ESRD) developed in 33 patients (27.7%). On multivariate Cox regression, higher serum creatinine levels, higher systolic blood pressure, longer duration of diabetes, and the presence of diabetic nephropathy were identified as significant independent predictors of ESRD. When the presence of diabetic retinopathy was included in the multivariate model, higher serum creatinine levels, higher systolic blood pressure, and the presence of retinopathy were shown to be independent predictors of ESRD. CONCLUSIONS: Since diabetic patients with NDRD have significantly better renal outcomes compared to patients with biopsy-proven diabetic nephropathy, it is important to suspect, identify, and manage NDRD as early as possible, especially in type 2 diabetic patients with short duration of diabetes and those without diabetic retinopathy or anemia. PMID- 21320735 TI - Changes in aromatase (CYP19) gene promoter usage in non-small cell lung cancer. AB - In humans, aromatase (CYP19) gene expression is regulated via alternative promoters. Activation of each promoter gives rise to a CYP19 mRNA species with a unique 5'-untranslated region. Inhibition of aromatase has been reported to downregulate lung tumor growth. The genetic basis for CYP19 gene expression and aromatase activity in lung cancer remains poorly understood. We analyzed tissues from 15 patients with non-small cell lung cancer (NSCLC) to evaluate CYP19 promoter usage and promoter-specific aromatase mRNA levels in NSCLC tumor tissues and adjacent non-malignant tissues. CYP19 promoter usage was determined by multiplex RT-PCR and aromatase mRNA levels were measured with real-time RT-PCR. In non-malignant tissues, aromatase mRNA was primarily derived from activation of CYP19 promoter I.4. Although promoter I.4 usage was also dominant in tumor tissues, I.4 activation was significantly lower compared with adjacent non malignant tissues. Activity of promoters I.3, I.1 and I.7 was significantly higher in tumor tissues compared with non-malignant tissues. In 4 of 15 cases of non-small cell lung cancer, switching from CYP19 promoter I.4 to the alternative promoters II, I.1 or I.7 was observed. In 9 cases, there were significantly higher levels of aromatase mRNA in lung tumor tissues compared with adjacent non malignant tissues. These findings suggest aberrant activation of alternative CYP19 promoters that may lead to upregulation of local aromatase expression in some cases of NSCLC. Further studies are needed to examine the impact of alternative CYP19 promoter usage on local estrogen levels and lung tumor growth. PMID- 21320736 TI - Vertical small scale variations of sorption and mineralization of three herbicides in subsurface limestone and sandy aquifer. AB - Vertical variation in sorption and mineralization potential of mecoprop (MCPP), isoproturon and acetochlor were investigated at low concentrations (MUg-range) at the cm-scale in unsaturated sub-surface limestone samples and saturated sandy aquifer samples from an agricultural catchment in Brevilles, France. From two intact core drills, four heterogenic limestone sections were collected from 4.50 to 26.40m below surface (mbs) and divided into 12 sub-samples of 8-25cm length, and one sandy aquifer section from 19.20 to 19.53m depth divided into 7 sub samples of 4-5cm length. In the sandy aquifer section acetochlor and isoproturon sorption increased substantially with depth; in average 78% (acetochlor) and 61% (isoproturon) per 5cm. Also the number of acetochlor and isoproturon degraders (most-probable-number) was higher in the bottom half of the aquifer section (93 >16000/g) than in the upper half (4-71/g). One 50cm long limestone section with a distinct shift in color showed a clear shift in mineralization, number of degraders and sorption: In the two brown, uppermost samples, up to 31% mecoprop and up to 9% isoproturon was mineralized during 231 days, the numbers of mecoprop and isoproturon degraders were 1300 to >16000/g, and the sorption of both isoproturon and acetochlor was more than three times higher, compared to the two deeper, grayish samples just below where mineralization (<=4%) and numbers of degraders (1-520/g) were low for all three herbicides. In both unsaturated limestone and sandy aquifer, variations and even distinct shifts in both mineralization, number of specific degraders and sorption were seen within just 4 15cm of vertical distance. A simple conceptual model of herbicides leaching to groundwater through a 10m unsaturated limestone was established, and calculations showed that a 30cm active layer with the measured sorption and mineralization values hardly impacted the fate of the investigated herbicides, whereas a total thickness of layers of 1m would substantially increase natural attenuation. PMID- 21320737 TI - Glucomannan is not effective for the treatment of functional constipation in children: a double-blind, placebo-controlled, randomized trial. AB - BACKGROUND & AIMS: Treatment measures for constipation in children are often not satisfactory. The aim was to assess the efficacy of glucomannan (GNN) as a sole treatment for functional constipation. METHODS: Children aged 3-16 years with functional constipation according to Rome III criteria were randomly assigned to receive GNN (2.52 g/d) or placebo for 4 weeks. RESULTS: Of the 80 children, 72 (90%) completed the study. The primary outcome, treatment success (>=3 stools per week with no soiling), was similar in the GNN (n = 36) and placebo (n = 36) groups (relative risk 0.95, 95% CI 0.6 to 1.4). In the GNN group, the stool consistency score was higher at week 1 (P < 0.0001), lower at week 3 (P = 0.008), and similar at weeks 2 and 4. Stool frequency was higher only at week 3 (P = 0.007). Abdominal pain episodes were more frequent in the GNN group at week 1 (P = 0.04) and week 4 (P < 0.0001) but were similar between groups at weeks 2 and 3. No difference was observed in the frequency of any other secondary outcome or adverse event. CONCLUSIONS: In our setting, GNN, as dosed in this study, was not more effective than placebo in achieving therapeutic success in constipated children. The trial was registered at ClinicalTrials.gov (http://clinicaltrials.gov), number NCT01151878. PMID- 21320738 TI - Amending greenroof soil with biochar to affect runoff water quantity and quality. AB - Numbers of greenroofs in urban areas continue to grow internationally; so designing greenroof soil to reduce the amount of nutrients in the stormwater runoff from these roofs is becoming essential. This study evaluated changes in extensive greenroof water discharge quality and quantity after adding biochar, a soil amendment promoted for its ability to retain nutrients in soils and increase soil fertility. Prototype greenroof trays with and without biochar were planted with sedum or ryegrass, with barren soil trays used as controls. The greenroof trays were subjected to two sequential 7.4cm/h rainfall events using a rain simulator. Runoff from the rain events was collected and evaluated. Trays containing 7% biochar showed increased water retention and significant decreases in discharge of total nitrogen, total phosphorus, nitrate, phosphate, and organic carbon. The addition of biochar to greenroof soil improves both runoff water quality and retention. PMID- 21320739 TI - Do local landmark bridges increase the suicide rate? An alternative test of the likely effect of means restriction at suicide-jumping sites. AB - A number of recent studies have examined the effect of installing physical barriers or otherwise restricting access to public sites that are frequently used for suicides by jumping. While these studies demonstrate that barriers lead to a reduction in the number of suicides by jumping at the site where they are installed, thus far no study has found a statistically significant reduction in the local suicide rate attributable to a barrier. All previous studies are case studies of particular sites, and thus have limited statistical power and ability to control for confounding factors, which may obscure the true relationship between barriers and the suicide rate. This study addresses these concerns by examining the relationship between large, well-known bridges ("local landmark" bridges) of the type that are often used as suicide-jumping sites and the local suicide rate, an approach that yields many more cases for analysis. If barriers at suicide-jumping sites decrease the local suicide rate, then this implies that the presence of an unsecured suicide-jumping site will lead to a higher local suicide rate in comparison to areas without such a site. The relationship between suicides and local landmark bridges is examined across 3116 US counties or county equivalents with negative binomial regression models. I found that while exposure to local landmark bridges was associated with an increased number of suicides by jumping, no positive relationship between these bridges and the overall number of suicides was detected. It may be impossible to conclusively determine if barriers at suicide-jumping sites reduce the local suicide rate with currently available data. However, the method introduced in this paper offers the possibility that better data, or an improved understanding of which potential jumping sites attract suicidal individuals, may eventually allow researchers to determine if means restriction at suicide-jumping sites reduces total suicides. PMID- 21320740 TI - Manipulation of voice onset time during dichotic listening. AB - The manipulation of voice onset time (VOT) during dichotic listening has provided novel insights regarding brain function. To date, the most common design is the utilisation of four VOT conditions: short-long pairs (SL), where a CV syllable with a short VOT is presented to the left ear and a CV syllable with a long VOT is presented to the right ear as well as long-short (LS), short-short (SS) and long-long (LL) pairs. Rimol, Eichele, and Hugdahl (2006) first reported that in healthy adults SL pairs elicit the largest REA while, in fact, LS pairs elicit a significant left ear advantage (LEA). This VOT effect was replicated by Sandmann et al. (2007). A study of children aged 5-8years of age has shown a developmental trajectory whereby long VOTs gradually start to dominate over short VOTs when LS pairs are being presented under dichotic conditions (Westerhausen, Helland, Ofte, & Hugdahl, 2010). Two studies have investigated attentional modulation of the VOT effect in children and adults. The converging evidence from these studies shows that at around 9years of age children lack the adult-like cognitive flexibility required to exert top-down control over stimulus-driven bottom-up processes (Andersson, Llera, Rimol, & Hugdahl, 2008; Arciuli, Rankine, & Monaghan, 2010). Arciuli et al. further demonstrated that this kind of cognitive flexibility is a predictor of proficiency with complex tasks such as reading. A review of each of these studies, the possible mechanisms underlying the VOT effect and directions for future research are discussed. PMID- 21320742 TI - Interdomain compactization in human tyrosyl-tRNA synthetase studied by the hierarchical rotations technique. AB - Aminoacyl-tRNA synthetases are key enzymes of protein biosynthesis which usually possess multidomain structures. Mammalian tyrosyl-tRNA synthetase is composed of two structural modules: N-terminal catalytic core and an EMAPII-like C-terminal domain separated by long flexible linker. The structure of full-length human cytoplasmic tyrosyl-tRNA synthetase is still unknown. The structures of isolated N-terminal and C-terminal domains of the protein are resolved, but their compact packing in a functional enzyme is a subject of debates. In this work we studied putative compactization of the N- and C-terminal modules of human tyrosyl-tRNA synthetase by the coarse-grained hierarchical rotations technique (HIEROT). The large number of distinct types of binding interfaces between N- and C-terminal modules is revealed in the absence of enzyme substrates. The binding propensities of different residues are computed and several binding "hot spots" are observed on the surfaces of N and C modules. These results could be used to govern atomistic molecular dynamics simulations, which will sample preferable binding interfaces effectively. PMID- 21320741 TI - Dual-task processing in younger and older adults: similarities and differences revealed by fMRI. AB - fMRI was used to explore age differences in the neural substrate of dual-task processing. Brain activations when there was a 100 ms SOA between tasks, and task overlap was high, were contrasted with activations when there was a 1000 ms SOA, and first task processing was largely complete before the second task began. Younger adults (M=21 yrs) showed activation in dorsolateral prefrontal cortex and in parietal areas as well as in ventral medial frontal cortex and sub-lobar areas. Activations in older adults (M=71 yrs) did not differ significantly from younger adults except for higher activations in occipital and polar prefrontal cortex. The results were well fit by a model with two networks managing dual-task interference, a medial prefrontal network that detects changes in the stimulus situation and maps them to associated changes in the valence of response mappings and a lateral frontal-parietal network that initiates and carries out the shift from one task to the other. The additional activations in older adults as a group and the correlations of individual differences in activation with performance were consistent with recruitment within each of these networks. Alternative explanations such as hemispheric asymmetry reduction and reactive rather than proactive processing in older adults were not supported. PMID- 21320743 TI - Characteristics of major secondary ions in typical polluted atmospheric aerosols during autumn in central Taiwan. AB - In autumn of 2008, the chemical characteristics of major secondary ionic aerosols at a suburban site in central Taiwan were measured during an annually occurring season of high pollution. The semicontinuous measurement system measured major soluble inorganic species, including NH(4)(+), NO(3)(-), and SO(4)(2-), in PM(10) with a 15 min resolution time. The atmospheric conditions, except for the influences of typhoons, were dominated by the local sea-land breeze with clear diurnal variations of meteorological parameters and air pollutant concentrations. To evaluate secondary aerosol formation at different ozone levels, daily ozone maximum concentration (O(3,daily max)) was used as an index of photochemical activity for dividing between the heavily polluted period (O(3,daily max) ?80 ppb) and the lightly polluted period (O(3,daily max)<80 ppb). The concentrations of PM(10), NO(3)(-), SO(4)(2-), NH(4)(+) and total major ions during the heavily polluted period were 1.6, 1.9, 2.4, 2.7 and 2.3 times the concentrations during the lightly polluted period, respectively. Results showed that the daily maximum concentrations of PM(10) occurred around midnight and the daily maximum ozone concentration occurred during daytime. The average concentration of SO(2) was higher during daytime, which could be explained by the transportation of coastal industry emissions to the sampling site. In contrast, the high concentration of NO(2) at night was due to the land breeze flow that transport inland urban air masses toward this site. The simulations of breeze circulations and transitions were reflected in transports and distributions of these pollutants. During heavily polluted periods, NO(3)(-) and NH(4)(+) showed a clear diurnal variations with lower concentrations after midday, possibly due to the thermal volatilization of NH(4)NO(3) during daytime and transport of inland urban plume at night. The diurnal variation of PM(10) showed the similar pattern to that of NO(3)(-) and NH(4)(+) aerosols. This indicated that the formatted secondary aerosols in the inland urban area could be transported to the coastal area by the weak land breeze and deteriorated the air quality in the coastal area at night. PMID- 21320744 TI - Modeling of the denitrification/anaerobic digestion process of salmon fishery wastewater in a biofilm tubular reactor. AB - The literature has paid scarce attention to the modeling of the denitrification anaerobic digestion process in packed bed biofilm tubular reactors used to treat wastewater. The present study obtained a steady-state model for industrial salmon fishery wastewater treatment in a biofilm tubular reactor, including pH as a variable and the effect of biomass on hydrolysis. The axial profile of the reactor components and process efficiency were predicted with deviations below 6%. The optimal operating zone for the process was found at hydraulic retention time (HRT)>1.5d and inlet protein concentration (S(prot,0))<3000 mgTOCL(-1). Based on our results, we concluded that the removal of organic matter and nitrogen compounds depended mainly on HRT. The effluent pH was mainly affected by the C/N ratio, where a decrease increases pH. Organic matter removal was related with the anaerobic digestion process, while denitrification influenced mostly nitrate and nitrite removal. PMID- 21320745 TI - Acute Parkinsonian syndrome after ventriculoperitoneal shunt malfunction caused by a roller coaster ride. PMID- 21320746 TI - Stem cell factor/c-kit signaling enhances invasion of pancreatic cancer cells via HIF-1alpha under normoxic condition. AB - The SCF/c-kit signaling plays an important role in invasion of c-kit-expressing tumor cells, however, the molecular mechanisms have not been studied yet. Using a pancreatic cancer model, we demonstrate that SCF/c-kit binding up-regulates the expression of invasion-related genes through the accumulation of HIF-1alpha. Furthermore, the expression of HIF-1alpha induced by SCF is not dependent on the oxygen level, but rather on both the PI3K/Akt and Ras/MEK/ERK signaling pathways. In conclusion, under normoxic conditions, SCF/c-kit binding increases expression of HIF-1alpha through the PI3K/Akt and Ras/MEK/ERK pathways, and the accumulation of HIF-1alpha up-regulates expression of invasion-related genes that augment the invasiveness of pancreatic cancer, a fatal cancer. Therefore, our results suggest that the inhibition of both c-kit and HIF-1alpha may be an effective strategy for pancreatic cancer therapy. PMID- 21320747 TI - Sulfidogenic biotreatment of synthetic acid mine drainage and sulfide oxidation in anaerobic baffled reactor. AB - The treatment of synthetic acid mine drainage (AMD) water (pH 3.0-6.5) containing sulfate (3.0-3.5 g L(-1)) and various metals (Co, Cu, Fe, Mn, Ni, and Zn) was studied in an ethanol-fed sulfate-reducing 4-compartment anaerobic baffled reactor (ABR) at 32 degrees C. The reactor was operated for 160 days at different chemical oxygen demand (COD)/sulfate ratios, hydraulic retention times (HRT), pH, and metal concentrations to study the robustness of the process. The last compartment of the reactor was aerated at different rates to study the bio oxidation of sulfide to elemental sulfur. The highest sulfate reduction efficiency (88%) was obtained with a feed sulfate concentration of 3.5 g L(-1), COD/sulfate mass ratio of 0.737, feed pH of 3.0 and HRT of 2 days without aeration in the 4th compartment. The corresponding COD removal efficiency was about 92%. The alkalinity produced in the sulfidogenic ethanol oxidation neutralized the acidic mine water from pH 3.0-4.5 to pH 7.0-8.0. Effluent soluble and total heavy metal concentrations were substantially reduced with removal efficiencies generally higher than 99%, except for Mn (25-77%). Limited aeration in the 4th compartment of ABR promoted incomplete oxidation of sulfide to elemental sulfur rather than complete oxidation to sulfate. Depending on the aeration rate and HRT, 32-74% of produced sulfide was oxidized to elemental sulfur. This study demonstrates that by optimizing operating conditions, sulfate reduction, metal removal, alkalinity generation, and excess sulfide oxidation can be achieved in a single ABR treating AMD. PMID- 21320748 TI - A weak-base fibrous anion exchanger effective for rapid phosphate removal from water. AB - This work investigated that weak-base anion exchange fibers named FVA-c and FVA-f were selectively and rapidly taken up phosphate from water. The chemical structure of both FVA-c and FVA-f was the same; i.e., poly(vinylamine) chains grafted onto polyethylene coated polypropylene fibers. Batch study using FVA-c clarified that this preferred phosphate to chloride, nitrate and sulfate in neutral pH region and an equilibrium capacity of FVA-c for phosphate was from 2.45 to 6.87 mmol/g. Column study using FVA-f made it clear that breakthrough capacities of FVA-f were not strongly affected by flow rates from 150 to 2000 h( 1) as well as phosphate feed concentration from 0.072 to 1.6mM. Under these conditions, breakthrough capacities were from 0.84 to 1.43 mmol/g indicating high kinetic performances. Trace concentration of phosphate was also removed from feeds containing 0.021 and 0.035 mM of phosphate at high feed flow rate of 2500 h(-1), breakthrough capacities were 0.676 and 0.741 mmol/g, respectively. The column study also clarified that chloride and sulfate did not strongly interfere with phosphate uptake even in their presence of equimolar and fivefold molar levels. Adsorbed phosphate on FVA-f was quantitatively eluted with 1M HCl acid and regenerated into hydrochloride form simultaneously for next phosphate adsorption operation. Therefore, FVA-f is able to use long time even under rigorous chemical treatment of multiple regeneration/reuse cycles without any noticeable deterioration. PMID- 21320749 TI - Oxalic acid mineralization by electrochemical oxidation processes. AB - In this study, two electrochemical oxidation processes were utilized to mineralize oxalic acid which was a major intermediate compound in the oxidation of phenols and other aromatic compounds. The anode rod and cathode net were made of a titanium coated with RuO(2)/IrO(2) (Ti-DSA) and stainless steel (S.S. net, SUS304), respectively. First, the Fered-Fenton process, which used H(2)O(2) and Fe(2+) as additive reagents, achieved 85% of TOC removal. It proceeded with ligand-to-metal charge-transfer (LMCT), which was evidenced by the accumulation of metallic foil on the selected cathode. However, in the absence of H(2)O(2)/Fe(2+), it showed a higher TOC removal efficiency while using Cl(-) only as an additive reagent due to the formation of hypochlorite on the anode. It was also found that the mineralization of oxalic acid by electrolysis generated hypochlorite better than the dosage of commercial hypochlorite without electricity. Also, pH value was a major factor that affected the mineralization efficiency of the oxalic acid due to the chlorine chemistry. 99% TOC removal could be obtained by Cl(-) electrolysis in an acidic environment. PMID- 21320750 TI - Catalytic combustion of chlorobenzene over Mn-Ce-La-O mixed oxide catalysts. AB - A series of Mn(x)-CeLa mixed oxide catalysts with different compositions prepared by sol-gel method were tested for the catalytic combustion of chlorobenzene (CB), as a model of chlorinated aromatics. Mn(x)-CeLa catalysts with the ratios of Mn/(Mn + Ce + La) in the range from 0.69 to 0.8 were found to possess high catalytic activity in the catalytic combustion of CB. The stability and deactivation of Mn(x)-CeLa catalysts were studied by other assistant experiments. Mn(x)-CeLa catalysts can deactivate below 330 degrees C, due to the strong adsorption of Cl species produced during the decomposition of CB. Nevertheless, the increase in oxygen concentration can enhance the resistance to Cl poisoning through the reaction of surface oxygen species with residual chlorine. At 350 degrees C, high activity, good selectivity and desired stability were observed over Mn(x)-CeLa catalysts. PMID- 21320751 TI - Potential of Leersia hexandra Swartz for phytoextraction of Cr from soil. AB - Research on the phytoextraction of Cr from contaminated soils has been scarce, because very few plant species have been reported to accumulate Cr to high concentrations in their aerial parts. In this study, a Cr-hyperaccumulator, Leersia hexandra was investigated for its potential to remove Cr from the soil in a series of pot experiments. The results showed that L. hexandra had a high extraction capacity for chromium in soil, with the highest Cr concentration in shoot of 1844 mg/kg. Model calculation based on the negative linear relationship between the bioconcentration factors (BCF) and the concentrations of soil Cr indicated that phytoremediation using L. hexandra was feasible when soil was only moderately contaminated with Cr. Three sequential harvests did not significantly alter Cr accumulation and shoot biomass (p > 0.05), indicating that sequential harvest might be an available and convenient way to achieve the decontamination of Cr-contaminated soils by L. hexandra. On average, fertilization increased the shoot biomass by 45% and the total amount of extracted-Cr by 26%, suggesting that fertilization is able to enhance Cr phytoextraction of L. hexandra. Although EDTA increased the concentrations of Cr in shoots by 1.4 times, it also resulted in low plant biomass, thereby decreasing the amount of Cr accumulation. PMID- 21320752 TI - Verification of competitive kinetics technique and oxidation kinetics of 2,6 dimethyl-aniline and o-toluidine by Fenton process. AB - The competitive kinetics technique is shown to be a useful and reliable tool for determining rate constants. Regardless of the conditions of the reaction and the operation mode, the intrinsic second-order rate constants of 2,6-dimethyl-aniline and hydroxyl radicals were 1.65 * 10(10), 1.60 * 10(10), and 1.71 * 10(10)M(-1)s( 1) in the absence of SiO(2) under complete-mix conditions, in the presence of SiO(2) under complete-mix conditions, and in a fluidized-bed Fenton reactor with SiO(2) as the media, respectively, demonstrating that the rates are comparable under a variety of reaction conditions. The average intrinsic second-order rate constant of o-toluidine and hydroxyl radicals obtained in a homogeneous system under various conditions was 7.36 * 10(9)M(-1)s(-1), indicating that o-toluidine is less susceptible to hydroxyl radicals than 2,6-dimethyl-anilne. Hydroxyl radicals primarily attacked the amine group rather than the methyl group of the o toluidine to form o-cresol and 2-nitrotoluene, which sequentially transformed to carboxylic acids including acetic, oxalic, lactic, and maleic acids after the collapse of the benzene ring. PMID- 21320753 TI - Field bioassay of Metarhizium anisopliae strains to control the poultry red mite Dermanyssus gallinae. AB - The poultry red mite, Dermanyssus gallinae is one of the most economically deleterious ectoparasite of laying hens worldwide. To evaluate the efficacy of three strains (V245, 3247 and 715C) of entomopathogenic fungus Metarhizium anisopliae with potential as acaricides against D. gallinae, this investigation was carried out in a commercial caged laying poultry farm in Naghedeh, West Azarbaijan of Iran. The parasite infestation already existed in the farm. Sunflower oil suspension of all fungal strains, each in two concentrations (1*10(7) and 1*10(9) conidia/ml) were used separately as spray on hens and cages, and in the control group the cages were only sprayed with sunflower oil and sterile distilled water. For estimating the population rate of mites before and after treatment, special cardboard traps were fixed to cages during a 1-month period. The traps were placed on weeks -1, 0, 1, 2 and 3 and always removed after 1 w. The results showed that the population rates post fungal treatment with the lower concentration were not significantly different compared to the control group. However, the reduction in mite numbers induced by all three strains at the concentration of 1*10(9) conidia/ml was significantly higher than the control (P<0.05). The results revealed that under field conditions, higher concentrations of M. anisopliae will be required for controlling D. gallinae. PMID- 21320754 TI - Innate and adaptive resistance of Indonesian Thin Tail sheep to liver fluke: a comparative analysis of Fasciola gigantica and Fasciola hepatica infection. AB - In the current study, three independent trials directly compared Fasciola gigantica and Fasciola hepatica infection of ITT sheep. In all trials, F. hepatica infection resulted in higher worm burden recoveries and greater physiological damage to ITT sheep. Developmental differences of the two Fasciola species were also observed during the first twelve weeks of a primary infection, where the migration and growth of F. hepatica was more rapid than F. gigantica. Various immunological blood parameters were measured and indicated similar kinetics in the humoral and cellular responses during the time course of infection with each Fasciola species. In contrast to F. hepatica infection, we demonstrate an innate and adaptive comparative ability of ITT sheep to resist the early stages of infection with F. gigantica infection. Unraveling the mechanisms leading to this differential resistance may potentially lead to new methods for the control of fasciolosis and other human liver flukes. PMID- 21320755 TI - In vitro effect of Aloe vera, Coriandrum sativum and Ricinus communis fractions on Leishmania infantum and on murine monocytic cells. AB - In South America, visceral leishmaniasis is a zoonosis caused by the protozoan species Leishmania infantum (syn. L. chagasi) and is primarily transmitted through the bite of the female Lutzomyia longipalpis. Its main reservoir in urban areas is the dog. The application of control measures recommended by health agencies have not achieved significant results in reducing the incidence of human cases, and the lack of effective drugs to treat dogs resulted in the prohibition of this course of action in Brazil. Therefore, it is necessary to search new alternatives for the treatment of canine and human visceral leishmaniasis. The objectives of this study were to evaluate the in vitro effect of fractions from Aloe vera (aloe), Coriandrum sativum (coriander), and Ricinus communis (castor) on promastigotes and amastigotes of L. infantum and to analyze the toxicity against the murine monocytic cells RAW 264.7. To determine the viability of these substances on 50% parasites (IC50), we used a tetrazolium dye (MTT) colorimetric assay (bromide 3-4.5-dimethylthiazol-2-yl-2,5-dephenyltetrazolium), and on amastigotes we performed an in situ ELISA. All fractions were effective against L. infantum promastigotes and did not differ from the positive control pentamidine (p>0.05). However, the R. communis ethyl acetate and chloroform fractions, as well as the C. sativum methanol fraction, were the most effective against amastigotes and did not differ from the positive control amphotericin B (p>0.05). The R. communis ethyl acetate fraction was the least toxic, presenting 83.5% viability of RAW 264.7 cells, which was similar to the results obtained with amphotericin B (p>0.05). Based on these results, we intend to undertake in vivo studies with R. communis ethyl acetate fractions due the high effectiveness against amastigotes and promastigotes of L. infantum and the low cytotoxicity towards murine monocytic cells. PMID- 21320756 TI - Therapeutic implications of molecular imaging with PET in the combined modality treatment of lung cancer. AB - Molecular imaging with PET, and certainly integrated PET-CT, combining functional and anatomical imaging, has many potential advantages over anatomical imaging alone in the combined modality treatment of lung cancer. The aim of the current article is to review the available evidence regarding PET with FDG and other tracers in the combined modality treatment of locally advanced lung cancer. The following topics are addressed: tumor volume definition, outcome prediction and the added value of PET after therapy, and finally its clinical implications and future perspectives. The additional value of FDG-PET in defining the primary tumor volume has been established, mainly in regions with atelectasis or post treatment effects. Selective nodal irradiation (SNI) of FDG-PET positive nodal stations is the preferred treatment in NSCLC, being safe and leading to decreased normal tissue exposure, providing opportunities for dose escalation. First results in SCLC show similar results. FDG-uptake on the pre-treatment PET scan is of prognostic value. Data on the value of pre-treatment FDG-uptake to predict response to combined modality treatment are conflicting, but the limited data regarding early metabolic response during treatment do show predictive value. The FDG response after radical treatment is of prognostic significance. FDG-PET in the follow-up has potential benefit in NSCLC, while data in SCLC are lacking. Radiotherapy boosting of radioresistant areas identified with FDG-PET is subject of current research. Tracers other than (18)FDG are promising for treatment response assessment and the visualization of intra-tumor heterogeneity, but more research is needed before they can be clinically implemented. PMID- 21320758 TI - Low doses of dextromethorphan attenuate morphine-induced rewarding via the sigma 1 receptor at ventral tegmental area in rats. AB - Chronic use of morphine causes rewarding and behavioral sensitization, which may lead to the development of psychological craving. In our previous study, we found that a widely used antitussive dextromethorphan (known as a low affinity NMDA receptor antagonist), at doses of 10-20 mg/kg (i.p.), effectively decreased morphine rewarding in rats. In this study, we further investigated the effects and mechanisms of low doses of DM (MUg/kg range) on morphine rewarding and behavioral sensitization. A conditioned place preference test was used to determine the rewarding and a locomotor activity test was used to determine the behavioral sensitization induced by the drug(s) in rats. When a low dose of DM (3 or 10 MUg/kg, i.p.) was co-administered with morphine (5 mg/kg, s.c.), the rewarding effect, but not behavioral sensitization, induced by morphine was inhibited. The inhibiting effect of DM could be blocked by systemically administering a sigma-1 receptor antagonist, BD1047 (3 mg/kg, i.p.). When BD1047 (5 nmole/site) was locally given at the VTA, it also blocked the effects of a low dose of DM in inhibiting morphine rewarding. Our findings suggest that the activation of the sigma-1 receptor at the VTA may be involved in the mechanism of low doses of DM in inhibiting the morphine rewarding effect and the possibility of using extremely low doses of DM in treatment of opioid addiction in clinics. PMID- 21320757 TI - Does initiation of HIV antiretroviral therapy influence patterns of syringe lending among injection drug users? AB - The delivery of antiretroviral therapy (ART) to injection drug users (IDU) may be influenced by provider concerns regarding the potential for increased HIV-related risk behavior following the initiation of HIV treatment. We evaluated whether ART initiation was associated with changes in syringe lending patterns among a long term prospective cohort of HIV-positive IDU in Vancouver, Canada. Among 380 ART naive individuals eligible for this analysis, the median age was 34.2 (interquartile range [IQR] 27.7-40.8), 171 (45.0%) were female, and the median follow-up duration was 60 months (IQR=18-113). Between May 1996 and April 2008, 260 (68.4%) participants initiated ART. In a generalized linear mixed-effects model which compared each individual's likelihood of sharing syringes prior to and following the initiation of ART, syringe lending was not significantly associated with ART initiation in unadjusted (odds ratio=0.72, 95% CI: 0.38-1.36) or adjusted (odds ratio=0.78, 95% CI: 0.42-1.45) analyses. Concerns regarding increased injection risk behaviors following the initiation of ART were not observed in this setting. PMID- 21320759 TI - Case report: Forensic anthropological assessment in a suspected case of child abuse from South Africa. AB - Not many case reports of suspected child abuse as assessed solely on skeletal remains are available. Forensic anthropologists have intimate knowledge of normal skeletal anatomy, bone trauma and processes of healing of bone and may therefore be of help in suspected cases of child abuse. Patterns of trauma in juvenile skeletal remains which are suggestive of abuse include fractures in different phases of healing, multiple fractures, typical fractures on ribs and long bones and severe, complicated cranial fractures. The aim of this paper is to report on the findings of the analysis of the skeletal remains of a 3.5 years old boy. Forensic pathological examination indicated that the boy had died from a massive cranial fracture, with multiple injuries present to the rest of the body. After the body had been buried for some time, it was exhumed and we were requested to look for signs of chronic, long-term abuse. Findings included a massive cranial fracture, another fracture in the roof of the orbit, two areas of non-specific subperiosteal bone growth and several untreated carious teeth. No clear healed fracture could be found, except for a possible healed cranial base fracture which stretched transversely across the petrosal bone. This area showed signs of recent bone activity. The court decided that this was not enough evidence of chronic abuse and found the accused guilty of murder but not of chronic child abuse. This case illustrates the difficulty to obtain clear signs of chronic injury on juvenile remains. PMID- 21320760 TI - Methadone determination in puparia and its effect on the development of Lucilia sericata (Diptera, Calliphoridae). AB - This paper describes a sensitive UPLC-MS/MS method for quantification of methadone and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in single empty puparial case of Lucilia sericata. Larvae were reared on substrates spiked with different concentrations of methadone (0-4 MUg/g). Methadone was quantified in puparia reared on high concentrated substrates (0.8-4 MUg/g). The major metabolite of methadone (EDDP) was not detected, confirming rapid elimination of metabolites by the larvae before pupation. The effects of methadone on the development of L. sericata were also investigated. No effect on sex ratio was detected. A significant difference was calculated for emerged adults but no trends could be observed. Concerning the developmental curve, a significant difference was observed between control and high methadone concentrations using the Kolmogorov-Smirnov test. PMID- 21320761 TI - Do the laryngopharyngeal symptoms and signs ameliorate by empiric treatment in patients with suspected laryngopharyngeal reflux? AB - OBJECTIVES: In clinical practice, antireflux medication is given almost always empirically without pH monitorization. We aimed to evaluate the improving effect of empiric antireflux treatment on layngopharyngeal symptoms and signs in patients with gastroesophageal reflux (GER) and suspected laryngopharyngeal reflux (LPR) according to reflux symptom index (RSI) and reflux finding score (RFS). METHODS: GER was determined by esophagogastroduedonoscopy and biopsy in 127 patients. RSI and RFS were calculated for each patient. The patients with a pathology other than LFR which may be responsible from laryngopharyngeal symptoms and signs were excluded from the study. Fifty patients whom were thought to have LPR according to RSI and RFS comprised the study group. After 12-weeks of antireflux treatment, RSI and RFS were calculated again. The statistical analyses were made according to the changes in the severity and frequency of each symptom and sign. RESULTS: There was statistically significant improvement in RSI and RFS after treatment when compared with initial scores. There was statistically significant improvement in severity of all symptoms and signs. Although there was quantitively decrease in frequency of some signs and symptoms, complete resolution of the disease was not observed generally. CONCLUSION: Empiric antireflux treatment according to RSI and RFS is an effective method. Antireflux treatment has a significant improving effect on laryngopharyngeal symptoms and signs. There may be needed longer times of treatment for complete resolution of symptoms and signs. PMID- 21320762 TI - Tracheoesophageal fistula with tracheal stenosis resulting from retained esophageal foreign body. AB - Although a foreign body ingestion is common in infants and young children, serious complication such as penetration of the esophagus is a relatively rare event. Delayed diagnosis may result from lack of classical symptoms and history, leading to serious result, even to death. A 2-year-old boy was admitted to the emergency room with dyspnea. He had wheezing and stridor for a 1.5-year and unfortunately treated as a bronchial asthma for a long time. Chest X-ray and cervical CT scan revealed esophageal foreign body. Intraoperative findings showed a plastic material in the esophagus and tracheoesophageal fistula with tracheal stenosis as a complication of the retained foreign body. Therefore, we should keep in mind that foreign body can present atypical symptoms like respiratory symptoms, especially in infant and young children. PMID- 21320763 TI - Radiologic identification of disaster victims: a simple and reliable method using CT of the paranasal sinuses. AB - OBJECTIVE: To assess the reliability of radiologic identification using visual comparison of ante and post mortem paranasal sinus computed tomography (CT). SUBJECTS AND METHODS: The study was approved by the responsible justice department and university ethics committee. Four blinded readers with varying radiological experience separately compared 100 post mortem to 25 ante mortem head CTs with the goal to identify as many matching pairs as possible (out of 23 possible matches). Sensitivity, specificity, positive and negative predictive values were calculated for all readers. The chi-square test was applied to establish if there was significant difference in sensitivity between radiologists and non-radiologists. RESULTS: For all readers, sensitivity was 83.7%, specificity was 100.0%, negative predictive value (NPV) was 95.4%, positive predictive value (PPV) was 100.0%, and accuracy was 96.3%. For radiologists, sensitivity was 97.8%, NPV was 99.4%, and accuracy was 99.5%. For non radiologists, average sensitivity was 69.6%, negative predictive value (NPV) was 91.7%, and accuracy was 93.0%. Radiologists achieved a significantly higher sensitivity (p < 0.01) than non-radiologists. CONCLUSIONS: Visual comparison of ante mortem and post mortem CT of the head is a robust and reliable method for identifying unknown decedents, particularly in regard to positive matches. The sensitivity and NPV of the method depend on the reader's experience. PMID- 21320764 TI - Williams syndrome hypersociability: a neuropsychological study of the amygdala and prefrontal cortex hypotheses. AB - Individuals with Williams syndrome display indiscriminate approach towards strangers. Neuroimaging studies conducted so far have linked this social profile to structural and/or functional abnormalities in WS amygdala and prefrontal cortex. In this study, the neuropsychological hypotheses of amygdala and prefrontal cortex involvement in WS hypersociability was explored using three behavioral tasks--facial emotional recognition task, a social approach task and a go no/go task. Thus, a group 15 individuals with Williams syndrome was compared to two groups of normal developing individuals--a group of 15 individuals matched for chronological age (CA) and 15 individuals matched for mental age (MA), and sex. Individuals with WS present a specific impairment in recognizing negative facial expressions and do not display impairments in response inhibition when compared with typically developing groups. Although these findings partially support the amygdala contribution to WS hypersociability, we found that general cognitive functioning predicted this performance. Additionally, individuals with WS did not differ from both CA and MA groups in the recognition of angry facial expressions, a finding suggesting that they are actually able to identify stimuli associated with social threat. Overall, the results seem to indicate that this social profile must be understood within a developmental framework. PMID- 21320765 TI - Adaptive behavior of children and adolescents with visual impairments. AB - The present study explored the total adaptive behavior of children and adolescents with visual impairments, as well as their adaptive behavior in each of the domains of Communication, Daily Living Skills, and Socialization. Moreover, the predictors of the performance and developmental delay in adaptive behavior were investigated. Instrumentation included an informal questionnaire and the Vineland Adaptive Behavior Scales (Survey Form). Forty-six children and adolescents with visual impairments participated. The results reveal the effect of age on total adaptive behavior and on each of the domains of Communication, Daily Living Skills, and Socialization; the older individuals with visual impairments present better performance but also a higher rate of delay in comparison with younger individuals. Moreover, the ability of independent movement is a predictor of performance and developmental delay on the Daily Living Skills and Socialization. The more independent the mobility of individuals with visual impairments is the better the performance and the lower the level of developmental delay. Moreover, the educational level of parents is a predictor of performance and developmental delay on the Communication and Socialization. The higher the educational level of parents the better the performance and the lower the developmental delay. PMID- 21320766 TI - Clinical course and analysis of ten fatal cases of clozapine-induced myocarditis and comparison with 66 surviving cases. AB - BACKGROUND: Fatal clozapine-induced myocarditis has not been investigated systematically. We describe the clinical course of 10 fatal cases of myocarditis with clozapine and identify factors associated with fatality. METHODS: Cases of myocarditis were documented from the patient's medical records and fatal cases also from autopsy reports. RESULTS: The fatal cases of myocarditis occurred 1996 2009 and were diagnosed at autopsy. Before death, three had no symptoms of illness and only three had cardiac-specific diagnostic results. None was investigated by cardiac imaging techniques, and in none was myocarditis suspected before death. Duration of clozapine for the fatal cases was 14-33 days with an outlier at 4.5 months. Only 3 cases had significant coronary artery disease at autopsy. Comparison of these ten cases with 66 non-fatal cases indicated no significant difference in gender, age, smoking status, dose at onset or concomitant sodium valproate. However, obesity (BMI > 30 kg/m2) was significantly more frequent among fatal than non-fatal cases (60% vs. 26%; p < 0.03) and duration of clozapine was significantly longer for fatal cases (20.8 vs. 17.0 days; p < 0.006), after exclusion of one outlier. Creatine kinase (CK) > 1000 U/L was also associated with death (p = 0.0004). CONCLUSIONS: Routine monitoring for myocarditis for the first 4 weeks of clozapine, and discontinuation of clozapine in the presence of evidence consistent with myocarditis may assist to prevent fatalities occurring from early-onset myocarditis. Investigation by cardiac imaging will give a measure of severity and need for intervention. Obesity may increase the risk of mortality and CK > 1000 U/L may indicate life-threatening illness. PMID- 21320767 TI - Chitosan microspheres as a delivery system for nasal insufflation. AB - The aim of the present study was to develop and characterize chitosan mucoadhesive microspheres for nasal delivery. The microspheres were prepared by emulsification-crosslinking method and evaluated for morphology, particle size, swelling index, in vitro mucoadhesion and delivery properties from Miat((r)) nasal insufflator. The results showed that the microspheres were spherical in shape with smooth surfaces. The particle size of microspheres was found to be dependent on the concentration of the chitosan. The mean particle size was significantly increased when high concentration of chitosan was used. Aqueous to oil phase ratio, stirring rate and dioctyl sodium sulfosuccinate (DOSS) concentration also influenced the particle size distribution of the microspheres. It was found that, as stirring rate was increased, the size of the microspheres was decreased. The volume of glutaraldehyde and crosslinking time had very slight effect on particle size distribution. The % equilibrium water uptake of the microspheres was ranged from 124% to 232% and the mucoadhesive strength from 70.64+/-2.14 to 86.32+/-3.96%. The results of powder delivery from the device showed that, almost entire amount was delivered after three puffs. The images of the delivery sequences of microsphere powder clouds demonstrated that microspheres were delivered forming an elongated puff. The core of the clouds was homogeneous which can be expected to provide effective distribution pattern. PMID- 21320769 TI - Validity and underrecording of diagnosis of COPD in the Danish National Patient Registry. AB - INTRODUCTION: We examined the positive predictive value of diagnoses of acute exacerbation of chronic obstructive pulmonary disease (COPD) in the Danish National Patient Registry. We also examined the negative predictive value of acute pneumonia or respiratory failure discharge diagnoses for absence of underlying COPD. METHODS: We identified all patients aged 30 years or older with acute hospital admission in Denmark from January 1st to December 31st 2008. Physicians at 34 Danish hospitals retrieved and reviewed medical records for 1581 patients with a discharge diagnosis of COPD, and for 1546 patients with a discharge diagnosis of either pneumonia or respiratory failure but no COPD diagnosis. Presence of COPD was assessed based on medical history, clinical symptoms and findings, and spirometry results. RESULTS: The overall positive predictive value for COPD was 92% (95% confidence interval [CI] = 91-93%). Among patients coded with pneumonia or respiratory failure but not COPD, 19% (95% CI = 17-21%) had COPD, corresponding to a negative predictive value for COPD of 81% (95% CI = 79-83%). CONCLUSIONS: The positive predictive value of acute COPD discharge diagnoses in the Danish National Patient Registry is high. At the same time, there is a substantial underrecording of COPD during hospitalizations with other acute respiratory disorders like pneumonia and respiratory failure. PMID- 21320770 TI - Three-dimensional modeling of protein interactions and complexes is going 'omics. AB - High-throughput interaction discovery initiatives have revealed the existence of hundreds of multiprotein complexes whose functions are regulated through thousands of protein-protein interactions (PPIs). However, the structural details of these interactions, often necessary to understand their function, are only available for a tiny fraction, and the experimental difficulties surrounding complex structure determination make computational modeling techniques paramount. In this manuscript, we critically review some of the most recent developments in the field of structural bioinformatics applied to the modeling of protein interactions and complexes, from large macromolecular machines to domain-domain and peptide-mediated interactions. In particular, we place a special emphasis on those methods that can be applied in a proteome-wide manner, and discuss how they will help in the ultimate objective of building 3D interactome networks. PMID- 21320772 TI - Biodegradability of injection molded bioplastic pots containing polylactic acid and poultry feather fiber. AB - The biodegradability of three types of bioplastic pots was evaluated by measuring carbon dioxide produced from lab-scale compost reactors containing mixtures of pot fragments and compost inoculum held at 58 degrees C for 60 days. Biodegradability of pot type A (composed of 100% polylactic acid (PLA)) was very low (13 +/- 3%) compared to literature values for other PLA materials. Near infrared spectroscopy (NIRS) results suggest that the PLA undergoes chemical structural changes during polymer extrusion and injection molding. These changes may be the basis of the low biodegradability value. Biodegradability of pot types B (containing 5% poultry feather, 80% PLA, 15% starch), and C (containing 50% poultry feather, 25% urea, 25% glycerol), were 53 +/- 2% and 39 +/- 3%, respectively. More than 85% of the total biodegradation of these bioplastics occurred within 38 days. NIRS results revealed that poultry feather was not degraded during composting. PMID- 21320771 TI - Thermophilic co-digestion of organic fraction of municipal solid wastes with FOG wastes from a sewage treatment plant: reactor performance and microbial community monitoring. AB - Working at thermophilic conditions instead of mesophilic, and also the addition of a co-substrate, are both the ways to intend to improve the anaerobic digestion of the source-collected organic fraction of municipal solid wastes (SC-OFMSW). Addition of sewage treatment plant fat, oil and grease wastes (STP-FOGW), that are nowadays sent to landfill, would represent an opportunity to recover a wasted methane potential and, moreover, improve the whole process. In this study, after a first period feeding only SC-OFMSW, a co-digestion step was performed maintaining thermophilic conditions. During the co-digestion period enhancements in biogas production (52%) and methane yield (36%) were achieved. In addition, monitoring of microbial structure by using PCR-DGGE and cloning techniques showed that bacterial community profiles clustered in two distinct groups, before and after the extended contact with STP-FOGW, being more affected by the STP-FOGW addition than the archaeal one. PMID- 21320773 TI - A membrane-free baffled microbial fuel cell for cathodic reduction of Cu(II) with electricity generation. AB - A membrane-free baffled microbial fuel cell (MFC) was developed to treat synthetic Cu(II) sulfate containing wastewater in cathode chamber and synthetic glucose-containing wastewater fed to anode chamber. Maximum power density of 314 mW/m(3) with columbic efficiency of 5.3% was obtained using initial Cu(2+) concentration of 6400 mg/L. Higher current density favored the cathodic reduction of Cu(2+), and removal of Cu(2+) by 70% was observed within 144 h using initial concentration of 500 mg/L. Powder X-ray diffraction (XRD) analysis indicated that the Cu(2+) was reduced to Cu(2)O or Cu(2)O plus Cu which deposited on the cathode, and the deficient cathodic reducibility resulted in the formation of Cu(4)(OH)(6)SO(4) at high initial Cu(2+) concentration (500-6400 mg/L). This study suggested a novel low-cost approach to remove and recover Cu(II) from Cu(2+)-containing wastewater using MFC-type reactor. PMID- 21320774 TI - Influence of sward maturity and pre-conditioning temperature on the energy production from grass silage through the integrated generation of solid fuel and biogas from biomass (IFBB): 1. The fate of mineral compounds. AB - The IFBB process, which separates biomass into a press fluid for biogas production and a press cake for combustion, is aimed at converting low-input high diversity grasslands into energy, which is problematic with conventional conversion techniques. Herbage from a lowland hay meadow (Arrhenaterion) was sampled on eight dates between 24 April and 21 June 2007. Silage from each date was processed in six treatments without and with hydrothermal conditioning at different temperatures. The impact on mass flows of plant compounds and on elemental concentrations in the press cake was investigated. Elements detrimental for combustion were significantly reduced in the press cake compared to the silage. Mass flows and elemental concentrations in the press cake were strongly influenced by conditioning temperature as well as concentration of neutral detergent fiber and dry matter in the silage (R(2) from 0.70 to 0.99). Press cakes of late sampling dates were considered best suitable for combustion. PMID- 21320775 TI - Removal of phenols, thiocyanate and ammonium from coal gasification wastewater using moving bed biofilm reactor. AB - A laboratory-scale moving bed biofilm reactor (MBBR) with a volume of 4 L was used to study the biodegradation of coal gasification wastewater. Maximum removal efficiencies of 81%, 89%, 94% and 93% were obtained for COD, phenols, SCN(-) and NH(4)(+)-N, respectively. NO(2)(-)-N accumulation induced increase of effluent COD concentration when the hydraulic residence time (HRT) decreased. Phenols removal was not affected when the HRT decreased from 48 to 32 h. Effluent SCN(-) and NH(4)(+)-N concentration increased with the decrease of the HRT, and decreased gradually when the HRT returned to 48 h. Batch experiments were carried out to study performance of the suspended and attached growth biomass in the MBBR. PMID- 21320776 TI - Synthesis and SAR of sulfoxide substituted carboxyquinolines as NK3 receptor antagonists. AB - The neurokinin-3 (NK3) receptor is regarded as a potential novel target for treating patients with schizophrenia. Herein we report the synthesis and SAR of a series of C3-alkylsulfoxide substituted quinolines as potent NK3 receptor antagonists. These compounds have excellent NK3 functional activity, good selectivity and drug-like properties. Several key compounds have good in vitro/in vivo DMPK characteristics, and are active in a gerbil locomotor activity model. PMID- 21320777 TI - Synthesis and evaluation of [(1R)-1-amino-2-(2,5 difluorophenyl)ethyl]cyclohexanes and 4-[(1R)-1-amino-2-(2,5 difluorophenyl)ethyl]piperidines as DPP-4 inhibitors. AB - A series of 4-amino cyclohexanes and 4-substituted piperidines were prepared and evaluated for inhibition of DPP-4. Analog 20q displayed both good DPP-4 potency and selectivity against other proteases, while derivative 20k displayed long half life and modest oral bioavailability in rat. The most potent analog, 3-(5 aminocarbonylpyridyl piperidine 53j, displayed excellent DPP-4 activity with good selectivity versus other proline enzymes. PMID- 21320779 TI - Microwave assisted one-pot synthesis of highly potent novel isoniazid analogues. AB - A series of novel isoniazid (INH) analogues were synthesized by microwave assisted one pot reaction of INH, various benzaldehydes and dimedone in water with catalytic amount of DBSA. The synthesized compounds were evaluated for their anti-TB activity against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug resistant Mycobacterium tuberculosis (MDR-TB). Among the 29 compounds, compound N [9-[2-(benzyloxy)phenyl]-3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro 10(1H)-acridinyl]isonicotinamide (12) inhibited MTB with MIC of <0.17 MUM and MDR TB with MIC of 0.69 MUM. PMID- 21320778 TI - On the function of the internal cavity of histone deacetylase protein 8: R37 is a crucial residue for catalysis. AB - Biochemical studies reveal that a conserved arginine residue (R37) at the centre of the 14A internal cavity of histone deacetylase (HDAC) 8 is important for catalysis and acetate affinity. Computational studies indicate that R37 forms multiple hydrogen bonding interactions with the backbone carbonyl oxygen atoms of two conserved glycine residues, G303 and G305, resulting in a 'closed' form of the channel. One possible rationale for these data is that water or product (acetate) transit through the catalytically crucial internal channel of HDAC8 is regulated by a gating interaction between G139 and G303 tethered in position by the conserved R37. PMID- 21320780 TI - [11C]enzastaurin, the first design and radiosynthesis of a new potential PET agent for imaging of protein kinase C. AB - Enzastaurin (LY317615) is a potent and selective protein kinase C (PKC) inhibitor with an IC(50) value of ~6 nM. [(11)C]Enzastaurin (3-(1-[(11)C]methyl-1H-indol-3 yl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-1H-indol-3-yl]-1H-pyrrole-2,5 dione), a new potential PET agent for imaging of PKC, was first designed and synthesized in 20-25% decay corrected radiochemical yield and 370-555 GBq/MUmol specific activity at end of bombardment (EOB). The synthetic strategy was to prepare a carbon-11-labeled maleic anhydride intermediate followed by the conversion to maleimide. PMID- 21320781 TI - hNK2 receptor antagonists. The use of intramolecular hydrogen bonding to increase solubility and membrane permeability. AB - Starting from in-house capped tripeptide libraries, we have developed two series of compounds as potent antagonists of the hNK(2) receptor with a reduced peptide character. These two series maintained a crucial amide bond, which could not be methylated or substituted with classical isostere without a dramatic loss in binding affinity, very likely due conformational changes. We report here the planning, synthesis and evaluation of molecules belonging to the selected chemical series, which contain a strategically placed hydrogen bond acceptor. The aim of the work was to improve membrane permeability via the formation of an intramolecular hydrogen bonding, and at the same time to maintain the structural characteristics geometry and polarity of the amide linkage so as to retain a relevant binding affinity for the biological target. PMID- 21320782 TI - One step synthesis of 2-hydroxymethylisoflavone and their osteogenic activity. AB - An efficient one step synthesis of new 2-hydroxymethylisoflavone is reported. A series of deoxybenzoin was subjected to cyclization with glyoxal in the presence of basic condition (KOH/EtOH) to afford the 2-hydroxymethyl isoflavone. The structures of compounds 5a-g were confirmed by NMR experiments including (1)H, (13)C, HMBC, HSQC and COSY. These compounds were assessed for stimulation of osteoblast function using primary culture of rat calvarial osteoblasts in vitro. Compounds 5a, 5d, 5f and 5g were potent in stimulating differentiation of osteoblasts as assessed by measuring alkaline phosphatase (ALP) activity. Besides, effect of these analogs was also seen on the transcript levels of osteogenic genes like Runx-2, osteocalcin and Bone morphogenetic protein-2 (BMP 2), involved in osteoblast differentiation and mineralization. Based on quantitative PCR data, compound 5f was found to be the potent followed by 5d. Compound 5f robustly increased the mRNA levels of Runx-2 (8.0 fold), BMP-2 (~2 fold) and osteocalcin (~2.0 fold) in osteoblasts. Collectively, we demonstrate osteogenic activity of the novel 2-hydroxymethyl isoflavones with 5f having the most potent activity. PMID- 21320783 TI - Towards more specific O6-methylguanine-DNA methyltransferase (MGMT) inactivators. AB - Searching for a novel family of inactivators of the human DNA repair protein O(6) methylguanine-DNA methyltransferase (MGMT) which is known to bind to the DNA minor groove, we have computationally modelled and synthesised two series of 2 amino-6-aryloxy-5-nitropyrimidines with morpholino or aminodiaryl substituents (potential minor groove binders) at the 4-position. Synthesis of these compounds was achieved by successive substitution of each of the two Cl atoms of 2-amino 4,6-dichloro-5-nitropyrimidine by the corresponding amino and aryloxy derivatives. Biochemical evaluation of these compounds as MGMT inactivators showed poor activities, but in general the 4-bromothenyloxy derivatives showed better inactivation than the benzyloxy versions. DNA binding assessment was not possible due to insolubility problems. PMID- 21320784 TI - ACC oxidase (ACO) genes in Trifolium occidentale (L.) and their relationship to ACO genes in white clover (T. repens L.) and T. pallescens (L.). AB - The identification and expression of two ACC oxidase (ACO) genes during leaf development in Trifolium occidentale (L.), one of the putative ancestral genomes of the allotetraploid, T. repens (L.; white clover), is described. In common with observations made in T. repens, the ACO genes displayed differential expression, with a TR-ACO2-like gene (designated TO-ACO2) confined to developing and early mature-green leaf tissue while expression of a TR-ACO3-like gene (designated TO ACO3) is highest in leaves at the onset and during senescence. Biochemical analysis of TO-ACO2 revealed that both accumulation of the protein (determined by western analysis with a TR-ACO2 antibody) and enzyme activity matched the transcriptional activity of TO-ACO2. Western analysis also revealed that the Tr ACO2 antibody recognised a protein of 37 kDa as a putative TP-ACO2 in T. pallescens. The 3'-UTRs of TO-ACO2 and TO-ACO3 were then compared with the 3' UTRs of a TR-ACO2-like and TR-ACO3-like gene from T. pallescens, the other proposed ancestral genome (or closely related to the ancestor) of T. repens, with identity values of 87.8% for the ACO2-like genes and 94.8% for the ACO3-like genes. Comparison of the 3'-UTRs of TO-ACO2 with a TO-ACO2-like gene in T. repens (designated TR(O)-ACO2) and TP-ACO2 with a TP-ACO2-like gene in T. repens (designated TR(P)-ACO2) revealed identities of 100% and 96.6%, respectively, lending good support to T. occidentale as one of the ancestral genomes of T. repens. A similar comparison of the 3'-UTRs of TO-ACO3 with a TO-ACO3-like gene in T. repens (designated TR(O)-ACO3) and TP-ACO3 with a TP-ACO3-like gene in T. repens (designated TR(P)-ACO3) revealed identities of 99.5% and 97.9%, respectively, again supporting T. occidentale as one of the ancestral genomes. Further, these data confirm that both TO-ACO-like and TP-ACO-like genes are expressed in the allotetraploid T. repens. PMID- 21320786 TI - Macrophage migration inhibitory factor induced by dengue virus infection increases vascular permeability. AB - Dengue virus (DENV) infection can cause mild dengue fever or severe dengue hemorrhage fever (DHF) and dengue shock syndrome (DSS). Serum levels of the macrophage migration inhibitory factor (MIF) have been shown to be correlated with severity and mortality in DENV patients, but the pathogenic roles of MIF in DHF/DSS are still unclear. Increase in vascular permeability is an important hallmark of DHF/DSS. In this study, we found that DENV infection of the human hepatoma cell line (Huh 7) induced MIF production. Conditioned medium collected from DENV-infected Huh 7 cells enhanced the permeability of the human endothelial cell line (HMEC-1) which was reduced in the presence of a MIF inhibitor, ISO-1 or medium from DENV-infected MIF knockdown Huh 7 cells. To further identify whether MIF can alter vascular permeability, we cloned and expressed both human and murine recombinant MIF (rMIF) and tested their effects on vascular permeability both in vitro and in vivo. Indirect immunofluorescent staining showed that the tight junction protein ZO-1 of HMEC-1 was disarrayed in the presence of rMIF and partially recovered when cells were treated with ISO-1 or PI3K/MEK-ERK/JNK signaling pathway inhibitors such as Ly294002, U0126, and SP600215. In addition, ZO-1 disarray induced by MIF was also recovered when CD74 or CXCR2/4 expression of HMEC-1 were inhibited. Last but not least, the vascular permeabilities of the peritoneal cavity and dorsal cutaneous capillary were also increased in mice treated with rMIF. Taken together; these results suggest that MIF induced by DENV infection may contribute to the increase of vascular permeability during DHF/DSS. Therapeutic intervention of MIF by its inhibitor or neutralizing antibodies may prevent DENV-induced lethality. PMID- 21320785 TI - Cloning and characterization of two new Class III peroxidase genes from Catharanthus roseus. AB - We report here the cloning and characterization of two new class III peroxidase genes, CrPrx3 and CrPrx4 from Catharanthus roseus. The full length cDNA of CrPrx3 is 1233 bp long encoding 330 amino acid residues. The CrPrx4 cDNA contains an ORF of 1055 bp, and encodes for 318 amino acids. Hypothetical 3-D structure model of CrPrx3 and CrPrx4 detected the presence of two Ca(2+) ion binding sites at proximal and distal end, and a heme group coordinate at central position. CrPrx3 and CrPrx4 are present in single copy number in C. roseus. Confocal scanning microscopy and phylogenetic analysis showed that CrPrx3 and CrPrx4 are apoplastic in nature. Phylogenetic analysis revealed that both genes have diverse expression patterns in a variety of plant tissues. Quantitative real-time PCR confirmed their maximum expression in stem tissues followed by flower tissue. The expression levels of CrPrx3 and CrPrx4 were down-regulated under salt and dehydration stress, respectively. PMID- 21320787 TI - Pattern of activin A and follistatin release in a sheep model of cardiopulmonary bypass. AB - OBJECTIVE: Activin A, a member of transforming growth factor-beta superfamily, has been established as a critical cytokine released early in endotoxemia and other inflammatory syndromes. The release of activin A and its binding protein, follistatin during cardiopulmonary bypass (CPB) has not been previously reported. Our study aimed to define the pattern of activin A and follistatin release in a sheep CPB model. METHODS: Control group consisted of left thoractomy alone (n=6). CPB was performed using either unfractionated heparin (n=6) or lepirudin (n=6) as anticoagulant. Unlike heparin, lepirudin does not cause activin A and follistatin release on its own. Serum samples were assayed for activin A, follistatin, tumour necrosis factor-alpha and interleukin-6. RESULTS: Compared with the control group, CPB using lepirudin was associated with a biphasic release of activin A. The first peak occurred within the first hour of CPB and a second peak occurred within the early post-operative period, coincident with a large release of follistatin. Close correlation was found between follistatin and IL-6 in the control and lepirudin groups, indicative of a role for follistatin in the acute phase response. In contrast to the control and lepirudin groups, CPB using heparin resulted in a concurrent release of activin A and follistatin. CONCLUSIONS: CPB is a trigger for the release of biologically-active free activin A into the circulation, at levels considerably greater than that induced by surgery alone. Triggering release of this critical inflammatory cytokine suggests that activin A may contribute to the adverse outcomes associated with systemic inflammation in cardiac surgery. PMID- 21320789 TI - Sequential CW-EPR image acquisition with 760-MHz surface coil array. AB - This paper describes the development of a surface coil array that consists of two inductively coupled surface-coil resonators, for use in continuous-wave electron paramagnetic resonance (CW-EPR) imaging at 760 MHz. To make sequential EPR image acquisition possible, we decoupled the surface coils using PIN-diode switches, to enable the shifting of the resonators resonance frequency by more than 200 MHz. To assess the effectiveness of the surface coil array in CW-EPR imaging, two dimensional images of a solution of nitroxyl radicals were measured with the developed coil array. Compared to equivalent single coil acquired images, we found the visualized area to be extended approximately 2-fold when using the surface coil array. The ability to visualize larger regions of interest through the use of a surface coil array, may offer great potential in future EPR imaging studies. PMID- 21320788 TI - Identification of patient safety improvement targets in successful vascular and endovascular procedures: analysis of 251 hours of complex arterial surgery. AB - OBJECTIVES: To investigate failures in patient safety for patients undergoing vascular and endovascular procedures to guide future quality and safety interventions. DESIGN: Single centre prospective observational study. METHODS: 66 procedures (17 thoracoabdominal and 23 abdominal aortic aneurysms, 4 carotid and 22 limb procedures) were observed prospectively over a 9-month period (251 h operating time) by two trained observers. Event logs were recorded for each procedure. Two blinded experts identified and independently categorised failures into 22 types (using a validated category tool) and severity (5-point scale). Data are expressed as median (range). Statistical analysis was performed using Mann-Whitney U, Kruskal-Wallis and Spearman's Rank tests. RESULTS: 1145 failures were identified with good inter-assessor reliability (Cronbach's alpha 0.844). The commonest failure types related to equipment (including unavailability, configuration and other failures) (269/1145 [23.5%]) and communication (240/1145 [21.0%]). A comparatively lower number of technical and psychomotor failures were identified (103 [9.0%]). The number of failures correlated with procedure duration (rho = 0.695, p < 0.001) but not anatomical site of the procedure or pathology of the disease process. Failure rate was higher in patients undergoing combined surgical/endovascular procedures compared to open surgery (median 5.7/h [IQR 4.2-8.1] vs 3.0/h [2.5-3.5]; p < 0.001). The severity of failures was similar (1.5/5 [1-2] vs 1/5 [1-2] respectively; p = 0.095). For combined procedures, failure rates were significantly higher during the endovascular phase (9.6/h [7.5-13.7]) compared to the non-endovascular phase (3.0/h [1.0-5.0]; p < 0.001). CONCLUSIONS: Failures in patient safety are common during complex arterial procedures. Few failures were severe, although minor failures during critical stages and accumulation of multiple minor failures may potentially be important. Failures occurred especially during the endovascular phase and were often related to equipment or communication aspects. Interventions to improve procedural safety and quality of care should primarily target these specific areas. PMID- 21320790 TI - Variable radio frequency proton-electron double-resonance imaging: application to pH mapping of aqueous samples. AB - Proton-electron double-resonance imaging (PEDRI) offers rapid image data collection and high resolution for spatial distribution of paramagnetic probes. Recently we developed the concept of variable field (VF) PEDRI which enables extracting a functional map from a limited number of images acquired at pre selected EPR excitation fields using specific paramagnetic probes (Khramtsov et al., J. Magn. Reson. 202 (2010) 267-273). In this work, we propose and evaluate a new modality of PEDRI-based functional imaging with enhanced temporal resolution which we term variable radio frequency (VRF) PEDRI. The approach allows for functional mapping (e.g., pH mapping) using specifically designed paramagnetic probes with high quality spatial resolution and short acquisition times. This approach uses a stationary magnetic field but different EPR RFs. The ratio of Overhauser enhancements measured at each pixel at two different excitation frequencies corresponding to the resonances of protonated and deprotonated forms of a pH-sensitive nitroxide is converted to a pH map using a corresponding calibration curve. Elimination of field cycling decreased the acquisition time by exclusion periods of ramping and stabilization of the magnetic field. Improved magnetic field homogeneity and stability allowed for the fast MRI acquisition modalities such as fast spin echo. In total, about 30-fold decrease in EPR irradiation time was achieved for VRF PEDRI (2.4s) compared with VF PEDRI (70s). This is particularly important for in vivo applications enabling one to overcome the limiting stability of paramagnetic probes and sample overheating by reducing RF power deposition. PMID- 21320791 TI - Oral administration of recombinant human acid alpha-glucosidase reduces specific antibody formation against enzyme in mouse. AB - Animal and human studies of enzyme replacement therapy for Pompe disease have indicated that antibodies generated against the infused recombinant human acid alpha-glucosidase (rhGAA) can negatively impact therapeutic outcome. In this study, we show that oral administration of rhGAA into mice can reduce the titer of anti-rhGAA antibody following immunization with rhGAA. Oral administration of rhGAA is safe and antigen specific, it offers advantages over other immunosuppressive drugs. PMID- 21320792 TI - Improved assay for differential diagnosis between Pompe disease and acid alpha glucosidase pseudodeficiency on dried blood spots. AB - The high frequency (3.3-3.9%) of acid alpha-glucosidase pseudodeficiency, c.[1726G>A; 2065G>A] homozygote (AA homozygote), in Asian populations complicates newborn screening for Pompe disease (glycogen storage disease type II or acid maltase deficiency) on dried blood spots, since AA homozygotes have a considerably low enzyme activity. We observed that hemoglobin in the enzyme reaction solution strongly interferes with the fluorescence of 4 methylumbelliferone released from 4-methylumbelliferyl alpha-D-glucopyranoside (4MU-alphaGlc) by acid alpha-glucosidase. Therefore, we have searched for a method to effectively eliminate hemoglobin in the reaction solution. Hemoglobin precipitation with barium hydroxide and zinc sulfate (Ba/Zn method) carried out after the enzyme reaction considerably enhances the fluorescence intensity while it does not reduce the intensity to any extent as can occur with conventional deproteinization agents like trichloroacetic acid. The Ba/Zn method greatly improved the separation between 18 Japanese patients with Pompe disease and 70 unaffected AA homozygotes in a population of Japanese newborns in the assay with 4MU-alphaGlc on dried blood spots. No overlap was observed between both groups. We further examined acid alpha-glucosidase activity in fibroblasts from 11 Japanese patients and 57 Japanese unaffected individuals including 31 c.[1726G; 2065G] homozygotes, 18 c.[1726G; 2065G]/[1726A; 2065A] heterozygotes and 8 AA homozygotes to confirm that fibroblasts can be used for definitive diagnosis. The patients were reliably distinguished from three control groups. These data provide advanced information for the development of a simple and reliable newborn screening program with dried blood spots for Pompe disease in Asian populations. PMID- 21320793 TI - Uric acid and cognition in Parkinson's disease: a follow-up study. AB - Cognitive changes are common in Parkinson's disease (PD). Low plasma uric acid (UA) level is associated with risk of PD and predicts faster progression of motor symptoms in established disease. Whether UA levels predict cognitive changes has not been studied. In a crossectional study, our group has previously shown an association of plasma and urine UA levels with cognition in PD. The aim of the present controlled longitudinal study was to examine the evolution of cognitive changes and the prognostic value of the UA levels on cognition in the previously reported PD-patient cohort. Of the original 40 patients, 31 were available for follow-up after three years. Both plasma and daily urine UA levels were measured, nutrition was evaluated using 4-day dietary recall diary and cognition was assessed by a thorough neuropsychological examination including computerized tasks with Cognispeed(c). The plasma and urine UA levels of the patients remained stable during the follow-up. At the same time, the rate of cognitive decline was unexpectedly slow. A statistically significant deterioration was noted in verbal fluency (p=0.04) and in Cognispeed(c)'s vigilance task (p=0.0001). In forward linear regression analysis only the baseline daily urine UA level contributed to verbal fluency (p=0.01), picture completion (p=0.001), block design (p=0.006), vigilance (p=0.006), subtraction (p=0.01) and statement verification (p=0.04) tasks. The implications of the study results are discussed. PMID- 21320794 TI - Synthesis, physical studies and uptake behavior of: copper(II) and lead(II) by Schiff base chelating resins. AB - Two new chelating resins possessing multiple functional groups capable of coordinating with several metal ions are reported. The resins were synthesized by condensing Schiff bases derived from 2-aminophenol, 2-hydroxy-5-chloroaniline and terephthaldehyde with formaldehyde in an alkaline medium. The effects of pH and contact time of the Cu(2+) and Pb(2+) in aqueous solutions on the uptake behavior of the resins were studied. The metal ion uptake behavior of the resins was investigated by the batch method. Both the uptake and the selectivity of the resins towards the investigated metal ions were related to the structure of the resins, type of the metal ion and the uptake conditions. The resins showed maximum uptake capacity for Cu(2+) and Pb(2+) at pH 10. Cu(2+) was seen to undergo preferential adsorption in separate and mixture solutions of Cu(2+) and Pb(2+). Kinetic studies for the resins using Langmiur equation were also performed. The Schiff base monomers and their formaldehyde resins were characterized by elemental analyses, FTIR and (1)H NMR spectroscopy. The thermal stability of the resins was studied using TGA/DTG analysis. PMID- 21320795 TI - Interaction of monosulfonate tetraphenyl porphyrin (H2TPPS1) with plant-esterase: determination of the binding mechanism by spectroscopic methods. AB - The interaction of monosulfonate tetraphenyl porphyrin (H(2)TPPS(1)) with plant esterase was investigated using fluorescence and UV-vis absorption spectroscopy. Fluorescence quenching, from which the binding parameters were evaluated, revealed that the quenching of the esterase by H(2)TPPS(1) resulted from the formation of a dye-esterase complex. According to the modified Stern-Volmer equation, the effective quenching constants (K(a)) between H(2)TPPS(1) and plant esterase at four different temperatures (297 K, 300 K, 303 K, and 306 K) were obtained to be 14.132*10(5), 5.734*10(5), 2.907*10(5), and 2.291*10(5) M(-1), respectively. The thermodynamic parameters, enthalpy change (DeltaH) and entropy change (DeltaS) for the reaction were calculated to be -181.67 kJ M(-1) and -0.49 kJ M(-1)K(-1), indicating that van der Waals force and hydrogen bonds were the dominant intermolecular force in stabilizing the complex. Site marker competitive experiments showed that the binding of H(2)TPPS(1) to plant-esterase primarily took place in the active site. The binding distance (r) was obtained to be 5.99 nm according to Forster theory of non-radioactive energy transfer. The conformation of plant-esterase was investigated by synchronous fluorescence and UV-vis absorption spectroscopy, and the results confirmed some micro environmental and conformational changes of plant-esterase molecules. PMID- 21320796 TI - Innovation and translation in sports medicine and sports science research. PMID- 21320797 TI - 5-HT and bone biology. AB - Bone formation and bone resorption, the two processes occurring constantly and in a balanced fashion throughout the skeleton, are regulated by signals as various as local and low range growth factors, hormones, and neuronal outputs. Adding to the long list of molecules involved in these regulations, gut-derived and brain derived serotonin were recently shown to control one or both of these processes. They do so, however, by targeting different cells, respectively acting as a hormone and as a neuromediator. Moreover, while brain serotonin positively regulates bone mass accrual peripheral serotonin is a potent inhibitor of bone formation. These findings raise the prospect that pharmacologically manipulating serotonin production could therefore become a novel strategy to treat bone loss disorders. PMID- 21320798 TI - Communication between 5-HT and small GTPases. AB - Advances over the past decade have improved our understanding of the serotonin (5 HT) biology outside the central nervous system specifically the molecular mechanisms of serotonergic signaling in association with small GTPases. It is now recognized that the communication between 5-HT and GTPases plays important roles in peripheral tissues, vascular cells and are involved in coagulation, hypertension, inflammation, healing and protection. Furthermore, 5-HT receptors as heterotrimeric GTP-binding protein-coupled receptors act as effector protein on the small GTPases. Therefore, the antagonists or agonists of the effector proteins of small GTPases could be useful therapeutic agents for the treatment of several diseases and disorders. PMID- 21320799 TI - Changing therapeutic landscape--the last decade. AB - Undoubtedly the most important event in the previous decade in lymphoma treatment was the establishment of immunotherapy as a prime modality. Addition of rituximab improves survival in almost every group of patients with CD20+ tumors. This has led to the appearance of a number of "me too" monoclonal antibodies (MoAbs) as well as MoAbs directed against other antigens whose usefulness remains to be proven during the next decade. We have also seen the raise and, probably unwarranted, fall of radioimmunotherapy. Conventional radiotherapy is losing ground. Regarding chemotherapy, the success of attempts to supplant R-CHOP-21 for front-line treatment of DLBCL with more dose-dense or dose-intense regimens remains doubtful and this issue is still unresolved. Bendamustine appeared as possibly the most effective cytotoxic agent for treatment of indolent lymphomas, while treatment of HL is becoming more tailored to prognostic features. This decade has also seen the advent of targeted drugs for lymphoma treatment. Their real impact will become known in the years to come. Finally, we may hope that advances in understanding the biology of lymphomas, made in the last decade, will help resolve remaining critical issues, treatment of T-NHLs and high-risk DLBCLs, being probably the most prominent. PMID- 21320800 TI - Detection of IgG anti-A/B must be essential for safe transfusion support in patients undergoing ABO incompatible allogeneic HSCT. AB - Recipients of ABO incompatible allogeneic HSCT present with unusual ABO groups and crossmatch problems accompanied by change of the ABO group from that of the host to the donor. We report on a patient undergoing major ABO incompatible allogeneic HSCT (donor/recipient: A/O) whose blood group was wrongly established to have completely switched to blood group A when using a routine tube method and micro gel column blood grouping card on the 68th day post transplantation. The major crossmatch test with added antiglobulin and blood group A red cells was still positive. After further investigation, an explanation was found because we could not detect IgG anti-A in the serum. At the same time, anti-A coated the patient's RBCs and could be identified using a heat elution method although the DAT was negative. We also found an obvious mixed field with the LISS-IAT gel card. Hence, routine methods of ABO grouping are unfit for ABO incompatible allogeneic HSCT patients and a micro column neutral gel card is recommended for forward typing especially to detect mixed fields and a LISS-IAT gel card or IAT tube method for detecting IgG anti-A/B in reverse typing. PMID- 21320801 TI - Large volume leukapheresis: Efficacy and safety of processing patient's total blood volume six times. AB - Large-volume leukapheresis (LVL) differs from standard leukapheresis by increased blood flow and an altered anticoagulation regimen. An open issue is to what degree a further increase in processed blood volume is reasonable in terms of higher yields and safety. In 30 LVL performed in patients with hematologic malignancies, 6 total blood volumes were processed. LVL resulted in a higher CD34+ cell yield without a change in graft quality. Although a marked platelet decrease can be expected, LVL is safe and can be recommended as the standard procedure for patients who mobilize low numbers of CD34+ cells and when high number of CD34+ cells are required. PMID- 21320802 TI - Treatment of a patient with adnexal lymphoma with Rituximab. AB - Orbital lymphoma is a very rare type of primary Non-Hodgkin lymphoma. The disorder is often small B-cell lymphoma, although large cell morphology may also be identified in rare cases. It may sometimes be confused with non-malignant, benign-course lymphoid hyperplasia. Although involvement is usually unilateral (80%), bilateral cases are also reported. Response to radiotherapy is achieved in the majority of cases, whereas the prognosis is poor in orbital involvement with large cell lymphoma and response to combined chemotherapy is inadequate. In this paper, we report a case with a diagnosis of unilateral adnexal involvement, who previously received CHOP treatment and developed a relapse 6 months later, then responded to treatment with Rituximab. PMID- 21320803 TI - Theoretical improvement of the specific inhibitor of human carbonic anhydrase VII. AB - The selectivity of a known arylsulfonamides inhibitor for two isozymes II and VII of human carbonic anhydrases (hCAs) was studied by homology modeling, molecular docking and molecular dynamics methods. The results show that the selectivity of the inhibitor for two isozymes is due to the different side chain lengths between N67 of hCA II and Q64 of hCA VII. One more methene group in the side chain of Q64 of hCA VII makes it possible to form the hydrogen bond with the bromide atom of the known inhibitor. From the point of view, the modification to the known inhibitor was performed to obtain an inhibitor with higher selectivity. The complex conformations of the new designed inhibitor and two isozymes designate the formation of the hydrogen bond between the newly added group (hydroxypropyl group) and Q64 of hCA VII but N67 of hCA II. The results of the binding free energy from the MM/PBSA approach also prove the selectivity improvement of the new inhibitor in comparison with the known inhibitor. The work will help the design of the isozyme-specific inhibitors of hCA VII. PMID- 21320804 TI - [Introduction. Chronic obstructive pulmonary disease]. PMID- 21320805 TI - [Introduction. COPD treatment]. PMID- 21320806 TI - [The National Forum of Pulmonologists in Training: advancing in pulmonology]. PMID- 21320807 TI - [Introduction. Respiratory disease emergencies]. PMID- 21320808 TI - [ALERTA 2 guidelines. Latin America and Spain: recommendations for the prevention and treatment of asmatic exacerbations. Spanish Pulmonology and Thoracic Surgery Society (SEPAR). Asthma Department of the Latinamerican Thoracic Association (ALAT)]. PMID- 21320809 TI - [Impact of new therapeutic options in COPD]. PMID- 21320810 TI - [Phosphodiesterase 4 inhibitors: a new pharmacologic group in the treatment of chronic inflammation of the airways]. PMID- 21320811 TI - [Roflumilast: clinical review of a new option for the treatment of inflammation in COPD]. PMID- 21320812 TI - [Failure to offer parasitology screening to vulnerable migrants in France: Epidemiology and consequences]. AB - The "Consultations de Diagnostic et d'Orientation" (CDO), created in 1998 by the Paris Health Department, are medical consultations for vulnerable populations, which are held in municipal clinics, free of charge. More than two-thirds of CDO patients come from Africa. Our study was designed to assess and analyze whether these clinics offered consulting migrants screening for intestinal parasitic and Schistosoma haematobium infections.Material and methodsThis retrospective study included all immigrants attending CDO for the first time at four Parisian municipal free clinics during 2003. Univariate and multivariate analysis adjusted for age, sex, and geographic origin were conducted. An interview with one of the CDO physicians provided qualitative data to round out the quantitative data from the record analysis.ResultsThe study included 503 migrants eligible for screening for intestinal parasitic infections because they come from regions where these infections are endemic; among them 481 were also eligible for urine screening for Schistosoma haematobium (SH). The sociodemographic characteristics for the entire sample (not significantly different from the 481-person subgroup) were: sex ratio (M/W): 4:1; more than 50% were 35 years old or younger; and more than 50% had no health insurance coverage. Overall, around 80% came from sub-Saharan Africa, around 16% from North Africa or the Middle East, and 4.5% from Asia or South America. Screening for intestinal or urinary parasitic infections was not offered to 3 out of 5 migrants from endemic areas. Screening for intestinal parasites was offered less often to migrants from regions other than sub-Saharan Africa, to those older than 35 years of age, and to those without abdominal symptoms. Schistosoma haematobium urine screening was proposed less often to those from North Africa or the Middle East, to those older than 35 years of age, and to those without either abdominal or genitourinary symptoms. Microscopic examination of urine for Schistosoma haematobium was performed for 171 patients; 22 positive results were reported, with viable SH eggs (13%). Microscopic examination of stool for ova and parasites was performed for 161 patients; 32 had positive results (20%). These included 14 cases of Entamoeba histolytica/dispar (our laboratory cannot distinguish the 2 strains).DiscussionThe failure to offer screening affects sub-Saharan Africans less than other migrants, perhaps because of a particular visibility due to their mass (they are the most prominent subgroup of migrants) or their higher frequency of abdominal/genitourinary symptoms. Nevertheless, more than 50% of them were not asked to undergo parasite screening, although they are the group with the highest rate of intestinal/urinary parasitosis. The most common and dangerous parasite found was Schistosoma haematobium; we do not know the pathogenicity of the Entamoeba found. Reasons for the frequent failure to suggest these screenings may include that physicians consider parasitosis as diseases of secondary importance, or have forgotten its symptoms, epidemiology, cycles, means of diagnosis, or treatment. Patients accepted the screening well when it was offered. Reasons during the course of consultation might have included insufficient time for pre-test counselling, some difficulties in communicating with the patient in French, or an overriding request or complaint from the patient. We propose the following strategy for parasite screening in CDO: standard "stool ova and parasite exams" proposed to any migrant in France for less than 5 years except sub-Saharan Africans, who should receive presumptive anti-parasite treatment instead; microscopic examination of urine for Schistosoma haematobium for sub-Saharan Africans from endemic regions. This detection can avoid - if treatment is early enough - severe uronephrological complications, which are rare but costly from a health care perspective (bladder tumor, renal failure). Physicians in non tropical settings must remember to consider parasite infections when they see patients from endemic regions. PMID- 21320813 TI - [Aspects of the epidemiology, diagnosis and management of sickle cell osteomyelitis in children in Africa]. AB - IntroductionSickle cell osteomyelitis in children is one of the complications of osteoarthritis in sickle cell disease.ObjectiveTo describe the epidemiology, diagnosis and treatment of sickle cell osteomyelitis in children in Africa to improve management.Tools and methodA review of records showed that from April 2004 through September 2009, eleven cases of osteomyelitis in children aged 0 to 15 years who carried the sickle cell trait were treated in the surgical and pediatric unit of the Women's and Children's Hospital of Yaounde.ResultThe children's mean age was 7 years, but frequency was highest for those aged 1 to 5 years. The sex ratio was 2:1 male. The portal of entry was found for only 30% of cases. The predilection of the disease for long bones, the non-fistulated forms, the homozygous type, and the frequency of Salmonella were all remarkable. Medical and preventive treatment, always applied, were followed by orthopedic treatment. The usefulness of surgery, on the other hand, is subject to debate. Healing was obtained in 80% of cases.ConclusionThe authors describe the profile of osteomyelitis in children with sickle cell disease in Africa. PMID- 21320814 TI - [Laboratory diagnostic and prognostic factors: Multiple myeloma in Morocco]. AB - ObjectivesThe purpose of this retrospective study was to clarify the factors for a laboratory diagnosis of multiple myeloma (Kahler's disease) and assess their prognostic value.MethodsThe study of all 10 patients with multiple myeloma seen during 2009 in the department of internal medicine and the haematology laboratory of HASSAN II University Hospital Centre in Fez. Work-ups for all patients included hemograms, sedimentation speed, electrophoresis of serum and urinary proteins, myelograms, creatinemia, calcemia, beta2-microglobulin, LDH and CRP.ResultsIn this series, the average age of the patients was 59 years and the sex ratio 1.3 (men). The laboratory tests showed anemia below 12 g/dl in 80% of the cases, with IgG accounting for 50% of the cases. The median concentration of the monoclonal component was 28 g/l. The prognostic assessments showed an increase in beta2-microglobulins and creatinemia in one case. CRP was elevated in all patients.ConclusionThe results from this study are consistent with those from other series. Protein electrophoresis and myelography results are major diagnostic elements, because they make it possible to rule out a monoclonal gammopathy of undetermined significance, for which treatment differs completely from that for multiple myeloma. beta2-microglobulin and CRP are independent prognostic factors providing important information about survival. PMID- 21320815 TI - Blood pressure and acute ischemic stroke. PMID- 21320816 TI - Too much of a good thing? Brain hyper excitability and migraine. PMID- 21320817 TI - CURES and the dilemma of unruptured intracranial aneurysms. PMID- 21320818 TI - Decision making, bias, and low grade glioma. PMID- 21320819 TI - Not just numbers: qualitative research and the clinical neurosciences. PMID- 21320820 TI - Histories of our professions. PMID- 21320821 TI - Reflections on the TEAM trial: why clinical care and research should be reconciled. AB - The current clinical and research environment is one that renders any true enquiry into the value of commonly performed surgical acts practically impossible. Drawing from the recent failure of Trial on Endovascular Aneurysm Management (TEAM), a trial on the endovascular management of unruptured intracranial aneurysms, I attempt to identify some principles that sustain the current ways of doing clinical research that have paradoxically become major obstacles to trials that aim to assess the potential benefit or harm due to interventions as currently practiced. Clinical research and practice must coalesce into "clinical care trials" if we are to provide patients with optimal, prudent care in the context of uncertainty. This may require a major change in the mentalities of clinicians, scientists, and patients alike, and the adoption of novel strategies for public agencies to support the integration of clinical research and care. PMID- 21320822 TI - A history of neurosurgery in Canada. AB - Canada existed for more than half a century before there were glimmerings of modern neurosurgical activity. Neurosurgery had advanced significantly in Europe and the United States prior to its being brought to Toronto and Montreal from American centers. The pioneers responsible for the rapid evolution in practice, teaching and research are described. The interplay of scientific, professional, demographic and economic forces with general historical trends has produced dramatic changes in the way that neurosurgery is now practiced. PMID- 21320823 TI - My front row seat memoir V. Further encounters at the greatest show on earth. PMID- 21320824 TI - Blood pressure and early clinical outcome among acute ischemic stroke patients. AB - OBJECTIVES: The association between blood pressure (BP) and short-term clinical outcome of acute ischemic stroke is inconclusive. We investigated the association between BP in the first 72 hours following admission and death in-hospital and neurologic deficiency at discharge among patients with acute ischemic stroke. METHODS: A total of 2675 acute ischemic stroke patients confirmed by a computed tomography scan or magnetic resonance imaging were included in the present study. Blood pressure in the first 72 hours after admission and other study variables were collected for all ischemic stroke patients. Neurological functions National Institute of Health Stroke Scale (NIHSS) were evaluated by trained neurologists at discharge. The study outcome was defined as death in-hospital and neurologic deficiency (NIHSS>=10) at discharge. RESULTS: Systolic and diastolic BP were significantly and positively associated with odds of study outcome in acute ischemic stroke. For example, compared to those with a systolic BP<140 mmHg, multiple-adjusted odds ratio (95% confidence interval) of study outcome was 3.29(1.22, 8.90) among participants with systolic BP of 180-219 mmHg, P<0.05; compared to those with a diastolic BP<90 mmHg, multiple-adjusted odds ratio of study outcome was 7.05(1.32, 37.57) among participants with diastolic BP>=120 mmHg, P<0.05. CONCLUSION: Systolic BP>=180 and diastolic BP>=120 were significantly and positively associated with death in-hospital or neurologic deficiency at discharge among patients with acute ischemic stroke. PMID- 21320825 TI - Carotid endarterectomy versus stenting: a meta-analysis of randomized trials. AB - BACKGROUND: A meta-analysis of randomized controlled trials (RCTs) was conducted to update the available evidence on the safety and efficacy of carotid endarterectomy (CEA) versus carotid artery stenting (CAS) in the treatment of carotid artery stenosis. METHODS: A comprehensive search was performed of MEDLINE, EMBASE, CENTRAL, bibliographies of included articles and past systematic reviews, and abstract lists of recent scientific conferences. For each reported outcome, a Mantel-Haenszel random-effects model was used to calculate odds ratios (ORs) and 95% confidence intervals (CI). The I2 statistic was used as a measure of heterogeneity. RESULTS: Twelve RCTs enrolling 6,973 patients were included in the meta-analysis. Carotid artery stenting was associated with a significantly greater odds of periprocedural stroke (OR 1.72, 95% CI 1.20 to 2.47) and a significantly lower odds of periprocedural myocardial infarction (OR 0.47, 95% CI 0.29 to 0.78) and cranial neuropathy (OR 0.08, 95% CI, 0.04 to 0.16). The odds of periprocedural death (OR 1.11, 95% CI 0.56 to 2.18), target vessel restenosis (OR 1.95, 95% CI 0.63 to 6.06), and access-related hematoma were similar following either intervention (OR 0.60, 95% CI 0.30 to 1.21). CONCLUSIONS: In comparison with CEA, CAS is associated with a greater odds of stroke and a lower odds of myocardial infarction. While the results our meta-analysis support the continued use of CEA as the standard of care in the treatment of carotid artery stenosis, CAS is a viable alternative in patients at elevated risk of cardiac complications. PMID- 21320826 TI - The design of the Canadian UnRuptured Endovascular versus Surgery (CURES) trial. AB - BACKGROUND: Once a decision has been made to treat an intact aneurysm, the best treatment remains uncertain. Both surgical and endovascular management strategies are commonly performed for these lesions. Surgical clipping, for years the standard treatment, is gradually becoming supplanted by endovascular treatment. However, there is no randomized data available to compare the results of surgery versus endovascular treatment of unruptured aneurysms (UIAs). METHODS: We report the design of the Canadian UnRuptured Endovascular versus Surgery (CURES) trial to compare angiographic and clinical outcomes following treatment of UIAs. RESULTS: The Canadian pilot phase will serve two purposes: i) to determine feasibility of the pivotal international study, and ii) to determine the incidence of treatment failure, a composite primary end-point comprising the occurrence of either: failure to accomplish aneurysm obliteration with the initial treatment modality, a major saccular aneurysm remnant or recurrence, or intracranial hemorrhage following treatment at one year. The pivotal international study will address which strategy leads to the best overall clinical outcomes in terms of mortality, morbidity, and clinical efficacy. CURES is designed to be a pragmatic management trial with loose inclusion criteria. The pilot study plans to enroll 260 patients, a size sufficient (at 80% power and 0.05 significance) to detect a decrease in the incidence of treatment failure from 13% to 4%. The formulation of specific hypotheses for the pivotal phase awaits the preliminary CURES morbidity and mortality results. CONCLUSIONS: The CURES trial intends to test surgical versus endovascular management strategies for the treatment of unruptured intracranial aneurysms. PMID- 21320827 TI - Frontal assessment battery to evaluate frontal lobe dysfunction in ALS patients. AB - BACKGROUND: Assessment of frontal lobe impairment in amyotrophic lateral sclerosis (ALS) is a matter of great importance, since it often causes ALS patients to decrease medication and nursing compliance, thus shortening their survival time. METHODS: The frontal assessment battery (FAB) is a short and rapid method for assessing frontal executive functions. We investigated the applicability of the FAB as a screening method for assessing cognitive impairments in 61 ALS patients. Depending on the results of the FAB, we classified patients into two subgroups: FAB-normal and FAB-abnormal. We then performed additional evaluations of cognitive function using the Korean version of the mini-mental state examination (K-MMSE), a verbal fluency test (COWAT), and a neuropsychiatric inventory (NPI). Results of these tests were compared between the two groups using Mann-Whitney U-tests, and Spearman correlation analyses were used to investigate the relationships between FAB score and disease duration and severity. RESULTS: Of the 61 sporadic ALS patients included in this study, 14 were classified as FAB-abnormal and 47 were classified as FAB-normal. The FAB normal and FAB-abnormal patients performed significantly differently in all domains of the COWAT. There was no difference in behavioral disturbance, as assessed by the NPI, between the two groups. The FAB scores were found to significantly correlate with both disease duration and severity. CONCLUSIONS: The FAB shows promise as a method of screening for frontal lobe dysfunction in ALS, as it is not only quick and easy, but also reliable. Additional studies should examine how FAB performance changes as ALS progresses. PMID- 21320828 TI - Stereotactic radiotherapy: an emerging treatment for spinal metastases. AB - AIM: The purpose of this concise update is to describe the emerging treatment of stereotactic body radiotherapy (SBRT) for spinal metastases. RATIONALE: Spinal metastases are common and can present complex clinical challenges that conventional treatment cannot always meet satisfactorily. Examples include a history of prior irradiation at the same site or radio-resistant tumor histology. Stereotactic body radiotherapy makes it possible to deliver high doses of radiation with the aim of improving tumor control and palliation. It is increasingly being offered to selected patients including those requiring re irradiation and post-operative treatment. CONCLUSION: It is important that specialists managing patients with spinal metastases are aware of the potential advantages of SBRT and how this can complement and extend existing treatment approaches, including spinal decompression and stabilization. PMID- 21320829 TI - Web-based software to assist in the localization of neuroanatomical lesions. AB - OBJECTIVE: To evaluate the educational effectiveness of a novel, web-based neuroanatomical localization application. METHODS: A prototype version of a neuroanatomical localization application was developed, limited to lesions involving Cranial Nerve (CN) VII. Second year medical students at the University of Ottawa were recruited to participate in the study. Participants were exposed to a didactic teaching session on CN VII anatomy. They were subsequently randomized to two groups - one group was granted access to the localization application (the "intervention group"), while the other group was given a booklet of standard textbook resources (the "control group"). Participants then completed a case-based multiple choice test on localization of neurologic lesions associated with CN VII, followed by a questionnaire regarding the experience. RESULTS: Thirty-nine students volunteered to participate. Twenty were randomized to the intervention group and 19 to the control group. There was a mean test score difference of 1.3 (CI.95=0.2, 2.3) that was significantly higher in the intervention group when compared to the control group. Significance was determined by a Wilcoxon rank test (p=0.028). Questionnaire results were similar for both groups, showing an overall favourable evaluation of the localization application. CONCLUSIONS: The results support our hypotheses that students using the application would perform better on the multiple choice question (MCQ) test and there would be an overall preference for its use. The demonstrated educational benefit of the application, in addition to the demand for such a resource expressed by the participants, warrant further investigation into the development of a neurological localization application. PMID- 21320830 TI - Low grade glioma: a qualitative study of the wait and see approach. AB - BACKGROUND: There is no consensus on the best management of adults with presumed low grade glioma (LGG). Studies have suggested uncertainty and anxiety associated with a wait and see approach contribute to reduced quality of life. This study aims to explore the impact of a diagnosis of LGG, to address concerns regarding the uncertainty of the diagnosis and the role of wait and see from the patient's perspective. METHODS: Qualitative research methodology was used. A semi structured interview was conducted with 24 patients with imaging evidence of LGG but no prior intervention. All patients had been followed for at least one year prior to interview. Verbatim transcripts were subjected to thematic analysis. RESULTS: The median age of participants was 47 (range 21-82) and the median duration of follow-up 37 months (range 12-156 months). Fifty percent presented with seizures. Five overarching themes emerged from the data; 1) patients experience initial devastation followed by acceptance and low anxiety; 2) absence of symptoms mitigates anxiety concerning the possibility of progression; 3) patients would prefer to defer surgery until there is progression or a change in their quality of life; 4) anxiety is reduced by trust in the physician; 5) quality of life is not affected by the diagnosis, as fear of morbidity from intervention is greater than the fear of uncertainty. CONCLUSIONS: The wait and see approach does not contribute to anxiety or reduction in quality of life in patients with LGG. PMID- 21320831 TI - Minimally invasive versus open approach for cervical laminoforaminotomy. AB - BACKGROUND: Minimally invasive posterior cervical foraminotomy for radicular symptoms has become more prevalent. The reported experience with microscopic tubular assisted posterior cervical laminoforaminotomy (MTPF) for the treatment of radicular pain is lacking. Tubular assisted techniques have been considered to offer significant benefit, over open procedures, in terms of minimizing tissue damage, operative time, blood loss, analgesic requirements and length of hospital stay. We hypothesized that MTPF reduces post-operative analgesic requirements and length of hospital stay over the traditional open laminoforaminotomy, with no difference in complication rates and, secondly, that MTPF is comparable to endoscopic posterior foraminotomy (EPF). METHODS: We conducted a retrospective review of 107 patients who underwent posterior cervical laminoforaminotomy for radicular pain between 1999 and 2009. Patient demographics, intra-operative parameters, length of hospitalization, post-operative analgesic use, complications and short-term neurological outcome were compared between groups. RESULTS: Between 1999 and 2009, a total of 107 patients were identified to have undergone a cervical foraminotomy. An open approach was used in 65 patients, while 42 underwent MTPF. Operative time and complications were comparable between groups. Significant differences favoring MTPF were observed in operative blood loss, post-operative analgesic use and length of hospital stay (p<0.001). All results were comparable to previous reports utilizing EPF. CONCLUSIONS: MTPF for the treatment of cervical radiculopathy significantly reduces blood loss, post operative analgesic use and length of hospital stay compared to the standard open approach. Operative time and complication rates were comparable between both techniques, whilst MTPF offered similar results compared to EPF. PMID- 21320832 TI - Patients' perceptions of carpal tunnel and ulnar nerve decompression surgery. AB - BACKGROUND: Carpal tunnel syndrome and ulnar nerve entrapment at the elbow are the most common entrapment neuropathies seen in adults. Surgery for nerve decompression is a safe and effective treatment option, and is usually performed under local anesthesia and as an outpatient procedure. This study aimed to explore patients' satisfaction and other aspects of the overall experience with this type of surgery. METHODS: Qualitative research methodology was used. Semi structured, open-ended interviews were conducted with 30 adult patients who had undergone carpal tunnel release or ulnar nerve decompression at the elbow 6-24 months prior. Interviews were digitally audio recorded and transcribed, and the data subjected to thematic analysis. RESULTS: Four overarching themes emerged from the data: (1) most patients did not perceive their condition to be serious; (2) patients were satisfied with the overall surgical experience; (3) the outcome was more important to patients than the process; and (4) majority of patients had a realistic expectation of outcomes. CONCLUSIONS: Patients had a positive experience with carpal tunnel and ulnar nerve decompression surgery, although their level of satisfaction was dependent on the surgical outcome. Areas requiring improvement, specifically information about post-operative care and expectations of recovery, will be implemented in the future care of patients. PMID- 21320833 TI - Normal-pressure hydrocephalus: is there a genetic predisposition? AB - BACKGROUND: Normal-pressure hydrocephalus (NPH) is characterized by gait disturbance, cognitive impairment, with or without urinary incontinence, enlarged ventricles with or without cerebral atrophy and normal cerebrospinal fluid pressure. METHODS: We report two sisters with NPH who lived together their entire lives and whose natural history might provide insights into genetic and environmental mechanisms underlying this disorder. Both patients were in their early seventies, single, had similar daily habits and hypertension. No other family members had NPH. RESULTS: They both underwent shunt placement and showed improvement documented by history and neuropsychological assessment. Both showed a delayed deterioration due to vasculopathy. Both patients were homozygous for the apolipoprotein E (ApoE) e3 allele on chromosome 19. No environmental factors that might have influenced the development of NPH were identified. CONCLUSION: Our report of two sisters with NPH may indicate the presence of genetic predisposition and further studies involving genetics and environmental factors are necessary to elucidate their role in the pathogenesis of NPH. PMID- 21320834 TI - Meaningful change in cognition in multiple sclerosis: method matters. AB - OBJECTIVE: To determine if different methods of evaluating cognitive change over time yield measurably different outcomes. METHODS: Twelve cognitively impaired patients with clinically definite Multiple sclerosis (10 relapsing-remitting, 2 secondary progressive) underwent neuropsychological testing (baseline, 6, 12 months). Data was analysed using: t-tests evaluating group differences on individual tests, group differences in composite scores, reliable change analyses at the level of the individual, and comparisons regarding number of tests failed at each time point. RESULTS: Group t-tests on individual tests yielded no change. When tests were grouped according to theoretical constructs, analyses revealed change in processing speed. Reliable change estimates revealed that 16% of the sample deteriorated. When change was measured with respect to the number of domains affected at each time point, 58% of the sample deteriorated on at least one subtest. CONCLUSIONS: Methodology has a significant impact on interpretation of longitudinal data. In the same group of subjects, traditional group analyses documented no change in individual test scores or change on a single composite score. Analyses of individual results documented change from 16 to 58% of the sample. Advantages and disadvantages of each method were discussed. Findings have implications for interpretation of longitudinal studies. PMID- 21320835 TI - The neuropathies of Waldenstrom's macroglobulinemia (WM) and IgM-MGUS. AB - BACKGROUND: Neuropathy is common in Waldenstrom's macroglobulinemia (WM, an IgM associated lymphoplasmacytic lymphoma) and in IgM-monoclonal gammopathy of undetermined significance (IgM-MGUS). Paraneoplastic or paraimmune mechanisms are thought to be involved in the pathogenesis of these neuropathies. Attempts at distinguishing WM and IgM-MGUS neuropathies are lacking especially among bone marrow (BM) confirmed patients. METHODS: Retrospective analyses were performed on BM confirmed WM (N=30) and IgM-MGUS (N=73) neuropathy patients with neurologic assessments and hematologic features. RESULTS: The presence of anemia and quantity of IgM monoclonal protein were significantly greater in WM. Based on multiple neurologic assessments differences were not found for: 1) length of time from neurologic symptom onset to evaluation; 2) chief complaint of painless loss of feeling in the feet, Romberg's sign and tremor; and 3) clinical motor, sensory and reflex abnormalities. Autonomic testing was normal in both diseases. Using nerve conduction (NCS) criteria for demyelination, 62% of IgM-MGUS and 27% of WM met this criteria (p=0.013). IgM MGUS patients had greater terminal conduction slowing by ulnar residual latency calculation (<0.01). The degree of axonal loss as measured by summated compound muscle action potentials and available nerve biopsy was not significantly different between diseases. CONCLUSION: Although WM and IgM-MGUS must be distinguished for hematologic prognosis and treatment, clinical neuropathy presentations of WM and IgM-MGUS are similar and likely related to comparable axonal loss in both conditions. Despite these similarities, evidence of demyelination was found by electrophysiologic studies much more commonly in IgM-MGUS. This difference may reflect varied immune mechanism(s) in the two disorders. PMID- 21320836 TI - Early treatment of a progressive Rasmussen's like syndrome with ganciclovir. AB - BACKGROUND: Escalating focal sensorimotor seizures, progressive neurologic deficit and cognitive decline with associated typical magnetic resonance imaging (MRI) findings or pathological confirmation constitute the syndrome of Rasmussen's encephalitis. METHODS: Three patients with this clinical scenario had long-term follow-up after being given the antiviral drug ganciclovir 10 mg/kg/day IV for ten days within one to three months of disease onset. RESULTS: Seizures occurred at least hourly and were localized to the Rolandic region. The MRIs were normal in one patient and in two showed changes consistent with ongoing seizures. Two patients, one whose short-term outcome was reported previously, had immediate and sustained cessation of seizures and resolution of their neurologic deficit. One patient with seizures from both hemispheres did not respond and went on to hemispherectomy that confirmed chronic encephalitis. Seizures continued in five other patients treated 6 to 72 months after disease onset. CONCLUSION: The sustained seizure control after ganciclovir in two of three patients suggests this drug may be effective when given early in the course of this subacute intractable focal epilepsy syndrome. PMID- 21320837 TI - Stereopsis in drug naive Parkinson's disease patients. AB - BACKGROUND: Motor deficits associated with Parkinson's disease (PD) have been well described, yet little attention has been paid to non-motor symptoms, especially cortical visual dysfunction. We investigated stereopsis, as well as the relationship between stereopsis and other cognitive function, in a sample of PD patients. METHODS: We used Titmus stereotest plates for assessing stereopsis. Fifty-nine subjects (29 PD patients and 30 normal controls) were included in this study. The included patients underwent a neurological examination, clinical rating scale and neuropsychological tests. RESULTS: Drug naive PD patients showed decreased stereopsis on the Titmus fly stereopsis test (Pearson chi2=23.80, p<0.001) compared to PD patients with normal stereopsis. The Hoehn-Yahr stages and Unified Parkinson's Disease Rating Scale motor scores were significantly higher in patients with PD with abnormal stereopsis than in patients with PD with normal stereopsis (p=0.026; p=0.046). The frequency of abnormal visual perception/constructive function was greater in patients with PD with abnormal stereopsis compared to patients with PD with normal stereopsis (Pearson chi2=5.11, p=0.024). CONCLUSION: These findings suggest that stereopsis deficits and visual perception/constructive dysfunction are common in de novo PD patients. PMID- 21320838 TI - Variations in 5-HT2A influence spatial cognitive abilities and working memory. AB - BACKGROUND: 5-hydroxytryptamine receptor 2A (5-HT2A) participates in diverse psychiatric disorders by regulating the activity of serotonin. Some previous studies have also suggested that the receptor is involved in cognitive abilities of disease groups. We hypothesize that some functional genetic variants in 5-HT2A have certain specific influences on cognitive abilities in a normal population. METHOD: To confirm this hypothesis, two polymorphisms (rs6313 and rs4941573) in 5 HT2A were selected, and a population-based study was performed in a young healthy Chinese Han cohort. RESULTS: The results indicated that the rs6313 and rs4941573 were associated with touching blocks and mental rotation-3D error ratio in males, and the rs4941573 was associated with visuo-spatial working memory in the whole cohort. CONCLUSION: All the findings suggest that 5-HT2A participates in human spatial cognitive abilities and spatial working memory. PMID- 21320839 TI - Subcortical hyperexcitability in migraineurs: a high-frequency oscillation study. AB - OBJECTIVE: An abnormal central nervous system excitability level was found in patients with migraine. Whether it is hyper- or hypo-excitable is still debated. This study aimed to compare the somatosensory high-frequency oscillations (HFOs), which reflected subcortical excitability (early phase) and intracortical inhibition (late phase), between patients with migraine and control subjects. METHODS: HFOs were recorded from C3'-Fz, using a 500-1000 Hz frequency filter after stimulation at right median nerves at the wrists, and divided into early and late phases based on the N20 peak. Fifty-nine untreated patients (n=24 during ictal period; n=35, interictal) and 22 controls finished the study. RESULTS: In early HFOs, patients both during ictal and interictal periods had higher maximal amplitudes (p=0.039) and area-under-curve (p=0.029) than those of the controls. Regarding the late HFOs, there were no significant differences among these groups. CONCLUSION: Our study suggests a hyper-excitable state in the subcortical regions in patients with migraine both during interictal and ictal periods. PMID- 21320840 TI - Interprofessional stroke rehabilitation for stroke survivors using home care. AB - OBJECTIVE: To compare a specialized interprofessional team approach to community based stroke rehabilitation with usual home care for stroke survivors using home care services. METHODS: Randomized controlled trial of 101 community-living stroke survivors (<18 months post-stroke) using home care services. Subjects were randomized to intervention (n=52) or control (n=49) groups. The intervention was a 12-month specialized, evidence-based rehabilitation strategy involving an interprofessional team. The primary outcome was change in health-related quality of life and functioning (SF-36) from baseline to 12 months. Secondary outcomes were number of strokes during the 12-month follow-up, and changes in community reintegration (RNLI), perceived social support (PRQ85-Part 2), anxiety and depressive symptoms (Kessler-10), cognitive function (SPMSQ), and costs of use of health services from baseline to 12 months. RESULTS: A total of 82 subjects completed the 12-month follow-up. Compared with the usual care group, stroke survivors in the intervention group showed clinically important (although not statistically significant) greater improvements from baseline in mean SF-36 physical functioning score (5.87, 95% CI -3.98 to 15.7; p=0.24) and social functioning score (9.03, CI-7.50 to 25.6; p=0.28). The groups did not differ for any of the secondary effectiveness outcomes. There was a higher total per-person costs of use of health services in the intervention group compared to usual home care although the difference was not statistically significant (p=0.76). CONCLUSIONS: A 12-month specialized, interprofessional team is a feasible and acceptable approach to community-based stroke rehabilitation that produced greater improvements in quality of life compared to usual home care. Clinicaltrials.gov identifier: NCT00463229. PMID- 21320841 TI - Susac's Syndrome. PMID- 21320842 TI - Pediatric traumatic retroclival epidural hematoma. PMID- 21320843 TI - Autonomic, EEG, and behavioral arousal signs in a PVS case after Zolpidem intake. PMID- 21320844 TI - Generalized nonconvulsive status epilepticus with reactive alpha rhythm. PMID- 21320845 TI - Neuroimaging and neurophysiology studies in carriers of cree leukoencephalopathy. PMID- 21320846 TI - IV thrombolysis in stroke from a cavernous carotid aneurysm to artery embolus. PMID- 21320847 TI - An unusual case of myelopathy: surfer's myelopathy. PMID- 21320848 TI - A case of mistaken identity: spinal epidural angiolipoma. PMID- 21320849 TI - Transient executive dysfunction following STNDBS in Parkinson's disease. PMID- 21320850 TI - Traumatic spinal cord injury without initial MRI abnormality: SCIWORA revisited. PMID- 21320851 TI - Superficial siderosis as a manifestation of a dural arteriovenous fistula. PMID- 21320852 TI - Out of Africa, for now. PMID- 21320853 TI - Is prophylactic lumbar discectomy ever indicated? PMID- 21320854 TI - Online interventions for social marketing health behavior change campaigns: a meta-analysis of psychological architectures and adherence factors. AB - BACKGROUND: Researchers and practitioners have developed numerous online interventions that encourage people to reduce their drinking, increase their exercise, and better manage their weight. Motivations to develop eHealth interventions may be driven by the Internet's reach, interactivity, cost effectiveness, and studies that show online interventions work. However, when designing online interventions suitable for public campaigns, there are few evidence-based guidelines, taxonomies are difficult to apply, many studies lack impact data, and prior meta-analyses are not applicable to large-scale public campaigns targeting voluntary behavioral change. OBJECTIVES: This meta-analysis assessed online intervention design features in order to inform the development of online campaigns, such as those employed by social marketers, that seek to encourage voluntary health behavior change. A further objective was to increase understanding of the relationships between intervention adherence, study adherence, and behavioral outcomes. METHODS: Drawing on systematic review methods, a combination of 84 query terms were used in 5 bibliographic databases with additional gray literature searches. This resulted in 1271 abstracts and papers; 31 met the inclusion criteria. In total, 29 papers describing 30 interventions were included in the primary meta-analysis, with the 2 additional studies qualifying for the adherence analysis. Using a random effects model, the first analysis estimated the overall effect size, including groupings by control conditions and time factors. The second analysis assessed the impacts of psychological design features that were coded with taxonomies from evidence-based behavioral medicine, persuasive technology, and other behavioral influence fields. These separate systems were integrated into a coding framework model called the communication-based influence components model. Finally, the third analysis assessed the relationships between intervention adherence and behavioral outcomes. RESULTS: The overall impact of online interventions across all studies was small but statistically significant (standardized mean difference effect size d=0.19, 95% confidence interval [CI]=0.11-0.28, P<.001, number of interventions k=30). The largest impact with a moderate level of efficacy was exerted from online interventions when compared with waitlists and placebos (d=0.28, 95% CI=0.17-0.39, P<.001, k=18), followed by comparison with lower-tech online interventions (d=0.16, 95% CI=0.00-0.32, P=.04, k=8); no significant difference was found when compared with sophisticated print interventions (d=-0.11, 95% CI= 0.34 to 0.12, P=.35, k=4), though online interventions offer a small effect with the advantage of lower costs and larger reach. Time proved to be a critical factor, with shorter interventions generally achieving larger impacts and greater adherence. For psychological design, most interventions drew from the transtheoretical approach and were goal orientated, deploying numerous influence components aimed at showing users the consequences of their behavior, assisting them in reaching goals, and providing normative pressure. Inconclusive results suggest a relationship between the number of influence components and intervention efficacy. Despite one contradictory correlation, the evidence suggests that study adherence, intervention adherence, and behavioral outcomes are correlated. CONCLUSIONS: These findings demonstrate that online interventions have the capacity to influence voluntary behaviors, such as those routinely targeted by social marketing campaigns. Given the high reach and low cost of online technologies, the stage may be set for increased public health campaigns that blend interpersonal online systems with mass-media outreach. Such a combination of approaches could help individuals achieve personal goals that, at an individual level, help citizens improve the quality of their lives and at a state level, contribute to healthier societies. PMID- 21320855 TI - A randomized control trial comparing two enteral feeding volumes in very low birth weight babies. AB - Poor post-natal growth of preterm neonates is common and fortification is recommended. However, this is not always practical in low-resource areas. Hypothesizing that increasing the volume of feeds would be safe and lead to better post-natal weight gain, we randomized 64 babies with birth weight <1500 g, once they reached full feeds, to continue feeds at 200 ml/kg/day (standard volume) or increase to 300 ml/kg/day (high volume) of expressed breast milk. There was a significantly higher daily weight gain in the high-volume group as compared to the standard volume group (24.9 vs. 18.7 g/kg/day, p < 0.0001). There were no differences in complications like feed intolerance, tachypnoea, sepsis, patent ductus arteriosus or necrotizing enterocolitis. High-volume feeds at 300 ml/kg/day was safe and resulted in better weight gain than standard volume feeds in very low birth weight babies. PMID- 21320856 TI - Primary intracranial abscess localized in the basal ganglia: a case report. AB - Brain abscesses are serious infections that cause neurological problems and generally require antibiotic treatment and surgical drainage. Hematogenous brain abscesses are generally located in the region fed by the middle cerebral artery, but are occasionally found in deep tissues, such as the basal ganglia and thalamus. PMID- 21320857 TI - Massive cerebral air embolism on ante mortem CT head following pneumothorax in a child with pneumonia. AB - Cerebral air embolism (CAE) is a rarely reported complication of a common condition like pneumothorax, presenting with deterioration of sensorium and cardiovascular instability. We report a case of 3-year-old male who developed pneumothorax after positive pressure ventilation followed by deterioration of sensorium. CT head revealed massive CAE. PMID- 21320858 TI - Calcifying nested stroma-epithelial tumor of the liver: a case report and review of literature. AB - Calcifying nested stromal-epithelial tumor (CNSET) of the liver is extremely rare. This tumor is characterized by nests of epithelial and spindle cells, an associated desmoplastic stroma, as well as variable calcifications and ossifications. Only 24 cases have been reported in the literature whereas none has been reported in Asian descendants. The authors report the first case of CNSET in a 34-year-old Asian woman and provide detailed histological and clinical follow-up data. Compared with those reported earlier, the present case with a history of oral contraceptive use displayed most typical features and the oldest age of onset. A retrospective study was made and the characteristics of CNSET were summarized. PMID- 21320859 TI - Aberrant calretinin and D2-40 expression in Krukenberg tumor (HER2/neu amplified). PMID- 21320860 TI - Are the major risk/need factors predictive of both female and male reoffending?: a test with the eight domains of the level of service/case management inventory. AB - The Level of Service/Case Management Inventory (LS/CMI) and the Youth version (YLS/CMI) generate an assessment of risk/need across eight domains that are considered to be relevant for girls and boys and for women and men. Aggregated across five data sets, the predictive validity of each of the eight domains was gender-neutral. The composite total score (LS/CMI total risk/need) was strongly associated with the recidivism of males (mean r = .39, mean AUC = .746) and very strongly associated with the recidivism of females (mean r = .53, mean AUC = .827). The enhanced validity of LS total risk/need with females was traced to the exceptional validity of Substance Abuse with females. The intra-data set conclusions survived the introduction of two very large samples composed of female offenders exclusively. Finally, the mean incremental contributions of gender and the gender-by-risk level interactions in the prediction of criminal recidivism were minimal compared to the relatively strong validity of the LS/CMI risk level. Although the variance explained by gender was minimal and although high-risk cases were high-risk cases regardless of gender, the recidivism rates of lower risk females were lower than the recidivism rates of lower risk males, suggesting possible implications for test interpretation and policy. PMID- 21320861 TI - Estimation of wave fields of incident beams in a transmission electron microscope by using a small selected-area aperture. AB - The direction of an electron beam in a nanometer-sized area is measured directly by utilizing a selected-area aperture. By the measurements at several areas in a beam, the wavefront curvature and thus the defocus value of the beam are detected. From the defocus value, the wave field at the specimen plane is also reproduced in consideration of the influences of the condenser aperture and spherical aberration of the illumination lens. The result shows that phase deviation of 2pi is caused only at about 10 nm apart from the beam center in a beam with a typical diameter for high-resolution transmission electron microscopy. Based on the defocus value, the convergence angle of the beam is also estimated to be about 6 mrad without being influenced by the partial coherence, that is, independently of the type of the electron gun. Measuring the defocus values for only two beam diameters enables us to determine geometrical parameters peculiar to the illumination system, based on which wave fields of any beam diameters by any condenser aperture sizes can be estimated. The technique proposed in this paper is effective in evaluating the influence of wavefront curvature of incident beams on various kinds of precise measurements conducted in transmission electron microscopes. PMID- 21320862 TI - Perioperative care of an infant with an anomalous left innominate artery arising from the main pulmonary artery. AB - A 1.4-kilogram, male infant was born at 27 weeks gestation at an outside hospital. After birth, the patient's trachea was intubated and surfactant administered. Initial echocardiogram showed a patent ductus arteriosus (PDA) and a ventricular septal defect (VSD), with a possible aberrant vessel arising from the carotid artery. The patient was transferred to our hospital for further management. Repeat echocardiogram showed a right aortic arch with the left common carotid/innominate artery arising from the pulmonary artery. The infant was subsequently brought to the operating room where following sternotomy, the aberrant left innominate artery was reimplanted into the aorta. The origin of the left carotid artery or innominate artery from the pulmonary artery is an extremely rare form of congenital heart disease with a limited number of reports in the literature. The differential pressure gradient between the systemic and pulmonary beds may lead to a steal phenomenon, with shunting of blood from the carotid system into the pulmonary vascular bed, resulting in decreased cerebral blood flow. The left-to-right shunting from the systemic to pulmonary bed may also lead to volume overload of the left side of the heart. In the perioperative care of such patients, control of physiologic factors that control the balance between the pulmonary and systemic vascular resistance is mandatory to ensure that cerebral blood flow is maintained. PMID- 21320863 TI - B-type natriuretic peptide: diagnostic and therapeutic applications in infants and children. AB - The natriuretic peptide system plays an active role in the regulation of fluid balance and systemic vascular resistance. Peptides of the natriuretic system produced through recombinant DNA technology are now available for clinical use including both atrial natriuretic peptide (ANP) and brain-type natriuretic peptide (BNP). Assays of BNP are available and may be used for both diagnostic and prognostic purposes in various clinical scenarios. The basic physiology of the natriuretic peptide system is presented, applications of BNP monitoring as a diagnostic tool are reviewed, and reports regarding the use of recombinant BNP in the pediatric population are discussed. PMID- 21320864 TI - Prolonged mechanical support in children with severe adenoviral infections: a case series and review of the literature. AB - Adenovirus infections occur primarily in infants and children less than 5 years of age, accounting for 2% to 5% of respiratory illnesses in the pediatric population and 4% to 10% of childhood pneumonias. Although the majority of children with adenovirus disease develop mild upper respiratory tract disease, more severe disease may occur with involvement of the lower respiratory tract characterized by pneumonitis and/or small airways disease. The authors present a case series of 3 high-risk children with severe lower respiratory tract adenoviral infections. These cases demonstrate the potential for the development of severe respiratory involvement from adenovirus in infants and children with comorbid conditions and illustrate that there may be a rapid progression of the disease as well as the need, in selected circumstances, for prolonged mechanical support. We review the role of adenovirus in lower respiratory tract infections in infants and children, its potential to result in life-threatening complications in pediatric patients with comorbid conditions, and the potential life-saving role of mechanical ventilation and extracorporeal life support (ECLS) in these children. PMID- 21320865 TI - Improving SNP discovery by base alignment quality. AB - I propose a new application of profile Hidden Markov Models in the area of SNP discovery from resequencing data, to greatly reduce false SNP calls caused by misalignments around insertions and deletions (indels). The central concept is per-Base Alignment Quality, which accurately measures the probability of a read base being wrongly aligned. The effectiveness of BAQ has been positively confirmed on large datasets by the 1000 Genomes Project analysis subgroup. AVAILABILITY: http://samtools.sourceforge.net CONTACT: hengli@broadinstitute.org. PMID- 21320866 TI - Risk of hypertension among young adults who were born preterm: a Swedish national study of 636,000 births. AB - Previous studies have reported an association between preterm birth and elevated blood pressure in adolescence and young adulthood. These studies were based on single-day blood pressure measurements and had limited ability to estimate risk of hypertension measured over a longer period and across the full range of gestational ages. The authors conducted a national cohort study of all infants born in Sweden from 1973 through 1979 (n = 636,552), including 28,220 born preterm (<37 weeks), followed to ages 25.5-37.0 years to determine whether individuals born preterm were more likely to be prescribed antihypertensive medications in 2005-2009 than those born full term. Antihypertensive medication data were obtained from all outpatient and inpatient pharmacies throughout Sweden. Young adults who were born preterm had an increased relative rate of antihypertensive medication prescription that increased monotonically by earlier gestational age and that was independent of fetal growth. The adjusted odds ratio for >=1 antihypertensive medications/year ranged from 1.25 (95% confidence interval: 1.12, 1.39) for those born near term (35-36 weeks) to 2.51 (95% confidence interval: 1.11, 5.68) for those born extremely preterm (23-27 weeks) relative to those born full term. These findings suggest that preterm birth is strongly associated with hypertension in young adulthood, including an increased risk among those born near term. PMID- 21320867 TI - Trajectories of injection drug use over 20 years (1988-2008) in Baltimore, Maryland. AB - The objective of this study was to identify longitudinal patterns of injection drug use over 20 years in the AIDS Linked to the Intravenous Experience (ALIVE) Study, a community-based cohort of injection drug users (IDUs) in Baltimore, Maryland, with a focus on injection cessation. Starting in 1988, persons over 18 years of age with a history of injection drug use were recruited into the study. Participants provided information on their injection drug use semiannually through 2008. The analysis was restricted to 1,716 IDUs with at least 8 study visits. Finite mixture models were used to identify trajectories and predictors of injection patterns over time. The mean age of participants was 35 years; 75% were male, and 95% were African-American. Five distinct patterns were identified: 2 usage patterns (32% engaged in persistent injection and 16% had frequent relapse) and 3 cessation patterns (early cessation (19%), delayed cessation (16%), and late cessation (18%)). A history of drug treatment, no recent use of multiple substances, and less frequent injection distinguished the early cessation group from the other groups. This study demonstrated multiple trajectories of drug injection behaviors, with a substantial proportion of IDUs stopping injection over extended time frames. For maximum effectiveness, public health programs for IDUs should be long-term, comprehensive, and targeted toward individual patterns of use. PMID- 21320868 TI - Lack of plakoglobin leads to lethal congenital epidermolysis bullosa: a novel clinico-genetic entity. AB - Epidermal integrity is essential for skin functions. It is maintained by adhesive structures between keratinocytes, mainly the desmosomes and adherens junctions, which provide resistance against mechanical stress and regulate the formation of the skin barrier. As a constituent of both types of intercellular junctions, plakoglobin has multiple interaction partners and mutations in its gene [junction plakoglobin (JUP)] have been associated with mild cutaneous disease, palmoplantar keratoderma and arrhythmogenic heart disease. Here we report a novel lethal phenotype caused by a homozygous nonsense JUP mutation, c.1615C>T, p.Q539X, which is very different from any human or murine JUP phenotype described so far. The patient suffered from severe congenital skin fragility with generalized epidermolysis and massive transcutaneous fluid loss, but apparently no cardiac dysfunction. In contrast to previously reported JUP mutations where truncated proteins were still present, in this case there was complete loss of plakoglobin in the patient's skin, as demonstrated by immunofluorescence and immunoblot analysis. As a consequence, only very few abnormal desmosomes were formed and no adhesion structures between keratinocytes were recognizable. The expression and distribution of desmosomal components was severely affected, suggesting an essential role for plakoglobin in desmosomal assembly. Adherens junction proteins were localized to keratinocyte plasma membrane, but did not provide proper cell cell adhesion. This lethal congenital epidermolysis bullosa highlights the fundamental role of plakoglobin in epidermal cohesion. PMID- 21320869 TI - Matrix metalloproteinase-2 ablation in dystrophin-deficient mdx muscles reduces angiogenesis resulting in impaired growth of regenerated muscle fibers. AB - Matrix metalloproteases (MMPs) are a family of endopeptidases classified into subgroups based on substrate preference in normal physiological processes such as embryonic development and tissue remodeling, as well as in various disease processes via degradation of extracellular matrix components. Among the MMPs, MMP 9 and MMP-2 have been reported to be up-regulated in skeletal muscles in the lethal X-linked muscle disorder Duchenne muscular dystrophy (DMD), which is caused by loss of dystrophin. A recent study showed that deletion of the MMP9 gene in mdx, a mouse model for DMD, improved skeletal muscle pathology and function; however, the role of MMP-2 in the dystrophin-deficient muscle is not well known. In this study, we aimed at verifying the role of MMP-2 in the dystrophin-deficient muscle by using mdx mice with genetic ablation of MMP-2 (mdx/MMP-2(-/-)). We found impairment of regenerated muscle fiber growth with reduction of angiogenesis in mdx/MMP-2(-/-) mice at 3 months of age. Expression of vascular endothelial growth factor-A (VEGF-A), an important angiogenesis related factor, decreased in mdx/MMP-2(-/-) mice at 3 months of age. MMP-2 had not a critical role in the degradation of dystrophin-glycoprotein complex (DGC) components such as beta-dystroglycan and beta-sarcoglycan in the regeneration process of the dystrophic muscle. Accordingly, MMP-2 may be essential for growth of regenerated muscle fibers through VEGF-associated angiogenesis in the dystrophin-deficient skeletal muscle. PMID- 21320870 TI - Cerebral small-vessel disease protein HTRA1 controls the amount of TGF-beta1 via cleavage of proTGF-beta1. AB - Cerebral small-vessel disease is a common disorder in elderly populations; however, its molecular basis is not well understood. We recently demonstrated that mutations in the high-temperature requirement A (HTRA) serine peptidase 1 (HTRA1) gene cause a hereditary cerebral small-vessel disease, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). HTRA1 belongs to the HTRA protein family, whose members have dual activities as chaperones and serine proteases and also repress transforming growth factor-beta (TGF-beta) family signaling. We demonstrated that CARASIL associated mutant HTRA1s decrease protease activity and fail to decrease TGF-beta family signaling. However, the precise molecular mechanism for decreasing the signaling remains unknown. Here we show that increased expression of ED-A fibronectin is limited to cerebral small arteries and is not observed in coronary, renal arterial or aortic walls in patients with CARASIL. Using a cell mixing assay, we found that HTRA1 decreases TGF-beta1 signaling triggered by proTGF-beta1 in the intracellular space. HTRA1 binds and cleaves the pro-domain of proTGF-beta1 in the endoplasmic reticulum (ER), and cleaved proTGF-beta1 is degraded by ER-associated degradation. Consequently, the amount of mature TGF beta1 is reduced. These results establish a novel mechanism for regulating the amount of TGF-beta1, specifically, the intracellular cleavage of proTGF-beta1 in the ER. PMID- 21320871 TI - Puromycin-sensitive aminopeptidase (PSA/NPEPPS) impedes development of neuropathology in hPSA/TAU(P301L) double-transgenic mice. AB - Accumulation of neurotoxic hyperphosphorylated TAU protein is a major pathological hallmark of Alzheimer disease and other neurodegenerative dementias collectively called tauopathies. Puromycin-sensitive aminopeptidase (PSA/NPEPPS) is a novel modifier of TAU-induced neurodegeneration with neuroprotective effects via direct proteolysis of TAU protein. Here, to examine the effects of PSA/NPEPPS overexpression in vivo in the mammalian system, we generated and crossed BAC PSA/NPEPPS transgenic mice with the TAU(P301L) mouse model of neurodegeneration. PSA/NPEPPS activity in the brain and peripheral tissues of human PSA/NPEPPS (hPSA) mice was elevated by ~2-3-fold with no noticeable deleterious physiological effects. Double-transgenic animals for hPSA and TAU(P301L) transgenes demonstrated a distinct trend for delayed paralysis and showed significantly improved motor neuron counts, no gliosis and markedly reduced levels of total and hyperphosphorylated TAU in the spinal cord, brain stem, cortex, hippocampus and cerebellum of adult and aged animals when compared with TAU(P301L) mice. Furthermore, endogenous TAU protein abundance in human neuroblastoma SH-SY5Y cells was significantly reduced or augmented by overexpression or knockdown of PSA/NPEPPS, respectively. This study demonstrated that without showing neurotoxic effects, elevation of PSA/NPEPPS activity in vivo effectively blocks accumulation of soluble hyperphosphorylated TAU protein and slows down the disease progression in the mammalian system. Our data suggest that increasing PSA/NPEPPS activity may be a feasible therapeutic approach to eliminate accumulation of unwanted toxic substrates such as TAU. PMID- 21320872 TI - Mechanisms underlying differences in systemic exposure of structurally similar active metabolites: comparison of two preclinical hepatic models. AB - Selection of in vitro models that accurately characterize metabolite systemic and hepatobiliary exposure remains a challenge in drug development. In the present study, mechanisms underlying differences in systemic exposure of two active metabolites, furamidine and 2,5-bis (5-amidino)-2-pyridyl furan (CPD-0801), were examined using two hepatic models from rats: isolated perfused livers (IPLs) and sandwich-cultured hepatocytes (SCH). Pafuramidine, a prodrug of furamidine, and 2,5-bis [5-(N-methoxyamidino)-2-pyridyl] furan (CPD-0868), a prodrug of CPD-0801, were selected for investigation because CPD-0801 exhibits greater systemic exposure than furamidine, despite remarkable structural similarity between these two active metabolites. In both IPLs and SCH, the extent of conversion of CPD 0868 to CPD-0801 was consistently higher than that of pafuramidine to furamidine over time (at most 2.5-fold); area under the curve (AUC) of CPD-0801 in IPL perfusate and SCH medium was at least 7-fold higher than that of furamidine. Pharmacokinetic modeling revealed that the rate constant for basolateral (liver to blood) net efflux (k(A_net efflux)) of total formed CPD-0801 (bound + unbound) was 6-fold higher than that of furamidine. Hepatic accumulation of both active metabolites was extensive (>95% of total formed); the hepatic unbound fraction (f(u,L)) of CPD-0801 was 5-fold higher than that of furamidine (1.6 versus 0.3%). Incorporation of f(u,L) into the pharmacokinetic model resulted in comparable k(A_net efflux,u) between furamidine and CPD-0801. In conclusion, intrahepatic binding markedly influenced the disposition of these active metabolites. A higher f(u,L) explained, in part, the enhanced perfusate AUC of CPD-0801 compared with furamidine in IPLs. SCH predicted the disposition of prodrug/metabolite in IPLs. PMID- 21320873 TI - Polar body-based preimplantation genetic diagnosis for Mendelian disorders. AB - Introduced >20 years ago, the use of polar bodies (PBs), involving sequential removal and genetic analysis of the first (PB1) and second (PB2) PB, provides the option for pre-embryonic diagnosis, when the objection to the embryo biopsy procedures makes preimplantation genetic diagnosis (PGD) non-applicable. PB-based approach has presently been utilized in PGD for genetic and chromosomal disorders, applied either separately, or together with embryo biopsy approaches, especially if there are two or more PGD indications. We present here the world's largest experience of 938 PGD cycles for single-gene disorders performed by PB testing for 146 different monogenic conditions, which resulted in the birth of 345 healthy children (eight pregnancies are still ongoing), providing strong evidence that PB-based PGD is a reliable and safe procedure, with an extremely high accuracy rate of over 99%. With application of microarray technology, PB based approach will be utilized for increasing number of indications, involving simultaneous testing for 24 chromosomes and single-gene disorders. PMID- 21320874 TI - Knowledge, attitudes and practices of voluntary HIV counselling and testing among rural migrants in central China: a cross-sectional study. AB - OBJECTIVE: To document knowledge, attitudes and practices of voluntary HIV counselling and testing (VCT) among rural migrants in central China. METHODS: A cross-sectional study with face-to-face anonymous questionnaire interviews was conducted using a structured questionnaire. RESULTS: Among 1280 participants, 87.9% reported having had sexual intercourse during their lifetime, with 69% of singles reporting having had sexual intercourse and 49.1% having had sex in the past month. Only 21% always used condoms, 84.4% knew HIV infection was diagnosed through blood testing, 56.6% had heard of VCT, but only 3.8% perceived their own risk for HIV infection. Only 43 (2.3%) had ever been tested for HIV, and none had ever been tested at a VCT site. About two-thirds (64.5%) would be willing to use VCT services upon awareness of HIV risk. A logistic regression model showed that females, those having little knowledge of HIV/AIDS, those unwilling to work with HIV-infected individuals, never having been tested for HIV and having low awareness regarding HIV risk were less willing to use VCT. CONCLUSIONS: The results of this study indicated that much greater efforts are needed to improve HIV/AIDS and VCT knowledge, to promote safer sex and to improve VCT acceptance among rural migrants in central China, particularly those engaging in risky behaviours. PMID- 21320875 TI - Policy measures and the survival of foster infants in Stockholm 1878-1925. AB - BACKGROUND: At the end of the 19th century, infant mortality was high in urban and rural areas in Sweden. In Stockholm, the mortality rate was particularly high among foster children. This study addresses the importance for health of targeted public policies and their local implementation in the reduction of excess mortality among foster children in Stockholm at the turn of the 19th century. In response to public concern, a law was passed in 1902 on inspections of foster homes. Stockholm city employed a handful of inspectors who visited foster homes and advised parents on child care and feeding. METHODS: Analysis of historical records from the City of Stockholm was combined with epidemiological analysis of mortality rates and hazard ratios on individual-level data for 112, 746 children aged <1 year residing in one part of Stockholm between 1878 and 1925. Hazard ratios of mortality were calculated using Cox' regression analysis. RESULTS: Mortality rates of foster infants exceeded 300/1000 before 1903. Ten years later the mortality rates among foster children had declined and were similar to other children born in and out of wedlock. Historical accounts and epidemiological analysis of individual-level data over a longer time period showed similar results. CONCLUSIONS: Targeted policy measures to foster children may have potentiated the positive health effects of other universal policies, such as improved living conditions, clean water and sanitation for the whole population in the city, contributing to an equalization of mortality rates between different groups. PMID- 21320876 TI - Mixed mating in androdioecious Mercurialis annua inferred using progeny arrays and diploid-acting microsatellite loci in a hexaploid background. AB - BACKGROUND AND AIMS: The frequency at which males can be maintained with hermaphrodites in androdioecious populations is predicted to depend on the selfing rate, because self-fertilization by hermaphrodites reduces prospective siring opportunities for males. In particular, high selfing rates by hermaphrodites are expected to exclude males from a population. Here, the first estimates are provided of the mating system from two wild hexaploid populations of the androdioecious European wind-pollinated plant M. annua with contrasting male frequencies. METHODS: Four diploid microsatellite loci were used to genotype 19-20 progeny arrays from two populations of M. annua, one with males and one without. Mating-system parameters were estimated using the program MLTR. KEY RESULTS: Both populations had similar, intermediate outcrossing rates (t(m) = 0.64 and 0.52 for the population with and without males, respectively). The population without males showed a lower level of correlated paternity and biparental inbreeding and higher allelic richness and gene diversity than the population with males. CONCLUSIONS: The results demonstrate the utility of new diploid microsatellite loci for mating system analysis in a hexaploid plant. It would appear that androdioecious M. annua has a mixed-mating system in the wild, an uncommon finding for wind-pollinated species. This study sets a foundation for future research to assess the relative importance of the sexual system, plant density variation and stochastic processes for the regulation of male frequencies in M. annua over space and time. PMID- 21320877 TI - Unique stigmatic hairs and pollen-tube growth within the stigmatic cell wall in the early-divergent angiosperm family Hydatellaceae. AB - BACKGROUND AND AIMS: The ultrastructure of the pollen tubes and the unusual multicellular stigmatic hairs of Trithuria, the sole genus of Hydatellaceae, are described in the context of comparative studies of stigmatic and transmitting tissue in other early-divergent angiosperms. METHODS: Scanning and transmission electron microscopy and immunocytochemistry are used to study the structure and composition of both mature and immature stigmatic hair cells and pollen-tube growth in Trithuria. KEY RESULTS: Trithuria possesses a dry-type stigma. Pollen tubes grow within the cell walls of the long multicellular stigmatic hairs. Immunocytochemistry results suggest that arabinogalactan proteins are involved in attracting the pollen tubes through the stigmatic cuticle. Most tubes grow along the hair axis towards its base, but some grow towards the hair apex, suggesting that pollen tubes are guided by both physical constraints such as microfibril orientation and the presence of binding factors such as unesterified pectins and adhesive proteins. CONCLUSIONS: The presence of a dry-type stigma in Trithuria supports the hypothesis that this condition is ancestral in angiosperms. Each multicellular stigmatic hair of Hydatellaceae is morphologically homologous with a stigmatic papilla of other angiosperms, but functions as an independent stigma and style. This unusual combination of factors makes Hydatellaceae a useful model for comparative studies of pollen-tube growth in early angiosperms. PMID- 21320878 TI - Does the silver moss Bryum argenteum exhibit sex-specific patterns in vegetative growth rate, asexual fitness or prezygotic reproductive investment? AB - BACKGROUND AND AIMS: Expected life history trade-offs associated with sex differences in reproductive investment are often undetected in seed plants, with the difficulty arising from logistical issues of conducting controlled experiments. By controlling genotype, age and resource status of individuals, a bryophyte was assessed for sex-specific and location-specific patterns of vegetative, asexual and sexual growth/reproduction across a regional scale. METHODS: Twelve genotypes (six male, six female) of the dioecious bryophyte Bryum argenteum were subcultured to remove environmental effects, regenerated asexually to replicate each genotype 16 times, and grown over a period of 92 d. Plants were assessed for growth rates, asexual and sexual reproductive traits, and allocation to above- and below-ground regenerative biomass. KEY RESULTS: The degree of sexual versus asexual reproductive investment appears to be under genetic control, with three distinct ecotypes found in this study. Protonemal growth rate was positively correlated with asexual reproduction and sexual reproduction, whereas asexual reproduction was negatively correlated (appeared to trade-off) with vegetative growth (shoot production). No sex-specific trade-offs were detected. Female sex-expressing shoots were longer than males, but the sexes did not differ in growth traits, asexual traits, sexual induction times, or above- and below-ground biomass. Males, however, had much higher rates of inflorescence production than females, which translated into a significantly higher (24x) prezygotic investment for males relative to females. CONCLUSIONS: Evidence for three distinct ecotypes is presented for a bryophyte based on regeneration traits. Prior to zygote production, the sexes of this bryophyte did not differ in vegetative growth traits but significantly differed in reproductive investment, with the latter differences potentially implicated in the strongly biased female sex ratio. The disparity between males and females for prezygotic reproductive investment is the highest known for bryophytes. PMID- 21320879 TI - Insights from ANA-grade angiosperms into the early evolution of CUP-SHAPED COTYLEDON genes. AB - BACKGROUND AND AIMS: The closely related NAC family genes NO APICAL MERISTEM (NAM) and CUP-SHAPED COTYLEDON3 (CUC3) regulate the formation of boundaries within and between plant organs. NAM is post-transcriptionally regulated by miR164, whereas CUC3 is not. To gain insight into the evolution of NAM and CUC3 in the angiosperms, we analysed orthologous genes in early-diverging ANA-grade angiosperms and gymnosperms. METHODS: We obtained NAM- and CUC3-like sequences from diverse angiosperms and gymnosperms by a combination of reverse transcriptase PCR, cDNA library screening and database searching, and then investigated their phylogenetic relationships by performing maximum-likelihood reconstructions. We also studied the spatial expression patterns of NAM, CUC3 and MIR164 orthologues in female reproductive tissues of Amborella trichopoda, the probable sister to all other flowering plants. KEY RESULTS: Separate NAM and CUC3 orthologues were found in early-diverging angiosperms, but not in gymnosperms, which contained putative orthologues of the entire NAM + CUC3 clade that possessed sites of regulation by miR164. Multiple paralogues of NAM or CUC3 genes were noted in certain taxa, including Brassicaceae. Expression of NAM, CUC3 and MIR164 orthologues from Am. trichopoda was found to co-localize in ovules at the developmental boundary between the chalaza and nucellus. CONCLUSIONS: The NAM and CUC3 lineages were generated by duplication, and CUC3 was subsequently lost regulation by miR164, prior to the last common ancestor of the extant angiosperms. However, the paralogous NAM clade genes CUC1 and CUC2 were generated by a more recent duplication, near the base of Brassicaceae. The function of NAM and CUC3 in defining a developmental boundary in the ovule appears to have been conserved since the last common ancestor of the flowering plants, as does the post-transcriptional regulation in ovule tissues of NAM by miR164. PMID- 21320880 TI - Variation in the functioning of autonomous self-pollination, pollinator services and floral traits in three Centaurium species. AB - BACKGROUND AND AIMS: Reproductive assurance through autonomous selfing is thought to be one of the main advantages of self-fertilization in plants. Floral mechanisms that ensure autonomous seed set are therefore more likely to occur in species that grow in habitats where pollination is scarce and/or unpredictable. METHODS: Emasculation and pollen supplementation experiments were conducted under laboratory conditions to investigate the capacity for, and timing of autonomous selfing in three closely related Centaurium species (Centaurium erythraea, C. littorale and C. pulchellum). In addition, observations of flower visitors were combined with emasculation and pollen addition experiments in natural populations to investigate the degree of pollinator limitation and pollination failure and to assess the extent to which autonomous selfing conferred reproductive assurance. RESULTS: All three species were capable of autonomous selfing, although this capacity differed significantly between species (index of autonomous selfing 0.55 +/- 0.06, 0.68 +/- 0.09 and 0.92 +/- 0.03 for C. erythraea, C. littorale and C. pulchellum, respectively). The efficiency and timing of autogamous selfing was primarily associated with differences in the degree of herkogamy and dichogamy. The number of floral visitors showed significant interspecific differences, with 1.6 +/- 0.6, 5.4 +/- 0.6 and 14.5 +/- 2.1 floral visitors within a 2 * 2 m(2) plot per 20-min observation period, for C. pulchellum, C. littorale and C. erythraea, respectively. Concomitantly, pollinator failure was highest in C. pulchellum and lowest in C. erythraea. Nonetheless, all three study species showed very low levels of pollen limitation (index of pollen limitation 0.14 +/- 0.03, 0.11 +/- 0.03 and 0.09 +/- 0.02 for C. erythraea, C. littorale and C. pulchellum, respectively), indicating that autonomous selfing may guarantee reproductive assurance. CONCLUSIONS: These findings show that limited availability of pollinators may select for floral traits and plant mating strategies that lead to a system of reproductive assurance via autonomous selfing. PMID- 21320881 TI - Proteins implicated in mediating self-incompatibility-induced alterations to the actin cytoskeleton of Papaver pollen. AB - BACKGROUND AND AIMS: Sexual reproduction in angiosperms involves a network of signalling and interactions between pollen and pistil. To promote out-breeding, an additional layer of interactions, involving self-incompatibility (SI), is used to prevent self-fertilization. SI is generally controlled by the S-locus, and comprises allelic pollen and pistil S-determinants. This provides the basis of recognition, and consequent rejection, of incompatible pollen. In Papaver rhoeas, SI involves interaction of pistil PrsS and pollen PrpS, triggering a Ca(2+) dependent signalling network. This results in rapid and distinctive alterations to both the actin and microtubule cytoskeleton being triggered in 'self' pollen. Some of these alterations are implicated in mediating programmed cell death, involving activation of several caspase-like proteases. SCOPE: Here we review and discuss our current understanding of the cytoskeletal alterations induced in incompatible pollen during SI and their relationship with programmed cell death. We focus on data relating to the formation of F-actin punctate foci, which have, to date, not been well characterized. The identification of two actin-binding proteins that interact with these structures are reviewed. Using an approach that enriched for F-actin from SI-induced pollen tubes using affinity purification followed by mass spectrometry, further proteins were identified as putative interactors with the F-actin foci in an SI situation. KEY RESULTS: Previously two important actin-binding proteins, CAP and ADF, had been identified whose localization altered with SI, both showing co-localization with the F-actin punctate foci based on immunolocalization studies. Further analysis has identified differences between proteins associated with F-actin from SI-induced pollen samples and those associated with F-actin in untreated pollen. This provides candidate proteins implicated in either the formation or stabilization of the punctate actin structures formed during SI. CONCLUSIONS: This review brings together for the first time, our current understanding of proteins and events involved in SI-induced signalling to the actin cytoskeleton in incompatible Papaver pollen. PMID- 21320883 TI - Loss of visceral pain following colorectal distension in an endothelin-3 deficient mouse model of Hirschsprung's disease. AB - Endothelin peptides and their endogenous receptors play a major role in nociception in a variety of different organs. They also play an essential role in the development of the enteric nervous system. Mice with deletions of the endothelin-3 gene (lethal spotted mice, ls/ls) develop congenital aganglionosis. However, little is known about how nociception might be affected in the aganglionic rectum of mice deficient in endothelin-3. In this study we investigated changes in spinal afferent innervation and visceral pain transmission from the aganglionic rectum in ls/ls mice. Electromyogram recordings from anaesthetized ls/ls mice revealed a deficit in visceromotor responses arising from the aganglionic colorectum in response to noxious colorectal distension. Loss of visceromotor responses (VMRs) in ls/ls mice was selective, as no reduction in VMRs was detected after stimulation of the bladder or somatic organs. Calcitonin gene related peptide (CGRP) immunoreactivity, retrograde neuronal tracing and extracellular afferent recordings from the aganglionic rectum revealed decreased colorectal spinal innervation, combined with a reduction in mechanosensitivity of rectal afferents. The sensory defect in ls/ls mice is primarily associated with changes in low threshold wide dynamic range rectal afferents. In conclusion, disruption of endothelin 3 gene expression not only affects development and function of the enteric nervous system, but also specific classes of spinal rectal mechanoreceptors, which are required for visceral nociception from the colorectum. PMID- 21320885 TI - Age-related changes in skeletal muscle reactive oxygen species generation and adaptive responses to reactive oxygen species. AB - Skeletal muscle generates superoxide and nitric oxide at rest and this generation is increased by contractile activity. In young and adult animals and man, an increase in activities of these species and the secondary products derived from them (reactive oxygen species, ROS) stimulate redox-sensitive signalling pathways to modify the cellular content of cytoprotective regulatory proteins such as the superoxide dismutases, catalase and heat shock proteins that prevent oxidative damage to tissues. The mechanisms underlying these adaptive responses to contraction include activation of redox-sensitive transcription factors such as nuclear factor B (NFB), activator protein-1 (AP1) and heat shock factor 1 (HSF1). During ageing all tissues, including skeletal muscle, demonstrate an accumulation of oxidative damage that may contribute to loss of tissue homeostasis. The causes of this increased oxidative damage are uncertain, but substantial data now indicate that the ability of skeletal muscle from aged organisms to respond to an increase in ROS generation by increased expression of cytoprotective proteins through activation of redox-sensitive transcription factors is severely attenuated. This age-related lack of physiological adaptations to the ROS induced by contractile activity appears to contribute to a loss of ROS homeostasis and increased oxidative damage in skeletal muscle. PMID- 21320886 TI - Beyond atrophy: redox mechanisms of muscle dysfunction in chronic inflammatory disease. AB - Chronic inflammatory diseases such as heart failure, cancer and arthritis have secondary effects on skeletal muscle that cause weakness and exercise intolerance. These symptoms exacerbate illness and make death more likely. Weakness is not simply a matter of muscle atrophy. Functional studies show that contractile dysfunction, i.e. a reduction in specific force, makes an equally important contribution to overall weakness. The most clearly defined mediator of contractile dysfunction is tumour necrosis factor (TNF). TNF serum levels are elevated in chronic disease, correlate with muscle weakness, and are a predictor of morbidity and mortality. Research is beginning to unravel the mechanism by which TNF depresses specific force. TNF acts via the TNFR1 receptor subtype to depress force by increasing cytosolic oxidant activity. Oxidants depress myofibrillar function, decreasing specific force without altering calcium regulation or other aspects of myofibrillar mechanics. Beyond these concepts, the intracellular mechanisms that depress specific force remain undefined. We do not know the pathway by which receptor-ligand interaction stimulates oxidant production. Nor do we know the type(s) of oxidants stimulated by TNF, their intracellular source(s), or their molecular targets. Investigators in the field are pursuing these issues with the long-term goal of preserving muscle function in individuals afflicted by chronic disease. PMID- 21320887 TI - Redox homeostasis, oxidative stress and disuse muscle atrophy. AB - A pivotal role has been ascribed to oxidative stress in determining the imbalance between protein synthesis and degradation leading to muscle atrophy in many pathological conditions and in disuse. However, a large variability in disuse induced alteration of redox homeostasis through muscles, models and species emerges from the literature. Whereas the causal role of oxidative stress appears well established in the mechanical ventilation model, findings are less compelling in the hindlimb unloaded mice and very limited in humans. The mere coexistence of muscle atrophy, indirect indexes of increased reactive oxygen species (ROS) production and impairment of antioxidant defence systems, in fact, does not unequivocally support a causal role of oxidative stress in the phenomenon. We hypothesise that in some muscles, models and species only, due to a large redox imbalance, the leading phenomena are activation of proteolysis and massive oxidation of proteins, which would become more susceptible to degradation. In other conditions, due to a lower extent and variable time course of ROS production, different ROS-dependent, but also -independent intracellular pathways might dominate determining the variable extent of atrophy and even dispensable protein oxidation. The ROS production and removal are complex and finely tuned phenomena. They are indeed important intracellular signals and redox balance maintains normal muscle homeostasis and can underlie either positive or negative adaptations to exercise. A precise approach to determine the levels of ROS in living cells in various conditions appears to be of paramount importance to define and support such hypotheses. PMID- 21320888 TI - Minimal alterations in T-type calcium channel gating markedly modify physiological firing dynamics. AB - T-type calcium channel isoforms expressed in heterologous systems demonstrate marked differences in the biophysical properties of the resulting calcium currents. Such heterogeneity in gating behaviour not only reflects structural differences but is also observed following the regulation of channel activity by a number of ligands. However, the physiological impact of these differences in gating parameters of the T channels has never been evaluated in situ where the unique interplay between T-type calcium and other intrinsic currents is conserved, and T channel activation can be triggered by synaptic stimulation. Here, using the dynamic clamp technique, artificial T conductances were re incorporated in thalamic neurons devoid of endogenous T currents to dissect the physiological role of the T current gating diversity on neuronal excitability. We demonstrate that the specific kinetics of the T currents in thalamocortical and nucleus reticularis thalami neurons determine the characteristic firing patterns of these neurons. We show that subtle modifications in T channel gating that are at the limit of the resolution achieved in classical biophysical studies in heterologous expression systems have profound consequences for synaptically evoked firing dynamics in native neurons. Moreover, we demonstrate that the biophysical properties of the T current in the voltage region corresponding to the foot of the activation and inactivation curves drastically condition physiologically evoked burst firing with a high degree of synaptic input specificity. PMID- 21320890 TI - The temporal relationship between non-respiratory burst activity of expiratory laryngeal motoneurons and phrenic apnoea during stimulation of the superior laryngeal nerve in rat. AB - A striking effect of stimulating the superior laryngeal nerve (SLN) is its ability to inhibit central inspiratory activity (cause 'phrenic apnoea'), but the mechanism underlying this inhibition remains unclear. Here we demonstrate, by stimulating the SLN at varying frequencies, that the evoked non-respiratory burst activity recorded from expiratory laryngeal motoneurons (ELMs) has an intimate temporal relationship with phrenic apnoea. During 1-5 Hz SLN stimulation, occasional absences of phrenic nerve discharge (PND) occurred such that every absent PND was preceded by an ELM burst activity. During 10-20 Hz SLN stimulation, more bursts were evoked together with more absent PNDs, leading eventually to phrenic apnoea. Interestingly, subsequent microinjections of isoguvacine (10 mm, 20-40 nl) into ipsilateral Botzinger complex (BotC) and contralateral nucleus tractus solitarii (NTS) significantly attenuated the apnoeic response but not the ELM burst activity. Our results suggest a bifurcating projection from NTS to both the caudal nucleus ambiguus and BotC, which mediates the closely related ELM burst and apnoeic response, respectively. We believe that such an intimate timing between laryngeal behaviour and breathing is crucial for the effective elaboration of the different airway protective behaviours elicited following SLN stimulation, including the laryngeal adductor reflex, swallowing and cough. PMID- 21320891 TI - Evaluation of fluoride varnish and its comparison with pumice prophylaxis using self-etching primer in orthodontic bonding--an in vivo study. AB - The aim of this study was to evaluate the use of fluoride varnish as a prophylaxis method with self etching primer (SEP) and its comparison with pumice before orthodontic bonding. Thirty seven orthodontic patients participated in a prospective clinical trial. A split mouth technique was used in each patient, one quadrant was assigned to fluoride varnish and the contralateral quadrant to pumice prophylaxis. A total of 684 teeth were bonded with SEP (Transbond plus; 3M Unitek) and monitored for 6 months for bond failures. A total of 42 (6.1%) failures were recorded, 9 (2.6%) in the pumice group and 33 (9.6%) in the fluoride varnish group. Chi-square analysis was used to compare the number of bracket failures between the pumice and fluoride varnish groups and the number of patients in each group experiencing at least one bond failure. Statistically significant differences were found both in total number of bond failures (P < 0.001) and in the number of patients with bond failures (P < 0.05) between both groups. A significantly lower and clinically acceptable bond failure rate was observed with Transbond Plus self etching primer after pumice prophylaxis. PMID- 21320889 TI - Preferential skeletal muscle myosin loss in response to mechanical silencing in a novel rat intensive care unit model: underlying mechanisms. AB - The muscle wasting and impaired muscle function in critically ill intensive care unit (ICU) patients delay recovery from the primary disease, and have debilitating consequences that can persist for years after hospital discharge. It is likely that, in addition to pernicious effects of the primary disease, the basic life support procedures of long-term ICU treatment contribute directly to the progressive impairment of muscle function. This study aims at improving our understanding of the mechanisms underlying muscle wasting in ICU patients by using a unique experimental rat ICU model where animals are mechanically ventilated, sedated and pharmacologically paralysed for duration varying between 6 h and 14 days. Results show that the ICU intervention induces a phenotype resembling the severe muscle wasting and paralysis associated with the acute quadriplegic myopathy (AQM) observed in ICU patients, i.e. a preferential loss of myosin, transcriptional down-regulation of myosin synthesis, muscle atrophy and a dramatic decrease in muscle fibre force generation capacity. Detailed analyses of protein degradation pathways show that the ubiquitin proteasome pathway is highly involved in this process. A sequential change in localisation of muscle-specific RING finger proteins 1/2 (MuRF1/2) observed during the experimental period is suggested to play an instrumental role in both transcriptional regulation and protein degradation. We propose that, for those critically ill patients who develop AQM, complete mechanical silencing, due to pharmacological paralysis or sedation, is a critical factor underlying the preferential loss of the molecular motor protein myosin that leads to impaired muscle function or persisting paralysis. PMID- 21320892 TI - Randomization in clinical trials in orthodontics: its significance in research design and methods to achieve it. AB - Randomization is a key step in reducing selection bias during the treatment allocation phase in randomized clinical trials. The process of randomization follows specific steps, which include generation of the randomization list, allocation concealment, and implementation of randomization. The phenomenon in the dental and orthodontic literature of characterizing treatment allocation as random is frequent; however, often the randomization procedures followed are not appropriate. Randomization methods assign, at random, treatment to the trial arms without foreknowledge of allocation by either the participants or the investigators thus reducing selection bias. Randomization entails generation of random allocation, allocation concealment, and the actual methodology of implementing treatment allocation randomly and unpredictably. Most popular randomization methods include some form of restricted and/or stratified randomization. This article introduces the reasons, which make randomization an integral part of solid clinical trial methodology, and presents the main randomization schemes applicable to clinical trials in orthodontics. PMID- 21320893 TI - The entangled (and constructed) human bank. PMID- 21320894 TI - Human niche construction in interdisciplinary focus. AB - Niche construction is an endogenous causal process in evolution, reciprocal to the causal process of natural selection. It works by adding ecological inheritance, comprising the inheritance of natural selection pressures previously modified by niche construction, to genetic inheritance in evolution. Human niche construction modifies selection pressures in environments in ways that affect both human evolution, and the evolution of other species. Human ecological inheritance is exceptionally potent because it includes the social transmission and inheritance of cultural knowledge, and material culture. Human genetic inheritance in combination with human cultural inheritance thus provides a basis for gene-culture coevolution, and multivariate dynamics in cultural evolution. Niche construction theory potentially integrates the biological and social aspects of the human sciences. We elaborate on these processes, and provide brief introductions to each of the papers published in this theme issue. PMID- 21320895 TI - Adaptation and niche construction in human prehistory: a case study from the southern Scandinavian Late Glacial. AB - The niche construction model postulates that human bio-social evolution is composed of three inheritance domains, genetic, cultural and ecological, linked by feedback selection. This paper argues that many kinds of archaeological data can serve as proxies for human niche construction processes, and presents a method for investigating specific niche construction hypotheses. To illustrate this method, the repeated emergence of specialized reindeer (Rangifer tarandus) hunting/herding economies during the Late Palaeolithic (ca 14.7-11.5 kyr BP) in southern Scandinavia is analysed from a niche construction/triple-inheritance perspective. This economic relationship resulted in the eventual domestication of Rangifer. The hypothesis of whether domestication was achieved as early as the Late Palaeolithic, and whether this required the use of domesticated dogs (Canis familiaris) as hunting, herding or transport aids, is tested via a comparative analysis using material culture-based phylogenies and ecological datasets in relation to demographic/genetic proxies. Only weak evidence for sustained niche construction behaviours by prehistoric hunter-gatherer in southern Scandinavia is found, but this study nonetheless provides interesting insights into the likely processes of dog and reindeer domestication, and into processes of adaptation in Late Glacial foragers. PMID- 21320896 TI - From hominins to humans: how sapiens became behaviourally modern. AB - This paper contributes to a debate in the palaeoarchaeological community about the major time-lag between the origin of anatomically modern humans and the appearance of typically human cultural behaviour. Why did humans take so long--at least 100 000 years--to become 'behaviourally modern'? The transition is often explained as a change in the intrinsic cognitive competence of modern humans: often in terms of a new capacity for symbolic thought, or the final perfection of language. These cognitive breakthrough models are not satisfactory, for they fail to explain the uneven palaeoanthropological record of human competence. Many supposed signature capacities appear (and then disappear) before the supposed cognitive breakthrough; many of the signature capacities disappear again after the breakthrough. So, instead of seeing behavioural modernity as a simple reflection of a new kind of mind, this paper presents a niche construction conceptual model of behavioural modernity. Humans became behaviourally modern when they could reliably transmit accumulated informational capital to the next generation, and transmit it with sufficient precision for innovations to be preserved and accumulated. In turn, the reliable accumulation of culture depends on the construction of learning environments, not just intrinsic cognitive machinery. I argue that the model is (i) evolutionarily plausible: the elements of the model can be assembled incrementally, without implausible selective scenarios; (ii) the model coheres with the broad palaeoarchaeological record; (iii) the model is anthropologically and ethnographically plausible; and (iv) the model is testable, though only in coarse, preliminary ways. PMID- 21320897 TI - Runaway cultural niche construction. AB - Cultural niche construction is a uniquely potent source of selection on human populations, and a major cause of recent human evolution. Previous theoretical analyses have not, however, explored the local effects of cultural niche construction. Here, we use spatially explicit coevolutionary models to investigate how cultural processes could drive selection on human genes by modifying local resources. We show that cultural learning, expressed in local niche construction, can trigger a process with dynamics that resemble runaway sexual selection. Under a broad range of conditions, cultural niche-constructing practices generate selection for gene-based traits and hitchhike to fixation through the build up of statistical associations between practice and trait. This process can occur even when the cultural practice is costly, or is subject to counteracting transmission biases, or the genetic trait is selected against. Under some conditions a secondary hitchhiking occurs, through which genetic variants that enhance the capability for cultural learning are also favoured by similar dynamics. We suggest that runaway cultural niche construction could have played an important role in human evolution, helping to explain why humans are simultaneously the species with the largest relative brain size, the most potent capacity for niche construction and the greatest reliance on culture. PMID- 21320898 TI - General patterns of niche construction and the management of 'wild' plant and animal resources by small-scale pre-industrial societies. AB - Niche construction efforts by small-scale human societies that involve 'wild' species of plants and animals are organized into a set of six general categories based on the shared characteristics of the target species and similar patterns of human management and manipulation: (i) general modification of vegetation communities, (ii) broadcast sowing of wild annuals, (iii) transplantation of perennial fruit-bearing species, (iv) in-place encouragement of economically important perennials, (v) transplantation and in-place encouragement of perennial root crops, and (vi) landscape modification to increase prey abundance in specific locations. Case study examples, mostly drawn from North America, are presented for each of the six general categories of human niche construction. These empirically documented categories of ecosystem engineering form the basis for a predictive model that outlines potential general principles and commonalities in how small-scale human societies worldwide have modified and manipulated their 'natural' landscapes throughout the Holocene. PMID- 21320899 TI - Foraging and farming as niche construction: stable and unstable adaptations. AB - All forager (or hunter-gatherer) societies construct niches, many of them actively by the concentration of wild plants into useful stands, small-scale cultivation, burning of natural vegetation to encourage useful species, and various forms of hunting, collectively termed 'low-level food production'. Many such niches are stable and can continue indefinitely, because forager populations are usually stable. Some are unstable, but these usually transform into other foraging niches, not geographically expansive farming niches. The Epipalaeolithic (final hunter-gatherer) niche in the Near East was complex but stable, with a relatively high population density, until destabilized by an abrupt climatic change. The niche was unintentionally transformed into an agricultural one, due to chance genetic and behavioural attributes of some wild plant and animal species. The agricultural niche could be exported with modifications over much of the Old World. This was driven by massive population increase and had huge impacts on local people, animals and plants wherever the farming niche was carried. Farming niches in some areas may temporarily come close to stability, but the history of the last 11,000 years does not suggest that agriculture is an effective strategy for achieving demographic and political stability in the world's farming populations. PMID- 21320901 TI - Gene-culture coevolution and the nature of human sociality. AB - Human characteristics are the product of gene-culture coevolution, which is an evolutionary dynamic involving the interaction of genes and culture over long time periods. Gene-culture coevolution is a special case of niche construction. Gene-culture coevolution is responsible for human other-regarding preferences, a taste for fairness, the capacity to empathize and salience of morality and character virtues. PMID- 21320900 TI - Evolution of lactase persistence: an example of human niche construction. AB - Niche construction is the process by which organisms construct important components of their local environment in ways that introduce novel selection pressures. Lactase persistence is one of the clearest examples of niche construction in humans. Lactase is the enzyme responsible for the digestion of the milk sugar lactose and its production decreases after the weaning phase in most mammals, including most humans. Some humans, however, continue to produce lactase throughout adulthood, a trait known as lactase persistence. In European populations, a single mutation (-13910*T) explains the distribution of the phenotype, whereas several mutations are associated with it in Africa and the Middle East. Current estimates for the age of lactase persistence-associated alleles bracket those for the origins of animal domestication and the culturally transmitted practice of dairying. We report new data on the distribution of 13910*T and summarize genetic studies on the diversity of lactase persistence worldwide. We review relevant archaeological data and describe three simulation studies that have shed light on the evolution of this trait in Europe. These studies illustrate how genetic and archaeological information can be integrated to bring new insights to the origins and spread of lactase persistence. Finally, we discuss possible improvements to these models. PMID- 21320902 TI - Evolution of culture-dependent discriminate sociality: a gene-culture coevolutionary model. AB - Animals behave cooperatively towards certain conspecifics while being indifferent or even hostile to others. The distinction is made primarily according to kinship as predicted by the kin selection theory. With regards to humans, however, this is not always the case; in particular, humans sometimes exhibit a discriminate sociality on the basis of culturally transmitted traits, such as personal ornaments, languages, rituals, etc. This paper explores the possibility that the human faculty of cultural transmission and resultant cultural variation among individuals may have facilitated the evolution of discriminate sociality in humans. To this end, a gene-culture coevolutionary model is developed focusing on competition over control of resource as a context in which discriminate sociality may have evolved. Specifically, two types of culture-dependent discriminate sociality are considered: ingroup favouritism, with ingroup and outgroup being distinguished by the presence or absence of a cultural trait; and prestige hierarchies, with the prestige being conferred on the bearer of a cultural trait. The model specifies the conditions under which emergence and evolutionary stability of the two types of discriminate sociality are promoted by the presence of cultural variation among individuals. PMID- 21320903 TI - The influence of social niche on cultural niche construction: modelling changes in belief about marriage form in Taiwan. AB - With introduction of social niche effects into a model of cultural change, the frequency of a practice cannot predict the frequency of its underlying belief. The combination of a general model with empirical data from a specific case illustrates the importance of collaboration between modellers and field researchers, and identifies the type of quantitative data necessary for analysing case studies. Demographic data from colonial-period household registers in Taiwan document a shift in marriage form within 40 years, from a mixture of uxorilocal marriages and virilocal marriages to the latter's dominance. Ethnographic data indicate marriage-related beliefs, costs, ethnic effects and colonial policies as well as the importance of horizontal cultural transmission. We present a formal model for the effects of moral beliefs about marriage and a population economic index on the decline of uxorilocal marriage. We integrate empirical marriage rates and an estimated economic index to produce five projections of the historical frequencies of one belief. These projections demonstrate how economic development may affect a cultural niche. They also indicate the need for future research on the relationship between wealth and cultural variability, the motivational force of cultural versus social factors, and the process of cultural niche construction. PMID- 21320904 TI - Property and wealth inequality as cultural niche construction. AB - In contrast to other approaches, evolutionary perspectives on understanding the power and wealth inequalities in human societies view wealth and power not as ends in themselves but as proximate goals that contribute to the ultimate Darwinian goal of achieving reproductive success. The most successful means of achieving it in specific times and places depend on local conditions and these have changed in the course of human history, to such an extent that strategies focused on the maintenance and increase of wealth can even be more successful in reproductive terms than strategies directed at maximizing reproductive success in the short term. This paper argues that a major factor leading to such changes is a shift in the nature of inter-generational wealth transfers from relatively intangible to material property resources and the opportunities these provided for massively increased inequality. This shift can be seen as a process of niche construction related to the increasing importance of fixed and defensible resources in many societies after the end of the last Ice Age. It is suggested that, despite problems of inference, the evidence of the archaeological record can be used to throw light on these processes in specific places and times. PMID- 21320905 TI - Niche construction on Bali: the gods of the countryside. AB - Human niche construction encompasses both purely biological phenomena, such as the evolution of lactose tolerance, and dual inheritance theory, which investigates the transmission of cultural information. But does niche construction help to explain phenomena in which conscious intention also plays a role? The creation of the engineered landscape of Balinese rice terraces offers a test case. Population genetic analysis and archaeological evidence are used to investigate whether this phenomenon emerged historically from trial and error by generations of farmers, or alternatively was designed by Bali's rulers. In light of strong support for the former hypothesis, two models are developed to explore the emergence of functional structure at both local and global scales. As time goes forward and selected patterns of irrigation schedules are implemented, local variation in rice harvests influences future decisions by the farmers, creating a coupled human-natural system governed by feedback from the environment. This mathematical analysis received a measure of empirical support when government agricultural policies severed the local feedback channels, resulting in the almost instantaneous collapse of rice harvests. The historical process of niche construction may also have included an evolution of religious consciousness, reflected in the beliefs and practices of the water temple cult. PMID- 21320906 TI - Prognostic value of cardiac hybrid imaging integrating single-photon emission computed tomography with coronary computed tomography angiography. AB - Aims Although cardiac hybrid imaging, fusing single-photon emission computed tomography (SPECT) myocardial perfusion imaging with coronary computed tomography angiography (CCTA), provides important complementary diagnostic information for coronary artery disease (CAD) assessment, no prognostic data exist on the predictive value of cardiac hybrid imaging. Hence, the aim of this study was to assess the prognostic value of hybrid SPECT/CCTA images. Methods and results Of 335 consecutive patients undergoing a 1-day stress/rest (99m)Tc-tetrofosmin SPECT and a CCTA, acquired on stand-alone scanners and fused to obtain cardiac hybrid images, follow-up was obtained in 324 patients (97%). Survival free of all-cause death or non-fatal myocardial infarction (MI) and free of major adverse cardiac events (MACE: death, MI, unstable angina requiring hospitalization, coronary revascularizations) was determined using the Kaplan-Meier method for the following groups: (i) stenosis by CCTA and matching reversible SPECT defect; (ii) unmatched CCTA and SPECT finding; and (iii) normal finding by CCTA and SPECT. Cox's proportional hazard regression was used to identify independent predictors for cardiac events. At a median follow-up of 2.8 years (25th-75th percentile: 1.9 3.6), 69 MACE occurred in 47 patients, including 20 death/MI. A corresponding matched hybrid image finding was associated with a significantly higher death/MI incidence (P < 0.005) and proved to be an independent predictor for MACE. The annual death/MI rate was 6.0, 2.8, and 1.3% for patients with matched, unmatched, and normal findings. Conclusion Cardiac hybrid imaging allows risk stratification in patients with known or suspected CAD. A matched defect on hybrid image is a strong predictor of MACE. PMID- 21320907 TI - The use of pocket size imaging devices: a position statement by the European Association of Echocardiography. PMID- 21320908 TI - Nonlinear phenomena, optical and quantum solitons. PMID- 21320909 TI - Isochronous dynamical systems. AB - This is a terse review of recent results on isochronous dynamical systems, namely systems of (first-order, generally nonlinear) ordinary differential equations (ODEs) featuring an open set of initial data (which might coincide with the entire set of all initial data), from which emerge solutions all of which are completely periodic (i.e. periodic in all their components) with a fixed period (independent of the initial data, provided they are within the isochrony region). A leitmotif of this presentation is that 'isochronous systems are not rare'. Indeed, it is shown how any (autonomous) dynamical system can be modified or extended so that the new (also autonomous) system thereby obtained is isochronous with an arbitrarily assigned period T, while its dynamics, over time intervals much shorter than the period T, mimics closely that of the original system, or even, over an arbitrarily large fraction of its period T, coincides exactly with that of the original system. It is pointed out that this fact raises the issue of developing criteria providing, for a dynamical system, some kind of measure associated with a finite time scale of the complexity of its behaviour (while the current, standard definitions of integrable versus chaotic dynamical systems are related to the behaviour of a system over infinite time). PMID- 21320910 TI - The Dicke model in quantum optics: Dicke model revisited. AB - A short review of recent developments of the Dicke model in quantum optics is presented. The focus is on the model in a cavity at zero temperature and in the rotating wave approximation. Topics discussed include spectroscopic structures, the giant quantum oscillator, entanglement and phase transitions. PMID- 21320911 TI - Extreme events in solutions of hydrostatic and non-hydrostatic climate models. AB - Initially, this paper reviews the mathematical issues surrounding hydrostatic primitive equations (HPEs) and non-hydrostatic primitive equations (NPEs) that have been used extensively in numerical weather prediction and climate modelling. A new impetus has been provided by a recent proof of the existence and uniqueness of solutions of viscous HPEs on a cylinder with Neumann-like boundary conditions on the top and bottom. In contrast, the regularity of solutions of NPEs remains an open question. With this HPE regularity result in mind, the second issue examined in this paper is whether extreme events are allowed to arise spontaneously in their solutions. Such events could include, for example, the sudden appearance and disappearance of locally intense fronts that do not involve deep convection. Analytical methods are used to show that for viscous HPEs, the creation of small-scale structures is allowed locally in space and time at sizes that scale inversely with the Reynolds number. PMID- 21320912 TI - Nonlinear theory of slow light. AB - In the framework of the nonlinear Lambda model, propagation of solitons was analysed in atomic vapours and Bose-Einstein condensates. The complicated nonlinear interplay between fast and slow-light solitons in a Lambda-type medium was shown to facilitate control of its optical transparency and formation of optical gates. An exact analytical description was given for the deceleration, stopping and revival of slow-light solitons in the experimentally relevant non adiabatic regime. A stopping slow-light soliton imprints a localized immobile polarization pattern in the medium, which, as explicitly demonstrated here, can be used as a bit of readable optical memory. The whole process can be controlled with the background field and an auxiliary laser field. The latter regulates the signal velocity, while the slow-light soliton can be stopped by switching off the former. The location and shape of the imprinted memory bit were also determined. With few assumptions characteristic of slow light, the Lambda model was reduced to a simpler nonlinear model that also describes two-dimensional dilatonic gravity. Exact solutions could now be derived also in the presence of relaxation. Spontaneous decay of the upper atomic level was found to be strongly suppressed, and the spatial form of the decelerating slow-light soliton was preserved, even if the optical relaxation time was much shorter than the typical time scale of the soliton. The effective relaxation coefficient of the slow-light soliton was significantly smaller than that of an arbitrary optical pulse. Such features are obviously of great importance when this kind of system is applied, in practice, to information processing. A number of experimentally observable properties of the solutions reported were found to be in good agreement with recent experimental results, and a few suggestions are also made for future experiments. PMID- 21320913 TI - Memories of Hirota's method: application to the reduced Maxwell-Bloch system in the early 1970s. AB - Who remembers 'Hirota's method'? In the early days of solitons, although the Korteweg-de Vries equation had been solved by the 'inverse scattering method' most solutions to integrable non-linear equations were found by simpler more direct methods. Outstanding among these was a method due mainly to Hirota, which involved casting the equation into a 'bilinear form' and then applying intelligent guesswork. In this paper, I shall take a journey down memory lane, looking again at this method. PMID- 21320914 TI - Non-relativistic and relativistic scattering by short-range potentials. AB - Relativistic and non-relativistic scattering by short-range potentials is investigated for selected problems. Scattering by the delta' potential in the Schrodinger equation and delta potentials in the Dirac equation must be solved by regularization, efficiently carried out by a perturbation technique involving a stretched variable. Asymmetric regularizations yield non-unique scattering coefficients. Resonant penetration through the potentials is found. Approximative Schrodinger equations in the non-relativistic limit are discussed in detail. PMID- 21320915 TI - Addition formulae for Abelian functions associated with specialized curves. AB - We discuss a family of multi-term addition formulae for Weierstrass functions on specialized curves of low genus with many automorphisms, concentrating mostly on the case of genus 1 and 2. In the genus 1 case, we give addition formulae for the equianharmonic and lemniscate cases, and in genus 2 we find some new addition formulae for a number of curves. PMID- 21320916 TI - Mutation-periodic quivers, integrable maps and associated Poisson algebras. AB - We consider a class of map, recently derived in the context of cluster mutation. In this paper, we start with a brief review of the quiver context, but then move onto a discussion of a related Poisson bracket, along with the Poisson algebra of a special family of functions associated with these maps. A bi-Hamiltonian structure is derived and used to construct a sequence of Poisson-commuting functions and hence show complete integrability. Canonical coordinates are derived, with the map now being a canonical transformation with a sequence of commuting invariant functions. Compatibility of a pair of these functions gives rise to Liouville's equation and the map plays the role of a Backlund transformation. PMID- 21320917 TI - The fascinating world of the Landau-Lifshitz-Gilbert equation: an overview. AB - The Landau-Lifshitz-Gilbert (LLG) equation is a fascinating nonlinear evolution equation both from mathematical and physical points of view. It is related to the dynamics of several important physical systems such as ferromagnets, vortex filaments, moving space curves, etc. and has intimate connections with many of the well-known integrable soliton equations, including nonlinear Schrodinger and sine-Gordon equations. It can admit very many dynamical structures including spin waves, elliptic function waves, solitons, dromions, vortices, spatio-temporal patterns, chaos, etc. depending on the physical and spin dimensions and the nature of interactions. An exciting recent development is that the spin torque effect in nanoferromagnets is described by a generalization of the LLG equation that forms a basic dynamical equation in the field of spintronics. This article will briefly review these developments as a tribute to Robin Bullough who was a great admirer of the LLG equation. PMID- 21320918 TI - Exactly and quasi-exactly solvable 'discrete' quantum mechanics. AB - A brief introduction to discrete quantum mechanics is given together with the main results on various exactly solvable systems. Namely, the intertwining relations, shape invariance, Heisenberg operator solutions, annihilation/creation operators and dynamical symmetry algebras, including the q-oscillator algebra and the Askey-Wilson algebra. A simple recipe to construct exactly and quasi-exactly solvable (QES) Hamiltonians in one-dimensional 'discrete' quantum mechanics is presented. It reproduces all the known Hamiltonians whose eigenfunctions consist of the Askey scheme of hypergeometric orthogonal polynomials of a continuous or a discrete variable. Several new exactly and QES Hamiltonians are constructed. The sinusoidal coordinate plays an essential role. PMID- 21320919 TI - Correlation functions for a strongly coupled boson system and plane partitions. AB - A quantum phase model is introduced as a limit for very strong interactions of a strongly correlated q-boson hopping model. The exact solution of the phase model is reviewed, and solutions are also provided for two correlation functions of the model. Explicit expressions, including both amplitude and scaling exponent, are derived for these correlation functions in the low temperature limit. The amplitudes were found to be related to the number of plane partitions contained in boxes of finite size. PMID- 21320920 TI - A short proof of the Buchstaber-Rees theorem. AB - We give a short proof of the Buchstaber-Rees theorem concerning symmetric powers. The proof is based on the notion of a formal characteristic function of a linear map of algebras. PMID- 21320921 TI - The development of telemedicine in Madagascar. PMID- 21320922 TI - Meta-analysis: cardiac resynchronization therapy for patients with less symptomatic heart failure. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality in patients with advanced symptoms of heart failure. PURPOSE: To assess the benefits and harms of CRT in patients with advanced heart failure and those with less symptomatic disease. DATA SOURCES: A search of electronic databases (1950 to December 2010), hand-searching of reference lists, and unpublished data from principal investigators. Searches were not limited to the English language. STUDY SELECTION: Randomized, controlled trials of CRT compared with usual care and right or left ventricular pacing in adults with heart failure and a left ventricular ejection fraction of 0.40 or less. DATA EXTRACTION: Two reviewers performed independent study selection, data abstraction, and quality assessment by using the Cochrane tool for assessing risk for bias. DATA SYNTHESIS: There were 9082 patients in 25 trials. In patients with New York Heart Association (NYHA) class I and II symptoms, CRT reduced all-cause mortality (6 trials, 4572 participants; risk ratio [RR], 0.83 [95% CI, 0.72 to 0.96]) and heart failure hospitalizations (4 trials, 4349 participants; RR, 0.71 [CI, 0.57 to 0.87]) without improving functional outcomes or quality of life. In patients with NYHA class III or IV symptoms, CRT improved functional outcomes and reduced both all cause mortality (19 trials, 4510 participants; RR, 0.78 [CI, 0.67 to 0.91]) and heart failure hospitalizations (11 trials, 2663 participants; RR, 0.65 [CI, 0.50 to 0.86]). The implant success rate was 94.4%; peri-implantation deaths occurred in 0.3% of trial participants, mechanical complications in 3.2%, lead problems in 6.2%, and infections in 1.4%. LIMITATION: Subgroup analyses were underpowered and lack data for persons with NYHA class I symptoms, atrial fibrillation, chronic kidney disease, or right bundle branch block. CONCLUSION: Cardiac resynchronization therapy is beneficial for patients with reduced left ventricular ejection fraction, symptoms of heart failure, and prolonged QRS, regardless of NYHA class. PRIMARY FUNDING SOURCE: None. PMID- 21320924 TI - Translating the benefits of cardiac resynchronization therapy widely and wisely: challenges remain. PMID- 21320925 TI - ACP Journal Club. Adding colchicine to standard therapy after cardiac surgery reduced risk for the postpericardiotomy syndrome. PMID- 21320926 TI - ACP Journal Club. Estrogen plus progestin increased long-term risk for invasive breast cancer in postmenopausal women. PMID- 21320927 TI - ACP Journal Club. Review: Several bedside instruments are accurate for diagnosing delirium in hospitalized patients. PMID- 21320928 TI - ACP Journal Club. Severe hypoglycemia was associated with increased risk for adverse clinical outcomes in type 2 diabetes. PMID- 21320923 TI - Atazanavir plus ritonavir or efavirenz as part of a 3-drug regimen for initial treatment of HIV-1. AB - BACKGROUND: Limited data compare once-daily options for initial therapy for HIV 1. OBJECTIVE: To compare time to virologic failure; first grade-3 or -4 sign, symptom, or laboratory abnormality (safety); and change or discontinuation of regimen (tolerability) for atazanavir plus ritonavir with efavirenz-containing initial therapy for HIV-1. DESIGN: A randomized equivalence trial accrued from September 2005 to November 2007, with median follow-up of 138 weeks. Regimens were assigned by using a central computer, stratified by screening HIV-1 RNA level less than 100 000 copies/mL or 100 000 copies/mL or greater; blinding was known only to the site pharmacist. (ClinicalTrials.gov registration number: NCT00118898) SETTING: 59 AIDS Clinical Trials Group sites in the United States and Puerto Rico. PATIENTS: Antiretroviral-naive patients. INTERVENTION: Open label atazanavir plus ritonavir or efavirenz, each given with with placebo controlled abacavir-lamivudine or tenofovir disoproxil fumarate (DF) emtricitabine. MEASUREMENTS: Primary outcomes were time to virologic failure, safety, and tolerability events. Secondary end points included proportion of patients with HIV-1 RNA level less than 50 copies/mL, emergence of drug resistance, changes in CD4 cell counts, calculated creatinine clearance, and lipid levels. RESULTS: 463 eligible patients were randomly assigned to receive atazanavir plus ritonavir and 465 were assigned to receive efavirenz, both with abacavir-lamivudine; 322 (70%) and 324 (70%), respectively, completed follow-up. The respective numbers of participants in each group who received tenofovir DF emtricitabine were 465 and 464; 342 (74%) and 343 (74%) completed follow-up. Primary efficacy was similar in the group that received atazanavir plus ritonavir and and the group that received efavirenz and did not differ according to whether abacavir-lamivudine or tenofovir DF-emtricitabine was also given. Hazard ratios for time to virologic failure were 1.13 (95% CI, 0.82 to 1.56) and 1.01 (CI, 0.70 to 1.46), respectively, although CIs did not meet prespecified criteria for equivalence. The time to safety (P = 0.048) and tolerability (P < 0.001) events was longer in persons given atazanavir plus ritonavir than in those given efavirenz with abacavir-lamivudine but not with tenofovir DF-emtricitabine. LIMITATIONS: Neither HLA-B*5701 nor resistance testing was the standard of care when A5202 enrolled patients. The third drugs, atazanavir plus ritonavir and efavirenz, were open-label; the nucleoside reverse transcriptase inhibitors were prematurely unblinded in the high viral load stratum; and 32% of patients modified or discontinued treatment with their third drug. CONCLUSION: Atazanavir plus ritonavir and efavirenz have similar antiviral activity when used with abacavir-lamivudine or tenofovir DF-emtricitabine. PRIMARY FUNDING SOURCE: National Institutes of Health. PMID- 21320929 TI - ACP Journal Club. Palliative oxygen and room air did not differ for relief of breathlessness in patients with refractory dyspnea. PMID- 21320930 TI - ACP Journal Club. Fondaparinux reduced a composite of VTE complications or death in superficial leg-vein thrombosis. PMID- 21320931 TI - ACP Journal Club. Tiotropium plus beclomethasone was more effective than doubling beclomethasone for asthma. PMID- 21320932 TI - ACP Journal Club. Review: Corticosteroids improve short-term outcomes but worsen longer-term outcomes in some types of tendinopathy. PMID- 21320933 TI - ACP Journal Club. Review: Topical nitroglycerin reduces pain during ADL in patients with chronic tendinopathies. PMID- 21320934 TI - ACP Journal Club. Immediate surgery reduced long-term risk for nonperioperative stroke in severe asymptomatic carotid artery stenosis. PMID- 21320935 TI - ACP Journal Club. B-vitamin supplements did not reduce vascular events in patients with recent stroke or TIA. PMID- 21320936 TI - ACP Journal Club. Pharmacist-physician hypertension comanagement reduced 24-hour ambulatory blood pressure. PMID- 21320937 TI - Impact of obesity and knee osteoarthritis on morbidity and mortality in older Americans. AB - BACKGROUND: Obesity and knee osteoarthritis are among the most frequent chronic conditions affecting Americans aged 50 to 84 years. OBJECTIVE: To estimate quality-adjusted life-years lost due to obesity and knee osteoarthritis and health benefits of reducing obesity prevalence to levels observed a decade ago. DESIGN: The U.S. Census and obesity data from national data sources were combined with estimated prevalence of symptomatic knee osteoarthritis to assign persons aged 50 to 84 years to 4 subpopulations: nonobese without knee osteoarthritis (reference group), nonobese with knee osteoarthritis, obese without knee osteoarthritis, and obese with knee osteoarthritis. The Osteoarthritis Policy Model, a computer simulation model of knee osteoarthritis and obesity, was used to estimate quality-adjusted life-year losses due to knee osteoarthritis and obesity in comparison with the reference group. SETTING: United States. PARTICIPANTS: U.S. population aged 50 to 84 years. MEASUREMENTS: Quality-adjusted life-years lost owing to knee osteoarthritis and obesity. RESULTS: Estimated total losses of per-person quality-adjusted life-years ranged from 1.857 in nonobese persons with knee osteoarthritis to 3.501 for persons affected by both conditions, resulting in a total of 86.0 million quality-adjusted life-years lost due to obesity, knee osteoarthritis, or both. Quality-adjusted life-years lost due to knee osteoarthritis and/or obesity represent 10% to 25% of the remaining quality-adjusted survival of persons aged 50 to 84 years. Hispanic and black women had disproportionately high losses. Model findings suggested that reversing obesity prevalence to levels seen 10 years ago would avert 178,071 cases of coronary heart disease, 889,872 cases of diabetes, and 111,206 total knee replacements. Such a reduction in obesity would increase the quantity of life by 6,318,030 years and improve life expectancy by 7,812,120 quality-adjusted years in U.S. adults aged 50 to 84 years. LIMITATIONS: Comorbidity incidences were derived from prevalence estimates on the basis of life expectancy of the general population, potentially resulting in conservative underestimates. Calibration analyses were conducted to ensure comparability of model-based projections and data from external sources. CONCLUSION: The number of quality-adjusted life-years lost owing to knee osteoarthritis and obesity seems to be substantial, with black and Hispanic women experiencing disproportionate losses. Reducing mean body mass index to the levels observed a decade ago in this population would yield substantial health benefits. PRIMARY FUNDING SOURCE: The National Institutes of Health and the Arthritis Foundation. PMID- 21320938 TI - Exceptions to outpatient quality measures for coronary artery disease in electronic health records. AB - BACKGROUND: Physicians report outpatient quality measures from data in electronic health records to facilitate care improvement and qualify for incentive payments. OBJECTIVE: To determine the frequency and validity of exceptions to quality measures and to test a system for classifying the reasons for these exceptions. DESIGN: Cross-sectional observational study. SETTING: 5 internal medicine or cardiology practices. PARTICIPANTS: 47,075 patients with coronary artery disease between 2006 and 2007. MEASUREMENTS: Counts of adherence with and exceptions to 4 quality measures, on the basis of automatic reports of recommended drug therapy by computer software and separate manual reviews of electronic health records. RESULTS: 3.5% of patients who had a drug recommended had an exception to the drug and were not prescribed it (95% CI, 3.4% to 3.7%). Clinicians did prescribe the recommended drug for many other patients with exceptions. In 538 randomly selected records, 92.6% (CI, 90.3% to 94.9%) of the exceptions reported automatically by computer software were also exceptions during manual review. Most medical exceptions were clinical contraindications, drug allergies, or drug intolerances. In 592 randomly selected records, an unreported exception or a drug prescription was found during manual review for 74.6% (CI, 71.1% to 78.1%) of patients for whom automatic reporting recorded a quality failure. LIMITATION: The study used a convenience sample of practices, nonstandardized data extraction methods, only drug-related quality measures, and no financial incentives. CONCLUSION: Exceptions to recommended therapy occur infrequently and are usually valid. Physicians frequently prescribed drugs even when exceptions were present. Automated reports of quality failure often miss critical information. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. PMID- 21320939 TI - Determinants of medical expenditures in the last 6 months of life. AB - BACKGROUND: End-of-life medical expenditures exceed costs of care during other years, vary across regions, and are likely to be unsustainable. Identifying determinants of expenditure variation may reveal opportunities for reducing costs. OBJECTIVE: To identify patient-level determinants of Medicare expenditures at the end of life and to determine the contributions of these factors to expenditure variation while accounting for regional characteristics. It was hypothesized that race or ethnicity, social support, and functional status are independently associated with treatment intensity and controlling for regional characteristics, and that individual characteristics account for a substantial proportion of expenditure variation. DESIGN: Using data from the Health and Retirement Study, Medicare claims, and The Dartmouth Atlas of Health Care, relationships were modeled between expenditures and patient and regional characteristics. SETTING: United States, 2000 to 2006. PARTICIPANTS: 2394 Health and Retirement Study decedents aged 65.5 years or older. MEASUREMENTS: Medicare expenditures in the last 6 months of life were estimated in a series of 2-level multivariable regression models that included patient, regional, and patient and regional characteristics. RESULTS: Decline in function (rate ratio [RR], 1.64 [95% CI, 1.46 to 1.83]); Hispanic ethnicity (RR, 1.50 [CI, 1.22 to 1.85]); black race (RR, 1.43 [CI, 1.25 to 1.64]); and certain chronic diseases, including diabetes (RR, 1.16 [CI, 1.06 to 1.27]), were associated with higher expenditures. Nearby family (RR, 0.90 [CI, 0.82 to 0.98]) and dementia (RR, 0.78 CI, 0.71 to 0.87]) were associated with lower expenditures, and advance care planning had no association. Regional characteristics, including end-of-life practice patterns (RR, 1.09 [CI, 1.06 to 1.14]) and hospital beds per capita (RR, 1.01 [CI, 1.00 to 1.02]), were associated with higher expenditures. Patient characteristics explained 10% of overall variance and retained statistically significant relationships with expenditures after regional characteristics were controlled for. LIMITATION: The study limitations include the decedent sample, proxy informants, and a large proportion of unexplained variation. CONCLUSION: Patient characteristics, such as functional decline, race or ethnicity, chronic disease, and nearby family, are important determinants of expenditures at the end of life, independent of regional characteristics. PRIMARY FUNDING SOURCE: The Brookdale Foundation. PMID- 21320940 TI - Measuring the performance of markers for guiding treatment decisions. AB - Treatment selection markers, sometimes called predictive markers, are factors that help clinicians select therapies that maximize good outcomes and minimize adverse outcomes for patients. Existing statistical methods for evaluating a treatment selection marker include assessing its prognostic value, evaluating treatment effects in patients with a restricted range of marker values, and testing for a statistical interaction between marker value and treatment. These methods are inadequate, because they give misleading measures of performance that do not answer key clinical questions about how the marker might help patients choose treatment, how treatment decisions should be made on the basis of a continuous marker measurement, what effect using the marker to select treatment would have on the population, or what proportion of patients would have treatment changes on the basis of marker measurement. Marker-by-treatment predictiveness curves are proposed as a more useful aid to answering these clinically relevant questions, because they illustrate treatment effects as a function of marker value, outcomes when using or not using the marker to select treatment, and the proportion of patients for whom treatment recommendations change after marker measurement. Randomized therapeutic clinical trials, in which entry criteria and treatment regimens are not restricted by the marker, are also proposed as the basis for constructing the curves and evaluating and comparing markers. PMID- 21320941 TI - Use of intensive insulin therapy for the management of glycemic control in hospitalized patients: a clinical practice guideline from the American College of Physicians. AB - DESCRIPTION: The American College of Physicians (ACP) developed this guideline to present the evidence for the link between the use of intensive insulin therapy to achieve different glycemic targets and health outcomes in hospitalized patients with or without diabetes mellitus. METHODS: Published literature on this topic was identified by using MEDLINE and the Cochrane Library. Additional articles were obtained from systematic reviews and the reference lists of pertinent studies, reviews, and editorials, as well as by consulting experts; unpublished studies on ClinicalTrials.gov were also identified. The literature search included studies published from 1950 through March 2009. Searches were limited to English-language publications. The primary outcomes of interest were short-term mortality and hypoglycemia. This guideline grades the evidence and recommendations by using the ACP clinical practice guidelines grading system. RECOMMENDATION 1: ACP recommends not using intensive insulin therapy to strictly control blood glucose in non-surgical intensive care unit (SICU)/medical intensive care unit (MICU) patients with or without diabetes mellitus (Grade: strong recommendation, moderate-quality evidence). RECOMMENDATION 2: ACP recommends not using intensive insulin therapy to normalize blood glucose in SICU/MICU patients with or without diabetes mellitus (Grade: strong recommendation, high-quality evidence). RECOMMENDATION 3: ACP recommends a target blood glucose level of 7.8 to 11.1 mmol/L (140 to 200 mg/dL) if insulin therapy is used in SICU/MICU patients (Grade: weak recommendation, moderate-quality evidence). PMID- 21320942 TI - Intensive insulin therapy in hospitalized patients: a systematic review. AB - BACKGROUND: The benefits and harms of intensive insulin therapy (IIT) titrated to strict glycemic targets in hospitalized patients remain uncertain. PURPOSE: To evaluate the benefits and harms of IIT in hospitalized patients. DATA SOURCES: MEDLINE and Cochrane Database of Systematic Reviews from 1950 to January 2010, reference lists, experts, and unpublished sources. STUDY SELECTION: English language randomized, controlled trials comparing protocols titrated to strict or less strict glycemic targets. DATA EXTRACTION: Two reviewers independently abstracted data from each study on sample, setting, glycemic control interventions, glycemic targets, mean glucose levels achieved, and outcomes. Results were grouped by patient population or setting. A random-effects model was used to combine trial data on short-term mortality (<=28 days), long-term mortality (90 or 180 days), infection, length of stay, and hypoglycemia. The Grading of Recommendations Assessment, Development, and Evaluation system was used to rate the overall body of evidence for each outcome. DATA SYNTHESIS: In a meta-analysis of 21 trials in intensive care unit, perioperative care, myocardial infarction, and stroke or brain injury settings, IIT did not affect short-term mortality (relative risk, 1.00 [95% CI, 0.94 to 1.07]). No consistent evidence showed that IIT reduced long-term mortality, infection rates, length of stay, or the need for renal replacement therapy. No evidence of benefit from IIT was reported in any hospital setting, although the best evidence for lack of benefit was in intensive care unit settings. Data combined from 10 trials showed that IIT was associated with a high risk for severe hypoglycemia (relative risk, 6.00 [CI, 4.06 to 8.87]; P < 0.001). Risk for IIT-associated hypoglycemia was increased in all hospital settings. LIMITATIONS: Methodological shortcomings and inconsistencies limit the data in perioperative care, myocardial infarction, and stroke or brain injury settings. Differences in insulin protocols and patient and hospital characteristics may affect generalizability across treatment settings. CONCLUSION: No consistent evidence demonstrates that IIT targeted to strict glycemic control compared with less strict glycemic control improves health outcomes in hospitalized patients. Furthermore, IIT is associated with an increased risk for severe hypoglycemia. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs Health Services Research and Development Service. PMID- 21320943 TI - What is the "right" intensity of care at the end of life and how do we get there? PMID- 21320944 TI - Famous last words. PMID- 21320945 TI - CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. PMID- 21320946 TI - Diagnostic accuracy and clinical utility of noninvasive testing for coronary artery disease. PMID- 21320947 TI - Lipid emulsion therapy for verapamil overdose. PMID- 21320948 TI - Modelling the time profiles of organic solvent concentrations for occupational exposure assessment purposes. AB - OBJECTIVES: Confronted by variable exposure scenarios characterized by intermittent concentration peaks, our study aimed to develop methods and determine mathematical functions reproducing organic solvent concentration profiles in order to assess health risks. METHODS: Two similar repetitive decanting tasks using either formalin or toluene (TOL) were studied at a teaching hospital pathology laboratory. Real-time air monitoring performed in the immediate vicinity of pollutant sources over a 1-year period identified intermittent concentration peaks. In order to describe these specific exposure profiles, two different methods were used. In a first descriptive approach, concentration peaks were either assimilated to an equivalent series of rectangle functions or described by a mathematical bell-shaped function. As an alternative approach, a model based on the schedule of decanting tasks was constructed. To this end, a time-varying emission function was incorporated into three deterministic exposure models of increasing complexity (well-mixed room, two zone, spherical turbulent diffusion) and field-derived emission parameters were estimated by fitting model outputs to measured concentration profiles. RESULTS: Real-time measurements revealed highly variable concentration profiles, consisting of 1-8 peaks ranging from 5 to 220 s per decanting task, and average concentrations within peaks varying over 1-2 orders of magnitude. Acceptable fits were obtained by both descriptive approaches. The tested emission function seemed relevant in reproducing intermittent pollutant releases. Only advanced models (two-zone and diffusion) gave satisfying fits within assigned input parameter ranges. Average emission rate estimates varied in the range 10-47 mg min(-1) for formaldehyde and 360-1780 mg min(-1) for TOL, depending on the model tested. CONCLUSIONS: Both descriptive approaches and deterministic models accurately reproduced the patterns of measured concentration peaks. However, only deterministic models provided an understanding of the relations between pollutant releases, air movements, and the resulting concentrations and may thus be recommended for exposure variability assessment purposes. PMID- 21320949 TI - Assessing sleep architecture in dementia caregivers at home using an ambulatory polysomnographic system. AB - Findings from previous research assessing sleep quality in caregivers are inconsistent due to differences in sleep assessment methods. This study evaluated sleep in dementia caregivers using a comprehensive sleep assessment utilizing an ambulatory polysomnography (PSG) device. A total of 20 caregivers and 20 noncaregivers rated their perceived sleep quality, stress, and depressive symptoms; provided samples of cortisol and inflammatory biomarkers; and completed an objective sleep assessment using a portable PSG device. Caregivers reported greater perceived stress than noncaregivers. Next, the groups had different sleep architecture: caregivers spent less proportion of their sleep in restorative sleep stages compared to noncaregivers. Further, levels of C-reactive protein and awakening salivary cortisol were greater in caregivers than in noncaregivers, and these measures were related to sleep quality. Our findings indicate that sleep disruption is a significant concomitant of caregiving and may affect caregiver's health. Sleep quality of caregivers might be a useful target for a clinical intervention. PMID- 21320950 TI - Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience. AB - OBJECTIVE: To determine whether intra-arterial chemotherapy is safe and effective in advanced intraocular retinoblastoma. Retinoblastoma often presents with advanced intraocular disease and, despite conventional treatment with intravenous chemotherapy and external beam radiation therapy, may still require enucleation. DESIGN: Single-arm, prospective registry from May 30, 2006, to May 30, 2010, at an ophthalmic oncology referral center with ambulatory care. A total of 95 eyes of 78 patients with unilateral or bilateral retinoblastoma were treated. The intervention was selective catheterization of the ophthalmic artery and injection of chemotherapy, usually melphalan with or without topotecan. Drug dosage was determined by age and angioanatomy. The main outcome measures were procedural success, event-free (enucleation or radiotherapy) ocular survival, and ocular and extraocular complications. RESULTS: Catheterization succeeded in 98.5% of procedures. There were 289 chemotherapy injections (median, 3 per eye). The Kaplan-Meier estimates of ocular event-free survival rates at 2 years were 70.0% (95% confidence interval, 57.9%-82.2%) for all eyes, 81.7% (95% confidence interval, 66.8%-96.6%) for eyes that received intra-arterial chemotherapy as primary treatment, and 58.4% (95% confidence interval, 39.5%-77.2%) for eyes that had previous treatment failure with intravenous chemotherapy and/or external beam radiation therapy. There were no permanent extraocular complications. CONCLUSION: Our experience suggests that intra-arterial chemotherapy is safe and effective in the treatment of advanced intraocular retinoblastoma. PMID- 21320951 TI - Corneal transplantation for keratoconus: a registry study. AB - OBJECTIVE: To determine factors influencing long-term graft survival and visual acuity in 4834 eyes of 4060 patients receiving their first penetrating corneal graft for keratoconus. METHODS: A large cohort study was performed from a national register of corneal grafts in which data were recorded prospectively and analyzed retrospectively. Main outcome measures were graft survival and Snellen visual acuity. Follow-up extended up to 23 years. RESULTS: Kaplan-Meier survival rates of first grafts for keratoconus were 89%, 49%, and 17% at 10, 20, and 23 years, respectively. After 15 years, the graft survival rate was no better than that of all other penetrating grafts (P = .36). Multivariate risk factors influencing failure of first grafts for keratoconus included time to suture removal, postgraft uveitis or microbial keratitis, corneal vascularization prior to or after graft, geographic location of surgery and follow-up (center effect), recipient age at graft, occurrence of rejection episodes, graft size, and surgeon workload. The timing of bilateral grafts made no difference to the risk of rejection. A Snellen visual acuity of 20/40 or better at the most recent follow up was recorded in 74% of grafts. CONCLUSIONS: Penetrating grafts performed for keratoconus exhibited better visual outcome and graft survival than grafts performed for other indications. However, the Kaplan-Meier survival rate of first penetrating grafts for keratoconus was 17% at 23 years after graft and had not plateaued at this time, indicating that young patients are likely to need 1 or more repeated grafts during their lifetime. PMID- 21320952 TI - Lifestyle and risk of developing open-angle glaucoma: the Rotterdam study. AB - OBJECTIVE: To determine whether lifestyle-related risk factors, such as socioeconomic status, smoking, alcohol consumption, and obesity, are associated with open-angle glaucoma (OAG). METHODS: Participants from the Rotterdam Study, a prospective population-based cohort study, were considered eligible if they participated at both baseline and follow-up and if they had no OAG at baseline. All participants underwent an identical ophthalmologic examination at all visits, including intraocular pressure measurements, optic nerve head assessment, and perimetry. Lifestyle-related factors were assessed by questionnaires by trained research assistants or measured during the examinations (body mass index and waist to hip ratio). Cox proportional hazard regression analysis was applied to calculate hazard ratios. RESULTS: Of 3939 eligible participants, 108 (2.7%) developed OAG during 9.7 years' mean follow-up. No statistically significant effect of socioeconomic status, smoking, or alcohol intake was found. In women, each unit increase in body mass index resulted in a 7% decrease in the risk of developing OAG (P = .04). There was a significant increasing effect of body mass index on intraocular pressure (P < .001) in women. CONCLUSIONS: Obesity appears to be associated with a higher intraocular pressure and a lower risk of developing OAG. These associations were only present in women. Other lifestyle related factors, such as socioeconomic status, smoking, and alcohol consumption, were not associated with OAG. PMID- 21320953 TI - Foveal damage in habitual poppers users. AB - OBJECTIVE: To describe foveal damage in habitual use of poppers, a popular recreational drug. METHODS: Retrospective observational case series. Six patients with bilateral vision loss after chronic popper inhalation were seen in 4 university-based ophthalmology departments. Symptoms, medical history, ophthalmic examination, and functional and morphological tests are described. RESULTS: All patients experienced progressive bilateral vision loss, with central photopsia in 2 cases. Initial visual acuities ranged from 20/50 to 20/25. In all patients, a bilateral yellow foveal spot was present that, by optical coherence tomography, was associated with disruption of the outer segments of foveal cones. Functional and anatomical damage was restricted to the fovea. The poppers involved were identified as isopropyl nitrite in 3 cases. Four patients showed anatomical and/or functional improvement over several months after discontinuing popper inhalation. CONCLUSIONS: Repeated inhalation of poppers may be associated with prolonged bilateral vision loss due to the disruption of foveal cone outer segments. Retinal damage may progressively improve following drug discontinuation. PMID- 21320954 TI - Visual field extent at 6 years of age in children who had high-risk prethreshold retinopathy of prematurity. AB - OBJECTIVE: To compare monocular visual field extent at 6 years of age in eyes with high-risk prethreshold retinopathy of prematurity (ROP) randomized to early treatment (ET) with eyes that underwent conventional management (CM) and were treated at threshold or regressed without treatment. METHODS: Subjects were 370 surviving study participants who developed high-risk prethreshold ROP and were enrolled in the Early Treatment for Retinopathy of Prematurity Study between October 1, 2000, and September 30, 2002. When the participants were 6 years of age, vision testers unaware of ROP status used white-sphere kinetic perimetry to measure visual field extent along the superotemporal, inferotemporal, inferonasal, and superonasal meridians. RESULTS: The extent of the visual field was 0.1 degrees to 3.7 degrees larger in ET eyes when blind eyes were assigned a score of 0 degrees . When data were examined from eyes of participants with 1 sighted ET eye and 1 sighted CM eye, ET eyes showed a small (1.3 degrees -3.1 degrees ) reduction, which was statistically significant only along the superonasal meridian (P = .005). In bilaterally sighted children, visual field extent was not significantly reduced for high-risk type 1 ET eyes (-0.9 degrees to 1.8 degrees ). However, in ET eyes with high-risk type 2 disease, visual field extent was significantly smaller compared with that of CM eyes (3.6 degrees -8.7 degrees superonasal field [P = .003]; inferonasal field [P < .001]). CONCLUSION: Early treatment preserves peripheral vision, with only a small reduction of visual field extent. APPLICATION TO CLINICAL PRACTICE: Early treatment for high risk prethreshold ROP does not adversely affect visual field extent clinically. PMID- 21320955 TI - Effects of time, temperature, and storage container on the growth of Fusarium species: implications for the worldwide Fusarium keratitis epidemic of 2004-2006. AB - OBJECTIVE: To demonstrate the effects of time, temperature, and container properties on the ability of ReNu with MoistureLoc (ReNuML; contains the antimicrobial agent alexidine) to inhibit growth of Fusarium species. METHODS: ReNu with MoistureLoc was stored in its Bausch & Lomb (Rochester, New York) plastic or similarly sized glass containers for 1 and 4 weeks at room temperature, 42 degrees C, and 56 degrees C, and then tested for its ability to inhibit growth of 7 Fusarium isolates. RESULTS: ReNu with MoistureLoc stored in glass containers for 1 or 4 weeks at all 3 temperatures demonstrated no significant fungistatic deterioration. However, ReNuML stored at 56 degrees C in its Bausch & Lomb plastic container demonstrated a statistically significant fungistatic deterioration compared with room temperature storage in its original plastic container or with glass container storage at any temperature. CONCLUSION: When exposed to elevated storage temperature, it appears that an interaction between ReNuML and its Bausch & Lomb plastic container adversely affects the fungistatic properties of ReNuML, which could have contributed to the Fusarium keratitis epidemic of 2004 through 2006. PMID- 21320956 TI - Outcome of penetrating keratoplasty for mucopolysaccharidoses. AB - OBJECTIVE: To describe the outcome of penetrating keratoplasty (PK) for corneal opacification in the setting of systemic mucopolysaccharidoses (MPS). METHODS: A consecutive case series and literature review. RESULTS: Eight eyes from 5 patients with MPS (MPS I, MPS IV, and MPS VI) and a history of PK met inclusion criteria for our case series at the University of Minnesota Medical Center. The mean age at the time of PK was 40.5 years (range, 11.7-65.3 years). Mean follow up time after the PK was 4.9 years (range, 1-11 years). Mean (SD) visual acuity before PK was 0.90 (0.38) logMAR. The mean (SD) visual acuity at the last visit for all 8 eyes was 0.32 (0.16) logMAR. Visual acuity improved in 7 of 8 eyes (P = .002). Although early rejection led to repeat PK in 1 eye, no recurrent opacity consistent with MPS was noted in any of the corneal grafts. In a literature review, we found 23 reports documenting 40 initial and 3 repeat cases of PK in the setting of MPS. Of these, 31 initial and 2 repeat corneal grafts were reportedly clear during follow-up, ranging from 0.25 to 13 years. CONCLUSIONS: Penetrating keratoplasty is often a beneficial intervention in appropriate patients with corneal clouding due to MPS. Improvement in vision can be obtained with stable, clear corneal grafts in this population. PMID- 21320957 TI - Intravitreal bevacizumab in refractory neovascular glaucoma: a prospective, observational case series. AB - OBJECTIVE: To examine the efficacy of intravitreal bevacizumab for pain relief in eyes with refractory neovascular glaucoma. METHODS: In this prospective case series, 52 eyes with neovascular glaucoma were administered intravitreal bevacizumab, 1.25 mg, and monitored for 6 months. The primary outcome measure was change in subjective pain score. Intraocular pressure and iris neovascularization were evaluated at each visit. Surgical intervention for control of intraocular pressure was performed according to clinical need. RESULTS: Forty-two patients (44 eyes) completed the 6-month follow-up. Subjective pain score was reduced significantly 1 week after intravitreal bevacizumab injection and lasted throughout the follow-up period (median [interquartile range]: baseline, 3 [0-6]; week 1, 1 [0-3]; month 1, 0 [0-1]; month 3, 0 [0-1]; and month 6, 0 [0-0]; Kruskal-Wallis chi(2) 31.03; P < .001). A rapid, yet relatively transient, reduction in iris neovascularization was also noted (iris neovascularization grade at baseline, 4.0 [3-4]; week 1, 2.5 [1-4]; month 1, 2.0 [1-4]; month 3, 3.0 [2-4]; and month 6, 3.0 [2-4], chi(2) 23.33; P < .001). Four eyes (8%) required more than 1 injection to facilitate further intraocular surgery. CONCLUSIONS: Intravitreal bevacizumab is a useful adjunct in the management of refractory neovascular glaucoma, producing rapid relief of pain. However, we found no evidence to suggest that intravitreal bevacizumab lowers intraocular pressure in eyes with angle closure; conventional medical, laser, and surgical treatment are still needed in these eyes. PMID- 21320958 TI - Trabeculectomy with mitomycin for open-angle glaucoma in phakic vs pseudophakic eyes after phacoemulsification. AB - OBJECTIVE: To determine whether previous phacoemulsification adversely affects surgical prognosis of trabeculectomy with mitomycin for open-angle glaucoma. METHODS: The study is a retrospective, consecutive, comparative case series. At 2 clinical centers, we reviewed 226 medical records of eyes with open-angle glaucoma undergoing initial trabeculectomy, including 175 phakic eyes (phakic group) and 51 pseudophakic eyes that had previously undergone phacoemulsification with superior conjunctival incision (pseudophakic group). Primary outcome was the probability of success after trabeculectomy. Surgical failure was defined as an additional glaucoma surgery or 1 of the following 3 criteria: intraocular pressure (IOP) of 21 mm Hg or greater (A); IOP of 18 mm Hg or greater (B); and IOP of 15 mm Hg or greater (C). Multivariable analysis was performed using the Cox proportional hazards model. RESULTS: The mean follow-up period was 37.5 months. The probability of success for criteria A, B, and C at 1 and 3 years in the phakic vs the pseudophakic group was 97.8% and 92.6%, respectively, vs 78.6% and 65.1%, respectively, for criterion A (P < .001); 92.9% and 81.3%, respectively, vs 72.8% and 63.7%, respectively, for criterion B (P = .004); and 73.1% and 54.2%, respectively, vs 53.1% and 38.4%, respectively, for criterion C (P = .009). The multivariable model confirmed that pseudophakia independently contributes to surgical failure (criterion A relative risk, 4.59 [P < .001]; criterion B, 2.88 [P = .004]; and criterion C, 2.02 [P = .009]). The pseudophakic group required more postoperative laser suture lysis (P = .01). CONCLUSION: Previous phacoemulsification is a prognostic factor for surgical failure of trabeculectomy with mitomycin for open-angle glaucoma. PMID- 21320959 TI - Subfoveal serous retinal detachment in patients with uveitic macular edema. AB - OBJECTIVE: To assess the clinical characteristics and effect on visual acuity (VA) of a subfoveal serous retinal detachment (SRD) associated with macular edema (ME) in patients with uveitis. METHODS: Clinical and optical coherence tomograph characteristics were retrospectively assessed in 37 patients with uveitic ME with a subfoveal SRD (case individuals) and 61 patients with uveitic ME without a subfoveal SRD (control individuals), matched for uveitis location, sex, and age. Scans of the case and control individuals took place between September 19, 2003, and July 21, 2008. RESULTS: Patients with a subfoveal SRD had a shorter history of uveitis (P = .03) and ME (P = .03) and a lower VA (P = .003). Mean total retinal thickness (TRT) in cases exceeded that of controls (449 vs 326 MUm; P < .001). The median subfoveal SRD duration was 2 months, and 29 of 36 SRDs (81%) had disappeared at the 3-month follow-up examination. The improvement in VA and the decrease in TRT after 3 months were better in the subfoveal SRD group than in the control group (P = .001 for VA and P = .001 for TRT), resulting in similar VA and TRT after 3 months. CONCLUSIONS: A subfoveal SRD was associated with lower VA and developed typically in the early stages of uveitis and ME. The subfoveal SRD and VA reacted favorably to treatment with periocular and systemic steroids and/or oral acetazolamide. PMID- 21320960 TI - Clinical characteristics affecting the outcome of pneumatic retinopexy. AB - OBJECTIVES: To review characteristics and outcomes of patients who underwent primary pneumatic retinopexy (PR) for repair of rhegmatogenous retinal detachment in a multioffice retina practice and to determine what preoperative characteristics were associated with success or failure of PR. METHODS: A retrospective medical record review was conducted of patients who underwent primary PR from September 2001 to March 2009. Patients with less than 6 months of follow-up were excluded. Data collected on each patient included age, sex, affected eye, preoperative visual acuity, lens status, presence of posterior vitreous detachment, presence of vitreous hemorrhage, macular status, presence of lattice degeneration, number and location of retinal breaks, clock hour extent of detachment, final visual acuity, final retinal status, number of procedures to reattach retina, and duration of follow-up. RESULTS: Two hundred thirteen patients were included. The mean age was 59.3 years and 53.5% were male. Mean follow-up was 24.6 months, and 64.8% of patients had a successful PR. Vitreous hemorrhage and retinal detachment greater than 4.5 clock hours were the 2 factors that significantly affected successful outcome (P = .04 and .01, respectively). The overall mean final visual acuity was 20/40, with a mean of 20/30 in the success group and a mean of 20/60 in the failure group (P < .001). CONCLUSIONS: Pneumatic retinopexy is a treatment option for certain types of rhegmatogenous retinal detachment. In patients with vitreous hemorrhage and detachments greater than 4.5 clock hours, the success rate may be lower. Final visual acuity is better with successful reattachment with a single procedure. PMID- 21320961 TI - Screening for retinopathy of prematurity in infants born before 27 weeks' gestation in Sweden. AB - OBJECTIVE: To analyze screening for retinopathy of prematurity (ROP) during a 3 year period in a national cohort of infants born before 27 weeks' gestation. METHODS: A national prospective study of neonatal morbidity in extremely preterm infants was performed in Sweden between April 1, 2004, and March 31, 2007. Screening for ROP was to start in the fifth postnatal week and to continue weekly until complete vascularization of the retina or until regression of ROP. RESULTS: The first eye examination was performed no later than the sixth postnatal week in 84.8% of 506 infants, and the last examination was performed at postmenstrual age (PMA) of 38 weeks or later in 96.2% of infants. The mean and median numbers of days between examinations in the total cohort were 8.6 and 7.9 days, respectively (range, 1-27.8 days), and the mean and median numbers of examinations were 12 and 10, respectively. Most infants were treated during a limited period (eg, at PMA of 39 weeks, 75.0% of infants had been treated). CONCLUSIONS: The objective of screening for ROP is timely detection of ROP before reaching treatment of criteria, ie, type 1 ROP, according to the Early Treatment for ROP recommendations. In our population of infants born before 27 weeks' gestation, the first examination could safely be postponed until PMA of 31 weeks because the onset of ROP stage 3 did not occur before then and criteria for treatment were not reached before PMA of 32 weeks. Gestational age at birth and PMA at the time of examination should be considered when deciding when and where the next examination should be performed. PMID- 21320962 TI - Surgical management of residual or recurrent esotropia following maximal bilateral medial rectus recession. AB - OBJECTIVE: To describe the effect of graded unilateral vs bilateral lateral rectus resection in the treatment of residual or recurrent esotropia after maximal medial rectus muscle recession. METHODS: Retrospective case series of children with residual or recurrent esotropia. All children underwent initial eye muscle surgery for angles of 40 to 60 prism diopters (medial rectus recession of 5.5-6.5 mm; 11.0-11.5 mm from surgical limbus). If significant esotropia persisted or recurred, surgical results from graded lateral rectus resection were recorded. RESULTS: Thirty-eight children were identified for the study. Unilateral lateral rectus resection ranging from 4 to 7 mm resulted in mean esotropic corrections of 10.5 to 14.9 prism diopters. Differences in surgical response per millimeter of unilateral lateral rectus resection were not significant. Bilateral lateral rectus resection of 5, 6, and 7 mm resulted in a mean correction of 19.75, 28.75, and 33.5 prism diopters, respectively. CONCLUSIONS: Graded lateral rectus resection can produce highly variable results on a case-to-case basis, but mean values trend in the expected direction. Residual deviations larger than 15 prism diopters need to be addressed with bilateral surgery. PMID- 21320963 TI - Deficits in perception of images of real-world scenes in patients with a history of amblyopia. AB - OBJECTIVES: To investigate the perception of images of real-world scenes in patients with amblyopia and to compare their performance with that of visually normal participants by viewing conditions (monocular vs binocular) and by treatment outcomes (successfully vs unsuccessfully treated vs normal eyes). METHODS: Thirty-nine healthy and 26 amblyopic individuals who had undergone previous amblyopia treatment were recruited to perform a match-to-sample task that used images of real-world scenes. Rates of correct, incorrect, and no responses and mean reaction time were recorded. RESULTS: Performance during monocular viewing showed that the mean correct response rate was 59% in the amblyopic eyes, 62% in the fellow eyes, and 67% in the normal eyes (P = .008). During binocular viewing, the correct response rate remained reduced at 58% in amblyopic patients compared with 68% in participants with normal vision (P = .03). Performance by treatment outcomes showed that the mean correct response rate was 59% in the unsuccessfully treated group, 64% in the successfully treated group, and 67% in the normal group (P = .002). There was no difference in performance among amblyopia subtypes. CONCLUSIONS: Real-world scene perception is impaired in amblyopia, with the poorest performance during amblyopic monocular and binocular viewing. Despite successful treatment of the amblyopic eye to normal acuity levels, perception of images in real-world scenes remains deficient in patients with a history of amblyopia. PMID- 21320964 TI - Varying difficulty of Snellen letters and common errors in amblyopic and fellow eyes. AB - OBJECTIVE: To investigate the varying difficulty of Snellen letters in children with amblyopia. METHODS: We tabulated the letter-by-letter responses of amblyopic and nonamblyopic fellow eyes on random, computer-generated Snellen lines. Participants were 60 children, aged 5 to 13 years, with a history of amblyopia. Main outcome measures were relative difficulties of Snellen letters and common misidentifications. RESULTS: Errors were 7.5 times more common with certain letters (B, C, F, S) than with others (A, L, Z, T), this difference increasing to 17.6-fold at threshold. Similar relative letter difficulty was demonstrated at lines above and at visual acuity thresholds, and both difficult and easy letters were the same for amblyopic and nonamblyopic fellow eyes. Specific misidentification errors were often repeated and were often reciprocal (eg, B for E and E for B). CONCLUSION: Since therapeutic decisions in amblyopia management are often based on small differences in visual acuities, the relative difficulties of letters used in their measurement should be considered. The Early Treatment Diabetic Retinopathy Study system should be considered for use in this clinical setting. PMID- 21320966 TI - Diabetes mellitus and early age-related macular degeneration. AB - OBJECTIVE: To examine the association of diabetes mellitus and early age-related macular degeneration (AMD) in Korean adults 50 years and older. METHODS: This study included 3008 participants aged 50 to 87 years. Early AMD was assessed from retinal photographs based on a modified Wisconsin AMD grading system. Diabetes mellitus was defined as a fasting glucose level of 126 mg/dL or greater or the use of antidiabetic medications. Logistic regression was used to examine the association between diabetes mellitus and early AMD. RESULTS: There were 88 subjects with early AMD and 315 subjects with diabetes mellitus. After adjusting for age, sex, current smoking, obesity, and hypertension, significant association was found between diabetes mellitus and early AMD. Subjects with diabetes mellitus were more likely to have early AMD (odds ratio, 1.87; 95% confidence interval, 1.07-3.28) than were those without diabetes mellitus. CONCLUSION: There is a relationship between diabetes mellitus and early AMD in Korean adults 50 years and older. The underlying biological processes remain to be determined. PMID- 21320965 TI - Hemoglobin A1c and fasting plasma glucose levels as predictors of retinopathy at 10 years: the French DESIR study. AB - OBJECTIVE: To evaluate the predictive values of hemoglobin A(1c) (HbA(1c)) and fasting plasma glucose (FPG) for retinopathy 10 years after the baseline examination. METHODS: Seven hundred men and women from the DESIR (Data From an Epidemiological Study on the Insulin Resistance Syndrome) Study underwent evaluation for retinopathy using a nonmydriatic digital camera. During the preceding 9 years, 235 had diabetes mellitus (treated or FPG level of >=126 mg/dL at least once), 227 had an impaired FPG level (110-125 mg/dL) at least once, and 238 always had glucose levels within reference limits (<110 mg/dL). RESULTS: Compared with those without retinopathy, the 44 participants with retinopathy at 10 years had higher baseline mean (SD) levels of FPG (130 [49] vs 106 [22] mg/dL) and HbA(1c) (6.4% [1.6%] vs 5.7% [0.7%]) (both, P < .001). The frequency of retinopathy at 10 years, standardized according to the distribution of glycemia across the entire DESIR population, was 3.6%. In our population, FPG levels of 108 and 116 mg/dL had positive predictive values of 8.4% and 14.0%, respectively, for retinopathy at 10 years; HbA(1c) levels of 6.0% and 6.5% had positive predictive values of 6.0% and 14.8%, respectively. After 10 years of follow-up, retinopathy was equally frequent in participants with impaired FPG levels and in those who became diabetic during the study (8.6% and 6.7%, respectively), lower than in those with diabetes at baseline (13.9%). CONCLUSION: Because the positive predictive values for retinopathy increase sharply from 108 mg/dL for FPG and from 6.0% for HbA(1c) levels, these thresholds are proposed to identify those at risk of retinopathy 10 years later. PMID- 21320967 TI - Patient-reported outcomes among sham vs no-treatment controls from randomized trials. AB - OBJECTIVE: To compare 2-year changes from baseline scores on the National Eye Institute Visual Function Questionnaire (NEI-VFQ) between similar participants assigned to sham and no-treatment control arms in randomized clinical trials of treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration. METHODS: We retrospectively matched sham controls from a randomized trial to no-treatment controls (no sham or placebo) from another trial on 7 baseline prognostic criteria. Two-year changes in overall and subscale scores were compared using data from those who had 2-year interviews and also using the last follow-up observation carried forward to impute missing 2-year interview scores. RESULTS: A match to a no-treatment control on all 7 criteria was identified for 62 of 238 sham controls. Among the 42 matched pairs of controls interviewed at 2 years, no important difference in 2-year change in NEI VFQ scores overall or by subscale was observed. Findings were similar for the 56 matched pairs of controls who could be analyzed for 2-year changes in scores using the method of last follow-up observation carried forward. CONCLUSIONS: Findings from this retrospective matched-pairs analysis suggest that sham treatment to mask patient participants in clinical trials may be unnecessary when patient-reported outcomes are of interest and standard instruments are administered by interviewers masked to treatment assignment. This analysis, together with our earlier analysis of visual acuity outcomes, questions the necessity for sham (placebo) controls in randomized clinical trials in ophthalmology when other methods to minimize outcome assessment bias are incorporated into the design. PMID- 21320968 TI - An investigation into LOXL1 variants in black South African individuals with exfoliation syndrome. AB - OBJECTIVE: To investigate the association between 2 lysyl oxidase-like 1 (LOXL1) polymorphisms, rs1048661 (R141L) and rs3825942 (G153D), and exfoliation syndrome (XFS) in black South African individuals. METHODS: A total of 43 black patients with XFS and 47 ethnically matched controls were recruited for genetic analysis. Samples were analyzed for presence of the LOXL1-R141L and G153D variants using restriction fragment length polymorphism analysis. A case-control association study was performed. RESULTS: The R141L and G153D single-nucleotide polymorphisms (SNPs) were both significantly associated with XFS (P = .00582 and P < .00001, respectively). Consistent with findings in white populations but not in Asian cohorts, the GG genotype of the R141L SNP was present in significantly more XFS cases than controls (P = .00582). However, in this black South African study population, the AA genotype of G153D was present in an overwhelming majority of cases with XFS (P < .00001; odds ratio, 17.10; 95% confidence interval, 4.91 59.56), contrary to all previous articles in which the GG genotype was strongly associated with the disease phenotype. CONCLUSION: The LOXL1 SNPs R141L and G153D are significantly associated with XFS in this black South African population. The AA genotype of G153D confers XFS risk in this population, as opposed to the GG genotype described in all other populations, suggesting that unidentified genetic or environmental factors independent of these LOXL1 SNPs may influence phenotypic expression of the syndrome. CLINICAL RELEVANCE: Elucidation of the role of genetic factors, including the LOXL1 gene, in XFS will facilitate identification of individuals predisposed to developing this condition. PMID- 21320969 TI - Autosomal recessive best vitelliform macular dystrophy: report of a family and management of early-onset neovascular complications. AB - OBJECTIVES: To report a child with early-onset autosomal recessive Best vitelliform macular dystrophy and compound heterozygous BEST1 mutations, the management of a choroidal neovascular membrane with intravitreal bevacizumab in the proband, the benefits of amblyopia therapy in the fellow eye, and the findings in the parents, carriers of heterozygous BEST1 mutations. METHODS: A 5 year-old white girl presented with monocular visual acuity loss and bilateral vitelliform macular lesions. Her parents were also examined. Examinations included electro-oculograms (EOGs), electroretinograms, imaging studies, and BEST1 gene testing. Interventions included off-label treatment with intravitreal bevacizumab in the left eye and amblyopia therapy in the right eye. RESULTS: The proband presented with visual acuity of 20/200 OD with an atypical subfoveal vitelliform scar and 20/16 OS with asymptomatic vitelliform deposits. Subfoveal choroidal neovascularization developed at age 6 years, causing marked vision loss (20/200 OS). Visual acuity recovered to 20/20 OS after serial intravitreal bevacizumab injections. Amblyopia therapy improved visual acuity to 20/50 OD. The proband showed subnormal EOG Arden ratios and mild electroretinogram changes. Molecular testing showed missense BEST1 mutations (R141S and R141H) in the proband. Unlike dominant Best vitelliform macular dystrophy, in the heterozygous parents EOGs were normal and minimal autofluorescence changes were seen. CONCLUSIONS: Choroidal neovascularization treatment with bevacizumab was associated with vision restoration. Amblyopia treatment also yielded significant benefit. Patients presenting with vitelliform lesions should be screened for BEST1 mutations, even when parents have normal EOG and imaging results. CLINICAL RELEVANCE: Prompt recognition and treatment of choroidal neovascularization and amblyopia management effectively restores vision. Awareness and recognition of recessive inheritance permits correct diagnosis and counseling. PMID- 21320970 TI - Limbal allograft transplantation using fibrin glue. AB - Limbal transplantation is now widely accepted as the treatment of advanced limbal stem cell deficiency. Herein, we describe a technique for harvesting thin limbal grafts from cadaveric corneoscleral rims and a sutureless method to secure the grafts to the recipient eye using fibrin glue. We report the results of fibrin glue-assisted keratolimbal allograft in 19 eyes of 16 patients, with the outcome measures being ocular surface stability, visual acuity, and postoperative complications. The results indicate that limbal allograft transplantation can be performed safely and successfully using only fibrin glue to secure the grafts. This can potentially improve surgical efficiency and patient comfort postoperatively. PMID- 21320971 TI - A brief history of the Bressler Prize and Symposium: recognizing excellence in vision care and vision science. PMID- 21320972 TI - The burgeoning public health impact of diabetes: the role of the ophthalmologist. AB - With the recent increases and future projected increases in the incidence of type 2 diabetes mellitus and with the incidence increasing in teenagers and young adults, the already substantial public health effect of diabetes and diabetic retinopathy will become greater in years to come. Despite the strength of the evidence that optimizing control of glucose, blood pressure, and lipid levels will reduce the incidence and progression of diabetic retinopathy, metabolic control remains suboptimal for many patients with diabetes. In addition, many patients do not follow recommended guidelines for regular eye examinations, which is unfortunate because there is good evidence that with regular follow-up and intervention with photocoagulation as indicated, severe vision loss from diabetic retinopathy is uncommon. Yet, diabetic retinopathy is a leading cause of severe vision loss in adults. The current health care system too often fails to adequately manage diabetes and is lacking in providing proper education and motivation for patients to optimize their metabolic control. In addition to treating retinopathy, ophthalmologists can play an important role in educating and motivating patients to achieve better metabolic control, which, if successful, potentially could do more to reduce the progression of retinopathy than any of the ocular treatments currently in the armamentarium of the ophthalmologist. PMID- 21320973 TI - An integrated approach to diabetic retinopathy research. AB - This review discusses the pathophysiology of diabetic retinopathy related to direct effects of loss of insulin receptor action and metabolic dysregulation on the retina. The resulting sensory neuropathy can be diagnosed by structural and functional tests in patients with mild nonproliferative diabetic retinopathy. Research teams can collaborate to integrate ocular and systemic factors that impair vision and to design strategies to maintain retinal function in persons with diabetes mellitus. Evolving concepts may lead to inclusion of tests of retinal function in the detection of diabetic retinopathy and neuroprotective strategies to preserve vision for persons with diabetes. PMID- 21320974 TI - Telemedicine and diabetic retinopathy: moving beyond retinal screening. AB - Current projections estimate that diabetes mellitus will afflict over 439 million individuals worldwide by 2030. The task of detecting and evaluating for the presence and severity of retinopathy in the populations with diabetes mellitus is enormous. Although current methods of treatment are effective in reducing the risk for vision loss, a substantial proportion of patients still do not receive appropriate eye care. The use of an ocular telemedicine-based approach has the potential to expand the reach of these highly effective treatments to virtually any location. Novel methods of image acquisition and analysis, as well as the identification of predictive biomarkers, will need to be developed to further enhance this approach of eye care delivery. In addition, such programs will allow the rapid transfer of clinically relevant discoveries and will allow a considerably larger benefit to a broader patient population. PMID- 21320975 TI - Glaucoma medication adherence: room for improvement in both performance and measurement. PMID- 21320976 TI - Late capsular block syndrome associated with Propionibacterium acnes. PMID- 21320977 TI - Temporal macular thinning on spectral-domain optical coherence tomography in proliferative sickle cell retinopathy. PMID- 21320978 TI - Successful treatment of refractory sympathetic ophthalmia in a child with infliximab. PMID- 21320979 TI - Photographic monitoring of herpes simplex virus keratitis during anti inflammatory treatment. PMID- 21320980 TI - An unusual manifestation of herpes simplex virus-associated acute iris depigmentation and pigmentary glaucoma. PMID- 21320982 TI - Inclusion body myopathy with Paget disease of bone and frontotemporal dementia linked to VCP p.Arg155Cys in a Korean family. AB - BACKGROUND: Missense mutations in the valosin-containing protein (VCP) gene on chromosome 9p13.3-p12 cause inclusion body myopathy with Paget disease of bone and frontotemporal dementia (hereafter referred to as IBMPFD; OMIM 167320). OBJECTIVE: To describe detailed clinical, electrophysiological, biochemical, and neuroimaging findings in IBMPFD linked to VCP p.Arg155Cys in a Korean family. DESIGN: Case series. Clinical, electrophysiological, biochemical, and neuroimaging findings were obtained by direct evaluation and from previous medical records. SETTING: Tertiary referral hospital. PARTICIPANTS: Three affected family members in a Korean family. RESULTS: The clinical features of myopathy, Paget disease of bone, and semantic dementia (a clinical subtype of frontotemporal dementia) in our patients were similar to those of previously reported cases. However, the brain magnetic resonance imaging features in our patients, including asymmetric anterior and lateral temporal and inferior parietal atrophy with ventricular dilatation on the affected side, differed from those of previously published features in patients with IBMPFD and in patients with typical semantic dementia who show anterior temporal and frontal atrophy. CONCLUSION: To our knowledge, this report provides the first documented IBMPFD family in Asia and broadens the phenotypic spectrum of VCP mutation-associated frontotemporal dementia. PMID- 21320981 TI - Observational study of spinal muscular atrophy type 2 and 3: functional outcomes over 1 year. AB - OBJECTIVE: To characterize the short-term course of spinal muscular atrophy (SMA) in a genetically and clinically well-defined cohort of patients with SMA. DESIGN: A comprehensive multicenter, longitudinal, observational study. SETTING: The Pediatric Neuromuscular Clinical Research Network for SMA, a consortium of clinical investigators at 3 clinical sites. PARTICIPANTS: Sixty-five participants with SMA types 2 and 3, aged 20 months to 45 years, were prospectively evaluated. INTERVENTION: We collected demographic and medical history information and determined the SMN 2 copy number. MAIN OUTCOME MEASURES: Clinical outcomes included measures of motor function (Gross Motor Function Measure and expanded Hammersmith Functional Motor Scale), pulmonary function (forced vital capacity), and muscle strength (myometry). Participants were evaluated every 2 months for the initial 6 months and every 3 months for the subsequent 6 months. We evaluated change over 12 months for all clinical outcomes and examined potential correlates of change over time including age, sex, SMA type, ambulatory status, SMN2 copy number, medication use, and baseline function. RESULTS: There were no significant changes over 12 months in motor function, pulmonary function, and muscle strength measures. There was evidence of motor function gain in ambulatory patients, especially in those children younger than 5 years. Scoliosis surgery during the observation period led to a subsequent decline in motor function. CONCLUSIONS: Our results confirm previous clinical reports suggesting that SMA types 2 and 3 represent chronic phenotypes that have relatively stable clinical courses. We did not detect any measurable clinical disease progression in SMA types 2 and 3 over 12 months, suggesting that clinical trials will have to be designed to measure improvement rather than stabilization of disease progression. PMID- 21320983 TI - Functional magnetic resonance imaging evidence of incomplete maternal imprinting in myoclonus-dystonia. AB - BACKGROUND: Myoclonus-dystonia is an autosomal dominantly inherited movement disorder, clinically characterized by myoclonic jerks and dystonic postures or movements. A previous functional magnetic resonance imaging study showed altered cortical activation patterns in clinically affected SGCE mutation carriers when compared with controls consistent with defective sensorimotor integration. Genetically, the disorder is characterized by the maternal imprinting mechanism; ie, patients who inherit the mutation from their fathers will develop symptoms. However, several clinically manifest patients with myoclonus-dystonia who inherited the mutation from their mother have been described. OBJECTIVE: To compare cerebral activation patterns of paternally inherited SGCE mutation carriers are with maternally inherited mutation carriers and a control group. DESIGN: Case-control study using functional magnetic resonance imaging. PARTICIPANTS: Eight paternally inherited SGCE mutation carriers, 8 asymptomatic or slightly affected (4 of 8) symptomatic maternally inherited mutation carriers, and 11 control subjects. INTERVENTIONS: Participants were studied using a 3-T functional magnetic resonance imaging scanner with a finger tapping task. RESULTS: When paternal and maternal gene mutation carriers were compared, hyperresponsiveness was seen in the contralateral secondary somatosensory cortex. When maternal mutation carriers and control subjects were compared, hyperresponsiveness of the ipsilateral cerebellum and supplementary motor area were found. Using a nonparametric analysis to study only the 4 clinically asymptomatic patients, no significant differences were found between groups. Contrast estimates were plotted for the known affected sensorimotor brain areas, showing intermediate activation in maternally inherited mutation carriers, even when this was performed for only the 4 clinically unaffected mutation carriers. CONCLUSIONS: The results suggest biased gene expression based on parent of origin rather than a strictly dichotomous maternal imprinting mechanism, consistent with clinical observations. PMID- 21320984 TI - Population-based analysis of morbidity and mortality following surgery for intractable temporal lobe epilepsy in the United States. AB - OBJECTIVE: To assess the morbidity of temporal lobe epilepsy (TLE) surgery on a nationwide level in order to address reservations regarding the morbidity of anterior temporal lobectomy (ATL) for TLE despite class I evidence demonstrating the superiority of ATL over continued medical therapy. DESIGN: Retrospective cohort study. SETTING: The Nationwide Inpatient Sample from 1988 to 2003 was used for analysis. PATIENTS: Only patients who were admitted for ATL for TLE (International Classification of Diseases, Ninth Revision, Clinical Modification codes 345.41 and 345.51; primary procedure code, 01.53) were included. MAIN OUTCOME MEASURES: Morbidity and mortality. Analysis was adjusted for several variables including patient age, race, sex, admission type, primary payer for care, income in zip code of residence, and hospital volume of care. RESULTS: Multivariate analyses revealed that the overall morbidity (postoperative morbidity and/or adverse discharge disposition) following ATL for TLE was 10.8%, with no mortality. Private insurance decreased postoperative morbidity (odds ratio [OR] = 0.52; 95% confidence interval [CI] = 0.28-0.98; P = .04) and adverse discharge disposition (OR = 0.31; 95% CI = 0.12-0.81; P = .02). Increased patient age increased postoperative morbidity (OR = 1.04; 95% CI = 1.01-1.07; P = .03) and adverse discharge disposition (OR = 1.08; 95% CI = 1.02-1.13; P = .004). Neither sex, income, race, nor hospital volume was predictive of postoperative morbidity. The degree of medical comorbidity directly correlated with the incidence of postoperative morbidity. CONCLUSIONS: Morbidity following ATL for TLE is low throughout the United States regardless of sex, race, insurance status, or income. Younger age and private insurance status are independently predictive of reduced postoperative morbidity. In patients with low medical comorbidity, ATL for TLE is safe, with low morbidity and no mortality. PMID- 21320985 TI - Translational research in neurology and neuroscience 2011: movement disorders. AB - We provide an update on the state of translational research in movement disorders, using examples of Huntington disease, Parkinson disease, and dystonia. While substantial progress in our understanding of these disorders has been achieved, development of neuroprotective treatments remains an unrealized goal. Here we highlight some of the emerging research areas that show the most promise for translational research in Huntington disease, Parkinson disease, and dystonia. Aetiology and pathogenesis, biomarker directions, and causal treatment opportunities are discussed for each disease, followed by a brief discussion drawing attention to important translational initiatives. PMID- 21320986 TI - Skin denervation and its clinical significance in late-stage chronic kidney disease. AB - OBJECTIVE: To investigate the skin innervation and its clinical significance in late-stage chronic kidney disease (CKD). DESIGN: Case series. SETTING: National Taiwan University Hospital, Taipei, Taiwan. PATIENTS: Forty consecutive nondiabetic patients with late-stage CKD (14 female and 26 male; mean [SD] age, 60.7 [12.3] years), including 2 cases with stage 3 CKD, 6 with stage 4 CKD, and 32 with stage 5 CKD, ie, end-stage kidney disease. INTERVENTIONS: Clinical evaluation of neurological deficits, nerve conduction study, autonomic function tests, and a 3-mm-diameter skin biopsy specimen taken from the distal leg. MAIN OUTCOME MEASURES: Quantitation of epidermal innervation, parameters of nerve conduction study, R-R interval variability, and sympathetic skin response. RESULTS: Clinically, 21 patients (52.5%) were symptomatic with paresthesia over the limbs or autonomic symptoms. The intraepidermal nerve fiber (IENF) density was markedly reduced in patients with CKD compared with age- and sex-matched controls (mean [SD], 2.8 [2.0] vs 8.6 [2.8] fibers/mm; P < .001). Skin denervation was observed in 27 patients (67.5%). Fifteen patients (37.5%) had abnormalities on nerve conduction studies, and 29 patients (72.5%) had abnormal results on autonomic function tests. By analysis with multiple regression models, the IENF density was negatively correlated with the duration of renal disease (P = .02). Additionally, the R-R interval variability at rest was linearly correlated with the IENF density (P = .02) and the absence of sympathetic skin responses at the soles was associated with reduced IENF density (P = .03). CONCLUSIONS: Small-fiber sensory and autonomic neuropathies constitute the major form of neuropathy in late-stage CKD. Furthermore, skin denervation was associated with the duration of renal disease. PMID- 21320987 TI - Smoking and risk of amyotrophic lateral sclerosis: a pooled analysis of 5 prospective cohorts. AB - BACKGROUND: Cigarette smoking has been proposed as a risk factor for amyotrophic lateral sclerosis (ALS), but epidemiological studies supporting this hypothesis have been small and mostly retrospective. OBJECTIVE: To prospectively examine the relation between smoking and ALS in 5 well-established large cohorts. DESIGN: Five prospective cohorts with study-specific follow-up ranging from 7 to 28 years. SETTING: Academic research. PATIENTS: Participants in the Nurses' Health Study, the Health Professionals Follow-up Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort, and the National Institutes of Health AARP (formerly known as the American Association of Retired Persons) Diet and Health Study. MAIN OUTCOME MEASURES: Amyotrophic lateral sclerosis deaths identified through the National Death Index. In the Nurses' Health Study and the Health Professionals Follow-up Study, confirmed nonfatal incident ALS was also included. RESULTS: A total of 832 participants with ALS were documented among 562,804 men and 556,276 women. Smokers had a higher risk of ALS than never smokers, with age- and sex-adjusted relative risks of 1.44 (95% confidence interval, 1.23-1.68; P < .001) for former smokers and 1.42 (95% confidence interval, 1.07-1.88; P = .02) for current smokers. Although the risk of ALS was positively associated with pack-years smoked (P < .001), duration of smoking (9% increase for each 10 years of smoking, P = .006), and the number of cigarettes smoked per day (10% increase for each increment of 10 cigarettes smoked per day, P < .001), these associations did not persist when never smokers were excluded. However, among ever smokers, the risk of ALS increased as age at smoking initiation decreased (P = .03). CONCLUSIONS: Results of this large longitudinal study support the hypothesis that cigarette smoking increases the risk of ALS. The potential importance of age at smoking initiation and the lack of a dose response deserve further investigation. PMID- 21320988 TI - Hearing loss and incident dementia. AB - OBJECTIVE: To determine whether hearing loss is associated with incident all cause dementia and Alzheimer disease (AD). DESIGN: Prospective study of 639 individuals who underwent audiometric testing and were dementia free in 1990 to 1994. Hearing loss was defined by a pure-tone average of hearing thresholds at 0.5, 1, 2, and 4 kHz in the better-hearing ear (normal, <25 dB [n = 455]; mild loss, 25-40 dB [n = 125]; moderate loss, 41-70 dB [n = 53]; and severe loss, >70 dB [n = 6]). Diagnosis of incident dementia was made by consensus diagnostic conference. Cox proportional hazards models were used to model time to incident dementia according to severity of hearing loss and were adjusted for age, sex, race, education, diabetes mellitus, smoking, and hypertension. SETTING: Baltimore Longitudinal Study of Aging. PARTICIPANTS: Six hundred thirty-nine individuals aged 36 to 90 years. MAIN OUTCOME MEASURE: Incident cases of all-cause dementia and AD until May 31, 2008. RESULTS: During a median follow-up of 11.9 years, 58 cases of incident all-cause dementia were diagnosed, of which 37 cases were AD. The risk of incident all-cause dementia increased log linearly with the severity of baseline hearing loss (1.27 per 10-dB loss; 95% confidence interval, 1.06 1.50). Compared with normal hearing, the hazard ratio (95% confidence interval) for incident all-cause dementia was 1.89 (1.00-3.58) for mild hearing loss, 3.00 (1.43-6.30) for moderate hearing loss, and 4.94 (1.09-22.40) for severe hearing loss. The risk of incident AD also increased with baseline hearing loss (1.20 per 10 dB of hearing loss) but with a wider confidence interval (0.94-1.53). CONCLUSIONS: Hearing loss is independently associated with incident all-cause dementia. Whether hearing loss is a marker for early-stage dementia or is actually a modifiable risk factor for dementia deserves further study. PMID- 21320989 TI - Excessive daytime sleepiness in multiple system atrophy (SLEEMSA study). AB - BACKGROUND: Sleep disorders are common in multiple system atrophy (MSA), but the prevalence of excessive daytime sleepiness (EDS) is not well known. OBJECTIVE: To assess the frequency and associations of EDS in MSA. DESIGN: Survey of EDS in consecutive patients with MSA and comparison with patients with Parkinson disease (PD) and individuals without known neurologic disease. SETTING: Twelve tertiary referral centers. PARTICIPANTS: Eighty-six consecutive patients with MSA; 86 patients with PD matched for age, sex, and Hoehn and Yahr stage; and 86 healthy subject individuals matched for age and sex. MAIN OUTCOME MEASURES: Epworth Sleepiness Scale (ESS), modified ESS, Sudden Onset of Sleep Scale, Tandberg Sleepiness Scale, Pittsburgh Sleep Quality Index, disease severity, dopaminergic treatment amount, and presence of restless legs syndrome. RESULTS: Mean (SD) ESS scores were comparable in MSA (7.72 [5.05]) and PD (8.23 [4.62]) but were higher than in healthy subjects (4.52 [2.98]) (P < .001). Excessive daytime sleepiness (ESS score >10) was present in 28% of patients with MSA, 29% of patients with PD, and 2% of healthy subjects (P < .001). In MSA, in contrast to PD, the amount of dopaminergic treatment was not correlated with EDS. Disease severity was weakly correlated with EDS in MSA and PD. Restless legs syndrome occurred in 28% of patients with MSA, 14% of patients with PD, and 7% of healthy subjects (P < .001). Multiple regression analysis (with 95% confidence intervals obtained using nonparametric bootstrapping) showed that sleep-disordered breathing and sleep efficiency predicted EDS in MSA and amount of dopaminergic treatment and presence of restless legs syndrome in PD. CONCLUSIONS: More than one-quarter of patients with MSA experience EDS, a frequency similar to that encountered in PD. In these 2 conditions, EDS seems to be associated with different causes. PMID- 21320990 TI - In vivo fibrillar beta-amyloid detected using [11C]PiB positron emission tomography and neuropathologic assessment in older adults. AB - BACKGROUND: In demented older adults, in vivo amyloid imaging shows agreement with diagnostic neuropathologic assessment of beta-amyloid (Abeta). However, the extent of agreement in nondemented older adults remains unclear. OBJECTIVE: To compare Abeta quantified using in vivo carbon 11-labeled Pittsburgh Compound B positron emission tomography and postmortem neuropathologic assessment of Abeta in older adults. DESIGN: Case series. SETTING: Community-dwelling older adults who came to autopsy. PARTICIPANTS: Five nondemented and 1 demented participant from the Baltimore Longitudinal Study of Aging. MAIN OUTCOME MEASURE: Agreement between the mean cortical distribution volume ratio and the Consortium to Establish a Registry for AD (CERAD) neuritic plaque (NP) score used for pathologic diagnosis of Alzheimer disease. RESULTS: Of the 6 participants, 4 had moderate NPs, 2 had sparse or no detectable NPs, and 3 had microscopic findings of cerebral amyloid angiopathy at autopsy. On in vivo imaging, the mean cortical distribution volume ratio ranged from 0.96 to 1.59. Although there was agreement between in vivo amyloid imaging and CERAD NP scores in participants with either high or negligible Abeta levels in vivo, only limited agreement was observed among those with intermediate levels of Abeta. The best overall agreement was achieved at a distribution volume ratio of 1.2. CONCLUSIONS: In older adults, variable agreement between in vivo imaging and CERAD NP score was observed. The limited agreement may, in part, reflect differences in typical measurements of Abeta using imaging compared with the CERAD neuropathologic protocol. Direct quantification of regional Abeta in relation to in vivo imaging is necessary to further enhance our understanding of the imaging-pathologic assessment correlation. PMID- 21320991 TI - Preserved musical semantic memory in semantic dementia. AB - OBJECTIVE: To understand the scope of semantic impairment in semantic dementia. DESIGN: Case study. SETTING: Academic medical center. PATIENT: A man with semantic dementia, as demonstrated by clinical, neuropsychological, and imaging studies. MAIN OUTCOME MEASURES: Music performance and magnetic resonance imaging results. RESULTS: Despite profoundly impaired semantic memory for words and objects due to left temporal lobe atrophy, this semiprofessional musician was creative and expressive in demonstrating preserved musical knowledge. CONCLUSION: Long-term representations of words and objects in semantic memory may be dissociated from meaningful knowledge in other domains, such as music. PMID- 21320992 TI - Metabolic imaging correlate of truncal onset seizures. AB - OBJECTIVE: To denote the metabolic imaging localization of seizure onset with ictal and interictal Neurolite single-photon emission computed tomographic scans and difference images made by subtracting activity at individual voxels of these images, which ultimately identify intense focal uptake in the trunk motor region and other, probably secondarily, propagated pathways. DESIGN: Retrospective review of a unique case report. SETTING: A suburban epilepsy referral center. PATIENT: A 59-year-old man with truncal-onset seizure. INTERVENTIONS: Ictal and interictal metabolic imaging. MAIN OUTCOME MEASURES: Onset location of ictal events. RESULTS: The patient had a gliotic lesion in a focal region on magnetic resonance imaging undercutting the trunk motor area in the cortex of the precentral gyrus with concordant single-photon emission computed tomographic imaging. CONCLUSIONS: While truncal-onset seizures have been described previously in a few case reports, they are clinically rare. As far as we know, this is the only case report in the literature in which metabolic imaging was carried out with this entity and is consistent with the anatomical localization of seizure onset in the trunk motor area. PMID- 21320993 TI - Anterior opercular syndrome caused by acute, simultaneous, isolated bilateral infarcts. PMID- 21320994 TI - Carotid cavernous fistula imitating brainstem glioma. PMID- 21320995 TI - Hyoid bone compression-induced repetitive occlusion and recanalization of the internal carotid artery in a patient with ipsilateral brain and retinal ischemia. PMID- 21320996 TI - No association between genetic polymorphism at codon 129 of the prion protein gene and primary progressive multiple sclerosis. PMID- 21320997 TI - Validation of plasma branched chain amino acids as biomarkers in Huntington disease. PMID- 21320998 TI - Improving risk scores for dementia. PMID- 21320999 TI - Vascular risk scores for dementia: age matters. PMID- 21321000 TI - Accuracy of summary risk score for prediction of Alzheimer disease: better than demographics alone? PMID- 21321001 TI - Different phenotypes among Lesch-Nyhan variants: clinical reality or limitation of ascertainment? PMID- 21321002 TI - Physical disability in rheumatoid arthritis is associated with cartilage damage rather than bone destruction. AB - BACKGROUND: Joint destruction in rheumatoid arthritis is comprised of cartilage and bone damage, which can be evaluated radiographically separately by the joint space narrowing (JSN) and erosion (ERO) scores. It is currently unclear to which extent these components affect irreversible functional disability. The aim of the present work was to determine these contributions. METHODS: Data, kindly provided by the sponsors, was evaluated from several randomised controlled clinical trials on adalimumab, etanercept, infliximab and leflunomide. Patients who reached stringent remission according to the Simplified Disease Activity Index (SDAI<=3.3) were extracted to eliminate the activity related (ie, reversible) component of disability. In these patients, residual Health Assessment Questionnaire Disability Index (HAQ-DI) score at the time of remission (to reflect the level of 'irreversible' disability) was determined and related to baseline measures of ERO and JSN scores univariately, by stratification and in adjusted regression models. RESULTS: A total of 748 patients who achieved a state of remission were analysed (16.3% of the total pooled population of 4602 patients). In the univariate analyses, mean residual HAQ-DI values in remission were significantly larger in higher tertiles of JSN and ERO (ERO: 0.21, 0.25, 0.35; JSN: 0.19, 0.24, 0.39; p<0.001 for both). In stratified analyses, mean residual HAQ-DI scores were larger in higher tertiles of JSN within the first tertile of ERO (0.18, 0.25, 0.29; p=0.05), as well as the second (0.21, 0.24, 0.29; p=0.19) and the third (0.12, 0.23, 0.42; p<0.001). In contrast, there was no such trend across ERO tertiles within the first JSN tertile (0.18, 0.21, 0.12; p=0.99) and the second tertile (0.25, 0.24, 0.23; p=0.77), and only marginally within the third tertile of JSN (0.29, 0.29, 0.42; p=0.07). Adjusted multivariate regression models supported the significant association of JSN on residual disability. CONCLUSIONS: Cartilage damage appears to be the more clearly associated with irreversible physical disability than bony damage. These data suggest that particular attention should be given to therapeutic interference with cartilage destruction. PMID- 21321003 TI - Do geriatric conditions increase risk of adverse drug reactions in ambulatory elders? Results from the VA GEM Drug Study. AB - BACKGROUND: Many clinicians prescribe cautiously to older adults with common geriatric conditions for fear of causing adverse drug reactions (ADRs). However, little is known about the association between these conditions and risk of ADRs. METHODS: Using data from the VA Geriatric Evaluation and Management Drug Study, we determined any, preventable, and serious ADRs in 808 elders for 12 months after hospital discharge using a validated process involving patient self-report and chart review adjudicated by two health care professionals. Eight common geriatric conditions (activities of daily living, dementia, incontinence, falls, difficulty ambulating, malnourishment, depression, and prolonged bed rest) were evaluated at study baseline through self-report and structured assessments. We used Poisson regression to model the relationship between these geriatric conditions and ADRs. RESULTS: Participants had a mean of 2.9 +/- 1.2 geriatric conditions. Over the 12-month follow-up period, 497 ADRs occurred in 269 participants, including 187 ADRs considered preventable and 127 considered severe. On multivariable analyses, participants with dependency in one or more activities of daily living were less likely to suffer ADRs than those who were fully independent (incidence rate ratio: 0.78, 95% confidence interval = 0.62 1.00). None of the other seven geriatric conditions assessed were associated with ADR risk. Results were similar for preventable and serious ADRs, although participants with a history of falls were more likely to develop serious ADRs (incidence rate ratio: 1.49, 95% confidence interval = 1.00-2.21). CONCLUSIONS: Many geriatric conditions were not associated with risk of ADRs. Although it is prudent to prescribe judiciously in patients with these conditions, excessive caution may not be warranted. PMID- 21321005 TI - Post-transplant nuclear renal scans correlate with renal injury biomarkers and early allograft outcomes. AB - BACKGROUND: Clinical- and histopathology-based scores are limited predictors of allograft outcome. In addition, more objective markers of early transplant function are needed to identify and validate biomarkers and predictive scores. We evaluated existing scores and transcriptome biomarkers of kidney injury as predictors of early transplant function measured by renal scan. METHODS: Clinical, histopathologic and transcriptome data were collected in 143 consecutive kidney transplant recipients. A post-operative renal scan was performed within 48 h. Prediction scores for early outcomes were calculated. RESULTS: Patients were stratified into three groups by renal scan: normal, mild to-moderate or severe dysfunction. Kidneys with severe dysfunction were more often from deceased donors (P < 0.001), had greater HLA antigen mismatches (P < 0.001), were transplanted into older recipients (P = 0.040), had lower urine output during the first 8 h (P < 0.001), higher Day 7 serum creatinine (P < 0.001) and higher incidence of delayed graft function (P < 0.001). Clinical- and pathology-based scores did not discriminate between scan groups. In contrast, the overall transcriptome (P < 0.001) and transcripts of preselected acute kidney injury (AKI) genes were significantly different between the groups, with kidney injury molecule 1 (P = 0.001) and neutrophil gelatinase-associated lipocalin (P = 0.002) being most highly expressed and genes associated with glutathione metabolism (GSTA1, 3 and 4) most down-regulated in kidneys with subsequent severe dysfunction. CONCLUSIONS: Renal scans reflect early transplant function and allow for a more objective assessment of scores predicting early outcome and for identification of biomarkers. The study shows that transcript levels of AKI genes correlate better with renal scans than clinical- or histopathology-based scores. PMID- 21321004 TI - Is standardized cardiac assessment of asymptomatic high-risk renal transplant candidates beneficial? AB - BACKGROUND: Perioperative cardiovascular events in renal transplantation are common and non-invasive cardiac stress tests are recommended in high-risk renal transplant candidates. In 2004, we introduced a standardized preoperative cardiac risk assessment programme with the aim of reducing perioperative cardiac events. METHODS: Since 2004, all asymptomatic high-risk renal transplant candidates had to undergo non-invasive cardiac stress testing. Patients with a positive stress test went for a coronary angiography and if indicated for revascularization. The incidence of perioperative cardiac events (<=30 days of transplantation) was analysed in all high-risk patients who received a transplantation (screening group) and compared with high-risk renal transplant recipients evaluated in the 4 years before the introduction of the cardiac assessment programme (historical control group). RESULTS: Since 2004, 227 of 349 asymptomatic high-risk renal transplant candidates underwent non-invasive cardiac stress testing. In 15 patients (6.6%), significant ischaemia was found. Ten of these 15 patients underwent coronary angiography (eight patients had significant coronary artery disease and in five patients, percutaneous coronary intervention was performed). One hundred and sixty of 349 renal transplant candidates have received renal transplantation so far (screening group). In the screening group, 6 perioperative cardiac events (3.8%) occurred compared to 13 perioperative events (7.6%) in the historical control group (n = 172) (P = 0.136). CONCLUSIONS: The incidence of significant cardiac ischaemia in high-risk renal transplant patients was low and was followed by revascularization in a small percentage of patients. No significant decrease in perioperative cardiac events was observed after the introduction of the standardized cardiac assessment programme. PMID- 21321006 TI - Fetal alcohol spectrum disorders--a case-control study from India. AB - BACKGROUND: Maternal alcohol abuse during pregnancy can lead to fetal neurotoxicity and fetal alcohol spectrum disorder (FASD). AIMS: To compare the clinical features and neurobehavioral profiles of children exposed to alcohol during pregnancy with controls. METHODOLOGY: Children exposed to alcohol in utero (n = 26) and 27-years age- and sex-matched controls were compared on FAS facial features, minor physical anomalies (MPAs), anthropometric measures, behavioral problems and intellectual functioning. RESULTS: MPAs were more common in cases (p = 0.001). Among FAS facial features, only philtrum smoothness varied significantly between the groups (p = 0.001). Behavioral problems (on Childhood Behavior Check List) were more pronounced (p = 0.001) and intellectual functioning significantly poorer in cases (p = 0.001) compared to controls. CONCLUSIONS: Children prenatally exposed to alcohol manifest several neurobehavioral problems compared to controls. Underlying malnutrition may have altered some of the clinical findings. PMID- 21321007 TI - Galactosemia presenting as recurrent sepsis. AB - Galactosemia is a treatable metabolic disorder caused by the deficiency of enzyme galactose-1-phosphate uridyl transferase (GALT) and inherited as an autosomal recessive trait. A case of neonate manifesting with recurrent Escherichia coli sepsis is presented here which turned out to be a classic galactosemia. No other common presenting features were observed in this infant except cataract on slit lamp examination. To the best of our knowledge, there is no case of galactosemia reported in literature which presented with recurrent neonatal sepsis without hepatomegaly, hyperbilirubinemia, bleeding disorder, vomiting, diarrhea, failure to thrive, hypoglycemia, coagulopathy, hemolysis or renal tubular acidosis. PMID- 21321008 TI - What are the most effective intervention techniques for changing physical activity self-efficacy and physical activity behaviour--and are they the same? AB - There is convincing evidence that targeting self-efficacy is an effective means of increasing physical activity. However, evidence concerning which are the most effective techniques for changing self-efficacy and thereby physical activity is lacking. The present review aims to estimate the association between specific intervention techniques used in physical activity interventions and change obtained in both self-efficacy and physical activity behaviour. A systematic search yielded 27 physical activity intervention studies for 'healthy' adults that reported self-efficacy and physical activity data. A small, yet significant (P < 0.01) effect of the interventions was found on change in self-efficacy and physical activity (d = 0.16 and 0.21, respectively). When a technique was associated with a change in effect sizes for self-efficacy, it also tended to be associated with a change (r(s) = 0.690, P < 0.001) in effect size for physical activity. Moderator analyses found that 'action planning', 'provide instruction' and 'reinforcing effort towards behaviour' were associated with significantly higher levels of both self-efficacy and physical activity. 'Relapse prevention' and 'setting graded tasks' were associated with significantly lower self-efficacy and physical activity levels. This meta-analysis provides evidence for which psychological techniques are most effective for changing self-efficacy and physical activity. PMID- 21321009 TI - Adolescents risky MP3-player listening and its psychosocial correlates. AB - Analogue to occupational noise-induced hearing loss, MP3-induced hearing loss may be evolving into a significant social and public health problem. To inform prevention strategies and interventions, this study investigated correlates of adolescents' risky MP3-player listening behavior primarily informed by protection motivation theory. We invited 1687 adolescents (12- to 19-year old) of Dutch secondary schools to complete questionnaires about their MP3-player listening, sociodemographic characteristics and presumed psychosocial determinants of MP3 player listening. Of all participants, 90% reported listening to music through earphones on MP3 players; 28.6% were categorized as listeners at risk for hearing loss due to estimated exposure of 89 dBA for >=1 hour per day. Compared with listeners not at risk for hearing loss, listeners at risk were more likely not to live with both parents, to experience rewards of listening to high-volume levels, to report a high habit strength related to risky MP3 listening, and were less likely to be motivated to protect their hearing. Habit strength was the strongest correlate of risky listening behavior, suggesting that voluntary behavior change among adolescents might be difficult to achieve and that a multiple strategy approach may be needed to prevent MP3-induced hearing loss. PMID- 21321011 TI - Four in 100 deaths worldwide are caused by alcohol, says WHO. PMID- 21321012 TI - Competition in the NHS in England. PMID- 21321013 TI - Spanish government appeals against new law on generics in Galicia that is set to save 93 m euro a year. PMID- 21321014 TI - Ruling prevents women taking second abortion pill at home. PMID- 21321015 TI - Baby P doctor is allowed to remove herself from medical register. PMID- 21321017 TI - Detecting common copy number variants in high-throughput sequencing data by using JointSLM algorithm. AB - The discovery of genomic structural variants (SVs), such as copy number variants (CNVs), is essential to understand genetic variation of human populations and complex diseases. Over recent years, the advent of new high-throughput sequencing (HTS) platforms has opened many opportunities for SVs discovery, and a very promising approach consists in measuring the depth of coverage (DOC) of reads aligned to the human reference genome. At present, few computational methods have been developed for the analysis of DOC data and all of these methods allow to analyse only one sample at time. For these reasons, we developed a novel algorithm (JointSLM) that allows to detect common CNVs among individuals by analysing DOC data from multiple samples simultaneously. We test JointSLM performance on synthetic and real data and we show its unprecedented resolution that enables the detection of recurrent CNV regions as small as 500 bp in size. When we apply JointSLM to analyse chromosome one of eight genomes with different ancestry, we identify 3000 regions with recurrent CNVs of different frequency and size: hierarchical clustering on these regions segregates the eight individuals in two groups that reflect their ancestry, demonstrating the potential utility of JointSLM for population genetics studies. PMID- 21321018 TI - Sequence specificity is obtained from the majority of modular C2H2 zinc-finger arrays. AB - C2H2 zinc fingers (C2H2-ZFs) are the most prevalent type of vertebrate DNA binding domain, and typically appear in tandem arrays (ZFAs), with sequential C2H2-ZFs each contacting three (or more) sequential bases. C2H2-ZFs can be assembled in a modular fashion, providing one explanation for their remarkable evolutionary success. Given a set of modules with defined three-base specificities, modular assembly also presents a way to construct artificial proteins with specific DNA-binding preferences. However, a recent survey of a large number of three-finger ZFAs engineered by modular assembly reported high failure rates (~70%), casting doubt on the generality of modular assembly. Here, we used protein-binding microarrays to analyze 28 ZFAs that failed in the aforementioned study. Most (17) preferred specific sequences, which in all but one case resembled the intended target sequence. Like natural ZFAs, the engineered ZFAs typically yielded degenerate motifs, binding dozens to hundreds of related individual sequences. Thus, the failure of these proteins in previous assays is not due to lack of sequence-specific DNA-binding activity. Our findings underscore the relevance of individual C2H2-ZF sequence specificities within tandem arrays, and support the general ability of modular assembly to produce ZFAs with sequence-specific DNA-binding activity. PMID- 21321019 TI - An unusual tRNAThr derived from tRNAHis reassigns in yeast mitochondria the CUN codons to threonine. AB - The standard genetic code is used by most living organisms, yet deviations have been observed in many genomes, suggesting that the genetic code has been evolving. In certain yeast mitochondria, CUN codons are reassigned from leucine to threonine, which requires an unusual tRNA(Thr) with an enlarged 8-nt anticodon loop ( ). To trace its evolutionary origin we performed a comprehensive phylogenetic analysis which revealed that evolved from yeast mitochondrial tRNA(His). To understand this tRNA identity change, we performed mutational and biochemical experiments. We show that Saccharomyces cerevisiae mitochondrial threonyl-tRNA synthetase (MST1) could attach threonine to both and the regular , but not to the wild-type tRNA(His). A loss of the first nucleotide (G(-1)) in tRNA(His) converts it to a substrate for MST1 with a K(m) value (0.7 MUM) comparable to that of (0.3 MUM), and addition of G(-1) to allows efficient histidylation by histidyl-tRNA synthetase. We also show that MST1 from Candida albicans, a yeast in which CUN codons remain assigned to leucine, could not threonylate , suggesting that MST1 has coevolved with . Our work provides the first clear example of a recent recoding event caused by alloacceptor tRNA gene recruitment. PMID- 21321020 TI - A role for the arginine methylation of Rad9 in checkpoint control and cellular sensitivity to DNA damage. AB - The genome stability is maintained by coordinated action of DNA repairs and checkpoints, which delay progression through the cell cycle in response to DNA damage. Rad9 is conserved from yeast to human and functions in cell cycle checkpoint controls. Here, a regulatory mechanism for Rad9 function is reported. In this study Rad9 has been found to interact with and be methylated by protein arginine methyltransferase 5 (PRMT5). Arginine methylation of Rad9 plays a critical role in S/M and G2/M cell cycle checkpoints. The activation of the Rad9 downstream checkpoint effector Chk1 is impaired in cells only expressing a mutant Rad9 that cannot be methylated. Additionally, Rad9 methylation is also required for cellular resistance to DNA damaging stresses. In summary, we uncovered that arginine methylation is important for regulation of Rad9 function, and thus is a major element for maintaining genome integrity. PMID- 21321021 TI - Depletion of key protein components of the RISC pathway impairs pre-ribosomal RNA processing. AB - Little is known about whether components of the RNA-induced silencing complex (RISC) mediate the biogenesis of RNAs other than miRNA. Here, we show that depletion of key proteins of the RISC pathway by antisense oligonucleotides significantly impairs pre-rRNA processing in human cells. In cells depleted of Drosha or Dicer, different precursors to 5.8S rRNA strongly accumulated, without affecting normal endonucleolytic cleavages. Moderate yet distinct processing defects were also observed in Ago2-depleted cells. Physical links between pre rRNA and these proteins were identified by co-immunoprecipitation analyses. Interestingly, simultaneous depletion of Dicer and Drosha led to a different processing defect, causing slower production of 28S rRNA and its precursor. Both Dicer and Ago2 were detected in the nuclear fraction, and reduction of Dicer altered the structure of the nucleolus, where pre-rRNA processing occurs. Together, these results suggest that Drosha and Dicer are implicated in rRNA biogenesis. PMID- 21321022 TI - The Rat Genome Database curation tool suite: a set of optimized software tools enabling efficient acquisition, organization, and presentation of biological data. AB - The Rat Genome Database (RGD) is the premier repository of rat genomic and genetic data and currently houses over 40,000 rat gene records as well as human and mouse orthologs, 1771 rat and 1911 human quantitative trait loci (QTLs) and 2209 rat strains. Biological information curated for these data objects includes disease associations, phenotypes, pathways, molecular functions, biological processes and cellular components. A suite of tools has been developed to aid curators in acquiring and validating data objects, assigning nomenclature, attaching biological information to objects and making connections among data types. The software used to assign nomenclature, to create and edit objects and to make annotations to the data objects has been specifically designed to make the curation process as fast and efficient as possible. The user interfaces have been adapted to the work routines of the curators, creating a suite of tools that is intuitive and powerful. Database URL: http://rgd.mcw.edu. PMID- 21321023 TI - Alternative rehydration methods: a systematic review and lessons for resource limited care. AB - OBJECTIVE: Dehydration is a significant threat to the health of children worldwide and a major cause of death in resource-scarce settings. Although multiple studies have revealed that oral and intravenous (IV) methods for rehydration in nonsevere dehydration are nearly equally effective, little is known about effectiveness beyond these 2 techniques. With this systematic review we analyzed the effectiveness of nonoral and nonintravenous methods of rehydration. METHODS: The Medline, Cochrane, Global Health, Embase, and CINAHL (Cumulative Index to Nursing and Allied Health Literature) databases were searched for articles on intraosseous (IO), nasogastric (NG), intraperitoneal (IP), subcutaneous (hypodermoclysis), and rectal (proctoclysis) rehydration through December 2009. Only human pediatric studies that included data on the effectiveness or complications of these methods were included. RESULTS: The search identified 38 articles that met the inclusion criteria: 12 articles on NG, 16 on IO, 7 on IP, 3 on subcutaneous, and none on rectal rehydration. NG rehydration was as effective as IV rehydration for moderate-to-severe dehydration. IO rehydration was effective and easy to obtain, although only 1 randomized trial was identified. IP rehydration had some benefit for moderate dehydration, although none of the trials had control groups. Limited data were available on subcutaneous rehydration, and only 1 case series showed benefit. CONCLUSIONS: NG rehydration should be considered second-line therapy, after oral rehydration, particularly in resource-limited environments. IO rehydration seems to be an effective alternative when IV access is not readily obtainable. Additional evidence is needed before IP and subcutaneous rehydration can be endorsed. PMID- 21321024 TI - Late preterm infants have worse 24-month neurodevelopmental outcomes than term infants. AB - BACKGROUND: Late preterm infants (34-37 weeks' gestation) are often perceived at similar risks for morbidity and mortality as term infants. OBJECTIVE: To compare the neurodevelopmental outcomes of late preterm to term infants. METHODS: Our study sample of 6300 term and 1200 late preterm infants came from the Early Childhood Longitudinal Study-Birth Cohort. We used general estimating equations to get weighted odds of having developmental delay, mental index scores (MDI) or psychomotor index scores (PDI) < 70, at 24 months of age. RESULTS: Late preterm infants compared with term infants had lower MDI (85 vs 89) and PDI (88 vs 92), both P < .0001, respectively. A higher proportion of late preterm infants compared with term infants had an MDI <70 (21% vs 16%; P < .0001). An equal number had PDIs <70 (6.1% vs 6.5%). After controlling for statistically significant and clinically relevant descriptive characteristics, late preterm infants still had higher odds of mental (odds ratio: 1.52 [95% confidence interval: 1.26-1.82] P < .0001) or physical (odds ratio: 1.56 [95% confidence interval: 1.30-1.89] P < .0001) developmental delay. CONCLUSIONS: Late preterm infants have poorer neurodevelopmental outcomes than term infants and have increased odds to have a mental and/or physical developmental delay. PMID- 21321025 TI - Microbiology and antibiotic management of orbital cellulitis. AB - OBJECTIVES: Orbital infections caused by methicillin-resistant Staphylococcus aureus may be increasing. Because Staphylococcus aureus infections have important treatment implications, our objective was to review the microbiology and antibiotic management of children hospitalized with orbital cellulitis and abscesses. PATIENTS AND METHODS: This study was a retrospective chart review of all patients admitted to a tertiary care children's hospital between 2004 and 2009 with orbital infections confirmed by a computed tomography scan. Patients with preceding surgery or trauma, anatomic eye abnormalities, malignancy, immunodeficiency, or preseptal infections were excluded. RESULTS: There were 94 children with orbital infections. A true pathogen was recovered in 31% of patients. The most commonly identified bacteria was the Streptococcus anginosus group (14 of 94 patients [15%]). Staphylococcus aureus (1 patient with methicillin-resistant Staphylococcus aureus) was identified in 9% of patients. Combination antimicrobial agents were frequently used (62%), and vancomycin use increased from 14% to 57% during the study period. Patients treated with a single antibiotic during hospitalization (n = 32), in contrast to combination therapy (n = 58), were more likely to be discharged on a single antibiotic (P < .001). Twenty-five (27%) patients were discharged on combination antibiotics. Thirteen (14%) patients were discharged on intravenous therapy. CONCLUSIONS: The Streptococcus anginosus group is an emerging pathogen in pediatric orbital infections. Although methicillin-resistant Staphylococcus aureus was uncommon, patients frequently received vancomycin and combination antibiotics. A simplified antibiotic regimen may help limit the development of resistant organisms and facilitate transition to an oral agent. PMID- 21321026 TI - Increased enoxaparin dosing is required for obese children. AB - Weight-based dosing for enoxaparin is recommended in the 2008 American College of Chest Physicians (ACCP) guidelines for venous thromboembolism (VTE) prophylaxis. Enoxaparin 0.5 mg/kg per dose administered subcutaneously every 12 hours is recommended for this indication in children. There is no established upper dosing limit of enoxaparin for prophylaxis in children, and the US Food and Drug Administration-approved enoxaparin dose for adults for VTE prophylaxis is 30 mg subcutaneously every 12 hours or 40 mg subcutaneously daily. Therefore, we assumed that the upper limit for children is 40 mg subcutaneously daily. We reviewed 3 cases of obese adolescent boys who required large doses of enoxaparin to achieve the ACCP-recommended anti-factor Xa range of 0.1 to 0.3 IU/mL for the prevention of VTE. All 3 patients required doses of enoxaparin that are higher than that recommended for adults for VTE prophylaxis: patient A (BMI: 105.9) required >0.28 mg/kg per dose, patient B (BMI: 95.7) required 0.15 mg/kg per dose, and patient C (BMI: 29.9) required 0.49 mg/kg per dose. The desired anti factor Xa range was achieved when enoxaparin was administered every 12 hours in each patient with no reported episodes of VTE. One patient had minor bruising, but no other adverse events were noted. Because of the variability in dose requirements and unpredictability in patient responses demonstrated in our 3 adolescents, prospective studies are needed to provide definitive recommendations on dosing of enoxaparin for VTE prophylaxis in this subset of obese pediatric patients. PMID- 21321027 TI - Interventions to improve parental communication about sex: a systematic review. AB - CONTEXT: The relative effectiveness of interventions to improve parental communication with adolescents about sex is not known. OBJECTIVE: To compare the effectiveness and methodologic quality of interventions for improving parental communication with adolescents about sex. METHODS: We searched 6 databases: OVID/Medline, PsychInfo, ERIC, Cochrane Review, Communication and Mass Media, and the Cumulative Index to Nursing and Allied Health Literature. We included studies published between 1980 and July 2010 in peer-reviewed English-language journals that targeted US parents of adolescents aged 11 to 18 years, used an experimental or quasi-experimental design, included a control group, and had a pretest/posttest design. We abstracted data on multiple communication outcomes defined by the integrative conceptual model (communication frequency, content, skills, intentions, self-efficacy, perceived environmental barriers/facilitators, perceived social norms, attitudes, outcome expectations, knowledge, and beliefs). Methodologic quality was assessed using the 11-item methodologic quality score. RESULTS: Twelve studies met inclusion criteria. Compared with controls, parents who participated in these interventions experienced improvements in multiple communication domains including the frequency, quality, intentions, comfort, and self-efficacy for communicating. We noted no effects on parental attitudes toward communicating or the outcomes they expected to occur as a result of communicating. Four studies were of high quality, 7 were of medium quality, and 1 was of lower quality. CONCLUSIONS: Our review was limited by the lack of standardized measures for assessing parental communication. Still, interventions for improving parent-adolescent sex communication are well designed and have some targeted effects. Wider dissemination could augment efforts by schools, clinicians, and health educators. PMID- 21321028 TI - Pericarditis as the presenting feature of adrenoleukodystrophy. AB - X-linked adrenoleukodystrophy is characterized by elevated levels of very long chain fatty acids in the serum, brain, and adrenal glands that can lead to neurodevelopmental impairment and decreased adrenal function. We report here the case of a pediatric patient with pericarditis who was found to have adrenoleukodystrophy. More common causes of pericarditis (such as infectious, autoimmune, and metabolic) were excluded. On the basis of the examination finding of cutaneous hyperpigmentation, hypocortisolism was discovered. Further evaluation revealed elevated serum levels of very long chain fatty acids and a partial deletion of the ABCD1 gene, consistent with the diagnosis of X-linked adrenoleukodystrophy. Two of the index patient's brothers were subsequently found to have the same disease. Although pericarditis has been reported previously in association with autoimmune diseases that affect the adrenal glands, this is the first reported case (to our knowledge) of pericarditis in association with hypocortisolism from a nonautoimmune cause. Therefore, we suggest that hypocortisolism itself may lead to pericarditis in some patients. PMID- 21321029 TI - Literacy promotion for families participating in the women, infants and children program. AB - OBJECTIVE: This article describes the impact of a bilingual literacy intervention conducted with nearly 118,000 children in Special Supplemental Nutrition Program for Women, Infants and Children (WIC) sites in Los Angeles County, California. METHODS: All WIC participants at 6 WIC sites in Los Angeles County participated in the literacy intervention. Three cohorts of participants were selected to participate in the evaluation of the intervention. A control group of 200 families received no intervention, 103 families received 2 years of intervention, and 102 families received 4 years of intervention. Participants were predominantly Hispanic (92%), 3- to 4-year-old children and their parents. All families had low income levels, and more than one-half were Spanish-speaking. School readiness assessments were conducted with the children; parent literacy resources and activities at home were observed. Structural equation modeling was used to allow for simultaneous testing of relationships between variables. RESULTS: The Spanish-speaking subset showed a strong intervention effect. Among Spanish speakers, the 4-year intervention group (P < .001) and the 2-year intervention group (P < .05) had significantly higher school readiness scores, compared with the control group. The structural equation model revealed that exposure to the intervention significantly enhanced literacy resources and activities at home, which in turn led to greater school readiness. CONCLUSION: WIC-based literacy intervention significantly increased low-income, Spanish speaking children's school readiness. PMID- 21321030 TI - Outcomes of a universal shared reading intervention by 2 years of age: the Let's Read trial. AB - BACKGROUND: Early shared reading and literacy promotion benefits have stimulated international interest in the development of early-years literacy-promotion programs despite limited evidence of effectiveness at a broader population level. OBJECTIVE: To determine whether a population-based primary care literacy promotion intervention during the first 2 years of life improves early markers of subsequent literacy by 2 years of age. DESIGN AND METHODS: This cluster randomized controlled trial took place in 5 relatively disadvantaged areas in Melbourne, Australia. Infants attending their maternal and child health centers were recruited at age 1-2 months. The intervention (4-8, 12, and 18 months) comprised maternal and child health nurses modelling shared reading activities to parents, supported by parent information and free books. Outcomes (at 2 years) included expressive vocabulary (MacArthur Bates Communicative Development Inventory), communication (Communication and Symbolic Behavior Scales), and home literacy environment (StimQ-Toddler). We analyzed the outcomes using random effects (linear regression) models allowing for clustering. RESULTS: A total of 552 families (87.6%; 324 intervention and 228 control families) of 630 recruited families (66.5% response) were retained to outcome. A total of 97.3% of intervention parents received some (93.7% to all) of the intervention. At 2 years, the trial arms had similar vocabulary (adjusted mean difference: -2.0 [95% confidence interval: -6.2 to 2.2]; P = .36), communication (adjusted mean difference: 0.2 [95% confidence interval: -2.3 to 2.7]; P = .87), and home literacy (adjusted mean difference: -0.4 [95% confidence interval: -1.0 to 0.2]; P = .21). CONCLUSIONS: This universal literacy-promotion program was not beneficial in relatively disadvantaged communities by the age of 2 years and may be ineffective. Alternative interpretations may relate to program intensity, reach and/or sleeper effects. Definitive outcomes at 4 years are awaited. PMID- 21321031 TI - Prediction of neurodevelopmental and sensory outcome at 5 years in Norwegian children born extremely preterm. AB - OBJECTIVE: To examine the prevalence of neurodevelopmental disability and the predictive value of pre-, peri-, and postnatal data on neurologic, sensory, cognitive, and motor function in children born extremely preterm. METHODS: This was a prospective observational study of all infants born in Norway between 1999 and 2000 with gestational ages between 22 and 27 weeks or birth weights between 500 and 999 g. Cognitive function was assessed with the Wechsler Preschool and Primary Scale of Intelligence-Revised, motor function with the Movement Assessment Battery for Children, and severity of cerebral palsy with the Gross Motor Function Classification for Cerebral Palsy. Disabilities were described as mild, moderate, or severe. RESULTS: Of 371 eligible children, 306 (82%) were examined at a mean (SD) age of 5 years and 10 (4) months. For gestational age less than 28 weeks (n = 239), 26 (11%) children had cerebral palsy alone (n = 21) or in combination with blindness (n = 3) or deafness (n = 2); 1 was blind and 1 was deaf. Of the remaining children, the mean full-scale IQ was 94 +/- 15, and significant predictors were (values given as the difference in IQ points [95% confidence intervals]) high maternal education (9.6 [5.7-13.4]), preeclampsia ( 7.7 [-12.7 to -2.7]), and retinopathy of prematurity higher than grade 2 (-17.5 [ 27.1 to -8.0]). Movement Assessment Battery for Children scores were positively associated with gestational age and prenatal steroids and negatively associated with being small for gestational age, male gender, and having retinopathy of prematurity. Moderate to severe neurodevelopmental disability was more common for gestational ages 25 weeks or less (28 of 87 children) than for 26 to 27 weeks (12 of 152 children; P < .001) and 28 weeks or more (7 of 67 children; P = .001). CONCLUSIONS: The outcome was poorer for children with gestational ages of 25 weeks or less compared with those with gestational ages between 26 and 27 weeks. For those without cerebral palsy, blindness, or deafness, however, gestational age had a limited association with cognitive and motor function. PMID- 21321032 TI - Increasing VLBW deliveries at subspecialty perinatal centers via perinatal outreach. AB - OBJECTIVES: To test the hypothesis that the promotion of national guidelines recommending the transfer of high-risk mothers to subspecialty perinatal centers reduces mortality and morbidity through the reduction of preterm infants delivered at nontertiary maternity hospitals. METHODS: After implementation of hospital-based educational and communication programs emphasizing the importance of maternal transfer to subspecialty perinatal centers, we conducted a population based cohort study of all live births delivered at maternity hospitals in greater Cincinnati from 2003 through 2007 (n = 1825). Birth weights measured between 500 and 1499 g and gestational ages were less than 32 weeks. Risk-adjusted outcomes were measured by multivariate logistic regression in 2 stages. We compared these findings with those from a similar study conducted at our institution that included infants with birth weights less than 1500 g born between September 1, 1995, and December 31, 1997 (n = 848). The primary outcome was the percentage decrease in infants born with very low birth weights at nontertiary centers compared with our previous study. RESULTS: The number of infants born with birth weights less than 1500 g and at less than 32 weeks' gestation delivered at hospitals without tertiary perinatal and neonatal care decreased from 25% to 11.8% between the 2 study periods. The odds of death or major morbidity for infants born with very low birth weights at nontertiary perinatal centers is 3 times that of infants born at subspecialty perinatal centers after controlling for demographic variations (odds ratio: 3.05 [95% confidence interval: 2.1-4.4]). CONCLUSIONS: Local promotion of national guidelines by neonatologists coincided with a significant reduction in the percentage of infants born with birth weights less than 1500 g and at less than 32 weeks' gestation who were not delivered at subspecialty perinatal centers, and, at 88.2%, this nearly achieves the Healthy People 2010 objective to deliver 90% of infants born with very low birth weights in subspecialty perinatal centers. PMID- 21321033 TI - Kingella kingae: an emerging pathogen in young children. AB - Kingella kingae is being recognized increasingly as a common etiology of pediatric osteoarticular infections, bacteremia, and endocarditis, which reflects improved culture methods and use of nucleic acid-amplification techniques in clinical microbiology laboratories. K kingae colonizes the posterior pharynx of young children and is transmitted from child to child through close personal contact. Day care attendance increases the risk for colonization and transmission, and clusters of K kingae infections among day care center attendees have been reported. Key virulence factors in K kingae include type IV pili and a potent RTX toxin. In previously healthy children, >95% of K kingae infections are diagnosed between the ages of 6 and 48 months. Among children with underlying medical conditions, K kingae disease may occur at older ages as well. The clinical presentation of K kingae disease is often subtle and may be associated with normal levels of acute-phase reactants, which underscores the importance of a high index of suspicion. K kingae is usually susceptible to beta-lactam antibiotics, and infections typically respond well to medical treatment, with the exception of cases of endocarditis. PMID- 21321034 TI - A new risk-based screening criterion for treatment-demanding retinopathy of prematurity in Denmark. AB - OBJECTIVE: The aim of this study was to uncover the most effective and safe criterion to implement for retinopathy of prematurity screening in Denmark. METHODS: This retrospective national cohort study is based on data from 3 national registers. These registers provided on infants treated for retinopathy of prematurity, infants in need of treatment but missed by the present screening program, and the candidate neonates for advanced retinopathy of prematurity development A nonlinear logistic regression model was fitted to the data, and various screening criteria were evaluated. RESULTS: During the study period (2002 2006), 116 infants were treated for retinopathy of prematurity, no treatment demanding retinopathy of prematurity infants were missed by the screening program, and 182 premature infants were candidates for developing treatment demanding retinopathy of prematurity. Screening criteria combining gestational age at delivery and birth weight limits and new risk-based criteria were compared with regards to their effectiveness. The risk-based criteria were the most effective. Use of the 0.13% risk-based criterion to define the population to be screened resulted in the detection of all treated infants in the study period and 17.4% fewer infants to screen. The model predicted this criterion to result in 1 missed case of treatment-demanding retinopathy of prematurity every 11 years and 1 case of blindness every 18 years in Denmark. CONCLUSIONS: Screening criteria based on risk estimates of developing treatment-demanding retinopathy of prematurity are the most effective for retinopathy-of-prematurity screening. The risk-based criterion of 0.13% can safely be implemented for future retinopathy-of prematurity screening in Denmark. PMID- 21321035 TI - Health effects of energy drinks on children, adolescents, and young adults. AB - OBJECTIVE: To review the effects, adverse consequences, and extent of energy drink consumption among children, adolescents, and young adults. METHODS: We searched PubMed and Google using "energy drink," "sports drink," "guarana," "caffeine," "taurine," "ADHD," "diabetes," "children," "adolescents," "insulin," "eating disorders," and "poison control center" to identify articles related to energy drinks. Manufacturer Web sites were reviewed for product information. RESULTS: According to self-report surveys, energy drinks are consumed by 30% to 50% of adolescents and young adults. Frequently containing high and unregulated amounts of caffeine, these drinks have been reported in association with serious adverse effects, especially in children, adolescents, and young adults with seizures, diabetes, cardiac abnormalities, or mood and behavioral disorders or those who take certain medications. Of the 5448 US caffeine overdoses reported in 2007, 46% occurred in those younger than 19 years. Several countries and states have debated or restricted energy drink sales and advertising. CONCLUSIONS: Energy drinks have no therapeutic benefit, and many ingredients are understudied and not regulated. The known and unknown pharmacology of agents included in such drinks, combined with reports of toxicity, raises concern for potentially serious adverse effects in association with energy drink use. In the short-term, pediatricians need to be aware of the possible effects of energy drinks in vulnerable populations and screen for consumption to educate families. Long-term research should aim to understand the effects in at-risk populations. Toxicity surveillance should be improved, and regulations of energy drink sales and consumption should be based on appropriate research. PMID- 21321037 TI - Preliteracy intervention: lessons to be learned from seemingly discrepant results. PMID- 21321036 TI - A clinical prediction model to stratify retinopathy of prematurity risk using postnatal weight gain. AB - OBJECTIVE: To develop an efficient clinical prediction model that includes postnatal weight gain to identify infants at risk of developing severe retinopathy of prematurity (ROP). Under current birth weight (BW) and gestational age (GA) screening criteria, <5% of infants examined in countries with advanced neonatal care require treatment. PATIENTS AND METHODS: This study was a secondary analysis of prospective data from the Premature Infants in Need of Transfusion Study, which enrolled 451 infants with a BW < 1000 g at 10 centers. There were 367 infants who remained after excluding deaths (82) and missing weights (2). Multivariate logistic regression was used to predict severe ROP (stage 3 or treatment). RESULTS: Median BW was 800 g (445-995). There were 67 (18.3%) infants who had severe ROP. The model included GA, BW, and daily weight gain rate. Run weekly, an alarm that indicated need for eye examinations occurred when the predicted probability of severe ROP was >0.085. This identified 66 of 67 severe ROP infants (sensitivity of 99% [95% confidence interval: 94%-100%]), and all 33 infants requiring treatment. Median alarm-to-outcome time was 10.8 weeks (range: 1.9-17.6). There were 110 (30%) infants who had no alarm. Nomograms were developed to determine risk of severe ROP by BW, GA, and postnatal weight gain. CONCLUSION: In a high-risk cohort, a BW-GA-weight-gain model could have reduced the need for examinations by 30%, while still identifying all infants requiring laser surgery. Additional studies are required to determine whether including larger-BW, lower-risk infants would reduce examinations further and to validate the prediction model and nomograms before clinical use. PMID- 21321038 TI - Ambulatory visit rates and antibiotic prescribing for children with pneumonia, 1994-2007. AB - BACKGROUND: The incidence of pediatric hospitalizations for community-acquired pneumonia (CAP) has declined after the widespread use of the heptavalent pneumococcal conjugate vaccine. The national incidence of outpatient visits for CAP, however, is not well established. Although no pediatric CAP treatment guidelines are available, current data support narrow-spectrum antibiotics as the first-line treatment for most patients with CAP. OBJECTIVE: To estimate the incidence rates of outpatient CAP, examine time trends in antibiotics prescribed for CAP, and determine factors associated with broad-spectrum antibiotic prescribing for CAP. PATIENTS AND METHODS: The National Ambulatory and National Hospital Ambulatory Medical Care Surveys (1994-2007) were used to identify children aged 1 to 18 years with CAP using a validated algorithm. We determined age group-specific rates of outpatient CAP and examined trends in antibiotic prescribing for CAP. Data from 2006-2007 were used to study factors associated with broad-spectrum antibiotic prescribing. RESULTS: Overall, annual CAP visit rates ranged from 16.9 to 22.4 per 1000 population, with the highest rates occurring in children aged 1 to 5 years (range: 32.3-49.6 per 1000). Ambulatory CAP visit rates did not change between 1994 and 2007. Antibiotics commonly prescribed for CAP included macrolides (34% of patients overall), cephalosporins (22% overall), and penicillins (14% overall). Cephalosporin use increased significantly between 2000 and 2007 (P = .002). Increasing age, a visit to a nonemergency department office, and obtaining a radiograph or complete blood count were associated with broad-spectrum antibiotic prescribing. CONCLUSIONS: The incidence of pediatric ambulatory CAP visits has not changed significantly between 1994 and 2007, despite the introduction of heptavalent pneumococcal conjugate vaccine in 2000. Broad-spectrum antibiotics, particularly macrolides, were frequently prescribed despite evidence that they provide little benefit over penicillins. PMID- 21321040 TI - Effects of open-air temperature on air temperature inside biological safety cabinet. AB - OBJECTIVE: In Japan, biological safety cabinets (BSCs) are normally used by medical staff while handling antineoplastic agents. We have also set up a class II B2 BSC at the Division of Chemotherapy for Outpatients. The air temperature inside this BSC, however, decreases in winter. We assumed that this decrease is caused by the intake of open-air. Therefore, we investigated the effects of low open-air temperature on the BSC temperature and the time of admixtures of antineoplastic agents. METHODS: The studies were conducted from January 1 to March 31, 2008. The outdoor air temperature was measured in the shade near the intake nozzle of the BSC and was compared with the BSC temperature. The correlation between the outdoor air temperature and the BSC temperature, the dissolution time of cyclophosphamide (CPA) and gemcitabine (GEM), and accurate weight measurement of epirubicin (EPI) solution were investigated for low and normal BSC temperatures. RESULT: The BSC temperature was correlated with the open air temperature for open-air temperatures of 5-20 degrees C (p < 0.0001). The dissolution of CPA and GEM at these temperatures was significantly delayed as compared to that at 25 degrees C (p < 0.01 and p < 0.0001, respectively). The weight measurement of EPI solution using a syringe method lacks accuracy because of its high coefficient of viscosity at low temperatures (p < 0.01). CONCLUSION: These results suggest that the BSC temperature decreases below room temperature in winter when air is drawn from outdoors. We showed that the BSC temperature affects the dissolution rate of antineoplastic agents. Further, we suggested that the BSC temperature drop might delay the affair of the admixtures of antineoplastic agents and increase the waiting time of outpatients for chemotherapy. PMID- 21321039 TI - Newborns with sonographically dysplastic and potentially unstable hips: 6-year follow-up of an RCT. AB - OBJECTIVE: To examine the long-term outcome of early abduction splinting versus active sonographic surveillance in newborns with mildly dysplastic hips. PATIENTS AND METHODS: Between 1997 and 2003, 128 newborns with mildly dysplastic and potentially unstable hips on ultrasound (43 degrees <= alpha-angle < 50 degrees ) were randomly assigned to immediate abduction treatment or sonographic surveillance. All were invited for a radiographic follow-up at 6 years. The radiographs were analyzed by a single radiologist masked to the randomization allocation, and markers of hip dysplasia (acetabular index, center-edge angle of Wiberg) and avascular necrosis were reported. RESULTS: Eighty-three participants (65%) agreed to participate in the follow-up (42 participants from the treatment group). The mean acetabular index was 14.7 degrees (SD: 5.6 degrees ) for the treatment group and 13.9 degrees (SD: 3.9 degrees ) for the control group (mean difference: -0.8 degrees [95% confidence interval: -2.9 degrees to 1.3 degrees ]). Values were within normal ranges for age for all participants except for 1 female subject from the treatment group. The mean center edge was 26.6 degrees for those treated and 26.4 degrees for the active surveillance group (mean difference: -0.3 degrees [95% confidence interval: -2.5 degrees to 2.0 degrees ]). None had markers suggestive of avascular necrosis. CONCLUSIONS: We found no difference in radiographic outcome at 6 years of age between children allocated to initial splintage for 6 weeks and those offered active sonographic surveillance. The delayed acetabular ossification or persistent dysplasia seen in a third of infants from both groups at 1 year of age had completely resolved in all but 1 of the female subjects from the treatment group. PMID- 21321041 TI - Ventricular fibrillation as a likely consequence of capecitabine-induced coronary vasospasm. AB - Capecitabine is a member of the fluoropyrimidine family of chemotherapeutic agents that selectively delivers 5-fluorouracil (5-FU) to tumors. It is increasingly used as part of combined modality treatment for gastrointestinal malignancies. Cardiotoxicity has been documented to occur with 5-FU, but due to an expansion in capecitabine use, reports exist of its propensity to coronary vasospasm. We report the case of a 28-year-old man, with no preceding angina, presenting with a reversible episode of ventricular fibrillation (VF) at rest in his fifth course of capecitabine chemotherapy for metastatic colorectal cancer. Emergency resuscitation successfully restored spontaneous circulation, with initial ST segment elevation in the inferolateral leads on electrocardiogram prompting emergency coronary angiography. This demonstrated normal coronary arteries. ST segments normalized post-angiography and the patient rapidly recovered with no myocardial damage sustained. An implantable cardioverter defibrillator was placed for secondary prevention of sudden death, and capecitabine was implicated as the cause of coronary vasospasm which resulted in his presentation of VF. To our knowledge, this is the first episode of VF as a consequence of suspected capecitabine-induced coronary vasospasm occurring at rest. Our case highlights the potential for severe cardiotoxic consequences of capecitabine including sudden death from VF, and given the multi-disciplinary approach to managing oncology patients, health professionals should be aware of this. PMID- 21321042 TI - How many working days would be missed due to moderate or severe influenza pandemic in China? AB - BACKGROUND: Under the current situation of influenza pandemic outbreak, it is urgent to estimate the potential work days lost in China. METHOD: We used a Monte Carlo simulation model based on the analysis framework of the FluWorkLoss 1.0 software to estimate the number of work days lost. RESULTS: Work days lost caused by caring for family members were more than that caused by one's own illness. The care of a child caused more work days missed than the care of an elderly. CONCLUSIONS: During a mild to moderate pandemic, outpatients and children need more attention. During a severe pandemic, inpatients and working adults will be the focus. PMID- 21321043 TI - Residents' perspectives on safety support needs in different types of housing areas. AB - BACKGROUND: Knowledge about conditions that are understood to support safety is important for planning residential safety promotion in interactions with residents. How residents themselves perceive and reason about their own safety needs has seldom been investigated in Scandinavia. AIM: To identify factors perceived to be necessary to feel safe by residents in areas with blocks of flats and detached houses. METHODS: Residents in a Swedish municipality were asked an open-ended question on the research topic by a mail survey; 787 residents provided narrative data that were fed into a summative qualitative and quantitative content analysis. RESULTS: A stable social structure in the housing area was perceived to be the central factor in a safety-supportive residential environment. Whereas maintenance of good and reassuring relations was emphasised in detached housing areas, support for management of poor or even fear-provoking neighbour relations was requested from areas with blocks of flats. This finding emphasises the need to reduce the differential exposure to safety-related factors in the living environment. CONCLUSIONS: The results of our study encourage the continued use of a setting-orientated safety promotion approach in which residents and other stakeholders are involved. The policy recommendation that can be drawn from the study is that both the subjective and objective dimensions of safety should be identified and considered when developing local safety promotion interventions in community contexts. PMID- 21321044 TI - Confidentiality and parental involvement in adolescent sexual and reproductive health care: a cross-sectional study of Lithuanian general practitioners. AB - AIM: We surveyed Lithuanian general practitioners' (GPs) views on the importance of confidentiality for adolescents and on their practices in informing parents about sexual and reproductive health consultations with this age group. METHODS: In this cross-sectional study, a 41-item questionnaire was sent to a random sample of 607 Lithuanian GPs. The purpose of this questionnaire was to gain knowledge about current practices of GPs in informing parents on the importance of confidentiality as well as in protecting the privacy of minors. GPs' knowledge of the current legal age limit of confidentiality protection in patient-provider settings was also assessed. RESULTS: Although 67.5% of the responding GPs (response rate 73.5%) stated that they inform the parents or guardians of adolescent patients about the importance of confidentiality, 82.9% of them only did so if the opportunity arose. When consulting on general sexual issues, more than 70% stated that they would guarantee their minor patients confidentiality. However, when cases involved sexually transmitted infections or pregnancy, nearly the same percentage said they would inform the parents. 62.3% of GPs incorrectly believed that the law only protects the right to confidentiality for patients who are 18 or older. CONCLUSIONS: Our findings indicate that Lithuanian GPs frequently violate adolescents' right to confidential health services. The study highlights the need for a comprehensive strategy to strengthen the confidentiality of sexual and reproductive health services for this group in Lithuanian primary care. PMID- 21321045 TI - Is temporary employment related to health status? Analysis of the Northern Swedish Cohort. AB - AIMS: The aim of this study was to investigate whether temporary employment was related to non-optimal self-rated health and psychological distress at age 42 after adjustment for the same indicators at age 30, and to analyze the effects of job insecurity, low cash margin and high job strain on this relationship. METHODS: A subcohort of the Northern Swedish Cohort that was employed at the 2007 follow-up survey (n = 907, response rate of 94%) was analyzed using data from 1995 and 2007 questionnaires. RESULTS: Temporary employees had a higher risk of both non-optimal self-rated health and psychological distress. After adjustment for non-optimal self-rated health at age 30 and psychological distress at age 30 as well as for sociodemographic variables, the odds ratios decreased but remained significant. However, after adjustment for job insecurity, high job strain and low cash margin the odds ratio dropped for non-optimal self-rated health but remained significant for psychological distress. CONCLUSIONS: Temporary employment may have adverse effects on self-rated health and psychological health after adjustment for previous health status and sociodemographic variables. Our findings indicate that low cash margin and job insecurity may partially mediate the association between temporary employment and health status. PMID- 21321046 TI - Do lifestyle factors and general health predict dropout among recently qualified eldercare workers? A two-year follow-up study. AB - BACKGROUND: The eldercare sector in Denmark as in many industrialised countries is characterised by difficulties in retaining labour. Research suggests a possible imbalance between lifestyle and health among eldercare trainees and the demanding work encountered as eldercare employees. The aim of the present study was to determine the predictive effect of lifestyle and self-rated health on dropout from the Danish eldercare sector two years after qualification. METHODS: We included 4,526 female eldercare trainees in the analyses of lifestyle parameters and 5,023 in the analyses of self-rated health. The participants in this prospective study were recruited from 27 of the 28 Danish colleges for eldercare. We linked survey data with national register data to obtain information about labour market attachment two years after qualification. RESULTS: The results of the present study showed that the poorer self-rated health, the higher the risk for dropout from the labour market (p < 0.0001). However, the results were less consistent regarding the predictive effect of a detrimental lifestyle. We found that overweight/obesity (p = 0.0021 and p = 0.0012) as well as smoking (p = 0.0017) decreased the risk of dropout from eldercare into education. We found no support for increased likelihood of dropout among physically inactive. CONCLUSIONS: The results of the present study show that a poorer self-rated health is a predictor for dropout, not only from the eldercare two years after qualification, but from the labour market as a whole. However, the results were less consistent regarding the predictive effect of a detrimental lifestyle on dropout. PMID- 21321047 TI - Primary care visits to occupational health physicians and nurses in Finland. AB - AIMS: In Finland, 91% of employer-arranged occupational health services (OHS) include primary care for employees. Occupational health (OH) physicians and OH nurses carry the main responsibility for primary care in OHS. This study analyses work- and health-related factors associated with primary care visits to OH physicians and OH nurses. METHODS: This population-based cross-sectional survey encompassed 1636 randomly selected working employees aged 25-64 covered by OHS which included primary care. The associations between factors and visits during the previous 6 months were tested by Poisson regression analysis. RESULTS: The proportion of employees who visited OH physicians or OH nurses was 57%. Men visited OH nurses more often than women, but the number of visits to OH physicians was similar. Long-standing illnesses impairing work ability, work related symptoms, and type of OHS provision were associated with visits to both OH physicians and nurses. Moderate psychological stress was associated with visits to OH physicians. Among men, the requirement of obtaining a sick-leave certificate on the first day of absence was associated with visits. Less possibilities to influence one's work was associated with visits to OH nurses, and among women also to OH physicians. Poor support from supervisors and co workers had non-significant or inverse associations. CONCLUSIONS: The wide use of OHS and both the type and similarities between factors associated with visits may signify that both OH physicians and OH nurses are likely to encounter work related health problems through primary care in OHS. PMID- 21321048 TI - An outbreak of gastroenteritis among schoolchildren staying in a wildlife reserve: thorough investigation reveals Norway's largest cryptosporidiosis outbreak. AB - AIMS: In March and April 2009, the Norwegian Institute of Public Health was notified about two groups of schoolchildren with gastroenteritis following a stay at a Norwegian wildlife reserve. Although at first considered a typical norovirus outbreak, an investigation that considered other possibilities was initiated. METHODS: A retrospective cohort study was conducted among schoolchildren visiting the reserve in the relevant weeks. A web-based questionnaire was distributed by email. Faecal samples of visitors and employees were analysed. The premises were inspected, and water samples and animal faeces analysed. RESULTS: We received 141 replies (response rate 84%); 74 cases were identified. Cryptosporidium oocysts were detected in faecal samples from 9/12 (75%) visitors and 2/15 (13%) employees. One employee diagnosed with Cryptosporidium infection helped in the kitchen. Additionally, one pupil was diagnosed with norovirus infection. No food item was identified as a source of the outbreak. Pathogens were not detected in water samples taken in week 12, one week from the start of the outbreak. Escherichia coli, but not Cryptosporidium oocysts, were detected in water samples taken one month later. CONCLUSIONS: Although Cryptosporidium is seldom considered as an aetiological agent of gastrointestinal illness in Norway, this outbreak indicates that it should not be excluded. In this cryptosporidiosis outbreak, the largest in Norway to date, the transmission vehicle was not definitively identified, but a food handler, water, and animal contact could not be excluded. We recommend improving hand hygiene routines, boiling drinking water, and emphasise that people who are unwell, particularly those working in catering, should stay away from work. PMID- 21321049 TI - Decidual HtrA3 negatively regulates trophoblast invasion during human placentation. AB - BACKGROUND Controlled trophoblast invasion into the maternal decidua (interstitial invasion) is important for placental development. Factors secreted by the maternal decidual cells and the extravillous trophoblast can influence trophoblast invasion and abnormalities in the invasion process may lead to pregnancy complications. Serine protease HtrA3 is highly expressed in the decidual cells in the late secretory phase of the menstrual cycle and throughout pregnancy, and in most trophoblast cell types, apart from the invading interstitial trophoblast during the first trimester. HtrA3 and its family members are down-regulated in a number of cancers and are proposed as tumour suppressors. The current study aimed to investigate whether HtrA3 is secreted by decidual cells, and whether inhibiting such secretion alters trophoblast invasion. METHODS AND RESULTS Human endometrial stromal cells (HESCs) were decidualized with estradiol, medroxyprogesterone acetate and cyclic adenosine monophosphate. Real time RT-PCR, western blotting and immunocytochemistry confirmed that HtrA3 mRNA and protein expression increased during decidualization. HtrA3 was also detected in the conditioned media (CM) of the decidualized HESCs, confirming its secretion. For functional studies, a protease-inactive mutant form of HtrA3 which was previously confirmed to be a dominant-negative inhibitor was produced using wheat germ cell-free technology. CM from decidualized HESCs significantly suppressed invasion of trophoblast HTR-8 cells (P < 0.01), whereas inhibition of HtrA3 in this CM by exogenous HtrA3 mutant resulted in increased trophoblast HTR 8 cell invasion (P < 0.001). CONCLUSIONS These results strongly support the hypothesis that decidual HtrA3 negatively regulates trophoblast invasion. PMID- 21321050 TI - Evolution of cytokinin biosynthesis and degradation. AB - Cytokinin hormones are important regulators of development and environmental responses of plants that execute their action via the molecular machinery of signal perception and transduction. The limiting step of the whole process is the availability of the hormone in suitable concentrations in the right place and at the right time to interact with the specific receptor. Hence, the hormone concentrations in individual tissues, cells, and organelles must be properly maintained by biosynthetic and metabolic enzymes. Although there are merely two active cytokinins, isopentenyladenine and its hydroxylated derivative zeatin, a variety of conjugates they may form and the number of enzymes/isozymes with varying substrate specificity involved in their biosynthesis and conversion gives the plant a variety of tools for fine tuning of the hormone level. Recent genome wide studies revealed the existence of the respective coding genes and gene families in plants and in some bacteria. This review summarizes present knowledge on the enzymes that synthesize cytokinins, form cytokinin conjugates, and carry out irreversible elimination of the hormones, including their phylogenetic analysis and possible variations in different organisms. PMID- 21321052 TI - The role of proteins in C(3) plants prior to their recruitment into the C(4) pathway. AB - Our most productive crops and native vegetation use a modified version of photosynthesis known as the C(4) pathway. Leaves of C(4) crops have increased nitrogen and water use efficiencies compared with C(3) species. Although the modifications to leaves of C(4) plants are complex, their faster growth led to the proposal that C(4) photosynthesis should be installed in C(3) crops in order to increase yield potential. Typically, a limited set of proteins become restricted to mesophyll or bundle sheath cells, and this allows CO(2) to be concentrated around the primary carboxylase RuBisCO. The role that these proteins play in C(3) species prior to their recruitment into the C(4) pathway is addressed here. Understanding the role of these proteins in C(3) plants is likely to be of use in predicting how the metabolism of a C(3) leaf will alter as components of the C(4) pathway are introduced as part of efforts to install characteristics of C(4) photosynthesis in leaves of C(3) crops. PMID- 21321051 TI - Characterization of JAZ-interacting bHLH transcription factors that regulate jasmonate responses in Arabidopsis. AB - The plant hormone jasmonate (JA) plays important roles in the regulation of plant defence and development. JASMONATE ZIM-DOMAIN (JAZ) proteins inhibit transcription factors that regulate early JA-responsive genes, and JA-induced degradation of JAZ proteins thus allows expression of these response genes. To date, MYC2 is the only transcription factor known to interact directly with JAZ proteins and regulate early JA responses, but the phenotype of myc2 mutants suggests that other transcription factors also activate JA responses. To identify JAZ1-interacting proteins, a yeast two-hybrid screen of an Arabidopsis cDNA library was performed. Two basic helix-loop-helix (bHLH) proteins, MYC3 and MYC4, were identified. MYC3 and MYC4 share high sequence similarity with MYC2, suggesting they may have similar biological functions. MYC3 and MYC4 interact not only with JAZ1 but also with other JAZ proteins (JAZ3 and JAZ9) in both yeast two hybrid and pull-down assays. MYC2, MYC3, and MYC4 were all capable of inducing expression of JAZ::GUS reporter constructs following transfection of carrot protoplasts. Although myc3 and myc4 loss-of-function mutants showed no phenotype, transgenic plants overexpressing MYC3 and MYC4 had higher levels of anthocyanin compared to the wild-type plants. In addition, roots of MYC3 overexpression plants were hypersensitive to JA. Quantitative real-time RT-PCR expression analysis of nine JA-responsive genes revealed that eight of them were induced in MYC3 and MYC4 overexpression plants, except for a pathogen-responsive gene, PDF1.2. Similar to MYC2, MYC4 negatively regulates expression of PDF1.2. Together, these results suggest that MYC3 and MYC4 are JAZ-interacting transcription factors that regulate JA responses. PMID- 21321053 TI - The genetics and structure of the O-specific polysaccharide of Yersinia pseudotuberculosis serotype O:10 and its relationship with Escherichia coli O111 and Salmonella enterica O35. AB - The O-specific polysaccharide (OPS) is a variable constituent of the lipopolysaccharide of Gram-negative bacteria. The polymorphic nature of OPSs within a species is usually first defined serologically, and the current serotyping scheme for Yersinia pseudotuberculosis consists of 21 O serotypes of which 15 have been characterized genetically and structurally. Here, we present the structure and DNA sequence of Y. pseudotuberculosis O:10 OPS. The O unit consists of one residue each of d-galactopyranose, N-acetyl-d-galactosamine (2 amino-2-deoxy-d-galactopyranose) and d-glucopyranose in the backbone, with two colitose (3,6-dideoxy-l-xylo-hexopyranose) side-branch residues. This structure is very similar to that shared by Escherichia coli O111 and Salmonella enterica O35. The gene cluster sequences of these serotypes, however, have only low levels of similarity to that of Y. pseudotuberculosis O:10, although there is significant conservation of gene order. Within Y. pseudotuberculosis, the O10 structure is most closely related to the O:6 and O:7 structures. PMID- 21321054 TI - Structural characterization and MHCII-dependent immunological properties of the zwitterionic O-chain antigen of Morganella morganii. AB - Morganella morganii is a commensal Gram-negative bacterium that has long been known to produce an antigen bearing phosphocholine groups. We determined the structure of this O-chain antigen and found that its repeating unit also contains a free amino group and a second phosphate: This alternating charge character places the M. morganii O-chain polysaccharide into a small family of zwitterionic polysaccharides (ZPSs) known to induce T-cell-dependent immune responses via presentation by class II major histocompatibility complex (MHCII) molecules. In vitro binding assays demonstrate that this O-chain interacts with MHCII in a manner that competes with binding of the prototypical ZPS antigen PSA from Bacteroides fragilis, despite its lack of a helical structure. Cellular studies also showed that the M. morganii polysaccharide induces activation of CD4(+) T cells. Antibody binding experiments using acid hydrolyzed fragments representing the monomer and higher oligomers of the repeating unit showed that the phosphocholine group was the dominant element of the epitope with an overall affinity (K(D)) of about 5 * 10(-5) M, a typical value for an IgM anti carbohydrate antibody but much lower than the affinity for phosphocholine itself. These data show that the structure of the M. morganii polysaccharide contains a unique zwitterionic repeating unit which allows for immune recognition by T cells, making it the first identified T-cell-dependent O-chain antigen. PMID- 21321055 TI - Cerebellar ataxia: pathophysiology and rehabilitation. AB - This series of articles for rehabilitation in practice aims to cover a knowledge element of the rehabilitation medicine curriculum. Nevertheless they are intended to be of interest to a multidisciplinary audience. The competency addressed in this article is 'The trainee consistently demonstrates a knowledge of management approaches for specific impairments including spasticity, ataxia.' PMID- 21321056 TI - Survey of wheelchair skills tests: making the case for broadening the search and assessment criteria. PMID- 21321057 TI - K(ATP) channel-dependent metaboproteome decoded: systems approaches to heart failure prediction, diagnosis, and therapy. AB - Systems biology provides an integrative platform by which to account for the biological complexity related to cardiac health and disease. In this way, consequences of ATP-sensitive K(+) (K(ATP)) channel deficiency for heart failure prediction, diagnosis, and therapy were resolved recently at a proteomic level. Under stress-free conditions, knockout of the Kir6.2 K(ATP) channel pore induced metabolic proteome remodelling, revealing overrepresentation of markers of cardiovascular disease. Imposed stress precipitated structural and functional defects in Kir6.2-knockout hearts, decreasing survival and validating prediction of disease susceptibility. In the setting of hypertension, a leading risk for heart failure development, proteomic analysis diagnosed the metabolism-centric impact of K(ATP) channel deficiency in disease. Bioinformatic interrogation of K(ATP) channel-dependent proteome prioritized heart-specific adverse effects, exposing cardiomyopathic traits of aggravated contractility, fibrosis, and ventricular hypertrophy. In dilated cardiomyopathy induced by Kir6.2-knockout pressure overload, proteomic remodelling was exacerbated, underlying a multifaceted molecular pathology that indicates the necessity for a broad-based strategy to achieve repair. Embryonic stem cell intervention in cardiomyopathic K(ATP) channel knockout hearts elicited a distinct proteome signature that forecast amelioration of adverse cardiac outcomes. Functional/structural measurements validated improved contractile performance, reduced ventricular size, and decreased cardiac damage in the treated cohort, while systems assessment unmasked cardiovascular development as a prioritized biological function in stem cell-reconstructed hearts. Thus, proteomic deconvolution of K(ATP) channel-deficient hearts provides definitive evidence for the channel's homeostatic contribution to the cardiac metaboproteome and establishes the utility of systems-oriented approaches to predict disease susceptibility, diagnose consequences of heart failure progression, and monitor therapy outcome. PMID- 21321058 TI - Smooth muscle cells in pathogenesis of vascular medial cartilaginous metaplasia. PMID- 21321059 TI - Pharmacokinetic interaction of the antiparasitic agents ivermectin and spinosad in dogs. AB - Neurological side effects consistent with ivermectin toxicity have been observed in dogs when high doses of the common heartworm prevention agent ivermectin are coadministered with spinosad, an oral flea prevention agent. Based on numerous reports implicating the role of the ATP-binding cassette drug transporter P glycoprotein (P-gp) in ivermectin efflux in dogs, an in vivo study was conducted to determine whether ivermectin toxicity results from a pharmacokinetic interaction with spinosad. Beagle dogs were randomized to three groups treated orally in parallel: Treatment group 1 (T01) received ivermectin (60 MUg/kg), treatment group 2 (T02) received spinosad (30 mg/kg), and treatment group 3 (T03) received both ivermectin and spinosad. Whereas spinosad pharmacokinetics were unchanged in the presence of ivermectin, ivermectin plasma pharmacokinetics revealed a statistically significant increase in the area under the curve (3.6 fold over the control) when ivermectin was coadministered with spinosad. The majority of the interaction is proposed to result from inhibition of intestinal and/or hepatic P-gp-mediated secretory pathways of ivermectin. Furthermore, in vitro Transwell experiments with a human multidrug resistance 1-transfected Madin Darby canine kidney II cell line showed polarized efflux at concentrations <= 2 MUM, indicating that spinosad is a high-affinity substrate of P-gp. In addition, spinosad was a strong inhibitor of the P-gp transport of digoxin, calcein acetoxymethyl ester (IC(50) = 3.2 MUM), and ivermectin (IC(50) = 2.3 MUM). The findings suggest that spinosad, acting as a P-gp inhibitor, increases the risk of ivermectin neurotoxicity by inhibiting secretion of ivermectin to increase systemic drug levels and by inhibiting P-gp at the blood-brain barrier. PMID- 21321060 TI - CYP2C9-mediated metabolic activation of losartan detected by a highly sensitive cell-based screening assay. AB - Drug-induced hepatotoxicity is a major problem in drug development, and reactive metabolites generated by cytochrome P450s are suggested to be one of the causes. CYP2C9 is one of the major enzymes in hepatic drug metabolism. In the present study, we developed a highly sensitive cell-based screening system for CYP2C9 mediated metabolic activation using an adenovirus vector expressing CYP2C9 (AdCYP2C9). Human hepatocarcinoma HepG2 cells infected with our constructed AdCYP2C9 for 2 days at multiplicity of infection 10 showed significantly higher diclofenac 4'-hydroxylase activity than human hepatocytes. AdCYP2C9-infected cells were treated with several hepatotoxic drugs, resulting in a significant increase in cytotoxicity by treatment with losartan, benzbromarone, and tienilic acid. Metabolic activation of losartan by CYP2C9 has never been reported, although the metabolic activations of benzbromarone and tienilic acid have been reported. To identify the reactive metabolites of losartan, the semicarbazide adducts of losartan were investigated by liquid chromatography-tandem mass spectrometry. Two CYP2C9-specific semicarbazide adducts of losartan (S1 and S2) were detected. S2 adduct formation suggested that a reactive metabolite was produced from the aldehyde metabolite E3179, but a possible metabolite from S1 adduct formation was not produced via E3179. In conclusion, a highly sensitive cell-based assay to evaluate CYP2C9-mediated metabolic activation was established, and we found for the first time that CYP2C9 is involved in the metabolic activation of losartan. This cell-based assay system would be useful for evaluating drug-induced cytotoxicity caused by human CYP2C9. PMID- 21321061 TI - Quantitative analysis reveals multiple mechanisms of allosteric modulation of the mGlu5 receptor in rat astroglia. AB - Positive and negative allosteric modulators (PAMs and NAMs, respectively) of the type 5 metabotropic glutamate (mGlu5) receptor have demonstrable therapeutic potential in an array of neurological and psychiatric disorders. Here, we have used rat cortical astrocytes to investigate how PAMs and NAMs mediate their activity and reveal marked differences between PAMs with respect to their modulation of orthosteric agonist affinity and efficacy. Affinity cooperativity factors (alpha) were assessed using [(3)H]2-methyl-6-(phenylethynyl)-pyridine (MPEP)-PAM competition binding in the absence and presence of orthosteric agonist, whereas efficacy cooperativity factors (beta) were calculated from net affinity/efficacy cooperativity parameters (alphabeta) obtained from analyses of the abilities of PAMs to potentiate [(3)H]inositol phosphate accumulation in astrocytes stimulated with a submaximal (EC(20)) concentration of orthosteric agonist. We report that whereas 3,3'-difluorobenzaldazine (DFB) and 3-cyano-N (1,3-diphenyl-1H-prazol-5-yl)benzamide (CDPPB) primarily exert their allosteric modulatory effects through modifying the apparent orthosteric agonist affinity at the astrocyte mGlu5 receptor, the effects of S-(4-fluoro-phenyl)-{3-[3-(4-fluoro phenyl)-[1,2,4]oxadiazol-5-yl]-piperidinl-1-yl}-methanone (ADX47273) are mediated primarily via efficacy-driven modulation. In [(3)H]MPEP-NAM competition binding assays, both MPEP and 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine (M-5MPEP) defined similar specific binding components, with affinities that were unaltered in the presence of orthosteric agonist, indicating wholly negative efficacy driven modulations. It is noteworthy that whereas M-5MPEP only partially inhibited orthosteric agonist-stimulated [(3)H]inositol phosphate accumulation in astrocytes, it could completely suppress Ca(2+) oscillations stimulated by quisqualate or (S)-3,5-dihydroxyphenylglycine. In contrast, MPEP was fully inhibitory with respect to both functional responses. The finding that M-5MPEP has different functional effects depending on the endpoint measured is discussed as a possible example of permissive allosteric antagonism. PMID- 21321062 TI - Altered folate availability modifies the molecular environment of the human colorectum: implications for colorectal carcinogenesis. AB - Low folate status increases colorectal cancer risk. Paradoxically, overly abundant folate supplementation, which is not uncommon in the United States, may increase risk. The mechanisms of these effects are unknown. We conducted two translational studies to define molecular pathways in the human colon altered either by folate supplementation or by dietary folate depletion (followed by repletion). In the first study, 10 healthy, at-risk volunteers (with documented stable/normal folate intake) received supplemental folic acid (1 mg/d) for 8 weeks. In the second study, 10 similar subjects were admitted to a hospital as inpatients for 12 weeks to study folate depletion induced by a low folate diet. A repletion regimen of folic acid (1 mg/d) was provided for the last 4 of these weeks. Both studies included an 8-week run-in period to ensure stabilized folate levels prior to intervention. We obtained 12 rectosigmoid biopsies (from 4 quadrants of normal-appearing mucosa 10-15 cm from the anal verge) at baseline and at measured intervals in both studies for assessing the primary endpoints: genome-wide gene expression, genomic DNA methylation, promoter methylation (depletion/repletion study only), and p53 DNA strand breaks. Serum and rectosigmoid folate concentrations accurately tracked all changes in folate delivery (P < 0.05). In the first study, gene array analysis revealed that supplementation upregulated multiple inflammation- and immune-related pathways in addition to altering several 1-carbon-related enzymes (P < 0.001). In the second study, folate depletion downregulated genes involved in immune response, inflammation, the cell cycle, and mitochondrial/energy pathways; repletion reversed most of these changes. However, changes in gene expression after repletion in the second study (involving immune response and inflammation) did not reach the levels seen after supplementation in the first study. Neither genomic nor promoter-specific DNA methylation changed during the course of the depletion/repletion protocol, and genomic methylation did not change with supplementation in the first study. p53 DNA strand breaks increased with depletion after 12 weeks. In sum, depletion downregulates, whereas repletion or supplementation upregulates pathways related to inflammation and immune response. These findings provide novel support to the concept that excessive folate supplementation might promote colorectal carcinogenesis by enhancing proinflammatory and immune response pathways. These results indicate that modest changes in folate delivery create substantial changes in the molecular milieu of the human colon. PMID- 21321063 TI - Adverse childhood experiences and risk of physical violence in adolescent dating relationships. AB - BACKGROUND: This study evaluates associations of commonly co-occurring childhood adversities with physical violence in dating relationships to identify potential strategies for refining and targeting dating violence prevention programmes. METHODS: Data on 5130 adult respondents to a nationally representative survey with at least one dating relationship before the age of 21 years were analysed. Logistic regression models assessed associations between 12 childhood adversities and physical dating violence (PDV). RESULTS: Adjusting for the number of co occurring adversities, 10 of the 12 childhood adversities were significantly associated with PDV perpetration or victimisation (OR 1.5-2.8). The population attributable risk proportion of PDV due to all 12 childhood adversities was 53.4%. Childhood adversities with the highest attributable risk proportions were sexual abuse (13.8%), interparental violence (11.6%) and parent mental illness (10.7%). Multivariate prediction equations ranked respondents by their childhood adversity risk profiles; 46.4% of PDV cases occurred in the top two risk deciles. CONCLUSIONS: Assessment of a broad range of childhood exposures to familial adversities may help to identify adolescents at particularly high risk of PDV and to guide prevention efforts. PMID- 21321064 TI - Geographical variation in cancer survival in England, 1991-2006: an analysis by Cancer Network. AB - BACKGROUND: Reducing geographical inequalities in cancer survival in England was a key aim of the Calman-Hine Report (1995) and the NHS Cancer Plan (2000). This study assesses whether geographical inequalities changed following these policy developments by analysing the trend in 1-year relative survival in the 28 cancer networks of England. METHODS: Population-based age-standardised relative survival at 1 year is estimated for 1.4 million patients diagnosed with cancer of the oesophagus, stomach, colon, lung, breast (women) or cervix in England during 1991 2006 and followed up to 2007. Regional and deprivation-specific life tables are built to adjust survival estimates for differences in background mortality. Analysis is divided into three calendar periods: 1991-5, 1996-2000 and 2001-6. Funnel plots are used to assess geographical variation in survival over time. RESULTS: One-year relative survival improved for all cancers except cervical cancer. There was a wide geographical variation in survival with generally lower estimates in northern England. This north-south divide became less marked over time, although the overall number of cancer networks that were lower outliers compared with the England value remained stable. Breast cancer was the only cancer for which there was a marked reduction in geographical inequality in survival over time. CONCLUSION: Policy changes over the past two decades coincided with improved relative survival, without an increase in geographical variation. The north-south divide in relative survival became less pronounced over time but geographical inequalities persist. The reduction in geographical inequality in breast cancer survival may be followed by a similar trend for other cancers, provided government recommendations are implemented similarly. PMID- 21321065 TI - Body mass index and mortality in elderly men and women: the Tromso and HUNT studies. AB - BACKGROUND: The impact of body mass index (BMI; kg/m(2)) and waist circumference (WC) on mortality in elderly individuals is controversial and previous research has largely focused on obesity. METHODS: With special attention to the lower BMI categories, associations between BMI and both total and cause-specific mortality were explored in 7604 men and 9107 women aged >= 65 years who participated in the Tromso Study (1994-1995) or the North-Trondelag Health Study (1995-1997). A Cox proportional hazards model adjusted for age, marital status, education and smoking was used to estimate HRs for mortality in different BMI categories using the BMI range of 25-27.5 as a reference. The impact of each 2.5 kg/m(2) difference in BMI on mortality in individuals with BMI < 25.0 and BMI >= 25.0 was also explored. Furthermore, the relations between WC and mortality were assessed. RESULTS: We identified 7474 deaths during a mean follow-up of 9.3 years. The lowest mortality was found in the BMI range 25-29.9 and 25-32.4 in men and women, respectively. Mortality was increased in all BMI categories below 25 and was moderately increased in obese individuals. U-shaped relationships were also found between WC and total mortality. About 40% of the excess mortality in the lower BMI range in men was explained by mortality from respiratory diseases. CONCLUSIONS: BMI below 25 in elderly men and women was associated with increased mortality. A modest increase in mortality was found with increasing BMI among obese men and women. Overweight individuals (BMI 25-29.9) had the lowest mortality. PMID- 21321067 TI - Viscoelasticity of human oral mucosa: implications for masticatory biomechanics. AB - The dynamic behavior of oral soft tissues supporting removable prostheses is not well understood. We hypothesized that the stress and strain of the mucosa exhibited time-dependent behavior under masticatory loadings. Displacement of the mucosa on the maxillary residual ridge was measured in vivo by means of a magnetic actuator/sensor under vertical loading in partially edentulous individuals. Subject-specific finite element models of homogeneous bone and mucosa were constructed based on computed tomography images. A mean initial elastic modulus of 8.0 * 10(-5) GPa and relaxation time of 494 sec were obtained from the curve adaptation of the finite element output to the in vivo time displacement relationship. Delayed increase of the maximum compressive strain on the surface of the mucosa was observed under sustained load, while the maximum strain inside the mucosa was relatively low and uninfluenced by the duration of the load. The compressive stress showed a slight decrease with sustained load, due to stress relaxation of the mucosa. On simulation of cyclic load, the increment of the maximum strain and the evidence of residual strain were revealed after each loading. The results support our hypothesis, and suggest that sustained and repetitive loads accumulate as surface strain on the mucosa. PMID- 21321066 TI - Targeting the replication checkpoint using SCH 900776, a potent and functionally selective CHK1 inhibitor identified via high content screening. AB - Checkpoint kinase 1 (CHK1) is an essential serine/threonine kinase that responds to DNA damage and stalled DNA replication. CHK1 is essential for maintenance of replication fork viability during exposure to DNA antimetabolites. In human tumor cell lines, ablation of CHK1 function during antimetabolite exposure led to accumulation of double-strand DNA breaks and cell death. Here, we extend these observations and confirm ablation of CHK2 does not contribute to these phenotypes and may diminish them. Furthermore, concomitant suppression of cyclin-dependent kinase (CDK) activity is sufficient to completely antagonize the desired CHK1 ablation phenotypes. These mechanism-based observations prompted the development of a high-content, cell-based screen for gamma-H2AX induction, a surrogate marker for double-strand DNA breaks. This mechanism-based functional approach was used to optimize small molecule inhibitors of CHK1. Specifically, the assay was used to mechanistically define the optimal in-cell profile with compounds exhibiting varying degrees of CHK1, CHK2, and CDK selectivity. Using this approach, SCH 900776 was identified as a highly potent and functionally optimal CHK1 inhibitor with minimal intrinsic antagonistic properties. SCH 900776 exposure phenocopies short interfering RNA-mediated CHK1 ablation and interacts synergistically with DNA antimetabolite agents in vitro and in vivo to selectively induce dsDNA breaks and cell death in tumor cell backgrounds. PMID- 21321068 TI - Novel endothelial biomarkers: implications for periodontal disease and CVD. AB - Endothelial cells are actively involved in various aspects of vascular biology and different stages of atherosclerosis. Endothelial function is increasingly used as an important outcome measure in cardiovascular research. Endothelial progenitor cells (EPCs) are closely linked to endothelial function, and their biomarkers have received much attention. EPCs may not only serve as a pool of progenitor cells and possess the capacity to repair the damaged vasculature, but also act as potent effectors in systemic inflammation, suggesting that EPCs may play a critical role in maintaining endothelial function and the progression of cardiovascular disease (CVD). Emerging evidence shows an association of periodontal infections (gingivitis and periodontitis) with endothelial dysfunction, while the relevant mechanisms remain unknown. Our recent finding of the association of periodontitis with EPCs warrants their utilization as additional biomarkers in future studies on periodontal medicine. This review starts with a brief account on the current understanding of the nature of periodontal infections and their link with systemic inflammation and endothelial dysfunction. The paper also provides an update on endothelial biology and function as well as the novel biomarkers of EPCs and concludes with clinical studies on periodontal diseases and CVD. PMID- 21321069 TI - N-terminal transmembrane domain of SUR1 controls gating of Kir6.2 by modulating channel sensitivity to PIP2. AB - Functional integrity of pancreatic adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channels depends on the interactions between the pore-forming potassium channel subunit Kir6.2 and the regulatory subunit sulfonylurea receptor 1 (SUR1). Previous studies have shown that the N-terminal transmembrane domain of SUR1 (TMD0) interacts with Kir6.2 and is sufficient to confer high intrinsic open probability (P(o)) and bursting patterns of activity observed in full-length K(ATP) channels. However, the nature of TMD0-Kir6.2 interactions that underlie gating modulation is not well understood. Using two previously described disease causing mutations in TMD0 (R74W and E128K), we performed amino acid substitutions to study the structural roles of these residues in K(ATP) channel function in the context of full-length SUR1 as well as TMD0. Our results revealed that although R74W and E128K in full-length SUR1 both decrease surface channel expression and reduce channel sensitivity to ATP inhibition, they arrive there via distinct mechanisms. Mutation of R74 uniformly reduced TMD0 protein levels, suggesting that R74 is necessary for stability of TMD0. In contrast, E128 mutations retained TMD0 protein levels but reduced functional coupling between TMD0 and Kir6.2 in mini-K(ATP) channels formed by TMD0 and Kir6.2. Importantly, E128K full-length channels, despite having a greatly reduced P(o), exhibit little response to phosphatidylinositol 4,5-bisphosphate (PIP(2)) stimulation. This is reminiscent of Kir6.2 channel behavior in the absence of SUR1 and suggests that TMD0 controls Kir6.2 gating by modulating Kir6.2 interactions with PIP(2). Further supporting this notion, the E128W mutation in full-length channels resulted in channel inactivation that was prevented or reversed by exogenous PIP(2). These results identify a critical determinant in TMD0 that controls Kir6.2 gating by controlling channel sensitivity to PIP(2). Moreover, they uncover a novel mechanism of K(ATP) channel inactivation involving aberrant functional coupling between SUR1 and Kir6.2. PMID- 21321071 TI - Immunoregulatory cytokines are associated with protection from immunopathology following Mycobacterium avium subspecies paratuberculosis infection in red deer. AB - Although the causative agent of Johne's disease, Mycobacterium avium subsp. paratuberculosis, is well known, the etiology of disease and the immune responses generated in response to infection are still poorly understood. Knowledge of definitive markers of protective immunity, infection, and the establishment of chronic granulomatous Johne's disease is necessary to advance vaccine and diagnostic development. We sought to profile the immune responses occurring within jejunal lymph nodes of experimentally challenged red deer (Cervus elaphus). Quantitative PCR was utilized to measure a range of cytokines, signaling molecules, and transcription factors involved in Th1, Th2, Treg, and Th17 immune responses. Significant differences in gene expression were observed between control, minimally diseased, and severely diseased animals, with severely diseased animals showing elevated proinflammatory transcripts and reduced anti inflammatory transcripts. We identified a proinflammatory cytokine milieu of gamma interferon, interleukin-1alpha (IL-1alpha), and IL-17, which may contribute to the immunopathology observed during clinical Johne's disease and suggest that Th2 and Treg immune responses may play an important role in controlling the development of immunopathology in infected animals. PMID- 21321070 TI - Voltage- and temperature-dependent activation of TRPV3 channels is potentiated by receptor-mediated PI(4,5)P2 hydrolysis. AB - TRPV3 is a thermosensitive channel that is robustly expressed in skin keratinocytes and activated by innocuous thermal heating, membrane depolarization, and chemical agonists such as 2-aminoethyoxy diphenylborinate, carvacrol, and camphor. TRPV3 modulates sensory thermotransduction, hair growth, and susceptibility to dermatitis in rodents, but the molecular mechanisms responsible for controlling TRPV3 channel activity in keratinocytes remain elusive. We show here that receptor-mediated breakdown of the membrane lipid phosphatidylinositol (4,5) bisphosphate (PI(4,5)P(2)) regulates the activity of both native TRPV3 channels in primary human skin keratinocytes and expressed TRPV3 in a HEK-293-derived cell line stably expressing muscarinic M(1)-type acetylcholine receptors. Stimulation of PI(4,5)P(2) hydrolysis or pharmacological inhibition of PI 4 kinase to block PI(4,5)P(2) synthesis potentiates TRPV3 currents by causing a negative shift in the voltage dependence of channel opening, increasing the proportion of voltage-independent current and causing thermal activation to occur at cooler temperatures. The activity of single TRPV3 channels in excised patches is potentiated by PI(4,5)P(2) depletion and selectively decreased by PI(4,5)P(2) compared with related phosphatidylinositol phosphates. Neutralizing mutations of basic residues in the TRP domain abrogate the effect of PI(4,5)P(2) on channel function, suggesting that PI(4,5)P(2) directly interacts with a specific protein motif to reduce TRPV3 channel open probability. PI(4,5)P(2)-dependent modulation of TRPV3 activity represents an attractive mechanism for acute regulation of keratinocyte signaling cascades that control cell proliferation and the release of autocrine and paracrine factors. PMID- 21321072 TI - Protein kinase LegK2 is a type IV secretion system effector involved in endoplasmic reticulum recruitment and intracellular replication of Legionella pneumophila. AB - Legionella pneumophila is the etiological agent of Legionnaires' disease. Crucial to the pathogenesis of this intracellular pathogen is its ability to subvert host cell defenses, permitting intracellular replication in specialized vacuoles within host cells. The Dot/Icm type IV secretion system (T4SS), which translocates a large number of bacterial effectors into host cell, is absolutely required for rerouting the Legionella phagosome. Many Legionella effectors display distinctive eukaryotic domains, among which are protein kinase domains. In silico analysis and in vitro phosphorylation assays identified five functional protein kinases, LegK1 to LegK5, encoded by the epidemic L. pneumophila Lens strain. Except for LegK5, the Legionella protein kinases are all T4SS effectors. LegK2 plays a key role in bacterial virulence, as demonstrated by gene inactivation. The legK2 mutant containing vacuoles displays less-efficient recruitment of endoplasmic reticulum markers, which results in delayed intracellular replication. Considering that a kinase-dead substitution mutant of legK2 exhibits the same virulence defects, we highlight here a new molecular mechanism, namely, protein phosphorylation, developed by L. pneumophila to establish a replicative niche and evade host cell defenses. PMID- 21321073 TI - Induction of experimental endocarditis by continuous low-grade bacteremia mimicking spontaneous bacteremia in humans. AB - Transient high-grade bacteremia following invasive procedures carries a risk of infective endocarditis (IE). This is supported by experimental endocarditis. On the other hand, case-control studies showed that IE could be caused by cumulative exposure to low-grade bacteremia occurring during daily activities. However, no experimental demonstration of this latter possibility exists. This study investigated the infectivity in animals of continuous low-grade bacteremia compared to that of brief high-grade bacteremia. Rats with aortic vegetations were inoculated with Streptococcus intermedius, Streptococcus gordonii or Staphylococcus aureus (strains Newman and P8). Animals were challenged with 10(3) to 10(6) CFU. Identical bacterial numbers were given by bolus (1 ml in 1 min) or continuous infusion (0.0017 ml/min over 10 h). Bacteremia was 50 to 1,000 times greater after bolus than during continuous inoculation. Streptococcal bolus inoculation of 10(5) CFU infected 63 to 100% vegetations compared to 30 to 71% infection after continuous infusion (P > 0.05). When increasing the inoculum to 10(6) CFU, bolus inoculation infected 100% vegetations and continuous infusion 70 to 100% (P > 0.05). S. aureus bolus injection of 10(3) CFU infected 46 to 57% valves. This was similar to the 53 to 57% infection rates produced by continuous infusion (P > 0.05). Inoculation of 10(4) CFU of S. aureus infected 80 to 100% vegetations after bolus and 60 to 75% after continuous infusion (P > 0.05). These results show that high-level bacteremia is not required to induce experimental endocarditis and support the hypothesis that cumulative exposure to low-grade bacteremia represents a genuine risk of IE in humans. PMID- 21321074 TI - Analysis of murine genetic predisposition to pneumococcal infection reveals a critical role of alveolar macrophages in maintaining the sterility of the lower respiratory tract. AB - The study of pathogenic mechanisms of disease can be greatly facilitated by studying genetic differences in susceptibility to infection. In the present study, we compared the severity of pneumococcal infection in C57BL/6 (B6) and 129Sv mice. The results showed that 129Sv mice were remarkably more susceptible to pneumococcal infection than B6 mice. Bacterial clearance, proinflammatory mediators, leukocyte recruitment, and phagocyte activities were measured to examine potential immune factors associated with differences in susceptibility to pneumococcal infection. The greater susceptibility of 129Sv mice was associated only with inadequate alveolar macrophage bacterial killing, as indicated by significantly decreased initial bacterial clearance from the respiratory tract. Effective pneumococcal clearance was not dependent upon Toll-like receptor 2 (TLR2) expression, oxidative stress, or matrix metallopeptidase 12 (MMP-12) expression. Furthermore, phagocytosis analysis suggested that the deficiency found in 129Sv alveolar macrophages was not due to a lack of bacterial recognition but, rather, to reduced bacterial uptake. In conclusion, our findings indicate a crucial role of alveolar macrophage phagocytosis during innate defense against pneumococcal infection, which may explain the association of host genetic risk factors with predisposition to pneumococcal infection. PMID- 21321075 TI - Impact of salmonella infection on host hormone metabolism revealed by metabolomics. AB - The interplay between pathogens and their hosts has been studied for decades using targeted approaches, such as the analysis of mutants and host immunological responses. Although much has been learned from such studies, they focus on individual pathways and fail to reveal the global effects of infection on the host. To alleviate this issue, high-throughput methods, such as transcriptomics and proteomics, have been used to study host-pathogen interactions. Recently, metabolomics was established as a new method to study changes in the biochemical composition of host tissues. We report a metabolomic study of Salmonella enterica serovar Typhimurium infection. Our results revealed that dozens of host metabolic pathways are affected by Salmonella in a murine infection model. In particular, multiple host hormone pathways are disrupted. Our results identify unappreciated effects of infection on host metabolism and shed light on mechanisms used by Salmonella to cause disease and by the host to counter infection. PMID- 21321076 TI - Reductionistic and holistic science. AB - A reductionistic approach to science, epitomized by molecular biology, is often contrasted with the holistic approach of systems biology. However, molecular biology and systems biology are actually interdependent and complementary ways in which to study and make sense of complex phenomena. PMID- 21321077 TI - Antibiotic treatment alters the colonic mucus layer and predisposes the host to exacerbated Citrobacter rodentium-induced colitis. AB - Antibiotics are often used in the clinic to treat bacterial infections, but the effects of these drugs on microbiota composition and on intestinal immunity are poorly understood. Citrobacter rodentium was used as a model enteric pathogen to investigate the effect of microbial perturbation on intestinal barriers and susceptibility to colitis. Streptomycin and metronidazole were used to induce alterations in the composition of the microbiota prior to infection with C. rodentium. Metronidazole pretreatment increased susceptibility to C. rodentium induced colitis over that of untreated and streptomycin-pretreated mice, 6 days postinfection. Both antibiotic treatments altered microbial composition, without affecting total numbers, but metronidazole treatment resulted in a more dramatic change, including a reduced population of Porphyromonadaceae and increased numbers of lactobacilli. Disruption of the microbiota with metronidazole, but not streptomycin treatment, resulted in an increased inflammatory tone of the intestine characterized by increased bacterial stimulation of the epithelium, altered goblet cell function, and thinning of the inner mucus layer, suggesting a weakened mucosal barrier. This reduction in mucus thickness correlates with increased attachment of C. rodentium to the intestinal epithelium, contributing to the exacerbated severity of C. rodentium-induced colitis in metronidazole pretreated mice. These results suggest that antibiotic perturbation of the microbiota can disrupt intestinal homeostasis and the integrity of intestinal defenses, which protect against invading pathogens and intestinal inflammation. PMID- 21321078 TI - Role for miR-204 in human pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is characterized by enhanced proliferation and reduced apoptosis of pulmonary artery smooth muscle cells (PASMCs). Because microRNAs have been recently implicated in the regulation of cell proliferation and apoptosis, we hypothesized that these regulatory molecules might be implicated in the etiology of PAH. In this study, we show that miR-204 expression in PASMCs is down-regulated in both human and rodent PAH. miR-204 down-regulation correlates with PAH severity and accounts for the proliferative and antiapoptotic phenotypes of PAH-PASMCs. STAT3 activation suppresses miR-204 expression, and miR 204 directly targets SHP2 expression, thereby SHP2 up-regulation, by miR-204 down regulation, activates the Src kinase and nuclear factor of activated T cells (NFAT). STAT3 also directly induces NFATc2 expression. NFAT and SHP2 were needed to sustain PAH-PASMC proliferation and resistance to apoptosis. Finally, delivery of synthetic miR-204 to the lungs of animals with PAH significantly reduced disease severity. This study uncovers a new regulatory pathway involving miR-204 that is critical to the etiology of PAH and indicates that reestablishing miR-204 expression should be explored as a potential new therapy for this disease. PMID- 21321079 TI - Not4 E3 ligase contributes to proteasome assembly and functional integrity in part through Ecm29. AB - In this study we determine that the Not4 E3 ligase is important for proteasome integrity. Consequently, deletion of Not4 leads to an accumulation of polyubiquitinated proteins and reduced levels of free ubiquitin. In the absence of Not4, the proteasome regulatory particle (RP) and core particle (CP) form salt resistant complexes, and all other forms of RPs are unstable. Not4 can associate with RP species present in purified proteasome holoenzyme but not with purified RP. Additionally, Not4 interacts with Ecm29, a protein that stabilizes the proteasome. Interestingly, Ecm29 is identified in RP species that are inactive and not detectable in cells lacking Not4. In the absence of Not4, Ecm29 interacts less well with the proteasome and becomes ubiquitinated and degraded. Our results characterize Ecm29 as a proteasome chaperone whose appropriate interaction with the proteasome requires Not4. PMID- 21321080 TI - Epigenetic regulation of transcription and virulence in Trypanosoma cruzi by O linked thymine glucosylation of DNA. AB - Unlike other eukaryotes, the protein-coding genes of Trypanosoma cruzi are arranged in large polycistronic gene clusters transcribed by polymerase II (Pol II). Thus, it is thought that trypanosomes rely solely on posttranscriptional processes to regulate gene expression. Here, we show that the glucosylated thymine DNA base (beta-d-glucosyl-hydroxymethyluracil or base J) is present within sequences flanking the polycistronic units (PTUs) in T. cruzi. The loss of base J at sites of transcription initiation, via deletion of the two enzymes that regulate base J synthesis (JBP1 and JBP2), correlates with an increased rate of Pol II transcription and subsequent genome-wide increase in gene expression. The affected genes include virulence genes, and the resulting parasites are defective in host cell invasion and egress. These studies indicate that base J is an epigenetic factor regulating Pol II transcription initiation in kinetoplastids and provides the first biological role of the only hypermodified DNA base in eukaryotes. PMID- 21321081 TI - Polymerase epsilon is required to maintain replicative senescence. AB - Replicative senescence is a permanent cell cycle arrest in response to extensive telomere shortening. To understand the mechanisms behind a permanent arrest, we screened for factors affecting replicative senescence in budding yeast lacking telomere elongation pathways. Intriguingly, we found that DNA polymerase epsilon (Pol epsilon) acts synergistically with Exo1 nuclease to maintain replicative senescence. In contrast, the Pol epsilon-associated checkpoint and replication protein Mrc1 facilitates escape from senescence. To understand this paradox, in which DNA-synthesizing factors cooperate with DNA-degrading factors to maintain arrest, whereas a checkpoint protein opposes arrest, we analyzed the dynamics of double- and single-stranded DNA (ssDNA) at chromosome ends during senescence. We found evidence for cycles of DNA resection, followed by resynthesis. We propose that resection of the shortest telomere, activating a Rad24(Rad17)-dependent checkpoint pathway, alternates in time with an Mrc1-regulated Pol epsilon resynthesis of a short, double-stranded chromosome end, which in turn activates a Rad9(53BP1)-dependent checkpoint pathway. Therefore, instead of one type of DNA damage, different types (ssDNA and a double-strand break-like structure) alternate in a "vicious circle," each activating a different checkpoint sensor. Every time resection and resynthesis switches, a fresh signal initiates, thus preventing checkpoint adaptation and ensuring the permanent character of senescence. PMID- 21321082 TI - Chromosome-wide analysis of parental allele-specific chromatin and DNA methylation. AB - To reveal the extent of domain-wide epigenetic features at imprinted gene clusters, we performed a high-resolution allele-specific chromatin analysis of over 100 megabases along the maternally or paternally duplicated distal chromosome 7 (Chr7) and Chr15 in mouse embryo fibroblasts (MEFs). We found that reciprocal allele-specific features are limited to imprinted genes and their differentially methylated regions (DMRs), whereas broad local enrichment of H3K27me3 (BLOC) is a domain-wide feature at imprinted clusters. We uncovered novel allele-specific features of BLOCs. A maternally biased BLOC was found along the H19-Igf2 domain. A paternal allele-specific gap was found along Kcnq1ot1, interrupting a biallelic BLOC in the Kcnq1-Cdkn1c domain. We report novel allele specific chromatin marks at the Peg13 and Slc38a4 DMRs, Cdkn1c upstream region, and Inpp5f_v2 DMR and paternal allele-specific CTCF binding at the Peg13 DMR. Additionally, we derived an imprinted gene predictor algorithm based on our allele-specific chromatin mapping data. The binary predictor H3K9ac and CTCF or H3K4me3 in one allele and H3K9me3 in the reciprocal allele, using a sliding window approach, recognized with precision the parental allele specificity of known imprinted genes, H19, Igf2, Igf2as, Cdkn1c, Kcnq1ot1, and Inpp5f_v2 on Chr7 and Peg13 and Slc38a4 on Chr15. Chromatin features, therefore, can unequivocally identify genes with imprinted expression. PMID- 21321083 TI - SUV420H2-mediated H4K20 trimethylation enforces RNA polymerase II promoter proximal pausing by blocking hMOF-dependent H4K16 acetylation. AB - Many human genes exhibit evidence of initiated RNA polymerase II (Pol II) at their promoters, despite a lack of significant full-length transcript. Such genes exhibit promoter-proximal "pausing," wherein initiated Pol II accumulates just downstream of the transcription start site due to a rate-limiting step mediating the transition to elongation. The mechanisms that regulate the escape of Pol II from pausing and the relationship to chromatin structure remain incompletely understood. Recently, we showed that CpG island hypermethylation and epigenetic silencing of TMS1/ASC in human breast cancers are accompanied by a local shift from histone H4 lysine 16 acetylation (H4K16Ac) to H4 lysine 20 trimethylation (H4K20me3). Here, we show that hMOF-mediated H4K16Ac and SUV420H2-mediated H4K20me3 play opposing roles in the regulation of Pol II pausing. We found that H4K16Ac promoted the release of Pol II from pausing through the recruitment of BRD4 and pTEFb. Aberrant methylation of CpG island DNA blocked Pol II recruitment to gene promoters. Whereas the inhibition of DNA methylation allowed for the reassociation and initiation of Pol II at the TMS1 promoter, Pol II remained paused in the presence of H4K20me3. Combined inhibition of H4K20me3 and DNA methylation resulted in the rerecruitment of hMOF and subsequent H4K16Ac, release of Pol II into active elongation, and synergistic reactivation of TMS1 expression. Marking by H4K20me3 was not restricted to TMS1 but also occurred at other genes independently of DNA methylation, where it similarly imposed a block to Pol II promoter escape through a mechanism that involved the local inhibition of H4K16Ac. These data indicate that H4K20me3 invokes gene repression by antagonizing hMOF-mediated H4K16Ac and suggest that overcoming Pol II pausing might be a rate-limiting step in achieving tumor suppressor gene reactivation in cancer therapy. PMID- 21321084 TI - Rheb is essential for murine development. AB - Ras homolog enriched in brain (Rheb) couples growth factor signaling to activation of the target of rapamycin complex 1 (TORC1). To study its role in mammals, we generated a Rheb knockout mouse. In contrast to mTOR or regulatory associated protein of mTOR (Raptor) mutants, the inner cell mass of Rheb(-/-) embryos differentiated normally. Nevertheless, Rheb(-/-) embryos died around midgestation, most likely due to impaired development of the cardiovascular system. Rheb(-/-) embryonic fibroblasts showed decreased TORC1 activity, were smaller, and showed impaired proliferation. Rheb heterozygosity extended the life span of tuberous sclerosis complex 1-deficient (Tsc1(-/-)) embryos, indicating that there is a genetic interaction between the Tsc1 and Rheb genes in mouse. PMID- 21321085 TI - Regulation of mTORC1 complex assembly and signaling by GRp58/ERp57. AB - The mammalian target of rapamycin (mTOR) regulates cell growth and survival via two different multiprotein complexes, mTORC1 and mTORC2. The assembly of these serine-threonine kinase multiprotein complexes occurs via poorly understood molecular mechanisms. Here, we demonstrate that GRp58/ERp57 regulates the existence and activity of mTORC1. Endogenous mTOR interacts with GRp58/ERp57 in different mammalian cells. In vitro, recombinant GRp58/ERp57 preferentially interacts with mTORC1. GRp58/ERp57 knockdown reduces mTORC1 levels and phosphorylation of 4E-BP1 and p70(S6K) in response to insulin. In contrast, GRp58/ERp57 overexpression increases mTORC1 levels and activity. A redox sensitive mechanism that depends on GRp58/ERp57 expression activates mTORC1. Although GRp58/ERp57 is known as an endoplasmic reticulum (ER) resident, we demonstrate its presence at the cytosol, together with mTOR, Raptor, and Rictor as well as a pool of these proteins associated to the ER. In addition, the presence of GRp58/ERp57 at the ER decreases in response to insulin or leucine. Interestingly, a fraction of p70(S6K), but not 4E-BP1, is associated to the ER and phosphorylated in response to serum, insulin, or leucine. Altogether, our results suggest that GRp58/ERp57 is involved in the assembly of mTORC1 and positively regulates mTORC1 signaling at the cytosol and the cytosolic side of the ER. PMID- 21321086 TI - A phase II, multicenter, open-label randomized study of motesanib or bevacizumab in combination with paclitaxel and carboplatin for advanced nonsquamous non-small cell lung cancer. AB - BACKGROUND: This phase II study estimated the difference in objective response rate (ORR) among patients with advanced nonsquamous non-small-cell lung cancer (NSCLC) receiving paclitaxel-carboplatin (CP) plus motesanib or bevacizumab. PATIENTS AND METHODS: Chemotherapy-naive patients (N = 186) were randomized 1:1:1 to receive CP plus motesanib 125 mg once daily (qd) (arm A), motesanib 75 mg twice daily (b.i.d.) 5 days on/2 days off (arm B), or bevacizumab 15 mg/kg every 3 weeks (q3w) (arm C). The primary end point was ORR (per RECIST). Other end points included progression-free survival (PFS), overall survival (OS), motesanib pharmacokinetics, and adverse events (AEs). RESULTS: ORRs in the three arms were as follows: arm A, 30% (95% confidence interval 18% to 43%); arm B, 23% (13% to 36%); and arm C, 37% (25% to 50%). Median PFS in arm A was 7.7 months, arm B 5.8 months, and arm C 8.3 months; median OS for arm A was 14.0 months, arm B 12.8 months, and arm C 14.0 months. Incidence of AEs was greater in arms A and B than in arm C. More grade 5 AEs not attributable to disease progression occurred in arm B (n = 10) than in arms A (n = 4) and C (n = 4). Motesanib plasma C(max) and C(min) values were consistent with its pharmacokinetic properties observed in previous studies. CONCLUSIONS: The efficacy of 125 mg qd motesanib or bevacizumab plus CP was estimated to be comparable. Toxicity was higher but manageable in both motesanib arms. Efficacy and tolerability of motesanib 125 mg qd plus CP in advanced nonsquamous NSCLC are being further investigated in a phase III study. PMID- 21321087 TI - Sorafenib may induce hypophosphatemia through a fibroblast growth factor-23 (FGF23)-independent mechanism. PMID- 21321088 TI - Type and trends in outcomes research in breast cancer between 2000 and 2007. AB - BACKGROUND: Interest in outcomes research (OR) derives from the need to know the value and the effectiveness of health interventions, especially for oncology. We focused our research on OR in breast cancer, providing an overview of the trend of publications. PATIENTS AND METHODS: We carried out a Medline search to retrieve all articles in English published from 2000 through 2007. The abstracts were reviewed and classified according to the research topics and the primary design of the trial. RESULTS: We selected 405 articles: their number remained constant until 2003, rose during 2004-2005 and decreased during the last 2 years. The most common topic was surgery (n = 234), alone or in association with other interventions. The category more investigated was the process. Clinical outcomes, and among them disease-free survival, were more frequent than other outcomes. The median value of 2007 Impact Factor of the journals publishing the selected references was 2.466 (range 0.272-25.547) and the median value of Citation Index was 8 (range 0-143). CONCLUSIONS: Our research showed a decreasing interest in OR during the more recent years. We are hopeful that it will regenerate interest, particularly by the light of the funds allocated to the comparative effectiveness research in the United States. PMID- 21321089 TI - Pemetrexed and cisplatin as first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) with asymptomatic inoperable brain metastases: a multicenter phase II trial (GFPC 07-01). AB - BACKGROUND: Brain metastases (BM) occur in up to 40% of non-small-cell lung cancer (NSCLC) patients. This trial assessed the safety and efficacy of pemetrexed-cisplatin in this population. PATIENTS AND METHODS: Chemonaive NSCLC patients with BM ineligible for (radio)surgery, performance status (PS) of 0 to 2, were eligible for up to six cycles of cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) every 3 weeks. Whole -brain radiotherapy was given in case of disease progression or at chemotherapy completion. Primary end point was objective response rate (RR) on BM. Secondary end points included extracerebral and overall RR, safety profile and survival. RESULTS: Forty-three patients were enrolled. Initial characteristics were mean age 60.4 years; males 29; PS: 0 in 37.2%, 1 in 60.5% and 2 in 22.3% of patients; adenocarcinoma in 36 patients, large cell in 4 patients (nonsquamous, 93%) and squamous carcinoma in 3 patients. Functional classification of neurological status was stage I/II 86.0%, III 2.3% and IV 11.6%. Grade 3-4 hematological toxic effects were neutropenia, 11 patients (febrile neutropenia, 1 patient), and anemia, 6 patients. Non-hematological toxic effects were grade 2 urinary infection, one patient; grade 3 pneumonia, two patients; and grade 3 hypoacousia, one patient. Cerebral, extracerebral and overall RR by intent to treat analysis were 41.9%, 34.9% and 34.9%, respectively. Median survival time and time to progression were 7.4 and 4.0 months, respectively. CONCLUSION: Pemetrexed-cisplatin is an effective and well-tolerated regimen as first-line therapy for NSCLC patients with BM who always suffer a poor prognosis. PMID- 21321090 TI - Addressing an unmet need in oncology patients: rehabilitation of upper aerodigestive tract function. AB - BACKGROUND: Laryngeal dysfunction in the oncology population is common and may detract from quality of life (QoL) due to vocal restriction and aspiration. Therapies to address this complex issue have not been explored to date. We examined the outcomes among oncology patients treated with a minimally invasive office-based surgical approach for the rehabilitation of laryngeal dysfunction. PATIENTS AND METHODS: A retrospective analysis was carried out of oncology patients referred for laryngeal dysfunction. Patients who underwent minimally invasive injection laryngoplasty (IL) were selected. Subjective outcome measures, objective voice analysis parameters, and swallowing studies were annotated. RESULTS: Sixty-one patients underwent IL for the management of laryngeal dysfunction. Lung cancer was the most common cancer diagnosis (39.3%), and 52% of patients had thoracic malignancies. All patients had a self-reported improvement in vocal function with a single injection, and 55 patients (90%) reported lasting effects at 3 months. In patients with pre- and postoperative voice analysis, phonatory function increased from 5.0 to 10.5 s, more than twofold improvement compared with baseline functioning. Seventy-one percent of patients who aspirated before injection no longer required a modified diet. There were no major complications. CONCLUSIONS: Interventions to improve the QoL in oncology patients continue to evolve. We report significant improvements in both subjective and objective measures of laryngeal function after IL for vocal fold dysfunction that are both immediate and sustained. We conclude that IL is a safe and efficacious procedure for the treatment of laryngeal dysfunction in oncology patients, resulting in palliation and improved QoL. PMID- 21321091 TI - Sagopilone (ZK-EPO, ZK 219477) for recurrent glioblastoma. A phase II multicenter trial by the European Organisation for Research and Treatment of Cancer (EORTC) Brain Tumor Group. AB - BACKGROUND: Sagopilone (ZK 219477), a lipophylic and synthetic analog of epothilone B, that crosses the blood-brain barrier has demonstrated preclinical activity in glioma models. PATIENTS AND METHODS: Patients with first recurrence/progression of glioblastoma were eligible for this early phase II and pharmacokinetic study exploring single-agent sagopilone (16 mg/m(2) over 3 h every 21 days). Primary end point was a composite of either tumor response or being alive and progression free at 6 months. Overall survival, toxicity and safety and pharmacokinetics were secondary end points. RESULTS: Thirty-eight (evaluable 37) patients were included. Treatment was well tolerated, and neuropathy occurred in 46% patients [mild (grade 1) : 32%]. No objective responses were seen. The progression-free survival (PFS) rate at 6 months was 6.7% [95% confidence interval (CI) 1.3-18.7], the median PFS was just over 6 weeks, and the median overall survival was 7.6 months (95% CI 5.3-12.3), with a 1 year survival rate of 31.6% (95% CI 17.7-46.4). Maximum plasma concentrations were reached at the end of the 3-h infusion, with rapid declines within 30 min after termination. CONCLUSIONS: No evidence of relevant clinical antitumor activity against recurrent glioblastoma could be detected. Sagopilone was well tolerated, and moderate-to-severe peripheral neuropathy was observed in despite prolonged administration. PMID- 21321092 TI - Thymidylate synthase (TS) gene expression in primary lung cancer patients: a large-scale study in Japanese population. AB - BACKGROUND: Previous small-sized studies showed lower thymidylate synthase (TS) expression in adenocarcinoma of the lung, which may explain higher antitumor activity of TS-inhibiting agents such as pemetrexed. PATIENTS AND METHODS: To quantitatively measure TS gene expression in a large-scale Japanese population (n = 2621) with primary lung cancer, laser-captured microdissected sections were cut from primary tumors, surrounding normal lung tissues and involved nodes. RESULTS: TS gene expression level in primary tumor was significantly higher than that in normal lung tissue (mean TS/beta-actin, 3.4 and 1.0, respectively; P < 0.01), and TS gene expression level was further higher in involved node (mean TS/beta-actin, 7.7; P < 0.01). Analyses of TS gene expression levels in primary tumor according to histologic cell type revealed that small-cell carcinoma showed highest TS expression (mean TS/beta-actin, 13.8) and that squamous cell carcinoma showed higher TS expression as compared with adenocarcinoma (mean TS/beta-actin, 4.3 and 2.3, respectively; P < 0.01); TS gene expression was significantly increased along with a decrease in the grade of tumor cell differentiation. There was no significant difference in TS gene expression according to any other patient characteristics including tumor progression. CONCLUSION: Lower TS expression in adenocarcinoma of the lung was confirmed in a large-scale study. PMID- 21321093 TI - A stimulatory TSH receptor antibody enhances adipogenesis via phosphoinositide 3 kinase activation in orbital preadipocytes from patients with Graves' ophthalmopathy. AB - Graves' ophthalmopathy (GO) is characterized by expanded volume of the orbital tissues associated with elevated serum levels of TSH receptor (TSHR) autoantibodies. Because previous studies have demonstrated evidence of adipogenesis within the GO orbit, we sought to determine whether M22, a human monoclonal antibody directed against TSHR, enhances adipogenesis in orbital fibroblasts from patients with GO and, if so, to identify signaling mechanisms involved. GO orbital fibroblast cultures (n=10) were treated for 10 days with bovine TSH (1 or 10.0 U/l) or M22 (1 or 10 ng/ml) in serum-free adipocyte differentiation medium. Some cultures also received a phosphoinositide 3-kinase (PI3K) inhibitor or an inhibitor of cAMP production. In other experiments, confluent cultures (n=8) were treated for between 1 and 30 min with TSH (0.1 10.0 U/l) or M22 (0.1-100 ng/ml) with measurement of cAMP production or levels of phosphorylated AKT (pAKT). We found levels of adiponectin, leptin, and TSHR mRNA to be increased in GO cultures treated for 10 days with either M22 (2.6 mean fold +/- 0.7; P=0.03) or TSH (13.2 +/- 5.8-fold, P=0.048). In other studies, M22 and TSH stimulated cAMP production and pAKT levels in GO cells. Inhibition of PI3K activity during 10 days in culture decreased the levels of M22-stimulated mRNA encoding adiponectin (67 +/- 12%; P=0.021), as well as adiponectin and CCAAT/enhancer-binding protein alpha protein levels. In conclusion, M22 is a pro adipogenic factor in GO orbital preadipocytes. This antibody appears to act via the PI3K signaling cascade, suggesting that inhibition of PI3K signaling may represent a potential novel therapeutic approach in GO. PMID- 21321094 TI - Uncoupling protein-2 increases nitric oxide production and TNFAIP3 pathway activation in pancreatic islets. AB - Mutations in the uncoupling protein 2 (Ucp2) gene are linked to type-2 diabetes. Here, a potential mechanism by which lack of UCP2 is cytoprotective in pancreatic beta-cells was investigated. Nitric oxide (NO) production was elevated in Ucp2(-/ ) islets. Proliferation (cyclin D2, Ccnd2) and anti-apoptosis (Tnfaip3) genes had increased expression in Ucp2(-/-) islets, whereas the mRNA of pro-apoptosis genes (Jun, Myc) was reduced. TNFAIP3 cellular localization was detected in both alpha- and beta-cells of Ucp2(-/-) islets but in neither alpha- nor beta-cells of UCP2(+)(/)(+) islets, where it was detected in pancreatic polypeptide-expressing cells. TNFAIP3 distribution was not markedly altered 14 days after streptozotocin treatment. Basal apoptosis was attenuated in Ucp2(-/-) beta-cells, while the nuclear factor kappaB (NF-kappaB) pathway was transactivated after islet isolation. Ucp2(+/+) and Ucp2(-/-) islets were treated with cytokines for 24 h. Cytokines did not increase NF-kappaB transactivation or apoptosis in Ucp2(-/-) islets and TNFAIP3 was more strongly induced in Ucp2(-/-) islets. Inhibition of NO production strongly reduced NF-kappaB activation and apoptosis. These data show that null expression of Ucp2 induces transactivation of NF-kappaB in isolated islets, possibly due to NO-dependent up-regulation of inhibitor of kappaB kinase beta activity. NF-kappaB transactivation appears to result in altered expression of genes that enhance a pro-survival phenotype basally and when beta-cells are exposed to cytokines. TNFAIP3 is of particular interest because of its ability to regulate NF-kappaB signaling pathways. PMID- 21321095 TI - Pharmacological inhibition of sphingosine kinase isoforms alters estrogen receptor signaling in human breast cancer. AB - Recently, crosstalk between sphingolipid signaling pathways and steroid hormones has been illuminated as a possible therapeutic target. Sphingosine kinase (SK), the key enzyme metabolizing pro-apoptotic ceramide to pro-survival sphingosine-1 phosphate (S1P), is a promising therapeutic target for solid tumor cancers. In this study, we examined the ability of pharmacological inhibition of S1P formation to block estrogen signaling as a targeted breast cancer therapy. We found that the Sphk1/2 selective inhibitor (SK inhibitor (SKI))-II, blocked breast cancer viability, clonogenic survival and proliferation. Furthermore, SKI II dose-dependently decreased estrogen-stimulated estrogen response element transcriptional activity and diminished mRNA levels of the estrogen receptor (ER) regulated genes progesterone receptor and steroid derived factor-1. This inhibitor binds the ER directly in the antagonist ligand-binding domain. Taken together, our results suggest that SKIs have the ability to act as novel ER signaling inhibitors in breast carcinoma. PMID- 21321096 TI - Suppression of the C/EBP family of transcription factors in adipose tissue causes lipodystrophy. AB - Adipose-specific inactivation of both AP-1 and CCAAT-enhancer-binding protein (C/EBP) families of B-ZIP transcription factors in transgenic mice causes severe lipoatrophy. To evaluate whether inactivation of only C/EBP members was critical for lipoatrophy, A-C/EBP, a dominant-negative protein that specifically inhibits the DNA binding of the C/EBP members, was expressed in adipose tissue. For the first 2 weeks after birth, aP2-A-C/EBP mice had no white adipose tissue (WAT), drastically reduced brown adipose tissue (BAT), and exhibited marked hepatic steatosis, hyperinsulinemia, and hyperlipidemia. However, WAT appeared during the third week, coinciding with significantly improved metabolic functioning. In adults, BAT remained reduced, causing cold intolerance. At 30 weeks, the aP2-A C/EBP mice had only 35% reduced WAT, with clear morphological signs of lipodystrophy in subcutaneous fat. Circulating leptin and adiponectin levels were less than the wild-type levels, and these mice exhibited impaired triglyceride clearance. Insulin resistance, glucose intolerance, and reduced free fatty acid release in response to beta3-adrenergic agonist suggest improper functioning of the residual WAT. Gene expression analysis of inguinal WAT identified reduced mRNA levels of several enzymes involved in fatty acid synthesis and glucose metabolism that are known C/EBPalpha transcriptional targets. There were increased levels for genes involved in inflammation and muscle differentiation. However, when dermal fibroblasts from aP2-A-C/EBP mice were differentiated into adipocytes in tissue culture, muscle markers were elevated more than the inflammatory markers. These results demonstrate that the C/EBP family is essential for adipose tissue development during the early postnatal period, the regulation of glucose and lipid homeostasis in adults, and the suppression of the muscle lineage. PMID- 21321097 TI - Polycystin-2 takes different routes to the somatic and ciliary plasma membrane. AB - Polycystin-2 (also called TRPP2), an integral membrane protein mutated in patients with cystic kidney disease, is located in the primary cilium where it is thought to transmit mechanical stimuli into the cell interior. After studying a series of polycystin-2 deletion mutants we identified two amino acids in loop 4 that were essential for the trafficking of polycystin-2 to the somatic (nonciliary) plasma membrane. However, polycystin-2 mutant proteins in which these two residues were replaced by alanine were still sorted into the cilium, thus indicating that the trafficking routes to the somatic and ciliary plasma membrane compartments are distinct. We also observed that the introduction of dominant-negative Sar1 mutant proteins and treatment of cells with brefeldin A prevented the transport into the ciliary plasma membrane compartment, whereas metabolic labeling experiments, light microscopical imaging, and high-resolution electron microscopy revealed that full-length polycystin-2 did not traverse the Golgi apparatus on its way to the cilium. These data argue that the transport of polycystin-2 to the ciliary and to the somatic plasma membrane compartments originates in a COPII-dependent fashion at the endoplasmic reticulum, that polycystin-2 reaches the cis side of the Golgi apparatus in either case, but that the trafficking to the somatic plasma membrane goes through the Golgi apparatus whereas transport vesicles to the cilium leave the Golgi apparatus at the cis compartment. Such an interpretation is supported by the finding that mycophenolic acid treatment resulted in the colocalization of polycystin-2 with GM130, a marker of the cis-Golgi apparatus. Remarkably, we also observed that wild-type Smoothened, an integral membrane protein involved in hedgehog signaling that under resting conditions resides in the somatic plasma membrane, passed through the Golgi apparatus, but the M2 mutant of Smoothened, which is constitutively located in the ciliary but not in the somatic plasma membrane, does not. Finally, a dominant-negative form of Rab8a, a BBSome-associated monomeric GTPase, prevented the delivery of polycystin-2 to the primary cilium whereas a dominant negative form of Rab23 showed no inhibitory effect, which is consistent with the view that the ciliary trafficking of polycystin-2 is regulated by the BBSome. PMID- 21321098 TI - Four faces of cellular senescence. AB - Cellular senescence is an important mechanism for preventing the proliferation of potential cancer cells. Recently, however, it has become apparent that this process entails more than a simple cessation of cell growth. In addition to suppressing tumorigenesis, cellular senescence might also promote tissue repair and fuel inflammation associated with aging and cancer progression. Thus, cellular senescence might participate in four complex biological processes (tumor suppression, tumor promotion, aging, and tissue repair), some of which have apparently opposing effects. The challenge now is to understand the senescence response well enough to harness its benefits while suppressing its drawbacks. PMID- 21321099 TI - Tem1 localization to the spindle pole bodies is essential for mitotic exit and impairs spindle checkpoint function. AB - The mitotic exit network (MEN) is a signaling cascade that triggers inactivation of the mitotic cyclin-dependent kinases and exit from mitosis. The GTPase Tem1 localizes on the spindle pole bodies (SPBs) and initiates MEN signaling. Tem1 activity is inhibited until anaphase by Bfa1-Bub2. These proteins are also part of the spindle position checkpoint (SPOC), a surveillance mechanism that restrains mitotic exit until the spindle is correctly positioned. Here, we show that regulation of Tem1 localization is essential for the proper function of the MEN and the SPOC. We demonstrate that the dynamics of Tem1 loading onto SPBs determine the recruitment of other MEN components to this structure, and reevaluate the interdependence in the localization of Tem1, Bfa1, and Bub2. We also find that removal of Tem1 from the SPBs is critical for the SPOC to impede cell cycle progression. Finally, we demonstrate for the first time that localization of Tem1 to the SPBs is a requirement for mitotic exit. PMID- 21321100 TI - Sphingosine kinases and their metabolites modulate endolysosomal trafficking in photoreceptors. AB - Internalized membrane proteins are either transported to late endosomes and lysosomes for degradation or recycled to the plasma membrane. Although proteins involved in trafficking and sorting have been well studied, far less is known about the lipid molecules that regulate the intracellular trafficking of membrane proteins. We studied the function of sphingosine kinases and their metabolites in endosomal trafficking using Drosophila melanogaster photoreceptors as a model system. Gain- and loss-of-function analyses show that sphingosine kinases affect trafficking of the G protein-coupled receptor Rhodopsin and the light-sensitive transient receptor potential (TRP) channel by modulating the levels of dihydrosphingosine 1 phosphate (DHS1P) and sphingosine 1 phosphate (S1P). An increase in DHS1P levels relative to S1P leads to the enhanced lysosomal degradation of Rhodopsin and TRP and retinal degeneration in wild-type photoreceptors. Our results suggest that sphingosine kinases and their metabolites modulate photoreceptor homeostasis by influencing endolysosomal trafficking of Rhodopsin and TRP. PMID- 21321101 TI - Xenopus HJURP and condensin II are required for CENP-A assembly. AB - Centromeric protein A (CENP-A) is the epigenetic mark of centromeres. CENP-A replenishment is necessary in each cell cycle to compensate for the dilution associated to DNA replication, but how this is achieved mechanistically is largely unknown. We have developed an assay using Xenopus egg extracts that can recapitulate the spatial and temporal specificity of CENP-A deposition observed in human cells, providing us with a robust in vitro system amenable to molecular dissection. Here we show that this deposition depends on Xenopus Holliday junction-recognizing protein (xHJURP), a member of the HJURP/Scm3 family recently identified in yeast and human cells, further supporting the essential role of these chaperones in CENP-A loading. Despite little sequence homology, human HJURP can substitute for xHJURP. We also report that condensin II, but not condensin I, is required for CENP-A assembly and contributes to retention of centromeric CENP A nucleosomes both in mitosis and interphase. We propose that the chromatin structure imposed by condensin II at centromeres enables CENP-A incorporation initiated by xHJURP. PMID- 21321102 TI - Successful strategies for recruitment of emergency medical volunteers. AB - OBJECTIVES: A robust medical volunteer program is critical to ensuring a successful response to public health and medical emergencies. The New York City (NYC) Department of Health and Mental Hygiene created the NYC Medical Reserve Corps in 2003 to build a multidisciplinary team of health professionals who wish to assist NYC with response during large-scale health emergencies. This article reports on the search to determine which recruitment activities have been most successful to date, with the goal of modeling future activities upon those that worked best. METHODS: A retrospective review of effectiveness of recruitment strategies to identify and register new NYC Medical Reserve Corps volunteers was undertaken. RESULTS: A broad range of recruitment activities have been implemented since the program's inception, with varying degrees of success. Various recruitment modalities were tried, including direct invitations to licensed professionals by the NYC Health Commissioner and announcements through professional organization partners. The direct invitation by the NYC Health Commissioner to health professionals licensed in 1 of the 5 boroughs of NYC has proved to be the most successful recruitment tool to date. CONCLUSIONS: The local health commissioner or other trusted community figure is an excellent messenger for recruiting emergency volunteers. It is also critical that recruitment messages reach as many potential volunteers as possible to ensure that the requisite number of volunteers and mix of professional disciplines are identified. PMID- 21321103 TI - Murine Chlamydia trachomatis genital infection is unaltered by depletion of CD4+ T cells and diminished adaptive immunity. AB - Chlamydia muridarum and Chlamydia trachomatis mouse models of genital infection have been used to study chlamydial immunity and vaccine development. To assess the protective role of CD4(+) T cells in resolving C. trachomatis and C. muridarum genital tract infections, we used the female mouse model and evaluated infection in the presence and absence of CD4(+) T cells. In contrast to C. muridarum infection, C. trachomatis infection was unaltered in the absence of CD4(+) T cells. Mice infected with C. trachomatis developed protective immunity to re-challenge, but unlike C. muridarum infection, optimum resistance required multiple infectious challenges, despite the generation of adaptive serum and local chlamydial specific immune responses. Thus, understanding the chlamydial pathogenic and host immunologic factors that result in a diminished protective role for CD4(+) T cells in C. trachomatis murine infection might lead to new insights important to human immunity and vaccine development. PMID- 21321104 TI - Early lesions of articular osteochondrosis in the distal femur of foals. AB - Failure of the cartilage canal blood supply to epiphyseal growth cartilage has been implicated in the pathogenesis of articular osteochondrosis in horses and other animal species. In a previous study of the developmental pattern of the blood supply in the tarsus of foals, early lesions of osteochondrosis were consistently found in regions where the cartilage canal vessels traversed the chondro-osseous junction. The developmental pattern of blood vessels has also been described in the distal femoral epiphysis; however, the group of foals examined in that study did not have lesions of osteochondrosis in this location. Therefore, the relationship between the occurrence of early lesions of osteochondrosis and the developmental pattern of the blood supply to epiphyseal growth cartilage in this site in foals has not been examined. Distal femora were collected from 30 fetuses and foals (up to 11 months old) submitted for postmortem examination. Sections from the lateral trochlear ridge and medial femoral condyle of both hind limbs were examined histologically. Sixteen cartilage lesions were found in 7 of the 30 fetuses and foals. All lesions contained evidence of cartilage canal necrosis and ischemic chondronecrosis. The lesions were located in regions where cartilage canal vessels traversed the chondro-osseous junction, as previously observed in the tarsus. The location and morphology of lesions indicated that a subclinical stage of ischemic chondronecrosis existed that preceded and predisposed to the development of osteochondrosis dissecans and subchondral bone cysts. PMID- 21321105 TI - A polymorphism in the coding region of Il12b promotes IL-12p70 and IL-23 heterodimer formation. AB - IL-12 and IL-23 are heterodimeric cytokines involved in the induction of Th1 and Th17 immune responses. Previous work indicated that a region on chromosome 11 encoding the IL-12p40 subunit regulates strain differences in susceptibility to murine trinitrobenzene sulfonic acid-induced colitis. In addition, this region determines strain differences in LPS-induced IL-12 responses. In this study, we investigated how polymorphisms in the coding region of murine Il12b influence IL 12 and IL-23 heterodimer formation. Transfection studies using constructs containing IL-12p35 linked to IL-12p40 from the colitis-resistant C57BL/6 strain or to the polymorphic p40 variant from the colitis-susceptible SJL/J strain demonstrated that SJL/J-derived p40 constructs synthesized significantly more IL 12p70 than did constructs harboring the C57BL/6-p40 variant. This could not be attributed to differences in synthesis rate or secretion, implicating a greater affinity of SJL/J-derived IL-12p40 for its IL-12p35 subunit. This greater affinity is also associated with increased IL-23 synthesis. In addition, C57BL/6 mice transgenic for the SJL/J 40 variant synthesized significantly more IL-12p70 upon LPS challenge and were more prone to develop colonic inflammation than did C57BL/6 mice transgenic for the C57BL/6-p40 variant. The more efficient binding of the polymorphic Il12b variant to p35 and p19 is most likely due to conformational changes following differential glycosylation as a consequence of the polymorphism. The high synthesis rate of the mature cytokines resulting from this efficient binding can lead to rapid proinflammatory skewing of immune responses and distortion of the homeostatic balance underlying the greater susceptibility for colitis. PMID- 21321106 TI - IL-12 enhances the antitumor actions of trastuzumab via NK cell IFN-gamma production. AB - The antitumor effects of therapeutic mAbs may depend on immune effector cells that express FcRs for IgG. IL-12 is a cytokine that stimulates IFN-gamma production from NK cells and T cells. We hypothesized that coadministration of IL 12 with a murine anti-HER2/neu mAb (4D5) would enhance the FcR-dependent immune mechanisms that contribute to its antitumor activity. Thrice-weekly therapy with IL-12 (1 MUg) and 4D5 (1 mg/kg) significantly suppressed the growth of a murine colon adenocarcinoma that was engineered to express human HER2 (CT-26(HER2/neu)) in BALB/c mice compared with the result of therapy with IL-12, 4D5, or PBS alone. Combination therapy was associated with increased circulating levels of IFN gamma, monokine induced by IFN-gamma, and RANTES. Experiments with IFN-gamma deficient mice demonstrated that this cytokine was necessary for the observed antitumor effects of therapy with IL-12 plus 4D5. Immune cell depletion experiments showed that NK cells (but not CD4(+) or CD8(+) T cells) mediated the antitumor effects of this treatment combination. Therapy of HER2/neu-positive tumors with trastuzumab plus IL-12 induced tumor necrosis but did not affect tumor proliferation, apoptosis, vascularity, or lymphocyte infiltration. In vitro experiments with CT-26(HER2/neu) tumor cells revealed that IFN-gamma induced an intracellular signal but did not inhibit cellular proliferation or induce apoptosis. Taken together, these data suggest that tumor regression in response to trastuzumab plus IL-12 is mediated through NK cell IFN-gamma production and provide a rationale for the coadministration of NK cell-activating cytokines with therapeutic mAbs. PMID- 21321107 TI - Primordial linkage of beta2-microglobulin to the MHC. AB - beta2-Microglobulin (beta2M) is believed to have arisen in a basal jawed vertebrate (gnathostome) and is the essential L chain that associates with most MHC class I molecules. It contains a distinctive molecular structure called a constant-1 Ig superfamily domain, which is shared with other adaptive immune molecules including MHC class I and class II. Despite its structural similarity to class I and class II and its conserved function, beta2M is encoded outside the MHC in all examined species from bony fish to mammals, but it is assumed to have translocated from its original location within the MHC early in gnathostome evolution. We screened a nurse shark bacterial artificial chromosome library and isolated clones containing beta2M genes. A gene present in the MHC of all other vertebrates (ring3) was found in the bacterial artificial chromosome clone, and the close linkage of ring3 and beta2M to MHC class I and class II genes was determined by single-strand conformational polymorphism and allele-specific PCR. This study satisfies the long-held conjecture that beta2M was linked to the primordial MHC (Ur MHC); furthermore, the apparent stability of the shark genome may yield other genes predicted to have had a primordial association with the MHC specifically and with immunity in general. PMID- 21321108 TI - Acid-sensing ion channels contribute to the effect of acidosis on the function of dendritic cells. AB - As an H(+)-gated subgroup of the degenerin/epithelial Na(+) channel family, acid sensing ion channels (ASICs) were reported to be involved in various physiological and pathological processes in neurons. However, little is known about the role of ASICs in the function of dendritic cells (DCs). In this study, we investigated the expression of ASICs in mouse bone marrow-derived DCs and their possible role in the function of DCs. We found that ASIC1, ASIC2, and ASIC3 are expressed in DCs at the mRNA and protein levels, and extracellular acid can evoke ASIC-like currents in DCs. We also demonstrated that acidosis upregulated the expression of CD11c, MHC class II, CD80, and CD86 and enhanced the Ag presenting ability of DCs via ASICs. Moreover, the effect of acidosis on DCs can be abolished by the nonsteroidal anti-inflammatory drugs ibuprofen and diclofenac. These results suggest that ASICs are involved in the acidosis mediated effect on DC function. PMID- 21321109 TI - Multiscale computational modeling reveals a critical role for TNF-alpha receptor 1 dynamics in tuberculosis granuloma formation. AB - Multiple immune factors control host responses to Mycobacterium tuberculosis infection, including the formation of granulomas, which are aggregates of immune cells whose function may reflect success or failure of the host to contain infection. One such factor is TNF-alpha. TNF-alpha has been experimentally characterized to have the following activities in M. tuberculosis infection: macrophage activation, apoptosis, and chemokine and cytokine production. Availability of TNF-alpha within a granuloma has been proposed to play a critical role in immunity to M. tuberculosis. However, in vivo measurement of a TNF-alpha concentration gradient and activities within a granuloma are not experimentally feasible. Further, processes that control TNF-alpha concentration and activities in a granuloma remain unknown. We developed a multiscale computational model that includes molecular, cellular, and tissue scale events that occur during granuloma formation and maintenance in lung. We use our model to identify processes that regulate TNF-alpha concentration and cellular behaviors and thus influence the outcome of infection within a granuloma. Our model predicts that TNF-alphaR1 internalization kinetics play a critical role in infection control within a granuloma, controlling whether there is clearance of bacteria, excessive inflammation, containment of bacteria within a stable granuloma, or uncontrolled growth of bacteria. Our results suggest that there is an interplay between TNF alpha and bacterial levels in a granuloma that is controlled by the combined effects of both molecular and cellular scale processes. Finally, our model elucidates processes involved in immunity to M. tuberculosis that may be new targets for therapy. PMID- 21321110 TI - Up-regulation and sustained activation of Stat1 are essential for interferon gamma (IFN-gamma)-induced dual oxidase 2 (Duox2) and dual oxidase A2 (DuoxA2) expression in human pancreatic cancer cell lines. AB - Dual oxidase 2 is a member of the NADPH oxidase (Nox) gene family that plays a critical role in the biosynthesis of thyroid hormone as well as in the inflammatory response of the upper airway mucosa and in wound healing, presumably through its ability to generate reactive oxygen species, including H2O2. The recently discovered overexpression of Duox2 in gastrointestinal malignancies, as well as our limited understanding of the regulation of Duox2 expression, led us to examine the effect of cytokines and growth factors on Duox2 in human tumor cells. We found that exposure of human pancreatic cancer cells to IFN-gamma (but not other agents) produced a profound up-regulation of the expression of Duox2, and its cognate maturation factor DuoxA2, but not other members of the Nox family. Furthermore, increased Duox2/DuoxA2 expression was closely associated with a significant increase in the production of both intracellular reactive oxygen species and extracellular H2O2. Examination of IFN-gamma-mediated signaling events demonstrated that in addition to the canonical Jak-Stat1 pathway, IFN-gamma activated the p38-MAPK pathway in pancreatic cancer cells, and both played an important role in the induction of Duox2 by IFN-gamma. Duox2 up regulation following IFN-gamma exposure is also directly associated with the binding of Stat1 to elements of the Duox2 promoter. Our findings suggest that the pro-inflammatory cytokine IFN-gamma initiates a Duox2-mediated reactive oxygen cascade in human pancreatic cancer cells; reactive oxygen species production in this setting could contribute to the pathophysiologic characteristics of these tumors. PMID- 21321111 TI - mTOR complex 2 targets Akt for proteasomal degradation via phosphorylation at the hydrophobic motif. AB - The protein kinase Akt (also known as protein kinase B) is a critical signaling hub downstream of various cellular stimuli such as growth factors that control cell survival, growth, and proliferation. The activity of Akt is tightly regulated, and the aberrant activation of Akt is associated with diverse human diseases including cancer. Although it is well documented that the mammalian target of rapamycin complex 2 (mTORC2)-dependent phosphorylation of the Akt hydrophobic motif (Ser-473 in Akt1) is essential for full Akt activation, it remains unclear whether this phosphorylation has additional roles in regulating Akt activity. In this study, we found that abolishing Akt Ser-473 phosphorylation stabilizes Akt following agonist stimulation. The Akt Ser-473 phosphorylation promotes a Lys-48-linked polyubiquitination of Akt, resulting in its rapid proteasomal degradation. Moreover, blockade of this proteasomal degradation pathway prolongs agonist-induced Akt activation. These data reveal that mTORC2 plays a central role in regulating the Akt protein life cycle by first stabilizing Akt protein folding through the turn motif phosphorylation and then by promoting Akt protein degradation through the hydrophobic motif phosphorylation. Taken together, this study reveals that the Akt Ser-473 phosphorylation-dependent ubiquitination and degradation is an important negative feedback regulation that specifically terminates Akt activation. PMID- 21321112 TI - An early response transcription factor, Egr-1, enhances insulin resistance in type 2 diabetes with chronic hyperinsulinism. AB - One of the most important characteristics of type 2 diabetes is insulin resistance, during which the patients normally experienced hyperinsulinism stress that would alter insulin signal transduction in insulin target tissues. We have previously found that early growth responsive gene-1 (Egr-1), a zinc finger transcription factor, is highly expressed in db/db mice and in the fat tissue of individuals with type 2 diabetes. In this report, we found that chronic exposure to hyperinsulinism caused persistent Erk/MAPK activity in adipocytes and enhanced insulin resistance in an Egr-1-dependent manner. An elevation in Egr-1 augmented Erk1/2 activation via geranylgeranyl diphosphate synthase (GGPPS). Egr-1-promoted GGPPS transcription increased Ras prenylation and caused Erk1/2 activation. The sustained activation of Erk1/2 resulted in the phosphorylation of insulin receptor substrate-1 at Serine 612. Phosphorylation at this site impaired insulin signaling in adipocytes and reduced glucose uptake. The loss of Egr-1 function, knockdown of GGPPS, or inhibition of Erk1/2 activity in insulin-resistant adipocytes restored insulin receptor substrate-1 tyrosine phosphorylation and increased insulin sensitivity. Our results suggest a new mechanism by which the Egr-1/GGPPS/Erk1/2 pathway is responsible for insulin resistance during hyperinsulinism. This pathway provides a new therapeutic target for increasing insulin sensitivity: inhibiting the function of Egr-1. PMID- 21321113 TI - Identification of key amino acid residues that determine the ability of high risk HPV16-E7 to dysregulate major histocompatibility complex class I expression. AB - High risk human Papillomavirus (HPV) types are the major causative agents of cervical cancer. Reduced expression of major histocompatibility complex class I (MHC I) on HPV-infected cells might be responsible for insufficient T cell response and contribute to HPV-associated malignancy. The viral gene product required for subversion of MHC I synthesis is the E7 oncoprotein. Although it has been suggested that high and low risk HPVs diverge in their ability to dysregulate MHC I expression, it is not known what sequence determinants of HPV E7 are responsible for this important functional difference. To investigate this, we analyzed the capability to affect MHC I of a set of chimeric E7 variants containing sequence elements from either high risk HPV16 or low risk HPV11. HPV16 E7, but not HPV11-E7, causes significant diminution of mRNA synthesis and surface presentation of MHC I, which depend on histone deacetylase activity. Our experiments demonstrate that the C-terminal region within the zinc finger domain of HPV-E7 is responsible for the contrasting effects of HPV11- and HPV16-E7 on MHC I. By using different loss- and gain-of-function mutants of HPV11- and HPV16 E7, we identify for the first time a residue variation at position 88 that is highly critical for HPV16-E7-mediated suppression of MHC I. Furthermore, our studies suggest that residues at position 78, 80, and 88 build a minimal functional unit within HPV16-E7 required for binding and histone deacetylase recruitment to the MHC I promoter. Taken together, our data provide new insights into how high risk HPV16-E7 dysregulates MHC I for immune evasion. PMID- 21321114 TI - A modular approach to assembly of totally synthetic self-adjuvanting lipopeptide based vaccines allows conformational epitope building. AB - The technology described here allows the chemical synthesis of vaccines requiring correctly folded epitopes and that contain difficult or long peptide sequences. The final self-adjuvanting product promotes strong humoral and/or cell-mediated immunity. A module containing common components of the vaccine (T helper cell epitope and the adjuvanting lipid moiety S-[2,3-bis(palmitoyloxy)propyl]cysteine) was assembled to enable a plug and play approach to vaccine assembly. The inclusion within the module of a chemical group with chemical properties complementary and orthogonal to a chemical group present in the target epitope allowed chemoselective ligation of the two vaccine components. The heat-stable enterotoxin of enterotoxigenic Escherichia coli that requires strict conformational integrity for biological activity and the reproductive hormone luteinizing hormone-releasing hormone were used as the target epitopes for the antibody vaccines. An epitope from the acid polymerase of influenza virus was used to assemble a CD8(+) T cell vaccine. Evaluation of each vaccine candidate in animals demonstrated the feasibility of the approach and that the type of immune response required, viz. antibody or cytotoxic T lymphocyte, dictates the nature of the chemical linkage between the module and target epitope. The use of a thioether bond between the module and target epitope had little or no adverse effect on antibody responses, whereas the use of a disulfide bond between the module and target epitope almost completely abrogated the antibody response. In contrast, better cytotoxic T lymphocyte responses were obtained when a disulfide bond was used. PMID- 21321115 TI - Engineered conformation-dependent VEGF peptide mimics are effective in inhibiting VEGF signaling pathways. AB - Angiogenesis, or formation of new blood vessels, is crucial to cancer tumor growth. Tumor growth, progression, and metastasis are critically influenced by the production of the pro-angiogenic vascular endothelial growth factor (VEGF). Promising anti-angiogenic drugs are currently available; however, their susceptibilities to drug resistance and long term toxicity are serious impediments to their use, thus requiring the development of new therapeutic approaches for safe and effective angiogenic inhibitors. In this work, peptides were designed to mimic the VEGF-binding site to its receptor VEGFR-2. The VEGF conformational peptide mimic, VEGF-P3(CYC), included two artificial cysteine residues, which upon cyclization constrained the peptide in a loop native-like conformation to better mimic the anti-parallel structure of VEGF. The engineered cyclic VEGF mimic peptide demonstrated the highest affinity to VEGFR-2 by surface plasmon resonance assay. The VEGF peptide mimics were evaluated as inhibitors in several in vitro assays in which VEGF-dependent signaling pathways were observed. All VEGF mimics inhibited VEGFR-2 phosphorylation with VEGF-P3(CYC) showing the highest inhibitory effects when compared with unstructured peptides. Additionally, we show in several angiogenic in vitro assays that all the VEGF mimics inhibited endothelial cell proliferation, migration, and network formation with the conformational VEGF-P3 (CYC) being the best. The VEGF-P3(CYC) also caused a significant delay in tumor development in a transgenic model of VEGF(+/ )Neu2-5(+/-). These results indicate that the structure-based design is important for the development of this peptidomimetic and for its anti-angiogenic effects. PMID- 21321116 TI - Notch1-mediated signaling induces MHC class II expression through activation of class II transactivator promoter III in mast cells. AB - Mast cells constitutively express Notch1 and Notch2 on the cell surface. Notch ligand Dll1 (Delta-like 1) stimulation induces MHC class II expression in mast cells and renders them as antigen-presenting cells. However, nothing is known about the mechanism by which Notch signaling induces MHC class II expression in mast cells. MHC class II genes are regulated by the class II transactivator (CIITA). In mice, transcription of the CIITA gene is controlled by three cell type-specific promoters (pI, pIII, and pIV). Here, we show that CIITA expression induced by Dll1 stimulation in mouse bone marrow-derived mast cells (BMMCs) depends critically on the signal mediated by Notch1 and that the most dominant promoter in Notch signaling-mediated CIITA expression in BMMCs is pIII, which is a lymphoid lineage-specific promoter. ChIP assays indicated that Notch signaling increased the binding of the transcription factor PU.1 to CIITA pIII in BMMCs. The knockdown of PU.1 expression using a specific siRNA suppressed Notch signaling-mediated CIITA expression, suggesting that PU.1 contributes to the expression of MHC class II induced by Notch signaling in mast cells. Furthermore, we show that a portion of freshly isolated splenic mast cells express MHC class II and that the most dominant promoter of CIITA in mast cells is pIII. These findings indicate that activation of CIITA pIII plays an important role in MHC class II expression in mast cells. PMID- 21321117 TI - Overexpression of IL-32alpha increases natural killer cell-mediated killing through up-regulation of Fas and UL16-binding protein 2 (ULBP2) expression in human chronic myeloid leukemia cells. AB - IL-32 was recently identified as a proinflammatory cytokine that is induced by IL 18 in natural killer (NK) cells and is highly correlated with inflammatory disorders. However, the relationship between IL-32 and tumor progression is still unknown. In this study, we investigated whether overexpression of IL-32 affects susceptibility of chronic myeloid leukemia (CML) cells to NK cells. Interestingly, IL-32alpha-overexpressing CML cell lines, K562, Kcl22, and BV173, showed higher NK cell-mediated killing. Flow cytometry analysis revealed that overexpression of IL-32alpha induced increased expression of Fas and UL16-binding protein 2 (ULBP2) in CML cells. The direct relationship between overexpression of surface molecules by IL-32alpha and increased NK cell-mediated killing was confirmed by Fas or ULBP2 siRNA transfection. IL-32alpha-induced Fas and ULBP2 expression are regulated p38 MAPK. In addition, the transcription factor Ets1 plays a key role in ULBP2 specific expression by IL-32alpha overexpression in ULBP family members. Taken together, these data show that IL-32alpha stimulates Fas and ULBP2 expression via activation of p38 MAPK, which increases NK susceptibility of CML cells. Enhanced NK cell susceptibility of CML cells by IL 32alpha overexpression may improve the efficiency of NK cell-based immunotherapy. PMID- 21321118 TI - Oxidative modifications of the C-terminal domain of tropoelastin prevent cell binding. AB - Tropoelastin (TE), the soluble monomer of elastin, is synthesized by elastogenic cells, such as chondrocytes, fibroblasts, and smooth muscle cells (SMCs). The C terminal domain of TE interacts with cell receptors, and these interactions play critical roles in elastic fiber assembly. We recently found that oxidation of TE prevents elastic fiber assembly. Here, we examined the effects of oxidation of TE on cell interactions. We found that SMCs bind to TE through heparan sulfate (HS), whereas fetal lung fibroblasts (WI-38 cells) bind through integrin alpha(v)beta(3) and HS. In addition, we found that oxidation of TE by peroxynitrite (ONOO(-)) prevented binding of SMCs and WI-38 cells and other elastogenic cells, human dermal fibroblasts and fetal bovine chondrocytes. Because the C-terminal domain of TE has binding sites for both HS and integrin, we examined the effects of oxidation of a synthetic peptide derived from the C terminal 25 amino acids of TE (CT-25) on cell binding. The CT-25 peptide contains the only two Cys residues in TE juxtaposed to a cluster of positively charged residues (RKRK) that are important for cell binding. ONOO(-) treatment of the CT 25 peptide prevented cell binding, whereas reduction of the CT-25 peptide had no effect. Mass spectrometric and circular dichroism spectroscopic analyses showed that ONOO(-) treatment modified both Cys residues in the CT-25 peptide to sulfonic acid derivatives, without altering the secondary structure. These data suggest that the mechanism by which ONOO(-) prevents cell binding to TE is by introducing negatively charged sulfonic acid residues near the positively charged cluster. PMID- 21321119 TI - Quantitative analysis of Tat peptide binding to import carriers reveals unconventional nuclear transport properties. AB - A detailed study of nuclear import mediated by the HIV-1 Tat peptide (47YGRKKRRQRRR57, TatRRR) is reported. Fluorescence-based measurements, calibration of protein concentrations, and binding assays are exploited to address the physicochemical mechanisms of Tat peptide recognition by the classical importin alpha (Impalpha) and importin beta (Impbeta) receptors both in vitro and in intact cells. We show that TatRRR is an unconventional nuclear localization sequence that binds directly to both Impalpha and Impbeta carriers in the absence of competitors (in vitro), whereas this property is silenced in the actual cellular environment. In the latter case, Impalpha/beta-dependent nuclear import can be successfully restored by replacing the "RRR" stretch with "GGG". We apply a recently developed method to determine quantitatively TatGGG affinity for each receptor. Based on these results, we can rationalize previous controversial reports on the Tat peptide and provide coherent guidelines for the design of novel intracellular targeting sequences. PMID- 21321120 TI - STIM1 and STIM2 are located in the acidic Ca2+ stores and associates with Orai1 upon depletion of the acidic stores in human platelets. AB - Mammalian cells accumulate Ca2+ into agonist-sensitive acidic organelles, vesicles that possess a vacuolar proton-ATPase. Acidic Ca2+ stores include secretory granules and lysosome-related organelles. Current evidence clearly indicates that acidic Ca2+ stores participate in cell signaling and function, including the activation of store-operated Ca2+ entry in human platelets upon depletion of the acidic stores, although the mechanism underlying the activation of store-operated Ca2+ entry controlled by the acidic stores remains unclear. STIM1 has been presented as the endoplasmic reticulum Ca2+ sensor, but its role sensing intraluminal Ca2+ concentration in the acidic stores has not been investigated. Here we report that STIM1 and STIM2 are expressed in the lysosome related organelles and dense granules in human platelets isolated by immunomagnetic sorting. Depletion of the acidic Ca2+ stores using the specific vacuolar proton-ATPase inhibitor, bafilomycin A1, enhanced the association between STIM1 and STIM2 as well as between these proteins and the plasma membrane channel Orai1. Depletion of the acidic Ca2+ stores also induces time-dependent co immunoprecipitation of STIM1 with the TRPC proteins hTRPC1 and hTRPC6, as well as between Orai1 and both TRPC proteins. In addition, bafilomycin A1 enhanced the association between STIM2 and SERCA3. These findings demonstrate the location of STIM1 and STIM2 in the acidic Ca2+ stores and their association with Ca2+ channels and ATPases upon acidic stores discharge. PMID- 21321121 TI - Unusual outer membrane lipid composition of the gram-negative, lipopolysaccharide lacking myxobacterium Sorangium cellulosum So ce56. AB - The gram-negative myxobacterium Sorangium cellulosum So ce56 bears the largest bacterial genome published so far, coding for nearly 10,000 genes. Careful analysis of this genome data revealed that part of the genes coding for the very well conserved biosynthesis of lipopolysaccharides (LPS) are missing in this microbe. Biochemical analysis gave no evidence for the presence of LPS in the membranes of So ce56. By analyzing the lipid composition of its outer membrane sphingolipids were identified as the major lipid class, together with ornithine containing lipids (OL) and ether lipids. A detailed analysis of these lipids resulted in the identification of more than 50 structural variants within these three classes, which possessed several interesting properties regarding to LPS replacement, mediators in myxobacterial differentiation, as well as potential bioactive properties. The sphingolipids with the basic structure C9-methyl-C(20) sphingosine possessed as an unusual trait C9-methylation, which is common to fungi but highly uncommon to bacteria. Such sphingolipids have not been found in bacteria before, and they may have a function in myxobacterial development. The OL, also identified in myxobacteria for the first time, contained acyloxyacyl groups, which are also characteristic for LPS and might replace those in certain functions. Finally, the ether lipids may serve as biomarkers in myxobacterial development. PMID- 21321122 TI - Human papillomavirus (HPV) E7 induces prolonged G2 following S phase reentry in differentiated human keratinocytes. AB - The productive program of human papillomaviruses occurs in differentiated squamous keratinocytes. We have previously shown that HPV-18 DNA amplification initiates in spinous cells in organotypic cultures of primary human keratinocytes during prolonged G(2) phase, as signified by abundant cytoplasmic cyclin B1 (Wang, H. K., Duffy, A. A., Broker, T. R., and Chow, L. T. (2009) Genes Dev. 23, 181-194). In this study, we demonstrated that the E7 protein, which induces S phase reentry in suprabasal cells by destabilizing the p130 pocket protein (Genovese, N. J., Banerjee, N. S., Broker, T. R., and Chow, L. T. (2008) J. Virol. 82, 4862-4873), also elicited extensive G(2) responses. Western blots and indirect immunofluorescence assays were used to probe for host proteins known to control G(2)/M progression. E7 expression induced cytoplasmic accumulation of cyclin B1 and cdc2 in the suprabasal cells. The elevated cdc2 had inactivating phosphorylation on Thr(14) or Tyr(15), and possibly both, due to an increase in the responsible Wee1 and Myt1 kinases. In cells that harbored cytoplasmic cyclin B1 or cdc2, there was also an accumulation of the phosphatase-inactive cdc25C phosphorylated on Ser(216), unable to activate cdc2. Moreover, E7 expression induced elevated expression of phosphorylated ATM (Ser(1981)) and the downstream phosphorylated Chk1, Chk2, and JNKs, kinases known to inactivate cdc25C. Similar results were observed in primary human keratinocyte raft cultures in which the productive program of HPV-18 took place. Collectively, this study has revealed the mechanisms by which E7 induces prolonged G(2) phase in the differentiated cells following S phase induction. PMID- 21321123 TI - LIM kinase 1 modulates cortical actin and CXCR4 cycling and is activated by HIV-1 to initiate viral infection. AB - Almost all viral pathogens utilize a cytoskeleton for their entry and intracellular transport. In HIV-1 infection, binding of the virus to blood resting CD4 T cells initiates a temporal course of cortical actin polymerization and depolymerization, a process mimicking the chemotactic response initiated from chemokine receptors. The actin depolymerization has been suggested to promote viral intracellular migration through cofilin-mediated actin treadmilling. However, the role of the virus-mediated actin polymerization in HIV infection is unknown, and the signaling molecules involved remain unidentified. Here we describe a pathogenic mechanism for triggering early actin polymerization through HIV-1 envelope-mediated transient activation of the LIM domain kinase (LIMK), a protein that phosphorylates cofilin. We demonstrate that HIV-mediated LIMK activation is through gp120-triggered transient activation of the Rack-PAK-LIMK pathway, and that knockdown of LIMK through siRNA decreases filamentous actin, increases CXCR4 trafficking, and diminishes viral DNA synthesis. These results suggest that HIV-mediated early actin polymerization may directly regulate the CXCR4 receptor during viral entry and is involved in viral DNA synthesis. Furthermore, we also demonstrate that in resting CD4 T cells, actin polymerization can be triggered through transient treatment with a pharmacological agent, okadaic acid, that activates LIMK and promotes HIV latent infection of resting CD4 T cells. Taken together, our results suggest that HIV hijacks LIMK to control the cortical actin dynamics for the initiation of viral infection of CD4 T cells. PMID- 21321124 TI - Chronic inhibition of pyruvate dehydrogenase in heart triggers an adaptive metabolic response. AB - Diabetic cardiac dysfunction is associated with decreased rates of myocardial glucose oxidation (GO) and increased fatty acid oxidation (FAO), a fuel shift that has been shown to sensitize the heart to ischemic insult and ventricular dysfunction. We sought to evaluate the metabolic and functional consequences of chronic suppression of GO in heart as modeled by transgenic mice with cardiac specific overexpression of pyruvate dehydrogenase kinase 4 (myosin heavy chain (MHC)-PDK4 mice), an inhibitor of pyruvate dehydrogenase. Hearts of MHC-PDK4 mice were shown to exhibit an insulin-resistant substrate utilization profile, characterized by low GO rates and high FAO flux. Surprisingly, MHC-PDK4 mice were not sensitized to cardiac ischemia-reperfusion injury despite a fuel utilization pattern that phenocopied the diabetic heart. In addition, MHC-PDK4 mice were protected against high fat diet-induced myocyte lipid accumulation, likely related to increased capacity for FAO. The high rates of mitochondrial FAO in the MHC-PDK4 heart were related to heightened activity of the AMP-activated protein kinase, reduced levels of malonyl-CoA, and increased capacity for mitochondrial uncoupled respiration. The expression of the known AMP-activated protein kinase target, peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC 1alpha), a master regulator of mitochondrial function and biogenesis, was also activated in the MHC-PDK4 heart. These results demonstrate that chronic activation of PDK4 triggers transcriptional and post-transcriptional mechanisms that re-program the heart for chronic high rates of FAO without the expected deleterious functional or metabolic consequences. PMID- 21321125 TI - PKC alpha mediates beta-arrestin2-dependent nephrin endocytosis in hyperglycemia. AB - Nephrin, the key molecule of the glomerular slit diaphragm, is expressed on the surface of podocytes and is critical in preventing albuminuria. In diabetes, hyperglycemia leads to the loss of surface expression of nephrin and causes albuminuria. Here, we report a mechanism that can explain this phenomenon: hyperglycemia directly enhances the rate of nephrin endocytosis via regulation of the beta-arrestin2-nephrin interaction by PKCalpha. We identified PKCalpha and protein interacting with c kinase-1 (PICK1) as nephrin-binding proteins. Hyperglycemia induced up-regulation of PKCalpha and led to the formation of a complex of nephrin, PKCalpha, PICK1, and beta-arrestin2 in vitro and in vivo. Binding of beta-arrestin2 to the nephrin intracellular domain depended on phosphorylation of nephrin threonine residues 1120 and 1125 by PKCalpha. Further, cellular knockdown of PKCalpha and/or PICK1 attenuated the nephrin-beta-arrestin2 interaction and abrogated the amplifying effect of high blood glucose on nephrin endocytosis. In C57BL/6 mice, hyperglycemia over 24 h caused a significant increase in urinary albumin excretion, supporting the concept of the rapid impact of hyperglycemia on glomerular permselectivity. In summary, we have provided a molecular model of hyperglycemia-induced nephrin endocytosis and subsequent proteinuria and highlighted PKCalpha and PICK1 as promising therapeutic targets for diabetic nephropathy. PMID- 21321126 TI - Osteopontin undergoes polymerization in vivo and gains chemotactic activity for neutrophils mediated by integrin alpha9beta1. AB - Osteopontin (OPN) is an integrin-binding inflammatory cytokine that undergoes polymerization catalyzed by transglutaminase 2. We have previously reported that polymeric OPN (polyOPN), but not unpolymerized OPN (OPN*), attracts neutrophils in vitro by presenting an acquired binding site for integrin alpha9beta1. Among many in vitro substrates for transglutaminase 2, only a few have evidence for in vivo polymerization and concomitant function. Although polyOPN has been identified in bone and aorta, the in vivo functional significance of polyOPN is unknown. To determine whether OPN polymerization contributes to neutrophil recruitment in vivo, we injected OPN* into the peritoneal space of mice. Polymeric OPN was detected by immunoblotting in the peritoneal wash of mice injected with OPN*, and both intraperitoneal and plasma OPN* levels were higher in mice injected with a polymerization-incompetent mutant, confirming that OPN* polymerizes in vivo. OPN* injection induced neutrophil accumulation, which was significantly less following injection of a mutant OPN that was incapable of polymerization. The importance of in vivo polymerization was further confirmed with cystamine, a transglutaminase inhibitor, which blocked the polymerization and attenuated OPN*-mediated neutrophil recruitment. The thrombin-cleaved N terminal fragment of OPN, another ligand for alpha9beta1, was not responsible for neutrophil accumulation because a thrombin cleavage-incompetent mutant recruited similar numbers of neutrophils as wild type OPN*. Neutrophil accumulation in response to both wild type and thrombin cleavage-incompetent OPN* was reduced in mice lacking the integrin alpha9 subunit in leukocytes, indicating that alpha9beta1 is required for polymerization-induced recruitment. We have illustrated a physiological role of molecular polymerization by demonstrating acquired chemotactic properties for OPN. PMID- 21321127 TI - Methylsulfonylnitrobenzoates, a new class of irreversible inhibitors of the interaction of the thyroid hormone receptor and its obligate coactivators that functionally antagonizes thyroid hormone. AB - Thyroid hormone receptors (TRs) are members of the nuclear hormone receptor (NR) superfamily and regulate development, growth, and metabolism. Upon binding thyroid hormone, TR undergoes a conformational change that allows the release of corepressors and the recruitment of coactivators, which in turn regulate target gene transcription. Although a number of TR antagonists have been developed, most are analogs of the endogenous hormone that inhibit ligand binding. In a screen for inhibitors that block the association of TRbeta with steroid receptor coactivator 2 (SRC2), we identified a novel methylsulfonylnitrobenzoate (MSNB) containing series that blocks this interaction at micromolar concentrations. Here we have studied a series of MSNB analogs and characterized their structure activity relationships. MSNB members do not displace thyroid hormone T3 but instead act by direct displacement of SRC2. MSNB series members are selective for the TR over the androgen, vitamin D, and PPARgamma NR members, and they antagonize thyroid hormone-activated transcription action in cells. The methylsulfonylnitro group is essential for TRbeta antagonism. Side-chain alkylamine substituents showed better inhibitory activity than arylamine substituents. Mass spectrum analysis suggested that MSNB inhibitors bind irreversibly to Cys-298 within the AF-2 cleft of TRbeta to disrupt SRC2 association. PMID- 21321128 TI - Exploration of dimensions of estrogen potency: parsing ligand binding and coactivator binding affinities. AB - The estrogen receptors, ERalpha and ERbeta, are ligand-regulated transcription factors that control gene expression programs in target tissues. The molecular events underlying estrogen action involve minimally two steps, hormone binding to the ER ligand-binding domain followed by coactivator recruitment to the ER.ligand complex; this ligand.receptor.coactivator triple complex then alters gene expression. Conceptually, the potency of an estrogen in activating a cellular response should reflect the affinities that characterize both steps involved in the assembly of the active ligand.receptor.coactivator complex. Thus, to better understand the molecular basis of estrogen potency, we developed a completely in vitro system (using radiometric and time-resolved FRET assays) to quantify independently three parameters: (a) the affinity of ligand binding to ER, (b) the affinity of coactivator binding to the ER.ligand complex, and (c) the potency of ligand recruitment of coactivator. We used this system to characterize the binding and potency of 12 estrogens with both ERalpha and ERbeta. Some ligands showed good correlations between ligand binding affinity, coactivator binding affinity, and coactivator recruitment potency with both ERs, whereas others showed correlations with only one ER subtype or displayed discordant coactivator recruitment potencies. When ligands with low receptor binding affinity but high coactivator recruitment potencies to ERbeta were evaluated in cell-based assays, elevation of cellular coactivator levels significantly and selectively improved their potency. Collectively, our results indicate that some low affinity estrogens may elicit greater cellular responses in those target cells that express higher levels of specific coactivators capable of binding to their ER complexes with high affinity. PMID- 21321129 TI - Functional and topological analysis of yeast acyl-CoA:diacylglycerol acyltransferase 2, an endoplasmic reticulum enzyme essential for triacylglycerol biosynthesis. AB - Acyl-CoA:diacylglycerol acyltransferase (EC 2.3.1.20) is a membrane protein present mainly in the endoplasmic reticulum. It catalyzes the final and committed step in the biosynthesis of triacylglycerol, which is the principal repository of fatty acids for energy utilization and membrane formation. Two distinct family members of acyl-CoA:diacylglycerol acyltransferase, known as DGAT1 and DGAT2, have been characterized in different organisms, including mammals, fungi, and plants. In this study, we characterized the functional role and topological orientation of signature motifs in yeast (Saccharomyces cerevisiae) DGAT2 using mutagenesis in conjunction with chemical modification. Our data provide evidence that both the N and C termini are oriented toward the cytosol and have different catalytic roles. A highly conserved motif, (129)YFP(131), and a hydrophilic segment exclusive to yeast DGAT2 reside in a long endoplasmic reticulum luminal loop following the first transmembrane domain and play an essential role in enzyme catalysis. In addition, the strongly conserved His(195) within the motif HPHG, which may play a role in the active site of DGAT2, is likely embedded in the membrane. These results indicate some similarities to the topology model of murine DGAT2 but also reveal striking differences suggesting that the topological organization of DGAT2 is not ubiquitously conserved. PMID- 21321131 TI - On computing the coalescence time density in an isolation-with-migration model with few samples. PMID- 21321130 TI - DeltAMT: a statistical algorithm for fast detection of protein modifications from LC-MS/MS data. AB - Identification of proteins and their modifications via liquid chromatography tandem mass spectrometry is an important task for the field of proteomics. However, because of the complexity of tandem mass spectra, the majority of the spectra cannot be identified. The presence of unanticipated protein modifications is among the major reasons for the low spectral identification rate. The conventional database search approach to protein identification has inherent difficulties in comprehensive detection of protein modifications. In recent years, increasing efforts have been devoted to developing unrestrictive approaches to modification identification, but they often suffer from their lack of speed. This paper presents a statistical algorithm named DeltAMT (Delta Accurate Mass and Time) for fast detection of abundant protein modifications from tandem mass spectra with high-accuracy precursor masses. The algorithm is based on the fact that the modified and unmodified versions of a peptide are usually present simultaneously in a sample and their spectra are correlated with each other in precursor masses and retention times. By representing each pair of spectra as a delta mass and time vector, bivariate Gaussian mixture models are used to detect modification-related spectral pairs. Unlike previous approaches to unrestrictive modification identification that mainly rely upon the fragment information and the mass dimension in liquid chromatography-tandem mass spectrometry, the proposed algorithm makes the most of precursor information. Thus, it is highly efficient while being accurate and sensitive. On two published data sets, the algorithm effectively detected various modifications and other interesting events, yielding deep insights into the data. Based on these discoveries, the spectral identification rates were significantly increased and many modified peptides were identified. PMID- 21321132 TI - Modifier genes for mouse phosphatidylinositol transfer protein alpha (vibrator) that bypass juvenile lethality. AB - Phosphatidylinositol transfer proteins (PITPs) mediate lipid signaling and membrane trafficking in eukaryotic cells. Loss-of-function mutations of the gene encoding PITPalpha in mice result in a range of dosage-sensitive phenotypes, including neurological dysfunction, neurodegeneration, and premature death. We have previously reported genetic suppression of a strong hypomorphic allele, vibrator, by a wild-derived variant of Nxf1, which increases the level of PITPalpha made from vibrator alleles and suppresses each of the neurological and survival phenotypes. Here we report discovery and genetic mapping of additional vibrator modifiers, Mvb2 and Mvb3, from a different strain background that suppresses juvenile lethality without suppressing visible phenotypes or gene expression. Genotype-specific survival analysis predicts molecular heterosis at Mvb3. These results indicate a mechanism of suppression that bypasses a quantitative requirement for PITPalpha function. PMID- 21321133 TI - Gene expression differences among primates are associated with changes in a histone epigenetic modification. AB - Changes in gene regulation are thought to play an important role in speciation and adaptation, especially in primates. However, we still know relatively little about the mechanisms underlying regulatory evolution. In particular, the extent to which epigenetic modifications underlie gene expression differences between primates is not yet known. Our study focuses on an epigenetic histone modification, H3K4me3, which is thought to promote transcription. To investigate the contribution of H3K4me3 to regulatory differences between species, we collected gene expression data and identified H3K4me3-associated genomic regions in lymphoblastoid cell lines (LCLs) from humans, chimpanzees, and rhesus macaques, using three cell lines from each species. We found strong evidence for conservation of H3K4me3 localization in primates. Moreover, regardless of species, H3K4me3 is consistently enriched near annotated transcription start sites (TSS), and highly expressed genes are more likely than lowly expressed genes to have the histone modification near their TSS. Interestingly, we observed an enrichment of interspecies differences in H3K4me3 at the TSS of genes that are differentially expressed between species. We estimate that as much as 7% of gene expression differences between the LCLs of humans, chimpanzees, and rhesus macaques may be explained, at least in part, by changes in the status of H3K4me3 histone modifications. Our results suggest a modest, yet important role for epigenetic changes in gene expression differences between primates. PMID- 21321134 TI - The 19 genomes of Drosophila: a BAC library resource for genus-wide and genome scale comparative evolutionary research. AB - The genus Drosophila has been the subject of intense comparative phylogenomics characterization to provide insights into genome evolution under diverse biological and ecological contexts and to functionally annotate the Drosophila melanogaster genome, a model system for animal and insect genetics. Recent sequencing of 11 additional Drosophila species from various divergence points of the genus is a first step in this direction. However, to fully reap the benefits of this resource, the Drosophila community is faced with two critical needs: i.e., the expansion of genomic resources from a much broader range of phylogenetic diversity and the development of additional resources to aid in finishing the existing draft genomes. To address these needs, we report the first synthesis of a comprehensive set of bacterial artificial chromosome (BAC) resources for 19 Drosophila species from all three subgenera. Ten libraries were derived from the exact source used to generate 10 of the 12 draft genomes, while the rest were generated from a strategically selected set of species on the basis of salient ecological and life history features and their phylogenetic positions. The majority of the new species have at least one sequenced reference genome for immediate comparative benefit. This 19-BAC library set was rigorously characterized and shown to have large insert sizes (125-168 kb), low nonrecombinant clone content (0.3-5.3%), and deep coverage (9.1-42.9*). Further, we demonstrated the utility of this BAC resource for generating physical maps of targeted loci, refining draft sequence assemblies and identifying potential genomic rearrangements across the phylogeny. PMID- 21321135 TI - Azole resistance of Aspergillus fumigatus biofilms is partly associated with efflux pump activity. AB - This study investigated the phase-dependent expression and activity of efflux pumps in Aspergillus fumigatus treated with voriconazole. Fourteen strains were shown to become increasingly resistant in the 12-h (16- to 128-fold) and 24-h (>512-fold) phases compared to 8-h germlings. An Ala-Nap uptake assay demonstrated a significant increase in efflux pump activity in the 12-h and 24-h phases (P<0.0001). The efflux pump activity of the 8-h germling cells was also significantly induced by voriconazole (P<0.001) after 24 h of treatment. Inhibition of efflux pump activity with the competitive substrate MC-207,110 reduced the voriconazole MIC values for the A. fumigatus germling cells by 2- to 8-fold. Quantitative expression analysis of AfuMDR4 mRNA transcripts showed a phase-dependent increase as the mycelial complexity increased, which was coincidental with a strain-dependent increase in azole resistance. Voriconazole also significantly induced this in a time-dependent manner (P<0.001). Finally, an in vivo mouse biofilm model was used to evaluate efflux pump expression, and it was shown that AfuMDR4 was constitutively expressed and significantly induced by treatment with voriconazole after 24 h (P<0.01). Our results demonstrate that efflux pumps are expressed in complex A. fumigatus biofilm populations and that this contributes to azole resistance. Moreover, voriconazole treatment induces efflux pump expression. Collectively, these data may provide evidence for azole treatment failures in clinical cases of aspergillosis. PMID- 21321136 TI - Rationale-based, de novo design of dehydrophenylalanine-containing antibiotic peptides and systematic modification in sequence for enhanced potency. AB - Increased microbial drug resistance has generated a global requirement for new anti-infective agents. As part of an effort to develop new, low-molecular-mass peptide antibiotics, we used a rationale-based minimalist approach to design short, nonhemolytic, potent, and broad-spectrum antibiotic peptides with increased serum stability. These peptides were designed to attain an amphipathic structure in helical conformations. VS1 was used as the lead compound, and its properties were compared with three series of derivates obtained by (i) N terminal amino acid addition, (ii) systematic Trp substitution, and (iii) peptide dendrimerization. The Trp substitution approach underlined the optimized sequence of VS2 in terms of potency, faster membrane permeation, and cost-effectiveness. VS2 (a variant of VS1 with two Trp substitutions) was found to exhibit good antimicrobial activity against both the Gram-negative Escherichia coli and the Gram-positive bacterium Staphylococcus aureus. It was also found to have noncytolytic activity and the ability to permeate and depolarize the bacterial membrane. Lysis of the bacterial cell wall and inner membrane by the peptide was confirmed by transmission electron microscopy. A combination of small size, the presence of unnatural amino acids, high antimicrobial activity, insignificant hemolysis, and proteolytic resistance provides fundamental information for the de novo design of an antimicrobial peptide useful for the management of infectious disease. PMID- 21321138 TI - Formulation development of retrocyclin 1 analog RC-101 as an anti-HIV vaginal microbicide product. AB - RC-101 is a synthetic microbicide analog of retrocyclin, which has shown in vitro activity against X4 and R5 HIV-1. In an effort to develop a safe and effective RC 101 vaginal microbicide product, we assessed safety in ex vivo macaque and human models and efficacy using in vitro and ex vivo models. A polyvinyl-alcohol vaginal film containing RC-101 (100 MUg/film) was developed. Formulation assessment was conducted by evaluating disintegration, drug content, mechanical properties, and stability. Efficacy was evaluated by in vitro peripheral blood mononuclear cells (PBMC) assay and ex vivo human ectocervical tissue explant model. Ex vivo safety studies were conducted by exposing RC-101 to an excised monkey reproductive tract and excised human ectocervical tissue. RC-101 100 MUg films were shown to be safe to human and monkey tissue and effective against HIV 1 in vitro and ex vivo in human ectocervical tissue. The 90% inhibitory concentration (IC90) for RC-101 films at 2,000 MUg (IC90=57.5 MUM) using an ex vivo model was 10-fold higher than the IC90 observed using an in vitro model (IC90=5.0 MUM). RC-101 films were stable for 1 month at 25 degrees C, with in vitro bioactivity maintained for up to 6 months. RC-101 was developed in a quick dissolve film formulation that was shown to be safe in an ex vivo model and effective in in vitro and ex vivo models. RC-101 film formulations were shown to maintain bioactivity for a period of 6 months. Findings from the present study contribute to the development of a safe and effective topical microbicide product. PMID- 21321137 TI - Impact of a low-oxygen environment on the efficacy of antimicrobials against intracellular Chlamydia trachomatis. AB - Emergence of chronic inflammation in the urogenital tract induced by Chlamydia trachomatis infection in females is a long-standing concern. To avoid the severe sequelae of C. trachomatis infection, such as pelvic inflammatory diseases (PID), ectopic pregnancies, and tubal infertility, antibiotic strategies aim to eradicate the pathogen even in asymptomatic and uncomplicated infections. Although first-line antimicrobials have proven successful for the treatment of C. trachomatis infection, treatment failures have been observed in a notable number of cases. Due to the obligate intracellular growth of C. trachomatis, reliable antimicrobial susceptibility assays have to consider environmental conditions and host cell-specific factors. Oxygen concentrations in the female urogenital tract are physiologically low and decrease further during an inflammatory process. We compared MIC testing and time-kill curves (TKC) for doxycycline, azithromycin, rifampin, and moxifloxacin under hypoxia (2% O2) and normoxia (20% O2). While low oxygen availability only moderately decreased the antichlamydial activity of azithromycin in conventional MIC testing (0.08 MUg/ml versus 0.04 MUg/ml; P<0.05), TKC analyses revealed profound divergences for antibiotic efficacies between the two conditions. Thus, C. trachomatis was significantly less rapidly killed by doxycycline and azithromycin under hypoxia, whereas the efficacies of moxifloxacin and rifampin remained unaffected using concentrations at therapeutic serum levels. Chemical inhibition of multidrug resistance protein 1 (MDR-1), but not multidrug resistance-associated protein 1 (MRP-1), restored doxycycline activity against intracellular C. trachomatis under hypoxia. We suggest careful consideration of tissue-specific characteristics, including oxygen availability, when testing antimicrobial activities of antibiotics against intracellular bacteria. PMID- 21321139 TI - Activity of and development of resistance to corallopyronin A, an inhibitor of RNA polymerase. AB - We explored the properties of corallopyronin A (CorA), a poorly characterized inhibitor of bacterial RNA polymerase (RNAP). It displayed a 50% inhibitory concentration of 0.73 MUM against RNAP, compared with 11.5 nM for rifampin. The antibacterial activity of CorA was also inferior to rifampin, and resistant mutants of Staphylococcus aureus were easily selected. The mutations conferring resistance resided in the rpoB and rpoC subunits of RNAP. We conclude that CorA is not a promising antibacterial drug candidate. PMID- 21321140 TI - High prevalence of KPC-2-type carbapenemase coupled with CTX-M-type extended spectrum beta-lactamases in carbapenem-resistant Klebsiella pneumoniae in a teaching hospital in China. PMID- 21321141 TI - Aspergillus fumigatus strains with mutations in the cyp51A gene do not always show phenotypic resistance to itraconazole, voriconazole, or posaconazole. AB - We performed molecular identification of 98 Aspergillus fumigatus complex isolates with MICs of 1 to 4 MUg/ml for itraconazole and searched for the presence of mutations in cyp51A. Most of the isolates (91%) belonged to A. fumigatus sensu stricto. We found 14 different mutations in nine isolates at codons different from G54, M220, G138, G448, and L98. We report new mutations at positions 165, 262, 479, and 497 (silent). The role of these mutations should be analyzed. PMID- 21321142 TI - In vitro susceptibility of Burkholderia vietnamiensis to aminoglycosides. AB - Burkholderia cepacia complex (BCC) bacteria are opportunistic pathogens that can cause severe disease in cystic fibrosis (CF) patients and other immunocompromised individuals and are typically multidrug resistant. Here we observed that unlike other BCC species, most environmental and clinical Burkholderia vietnamiensis isolates were intrinsically susceptible to aminoglycosides but not to cationic antimicrobial peptides or polymyxin B. Furthermore, strains acquired aminoglycoside resistance during chronic CF infection, a phenomenon that could be induced under tobramycin or azithromycin pressure in vitro. In comparing susceptible and resistant B. vietnamiensis isolates, no gross differences in lipopolysaccharide structure were observed, all had lipid A-associated 4-amino-4 deoxy-L-arabinose residues, and all were resistant to the permeabilizing effects of aminoglycosides, a measure of drug entry via self-promoted uptake. However, susceptible isolates accumulated 5 to 6 times more gentamicin than a resistant isolate, and aminoglycoside susceptibility increased in the presence of an efflux pump inhibitor. B. vietnamiensis is therefore unusual among BCC bacteria in its susceptibility to aminoglycosides and capacity to acquire resistance. Aminoglycoside resistance appears to be due to decreased cellular accumulation as a result of active efflux. PMID- 21321143 TI - Synergism between outer membrane proteins and antimicrobials. AB - Antibiotic-resistant bacteria are becoming one of the most important problems in health care because of the number of resistant strains and the paucity of new effective antimicrobials. Since antibiotic-resistant bacteria will continue to increase, it is necessary to look for new alternative strategies to fight against them. It is generally accepted that Gram-negative bacteria are intrinsically less susceptible than Gram-positive bacteria to antimicrobials. The main reason is that Gram-negative bacteria are surrounded by a permeability barrier known as the outer membrane (OM). Hydrophilic solutes most often cross the OM through water filled channels formed by a particular family of proteins known as porins. This work explores the possibility of using exogenous porins to lower the required amounts of antibiotics (ampicillin, ciprofloxacin, cefotaxime, clindamycin, erythromycin, and tetracycline). Porins had a bactericidal effect on Escherichia coli cultures, mainly in the logarithmic phase of growth, when combined with low antibiotic concentrations. The use of different antibiotic-porin mixtures showed a bactericidal effect greater than those of antibiotics and porins when used separately. It was possible to observe different behaviors according to the antibiotic type used. PMID- 21321144 TI - In vitro interactions of antimicrobial combinations with fosfomycin against KPC-2 producing Klebsiella pneumoniae and protection of resistance development. AB - Using time-kill methodology, we investigated the interactions of fosfomycin with meropenem or colistin or gentamicin against 17 genetically distinct Klebsiella pneumoniae clinical isolates carrying blaKPC-2. Synergy was observed with meropenem or colistin against 64.7 and 11.8% of tested isolates, while the combination with gentamicin resulted in indifference. All studied combinations showed improved bactericidal activity, compared to fosfomycin alone and prevented the development of fosfomycin resistance in 69.2, 53.8, and 81.8% of susceptible isolates, respectively. PMID- 21321145 TI - Exploring platelet chemokine antimicrobial activity: nuclear magnetic resonance backbone dynamics of NAP-2 and TC-1. AB - The platelet chemokines neutrophil-activating peptide-2 (NAP-2) and thrombocidin 1 (TC-1) differ by only two amino acids at their carboxy-terminal ends. Nevertheless, they display a significant difference in their direct antimicrobial activities, with the longer NAP-2 being inactive and TC-1 being active. In an attempt to rationalize this difference in activity, we studied the structure and the dynamics of both proteins by nuclear magnetic resonance (NMR) spectroscopy. Using 15N isotope-labeled protein, we confirmed that the two monomeric proteins essentially have the same overall structure in aqueous solution. However, NMR relaxation measurements provided evidence that the negatively charged carboxy terminal residues of NAP-2 experience a restricted motion, whereas the carboxy terminal end of TC-1 moves in an unrestricted manner. The same behavior was also seen in molecular dynamic simulations of both proteins. Detailed analysis of the protein motions through model-free analysis, as well as a determination of their overall correlation times, provided evidence for the existence of a monomer-dimer equilibrium in solution, which seemed to be more prevalent for TC-1. This finding was supported by diffusion NMR experiments. Dimerization generates a larger cationic surface area that would increase the antimicrobial activities of these chemokines. Moreover, these data also show that the negatively charged carboxy terminal end of NAP-2 (which is absent in TC-1) folds back over part of the positively charged helical region of the protein and, in doing so, interferes with the direct antimicrobial activity. PMID- 21321147 TI - In vitro activity of nifuratel on vaginal bacteria: could it be a good candidate for the treatment of bacterial vaginosis? AB - Bacterial vaginosis is characterized by a shift of the physiological flora to a diverse spectrum of bacteria, where Gardnerella vaginalis and Atopobium vaginae are the most important markers. In this study, the antimicrobial activity of nifuratel against G. vaginalis, A. vaginae, and lactobacilli was compared with that of the two currently used antibiotics metronidazole and clindamycin. Results suggest that nifuratel has a better spectrum of activity, being highly active against G. vaginalis and A. vaginae without affecting lactobacilli. PMID- 21321146 TI - Loss of mitochondrial functions associated with azole resistance in Candida glabrata results in enhanced virulence in mice. AB - Mitochondrial dysfunction is one of the possible mechanisms by which azole resistance can occur in Candida glabrata. Cells with mitochondrial DNA deficiency (so-called "petite mutants") upregulate ATP binding cassette (ABC) transporter genes and thus display increased resistance to azoles. Isolation of such C. glabrata mutants from patients receiving antifungal therapy or prophylaxis has been rarely reported. In this study, we characterized two sequential and related C. glabrata isolates recovered from the same patient undergoing azole therapy. The first isolate (BPY40) was azole susceptible (fluconazole MIC, 4 MUg/ml), and the second (BPY41) was azole resistant (fluconazole MIC, >256 MUg/ml). BPY41 exhibited mitochondrial dysfunction and upregulation of the ABC transporter genes C. glabrata CDR1 (CgCDR1), CgCDR2, and CgSNQ2. We next assessed whether mitochondrial dysfunction conferred a selective advantage during host infection by testing the virulence of BPY40 and BPY41 in mice. Surprisingly, even with in vitro growth deficiency compared to BPY40, BPY41 was more virulent (as judged by mortality and fungal tissue burden) than BPY40 in both systemic and vaginal murine infection models. The increased virulence of the petite mutant correlated with a drastic gain of fitness in mice compared to that of its parental isolate. To understand this unexpected feature, genome-wide changes in gene expression driven by the petite mutation were analyzed by use of microarrays during in vitro growth. Enrichment of specific biological processes (oxido-reductive metabolism and the stress response) was observed in BPY41, all of which was consistent with mitochondrial dysfunction. Finally, some genes involved in cell wall remodelling were upregulated in BPY41 compared to BPY40, which may partially explain the enhanced virulence of BPY41. In conclusion, this study shows for the first time that mitochondrial dysfunction selected in vivo under azole therapy, even if strongly affecting in vitro growth characteristics, can confer a selective advantage under host conditions, allowing the C. glabrata mutant to be more virulent than wild-type isolates. PMID- 21321148 TI - Impact of dose de-escalation and escalation on daptomycin's pharmacodynamics against clinical methicillin-resistant Staphylococcus aureus isolates in an in vitro model. AB - De-escalation and escalation therapeutic strategies are commonly employed by clinicians on the basis of susceptibility results and patient response. Since no in vitro or in vivo data are currently available to support one strategy over the other for daptomycin, we attempted to evaluate the effects of dose escalation and de-escalation on daptomycin activity against methicillin-resistant Staphylococcus aureus (MRSA) isolates using an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model with simulated endocardial vegetations. Three clinical MRSA isolates, including one heterogeneous vancomycin-intermediate S. aureus (hVISA) isolate and one vancomycin-intermediate S. aureus (VISA) isolate, were exposed to daptomycin at 10 or 6 mg/kg of body weight/day for 8 days using a starting inoculum of ~10(9) CFU/g of vegetations, with dose escalation and de-escalation initiated on the fourth day. Daptomycin MIC values ranged from 0.5 to 1 MUg/ml. In the PK/PD model, high-dose daptomycin (10 mg/kg/day) and de-escalation simulation (10 to 6 mg/kg/day) appeared to be the most efficient regimens against the three tested isolates, exhibiting the fastest bactericidal activity (4 to 8 h) compared to that of the standard regimen of 6 mg/kg/day and the escalation therapy of 6 to 10 mg/kg/day. The differences in the numbers of CFU/g observed between dose escalation and de-escalation were significant for the hVISA strain, with the de escalation simulation exhibiting a better killing effect than the escalation simulation (P<0.024). Although our results need to be carefully considered, the use of high-dose daptomycin up front demonstrated the most efficient activity against the tested isolates. Different therapeutic scenarios including isolates with higher MICs and prolonged drug exposures are warranted to better understand the outcomes of escalation and de-escalation strategies. PMID- 21321149 TI - Antimicrobial activity of CXA-101, a novel cephalosporin tested in combination with tazobactam against Enterobacteriaceae, Pseudomonas aeruginosa, and Bacteroides fragilis strains having various resistance phenotypes. AB - CXA-101, a novel oxyimino-aminothiazolyl cephalosporin, CXA-201 (CXA-101 combined with tazobactam), and various comparators were susceptibility tested by broth microdilution methods against 1,301 well-characterized clinical strains collected worldwide, including ceftazidime-resistant members of the family Enterobacteriaceae and Klebsiella pneumoniae carbapenemase (KPC)- and extended spectrum beta-lactamase (ESBL)-producing strains of Pseudomonas aeruginosa and Bacteroides fragilis. CXA-201 was 2- to 32-fold more active than ceftazidime and piperacillin-tazobactam against ceftazidime-resistant Enterobacteriaceae species but less active than cefepime for some species. CXA-101 and CXA-201 were very active against P. aeruginosa (MIC50, 1 MUg/ml for both compounds), including imipenem-resistant strains. PMID- 21321150 TI - Hypertension, white matter hyperintensities, and concurrent impairments in mobility, cognition, and mood: the Cardiovascular Health Study. AB - BACKGROUND: Our objective was to investigate the association between hypertension and concurrent impairments in mobility, cognition, and mood; the role of brain white matter hyperintensities in mediating this association; and the impact of these impairments on disability and mortality in elderly hypertensive individuals. METHODS AND RESULTS: -Blood pressure, gait speed, digit symbol substitution test, and the Center for Epidemiological Studies Depression Scale were measured yearly (1992-1999) on 4700 participants in the Cardiovascular Health Study (age: 74.7, 58% women, 17% blacks, 68% hypertension, 3600 had brain magnetic resonance imaging in 1992-1993, survival data 1992-2005). Using latent profile analysis at baseline, we found that 498 (11%) subjects had concurrent impairments and 3086 (66%) were intact on all 3 measures. Between 1992 and 1999, 651 (21%) became impaired in all 3 domains. Hypertensive individuals were more likely to be impaired at baseline (odds ratio 1.23, 95% confidence interval 1.04 to 1.42, P=0.01) and become impaired during the follow-up (hazard ratio=1.3, 95% confidence interval 1.02 to 1.66, P=0.037). A greater degree of white matter hyperintensities was associated with impairments in the 3 domains (P=0.007) and mediated the association with hypertension (P=0.19 for hypertension after adjusting for white matter hyperintensities in the model, 21% hazard ratio change). Impairments in the 3 domains increased subsequent disability with hypertension (P<0.0001). Hypertension mortality also was increased in those impaired (compared with unimpaired hypertensive individuals: HR=1.10, 95% confidence interval 1.04 to 1.17, P=0.004). CONCLUSIONS: Hypertension increases the risk of concurrent impairments in mobility, cognition, and mood, which increases disability and mortality. This association is mediated in part by microvascular brain injury. PMID- 21321151 TI - Congenital heart defects in Europe: prevalence and perinatal mortality, 2000 to 2005. AB - BACKGROUND: This study determines the prevalence of Congenital Heart Defects (CHD), diagnosed prenatally or in infancy, and fetal and perinatal mortality associated with CHD in Europe. METHODS AND RESULTS: Data were extracted from the European Surveillance of Congenital Anomalies central database for 29 population based congenital anomaly registries in 16 European countries covering 3.3 million births during the period 2000 to 2005. CHD cases (n=26 598) comprised live births, fetal deaths from 20 weeks gestation, and terminations of pregnancy for fetal anomaly (TOPFA). The average total prevalence of CHD was 8.0 per 1000 births, and live birth prevalence was 7.2 per 1000 births, varying between countries. The total prevalence of nonchromosomal CHD was 7.0 per 1000 births, of which 3.6% were perinatal deaths, 20% prenatally diagnosed, and 5.6% TOPFA. Severe nonchromosomal CHD (ie, excluding ventricular septal defects, atrial septal defects, and pulmonary valve stenosis) occurred in 2.0 per 1000 births, of which 8.1% were perinatal deaths, 40% were prenatally diagnosed, and 14% were TOPFA (TOPFA range between countries 0% to 32%). Live-born CHD associated with Down syndrome occurred in 0.5 per 1000 births, with > 4-fold variation between countries. CONCLUSION: Annually in the European Union, we estimate 36 000 children are live born with CHD and 3000 who are diagnosed with CHD die as a TOFPA, late fetal death, or early neonatal death. Investing in primary prevention and pathogenetic research is essential to reduce this burden, as well as continuing to improve cardiac services from in utero to adulthood. PMID- 21321152 TI - Outcome of patients with low-gradient "severe" aortic stenosis and preserved ejection fraction. AB - BACKGROUND: Retrospective studies have suggested that patients with a low transvalvular gradient in the presence of an aortic valve area < 1.0 cm2 and normal ejection fraction may represent a subgroup with an advanced stage of aortic valve disease, reduced stroke volume, and poor prognosis requiring early surgery. We therefore evaluated the outcome of patients with low-gradient "severe" stenosis (defined as aortic valve area < 1.0 cm2 and mean gradient <= 40 mm Hg) in the prospective Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. METHODS AND RESULTS: Outcome in patients with low-gradient "severe" aortic stenosis was compared with outcome in patients with moderate stenosis (aortic valve area 1.0 to 1.5 cm2; mean gradient 25 to 40 mm Hg). The primary end point of aortic valve events included death from cardiovascular causes, aortic valve replacement, and heart failure due to aortic stenosis. Secondary end points were major cardiovascular events and cardiovascular death. In 1525 asymptomatic patients (mean age, 67 +/- 10 years; ejection fraction, >= 55%), baseline echocardiography revealed low-gradient severe stenosis in 435 patients (29%) and moderate stenosis in 184 (12%). Left ventricular mass was lower in patients with low-gradient severe stenosis than in those with moderate stenosis (182 +/- 64 versus 212 +/- 68 g; P < 0.01). During 46 months of follow-up, aortic valve events occurred in 48.5% versus 44.6%, respectively (P = 0.37; major cardiovascular events, 50.9% versus 48.5%, P = 0.58; cardiovascular death, 7.8% versus 4.9%, P = 0.19). Low-gradient severe stenosis patients with reduced stroke volume index (<= 35 mL/m2; n = 223) had aortic valve events comparable to those in patients with normal stroke volume index (46.2% versus 50.9%; P = 0.53). CONCLUSIONS: Patients with low-gradient "severe" aortic stenosis and normal ejection fraction have an outcome similar to that in patients with moderate stenosis. PMID- 21321153 TI - Notch1 in bone marrow-derived cells mediates cardiac repair after myocardial infarction. AB - BACKGROUND: The signaling mechanisms that regulate the recruitment of bone marrow (BM)-derived cells to the injured heart are not well known. Notch receptors mediate binary cell fate determination and may regulate the function of BM derived cells. However, it is not known whether Notch1 signaling in BM-derived cells mediates cardiac repair after myocardial injury. METHODS AND RESULTS: Mice with postnatal cardiac-specific deletion of Notch1 exhibit infarct size and heart function after ischemic injury that is similar to that of control mice. However, mice with global hemizygous deletion of Notch1 (N1(+/-)) developed larger infarct size and worsening heart function. When the BM of N1(+/-) mice were transplanted into wild-type (WT) mice, infarct size and heart function were worsened and neovascularization in the infarct border area was reduced compared with WT mice transplanted with WT BM. In contrast, transplantation of WT BM into N1(+/-) mice lessened the myocardial injury observed in N1(+/-) mice. Indeed, hemizygous deletion of Notch1 in BM-derived cells leads to decreased recruitment, proliferation, and survival of mesenchymal stem cells (MSC). Compared with WT MSC, injection of N1(+/-) MSC into the infarcted heart leads to increased myocardial injury whereas injection of MSC overexpressing Notch intracellular domain leads to decreased infarct size and improved cardiac function. CONCLUSIONS: These findings indicate that Notch1 signaling in BM-derived cells is critical for cardiac repair and suggest that strategies that increase Notch1 signaling in BM-derived MSC could have therapeutic benefits in patients with ischemic heart disease. PMID- 21321154 TI - Low prevalence of "ideal cardiovascular health" in a community-based population: the heart strategies concentrating on risk evaluation (Heart SCORE) study. AB - BACKGROUND: Cardiovascular health is a new construct defined by the American Heart Association (AHA) as part of its 2020 Impact Goal definition. The applicability of this construct to community-based populations and the distributions of its components by race and sex have not been reported. METHODS AND RESULTS: The AHA construct of cardiovascular health and the AHA ideal health behaviors index and ideal health factors index were evaluated among 1933 participants (mean age 59 years; 44% blacks; 66% women) in the community-based Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study. One of 1933 participants (0.1%) met all 7 components of the AHA's definition of ideal cardiovascular health. Less than 10% of participants met >= 5 components of ideal cardiovascular health in all subgroups (by race, sex, age, and income level). Thirty-nine subjects (2.0%) had all 4 components of the ideal health behaviors index and 27 (1.4%) had all 3 components of the ideal health factors index. Blacks had significantly fewer ideal cardiovascular health components than whites (2.0 +/- 1.2 versus 2.6 +/- 1.4; P < 0.001). After adjustment by sex, age, and income level, blacks had 82% lower odds of having >= 5 components of ideal cardiovascular health (odds ratio 0.18, 95% confidence interval, 0.10 to 0.34; P<0.001). No interaction was found between race and sex. CONCLUSION: The prevalence of ideal cardiovascular health is extremely low in a middle-aged community-based study population. Comprehensive individual and population-based interventions must be developed to support the attainment of the AHA's 2020 Impact Goal for cardiovascular health. PMID- 21321155 TI - 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on Dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. PMID- 21321156 TI - Is hypothermia after cardiac arrest effective in both shockable and nonshockable patients?: insights from a large registry. AB - BACKGROUND: Although the level of evidence of improvement is significant in cardiac arrest patients resuscitated from a shockable rhythm (ventricular fibrillation or pulseless ventricular tachycardia [VF/Vt]), the use of therapeutic mild hypothermia (TMH) is more controversial in nonshockable patients (pulseless electric activity or asystole [PEA/asystole]). We therefore assessed the prognostic value of hypothermia for neurological outcome at hospital discharge according to first-recorded cardiac rhythm in a large cohort. METHODS AND RESULTS: Between January 2000 and December 2009, data from 1145 consecutive out-of-hospital cardiac arrest patients in whom a successful resuscitation had been achieved were prospectively collected. The association of TMH with a good neurological outcome at hospital discharge (cerebral performance categories level 1 or 2) was quantified by logistic regression analysis. TMH was induced in 457/708 patients (65%) in VF/Vt and in 261/437 patients (60%) in PEA/asystole. Overall, 342/1145 patients (30%) reached a favorable outcome (cerebral performance categories level 1 or 2) at hospital discharge, respectively 274/708 (39%) in VF/Vt and 68/437 (16%) in PEA/asystole (P<0.001). After adjustment, in VF/Vt patients, TMH was associated with increased odds of good neurological outcome (adjusted odds ratio, 1.90; 95% confidence interval, 1.18 to 3.06) whereas in PEA/asystole patients, TMH was not significantly associated with good neurological outcome (adjusted odds ratio, 0.71; 95% confidence interval, 0.37 to 1.36). CONCLUSIONS: In this large cohort of cardiac arrest patients, hypothermia was independently associated with an improved outcome at hospital discharge in patients presenting with VF/Vt. By contrast, TMH was not associated with good outcome in nonshockable patients. Further investigations are needed to clarify this lack of efficiency in PEA/asystole. PMID- 21321157 TI - Comparison of the structure of the aortic valve and ascending aorta in adults having aortic valve replacement for aortic stenosis versus for pure aortic regurgitation and resection of the ascending aorta for aneurysm. AB - BACKGROUND: There is debate concerning whether an aneurysmal ascending aorta should be replaced when associated with a dysfunctioning aortic valve that is to be replaced. To examine this issue, we divided the patients by type of aortic valve dysfunction-either aortic stenosis (AS) or pure aortic regurgitation (AR) something not previously undertaken. METHODS AND RESULTS: Of 122 patients with ascending aortic aneurysm (unassociated with aortitis or acute dissection), the aortic valve was congenitally malformed (unicuspid or bicuspid) in 58 (98%) of the 59 AS patients, and in 38 (60%) of the 63 pure AR patients. Ascending aortic medial elastic fiber loss (EFL) (graded 0 to 4+) was zero or 1+ in 53 (90%) of the AS patients, in 20 (53%) of the 38 AR patients with bicuspid valves, and in all 12 AR patients with tricuspid valves unassociated with the Marfan syndrome. An unadjusted analysis showed that, among the 96 patients with congenitally malformed valves, the 38 AR patients had a significantly higher likelihood of 2+ to 4+ EFL than the 58 AS patients (crude odds ratio: 8.78; 95% confidence interval: 2.95, 28.13). CONCLUSIONS: These data strongly suggest that the type of aortic valve dysfunction-AS versus pure AR-is very helpful in predicting loss of aortic medial elastic fibers in patients with ascending aortic aneurysms and aortic valve disease. PMID- 21321158 TI - Is ideal cardiovascular health attainable? PMID- 21321159 TI - Low-gradient "severe" aortic stenosis with normal systolic function: time to refine the guidelines? PMID- 21321160 TI - Training family medicine residents to care for children: What is the best approach? AB - Problem addressed There is a lack of consensus around the optimal way to train family medicine residents to care for children. Objective of program Evaluation of an ambulatory versus an inpatient pediatrics rotation for family medicine residents. Program description A 4-week pediatrics rotation for second-year family medicine residents was introduced involving half-day ambulatory pediatric clinics. A nonequivalent control group evaluation study design was followed. Patient logbook entries, as well as residents' satisfaction, knowledge, and self reported confidence outcomes were compared between family medicine residents completing the new ambulatory rotation and those completing a traditional inpatient-ambulatory pediatrics rotation. Conclusion An ambulatory rotation in pediatrics is a feasible option for facilitating family medicine resident learning in child health care. Residents report exposure to more patient cases that reflect a family practice office setting and the same level of knowledge and confidence as residents completing an inpatient-ambulatory rotation. Intraprofessional collaboration, flexibility in scheduling, and the support of pediatric preceptors are key factors in the organization and implementation of an ambulatory rotation. PMID- 21321161 TI - The faces of family medicine: David White MD CCFP FCFP. PMID- 21321162 TI - Suicide among men. PMID- 21321163 TI - Men and depression. PMID- 21321164 TI - Drug-related problems in the frail elderly. PMID- 21321165 TI - Doctors should not evaluate competence to drive. PMID- 21321166 TI - Revamping to save time and money. PMID- 21321167 TI - Fitness does not equal competence. PMID- 21321168 TI - Common nail changes and disorders in older people: Diagnosis and management. AB - Objective To present family physicians with common nail alterations and disorders occurring in the elderly population and their management options. Quality of evidence The evidence relating to different nail conditions is mostly derived from randomized controlled trials, meta-analyses, and review articles. However, given the scarcity of evidence on some conditions, articles with weaker levels of evidence were also included in our review. Main message Given the growing elderly population and the associated demographic changes and longer lifespans, geriatric care is becoming more of a complicated and multidisciplinary effort in which the role of the family physician is increasingly important. Although common among the elderly, nail changes are often not brought to the attention of primary caregivers and are thus overlooked. These nail changes can affect various components of the nail unit and might represent normal age-related nail alterations or nail abnormalities that require immediate intervention. Knowledge and familiarity with these common nail abnormalities and their underlying causes is important for the family practitioner in order to effectively reach an accurate diagnosis and provide better care of this large and growing elderly population. Conclusion Nail changes are common in the elderly, and family physicians are best placed to diagnose and treat these common problems. It is important that family physicians also recognize less common but more serious nail problems that require immediate treatment. PMID- 21321169 TI - Primary hyperparathyroidism: Update on presentation, diagnosis, and management in primary care. AB - Objective To discuss the presentation, diagnosis, and management of primary hyperparathyroidism (PHPT) in family medicine. Quality of evidence MEDLINE was searched from 2002 to 2009 using the terms presentation, diagnosis, and treatment of PHPT. Proceedings and guidelines from the Third International Workshop on Primary Hyperparathyroidism in May 2008 were reviewed in detail. Most studies offered level II and III evidence, although there were a number of single randomized controlled trials on PHPT (level I evidence). References from pertinent papers were also searched for relevant articles. Articles most relevant to family medicine and primary care practitioners are presented. Main message Primary hyperparathyroidism is the most common cause of hypercalcemia in outpatients. In the Western world, most patients with PHPT present with nonspecific symptoms such as fatigue, mood disturbances, and cognitive impairments. Diagnosis is established when intact parathyroid hormone levels are elevated or at the high end of the normal range in the setting of elevated total or ionized calcium levels (following exclusion of conditions that can mimic PHPT). Criteria for surgery have recently been modified. Surgery is always a suitable option in those with symptomatic PHPT and no contraindications. Those with contraindications or with asymptomatic PHPT not meeting the criteria for surgery can generally be safely monitored and considered for medical management. This might include treatment with bisphosphonates, hormone replacement therapy, raloxifene, or calcimimetic agents; however, there are currently no fracture data for any of these options. Conclusion The definitive therapy for symptomatic and asymptomatic PHPT is parathyroidectomy. In patients with asymptomatic PHPT not meeting the criteria for surgery, monitoring is safe and medical management designed to target skeletal protection or lower serum calcium is a suitable option. PMID- 21321170 TI - Medical management of renal stones: More than analgesia? PMID- 21321171 TI - Question: Can you identify this condition? PMID- 21321172 TI - Part 3. The reward chart. PMID- 21321173 TI - True mentorship in medicine. PMID- 21321174 TI - Planting seeds. PMID- 21321175 TI - Unacceptable emergency wait times. PMID- 21321176 TI - Cardiac magnetic resonance aids in the diagnosis of mitochondrial cardiomyopathy. PMID- 21321177 TI - Coronary angiitis and cardiac arrest in antineutrophil cytoplasmic-antibody associated systemic vasculitis. PMID- 21321178 TI - Letter by Goetze et al regarding article, "B-type natriuretic peptide signal peptide circulates in human blood: evaluation as a potential biomarker of cardiac ischemia". PMID- 21321179 TI - Letter by Kavsak et al regarding article, "B-type natriuretic peptide signal peptide circulates in human blood: evaluation as a potential biomarker of cardiac ischemia". PMID- 21321180 TI - Assessment of systolic dyssynchrony for cardiac resynchronization therapy is clinically useful. PMID- 21321181 TI - Assessment of systolic dyssynchrony for cardiac resynchronization therapy is not clinically useful. PMID- 21321182 TI - Optimal duration of anticoagulation after venous thromboembolism. PMID- 21321183 TI - Cardiopulmonary exercise testing in the clinical evaluation of patients with heart and lung disease. PMID- 21321184 TI - Evidence and education. PMID- 21321185 TI - Atrioventricular valve dyssynchrony resulting from severe mitral regurgitation. PMID- 21321186 TI - A robust in vivo positive-readout system for monitoring siRNA delivery to xenograft tumors. AB - Delivering small interfering RNA (siRNA) to tumors is the major technical hurdle that prevents the advancement of siRNA-based cancer therapy. One of the difficulties associated with the development of clinically relevant delivery systems is the lack of reliable tools for monitoring siRNA delivery to tumors in vivo. We describe here a novel, positive-readout system where siRNA-mediated target knockdown elicits a rapid and robust increase of reporter activity. Using the positive-readout system, we created (1) beta-galactosidase-based tumor models that allow the detection of target knockdown in 1%-2% of tumor cells and can distinguish between tumor areas where effective target knockdown occurs versus tumor areas that are not accessible to delivery, and (2) luciferase-based tumor models that allow the quantitative assessment of a large number of delivery systems. Using these positive-readout models, we screened a number of literature described siRNA delivery systems and identified lipid nanoparticles as a promising delivery platform for siRNA-based cancer therapy. PMID- 21321187 TI - Modification of Akt1 by methylglyoxal promotes the proliferation of vascular smooth muscle cells. AB - Methylglyoxal (MG), a reactive dicarbonyl molecule, can modify protein to form advanced glycation endproducts. Increased MG level has been implicated in proliferative vascular diseases, but the underlying mechanisms are not clear yet. The serine/threonine kinase, Akt, regulates multiple signaling pathways that control cell proliferation. Using mass spectrometric analysis, we have detected the modification of Akt1 by MG at Cys(77). This structural modification increased Akt1 phosphorylation at Ser(473) and Thr(308). Akt1 phosphorylation and activity were also increased by MG treatment (<50 MUM) in cultured vascular smooth muscle cells (VSMCs). MG treatment of VSMCs led to increased DNA synthesis (EC(50)=5.8 MUM), cell proliferation, phosphorylation of p21 and glycogen synthase kinase 3alpha/beta (GSK-3alpha/beta), and increased cyclin-dependent kinase 2 (CDK2) activity. These effects of MG were significantly inhibited by silencing Akt1 or by an Akt inhibitor. Overexpression of Akt1 Cys(77)Ser mutant in HEK-293 cells increased cell proliferation and DNA synthesis, concurrent with an increase in Akt1 activity, which could not be further augmented by MG treatment. It is concluded that MG-induced VSMC proliferation is mediated by the activation of Akt1 via the modification of Akt1 at Cys(77). PMID- 21321188 TI - Resolution of Toll-like receptor 4-mediated acute lung injury is linked to eicosanoids and suppressor of cytokine signaling 3. AB - The purpose of this study was to investigate roles for Toll-like receptor 4 (TLR4) in host responses to sterile tissue injury. Hydrochloric acid was instilled into the left mainstem bronchus of TLR4-defective (both C3H/HeJ and congenic C.C3-Tlr4(Lps-d)/J) and control mice to initiate mild, self-limited acute lung injury (ALI). Outcome measures included respiratory mechanics, barrier integrity, leukocyte accumulation, and levels of select soluble mediators. TLR4 defective mice were more resistant to ALI, with significantly decreased perturbations in lung elastance and resistance, resulting in faster resolution of these parameters [resolution interval (R(i)); ~6 vs. 12 h]. Vascular permeability changes and oxidative stress were also decreased in injured HeJ mice. These TLR4 defective mice paradoxically displayed increased lung neutrophils [(HeJ) 24*10(3) vs. (control) 13*10(3) cells/bronchoalveolar lavage]. Proresolving mechanisms for TLR4-defective animals included decreased eicosanoid biosynthesis, including cysteinyl leukotrienes (80% mean decrease) that mediated CysLT1 receptor dependent vascular permeability changes; and induction of lung suppressor of cytokine signaling 3 (SOCS3) expression that decreased TLR4-driven oxidative stress. Together, these findings indicate pivotal roles for TLR4 in promoting sterile ALI and suggest downstream provocative roles for cysteinyl leukotrienes and protective roles for SOCS3 in the intensity and duration of host responses to ALI. PMID- 21321189 TI - Hepatic overexpression of SIRT1 in mice attenuates endoplasmic reticulum stress and insulin resistance in the liver. AB - Endoplasmic reticulum (ER) stress has been implicated in the pathophysiology of human type 2 diabetes (T2DM). Although SIRT1 has a therapeutic effect on metabolic deterioration in T2DM, the precise mechanisms by which SIRT1 improves insulin resistance remain unclear. Here, we demonstrate that adenovirus-mediated overexpression of SIRT1 in the liver of diet-induced insulin-resistant low density lipoprotein receptor-deficient mice and of genetically obese ob/ob mice attenuates hepatic steatosis and ameliorates systemic insulin resistance. These beneficial effects were associated with decreased mammalian target of rapamycin complex 1 (mTORC1) activity, inhibited the unfolded protein response (UPR), and enhanced insulin receptor signaling in the liver, leading to decreased hepatic gluconeogenesis and improved glucose tolerance. The tunicamycin-induced splicing of X-box binding protein-1 and expression of GRP78 and CHOP were reduced by resveratrol in cultured cells in a SIRT1-dependent manner. Conversely, SIRT1 deficient mouse embryonic fibroblasts challenged with tunicamycin exhibited markedly increased mTORC1 activity and impaired ER homeostasi and insulin signaling. These effects were abolished by mTORC1 inhibition by rapamycin in human HepG2 cells. These studies indicate that SIRT1 serves as a negative regulator of UPR signaling in T2DM and that SIRT1 attenuates hepatic steatosis, ameliorates insulin resistance, and restores glucose homeostasis, largely through the inhibition of mTORC1 and ER stress. PMID- 21321190 TI - Wnt1 is a proangiogenic molecule, enhances human endothelial progenitor function, and increases blood flow to ischemic limbs in a HGF-dependent manner. AB - Human endothelial progenitor cells (hEPCs) participate in neovascularization of ischemic tissues. Function and number of hEPCs decline in patients with cardiovascular disease, and therapeutic strategies to enhance hEPC function remain an important field of investigation. The Wnt signaling system, comprising 19 lipophilic proteins, regulates vascular patterning in the developing embryo. However, the effects of Wnts on hEPCs and the adult vasculature remain unclear. We demonstrate here that Wnt1 is expressed in a subset of endothelial cells lining the murine embryonic dorsal aorta and is reactivated in malignant angiosarcoma, suggesting a strong association of Wnt1 with angiogenesis. We investigate the effects of Wnt1 in enhancing hEPC function and blood flow to ischemic tissues and show that Wnt1 enhances the proliferative and angiogenic functions of hEPCs in a hepatocyte growth factor (HGF)-dependent manner. Injection of Wnt1-expressing hEPCs increases blood flow and capillary density in murine ischemic hindlimbs. Furthermore, injection of Wnt1 protein alone similarly increases blood flow and capillary density in ischemic hindlimbs, and this effect is associated with increased HGF expression in ischemic muscle. These findings demonstrate that Wnt1, a marker of neural crest cells and hitherto unknown angiogenic function, is a novel angiogenic protein that is expressed in developing endothelial cells, exerts salutary effects on postnatal hEPCs, and can be therapeutically deployed to increase blood flow and angiogenesis in ischemic tissues. PMID- 21321191 TI - Activation of the NF-kappaB pathway by adeno-associated virus (AAV) vectors and its implications in immune response and gene therapy. AB - Because our in silico analysis with a human transcription factor database demonstrated the presence of several binding sites for NF-kappaB, a central regulator of cellular immune and inflammatory responses, in the adeno-associated virus (AAV) genome, we investigated whether AAV uses NF-kappaB during its life cycle. We used small molecule modulators of NF-kappaB in HeLa cells transduced with recombinant AAV vectors. VP16, an NF-kappaB activator, augmented AAV vector mediated transgene expression up to 25-fold. Of the two NF-kappaB inhibitors, Bay11, which blocks both the canonical and the alternative NF-kappaB pathways, totally ablated transgene expression, whereas pyrrolidone dithiocarbamate, which interferes with the classical NF-kappaB pathway, had no effect. Western blot analyses confirmed the abundance of the nuclear p52 protein component of the alternative NF-kappaB pathway in the presence of VP16, which was ablated by Bay11, suggesting that AAV transduction activates the alternative NF-kappaB pathway. In vivo, hepatic AAV gene transfer activated the canonical NF-kappaB pathway within 2 h, resulting in expression of proinflammatory cytokines and chemokines (likely reflecting the sensing of viral particles by antigen presenting cells), whereas the alternative pathway was activated by 9 h. Bay11 effectively blocked activation of both pathways without interfering with long term transgene expression while eliminating proinflammatory cytokine expression. These studies suggest that transient immunosuppression with NF-kappaB inhibitors before transduction with AAV vectors should lead to a dampened immune response, which has significant implications in the optimal use of AAV vectors in human gene therapy. PMID- 21321192 TI - Antagonists of growth hormone-releasing hormone (GHRH) reduce prostate size in experimental benign prostatic hyperplasia. AB - Growth hormone-releasing hormone (GHRH), a hypothalamic polypeptide, acts as a potent autocrine/paracrine growth factor in many cancers. Benign prostatic hyperplasia (BPH) is a pathologic proliferation of prostatic glandular and stromal tissues; a variety of growth factors and inflammatory processes are inculpated in its pathogenesis. Previously we showed that potent synthetic antagonists of GHRH strongly inhibit the growth of diverse experimental human tumors including prostate cancer by suppressing various tumoral growth factors. The influence of GHRH antagonists on animal models of BPH has not been investigated. We evaluated the effects of the GHRH antagonists JMR-132 given at doses of 40 MUg/d, MIA-313 at 20 MUg/d, and MIA-459 at 20 MUg/d in testosterone induced BPH in Wistar rats. Reduction of prostate weights was observed after 6 wk of treatment with GHRH antagonists: a 17.8% decrease with JMR-132 treatment; a 17.0% decline with MIA-313 treatment; and a 21.4% reduction with MIA-459 treatment (P < 0.05 for all). We quantified transcript levels of genes related to growth factors, inflammatory cytokines, and signal transduction and identified significant changes in the expression of more than 80 genes (P < 0.05). Significant reductions in protein levels of IL-1beta, NF-kappabeta/p65, and cyclooxygenase-2 (COX-2) also were observed after treatment with a GHRH antagonist. We conclude that GHRH antagonists can lower prostate weight in experimental BPH. This reduction is caused by the direct inhibitory effects of GHRH antagonists exerted through prostatic GHRH receptors. This study sheds light on the mechanism of action of GHRH antagonists in BPH and suggests that GHRH antagonists should be considered for further development as therapy for BPH. PMID- 21321193 TI - Interleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica. AB - Neuromyelitis optica (NMO) is an inflammatory disease affecting the optic nerve and spinal cord, in which autoantibodies against aquaporin 4 (AQP4) water channel protein probably play a pathogenic role. Here we show that a B-cell subpopulation, exhibiting the CD19(int)CD27(high)CD38(high)CD180(-) phenotype, is selectively increased in the peripheral blood of NMO patients and that anti-AQP4 antibodies (AQP4-Abs) are mainly produced by these cells in the blood of these patients. These B cells showed the morphological as well as the phenotypical characteristics of plasmablasts (PB) and were further expanded during NMO relapse. We also demonstrate that interleukin 6 (IL-6), shown to be increased in NMO, enhanced the survival of PB as well as their AQP4-Ab secretion, whereas the blockade of IL-6 receptor (IL-6R) signaling by anti-IL-6R antibody reduced the survival of PB in vitro. These results indicate that the IL-6-dependent B-cell subpopulation is involved in the pathogenesis of NMO, thereby providing a therapeutic strategy for targeting IL-6R signaling. PMID- 21321194 TI - Genetic manipulation of lignin reduces recalcitrance and improves ethanol production from switchgrass. AB - Switchgrass is a leading dedicated bioenergy feedstock in the United States because it is a native, high-yielding, perennial prairie grass with a broad cultivation range and low agronomic input requirements. Biomass conversion research has developed processes for production of ethanol and other biofuels, but they remain costly primarily because of the intrinsic recalcitrance of biomass. We show here that genetic modification of switchgrass can produce phenotypically normal plants that have reduced thermal-chemical (<=180 degrees C), enzymatic, and microbial recalcitrance. Down-regulation of the switchgrass caffeic acid O-methyltransferase gene decreases lignin content modestly, reduces the syringyl:guaiacyl lignin monomer ratio, improves forage quality, and, most importantly, increases the ethanol yield by up to 38% using conventional biomass fermentation processes. The down-regulated lines require less severe pretreatment and 300-400% lower cellulase dosages for equivalent product yields using simultaneous saccharification and fermentation with yeast. Furthermore, fermentation of diluted acid-pretreated transgenic switchgrass using Clostridium thermocellum with no added enzymes showed better product yields than obtained with unmodified switchgrass. Therefore, this apparent reduction in the recalcitrance of transgenic switchgrass has the potential to lower processing costs for biomass fermentation-derived fuels and chemicals significantly. Alternatively, such modified transgenic switchgrass lines should yield significantly more fermentation chemicals per hectare under identical process conditions. PMID- 21321195 TI - Efficiency of the CO2-concentrating mechanism of diatoms. AB - Diatoms are responsible for a large fraction of CO(2) export to deep seawater, a process responsible for low modern-day CO(2) concentrations in surface seawater and the atmosphere. Like other photosynthetic organisms, diatoms have adapted to these low ambient concentrations by operating a CO(2) concentrating mechanism (CCM) to elevate the concentration of CO(2) at the site of fixation. We used mass spectrometric measurements of passive and active cellular carbon fluxes and model simulations of these fluxes to better understand the stoichiometric and energetic efficiency and the physiological architecture of the diatom CCM. The membranes of diatoms are highly permeable to CO(2), resulting in a large diffusive exchange of CO(2) between the cell and external milieu. An active transport of carbon from the cytoplasm into the chloroplast is the main driver of the diatom CCM. Only one third of this carbon flux is fixed photosynthetically, and the rest is lost by CO(2) diffusion back to the cytoplasm. Both the passive influx of CO(2) from the external medium and the recycling of the CO(2) leaking out of the chloroplast are achieved by the activity of a carbonic anhydrase enzyme combined with the maintenance of a low concentration of HCO(3)(-) in the cytoplasm. To achieve the CO(2) concentration necessary to saturate carbon fixation, the CO(2) is most likely concentrated within the pyrenoid, an organelle within the chloroplast where the CO(2)-fixating enzyme is located. PMID- 21321196 TI - Brain-state-independent neural representation of peripheral stimulation in rat olfactory bulb. AB - It is critical for normal brains to perceive the external world precisely and accurately under ever-changing operational conditions, yet the mechanisms underlying this fundamental brain function in the sensory systems are poorly understood. To address this issue in the olfactory system, we investigated the responses of olfactory bulbs to odor stimulations under different brain states manipulated by anesthesia levels. Our results revealed that in two brain states, where the spontaneous baseline activities differed about twofold based on the local field potential (LFP) signals, the levels of neural activities reached after the same odor stimulation had no significant difference. This phenomenon was independent of anesthetics (pentobarbital or chloral hydrate), stimulating odorants (ethyl propionate, ethyl butyrate, ethyl valerate, amyl acetate, n heptanal, or 2-heptanone), odor concentrations, and recording sites (the mitral or granular cell layers) for LFPs in three frequency bands (12-32 Hz, 33-64 Hz, and 65-90 Hz) and for multiunit activities. Furthermore, the activity patterns of the same stimulation under these two brain states were highly similar at both LFP and multiunit levels. These converging results argue the existence of mechanisms in the olfactory bulbs that ensure the delivery of peripheral olfactory information to higher olfactory centers with high fidelity under different brain states. PMID- 21321197 TI - Natural selection stops the evolution of male attractiveness. AB - Sexual selection in natural populations acts on highly heritable traits and tends to be relatively strong, implicating sexual selection as a causal agent in many phenotypic radiations. Sexual selection appears to be ineffectual in promoting phenotypic divergence among contemporary natural populations, however, and there is little evidence from artificial selection experiments that sexual fitness can evolve. Here, we demonstrate that a multivariate male trait preferred by Drosophila serrata females can respond to selection and results in the maintenance of male mating success. The response to selection was associated with a gene of major effect increasing in frequency from 12 to 35% in seven generations. No further response to selection, or increase in frequency of the major gene, was observed between generations 7 and 11, indicating an evolutionary limit had been reached. Genetic analyses excluded both depletion of genetic variation and overdominance as causes of the evolutionary limit. Relaxing artificial selection resulted in the loss of 52% of the selection response after a further five generations, demonstrating that the response under artificial sexual selection was opposed by antagonistic natural selection. We conclude that male D. serrata sexually selected traits, and attractiveness to D. serrata females conferred by these traits, were held at an evolutionary limit by the lack of genetic variation that would allow an increase in sexual fitness while simultaneously maintaining nonsexual fitness. Our results suggest that sexual selection is unlikely to cause divergence among natural populations without a concomitant change in natural selection, a conclusion consistent with observational evidence from natural populations. PMID- 21321198 TI - Neuronal assembly dynamics in the beta1 frequency range permits short-term memory. AB - Cell assemblies have long been thought to be associated with brain rhythms, notably the gamma rhythm. Here, we use a computational model to show that the beta1 frequency band, as found in rat association cortex, has properties complementary to the gamma band for the creation and manipulation of cell assemblies. We focus on the ability of the beta1 rhythm to respond differently to familiar and novel stimuli, and to provide a framework for combining the two. Simulations predict that assemblies of superficial layer pyramidal cells can be maintained in the absence of continuing input or synaptic plasticity. Instead, the formation of these assemblies relies on the nesting of activity within a beta1 rhythm. In addition, cells receiving further input after assembly formation produce coexistent spiking activity, unlike the competitive spiking activity characteristic of assembly formation with gamma rhythms. PMID- 21321199 TI - Wounding enhances epidermal tumorigenesis by recruiting hair follicle keratinocytes. AB - Chronic wounds and acute trauma constitute well-established risk factors for development of epithelial-derived skin tumors, although the underlying mechanisms are largely unknown. Basal cell carcinomas (BCCs) are the most common skin cancers displaying a number of features reminiscent of hair follicle (HF)-derived cells and are dependent on deregulated Hedgehog (Hh)/GLI signaling. Here we show, in a mouse model conditionally expressing GLI1 and in a model with homozygous inactivation of Ptch1, mimicking the situation in human BCCs, that the wound environment accelerates the initiation frequency and growth of BCC-like lesions. Lineage tracing reveals that both oncogene activation and wounding induce emigration of keratinocytes residing in the lower bulge and the nonpermanent part of the HFs toward the interfollicular epidermis (IFE). However, only oncogene activation in combination with a wound environment enables the participation of such cells in the initiation of BCC-like lesions at the HF openings and in the IFE. We conclude that, in addition to the direct enhancement of BCC growth, the tumor-promoting effect of the wound environment is due to recruitment of tumor initiating cells originating from the neighboring HFs, establishing a link between epidermal wounds and skin cancer risk. PMID- 21321200 TI - Association of IL28B gene variations with mathematical modeling of viral kinetics in chronic hepatitis C patients with IFN plus ribavirin therapy. AB - Asian patients with chronic hepatitis C (CHC) are known to have better virological responses to pegylated (Peg) IFN-based therapy than Western patients. Although IL28B gene polymorphisms may contribute to this difference, whether favorable hepatitis C virus (HCV) kinetics during treatment plays a role remains unclear. We enrolled 145 consecutive Taiwanese patients with CHC receiving Peg IFN alpha-2a plus ribavirin for the study. Blood samples were taken more frequently at defined intervals in the first 3 d. Peg-IFN was administered at week 1. It was then administered weekly in combination with daily ribavirin for 24 or 48 wk. A mathematical model fitted to the observed HCV kinetics was constructed, which could interpret the transient HCV titer elevation after Peg IFN treatment. The results demonstrated a comparable viral clearance rate (c = 3.45 +/- 3.73) (day(-1), mean +/- SD) but lower daily viral production rate (P = 10(6)-10(12)) in our patients than those reported previously in Western patients. Of 110 patients with a sustained virological response (SVR), 47 (43%) had a transient elevation of viral titer within 12 h (proportion of 12 h/3 d: 44% in non-SVR vs. 70% in SVR; P = 0.029). Among 91 patients with available rs8099917 data, patients with the TT genotype had an early surge of viral titer after therapy and a higher SVR and viral clearance rate than those with the GT genotype. In conclusion, Taiwanese patients with CHC receiving Peg-IFN plus ribavirin therapy have a lower daily viral production rate than Western patients, and the rs8099917 TT genotype may contribute to the increased viral clearance rate and better virological responses in these patients. PMID- 21321201 TI - DNA methyltransferase 1, cytosine methylation, and cytosine hydroxymethylation in mammalian mitochondria. AB - Mitochondrial DNA (mtDNA) has been reported to contain 5-methylcytosine (5mC) at CpG dinucleotides, as in the nuclear genome, but neither the mechanism generating mtDNA methylation nor its functional significance is known. We now report the presence of 5-hydroxymethylcytosine (5hmC) as well as 5mC in mammalian mtDNA, suggesting that previous studies underestimated the level of cytosine modification in this genome. DNA methyltransferase 1 (DNMT1) translocates to the mitochondria, driven by a mitochondrial targeting sequence located immediately upstream of the commonly accepted translational start site. This targeting sequence is conserved across mammals, and the encoded peptide directs a heterologous protein to the mitochondria. DNMT1 is the only member of the three known catalytically active DNA methyltransferases targeted to the mitochondrion. Mitochondrial DNMT1 (mtDNMT1) binds to mtDNA, proving the presence of mtDNMT1 in the mitochondrial matrix. mtDNMT1 expression is up-regulated by NRF1 and PGC1alpha, transcription factors that activate expression of nuclear-encoded mitochondrial genes in response to hypoxia, and by loss of p53, a tumor suppressor known to regulate mitochondrial metabolism. Altered mtDNMT1 expression asymmetrically affects expression of transcripts from the heavy and light strands of mtDNA. Hence, mtDNMT1 appears to be responsible for mtDNA cytosine methylation, from which 5hmC is presumed to be derived, and its expression is controlled by factors that regulate mitochondrial function. PMID- 21321202 TI - Expression, signaling proficiency, and stimulatory function of the NKG2D lymphocyte receptor in human cancer cells. AB - The stimulatory natural killer group 2 member D (NKG2D) lymphocyte receptor and its tumor-associated ligands are important mediators in the immune surveillance of cancer. With advanced human tumors, however, persistent NKG2D ligand expression may favor tumor progression. We have found that cancer cells themselves express NKG2D in complex with the DNAX-activating protein 10 (DAP10) signaling adaptor. Triggering of NKG2D on ex vivo cancer cells or on tumor lines which express only few receptor complexes activates the oncogenic PI3K-protein kinase B (PKB/AKT)-mammalian target of rapamycin (mTOR) signaling axis and downstream effectors, the ribosomal protein S6 kinase 1 (S6K1) and the translation initiation factor 4E-binding protein 1 (4E-BP1). In addition, as in lymphocytes, NKG2D ligand engagement stimulates phosphorylation of JNK and ERK in MAP kinase cascades. Consistent with these signaling activities, above-threshold expression of NKG2D-DAP10 in a ligand-bearing tumor line increases its bioenergetic metabolism and proliferation, thus suggesting functional similarity between this immunoreceptor and tumor growth factor receptors. This relationship is supported by significant correlations between percentages of cancer cells that are positive for surface NKG2D and criteria of tumor progression. Hence, in a conceptual twist, these results suggest that tumor co-option of NKG2D immunoreceptor expression may complement the presence of its ligands for stimulation of tumor growth. PMID- 21321203 TI - Purkinje cell-specific males absent on the first (mMof) gene deletion results in an ataxia-telangiectasia-like neurological phenotype and backward walking in mice. AB - The brains of ataxia telangiectasia (AT) patients display an aberrant loss of Purkinje cells (PCs) that is postulated to contribute to the observed deficits in motor coordination as well as in learning and cognitive function. AT patients have mutations in the ataxia telangiectasia mutated (ATM) gene [Savitsky et al. (1995) Science 268:1749-1753]. However, in Atm-deficient mice, the neurological defects are limited, and the PCs are not deformed or lost as observed in AT patients [Barlow et al. (1996) Cell 86:159-171]. Here we report that PC-specific deletion of the mouse males absent on the first (mMof) gene (Cre(-)), which encodes a protein that specifically acetylates histone H4 at lysine 16 (H4K16ac) and influences ATM function, is critical for PC longevity. Mice deficient for PC specific Mof display impaired motor coordination, ataxia, a backward-walking phenotype, and a reduced life span. Treatment of Mof(F/F)/Pcp2-Cre(+) mice with histone deacetylase inhibitors modestly prolongs PC survival and delays death. Therefore, Mof expression and H4K16 acetylation are essential for PC survival and function, and their absence leads to PC loss and cerebellar dysfunction similar to that observed in AT patients. PMID- 21321204 TI - Reprogramming of the paternal genome upon fertilization involves genome-wide oxidation of 5-methylcytosine. AB - Genome-wide erasure of DNA cytosine-5 methylation has been reported to occur along the paternal pronucleus in fertilized oocytes in an apparently replication independent manner, but the mechanism of this reprogramming process has remained enigmatic. Recently, considerable amounts of 5-hydroxymethylcytosine (5hmC), most likely derived from enzymatic oxidation of 5-methylcytosine (5mC) by TET proteins, have been detected in certain mammalian tissues. 5hmC has been proposed as a potential intermediate in active DNA demethylation. Here, we show that in advanced pronuclear-stage zygotes the paternal pronucleus contains substantial amounts of 5hmC but lacks 5mC. The converse is true for the maternal pronucleus, which retains 5mC but shows little or no 5hmC signal. Importantly, 5hmC persists into mitotic one-cell, two-cell, and later cleavage-stage embryos, suggesting that 5mC oxidation is not followed immediately by genome-wide removal of 5hmC through excision repair pathways or other mechanisms. This conclusion is supported by bisulfite sequencing data, which shows only limited conversion of modified cytosines to cytosines at several gene loci. It is likely that 5mC oxidation is carried out by the Tet3 oxidase. Tet3, but not Tet1 or Tet2, was expressed at high levels in oocytes and zygotes, with rapidly declining levels at the two-cell stage. Our results show that 5mC oxidation is part of the early life cycle of mammals. PMID- 21321205 TI - Phagosomal signaling by Borrelia burgdorferi in human monocytes involves Toll like receptor (TLR) 2 and TLR8 cooperativity and TLR8-mediated induction of IFN beta. AB - Phagocytosed Borrelia burgdorferi (Bb) induces inflammatory signals that differ both quantitatively and qualitatively from those generated by spirochetal lipoproteins interacting with Toll-like receptor (TLR) 1/2 on the surface of human monocytes. Of particular significance, and in contrast to lipoproteins, internalized spirochetes induce transcription of IFN-beta. Using inhibitory immunoregulatory DNA sequences (IRSs) specific to TLR7, TLR8, and TLR9, we show that the TLR8 inhibitor IRS957 significantly diminishes production of TNF-alpha, IL-6, and IL-10 and completely abrogates transcription of IFN-beta in Bb stimulated monocytes. We demonstrate that live Bb induces transcription of TLR2 and TLR8, whereas IRS957 interferes with their transcriptional regulation. Using confocal and epifluorescence microscopy, we show that baseline TLR expression in unstimulated monocytes is greater for TLR2 than for TLR8, whereas expression of both TLRs increases significantly upon stimulation with live spirochetes. By confocal microscopy, we show that TLR2 colocalization with Bb coincides with binding, uptake, and formation of the phagosomal vacuole, whereas recruitment of both TLR2 and TLR8 overlaps with degradation of the spirochete. We provide evidence that IFN regulatory factor (IRF) 7 is translocated into the nucleus of Bb-infected monocytes, suggesting its activation through phosphorylation. Taken together, these findings indicate that the phagosome is an efficient platform for the recognition of diverse ligands; in the case of Bb, phagosomal signaling involves a cooperative interaction between TLR2 and TLR8 in pro- and antiinflammatory cytokine responses, whereas TLR8 is solely responsible for IRF7 mediated induction of IFN-beta. PMID- 21321206 TI - Nucleoid occlusion factor SlmA is a DNA-activated FtsZ polymerization antagonist. AB - The tubulin-like FtsZ protein initiates assembly of the bacterial cytokinetic machinery by polymerizing into a ring structure, the Z ring, at the prospective site of division. To block Z-ring formation over the nucleoid and help coordinate cell division with chromosome segregation, Escherichia coli employs the nucleoid associated division inhibitor, SlmA. Here, we investigate the mechanism by which SlmA regulates FtsZ assembly. We show that SlmA disassembles FtsZ polymers in vitro. In addition, using chromatin immunoprecipitation (ChIP), we identified 24 SlmA-binding sequences (SBSs) on the chromosome. Remarkably, SlmA binding to SBSs dramatically enhanced its ability to interfere with FtsZ polymerization, and ChIP studies indicate that SlmA regulates FtsZ assembly at these sites in vivo. Because of the dynamic and highly organized nature of the chromosome, coupling SlmA activation to specific DNA binding provides a mechanism for the precise spatiotemporal control of its anti-FtsZ activity within the cell. PMID- 21321207 TI - Wounding mobilizes hair follicle stem cells to form tumors. AB - A wide variety of human cancers are associated with injury. Although stem cells participate in tissue regeneration after wounding, it is unclear whether these cells also contribute to epithelial tumors. Human basal cell carcinomas (BCCs) are associated with misactivation of Hedgehog (Hh) signaling, commonly through acquisition of mutations in Smoothened (Smo). We have found that expression of an activated form of Smo by stem cells of the hair-follicle bulge and secondary hair germ does not induce robust Hh signaling or produce BCCs. However, wounding recruits these cells from the follicle to the wound site, where downstream Hh signal transduction is derepressed, giving rise to superficial BCC-like tumors. These findings demonstrate that BCC-like tumors can originate from follicular stem cells and provide an explanation for the association between wounding and tumorigenesis. PMID- 21321208 TI - Listeria monocytogenes transiently alters mitochondrial dynamics during infection. AB - Mitochondria are essential and highly dynamic organelles, constantly undergoing fusion and fission. We analyzed mitochondrial dynamics during infection with the human bacterial pathogen Listeria monocytogenes and show that this infection profoundly alters mitochondrial dynamics by causing transient mitochondrial network fragmentation. Mitochondrial fragmentation is specific to pathogenic Listeria monocytogenes, and it is not observed with the nonpathogenic Listeria innocua species or several other intracellular pathogens. Strikingly, the efficiency of Listeria infection is affected in cells where either mitochondrial fusion or fission has been altered by siRNA treatment, highlighting the relevance of mitochondrial dynamics for Listeria infection. We identified the secreted pore forming toxin listeriolysin O as the bacterial factor mainly responsible for mitochondrial network disruption and mitochondrial function modulation. Together, our results suggest that the transient shutdown of mitochondrial function and dynamics represents a strategy used by Listeria at the onset of infection to interfere with cellular physiology. PMID- 21321209 TI - Alloreactivity is limited by the endogenous peptide repertoire. AB - A significant portion of the naive T-cell repertoire is capable of responding to allogeneic MHC, violating the paradigm of self-MHC restriction. Recent studies have demonstrated convincing evidence for germ-line affinity of T-cell receptors (TCR) for MHC, providing explanation for recognition of MHC not encountered during thymic development. However, although germ-line affinity proposes all TCR have inherent affinity for MHC, most T cells are not alloreactive to a given MHC. We propose that specific recognition of endogenous presented peptides, rather than inability to interact with allogeneic MHC molecules, is the primary determinant of alloreactivity. Here, we demonstrate that alloreactive and nonalloreactive TCR differ specifically in the CDR3 sequences responsible primarily for the peptide specificity of T-cell recognition. Limitations on alloreactivity imposed by a requirement for recognition of presented peptides are directly demonstrated by expansion of the alloreactive T-cell repertoire through the addition of peptide mimotopes enabling response to two distinct allogeneic MHC by otherwise nonalloreactive T cells. Responses to peptide mimotopes were specific and depended on TCR interaction with MHC. These results demonstrate that recognition of presented endogenous peptides, and not the inability to interact with allogeneic MHC, is the primary limiter on alloreactivity. This observation reconciles the concept of an inherently MHC-reactive TCR repertoire with observed frequencies of T cells responding to allogeneic stimulation and underscores the fundamental nature of TCR recognition of ligands, where both MHC and presented peptides contribute critically to T-cell recognition. PMID- 21321210 TI - Endothelial focal adhesion kinase mediates cancer cell homing to discrete regions of the lungs via E-selectin up-regulation. AB - Primary tumors secrete factors that alter the microenvironment of distant organs, rendering those organs as fertile soil for subsequent metastatic cancer cell colonization. Although the lungs are exposed to these factors ubiquitously, lung metastases usually develop as a series of discrete lesions. The underlining molecular mechanisms of the formation of these discrete lesions are not understood. Here we show that primary tumors induce formation of discrete foci of vascular hyperpermeability in premetastatic lungs. This is mediated by endothelial cell-focal adhesion kinase (FAK), which up-regulates E-selectin, leading to preferential homing of metastatic cancer cells to these foci. Suppression of endothelial-FAK or E-selectin activity attenuates the number of cancer cells homing to these foci. Thus, localized activation of endothelial FAK and E-selectin in the lung vasculature mediates the initial homing of metastatic cancer cells to specific foci in the lungs. PMID- 21321211 TI - Global land use change, economic globalization, and the looming land scarcity. AB - A central challenge for sustainability is how to preserve forest ecosystems and the services that they provide us while enhancing food production. This challenge for developing countries confronts the force of economic globalization, which seeks cropland that is shrinking in availability and triggers deforestation. Four mechanisms-the displacement, rebound, cascade, and remittance effects-that are amplified by economic globalization accelerate land conversion. A few developing countries have managed a land use transition over the recent decades that simultaneously increased their forest cover and agricultural production. These countries have relied on various mixes of agricultural intensification, land use zoning, forest protection, increased reliance on imported food and wood products, the creation of off-farm jobs, foreign capital investments, and remittances. Sound policies and innovations can therefore reconcile forest preservation with food production. Globalization can be harnessed to increase land use efficiency rather than leading to uncontrolled land use expansion. To do so, land systems should be understood and modeled as open systems with large flows of goods, people, and capital that connect local land use with global-scale factors. PMID- 21321212 TI - Loss of cerebral cavernous malformation 3 (Ccm3) in neuroglia leads to CCM and vascular pathology. AB - Communication between neural cells and the vasculature is integral to the proper development and later function of the central nervous system. A mechanistic understanding of the interactions between components of the neurovascular unit has implications for various disorders, including cerebral cavernous malformations (CCMs) in which focal vascular lesions form throughout the central nervous system. Loss of function mutations in three genes with proven endothelial cell autonomous roles, CCM1/krev1 interaction trapped gene 1, CCM2, and CCM3/programmed cell death 10, cause familial CCM. By using neural specific conditional mouse mutants, we show that Ccm3 has both neural cell autonomous and nonautonomous functions. Gfap- or Emx1-Cre-mediated Ccm3 neural deletion leads to increased proliferation, increased survival, and activation of astrocytes through cell autonomous mechanisms involving activated Akt signaling. In addition, loss of neural CCM3 results in a vascular phenotype characterized by diffusely dilated and simplified cerebral vasculature along with formation of multiple vascular lesions that closely resemble human cavernomas through cell nonautonomous mechanisms. RNA sequencing of the vascular lesions shows abundant expression of molecules involved in cytoskeletal remodeling, including protein kinase A and Rho GTPase signaling. Our findings implicate neural cells in the pathogenesis of CCMs, showing the importance of this pathway in neural/vascular interactions within the neurovascular unit. PMID- 21321213 TI - Unraveling the role of zinc in memory. PMID- 21321214 TI - Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients. AB - Clinical benefits from trastuzumab and other anti-HER2 therapies in patients with HER2 amplified breast cancer remain limited by primary or acquired resistance. To identify potential mechanisms of resistance, we established trastuzumab-resistant HER2 amplified breast cancer cells by chronic exposure to trastuzumab treatment. Genomewide copy-number variation analyses of the resistant cells compared with parental cells revealed a focal amplification of genomic DNA containing the cyclin E gene. In a cohort of 34 HER2(+) patients treated with trastuzumab-based therapy, we found that cyclin E amplification/overexpression was associated with a worse clinical benefit (33.3% compared with 87.5%, P < 0.02) and a lower progression-free survival (6 mo vs. 14 mo, P < 0.002) compared with nonoverexpressing cyclin E tumors. To dissect the potential role of cyclin E in trastuzumab resistance, we studied the effects of cyclin E overexpression and cyclin E suppression. Cyclin E overexpression resulted in resistance to trastuzumab both in vitro and in vivo. Inhibition of cyclin E activity in cyclin E-amplified trastuzumab resistant clones, either by knockdown of cyclin E expression or treatment with cyclin-dependent kinase 2 (CDK2) inhibitors, led to a dramatic decrease in proliferation and enhanced apoptosis. In vivo, CDK2 inhibition significantly reduced tumor growth of trastuzumab-resistant xenografts. Our findings point to a causative role for cyclin E overexpression and the consequent increase in CDK2 activity in trastuzumab resistance and suggest that treatment with CDK2 inhibitors may be a valid strategy in patients with breast tumors with HER2 and cyclin E coamplification/overexpression. PMID- 21321215 TI - Identification of the meiotic life cycle stage of Trypanosoma brucei in the tsetse fly. AB - Elucidating the mechanism of genetic exchange is fundamental for understanding how genes for such traits as virulence, disease phenotype, and drug resistance are transferred between pathogen strains. Genetic exchange occurs in the parasitic protists Trypanosoma brucei, T. cruzi, and Leishmania major, but the precise cellular mechanisms are unknown, because the process has not been observed directly. Here we exploit the identification of homologs of meiotic genes in the T. brucei genome and demonstrate that three functionally distinct, meiosis-specific proteins are expressed in the nucleus of a single specific cell type, defining a previously undescribed developmental stage occurring within the tsetse fly salivary gland. Expression occurs in clonal and mixed infections, indicating that the meiotic program is an intrinsic but hitherto cryptic part of the developmental cycle of trypanosomes. In experimental crosses, expression of meiosis-specific proteins usually occurred before cell fusion. This is evidence of conventional meiotic division in an excavate protist, and the functional conservation of the meiotic machinery in these divergent organisms underlines the ubiquity and basal evolution of meiosis in eukaryotes. PMID- 21321217 TI - Profile of Donald E. Canfield. PMID- 21321216 TI - Toxoplasma gondii sequesters centromeres to a specific nuclear region throughout the cell cycle. AB - Members of the eukaryotic phylum Apicomplexa are the cause of important human diseases including malaria, toxoplasmosis, and cryptosporidiosis. These obligate intracellular parasites produce new invasive stages through a complex budding process. The budding cycle is remarkably flexible and can produce varied numbers of progeny to adapt to different host-cell niches. How this complex process is coordinated remains poorly understood. Using Toxoplasma gondii as a genetic model, we show that a key element to this coordination is the centrocone, a unique elaboration of the nuclear envelope that houses the mitotic spindle. Exploiting transgenic parasite lines expressing epitope-tagged centromeric H3 variant CenH3, we identify the centromeres of T. gondii chromosomes by hybridization of chromatin immunoprecipitations to genome-wide microarrays (ChIP chip). We demonstrate that centromere attachment to the centrocone persists throughout the parasite cell cycle and that centromeres localize to a single apical region within the nucleus. Centromere sequestration provides a mechanism for the organization of the Toxoplasma nucleus and the maintenance of genome integrity. PMID- 21321218 TI - QnAs with Gilbert Strang. Interviewed by Farooq Ahmed. PMID- 21321219 TI - Molecular vibration-sensing component in Drosophila melanogaster olfaction. AB - A common explanation of molecular recognition by the olfactory system posits that receptors recognize the structure or shape of the odorant molecule. We performed a rigorous test of shape recognition by replacing hydrogen with deuterium in odorants and asking whether Drosophila melanogaster can distinguish these identically shaped isotopes. We report that flies not only differentiate between isotopic odorants, but can be conditioned to selectively avoid the common or the deuterated isotope. Furthermore, flies trained to discriminate against the normal or deuterated isotopes of a compound, selectively avoid the corresponding isotope of a different odorant. Finally, flies trained to avoid a deuterated compound exhibit selective aversion to an unrelated molecule with a vibrational mode in the energy range of the carbon-deuterium stretch. These findings are inconsistent with a shape-only model for smell, and instead support the existence of a molecular vibration-sensing component to olfactory reception. PMID- 21321220 TI - Regulatory T-cell expansion during chronic viral infection is dependent on endogenous retroviral superantigens. AB - Regulatory T cells (Treg) play critical roles in the modulation of immune responses to infectious agents. Further understanding of the factors that control Treg activation and expansion in response to pathogens is needed to manipulate Treg function in acute and chronic infections. Here we show that chronic, but not acute, infection of mice with lymphocytic choriomeningitis virus results in a marked expansion of Foxp3(+) Treg that is dependent on retroviral superantigen (sag) genes encoded in the mouse genome. Sag-dependent Treg expansion was MHC class II dependent, CD4 independent, and required dendritic cells. Thus, one unique mechanism by which certain infectious agents evade host immune responses may be mediated by endogenous Sag-dependent activation and expansion of Treg. PMID- 21321222 TI - Solving structure in the CP29 light harvesting complex with polarization-phased 2D electronic spectroscopy. AB - The CP29 light harvesting complex from green plants is a pigment-protein complex believed to collect, conduct, and quench electronic excitation energy in photosynthesis. We have spectroscopically determined the relative angle between electronic transition dipole moments of its chlorophyll excitation energy transfer pairs in their local protein environments without relying on simulations or an X-ray crystal structure. To do so, we measure a basis set of polarized 2D electronic spectra and isolate their absorptive components on account of the tensor relation between the light polarization sequences used to obtain them. This broadly applicable advance further enhances the acuity of polarized 2D electronic spectroscopy and provides a general means to initiate or feed back on the structural modeling of electronically-coupled chromophores in condensed phase systems, tightening the inferred relations between the spatial and electronic landscapes of ultrafast energy flow. We also discuss the pigment composition of CP29 in the context of light harvesting, energy channeling, and photoprotection within photosystem II. PMID- 21321221 TI - Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma. AB - Bevacizumab, an antibody against vascular endothelial growth factor (VEGF), is a promising, yet controversial, drug in human glioblastoma treatment (GBM). Its effects on tumor burden, recurrence, and vascular physiology are unclear. We therefore determined the tumor response to bevacizumab at the phenotypic, physiological, and molecular level in a clinically relevant intracranial GBM xenograft model derived from patient tumor spheroids. Using anatomical and physiological magnetic resonance imaging (MRI), we show that bevacizumab causes a strong decrease in contrast enhancement while having only a marginal effect on tumor growth. Interestingly, dynamic contrast-enhanced MRI revealed a significant reduction of the vascular supply, as evidenced by a decrease in intratumoral blood flow and volume and, at the morphological level, by a strong reduction of large- and medium-sized blood vessels. Electron microscopy revealed fewer mitochondria in the treated tumor cells. Importantly, this was accompanied by a 68% increase in infiltrating tumor cells in the brain parenchyma. At the molecular level we observed an increase in lactate and alanine metabolites, together with an induction of hypoxia-inducible factor 1alpha and an activation of the phosphatidyl-inositol-3-kinase pathway. These data strongly suggest that vascular remodeling induced by anti-VEGF treatment leads to a more hypoxic tumor microenvironment. This favors a metabolic change in the tumor cells toward glycolysis, which leads to enhanced tumor cell invasion into the normal brain. The present work underlines the need to combine anti-angiogenic treatment in GBMs with drugs targeting specific signaling or metabolic pathways linked to the glycolytic phenotype. PMID- 21321223 TI - Membrane-inlet mass spectrometry reveals a high driving force for oxygen production by photosystem II. AB - Oxygenic photosynthesis is the basis for aerobic life on earth. The catalytic Mn(4)O(x)CaY(Z) center of photosystem II (PSII), after fourfold oxidation, extracts four electrons from two water molecules to yield dioxygen. This reaction cascade has appeared as a single four-electron transfer that occurs in typically 1 ms. Inevitable redox intermediates have so far escaped detection, probably because of very short lifetime. Previous attempts to stabilize intermediates by high O(2)-back pressure have revealed controversial results. Here we monitored by membrane-inlet mass spectrometry (MIMS) the production of from (18)O-labeled water against a high background of in a suspension of PSII-core complexes. We found neither an inhibition nor an altered pattern of O(2) production by up to 50 fold increased concentration of dissolved O(2). Lack of inhibition is in line with results from previous X-ray absorption and visible-fluorescence experiments, but contradictory to the interpretation of previous UV-absorption data. Because we used essentially identical experimental conditions in MIMS as had been used in the UV work, the contradiction was serious, and we found it was not to be resolved by assuming a significant slowdown of the O(2) release kinetics or a subsequent slow conformational relaxation. This calls for reevaluation of the less direct UV experiments. The direct detection of O(2) release by MIMS shows unequivocally that O(2) release in PSII is highly exothermic. Under the likely assumption that one H(+) is released in the S(4) -> S(0) transition, the driving force at pH 6.5 and atmospheric O(2) pressure is at least 220 meV, otherwise 160 meV. PMID- 21321224 TI - Multispectral labeling of antibodies with polyfluorophores on a DNA backbone and application in cellular imaging. AB - Most current approaches to multiantigen fluorescent imaging require overlaying of multiple images taken with separate filter sets as a result of differing dye excitation requirements. This requirement for false-color composite imaging prevents the user from visualizing multiple species in real time and disallows imaging of rapidly moving specimens. To address this limitation, here we investigate the use of oligodeoxyfluoroside (ODF) fluorophores as labels for antibodies. ODFs are short DNA-like oligomers with fluorophores replacing the DNA bases and can be assembled in many colors with excitation at a single wavelength. A DNA synthesizer was used to construct several short ODFs carrying a terminal alkyne group and having emission maxima of 410-670 nm. We developed a new approach to antibody conjugation, using Huisgen-Sharpless cycloaddition, which was used to react the alkynes on ODFs with azide groups added to secondary antibodies. Multiple ODF-tagged secondary antibodies were then used to mark primary antibodies. The set of antibodies was tested for spectral characteristics in labeling tubulin in HeLa cells and revealed a wide spectrum of colors, ranging from violet-blue to red with excitation through a single filter (340-380 nm). Selected sets of the differently labeled secondary antibodies were then used to simultaneously mark four antigens in fixed cells, using a single image and filter set. We also imaged different surface tumor markers on two live cell lines. Experiments showed that all colors could be visualized simultaneously by eye under the microscope, yielding multicolor images of multiple cellular antigens in real time. PMID- 21321225 TI - Bisubstrate specificity in histidine/tryptophan biosynthesis isomerase from Mycobacterium tuberculosis by active site metamorphosis. AB - In histidine and tryptophan biosynthesis, two related isomerization reactions are generally catalyzed by two specific single-substrate enzymes (HisA and TrpF), sharing a similar (beta/alpha)(8)-barrel scaffold. However, in some actinobacteria, one of the two encoding genes (trpF) is missing and the two reactions are instead catalyzed by one bisubstrate enzyme (PriA). To unravel the unknown mechanism of bisubstrate specificity, we used the Mycobacterium tuberculosis PriA enzyme as a model. Comparative structural analysis of the active site of the enzyme showed that PriA undergoes a reaction-specific and substrate-induced metamorphosis of the active site architecture, demonstrating its unique ability to essentially form two different substrate-specific actives sites. Furthermore, we found that one of the two catalytic residues in PriA, which are identical in both isomerization reactions, is recruited by a substrate dependent mechanism into the active site to allow its involvement in catalysis. Comparison of the structural data from PriA with one of the two single-substrate enzymes (TrpF) revealed substantial differences in the active site architecture, suggesting independent evolution. To support these observations, we identified six small molecule compounds that inhibited both PriA-catalyzed isomerization reactions but had no effect on TrpF activity. Our data demonstrate an opportunity for organism-specific inhibition of enzymatic catalysis by taking advantage of the distinct ability for bisubstrate catalysis in the M. tuberculosis enzyme. PMID- 21321226 TI - Dynamics of the folded and unfolded villin headpiece (HP35) measured with ultrafast 2D IR vibrational echo spectroscopy. AB - A series of two-dimensional infrared vibrational echo experiments performed on nitrile-labeled villin headpiece [HP35-(CN)(2)] is described. HP35 is a small peptide composed of three alpha helices in the folded configuration. The dynamics of the folded HP35-(CN)(2) are compared to that of the guanidine-induced unfolded peptide, as well as the nitrile-functionalized phenylalanine (PheCN), which is used to differentiate the peptide dynamic contributions to the observables from those of the water solvent. Because the viscosity of solvent has a significant effect on fast dynamics, the viscosity of the solvent is held constant by adding glycerol. For the folded peptide, the addition of glycerol to the water solvent causes observable slowing of the peptide's dynamics. Holding the viscosity constant as GuHCl is added, the dynamics of unfolded peptide are much faster than those of the folded peptide, and they are very similar to that of PheCN. These observations indicate that the local environment of the nitrile in the unfolded peptide resembles that of PheCN, and the dynamics probed by the CN are dominated by the fluctuations of the solvent molecules, in contrast to the observations on the folded peptide. PMID- 21321227 TI - Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells. AB - Deposition of proteins of aberrant conformation is the hallmark of many neurodegenerative diseases. Misfolding of the normally globular mutant superoxide dismutase-1 (SOD1) is a central, early, but poorly understood event in the pathogenic cascade leading to familial forms of ALS. Here we report that aggregates composed of an ALS-causing SOD1 mutant penetrate inside cells by macropinocytosis and rapidly exit the macropinocytic compartment to nucleate aggregation of the cytosolic, otherwise soluble, mutant SOD1 protein. Once initiated, mutant SOD1 aggregation is self-perpetuating. Mutant SOD1 aggregates transfer from cell to cell with remarkable efficiency, a process that does not require contacts between cells but depends on the extracellular release of aggregates. This study reveals that SOD1 aggregates, propagate in a prion-like manner in neuronal cells and sheds light on the mechanisms underlying aggregate uptake and cell-to-cell transfer. PMID- 21321228 TI - Tightening of DNA knots by supercoiling facilitates their unknotting by type II DNA topoisomerases. AB - Using numerical simulations, we compare properties of knotted DNA molecules that are either torsionally relaxed or supercoiled. We observe that DNA supercoiling tightens knotted portions of DNA molecules and accentuates the difference in curvature between knotted and unknotted regions. The increased curvature of knotted regions is expected to make them preferential substrates of type IIA topoisomerases because various earlier experiments have concluded that type IIA DNA topoisomerases preferentially interact with highly curved DNA regions. The supercoiling-induced tightening of DNA knots observed here shows that torsional tension in DNA may serve to expose DNA knots to the unknotting action of type IIA topoisomerases, and thus explains how these topoisomerases could maintain a low knotting equilibrium in vivo, even for long DNA molecules. PMID- 21321229 TI - Searching for the missing baryons in clusters. AB - Observations of clusters of galaxies suggest that they contain fewer baryons (gas plus stars) than the cosmic baryon fraction. This "missing baryon" puzzle is especially surprising for the most massive clusters, which are expected to be representative of the cosmic matter content of the universe (baryons and dark matter). Here we show that the baryons may not actually be missing from clusters, but rather are extended to larger radii than typically observed. The baryon deficiency is typically observed in the central regions of clusters (~0.5 the virial radius). However, the observed gas-density profile is significantly shallower than the mass-density profile, implying that the gas is more extended than the mass and that the gas fraction increases with radius. We use the observed density profiles of gas and mass in clusters to extrapolate the measured baryon fraction as a function of radius and as a function of cluster mass. We find that the baryon fraction reaches the cosmic value near the virial radius for all groups and clusters above ~5 x 10(13)h(-1)(72)M. This suggests that the baryons are not missing, they are simply located in cluster outskirts. Heating processes (such as shock-heating of the intracluster gas, supernovae, and Active Galactic Nuclei feedback) likely contribute to this expanded distribution. Upcoming observations should be able to detect these baryons. PMID- 21321230 TI - Cargo recognition mechanism of myosin X revealed by the structure of its tail MyTH4-FERM tandem in complex with the DCC P3 domain. AB - Myosin X (MyoX), encoded by Myo10, is a representative member of the MyTH4-FERM domain-containing myosins, and this family of unconventional myosins shares common functions in promoting formation of filopodia/stereocilia structures in many cell types with unknown mechanisms. Here, we present the structure of the MyoX MyTH4-FERM tandem in complex with the cytoplasmic tail P3 domain of the netrin receptor DCC. The structure, together with biochemical studies, reveals that the MyoX MyTH4 and FERM domains interact with each other, forming a structural and functional supramodule. Instead of forming an extended beta-strand structure in other FERM binding targets, DCC_P3 forms a single alpha-helix and binds to the alphabeta-groove formed by beta5 and alpha1 of the MyoX FERM F3 lobe. Structure-based amino acid sequence analysis reveals that the key polar residues forming the inter-MyTH4/FERM interface are absolutely conserved in all MyTH4-FERM tandem-containing proteins, suggesting that the supramodular nature of the MyTH4-FERM tandem is likely a general property for all MyTH4-FERM proteins. PMID- 21321231 TI - Trypanosome REH1 is an RNA helicase involved with the 3'-5' polarity of multiple gRNA-guided uridine insertion/deletion RNA editing. AB - Uridine insertion/deletion RNA editing in kinetoplastid mitochondria corrects encoded frameshifts in mRNAs. The genetic information for editing resides in small guide RNAs (gRNAs), which form anchor duplexes just downstream of an editing site and mediate editing within a single editing "block." Many mRNAs require multiple gRNAs; the observed overall 3' to 5' polarity of editing is determined by the formation of upstream mRNA anchors by downstream editing. Hel61, a mitochondrial DEAD-box protein, was previously shown to be involved in RNA editing, but the functional role was not clear. Here we report that down regulation of Hel61 [renamed REH1 (RNA editing helicase 1)] expression in Trypanosoma brucei selectively affects editing mediated by two or more overlapping gRNAs but has no effect on editing within a single block. Down regulation produces an increased abundance of the gRNA/edited mRNA duplex for the first editing block of the A6 mRNA. Recombinant REH1 has an ATP-dependent double strand RNA unwinding activity in vitro with a model gRNA-mRNA duplex. These data indicate that REH1 is involved in gRNA displacement either directly by unwinding the gRNA/edited mRNA duplex or indirectly, to allow the 5' adjacent upstream gRNA to form an anchor duplex with the edited mRNA to initiate another block of editing. Purified tagged REH1 is associated with the RNA editing core complex by RNA linkers and a colocalization of REH1, REL1, and two kinetoplast ribosomal proteins with the kinetoplast DNA was observed by immunofluorescence, suggesting that editing, transcription, and translation may be functionally linked. PMID- 21321232 TI - Transition from one-dimensional water to ferroelectric ice within a supramolecular architecture. AB - Ferroelectric materials are characterized by spontaneous electric polarization that can be reversed by inverting an external electric field. Owing to their unique properties, ferroelectric materials have found broad applications in microelectronics, computers, and transducers. Water molecules are dipolar and thus ferroelectric alignment of water molecules is conceivable when water freezes into special forms of ice. Although the ferroelectric ice XI has been proposed to exist on Uranus, Neptune, or Pluto, evidence of a fully proton-ordered ferroelectric ice is still elusive. To date, existence of ferroelectric ice with partial ferroelectric alignment has been demonstrated only in thin films of ice grown on platinum surfaces or within microdomains of alkali-hydroxide doped ice I. Here we report a unique structure of quasi-one-dimensional (H(2)O)(12n) wire confined to a 3D supramolecular architecture of H(4)CDTA, trans-1,2 diaminocyclohexane-N,N,N',N'-tetraacetic acid; 4,4'-bpy, 4,4'-bipyridine). In stark contrast to the bulk, this 1D water wire not only exhibits enormous dielectric anomalies at approximately 175 and 277 K, respectively, but also undergoes a spontaneous transition between "1D liquid" and "1D ferroelectric ice" at approximately 277 K. Hitherto unrevealed properties of the 1D water wire will be valuable to the understanding of anomalous properties of water and synthesis of novel ferroelectric materials. PMID- 21321233 TI - Glass-like dynamics of collective cell migration. AB - Collective cell migration in tissues occurs throughout embryonic development, during wound healing, and in cancerous tumor invasion, yet most detailed knowledge of cell migration comes from single-cell studies. As single cells migrate, the shape of the cell body fluctuates dramatically through cyclic processes of extension, adhesion, and retraction, accompanied by erratic changes in migration direction. Within confluent cell layers, such subcellular motions must be coupled between neighbors, yet the influence of these subcellular motions on collective migration is not known. Here we study motion within a confluent epithelial cell sheet, simultaneously measuring collective migration and subcellular motions, covering a broad range of length scales, time scales, and cell densities. At large length scales and time scales collective migration slows as cell density rises, yet the fastest cells move in large, multicell groups whose scale grows with increasing cell density. This behavior has an intriguing analogy to dynamic heterogeneities found in particulate systems as they become more crowded and approach a glass transition. In addition we find a diminishing self-diffusivity of short-wavelength motions within the cell layer, and growing peaks in the vibrational density of states associated with cooperative cell-shape fluctuations. Both of these observations are also intriguingly reminiscent of a glass transition. Thus, these results provide a broad and suggestive analogy between cell motion within a confluent layer and the dynamics of supercooled colloidal and molecular fluids approaching a glass transition. PMID- 21321235 TI - Magnetometry with mesospheric sodium. AB - Measurement of magnetic fields on the few 100-km length scale is significant for many geophysical applications including mapping of crustal magnetism and ocean circulation measurements, yet available techniques for such measurements are very expensive or of limited accuracy. We propose a method for remote detection of magnetic fields using the naturally occurring atomic sodium-rich layer in the mesosphere and existing high-power lasers developed for laser guide star applications. The proposed method offers a dramatic reduction in cost and opens the way to large-scale, parallel magnetic mapping and monitoring for atmospheric science, navigation, and geophysics. PMID- 21321234 TI - Transmembrane orientation and possible role of the fusogenic peptide from parainfluenza virus 5 (PIV5) in promoting fusion. AB - Membrane fusion is required for diverse biological functions ranging from viral infection to neurotransmitter release. Fusogenic proteins increase the intrinsically slow rate of fusion by coupling energetically downhill conformational changes of the protein to kinetically unfavorable fusion of the membrane-phospholipid bilayers. Class I viral fusogenic proteins have an N terminal hydrophobic fusion peptide (FP) domain, important for interaction with the target membrane, plus a C-terminal transmembrane (C-term-TM) helical membrane anchor. The role of the water-soluble regions of fusogenic proteins has been extensively studied, but the contributions of the membrane-interacting FP and C term-TM peptides are less well characterized. Typically, FPs are thought to bind to membranes at an angle that allows helix penetration but not traversal of the lipid bilayer. Here, we show that the FP from the paramyxovirus parainfluenza virus 5 fusogenic protein, F, forms an N-terminal TM helix, which self-associates into a hexameric bundle. This FP also interacts strongly with the C-term-TM helix. Thus, the fusogenic F protein resembles SNARE proteins involved in vesicle fusion by having water-soluble coiled coils that zipper during fusion and TM helices in both membranes. By analogy to mechanosensitive channels, the force associated with zippering of the water-soluble coiled-coil domain is expected to lead to tilting of the FP helices, promoting interaction with the C-term-TM helices. The energetically unfavorable dehydration of lipid headgroups of opposing bilayers is compensated by thermodynamically favorable interactions between the FP and C-term-TM helices as the coiled coils zipper into the membrane phase, leading to a pore lined by both lipid and protein. PMID- 21321236 TI - X-ray crystal structures elucidate the nucleotidyl transfer reaction of transcript initiation using two nucleotides. AB - We have determined the X-ray crystal structures of the pre- and postcatalytic forms of the initiation complex of bacteriophage N4 RNA polymerase that provide the complete set of atomic images depicting the process of transcript initiation by a single-subunit RNA polymerase. As observed during T7 RNA polymerase transcript elongation, substrate loading for the initiation process also drives a conformational change of the O-helix, but only the correct base pairing between the +2 substrate and DNA base is able to complete the O-helix conformational transition. Substrate binding also facilitates catalytic metal binding that leads to alignment of the reactive groups of substrates for the nucleotidyl transfer reaction. Although all nucleic acid polymerases use two divalent metals for catalysis, they differ in the requirements and the timing of binding of each metal. In the case of bacteriophage RNA polymerase, we propose that catalytic metal binding is the last step before the nucleotidyl transfer reaction. PMID- 21321237 TI - Broadly neutralizing DNA vaccine with specific mutation alters the antigenicity and sugar-binding activities of influenza hemagglutinin. AB - The rapid genetic drift of influenza virus hemagglutinin is an obstacle to vaccine efficacy. Previously, we found that the consensus hemagglutinin DNA vaccine (pCHA5) can only elicit moderate neutralization activities toward the H5N1 clade 2.1 and clade 2.3 viruses. Two approaches were thus taken to improve the protection broadness of CHA5. The first one was to include certain surface amino acids that are characteristic of clade 2.3 viruses to improve the protection profiles. When we immunized mice with CHA5 harboring individual mutations, the antibodies elicited by CHA5 containing P157S elicited higher neutralizing activity against the clade 2.3 viruses. Likewise, the viruses pseudotyped with hemagglutinin containing 157S became more susceptible to neutralization. The second approach was to update the consensus sequence with more recent H5N1 strains, generating a second-generation DNA vaccine pCHA5II. We showed that pCHA5II was able to elicit higher cross-neutralization activities against all H5N1 viruses. Comparison of the neutralization profiles of CHA5 and CHA5II, and the animal challenge studies, revealed that CHA5II induced the broadest protection profile. We concluded that CHA5II combined with electroporation delivery is a promising strategy to induce antibodies with broad cross-reactivities against divergent H5N1 influenza viruses. PMID- 21321238 TI - Absence of CD155 aggravates acute graft-versus-host disease. PMID- 21321239 TI - Benefits of tropical crops for food security. PMID- 21321240 TI - Cerebral maturation in IUGR and appropriate for gestational age preterm babies. AB - Intrauterine growth restriction (IUGR) is associated with increased risk of perinatal morbidity and mortality, as well as long-term neurological deficits. However, neurostructural correlations with observed developmental disabilities have not yet been established. Magnetic resonance imaging (MRI) could prove useful for assessing brain development in the early neonatal period. We evaluated cerebral lesions and morphological maturation by MRIs in 59 preterm neonates, in order to verify the hypothesis that IUGR interferes on human brain development. A total of 26 pregnancies were complicated by IUGR and 33 pregnancies delivered preterm at a comparable gestational age with appropriate for gestational age (AGA). Magnetic resonance examination was performed at the completion of 41 weeks' gestation. White matter disease studied with MR included periventricular cavitations and punctuate lesions characterized by increased signal on T1 weighted and decreased signal on T2-weighted images. Cerebral maturation was defined by the total maturation score, on the basis of 4 morphological parameters of cerebral maturation: myelination (M), cortical infolding (C), germinal matrix distribution (GM), and glial cell migration pattern (G). No difference in brain lesions and in the level of cerebral maturation was found between preterm AGA and IUGR neonates. However, myelination was significantly reduced in IUGR neonates with brain sparing compared to IUGR neonates with normal Doppler of middle cerebral artery. Our study could not demonstrate any major significant difference between preterm AGA and IUGR neonates in terms of lesion occurrence and cerebral maturation. We observed, however, a mild delay in myelination in IUGR with brain sparing in utero. The relevance of this finding needs to be investigated with long-term follow-up. PMID- 21321241 TI - Beautiful british parents have more daughters. AB - The generalized Trivers-Willard hypothesis proposes that parents who possess any heritable trait that increases male reproductive success at a greater rate than female reproductive success in a given environment will have a higher-than expected offspring sex ratio (more sons), and parents who possess any heritable trait that increases female reproductive success at a greater rate than male reproductive success in a given environment will have a lower-than-expected offspring sex ratio (more daughters). One heritable trait that increases the reproductive success of daughters much more than that of sons is physical attractiveness. The generalized Trivers-Willard hypothesis therefore predicts that physically attractive parents have more daughters. Further, if beautiful parents have more daughters and physical attractiveness is heritable, then over evolutionary history women on average should gradually become more attractive than men. The analysis of the prospectively longitudinal National Child Development Study in the United Kingdom replicates earlier findings with an American sample and confirms both hypotheses. British children who are rated by their teachers as "attractive" at age 7 have 23% higher odds of having a daughter 40 years later (proportion sons = 0.50127); those who are rated by their teachers as "unattractive" at age 7 have 25% higher odds of having a son 40 years later (proportion sons = 0.56285). PMID- 21321242 TI - Placental vascularization in early onset small for gestational age and preeclampsia. AB - The objective was to determine whether chorionic villous vascularization is diminished in cases of early onset (<34 weeks) small for gestational age (SGA) and/or preeclampsia (PE). Placental morphometrical measurements were performed in 4 gestational-age-matched groups complicated by SGA, SGA with PE, PE, and spontaneous preterm delivery without SGA or PE as the reference group. Using a video image analysis system, in randomly selected intermediate and terminal villi, the stromal area and the following villous vascular parameters were manually traced and analyzed: number of total, centrally and peripherally localized vessels, vascular area, and vascular area density. No differences were observed in intermediate and terminal villous vascular area. Preeclampsia was associated with smaller terminal villous stromal area (reference 2299 MUm2, SGA 2412 MUm2, SGA + PE 2073 MUm2, and PE 2164 MUm2, P = .011), whereas SGA was associated with an increased terminal villous vascular area density (reference 26.1%, SGA 35.7%, SGA + PE 33.4%, and PE 32.0%, P = .029). Compared with preserved flow, lower terminal villous vascular area density was found in cases with absent or reversed end-diastolic (ARED) umbilical artery flow (39.3% vs. 30.3%, P = .013). These data demonstrate that villous vascularization was not influenced by PE, whereas in terminal villi an increased vascular area density was associated with SGA. Lower terminal villous vascular area density was associated with ARED flow in SGA pregnancies, indicating an increased risk of fetal compromise. PMID- 21321243 TI - Elevated ratio of maternal plasma ApoCIII to ApoCII in preeclampsia. AB - Preeclampsia is a hypertensive disorder unique to pregnancy. Although the pathogenesis of the disease begins with aberrant spiral artery invasion in the first trimester, clinical symptoms usually do not present until late in pregnancy. Apolipoprotein CII (ApoCII) and its negative regulator, apolipoprotein CIII (ApoCIII), have recently been described as atherogenesis biomarkers in models of cardiovascular disease. Given the similarities in pathology, etiology, and clinical presentation between cardiovascular disease and preeclampsia, we hypothesized that the ratio of ApoCIII to ApoCII in maternal first trimester plasma would predict preeclampsia later in pregnancy. To test this hypothesis, plasma was prospectively collected from 311 nulliparas at 8 to 12 weeks gestation. After delivery, patients were divided into cohorts based on preeclampsia diagnosis. Conditioning monocytes with preeclamptic plasma potentiated monocyte adhesion to endothelial cells in an in vitro model. The ratio of ApoCIII to ApoCII was significantly elevated in patients with severe preeclampsia relative to normotensive and gestational hypertensive individuals (P < .05) as determined by mass spectrometry and competitive enzyme-linked immunosorbent assay (ELISA) assays. These results support a predictive change in the ratio of ApoCIII to ApoCII in pregnancies complicated by severe preeclampsia. PMID- 21321244 TI - Distinct expression of the calcium exchangers, NCKX3 and NCX1, and their regulation by steroid in the human endometrium during the menstrual cycle. AB - Plasma membrane sodium/calcium exchangers are an important component of intracellular calcium homeostasis and electrical conduction. The potassium dependent sodium/calcium exchangers NCKX3 (gene SLC24A3) and NCX1 (gene SLC8A1) play a critical role in the transport of intracellular calcium across the cell membrane in exchange for extracellular sodium ions. NCKX3 and NCX1 transcripts are most abundant in the brain and smooth muscle, but many other tissues, particularly the uterus, aorta, and intestine, also express this gene at lower levels. However, the expression patterns and physiological roles of NCKX3 and NCX1 in the human endometrium during the menstrual cycle are unknown. Thus, we examined the endometrial expression of NCKX3 and NCX1 messenger RNA (mRNA) and protein throughout the different phases of the menstrual cycle. Endometrial expression of NCKX3 mRNA and protein was increased 1.5- to 2.5-fold during the early-proliferative, mid-proliferative, and early-secretory phases compared with the other phases; however, no significant alteration in NCX1 expression level was observed. The effects of the sex-steroid hormones, 17beta-estradiol (E2) and progesterone (P4), on the expression of NCKX3 and NCX1 in Ishikawa cells was also investigated. NCKX3 expression was significantly increased by E2 (10(-8) mol/L). However, the expression of NCX1 was not affected by E2 and P4. Subsequent immunohistochemical analysis revealed that the uterine NCKX3 and NCX1 proteins were abundantly localized in the cytoplasm of luminal and glandular epithelial cells throughout the menstrual cycle. Taken together, these results indicate that NCKX3 is abundantly expressed within the human endometrium at the transcriptional and translational levels, and its level appears to be regulated by a steroid hormone, in particular, E2 during the human menstrual cycle. PMID- 21321245 TI - Vaccination with OK-432 followed by TC-1 tumor lysate leads to significant antitumor effects. AB - Human papillomavirus (HPV) infects large numbers of women worldwide and is present in more than 99% of all cervical cancer. TC-1 cell is a cell line with high expression of E7 antigen of HPV type 16 and its cell lysate has been demonstrated as an ideal inducer of E7-specific, antitumor immunity. OK-432 (Picibanil), a penicillin-killed Streptococcus pyogenes, has been reported with potent immunomodulation properties in cancer treatment by stimulating the maturation of dendritic cells (DCs) and secretion of Th-1 type cytokines. The current study demonstrated that a protocol to immunize the C57BL/6 mice with OK 432 followed by treatment with TC-1 lysate can generate markedly increased immune responses of E7-specific CD4(+) T cells and a moderate increase of natural killer (NK) cell, as well as a satisfactorily protective and therapeutic antitumor effect by triggering the DCs to prime T cells. Depletion of lymphocyte subset in vivo suggested that the antitumor effects could be dominantly executed by CD8+ T cells and followed by NK cells, and both of these reactions were induced by the generation of robust E7-specific CD4(+) T helper cell response. These findings warrant OK-432 combination with tumor-lysate as an effective and safe vaccine in future clinical application of cervical cancer. PMID- 21321246 TI - Informed consent in the nuclear medicine setting. AB - In the nuclear medicine setting, the task of obtaining informed consent for procedures that require it is frequently left to the nuclear medicine technologist. Unfortunately, a patient's signature on a consent form does not mean the patient has given informed consent, or what legal scholars call valid consent. On completion of this scholarly bioethics article, the reader will understand the troubled history that led to informed consent as social and regulatory policy. Additionally, the reader will discover the meaning of "informed consent," which includes 3 critical components: disclosure, decision making capacity, and voluntariness. Finally, this article will discuss which nuclear medicine procedures require informed consent, how to assess whether patients have given informed consent, what to do when the patient refuses a procedure, and what to do when informed consent is unachievable. PMID- 21321247 TI - Impact of obesity on nuclear medicine imaging. AB - Obesity, with its alarming increase among adults and children, represents a significant health problem with serious medical, social, psychologic, and economic reverberations. The burden of this problem significantly affects the medical care system, including medical imaging. The effect of obesity on nuclear medicine imaging spans many aspects, from preimaging patient preparation to radiotracer administration, image acquisition, and image interpretation. The acquired images may be suboptimal because of artifacts due to soft-tissue attenuation and incomplete whole-body coverage, and quantification may be suboptimal, especially for PET. Other difficulties include mechanical problems such as the weight limit of the imaging table and the bore size of the PET or SPECT/CT scanner and the need to alter the timing, duration, or protocol of many imaging procedures. These issues are discussed in this review, which clarifies the impact of this epidemic health problem on nuclear medicine services and proposes possible solutions to overcome obesity-related difficulties encountered in nuclear medicine practice. PMID- 21321248 TI - Characterization and reduction of noise in dynamic PET data using masked volumewise principal component analysis. AB - Masked volumewise principal component (PC) analysis (PCA) is used in PET to distinguish structures that display different kinetic behaviors after administration of a tracer. When masked volumewise PCA was introduced, one article proposed noise prenormalization because of temporal and spatial variations of the noise between slices. However, the noise prenormalization proposed in that article was applicable only to datasets reconstructed using filtered backprojection (FBP). The study presented in this article aimed at developing a new noise prenormalization that is applicable to datasets regardless of whether they were reconstructed with FBP or an iterative reconstruction algorithm, such as ordered-subset expectation maximization (OSEM). METHODS: A phantom study was performed to investigate differences in the expectation values and SDs of datasets reconstructed with FBP and OSEM. A novel method, higher-order PC noise prenormalization, was suggested and evaluated against other prenormalization methods on clinical datasets. RESULTS: Masked volumewise PCA of data reconstructed with FBP was much more dependent on an appropriate prenormalization than was analysis of data reconstructed with OSEM. Higher-order PC noise prenormalization showed an overall good performance with both FBP and OSEM reconstructions, whereas the other prenormalization methods performed well with only 1 of the 2 methods. CONCLUSION: Higher-order PC noise prenormalization has potential for improving the results from masked volumewise PCA on dynamic PET datasets independent of the type of reconstruction algorithm. PMID- 21321249 TI - Volume-of-interest assessment of oncologic response using 18F-FDG PET/CT: a phantom study. AB - The aim of this study was to evaluate the volume-of-interest (VOI) technique in the measurement of volume radioactivity and in the differentiation of necrotic sites from residual tumor activity in a phantom. METHODS: PET/CT was performed on a phantom filled with (18)F-FDG solution at different concentrations. The VOI was quantified in 2 sessions to evaluate the VOI measurements as a function of activity concentration in the phantom. Software was used to build the VOI, determine the volume radioactivity of the cylindric inserts (cm(3)), and compare them with their real volumes. The VOI technique was also used to discern the mixed distribution of regions of (18)F-FDG activity from cold regions that represent areas of necrosis without tumor activity. RESULTS: Volumes measured with the VOI technique were similar to the actual volumes of cylinders in the phantom (no statistical differences; P > 0.05 after t test analysis). The diameter of cold inserts correlated positively with the percentage of visualization (P < 0.01); in both sessions, it was possible to visualize 100% of the 12.7-, 11.1-, and 9.5-mm cold rods. CONCLUSION: VOI technique has shown great potential for evaluating volume radioactivity and differentiating hot and cold regions in a phantom; clinical studies should be performed with this technique to evaluate its utility. PMID- 21321250 TI - Exposure to technologists from preparing and administering therapeutic 131I: how frequently should we bioassay? AB - It is common for nuclear medicine technologists to perform procedures involving the preparation and administration of therapeutic levels of (131)I-sodium iodide. This small study looked at the question of how much internal exposure a technologist receives, on average, while preparing and administering a therapeutic dose of (131)I. METHODS: The study estimated technologists' intake of airborne (131)I by measuring air concentrations in their breathing zone during therapeutic procedures using (131)I capsules. The measurement was made by determining the radioactivity collected on a charcoal filter contained within a personal air sampler. The radioactivity captured by the charcoal filter was assessed in a well counter. RESULTS: Given these data, we were able to estimate the average (131)I intake of a technologist working in a general nuclear medicine department over a period of 1 y: about 19.2 kBq (0.52 MUCi). CONCLUSION: The NRC requirement is to monitor workers who could inhale or ingest more than 185 kBq (5 MUCi) of (131)I in 1 y. The results of this small study suggest internal exposure rates that are well below the annual Nuclear Regulatory Commission trigger limits for individual bioassay. PMID- 21321251 TI - Radiation dose to technologists per nuclear medicine examination and estimation of annual dose. AB - Conventional diagnostic nuclear medicine applications have been continuously increasing in most nuclear medicine departments in Turkey, but to our knowledge no one has studied the doses to technologists who perform nuclear medicine procedures. Most nuclear medicine laboratories do not have separate control rooms for technologists, who are quite close to the patient during data acquisition. Technologists must therefore stay behind lead shields while performing their task if they are to reduce the radiation dose received. The aim of this study was to determine external radiation doses to technologists during nuclear medicine procedures with and without a lead shield. Another aim was to investigate the occupational annual external radiation doses to Turkish technologists. METHODS: This study used a Geiger-Muller detector to measure dose rates to technologists at various distances from patients (0.25, 0.50, 1, and 2 m and behind a lead shield) and determined the average time spent by technologists at these distances. Deep-dose equivalents to technologists were obtained. The following conventional nuclear medicine procedures were considered: thyroid scintigraphy performed using (99m)Tc pertechnetate, whole-body bone scanning performed using (99m)Tc-methylene diphosphonate, myocardial perfusion scanning performed using (99m)Tc-methoxyisobutyl isonitrile, and (201)Tl (thallous chloride) and renal scanning performed using (99m)Tc-dimercaptosuccinic acid. RESULTS: The measured deep-dose equivalent to technologists per procedure was within the range of 0.13 +/- 0.05 to 0.43 +/- 0.17 MUSv using a lead shield and 0.21 +/- 0.07 to 1.01 +/- 0.46 MUSv without a lead shield. Also, the annual individual dose to a technologist performing only a particular scintigraphic procedure throughout a year was estimated. CONCLUSION: For a total of 95 clinical cases (71 patients), effective external radiation doses to technologists were found to be within the permissible levels. This study showed that a 2-mm lead shield markedly reduced the external dose to technologists. The doses to technologists varied significantly for different diagnostic applications. Consequently, the estimated annual dose to a technologist performing only a particular scintigraphic procedure is very different from one type of procedure to another. The results of this study should help in determining the rotation time of technologists in different procedures and differences in their individual techniques. PMID- 21321252 TI - Assessment of a new 18F-FDG PET/CT protocol in the staging of oral cavity carcinomas. AB - Because image fusion using (18)F-FDG PET/CT allows a better localization of the pathologic uptake, this modality has a greater sensitivity than PET alone in examining the head-neck region. However, examination of this area is particularly critical because the head and neck are close to other anatomic structures and because of the high physiologic uptake of the radiocompound. The purpose of this study was to evaluate the utility of a new imaging protocol in the staging of oral carcinoma. METHODS: Thirty-four consecutive patients (21 women and 13 men; age range, 20-84 y) with untreated biopsy-proven oral squamous cell carcinomas were examined using whole-body (18)F-FDG PET/CT fusion imaging. All patients observed strict regulations before undergoing the PET/CT examination. At the end of the whole-body acquisition, another open-mouth scan was obtained. To compare the open- and closed-mouth methods, we analyzed features such as the feasibility of an accurate topographic localization of the tumor, evaluation of tumor extent, detection of tumor involvement with adjacent structures, and involvement of lymph nodes to which we assigned a score from 1 to 5. RESULTS: No cases of (18)F-FDG physiologic uptake in the tongue or muscles were observed. The open-mouth scan obtained a better score than did the closed-mouth scan when considering the tumor localization, tumor extent, and evaluation of adjacent anatomic structures near the clinically evident tumor. For lymph node involvement, the 2 methods showed similar results. CONCLUSION: The open-mouth scan improved the anatomic tumor localization and extent and detection of tumor involvement in adjacent anatomic structures achieved by the standard PET/CT procedure. In addition, time of the examination (mid morning), relaxation of muscles before the compound was administered, and an upright position while the patient waited caused a reduction of the frequent equivocal physiologic uptake in the head and neck region. The open-mouth method does not influence the nodal staging. PMID- 21321253 TI - Improved delineation of parathyroid lesions in patients with chronic renal failure using magnified pinhole imaging. AB - (99m)Tc-sestamibi dual-phase scintigraphy is currently established for parathyroid localization. However, the imaging technique is not standardized, and the role of the pinhole collimator, especially, is not fully recognized in the imaging protocol. The aim of this study was to check whether the use of a pinhole collimator in parathyroid scintigraphy would enhance lesion detectability and delineation more than does a parallel-hole collimator or SPECT in patients with secondary hyperparathyroidism due to chronic renal failure with a mixed pattern of abnormalities. METHODS: Thirty-five patients referred for a parathyroid scan were included. Imaging was performed at 10 min and 2 h after injection of 925 MBq (25 mCi) of (99m)Tc-sestamibi using both a pinhole collimator and a high resolution parallel-hole collimator fitted to a scintillation camera. SPECT was also performed at 1.5 h after injection. The images were reviewed by 2 experienced nuclear medicine physicians, and the results were analyzed. In addition, the contrast of visualized lesions was evaluated. RESULTS: Twenty-three patients (65.7%) had abnormal scan findings. The McNemar test revealed better detection of parathyroid lesions using pinhole imaging than with planar parallel hole imaging and SPECT (P < 0.001 and P < 0.03, respectively). Both observers showed good agreement in evaluating different imaging techniques (kappa = 0.76). Observers were in favor of pinhole imaging because SPECT suffered from noise. Lesion contrast was significantly higher in pinhole imaging than in parallel-hole imaging and SPECT (P < 0.05), with a 16% and 11% improvement in contrast, respectively. CONCLUSION: Pinhole imaging better delineates and detects lesions in parathyroid scintigraphy than does parallel-hole imaging and SPECT. Pinhole imaging increases confidence in image interpretation because of high lesion contrast and better magnification and resolution. The use of this technique is therefore recommended as part of the routine imaging protocol for (99m)Tc sestamibi parathyroid scintigraphy. PMID- 21321255 TI - Phenotypic and genomic analyses of a fast neutron mutant population resource in soybean. AB - Mutagenized populations have become indispensable resources for introducing variation and studying gene function in plant genomics research. In this study, fast neutron (FN) radiation was used to induce deletion mutations in the soybean (Glycine max) genome. Approximately 120,000 soybean seeds were exposed to FN radiation doses of up to 32 Gray units to develop over 23,000 independent M2 lines. Here, we demonstrate the utility of this population for phenotypic screening and associated genomic characterization of striking and agronomically important traits. Plant variation was cataloged for seed composition, maturity, morphology, pigmentation, and nodulation traits. Mutants that showed significant increases or decreases in seed protein and oil content across multiple generations and environments were identified. The application of comparative genomic hybridization (CGH) to lesion-induced mutants for deletion mapping was validated on a midoleate x-ray mutant, M23, with a known FAD2-1A (for fatty acid desaturase) gene deletion. Using CGH, a subset of mutants was characterized, revealing deletion regions and candidate genes associated with phenotypes of interest. Exome resequencing and sequencing of PCR products confirmed FN-induced deletions detected by CGH. Beyond characterization of soybean FN mutants, this study demonstrates the utility of CGH, exome sequence capture, and next generation sequencing approaches for analyses of mutant plant genomes. We present this FN mutant soybean population as a valuable public resource for future genetic screens and functional genomics research. PMID- 21321254 TI - Regulation of seed germination in the close Arabidopsis relative Lepidium sativum: a global tissue-specific transcript analysis. AB - The completion of germination in Lepidium sativum and other endospermic seeds (e.g. Arabidopsis [Arabidopsis thaliana]) is regulated by two opposing forces, the growth potential of the radicle (RAD) and the resistance to this growth from the micropylar endosperm cap (CAP) surrounding it. We show by puncture force measurement that the CAP progressively weakens during germination, and we have conducted a time-course transcript analysis of RAD and CAP tissues throughout this process. We have also used specific inhibitors to investigate the importance of transcription, translation, and posttranslation levels of regulation of endosperm weakening in isolated CAPs. Although the impact of inhibiting translation is greater, both transcription and translation are required for the completion of endosperm weakening in the whole seed population. The majority of genes expressed during this process occur in both tissues, but where they are uniquely expressed, or significantly differentially expressed between tissues, this relates to the functions of the RAD as growing tissue and the CAP as a regulator of germination through weakening. More detailed analysis showed that putative orthologs of cell wall-remodeling genes are expressed in a complex manner during CAP weakening, suggesting distinct roles in the RAD and CAP. Expression patterns are also consistent with the CAP being a receptor for environmental signals influencing germination. Inhibitors of the aspartic, serine, and cysteine proteases reduced the number of isolated CAPs in which weakening developed, and inhibition of the 26S proteasome resulted in its complete cessation. This indicates that targeted protein degradation is a major control point for endosperm weakening. PMID- 21321256 TI - A randomized controlled trial of cognitive behavior therapy tailored to psychological adaptation to an implantable cardioverter defibrillator. AB - OBJECTIVES: To evaluate a eight-session cognitive behavior therapy (CBT) intervention tailored to adaptation in implantable cardioverter defibrillator (ICD) patients; and to test for treatment group by gender interaction effects. METHODS: Patients receiving their first ICD implant were randomized to CBT or usual cardiac care. Primary outcomes measured at baseline, 6-month, and 12-month follow-ups were symptoms of anxiety and depression (Hospital Anxiety and Depression Scale), posttraumatic stress disorder symptoms (Impact of Events Scale Revised), and phobic anxiety (Crown-Crisp Experiential Index). Secondary outcomes were quality of life (Short Form-36 Physical Component Summary and Short Form-36 Mental Component Summary) and ICD shocks or antitachycardia pacing therapies. RESULTS: Of 292 eligible patients, 193 consented and were randomized to CBT (n = 96) or usual cardiac care (n = 97). Eighty percent were male; mean age was 64.4 years (standard deviation = 14.3); and 70% received an ICD for secondary prevention. No baseline differences were observed between the treatment conditions; however, women scored worse than men on all psychological and quality of life variables (p < .05). Eighty-three percent completed follow-up. Repeated measures analyses of covariance revealed significantly greater improvement with CBT on posttraumatic stress disorder total and avoidance symptoms for men and women combined (p < .05) and significantly greater improvement in depressive symptoms and Short Form-36 Mental Component Summary only in women (p < .01). No differences were observed between treatment conditions on ICD therapies over follow-up. CONCLUSION: A CBT intervention to assist adaptation to an ICD enhanced psychological functioning over the first year post implant. PMID- 21321258 TI - Adrenal suppression following intralesional corticosteroids for periocular haemangiomas. AB - BACKGROUND/AIMS: Treatment with intralesional triamcinolone/betamethasone is recommended for infantile sight-threatening periocular haemangiomas. This study investigates the endocrine and weight changes in 15 infants undergoing therapy over 12 years. METHODS: 15 infants, median age 19 weeks (range 10-56) receiving intra/perilesional triamcinolone/betamethasone underwent serial measurement of weight, early morning serum cortisol and adrenocorticotropic hormone (ACTH) before and after injection. RESULTS: Cortisol fell from a median (range) of 383 (112-594) to 28 (<10-506) nmol/l (p=0.005) and ACTH from 26 (14-134) to 9 (5-20) ng/l (p=0.05) from before injection to 4 weeks after treatment. Prolonged adrenal suppression occurred in 13 out of 15 cases with time to recovery being 19.5 (4 65) weeks. Failure to gain weight appropriately was observed in 14 infants but recovered once normal adrenal function was re-established. CONCLUSION: Prolonged adrenal suppression following triamcinolone/betamethasone injection for periocular haemangiomas is common and associated with faltering weight gain. PMID- 21321257 TI - Timing of prenatal maternal exposure to severe life events and adverse pregnancy outcomes: a population study of 2.6 million pregnancies. AB - OBJECTIVE: To identify the impact of timing of prenatal stress exposure on offspring risk for shortened gestational age, preterm birth (PTB), low birth weight (LBW), and small for gestational age (SGA), using a population-based sample. METHODS: Swedish longitudinal population registries were linked to study all individuals born in Sweden from 1973 to 2004. Prenatal maternal stress exposure was defined as death of the father of the child or first-degree relative of the mother. Using linear and logistic regression, timing of stress exposure was examined across pregnancy, by month, and by novel periods created based on month of stress exposure findings. RESULTS: A total of 2,618,777 live-born, singleton infants without congenital anomalies were included; 32,286 were exposed to prenatal maternal stress. Examining associations between stress exposure and outcome by the month revealed that risk increases midgestation, particularly after months 5 and 6. Combining months 1 to 4, 5 and 6, and 7 to 9 as potential periods of differing vulnerability, it was found that stress during period 2 (months 5 and 6) was associated with the greatest risk for shortened gestational age (-0.52 days, standard error = 0.15, p = .0006), PTB (odds ratio [OR], 1.24; 99% confidence interval [CI], 1.08-1.42), LBW (OR, 1.38; 99% CI, 1.19-1.61), and SGA (OR, 1.25; 99% CI, 1.05-1.49). CONCLUSIONS: Risk for shortened GA, PTB, LBW, and SGA are greater post stress exposure during the 5th and/or 6th month of pregnancy. It may be beneficial to refine future analyses to these months. Possible mechanisms include alterations in the hypothalamic-pituitary-adrenal axis and associated stress-responsive molecular regulators. PMID- 21321259 TI - Micro-SPECT/CT-based pharmacokinetic analysis of 99mTc diethylenetriaminepentaacetic acid in rats with blood-brain barrier disruption induced by focused ultrasound. AB - This study evaluated the pharmacokinetics of (99m)Tc-diethylenetriamine pentaacetate acid ((99m)Tc-DTPA) after intravenous administration in healthy and F98 glioma-bearing F344 rats in the presence of blood-brain barrier disruption (BBB-D) induced by focused ultrasound (FUS). The pharmacokinetics of the healthy and tumor-containing brains after BBB-D were compared to identify the optimal time period for combined treatment. METHODS: Healthy and F98 glioma-bearing rats were injected intravenously with Evans blue (EB) and (99m)Tc-DTPA; these treatments took place with or without BBB-D induced by transcranial FUS of 1 hemisphere of the brain. The permeability of the BBB was quantified by EB extravasation. Twelve rats were scanned for 2 h to estimate uptake of (99m)Tc radioactivity with respect to time for the pharmacokinetic analysis. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining was performed to examine tissue damage. RESULTS: The accumulations of EB and (99m)Tc DTPA in normal brains or brains with a tumor were significantly elevated after the intravenous injection when BBB-D was induced. The disruption-to-nondisruption ratio of the brains and the tumor-to-ipsilateral brain ratio of the tumors in terms of radioactivity reached a peak at 45 and 60 min, respectively. EB injection followed by sonication showed that there was an increase of about 2 fold in the tumor-to-ipsilateral brain EB ratio of the target tumors (7.36), compared with the control tumors (3.73). TUNEL staining showed no significant differences between the sonicated tumors and control tumors. CONCLUSION: This study demonstrates that (99m)Tc-DTPA micro-SPECT/CT can be used for the pharmacokinetic analysis of BBB-D induced by FUS. This method should be able to provide important information that will help with establishing an optimal treatment protocol for drug administration after FUS-induced BBB-D in clinical brain disease therapy. PMID- 21321260 TI - Recording intracellular molecular events from the outside: glycosylphosphatidylinositol-anchored avidin as a reporter protein for in vivo imaging. AB - With the emergence of multimodal imaging strategies, genetically encoded reporters that can be flexibly combined with any imaging modality become highly attractive. Here we describe the use of glycosylphosphatidylinositol (GPI) anchored avidin, an avidin moiety targeted to the extracellular side of cell membranes via a GPI anchor, as a reporter for in vivo imaging. Being present on the outside of cells, avidin can be visualized with any type of biotinylated imaging agent, without the requirement that the probe be membrane-permeable. We used the avidin-GPI system to monitor the activity of hypoxia-inducible factors (HIFs)-oxygen-sensing transcription factors, which play a major role in regulating cancer progression-in a mouse tumor allograft model. METHODS: Mouse C51 cells were stably transfected with pH3SVG, a reporter construct driving the expression of avidin-GPI from an HIF-sensitive promoter. The transfected cells were subcutaneously implanted into BALB/c nude mice. At 10 d after tumor inoculation, mice received an intravenous injection of either alexa-594-biocytin or (67)Ga-DOTA-biotin, and tumor HIF activity was imaged using fluorescence reflectance imaging or SPECT. RESULTS: In vitro cell experiments demonstrated the functionality and HIF-dependent regulation of the avidin-GPI reporter construct. In vivo, avidin-GPI was targeted specifically in allograft tumors with biotinylated imaging probes using both fluorescence imaging and SPECT. Analysis of the reporter expression pattern on ex vivo tumor tissue sections indicated a good overlap, with areas of hypoxia. CONCLUSION: We have demonstrated the utility of avidin-GPI as a reporter for multimodal in vivo imaging using both a fluorescence and a SPECT approach to assess intracellular oxygen signaling in a mouse tumor model. PMID- 21321261 TI - Observation of glucose metabolism in the thalamic nuclei by fusion PET/MRI. AB - The anatomy of the thalamus and its connectivity with surrounding areas are known. Localized metabolic activities at the thalamic substructural level have not been measured in vivo in human brains because of limited resolution and contrast. METHODS: The energy metabolism and fine anatomic structures of the thalamus were measured simultaneously in 5 healthy subjects using a PET/MRI fusion imaging system. Measured metabolism in individual thalamic nuclei was quantified by corresponding PET/MRI images. RESULTS: Substructures of the thalamus were clearly distinguished in 7.0-T MRI images, and the corresponding metabolic activities measured by PET were integrated by the PET/MRI system. The medial dorsal thalamic nucleus consistently showed the highest glucose uptake among the thalamic nuclei. CONCLUSION: These results demonstrate that substructure-specific metabolic activities in the thalamus can be measured with a PET/MRI system consisting of an ultra-high-resolution PET component and an ultra high-field MRI component. PMID- 21321262 TI - 18F-fluromisonidazole PET imaging as a biomarker for the response to 5,6 dimethylxanthenone-4-acetic acid in colorectal xenograft tumors. AB - The aim of this study was to evaluate (18)F-fluromisonidazole ((18)F-FMISO) PET for monitoring the tumor response to the antivascular compound 5,6 dimethylxanthenone-4-acetic acid (DMXAA; vadimezan). METHODS: (18)F-FMISO PET was performed 3 h before and 24 h after treatment with DMXAA (20 mg/kg) in mice bearing HT29 xenograft tumors. Pimonidazole was coadministered with the first (18)F-FMISO injection, and 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3 pentafluoropropyl)acetamide (EF5) was coadministered with the second one. Hoechst 33342 was administered 5 min before sacrifice. Digital autoradiograms of tumor sections were acquired; this acquisition was followed by immunofluorescence microscopic visualization of pimonidazole, EF5, the Hoechst 33342, CD31, and alpha-smooth muscle actin. RESULTS: DMXAA treatment resulted in a marked reduction in the (18)F-FMISO mean standardized uptake value (SUV(mean)) in approximately half of the treated tumors. The reduction in SUV(mean) correlated with a decrease in the fraction of tumor area staining positive for both EF5 and pimonidazole. Compared with untreated controls, tumors with decreasing SUV(mean) had significantly fewer perfused microvessels. CONCLUSION: (18)F-FMISO PET could distinguish between different tumor responses to DMXAA treatment. However, a reduction in (18)F-FMISO SUV(mean) after DMXAA treatment was indicative of reduced perfusion and therefore delivery of (18)F-FMISO, rather than a reduction in tumor hypoxia. PMID- 21321263 TI - Shortened acquisition protocols for the quantitative assessment of the 2-tissue compartment model using dynamic PET/CT 18F-FDG studies. AB - (18)F-FDG kinetics are quantified by a 2-tissue-compartment model. The routine use of dynamic PET is limited because of this modality's 1-h acquisition time. We evaluated shortened acquisition protocols up to 0-30 min regarding the accuracy for data analysis with the 2-tissue-compartment model. METHODS: Full dynamic series for 0-60 min were analyzed using a 2-tissue-compartment model. The time activity curves and the resulting parameters for the model were stored in a database. Shortened acquisition data were generated from the database using the following time intervals: 0-10, 0-16, 0-20, 0-25, and 0-30 min. Furthermore, the impact of adding a 60-min uptake value to the dynamic series was evaluated. The datasets were analyzed using dedicated software to predict the results of the full dynamic series. The software is based on a modified support vector machines (SVM) algorithm and predicts the compartment parameters of the full dynamic series. RESULTS: The SVM-based software provides user-independent results and was accurate at predicting the compartment parameters of the full dynamic series. If a squared correlation coefficient of 0.8 (corresponding to 80% explained variance of the data) was used as a limit, a shortened acquisition of 0-16 min was accurate at predicting the 60-min 2-tissue-compartment parameters. If a limit of 0.9 (90% explained variance) was used, a dynamic series of at least 0-20 min together with the 60-min uptake values is required. CONCLUSION: Shortened acquisition protocols can be used to predict the parameters of the 2-tissue compartment model. Either a dynamic PET series of 0-16 min or a combination of a dynamic PET/CT series of 0-20 min and a 60-min uptake value is accurate for analysis with a 2-tissue-compartment model. PMID- 21321264 TI - In vitro and in vivo evaluation of 64Cu-labeled SarAr-bombesin analogs in gastrin releasing peptide receptor-expressing prostate cancer. AB - Bombesin is a 14-amino-acid amphibian peptide that binds with high affinity to the gastrin-releasing peptide receptor (GRPR), which is overexpressed on a variety of solid tumors. It has been demonstrated that bombesin analogs can be radiolabeled with a variety of radiometals for potential diagnosis and treatment of GRPR-positive tumors. In this regard, several studies have used different chelators conjugated to the 8 C-terminal amino acids of bombesin(7-14) for radiolabeling with (64)Cu. These analogs have demonstrated GRPR-specific small animal PET of tumors but have various advantages and disadvantages. The objective of this study was to conjugate the previously described (1-N-(4-aminobenzyl) 3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosane-1,8-diamine) (SarAr) chelator to bombesin(7-14), radiolabel the conjugate with (64)Cu, and evaluate in vitro and in vivo. METHODS: SarAr was synthesized as previously published and conjugated to bombesin(7-14) by solid-phase peptide synthesis using standard Fmoc chemistry. Succinic acid (SA), 8-aminooctanoic acid (Aoc), and Gly-Ser-Gly (GSG) were used as linkers between SarAr and bombesin(7-14) to yield the resulting SarAr-SA-Aoc bombesin(7-14) and SarAr-SA-Aoc-GSG-bombesin(7-14) peptides. The unlabeled peptides were evaluated in a competitive binding assay using PC-3 prostate cancer cells and (125)I-Tyr(4)-bombesin to determine the inhibitory concentration of 50%. The peptides were radiolabeled with (64)Cu and evaluated for internalization into PC-3 cells in vitro and for in vivo tumor uptake in mice bearing PC-3 xenografts using biodistribution and small-animal PET/CT studies. RESULTS: The competitive binding assay demonstrated that both SarAr-SA-Aoc-bombesin(7-14) and SarAr-SA-Aoc-GSG-bombesin(7-14) bound with high affinity to GRPR with an inhibitory concentration of 50% of 3.5 and 4.5 nM, respectively. Both peptides were radiolabeled with (64)Cu at room temperature without further purification and demonstrated similar internalization into PC-3 cells. In vivo, the radiolabeled peptides demonstrated tumor-specific uptake (13.0 and 8.5 percentage injected dose per gram for (64)Cu-SarAr-SA-Aoc-bombesin(7-14) and (64)Cu-SarAr-SA Aoc-GSG-bombesin(7-14), respectively, at 1 h) and imaging that was comparable to, or better than, that of the previously reported (64)Cu-labeled bombesin analogs. The (64)Cu-SarAr-SA-Aoc-GSG-bombesin(7-14) had more rapid blood clearance and lower tumor and normal-tissue uptake than (64)Cu-SarAr-SA-Aoc-bombesin(7-14), resulting in similar tumor-to-blood ratios for each analog (15.1 vs. 11.3 for (64)Cu-SarAr-SA-Aoc-bombesin(7-14) and (64)Cu-SarAr-SA-Aoc-GSG-bombesin(7-14), respectively, at 1 h). CONCLUSION: These studies demonstrate that (64)Cu-SarAr-SA Aoc-bombesin(7-14) and (64)Cu-SarAr-SA-Aoc-GSG-bombesin(7-14) bound with high affinity to GRPR-expressing cells and that these peptides can be used for PET of GRPR-expressing prostate cancer. PMID- 21321265 TI - Improvement in lesion detection with whole-body oncologic time-of-flight PET. AB - Time-of-flight (TOF) PET has great potential in whole-body oncologic applications, and recent work has demonstrated qualitatively in patient studies the improvement that can be achieved in lesion visibility. The aim of this work was to objectively quantify the improvement in lesion detectability that can be achieved in lung and liver lesions with whole-body (18)F-FDG TOF PET in a cohort of 100 patients as a function of body mass index, lesion location and contrast, and scanning time. METHODS: One hundred patients with BMIs ranging from 16 to 45 were included in this study. Artificial 1-cm spheric lesions were imaged separately in air at variable locations of each patient's lung and liver, appropriately attenuated, and incorporated in the patient list-mode data with 4 different lesion-to-background contrast ranges. The fused studies with artificial lesion present or absent were reconstructed using a list-mode unrelaxed ordered subsets expectation maximization with chronologically ordered subsets and a gaussian TOF kernel for TOF reconstruction. Conditions were compared on the basis of performance of a 3-channel Hotelling observer signal-to-noise ratio in detecting the presence of a sphere of unknown size on an anatomic background while modeling observer noise. RESULTS: TOF PET yielded an improvement in lesion detection performance (3-channel Hotelling observer signal-to-noise ratio) over non-TOF PET of 8.3% in the liver and 15.1% in the lungs. The improvement in all lesions was 20.3%, 12.0%, 9.2%, and 7.5% for mean contrast values of 2.0:1, 3.2:1, 4.4:1, and 5.7:1, respectively. Furthermore, this improvement was 9.8% in patients with a BMI of less than 30 and 11.1% in patients with a BMI of 30 or more. Performance plateaued faster as a function of number of iterations with TOF than non-TOF. CONCLUSION: Over all contrasts and body mass indexes, oncologic TOF PET yielded a significant improvement in lesion detection that was greater for lower lesion contrasts. This improvement was achieved without compromising other aspects of PET imaging. PMID- 21321266 TI - PET of alphavbeta3-integrin and alphavbeta5-integrin expression with 18F fluciclatide for assessment of response to targeted therapy: ready for prime time? PMID- 21321267 TI - The sentinel node procedure in breast cancer: nuclear medicine as the starting point. AB - Axillary node status is a major prognostic factor in early breast cancer. Staging with sentinel node biopsy (SNB) leads to a substantial reduction in surgical morbidity. Recent multiinstitutional studies revealed SNB false-negative rates ranging from 5.5% to 16.7%, higher than the target (<5%) set by the 2005 guidelines of the American Society of Clinical Oncology. These alarming data point to the necessity of optimization. Dual mapping with radiotracer and blue dye, combining 2 different injection sites, and routinely using lymphoscintigraphy may improve accuracy. Factors associated with decreased sensitivity, such as prior excisional biopsy or neoadjuvant chemotherapy, should be recognized. The use of SNB in situations with a high prevalence of node positivity (large tumor, multifocality) is controversial. The risk of missed disease after negative SNB ranges from 1% to 4% in patients with T1 tumor and up to 15% in patients with T3. With peritumoral injection, internal mammary drainage is seen in about 20% of cases. Patients combining internal mammary drainage with a positive axillary sentinel node have close to a 50% probability of internal mammary involvement. Lymphoscintigraphy might thus be helpful in selecting patients for whom internal mammary radiation has a high benefit-to-risk ratio. PMID- 21321268 TI - Monitoring tumor response to antiangiogenic sunitinib therapy with 18F fluciclatide, an 18F-labeled alphaVbeta3-integrin and alphaV beta5-integrin imaging agent. AB - Arginine-glycine-aspartate (RGD)-binding alpha(V)beta(3)-integrin and alpha(V)beta(5)-integrin play key roles in tumor angiogenesis. We examined an (18)F-labeled small peptide (fluciclatide [United States Adopted Name (ASAN) approved, International Nonproprietary Name (INN)-proposed name], previously referred to as AH111585) containing an RGD sequence. Fluciclatide binds with a high (nM) affinity to alpha(V)beta(3)-integrin and alpha(V)beta(5)-integrin, which are highly expressed on tumors and the tumor neovasculature. In this study, (18)F-fluciclatide was used to examine the response of human glioblastoma xenografts to treatment with the antiangiogenic agent sunitinib. METHODS: U87-MG tumor uptake of (18)F-fluciclatide was determined by small-animal PET after longitudinal administration of the antiangiogenic agent sunitinib (a 2-wk dosing regimen). Tumor sizes were measured throughout the study, and tumor volumes were calculated. Tumor microvessel density (MVD) after therapy was also analyzed. RESULTS: Dynamic small-animal PET of (18)F-fluciclatide uptake after administration of the clinically relevant antiangiogenic agent sunitinib revealed a reduction in the tumor uptake of (18)F-fluciclatide compared with that in vehicle-treated controls over the 2-wk dosing regimen. Skeletal muscle, used as a reference tissue, showed equivalent (18)F-fluciclatide uptake in both therapy and control groups. A reduction in tumor MVD was also observed after treatment with the antiangiogenic agent. No significant changes in tumor volume were observed in the 2 groups. CONCLUSION: The data demonstrated that (18)F-fluciclatide detected changes in tumor uptake after acute antiangiogenic therapy markedly earlier than any significant volumetric changes were observable. These results suggest that this imaging agent may provide clinically important information for guiding patient care and monitoring the response to antiangiogenic therapy. PMID- 21321269 TI - Dual-biomarker imaging of regional cerebral amyloid load and neuronal activity in dementia with PET and 11C-labeled Pittsburgh compound B. AB - PET studies with biomarkers of regional neuronal activity (cerebral glucose metabolism or blood flow [CBF]) and amyloid-beta (Abeta) depositions provide complementary information for the early diagnosis of dementia and follow-up of patients with dementia. We investigated the validity of relative regional CBF estimates (R(1)) gained from pharmacokinetic analyses of (11)C-labeled Pittsburgh compound B ((11)C-PIB) PET studies as a marker of neuronal activity and neurodegeneration. METHODS: Twenty-two patients with cognitive impairment (16 patients with early Alzheimer disease) underwent (18)F-FDG and (11)C-PIB PET studies for the assessment of regional glucose metabolism and Abeta load. Parametric images of R(1) (relative CBF) and binding potential (BP(ND); Abeta load) were generated by 2-step simplified reference tissue model (SRTM2) analyses of dynamic (11)C-PIB data. Volume-of-interest and voxel-based statistical analyses were performed to investigate the association between normalized (18)F FDG uptake and (11)C-PIB R(1) and the correlation of these measures with symptom severity (Mini-Mental State Examination [MMSE] scores) in patients with Alzheimer disease. RESULTS: SRTM2 analyses provided high-quality (11)C-PIB R(1) images that were comparable to (18)F-FDG PET images. Regional (11)C-PIB R(1) values strongly correlated with normalized regional (18)F-FDG uptake when correlations were calculated separately for each patient (R(2) [mean +/- SD], 0.73 +/- 0.11) or across all regions of all patients (R(2), 0.62). A regression model including (18)F-FDG uptake, subject identification, and region grouping (into cortical, subcortical, and limbic regions to allow for possible differences in flow/metabolism coupling) accounted for 86% of total (11)C-PIB R(1) variability. Voxel-based correlation analyses of (18)F-FDG uptake and (11)C-PIB R(1) with MMSE scores revealed similar core findings of positive correlations in the posterior cingulate gyrus/precuneus and negative correlations (preserved activity) in the bilateral sensorimotor cortex. There was no correlation between Abeta load (BP(ND)) and MMSE scores. CONCLUSION: These results strongly suggest that (11)C PIB R(1) can serve as a complementary biomarker of neuronal activity and, thus, neurodegeneration in addition to Abeta load given by (11)C-PIB BP(ND). Further studies are needed to validate the diagnostic value of dual-biomarker (11)C-PIB PET studies in comparison with combined (18)F-FDG and (11)C-PIB PET studies. Compared with the latter, dual-biomarker (11)C-PIB PET greatly reduces costs and burden for patients. PMID- 21321270 TI - Intratumor heterogeneity characterized by textural features on baseline 18F-FDG PET images predicts response to concomitant radiochemotherapy in esophageal cancer. AB - (18)F-FDG PET is often used in clinical routine for diagnosis, staging, and response to therapy assessment or prediction. The standardized uptake value (SUV) in the primary or regional area is the most common quantitative measurement derived from PET images used for those purposes. The aim of this study was to propose and evaluate new parameters obtained by textural analysis of baseline PET scans for the prediction of therapy response in esophageal cancer. METHODS: Forty one patients with newly diagnosed esophageal cancer treated with combined radiochemotherapy were included in this study. All patients underwent pretreatment whole-body (18)F-FDG PET. Patients were treated with radiotherapy and alkylatinlike agents (5-fluorouracil-cisplatin or 5-fluorouracil carboplatin). Patients were classified as nonresponders (progressive or stable disease), partial responders, or complete responders according to the Response Evaluation Criteria in Solid Tumors. Different image-derived indices obtained from the pretreatment PET tumor images were considered. These included usual indices such as maximum SUV, peak SUV, and mean SUV and a total of 38 features (such as entropy, size, and magnitude of local and global heterogeneous and homogeneous tumor regions) extracted from the 5 different textures considered. The capacity of each parameter to classify patients with respect to response to therapy was assessed using the Kruskal-Wallis test (P < 0.05). Specificity and sensitivity (including 95% confidence intervals) for each of the studied parameters were derived using receiver-operating-characteristic curves. RESULTS: Relationships between pairs of voxels, characterizing local tumor metabolic nonuniformities, were able to significantly differentiate all 3 patient groups (P < 0.0006). Regional measures of tumor characteristics, such as size of nonuniform metabolic regions and corresponding intensity nonuniformities within these regions, were also significant factors for prediction of response to therapy (P = 0.0002). Receiver-operating-characteristic curve analysis showed that tumor textural analysis can provide nonresponder, partial-responder, and complete responder patient identification with higher sensitivity (76%-92%) than any SUV measurement. CONCLUSION: Textural features of tumor metabolic distribution extracted from baseline (18)F-FDG PET images allow for the best stratification of esophageal carcinoma patients in the context of therapy-response prediction. PMID- 21321271 TI - Accuracy and reproducibility of absolute quantification of myocardial focal tracer uptake from molecularly targeted SPECT/CT: a canine validation. AB - Accurate and reproducible SPECT quantification of myocardial molecular processes remains a challenge because of the complication of heterogeneous background and extracardiac activity adjacent to the heart, which causes errors in the estimation of myocardial focal tracer uptake. Our aim in this study was to introduce a heuristic method for the correction of extracardiac activity into SPECT quantification and validate the modified quantification method for accuracy and reproducibility using a canine model. METHODS: Dual-isotope-targeted (99m)Tc and (201)Tl perfusion SPECT images were acquired using a hybrid SPECT/CT camera in 6 dogs at 2 wk after myocardial infarction. Images were reconstructed with and without CT-based attenuation correction, and the reconstructed SPECT images were filtered and quantified simultaneously with incorporation of extracardiac radioactivity correction, gaussian fitting, and total-count sampling. Absolute myocardial focal tracer uptake was quantified from SPECT images using 3 different normal limits (maximum entropy [ME], mean-squared-error minimization [MSEM], and global minimum [GM]). SPECT-quantified percentage injected dose (%ID) was calculated and compared with the well-counted radioactivity measured from the postmortem myocardial tissue. SPECT quantitative processing was performed by 2 different individuals with extensive experience in cardiac image processing, to assess reproducibility of the quantitative analysis. RESULTS: Correlations between SPECT-quantified and well-counted %IDs using 3 different normal limits were excellent (ME: r = 0.82, y = 0.932 x - 0.0102; MSEM: r = 0.73, y = 1.1413 x 0.0052; and GM: r = 0.7, y = 1.2147 x - 0.0002). SPECT quantification using ME normal limits resulted in an underestimation of %ID, as compared with well counted %ID. Myocardial focal tracer uptake quantified from SPECT images without CT-based attenuation correction was significantly lower than that with the attenuation correction. The %IDs quantified from attenuation-corrected SPECT images using MSEM and GM normal limits were not significantly different from well counted %IDs. Reproducibility of the SPECT quantitative analysis was excellent (ME: r = 0.98, y = 0.9221 x + 0.0001; MSEM: r = 0.97, y = 0.9357 x + 0.0004; and GM: r = 0.96, y = 0.9026 x + 0.001). CONCLUSION: Our SPECT/CT quantification algorithm for the assessment of regional radioactivity may allow for accurate and reproducible serial noninvasive evaluation of molecularly targeted tracers in the myocardium. PMID- 21321272 TI - Total abdominal 18F-FDG uptake reflects intestinal adenoma burden in Apc mutant mice. AB - Apc mutant (Apc(Min)) mice develop multiple adenomas in their intestines and are widely used to study colorectal carcinogenesis and chemopreventive approaches. Molecular imaging of intestinal adenomas could potentially provide noninvasive longitudinal evaluation of these lesions in living mice. Therefore, the aim of this study was to investigate the role of (18)F-FDG PET in the Apc(Min) mouse model. METHODS: Apc(Min) mice (n = 8) fed a purified diet were imaged serially after injection of (18)F-FDG at age 9 and 12 wk using a small-animal PET scanner. Abdominal uptake of the tracer was quantified. After dissection, intestines were imaged separately, and intestinal tracer uptake was quantified. Tracer distribution was compared with results from microscopic examination regarding adenoma number and size. Thereafter, findings were validated serially in 20 Apc(Min) mice aged 6, 8, 10, and 12 wk that received standard chow to increase adenoma numbers. In vivo abdominal (18)F-FDG uptake was correlated with microscopy results. RESULTS: Microscopic examination showed that the mice developed 25-35 intestinal adenomas at age 12 wk. Ex vivo (18)F-FDG PET of the dissected intestines visualized all large adenomas and most small adenomas. Ex vivo total intestinal (18)F-FDG uptake correlated with in vivo total abdominal uptake and with the number of large adenomas at age 9 and 12 wk. At 12 wk, there was a clear correlation between in vivo abdominal tracer uptake and the number of large adenomas but not the total number of lesions. CONCLUSION: Intestinal adenomas in Apc(Min) mice are metabolically active lesions that take up (18)F FDG. Abdominal (18)F-FDG uptake at age 12 wk serves as a readout modality for large intestinal adenomas. PMID- 21321274 TI - Transport of selected PET radiotracers by human P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2): an in vitro screening. AB - Radiolabeled compounds used for brain imaging with PET must readily cross the blood-brain barrier (BBB) to reach their target. Efflux transporters at the BBB-P glycoprotein (P-gp) and the breast cancer resistance protein (BCRP)-could limit their uptake by the brain. METHODS: We developed and validated an in vitro model using MDCKII cells transfected with human multidrug resistance (MDR1) or BCRP genes and assessed the transport of selected PET ligands by the concentration equilibrium technique. The tested compounds included befloxatone, (R,S)-CGP 12177, clorgyline, R-(-)-deprenyl, diprenorphine, DPA-714, fallypride, flumazenil, 2-fluoro-A-85380, LBT-999, loperamide, p-MPPF, PE2I, Pittsburgh compound B (PIB), (R,S)-PK11195, raclopride, R-(+)-verapamil, and WAY-100635. The assays were performed using the nonradioactive form of each compound (ultraviolet high-performance liquid chromatography analysis) and, when available, the (18)F labeled analogs (gamma-counting). RESULTS: Befloxatone appeared to be transported solely by BCRP. Loperamide, verapamil, and diprenorphine were the only P-gp substrates. Other ligands were transported by neither P-gp nor BCRP. CONCLUSION: The present method can readily be used to screen new-compound transport by P-gp or BCRP, even before any radiolabeling. Compounds that were previously thought to be transported by P-gp in rodents, such as p-MPPF, WAY-100635, and flumazenil, cannot be considered substrates of human P-gp. The impact of BCRP and P-gp at the BBB on the transport of befloxatone and diprenorphine in vivo remains to be evaluated with PET. PMID- 21321273 TI - Avoiding barriers to PET radioligand development: cellular assays of brain efflux transporters. PMID- 21321275 TI - Radiation dosimetry of 82Rb in humans under pharmacologic stress. AB - (82)Rb is used with PET for cardiac perfusion studies. Using human biokinetic measurements, in vivo, we recently reported on the resting-state dosimetry of this agent. The objective of this study was to obtain (82)Rb dose estimates under stress. METHODS: (82)Rb biokinetics were obtained in 10 healthy volunteers (5 male, 5 female; mean age +/- SD, 33 +/- 10 y; age range, 18-50 y) using whole body PET/CT. The 76-s half-life of (82)Rb and the corresponding need for pharmacologic vasodilation require that all imaging be completed within 10 min. To accommodate these constraints, while acquiring the data needed for dosimetry we used the following protocol. First, a whole-body attenuation correction CT scan was obtained. Then, a series of 3 whole-body PET scans was acquired after a single infusion of 1.53 +/- 0.12 GBq of (82)Rb at rest. Four minutes after the infusion of a 0.56 mg/kg dose of the vasodilator, dipyridamole, 3 serial whole body PET scans were acquired after a single infusion of 1.50 +/- 0.16 GBq of (82)Rb under stress. The time-integrated activity coefficient (TIAC) for stress was obtained by scaling the mean rest TIAC obtained from our previous rest study by the stress-to-rest TIAC ratio obtained from the rest-stress measurements described in this report. RESULTS: The highest mean organ-absorbed doses under stress were as follows: heart wall, 5.1, kidneys, 5.0, lungs, 2.8, and pancreas, 2.4 MUGy/MBq (19, 19, 10.4, and 8.9 mrad/mCi, respectively). The mean effective doses under stress were 1.14 +/- 0.10 and 1.28 +/- 0.10 MUSv/MBq using the tissue weighting factors of the International Commission on Radiological Protection, publications 60 and 103, respectively. CONCLUSION: Appreciable differences in source-organ biokinetics were observed for heart wall and kidneys during stress when compared with the previously reported rest study. The organ receiving the highest dose during stress was the heart wall. The mean effective dose calculated during stress was not significantly different from that obtained at rest. PMID- 21321276 TI - In vivo imaging of mineral deposition in carotid plaque using 18F-sodium fluoride PET/CT: correlation with atherogenic risk factors. AB - The purpose of this study was to correlate (18)F-sodium fluoride accumulation in the common carotid arteries of neurologically asymptomatic patients with cardiovascular risk factors and carotid calcified plaque burden. METHODS: Two hundred sixty-nine oncologic patients were examined by (18)F-sodium fluoride PET/CT. Tracer accumulation in the common carotid arteries was analyzed both qualitatively and semiquantitatively by measuring the blood-pool-corrected standardized uptake value (target-to-background ratio) and comparing it with cardiovascular risk factors and calcified plaque burden. RESULTS: (18)F-sodium fluoride uptake was observed at 141 sites in 94 (34.9%) patients. Radiotracer accumulation was colocalized with calcification in all atherosclerotic lesions. (18)F-sodium fluoride uptake was significantly associated with age (P < 0.0001), male sex (P < 0.0001), hypertension (P < 0.002), and hypercholesterolemia (P < 0.05). The presence of calcified plaque correlated significantly with these risk factors but also with diabetes (P < 0.0001), history of smoking (P = 0.03), and prior cardiovascular events (P < 0.01). There was a highly significant correlation between the presence of (18)F-sodium fluoride uptake and number of present cardiovascular risk factors (r = 0.30, P < 0.0001). CONCLUSION: Carotid (18)F-sodium fluoride uptake is a surrogate measure of calcifying carotid plaque, correlates with cardiovascular risk factors, and is more frequent in patients with a high-risk profile for atherothrombotic events but demonstrates a weaker correlation with risk factors than does calcified plaque burden. This study provides a rationale to conduct further prospective studies to determine whether (18)F-sodium fluoride uptake can predict vascular events, or if it may be used to monitor pharmacologic therapy. PMID- 21321278 TI - Beta-cell imaging: opportunities and limitations. PMID- 21321279 TI - 18F-FDG PET/CT for early response assessment in diffuse large B-cell lymphoma: poor predictive value of international harmonization project interpretation. AB - PET using (18)F-FDG has prognostic value when performed at the completion of initial chemotherapy in patients with diffuse large B-cell lymphoma (DLBCL). (18)F-FDG PET may also be predictive of outcome when performed during the treatment course of DLBCL, but robust prospective studies and standardization of (18)F-FDG PET interpretation in this setting are lacking. METHODS: In this prospective study, patients with advanced-stage DLBCL were treated with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, and (18)F-FDG PET/CT was performed after cycle 2 or 3 and at the end of therapy. The (18)F-FDG PET/CT scans were interpreted according to the International Harmonization Project for Response Criteria in Lymphoma, and the maximum standardized uptake value (SUV) of the most (18)F-FDG-avid lesions was recorded. RESULTS: Fifty patients were enrolled, and all underwent interim (18)F FDG PET/CT. At a median follow-up of 33.9 mo, the positive predictive value (PPV) of interim (18)F-FDG PET/CT for relapse or progression was 42%, and the negative predictive value (NPV) was 77%. Interim (18)F-FDG PET/CT was significantly associated with event-free survival (P = 0.017) and with progression-free survival (P = 0.04) but not with overall survival (P = 0.08). End-of-therapy (18)F-FDG PET/CT had high PPV and NPV (71% and 80%, respectively) and was significantly associated with event-free survival, progression-free survival, and overall survival (P < 0.001). SUV measurements did not discriminate patients who relapsed or progressed from those who remained in remission. CONCLUSION: When performed after 2 cycles of immunochemotherapy and interpreted according to International Harmonization Project criteria, early response assessment with PET/CT has a high NPV but low PPV in patients with advanced-stage DLBCL. Prospective trials are required to validate different criteria for the interpretation of interim (18)F-FDG PET/CT and establish the role of interim (18)F-FDG PET/CT in the management of patients with DLBCL. PMID- 21321280 TI - Molecular design and optimization of 99mTc-labeled recombinant affibody molecules improves their biodistribution and imaging properties. AB - Affibody molecules are a recently developed class of targeting proteins based on a nonimmunoglobulin scaffold. The small size (7 kDa) and subnanomolar affinity of Affibody molecules enables high-contrast imaging of tumor-associated molecular targets, particularly human epidermal growth factor receptor type 2 (HER2). (99m)Tc as a label offers advantages in clinical practice, and earlier studies demonstrated that (99m)Tc-labeled recombinant Affibody molecules with a C terminal cysteine could be used for HER2 imaging. However, the renal retention of radioactivity exceeded tumor uptake, which might complicate imaging of metastases in the lumbar region. The aim of this study was to develop an agent with low renal uptake and preserved tumor targeting. METHODS: A series of recombinant derivatives of the HER2-binding Z(HER2)(:342) Affibody molecule with a C-terminal chelating sequence, -GXXC (X denoting glycine, serine, lysine, or glutamate), was designed. The constructs were labeled with (99m)Tc and evaluated in vitro and in vivo. RESULTS: All variants were stably labeled with (99m)Tc, with preserved capacity to bind specifically to HER2-expressing cells in vitro and in vivo. The composition of the chelating sequence had a clear influence on the cellular processing and biodistribution properties of the Affibody molecules. The best variant, (99m)Tc-Z(HER2)(:V2), with the C-terminal chelating sequence -GGGC, provided the lowest radioactivity retention in all normal organs and tissues including the kidneys. (99m)Tc-Z(HER2)(:V2) displayed high uptake of radioactivity in HER2-expressing xenografts, 22.6 +/- 4.0 and 7.7 +/- 1.5 percentage injected activity per gram of tissue at 4 h after injection in SKOV-3 (high HER2 expression) and DU-145 (low HER2 expression) tumors, respectively. In both models, the tumor uptake exceeded the renal uptake. CONCLUSION: These results demonstrate that the biodistribution properties of recombinant (99m)Tc labeled Affibody molecules can be optimized by modification of the C-terminal cysteine-containing chelating sequence. (99m)Tc-Z(HER2)(:V2) is a promising candidate for further development as a diagnostic radiopharmaceutical for imaging of HER2-expressing tumors. These results may be useful for the development of imaging agents based on other Affibody molecules and, hopefully, other scaffolds. PMID- 21321281 TI - Molecular imaging in radiotherapy planning for head and neck tumors. AB - Molecular imaging uses noninvasive techniques to visualize various biologic pathways and physiologic characteristics of tumors and normal tissues. In relation to radiation therapy, PET with the tracer (18)F-FDG offers a unique opportunity to refine the target volume delineation in patients with squamous cell carcinoma of the head and neck, in turn affecting dose distribution and, it is hoped, patient outcome. Even more so, in the framework of adaptive treatment and theragnostics, whereby dose distribution is adapted in space and time over the typical course of radiotherapy, molecular imaging with PET offers an elegant research avenue to further improve the therapeutic ratio. Such implementation could be of particular interest with tracers other than (18)F-FDG, such as tracers of hypoxia and proliferation. PMID- 21321282 TI - Preliminary study of 11C-choline PET/CT for T staging of locally advanced nasopharyngeal carcinoma: comparison with 18F-FDG PET/CT. AB - Evaluation of nasopharyngeal carcinoma (NPC) using (18)F-FDG PET/CT is limited by the intense physiologic uptake of (18)F-FDG in the brain. We attempted to improve detection of intracranial tumor invasion (including better delineation of invasion near the skull base) in locally advanced NPC using(11)C-choline PET/CT. METHODS: Fifteen patients with newly diagnosed or recurrent locally advanced NPC were enrolled in the study. (18)F-FDG and (11)C-choline PET/CT was performed on all patients. PET/CT images obtained using the 2 tracers were compared using both maximum standardized uptake value (SUVmax) and tumor-to-brain (T/B) ratios. All patients were followed up for more than 1 y. RESULTS: The sensitivity of (18)F FDG PET/CT in detecting locally advanced NPC was 86.6%, compared with a 100% sensitivity for (11)C-choline PET/CT (t = 2.143, P = 0.483). The SUVmax of lesions detected was higher using (18)F-FDG than using (11)C-choline (12.81 +/- 5.00 vs. 6.84 +/- 2.76, t = 6.416, P < 0.001), but the T/B ratio was much higher for (11)C-choline than for (18)F-FDG (18.62 +/- 7.95 vs. 1.38 +/- 0.59, t = 8.801, P < 0.001). Compared with (18)F-FDG PET/CT, (11)C-choline PET/CT improved the delineation of intracranial invasion in 6 of 12 patients (chi(2) = 8.00, P = 0.014), skull base invasion in 4 of 14 patients, and orbital invasion in 3 of 3 patients. CONCLUSION: (11)C-choline can improve the quality of PET/CT in the T staging of NPC. PMID- 21321283 TI - Medical device recalls and the FDA approval process. AB - BACKGROUND: Unlike prescription drugs, medical devices are reviewed by the US Food and Drug Administration (FDA) using 2 alternative regulatory standards: (1) premarket approval (PMA), which requires clinical testing and inspections; or (2) the 510(k) process, which requires that the device be similar to a device already marketed (predicate device). The second standard is intended for devices that the FDA deems to involve low or moderate risk. METHODS: We analyzed the FDA's high risk List of Device Recalls from 2005 through 2009. Using FDA data, we determined whether the recalled devices were approved by the more rigorous (PMA) process, the 510(k) process, or were exempt from FDA review. RESULTS: There were 113 recalls from 2005 through 2009 that the FDA determined could cause serious health problems or death. Only 21 of the 113 devices had been approved through the PMA process (19%). Eighty were cleared through the 510(k) process (71%), and an additional 8 were exempt from any FDA regulation (7%). Cardiovascular devices comprised the largest recall category, with 35 of the high-risk recalls (31%); two-thirds were cleared by the 510(k) process (66%; n = 23). Fifty-one percent of the high-risk recalls were in 5 other device categories: general hospital, anesthesiology, clinical chemistry, neurology, or ophthalmology. CONCLUSIONS: Most medical devices recalled for life-threatening or very serious hazards were originally cleared for market using the less stringent 510(k) process or were considered so low risk that they were exempt from review (78%). These findings suggest that reform of the regulatory process is needed to ensure the safety of medical devices. PMID- 21321284 TI - Do the health benefits of dietary fiber extend beyond cardiovascular disease? PMID- 21321285 TI - Acid-suppressive medication use and the risk for nosocomial gastrointestinal tract bleeding. AB - BACKGROUND: Acid-suppressive medications are increasingly prescribed for noncritically ill hospitalized patients, although the incidence of nosocomial gastrointestinal (GI) tract bleeding (GI bleeding) and magnitude of potential benefit from this practice are unknown. We aimed to define the incidence of nosocomial GI bleeding outside of the intensive care unit and examine the association between acid-suppressive medication use and this complication. METHODS: We conducted a pharmacoepidemiologic cohort study of patients admitted to an academic medical center from 2004 through 2007, at least 18 years of age, and hospitalized for 3 or more days. Admissions with a primary diagnosis of GI bleeding were excluded. Acid-suppressive medication use was defined as any order for a proton pump inhibitor or histamine-2-receptor antagonist. The main outcome measure was nosocomial GI bleeding. A propensity matched generalized estimating equation was used to control for confounders. RESULTS: The final cohort included 78,394 admissions (median age, 56 years; 41% men). Acid-suppressive medication was ordered in 59% of admissions, and nosocomial GI bleeding occurred in 224 admissions (0.29%). After matching on the propensity score, the adjusted odds ratio for nosocomial GI bleeding in the group exposed to acid-suppressive medication relative to the unexposed group was 0.63 (95% confidence interval, 0.42-0.93). The number needed to treat to prevent 1 episode of nosocomial GI bleeding was 770. CONCLUSIONS: Nosocomial GI bleeding outside of the intensive care unit was rare. Despite a protective effect of acid-suppressive medication, the number needed to treat to prevent 1 case of nosocomial GI bleeding was relatively high, supporting the recommendation against routine use of prophylactic acid-suppressive medication in noncritically ill hospitalized patients. PMID- 21321286 TI - Medical device recalls: get it right the first time: Comment on "Medical device recalls and the FDA approval process". PMID- 21321287 TI - Proton pump inhibitor use and the antifracture efficacy of alendronate. AB - BACKGROUND: Proton pump inhibitors (PPIs) are widely used in elderly patients and are frequently coadministered in users of oral bisphosphonates. Biologically, PPIs could affect the absorption of calcium, vitamin B(12), and bisphosphonates and could affect the osteoclast proton pump, thus interacting with bisphosphonate antifracture efficacy. Moreover, PPIs themselves have been linked to osteoporotic fractures. METHODS: Population-based, national register-based, open cohort study of 38,088 new alendronate sodium users with a mean duration of follow-up of 3.5 years. We related risk of hip fracture to recent pharmacy records of refill of prescriptions for alendronate. RESULTS: For hip fractures, there was statistically significant interaction with alendronate for PPI use (P < .05). The treatment response associated with complete refill compliance to alendronate was a 39% risk reduction (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.52 0.71; P < .001) in patients who were not PPI users, while the risk reduction in concurrent PPI users was not significant (19%; HR, 0.81; 95% CI, 0.64-1.01; P = .06). The attenuation of the risk reduction was dose and age dependent. In contrast, there was no significant impact of concurrent use of histamine H(2) receptor blockers. CONCLUSIONS: Concurrent PPI use was associated with a dose dependent loss of protection against hip fracture with alendronate in elderly patients. This is an observational study, so a formal proof of causality cannot be made, but the dose-response relationship and the lack of impact of prior PPI use provides reasonable grounds for discouraging the use of PPIs to control upper gastrointestinal tract complaints in patients treated with oral bisphosphonates. PMID- 21321288 TI - Dietary fiber intake and mortality in the NIH-AARP diet and health study. AB - BACKGROUND: Dietary fiber has been hypothesized to lower the risk of coronary heart disease, diabetes, and some cancers. However, little is known of the effect of dietary fiber intake on total death and cause-specific deaths. METHODS: We examined dietary fiber intake in relation to total mortality and death from specific causes in the NIH (National Institutes of Health)-AARP Diet and Health Study, a prospective cohort study. Diet was assessed using a food-frequency questionnaire at baseline. Cause of death was identified using the National Death Index Plus. Cox proportional hazard models were used to estimate relative risks and 2-sided 95% confidence intervals (CIs). RESULTS: During an average of 9 years of follow-up, we identified 20 126 deaths in men and 11 330 deaths in women. Dietary fiber intake was associated with a significantly lowered risk of total death in both men and women (multivariate relative risk comparing the highest with the lowest quintile, 0.78 [95% CI, 0.73-0.82; P for trend, <.001] in men and 0.78 [95% CI, 0.73-0.85; P for trend, <.001] in women). Dietary fiber intake also lowered the risk of death from cardiovascular, infectious, and respiratory diseases by 24% to 56% in men and by 34% to 59% in women. Inverse association between dietary fiber intake and cancer death was observed in men but not in women. Dietary fiber from grains, but not from other sources, was significantly inversely related to total and cause-specific death in both men and women. CONCLUSIONS: Dietary fiber may reduce the risk of death from cardiovascular, infectious, and respiratory diseases. Making fiber-rich food choices more often may provide significant health benefits. PMID- 21321289 TI - Opportunities to decrease inappropriate uses of proton pump inhibitors: Comment on "Proton pump inhibitor use and the antifracture efficacy of alendronate". PMID- 21321290 TI - Quality of randomized controlled trials reporting in the treatment of sarcomas. AB - PURPOSE: Randomized controlled trials (RCTs) represent the best evidence in oncology practice. The aim of this study was to assess the reporting quality of sarcoma RCTs and to identify significant predictors of quality. PATIENTS AND METHODS: Two investigators searched MEDLINE for pediatric and adult bone and soft tissue sarcoma RCTs published between January 1988 and December 2008. The quality of each report was assessed by using a 15-point overall reporting quality score based on 15 items from the revised Consolidated Standards of Reporting Trials (CONSORT) statement (overall quality score [OQS] range, 0 to 15 points). Concealment of allocation, appropriate blinding, and analysis according to intention-to-treat principle were assessed separately because of their crucial methodologic importance by using a 3-point key methodologic index score (MIS; range, 0 to 3). RESULTS: We retrieved 72 relevant RCTs that included 16,029 patients. The median OQS was 9.5. Allocation concealment, blinding, and analysis by intent to treat were reported only in 21 (29%), nine (12.5%), and 23 (32%) of the 72 RCTs, respectively. The median MIS was 1 with a minimum of 0 and a maximum of 2. On multivariate analysis, publication after 1996 and high impact factor remained independent and significant predictors of improved OQS. The sole variable associated with improved MIS was the publication of chemotherapy-only trials. CONCLUSION: Although the overall quality of sarcoma RCTs reporting has improved over time, reporting of key methodologic issues remains poor. This may lead to biased interpretation of sarcoma trial results. PMID- 21321291 TI - Successful treatment of a large soft tissue sarcoma with irreversible electroporation. PMID- 21321294 TI - Follicular dendritic cell sarcoma and associated myasthenia gravis: true, true, related? PMID- 21321292 TI - Chemoimmunotherapy with fludarabine and rituximab produces extended overall survival and progression-free survival in chronic lymphocytic leukemia: long-term follow-up of CALGB study 9712. AB - PURPOSE: The addition of rituximab to fludarabine-based regimens in chronic lymphocytic leukemia (CLL) has been shown to produce high response rates with extended remissions. The long-term follow-up of these regimens with respect to progression, survival, risk of secondary leukemia, and impact of genomic risk factors has been limited. METHODS: We report the long-term follow-up of the chemoimmunotherapy trial CALGB 9712 from the Cancer and Leukemia Group B, for which treatment regimen was previously reported, to examine end points of progression-free survival (PFS), overall survival (OS), impact of genomic features, and risk of therapy-related myeloid neoplasm (t-MN). RESULTS: A total of 104 patients were enrolled on this study and now have a median follow-up of 117 months (range, 66 to 131 months). The median OS was 85 months, and 71% of patients were alive at 5 years. The median PFS was 42 months, and 27% were progression free at 5 years. An estimated 13% remained free of progression at almost 10 years of follow-up. Multivariable models of PFS and OS showed that immunoglobulin heavy chain variable region mutational status was significant for both, whereas cytogenetic abnormalities were significant only for OS. No patient developed t-MN before relapse. CONCLUSION: Long-term follow-up of CALGB 9712 demonstrates extended OS and PFS with fludarabine plus rituximab. Patients treated with fludarabine plus rituximab administered concurrently or sequentially have a low risk of t-MN. These long-term data support fludarabine plus rituximab as one acceptable first-line treatment for symptomatic patients with CLL. PMID- 21321295 TI - Clinical research: show us the data. PMID- 21321296 TI - Use of bisphosphonates and reduced risk of colorectal cancer. AB - PURPOSE: Bisphosphonates are commonly used for the treatment of osteoporosis and bone metastases caused by breast cancer and were recently reported to be associated with a reduced risk of breast cancer, possibly acting through the mevalonate pathway, but their association with risk of other cancers is unknown. PATIENTS AND METHODS: The Molecular Epidemiology of Colorectal Cancer study is a population-based, case-control study in northern Israel of patients with colorectal cancer and age-, sex-, clinic-, and ethnic group-matched controls. Long-term use of bisphosphonates before diagnosis was assessed in a subset of 933 pairs of postmenopausal female patients and controls, enrolled in Clalit Health Services, using computerized pharmacy records. RESULTS: The use of bisphosphonates for more than 1 year before diagnosis, but not for less than 1 year, was associated with a significantly reduced relative risk (RR) of colorectal cancer (RR, 0.50; 95% CI, 0.35 to 0.71). This association remained statistically significant after adjustment in a model for vegetable consumption, sports activity, family history of colorectal cancer, body mass index, and use of low-dose aspirin, statins, vitamin D, and postmenopausal hormones (RR, 0.41; 95% CI, 0.25 to 0.67). Concomitant use of bisphosphonates and statins did not further reduce the risk. CONCLUSION: The use of oral bisphosphonates for more than 1 year was associated with a 59% relative reduction in the risk of colorectal cancer, similar to the recently reported association of this drug class with reduction in breast cancer risk. PMID- 21321297 TI - Correcting for discretionary treatment crossover in an analysis of survival in the Breast International Group BIG 1-98 trial by using the inverse probability of censoring weighted method. PMID- 21321298 TI - Analyses adjusting for selective crossover show improved overall survival with adjuvant letrozole compared with tamoxifen in the BIG 1-98 study. AB - PURPOSE: Among postmenopausal women with endocrine-responsive breast cancer, the aromatase inhibitor letrozole, when compared with tamoxifen, has been shown to significantly improve disease-free survival (DFS) and time to distant recurrence (TDR). We investigated whether letrozole monotherapy prolonged overall survival (OS) compared with tamoxifen monotherapy. PATIENTS AND METHODS: Of 8,010 postmenopausal women with hormone receptor-positive, early breast cancer enrolled on the Breast International Group (BIG) 1-98 study, 4,922 were randomly assigned to 5 years of continuous adjuvant therapy with either letrozole or tamoxifen. Of 2,459 patients enrolled in the tamoxifen treatment arm, 619 (25.2%) selectively crossed over to either adjuvant or extended letrozole after initial trial results were presented in January 2005. To gain better estimates of relative treatment effects in the presence of selective crossover, we used inverse probability of censoring weighted (IPCW) modeling. RESULTS: Weighted Cox models, by using IPCW, estimated a statistically significant, 18% reduction in the hazard of an OS event with letrozole treatment (hazard ratio [HR], 0.82; 95% CI, 0.70 to 0.95). Estimates of 5-year OS on the basis of IPCW were 91.8% and 90.4% for letrozole and tamoxifen, respectively. The HRs of DFS and TDR events by using IPCW modeling were 0.83 (95% CI, 0.74 to 0.94) and 0.80 (95% CI, 0.67 to 0.94), respectively (P < .05 for DFS, OS, and TDR). Median follow-up was 74 months. CONCLUSION: Adjuvant treatment with letrozole, compared with tamoxifen, significantly reduces the risk of death, the risk of recurrent disease, and the risk of recurrence at distant sites in postmenopausal women with hormone receptor-positive breast cancer. PMID- 21321299 TI - Allogeneic stem-cell transplantation as salvage therapy for patients with diffuse large B-cell non-Hodgkin's lymphoma relapsing after an autologous stem-cell transplantation: an analysis of the European Group for Blood and Marrow Transplantation Registry. AB - PURPOSE: To analyze the outcome, including nonrelapse mortality (NRM), relapse rate (RR), progression-free survival (PFS), and overall survival (OS), of patients with diffuse large B-cell non-Hodgkin's lymphoma (DLBCL) relapsed after an autologous stem-cell transplantation (ASCT) and treated with an allogeneic stem-cell transplantation (allo-SCT). PATIENTS AND METHODS: The European Group for Blood and Marrow Transplantation database was scanned for a first allo-SCT in relapsed DLBCL after a previous ASCT between 1997 and 2006. Other inclusion criteria were age at allo-SCT >= 18 years and availability of an HLA-identical sibling or a matched unrelated donor. A total of 101 patients (57 males; median age, 46 years) were included. Median follow-up for survivors was 36 months. RESULTS: Myeloablative conditioning regimen was used in 37 patients and reduced intensity conditioning (RIC) was used in 64 patients. Three-year NRM was 28.2% (95% CI, 20% to 39%), RR was 30.1% (95% CI, 22% to 41%), PFS was 41.7% (95% CI, 32% to 52%), and OS was 53.8% (95% CI, 44% to 64%). NRM was significantly increased in patients >= 45 years (P = .01) and in those with an early relapse (< 12 months) after ASCT (P = .01). RR was significantly higher in refractory patients (P = .03). A time interval to relapse after ASCT of < 12 months was associated with lower PFS (P = .03). The use of RIC regimens was followed by a trend to a lower NRM (P = .1) and a trend to a higher RR (P = .1), with no differences in PFS and OS. No differences were seen between HLA-identical siblings and matched unrelated donors. CONCLUSION: Allo-SCT in relapsed DLBCL after ASCT is a promising therapeutic modality. Patients with a long remission after ASCT and with sensitive disease at allo-SCT are the best candidates for this approach. PMID- 21321300 TI - Substitution of formaldehyde in cross anatomy is possible. PMID- 21321301 TI - Androgen-dependent hypertension is mediated by 20-hydroxy-5,8,11,14 eicosatetraenoic acid-induced vascular dysfunction: role of inhibitor of kappaB Kinase. AB - Increased vascular synthesis of 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20 HETE) is associated with increased vascular contraction, endothelial dysfunction, and endothelial activation; all are believed to account for 20-HETE prohypertensive properties. We demonstrated previously that the 20-HETE-dependent inhibition of NO production is mediated through inhibitor of kappaB kinase (IKK), suggesting a cross-talk between 20-HETE-mediated endothelial dysfunction and activation. In this study, we examined the temporal relationship among blood pressure, endothelial dysfunction, and endothelial activation and the role of IKK in the rat model of androgen-driven 20-HETE-mediated hypertension. In Sprague Dawley rats treated with 5alpha-dihydrotestosterone, renal vascular 20-HETE levels increased by day 2 of treatment from 17.7+/-2.4 to 57.7+/-9.7 ng/mg, whereas blood pressure elevation reached significance by day 3 (132.7+/-1.7 versus 117.2+/-0.8 mm Hg). In renal interlobar arteries, when compared with vehicle, 5alpha-dihydrotestosterone treatment increased the sensitivity to phenylephrine-induced vasoconstriction by 3.5-fold, decreased acetylcholine induced vasorelaxation, and increased nuclear factor kappaB activity, all of which were attenuated by treatment with the 20-HETE antagonist, 20 hydroxyeicosa 6(Z),15(Z)-dienoic acid, (20-6,15-HEDE). Cotreatment with parthenolide, an IKK inhibitor, attenuated the androgen-dependent 20-HETE-mediated elevation in blood pressure (from 133.7+/-3.1 to 109.8+/-3.0 mm Hg). In addition, parthenolide treatment negated 20-HETE-mediated inhibition of the relaxing response to acetylcholine and 20-HETE-mediated increase in vascular nuclear factor kappaB activity. These findings suggest that inhibition of IKK attenuates the androgen dependent 20-HETE-mediated increase in blood pressure by inhibiting both 20-HETE dependent endothelial activation and dysfunction. PMID- 21321302 TI - The mineralocorticoid receptor in heart: different effects in different cells. PMID- 21321303 TI - Handle region peptide counteracts the beneficial effects of the Renin inhibitor aliskiren in spontaneously hypertensive rats. AB - To investigate whether the putative (pro)renin receptor blocker, the handle region peptide (HRP), exerts effects on top of the blood pressure-lowering and cardioprotective effects of the renin inhibitor aliskiren, spontaneously hypertensive rats were implanted with telemetry transmitters to monitor heart rate and mean arterial pressure (MAP). After a 2-week recovery period, vehicle, aliskiren, HRP (100 and 1 mg/kg per day, respectively), and HRP+aliskiren were infused for 3 weeks using osmotic minipumps. Subsequently, the heart was removed to study coronary function according to Langendorff. Baseline MAP and heart rate in vehicle-treated rats were 146+/-3 mm Hg and 326+/-4 bpm. HRP did not affect MAP, whereas aliskiren and HRP+aliskiren lowered MAP (by maximally 29+/-2 and 20+/-1 mm Hg, respectively) without affecting heart rate. Aliskiren significantly reduced MAP throughout the 3-week infusion period, whereas the blood pressure lowering effect of HRP+aliskiren returned to baseline within 2 weeks of treatment. In comparison with vehicle, aliskiren increased the endothelium dependent response to bradykinin and decreased the response to angiotensin II in the coronary circulation, whereas these responses were not altered after treatment with HRP or HRP+aliskiren. HRP did not alter plasma renin activity, plasma angiotensin levels, or the renal angiotensin content, either alone or on top of aliskiren, nor did it alter the aliskiren-induced decrease in renal Ang II type 1 receptor expression. Yet, it did reverse the aliskiren-induced reduction in cardiomyocyte area, without affecting this area when given alone. In conclusion, HRP counteracts the beneficial effects of aliskiren on blood pressure, coronary function, and cardiac hypertrophy in an angiotensin independent manner. PMID- 21321304 TI - Androgens and hypertension: role in both males and females? PMID- 21321305 TI - Ablation of mineralocorticoid receptors in myocytes but not in fibroblasts preserves cardiac function. AB - Antagonists of the mineralocorticoid receptor improve morbidity and mortality in patients with severe heart failure. However, the cell types involved in these beneficial effects are only partially known. The aim of this work was to evaluate whether genetic deletion of mineralocorticoid receptors in mouse cardiomyocytes or fibroblasts in vivo is cardioprotective after chronic left ventricular pressure overload. After transverse aortic constriction, mice deficient in myocyte mineralocorticoid receptors but not those deficient in fibroblast mineralocorticoid receptors were protected from left ventricular dilatation and dysfunction. After pressure overload, left ventricular ejection fraction was significantly higher in mice lacking myocyte mineralocorticoid receptors (70.2+/ 4.4%) as compared with control mice (54.3+/-2.5%; P<0.01). Myocyte mineralocorticoid receptor-deficient mice showed mild cardiac hypertrophy at baseline, contributing to reduced left ventricular wall tension at baseline and after pressure overload. Cardiac levels of phospho-extracellular signal-regulated kinase 1/2 were higher in myocyte mineralocorticoid receptor-deficient mice than in control mice after pressure overload. Neither fibroblast nor myocyte mineralocorticoid receptor ablation altered the development of cardiac hypertrophy or fibrosis after pressure overload. Both mineralocorticoid receptor mutant mouse strains developed similar degrees of myocyte apoptosis, proinflammatory gene expression, and macrophage infiltration after pressure overload. Thus, mineralocorticoid receptors in cardiac myocytes but not in fibroblasts protect from cardiac dilatation and failure after chronic pressure overload. PMID- 21321306 TI - Soluble form of the (pro)renin receptor is augmented in the collecting duct and urine of chronic angiotensin II-dependent hypertensive rats. AB - Renin synthesis and secretion by principal cells of the collecting duct are enhanced in angiotensin (Ang) II-dependent hypertension. The presence of renin/(pro)renin and its receptor, the (pro)renin receptor ([P]RR), in the collecting duct may provide a pathway for Ang I generation with further conversion to Ang II. To assess whether (P)RR activation occurs during Ang II dependent hypertension, we examined renal (P)RR levels and soluble (P)RR excretion in the urine of chronic Ang II-infused rats (80 ng/min; for 2 weeks; n=10) and sham-operated rats (n=10). Systolic blood pressure and Ang II levels in the plasma and kidney were increased whereas plasma renin activity was suppressed in Ang II-infused rats. Renal (P)RR transcripts were upregulated in the cortex and medulla of Ang II-infused rats. (P)RR immunoreactivity in collecting duct cells and the protein levels of the full-length form (37-kDa band) were significantly decreased in the medulla of Ang II-infused rats. The soluble (P)RR (28-kDa band) was detected in the renal medulla and urine samples of Ang II infused rats, which also showed increases in urinary renin content. To determine whether the soluble (P)RR could stimulate Ang I formation, urine samples were incubated with recombinant human (pro)renin. Urine samples of Ang II-infused rats exhibited increased Ang I formation compared with sham-operated rats. Thus, in chronic Ang II-infused rats, the catalytic activity of the augmented renin produced in the collecting duct may be enhanced by the intraluminal soluble (P)RR and cell-surface located (P)RR, thus contributing to enhanced intratubular Ang II formation. PMID- 21321307 TI - P2X1 receptor-mediated vasoconstriction of afferent arterioles in angiotensin II infused hypertensive rats fed a high-salt diet. AB - Experiments tested the hypothesis that P2 receptor reactivity is impaired in angiotensin (Ang) II hypertensive rats fed an 8%NaCl diet (Ang II+HS). Juxtamedullary afferent arteriolar autoregulatory behavior was determined over a pressure range of 65 to 200 mm Hg. Arteriolar responsiveness to P2X1 (beta,gamma methylene ATP) or P2Y2 receptor (uridine triphosphate) activation was determined in vitro. Systolic blood pressure averaged 126+/-3 and 225+/-4 mm Hg in control and Ang II+HS rats, respectively (P<0.05). In control kidneys, beta,gamma methylene ATP (10(-8) to 10(-4) mol/L) reduced arteriolar diameter by 8+/-3%, 13+/-5%, 19+/-5%, 22+/-6%, and 24+/-9%, respectively, whereas uridine triphosphate reduced diameter by 2+/-1%, 2+/-2%, 9+/-3%, 37+/-7%, and 58+/-7%. Autoregulation was markedly blunted in Ang II+HS kidneys, with arteriolar diameter remaining essentially unchanged when perfusion pressure increased to 200 mm Hg compared with a 40+/-2% decline in diameter observed in normal kidneys over the same pressure range (P<0.05). P2X1 receptor-mediated vasoconstriction was significantly attenuated in Ang II+HS kidneys. beta,gamma-Methylene ATP reduced arteriolar diameter by 1+/-1%, 3+/-2%, 6+/-1%, 9+/-3%, and 7+/-1%, respectively (P<0.05), versus control rats. Similar patterns were noted when hypertensive perfusion pressures were used. Uridine triphosphate-mediated responses were unchanged in Ang II+HS rats compared with control, indicating preservation of P2Y2 receptor function. Ang II+HS blunted P2X1-mediated increases in intracellular Ca2+ concentration in preglomerular smooth muscle cells. Therefore, Ang II+HS rats exhibit attenuated afferent arteriolar responses to P2X1 receptor stimulation. These data support the hypothesis that P2X1 receptors are important for pressure-mediated autoregulatory responses. Impairment of P2X1 receptor function may explain the hypertension-induced decline in renal autoregulatory capability. PMID- 21321308 TI - microRNAs in hypertrophy and heart failure. AB - microRNAs (miRNAs) are highly conserved, short non-coding RNAs that have become established as having an important role in regulatory networks. We review here the progress made in our understanding of heart-related microRNAs over the last two years, focusing mainly on hypertrophic growth and heart failure. PMID- 21321309 TI - The role of magnetic forces in biology and medicine. AB - The Lorentz force (the force acting on currents in a magnetic field) plays an increasingly larger role in techniques to image current and conductivity. This review will summarize several applications involving the Lorentz force, including (1) magneto-acoustic imaging of current; (2) 'Hall effect' imaging; (3) ultrasonically-induced Lorentz force imaging of conductivity; (4) magneto acoustic tomography with magnetic induction; and (5) Lorentz force imaging of action currents using magnetic resonance imaging. PMID- 21321310 TI - Functional inhibition of the human middle temporal cortex affects non-visual motion perception: a repetitive transcranial magnetic stimulation study during tactile speed discrimination. AB - The visual motion-responsive middle temporal complex (hMT+) is activated during tactile and aural motion discrimination in both sighted and congenitally blind individuals, suggesting a supramodal organization of this area. Specifically, non visual motion processing has been found to activate the more anterior portion of the hMT+. In the present study, repetitive transcranial magnetic stimulation (rTMS) was used to determine whether this more anterior portion of hMT+ truly plays a functional role in tactile motion processing. Sixteen blindfolded, young, healthy volunteers were asked to detect changes in the rotation velocity of a random Braille-like dot pattern by using the index or middle finger of their right hand. rTMS was applied for 600 ms (10 Hz, 110% motor threshold), 200 ms after the stimulus onset with a figure-of-eight coil over either the anterior portion of hMT+ or a midline parieto-occipital site (as a control). Accuracy and reaction times were significantly impaired only when TMS was applied on hMT+, but not on the control area. These results indicate that the recruitment of hMT+ is necessary for tactile motion processing, and thus corroborate the hypothesis of a 'supramodal' functional organization for this sensory motion processing area. PMID- 21321311 TI - Prognostic significance of cytoplasmic SOX9 in invasive ductal carcinoma and metastatic breast cancer. AB - SOX9, a high mobility group (HMG) box transcription factor, is required for development, differentiation and lineage commitment. It is known to exert its effects through nuclear translocation, such as cell cycle changes in response to retinoic acid treatment in breast cancer cells. However, it is not known whether SOX9 has prognostic significance in human breast cancer. Over-expression and cytoplasmic sequestration of nuclear proteins are implicated in tumor progression. To determine whether SOX9 has any prognostic significance in human breast cancer, its expression and subcellular localization were analyzed in more than 200 human breast carcinomas (BCs). SOX9 mRNA expression data for human BCs were computed from microarray studies available in public databases and correlated with known poor prognostic parameters of BCs. SOX9 protein expression and its correlation with Ki-67 staining in human BCs were assessed using immunohistochemistry. Higher SOX9 mRNA levels were significantly associated with estrogen receptor negative (P <= 0.001) and higher grade (P <= 0.01) human breast tumors. Patients with higher SOX9 mRNA level had significantly shorter overall survival (P <= 0.0001). SOX9 protein, which is normally nuclear, was instead localized in the cytoplasm of 25-30% invasive ductal carcinomas (IDCs) and lymph node metastases. Its cytoplasmic accumulation significantly correlated with enhanced proliferation in breast tumors (Kendall's tau = 0.337 with a P value < 0.0001). Cytoplasmic SOX9 can serve as a valuable prognostic marker for IDCs and metastatic breast cancer. Its significant correlation with breast tumor cell proliferation implies that SOX9 directly contributes to the poor clinical outcomes associated with invasive breast cancer. PMID- 21321312 TI - Decreased expression level of apoptosis-related genes and/or proteins in skeletal muscles, but not in hearts, of growth hormone receptor knockout mice. AB - The long-lived growth hormone (GH) receptor knockout (GHRKO; KO) mice are GH resistant due to targeted disruption of the GH receptor (Ghr) gene. Apoptosis is a physiological process in which cells play an active role in their own death and is a normal component of the development and health of multicellular organisms. Aging is associated with the progressive loss of strength of skeletal and heart muscles. Calorie restriction (CR) is a well-known experimental model to delay aging and increase lifespan. The aim of the study was to examine the expression of the following apoptosis-related genes: caspase-3, caspase-9, caspase-8, bax, bcl-2, Smac/DIABLO, p53 and cytochrome c1 (cyc1) in the skeletal muscles and hearts of female normal and GHRKO mice, fed ad libitum or subjected to 40% CR for six months, starting at two months of age. Moreover, skeletal muscle caspase-3, caspase-9, caspase-8, bax, bcl-2, Smac/DIABLO, Apaf-1, bad, phospho-bad (pbad), phospho-p53 and cytochrome c (cyc) protein expression levels were assessed. Expression of caspase-3, caspase-9, bax and Smac/DIABLO genes and proteins was decreased in GHRKO's skeletal muscles. The Apaf-1 protein expression also was diminished in this tissue. In contrast, bcl-2 and pbad protein levels were increased in skeletal muscles in knockouts. No changes were demonstrated for the examined genes' expression in GHRKO's hearts except for the increased level of cyc1 mRNA. CR did not alter the expression of the examined genes and proteins in skeletal muscles of knockouts versus normal (N) mice. In heart homogenates, CR increased caspase-3 mRNA level as compared with ad libitum mice. Decreased expression of certain proapoptotic genes and/or proteins may constitute the potential mechanism of prolonged longevity in GHRKO mice, protecting these animals from aging; this potential beneficial mechanism is not affected by CR. PMID- 21321313 TI - Hydrogen sulfide inhibits macrophage-derived foam cell formation. AB - Recent evidence indicates that hydrogen sulfide (H(2)S) exerts an antiatherogenic effect, but the mechanism is unclear. Formation of macrophage-derived foam cells is a crucial event in the development of atherosclerosis. Thus, we explore the effect of H(2)S on the formation of macrophage-derived foam cells. Incubation of monocyte-derived macrophages with oxidized LDL (oxLDL) alone caused significant increases both in intracellular lipids revealed by Oil-red O staining and in intracellular total cholesterol (TC) and esterified cholesterol (EC) concentrations assessed by high-performance liquid chromatography. Sodium hydrosulfide (NaHS, an H(2)S donor) remarkably abrogated oxLDL-induced intracellular lipid accumulation, and attenuated TC and EC concentrations and EC/TC ratio, whereas dl-propargylglycine (PPG) (a H(2)S-generating enzyme cystathionine gamma lyase inhibitor) exacerbated lipid accumulation and augmented TC and EC concentrations and EC/TC ratio. Incubation of 1,1'-dioctadecyl 3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-oxLDL led to lipoprotein binding and uptake of macrophages, which was blunted by NaHS, but enhanced by PPG. Furthermore, OxLDL markedly induced CD36, scavenger receptor A (SR-A) and acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) expressions in macrophages, which was suppressed by NaHS (50-200 MUmol/L). Finally, the down regulations of TC and EC concentrations as well as CD36 and ACAT-1 expressions by NaHS were suppressed by glibenclamide, a K(ATP) channel blocker, but facilitated by PD98059, an extracellular signal-regulated kinases 1 and 2 (ERK1/2) inhibitor. These results suggested that H(2)S inhibits foam cell formation by down regulating CD36, SR-A and ACAT1 expressions via the K(ATP)/ERK1/2 pathway in human monocyte-derived macrophages. PMID- 21321314 TI - Salmonella-mediated gene therapy in experimental colitis in mice. AB - Bacterial gene therapy - bactofection is a simple and effective method to deliver plasmid DNA into target tissue. We hypothesize that oral in vivo bactofection can be an interesting approach to influence the course of inflammatory bowel diseases. The aim of this study was to prove the effects of antioxidative and anti-inflammatory bactofection in dextran sulfate sodium (DSS)-treated mice. Attenuated bacteria Salmonella Typhimurium SL7207 carrying plasmids with genes encoding Cu-Zn superoxide dismutase and an N-terminal deletion mutant of monocyte chemoattractant protein-1 were prepared. Male Balb/c mice had ad libitum access to 1% DSS solution in drinking water during 10 days (mild model of colitis). The animals were daily fed with 200 Mio bacteria via gastric gavage during the experiment. Fecal consistency, clinical status, food and water intake were monitored. After 10 days samples were taken and markers of oxidative stress and inflammatory cytokine levels were measured. Colonic tissue was scored histologically by a blinded investigator. DSS treatment significantly increased the levels of inflammatory cytokines and malondialdehyde as a marker of lipoperoxidation in the colon. Anti-inflammatory gene therapy improved the total antioxidative capacity. In comparison with the untreated group, bacterial gene therapy lowered the histological colitis score. Salmonella-mediated antioxidative and anti-inflammatory gene therapy alleviated colitis in mice. The effect seems to be mediated by increased antioxidative status. Further studies will show whether recombinant probiotics expressing therapeutic gene might be used for the therapy of inflammatory bowel diseases. PMID- 21321315 TI - Over-expressing transient receptor potential cation channel 6 in podocytes induces cytoskeleton rearrangement through increases of intracellular Ca2+ and RhoA activation. AB - Transient receptor potential cation channel 6 (TRPC6) is one of the key molecules for filtration barrier function of podocytes. Over-expression of TRPC6 in podocytes is frequently found in acquired or inherited proteinuric kidney diseases, and animal model over-expression of TRPC6 may lead to proteinuria. To investigate the impact of TRPC6 over-expression in podocytes on its function and its relation to proteinuria in kidney diseases, we over-expressed TRPC6 in mouse podocytes by transient transfection of TRPC6 cDNA plasmid, and observed their changes in foot processes, intracellular F-actin distribution, nephrin and synaptopodin expression, electrophysiology, RhoA activity and intracellular Ca(2+). In podocytes over-expressing TRPC6, cell processes were reduced remarkably in association with the derangement of cytoskeleton demonstrated by the abnormal distribution of intracellular F-actin. These cells also displayed a higher increase of intracellular Ca(2+) ion to the TRPC6 agonist 1-oleoyl-acetyl sn-glycerol and a higher current in the patch-clamp experiment, down-regulation of nephrin and synaptopodin expression and increase of activated RhoA. These changes could be rescued by the treatment of the cells with U73122 to block TRPC6 channel or BAPTA-AM to chelate intracellular Ca(2+) ion. Additionally, the podocytes over-expressing TRPC6 treated with RhoA inhibitor Y-27632 showed an improvement in F-actin arrangement in the cells and increase of nephrin and synaptopodin expression. From these results, we therefore propose that over expression of TRPC6 in podocytes may be one of the fundamental changes relating to the dysfunction of the slit diaphragm and proteinuria. Podocytes over expressing TRPC6 may lead to higher intracellular Ca(2+) ion concentration in the presence of stimuli. The increase of intracellular Ca(2+) down-regulates the expression of two important molecules, nephrin on slit diaphragm and synaptopodin in cytoskeleton, and stimulates RhoA activity, which in turn causes F-actin derangement and the decrease of foot processes. PMID- 21321316 TI - A ketogenic diet impairs energy and glucose homeostasis by the attenuation of hypothalamic leptin signaling and hepatic insulin signaling in a rat model of non obese type 2 diabetes. AB - Ketogenic diets (KTD) are reported to have beneficial effects on the regulation of energy and glucose homeostasis, but remain controversial. We investigated the effects of KTD and ketones on insulin resistance and secretion in non-obese type 2 diabetic rats and their mechanism. KTD (82% energy as fat), intraperitoneal injection of beta-hydroxybutyrate (IHB; 150 mg/kg bw/12 h) with a control diet (COD; 20% energy as fat) or saline injection with COD was given to 90% pancreatectomized (Px) diabetic rats for five weeks. KTD increased epididymal fat pads and serum leptin levels without increasing energy intake, but IHB decreased them. KTD, but not IHB, attenuated hypothalamic signal transducer and activator of transcription 3 and 5'-adenosine monophosphate-activated protein kinase (AMPK) phosphorylation in KTD. Serum glucagon levels were markedly higher in the KTD group than in other groups. During an oral glucose tolerance test, serum glucose levels slowly increased until 80 min in the KTD group and then decreased very slowly. Insulin secretion capacity during a hyperglycemic clamp was significantly lower in the IHB group than in other groups. However, a euglycemic hyperinsulinemic clamp revealed that KTD decreased glucose infusion rates and increased hepatic glucose output in hyperinsulinemic states while IHB had opposite effects to KTD. The increased hepatic glucose output in KTD was associated with increased hepatic phosphoenolpyruvate carboxykinase expression through attenuated tyrosine phosphorylation of IRS2 and phosphorylation of Akt(Ser473). Hepatic AMPK(Thr172) phosphorylation was reduced in KTD. In conclusion, KTD impairs energy and glucose homeostasis by exacerbating insulin resistance and attenuating hypothalamic leptin signaling in non-obese type 2 diabetic rats. These changes are not associated with increased serum ketone levels. PMID- 21321317 TI - Growth hormone upregulates intestinal trefoil factor expression in the ileum of rats after gamma-radiation. AB - Growth hormone (GH) and intestinal trefoil factor (ITF) have been involved in intestinal protection and repair. This study investigates the effects of GH administration on ITF expression and histological changes associated with tissue injury in an intestinal rat model of radiation. Adult male rats were divided into four groups: control, GH, radiation and radiation + GH (GHyRAD). Ileum samples were obtained at 2 or 72 h after radiation and processed to determine ITF levels (mRNA and protein) by quantitative polymerase chain reaction, Western blot and immunohistochemistry. In addition, goblet ITF-positive cells were identified by immunohistochemistry at 72 h. Our results showed an upregulation of mRNA and protein production of ITF in ileum samples after GH and radiation + GH compared with control and irradiated samples. Irradiation alone affected ITF protein expression. However, irradiation after GH pretreatment produced the highest ITF mRNA and protein levels at both the tested time points. ITF-producing goblet cells were identified in intestinal villi (apical location). GH treatment increased the number of ITF-producing goblet cells, and radiation after GH treatment displayed further increase in the number of ITF-positive goblet cells. GH upregulates ITF in normal intestinal tissue. This upregulation is higher when radiation is given after GH treatment. Nevertheless, the mechanism by which GH regulates ITF expression remains unclear and is still under investigation. These results could open up new avenues in the therapeutic reparative and protective effects of GH during radiotherapy and chemotherapy. PMID- 21321318 TI - Treatment and risk factor analysis of hypoglycemia in diabetic rhesus monkeys. AB - In order to anticipate and promptly treat hypoglycemia in diabetic monkeys treated with insulin or other glucose-lowering drugs, the relationships between the incidence and symptoms of hypoglycemia in these animals, and many factors involved in model development and sustainment were analyzed. Different procedures were performed on 22 monkeys for the induction of diabetes. The monkey models were evaluated by blood glucose, insulin, C-peptide levels and intravenous glucose tolerance tests. A glucose treatment program for the diabetic monkeys was administered and laboratory tests were regularly performed. A standard procedure of hypoglycemia treatment was established and the risk factors of hypoglycemia were analyzed by a logistic regression model. Furthermore, the relationships between the four methods of diabetes induction, renal function, glycemic control and hypoglycemia were studied using one-way analysis of variance and t-test. We found that the hypoglycemic conditions of diabetic monkeys were improved rapidly by our treatment. The statistical analysis suggested that the modeling methods, renal function and glycemic control were related to the incidence of hypoglycemia. In detail, the progress of diabetes, effects of glycemic control and, particularly, the severity of the hypoglycemia differed according to the induction strategy used. The models induced by partial pancreatectomy with low dose streptozotocin were not prone to hypoglycemia and their glycemic controls were stable. However, the models induced by total pancreatectomy were more vulnerable to severe hypoglycemia and their glycemic controls were the most unstable. Moreover, the levels of blood creatinine and triglyceride increased after the development of diabetes, which was related to the occurrence of hypoglycemia. In conclusion, we suggested that total pancreatectomy and renal impairment are two important risk factors for hypoglycemia in diabetic monkeys. More attention should be paid to daily care of diabetic monkeys, particularly monitoring and protecting their renal function. PMID- 21321319 TI - Mutation in fucose synthesis gene of Klebsiella pneumoniae affects capsule composition and virulence in mice. AB - The emerging pathogenicity of Klebsiella pneumoniae (KP) is evident by the increasing number of clinical cases of liver abscess (LA) due to KP infection. A unique property of KP is its thick mucoid capsule. The bacterial capsule has been found to contain fucose in KP strains causing LA but not in those causing urinary tract infections. The products of the gmd and wcaG genes are responsible for converting mannose to fucose in KP. A KP strain, KpL1, which is known to have a high death rate in infected mice, was mutated by inserting an apramycin resistance gene into the gmd. The mutant expressed genes upstream and downstream of gmd, but not gmd itself, as determined by reverse transcriptase polymerase chain reaction. The DNA mapping confirmed the disruption of the gmd gene. This mutant decreased its ability to kill infected mice and showed decreased virulence in infected HepG2 cells. Compared with wild-type KpL1, the gmd mutant lost fucose in capsular polysaccharides, increased biofilm formation and interacted more readily with macrophages. The mutant displayed morphological changes with long filament forms and less uniform sizes. The mutation also converted the serotype from K1 of wild-type to K2 and weak K3. The results indicate that disruption of the fucose synthesis gene affected the pathophysiology of this bacterium and may be related to the virulence of this KpL1 strain. PMID- 21321320 TI - Paradoxical increase in liver ketogenesis during long-term insulin-induced hypoglycemia in diabetic rats. AB - It is well established that insulin inhibits liver ketogenesis. However, during insulin-induced hypoglycemia (IIH) the release of counterregulatory hormones could overcome the insulin effect on ketogenesis. To clarify this question the ketogenic activity in livers from alloxan-diabetic rats submitted to long-term IIH was investigated. Moreover, liver glycogenolysis, gluconeogensis, ureagenesis and the production of L-lactate were measured, and its correlation with blood levels of ketone bodies (KB), L-lactate, glucose, urea and ammonia was investigated. For this purpose, overnight fasted alloxan-diabetic rats (DBT group) were compared with control non-diabetic rats (NDBT group). Long-term IIH was obtained with an intraperitoneal injection of Detemir insulin (1 U/kg), and KB, glucose, L-lactate, ammonia and urea were evaluated at 0, 2, 4, 6, 8 or 10 h after insulin injection. Because IIH was well established two hours after insulin injection this time was used for liver perfusion experiments. The administration of Detemir insulin decreased (P < 0.05) blood KB and glucose levels, but there was an increase in the blood L-lactate levels and a rebound increase in blood KB during the glucose recovery phase of IIH. In agreement with these results, the capacity to produce KB from octanoate was increased in the livers of DBT rats. Moreover, the elevated blood L-lactate levels in DBT rats could be attributed to the higher (P < 0.05) glycogenolysis when part of glucose from glycogenolysis enters glycolysis, producing L-lactate. In contrast, except glycerol, gluconeogenesis was negligible in the livers of DBT rats. Therefore, during long term IIH the higher liver ketogenic capacity of DBT rats increased the risk of hyperketonemia. In addition, in spite of the fact that the insulin injection decreased blood KB, there was a risk of worsening lactic acidosis. PMID- 21321321 TI - Realgar, cinnabar and An-Gong-Niu-Huang Wan are much less chronically nephrotoxic than common arsenicals and mercurials. AB - Realgar (As(4)S(4)) and cinnabar (HgS) are frequently included in traditional Chinese medicines and Indian Ayurvedic medicines. Both As and Hg are well known for toxic effects, and their safety is of concern. The aim of this study was to compare chronic nephrotoxicity of An-Gong-Niu-Huang Wan (AGNH), realgar and cinnabar with common arsenicals and mercurials. Mice were orally administrated with AGNH (3 g/kg, 6-fold of clinical dose), cinnabar (0.3 g/kg, amount in AGNH) and realgar (0.3 g/kg, amount in AGNH), HgCl(2) (0.118 mmol/kg, 1/10 of cinnabar), MeHg (0.012 mmol/kg, 1/100 of cinnabar), NaAsO(2) (As(3+) 0.028 mmol/kg, 1/100 of realgar) or Na(2)HAsO(4) (As(5+) 0.056 mmol/kg, 1/50 of realgar), daily for six weeks, and nephrotoxicity was examined. Animal body weights were decreased by MeHg and HgCl(2). Blood urea nitrogen and creatinine levels were elevated by MeHg. Renal pathology was severe in the MeHg and HgCl(2) groups, moderate in the arsenite, arsenate and realgar groups and mild in the cinnabar and AGNH groups. Renal Hg accumulation in the MeHg and HgCl(2) groups was 50-200 folds higher than the cinnabar group. Expressions of metallothionein-1 and heme oxygenase-1, biomarkers for metal toxicity, were increased 2-5 folds by arsenite, arsenate, MeHg and HgCl(2), but not by realgar, cinnabar and AGNH. The chemokine and glutathione-S transferase-alpha4, markers for inflammation, were also increased by MeHg and HgCl(2). Expressions of cell adhesion gene S100a9 and E-cadherin were altered by HgCl(2), arsenite and realgar. Taken together, chemical forms of mercury and arsenic are major determinants in their disposition and toxicity. PMID- 21321322 TI - Suppression of mast-cell-mediated allergic inflammation by Lindera obtusiloba. AB - Allergic disease is a consequence of exposure to normally innocuous substances that elicit the activation of mast cells. Mast-cell-mediated allergic response is involved in many diseases such as anaphylaxis, allergic rhinitis, asthma and atopic dermatitis. The discovery of drugs for the treatment of allergic disease is an important subject in human health. In this study, we investigated the effect of Lindera obtusiloba water extract (LOWE) on the mast-cell-mediated allergic inflammation and possible mechanism of action using in vitro and in vivo models. LOWE reduced histamine release from various types of mast cells activated by immunoglobulin E (IgE) or phorbol 12-myristate 13-acetate and calcium ionophore A23187 (PMACI). The inhibitory effect of LOWE on histamine release was mediated by calcium signal. LOWE decreased the PMACI-stimulated gene expression of proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin 6 in human mast cells. The inhibitory effect of LOWE on the proinflammatory cytokines was nuclear factor (NF)-kappaB dependent. In addition, LOWE suppressed compound 48/80-induced systemic allergic reaction and serum histamine release in mice and IgE-mediated local allergic reactions. Our results indicate that LOWE inhibits mast-cell-derived allergic inflammation and involvement of calcium, histamine, proinflammatory cytokines and NF-kappaB in these effects. PMID- 21321323 TI - Novel X-linked inhibitor of apoptosis protein inhibitors as probes of apoptosis in biology and medicine. AB - We report here a series of new inhibitors of the X-linked inhibitor of apoptosis protein (XIAP protein) based on the SMAC-tetrapeptide AVPI. The structural novelty of these molecules is the presence of the proline mimetic exo-2 azabicyclo[2.2.1]heptane-3-carboxylic acid, leading to analogs with similar activity to the natural ligand peptide. The structure-activity relationship and computational docking studies support the convenience of this unnatural amino acid as a building block to develop new peptides or small molecules targeting the XIAP-BIR3 domain. PMID- 21321324 TI - Nucleoskeleton mechanics at a glance. PMID- 21321325 TI - Rho GTPases and their role in organizing the actin cytoskeleton. PMID- 21321326 TI - Cohesin loading and sliding. AB - Cohesin is best known as a crucial component of chromosomal stability. Composed of several essential subunits in budding yeast, cohesin forms a ring-like complex that is thought to embrace sister chromatids, thereby physically linking them until their timely segregation during cell division. The ability of cohesin to bind chromosomes depends on the Scc2-Scc4 complex, which is viewed as a loading factor for cohesin onto DNA. Notably, in addition to its canonical function in sister chromatid cohesion, cohesin has also been implicated in gene regulation and development in organisms ranging from yeast to human. Despite its importance, both as a mediator of sister chromatid cohesion and as a modulator of gene expression, the nature of the association of cohesin with chromosomes that enables it to fulfil both of these roles remains incompletely understood. The mechanism by which cohesin is loaded onto chromosomes, and how cohesin and the related condensin and Smc5-Smc6 complexes promote DNA interactions require further elucidation. In this Commentary, we critically review the evidence for cohesin loading and its subsequent apparent sliding along chromosomes, and discuss the implications gained from cohesin localisation studies for its important functions in chromosome biology. PMID- 21321327 TI - A distinct trans-Golgi network subcompartment for sorting of synaptic and granule proteins in neurons and neuroendocrine cells. AB - Golgi-to-plasma-membrane trafficking of synaptic-like microvesicle (SLMV) proteins, vesicular acetylcholine transporter (VAChT) and synaptophysin (SYN), and a large dense-core vesicle (LDCV) protein, chromogranin A (CgA), was investigated in undifferentiated neuroendocrine PC12 cells. Live cell imaging and 20 degrees C block-release experiments showed that VAChT-GFP, SYN-GFP and CgA-RFP specifically and transiently cohabitated in a distinct sorting compartment during cold block and then separated into synaptic protein transport vesicles (SPTVs) and LDCVs, after release from temperature block. We found that in this trans Golgi subcompartment there was colocalization of SPTV and LDCV proteins, most significantly with VAMP4 and Golgin97, and to some degree with TGN46, but not at all with TGN38. Moreover, some SNAP25 and VAMP2, two subunits of the exocytic machinery, were also recruited onto this compartment. Thus, in neuroendocrine cells, synaptic vesicle and LDCV proteins converge briefly in a distinct trans Golgi network subcompartment before sorting into SPTVs and LDCVs, ultimately for delivery to the plasma membrane. This specialized sorting compartment from which SPTVs and LDCVs bud might facilitate the acquisition of common exocytic machinery needed on the membranes of these vesicles. PMID- 21321328 TI - Regulation of the NKCC2 ion cotransporter by SPAK-OSR1-dependent and -independent pathways. AB - Ion cotransporters, such as the Na(+)/Cl(-) cotransporter (NCC), control renal salt re-absorption and are regulated by the WNK-signalling pathway, which is over stimulated in patients suffering from Gordon's hypertension syndrome. Here, we study the regulation of the NKCC2 (SLC12A1) ion cotransporter that contributes towards ~25% of renal salt re-absorption and is inhibited by loop-diuretic hypertensive drugs. We demonstrate that hypotonic low-chloride conditions that activate the WNK1-SPAK and OSR1 pathway promote phosphorylation of NKCC2 isoforms (A, B and F) at five residues (Ser91, Thr95, Thr100, Thr105 and Ser130). We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91. Our data indicate that a SPAK-OSR1-independent kinase, perhaps AMP activated protein kinase (AMPK), phosphorylates Ser130 and that phosphorylation of Thr105 and Ser130 plays the most important roles in stimulating NKCC2 activity. In contrast with NCC, whose membrane translocation is triggered by SPAK OSR1 phosphorylation, NKCC2 appears to be constitutively at the membrane. Our findings provide new insights into how NKCC2 is regulated and suggest that inhibitors of SPAK and/or OSR1 for the treatment of hypertension would be therapeutically distinct from thiazide or loop diuretics, as they would suppress the activity of both NCC and NKCC2. PMID- 21321329 TI - Endosomal clathrin drives actin accumulation at the immunological synapse. AB - Antigen-specific cognate interaction of T lymphocytes with antigen-presenting cells (APCs) drives major morphological and functional changes in T cells, including actin rearrangements at the immune synapse (IS) formed at the cell-cell contact area. Here we show, using cell lines as well as primary cells, that clathrin, a protein involved in endocytic processes, drives actin accumulation at the IS. Clathrin is recruited towards the IS with parallel kinetics to that of actin. Knockdown of clathrin prevents accumulation of actin and proteins involved in actin polymerization, such as dynamin-2, the Arp2/3 complex and CD2AP at the IS. The clathrin pool involved in actin accumulation at the IS is linked to multivesicular bodies that polarize to the cell-cell contact zone, but not to plasma membrane or Golgi complex. These data underscore the role of clathrin as a platform for the recruitment of proteins that promote actin polymerization at the interface of T cells and APCs. PMID- 21321330 TI - Teaching NeuroImages: traumatic vertebral arteriovenous fistula. PMID- 21321331 TI - A diagnostic test to distinguish psychogenic dystonia from organic dystonia? PMID- 21321332 TI - Faulty brakes? Inhibitory processes in attention-deficit/hyperactivity disorder. PMID- 21321333 TI - Intermittent theta-burst transcranial magnetic stimulation for treatment of Parkinson disease. AB - OBJECTIVE: To investigate the safety and efficacy of intermittent theta-burst stimulation (iTBS) in the treatment of motor symptoms in Parkinson disease (PD). BACKGROUND: Progression of PD is characterized by the emergence of motor deficits, which eventually respond less to dopaminergic therapy and pose a therapeutic challenge. Repetitive transcranial magnetic stimulation (rTMS) has shown promising results in improving gait, a major cause of disability, and may provide a therapeutic alternative. iTBS is a novel type of rTMS that may be more efficacious than conventional rTMS. METHODS: In this randomized, double-blind, sham-controlled study, we investigated safety and efficacy of iTBS of the motor and dorsolateral prefrontal cortices in 8 sessions over 2 weeks (evidence Class I). Assessment of safety and clinical efficacy over a 1-month period included timed tests of gait and bradykinesia, Unified Parkinson's Disease Rating Scale (UPDRS), and additional clinical, neuropsychological, and neurophysiologic measures. RESULTS: We investigated 26 patients with mild to moderate PD: 13 received iTBS and 13 sham stimulation. We found beneficial effects of iTBS on mood, but no improvement of gait, bradykinesia, UPDRS, and other measures. EEG/EMG monitoring recorded no pathologic increase of cortical excitability or epileptic activity. Few reported discomfort or pain and one experienced tinnitus during real stimulation. CONCLUSION: iTBS of the motor and prefrontal cortices appears safe and improves mood, but failed to improve motor performance and functional status in PD. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that iTBS was not effective for gait, upper extremity bradykinesia, or other motor symptoms in PD. PMID- 21321334 TI - The blink reflex recovery cycle differs between essential and presumed psychogenic blepharospasm. AB - BACKGROUND: Psychogenic blepharospasm is difficult to distinguish clinically from benign essential blepharospasm (BEB). The blink reflex recovery cycle measures the excitability of human brainstem interneurons and is abnormal in BEB. We wished to study the blink reflex recovery cycle in patients with atypical (presumed psychogenic) blepharospasm (AB). METHODS: This was a prospective data collection study investigating the R2 blink reflex recovery cycle at interstimulus intervals (ISI) of 200, 300, 500, 1,000, and 3,000 msec in 10 patients with BEB, 9 patients with AB, and 9 healthy controls. All patients had spasm of the orbicularis oculi muscles. To compare individual patients, an R2 recovery index was calculated as average of the recovery values at ISIs of 200, 300, and 500 msec, with the upper limit of normal defined as mean (control group) + 2 SD. RESULTS: The R2 recovery cycle was significantly disinhibited in patients with BEB, whereas patients with AB did not differ from controls on a group level. The upper limit of normal for the R2 recovery index was 61%. The R2 index was abnormal in 9 out of 10 patients with BEB and in none of the patients with AB. CONCLUSIONS: A normal blink reflex recovery cycle indicates normal brainstem interneuron excitability. Assessment of the R2 recovery cycle may provide a useful diagnostic tool to distinguish patients with psychogenic blepharospasm from BEB and is worthy of further study. PMID- 21321335 TI - Motor cortex inhibition: a marker of ADHD behavior and motor development in children. AB - OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is a childhood-onset behavioral diagnosis in which children often fail to meet age norms in development of motor control, particularly timed repetitive and sequential movements, motor overflow, and balance. The neural substrate of this motor delay may include mechanisms of synaptic inhibition in or adjacent to the motor cortex. The primary objective of this study was to determine whether transcranial magnetic stimulation (TMS)-evoked measures, particularly short interval cortical inhibition (SICI), in motor cortex correlate with the presence and severity of ADHD in childhood as well as with commonly observed delays in motor control. METHODS: In this case-control study, behavioral ratings, motor skills, and motor cortex physiology were evaluated in 49 children with ADHD (mean age 10.6 years, 30 boys) and 49 typically developing children (mean age 10.5 years, 30 boys), all right-handed, aged 8-12 years. Motor skills were evaluated with the Physical and Neurological Examination for Subtle Signs (PANESS) and the Motor Assessment Battery for Children version 2. SICI and other physiologic measures were obtained using TMS in the left motor cortex. RESULTS: In children with ADHD, mean SICI was reduced by 40% (p < 0.0001) and less SICI correlated with higher ADHD severity (r = -0.52; p = 0.002). Mean PANESS motor development scores were 59% worse in children with ADHD (p < 0.0001). Worse PANESS scores correlated modestly with less SICI (r = -.30; p = 0.01). CONCLUSION: Reduced TMS-evoked SICI correlates with ADHD diagnosis and symptom severity and also reflects motor skill development in children. PMID- 21321336 TI - Quantifying excessive mirror overflow in children with attention deficit/hyperactivity disorder. AB - OBJECTIVES: Qualitative observations have revealed that children with attention deficit/hyperactivity disorder (ADHD) show increased overflow movements, a motor sign thought to reflect impaired inhibitory control. The goal of this study was to develop and implement methods for quantifying excessive mirror overflow movements in children with ADHD. METHODS: Fifty right-handed children aged 8.2 13.3 years, 25 with ADHD (12 girls) and 25 typically developing (TD) control children (10 girls), performed a sequential finger-tapping task, completing both left-handed (LHFS) and right-handed finger sequencing (RHFS). Phasic overflow of the index and ring fingers was assessed in 34 children with video recording, and total overflow in 48 children was measured by calculating the total angular displacement of the index and ring fingers with electrogoniometer recordings. RESULTS: Phasic overflow and total overflow across both hands were greater in children with ADHD than in TD children, particularly during LHFS. Separate gender analyses revealed that boys, but not girls, with ADHD showed significantly more total phasic overflow and total overflow than did their gender-matched control children. CONCLUSIONS: The quantitative overflow measures used in this study support past qualitative findings that motor overflow persists to a greater degree in children with ADHD than in age-matched TD peers. The quantitative findings further suggest that persistence of mirror overflow is more prominent during task execution of the nondominant hand and reveal gender-based differences in developmental neural systems critical to motor control. These quantitative measures will assist future physiologic investigation of the brain basis of motor control in ADHD. PMID- 21321337 TI - Sex differences in risk factors for aneurysmal subarachnoid hemorrhage: a cohort study. AB - OBJECTIVE: The purpose of this study was to investigate sex differences in the major established risk factors for aneurysmal subarachnoid hemorrhage (aSAH) in a large, population-based cohort. METHODS: Sex differences in the established risk factors for aSAH (smoking, hypertension, and alcohol consumption) were examined in a prospective, population-based cohort consisting of 92,462 participants of the Nord-Trondelag and the Tromso Health Studies in Norway. RESULTS: We identified 120 cases of aSAH during 1,002,148 person-years at risk. Compared with the risk in nonsmokers, the risk of aSAH was higher in current cigarette-smoking women than in men (hazard ratio = 8.9, 95% confidence interval [CI] 4.7-17.0 vs hazard ratio = 2.8, 95% CI 1.3-6.1, after adjustment for age and alcohol consumption). The interaction between sex and current smoking was present on an additive scale (relative excess risk due to interaction 3.1, 95% CI 0.5-5.8), indicating a higher risk of aSAH associated with current cigarette smoking in women than in men. No sex differences in the risk of aSAH were observed with respect to hypertension or alcohol consumption. CONCLUSIONS: This prospective, population-based cohort study showed that compared with the risk in nonsmokers, the risk of aSAH was higher in current cigarette-smoking women than in men. This finding may at least partially explain the gender gap in aSAH incidence. A more intensive smoking cessation intervention should be considered in women at risk of aSAH. PMID- 21321339 TI - Heat shock proteins: multiple neuroprotective functions and implications for neurologic disease. PMID- 21321338 TI - Global clinical dementia rating of 0.5 in MCI masks variability related to level of function. AB - OBJECTIVE: To evaluate whether ratings on Clinical Dementia Rating (CDR) items related to instrumental activities of daily living (IADL) are associated with cognitive or brain morphometric characteristics of participants with mild cognitive impairment (MCI) and global CDR scores of 0.5. METHODS: Baseline cognitive and morphometric data were analyzed for 283 individuals with MCI who were divided into 2 groups (impaired and intact) based on their scores on the 3 CDR categories assessing IADL. Rates of progression to Alzheimer disease (AD) over 2 years were also compared in the 2 groups. RESULTS: The impaired IADL MCI group showed a more widespread pattern of gray matter loss involving frontal and parietal regions, worse episodic memory and executive functions, and a higher percentage of individuals progressing to AD than the relatively intact IADL MCI group. CONCLUSIONS: The results demonstrate the importance of considering functional information captured by the CDR when evaluating individuals with MCI, even though it is not given equal weight in the assignment of the global CDR score. Worse impairment on IADL items was associated with greater involvement of brain regions beyond the mesial temporal lobe. The conventional practice of relying on the global CDR score as currently computed underutilizes valuable IADL information available in the scale, and may delay identification of an important subset of individuals with MCI who are at higher risk of clinical decline. PMID- 21321340 TI - The epilepsy of Franklin Delano Roosevelt. PMID- 21321341 TI - MAPT H1 haplotype is a risk factor for essential tremor and multiple system atrophy. PMID- 21321342 TI - Tumefactive demyelination, an uncommon form of tacrolimus neurotoxicity. PMID- 21321343 TI - High insulinlike growth factor I is associated with cognitive decline in Huntington disease. PMID- 21321344 TI - Harlequin syndrome caused by lesion of sympathetic regulatory neurons. PMID- 21321345 TI - Amyotrophic lateral sclerosis: ethical challenges. PMID- 21321346 TI - Myopathy: five new things. PMID- 21321347 TI - Epilepsy: five new things. PMID- 21321348 TI - Dementia: five new things. PMID- 21321349 TI - Current understanding and treatment of headache disorders: five new things. PMID- 21321350 TI - Chronic daily headache: an evidence-based and systematic approach to a challenging problem. PMID- 21321351 TI - Driving and neurologic disorders. PMID- 21321352 TI - Approach to severe hemispheric stroke. PMID- 21321353 TI - How positioning can help boost your neurology practice and drive business success. PMID- 21321354 TI - The evaluation of polyneuropathies. PMID- 21321356 TI - Prolonged follow-up and CSF antibody titers in a patient with anti-NMDA receptor encephalitis. PMID- 21321355 TI - Acalculia in autopsy-proven corticobasal degeneration. PMID- 21321357 TI - A tale of two tauopathies. PMID- 21321358 TI - Deep brain stimulation in "on"-state Parkinson hyperpyrexia. PMID- 21321359 TI - Transcriptional regulation of fetal to adult hemoglobin switching: new therapeutic opportunities. AB - In humans, embryonic, fetal, and adult hemoglobins are sequentially expressed in developing erythroblasts during ontogeny. For the past 40 years, this process has been the subject of intensive study because of its value to enlighten the biology of developmental gene regulation and because fetal hemoglobin can significantly ameliorate the clinical manifestations of both sickle cell disease and beta thalassemia. Understanding the normal process of loss of fetal globin expression and activation of adult globin expression could potentially lead to new therapeutic approaches for these hemoglobin disorders. Herein, we briefly review the history of the study of hemoglobin switching and then focus on recent discoveries in the field that now make new therapeutic approaches seem feasible in the future. Erythroid-specific knockdown of fetal gene repressors or enforced expression of fetal gene activators may provide clinically applicable approaches for genetic treatment of hemoglobin disorders that would benefit from increased fetal hemoglobin levels. PMID- 21321361 TI - Promotion and maintenance of leukemia by ERG. AB - The Ets-related gene (ERG) located on human chromosome 21 encodes a transcription factor and is thought to be causally related to Down syndrome-associated acute megakaryocytic leukemia in childhood. In clinical adult leukemia, however, increased expression of ERG is indicative of poor prognosis in T-cell acute lymphoblastic leukemia and cytogenetically normal acute myeloid leukemia, although the involvement of ERG in the development of adult leukemia remains elusive. Here, we show that forced expression of ERG in adult BM cells alters differentiation and induces expansion of T and erythroid cells and increases frequencies of myeloid progenitors in mouse BM transplantation models. The expanded T cells then develop T-cell acute lymphoblastic leukemia after acquisition of mutations in the Notch1 gene. Targeted expression of ERG into B cells also altered differentiation and promoted growth of precursor B cells. Overall, these findings suggest a general role of ERG in promoting growth of adult hematopoietic cells in various lineages. In line with this, shRNA-mediated silencing of ERG expression attenuated growth of human leukemia cell lines of various lineages. Thus, ERG is capable of promoting the development of leukemia and is crucial for its maintenance. PMID- 21321362 TI - An embryonic stage-specific enhancer within the murine beta-globin locus mediates domain-wide histone hyperacetylation. AB - In mammalian nuclei, a select number of tissue-specific gene loci exhibit broadly distributed patterns of histone modifications, such as histone hyperacetylation, that are normally associated with active gene promoters. Previously, we characterized such hyperacetylated domains within mammalian beta-globin gene loci, and determined that within the murine locus, neither the beta-globin locus control region nor the gene promoters were required for domain formation. Here, we identify a developmentally specific erythroid enhancer, hypersensitive site embryonic 1 (HS-E1), located within the embryonic beta-globin domain in mouse, which is homologous to a region located downstream of the human embryonic epsilon globin gene. This sequence exhibits nuclease hypersensitivity in primitive erythroid cells and acts as an enhancer in gain-of-function assays. Deletion of HS-E1 from the endogenous murine beta-globin locus results in significant decrease in the expression of the embryonic beta-globin genes and loss of the domain-wide pattern of histone hyperacetylation. The data suggest that HS-E1 is an enhancer that is uniquely required for beta-like globin expression in primitive erythroid cells, and that it defines a novel class of enhancer that works in part by domain-wide modulation of chromatin structure. PMID- 21321360 TI - Lenalidomide targets clonogenic side population in multiple myeloma: pathophysiologic and clinical implications. AB - Recurrence of multiple myeloma (MM) after therapy suggests the presence of tumor initiating subpopulations. In our study, we performed flow cytometry-based Hoechst 33342 staining to evaluate the existence of a MM population with stem like features known as side population (SP) cells. SP cells exhibit substantial heterogeneity in MM cell lines and primary MM cells; express CD138 antigen in MM cell lines; display higher mRNA expression and functional activity of ABCG2 transporter; and have a higher proliferation index compared with non-SP cells. We observed evidence for clonogenic potential of SP cells, as well as the ability of SP cells to regenerate original population. Moreover, SP cells revealed higher tumorigenicity compared with non-SP cells. Importantly, lenalidomide decreased the percentage and clonogenicity of SP cells, and also induced phosphorylation changes in Akt, GSK-3alpha/beta, MEK1, c-Jun, p53, and p70S6K in SP cells. Adherence to bone marrow stromal cells (BMSCs) increased the percentage, viability, and proliferation potential of SP cells. Lenalidomide and thalidomide abrogated this stimulatory effect of BMSCs and significantly decreased the percentage of SP cells. Our studies demonstrate a novel mechanism of action for lenalidomide, namely targeting SP fraction, providing the framework for new therapeutic strategies targeting subpopulations of MM cells including presumptive stem cells. PMID- 21321363 TI - Chemical composition and antifungal activity of the essential oils of Lavandula viridis L'Her. AB - In the present work we report for what we believe to be the first time the antifungal activity and mechanism of action of the essential oils of Lavandula viridis from Portugal. The essential oils were isolated by hydrodistillation and analysed by GC and GC/MS. The MIC and the minimal lethal concentration (MLC) of the essential oil and its major compounds were determined against several pathogenic fungi. The influence of subinhibitory concentrations of the essential oil on the dimorphic transition in Candida albicans was also studied, as well as propidium iodide and FUN-1 staining of Candida albicans cells by flow cytometry following short treatments with the essential oil. The oils were characterized by a high content of oxygen-containing monoterpenes, with 1,8-cineole being the main constituent. Monoterpene hydrocarbons were present at lower concentrations. According to the determined MIC and MLC values, the dermatophytes and Cryptococcus neoformans were the most sensitive fungi (MIC and MLC values ranging from 0.32 to 0.64 ul ml-1), followed by Candida species (at 0.64-2.5 ul ml-1). For most of these strains, MICs were equivalent to MLCs, indicating a fungicidal effect of the essential oil. The oil was further shown to completely inhibit filamentation in Candida albicans at concentrations well below the respective MICs (as low as MIC/16). Flow cytometry results suggested a mechanism of action ultimately leading to cytoplasmic membrane disruption and cell death. Our results show that L. viridis essential oils may be useful in the clinical treatment of fungal diseases, particularly dermatophytosis and candidosis, although clinical trials are required to evaluate the practical relevance of our in vitro research. PMID- 21321364 TI - Pain in osteochondral lesions. AB - Pain is the key symptom of patients suffering from osteochondral lesions (OCLs) of the ankle joint. Routine radiographic imaging methods for diagnosis and staging of OCL fail to visualize the pain-inducing focus within the joint. SPECT CT (Single-photon emission computed tomography-computed tomography) is a new hybrid imaging technique allowing exact digital fusion of scintigraphic and computer tomographic images. This allows precise localization and size determination of an OCL within the joint. Using this novel imaging method, we conducted a study to evaluate the correlation between pathological uptake within an OCL and pain experienced by patients suffering from this condition; 15 patients were assessed in the orthopaedic ambulatory clinic for unilateral OCL of the ankle joint. Pain status was measured with the Visual Analogue Scale (VAS). A SPECT-CT was performed. All patients underwent CT-guided ankle injection with a local anesthetic and iodine contrast medium. The VAS score assessed immediately postinfiltration was compared with the preinterventional VAS score obtained in the outpatient clinic. Pain relief was defined as a reduction of the VAS score to <=50% of the preinterventional score, if expected immediately after infiltration. Pain relief was found in all 15 patients. The results of our study show that there is a highly significant correlation between pain and pathological uptake seen on SPECT-CT, indicating that pathologically remodeled bone tissue is an important contributor to pain in OCL. Adequate addressing of involved bone tissue needs to be taken into consideration when choosing a surgical treatment method. PMID- 21321365 TI - C4: Exploring Multiple Solutions in Graphical Models by Cluster Sampling. AB - This paper presents a novel Markov Chain Monte Carlo (MCMC) inference algorithm called C(4)--Clustering with Cooperative and Competitive Constraints--for computing multiple solutions from posterior probabilities defined on graphical models, including Markov random fields (MRF), conditional random fields (CRF), and hierarchical models. The graphs may have both positive and negative edges for cooperative and competitive constraints. C(4) is a probabilistic clustering algorithm in the spirit of Swendsen-Wang. By turning the positive edges on/off probabilistically, C(4) partitions the graph into a number of connected components (ccps) and each ccp is a coupled subsolution with nodes connected by positive edges. Then, by turning the negative edges on/off probabilistically, C(4) obtains composite ccps (called cccps) with competing ccps connected by negative edges. At each step, C(4) flips the labels of all nodes in a cccp so that nodes in each ccp keep the same label while different ccps are assigned different labels to observe both positive and negative constraints. Thus, the algorithm can jump between multiple competing solutions (or modes of the posterior probability) in a single or a few steps. It computes multiple distinct solutions to preserve the intrinsic ambiguities and avoids premature commitments to a single solution that may not be valid given later context. C(4) achieves a mixing rate faster than existing MCMC methods, such as various Gibbs samplers and Swendsen-Wang cuts. It is also more "dynamic" than common optimization methods such as ICM, LBP, and graph cuts. We demonstrate the C(4) algorithm in line drawing interpretation, scene labeling, and object recognition. PMID- 21321366 TI - Compactly Supported Basis Functions as Support Vector Kernels for Classification. AB - Wavelet kernels have been introduced for both support vector regression and classification. Most of these wavelet kernels do not use the inner product of the embedding space, but use wavelets in a similar fashion to radial basis function kernels. Wavelet analysis is typically carried out on data with a temporal or spatial relation between consecutive data points. We argue that it is possible to order the features of a general data set so that consecutive features are statistically related to each other, thus enabling us to interpret the vector representation of an object as a series of equally or randomly spaced observations of a hypothetical continuous signal. By approximating the signal with compactly supported basis functions and employing the inner product of the embedding L2 space, we gain a new family of wavelet kernels. Empirical results show a clear advantage in favor of these kernels. PMID- 21321367 TI - Intensity-Based Image Registration by Nonparametric Local Smoothing. AB - Image registration is used widely in applications for mapping one image to another. Existing image registration methods are either feature-based or intensity-based. Feature-based methods first extract relevant image features and then find the geometrical transformation that best matches the two corresponding sets of features extracted from the two images. Because identification and extraction of image features is often a challenging and time-consuming process, intensity-based image registration, by which the mapping transformation is estimated directly from the observed image intensities of the two images, has received much attention recently. In the literature, most existing intensity based image registration methods estimate the mapping transformation globally by solving a minimization/maximization problem defined by the two entire images to register. To this end, it needs to be assumed that the mapping transformation has a certain type of parametric form or it is a continuous bivariate function satisfying certain regularity conditions. In this paper, we propose a novel intensity-based image registration method using nonparametric local smoothing. By this method, the mapping transformation at a given pixel is estimated locally in a neighborhood after certain image features are accommodated in the estimation. Due to the flexibility of local smoothing, this method does not require any parametric form for the mapping transformation. It even allows the transformation to be a discontinuous function. Numerical examples show that it is effective in various applications. PMID- 21321368 TI - Asymmetric comparison and querying of biological networks. AB - Comparing and querying the protein-protein interaction (PPI) networks of different organisms is important to infer knowledge about conservation across species. Known methods that perform these tasks operate symmetrically, i.e., they do not assign a distinct role to the input PPI networks. However, in most cases, the input networks are indeed distinguishable on the basis of how the corresponding organism is biologically well characterized. In this paper a new idea is developed, that is, to exploit differences in the characterization of organisms at hand in order to devise methods for comparing their PPI networks. We use the PPI network (called Master) of the best characterized organism as a fingerprint to guide the alignment process to the second input network (called Slave), so that generated results preferably retain the structural characteristics of the Master network. Technically, this is obtained by generating from the Master a finite automaton, called alignment model, which is then fed with (a linearization of) the Slave for the purpose of extracting, via the Viterbi algorithm, matching subgraphs. We propose an approach able to perform global alignment and network querying, and we apply it on PPI networks. We tested our method showing that the results it returns are biologically relevant. PMID- 21321369 TI - Two-step cross-entropy feature selection for microarrays-power through complementarity. AB - Current feature selection methods for supervised classification of tissue samples from microarray data generally fail to exploit complementary discriminatory power that can be found in sets of features. Using a feature selection method with the computational architecture of the cross-entropy method, including an additional preliminary step ensuring a lower bound on the number of times any feature is considered, we show when testing on a human lymph node data set that there are a significant number of genes that perform well when their complementary power is assessed, but "pass under the radar" of popular feature selection methods that only assess genes individually on a given classification tool. We also show that this phenomenon becomes more apparent as diagnostic specificity of the tissue samples analysed increases. PMID- 21321370 TI - [Cognitive, emotional and behavioral impairments following traumatic brain injury and the neuro-radiological diagnosis]. PMID- 21321371 TI - [Surgery for partially thrombosed giant aneurysms of the middle cerebral artery]. PMID- 21321372 TI - [Transsphenoidal surgery for pituitary tumors from microsurgery to the endoscopic surgery: single surgeon's experience]. AB - We reviewed results of the surgical outcome of pituitary tumors treated via the transsphenoidal approach between January, 1994 and January, 2010 at our institution. This data included 100 patients (124 procedures) treated through the sublabial transsphenoidal approach and 45 patients (54 procedures) treated through the endoscopic endonasal (bilateral nostrils) transsphenoidal approach performed by a single surgeon. The extent of tumor removal was significantly improved with endoscopic surgery; adjuvant gamma knife radiosurgery was needed for 65% of patients undergoing microsurgery vs. 30% for patients who had endoscopic surgery (p<0.0001). Patients who underwent endoscopic surgery had less intraoperative blood loss (mean volume: 100 mL for microsurgery patients vs. 30 mL for endoscopic surgery patients, p<0.0001), less pain, and less need for postoperative hormone replacement therapy (19% for microsurgery patients vs. 6% for endoscopic surgery patients; p<0.05). CSF leakage and meningitis were experienced in one microsurgery patient (1%) and one endoscopic surgery patient (2.2%). Endoscopic surgery is a reasonable alternative to microsurgery and our experience supports the concept that an otolaryngologist/neurosurgeon team skilled in endoscopic techniques and pituitary surgery can safely make the transition from microsurgery to endoscopic surgery. PMID- 21321373 TI - [Left to right ratio of transcranial color-coded sonography for monitoring hyperperfusion syndrome after carotid artery stenting: a case report]. AB - Hyperperfusion syndrome is a significant complication after carotid endarterectomy (CEA) or carotid artery stenting (CAS). A few reports have shown that an increase in the ratio of mean flow velocity (MFV) of the middle cerebral artery (MCA) of the affected side by transcranial color-coded sonography (TCCS) is useful for the evaluation of hyperperfusion after CEA or CAS. We report a case of hyperperfusion syndrome after CAS in which not only the increased ratio of the affected side based on preoperative mean flow velocity, but also the left to right ratio (L/R ratio) was useful for monitoring hyperperfusion. A 48-year-old man was admitted to our hospital because of cerebral infarction of the right internal carotid artery (ICA) due to stenosis of the right ICA at origin. The preoperative L/R ratio of MFV of the MCA by TCCS was 0.58. We performed CAS and the patient then developed hyperperfusion syndrome with epilepsy and was intubated under the management of strict blood control. We performed TCCS daily and the patient was extubated when the L/R ratio of MFV of the MCA decreased to 1.1 from a maximum of 2.6, although the increased ratio of MFV of the MCA of the affected side was still higher than 1.4. The patient went home without any complications from hyperperfusion. When there is preoperative laterality of cerebral blood flow, the L/R ratio of MFV by TCCS can be useful for monitoring hyperperfusion after CEA or CAS. PMID- 21321374 TI - [Invasive paranasal sinus fungal infection developing orbital apex syndrome and causing internal carotid artery infiltration: reports of 3 cases]. AB - Fungal infection is an increasing problem in patients treated with intensive chemotherapy or immunosuppressive therapy. Of these, invasive aspergillosis or mucormycosis on rare occasions, infiltrate the internal carotid artery (ICA) by contiguous spread from an infected paranasal sinus. Here, we report three cases of ICA infiltration secondary to the fungal infections of the paranasal sinus. All cases developed orbital apex syndrome when the lesion spread to the orbital apex or cavernous sinus, and aggressive progression led to ICA invasion causing life-threatening cerebral infarction or hemorrhage. In this case report, we describe the aggressive clinical course of the fungal ICA invasion from the paranasal sinus, and then discuss the clinical feature, diagnostic methods, and current treatment of intracranial fungal infection. PMID- 21321375 TI - [Case of calvarial fibrous dysplasia presenting with cyst degeneration]. AB - A 49-year-old female developed a painful dysesthesia in the left forehead 10 years after having become aware of a subcutaneous mass accompanied with mild tenderness. Her medical history was unremarkable. Neurological examination showed normal findings with intact facial nerve function. Blood examination was normal. Neuroimaging revealed a cystic bony mass and an adjacent patchy diploic lesion in the left temporal bone. She underwent total tumor resection by frontotemporal craniotomy. Intraoperatively, a bony defect was noted in the lower surface of the patchy lesion communicating with the diploic venous system. A part of the dura mater was invaginated in the bony defect. The patchy lesion was found to communicate with the bony cyst through the diploic structure. Histological appearance of the bony cyst was consistent with the fibrous dysplasia accompanying cyst degeneration. Histological findings of the patchy lesion were identical to those of the bony cyst except for cyst degeneration. We assumed that the diploic venous system and the meningeal vessel might have been associated with the etiology of cyst degeneration in the present case of fibrous dysplasia. PMID- 21321376 TI - [Coil embolization of a ruptured posterior cerebral artery aneurysm via the internal carotid artery and a posterior communicating artery: a case report]. AB - A posterior cerebral artery aneurysm is a rare condition. Various surgical approaches have to be considered for operating on these aneurysms because the position of the aneurysm and the surrounding structures restrict the operative field and render the operation difficult. Recently, endovascular treatments for posterior cerebral artery aneurysms have been reported to provide a good outcome. We present a case of a ruptured posterior cerebral artery aneurysm treated with coil embolization. We adopted endovascular treatment because a large vein of Labbe was expected to restrict the operative field. The internal carotid artery and a fetal-type posterior communicating artery (PCoA) were chosen as the access route because of P1 hypoplasty, and a coaxial guiding system was used because of the tortuous access route. The aneurysm was suitably embolized using Guglielmi detachable coils (GDCs). In a case of posterior cerebral artery aneurysm, we report the usefulness of endovascular treatment performed through the internal carotid artery and a fetal-type PCoA. PMID- 21321377 TI - [Congenital anomalies in the central nervous system. (3) Aqueductal stenosis]. PMID- 21321378 TI - AKT1/BRCA1 in the control of homologous recombination and genetic stability: the missing link between hereditary and sporadic breast cancers. AB - Endogenous replicative stress could be one trigger leading to tumor initiation: indeed, activation of the DNA damage response (DDR), considered the result of replicative stress, is observed in pre-cancerous cells; moreover, in hereditary breast cancers, almost all of the genes affected relate to the DDR. The most frequently mutated gene in hereditary breast cancers, BRCA1, is essential for homologous recombination (HR), a fundamental process for maintaining genome stability that permits the reactivation of blocked replication forks . Recent studies have established links between DDR and the oncogenic kinase AKT1, which is upregulated in about 50% of sporadic breast cancers. More specifically, the activation of AKT1 shows a deficient phenotype in BRCA1 and HR, revealing molecular similarities between hereditary and sporadic breast cancers. However, these results reveal a paradox regarding the physiological role of AKT1: in non tumor cells, AKT1 promotes cellular proliferation, but consequently endangers genome integrity during replication if HR is inhibited. Since HR could itself lead to genetic instability, we propose that, under physiological conditions, moderate activation of AKT1 does not inhibit but prevents an excess of HR. The regulation of AKT1 would represent a fine transitory system for controlling HR and maintaining genomic integrity. PMID- 21321379 TI - Tie2/TEK modulates the interaction of glioma and brain tumor stem cells with endothelial cells and promotes an invasive phenotype. AB - Malignant gliomas are the prototype of highly infiltrative tumors and this characteristic is the main factor for the inevitable tumor recurrence and short survival after most aggressive therapies. The aberrant communication between glioma cells and tumor microenvironment represents one of the major factors regulating brain tumor dispersal. Our group has previously reported that the tyrosine kinase receptor Tie2/TEK is expressed in glioma cells and brain tumor stem cells and is associated with the malignant progression of these tumors. In this study, we sought to determine whether the angiopoietin 1 (Ang1)/Tie2 axis regulates crosstalk between glioma cells and endothelial cells. We found that Ang1 enhanced the adhesion of Tie2-expressing glioma and brain tumor stem cells to endothelial cells. Conversely, specific small interfering RNA (siRNA) knockdown of Tie2 expression inhibited the adhesion capability of glioma cells. Tie2 activation induced integrin beta1 and N-cadherin upregulation, and neutralizing antibodies against these molecules inhibited the adhesion of Tie2 positive glioma cells to endothelial cells. In 2D and 3D cultures, we observed that Ang1/Tie2 axis activation was related to increased glioma cell invasion, which was inhibited by using Tie2 siRNA. Importantly, intracranial co implantation of Tie2-positive glioma cells and endothelial cells in a mouse model resulted in diffusely invasive tumors with cell clusters surrounding glomeruloid vessels mimicking a tumoral niche distribution. Collectively, our results provide new information about the Tie2 signaling in glioma cells that regulates the cross talk between glioma cells and tumor microenvironment, envisioning Tie2 as a multi compartmental target for glioma therapy. PMID- 21321380 TI - miR-101 is down-regulated in glioblastoma resulting in EZH2-induced proliferation, migration, and angiogenesis. AB - BACKGROUND: Glioblastoma (GBM) is a malignant brain tumor with dismal prognosis. GBM patients have a median survival of less than 2 years. GBM is characterized by fast cell proliferation, infiltrative migration, and by the induction of angiogenesis. MicroRNAs and polycomb group (PcG) proteins have emerged as important regulators of gene expression. METHODS: Here we determined that miR-101 is down-regulated in GBM, resulting in overexpression of the miR-101 target PcG protein EZH2, a histone methyltransferase affecting gene expression profiles in an epigenetic manner. RESULTS: Inhibition of EZH2 in vitro by pre-miR-101, EZH2 siRNA, or small molecule DZNep, attenuated GBM cell growth, migration/invasion, and GBM-induced endothelial tubule formation. In addition, for each biological process we identified ontology-associated transcripts that significantly correlate with EZH2 expression. Inhibition of EZH2 in vivo by systemic DZNep administration in a U87-Fluc-mCherry GBM xenograft mouse imaging model resulted in reduced tumor growth. CONCLUSION: Our results indicate that EZH2 has a versatile function in GBM progression and that its overexpression is at least partly due to decreased miR-101 expression. Inhibition of EZH2 may be a potential therapeutic strategy to target GBM proliferation, migration, and angiogenesis. PMID- 21321381 TI - Targeting tumors with salmonella Typhimurium- potential for therapy. AB - When one considers the organism Salmonella enterica serotype Typhimurium (S. Typhimurium), one usually thinks of the Gram-negative enteric pathogen that causes the severe food borne illness, gastroentertitis. In this context, the idea of Salmonella being exploited as a cancer therapeutic seems pretty remote. However, there has been an escalating interest in the development of tumor therapeutic bacteria for use in the treatment of a variety of cancers. This strategy takes advantage of the remarkable ability of certain bacteria to preferentially replicate and accumulate within tumors. In the case of S. Typhimurium, this organism infects and selectively grows within implanted tumors, achieving tumor/normal tissue ratios of approximately 1,000:1. Salmonella also has some attractive properties well suited for the design of a chemotherapeutic agent. In particular, this pathogen can easily be manipulated to carry foreign genes, and since this species is a facultative anaerobe, it is able to survival in both oxygenated and hypoxic conditions, implying this organism could colonize both small metastatic lesions as well as larger tumors. These observations are the impetus to a burgeoning field focused on the development of Salmonella as a clinically useful anti-cancer agent. We will discuss three cutting edge technologies employing Salmonella to target tumors. PMID- 21321382 TI - A beta version of life: p110beta takes center stage. AB - The PI3K pathway is frequently activated in tumors, most commonly through p110alpha mutation or PTEN deletion. In contrast to p110alpha, p110beta is oncogenic when over-expressed in the wild-type state, suggesting that its regulation by p85 is different than that of p110alpha. In this perspective, we summarize recent data concerning the regulation of p110beta, which shows that wild-type p110beta acts like an oncogenic mutant of p110alpha. We also discuss the significance of this altered regulation in tumor models of PTEN deletion, as well as the potential implications of the unique p110beta regulation on GPCR driven tumorigenesis. PMID- 21321383 TI - Differential activation of Toll-like receptor-mediated apoptosis induced by hypoxia. AB - Ischemia-reperfusion injury induces intense inflammatory response and tissue damages resulting from the capacity of endogenous constituents called damageassociated molecular patterns (DAMPs) released by damaged or necrotic cells, to activate signaling pathways mediated by receptors of the innate immune systems. Among them, two members of the Toll-like receptors (TLR) family, TLR2 and TLR4 have been shown to play key roles in the induction of inflammatory response and cell apoptosis in a variety of ischemic tissues. The oxidative stress injury caused by I/R injury has been attributed to the activation of MAP kinase pathways, including those of ERK, JNK and p38. Here, we summarise recent findings concerning the role of the protein phosphatase 5 involved in the selective regulation of TLR2-mediated ERK1/2 signaling and the identification of the key role of the non-phagocytic NADPH oxidase 4 producing reactive oxygen species in the control of TLR4-mediated apoptosis in murine models of renal I/R injury and in post-hypoxic kidney tubule cells. The identification of molecules signaling involved in the ER stress-induced apoptotic signaling cascade may therefore represent potential targets to prevent the induction of apoptosis in hypoxic tissues. PMID- 21321385 TI - A method for suppressing cardiogenic oscillations in impedance pneumography. AB - The transthoracic electrical impedance signal originates from the cardiac and respiratory functions. In impedance pneumography (IP) the lung function is assessed and the cardiac impedance signal, cardiogenic oscillations (CGOs), is considered an additive noise in the measured signal. In order to accurately determine pulmonary flow parameters from the signal, the CGO needs to be attenuated without distorting the respiratory part of the signal. We assessed the suitability of a filtering technique, originally described by Schuessler et al (1998 Ann. Biomed. Eng. 26 260-7) for an esophageal pressure signal, for CGO attenuation in the IP signal. The technique is based on ensemble averaging the CGO events using the electrocardiogram (ECG) R-wave as the trigger signal. Lung volume is known to affect the CGO waveforms. Therefore we modified the filtering method to produce a lung volume-dependent parametric model of the CGO waveform. A simultaneous recording of ECG, IP and pneumotachograph (PNT) was conducted on 41 healthy, sitting adults. The performance of the proposed method was compared to a low-pass filter and a Savitzky-Golay filter in terms of CGO attenuation and respiratory signal distortion. The method was found to be excellent, exhibiting CGO attenuation of 35.0+/-12.5 dB (mean+/-SD) and minimal distortion of the respiratory part of the impedance signal. PMID- 21321384 TI - The BRAFV600E mutation: what is it really orchestrating in thyroid cancer? AB - BRAFV600E is a constitutively active onco-kinase and is the most common genetic alteration in papillary thyroid carcinoma (PTC), and in anaplastic thyroid carcinoma as well, albeit at a lower frequency. The BRAFV600E mutation in some studies has been significantly associated with extra-thyroidal extension, metastases, recurrence, and mortality in patients with PTC. A recent genome-wide expression profiling approach (Gene Set Enrichment Analysis (GSEA)) and in vitro and in vivo functional studies revealed that BRAFV600E affects extracellular matrix composition (i.e. increased expression of some collagens and laminins) and promotes thyroid cancer migration and invasion. BRAFV600E through the phospho MEK1/2 and phospho-ERK1/2 pathway may control a network of genes crucial in integrating and regulating the extracellular and intracellular signaling in thyroid cancer cells, which may be fundamental to trigger an abnormal cell differentiation/totipotency and shape/polarity, and contribute to tumor aggressiveness mechanisms (i.e. cell adhesion, migration, and invasion). Increasing our knowledge of BRAFV600E-modulated ECM genes and targeting the subset of genes essential for tumor aggressiveness will help establish a novel paradigm for treatment of thyroid cancers harboring BRAFV600E. Furthermore, identifying downstream events from the BRAFV600E/ERK1/2 pathway will eventually identify novel biomarkers that can be used to correlate with disease outcome and overall survival. PMID- 21321386 TI - Characterization of a rotating slat collimator system dedicated to small animal imaging. AB - Some current investigations based on small animal models are dedicated to functional cerebral imaging. They represent a fundamental tool to understand the mechanisms involved in neurodegenerative diseases. In the radiopharmaceutical development approach, the main challenge is to measure the radioactivity distribution in the brain of a subject with good temporal and spatial resolutions. Classical SPECT systems mainly use parallel hole or pinhole collimators. In this paper we investigate the use of a rotating slat collimator system for small animal brain imaging. The proposed prototype consists of a 64 channel multi-anode photomultiplier tube (H8804, Hamamatsu Corp.) coupled to a YAP:Ce crystal highly segmented into 32 strips of 0.575 * 18.4 * 10 mm(3). The parameters of the rotating slat collimator are optimized using GATE Monte Carlo simulations. The performance of the proposed prototype in terms of spatial resolution, detection efficiency and signal-to-noise ratio is compared to that obtained with a gamma camera equipped with a parallel hole collimator. Preliminary experimental results demonstrate that a spatial resolution of 1.54 mm can be achieved with a detection efficiency of 0.012% for a source located at 20 mm, corresponding to the position of the brain in the prototype field of view. PMID- 21321387 TI - High-energy radiation monitoring based on radio-fluorogenic co-polymerization II: fixed fluorescent images of collimated x-ray beams using an RFCP gel. AB - We have produced an optically clear, close to water-equivalent gel that is radio fluorogenic, i.e. fluoresces in UV light after exposure to high-energy radiation. Its potential as a 2D and 3D dosimetric medium is demonstrated by fixed fluorescent images of the cross-section, track and intersection of collimated (10 * 10 or 5 * 5 mm(2)) 205 kVp x-ray beams. The images, produced by doses on the order of 10 Gy, are formed instantaneously and can be digitally recorded and scanned with a spatial resolution on the order of 0.1 mm. No loss of spatial resolution occurs on standing under ambient conditions for at least 3 days. PMID- 21321389 TI - Cotinine reduces amyloid-beta aggregation and improves memory in Alzheimer's disease mice. AB - Alzheimer's disease (AD) affects millions of people world-wide and new effective and safe therapies are needed. Cotinine, the main metabolite of nicotine, has a long half-life and does not have cardiovascular or addictive side effects in humans. We studied the effect of cotinine on amyloid-beta (Abeta) aggregation as well as addressed its impact on working and reference memories. Cotinine reduced Abeta deposition, improved working and reference memories, and inhibited Abeta oligomerization in the brains of transgenic (Tg) 6799 AD mice. In vitro studies confirmed the inhibitory effect of cotinine on Abeta1-42 aggregation. Cotinine stimulated Akt signaling, including the inhibition of glycogen synthase kinase 3beta (GSK3beta), which promotes neuronal survival and the synaptic plasticity processes underlying learning and memory in the hippocampus and cortex of wild type and Tg6799 AD mice. Simulation of the cotinine-Abeta1-42 complex using molecular dynamics showed that cotinine may interact with key histidine residues of Abeta1-42, altering its structure and inhibiting its aggregation. The good safety profile in humans and its beneficial effects suggest that cotinine may be an excellent therapeutic candidate for the treatment of AD. PMID- 21321388 TI - Excitation-resolved fluorescence tomography with simplified spherical harmonics equations. AB - Fluorescence tomography (FT) reconstructs the three-dimensional (3D) fluorescent reporter probe distribution inside biological tissue. These probes target molecules of biological function, e.g. cell surface receptors or enzymes, and emit fluorescence light upon illumination with an external light source. The fluorescence light is detected on the tissue surface and a source reconstruction algorithm based on the simplified spherical harmonics (SP(N)) equations calculates the unknown 3D probe distribution inside tissue. While current FT approaches require multiple external sources at a defined wavelength range, the proposed FT method uses only a white light source with tunable wavelength selection for fluorescence stimulation and further exploits the spectral dependence of tissue absorption for the purpose of 3D tomographic reconstruction. We will show the feasibility of the proposed hyperspectral excitation-resolved fluorescence tomography method with experimental data. In addition, we will demonstrate the performance and limitations of such a method under ideal and controlled conditions by means of a digital mouse model and synthetic measurement data. Moreover, we will address issues regarding the required amount of wavelength intervals for fluorescent source reconstruction. We will explore the impact of assumed spatially uniform and nonuniform optical parameter maps on the accuracy of the fluorescence source reconstruction. Last, we propose a spectral re-scaling method for overcoming the observed limitations in reconstructing accurate source distributions in optically non-uniform tissue when assuming only uniform optical property maps for the source reconstruction process. PMID- 21321390 TI - Gene expression biomarkers in the brain of a mouse model for Alzheimer's disease: mining of microarray data by logic classification and feature selection. AB - The identification of early and stage-specific biomarkers for Alzheimer's disease (AD) is critical, as the development of disease-modification therapies may depend on the discovery and validation of such markers. The identification of early reliable biomarkers depends on the development of new diagnostic algorithms to computationally exploit the information in large biological datasets. To identify potential biomarkers from mRNA expression profile data, we used the Logic Mining method for the unbiased analysis of a large microarray expression dataset from the anti-NGF AD11 transgenic mouse model. The gene expression profile of AD11 brain regions was investigated at different neurodegeneration stages by whole genome microarrays. A new implementation of the Logic Mining method was applied both to early (1-3 months) and late stage (6-15 months) expression data, coupled to standard statistical methods. A small number of "fingerprinting" formulas was isolated, encompassing mRNAs whose expression levels were able to discriminate between diseased and control mice. We selected three differential "signature" genes specific for the early stage (Nudt19, Arl16, Aph1b), five common to both groups (Slc15a2, Agpat5, Sox2ot, 2210015, D19Rik, Wdfy1), and seven specific for late stage (D14Ertd449, Tia1, Txnl4, 1810014B01Rik, Snhg3, Actl6a, Rnf25). We suggest these genes as potential biomarkers for the early and late stage of AD like neurodegeneration in this model and conclude that Logic Mining is a powerful and reliable approach for large scale expression data analysis. Its application to large expression datasets from brain or peripheral human samples may facilitate the discovery of early and stage-specific AD biomarkers. PMID- 21321391 TI - Matrix metalloproteinase-9 participates in NGF-induced alpha-secretase cleavage of amyloid-beta protein precursor in PC12 cells. AB - Amyloid-beta protein precursor (AbetaPP) is a ubiquitously expressed glycoprotein, which under physiological conditions can be cleaved following two alternative routes; the non-amyloidogenic and the amyloidogenic pathway. Shift of AbetaPP processing in favor of the amyloidogenic pathway is a key event in the pathogenesis of Alzheimer's disease (AD). Among the factors that regulate AbetaPP processing, nerve growth factor (NGF) appears to play an important role; abnormal NGF signaling has been implicated in the onset of AD. In the present study, we used PC12 cells to study the effects of NGF on AbetaPP processing and provide evidence that NGF, through binding to its high affinity receptor, TrkA moderately down-regulates the expression of the beta-secretase beta-site AbetaPP cleaving enzyme-1 and, most importantly, upregulates the expression of two enzymes with alpha-secretase activity, a disintegrin and metalloprotease-17 and to a greater extent matrix metalloproteinase-9 (MMP9) in a phosphoinositide kinase-3 dependent manner. Finally, we demonstrate that MMP9 actively participates in NGF-induced alpha-secretase cleavage of AbetaPP, thus it contributes to the shift of AbetaPP processing towards the non-amyloidogenic pathway precluding the formation of neurotoxic Abeta peptides. PMID- 21321392 TI - Three postulates to help identify the cause of Alzheimer's disease. AB - Two centuries ago, the German bacteriologist Robert Koch proposed three postulates to support a causal relationship between a specific microbe and an infectious disease. Similarly, three postulates are formulated here to help evaluate hypothetical proposals attempting to explain the pathogenesis of Alzheimer's disease (AD). The first postulate requires that the cause of AD precedes the cognitive decline and neurodegenerative pathology that characterize AD. This rule identifies a primary event from a neuropathological effect generated by the disease process. The second postulate stipulates that interventions aimed at the proposed causal event should prevent or reverse the cognitive and neurodegenerative pathology associated with AD prior to disease onset. This postulate emphasizes prevention or reversal of emerging neurocognitive pathology considerably before AD onset. If the first and second postulate requirements are met, the third postulate follows that interventions targeting the causal event should significantly lower the incidence of AD. For a causal hypothesis to be considered "likely" pathogenic to AD, support from all three postulates is a requisite. The pragmatic potential of the three postulates was applied to seven proposals using evidence-based meta-analysis mainly from randomized controlled trials. Proposals included the amyloid-beta, cell cycle, cholinergic, inflammatory, oxidative stress, tau, and vascular hypotheses. Clinical evidence derived from each proposal formed the basis for an inferential conclusion based on the level of confidence provided by the trial data. The three postulates may challenge or help validate a proposed cause-effect relationship to AD and serve as a useful model for designing more intelligent therapeutic interventions aimed at preventing AD. PMID- 21321393 TI - Antibodies against extracellular domains of alpha4 and alpha7 subunits alter the levels of nicotinic receptors in the mouse brain and affect memory: possible relevance to Alzheimer's pathology. AB - Nicotinic acetylcholine receptors (nAChRs) of alpha4beta2 and alpha7 subtypes expressed in the brain neurons are involved in regulating memory and cognition. Their level is decreased upon several neurodegenerative disorders including Alzheimer's disease (AD), although the reasons for such a decrease are not completely understood. To test whether the nAChR-specific antibodies can affect the brain nAChRs and influence the behavior, we either immunized mice with recombinant extracellular domains of alpha4 and alpha7, subunits alpha4(1-209) and alpha7(1-208), or injected them with alpha7(1-208)-specific antibodies. A decrease of alpha4beta2- and alpha7-nAChRs accompanied with an increase of alpha4beta4-nAChRs in brain membranes of immunized mice was observed. Both alpha4(1-209)- and alpha7(1-208)-specific antibodies were detected in the brain membrane lysates of immunized mice. Antibody injection resulted in brain nAChR decrease only if mice were co-injected intraperitoneally with bacterial lipopolysaccharide. Brain sections of immunized mice were analyzed for the binding of [125I]-alpha-bungarotoxin and [125I]-epibatidine. A decrease in alpha bungarotoxin binding in striatum (nucleus accumbens and caudate putamen) accompanied with an increase of epibatidine binding in the forebrain and caudate putamen was observed in mice immunized with either alpha4 or alpha7 nAChR domains compared to those immunized with BSA. Mice immunized with alpha7(1-208) demonstrated significantly worse episodic memory measured in a novel object recognition task compared to non-immunized animals but did not differ from the controls in locomotor or anxiety-related tests. These results suggest that nAChR specific antibodies are able to penetrate the brain upon inflammation with resulting decreases of brain nAChRs and worsening episodic memory. PMID- 21321394 TI - Long-term treatment with lithium alleviates memory deficits and reduces amyloid beta production in an aged Alzheimer's disease transgenic mouse model. AB - The glycogen synthase kinase-3beta (GSK3beta) pathway plays a central role in Alzheimer's disease (AD) and its deregulation accounts for many of the pathological hallmarks of AD. Lithium, which modulates GSK3beta activity, has been shown to reduce amyloid production and tau phosphorylation in pre pathological AD mouse models. In this study, we investigated the effects of chronic LiCl treatment in aged double transgenic mice (AbetaPPSwe/PS1A246E). We found that chronic lithium treatment decreased the gamma-cleavage of amyloid-beta protein precursor, further reduced amyloid-beta production and senile plaque formation, accompanied by the improvement in spatial learning and memory abilities. Because autophagy may play an important role in the pathology of AD, we also assessed the autophagy activity and found that the chronic lithium treatment attenuated the autophagy activation in this AD mouse model. Our results suggest that prolonged lithium treatment, even during the later stages of AD, could be an effective therapeutics. PMID- 21321396 TI - Replication of BIN1 association with Alzheimer's disease and evaluation of genetic interactions. AB - The most recent late-onset Alzheimer's disease (LOAD) genome-wide association study revealed genome-wide significant association of two new loci: rs744373 near BIN1 (p = 1.6 * 10-11) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (p = 6.5 * 10-9). We have genotyped these variants in a large (3,287 LOAD, 4,396 controls), independent dataset comprising eleven case-control series from the USA and Europe. We performed meta-analyses of the association of these variants with LOAD and also tested for association using logistic regression adjusted by age-at diagnosis, gender, and APOE epsilon4 status. Meta-analysis results showed no evidence of series heterogeneity and logistic regression analysis successfully replicated the association of BIN1 (rs744373) with LOAD with an odds ratio (OR = 1.17, p = 1.1 * 10-4) comparable to that previously reported (OR = 1.15). The variant near EXOC3L2 (rs597668) showed only suggestive association with LOAD (p = 0.09) after correcting for the presence of the APOE epsilon4 allele. Addition of our follow-up data to the results previously reported increased the strength of evidence for association with BIN1 (11,825 LOAD, 32,570 controls, rs744373 Fisher combined p = 3.8 * 10-20). We also tested for epistatic interaction between these variants and APOE epsilon4 as well as with the previously replicated LOAD GWAS genes (CLU: rs11136000, CR1: rs3818361, and PICALM: rs3851179). No significant interactions between these genes were detected. In summary, we provide additional evidence for the variant near BIN1 (rs744373) as a LOAD risk modifier, but our results indicate that the effect of EXOC3L2 independent of APOE epsilon4 should be studied further. PMID- 21321395 TI - Analysis of postmortem ventricular cerebrospinal fluid from patients with and without dementia indicates association of vitamin E with neuritic plaques and specific measures of cognitive performance. AB - Ventricular cerebrospinal fluid (vCSF) obtained at autopsy from 230 participants in the Religious Orders Study was analyzed for alpha tocopherol (alphaT, vitamin E) and gamma tocopherol (gammaT) in relation to brain tissue neuropathological diagnoses (NIA-Reagan criteria); neuritic plaque density and neurofibrillary tangle state (Braak stage); and cognitive function proximate to death. Neither vCSF alphaT nor gammaT was related to the pathological diagnosis of Alzheimer's disease, but vCSF alphaT concentration was inversely related to neuritic plaque density (beta = -0.21, SE = 0.105, p = 0.04) in regression models adjusted for age, gender, education, and APOE-4. Ventricular CSF alphaT concentration was positively associated with perceptual speed (beta = 0.27, SE = 0.116, p = 0.02) whereas the gammaT/alphaT ratio was negatively associated with episodic memory (beta = -0.037, SE = 0.017, p = 0.04). Only vCSF alphaT, but not gammaT, was correlated with postmortem interval (PMI). Adjustment for PMI had no effect on significance of associations between alphaT and perceptual speed or gammaT/alphaT and episodic memory, but after this adjustment the alphaT concentration was no longer significantly associated with neuritic plaques. These data suggest that vCSF alphaT, but not gammaT, is weakly associated with less Alzheimer's disease neuropathology, specifically neuritic plaques, and correlates with better performance on tests of perceptual speed. PMID- 21321397 TI - The gamma-secretase modulator CHF5074 restores memory and hippocampal synaptic plasticity in plaque-free Tg2576 mice. AB - Abnormal amyloid-beta (Abeta) production and deposition is believed to represent one of the main causes of Alzheimer's disease (AD). gamma-Secretase is the enzymatic complex responsible for Abeta generation from its precursor protein. Inhibition or modulation of gamma-secretase represents an attractive therapeutic approach. CHF5074 is a new gamma-secretase modulator that has been shown to inhibit brain plaque deposition and to attenuate memory deficit in adult AD transgenic mice after chronic treatment. To date, it is not known whether the positive behavioral effects of this compound also occur in young transgenic mice without plaque deposition. Here, we evaluated the effects of acute and subchronic treatment with CHF5074 on contextual and recognition memory and on hippocampal synaptic plasticity in plaque-free Tg2576 mice. We found that at 5 months of age, contextual memory impairment was significantly attenuated after acute subcutaneous administration of 30 mg/kg CHF5074. At 6 months of age, recognition memory impairment was fully reversed after a 4-week oral treatment in the diet (~60 mg/kg/day). These cognitive effects were associated with a reversal of long term potentiation (LTP) impairment in the hippocampus. A significant reduction in brain intraneuronal AbetaPP/Abeta levels and hyperphosphorylated tau, but no change in soluble or oligomeric Abeta levels was detected in Tg2576 mice showing functional recovery following CHF5074 treatment. We conclude that the beneficial effects of CHF5074 treatment in young transgenic mice occurred at a stage that precedes plaque formation and were associated with a reduction in intraneuronal AbetaPP/Abeta and hyperphosphorylated tau. PMID- 21321398 TI - Independent component analysis-based classification of Alzheimer's disease MRI data. AB - There is an unmet medical need to identify neuroimaging biomarkers that allow us to accurately diagnose and monitor Alzheimer's disease (AD) at its very early stages and to assess the response to AD-modifying therapies. To a certain extent, volumetric and functional magnetic resonance imaging (fMRI) studies can detect changes in structure, cerebral blood flow, and blood oxygenation that distinguish AD and mild cognitive impairment (MCI) subjects from healthy control (HC) subjects. However, it has been challenging to use fully automated MRI analytic methods to identify potential AD neuroimaging biomarkers. We have thus proposed a method based on independent component analysis (ICA) for studying potential AD related MR image features that can be coupled with the use of support vector machine (SVM) for classifying scans into categories of AD, MCI, and HC subjects. The MRI data were selected from the Open Access Series of Imaging Studies (OASIS) and the Alzheimer's Disease Neuroimaging Initiative databases. The experimental results showed that the ICA method coupled with SVM classifier can differentiate AD and MCI patients from HC subjects, although further methodological improvement in the analytic method and inclusion of additional variables may be required for optimal classification. PMID- 21321399 TI - Dysfunction of the fusion of pre-synaptic plasma membranes and synaptic vesicles caused by oxidative stress, and its prevention by vitamin E. AB - To define whether hyperoxia induces the dysfunction of membrane fusion between synaptic vesicles with pre-synaptic plasma membranes in the nerve terminals, and whether vitamin E prevents this abnormal event, we investigated the influence of hyperoxia on the fusion ability of isolated synaptic vesicles and the inside-out type pre-synaptic plasma membrane vesicles from rat brain using the fluorescence tracing method. The membrane fusion ability of both membranes from rats subjected to hyperoxia was markedly decreased compared with the membranes from a normal rat. Rats subjected to hyperoxia in the form of oxidative stress showed significant increases in the levels of thiobarbituric acid reactive substances (TBARS), conjugated dienes, and protein carbonyl moieties in both synaptic vesicles and pre-synaptic plasma membranes. When rats were supplemented with vitamin E, these abnormalities were inhibited even when rats were subjected to hyperoxia. PMID- 21321400 TI - Lysosomal beta-galactosidase and beta-hexosaminidase activities correlate with clinical stages of dementia associated with Alzheimer's disease and type 2 diabetes mellitus. AB - Multiple epidemiological studies have shown that individuals affected by type-2 diabetes mellitus (T2DM) carry a 2-to-5-fold higher risk of developing Alzheimer's disease (AD) when compared to non-diabetic subjects. Thus, biochemical parameters that can be easily and routinely assessed for high confidence evaluation of diabetic conditions leading to AD (AD-T2DM) are regarded as efficient tools aimed at early diagnosis and, in turn, timely AD treatment. In this regard, the activity of lysosomal glycohydrolases may of use, in light of the implication of these enzymes in early events that underlie AD pathology and an overt correlation, in diabetes, between altered metabolic homeostasis, abnormal glycohydrolase secretion in body fluids, and occurrence of diabetic complications. Based on marked up-regulation previously shown in a peripheral, cell-based model of AD, we selected beta-Galactosidase, beta-Hexosaminidase, and alpha-Mannosidase to discriminate T2DM from AD-T2DM subjects. A screen of 109, 114, and 116 patients with T2DM, AD and AD-T2DM, respectively, was performed by testing enzyme activities in both blood plasma and peripheral blood mononuclear cells. Compared to age-matched, healthy controls (n = 122), beta-Galactosidase and beta-Hexosaminidase activities markedly diverged across the three groups, whereas virtually unchanged values were observed for alpha-Mannosidase. In particular, plasma beta-Galactosidase and beta-Hexosaminidase levels were higher in patients with AD-T2DM compared to those with T2DM, suggesting different mechanisms leading to enzyme secretion. Statistical analyses based on ROC curves showed that both beta-Galactosidase and beta-Hexosaminidase activities, either intracellular or plasma-secreted, may be used to discriminate AD patients from controls and AD-T2DM from T2DM patients. PMID- 21321401 TI - JNK3 as a therapeutic target for neurodegenerative diseases. AB - c-Jun N-terminal kinases (JNKs) and in particular JNK3 the neuronal specific isoform, have been recognized as important enzymes in the pathology of diverse neurological disorders. Indeed, several efforts have been made to design drugs that inhibit JNK signaling. The success that characterized the new generation of cell permeable peptides raise the hope in the field of neurodegeneration for new therapeutic routes. However, in order to design new and more efficient therapeutical approaches careful re-examination of current knowledge is required. Scaffold proteins are key endogenous regulators of JNK signaling: they can modulate spatial and temporal activation of the JNK signaling and can thus provide the basis for the design of more specific inhibitors. This review focuses on delineating the role of scaffold proteins on the regulation of JNK signaling in neurons. Furthermore the possibility to design a new JNK3 cell permeable peptide inhibitor by targeting the beta-arrestin-JNK3 interaction is discussed. PMID- 21321403 TI - Microcirculatory effects of fluid therapy and dopamine, associated or not to fluid therapy, in endotoxemic hamsters. AB - Classically septic shock treatment takes into consideration only systemic parameters but failure in retaining arteriolar blood flow and functional capillary density (FCD) during sepsis worsens the outcome. Thus, we have investigated the effects of vigorous volume resuscitation (VR), two doses of dopamine and their combination upon the microcirculation during endotoxemia to evaluate if improvement on FCD and arteriolar blood flow would increase survival time. Sixty-seven adult male hamsters were studied using the window chamber model. Animals were randomized 1 h after the intravenous injection of 1 mg/kg of E. coli lipopolysaccharide (LPS) in LPS, no treatment; LPS/dopamine 3.0 MUg/kg/min; LPS/dopamine 7.5 MUg/kg/min; LPS/VR 20 ml/kg in 30 min followed by 20 ml/kg/h of saline; LPS/VR/Dopa 3.0, 20 ml/kg in 30 min followed by 20 ml/kg/h of saline associated to dopamine 3.0 MUg/kg/min; LPS/VR/Dopa 7.5 (n = 6), 20 ml/kg in 30 min followed by 20 ml/kg/h of saline associated to dopamine 7.5 MUg/kg/min and compared them to a Control group, no LPS. When present, treatment lasted 5 h. VR improved FCD and arteriolar blood flow score while dopamine did not. In conclusion, (1) improvement of FCD and arteriolar blood flow improved survival time; (2) VR recovered FCD and arteriolar blood flow and (3) in combination to VR, both dopamine doses reduced tissue perfusion (its low dose yielded the worst result). PMID- 21321404 TI - Effect of strenuous physical exercise on circulating cell-derived microparticles. AB - Strenuous exercise is associated with an inflammatory response involving the activation of several types of blood cells. In order to document the specific activation of these cell types, we studied the effect of three maximal exercise tests conducted to exhaustion on the quantitative and qualitative pattern of circulating cell-derived microparticles and inflammatory molecules in healthy subjects. This study mainly indicated that the plasma concentration of microparticles from platelets and polymorphonuclear neutrophils (PMN) was increased immediately after the strenuous exercise. In addition, the increase in plasma concentration of microparticles from PMN and platelets was still observed after 2 hours of recovery. A similar pattern was observed for the IL-6 plasma level. In contrast, no change was observed for either soluble selectins or plasma concentration of microparticles from red blood cells, monocytes and endothelial cells. In agreement, sVCAM-1 and sICAM-1 levels were not changed by the exercise. We conclude that a strenuous exercise is accompanied by platelet- and PMN-derived microparticle production that probably reflects the activation of these two cell types. PMID- 21321405 TI - Blood viscosity changes in slow coronary flow patients. AB - Microvascular dysfunction is implicated in the pathogenesis of slow coronary flow (SCF), but less attention has been paid to intrinsic properties of blood that can also impair the microcirculatory flow. In this study we aimed to evaluate the blood viscosity focusing on erythrocyte aggregation, erythrocyte deformability and plasma viscosity in SCF. Thirty-three patients with SCF (21 male, 54 +/- 12.8 years) and 23 subjects with normal coronary arteries (13 male, 59 +/- 10.3 years) were included in the study. Coronary flow was quantified by means of thrombolysis in myocardial infarction (TIMI) frame count and aggregation and deformability of erythrocytes were measured by an ektacytometer. Plasma viscosity was measured by a cone-plate viscometer. Aggregation amplitude (23 +/- 3.8 au vs. 15.7 +/- 6.1 au, respectively, p < 0.001) and area A index (area above syllectogram) (153.2 +/ 30.7 au.s vs. 124.9 +/- 49.3 au.s, respectively, p < 0.01) were higher in SCF patients. Aggregation half-time, aggregation index, elongation index and plasma viscosity values were similar between two groups. Correlation analysis revealed a significant relationship between the TIMI frame count for left anterior descending artery and aggregation amplitude in SCF patients (r = 0.679, p < 0.0001). The result of this study reveals changes in erythrocyte aggregation which may contribute to the pathophysiology of SCF. Larger studies are needed to make more robust conclusions on this issue. PMID- 21321406 TI - Preserved cerebral microcirculation in early stages of endotoxemia in mechanically-ventilated rabbits. AB - The purpose of our study was to evaluate changes of the cerebral microcirculation during the early stages of endotoxemia in mechanically-ventilated rabbits using Sidestream dark-field (SDF) imaging. Images were obtained using SDF imaging from the surface of the brain via craniotomy before and after rapid administration of a high dose of endotoxin or saline (control group). Although endotoxin shock was successfully induced, we have not found any significant alteration of the cerebral microcirculation during the shock. We speculate that either the model of sepsis with a rapid high dose of endotoxin does not reflect the usual progression of septic encephalopathy or some components other than cerebral microcirculatory alteration play a role at the early stage of septic encephalopathy and the cerebral microcirculation is still preserved. Further studies are needed to clarify our findings. PMID- 21321407 TI - Effects of oral acrylamide intake on blood viscosity parameters in rats. AB - Acrylamide which is formed via reaction of reducing sugars with amino acids during food processing at high temperatures is not only neurotoxic and carcinogenic, but it also damages erythrocyte membrane and generates micronucleated erythrocytes. In the present study, effects of chronic administration of acrylamide at a dose which does not induce neurotoxicity were evaluated on blood viscosity parameters (hematocrit, erythrocyte deformability, erythrocyte aggregation and plasma viscosity). Twenty adult male Sprague-Dawley rats were divided into control and acrylamide groups. The acrylamide group received 10 mg/kg/day acrylamide, whereas the control group received saline (vehicle), both in 10 ml/kg/day volume via gastric gavage. Erythrocyte aggregation and deformability were measured with LORCA and plasma viscosity with cone-plate viscometer. Erythrocyte deformability was measured before, and at the end of the 3rd and the 5th weeks of acrylamide administration. Hematocrit, erythrocyte aggregation and plasma viscosity were measured only at the end of the 5th week. Acrylamide caused a significant decrease in the deformability index of erythrocytes (at the end of the 3rd week, control: 0.606 +/- 0.003, acrylamide: 0.595 +/- 0.003, p < 0.05) (at the end of the 5th week, control: 0.606 +/- 0.002, acrylamide: 0.588 +/- 0.002, p < 0.01). Aggregation tendency and plasma viscosity were slightly higher in the acrylamide group, however the difference was not statistically significant. These results imply that acrylamide which does not cause neurotoxicity in rats may alter blood viscosity if chronically taken. PMID- 21321408 TI - Hyperhomocysteinemia, obesity and cryptogenic stroke. AB - BACKGROUND: The pathogenic role of hyperhomocysteinemia in cryptogenic stroke is not well established. We aimed to determine homocysteine levels in patients with cryptogenic stroke considering the possible variables that may act as confounders and analyze the influence of obesity on this association. PATIENTS AND METHODS: We conducted a case-control study in 123 patients with cryptogenic stroke aged 42 +/- 12 years and in 153 control subjects aged 42 +/- 13 years. Serum homocysteine was determined by fluorescence polarization immunoassay. RESULTS: Patients showed statistically higher levels of homocysteine, creatinine and higher BMI than controls (p = 0.045, p = 0.014, p = 0.013), respectively. After multivariate adjustment the differences in homocysteine levels disappeared (p = 0.774). When subjects were classified according to the presence or absence of obesity, the differences in the prevalence of hyperhomocysteinemia (homocysteine >15 MUM) were highly significant, being higher in patients than in controls (p = 0.009). Likewise, mean values of homocysteine in obese were higher in cases than in controls (16.9 +/- 9.5 MUM vs. 10.12 +/- 2.5 MUM; p = 0.020), remaining significant after adjusting for the above mentioned confounders. CONCLUSION: Although in general, hyperhomocysteinemia does not seem to constitute an independent risk factor for cryptogenic stroke, it significantly increases the risk in obese subjects; therefore it is convenient to decrease its levels in this sub-group to minimize the risk. PMID- 21321409 TI - Homocysteine levels and the metabolic syndrome in a Mediterranean population: a case-control study. AB - Hyperhomocysteinemia (HH) and metabolic syndrome (MS) are associated with increased cardiovascular risk. However, whether there is a link between MS or its components and homocysteine levels in a population without cardiovascular disease is not well established. We conducted a case-control study in 61 MS patients (41 males, 20 females, aged 51 +/- 11 years) and in 98 controls without MS (59 males, 39 females, aged 50 +/- 10 years) to ascertain the association between MS and HH, and with inflammatory markers. MS was classified according to the updated ATPIII criteria [17]. No differences in homocysteine levels were observed when comparing MS patients and controls (12.0 +/- 3.18 MUM vs. 11.9 +/- 3.5 MUM, p = 0.829). No association was found between HH (homocysteine >15 MUM) and MS, its components (abdominal obesity (p = 0.635), hypertension (0.229), low-HDL cholesterol (p = 0.491), glucose >100 mg/dL (0.485), hypertriglyceridemia (p = 0.490)) or the number of MS components (p = 272). When considering glucose >110 mg/dL (NCEP ATPIII criteria, 2001) instead of glucose intolerancen >100 mg/dl (updated ATPIII criteria, Grundy, 2005), a borderline association with HH was observed (p = 0.054) of statistical significance (p = 0.008) when glucose >126 mg/dL was considered. In a multivariate regression model, creatinine, folic acid and vitamin B12 were the only independent predictors of homocysteine levels (p < 0.05). Although MS correlated with inflammatory parameters (fibrinogen, hs-RCP, plasma viscosity and leukocyte count, p < 0.001), no association was found between HH and the above-mentioned parameters (p > 0.05). Our results do not indicate a link between SM or its individual components with HH, and diabetes was the only relevant contribution. Cardiovascular disease risk due to MS and HH seems to share no common mechanisms. PMID- 21321410 TI - The effect of aging on blood and plasma viscosity. An 11.6 years follow-up study. AB - OBJECTIVE: Alterations of blood and plasma viscosity can promote atherosclerosis. The relationship between viscosity and aging is still controversial. The present study evaluated the influence of aging on blood and plasma viscosity in a group of subjects followed for 11.6 years. METHODS: Forty-five subjects have been evaluated twice 11.6 years apart for hemorheological parameters and coronary heart disease (CHD) risk factors. Plasma viscosity and blood viscosity have been measured with a cone-plate viscometer. Tk has been calculated as index of red blood cell rigidity. CHD risk factors, i.e. obesity, hypertension, hyperlipidemia and diabetes, have been evaluated by routine methods. RESULTS: Hematocrit and plasma viscosity did not change during the study, whereas blood viscosity (shear rate 225/sec: 4.46 +/- 0.49 vs. 4.81 +/- 0.54 cP, p < 0.0001; shear rate 45/sec: 6.19 +/- 0.67 vs. 6.65 +/- 0.79 cP, p < 0.0001) and Tk (0.80 +/- 0.05 vs. 0.83 +/ 0.06, p < 0.005) significantly increased. The percent variation in blood viscosity was not associated with the percent variation in any of the CHD risk factors. Furthermore, the increase in blood viscosity was similar in males and females and in subjects with CHD risk profile worsening or not. CONCLUSION: The present findings demonstrate that blood viscosity increases with age. This increase seems independent of classical CHD risk factors and is disjoined from haematocrit and plasma viscosity, suggesting a possible direct effect of aging on red blood cells. PMID- 21321411 TI - Association between high red blood cell distribution width and metabolic syndrome. Influence of abdominal obesity. PMID- 21321412 TI - Dual dual-use research of concern: publish and perish? PMID- 21321413 TI - Celiac disease: can we avert the impending epidemic in India? PMID- 21321414 TI - Health insurance & responsiveness to communities & patients: the future of health systems in India. PMID- 21321415 TI - Management of chronic hepatitis B patients: efficacy & limitation of nucleos(t)ide analogues. PMID- 21321416 TI - Potential of immunosuppressive agents in cerebral ischaemia. AB - Ischaemic stroke is a disorder involving multiple mechanisms of injury progression including activation of glutamate receptors, release of proinflammatory cytokines, nitric oxide (NO), free oxygen radicals and proteases. Presently, recombinant tissue plasminogen activator (rtPA) is the only drug approved for the management of acute ischaemic stroke. This drug, however, is associated with limitations like narrow therapeutic window and increased risk of intracranial haemorrhage. A large number of therapeutic agents have been tested including N-methyl-D-aspartate (NMDA) receptor antagonist, calcium channel blockers and antioxidants for management of stroke, but none has provided significant neuroprotection in clinical trials. Therefore, searching for other potentially effective drugs for ischaemic stroke management becomes important. Immunosuppressive agents with their wide array of mechanisms have potential as neuroprotectants. Corticosteroids, immunophilin ligands, mycophenolate mofetil and minocycline have shown protective effect on neurons by their direct actions or attenuating toxic effects of mediators of inflammation. This review focuses on the current status of corticosteroids, cyclosporine A, FK506, rapamycin, mycophenolate mofetil and minocycline in the experimental models of cerebral ischaemia. PMID- 21321417 TI - Visceral leishmaniasis: experimental models for drug discovery. AB - Visceral leishmaniasis (VL) or kala-azar is a chronic protozoan infection in humans associated with significant global morbidity and mortality. The causative agent is a haemoflagellate protozoan Leishmania donovani, an obligate intracellular parasite that resides and multiplies within macrophages of the reticulo-endothelial system. Most of the existing anti-leishmanial drugs have serious side effects that limit their clinical application. As an alternate strategy, vaccination is also under experimental and clinical trials. The in vitro evaluation designed to facilitate rapid testing of a large number of drugs has been focussed on the promastigotes milt little attention on the clinically relevant parasite stage, amastigotes. Screening designed to closely reflect the situation in vivo is currently time consuming, laborious, and expensive, since it requires intracellular amastigotes and animal model. The ability to select transgenic Leishmania expressing reporter proteins, such as the green fluorescent proteins (GFP) or the luciferase opened up new possibilities for the development of drug screening models. Many experimental animal models like rodents, dogs and monkeys have been developed, each with specific features, but none accurately reproduces what happens in humans. Available in vitro and in vivo methodologies for antileishmanial drug screening and their respective advantages and disadvantages are reviewed. PMID- 21321418 TI - Community health insurance schemes & patient satisfaction--evidence from India. AB - BACKGROUND & OBJECTIVES: Quality of care is an important determinant for utilizing health services. In India, the quality of care in most health services is poor. The government recognizes this and has been working on both supply and demand aspects. In particular, it is promoting community health insurance (CHI) schemes, so that patients can access quality services. This observational study was undertaken to measure the level of satisfaction among insured and uninsured patients in two CHI schemes in India. METHODS: Patient satisfaction was measured, which is an outcome of good quality care. Two CHI schemes, Action for Community Organisation, Rehabilitation and Development (ACCORD) and Kadamalai Kalanjiam Vattara Sangam (KKVS), were chosen. Randomly selected, insured and uninsured households were interviewed. The household where a patient was admitted to a hospital was interviewed in depth about the health seeking behaviour, the cost of treatment and the satisfaction levels. RESULTS: It was found that at both ACCORD and KKVS, there was no significant difference in the levels of satisfaction between the insured and uninsured patients. The main reasons for satisfaction were the availability of doctors and medicines and the recovery by the patient. INTERPRETATION & CONCLUSIONS: Our study showed that insured hospitalized patients did not have significantly higher levels of satisfaction compared to uninsured hospitalized patients. If CHI schemes want to improve the quality of care for their clients, so that they adhere to the scheme, the scheme managers need to negotiate actively for better quality of care with empanelled providers. PMID- 21321420 TI - Socio-economic inequalities in the financing of cardiovascular & diabetes inpatient treatment in India. AB - BACKGROUND & OBJECTIVES: Cardiovascular disease (CVD) and diabetes have become a leading threat to public health in India. This study examines socio-economic differences in self-reported morbidity due to CVD and diabetes, where people having these conditions seek care, how much households pay for and how they finance hospital treatment for these conditions. METHODS: Data for this study are taken from the National Sample Survey Organization (NSSO) 60 th round on 'Morbidity and Health Care' conducted between January and June 2004. Information from 2,129 and 438 individuals hospitalized for CVD and diabetes was analyzed. RESULTS: The self-reported prevalence among adults was 12 per cent for CVD, 4 per cent (7% urban and 3% rural) for heart disease and 6 per cent (10% in urban and 4% in rural) for diabetes. Both self-reported CVD and diabetes appeared to afflict the wealthier more. The private sector was the main provider of outpatient and inpatient care for CVD and diabetes treatment, though the poor depended more on the public sector. Out-of-pocket payments (OOPS) for hospital treatment claimed a large share of annual household expenditures; 30 per cent for CVD and 17 per cent for diabetes. The OOPS share for diabetes treatment declined with increasing income. The majority of OOPS for hospital treatment paid by the poor was financed through borrowings. INTERPRETATION & CONCLUSIONS: The considerable financial strain which households, particularly the poor, face in treating CVD and diabetes is alarming. As the burden due to CVD and diabetes increases in India, more households will be subject to these financial strains and unfortunately, the economically vulnerable among them will be the worst affected. While primary prevention of these conditions need more emphasis, in addition, insurance schemes targeted at the poor like the RSBY have an important role to play in financially protecting vulnerable households. PMID- 21321419 TI - Evaluation of adefovir & lamivudine in chronic hepatitis B: correlation with HBV viral kinetic, hepatic-necro inflammation & fibrosis. AB - BACKGROUND & OBJECTIVES: Chronic hepatitis B is an important cause of morbidity and mortality. We conducted a study comparing the efficacy of adefovir and lamivudine with respect to their impact on serum and hepatic viral DNA clearance, and improvement in hepatic necro-inflammatory score, in naive patients of chronic hepatitis B. METHODS: This prospective randomized pilot study was conducted in Lok Nayak Hospital, New Delhi, involving 30 patients of chronic hepatitis B (both e antigen positive and negative); 15 were randomly selected to receive either adefovir or lamivudine for a period of 6 months. Quantification of serum and hepatic HBV DNA levels was done by real time PCR and liver biopsy was done at the beginning and end of 6 months. RESULTS: Serum ALT was elevated to 2 or more times normalized in both the groups. In the adefovir group, two patients became HBeAg negative. In the lamivudine group, one patient became HBeAg negative. After therapy HBV DNA was negative in 26.7 per cent patients from adefovir group and 13.3 per cent patients from lamivudine group. Serum HBV DNA levels were correlated with the hepatic levels before therapy (r=0.843; P<0.001) and after therapy (r=0.713, P<0.001) showing strong correlation. There was a median reduction of 1.92 and 2.06 log copies per ml in serum HBV DNA load after adefovir and lamivudine therapy, respectively. The mean reduction in the histology activity index (HAI) score was 2 and 1.53, fibrosis score was 2.33 and 3.06 after adefovir and lamivudine therapy respectively. INTERPRETATION & CONCLUSIONS: Adefovir and lamivudine treatment caused biochemical and serological improvement when administered for about 6 months with significant reduction in HBV DNA, serum and hepatic viral load without completely clearing the virus from either serum or liver. It also helped in reduction of the necro-inflammatory and fibrosis score of patients with chronic hepatitis B. Our study also showed significant correlation between serum and hepatic HBV DNA levels both before and after therapy. There was not enough evidence to show therapeutic advantage of one drug over the other in any of the parameters measured. PMID- 21321421 TI - Field test results of the motherhood method to measure maternal mortality. AB - BACKGROUND & OBJECTIVES: Measuring maternal mortality in developing countries poses a major challenge. In Nepal, vital registration is extremely deficient. Currently available methods to measure maternal mortality, such as the sisterhood method, pose problems with respect to validity, precision, cost and time. We conducted this field study to test a community-based method (the motherhood method), to measure maternal and child mortality in a developing country setting. METHODS: Motherhood method was field tested to derive measures of maternal and child mortality at the district and sub-regional levels in Bara district, Nepal. Information on birth, death, risk factors and health outcomes was collected within a geographic area as in an unbiased census, but without visiting every household. The sources of information were a vaccination registry, focus group discussions with local health workers, and most importantly, interview in group setting with women who share social bonds formed by motherhood and aided by their peer memory. Such groups included all women who have given birth, including those whose babies died during the measurement period. RESULTS: A total of 15,161 births were elicited in the study period of two years. In the same period 49 maternal deaths, 713 infant deaths, 493 neonatal deaths and 679 perinatal deaths were also recorded. The maternal mortality ratio was 329 (95%CI: 243-434)/100,000 live birth, infant mortality rate was 48 (44-51)/1000LB, neonatal mortality rate was 33 (30-36)/1000LB, and perinatal mortality rate was 45 (42-48)/1000 total birth. INTERPRETATION & CONCLUSIONS: The motherhood method estimated maternal, perinatal, neonatal and infant mortality rates and ratios. It has been field tested and validated against census data, and found to be efficient in terms of time and cost. Motherhood method can be applied in a time and cost-efficient manner to measure and monitor the progress in the reduction of maternal and child deaths. It can give current estimates of mortalities as well as averages over the past few years. It appears to be particularly well-suited to measuring and monitoring programmes in community and districts levels. PMID- 21321422 TI - Clinical outcome of adjuvant endocrine treatment according to Her-2/neu status in breast cancer. AB - BACKGROUND & OBJECTIVES: An association between over-expression of proto-oncogene Her-2/neu and resistance to tamoxifen in estrogen receptor (ER) positive, primary and metastatic breast cancer has been suggested. HR+/Her-2/neu+ patients have a poor response to endocrine therapy, making this group a matter of debate. The present study was carried out to examine whether Her-2/neu expression in breast cancer patients predicted tamoxifen effectiveness. METHODS: An enzyme-linked immunosorbent assay (ELISA) specific for the extracellular domain of the Her 2/neu oncoprotein product was used to detect serum Her-2/neu levels in 207 patients with histological confirmed breast cancer. Tissue Her-2 /neu expression was studied in 100 breast cancer patients by immunohistochemistry (IHC) and compared with serum Her-2/neu levels by ELISA. RESULTS: Among 207 histologically confirmed breast cancer patients, 53 were serum Her-2/neu positive. Patients who were treated with surgery, chemotherapy, and radiotherapy showed significantly (P<0.05) reduced serum Her-2/neu levels, showing good response to treatment. Patients who were treated with tamoxifen in addition to the above regimen did not show any significant reduction in serum Her-2/neu levels showing resistance to treatment. INTERPRETATION & CONCLUSIONS: The present findings study support the hypothesis that Her-2/neu overexpression contributes to tamoxifen resistance. Trastuzumab or other growth factor inhibitors should be used in combination with tamoxifen, since monotherapy is not likely to be optimal in HR+/Her-2/neu+ tumours. PMID- 21321423 TI - Tsunami, post-tsunami malaria situation in Nancowry group of islands, Nicobar district, Andaman and Nicobar Islands. AB - BACKGROUND & OBJECTIVES: Due to tsunami in 2004 a large proportion of population in Nicobar group of Islands become homeless, and in 2006 large scale labour migration took place to construct the houses. In 2008, a significant increase in malaria incidence was observed in this area. Therefore, in March 2008, the situation of malaria was assessed in Nancowry Islands in Nicobar District to study the reasons for the observed upsurge in the number of cases, and to suggest public health measures to control the infection. METHODS: The methods included a retrospective analysis of long term trend in the behaviour of malaria over the years from 2001 to 2008, analysis of the acute malaria situation, and rapid fever and malaria parasitemia survey along with environmental component. Mass radical therapy (MRT) and post-intervention parasitemia survey were carried out. The malaria situation in the aftermath of MRT was analysed. RESULTS: During the post tsunami year (2005) there was a large increase in the incidence of malaria and this trend continued till 2008. The percentage of Plasmodium falciparum increased from 23 to 53 per cent from 2006 to 2007 that coincides with the labour influx from mainland. The study showed that Nancowry was highly endemic, with high transmission setting, and high risk area for malaria. Though, more number of migrant labourers suffered fever (75 vs 20%) and sought malaria treatment over past month but parasitemia survey showed higher point prevalence of malaria among native tribes (7.4 vs 6.5%). Post-MRT, there was a decline in the occurrence of malaria, though it did not last long. INTERPRETATION & CONCLUSIONS: The study findings suggest that the migrant workers hailing from non-endemic or moderately endemic settings became victims of malaria in epidemic proportion in high endemic and high transmission setting. To find out the reasons for deterioration of malaria situation at Nancowry in the aftermath of tsunami requires further research. PMID- 21321424 TI - Fluorescence amplified fragment length polymorphism for subtyping of genotypes of Acanthamoeba isolated from patients with keratitis. AB - BACKGROUND & OBJECTIVES: Acanthamoeba keratitis (AK) is a painful and vision threatening ocular infection. The differentiation of Acanthamoeba at the species and subspecies level is complicated. Nearly all the AK isolates have been shown to belong to T4 genotype when analysed by ribosomal RNA gene sequences and there is no universally acceptable method for differentiation of different subtypes of T4. The purpose of this study was to attempt further discrimination of T4 genotypes. METHODS: In the present investigation, 15 Acanthamoeba isolates obtained from cornea of keratitis patients were subjected to fluorescence amplified fragment length polymorphism (FAFLP) genotyping to differentiate T4 subtypes. RESULTS: FAFLP profiles showed five distinct clusters (I to V) within T4 clonal complex which clearly depicted genetic differences among the isolates of T4 sequence type of Acanthamoeba. INTERPRETATION & CONCLUSIONS: Our study demonstrated the usefulness of FAFLP for reliable differentiation of T4 clonal complex of Acanthamoeba. PMID- 21321425 TI - Phenotypic & genetic characterization of Bacillus cereus isolated from the acute diarrhoeal patients. AB - BACKGROUND & OBJECTIVES: Bacillus cereus is one of the pathogens responsible for human diarrhoea, mainly due to consumption of contaminated food. The present study was undertaken to determine the occurrence of B. cereus among diarrhoeal patients and its phenotypic and genetic characteristics that determine the virulence and clonal features. METHODS: Stool specimens were collected for two years from acute diarrhoeal patients attending the two referral hospitals in Kolkata. Presence of virulence genes in B. cereus was determined by PCR. Clonality was assessed by pulsed-field gel analysis (PFGE) by restriction digestion with SmaI and NotI enzymes. Enterotoxins were detected by haemolysin assay and using BCET-RPLA kit. Invasion assay was done on Hep-2 cell line. Antimicrobial susceptibility was tested by disc diffusion method. RESULTS: B. cereus was identified in 54 (3.5%) of the 1536 diarrhoeal cases studied. Majority of the isolates were susceptible to many antibiotics but showed resistant to amoxyclav and cephalosporins. Six genes covering the two different enterotoxic complexes determining the pathogenicity of B. cereus have been characterized by PCR. The nhe genes were detected in a higher proportion than hbl. Except in two, clonal diversity was noticed among 21 B. cereus isolates. Haemolytic enterotoxin was detected in 76 per cent of the isolates. Majority of the isolates (67%) produced in vitro enterotoxin (BCET) confirming its involvement in the infection. INTERPRETATION & CONCLUSIONS: Though the presence of B. cereus was not high in patients with diarrhoea, several virulence factors confirm their association with diarrhoea. Distinct clonality was identified in majority of the isolates indicating their origin from different sources. PMID- 21321426 TI - Effects of acute supplementation of Panax ginseng on endurance running in a hot & humid environment. AB - BACKGROUND & OBJECTIVES: Athletes in Malaysia need to perform in a hot and humid environment due to the climatic nature of the country. Chronic supplementation of Panax ginseng (PG) (a deciduous perennial plant belonging to the Araliaceae family) enhances physical performance. As the ergogenic effect of acute supplementation of PG on endurance performance has not been explored in the Malaysian population especially in a hot and humid condition this study was taken up. METHODS: Nine heat adapted recreational runners (age: 25.4 +/- 6.9 yr, body mass: 57.6 +/- 8.4 kg; body height: 168.3 +/- 7.6 cm) were recruited in this placebo-controlled double-blind randomized study. Subjects ingested 200 mg of PG one hour before the exercise test on treadmill at 70 per cent of their VO2max in a laboratory environment of 31 degrees C and 70 per cent relative humidity. They drank 3 ml/kg body weight of cool water every 20 min during the exercise to prevent adverse effects of dehydration. Blood samples were drawn every 20 min for the analysis of glucose, lactate, insulin and free fatty acids. Oxygen uptake was determined every 20 min while heart rate, body and skin temperatures, and ratings of perceived exertion (RPE) were recorded every 10 min during the trials. RESULTS: Endurance running time to exhaustion did not differ between PG and placebo trials. Heart rate, skin temperature, core body temperature, oxygen uptake, RPE, plasma insulin, glucose, free fatty acid and lactate levels during the endurance exercise did not show any significant differences between the trials. INTERPRETATION & CONCLUSIONS: We conclude that acute supplementation of 200 mg of PG did not affect the endurance running performance of the heat-adapted male recreational runners in the heat. PMID- 21321428 TI - Group A Streptococcus virulence factors genes in north India & their association with emm type in pharyngitis. AB - BACKGROUND & OBJECTIVES: Group A streptococcal (GAS) pharyngitis, especially among children, leads to high prevalence of rheumatic fever (RF)/rheumatic heart disease (RHD) in India, as compared to the western world where invasive diseases are common. GAS encodes numerous virulence factors that cause diseases by exhibiting extraordinary biological diversity. Hence, we studied the virulence factors genes of GAS isolated from the throat of children with pharyngitis and also asymptomatic carriers. METHODS: Fifty GAS isolates cultured from throats of north Indian children aged 5-15 yr with mild pharyngitis (20), severe pharyngitis (24) and asymptomatic pharyngeal carriers (6), during 2000-2003 along with reference M1 strain were emm typed and characterized for virulence factors genes by PCR. The presence of virulence factors was also checked for their association with emm type in pharyngitis. RESULTS: Twenty emm types, six sequence types, and one non-typeable strain were found circulating in north India. The five most prevalent types were emm 74 (12%), 11 & StI129 (8% each) and emm 68 and NS292 (6% each). The spe B gene was found to be significantly higher (P=0.0007) in opacity factor (OF) negative isolates. emm 3, 11, 77, 86, 87, 109 and StI129 showed maximum virulence factors genes. INTERPRETATION & CONCLUSIONS: GAS isolates collected from throats of children from north India possess highly virulent antigens. This study also supports concept of isolate-associated virulence rather than type relatedness. PMID- 21321427 TI - Persistence of goitre in the post-iodization phase: micronutrient deficiency or thyroid autoimmunity? AB - BACKGROUND & OBJECTIVES: Despite years of salt iodization, goitre continues to be a major public health problem worldwide. We examined the prevalence of goitre in the post-iodization phase and the relationship of goitre with micronutrient status and thyroid autoimmunity in school children of Chandigarh, north India. METHODS: Two phase study; in the first phase, 2148 children of 6 to 16 yr were screened for goitre by two independent observers as per the WHO grading system. In the second phase, a case-control study, 191 children with goitre and 165 children without goitre were compared with respect to urinary iodine, iodine content of salt, serum levels of T3, T4, TSH, anti-TPO (thyroid peroxidase) antibody, haemoglobin, ferritin and selenium. RESULTS: Prevalence of goitre in the studied subjects was 15.1 per cent (13.9% in 6 to 12 yr and 17.7% in 13 to 16 yr age group, P = 0.03). Median urinary iodine excretion in both the groups was sufficient and comparable (137 and 130 MUg/l). 3.2 per cent children with goitre and 2.4 per cent without goitre had hypothyroidism (subclinical and clinical) and only one child with goitre had subclinical hyperthyroidism. Nine (4.9%) children in the goitre group and 3 (1.9%) in control group had anti-TPO antibody positivity. The median serum selenium levels were not different in both the groups (181.9 and 193.5 MUg/l). Seventy one (37.4%) of the goitrous children had anaemia (haemoglobin <12 g/dl) as compared to 41 (24.8%) of the control group (P < 0.01). More number of goitrous children (39, 20.6%) were depleted of tissue iron stores (serum ferritin <12 MUg/l) as compared to controls (11, 6.4%; P < 0.001). Serum ferritin level negatively correlated with the presence of goitre (r = -0.22, P = 0.008) and had an OR of 2.8 (CI 1.20-6.37, P = 0.017). INTERPRETATION & CONCLUSIONS: There was a high prevalence of goitre in young children despite iodine repletion and low thyroid autoimmunity. The concurrent iron deficiency correlated with the presence of goiter. However, the cause and effect relationship between iron deficiency state and goitre requires further elucidation. PMID- 21321429 TI - Extended spectrum beta-lactamase producing Enterobacteriaceae & antibiotic co resistance. PMID- 21321431 TI - Advances in scanning probe microscopies for nanomaterial analyses--from basic science to quantitative nanofunctionality analyses--. PMID- 21321430 TI - Low socio-economic groups are not overweight in India. PMID- 21321432 TI - Theoretical simulation of scanning probe microscopy. AB - Methods of theoretical simulation of scanning probe microscopy, including scanning tunneling microscopy (STM), atomic force microscopy(AFM) and Kelvin prove force microscopy (KPFM) have been reviewed with recent topics as case studies. For the case of the STM simulation, the importance of the tip electronic states is emphasized and some advanced formalism is presented based on the non equilibrium Green's function theory beyond Bardeen's perturbation theory. For the simulation of AFM, we show examples of 3D-force map for AFM in water, and theoretical analyses for a nano-mechanical experiment on a protein molecule. An attempt to simulate KPFM images based on the electrostatic multi-pole interaction between a tip and a sample is also introduced. PMID- 21321433 TI - Two-dimensional polymerization and reaction at the solid/liquid interface: scanning tunneling microscopy study. AB - The two-dimensional polymerization and reaction at the solid/liquid interface has caused considerable attention in recent years because of its fundamental importance and many potential applications. Scanning tunneling microscopy (STM) provides the possibility for the observation and manipulation of polymerization and reaction occurring at the solid/liquid interface at the atomic level. Two dimensional polymerization and reaction could be induced by external stimuli, such as electrochemistry-induced, STM tip-induced, or light-induced. The polymerization at the solid/liquid interface is the focus of this review, including the mechanism of polymerization and characterization of structural and electrical properties of the resulting polymers. Finally, the outlooks for developments in this field are described. PMID- 21321434 TI - Standardization of excitation efficiency in near-field scanning optical microscopy. AB - Near-field scanning optical microscope (NSOM or SNOM) is a form of scanning probe microscope (SPM), which is used to observe the optical properties of a sample surface with a nanometer-scale spatial resolution. Since the near-field light strongly interacts with the sample surface, or with nanometer-scale objects on the substrate's surface, NSOM is advantageous to excite only the vicinity of a sample surface. From the view point of surface chemical analysis, a discussion about the light energy concentration within a nanometer-scale region, and an estimation of its efficiency are indispensable for accurate measurements of the optical properties in a nanometer-scale region. In this paper, we describe the concept, the cautions and the general guidelines of a method to measure the excitation efficiency of aperture-type NSOM instruments. PMID- 21321435 TI - Cantilever tilt causing amplitude related convolution in dynamic mode atomic force microscopy. AB - It is well known that the topography in atomic force microscopy (AFM) is a convolution of the tip's shape and the sample's geometry. The classical convolution model was established in contact mode assuming a static probe, but it is no longer valid in dynamic mode AFM. It is still not well understood whether or how the vibration of the probe in dynamic mode affects the convolution. Such ignorance complicates the interpretation of the topography. Here we propose a convolution model for dynamic mode by taking into account the typical design of the cantilever tilt in AFMs, which leads to a different convolution from that in contact mode. Our model indicates that the cantilever tilt results in a dynamic convolution affected by the absolute value of the amplitude, especially in the case that corresponding contact convolution has sharp edges beyond certain angle. The effect was experimentally demonstrated by a perpendicular SiO(2)/Si super lattice structure. Our model is useful for quantitative characterizations in dynamic mode, especially in probe characterization and critical dimension measurements. PMID- 21321436 TI - Methods for vertical drift measurements of scanning probe microscopes. AB - Time stability plays an important role in the applications of scanning probe microscopes (SPMs). Although SPMs integrated with a closed-loop control system could reduce the drift greatly, drift would still exist. The SPM drift in the lateral direction has been well studied, and several measurement methods have also been developed. However, due to coupling of the lateral drift, it is still difficult to determine the drift in the vertical direction. In this paper, we propose a method to measure the vertical drift of an SPM based on scanned topography images. This method considers the influence of the lateral drift. Experimental results show that the vertical drift of the SPM is non-negligible, and the vertical drift on each pixel of one scanned image is different from each other. By such a method, instability in the vertical direction of the SPM instrument could be revealed and evaluated. PMID- 21321437 TI - Automatic glitch elimination of scanning probe microscopy images. AB - Glitch artifacts appear in many scanning probe microscopy (SPM) images due to transient instabilities. Such artifacts can distort any quantitative analyses based on the measured images. A robust smoothing method has been adopted to eliminate the glitch artifacts. Results on different kinds of sample images demonstrate that this method is quite efficient. However, the smoothing operation will cause information loss in certain cases, especially on sharp structures. If these features are also crucial in analysis, the compromise between the elimination of glitches and the reservation of signal details should be settled. Post-restoration of image details from analyzing extracted glitch artifacts can meet this demand. Glitch elimination can help to improve the value of SPM in quantitative nanoscale measurements. PMID- 21321438 TI - Novel tip shape reconstruction method for restoration of AFM topography images using nano-structures with given shapes. AB - The establishment of more accurate imaging of surface microstructures is needed. The most significant distortion in atomic force microscopy (AFM) imaging is induced by the probe tip shape, whenever the sample surface contains features whose dimensions are comparable to the probe tip size. The acquired AFM image is the dilation between the tip shape and the sample topography. To restore the original topographical profile, a numerical erosion procedure using a precise probe shape function is required. Here, a new technique for reconstruction of probe shape function using a well-defined nanostructure is proposed. First, AFM topography images of the given-shape nanostructure dispersed on flat substrates are taken. Then, a probe shape function is determined by a numerical calculation procedure. By using the experimentally determined probe shape function, the most probable surface morphologies from the observed AFM topography images of unknown samples can be extracted. PMID- 21321439 TI - Mass spectrometry for cellular and tissue analyses in a very small region. AB - The analysis of biological specimens is now expected to shift from multi-cell analysis to single cells to know about the molecular and cellular behavior precisely. Mass spectrometric approaches to clarify molecular profiles in a cell or very small region have been developed. Such techniques include matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS), secondary-ion mass spectrometry (SIMS), single-cell MALDI and live single-cell mass spectrometry. In this paper, these methods are reviewed, and their characteristics are discussed concerning how these methods achieve our aim. PMID- 21321440 TI - New apparatus for liquid-liquid extraction, "emulsion flow" extractor. AB - A simple and low-cost apparatus for continuous and efficient liquid-liquid extraction, which does not need continual mechanical forces (stirring, shaking, etc.) other than solution sending, has newly been developed. This apparatus, named "emulsion flow" extractor, is composed of a column part where an emulsified state fluid flow (emulsion flow) is generated by spraying micrometer-sized droplets of an aqueous phase into an organic phase and a phase-separating part where the emulsion flow is destabilized by means of a sudden decrease in its vertical liner velocity due to a drastic increase in cross-section area of the emulsion flow passing through. In the present study, the performance of a desktop emulsion flow extractor in the extraction of Yb(III) and U(VI) from aqueous HNO(3) solutions into isooctane containing bis(2-ethylhexyl) phosphoric acid (D2EHPA) was evaluated. The mixing efficiency of the emulsion flow extractor was found to be comparable with that of a popular liquid-liquid extractor, mixer settler. Moreover, the emulsion flow extractor proved to have an overwhelming advantage in terms of phase-separating ability. PMID- 21321441 TI - Quantitative analysis of ions in spring water in three different areas of Hyogo Prefecture in Japan by far ultraviolet spectroscopy. AB - Far-ultraviolet (FUV) spectra in the 190-300 nm region were measured for spring water in Awaji-Akashi area, Tamba area and Rokko-Arima area in Hyogo Prefecture, Japan, these areas have quite different geology features. The spectra of the spring water in the Awaji-Akashi area can be divided into two groups: the spring water samples containing large amounts of NO(3)(-) and/or Cl(-), and those containing only small amounts of NO(3)(-) and Cl(-). The former shows a saturated band below 190 nm due to NO(3)(-) and/or Cl(-). These two types of spectra correspond to different lithological areas: sedimentary lithology near the sea shore containing many ions in the seawater and gravitic lithology far from the sea side, in the Awaji-Akashi area. The spring water from the Tamba area, which is far from the sea, contains relatively small amounts of NO(3)(-) and Cl(-); it does not yield a strong band in the region observed. The FUV spectra of three of four kinds of spring water samples in the Arima Hotspring show characteristic spectral patterns. They are quite different from the spectra of the spring water samples of the Rokko area. Calibration models were developed for NO(3)(-), Cl(-), SO(4)(2-), Na(+), and Mg(2+) in the nine kinds of spring water collected in the Awaji-Akashi area, Tamba, and Rokko-Arima area by using univariate analysis of the first derivative spectra and the actual values obtained by ion chromatography. NO(3)(-) yields the best results: correlation coefficient of 0.999 and standard deviation of 0.09 ppm with the wavelength of 212 nm. Cl(-) also gives good results: correlation coefficient of 0.993 and standard deviation of 0.5 ppm with the wavelength of 192 nm. PMID- 21321442 TI - Determination of sulfide with acidic permanganate chemiluminescence for development of deep-sea in-situ analyzers. AB - A new chemiluminescence method is proposed for the determination of sulfide in seawater based on the chemiluminescence reaction between sulfide and an acidic permanganate solution. 3-Cyclohexylaminopropanesulfonic acid was used as a chemiluminescence enhancer. By use of this method, 1-150 uM of sulfide could be determined in artificial seawater. The limit of detection was 0.17 uM sulfide. We investigated the effects of salinity, water temperature, and interfering chemicals such as heavy-metal ions and organic matter. In addition, natural seawater spiked with sulfide was analyzed. The results showed that the CL method could be applied to a deep-sea sulfide analyzer. PMID- 21321443 TI - Rapid method for simultaneous determination of nitrite and nitrate in water samples using short-column ion-pair chromatographic separation, photochemical reaction, and chemiluminescence detection. AB - A rapid method has been developed for the simultaneous determination of nitrite and nitrate. The separation of nitrite and nitrate was achieved using an octadecylsilane (ODS) short column (5 um, 20 * 4.6 mm) with 10 mM of borate buffer-methanol (99.5:0.5, v/v; pH 10.0), containing 5 mM of lauryltrimethylammonium chloride and 50 mM of NaBr. These ions were detected by luminol chemiluminescence following online UV irradiation. The calibration curves of nitrite and nitrate were linear in the range of 1.0 * 10(-7) to 2.0 * 10(-5) M and 1.0 * 10(-6) to 2.0 * 10(-4) M, respectively. The detection limits for nitrite and nitrate were 0.05 and 0.4 uM, respectively (with a signal-to-noise ratio of 3). The precisions of peak heights for 7 identical injections of a standard mixture of 0.50 uM of nitrite and 5.0 uM of nitrate were 2.7 and 2.1%, respectively. Analysis time per sample was less than 2 min, and system pressure was low (2.1 MPa). The proposed method was successfully applied to water samples from various sources. PMID- 21321444 TI - Electrogenerated chemiluminescence detection of mercury(II) ions based on DNA probe labeled with ruthenium complex. AB - A novel mercury(II) ion (Hg(2+)) biosensor with electrogenerated chemiluminescence (ECL) detection using tris(2,2'-bipyridyl) ruthenium derivatives (ruthenium complex) as labeling was developed in the prescent work. One thymine (T)-rich single-strand DNA (ssDNA) labeled with a ruthenium complex was taken as an ECL probe. When the other T-rich capture ssDNA was self-assembled onto the surface of a gold electrode with a thiol group, and then hybridized with the ECL probe to form double-strand DNA (dsDNA) structures in the presence of Hg(2+), a strong ECL response was electrochemically generated. The ECL intensity was linearly related to the concentration of Hg(2+) in the range from 1.0 * 10( 6) to 1 * 10(-9) M with a detection limit of 3.0 * 10(-10) M. The relative standard deviation was 4.1% at 1.0 * 10(-7) M Hg(2+) (n = 5). This work demonstrates that the combination of the strongly binding T-rich DNA to Hg(2+) with the highly sensitive ECL technique to design an ECL Hg(2+) biosensor is a great promising approach for the determination of metal ions. PMID- 21321445 TI - Determination of triclosan in aqueous samples using solid-phase extraction followed by on-line derivatization gas chromatography-mass spectrometry. AB - An efficient and eco-friendly injection-port tert-butyldimethylsilylated (TBDMS) derivatization and gas chromatography-mass spectrometry (GC/MS) were developed to determine an antibacterial agent, triclosan (TCS), and its metabolite: methyltriclosan (MTCS), in wastewater and surface water samples. The effects of several parameters related to the TBDMS-derivatization process (i.e., injection port temperature, residence time and volume of silylating agent) were investigated. This on-line derivatization-coupled large-volume (10 uL) sample introduction provides sensitive, fast and reproducible results for TCS residue analyses. Each water sample was extracted by reversed-phase C18 solid-phase extraction (SPE) cartridge, and then the recovery efficiency was evaluated using various eluting solutions. Limits of quantitation (LOQs) for MTCS and TCS were 3.0 and 1.0 ng/L in 100 mL of water samples, respectively. Intra- and inter-batch precision with their accuracy were also investigated. The precision for these analytes, as indicated by relative standard deviations (RSDs), proved to be less than 7 and 11%, respectively, for intra- and inter-batch. Accuracy, expressed as the mean recovery, was between 80 and 95%. The method was then applied to environmental water samples, showing the occurrence of TCS in both surface water and municipal wastewater treatment plant (MWTP) influent/effluent samples. PMID- 21321446 TI - Influence of e-beam irradiation on sulfamethoxazole in solid state. AB - The effects of ionizing radiation generated by a beam of electrons, in that doses varied from 25-800 kGy, on the physico-chemical properties of sulfamethoxazole (SMX) in solid state have been studied at room temperature and in the air atmosphere. The changes appearing after the irradiation were detected and evaluated by the spectroscopic methods (UV, IR, MS, EPR), chromatography (TLC and HPLC) and SEM, XRD and DSC. Already the lowest dose of 25 kGy was found to change the color of SMX from white to pale cream; such change became more intense with our increasing the irradiation dose. Products of radiodegradation and decreases in the drug content were detected by TLC and HPLC only after irradiation with 400 kGy. Since the SMX radiolysis products (sulfanilamide and sulfanilic acid) are colorless compounds, it is supposed that the color results from trapping of free radicals in the crystal lattice; the concentration of free radicals was 1.04 * 10(15) spin/g. Our results indicate that the radiolysis of SMX in the solid state caused by e-beams involves breaking of the S-N and N-C bonds. The mean radiolytic yield of this process is G((-SMX)) = 1.89 * 10(-7) mol/J, whereas the yield of formation of the two products of radiolysis is close and equal to 2.18 * 10(-8) mol/J (sulfanilamide) and 2.13 * 10(-8) mol/J (sulfanilic acid). PMID- 21321447 TI - Application of terahertz absorption spectroscopy to evaluation of aging variation of medicine. AB - The absorption spectra of three kinds of medicines both before and after the expiration date: Amlodin OD((r)) (5 mg), Basen OD((r)) (0.2 mg) and Gaster D((r)) (10 mg) have been measured by terahertz time domain spectroscopy (THz-TDS). All the medicines show some differences in the THz absorption spectra between medicines before and after the expiration dates. X-Ray powder diffraction (XRD) studies of all medicines suggest that the polymorph of the main effective compound is not changed before and after the expiration date. Therefore, the differences in the THz spectra between medicines before and after the expiration dates arise from aging variation of diluting agents and/or from modifications of intermolecular interaction between the effective compounds and diluting agents. PMID- 21321448 TI - Selective removal of endotoxin from a DNA solution by cross-linked cyclodextrin beads. AB - The removal of lipopolysaccharide (LPS) from a contaminated DNA solution was achieved using cross-linked cyclodextrin (CyD polymer) beads as LPS adsorbents. The LPS-removing activity of the beta- and gamma-CyD polymer beads was compared with that of common cationic LPS adsorbents. The gamma-CyD polymer beads selectively removed LPS from a DNA solution (50 ug mL(-1), pH 6, ionic strength MU = 0.2) containing natural LPS (15 EU mL(-1)), without the adsorption of DNA. The adsorptions of LPS and DNA were 85% and <1%, respectively. PMID- 21321449 TI - Functional preconcentration tip of total volume injection for ESI/MS analysis of DNA adducts. AB - We have developed a simple method to significantly improve the sensitivity in the LC/MS analysis of DNA adducts. A preconcentration tip for the selective recovery of DNA adducts was prepared. Using this tip, the total amount of DNA adducts in a treated DNA sample was injected in a one-shot manner into an LC/MS system. We were able to improve the sensitivity by more than one order of magnitude in concentration. This method will be a useful tool for the quantitative determination of trace DNA adducts. PMID- 21321451 TI - [Pharmacological knowledge required by Primary Care Physicians]. PMID- 21321452 TI - [Pharmacological knowledge for sports pharmacists]. PMID- 21321453 TI - [Importance of pharmacological knowledge in clinical practice]. PMID- 21321454 TI - [Development of improved adenovirus vectors and transduction into neural cells]. PMID- 21321455 TI - [Translational research of DDS based on polymeric micelles]. PMID- 21321456 TI - [Translational research for mental disorder -schizophrenia]. PMID- 21321457 TI - [Translational research on ghrelin]. PMID- 21321458 TI - [Pharmacological properties and clinical efficacy of abatacept (Orencia((r))) for the treatment of rheumatoid arthritis]. PMID- 21321459 TI - [Pharmacology and clinical results of levetiracetam (E Keppra((r)) Tablets), a new antiepileptic drug]. PMID- 21321460 TI - Early statin therapy within 48 hours decreased one-year major adverse cardiac events in patients with acute myocardial infarction. AB - HMG-CoA reductase inhibitors (statins) reduce major adverse cardiac events (MACE) and mortality in patients with acute coronary syndrome. We investigated whether early statin therapy would be effective at reducing MACE in patients with acute myocardial infarction (AMI).A total of 1,159 patients were analyzed. They were grouped by initiation time of statin administration after admission as follows: group I; n = 945, <= 48 hours, group II; n = 214, > 48 hours.Cardiovascular risk factors and noncardiac comorbidities were not different between the two groups. ST-elevation MI as initial diagnosis was more prevalent in group I (68.4% versus 59.3%, P = 0.013). In-hospital mortality was not different in the two groups (0.8% versus 0.5%, P = 0.483). In one-year clinical follow-up, MACE and repercutaneous coronary intervention were lower in group I (17.8% versus 24.6%, P = 0.016, 10.2% versus 15.5%, P = 0.021, respectively). However, there was no difference in mortality (3.8% versus 4.7%, P = 0.319). In multivariate analysis, statin initiation within 48 hours after admission was an independent predictor of one-year MACE (OR 1.49, 95% CI = 1.00-2.21, P = 0.045).Consequently, early statin therapy within 48 hours after admission reduced MACE at one-year follow-up in patients with AMI. PMID- 21321461 TI - Role of preoperative atorvastatin administration in protection against postoperative atrial fibrillation following conventional coronary artery bypass grafting. AB - Atrial fibrillation (AF) is one of the most common postoperative arrhythmias in patients who undergo coronary artery bypass grafting (CABG). The aim of this study was to evaluate the effect of preoperative atorvastatin on postoperative atrial fibrillation following coronary artery bypass grafting with cardiopulmonary bypass (CCABG). One hundred consecutive patients undergoing elective CCABG, without history of AF or previous statin treatment, were enrolled and randomly assigned to a statin group (atorvastatin 20 mg/d, n = 49) or a control group (placebo, n = 51) starting 7 days preoperatively. The primary endpoint was the occurrence of postoperative AF. C-reactive protein (CRP) levels were assessed in all selected patients before surgery and every 24 hours postoperatively until discharge from hospital. Atorvastatin significantly reduced the incidence of postoperative AF and postoperative peak CRP level versus placebo (18% versus 41%, P = 0.017; 129.3 +/- 24.3 mg/L versus 149.3 +/- 32.5 mg/L, P < 0.0001). Kaplan-Meier curves confirmed a significantly better postoperative atrial fibrillation-free survival in the statin group (chi(2) = 7.466, P = 0.006). Logistic regression analysis showed preoperative atorvastatin treatment was an independent factor associated with a significant reduction in postoperative AF (OR = 0.235, P = 0.007), whereas high postoperative CRP levels were associated with increased risk (OR = 2.421, P = 0.015). Preoperative atorvastatin administration may inhibit inflammatory reactions to prevent atrial fibrillation following coronary artery bypass grafting with cardiopulmonary bypass. PMID- 21321462 TI - Possible role of damaged neoendothelial cells in the genesis of coronary stent thrombus in chronic phase. A dye staining angioscopic study. AB - The mechanism(s) underlying formation of coronary stent thrombus (ST) in chronic phase is yet unclear. Endothelial cells are highly antithrombotic, therefore, it is conceivable that neoendothelial cells (NECs) covering stent struts are damaged and cause ST. This study was performed to examine the role of damaged NECs covering coronary stent struts in the genesis of occlusive or nonocclusive ST in chronic phase.(1) Forty-four patients with acute coronary syndrome (17 females and 27 males) underwent dye-staining coronary angioscopy, using Evans blue which selectively stains damaged endothelial cells, 6 months after bare-metal stent (BMS) deployment. Neointimal coverage was classified into not covered (grade 0), covered by a thin layer (grade 1), and buried under neointima (grade 2) groups. (2) In 7 beagles, the relationships between neointimal thickness and ST were examined 6 months after BMS deployment. (3) The NECs on the struts were stained blue in 4 of 25 patients with grade 2 and in 11 of 20 patients with grade 0/1 (P < 0.05). ST was observed in none of the former and in 5 of the latter (P < 0.05). (4) In beagles, neointimal coverage was grade 0/1 when neointimal thickness was 80.2 +/- 40.0 um, whereas grade 2 when thickness was 184 +/- 59.4 um. ST was observed in 9 of 15 struts with neointimal thickness within 100 um and in one of 17 struts with thickness over 100 um (P < 0.05). ST arose from damaged NECs covering the stent struts. NECs may have been damaged due to friction between them and struts due to thin interposed neointima which might have acted as a cushion, resulting in ST. PMID- 21321463 TI - Association of circulating levels of leptin and adiponectin with metabolic syndrome and coronary heart disease in patients with various coronary risk factors. AB - The aim of this study was to investigate the associations of adiponectin and leptin with metabolic syndrome (MetS) and coronary heart disease (CHD) in patients with various coronary risk factors. We determined serum adiponectin, leptin, and metabolic syndrome components in 104 patients (59 men and 45 women; aged 40-86 years) with various coronary risk factors at a cardiovascular out patient clinic. Natural logarithmic transformed (ln) leptin was lower in men and smokers, and positively correlated with body mass index (BMI) (r = 0.59, P < 0.0001), waist circumference (r = 0.60, P < 0.0001), and homeostasis model assessment of insulin resistance (HOMA-IR) levels (r = 0.24, P < 0.02). Ln adiponectin was higher in women and nonsmokers, and was correlated with age and high-density lipoprotein cholesterol (HDL-C). Patients with MetS (n = 69) had significantly higher BMI, HOMA-IR, and ln leptin and lower ln adiponectin than those without Mets (Ln leptin, 2.14 +/- 0.08 versus 1.30 +/- 0.11; Ln adiponectin, 2.29 +/- 0.06 versus 2.54 +/- 0.09). In contrast, patients with coronary heart disease (CHD: n = 40) had significantly lower serum ln adiponectin concentrations than non-CHD patients (n = 64) (1.79 +/- 0.12 versus 1.91 +/- 0.10) as well as lower HDL-C and a higher smoking percentage. Consistent results were obtained by multivariate analyses. In conclusion, this study disclosed factors associated with the increase in serum leptin and adiponectin. Serum levels of leptin may be associated positively with MetS, whereas adiponectin levels are associated negatively with MetS and CHD, even in patients with various coronary risk factors. PMID- 21321464 TI - Influence of menstrual cycle on p wave dispersion. AB - Female gender is an independent risk factor for some types of arrhythmias. We sought to determine whether the menstrual cycle affects P wave dispersion, which is a predictor of atrial fibrillation. The study population consisted of 59 women in follicular phase (mean age, 29.3 +/- 7.7 years) (group F) and 53 women in luteal phase (mean age, 28.1 +/- 6.8 years) (group L). The ECGs of 35 patients (mean age, 26.4 +/- 4.5) were obtained in both follicular and luteal phase. Both groups underwent a standard 12-lead surface electrocardiogram recorded at 50 mm/s. Maximal (Pmax) and minimal P wave durations (Pmin) were measured. P wave dispersion (PD) was defined as the difference between Pmax and Pmin. PD was significantly higher in group L than group F (46.6 +/- 18.5 versus 40.1 +/- 12.7; P < 0.05). Pmin was significantly lower in group L than group F (51.6 +/- 12.1 versus 59.1 +/- 12.1; P = 0.002). When we compared ECGs in different phases of the 35 patients, PD was significantly higher in luteal phase than follicular phase (53.2 +/- 12.3 versus 42.8 +/- 10.2; P < 0.05). Pmin was significantly lower in luteal phase than follicular phase (47.6 +/- 6.6 versus 56 +/- 10.1; P = 0.05). We detected a significant correlation between the day of the menses and PD (r = 0.27; P < 0.05). PD was increased in luteal phase compared to follicular phase, and this difference was more prominent as the days of the cycle progressed. PMID- 21321465 TI - Identification of six novel SCN5A mutations in Japanese patients with Brugada syndrome. AB - Mutations in SCN5A are linked to Brugada syndrome in approximately 20% of all cases (BrS1). Several dozen distinct SCN5A mutations in BrS1 have been associated with the increased risk of cardiac arrhythmias. However, the genotype-phenotype relationship remains elusive. The current study analyzed the SCN5A gene to elucidate the potential variability of clinical features in Japanese BrS1 subjects. Subjects of the present study included 30 probands (25 male subjects, 45 +/- 15 years of age) with Brugada-pattern ECG. Seven patients had been resuscitated from cardiopulmonary arrest (CPA group). Another 10 patients had a history of syncope (Sy group), and 13 more remain asymptomatic (Asy group). We identified 8 different SCN5A mutations, including 6 novel mutations (CPA group: 1/7, Sy group: 3/10, Asy group: 4/13). An A735E mutation (located at segment (S)1 in domain (D)2) was identified in the CPA group. A novel splice acceptor site mutation (c.393-1c>t), which may produce a prematurely truncated protein, was identified in the Sy group. An E1784K mutation (C-terminus) and a novel mutation V1951M (C-terminus) were also identified in the Sy group. Four novel missense mutations, A586T (D1-D2 linker), R689H (D1-D2 linker), S1553R (S1-S2 in D4), and Q1706H (S5-Pore in D4) were identified in the Asy group. These data may help us understand the genetic heterogeneity of BrS1, which is more prevalent in Japanese than in whites and other ethnic groups. PMID- 21321466 TI - Clinical profiles, efficacy of antiarrhythmic drug therapy, and cardiovascular prognosis in patients with first detected paroxysmal atrial fibrillation. AB - Little information is available concerning clinical profiles and outcomes of treatment in Japanese patients with first detected atrial fibrillation (AF). In the present study, 459 patients with paroxysmal AF (309 males, mean age, 66 +/- 12 years) were divided into a first detected AF group (group A, n = 143) and a non-first detected AF group (group B, n = 316). Clinical profiles, prophylactic efficacy of antiarrhythmic drug therapy (AAD), and cardiovascular prognosis during a mean follow-up period of 50 +/- 35 months were compared between the two groups. The number of AF recurrences in the individual patients regardless of AAD were significantly lower in group A than in group B (0.8 +/- 1.4 versus 1.7 +/- 1.9)(P < 0.05). The percentages of patients free from conversion to chronic AF at 12, 36, 60, and 120 months were significantly higher in group A (98%, 96%, 93%, and 91%, respectively) than in group B (95%, 86%, 83%, and 79%, respectively)(P < 0.01). The annual rates of hospitalization for thromboembolism, heart failure, and cardiovascular death did not differ between group A (2.2%, 1.1% and 1.0%, respectively) and group B (2.2%, 1.9% and 1.1%, respectively). In multivariate logistic regression analysis, a CHADS2 score >= 2 points (odds ratio 13.1, 95% confidence interval 3.36-51.0, P = 0.001), nocturnal AF onset (OR 0.201, 95% CI 0.050-0.815, P = 0.025), left ventricular diastolic dimension (LVDd) >= 50 mm (OR 3.845, 95% CI 1.078-13.71, P = 0.038), and conversion to chronic AF (OR 3.547, 95% CI 1.002-13.64, P = 0.048) were associated with cardiovascular events in group A. Rhythm control therapy with antiarrhythmic drugs was shown to be more effective for patients in group A than in group B. It is particularly important to prevent cardiovascular events in first detected AF patients with a CHADS2 score >= 2 points, LVDd >= 50 mm, and conversion to chronic AF. PMID- 21321467 TI - Feasibility evaluation of a remote monitoring system for implantable cardiac devices in Japan. AB - The number of implanted cardiac devices has been growing steadily over the last several years. Systems to monitor device data remotely have been introduced with the goal of reducing follow-up burden for both patients and physicians. Since the introduction of telemedicine depends greatly on the situations that are unique to each country, the acceptance of cardiac device remote monitoring in Japan was analyzed.A total of 203 patients who had previously undergone cardiac device implantation were enrolled. The subjects were provided with a CareLink Monitor that performed interrogation and transmission of device data at home, and then the physicians reviewed the data via a website at one and 3 months after baseline visits. A total of 470 transmissions were made. Questionnaires were completed by subjects and physicians to evaluate acceptance, ease of use, and satisfaction with the system. More than 87% of the subjects felt the Monitor was easy to use and nearly all of the physicians were satisfied with the system. A majority of patients felt reassured by having their devices assessed from a remote location and preferred the decreased number of clinic visits that were possible when using the Monitor. The patients spent an average of 168.2 minutes per clinic visit, whereas follow-up time was reduced to 13.0 minutes by remote monitoring. Physician consultation time was reduced by 2.7 minutes.The CareLink Network was well accepted by both the patients and physicians. Underlying issues did emerge, but once they are overcome, the system appears to have great potential to improve the quality of care given by healthcare providers. PMID- 21321468 TI - Clinical significance of combined CYP2C9 and VKORC1 genotypes in Japanese patients requiring warfarin. AB - The individual management of anticoagulation therapy is important for safe medical outcomes, including those of oral surgery. Here, Japanese patients who received warfarin (n = 35) and normal controls (n = 125) were analyzed by real time PCR to determine the frequencies of single nucleotide polymorphisms in VKORC1 (vitamin K epoxide reductase complex, subunit 1) and CYP2C9 and how these frequencies related to warfarin dose and PT-INR. The genetic polymorphisms CYP2C9(*2) (416 C > T), CYP2C9(*3) (1061 A > C), and intron 1-136 C > T in VKORC1 (1173 C > T) were measured. All patients had the wild-type CYP2C9 gene (*1/*1). All 160 cases had the wild-type (CC) type CYP2C9(*2), 93.8% had AA type CYP2C9(*3), 6.2% had AC type CYP2C9(*3), 1.2% had CC type VKORC1, 13.8% had CT type VKORC1, and 85% had TT type VKORC1. The CC type VKORC1 genetic polymorphism was associated with a significantly higher mean warfarin maintenance dose (4.5 +/ 0.5 mg) than other VKORC1 genotypes (TT type 2.9 +/- 0.1 mg: CT type 3.4 +/- 0.3 mg). Categorization of the patients in terms of the combined CYP2C9 and VKORC1 haplotype (the warfarin-responsive index; WRI) revealed the mean daily warfarin maintenance dose was 3.0 +/- 0.1 mg for WRI 1 and 3.7 +/- 0.3 mg for WRI 2 (P < 0.012). The event survey revealed 2 patients with nonfatal cerebral hemorrhage had a WRI score of 2 (VKORC1 C/T heterozygosity genotype). Thus, CYP2C9 and VKORC1 haplotype analysis allows prediction of warfarin maintenance dosage. The findings may provide a personalized use of warfarin in the field of oral surgery. PMID- 21321469 TI - Temperature-controlled cooled-tip radiofrequency linear ablation of the atria guided by a realtime position management system. AB - Due to the difficulty in producing a transmural linear lesion and the possibility of complications such as thrombus formation leading to thromboembolism, the catheter-based maze procedure remains problematic. We tested, in pigs, the possibility of using a temperature-controlled cooled-tip radiofrequency (RF) ablation system together with a realtime position management (RPM) system to create a transmural linear lesion uncomplicated by thrombus formation.Nine pigs underwent insertion of two electrode catheters (each with two ultrasound electrodes), one into the coronary sinus (CS) and one into the right ventricular apex (references for ultrasound-based non-fluoroscopic three-dimensional mapping). A cooled-tip catheter (with two ultrasound electrodes) was introduced into the right atrium. Linear right atrial ablation was performed with a custom radiofrequency (RF) generator. The catheter was perfused with 0.66 mL/second of saline. RF was delivered for 60 seconds at a target temperature of 40 degrees C. A linear ablation line was created between the superior vena cava and inferior vena cava. Three-dimensional isochronal maps were created during CS pacing before and after ablation. In 4 of the 9 pigs, a transmural linear ablation line was confirmed by three-dimensional mapping and postmortem macroscopic examination. No endocardial thrombus formation was noted. Temperature-controlled cooled-tip RF linear ablation guided by an RPM system appears to have potential for creating linear lesions in the atria. Further studies are needed to determine whether such an ablation technique and the parameters used will facilitate successful completion of the catheter-based maze procedure. PMID- 21321470 TI - Mechanism of pressure-overload right ventricular hypertrophy in infant rabbits. AB - Although pressure-overload right ventricular hypertrophy is a long-term risk in some congenital heart diseases such as tetralogy of Fallot, how it develops is unclear. The aim of this study was to investigate the mechanism of development of this right ventricular heart failure.Pulmonary artery banding in 10-day-old rabbits induced pressure-overload right ventricular hypertrophy as they grew. Comparisons were made with age-matched sham controls (n = 24 per group). In weekly serial echocardiography, the right ventricular contraction and diastolic function decreased from 3 weeks after surgery (P < 0.01), and the right ventricle became hypertrophic from 4 weeks after (P < 0.05). Pressure-overload increased cardiomyocyte apoptosis from 4 weeks postoperatively (TUNEL staining and Western blotting analysis, P < 0.05); and fibrosis occurred in the right ventricular cardiomyocytes at 8 weeks after operation (Masson's trichrome stain, P < 0.01). In our model, pressure-overload to the right ventricle caused the right ventricular disorder, hypertrophy, and fibrosis. Apoptosis of right ventricular cardiomyocytes was involved in progression. We have shown for the first time the mechanism whereby pressure-overload right ventricular hypertrophy develops in an infant rabbit model. PMID- 21321471 TI - Recurrent in-stent restenosis with total occlusion remedied with drug-eluting balloon angioplasty. AB - We report a 69 year old female who presented with chest pain to the Emergency Department of the National Heart Institute Malaysia. Her history revealed that she had had 2 separate episodes of chest pain beginning in 2002, resulting in total occlusion of her mid left anterior descending artery (LAD) requiring percutaneous coronary intervention and stenting on both occasions. Cine angiogram on her current admission revealed recurrent target lesion in-stent restenosis with total occlusion of the distal LAD. Intravascular ultrasound revealed multilayered suboptimally deployed stents in the LAD. Successive drug-eluting balloon deployments resulted in sustained patency of the LAD after 1 year. PMID- 21321472 TI - Is the statistics for occupational diseases relating to chemical exposures in Japan working effectively? PMID- 21321473 TI - Assessment of the charged aerosol value in copy centers. AB - This study was performed to examine the potential health effects of copiers on their users and relevant workers by evaluating the charged aerosol current generation characteristics and indoor air quality (IAQ) in the copy center. In the 10 copy centers and one control site that were investigated in this study, the charged aerosol generation characteristics (effective levels, charged aerosol current, and charged aerosol concentration) and air pollutants (fine particles, ozone, and nitrogen oxide) were measured indoors and outdoors, and compared. In addition, a six-day continuous measurement was performed in a copy center to assess the charged aerosol generation characteristics according to the copying volume and the copier operation, and their correlation with indoor air pollutants. The indoor and outdoor charged aerosol effective levels in the 10 copy centers were 93.4% and 82.4%, respectively, and they were about 1.4 times higher than the charged aerosol effective level in the indoor control site (66.2%). The comparison of the negative and positive ion currents by space showed that the positive ion current was about 4.2 times higher indoors than outdoors, and about 2.5 times higher during the operation time than during the non operation time. The indoor charged aerosol concentration (1,512.3 ions/cm(3)) was about 4.6 times higher than the outdoor concentration (325.8 ions/cm(3)), and 19.5 times higher than the indoor charged aerosol concentration in the control site (77.3 ions/cm(3)). Based on these results, it was found that the operation of the copier was an important influential factor of the charged aerosol generation level in the copy center, and that the positive ions were dominant. In the analysis of the correlation between the indoor charged aerosol generation and the air pollutants, the effective level had high positive correlations with the charged aerosol concentration (r=0.938, p<0.01) and O(3) (r = 0.870, p<0.05). The charged aerosol concentration had positive correlations with O(3) (r=0.700) and PM(10) (r=0.479), although the correlations were not statistically significant. In conclusion, it seems that the ultra-fine particles (UFPs, d < 0.1 um <= 100 nm) may affect the human respiratory and circulatory systems because they have charged aerosol characteristics. Based on these results, it was found that the operation of the copier was an important influential factor of the charged aerosol generation level in the copy center, and that the positive ions were dominant. PMID- 21321474 TI - Evaluation of a PCR-restriction fragment length polymorphism (PCR-RFLP) assay for molecular epidemiological study of Shiga toxin-producing Escherichia coli. AB - In this study, we have evaluated our recently developed polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay for the molecular subtyping of Shiga toxin-producing Escherichia coli (STEC). A total of 200 STEC strains including O157 (n=100), O26 (n=50), O111 (n=10), and non-O26/O111/O157 (n=40) serogroups isolated during 2005-2006 in Japan, which were identified to be clonally different by pulsed-field gel electrophoresis (PFGE) were further analyzed by the PCR-RFLP assay in comparison to PFGE. Ninety-five of O157, 48 of O26, five of O111 and 19 of non-O26/O111/O157 STEC strains yielded one to three amplicons ranging from 6.0 to 15.5 kb in size by the specific primer set targeting region V which is located in the upstream of stx genes. These strains were classified into 41 (O157), 8 (O26), 4 (O111) and 17 (non-O26/O111/O157) groups based on the RFLP patterns obtained by subsequent restriction digestion, respectively. Although the discriminatory power of PCR-RFLP assay was somewhat less than that of PFGE, it is more convenient for molecular subtyping of STEC strains especially for O157, the most important serogroup implicated in human diseases, as well as to identify the outbreak-associated isolates because of its simplicity, rapidity, ease and good reproducibility. PMID- 21321475 TI - Trehalose may prevent postsurgical adhesions in a rabbit model of hysterotomy. AB - The adhesion-preventing effect of trehalose in visceral organs was evaluated in a rabbit model. All rabbits underwent a hysterotomy, during which mild abrasion and desiccation was induced on the surfaces of visceral organs. In the control group, the intestines were kept dry during hysterotomy. In the saline and trehalose groups, saline solution and 7% trehalose solution, respectively, were sprayed on the organ surfaces. Adhesion formation on organ surfaces on which abrasion and desiccation were induced declined significantly in the trehalose group compared with the other groups. In contrast, at the hysterotomy site, there was no significant difference in adhesions between groups, suggesting that trehalose prevents adhesions in organs that have developed minor inflammation by abrasion and desiccation. PMID- 21321476 TI - Mutations in the melanocortin 1 receptor, beta-defensin103 and agouti signaling protein genes, and their association with coat color phenotypes in Akita-inu dogs. AB - To identify factors that control coat color in Akita-inu dogs, we sequenced all the exons of the melanocortin 1 receptor (MC1R), beta-defensin103 (CBD103) and agouti signaling protein (ASIP) genes of dogs with four distinct coat colors, namely, brindle, sesame, red and white. Then we examined correlations among specific alleles and coat color. In the case of the MC1R gene, all white dogs were homozygous for a nonsense mutation, R306ter, while brindle, sesame, and red dogs had at least one R306 allele. In the case of the CBD103 gene, all brindle dogs were heterozygous for the G23del mutation (deletion of codon 23, encoding glycine), while all sesame and red dogs were homozygous for G23. In the case of the ASIP gene, all dogs, regardless of coat color, had at least one S82 H83 allele. A missense mutation in the ASIP gene, P87L, was identified for the first time in some Akita-inu dogs but was not associated with any specific coloration. Our results indicate that the 2 key mutations, R306ter in the MC1R gene and G23del in the CBD103 gene, are associated with the phenotypic discriminations among brindle, red/sesame, and white coats, while no mutation that might potentially be associated with the discrimination of a sesame coat from a red coat is present in the coding sequences of these three genes. PMID- 21321477 TI - Evaluation of refractive value by skiascopy in healthy Beagles. AB - We examined the refractive value in healthy Beagles by skiascopy. The mean refractive value of 54 eyes of 27 Beagles was 0.08 +/- 0.87 (mean +/- SD) diopters (D). The numbers of eyes defined as having emmetropia, myopia and hyperopia were 34, 8 and 12, respectively. Anisometropia was detected in 4 dogs. The mean refractive values in the 3-6-year-old and 8-9-year-old groups were 0.26 +/- 0.84 and -0.29 +/- 0.82 D, respectively, with a significant difference between the two groups (P<0.05). PMID- 21321478 TI - Ivermectin, 'wonder drug' from Japan: the human use perspective. AB - Discovered in the late-1970s, the pioneering drug ivermectin, a dihydro derivative of avermectin--originating solely from a single microorganism isolated at the Kitasato Institute, Tokyo, Japan from Japanese soil--has had an immeasurably beneficial impact in improving the lives and welfare of billions of people throughout the world. Originally introduced as a veterinary drug, it kills a wide range of internal and external parasites in commercial livestock and companion animals. It was quickly discovered to be ideal in combating two of the world's most devastating and disfiguring diseases which have plagued the world's poor throughout the tropics for centuries. It is now being used free-of-charge as the sole tool in campaigns to eliminate both diseases globally. It has also been used to successfully overcome several other human diseases and new uses for it are continually being found. This paper looks in depth at the events surrounding ivermectin's passage from being a huge success in Animal Health into its widespread use in humans, a development which has led many to describe it as a "wonder" drug. PMID- 21321480 TI - The vaccine renaissance. PMID- 21321479 TI - Structure-based development of specific inhibitors for individual cathepsins and their medical applications. AB - Specific inhibitors for individual cathepsins have been developed based on their tertiary structures of X-ray crystallography. Cathepsin B-specific inhibitors, CA 074 and CA-030, and cathepsin L specific inhibitors, CLIK-148 and CLIK-195, were designed as the epoxysuccinate derivatives. Cathepsin S inhibitor, CLIK-060, and cathepsin K inhibitor, CLIK-166, were synthesized. These inhibitors can use in vitro and also in vivo, and show no toxicity for experimental animals by the amounts used as the cathepsin inhibitor. Various cathepsins are used in the processing of antigenic proteins. The CLIK-060 treatment to the autoimmune disease, Sjogren model mice, led to strongly suppress the expression of the pathological symptoms. Cathepsins L or K participates to the degradation of bone collagen. The CLIK-148 protects osteoporosis in animals and also protects the bone metastasis of cancer cells. Cathepsin L also enhances insulin-induced glucose uptake into 3T3-L1 adipocytes, suggesting cathepsin L plays the roles in adipogenesis and glucose tolerance in type 2 diabetes. PMID- 21321481 TI - Glycan mediated immune responses to tumor cells. AB - Preclinical animal studies convincingly demonstrate that tumor immunity to self antigens can be actively induced and can translate into effective anti-tumor responses. Among the most challenging of clinical targets for cancer immunotherapy is Tumor Associated Carbohydrate Antigens (TACA). The molecular characterization of TACA suggest that these glycans are both altered and self antigens. A new appreciation of the interaction of glycans with immune effector cells that will benefit immunotherapy strategies is emerging as more information on the nature of molecular interactions of glycan recognition molecules is obtained. Carbohydrate recognition affects more or less every aspect of the innate and adaptive immune response and their role in immunotherapy of cancer should be considered beyond the existing paradigm of traditional TACA based vaccines. PMID- 21321482 TI - Novel therapies for treatment of multi-drug resistant Acinetobacter baumannii skin infections. AB - The Gram-negative coccobacillus Acinetobacter baumannii (Ab) has become an increasingly prevalent cause of hospital-acquired infections during the last two decades primarily resulting in pneumonia and complicated infections, including wound infections in troops injured in Afghanistan and Iraq. Moreover, the majority of clinical Ab isolates display high-level resistance to commonly utilized antimicrobial drugs, which severely compromises our capacity to care for patients with Ab disease. Thus, radically new approaches are urgently needed. This review focuses on novel therapies that can challenge the evolving ability of Ab to develop resistance and cause disease. PMID- 21321483 TI - beta-catenin and Gli1 are prognostic markers in glioblastoma. AB - Glioblastomas (GBMs), the most common primary malignancies of the central nervous system, are highly aggressive and heterogeneous, and remain a dramatic therapeutic challenge. Markers mirroring the complex molecular profile of GBMs that are predictive of patient outcomes are needed to define novel multi-targeted treatment strategies. Resistance to current GBM therapies is partly due to a subpopulation of stem-like and other self-renewing cells (hereafter called glioma stem-like cancer cells, GSCC), which are therefore of key interest as therapeutic entry points. Wnt and Hedgehog are among the main pathways involved in GSCC renewal. beta-catenin and Gli1 are markers of Wnt and Hedgehog activation respectively and both pathways are known to be altered in gliomas. To date, there are no investigations of Gli1 protein expression in GBM tissue, and recently a high expression of beta-catenin has been found to have a poor prognostic impact in GBM patients in a study. We have therefore quantified the positivity for beta catenin, Gli1, as well as Ki-67, p53, and EGFR proteins on immunohistochemically stained GBM sections from 106 patients in an investigation for potential predictive biomarkers. Correlation between these markers and survival was evaluated by pair-wise Pearson correlation coefficient and by bi-dimensional hierarchical clustering, followed by survival estimations using linear regression models and classification trees. We demonstrated that both beta-catenin and, for the first time, Gli1 proteins are highly predictive markers of short survival, being found in 75 and 90% of the highly predictive trees, respectively, whereas Ki-67, p53 and EGFR were under 30% and thus, not considered as predictive. Our results indicate a role of beta-catenin and Gli1 in GBM malignant behaviour, and suggest that inhibiting members of Wnt and Hedgehog pathways could be a valuable therapeutic strategy for GBM patients. PMID- 21321484 TI - Folate receptor alpha: a storied past and promising future in immunotherapy. AB - Folate receptor alpha (FR alpha) is a membrane-bound transport protein with several features which make it an attractive target for cancer immunotherapy. FR alpha is largely shielded from the immune system in normal tissue but exposed while expressed on a variety of malignancies; it is functionally active in cancer pathogenesis; and it is immunogenic. A variety of different immunotherapeutic methods targeting FR alpha are being explored to treat cancer. Passive immunotherapy includes monoclonal antibodies, antibodies modified to deliver treatments, and modified T cell therapy. Active immunotherapy has focused on using FR alpha to increase the immunogenicity of cancer or to generate active FR alpha-directed immunity through a range of vaccination techniques. We will review the rationale behind targeting immunotherapy to FR alpha and cover the various techniques designed to do this. Folate receptor alpha (FRalpha) is a unique tumor associated antigen (TAA) with many characteristics that make it an attractive target for immunotherapy in cancer. Many different immunotherapeutic modalities utilizing FRalpha are being explored to treat cancer. The research is in various stages: some are just beyond conception, others have been tried and abandoned, and others still are progressing through human clinical trials. This review will cover immunotherapeutic methods, both active and passive, that target FRalpha. PMID- 21321485 TI - Cross-protective immunity against influenza virus infections induced by intranasal vaccination together with a TLR3-mucosal adjuvant. AB - A new pandemic of influenza virus could result from the emergence of an unpredictable viral strain in an unexpected fashion. Thus, developing methods to protect the population from the spread of a new influenza virus is an urgent and important public health concern. Although vaccines can induce protective and prophylactic immune responses, the immunity induced by the current parenteral inactivated vaccine preparation is less effective in preventing heterologous virus infection. The induction of cross-protective mucosal immunity in the respiratory tract, the initial site of infection, is the most effective method for defending against heterologous influenza virus infection. Secretory immunoglobulin A plays a critical role in cross-protective mucosal immunity. Such cross-protective immunity can be induced by the intranasal administration of a vaccine together with an appropriate adjuvant that can mimic natural influenza virus infection. In this review, we describe the development of mucosal vaccines against influenza viruses and discuss their advantages. In addition, we describe data indicating that synthetic double-stranded RNAs, agonists of Toll-like receptor 3, are effective mucosal adjuvants for intranasally administered inactivated influenza virus vaccines. PMID- 21321486 TI - Resistance of canine lymphoma cells to adenoviral infection due to reduced cell surface RGD binding integrins. AB - Recombinant adenovirus vectors (Ad) have been recognized as effective in vivo gene delivery vehicles and utilized as gene therapy agents for a number of cancers. The elucidation of viral entry mechanisms has allowed the development of recombinant vectors that exploit existing cell surface receptors to achieve entry into the cell. B lymphocytes are normally resistant to infection by adenovirus 5, likely due to the lack of the Coxsackie and Adenovirus receptor (CAR). Using reverse-transcriptase PCR and flow cytometry, the CD40 receptor has been shown to be expressed on many lymphoma cells. We exploited this finding to develop a gene therapy strategy for treatment of canine B cell lymphoma. Ad5 was targeted to cells expressing CD40 via CD40 ligand (CD40L) and was effective in infecting CD40 expressing control cells; however, both primary canine lymphoma cells and cell lines demonstrated limited evidence of transduction. Following receptor binding, adenovirus entry into cells may require interaction with alpha(v)beta(3/5) integrins; we demonstrate that canine lymphoma cells are deficient in these integrins. Reduced alpha(v)beta(3) integrin expression may render these cells incapable of internalizing Ad vectors. Thus, any viral targeting approaches for treatment of canine lymphoma must also take into account the potential lack of internalization signals. PMID- 21321488 TI - Posterior reversible encephalopathy syndrome resulting from Guillain-Barre-like syndrome secondary to West Nile virus infection. AB - A 67-year-old woman developed hypertension, drowsiness, hemianopia, ascending flaccid tetraparesis, and areflexia. Nerve conduction studies revealed a demyelinating polyneuropathy. Brain magnetic resonance imaging demonstrated hyperintense white matter lesions. IgM antibodies against West Nile virus were positive. She was treated for hypertension and with intravenous immunoglobulins and recovered completely within 2 months. To our knowledge, this is the first case in which West Nile virus infection presented as posterior reversible encephalopathy syndrome associated with Guillain-Barre-like syndrome. PMID- 21321489 TI - Hyperalgesia after volar wrist tattoo: a case of complex regional pain syndrome? AB - Hyperalgesia after a volar wrist tattoo with features consistent with complex regional pain syndrome and a brief literature review is presented. This is the first case of disseminated hyperalgesia reported from a tattoo. It could be related to the increased pain associated with wrist tattooing and the proximity to the palmar cutaneous branch of the median nerve. The response to prednisone was robust. Further cases may appear considering popularization of wrist tattoos by celebrities. PMID- 21321490 TI - Copper supplementation improves functional activities of daily living in adults with copper deficiency. AB - OBJECTIVE: Neurologic manifestations of copper deficiency in adults are increasingly recognized. We sought to determine if copper supplementation over a period of 12 months would improve functional activities of daily living (ADLs) in patients with copper deficiency. METHODS: We studied 15 consecutively diagnosed patients with copper deficiency that received 12 months of copper supplementation. Functional ADLs were evaluated by the Barthel Index (BI), administered at the time of diagnosis and repeated after 12 months of copper supplementation. RESULTS: BI scores were significantly higher after 12 months of continued supplementation when compared with initial scores [(mean +/- SD), 74 +/ 11.7 versus 83 +/- 13.2, P = 0.007, paired t-test]. A significant inverse linear correlation between the duration of symptoms before treatment and the change in the BI scores was noted (P = 0.005). CONCLUSIONS: Early initiation and sustained supplementation with copper for at least 12 months may improve functional ADLs in patients with copper deficiency. PMID- 21321492 TI - Comparison of sudomotor and sensory nerve testing in painful sensory neuropathies. AB - OBJECTIVE: To compare results of quantitative sudomotor axon reflex testing (QSART), dorsal sural, and sural sensory nerve testing in patients with painful sensory neuropathy (PSN). METHODS: Fifty-six patients with symptoms and neurologic examinations consistent with PSN who had both autonomic and nerve conduction studies were identified from 376 patients with a clinical diagnosis of painful neuropathy. Cases were clinically categorized as large-fiber or small fiber neuropathies by described criteria. The results of sural, dorsal sural, and QSART tests were then analyzed in relationship to these two clinical groups. RESULTS: Evidence of unmyelinated fiber abnormalities by QSART was noted in 85% of clinical large-fiber and 69% of clinical small-fiber groups. Dorsal sural potentials were absent in all the large-fiber group but also in 52% of clinically classified small-fiber neuropathies. When QSART and dorsal sural abnormalities were combined, the identification of abnormalities in all the cases of PSN was 89% with 75% of cases (42) showing mixed large and small fiber abnormalities, 14% unmyelinated sensory fiber abnormalities (by QSART), and 11% normal studies. CONCLUSION: This study demonstrates the value of combining both QSART and dorsal sural sensory testing in verifying the diagnosis of PSN. The majority of cases demonstrate involvement of unmyelinated C fibers as well as large/medium myelinated fibers, thereby separating mixed large- and small-fiber sensory neuropathies from those cases classified by clinical criteria solely as small fiber neuropathy. PMID- 21321491 TI - Effects of 3-4 diaminopyridine (DAP) in motor neuron diseases. AB - OBJECTIVE: To study the safety of 3-4 diaminopyridine (DAP) in patients with motor neuron diseases and to examine its efficacy in reducing muscle fatigue and weakness and in improving objective parameters of muscle function. DESIGN: Assessments of safety included a questionnaire of symptoms, clinical examination, blood testing, and electrocardiography at each visit; efficacy was assessed by subjective scores of fatigue and weakness; an Amyotrophic Lateral Sclerosis Functional Rating Scale and functional ability scores, including timed verbal scores; manual muscle testing; grip dynamometry; pulmonary function tests; timed functional tests; and electrophysiological studies. PARTICIPANTS: Thirteen subjects with amyotrophic lateral sclerosis and seven subjects with only a lower motor neuron syndrome. MAIN OUTCOMES: Assess tolerability of DAP and determine if there was symptomatic improvement of muscle fatigue. SECONDARY OUTCOME: To determine the effects of DAP on objective parameters of muscle function. RESULTS: The drug was well tolerated with only four subjects reporting tingling of lips and fingers during the active drug period. The subjective scores for fatigue and weakness showed a mild improvement after 4 weeks on DAP compared with placebo. A significant benefit of DAP was also demonstrated in the timed verbal scores. CONCLUSION: 3-4 DAP appeared to be safe and produced subjective benefit in motor neuron diseases. The drug could be added for symptomatic treatment in these diseases. Larger studies are necessary to demonstrate efficacy. PMID- 21321493 TI - Hereditary spastic paraplegia associated with axonal neuropathy: a novel mutation of SPG3A in a large family. AB - Spastic paraplegia Type 3A is an autosomal-dominant pure or uncomplicated hereditary spastic paraplegia. It is caused by mutations in SPG3A, the only gene associated with this condition. We identified a novel mutation, c.1040T>C (p. M347T), in a family with axonal neuropathy in addition to spastic paraplegia. This expands the spectrum of neurologic complications associated with SPG3A and highlights the importance of long-term follow-up and neurological surveillance in this patient population. PMID- 21321495 TI - Herpes zoster with motor involvement: discordance between the distribution of skin rash and localization of peripheral nervous system dysfunction. AB - Herpes zoster viral infection (shingles) frequently appears in the thoracic dermatomes with no detectable weakness. We describe three patients who exhibited classic symptoms of herpes zoster infection of the upper limb with various neuropathic findings, including multiple mononeuropathies, radiculopathy, and brachial plexopathy. The distribution of weakness and electrodiagnostic findings was not limited to the involved dermatomes. Furthermore, the electrodiagnostic studies in one patient show evidence of acquired demyelination; hence, the infectious process may include the axon and/or the myelin sheath of the peripheral nerves. In the upper limb, we suggest that a mismatch between the distribution of the vesicular herpetic rash and weakness, as corroborated by the clinical examination and the electrodiagnostic studies, may occur. PMID- 21321494 TI - Delayed cervicobulbar neuronopathy and myokymia after head and neck radiotherapy for nasopharyngeal carcinoma: a case report. AB - INTRODUCTION: Delayed progressive cervicobulbar palsy with secondary lingual, facial, and neck myokymia after radiation therapy to the head and neck is a known but rare event with few reported case descriptions. CASE PRESENTATION: We report a case with a video description of a young Asian woman who developed progressive dysarthria and dysphagia after approximately 1 year after radiation treatment for nasopharyngeal carcinoma. Her symptoms, clinical, and electromyographic findings are discussed and were felt to be secondary to a cervicobulbar neuronopathy secondary to the previous radiation she received. A brief literature review was performed and pathophysiological mechanisms and treatment options are discussed. CONCLUSION: Delayed progressive cervicobulbar neuronopathy with myokymia is an uncommon complication of radiotherapy for nasopharyngeal carcinoma. Clinicians should be aware of this entity to prevent misdiagnosis with other neuromuscular and nonneuromuscular diseases. PMID- 21321496 TI - Motor root conduction block in the Lewis-Sumner syndrome. AB - BACKGROUND: The Lewis-Sumner syndrome (LSS) is a rare immune-mediated peripheral nerve disorder presenting with asymmetric upper limb sensory complaints and motor weakness. Asian patients with LSS have not been reported in the English literature. METHODS: Three Asian patients with features of LSS were prospectively studied. RESULTS: Our patients tended to older, female, and have involvement of the upper limbs exclusively than those in the West. They have a markedly longer disease duration before a diagnosis was made, which could also be the result of difficulty in eliciting motor root conduction block as a sign of proximal demyelination as observed in every patient. Pain is a universal feature as is sensory nerve conduction abnormality. None responded to immunotherapy, but disease stabilization was observed over the chronic course. CONCLUSIONS: Although rare, these unique observations in Asian patients with LSS differ from those reported in Western literature. The presence of motor root conduction block demonstrated for the first time is instrumental in establishing a diagnosis. PMID- 21321497 TI - Rituximab in the treatment of MuSK antibody-positive myasthenia gravis. PMID- 21321500 TI - Clavicle Hook Plate for Neer Type II Lateral Clavicle Fractures. PMID- 21321502 TI - Posterolateral transfibular approach to tibial plateau fractures. PMID- 21321505 TI - A simple solution for wound coverage by skin stretching. AB - Viscoelastic properties of skin, ie, creep and stress relaxation, allow it to stretch beyond its normal state within a short period of time. Presented here is a technique of "wound coverage by skin stretching" that uses this principle. Kirschner wires were passed through the skin edges on either side of the wound margins. Dynamic traction was applied with traction bands improvised by the surgeon from surgical glove wrist rings. We used this method in eight patients to close 10 wounds that were not feasible to close with direct methods. We have found that this simple, economic, and effective method provides rapid functional wound closure when bone and other structures are exposed. It does not require specialized training or devices. Careful attention to the described surgical technique gives good results and few complications. PMID- 21321507 TI - Bone transport for postinfectious segmental tibial bone defects with a combined ilizarov/taylor spatial frame technique. AB - OBJECTIVE: To assess and compare the results of trifocal (two-level bone lengthening with compression at the nonunion site) and bifocal (one-level bone lengthening with compression at the nonunion site) bone transport using the Taylor Spatial Frame (TSF; Smith and Nephew, Inc, Memphis, TN) for postinfectious segmental tibial bone defects. DESIGN: Retrospective study of 12 patients with atrophic tibial nonunions. These patients were treated with resection of the nonunion followed by bone transport using the TSF for the segmental tibial bone defects. All patients were treated by the same surgeon (F.S.). SETTING: Level I trauma center. PATIENTS/PARTICIPANTS: Twelve consecutive patients treated for postinfectious segmental tibial bone defects between November 2004 and September 2007. INTERVENTION: All patients were treated using the TSF for a trifocal or bifocal technique of bone transport along with associated soft tissue reconstructive surgeries. All patients were additionally treated with 45 days of culture-specific antibiotics. OUTCOME MEASUREMENT: All patients were evaluated by the guidelines of the Association for the Study of the Method of Ilizarov. RESULTS AND CONCLUSION: All patients achieved complete union and eradication of infection. The results were evaluated according to Association for the Study of the Method of Ilizarov criteria: 83% were excellent and 17% were good in terms of bony outcomes; functional results were excellent in 50%, good in 42%, and fair in 8%. Combined Ilizarov/TSF trifocal and bifocal techniques for the treatment of segmental tibial bone defects achieve union without malalignment of the mechanical axis. PMID- 21321506 TI - Fasciotomy rates in operations enduring freedom and iraqi freedom: association with injury severity and tourniquet use. AB - OBJECTIVE: To compare fasciotomy rates and Injury Severity Scores (ISSs) before and after tourniquets were fielded for combat casualties in March 2005. METHODS: A military trauma registry was used to identify 4332 casualties with limb injury between 2003 and 2006. Descriptive statistics and regression analysis were used to compare changes in ISSs, limb Abbreviated Injury Scale (AIS) scores, and fasciotomy rates. An item of specific interest was whether changes in fasciotomy rates occurred before and after March 2005, when tourniquets were fielded. Therefore, this time point served as a specific comparator in the statistical analyses. RESULTS: Among the 4332 limb casualties, 669 (15%) underwent fasciotomy. The ISS doubled (100% increase) during the study. Limb AIS increased 35%. The increase in limb AIS constituted most of the increase in ISS. Monthly fasciotomy rates increased 500% (5% to 30%) during the study. When controlling injury severity (both AIS and ISS), fasciotomy rates tripled (200% increase); but when comparing fasciotomy before and after tourniquet fielding by AIS and ISS, rates only doubled (100% increase). On logistic regression for predicting fasciotomy, the model was unable to determine a good fit for the data because the variables were not significant except weakly for injury severity. CONCLUSIONS: During the period of the study, fasciotomy rates increased as a result of a combination of factors: increasing injury severity, increasing use of tourniquets, and increased awareness of the need to perform prophylactic fasciotomy. Further research should be aimed at determining what the optimum rate of fasciotomy is in such an environment. PMID- 21321508 TI - Late dynamization by reduced fixation stiffness enhances fracture healing in a rat femoral osteotomy model. AB - OBJECTIVES: This study evaluated the effect of late dynamization on callus stiffness and size in a rat diaphyseal femoral osteotomy model. It was hypothesized that late dynamization, after bony bridging, would enhance healing. METHODS: The external unilateral fixator was dynamized by removal of the inner fixator bar at either 3 weeks (D3 group) or 4 weeks (D4 group) postoperation. After 5 weeks, the rats were euthanized and healing was evaluated by biomechanical and densitometric methods. Published data of control groups, constant rigid (R group), and flexible fixation (F group) were included for comparison. RESULTS: Enhanced healing was observed in both the 3- and 4-week dynamized groups compared with the constant flexible and constant rigid fixation. Late dynamization after both 3 and 4 weeks postoperation led to a stiffer callus (percent flexural rigidity relative to the intact side and elastic modulus) with a smaller callus bone volume compared with the F group. Both late dynamized groups (D3 and D4) had a similar flexural rigidity and bone mineral density as that of the R group. However, the D4 group had a significantly greater elastic modulus and significantly smaller callus bone volume compared with the R group suggesting increased remodeling occurred in the D4 group indicative of more advanced healing. CONCLUSIONS: Late dynamization enhanced fracture healing in this animal model compared with a constant rigid or constant flexible fixation. Although results of the small animal study cannot directly be transferred to humans, these results indicate that once bony bridging has occurred, dynamization may accelerate bone remodeling processes. PMID- 21321510 TI - Management of severe open ankle-foot trauma by a simple external fixation technique: an alternative during war and in resource-poor and low-technology environments. AB - Severe open foot and ankle injuries are still a challenge for the orthopaedic surgeon. Their treatment is even more difficult in third world countries and in war settings where high-energy trauma with severe soft tissue damage is more frequent. Lack of equipment, poor resources and hygiene, and different cultural systems make most of the standard proposed treatments difficult to apply. The authors describe an inexpensive, rapid, minimally invasive, and easy-to-apply external fixation technique for the treatment of severe open ankle-foot fractures. With the main goal of soft tissue management rather than definitive treatment of any bony injuries, this technique was developed over time during many consecutive missions in Sierra Leone and Afghanistan as an alternative to more appropriate treatments with surprisingly satisfactory short- and long-term results. PMID- 21321512 TI - Potential risk factors for developing heterotopic ossification in patients with severe traumatic brain injury. AB - BACKGROUND: Heterotopic ossification (HO) is a frequent complication after traumatic brain injury (TBI). The current preliminary study is intended to provide additional data on the potential roles that brain injury severity, concomitant orthopaedic trauma, and specific intensive care complicating events may play in the prediction of HO in patients who have sustained severe TBI. METHODS: A prospective cohort study in patients with severe TBI. RESULTS: Ninety seven of the 176 patients were eligible for follow-up; 13 patients (13%) developed 19 clinically relevant HOs at 1 or more sites. Univariate analysis indicated that patients with HO remained in coma longer (P < .001) and were ventilated during a longer period (P = .002). Autonomic dysregulation (relative risk = 6.11, 95% confidence interval: 2.53-14.76) and surgically treated extremity fractures (relative risk = 5.02, 95% confidence interval: 1.68-15.04) also showed significant associations with the development of HO. CONCLUSION: Prolonged coma duration and mechanical ventilation, coexistent surgically treated bone fractures and clinical signs of autonomic dysregulation should be given further consideration as potential risk factors for developing clinically relevant HO. Larger-scale studies are needed to develop a valid risk profile that takes into account the interrelationships between variables. PMID- 21321516 TI - Current world literature. PMID- 21321519 TI - Biomarkers in cancer research and treatment: promises and challenges. PMID- 21321520 TI - Current world literature. PMID- 21321522 TI - Current world literature. PMID- 21321524 TI - Thoracic anesthesia. PMID- 21321525 TI - Bibliography. Current world literature. Thoracic anesthesia. PMID- 21321526 TI - Evaluation of an intraperitoneal ovarian cancer syngeneic mouse model using 18F FDG MicroPET imaging. AB - OBJECTIVES: The objective of this study was to evaluate the syngeneic immunocompetent mouse model by using the micro-positron emission tomography with 2-[fluorine-18]-fluoro-2-deoxy-d-glucose (F-FDG microPET) imaging of ovarian tumor growth. METHODS: ID8 ovarian carcinoma cells derived from C57BL/6 mice were intraperitoneally injected into female C57BL/6 mice. Mice were injected with F FDG (7.4 MBq, intravenous injection), and microPET images were obtained 40 minutes later. Micro-computed tomographic images were also obtained immediately after microPET images for anatomical reference. F-FDG microPET images were acquired at baseline and at 4, 8, 10, and 11 weeks after tumor cell injection. The maximum standardized uptake value (SUVmax) in each time point was obtained from the images and compared to follow the tumor growth. RESULTS: Physiological uptake of F-FDG was intensely found in the bladder and heart and frequently in the gastrointestinal tract. Diffused uptake of F-FDG was observed in the peritoneal cavity of all tumor-bearing mice at 4 weeks, and high focal uptakes were developed in the peritoneal cavity at 8 to 11 weeks. High focal uptakes increased over time, correlating with a progressive increase in the SUVmax of F FDG. At 11 weeks, the SUVmax value was significantly increased (1.49 +/- 0.10 at 11 weeks vs 0.29 +/- 0.03 at baseline, P < 0.01). Tumors in the gut and peritoneum were confirmed by anatomical and histopathological examination. CONCLUSIONS: Our results demonstrate that the peritoneal tumor growth in the syngeneic ovarian cancer model can be detected by the F-FDG microPET imaging. PMID- 21321527 TI - Total occlusion of aortic arch in a 62-year-old man presenting with acute myocardial infarction. PMID- 21321528 TI - Challenges in optimizing a prostate carcinoma binding peptide, identified through the phage display technology. AB - The transfer of peptides identified through the phage display technology to clinical applications is difficult. Major drawbacks are the metabolic degradation and label instability. The aim of our work is the optimization of DUP-1, a peptide which was identified by phage display to specifically target human prostate carcinoma. To investigate the influence of chelate conjugation, DOTA was coupled to DUP-1 and labeling was performed with 111In. To improve serum stability cyclization of DUP-1 and targeted D-amino acid substitution were carried out. Alanine scanning was performed for identification of the binding site and based on the results peptide fragments were chemically synthesized. The properties of modified ligands were investigated in in vitro binding and competition assays. In vivo biodistribution studies were carried out in mice, carrying human prostate tumors subcutaneously. DOTA conjugation resulted in different cellular binding kinetics, rapid in vivo renal clearance and increased tumor-to-organ ratios. Cyclization and D-amino acid substitution increased the metabolic stability but led to binding affinity decrease. Fragment investigation indicated that the sequence NRAQDY might be significant for target-binding. Our results demonstrate challenges in optimizing peptides, identified through phage display libraries, and show that careful investigation of modified derivatives is necessary in order to improve their characteristics. PMID- 21321529 TI - In vitro and in vivo antioxidant activity of a water-soluble polysaccharide from Dendrobium denneanum. AB - The water-soluble crude polysaccharide (DDP) obtained from the aqueous extracts of the stem of Dendrobium denneanum through hot water extraction followed by ethanol precipitation, was found to have an average molecular weight (Mw) of about 484.7 kDa. Monosaccharide analysis revealed that DDP was composed of arabinose, xylose, mannose, glucose and galactose in a molar ratio of 1.00:2.66:8.92:34.20:10.16. The investigation of antioxidant activity both in vitro and in vivo showed that DDP is a potential antioxidant. PMID- 21321530 TI - Synthesis and anti-intestinal nematode activity of variously substituted benzonaphthyridine derivatives. AB - A series of benzonaphthyridine derivatives bearing the C=N linkage moiety were designed and synthesized. The structures of all the newly synthesized compounds were identified by elemental analysis, 1H-NMR, 13C-NMR and MS. Their anti intestinal nematode activities against Nippostrongylus brazilliensis were evaluated in vivo by an oral route in male rats. Among these compounds, at concentrations of 10 mg/kg of rat, the compound 7-chloro-2-methoxy-10-(4-(4'-(1H indol-5'-yl)methylene)aminophenyl)-amino-benzo[b][1,5] naphthyridine (4n) produced the highest activity, with 80.2% deparasitization. These compounds may find usefulness in the discovery and development of new anti-intestinal drugs. PMID- 21321531 TI - Synthesis and conformation of substituted chiral binaphthyl-azobenzene cyclic dyads with chiroptical switching capabilities. AB - Optically active binaphthyl-azobenezene cyclic dyads were synthesized to develop a photochromic switching molecule. Azobenezene moieties were cis-trans isomerized by photoirradiation. As a reflection of the structural change, the specific optical rotation and circular dichroism underwent significant shifts. Under certain conditions, the positive-negative and zero-positive (or zero-negative) signals were reversed. Optical rotation may potentially be applied in noise cancelling nondestructive photoswiches. The conformations were studied by experimental and theoretical methods. The results revealed that the helical chirality, (P) or (M), of the cis-azobenzene moiety was induced by intramolecular axial chirality. The twist direction depended on the axial chirality as well as the azobenzene linkage position to the binaphthyls, but was independent of the identity of substituted groups. 2,2'-Linked-(R)-binaphthyl was found to induce cis-(P)-azobenzene, whereas symmetrically 7,7'-linked-(R)-binaphthyl was found to induce cis-(M)-azobenzene. PMID- 21321532 TI - Blockade of IL-6 signaling exacerbates liver injury and suppresses antiapoptotic gene expression in methionine choline-deficient diet-fed db/db mice. AB - Our previous study revealed that blockade of interleukin-6 (IL-6)-STAT3 signaling ameliorated liver injury, although hepatic STAT3(-/-) or GP130(-/-) mice have been reported to develop severe liver injury, in a murine methionine choline deficient (MCD) diet-induced model of non-alcoholic steatohepatitis (NASH). In this study, to determine whether profound blockade of IL-6-STAT3 signaling may still ameliorate liver injury, we studied db/db mice, which have impaired leptin mediated STAT3 activation, using the MCD diet-induced NASH model. Male lean and db/db mice (6 weeks old) were fed either control chow or an MCD diet for 8 or 12 weeks. Half of the mice were treated with 15 mg/kg rat anti-mouse IL-6 receptor neutralizing antibody (MR16-1) intraperitoneally twice weekly, the remainder were injected with 15 mg/kg rat IgG as a control. Hepatic steatosis, injury, fibrosis, markers of lipid peroxidation/oxidant stress and antiapoptotic gene expression were evaluated. Plasma IL-6 levels were elevated in all groups of db/db mice. Although hepatic IL-6/ GP130 signaling was activated in chow-fed db/db mice, this was suppressed in MCD diet-fed db/db mice, accompanied by downregulation of hepatic IL-6 receptor and GP130 mRNA expression. MR16-1 treatment of MCD diet-fed db/db mice further repressed STAT3 activities and expression of STAT3-related antiapoptotic genes, such as Bcl-2 and Ref-1, but increased plasma-free fatty acid and hepatic markers of lipid peroxidation/oxidant stress, leading to increased liver injury, hepatocyte apoptosis and liver fibrosis. Although 'moderate' blockade of enhanced IL-6-STAT3 signaling may be beneficial in NASH, as we reported previously, these findings demonstrate that a profound defect in STAT3 activation is detrimental in terms of liver injury, hepatocyte apoptosis and liver fibrosis, indicating the hepato-protective role of IL-6 signaling in this severe NASH model. PMID- 21321533 TI - Complementary inhibition of cerebral aneurysm formation by eNOS and nNOS. AB - The rupture of cerebral aneurysm (CA) and subsequent subarachnoid hemorrhage can cause fatal results. Recent experimental findings have suggested that the mechanism of CA formation is based on chronic inflammation in arterial walls by hemodynamic force. Endothelial nitric oxide synthase (eNOS) protects arterial walls from vascular inflammation by relieving hemodynamic force through nitric oxide (NO) production. Thus, the expression and protective role of eNOS in CA formation have been investigated in this study. In this study, experimental induced rodent CA models by carotid ligation and systemic hypertension were used. The expression of eNOS was examined in rat CA models and revealed that it was decreased at the site of CA formation. Next, CA was induced in eNOS(-/-) mice to clarify the role of eNOS in CA formation. In eNOS(-/-) mice, the incidence of CA formation was similar to that found in wild-type mice. In CA walls of eNOS(-/-) mice, the expression of neuronal nitric oxide synthase (nNOS) was upregulated compared with that in wild-type mice, suggesting the compensatory effect of nNOS. Hence, eNOS(-/-) nNOS(-/-) mice were generated, underwent CA induction and confirmed that eNOS(-/-) nNOS(-/-) mice exhibited an increased incidence of CA formation accompanied by accelerated macrophage infiltration. These results suggested that the deficiency of eNOS could be compensated by nNOS upregulation in cerebral arteries and that the eNOS and nNOS complementarily had the protective role in CA formation. The results of this study will provide us with new insight about the mechanisms of CA formation and the functional redundancy between eNOS and nNOS in cerebral arteries. PMID- 21321534 TI - Interferon-gamma-induced increases in intestinal epithelial macromolecular permeability requires the Src kinase Fyn. AB - Interferon-gamma (IFNgamma) is an important immunoregulatory cytokine that can also decrease intestinal epithelial barrier function. Little is known about the intracellular signalling events immediately subsequent to IFNgamma/IFNgamma receptor interaction that mediate increases in epithelial permeability; data that could be used to ablate this effect of IFNgamma while leaving its immunostimulatory effects intact. This study assessed the potential involvement of Src family kinases in IFNgamma-induced increases in epithelial permeability using confluent filter-grown monolayers of the human colon-derived T84 epithelial cell line. Inhibition of Src kinase with the pharmacologic PP1 and use of Fyn kinase-specific siRNA significantly reduced IFNgamma-induced increases in epithelial permeability as gauged by translocation of noninvasive E. coli (HB101 strain) and flux of horseradish peroxidase (HRP) across monolayers of T84 cells. However, the drop in transepithelial resistance elicited by IFNgamma was not affected by either treatment. Immunoblotting revealed that IFNgamma activated the transcription factor STAT5 in T84 cells, and immunoprecipitation studies identified an IFNgamma-inducible interaction between STAT5b and the PI3K regulatory subunit p85alpha through formation of a complex requiring the adaptor molecule Gab2. siRNA targeting STAT5b and Gab2 reduced IFNgamma-induced increases in epithelial permeability and phosphorylation of PI3K(p85alpha). PP1 and Fyn siRNA reduced IFNgamma-induced PI3K activity (indicated by decreased phospho-Akt) and the formation of the STAT5b/PI3K(p85alpha) complex. Collectively, the results suggest the formation of a Fyn-dependent STAT5b/Gab2/PI3K complex that links IFNgamma to PI3K signalling and the regulation of macromolecular permeability in a model enteric epithelium. PMID- 21321535 TI - Kinase inhibitor Sorafenib modulates immunosuppressive cell populations in a murine liver cancer model. AB - Accumulating evidence suggests that regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSC) are elevated in cancer patients and tumor-bearing hosts, and that depletion of Tregs and MDSC may enhance the anti-tumor immunity of the host. Sorafenib, a novel multi-kinase inhibitor, is approved for the treatment of several human cancers, including advanced hepatocellular carcinoma (HCC). Sorafenib is believed to inhibit tumor growth via anti-angiogenesis, cell cycle arrest, and inducing apoptosis. However, the impact of Sorafenib on immune cell populations in tumor-bearing hosts is unclear. In this report, we show that Tregs and MDSC are increased in the spleens and bone marrows of the BALB/c mice with liver hepatoma. The increase in Tregs and MDSC was positively correlated with tumor burden. Treatment of Sorafenib not only inhibited HCC cell growth in mice but also significantly decreased the suppressive immune cell populations: Tregs and MDSC. In conclusion, our study strongly suggests that Sorafenib can enhance anti-tumor immunity via modulating immunosuppressive cell populations in the murine liver cancer model. PMID- 21321536 TI - Carnitine is necessary to maintain the phenotype and function of brown adipose tissue. AB - The juvenile visceral steatosis (JVS) mouse is a mutant strain with an inherited systemic carnitine deficiency. Mice of this strain show clinical signs attributable to impaired heat production and disturbed energy production. Brown adipose tissue (BAT) is the primary site of non-shivering thermogenesis in the presence of uncoupling protein-1 (UCP-1) in rodents and humans, especially in infants. To investigate the possible cause of impaired heat production in BAT, we studied the morphological features, carnitine concentration, and UCP-1 production of BAT in JVS mice. The effect of carnitine administration on these parameters was also examined. JVS mice aged 5 or 10 days (60 each) and age-matched control mice were used in this study, along with 10-day-old JVS mice treated subcutaneously with L-carnitine once a day between postpartum days 5 and 10. JVS mice showed lower body temperatures and lower concentrations of carnitine in BAT. Morphologically, BAT cells in JVS mice contained large lipid vacuoles and small mitochondria, similar to those present in white adipose tissue cells. In addition, UCP-1 mRNA and protein expression levels were significantly reduced in JVS as compared with control mice. Carnitine treatment resulted in significant increases in body temperature and carnitine concentrations in BAT, together with the recovery of normal morphological features. UCP-1 mRNA and protein expression levels were also significantly increased. These findings strongly suggest that carnitine is essential for maintaining the function and morphology of BAT. PMID- 21321537 TI - Phospholipase CE has a crucial role in ultraviolet B-induced neutrophil associated skin inflammation by regulating the expression of CXCL1/KC. AB - Phospholipase C (PLC) E is a phosphoinositide-specific PLC regulated by small GTPases including Ras and Rap. We previously demonstrated that PLCE has an important role in the development of phorbol ester-induced skin inflammation. In this study, we investigated the role of PLCE in ultraviolet (UV) B-induced acute inflammatory reactions in the skin. Wild-type (PLCE+/+) and PLCE gene knockout (PLCE-/-) mice were irradiated with a single dose of UVB at 1, 2.5, and 10 kJ/m2 on the dorsal area of the skin, and inflammatory reactions in the skin were histologically evaluated up to 168 h after irradiation. In PLCE+/+ mice, irradiation with 1 and 2.5 kJ/m2 UVB resulted in dose-dependent neutrophil infiltration in the epidermis at 24 and 48 h after irradiation. When mice were irradiated with 10 kJ/m2 of UVB, most mice developed skin ulcers by 48 h and these ulcers became more severe at 168 h. In PLCE-/- mice, UVB (1 or 2.5 kJ/m2) induced neutrophil infiltration was markedly suppressed compared with PLCE+/+ mice. The suppression of neutrophil infiltration in PLCE-/- mice was accompanied by attenuation of UVB-induced production of CXCL1/keratinocyte-derived chemokine (KC), a potent chemokine for neutrophils, in the whole skin. Cultured epidermal keratinocytes and dermal fibroblasts produced CXCL1/KC in a PLCE-dependent manner after UVB irradiation, and the UVB-induced upregulation of CXCL1/KC in these cells was significantly abolished by a PLC inhibitor. Furthermore, UVB-induced epidermal thickening was noticeably reduced in the skin of PLCE-/- mice. These results indicate that PLCE has a crucial role in UVB-induced acute inflammatory reactions such as neutrophil infiltration and epidermal thickening by at least in part regulating the expression of CXCL1/KC in skin cells such as keratinocytes and fibroblasts. PMID- 21321542 TI - PWV measurement influenced by distance between two recording sites. PMID- 21321538 TI - Exacerbated experimental autoimmune encephalomyelitis in mast-cell-deficient Kit W-sh/W-sh mice. AB - Mast cell (MC)-deficient c-Kit mutant Kit(W/W-v) mice are protected against experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, suggesting a detrimental role for MCs in this disease. To further investigate the role of MCs in EAE, we took advantage of a recently characterized model of MC deficiency, Kit(W-sh/W-sh). Surprisingly, we observed that myelin oligodendrocyte glycoprotein (MOG)(35-55)-induced chronic EAE was exacerbated in Kit(W-sh/W-sh) compared with Kit(+/+) mice. Kit(W-sh/W-sh) mice showed more inflammatory foci in the central nervous system (CNS) and increased T-cell response against myelin. To understand whether the discrepant results obtained in Kit(W-sh/W-sh) and in Kit(W/W-v) mice were because of the different immunization protocols, we induced EAE in these two strains with varying doses of MOG(35-55) and adjuvants. Although Kit(W-sh/W-sh) mice exhibited exacerbated EAE under all immunization protocols, Kit(W/W-v) mice were protected from EAE only when immunized with high, but not low, doses of antigen and adjuvants. Kit(W-sh/W-sh) mice reconstituted systemically, but not in the CNS, with bone marrow-derived MCs still developed exacerbated EAE, indicating that protection from disease could be exerted by MCs mainly in the CNS, and/or by other cells possibly dysregulated in Kit(W-sh/W-sh) mice. In summary, these data suggest to reconsider MC contribution to EAE, taking into account the variables of using different experimental models and immunization protocols. PMID- 21321543 TI - Is isolated systolic nondipping pattern related to prevalent subclinical organ damage? PMID- 21321544 TI - Arterial stiffness, vascular aging, and intracranial large artery disease. PMID- 21321546 TI - Talking science. PMID- 21321548 TI - Structural biology: One domain, multiple conformations. PMID- 21321549 TI - Carbohydrate dynamics: Antibody glycans wiggle and jiggle. PMID- 21321550 TI - Enzymology: Radical break-up, blissful make-up. PMID- 21321551 TI - Molecular recognition: O-GlcNAc transfer: size matters. PMID- 21321552 TI - Chemical contrast for imaging living systems: molecular vibrations drive CARS microscopy. AB - Cellular biomolecules contain unique molecular vibrations that can be visualized by coherent anti-Stokes Raman scattering (CARS) microscopy without the need for labels. Here we review the application of CARS microscopy for label-free imaging of cells and tissues using the natural vibrational contrast that arises from biomolecules like lipids as well as for imaging of exogenously added probes or drugs. High-resolution CARS microscopy combined with multimodal imaging has allowed for dynamic monitoring of cellular processes such as lipid metabolism and storage, the movement of organelles, adipogenesis and host-pathogen interactions and can also be used to track molecules within cells and tissues. The CARS imaging modality provides a unique tool for biological chemists to elucidate the state of a cellular environment without perturbing it and to perceive the functional effects of added molecules. PMID- 21321555 TI - World Kidney Day 2011: protect your kidneys, save your heart. PMID- 21321557 TI - Candidate biomarkers for erythropoietin response in end-stage renal disease. AB - Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) is important clinically and economically. Escalation of dose may produce harm. Post hoc analyses of clinical trials showed that responsiveness could be predicted by hemoglobin response to a fixed dose escalation. This maneuver requires weeks to months. The study by Merchant et al. offers promise that peptidomic analyses of patient sera and mass spectrometry can identify biomarkers of both responsiveness and resistance to ESAs. PMID- 21321558 TI - Prevention of vascular calcification: is pyrophosphate therapy a solution? AB - Pyrophosphate, a ubiquitous small-molecule inhibitor of mineralization abundantly present in the extracellular environment, binds to calcium and mineral surfaces to inhibit crystal growth. O'Neill and colleagues show in uremic rats that systemic administration of pyrophosphate prevents or reduces uremia-related vascular calcification, without overt negative consequences for bone and without calcium pyrophosphate deposition disease. These findings prompt further research into the potential of pyrophosphate as treatment for vascular calcification in chronic kidney disease patients. PMID- 21321559 TI - Incidence of ESRD in India. PMID- 21321560 TI - Acute kidney injury due to crystalluria following acute valacyclovir overdose. PMID- 21321561 TI - Pharmacological strategies for lowering LDL cholesterol: statins and beyond. AB - A continuous, graded relationship exists between LDL cholesterol (LDL-C) levels and risk of cardiovascular disease (CVD). This finding has been confirmed at progressively lower levels of LDL-C by results from clinical trials of therapies, particularly high-potency statins, which provide increasingly greater reductions in LDL-C levels. On the basis of this clinical trial evidence, progressively lower LDL-C goals for increasing numbers of patients, stratified by absolute CVD risk, have been recommended in guidelines for cholesterol management and CVD prevention. Some notable exceptions have been made, however, such as patients with end-stage renal disease or heart failure. To achieve low LDL-C goals, statins are first-line pharmacological therapy and can be combined with other agents to provide additional reductions in LDL-C levels as well as improvements in other lipoprotein fractions. Investigational agents that reduce LDL-C levels by other mechanisms are under development and could provide additional therapeutic strategies to achieve optimal LDL-C levels. These agents could be particularly appropriate for patients with severely elevated LDL-C levels, such as those with genetic dyslipidemia, for whom maximal drug therapy is insufficient to reduce LDL-C concentrations to recommended levels. PMID- 21321563 TI - Synaptic modulators Nrxn1 and Nrxn3 are disregulated in a Disc1 mouse model of schizophrenia. PMID- 21321564 TI - High risk of lifetime history of suicide attempts among CYP2D6 ultrarapid metabolizers with eating disorders. PMID- 21321562 TI - Utility of genetic determinants of lipids and cardiovascular events in assessing risk. AB - The prevention of coronary heart disease (CHD) is a major public-health goal, but disease architecture is such that a larger proportion of clinical events occur among the average majority than among the high-risk minority--the prevention paradox. Genetic findings over the past few years have resulted in the reopening of the old debate on whether an individualized or a population-based approach to prevention is preferable. Genetic testing is an attractive tool for CHD risk prediction because it is a low-cost, high-fidelity technology with multiplex capability. Moreover, by contrast with nongenetic markers, genotype is invariant and determined from conception, which eliminates biological variability and makes prediction from early life possible. Mindful of the prevention paradox, this Review examines the potential applications and challenges of using genetic information for predicting CHD, focusing on lipid risk factors and drawing on experience in the evaluation of nongenetic risk factors as screening tests for CHD. Many of the issues we discuss hold true for any late-onset common disease with modifiable risk factors and proven preventative strategies. PMID- 21321565 TI - New structural brain imaging endophenotype in bipolar disorder. AB - Neuroimaging studies suggest anterior-limbic structural brain abnormalities in patients with bipolar disorder (BD), but few studies have shown these abnormalities in unaffected but genetically liable family members. In this study, we report morphometric correlates of genetic risk for BD using voxel-based morphometry. In 35 BD type I (BD-I) patients, 20 unaffected first-degree relatives (UAR) of BD patients and 40 healthy control subjects underwent 3 T magnetic resonance scanner imaging. Preprocessing of images used DARTEL (diffeomorphic anatomical registration through exponentiated lie algebra) for voxel-based morphometry in SPM8 (Wellcome Department of Imaging Neuroscience, London, UK). The whole-brain analysis revealed that the gray matter (GM) volumes of the left anterior insula and right inferior frontal gyrus showed a significant main effect of diagnosis. Multiple comparison analysis showed that the BD-I patients and the UAR subjects had smaller left anterior insular GM volumes compared with the healthy subjects, the BD-I patients had smaller right inferior frontal gyrus compared with the healthy subjects. For white matter (WM) volumes, there was a significant main effect of diagnosis for medial frontal gyrus. The UAR subjects had smaller right medial frontal WM volumes compared with the healthy subjects. These findings suggest that morphometric brain abnormalities of the anterior-limbic neural substrate are associated with family history of BD, which may give insight into the pathophysiology of BD, and be a potential candidate as a morphological endophenotype of BD. PMID- 21321566 TI - Implementing prognostic and predictive biomarkers in CRC clinical trials. AB - Over the past two decades, several protein and genomic markers have refined the prognostic information of colorectal cancer (CRC) and helped to predict which patient group may benefit most from systemic treatment or targeted therapies. Of all these markers, KRAS represents the first biomarker integrated into clinical practice for CRC. Microarray-based gene-expression profiling has been used to identify prognostic signatures and to a lesser degree predictive signatures in CRC; however, common challenges with these types of studies are clinical study design, reproducibility, interpretation and reporting of the results. We focus on the clinical application of a range of published prognostic and predictive protein and genomic markers in CRC and discuss the different challenges associated with microarray-based gene-expression profiling. While none of these genomic signatures is currently in routine clinical use in CRC, novel adaptive clinical trial designs that incorporate putative genomic prognostic/predictive markers in prospective randomized trials, will enable a clinical validation of these markers and may facilitate the implementation of these biomarkers into routine medical practice. PMID- 21321567 TI - A premenopausal woman with virilization secondary to an ovarian Leydig cell tumor. AB - BACKGROUND: A 33-year-old woman presented to an endocrinology clinic with a 5 year history of secondary amenorrhea. 2 years before presentation, she had noticed progressively worsening signs of virilization. INVESTIGATIONS: Measurement of levels of serum free and total testosterone, androstenedione, dehydroepiandrosterone sulfate and gonadotropins; transvaginal ultrasonography, abdominal and pelvic MRI and (18)F-fluorodeoxyglucose PET imaging. DIAGNOSIS: Virilization secondary to an ovarian Leydig cell tumor. MANAGEMENT: The patient underwent a left salpingo-oophorectomy that confirmed the diagnosis of a unilateral Leydig cell tumor. Complete normalization of androgens and gonadotropin levels was achieved after surgery. PMID- 21321568 TI - Challenges of conducting a trial of uric-acid-lowering therapy in CKD. AB - Observational studies have shown that asymptomatic hyperuricemia is associated with increased risks of hypertension, chronic kidney disease (CKD), end-stage renal disease, cardiovascular events, and mortality. Whether these factors represent cause, consequence or incidental associations, however, remains uncertain. Hyperuricemia could be a consequence of impaired kidney function, diuretic therapy or oxidative stress, such that elevated serum urate level represents a marker, rather than a cause, of CKD. On the other hand, small, short term, single-center studies have shown improvements in blood-pressure control and slowing of CKD progression following serum urate lowering with allopurinol. An adequately powered randomized controlled trial is required to determine whether uric-acid-lowering therapy slows the progression of CKD. This article discusses the rationale for and the feasibility of such a trial. International collaboration is required to plan and conduct a large-scale multicenter trial in order to better inform clinical practice and public health policy about the optimal management of asymptomatic hyperuricemia in patients with CKD. PMID- 21321570 TI - Laser microdissection for the assessment of the clonal relationship between chronic lymphocytic leukemia/small lymphocytic lymphoma and proliferating B cells within lymph node pseudofollicles. PMID- 21321569 TI - Escalation of daunorubicin and addition of etoposide in the ADE regimen in acute myeloid leukemia patients aged 60 years and older: Cancer and Leukemia Group B Study 9720. AB - Untreated de novo (n=421) and secondary (n=189) acute myeloid leukemia (AML) patients >=60 years received intensified chemotherapy, including daunorubicin 60 mg/m(2) and etoposide 100 mg/m(2) during days 1, 2, 3 with cytarabine 100 mg/m(2) during days 1-7, with a second induction if needed and one consolidation course with these drugs and doses for 2, 2 and 5 days, respectively. In all, 287 (47%) achieved complete remission (CR), 136 (22%) died and 187 (31%) were non responders. CR rates were 27, 44 and 52% for complex karyotypes, rare aberrations and neither (P<0.001), 52 and 37% for de novo and secondary AML (P=0.003), and 53 and 42% for age 60-69 and >=70 years (P=0.015). In multivariable analysis, CR predictors included non-complex/non-rare karyotypes (P<0.001), de novo AML (P<0.001), better performance status (PS) (P<0.001) and younger age (P=0.001). Disease-free (DFS) and overall (OS) survival medians were 6.8 (95% CI: 6.2, 7.8) and 7.2 (95% CI: 6.4, 8.6) months. In multivariable analysis, DFS was shorter for complex karyotypes (P<0.001) and increasing white blood count (WBC) (P<0.001) and age (P=0.038), and OS for complex karyotypes (P<0.001), increasing WBC (P=0.001) and age (P<0.001), poorer PS (P<0.001) and secondary AML (P=0.010). Outcomes and prognostic factors were similar to those in previous Cancer and Leukemia Group B studies. PMID- 21321571 TI - Phase I study of the anti insulin-like growth factor 1 receptor (IGF-1R) monoclonal antibody, AVE1642, as single agent and in combination with bortezomib in patients with relapsed multiple myeloma. PMID- 21321573 TI - Imaging: standardizing the use of functional MRI in prostate cancer. PMID- 21321572 TI - Novel biomarkers for overactive bladder. AB - Biomarkers constitute any objectively measurable indicator of a biological process. The classic biomarker used in the diagnosis of overactive bladder (OAB) has been detrusor overactivity, which is assessed urodynamically. In the search for a reliable, noninvasive alternative to urodynamics, interest has focused on genetic, imaging, and urinary factors. Along with other cytokines detectable in urine, prostaglandin E2 and nerve growth factor are indicators of low-grade inflammation. Although they correlate with OAB symptom severity, they have not been shown to have independent prognostic benefit. Imaging biomarkers have been investigated since the earliest days of video urodynamics. Despite extensive research on the ultrasonographic estimation of bladder wall thickness, further standardization of the technique is required before conclusions can be reached regarding diagnostic accuracy. Genetic factors contribute approximately half of the total risk for urgency incontinence. Functional polymorphisms of the cytochrome P450 IID6 gene significantly alter the metabolism of some commonly used anticholinergic drugs, but no genetic loci that influence risk of OAB have been definitively identified. The first genome-wide association studies for OAB are in progress, and should identify new susceptibility genes. Although current putative biomarkers correlate with OAB severity, much future work is required to assess their prognostic value, and establish their role in clinical practice. PMID- 21321574 TI - Dietary therapy for patients with hypocitraturic nephrolithiasis. AB - Citrate is an inhibitor of urinary stone formation. Clinical and in vitro data suggest that increasing urine citrate levels will decrease the precipitation of calcium stones. Historically, low urinary citrate has been treated with oral potassium citrate or sodium citrate supplementation, but recent studies have shown the potential of dietary interventions to raise urine citrate levels. Dietary therapy with commercial or homemade beverages is attractive to patients who would prefer nonpharmacological intervention. To date, several drinks have shown promise but no single beverage has been found to consistently raise urine citrate levels in a reproducible fashion. Further research is necessary to develop the ideal dietary therapy for hypocitraturic calcium nephrolithiasis. PMID- 21321576 TI - Suicide bombing as an unusual cause of spinal cord injury: a case series from Pakistan. AB - STUDY DESIGN: Descriptive case series. OBJECTIVES: Describe the unusual etiology and pattern of spinal cord injury due to terrorist suicide bombings in Pakistan. SETTINGS: Spinal Rehabilitation Unit, Armed Forces Institute of Rehabilitation Medicine, Rawalpindi, Pakistan. METHODS: Hundreds of suicide attacks on civil and military forces have occurred over the last 6 years in Pakistan. These have resulted in thousands of death and many more injured. Six victims of terrorist suicide bombings were admitted over the years 2006 to 2009, who had a spinal cord injury (SCI). This is the first case series of SCI, secondary to terrorist suicide blast. RESULTS: All patients were males. The mean age was 30+/-11 years. Most (five) were injured directly due to splinters from the blast. On admission to rehabilitation, all patients had thoracic complete paraplegia and their SCI was managed conservatively for their spinal injuries. Associated injuries included intestinal perforations, fracture metatarsals, humerus and brachial plexus injury. Pressure ulcer was the commonest complication (3 patients). Two patients had neurological improvement at 1-year follow-up. CONCLUSION: Suicide bombing is an effective weapon of terrorists in the modern world of today. The resulting injuries can be diverse and devastating. Spinal cord injury is an uncommon sequel of suicide bombing, which should be kept in mind while dealing with victims of suicide bombing. PMID- 21321577 TI - Neoplastic myelopathies and traumatic spinal cord lesions: an Italian comparison of functional and neurological outcomes. AB - BACKGROUND: Although neoplastic spinal cord injuries (NSCIs) constitute ~25% of all non-traumatic spinal cord lesions, patients with such pathologies are seldom, if ever, admitted to specialized centers; further, their rehabilitation typically is short because of the perception that rehabilitation prolongs hospital stays unnecessarily and is reserved only for patients with very good prognoses. STUDY DESIGN: This study is a retrospective analysis. OBJECTIVE: The objective of this study is to evaluate the neurological and functional outcomes of patients with NSCIs compared with those of patients with traumatic spinal cord injury (TSCI). METHODS: We evaluated 208 patients with TSCIs and 63 with NSCIs; using a matching cohorts procedure, 43 comparable couples were selected from each group. The measures used to assess these patients were the American Spinal Injury Association standards, the Barthel Index (BI), the Rivermead Mobility Index and the Walking Index for Spinal Cord Injury. RESULTS: In the general population, NSCI patients are older and have longer lesion-to-admission times and more incomplete lesions than TSCI patients. Therefore, the functional status at admission and outcomes differed between the groups. In the matching cohorts, TSCI patients had lower BI scores at admission than NSCI subjects. At discharge, the two groups had comparable functional outcomes. Neurological status was similar at admission and at discharge. CONCLUSIONS: Although they had slightly disparate functional levels at admission, NSCI and TSCI patients had the same outcomes at discharge. Our data suggest that in a selected cohort of NSCI patients, rehabilitation is as successful as that in TSCI subjects and allows most patients to be discharged instead of being institutionalized. PMID- 21321578 TI - Barriers to sexual activity: counselling spinal cord injured women in Malaysia. AB - STUDY DESIGN: This study is a cross-sectional, face-to-face interview. OBJECTIVES: To examine the sexual activity in a sample of Malaysian women with traumatic spinal cord injuries (SCIs), identify the physical and psychological barriers to it, and explore their experiences with sexual counseling and rehabilitation. SETTING: This study was conducted at the Spinal Rehabilitation Unit of a teaching hospital. METHODS: All women who attended scheduled check-ups, over 1 year, and who met the inclusion criteria (age above 18 years, spinal injury of traumatic aetiology, living in the community and having completed the rehabilitation) were consecutively included in a face-to-face interview using a self-constructed questionnaire. Sociodemographic and disability-related variables, barriers to sexual activity/satisfaction and experiences of sexual rehabilitation services were obtained. RESULTS: During the study period, 33/36 subjects were recruited. Although 67% indicated interest in sexual activity, only 24% was sexually active. The frequency of sexual activity declined after the injury, from 4.6 times per month to 1.5 times per month. Feeling unattractive, unable to satisfy the partner and less confident about sexual ability were top three psychological barriers to sexual activity, and the top three physical barriers were impaired genital sensation, positioning and vaginal lubrication. In all, 50% received some sexual information during rehabilitation. Rehabilitation professionals were expected to initiate sexual counseling by 62.5% of subjects. CONCLUSION: The effect of SCIs on sexual function is tremendous. Sexual counseling services must be improved and take into account the impact of psychological factors. PMID- 21321579 TI - Lactobacillus bulgaricus OLL1181 activates the aryl hydrocarbon receptor pathway and inhibits colitis. AB - Increasing evidence suggests that the aryl hydrocarbon receptor (AhR) pathway has an important role in the regulation of inflammatory responses. Most recently, we have shown that the activation of the AhR pathway by a potent AhR agonist inhibits the development of dextran sodium sulfate (DSS)-induced colitis, a model of human ulcerative colitis, by the induction of prostaglandin E2 (PGE2) in the large intestine. Because several strains of probiotic lactic acid bacteria have been reported to inhibit DSS-induced colitis by unidentified mechanisms, we hypothesized that particular strains of lactic acid bacterium might have the potential to activate the AhR pathway, thereby inhibiting DSS-induced colitis. This study investigated whether there are specific lactic acid bacterial strains that can activate the AhR pathway, and if so, whether this AhR-activating potential is associated with suppression of DSS-induced colitis. By using AhR signaling reporter cells, we found that Lactobacillus bulgaricus OLL1181 had the potential to activate the AhR pathway. OLL1181 also induced the mRNA expression of cytochrome P450 family 1A1 (CYP1A1), a target gene of the AhR pathway, in human colon cells, which was inhibited by the addition of an AhR antagonist, alpha-naphthoflavon (alphaNF). In addition, mice treated orally with OLL1181 showed an increase in CYP1A1 mRNA expression in the large intestine and amelioration of DSS-induced colitis. Thus, OLL1181 can induce activation of the intestinal AhR pathway and inhibit DSS-induced colitis in mice. This strain of lactic acid bacterium has therefore the potential to activate the AhR pathway, which may be able to suppress colitis. PMID- 21321580 TI - Gp91(phox) contributes to the development of experimental inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) is related to dysfunction of intestinal immunity. Neutrophils have an important role in innate immunity via the oxidative burst, using the p47phox- and gp91(phox)-containing NAD(P)H oxidase known as Nox2. In dextran sulphate sodium (DSS)-induced colitis, no significant difference in inflammation between p47(phox-/-) and wild-type (WT) mice was reported, but there was improved endothelium-dependent arteriolar dilation in gp91(phox-/-) mice, compared with that in WT mice. Gp91(phox) and p47 (phox) are not only essential components of phagocyte Nox2, but also have roles in other enzymes. Thus the differences in response of their respective gene knockout mice to DSS challenge are not completely unexpected, but need further investigation. The clinicopathological changes and immunological responses to DSS challenge have not been fully described in gp91(phox-/-) mice. Thus we treated WT and gp91(phox-/-) mice with 2.5% DSS for 7 days. The gp91(phox-/-) mice developed less severe colitis than WT mice following DSS treatment, reflected by a smaller body weight loss, less rectal bleeding and fewer histopathological changes. Less colonic myeloperoxidase was observed in gp91(phox-/-), compared with WT mice, following DSS challenge, correlating with interleukin (IL)-6 production. IL-10 was upregulated in both gp91(phox-/-) and WT mice, but was significantly higher in the latter, following 7 days DSS challenge. These results suggest that gp91(phox /-) mice are less susceptible to acute DSS-induced colitis, possibly because of a reduced oxidative burst in the intestine and, consequently, less tissue damage. PMID- 21321581 TI - Chromatin remodeling resets the immune system to protect against autoimmune diabetes in mice. AB - Epigenetic alteration of the genome has been shown to provide palliative effects in mouse models of certain human autoimmune diseases. We have investigated whether chromatin remodeling could provide protection against autoimmune diabetes in NOD mice. Treatment of female mice during the transition from prediabetic to diabetic stage (18-24 weeks of age) with the well-characterized histone deacetylase inhibitor, trichostatin A effectively reduced the incidence of diabetes. However, similar treatment of overtly diabetic mice during the same time period failed to reverse the disease. Protection against diabetes was accompanied by histone hyperacetylation in pancreas and spleen, enhanced frequency of CD4(+) CD62L(+) cells in the spleen, reduction in cellular infiltration of islets, restoration of normoglycemia and glucose-induced insulin release by beta cells. Activation of splenic T lymphocytes derived from protected mice in vitro with pharmacological agents that bypass the antigen receptor or immobilized anti-CD3 antibody resulted in enhanced expression of Ifng mRNA and protein without altering the expression of Il4, Il17, Il18, Inos and Tnfa genes nor the secretion of IL-2, IL-4, IL-17 and TNF-alpha proteins. Consistently, expression of the transcription factor involved in Ifng transcription, Tbet/Tbx21 but not Gata3 and Rorgt, respectively, required for the transcription of Il4 and Il17, was upregulated in activated splenocytes of protected mice. These results indicate that chromatin remodeling can lead to amelioration of diabetes by using multiple mechanisms including differential gene transcription. Thus, epigenetic modulation could be a novel therapeutic approach to block the transition from benign to frank diabetes. PMID- 21321582 TI - Survey of US public attitudes toward pharmacogenetic testing. AB - To assess public attitudes and interest in pharmacogenetic (PGx) testing, we conducted a random-digit-dial telephone survey of US adults, achieving a response rate of 42% (n=1139). Most respondents expressed interest in PGx testing to predict mild or serious side effects (73+/-3.29 and 85+/-2.91%, respectively), guide dosing (91%) and assist with drug selection (92%). Younger individuals (aged 18-34 years) were more likely to be interested in PGx testing to predict serious side effects (vs aged 55+ years), as well as Whites, those with a college degree, and who had experienced side effects from medications. However, most respondents (78+/-3.14%) were not likely to have a PGx test if there was a risk that their DNA sample or test result could be shared without their permission. Given differences in interest among some groups, providers should clearly discuss the purpose of testing, alternative testing options (if available) and policies to protect patient privacy and confidentiality. PMID- 21321583 TI - Genetic testing for aldehyde dehydrogenase 2 deficiency in young adults. PMID- 21321584 TI - Efforts to resolve the contradictions in early diagnosis of prostate cancer: a comparison of different algorithms of sarcosine in urine. AB - Controversial data on sarcosine as a promising biomarker for prostate cancer (PCa) detection are present. The objective was to clarify these discrepancies and reevaluate the potential value of sarcosine in PCa. Sarcosine algorithms (supernatant and sediment sarcosine/creatinine, supernatant and sediment log2 (sarcosine/alanine)) in urine samples from 71 untreated patients with PCa, 39 patients with no evidence of malignancy (NEM) and 20 healthy women and men were quantified by liquid chromatography/tandem mass spectrometry. Although any sarcosine algorithms were significantly higher in PCa patients than in NEM patients (all P<0.05), comparable sarcosine values were measured in healthy women and men. Additionally, neither biopsy Gleason score nor clinical T-stage were correlated with sarcosine algorithms (all P>0.05), and receiver operating characteristic curve analysis indicated that the diagnostic power of any of sarcosine algorithms was nonsignificantly higher than that of serum and urine PSA, but nonsignificantly lower than prostate cancer antigen 3 (PCA3) and the percent-free PSA (%fPSA). Improved diagnostic performances were observed when any of sarcosine algorithms was combined with PCA3 or %fPSA. In conclusion, the predictive power of sarcosine in PCa is modest compared with PCA3 and %fPSA. Sarcosine, which awaits more validation before it reaches the clinic, could be included into the list of candidate PCa biomarkers. PMID- 21321585 TI - Lower incidence of inguinal hernia after radical prostatectomy using open gasless endoscopic single-site surgery. AB - Inguinal hernia is one of the long-term complications requiring surgical interventions after retropubic radical prostatectomy (RRP), and its incidence has been reported to range from 12 to 21%. The number of open gasless laparoendoscopic single-site surgery, especially minimum incision endoscopic radical prostatectomy (MIES-RRP) is increasing in Japan. The incidence of post operative inguinal hernia was compared between conventional RRP and MIES-RRP. The medical records of 333 patients who underwent conventional RRP (n=214) or MIES RRP (n=119) with pelvic lymphadenectomy at our hospital were retrospectively evaluated. There were no significant differences between the two groups in age, pre-operative PSA levels, or previous major abdominal surgery (cholecystectomy, gastrectomy and colectomy), appendectomy or inguinal hernia repair. MIES-RRP was carried out with a 5-8-cm lower abdominal midline incision. Inguinal hernia developed postoperatively in 41 (19%) of the 214 men undergoing conventional RRP during mean follow-up of 58 months (range: 7-60 months). In contrast, 7 (5.9%) of the 119 men receiving MIES-RRP, developed inguinal hernia during mean follow-up of 21 months (range: 13-31 months). The hernia-free survival was significantly higher after MIES-RRP than after conventional RRP (P=0.037). Our results suggest that MIES-RRP is less associated with post-operative inguinal hernia than conventional RRP. PMID- 21321586 TI - Prostate atypia: clinical and pathological variables associated with cancer diagnosis on repeat biopsy. AB - The clinical significance of atypical glands suspicious for malignancy (atypia) on prostate biopsy is unclear. We studied a cohort of 139 patients with atypia who underwent repeat prostate biopsy. We analyzed clinical and pathological variables that may be associated with cancer on repeat biopsy. Cancer was diagnosed in 41 (29%) of patients with atypia: 26 of 41 (66%) were Gleason 6, 20% were Gleason 7 and 7% were Gleason 8 (Gleason < 6 not reported). There were no significant associations of age, race, family history, PSA, PSA density (PSAd), number of previous biopsies or time to repeat biopsy with cancer diagnosis. In multivariate regression, histological inflammation was associated with an 85% decreased probability of cancer on repeat biopsy (odds ratio; OR 0.15; 95% confidence interval; CI 0.04-0.57; P=0.04). Radical prostatectomy was performed in 14 of 41 (34%) patients with cancer; 6 (43%) were Gleason sum >=7, 3 (21%) were pT3a and 1 (7%) had lymph node metastases. In conclusion, inflammation was independently associated with a significantly decreased risk of cancer on repeat biopsy. However, some patients with initial atypia have higher-risk prostate cancer. Additional studies are needed to elucidate these associations. PMID- 21321587 TI - New directions. PMID- 21321588 TI - Challenges in infant immunity: implications for responses to infection and vaccines. PMID- 21321589 TI - Epithelial cell microRNAs in gut immunity. PMID- 21321590 TI - AIDing the pursuit of IgA diversity. PMID- 21321591 TI - Mitochondrial control of the NLRP3 inflammasome. PMID- 21321592 TI - A phagocyte dilemma... PMID- 21321594 TI - The immune system in atherosclerosis. AB - Cardiovascular disease, a leading cause of mortality worldwide, is caused mainly by atherosclerosis, a chronic inflammatory disease of blood vessels. Lesions of atherosclerosis contain macrophages, T cells and other cells of the immune response, together with cholesterol that infiltrates from the blood. Targeted deletion of genes encoding costimulatory factors and proinflammatory cytokines results in less disease in mouse models, whereas interference with regulatory immunity accelerates it. Innate as well as adaptive immune responses have been identified in atherosclerosis, with components of cholesterol-carrying low density lipoprotein triggering inflammation, T cell activation and antibody production during the course of disease. Studies are now under way to develop new therapies based on these concepts of the involvement of the immune system in atherosclerosis. PMID- 21321600 TI - Reprogramming to pluripotency: stepwise resetting of the epigenetic landscape. AB - In 2006, the "wall came down" that limited the experimental conversion of differentiated cells into the pluripotent state. In a landmark report, Shinya Yamanaka's group described that a handful of transcription factors (Oct4, Sox2, Klf4 and c-Myc) can convert a differentiated cell back to pluripotency over the course of a few weeks, thus reprograming them into induced pluripotent stem (iPS) cells. The birth of iPS cells started off a rush among researchers to increase the efficiency of the reprogramming process, to reveal the underlying mechanistic events, and allowed the generation of patient- and disease-specific human iPS cells, which have the potential to be converted into relevant specialized cell types for replacement therapies and disease modeling. This review addresses the steps involved in resetting the epigenetic landscape during reprogramming. Apparently, defined events occur during the course of the reprogramming process. Immediately, upon expression of the reprogramming factors, some cells start to divide faster and quickly begin to lose their differentiated cell characteristics with robust downregulation of somatic genes. Only a subset of cells continue to upregulate the embryonic expression program, and finally, pluripotency genes are upregulated establishing an embryonic stem cell-like transcriptome and epigenome with pluripotent capabilities. Understanding reprogramming to pluripotency will inform mechanistic studies of lineage switching, in which differentiated cells from one lineage can be directly reprogrammed into another without going through a pluripotent intermediate. PMID- 21321602 TI - Transport of receptors, receptor signaling complexes and ion channels via neuropeptide-secretory vesicles. AB - Stimulus-induced exocytosis of large dense-core vesicles (LDCVs) leads to discharge of neuropeptides and fusion of LDCV membranes with the plasma membrane. However, the contribution of LDCVs to the properties of the neuronal membrane remains largely unclear. The present study found that LDCVs were associated with multiple receptors, channels and signaling molecules, suggesting that neuronal sensitivity is modulated by an LDCV-mediated mechanism. Liquid chromatography mass spectrometry combined with immunoblotting of subcellular fractions identified 298 proteins in LDCV membranes purified from the dorsal spinal cord, including G-protein-coupled receptors, G-proteins and other signaling molecules, ion channels and trafficking-related proteins. Morphological assays showed that delta-opioid receptor 1 (DOR1), beta2 adrenergic receptor (AR), G(alphai2), voltage-gated calcium channel alpha2delta1 subunit and P2X purinoceptor 2 were localized in substance P (SP)-positive LDCVs in small-diameter dorsal root ganglion neurons, whereas beta1 AR, Wnt receptor frizzled 8 and dishevelled 1 were present in SP-negative LDCVs. Furthermore, DOR1/G(alphai2)/G(beta1gamma5)/phospholipase C beta2 complexes were associated with LDCVs. Blockade of the DOR1/G(alphai2) interaction largely abolished the LDCV localization of G(alphai2) and impaired stimulation-induced surface expression of G(alphai2). Thus, LDCVs serve as carriers of receptors, ion channels and preassembled receptor signaling complexes, enabling a rapid, activity-dependent modulation of neuronal sensitivity. PMID- 21321603 TI - Cisplatin ototoxicity involves cytokines and STAT6 signaling network. AB - We herein investigated the role of the STAT signaling cascade in the production of pro-inflammatory cytokines and cisplatin ototoxicity. A significant hearing impairment caused by cisplatin injection was observed in Balb/c (wild type, WT) and STAT4(-/-), but not in STAT6(-/-) mice. Moreover, the expression levels of the protein and mRNA of pro-inflammatory cytokines, including TNF-alpha, IL 1beta, and IL-6, were markedly increased in the serum and cochlea of WT and STAT4(-/-), but not STAT6(-/-) mice. Organotypic culture revealed that the shape of stereocilia bundles and arrays of sensory hair cell layers in the organ of Corti from STAT6(-/-) mice were intact after treatment with cisplatin, whereas those from WT and STAT4(-/-) mice were highly distorted and disarrayed after the treatment. Cisplatin induced the phosphorylation of STAT6 in HEI-OC1 auditory cells, and the knockdown of STAT6 by STAT6-specific siRNA significantly protected HEI-OC1 auditory cells from cisplatin-induced cell death and inhibited pro inflammatory cytokine production. We further demonstrated that IL-4 and IL-13 induced by cisplatin modulated the phosphorylation of STAT6 by binding with IL-4 receptor alpha and IL-13Ralpha1. These findings suggest that STAT6 signaling plays a pivotal role in cisplatin-mediated pro-inflammatory cytokine production and ototoxicity. PMID- 21321601 TI - Regulation and function of DNA methylation in plants and animals. AB - DNA methylation is an important epigenetic mark involved in diverse biological processes. In plants, DNA methylation can be established through the RNA-directed DNA methylation pathway, an RNA interference pathway for transcriptional gene silencing (TGS), which requires 24-nt small interfering RNAs. In mammals, de novo DNA methylation occurs primarily at two developmental stages: during early embryogenesis and during gametogenesis. While it is not clear whether establishment of DNA methylation patterns in mammals involves RNA interference in general, de novo DNA methylation and suppression of transposons in germ cells require 24-32-nt piwi-interacting small RNAs. DNA methylation status is dynamically regulated by DNA methylation and demethylation reactions. In plants, active DNA demethylation relies on the repressor of silencing 1 family of bifunctional DNA glycosylases, which remove the 5-methylcytosine base and then cleave the DNA backbone at the abasic site, initiating a base excision repair (BER) pathway. In animals, multiple mechanisms of active DNA demethylation have been proposed, including a deaminase- and DNA glycosylase-initiated BER pathway. New information concerning the effects of various histone modifications on the establishment and maintenance of DNA methylation has broadened our understanding of the regulation of DNA methylation. The function of DNA methylation in plants and animals is also discussed in this review. PMID- 21321604 TI - Osteoclast activity modulates B-cell development in the bone marrow. AB - B-cell development is dependent on the interactions between B-cell precursors and bone marrow stromal cells, but the role of osteoclasts (OCLs) in this process remains unknown. B lymphocytopenia is a characteristic of osteopetrosis, suggesting a modulation of B lymphopoiesis by OCL activity. To address this question, we first rescued OCL function in osteopetrotic oc/oc mice by dendritic cell transfer, leading to a restoration of both bone phenotype and B-cell development. To further explore the link between OCL activity and B lymphopoiesis, we induced osteopetrosis in normal mice by injections of zoledronic acid (ZA), an inhibitor of bone resorption. B-cell number decreased specifically in the bone marrow of ZA-treated mice. ZA did not directly affect B cell differentiation, proliferation and apoptosis, but induced a decrease in the expression of CXCL12 and IL-7 by stromal cells, associated with reduced osteoblastic engagement. Equivalent low osteoblastic engagement in oc/oc mice confirmed that it resulted from the reduced OCL activity rather than from a direct effect of ZA on osteoblasts. These dramatic alterations of the bone microenvironment were disadvantageous for B lymphopoiesis, leading to retention of B-cell progenitors outside of their bone marrow niches in the ZA-induced osteopetrotic model. Altogether, our data revealed that OCLs modulate B-cell development in the bone marrow by controlling the bone microenvironment and the fate of osteoblasts. They provide novel basis for the regulation of the retention of B cells in their niche by OCL activity. PMID- 21321605 TI - Cancer epigenetics: linking basic biology to clinical medicine. AB - Cancer evolution at all stages is driven by both epigenetic abnormalities as well as genetic alterations. Dysregulation of epigenetic control events may lead to abnormal patterns of DNA methylation and chromatin configurations, both of which are critical contributors to the pathogenesis of cancer. These epigenetic abnormalities are set and maintained by multiple protein complexes and the interplay between their individual components including DNA methylation machinery, histone modifiers, particularly, polycomb (PcG) proteins, and chromatin remodeling proteins. Recent advances in genome-wide technology have revealed that the involvement of these dysregulated epigenetic components appears to be extensive. Moreover, there is a growing connection between epigenetic abnormalities in cancer and concepts concerning stem-like cell subpopulations as a driving force for cancer. Emerging data suggest that aspects of the epigenetic landscape inherent to normal embryonic and adult stem/progenitor cells may help foster, under the stress of chronic inflammation or accumulating reactive oxygen species, evolution of malignant subpopulations. Finally, understanding molecular mechanisms involved in initiation and maintenance of epigenetic abnormalities in all types of cancer has great potential for translational purposes. This is already evident for epigenetic biomarker development, and for pharmacological targeting aimed at reversing cancer-specific epigenetic alterations. PMID- 21321606 TI - Epigenetic inheritance: uncontested? AB - "Epigenetics" is currently defined as "the inheritance of variation (-genetics) above and beyond (epi-) changes in the DNA sequence". Despite the fact that histones are believed to carry important epigenetic information, little is known about the molecular mechanisms of the inheritance of histone-based epigenetic information, including histone modifications and histone variants. Here we review recent progress and discuss potential models for the mitotic inheritance of histone modifications-based epigenetic information. PMID- 21321607 TI - Regulation of chromatin by histone modifications. AB - Chromatin is not an inert structure, but rather an instructive DNA scaffold that can respond to external cues to regulate the many uses of DNA. A principle component of chromatin that plays a key role in this regulation is the modification of histones. There is an ever-growing list of these modifications and the complexity of their action is only just beginning to be understood. However, it is clear that histone modifications play fundamental roles in most biological processes that are involved in the manipulation and expression of DNA. Here, we describe the known histone modifications, define where they are found genomically and discuss some of their functional consequences, concentrating mostly on transcription where the majority of characterisation has taken place. PMID- 21321608 TI - Nuclear organization in genome stability: SUMO connections. AB - Recent findings show that chromatin dynamics and nuclear organization are not only important for gene regulation and DNA replication, but also for the maintenance of genome stability. In yeast, nuclear pores play a role in the maintenance of genome stability by means of the evolutionarily conserved family of SUMO-targeted Ubiquitin ligases (STUbLs). The yeast Slx5/Slx8 STUbL associates with a class of DNA breaks that are shifted to nuclear pores. Functionally Slx5/Slx8 are needed for telomere maintenance by an unusual recombination mediated pathway. The mammalian STUbL RNF4 associates with Promyelocytic leukaemia (PML) nuclear bodies and regulates PML/PML-fusion protein stability in response to arsenic-induced stress. A subclass of PML bodies support telomere maintenance by the ALT pathway in telomerase-deficient tumors. Perturbation of nuclear organization through either loss of pore subunits in yeast, or PML body perturbation in man, can lead to gene amplifications, deletions, translocations or end-to-end telomere fusion events, thus implicating SUMO and STUbLs in the subnuclear organization of select repair events. PMID- 21321609 TI - A diterpenoid derivative 15-oxospiramilactone inhibits Wnt/beta-catenin signaling and colon cancer cell tumorigenesis. AB - The Wnt/beta-catenin signaling pathway is a highly conserved pathway in organism evolution and regulates many biological processes. Aberrant activation of the Wnt/beta-catenin signaling pathway is closely related to tumorigenesis. In order to identify potent small molecules to treat the over-activated Wnt signaling mediated cancer, such as colon cancer, we established a mammalian cell line-based reporter gene screening system. The screen revealed a diterpenoid derivative, 15 oxospiramilactone (NC043) that inhibits Wnt3a or LiCl-stimulated Top-flash reporter activity in HEK293T cells and growth of colon cancer cells, SW480 and Caco-2. Treatment of SW480 cells with NC043 led to decreases in the mRNA and/or protein expression of Wnt target genes Axin2, Cyclin D1 and Survivin , as well as decreases in the protein levels of Cdc25c and Cdc2. NC043 did not affect the cytosol-nuclear distribution and protein level of soluble beta-catenin, but decreased beta-catenin/TCF4 association in SW480 cells. Moreover, NC043 inhibited anchorage-independent growth and xenograft tumorigenesis of SW480 cells. Collectively these results demonstrate that NC043 is a novel small molecule that inhibits canonical Wnt signaling downstream of beta-catenin stability and may be a potential compound for treating colorectal cancer. PMID- 21321610 TI - iPS cells generated without c-Myc have active Dlk1-Dio3 region and are capable of producing full-term mice through tetraploid complementation. PMID- 21321612 TI - [Functional maxillary reconstruction with free composite fibula flap]. AB - Maxillary defects resulting from tumor resection or trauma can cause severe functional and cosmetic deformities. Maxillary reconstruction has long been a challenge for oral maxillofacial surgeons. Functional maxillary reconstruction with vascularized composite bone flap and osseointegrated implants is one of the most important improvements in head and neck reconstructive surgery. Since 1999, our research group has performed a comprehensive research on functional maxillary reconstruction with free composite fibula flap. Clinical data of the patients with maxillary reconstruction using free fibula flap were analyzed to describe the indications and principles of perioperative period of this technique. The modified free fibula flexor-hallucis longus myofascial flap was introduced, which could overcome the disadvantages of traditional free composite fibula flap. The donor site morbidity, post-operative speech outcome, mastication function, and quality of life were evaluated objectively. The biomechanical effects of stress distribution on maxilla reconstructed by free fibula composite flap were analyzed by three-dimensional finite element analysis. These studies demonstrated maxillary defects can be reconstructed successfully using free fibula flaps. This procedure also allows dental implant or conventional denture rehabilitation, which can improve the patient's appearance and oral function and enhance the overall quality of life. The fibula free flap transfer has a high success rate and low perioperative complication rate, making it an ideal choice for maxillary defect reconstruction. PMID- 21321613 TI - [Effect of oral rinse with Turkish gall on the clinical periodontal parameters and halitosis]. AB - OBJECTIVE: To assess the effect of traditional Chinese medicine, oral rinse of Turkish gall (extracts from Turkish gall) on periodontal and halitosis parameters. METHODS: This single-blinded randomized controlled trial recruited 70 patients with gingivitis or mild to moderate chronic periodontitis. All the patients received the same professional oral hygiene instruction and using toothbrush and fluoride-only paste with same brand and size dispatched by the investigator from baseline to the end. The tested group by oral rinse of Turkish gall on the base of conventional oral hygiene, and control group with conventional oral hygiene only, were assigned randomly at baseline. Then periodontal parameters including Plaque index (PlI), Bleeding index (BI), Probing depth (PD) and Staining index (SI), halitosis index including volatile sulphur compounds (VSCs) by Halimeter, organoleptic score (OS), area of tongue coating (Ta), thickness of tongue coating (Tt), were measured at baseline and two-weeks after. RESULTS: After two weeks, all the periodontal parameters except for SI were significantly improved within each group (P<0.001). As compared to those in control group, the patients in tested group only exhibited significant improvement of PlI after two-week-use of oral rinse of Turkish gall (P<0.05). Though values of OS and Tt in tested group, OS only in control group, decreased significantly (P<0.05) respectively after two weeks, there were no statistical difference on the improvement of halitosis parameters. CONCLUSION: For untreated patients with gingivitis and periodontitis, oral rinse of Turkish gall displayed significant inhibition of dental plaque, while no predominated effect on halitosis when compared to correct conventional plaque control methods. PMID- 21321614 TI - [Status of bacterial colonization in infected root canal]. AB - OBJECTIVE: To investigate the morphology,distribution and relative position of the bacteria in infected root canals with chronic apical periodontitis and make some clinical inferences. METHODS: Seven extracted roots with chronic apical periodontitis were collected. Immediately after extraction, all specimens were rinsed in sterile saline solution. The remaining tooth crowns were cut off with carborundum disks under water spray. Longitudinal grooves following the root length axis were cut along the entire root by using tapered diamond burs under water spray, and the roots were then split with a chisel into two halves. One half of the roots were decalcified, and after dehydration and embedding in paraffin, serial sections of 4 MUm were cut, parallel to the long axis of the roots. The sections were stained using the Brown & Brenn methods, which were examined with a light-transmitting microscope for the distribution of bacteria in the root canals. The other half of the roots were dehydrated, sputtered coated with gold, and then examined for the occurrence of bacteria in the root canals using a scanning electron microscope. RESULTS: Histobacteriologic observation showed that bacteria were found in all the seven specimens, which were clogged with a dense bacterial biofilm in the apical third of the main canal. Bacteria could penetrate into the dentinal tubules about 140-1 000 MUm. Scanning electron microscopy observation showed that bacteria consisting of cocci, rods and/or filaments with amorphous materials formed the typical biofilm structure in the apical third of the root canals. CONCLUSION: The findings support the view that bacteria colonizing the root canal system play an essential role in the pathogenesis of periradicular diseases. In all the seven specimens, bacteria usually formed dense aggregates on the root canal walls, penetrating the dentinal tubules in the apical third of the main canal. Dense bacteria and amorphous materials filled the inter-bacterial spaces and formed the typical biofilm structure. PMID- 21321615 TI - [Effect of supportive periodontal therapy in maintaining the long-term effect of the initial therapy]. AB - OBJECTIVE: To evaluate the influence of supportive periodontal therapy to the long-term effect after initial therapy. METHODS: The investigation was conducted as a retrospective longitudinal study over a period of at least 2 years, a total of 39 patients recruited in the study and divided into non-maintenance group (n=22) and maintenance group (n=17). Non-maintenance group were monitored for an average of 5.09 years, maintenance group were monitored for an average of 7.53 years. The changes of following variables were recorded and analyzed: the number of loss tooth, probing depth (PD), bleeding index, alveolar bone level in full mouth radiographs. RESULTS: It was observed that (1) patients without maintenance lost more teeth compared to the maintenance groups, showed no changes of PD percentage but significant decrease in bone level; (2) patients received maintenance showed significant decreases in PD, bone level keep stable during the observation compared to the non-maintenance group. CONCLUSION: Supportive periodontal therapy not only decreased the probing depth, but also prevented alveolar bone loss. Supportive periodontal therapy after initial therapy plays a crucial role in keeping periodontal health for long-term. PMID- 21321616 TI - [Detection of the parameters for early atherosclerosis in patients with metabolic syndrome and periodontitis]. AB - OBJECTIVE: To observe whether chronic periodontitis (CP) and metabolic syndrome (MS) have synergistic effect on atherosclerosis. METHODS: Fifty-nine patients with CP from dental clinic were enrolled in this study. According to the latest definition on MS, Twenty-six patients were diagnosed as MS by physicians. The periodontal status including plaque index, bleeding index, probing depth and attachment loss (AL) as well as missing teeth number were recorded by one periodentist. Intima-media thickness (IMT) and prevalence of atherosclerosis plaque of bilateral carotid common arteries and endothelial function (flow mediated dilatation, FMD) were measured by high-frequency color Doppler. Carotid IMT and FMD were chosen to reflect the early vascular change in atherosclerosis. RESULTS: AL in MS group was significantly higher than that in non-MS group [(2.91+/-1.84) vs. (1.97+/-1.74) mm, P=0.03],IMT and prevalence of atherosclerotic plaque in carotid common arteries was higher in MS group than that in non-MS group, statistically significant on left side [left: IMT (1.00+/ 0.45) vs. (0.80+/-0.26) mm, P=0.04, right: IMT (0.87+/-0.44) vs. (0.78+/-0.31) mm , P=0.23;left prevalence of atherosclerotic plaque 34.62% vs. 9.09%, P=0.02,right prevalence of atherosclerotic plaque 19.23% vs. 9.09%, P=0.26]. FMD was significantly lower in the MS group than in the control group [(7.67+/-5.06) vs. (11.82+/-7.00), P=0.02]. As general condition and CP aggravating (No/mild periodontitis plus non-MS group, Moderate/severe periodontitis plus non-MS group, No/mild periodontitis plus MS group, Moderate/severe periodontitis plus MS group), carotid IMT increasing but not significantly [left: (0.76+/-0.27) mm, (0.85+/-0.24) mm, (0.84+/-0.33) mm, (1.08+/-0.49) mm correspondingly, P=0.06; right: (0.67+/-0.18) mm, (0.89+/- 0.37) mm, (0.78+/-0.30) mm, (0.92+/-0.49) mm correspondingly, P=0.08] and FMD decreasing, almost reach the statistical significance [(13.12+/-6.57)%, (10.43 +/-7.43)%, (9.22+/-5.43)%, (6.98+/-4.89)% correspondingly, P=0.05]. Multiple linear regression showed that after adjusting factors of gender and smoking, the patient age was significant impact factor on carotid IMT [odds ratio (OR)=0.016, 95% confidence interval (CI): 0.01 to 0.02,P<0.01), after adjusting age, gender, smoking, MS (OR=-3.36, 95%CI-6.61 to 0.10,P=0.04) and severity of CP (OR=-2.67, 95%CI-4.70 to-0.62, P=0.01) were all significant impact factors on FMD. CONCLUSION: CP and MS may have synergistic effect on the progression of atherosclerosis. PMID- 21321617 TI - [Effects of bio-glass in subgingival scaling and root planing]. AB - OBJECTIVE: To evaluate the effect of locally applied bio-glass on the teeth hypersentivity and periodontal recovery after subgingival scaling and root planing. METHODS: In this double blind study, 60 patients with chronic periodontitis were included and were randomly divided into four groups of 15 patients: bio-glass powder and bio-glass paste group (Po+Pa), bio-glass powder group (Po), bio-glass paste group (Pa) and control group. Powder was applied in pockets after subgingival scaling and root planning (SRP) and paste was used as toothpaste for 6 weeks. Periodontal indices and the severity of tooth hypersensitivity were recorded. RESULTS: Obvious mitigation of tooth hypersensitivity was observed in bio-glass powder or paste applied patients within the fist three weeks after SRP. Only few patients presented teeth hypersensitivity in the 6th week after SRP. In the 6th week after SRP, bleeding index significantly decreased in bio-glass powder or paste applied patients. More pocket depth and clinical attachment level reduction was found in bio-glass powder applied patients. Application of bio-glass powder or paste improved clinical attachment level in the 3rd month after SRP. CONCLUSION: The hypersensitivity after subgingival scaling could be relieved without any treatment in 6 weeks, while the bio-glass powder and the 7% bio-glass paste could reduce the prevalence and the severity of it. Further more, bio-glass also improved the clinical outcomes of subgingival scaling via its bacteriostatic action. PMID- 21321618 TI - [Clinical evaluation of gingival composite resin restoring cervical defects in anterior teeth]. AB - OBJECTIVE: To evaluate the clinical effects of gingival composite resin used for restoring cervical defects in anterior teeth. METHODS: Eighty cervical defects of anterior teeth were involved. Firstly, they were restored with simulated restorations using only tooth colored composite resin. Then, the simulated restorations were removed and the defects were restored with simulated restorations using gingival composite resin combined with tooth colored composite resin. Visual analogue scale (VAS) was employed to survey the patient satisfaction with the esthetic results of the two methods. The defects were filled with gingival composite resin and tooth colored composite resin.Then, longitudinal clinical evaluation were made at 1-week, 6-month, 1-year and 2-year recalls respectively using modified United States Public Health Service (USPHS) criteria. RESULTS: Simulated restorations made of gingival composite resin and tooth colored composite resin obtained more satisfaction in overall impression, gingival position and tooth contour than simulated restorations simply made of tooth colored composite resin (P<0.1). In the longitudinal clinical evaluation, no significant differences among the recalls were found in color match,restoration morphology, marginal adaptation, marginal discoloration, secondary caries or pulp sensitivity (P>0.1). CONCLUSION: Using gingival composite resin in restoring cervical defects in anterior teeth achieved not only satisfactory treatment effect but also ideal esthetic results. PMID- 21321619 TI - [Recurrence and malignant transformation of intraosseous dentinogenic ghost cell tumor]. AB - OBJECTIVE: To describe the histologic and clinical findings of recurrent intraosseous dentinogenic ghost cell tumor (DGCT) and its malignant transformation. METHODS: The clinical features, treatment, pathology and prognosis of recurrent intraosseous DGCT patients from 53 cases of mixed odontogenic tumors with ghost cells and mesenchymal inductive components were retrospectively reviewed. RESULTS: Ten recurrent cases from 14 DGCT were all male and the age at diagnosis ranged from 18 to 60 years with an average of 32.4 years. The main manifestation was progressive bone bulging. Radiographically the tumor was characterized by ill-defined radiolucency. Most recurrent tumors had entrenched the surrounding tissues. Seven cases occurred in the maxilla among which 2 cases were transformed into ghost cell odontogenic carcinoma and 2 showed features of increased cell proliferation. Three cases occurred in the mandible among which 1 case showed a high proliferative activity. The initial surgery of all recurrent cases was curettage. CONCLUSION: The microscopic findings and prognosis suggested that intraosseous DGCT was locally aggressive. Multiple recurrences increased the risk of malignant transformation. Curettage alone might not be adequate for the management of DGCT. Maxillary cases with ill-defined borders, especially those showing an increased proliferative activity in biopsy or frozen section examination, should be treated more radically. PMID- 21321620 TI - [A clinicopathologic study on oncocytoma and oncocytic carcinoma of the salivary glands]. AB - OBJECTIVE: To investigate the clinicopathologic features, differential diagnosis, treatment and prognosis of oncocytoma and oncocytic carcinoma of the salivary glands. METHODS: The clinicopathologic features were studied in 23 cases of oncocytomas and 15 cases of oncocytic carcinomas, and immunohistochemical staining as well as electron microscopy were performed. RESULTS: Most oncocytomas occurred in the parotid gland (95.6%) with no recurrence. The diagnosis was made based on histopathological features. Oncocytic carcinomas were high-grade tumors, mainly occurring in the parotid gland. The diagnosis was based not only on histopathology but also on ultrastructural findings, phosphotungstic acid hematoxylin (PTAH), and immunohistochemistry. Of the 14 cases with follow-up information, 7 cases recurred. Regional or distant metastases were found in 7 and 4 cases, respectively. CONCLUSION: Oncocytoma is a rare tumor with well prognosis, whereas oncocytic carcinoma of the salivary glands is a high-grade tumor, with frequent local recurrence, regional or distant metastasis, the diagnosis of which should be based on a combination of clinical and histopathological features. Immunohistochemistry for mitochondria is considered as a practical and helpful adjuvant for diagnosis. PMID- 21321621 TI - [Effect of light power density on the anti-aging property of light-cure composite resin]. AB - OBJECTIVE: The purpose of this study was to investigate the effect of light power density on anti-aging property of composite resins. METHODS: Three light curing modes with different power density (1. Mode A: low power density, 500 mW/cm(2) for 22 s; 2. Mode B: high power density, 1 100 mW/cm(2) for 10 s; 3. Mode C: gradually enhanced power density, 0~650 mW/cm(2) for 5 s + 1 100 mW/cm(2) for 8.5 s) were used. The total energy density of these modes was all 11 J/cm(2). Composite resin specimens were cured with three light curing modes respectively and divided into 4 groups randomly (n=15). Three groups were reserved in absolute ethanol for 24 h, 7 d and 30 d respectively for aging and one group was stored in water for 24 h as control. Vicker hardness (VHN) was measured with microhardness tester. Volumetric shrinkage was measured with Acuvol (n=7). RESULTS: The hardness of three light curing modes was: Mode A 44.26+/-6.16, Mode B 42.31+/ 2.33 and Mode C 45.60+/-2.76. After aging in ethanol for 24 h, the hardness of all composites specimen decreased (P<0.05). Samples cured by Mode A (31.83+/ 2.90) and Mode C (32.13+/-2.77) showed significantly lower hardness than Mode B (36.14+/-2.65) (P<0.05). After aging in ethanol for 7 d, the hardness of composites continuously decreased (P<0.05) and was: Mode A 28.36+/-2.35, Mode B 27.80+/-1.19 and Mode C 28.20+/-0.97. There was no significant difference among three curing modes (P>0.05). The hardness of samples stored in ethanol for 30 d was no longer decreased and was: Mode A 28.53+/-0.86, Mode B 28.55+/-1.53 and Mode C 29.08+/-1.60. There was no significant difference between composite specimen stored for 7 d and 30 d (P>0.05). The polymerization shrinkage of composite resin was: Mode A 2.67%+/-0.28%, Mode B 2.76%+/-0.29% and Mode C 2.73%+/-0.06%. No significant difference existed among polymerization shrinkage of composites cured by the three light curing modes with different power density (P>0.05). CONCLUSION: The power density of curing light affected the anti-aging property of composite resin which was aging time dependent. The polymerization shrinkage was not affected by light power density with same energy density. PMID- 21321622 TI - [Implant restoration for patients with congenital missing teeth]. AB - OBJECTIVE: To evaluate the treatment plan, clinical outcome and related problems in patients with congenital missing teeth. METHODS: From November 2000 to February 2009, thirty seven patients with congenital missing teeth underwent thorough diagnostic workup, treatment planning and an interdisciplinary approach to ensure optimal treatment in Department of Implant Dentistry, Peking University, School and Hospital of Stomatology. A standard follow-up protocol was conducted for all the patients. RESULTS: The enrolled cases in this study were classified in to 3 types: single tooth missing, multiple teeth missing and edentulous. Among them single tooth missing was found in 21 cases, multiple teeth missing was found in 12 cases and 4 cases were edentulous. 120 implants were placed and restored in 37 patients with the mean follow-up 39.3 months (10-109 months) after prosthetic functioning. Two implants lost after function about 6 months and the remaining implants functioned well until the last review. No adverse complications such as pain and nerve trauma was observed and the mean bone resorption was 1.91 mm. CONCLUSION: An interdisciplinary approach ensures optimal treatment for patients with congenital missing teeth. Implant restorations provide an alternative way with predictable clinical results. PMID- 21321623 TI - [Cytological study on osteoblasts and in-situ setting calcium phosphate cements]. AB - OBJECTIVE: To evaluate biocompatibility of three kinds of self-developed injectable calcium phosphate cements (CPCs): chitosan microspheres/CPC, beta tricalcium phosphate (beta-TCP)/CPC, and K(+)/CPC and the viability of the osteogenic cells cultured with CPC pastes and discs for 10 days. METHODS: The rabbit marrow stromal cells (rMSCs), isolated from rabbit bone marrow with density gradient centrifugation and flow cytometer, were cultured, expended and induced into osteoblasts. Alizarin red staining was used to determine the function of ossification. Then, rMSCs were incubated randomly on both the pastes and solidified discs of the 3 kinds of CPCs. The cells cultured on a 24-well plate were as blank control. Each group had 4 samples. The proliferation and differentiation of each group were observed using acid phosphatase assay (APA) and by testing the activity of alkaline phosphatase (ALP) at day 1, 4, 7, and 10. After stained by acridine orange(AO), the cells were observed, counted and analyzed with an epifluorescence microscopy. The morphology of the cells on CPCs was observed with scanning electron microscope(SEM).The data was subjected to two way ANOVA followed by LSD test to compare between groups. RESULTS: The process of solidification of the three kinds of CPC pastes has the toxic effect on cells, which is irreversible. The proliferation( the average absortion of pastes are 0.049,0.050,0.049; the discs are 0.898,0.867,0.909;P<0.001), function(the average ALP activity of pastes after ten days are 0.775,0.782,0.798 U/g protein; the discs are 49.288,49.631, 49.744 U/g protein;P<0.001) and number of cells(the average number of cells of pastes after ten days are 3.7,3.7,3.7; the discs are 91.1,89.7,93.7;P<0.001) directly exposed to CPC paste significantly decreased compared with those contacting with the discs. By contrast, cells on the three kinds of discs showed better viability, proliferation, and ossification and cell numbers increased obviously with culture days. CONCLUSION: The process of solidification of the three kinds of CPC pastes has toxic effect on cells. Further study needs to explore a method to protect osteoblasts when seeded into the CPC paste. PMID- 21321624 TI - [Three-dimensional model analysis of the gingival sulcus width from different retraction time]. AB - OBJECTIVE: To explore the effect of gingival retraction time on the gingival sulcus width in different gingival areas, using three-dimensional (3D) model analysis. METHODS: Forty-six premolars from 10 volunteers were included, gingival retraction cords were applied on the buccal sulcus for three times, and the retraction time was 5, 10 and 15 minutes respectively. The least interval between two retraction procedures was 2 weeks. Impressions and stone models were made before and after gingival retraction. 3D data of the models were acquired by a 3D line laser scanner. Models were superimposed and tooth coordinate was set up with special software. Sulcus widths from different retraction time and different gingival areas were measured and compared. RESULTS: Sulcus widths between retraction of 5 and 10 minutes were significantly different at midbuccal and transitional line angle (TLA) gingival areas. At TLA areas, sulcus widths between retraction of 10 and 15 minutes were also statistically different, but the difference was not significant when compared with that of 5 and 10 minutes. Sulcus widths at midbuccal areas were significantly greater than that at TLA areas for all three retraction time. CONCLUSION: Before making impressions, gingival retraction time of single-cord mechanical technique should be at least 10 minutes. For different gingival areas, the enlargement of gingival sulcus from gingival retraction and the optimal retraction time were different. 3D model analysis could be used as a new objective method to evaluate gingival retraction effect from different retraction time. PMID- 21321625 TI - [All-ceramic resin bonded fixed partial denture made of IPS hot-pressed casting porcelain restore anterior missing teeth: a three years clinical observation]. AB - OBJECTIVE: To clinic observation of IPS Empress2 and IPS e.max all ceramic resin bonded fixed partial dentures used in one anterior teeth lost in upper jaw or less than two anterior tooth lost in lower jaw. METHODS: 22 patients, 26 restorations had been made, which included 16 single-retainer all ceramic resin bonded fixed partial dentures and 10 two-retainers all ceramic resin bonded fixed partial dentures. Secondary caries of the abutments, shade in the margin of the retainers and the integrity of the restorations had been observed at 3 months, 6 months, 1 year, 2 years and 3 years after all ceramic resin bonded fixed partial dentures having been bonded. RESULTS: In the 3 years of clinic observation of the anterior all ceramic resin bonded fixed partial dentures, 1 two-retainers restoration lost bond after it had been made for 3 months, a retainer of one two retainers restoration was broken after 6 months, but they are still used after modified as one-retainer all ceramic resin bonded fixed partial dentures, 1 two retainers restoration lost bond two year later, It was integrity and re-bonded again that was still stable. No secondary carries and no shade in margin of the retainers had been found. Their color matches with the nature teeth excellently. The success rate was 88.5%. CONCLUSION: IPS Empress 2 and IPS e.max all ceramic resin bonded fixed partial dentures should be a good selection in one or two teeth lose in anterior jaws. PMID- 21321626 TI - [Clinical observation of the 2-unit cantilever metal plate resin bonded fixed partial dentures]. AB - OBJECTIVE: To observe a short term effect of clinical application of the 2-unit metal plate resin bonded fixed partial dentures (RBFPDs). METHODS: Sixteen patients were restored with the 2-unit cantilever metal plate RBFPDs during the period of 2005 to 2009. Retention and margin integrity of RBFPDs, and health condition of abutments were evaluated immediately after cementation and every 6 12 months period later. RESULTS: A total of 20 RBFPDs were made for all 16 patients. The observation period vary from 15 months to 53 months. The mean observation period was 34 months. There were 1 RBFPDs debonded. The debonding rate was 5%. CONCLUSION: The 2-unit cantilever metal plate RBFPDs could achieve a favorable clinical outcome in the short term. PMID- 21321627 TI - [H(2)O(2) treatment improves the bond strength between glass fiber posts and resin cement]. AB - OBJECTIVE: To evaluate the effect of etching with H2O2 on the bond strength between epoxy-based glass fiber posts and resin cement. METHODS: Sixteen epoxy based glass fiber posts were randomly divided into 4 groups (4 posts in each group) for different surface treatments. Group 1, no surface treatment (Control group); Group 2, treated with silane coupling agent for 60 s; Group 3, immersed in 10% H2O2 for 10 min then treated with silane coupling agent for 60 s; Group 4, immersed in 30% H2O2 for 10 min then treated with silane coupling agent for 60 s. Resin cement was used for the post cementation to form resin slabs which were then sectioned and trimmed into dumbbell shape to obtain microtensile specimens. Microtensile bond strengths were tested and the failure modes were examined with a stereomicroscope. Statistical analysis of microtensile bond strengths was performed with Kruskal-Wallis test. RESULTS: The microtensile bond strengths (standard deviation) were 18.81 (4.04) MPa for Group 1, 26.70 (9.63) MPa for Group 2, 39.07 (6.47) MPa for Group 3, 46.05 (5.97) MPa for Group 4. CONCLUSION: Etching with H2O2 followed by silanization could significantly improve the bond strength between epoxy-based glass fiber posts and resin cement. PMID- 21321628 TI - [Influence of experimental palatal plate on mandibular position during continuous [n] phonation in complete denture wearers]. AB - OBJECTIVE: To clarify the influence of an experimental palatal plate on the mandibular position during continuous [n] phonation and at the physiological rest position in complete denture wearers. METHODS: Ten complete denture wears volunteers were investigated. Two kinds of experimental palatal plate with a thickness of 3 mm and 5 mm (from the denture basal surface to denture polished surface) were fabricated and used for each subject. The mandibular position was recorded by a K7 mandibular kinesiograph during continuous [n] phonation and at the physiological rest position under three conditions: wearing a palatal plate with different thickness of 3 mm, 5 mm and without a plate(control). The interocclusal distance both in vertical and anteroposterior direction during continuous phonation and physiological rest position under all three conditions were measured and compared. RESULTS: Under the control condition without wearing of a plate, the mean values of interocclusal distance (IOD) during continuous [n] phonation were (1.69+/-1.26) mm vertically and (1.74+/-1.18) mm anteroposteriorly. After insertion of the experimental plates, there was an increase in the IOD during continuous [n] phonation, but this difference from the normal condition was not statistically significant. The mean IOD at the physiological rest position in these 2 directions were (2.91+/-2.28) mm and (2.56+/-1.88) mm, respectively. After insertion of the experimental plates, there was a decrease in the IOD, with the 3 mm plate, (2.52+/-1.88) mm vertically and (2.46+/-1.64) mm anteroposteriorly; with 5 mm plate, (2.45+/-1.70) mm vertically and (2.22+/-1.31) mm anteroposteriorly. No significant differences were found between the control and 2 experimental conditions. CONCLUSION: The mandibular position during continuous [n] phonation was not influenced by the experimental palatal plates and physiological rest position was also not affected by experimental palatal plates. PMID- 21321629 TI - [Study on low temperature degradation of dental zirconia ceramic]. AB - OBJECTIVE: To evaluate the properties of low temperature degradation (LTD) of dental Y-TZP by experiments. METHODS: According to ISO 13356-2008 standards, 72 blanks of Y-TZP were sintered at different temperature (1 400 degrees C,1 450 degrees Cor 1 530 degrees C) and in different heat preserving time(2 h or 5 h), and then the specimens were grounded and polished. The blanks were divided into 12 groups according to the different sintering temperature, heat preserving time and aging time. The surface of specimens was observed by SEM to evaluate the grain size of specimens; Each group of specimens was exposed to 140 degrees C hydrothermal aging environment for 0 h, 5 h or 24 h. After aging, XRD analysis was undertaken to determine the amount of phase transformation from tetragonal to monoclinic for each groups. At last, the biaxial flexural strengths of all specimens were measured and calculated. RESULTS: The SEM showed that the grain size of each group of Y-TZP increased with the increase of sintering temperature and heat preserving time, however, all of them were below 1 MUm. The XRD analysis showed the contents of monoclinic of each group varied with different sintering temperatures, heat preserving times and aging time. The flexural strength of 24 h aging groups declined significantly; but that of 5 h aging group showed increase or decrease according to the different sintering temperatures and heat preserving times. CONCLUSION: Different sintering procedures to some extent may affect the Y TZP aging properties. PMID- 21321630 TI - [Analysis of root resorption and dental structure in patients with cleidocranial dysplasia]. AB - OBJECTIVE: To observe the morphologic characteristic of root resorption surfaces and the histological structure of primary teeth in patients with cleidocranial dysplasia (CCD). METHODS: The primary teeth of CCD patients were collected, the resorption lacunae of which were analyzed by scanning electron microscope and the histological structure was analyzed by the polarized light microscope. RESULTS: Comparing with the normal teeth, the patients have typically clinical characteristics of CCD. Scanning electron microscopy examination revealed shallower and smoother resorption lacunae at the cervical thirds of the roots, and dentinal tubules were relatively uncommon. Ground examination of primary teeth under the polarized light microscope showed massive and irregular calcification formed in the pulp chamber in response to root resportion. The apical thirds of roots were covered by cellular or acellular cementum. CONCLUSION: Root resorption lacunae of primary teeth from CCD patients were different with that of normal children. The abnormal dentin in the pulp chamber may be related to disfunction of pulp cells when root resorption took place. The presumption that a lack of cellular cementum causes the increased number of retained primary teeth in patients with CCD is not supported by the present study. PMID- 21321631 TI - [Combined external radiotherapy and 125I-particle implantation for treatment of head and neck cancers]. AB - OBJECTIVE: To evaluate the relative incidence of local control and toxicity in patients with head and neck cancers who underwent external beam radiotherapy (EBRT) plus (125)I seeds implantation. METHODS: Ten patients diagnosed as head and neck cancers at the department of oral and maxillofacial surgery of Peking University School of Stomatology during the period of February 2008 to July 2010 were collected. The histologic types included squamous cell carcinoma in 8 patients, poorly differentiated adenocarcinoma of salivary gland in 2 patients. All patients could not receive surgical treatment due to poor medical status or unresectable advanced-stage tumors and underwent EBRT plus (125)I seeds implantation. Eight patients with squamous cell carcinoma had conventional fractionated EBRT with a total dose of 50 Gy; two patients with poorly differentiated adenocarcinoma had conventional fractionated EBRT with a total dose of 70 Gy. They all then had (125)I seeds implantation with matched peripheral dose of 60 Gy (TNM stage I-II) or 80 Gy (TNM stage III-IV ). The apparent activity per seed ranged from 25.9 to 29.6 MBq. follow-up of the patients was done to analyze acute and late toxicity, local control, and survival. RESULTS: After a median follow-up of 12 months (range 2-28 months), soft tissue necrosis was seen in one patient, dysphagia and hemorrhage in another. No other serious side effects were observed. All the tumor mass of 10 cases disappeared within 6 months, regional metastases was observed in one patient, and distant metastases was observed in another. Seven of 10 patients survived till the date of investigation. CONCLUSION: External beam radiotherapy plus (125)I seeds implantation is a safe and effective therapy regimen for patients with unrectable head and neck cancers. PMID- 21321632 TI - [Surgical treatment of transected peripheral facial nerve injury]. AB - OBJECTIVE: To evaluate the results of peripheral facial nerve reconstruction by surgical treatment and determine the influence factors for recovery. METHODS: From 1999 to 2009, 104 patients underwent surgical rehabilitation for transected peripheral facial nerve injury in the department of oral and maxillofacial surgery, Peking University School and Hospital of Stomatology. The age ranged from 2 to 77 years with a median age of 30 years. Sixty-five of the 72 cases (90.2%) who underwent facial nerve anastomosis and 24 of the 32 patients (75.0%) underwent facial nerve grafting. All these patients were followed for the final results. Facial nerve function was scored by the gross and regional House Brackmann (HB) facial grading system. Statistical analysis was performed using SPSS 13.0 software package by chi2 test or Fisher exact test. RESULTS: In the facial nerve anastomosis group, HB I, HB II, HB III and HB IV function were achieved in 37 (56.9%), 11 (16.9%), 15 (23.1%) and 2 (3.1%) patients respectively. The regional grades showed that the recovery rate of HB I and II were 27.3% in forehead, 97.6% in eye region, 97.9% in midface and 78.6% in the mouth region. In the facial nerve grafting group, HB grades I, II, III and IV were achieved in 4 (16.7%), 5 (20.8%), 7 (29.2%) and 8 (33.3%) patients respectively. By regional HB grades, HB I and II rate were 37.5% in forehead, 73.7% in eye region, 72.7% in midface, 44.4% in mouth region. The facial nerve anastomosis group had a higher HB I and II recovery rate than facial nerve grafting group (P=0.002). CONCLUSION: Facial nerve anastomosis and facial nerve grafting are effective surgical options for transected peripheral facial nerve injury. The site and range of facial nerve injury, the time post onset until repair, and the age of patient are factors that influence the clinical outcomes. PMID- 21321633 TI - [A clinical study on the effectiveness of desensitizing toothpaste in patients with dentine hypersensitivity]. AB - OBJECTIVE: To evaluate the effectiveness of desensitizing toothpaste containing 5.53% potassium citrate on dentine hypersensitivity. METHODS: This was a randomized, double-blinded, controlled, clinical trial. Those, who satisfied the inclusion criteria, were recruited into the study and randomized allocated into test group and control group according to gender and age group. At baseline, 67 subjects (36 in test group, 31 in control group) were recruited into the study. The dentine hypersensitivity was evaluated by a subject self-perceived short, sharp pain in visual analogue scale (VAS) in response to a blast of cold air from a triple syringe administered to a tooth surface in 1 cm. Test toothpastes, containing 5.53% potassium citrate and 0.76% sodium monofluorophosphate, and control toothpastes, containing only 0.76% sodium monofluorophosphate were delivered to the study subjects in the test and control group respectively. The subjects were asked to brush their teeth twice a day, and at least one minute each time. During the 8-week study period, a subjective evaluation of changes in the individuals overall sensitivity to everyday stimuli was also scored in VAS. RESULTS: At the end of the trial data of 57 subjects (31 in test group, 26 in control group) was used for analysis. From baseline to 8-week evaluation, the mean VAS values to cold air and subjects' self-perceived VAS values of the subjects decreased both in the test and control groups. Furthermore, the reduction in mean VAS values to cold air from baseline to 4-week of the test subjects was statistically significant higher than that of the control (1.12 vs. 0.32, P<0.05). The reduction in mean subjects' self-perceived VAS values from baseline to 8-week of the test subjects was statistically significant higher than that of the control (1.59 vs. 0.24, P<0.05). CONCLUSION: RESULTS of the clinical trial showed that toothpastes containing 5.53% potassium citrate were effective in reducing dentine hypersensitivity. PMID- 21321634 TI - [Expression of aquaporin 7 in perirenal adipose tissue of Otsuka Long-Evans Tokushima Fatty diabetic rats]. AB - OBJECTIVE: To observe perirenal adipose tissue aquaporin 7 (AQP7) mRNA and protein expression in the spontaneous type 2 diabetes animal model Otsuka Long Evans Tokushima Fatty (OLETF) rats in different stages of diabetes and explore the role of AQP7 in obesity development and diabetes. METHODS: OLETF rats (n=30) were studied, with the same strains of non-diabetic Long-Evans Tokushima Otsuka (LETO) rats (n=18) used as age-matched normal controls. After 8 weeks (baseline), 6 rats in each of the two groups were sacrificed. Then the rest of the OLETF rats were divided into untreated group (OLETF group, n=12) and metformin hydrochloride treated group (OLETF/M group, n=12). At the age of 8 , 18 and 28 weeks, their body weights were obtained, and biochemical items were measured including serum triglyceride, cholesterol, glycerol, glucose and insulin levels with oral glucose tolerance test (OGTT), and the perirenal adipose tissue (PAT) was obtained to measure the AQP7 mRNA expression (by Real-time PCR) and AQP7 protein relative expression (by Western blotting). RESULTS: (1) OLETF group rats developed diabetes at week 18 [60 min glucose: (25.67 +/- 6.78) mmol/L, 120 min glucose: (16.19 +/- 2.98)mmol/L]. The body weights and biochemical items including serum triglyceride, serum cholesterol, glucose and insulin levels of OGTT, were increased with the rats' age. The serum glycerol level was increased at week 18, but decreased at week 28. The serum glycerol level at weeks 8, 18, 28 were(52.61 +/- 11.80)MUmol/L, (156.03 +/- 39.56)MUmol/L and (130.84 +/- 25.46)MUmol/L , respectively. (2) OLETF/M group rats developed diabetes at week 18 [60 min glucose: (18.64 +/- 6.67)mmol/L, 120 min glucose: (14.13 +/- 5.21)mmol/L], but the glucose level at week 28 [60 min glucose: (11.72 +/- 3.06)mmol/L, 120 min glucose: (12.42 +/- 2.30)mmol/L] became lower than that at week 18. The body weights and Biochemical items including serum triglyceride, serum cholesterol, serum glycerol and insulin levels of OGTT of the OLETF/M group rats, were of no significant difference from those of the OLETF group rats. The two groups were compared: in serum triglyceride [at week 18: (0.88 +/- 0.14) vs. (1.09+/ 0.44)mmol/L;at week 28 (1.06 +/- 0.51) vs. (2.20 +/- 1.51)mmol/L];serum cholesterol [at week 18 (2.18+/-0.14) vs. (2.30 +/- 0.21)mmol/L,at week 28 (1.90 +/- 0.19) vs. (2.36 +/- 0.35) mmol/L,P<0.05];serum glycerol [at week 18 (77.28 +/ .06) vs. (156.03 +/- 39.56)MUmol/L,P<0.05,at week 28 (58.44 +/- 14.03) vs. (130.84 +/- 25.46)MUmol/L, P<0.01]. (3) Expression of perirenal adipose tissue AQP7 mRNA and protein levels: with rats age and obesity developed, compared with the same group rats at 8 week, the AQP7 mRNA expression of OLETF group increased 67.5% at 18 week and 41.7% at 28 week respectively, the AQP7 protein expression of OLETF group increased 21.9% at 18 week and 8.9% at 28 week respectively, the AQP7 mRNA expression of OLETF/M group increased 25% at 18 week and 8.3% at 28 week respectively, the AQP7 protein expression of OLETF/M group increased 14.6% at 18 week and 1.6% at 28 week respectively. AQP7 mRNA and protein expression were increased at 18 weeks and decreased at 28 weeks not only in OLETF groups but also in OLETF/M groups as it were consistent with serum glycerol. In the OLETF/M group, the expression of AQP7 mRNA and protein levels were lower than those in age-matched OLETF groups, though there was no statistic difference between the two groups. In the OLETF/M group, the expression of AQP7 mRNA and protein levels were lower than those in the age-matched OLETF group, though there was no statistic difference between the two groups. CONCLUSION: AQP7 of visceral adipose tissue may participate in glucose and lipid metabolism associated with diabetes and obesity. Metformin can improve OLETF rat glucose and lipid, but not contribute to AQP7 mRNA and AQP7 protein expression of perirenal adipose tissue. PMID- 21321635 TI - [Clinical characteristics of borderline ovarian tumors and stage I epithelial ovarian cancer: an analysis of 143 cases]. AB - OBJECTIVE: To study the clinical pathological characteristics and high risk factors for borderline ovarian tumor (BOT) and stage I epithelial ovarian cancer (EOC). METHODS: A total of 91 patients with BOT and 52 patients with stage IEOC who were diagnosed and treated in the Department of Gynecology, Peking University People's Hospital from November 2002 to May 2010 were recruited in this study. The patients' clinical characteristics were reviewed respectively and compared between the two groups. RESULTS: The women in BOT group were significantly younger than those in EOC group (41.16 +/- 14.95 vs. 50.90 +/- 14.37,P<0.01). Compared with women with BOT, women with EOC were more likely to be post menopausal(42.3% vs. 23.1%,P=0.016) and more with family history of malignant tumors (26.9% vs. 13.2%,P=0.04).There were no significant differences in the size of tumors and the serum level of tumor markers. But the size of solid portion of the tumor of EOC was significantly larger than that of BOT(P<0.01). The extent of the increase of CP2 among the patients with EOC was higher than that among the patients with BOT(256.99 vs. 116.59, P=0.028). There was a statistically significant difference between the two groups in tumors' histopathological type(P<0.01). The serous and mucous tumors were more common in EOC group (90.1%, 82/91). In contrary, endometrioid, clear cells and mixed epithelial cancers were more common in EOC group than serous and mucous cancers (44.2%, 23/52). CONCLUSION: Although the clinical presentation of patients with stage I EOC was similar to that of those with BOT, there were significant differences in the patients' age, post-menopausal or not, family history of malignant tumors, size of solid portion of tumors, extent of the increase of the tumor biomarker, especially of CP2 and tumors histopathological type. These clinicopathological characteristics might be helpful for us to make different diagnosis. PMID- 21321636 TI - [miR-449b and miR-34c on inducing down-regulation of cell cycle-related proteins and cycle arrests in SKOV3-ipl cell, an ovarian cancer cell line]. AB - OBJECTIVE: To investigate the effects of miR-449 and miR-34 on cell growth, cell cycle and target gene expression based on these miRNA different expressions in ovarian cancer cell lines SKOV3 and SKOV3-ipl both with mutation of p53. METHODS: The expressions of miR-449a/b and miR-34b,c in SKOV3 and SKOV3-ipl were detected by RT-PCR. miR-449a,b and miR-34b,c were ectopically expressed by transfection of SKOV3-ipl. The cell growth rate was assayed by MTS method. The changes of cell cycle were measured by FCM. The changes of expression of cell cycle related proteins were detected by Western blot. RESULTS: Ectopic expression of miR-449b and miR-34c resulted in lowered adhesion activities by 28%-34%, and in cell cycle arrests with increased cell number of 15.62% and 15.71% in G1 and with decreased cell number of 15.96% and 16.56% in S. Cell cycle related proteins CDK6 and CDC25A were down-regulated. The decreases of CDK6 and CDC25A by miR-449b were 39% and 22% respecyively; 49% and 32% by miR-34c respectively. The more decreases were seen in co-action by miR-449b and miR-34c with decreases of 69% in CDK6, 86% in CDC25A, and 59% in CyclinA. CONCLUSION: miR-449b and miR-34c resulted in cell cycle arrests and down-regulation of CDK6, CDC25A and CyclinA in high malignant ovarian cancer cell line SKOV3-ipl. PMID- 21321637 TI - [Risk factors for operative mortality in 1,098 patients with coronary artery bypass grafting surgery: a single center report]. AB - OBJECTIVE: To analyze the risk factors for operative mortality in 1 098 cases of coronary artery bypass grafting (CABG) procedures. METHODS: A total of 1 098 cases of CABG including 113 cases of left ventricular ejection fraction (LVEF) lower than 35% from December 1999 through December 2009 were chosen for the retrospective study. Univariate and multivariate stepwise logistic analyses were performed based on the data of the whole group to locate the mortality risk factors. RESULTS: Age, acute coronary syndrome, emergent surgery, chronic renal failure (CRF), concomitant peripheral vascular disease, LVEF <= 35%, left ventricular end diastolic diameter (LVEDD), moderate to severe mitral regurgitation, aneurysm of the heart wall, aortic regurgitation, mitral repair/replacement, resection of aneurysm, concomitant aortic valve replacement, peri-operative intra-aortic balloon pump (IABP), left ventricular assist device (LVAD), and off-pump CABG were the risk factors for the univariate analysis. In the further multivariate regression analysis, off-pump CABG appeared statistically as a protective factor while age, female, emergent surgery, CRF, and the peri-operative application of IABP were the risk factors correspondingly for the whole group. CONCLUSION: Age, female, emergent surgery, CRF, and the application of IABP, were the risk factors for mortality in the entire group of patients, implicating the necessity of specific and cautious management. CABG concomitant with non-cardiac surgery, concomitant with the treatment of moderate severe mitral regurgitation and resection of heart wall aneurysm were not the risk factors for peri-operative mortality. PMID- 21321638 TI - [Digital inlaid design based on anatomical characteristics and preliminary implementation of its program]. AB - OBJECTIVE: To explore the technical guideline of inlays computer aided design (CAD) for further development, to test the feasibility of processing for the design results of the technical guideline, and to assist co-operation with automatic inlay CAD software development. METHODS: On the basis of point cloud data of right mandibular first molar of standard crown, we established the coordinate system,the landmarks and lines and the characteristic curves. A dental cast of right mandibular first molar MOD-inlay of an individual normal occlusion was scanned. The following objects were digitized: prepared tooth, neighbor teeth and intercuspal bite record. On the basis of parametric standard crown established in the research, using Surfacer 11.0, we achieved the reconstruction of MOD-inlay by extracting margin line, constructing tissue surface, constructing outer surface and occlusal grinding, then the design result was processed and try in on the cast. We also developed automatic inlay CAD software based on the guideline of inlay CAD. RESULTS: The guideline of inlay CAD was established, the design results were processed and an automatic inlay CAD software was developed on basis of Surfacer 11.0. CONCLUSION: It is a feasible method to establish technical guideline of inlay based on reverse engineering technology and process its design result, and a automatic inlay CAD software could be developed based on the technical guideline. PMID- 21321639 TI - [Denture-like applicators with radioactive seeds for treatment of palatal malignant tumors]. AB - OBJECTIVE: To design and make denture-like applicators containing radioactive seeds for treatment of malignant tumors in the hard palate where only thin layers of soft tissues are available. METHODS: Forty-two patients were treated with denture-like applicators containing (125)I radioactive seeds after local resection of malignant salivary gland tumors the hard palate. Sixteen patients were male, and 26 patients were female. The average age was 37.6 years old (18-74 years old). The denture-like applicators were consisted of three parts: resin layer (about 1.0 mm in thickness) which contacted with surgical area and contained radioactive seeds; the cobalt-chromium alloy layer (about 1.0 mm in thickness) which protected surrounding normal tissues; the clasps which acted as retainers for applicators. The resin layer and the alloy layer were connected together mechanically. Artificial teeth were applied on the applicators to restore the masticatory function when partially edentulous upper jaws were available. All these patients were followed up for 12-72 months. The complications in target areas and adjacent normal tissues were observed. The stability of radioactive seeds, the recurrence of the tumor was also observed during the follow-up. RESULTS: No patients complained about hurt or burning of adjacent normal tissues. 8/42 patients felt some uncomfortable, such as gagging, more saliva on the first one or two days. No radioactive seeds were lost and dislocated during the treatment. The surgical wounds healed perfectly. No mucosal ulcer, no recurrence of tumor, and no other complications for the target areas were observed. The living standard of the patients was improved. CONCLUSION: The denture-like applicator containing (125)I radioactive seeds is a feasible, effective, and convenient way to treat malignant tumors around the hard palate, where there is no enough room to implant radioactive seeds. This method can effectively irradiate the target areas when treating the malignant tumors in the palate. PMID- 21321640 TI - [Application of three-dimensional reconstruction of the enhanced CT in infratemporal fossa and parapharygeal space tumors]. AB - OBJECTIVE: To reconstruct three-dimensional CT image of the skull, the blood vessels and the infratemporal fossa and parapharyngeal space tumors using Mimics software, and to discuss the clinical significance of the three-dimensional CT in diagnosis and preoperative surgical design. METHODS: Four infratemporal fossa and parapharyngeal space tumors were studied using spiral CT Siemens 16 scanning technology, based on 2 mm thickness, and Mimics software was used to directly read the original image, and surface shaded technology was applied for reconstructing the spatial relationship of the vascular, skull and tumor structures. RESULTS: The three-dimensional reconstruction images can clearly demonstrate the extent of the tumor size, location, and its relation to blood vessels and the skull. CONCLUSION: The three-dimensional reconstruction of enhanced CT image is conducive to operation plan designed to avoid damaging important anatomical structures. PMID- 21321641 TI - [Randomized clinical case-control trial for the comparison of docetaxel plus thiotepa versus docetaxel plus capecitabine in patients with metastatic breast cancer]. AB - OBJECTIVE: To evaluate the efficacy and safety of docetaxel plus thiotepa(TXT/TSPA) and docetaxel plus capecitabine(TXT/CAPE) in patients with metastatic breast cancer. METHODS: The patients were randomized to give intravenous TXT 35 mg/m2 on days 1 and 8 plus intravenous TSPA 60-65 mg/m(2) on day 1 every 3 weeks, or intravenous TXT 35 mg/m(2) on days 1 and 8 plus oral CAPE 1 000 mg/m(2) twice daily on days 1 to 14 every 3 weeks, at least 2 cycles applied. RESULTS: TXT/TSPA group (22 patients) and TXT/CAPE group (24 patients) had consistent baseline. Docetaxel thiotepa group (21 cases) and docetaxel combined with capecitabine group (22 cases) were evaluated for their clinical responses, which showed that 2 of the 21 (9.52%) from TXT/TSPA group and 6 of the 22 (27.27%) from TXT/CAPE group had achieved partial remission; 11 of the 21 (52.38%) from TXT/TSPA group versus 7 of the 22 (31.82%) from TXT/CAPE group for stable diseases; 8 of the 21 (38.10%) from TXT/TSPA group versus and 9 of the 22 (40.91%) from TXT/CAPE group for progressive diseases, respectively. The disease control rate was 61.90% (13/21) and 59.09% (13/22) for TXT/TSPA and TXT/CAPE groups, the median progression-free survival(PFS) was 7.9 months [95% confidence interval(CI) 0.77 to 15.03] from TXT/TSPA group versus 8.3 months (95% CI 4.01 to 11.79) from TXT/CAPE group. One year survival rate was 88.20% for TXT/TSPA versus 81.00% for TXT/CAPE group, respectively. P values all exceeded 0.05, and the two groups showed no difference. No chemotherapy-related deaths occurred. Myelosuppression was the major side effect. The adverse events of grades 3 to 4 respectively occurred in TXT/TSPA and TXT/CAPE groups:leucocytopenia was 45.45% vs. 26.09%; neutropenia 45.45% vs. 21.74%; thrombocytopenia 9.09% vs. 0%; hand foot syndrome 0% vs. 13.04%. P values all exceeded 0.05, and the two groups showed no difference. CONCLUSION: Combination of docetaxel and thiotepa in the treatment of metastatic breast cancer has some curative effect and adverse reactions can be tolerated. It can be used as an economical and effective rescue plan. PMID- 21321642 TI - What is new in burn care? PMID- 21321643 TI - Rehabilitation of the burn patient. AB - Rehabilitation is an essential and integral part of burn treatment. It is not something which takes place following healing of skin grafts or discharge from hospital; instead it is a process that starts from day one of admission and continues for months and sometimes years after the initial event. Burns rehabilitation is not something which is completed by one or two individuals but should be a team approach, incorporating the patient and when appropriate, their family. The term 'Burns Rehabilitation' incorporates the physical, psychological and social aspects of care and it is common for burn patients to experience difficulties in one or all of these areas following a burn injury. Burns can leave a patient with severely debilitating and deforming contractures, which can lead to significant disability when left untreated. The aims of burn rehabilitation are to minimise the adverse effects caused by the injury in terms of maintaining range of movement, minimising contracture development and impact of scarring, maximising functional ability, maximising psychological wellbeing, maximising social integration. PMID- 21321644 TI - Research in burns - Present and future. AB - There have been tremendous advances in burns care over the past 50 years. Much of this, but not all, can be attributed to basic science and clinically related research. Out of the best centres in the world, centres that are fully funded and richly resourced, best practice guidelines result in impressive outcomes not only in terms of survival but also in terms of a quality of survival. Indeed the remaining clinical challenges in these centres are the elderly, the inhalational burns, and the very extensive burns. There are however other challenges when looking at burns care in a global context and in particular is the provision of even minimal standards of acceptable care for burns patients in many parts of the world. Whilst the justification for research funding in the wealthy countries becomes increasingly esoteric, for example looking at the immunology of face transplantation, the global health challenges of burns care still remain. Perhaps, the greatest research challenge in burns care in the 21st century lies not in furthering our understanding of the phenomenon we observe but the global application of the knowledge we already possess. PMID- 21321646 TI - Training of medical and paramedical personnel in burn care and prevention. AB - This paper discusses the requirements for training in burn care within a resource limited environment, what is currently practiced and goes on to suggest a strategy for effective delivery of education and training. PMID- 21321645 TI - Deceased donor skin allograft banking: Response and utilization. AB - BACKGROUND: In the absence of xenograft and biosynthetic skin substitutes, deceased donor skin allografts is a feasible option for saving life of patient with extensive burn injury in our country. AIMS: The first deceased donor skin allograft bank in India became functional at Lokmanya Tilak Municipal (LTM) medical college and hospital on 24(th) April 2000. The response of Indian society to this new concept of skin donation after death and the pattern of utilization of banked allografts from 2000 to 2010 has been presented in this study. SETTINGS AND DESIGN: This allograft skin bank was established by the department of surgery. The departments of surgery and microbiology share the responsibility of smooth functioning of the bank. MATERIALS AND METHODS: The response in terms of number of donations and the profile of donors was analyzed from records. Pattern and outcome of allograft utilization was studied from specially designed forms. RESULTS: During these ten years, 262 deceased donor skin allograft donations were received. The response showed significant improvement after counselling was extended to the community. Majority of the donors were above 70 years of age and procurement was done at home for most. Skin allografts from 249 donors were used for 165 patients in ten years. The outcome was encouraging with seven deaths in 151 recipients with burn injuries. CONCLUSIONS: Our experience shows that the Indian society is ready to accept the concept of skin donation after death. Use of skin allografts is life saving for large burns. We need to prepare guidelines for the establishment of more skin banks in the country. PMID- 21321647 TI - Training and burn care in rural India. AB - Burn care is a huge challenge in India, having the highest female mortality globally due to flame burns. Burns can happen anywhere, but are more common in the rural region, affecting the poor. Most common cause is flame burns, the culprit being kerosene and flammable flowing garments worn by the women. The infrastructure of healthcare network is good but there is a severe resource crunch. In order to bring a positive change, there will have to be more trained personnel willing to work in the rural areas. Strategies for prevention and training of burn team are discussed along with suggestions on making the career package attractive and satisfying. This will positively translate into improved outcomes in the burns managed in the rural region and quick transfer to appropriate facility for those requiring specialised attention. PMID- 21321648 TI - Managing burn patients in a fire disaster: Experience from a burn unit in Bangladesh. AB - Although burn disaster is not a frequent event, with urbanisation and industrialisation, burn disaster is becoming an emerging problem in Bangladesh. On 3 June 2010, a fire disaster killed 124 people in Neemtali, Dhaka, Bangladesh. This paper narrates the management of burn patients of this disaster in the burn unit of Dhaka Medical College Hospital. The burn unit managed 192 burn victims of the disaster. Forty-two victims were admitted and 150 of them received primary care at the emergency room and were sent back home. Ten patients among 42 in patients died. The in-patient mortality was 23.8%. Burn unit in Dhaka Medical College Hospital is the only burn management centre in Bangladesh. Proper planning and coordinated effort by all sectors and persons concerned were the key elements in this successful management. PMID- 21321650 TI - Legal scenario in burn care in India. AB - Physicians engaged in management of burn patients in India need to keep themselves abreast with the legal requirements. Clinical burn management and liaison with local authorities go almost parallel. Concept of the legal rights of Burn Survivor and the family are emerging now in India. Demarcation between physical impairment status and disability to sustain are discussed. Burn Physicians can help their patients by imparting this information. Pertinent details about Workmen's compensation act, Persons with disabilities act and guidelines for calculation of physical impairments are listed. PMID- 21321649 TI - Psychiatric aspects of burn. AB - Burn injuries and their subsequent treatment cause one of the most excruciating forms of pain imaginable. The psychological aspects of burn injury have been researched in different parts of the world, producing different outcomes. Studies have shown that greater levels of acute pain are associated with negative long term psychological effects such as acute stress disorder, depression, suicidal ideation, and post-traumatic stress disorder for as long as 2 years after the initial burn injury. The concept of allostatic load is presented as a potential explanation for the relationship between acute pain and subsequent psychological outcomes. A biopsychosocial model is also presented as a means of obtaining better inpatient pain management and helping to mediate this relationship. PMID- 21321651 TI - Pre-hospital care in burn injury. AB - The care provided to the victims of burn injury immediately after sustaining burns can largely affect the extent and depth of the wound. Although standard guidelines have been formulated by various burn associations, they are still not well known to public at large in our country. In burn injuries, most often, the bystanders are the first care providers. The swift implementation of the measures described in this article for first aid in thermal, chemical, electrical and inhalational injuries in the practical setting, within minutes of sustaining the burn, plays a vital role and can effectively reduce the morbidity and mortality to a great extent. In case of burn disasters, triage needs to be carried out promptly as per the defined protocols. Proper communication and transport from the scene of the accident to the primary care centre and onto the burn care facility greatly influences the execution of the management plans. PMID- 21321652 TI - Biologic and synthetic skin substitutes: An overview. AB - The current trend of burn wound care has shifted to more holistic approach of improvement in the long-term form and function of the healed burn wounds and quality of life. This has demanded the emergence of various skin substitutes in the management of acute burn injury as well as post burn reconstructions. Skin substitutes have important roles in the treatment of deep dermal and full thickness wounds of various aetiologies. At present, there is no ideal substitute in the market. Skin substitutes can be divided into two main classes, namely, biological and synthetic substitutes. The biological skin substitutes have a more intact extracellular matrix structure, while the synthetic skin substitutes can be synthesised on demand and can be modulated for specific purposes. Each class has its advantages and disadvantages. The biological skin substitutes may allow the construction of a more natural new dermis and allow excellent re epithelialisation characteristics due to the presence of a basement membrane. Synthetic skin substitutes demonstrate the advantages of increase control over scaffold composition. The ultimate goal is to achieve an ideal skin substitute that provides an effective and scar-free wound healing. PMID- 21321653 TI - Fluid management in major burn injuries. AB - It is a widely accepted fact that severe fluid loss is the greatest problem faced following major burn injuries. Therefore, effective fluid resuscitation is one of the cornerstones of modern burn treatment. The aim of this article is to review the current approaches available for modern trends in fluid management for major burn patients. As these current approaches are based on various experiences all over the world, the knowledge is essential to improve the status of this patient group. PMID- 21321654 TI - Burns demand our attention. PMID- 21321655 TI - Fungal infections in burns: Diagnosis and management. AB - Burn wound infection (BWI) is a major public health problem and the most devastating form of trauma worldwide. Fungi cause BWI as part of monomicrobial or polymicrobial infection, fungaemia, rare aggressive soft tissue infection and as opportunistic infections. The risk factors for acquiring fungal infection in burns include age of burns, total burn size, body surface area (BSA) (30-60%), full thickness burns, inhalational injury, prolonged hospital stay, late surgical excision, open dressing, artificial dermis, central venous catheters, antibiotics, steroid treatment, long-term artificial ventilation, fungal wound colonisation (FWC), hyperglycaemic episodes and other immunosuppressive disorders. Most of the fungal infections are missed owing to lack of clinical awareness and similar presentation as bacterial infection coupled with paucity of mycology laboratories. Expedient diagnosis and treatment of these mycoses can be life-saving as the mortality is otherwise very high. Emergence of resistance in non-albicans Candida spp., unusual yeasts and moulds in fungal BWI, leaves very few fungi susceptible to antifungal drugs, leaving many patients susceptible. There is a need to speciate fungi as far as the topical and systemic antifungal is concerned. Deep tissue biopsy and other relevant samples are processed by standard mycological procedures using direct microscopy, culture and histopathological examination. Patients with FWC should be treated by aggressive surgical debridement and, in the case of fungal wound infection (FWI), in addition to surgical debridement, an intravenous antifungal drug, most commonly amphotericin B or caspofungin, is prescribed followed by de-escalating with voriconazole or itraconazole, or fluconazole depending upon the species or antifungal susceptibility, if available. The propensity for fungal infection increases, the longer the wound is present. Therefore, the development of products to close the wound more rapidly, improvement in topical antifungal therapy with mould activity and implementation of appropriate systemic antifungal therapy guided by antifungal susceptibility may improve the outcome for severely injured burn victims. PMID- 21321656 TI - Padmashri Noshir Antia: Lotus of Indian plastic surgery. PMID- 21321657 TI - Special considerations in paediatric burn patients. AB - Burn injuries are a major cause of morbidity and mortality in children. In India, the figure constitutes about one-fourth of the total burn accidents. The management of paediatric burns can be a major challenge for the treating unit. One has to keep in mind that "children are not merely small adults"; there are certain features in this age group that warrant special attention. The peculiarities in the physiology of fluid and electrolyte handling, the uniqueness of the energy requirement and the differences in the various body proportions in children dictate that the paediatric burn management should be taken with a different perspective than for adults. This review article would deal with the special situations that need to be addressed while treating this special class of thermal injuries. We must ensure that not only the children survive the initial injury, but also the morbidity and complications are minimized. If special care is taken during the initial management of paediatric burn injuries, these children can be effectively integrated into the society as very useful and productive members. PMID- 21321658 TI - Review of therapeutic agents for burns pruritus and protocols for management in adult and paediatric patients using the GRADE classification. AB - To review the current evidence on therapeutic agents for burns pruritus and use the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) classification to propose therapeutic protocols for adult and paediatric patients. All published interventions for burns pruritus were analysed by a multidisciplinary panel of burns specialists following the GRADE classification to rate individual agents. Following the collation of results and panel discussion, consensus protocols are presented. Twenty-three studies appraising therapeutic agents in the burns literature were identified. The majority of these studies (16 out of 23) are of an observational nature, making an evidence-based approach to defining optimal therapy not feasible. Our multidisciplinary approach employing the GRADE classification recommends the use of antihistamines (cetirizine and cimetidine) and gabapentin as the first-line pharmacological agents for both adult and paediatric patients. Ondansetron and loratadine are the second-line medications in our protocols. We additionally recommend a variety of non-pharmacological adjuncts for the perusal of clinicians in order to maximise symptomatic relief in patients troubled with postburn itch. Most studies in the subject area lack sufficient statistical power to dictate a 'gold standard' treatment agent for burns itch. We encourage clinicians to employ the GRADE system in order to delineate the most appropriate therapeutic approach for burns pruritus until further research elucidates the most efficacious interventions. This widely adopted classification empowers burns clinicians to tailor therapeutic regimens according to current evidence, patient values, risks and resource considerations in different medical environments. PMID- 21321659 TI - National programme for prevention of burn injuries. AB - The estimated annual burn incidence in India is approximately 6-7 million per year. The high incidence is attributed to illiteracy, poverty and low level safety consciousness in the population. The situation becomes further grim due to the absence of organized burn care at primary and secondary health care level. But the silver lining is that 90% of burn injuries are preventable. An initiative at national level is need of the hour to reduce incidence so as to galvanize the available resources for more effective and standardized treatment delivery. The National Programme for Prevention of Burn Injuries is the endeavor in this line. The goal of National programme for prevention of burn injuries (NPPBI) would be to ensure prevention and capacity building of infrastructure and manpower at all levels of health care delivery system in order to reduce incidence, provide timely and adequate treatment to burn patients to reduce mortality, complications and provide effective rehabilitation to the survivors. Another objective of the programme will be to establish a central burn registry. The programme will be launched in the current Five Year Plan in Medical colleges and their adjoining district hospitals in few states. Subsequently, in the next five year plan it will be rolled out in all the medical colleges and districts hospitals of the country so that burn care is provided as close to the site of accident as possible and patients need not to travel to big cities for burn care. The programme would essentially have three components i.e. Preventive programme, Burn injury management programme and Burn injury rehabilitation programme. PMID- 21321660 TI - Post-burn scars and scar contractures. AB - The mortality and morbidity from burns have diminished tremendously over the last six to seven decades. However, these do not truly reflect whether the victim could go back to society as a useful person or not and lead a normal life because of the inevitable post-burn scars, contractures and other deformities which collectively have aesthetic and functional considerations. This article gives an overview of the post-burn scars and scar contractures, especially their prevention, minimisation and principles of management. PMID- 21321661 TI - Management of post burn hand deformities. AB - The hand is ranked among the three most frequent sites of burns scar contracture deformity. One of the major determinants of the quality of life in burns survivors is the functionality of the hands. Burns deformities, although largely preventable, nevertheless do occur when appropriate treatment is not provided in the acute situation or when they are part of a major burns. Reconstructive procedures can greatly improve the function of the hands. Appropriate choice of procedures and timing of surgery followed by supervised physiotherapy can be a boon for a burns survivor. PMID- 21321662 TI - Free groin flap for recurrent severe contractures of the neck in children. AB - CONTEXT: Severe post burns contracture in children not only leads to functional impairment but also has profound psychological impact on the child. Untreated neck contractures have been shown to inhibit mandibular growth. Skin grafting in children has a higher rate of recurrence and in these cases a thin pliable flap seems to provide a durable solution. AIM: To study the feasibility of using primarily thinned free groin flap in the treatment of recurrent neck contractures in children. MATERIALS AND METHODS: Five patients, in the age group of 5-10 years, with recurrent neck contractures and operated between 2005 and 2008 were included in this study. The sternomental distance, lateral flexion angle and cervicomental angle were measured preoperatively, postoperatively and during the subsequent follow-up visits. The patients were followed up for a period between 1 and 3 years with a mean of 29 months. RESULTS: All the flaps survived. The cervicomental angle improved significantly to 90-105 degrees , the lateral flexion angle improved to 35-45 degrees and the sternomental distance increased considerably. CONCLUSIONS: Recurrent post burns contracture of the neck in children causes not only functional and aesthetic impairment but also psychological problems. A free microthinned groin flap provides a very attractive solution for this problem and should be seen as an effective alternative in recurrent cases. PMID- 21321663 TI - A new method for release of severe mentosternal contractures under central neuraxial blockade. AB - A new method for release of severe mentosternal contractures has been described in this paper under central neuraxial blockade. The contracture release was performed under thoracic epidural analgesia. This technique can benefit patients with mentosternal contractures to avoid the problems of entubation and it can also assist in postoperative recovery and analgesia. The epidural catheter can be used to extend the height or duration of intraoperative block and is also useful to provide postoperative epidural analgesia. PMID- 21321664 TI - Accidental radioisotope burns - Management of late sequelae. AB - Accidental radioisotope burns are rare. The major components of radiation injury are burns, interstitial pneumonitis, acute bone marrow suppression, acute renal failure and adult respiratory distress syndrome. Radiation burns, though localized in distribution, have systemic effects, and can be extremely difficult to heal, even after multiple surgeries. In a 25 year old male who sustained such trauma by accidental industrial exposure to Iridium192 the early presentation involved recurrent haematemesis, pancytopenia and bone marrow suppression. After three weeks he developed burns in contact areas in the left hand, left side of the chest, abdomen and right inguinal region. All except the inguinal wound healed spontaneously but the former became a non-healing ulcer. Pancytopenia and bone marrow depression followed. He was treated with morphine and NSAIDs, epidural buprinorphine and bupivicaine for pain relief, steroids, antibiotics followed by wound excision and reconstruction with tensor fascia lata(TFL) flap. Patient had breakdown of abdominal scar later and it was excised with 0.5 cm margins up to the underlying muscle and the wound was covered by a latissimis dorsi flap. Further scar break down and recurrent ulcers occurred at different sites including left wrist, left thumb and right heel in the next two years which needed multiple surgical interventions. PMID- 21321665 TI - Radiation injury. PMID- 21321666 TI - The pivotal role of nursing personnel in burn care. AB - The nurses play an important role in the overall management of a burn patient. They must be well versed with the various protocols available that can be used to rationally manage a given situation. The management not only involves medical care but also a psychological assessment of the victim and the family. The process uses a scientific method to combine systems theory with the art of nursing, entailing both problem solving techniques and a decision making process. It involves assessment of the patient to arrive at a diagnosis and then determining the patient goals.An action plan is implemented and is evaluated in the context of patient response. The article discusses many such scenarios in burn patients and outlines the nursing care plans. PMID- 21321667 TI - Out of Our Heads! Four perspectives on the curation of an on-line exhibition of medically themed artwork by UK medical undergraduates. AB - The Medical School at Bristol University is noted for offering, and in some instances requiring, its students to work creatively with medical themes. Students, artists, educationalists and a web designer have worked to create an on line exhibition of the resulting creative output. This can be viewed at www.outofourheads.net. This site is a themed repository of poetry, prose, drawings, paintings, cartoons, films, music, dance and rap. Most works come with commentaries that can be as illuminating as the works they describe. The site invites comment and welcomes new postings from anyone connected to medicine. As an alternative to the conventional pedagogical report, and in keeping with the subject matter, in this paper we tell the story of this unique educational enterprise through the narratives of four of its principle architects. The 'Teacher's Tale', the 'Designer's Tale', the 'Curator's Tale' and the 'Artist's Tale' offer different, personal, tellings of how the site came to be. Each tale contains hypertext links to notable works on the site some of which have become teaching resources within the institution. This paper is of relevance to anyone who seeks to explore and champion the human insights of this privileged community. PMID- 21321668 TI - 'Compulsory creativity': rationales, recipes, and results in the placement of mandatory creative endeavour in a medical undergraduate curriculum. AB - Since 2004, medical students at the University of Bristol have been required as part of their core curriculum to submit creative works for assessment. This requirement, which we term, ironically, compulsory creativity, may be unique within medical education where arts-based modules are typically elective. Such courses often harness the insights of established artists and writers in the illumination of medical themes. Less commonly students are called upon to link their own creative work with clinical and other life experience. Occasions for students to develop such an interpretative voice are generally sparse but the benefits can be argued theoretically and practically. In this paper we explore the rationale for the inclusion of such opportunities, the ways in which we have woven creativity into the curriculum and the sorts of artistic outputs we have witnessed. Contextualised links to a wide range of original student works from the www.outofourheads.net website are provided, as is a range of student reflection on the creative process ranging from the bemused to the ecstatic. The paper provides a model and a guide for educationalists interested in developing artistic creativity within the medical curriculum. PMID- 21321669 TI - A 556 kb deletion in the downstream region of the PAX6 gene causes familial aniridia and other eye anomalies in a Chinese family. AB - PURPOSE: The paired box gene 6 (PAX6) on human chromosome 11p13 is an essential transcription factor for eye formation in animals. Mutations in PAX6 can lead to varieties of autosomal-dominant ocular malformations with aniridia as the major clinical signs. Known genetic alterations causing haplo-insufficiency of PAX6 include nonsense mutations, frame-shift mutations, splicing errors, or genomic deletions. The purpose of this study was to identify genetic defects as the underlying cause of familial aniridia in a large Chinese family. METHODS: All exons of PAX6 in the proband were sequenced by the Sanger sequencing technique. The genome of the proband was evaluated by a microarray-based comparative genomic hybridization (aCGH). Quantitative real-time PCR was applied to verify the abnormal aCGH findings in the proband and to test five other family members. RESULTS: There were no detectable pathogenic mutations in the exons of PAX6 in the proband. The aCGH analysis showed two copies of PAX6 but revealed a 566 kb hemizygous deletion of chromosome 11p13, including four annotated genes doublecortin domain containing 1 (DCDC1), DnaJ homolog subfamily C member 24 (DNAJC24), IMP1 inner mitochondrial membrane(IMMP1L), andelongation factor protein 4 (ELP4) downstream of PAX6. Quantitative real-time PCR verified the deletion in the proband and further identified the deletion in a blind fashion in four affected family members but not in the one with a normal phenotype. CONCLUSIONS: The 566 kb hemizygous deletion of chromosome 11p13 downstream of PAX6 should be the cause of the familial aniridia in this Chinese family, although two copies of PAX6 are intact. aCGH evaluation should be applied if there is a negative result for the mutation detection of PAX6 in patients with aniridia. PMID- 21321670 TI - Chromosome 7q31 POAG locus: ocular expression of caveolins and lack of association with POAG in a US cohort. AB - PURPOSE: To determine the role of the recently discovered primary open angle glaucoma (POAG) risk factor mapped to chromosome 7q31 in glaucoma patients from Iowa and to determine the expression pattern of genes in the locus in human eyes. METHODS: A cohort of 545 POAG patients and 297 control subjects from Iowa were genotyped with a single nucleotide polymorphism (SNP; rs4236601) in the chromosome 7q31 locus using a quantitative polymerase chain reaction (PCR) assay. The expression of genes within the 7q31 locus, caveolin-1 (CAV1) and caveolin-2 (CAV2) in human eyes was investigated with immunohistochemistry. RESULTS: The minor allele frequency (MAF) of rs4236601 was 27% in control subjects and 29% in POAG patients. We detected no statistical difference when we compared the allele frequencies of rs4236601 between POAG patients and control subjects (p=0.5). Similarly, we detected no statistical difference in the frequency of the three possible rs4236601 genotypes between patients and controls (p=0.22). Immunohistochemistry showed caveolin expression in human retina, ciliary muscle, trabecular meshwork, and Schlemm's canal. In our small cohort of donor eyes, the genotype of rs4236601 did not obviously influence labeling intensity or distribution of CAV1 and CAV2 in the retina. CONCLUSIONS: A genome-wide association study of subjects from Iceland mapped the first common genetic risk factor for POAG to a small region of the genome on chromosome 7q31 that contains the caveolin genes CAV1 and CAV2. We were unable to detect this association in our patients from Iowa, suggesting that this risk factor may not have a strong effect in all populations. PMID- 21321671 TI - Genetic analysis of the FOXL2 gene using quantitative real-time PCR in Chinese patients with blepharophimosis-ptosis-epicanthus inversus syndrome. AB - PURPOSE: The purpose of this study was to identify the mutation(s) or deletion(s) of the forkhead box protein L2 (FOXL2) gene in Chinese patients with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). METHODS: Genomic DNA extracted from peripheral blood was collected from two Chinese families and from one sporadic case. PCR direct sequencing and quantitative real-time PCR-based copy number screening for the whole exon of FOXL2 were performed. RESULTS: Direct sequencing revealed an indel mutation c.50C->TA in the sporadic case which resulted in a frameshift generating 78 novel amino acids and terminating prematurely at codon 95. Deletions in the FOXL2 gene were confirmed by quantitative real-time PCR (q-real-time PCR) in two families in which intragenic mutations were excluded by direct sequencing. These changes containing deletions and a de novo mutation were not detected either in the non-carrier relatives or in 100 normal controls. CONCLUSIONS: This study identified two deletions and a de novo mutation in the FOXL2 gene in Chinese BPES patients. This is the first study to report FOXL2 gene deletions detected by q-real-time PCR in this ethnic group. This technique enriches the diagnostic methods of molecular genetics in BPES patients. The de novo mutation expands the mutation spectrum of FOXL2. PMID- 21321672 TI - A comprehensive flow-cytometric analysis of graft infiltrating lymphocytes, draining lymph nodes and serum during the rejection phase in a fully allogeneic rat cornea transplant model. AB - PURPOSE: To establish a cornea transplant model in a pigmented rat strain and to define the immunologic reaction toward corneal allografts, by studying the cellular and humoral immune response after keratoplasty. METHODS: Full thickness penetrating keratoplasty was performed on Brown Norway (RT1n) recipients using fully major histocompatibility complex (MHC)-mismatched Piebald-Viral-Glaxo (PVG; RT1c) donors. Using multicolor flow cytometry (FACS) we quantified and compared the cellular composition of draining versus non-draining lymph nodes (LN). Furthermore, we developed an isolation method to release viable graft infiltrating lymphocytes (GIL) and subjected them to phenotypic analysis and screened serum from transplanted animals for allo-antibodies. RESULTS: Assessing ipsi-lateral submandibular LN we find ample evidence for post surgical inflammation such as elevated absolute numbers of cluster of differentiation (CD)4+, CD8+, B-cells, and differential expression of CD134. However, we could not unequivocally identify an allo-antigen-specific immune response. FACS analysis of lymphocytes isolated from collagenase digested rejected corneas revealed the following six distinct subpopulations: MHC-2+ cells, CD4+ T-cells, CD8+ T-cells, CD161(dull) large granular lymphocytes, CD3+ CD8+ CD161(dull) natural killer (NK)-T-cells and CD161(high) CD3- NK cells. At post-operation day (POD)-07 only CD161(dull) MHC-2(neg) large granular lymphocytes (LGLs) were detected in syngeneic and allo-grafts. In concordance with an increase in B-cell numbers we often detected copious amounts of allo-antibodies in serum of rejecting animals, in particular immunoglobulin (Ig) M (IgM), immunoglobulin (Ig) G1 (IgG1), and IgG2a. CONCLUSIONS: Our results demonstrate that despite its immune privileged status and low-responder characteristics of the strain combination, allogeneic corneal grafts mount a full fledged T helper1 (Th1) and Th2 response. The presence of NK-T-cells and NK-cells in rejecting corneas shows the synergy between innate and adaptive immunity during allograft destruction. PMID- 21321673 TI - Investigation of oxidative stress in pterygium tissue. AB - PURPOSE: To investigate changes in the oxidant-antioxidant system in pterygium tissue. METHODS: Tissue samples ablated from 40 patients during pterygium surgery constituted the study material, while normal nasal conjunctiva tissue samples from 20 patients matched for age group (who had undergone surgery for strabismus or extracapsular cataract surgery) were used as controls. The samples were kept at -70 degrees C until the time of analysis. Catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) enzymatic activity and the levels of nitric oxide (NO) and malone dialdehyde (MDA) were studied in both groups. RESULTS: The mean age was 54.0+/-12 years in the pterygium patients and 49.0+/-19 in the controls (p=0.270). The enzyme activity levels were significantly lower in the pterygium group when compared to the controls (p<0.001 in each case), while in the same group a significant increase was observed in the MDA and NO levels (also p<0.001, in both cases). CONCLUSIONS: These findings indicating oxidative stress in the pterygium tissue suggest that oxidative stress can play a role in pterygium etiopathogenesis. PMID- 21321674 TI - The Role of Frozen Spins in the Exchange Anisotropy of Core-Shell Fe@Fe(3)O(4) Nanoparticles. AB - Core-shell Fe@Fe(3)O(4) nanoparticles exhibit substantial exchange bias at low temperatures, mediated by unidirectionally aligned moments at the core-shell interface. These spins are frozen into magnetic alignment with field cooling, and are depinned in a temperature-dependent manner. The population of such frozen spins has a direct impact on both coercivity (H(C)) and the exchange-bias field (H(E)), which are modulated by external physical parameters such as the strength of the applied cooling field and the cycling history of magnetic field sweeps (training effect). Aging of the core-shell nanoparticles under ambient conditions results in a gradual decrease in magnetization but overall retention of H(C) and H(E), as well as a large increase in the population of frozen spins. These changes are accompanied by a structural evolution from well-defined core-shell structures to particles containing multiple voids, attributable to the Kirkendall effect. Energy-filtered and high-resolution transmission electron microscopy both indicate further oxidation of the shell layer, but the Fe core is remarkably well preserved. The increase in frozen spin population with age is responsible for the overall retention of exchange bias, despite void formation and other oxidation dependent changes. The exchange-bias field becomes negligible upon deliberate oxidation of Fe@Fe(3)O(4) nanoparticles into yolk-shell particles, with a nearly complete physical separation of core and shell. PMID- 21321675 TI - An evidence based review of acute and long-term effects of cannabis use on executive cognitive functions. AB - Cannabis use has been shown to impair cognitive functions on a number of levels from basic motor coordination to more complex executive function tasks, such as the ability to plan, organize, solve problems, make decisions, remember, and control emotions and behavior. These deficits differ in severity depending on the quantity, recency, age of onset and duration of marijuana use. Understanding how cannabis use impairs executive function is important. Individuals with cannabis related impairment in executive functions have been found to have trouble learning and applying the skills required for successful recovery, putting them at increased risk for relapse to cannabis use. Here we review the research on the acute, residual, and long-term effects of cannabis use on executive functions, and discuss the implications for treatment. PMID- 21321676 TI - A simple, innovative way to reduce rhinitis symptoms after sedation during endoscopy. AB - BACKGROUND: Supplmental oxygen is routinely given via nasal cannula (NC) to patients undergoing moderate sedation for endoscopy. Some patients complain of profuse rhinorrhea and/or sneezing after the procedure, which results in additional medical costs and patient dissatisfaction. OBJECTIVES: To determine the causal relationship between the route of oxygen delivery and troublesome nasal symptoms, and to seek possible solutions. METHODS: Patients (n=836) were randomly assigned to one of the three following groups: the NC group (n=294), the trimmed NC (TNC) group (n=268) and the nasal mask (NM) group (n=274). All received alfentanil 12.5 MUg/kg and midazolam 0.06 mg/kg, and adjunct propofol for sedation. Supplemental oxygen at a flow rate of 4 L/min was used in the NC and TNC groups, and 6 L/min in the NM group. The incidence of nasal symptoms and hypoxia were assessed. RESULTS: The incidence of rhinitis symptoms was significantly higher in the NC group (7.1%) than in the TNC (0.4%) and NM (0%) groups (P<0.001). The incidence of hypoxia was lower in the NC group (3.1%) (P=0.040). All hypoxia events were transient (ie, less than 30 s in duration). On spirometry, the mean value of the lowest saturation of peripheral oxygen was found to be significantly lower in the NM group (96.8%) than in the NC group (97.7%) (P=0.004). CONCLUSIONS: Trimming the NC or using NMs reduced the incidence of rhinitis symptoms; however, the incidence of hypoxia was higher. Further investigation regarding the efficiency of oxygen supplementation is warranted in the design of novel oxygen delivery devices. PMID- 21321677 TI - Ethnic variation in the annual rates of adult inflammatory bowel disease in hospitalized patients in Vancouver, British Columbia. AB - BACKGROUND: There is currently little available information regarding the impact of ethnicity on the clinical features of inflammatory bowel disease (IBD). Migrating populations and changing demographics in Vancouver, British Columbia (BC) provide a unique opportunity to examine the role of ethnicity in the prevalence, expression and complications of IBD. OBJECTIVES: To determine the demographics of IBD and its subtypes leading to hospitalization in the adult population of BC. METHODS: A one-year retrospective study was performed for all patients who presented acutely with IBD to Vancouver General Hospital from January 1, 2006 to December 31, 2006. Data regarding sex, age, ethnicity, IBD type and extent of disease, complications and management strategies were collected. Clinical data were confirmed by pathology and radiology reports. RESULTS: There were 186 cases of IBD comprising Crohn's disease (CD) 56%, ulcerative colitis (UC) 43% and indeterminate colitis (1%) 1%. The annual rate of IBD cases warranting hospitalization in Caucasians was 12.9 per 100,000 persons (7.9 per 100,000 persons for CD and 5.0 per 100,000 persons for UC). This was in contrast to the annual rate of IBD in South Asians at 7.7 per 100,000 persons (1.0 per 100,000 persons for CD and 6.8 per 100,000 persons for UC) and in Pacific Asians at 2.1 per 100,000 persons (1.3 per 100,000 persons for CD, 0.8 per 100,000 persons for UC). The male to female ratio was higher in South Asians and Pacific Asians than in Caucasians. The extent of disease was significantly different across racial groups, as was the rate of complications. CONCLUSIONS: These early results suggest that there are ethnic disparities in the annual rates of IBD warranting hospitalization in the adult population of BC. There was a significantly higher rate of CD in the Caucasian population than in South Asian and Pacific Asian populations. The South Asian population had a higher rate of UC, with an increased rate of complications and male predominance. Interestingly, the rate of CD and UC was lowest in the Pacific Asian population. These racial differences - which were statistically significant - suggest a role for ethnodiversity and environmental changes in the prevalence of IBD in Vancouver. PMID- 21321678 TI - A comparison of hospital and nonhospital colonoscopy: wait times, fees and guideline adherence to follow-up interval. AB - BACKGROUND: Although colonoscopy is increasingly performed in nonhospital facilities, studies to date examining differences between colonoscopy services in hospital and nonhospital settings have been limited, in large part, to administrative databases. OBJECTIVES: To describe the experiences of patients receiving colonoscopy in hospital and nonhospital settings, and to compare these settings with respect to wait times and recommended follow-up interval to the next colonoscopy. METHODS: A postal survey of 2000 patients, 50 to 70 years of age, from an urban academic family practice was conducted. Most recent colonoscopy was classified as either occurring in a hospital or nonhospital setting. Multivariable logistic regression analysis was used to examine the association among wait times, follow-up intervals and patient factors with respect to colonoscopy setting. RESULTS: Patients who underwent their most recent colonoscopy outside of a hospital were more likely to be men (P=0.01) and to have undergone more than one previous colonoscopy (P=0.02). For patients with a normal screening colonoscopy and no family history of colorectal cancer or polyps, nonhospital clinics less often recommended a 10-year follow-up interval (OR 0.13 [95% CI 0.04 to 0.47]). Reported wait times at nonhospital clinics were shorter for patients receiving screening colonoscopy (OR 2.11 [95% CI 1.28 to 3.47]), but not for symptomatic patients (OR 1.74 [95% CI 0.88 to 3.43]). For individuals attending nonhospital clinics, 10% were referred from a hospital by the same specialist performing the procedure; 31.7% reported paying a fee. CONCLUSION: Nonhospital clinics were far less likely to adhere to guidelines regarding follow up intervals for low-risk patients. Given the implications for both health care costs and patient safety, further study is needed to determine the cause of this disparity. PMID- 21321679 TI - A nine-year audit of open-access upper gastrointestinal endoscopic procedures: results and experience of a single centre. AB - BACKGROUND: The appropriateness and safety of open-access endoscopy are very important issues as its use continues to increase. OBJECTIVE: To present a review of a nine-year experience with open-access upper gastrointestinal endoscopy with respect to indications, diagnostic efficacy, safety and diseases diagnosed. METHODS: A retrospective, observational case series of all patients who underwent open-access endoscopy between January 2000 and December 2008 was conducted. Indications were classified as appropriate or not appropriate according to American Society of Gastrointestinal Endoscopy (ASGE) guidelines. Endoscopic diagnoses were based on widely accepted criteria. Major complication rates were assessed. RESULTS: A total of 20,620 patients with a mean age of 58 years were assessed, of whom 11,589 (56.2%) were women and 9031 (43.8%) were men. Adherence to ASGE indications led to statistically significant, clinically relevant findings. The most common indications in patients older than age 45 years of age were dyspepsia (28.5%) and anemia (19.7%) in the ASGE-appropriate group, and dyspepsia in patients younger than 45 years of age without therapy trial (6.6%) in the nonappropriate group. Of the examinations, 38.57% were normal. Hiatal hernia and nonerosive gastritis were the most common findings. Important diagnoses such as malignancies and duodenal ulcers would have been missed if endoscopies were performed only according to appropriateness. There were only two major complications and no mortalities. CONCLUSIONS: Open-access upper gastrointestinal endoscopy is a safe and effective system. More relevant findings were found when adhering to the ASGE guidelines. However, using these guidelines as the sole determining factor in whether to perform an endoscopy is not advisable because many clinically relevant diagnoses may be overlooked. PMID- 21321680 TI - Comparing the efficacy of biofeedback and balloon-assisted training in the treatment of dyssynergic defecation. AB - BACKGROUND: Dyssynergic defecation does not respond appropriately to routine treatments for constipation. Recently, research has shown that biofeedback therapy is useful in anorectal dyssynergia. OBJECTIVE: To compare two treatment modalities for patients experiencing dyssynergic defecation. METHODS: Sixty-five subjects with dyssynergic defecation were recruited and randomly allocated to one of two treatment groups: balloon defecation training and biofeedback therapy. In the first group, a balloon was inserted into the rectum and inflated by water injection so that the patient experienced the sensation of a full rectum and, thus, the need to defecate. The patient was subsequently asked to reject the balloon. In the biofeedback group, the pen electrode of an electromyographic biofeedback device was inserted into the rectum, with the patient subsequently being asked to increase abdominal pressure and relax the rectal muscles accordingly. RESULTS: The findings showed a reduction in constipation in both groups. The ability to reject the balloon (volume and time) was significantly better in postintervention measurements; however, better results were found in the biofeedback arm of the study. Patient satisfaction after treatment reached 52% with balloon training and 79% in the biofeedback group. Reports of incomplete evacuation and the need for digit use during defecation remained constant after treatment in balloon-trained patients. CONCLUSION: Biofeedback training appeared to be superior to balloon defecation training and resulted in measurable changes in subjective and objective variables of dyssynergia. PMID- 21321681 TI - Quality of Internet-based information on gastrointestinal diseases. AB - BACKGROUND: The Internet is becoming an increasingly common source of health information for patients. OBJECTIVE: To examine the quality of gastrointestinal disease- and symptom-related Internet sites that might be searched by patients. METHODS: A total of 120 websites were evaluated from July to November 2009 using the DISCERN instrument to determine the quality of content of health and treatment information. RESULTS: There was substantial variability in the quality of Internet resources regarding gastrointestinal diseases and their symptoms. Information-based and institutional websites were rated highest. Resources related to celiac disease, colon cancer and abdominal pain scored the highest. CONCLUSIONS: Overall, the quality of web-based resources was variable. Because patient education is important in the management of gastroenterological diseases, the increasing use of the Internet poses new opportunities and challenges for physicians. PMID- 21321682 TI - Treatment of gastric epithelial tumours by endoscopic submucosal dissection using an insulated-tip diathermic knife. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) is a promising technique for the treatment of large, pre- and early malignant gastrointestinal lesions. OBJECTIVE: To assess the rates of en bloc resection, incidence of complications, procedure times and therapeutic outcomes of ESD using an insulated-tip diathermic knife; and to investigate predictors of these outcomes based on the final pathological features of biopsy specimens. METHODS: One hundred twenty patients with endoscopically suspected gastric epithelial tumours who were treated with ESD from January 2006 to December 2009 were evaluated. RESULTS: The mean diameter of the gastric epithelial tumours in the present cohort was 1.88 cm. The mean diameter of the resected specimens was 3.33 cm. The en bloc resection rate was 90% (108 of 120). The median length of the operation was 64.6 min. The bleeding and perforation complication rates were 5.0% (six of 120) and 2.5% (three of 120), respectively. Of 10 gastric tumours initially diagnosed as adenocarcinoma on biopsy, four were found to be low-grade dysplasia and six were found to be high-grade dysplasia after resection and final pathological examination. A total of 112 (93.33%) patients underwent curative treatment, eight patients (6.67%) underwent noncurative treatment with ESD, and two patients (1.67%) experienced local recurrence and subsequently underwent surgery. CONCLUSIONS: ESD is a promising local curative treatment option for gastric epithelial tumours, but still carries the risks of bleeding and/or perforation. Differences in the interpretation of histological results among different pathologists and/or between biopsy specimens before ESD and the en bloc tissue specimens after ESD will result in discrepancies. PMID- 21321683 TI - A novel Surface Plasmon Resonance enhanced Total Internal Reflection Ellipsometric application: electrochemically grafted isophthalic acid nanofilm on gold surface. AB - The scope of this study is to modify a Surface Plasmon Resonance (SPR) sensor slide with isophthalic acid to evaluate the possible application on the detection of copper(II) ions in aqueous media by total internal reflection ellipsometry. A gold sensor surface was modified by an electrochemical diazonium reduction modification method. The modified surfaces are characterized with cyclic voltammetry (CV) and ellipsometry. Isophthalic acid monolayer modified gold slides were used for in situ detection of aqueous Cu(2+) solution with the SPR enhanced total internal reflection ellipsometry (SPRe-TIRE) technique. Layer formation, pH dependency of adsorption, sensor response of the SPRe-TIRE and isothermal kinetic parameters were examined. A high dependency on the number of CV cycles in the monolayer-multiple layer transition was observed. The suggested sensor gave a linear response over a wide range of Cu(2+) concentrations. It was also reported that adsorption on the SPRe-TIRE sensor gave Langmuir adsorption model behavior. PMID- 21321684 TI - Enantioseparation of dansyl amino acids by ultra-high pressure liquid chromatography using cationic beta-cyclodextrins as chiral additives. AB - This work reports the application of ultra-high pressure liquid chromatography (UHPLC) for reasonably fast enantiorecognition of some dansyl amino acids by employing three cationic beta-cyclodextrins (beta-CDs) as chiral additives. Good resolutions were obtained on an Agilent C18 column (2.1 mm i.d.; 1.8 MUm; 50 mm length) with 1% (v/v) triethylammonium acetate buffered at pH 4.7 and acetonitrile as the mobile phase. Most of the analytes could be baseline resolved within 10 min. Increased cationic CD concentration or acetonitrile proportion in the mobile phase results in a decreased retention factor but accentuated selectivity. Furthermore, molecular mechanics calculation was performed and found to be consistent with the experimental results. PMID- 21321685 TI - Noise incorporated subwindow permutation analysis for informative gene selection using support vector machines. AB - Selecting a small subset of informative genes plays an important role in accurate prediction of clinical tumor samples. Based on model population analysis, a novel variable selection method, called noise incorporated subwindow permutation analysis (NISPA), is proposed in this study to work with support vector machines (SVMs). The essence of NISPA lies in the point that one noise variable is added into each sampled sub-dataset and then the distribution of variable importance of the added noise could be computed and serves as the common reference to evaluate the experimental variables. Further, by using the non-parametric Mann-Whitney U test, a P value can be assigned to each variable which describes to what extent the distributions of the gene variable and the noise variable are different. According to the computed P values, all the variables could be ranked and then a small subset of informative variables could be determined to build the model. Moreover, by NISPA, we are the first to distinguish the variables into a more detailed classification as informative, uninformative (noise) and interfering variables in comparison with other methods. In this study, two microarray datasets are employed to evaluate the performance of NISPA. The results show that the prediction errors of SVM classifiers could be significantly reduced by variable selection using NISPA. It is concluded that NISPA is a good alternative of variable selection algorithm. PMID- 21321686 TI - Investigation of the signaling mechanism and verification of the performance of an electrochemical real-time PCR system based on the interaction of methylene blue with DNA. AB - The operation of an electrochemical real-time PCR system, based on intercalative binding of methylene blue (MB) with dsDNA, has been demonstrated. PCR was performed on a fabricated electrode-patterned glass chip containing MB while recording the cathodic current peak by measuring the square wave voltammogram (SWV). The current peak signal was found to decrease with an increase in the PCR cycle number. This phenomenon was found to be mainly a consequence of the lower apparent diffusion rate of the MB-DNA complex (D(b) = 6.82 * 10(-6) cm(2) s(-1) with 612 bp dsDNA) as compared to that of free MB (D(f) = 5.06 * 10(-5) cm(2) s( 1)). Utilizing this signal changing mechanism, we successfully demonstrated the feasibility of an electrochemical real-time PCR system by accurately quantifying initial copy numbers of Chlamydia trachomatis DNA templates on a direct electrode chip. A standard calibration plot of the threshold cycle (C(t)) value versus the log of the input template quantity demonstrated reliable linearity and a good PCR efficiency (106%) that is comparable to that of a conventional TaqMan probe-based real time PCR. Finally, the system developed in this effort can be employed as a key technology for the achievement of point-of-care genetic diagnosis based on the electrochemical real-time PCR. PMID- 21321687 TI - A procedure for identifying stem cell compartments with multi-lineage differentiation potential. AB - Stem cells isolated from adult human tissue have received increasing attention because of their potential to repair and/or regenerate damaged tissue. However, identification and characterization of such cell populations have been limited due to the lack of adequate methodology for assessing their multi-lineage potential. In the present study, using adult human ligament tissue as a model, we have developed a combination of methods which together can be used to identify adult stem cell compartments based on their ability to undergo a range of differentiation pathways, including osteogenesis, adipogenesis, chondrogenesis, myogenesis, vasculogenesis, angiogenesis, neurogenesis and gliogenesis in vitro. This was carried out using the conventional reverse transcription polymerase chain reaction technique to assess the expression of selected key lineage associated marker genes and by using histological, immunological and morphological criteria to assess characteristic features of lineage-specific 'terminal' differentiation in vitro. PMID- 21321688 TI - Potential controlling highly-efficient catalysis of wheat-like silver particles for electrochemiluminescence immunosensor labeled by nano-Pt@Ru and multi-sites biotin/streptavidin affinity. AB - The potential controlling silver catalysis for Ru(bpy)(3)(2+) electrochemiluminescence (ECL) signal at a special potential -0.4~1.25 V was newly developed as the new ECL signal amplification strategy for ultrasensitive protein detection. Firstly, the wheat-like deposited silver (DpAg) particles were modified on the bare glass carbon electrode (GCE) surface by cyclic voltammetry deposition to capture the primary antibodies and then bind the antigen analytes. Secondly, as a sandwich immunoreaction format, the secondary antibodies conjugated with the Ru(bpy)(3)(2+)-doped Pt (Pt@Ru) nanoparticles by the multi sites biotin/streptavidin (SA) affinity can be captured onto the electrode surface to generate ECL signal. In the proposed Ru(bpy)(3)(2+) ECL system without any co-reactant, the detected ECL signal was amplified due to following multiple amplification strategies: (1) the ECL catalysis for Ru(bpy)(3)(2+) was performed by electro-inducing the DpAg particles to generate Ag(+) ion and controlled by the special potential. The catalyzer Ag(+) was produced near the electrode surface and reproduced by cyclic potential scan, which improved the catalytic efficiency. (2) The amount of the ECL signal probes linked to secondary antibodies were amplified by the adsorption of Pt nanoparticles and the multiple sites bridge linkage of biotin/SA. These new multiple signal amplification strategies made the proposed ECL immunosensor achieve ultrasensitive detection for model protein human IgG with a detection limit down to 3 pg mL(-1), which can be further extended to the detection of disease biomarkers. PMID- 21321689 TI - Biologically modified hydrogels for chemical and biochemical analysis. AB - This review focuses on recent advances in the use of hydrogels for chemical and biochemical analysis. Specifically, we discuss recognition elements encapsulated within synthetic hydrogels, synthetic polymers grafted with biological molecules that form freestanding gels, and gels made of naturally occurring polymers, such as proteins or polysaccharides. Gels considered here serve as a platform for the analysis or separation of chemical systems with a high degree of selectivity. Analysis or separation was achieved primarily by incorporating biologically active molecules into a gel matrix. Future developments in biologically integrated gel research for chemical analysis are promising due to the diversity of chemical systems yet to be investigated by these versatile analytical platforms. PMID- 21321690 TI - Selection of DNA aptamers recognizing small cell lung cancer using living cell SELEX. AB - We applied Systematic Evolution of Ligands by EXponential enrichment using Small Cell Lung Cancer (SCLC) cells. A DNA aptamer was identified and evaluated by fluorescent confocal microscopy and flow cytometry. Our results showed that the DNA aptamer binds to molecules that exist predominantly on target SCLC cell surfaces compared with other types of SCLC cells. PMID- 21321691 TI - A novel pH-responsive polysaccharidic ionic complex for proapoptotic D-(KLAKLAK)2 peptide delivery. AB - We report charge-switching ionic nanocomplexes comprised of glycol chitosan grafted with 2,3-dimethylmaleic acid (DMA) (denoted as 'GCS-g-DMA' hereafter) and a proapoptotic peptide. This system allowed for improved peptide delivery to tumor sites via a mechanism of selective peptide release when the pH was dropped from 7.4 to 6.8. PMID- 21321692 TI - Excited-state annihilation in a homodinuclear ruthenium complex. AB - Ultrafast excited-state annihilation in a homodinuclear ruthenium complex is observed. This coordination compound constitutes a model system for approaches towards artificial photosynthetic systems. The observation of pump-intensity dependent triplet-triplet annihilation highlights the importance of considering various loss mechanisms in the design of artificial photosynthetic assemblies. PMID- 21321693 TI - Triarylboron-functionalized 8-hydroxyquinolines and their aluminium(III) complexes. AB - The first examples of triarylboron-functionalized 8-hydroxyquinoline ligands and their aluminium complexes have been synthesized. These luminescent derivatives of the well-known electron transport material tris(8-hydroxyquinoline)aluminium (Alq(3)) display enhanced electron-accepting ability relative to Alq(3), and can also be used as an indicator for small F(-) and CN(-) anions. PMID- 21321694 TI - The first ionothermal synthesis of a 3D ferroelectric metal-organic framework with colossal dielectric constant. AB - A novel 3D (4,6)-connected topological architecture, obtained under ionothermal conditions by using 1-ethyl-3-methyl imidazolium bromide ([EMI]Br) as solvent and structure-directing agent, presents a non-centrosymmetric polar packing arrangement showing an interesting ferroelectric property. PMID- 21321695 TI - Controllable synthesis of Cu-based nanocrystals in ODA solvent. AB - We exploited a solution-based route for preparation of Cu, Cu(2)O, Cu(3)N, and Cu(2)S nanocrystals, that is, direct thermal decomposition of copper salts (Cu(NO(3))(2), CuSO(4)) in octadecylamine (ODA) solvent, which is a novel and ingenious chemical process. PMID- 21321696 TI - Functionalized Ag nanoparticles with tunable optical properties for selective protein analysis. AB - We present a preparation procedure for small sized biocompatibly coated Ag nanoparticles with tunable surface plasmon resonances. The conditions were optimised with respect to the resonance Raman signal enhancement of heme proteins and to the preservation of the native protein structure. PMID- 21321697 TI - Controlled structures of a 1D chiral metallosalen polymer by photo- and solvent induced partial depolymerization. AB - A 1D chiral metallosalen polymer with free pyridine groups is self-assembled and its molecular weight, conformation, architecture and optical property are controlled by depolymerization through sunlight irradiation or alcohol inclusions. PMID- 21321698 TI - A nanoscale DNA-Au dendrimer as a signal amplifier for the universal design of functional DNA-based SERS biosensors. AB - The use of a nanoscale DNA-Au dendrimer as a signal amplifier was proposed for the universal design of functional DNA-based ultra-sensitive SERS biosensors. This novel design combines the high specificity of functional DNA with the high sensitivity of surface-enhanced Raman scattering (SERS) spectroscopy, resulting in sensitivity superior to that of previously reported sensors. PMID- 21321699 TI - Perpendicular growth of catalyst-free germanium nanowire arrays. AB - High yields of single-crystalline Ge nanowires (NWs) were synthesised in the vapour phase of a high boiling point organic solvent without the need for metal catalyst particles. High density, perpendicular arrays of Ge NWs were subsequently grown from ITO coated substrates. The approach represents a convenient route toward orientated arrays of catalyst-free Ge NWs. PMID- 21321700 TI - One of the most complex "small molecule structures" ever reported: 16 independent molecules in the asymmetric unit for an ortho-palladated primary amine. AB - The presumably "small molecule structure" of the organopalladium complex rac PdCl(C(6)H(3)-4-OMe-CHMeNH(2))(py) crystallizes with 16 molecules in the asymmetric unit, a highly unusual situation according to the CSD database. The symmetrically independent residues differ with respect to soft conformational degrees of freedom. Packing in the acetonitrile solvate of the same compound is unexceptional. PMID- 21321701 TI - Discrete Ag6L6 coordination nanotubular structures based on a T-shaped pyridyl diphosphine. AB - Ag(6)L(6)-type coordination nanotubular structures have been assembled from 6 Ag(I) ions and 6 T-shaped ligands, 4-(3,5-bis(diphenylphosphino)phenyl)pyridine; the nanotubes represent a discrete molecular architecture of a number of polymeric structures assembled from dimeric building blocks. PMID- 21321702 TI - Microwave synthesis of zinc sulfite and porous zinc oxide microrods. AB - ZnSO(3) microrods with uniform size and shape can be prepared under microwave irradiation at much higher speed than a conventional heating bath, usually in minutes. The annealing of ZnSO(3) microrods produced porous ZnO microrods with pore size between 50-200 nm. PMID- 21321703 TI - One-pot efficient synthesis of dimeric, trimeric, and tetrameric BODIPY dyes for panchromatic absorption. AB - One-pot Knoevenagel self-condensation reaction of beta-formyl BODIPY dye bearing a formyl group at 2-position offered dimeric, trimeric and tetrameric BODIPY dyes containing a formyl capping end group, exhibiting panchromatic absorption. PMID- 21321704 TI - FITC-modified PPy nanotubes embedded in nanoporous AAO membrane can detect trace PCB20 via fluorescence ratiometric measurement. AB - A highly sensitive and selective fluorescence ratiometric sensor membrane for 2,3,3'-trichlorobiphenyl has been achieved, via depositing polypyrrole nanotubes (PPyNTs, the fluorescence indicator) in nano-porous anodic aluminium oxide (NPAAO) template and subsequently immobilizing fluorescein isothiocyanate (as an internal reference) onto the inner walls of the PPyNTs embedded in the NPAAO. PMID- 21321705 TI - Photocontrolled reversible room temperature phosphorescence (RTP) encoding beta cyclodextrin pseudorotaxane. AB - Photocontrolled reversible room temperature phosphorescence (RTP) emission engendered by the complexation of beta-cyclodextrin (beta-CD) and alpha bromonaphthalene (alpha-BrNp) can be employed to address the threading and dethreading of the pseudorotaxane formed between beta-CD and sodium 2-hydroxy-5 ((4-nitrophenyl)diazenyl)benzoate (DAYR) in the ternary system in aqueous solution. PMID- 21321706 TI - Efficient disc on pillar substrates for surface enhanced Raman spectroscopy. AB - In this work, geometrical optimizations of Ag disc on pillar (DOP) hybrid plasmonic nanostructures were conducted and allowed us to achieve reproducible average enhancement factors of 1 * 10(9) and greater. PMID- 21321707 TI - Redox strategy for reversible attachment of biomolecules using bifunctional linkers. AB - Soft attachment of streptavidin to beta-cyclodextrin-modified pegylated SAMs was efficiently performed in a reversible and repetitive way via orthogonal bifunctional linkers involving streptavidin-biotin recognition and redox-driven multivalent host-guest (beta-cyclodextrin-ferrocene) interactions. PMID- 21321708 TI - Hydrosilylation of epoxides catalyzed by a cationic eta1-silane iridium(III) complex. AB - Cationic silane complex 2, catalyzes the hydrosilylation of epoxides and cyclic ethers to give the silyl-protected alcohols, regioselectively. A mechanistic study shows that the epoxide undergoes isomerization to the ketone, followed by hydrosilylation. PMID- 21321709 TI - A novel allylic transfer reaction of chirally modified 2-borylbutadiene: synthesis of chiral homoallenyl alcohols. AB - An enantioselective synthesis of the homoallenyl alcohols was achieved from the reaction of chiral 2-borylbutadiene with aldehydes through an allylic transfer reaction in good yields and enantioselectivities. PMID- 21321710 TI - Unusual enhancement in electrical conductivity of tin oxide thin films with zinc doping. AB - Electrical conductivity of SnO(2)-based oxides is of great importance for their application as transparent conducting oxides (TCO) and gas sensors. In this paper, for the first time, an unusual enhancement in electrical conductivity was observed for SnO(2) films upon zinc doping. Films with Zn/(Zn + Sn) reaching 0.48 were grown by pulsed spray-evaporation chemical vapor deposition. X-Ray diffraction (XRD) shows that pure and zinc-doped SnO(2) films grow in the tetragonal rutile-type structure. Within the low doping concentration range, Zn leads to a significant decrease of the crystallite size and electrical resistivity. Increasing Zn doping concentration above Zn/(Zn + Sn) = 0.12 leads to an XRD-amorphous film with electrical resistivity below 0.015 Omega cm at room temperature. Optical measurements show transparencies above 80% in the visible spectral range for all films, and doping was shown to be efficient for the band gap tuning. PMID- 21321711 TI - A site energy distribution function from Toth isotherm for adsorption of gases on heterogeneous surfaces. AB - A site energy distribution function based on a condensation approximation method is proposed for gas-phase adsorption systems following the Toth isotherm. The proposed model is successfully applied to estimate the site energy distribution of three pitch-based activated carbons (PA, PFeA and PBA) developed in our laboratory and also for other common adsorbent materials for different gas molecules. According to the proposed model the site energy distribution curves of the activated carbons are found to be exponential for hydrogen at 77 K. The site energy distribution of some of the activated carbon fibers, ambersorb, Dowex optipore, 13X Zeolite for different adsorbate molecules represents a quasi Gaussian curve with a widened left hand side, indicating that most sites have adsorption energies lower than a statistical mean value. PMID- 21321712 TI - Exploring dynamical electron theory beyond the Born-Oppenheimer framework: from chemical reactivity to non-adiabatically coupled electronic and nuclear wavepackets on-the-fly under laser field. AB - Chemical theory and its application to dynamical electrons in molecules under intense electromagnetic fields is explored, in which we take an explicit account of nuclear nonadiabatic (kinematic) interactions along with simultaneous coupling with intense optical interactions. All the electronic wavefunctions studied here are necessarily time-dependent, and thereby beyond stationary state quantum chemistry based on the Born-Oppenheimer framework. As a general and tractable alternative framework with which to track the electronic and nuclear simultaneous dynamics, we propose an on-the-fly method to calculate the electron and nuclear wavepackets coupled along the branching non-Born-Oppenheimer paths, through which their bifurcations, strong quantum entanglement between nuclear electronic motions, and coherence and decoherence among the phases associated with them are properly represented. Some illustrative numerical examples are also reported, which are aimed at our final goals; real time tracking of nonadiabatic electronic states, chemical dynamics in densely degenerate electronic states coupled with nuclear motions and manipulation and/or creation of new electronic states in terms of intense lasers, and so on. Other examples are also presented as to how the electron wavepacket dynamics can be used to analyze chemical reactions, shedding a new light on some typical and conventional chemical reactions such as proton transfer followed by tautomerization. PMID- 21321713 TI - Hierarchical superstructure of alkylamine-coated ZnS nanoparticle assemblies. AB - We describe methodology for producing highly uniform, ordered and reproducible superstructures of surfactant-coated ZnS nanorod and nanowire assemblies, and propose a predictive multiscale "packing model" for superstructure formation based on electron microscopy and powder X-ray diffraction data on the superstructure, as well as on individual components of the nanostructured system. The studied nanoparticles showed a hierarchical structure starting from the individual faceted ZnS inorganic cores, onto which the crystalline surfactant molecules are adsorbed, to the superstructure of the nanoparticle arrays. Our results point out the critical role of the surfactant headgroup and polarity in nanoparticle assembly, and demonstrate the relationship between the molecular structure of the surfactant and the resulting superstructure of the nanoparticle assemblies. PMID- 21321714 TI - Analytical theory of ideal polydisperse polymers at interfaces. AB - We use a recently developed continuum theory to present an exact treatment of the interfacial properties of ideal polymers displaying Schulz-Flory polydispersity. Our results are remarkably compact and can be derived from the properties of equilibrium, ideal polymers at interfaces. We apply our theory to a number of cases, including, non-adsorbing and adsorbing surfaces, as well as telechelic chains. PMID- 21321715 TI - Theoretical study of dynamic electron-spin-polarization via the doublet-quartet quantum-mixed state and time-resolved ESR spectra of the quartet high-spin state. AB - The mechanism of the unique dynamic electron polarization of the quartet (S = 3/2) high-spin state via a doublet-quartet quantum-mixed state and detail theoretical calculations of the population transfer are reported. By the photo induced electron transfer, the quantum-mixed charge-separate state is generated in acceptor-donor-radical triad (A-D-R). This mechanism explains well the unique dynamic electron polarization of the quartet state of A-D-R. The generation of the selectively populated quantum-mixed state and its transfer to the strongly coupled pure quartet and doublet states have been treated both by a perturbation approach and by exact numerical calculations. The analytical solutions show that generation of the quantum-mixed states with the selective populations after de coherence and/or accompanying the (complete) dephasing during the charge recombination are essential for the unique dynamic electron polarization. Thus, the elimination of the quantum coherence (loss of the quantum information) is the key process for the population transfer from the quantum-mixed state to the quartet state. The generation of high-field polarization on the strongly coupled quartet state by the charge-recombination process can be explained by a polarization transfer from the quantum-mixed charge-separate state. Typical time resolved ESR patterns of the quantum-mixed state and of the strongly coupled quartet state are simulated based on the generation mechanism of the dynamic electron polarization. The dependence of the spectral pattern of the quartet high spin state has been clarified for the fine-structure tensor and the exchange interaction of the quantum-mixed state. The spectral pattern of the quartet state is not sensitive towards the fine-structure tensor of the quantum-mixed state, because this tensor contributes only as a perturbation in the population transfer to the spin-sublevels of the quartet state. Based on the stochastic Liouville equation, it is also discussed why the selective population in the quantum-mixed state is generated for the "finite field" spin-sublevels. The numerical calculations of the elimination of the quantum coherence (de-coherence and/or dephasing) are demonstrated. A new possibility of the enhanced intersystem crossing pathway in solution is also proposed. PMID- 21321716 TI - Excitation energy migration in oligo(p-phenylenevinylene) based organogels: structure-property relationship and FRET efficiency. AB - Excitation energy migration (EM) and assisted energy transfer (ET) properties of a few oligo(p-phenylenevinylene) (OPV) based organogelators with different end functional groups have been studied using picosecond time-resolved emission spectroscopy (TRES). EM was found to be more efficient in OPV gelators with small end functional groups (OPV3-4) when compared to that of the gelators with bulky end groups (OPV1-2) in the gel state. TRES studies at elevated temperature and in chloroform solution highlight the role of the self-assembled scaffolds in assisting the EM and ET processes. Increase in temperature and solvent polarity leads to the aggregate breaking and hence adversely affects the EM and ET efficiencies. The effect of EM efficiency on the fluorescence resonance energy transfer (FRET) properties of the OPV gels was studied by using OPV1 and OPV3 as the donors and OPV5 as the acceptor. Better transfer of excitation energy was observed in the donor system (OPV3) having higher EM efficiency even at very low concentration (3.1 mol%) of the acceptor molecules, whereas ET efficiency was lower in the donor system (OPV1) with low EM efficiency. PMID- 21321717 TI - A permanent optical storage medium exhibiting ultrahigh contrast, superior stability, and a broad working wavelength regime. AB - In this paper we demonstrate an optical storage medium having advantages of ultrahigh contrast, superior stability, and broadband working wavelengths. Combining a single shot of deep-ultraviolet (UV) laser illumination with a Au particle-assisted etching process, we formed broadband antireflective, one dimensional silicon nanowire arrays (SiNWs) with selectively at specific positions. Optical measurements and three-dimensional finite-difference time domain (3D-FDTD) simulations revealed ultrahigh reflection contrast between the Au and the SiNWs for both far- and near-field regimes. Relative to typical organic-based storage media, Au films and SiNWs are more stable, both chemically and thermally; therefore, we suspect that this new storage medium would exhibit high stability toward moisture, sunshine, and elevated temperatures. PMID- 21321718 TI - Ionization-loss stimulated Raman spectroscopy for conformational probing of flexible molecules. AB - The approach of studying structural and dynamical properties of flexible molecules is of substantial interest, as it allows decoding the shapes and intrinsic properties of isolated molecular constituents, which have an influence on the selectivity and functionality in biological processes. Combining quantum computation methods with double resonance or infrared hole burning techniques, mainly covering hydride stretch vibrations, recently led to great progress in understanding the structure of a variety of biological building blocks. Measurements of spectra in the lower frequency range, with relatively compact and convenient laser sources, still pose major challenges. For this reason, the method of ionization-loss stimulated Raman spectroscopy (ILSRS) has been developed and applied for monitoring the spectral features of the 2-phenylethanol prototype. The bands observed in the Raman spectra of its two conformers uniquely identify their structures and are in accord with anharmonic results obtained by density functional theory calculations. These findings point to future opportunities for ILSRS as a powerful conformational probe and set new standards for detailed interrogation of structure and intra- and inter-molecular interactions. PMID- 21321719 TI - Towards homonuclear J solid-state NMR correlation experiments for half-integer quadrupolar nuclei: experimental and simulated 11B MAS spin-echo dephasing and calculated 2J(BB) coupling constants for lithium diborate. AB - Magic-angle spinning (MAS) NMR spin-echo dephasing is systematically investigated for the spin I = 3/2 (11)B nucleus in lithium diborate, Li(2)O.2B(2)O(3). A clear dependence on the quadrupolar frequency (omega(Q)(PAS)/2pi = 3C(Q)/[4I(2I- 1)]) is observed: the B3 (larger C(Q)) site dephases more slowly than the B4 site at all investigated MAS frequencies (5 to 20 kHz) at 14.1 T. Increasing the MAS frequency leads to markedly slower dephasing for the B3 site, while there is a much less evident effect for the B4 site. Considering samples at 5, 25, 80 (natural abundance) and 100% (11)B isotopic abundance, dephasing becomes faster for both sites as the (11)B isotopic abundance increases. The experimental behaviour is rationalised using density matrix simulations for two and three dipolar-coupled (11)B nuclei. The experimentally observed slower dephasing for the larger C(Q) (B3) site is reproduced in all simulations and is explained by the reintroduction of the dipolar coupling by the so-called "spontaneous quadrupolar-driven recoupling mechanism" having a different dependence on the MAS frequency for different quadrupolar frequencies. Specifically, isolated spin-pair simulations show that the spontaneous quadrupolar-driven recoupling mechanism is most efficient when the quadrupolar frequency is equal to twice the MAS frequency. While for isolated spin-pair simulations, increasing the MAS frequency leads to faster dephasing, agreement with experiment is observed for three-spin simulations which additionally include the homogeneous nature of the homonuclear dipolar coupling network. First-principles calculations, using the GIPAW approach, of the (2)J(11B-11B) couplings in lithium diborate, metaborate and triborate are presented: a clear trend is revealed whereby the (2)J(11B-11B) couplings increase with increasing B-O-B bond angle and B-B distance. However, the calculated (2)J(11B-11B) couplings are small (0.95, 1.20 and 2.65 Hz in lithium diborate), thus explaining why no zero crossing due to J modulation is observed experimentally, even for the sample at 25% (11)B where significant spin echo intensity remains out to durations of ~200 ms. PMID- 21321720 TI - nsigma* and pisigma* excited states in aryl halide photochemistry: a comprehensive study of the UV photodissociation dynamics of iodobenzene. AB - A recent review (Ashfold et al., Phys. Chem. Chem. Phys., 2010, 12, 1218) highlighted the important role of dissociative excited states formed by electron promotion to sigma* orbitals in establishing the photochemistry of many molecular hydrides. Here we extend such considerations to molecular halides, with a particular focus on iodobenzene. Two experimental techniques (velocity mapped ion imaging (VMI) and time resolved infrared (IR) diode laser absorption) and electronic structure calculations have been employed in a comprehensive study of the near ultraviolet (UV) photodissociation of gas phase iodobenzene molecules. The VMI studies yield the speeds and angular distributions of the I((2)P(3/2)) and I*((2)P(1/2)) photofragments formed by photolysis in the wavelength range 330 >=lambda>= 206 nm. Four distinct dissociation channels are observed for the I((2)P(3/2)) atom products, and a further three channels for the I*((2)P(1/2)) fragments. The phenyl (Ph) radical partners formed via one particular I* product channel following excitation at wavelengths 305 >=lambda>= 250 nm are distributed over a sufficiently select sub-set of vibrational (v) states that the images allow resolution of specific I* + Ph(v) channels, identification of the active product mode (nu(10), an in-plane ring breathing mode), and a refined determination of D(0)(Ph-I) = 23,390 +/- 50 cm(-1). The time-resolved IR absorption studies allow determination of the spin-orbit branching ratio in the iodine atom products formed at lambda = 248 nm (phi(I*) = [I*]/([I] + [I*]) = 0.28 +/- 0.04) and at 266 nm (phi(I*) = 0.32 +/- 0.05). The complementary high level, spin-orbit resolved ab initio calculations of sections (along the C-I bond coordinate) through the ground and first 19 excited state potential energy surfaces (PESs) reveal numerous excited states in the energy range of current interest. Except at the very shortest wavelength, however, all of the observed I and I* products display limiting or near limiting parallel recoil anisotropy. This encourages discussion of the fragmentation dynamics in terms of excitation to states of A(1) total symmetry and dissociation on the 2A(1) and 4A(1) (sigma* <- n/pi) PESs to yield, respectively, I and I* products, or via non-adiabatic coupling to other sigma* <- n/pi PESs that correlate to these respective limits. Similarities (and differences) with the available UV photochemical data for the other aryl halides, and with the simpler (and more thoroughly studied) iodides HI and CH(3)I, are summarised. PMID- 21321721 TI - Understanding the nitrate coordination to Eu3+ ions in solution by potential of mean force calculations. AB - Coordination of nitrate anions with lanthanoid cations (Ln(3+)) in water, methanol and octanol-1 has been studied by means of molecular dynamics simulations with explicit polarization. Potential of mean force (PMF) profiles have been calculated for a mono-complex of lanthanoid nitrate (Ln(NO(3))(2+)) in these solvents using umbrella-sampling molecular dynamics. In pure water, no difference in the nitrato coordination to lanthanoids (Nd(3+), Eu(3+) and Dy(3+)) is observed, i.e. the nitrate anion prefers the monodentate coordination, which promotes the salt dissociation. Then, the influence of the nature of the solvating molecules on the nitrato coordination to Eu(3+) has been investigated. PMF profiles point out that both monodenate and bidentate coordinations are stable in neat methanol, while in neat octanol, only the bidentate one is. MD simulations of Eu(NO(3))(3) in water-octanol mixtures with different concentrations of water have been then performed and confirm the importance of the water molecules' presence on the nitrate ion's coordination mode. PMID- 21321722 TI - Effect of surface chemical composition on the surface potential and iso-electric point of silicon substrates modified with self-assembled monolayers. AB - Self-assembled monolayer (SAM)-modified nano-materials are a new technology to deliver drug molecules. While the majority of these depend on covalently immobilizing molecules on the surface, it is proposed that electrostatic interactions may be used to deliver drugs. By tuning the surface potential of solid substrates with SAMs, drug molecules could be either absorbed on or desorbed from substrates through the difference in electrostatic interactions around the selected iso-electric point (IEP). In this work, the surface of silicon substrates was tailored with various ratios of 3 aminopropyltrimethoxysilane (APTMS) and 3-mercaptopropyltrimethoxysilane (MPTMS), which form amine- and thiol-bearing SAMs, respectively. The ratio of the functional groups on the silicon surface was quantified by X-ray photoelectron spectrometry (XPS); in general, the deposition kinetics of APTMS were found to be faster than those of MPTMS. Furthermore, for solutions with high MPTMS concentrations, the relative deposition rate of APTMS increased dramatically due to the acid-base reaction in the solution and subsequent electrostatic interactions between the molecules and the substrate. The zeta potential in aqueous electrolytes was determined with an electro-kinetic analyzer. By depositing SAMs of binary functional groups in varied ratios, the surface potential and IEP of silicon substrates could be fine-tuned. For <50% amine concentration in SAMs, the IEP changed linearly with the chemical composition from <2 to 7.18. For higher amine concentrations, the IEP slowly increased with concentration to 7.94 because the formation of hydrogen-bonding suppressed the subsequent protonation of amines. PMID- 21321723 TI - Carbon nanotubes as photoprotectors of organic dyes: reversible photoreaction instead of permanent photo-oxidation. AB - In this paper we report that single-walled carbon nanotubes (SWNTs) can protect surface adsorbed Rhodamine B (RhB) molecules from permanent photo-oxidation via a reversible reaction. Upon strong light irradiation at 514 nm, the SWNT-adsorbed RhB molecules were switched to a non-fluorescent form, which looked like ordinary bleaching behavior. However, after staying without light for several hours the non-fluorescent dye species turned back to the original fluorescent form. This on/off switching can be considered as a reversible photobleaching process of the dye molecules. Other irreversible photochemical pathways of RhB were strongly prohibited due to the presence of SWNTs, providing the dye molecules with a high resistance against permanent photodegradation. By determining the maximum number of reconvertable RhB molecules per unit length of the nanotubes, we have further proved that this effect only works for the first layer of adsorbed dye molecules on the SWNT surfaces. PMID- 21321724 TI - Recognition of amino acids by functionalized calixarenes. AB - The calixarenic receptors exhibit remarkable host-guest properties towards biologically relevant guests. Aspects of complex formation reactions between both native and derivatized amino acids, di-and tripeptides with calixarenic (chiral or not) receptors are summarized in this critical review. Thus, the discussions emphasize the parameters that affect the molecular binding selectivity and efficiency of functionalized calix[n]arenes towards these substrates. A brief survey on their application in separation of amino acids is also considered (123 references). PMID- 21321725 TI - Calculation of microscopic exchange interactions and modelling of macroscopic magnetic properties in molecule-based magnets. AB - The state-of-the-art theoretical evaluation and rationalization of the magnetic interactions (J(AB)) in molecule-based magnets is discussed in this critical review, focusing first on isolated radical...radical pair interactions and afterwards on how these interactions cooperate in the solid phase. Concerning isolated radical pairwise magnetic interactions, an initial analysis is done on qualitative grounds, concentrating also on the validity of the most commonly used models to predict their size and angularity (namely, McConnell-I and McConnell-II models, overlap of magnetic orbitals,...). The failure of these models, caused by their oversimplified description of the magnetic interactions, prompted the introduction of quantitative approaches, whose basic principles and relative quality are also evaluated. Concerning the computation of magnetic interactions in solids, we resort to a sum of pairwise magnetic interactions within the Heisenberg Hamiltonian framework, and follow the First-principles Bottom-Up procedure, which allows the accurate study of the magnetic properties of any molecule-based magnet in an unbiased way. The basic principles of this approach are outlined, applied in detail to a model system, and finally demonstrated to properly describe the magnetic properties of molecule-based systems that show a variety of magnetic topologies, which range from 1D to 3D (152 references). PMID- 21321726 TI - Early metal bis(phosphorus-stabilised)carbene chemistry. AB - Since the discovery of covalently-bound mid- and late-transition metal carbenes there has been a spectacular explosion of interest in their chemistry, but their early metal counterparts have lagged behind. In recent years, bis(phosphorus stabilised)carbenes have emerged as valuable ligands for metals across the periodic table, and their use has in particular greatly expanded covalently-bound early metal carbene chemistry. In this tutorial review we introduce the reader to bis(phosphorus-stabilised)carbenes, and cover general preparative methods, structure and bonding features, and emerging reactivity studies of early metal derivatives (groups 1-4 and the f-elements). PMID- 21321727 TI - Coordination assemblies of polyoxomolybdate cluster framework: from labile building blocks to stable functional materials. AB - Polyoxomolybdates, an important branch in polyoxometalates chemistry, present complicated solution chemistry and unmatched physicochemical properties, which endows us with both great opportunities and considerable challenges in creating new functional materials. This perspective highlights the recent development on the coordination assembly of transition-metal-substituted heteropolymolybdates by using labile lacunary heteropolymolybdates as inorganic multidentate ligands. A series of strategies have been used to stabilize the lacunary heteropolymolybdate building blocks. Finally, we introduce some researches on the modification of polymolybdates by organic groups in aqueous media, which may shed light on the green chemistry of the functionalization of polyoxomolybdates. PMID- 21321728 TI - The shape of metallosupramolecular assemblies. AB - Despite original doubts on its feasibility, the control of the stereochemistry in ligand-bridged oligonuclear assemblies based on tris(bidentate) components has seen considerable progress in the last two decades, and differences have been observed in the physical characteristics of stereoisomers of such species. This retrospective review examines the background to this "stereochemical problem" and shows how the control of the stereochemical integrity of dinuclear and trinuclear ligand-bridged complexes has been utilised in studies of intramolecular electron transfer within the oligonuclear assemblies, and in probing the sequence- and structure-selectivity of the interaction of these species with nucleic acids. PMID- 21321729 TI - Dissymmetric gold(I) N-heterocyclic carbene complexes: a key unexpected structural parameter for highly efficient catalysts in the addition of alcohols to internal alkynes. AB - Gold(I) N-heterocyclic carbene complexes (Au-NHC) with symmetric (bis-benzyl, propyl and -mesityl substituents) and dissymmetric (mesityl and alkyl--benzyl or propyl--substituents) NHC ligands were synthesized and tested as catalysts for the addition of methanol to 3-hexyne, as a representative internal alkyne. While symmetric ones--bis-alkyl (propyl or benzyl) or bis-mesityl systems--displayed low activity, dissymmetric Au-NHC systems with one alkyl (benzyl or propyl) and one mesityl groups on the NHC unit were unexpectedly highly active with rates and turnover numbers up to 294,000 h(-1) and 800,000 mol.mol(Au)(-1). PMID- 21321730 TI - Bioinorganic and medicinal chemistry: aspects of gold(I)-protein complexes. AB - Gold(I)-based drugs have been used successfully for the treatment of rheumatoid arthritis (RA) for several years. Although the exact mechanism of action of these gold(I) drugs for RA has not been clearly established, the interaction of these compounds with mammalian enzymes has been extensively studied. In this paper, we describe the interaction of therapeutic gold(I) compounds with mammalian proteins that contain cysteine (Cys) and selenocysteine (Sec) residues. Owing to the higher affinity of gold(I) towards sulfur and selenium, gold(I) drugs rapidly react with the activated cysteine or selenocysteine residues of the enzymes to form protein-gold(I)-thiolate or protein-gold(I)-selenolate complexes. The formation of stable gold(I)-thiolate/selenolate complexes generally lead to inhibition of the enzyme activity. The gold-thiolate/selenolate complexes undergo extensive ligand exchange reactions with other nucleophiles and such ligand exchange reactions alter the inhibitory effects of gold(i) complexes. Therefore, the effect of gold(I) compounds on the enzymatic activity of cysteine- or selenocysteine-containing proteins may play important roles in RA. The interaction of gold(I) compounds with different enzymes and the biochemical mechanism underlying the inhibition of enzymatic activities may have broad medicinal implications for the treatment of RA. PMID- 21321731 TI - Rare earth metal bis(amide) complexes bearing amidinate ancillary ligands: synthesis, characterization, and performance as catalyst precursors for cis-1,4 selective polymerization of isoprene. AB - A family of rare earth metal bis(amide) complexes bearing monoanionic amidinate [RC(N-2,6-Me(2)C(6)H(3))(2)](-) (R = cyclohexyl (Cy), phenyl (Ph)) as ancillary ligands were synthesized and characterized. One-pot salt metathesis reaction of anhydrous LnCl(3) with one equivalent of amidinate lithium [RC(N-2,6 Me(2)C(6)H(3))(2)]Li, following the introduction of two equivalents of NaN(SiMe(3))(2) in THF at room temperature afforded the neutral and unsolvated mono(amidinate) rare earth metal bis(amide) complexes [RC(N-2,6 Me(2)C(6)H(3))(2)]Y[N(SiMe(3))(2)](2) (R = Cy (1); R = Ph (2)), and the "ate" mono(amidinate) rare earth metal bis(amide) complex [CyC(N-2,6 Me(2)C(6)H(3))(2)]Lu[N(SiMe(3))(2)](2)(MU-Cl)Li(THF)(3) (3) in 61-72% isolated yields. These complexes were characterized by elemental analysis, NMR spectroscopy, FT-IR spectroscopy, and X-ray single crystal diffraction. Single crystal structural determination revealed that the central metal in complexes 1 and 2 adopts a distorted tetrahedral geometry, and in complex 3 forms a distorted trigonal bipyramidal geometry. In the presence of AlMe(3), and in combination with one equimolar amount of [Ph(3)C][B(C(6)F(5))(4)], complexes 1 and 2 showed high activity towards isoprene polymerization to give high molecular weight polyisoprene (M(n) > 10(4)) with good cis-1,4 selectivity (>90%). PMID- 21321732 TI - Preparation of metal "nanosalts" and their application in catalysis: heterogeneous and homogeneous pathways. AB - A novel type of nanoparticles have been designed based on self-organization of the metal centers with organic functional groups. Size- and shape-controlled synthetic procedures were developed to prepare nanostructured Pd and Ni particles in high yields from easily available precursors. The presence of the non-metallic functional groups in the particle's core forced the metal centers to adopt a divalent oxidation state bearing polar chemical bonds ("nanosalt"). The Pd and Ni particles were excellent catalysts to accomplish a highly selective synthetic route to vinyl chalcogenides. The mechanisms of the catalytic reactions via the heterogeneous and homogeneous pathways were revealed and studied in detail. PMID- 21321733 TI - New binuclear Mn(II) and Fe(II) complexes supported by 1,4,8-triazacycloundecane. AB - Two new binuclear metal complexes supported by 1,4,8-triazacycloundecane (tacud) are reported. [Fe(2)(tacud)(2)(MU-Cl)(2)Cl(2)] (1) and [Mn(2)(tacud)(2)(MU Cl)(2)Cl(2)] (2) are isomorphs consisting of bis(MU-chloro) bridged metal centers along with terminal chloro groups and tacud ligands. Both compounds 1 and 2 crystallize in the P1 space group. For 1, a = 7.7321(12) A, b = 7.8896(12) A, c = 11.4945(17) A, alpha = 107.832(2) degrees , beta = 107.827(2) degrees , gamma = 92.642(2) degrees , V = 627.85(17) A(3) and Z = 1. For 2, a = 7.7607(12) A, b = 7.9068(12) A, c = 11.6111(18) A, alpha = 108.201(2) degrees , beta = 108.041(2) degrees , gamma = 92.118(3) degrees , V = 636.47(17) A(3) and Z = 1. Variable temperature and variable-field magnetic susceptibility studies on 1 indicate the presence of weak ferromagnetic interactions between the high-spin iron(ii) centers in the dimer (J = + 1.6 cm(-1)) and the crystalline field anisotropy of the ferrous ion (D = - 2.8, E = - 0.1 cm(-1)). Variable temperature magnetic susceptometry studies on 2 indicate that weak antiferromagnetic coupling exists between the manganese(ii) centers (J = - 1.8 cm(-1)). Compounds 1 and 2 retain their dinuclearity in weakly coordinating or low polarity solvents, while both become mononuclear in solvents such as methanol. PMID- 21321735 TI - Highly porous Co(II)-salicylate metal-organic framework: synthesis, characterization and magnetic properties. AB - A new porous Co(II)-salicylate metal-organic framework material has been synthesized hydrothermally through the reaction of Co(II) chloride with sodium salicylate under mild alkaline pH conditions. To get an idea about the structural aspect of the material from the powder X-ray diffraction (PXRD) pattern, MAUD program has been successfully utilized and the assigned peaks match very well with a new tetragonal phase (space group, P4mm) having the unit cell parameters: a = b = 12.957 (0.042) A; c = 12.738 (0.019) A; alpha = beta = gamma = 90 degrees , V = 2138.73 A(3). N(2) adsorption/desorption analyses suggested the material is highly porous in nature having high BET surface area and pore dimensions of 2.0 3.0 nm, which is within the range of small mesopores. Thermogravimetric analysis (TGA) revealed that the H(2)O molecules may be removed from the framework without collapsing the structure and the material is stable up to ca. 573 K. The material is characterized thoroughly by using different characterization tools such as TEM, SEM, UV-visible reflectance spectroscopy, FT IR spectroscopy and photoluminescence spectroscopy. X-Ray photoelectron spectroscopic (XPS) analysis was employed to understand the oxidation state of the cobalt atom and presence of other elements within the framework. The material shows interesting magnetic properties, where the magnetic moments monotonically increase with the decrease in temperature down to 9 K. Below 9 K there is a steep increase in magnetization on further lowering the temperature, thereby suggesting the onset of a long range ferromagnetic transition with ferromagnetic Curie temperature, T(C) = 8.5 K. Furthermore, the M-H curve at 2 K shows a clear hysteresis loop with a coercive field 150 Oe and remnant magnetization 0.8 MU(B)/f.u. PMID- 21321734 TI - New conjugates of beta-cyclodextrin with manganese(III) salophen and porphyrin complexes as antioxidant systems. AB - Oxidative stress is the hallmark of several pathologies like arthritis, hypertension and many neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. In this scenario, antioxidant compounds can play a pivotal role in treating these severe pathologies. The synthesis of molecules able to mimic physiologically-relevant proteins is nowadays of particular interest. Several transition metal complexes, especially manganese(III) complexes with porphyrin and salen-type ligands, have been reported to be superoxide scavengers. Here we report the synthesis and spectroscopic characterization of manganese(III) complexes of 5[4-(6-O-beta-cyclodextrin)-phenyl],10,15,20-tri(4-hydroxyphenyl) porphyrin and of 6(A)-deoxy-6(A)[(S-cysteamidobenzoyl(3,4-diamino)-N,N' bis(salicylidene))]-beta-cyclodextrin. The superoxide dismutase activity of the metal complexes was investigated by indirect methods. The catalase and peroxidase activities were tested using ABTS assays. PMID- 21321736 TI - Open-framework aluminoborates co-templated by two types of primary amines. AB - A series of open-framework aluminoborates (ABOs), [CH(3)NH(3)][(CH(3)CH(2))(2)NH(2)][Al(B(5)O(10))] (1), [CH(3)CH(2)NH(3)][(CH(3)CH(2))(2)NH(2)][Al(B(5)O(10))] (2), [CH(3)CH(2)NH(3)][(CH(3))(2)NH(2)](H(2)O)(0.5)[Al(B(5)O(10))] (3) and [CH(3)NH(3)][CH(3)CH(2)NH(3)](H(2)O)(2)[Al(B(5)O(10))] (4) have been made co templated by two types of primary amines under solvothermal conditions and characterized by elemental analysis, IR, TGA, UV-Vis, powder XRD, single crystal XRD and NLO determination, respectively. These four ABOs display two structural types: 1, 2 and 3 are isostructural and exhibit CrB(4) topology, showing three different layers along three different directions; while 4 contains 8-, 14-ring layers, which are packed along the [001] direction to form a noncentrosymmetric 3D framework with 8-, 14-ring channels, showing second harmonic generation (SHG) response that is about 0.5 times that of KDP (KH(2)PO(4)). The electronic structure calculations for 1 and 4 also have been performed. PMID- 21321737 TI - Creation of cationic iridium(III) complexes with aggregation-induced phosphorescent emission (AIPE) properties by increasing rotation groups on carbazole peripheries. AB - Three cationic iridium complexes containing 4,7-bis(3,6-di-tert-butyl-9H-carbazol 9-yl)-1,10-phenanthroline (L(1)) and 4,7-bis(3',6'-di-tert-butyl-6-(3,6-di-tert butyl-9H-carbazol-9-yl)-3,9'-bi(9H-carbazol)-9-yl)-1,10-phenanthroline (L(2)) as the ancillary ligands, namely, [Ir(ppy)(2)(L(1))]PF(6) (1), [Ir(ppy)(2)(L(2))]PF(6) (2) and [Ir(oxd)(2)(L(2))]PF(6) (3) (ppy is 2 phenylpyridine, oxd is 2,5-diphenyl-1,3,4-oxadiazole), have been designed and prepared. With more intramolecular rotational units on the ancillary ligand (L(2)), 2 and 3 possess a unique aggregation-induced phosphorescent emission (AIPE) property. This phenomenon was unprecedentedly observed in the cationic iridium(III) complexes. In order to investigate the underlying mechanism of this AIPE behavior, their photophysical, temperature-dependent aggregation properties as well as theoretical calculations, were performed. The results suggest that restricted intramolecular rotation is responsible for the AIPE of cationic complexes. Moreover, photoluminescent quantum yields in the neat film, thermal stabilities and off/on luminescence switching of 2 were investigated, revealing its potential application as a candidate for LECs and organic vapor sensing. PMID- 21321738 TI - On vanadate phosphate and arsenate framework structures based on the NbO-net. AB - The recently described framework structure of composition [As(6)V(4+)(12)V(5+)(3) O(51)](-9) is analogous to previously known vanadate phosphate frameworks. PMID- 21321739 TI - An octanuclear coordination cage with a 'cuneane' core--a topological isomer of a cubic cage. AB - The octanuclear coordination cage [Ni(8)(L(14Naph))(12)](BF(4))(16) has the core structure of a 'cuneane'--a toplogical isomer of a cube--with a metal ion at each of the eight vertices and bridging ligand spanning each of the twelve edges; this is the only possible 8-vertex polyhedron other than a cube that will form a cage in which each metal is connected to three others. PMID- 21321740 TI - Design and laboratory testing of a new flow-through directional passive air sampler for ambient particulate matter. AB - A new type of directional passive air sampler (DPAS) is described for collecting particulate matter (PM) in ambient air. The prototype sampler has a non-rotating circular sampling tray that is divided into covered angular channels, whose ends are open to winds from sectors covering the surrounding 360 degrees . Wind-blown PM from different directions enters relevant wind-facing channels, and is retained there in collecting pools containing various sampling media. Information on source direction and type can be obtained by examining the distribution of PM between channels. Wind tunnel tests show that external wind velocities are at least halved over an extended area of the collecting pools, encouraging PM to settle from the air stream. Internal and external wind velocities are well correlated over an external velocity range of 2.0-10.0 m s-1, which suggests it may be possible to relate collected amounts of PM simply to ambient concentrations and wind velocities. Measurements of internal wind velocities in different channels show that velocities decrease from the upwind channel round to the downwind channel, so that the sampler effectively resolves wind directions. Computational fluid dynamics (CFD) analyses were performed on a computer generated model of the sampler for a range of external wind velocities; the results of these analyses were consistent with those from the wind tunnel. Further wind tunnel tests were undertaken using different artificial particulates in order to assess the collection performance of the sampler in practice. These tests confirmed that the sampler can resolve the directions of sources, by collecting particulates preferentially in source-facing channels. PMID- 21321741 TI - Persistent organic pollutants in Antarctica: current and future research priorities. AB - As Antarctica's pivotal role in influencing global climate processes gains increasing attention so too does public and scientific interest in the general state of Antarctic ecosystem health as a function of multiple stressors, including contamination by anthropogenic chemicals. Persistent organic pollutant (POP) research internationally has sought to elucidate the impacts of an ever increasing diversity of POPs on the environment. The challenges of this research are compounded in the Antarctic context, by key gaps in historical data and our understanding of chemical behaviour in polar landscapes. In order to ensure maximum longevity and value of research outputs, efforts must be centred upon addressing these research gaps. Ultimately, Antarctic POP research will benefit from co-ordinated investment into spatially and temporally comprehensive research and monitoring efforts such as those responsible for the continued progress of this research field in the Arctic and other global regions. PMID- 21321742 TI - Distribution and ecotoxicological significance of trace element contamination in a ~150 yr record of sediments in Lake Chaohu, Eastern China. AB - This paper presents the concentrations, vertical profiles and possible sources of selected major and trace elements in a sediment core covering ~150 years of sedimentation in Lake Chaohu, eastern China. Element concentrations were measured by portable X-ray Fluorescence Spectroscopy (XRF) and were used to evaluate possible environmental consequences of the recent industrialization in China. Statistical analyses identify four groups: (1) organic carbon (OC), total nitrogen (TN), Pb, Zn, and As associated with the use of chemical fertilizers and pesticides; (2) Mn, Cr, Ni and Cu from industrial and mining activities; (3) Fe, Rb, K, Co, Ti and Ca influenced by post-depositional processes and land exploitation; and (4) Zr and Sr from the soil. The vertical profiles of elements placed in the first two groups show distinct increases in concentrations above depths of 20 cm (~1978), coincident with the timing of industrialization in China, and the anthropogenic-derived fluxes are higher than the lithogenic derived fluxes over the last three decades. With the exception of Zr and Sr, association of the measured metals with organic carbon and nitrogen suggests that organic matter may act as a carrier phase. The geoaccumulation index (I(geo)) reveals increased contamination from elements in the first two groups in recent years. Element concentrations, compared with the Effects Range-Low (ERL) and Effects Range-Median (ERM) levels set by NOAA, suggest that adverse biological effects from Ni contamination are very likely. PMID- 21321743 TI - Layered assembly of graphene oxide and Co-Al layered double hydroxide nanosheets as electrode materials for supercapacitors. AB - An innovative strategy of fabricating electrode material by layered assembling two kinds of one-atom-thick sheets, carboxylated graphene oxide (GO) and Co-Al layered double hydroxide nanosheet (Co-Al LDH-NS) for the application as a pseudocapacitor is reported. The Co-Al LDH-NS/GO composite exhibits good energy storage properties. PMID- 21321744 TI - Bringing an important macrocycle into a polyoxometalate matrix: synthesis, crystal structure, spectroscopy and electrochemistry of [Co(III)(transdiene)(Cl)2]2[Mo6O19], [Ni(II)(transdiene)][W6O19].DMSO.DCM and [Zn(II)(transdsiene)(Cl)]2[W6O19]. AB - Three polyoxometalate based ion pair solids (1-3), in which Co(III) (d(6)), Ni(II) (d(8)) and Zn(II) (d(10)) complexes of a tetra-aza macrocycle, Me(6)-trans [14]-diene act as the cationic moieties, have been reported. The title complexes, formulated as [Co (C(16)H(32)N(4))(Cl)(2)](2)[Mo(6)O(19)] (1), [Ni(C(16)H(32)N(4))][W(6)O(19)].DMSO.DCM (2) and [Zn(C(16)H(32)N(4))(Cl)](2)[W(6)O(19)] (3) (C(16)H(32)N(4) = Me(6)-trans-[14] diene), are the first crystallographic paradigms where transition metal complexes of a Schiff condensed tetra-aza macrocycle have been associated with an isopolyanion, [M(6)O(19)](2-) (M = Mo(vi) and W(vi)). Compounds 1-3 have been characterized through routine spectroscopic analyses including elemental analysis and their structures have been unambiguously determined through single crystal X ray crystallography. The molecules of compound 1 assemble obeying P1 (#2) space symmetry, whereas those of compounds 2 and 3 follow the higher symmetrical ensemble P2(1)/c (#14). The ESR spectral studies of compounds 1-3 have revealed their diamagnetic (low-spin) nature. The last part of this article describes the electrochemical properties of the title compounds. PMID- 21321745 TI - Deciphering the structure of DNA toroids. AB - Toroids are small donut shaped organizational units within sperm chromatin and viruses containing DNA and protein. Investigators first characterized the dimensions of toroids created in vitro, in viruses and in decondensed sperm chromatin using transmission electron and atomic force microscopy. More recent measurements, performed using cryo-electron microscopy, have allowed experimenters to observe the hexagonal organization of DNA within viruses, and toroids created from DNA and cobalt hexammine. However, it has been difficult to obtain information about the assembly of DNA into a toroid, its structure and the biomechanical forces involved because of the limitations of these techniques. Similarly, biophysical studies of toroids utilizing techniques such as circular dichroism or light scattering are difficult to perform and interpret because toroids created using bulk DNA can aggregate and precipitate out of solution even at very low concentrations. The development of optical and magnetic traps has allowed experimenters to manipulate single DNA molecules within microfluidic, multichannel flow cells and measure the structural changes they undergo as they are transformed into toroids. During the past few years investigators have demonstrated that toroids consist of loops of DNA. They have observed the stepwise incorporation of these loops into a toroid that is not in contact with charged surfaces, which might affect its formation. The condensation of a constrained DNA molecule into a toroid was observed to significantly increase its tension, which reduced the size of the DNA loops that form the toroid. This structural information is important for understanding how genomic DNA is assembled and organized within the sperm cell and viruses. In this perspective we discuss what is known about the structure and formation of toroids, what has been learned recently using single molecule techniques and what remaining questions have the potential to be answered using these emerging technologies. PMID- 21321747 TI - Massively parallel concentration device for multiplexed immunoassays. AB - A massively parallel nanofluidic concentration device array for multiplexed and high-throughput biomolecule detection is demonstrated. By optimizing the microchannel/nanojunction design and channel conductivity, an array of up to 128 nanofluidic concentration devices were fabricated. Operation of the entire array requires only one inlet and one outlet reservoir, with the application of a single operational voltage bias across them. Concentration efficiencies of the devices were found to be uniform within the array, within 5% error. Alternatively, concentration speed in each channel can be individually tuned by controlling the length of the inlet microchannel and thus controlling the flow rate based on change of the tangential electric field. This allows immuno-binding reactions at different concentration ranges to be performed in parallel. Using multiplexed, successive-concentration enhanced detection in the device, we have shown that the dynamic range and reliability of the immunoassay can be significantly increased. PMID- 21321749 TI - Droplet size based separation by deterministic lateral displacement-separating droplets by cell--induced shrinking. AB - We present a novel method for passive separation of microfluidic droplets by size at high throughput using deterministic lateral displacement (DLD). We also show that droplets containing Saccharomyces cerevisiae shrink significantly during incubation while droplets containing only yeast media retain or slightly increase their size. We demonstrate the DLD device by sorting out shrunken yeast-cell containing droplets from 31% larger diameter droplets which were generated at the same time containing only media, present at a >40-fold excess. This demonstrates the resolving power of droplet separation by DLD and establishes that droplets can be separated for a biological property of the droplet contents discriminated by a change of the physical properties of the droplet. Thus suggesting that this technique may be used for e.g. clonal selection. The same device also separates 11 um from 30 um droplets at a rate of 12,000 droplets per second, more than twofold faster than previously demonstrated passive hydrodynamic separation devices. PMID- 21321748 TI - On-chip multi-electrochemical sensor array platform for simultaneous screening of nitric oxide and peroxynitrite. AB - In this work we report on the design, microfabrication and analytical performances of a new electrochemical sensor array (ESA) which allows for the first time the simultaneous amperometric detection of nitric oxide (NO) and peroxynitrite (ONOO(-)), two biologically relevant molecules. The on-chip device includes individually addressable sets of gold ultramicroelectrodes (UMEs) of 50 um diameter, Ag/AgCl reference electrode and gold counter electrode. The electrodes are separated into two groups; each has one reference electrode, one counter electrode and 110 UMEs specifically tailored to detect a specific analyte. The ESA is incorporated on a custom interface with a cell culture well and spring contact pins that can be easily interconnected to an external multichannel potentiostat. Each UME of the network dedicated to the detection of NO is electrochemically modified by electrodepositing thin layers of poly(eugenol) and poly(phenol). The detection of NO is performed amperometrically at 0.8 V vs. Ag/AgCl in phosphate buffer solution (PBS, pH = 7.4) and other buffers adapted to biological cell culture, using a NO-donor. The network of UMEs dedicated to the detection of ONOO(-) is used without further chemical modification of the surface and the uncoated gold electrodes operate at -0.1 V vs. Ag/AgCl to detect the reduction of ONOOH in PBS. The selectivity issue of both sensors against major biologically relevant interfering analytes is examined. Simultaneous detection of NO and ONOO(-) in PBS is also achieved. PMID- 21321746 TI - A perspective on vascular disrupting agents that interact with tubulin: preclinical tumor imaging and biological assessment. AB - The tumor microenvironment provides a rich source of potential targets for selective therapeutic intervention with properly designed anticancer agents. Significant physiological differences exist between the microvessels that nourish tumors and those that supply healthy tissue. Selective drug-mediated damage of these tortuous and chaotic microvessels starves a tumor of necessary nutrients and oxygen and eventually leads to massive tumor necrosis. Vascular targeting strategies in oncology are divided into two separate groups: angiogenesis inhibiting agents (AIAs) and vascular disrupting agents (VDAs). The mechanisms of action between these two classes of compounds are profoundly distinct. The AIAs inhibit the actual formation of new vessels, while the VDAs damage and/or destroy existing tumor vasculature. One subset of small-molecule VDAs functions by inhibiting the assembly of tubulin into microtubules, thus causing morphology changes to the endothelial cells lining the tumor vasculature, triggered by a cascade of cell signaling events. Ultimately this results in catastrophic damage to the vessels feeding the tumor. The rapid emergence and subsequent development of the VDA field over the past decade has led to the establishment of a synergistic combination of preclinical state-of-the-art tumor imaging and biological evaluation strategies that are often indicative of future clinical efficacy for a given VDA. This review focuses on an integration of the appropriate biochemical and biological tools necessary to assess (preclinically) new small-molecule, tubulin active VDAs for their potential to be clinically effective anticancer agents. PMID- 21321750 TI - Identification and differential induction of the expression of aquaporins by salinity in broccoli plants. AB - Plant aquaporins belong to a large superfamily of conserved proteins called the major intrinsic proteins (MIPs). There is limited information about the diversity of MIPs and their water transport capacity in broccoli (Brassica oleracea) plants. In this study, the cDNAs of isoforms of Plasma Membrane Intrinsic Proteins (PIPs), a class of aquaporins, from broccoli roots have been partially sequenced. Thus, sequencing experiments led to the identification of eight PIP1 and three PIP2 genes encoding PIPs in B. oleracea plants. The occurrence of different gene products encoding PIPs suggests that they may play different roles in plants. The screening of their expression as well as the expression of two specific PIP2 isoforms (BoPIP2;2 and BoPIP2;3), in different organs and under different salt-stress conditions in two varieties, has helped to unravel the function and the regulation of PIPs in plants. Thus, a high degree of BoPIP2;3 expression in mature leaves suggests that this BoPIP2;3 isoform plays important roles, not only in root water relations but also in the physiology and development of leaves. In addition, differences between gene and protein patterns led us to consider that mRNA synthesis is inhibited by the accumulation of the corresponding encoded protein. Therefore, transcript levels, protein abundance determination and the integrated hydraulic architecture of the roots must be considered in order to interpret the response of broccoli to salinity. PMID- 21321751 TI - Xanthane sesquiterpenoids: structure, synthesis and biological activity. AB - The aim of this review is to survey the naturally occurring xanthanes and xanthanolides, their structures, biological activities, structure-activity relationships and synthesis. There has been no comprehensive review of this topic previously. On the basis of 126 references, 112 compounds are summarized. PMID- 21321752 TI - Carotenoids and their cleavage products: biosynthesis and functions. AB - This review focuses on plant carotenoids, but it also includes progress made on microbial and animal carotenoid metabolism to better understand the functions and the evolution of these structurally diverse compounds with a common backbone. Plants have evolved isogenes for specific key steps of carotenoid biosynthesis with differential expression profiles, whose characteristic features will be compared. Perhaps the most exciting progress has been made in studies of carotenoid cleavage products (apocarotenoids) with an ever-expanding variety of novel functions being discovered. This review therefore covers structural, molecular genetic and functional aspects of carotenoids and apocarotenoids alike. Apocarotenoids are specifically tailored from carotenoids by a family of oxidative cleavage enzymes, but whether there are contributions to their generation from chemical oxidation, photooxidation or other mechanisms is largely unknown. Control of carotenoid homeostasis is discussed in the context of biosynthetic and degradative reactions but also in the context of subcellular environments for deposition and sequestration within and outside of plastids. Other aspects of carotenoid research, including metabolic engineering and synthetic biology approaches, will only be covered briefly. PMID- 21321753 TI - Synthesis of ellagitannin natural products. PMID- 21321754 TI - Electrostatics at the nanoscale. AB - Electrostatic forces are amongst the most versatile interactions to mediate the assembly of nanostructured materials. Depending on experimental conditions, these forces can be long- or short-ranged, can be either attractive or repulsive, and their directionality can be controlled by the shapes of the charged nano-objects. This Review is intended to serve as a primer for experimentalists curious about the fundamentals of nanoscale electrostatics and for theorists wishing to learn about recent experimental advances in the field. Accordingly, the first portion introduces the theoretical models of electrostatic double layers and derives electrostatic interaction potentials applicable to particles of different sizes and/or shapes and under different experimental conditions. This discussion is followed by the review of the key experimental systems in which electrostatic interactions are operative. Examples include electroactive and "switchable" nanoparticles, mixtures of charged nanoparticles, nanoparticle chains, sheets, coatings, crystals, and crystals-within-crystals. Applications of these and other structures in chemical sensing and amplification are also illustrated. PMID- 21321755 TI - One-dimensional extended lines of divacancy defects in graphene. AB - Since the outstanding transport properties of graphene originate from its specific structure, modification at the atomic level of the graphene lattice is needed in order to change its electronic properties. Thus, topological defects play an important role in graphene and related structures. In this work, one dimensional (1D) arrangement of topological defects in graphene are investigated within a density functional theory framework. These 1D extended lines of pentagons, heptagons and octagons are found to arise either from the reconstruction of divacancies, or from the epitaxial growth of graphene. The energetic stability and the electronic structure of different ideal extended lines of defects are calculated using a first-principles approach. Ab initio scanning tunneling microscopy (STM) images are predicted and compared to recent experiments on epitaxial graphene. Finally, local density of states and quantum transport calculations reveal that these extended lines of defects behave as quasi-1D metallic wires, suggesting their possible role as reactive tracks to anchor molecules or atoms for chemical or sensing applications. PMID- 21321756 TI - Microwave frequency effect in the formation of Au nanocolloids in polar and non polar solvents. AB - Given earlier observations that microwave frequencies can have a substantial effect on the photoactivity of a well-known photocatalyst (TiO(2)), in the synthesis of 3,6-diphenyl-4-n-butylpyridazine through a Diels-Alder process, and in the one-pot solvent-free synthesis of a room-temperature ionic liquid, we proceeded to examine the frequency effects of the 5.8 and 2.45 GHz microwave (MW) radiation in the synthesis of gold nanoparticles in non-polar media, such as oleylamine, which have a low dielectric constant (epsilon'), and we further examine differences in shape and size under otherwise identical temperature conditions when the synthesis of the gold nanoparticles was carried out in an ethylene glycol polar medium in the presence of polyvinylpyrrolidone. Whereas a change in microwave frequency from 2.45 to 5.8 GHz at equal microwave power levels led to the synthesis of gold nanoparticles in the non-polar media, a change in the microwave frequency had no effect on the size and shape of the gold nanoparticles synthesized in polar media for identical microwave power levels. PMID- 21321757 TI - Unexpected reactivity of Au25(SCH2CH2Ph)18 nanoclusters with salts. AB - We report some interesting results of the chemical reactivity of thiolate protected [Au(25)(SCH(2)CH(2)Ph)(18)](0) nanoclusters with two types of salts, including tetraoctylammonium halide (TOAX) and NaX. At the early stage of the reaction, [Au(25)(SCH(2)CH(2)Ph)(18)](0) was found to spontaneously convert to its anionic form ([Au(25)(SCH(2)CH(2)Ph)(18)](-)) in the presence of either type of salt. However, a large difference was observed in the second stage of the reaction. With NaX, we observed decomposition of anionic clusters, while with TOAX, the clusters show excellent stability. We have gained some insight into the reaction mechanism. The X(-) ions seem to attack [Au(25)(SCH(2)CH(2)Ph)(18)](q) surface and displace some thiolates, evidenced by the observation of halide-bound clusters such as Au(25)(SCH(2)CH(2)Ph)(18-x)Br(x) in mass spectrometry analysis. These halide-bound clusters show a reduced stability, and their decomposition into Au(I) complexes leads to the release of gold valence electrons of the clusters; concurrently, the non-halide-bound [Au(25)(SCH(2)CH(2)Ph)(18)](0) clusters are reduced into [Au(25)(SCH(2)CH(2)Ph)(18)](-). For the second stage of reaction with organic salts such as TOA-Br, after [Au(25)(SCH(2)CH(2)Ph)(18)](0) clusters are converted to [Au(25)(SCH(2)CH(2)Ph)(18)](-)) the TOA(+) counterions surprisingly protect the anionic clusters from further attack by halide ions, hence, TOA(+) cations can stabilize [Au(25)(SCH(2)CH(2)Ph)(18)](-) clusters. In contrast, with NaX salts the Na(+) ions do not provide any steric stabilization of the [Au(25)(SCH(2)CH(2)Ph)(18)](-) clusters, hence, degradation occurs when being further attacked by halide ions, especially Br(-) and I(-). PMID- 21321758 TI - Colloidal gold nanoparticle formation derived from self-assembled supramolecular structure of cyclodextrin/Au salt complex. AB - We present a novel procedure for the formation of colloidal gold nanoparticles (AuNPs) derived from the supramolecular self-assembled structure of a cyclodextrin (CD)/Au salt complex (SCA) without the necessity for additional reducing or stabilizing agents. The SCA served as a solid template for the formation of gold seeds by solid-state thermal treatment within the confining environment of the alpha-CD, i.e., the matrix of the SCA. Subsequently, thermally treated SCA, denoted as T-SCA, was placed (without further treatment) into an aqueous medium and gold seeds were nucleated for the formation of alpha-CD stabilized AuNPs at room temperature. The surface topology of SCA, as revealed by field-emission scanning electron microscopy (FE-SEM), consisted of flaky plate like structures. Wide angle X-ray diffraction (WXRD) revealed that the surface topology of SCA resulted from a transformation in the crystalline structure of alpha-CD from the cage-type to the hexagonally ordered channel-type. The structure transformation on the surface of SCA was attributed to the nucleated self-assembly of surface alpha-CD molecules by Au salt. From combined FE-SEM, energy-dispersed X-ray spectroscopy (EDXS), WXRD and differential scanning calorimetry (DSC) results, it was concluded that the thermal treatment of SCA led to the formation of gold seeds, attributed to the reduction and aggregation of some Au salt molecules, confined within the interface between the cage-type and channel type structure of the SCA. After placement of T-SCA into an aqueous solution, the growth and stabilization of AuNPs by alpha-CD were verified by UV vis spectroscopy. The formation of AuNPs, by this novel method, can be considered a one step seed-mediated growth process. The resulting AuNPs are spherical in morphology, narrowly size distributed and possesses excellent stability. Furthermore, the AuNPs size is tunable by simply controlling water content during nanoparticle growth. PMID- 21321759 TI - "Naked" gold nanoparticles supported on HOPG: melanin functionalization and catalytic activity. AB - Reductive electrodesorption has been used to produce "naked" gold nanoparticles (AuNPs) 3 nm in size on HOPG from different thiolate-capped AuNPs. The clean AuNPs transform the electrocatalytic inert HOPG into an active surface for hydrogen peroxide electroreduction, causing a lowering of the cathodic overpotential of 0.25 V with respect to the Au(111) surface. Compared to the plain gold substrates, the nanostructures promote only a slight increase in the hydrogen evolution reaction. In a second modification step a ~1 nm thick melanin iron coating is electrochemically formed around the AuNPs. This ultrathin melanin iron coating largely improves the catalytic activity of the bare AuNPs for both hydrogen peroxide electroreduction and hydrogen evolution reaction. This strategy, which integrates electrochemistry and nanotechnology, can be applied to the preparation of efficient "naked" AuNPs and organic-iron capped AuNPs catalysts. PMID- 21321760 TI - Gold nanocages covered with thermally-responsive polymers for controlled release by high-intensity focused ultrasound. AB - This paper describes the use of Au nanocages covered with smart, thermally responsive polymers for controlled release with high-intensity focused ultrasound (HIFU). HIFU is a highly precise medical procedure that uses focused ultrasound to heat and destroy pathogenic tissue rapidly and locally in a non-invasive or minimally invasive manner. The released dosage could be remotely controlled by manipulating the power of HIFU and/or the duration of exposure. We demonstrated localized release within the focal volume of HIFU by using gelatin phantom samples containing dye-loaded Au nanocages. By placing chicken breast tissues on top of the phantoms, we further demonstrated the feasibility of this system for controlled release at depths up to 30 mm. Because it can penetrate more deeply into soft tissues than near-infrared light, HIFU is a potentially more effective external stimulus for rapid, on-demand drug release. PMID- 21321761 TI - Peptide bond formation by aminolysin-A catalysis: a simple approach to enzymatic synthesis of diverse short oligopeptides and biologically active puromycins. AB - A new S9 family aminopeptidase derived from the actinobacterial thermophile Acidothermus cellulolyticus was cloned and engineered into a transaminopeptidase by site-directed mutagenesis of catalytic Ser(491) into Cys. The engineered biocatalyst, designated aminolysin-A, can catalyze the formation of peptide bonds to give linear homo-oligopeptides, hetero-dipeptides, and cyclic dipeptides using cost-effective substrates in a one-pot reaction. Aminolysin-A can recognize several C-terminal-modified amino acids, including the l- and d-forms, as acyl donors as well as free amines, including amino acids and puromycin aminonucleoside, as acyl acceptors. The absence of amino acid esters prevents the formation of peptides; therefore, the reaction mechanism involves aminolysis and not a reverse reaction of hydrolysis. The aminolysin system will be a beneficial tool for the preparation of structurally diverse peptide mimetics by a simple approach. PMID- 21321762 TI - Aromatic A-ring analogues of orobanchol, new germination stimulants for seeds of parasitic weeds. AB - Strigolactones are signaling compounds in plants of increasing importance. In this paper the focus is on their activity as germinating agents for seeds of parasitic weeds. The syntheses of aromatic A-ring analogues of the germination stimulant orobanchol have been described. Starting substrate is the ABC unit of the stimulant GR24. Oxidation at the C-4 position gives a 4-oxo derivative which on subsequent reduction produces two C-4 epimeric alcohols, syn and anti in a ratio of 82 : 3. For practical access of the C-4 anti alcohol, the predominant syn epimer is inverted by a Mitsunobu procedure. The anti C-4 alcohol is then coupled with the D-ring in a one-pot two-step process involving a formylation and a reaction with bromobutenolide to give a mixture of the diastereomeric aromatic A-ring analogues of orobanchol. In contrast, the syn C-4 alcohol cannot be coupled directly with the D-ring. Protection of the C-4 syn OH is a prequisite. The best protecting function is the SEM group as deprotection after coupling with the D-ring can then readily be achieved. The structures of these new analogues have been ascertained by X-ray analyses. Both diastereomers of the C-4 syn as well as the C-4 anti orobanchol analogues have been tested as germination agents of seeds of Striga hermonthica and Orobanche ramosa. In addition, the acetates of both epimeric C-4 alcohols have been prepared and tested. Both diastereomers of the 4-oxo derivative have been prepared and bioassayed as well. The bioassays reveal that the diastereomers having the natural relative configuration are most active. The data also suggest that hydrogen bonding is not an important factor in the binding of the stimulant molecules in the receptor. PMID- 21321763 TI - Synthesis of fluorinated fused benzofurans and benzothiophenes: Smiles-type rearrangement and cyclisation of perfluoro(het)aryl ethers and sulfides. AB - Lithium-bromine exchange in 2-bromophenyl perfluoroaryl ethers or sulfides affords fused fluorinated benzofurans or benzothiophenes respectively by S(N)Ar substitution of the adjacent fluorine in the perfluoroaryl substituent. The structures of the new compounds were confirmed by NMR spectroscopy and single crystal X-ray diffraction analysis. In the case of 2-bromophenyl tetrafluoropyrid 4-yl ether, lithiation promoted a Smiles-type rearrangement which led to formation of 4-(2-hydroxyphenyl)tetrafluoropyridine, for which the structure was confirmed by X-ray crystallography. PMID- 21321764 TI - Synthesis and luminescence properties of new red-shifted absorption lanthanide(III) chelates suitable for peptide and protein labelling. AB - The synthesis and photo-physical properties of an original bis-pyridinylpyrazine chromophore efficiently sensitising europium(III) and samarium(III) are described. The corresponding lanthanide(III) complexes display in aqueous solutions a maximum excitation wavelength which is significantly red-shifted compared to the usual terpyridine-based chelates, and a valuable luminescence brightness above 2,000 dm(3) mol(-1) cm(-1) at 345 nm was obtained with a europium(III) derivative. Further functionalisation with three different bioconjugatable handles was also investigated and their ability to efficiently label a model hexapeptide was evaluated and compared. Finally, the best bioconjugatable europium(III) chelate was used in representative labelling experiments involving monoclonal antibodies and the luminescence features of the corresponding bioconjugates remained satisfactory. PMID- 21321765 TI - Switching of the enzymatic activity synchronized with signal recognition by an artificial DNA receptor on a liposomal membrane. AB - We constructed a supramolecular system on a liposomal membrane that is capable of activating an enzyme via DNA hybridization. The design of the system was inspired by natural signal transduction systems, in which enzymes amplify external signals to control signal transduction pathways. The liposomal membrane, providing a platform for the system, was prepared by the self-assembly of an oligonucleotide lipid, a phospholipid and a cationic synthetic lipid. The enzyme was immobilized on the liposomal surface through electrostatic interactions. Selective recognition of DNA signals was achieved by hybridizing the DNA signals with the oligonucleotide lipid embedded in the liposome. The hybridized DNA signal was sent to the enzyme by a copper ion acting as a mediator species. The enzyme then amplified the event by the catalytic reaction to generate the output signal. In addition, our system demonstrated potential for the discrimination of single nucleotide polymorphisms. PMID- 21321766 TI - Unexpected hydroxylamine-induced ring-closure reactions of meso tetraphenylsecochlorin bisaldehyde. AB - Reaction of meso-tetraphenylsecochlorin bisaldehyde with hydroxylamine results in the formation of the known meso-tetraphenyl-2-nitroporphyrin and the novel meso tetraphenylimidazolophorphyrin. The products are the result of two diverging pathways of the presumed intermediate monooxime monoaldehyde that are unusual and surprising, but fully rationalized. The structures of both products were confirmed by spectroscopic techniques and single crystal X-ray diffractometry. This reaction represents the first reaction in which a pyrrole in a porphyrin was formally replaced by an imidazole moiety. The optical properties of the free base and metalloimidazoloporphyrin under neutral and acidic conditions are discussed. Further, an alternative synthesis of the imidazoloporphyrin Ni(II) based on meso tetraphenyl-1-formyl-chlorophin is presented. PMID- 21321767 TI - 8-Hydroxyquinoline as a building block for artificial receptors: binding preferences in the recognition of glycopyranosides. AB - 8-Hydroxyquinoline-based receptors 1-3, containing a trisubstituted triethylbenzene core, were prepared and their binding properties towards glycosides were evaluated. (1)H NMR and fluorescence titrations as well as binding studies in two-phase systems, such as dissolution of solid carbohydrates in apolar media and phase transfer of sugars from aqueous into organic solvents, revealed beta- vs.alpha-anomer binding preferences in the recognition of glycosides. Compared to the previously described three-armed aminopyridine-based receptor, compounds 1 and 2 showed significantly increased affinity to beta galactoside. Receptor 2, incorporating two 8-hydroxyquinoline units, was shown to be the most effective receptor for beta-galactoside. Compound 3, bearing one 8 hydroxyquinoline group, was found to be a highly effective receptor for beta glucoside and shown to be a more powerful receptor than the quinoline-based compound 4, indicating an important role of the quinoline hydroxy group in the complex formation. PMID- 21321768 TI - An efficient biomaterial supported bifunctional organocatalyst (ES-SO3- C5H5NH+) for the synthesis of beta-amino carbonyls. AB - A biomaterial supported organocatalyst, readily synthesized by the reaction of chemically modified sulfonic group containing expanded corn starch with pyridine exhibited excellent catalytic activity for the synthesis of beta-amino carbonyls in excellent yields via aza-Michael addition of amines to electron deficient alkenes. A remarkable enhancement in the reaction rates was observed with the prepared bifunctional organocatalyst in comparison to the either starch grafted sulfonic acid or the corresponding homogeneous pyridinium p-toluenesulfonate. PMID- 21321769 TI - In search of a new class of stable nitroxide: synthesis and reactivity of a peri substituted N,N-bissulfonylhydroxylamine. AB - Acyclic bissulfonylnitroxides have never been isolated, and degrade through fragmentation. In an approach to stabilising a bissulfonylnitroxide radical, the cyclic, peri-substituted N,N-bissulfonylhydroxylamine, 2-hydroxynaphtho[1,8 de][1,3,2]dithiazine 1,1,3,3-tetraoxide (1), has been prepared by formal nitrogen insertion into the sulfur-sulfur bond of a sulfinylsulfone, naphtho[1,8 cd][1,2]dithiole 1,1,2-trioxide. The heterocyclic ring of 1 is shown to adopt a sofa conformation by X-ray crystallography, with a pseudo-axial hydroxyl group. N,N-Bissulfonylhydroxylamine 1 displays high thermal, photochemical and hydrolytic stability compared to acyclic systems. EPR analysis reveals formation of the corresponding bissulfonylnitroxide 2 upon oxidation of 1 with the Ce(IV) salts CAN and CTAN. Although 2 does not undergo fragmentation, it cannot be isolated, since hydrogen atom abstraction to reform 1 occurs in situ. The stability and reactivity of 1 and 2 are compared with the known cyclic benzo fused N,N-bissulfonylhydroxylamine, N-hydroxy-O-benzenedisulfonimide (6), for which the X-ray data, and EPR of the corresponding nitroxide 10, are also reported for the first time. PMID- 21321770 TI - "In silico" mechanistic studies as predictive tools in microwave-assisted organic synthesis. AB - Computational calculations can be used as a predictive tool in Microwave-Assisted Organic Synthesis (MAOS). A DFT study on Intramolecular Diels-Alder reactions (IMDA) indicated that the activation energy of the reaction and the polarity of the stationary points are two fundamental parameters to determine "a priori" if a reaction can be improved by using microwave irradiation. PMID- 21321771 TI - Aggregation behaviour of peptide-polymer conjugates containing linear peptide backbones and multiple polymer side chains prepared by nitroxide-mediated radical polymerization. AB - A series of peptides with an alternating sequence of alkoxyamine conjugated lysine and glycine residues were synthesized by classical solution phase peptide coupling. The resulting peptides containing up to eight alkoxyamine moieties were used as initiators in nitroxide-mediated polymerization (NMP) to obtain peptide polymer conjugates with well defined linear peptide backbones and a defined number of polymeric side chains. Polymerization of styrene and N isopropylacrylamide (NIPAM) occurred in a highly controlled fashion. Molecular weight and polydispersity index (PDI) were determined by gel permeation chromatography (GPC). Aggregation behaviour of these hybrid materials was investigated by dynamic light scattering (DLS) and atomic force microscopy (AFM). Depending on composition, number and length of the polymer side chains, the conjugates aggregate to different topologies. Whereas peptide-polystyrene conjugates may aggregate to so called honeycomb structures, peptide-poly-N isopropylacrylamide conjugates show differentiated aggregation behaviour. PMID- 21321772 TI - A convenient pathway to Sm(II)-mediated chemistry in acetonitrile. AB - In this communication we show that the instability of samarium diiodide (SmI(2)) in acetonitrile is a consequence of ionization of the reductant in this solvent. Samarium triflate (Sm(OTf)(2)) is exceptionally stable in acetonitrile for periods over six months and can be used with appropriate additives to initiate a ketyl-olefin coupling reaction in high yield. PMID- 21321773 TI - Triple substitution G216N/A217L/S398M leads to the active and thermostable Luciola mingrelica firefly luciferase. AB - Insufficient thermal stability of firefly luciferases often limits their application in a wide range of fields. The substitution A217L is known to greatly increase thermal stability of many firefly luciferases. However, for Hotaria parvula firefly luciferase, that shares 98% degree of homology with Luciola mingrelica luciferase, the A217L mutation is known to dramatically decrease catalytic activity. We analyzed the environment of A217 in the 3D-structure of L. mingrelica luciferase with the purpose of identifying possible additional mutations that would allow retention of the high thermal stability of the A217L mutant while preserving the high level of activity. The G216N/A217L double mutant of L. mingrelica luciferase demonstrated significantly improved stability at 42 and 45 degrees C but retained only 10% of activity; the loss in activity was accompanied by a large red shift of bioluminescence emission maximum from 566 to 611 nm compared with the wild-type enzyme. The triple mutant G216N/A217L/S398M exhibited high thermal stability of the double mutant together with the high activity and bioluminescence spectra close to that of the wild-type luciferase. PMID- 21321774 TI - Line tension action on 2D networks of gold nanoparticles obtained by the Bubble Deposition Method. AB - The self-assembling properties of surfactant black films are used to obtain sizeable, dense islands of nanoparticles. Using the "Bubble Deposition Method" (BDM) these films are transferred onto solid substrates. The organisation within the islands evolves when the films are allowed to equilibrate before deposition. The results on model gold particles are discussed in terms of line tension. PMID- 21321775 TI - Enantioselective Prevost and Woodward reactions using chiral hypervalent iodine(III): switchover of stereochemical course of an optically active 1,3 dioxolan-2-yl cation. AB - Optically active 1,3-dioxolan-2-yl cation intermediates were generated during enantioselective dioxyacetylation of alkene with chiral hypervalent iodine(III). Regioselective attack of a nucleophile toward the intermediate resulted in reversal of enantioselectivity of the dioxyacetylation. PMID- 21321776 TI - Metastable state nanoparticle-enhanced Raman spectroscopy for highly sensitive detection. AB - Metastable state silver nanoparticle surface-enhanced Raman scattering has been experimentally and theoretically demonstrated; the signal is two to three orders of magnitude higher than that for the traditional method. Ultrasensitive surface enhanced Raman scattering signals of illicit drug cocaine and organophosphate pesticide methyl-parathion were observed. PMID- 21321777 TI - Catalytic enantioselective synthesis of A-86929, a dopamine D1 agonist. AB - A-86929, a dopamine D1 agonist was synthesized with 95% ee in five steps with overall yield of 56% via catalytic enantioselective one-pot aziridination followed by Friedel-Crafts cyclization and a mild Pictet-Spengler cyclization protocol. PMID- 21321778 TI - Cu(II) assisted self-sorting towards pseudorotaxane formation. AB - A new triamino macrocycle shows Cu(II) templated self-sorting of a pseudorotaxane out of sixteen such possibilities from the mixture of nine components of a tridentate, four bidentate ligands and four transition metal ions. PMID- 21321782 TI - Sensitive electrochemical detection of superoxide anion using gold nanoparticles distributed poly(methyl methacrylate)-polyaniline core-shell electrospun composite electrode. AB - In the present communication, a novel composite nanofibrous electrode is developed for the detection of superoxide anion (O(2)(-)) in phosphate buffered saline (PBS). The composite fiber electrode is fabricated by dispersing gold nanoparticles onto poly(methyl methacrylate) (PMMA)-polyaniline (PANI) core-shell electrospun nanofibers. The constructed architecture is proven to be a favorable environment for the immobilization of the enzyme, superoxide dismutase (SOD). Direct electron transfer is achieved between SOD and the electrode with an electron transfer rate constant of 8.93 s(-1). At an applied potential of +300 mV, PMMA/PANI-Au(nano)/SOD-ESCFM shows highly sensitive detection of O(2)(-). In addition to this, quantification of different activities of SOD is realized at PMMA/PANI-Au(nano)/SOD-ESCFM. These analytical features offer great potential for construction of the third-generation O(2)(-) biosensor. PMID- 21321783 TI - Nanomolar concentrations determination of hydrazine by a modified carbon paste electrode incorporating TiO2 nanoparticles. AB - In the present paper, the use of a carbon paste electrode modified by quinizarine (QZ) and TiO(2) nanoparticles prepared by a simple and rapid method was described. The heterogeneous electron-transfer properties of quinizarine coupled to TiO(2) nanoparticles at a carbon paste electrode was investigated using cyclic voltammetry and chronoamperometry in aqueous buffer solutions. The modified electrode showed excellent character for the electrocatalytic oxidization of hydrazine (HZ). Differential pulse voltammetric peak currents of HZ increased linearly with their concentrations at the range of 0.5 uM to 1900.0 uM and the detection limit (2sigma) was determined to be 77 nM. Finally, this method was used for the determination of HZ in water samples, using a standard addition method. PMID- 21321784 TI - A novel approach for the separation of neutral analytes by means of electrochemically assisted injection coupled to capillary electrophoresis-mass spectrometry. AB - A novel concept for capillary electrophoresis-mass spectrometry (CE-MS) studies of neutral analytes is presented. The experimental approach is based on the implementation of electrochemically assisted injection (EAI) which enables the generation of charged species from neutral analytes. In this way electrophoretic separations can be performed without the use of surfactants leading to an excellent compatibility with ESI-MS. Various ferrocene species have been used as model compounds to demonstrate the potential of the EAI-CE-MS technique. PMID- 21321785 TI - Self-assembled molecular squares containing metal-based donor: synthesis and application in the sensing of nitro-aromatics. AB - Self-assemblies between a linear Pt-based donor and ferrocene- chelated metallic acceptors produced novel heterometallic squares 4 and 5, which show fluorescence quenching upon the addition of nitro-aromatics. PMID- 21321786 TI - Cationic lipo-thiophosphoramidates for gene delivery: synthesis, physico-chemical characterization and gene transfection activity--comparison with lipo phosphoramidates. AB - The synthesis of cationic lipo-thiophosphoramidates, a new family of cationic lipids designed for gene delivery, is reported herein. This new class of lipids is less polar than its oxygenated equivalent the lipo-phosphoramidates. Fluorescence anisotropy and FRET were used to determine the fluidity and fusogenicity of the lipo-phosphoramidates 3a-b and lipo-thiophosphoramidates 7a b. The determination of both the size and the zeta potential of the nano-objects (liposomes and lipoplexes) and the determination of the DNA binding ability of the liposomes have completed the physico-chemical characterizations of the cationic lipids studied. Finally, the cationic lipids 3a-b and 7a-c have been evaluated as synthetic vectors for gene transfection into a variety of mammalian cell lines. The lipo-thiophosphoramidate 7a proved to be an efficient and low toxicity synthetic vector even when used at low lipid to DNA charge ratios. PMID- 21321787 TI - Effect of job maintenance training program for employees with chronic disease - a randomized controlled trial on self-efficacy, job satisfaction, and fatigue. AB - OBJECTIVE: Employees with a chronic physical condition may be hampered in job performance due to physical or cognitive limitations, pain, fatigue, psychosocial barriers, or because medical treatment interferes with work. This study investigates the effect of a group-training program aimed at job maintenance. Essential elements of the program are exploration of work-related problems, communication at the workplace, and the development and implementation of solutions. METHODS: Participants with chronic physical diseases were randomly assigned to the intervention (N=64) or the control group (N=58). Participants were eligible for the study if they had a chronic physical disease, paid employment, experienced work-related problems, and were not on long-term 100% sick leave. Primary outcome measures were self-efficacy in solving work- and disease-related problems (14-70), job dissatisfaction (0-100), fatigue (20-140) and job maintenance measured at 4-, 8-, 12- and 24-month follow-up. We used GLM repeated measures for the analysis. RESULTS: After 24 months, loss to follow-up was 5.7% (7/122). Self-efficacy increased and fatigue decreased significantly more in the experimental than the control group [10 versus 4 points (P=0.000) and 19 versus 8 points (P=0.032), respectively]. Job satisfaction increased more in the experimental group but not significantly [6 versus 0 points (P=0.698)]. Job maintenance was 87% in the experimental and 91% in the control group, which was not a significant difference. Many participants in the control group also undertook actions to solve work-related problems. CONCLUSIONS: Empowerment training increases self-efficacy and helps to reduce fatigue complaints, which in the long term could lead to more job maintenance. Better understanding of ways to deal with work-related problems is needed to develop more efficient support for employees with a chronic disease. PMID- 21321788 TI - N-nitrosamines are associated with shorter telomere length. AB - OBJECTIVES: Telomeres are critical to maintain the integrity of the chromosomes, and telomere abnormalities are important features of carcinogenesis. Telomere length differs among individuals due to genetic and environmental factors. Aiming to examine the relationship between DNA-damaging agents and average telomere length in peripheral blood, we conducted a cross-sectional study among 157 workers working in the rubber industry in Sweden. METHODS: N-nitrosamines were measured in air by personal sampling on Thermosorb/N tubes and analyzed by liquid chromatography tandem mass spectrometry (LC/MS/MS) for 60 individuals. Based on a similar working situation, the exposure was estimated for all workers. Polycyclic aromatic hydrocarbons (PAH) were measured as the metabolite 1-hydroxypyrene (1 HP) in urine by LC. Carbon disulphide (CS2) was measured as the metabolite 2 thiothiazolidine-4-carboxylic acid (TTCA) in urine by LC/MS/MS. Toluidines (orto , meta-, and para-) were measured in urine by gas chromatography (GC)/MS. The average telomere length in peripheral blood was determined by quantitative polymerase chain reaction (PCR). RESULTS: There was a reduction in telomere length with increasing exposure to N-nitrosamines in air [measured (N=60) N nitrosamines beta-coefficient= -10, (95% confidence interval [95% CI] -17- -1.9) P=0.016; estimated (N=157) N-nitrosamines beta-coefficient = -5.3, (95% CI -9.5- 0.97) P=0.016]. Also, there were negative associations between para-toluidine [beta-coefficient= -0.031 (95% CI -0.055- -0.0063) P=0.014], as well as age beta coefficient= -0.005 (95% CI -0.007- -0.002) P=0.001] and telomere length. There were no strong associations between other exposures and telomere length nor did smoking modify the effect. CONCLUSION: N-nitrosamines exposure may lead to telomere shortening. PMID- 21321789 TI - Smoking and alcohol drinking increased the risk of esophageal cancer among Chinese men but not women in a high-risk population. AB - Although the association for esophageal cancer with tobacco smoking and alcohol drinking has been well established, the risk appears to be less strong in China. To provide more evidence on the effect of smoking and alcohol consumption with esophageal cancer in China, particularly among Chinese women, a population-based case-control study has been conducted in Jiangsu, China, from 2003 to 2007. A total of 1,520 cases and 3,879 controls were recruited. Unconditional multivariate logistic regression analysis was applied. Results showed that the odds ratio (OR) and confidence interval (CI) for ever smoking and alcohol drinking were 1.57 (95% CI: 1.34-1.83) and 1.50 (95% CI: 1.29-1.74). Dose response relationships were observed with increased intensity and longer duration of smoking/drinking. Risk of smoking and alcohol drinking at the highest joint level was 7.32 (95% CI: 4.58-11.7), when compared to those never smoked and never drank alcohol. Stratifying by genders, smoking and alcohol drinking increased the risk among men with an OR of 1.74 (95% CI: 1.44-2.09) and 1.76 (95% CI: 1.48 2.09); however, neither smoking nor alcohol consumption showed a significant association among women. In conclusion, smoking and alcohol drinking were associated with esophageal cancer risk among Chinese men, but not among Chinese women. PMID- 21321790 TI - The role of N-acetyltransferase 2 polymorphism in the etiopathogenesis of inflammatory bowel disease. AB - BACKGROUND AND PURPOSE: Inflammatory bowel disease (IBD) consists of ulcerative colitis (UC) and Crohn's disease (CD), which are complex genetic disorders resulting from the interplay between several genetic and environmental risk factors. The arylamine N-acetyltransferase 2 (NAT2) enzyme detoxifies a wide spectrum of naturally occurring xenobiotics including carcinogens and drugs. Acetylation catalyzed by NAT2 is an important process in metabolic activation of arylamines to electrophilic intermediates that initiate carcinogenesis. The aim of our study was to determine whether there is any association between the susceptibility to inflammatory bowel disease among the variations of NAT2 genotypes. METHODS: This study was carried out in 80 patients with IBD. The control group consisted of 100 healthy volunteers. The most common mutations found in the Caucasian population are at the positions 481T, 803G, 590A and 857A on the NAT2 gene. This was determined using the polymerase chain reaction restriction fragment length polymorphism method with DNA extracted from peripheral blood. RESULTS: Risk of IBD development was 3.86 for the carriers of the NAT2*5/NAT2*7 genotype and 2.53 for the carriers with NAT2*6/NAT2*7, but it was not statistically significant. A statistically significant correlation between the NAT2*7 allele prevalence and the risk for developing IBD was found (OR = 5.8; P = 0.005). CONCLUSIONS: Higher prevalence of the NAT2*7 allele in patients with IBD and the obtained OR values could suggest that this mutation has the effect of increasing IBD development. Future studies are needed to confirm our assumptions on larger group of patients. PMID- 21321792 TI - Application of silicon photomultipliers to positron emission tomography. AB - Historically, positron emission tomography (PET) systems have been based on scintillation crystals coupled to photomultipliers tubes (PMTs). However, the limited quantum efficiency, bulkiness, and relatively high cost per unit surface area of PMTs, along with the growth of new applications for PET, offers opportunities for other photodetectors. Among these, small-animal scanners, hybrid PET/MRI systems, and incorporation of time-of-flight information are of particular interest and require low-cost, compact, fast, and magnetic field compatible photodetectors. With high quantum efficiency and compact structure, avalanche photodiodes (APDs) overcome several of the drawbacks of PMTs, but this is offset by degraded signal-to-noise and timing properties. Silicon photomultipliers (SiPMs) offer an alternative solution, combining many of the advantages of PMTs and APDs. They have high gain, excellent timing properties and are insensitive to magnetic fields. At the present time, SiPM technology is rapidly developing and therefore an investigation into optimal design and operating conditions is underway together with detailed characterization of SiPM based PET detectors. Published data are extremely promising and show good energy and timing resolution, as well as the ability to decode small scintillator arrays. SiPMs clearly have the potential to be the photodetector of choice for some, or even perhaps most, PET systems. PMID- 21321791 TI - 99mTc-besilesomab (Scintimun) in peripheral osteomyelitis: comparison with 99mTc labelled white blood cells. AB - PURPOSE: The diagnosis of osteomyelitis is a challenge for diagnostic imaging. Nuclear medicine procedures including white blood cell imaging have been successfully used for the identification of bone infections. This multinational, phase III clinical study in 22 European centres was undertaken to compare anti granulocyte imaging using the murine IgG antibody besilesomab (Scintimun) with (99m)Tc-labelled white blood cells in patients with peripheral osteomyelitis. METHODS: A total of 119 patients with suspected osteomyelitis of the peripheral skeleton received (99m)Tc-besilesomab and (99m)Tc-hexamethylpropyleneamine oxime (HMPAO)-labelled white blood cells (WBCs) in random order 2-4 days apart. Planar images were acquired at 4 and 24 h after injection. All scintigraphic images were interpreted in an off-site blinded read by three experienced physicians specialized in nuclear medicine, followed by a fourth blinded reader for adjudication. In addition, clinical follow-up information was collected and a final diagnosis was provided by the investigators and an independent truth panel. Safety data including levels of human anti-mouse antibodies (HAMA) and vital signs were recorded. RESULTS: The agreement in diagnosis across all three readers between Scintimun and (99m)Tc-HMPAO-labelled WBCs was 0.83 (lower limit of the 95% confidence interval 0.8). Using the final diagnosis of the local investigator as a reference, Scintimun had higher sensitivity than (99m)Tc-HMPAO-labelled WBCs (74.8 vs 59.0%) at slightly lower specificity (71.8 vs 79.5%, respectively). All parameters related to patient safety (laboratory data, vital signs) did not provide evidence of an elevated risk associated with the use of Scintimun except for two cases of transient hypotension. HAMA were detected in 16 of 116 patients after scan (13.8%). CONCLUSION: Scintimun imaging is accurate, efficacious and safe in the diagnosis of peripheral bone infections and provides comparable information to (99m)Tc-HMPAO-labelled WBCs. PMID- 21321793 TI - Assessing the mental health needs and barriers to care among a diverse sample of Asian American older adults. AB - BACKGROUND: Asian Americans represent a mix of cultures and immigration experiences, which may put them differentially at risk for mental health problems. Yet, little is known about the mental health needs of older adults from various Asian subgroups compared to non-Hispanic whites. OBJECTIVES: To compare the prevalence rates of mental distress of Chinese, Filipino, South Asian, Japanese, Korean, and Vietnamese older adults (aged 55 and older) to that of non Hispanic whites; and to examine subgroup differences in utilization of mental health services. METHODS: A cross-sectional analysis of a population-based sample of California adults responding to the 2007 California Health Interview Survey. Multivariable logistic regression analysis was used to examine subgroup differences in mental health status and use of mental health services among the six different Asian subgroups and non-Hispanic whites, adjusting for respondents' demographic and health characteristics, socioeconomic status, and English language proficiency. RESULTS: A total of 20,712 respondents were included. Filipino [aOR=2.25; 95% CI=1.14-4.47] and Korean Americans [aOR=2.10; 95% CI=1.06 4.17] were more likely to report symptoms indicative of mental distress compared to non-Hispanic whites, yet were less likely to have seen a primary care provider [Filipino: aOR=0.41; 95% CI=0.18-0.90; Korean: aOR=0.24; 95% CI = 0.08-0.69] or have taken a prescription medication [Filipino: aOR=0.20; 95% CI=0.10-0.40; Korean: aOR=0.15; 95% CI=0.05-0.40], even after adjusting for indicators of respondents' demographic and health characteristics, socioeconomic status, and English-language proficiency. In contrast, Japanese Americans were less likely to report symptoms indicative of mental distress [aOR=0.43; 95% CI=0.21-0.90], and were less likely to make use of mental health services compared to non-Hispanic whites. DISCUSSION/CONCLUSIONS: The findings from this study not only highlight the unmet mental health needs among older Asian Americans, but also illustrate significant variations among the various Asian subgroups. Clinicians who work closely with these patients should regularly screen and assess older Asian adults for symptoms related to their mental health needs. PMID- 21321794 TI - Constraints on the processes responsible for the extrinsic normalization of vowels. AB - Listeners tune in to talkers' vowels through extrinsic normalization. We asked here whether this process could be based on compensation for the long-term average spectrum (LTAS) of preceding sounds and whether the mechanisms responsible for normalization are indifferent to the nature of those sounds. If so, normalization should apply to nonspeech stimuli. Previous findings were replicated with first-formant (F1) manipulations of speech. Targets on a [pt] [pEt] (low-high F1) continuum were labeled as [pt] more after high-F1 than after low-F1 precursors. Spectrally rotated nonspeech versions of these materials produced similar normalization. None occurred, however, with nonspeech stimuli that were less speechlike, even though precursor-target LTAS relations were equivalent to those used earlier. Additional experiments investigated the roles of pitch movement, amplitude variation, formant location, and the stimuli's perceived similarity to speech. It appears that normalization is not restricted to speech but that the nature of the preceding sounds does matter. Extrinsic normalization of vowels is due, at least in part, to an auditory process that may require familiarity with the spectrotemporal characteristics of speech. PMID- 21321796 TI - Effects of enflurane on gill withdrawal behaviors and the ability of gill motor neurones to elicit gill Contractions in Aplysia. AB - We used the Aplysia gill withdrawal reflex model system in order to study how enflurane effected both gill withdrawal adaptive behaviors and the activity of single identified neurones which are involved with the mediation of the gill withdrawal response. We found that a continuous superfusion of enflurane (O.S and 1.0%) solution over the abdominal ganglion (the CNS) resulted in an increase in the spontaneous gill respiratory movements; an increase in the spontaneous discharges in identified central motor neurones; and a depolarizing shift in the resting membrane potential of these neurones. Enflurane also significantly effected the ability of the gill motor neurones to elicit a gill contraction when the motor neurone was depolarized to produce action potentials by passing depolarizing current into the neurone. Although in most cases the ability of the motor neurone to elicit a gill withdrawal contraction was decreased, that in one third of the cases was increased. Enflurane may exert its actions by effecting the activity of CNS control neurones which exert both facilitatory and suppressive control over the peripheral nervous system in the gill as well as by having direct effects on the motor neurones. PMID- 21321797 TI - Changes in plasma concentrations of free amino acids during and after the anhepaic period. PMID- 21321798 TI - To the editor. PMID- 21321799 TI - Time-dependent density functional response theory for electronic chiroptical properties of chiral molecules. AB - Methodology to calculate electronic chiroptical properties from time-dependent density functional theory (TDDFT) is outlined. Applications of TDDFT to computations of electronic circular dichroism, optical rotation, and optical rotatory dispersion are reviewed. Emphasis is put on publications from 2005 to 2010, but much of the older literature is also cited and discussed. The determination of the absolute configuration of chiral molecules by combined measurements and computations is an important application of TDDFT chiroptical methods and discussed in some detail. Raman optical activity (ROA) spectra are obtained from normal-mode derivatives of the optical rotation tensor and other linear response tensors. A few selected (ROA) benchmarks are reviewed. PMID- 21321800 TI - Recent theoretical and experimental advances in the electronic circular dichroisms of planar chiral cyclophanes. AB - The chiroptical properties, such as electronic and vibrational circular dichroism and optical rotation, of planar chiral cyclophanes have attracted much attention in recent years. Although the chemistry of cyclophanes has been extensively explored for more than 60 years, the studies on chiral cyclophanes are rather limited. Experimentally, the use of chiral stationary phases in HPLC becomes more popular and facilitates the enantiomer separation of chiral cyclophanes of interest. Almost all chiral cyclophanes can be readily separated, in analytical and preparative scales, most typically on a Daicel OD type column, which is based on cellulose tris(3,5-dimethylphenylcarbamate). The CD spectra of chiral cyclophanes are unique in their fairly large, significantly coupled Cotton effects observed in all the 1B (b), 1L (a), and 1L (b) band regions. Theoretically, the time-dependent density functional theory, or TD-DFT, method becomes a cost-efficient, yet accurate, theoretical method to reproduce the electronic circular dichroisms and the absorption spectra of a variety of cyclophanes. The direct comparison of the experimental CD spectra with the theoretical ones readily leads to the unambiguous assignment of the absolute configuration of cyclophanes. In addition, the analysis of configuration interaction and molecular orbitals allows detailed interpretation of the electronic transitions and Cotton effects in the UV and CD spectra. Through the study of the CD spectra of chiral cyclophanes as model systems, the effects of intra- and intermolecular interactions on the chiroptical properties of molecules can be explored, and the results thus obtained are valuable in comprehensively elucidating the structure-chiroptical property relationship. In this review the recent progress in experimental and theoretical investigations of the electronic CD spectra of chiral cyclophanes is discussed. PMID- 21321801 TI - G-C content independent long-range charge transfer through DNA. AB - The interest in DNA as a building block for nano-electric sensors and devices stemmed from the ability to construct various nanometer-sized two and three dimensional structures and its amazing positive charge conducting properties. However, since a positive charge migrates along DNA through the HOMO of G-C base pairs, the conductivity of DNA strongly decreases with the increasing A-T base pair content hampering the construction of nano-electric circuits in which the use of various sequence patterns is indispensable. In this chapter, we demonstrated that the charge transfer efficiency can be drastically increased in a G-C content independent manner by adjusting the HOMO-level of the A-T base-pair closer to that of the G-C base-pair. This was achieved either by substituting the N7 nitrogen of A with a C-H group (deazaadenine: Z) or substituting C2 hydrogen with an amino group (diaminopurine: D). Since Z and D selectively pair with T without significantly perturbing the thermo-stability of the duplex, Z and D can be used to increase the charge transfer efficiency through DNA while properly maintaining the sequence information carried by DNA. PMID- 21321802 TI - Transfer of chirality for memory and separation. AB - Transfer of chirality is an intriguing issue worth studying to understand better the origin of life and for possible technological applications. In the last few years we have been working in this area studying the chain of events that begins with induction, reaches a permanent transfer (chiral memory) and extends in some cases to a (quasi-)reversible situation in which induced and permanently memorized chirality coexists. This can happen thanks to a designed blend of thermodynamics and kinetics. PMID- 21321803 TI - Vibrational circular dichroism spectroscopy of chiral molecules. AB - In this chapter, new developments and main applications of vibrational circular dichroism (VCD) spectroscopy reported in the last 5 years are described. This includes the determinations of absolute configurations of chiral molecules, understanding solvent effects and modeling solvent-solute explicit hydrogen bonding networks using induced solvent chirality, studies of transition metal complexes and their peculiar and enormous intensity enhancements in VCD spectra, investigations of conformational preference of chiral ligands bound to gold nano particles, and two new advances in applying matrix isolation VCD spectroscopy to flexible, multi-conformational chiral molecules and complexes, and in development of femtosecond laser based VCD instruments for transient VCD monitoring. A brief review of the experimental techniques and theoretical methods is also given. The purpose of this chapter is to provide an up-to-date perspective on the capability of VCD to solve significant problems about chiral molecules in solution, in thin film states, or on surfaces. PMID- 21321804 TI - Spin selective electron transmission through monolayers of chiral molecules. AB - Self-assembled monolayers (SAMs) of organic dipolar molecules have new electronic and magnetic properties that result from their organization, despite the relatively weak interaction among the molecules themselves. Here we review the origin of this cooperative effect and summarize results obtained on spin selective electron transmission through such monolayers that are made from chiral molecules. We show that SAMs containing chiral dipolar molecules behave like magnetic layers which may serve as spin filters, even without applying an external magnetic field to the layer. PMID- 21321805 TI - Chiral control of current transfer in molecules. AB - Electron transmission through chiral molecules induced by circularly polarized light can be very different for mirror image structures. This behavior is described in terms of current transfer: the transfer of both charge and momentum. We review recent theoretical developments on the theory of current transfer and discuss related experimental studies of electron transmission through chiral molecular structures adsorbed on surfaces. PMID- 21321806 TI - Spin-polarized electron induced asymmetric reactions in chiral molecules. AB - Understanding the origin of chirality in nature has been an active area of research since the time of Pasteur. In this chapter we examine one possible route by which this asymmetry could have arisen, namely chiral-specific chemistry induced by spin-polarized electrons. The various sources of spin-polarized electrons (parity violation, photoemission, and secondary processes) are discussed. Experiments aimed at exploring these interactions are reviewed starting with those based on the Vester-Ulbricht hypothesis through recent studies of spin polarized secondary electrons from a magnetic substrate. We will conclude with a discussion of possible new avenues of research that could impact this area. PMID- 21321807 TI - Innate responses of the predatory mite Phytoseiulus persimilis to a herbivore induced plant volatile. AB - The responses of the predatory mite P. persimilis to herbivore-induced plant volatiles are at least partly genetically determined. Thus, there is potential for the evolution of this behaviour by natural selection. We tested whether distinct predator genotypes with contrasting responses to a specific herbivore induced plant volatile, i.e. methyl salicylate (MeSa), could be found in a base population collected in the field (Sicily). To this end, we imposed purifying selection on individuals within iso-female lines of P. persimilis such that the lines were propagated only via the individual that showed either a preference or avoidance of MeSa. The responses of the lines were characterized as the mean proportion of individuals choosing MeSa when given a choice between MeSa and clean air. Significant variation in predator responses was detected among iso female lines, thus confirming the presence of a genetic component for this behaviour. Nevertheless, we did not find a significant difference in the response to MeSa between the lines that were selected to avoid MeSa and the lines selected to prefer MeSa. Instead, in the course of selection the lines selected to avoid MeSa shifted their mean response towards a preference for MeSa. An inverse, albeit weaker, shift was detected for the lines selected to prefer MeSa. We discuss the factors that may have caused the apparent lack of a response to selection within iso-female line in this study and propose experimental approaches that address them. PMID- 21321808 TI - Candidate screening of the TRPC3 gene in cerebellar ataxia. AB - The hereditary cerebellar ataxias are a diverse group of neurodegenerative disorders primarily characterised by loss of balance and coordination due to dysfunction of the cerebellum and its associated pathways. Although many genetic mutations causing inherited cerebellar ataxia have been identified, a significant percentage of patients remain whose cause is unknown. The transient receptor potential (TRP) family member TRPC3 is a non-selective cation channel linked to key signalling pathways that are affected in cerebellar ataxia. Furthermore, genetic mouse models of TRPC3 dysfunction display cerebellar ataxia, making the TRPC3 gene an excellent candidate for screening ataxic patients with unknown genetic aetiology. Here, we report a genetic screen for TRPC3 mutations in a cohort of 98 patients with genetically undefined late-onset cerebellar ataxia and further ten patients with undefined episodic ataxia. We identified a number of variants but no causative mutations in TRPC3. Our findings suggest that mutations in TRPC3 do not significantly contribute to the cause of late-onset and episodic human cerebellar ataxias. PMID- 21321812 TI - [Anterior esthetics with adhesive porcelain veneers]. PMID- 21321813 TI - [Hand surgery: quo vadis?]. PMID- 21321814 TI - [Prophylaxis of CRPS I and recurrent CRPS I]. AB - In the foreground of the avoidance of a CRPS as well as a recurrent CRPS, also pathophysiological considerations and use-possibilities of different drugs stand beside the observance of generally valid principles for treatment. Its consistent transposition cannot certainly prevent the CRPS in each case admittedly, the installment of the appearance or recurrence of a CRPS clearly lowers however. PMID- 21321815 TI - [A rare toxicological emergency case: snakebite of the Saharan horned viper]. AB - We report on the snakebite injury of a 27-year-old male patient by a Saharan horned viper in his left middle finger. General symptoms (thrombocytopenia, fibrinolysis and rhabdomyolysis) were leading and required observation at close intervals on intensive care unit and the application of a specific antiserum. At the finger a local necrectomy for the haemorrhagic necrosis was needed, followed by split-skin grafting for tissue coverage. PMID- 21321816 TI - [On the 50th anniversary of the Journal DIE REHABILITATION]. PMID- 21321817 TI - [Needs assessment: legal foundations, current practice and research topics - thinking outside the box ...]. PMID- 21321818 TI - [Legal questions concerning needs assessment for participation benefits]. AB - Needs Assessment for participation benefits (rehabilitation) in Germany is part of the administrative proceedings. It is condition for the decision of the responsible administrative bodies. It is underlying the principles of public inquiry, which can be carried out by experts of social medicine. It has to be carried out within a 3-week period and within a maximum of 7 weeks if a certificate has to be given. Following the principle of cooperation the need has to be assessed for all administrative bodies possibly involved as responsible for a participation benefit to be provided. In practice, however, needs assessment is still focussed on issues within the specific domain of the various administrative bodies. There is hardly any research on the implementation of needs assessment under a legal point of view. It could be started by carrying out an analysis of official files and by expert interviews. PMID- 21321819 TI - [Needs assessment across social insurance agencies - potential approaches and prospects]. AB - To enable self-determination and participation equal with others for persons with disabilities, the social insurance agencies involved in rehabilitation provide benefits for rehabilitation and participation. In order to initiate and perform those benefits individually and purposively, it is necessary to detect and assess a potential need early across social insurance agencies. This requirement was strengthened by the UN Convention on the Rights of Persons with Disabilities. The article outlines the legal background and practical framework conditions for the present assessment duty and refers to examples of existing methods for needs assessment, which in general are still too much aligned to specific benefits. In light of these circumstances, a need for action exists in order to implement legal demands relative to needs assessments across social insurance agencies and to advance approaches already in place. PMID- 21321820 TI - [Disability assessment for the statutory pension insurance: significance, need for research, and opportunities]. AB - Disability assessment is a complex and multifaceted process of exploration and evaluation, which in terms of legal evidence can be of far-reaching consequence for the claimant, the statutory pension insurance and finally for society as well. In the article the specifics of the assignment, the assessment situation, and the process of evaluation are described. Based upon an analysis of the so far only little research activities, the future need for research is subdivided into 4 thematic groups: 1 Operationalization and validation of central dimensions of evaluation; 2 Investigation of the structure of the expert decision-making process and the factors influencing it; 3 Investigation of the influence of sociopolitical, labour market-related and economical aspects on the evaluation; 4 Quality assurance. On the other hand the article describes the special quality of disability assessment. In a unique way it offers an integrated reflection of the medical history, limitation in capacity and participation and options for treatment and rehabilitation. Beyond the assessment of functional capacity, it could be of use for the development of innovative forms of support for the rehabilitation of working capacity. PMID- 21321821 TI - [Practice problems in disability assessment of applications for psychosomatic rehabilitation]. AB - In 2008 the German statutory pension insurance handled about 1 600 000 applications for medical rehabilitation. The overall approval rate was 70%, with a range between 60 and 86% in regional pension insurances. The majority of applications were refused on the ground that ambulatory medical or psychotherapeutic treatment was sufficient. Physicians frequently argued that ambulatory psychotherapy was unavailable due to long waiting lists or lack of psychotherapists. The problem whether shortcomings in ambulatory care can constitute sufficient reason to affirm a need for inpatient rehabilitation is discussed. It is necessary to improve the basis for needs assessment by the medical services (e. g. personal assessment, contacting family doctors). A survey of the further development (e. g. course of disease, disability days, and early retirement) of insurees whose applications for rehabilitation were rejected is recommended. PMID- 21321822 TI - [Work related psychosocial factors and the risk of early disability pensioning: a contribution to assessing the need for rehabilitation]. AB - BACKGROUND: Predicting the risk of disability in injured or sick workers is important to adequately assess the need for prevention and rehabilitation. Work related factors could modify the risk of disability in a sustainable manner, and assessment of these factors might contribute to better risk prediction. AIM: Using the example of psychosocial work factors, empirical studies examining the question whether those exposures predict forthcoming events of disability retirement were to be identified. The review was expected to help quantify disability risks related to specific psychosocial factors at work. METHODS: A systematic review was conducted. 20 studies were found which studied associations between disability retirement and different aspects of the psychosocial work environment in a longitudinal design. RESULTS: Most studies found elevated disability risks in persons exposed to psychosocial factors at work. Important single factors were low control, monotonous work, work stress (job strain, effort reward imbalance), a lack of social support, problems related to the organization of work and to leadership behaviours. CONCLUSION: There is evidence that psychosocial work factors influence the short- and long-term risk of disability pensioning. PMID- 21321823 TI - [Occupational rehabilitation of neurological patients - long-term outcome data]. AB - Occupational rehabilitation in Germany is done in specialized centres (so-called "Phase II" centres). In the present study, long-term outcome data of 237 neurological rehabilitation patients (mean age 38.3 years) were analyzed. Most of the patients had suffered brain injuries. The examination took place some 7 years after the end of occupational rehabilitation and approximately 10 years after the injury. About 60% of patients returned to work (35% worked, 9.3% were seeking a job, 13.5% underwent training). Positive predictors for return to work were lower age and high educational level. The results from this study suggest that occupational rehabilitation is effective. Controlled and multi-centre studies should be carried out. PMID- 21321824 TI - ["Vocational perspective" - concept and acceptance of a group treatment for patients with extensive work-related problems]. AB - BACKGROUND: The treatment programme "Vocational Perspective" was developed for patients with health-related social problems, e. g. long-term sick leave, job loss due to disability, job insecurity and psychosocial disabilities. It intends the patient-oriented imparting of information referring to social system, legal rights, earning capacity and occupational reintegration as well as an early feedback of the sociomedical assessment by the physicians. Participants during in patient rehabilitation are supported to deal with their occupational situation; motivation to stay employed is strengthened. The group programme contains five psychoeducative modules and an additional sociomedical "ward round". The aim of the study was to examine the acceptance of the newly developed sociomedical vocational therapy module. METHOD: A total of 179 patients participated in 21 "vocational perspective" seminars within the scope of a controlled quasi experimental trial. In the experimental group the data on acceptance of the treatment was assessed by questionnaire at the end of the intervention. Experiences with implementation of the programme are described in order to complete the patient-related perspective. RESULTS: The identification of a demand for work-related interventions in medical rehabilitation seemed successful: Sociodemographic and socioeconomical parameters of the sample proved high risk in view of the social-medical perspective (poor education, high unemployment rates and long-term sick leave). Self-estimations revealed high suffering of the participants, e. g. due to the occupational situation, anxiety and depression, and confirmed high interest in work-related issues. The patients showed quite high acceptance of the programme (regarding importance of seminar, comprehensibility, usefulness of information, atmosphere of the group, mode and extent of the programme). 82.7% of the participants would recommend the programme to other people with work-related problems. Altogether, the experiences during the implementation of the programme can be described as positive. Nevertheless, organizing took much effort and the treatment was very demanding for the therapists. Finally, it is also necessary that the physicians agree to realize high transparency in the process of sociomedical assessment. CONCLUSION: The sociomedical programme "Vocational Perspective" helps patients to deal with relevant information referring to social system and occupational reintegration. Problematical sociomedical issues can be handled in a therapeutic way during rehabilitation process. Therefore, the programme can be used as meaningful supplement in regular medical rehabilitation. For final conclusions, the results of short-term and follow-up evaluations described elsewhere have to be considered. PMID- 21321825 TI - ["About me and my disease" - the making of an individual book within an art therapy course for cancer patients]. AB - AIMS: Art therapy is increasingly gaining in importance in psychooncological care. At the university of Leipzig an art therapy intervention was developed for cancer patients in ambulant aftercare and was tested in retrospect. The aim of the course was making an individual book-object, in which the cancer could be a central topic. METHODS: Before and after the intervention the participants were questioned using semi-structured interviews. Beside the qualitative analysis of the interviews the process of the course and the making of the book were demonstrated using the example of a breast cancer patient. RESULTS: The participants reported various effects of the intervention. In all, 17 of 23 participants have created her own book. More than 75 % of the books created pick out their own cancer disease as a central theme. The participants deal with the subject in different ways. All participants placed themselves at the center and the majority created the book for themselves. CONCLUSION: The results show that the making of an individual book permits a constructive analysis with the cancer disease in a protected framework and can have a supportive effect on the participants in dealing with their disease. PMID- 21321826 TI - [On the ICF update process]. PMID- 21321827 TI - Devon I. Rubin. PMID- 21321828 TI - Office-based neurology. PMID- 21321829 TI - Headache. AB - Headache is one of the most common complaints among patients presenting to an outpatient neurology practice. The evaluation, diagnosis, and treatment of headache can be rather cumbersome and at times quite challenging for even the most seasoned neurologist. Many complex issues that although not causative, can play an exacerbating role in the genesis of headaches. In this article, the authors review some of the essential elements that are part of headache evaluation including headache-specific history, physical examination, warning signs of secondary headache disorders, and when to consider further studies. They then provide a brief review on the diagnosis of primary headache disorders according to the International Headache Society's International Classification of Headache Disorders, 2nd Edition (ICHD-2), and treatment strategies of the more common primary headache disorders with a focus on migraine, trigeminal autonomic cephalalgias, tension-type headache, and chronic daily headache. PMID- 21321830 TI - Disorders of cognition. AB - Cognitive complaints are common in any adult neurology practice, and may present in a variety of ways other than classic "memory loss." In this article, the author reviews a simple approach to a symptom-based differential diagnosis, including recognition of impairment in several key cognitive domains as well as associated symptoms such as motor disorders, psychosis, and sleep disturbance. Standard evaluation and management strategies of the most common presentations of cognitive decline in an outpatient setting are reviewed. PMID- 21321831 TI - Evaluation of "dizziness" in the neurology office. AB - "Dizziness" is a common presenting symptom to a neurologist in the outpatient setting. Dizziness can occur as a result of a vestibular disorder involving the peripheral or central vestibular pathways or nonvestibular centers as the result of a disorder of balance, proprioceptive input, or autonomic nervous system dysfunction. A careful clinical history and examination along with ancillary testing can usually lead to determination of the underlying disorder and implementation of the appropriate treatment. The authors review the general approach to the "dizzy" patient in an office-based neurology practice, focusing on the clinical diagnostic features that may help to determine the etiology and treatment options for the dizzy patient. PMID- 21321832 TI - Office evaluation of the "tired" or "sleepy" patient. AB - In an outpatient neurologic practice, the patient complaint of being "tired" is frequently encountered yet often not specifically addressed. Clarifying the symptoms and determining whether the tiredness is the result of excessive daytime sleepiness versus fatigue or weakness is the first step in diagnosing and treating the patient. A detailed neurologic and sleep history and exam can often distinguish among these different symptoms, establish the potential causes of excessive sleepiness, and decide on the additional ancillary tests that may be helpful to determine the underlying etiology. Understanding the etiology of patient's symptoms is necessary to initiate appropriate treatment. PMID- 21321833 TI - Seizures: diagnosis and management in the outpatient setting. AB - Epilepsy and seizures are common, and can significantly affect quality of life. A careful history and guided evaluation is necessary to avoid misdiagnosis, to establish causation, and to determine prognosis. Medical therapy is effective in controlling seizures in two thirds of people with epilepsy. In choosing which antiepileptic drug to use, it is important to consider epilepsy type, side effect profile, and cost. Even when seizures are controlled, dose-related side effects from antiepileptic medication, such as fatigue and imbalance, can negatively impact health-related quality of life. Teratogenic side effects are also of concern for women of childbearing age. Monotherapy is generally preferred, and with dose titration, a successful balance between efficacy and tolerability can be reached in the majority of patients. Epilepsy that is medically refractory may respond to epilepsy surgery or vagus nerve stimulation. PMID- 21321835 TI - Office assessment of gait and station. AB - Gait and station disorders are among the most common reasons patients seek outpatient neurologic consultation. A careful assessment of gait and station provides the clinician with an overview of the integrity of a patient's central and peripheral nervous systems. Therefore, clinicians may consider performing a gait and station examination as the prelude to their formal neurologic examination of the patient, regardless of their chief complaint, to gain insight into which areas of the remainder of the neurologic examination they should particularly focus on, to localize the patient's neurologic dysfunction. In this review, the author describes how a structured gait and station examination may be performed in the ambulatory setting, without any special equipment. Then, the precise mechanics of each component of normal gait and station are discussed, so that the potential localizations and significance of abnormalities, which may occur during various phases of the gait cycle, can be highlighted. In particular, some less common findings are emphasized, which may be mistaken as psychogenic in etiology. PMID- 21321834 TI - Diagnosis and treatment of common forms of tremor. AB - Tremor is the most common movement disorder presenting to an outpatient neurology practice and is defined as a rhythmical, involuntary oscillatory movement of a body part. The authors review the clinical examination, classification, and diagnosis of tremor. The pathophysiology of the more common forms of tremor is outlined, and treatment options are discussed. Essential tremor is characterized primarily by postural and action tremors, may be a neurodegenerative disorder with pathologic changes in the cerebellum, and can be treated with a wide range of pharmacologic and nonpharmacologic methods. Tremor at rest is typical for Parkinson's disease, but may arise independently of a dopaminergic deficit. Enhanced physiologic tremor, intention tremor, and dystonic tremor are discussed. Further differential diagnoses described in this review include drug- or toxin induced tremor, neuropathic tremor, psychogenic tremor, orthostatic tremor, palatal tremor, tremor in Wilson's disease, and tremor secondary to cerebral lesions, such as Holmes' tremor (midbrain tremor). An individualized approach to treatment of tremor patients is important, taking into account the degree of disability, including social embarrassment, which the tremor causes in the patient's life. PMID- 21321836 TI - Office evaluation of spine and limb pain: spondylotic radiculopathy and other nonstructural mimickers. AB - Low back and neck pain, with or without radiculopathy, are one of the most common reasons for referral to an outpatient neurology practice. Determining appropriate treatment relies on establishing an accurate diagnosis of the etiology of the spine or limb pain. The author reviews structural radiculopathies as a result of diskogenic and spondylotic etiologies with an emphasis on the clinical approach and evaluation of these patients (including imaging and electrodiagnostics), identifying management altering neurogenic mimickers of structural radiculopathies (such as infectious, inflammatory, and neoplastic myeloradiculitis and radiculoplexopathies), and stratifying patients for treatment. PMID- 21321837 TI - The peripheral neuropathy evaluation in an office-based neurology setting. AB - Peripheral neuropathy is the most common neuromuscular disorder encountered in a neurologic practice. The evaluation of patients with suspected peripheral neuropathy can be a challenging endeavor for the neurologist. Determining the pattern of clinical involvement and the nerve modalities affected can help to generate a differential diagnosis and design an approach to determine a potential cause. The combination of clinical features, electrodiagnostic testing, and ancillary laboratory studies may be used to determine the etiology. As the most common acquired etiology of peripheral neuropathy is diabetes, careful testing for impaired glucose metabolism is an important part of any diagnostic evaluation. PMID- 21321838 TI - The office evaluation of weakness. AB - The office evaluation of weakness can be a daunting task. Many different disorders affecting many different parts of the nervous system can manifest with "weakness," and several nonneurologic conditions may present with complaints of weakness. It is the job of the neurologist to determine whether a patient has neurologic weakness or suffers simply from fatigue. The physician then must properly localize the pathophysiologic site of weakness. The author focuses on neuromuscular causes of weakness affecting muscle, the neuromuscular junction, peripheral nerve, or the anterior horn cell. General historical and examination clues to localization will be discussed. A localization-based evaluation will be outlined, with more specific recommendations regarding the evaluation of a few specific disorders offered. Localization-specific laboratory, electrodiagnostic, imaging, and pathologic investigations will be presented. PMID- 21321839 TI - Rosiglitazone and pioglitazone inhibit estrogen synthesis in human granulosa cells by interfering with androgen binding to aromatase. AB - The effects of rosiglitazone or pioglitazone (thiazolidinediones, TZDs) on estrogen production and aromatase activity in human ovarian cells were examined. Human granulosa cells were incubated in the tissue culture medium supplemented with androstenedione or testosterone, with or without insulin, TZDs, or type 1 17beta-hydroxysteroid-dehydrogenase (17beta-HSD) inhibitor. Estrogen concentrations in the conditioned medium, aromatase mRNA and protein expression in the cells and androgen substrate binding to aromatase were measured. With androstenedione as substrate, rosiglitazone or pioglitazone inhibited estrone production by up to 22% (p<0.012) while type 1 17beta-HSD inhibitor enhanced this effect of rosiglitazone or pioglitazone by 37% (p<0.001) and by 67% (p<0.001), respectively. With testosterone as substrate, rosiglitazone or pioglitazone inhibited estradiol production by 32% (p<0.001). With (3)H-testosterone as substrate, rosiglitazone or pioglitazone inhibited the (3)H-tritiated water release by the cultured cells by 45% and 35%, respectively, thus directly demonstrating inhibition of aromatase. Rosiglitazone or pioglitazone, however, had no significant effect on aromatase mRNA or protein expression. Rosiglitazone or pioglitazone inhibited (125)I-androstenedione and (125)I-testosterone binding to aromatase by 38% (p<0.001). It was concluded that rosiglitazone or pioglitazone inhibit estrogen synthesis in human granulosa cells by interfering with androgen binding to aromatase. PMID- 21321840 TI - Change in the amount of body fat and IL-6 levels is related to altered insulin sensitivity in type 1 diabetes patients with or without diabetic nephropathy. AB - Insulin resistance (IR) is found early-on in renal disease. The aim of this study was to prospectively evaluate if a change in glomerular filtration rate (GFR) or in endocrine and inflammatory factors over time alters insulin sensitivity in patients with type 1 diabetes (T1D) or without diabetic nephropathy (DN) at baseline. 20 T1D with (DN+, n = 12) or without DN (DN-, n = 8) were re-examined after 5.0 +/- 0.4 years. GFR was determined by 51Cr-EDTA clearance. Insulin sensitivity was assessed by hyperinsulinemic (56 mU/m2/min), euglycemic clamp (M value at steady state during clamp) and calculated per lean body mass. Body composition was determined by bioimpedance. No association was found between change in GFR and change in M-value over time. Instead, change in M-value was associated to change in fat mass (%) and change in IL-6 levels in all subjects taken together (r = -0.55, p = 0.012 and r = -0.62, p = 0.006). These association were verified in the multivariate regression analyses. Findings were similar in DN - and DN +, respectively, but the change in IL-6 was only significantly associated with altered M-value in DN+ subjects. This prospective study indicates that change in amount body fat and levels of inflammatory cytokines, such as IL 6, contribute to change in insulin resistance over time in type 1 diabetes patients with and without diabetic nephropathy. PMID- 21321841 TI - Thyroid stiffness assessment by acoustic radiation force impulse elastography (ARFI). AB - PURPOSE: To evaluate and compare the values of thyroid tissue elasticity in subjects without known thyroid pathology, in patients with Graves' disease and with chronic autoimmune thyroiditis (CAT). PATIENTS AND METHODS: We performed a prospective study that included 74 subjects, 23 without thyroid pathology, 29 with Graves' disease and 22 with CAT (diagnosed by specific tests). In all patients, 10 elastographic measurements were performed in the right thyroid lobe (RTL) and 10 in the left thyroid lobe (LTL) using a 2-6 MHz convex probe. Median values were calculated for each thyroid lobe, measured in meters/second (m/sec). We calculated a mean ARFI value from measurements made in the RTL and LTL. RESULTS: Thyroid stiffness was statistically significant lower in normal subjects vs. those with Graves' disease (2.07+/-0.44 m/sec vs. 2.82+/-0.47 m/sec, p<0.001) and with CAT (2.07+/-0.44 m/sec vs. 2.49+/-0.48 m/sec, p=0.004). We also found a statistically significant difference between subjects without thyroid pathology and those with autoimmune thyroid pathology (Graves' disease and CAT) (2.07+/ 0.44 m/sec vs. 2.68+/-0.50 m/sec, p<0.001). CONCLUSION: ARFI seems to be a useful method for the evaluation of diffuse thyroid gland pathology and is able to predict with sufficient accuracy the presence of thyroid diffuse diseases (AUROC=0.80). PMID- 21321842 TI - Accuracy of VirtualTouch Acoustic Radiation Force Impulse (ARFI) imaging for the diagnosis of cirrhosis during liver ultrasonography. AB - PURPOSE: VirtualTouch is a new technique recently proposed to evaluate liver stiffness during B-mode ultrasonography. The goal of the present study was to analyze the diagnostic accuracy of VirtualTouch in the diagnosis of cirrhosis and its correlation with transient elastography (Fibroscan). MATERIALS AND METHODS: A total of 133 patients with chronic liver disease were enrolled. 90 of 133 underwent VirtualTouch and transient elastography and 70 patients assessed with VirtualTouch were submitted to liver biopsy. Stiffness was assessed by both techniques in the right liver lobe. The diagnostic accuracy for cirrhosis was first assessed in the 90 patients submitted to transient elastography with > 13 kPa (47 % of patients) as diagnostic for cirrhosis values. The best cut-off for cirrhosis with VirtualTouch was then tested in the 70 patients with biopsy (cirrhosis in 38 % of patients). 41 patients were assessed by VirtualTouch by two different operators. RESULTS: The VirtualTouch values in controls, chronic hepatitis and cirrhosis were respectively 113, 147 and 255 cm/sec. The AUROC of liver VirtualTouch for the diagnosis of cirrhosis (reference Fibroscan) was 0.941 with 175 cm/sec as the best cut-off (sensitivity 93.0 %; specificity 85.1 %). VirtualTouch confirmed good performance also in patients with bioptic diagnosis of cirrhosis (AUROC 0.908, sensitivity 81.5 %, specificity 88.4 %,). The correlation of VirtualTouch with transient elastography was strict (r = 0.891) and the correlation in VirtualTouch measurements between two operators was also good (r = 0.874). CONCLUSION: VirtualTouch is able to identify the presence of cirrhosis with good accuracy, shows good interobserver reproducibility and the correlation of its values with those obtained by transient elastography with Fibroscan is good. PMID- 21321843 TI - Evaluation of an OSCE assessment tool for abdominal ultrasound courses. AB - PURPOSE: The purpose of this study was the conception and evaluation of a standardized and reliable assessment tool in the OSCE format to measure the performance and practical skills of abdominal ultrasound users in PGME. MATERIALS AND METHODS: The design, logistics, pacing and the choice of tested competencies of a rotating OSCE parcours, as well as the options for quality control using detailed checklists versus global rating scales and different approaches to the training of the involved raters are described. Over the last 15 years the parcours has undergone incremental improvement and has been used in final examinations of abdominal ultrasound courses with approximately 5000 medical students and 2000 residents and fellows. For evaluation, all item difficulties and discrimination coefficients of the individual stations and the reliability (Cronbach's alpha) were calculated for the last 626 assessments. RESULTS: All 14 hands-on stations showed discrimination coefficients from 0.31 to 0.65 (mean 0.48; SD 0.09). The 13 diagram stations showed mean values of 0.50 (SD 0.16). Data analysis revealed mean homogeneous item difficulties of 0.78 (SD 0.02) and 0.62 (SD 0.04), respectively. Cronbach's alpha was 0.69 with five stations and reached values above 0.8 when more than 8 stations are combined in one parcours. CONCLUSION: The homogeneous distribution of item difficulties provides an opportunity for designing different OSCE versions with different levels of reliability. Several options to adjust the cut-off values, the choice of the examined contents and factors that influence the examinees' acceptance of this assessment tool for PGME or CME ultrasound courses are discussed. Overall, the values of reliability and accuracy of this assessment tool are high enough to be used also for high-stakes examinations in the field of abdominal ultrasound. PMID- 21321859 TI - [Wrongful birth - a step in the right direction?]. PMID- 21321885 TI - Laparoscopic rossetti fundoplication. AB - A fundal wrap of the abdominal segment of the esophagus, transposed from the Rossetti modification of the classic Nissen fundopfication, is the operation of choice for surgical treatment of gastroesophageal reflux refractory to medical therapy. Previously validated by open anti-reflux surgery, fundoplication has also proven reliable, effective, and reproducible when performed by laparoscopy, a technique the authors have used routinely since 1989 thanks to the experience gained in vagotomy by a trans hiatal approach. PMID- 21321886 TI - Laparoscopic treatment of peptic ulcer disease and its complications. AB - Peptic ulcer disease will eventually affect more than 3-4% of the Occidental population. The medical management of this disease, including H2 Blockers, proton pump inhibitors and antihelicobacter therapy, has been well defined and has been very successful. However, the treatment of chronic duodenal ulcer disease has been less successful, thus subjecting these patients to long term disability. It is with chronic duodenal ulcer disease as well as with its complications, such as bleeding, obstruction or perforation, where the surgeon can impact, using laparoscopic surgical techniques as an added therapeutic option. PMID- 21321887 TI - Laparoscopic Intra-gastric Surgery for Early Gastric Cancer: A New Technique in Laparoscopic Surgery. AB - A new laparoscopic operation for the treatment of mucosal or submucosal gastric lesions has been designed and performed on 12 patients. In this procedure, all three trocars are placed in the gastric cavity, penetrating both the abdominal and gastric walls in order to perform a laparoscopic removal of gastric lesions. The operation is then carried out in the gastric cavity using currently available laparoscopic instruments and laparoscopic monitoring. The procedure is easy, safe and feasible for mucosal or submucosal lesion of the stomach that cannot be treated by gastrofiberscopic technique. In this series, we treated a total of 12 patients: 10 patients with early gastric cancer, 1 with a submucosal leiomyoma and 1 with giant polyps of the stomach - all of which were treated uneventfully. Since this technique is based on a new concept in laparoscopic surgery, the author has named this operation "Laparoscopic Intra-gastric Surgery" (L.I.G.S.). PMID- 21321891 TI - Laparoscopic management of complete rectal prolapse: description of technique. AB - Laparoscopic surgery has been successfully employed for many years by gynecological surgeons. Following the widespread success of laparoscopic cholecystectomy, minimally invasive surgery has expanded to be adapted to all general surgical procedures including hernia repair, oesophagectomy, appendicectomy, Meckel's diverticulectomy, and Nissen fundoplication. Laparoscopic colonic surgery has not developed at the same rate as other procedures because of the requirement for advanced laparoscopic surgical skills, deficiencies in instrumentation and concerns about the potential risks of laparoscopic surgery for neoplasia. However, laparoscopic procedures for treating rectal prolapse may constitute some of the best applications for colorectal laparoscopic techniques. A technique of laparoscopic rectopexy performed using the endoscopic stapler and intracorporal suturing of mesh is described. PMID- 21321928 TI - Essential role of microRNA-155 in the pathogenesis of autoimmune arthritis in mice. AB - OBJECTIVE: MicroRNAs (miRNA) are a new class of regulatory elements. Altered expression of miRNA has been demonstrated in the inflamed joints of patients with rheumatoid arthritis (RA). The aim of this study was to examine the role of miRNA in the pathogenesis of autoimmune arthritis, using 2 murine models. METHODS: Collagen-induced arthritis (CIA) and K/BxN serum-transfer arthritis were induced in wild-type (WT) and miR-155-deficient (miR-155(-/-) ) mice. The severity of arthritis was determined clinically and histologically. Anticollagen antibodies and cytokines were measured by enzyme-linked immunosorbent assay. The cellular composition of the draining lymph nodes after induction of CIA was measured by flow cytometry. RESULTS: The miR-155(-/-) mice did not develop CIA. Deficiency in miR-155 prevented the generation of pathogenic autoreactive B and T cells, since anticollagen antibodies and the expression levels of antigen-specific T cells were strongly reduced in miR-155(-/-) mice. Moreover, Th17 polarization of miR 155(-/-) mouse T cells was impaired, as shown by a significant decrease in the levels of interleukin-17 (IL-17) and IL-22. In the K/BxN serum-transfer arthritis model, which only depends on innate effector mechanisms, miR-155(-/-) mice showed significantly reduced local bone destruction, attributed to reduced generation of osteoclasts, although the severity of joint inflammation was similar to that in WT mice. CONCLUSION: These results demonstrate that miR-155 is essentially involved in the adaptive and innate immune reactions leading to autoimmune arthritis, and therefore miR-155 might provide a novel target for the treatment of patients with RA. PMID- 21321933 TI - Insulin regulates GLUT1-mediated glucose transport in MG-63 human osteosarcoma cells. AB - Osteosarcoma is the most common type of malignant bone cancer, accounting for 35% of primary bone malignancies. Because cancer cells utilize glucose as their primary energy substrate, the expression and regulation of glucose transporters (GLUT) may be important in tumor development and progression. GLUT expression has not been studied previously in human osteosarcoma cell lines. Furthermore, although insulin and insulin-like growth factor (IGF-I) play an important role in cell proliferation and tumor progression, the role of these hormones on GLUT expression and glucose uptake, and their possible relation to osteosarcoma, have also not been studied. We determined the effect of insulin and IGF-I on GLUT expression and glucose transport in three well-characterized human osteosarcoma cell lines (MG-63, SaOs-2, and U2-Os) using immunocytochemical, RT-PCR and functional kinetic analyses. Furthermore we also studied GLUT isoform expression in osteosarcoma primary tumors and metastases by in situ hybridization and immunohistochemical analyses. RT-PCR and immunostaining show that GLUT1 is the main isoform expressed in the cell lines and tissues studied, respectively. Immunocytochemical analysis shows that although insulin does not affect levels of GLUT1 expression it does induce a translocation of the transporter to the plasma membrane. This translocation is associated with increased transport of glucose into the cell. GLUT1 is the main glucose transporter expressed in osteosarcoma, furthermore, this transporter is regulated by insulin in human MG-63 cells. One possible mechanism through which insulin is involved in cancer progression is by increasing the amount of glucose available to the cancer cell. PMID- 21321929 TI - The c-Abl tyrosine kinase controls protein kinase Cdelta-induced Fli-1 phosphorylation in human dermal fibroblasts. AB - OBJECTIVE: We have previously demonstrated that in response to transforming growth factor beta (TGFbeta), Fli-1 activity is repressed through a series of sequential posttranslational modifications, consisting of protein kinase Cdelta (PKCdelta)-induced Thr312 phosphorylation, acetylation by p300/CREB binding protein-associated factor, and detachment from the collagen promoter. The purpose of this study was to further investigate the upstream events that lead to Fli-1 phosphorylation in response to TGFbeta. METHODS: Dermal fibroblasts were isolated from systemic sclerosis (SSc) patients and healthy control subjects matched for age, sex, and ethnicity. Western blotting was used to analyze protein levels and real-time quantitative reverse transcription-polymerase chain reaction analysis was used to measure messenger RNA expression. Cells were transduced with constitutively active PKCdelta adenovirus or were transiently transfected with a Bcr-Abl-overexpressing plasmid. Subcellular localization of PKCdelta was examined by immunocytochemistry. RESULTS: Western blot analysis of cell lysates demonstrated that the levels of phospho-Fli-1 (Thr312) were up-regulated in SSc fibroblasts, correlating with increased levels of type I collagen and c-Abl protein. Experiments using a constitutively activated form of c-Abl, small interfering RNA against c-Abl and the specific tyrosine kinase inhibitor imatinib, demonstrated the requirement of c-Abl for the TGFbeta-induced phosphorylation of Fli-1. Additionally, we showed that c-Abl kinase activity was required for nuclear localization of PKCdelta. CONCLUSION: Our results demonstrate that in SSc fibroblasts, c-Abl is an upstream regulator of the profibrotic PKCdelta/phospho-Fli-1 pathway, via induction of PKCdelta nuclear localization. Additionally, the finding that Fli-1 is phosphorylated at higher levels in SSc fibroblasts supports the notion that the c-Abl/PKCdelta/phospho-Fli 1 pathway is constitutively activated in these cells. Thus, blocking the TGFbeta/c-Abl/PKCdelta/phospho-Fli-1 pathway could be an attractive alternative approach to therapy for scleroderma. PMID- 21321934 TI - Multipotent progenitor cells derived from adult peripheral blood of swine have high neurogenic potential in vitro. AB - Peripheral blood-derived multipotent adult progenitor cells (PBD-MAPCs) are a novel population of stem cells, isolated from venous blood of green fluorescent protein transgenic swine, which proliferate as multicellular non-adherent spheroids. Using a simple differentiation protocol, a large proportion of these cells developed one of five distinct neural cell phenotypes, indicating that these primordial cells have high neurogenic potential. Cells exhibiting neural morphologies developed within 48 h of exposure to differentiation conditions, increased in percentage over 2 weeks, and stably maintained the neural phenotype for three additional weeks in the absence of neurogenic signaling molecules. Cells exhibited dynamic neural-like behaviors including extension and retraction of processes with growth cone-like structures rich in filamentous actin, cell migration following a leading process, and various cell-cell interactions. Differentiated cells expressed neural markers, NeuN, beta-tubulin III and synaptic proteins, and progenitor cells expressed the stem cell markers nestin and NANOG. Neurally differentiated PBD-MAPCs exhibited voltage-dependent inward and outward currents and expressed voltage-gated sodium and potassium channels, suggestive of neural-like membrane properties. PBD-MAPCs expressed early neural markers and developed neural phenotypes when provided with an extracellular matrix of laminin without the addition of cytokines or growth factors, suggesting that these multipotent cells may be primed for neural differentiation. PBD-MAPCs provide a model for understanding the mechanisms of neural differentiation from non-neural sources of adult stem cells. A similar population of cells, from humans or xenogeneic sources, may offer the potential of an accessible, renewable and non-tumorigenic source of stem cells for treating neural disorders. PMID- 21321936 TI - Ascorbic acid-dependent GLUT3 inhibition is a critical step for switching neuronal metabolism. AB - Intracellular ascorbic acid is able to modulate neuronal glucose utilization between resting and activity periods. We have previously demonstrated that intracellular ascorbic acid inhibits deoxyglucose transport in primary cultures of cortical and hippocampal neurons and in HEK293 cells. The same effect was not seen in astrocytes. Since this observation was valid only for cells expressing glucose transporter 3 (GLUT3), we evaluated the importance of this transporter on the inhibitory effect of ascorbic acid on glucose transport. Intracellular ascorbic acid was able to inhibit (3)H-deoxyglucose transport only in astrocytes expressing GLUT3-EGFP. In C6 glioma cells and primary cultures of cortical neurons, which natively express GLUT3, the same inhibitory effect on (3)H deoxyglucose transport and fluorescent hexose 2-[N-(7-nitrobenz-2-oxa-1,3-diazol 4-yl)amino]-2-deoxyglucose (2-NBDG) was observed. Finally, knocking down the native expression of GLUT3 in primary cultured neurons and C6 cells using shRNA was sufficient to abolish the ascorbic acid-dependent inhibitory effect on uptake of glucose analogs. Uptake assays using real-time confocal microscopy demonstrated that ascorbic acid effect abrogation on 2-NBDG uptake in cultured neurons. Therefore, ascorbic acid would seem to function as a metabolic switch inhibiting glucose transport in neurons under glutamatergic synaptic activity through direct or indirect inhibition of GLUT3. PMID- 21321937 TI - Amyloid-beta-induced reactive oxygen species production and priming are differentially regulated by ion channels in microglia. AB - Production of reactive oxygen species (ROS) by microglial cells and subsequent oxidative stress are strongly implicated in the pathogenesis of Alzheimer's disease. Although it is recognized that amyloid-beta (Abeta) plays a major role in inducing and regulating microglial ROS production in Alzheimer's disease, to date little is known about cellular mechanisms underlying Abeta-stimulated ROS production. Here, we identified ion channels involved in Abeta-induced microglial ROS production and in Abeta-induced microglial priming. Acute stimulation of microglial cells with either fibrillar Abeta(1-42) (fAbeta(1-42) ) or soluble Abeta(1-42) (sAbeta(1-42) ) caused significant increases in microglial ROS production, which were abolished by inhibition of TRPV1 cation channels with 5 iodo-resiniferatoxin (I-RTX), but were unaffected by inhibition of K(+) channels with charybdotoxin (CTX). Furthermore, pretreatment with either fAbeta(1-42) or sAbeta(1-42) induced microglial priming, that is, increased ROS production upon secondary stimulation with the phorbol ester PMA. Microglial priming induced by fAbeta(1-42) or sAbeta(1-42) remained unaffected by TRPV1 channel inhibition with I-RTX. However, sAbeta(1-42) -induced priming was inhibited by CTX and margatoxin, but not by TRAM-34 or paxilline, indicating a role of Kv1.3 voltage gated K(+) channels, but not of Ca(2+) -activated K(+) channels, in the priming process. In summary, our data suggest that in microglia Abeta-induced ROS production and priming are differentially regulated by ion channels, and that TRPV1 cation channels and Kv1.3 K(+) channels may provide potential therapeutic targets to reduce microglia-induced oxidative stress in Alzheimer's disease. PMID- 21321935 TI - Estrogen in cycling rats alters gene expression in the temporomandibular joint, trigeminal ganglia and trigeminal subnucleus caudalis/upper cervical cord junction. AB - Females report temporomandibular joint (TMJ) pain more than men and studies suggest estrogen modulates this pain response. Our goal in this study was to determine genes that are modulated by physiological levels of 17beta-estradiol that could have a role in TMJ pain. To complete this goal, saline or complete Freund's adjuvant was injected in the TMJ when plasma 17beta-estradiol was low or when it was at a high proestrus level. TMJ, trigeminal ganglion, and trigeminal subnucleus caudalis/upper cervical cord junction (Vc/C(1-2) ) tissues were isolated from the treated rats and expression of 184 genes was quantitated in each tissue using real-time PCR. Significant changes in the amount of specific transcripts were observed in the TMJ tissues, trigeminal ganglia, and Vc/C(1-2) region when comparing rats with high and low estrogen. GABA A receptor subunit alpha6 (Gabra6) and the glycine receptor alpha2 (Glra2) were two genes of interest because of their direct function in neuronal activity and a >29-fold increase in the trigeminal ganglia was observed in proestrus rats with TMJ inflammation. Immunohistochemical studies showed that Gabralpha6 and Glralpha2 neuronal and not glial expression increased when comparing rats with high and low estrogen. Estrogen receptors alpha and beta are present in neurons of the trigeminal ganglia, whereby 17beta-estradiol can alter expression of Gabralpha6 and Glralpha2. Also, estrogen receptor alpha (ERalpha) but not ERbeta was observed in satellite glial cells of the trigeminal ganglia. These results demonstrate that genes associated with neurogenic inflammation or neuronal excitability were altered by changes in the concentration of 17beta-estradiol. PMID- 21321938 TI - Interleukin-18/WNT1-inducible signaling pathway protein-1 signaling mediates human saphenous vein smooth muscle cell proliferation. AB - We demonstrate for the first time that the pro-inflammatory cytokine interleukin (IL)-18 stimulates rapid and significant proliferation of SMC derived from human saphenous vein (VSMC), but not coronary artery. IL-18 also stimulates VSMC growth. Further investigations revealed that IL-18-induced VSMC proliferation was Wnt inducible secreted protein-1 (WISP1) dependent. In addition to inducing its own expression via phosphatidylinositol 3-kinase/Akt-dependent IKK/NF-kappaB activation, IL-18 stimulated glycogen synthase kinase 3beta phosphorylation and degradation, beta-catenin nuclear translocation and stabilization, T-cell factor lymphoid enhancer binding factor (TCF-LEF) activation, and WISP1 induction. Moreover, WISP1 induced its own expression, and that of survivin and multiple matrix metalloproteinases via beta-catenin/TCF-LEF interaction. WISP1 also activated AP-1, but not NF-kappaB, and induced matrix metalloproteinase (MMP)9 transcription in part via AP-1. Interestingly, WISP1 failed to regulate tissue inhibitors of matrix metalloproteinases (TIMP) expression. These novel findings indicate that IL-18 induces a series of signaling events that result in WISP1 mediated VSMC proliferation, survival and MMP induction that are key components of vein graft stenosis and this may be amplified by IL-18 and WISP1 autoregulation and cross-regulation. PMID- 21321939 TI - Enterovirus 71 induces integrin beta1/EGFR-Rac1-dependent oxidative stress in SK N-SH cells: role of HO-1/CO in viral replication. AB - Oxidative stress became emerged as a key player in the development and progression of many pathological conditions including virus-induced encephalitis. Heme oxygenase-1 (HO-1) plays a crucial role in defending the body against oxidant-induced injury during inflammatory processes. Therefore, we investigated the induction of HO-1 level in host cells, which may exert a beneficial effect to minimize viral replication in SK-N-SH cells. In this study, we found that enterovirus 71 (EV71) induced the generation of reactive oxygen species (ROS) and activation of NADPH oxidase. EV71-induced ROS generation was mediated through activation of integrin beta1, an epidermal growth factor receptor (EGFR), Rac1 and NADPH oxidase which revealed by using selective pharmacological inhibitors or transfection with respective siRNAs. In addition, the reduction of viral load was observed with NADPH oxidase inhibitors (apocynin and diphenyleneiodonium chloride), ROS scavenger (N-acetylcysteine), and transfection with p47(phox) siRNA in Western blot and real-time PCR analyses. Consistently, overexpression of HO-1 attenuated EV71-induced NADPH oxidase/ROS generation and EV71 replication which were abrogated by pretreatment with an HO-1 inhibitor, zinc protoporphyrin IX (ZnPP IX). Moreover, metabolite of HO-1, carbon monoxide (CO), also diminished ROS formation and EV71 replication which were reversed by pretreatment with a CO scavenger (hemoglobin) and a cyclic GMP-dependent protein kinase (PKG) inhibitor (KT5823). These findings suggest that up-regulation of HO-1 exerts as a host cellular defense mechanism against EV71 infection in SK-N-SH cells. PMID- 21321940 TI - beta Common receptor integrates the erythropoietin signaling in activation of endothelial nitric oxide synthase. AB - Erythropoietin (EPO), the key hormone for erythropoiesis, also increases nitric oxide (NO) bioavailability in endothelial cells (ECs), yet the definitive mechanisms are not fully understood. Increasing evidence has demonstrated that beta common receptor (betaCR) plays a crucial role in EPO-mediated non hematopoietic effects. We investigated the role of betaCR in EPO-induced endothelial NO synthase (eNOS) activation in bovine aortic ECs (BAECs) and the molecular mechanisms involved. Results of confocal microscopy and immunoprecipitation analyses revealed that betaCR was colocalized and interacted with EPO receptor (EPOR) in ECs. Inhibition of betaCR or EPOR by neutralizing antibodies or small interfering RNA abolished the EPO-induced NO production. Additionally, blockage of betaCR abrogated the EPO-induced increase in the phosphorylation of eNOS, Akt, Src, or Janus kinase 2 (JAK2). Immunoprecipitation analysis revealed that treatment with EPO increased the interaction between betaCR and eNOS, which was suppressed by inhibition of Src, JAK2, or Akt signaling with specific pharmacological inhibitors. Furthermore, EPO-induced EC proliferation, migration, and tube formation were blocked by pretreatment with betaCR antibody and Src, JAK2, or PI3K/Akt inhibitors. Moreover, in vivo experiments showed that EPO increased the level of phosphorylated eNOS, Src, JAK2, and Akt, as well as betaCR-eNOS association in aortas and promoted the angiogenesis in Matrigel plug, which was diminished by betaCR or EPOR neutralizing antibodies. Our findings suggest that betaCR may play an integrative role in the EPO signaling-mediated activation of eNOS in ECs. PMID- 21321941 TI - The regulatory role of histone deacetylase inhibitors in Fgf4 expression is dependent on the differentiation state of pluripotent stem cells. AB - The identity of embryonic stem cells (ESCs) is controlled by a set of pluripotency genes, including Oct4, Sox2, Nanog, and Fgf4. How their expression is repressed during differentiation and reactivated during reprogramming is largely unknown. Here, using mouse ESCs as well as F9 and P19 cells (mouse embryonal carcinoma cell lines, P19 being considered further differentiated than F9 cells) as models, we found that HDAC inhibitors elevated Fgf4 expression in P19 cells, but reduced it in F9 cells. We also observed that HDAC inhibitors enhanced the expression of Fgf4 and a subset of pluripotency genes in differentiated ESCs, but reduced their expression in undifferentiated and less differentiated ESCs. Mechanistically, we observed more HDAC1 recruitment and a weaker association of histone 4 lysine 5 acetylation at the Fgf4 enhancer in P19 cells compared to F9 cells. Additionally, we demonstrated the interaction between Sox2 and HDAC1 both in vitro and in vivo, implicating a possible role for Sox2 in the recruitment of HDAC1 to the Fgf4 enhancer. We also found that Nanog bound to the Fgf4 enhancer, and this binding was stronger in F9 cells, indicating the involvement of Nanog in the regulation of Fgf4 expression in undifferentiated and less differentiated pluripotent stem cells. This study uncovers an important role of HDAC1 and histone modifications in the repression of Fgf4 and perhaps other pluripotency genes during ESC differentiation. Our results also suggest that HDAC inhibitors may promote reprogramming partially through activating pluripotency genes at some intermediate stages. PMID- 21321942 TI - Role of laminin-111 in neurotrophin-3 production of canine adipose-derived stem cells: involvement of Akt, mTOR, and p70S6K. AB - Extracellular matrix (ECM) components play an important role in the regulation and maintenance of neural stem cells (NSCs). Laminin, an ECM component, is a key factor in promoting axonal regeneration and differentiation of NSCs. Since NSCs cannot be easily harvested with low morbidity, adipose-derived stem cells have been suggested for therapeutic applications of neural tissue damage. Therefore, the potential of laminin-111 to enhance the production of neurotrophin-3 (NT3) and its related signal pathways from canine adipose tissue-derived stem cells (cADSCs) was investigated. Laminin-111 enhanced NT3 production in neural induction medium (NIM). Treatment of NIM or laminin-111 on cADSCs distinctively changed integrin beta1 mRNA and protein expression levels. In addition, laminin 111-induced Akt phosphorylation was inhibited by integrin beta1 small interfering RNA (siRNA) and PI3K inhibitors (LY294002 and wortmannin). Furthermore, increased phosphorylations of mTOR and p70S6K by laminin-111 were blocked by inhibitors or specific siRNA, respectively. Moreover, laminin-111-induced NT3 production was blocked by these inhibitors. In experiments to induce the differentiation of cADSCs, laminin-111 increased the expression of neuronal markers beta 3 tubulin, MAP2, and NeuN, and decreased the expression of the NSC markers nestin and vimentin. In conclusion, laminin-111 increases NT3 production through Akt, mTOR, and p70S6K pathways via integrin beta1 in cADSCs cultured in NIM. PMID- 21321943 TI - Coronary stenting after failure of conservative treatment for spontaneous coronary dissection: Usefulness of the intravascular ultrasound. AB - Spontaneous coronary dissection of a coronary artery is a rare cause of acute coronary syndrome. Optimal treatment has not yet been established. We describe a woman with spontaneous dissection of the left anterior descending artery who presented transitory angina and electrocardiographic ST segment elevation in precordial leads. Conservative treatment was carried out. The angina and electrocardiographic changes recurred 3 days later. An intravascular vascular ultrasound was performed and the patient was stabilized following stenting. Stress testing was negative at 6-month follow-up and she remained asymptomatic at 18 months. We discuss the usefulness of an intravascular ultrasound study to establish the therapeutic strategy. PMID- 21321944 TI - Pharmacokinetic properties of lutein emulsion after oral administration to rats and effect of food intake on plasma concentration of lutein. AB - Lutein is a carotenoid found mainly in green leafy vegetables and is located in the macula lutea in the human eye. An intake of lutein as food is needed since humans cannot synthesize it de novo. Although lutein has received much attention recently due to its antioxidant activities, little information about the pharmacokinetic properties of lutein is available. Lutein emulsion formulation was used and the pharmacokinetics of lutein emulsion after oral administration to rats was investigated. The bioavailability of lutein using this formulation was calculated to be 5.20%. It was found that a large amount of lutein was accumulated in the intestinal mucosa. The absorption of orally administered compounds in the intestine can be enhanced by interaction with food or food components. Thus, the effect of food intake on the intestinal absorption of lutein was investigated. The plasma concentration of lutein after oral administration of the emulsion formulation was improved significantly by food intake. It is possible that the absorption of lutein in the intestine is improved significantly by some food components. Bile acids may also play important roles in the intestinal absorption of lutein since the absorption of lipophilic compounds such as cholesterol is related to bile acids. The results of these studies should contribute to an improvement of lutein absorption and provide important information for obtaining more effective pharmacological effects of lutein. PMID- 21321947 TI - Alcohol-related peripheral neuropathy: nutritional, toxic, or both? AB - Alcohol-related peripheral neuropathy (ALN) is a potentially debilitating complication of alcoholism that results in sensory, motor, and autonomic dysfunction. Unfortunately, ALN is rarely discussed as a specific disease entity in textbooks because it is widely assumed to primarily reflect consequences of nutritional deficiency. This hypothesis is largely based on observations first made over eight decades ago when it was demonstrated that thiamine deficiency (beriberi) neuropathy was clinically similar to ALN. In recent studies, failure of thiamine treatment to reverse ALN, together with new information demonstrating clinical and electrophysiological distinctions between ALN and nutritional deficiency neuropathies, suggests that alcohol itself may significantly predispose and enhance development of neuropathy in the appropriate clinical setting. We reviewed the evidence on both sides and conclude that ALN should be regarded as a toxic rather than nutritional neuropathy. PMID- 21321948 TI - Assessment of symptomatic diabetic patients with normal nerve conduction studies: utility of cutaneous silent periods and autonomic tests. AB - Established electrophysiological methods have limited clinical utility in the diagnosis of small-fiber neuropathy (SFN). In this study, diabetic patients with clinically diagnosed SFN were evaluated with autonomic tests and cutaneous silent periods (CSPs). Thirty-one diabetic patients with clinically suspected SFN and normal nerve conduction studies were compared with 30 controls. In the upper extremities (UE), the CSP parameters did not differ statistically between the patient and control groups, whereas, in the lower extremities (LE), patients had prolonged CSP latencies (P = 0.018) and shortened CSP durations (P < 0.001). The sensitivity of the CSP duration was 32.6%, and the specificity was 96.7%. The expiration-to-inspiration ratios and amplitudes of the sympathetic skin responses in the lower extremities were also reduced. Our findings indicate that the diagnostic utility of CSPs was higher than that of the autonomic tests to support the clinically suspected diagnosis of SFN. PMID- 21321949 TI - Influence of muscle contraction and intensity of stimulation on the cutaneous silent period. AB - We evaluated the influence of stimulus intensity (SI) and the amount of voluntary muscle contraction (VMC) on parameters of the cutaneous silent period (CSP). The CSP was measured in 15 healthy subjects at 20%, 40%, and 60% of maximal VMC and after an electric stimulus of 10, 15, and 20 times the sensory threshold. Average EMG amplitudes prior to stimulus and during the CSP increased with the amount of VMC. The CSP duration increased, and suppression index decreased, with increasing SI. The CSP onset and end latencies seemed to shorten and prolong, respectively, with the increasing SI, although this was not statistically significant. Considering the more meaningful temporal parameters of the CSP and the suppression index, it is not necessary to control the VMC, but it is advisable to control the SI. PMID- 21321950 TI - Turns-amplitude analysis in normal and myopathic facial muscles. AB - The purpose of this study was to assess turns/amplitude analysis (TAA) as an objective alternative to conventional qualitative electromyography (EMG) for detection of myopathy in facial muscles. Normal values of TAA parameters were calculated in the frontalis and mentalis muscles of 26 control subjects. We estimated the slope of the regression line of mean amplitude/turn values (MA) plotted against the number of turns/second (NT) and the resulting clouds. The 95% confidence limits of the cloud data were drawn as an ellipse. The sensitivity of TAA was determined from a group of 35 myopathic patients and specificity from a second group of 25 control subjects. Significant differences for every TAA parameter were found between frontalis and mentalis. Cumulative sensitivity and specificity of TAA for frontalis and mentalis were 74.6%, 56.5%, and 73.3%, 70.8%, respectively. With at least two of the aforementioned criteria abnormal, the sensitivity and specificity for frontalis and mentalis were 61.3%, 82.6%, and 56.7%, 100.0%, respectively. PMID- 21321951 TI - Sudden loading perturbation to determine the reflex response of different back muscles: a reliability study. AB - In this study we estimate the reliability of reflex response variables to identify the main sources of variability and to estimate appropriate measurement strategies to obtain more reliable measures. Back muscle surface electromyography (EMG) was recorded in healthy males during anteriorly-directed sudden loading perturbations applied to the trunk. Measures of EMG reflex latency and amplitude were obtained. The generalizability theory was used as a framework to estimate the magnitude of the different variance components and the reliability of the measures corresponding to various simulations of different measurement strategies. Reliability of the different variables was poor to moderate (intraclass correlation coefficient range 0-0.62). Averaging scores across homologous muscles and several trials were strategies to achieve more acceptable reliability. The reflex response of back muscles is inherently variable, and a large measurement effort is necessary to obtain reliable and, consequently, valid and responsive estimations of this neuromuscular function. PMID- 21321952 TI - Twitch potentiation induced by stimulated and voluntary isometric contractions at various torque levels in human knee extensor muscles. AB - The purpose of this study was to compare the extent of twitch potentiation (TP) after stimulated or voluntary contractions at identical intensities for the human knee extensor muscles. Isometric knee extensions of 10 s were performed at 20%, 40%, and 60% of maximal voluntary contraction (MVC) torque level, through percutaneous electrical stimulation of the quadriceps at 80 Hz or voluntary contraction. Twitch responses were evoked by stimulating the femoral nerve percutaneously with supramaximal intensity. The extent of TP after the stimulated contraction was greater than that after the voluntary contraction at the 20% MVC torque level, whereas a stimulated contraction induced a smaller extent of TP than did a voluntary contraction at contraction intensities higher than 40% MVC. We suggest that this contraction intensity dependence of differences in TP after stimulated and voluntary isometric conditioning contractions is responsible for differences in the recruitment pattern of motor units during the conditioning contractions. PMID- 21321953 TI - Early, progressive, and sustained dysfunction of sensory axons underlies paclitaxel-induced neuropathy. AB - Paclitaxel is used in the adjuvant treatment of breast cancer. It induces disabling and potentially long-lasting sensory neuropathy. This study systematically and prospectively investigated sensory function, using clinical grading scales, quantitative sensory testing, and neurophysiological and nerve excitability studies in 28 patients with early-stage breast cancer. After administration of 529 +/- 41 mg/m(2) paclitaxel, 71% of patients developed neuropathic symptoms by 6 weeks of treatment. Early and progressive increases in stimulus threshold (P < 0.05) and reduction in sensory amplitudes from 47.0 +/- 3.3 MUV to 42.4 +/- 3.4 MUV (P < 0.05) occurred by 4 weeks, with a further reduction by final treatment (33.7 +/- 3.0 MUV, P < 0.001). The majority of patients (63%) did not experience recovery of neuropathic symptoms at follow-up. Axonal disruption did not relate to membrane conductance dysfunction. We found that paclitaxel produces early sensory dysfunction and leads to persistent neuropathy. Importantly, significant axonal dysfunction within the first month of treatment predated symptom onset, suggesting a window for neuroprotective therapies. PMID- 21321954 TI - Impact of resistance exercise training on interleukin-6 and JAK/STAT in young men. AB - The JAK/STAT signaling pathway is essential for myogenic regeneration and is regulated by a diverse range of ligands, including interleukin-6 (IL-6) and platelet-derived growth factor-BB (PDGF-BB). Our aim was to evaluate the responsiveness of IL-6 and PDGF-BB to intense exercise, along with STAT3 activation, before and after 12 weeks of resistance training. In young men, IL-6 and PDGF-BB protein concentrations were quantified in biopsied muscle and increased at 3 h post-exercise (17.5-fold and 3-fold, respectively). The response was unaltered by 12 weeks of training. Similarly, STAT3 phosphorylation was elevated post-exercise (12.5-fold), irrespective of training status, as was the expression of downstream targets c-MYC (8-fold), c-FOS (4.5-fold), and SOCS3 (2.3 fold). Thus, intense exercise transiently increases IL-6 and PDGF-BB proteins, and STAT3 phosphorylation is increased. These responses are preserved after intense exercise. This suggests they are not modified by training and may be an essential component of the adaptive responses to intense exercise. PMID- 21321955 TI - Continuous endurance-type exercise training does not modulate satellite cell content in obese type 2 diabetes patients. AB - Endurance-type exercise training represents a cornerstone in type 2 diabetes treatment. However, the effects of prolonged continuous, endurance-type exercise on muscle fiber characteristics remain equivocal. Fifteen obese male type 2 diabetes patients (61 +/- 6 years) participated in a 6-month continuous, endurance-type exercise program. Muscle biopsies were collected before, and after 2 and 6 months of intervention. Muscle fiber type-specific composition, size, and satellite cell (SC) and myonuclear content were determined by immunohistochemistry. Although continuous endurance-type exercise training lowered total body weight and reduced fat mass, no changes were observed in leg lean mass. At baseline, SC content was significantly lower in type II compared with type I muscle fibers. No change in SC content was observed after exercise training. Continuous endurance-type exercise training lowers fat mass, but it does not increase leg lean mass and/or modulate muscle fiber characteristics in type 2 diabetes patients. PMID- 21321956 TI - Clinical and pathological features in 15 Chinese patients with calpainopathy. AB - BACKGROUND: Calpainopathy is comprised of a group of myopathies caused by deficiency in calcium-activated, neutral protease (calpain-3). In this study we identify calpainopathy in a cohort of Chinese patients with unclassified myopathy and analyze its clinical and pathological features. METHODS: Sixty-six muscle biopsies were selected for combined Western blotting of dysferlin and calpain-3 after immunohistochemical staining. Clinical and pathological parameters of 15 confirmed calpainopathy cases were determined. RESULTS: The diagnosis of calpainopathy in 15 Chinese patients was confirmed by Western blot analysis. Fourteen subjects had progressive proximal muscle weakness; 1 presented with bilateral distal muscle atrophy of the lower extremities. Scapular winging was observed in 12 patients (80%), and joint contractures were found in 10 others (66.7%). Histopathological studies showed a high prevalence of lobulated fibers (66.7%). CONCLUSIONS: Chinese patients with calpainopathy share some common clinical and pathological features with the reported characteristics of non Chinese patients. PMID- 21321957 TI - Proximal axonal changes after peripheral nerve injury in man. AB - Peripheral nerve injury leads to changes in the proximal axon. Traumatic nerve injuries in humans were investigated to characterize such electrophysiological changes. Mixed nerve conduction studies (MNCS) and motor conduction studies (MCS) were performed proximal to the injury. Control values were obtained from the uninjured limb. Median (n = 24) and ulnar (n = 35) nerve injuries were studied. The injured nerves had significant mixed nerve action potential (MNAP) amplitude reductions (median: P < 0.0001; ulnar: P < 0.0001). The majority of the MNAP amplitude reductions were severe and early. There was slowing in the mixed nerve conduction velocity (MNCV) (median: P = 0.09; ulnar: P = 0.04) and motor conduction velocity (MCV) (median: P = 0.046; ulnar: P = 0.005). Axonal loss appears to play a significant role in producing the MNCS changes observed, and its early occurrence is noteworthy. Proximal MCV reduction could be secondary to the effects of injury as well as collateral sprouting of uninjured axons. Proximal axonal changes may have an impact on recovery. PMID- 21321958 TI - Electromechanical delay in biceps brachii assessed by ultrafast ultrasonography. AB - Using ultrasound we tested the utility of determining the relative contribution of the main muscle structures/mechanisms to the electromechanical delay in the biceps brachii. Nine subjects underwent electrically evoked contractions with the echographic probe maintained over the muscle and the myotendinous junction. No difference was found between the onset of muscle fascicle motion (Dm, 5.57 +/- 1.37 ms) and the onset of myotendinous junction motion (Dt, 5.47 +/- 1.38 ms), whereas significant differences were found between Dm/Dt and electromechanical delay (approximately 10 ms). Electromechanical delay can be used as a model for studying the effects of neuromuscular disorders or various constraints that affect excitation-contraction coupling and/or muscle force transmission. PMID- 21321959 TI - Subacute myopathy in a mature patient due to multiple acyl-coenzyme A dehydrogenase deficiency. AB - INTRODUCTION: Multiple acyl-coenzyme A dehydrogenase deficiency (MADD), also called glutaric aciduria type II, is an inherited metabolic disorder resulting from a deficiency in electron transfer flavoprotein (ETF) or of its ubiquinone oxidoreductase (ETF-QO). It usually occurs in the neonatal period or in early infancy and, very rarely, in adolescents and young adult patients. METHODS: We report the case of a 55-year-old woman who developed a painful subacute myopathy. RESULTS: Lipid accumulation was found at biopsy. MADD was confirmed by plasma acylcarnitine profile and by assessment of ETF-QO activity in muscle. CONCLUSIONS: This study demonstrates that metabolic myopathies usually found in infancy may be also diagnosed in older patients. MADD may be easily treated by riboflavin and coenzyme Q10 and therefore should be included in the differential diagnosis of adult-onset painful myopathy. PMID- 21321960 TI - Recurrent multiple cranial nerve palsy and anti-GD1a antibodies. PMID- 21321961 TI - Thermosensitive hereditary neuropathy with liability to pressure palsy. PMID- 21321962 TI - Phenotypical variability in glycogen storage disease type III with a recurrent AGL mutation c.750-753delAGAC. PMID- 21321963 TI - High-resolution ultrasonography in the detection of postoperative recurrence of ulnar neuropathy. PMID- 21321964 TI - Comment on intragastric botulinum neurotoxin A injection: from safety to warnings. PMID- 21321968 TI - Prenatal diagnosis and postnatal outcome of pelvic kidneys. AB - OBJECTIVE: To assess the prevalence of pelvic kidneys during prenatal sonographic examinations in the second and third trimesters and to examine postnatal outcome. METHODS: Prenatal sonographic findings and postnatal follow-up data of fetuses with prenatal diagnosis of pelvic kidneys were analyzed. Routine (n = 10 079) and indicated (n = 17 732) second and third trimester scans were performed in 27 811 fetuses. A pelvic kidney was defined as one located within the fetal bony pelvis and in close approximation to the bladder. Postnatal evaluation consisted of renal ultrasound and/or dimercapto-succinic acid scan. RESULTS: A total of 36 newborns with postnatally confirmed pelvic kidneys were included in this analysis. Median gestational age at diagnosis was 25 weeks; half (18/36) were recognized after 24 weeks. The prevalence of pelvic kidneys in this cohort was 0.14%. Postnatally impaired renal function was present in 33% of the pelvic kidneys of children, but overall renal function remained normal. No serious complications occurred in the 31 fetuses with long-term follow-up, except in 1 case, which required nephrectomy due to multicystic dysplasia of the pelvic kidney. CONCLUSION: Pelvic kidneys are common and can be easily detected prenatally. Prognosis is favorable in the vast majority of the cases. PMID- 21321969 TI - Genetic assessment following increased nuchal translucency and normal karyotype. AB - OBJECTIVE: The objective of this study was to assess the first formal approach for monitoring genetic/developmental syndromes associated with the presence of an increased nuchal translucency (NT) thickness (>3 mm) in the first trimester of pregnancy. METHODS: Multiple technologies-a DNA chip using the APEX technology, qPCR, microfluidic PCR, and sequencing-were applied to assay 310 mutations across five conditions-Noonan syndrome, congenital adrenal hyperplasia, spinal muscular atrophy (SMA), DiGeorge syndrome, and Smith-Lemli Opitz syndrome. RESULTS: We report the results of assessing the first 120 patients in which 8 cases of Noonan syndrome were detected as well as an unusually high rate of heterozygosity for SMA. CONCLUSION: While testing for Noonan syndrome in association with increased NT appears warranted, the reported association of the remaining four genetic syndromes is likely to be weak and possibly insignificant. PMID- 21321970 TI - Arsenic: toxicity, oxidative stress and human disease. AB - Arsenic (As) is a toxic metalloid element that is present in air, water and soil. Inorganic arsenic tends to be more toxic than organic arsenic. Examples of methylated organic arsenicals include monomethylarsonic acid [MMA(V)] and dimethylarsinic acid [DMA(V)]. Reactive oxygen species (ROS)-mediated oxidative damage is a common denominator in arsenic pathogenesis. In addition, arsenic induces morphological changes in the integrity of mitochondria. Cascade mechanisms of free radical formation derived from the superoxide radical, combined with glutathione-depleting agents, increase the sensitivity of cells to arsenic toxicity. When both humans and animals are exposed to arsenic, they experience an increased formation of ROS/RNS, including peroxyl radicals (ROO*), the superoxide radical, singlet oxygen, hydroxyl radical (OH*) via the Fenton reaction, hydrogen peroxide, the dimethylarsenic radical, the dimethylarsenic peroxyl radical and/or oxidant-induced DNA damage. Arsenic induces the formation of oxidized lipids which in turn generate several bioactive molecules (ROS, peroxides and isoprostanes), of which aldehydes [malondialdehyde (MDA) and 4 hydroxy-nonenal (HNE)] are the major end products. This review discusses aspects of chronic and acute exposures of arsenic in the etiology of cancer, cardiovascular disease (hypertension and atherosclerosis), neurological disorders, gastrointestinal disturbances, liver disease and renal disease, reproductive health effects, dermal changes and other health disorders. The role of antioxidant defence systems against arsenic toxicity is also discussed. Consideration is given to the role of vitamin C (ascorbic acid), vitamin E (alpha tocopherol), curcumin, glutathione and antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase in their protective roles against arsenic-induced oxidative stress. PMID- 21321971 TI - IgLONs form heterodimeric complexes on forebrain neurons. AB - IgLONs are a family of four GPI-anchored cell adhesion molecules that regulate neurite outgrowth and synaptogenesis and may act as tumour suppressor genes. Recently we have proposed that two members of the IgLON family act as a heterodimeric complex termed DIgLON. Neurons isolated from chick forebrain co express all six combinations of IgLONs and the intensity of fluorescence for each pair of IgLONs was highly correlated. Antibody-patching experiments on forebrain neurons show complex formation for IgLON pairs but not between unrelated GPI anchored glycoproteins. Thus IgLONs are the first GPI-anchored family of glycoproteins shown to form heterodimeric complexes in the plane of the membrane. PMID- 21321972 TI - Efficient method for screening and identification of radical scavengers in the leaves of Olea europaea L. AB - In this article, an efficient method was developed to screen, isolate and identify the major radical scavengers in the leaves of Olea europaea L. by DPPH HPLC-DAD, HSCCC and NMR. The method of DPPH-HPLC-DAD was used to screen the major radical scavengers. It was found that three major constituents (A, B, C) in the extract of the leaves of O. europaea L. possessed potential antioxidant activities. In order to identify the chemical structures of those compounds, the HSCCC method with a two-phase solvent system composed of petroleum ether-ethyl acetate-water at an optimized volume ratio of 6:600:700 (v/v/v) together with column chromatography was developed to isolate and purify the active compounds. Pure compounds A (225 mg), B (10 mg) and C (12 mg) with purities 92.6, 95.1 and 96.4%, respectively, were obtained from the crude sample (500 mg). Their structures were identified as oleuropein (A), luteolin-7-O-glucoside (B) and verbascoside (C) by (1) H-NMR and (13) C-NMR. PMID- 21321973 TI - Determination of volatile organic compounds in human breath for Helicobacter pylori detection by SPME-GC/MS. AB - Helicobacter pylori living in the human stomach release volatile organic compounds (VOCs) that can be detected in expired air. The aim of the study was the application of breath analysis for bacteria detection. It was accomplished by determination of VOCs characteristic for patients with H. pylori and the analysis of gases released by bacteria in suspension. Solid-phase microextraction was applied as a selective technique for preconcentration and isolation of analytes. Gas chromatography coupled with mass spectrometry was used for the separation and identification of volatile analytes in breath samples and bacterial headspace. For data calculation and processing, discriminant and factor analyses were used. Endogenous substances such as isobutane, 2-butanone and ethyl acetate were detected in the breath of persons with H. pylori in the stomach and in the gaseous mixture released by the bacteria strain but they were not identified in the breath of healthy volunteers. The canonical analysis of discrimination functions showed a strong difference between the three examined groups. Knowledge of substances emitted by H. pylori with the application of an optimized breath analysis method might become a very useful tool for noninvasive detection of this bacterium. PMID- 21321974 TI - Development and validation of a HPLC-MS/MS method for the determination of venlafaxine enantiomers and application to a pharmacokinetic study in healthy Chinese volunteers. AB - An HPLC-MS/MS method has been developed and validated for the determination of venlafaxine enantiomers in human plasma and applied to a pharmacokinetic study in healthy Chinese volunteers. The method was carried out on a vancomycin chiral column (5 um, 250 * 4.6 mm) maintained at 25 degrees C. The mobile phase was methanol-water containing 30 mmol/L ammonium acetate, pH 3.3 adjusted with aqueous ammonia (8:92, v/v) at the flow rate 1.0 mL/min. A tandem mass spectrometer with an electrospray interface was operated in the multiple reaction monitoring mode to detect the selected ions pair at m/z 278.0 -> 120.8 for venlafaxine enantiomers and m/z 294.8 -> 266.7 for estazolanm (internal standard). The method was linear in the concentration range of 0.28-423.0 ng/mL. The lower limit of quantification was 0.28 ng/mL. The intra-and inter-day relative standard deviations were less than 9.7%. The method was successfully applied for the evaluation of pharmacokinetic profiles of venlafaxine enantiomers in 18 healthy volunteers. Validation parameters such as the specificity, linearity, precision, accuracy and stability were evaluated, giving results within the acceptable range. Pharmacokinetic parameters of the venlafaxine enantiomers were measured in the 18 healthy Chinese volunteers who received a single regimen with venlafaxine hydrochloride capsules. The results show that AUC((0-infinity)) , C(max) and t(1/2) between S-venlafaxine and R-venlafaxine are significantly different (p < 0.05). PMID- 21321975 TI - Metabolic analysis of rhubarb extract by rat intestinal bacteria using liquid chromatography-tandem mass spectrometry. AB - Through investigation of the metabolism of rhubarb extract by rat intestinal bacteria, a total of 14 components in rhubarb extract were found to be biotransformed. These components included aloe-emodin-O-glucosides, emodin-O glucosides, chrysophanol-O-glucosides, physcion-O-glucosides and the corresponding aglycones. Rhein also could be biotransformed by rat intestinal bacteria. Twelve major metabolites were detected in the incubation sample. Under ESI tandem mass conditions, the sequential fragmentation patterns of [M H](-) ions were similar to those of free anthraquinones, thus allowing the rapid identification of the metabolites formed in incubation samples. The results suggested that the proposed hydrolysis of glycoside group followed by hydrogenation in quinoid moiety and/or further acetylation was the major biotransformation pathway for these anthraquinone glycosides by rat intestinal bacteria. PMID- 21321977 TI - TGF-beta1-induced EMT of non-transformed prostate hyperplasia cells is characterized by early induction of SNAI2/Slug. AB - BACKGROUND: Epithelial-mesenchymal transition (EMT) underlying cancer cell invasion and metastasis has been thoroughly studied in prostate cancer. Although EMT markers have been clinically observed in benign prostate hyperplasia, molecular events underlying the onset and progression of EMT in benign prostate cells have not been described. METHODS: EMT in BPH-1 cells was induced by TGF beta1 treatment and the kinetics of expression of EMT markers, regulators, and selected miRNAs was assessed by western blotting and quantitative RT-PCR. RESULTS: EMT in BPH-1 cells was accompanied by rapid up-regulation of SNAI2/Slug and ZEB1 transcription factors, while changes in expression levels of ZEB2 and miR-200 family members were observed after extended time intervals. Invasive phenotype with EMT hallmarks, characterizing tumorigenic clones derived from BPH 1 cells, was associated with increased mRNA levels of SNAI2, ZEB1, and ZEB2, but was not associated with significant changes in basal levels of miR-200 family members. RNA interference revealed that SNAI2/Slug is crucial for TGF-beta1 induced vimentin up-regulation and migration of BPH-1 cells. CONCLUSIONS: This study suggests that in BPH-1 cells the transcription factor SNAI2/Slug is important for EMT initiation, while the ZEB family of transcription factors in cooperation with the miR-200 family may oppose the reversal of the EMT phenotype. PMID- 21321976 TI - Development of a brain metastatic canine prostate cancer cell line. AB - BACKGROUND: Prostate cancer in men has a high mortality and morbidity due to metastatic disease. The pathobiology of prostate cancer metastasis is not well understood and cell lines and animal models that recapitulate the complex nature of the disease are needed. Therefore, the goal of the study was to establish and characterize a new prostate cancer line derived from a dog with spontaneous prostate cancer. METHODS: A new cell line (Leo) was derived from a dog with spontaneous prostate cancer. Immunohistochemistry and PCR were used to characterize the primary prostate cancer and xenografts in nude mice. Subcutaneous tumor growth and metastases in nude mice were evaluated by bioluminescent imaging, radiography and histopathology. In vitro chemosensitivity of Leo cells to therapeutic agents was measured. RESULTS: Leo cells expressed the secretory epithelial cytokeratins (CK)8, 18, and ductal cell marker, CK7. The cell line grew in vitro (over 75 passages) and was tumorigenic in the subcutis of nude mice. Following intracardiac injection, Leo cells metastasized to the brain, spinal cord, bone, and adrenal gland. The incidence of metastases was greatest to the central nervous system (80%) with a lower incidence to bone (20%) and the adrenal glands (16%). In vitro chemosensitivity assays demonstrated that Leo cells were sensitive to Velcade and an HDAC-42 inhibitor with IC(50) concentrations of 1.9 nm and 0.95 um, respectively. CONCLUSION: The new prostate cancer cell line (Leo) will be a valuable model to investigate the mechanisms of the brain and bone metastases. PMID- 21321978 TI - Prostate tumor cells with cancer progenitor properties have high telomerase activity and are rapidly killed by telomerase interference. AB - BACKGROUND: Cancer progenitor cells (CPCs) have been postulated to promote treatment resistance and disease progression in prostate and other malignancies. We investigated whether the enzyme telomerase, which is active in cancer cells and in normal stem cells, plays an important role in CPC which can be exploited to neutralize these cells. METHODS: We used flow cytometry and assays of gene expression, clonogenicity, and invasiveness to isolate and characterize a putative CPC subpopulation from freshly resected human prostatectomy specimens. Telomerase activity was measured by qPCR-based Telomeric Repeat Amplification Protocol (TRAP). Telomerase interference was achieved by ectopic expression of a mutated telomerase RNA construct which reprograms telomerase to generate "toxic" uncapped telomeres. Treated cells were assayed for apoptosis, proliferation in culture, and xenograft tumor formation. RESULTS: CPC in prostate tumors expressed elevated levels of genes associated with a progenitor phenotype and were highly clonogenic and invasive. Significantly, CPC telomerase activity was 20- to 200 fold higher than in non-CPC from the same tumors, and CPC were exquisitely sensitive to telomerase interference which induced rapid apoptosis and growth inhibition. Similarly, induction of telomerase interference in highly tumorigenic CPC isolated from a prostate cancer cell line abrogated their ability to form tumor xenografts. CONCLUSIONS: Human prostate tumors contain a CPC subpopulation with markedly elevated telomerase activity which renders them acutely susceptible to telomerase interference. These findings offer the first tumor-derived and in vivo evidence that telomerase may constitute a CPC "Achilles heel" which may ultimately form the basis for more effective new CPC-targeting therapies. PMID- 21321979 TI - Antiandrogenic and growth inhibitory effects of ring-substituted analogs of 3,3' diindolylmethane (ring-DIMs) in hormone-responsive LNCaP human prostate cancer cells. AB - BACKGROUND: Cruciferous vegetables protect against prostate cancer. Indole-3 carbinol (I3C) and its major metabolite 3,3'-diindolylmethane (DIM), exhibit antitumor activities in vitro and in vivo. Several synthetic ring-substituted dihaloDIMs (ring-DIMs) appear to have increased anticancer activity. METHODS: Inhibition of LNCaP prostate cancer cell growth was measured by a WST-1 cell viability assay. Cytoplasmic and nuclear proteins were analyzed by immunoblotting and immunofluorescence. Androgen receptor (AR) activation was assessed by measuring prostate-specific antigen (PSA) expression and using LNCaP cells containing human AR and an AR-dependent probasin promoter-green fluorescent protein (GFP) construct. RESULTS: Like DIM, several ring-substituted dihaloDIM analogs, namely 4,4'-dibromo-, 4,4'-dichloro-, 7,7'-dibromo-, and 7,7' dichloroDIM, significantly inhibited DHT-stimulated growth of LNCaP cells at concentrations >=1 uM. We observed structure-dependent differences for the effects of the ring-DIMs on AR expression, nuclear AR accumulation and PSA levels in LNCaP cells after 24 hr. Both 4,4'- and 7,7'-dibromoDIM decreased AR protein and mRNA levels, whereas 4,4'- and 7,7'-dichloroDIM had minimal effect. All four dihaloDIMs (10 and 30 uM) significantly decreased PSA protein and mRNA levels. Immuofluorescence studies showed that only the dibromoDIMs increased nuclear localization of AR. All ring-DIMs caused a concentration-dependent decrease in fluorescence induced by the synthetic androgen R1881 in LNCaP cells transfected with wild-type human AR and an androgen-responsive probasin promoter-GFP gene construct, with potencies up to 10-fold greater than that of DIM. CONCLUSION: The antiandrogenic effects of ring-DIMs suggest they may form the basis for the development of novel agents against hormone-sensitive prostate cancer, alone or in combination with other drugs. PMID- 21321980 TI - Blockade of transforming growth factor-beta (TGFbeta) signaling inhibits osteoblastic tumorigenesis by a novel human prostate cancer cell line. AB - BACKGROUND: The skeleton is the most common site of prostate cancer metastasis, which often results in osteoblastic lesions. The role of transforming growth factor-beta (TGFbeta) signaling in prostate cancer-induced osteoblastic metastasis is not clear. We investigated the role of TGFbeta signaling in prostate cancer-induced bone metastasis using a novel human prostate cancer cell line, PacMetUT1. METHODS: We injected PacMetUT1/Luc-GFP cells in male nude mice by intracardiac and intratibia injections and then investigated the effect of TGFbeta signaling abrogation on osteoblastic tumor growth and incidence in vivo by using fluorescence and bioluminescence imaging analysis and quantifying bone and tumor volume by histomorphometry analysis. Osteoclasts were counted using TRAP assay. RESULTS: Osteoblastic bone metastasis in skull, rib, and femur was detected after 10-16 weeks of intracardiac injection of the PacMetUT1 cells. Stable knockdown of TGFbeta1 with an shRNA resulted in decreased tumor incidence and bone formation when the cells were directly injected into the tibiae. Systemic administration of either a small inhibitor of TGFbeta type I receptor kinase or a pan TGFbeta binding protein (BG(E) RII) also decreased bone tumor growth and osteoblastic bone formation in vivo after 7 weeks of treatment. CONCLUSIONS: Our results for the first time indicate that blockade of TGFbeta signaling in the PacMetUT1 model significantly inhibits osteoblastic bone formation and tumor incidence. Thus, TGFbeta signaling pathway may be a viable target for the prevention and treatment of prostate cancer-induced bone metastasis. PMID- 21321981 TI - The anti-interleukin-6 antibody siltuximab down-regulates genes implicated in tumorigenesis in prostate cancer patients from a phase I study. AB - BACKGROUND: Interleukin-6 (IL-6) is associated with prostate cancer morbidity. In several experimental models, IL-6 has been reported to have anti-apoptotic and pro-angiogenic effects. Siltuximab (CNTO 328) is a monoclonal anti-IL-6 antibody which has been successfully applied in several models representing prostate cancer. This study was designed to assess preliminary safety of siltuximab in patients with early prostate cancer. PATIENTS AND METHODS: Twenty patients scheduled to undergo radical prostatectomy received either no drug or siltuximab (6 mg/kg, five patients per group with administration once, two times, and three times prior to surgery). Blood samples were collected for pharmacokinetic and pharmacodynamic analyses. Expression of elements of IL-6 signaling pathways was analyzed in tumor tissue by immunohistochemistry. Gene analysis in tumor specimens was performed with the DASL array. RESULTS: No adverse events related to siltuximab were observed. Patients treated with siltuximab presented with higher levels of proliferation and apoptosis markers. Following a single dose, serum concentrations of siltuximab declined in a biexponential manner. This study revealed a decrease in phosphorylation of Stat3 and p44/p42 mitogen-activated protein kinases. In addition, gene expression analyses indicate down-regulation of genes immediately downstream of the IL-6 signaling pathway and key enzymes of the androgen signaling pathway. CONCLUSIONS: Preliminary safety of siltuximab is favorable. Future studies in which siltuximab could be combined with androgen deprivation therapy and experimental therapies in advanced prostate cancer are justified. PMID- 21321982 TI - Androgen receptor and heterogeneous nuclear ribonucleoprotein K colocalize in the nucleoplasm and are modulated by bicalutamide and 4-hydroxy-tamoxifen in prostatic cancer cell lines. AB - BACKGROUND: Bicalutamide (BIC) is widely used in prostate cancer therapy. The dose and schedule employed are well tolerated, but about 50% of patients develop gynecomastia. Several studies have shown a significant reduction of the troublesome effects when Tamoxifen is concomitantly administered with BIC. However, the results reported in the literature seem to be preliminary and possible interferences could be present. In order to clarify the molecular mechanisms of the combination of the two drugs, we have investigated whether the expression of the proteins belonging to nuclear matrix (NM), one modulator of hormone action, is altered by BIC and/or 4-hydroxy-tamoxifen (4OHT) in LNCaP cells. We focused above all on heterogeneous nuclear ribonucleoprotein K (hnRNP K) a NM protein with a key role in prostate carcinoma. METHODS: NM proteins were analyzed by two-dimensional gel electrophoresis. Modulation and compartmentalization of the androgen receptor and the hnRNP K were studied by Western blotting, confocal microscopy, and immunoprecipitation. RESULTS: Proteomic analysis revealed that there is a similarity in the changes of the NM proteins elicited by drugs alone but that their combination does not result in a simple additive effect. Moreover, we found that in the nucleoplasm the androgen receptor and the hnRNP K colocalize in a complex that is highly proximal to DNA and that both proteins were synchronously modulated by BIC and/or 4OHT treatment. CONCLUSION: This study confirm the pivotal role of hnRNP K in prostate carcinoma and suggest that this role might be played by the interaction with the androgen receptor. PMID- 21321983 TI - Phosphorylated Akt up-regulates angiotensin II type-1 receptor expression in castration resistant prostate cancer. AB - BACKGROUND: Accumulating evidences has suggested that the renin-angiotensin system (RAS) participates in the regulation of tumor angiogenesis. We previously demonstrated that castration-resistant prostate cancer (CRPC) showed significantly higher angiotensin II (Ang II) type-1 receptor (AT1R) expression, and that AT1R blockade (ARB) exerted protective effects by inhibiting angiogenesis. However, the detailed molecular mechanisms for the increase of AT1R expression in CRPC has not been fully elucidated yet. METHODS: In this study we used C4-2 and C4-2AT6 cells, which were PTEN-null, androgen receptor (AR) positive, PSA-producing CRPC cell lines. We investigated the association between phosphorylated Akt (pAkt) and AT1R expression, and used LY294002 as a PI3K/Akt inhibitor. RESULTS: Western blot analysis revealed C4-2AT6 cells showed significantly higher pAkt expression than C4-2 cells, although there were no significant differences in total Akt (tAkt) expression. Immunohistochemical (IHC) analysis also revealed significant higher pAkt expression in C4-2AT6 tumors obtained from castrated male nude mice. These results indicated that C4-2AT6 cells acquired elevated pAkt status under androgen-ablated treatment in vitro. Treatment with LY294002 at the same dose reduced the viability of C4-2AT6 more effectively than that of C4-2, reflecting the dependency of cancer cells on PI3K/Akt pathway. The up-regulated AT1R expression in C4-2AT6 cells was reduced by LY294002 in a dose-dependent manner. On the other hand, in C4-2 cells, serum starvation induced pAkt up-regulation, which led to an increase of AT1R expression. CONCLUSIONS: These findings indicated that up-regulation of pAkt contributed to elevated AT1R expression in CRPC. PMID- 21321984 TI - Comparison of DSM-IV versus proposed DSM-5 diagnostic criteria for eating disorders: reduction of eating disorder not otherwise specified and validity. AB - OBJECTIVE: Revised Eating Disorder (ED) diagnostic criteria have been proposed for the Diagnostic and Statistical Manual (DSM)-5 to reduce the preponderance of eating disorder not otherwise specified (EDNOS) and increase the validity of diagnostic groups. This article compares DSM-IV and proposed DSM-5 diagnostic criteria on number of EDNOS cases and validity. METHOD: Participants (N = 397; 91% female) completed structured clinical interviews in a two-stage epidemiological study of EDs. Interviewers did not follow standard skip rules, making it possible to evaluate alternative ED diagnostic criteria. RESULTS: Using DSM-IV versus DSM-5 criteria, 34 (14%) versus 48 (20%) had anorexia nervosa, 43 (18%) versus 44 (18%) had bulimia nervosa, and 163 (68%) had EDNOS versus 20 (8%) had binge eating disorder (BED), and 128 (53%) had EDNOS, respectively, reflecting a significant decrease in EDNOS. Validation analyses supported significant differences among groups with some improvement associated with delineation of BED. DISCUSSION: Proposed revisions to EDs in the DSM-5 significantly reduced reliance on EDNOS without loss of information. PMID- 21321985 TI - Examining the interpersonal model of binge eating and loss of control over eating in women. AB - OBJECTIVE: This study examined the interpersonal model of binge eating (Wilfley et al., Interpersonal Psychotherapy for Group, New York: Basic Books, 2000; Wilfley et al., Arch Gen Psychiatry, 8, 713-721, 2002; Elliott et al., Behav Res Ther, 48, 424-428, 2010) which posits that interpersonal problems lead to negative affect which, in turn, triggers disordered eating. METHOD: The model was tested using data from 350 women obtained via an internet assessment method. Analyses examined direct and indirect effects, via depressive/negative affect, of interpersonal problems, including domains of affiliation and dominance on loss of control over eating, binge eating, and eating disorder psychopathology. RESULTS: Interpersonal problems showed significant effects on binge eating and eating disorder psychopathology that were statistically mediated by depressive/negative affect. Affiliation showed significant effects on binge eating and eating disorder psychopathology with low affiliation effects statistically mediated by depressive/negative affect and high affiliation effects independent of depressive/negative affect. DISCUSSION: These findings support the interpersonal model of binge eating and highlight the importance of examining specific types of interpersonal problems in understanding heterogeneity of individuals with eating disorder psychopathology. PMID- 21321986 TI - Compulsive exercise: the role of personality, psychological morbidity, and disordered eating. AB - OBJECTIVE: Compulsive exercise has been closely linked with eating disorders, and has been widely reported in both clinical and nonclinical settings. It has been shown to have a negative impact on eating disorder treatment and outcome. However, the risk factors for compulsive exercise have not been examined. This study aimed to provide a first step in identifying potential cross-sectional predictors of compulsive exercise. METHOD: The sample consisted of 1,488 male and female adolescents, aged 12-14 years old, recruited from schools in the United Kingdom. Participants completed measures of compulsive exercise, personality, psychological morbidity, and disordered eating attitudes during a school class period. RESULTS: Multiple stepwise regressions showed that the strongest cross sectional predictors of compulsive exercise were a drive for thinness, perfectionism, and obsessive-compulsiveness. DISCUSSION: These results are discussed in terms of the role that personal factors may play in the development of compulsive exercise. PMID- 21321987 TI - Personality pathology in purging disorder and bulimia nervosa. AB - OBJECTIVE: To compare levels of personality pathology in women with purging disorder (PD), bulimia nervosa (BN), and controls and to compare women with PD and BN on associations between personality pathology and shared eating disorder features. METHOD: Women with BN (n = 73), PD (n = 48), and controls (n = 64) completed interviews and self-report questionnaires. RESULTS: BN and PD were associated with significantly greater personality pathology compared to controls. Cluster C symptoms and trait anxiety were greater in BN compared to PD, but groups did not differ on Cluster B symptoms or impulsivity. Subjective binge episodes were associated with anxious and impulsive personality traits in PD but not BN. Purging in PD was associated with trait anxiety, while purging in BN was associated with impulsivity. DISCUSSION: Although BN and PD share eating disorder features and personality disturbance, some of the underlying associations between these eating disorder and personality features differ between groups. PMID- 21321988 TI - Respiratory acidosis in adolescents with anorexia nervosa hospitalized for medical stabilization: a retrospective study. AB - OBJECTIVE: To examine the effect of malnutrition due to anorexia nervosa (AN) on venous blood gases of adolescents with AN hospitalized for medical stabilization. METHOD: This retrospective study included 45 adolescents with recent onset (<1 year) AN diagnosed by DSM-IV criteria and excluded subjects with a history of lung disease. RESULTS: Mean (+/- SD) age at hospitalization was 15.0 +/- 2.0 years; time from onset of symptoms was 6.8 +/- 3.0 months; body mass index (BMI) was 15.2 +/- 1.5 kg/m(2) ; and minimal nocturnal heart rate (MNHR) was 39.8 +/- 7.2 beats/min. On admission, pH was 7.32 +/- 0.02, pCO(2) was 53.8 +/- 4.6 mm Hg, and HCO(3) was 28.1 +/- 2.1 mEq/l. Significant changes (p < .001) occurred during the relatively short hospitalization (9.7 +/- 5.1 days): venous pH increased, pCO(2) decreased, HCO(3) decreased, MNHR increased, and heart rate orthostasis decreased. Mild respiratory acidosis (pH < 7.35 and pCO(2) > 45 mm Hg) was observed in 78% of the patients on admission and only in 35% at discharge (p = .0003). Positive correlations were found between % of weight loss and pCO(2) on admission and between BMI on admission and the delta pCO(2) during hospitalization. DISCUSSION: Mild respiratory acidosis is common in adolescents with recently diagnosed AN, hospitalized for medical stabilization. Respiratory acidosis improves with bed rest and refeeding. The clinical significance of these findings should be further evaluated. PMID- 21321989 TI - The therapeutic alliance in the early part of cognitive-behavioral therapy for the eating disorders. AB - OBJECTIVE: This study examined the strength of the therapeutic alliance in the early stages of cognitive-behavioral therapy (CBT) for the eating disorders, and whether the strength of that alliance is associated with early eating characteristics, comorbid Axis 1 and 2 features. METHOD: Forty-four eating disordered patients completed measures of eating and Axis 1 and 2 characteristics at the start of therapy, and measures of the therapeutic alliance and eating characteristics at the sixth session of CBT. RESULTS: The therapeutic alliance was strong, including in the domain of attachment. It was unrelated to initial eating pathology and early changes in eating cognitions and behaviors. However, there were links between initial emotional and interpersonal features and therapeutic alliance by the sixth session. DISCUSSION: The findings counter suggestions that CBT for eating disorders is characterized by a poor therapeutic relationship. The therapeutic alliance is likely to be enhanced by addressing high levels of emotional distress and difficulties in interpersonal function where appropriate. This research needs to be extended to other therapies, other domains of function and different time points in therapy, to build a fuller picture of the role of the therapeutic relationship in working with the eating disorders. PMID- 21321990 TI - "Do you still want to be seen?": the pros and cons of active waiting list management. AB - OBJECTIVE: This study examined the impact on a clinic waiting list of introducing an "opt-in" system for patients awaiting individual outpatient cognitive behavioral therapy. The proportion of patients opting in was identified, along with demographic, eating, and psychopathological factors that might make some more likely to opt out. METHOD: The sample consisted of 116 patients with eating disorder. Each completed measures of eating and axis 1 and 2 characteristics at assessment. They received one opt-in letter and a reminder. Those who opted in immediately or after a reminder were compared with those who did not. RESULTS: Just over two-thirds of the patients opted to remain on the waiting list. No demographic or eating characteristics differentiated those individuals. Those who did not opt in immediately had higher levels of depression, psychoticism, and borderline personality disorder cognitions. However, that difference disappeared when the reminder letter was sent. DISCUSSION: Waiting list reductions can be achieved through an active "opt-in" mechanism, and this approach does not disadvantage specific individuals but speeds access to treatment for the majority of patients. However, further research is needed to track pathways of care to determine whether such initiatives have longer term positive or negative impacts. PMID- 21321991 TI - Wnt10b activates the Wnt, notch, and NFkappaB pathways in U2OS osteosarcoma cells. AB - Although osteosarcoma represents the most common bone malignancy, the molecular and cellular mechanisms influencing its pathogenesis have remained elusive. Recent evidence has suggested that the Wnt signaling pathway may play a crucial role in osteosarcoma. This study employed a microarray approach to discover novel genes and pathways involved in Wnt signaling in osteosarcoma. We developed a Wnt10b-expressing cell line using the human U2OS osteosarcoma model (U2OS-Wnt10b) and performed microarray and pathway analyses using parental U2OS cells as control. Differential expression of 1,003 genes encompassing 28 pathways was noted. The Wnt, NFkappaB, and Notch pathways were chosen for further study based on their known importance in bone biology. Known Wnt-responsive genes Axin-2 (4.9 fold), CD44 (2.1-fold), endothelin-1 (4.2-fold) and sclerostin domain containing 1 (43-fold) were regulated by Wnt10b. The proinflammatory cytokines interleukin 1alpha and tumor necrosis factor-alpha, known inducers of NFkappaB, were upregulated both at the transcript and protein level, and NFkappaB reporter activity was stimulated 3.8-fold, confirming NFkappaB activation. Interestingly, genes involved in Notch signaling [Notch-1 (2.4-fold) and Jagged-1 (3.1-fold)] were upregulated, whereas the Notch inhibitor, lunatic fringe, was downregulated (8.2-fold). This resulted in the activation of the classic Notch-responsive genes, hairy and enhancer of split-1 (Hes-1; 2.2-fold) and hairy/enhancer-of split related with YRPW motif-1 (Hey-1; 2.5-fold). A Hey-1 reporter construct was regulated 9.1-fold in U2OS-Wnt10b cells, confirming Notch activation. Interestingly, Wnt3a failed to induce the Notch and NFkappaB pathways, demonstrating Wnt-specificity. In conclusion, our data demonstrate that Wnt10b, but not Wnt3a, stimulates the NFkappaB and Notch pathways in U2OS osteosarcoma cells. PMID- 21321992 TI - Synthetic small interfering RNA down-regulates caspase-3 and affects apoptosis, IL-1 beta, and viability of porcine proximal tubular cells. AB - Proximal tubular cells are most vulnerable to ischemia reperfusion injury (IRI) in renal transplantation. Caspase-3 can be up-regulated by IRI due to a variety of pathogenic processes such as oxidative damage. This study utilized synthetic small interfering RNA (siRNA) to posttranscriptionally silence target gene, caspase-3, may represent a feasible approach to produce transient effects, but avoid side actions caused by viral vectors. The porcine proximal tubular cells (LLC-PK1), with or without the stimulation of hydrogen peroxide (H(2) O(2) , an oxidizer), were transfected with synthetic caspase-3 siRNA using a cationic lipid based transfection regent. The expression of caspase-3 at mRNA and protein level was assessed at different times posttransfection and its downstream biological events were also monitored. The caspase-3 mRNA was posttranscriptionally silenced by its siRNA up to 50% after 24 h. The active caspase-3 protein was increased by transfection reagent alone and H(2) O(2) in a dose- and time-dependent manner. Both the precursor and active protein of caspase-3 were decreased by siRNA after 48 h and maintained up to 96 h at least, with a consistent change in its activity. Consequently, apoptotic cells and active IL-1beta protein expression was reduced by caspase-3 siRNA; cell viability, especially with H(2) O(2) treatment, was also improved. Taken together, caspase-3 and apoptosis are sensitive markers for cellular injury; using synthetic siRNA silencing caspase-3 may provide not only a valid approach for underlying mechanisms of diseases, but also a potential therapeutic intervention for a wide range of acute clinical disorders including IRI in renal transplantation. PMID- 21321993 TI - The role of mechanical stretching in the activation and localization of adhesion proteins and related intracellular molecules. AB - The molecular complexity of the processes which lead to cell adhesion includes membrane and cytoskeletal proteins, involved in the focal adhesion formation, as well as signaling molecules tightly associated with the main intracellular regulatory cascades (Akt/PKB and MAPK/Erk). Dynamic environments, which create substrate deformations at determined frequencies and timing, have significant influences on adhesion mechanisms and in general in cellular behavior. In this work, we investigated the role of mechanical stretching (10% substrate deformation, 1 Hz frequency applied up to 60 min) on adhesion proteins (vinculin and focal adhesion kinase-FAK), related RhoGTPases (Rac1 and RhoA), and intracellular pathways (Akt/PKB and MAPK/Erk) in terms of activation and membrane recruitment in relation with cytoskeletal changes observed (membrane ruffling and filopodia formation). These changes are due to intracellular molecular rearrangements, acting with sequential concerted dynamics, able to modify the cytoskeletal conformation. The observed cellular response adds some important issues for better understanding the cellular behavior in environment which mimic as close as possible the physiological conditions. PMID- 21321994 TI - Pax7-FKHR transcriptional activity is enhanced by transcriptionally repressed MyoD. AB - Alveolar rhabdomyosarcoma (ARMS) are characterized by the expression of chimeric transcription factors Pax3-FKHR and Pax7-FKHR, due to chromosomal translocations fusing PAX3 or PAX7 with the FKHR gene. Although ARMS exhibits a muscle lineage phenotype, the cells evade terminal differentiation despite expressing the potent myogenic transcriptional regulator MyoD. Here we show that while Pax7-FKHR inhibits MyoD-dependent transcription, MyoD enhances Pax7-FKHR activity in myogenic cell cultures. Importantly, this effect is not recapitulated by close related transcription factor myogenin and involves specific MyoD functional domains, distinct from those required for Pax7 to regulate MyoD during muscle formation. Together, these results suggest that although repressed as a myogenic regulatory factor, MyoD can play an active role in ARMS by augmenting Pax7-FKHR function. PMID- 21321995 TI - Comparison of alternative mesenchymal stem cell sources for cell banking and musculoskeletal advanced therapies. AB - With the continuous discovery of new alternative sources containing mesenchymal stem cells (MSCs), regenerative medicine therapies may find tailored applications in the clinics. Although these cells have been demonstrated to express specific mesenchymal markers and are able to differentiate into mesenchymal lineages in ad hoc culture conditions, it is still critical to determine the yield and differentiation potential of these cells in comparative studies under the same standardized culture environment. Moreover, the opportunity to use MSCs from bone marrow (BM) of multiorgan donors for cell banking is of relevant importance. In the attempt to establish the relative potential of alternative MSCs sources, we analyzed and compared the yield and differentiation potential of human MSCs from adipose and BM tissues of cadaveric origins, and from fetal annexes (placenta and umbilical cord) after delivery using standardized isolation and culture protocols. BM contained a significantly higher amount of mononuclear cells (MNCs) compared to the other tissue sources. Nonetheless, a higher cell seeding density was needed for these cells to successfully isolate MSCs. The MNCs populations were highly heterogeneous and expressed variable MSCs markers with a large variation from donor to donor. After MSCs selection through tissue culture plastic adhesion, cells displayed a comparable proliferation capacity with distinct colony morphologies and were positive for a pool of typical MSCs markers. In vitro differentiation assays showed a higher osteogenic differentiation capacity of adipose tissue and BM MSCs, and a higher chondrogenic differentiation capacity of BM MSCs. PMID- 21321996 TI - Adiponectin increases MMP-3 expression in human chondrocytes through AdipoR1 signaling pathway. AB - Articular adipose tissue is a ubiquitous component of human joints, and adiponectin is a protein hormone secreted predominantly by differentiated adipocytes and involved in energy homeostasis. The adiponectin is significantly higher in synovial fluid of patients with osteoarthritis and rheumatoid arthritis. Matrix metalloproteinases (MMP)-3 may contribute to the breakdown of articular cartilage during arthritis. We investigated the signaling pathway involved in MMP-3 caused by adiponectin in human chondrocytes. Adiponectin increased the secretion of MMP-3 in cultured human chondrocytes, as shown by qPCR, Western blot, and ELISA analysis. Adiponectin-mediated MMP-3 expression was attenuated by AdipoR1 but not AdipoR2 siRNA. Pretreatment with 5'-AMP-activated protein kinase (AMPK) inhibitor (araA and compound C), p38 inhibitor (SB203580), and NF-kappaB inhibitor (PDTC and TPCK) also inhibited the potentiating action of adiponectin. Activations of p38, AMPK, and NF-kappaB pathways after adiponectin treatment were demonstrated. Taken together, our results provide evidence that adiponectin acts through AdipoR1 to activate p38 and AMPK, resulting in the activations of NF-kappaB on the MMP-3 promoter and contribute cartilage destruction during arthritis. PMID- 21321997 TI - Directed neural differentiation of duck embryonic germ cells. AB - Although the avian primordial germ cells (PGCs) have been used to produce transgenic birds, their characteristics largely remain unknown. The isolation, culture, biological characterization, and directed neural differentiation of duck EG cells were assayed in this study. The Results showed that the EG cells were got by isolating embryonic gonad and surrounding tissue from 7-day-old duck embryo. The PGCs co-cultured with their gonadal somatic cells were well grown. After passaging, the EG cells were incubated in medium with cytokines and Mitomycin C on inactivated duck embryonic fibroblasts (DEFs) feeder layers. After several passages, alkaline phosphatase (ALP) and periodic acid-Schiff (PAS) resulted positive, cellular markers detection positive for SSEA-1, SSEA-4, TRA-1 60, and TRA-1-81. Karyotype analysis showed the EG cells kept diploid condition and the hereditary feature was stable in accordance with varietal characteristics of duck. These cells grew continuously for 11 passages on DEFs. Under induction of medium with BME, RA, and IBMX, the EG cells lost undifferentiated state, large amount of neural cells appeared with the formation of neural cells networks. Special Nissl body was found by toluidine blue stain after induced for 7 days. Immunofluorescence staining results indicated that differentiated EG cells expressed Nestin, NSE, and GFAP positive. The expression of Nestin, NSE, and GFAP mRNA were positive by RT-PCR. The results revealed that RA can obviously promote the directed differentiation of duck EG cells into neural lineage. The duck EG cells will be useful for the production of transgenic birds, for cell replacement therapy and for studies of germ cell differentiation. PMID- 21321998 TI - Effect of beta-amyloid (25-35) on mitochondrial function and expression of mitochondrial permeability transition pore proteins in rat hippocampal neurons. AB - The aim of this study was to assess the effect of the beta-amyloid fragment Abeta(25-35) on mitochondrial structure and function and on the expression of proteins associated with the mitochondrial permeability transition pore (MPTP) in rat hippocampal neurons. Ninety clean-grade Sprague-Dawley rats were randomly assigned to six groups (n = 15 per group). Abeta(25-35) (1, 5, or 10 ug/rat) was injected into hippocampal area CA1. Normal saline was injected as a control. The effect of Abeta(25-35) injection on hippocampal structure was assessed by transmission electron microscopy. Ca(2+) -ATPase activity, [Ca(2+) ](i) , and mitochondrial membrane potential were measured. The expression of genes associated with the MPTP, including the voltage-dependent anion channel (VDAC), adenine nucleotide translocator (ANT), and cyclophilin D (Cyp-D), were evaluated. Results showed that Abeta(25-35) injection damaged the mitochondrial structure of hippocampal neurons, decreased Ca(2+) -ATPase activity and mitochondrial membrane potential, and increased [Ca(2+) ](i) . The expression levels for VDAC, ANT, and Cyp-D in all groups were significantly (P < 0.05) higher than those in the normal control group after Abeta(25-35) injection. These results indicate that Abeta(25 35) damages mitochondria in rat hippocampal neurons and effects mitochondrial dysfunction, as well as increasing the expression of genes associated with the MPTP. Mitochondrial dysfunction may result in increased MPTP gene expression, leading to neurodegenerative effects. PMID- 21321999 TI - The localization of hnRNP A2/B1 in nuclear matrix and the aberrant expression during the RA-induced differentiation of human neuroblastoma SK-N-SH cells. AB - Heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 is involved in the synthesis of RNA. Its expression is up-regulated in many tumor cell lines. In this study, we investigated the distribution of hnRNP A2/B1 in the nuclear matrix, including its co-localization with expression products of related genes. Results from 2-DE PAGE and MS showed that hnRNP A2/B1 is involved with components of nuclear matrix proteins of SK-N-SH cells, and that its expression level is down-regulated after retinoic acid (RA) treatment. Protein immunoblotting results further confirm the existence of hnRNP A2/B1 in the nuclear matrix, as well as its down-regulation after RA treatment. Immunofluorescence microscopy observation showed that hnRNP A2/B1 localized in nuclear matrix of SK-N-SH cells and its distribution regions were altered after RA treatment. Laser scanning confocal microscopy observation showed that hnRNP A2/B1 co-localized with c-Myc, c-Fos, P53, and Rb in SK-N-SH cells. The co-localized region was altered as a result of RA treatment. Our data proved that hnRNP A2/B1 is a nuclear matrix protein and can be up-regulated in human neuroblastoma. The expression and distribution of hnRNP A2/B1 can affect the differentiation of SK-N-SH cells, as well as its co localization with related oncogenes and tumor suppressor genes. PMID- 21322000 TI - Amphiphilic peptides with arginines and valines for the delivery of plasmid DNA. AB - A non-toxic and efficient gene carrier is one requirement for clinical gene therapy. In this study, amphiphilic peptides composed of arginines and valines were synthesized and characterized as plasmid DNA (pDNA) carriers. The peptides have a cationic region containing 1-4 arginines and a hydrophobic region containing 6 valines. The arginine-valine peptides (RV peptides) formed micelles in aqueous solution with a critical micelle concentration (CMC) of 1.35 mg/ml. In gel retardation assay, the RV peptides retarded all pDNA at weight ratios (pDNA:RV peptide) of 1:3 for R1V6, 1:2 for R2V6 and R3V6, and 1:1 for R4V6. A heparin competition assay showed that the R3V6 peptide formed tighter complexes with pDNA than poly-L-lysine (PLL). In vitro transfection assay into HEK293 cells showed that the R1V6 and R2V6 peptides had the highest transfection efficiencies at 1:30 weight ratios (pDNA:RV peptide), while the R3V6 and R4V6 peptides had the highest efficiencies at 1:20 weight ratios. Under optimal conditions, the R3V6 peptide had the highest transfection efficiency of all the RV peptides and PLL. MTT assay showed that the RV peptides did not have any detectable toxicity to cells. Therefore, the RV peptide may be useful for the development of non-toxic gene carriers. PMID- 21322001 TI - Successful therapeutic plasma exchange in a 3.2-kg body weight neonate with atypical hemolytic uremic syndrome. AB - Atypical hemolytic uremic syndrome (aHUS) is a rare form of complement dysregulation disease, and recently various reports have shown that it is associated with one or more mutations in the complement regulatory genes including complement factor H (CFH). Plasma exchange is a therapeutic option for adult patients, but not for a very young infant because of a potential side effect of therapeutic plasma exchange (TPE) itself. Herein, we describe a case of successful treatment of early onset aHUS associated with a novel CFH mutation with total 21 sessions of TPE over a period of 46 days in 3.2 kg 23-day-old neonate. PMID- 21322003 TI - Papers selected from the Second International Symposium on Insect Physiology. PMID- 21322004 TI - A midgut-specific chymotrypsin cDNA (Slctlp1) from Spodoptera litura: cloning, characterization, localization and expression analysis. AB - Serine proteases play important roles in food digestion and immune response during insect development. A full-length cDNA (Slctlp1) encoding a chymotrypsin like serine protease was cloned from Spodoptera litura and characterized for its cDNA structure, developmental and induced expression and localization. The deduced protein of the Slctlp1 cDNA contains a catalytic triad and a substrate specificity pocket found in most of the serine proteases. Both the transcripts and protein of Slctlp1 were predominately expressed in the midgut at the feeding stages during the larval development. Immunohistochemistry analysis indicated that the SLCTLP1 protein was predominately present in the midgut of the 6th instar feeding larvae. Starvation suppressed the expression of Slctlp1 gene and protein in 6th instar larvae and the protein expression was increased again by re feeding the insect. The results suggest that the cloned Slctlp1 cDNA may be involved in food protein digestion at the feeding stages during larval development. PMID- 21322005 TI - Interspecific competition between two endoparasitoids Cotesia vestalis (Hymenoptera: Braconidae) and Oomyzus sokolowskii (Hymenoptera: Eulophidae). AB - Two endoparasitoids, Cotesia vestalis and Oomyzus sokolowskii, parasitize the same host, larvae of Plutella xylostella. These two species have evolved different parasitization strategies. O. sokolowskii expresses a single factor, venom, and exerts virtually no detrimental effects on the development of its host. C. vestalis, on the other hand, injects polydnavirus (PDV) and venom during oviposition, and teratocytes are released into the host's hemolymph after egg hatching. Parasitization suppresses host immune reactions and redirects its developmental program. Because both these species parasitize the same stage of their hosts, there is the possibility of multiparasitism in nature. Only one species survives multiparasitism and because of its parasitic strategy, we hypothesized that C. vestalis would invariably be the stronger competitor. We designed competition experiments which revealed that C. vestalis is a stronger competitor than O. sokolowskii. We also show that C. vestalis survives intrinsic competition with O. sokolowskii through two mechanisms: physical attack and physiological suppression. We discovered melanized wounds on O. sokolowskii eggs and larvae, which is strong evidence of physical attacks. The physiological suppression is due to PDV and venom injected by C. vestalis. To test this idea more rigorously, we designed a pseudoparasitization experiment which revealed that no O. sokolowskii emerged from multiparasitized hosts when infertile C. vestlais eggs and normal O. sokolowskii larvae are both present inside the same host. These results support our hypothesis that C. vestalis is the stronger competitor and demonstrate two mechanisms that account for the outcome of intrinsic competition between these two endoparasitoids. PMID- 21322006 TI - C-type lectin from red swamp crayfish Procambarus clarkii participates in cellular immune response. AB - Lectins are potential immune recognition proteins. In this study, a novel C-type lectin (Pc-Lec1) is reported in freshwater crayfish Procambarus clarkii. Pc-Lec1 encodes a protein of 163 amino acids with a putative signal peptide and a single carbohydrate recognition domain. It was constitutively expressed in various tissues of a normal crayfish, especially in the hepatopancreas and gills. Expressions of Pc-Lec1 were up-regulated in the hepatopancreas and gills of crayfish challenged with Vibrio anguillarum, Staphylococcus aureus, or the white spot syndrome virus. Recombinant mature Pc-Lec1 bound bacteria and polysaccharides (peptidoglycan, lipoteichoic acid, and lipopolysaccharide) but did not agglutinate bacteria. Pc-Lec1 enhanced hemocyte encapsulation of the sepharose beads in vitro, and the blocking of beads by a polyclonal antibody inhibited encapsulation. Pc-Lec1 promoted clearance of V. anguillarum in vivo. These results suggest that Pc-Lec1 is a pattern recognition receptor and participates in cellular immune response. Pc-Lec1 performs its function as an opsonin by enhancing the encapsulation or clearance of pathogenic bacteria. PMID- 21322007 TI - Structure elucidation and complete NMR spectral assignment of an unusual aromatic monacolin analog from Monascus purpureus-fermented rice. AB - One unusual aromatic monacolin analog, monacophenyl, was isolated from the ethanolic extract of Monascus purpureus-fermented rice. Its structure was completely and unambiguously assigned by one- and two-dimensional NMR techniques ((1)H NMR, (13)C NMR, HSQC, HMBC and NOESY) and high-resolution ESI-MS spectrometry. PMID- 21322008 TI - Conformation of the tridimensional structure of 1,2,3,4,6-pentagalloyl-beta-D glucopyranose (PGG) by (1)H NMR, NOESY and theoretical study and membrane interaction in a simulated phospholipid bilayer: a first insight. AB - 1,2,3,4,6-Penta-O-galloyl-beta-D-glucopyranose (PGG) is a polyphenolic compound found in substantial amounts in a number of medicinal herbs. We report (i) its conformational analysis by solution NMR and molecular dynamics calculation and (ii) theoretical study of its interaction with a model membrane bilayer. The galloyl groups B and E appear to play important roles in the interaction with the phospholipid bilayer. PMID- 21322009 TI - ERETIC implemented in diffusion-ordered NMR as a diffusion reference: a clarification. AB - Additional information as to the objectives of our previous paper entitled 'ERETIC implemented in diffusion-ordered NMR as a diffusion reference' (Magn. Reson. Chem. 2008, 46, S63) is provided. The need for an optimal instrumental stability for the method proposed to be reliably applicable in view of these objectives is emphasized and illustrated. PMID- 21322010 TI - NMR property calculations and experimental study of the 1,6-epoxycarvone and alpha-epoxypinene: a comparison of models. AB - This work aims at using theoretical calculations of shielding tensors (sigma) through different methods [gauge-independent atomic orbital (GIAO), continuous set of gauge transformations (CSGT) and individual gauges for atoms in molecules (IGAIM)] and spin-spin coupling constants J using GIAO method to compare these methods and to corroborate the data obtained with the assignment of all of (1)H and (13)C NMR signals and the relative stereochemistry of the 1,6-epoxycarvone and the alpha-epoxypinene. All the (1)H and (13)C NMR signals were assigned unequivocally. The stereochemistry for the epoxides is trans and the B3LYP theory level with CSGT and IGAIM methods is the best choice to evaluate theoretical chemical shifts for compounds studied. PMID- 21322011 TI - Determination of substitution sites in monosubstituted five-membered aromatic heterocycles. AB - Similar magnitudes of proton-proton couplings across three, four, and five bonds and proton-carbon couplings across two and three bonds combined with difficult to predict substituent effects make the results of an indiscriminate use of routine (COSY, HSQC, HMBC, etc.) techniques for substitution site determination in C monosubstituted five-membered heteroaromatics suspect. As demonstrated on two examples of natural products, the use of 1,1-ADEQUATE leads to unambiguous substitution site determination lending thus further support to suggested inclusion of 1,1-ADEQUATE data into computer-assisted structure elucidation (CASE) protocols. PMID- 21322013 TI - Parkinson's disease, primates, and gene therapy: vive la difference? PMID- 21322014 TI - Glia: initiators and progressors of pathology in Parkinson's disease. AB - BACKGROUND: Glia are traditionally known as support cells for neurons, and their role in neurodegeneration has been largely considered secondary to neuronal dysfunction. We review newer concepts on glial function and assess glial changes in Parkinson's disease (PD) at the time of disease initiation when alpha synuclein is accumulating in brain tissue but there is limited neuronal loss, and also as the disease progresses and neuronal loss is evident. RESULTS: Of the two main types of astrocytes, only protoplasmic astrocytes are involved in PD, where they become nonreactive and accumulate alpha-synuclein. Experimental evidence has shown that astrocytic alpha-synuclein deposition initiates the noncell autonomous killing of neurons through microglial signaling. As the disease progresses, more protoplasmic astrocytes are affected by the disease with an increasing microglial response. Although there is still controversy on the role microglia play in neurodegeneration, there is evidence that microglia are activated early in PD and possibly assist with the clearance of extracellular alpha-synuclein at this time. Microglia transform to phagocytes and target neurons as the disease progresses but appear to become dysfunctional with increasing amounts of ingested debris. Only nonmyelinating oligodendroglial cells are affected in PD, and only late in the disease process. CONCLUSIONS: Glial cells are responsible for the progression of PD and play an important role in initiating the early tissue response. In particular, early dysfunction and alpha-synuclein accumulation in astrocytes causes recruitment of phagocytic microglia that attack selected neurons in restricted brain regions causing the clinical symptoms of PD. PMID- 21322015 TI - Tremor--some controversial aspects. AB - The commonest cause of pathological tremor is essential tremor (ET). However, it has proved difficult to identify genetic mutations causing ET, particularly because other causes of tremor continue to be misdiagnosed as ET. Whether subjects with dystonia or Parkinson's disease (PD) carry an increased genetic risk of developing ET, or vice versa, is controversial. In addition, the notion of a separate disorder of benign tremulous parkinsonism (BTP) has been debated. This article gives a selective viewpoint on some areas of uncertainty and controversy in tremor. PMID- 21322016 TI - Why catechol? AB - A brief history of the evolution of the term catechol amine and relationship to the treatment of Parkinson's disease. PMID- 21322017 TI - Bioactivity of AAV2-neurturin gene therapy (CERE-120): differences between Parkinson's disease and nonhuman primate brains. AB - BACKGROUND: AAV2-neurturin (CERE-120) is designed to deliver the neurotrophic factor, neurturin, to the striatum to restore and protect degenerating nigrostriatal neurons in Parkinson's disease (PD). A common hypothesis is that following expression in the striatum, neurotrophic-factors like neurturin (NRTN) will be transported from degenerating terminals to their cell bodies in the substantia nigra pars compacta (SNc). METHODS: We tested this concept using immunohistochemistry, comparing the bioactivity of AAV2-neurturin in brains of PD patients versus those of nonhuman primates similarly treated. RESULTS: NRTN immunostaining in the targeted striatum was seen in all PD cases (mean putaminal coverage: ~15% by volume); comparable expression was observed in young, aged, and parkinsonian monkeys. In the SNc cell bodies, however, only rare evidence of neurturin was seen in PD, while ample evidence of intense nigral-NRTN was observed in all monkeys. NRTN-expression was associated with occasional, sparse TH-induction in the striatum of PD, but nothing apparent in the SNc. In primates, NRTN produced robust TH-induction throughout the nigrostriatal neurons. DISCUSSION: These data provide the first evidence that gene therapy can increase expression of a neurotrophic-factor deep in the PD brain and that clear but modest enhancement of degenerating neurons can be induced. They also provide important insight regarding deficiencies in the status of nigrostriatal neurons in advanced PD, suggesting that serious axon-transport deficits reduced the bioactivity of AAV2-NRTN by limiting the protein exposed to the cell body. Thus, future efforts using neurotrophic-factors to treat neurodegenerative diseases will need to target both the terminal fields and the cell bodies of degenerating neurons to assure maximal benefit is achieved. PMID- 21322018 TI - The effect of drug treatment on neurogenesis in Parkinson's disease. AB - There has been recent interest in the possibility that impaired neurogenesis may contribute to the decline in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (PD). We have investigated the effects of commonly used treatments for PD on neural stem cell (NSC) activity in nondemented patients. Postmortem of brain tissue containing the subventricular zone (SVZ) and ependymal layer cells was obtained from 32 nondemented patients with PD. NSC activity was assessed by immunohistochemical staining for RNA-binding protein Musashi1. Regression analyses were then used to identify which clinical factors independently influenced NSC activity. Disease duration was negatively associated with SVZ Musashi1 staining, whereas lifetime levodopa was positively associated in this region. Our findings suggest a positive impact of chronic L-dopa use on the number of NSC in the SVZ of PD patients, which may have relevance for future studies on neuroprotection in neurodegenerative diseases. PMID- 21322019 TI - Clinical subtypes of Parkinson's disease. AB - The clinical heterogeneity of Parkinson's disease (PD) may point at the existence of subtypes. Because subtypes likely reflect distinct underlying etiologies, their identification may facilitate future genetic and pharmacotherapeutic studies. Aim of this study was to identify subtypes by a data-driven approach applied to a broad spectrum of motor and nonmotor features of PD. Data of motor and nonmotor PD symptoms were collected in 802 patients in two different European prevalent cohorts. A model-based cluster analysis was conducted on baseline data of 344 patients of a Dutch cohort (PROPARK). Reproducibility of these results was tested in data of the second annual assessment of the same cohort and validated in an independent Spanish cohort (ELEP) of 357 patients. The subtypes were subsequently characterized on clinical and demographic variables. Four similar PD subtypes were identified in two different populations and are largely characterized by differences in the severity of nondopaminergic features and motor complications: Subtype 1 was mildly affected in all domains, Subtype 2 was predominantly characterized by severe motor complications, Subtype 3 was affected mainly on nondopaminergic domains without prominent motor complications, while Subtype 4 was severely affected on all domains. The subtypes had largely similar mean disease durations (nonsignificant differences between three clusters) but showed considerable differences with respect to their association with demographic and clinical variables. In prevalent disease, PD subtypes are largely characterized by the severity of nondopaminergic features and motor complications and likely reflect complex interactions between disease mechanisms, treatment, aging, and gender. PMID- 21322020 TI - PRKN, DJ-1, and PINK1 screening identifies novel splice site mutation in PRKN and two novel DJ-1 mutations. AB - We present results of mutation screening of PRKN gene in 93 Iranian Parkinson's disease (PD) patients with average age at onset (AAO) of 42.2 years. The gene was screened by direct sequencing and by a semi-quantitative PCR protocol for detection of sequence rearrangements. Heterozygous rearrangements were tested by reverse transcription-polymerase chain reaction (RT-PCR). Nine different PRKN mutations were found. One of these, IVS9+1G>A, affects splicing and is novel. Two mutated PRKN alleles were observed in each of 6 patients whose average AAO was 25.7 years. Only 1 patient carried a single mutated allele and his AAO was 41 years. Among patients with AAO of <30 years, 31.3% had two mutated alleles, while only 2.6% with AAO of >30 years carried a PRKN mutation. Analysis of PRKN by RT PCR led to identification of a novel exon expressed in leukocytes of control and PD individuals. The alternatively spliced transcript if translated would code a protein without a RING Finger 2 domain. Its functional relevance remains to be shown. DJ-I and PINK1 were also screened. Two novel DJ-1 mutations, c.91-2A>G affecting splicing and c.319G>C causing Ala107Pro, were observed among patients with AAO of <31 years, suggesting that PD in a high fraction (>12%) of this group of Iranian patients may be due to mutations in DJ-1. Mutations in PINK1 were not observed. Our results complement previous findings on LRRK2 mutations among Iranian PD patients. PMID- 21322021 TI - Rotigotine effects on early morning motor function and sleep in Parkinson's disease: a double-blind, randomized, placebo-controlled study (RECOVER). AB - In a multinational, double-blind, placebo-controlled trial (NCT00474058), 287 subjects with Parkinson's disease (PD) and unsatisfactory early-morning motor symptom control were randomized 2:1 to receive rotigotine (2-16 mg/24 hr [n = 190]) or placebo (n = 97). Treatment was titrated to optimal dose over 1-8 weeks with subsequent dose maintenance for 4 weeks. Early-morning motor function and nocturnal sleep disturbance were assessed as coprimary efficacy endpoints using the Unified Parkinson's Disease Rating Scale (UPDRS) Part III (Motor Examination) measured in the early morning prior to any medication intake and the modified Parkinson's Disease Sleep Scale (PDSS-2) (mean change from baseline to end of maintenance [EOM], last observation carried forward). At EOM, mean UPDRS Part III score had decreased by -7.0 points with rotigotine (from a baseline of 29.6 [standard deviation (SD) 12.3] and by -3.9 points with placebo (baseline 32.0 [13.3]). Mean PDSS-2 total score had decreased by -5.9 points with rotigotine (from a baseline of 19.3 [SD 9.3]) and by -1.9 points with placebo (baseline 20.5 [10.4]). This represented a significantly greater improvement with rotigotine compared with placebo on both the UPDRS Part III (treatment difference: -3.55 [95% confidence interval (CI) -5.37, -1.73]; P = 0.0002) and PDSS-2 (treatment difference: -4.26 [95% CI -6.08, -2.45]; P < 0.0001). The most frequently reported adverse events were nausea (placebo, 9%; rotigotine, 21%), application site reactions (placebo, 4%; rotigotine, 15%), and dizziness (placebo, 6%; rotigotine 10%). Twenty-four-hour transdermal delivery of rotigotine to PD patients with early-morning motor dysfunction resulted in significant benefits in control of both motor function and nocturnal sleep disturbances. PMID- 21322022 TI - Prevalence and disease burden of primary restless legs syndrome: results of a general population survey in the United States. AB - To assess prevalence, disease burden, and costs of primary Restless Legs Syndrome (RLS) in the US. In 2007, 61,792 (20%) of 313,000 subjects from a representative US panel completed an online "global opinions" survey identifying respondents reporting all four diagnostic features of RLS. 4,484 met all criteria. 1,400 were randomly selected to complete a questionnaire to exclude those with diagnoses indicating possible secondary RLS. Those that did not have diagnoses associated with secondary RLS were asked to complete the Cambridge-Hopkins RLS questionnaire to exclude RLS mimics. Prevalence was estimated for the following groups: (1) RLS symptomatic, (2) primary RLS, and (3) primary RLS sufferers (symptoms >=2/wk with moderate-to-severe distress). The primary RLS completed a larger online survey including the IRLS, EuroQol, Work Productivity and Activity Impairment questionnaire, and questions about healthcare resource use. The validated diagnostic tools and exclusion of medical conditions likely to cause RLS provide a very conservative estimate of US census-weighted prevalence of 2.4% for primary RLS and 1.5% for primary RLS sufferers. About 33% of respondents had a physician diagnosis of RLS. Primary RLS sufferers had a mean productivity loss of 1 day/wk. All RLS-related costs increased with RLS symptom severity, with increasingly significant decrements in health status, sleep disturbance, and work productivity. Even this very conservative approach finds RLS in this cohort to be common, under-diagnosed, and carried a significant personal and social burden. PMID- 21322023 TI - The use of Fogs' test to assess associated movements in Parkinsonism, dystonia, and controls. AB - The Fogs' test elicits non-homologous associated movements which reflect underlying pathology or immaturity of the CNS, but has not been thoroughly studied. We filmed participants performing a modified Fogs' test and developed a reliable scoring system for the associated movements. We assessed scores in healthy controls of all ages and compared scores in dystonia and parkinsonism to age similar controls. Associated movements were marked in children, lessened as they matured into adults, and then increased in old age. Associated movements were marked in dystonia but not in parkinsonism. Our scoring system showed robust inter- and intra-rater reliability. The Fogs' test is a reliable addition to the clinical examination that can be used to screen for both normal and abnormal neurological status. We suggest a potential neural pathway via cervical lumbosacral connections within the spinal cord which are modulated by propriospinal and cerebral input. PMID- 21322024 TI - The number of CAG repeats within the normal allele does not influence the age of onset in Huntington's disease. AB - Huntington's disease (HD) is caused by the expansion of the number of CAG repeats on the chromosome 4p16.3, which results in elongated glutamine tract of huntingtin. The purpose of this work was to examine the interaction between the normal and mutant alleles of this gene and their effect on the clinical onset of HD. We hypothesized that in patients with identical number of CAG repeats within the mutant allele, the age of onset of HD is influenced by the number of CAG repeats within the normal allele. We analyzed the relations between the number of CAG repeats within the normal and mutant alleles, the age at HD onset, and the character of initial symptoms in 468 patients with clinically expressed HD. Although the Cox regression coefficient of 0.15 was significant (P < 0.0001), the regression model explained only 28% of the variance of the age at onset related to the effect of the number of CAG repeats within normal allele. Within the groups of patients with the same number of CAG repeats of the mutant allele, number of CAG repeats of the normal allele was found uncorrelated to the age at onset. Furthermore, when analyzing subgroups of patients with the same allelic composition on both alleles, we failed to observe any correlation with the age at the onset. Our analysis gives no corroboration to the idea of a normal allele having a share in the modification of the age at HD onset. We believe that with the current state of knowledge it is not possible to devise a mathematical model for HD onset prediction because too many entirely unknown modifying factors are still involved. PMID- 21322025 TI - Silent saliva aspiration in Parkinson's disease. AB - BACKGROUND: Silent laryngeal penetration and silent aspiration (SLP/SA) are common manifestations in Parkinson's disease (PD) patients and are frequently associated with dysphagia. However, little is known about saliva aspiration in this population. OBJECTIVE: We investigated the frequency and characteristics of saliva SLP/SA in PD patients with daily drooling (Group A) and in individuals without PD or daily drooling (Group B). METHOD: Both groups were evaluated by fiberoptic endoscopic evaluation of swallowing (FEES) after dyeing the oral cavity with blue dye. The oropharynx was assessed for the presence of the stasis of saliva, and sensitivity was tested by direct tactile stimuli. RESULTS: PD patients (n = 28) and controls (n = 18) were evaluated. We observed silent aspiration of saliva in 10.7% and silent laryngeal penetration of saliva near the vocal folds in 28.6% of Group A; however, none of these events was observed in Group B. Sensitivity in the epiglottis and posterior wall of the hypopharynx was decreased in 89.2% of Group A and in 33.3% of Group B, whereas in the aryepiglottic folds and interarytenoid area, a decrease in sensitivity was observed in 92.8% and in 44.4% of Groups A and B, respectively. CONCLUSION: Silent aspiration and laryngeal penetration of saliva are common features in PD patients with daily drooling. The presence of hypoesthesia of the laryngeal structures and the lack of protective reflexes in such patients may play a major role in the mechanisms of SLP/SA. PMID- 21322026 TI - D216H polymorphism within TOR1A does not affect penetrance in DRD and is not a general modifier in primary dystonia. PMID- 21322027 TI - Self estimated quality of life in monogenetic Parkinson's disease. PMID- 21322029 TI - Neuropsychiatric symptoms in Parkinson's disease. PMID- 21322030 TI - Kin relationship of caregivers and people with dementia: stress and response to intervention. AB - OBJECTIVE: This study examined the effects of kin relationship on response to use of adult day services (ADS) on feelings of overload, depressive symptoms, and positive affect for family caregivers of people with dementia. METHODS: The sample consisted of 341 participants drawn from two studies of ADS. The studies used a quasi-experimental design, comparing family caregivers enrolling their care receiver with dementia in an ADS program to a control group not using ADS. Using multilevel model analysis, we examined the main and interaction effects of kin relationship (wife vs. daughters/daughters-in-law), intervention (ADS vs. non ADS users), and time (baseline, 3 months, and 12 months) on overload, depressive symptoms, and positive affect. RESULTS: Kin relationship affected the response to intervention but in a somewhat different way for each outcome measure. For depressive symptoms, both wives and daughters using ADS had lower scores over time compared to controls. Both wives and daughters using ADS had lower feelings of overload over time, but daughters had a greater decline and wives' scores on this measure dropped only to the level found among controls. For positive affect, wives using ADS showed a considerable decline over time. CONCLUSIONS: These findings suggest that kin relationship is an important moderator of caregivers' response to intervention and warrant more attention both in the design and evaluation of interventions with family caregivers. PMID- 21322031 TI - Dynamic communication between androgen and coactivator: mutually induced conformational perturbations in androgen receptor ligand-binding domain. AB - The transcriptional activity of androgen receptor (AR) is regulated by the sequential binding of various ligands (e.g., dihydrotestosterone, DHT) and coactivators (e.g., SRC/p160) to the AR ligand binding domain (LBD) (Askew et al., J Biol Chem 2007; 282:25801-25816, Lee and Chang, Cell Mol Life Sci 2003;60:1613-1622). However, the synergism between the recruitments of coactivator (SRC 2-3) and ligand (such as DHT) to AR at atomic level remains unclear. Thus, in this work, extensive explicit-solvent molecular dynamics (MD) simulations on four independent trajectories, that is, AR-apo (unbound), DHT.AR, AR.SRC, and DHT.AR.SRC, are performed to investigate the potential communications between the two events in the AR transcriptional process. The MD simulations, analysis of the dynamical cross-correlation maps, comparisons of the binding energy, and thermodynamic analysis reveal a definite structural and functional link between Activation Function-2 (AF-2) surface and the ligand binding site influenced by the binding of ligand and coactivator to the LBD: (I) The DHT binding can increase the LBD volume to 753.0 A3 from its compact ligand-free state (372.1 A3), resulting in a group of helices (1, 2, 8, and loop 20) to move outward and exert added traction on the ligand binding pathway, which subsequently leads to rearrange the AF-2 region to well recruit the SRC; (II) Similarly, the SRC recruitment is also found to facilitate the ligand binding through transmitting a concomitant push-pull effort from the AF-2 surface to the DHT binding site, leading to the opening of entrance to the LBD formed by Val684, Met745, and Arg752, increase of the volume of binding pocket (896.4 A3) and stabilization of the dynamic structure of the LBD. These results, in a dynamic form, initially show a bidirectional structural and functional relay between the bound DHT and SRC that establishes AR functional potency. PMID- 21322032 TI - On the evolutionary origin of the chaperonins. AB - An analysis of the apical domain of the Group-I and Group-II chaperonins shows that they have structural similarities to two different protein folds: a "swivel domain" phosphotransferase and a thioredoxin-like peroxiredoxin. There is no significant sequence similarity that supports either similarity and the degree of similarity based on structure is comparable but weak for both relationships. Based on possible evolutionary transitions, we deduced that a phosphotransferase origin would require both a large insertion and deletion of structure whereas a peroxiredoxin origin requires only a peripheral rearrangement, similar to an internal domain-swap. We postulate that this change could have been triggered by the insertion of a peroxiredoxin into the ATPase domain that led to the modern chaperonin domain arrangement. The peroxidoxin fold is the most highly embellished member of the thioredoxin super-family and the insertion event may have "overloaded" the core, leading to a rearrangement. A peroxiredoxin origin for the domain also provides a functional explanation, as the peroxiredoxins can act as chaperones when they adopt a multimeric ring complex, similar to the chaperonin subunit configuration. In addition, several of the GroEL apical domain hydrophobic residues which interact with the unfolded protein are located in a position that corresponds to the protein substrate binding region of the peroxiredoxin fold. We suggest that the origin of the ur-chaperonin from a thioredoxin/peroxiredoxin fold might also account for the number of thioredoxin fold containing proteins that interact with chaperonins, such as tubulin and phosducin-like proteins. PMID- 21322033 TI - Is there nascent structure in the intrinsically disordered region of troponin I? AB - In striated muscle, the binding of calcium to troponin C (TnC) results in the removal of the C-terminal region of the inhibitory protein troponin I (TnI) from actin. While structural studies of the muscle system have been successful in determining the overall organization of most of the components involved in force generation at the atomic level, the structure and dynamics of the C-terminal region of TnI remains controversial. This domain of TnI is highly flexible, and it has been proposed that this intrinsically disordered region (IDR) regulates contraction via a "fly-casting" mechanism. Different structures have been presented for this region using different methodologies: a single alpha-helix, a "mobile domain" containing a small beta-sheet, an unstructured region, and a two helix segment. To investigate whether this IDR has in fact any nascent structure, we have constructed a skeletal TnC-TnI chimera that contains the N-domain of TnC (1-90), a short linker (GGAGG), and the C-terminal region of TnI (97-182) and have acquired 15N NMR relaxation data for this chimera. We compare the experimental relaxation parameters with those calculated from molecular dynamic simulations using four models based upon the structural studies. Our experimental results suggest that the C-terminal region of TnI does not contain any defined secondary structure, supporting the "fly-casting" mechanism. We interpret the presence of a "plateau" in the 15N NMR relaxation data as being an intrinsic property of IDRs. We also identified a more rigid adjacent region of TnI that has implications for muscle performance under ischemic conditions. PMID- 21322034 TI - Identification of CCR2-binding features in Cytl1 by a CCL2-like chemokine model. AB - Chemokines are small secreted proteins that play an important role in immune responses and have also been shown to be involved in cartilage development and contributing to pathogenesis of a variety of diseases. They present a conserved 3D structure, so-called IL8-like chemokine fold, which is supported by conserved cysteines forming intra-molecular disulfide bonds. These cysteine sequence motifs have often been used to find new chemokine family members by sequence-based database searches. However, it has been shown that different patterns can provide disulfide bonds fitting into an IL8-like architecture, which has been the key to identify new remote homologues of the IL8-like chemokine family. We report a structural-functional characterization of cytokine-like protein 1 (Cytl1) by a combination of different computational structure-based techniques. Previous studies based on sequence analysis and secondary structure predictions reported that Cytl1 might adopt a 4-helical cytokine fold. However, our detailed molecular modeling studies and structure-based functional analysis strongly suggest that Cytl1 is more likely to adopt an IL8-like chemokine fold, in particular similar to CCL2 (monocyte chemoattractant protein 1, MCP-1). Moreover, we identify in a CCL2-like 3D model of Cytl1 the necessary reported features to signal through the chemokine receptor CCR2. Those discovered structural features of Cytl1 as CCL2 like chemokine, together with the fact that both, CCL2 and Cytl1, are known to be involved in cartilage development and pathogenesis of osteoarthritis and rheumatoid arthritis, make us hypothesize that Cytl1 could be a structurally and functionally related analog of CCL2 signaling through the chemokine receptor CCR2. PMID- 21322035 TI - Extracardiac coronary arterial anastomoses. AB - The collateral arterial circulation of the heart has been extensively studied. However, less attention has been paid to extracardiac anastomoses, which may also be of significant clinical importance. In this review, we will describe the most common types of these anastomoses, which include bronchial to coronary arteries and internal thoracic to coronary arteries. In a much lesser degree, anastomoses between coronary arteries and pericardiacophrenic branches of the internal thoracic arteries, anterior mediastinal arteries, intercostal arteries, and esophageal arterial branches have also been described. Knowledge of the likely morphology and function of the anastomoses, therefore, could prove helpful in the clinical evaluation of patients with myocardial ischemia, particularly when selecting candidates for myocardial revascularization. PMID- 21322036 TI - Functional anatomy of the mandibular nerve: consequences of nerve injury and entrapment. AB - Various anatomic structures including bone, muscle, or fibrous bands may entrap and potentially compress branches of the mandibular nerve (MN). The infratemporal fossa is a common location for MN compression and one of the most difficult regions of the skull to access surgically. Other potential sites for entrapment of the MN and its branches include, a totally or partially ossified pterygospinous or pterygoalar ligament, a large lamina of the lateral plate of the pterygoid process, the medial fibers of the lower belly of the lateral pterygoid muscle and the inner fibers of the medial pterygoid muscle. The clinical consequences of MN entrapment are dependent upon which branches are compressed. Compression of the MN motor branches can lead to paresis or weakness in the innervated muscles, whereas compression of the sensory branches can provoke neuralgia or paresthesia. Compression of one of the major branches of the MN, the lingual nerve (LN), is associated with numbness, hypoesthesia, or even anesthesia of the tongue, loss of taste in the anterior two thirds of the tongue, anesthesia of the lingual gums, pain, and speech articulation disorders. The aim of this article is to review, the anatomy of the MN and its major branches with relation to their vulnerability to entrapment. Because the LN expresses an increased vulnerability to entrapment neuropathies as a result of its anatomical location, frequent variations, as well as from irregular osseous, fibrous, or muscular irregularities in the region of the infratemporal fossa, particular emphasis is placed on the LN. PMID- 21322037 TI - Surgery in early Jewish history. AB - The Hebrew writings in early history are dedicated primarily to the explanations and elucidations of Jewish law. In the context of such laws, several medical and anatomical references are made that provide some clues to the medical practices of the day. In particular, this article serves to compile references made to surgical interventions within these texts. Particular attention is paid to the possible use of anesthetics, the environment and equipment utilized in surgery, as well as the indication of knowledge of infection and hygienic practices. An understanding of human morphology was necessary for many of these surgical practices. PMID- 21322038 TI - A comparison of embalming fluids for use in surgical workshops. AB - There is a growing need to learn surgical skills without risk to patients. One of the major determining factors on the suitability of specimens for surgical workshops is the fluid used for embalming. This study sought to compare three different arterial embalming preparations to a single fresh cadaver. Eleven cadavers embalmed using Graz (single cadaver), Dodge (four cadavers) and Genelyn (five cadavers) preparations were compared using four criteria; joint flexibility measured with a goniometer, tissue pliability rated on standardized videos of instrument handling, tissue color analyzed on standardized photographs and resistance to fungal growth identified by inoculation and observation of tissue blocks. The cadaver embalmed according to the Graz method had joint flexibility comparable to fresh tissue while the Dodge and Genelyn cadavers were less flexible. Tissue pliability was significantly affected by the Dodge and Genelyn methods while the Graz method tissue remained most like fresh tissue. The Graz method cadaver had color that was most akin to fresh tissue and the Dodge method cadavers were relatively more like fresh than the Genelyn. The Dodge and Genelyn method had quite similar fungicidal properties (3/11 Dodge and 2/9 Genelyn embalmed cadavers susceptible) while the Graz method cadaver did not grow mould. Variation exists between cadavers; however, the Graz method produced a cadaver with more flexible joints, better tissue quality and muscle color closest to the fresh specimen. The Dodge and Genelyn methods are similar with the exception of tissue color where the Dodge method was more similar to fresh tissue. PMID- 21322039 TI - Brachialis insertion measurement: an anatomic cadaver study for plate fixation of the coronoid process fracture. AB - Detailed assessment of the proximity of the brachialis insertion to the anterior bundle of the medial collateral ligament and its potential influence on plate application for the treatment of the coronoid process fracture has not been reported previously. The purpose of this study was to describe the anatomic interval used for coronoid plate and the measurement of the brachialis insertion to confirm partial release of the insertion site may be required during plate fixation of the coronoid process fracture. After eight fresh-frozen cadaveric elbows were dissected, the interval between the brachialis insertion and the attachment of the anterior bundle of medial collateral ligament was identified, and the gross morphological characteristics of the brachialis insertion were also recorded. The average width of the interval was 4.14 mm, and the brachialis was found to be consisted of a superficial head and a deep head, and insertion of the deep head was composed of three units: a medial aponeurosis, a lateral aponeurosis, and muscle fibers inserted directly into the ulna. The interval between the brachialis insertion and the attachment of the anterior bundle of medial collateral ligament can be used for placement of the coronoid plate regardless of the plate type. Partial release of the brachialis insertion is necessary during the operation, while the width of the plate is larger than that of the interval. This study may provide some useful information on plate application for the treatment of the coronoid process fracture. PMID- 21322040 TI - Hamate-pisiform coalition: morphology, clinical significance, and a simplified classification scheme for carpal coalition. AB - Hamate-pisiform coalition is characterized by the abnormal union of the pisiform bone and hamulus of the hamate. Because most reported cases are isolated, and literature on the subject is sparse, relatively little is known about this condition and its clinical significance. The purpose of this report is to discuss the occurrence, morphology, and frequency of hamate-pisiform coalition identified in a skeletal sample of native South Africans, and to conduct a metaanalysis of all known cases in order to clarify the sex distribution, laterality, form, and clinical significance of this condition. Five new cases (three male, two female) of hamate-pisiform coalition were identified in 527 native South Africans. Results indicate that hamate-pisiform coalition is infrequent (0.76%) but may be more likely encountered in individuals of African ancestry. Morphologically, non osseous examples ranged in appearance from minor expressions involving pitting of an expanded hamulus base, to a variably pitted articulation between an elongated pisiform and hamulus. Osseous union between the two bones tends to extend beyond the hamulus base to adjacent areas of the hamate. Cases involving osseous union appear predisposed to fracture while ulnar neuropathy is significantly more frequent in individuals exhibiting non-osseous coalition. As both non-osseous and osseous cases can have clinical significance, awareness of the variable manifestations of this condition is necessary for hand specialists. A simplified classification system is suggested to more consistently characterize carpal coalitions. PMID- 21322041 TI - Deep palmar communications between the ulnar and median nerves. AB - Innervation of the hand is supplied via the radial, median, and ulnar nerves. A common border of sensory distribution between the ulnar and median nerves is along the fourth digit. However, this sensory distribution may be affected by communication between these two nerves. Among the known communications between the median and ulnar nerves, the deep anastomotic branch in the hand is the least described and rarely illustrated in the literature. This study aims to provide data on the prevalence of a deep communicating branch via cadaveric dissection. We examined 50 hands taken from 25 adult cadavers. Communicating branches were found in 16% of the hands examined, with rami occurring bilaterally in two specimens. By describing the origin and pathway of this communicating branch, we hope to provide surgeons and clinicians with knowledge that may help avoid iatrogenic injuries. PMID- 21322042 TI - A cadaver study to determine the minimum volume of methylene blue or black naphthol required to completely color the nerves relevant for anesthesia during breast surgery. AB - Regional anesthesia for breast surgery may require a large amount of local anesthetic solution to provide an adequate blockade of all relevant structures. The purpose of this study was to determine the minimal volume of fluid required to anesthetize all nerves to adequately provide anesthesia for breast surgery. This is an open randomized study. Cadavers were embalmed using Thiel's technique and were injected with different volumes of 0.2% methylene blue or 0.2% black naphthol for a superficial cervical plexus block (2, 5, 10, or 15 mL), an interscalene block (5, 10, 15, or 20 mL), paravertebral blocks from C(8) to T(6), and intercostal nerve blocks at 8 cm from the midline (2 or 3 mL) under ultrasound-guided or assisted techniques. The following minimal volumes of fluid were required for complete coloration of the nerves: 2 mL for the supraclavicular nerves; 20 mL for the nerve roots from C(5) to C(7), inclusive, if intraneural injection was avoided; 3 mL per root for the nerve roots from C(8) to T(6), inclusive, for a paravertebral block; and 2 mL per nerve for intercostal nerve blocks at T(4) and lower. With 20 mL of solution at the interscalene level, the roots of C(3) and C(4) were also colored; therefore, a separate injection for the supraclavicular nerves was unnecessary. We conclude that regional anesthesia for complex breast surgery can be achieved with a volume of local anesthetic as low as 41 mL. PMID- 21322043 TI - Sacralization is not associated with elongated cervical costal process and cervical rib. AB - Cervical rib/elongated costal process of the seventh cervical vertebra and sacralization of a lumbar vertebra are associated with clinical problems neurological, vascular, and obstetrical. A previous study reported an association between these morphologies, and suggested that clinicians use presence of one trait to predict presence of the other. This study tested three hypotheses from this association: costal process length among individuals with sacralization differs from that among individuals without sacralization for: (1) only the seventh cervical vertebra, (2) only transitional presacral vertebrae-seventh cervical, twelfth thoracic, and fifth lumbar, and (3) presacral vertebrae in general. Skeletons of 961 individuals between ages 20 and 49 years from the United States were surveyed for sacralization. Costal process length was measured on 100 individuals with sacralization and 184 without sacralization for cervical vertebrae 3 to 7, thoracic vertebrae 11 and 12, and all lumbar vertebrae. Cervical rib was evaluated for 102 individuals with sacralization and 472 without sacralization. Results showed that 11% (105 of 961) of individuals have sacralization. Compared to individuals without sacralization, those with sacralization: (1) have significantly longer costal process for the last lumbar vertebra, but are nonsignificantly different for costal process lengths of other vertebrae, (2) are nonsignificantly different in prevalence of cervical rib-2.9% with sacralization and 0.4% without sacralization, and (3) are significantly more likely to have an extra presacral vertebra. Clinically, results suggest that sacralization is not a predicate for either cervical rib or elongated costal process of the seventh cervical vertebra. PMID- 21322044 TI - Metric study of Egyptian sacrum for lumbo-sacral fixation procedures. AB - Lumbo-sacral fixation for the management of lumbo-sacral instability includes insertion of screws to the sacrum, most commonly into the posterior aspect of the pedicles of the first sacralvertebra. This study was carried out to determine the normal anatomical parameters of the Egyptian sacrum, particularly of the first sacral vertebra and its pedicles, to find the safest approach for sacral screw placement in lumbo-sacral fixation procedures, and to describe racial characteristics, if any. In this study, 45 adult Egyptian dry sacra of unknown sex were used. Eleven sacral parameters were measured using the Vernier sliding caliper which is accurate to 0.1 millimeter. In this study, the sacrum showed a mean height of 11.43 +/- 0.88 centimeters a mean width of 10.39 +/- 0.91 centimeters with a mean sacral index of 90.82 +/- 1.80 %. The first sacral pedicle had a mean anterior height of 1.83 +/- 0.49 centimeters, a mean depth of 2.99 +/- 0.53 centimeters and a mean posterior height of 2.38 +/- 0.50 centimeters. A medialtrajectory path (representing an anteromedially-oriented first sacral pedicle screw) starting from the infero-lateral border of the S1 facet to the sacral promontory in the middle line was 5.23 +/- 0.52 cm. The findings of the present study could provide accurate and specific parameters of the sacrum among Egyptians that could enhance the safety of insertion of sacral screws during lumbo-sacral fixation procedures upon Egyptian patients. PMID- 21322045 TI - The morphometry of patella and patellar ligament during the fetal period. AB - This study aims to determine the development and morphology of the patella and patellar tendon and to obtain morphometric data about these structures during the fetal period. One hundred five human fetuses (55 males and 50 females) aged 9-40 weeks were used in this study. Fetuses were divided into four groups between gestational weeks; Group I (9-12 weeks), Group II (13-25 weeks), Group III (26-37 weeks), and Group IV (38-40 weeks). The patella and patellar ligament were exposed via anatomical dissection; the dimensions (length, width, thickness) and the width of the lateral and medial articular surfaces of the patella, and the length and width of the patellar ligament, were measured using a Vernier's caliper. No significant differences were observed between genders or sides for any of the parameters (P > 0.05), and a significant correlation was found between gestational age and all parameters (P < 0.001). All parameters of the patella and patellar ligament were found to be different statistically between trimesters (P < 0.05). This study reveals the development, morphological changes, and the morphometric measurements of the patella and patellar ligament during the fetal period. We hope that the present results can be useful for future studies. PMID- 21322046 TI - Anatomic localization of motor entry point of superficial peroneal nerve to peroneus longus and brevis muscles. AB - This study examined the anatomic location of the motor entry point (MEP) and branching point at the proximal and distal points of the tendon of the peroneal muscle by visual observation. Forty-three fresh legs of 25 adult bodies which had been donated to science were investigated in this study. The mean length of the reference line between the most proximal point of the head of the fibula (PHF) and the most distal point of the malleolus of the fibula (DMF) was 33.4 +/- 2.5 cm. The MEPs of the peroneus longus (PL) and peroneus brevis (PB) gathered from 20 to 40% (7.0-13.0 cm) and 40 to 60%, respectively. The branching point where the nerve was divided to innervate the PL and PB was 10% and 28% from the PHF, respectively. These anatomic results suggest appropriate areas where to inject phenol or other agents for a MEP block in the case of a spastic lower extremity as well as guidelines for an electromyography conduction test. PMID- 21322047 TI - The use of plastinated prosections for teaching anatomy--the view of medical students on the value of this learning resource. AB - Over the past decade, the role of anatomical teaching in the undergraduate medical curriculum has changed considerably. At some medical schools, active dissection of cadaveric specimens is gradually being replaced by prosection-based methods and other resources such as e-learning. Warwick Medical School has recently obtained a large collection of plastinated prosections, which replace wet cadaveric specimens in undergraduate anatomy teaching. The aim of this study was to examine students' views on the use of plastinated prosections for their anatomical learning. A mixed method approach was employed using a questionnaire and focus group for data collection. The questionnaire was completed by 125 first year medical students (response rate 68%). The majority of students (94%) rated plastinated prosections as a valuable resource for their anatomical learning. Various features of the specimens were highlighted, such as the detailed view of relevant anatomy, appreciation of relations between structures, and visualization of anatomy in real life. However, learning on plastinated prosections was perceived to be compromised because of limitations in terms of tactile and emotional experience. We conclude that plastinated prosections are an adequate resource for the early stages of undergraduate training, but that the learning experience may be further enhanced by providing opportunity for the study of wet cadaveric material. PMID- 21322048 TI - Fluoroscopic angiography in the gross anatomy dissection laboratory: visualizing the aortic arch and its branches in a cadaver. AB - We present fluoroscopic images of the aortic arch and its branches obtained in a first year medical gross anatomy teaching laboratory after an aberrant right subclavian artery was discovered during dissection. The aortic arch and its branches in the cadaver were filled with contrast medium in molten agar. After the agar solidified, a portable fluoroscope was used to obtain radiographic images. These post-mortem images were then compared with computed tomography images obtained while the individual was living. The embryology, prevalence, and clinical findings of this arterial variation are reviewed, and the importance of recognizing the presence of an aberrant right subclavian artery before performing various procedures is discussed. This exercise gave students the unique opportunity to compare the three-dimensional anatomy seen in the dissection laboratory with the two-dimensional presentation of that same anatomy in the radiographic images that they will see in clinical practice. PMID- 21322050 TI - A rare case of a complete left inferior vena cava associated with the symptoms of Dunbar syndrome. AB - We report a case of an 82-year-old female with an anomalous left inferior vena cava. The left inferior vena cava ascends parallel and to the left of the descending abdominal aorta. At the level of the celiac trunk, the inferior vena cava courses anteriorly and to the right to reach the posterior surface of the liver. The patient also suffers from chronic mild postprandial abdominal pain. It is possible that position of inferior vena cava anterior to the aorta, at the level of the celiac trunk, may lead to intermittent celiac artery compression syndrome (Dunbar syndrome). PMID- 21322049 TI - The third time is the charm--anastomosis between the celiac trunk and the left colic artery. AB - An atypical case of abdominal vasculature, found in a 58-year-old woman is presented. The multidetector computed tomography angiogram revealed a large tortuous anastomotic vessel between the stem of the celiac trunk and the left colic artery, supplying branches for the left colon and pancreatic body and tail. We propose a simple embryological explanation for the development of this aberrant artery--the longitudinal ventral anastomosis, which connects the precursors of principal visceral arteries in a loop-like manner, loses its direct communication with the superior mesenteric artery but maintains its continuity above and below this level. This variation could pose a problem for radiological interpretation and affect surgical approaches to the aorta, left colon, and the pancreas. PMID- 21322051 TI - A left testicular artery arising from a middle mesenteric artery. PMID- 21322052 TI - The MRI appearance and importance of the "very" terminal branches of the recurrent articular branch in fibular intraneural ganglion cysts. PMID- 21322053 TI - Abductor digiti minimi: why is the name the same for both hand and foot muscles? PMID- 21322055 TI - Isolation, kinetic analysis, and structural characterization of an antibody targeting the Bacillus anthracis major spore surface protein BclA. AB - One method of laboratory- or field-based testing for anthrax is detection of Bacillus anthracis spores by high-affinity, high specificity binding reagents. From a pool of monoclonal antibodies, we selected one such candidate (A4D11) with high affinity for tBclA, a truncated version of the B. anthracis exosporium protein BclA. Kinetic analysis utilising both standard and kinetic titration on a Biacore biosensor indicated antibody affinities in the 300 pM range for recombinant tBclA, and the A4D11 antibody was also re-formatted into scFv configuration with no loss of affinity. However, assays against B. anthracis and related Bacilli species showed limited binding of intact spores as well as significant cross-reactivity between species. These results were rationalized by determination of the three-dimensional crystallographic structure of the scFv tBclA complex. A4D11 binds the side of the tBclA trimer, contacting a face of the antigen normally packed against adjacent trimers within the exosporium structure; this inter-spore interface is highly conserved between Bacilli species. Our results indicate the difficulty of generating a high-affinity antibody to differentiate between the highly conserved spore structures of closely related species, but suggest the possibility of future structure-based antibody design for this difficult target. PMID- 21322056 TI - Free-energy landscape of the GB1 hairpin in all-atom explicit solvent simulations with different force fields: Similarities and differences. AB - Although it is now possible to fold peptides and miniproteins in molecular dynamics simulations, it is well appreciated that force fields are not all transferable to different proteins. Here, we investigate the influence of the protein force field and the solvent model on the folding energy landscape of a prototypical two-state folder, the GB1 hairpin. We use extensive replica-exchange molecular dynamics simulations to characterize the free-energy surface as a function of temperature. Most of these force fields appear similar at a global level, giving a fraction folded at 300 K between 0.2 and 0.8 in all cases, which is a difference in stability of 2.8 kT, and are generally consistent with experimental data at this temperature. The most significant differences appear in the unfolded state, where there are different residual secondary structures which are populated, and the overall dimensions of the unfolded states, which in most of the force fields are too collapsed relative to experimental Forster Resonance Energy Transfer (FRET) data. PMID- 21322057 TI - Fibroblast growth factor 2 regulates astrocyte differentiation in a region specific manner in the hindbrain. AB - Fibroblast growth factor (FGF)-2 is known to have important pleiotropic effects in neuronal and glial cells during various physiological and pathological events. To investigate the role of endogenous FGF-2 in the differentiation of astrocytes, we studied the expression of glial fibrillary acidic protein (GFAP) in the hindbrain of the FGF-2 null mouse. GFAP was drastically decreased in a region specific manner in the hindbrain of the adult and developing FGF-2 null mouse without an associated change in the expression of alternate markers for astrocytes. The deficit was evident in the astrocytes of pontine and medullary gray matter but not in the white matter. The astrocytes of the gray and white matter were seen to express FGF-2 and FGF receptors in a distinct pattern. The methylation of histone H3 at lysine 4 residue (H3K4me2) associated with the STAT (signal transducer and activator of transcription)-binding site of the GFAP promoter was significantly decreased in the gray matter of the FGF-2 null mouse, suggesting a role for FGF-2 in the epigenetic regulation of astrocyte differentiation in vivo. These observations underscore the importance of FGF-2 in astroglial differentiation in the hindbrain and the heterogeneity of astrocytes in their requirement for FGF-2 as a differentiation inducing signal. PMID- 21322059 TI - The pattern of arrangement of the lumbrical muscles in an African population. AB - The pattern of arrangement of the lumbrical muscles in the hand of an African population was studied. Sixty-four upper limb specimen from 32 male cadavers between the ages 18 and 40 were obtained from the Department of Anatomy, University of Calabar, Nigeria were used. Ethical approval was granted by the Ethics Committee of the University, and each of the limbs of the cadavers was labeled. Observations were grouped as A, B, C, D, and E and their incidence calculated using simple percentages. Group A constituted 50% and represented the standard pattern. In this group, the first and second bellies of lumbrical muscles arose each from the radial sides of the corresponding flexor digitorum profundus (FDP) tendons, while the third and fourth bellies of the lumbrical muscles arose each from the contiguous sides of the FDP tendons of the middle and ring fingers, and the ring and little fingers, respectively. All the bellies were inserted to their corresponding sides in the radial part of the dorsal digital expansion. Groups B and E constituting 12.5 and 6.25%, respectively, presented single origins and insertions in all the four bellies of the lumbrical muscles. Groups C and D constituting 18.75 and 12.5%, respectively, showed double origins in the third belly of the lumbrical muscle, with the first, second, and fourth having single origins. In conclusion, our study showed variations already reported, and peculiar pattern of lumbrical muscle arrangement in a single hand. Therefore, this study is of anatomical, anthropological, and clinical importance. PMID- 21322060 TI - Meckel's diverticulum: a review. AB - Meckel's diverticulum is the most prevalent congenital abnormality of the gastrointestinal tract. This anomaly is due to the incomplete obliteration of the omphalomesenteric duct during the 7th week of gestation and is classically located 2 feet proximal to the ileocecal valve. Variations of this congenital malformation have been recorded based on location, size, and form. While most of the population may be asymptomatic, clinical manifestation, including gastrointestinal bleed and intestinal obstruction, can emerge. Despite the frequency of Meckel's diverticulum, it is commonly misdiagnosed due to its mimicry of appendicitis. This article aimed to review this derailment of embryological development. PMID- 21322058 TI - Mouse schwann cells need both NRG1 and cyclic AMP to myelinate. AB - Genetically modified mice have been a major source of information about the molecular control of Schwann-cell myelin formation, and the role of beta neuregulin 1 (NRG1) in this process in vivo. In vitro, on the other hand, Schwann cells from rats have been used in most analyses of the signaling pathways involved in myelination. To correlate more effectively in vivo and in vitro data, we used purified cultures of mouse Schwann cells in addition to rat Schwann cells to examine two important myelin-related signals, cyclic adenosine monophosphate (cAMP), and NRG1 and to determine whether they interact to control myelin differentiation. We find that in mouse Schwann cells, neither cAMP nor NRG1, when used separately, induced markers of myelin differentiation. When combined, however, they induced strong protein expression of the myelin markers, Krox-20 and P(0) . Importantly, the level of cAMP signaling was crucial in switching NRG1 from a proliferative signal to a myelin differentiation signal. Also in cultured rat Schwann cells, NRG1 promoted cAMP-induced Krox-20 and P(0) expression. Finally, we found that cAMP/NRG1-induced Schwann-cell differentiation required the activity of the cAMP response element binding family of transcription factors in both mouse and rat cells. These observations reconcile observations in vivo and on neuron-Schwann-cell cultures with studies on purified Schwann cells. They demonstrate unambiguously the promyelin effects of NRG1 in purified cells, and they show that the cAMP pathway determines whether NRG1 drives proliferation or induces myelin differentiation. PMID- 21322061 TI - Obturator hernia: anatomy, embryology, diagnosis, and treatment. AB - An obturator hernia is an infrequent but significant cause of intestinal obstruction. The incidence of obturator hernias is between 0.05 and 1.4% of all hernias. The mortality rate can be as high as 70% when acutely incarcerated due to the difficulty in diagnosis and delay in surgical treatment Three progressive stages of obturator herniation have been classified and can be one of three different varieties depending on the pathway the herniated sac follows. Knowledge of the anatomy and pathogenesis of obturator herniation is essential in diagnosis and treatment. The most common clinical presentation is intestinal obstruction (90%) and this is often seen in elderly, emaciated, multiparous women with predisposing conditions. Other classic signs, though not always present include obturator neuralgia, the Howship-Romberg sign and the Hannington-Kiff sign. Computed tomography scan is the most favored diagnostic imaging method. The abdominal surgical approach is most preferred when a diagnosis is uncertain and laparoscopy should be employed in elective early surgeries. This aim of this article is to review the diagnosis and treatment of obturator hernia by describing the anatomy, embryology, clinical presentation, diagnosis, and management currently in use. Increased awareness and proper management of this condition will result in decreased morbidity and mortality. PMID- 21322062 TI - Aberrant right subclavian artery and fluoroscopy in the dissection laboratory. PMID- 21322063 TI - Rib fracture timing in dynamic belt tests with human cadavers. AB - The purpose of this article is to present data from dynamic belt loading tests on the thorax of human cadavers where the exact timing of all rib fractures is known. To quantify rib fracture timing, a total of 47 strain gages were placed throughout the thorax of two human cadavers (one male, one female). To simulate thoracic loading observed in a severe car crash, a custom table-top belt loading device was developed. The belt loading pulse was configured to result in approximately 40% chest compression during a 150 ms load and unload cycle. The time histories of each strain gage were analyzed to determine the time of each rib fracture which was then directly compared with the reaction loads and chest displacements at that exact time, thereby creating a noncensored data set. In both cadavers, all rib fractures occurred within the first 35% compression of the thorax. As a general trend, fractures on the left side of the thorax, where the passenger belt passed over the abdomen, occurred first followed by fractures to the upper ribs on the right side of the thorax. By utilizing this technique, the exact timing of each injury level can be characterized relative to the mechanical parameters. For example, using rib fractures as the parameter for Abbreviated Injury Scale (AIS) scores in the female test, it was shown that AIS 1 injury occurred at a chest compression of 21.1%, AIS 2 at 21.6%, AIS 3 at 22.0%, and AIS 4 at 33.3%. PMID- 21322064 TI - The role of the anatomy of the sigmoid colon in developing sigmoid volvulus: a case-control study. AB - Sigmoid volvulus is a common condition throughout much of the world. To this date, there are no adequately controlled clinical trials examining the role of anatomy in sigmoid volvulus. Therefore, the objective of this study was to determine if the anatomic dimensions of the sigmoid colon differ in sigmoid volvulus compared to controls. This prospective case-control study was conducted at Kamuzu Central Hospital, Lilongwe, Malawi. Cases included individuals 18 years or older with surgically confirmed sigmoid volvulus, while controls included individuals undergoing surgery for reasons unrelated to the descending or sigmoid colon, or rectum. Intraoperative measurements of the sigmoid colon were taken, including mesosigmoid root width and mesosigmoid length. A total of 26 cases and 12 controls were enrolled. When compared to controls, the mesosigmoid of cases had a greater length and maximal width; however, mesosigmoid root width was similar between groups. These findings support the assertion that sigmoid volvulus is due to a long and wide mesosigmoid that rotates on a constant mesosigmoid root width. This is the first adequately controlled trial examining anatomy in sigmoid volvulus and provides strong evidence that refines prior hypotheses regarding the anatomic basis of sigmoid volvulus. PMID- 21322065 TI - Emerging transparent electrodes based on thin films of carbon nanotubes, graphene, and metallic nanostructures. AB - Transparent electrodes are a necessary component in many modern devices such as touch screens, LCDs, OLEDs, and solar cells, all of which are growing in demand. Traditionally, this role has been well served by doped metal oxides, the most common of which is indium tin oxide, or ITO. Recently, advances in nano-materials research have opened the door for other transparent conductive materials, each with unique properties. These include CNTs, graphene, metal nanowires, and printable metal grids. This review will explore the materials properties of transparent conductors, covering traditional metal oxides and conductive polymers initially, but with a focus on current developments in nano-material coatings. Electronic, optical, and mechanical properties of each material will be discussed, as well as suitability for various applications. PMID- 21322066 TI - High transfection efficiency of cationic lipids with asymmetric acyl-cholesteryl hydrophobic tails. AB - The ability of a nonviral gene delivery system to overcome extra- and intracellular barriers is a critical issue for the future clinical applications of gene therapy. In recent years much effort has been focused on the development of a variety of DNA carriers, and cationic liposomes have become the most common nonviral gene delivery system. One hundred and eighty novel cationic lipids with asymmetric acyl-cholesteryl hydrophobic tails were synthesized by parallel solid phase chemistry. The liposomes were prepared and gel retardation assays were used to study the binding efficiency between the prepared liposome and the DNA. Transfection efficiencies of the lipids were evaluated against various mammalian cells, such as human embryonic kidney (HEK293), human cervical adenocarcinoma (HeLa), canine osteosarcoma (D17), colorectal adenocarcinoma (COLO 205), and human prostate adenocarcinoma (PC3) cells. The lipids with an acyl portion at the terminal part of the polyamine backbone exhibited higher transfection efficiency than those with the acyl portion as an internal part of the backbone. These compounds also showed higher transfection efficiency and lower cytotoxicity than the commercially available agents, Effectene, DOTAP, and DC-Chol. PMID- 21322067 TI - Phthalocyanine analogues: unexpectedly facile access to non-peripherally substituted octaalkyl tetrabenzotriazaporphyrins, tetrabenzodiazaporphyrins, tetrabenzomonoazaporphyrins and tetrabenzoporphyrins. AB - Controlled syntheses of phthalocyanine/benzoporphyrin hybrid structures have been achieved. We report a simple means for obtaining non-peripherally octaalkyl substituted derivatives of tetrabenzotriazaporphyrin (TBTAP), tetrabenzodiazaporphyrin (TBDAP), tetrabenzomonoazaporphyrin (TBMAP) and tetrabenzoporphyrin (TBP) macrocycles by treating 3,6-dialkyl phthalonitriles with differing amounts of the Grignard reagent MeMgBr. This range of macrocyclic products is not obtained from corresponding reactions of a Grignard reagent with 4-substituted phthalonitriles, reported previously, or reaction of MeMgBr with a 4,5-dialkyl phthalonitrile. Attempts to form a meso-substituted TBTAP from 3,6 dialkyl phthalonitriles by reaction with benzyl and long-chain alkyl Grignard reagents unexpectedly gave only the parent macrocycle unsubstituted at the meso position. The synthetic protocols are by far the most straightforward and convenient means to access these interesting, but scarcely studied, classes of material. The new series of substituted macrocyclic compounds, obtained as the metal-free and magnesium- and copper(II)-metallated derivatives, show trends in the UV/Vis spectra consistent with those predicted elsewhere by Kobayashi. Characterisation of the new families allows further trends to be identified as meso-nitrogen atoms are sequentially replaced by methine bridges, for example, the compounds provide novel examples of macrocyclic structures that show columnar mesophase behaviour. Single-crystal X-ray structure determinations have been obtained for three magnesium-metallated derivatives bearing eight hexyl substituents and constitute the first set of structural data obtained for such a series. PMID- 21322068 TI - Dialkylamino-2,4-dihydroxybenzoic acids as easily synthesized analogues of platensimycin and platencin with comparable antibacterial properties. PMID- 21322069 TI - Photochemical charge separation in closely positioned donor-boron dipyrrin fullerene triads. AB - A series of molecular triads, composed of closely positioned boron dipyrrin fullerene units, covalently linked to either an electron donor (donor(1) acceptor(1)-acceptor(2)-type triads) or an energy donor (antenna-donor(1) acceptor(1)-type triads) was synthesized and photoinduced energy/electron transfer leading to stabilization of the charge-separated state was demonstrated by using femtosecond and nanosecond transient spectroscopic techniques. The structures of the newly synthesized triads were visualized by DFT calculations, whereas the energies of the excited states were determined from spectral and electrochemical studies. In the case of the antenna-donor(1)-acceptor(1)-type triads, excitation of the antenna moiety results in efficient energy transfer to the boron dipyrrin entity. The singlet-excited boron dipyrrin thus generated, undergoes subsequent energy and electron transfer to fullerene to produce a boron dipyrrin radical cation and a fullerene radical anion as charge-separated species. Stabilization of the charge-separated state in these molecular triads was observed to some extent. PMID- 21322070 TI - [Ir(PCy3)2(H)2(H2B-NMe2)]+ as a latent source of aminoborane: probing the role of metal in the dehydrocoupling of H3B?NMe2H and retrodimerisation of [H2BNMe2]2. AB - The Ir(III) fragment {Ir(PCy(3))(2)(H)(2)}(+) has been used to probe the role of the metal centre in the catalytic dehydrocoupling of H(3)B?NMe(2)H (A) to ultimately give dimeric aminoborane [H(2)BNMe(2)](2) (D). Addition of A to [Ir(PCy(3))(2)(H)(2)(H(2))(2)][BAr(F)(4)] (1; Ar(F) = (C(6)H(3)(CF(3))(2)), gives the amine-borane complex [Ir(PCy(3))(2)(H)(2)(H(3)B?NMe(2)H)][BAr(F)(4)] (2 a), which slowly dehydrogenates to afford the aminoborane complex [Ir(PCy(3))(2)(H)(2)(H(2)B-NMe(2))][BAr(F)(4)] (3). DFT calculations have been used to probe the mechanism of dehydrogenation and show a pathway featuring sequential BH activation/H(2) loss/NH activation. Addition of D to 1 results in retrodimerisation of D to afford 3. DFT calculations indicate that this involves metal trapping of the monomer-dimer equilibrium, 2 H(2)BNMe(2) ? [H(2)BNMe(2)](2). Ruthenium and rhodium analogues also promote this reaction. Addition of MeCN to 3 affords [Ir(PCy(3))(2)(H)(2)(NCMe)(2)][BAr(F)(4)] (6) liberating H(2)B-NMe(2) (B), which then dimerises to give D. This is shown to be a second-order process. It also allows on- and off-metal coupling processes to be probed. Addition of MeCN to 3 followed by A gives D with no amine-borane intermediates observed. Addition of A to 3 results in the formation of significant amounts of oligomeric H(3)B?NMe(2)BH(2)?NMe(2)H (C), which ultimately was converted to D. These results indicate that the metal is involved in both the dehydrogenation of A, to give B, and the oligomerisation reaction to afford C. A mechanism is suggested for this latter process. The reactivity of oligomer C with the Ir complexes is also reported. Addition of excess C to 1 promotes its transformation into D, with 3 observed as the final organometallic product, suggesting a B-N bond cleavage mechanism. Complex 6 does not react with C, but in combination with B oligomer C is consumed to eventually give D, suggesting an additional role for free aminoborane in the formation of D from C. PMID- 21322071 TI - The scope of ambiphilic acetate-assisted cyclometallation with half-sandwich complexes of iridium, rhodium and ruthenium. AB - C--H activation by acetate-assisted cyclometallation of a phenyl group with half sandwich complexes [{MCl(2)Cp*}(2)] (M=Ir, Rh) and [{RuCl(2)-(p-cymene)}(2)] can be directed by a wide range of nitrogen donor ligands including pyrazole, oxazoline, oxime, imidazole and triazole, and X-ray structures of a number of complexes are reported. All the ligands tested cyclometallated at iridium, however ruthenium and rhodium fail to cause cyclometallation in some cases. As a result, the nitrogen donors have been categorised based on their reactivity with the three metals used. The relevance of these cyclometallation reactions to catalytic synthesis of carbocycles and heterocycles is discussed. PMID- 21322072 TI - Synthesis, characterisation and cytotoxicity of polyoxometalate/carboxymethyl chitosan nanocomposites. AB - Chitosan and its derivates continue to attract considerable research interest as effective drug carriers with good biocompatibility and high cellular uptake rates. We used these versatile features to tap the considerable biomedical potential of polyoxometalates (POMs) through their encapsulation into a carboxymethyl chitosan (CMC) matrix. The nanocapsules were prepared by ionic gelification with Ca(2+); their size distribution ranges from 60 to 150 nm. Because [Co(4)(H(2)O)(2)(PW(9)O(34))(2)](10-) is well known for its manifold properties, such as antiviral activity, it was selected as a model POM. The resulting composites were characterised with a wide range of analytical methods, which pointed to quantitative encapsulation of intact POMs within the CMC matrix. We studied the biocompatibility of the POM/CMC nanocomposites on HeLa cells through MTT and proliferation assays. Even after prolonged incubation times at high concentrations, the composites did not display cytotoxicity, thereby drastically reducing the side effects of the pristine POMs. This opens up new avenues for designing novel inorganic drug prototypes from bioactive POMs. PMID- 21322073 TI - Total synthesis of the cytotoxic 1,10-seco-eudesmanolides britannilactone and 1,6 O,O-diacetylbritannilactone. PMID- 21322074 TI - Amination with Pd-NHC complexes: rate and computational studies on the effects of the oxidative addition partner. AB - Pd-PEPPSI-IPent, a recently-developed N-heterocyclic carbene (NHC) complex, has been evaluated in amination reactions with secondary amines and it has shown superb reactivity under the most mildly basic reaction conditions. Rate and computational studies were conducted to provide insight into the mechanism of the transformation. The IPent catalyst coordinates to the amine much more strongly than the IPr variant, thus favouring deprotonation with comparatively weak bases. Indeed the reaction is first order in base and only slightly more than zeroth order in amine. PMID- 21322075 TI - Organometallic calixarenes: syceelike tetrarhenium(I) cavitands with tunable size, color, functionality, and coin-slot complexation. PMID- 21322076 TI - A general synthetic strategy for the design of new BODIPY fluorophores based on pyrroles with polycondensed aromatic and metallocene substituents. AB - BODIPYrrole: A general strategy for the design of novel BODIPY fluorophores based on pyrroles with polycondensed aromatic and metallocene substituents has been developed. The strategy involves the acylation of the condensed substituent and treatment of the acylated derivative (as oxime) with acetylene in MOH/DMSO (M = alkali metal) to give pyrroles that were then used for assembly of the BODIPY fluorophores (see scheme). PMID- 21322077 TI - Split central venous sampling of parathyroid hormone: an adjunct to surgical exploration. AB - BACKGROUND: Minimally invasive parathyroid surgery mandates preoperative localization of the adenoma for a targeted operative approach. This technique uses split internal jugular vein parathyroid hormone (PTH) samples to determine a gradient that then directs the surgical exploration. METHODS: Blood samples were drawn low in the neck from the jugular veins after the neck was opened. The p values for the difference in PTH between the right and left internal jugular veins were calculated with independent sample t tests. RESULTS: For left-sided adenomas, the left internal jugular vein mean was significantly higher than the right p = .001). For right-sided adenomas, the right internal jugular vein mean was significantly higher than the left (p = .004). In hyperplasia, there was no significant difference (p = .43). CONCLUSIONS: This study demonstrates the usefulness of split PTH internal jugular vein samples in patients in whom preoperative localization failed. Eighty percent of these patients with a gradient were treated with site-directed unilateral exploration. PMID- 21322079 TI - Prognosis: a variable parameter: dynamic prognostic modeling in head and neck squamous cell carcinoma. AB - BACKGROUND: In general, the estimated prognosis of patients with cancer is based on patient characteristics known at the time of diagnosis and presented as if a lifetime verdict. However, the prognosis of patients with cancer who survive the first critical years changes, along with the prognosis for those with local or regional recurrences or distant metastases. METHODS: This study concerns 2927 patients with a primary head and neck squamous cell carcinoma (HNSCC). We developed prognostic models after initial treatment and at different time points during follow-up. RESULTS: The developed models show the effects of survival time, recurrences, and distant metastasis during follow-up. The C-statistics ranged from 0.76 to 0.69. CONCLUSION: Prognosis is dynamic: the passage of time and the occurrence of life events change the predicted probabilities of survival. The models enhance our insight in the effect of recurrences and metastasis during follow-up and could be used for better patient counseling. PMID- 21322078 TI - Altered metabolism in head and neck squamous cell carcinoma: an opportunity for identification of novel biomarkers and drug targets. AB - Tumor cells were first shown to exhibit a distinct metabolic phenotype over 80 years ago. Since then, it has become clear that multiple oncogenic events contribute to the development of a metabolic phenotype that supports rapid proliferation. Because this phenotype represents an essential component of tumorigenesis and disease progression, it also represents a potential source of biomarkers associated with aggressive disease. In addition, the addiction of tumor cells to specific nutrients and the up-regulation of key metabolic enzymes provide unique opportunities for pharmacologic manipulation. Despite the use of multimodality treatment, survival rates for patients with advanced head and neck squamous cell carcinoma (HNSCC) remain low, partially attributed to the development of drug resistance. In this review, we evaluate the role of altered HNSCC metabolism as both a source of novel biomarkers and a means to bypass resistance mechanisms to conventional forms of therapy. PMID- 21322080 TI - Novel head and neck cancer survival analysis approach: random survival forests versus Cox proportional hazards regression. AB - BACKGROUND: Electronic patient files generate an enormous amount of medical data. These data can be used for research, such as prognostic modeling. Automatization of statistical prognostication processes allows automatic updating of models when new data is gathered. The increase of power behind an automated prognostic model makes its predictive capability more reliable. Cox proportional hazard regression is most frequently used in prognostication. Automatization of a Cox model is possible, but we expect the updating process to be time-consuming. A possible solution lies in an alternative modeling technique called random survival forests (RSFs). RSF is easily automated and is known to handle the proportionality assumption coherently and automatically. Performance of RSF has not yet been tested on a large head and neck oncological dataset. This study investigates performance of head and neck overall survival of RSF models. Performances are compared to a Cox model as the "gold standard." RSF might be an interesting alternative modeling approach for automatization when performances are similar. METHODS: RSF models were created in R (Cox also in SPSS). Four RSF splitting rules were used: log-rank, conservation of events, log-rank score, and log-rank approximation. Models were based on historical data of 1371 patients with primary head-and-neck cancer, diagnosed between 1981 and 1998. Models contain 8 covariates: tumor site, T classification, N classification, M classification, age, sex, prior malignancies, and comorbidity. Model performances were determined by Harrell's concordance error rate, in which 33% of the original data served as a validation sample. RESULTS: RSF and Cox models delivered similar error rates. The Cox model performed slightly better (error rate, 0.2826). The log-rank splitting approach gave the best RSF performance (error rate, 0.2873). In accord with Cox and RSF models, high T classification, high N classification, and severe comorbidity are very important covariates in the model, whereas sex, mild comorbidity, and a supraglottic larynx tumor are less important. A discrepancy arose regarding the importance of M1 classification (see Discussion). CONCLUSION: Both approaches delivered similar error rates. The Cox model gives a clinically understandable output on covariate impact, whereas RSF becomes more of a "black box." RSF complements the Cox model by giving more insight and confidence toward relative importance of model covariates. RSF can be recommended as the approach of choice in automating survival analyses. PMID- 21322081 TI - Frequency of cells expressing CD44, a head and neck cancer stem cell marker: correlation with tumor aggressiveness. AB - BACKGROUND: We previously identified by flow cytometry a Lineage-CD44+ (Lin CD44+) subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma (HNSCC). We now correlate clinical and histologic factors with Lin-CD44+ cell frequency. METHODS: The study included 31 patients with HNSCC, of whom 87% had stage IV disease. The frequency of Lin-CD44+ cells and the success of xenografting patient tumors in mice were correlated with clinical and pathologic data. RESULTS: The mean frequency of Lin-CD44+ cells was 25% (0.4% 81%). It was 36% in patients who had recurrence versus 15% for those without recurrence (p = .04). Successful xenograft implantation occurred in 53%. Seventy five percent of patients with successful xenografts had recurrence versus 21% of patients with unsuccessful xenografts (p = .003). CONCLUSIONS: Successful xenograft implantation and a high frequency of Lin-CD44+ cells correlate with known poor prognostic factors such as advanced T classification and recurrence. These findings may support the stem cell concept in HNSCC. PMID- 21322082 TI - Effectiveness of narrow band imaging in patients with oral squamous cell carcinoma after treatment. AB - BACKGROUND: We evaluated the effectiveness of narrow band imaging (NBI) in patients with oral squamous cell carcinoma (OSCC) after treatment. METHODS: In all, 101 consecutive OSCC patients underwent NBI examination for posttreatment follow-up. Four patients had local recurrence. Twenty-six second primary malignancies were found in 18 patients; 6 patients (33%) had more than 1 lesion. Seventeen lesions (65%) were carcinoma in situ or severe dysplasia. Most of them occurred in the oral cavity (77%). RESULTS: A higher incidence (18% vs 9%, p = .037) and less-advanced stage (4% vs 37%, p = .0005) of second primary malignancies were found among the NBI group compared with a previous cohort without NBI examination, and fewer patients needed postoperative adjuvant therapy (12% vs 50%, p = .0005). CONCLUSIONS: NBI is an effective method to identify early lesions in the head and neck area, especially the oral cavity, among patients with OSCC after treatment. PMID- 21322083 TI - Utilization of anti-Parkinson drugs in Australia: 1995-2009. AB - PURPOSE: To examine trends in the prescribing of anti-Parkinsonian drugs (APD) in Australia from 1995 to 2009. METHODS: We analyzed the Medicare Australia and Drug Utilisation Sub-Committee (DUSC) databases for prescription data for overall APD dispensed use from 1995. We were able to examine prescribing by gender, age, and type of prescriber between 2002 and 2009. Prescriptions were converted to defined daily doses (DDD)/1000 population/day using Australian Bureau of Statistics population data. RESULTS: Dispensed use of levodopa + carbidopa remained steady from 1995 to 2009 (0.76-0.82 DDD/1000 population/day); levodopa + benserazide use increased from 0.34 to 0.55 DDD/1000 population/day. Since 2005 dispensed use of levodopa + carbidopa + entacapone has steadily increased, from 0.03 to 0.10 DDD/1000 population/day. In July 2009 levodopa + carbidopa was the most widely used agent, followed by levodopa + benserazide, then benztropine. Cabergoline increased from 1999, peaked in 2006, and thereafter declined. APD use peaked in males and females aged 60-69 years. Age-adjusted utilization was slightly higher in males than females. CONCLUSIONS: The amount of levodopa dispensed has slowly increased with levodopa + benserazide increasing faster than levodopa + carbidopa. Use of cabergoline fell when pramipexole became available and the risk of ergot-related serosal adverse effects was more widely appreciated. Use of centrally acting anti-cholinergics decreased over a period of time when use of atypical anti-psychotic agents increased. PMID- 21322084 TI - A model to correct for short-run inefficiencies in economic evaluations in healthcare. AB - Important assumptions that underlie cost-effectiveness analysis (CEA) are that production technologies are convex and that production processes always perform at constant returns to scale. However, in the short run these assumptions are likely to be violated. Therefore, CEAs might overestimate cost-effectiveness in the short run. To come up with a more precise cost-effectiveness outcome, we present a model that is able to correct the long-run incremental net benefit (INB) for short-run inefficiencies. This provides decision makers with a more realistic view of the expected efficiency gains. This model starts by determining the initial efficiency losses inflicted by inflexible resources. Then the model is made dynamic in order to adjust the efficiency losses by allowing for refilling and writing off freed capacity. Finally, the model calculates the length of the short-run time frame in which such efficiency losses exist, and a correction term with which the usual long-run INB should be adjusted to account for short-run inefficiencies. The model is applied to two cases: dialysis and digitizing a radiography department. The dialysis case shows moderate short-run efficiency losses while in the radiography case short-run efficiency losses are sufficiently large to cause a switch in cost-effectiveness from favorable to inefficient in the short run. PMID- 21322085 TI - Does retirement trigger ill health? AB - This paper investigates the effects of retirement on various health outcomes. Data stem from the first three waves of the English Longitudinal Study of Ageing (ELSA). With these informative data, non-parametric matching and instrumental variable (IV) methods are applied to identify causal effects. It is found that retirement significantly increases the risk of being diagnosed with a chronic condition. In particular, it raises the risk of a severe cardiovascular disease and cancer. This is also reflected in increased risk factors (e.g. BMI, cholesterol, blood pressure) and increased problems in physical activities. Furthermore, retirement worsens self-assessed health and an underlying health stock. PMID- 21322086 TI - Comparing costs and outcomes across programmes of health care. AB - This paper examines the expenditure choices of local health authorities operating under fixed budget constraints. It applies a theoretical model of budgeting to a data set from 303 English Primary Care Trusts (PCTs) across ten broad programmes of health care to derive estimates of the elasticity of expenditure in each programme with respect to the total income of the PCT. The results suggest quite similar income elasticities across most programmes, in the range 0.644-1.128. The only outlier is the musculoskeletal programme with an elasticity of about 0.46. The modelling also derives estimates of spending elasticities with respect to medical needs and thereby permits calculation of the implicit cost of saving a life year in five programmes of care. The results are important as they indicate to policy makers how specific programme areas might be affected by general budgetary reductions. PMID- 21322087 TI - The effect of job loss and unemployment duration on suicide risk in the United States: a new look using mass-layoffs and unemployment duration. AB - We examine the link between employment status and suicide risk using a panel of US states from 1996 to 2005 with monthly data on suicides, the duration of unemployment spells and the number of job losses associated with mass-layoff events. The use of aggregate data at the monthly level along with the distribution of unemployment duration allows us to separate the effect of job loss from the effect of unemployment duration, an important distinction for policy purposes, especially for the timing of potential interventions. Our results are consistent with unemployment duration being the dominant force in the relationship between job loss and suicide. Nevertheless, mass-layoffs may be powerful localized events where suicide risk increases shortly afterward. Implications for the design of unemployment insurance are discussed. PMID- 21322088 TI - Does the EU sugar policy reform increase added sugar consumption? An empirical evidence on the soft drink market. AB - Whereas National Health authorities recommend a decrease in the consumption of 'added' sugar, a reform on the sugar market will lead to a 36% decrease of the sugar price in the EU. Using French data on soft drinks purchases, this paper investigates the anticipated impact of this reform on the consumption of sugar sweetened beverages. The reform of the EU sugar policy leads to a decrease in regular soft drink prices by 3% and varies across brands. To assess substitution within this food category, we use a random-coefficients logit model that takes into account a large number of differentiated products and heterogeneity in consumers' behavior. Results suggest that price changes would lead to an increase in market shares of regular products by 7.5% and to substitutions between brands to the benefit of products with the highest sugar content. On the whole, it would raise consumption of regular soft drinks by more than 1 litre per person per year and consumption of added sugar by 124 g per person per year, this increase being larger in households composed of overweight and obese individuals. PMID- 21322089 TI - Survey on breast cancer patients in China toward breast-conserving surgery. AB - OBJECTIVE: We sought to investigate attitudes toward breast-conserving therapy (BCS) in early-stage breast cancer (EBC) patients from P. R. China and assess the factors influencing their decision. BACKGROUND: There exists geographical difference in decision to perform mastectomy or BCS for EBC patients. To date, there has been no report on attitudes toward BCS or factors influencing the surgical choice in mainland China. METHODS: A structured questionnaire was delivered to 1800 EBC patients. The questionnaire elicited information about general patients' characteristics, attitudes toward BCS, the roles of doctors and spouses, the levels of understanding of BCS, and the reasons for their preferences. RESULTS: Of 1590 participants, only 7.3% anticipated BCS and this was significantly associated with patient age, income, occupation, martial status, education, levels of self-understanding of the disease, and doctors' and spouses' suggestions (P<0.05). Approximately 70% of doctors (71.0%) and 40% spouses (39.6%) advised patients not to conserve their breasts. Although the percentage of patients endorsing BCS was higher than that of those opposing it (43.7 vs 15.1%) and more patient believed BCS was beneficial for women (39.2%), even if given another opportunity, only 32.5% of patients preferred to choose it. Moreover, the level of understanding BCS among patients is low (well-known: less known: never-heard, 2.3 vs 47.4 vs 13.3%). CONCLUSIONS: These results suggested that Chinese EBC patients lack accurate and comprehensive understanding of BCS. More efforts are needed to educate breast cancer patients in mainland China toward BCS. PMID- 21322090 TI - Mash1 is required for the differentiation of AADC-positive type III cells in mouse taste buds. AB - Mash1 is expressed in subsets of neuronal precursors in both the central nervous system and the peripheral nervous system. However, involvement of Mash1 in taste cell differentiation has not previously been demonstrated. In this study, we investigated the role of Mash1 in regulating taste bud differentiation using Mash1 KO mice to begin to understand the mechanisms that regulate taste bud cell differentiation. We found that aromatic L-amino acid decarboxylase (AADC) cells were not evident in either the circumvallate papilla epithelia or in taste buds in the soft palates of Mash1 KO mice. However gustducin was expressed in taste buds in the soft palates of Mash1 KO mice. These results suggest that Mash1 plays an important role in regulating the expression of AADC in type III cells in taste buds, which supports the hypothesis that different taste bud cell types have progenitor cells that are specific to each cell type. PMID- 21322093 TI - The evolving field of imaging mass spectrometry and its impact on future biological research. AB - Within the past decade, imaging mass spectrometry (IMS) has been increasingly recognized as an indispensable technique for studying biological systems. Its rapid evolution has resulted in an impressive array of instrument variations and sample applications, yet the tools and data are largely confined to specialists. It is therefore important that at this junction the IMS community begin to establish IMS as a permanent fixture in life science research thereby making the technology and/or the data approachable by non-mass spectrometrists, leading to further integration into biological and clinical research. In this perspective article, we provide insight into the evolution and current state of IMS and propose some of the directions that IMS could develop in order to stay on course to become one of the most promising new tools in life science research. PMID- 21322095 TI - Inhibition of bovine plasma semicarbazide-sensitive amine oxidase by caffeine. AB - Semicarbazide-sensitive amine oxidase (SSAO) is a copper-containing enzyme that catalyzes the oxidative deamination of endogenous and exogenous primary amines. SSAO exists in mammals both as a plasma-soluble and as a membrane-bound form, and its active site is able to come into contact with numerous xenobiotic, amine containing compounds. The kinetic studies performed in this work showed that caffeine inhibition of bovine serum amine oxidase was noncompetitive when benzylamine was used as substrate and mixed when the substrate used was methylamine. Since caffeine contains an imidazole ring, it cannot be excluded that it might bind to an inhibitory imidazoline-binding site on SSAO. PMID- 21322094 TI - Direct visualization of repair of oxidative damage by OGG1 in the nuclei of live cells. AB - Oxidative DNA damage caused by intracellular reactive oxygen species (ROS) is widely considered to be important in the pathology of a range of human diseases including cancer as well as in the aging process. A frequently occurring mutagenic base lesion produced by ROS is 8-oxo deoxyguanine (8-oxo dG) and the major enzyme for repair of 8-oxo dG is 8-oxoguanine-DNA glycosylase 1 (OGG1). There is now substantial evidence from bulk biochemical studies that a common human polymorphic variant of OGG1 (Ser326Cys) is repair deficient, and this has been linked to individual risk of pathologies related to oxidative stress. In the current study, we have used the technique of multiphoton microscopy to induce highly localized oxidative DNA damage in discrete regions of the nucleus of live cells. Cells transfected with GFP-tagged OGG1 proteins demonstrated rapid (<2 min) accumulation of OGG1 at sites of laser-induced damage as indicated by accumulation of GFP-fluorescence. This was followed by repair as evidenced by loss of the localized fluorescence over time. Quantification of the rate of repair confirmed that the Cys326 variant of OGG1 is repair deficient and that the initial repair rate of damage by Cys326 OGG1 was 3 to 4 fold slower than that observed for Ser326 OGG1. These values are in good agreement with kinetic data comparing the Ser326 and Cys326 proteins obtained by biochemical studies. PMID- 21322096 TI - The cardioprotective effects of a combination of quercetin and alpha-tocopherol on isoproterenol-induced myocardial infarcted rats. AB - The present study aims to evaluate the combined protective effects of quercetin and alpha-tocopherol on isoproterenol-treated myocardial infarcted rats. Male albino Wistar rats were pretreated with a combination of quercetin (10 mg/kg) and alpha-tocopherol (10 mg/kg) daily for 14 days. After the pretreatment, rats were injected isoproterenol (100 mg/kg) to induce myocardial infarction. Isoproterenol treated rats showed increased levels of serum troponins and increased intensities of serum lactate dehydrogenase-1 and -2 isoenzyme bands. Isoproterenol treatment also showed significant decreased levels of antioxidant system and significant increased levels of plasma lipid peroxidation, plasma uric acid, and the heart calcium. Furthermore, isoproterenol-treated rat's electrocardiogram showed elevated ST segments. Combined pretreatment with quercetin and alpha-tocopherol normalized all the biochemical parameters and minimized the alterations in electrocardiogram. Histopathology of myocardium also confirmed the cardioprotective effects of quercetin and alpha-tocopherol. In vitro studies confirmed the mechanism of action of quercetin and alpha-tocopherol. Thus, quercetin and alpha-tocopherol exhibited cardioprotective effects against isoproterenol-induced cardiotoxicity due to their scavenging free radicals, improving antioxidants and maintaining Ca(2+) levels. Our study also showed that combined pretreatment (quercetin and alpha-tocopherol) was highly effective than single pretreatment (quercetin or alpha-tocopherol). PMID- 21322098 TI - Stem cell antigen-1 positive cell-based systemic human growth hormone gene transfer strategy increases endosteal bone resorption and bone loss in mice. AB - BACKGROUND: The present study assesses the effect of the stem cell antigen-1 positive (Sca-1(+) ) cell-based human growth hormone (hGH) ex vivo gene transfer strategy on endosteal bone mass in the mouse. METHODS: Sublethally irradiated recipient mice were transplanted with Sca-1(+) cells transduced with lentiviral vectors expressing hGH or beta-galactosidase control genes. Bone parameters were assessed by micro-computed tomography and histomorphometry. RESULTS: This hGH strategy drastically increased hGH mRNA levels in bone marrow cells and serum insulin-like growth factor-I (IGF-I) (by nearly 50%, p < 0.002) in hGH recipient mice. Femoral trabecular bone volume of the hGH mice was significantly reduced by 35% (p < 0.002). The hGH mice also had decreased trabecular number (by 26%; p < 0.0001), increased trabecular separation (by 38%; p < 0.0002) and reduced trabecular connectivity density (by 64%; p < 0.001), as well as significantly more osteoclasts (2.5-fold; p < 0.05) and greater osteoclastic surface per bone surface (2.6-fold; p < 0.01). CONCLUSIONS: Targeted expression of hGH in cells of marrow cavity through the Sca-1(+) cell-based gene transfer strategy increased circulating IGF-I and decreased endosteal bone mass through an increase in resorption in recipient mice. These results indicate that high local levels of hGH or IGF-I in the bone marrow microenvironment enhanced resorption, which is consistent with previous findings in transgenic mice with targeted bone IGF-I expression showing that high local IGF-I expression increased bone remodeling, favoring a net bone loss. Thus, GH and/or IGF-I would not be an appropriate transgene for use in this Sca-1(+) cell-based gene transfer strategy to promote endosteal bone formation. Published 2011 John Wiley & Sons, Ltd. PMID- 21322099 TI - Complete restoration of phenylalanine oxidation in phenylketonuria mouse by a self-complementary adeno-associated virus vector. AB - BACKGROUND: Classical phenylketonuria (PKU) arises from a deficiency of phenylalanine hydroxylase (PAH) that catalyses phenylalanine oxidation in the liver. Lack of PAH activity causes massive hyperphenylalaninemia and consequently severe brain damage. Preclinical studies showed that conventional adeno associated virus (AAV) vectors could correct hyperphenylalaninemia in a mouse model of PKU, although limitations such as very large dose requirement and relative inefficiency in female animals were recognized. METHOD: An AAV8 pseudotyped vector was constructed with a self-complementary AAV (scAAV) genome for efficient liver transduction and expression. Following vector injection to PKU mice, blood Phe was periodically measured by an enzymatic fluorometric assay. In vivo Phe oxidation was evaluated by a non-invasive breath test using [1-(13) C]Phe. Vector copy number in the host tissues was determined by quantitative polymerase chain reaction. RESULTS: A single injection of 1 * 10(11) -1 * 10(12) particles of the scAAV8 vector resulted in a reduction of blood Phe to normal or near-normal levels for more than 1 year in both genders. The treated animals showed normal level of in vivo Phe oxidation. The presence of > 1 copy of vector DNA per diploid genome in the liver was associated with normal blood Phe in the AAV-treated PKU mice. CONCLUSIONS: Complete phenotypic correction of PKU mice was achieved by the scAAV8 vector for the longest duration reported to date. The vector overcame the female-specific disadvantage in AAV-mediated liver transduction; thus, it offers a promising platform of long-lasting gene therapy for PKU. PMID- 21322097 TI - Central nervous system cytokine gene expression: modulation by lead. AB - The environmental heavy metal toxicant, lead (Pb) has been shown to be more harmful to the central nervous system (CNS) of children than to adults, given that Pb exposure affects the neural system during development. Because growth factors and cytokines play very important roles in development of the CNS, we have examined the impact of Pb exposure on the expression of cytokines during CNS development. Cytokine expression was studied in post-natal-day 21 (pnd21) mice by microarray, real-time RT-PCR, Luminex, and ELISA methodologies. BALB/c mouse pups were exposed to Pb through the dam's drinking water (0.1 mM Pb acetate), from gestation-day 8 (gd8) to pnd21. Two cytokines, interleukin-6 (IL-6) and transforming growth factor-beta1 (TGF-beta1), displayed significantly changed transcript levels in the presence of Pb. IL-6 and TGF-beta1 both have signal transduction cascades that can cooperatively turn on the gene for the astrocyte marker glial-fibrillary acidic protein (GFAP). Microarray results indicated that Pb exposure significantly increased expression of GFAP. Pb also modulated IL-6, TGF-beta1, and IL-18 protein expression in select brain regions. The deleterious effects of Pb on learning and long-term memory are posited to result from excessive astrocyte growth and/or activation with concomitant interference with neural connections. Differential neural expression of cytokines in brain regions needs to be further investigated to mechanistically associate Pb and neuroinflammation with behavioral and cognitive changes. PMID- 21322100 TI - Infant lungs are preferentially infected by adenovirus and herpes simplex virus type 1 vectors: role of the tissue mesenchymal cells. AB - BACKGROUND: Adenovirus (AD) and herpes-simplex-virus-1 (HSV-1) have been extensively applied as vectors for gene and cancer therapy in clinical trials. AD5, from which the vector was constructed, is a common respiratory virus that infects mainly infants, yet the reasons for infant sensitivity to infection, other than immunity, are not clear. HSV-1, usually a neurotropic virus, may also cause severe pneumonia or disseminated diseases in infants and immunocompromised patients. METHODS: The tropism of these viruses to different human and mouse lung tissues of newborn and adult was studied in an ex vivo organ culture and it was also applied in vivo using a murine model. RESULTS: The data obtained indicated preferential viral infection of young lung tissues versus adult tissues in organ culture. Further studies indicated that the preferential infection of young tissues was not related to differences in receptor expression or exposure but rather to the different distribution of cell types in these tissues. Murine and human young lungs consist of a relative abundance of mesenchymal cells and these cells were much more susceptible to viral infection compared to adjacent epithelial-pneumocyte cells. These observations were further confirmed using an in vivo model of mouse infection. CONCLUSIONS: The similarity of the human and mouse tissues, with respect to viral vector tropism, validates the mouse model in studies of gene transfer to the lung. Furthermore, the results should facilitate the improved design of gene therapy trials for lung-related diseases in young and adults patients. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 21322101 TI - Intracellular efficacy of tumor-targeting group I intron-based trans-splicing ribozyme. AB - BACKGROUND: Group I intron-based trans-splicing ribozyme, which can specifically reprogram human telomerase reverse transcriptase (hTERT) RNA, could be a useful tool for tumor-targeted gene therapy. In the present study, the therapeutic feasibility of this ribozyme was investigated by analyzing trans-splicing efficacy in vivo as well as in cells. METHODS: We assessed transgene activation, degree of ribozyme expression, targeted hTERT mRNA level, or the level of trans splicing products in hTERT(+) cells or in human tumor nodules xenografted in animals after ribozyme administration. RESULTS: The activity and efficacy of the trans-splicing ribozyme in cells was dependent on the amount of endogenous hTERT mRNA and/or the accumulation of ribozyme RNA in cells. Intracellular activity of the ribozyme reached a plateau when no more targetable substrate mRNA was available or the ribozyme RNA level was fully saturated. In addition, the efficacy of ribozyme in xenografted tumor tissues was dependent on the dose of the delivered ribozyme-encoding adenoviral vector, indicating the potential of the ribozyme expression level as a determining factor for the in vivo efficacy of the trans-splicing ribozyme. On the basis of these results, we enhanced the intracellular ribozyme activity by increasing the ribozyme expression level transcriptionally and/or post-transcriptionally. CONCLUSIONS: We analyzed ribozyme efficacy and determined the most influential factors of its trans splicing reaction in mammalian cell lines as well as in vivo. The present study could provide insights into the optimization of the trans-splicing ribozyme-based RNA replacement approach to cancer treatment. PMID- 21322102 TI - Sustained inhibition of IL-6 and IL-8 expression by decoy ODN to NF-kappaB delivered through respirable large porous particles in LPS-stimulated cystic fibrosis bronchial cells. AB - BACKGROUND: Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Neutrophil-dominated inflammation and chronic bacterial infection are still considered the primary cause of bronchioectasis, respiratory failure and consequent death in CF patients. Activation of nuclear factor (NF)-kappaB is responsible for overproduction of cytokines, such as interleukin (IL)-6 and IL-8, in airways of CF patients. Thus, decoy oligodeoxynucleotides against NF-kappaB (dec-ODN) may limit lung inflammation in CF. In the present study, we studied the effects of dec-ODN delivered through biodegradable and respirable poly(D,L-lactide-co glycolide) large porous particles (LPP) on IL-6 and IL-8 mRNA expression as well as NF-kappaB/DNA binding activity in cystic fibrosis cells stimulated with lipopolysaccharide (LPS) from Pseudomonas aeruginosa. METHODS: dec-ODN LPP were prepared by a modified double emulsion technique and characterized in terms of size, morphology, tapped density and dec-ODN loading. Human epithelial bronchial IB3-1 (CFTR-mutated) as well as S9 (CFTR-corrected) were stimulated with LPS from P. aeruginosa for 24 and 72 h in the absence or presence of naked dec-ODN or dec ODN LPP. RESULTS: Stimulation of cells with LPS from P. aeruginosa caused an increase of IL-6 and IL-8 mRNA levels, which were significantly inhibited by dec ODN LPP at 24 and 72 h, whereas naked dec-ODN inhibited those only at 24 h. Similar effects were exhibited by dec-ODN LPP or naked dec-ODN on NF-kappaB/DNA binding activity. CONCLUSIONS: Our observations indicate that respirable biodegradable dec-ODN LPP may represent a promising strategy for inhibiting NF kappaB transcriptional activity and related gene expression and, thus, reduce lung chronic inflammation in CF patients. PMID- 21322103 TI - Structure-function relationships of phenoxazine nucleosides for identification of mismatches in duplex DNA by fluorescence spectroscopy. AB - The effects of the flanking sequence on the mismatch-detection capabilities of the fluorescent nucleoside phenoxazine (tC(O)) were examined in a systematic fashion, and compared to the previously reported fluorescent, phenoxazine-based nucleoside C(f) . We see some similarities for the two fluorescent nucleosides, for example, the emission intensity of the C-mismatched duplex is always the highest, and a three-peak pattern in the spectrum emerges when the fluorosides are base-paired with A. However, phenoxazine was only able to distinguish a mismatch from the fully base-paired duplex in 11 out of 16 flanking sequences, and was able to identify each of the mismatches in six of those sequences. Therefore, tC(O) shows poorer discrimination of mismatches than was previously reported for C(f) , which could be used to identify all base-pairing partners in all immediately flanking sequences, albeit in some cases by using mercuric ions to selectively quench the emission of the T-mismatched duplex. The mercuric titration might resolve the overlap of fluorescence curves of tC(O) in some flanking sequences, but not for 5'-d(CtC(O) G) and 5'-d(TtC(O) A) due to overlap of A-mismatch and G-match fluorescence curves. A pH titration was performed on C(f) , tC(O) and a N5-methylated derivative of tC(O) , which showed that the emergence of the three-peak pattern is associated with the de-protonation of N5 in the fluorosides. We also show that neither the alpha- nor beta-anomer of the phenothiazine nucleoside (tC) was able to detect a mismatch in any of the flanking sequences examined. PMID- 21322104 TI - Multiple charge-separation pathways in photosystem II: modeling of transient absorption kinetics. AB - We explain the transient absorption kinetics (E. Romero, I. H. M. van Stokkum, V. I. Novoderezhkin, J. P. Dekker, R. van Grondelle, Biochemistry 2010, 49, 4300) measured for isolated reaction centers of photosystem II at 77 K upon excitation of the primary donor band (680 nm). The excited-state dynamics is modeled on the basis of the exciton states of 6 cofactors coupled to 4 charge-transfer (CT) states. One CT state (corresponding to charge separation within the special pair) is supposed to be strongly coupled with the excited states, whereas the other radical pairs are supposed to be localized. Relaxation within the strongly coupled manifold and transfer to localized CT's are described by the modified Redfield and generalized Forster theories, respectively. A simultaneous and quantitative fit of the 680, 545, and 460 nm kinetics (corresponding to respectively the Q(y) transitions of the red-most cofactors, Q(x) transition of pheophytin, and pheophytin anion absorption) enables us to define the pathways and time scales of primary electron transfer. A consistent modeling of the data is only possible with a Scheme where charge separation occurs from both the accessory chlorophyll and from the special pair, giving rise to fast and slow components of the pheophytin anion formation, respectively. PMID- 21322105 TI - Stretched polyethylene films probed by single molecules. AB - Stretched films of low-density polyethylene (LDPE) doped with 2.3,8.9 dibenzanthanthrene (DBATT) were studied using polarization-selective single molecule spectroscopy at 1.8 K. By measuring the in-plane component of the electronic transition-dipole moments of individual chromophores, the alignment of dopant molecules is determined without averaging. The distributions of chromophore orientations reveal the presence of two fractions of dopant molecules: those oriented along the stretching direction and randomly oriented molecules. With increasing drawing ratio of the polyethylene films, the ratio of oriented to randomly oriented guest molecules increases, whereas the extent of chromophore orientation, that is, the width of the orientation distribution, remains the same. The results are consistent with the interpretation that oriented chromophores reside on the surfaces of polyethylene crystals, instead of in the amorphous polyethylene regions. Guest molecules in stretched polyethylene are oriented due to the alignment of the crystallites on which they are adsorbed. As such, the shape and width of the distributions of chromophore orientations are determined by the interaction of guest molecules with the crystal surfaces. PMID- 21322106 TI - Three-dimensional fluidic self-assembly by axis translation of two-dimensionally fabricated microcomponents in railed microfluidics. AB - A method for high-throughput 3D self-assembly of 2D photopatterned microstructures using railed microfluidics is presented. Vertical device patterning of heterogeneous materials requires high-level integration using conventional microelectromechanical system (MEMS) technology; however, 3D railed assembly enables easy and fast self-assembly via a fluidic axis-translation process and simple material exchange in microfluidic channels. Individually photopatterned 2D microstructures are axis-translated from in-plane to out-of plane and fluidically self-assembled, guided by side-rails in microfluidic channels to form a 3D morphology. Since the structures are fabricated in fluidic environments, there are no fixed initial points on the channel substrate allowing fluidic horizontal stacking of erected 2D structures. The guiding mechanism of railed microfluidics enables efficient fluidic handling and deterministic 3D self assembly of heterogeneous components such as electronic components or polymeric microstructures using only fluidic force. PMID- 21322107 TI - One-pot encapsulation of luminescent quantum dots synthesized in aqueous solution by amphiphilic polymers. AB - A simple one-pot polymer encapsulation method is developed for group II-VI semiconductor quantum dots (QDs) synthesized in aqueous solution. The micelles of amphiphilic polymers, such as octadecylamine-modified poly(acrylic acid), capture and encapsulate the QDs when the original hydrophilic ligands, namely 3 mercaptopropionic acid (MPA), capped on the CdTe/CdS core/shell QDs are partially or fully exchanged by the hydrophobic ligands, 1-dodecanethiol. The molar ratio of the amphiphilic polymer to QDs plays a crucial role in determining the final morphology of the encapsulated structures, including the number of QDs encapsulated in one polymeric micelle. Importantly, the polymer coating significantly improves the optical properties of the QDs, which enhances the photoluminescence quantum yield by about 50%. Furthermore, the photostability of the amphiphilic polymer-coated QDs is much better than that of the synthesized QDs capped with MPA. PMID- 21322108 TI - Impact of lipid substitution on assembly and delivery of siRNA by cationic polymers. AB - Characterization of a polymer library engineered to enhance their ability to protect and deliver their nucleotide cargo to the cells is reported. The zeta potential continuously increased with higher polymer:siRNA weight ratio, and the zeta-potential of lipid-modified polymers:siRNA complexes were higher than PEI2 at all ratios. At polymer:siRNA ratio of 1:1, all lipid-substituted polymers showed complete protection against degradation. Lipid-modified polymers significantly increased the cellular uptake of siRNA complexes and down regulation of GAPDH and P-gp (max. 66% and 67%, respectively). The results indicate that hydrophobic modification of low molecular PEI could render this otherwise ineffective polymer to a safe effective delivery system for intracellular siRNA delivery and protein silencing. PMID- 21322110 TI - Synthesis and biological evaluation of 6-substituted 5-alkyl-2 (phenylaminocarbonylmethylthio)pyrimidin-4(3H)-ones as potent HIV-1 NNRTIs. AB - A series of new 5-alkyl-2-phenylaminocarbonylmethylthiopyrimidin-4(3H)-ones bearing variously substituted arylmethyl moieties at the C6 position of the pyrimidine ring were synthesized and evaluated for anti-HIV activity in MT-4 cells. Most of these new congeners exhibited moderate to good activities against the wild-type virus, with EC(50) values in the range of 1.40-0.19 MUM. Among them, 2-[(4-cyanophenylamino)carbonylmethylthio]-6-(2-chloro-6-fluorobenzyl)-5 ethylpyrimidin-4(3H)-one 4 b6 is one of the compounds endowed with the highest broad-spectrum HIV-1 inhibitory activity, with EC(50) values of 0.19+/-0.005 MUM against the wild-type virus, 1.05+/-0.24 MUM (twofold resistance) against the E138K strain, and 2.38+/-0.13 MUM (4.5-fold resistance) against the Y181C strain. Furthermore, reverse transcriptase (RT) inhibition assays against wild-type HIV-1 RT were performed with selected derivatives, confirming that the main target of these compounds is HIV-1 RT and that these new S-DABO analogues act as non nucleoside RT inhibitors (NNRTIs). Structure-activity relationship and molecular modeling analyses of these new congeners are also discussed. PMID- 21322109 TI - Modulation of material properties of a decellularized myocardial matrix scaffold. AB - Injectable materials offer the potential for minimally invasive therapy for myocardial infarction (MI), either as an acellular scaffold or as a cell delivery vehicle. A recently developed myocardial matrix hydrogel, derived from decellularized porcine ventricular tissue, has the potential to aid in cardiac repair following an MI. Herein, we set out to study the effects of cross-linking on the cardiac hydrogel stiffness, degradation properties, cellular migration, and catheter injectability in vitro. Cross-linking increased stiffness, while slowing degradation and cellular migration through the gels. Additionally, the cross-linked material was pushed through a clinically relevant catheter. These results demonstrate that the material properties of myocardial matrix can be tuned via cross-linking, while maintaining appropriate viscosity for catheter injectability. PMID- 21322111 TI - Chiral separation by a pseudo membrane in a triple-laminar flow with a microfluidic contactor. PMID- 21322112 TI - Ferromagnetic homometallic Mn19 cluster and heterometallic Na2Mn15 cluster with large spin state as magnetic refrigerants. PMID- 21322113 TI - Self-assembly and aggregate-induced enhanced emission of amphiphilic fluorescence dyes in water and in the solid state. AB - 1-Cyano-1,2-bis(biphenyl)ethene (CNBE) derivatives with a hexa(ethylene glycol) group as an amphiphilic side chain were synthesized and the self-assembling character and fluorescence behavior were investigated. The amphiphilic derivatives showed aggregate-induced enhanced emission (AIEE) in water and in the solid state. The fluorescence quantum yield increased as the rigidity of the aggregates increased (i.e., in ethyl acetate81%) for both training and test sets. In addition, from the study of prostate cancer patients, CD14 also allows the distinction of BPH from cancer with high specificity (84-100%) when combined with urinary prostate-specific antigen. CONCLUSIONS AND CLINICAL RELEVANCE: Urinary CD14 is suggested to have a high specificity in the diagnosis of BPH in distinction from normal as well as cancer subjects. PMID- 21322117 TI - Subcritical water as reaction environment: fundamentals of hydrothermal biomass transformation. AB - Subcritical water, that is, water above the boiling and below critical point, is a unique and sustainable reaction medium. Based on its solvent properties, in combination with the often considerable intrinsic water content of natural biomass, it is often considered as a potential solvent for biomass processing. Current knowledge on biomass transformation in subcritical water is, however, still rather scattered without providing a consistent picture. Concentrating on fundamental physical and chemical aspects, this review summarizes the current state of knowledge of hydrothermal biomass conversion in subcritical water. After briefly introducing subcritical water as a reaction medium, its advantages for biomass processing compared to other thermal processes are highlighted. Subsequently, the physical-chemical properties of subcritical water are discussed in the light of their impact on the occurring chemical reactions. The influence of major operational parameters, including temperature, pressure, and reactant concentration on hydrothermal biomass transformation processes are illustrated for selected carbohydrates. Major emphasis is put on the nature of the carbohydrate monomers, since the conversion of the respective polymers is analogous with the additional prior step of hydrolytic depolymerization. PMID- 21322118 TI - Osteogenic activity of bone marrow-derived mesenchymal stem cells (BMSCs) seeded on irradiated allogenic bone. AB - Allogenic bone grafting, a technique used in orthopaedic surgery, has several problems, including low osteogenic activity. To overcome the problem, this study aimed to determine whether in vivo osteogenesis could be enhanced using allogenic irradiated bone grafts after seeding with autologous bone marrow-derived mesenchymal stem cells (BMSCs). The allogenic bone cylinders were extracted from ACI rats and sterilized by irradiation. Donor BMSCs were obtained from fresh Fischer 344 (F344) rat bone marrow by cell culture. The allogenic bone with or without BMSCs were transplanted subcutaneously into syngeneic F344 rats. At 4 weeks after transplantation, high alkaline phosphatase (ALP) activity, bone specific osteocalcin mRNA expression and newly formed bone were detected in the allogenic bone with BMSCs. The origin of the newly formed bone was derived from cultured donor BMSCs. However, none of these identifiers of osteogenesis were detected in either the fresh or the irradiated allogenic bone without BMSCs. These results indicate the availability of autologous BMSCs to heighten the osteogenic response of allogenic bone. Our present tissue-engineering method might contribute to a wide variety of allogenic bone grafting techniques in clinical settings. PMID- 21322119 TI - Adulterants in illicit drugs: a review of empirical evidence. AB - Widespread public perception is that illicit drugs contain substances that are a serious risk to health, even though adulterants are often not considered in clinical or forensic toxicology. This review attempts to present an evidence based overview of adulterants in illicit drugs, and their associated toxicity. Adulterants are deliberately added to increase bulk, enhance or mimic a pharmacological effect, or to facilitate drug delivery. Those present unintentionally are as a result of poor manufacturing techniques. From the reports gathered, adulterants are predominantly substances which are readily available, commonly being caffeine, procaine, paracetamol, and sugars. These are likely to have minimal impact on users' health at low dosages. Other adulterants, particularly in injectable drugs, have the potential to cause serious health issues, but the quantities reported, such as strychnine in heroin, are not life threatening. The most commonly identified bacterial contaminants identified are Bacillus and Clostridium species. When death or serious illness due to adulteration occurs, circulation of information is particularly vital, such as in the USA regarding heroin and cocaine adulterated with fentanyl, and in Scotland recently regarding anthrax contaminated heroin. The complex interactions of supply, demand, and control of illicit drugs have a tangible impact on their adulteration. Continuing vigilance and the circulation of information is, therefore, desirable as a public health issue. As part of that strategy, analyses performed for adulterants needs to be encouraged, which are considerably limited in number and scope at the moment. PMID- 21322120 TI - Ophthalmic delivery of sparfloxacin from in situ gel formulation for treatment of experimentally induced bacterial keratitis. AB - The objective of the present work was (1) to develop an in situ gelling ophthalmic delivery system by combining pluronic F127 and pluronic F68, with sparfloxacin; and (2) to examine the influence of incorporating a mucoadhesive polysaccharide such as sodium hyaluronate on the healing property due to bacterial keratitis. The formulations (F1-F6) were sterilized by gamma irradiated using Co(60) . Ultraviolet (UV) and infrared (IR) spectra studies were performed on sterilized and non-sterilized formulae. The formulations were evaluated for rheological characteristics, in vitro release behavior, and efficacy against induced bacterial conjunctivitis in rats' eyes. Moreover, histopathological evaluations were also done. All the samples passed sterility tests, and no change in physical appearance of the formulae due to gamma radiation was observed. The IR spectra of the formulae before and after sterilization showed similar peaks which confirmed that no ingredient was affected by gamma radiation. The formulations showed a flow index of 0.116-0.493 indicating pseudoplastic flow behavior. The release behavior of all formulae was non-Fickian anomalous release. The different formulae used to overcome the pathological alterations, produced by bacteria infections varied among each other depending on the duration of treatment; however, the effectiveness of formulation was arranged as F5, F4 and F3, respectively. The developed formulations were therapeutically efficacious, and provided sustained release of the drug over a 24-hour period. A better improvement in artificially induced bacterial conjunctivitis in rats' cornea was observed with the developed formulae; thus it can be considered as a viable alternative to conventional eye drops. PMID- 21322121 TI - Experimental and spectroscopic studies of charge transfer reaction between sulfasalazine antibiotic drug with different types of acceptors. AB - The charge-transfer (CT) interactions between the electron donor sulfasalazine (SS) and the acceptors 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), p chloranil (CHL), picric acid (PA) and iodine have been studied spectrophotometrically in CHCl(3) or CH(3) OH solutions. The formed solid CT complexes were also isolated and characterized through infrared, (1) H-NMR, mass spectra as well as elemental and thermal analysis. The CT complexes were discussed in terms of formation constant (K(CT) ), molar extinction coefficient (epsilon(CT) ), standard free energy (DeltaG degrees ), oscillator strength (f), transition dipole moment (u), resonance energy (R(N) ) and ionization potential (I(D) ). The stoichiometry of these complexes was found to be 1:1 molar ratio and having the formulae [(SS)(DDQ)], [(SS)(CHL)], [(SS)(PA)] and [(SS)(2) I](+) . I(3) (-) , respectively. The charge transfer interaction was successfully applied to the determination of SS drug using mentioned sigma and pi-acceptors also, the results obtained herein are satisfactory for estimation of SS compound in the pharmaceutical form. PMID- 21322122 TI - Molecularly imprinted polymer-based potentiometric sensor for 2-aminopyridine as a potential impurity in piroxicam. AB - A molecularly imprinted polymer-based potentiometric sensor was fabricated for determination of 2-aminopyridine (2-AP). The electroactive component is the 2 APH(+) . To form this specie the determination is carried out in a bufferic solution at pH 4.5 in which 2-AP is prevalently monoprotonated. Under these conditions, the membrane potential, increases with 2-AP concentration over a wide range of concentration (5 uM to 100 mM) with a near Nernstian response of 54.1 mV/decade and detection limit of 2.0 uM. The response time is less than 5 s and the sensor can be used for more than 3 months without any significant divergence in response. The selectivity coefficients of the proposed sensor were evaluated and exhibited good selectivity to 2-AP with respect to the electrode based on a non-imprinted polymer. The utility of the sensor was successfully tested by examining of 2-AP in piroxicam (PX) as a potential impurity. PMID- 21322123 TI - Cytological features of myxomatous fibroadenoma of the breast. AB - Fibroadenoma (FA) is a benign tumor that must be differentiated from carcinomas. FAs often exhibit myxedematous changes (myxomatous FA, M-FA). We previously reported on the clinical significance of M-FA. M-FA and (mucinous) carcinoma share clinical findings, rapid growth and a relatively large size, a high depth/width (D/W) ratio, a relatively round shape, and posterior echo enhancement with internal hyperechogenicity on ultrasonography (US). Next, a biopsy is required for differential diagnosis. In this study, we evaluated the diagnostic significance of the cytological findings of M-FA with US findings. Among 13 FAs that were diagnosed by cytology, we compared (i) a group of six mucinous carcinomas with acellular mucin and a D/W ratio >= 0.7 (a suspicious factor for malignancy) with a group with a D/W ratio of <0.7, and (ii) the frequency of metachromasia on Giemsa stain between M-FAs and non-M-FAs among eight FA cases confirmed by histology. (i) FA lesions (7 of 13) showed metachromasia with Giemsa staining significantly more frequently than did mucinous carcinoma (0/6) (Fisher's exact test, P < 0.044). FA lesions with a D/W ratio >= 0.7 (6/7) showed metachromasia significantly more frequently than did FA with a D/W ratio <0.7 (1/6) (Fisher's exact test, P < 0.029). Among eight FA cases confirmed by histology, M-FA cases (6/6) demonstrated metachromasia significantly more frequently than non-M-FA cases (0/2) (P < 0.036). M-FA cytologically exhibits marked metachromasia on Giemsa staining. Combining cytological examination and understanding the clinical features of M-FA may allow us to choose cytological examination as a first-line diagnostic method for tumor-forming lesions. PMID- 21322124 TI - Comparison of the quality of smears in transbronchial fine-needle aspirates using two staining methods for rapid on-site evaluation. AB - Transbronchial needle aspiration (TBNA) via flexible bronchoscopy is a well established sampling modality for lung masses. The procedure is useful in the diagnosis of neoplastic and non-neoplastic lesions as well as for staging of bronchogenic carcinoma. Rapid on-site evaluation (ROSE) adds value as it has the advantage of triaging material during the procedure so avoiding a battery of investigations. Frequently used rapid stains are the modified Wright-Giemsa water based stain (WG-ROSE) and the alcohol-based modified Papanicolaou stain (Pap ROSE). Final review of laboratory-based Giemsa and Pap stains supplemented by ancillary investigations is essential for quality assurance. To investigate whether and how ROSE influenced the quantity and quality of the material submitted to the laboratory we randomized 126 patients to WG-ROSE, requiring only one pathologist on-site, or combined WG- and Pap-ROSE, requiring an additional person on-site to assist with staining. In those patients with positive TBNA we graded the laboratory-based slides of the first pass containing diagnostic material into insufficient, suspicious, adequate and excellent. The first diagnostic pass was found after 3.06 +/- 1.94 (SD) passes and 3.13 +/- 2.16 passes with WG-ROSE and combined ROSE (P = 0.87), respectively. Following WG-ROSE and combined ROSE 69% and 71.1% (P = 0.509) of slides were diagnostic (adequate or excellent) on laboratory-based Giemsa stains, and 93.3% and 100% (P = 0.134) were scored adequate or excellent on laboratory-based Pap stains. We concluded that the less costly and labour intensive WG-ROSE procedure is adequate for TBNA. This has cost implications especially in resource poor settings. PMID- 21322126 TI - Morphogenetics of early thyroid development. AB - The thyroid develops from the foregut endoderm. Yet uncharacterized inductive signals specify endoderm progenitors to a thyroid cell fate that assembles in the pharyngeal floor from which the primordium buds and migrates to the final position of the gland. The morphogenetic process is regulated by both cell autonomous (e.g. activated by NKX2-1, FOXE1, PAX8, and HHEX) and mesoderm-derived (e.g. mediated by TBX1 and fibroblast growth factors) mechanisms acting in concert to promote growth and survival of progenitor cells. The developmental role of TSH is limited to thyroid differentiation set to work after the gross anatomy of the gland is already sculptured. This review summarizes recent advances on the molecular genetics of thyroid morphogenesis put into context of endoderm developmental traits and highlights established and novel mechanisms of thyroid dysgenesis of potential relevance to congenital hypothyroidism in man. PMID- 21322128 TI - [Characteristics of spino-bulbar-spinal reflex in central nervous system pathology]. PMID- 21322129 TI - [Changes in quality of life in patients with remitted multiple sclerosis during the specific treatment with disease-modifying drugs: a comparative study of populations of Moscow and Novosibirsk]. PMID- 21322130 TI - [The validation of international criteria for remission in schizophrenia in the outpatient population]. PMID- 21322131 TI - [The development of cardioneurology in the works of N.K. Bogolepov]. PMID- 21322125 TI - Epigenetics meets endocrinology. AB - Although genetics determines endocrine phenotypes, it cannot fully explain the great variability and reversibility of the system in response to environmental changes. Evidence now suggests that epigenetics, i.e. heritable but reversible changes in gene function without changes in nucleotide sequence, links genetics and environment in shaping endocrine function. Epigenetic mechanisms, including DNA methylation, histone modification, and microRNA, partition the genome into active and inactive domains based on endogenous and exogenous environmental changes and developmental stages, creating phenotype plasticity that can explain interindividual and population endocrine variability. We will review the current understanding of epigenetics in endocrinology, specifically, the regulation by epigenetics of the three levels of hormone action (synthesis and release, circulating and target tissue levels, and target-organ responsiveness) and the epigenetic action of endocrine disruptors. We will also discuss the impacts of hormones on epigenetics. We propose a three-dimensional model (genetics, environment, and developmental stage) to explain the phenomena related to progressive changes in endocrine functions with age, the early origin of endocrine disorders, phenotype discordance between monozygotic twins, rapid shifts in disease patterns among populations experiencing major lifestyle changes such as immigration, and the many endocrine disruptions in contemporary life. We emphasize that the key for understanding epigenetics in endocrinology is the identification, through advanced high-throughput screening technologies, of plasticity genes or loci that respond directly to a specific environmental stimulus. Investigations to determine whether epigenetic changes induced by today's lifestyles or environmental 'exposures' can be inherited and are reversible should open doors for applying epigenetics to the prevention and treatment of endocrine disorders. PMID- 21322132 TI - [Vasilii Alekseevich Giliarovskii (to 135-anniversary of birthday)]. PMID- 21322133 TI - [Prevalence of alexithymia in the medical student population from Karelia and Murmansk region]. PMID- 21322134 TI - [The additional possibilities to increase the efficacy in the treatment of different types of headaches]. PMID- 21322135 TI - [Facial pain]. PMID- 21322136 TI - [Neuromyotonia and myasthenia in a patient with thymoma]. PMID- 21322137 TI - [Posterior reversible encephalopathy syndrome]. PMID- 21322138 TI - [Hemifacial spasm]. PMID- 21322139 TI - [Posttraumatic vegetative state (some aspects of brain dysfunction)]. PMID- 21322140 TI - [Subject and basic definitions of the addictive medicine: the notion of addictive disorders]. AB - The definition and classification of psychoactive substances are presented. The basic clinical notions related to non-medical use of drugs are defined and characterized. The criteria of drug dependences are listed. The description of phasic states of addictive diseases is presented. The relationship between addictive disorders and abnormal activity of cerebral reward system is emphasized. The problem of treatment resistance of addictive disorders and low treatment efficacy in addictive medicine is designated. PMID- 21322141 TI - [Phenomenology of craving: from differentiation to adequate therapy]. AB - The author analyzes a phenomenon of addiction from the psychological/psychiatric position and differentiates it from psychopathological disorders, including parabulia, hyperbulia, paraphylia, commonly used for the definition of drive disorders. It has been concluded that addition is a specific complex of clinical symptoms which is not similar to other drive disorders. To avoid diagnostic and therapeutic errors, the author suggests to revise definitions by assigning the biological sense to the conception of addiction within psychoactive substance dependence and sexual addiction, some forms of eating dependence and to use the definition of paraaddictive drives in cases of over-valued drives (gambling, Internet dependence, fanaticism etc). PMID- 21322142 TI - [The role of unconscious emotional-motivational stimuli in heroin addiction]. AB - Eighty patients with heroin addiction, aged from 15 to 20 years (most of them over the age of 16), were examined. The duration of illness was from 6 months to 3 years. The examination was conducted 2-3 weeks after arresting of withdrawal syndrome. In that period, patients had different mental disorders: depressive dysphoric, neurosis-like, anxiety-hypochondriac, hysteriform and others. The aim of the examination was to find peculiarities of functioning of different cortical regions in the process of appraisal of conscious and unconscious stimuli using the method of visual evoked potentials with P300 recording. Stimuli were words highlighted on the screen--indifferent and potentially significant for a patient (e.g. heroin). The stimulus related to the dominating motivation caused in patients the higher diffuse cortical activation on the unconscious level compared to non-targeted stimuli. PMID- 21322143 TI - [Involvement of brain neurotrophic factors in the pathogenesis of chemical dependences]. AB - The involvement of brain neurotrophic factors (BNF) in the development and maintenance of the syndrome of psychic dependence on psychoactive substances is discussed. The implication of BNF in the pathogenesis of psychic dependence syndrome is supported by changes of the addictive power of psychostimulants, ethanol and morphine in conditions of metabolism modulation of these peptides as well as in rodents with defects in neurotrophin genes. Glial cell line derived BNF and tumor necrosis factor-alpha reduce the addictive potential of cocaine, methamphetamine, morphine and ethanol. Brain-derived neurotrophic factor, on the contrary, increases the addictive activity of cocaine suppressing the development of the syndrome of psychic dependence on ethanol. Thus, the BNF must be considered as an important group of neuroactive peptides implicated in the pathogenesis of chemical dependences. PMID- 21322144 TI - [Gender heteronomy of heroin addiction in adolescences]. AB - On the model of heroin addiction in adolescents the premises for grounding the concept of gender heteronomy of addictions have been identified. The clinical dynamic patterns associated with gender--so called gender associated types of disease in which the leading factors of difference formation are biological sex, valuable orientation structure, sexual experience and social status were singled out. The gender-associated types of heroin addiction in boys and girls were specified as dominant, repressive, partner, utilitarian, integrating and independent. Gender-differentiated programs of pharmaco- and psychotherapy are proposed. PMID- 21322145 TI - [Some features of teenage beer alcoholism combined with hashish addiction]. AB - Sixty male teenagers with beer alcoholism combined with hashish addiction were examined. The beer consumption was promoted by drinking customs existing in the microsociety, curiosity, pressure of other people, the existing opinion on harmlessness of beer and its availability. In all cases, subjects began to use hashish after the development of beer alcoholism. Peculiarities of combined pathologies were as follows: one disease (beer alcoholism) created conditions for the development of another one (hashish addiction); the polymorphism of clinical symptoms (the syndrome of addiction included symptoms of both diseases); reciprocity of these diseases. Psychosensory disorders played a central role in clinical presentations of mixed intoxication. There was the increase of tolerance to hashish while the amount of consumed beer remained stable. Symptoms characteristic of dependence of both psychoactive substances were present in the clinical presentations of the syndrome. Mental disorders (dysphoric signs) were observed more frequently in the abstinent syndrome in the combined beer and hashish reception. Personality changes in teenagers promoted criminal activity. PMID- 21322146 TI - [The study of characteristics of overdose among users of opioid drug injections]. AB - Overdose is a serious problem as for people addicted to opioid drug injections (ODI) as well as for the community in general. To study characteristics of overdose, authors examined 60 ODI users and analyzed 27 overdose death cases. It has been shown that overdose is rather common among ODI users. Fatal and nonfatal overdoses most frequently take place among men at home or in the street. People often did not receive sufficient help in the overdose situation. We confirm the role of alcohol, long abstinence and variability in drug quality in the development of overdose. Witnesses of overdose in other users reported more health problems, family and social relations, were more concerned with their own and others risk in future compared to those reporting no overdose. Additional predictors were determined: a higher number of overdoses in the past; disturbances of family relations and somatic disorders. Mental disorders predicted the opioid overdose risk among ODI users. ODI users are interested in counseling and training to prevent overdose. Family psychotherapy and early diagnosis of comorbid disorders may be important ways of overdose prevention. PMID- 21322147 TI - [Naltrexone and fluoxetine for maintenance of remission in patients with heroin addiction: a double-blind randomized placebo-controlled trial]. AB - Two hundreds and eighty patients with heroin addiction were randomized into 4 equal groups. Patients of the group 1 received naltrexone (N) in dosage 50 mg/day and fluoxetine (F) in dosage 20 mg/day during 6 months. Group 2 received N/F placebo (FN), group 3--N-placebo (NP)/F and group 4--NP/FP. All patients underwent a session of individual psychotherapy for the maintenance of remission. Express urine drugs tests were used for remission control. Compliance was controlled by a riboflavin marker. Clinical state, psychiatric status and social functioning were assessed using quantified international scales and tests. To the end of the 6 month course, 43% of patients of group 1, 36% of group 2, 21% of group 3 and 10% of group 4 were in remission. Therefore, N/F was more effective than F/NP (p < 0.01) and FP/NP (p < 0.001); N/FP was more effective than F/NP (p < 0.05) and NP/FP (p < 0.001); F/NP did not differ significantly from NP/FP (p = 0.1); N/F did not differ from N/FP (p = 0.2). However N/F was more effective compared to N/FP only in women, probably, due to the higher baseline levels of depression, anxiety and anhedonia. Naltrexone was superior to placebo and fluoxetine in the efficacy of maintenance of remission and preventing relapse in patients with heroin addiction. The combination of naltrexone and fluoxetine was more effective compared to the monotherapy with naltrexone in women only. PMID- 21322148 TI - [The peculiarities of remissions in opioid dependence]. PMID- 21322149 TI - [Comorbid addictive disorders and schizophrenia in the aspect of pathogenesis and treatment]. AB - Combinations of schizophrenia with addictive disorders are common in clinical practice. Some hypotheses were posited to explain this phenomenon with the biochemical hypothesis being the most common. A vast body of evidence supports the similarity in the pathogenesis of addiction and schizophrenia. Biochemical data on the pathogenesis of both diseases are used for treatment recommendations. However there are many discrepancies in this field and future research is needed. PMID- 21322150 TI - [The comparative analysis of high-risk behaviour related to HIV infection in users of psychoactive drugs with stimulating action and opioids]. AB - To study clinical and psychological characteristics associated with high-risk behaviour related to HIV infection in 2006-2007 years, we examined 68 patients with psychoactive drugs (with stimulating action) and opioids (heroin) dependencies. Patients were stratified into 2 groups: users of psychoactive drugs (UPS)--34 patients and opioid users (OU)--34. Behavior of UPS differed from that of OU by using more drug injections per day although the former used syringes of other users less often. Therefore, the risk of being infected was lower in the UPS group compared to the OU group. The evaluation of the risk through sexual transmission did not reveal significant between-group differences. PMID- 21322151 TI - [Issues of HIV prevention among injection drug users]. PMID- 21322152 TI - [Gambling addiction: the psychopathological structure of game-circle]. AB - Thirty-two pathological gamblers were examined. The SCL-90-R, the LSI (Life Style Index) and the CSW questionnaires were used to evaluate psychopathological disorders. Based on the data obtained and the analysis of the development of pathological behavior, authors singled out 6 periods of the game-circle: 1) distress that directly followed the game (anxiety-depressive, obsessive compulsive and paranoia disorders); 2) moderate anxiety-depressive disorders; 3) subdepressive disorders with predominance of asthenia and apathy; 4) anxiety and dysphoria comorbid with subdepression; 5) the narrow state of consciousness (game trans) preceding the relapse; 6) the return to game. PMID- 21322153 TI - [Food addictions]. PMID- 21322154 TI - [Emotional burn-out in narcologists]. AB - To study the prevalence, structure and risk factors of emotional burn-out in narcologists, 90 practitioners in the field of narcology were studied. Emotional burn-out syndrome was found in 37.7% of narcologists. The stage of "resistance" characterized by the lowered interest in professional duties, sparing of emotions and feeling of being tired from interpersonal contacts was observed most frequently. Emotions were totally removed from the professional activity at the stage of "exhaustion". The emotional burn-out syndrome was most prevalent within the first 10 years of professional activity. The personality factors increasing the risk of burn-out were increased impulsiveness, lowered control of motivations and incentives, increased rigidity, inertness of mental processes, inability to exclude the traumatic experiences. The ability to plan the problem solving process and act in a logic and consistent way decreased the risk of the burn-out syndrome while the increased self-control produced the increased level of anxiety and contributed to the burn-out syndrome. PMID- 21322155 TI - [Comparative scientometric analysis of the Proceedings of XIII and XIV Congresses of Russian psychiatrists: narcology]. AB - An analysis of the chapter "Medical help for the substance abuses, clinic, treatment of the abusers, biological studies of the abuses' in the Proceedings of the last two Russian congresses of psychiatrists (XIII in 2000 and XIV in 2005) reveals the vast multiplicity of topics. The majority of topics featured in the XIII Congress does not provide any follow-up information in the materials of the XIV Congress thus not allowing to figure out the tendencies or consequences in the field of addiction studies. There is no uniformity in the vocabulary used in the chapter analyzed. The dominant topics such as alcoholism and opiate abuse make up a small part of the total amount of papers. PMID- 21322156 TI - [Will peanut allergy respond to hyposensitization?]. PMID- 21322157 TI - ["Nurses can provide a major contribution in times of coordination as the patients cope with their care and health". Interview by Sylvie Warnet]. PMID- 21322158 TI - [Telehealth, the importance of informatics in health care]. PMID- 21322159 TI - Conference discussion: Removal of aprotinin from low-dose aprotinin/tranexamic acid antifibrinolytic therapy increases transfusion requirements in cardiothoracic surgery. PMID- 21322161 TI - Abstracts of the 1st International Congress on One Health. Melbourne, Australia. February 14-16, 2011. PMID- 21322160 TI - Conference discussion: Immediate results of bidirectional cavopulmonary anastomosis and Fontan operations in adults. PMID- 21322162 TI - Conference discussion: Does a relationship exist between the number of thoracoscopic thymectomies performed and the learning curve for thoracoscopic resection of thymoma in patients with myasthenia gravis? PMID- 21322163 TI - Conference discussion: Engineering bioartificial tracheal tissue using hybrid fibroblast-mesenchymal stem cell cultures in collagen hydrogels. PMID- 21322164 TI - Abstracts of the Annual Meeting of the United States and Canadian Academy of Pathology. February 26-March 4, 2011. San Antonio, Texas, USA. PMID- 21322165 TI - Hospital pharmacists scrambling amid vast drug shortages: emergency physicians between roc and a hard place. PMID- 21322167 TI - Abstracts of the United States and Canadian Academy of Pathology Annual Meeting. February 26-March 4, 2011. San Antonio, Texas, USA. PMID- 21322166 TI - Forget Paris: emergency physicians can soon sit for US critical care boards. PMID- 21322169 TI - Crop prices soar as climate and demand hammer markets. PMID- 21322170 TI - Europe challenged on GM crops. PMID- 21322171 TI - Biofuel policies under pressure. PMID- 21322173 TI - Gorilla success. PMID- 21322172 TI - Fresh swine flu worries. PMID- 21322174 TI - Kevin Foster. PMID- 21322175 TI - Abstracts of Acute Leukemias XIII: biology and treatment strategies. February 27 March 2, 2011. Munich, Germany. PMID- 21322177 TI - Handling the termination of an employee. PMID- 21322178 TI - Android ('an, droid). PMID- 21322176 TI - Internet sex ads for MSM and partner selection criteria: the potency of race/ethnicity online. PMID- 21322180 TI - The use of in vitro technologies and high-resolution/accurate-mass LC-MS to screen for metabolites of 'designer' steroids in the equine. AB - Detection of androgenic-anabolic steroid abuse in equine sports requires knowledge of the drug's metabolism in order to target appropriate metabolites, especially where urine is the matrix of choice. Studying 'designer' steroid metabolism is problematic since it is difficult to obtain ethical approval for in vivo metabolism studies due to a lack of toxicological data. In this study, the equine in vitro metabolism of eight steroids available for purchase on the Internet is reported; including androsta-1,4,6-triene-3,17-dione, 4 chloro,17alpha-methyl-androsta-1,4-diene-3,17beta-diol, estra-4,9-diene-3,17 dione, 4-hydroxyandrostenedione, 20-hydroxyecdysone, 11-keto-androstenedione, 17alpha-methyldrostanolone, and tetrahydrogestrinone. In order to allow for retrospective analysis of sample testing data, the use of a high-resolution (HR) accurate-mass Thermo LTQ-Orbitrap liquid chromatography-mass spectrometry (LC-MS) instrument was employed for metabolite identification of underivatized sample extracts. The full scan LC-HRMS Orbitrap data were complimented by LC-HRMS/MS and gas-chromatography-mass spectrometry (GC-MS) experiments in order to provide fragmentation information and to ascertain whether GC-MS was capable of detecting any metabolite not detected by LC-HRMS. With the exception of 20-hydroxyecdysone, all compounds were found to be metabolized by equine liver S9 and/or microsomes. With the exception of 17alpha-methyldrostanolone, which produced metabolites that could only be detected by GC-MS, the metabolites of all other compounds could be identified using LC-HRMS, thus allowing retrospective analysis of previously acquired full-scan data resulting from routine equine drug testing screens. In summary, while in vitro techniques do not serve as a replacement for more definitive in vivo studies in all situations, their use does offer an alternative in situations where it would not be ethical to administer untested drugs to animals. PMID- 21322181 TI - [The use of sirdalud MR in patients with multiple sclerosis]. AB - The study included 54 patients with multiple sclerosis, aged from 23 to 53 years (mean age 37.7 +/- 8.5 years). To reduce muscle tension, 34 patients of the main group received tizanidine with the modified release of active substance (sirdalud MR) in dosage one capsule (6 mg) per day. Twenty-two patients of the comparison group received a standard form of tizanidine--sirdalud in tablets (2 mg) 3 times daily. Patients were examined at baseline, 1, 2 and 4 weeks of the treatment and 2 weeks after the end of the trial. The use of different forms of sirdalud had no effect on disability (the EDSS) scores in patients. Spasticity scores (the Ashworth scale) were decreased during the treatment with different forms of sirdalud but sirdalud MR had more stable effect which remained for 2 weeks after the end of treatment (p < 0.05). Significant differences were observed between tolerability of two forms: side-effects (sleepiness, asthenia) were more frequents in patients treated with the standard form of sirdalud (p < 0.05), the rate of their reduction was significantly higher in the sirdalud MR group (p < 0.05). PMID- 21322182 TI - [On open door to hope for chronic fatigue syndrome]. PMID- 21322183 TI - [Diabetes mellitus in the elderly]. AB - In Spain is estimated that the overall prevalence of diabetes mellitus (DM) is 6 to 10%. Taking into account the population older than 65 years the prevalence reaches 10-15%, and those over age 80 years is 20%. The old is a period of life characterized by progressive decline of authority and organizational involution. This means that during this stage there is a decline in the personal adjustment and a slowdown and lower sensitivity of homeostasis. PMID- 21322184 TI - [Chronic fatigue syndrome: more than fatigue]. AB - Chronic fatigue syndrome (CFS) is a disease recognized by all international medical organizations and WHO, and is classified under the code G93.3 of the International Classification of Diseases. Its prevalence is estimated around 2.54% being more common in women than in men (8/2) aged between 20 and 40 Is defined as a chronic new description characterized by the presence of subjective feeling of fatigue and exhaustion long disabling of more than 6 months duration that is not relieved by rest. It is a multisystem disorder that often presents a significant number of comorbid phenomena. Not known until specific tests to confirm the diagnosis, nor is there a cure to solve this health problem definitively The strongest evidence is based on the multidisciplinary approach for the symptomatic treatment of pain, sleep disorders, neurocognitive dysfunction, autonomic and control of depression and anxiety. The specific contribution of nursing to care for the person who lives and live with the SFC should be developed primarily in the field of health education and supportive care, support and assistance to help the patient and their relatives are an adaptive response to changes in health. PMID- 21322185 TI - [Nursing role in patient management diagnosed chronic fatigue syndrome]. AB - Chronic fatigue syndrome is a serious, complex and debilitating fatigue characterized by intense physical and mental, that does not subside significantly after rest and worsens with activity The appearance of the disease requires the patient to reduce the activity diminished their quality of life. While there is no cure, the complexity of the disease requires an interdisciplinary approach where the mission of nursing is to identify the least healthy responses of each individual in relation to their health status and interfering with them by means of specific support, integrated support and follow a care plan tailored to the individual needs of each individual. Fatigue, pain, sleep pattern disturbance, anxiety and lack of knowledge are the most prevalent health problems in patients treated at the Chronic Fatigue Unit, University Hospital Vail d'Hebron. Thus, in these problems and by developing a customized care plan process we use for health education as a tool for influencing the control of symptoms through interventions to improve the learning support, emotional support and Accompanying with the aim of helping the patient and their relatives are an adaptive response to their new health status and thus improve the quality of life. PMID- 21322186 TI - [Anatomophysiological bases of drug administration. Dosage forms and routes of administration]. AB - The administration of the right dose to the right patient is of paramount importance to obtain an optimal drug response within the scope of clinical pharmacology and tailored medicine. The marketing of safer and more efficient drug entities, along with the development of new drug administration devices provide a major boost for the diagnosis and treatment of diseases, beyond our imagination. However dose adjustment is not enough to produced the desired effect, and drug therapy should include an appropriate route of drug administration. Currently, there are many different and sophisticated methods to incorporate drugs into the patients that nurses should be familiar with. When there is no contraindication, oral route of drug administration is of choice and most frequently used as a physiological pathway of drug intake. PMID- 21322187 TI - [Updated review on the prevention of biological hazards in the nursing students]. AB - If the carrying out a practices is something extremely important in all degree studies, in the case of nursing this is something even more fundamental and of great educational impact. During that period, students not only put their knowledge and theory into practice, they get in touch with reality and they also expose themselves to a series of risks inherent to our profession. In addition to that, one has to take into account the appearance of various factors that aggravate their susceptibility, their inexperience as professionals, their exposure to some degree of stress due to the variable conditions and uncertainties in their environment, the lack of coverage under the PRL law makes this group more vulnerable to the risks. PMID- 21322188 TI - [Historical evolution of breastfeeding. Rights and family conciliation]. AB - Human milk has been and it is an important means of survival for the human being. The history of the breastfeeding has been linked to the woman's social and cultural situation and it has gone by different vicissitudes. During a long period the breastfeeding was considered as an unsightly unworthy practice and characteristic of low classes, women that had resources nurses used. In the XIX century artificial nursing appears that will be developed significantly starting from half-filled of the following century relegating, again, to a second plane to the natural nursing. With the beginning of the XX century the first rights of the workers appear and among them it is regulated the right for the first time to the permission for nursing. With the advance of the century diverse norms enlarge their content. Arriving to the current moment in which the right enjoys a wide legal recognition inside the norms that regulate the family reconciliation. PMID- 21322189 TI - [Nutritional and metabolic pattern]. AB - Being overweight or obese are more frequent conditions in highly developed countries. Moreover, according to WHO, those people who suffer from a mental health-related pathology have a higher risk to suffer cardiovascular complications than the rest of the general population. The main objective of this observational descriptive study is to evaluate whether or not the percentage of patients who are either overweight or obese interned in an acute psychiatric ward is equal to or greater than the percentage in the general population. The sample is comprised by 180 patients, 86 men and 94 women, less than 18 years old who have an average age of 44 years and who have been interned during a year from June 2007 to June 2008. The investigators analyzed the patients' BMI values when they registered, evaluating their distribution in terms of sex, age and clinical diagnosis, obtaining a BMI average of 27, overweight, with 25% having a BMI >30, obesity Investigators classified six diagnostic groups; those patients diagnosed as schizophrenic and having psychotic disorders comprised the largest group at 40%, and also was the group which had the highest incidence of being overweight or obese. Among the Galician general population, 38.6% are overweight while 17% are obese; in the sample study group, 42% register as overweight and 23.3% obese. The 18 to 24-year-old group registered a 28.6% rate of obesity superior to the 7% registered as overweight. The other two groups classified in this study registered an obesity percentage less than that for being overweight. The researchers conclude that among patients who suffer from mental health pathology the perception of an increase in weight produced by medication is frequent. Nurses have a fundamental role helping to identify how the principal causes of being overweight, sedentary habits and a lack of a balanced diet, and to facilitate strategies to patients, without opting for abandoning their medication. As health professionals in general, we should push for a systematic detection of obesity or being overweight among patients interned in hospitals, especially due to the inherent risks patients who have psychiatric pathologies run; these risks include sedentary habits, medication, difficulty to care for themselves, etc. PMID- 21322190 TI - [Research in nursing care and health]. PMID- 21322191 TI - [Ethnographical situations at the hospital. "She is coming to see if we have a bone in the nose.."]. AB - The first tool of the anthropologist is himself/herself. As for "his/her" field it is constructed by the interrelations which are formed from the beginning of the survey and throughout this one between the researcher and the community of which he/she tries to get the explicit and implicit functionings. Beyond the common opposition between subjectivity and objectivity, between empathy and distance, or even between sensitive disorder and classificatory logic, the watchful use of floating attention and fortune founds the rigour of the approach. This way the method is not to have any, at least at first sight. This is what the article tries to show by its very construction. To mirror someone is never insignificant because of the tensions and conflicts which haunt every human group. It is particularly true when it is about fields as tormented as violent, such as certain hospital departments where the ethnologist, in position of listening in places where precisely this one lacks, has to deal with the complaints and crossed sufferings of the nursing staff and the patients. PMID- 21322192 TI - [The mixed design in nursing sciences or when a question of research calls for qualitative and quantitative strategies]. AB - The use of a mixed method research design raises many questions, especially regarding the paradigmatic position. With this paradigm, we may consider the mixed method design as the best way of answering a research question and the latter orients to one of the different subtypes of mixed method design. To illustrate the use of this kind of design, we propose a study such as conducted in nursing sciences. In this article, the challenges raised by the mixed method design, and the place of this type of research in nursing sciences is discussed. PMID- 21322193 TI - [Longitudinal analysis of personal and work-related factors associated with turnover among nurses]. AB - BACKGROUND: While many scholars have acknowledged the relationship between personal and work-related factors associated with job search and actual turnover, there is a lack of longitudinal designs that test this relationship empirically. OBJECTIVES: This longitudinal study examines specific determinant factors that differentiate between so-called 'stayers' and 'leavers' within the nursing profession, and identifies risk factors for premature leaving by comparing nurses who have left their job, or the nursing profession, with nurses who stay. METHODS: This cross-national exploratory European survey included 34,587 nurses (baseline measurement) working in 623 hospitals, nursing homes, and home care institutions, and comprised two measurements with a one-year time interval. The final samples for the follow-up measurement included 14,016 stayers and 866 leavers. As regards the leavers, the participating nurses were asked to indicate to what extent personal and work-related factors had contributed to the decision to leave their health care institution. RESULTS: Nurses' intent-to-leave scores were higher in the baseline measurement among those who left the organization during the following 12 months, than among those who stayed (24.0% versus 13.5%). A majority of nurses (86.8%) left their profession voluntarily. Involuntary departure occurred more often in Eastern European countries. Nurses indicated that the reasons for leaving were: working conditions (e.g., relationship problems, emotional difficulties,time pressure and quality of care, dissatisfaction with use of one's competence and lack of autonomy, work schedule difficulties, and dissatisfaction with pay) family reasons (e.g., caring for relatives). For a considerable number of nurses, health reasons and the desire for continuing education added to their decision to leave. DISCUSSION: Health care organizations should pay attention to preventive measures in order to protect labor market potential. Recommendations are made for human resource development in health care organizations and for further empirical research to better understand to what extent different policy systems across the European countries explain variance in outcomes. PMID- 21322194 TI - ["Being with" the person cared for in a rehabilitation context: a profound, therapeutic and transformative human relationship]. AB - Due to the relational nature of nursing, "being with" the person that is being cared for is an essential phenomenon in the nursing profession. Furthermore, this concept lies at the very core of the philosophy of Caring, which is, according to various authors, the essence of nursing. Using Watson's Human Caring philosophy as the disciplinary perspective, this phenomenological study has explored, with nurses working in rehabilitation (n=17), the meaning of the experience of "being with" the person cared for, as well as the nurses' perception of the contribution of this experience in the rehabilitation of the cared-for person. A total of 51 interviews, three for every participant, were analyzed using the Relational Caring Inquiry phenomenological method developed by Cara (1997). Through data analysis five eidos-themes have emerged; the following four related to the significance of "being with" the cared-for person: the importance of humanistic values at the core of care; the involvement of the nurse and the cared-for person; the reciprocal and relational dimensions of care, and the irreplaceable care experience of contextual complexity. The fifth and last eidos-theme- enhancing the body-soul-spirit harmony of the person cared-for and of the nurse- leads participants to perceive the therapeutic contribution of the experience of "being with" the cared-for person during their rehabilitation process. These results have contributed to the emergence of the meaning of the phenomenon studied: "a deep, therapeutic, and transforming human relationship". All the results lead to innovative implications and suggest possible interventions that can serve as guides to renew the clinical practice of nurses in rehabilitation, as well as the education and research in nursing science. PMID- 21322195 TI - [Constipation in the hospital. Ethical reflection on its care by the nursing staff]. AB - The intestinal elimination of the hospitalized patients is a function insufficiently taken into account by the nursing staff from a preventive point of view. Nevertheless, numerous patients present transit disorders which are mostly translated into a diagnosis of constipation requiring therapeutic prescriptions and sometimes even aggressive and expensive medical examinations. The objective of this work is to lead an ethical reflection on the care of intestinal elimination by the nursing staff. Through a questionnaire, we wish to answer 3 questions: how come the nursing staff have difficulties taking care of the intestinal elimination of the hospitalized patients? What are the determiners which influence the care of the intestinal elimination by the nursing staff? Does training prepare the nursing staff to take care of the intestinal elimination of the hospitalized patients? The questionnaire was distributed to doctors, male and female nurses, nursing auxiliaries and students in care of the sick working in medicine, surgery and intensive care of the same hospital. This survey allowed to question 130 persons among whom 36 doctors, 37 male and female nurses, 30 nursing auxiliaries and 27 students. We were able to confirm that the care of the intestinal elimination is insufficiently taken into account in a preventive way, because 56 % of the people interviewed explain that the problem of intestinal elimination is not approached before the complaint of the patient Several determiners make that the nursing staff are not in a preventive approach. This care does not meet much interest, is experienced as devaluing, taboo and the relation nursing staff-patient is hindered because everyone has difficulties to speak about it. Institutional difficulties are also discussed, such as the lack of coordination of the nursing staff and the lack of time. Another point of this survey shows that work experience is not an element which facilitates this care because the more the nursing staff have experience, the more they postpone this care and more the embarrassment is felt Finally, we were able to point out that the received training does not prepare the nursing staff to take care of this function. Indeed, 61% of the people interviewed explain that certain difficulties are inferred by the lack of social skills of the professionals, like the discomfort to speak about this particular need. This work thus allowed to lead this ethical reflection on the care of the intestinal elimination to understand its meaning.As Spinoza said: "One should not laugh, one should not despair, one should not curse, but one should understand". PMID- 21322196 TI - [Descriptive study of factors facilitating and restricting the development of critical care nursing competence]. AB - In the literature, few studies have examined the development of critical care nursing competence. Given that nursing practice is different in these units and that the nursing workforce is less and less experienced, the goal of this study is to describe the factors facilitating and restricting the development of critical care nursing competence. A semi-supervised interview conducted in the spirit of Chinn and Kramer (2008) was used to collect data from 10 nurses, categorized according to Benner's (1995) levels of competency. Results demonstrated that 27 factors grouped on the basis of individual, contextual and organizational perspectives facilitated or restricted the development of competence by nurses working in intensive care. Although some factors had already been documented in the literature, several factors listed in this study were clarified for the first time. PMID- 21322197 TI - [Evaluation of a conflict situation between two services in a seniors' residence according to the Herzberg Theory]. AB - The objectives of this research are to identify employee dissatisfaction in two seniors' residences and to find resolutions to these problems. Conflicts between employees from two different services are not unusual in health care. It remains a major preoccupation for supervisors. Such a conflict arose in a seniors' residence between employees from the food services and the health care members. At every opportunity the quarreling groups would antagonize each other. They were all self-proclaimed experts when it came to the nutritional needs of the residents. The employees were convinced they knew more about the likes and dislikes of the residents than anyone, even more than the nutritionist and the family. The directors wanted to know what originated such conflicting behavior amongst both groups. The Herzberg Theory on hygiene and motivation served as a reference guide for the identification and classification of these factors as well as proposed solutions by the groups of participants. This theoretical model defines the interpretation of dissatisfaction and guides the directors in decision-making and implementation of solutions. Results showed that the food services personnel were more concerned about hygiene whereas the health care noticed dissatisfaction related to motivational factors. Thanks to the application of this model the food service personnel who were experiencing difficulty with hygiene matters saw modifications in their environment and health care employees enjoyed improvements in their tasks. PMID- 21322198 TI - [Joint time-frequency analysis for removing the spectral interference of terahertz]. AB - Conventional Fourier-transform mixes the frequency components of the entire temporal terahertz waveform in one frequency domain; therefore, it cannot distinguish the terahertz frequency in the main pulse from the noise frequency in the pulse tail. Thus traditional Fourier-transform produces inconsistent spectra from different scanning lengths of terahertz pulse. And the interference spectrum appears when the THz echo pulse is recorded. The authors applied wavelet transform and removed the inconsistent spectra and the interference spectra. Wavelet-transform technique exhibited the local frequency of THz in different time locations. This technique would find applications in THz time-resolved spectroscopy. PMID- 21322199 TI - [System parameters selection and optimization of tunable diode laser absorption spectroscopy]. AB - The system performance of tunable diode laser absorption spectroscopy (TDLAS) is affected by the modulation parameters such as modulation index, modulation frequency, scanning amplitude and scanning frequency. There is a lack of definite parameters selection basis in practical measurement. Aiming at this problem, the influence of modulation parameters on second harmonic signals was observed by experiment based on a certain theory in the present paper, and the basis and method of modulation parameters optimization for various system functions and demands were summarized by analyzing the signal characteristic including amplitude, signal to noise ratio, symmetry and peak width. For the system of concentration or temperature detection the amplitude and signal to noise ratio will be taken into prior consideration which require optimum modulation index, lower modulation frequency and lower scanning frequency. In condition of pressure detection deduced by lineshape the signal symmetry and peak width are more important to ascertain the modulation parameters according to practical demands. Scanning amplitude will be adjusted to obtain complete signal waveforms, then scanning frequency can be adjusted according to system speed and accuracy requirement. The result of the experiment provided a definite basis for conforming the working state of such system. PMID- 21322200 TI - [Spectrum diagnostics for optimization of experimental parameters in thin films deposited by magnetron sputtering]. AB - The plasma emission spectra generated during the deposition process of Si-based thin films by radio frequency (RF) magnetron sputtering using Cu and Al targets in an argon atmosphere were acquired by the plasma analysis system, which consists of a magnetron sputtering apparatus, an Omni-lambda300 series grating spectrometer, a CCD data acquisition system and an optical fiber transmission system. The variation in Cu and Al plasma emission spectra intensity depending on sputtering conditions, such as sputtering time, sputtering power, the target-to substrate distance and deposition pressure, was studied by using the analysis lines Cu I 324. 754 nm, Cu I 327. 396 nm, Cu I 333. 784 nm, Cu I 353. 039 nm, Al I 394. 403 nm and Al I 396. 153 nm. Compared with the option of experimental parameters of thin films deposited by RF magnetron sputtering, it was shown that emission spectra analysis methods play a guiding role in optimizing the deposition conditions of thin films in RF magnetron sputtering. PMID- 21322201 TI - [Measurement of plasma parameters in slot microplasma by optical emission spectrum]. AB - Slot microplasma was generated in argon and air mixture by using dielectric barrier discharge device with two parallel water electrodes. The molecular vibrational temperature, molecular rotational temperature and average electron energy of the slot plasma were studied by optical emission spectrum. The molecular vibrational temperature was calculated using the second positive system of nitrogen molecules ( C3 pi(u) --> B3 pi(g)). The molecular rotational temperature was calculated using the first negative system of nitrogen molecular ions ( B 2sigma(u)+ --> X sigma(g)+). The relative intensities of the first negative system of nitrogen molecular ions (391.4 nm) and nitrogen molecules in the excitation level (337.1 nm) emission spectrum line were measured for studying the variations of electron energy. It was found that the molecular vibrational temperature, molecular rotational temperature and average electron energy decrease with gas pressure increasing. PMID- 21322202 TI - [Quantitative analysis of Mn and Si of alloy steels by laser-induced breakdown spectroscopy]. AB - The concentration of Mn and Si in different kinds of steels was determined by laser-induced breakdown spectroscopy (LIBS). The multivariate quadratic nonlinear function was adopted for calibration. Samples including common alloy steels, stainless steels and carbon tool steels were analyzed. The matrix effect was serious because of large difference in compositions of different kinds of steels and strong line overlaps in steel spectra. Therefore, the common calibration methods that only use one analytical line to calibrate the complex chemical compositions of alloy steels will lose much information. The multivariate calibration methods, however, can utilize more information of spectra, successfully reduce the matrix effect and improve the measurement repeatability and accuracy of LIBS. Compared with the common calibration method based on one analytical line, the relative standard deviation was reduced from above 20% to below 10%, and the accuracy was increased by more than 5 times for Mn and more than 6 times for Si. PMID- 21322203 TI - [Preparation and luminescence characteristics of Ba1.97 Ca1-x (B3O6)2: Eu(0.03)2+, Mn(x)2+ phosphor for white LED]. AB - The Ba1.97 Ca1-x (B3O6)2 : Eu2+, Mn(x)2+ (x = 0, 0.03, 0.06, 0.15) phosphors were synthesized by high temperature solid-state reaction, and their phase composition and luminescence properties were studied. In these phosphors, Eu2+ locates at the crystal sites of Ba2+ and Ca2+ ions. Under 317 nm UV light excitation, the 5d --> 4f transition of Eu2+ forms a broad blue emission band with a peak at 450 nm. With the energy transfer from Eu2+ ions, Mn2+ ions emit a broad red band with the peak at 600 nm. The mixture of the broad blue emission and a broad red emission forms an approximate white light with the CIE chromaticity (x = 0.371, y = 0.282). The phosphors can be excited effectively by UV light in the range of 250 400 nm, so they are the potential candidates for single white light-emitting phosphor excited by UV-LED. PMID- 21322204 TI - [Fourier transform infrared spectroscopic study on gallbladder carcinoma]. AB - Fourier transform infrared (FTIR) spectroscopy with an attenuated total reflection(ATR) probe was used to study the benign and malignant tissues of gallbladder. FTIR spectra of 18 tissues of gallbladder carcinoma and 139 benign tissues were collected and analyzed. The results demonstrated that bands related to lipid, carbohydrate, and nucleic acid from malignant samples were significantly different from those of benign ones: (1) The peak positions of 1 167 and 1 123 cm(-1) shifted toward lower wave number (P < 0.05) but that of 1 309 cm(-1)' to the higher one (P < 0.05); (2) The relative intensity ratios of I2 856/I1 461, I1 167/ I1 461, I1 123/I1 461, I1 082/I1 461, increased significantly (P < 0.05) (3) The half-widths of 1 167 and 1 082 cm(-1) increased significantly (P < 0.05), whereas the half-width of 1 461 cm(-1) decreased significantly (P < 0.05). (4) The probability of 1 750 cm(-1) band of gallbladder carcinoma tissues increased significantly (P < 0.05). PMID- 21322205 TI - [A new method of characteristic wavelength sub-range selection of near infrared spectroscopy]. AB - To improve and simplify the prediction model of carotenoid content of cucumber leaves, genetic algorithm (GA) combined with Metropolis acceptance criterion of simulated annealing algorithm (SAA) as well as interval partial least square (iPLS) were proposed and used to establish the calibration models of carotenoid content against cucumber leaves spectra. The cucumber leaves spectra data were divided into 40 intervals, among which 7 subsets, i. e. No. 3, 4, 14, 18, 21, 32 and 33, were selected by SAA-GA-iPLS. The comparison was made between SAA-GA-iPLS and traditional genetic algorithm interval partial least square (GA-iPLS), and the result of this study shows that SAA-GA-iPLS was better than traditional genetic algorithm interval partial least square (GA-iPLS). PMID- 21322206 TI - [Analysis of diffraction in Fourier-transform infrared spectrometer based on step mirrors]. AB - Diffraction in the Fourier-transform infrared spectrometer based on step mirrors was analyzed in the present paper, and the influence of diffraction on the spectrum reconstruction with different width of step mirrors, wavelengths and distance was also discussed. It is shown that the influence of diffraction is low when the distance is less than 10 cm and the width of mirror is more than 0.5 mm. Also, a method to reduce the noises in spectrum reconstuction is discussed in this paper. The results could be used in the design of the spectrometer and the data processing in the next step. PMID- 21322207 TI - [Analysis of milk and dairy products by near-infrared spectroscopy: a review]. AB - As a highly efficient, convenient and nondestructive detection method, near infrared spectroscopy (NIRS) is appropriate for the analysis of milk and dairy products. The present review discusses the principle of the near-infrared spectroscopy analysis technology and the evaluation standard criteria of milk and dairy products, and also reviews the hardware device technology and the data processing technique for the analysis of milk and dairy products in order to promote the application of near-infrared spectroscopy analysis technology in milk and dairy products quality control in China. PMID- 21322208 TI - [Feature analysis and discrimination of varieties of corn based on near infrared spectra]. AB - A new method for the discrimination of varieties of corn was proposed based on the data set of near-infrared spectroscopy range from 4 000 to 12 000 cm(-1) of corn seed varieties. Principal component analysis (PCA) method was used to study the feature of the data, and the authors found that the near-infrared spectroscopy of corn seed varieties has a clear feature of zonal distribution, so the correlativity between the change in the distribution of the principal component and the discrimination result was studied, according to which the normalized principal component analysis (NPCA) method was proposed. Besides, principal direction biomimetic pattern recognition (PBPR) was proposed according to the feature, which got a better discrimination result. The average correct recognition rate attained 97.67% for test set I, and the average correct rejection rate attained 98.40%, with 13 of the 30 varieties reaching the correct recognition rate of 100%; The average correct rejection rate attained 98.90% for the test set II , and 11 of the 30 varieties reached the correct rejection rate of 100%. It was proved that the method had a high correct discrimination rate. PMID- 21322209 TI - [The NIR spectra based variety discrimination for single soybean seed]. AB - With the development of soybean producing and processing, the quality breeding becomes more and more important for soybean breeders. Traditional sampling detection methods for soybean quality need to destroy the seed, and does not satisfy the requirement of earlier generation materials sieving for breeding. Near infrared (NIR) spectroscopy has been widely used for soybean quality detection. However, all these applications were referred to mass samples, and they were not suitable for little or single seed detection in breeding procedure. In the present study, the acousto--optic tunable filter (AOTF) NIR spectroscopy was used to measure the single soybean seed. Two varieties of soybean were measured, which contained 60 KENJIANDOU43 seeds and 60 ZHONGHUANG13 seeds. The results showed that NIR spectra combined with soft independent modeling of class analogy (SIMCA) could accurately discriminate the soybean varieties. The classification accuracy for KENJIANDOU43 seeds and ZHONGHUANG13 was 100%. The spectra of single soybean seed were measured at different positions, and it showed that the seed shape has significant influence on the measurement of spectra, therefore, the key point for single seed measurement was how to accurately acquire the spectra and keep their representativeness. The spectra for soybeans with glossy surface had high repeatability, while the spectra of seeds with external defects had significant difference for several measurements. For the fast sieving of earlier generation materials in breeding, one could firstly eliminate the seeds with external defects, then apply NIR spectra for internal quality detection, and in this way the influence of seed shape and external defects could be reduced. PMID- 21322210 TI - [Discrimination of seven species of Agrimonia pilosa Ledeb and its extracts by FTIR and 2D-IR]. AB - The objective of the present study is to discriminate seven species of Agrimonia pilosa Ledeb herbs and their total tannin extracts by Fourier transform infrared spectroscopy (FTIR), second derivative infrared spectroscopy, and two-dimensional correlation infrared spectroscopy (2D-IR) under thermal perturbation. The structural information of the samples indicated that Agrimonia pilosa Ledeb and their extract residues contain a large amount of starch and calcium oxalate, since some characteristic absorption peaks of the starch, such as 1 151, 1 101, 1 032 and 988 cm(-1) can be observed; and some characteristic absorption peaks of the calcium oxalate, such as 1 618, 1 318 and 780 cm(-1), can be observed. Further more, the characteristic absorption peaks of the sulfate which arouse at 1 711 and 1 447 cm(-1) in the IR spectra of Agrimonia pilosa Ledeb acetone extracts can be found. The macroscopical fingerprint characters of FTIR and 2D-IR spectra can not only provide the information of main chemical constituents in medicinal materials and their different extracts, but also compare the components differences among the similar samples. In conclusion, the multi-steps IR macro fingerprint method is rapid, effective, visual and accurate for pharmaceutical research. PMID- 21322211 TI - [Temperature dependent Raman spectra and micro-structure study of cuspidine in solid and liquid phases]. AB - Cuspidine plays an important role in conventional metallurgical continuous casting mould flux. An UV laser source was used to record its ambient and high temperature Raman spectra (temperature range: 298-1 723 K) combined with a charge coupled device (CCD) detector. Both increasing and decreasing processes as well as characteristic spectra and shifts in wavenumber were observed. Micro-structure of cuspidine in liquid state is not unitary and different from that in solid state, suggesting multi clusters coexisting. Density functional theory (DFT) simulation method was applied to calculate its wavenumbers of Raman active vibrations by introducing the crystal spatial configuration model of cuspidine. Thus the experimental vibrational wavenumbers of the characteristic peaks could be assigned. This will help study physical and chemical behavior of cuspidine in continuous casting mould flux and provide an unique in-situ method under varying temperature with Raman spectroscopic technique. PMID- 21322212 TI - [Characteristics of Raman spectra of natural clinochlore at 200 degrees C and 0.95-7.70 GPa]. AB - Variation of crystal structure of natural clinochlore with pressure was investigated by the approach of diamond anvil cell (DAC) and in situ micro-Raman spectroscopic measurement at 200 degrees C and up to 7.7 GPa. The 481 and 786 cm( 1) peaks shift towards high-frequency linearly with increasing pressure at 200 degrees C. The linear relations between Raman shift (N, cm(-1)) and pressure (P, GPa) for the two peaks are: N = 11.136P+482.6 (R2 = 0.987 4) and N = 5.055P+785.7 (R2 = 0.983 7), respectively. The 865 cm(-1) peak arising from the stretching mode of the Si-O(nb) shifts slightly because of the strong repulsion between T cations at the tetrahedral sites and M cations at the octahedral sites in the TOT layer. Raman shift of 481 cm(-1) and 786 means the shortening of the length of M O(br) and Si-CO(br) bonds since the peaks are contributed by the stretching mode of the M-O(br) and Si-O(br) respectively. No phase transition of clinochlore under the experimental condition was found. The results indicate that chlorite minerals may be stable at least at a depth of 80-90 km in the cold subduction zones, and the fluid derived from chlorite dehydration may be an important fact for earthquake occurrence in the subduction zones. PMID- 21322213 TI - [Raman spectra study of soy protein isolate structure treated with pulsed electric fields]. AB - The effect of pulsed electric field on molecular structure of soy protein isolate (SPI) was investigated by Raman spectroscopy method. The applied pulsed electric field was up to 50 kV * cm(-1) with pulse width 40 micros. It was demonstrated from the Raman spectra that the PEF treatment undei 50 kV * cm(-1) had induced disappearance significantly of peak near 2 886 cm(-1) bond. It was also explored that with the increase in treatment time, the polarity of microenvironment of aliphatic amino acid residues and the exposure of tryptophan residues from a buried hydrophobic microenvironment were increased. On the other hand, the interaction of serine acid residues, the C-H plane bend vibration, C-N stretch vibration, and the C=O stretch vibration of aspartic acid and glutamic acid were decreased. The embeding or participation of the tyrosine phenolic groups as hydrogen bond donors was firstly increased with the treatment time (less than 1 600 micros), and afterwards decreased (from 1 600 to 3 200 micros). PMID- 21322214 TI - [Self-assembly of two kinds of nanoparticles and their surface enhanced Raman spectroscopic study]. AB - Two kinds of nanoparticles (gold nanoparticles and Au core Pt shell nanoparticles) on silicon surfaces which were silanization were electrostatically self-assembled. The density of nanoparticles was controlled by changing the time of the substrate immersed in colloids. The substrate was characterized by scanning electron microscope (SEM), and the results indicated that Au and Au@Pt particles were dispersed on the substrate with mono/submonolayers. The authors used pyridine (Py) as a probing molecule, and surface enhanced Raman spectroscopy (SERS) effect was investigated on pure Au and Au-Au@Pt mixed nanoparticle surfaces under the excitation line of 632.8 nm. The results revealed that there is a significant shift of the two characteristic peaks of Py, but the enhancement factors of Au dropped off precipitously with the introduction of the Au@Pt nanoparticles. The authors attributed this effect to the introduction of metal d states from the metal, which would serve effectively to quench the surface plasmon excitation necessary for large (electromagnetic) enhancements in Raman spectroscopy. PMID- 21322215 TI - [Raman spectrum study of 3.3'-diethylthiatri carbocyanine iodide]. AB - 3.3'-Diethylthiatricarbocyanine iodide (DTTC) dye is an important infrared Raman probe molecule, and has received great attention in the past decades due to their potential applications in Raman imaging, single cell detection, and tumor marker. In the present work, ordinary Raman, surface enhanced Raman scattering (SERS), and theoretical Raman spectra were given to estimate the Raman spectrum of DTTC suspension. More specifically, the original gold nanospheres (60-nm diameter) and gold nanorods (NRs) were encoded with DTTC and stabilized with a layer of thiol polyethylene glycol (PEG) as Raman reporter, and SERS data were obtained from the samples. Density functional theory (DFT) calculation was applied to calculate the optimized Raman spectra of DTTC water solvent on a B3LYP/6-31G level. Subsequently, the obtained experimental spectra from the DTTC were carefully compared with the theoretically calculated spectra. From the spectra comparation, good agreements were obtained between the theoretical and experimental results. This work will facilitate the development of ultrasensitive SERS probes for advanced biomedical applications. PMID- 21322216 TI - [The study of dimethoate by means of vibrational and surface enhanced Raman spectroscopy on Au/Ag core-shell nanoparticles]. AB - The vibrational structure of dimethoate, with its solid state and saturated solutions at acidic and basic conditions, was characterized with combination of means of FTIR and FT-Raman vibrational spectroscopy technology, and the comprehensive information about the dimethoate molecular groups' vibrational features was obtained. The surface enhanced Raman scattering (SERS) spectra of dimethoate at different concentrations with different acidic and basic conditions, and adsorbed on the substrate's surface of the core-shell Au/Ag nanoparticles, were also obtained. The adsorption states of dimethoate's molecule on the substrate's surface of the core-shell Au/Ag nanoparticles and the effects by the different acid-base conditions were investigated, with speculation of the adsorption mechanism. From the results, v(as)(NH), v(as)(CH3), v(O=C-N), tau(O=C N), v(P-O), v(P=S), v(C-C) and delta(P-O-C) are the characteristic peaks of inner dimethoate structure's vibrations; and the concentration range in which dimethoate could interact with core-shell Au/Ag nanoparticles fully is about 1.0 x 10(-3) mol * L(-1) both in acidic and basic conditions. Dimethoate's molecule interacts with SERS' substrate surface mainly through P-O-C, O=C-C, (S-CH2), P=S, and CH3 structures; and the effects of dimethoate's hydrolysis path in acidic and basic conditions on the adsorption are discussed, which give some good references for the research of organophosphorus pesticides' transformations in different environmental systems. PMID- 21322217 TI - [Micro and nondestructive analysis of blue dyes from silk fabrics and decorative painting of historic building]. AB - Dye analysis is important to the understanding of fabric color degradation and technical development of ancient printing and dyeing. In the present study, thin layer chromatography and Raman spectroscopy were used for the analysis of blue dyes from 6 silk fabric of Tang dynasty and decorative painting of Jian Fu Gong, Forbidden City. The applicability of these two methods in the cultural heritages was also studied. The results indicate that all these blue substances are indigo; indigo was not only used as dye in ancient fabrics, but also as pigment in decorative painting of historic building, so it is used widely. Both analytic methods have advantages and disadvantages; Raman spectroscopy is nondestructive analysis; thin layer chromatography needs small amount of sample, but could give more information. PMID- 21322218 TI - [Cryogenic Raman spectroscopic characteristics of NaCl-H2O, CaCl2-H2O and NaCl CaCl2-H2O: application to analysis of fluid inclusions]. AB - Accurately diagnosing the types of the salt and calculating the salinity quantitatively are the significant content of fluid inclusions. The traditional method of testing fluid inclusions salinity is cooling. To overcome the difficulty for observing freezing phase transition, the authors tested the spectrum of NaCl-H2O, CaCl2-H2O and NaCl-CaCl2-H2O systems at -180 degrees C by laser Raman spectroscopy. The result demonstrates that the ratio of peak values has linear relationship with salinity. Calibration curves were established by typical ratio of hydro-halite at 3 420 cm(-1) to the ice at 3 092 cm(-1), and the ratio of antarcticite at 3 432 cm(-1) to the ice at 3 092 cm(-1). The calibration curves have very high correlation coefficient. This method is verified by synthetic hydrocarbon-bearing aqueous fluid inclusions and quartz aqueous fluid inclusions of well Fengshen 6 in Dongying sag. The results of the authors' experiments show that cryogenic Raman spectroscopy can not only identify the types of the salts but also determine the salinity effectively in fluid inclusions. PMID- 21322219 TI - [Fluorescence characterization of leachate organic matter in 717 resin adsorption process]. AB - Synchronous fluorescence spectroscopy and 3-dimensional excitation emission matrices spectra (3DEEM) were used to study the composition variation of dissolved organic matter (DOM) in landfill leachate in the adsorption process with 717 resin. The synchronous fluorescence spectra showed fluorescence intensities of longer wavelength went down greatly while those of shorter wavelength went up in the first 10 min, then there were little changes. 3DEEM results indicated that there were two fulvic-like fluorescence peaks, whose intensities decreased dramatically, the peak intensities ratio (I(UV)/I(Vis)) also decreased, and the blue shifts of emission wavelengths took place obviously with the time rising. It was indicated that the adsorption rate of DOM by 717 resin was fast, and the main adsorbed DOM had higher molecular weight and higher degree of complexity, which was potential to facilitate subsequent bio-treatment. PMID- 21322220 TI - [Detection of dissolved organic matter based on three-dimensional first-order derivative fluorescence spectrometry]. AB - Based on three-dimensional first-order derivative fluorescence spectrometry, an analysis method for detecting dissolved organ matter in water is proposed in the present paper. By using simplified least squares differentiation methods presented by Savitzky and Goly, the first-order partial derivatives for emission wavelength and excitation wavelength were calculated. As the fitting polynomial has the smoothing function in the calculation of derivative spectra, a separate smoothing method is not required to remove spectrometry noise. The regression model was calculated by partial least square for 4-dimension fluorescence data including emission wavelength, excitation wavelength and their first-order derivatives. The Experimental results for detecting total organic carbon (TOC) in water show that the proposed method has obvious advantage over the conventional fluorescence spectrometry analysis methods in the aspect of the root mean square error of prediction and correlation coefficient. PMID- 21322221 TI - [The influence of the redox conditions on the three-dimensional excitation emission matrix (3DEEM) fluorescence spectroscopy of the dissolved organic matter (DOM) in the overlying water]. AB - In the present study three-dimensional excitation-emission matrix (3DEEM) fluorescence spectroscopy was applied to characterize the dissolved organic matter (DOM) in the overlying water under aerobic and anaerobic condition. The effects of redox condition were significant on 3DEEM fluorescence spectra of DOM, and in the aerobic condition, the peak intensities of protein-like fluorophores were both higher than those of the humic-like fluorophores, however, the phenomenon of the oxidative degradation of humic-original DOM could be seen. While in anaerobic condition, the peak intensities of the humic-like fluorescence were increased with increasing the incubation time. After the 21 day anaerobic incubation, the peak intensities of the humic-like fluorescence can be as 3.51 and 3.78 times higher than those of protein-like fluorescence. The differences in the DOM fluorescence parameters, e.g., peak intensities, locations and fluorescence index, indicate the difference in the chemical structures and various origins of the DOM in the overlying water between sediment-water interfaces. PMID- 21322222 TI - [Study on the fluorescent characteristic of tryptophan in the process of the waste water treatment]. AB - Tryptophan is one kind of representative pollutants in waste water. The present paper focuses on the research on the relation between the consistence, pH, ionic strength and the fluorescent characteristic of tryptophan. The result shows that: (1) Tryptophan in the low consistence range (0.01-3 m x L(-1)) shows good linear relation, the correlation coefficient is up to 0.995 88, while the linear relation in the high consistence range (3-30 mg x L(-1)) is slightly worse and the correlation coefficient is only 0.942 24; (2) In the acidic condition, the relative fluorescence intensity of tryptophan strengthens while the pH arises, and when the pH is in the range (6.5, 7.5), the intensity is relatively steady, while when the pH reaches 12, it drops off; (3) With the enhancement of the ionic strength, the relative fluorescence intensity of tryptophan reduces to some extent, and when the nitrate ion reaches to a high consistence, the spectrogram shows EERS. PMID- 21322223 TI - [Spectrum analysis methods of protein adsorption and design of biomedical materials]. AB - Protein absorption happens firstly when biological materials contact environment of organisms. The competitive adsorption behavior of different protein and the impact of biomaterial surfaces characteristics on protein adsorption are summarized. Materials with small surface free energy, high hydrophility, and a negative charge, or with the presence of micro-phase separation structure are able to reduce fibrinogen adsorption, showing good anti-clotting properties. FTIR, CD, NMR and FL are applied in protein adsorption analysis. XPS, Raman, AFM and other modern instruments have also emerged in this area. QCM appears to be more intuitive in the study of protein adsorption mechanism. The development of study on protein adsorption would guide the design of biomedical materials. PMID- 21322224 TI - [The analysis of consistency between HJ-1B and Landsat 5 TM for retrieving LST based on the single-channel algorithm]. AB - To ascertain whether the thermal infrared image of HJ-1B which has the similar sensor parameter and setting to Landsat 5 TM6 image is applicable for retrieving the land surface temperature (LST), a comparison of retrieved LST between two types of sensors was conducted. Two scenes of thermal infrared images that came from different sensors were acquired in 5th, Apr 2009, which covered the same region in Beijing. To retrieve LST, a generalized single-channel algorithm developed by Jimenez-Munoz and Sobrino was applied. The LST of study area for both images was thus generated. Based on the LST mapping results and corresponding statistics, an apparent trend could be observed which indicated the consistency in both LST value and its spatial distribution. Consequently, the performance of HJ-IB IRS serving as the data source for LST retrieval was assessed and illustrated in this study. Besides, a high temporal resolution as well as wide swath of the HJ-IRS data suggested its potential in application. PMID- 21322225 TI - [Simple preparation and characterization of MTiO3 (M = Sr or Ba) supported on TiO2 nanorods]. AB - Cubic phase MTiO3 (M = Ba or Sr) nanoparticle-supported TiO2 nanocomposites were prepared using Sr(OH)2 or Ba(OH)2 and TiO2 nanobelts as precursors by hydrothermal process. Their component, phase, morphology, structure and optical property were characterized using various XRD, SEM, TEM, HRTEM and UV-Vis techniques. The measurement results show that the more or less MTiO3 nanoparticles are affected by the amount of added Sr(OH)2 or Ba(OH)2 and the change in reaction time, and to some extent, the content of the MTiO3 is increased with the increase in the added hydroxide precursor and the prolonging of reaction time. Either the pure TiO2 nanobelts or the nanocomposites show the similar absorption and emission spectra. Their visible photodegradation activities of rhodamine B appear much higher than that of P-25. PMID- 21322226 TI - [Study on spectral broadened characterization of cross phase modulation in photonic crystal fiber]. AB - Spectrum broadening induced by cross phase modulation (XPM) was investigated by exploiting the optical time-division multiplexing (OTDM) data signal and continue wave probe light co-propagation in dispersion flattened high nonlinear photonic crystal fiber (PCF). The effects of wavelength drift of probe lights, polarization mismatch, total power and power ration of pump and probe light on the spectrum broadening were analyzed. The results show that good XPM effects can be obtained in 36 nm wavelength range when the total power is higher than 23 dB, power ration of pump and probe light is appropriate and with identical polarization. Furthermore, polarization independent XPM effect can be achieved by using the remainder birefringence of the PCF with the pump state of polarization (SOP) aligned at 45 degrees to the PCF principal axes. The obtained results in this paper would be helpful for research on ultrahigh-speed all optical signal processing devices exploiting the XPM in PCF for future photonics network. PMID- 21322227 TI - [Spectral calibration of the atmosphere ultraviolet imaging spectrograph using a PtNe lamp]. AB - The atmospheric ultraviolet imaging spectrograph (AUVIS) is an ultraviolet imaging spectrograph that uses a two-dimensional charge-coupled device detector to collect both the spectrum and the swath perpendicular to the flight direction. The design of the system components, the principle, and the main specifications of the AUVIS are introduced. The calibration theory was studied. Considering the characteristics of the AUVIS, a PtNe hollow cathode lamp was chosen as the calibration source, a calibration setup was established, and the AUVIS was calibrated. After the experimental data processing, a function of pixel number wavelength was established. The uncertainty of the spectral calibration is 0.043 nm. PMID- 21322228 TI - [Effects of electric field on the energy-optical spectrum of the AB oscillation of a negatively charged exciton]. AB - The present paper discusses quantitatively the energy-optical spectrum and the AB oscillation of a negatively charged exciton on a quantum ring, under the influence of an uniform external electric field. The calculated optical spectrum agrees well with the experimental measurement. A negatively charged exciton is a system of three charged objects, making the numerical computations difficult due to the large size of the basic vector set and the Hamiltonian matrix. In this paper, a method is proposed to select an appropriate basic vector set I (K(min), K(max)) in order to reduce the number of basic vectors and to ensure minimal error due to the selection of the basic vectors. To verify the reliability of the suggested basic vector set I(K(min), K(max)), the authors also proposed a method to analyze D(K) which is the weight of the K component of the basic vector. The kinetic energy term (T) and the Coulomb action term (V) in the Hamiltonian, as well as the relationship between the external electric field term (E) and the radius of the ring R, are also discussed. PMID- 21322229 TI - [Two-photon ionization spectroscopy of methyl iodide in the region of 76 500-81 120 cm(-1)]. AB - Using the device for ion velocity imaging, the laser frequency is doubling with the wavelength in the region of 492-523 nm, and the laser after frequency doubling was used as the light source. The ion spectrum of methyl iodide parent molecular (CH3 I+) in the range of 76 500-81 120 cm(-1) was obtained by the way of two-photon ionization, with a very high-resolution. The mechanisms of the methyl iodide molecule two-photon ionization were also described, the CH3 I+ spectrum obtained in the experiment was marked based on Rydberg formula and the quantum defect, the split arising from p series, d series and f series levels was also explained, and the spectral assignment showed that the two-photon ionization of methyl iodide molecule can not only be used to observe the reported characteristics of single photon ionization, but also can find some transitions which is forbidden in the single photon ionization, such as f series transitions. PMID- 21322230 TI - [Improvement of the recognition probability about camouflage target based on BP neural network]. AB - Using static Michelson interferometer to get the spectrum information of measurement targets for spectrum identification, under the condition that the interference length is constant, the system can be optimized by BP neural network algorithm for the mixed spectral separation process. Thereby it can realize improving the recognition probability of camouflage target. Collecting the spectrum information in field of view (FOV) by the interferometer and linear array CCD detector, composing the set of mixed spectrum data, with known absorption spectrum of the material as a hidden layer of rules, it used BP neural network to separate the mixed spectrum data. Experiment with different distances, different combinations of mixed background spectrum as the initial data, using steel target (size: 1.5 m x 1.5 m) made of four kinds, the recognition probability of non-camouflage target is about 90% by BP neural network algorithm or the traditional algorithm, while the recognition probability of camouflage target is 75.5% with BP, better than 31.7% with the traditional, so it can effectively improve the recognition probability of camouflage target. PMID- 21322231 TI - [Spectral analysis and band gap of RbVO3]. AB - In the present paper, RbVO3 was prepared by wet chemistry synthesis from hybrid precursor. The structure of RbVO3 was characterized by X-ray diffraction (XRD) pattern and FTIR spectra. Photoluminescent (PL) properties were investigated by UV-Vis absorption spectrum and PL spectrum. In addition, the band gap of RbVO3 was calculated by using the CASTEP code with density-functional theory (DFT) method. The results indicated that RbVO3 could emit intense green-white fluorescence with peak wavelength at 525 nm and the color coordinates was (0.318 0, 0.430 9) under UV excitation at 357 nm. It was demonstrated that the theoretical result of band gap, which is 2.67 eV, agreed well with the experiment. PMID- 21322232 TI - [Modeling polarimetric BRDF of leaves surfaces]. AB - The purpose of the present paper is to model a physical polarimetric bidirectional reflectance distribution function (pBRDF), which can character not only the non-Lambertian but also the polarized features in order that the pBRDF can be applied to analyze the relationship between the degree of polarization and the physiological and biochemical parameters of leaves quantitatively later. Firstly, the bidirectional polarized reflectance distributions from several leaves surfaces were measured by the polarized goniometer developed by Changchun Institute of Optics, Fine Mechanics and Physics, Chinese Academy of Sciences. The samples of leaves include two pieces of zea mays L. leaves (young leaf and mature leaf) and a piece of E. palcherrima wild leaf. Non-Lambertian characteristics of directional reflectance from the surfaces of these three leaves are obvious. A Cook-Torrance model was modified by coupling the polarized Fresnel equations to simulate the bidirectional polarized reflectance properties of leaves surfaces. The three parameters in the modified pBRDF model, such as diffuse reflectivity, refractive index and roughness of leaf surface were inversed with genetic algorithm (GA). It was found that the pBRDF model can fit with the measured data well. In addition, these parameters in the model are related with both the physiological and biochemical properties and the polarized characteristics of leaves, therefore it is possible to build the relationships between them later. PMID- 21322233 TI - [Classification of wetlands in multispectral remote sensing image based on HPSO and FCM]. AB - The present paper analyzed the characteristics of particle swarm optimization(PSO), hybrid particle swarm optimization (HPSO) and fuzzy C-means (FCM), imported FCM into HPSO, and improved the HPSO-FCM arithmetic. An HPSO-FCM program was developed using Fortran language in MATLAB. Besides, a synthesis image combined with the former three principal components was obtained through band stacking and principal component analysis, taking the multispectral visible image of HJ-1 Satellite shot in June 2009 and the ASAR radar image of ENVISAT as basic data. And the paper has done a wetlands classification experiment in the synthesis image of the East Dongting Lake of Hunan province, using HPSO-FCM arithmetic and ISODATA separately. The results indicated: (1) The arithmetic which imported crossover operator of genetic algorithms and FCM into HPSO had better search speed and convergent precision, and it could search and optimize the best cluster center more efficiently. (2) The HPSO-FCM arithmetic has better precision in wetlands classification in multispectral remote sensing image, and it is an effective method in remote sensing image classification. PMID- 21322234 TI - [Study on spectral reflectance characteristics of hemp canopies]. AB - Hemp (Cannabis sativa L.) is a special economic crop and widely used in many field. It is significative for the government to master the information about planting acreage and spatial distribution of hemp for hemp industrial policy decision in China. Remote sensing offers a potential way of monitoring large area for the cultivation of hemp. However, very little study on the spectral properties of hemp is available in the scientific literature. In the present study, the spectral reflectance characteristics of hemp canopy were systematically analyzed based on the spectral data acquired with ASD FieldSpec portable spectrometer. The wavebands and its spectral resolution for discriminating hemp from other plants were identified using difference analysis. The major differences in canopy reflectance of hemp and other plants were observed near 530, 552, 734, 992, 1 213, 1 580 and 2 199 nm, and the maximal difference is near 734 nm. The spectral resolution should be 30 nm or less in visible and near infrared regions, and 50 nm or less in middle infrared regions. PMID- 21322235 TI - [Comparative study of reflectance spectroscopy of women's acupoints around menstruation]. AB - Acupoint was reaction of viscera and its optical parameter was an important characteristic of tissue. In the present work, in order to discuss specificity of acupuncture on the response of qi and blood in human body, we compared the diffuse reflectance of Taichong (LV3), Taibai (SP3), and Chongyang (ST42) before, during and after menstruation. All the acupoints had the same shape of the spectrum and troughs were all at 423.16, 544.06 and 577.47 nm. The values of reflectance during menstruation were greater than before and after menstruation, especially for SP3 and ST42 (P < 0.05). SP3 and ST42 were more sensitive to the changes of qi and blood than LV3, and it was asymmetric and we found no evidence for the imbalance of the left side and right. These results indicated that acupoint diffuse reflectance changed with qi and blood, and that SP3 and ST42 had close relationship with menstruation. Diffuse reflectance may be possibly used in the quantitative analysis of qi and blood. PMID- 21322236 TI - [Synthesis, characterization and interaction with ct-DNA of four novel secondary amine complexes]. AB - A novel ligand(L), (N, N'-bis (4-methylbenzyl) ethane-1, 2-diamine), and its transition metal(II) complex, [ML2 (H2O)2]2+ x 2NO3- (M = Cu(II), Co(II, Ni(II), Zn(II)), have been synthesized and characterized by elemental analysis, IR and 1H NMR. The crystal structure of the Cu-L complex was characterized by X-ray single crystal diffraction, and the results showed a regular octahedral structure in which each metal ion is six--coordinated with four nitrogen atoms from two ligands and two oxygen atoms from two water molecules. The interaction of the complex with calf thymus DNA was investigated by UV spectroscopy and fluorescence spectroscopy, and the results suggest that the complex binds to DNA by electrostatic interaction mode. The binding constant(Cu-L, Co-L, Ni-L, Zn-L) was 1.67 x 10(3), 2.5 x 10(3), 1.35 x 10(3) and 9.85 x 10(2), respectively. PMID- 21322237 TI - [Imaging port wine stain by optical coherence tomography]. AB - Optical coherence tomography is an appropriate imaging method for biomedical science, due to its advantages of noninvasive nature, high resolution and fast imaging speed. Because most biological tissues have the characteristic of high scattering coefficient, OCT system can just obtain the structural images several millimeters below the surface of the tissues. The superficial depth of OCT's penetration limits application in dermatology field. As a common disease, the port wine stain (PWS) is a indication of OCT, because of its superficial lesion and significant expansion of blood vessels. To get deeper penetration in the skin, the authors employed 1 310 nm superluminescent diode as light source, optimized the light intensity ratio of reference delay arm and sample arm and control polarization, and the research of PWS imaging in vivo was accomplished. Besides, OCT is able to gather clear image and key characteristic parameters, such as the depth of epidermis layer, the diameter of blood vessel, etc. OCT will play an important role in the diagnosis and therapy of PWS. PMID- 21322238 TI - [Interaction between cucurbit[n]urils (n = 7 and 8) and 2-amino-phenyl-thiazole]. AB - The interaction between cucurbiturils(Q[7], Q[8]) and the 2-amino-benzothiazole (g) was investigated by 1H NMR spectroscopy, electronic absorption spectroscopy and fluorescence spectroscopy. The results show that with 2 < pH < 9, using different spectrum methods was able to observe the interaction between the cucurbit[n]urils and the guest at pH between 2 and 9, Q[7] interacts with the guest with a 1 : 1 host : guest ratio, and Q[8] interacts with the guest with a 1 : 2 host : guest ratio. Also, the inclusion constant and the thermodynamic parameters of the interaction systems, such as the entropy and enthalpy of systems, were considered. PMID- 21322239 TI - [Black soil organic matter predicting model based on field hyperspectral reflectance]. AB - To develop soil organic matter (OM) quick measuring methods, deepen the application of remote sensing in agriculture, improve agricultural production and management way, and promote the development of quantitative remote sensing studies relating to terrestrial ecosystem, field hyperspectral reflectance in the visible/near infrared bands of black soil in Hailun city, northeast China, was collected and analyzed with spectral analysis methods to discover the spectral characteristics of field reflectance and its influencing factors, and the spectral indices were derived, then black soil organic matter predicting model based on the correlation between OM content and spectral indices was built. Root mean squared error (RMSE) was introduced to validate the predictability and precision of the models, and coefficient of the determination (R2) was used to evaluate stability of the models. The results are as follows: the main spectral region of remarkable differences between field black soil reflectance curves is less than 1 250 nm, especially less than 1 000 nm; OM is the main factor determining the curve shape of field black soil reflectance, anc there are single or double spectral wave troughs for different soil samples because of varying OM content at the spectral region less 1 100 nm; correlation between OM and differential coefficient of logarithmic reflectance reciprocal (DCLRR) is much more significant than that between OM and other reflectance or its transforms, and the maximum coefficient of correlation is at 1 260 nm; the predicting model for black soil OM content is built with DCLRR at 1 260 nm as independent varialble and OM as dependent variable, and the coefficients of determination R2 of the model is 0.71, RMSE is 0.42, so the model is quite good in stability and predictability, and can be used in fast testing of organic matter in black soil. PMID- 21322240 TI - [Error analysis of the land surface temperature retrieval using HJ-1B thermal infrared remote sensing data]. AB - Error analysis is playing an important role in the application of the remote sensing data and model. A theoretical analysis of error sensitivities in land surface temperature (LST) retrieval using radiance transfer model (RT) is introduced, which was applied to a new thermal infrared remote sensing data of HJ 1B satellite(IRS4). The modification of the RT model with MODTRAN 4 for IRS4 data is mentioned. Error sensitivities of the model are exhibited by analyzing the derivatives of parameters. It is shown that the greater the water vapor content and smaller the emissivity and temperature, the greater the LST retrieval error. The main error origin is from equivalent noise, uncertainty of water vapor content and emissivity, which lead to an error of 0.7, 0.6 and 0.5 K on LST in typical condition, respectively. Hence, a total error of 1 K for LST has been found. It is confirmed that the LST retrieved from HJ-1B data is incredible when application requirement is more than 1K, unless more accurate in situ measurements for atmospheric parameters and emissivity are applied. PMID- 21322241 TI - [Preliminary study on oxygen content monitoring for port wine stains during PDT using diffuse reflection spectra]. AB - To measure oxygen content in port wine stain (PWS) skin using diffuse reflectance spectroscopy and monitor the change in oxygen content during photodynamic therapy (PDT), the diffuse reflectance spectra of port wine stain skin were measured using the USB2000 miniature fiber optic spectrometer immediately 10, 20, 30 and 40 min after treatment began, then oxygen content at each time point was analyzed based on the difference of absorption spectra between Hb and HbO2, and the change trend can be observed. The diffuse reflectance spectra of 14 PWS patients were monitored during treatment, and the change trend of oxygen content were analyzed. Results showed that before treatment the oxygen content varies between patients with different type of PWS. During PDT, there was no obvious change in oxygen content for skin of most P4 and P5 PWS, while obvious decline was observed in oxygen content for P6 PWS. The current diffuse reflectance spectroscopy can be used to monitor oxygen content in PWS skin qualitatively and observe the change trend. To get more precise oxygen content in PWS skin, more work is needed to improve the sensitivity of diffuse reflectance spectroscopy and a spectra algorithm should be established. PMID- 21322242 TI - [Spectral modeling of marine suspended particulate matter: comparison between ADA and Mie computations]. AB - The present paper aimed at exploring the feasibility of modeling optical properties of marine suspended particulate matter (SPM) with anomalous diffraction approximation (ADA) method, which had advantage of computation speed over the classic Mie theory. Based on the marine SPM characteristics of refractive index and particle size, attenuation efficiency Q(c) absorption efficiency Q(a) and scattering efficiency Q(b) of SPM were computed by ADA and Mie to analyze their relative error delta(c), delta(a), delta(b) and the variations. The variations of delta(c), delta(a), delta(b) with the particle size, real and imaginary part of refractive index were different and complex. The minimum particle size R(min), with which ADA can be used to give computation results with enough accuracy (relative difference less than 5%), was determined and shown to be influenced by the refractive index and wavelength Classic Mie method, rather than ADA method, was recommended for the spectral modeling of ocean suspended particulate matter. PMID- 21322243 TI - [Complex refractive index measurement of fly ash particles using suspension spectral transmission method]. AB - Spectral complex refractive index of fly ash particles is an important parameter in the processing of scattering properties calculation. On the basis of theory about inversion of complex refraction index using transimission method, a novel method was proposed, in which fly ash particles were dispersed in the water to compose turbid liquid, and spectral transmissivity of turbid liquid was measured using visible spectrophotometer. Particles size distribution was measured using laser particles sizing. So complex refraction index of fly ash particles was inverted simply. The result indicated that no signifcant absorption appeared in the visible wavelength range for fly ash particles, but transmittance decreased with wavelength increasing. The inversion results from the proposed method agreed with KBr sampling method. The proposed method is simpler, and has fewer constraints, meanwhile the inverion wavelength will be expanded if using infrared spectrophotometer. PMID- 21322244 TI - [Near ultraviolet absorption spectral properties of chromophoric dissolved organic matter in the north area of Yellow Sea]. AB - Chromophoric dissolved organic matter (CDOM) near ultraviolet absorption spectra contains CDOM molecular structure, composition and other important physical and chemical information. Based on the measured data of CDOM absorption coefficient in March 2009 in the north area of Yellow Sea, the present paper analyzed near ultraviolet absorption spectral properties of CDOM. The results showed that due to the impact of near-shore terrigenous input, the composition of CDOM is quite different in the north area of Yellow Sea, and this area is a typical case II water; fitted slope with specific range of spectral band and absorption coefficient at specific band can indicate the relative size of CDOM molecular weight, correlation between spectral slope of the Sg,275-300), Sg,300-350, Sg,350 400 and Sg,250-275 and the relative size of CDOM molecular weight indicative parameter M increases in turn and the highest is up to 0.95. Correlation between a(g)(lambda) and M value increases gradually with the increase in wavelength, and the highest is up to 0.92 at 400 nm; being correlated or not between spectral slope and absorption coefficient is decided by the fitting-band wavelength range for the spectra slope and the wavelength for absorption coefficient. Correlation between Sg,275-300 and a(g)(400) is the largest, up to 0.87. PMID- 21322245 TI - [Research on concentration of multi-component pollution gas based on SVM with kernel optimized by rough set]. AB - This paper introduced the application of support vector machines (SVM) regression method based on kernel function optimized by the rough set in the infrared spectrum quantitative calculation. According to kernel function with the rough set classification's method, the spectrum data (characteristic wavelength section) is optimized. The kernel function leads support vector machines, and the SVM project the two-dimensional room to the multi-dimensional room, and calculate the concentration of every kind of gas in multi-component pollution gas. By using two kinds of typical spectrum data processing algorithm to make the contrast, the comparison of five kinds of gaseous mixture various proximate analysis is carried out, and when the spectrum separable rate is high, the predicted values of the three methods approach the normal value, and the average error is smaller than 0.13; but when the spectrum separable rate is low, the RS-SVM predicted value is more precise than the first two kinds. Experimental data show that the consequence is better when there are more testing types, and the precision and operation of this method is of more remarkable superiority. PMID- 21322246 TI - [The zonal characteristics and cultivated types difference of functional components in brown rice for core collection of Yunnan rice]. AB - The zonal characteristics and cultivated types difference of functional components in brown rice of 907 accessions for primary core collection for rice landrace from 16 prefectures of five rice regions in Yunnan Province were determined by ultraviolet spectrophotometry of DU640 type from BECKMAN. The analytical results showed that the contents mg x (100 g)(-1) of total flavone in brown rice is 306.98 +/- 192.75, the content of upland (341.74 +/- 185.11) is the most significantly higher than that of lowland (290.41 +/- 193.72), that of the glutinous (315.54 +/- 197.64) is significantly higher than non-glutinous (171.68 +/- 11.76), that of early-mid (318.25 +/- 197.93) is the most significantly higher than late (282.12 +/- 178.11), that of red rice (379.22 +/- 197.70) and purple rice (365.61 +/- 195.44) are the most significantly higher than white rice (216.96 +/- 142.11), and that of nuda (332.68 +/- 196.22) is significantly higher than non-nuda (300. 48 +/- 191.14). Among five rice regions, in turn III (327.13) > LL (324.23) > IV (273.11) > V (270.16) > I (258.26), namely it is the most significantly highest (p < 0.01) for contents of total flavone from South Yunnan (II, III) than that of middle Yunnan; It is the most significantly highest from Simao prefecture than that of 8 prefectures, but it is the most significantly low from Baoshan prefecture than that of 7 prefectures. The contents mg x (100 g)(-1) of g-amino butyric acid (GABA) in brown rice is 7.43 +/- 2.53, the content of lowland (7.59 +/- 2. 56) is the most significantly higher than that of upland (7.09 +/- 2.45), that of non-glutinous (8.55 +/- 2.88) is the most significantly higher than glutinous (7.10 +/- 2.32), that of late (7.88 +/- 2.64) is the most significantly higher than early-mid (7.23 +/- 2.45), that of white rice (8.38 +/- 2.66) is the most significantly higher than red rice (6.63 +/- 2.14) and purple rice (7.34 +/- 2.18); Among five rice regions in turn II (7.69) > I (7.40) > IV (7.39) > III (7.33) > V (6.64), viz. the content of GABA from South Yunnan single/double cropping rice region is clearly higher than that of Northwest Yunnan cold highland japonica rice region; It is significant difference of GABA content in brown rice for that Simao prefecture South Yunnan and Yuxi as well as Baoshan prefecture, at least than that of 5 prefectures. The contents (%) of resistant starch in brown rice is 0.75 +/- 0.29, the contents of indica (0.78 +/- 0.35) is significantly higher than japonica (0.74 +/- 0.24), that of glutinous (0.78 +/- 0.31) is the most significantly higher than non-glutinous (0. 67 +/- 0.22), that of late (0.77 +/- 0. 35) is the most significantly higher than early mid (0.75 +/- 0.26), that of red rice (0.81 +/- 0.30) and purple rice (0.70 +/- 0.30) is the most significantly higher than white rice (0.69 +/- 0.27); Among five rice regions in turn I (0.83) > II (0.79) > III (0.76) > V (0. 55) > IV (0.50), namely it is the highest (p < 0.01) for contents of resistant starch from the middle and South Yunnan province (I, II, III) than that of northern rice regions (V, IV), and the lowest for contents of resistant starch of Lijiang prefecture of northwestern and Zaotong of northeastern in this province compared to that of 13 prefectures except Diqing prefectures. These results not only reveal the most significant difference between lowland versus upland, glutinous versus nonglutinous, early/mid rice and red/purple versus white rice based on the contents of total flavone and resistant starch as well as g-amino butyric acid (GABA) in brown rice (p < 0.01), and no significant difference between indica and japonica, awn and no-awn, and common rice and aromatic/soft rice, but also elucidate obvious zonal characteristics of three functional components in brown rice of Yunnan rice. The above results provided theory bases for the genetic breeding and production of functional rice and solve the problems of chronic for human being. PMID- 21322247 TI - [Fast determination of the proportion of metalaxyl-M enantiomers by UV spectroscopy]. AB - In the present study, beta-cyclodextrin(betaCD) was used as chiral selector to detect the proportion of chiral isomers of metalaxyl. The proportion of metalaxyl enantiomers can be detected by ultraviolet (UV)spectroscopy since the interaction between the R, S isomer of metalaxyl with beta-CD is different. The quantitative models were established by partial least squares regression (PLS) and the robust of models was evaluated by independent validation samples. The determination coefficient R2 of calibration set in the quantitative model was 0.999 0. The standard error of calibration set (SEC) and the relative standard deviation (RSD) of the model was respectively 0.006 7 and 0.89%; The correlation coefficient r of estimated value and specified value of the 6 independent validation samples was 0.998 5. The standard error of prediction (SEP) and RSD was respectively 0.008 9 and 1.17%. This method is rapid and easy to operate in practical applications. PMID- 21322248 TI - [Determination of lignin distribution during ageing of bamboo culms (Phyllostachys pubescens) with visible-light spectrophotometry]. AB - The lignin distribution in different anatomical regions of developing moso bamboo Phyllostachys pubescens f. lutea Wen was investigated by means of optical microscope and visible-light microspectrophotometry coupled with the Wiesner and Maule reaction. The lignin is widely distributed in different tissues, in which there is a difference in lignin content between different ages, tissues and anatomical regions. Guaiacyl lignin and Syringyl lignin unit can be found in cell wall of fibre, parenchyma and vessel. Lignin content of secondary wall, cell corner and compound middle lamellae of fibre increased gradually within 12 months, then almost remained in the same level or decreased slowly in the culms with an age from 12 to 78 months. The lignification rate in secondary wall, cell corner and compound middle lamellae of fibre changed with age until they reached a relative steady value. There is no regular variation in lignin content with different radial location of culms and different location in fibre strands within one age. The secondary wall, compound middle lamellae of parenchyma and vessel secondary wall lignified rapidly within 12 months, and then changed slowly. PMID- 21322249 TI - [A rapid nondestructive measurement method for assessing the total plate count on chilled pork surface]. AB - The present paper proposed a method based on the hyperspectral technology for rapidly, nondestructively quantify the total plate count on chilled pork surface. In the research, 50 chilled pork samples stored at 4 degrees C for 1-14 days were used to study the relationship between the total plate count on chilled pork surface and their hyperspectral images collected in 400-1 100 nm. Two models were established using MLR and PLSR methods, and the prediction showed that they can both give satisfactory results with R(v) = 0.886 and 0.863 respectively. The overall research demonstrates that the hyperspectral technology can well quantify the total plate count on chilled pork surface, and so indicates that it is a valid tool to assess the quality and safety properties of chilled pork in the future. PMID- 21322250 TI - [The recycling rate of trace element Fe and Zn in agro-ecosystem using ICP-AES]. AB - Input of trace elements Fe and Zn in the lower reach of Liaohe Plain under different fertilization systems was studied by long-term field experiment and ICP AES analysis. The results showed that Fe and Zn were mainly from organic manure in agro-ecosystem. The residual rate of organic manure through a feeding composting cycle in the absence of bedding materials was 21.84%, which was lower than that of organic matter fertilized to soil after one year. The recycling rate of Zn through a feeding-composting cycle was 71.9%, and the recycling rate of Fe was 81.0%. PMID- 21322251 TI - [Determination of trace elements in cigarette flavours by closed-vessel microwave digestion-inductively coupled plasma mass spectrometry]. AB - Tobacco flavours have great effect on the aroma, taste and quality stabilization of cigarettes. In order to effectively control the quality of cigarette flavours and reduce the content level of toxic elements in cigarette mainstream smoke, a method for the simultaneous determination of Be, V, Cr, Mn, Ni, Cu, Zn, As, Se, Sr, Mo, Cd, Tl and Pb in cigarette flavours by inductively coupled plasma mass spectrometry (ICP-MS) with closed-vessel microwave assisted digestion was developed. The linear correlative coefficients for all elements are better than 0.999 4 and the precision of measurement ranges from 1.3% to 9.5% in terms of relative standard deviation (n = 5). The recoveries for the cigarette flavour samples and the limits of detection are in the range of 88.1%-109.3% and 0.003 0.13 microg x L(-1), respectively. The results of experiment show that the method can meet the requirements of trace analysis. Thirty eight cigarette flavours from different cigarette manufacturing enterprises were determined. The results indicate that: (1) the contents of Be, Tl, Mo, Cd, V, Pb and As in cigarette flavours are very lower, the average values of which are all lower than 0.1 microg x g(-1). The content levels of Mn, Zn and Sr in cigarette flavours are higher, and that of other 4 elements are moderate. (2) The content difference of Mn, Cd and Sr in different cigarette flavours is usually bigger, the coefficients of variation of which are 276.4%, 238.7% and 243.8%, respectively. PMID- 21322252 TI - [Determination of concentrations and distributions of Mn and Zn in maize under different fertilization regime using ICP-AES]. AB - A long-term field experiment and ICP-AES analysis were conducted to study concentration and content of micronutrients Mn and Zn in maize under different fertilization systems. The results were as follows: (1) Concentrations of Mn in maize under NPKM and NPK treatments were significantly higher than those in M and control treatments. The concentration of Zn in grain of maize was similar under different treatments. The control treatment had the highest concentration of Zn in stalk, while NPKM treatment had the lowest one. (2) Contents of Mn and Zn increased with increasing yields of maize, and the regression relationship between the contents and yield of stalk was better than that between the contents and yield of grain. (3) Most of Mn and almost half of Zn were concentrated in stalk. The distribution and use efficiency of micronutrients were optimized under NPKM and NPK treatments. Returning the stalk to soil is an effective strategy for micronutrients sustainable utilization in agro-ecosystem. PMID- 21322253 TI - [Investigation of determining strontium in M. nitida Benth. var. hirsutissima. Z. Wei. by flame atomic absorption spectra]. AB - The present paper is aimed to establish the method of determining the strontium in M. nitida Benth. var. hirsutissima. Z. Wei. by means of air-acetylene flame atomic absorption spectra, and also provide reference for the determination of the strontium in other traditional Chinese medicine. M. Nitida Benthvarhirsutissima Z. Wei. was taken as the object. The authors used nitric perchloric acid as digestion solution to digest samples by microwave which was controlled by pressure, and used EDTA-2Na as the releasing agent to add in the samples for determining the strontium in M. nitida Benth. var. hirsutissima. Z. Wei. by FAAS. The results showed that the samples were entirely digested by microwave. The working curve was Y = 0.036 5x -0.001 1, r = 0.999 4, the range was 0-1.6 microg x mL(-1), the average recovery rate was 101.5% with RSD 2.04%, and the method detection limit was 0.008 2 microg x mL(-1) (n = 21). It is concluded that this method is simple and accurate. It has high sensitivity and can be effectively used for determining the strontium in this traditional Chinese medicine. PMID- 21322254 TI - [X-ray absorption fine structure (XAFS) study of the effects of pH on Pb(II) sorption by soil]. AB - Combined batch sorption and in situ X-ray absorption fine structure (XAFS) provide direct assessment of the mechanisms for Pb(II) sorption at the soil-water interface under different pH conditions. The XAFS data indicated that the innersphere Pb sorption complex with ionic character (Pb4 (OH)4(4+)) dominated the Pb surface speciation, and the outer-sphere Pb sorption complex and the precipitation of calcium carbonate containing Pb(PbCaCO3) were also involved in the adsorption samples. Coordination number and radial distance of the first shell Pb-O decreased from 0.172 7 to 0.166 6 nm and the percentage of inner sphere complexes increased when the initial pH changed from 6.0 to 8.5, indicating that the mechanism of Pb(II) sorption by the soil was pH-dependent. PMID- 21322255 TI - [Study on the damage of SiO2 thin films on LiNbO3 crystal in optical parametric oscillator by XRD spectrometry]. AB - In an attempt to elucidate the damage in high transmission thin films on LiNbO3 crystal in optical parametric oscillator, the authors employed XRD spectrometry to investigate the spectrum of laser-induced damage in thin film as well as the morphology of the damage. The authors observed that the damage of thin film was characterized by the depressions/craters in the surface of the films, which were surrounded by a deposition layer with the deceasing thickness from the center of the craters. The XRD measurements indicate that the film was crystallized. The authors analyzed the causes of morphologies and the mechanism of crystallization with the aid of the model for impurity-induced damage in thin solid films. The crystallization was due to the solidification of liquid and gaseous mixtures that result from the strong absorbing to the incident laser. The crater was generated because the mixtures were ejected under the extensive pressure of the laser plasma shock wave. During the process that the mixtures deposit around the craters, the density of the mixtures will decrease and crystallization takes place. As a result, the color of the deposition layer becomes lighter from inside to outside, and the crystallization of the thin film materials was observed by XRD spectrometry. PMID- 21322256 TI - [Surgical management of hemifacial microsomia: a report of 24 cases]. AB - OBJECTIVE: To investigate the therapeutic effect of combined treatment for hemifacial microsomia (HFM). METHODS: From July 1991 to August 2006, 24 consecutive patients with HFM were retrospectively analyzed. They underwent orthognathic surgery, free flap transplantation, Medpor implant, distraction osteogenesis. The patients age, deformity type, surgical timing, treatment methods and complications were analyzed. RESULTS: The treatment was completed in all the patients. The facial symmetry was improved dramatically after operation. The occlusion relationship was improved also with good occlusion plane. 8 free flaps were survived with no necrosis. CONCLUSIONS: The surgical treatment should be designed based on the age and deformity type in HFM. The occlusion relationship and appearance can be both improve markedly. PMID- 21322257 TI - [Application of temporal-zygomatic expanded flaps pedicled with orbicularis oculi muscle for sub-orbital defects]. AB - OBJECTIVE: To investigate the therapeutic effect of temporal-zygomatic expanded flaps pedicled with orbicularis oculi muscle (00M) for sub-orbital defects. METHODS: 16 cases with sub-orbital defects were treated. The expanders were implanted at temporal-zygomatic region at the first stage. At the second stage, temporal-zygomatic expanded flaps pedicled with OOM were designed and transferred to repair the suborbital defects. RESULTS: All the expanded flaps survived completely. 11 cases were followed up for 3 months to 3 years. The flaps had no contracture with a good match of color and texture with surrounding tissue. The scar was also inconspicious. CONCLUSIONS: The temporal-zygomatic expanded flaps can be used for large size defects below orbit. It is very flexible, leaving minimal morbidity for the whole face. PMID- 21322258 TI - [Classification and surgical management of secondary nasal deformity of unilateral cleft lip]. AB - OBJECTIVE: To investigate the classification of alar base depression, so as to provide the reference for the surgical management of secondary nasal deformity of unilateral cleft lip. METHODS: From Jul. 2008 to Feb. 2009, 26 cases with secondary deformity of unilateral cleft lip were treated. All the patients underwent 3-dimensional CT for maxillary measurement. The nasal soft tissue measurement was performed pre- and post-operatively. The relationship between the maxillary and soft tissue at alar base was analyzed. The nasal deformity was classified. RESULTS: The location of alar base was not related to the form of piriform aperture, but the bony defect at the alar base was correlated to the patient satisfactory. The nasal deformity was graded as I when the depression at alar base was less than 4.5 mm in depth, as II when it was 4.5-5.0 mm in depth, and as III when it was more than 5 mm in depth. The deformity could be corrected with only soft tissue plasty for grade I, with soft tissue plasty or artificial implants for grade II, with combined bone autograft or alveolar cleft repair for grade III. CONCLUSIONS: The depression at maxillary does not necessarily result in alar base depression. The alar base can be adjust to proper position through operation. The operation should be designed based on the preoperative nasal measurement. PMID- 21322259 TI - [Repair of thumb tip defect with thumb island flaps at ulnar side by V-Y advancement]. AB - OBJECTIVE: To investigate the method for treatment of thumb tip defect. METHODS: The thumb tip defect was treated with thumb island flaps at ulnar side by V-Y advancement. The flap size ranged from 1.4 cm x 2.0 cm approximately 1.4 cmx 2.5 cm. The wounds at donor sites were covered by skin grafts. RESULTS: From March 2007 to October 2009, 10 cases of thumb tip defects were treated. All the flaps and skin grafts were survived with primary healing. The patients were followed up for 6-18 months with both satisfactory functional and cosmetic results. The two point discrimination was 5-6 mm at the thumb tip. CONCLUSIONS: The thumb tip defect can be successfully repaired with thumb island flaps at ulnar side by V-Y advancement. PMID- 21322261 TI - [Mammaplasty after polyacrylamide hydrophilic gel removal from breast]. AB - OBJECTIVE: To explore the relationship between mammaplasty and results after polyacrylamide hydrophilic gel (PAHG) removal from breast. METHODS: From Feb. 2003 to Aug. 2009, 130 patients with bilateral breast augmentation by PAHG injection were treated. Preoperative ultrasound examination and MRI were performed to know the distribution of PAHG and infiltration at the surrounding tissue. According to the conditions after removal, the patients were received implant augmentation immediately, or at the second stage, or no implant. RESULTS: The patients were followed up for 3 months at the most with a very satisfactory rate of 63.84% (83/120), a satisfactory rate of 31.53% (41/120) and a unsatisfactory rate of 4.63% (6/120). Slight capsular contracture (Baker I) occurred in 5 cases with 6 breasts in satisfactory group. All the patients in unsatisfactory groups who selected unsuitable implants by themselves were re operated to take out the implants. 3 cases with much residue PAHG insisted to receive breast implants. Among them, 2 cases achieved acceptable results even the surface of the breasts were not smooth. No other complication happened. CONCLUSIONS: The breast reaugmentation after PAHG removal should be performed based on the deformity and condition of breast. Both cosmetic result and psychological relief could be obtained after mammaplasty. PMID- 21322260 TI - [Study of distribution of dominant perforators arising from peroneal artery with color Doppler flow imaging and its clinical significance for sural neurocutaneous flap]. AB - OBJECTIVE: To study the distribution of the dominant perforators (the diameter > or = 0.8 mm) of the peroneal artery with color Doppler flow imaging (CDFI) for the purpose of anatomical preparations for the perforator sural neurocutaneous flap. METHODS: The dominant perforators of the peroneal artery (DPPA) were studied with CDFI on bilateral legs of 20 healthy volunteers. The numbers, diameters and locations of the perforators were recorded for a statistical analysis. From Jan. 2005 to Jan. 2009, 51 free or pedicled sural neurocutaneous flaps supplied by a single DPPA were designed and harvested to repair the defects near the ankle (n=22), at the leg (n=15) and the forefoot or hand dorsum (n=14). The perforators were located preoperatively with CDFI and accuracy of CDFI was evaluated intraoperatively. The causes of false results were analysed to improve examining techniques. RESULTS: The average number of DPPA was 4.2 with the average diameter of (1.13 +/- 0.24) mm (0.80-1.90 mm). They were located in the second to ninth segment of the line from the fibular caput to the tip of lateral malleolus which was equally divided into nine segments. The largest DPPA was (1.43 +/- 0.29) mm (1.00-1.90 mm) in diameter and most of them were located in the third to fifth segment (80.4%). The average diameter of the lowest DPPA was (1.02 +/- 0.16) mm( 0.80-1.30 mm) and they were located between the sixth to ninth segment. The total 169 DPPA as well as the largest ones mostly appeared in the middle third of the leg. All of the 51 flaps were transplanted successfully without necrosis, and no vascular problems occurred. Preoperative CDFI examination had a 93.6% true-positive rate and an 88.0% positive predictive value. What should be demonstrated was that if just considered the cases after Dec. 2007, the true-positive rate was 97%, and the positive predictive value was 93.9%. CONCLUSIONS: According to the distribution characteristics of DPPA, a sural neurocutaneous flap pedicled with one of this relatively large perforator can be designed and harvested to repair skin defects of leg and around ankle, but can not be utilized for that of forefoot. With anastomosis of the perforator, the flap based on the largest DPPA can be used as a free flap to cover defect anywhere. CDFI is reliable in preoperative location of DPPA, which makes the surgical procedures easier. PMID- 21322262 TI - [Lateral thoracic flaps pedicled with subscapular vessels for defects in the upper extremities]. AB - OBJECTIVE: To investigate the feasibility and therapeutic effect of lateral thoracic flaps pedicled with subscapular vessels for defects in the upper extremities. METHODS: From June 2003 to September 2009, 5 cases with large soft tissue defects in the upper extremities were treated with lateral thoracic flaps pedicled with subscapular vessels. The flap size ranged from 23 cm x 8 cm to 40 cm x 20 cm. The subscapular vessels, the thoracodorsal vessels, the lateral branch and the cutaneous perforators of thoracodorsal vessels were all included in the flap. A muscular sleeve of 2-3 cm in width was preserved to protect the musculocutaneous perforator. The defects in the donor area were closed directly or covered by skin graft. RESULTS: The lateral thoracic flaps were used in four cases. A combination of lateral thoracic flap and paraumbilical flap was used in one case. Partial necrosis happened at the distal portion of the flap in one case. All the other flaps survived completely. 4 cases were followed up for two to fourteen months with satisfactory cosmetic and functional results. The color, texture and thickness of the flaps were also satisfactory. CONCLUSIONS: The lateral thoracic flap pedicled with the subscapular vessel is flexible for repairing defects in the upper extremities with a reliable blood supply, leaving less morbidity to donor site. PMID- 21322263 TI - [Effect of high frequency electrocoagulation by ultrafine-needle on the cutaneous capillary hemangiomas: a preliminary study on cock combs]. AB - OBJECTIVE: To investigate the injury effect of high frequency electrocoagulation (HFE) by ultrafine-needle on the cutaneous capillary hemangiomas by histopathologic study of cock comb. METHODS: 32 male cocks were randomly divided into 4 groups with 8 animals in each group. 3 experimental groups received HFE with different power (6W, 8W, 10W) on the cock comb. Specimens were taken from cock combs for histologic study immediately after treatment and 7, 14, 21, 28 days later. RESULTS: After treatment, the cock combs turned pale and followed with scar formation. The shape of combs changed a lot after high power treatment. Immediately after treatment, the capillary number in the experimental groups decreased markedly under light microscope, compared with that in control group (P < 0.05). After that, the capillary number in experimental group increased. 7 days after treatment, the capillary number in experimental groups was still significantly lower than that in control groups (P < 0.01), but not markedly different between the three experiment groups (P > 0.05). Collagen formation also increased after treatment (P < 0.05), which was higher in experimental groups with high power (P < 0.05, correlation coefficient r > 0.5). CONCLUSIONS: HFE with ultrafine needle can effectively decrease the capillary number in cock comb. The 6W treatment is mini-invasive and will not destroy the comb shape with good cosmetic results. The technique may be used for the treatment of cutaneous capillary hemangioma. PMID- 21322264 TI - [Experimental study of repairing fat defect with human hair keratin material]. AB - OBJECTIVE: To investigate the feasibility of adipogenesis from human hair keratin (HHK) material, so as to provide a new method for fat defect and depression deformity. METHODS: 3 Tibet mini-pigs were used. 8 fat defects (1.5 cm in diameter) were made bilaterally on the back. The ball-shaped HHK material was implanted to repair the defects at one side. The defects at contralateral side were as controls. The absorption of the HHK material and adipogenesis were studied histologically. RESULTS: 2 weeks after implantation, connective tissue and capillary grew into the porous HHK material. 4 weeks after implantation, HHK material was almost totally absorbed, leaving some material debris and foreign body granuloma. Around them, there were clusters of adipocyte. 6 weeks after implantation, the HHK material was totally degraded and the granuloma was disappeared, and then de novo adipose tissue was observed. Its volume was close to the volume of peripheral HHK material that was planted originally. 10 weeks later, the new-formed fat tissue had less fibres and was very similar to the normal fat. CONCLUSIONS: New adipose tissue can be formed after HKK material implantation. It can also be remodeled to be similar to normal fat. PMID- 21322265 TI - [Preliminary research on the relationship between inhibitory effect of triamcinolone acetonide on hypertrophic scar and oxygen free radicals in rabbits]. AB - OBJECTIVE: To investigate the relationship between inhibitory effect of triamcinolone acetonide(TA) on hypertrophic scar and oxygen free radicals in rabbits. METHODS: 18 New Zealand rabbits were used. 14 rabbits were selected randomly to construct animal models of hypertrophic scar on the ears. Another 4 rabbits (8 ears) were used as controls. 6 weeks after operation, the hypertrophic scar on the ears were randomly divided to receive intra-lesion injection of TA (n=10), or normal saline (n=10), or nothing (n=8, sham group). 9 weeks after operation, scar specimens were taken for scar thickness measurement, fibroblast counting under microscopy and MDA content detection by spectrophotometric method. RESULTS: (1) 3 weeks after TA treatment, the scar became very thin and soft with a similar color to normal skin and a smooth surface; (2) Histologic study showed the collagen fibers in TA group were reduced markedly and arranged parallelly; (3) Compared with normal skin, the fibroblast density in sham and saline groups increased significantly (P < 0.05), while it was not markedly different in TA group (P > 0.05). There was also no significant difference in scar hypertrophic index between sham and saline groups (P > 0.05), but the scar hypertrophic index was decreased dramatically in TA group (P < 0.05); (4) The MDA content was highest in TA group (P < 0.05), followed by that in sham and saline groups (P < 0.05), while there was no difference between these two groups (P > 0.05). It was lowest in normal control group (P < 0.05). CONCLUSIONS: The oxygen free radicals in the hypertrophic scar can be further increased by local injection of TA. PMID- 21322266 TI - [The extracellular signal-regulated kinase was promoted by pyrroloquinoline quinine in cultured Schwann cells]. AB - OBJECTIVE: To investigate the effect of mitogen-activated protein kinase (MEK) kinase cascade, extracellular signal-regulated kinase (ERK1/2) signal pathway on Schwann cells proliferation promoted by Pyrroloquinoline Quinine (PQQ) and its molecular mechanisms. METHODS: Schwann cells were cultured and purified in vitro. The purity was identified by S-100. Different time and concentration of PQQ was added into culture medium. The expression of ERK1/2 and phosphorylated-ERK1/2 was detected by western blot. The expression of p-ERK1/2 after blocking of MEK signal pathway by specific inhibitor PD98059 was detected by western blot. RESULTS: Morphological change was observed in PQQ treated Schwann cells. 1-500 nmol/L PQQ could up-regulate the expression of p-ERK1/2, and 1000 nmol/L had no effects, while 10 000 nmol/L exhibited inhibitory effect (P < 0.05). p-ERK1/2 increased to peak 1 h after PQQ added, and this up-regulation of p-ERK1/2 was inhibited by PD98059 (P < 0.05). CONCLUSIONS: PQQ could affect morphology of Schwann cells and activation of ERK1/2. MEK inhibitor PD98059 could, block this activation. It suggests that MEK/ERK signal pathway should be involved in Schwann cells proliferation promoted by PQQ. PMID- 21322267 TI - [Anatomic study of mandibular bone flap pedicled with temporal muscle for midface bone defect]. AB - OBJECTIVE: To study the anatomy of mandibular bone flap pedicled with temporal muscle for midfacial bone defects. METHODS: The shape and blood supply of the temporal muscle and mandibular ramus, as well as their relationship, were observed and measured in 30 sides of adult head specimens. RESULTS: The temporal muscle has a fan-shaped main portion, then is scattered into three bundles as anterolateral, anteromedial, posterior bundles, which end respectively at anterior border of ramus, the temporal ridge and posterior portion of coronoid process. Then the muscle goes downward until it reaches the distal side of the third medial surface molar and attaches the 3/4 of medial surface of anterior portion of ramus. The blood supply of temporal muscle includes the medial temporal artery with external diameter of (0.76 +/- 0.20) mm, the anterior deep temporal arteries with external diameter of (0.79 +/- 0.21) mm, posterior deep temporal arteries with external diameter of (0.98 +/- 0.64) mm, the accessory deep temporal artery formed by many little branches. The anterior part of ramus is supplied by the periosteal arteries and the bony perforator of the deep temporal arteries. Rectangular ramus of mandible was divided into anterior portion and posterior portion by the line linking the lowest point of mandibular notch, mandibular foramen and mandibular canal. Anterior portion can supply a bone flap with a size of (46.67 +/- 6.85) mm x (17.98 +/- 2.64) mm x (11.49 +/- 0.99) mm. CONCLUSIONS: The mandibular bone flap pedicled with temporal muscle has a reliable blood supply and abundant bone volume. It is feasible to design a mandibular bone flap pedicled with temporal muscle for midfacial bone defect. PMID- 21322268 TI - [MRI of extraperitoneal rectal carcinoma]. AB - Last years technological developments in imaging field have made a substantial contribution to diagnosis and staging of rectal cancer. Endorectal ultrasound and MRI with endorectal coil are very useful in rectal cancer initial staging thanks to their ability to distinguish between the rectal wall layers. Major ultrasound limitations are presence of inflammations, desmoplastic reaction and small field of view which limits evaluation of perirectal invasion. MRI with phased-array coils, instead, allows depiction of mesorectum and to assess the distance between tumor and mesorectal fascia. Unfortunately CT shows low accuracy compared to MRI in local staging because it fails to distinguish the rectal wall layers. The criterion used in assessing nodal involvement remains unfortunately still the dimensional one even if new contrast media based on nano-iron particles look promising in this regard On reassessment after chemo-radiotherapy treatment, MRI proved to be a very accurate tool thanks to its ability to detect tumor downstaging, disappearance of mesorectal fascia infiltration or even to show a complete response. The presence of recurrence can be studied by contrast enhanced perfusion-MRI or with good accuracy using PET which, however, presents major technical limitations at present. PMID- 21322269 TI - [Extraperitoneal rectal cancer: chemo-radiotherapy treatments]. AB - PURPOSE: The determination of the best therapeutic approach in extraperitoneal rectal cancer patients is very complex both in the neoadjuvant/adjuvant and the metastatic setting. We tried to identify and summarize the current methods of diagnosis, staging and treatment from a multidisciplinary approach. METHODS: Five sections can be indentified: diagnosis and staging; neoadjuvant treatment; adjuvant treatment; liver metastases treatment and local recurrence therapy Data were collected from international guidelines (NCCN) and MEDLINE search. The main aim was the identification of the beast diagnostic and therapeutic approach in extraperitoneal rectal cancer patients in case of local recurrence and metastatic disease. RESULTS: Data from 2010 NCCN guidelines and 48 articles published in major international oncologic reviews were collected and evaluated from 1993 up to 2009. Three articles dealt with staging procedures, 24 dealt with neoadjuvant and adjuvant therapy; 18 were about with liver metastases and 3 about local recurrence treatment. CONCLUSIONS: The correct disease staging is necessary for pursuing the best therapeutic approach and it should involve different radiological techniques in order to evaluate the clinic TNM. Neoadjuvant treatment (chemo-radiotherapy) should be considered for stage II and stage III extraperitoneal rectal cancer patients, followed by post-operative adjuvant chemotherapy. Patients who underwent surgery and have a post-operative stage II or III disease, have to receive four months of adjuvant chemotherapy after surgical resection. Initial treatment options of asymptomatic patient with resectable liver metases include systemic chemotherapy in' order to obtain downstaging of the primary tumor and liver metastase shrinking followed by resection. The treatment of local recurrence is mainly surgical. If not previously administered, radiotherapy represents an alternative therapeutic treatment. PMID- 21322270 TI - [The surgical tratment of the subperitoneal rectal cancer]. AB - AIM: To value the results of "open" surgery with sphincter preservation, TME nerve-sparing, fast-track, without a protective stoma in a consecutive series of patients with subperitoneal rectal cancer (s.p.r.c.). MATERIALS AND METHODS: In January 1989, we started a prospective, non-randomized study designed to assess when a primary derivative stoma was warranted in a series of consecutive patients electively treated with open low and ultralow AR. The inclusion criteria were: all patients with middle and low rectal cancer who underwent elective low and ultralow AR, including those treated with neoadjuvant therapy. The exclusion criteria were: urgent surgery, incomplete rings in the stapler, a positive hydropneumatic test, preoperative involvement of the external sphincter and/or surrounding structures by the tumor as demonstrated by CT-scan and endorectal MR and/or transrectal ultrasound. Anastomoses between 7 cm and 4 cm from the pectinate line were defined as low colo-rectal anastomoses, while anastomoses lower than 4 cm from the pectinate line were defined as ultralow anastomoses. A fistula or anastomotic dehiscence was suspected when pelvic and/or peritoneal pain, fever, leucocytosis, fecaloid liquid in the drainage and/or perianal erythematosus swelling were present. An anastomotic leak was confirmed by means of angio-CT and/or endoscopy and/or contrast enema depending on the procedure available most promptly. Signs of peritoneal reaction were considered to be indicative of a major dehiscence, regardless of the diameter of the fistula; when diagnosed, a transverse colostomy was immediately performed. Clinically less serious cases were defined as minor dehiscences, for which a "wait and see" strategy or a transcutaneous CT or ultrasound guided drainage of an abscess were used. Sixty-five patients were treated according to a fast-track postoperative protocol. RESULTS: Between 1998 and 2007, 89 patients with s.p.r.c. were treated according to a prospective protocol. One hundred and nineteen patients (69.6%) underwent low anastomoses and 52 patients (30.4%) underwent ultra low anastomoses. Forty-two (24.6%) were treated with traditional AR, 129 (75.4%) with AR and nerve-sparing TME. Forty-six (26.9%) patients underwent neoadjuvant therapy. One hundred and two patients underwent a mechanical end-to-end anastomosis, 67 a double stapled anastomosis, and 2 a colo-anal anastomosis at the pectinate line performed according to our technique. All 6 patients with major dehiscences underwent a protective colostomy within hours of the onset of clinical symptoms immediately after the radiologically- or endoscopically confirmed diagnosis. The 7 minor dehiscences were successfully treated with conservative therapy (antibiotic and enteral feeding) using an out-patient regimen. Two (28.6%) required percutaneous drainage: one pelvic CT-guided drainage and the other (an ultralow dehiscence) perineal drainage. The 72.6% of the patients survived at 5-years follow-up. The incidence of local recurrences in 2-years followup was 3.2% (on 124 patients). We had no deaths in patients treated with fast-track protocol. CONCLUSION: Open, TME nerve-sparing A.R. with selective use of neoadjuvant therapy, can be successfully performed without a protective stoma in more than 80% of the patients. Fast-track protocol seems to increase quality of p.o. period and decrease hospital stay PMID- 21322271 TI - [Laparoscopic surgery of rectal cancer: state of art and long-term results]. AB - BACKGROUND: From the first laparoscopic colectomy that we performed 18 years ago, several studies showed equivalent oncologic results of this technique compared to open surgery Despite this evidence traditional surgeons remain skeptical in the use of this technique, although it may favor an early return of bowel function and therefore a shorter hospitalization, as reported in recent comparative studies. Many colorectal surgeons, who have appreciated the advantages of laparoscopic colectomy, extended this approach also in rectal cancer, finding a better view in the pelvis during dissection. METHOD: From 1992 to july 2009 we performed more than 400 laparoscopic resection and amputation for rectal cancer. One hundreds eighteen patients (TNM stage I-III) with a 36 month minimum follow up were enrolled in this analysis. Converted patients to open surgery and patients staged as iT1N0 are not present in this series because we treat with local excision by TEM. RESULTS: Mean operative time was 160 minutes (90-265). Mortality was 1% in 186 patients and conversion rate was 1.5%. Major complications occurred in 10.7%, including anastomotic leakage in 14 patients (7.5%) and mean hospital stay was 7.7 days. With a mean follow up of 96.8 (36 175) months in the stage I-III, the local recurrence rate was 12.5%. Systematic recurrence occurred in 13.1%. CONCLUSION: Laparoscopic resection in rectal cancer would allow the use of the same Heald's technique, respecting the Heald's principle of meticulous dissection during total mesorectal excision, furthermore we are waiting 5 years data from randomized trials (COLOR II and CLASICC). PMID- 21322272 TI - [Transanal endocopic microsurgery (TEM) in advanced rectal cancer disease treatment]. AB - After Heald's revolution in 1982, who introduced the total mesorectal excision, for improve the results in terms of recurrance and survival rate, there is a need to explore new therapeutic options in treatment of sub-peritoneal rectal cancer. In particular, local excision represent more often a valid technique for non advanced rectal cancer treatment in comparison with the more invasive procedure, especially in elderly and/or in poor health patients. The introduction of TEM by Buess (transanal endoscopy microsurgery), has extended the local treatment also to classes of patients who would normally have been candidates for TME. The author gives literature's details and his experience in the use of TEM for early rectal cancer sub-peritoneal. The aim of the study is to analyze short and long term results in terms of local recurrence and survival rate comparing TEM technique with the other transanal surgery in rectal cancer treatment. Preoperative Chemio-Radio therapy and rigorous Imaging Staging are the first steps to planning surgery. It's time, for local rectal cancer, has come to make the devolution a few decades ago has been accomplished in the treatment of breast cancer PMID- 21322273 TI - [Results of a National Questionnaire on "Treatment of the subperitoneal rectal cancer". Comparision among the international guidelines and metaanalysis]. AB - A questionnaire including 20 questions about different aspects of subperitoneal rectal cancer was sent to 2200 fellows of Italian Society of Surgery. The answers were compared with International guidelines and with more recent metaanalyses from the literature. On the whole less than half of Italian surgeons fulfil the terms of the guidelines and the prevalent trend of the International literature. This behaviour concerns the choice of surgical procedure and prevention and diagnosis of anastomotic fistulas. PMID- 21322274 TI - [The role of laparoscopy in surgical treatment of pancreatic cancer]. AB - AIM: The authors reviewed their experience in surgical treatment of pancreatic cancer between 2003-2008. METHODS: Eighty two pancreatic cancer patients (median age 66.7 +/- 12.5) with obstructive jaundice were enrolled in our study: 36 (44%) had an endoscopic biliary stent; 46 patients (56%) were eligible for surgery: 14 received a curative surgery (pancreatoduodenal resection; 4 had a laparoscopic procedure) and 32 patients with non resectable tumor a palliative surgery: 18 had a gastro-jejunal with a biliary anastomosis (in 4 patients the hepatic-jejunal anastomosis was performed in laparoscopy), 6 had a gastro-jejunal anastomosis (2 laparoscopic procedure and 8 patients had only an explorative laparoscopy. RESULTS: The resectability rates was 17.1%. Median age in patients treated with endoscopic biliary stent was significantly higher than those underwent surgery (72.3 +/- 12.2 vs. 63.5 +/- 9.6; p < 0.05). Hospital length of stay in patients underwent radical surgery was significantly higher than those who received palliative surgery (18 +/- 6 vs. 10 +/- 5; p < 0.05). Morbility rate, including operative mortality of .3%, was 15.2%. CONCLUSIONS: Laparoscopy is largerly used in major oncologic surgery for several reasons: it minimized surgical manipulations and so post-operative complications. There is enough scientific evidence of low incidence of post-operative complications and long-term results compared to those achieved with traditional surgery. PMID- 21322275 TI - [The intestinal infarct. Personal casistics and management of the patients]. AB - AIM OF THE STUDY: Intestinal infarction is caused by secondary ischemic damage due to partial or complete obstruction of blood flow usually of arterial origin. About 50% of acute mesenteric infarctions are due to superior mesenteric artery emboli. Arterial thrombosis are most commonly caused to atherosclerosis, less commonly vasculitis, or hypercoaguable states. Venous thrombosis represents only 5-10% of cases usually associated with an hypercoagulable state, less commonly inflammation, portal hypertension or trauma. Non occlusive ischemia may represent up to 25% of acute mesenteric infarction, and is most commonly associated with shock, cardiac arrhythmia or acute pulmonary edema. MATERIAL AND METHODS: From January 2002 to March 2007, 19 patients with intestinal infarction were treated, at the General Surgery and Oncology Department of Catania University. All patients were submitted to RX direct (RX) and computed tomography (CT). In 94.7% of patients RX has demonstrated clear bowel gaseous distension. Preoperative arteriography was carried out in 15.7%, whereas multislice angio-CT only in 36.8%. Second look laparotomy was executed to evaluate the effectiveness of treatments. RESULTS: In 2/19 (10.5%) embolectomy of superior mesenteric artery were executed and in one case 30 cm of ileo resection only. In another 10.5% cases a surgical revascolarization of intestinal arteries with an anterograde by pass technique was carried out. A resection with anastomosis has been necessary in 78.9% but in 26% of these procedures a second look laparotomy was necessary. DISCUSSION: Three months survival was showed in 36.8% of patients. Completion angiography showed successful recanalization of the superior mesenteric artery without any complication and with satisfactory distal flow. Symptoms of the patients were alleviated. CONCLUSION: Mesenteric ischaemia is a relatively uncommon cause of abdominal pain, but one with significant mortality. PMID- 21322276 TI - [Transanal haemorridal dearterialisation: personal experience]. AB - Transanal haemorroidal dearterialisation (THD) is a nonexcisional surgical technique for the treatment of piles, consisting in the ligation of the distal branches of the superior rectal artery, resulting in a reduction of blood flow and decongestion of the haemorroidal plexus. THD for 2 degrees and 3 degrees degree haemorroids is highly effective and painless. There are few complications and the technique can be performed as a day case. PMID- 21322277 TI - Continence coach: Closing care gaps across the globe. PMID- 21322278 TI - Are you a stomatologist and other ostomy language conundrums. PMID- 21322279 TI - [Influence of different blood purification treatment on the serum leptin and neuropeptide Y levels in patients with chronic renal failure]. AB - AIM: To study the influence of different blood purification technology on plasma leptin and neuropeptide Y (NPY). METHODS: 150 patients with chronic renal failure in our hospital were included, which were divided into hemodialysis (HD) group, hemoperfusion (HP) group, and hemofiltration (HF) group. The serum leptin and neuropeptide Y levels were measured by radioimmunoassay (RIA) before and after first treatment, after treatment for 3, 6 month. RESULTS: Serum leptin and NPY were significantly lower after HDF and HP (P < 0.05), but not after HD in single treatment and for 3, 6 months treatment (P > 0.05). Serum leptin and NPY in group HDF and HP patients in single treatment and for 3, 6 months treatment were significantly greater than those of group HD (P < 0.05). The clearance rate of leptin and NPY in group HDF and HP patients were significantly greater than those of group HD (P < 0.05). There is no correlation between serum leptin and NPY (P > 0.05). CONCLUSION: Hemodialysis can not lower serum leptin and NPY. But HDF and HP can eliminate serum leptin and NPY preferably, which may improve the patients' nutritional status. PMID- 21322280 TI - Metabolic capabilities of Escherichia coli: I. synthesis of biosynthetic precursors and cofactors. AB - Metabolism of living cells converts substrates into metabolic energy, redox potential and metabolic end products that are essential to maintain cellular function. The flux distribution among the various biochemical pathways is determined by the kinetic properties of enzymes which are subject to strict regulatory control. Simulation of metabolic behavior therefore requires the complete knowledge of biochemical pathways, enzyme kinetics as well as their regulation. Unfortunately, complete kinetic and regulatory information is not available for microbial cells, thus preventing accurate dynamic simulation of their metabolic behavior. However, it is possible to define wider limits on metabolic behavior based solely on flux balances of biochemical pathways. We present here comprehensive information about the catabolic pathways of the bacterium Escherichia coli. Using this biochemical database, we formulate a stoichiometric model of the bacterial network of fueling reactions. After logical structural reduction, the network consists of 53 metabolic fluxes and 30 metabolites. The solution space of this under-determined system of equations presents the bounds of metabolic flux distribution that the bacterial cell can achieve. We use specific objective functions and linear optimization to investigate the capability of E. coli catabolism to maximally produce the 12 biosynthetic precursors and three key cofactors within this solution space. For the three cofactors, the maximum yields are calculated to be 18.67 ATP, 11.6 NADH and 11 NADPH per glucose molecule, respectively. The yields of NADH and NADPH are less than 12 owing to the energy costs of importing glucose. These constraints are made explicit by the interpretation of shadow prices. The optimal yields of the 12 biosynthetic precursors are computed. Four of the 12 precursors (3 phosphoglycerate, phosphoenolpyruvate, pyruvate and oxaloacetate) can be made by E. coli with complete carbon conversion. Conversely, none of the sugar monophosphates can be made with 100% carbon conversion and analysis of the shadow prices reveals that this conversion is constrained by the energy cost of importing glucose. Three of the 12 precursors (acetyl-coA, alpha-ketoglutarate, and succinyl-coA) cannot be made with full carbon conversion owing to stoichiometric constraints; there is no route to these compounds without carrying out a decarboxylation reaction. Metabolite flux balances and linear optimization have thus been used to determine the catabolic capabilities of E. coli . PMID- 21322281 TI - [Study of SOD and PON-1 expression in type 2 diabetes mellitus nephropathy and its clinical significance]. AB - AIM: To investigate the clinical value of superoxide dismutase (SOD) and paraoxonase-1 (PON-1) in type 2 diabetes mellitus (T2DM) nephropathy. METHODS: 80 cases of T2DM patients were divided into T2DM nephropathy group (ND group, 40 cases), and non-T2DM nephropathy group (non-ND group, 40 cases), the SOD, PON-1 levels and biochemical levels of the two group were measured, the HOMA-IR was recorded. RESULTS: The SOD and PON-1 levels of the ND group were lower than the non-ND group, compared the difference was significant (P < 0.05). The FINS, FINS levels and HOMA-IR of the ND group were higher than the non-ND group, compared the difference was significant (P < 0.05). The FBG, PBG2h and HbAlc levels were no significantly different (P > 0.05). Serum SOD, PON-1 levels and HOMA-IR were significantly negatively correlated (r = -0.287, -0.509; P = 0.006, 0.000), serum SOD level and PON-1 level was no significantly correlated (P > 0.05). CONCLUSION: The serum SOD and PON-1 involve in the development of T2DM nephropathy. Combined detection of serum SOD and PON-1 have important clinical significance for early diagnosis, prevention, treatment and prognosis of T2DM nephropathy. PMID- 21322282 TI - [Clinical efficacy of treating infant cytomegalovirus hepatitis with ganciclovir and impact on cytokines]. AB - AIM: To observe the clinical efficacy of treating infant cytomegalovirus (CMV) hepatitis with ganciclovir and impact on cytokines. METHODS: 76 patients with CMV hepatitis infant were randomly divided into treatment group and control group. The patients of two groups were treated using conventional therapy, on the basis of conventional therapy the treatment group was treated using induction and maintenance treatment of ganciclovir. Before and after treatment the growth and decline in jaundice, liver function, side effects and IL-8 and IFN-gamma levels of the patients were detected, clinical efficacy was evaluated. RESULTS: The clinical total effective rate of the treatment group was 91.4%, it was significantly higher than that of the control group (71.4%), compared with the control group the difference was significant (P < 0.05). After treatment, the growth and decline of jaundice (TBIL and DBIL), liver enzymes (ALT and AST) and cytokines (IL-8 and IFN-gamma) levels increased, compared with the pre-treatment and the control group the difference was significant (P < 0.05). The treatment group was no adverse reaction. CONCLUSIONS: The induction and maintenance treatment of ganciclovir in treatment of infant CMV hepatitis can make the body to restore balance of specific cellular immunity, and can significantly improve the symptoms of jaundice, liver function and clinical efficay and it is worthy to be popularized. PMID- 21322283 TI - Social status, race, and the timing of marriage in Cuba's first constitutional era, 1902-1940. AB - This article examines the practice of marriage among whites, "mestizos," blacks, Cubans, and Spaniards during the first constitutional era, focusing upon the reported ages of brides and grooms. The study consists of a quantitative examination of trends found in the records of 900 Catholic marriages celebrated in Havana during the opening decades of independence. The first major finding of the research is that according to most major indicators of status, age was negatively correlated with rank. Thus, contrary to the conclusions of studies conducted in many other contexts, those in the highest strata of society married young. Furthermore, very significant differences were detected in the marital patterns of those identified as mixed-race and those labeled as black. This finding offers empirical weight to the notion that the early-mid twentieth century Cuban racial structure would best be characterized as tripartite, rather than binary in nature. PMID- 21322284 TI - Faces and voices of Canadian family medicine. PMID- 21322285 TI - Healthy fish consumption and reduced mercury exposure: counseling women in their reproductive years. AB - OBJECTIVE: To provide family physicians with a practical, evidence-based approach to counseling women about healthy fish eating. SOURCES OF INFORMATION: MEDLINE was searched for articles published between 1999 and 2008. Most studies described in this article provide level II or III evidence. MAIN MESSAGE: Fish is an important component of a healthy diet for women in their reproductive years owing to the beneficial effects of omega-3 fatty acids on the neurologic development of the fetus. However, some fish species contain considerable methylmercury, which crosses the placenta and has harmful effects on neurobehavioural development. As many jurisdictions have issued fish consumption advisories, which can be confusing, women would benefit from individualized assistance from a trusted source, their family physicians, to clarify the risks and benefits of eating fish. CONCLUSION: We recommend that family physicians counsel women in their reproductive years about healthy choices regarding fish in their diet, and provide appropriate resources. PMID- 21322287 TI - Part 2. Scalification. PMID- 21322286 TI - Complementary and alternative medicine for prevention and treatment of the common cold. AB - OBJECTIVE: To review the evidence supporting complementary and alternative medicine approaches to treatment and prevention of the common cold in adults. QUALITY OF EVIDENCE: MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews were searched from January 1966 to September 2009 combining the key words common cold or influenza with echinacea, garlic, ginseng, probiotics, vitamin C, and zinc. Clinical trials and prospective studies were included. MAIN MESSAGE: For prevention, vitamin C demonstrated benefit in a large meta-analysis, with possibly increased benefit in patients subjected to cold stress. There is inconsistent evidence for Asian ginseng (Panax ginseng) and North American ginseng (Panax quinquefolius). Allicin was highly effective in 1 small trial. For treatment, Echinacea purpurea is the most consistently useful variety; it was effective in 5 of 6 trials. Zinc lozenges were effective in 5 of 9 trials, likely owing to dose and formulation issues. Overall, the evidence suggests no benefit from probiotics for prevention or treatment of the common cold. CONCLUSION: Vitamin C can be recommended to Canadian patients for prevention of the common cold. There is moderate evidence supporting the use of Echinacea purpurea and zinc lozenges for treatment. Ginseng and allicin warrant further research. PMID- 21322288 TI - A qualitative evaluation of strategies to increase colorectal cancer screening uptake. AB - OBJECTIVE: To obtain data that could be used to optimize the content and design of the targeted, mailed invitations that Ontario's provincewide colorectal cancer (CRC) screening program plans to use to increase screening uptake; to identify other strategies to increase CRC screening uptake; and to describe the effects of this qualitative work on a subsequent quantitative pilot study. DESIGN: Qualitative study using semistructured focus groups. SETTING: Four different Ontario communities. PARTICIPANTS: Six focus groups comprising a total of 62 participants. METHODS: Six focus groups were conducted in 4 different Ontario communities. For 3 of the communities, participants were recruited from the general population by a private marketing firm, using random-digit dialing, and received a small honorarium for participating. In Sault Ste Marie, participants were convenience samples recruited from a large primary care practice and were not offered compensation. Responses were elicited regarding various strategies for promoting CRC screening. Findings represent all responses observed as well as recommendations to program planners based on focus groups observations. MAIN FINDINGS: Key themes identified included the importance of receiving a CRC screening invitation from one's family physician; a desire for personalized, brief communications; and a preference for succinct information in mailed materials. Strong support was indicated for direct mailing of the CRC screening kit (fecal occult blood test). Our findings substantially influenced the final design and content of the envelope and letter to be mailed in the subsequent quantitative pilot study. CONCLUSION: We report strong support from our focus groups for a succinct, personalized invitation for CRC screening from one's own family physician. We have also shown that qualitative evaluation can be used to provide decision makers with pertinent and timely knowledge. Our study is highly relevant to other public health programs, particularly other Canadian jurisdictions planning organized CRC screening programs. PMID- 21322289 TI - Marrying in the city in times of rapid urbanization. AB - Economic, social, political, and demographic processes changed Western European cities strongly during the nineteenth century. Especially during this time, the northern part of Belgium (Flanders) became highly urbanized. Investigating the long-term development of the marriage pattern in the cities of Antwerp, Aalst, and Ghent gives a detailed picture of the evolution of the urban marriage pattern. In this article, specific emphasis is on gender, social, and migration distinctions. The results confirm that there is a male-female difference and variation among various social and migrant groups in the age at first marriage during the period 1800-1906. Moreover, regional differences are also visible. In the port city of Antwerp, massive immigration caused a unique evolution in the age at first marriage during the last decades of the nineteenth century, which did not appear in the textile cities of Aalst and Ghent during this time. PMID- 21322290 TI - Genomics: driving cancer biology. AB - A new algorithm that combines gene expression and copy number alterations to identify driver genes and their possible function is reported. This was applied to melanoma samples, and vesicular trafficking was found to be an important process in this type of cancer. PMID- 21322291 TI - Sexual science and self-narrative: epistemology and narrative technologies of the self between Krafft-Ebing and Freud. AB - The aim of this article is to understand an important passage in the history of the sciences of the psyche: starting from the psychiatric problematization - and the consequent emergence - of the concept and the object called "sexuality" in the second half of the 19th century, it attempts to show a series of continuities and discontinuities between this kind of reasoning and the birth of psychoanalysis in the first years of the 20th century. The particular focus is therefore directed on two texts: Krafft-Ebing's "Psychopathia Sexualis" and Freud's "Three Essays on the Theory of Sexuality." The argument runs along three intertwined axes: (1) an historico-epistemological analysis of the concepts and their transformations in the field of the science of sexuality; (2) an analysis of the power relationships between patients and physicians; and (3) an account of the psychiatric technologies of the self that have as an effect the emergence of new forms of "objective" knowledge of the subject. The broader goal is to trace a map of the simultaneous and correlate coming into being and transformations both of new forms of objects and of new forms of subjects through the mediation of scientific concepts and techniques. PMID- 21322292 TI - Metabolism: choose your carbon source. AB - A new study identifies a regulatory mechanism controlling carbon source uptake. PMID- 21322293 TI - Cell signalling: weighing up TGFbeta signals. AB - The Hippo pathway couples cell polarity complexes to extrinsic signalling pathways. PMID- 21322294 TI - Signalling: REX rules. AB - The RAC-GEF PREX1 integrates signals from tyrosine kinase receptors and GPCRs to activate RAC1. PMID- 21322295 TI - The road to electronic health records is paved with operations. AB - The University of California, Los Angeles (UCLA) Health System seeks to align its purpose of "healing humankind" with its approaches for people and performance management. These approaches include lean process improvements initiatives, sustained by efforts to impact daily team member work flows. The electronic health record (EHR) serves as a powerful supportive instrument in improving processes and sustaining performance. For UCLA, the secret to EHR effectiveness lies in creating win-win situations, where organizational objectives are achieved and team member work flows also are improved. Recent UCLA initiatives with medication bar-coding and a stroke telemedicine network highlight such opportunities. Carried out on a national level, such efforts can significantly affect healthcare in the United States. The US Recovery and Reinvestment Act of 2009's EHR provisions provide a national impetus for broad improvements in healthcare. PMID- 21322296 TI - Alternative measures of electronic health record adoption among hospitals. AB - OBJECTIVE: To develop measures of the use of electronic health records (EHRs) that accurately reflect the full continuum of hospital adoption and progress toward meaningful use and to understand the intercorrelations and patterns associated with hospital adoption of specific EHR functions. STUDY DESIGN: This study analyzed the 2009 American Hospital Association (AHA) information technology (IT) supplement survey. The main section of this survey assessed the adoption and use of 24 EHR functionalities in the following major categories: electronic clinical documentation, results viewing, computerized provider order entry, and clinical decision support. METHODS: This study relied on descriptive statistical methods and a principal component factor analysis. RESULTS: We found that 11.4% of hospitals met all and 48.3% met half or more of the core criteria that are included in both the AHA IT survey and the final "meaningful-use" rule. The results from our factor analysis imply that hospitals adopt groups of similar EHR functions, but choices to adopt across major categories are relatively independent. CONCLUSIONS: Many hospitals have adopted multiple features of EHRs and tend to use a staged adoption strategy based on logical groupings of functions. These results indicate to policymakers that there is no single path toward adoption of advanced EHR systems. PMID- 21322297 TI - The importance of stories. PMID- 21322298 TI - Throw me a line. PMID- 21322299 TI - The power of listening. PMID- 21322300 TI - Review of Veterans Health Administration telemedicine interventions. AB - The Veterans Health Administration (VHA) is a leader in developing and implementing innovative healthcare technology. We review 19 exemplary peer reviewed articles published between 2000 and 2009 of controlled, VHA-supported telemedicine intervention trials that focused on health outcomes. These trials underscore the role of telemedicine in large managed healthcare organizations in support of (1) chronic disease management, (2) mental health service delivery through in-home monitoring and treatment, and (3) interdisciplinary team functioning through electronic medical record information interchange. Telemedicine is advantageous when ongoing monitoring of patient symptoms is needed, as in chronic disease care (eg, for diabetes) or mental health treatment. Telemedicine appears to enhance patient access to healthcare professionals and provides quick access to patient medical information. The sustainability of telemedicine interventions for the broad spectrum of veteran patient issues and the ongoing technology training of patients and providers are challenges to telemedicine-delivered care. PMID- 21322301 TI - Electronic health record feedback to improve antibiotic prescribing for acute respiratory infections. AB - OBJECTIVE: To examine whether the Acute Respiratory Infection (ARI) Quality Dashboard, an electronic health record (EHR)-based feedback system, changed antibiotic prescribing. STUDY DESIGN: Cluster randomized, controlled trial. METHODS: We randomly assigned 27 primary care practices to receive the ARI Quality Dashboard or usual care. The primary outcome was the intent-to-intervene antibiotic prescribing rate for ARI visits. We also compared antibiotic prescribing between ARI Quality Dashboard users and nonusers. RESULTS: During the 9-month intervention, there was no difference between intervention and control practices in antibiotic prescribing for all ARI visits (47% vs 47%; P = .87), antibiotic-appropriate ARI visits (65% vs 64%; P = .68), or non-antibiotic appropriate ARI visits (38% vs 40%; P = .70). Among the 258 intervention clinicians, 72 (28%) used the ARI Quality Dashboard at least once. These clinicians had a lower overall ARI antibiotic prescribing rate (42% vs 50% for nonusers; P = .02). This difference was due to less antibiotic prescribing for non-antibiotic-appropriate ARIs (32% vs 43%; P = .004), including nonstreptococcal pharyngitis (31% vs 41%; P = .01) and nonspecific upper respiratory infections (19% vs 34%; P = .01). CONCLUSIONS: The ARI Quality Dashboard was not associated with an overall change in antibiotic prescribing for ARIs, although when used, it was associated with improved antibiotic prescribing. EHR-based quality reporting, as part of "meaningful use," may not improve care in the absence of other changes to primary care practice. PMID- 21322302 TI - Placebo/nocebo: the "biochemical" power of words and suggestions. PMID- 21322303 TI - Using electronic prescribing transaction data to estimate electronic health record adoption. AB - OBJECTIVE: To determine whether electronic prescribing transaction data can be used to accurately and efficiently track national and regional electronic health record (EHR) adoption in order to evaluate progress toward national goals and identify and address regional disparities. STUDY DESIGN: This study compared national EHR use estimates derived from Surescripts electronic prescribing data for 2007 and 2008 with contemporary National Ambulatory Medical Care Survey (NAMCS) estimates. METHODS: The ratio of relative risks was adapted to test the statistical significance of the difference in the differences between Surescripts and NAMCS estimates in 2007 and 2008. RESULTS: In 2007, the relative ratio (RR) of NAMCS to Surescripts data was 3.73 (95% confidence interval [CI] = 3.27, 4.26). In 2008, the RR was 2.06 (95% CI = 1.75, 2.42). The ratio of RRs for 2007 compared with 2008 was 1.81 (P <.0001), suggesting that Surescripts transactional data for providers prescribing through an EHR is becoming better aligned with accepted measures of EHR adoption in the United States with time. Surescripts derived state estimates for EHR use ranged from less than 8% (North Dakota, New Jersey, New Mexico) to more than 37% (Minnesota, Wisconsin, Massachusetts, Iowa). CONCLUSIONS: Surescripts transactional data may allow for the ongoing identification of regional trends and assist policy makers in identifying and mitigating emerging disparities in EHR adoption. Further analysis is needed to ensure that Surescripts data continue to correlate with NAMCS results for 2009 2010. PMID- 21322304 TI - Understanding meaningful outcomes. AB - This commentary is meant to set the stage for further discussion about how the objective of a learning healthcare system can be advanced through better specifying requirements to support secondary data use. Recent federal initiatives seek to foster widespread health information technology adoption in the hopes of improving the efficiency and efficacy of our nation's health system. Development of a framework for codifying clinical outcomes would support those objectives primarily though making it easier to uncover associative patterns in patient care data. Put simply, the explicit classification of patient outcomes at the point of care seems to be a prerequisite to foster the most rapid exploration of achievable outcomes and their determinants. Considerations in such an endeavor include attributional validity, accounting for treatment appropriateness, incorporating patient perspectives, and evaluating the impacts of linkages to pay for-performance programs. PMID- 21322305 TI - Finding cancer at home. PMID- 21322306 TI - The plague: not just an historical curiosity. PMID- 21322307 TI - The NSW Immunisation Strategy 2008-2011: how are we doing? PMID- 21322308 TI - [Improved Ugeskrift for Laeger's economics following limited access on the net?]. PMID- 21322309 TI - [Is milk healthy because there is no contrary evidence?]. PMID- 21322310 TI - [Complications of invasive examinations]. PMID- 21322311 TI - [Development of animal models, and drug discovery for schizophrenia based on the glutamate hypothesis]. PMID- 21322312 TI - [Development of psychotropic agents for schizophrenia based on the glutamate hypothesis]. PMID- 21322313 TI - The fear factor. Malpractice reforms haven't done much to end defensive medicine and the costs it adds to the system. AB - The latest flurry of research seems to show that malpractice reforms haven't done much to stop defensive medicine. The solution depends on whom you ask. "The focus ought to be on preventing medical errors--and not on taking away people's rights and capping their damages once they've been injured," says Todd Smith, left, of the Illinois Trial Lawyers Association. PMID- 21322314 TI - A waiting game. Industry gives mixed reviews on R&D tax credits. PMID- 21322315 TI - Lessons from across the pond. U.K.'s NHS gets better outcomes at less cost by emphasizing primary-care docs. PMID- 21322316 TI - Largest post-acute-care companies. Ranked by 2009 net revenue, based on Modern Healthcare's 2010 Post-Acute-Care Survey. PMID- 21322317 TI - Taking care of business. By becoming a student of business principles and investing in people, tech, and ancillaries, Dr, Gregory Oliver's revenue is in overdrive. PMID- 21322318 TI - Acting up or acting out. Recognize and address underlying causes of destructive work behaviors. PMID- 21322319 TI - 2011 coding changes. What you need to know to maximize reimbursement to your practice. PMID- 21322320 TI - Avoiding medical negligence claims. A former plaintiffs' attorney and physician explains why practicing defensive medicine doesn't work--and tells you what does. PMID- 21322321 TI - Keep it simple. How administrative burdens cost you money, and what needs to change. PMID- 21322322 TI - Keeping your practice independent in the age of big medicine. If you're deciding whether to join a hospital system or large multispecialty practice, here are some points to consider. PMID- 21322323 TI - Good rapport with patients helps lessen lawsuit risk. PMID- 21322324 TI - Guidelines versus policies. How to improve your medical practice management. PMID- 21322325 TI - Productivity part three of three. A fighting chance of success. PMID- 21322326 TI - Older people. Never too old to make an impact. PMID- 21322327 TI - Commissioning. Ready to lay down the law? PMID- 21322328 TI - Professional nurses can and must prevent urinary tract infections. PMID- 21322329 TI - Emotional intelligence: do you have it? PMID- 21322330 TI - The elephant in the room: huge rates of nursing and healthcare worker injury- Part 2. PMID- 21322331 TI - Stephen Eames risky business. PMID- 21322332 TI - Staff development. No time to be reining in training. PMID- 21322333 TI - QIPP. Charities bid for a greater role. PMID- 21322334 TI - It barks, but will it bite? While HHS can review proposed insurance premium increases, it lacks the authority to actually stop them. AB - HHS has new authority to review proposed insurance premium increases, but no real power to stop them. But at least some states without a rate review process say they welcome any support. "We are borderline at market failure," says Michael McRaith, left, director of the Illinois Department of Insurance. "The expectation is not that rates are going to dramatically or miraculously decline. But that rates will be more stable". PMID- 21322335 TI - A crucible for Catholic care. Affiliated hospitals feel pressured by church, state. PMID- 21322336 TI - Reverse conversion. HCA and Phoebe Putney make peace with proposed Palmyra sale. PMID- 21322338 TI - What to expect from Washington: the prognosis for reform and changes likely under a divided Congress. PMID- 21322337 TI - SNF billing questioned. HHS report draws ire from industry members. PMID- 21322339 TI - Truth, death and life. A year of propaganda and disturbing questions closes. PMID- 21322340 TI - A regional solution. U.S. needs the political will, adequate funding to cover gaps in trauma care. PMID- 21322341 TI - Zero tolerance. Take steps to implement infection control. PMID- 21322342 TI - Nursing roles in the spotlight. Panelists discuss IOM's recommendations for new practice models. PMID- 21322343 TI - 2011 Outlook. Construction: plenty of work. PMID- 21322344 TI - 2011 Outlook. Devices: pent-up demand. PMID- 21322345 TI - 2011 Outlook. Finance: getting squeezed. PMID- 21322346 TI - 2011 Outlook. For-profits: more deals. PMID- 21322347 TI - 2011 Outlook. Nurses: a tougher sell. PMID- 21322348 TI - 2011 Outlook. Post-acute: year of parity. PMID- 21322349 TI - Unmanageable risk? Health systems make a case against capitation. PMID- 21322350 TI - Largest pharmaceutical companies. Ranked by U.S. retail sales, December 2009 to November 2010. PMID- 21322351 TI - A better thermometer. IOM report calls for collecting new data to accurately measure what makes Americans sick, but providers wonder how it will be paid for. AB - A new IOM report seeks to create a new mechanism for collecting and measuring data on public health to give policymakers better tools in steering health policy. Providers hope this doesn't mean they'll be stuck with the bill. "This is a public good and therefore I would not expect that it's reliant on hospital contributions. It should be resourced through public means," says the AHA's Nancy Foster, left. PMID- 21322352 TI - Pick up the pace. Panel pushes feds to speed up EHR conversion. PMID- 21322353 TI - Don't be fooled. Demographics ensure nursing shortage will return with better economy. PMID- 21322354 TI - Cyberbattle. Providers work to protect devices, patients. PMID- 21322355 TI - Consultations--are we becoming complacent? AB - Throughout my career I have been involved in an increasing amount of consultations--whether it be about fundamental change in healthcare or indeed whether my job is necessary within a changing organisation. These are two very different things; one feels very personal and the other something that happens at a distance and probably doesn't need me to comment as an individual because someone else will be. PMID- 21322356 TI - What's up doc? AB - Back in November 2010, I read an article in The Telegraph that reported the findings of a research project into how carotenoids including beta-carotene, alpha-carotene and lycopene contained in carrots (and other plants) act as antioxidants to counteract oxygen-related damage to DNA often found in heart disease. I am not surprised to learn that eating carrots not only to make you see better (well that's what my parents insisted) but they have additional properties that may prevent life-threatening illnesses. PMID- 21322357 TI - Winter pressures. PMID- 21322358 TI - The comparison of double gloving to single gloving in the theatre environment. AB - The role of surgical gloving is to minimise the risk of surgical site infection (SSI) and to protect the surgical team from cross infection. However, different practitioners have different views as to when double gloving is appropriate, with many factors like speciality and procedure dictating their use. This review will look at best practice through the evidence available and provide recommendations for practice. PMID- 21322359 TI - Advanced trauma life support radiographic trauma series: Part 3--The pelvis radiograph. AB - Pelvic fractures are often high energy injuries and are associated with a high morbidity and mortality. The plain antero-posterior pelvis radiograph is part of the advanced trauma life support radiographic trauma series and is used as a screening test. The main limitation of plain anteroposterior pelvic radiographs is the difficulty in identification of some fractures, in particular posterior fractures, therefore radiographic findings should be considered in conjunction with clinical assessment. PMID- 21322360 TI - Documentation and record keeping. AB - Documentation and record keeping is an important aspect of healthcare practice and perioperative practice is no exception to this rule. For some time now, recording every activity or intervention that a patient receives has assisted with enhancing perioperative practice; equally, it has played a key part in resolving legal and professional incidents that have occurred. There are numerous national guidelines that uphold accurate record keeping as an intrinsic aspect to patient safety (DH 2006, HPC 2008, NMC 2008, Scottish Executive 2008, DH 2009). The intention of this article is to identify and discuss some of the more common errors associated with record keeping which may have a direct or indirect effect on practitioners' misconceptions of using electronic record systems. PMID- 21322361 TI - Simple multidisciplinary education of junior doctors and nurses improves prescription of venous thromboembolism prophylaxis. AB - Venous thromboembolism is the most common preventable cause of hospital death. Rates of thromboprophylaxis were studied prospectively in 158 surgical patients before and after multidisciplinary intervention. Prescription of mechanical prophylaxis improved from 58.8% to 76.6% (p = 0.015) following multidisciplinary education. Non-significant increases were seen in pharmacological prescription. Simple multidisciplinary education improves prescription of thromboprophylaxis. As postgraduate curricula for junior doctors and nurses evolve, we advocate routine inclusion of such sessions. PMID- 21322362 TI - Glaucoma surgery. AB - Glaucoma is a potentially blinding condition that cannot be easily defined. There are various types of glaucoma which may vary in symptoms from none at all to sudden pain and redness. There is a characteristic optic neuropathy, or damage to the optic nerve, which results in progressive loss of visual field. The most important risk factor is an increase in the intraocular pressure (IOP) secondary to a reduction in the drainage of aqueous fluid from the drainage pathways in the eye, the filtration angle (Kanski 2007, Allingham et al 2011). PMID- 21322363 TI - The early days of ruptured ectopic pregnancy. AB - Today, when lives are routinely saved by early open or laparoscopic surgery, it is hard to imagine that young women suffering from ruptured ectopic pregnancy were left to their fate or submitted to procedures which had no possibility of dealing effectively with the haemorrhaging fallopian tube. As we shall describe, the first success in dealing with this emergency was not until 1883. PMID- 21322364 TI - An eye for the big picture. Interview by Paul O'Grady. PMID- 21322365 TI - Maxillary canine-first premolar transposition in the permanent dentition: treatment considerations and a case report. AB - Transposition is defined as the interchange of position between two adjacent teeth within the same quadrant of the dental arch. Permanent maxillary canine premolar transposition is the most commonly observed transposition in the human dentition. Its prevalence is relatively low and its aetiology remains unclear, although it has been associated with genetic factors. It may also be related to a combination of localised factors such as malformation of adjacent teeth, tooth agenesis, retention of the deciduous canine and a history of local trauma. Treatment is selected on an individual case basis after thoroughly considering the overall facial and dental characteristics, duration of treatment, cost, patient preference and the orthodontist's experience. This article provides a case report of maxillary canine transposition in the permanent dentition, successfully managed with orthodontic treatment. PMID- 21322366 TI - Management of acute dislocation of the temporomandibular joint in dental practice. AB - Acute dislocation of the temporomandibular joint is a situation that, although rare, may present to the dentist in practice at any time. A number of activities, such as removal of a tooth, may cause dislocation. The event is painful and distressing for the patient, their family and the dental team. Prompt management minimises discomfort, distress and long-term morbidity to the patient. We describe the aetiology of acute dislocation and outline a number of techniques that will aid the clinican in dealing with this event. PMID- 21322367 TI - Metal-ceramic versus all-ceramic restorations: part 2. PMID- 21322368 TI - Consent for adult patients. PMID- 21322369 TI - Does it matter what it looks like--as long as it works? PMID- 21322370 TI - Make politicians responsible. PMID- 21322371 TI - Why do you do it? PMID- 21322373 TI - Great expectations: a dental continuum. PMID- 21322372 TI - Q & A with Ian Elliott 2011 CDS President. Interview by Walter Lamacki. PMID- 21322374 TI - Market your membership. PMID- 21322375 TI - Risk management benefits dentists, patients. PMID- 21322376 TI - Be prepared for winter. PMID- 21322377 TI - Turf war came out of good intentions. PMID- 21322378 TI - How to care for your toothbrush. PMID- 21322379 TI - Dentists must unite against antitrust exemption. PMID- 21322380 TI - SCOT Data. Organ Transplantation in Saudi Arabia. PMID- 21322381 TI - Display quality of different monitors in feline digital radiography. AB - In human medical imaging, the performance of the monitor used for image reporting has a substantial impact on the diagnostic performance of the entire digital system. Our purpose was to compare the display quality of different monitors used in veterinary practice. Two medical-grade gray scale monitors (one cathode-ray tube [CRT], one liquid crystal display [LCD]) and two standard consumer-grade color monitors (one CRT, one LCD) were compared in the ability to display anatomic structures in cats. Radiographs of the stifle joint and the thorax of 30 normal domestic shorthair cats were acquired by use of a storage phosphor system. Two anatomic features of the stifle joint and five anatomic structures of the thorax were evaluated. The two medical-grade monitors had superior display quality compared with standard PC monitors. No differences were seen between the monochrome monitors. In comparison with the color CRT, the ratings of the color LCD were significantly worse. The ranking order was uniform for both the region and the criteria investigated. Differences in monitor luminance, bit depth, and screen size were presumed to be the reasons for the observed varying performance. The observed differences between monitors place an emphasis on the need for guidelines defining minimum requirements for the acceptance of monitors and for quality control in veterinary radiography. PMID- 21322382 TI - Contrast enhancement of extradural compressive material on magnetic resonance imaging. AB - Gadolinium-enhancement of compressive extradural material is detected occasionally with magnetic resonance (MR) imaging in dogs. Our goal was to characterize contrast enhancement of extradural compressive material associated with intervertebral disc herniation, and to evaluate the association between enhancement and histopathologic findings and the onset of clinical signs. Ninety three dogs with a total of 99 lesions diagnosed as intervertebral disc herniation on MR imaging were assessed. Images were evaluated for lesion location, type of herniation, degree of compression, intramedullary T2-weighted (T2W) intensities, and contrast enhancement. In 23 dogs, surgically removed compressive material was evaluated histopathologically for hemorrhage, inflammation, neovascularization, fibroplasia, fibrosis, mineralization, necrosis, and chronicity. Contrast enhancement of extradural compressive material, meninges, and both the compressive materials and meninges was present in 51.5%, 39.4%, and 17.2% of lesions, respectively. Extradural enhancement occurred more frequently in extrusions than protrusions (P = 0.001). Meningeal enhancement and more severe neurologic deficits were significantly associated with a shorter duration of clinical signs (P = 0.04 and 0.01, respectively). Intramedullary T2W hyperintensities, present with 44.4% of lesions, were associated with more severe neurologic deficits (P = 0.001). Lesions with extradural enhancement were more often considered subacute to chronic in duration and more frequently associated with hemorrhage compared with nonenhancing material; however, no statistically significant association was established between contrast enhancement and histopathologic findings. Contrast enhancement of extradural compressive material and the meninges was found to be common with intervertebral disc herniation, and should not be interpreted as a specific sign of a mass lesion such as neoplasia. PMID- 21322383 TI - Clinical, pathologic, and magnetic resonance imaging characteristics of canine disc extrusion accompanied by epidural hemorrhage or inflammation. AB - Our aim was to characterize the magnetic resonance (MR) imaging features of canine disc extrusion accompanied by epidural hemorrhage or inflammation. We correlated the imaging characteristics of this type of disc extrusion in 46 dogs and compared these features with clinical signs and pathologic findings. Data from 50 control dogs with MR imaging features of a disc extrusion with no associated hemorrhage or inflammation, characterized by a T2-hypointense extradural mass, were used for comparison of the relative location of the two types of lesions and prognosis. Disc extrusion causing epidural hemorrhage or inflammation is more common in the caudal aspect of the lumbar spine than disc extrusions that do not cause signs of hemorrhage or inflammation (P < 0.05) in MR images. In dogs with disc extrusion and associated epidural hemorrhage or inflammation, there was no association between MR imaging features and signalment, the presence or absence of hemorrhage, or pathologic findings. The appearance of the lesion created by disc extrusion with epidural hemorrhage and inflammation encompasses a wide variety of imaging features, likely related to the duration of the hemorrhage and associated inflammatory changes. In 10 of 46 dogs these secondary changes masked identification of the disc extrusion itself in the MR images. An awareness of the variety of MR imaging features of disc extrusion accompanied by extradural hemorrhage or inflammation is important to avoid making an incorrect diagnosis and to facilitate a proper surgical approach. The prognosis of dogs with disc extrusion accompanied by hemorrhage or inflammation does not appear to be different than for dogs with disc extrusion and without imaging signs of epidural hemorrhage or inflammation. PMID- 21322384 TI - Magnetic resonance imaging of the canine brain at 3 and 7 T. AB - Magnetic resonance (MR) imaging of the canine brain is commonly acquired at field strengths ranging from 0.2 to 1.5 T. Our purpose was to compare the MR image quality of the canine brain acquired at 3 vs. 7 T in dogs. Low-resolution turbo spin echo (TSE) T2-weighted images (T2W) were obtained in transverse, dorsal, and sagittal planes, and high-resolution TSE T2W and turbo spin echo proton density weighted images were obtained in the transverse and dorsal planes, at both 3 and 7 T. Three experienced reviewers evaluated 32 predetermined brain structures independently and without knowledge of field strength for spatial resolution and contrast. Overall image quality and evidence of artifacts were also evaluated. Contrast of gray and white matter was assessed quantitatively by measuring signal intensity in regions of interest for transverse plane images for the three pulse sequences obtained. Overall, 19 of the 32 neuroanatomic structures had comparable spatial resolution and contrast at both field strengths. The overall image quality for low-resolution T2W images was comparable at 3 and 7 T. High resolution T2W was characterized by superior image quality at 3 vs. 7 T. Magnetic susceptibility and chemical shift artifacts were slightly more noticeable at 7 T. MR imaging at 3 and at 7 T provides high spatial resolution and contrast images of the canine brain. The use of 3 and 7 T MR imaging may assist in the elucidation of the pathogenesis of brain disorders, such as epilepsy. PMID- 21322385 TI - Comparative magnetic resonance imaging findings between gliomas and presumed cerebrovascular accidents in dogs. AB - Cerebrovascular accidents, or strokes, and gliomas are common intraaxial brain lesions in dogs. An accurate differentiation of these two lesions is necessary for prognosis and treatment decisions. The magnetic resonance (MR) imaging characteristics of 21 dogs with a presumed cerebrovascular accident and 17 with a glioma were compared. MR imaging findings were reviewed retrospectively by three observers unaware of the final diagnosis. Statistically significant differences between the appearance of gliomas and cerebrovascular accidents were identified based on lesion location, size, mass effect, perilesional edema, and appearance of the apparent diffusion coefficient map. Gliomas were predominantly located in the cerebrum (76%) compared with presumed cerebrovascular accidents that were located mainly in the cerebellum, thalamus, caudate nucleus, midbrain, and brainstem (76%). Gliomas were significantly larger compared with presumed cerebrovascular accidents and more commonly associated with mass effect and perilesional edema. Wedge-shaped lesions were seen only in 19% of presumed cerebrovascular accidents. Between the three observers, 10-47% of the presumed cerebrovascular accidents were misdiagnosed as gliomas, and 0-12% of the gliomas were misdiagnosed as cerebrovascular accidents. Diffusion weighted imaging increased the accuracy of the diagnosis for both lesions. Agreement between observers was moderate (kappa = 0.48, P < 0.01). PMID- 21322386 TI - The VetMousetrap: a device for computed tomographic imaging of the thorax of awake cats. AB - The VetMousetrap, a novel device that allows computed tomography (CT) of awake cats and provides a clinically supportive environment, is described. Ten normal cats were used to test the device for ambient internal oxygen, carbon dioxide levels, and temperature. Twenty-two awake normal cats were imaged using a 16 multislice helical CT unit to evaluate dose-equivalent protocols. Two different X ray tube potentials (kV), 80 and 120, and two different helical pitches, 0.562 and 1.75, were evaluated. The signal intensity of the pulmonary parenchyma (SIlung), signal intensity of background (SIbackgr), contrast, noise, signal-to noise ratio (SNR), and contrast-to-noise ratio (CNR) were calculated. Three evaluators ranked the images for sharpness of liver margins, motion, helical, and windmill artifacts. CT was successfully completed in 20 of 22 cats. No artifacts directly related to the device were detected. Overall, 75 of 80 (94%) examinations were judged to have absent or minimal motion artifact. A statistically significant difference was found for SNR (P = 0.001) and CNR (P = 0.001) between all protocols. The higher pitch protocols had significantly lower noise and higher SNR and CNR, lower motion artifact but greater helical artifacts. A protocol using 80 kV, 130 mA, 0.5s, and 0.562 pitch with 1.25mm slice thickness, and 0.625 mm slice reconstruction interval is recommended. The VetMousetrap appears to provide the opportunity for diagnostic CT imaging of the thorax of awake cats. PMID- 21322387 TI - Radiography and computed tomography in the diagnosis of nonneoplastic equine mandibular disease. AB - We compared the information gained from computed tomography (CT) vs. radiography in horses with nonneoplastic disease of the mandible. We hypothesized that CT would provide additional diagnostic information. Medical records, radiographs, and CT images of horses with nonneoplastic mandibular disease evaluated between 1994 and 2008 were reviewed. Nineteen horses were identified; 11 had a tooth root abscess and related disease, four had a fracture of the teeth and/or mandible, and four had a nonneoplastic mass. Both CT images and radiographs allowed identification of diseased teeth that appeared clinically normal otherwise. CT allowed identification of teeth that were clinically affected but appeared normal radiographically. Parameters such as tooth pulp involvement, lamina dura destruction, presence of bone fragments, lingual and buccal mandibular bone periosteal reaction, and cortical bone destruction were more conspicuous with CT. Performing radiography and CT in horses with nonneoplastic mandibular disease provides a more complete evaluation than either technique alone. CT contributes additional information that could otherwise be overlooked with radiographs alone in horses with a mandibular fracture. CT provides ancillary information to radiographs in horses with dental infection or a nonneoplastic mass of the mandible. PMID- 21322388 TI - The appearance of the equine metacarpophalangeal region on high-field vs. standing low-field magnetic resonance imaging. AB - The appearance of the equine metacarpophalangeal (MCP) joint on high-field (1.5 T) vs. low-field standing (0.27 T) magnetic resonance (MR) images was evaluated. Objectives were (1) to describe the MR appearance of anatomic structures of clinical interest on images of the equine MCP joint obtained from 20 equine cadaver limbs from horses without lameness using high-field and low-field systems, (2) to categorize the clarity of appearance of anatomic structures on low-field MR images in comparison to high-field images as a gold standard. We found that larger anatomic structures were visible with sharp margins on both high- and low-field images, smaller structures were less distinct on low-field images and therefore interpretation of smaller structures on low-field images must be done with care. PMID- 21322389 TI - Computed tomographic characteristics of intrapelvic masses in dogs. AB - In people, the computed tomography (CT) characteristics of intrapelvic masses can be used to distinguish a malignant from a benign mass. As prognosis varies greatly between malignant and benign intrapelvic masses, knowledge of their biological behavior can aid treatment planning before surgery. The purpose of this study was to determine if CT characteristics exist to help differentiate benign from malignant intrapelvic masses in dogs. The CT images of 14 dogs with a histopathologically confirmed intrapelvic mass were evaluated. Postcontrast internal heterogeneity of the mass was the only characteristic significantly associated with malignancy (P = 0.005). Preoperative CT examination of intrapelvic masses in dogs can provide prognostic information before invasive surgical treatment. PMID- 21322390 TI - Does changing the orientation of a thoracic radiograph aid diagnosis of rib fractures? AB - To test the hypothesis that changing the orientation of a thoracic radiograph aids diagnosis of rib fractures, a case-control study was carried out using 120 radiographs of small animal patients with recent thoracic trauma. Six independent observers representing three levels of experience viewed the radiographs in randomized order in conventional and unconventional orientations at 15-s intervals in a PowerPoint presentation. Sensitivity for rib fractures was 53-69% and specificity was 74-97%, depending on the observer. Radiologists had higher specificity than less experienced observers (P = 0.0001), but comparable sensitivity for rib fractures. Radiologists had significantly higher accuracy than residents (P = 0.03), and residents had higher accuracy than interns (P = 0.02). Accuracy of diagnosis was reduced significantly when based on lateral radiographs compared with dorsoventral (DV)/ventrodorsal (VD) views (P = 0.02) mainly because of low sensitivity of lateral radiographs of dogs with rib fractures. Rotating radiographs 90 degrees clockwise was associated with increased specificity of one intern (from 74 to 90%, P = 0.03), but had no effect on accuracy of diagnosis by other observers (P > 0.16). Turning DV/VD views upside down had no effect on accuracy of diagnosis of any observers (P > 0.40). Changing the orientation of a thoracic radiograph may make it easier for some novices to examine the ribs; hence it could be considered a training aid rather than a technique that will benefit an experienced radiologist. PMID- 21322391 TI - Imaging diagnosis--Congenital lobar emphysema in a dog. AB - A 14-week-old female West Highland White Terrier developed acute dyspnea. Radiographically there was an enlarged, hyperlucent caudal portion of the left cranial lung lobe and a diffuse, severe interstitial-to-alveolar pattern in the remaining lung lobes that was accentuated caudodorsally. Computed tomography confirmed the presence of the emphysematous lobe and further showed it to have focal lobar bronchial collapse. Lung lobe resection was performed, and the diagnosis was congenital lobar emphysema secondary to bronchial cartilage hypoplasia. PMID- 21322392 TI - The effect of the sample size and location on contrast ultrasound measurement of perfusion parameters. AB - Contrast-enhanced ultrasound can be used to quantify tissue perfusion based on region of interest (ROI) analysis. The effect of the location and size of the ROI on the obtained perfusion parameters has been described in phantom, ex vivo and in vivo studies. We assessed the effects of location and size of the ROI on perfusion parameters in the renal cortex of 10 healthy, anesthetized cats using Definity contrast-enhanced ultrasound to estimate the importance of the ROI on quantification of tissue perfusion with contrast-enhanced ultrasound. Three separate sets of ROIs were placed in the renal cortex, varying in location, size or depth. There was a significant inverse association between increased depth or increased size of the ROI and peak intensity (P < 0.05). There was no statistically significant difference in the peak intensity between the ROIs placed in a row in the near field cortex. There was no significant difference in the ROIs with regard to arrival time, time to peak intensity and wash-in rate. When comparing two different ROIs in a patient with focal lesions, such as suspected neoplasia or infarction, the ROIs should always be placed at same depth and be as similar in size as possible. PMID- 21322393 TI - Clinical significance of renal pelvic dilatation on ultrasound in dogs and cats. AB - Renal pelvic dilatation is often recognized sonographically in dogs and cats, but ranges of measurements expected with different urologic conditions remain unknown. Ultrasound images of 81 dogs and 66 cats with renal pelvic dilatation were reviewed, and six groups were formed based on medical records: (I) clinically normal renal function, and (II) clinically normal renal function with diuresis; (III) pyelonephritis; (IV) noninfectious renal insufficiency; (V) outflow obstruction; (VI) miscellaneous nonobstructive anomalies. Medians for maximal pelvic width (range) for group I was 2.0 mm (1.0-3.8) in 11 dogs, and 1.6 mm (0.8-3.2) in 10 cats; for group II, 2.5 mm (1.3-3.6) in 15 dogs, and 2.3mm (1.1-3.4) in 16 cats; for group III, 3.6 mm (1.9-12.0) in nine dogs, and 4.0 mm (1.7-12.4) in seven cats; for group IV, 3.1 mm (0.5-10.8) in 33 dogs, and 2.8 mm (1.2-7.3) in 13 cats; for group V, 15.1mm (5.1-76.2) in six dogs, and 6.8mm (1.2 39.1) in 17 cats; and for group VI, 3.8mm (1.2-7.6) in seven dogs, and 3.0 mm (1.3-7.5) in three cats. Pelvic width in group I was lower than in groups III-V (P = 0.0001), but did not significantly differ from group II. Pelvic width > or =13 mm always indicated obstruction. While the proportion of bilateral pelvic dilatation was not different among groups, the difference in pelvic width (maximal-minimal) was greater in group V vs. groups I, II, and IV (P = 0.0009). These results confirm that renal pelvic dilatation can be detected sonographically in dogs and cats with clinically normal renal function, and that it increases with renal insufficiency, pyelonephritis, or outflow obstruction. Nevertheless, renal pelvic width varies substantially within groups and should be interpreted with caution. PMID- 21322394 TI - Ultrasonographic findings in horses with foot pain but without radiographically detectable osseous abnormalities. AB - Foot pain is an important cause of lameness in horses. When horses with foot pain have no detectable radiographic abnormalities, soft-tissue assessment remains a diagnostic challenge without magnetic resonance (MR) imaging. Ultrasonography can provide an alternative to MR imaging when that modality is not available but the extent of changes that might be seen has not been characterized. We reviewed the ultrasonographic findings in 39 horses with lameness responding positively to anesthesia of the palmar digital nerves and without radiographically detectable osseous abnormalities. Thirty of the 39 horses had lesions affecting the deep digital flexor tendon (DDFT), 27 had abnormalities in the distal interphalangeal joint of which six had a visible abnormality in the collateral ligament. Ultrasonographic abnormalities were seen in the podotrochlear bursa in 22 horses and in the ligaments of the navicular bone in two horses. Abnormalities of the navicular bone flexor surface were detected in eight horses. In three of the 39 horses, only the DDFT was affected. The other 36 horses had ultrasonographic abnormalities in more than one anatomical structure. Based on our results, ultrasonographic examination provides useful diagnostic information in horses without radiographic changes. PMID- 21322395 TI - Use of transsplenic injection of agitated saline and heparinized blood for the ultrasonographic diagnosis of macroscopic portosystemic shunts in dogs. AB - We describe the use of ultrasonography-guided percutaneous splenic injection of agitated saline and heparinized blood for the diagnosis of portosystemic shunts (PSS) in 34 dogs. Agitated saline mixed with 1 ml of heparinized autologous blood was injected into the spleen of 34 sedated dogs under sonographic guidance. The transducer was then sequentially repositioned to visualize the portal vein, the caudal vena cava, and the right atrium through different acoustic windows. It was possible to differentiate between intrahepatic and extrahepatic shunts depending on the entry point of the microbubbles into the caudal vena cava. Portoazygos shunts and portocaval shunts could be differentiated based on the presence of microbubbles in the caudal vena cava and/or the right atrium. In one dog, collateral circulation due to portal hypertension was identified. In dogs with a single extrahepatic shunt, the microbubbles helped identify the shunting vessel. The technique was also used postoperatively to assess the efficacy of shunt closure. All abnormal vessels were confirmed by exploratory laparotomy or with ultrasonographic identification of the shunting vessel. Ultrasound-guided transsplenic injection of agitated saline with heparinized blood should be considered as a valuable technique for the diagnosis of PSS; it is easy to perform, safe, and the results are easily reproducible. PMID- 21322396 TI - Contrast-enhanced ultrasound of the normal canine prostate gland. AB - Canine prostate gland abnormalities affect a large number of adult male dogs. In veterinary medicine, the commonly used methods to diagnose canine prostate gland disease are digital rectal examination and abdominal ultrasound. We evaluated the ability of ultrasound contrast agent to provide additional information about the vascularity of the canine prostate gland; such information could be useful in detecting early prostate gland disease and in staging disease known to be present. We characterized the ultrasonographic appearance of prostate gland vascularity in 10 healthy dogs before and after the injection of an ultrasound contrast agent (Levovist). Before injecting Levovist, the prostate gland blood flow was classified as poor in all dogs, whereas after contrast agent injection blood flow was classified as moderate or good, in 3 and 7 dogs respectively. Knowledge of the status of prostate gland vascularity could be useful for the characterization, diagnosis and therapeutic monitoring of canine prostate gland lesions. PMID- 21322397 TI - Imaging diagnosis-transcranial color-coded duplex sonography in a dog with hepatic encephalopathy. AB - We report the use of transcranial Doppler ultrasonography in a dog with hepatic encephalopathy secondary to a congenital portosystemic shunt. A severe increase in the pulsatility index was measured in the right middle cerebral artery, left middle cerebral artery, and basilar artery. These values returned to normal following medical stabilization of the patient and resolution of the neurologic signs. Transcranial Doppler ultrasonography appears to have value for monitoring the status of intracranial hypertension in patients with hepatic encephalopathy. PMID- 21322398 TI - 90Sr therapy for oral squamous cell carcinoma in two cats. AB - Two cats with a superficial oral squamous cell carcinoma responded favorably to treatment using a 90Sr probe. From one to six fields were applied per tumor, depending on tumor size. The surface dose per treatment ranged from 75 to 150 Gy and the total surface dose ranged from 200 to 500 Gy. Adverse effects were minimal. The cats survived 7 months and 5 years 9 months from the time of diagnosis. These data indicate that with careful patient selection 90Sr may be useful for the treatment of feline oral squamous cell carcinoma in some patients. PMID- 21322399 TI - Death: a new legal persepective. PMID- 21322400 TI - The consumable vice: caffeine, public health, and the law. PMID- 21322401 TI - Preemption or bust: a review of the recent trends in Medicaid preemption actions. PMID- 21322402 TI - America's organ donation crisis: how current legislation must be shaped by successes abroad. PMID- 21322403 TI - Do the ends justify the means? Compelling the use of HPV vaccination on men. PMID- 21322404 TI - Moses v. Providence Hospital: the Sixth Circuit dumps the federal regulations of the patient anti-dumping statute. PMID- 21322405 TI - Characterizing human embryonic stem cells: biological and social markers of identity. AB - Human embryonic stem cells are elusive, recalcitrant entities that resist characterization and standardization. Without agreements about what the cells are and how best to systematize cell culture and testing, data cannot be extracted meaningfully, the nascent field will be slow to stabilize, and significantly, there may be safety risks for patients. I discuss efforts to characterize cells definitively and standardize practices across uniquely derived lines, labs, and researchers. I argue that such efforts are made more complicated by layered identities imposed on them by classification conventions, interactions with researchers and laboratory environments, and inheritances from genetic ancestry. The need to understand and possibly capitalize on such distinct, cumulative identities is in tension with the desire to stabilize the field under conditions of political and scientific uncertainty. The article links STS work on standardization with anthropological perspectives on identity and material culture in science. PMID- 21322406 TI - State calculations of cultural survival in environmental risk assessment: consequences for Alaska Natives. AB - In 2007, the Alaska Division of Public Health issued their first-ever fish consumption advisory to reduce exposure to methylmercury. Interestingly, they utilized a toxicity level in their calculations of risk that is four times higher than the U.S. Environmental Protection Agency's (EPA) level, arguing that the EPA's calculation is "inappropriately restrictive" for Alaskans. This article explores the institutional reasoning and scientific calculations behind the state's fish consumption advice, with special attention paid to the consequences for Alaska Natives. I argue that a discourse of "Alaskan exceptionalism" is utilized by the health department to justify their assessment of risk. Although this exceptionalist discourse is intended to accommodate the unique lifestyles of Alaskan citizens, it may actually serve to undermine the very lifeways and traditions that it presumes to preserve. This article contributes insights into the ways that states can influence the social and material reproduction of communities through the deployment of "cultural difference" during the risk assessment process. PMID- 21322407 TI - Beyond the reproduction of official accounts: parental accounts concerning health and the daily life of a California family. AB - Considering the purported bias of interviews to elicit "official accounts"- conveying conventional teachings from health promotion--and limited insights individuals may have into their own health behaviors, the challenges of relating health as talk (directed at researchers) to health as enacted are examined. Focusing on one family from a study of dual-earner middle-class Los Angeles families, I propose and apply four analytic lenses to a conjoint analysis of ethnographic interviews and videorecordings of family life to examine the parental claim that their family is a "healthy family." Findings indicate that parental accounts enable deeper insights into health as entrenched in everyday life, here revealing the centrality of a relational view of health as "family well-being" (vs. individual health) extending into the social world. Discussion considers debates over the extent to which "discursive consciousness" in interview settings illuminates health-relevant practices in everyday life contexts. PMID- 21322408 TI - Tobacco talk: reflections on corporate power and the legal framing of consumption. AB - This article examines how North Carolina tobacco farmers think about the moral ambiguities of tobacco business. Drawing on ethnographic research with tobacco farmers and archival research on the tobacco industry, I specify the core psychological defense mechanisms that tobacco companies have crafted for people associated with the industry. I also document local social, cultural, and economic factors in rural North Carolina that underpin ongoing rural dependence on tobacco despite the negativity that surrounds tobacco and structural adjustments. This article contributes to our knowledge about tobacco farmers and tobacco farming communities, which is important for tobacco-control strategies. I reflect on ethical and economic paradoxes related to the rise of corporate social responsibility in the tobacco industry, where an official legal framing of consumption, focused on informed adult consumer autonomy and health education, is promoted to undermine more robust public health prevention efforts. PMID- 21322409 TI - Individual wealth rank, community wealth inequality, and self-reported adult poor health: a test of hypotheses with panel data (2002-2006) from native Amazonians, Bolivia. AB - Growing evidence suggests that economic inequality in a community harms the health of a person. Using panel data from a small-scale, preindustrial rural society, we test whether individual wealth rank and village wealth inequality affects self-reported poor health in a foraging-farming native Amazonian society. A person's wealth rank was negatively but weakly associated with self-reported morbidity. Each step up/year in the village wealth hierarchy reduced total self reported days ill by 0.4 percent. The Gini coefficient of village wealth inequality bore a positive association with self-reported poor health that was large in size, but not statistically significant. We found small village wealth inequality, and evidence that individual economic rank did not change. The modest effects may have to do with having used subjective rather than objective measures of health, having small village wealth inequality, and with the possibly true modest effect of a person's wealth rank on health in a small-scale, kin-based society. Finally, we also found that an increase in mean individual wealth by village was related to worse self-reported health. As the Tsimane' integrate into the market economy, their possibilities of wealth accumulation rise, which may affect their well-being. Our work contributes to recent efforts in biocultural anthropology to link the study of social inequalities, human biology, and human environment interactions. PMID- 21322410 TI - Social inequality and health: a commentary. PMID- 21322411 TI - Factors related to recovery in a cat treated for lidocaine intoxication. PMID- 21322412 TI - Combating the shortage of food animal veterinarians. PMID- 21322413 TI - Liberating sex, knowing desire: "scientia sexualis"and epistemic turning points in the history of sexuality. AB - This study considers the role of epistemic turning points in the historiography of sexuality. Disentangling the historical complexity of "scientia sexualis," I argue that the late 19th century and the mid-20th century constitute two critical epistemic junctures in the genealogy of sexual liberation, as the notion of free love slowly gave way to the idea of sexual freedom in modern western society. I also explore the value of the Foucauldian approach for the study of the history of sexuality in non-western contexts. Drawing on examples from Republican China (1912-49), I propose that the Foucauldian insight concerning the emergence of a "homosexual identity" in the West can serve as a useful guide for thinking about similar issues in the history of sexuality and the historical epistemology of sexology in modern East Asia. PMID- 21322418 TI - Landmark guidance puts childhood continence firmly in the spotlight. PMID- 21322419 TI - Principles of transitional care for young people with longstanding continence problems. AB - Medical advances over the past 30 years mean that increasing numbers of children with long term conditions are surviving to adulthood. This means the way transitional care from paediatric to adult services is managed has become a focus of debate. This article discusses the process of healthcare transition for young people who have continence problems or require long term bladder management in their adult life. PMID- 21322420 TI - NICE's first guideline on idiopathic childhood constipation aims to standardise practice. PMID- 21322421 TI - An accessible Website to boost independence in young people with physical impairments. AB - The Queen's Nursing Institute Fund for Innovation awarded the health transition team in Walsall pounds 7500 to fund their transition website project. This was intended to support young people with physical impairments to access a wide range of information independently. This article offers information to those who wish to improve practice and work innovatively. PMID- 21322422 TI - How to help families cope with bedwetting during childhood or adolescence. PMID- 21322423 TI - One step at a time: how to toilet train children with learning disabilities. AB - Toilet training children with learning disabilities can present challenges and requires careful assessmentand management. This article examines strategies for toilet training using a five step approach bladder and bowel control. PMID- 21322424 TI - Solving soiling problems needs collaboration between family, health and education services. PMID- 21322425 TI - Enabling school staff to undertake clean intermittent catheterisation. AB - Successful clean intermittent catheterisation depends on the ability of the child, parents and carers to undertake the procedure and effectively integrate it into both home and school life. Paediatric continence nurses need to support this process by addressing the concerns and anxieties of school staff. Inconsistencies in practice and the absence of local policy can exacerbate concerns and anxiety. This article highlights the main issues surrounding use of CIC in schools and discusses them in the light of current legislation and guidance. PMID- 21322426 TI - Tensions between universities and the NHS need ironing out. PMID- 21322427 TI - Would you swap your Yuletide log for textbooks? PMID- 21322428 TI - Finite element modeling for development and optimization of a bone plate for mandibular fracture in dogs. AB - This study aimed to develop a plate to treat fractures of the mandibular body in dogs and to validate the project using finite elements and biomechanical essays. Mandible prototypes were produced with 10 oblique ventrorostral fractures (favorable) and 10 oblique ventrocaudal fractures (unfavorable). Three groups were established for each fracture type. Osteosynthesis with a pure titanium plate of double-arch geometry and blocked monocortical screws of free angulation were used. The mechanical resistance of the prototype with unfavorable fracture was lower than that of the favorable fracture. In both fractures, the deflection increased and the relative stiffness decreased proportionally to the diminishing screw number The finite element analysis validated this plate study, since the maximum tension concentration observed on the plate was lower than the resistance limit tension admitted by the titanium. In conclusion, the double-arch geometry plate fixed with blocked monocortical screws has sufficient resistance to stabilize oblique fractures, without compromising mandibular dental or neurovascular structures. PMID- 21322429 TI - Tooth resorption in the Swedish Eurasion lynx (Lynx lynx). AB - The etiology of tooth resorption in the domestic cat remains unknown. The high prevalence and progressive nature of the disease complicates defining healthy control groups. In order to evaluate the possible influence of various life style changes on the prevalence of tooth resorption, healthy control groups are a prerequisite. This paper presents a prevalence study for tooth resorption in a free-ranging wild felidae population. Skulls from 46 free-ranging Eurasian lynx (Lynx lynx) were examined. The age of the animals had previously been estimated based on cementum annuli in the maxillary right canine tooth. The dental examination included both dental probing and radiographic imaging. Complicated fractures of the canine teeth were found in 9/46 (19.5%) skulls. In one fractured canine, apical root resorption and periapical lucency was detected. The root resorption was attributed to inflammatory resorption as a consequence of the initial dental trauma and necrotic pulp. No signs of tooth resorption were found in the remaining teeth. Supernumerary roots were detected in 18/46 skulls (39.1 %). Supernumerary "peg" teeth caudal to the mandibular first molar tooth were detected in 6/46 (13.0%) skulls. Although further studies on dental ultra structure are needed, the Swedish Eurasian lynx may, in the future, be useful as a healthy comparative model for studies on the etiopathogenesis of tooth resorption in the domestic cat. PMID- 21322430 TI - Lip avulsion and mandibular symphyseal separation repair in an immature cat. AB - A 12-week-old kitten was presented for symphyseal separation, comminuted rostral fractures of the mandibles, avulsion of the mandibular lip, andfractured teeth. Oral examination and intraoral dental radiographs demonstrated a mandibular symphyseal separation and the presence of developing tooth buds. Cerclage wire was placed circumferentially around the mandibles for 2-weeks to provide stabilization of the mandibular symphyseal separation. Clinical examination 9.5 months following surgery demonstrated normal occlusion with enamel hypoplasia affecting the mandibular canine teeth. Intraoral dental radiographs showed a partial bony union of the mandibular symphysis and vital, developing mandibular canine teeth. PMID- 21322431 TI - Intraosseous maxillary hemangioma in an immature Bassett Hound. AB - A 6-month-old Bassett Hound dog presented for evaluation of recurrent oral bleeding and a right maxillary swelling. Oral examination revealed right maxillary enlargement extending from the level of the right maxillary canine tooth to the area of the second and third premolar teeth. A discolored persistent right maxillary deciduous canine tooth and gingival inflammation was noted. Biopsies taken at the time of extraction of the persistent deciduous canine tooth resulted in significant hemorrhage and a biopsy report of reactive bone. The right maxillary enlargement did not resolve following the extraction procedure and empirical antimicrobial therapy. The owner elected euthanasia and post-mortem evaluation. Histopathologic assessment provided a diagnosis of maxillary hemangioma. PMID- 21322432 TI - Multifocal odontoblastic dysplasia in a dog. AB - A two-year-old Boerboel dog presented for a discolored left maxillary canine tooth. Dental radiographs revealed abnormally mineralized pulp within the discolored tooth. Similar radiographic findings were also seen in both maxillary third incisor teeth and in the remaining canine teeth to varying degrees. The discolored tooth was treated by surgical extraction and histopathology revealed abnormal dentin deposition within the canal indicative of dentin dysplasia. Although not previously documented in the dog, the pulpal changes in multiple teeth of the dog reported here were similar to those described for odontoblastic dysplasia in humans. This case report includes a review of developmental abnormalities of dentin in humans and pulpal response to inflammation and injury. PMID- 21322433 TI - The basics of saliva. PMID- 21322434 TI - Surgery for cervical, sublingual, and pharyngeal mucocele. PMID- 21322435 TI - A movement. Birth is a human rights issue. PMID- 21322436 TI - Marion's message. Human rights for breech mamas. PMID- 21322437 TI - Waterbirth and GBS. AB - The literature provides a single case of early onset newborn Group B Strep (GBS) among 4432 waterbirths, suggesting that low-risk women who give birth in water may have a far lower rate of newborn GBS than women who have a dry birth. The last reported rate of newborn GBS for dry births was 1 in 1450. Several theories for this phenomenon are suggested in this article: (1) inoculating the baby with mother's intestinal flora at birth protects against GBS infection; (2) water washes off the GBS bacteria acquired during the descent through the vagina; (3) the water dilutes the GBS bacteria and mixes it with a multitude of other intestinal bacteria that compete with GBS; (4) early onset GBS is elicited by complications and interventions at birth, which occur less often at water-births; (5) kangaroo care at birth promotes healthy newborns; (6) GBS and antibiotic resistant GBS are more prevalent in hospital environments, where waterbirths are not an option; (7) a higher rate of underreporting of adverse events at waterbirths compared to dry births; and/or (8) a massively successful international campaign has covered up the reporting of all deaths and disease from GBS after waterbirths. PMID- 21322438 TI - Journey to the water. PMID- 21322439 TI - Waterbirth makes the midwife's job easier. PMID- 21322440 TI - Henry's waterbirth. PMID- 21322441 TI - Waterbirth with a blind mother. PMID- 21322442 TI - Like cures like: homeopathy for pregnancy and babies. PMID- 21322443 TI - Birth as a shape-shifter. PMID- 21322444 TI - The birth of Jocelyn Mary. PMID- 21322445 TI - Unusual foetal positions: hand beside ear. PMID- 21322446 TI - A tale of two births: the healing power of VBAC. PMID- 21322447 TI - A motherless mother. PMID- 21322448 TI - My waterbirth. PMID- 21322449 TI - The second was a gift. PMID- 21322450 TI - The mindfulness of midwifery: creating a practice with intent. PMID- 21322451 TI - Belly mapping: put positioning into parents' hands. PMID- 21322452 TI - Midwifery educabion: trauma or transformation? PMID- 21322453 TI - With women. PMID- 21322454 TI - A primer on craniosynostosis. PMID- 21322455 TI - My life as a spiritual midwife. PMID- 21322456 TI - Preventing and healing infant birth trauma. AB - Birth trauma can affect infants in adverse ways. The results of birth trauma can include feeding problems, bonding issues and emotional health. There are many ways that midwives and parents can prevent such trauma as well as help infants and children heal from birth trauma. PMID- 21322457 TI - Response to wax meta-analysis. AB - The recent Wax et al. meta-analysis (1) review of previously published homebirth research reflects the willingness of some medical journals to publish faulty conclusions based on misinformation regarding the need for more data on maternal mortality and on data long ago dismissed as unreliable, in an attempt to discredit homebirth. PMID- 21322458 TI - Bringing natural birth back to India. PMID- 21322459 TI - Denise's birth. PMID- 21322460 TI - The same in any language. PMID- 21322461 TI - Midwives: sing the babies earthside. PMID- 21322462 TI - Is that the placenta? PMID- 21322463 TI - Manisha's birth experience. PMID- 21322464 TI - Stop the presses! PMID- 21322465 TI - How many deaths due to medical errors? Maybe we should have a recount. PMID- 21322466 TI - "There they go again"--hCG and weight loss. AB - Dr. Albrink's review of information available in 1969 did not allow her to determine a physiologic basis for the use of hCG or any proof of immediate or long term benefit. Subsequent discoveries and clinical studies only support her impressions. Despite these facts, this form of therapy has achieved a resurgence in popularity. The difference today is that patients no longer have to rely on health care providers to prescribe their medications since internet sites allow them to obtain medications "on line". This has potential adverse ramifications when we consider that the initial use of gonadotropins derived from the human pituitary was discontinued due to the iatrogenic transmission of Creutzfeld-Jakob disease. It is thought that the disease is transmitted by an abnormal protein called prion protein. Subclinical forms of the disease exist and the prions could potentially be transmitted in urine. No cases or transmission via urine have been reported and reputable sources of hCG would appear to be safe, but products from countries with greater risk have the potential for contamination. The increased demand for hCG from reputable sources has led to shortages and increased expense for the legitimate uses of hCG in treatment of endocrine disorders and infertility. Obesity and the adverse impact on health has become a priority in public health policies for the state of West Virginia and for our nation as a whole. The benefit of longevity in the practice of medicine is that one is given the opportunity to observe attempts to "reinvent the wheel" where medical practices that have been previously disproven are reintroduced. Fineberg and Hiatt state this more eloquently when they said: "What is unacceptable is to persist in demonstrably ineffective practices either because we fail to collect systematic information about the effects of our actions or because we establish and respond to inappropriate incentives." Systematic information has been obtained and has shown lack of evidence for the benefit of this therapy. The alternative explanation for the persistence and promotion of this treatment is unacceptable. PMID- 21322467 TI - Idiopathic itch, rash, and urticaria/angioedema merit serum vitamin D evaluation: a descriptive case series. AB - BACKGROUND: Vitamin D insufficiency is epidemic. Rarely are cutaneous consequences attributed to low vitamin D. METHODS: A retrospective case series of 63 patients describes an association of pruritus, rash, and urticaria/angioedema with low 25-hydroxyvitamin D (25[OH]D <32 ng/mL). The 90% (57/63) of patients with low vitamin D were treated with 8 to 12 weeks of vitamin D 50,000 IU weekly followed by daily supplementation. Concurrent diagnoses were treated routinely. Complete resolution of cutaneous symptoms defined response. RESULTS: Patients were 3 to 80 years of age. The 90% (57/63) with low vitamin D (25[OH]D < 32 ng/mL) had a mean age of 47 (11 to 80) years old, 70% were atopic, and 77% were female. Median duration of idiopathic cutaneous symptoms was 18 months. Mean 25[OH]D was 18.0 ng/mL. With vitamin D treatment 70% (40/57) had complete resolution of symptoms. Mean 25[OH]D for vitamin D responsive patients (16.8 ng/mL) was significantly lower than for vitamin D non-responsive treated patients (20.9 ng/mL, P = 0.02 by unpaired t-Test). Resolution of cutaneous symptoms with vitamin D supplementation occurred in a mean of 4.2 weeks. Symptom recurrence was seen in subsequent months only if vitamin D insufficiency recurred. CONCLUSION: This retrospective case-series, with a 70% (40/57) vitamin D treatment success, suggests that vitamin D status should be assessed in patients with idiopathic cutaneous symptoms. If vitamin D is low, symptom resolution is often possible with oral supplementation of vitamin D. Controlled clinical studies are required to confirm these associations. PMID- 21322468 TI - Altitude induced migraine. PMID- 21322469 TI - Isolated bladder vasculitis: a rare presentation of Wegener's granulomatosis. PMID- 21322471 TI - Completion of a death certificate--a physician's responsibility to medical science and public health. PMID- 21322470 TI - Rational care or rationing care? Updates and controversies in women's prevention. AB - Prevention has potential benefits, but the majority of people undergoing disease screening will receive no benefit and may actually be exposed to health risks. Public opinion is generally very favorable toward prevention. However, many recent guidelines recommend fewer preventive services in women than previously suggested. New recommendations are to wait until 50 for mammography screening, to screen only every other year, and to not teach self breast examinations. Papanicolaou tests for cervical cancer screening are recommended to be done less often (every 2-3 years) and to be started later than previously suggested (not before age 21). Screening for ovarian cancer is not recommended. Guidelines suggest avoiding hormone therapy for primary prevention of coronary heart disease, not giving aspirin to prevent myocardial infarctions in women, and not screening women without risk factors for hyperlipidemia. These recommendations have caused confusion and, because of being revealed during a national health reform debate, have even been perceived as "rationing care." Others see them as "rational care," because they encourage utilization of beneficial services while discouraging use of those that may lead to more harms than benefits. Development of prevention guidelines requires value judgments, so despite the use of evidence, these recommendations have not all achieved widespread support. Understanding the data behind the guidelines, health care providers can decide how to approach prevention in practice, taking into consideration individual patient risk factors and preferences. PMID- 21322472 TI - The rise and fall of neural tube defects in West Virginia. PMID- 21322473 TI - Electronic patient care records implemented for West Virginia Emergency Medical Services. PMID- 21322474 TI - Risk management: Can medical professional liability underwriting be of assistance in physician recruitment? PMID- 21322475 TI - Copper dioxygen (bio)inorganic chemistry. AB - Cu/O2 intermediates in biological, homogeneous, and heterogeneous catalysts exhibit unique spectral features that reflect novel geometric and electronic structures that make significant contributions to reactivity. This review considers how the respective intermediate electronic structures overcome the spin forbidden nature of O2 binding, activate O2 for electrophilic aromatic attack and H-atom abstraction, catalyze the 4 e- reduction of O2 to H2O, and discusses the role of exchange coupling between Cu ions in determining reactivity. PMID- 21322476 TI - Reductive cleavage of the O-O bond in multicopper oxidases: a QM/MM and QM study. AB - The key step in the reaction mechanism of multicopper oxidases (MCOs)--the cleavage of the O-O bond in O2--has been investigated using combined quantum mechanical and molecular mechanical (QM/MM) methods. This process represents a reaction pathway from the peroxy intermediate after it accepts one electron from the nearby type-1 Cu site to the experimentally-observed native intermediate, which is the only fully oxidised catalytically relevant state in MCOs. Scans of the QM(DFT)/MM potential energy surface have allowed us to obtain estimates of the activation energies. Furthermore, vacuum calculations on a smaller model of the active site have allowed us to estimate the entropy contributions to the barrier height and to obtain further insight into the reaction by comparing the small cluster model with the QM/MM model, which includes the entire protein. Owing to the complicated electronic structure of these low-spin exchange coupled systems, multireference quantum chemical calculations at the complete-active space second-order perturbation theory (CASPT2) were used in an attempt to benchmark the barrier heights obtained at the DFT(B3LYP) level. Our best estimate of the activation barrier is deltaG = 60-65 kJ mol(-1), in good agreement with the experimental barrier of approximately 55 kJ mol(-1), which can be inferred from the experimental rate constant of k > 350 s(-1). It has also been shown that the reaction involves protonation of the O2 moiety before bond cleavage. The proton likely comes from a nearby carboxylate residue which was recently suggested by the experiments. PMID- 21322477 TI - Theoretical simulation of the spectroscopy and dynamics of a red copper protein. AB - The electronic absorption, circular dichroism and X-ray absorption spectroscopy of the red copper protein nitrosocyanin is simulated with classical molecular dynamics simulations in conjunction with time-dependent density functional theory (TDDFT) and multireference configuration interaction (MRCI) calculations on the active site, with the remainder of the protein and solvent included via point charges. In the molecular dynamics simulations of the oxidised form of the protein an exogenous water coordinates with the copper centre. Both TDDFT and MRCI approaches predict accurate excitation energies and give qualitatively correct absorption spectra. The most significant discrepancy with experiment is an underestimation of the intensity for the Cys(pi) band. Circular dichroism spectra are more difficult to compute accurately, and the best agreement with experiment is found using the velocity formulation for the rotational strength. However, this predicts the Cys(sigma) band with an incorrect sign. In the X-ray region, TDDFT in conjunction with a short-range corrected functional provides an accurate description of the pre-edge features at the copper and sulfur K-edges. PMID- 21322479 TI - Proton-coupled electron transfers in biomimetic water bound metal complexes. The electrochemical approach. AB - Water-bound metal (M) complexes play a central role in the catalytic centers of natural systems such as Photosystem II (PSII), superoxide dismutase, cytochrome c oxidase and others. In these systems, electron transfer reactions involving the metal center are coupled to proton transfers. Besides its fundamental interest, comprehension of these reactions and of possible bio-inspired catalytic devices is an additional motivation for studying the coupling between proton and electron transfer (proton-coupled electron transfers, PCET), starting with an aqua M(II)/hydroxo-M(III) couple, and going to higher oxidation degrees as in the case of PSII (hydroxo-M(III)/oxo-M(IV) couple). Factors that determine the occurrence of the stepwise and concerted pathways are recalled from the illustrating example of a recently described mononuclear osmium complex, thus opening perspectives for further studies of the biomimicking complex. PCET in a mononuclear aqua/hydroxo manganese couple was then studied using the electrochemical approach. PMID- 21322480 TI - Comparison of QM-only and QM/MM models for the mechanism of tyrosinase. AB - Two previous studies on the mechanism of tyrosinase have given quite conflicting results. In a QM-only study using a rather small model, a mechanism was suggested in which the tyrosine proton is removed before catalysis. This was followed by catalytic cycles where a superoxo ligand attacks the phenolate ring. In another, more recent study, at the QM/MM level including the entire protein in the model, a quite different mechanism was instead advocated where a bridging O2H ligand was homolytically cleaved. That mechanism was rejected in the earlier QM-only study as having a prohibitively large barrier for O-O bond cleavage. In the present study, this discrepancy between the previous studies is investigated by new QM only and QM/MM calculations. PMID- 21322478 TI - Relating dynamic protein interactions of metallochaperones with metal transfer at the single-molecule level. AB - Metallochaperones undertake specific interactions with their target proteins to deliver metal ions inside cells. Understanding how these protein interactions are coupled with the underlying metal transfer process is important, but challenging because they are weak and dynamic. Here we use a nanovesicle trapping scheme to enable single-molecule FRET measurements of the weak, dynamic interactions between the copper chaperone Hahl and the fourth metal binding domain (MBD4) of WDP. By monitoring the behaviors of single interacting pairs, we visualize their interactions in real time in both the absence and the presence of various equivalents of Cu(1+). Regardless of the proteins' metallation state, we observe multiple, interconverting interaction complexes between Hah1 and MBD4. Within our experimental limit, the overall interaction geometries of these complexes appear invariable, but their stabilities are dependent on the proteins' metallation state. In apo-holo Hah1-MBD4 interactions, the complexes are stabilized relative to that observed in the apo-apo interactions. This stabilization is indiscernible when Hah1's Cu(1+)-binding is eliminated or when both proteins have Cu(1+) loaded. The nature of this Cu(1+)-induced complex stabilization and of the interaction complexes are discussed. These Cu(1+)-induced effects on the Hah1 MBD4 interactions provide a step toward understanding how the dynamic protein interactions of copper chaperones are coupled with their metal transfer function. PMID- 21322481 TI - An enquiry into theoretical bioinorganic chemistry: how heuristic is the character of present-day quantum chemical methods? AB - In this discussion we elaborate on the state of the art in computational bioinorganic chemistry and aim at identifying and defining the most difficult obstacles in the process of obtaining unambiguous and predictive results from quantum chemical calculations. We then proceed to discuss and analyse well-known as well as new concepts for overcoming some of these obstacles. PMID- 21322482 TI - What can molecular modelling bring to the design of artificial inorganic cofactors? AB - In recent years, the development of synthetic metalloenzymes based on the insertion of inorganic catalysts into biological macromolecules has become a vivid field of investigation. The success of the design of these composites is highly dependent on an atomic understanding of the recognition process between inorganic and biological entities. Despite facing several challenging complexities, molecular modelling techniques could be particularly useful in providing such knowledge. This study aims to discuss how the prediction of the structural and energetic properties of the host-cofactor interactions can be performed by computational means. To do so, we designed a protocol that combines several methodologies like protein-ligand dockings and QM/MM techniques. The overall approach considers fundamental bioinorganic questions like the participation of the amino acids of the receptor to the first coordination sphere of the metal, the impact of the receptor/cofactor flexibility on the structure of the complex, the cost of inserting the inorganic catalyst in place of the natural ligand/substrate into the host and how experimental knowledge can improve or invalidate a theoretical model. As a real case system, we studied an artificial metalloenzyme obtained by the insertion of a Fe(Schiff base) moiety into the heme oxygenase of Corynebacterium diphtheriae. The experimental structure of this species shows a distorted cofactor leading to an unusual octahedral configuration of the iron with two proximal residues chelating the metal and no external ligand. This geometry is far from the conformation adopted by similar cofactors in other hosts and shows that a fine tuning exists between the coordination environment of the metal, the deformability of its organic ligand and the conformational adaptability of the receptor. In a field where very little structural information is yet available, this work should help in building an initial molecular modelling framework for the discovery, design and optimization of inorganic cofactors. Moreover, the approach used in this study also lays the groundwork for the development of computational methods adequate for studying several metal mediated biological processes like the generation of realistic three dimensional models of metalloproteins bound to their natural cofactor or the folding of metal containing peptides. PMID- 21322483 TI - Channeling of electrons within SLAC, the small laccase from Streptomyces coelicolor. AB - The reduction kinetics of the fluorescently labeled small laccase (SLAC) from Streptomyces coelicolor was studied by stopped flow kinetic measurements. The tryptophan fluorescence and the emission from a covalently attached label were used to selectively follow the progress of the reduction of the trinuclear copper center (TNC) and the type-1 (T1) Cu site in the enzyme as a function of time. A numerical analysis of the kinetic traces provided new insight into the midpoint potential difference between the T1 and the TNC site as the TNC becomes stepwise charged with electrons. The change in fluorescence of the TNC as the reduction of the TNC proceeds provided evidence that the type-3 dinuclear part of the TNC becomes charged prior to the reduction of the type-2 (T2) center of the TNC. The rate of reduction of the enzyme by dithionite (DT) appeared proportional to the square root of the DT concentration with a rate constant of k(red) = 0.28 +/- 0.02 microM(-1/2) s(-1). PMID- 21322484 TI - Continuum electrostatic investigations of charge transfer processes in biological molecules using a microstate description. AB - Charge transfer through biological macromolecules is essential for many biological processes such as for instance photosynthesis and respiration. In these processes, protons or electrons are transferred between titratable residues or redox-active cofactors, respectively. Often their transfer is tightly coupled. Computational methods based on continuum electrostatics are widely used in theoretical biochemistry to analyze the function of even very complex biochemical systems. These methods allow one to consider the pH and the redox potential of the solution as well as explicitly considering membrane potentials in the calculations. Combining continuum electrostatic calculations with a statistical thermodynamic analysis, it is possible to calculate equilibrium parameters such as protonation or oxidation probabilities. Moreover, it is also possible to simulate reaction kinetics by using parameters calculated from continuum electrostatics. One needs to consider that the transfer rate between two sites depends on the current charge configuration of neighboring sites. We formulate the kinetics of charge transfer systems in a microstate formalism. A unique transfer rate constant can be assigned to the interconversion of microstates. Mutual interactions between sites participating in the transfer reactions are naturally taken into account. This formalism is applied to the kinetics of electron transfer in the tetraheme-subunit and the special pair of the reaction center of Blastochloris viridis. It is shown that continuum electrostatic calculations can be used in combination with an existing rate law to obtain electron transfer rate constants. The relaxation electron transfer kinetics after photo-oxidation of the special pair of photosynthetic reaction center is simulated by a microstate formalism and it is shown to be in good agreement with experimental data. A flux analysis is used to follow the individual electron transfer steps. This method of simulating the complex kinetics of biomolecules based on structural data is a first step on the way from structural biology to systems biology. PMID- 21322485 TI - How do enzymes reduce metals? The mechanism of the reduction of Cr(VI) in chromate by cytochrome c7 proteins proposed from DFT calculations. AB - Various bacteria are effective in metal reduction, and there is an increasing use of such micro-organisms for decontaminating polluted environments. Iron containing electron transfer proteins, particularly those of the cytochrome c7 family, can bind a number of toxic metals in their high oxidation states, and can reduce them via electron transfer mechanisms. We report a computational investigation of the binding of CrO4(2-) to the cytochrome c7 of Desulfuromonas acetoxidans and explore possible mechanisms for the subsequent reduction of Cr(VI) to Cr(III). Our modelling strategy is to identify the binding site of D. acetoxidans for the chromate di-anion, and to use this structure as a starting point to generate realistic models for DFT calculations of the structures and energetics of species along the pathway for reduction. We address the following aspects of the mechanism: (i) How do the neighbouring residues, particularly the nearby lysines, modulate the reduction process? (ii) What is the speciation of chromium as the oxidation state is reduced from VI? (iii) How is the electron transfer made energetically feasible, considering the initial species (chromate) has a high negative charge? We suggest that both electron transfer from the heme and proton transfer from the lysines occur, followed by a disproportionation mechanism involving Cr(V). This mechanism is compared with our proposed mechanism for the reduction of actinyl species. PMID- 21322486 TI - What is not required to make a single molecule magnet. AB - The widely accepted assumption that the development of more efficient single molecule magnets must involve ever higher total spin values has so far driven synthetic efforts towards molecular clusters of increasing nuclearity. In the present paper it is suggested that it might be worthwhile to reconsider this approach. There is evidence from theory and experiment to suggest that the race for multinuclear complexes with higher total spin might not necessarily be fruitful as a strategy for maximizing the magnetic relaxation barrier. Instead, we propose that more effort should be directed in understanding the parameters involved in maximizing the anisotropy of small, perhaps even mononuclear, molecules. Using multi-reference ab initio calculations we demonstrate the theory that can be applied and the principles of the computational approach for representative mononuclear complexes. Such small units may subsequently be employed as building blocks for the controlled assembly of larger and maximally anisotropic single molecule magnets. PMID- 21322487 TI - Resonance Raman study on the oxygenated and the ferryl-oxo species of indoleamine 2,3-dioxygenase during catalytic turnover. AB - Resonance Raman (RR) spectra of the oxygenated and Fe(IV)=O reaction intermediates of indoleamine 2,3-dioxygenase (IDO) are reported. Absorption and RR spectra reveal that the electronic and geometric structures of the two respective species at pH 6.5 and pH 8.0 are the same, although the enzymatic activity at pH 6.5 is 6 times higher than at pH 8.0. The results thus further support our current understanding that the Fe(IV)=O heme species is the active species in the IDO reaction cycle, although its presence was unexpected. The Fe O2 and the O-O stretching frequencies of the IDO-Trp-O2 ternary complex at Trp concentrations of 50 microM and 8 mM are essentially identical. These results suggest that "substrate inhibition" of enzymatic activity occurs by binding of a second substrate molecule to an unknown binding site and not to the heme pocket. PMID- 21322488 TI - Implications for the mechanism of sulfite oxidizing enzymes from pulsed EPR spectroscopy and DFT calculations for "difficult" nuclei. AB - The catalytic mechanisms of sulfite oxidizing enzymes (SOEs) have been investigated by multi-frequency pulsed EPR measurements of "difficult" magnetic nuclei (35.37Cl, 33S, 17O) associated with the Mo(v) center. Extensive DFT calculations have been used to relate the experimental magnetic resonance parameters of these nuclei to specific active site structures. This combined spectroscopic and computational approach has provided new insights concerning the structure/function relationships of the active sites of SOEs, including: (i) the exchange of oxo ligands; (ii) the nature of the blocked forms; and (iii) the role of Cl- in low pH forms. PMID- 21322489 TI - Dissecting the mechanism of oxygen trafficking in a metalloenzyme. AB - A key question in the biological activation of oxygen is how the protein matrix regulates the delivery of oxygen to its site of activation. We are using Escherichia coli copper amine oxidase as a model system to investigate the roles played by both local active site residues as well as long range interactions in this process. We have generated active site mutants, as well as mutants in the putative oxygen delivery channel and characterised their affects on enzyme structure and catalysis. PMID- 21322490 TI - Prediction of nitroxide spin label EPR spectra from MD trajectories: application to myoglobin. AB - We report the prediction of motional EPR spectra of the metalloprotein sperm whale myoglobin spin labelled with nitroxide directly from Molecular Dynamics (MD) simulations at the atomistic scale. We show that an accurate simulation of EPR spectra can be achieved from a single MD trajectory which is in excellent agreement with experiment. Simulations have been carried out using a general method reported previously by us for the simulation of EPR spectra form single dynamical trajectories. Our calculations demonstrate the complex nature of the dynamics of a spin label which is a superposition of the fast librational motions around dihedral states, of slow conformational flips among different rotameric states and of the slow rotational diffusion of the protein itself. The MD-EPR methodology reported does not require any additional stochastic modelling using adjustable parameters and opens, for the first time, the prospect of the simulation of EPR spectra entirely from single MD trajectories. Such a technique not only simplifies the interpretation and analysis of EPR spectra but also opens the possibility, for example, of "computer engineering" of spin-labelled proteins with the desired properties prior to actual EPR experiment. PMID- 21322491 TI - Elucidating mechanisms in haem copper oxidases: the high-affinity QH binding site in quinol oxidase as studied by DONUT-HYSCORE spectroscopy and density functional theory. AB - The Cytochrome bo3 ubiquinol oxidase (QOX) from Escherichia coli (E. coli) contains a redox-active quinone, the so-called "high-affinity" QH quinone. The location of this cofactor and its binding site has yet to be accurately determined by X-ray crystallographic studies. Based on site-directed mutagenesis studies, a putative quinone binding site in the protein has been proposed. The exact binding partner of this cofactor and also whether it is stabilised as an anionic semiquinone or as a neutral radical species is a matter of some speculation. Both Hyperfine Sub-level Correlation (HYSCORE) and Double Nuclear Coherence Transfer Spectroscopy (DONUT-HYSCORE) spectroscopy as well as density functional theory (DFT) have been applied to investigate the QH binding site in detail to resolve these issues. Use is made of site-directed variants as well as globally 15N/14N-exchanged protein. Comparison of computed and experimental 13C hyperfine tensors provides strong support for the binding of the semiquinone radical in an anionic rather than a neutral protonated form. These results are compared with the corresponding information available on other protein binding sites and/or on model systems and are discussed with regard to the location and potential function of QH in the overall mechanism of function of this family of haem copper oxidases. PMID- 21322492 TI - Development of an infrared spectroscopic approach for studying metalloenzyme active site chemistry under direct electrochemical control. AB - Direct electrochemical methods have been productive in revealing mechanistic details of catalysis by a range of metalloenzymes including hydrogenases and carbon and nitrogen cycling enzymes. In this approach, termed protein film electrochemistry, the protein is attached or adsorbed on the electrode surface and exchanges electrons directly, providing precise control over redox states or catalysis and avoiding diffusion-limited electron transfer. The 'edge' surface of pyrolytic graphite has proved to be a particularly good surface for adsorption of proteins in electroactive conformations. We now describe development of an approach that combines the precise control achieved in direct electrochemical measurements at a graphite electrode with surface infrared (IR) spectroscopic analysis of chemistry occurring at metallocentres in proteins. Hydrogenases are of particular interest: their unusual organo-metallic active sites--iron or nickel-iron centres coordinated by CO and CN(-)--give rise to IR v(CO) and v(CN) bands that are detected readily because these ligands are strong vibrational oscillators and are sensitive to changes in electron density and coordination at the metals. Small diatomic species also bind as exogenous ligands (as substrate, product, activator or inhibitor) to a range of other important metalloproteins, and understanding their reactivity and binding selectivity is critical in building up a multidimensional picture of enzyme chemistry and evolutionary history. The surface IR spectroelectrochemical approach we describe is based around Attenuated Total Reflectance (ATR) mode sampling of a film of pyrolytic graphite particles modified with a protein of interest. The particle network extends the electrode into three-dimensional space, providing sufficient adsorbed protein for spectroscopic analysis under precise electrochemical control. This strategy should open up new opportunities for detection of redox-dependent chemistry at metal centres in proteins, including short-lived catalytic intermediates and time-resolved details of catalysis and inhibition. PMID- 21322493 TI - Protonation of [FeFe]-hydrogenase sub-site analogues: revealing mechanism using FTIR stopped-flow techniques. AB - The formation of transient metal hydride(s) at the metallo-sulfur active sites of [FeFe]-hydrogenase is implicated in both hydrogen evolution and uptake reactions. Stopped-flow spectroscopic techniques can provide insight into the reactivity patterns of model {2Fe2S} sub-sites towards protons, and this information contributes to understanding the nature of the biological systems. In this study we have focussed on the influence of the nature of the bridging dithiolate ligand in influencing the kinetics and activation energy parameters for protonation in synthetic sub-sites including Fe2{micro-[S(CH2)(n)S]}(CO)4(PMe3)2 [n = 2, ethane 1,2-dithiolate (edt) or n = 3, propane-1,3-dithiolate (pdt)], Fe2[(micro SCH2)2NH](CO)4(PMe3)2 and (NEt4)2{Fe2[(micro-SCH2)2NH](CO)4(CN)2}. Notably we find that (i) the presence of a nitrogen in the dithiolate bridge does not accelerate metal-metal bond protonation, and that (ii) immobilisation of (NEt4)2[Fe2(micro-pdt)(CO)4(CN)2] in a polymer matrix stabilises otherwise short lifetime protonation products. PMID- 21322494 TI - Water as biocatalyst in cytochrome P450. AB - According to previous quantum mechanics/molecular mechanics (QM/MM) studies, camphor hydroxylation in cytochrome P450 is catalysed by a single water molecule which lowers the computed B3LYP/CHARMM barrier by about 4 kcal mol(-1). Gas-phase B3LYP model studies for a variety of different substrates show the generality of this effect. Its origin is an electrostatic enhancement of hydrogen bonding in the transition state for hydrogen abstraction. Attempts are made to correlate the slight variations in the calculated barrier lowerings with substrate properties. Individual water molecules also have a decisive influence on other reactions in cytochrome P450cam, for instance, on the relative propensity for coupling and uncoupling upon protonation of Compound 0 in the wild-type enzyme and its mutants. These and other examples are reviewed briefly. Finally, we address some methodological issues on how to handle the possible involvement of water molecules in biocatalysis at the QM/MM level. PMID- 21322495 TI - The quest for a functional substrate access tunnel in FeFe hydrogenase. AB - We investigated di-hydrogen transport between the solvent and the active site of FeFe hydrogenases. Substrate channels supposedly exist and serve various functions in certain redox enzymes which use or produce O2, H2, NO, CO, or N2, but the preferred paths have not always been unambiguously identified, and whether a continuous, permanent channel is an absolute requirement for transporting diatomic molecules is unknown. Here, we review the literature on gas channels in proteins and enzymes and we report on the use of site-directed mutagenesis and various kinetic methods, which proved useful for characterizing substrate access to the active site of NiFe hydrogenase to test the putative "static" H2 channel of FeFe hydrogenases. We designed 8 mutations in attempts to interfere with intramolecular diffusion by remodeling this putative route in Clostridium acetobutylicum FeFe hydrogenase, and we observed that none of them has a strong effect on any of the enzyme's kinetic properties. We suggest that H2 may diffuse either via transient cavities, or along a conserved water-filled channel. Nitrogenase sets a precedent for the involvement of a hydrophilic channel to conduct hydrophobic molecules. PMID- 21322496 TI - Fe-H/D stretching and bending modes in nuclear resonant vibrational, Raman and infrared spectroscopies: comparisons of density functional theory and experiment. AB - Infrared, Raman, and nuclear resonant vibrational (NRVS) spectroscopies have been used to address the Fe-H bonding in trans-HFe(CO) iron hydride compound, HFe(CO)(dppe)2, dppe = 1,2-bis(diphenylphosphino)ethane. H and D isotopomers of the compound, with selective substitution at the metal-coordinated hydrogen, have been considered in order to address the Fe-H/D stretching and bending modes. Experimental results are compared to the normal mode analysis by density functional theory (DFT). The results are that (i) the IR spectrum does not clearly show Fe-H stretching or bending modes; (ii) Fe-H stretching modes are clear but weak in the Raman spectrum, and Fe-H bending modes are weak; (iii) NRVS 57Fe spectroscopy resolves Fe-H bending clearly, but Fe-H or Fe-D stretching is above its experimentally resolved frequency range. DFT calculations (with no scaling of frequencies) show intensities and peak locations that allow unambiguous correlations between observed and calculated features, with frequency errors generally less than 15 cm(-1). Prospects for using these techniques to unravel vibrational modes of protein active sites are discussed. PMID- 21322497 TI - Engineering enzymes. AB - Fundamental research into bioinorganic catalysis of the kind presented at this Faraday Discussion has the potential to turn inspiration drawn from impressive natural energy and chemical transformations into artificial catalyst constructions useful to mankind. Creating bio-inspired artificial constructions requires a level of understanding well beyond simple description of structures and mechanisms of natural enzymes. To be useful, such description must be augmented by a practical sense of structural and energetic engineering tolerances of the mechanism. Significant barriers to achieving an engineering understanding of enzyme mechanisms arise from natural protein complexity. In certain cases we can surmount these barriers to understanding, such as natural electron tunneling, coupling of electron tunneling to light capture and proton exchange as well as simpler bond breaking redox catalysis. Hope for similar solutions of more complex bioinorganic enzymes is indicated in several papers presented in this Discussion. Armed with an engineering understanding of mechanism, the current serious frustrations to successful creation of functional artificial proteins that are rooted in protein complexity can fall away. Here we discuss the genetic and biological roots of protein complexity and show how to dodge and minimize the effects of complexity. In the best-understood cases, artificial enzymes can be designed from scratch using the simplest of protein scaffolds. PMID- 21322498 TI - Acute in-patient care in modern, community-based mental health services. Where and how? PMID- 21322499 TI - Is locating acute wards in the general hospital an essential element in psychiatric reform? The U.K. experience. AB - Locating psychiatric wards in general hospitals has long been seen in many countries as a key element in the reform of services to promote community integration of the mentally ill. In the U.K., however, this is no longer a policy priority, and the recent trend has been towards small freestanding inpatient units, located either within the communities they serve, or on general hospital sites, but separate from the main building. Whether locating the psychiatric wards in the general hospital is essential to psychiatric reform has been little discussed, and we can find no relevant evidence. Perceived strengths of general hospital psychiatric wards are in normalisation of mental health problems, accessibility to local communities, better availability of physical health care resources, and integration of psychiatry with the rest of the medical profession, which may faclilitate recruitment. However, difficulties seem to have been encountered in establishing well-designed psychiatric wards with access to open space in general hospitals. Also, physical proximity may not be enough to achieve the desired reduction in stigma, and complaints from the general hospital may sometimes result in undue restrictions on psychiatric ward patients. There are strong arguments both for and against locating psychiatric wards in general hospitals: an empirical evidence base would be helpful to inform important decisions about the best setting for wards. PMID- 21322500 TI - Improving the quality of acute inpatient care. AB - Over the past ten years, the National Health Service in England has introduced home treatment teams throughout the country. Despite this, and the fact that England now has the fourth lowest number of beds per capita in Europe, no mental health service has been able to dispense with acute admission beds altogether. One unintended consequence of new investment in community alternatives to inpatient care is that the threshold for admission has risen and acute wards now accommodate a patient group that is more severe with regard to levels of disturbance and social disadvantage. This has compounded the challenge of providing high quality inpatient care and repeated national surveys suggest that acute admission wards are the weakest link in the English mental healthcare system. In response to this, the Royal College of Psychiatrists has established an accreditation scheme for acute admission wards. Only 22 of the first 132 wards to have completed the review process so far are considered to be excellent. Although 59 wards (45% of the total) failed to meet one or more essential standard, 43 of these were able to rectify the problem. PMID- 21322501 TI - Inpatient psychiatry: why do we need it? AB - The author makes the case for the necessity of inpatient psychiatric services in a comprehensive, community based, system of care. The editorial begins with an historical perspective on mental hospitals. It then discusses acute and intermediate psychiatric inpatient units. A section also covers forensic units, also indispensable for a region or population of any size. The editorial concludes with a call for recognizing the purpose and value of inpatient services and thus using them most effectively. PMID- 21322502 TI - Assessing risk of bias in randomized controlled trials. AB - Even though randomised controlled trials are the design of choice for evaluating the efficacy of health care interventions, they are not immune to bias that may affect research process and validity of results. In the present paper we discussed how trial quality may be appraised considering both whether a clinical trial is reported in a comprehensive and complete way (consistently with what had been declared in the study protocol), and whether the characteristics of the trial itself are associated with risk of bias. PMID- 21322503 TI - Brain anatomy of major depression I. Focus on hippocampus. AB - Here we briefly summarize the most consistent structural MRI studies on hippocampus in major depression and debate the effects of clinical variables on hippocampal morphology. PMID- 21322504 TI - Development of a new spatial analysis tool in mental health: identification of highly autocorrelated areas (hot-spots) of schizophrenia using a Multiobjective Evolutionary Algorithm model (MOEA/HS). AB - AIMS: This study had two objectives: (1) to design and develop a computer-based tool, called Multi-Objective Evolutionary Algorithm/Hot-Spots (MOEA/HS), to identify and geographically locate highly autocorrelated zones or hot-spots and which merges different methods, and (2) to carry out a demonstration study in a geographical area where previous information about the distribution of schizophrenia prevalence is available and which can therefore be compared. METHODS: Local Indicators of Spatial Aggregation (LISA) models as well as the Bayesian Conditional Autoregressive Model (CAR) were used as objectives in a multicriteria framework when highly autocorrelated zones (hot-spots) need to be identified and geographically located. A Multi-Objective Evolutionary Algorithm (MOEA) model was designed and used to identify highly autocorrelated areas of the prevalence of schizophrenia in Andalusia. Hot-spots were statistically identified using exponential-based QQ-Plots (statistics of extremes). RESULTS: Efficient solutions (Pareto set) from MOEA/HS were analysed statistically and one main hot spot was identified and spatially located. Our model can be used to identify and locate geographical hot-spots of schizophrenia prevalence in a large and complicated region. CONCLUSIONS: MOEA/HS enables a compromise to be achieved between different econometric methods by highlighting very special zones in complex areas where schizophrenia shows a high autocorrelation. PMID- 21322505 TI - Employees with mental health problems: Survey of U.K. employers' knowledge, attitudes and workplace practices. AB - AIM: To investigate whether employers who have experience of hiring people with mental health problems differ significantly from those without such experience in terms of knowledge, attitudes and behaviours regarding mental health in the workplace, and the concerns which they report about employing people with mental health problems. We also examine whether non-workplace social contact is associated with the above variables. METHODS: A telephone survey was conducted with a randomly selected sample of British employers. The sample included a similar number of human resource managers and managers/executive employees in other roles. RESULTS: 502 employers took part. Having employed someone with a mental health problem was associated with closer non-workplace social contact. Those with experience of employing applicants with mental health problems had significant differences in knowledge (regarding the law), and behaviour (having a policy on hiring applicants with disabilities) but not in attitudes. CONCLUSIONS: Non-workplace social contact may be useful to consider in understanding hiring practices. The nature of social contact at work and possible lack of impact of this contact on employer attitudes and concerns warrants further study. Greater support is needed for employers to understand the law regarding mental health problems in the workplace. PMID- 21322506 TI - The effectiveness of electroconvulsive therapy: a literature review. AB - AIM: To review the literature on the efficacy of electroconvulsive therapy [ECT], with a particular focus on depression, its primary target group. METHODS: PsycINFO, Medline, previous reviews and meta-analyses were searched in an attempt to identify all studies comparing ECT with simulated-ECT [SECT]. RESULTS: These placebo controlled studies show minimal support for effectiveness with either depression or 'schizophrenia' during the course of treatment (i.e., only for some patients, on some measures, sometimes perceived only by psychiatrists but not by other raters), and no evidence, for either diagnostic group, of any benefits beyond the treatment period. There are no placebo-controlled studies evaluating the hypothesis that ECT prevents suicide, and no robust evidence from other kinds of studies to support the hypothesis. CONCLUSIONS: Given the strong evidence (summarised here) of persistent and, for some, permanent brain dysfunction, primarily evidenced in the form of retrograde and anterograde amnesia, and the evidence of a slight but significant increased risk of death, the cost-benefit analysis for ECT is so poor that its use cannot be scientifically justified. PMID- 21322507 TI - Individualized approach to screening patients for STIs. PMID- 21322508 TI - Running and osteoarthritis of the hip: is there an association? PMID- 21322509 TI - Sexual violence as a contributor to acute pelvic pain in women. PMID- 21322513 TI - Challenges of improving adherence to HIV therapy. PMID- 21322514 TI - Complications of HIV infection: a systems-based approach. AB - Patients with human immunodeficiency virus (HIV) infection often develop multiple complications and comorbidities. Opportunistic infections should always be considered in the evaluation of symptomatic patients with advanced HIV/AIDS, although the overall incidence of these infections has decreased. Primary care of HIV infection includes the early detection of some complications through screening at-risk and symptomatic patients with routine laboratory monitoring (e.g., comprehensive metabolic and lipid panels) and validated tools (e.g., the HIV Dementia Scale). Treatment of many chronic complications is similar for patients with HIV infection and those without infection; however, combination antiretroviral therapy has shown benefit for some conditions, such as HIV associated nephropathy. For other complications, such as cardiovascular disease and lipoatrophy, management may include switching antiretroviral regimens to reduce exposure to HIV medications known to cause toxicity. PMID- 21322515 TI - Diagnosis and treatment of urinary tract infections in children. AB - Acute urinary tract infections are relatively common in children, with 8 percent of girls and 2 percent of boys having at least one episode by seven years of age. The most common pathogen is Escherichia coli, accounting for approximately 85 percent of urinary tract infections in children. Renal parenchymal defects are present in 3 to 15 percent of children within one to two years of their first diagnosed urinary tract infection. Clinical signs and symptoms of a urinary tract infection depend on the age of the child, but all febrile children two to 24 months of age with no obvious cause of infection should be evaluated for urinary tract infection (with the exception of circumcised boys older than 12 months). Evaluation of older children may depend on the clinical presentation and symptoms that point toward a urinary source (e.g., leukocyte esterase or nitrite present on dipstick testing; pyuria of at least 10 white blood cells per high-power field and bacteriuria on microscopy). Increased rates of E. coli resistance have made amoxicillin a less acceptable choice for treatment, and studies have found higher cure rates with trimethoprim/sulfamethoxazole. Other treatment options include amoxicillin/clavulanate and cephalosporins. Prophylactic antibiotics do not reduce the risk of subsequent urinary tract infections, even in children with mild to moderate vesicoureteral reflux. Constipation should be avoided to help prevent urinary tract infections. Ultrasonography, cystography, and a renal cortical scan should be considered in children with urinary tract infections. PMID- 21322516 TI - Patient information. UTIs in children: what to expect. PMID- 21322517 TI - Adhesive capsulitis: a review. AB - Adhesive capsulitis is a common, yet poorly understood, condition causing pain and loss of range of motion in the shoulder. It can occur in isolation or concomitantly with other shoulder conditions (e.g., rotator cuff tendinopathy, bursitis) or diabetes mellitus. It is often self-limited, but can persist for years and may never fully resolve. The diagnosis is usually clinical, although imaging can help rule out other conditions. The differential diagnosis includes acromioclavicular arthropathy, autoimmune disease (e.g., systemic lupus erythematosus, rheumatoid arthritis), biceps tendinopathy, glenohumeral osteoarthritis, neoplasm, rotator cuff tendinopathy or tear (with or without impingement), and subacromial and subdeltoid bursitis. Several treatment options are commonly used, but few have high-level evidence to support them. Because the condition is often self-limited, observation and reassurance may be considered; however, this may not be acceptable to many patients because of the painful and debilitating nature of the condition. Nonsurgical treatments include analgesics (e.g., acetaminophen, nonsteroidal anti-inflammatory drugs), oral prednisone, and intra-articular corticosteroid injections. Home exercise regimens and physical therapy are often prescribed. Surgical treatments include manipulation of the joint under anesthesia and capsular release. PMID- 21322518 TI - Patient information. Adhesive capsulitis. PMID- 21322519 TI - Primary care for refugees. AB - Over the past decade, at least 600,000 refugees from more than 60 different countries have been resettled in the United States. The personal history of a refugee is often marked by physical and emotional trauma. Although refugees come from many different countries and cultures, their shared pattern of experiences allows for some generalizations to be made about their health care needs and challenges. Before being accepted for resettlement in the United States, all refugees must pass an overseas medical screening examination, the purpose of which is to identify conditions that could result in ineligibility for admission to the United States. Primary care physicians have the opportunity to care for members of this unique population once they resettle. Refugees present to primary care physicians with a variety of health problems, including musculoskeletal and pain issues, mental and social health problems, infectious diseases, and longstanding undiagnosed chronic illnesses. Important infectious diseases to consider in the symptomatic patient include tuberculosis, parasites, and malaria. Health maintenance and immunizations should also be addressed. Language barriers, cross-cultural medicine issues, and low levels of health literacy provide additional challenges to caring for this population. The purpose of this article is to provide primary care physicians with a guide to some of the common issues that arise when caring for refugee patients. PMID- 21322521 TI - Using nontraditional risk factors in coronary heart disease risk assessment. PMID- 21322522 TI - Precocious puberty in an eight-year-old girl. PMID- 21322524 TI - FPIN's clinical inquiries. Treatment of hyperhidrosis. PMID- 21322526 TI - Patient information. Allergic conjunctivitis. PMID- 21322527 TI - Patient information. Hay Fever. PMID- 21322528 TI - Patient information. Dust mites. PMID- 21322530 TI - Understanding the interaction of the porphyrin macrocycle to reactive metal substrates: structure, bonding, and adatom capture. AB - We investigate the adsorption and conformation of free-base porphines on Cu(110) using STM, reflection absorption infrared spectroscopy, and periodic DFT calculations in order to understand how the central polypyrrole macrocycle, common to all porphyrins, interacts with a reactive metal surface. We find that the macrocycle forms a chemisorption bond with the surface, arising from electron donation into down-shifted and nearly degenerate unoccupied porphine pi-orbitals accompanied with electron back-donation from molecular pi-orbitals. Our calculations show that van der Waals interactions give rise to an overall increase in the adsorption energy but only minor changes in the adsorption geometry and electronic structure. In addition, we observe copper adatoms being weakly attracted to adsorbed porphines at specific molecular sites. These results provide important insights into porphyrin-surface interactions that, ultimately, will govern the design of robust surface-mounted molecular devices based on this important class of molecules. PMID- 21322531 TI - Multifunctional triblock Nanocarrier (PAMAM-PEG-PLL) for the efficient intracellular siRNA delivery and gene silencing. AB - A novel triblock poly(amido amine)-poly(ethylene glycol)-poly-l-lysine (PAMAM-PEG PLL) nanocarrier was designed, synthesized, and evaluated for the delivery of siRNA. The design of the nanocarrier is unique and provides a solution to most of the common problems associated with the delivery and therapeutic applications of siRNA. Every component in the triblock nanocarrier plays a significant role and performs multiple functions: (1) tertiary amine groups in the PAMAM dendrimer work as a proton sponge and play a vital role in the endosomal escape and cytoplasmic delivery of siRNA; (2) PEG, a linker connecting PLL and PAMAM dendrimers renders nuclease stability and protects siRNA in human plasma; (3) PLL provides primary amines to form polyplexes with siRNA through electrostatic interaction and also acts as penetration enhancer; and (4) conjugation to PEG and PAMAM reduced toxicity of PLL and the entire triblock nanocarrier PAMAM-PEG-PLL. The data obtained show that the polyplexes resulted from the conjugation of siRNA, and the proposed nanocarriers were effectively taken up by cancer cells and induced the knock down of the target BCL2 gene. In addition, triblock nanocarrier/siRNA polyplexes showed excellent stability in human plasma. PMID- 21322532 TI - Growth from below: graphene bilayers on Ir(111). AB - We elucidate how graphene bilayers form on Ir(111). Low-energy electron diffraction (LEED) reveals that the two graphene layers are not always rotationally aligned. Monitoring this misalignment during growth shows that second-layer islands nucleate between the existing layer and the substrate. This mechanism occurs both when C segregates from the Ir and when elemental C is deposited from above. Low-energy electron microscopy (LEEM) and angle-resolved photoemission spectroscopy (ARPES) show that second-layer nucleation occurs preferentially under the first-layer rotational variants that are more weakly bound to the substrate. New-layer nucleation tends to occur inhomogeneously at substrate defects. Thus new-layer nucleation should be rapid on substrates that weakly bind graphene, making growth unstable toward mound formation initiated at substrate defects. In contrast, stronger binding permits layer-by-layer growth, as for Ru(0001). ARPES shows that bilayer graphene has two slightly p-doped pi bands. The work function of bilayer graphene is dominated by the orientation of the bottom layer. PMID- 21322533 TI - Synthesis of Si nanosheets by a chemical vapor deposition process and their blue emissions. AB - We synthesized free-standing Si nanosheets (NSs) with a thickness of about <2 nm using a chemical vapor deposition process and studied their optical properties. The Si NSs were formed by the formation of frameworks first along six different <110> directions normal to [111], its zone axis, and then by filling the spaces between the frameworks along the <112> directions under high flow rate of processing gas. The Si NSs showed blue emission at 435 nm, and absorbance and photoluminescence (PL) excitation measurements indicate that enhanced direct band transition attributes to the emission. Time-resolved PL measurement, which showed PL emission at 435 nm and a radiative lifetime of 1.346 ns, also indicates the enhanced direct band gap transition in these Si NSs. These outcomes indicate that dimensionality of Si nanostructures may affect the band gap transition and, in turn, the optical properties. PMID- 21322534 TI - High-resolution imaging of the intramolecular structure of indomethacin-carrying dendrimers by scanning tunneling microscopy. AB - Dendrimers have shown great potential in drug delivery because of their enhancement of drug solubility in aqueous media, leading to an increase in in vivo circulation and efficacy to targets. The structure of drug-dendrimer complexes however, is not well-known owing to the difficulties associated with visualizing individual drug molecules attached to dendrimers. Scanning tunneling microscopy (STM) enables visualization of dendrimer intramolecular structures using our approach of metal ion tagging. This work extends the approach to reveal the hierarchical structure of indomethacin-loaded poly(amidoamine) hydroxyl terminated dendrimers. STM imaging provides structural information such as their height, lateral dimensions, and volume. High-resolution STM images enable the identification and count of individual indomethacin molecules bound to the anterior of dendrimers. Removal of drug molecules by the STM tip allows the calculation of individual drug-dendrimer binding energy, which is consistent with 1-3 hydrogen bonds. These investigations provide new insight into the hierarchical structure and nature of indomethacin-dendrimer interactions and deepen our understanding of the stability and pharmacokinetic behavior of dendrimer-based drug delivery vehicles. PMID- 21322535 TI - SAR monitoring of evolving compound data sets using activity landscapes. AB - In pharmaceutical research, collections of active compounds directed against specific therapeutic targets usually evolve over time. Small molecule discovery is an iterative process. New compounds are discovered, alternative compound series explored, some series discontinued, and others prioritized. The design of new compounds usually takes into consideration prior chemical and structure activity relationship (SAR) knowledge. Hence, historically grown compound collections represent a viable source of chemical and SAR information that might be utilized to retrospectively analyze roadblocks in compound optimization and further guide discovery projects. However, SAR analysis of large and heterogeneous sets of active compounds is also principally complicated. We have subjected evolving compound data sets to SAR monitoring using activity landscape models in order to evaluate how composition and SAR characteristics might change over time. Chemotype and potency distributions in evolving data sets directed against different therapeutic targets were analyzed and alternative activity landscape representations generated at different points in time to monitor the progression of global and local SAR features. Our results show that the evolving data sets studied here have predominantly grown around seed clusters of active compounds that often emerged early on, while other SAR islands remained largely unexplored. Moreover, increasing scaffold diversity in evolving data sets did not necessarily yield new SAR patterns, indicating a rather significant influence of "me-too-ism" (i.e., introducing new chemotypes that are similar to already known ones) on the composition and SAR information content of the data sets. PMID- 21322536 TI - Dynamics of Cl (2Pj) atom formation in the photodissociation of fumaryl chloride (ClCO - CH = CH - COCl) at 235 nm: a resonance enhanced multiphoton ionization (REMPI) time-of-flight (TOF) study. AB - The photodissociation dynamics of fumaryl chloride (ClCO-CH?CH-COCl) has been studied in a supersonic molecular beam around 235 nm using resonance enhanced multiphoton ionization (REMPI) time-of-flight (TOF) technique by detecting the nascent state of the primary chlorine atom. A single laser has been used for excitation of fumaryl chloride and the REMPI detection of chlorine atoms in their spin-orbit states, Cl ((2)P(3/2)) and Cl* ((2)P(1/2)). We have determined the translational energy distribution, the recoil anisotropy parameter, beta, and the spin-orbit branching ratio for chlorine atom elimination channels. To obtain these, measured polarization-dependent and state-specific TOF profiles are converted into kinetic energy distributions, using a least-squares fitting method, taking into account the fragment recoil anisotropies, beta(i). The TOF profiles for both Cl and Cl* are found to be independent of laser polarization; i.e., beta is well characterized by a value of 0.0, within the experimental uncertainties. Two components, namely, the fast and the slow, are observed in the translational energy distribution, P(E(T)), of Cl and Cl* atoms, and assigned to be formed from different potential energy surfaces. The average translational energies for the fast components of the Cl and Cl* channels are 14.9 +/- 1.6 and 16.8 +/- 1.6 kcal/mol, respectively. Similarly, for the slow components, the average translational energies of the Cl and Cl* channels are 3.4 +/- 0.8 and 3.1 +/- 0.8 kcal/mol, respectively. The energy partitioning into the translational modes is interpreted with the help of various models, such as impulsive and statistical models. Apart from the chlorine atom elimination channel, molecular hydrogen chloride (HCl) elimination is also observed in the photodissociation process. The HCl product has been detected, using a REMPI scheme in the region of 236-237 nm. The observation of the molecular HCl in the dissociation process highlights the importance of the relaxation process, in which the initially excited parent molecule relaxes to the ground state from where the molecular (HCl) elimination takes place. PMID- 21322537 TI - Molecular dynamics study on the microscopic details of the evaporation of water. AB - Molecular dynamics simulations were conducted on a drop of water (containing 4890 TIP3P waters) at 350 K. About 70 evaporation events were found and characterized in enough detail to determine significant patterns relating to the mechanism of evaporation. It was found that in almost all evaporation events that a single, high-energy state immediately preceded the evaporation event. In ~50% of the cases, this high-energy state involved a short oxygen-oxygen distance, suggesting a van der Waals collision, whereas in the remaining cases, a short hydrogen hydrogen distance was found, suggesting an electrostatic "collision". Of the high energy states that led to evaporation, about half occurred when the coordination number of water was 1, and about half, when the coordination number was 2. It was found that the 1-coordinated waters (~1% of the surface waters) and 2-coordinated waters (6% of the surface waters) were responsible for almost all the evaporation events. PMID- 21322538 TI - Nanoalloy formation of Ta-containing trimetallic small clusters. AB - Trimetallic cluster ions containing Ta and other metal elements were prepared in the gas phase by a triple laser-ablation technique in a controlled manner. We have measured the abundances and their thermal stabilities, using time-of-flight mass spectrometry. Taking advantage of specific abundance distribution of the trimetallic cluster ions (magic stoichiometry), relative to the distinguished stabilities, the coalescence or the segregation of Ta and the other elements in the subnanometer sized clusters was discussed. We found that Nb, W, and Mo, which are categorized as elements with a high heat of vaporization, readily coalesce with Ta, while V, Al, Co, and Pt, which are categorized as elements with a low heat of vaporization, tend to be segregated from Ta. Our experiments, along with the calculation by another research group, suggest that the binding energies of atoms are related to the coalescence or segregation of clusters in the gas phase. PMID- 21322539 TI - Quasi-classical trajectory study of the Ne + H2(+) -> NeH(+) + H reaction based on global potential energy surface. AB - Using the multireference configuration interaction method with a Davidson correction and a large orbital basis set (aug-cc-pVQZ), we obtain an energy grid that includes 32 038 points for the construction of a new analytical potential energy surface (APES) for the Ne + H(2)(+) -> NeH(+) + H reaction. The APES is represented as a many-body expansion containing 142 parameters, which are fitted from 31 000 ab initio energies using an adaptive nonlinear least-squares algorithm. The geometric characteristics of the reported APES and the one presented here are also compared. On the basis of the APES we obtained, reaction cross sections are computed by means of quasi-classical trajectory (QCT) calculations and compared with the experimental and theoretical data in the literature. PMID- 21322540 TI - Pyrolysis of n-heptane: experimental and theoretical study. AB - An experimental study of n-heptane pyrolysis (2.0% n-heptane in argon) has been performed at low pressure (400 Pa) within the temperature range from 780 to 1780 K. The pyrolysis products were detected by using synchrotron vacuum ultraviolet photoionization mass spectrometry (SVUV-PIMS). Photoionization mass spectra and photoionization efficiency spectra were measured to identify pyrolysis products, especially radicals and isomers. Mole fraction profiles of pyrolysis products versus temperature were also measured, indicating that H(2), CH(4), C(2)H(2), and C2-C6 alkenes are major pyrolysis products of n-heptane. Meanwhile, the thermal decomposition pathways of n-heptane have been investigated using theoretical calculation. The calculation results are in good agreement with the experimental measurement. On the basis of the experimental observation and theoretical calculation, the pyrolysis channels of unimolecular dissociation are proposed to understand the pyrolysis process of n-heptane. PMID- 21322541 TI - Structures and energetics of neutral and ionic silicon-germanium clusters: density functional theory and coupled cluster studies. AB - We have calculated the structural and energetic properties of neutral and ionic (singly charged anionic and cationic) semiconductor binary silicon-germanium clusters Si(m)Ge(n) for s = m + n <= 12 using the density functional theory (DFT B3LYP) and coupled cluster [CCSD(T)] methods with Pople's 6-311++G(3df, 3pd) basis set. Neutral and anionic clusters share similar ground state structures for s = 3-7, independent of the stoichiometry and atom locations, but start to deviate at s = 8. The relative energetic stability of the calculated ground state structures among possible isomers has been analyzed through a bond strength propensity model where the pair interactions of Si-Si, Si-Ge, and Ge-Ge are competing. Electron affinities, ionization potentials, energy gaps between the highest and lowest occupied molecular orbitals (HOMO-LUMO gaps), and cluster mixing energies were calculated and analyzed. Overall, for a fixed s, the vertical ionization potential increases as the number of silicon atoms m increases, while the vertical electron affinity shows a dip at m = 2. As s increases, the ionization potentials increase from s = 2 to s = 3 and then decrease slowly to s = 8. The mixing energies for neutral and ionic clusters are all negative, indicating that the binary clusters are more stable than pure elemental clusters. Except for s = 4 and 8, cationic clusters are more stable than anionic ones and, thus, are more likely to be observed in experiments. PMID- 21322542 TI - Influence of the solvent on the charge distribution of anomeric compounds. AB - Conformational preferences of methanediol, dimethoxymethane, methanediamine, and fluoromethanol in the presence of solvents of diverse polarity (water, acetone, and chloroform), modeled with the polarizable continuum model, were analyzed within the framework of the Quantum Theory of Atoms in Molecules. The results indicate that the hydrogens bonded to the anomeric carbon experience the largest reorganization of electron density upon conformational change, as was obtained from previous calculations in the gas phase. When the water solvation is simulated by explicit inclusion of water molecules, the electron density reorganization involved in the cluster formation is significantly different for each conformer of methanediol. As a consequence, similar depletions of electron population are displayed by the hydrogens of hydroxyl and methylene groups in the cluster obtained for the most stable conformer of methanediol, with regard to that built for the completely antiperiplanar conformer. PMID- 21322543 TI - Theoretical modeling of peptide alpha-helical circular dichroism in aqueous solution. AB - Reliable modeling of protein and peptide circular dichroism (CD) spectra in the far UV presents a challenge for current theoretical approaches. In this study, the time-dependent density functional theory (TDDFT), configuration interaction with single excitation (CIS), and transition dipole coupling (TDC) were used to assess the most important factors contributing to the CD spectra of the alpha helical secondary structure. The dependence on the peptide chain length and also the role of the flexibility and solvent environment were investigated with a model oligopeptide Ac-(Ala)(N)-NH-Me, (N = 1, ..., 18). Both the TDDFT and TDC like methods suggest that the CD curve typical for the alpha-helix arises gradually, but its basic characteristic is discernible already for peptides with 4-5 amino acid residues. The calculated dependence was in a qualitative agreement with experimental spectra of short alpha-helices stabilized by the histidine metal binding. The TDDFT computations of the CD were found to be unusually sensitive to the basis set and solvent model. Explicit hydration and temperature fluctuations of the peptide geometry, simulated with the aid of molecular dynamics (MD), significantly influenced the CD and absorption spectral shapes. An extensive averaging over MD configurations is thus required to obtain a converged spectral profile in cluster simulations. On the other hand, both the TDDFT and TDC models indicate only a minor influence of the alanine side chains. The CIS and TDC calculations also point toward a relatively small effect of the helix helix interaction on the CD spectral profiles. For a model system of two helices, the CIS method predicted larger changes in the spectra than TDC. This suggests other than interactions between peptide chains, such as mutual polarization, can have a minor, but measurable, effect on the CD spectrum. PMID- 21322544 TI - Identification of StARD3 as a lutein-binding protein in the macula of the primate retina. AB - Lutein, zeaxanthin, and their metabolites are the xanthophyll carotenoids that form the macular pigment of the human retina. Epidemiological evidence suggests that high levels of these carotenoids in the diet, serum, and macula are associated with a decreased risk of age-related macular degeneration (AMD), and the AREDS2 study is prospectively testing this hypothesis. Understanding the biochemical mechanisms underlying the selective uptakes of lutein and zeaxanthin into the human macula may provide important insights into the physiology of the human macula in health and disease. GSTP1 is the macular zeaxanthin-binding protein, but the identity of the human macular lutein-binding protein has remained elusive. Prior identification of the silkworm lutein-binding protein (CBP) as a member of the steroidogenic acute regulatory domain (StARD) protein family and selective labeling of monkey photoreceptor inner segments with an anti CBP antibody provided an important clue for identifying the primate retina lutein binding protein. The homology of CBP with all 15 human StARD proteins was analyzed using database searches, Western blotting, and immunohistochemistry, and we here provide evidence to identify StARD3 (also known as MLN64) as a human retinal lutein-binding protein. Antibody to StARD3, N-62 StAR, localizes to all neurons of monkey macular retina and especially cone inner segments and axons, but does not colocalize with the Muller cell marker, glutamine synthetase. Further, recombinant StARD3 selectively binds lutein with high affinity (K(D) = 0.45 MUM) when assessed by surface plasmon resonance (SPR) binding assays. Our results demonstrate previously unrecognized, specific interactions of StARD3 with lutein and provide novel avenues for exploring its roles in human macular physiology and disease. PMID- 21322545 TI - Synthesis of polycyclic benzofused nitrogen heterocycles via a tandem ynamide benzannulation/ring-closing metathesis strategy. Application in a formal total synthesis of (+)-FR900482. AB - A two-stage "tandem strategy" for the synthesis of benzofused nitrogen heterocycles is described that is particularly useful for the construction of systems with a high level of substitution on the benzenoid ring. The first stage in the strategy involves a benzannulation based on the reaction of cyclobutenones with ynamides. This cascade process proceeds via a sequence of four pericyclic reactions and furnishes a multiply substituted aniline derivative which can bear a variety of functionalized substituents at the position ortho to the nitrogen. In the second stage of the tandem strategy, ring-closing metathesis generates the nitrogen heterocyclic ring. This two-step sequence provides efficient access to highly substituted dihydroquinolines, benzazepines, benzazocines, and related benzofused nitrogen heterocyclic systems. The application of this chemistry in a concise formal total synthesis of the anticancer agents (+)-FR900482 and (+) FR66979 is described. PMID- 21322546 TI - Tautomerism and thermal decomposition of tetrazole: high-level ab initio study. AB - The mutual interconversion and decomposition reactions of four tetrazole isomers (1H-TZ, 2H-TZ, 5H-TZ, and an N-heterocyclic carbene 14H) have been studied theoretically using the W1 high-level procedure. Computations allowed resolution of the existing discrepancies in the mechanism and key intermediates of TZ thermolysis. The tautomeric equilibria between 1H-TZ, 2H-TZ, and 14H turned out to play a very important role in the mechanism of thermal decomposition. Although the barriers of monomolecular tautomeric transformations were found to be high (~50-70 kcal/mol), the concerted double H atom transfer reactions in the H-bonded complexes of TZ tautomers have profoundly lower barriers (~18-28 kcal/mol). These reactions lead to fast interconversion between 1H-TZ, 2H-TZ, and 14H. The carbene 14H has never been considered before; however, it was predicted to be a key intermediate in the mechanism of thermal decomposition of TZ. For all species considered, the unimolecular reactions of N(2) elimination were predicted to dominate over the elimination of hydrazoic acid. In agreement with existing experimental data, the effective activation energy of thermolysis was calculated to be 36.2 kcal/mol. PMID- 21322547 TI - Evaluation of passive samplers for assessment of community exposure to toxic air contaminants and related pollutants. AB - The precision, accuracy, and sampling rates of Radiello and Ogawa passive samplers were evaluated in the laboratory using a flow-through chamber and under field conditions prior to their use in the 2007 Harbor Community Monitoring Study (HCMS), a saturation monitoring campaign in the communities adjacent to the Ports of Los Angeles and Long Beach. Passive methods included Radiello samplers for volatile organic compounds (benzene, toluene, ethylbenzene, xylenes, 1,3 butadiene), aldehydes (formaldehyde, acetaldehyde, acrolein) and hydrogen sulfide, and Ogawa samplers for nitrogen oxides and sulfur dioxide. Additional experiments were conducted to study the robustness of the passive sampling methods under variable ambient wind speed, sampling duration, and storage time before analysis. Our experimentally determined sampling rates were in agreement with the rates published by Radiello and Ogawa with the following exceptions: we observed a diffusion rate of 22.4 +/- 0.1 mL/min for benzene and 37.4 +/- 1.5 mL/min for ethylbenzene compared to the Radiello published values of 27.8 and 25.7 mL/min, respectively. With few exceptions, the passive monitoring methods measured one-week average ambient concentrations of selected pollutants with sensitivity and precision comparable to conventional monitoring methods averaged over the same period. Radiello Carbograph 4 VOC sampler is not suitable for the collection of 1,3-butadiene due to backdiffusion. Results for the Radiello aldehyde sampler were inconclusive due to lack of reliable reference methods for all carbonyl compounds of interest. PMID- 21322548 TI - Hepatic transcriptomics and protein expression in rainbow trout exposed to municipal wastewater effluent. AB - Municipal wastewater effluents (MWWEs) represent one of the largest point sources of contamination, but few studies have addressed the impact on fish populations. We tested the hypothesis that MWWEs disrupt multiple stress-related pathways by examining expression of genes and proteins in rainbow trout (Oncorhynchus mykiss). A caging study was undertaken by placing juvenile trout for 14 d either at an upstream control or 100%, 50%, and 10% MWWE sites. A custom-made low density rainbow trout cDNA microarray was utilized for transcriptomics, and select gene expression was confirmed with quantitative real-time PCR. MWWE exposure significantly elevated plasma cortisol, glucose, and vitellogenin levels, and altered the expression of a number of hepatic genes. Notably, expression of stress-related genes, hormone receptors, glucose transporter 2, and genes related to immune function were altered. The gene and protein expression of glucocorticoid receptor, heat shock proteins 70 and 90, and cytochrome P4501A1 were also impacted by MWWE exposure. Our results demonstrate that tertiary treated MWWEs elicit an organismal and cellular stress response in trout and may lead to an enhanced energy demand in the exposed fish. The disruption in multiple stress-related pathways suggests that tertiary-treated MWWEs exposure may reduce fish performance to subsequent stressors. PMID- 21322549 TI - Complexation of microcystins and nodularin by cyclodextrins in aqueous solution, a potential removal strategy. AB - Cyanotoxins are potent toxic compounds produced by cyanobacteria during algal blooms, which threaten drinking water supplies. These compounds can poison and kill animals and humans. The host-guest interactions of alpha-, beta-, and gamma cyclodextrins (CD) with problematic cyanotoxins, including microcystins (MCs) and nodularin (NOD), were investigated to demonstrate the potential application of CDs for the removal of these toxins from drinking water or applications related to their separation or purification. MCs and NOD have a hydrophobic Adda chain, which contains diene and benzene functional groups. The complexation of these cyanotoxins with CDs was monitored by nuclear magnetic resonance (NMR). The (1)H NMR spectra for MCs are unchanged upon addition of alpha-CD (smallest host). However, addition of larger hosts, beta-CD and gamma-CD, leads to significant changes in chemical shifts of the benzene and diene resonances on the 3-amino-9 methoxy-2,6,8-trimethal-10-phenyldeca-4,6-dienoic acid (Adda) chain of MCs and NOD. Solution pH, natural organic matter, and salinity do not appreciably influence the host-guest complexation under our experimental conditions. The experimental binding constants for MCs and NOD with gamma-CD are relatively strong, ranging from 1155 to 507 M(-1). The observed changes in chemical shifts for specific protons and competitive binding experiments demonstrate a 1:1 inclusion complex between gamma-CD and MCs or NOD, with the Adda chains threading through the CD ring, resulting in an inclusion complex. Our results suggest that CD-type substrates are useful hosts for the complexation of MCs and NOD. CDs can be readily attached to a number of polymeric or solid supports and their functionality tailored to strengthen specific host-guest interactions. With further development of such materials, CD host-guest chemistry may find direct application in the removal and/or separation science of these compounds. PMID- 21322550 TI - Synthetic glucocorticoids in the environment: first results on their potential impacts on fish. AB - Human pharmaceuticals have been shown to be entering the aquatic environment in quantities that may produce adverse effects to aquatic organisms. This paper investigates the impacts of synthetic glucocorticoids (GCs), which are used in large amounts as anti-inflammatory drugs, on fish. Mammalian cell lines were transiently transfected with trout corticosteroid receptors (GR1, GR2, and MR) and the transactivation abilities of ten of the most prescribed GCs in the UK were measured in vitro. They showed significantly higher activity with GR2 than with GR1. In order to assess any impacts in vivo, adult fathead minnows were exposed to either 1 MUg prednisolone/L or 1 MUg beclomethasone dipropionate/L for 21 days. Plasma glucose concentrations were increased and leucocytes were reduced significantly in GC-exposed groups compared to the control group. In another experiment, fish were exposed to three different concentrations of Beclomethasone dipropionate and a dose-dependent increase of plasma glucose was found. The results suggest that low concentrations of synthetic GCs present in water could cause adverse effects on fish. Therefore, quantification of GCs in the aquatic environment and the effects of GCs at environmentally relevant concentrations are required in order to determine if GCs pose a threat to wild fish populations. PMID- 21322551 TI - Determination of PbO2 formation kinetics from the chlorination of Pb(II) carbonate solids via direct PbO2 measurement. AB - Lead dioxide (PbO(2)), a new form of lead corrosion product discovered in the distribution system, is formed via the chlorination of Pb(II) solids and plays an important role in regulating lead concentration in drinking water. The kinetics of its formation, however, has not been quantitatively determined primarily because of the difficulties in accurately measuring PbO(2) concentration. In this study, we apply an iodometric method for direct PbO(2) measurement to determine its formation kinetics from the chlorination of cerussite (PbCO(3)) and hydrocerussite (Pb(3)(CO(3))(2)(OH)(2)). The obtained rate equations suggest that for both Pb(II) carbonate solids, the formation of PbO(2) is first-order with respect to the available Pb(II) solid surface area, free chlorine concentration, and OH(-) concentration. Dissolved inorganic carbon concentration (DIC) was found to inhibit PbO(2) formation because of the formation of carbonate-lead surface complexes that protect the surface Pb(II) sites from oxidation. The rate of PbO(2) formation from the chlorination of hydrocerussite was faster than that of cerussite under the same Pb(II) solid loading. However, after normalization of the surface area, the rate constants obtained for both Pb(II) solids are similar. The kinetics of PbO(2) formation is elucidated for the first time in this study. PMID- 21322552 TI - Stacked microbial desalination cells to enhance water desalination efficiency. AB - Microbial desalination cell (MDC) is a new method to obtain clean water from brackish water using electricity generated from organic matters by exoelectrogenic bacteria. Anions and cations, derived from salt solution filled in the desalination chamber between the anode and cathode, move to the anode and cathode chambers under the force of electrical field, respectively. On the basis of the primitive single-desalination-chambered MDC, stacked microbial desalination cells (SMDCs) were developed in order to promote the desalination rate in the present study. The effects of desalination chamber number and external resistance were investigated. Results showed that a remarkable increase in the total desalination rate (TDR) could be obtained by means of increasing the desalination cell number and reducing the external resistance, which caused the charge transfer efficiency increased since the SMDCs enabled more pairs of ions separated while one electron passed through the external circuit. The maximum TDR of 0.0252 g/h was obtained using a two-desalination-chambered SMDC with an external resistance of 10 Omega, which was 1.4 times that of single-desalination chambered MDC. SMDCs proved to be an effective approach to increase the total water desalination rate if provided a proper desalination chamber number and external resistance. PMID- 21322553 TI - Iron and arsenic cycling in intertidal surface sediments during wetland remediation. AB - The accumulation and behavior of arsenic at the redox interface of Fe-rich sediments is strongly influenced by Fe(III) precipitate mineralogy, As speciation, and pH. In this study, we examined the behavior of Fe and As during aeration of natural groundwater from the intertidal fringe of a wetland being remediated by tidal inundation. The groundwater was initially rich in Fe(2+) (32 mmol L(-1)) and As (1.81 MUmol L(-1)) with a circum-neutral pH (6.05). We explore changes in the solid/solution partitioning, speciation and mineralogy of Fe and As during long-term continuous groundwater aeration using a combination of chemical extractions, SEM, XRD, and synchrotron XAS. Initial rapid Fe(2+) oxidation led to the formation of As(III)-bearing ferrihydrite and sorption of >95% of the As(aq) within the first 4 h of aeration. Ferrihydrite transformed to schwertmannite within 23 days, although sorbed/coprecipitated As(III) remained unoxidized during this period. Schwertmannite subsequently transformed to jarosite at low pH (2-3), accompanied by oxidation of remaining Fe(2+). This coincided with a repartitioning of some sorbed As back into the aqueous phase as well as oxidation of sorbed/coprecipitated As(III) to As(V). Fe(III) precipitates formed via groundwater aeration were highly prone to reductive dissolution, thereby posing a high risk of mobilizing sorbed/coprecipitated As during any future upward migration of redox boundaries. Longer-term investigations are warranted to examine the potential pathways and magnitude of arsenic mobilization into surface waters in tidally reflooded wetlands. PMID- 21322554 TI - Turnover is rate-limited by deglycosylation for Micromonospora viridifaciens sialidase-catalyzed hydrolyses: conformational implications for the Michaelis complex. AB - A panel of seven isotopically substituted sialoside natural substrate analogues based on the core structure 7-(5-acetamido-3,5-dideoxy-d-glycero-alpha-d-galacto non-2-ulopyranosylonic acid)-(2->6)-beta-D-galactopyranosyloxy)-8-fluoro-4 methylcoumarin (1, Neu5Acalpha2,6GalbetaFMU) have been synthesized and used to probe the rate-limiting step for turnover by the M. viridifaciens sialidase. The derived kinetic isotope effects (KIEs) on k(cat) for the ring oxygen ((18)V), leaving group oxygen ((18)V), anomeric carbon ((13)V), C3-carbon ((13)V), C3-R deuterium ((D)V(R)), C3-S deuterium ((D)V(S)), and C3-dideuterium ((D)(2)V) are 0.986 +/- 0.003, 1.003 +/- 0.005, 1.021 +/- 0.006, 1.001 +/- 0.008, 1.029 +/- 0.007, 0.891 +/- 0.008, and 0.890 +/- 0.006, respectively. The solvent deuterium KIE ((D(2)O)V) for the sialidase-catalyzed hydrolysis of 1 is 1.585 +/- 0.004. In addition, a linear proton inventory was measured for the rate of hydrolysis, under saturating condition, as a function of n, the fraction of deuterium in the solvent. These KIEs are compatible with rate-determining cleavage of the enzymatic tyrosinyl beta-sialoside intermediate. Moreover, the secondary deuterium KIEs are consistent with the accumulating Michaelis complex in which the sialosyl ring of the carbohydrate substrate is in a (6)S(2) skew boat conformation. These KIE measurements are also consistent with the rate determining deglycosylation reaction occurring via an exploded transition state in which synchronous charge delocalization is occurring onto the ring oxygen atom. Finally, the proton inventory and the magnitude of the solvent KIE are consistent with deglycosylation involving general acid-catalyzed protonation of the departing tyrosine residue rather than general base-assisted attack of the nucleophilic water. PMID- 21322555 TI - Noninvasive imaging of cell death using an Hsp90 ligand. AB - Cell death plays a central role in normal physiology and in disease. Common to apoptotic and necrotic cell death is the eventual loss of plasma membrane integrity. We have produced a small organoarsenical compound, 4-(N-(S glutathionylacetyl)amino)phenylarsonous acid, that rapidly accumulates in the cytosol of dying cells coincident with loss of plasma membrane integrity. The compound is retained in the cytosol predominantly by covalent reaction with the 90 kDa heat shock protein (Hsp90), the most abundant molecular chaperone of the eukaryotic cytoplasm. The organoarsenical was tagged with either optical or radioisotope reporting groups to image cell death in cultured cells and in murine tumors ex vivo and in situ. Tumor cell death in mice was noninvasively imaged by SPECT/CT using an (111)In-tagged compound. This versatile compound should enable the imaging of cell death in most experimental settings. PMID- 21322556 TI - Chemical and genetic assessment of variability in commercial Radix Astragali (Astragalus spp.) by ion trap LC-MS and nuclear ribosomal DNA barcoding sequence analyses. AB - Radix Astragali (Huangqi) has been demonstrated to have a wide range of immunopotentiating effects and has been used as an adjuvant medicine during cancer therapy. Identity issues in the collection of Radix Astragali exist because many sympatric species of Astragalus occur in the northern regions of China. In order to assess the quality, purity, and uniformity of commercial Radix Astragali, 44 samples were purchased from herbal stores in Hong Kong and New York City. The main constituents, including four isoflavonoids and three saponins, were quantitatively determined by liquid chromatography mass spectrometry (LC MS). There was significant sample-to-sample variability in the amounts of the saponins and isoflavonoids measured. Furthermore, DNA barcoding utilizing the variable nuclear ITS spacer regions of the 44 purchased Radix Astragali samples were sequenced, aligned and compared. Eight polymorphic point mutations were identified which separated the Radix Astragali samples into three groups. These results indicate that the chemical and genetic variability that exists among Radix Astragali medicinal products is still a consistency and quality issue for this herbal. Two-way ANOVA analysis showed significant effects on the contents of the seven tested compounds when both phylogenetic and geographic (i.e., point of purchase) factors were considered. Therefore, chemical profiles determined by LC MS and DNA profiles in ITS spacer domains could serve as barcode markers for quality control of Radix Astragali. PMID- 21322557 TI - Palladium-catalyzed coupling reactions of tetrafluoroethylene with arylzinc compounds. AB - Organofluorine compounds are widely used in all aspects of the chemical industry. Although tetrafluoroethylene (TFE) is an example of an economical bulk organofluorine feedstock, the use of TFE is mostly limited to the production of poly(tetrafluoroethylene) and copolymers with other alkenes. Furthermore, no catalytic transformation of TFE that involves carbon-fluorine bond activation has been reported to date. We herein report the first example of a palladium catalyzed coupling reaction of TFE with arylzinc reagents in the presence of lithium iodide, giving alpha,beta,beta-trifluorostyrene derivatives in excellent yields. PMID- 21322559 TI - Interface segregating fluoralkyl-modified polymers for high-fidelity block copolymer nanoimprint lithography. AB - Block copolymer (BCP) lithography is a powerful technique to write periodic arrays of nanoscale features into substrates at exceptionally high densities. In order to place these features at will on substrates, nanoimprint offers a deceptively clear path toward high throughput production: nanoimprint molds are reusable, promote graphoepitaxial alignment of BCP microdomains within their topography, and are efficiently aligned with respect to the substrate using interferometry. Unfortunately, when thin films of BCPs are subjected to thermal nanoimprint, there is an overwhelming degree of adhesion at the mold-polymer interface, which compromises the entire process. Here we report the synthesis of additives to mitigate adhesion based on either PS or PDMS with short, interface active fluoroalkyl chains. When blended with PS-b-PDMS BCPs and subjected to a thermal nanoimprint, fluoroalkyl-modified PS in particular is observed to substantially reduce film adhesion to the mold, resulting in a nearly defect-free nanoimprint. Subsequent lithographic procedures revealed excellent graphoepitaxial alignment of sub-10 nm BCP microdomains, a critical step toward lower-cost, high-throughput nanofabrication. PMID- 21322558 TI - Improved sugar cane juice clarification by understanding calcium oxide-phosphate sucrose systems. AB - It is accepted that the efficiency of sugar cane clarification is closely linked with sugar juice composition (including suspended or insoluble impurities), the inorganic phosphate content, the liming condition and type, and the interactions between the juice components. These interactions are not well understood, particularly those between calcium, phosphate, and sucrose in sugar cane juice. Studies have been conducted on calcium oxide (CaO)/phosphate/sucrose systems in both synthetic and factory juices to provide further information on the defecation process (i.e., simple liming to effect impurity removal) and to identify an effective clarification process that would result in reduced scaling of sugar factory evaporators, pans, and centrifugals. Results have shown that a two-stage process involving the addition of lime saccharate to a set juice pH followed by the addition of sodium hydroxide to a final juice pH or a similar two stage process where the order of addition of the alkalis is reversed prior to clarification reduces the impurity loading of the clarified juice compared to that of the clarified juice obtained by the conventional defecation process. The treatment process showed reductions in CaO (27% to 50%) and MgO (up to 20%) in clarified juices with no apparent loss in juice clarity or increase in residence time of the mud particles compared to those in the conventional process. There was also a reduction in the SiO2 content. However, the disadvantage of this process is the significant increase in the Na2O content. PMID- 21322560 TI - Functional proteomic analysis of rice bran esterases/lipases and characterization of a novel recombinant esterase. AB - An esterase from rice ( Oryza sativa ) bran was identified on two-dimensional gel using 4-methylumbelliferyl butyrate as a substrate. The esterase cDNA (870 bp) encoded a 289 amino acid protein (designated OsEST-b) and was expressed in Escherichia coli . The molecular weight of recombinant OsEST-b (rOsEST-b) was 27 kDa, as measured by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Biochemical characterization demonstrated that rOsEST-b was active over a broad temperature range (optimum at 60 degrees C) and preferred alkaline conditions (optimum at pH 9.0). The rOsEST-b showed maximum activity toward p-nitrophenyl butyrate (C(4)) among various p-nitrophenyl esters (C(4)-C(18)), indicating that rOsEST-b is an esterase for short-chain fatty acids. The kinetic parameters under optimal conditions were K(m) = 27.03 MUM, k(cat) = 49 s(-1), and k(cat)/K(m) = 1.81 s(-1) MUM(-1). The activity of rOsEST-b was not influenced by ethylenediaminetetraacetic acid, suggesting that it is not a metalloenzyme. The amino acid sequence analysis revealed that OsEST-b had a conserved pentapeptide esterase/lipase motif but that the essential active site serine (GXSXG) was replaced by cysteine (C). These results suggest that OsEST-b is distinct from traditional esterases/lipases and is a novel lipolytic enzyme in rice bran. PMID- 21322561 TI - Inhibition of Lipopolysaccharide (LPS)-induced inflammatory responses by Sargassum hemiphyllum sulfated polysaccharide extract in RAW 264.7 macrophage cells. AB - Sargassum hemiphyllum , a kind of brown seaweed generally found along coastlines in East Asia, has long served as a traditional Chinese medicine. S. hemiphyllum has shown an anti-inflammatory effect; however, its mechanism has not been elucidated clearly. This study explored S. hemiphyllum for its biomedical effects. S. hemiphyllum sulfated polysaccharide extract (SHSP) was first prepared; the mouse macrophage cell line (RAW 264.7) activated by lipopolysaccharide (LPS) was used as a model system. The secretion profiles of pro-inflammatory cytokines, including IL-1beta, IL-6, TNF-alpha, and NO, were found significantly to be reduced in 1-5 mg/mL dose ranges of SHSP treatments. RT PCR analysis suggested SHSP inhibits the LPS-induced mRNA expressions of IL-beta, iNOS, and COX-2 in a dose-dependent manner. At protein levels, Western blot analysis demonstrated a similar result for NF-kappaB (p65) in cytosol/nuclear. Taken together, the anti-inflammatory properties of SHSP may be attributed to the down-regulation of NF-kappaB in nucleus. PMID- 21322563 TI - Curcumin nanoparticles: preparation, characterization, and antimicrobial study. AB - Curcumin is a highly potent, nontoxic, bioactive agent found in turmeric and has been known for centuries as a household remedy to many ailments. The only disadvantage that it suffers is of low aqueous solubility and poor bioavailability. The aim of the present study was to develop a method for the preparation of nanoparticles of curcumin with a view to improve its aqueous-phase solubility and examine the effect on its antimicrobial properties. Nanoparticles of curcumin (nanocurcumin) were prepared by a process based on a wet-milling technique and were found to have a narrow particle size distribution in the range of 2-40 nm. Unlike curcumin, nanocurcumin was found to be freely dispersible in water in the absence of any surfactants. The chemical structure of nanocurcumin was the same as that of curcumin, and there was no modification during nanoparticle preparation. A minimum inhibitory concentration of nanocurcumin was determined for a variety of bacterial and fungal strains and was compared to that of curcumin. It was found that the aqueous dispersion of nanocurcumin was much more effective than curcumin against Staphylococcus aureus , Bacillus subtilis , Escherichia coli , Pseudomonas aeruginosa , Penicillium notatum , and Aspergillus niger . The results demonstrated that the water solubility and antimicrobial activity of curcumin markedly improved by particle size reduction up to the nano range. For the selected microorganisms, the activity of nanocurcumin was more pronounced against Gram-positive bacteria than Gram-negative bacteria. Furthermore, its antibacterial activity was much better than antifungal activity. The mechanism of antibacterial action of curcumin nanoparticles was investigated by transmission electron micrograph (TEM) analysis, which revealed that these particles entered inside the bacterial cell by completely breaking the cell wall, leading to cell death. PMID- 21322562 TI - Total synthesis of brevenal. AB - This Article describes the total synthesis of the marine ladder toxin brevenal utilizing a convergent synthetic strategy. Critical to the success of this work was the use of olefinic-ester cyclization reactions and the utilization of glycal epoxides as precursors to C-C and C-H bonds. PMID- 21322564 TI - Harpagoside variation is positively correlated with temperature in Scrophularia ningpoensis Hemsl. AB - Scrophularia ningpoensis Hemsl. is an important Chinese medicinal herb with a history of domestication of over 1000 years. Phytochemical variation of S. ningpoensis in response to environmental gradients remains an attractive topic with both practiceal and theoretical significances. In the current study, HPLC fingerprinting and four major bioactive compounds of S. ningpoensis, that is, harpagoside, angroside C, acteoside, and cinnamic acid, were determined to explore its correlations with climatic, geographic, and soil factors. The present data confirmed the approximate three-group pattern of phytochemical differentiation among the five production regions, the population of Zhejiang (ZJ), the population of Hubei (HB), and the rest three populations of Chongqing, Hunan, and Shaanxi (CQ, HN, and SX). Harpagoside, the dominant bioactive compound of S. ningpoensis, contributed most to the phytochemical differentiation and displayed a significant positive correlation with monthly and annual average temperature and negative correlations with altitude and latitude. It was concluded that harpagoside variation was strongly positively correlated with environmental changes of temperature. PMID- 21322565 TI - Photosynthetic light-harvesting is tuned by the heterogeneous polarizable environment of the protein. AB - In photosynthesis, special antenna proteins that contain multiple light-absorbing molecules (chromophores) are able to capture sunlight and transfer the excitation energy to reaction centers with almost 100% quantum efficiencies. The critical role of the protein scaffold in holding the appropriate arrangement of the chromophores is well established and can be intuitively understood given the need to keep optimal dipole-dipole interactions between the energy-transferring chromophores, as described by Forster theory more than 60 years ago. However, the question whether the protein structure can also play an active role by tuning such dipole-dipole interactions has not been answered so far, its effect being rather crudely described by simple screening factors related to the refractive index properties of the system. Here, we present a combined quantum chemical/molecular mechanical approach to compute electronic couplings that accounts for the heterogeneous dielectric nature of the protein-solvent environment in atomic detail. We apply the method to study the effect of dielectric heterogeneity in the energy migration properties of the PE545 principal light-harvesting antenna of the cryptomonad Rhodomonas CS24. We find that dielectric heterogeneity can profoundly tune by a factor up to ~4 the energy migration rates between chromophore sites compared to the average continuum dielectric view that has historically been assumed. Our results indicate that engineering of the local dielectric environment can potentially be used to optimize artificial light-harvesting antenna systems. PMID- 21322566 TI - Discovery of 9-(6-aminopyridin-3-yl)-1-(3 (trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective, and orally available mammalian target of rapamycin (mTOR) inhibitor for treatment of cancer. AB - The mTOR mediated PI3K/AKT/mTOR signal transduction pathway has been demonstrated to play a key role in a broad spectrum of cancers. Starting from the mTOR selective inhibitor 1 (Torin1), a focused medicinal chemistry effort led to the discovery of an improved mTOR inhibitor 3 (Torin2), which possesses an EC(50) of 0.25 nM for inhibiting cellular mTOR activity. Compound 3 exhibited 800-fold selectivity over PI3K (EC(50): 200 nM) and over 100-fold binding selectivity relative to 440 other protein kinases. Compound 3 has significantly improved bioavailability (54%), metabolic stability, and plasma exposure relative to compound 1. PMID- 21322567 TI - Cysteine mapping in conformationally distinct kinase nucleotide binding sites: application to the design of selective covalent inhibitors. AB - Kinases have emerged as one of the most prolific therapeutic targets. An important criterion in the therapeutic success of inhibitors targeting the nucleotide binding pocket of kinases is the inhibitor residence time. Recently, covalent kinase inhibitors have attracted attention since they confer terminal inhibition and should thus be more effective than reversible inhibitors with transient inhibition. The most robust approach to design irreversible inhibitors is to capitalize on the nucleophilicity of a cysteine thiol group present in the target protein. Herein, we report a systematic analysis of cysteine residues present in the nucleotide binding site of kinases, which could be harnessed for irreversible inhibition, taking into consideration the different kinase conformations. We demonstrate the predictive power of this analysis with the design and validation of an irreversible inhibitor of KIT/PDGFR kinases. This is the first example of a covalent kinase inhibitor that combines a pharmacophore addressing the DFG-out conformation with a covalent trap. PMID- 21322568 TI - Proteomic analysis of temperature-dependent changes in stored UHT milk. AB - Molecular changes in milk proteins during storage of UHT-treated milk have been investigated using two-dimensional electrophoresis (2-DE) coupled to MALDI-TOF mass spectrometry. UHT-treated samples were stored at three different temperatures, 4 degrees C, 28 degrees C, and 40 degrees C, for two months. Three main changes could be observed on 2-DE gels following storage. They were (1) the appearance of diffuse staining regions above the position of the monomeric caseins caused by nondisulfide cross-linking of alpha and beta-caseins; (2) the appearance of additional acidic forms of proteins, predominantly of alpha(S1)-casein, caused by deamidation; and (3) the appearance of "stacked spots" caused by lactosylation of whey proteins. The extent of the changes increased with increased storage temperature. Mass spectrometric analysis of in gel tryptic digests showed that the cross-linked proteins were dominated by alpha(S1)-casein, but a heterogeneous population of cross-linked forms with alpha(S2)-casein and beta-casein was also observed. Tandem MS analysis was used to confirm deamidation of N(129) in alpha(S1)-casein. MS analysis of the stacked spots revealed lactosylation of 9/15 lysines in beta-lactoglobulin and 8/12 lysines in alpha-lactalbumin. More extensive analysis will be required to confirm the nature of the cross-links and additional deamidation sites in alpha(S1) casein as the highly phosphorylated nature of the caseins makes them challenging prospects for MS analysis. PMID- 21322569 TI - An ylide-like phosphasilene and striking formation of a 4pi-electron, resonance stabilized 2,4-disila-1,3-diphosphacyclobutadiene. AB - The first N-donor-stabilized phosphasilene LSi(SiMe(3))?PSiMe(3) (L = PhC(NtBu)(2)) has been synthesized in 87% yield through 1,2-silyl migration of the (Me(3)Si)(2)P-substituted, N-heterocyclic silylene [LSi-P(SiMe(3))(2)]. Remarkably, the latter reacts with dichlorotriphenylphosphorane Ph(3)PCl(2) to give the unprecedented 4pi-electron Si(2)P(2)-cycloheterobutadiene [(LSi)(2)P(2)] with two-coordinate phosphorus atoms. The striking molecular structures as well as the (29)Si and (31)P NMR spectroscopic features of both products indicate the presence of zwitterionic Si?P bonds which is also in accordance with results by DFT calculations. PMID- 21322571 TI - Measurement of surface effects on the rotational diffusion of a colloidal particle. AB - A growing number of nanotechnologies involve rotating particles. Because the particles are normally close to a solid surface, hydrodynamic interaction may affect particle rotation. Here, we track probes composed of two particles tethered to a solid surface by a DNA molecule to measure for the first time the effect of a surface on the rotational viscous drag. We use a model that superimposes solutions of the Stokes equation in the presence of a wall to confirm and interpret our measurements. We show that the hydrodynamic interaction between the surface and the probe increases the rotational viscous drag and that the effect strongly depends on the geometry of the probe. PMID- 21322570 TI - Dissociation of apolipoprotein E oligomers to monomer is required for high affinity binding to phospholipid vesicles. AB - The apolipoprotein apoE plays a key role in cholesterol and lipid metabolism. There are three isoforms of this protein, one of which, apoE4, is the major risk factor for Alzheimer's disease. At micromolar concentrations all lipid-free apoE isoforms exist primarily as monomers, dimers, and tetramers. However, the molecular weight form of apoE that binds to lipid has not been clearly defined. We have examined the role of self-association of apoE with respect to interactions with phospholipids. Measurements of the time dependence of turbidity clearance of small unilamellar vesicles of dimyristoyl-sn-glycero-3 phosphocholine (DMPC) upon addition of apoE show that higher molecular weight oligomers bind poorly if at all. The kinetic data can be described by a reaction model in which tetramers and dimers of apoE must first dissociate to monomers which then bind to the liposome surface in a fast and reversible manner. A slow but not readily reversible conformational conversion of the monomer then occurs. Prior knowledge of the rate constants for the association-dissociation process allows us to determine the rate constant of the conformational conversion. This rate constant is isoform dependent and appears to correlate with the stability of the apoE isoforms with the rate of dissociation of the apoE oligomers to monomers being the rate-limiting process for lipidation. Differences in the lipidation kinetics between the apoE isoforms arise from their differences in the self association behavior leading to the conclusion that self-association behavior may influence biological functions of apoE in an isoform-dependent manner. PMID- 21322572 TI - Protein adsorption at charged surfaces: the role of electrostatic interactions and interfacial charge regulation. AB - The understanding of protein adsorption at charged surfaces is important for a wide range of scientific disciplines including surface engineering, separation sciences and pharmaceutical sciences. Compared to chemical entities having a permanent charge, the adsorption of small ampholytes and proteins is more complicated as the pH near a charged surface can be significantly different from the value in bulk solution. In this work, we have developed a phenomenological adsorption model which takes into account the combined role of interfacial ion distribution, interfacial charge regulation of amino acids in the proximity of the surface, electroneutrality, and mass balance. The model is straightforward to apply to a given set of experimental conditions as most model parameters are obtained from bulk properties and therefore easy to estimate or are directly measurable. The model provides a detailed understanding of the importance of surface charge on adsorption and in particular of how changes in surface charge, concentration, and surface area may affect adsorption behavior. The model is successfully used to explain the experimental adsorption behavior of the two model proteins lysozyme and alpha-lactalbumin. It is demonstrated that it is possible to predict the pH and surface charge dependent adsorption behavior from experimental or theoretical estimates of a preferred orientation of a protein at a solid charged interface. PMID- 21322573 TI - Broad-ranging natural metabotype variation drives physiological plasticity in healthy control inbred rat strains. AB - Maintaining homeostasis in higher organisms involves a complex interplay of multiple ubiquitous and organ-specific molecular mechanisms that can be characterized using functional genomics technologies such as transcriptomics, proteomics, and metabonomics and dissected out through genetic investigations in healthy and diseased individuals. We characterized the genomic, metabolic, and physiological divergence of several inbred rat strains--Brown Norway, Lewis, Wistar Kyoto, Fisher (F344)--frequently used as healthy controls in genetic studies of the cardiometabolic syndrome. Hierarchical clustering of (1)H NMR based metabolic profiles (n = 20 for urine, n = 16 for plasma) identified metabolic phenotype (metabotype) divergence patterns similar to the phylogenetic variability based on single nucleotide polymorphisms. However, the observed urinary metabotype variation exceeded that explainable by genetic polymorphisms. To understand further this natural variation, we used an integrative, knowledge based network biology metabolic pathway analysis approach, coined Metabolite-Set Enrichment Analysis (MSEA). MSEA reveals that homeostasis and physiological plasticity can be achieved despite widespread divergences in glucose, lipid, amino acid, and energy metabolism in the host, together with different gut microbiota contributions suggestive of strain-specific transgenomic interactions. This work illustrates the concept of natural metabolomic variation, leading to physiologically stable albeit diverse strategies within the range of normality, all of which are highly relevant to animal model physiology, genetical genomics, and patient stratification in personalized healthcare. PMID- 21322574 TI - Water droplet motion control on superhydrophobic surfaces: exploiting the Wenzel to-Cassie transition. AB - Water droplets on rough hydrophobic surfaces are known to exist in two states; one in which the droplet is impaled on the surface asperities (Wenzel state) and the other, a superhydrophobic state in which air remains trapped beneath the droplet (Cassie state). Here, we demonstrate that water droplets can transit from the Wenzel-to-Cassie state even though the former is energetically favored. We find that two distinct superhydrophobic states are produced. One is a true Cassie state, whereas the other exhibits superhydrophobicity in the absence of a vapor phase being trapped in the surface roughness. Furthermore, we can selectively drive the motion of water droplets on tilted structured hydrophobic surfaces by exploiting Wenzel-to-Cassie transitions. This can be achieved by heating the substrate or by directly heating the droplet using a laser. PMID- 21322575 TI - Tetrachlorocarbonyliridates: water-soluble carbon monoxide releasing molecules rate-modulated by the sixth ligand. AB - A new family of compounds is presented as potential carbon monoxide releasing molecules (CORMs). These compounds, based on tetrachlorocarbonyliridate(III) derivatives, were synthesized and fully characterized by X-ray diffraction, electrospray mass spectrometry, IR, NMR, and density functional theory calculations. The rate of CO release was studied via the myoglobin assay. The results showed that the rate depends on the nature of the sixth ligand, trans to CO, and that a significant modulation on the release rate can be produced by changing the ligand. The reported compounds are soluble in aqueous media, and the rates of CO release are comparable with those for known CORMs, releasing CO at a rate of 0.03-0.58 MUM min(-1) in a 10 MUM solution of myoglobin and 10 MUM of the complexes. PMID- 21322576 TI - XPS analysis of combustion aerosols for chemical composition, surface chemistry, and carbon chemical state. AB - Carbonaceous aerosols can vary in elemental content, surface chemistry, and carbon nano-structure. Each of these properties is related to the details of soot formation. Fuel source, combustion process (affecting formation and growth conditions), and postcombustion exhaust where oxidation occurs all contribute to the physical structure and surface chemistry of soot. Traditionally such physical and chemical parameters have been measured separately by various techniques. Presented here is the unified measurement of these characteristics using X-ray photoelectron spectroscopy (XPS). In the present study, XPS is applied to combustion soot collected from a diesel engine (running biodiesel and pump-grade fuels); jet engine; and institutional, plant, and residential oil-fired boilers. Elemental composition is mapped by a survey scan over a broad energy range. Surface chemistry and carbon nanostructure are quantified by deconvolution of high-resolution scans over the C1s region. This combination of parameters forms a distinct matrix of identifiers for the soots from these sources. PMID- 21322577 TI - A cagelike polyanion with a Ag+ enwrapped, [AgAs2Mo15O54]11-. AB - The polyanion [AgAs(2)Mo(15)O(54)](11-) has an unusual cage-like structure composed of [AsMo(6)O(27)](15-) and [AsMo(6)O(24)](9-) subunits connected by three MoO(4) tetrahedra, and a Ag(+) cation is inclosed at the center of the cage and coordinated by two As atoms with a As-Ag-As bond angle of 180 degrees along with three MU(3)-oxo groups from MoO(4) tetrahedra to lead to a trigonal pyramidal coordination geometry. The compound was also characterized by IR, X-ray photoelectron spectroscopy, fluorescent spectroscopy, and thermogravimetry differential scanning calorimetry. The stability of [AgAs(2)Mo(15)O(54)](11-) in aqueous solution was investigated by using electronic absorbance spectroscopy and electrospray ionization mass spectrometry. PMID- 21322578 TI - Visualization of nitroxyl in living cells by a chelated copper(II) coumarin complex. AB - The coumarin-based probe Cu(II)-COT1 was successfully developed for the detection of HNO on the basis of the reduction reaction. In addition, highly selective "turn on" type fluorogenic behavior upon the addition of Angeli's salt (Na(2)N(2)O(3)) was also applied to bioimaging in A375 cells. PMID- 21322580 TI - Characterization of divalent and trivalent species generated in the chemical and electrochemical oxidation of a dimeric pincer complex of nickel. AB - The electrolytic and chemical oxidation of the dimeric pincer complex [kappa(P),kappa(C),kappa(N),MU(N)-(2,6-(i-Pr(2)POC(6)H(3)CH(2)NBn)Ni](2) (1; Bn = CH(2)Ph) has been investigated by various analytic techniques. Cyclic voltammetry measurements have shown that 1 undergoes a quasi-reversible, one electron, Ni based redox process (DeltaE(0)(1/2) = -0.07 V vs Cp(2)Fe/[Cp(2)Fe](+)), and spectroelectrochemical measurements conducted on the product of the electrolytic oxidation, [1](+*), have shown multiple low-energy electronic transitions in the range of 10,000-15,000 cm(-1). Computational studies using Density Functional Theory (B3LYP) have corroborated the experimentally obtained structure of 1, provided the electronic structure description, and helped interpret the experimentally obtained absorption spectra for 1 and [1](+.). These calculations indicate that the radical cation [1](+.) is a dimeric, mixed-valent species (class III) wherein most of the spin density is delocalized over the two nickel centers (Ni(+2.5)(2)N(2)), but some spin density is also present over the two nitrogen atoms (Ni(2+)(2)N(2).). Examination of alternative structures for open shell species generated from 1 has shown that the spin density distribution is highly sensitive toward changes in the ligand environment of the Ni ions. NMR, UV vis, electron paramagnetic resonance (EPR), and single crystal X-ray diffraction analyses have shown that chemical oxidation of 1 with N-Bromosuccinimide (NBS) follows a complex process that gives multiple products, including the monomeric trivalent species kappa(P),kappa(C),kappa(N)-{2,6-(i Pr(2)PO)(C(6)H(3))(CH?NBn)}NiBr(2) (2). These studies also indicate that oxidation of 1 with 1 equiv of NBS gives an unstable, paramagnetic intermediate that decomposes to a number of divalent species, including succinimide and the monomeric divalent complexes kappa(P),kappa(C),kappa(N)-{2,6-(i Pr(2)PO)(C(6)H(3))(CH?NBn)}NiBr (3) and kappa(P),kappa(C),kappa(N)-{2,6-(i Pr(2)PO)(C(6)H(3))(CH(2)N(H)Bn)}NiBr(2) (4); a second equivalent of NBS then oxidizes 3 and 4 to 2 and other unidentified products. The divalent complex 3 was synthesized independently and shown to react with NBS or bromine to form its trivalent homologue 2. The new complexes 2 and 3 have been characterized fully. PMID- 21322579 TI - Nanoparticle-functionalized porous polymer monolith detection elements for surface-enhanced Raman scattering. AB - The use of porous polymer monoliths functionalized with silver nanoparticles is introduced in this work for high-sensitivity surface-enhanced Raman scattering (SERS) detection. Preparation of the SERS detection elements is a simple process comprising the synthesis of a discrete polymer monolith section within a silica capillary, followed by physically trapping silver nanoparticle aggregates within the monolith matrix. A SERS detection limit of 220 fmol for Rhodamine 6G is demonstrated, with excellent signal stability over a 24 h period. The capability of the SERS-active monolith for label-free detection of biomolecules was demonstrated by measurements of bradykinin and cytochrome c. The SERS-active monoliths can be readily integrated into miniaturized micrototal-analysis systems for online and label-free detection for a variety of biosensing, bioanalytical, and biomedical applications. PMID- 21322581 TI - Quantitative analysis and application of tip position modulation-scanning electrochemical microscopy. AB - Tip position modulation (TPM) involves moving the ultramicroelectrode (UME) tip of a scanning electrochemical microscope (SECM) perpendicular to the substrate in a sinusoidal fashion with a small amplitude compared to the tip/sample separation. The UME, which serves as the working electrode in a conventional voltammetric setup, is held at a potential to detect a species in solution at a transport-limited rate and the resulting current (ac and dc) is measured. This paper shows that tip-induced convection is an important factor in TPM. A model has been developed that describes the TPM response for the most challenging case of an inert substrate, where tip-induced convective effects compared to diffusion are greatest. The model provides an improved description of the ac response compared to existing treatment, as evidenced by the analysis of TPM-SECM approach curves (current-distance characteristics). The extension of the model to SECM induced transfer is considered and it is shown that one can extract highly precise information on the permeability of a sample from such measurements, for which experiments and theory are compared. The prospects for using the technique more widely are highlighted and routes to improving the theoretical analysis further are briefly discussed. PMID- 21322582 TI - Real time detection of lysozyme by pulsed streaming potentials using polyclonal antibodies immobilized on a renewable nonfouling surface inside plastic microfluidic channels. AB - A composite surface was prepared on cyclic olefin copolymer (COC) microchannels by UV-photografting of polyethylene glycol acrylate (PEGA) and poly(acrylic acid) (PAA) films. A PEGA layer of globular particles with average thickness of 60 nm was formed after 15 min of polymerization. Real time monitoring by pulsed streaming potentials demonstrated the ability of the PEGA layer to inhibit the adhesion of five different nonspecific adsorbing proteins when compared with pristine COC. Roughness determined by atomic force microscopy (AFM) after PAA grafting on COC-PEGA at different UV illumination times suggests that PAA formation is initiated at the free space in between the PEGA particles. Carboxylic groups activated with N-hydroxysuccinimide and N-ethyl-N'-(3 dimethylaminopropyl) carbodiimide were used to bind anti-lysozyme polyclonal antibodies. The composite COC-PEGA-PAA-anti-lysozyme surface demonstrated its ability to detect lysozyme with a dynamic range between 140 and 860 nM. Linearity was maintained even when samples were spiked with 250 nM of cytochrome as interfering species. The equilibrium constant K(eq) for the adsorption of Ly on COC-PEGA-PAA-anti-Ly was estimated to be 2.7 * 10(6) M(-1), and it shows that this kinetic approach of monitoring the surface charge is also useful to estimate affinity interactions for proteins in label free fashion. The regeneration of the surface exhibited an average percentage of recovery of ~97% for each of six adsorption-regeneration cycles. This feature enables curve calibration on a single microfluidic chip because each point of the curve has a reproducible and renewable surface. PMID- 21322583 TI - What is the covalency of hydrogen bonding? PMID- 21322585 TI - Optimization of near-infrared spectroscopic process monitoring at low signal-to noise ratio. AB - An approach for the optimization of near-infrared (NIR) spectroscopic process monitoring at low signal-to-noise ratio is presented. It compromises the combined adjustment of different measurement variables and data pretreatments considering the prediction error, economic aspects of the application, and process constraints. The integration time, light intensity, and number of averaged spectra were varied; their mutual influence on the prediction error of partial least squares (PLS) models (i.e., root-mean-square error of cross-validation (RMSECV)) was evaluated in the laboratory. At low signal levels, the spectral uncertainty had a strong impact on the prediction error. It leveled off with increasing values of all three parameters and was finally dominated by other sources of uncertainty. The experimental findings could be characterized and explained by a mathematical equation, which was deduced from theoretical principles. The knowledge about the interaction of the measurement variables allowed their combined adjustment resulting in a reduced impact of spectral uncertainty on the prediction error (i.e., root-mean-square error of prediction (RMSEP)) without additional costs or process modifications. Moreover, a convenient procedure to compensate the stray light caused by strongly absorbing windows was developed. The whole approach was successfully applied to a challenging process, namely, the NIR inline monitoring of the liquid content of two model substances in a rotating suspension dryer. PMID- 21322584 TI - DFT calculations for intermediate and active states of the diiron center with a tryptophan or tyrosine radical in Escherichia coli ribonucleotide reductase. AB - Class Ia ribonucleotide reductase subunit R2 contains a diiron active site. In this paper, active-site models for the intermediate X-Trp48(*+) and X-Tyr122(*), the active Fe(III)Fe(III)-Tyr122(*), and the met Fe(III)Fe(III) states of Escherichia coli R2 are studied, using broken-symmetry density functional theory incorporated with the conductor-like screening solvation model. Different structural isomers and different protonation states have been explored. Calculated geometric, energetic, Mossbauer, hyperfine, and redox properties are compared with available experimental data. Feasible detailed structures of these intermediate and active states are proposed. Asp84 and Trp48 are most likely the main contributing residues to the result that the transient Fe(IV)Fe(IV) state is not observed in wild-type class Ia E. coli R2. Asp84 is proposed to serve as a proton-transfer conduit between the diiron cluster and Tyr122 in both the tyrosine radical activation pathway and the first steps of the catalytic proton coupled electron-transfer pathway. Proton-coupled and simple redox potential calculations show that the kinetic control of proton transfer to Tyr122(*) plays a critical role in preventing reduction from the active Fe(III)Fe(III)-Tyr122(*) state to the met state, which is potentially the reason why Tyr122(*) in the active state can be stable over a very long period. PMID- 21322587 TI - Combining surface plasmon resonance (SPR) spectroscopy with surface-enhanced Raman scattering (SERS). AB - The simultaneous measurement of surface plasmon resonance (SPR) spectroscopy and surface-enhanced Raman scattering (SERS) on flat metallic surfaces is demonstrated on a relatively simple experimental setup based on the Kretschmann configuration. This setup requires only minor modifications to standard Raman microscopes, and we show that it can be applied successfully to the most common conditions of SPR spectroscopy, i.e., water-based solutions on gold films. Our results emphasize the peculiar properties of the Kretschmann configuration for spectroscopy in general and SERS measurements in particular, especially in terms of the asymmetry between excitation and collection requirements. The combination of simultaneous SPR-SERS spectroscopy opens up interesting prospects in analytical science to study, for example, reaction kinetics at surfaces under conditions which are already available in commercial SPR instruments. PMID- 21322586 TI - Analysis of biogenic amines in a single Drosophila larva brain by capillary electrophoresis with fast-scan cyclic voltammetry detection. AB - Drosophila, the fruit fly, is a common model organism in biology; however, quantifying neurotransmitters in Drosophila is challenging because of the small size of the central nervous system (CNS). Here, we develop neurotransmitter quantification by capillary electrophoresis with fast-scan cyclic voltammetry (CE FSCV) detection, which allows peak identification by both migration time and the cyclic voltammogram, in contrast to traditional amperometric detection which provides no chemical identification. Tissue content of biogenic amine neurotransmitters was determined in a single CNS dissected from a Drosophila larva. Low detection limits, 1 nM for dopamine and serotonin, 2.5 nM for tyramine, and 4 nM for octopamine, were achieved using field-amplified sample stacking by diluting the homogenized tissue with percholoric acid and acetonitrile. Two different strains of wild-type flies, Oregon R and Canton S, have similar dopamine and serotonin levels but different octopamine content. When flies are fed NSD-1015, which inhibits dopamine decarboxylase (Ddc) a synthesis enzyme in the dopamine and serotonin pathways, dopamine significantly decreases by 52%. A genetically altered driver line, Ddc-GAL4, had lower serotonin and dopamine content as did w(118) flies. When the Ddc-GAL4 line was used to produce flies overexpressing the serotonin synthesis enzyme tryptophan hydroxylase (Ddc GAL4;UAS-Trh), the serotonin tissue content was greater than for Ddc-GAL4 but not significantly different than the wild-type. These results show that CE-FSCV is useful for monitoring the impact of genetic and pharmacological manipulations on the content of multiple neurotransmitters in a CNS from a Drosophila larva. PMID- 21322589 TI - Alternating-color quantum dot nanocomposites for particle tracking. AB - Because of their extraordinary brightness and photostability, quantum dots (QDs) have tremendous potential for long-term, particle tracking in heterogeneous systems (e.g., living cells, microfluidic flow). However, one of their major limitations is blinking, an intermittent loss of fluorescence, characteristic of individual and small clusters of QDs, that interrupts particle tracking. Recently, several research groups have reported "nonblinking QDs". However, blinking is the primary method used to confirm nanoparticle aggregation status in situ, and single or small clusters of nanoparticles with continuous fluorescence emission are difficult to discern from large aggregates. Here, we describe a new class of quantum dot-based composite nanoparticles that solve these two seemingly irreconcilable problems by exhibiting near-continuous, alternating-color fluorescence, which permits aggregation status discrimination by observable color changes even during motion across the focal plane. These materials will greatly enhance particle tracking in cell biology, biophysics, and fluid mechanics. PMID- 21322588 TI - Cobalt and manganese diphosphonates with one-, two-, and three-dimensional structures and field-induced magnetic transitions. AB - Reactions of 2-(1-Imidazole)-1-hydroxyl-1,1'-ethylidenediphosphonic acid (ImhedpH(4)) and cobalt or manganese salts under hydrothermal conditions result in three new metal diphosphonates: beta-Co(3)(ImhedpH)(2)(H(2)O)(4).2H(2)O (1), Co(3)(ImhedpH)(2)(H(2)O)(4) (2), and Mn(ImhedpH(2)).H(2)O (3). In compound 1, the columns made up of {Co1(2)O(2)} dimers and {PO(3)C} tetrahedra through corner sharing are cross-linked through {Co2O(6)} octahedra, forming an inorganic layer. Neighboring layers are pillared by coordinated imidazole groups of ImhedpH(-) ligands, leading to a three-dimensional open framework containing two kinds of channels with sizes of 8.256 * 9.851 A and 8.030 * 4.745 A (van der Waals radii not accounted for). Compound 2 shows a layer structure, in which Co(3)(ImhedpH)(2)(H(2)O)(4) trimer units are connected through the corner-sharing of {Co1O(5)} trigonal bipyramids and {PO(3)C} tetrahedra, forming an inorganic layer containing 20-member rings composed of six Co atoms, two MU(3)-O1 units, and four O-P-O units. The noncoordinated imidazole groups protrude from two sides of the layer. Compound 3 shows a ladder structure, where the Mn(II) ions are bridged by ImhedpH(2)(2-) ligands through double O-P-O units to form a single chain, and two such chains are further fused together by sharing edges of {MnO(5)} trigonal bipyramids. The magnetic properties of 1-3 have been studied. Ferrimagnetism and field-induced magnetic transition from ferrimagnetism to a fully polarized state are observed in 1. Compounds 2 and 3 reveal dominant antiferromagnetic interactions between metal centers, and two-step field-induced magnetic phase transitions are found in 2. PMID- 21322590 TI - Optical nanorod antennas modeled as cavities for dipolar emitters: evolution of sub- and super-radiant modes. AB - Optical antennas link objects to light. Here we derive an analytical model for the interaction of dipolar transitions with radiation through nanorod antenna modes, by modeling nanorods as cavities. The model includes radiation damping, accurately describes the complete emission process, and is summarized in a phase matching equation. We analytically discuss the quantitative evolution of antenna modes, in particular the gradual emergence of subradiant, super-radiant, and dark modes, as antennas become increasingly more bound, i.e., plasmonic. Our description is valid for the interaction of nanorods with light in general and is thus widely applicable. PMID- 21322591 TI - Edge effect on resistance scaling rules in graphene nanostructures. AB - We report an experimental investigation of the edge effect on the room temperature transport in graphene nanoribbon and graphene sheet (both single layer and bilayer). By measuring the resistance scaling behaviors at both low- and high-carrier densities, we show that the transport of single-layer nanoribbons lies in a strong localization regime, which can be attributed to an edge effect. We find that this edge effect can be weakened by enlarging the width, decreasing the carrier densities, or adding an extra layer. From graphene nanoribbon to graphene sheet, the data show a dimensional crossover of the transport regimes possibly due to the drastic change of the edge effect. PMID- 21322592 TI - Formation and stabilization of silver nanoparticles with cucurbit[n]urils (n = 5 8) and cucurbituril-based pseudorotaxanes in aqueous medium. AB - A series of silver/cucurbituril nanoparticles and aggregates have been prepared upon reduction of silver nitrate with sodium borohydride in the presence of different cucurbit[n]uril (CB[n]) macrocycles; CB[7] and CB[8] allow the formation of stable solutions of monocrystalline, narrowly dispersed nanoparticles (5.3 and 3.7 nm, respectively), while CB[5] and CB[6] induce rapid aggregation and sedimentation. The rigidity of CB[5] and CB[6], and their possible lack of suitable arrangement at the silver surface, may explain the poor stabilization of these silver assemblies, while the more flexible CB[7] and CB[8] may undergo some minor distortions and better adapt to the requirements of the metallic surface; computer modeling supports the existence of interactions between the silver nanoparticles and the oxygen atoms of the CB[n] carbonylated rim. The optimal silver nitrate/CB[7] ratio for the formation of stable nanoparticles is 1:1-2:1, while large excesses of silver or CB[7] trigger aggregation. Masking the portals of CB[7] by adding a bulky, positively charged guest into its cavity has a surprisingly minor effect on the stability of the silver/CB[7] assemblies; in such a case, the CB[7] rim is still expected to interact with the NPs, albeit via a fraction of its carbonyl oxygen atoms. PMID- 21322593 TI - Fragment growing induces conformational changes in acetylcholine-binding protein: a structural and thermodynamic analysis. AB - Optimization of fragment hits toward high-affinity lead compounds is a crucial aspect of fragment-based drug discovery (FBDD). In the current study, we have successfully optimized a fragment by growing into a ligand-inducible subpocket of the binding site of acetylcholine-binding protein (AChBP). This protein is a soluble homologue of the ligand binding domain (LBD) of Cys-loop receptors. The fragment optimization was monitored with X-ray structures of ligand complexes and systematic thermodynamic analyses using surface plasmon resonance (SPR) biosensor analysis and isothermal titration calorimetry (ITC). Using site-directed mutagenesis and AChBP from different species, we find that specific changes in thermodynamic binding profiles, are indicative of interactions with the ligand inducible subpocket of AChBP. This study illustrates that thermodynamic analysis provides valuable information on ligand binding modes and is complementary to affinity data when guiding rational structure- and fragment-based discovery approaches. PMID- 21322594 TI - An isothermal system that couples ligand-dependent catalysis to ligand independent exponential amplification. AB - A system was devised that enables quantitative, ligand-dependent exponential amplification for various ligands that can be recognized by an RNA aptamer. The aptamer is linked to an RNA enzyme that catalyzes the joining of two oligonucleotide substrates. The product of this reaction is another RNA enzyme that undergoes self-sustained replication at constant temperature, increasing in copy number exponentially. The concentration of the ligand determines the amount of time required for the replication products to reach a threshold concentration. A standardized plot of time to threshold versus ligand concentration can be used to determine the concentration of ligand in an unknown sample. This system is analogous to quantitative polymerase chain reaction (PCR), linking rare recognition events to subsequent exponential amplification, but unlike PCR can be applied to the quantitative detection of non-nucleic acid ligands. PMID- 21322595 TI - Liposome fusion rates depend upon the conformation of polycation catalysts. AB - Cryo-TEM and NaCl-leakage experiments demonstrated that the cationic polymer polylysine induces fusion of anionic liposomes but that the cationic polymer poly(N-ethyl-4-vinylpyridinium bromide) (PEVP) does not, although both polymers bind strongly to the liposomes. The difference was traced to the thickness of the coatings at constant charge coverage. Polylysine is believed to form planar beta sheets that are sufficiently thin to allow membrane fusion. In contrast, looping and disorganization among adsorbed PEVP molecules physically prevent fusion. A similar effect is likely to be applicable to important polycation-induced fusion of cell membranes. PMID- 21322596 TI - Role of liquid polymorphism during the crystallization of silicon. AB - Using molecular simulation, we establish the pivotal role played by liquid polymorphs during the crystallization of silicon. When undercooled at a temperature 20% below the melting point, a silicon melt is under the form of the highly coordinated, high-density liquid (HDL) polymorph. We find that crystallization starts with the formation, within the HDL liquid, of a nanosized droplet of the least stable liquid polymorph, known as the almost tetracoordinated low-density liquid (LDL) polymorph. We then show that the crystalline embryo forms within the LDL droplet, close to the interface with the surrounding HDL liquid, thereby following a pathway associated with a much lower free energy barrier than the direct formation of the crystalline embryo from the HDL liquid would have required. This implies that, for substances exhibiting liquid polymorphs, theories, like the classical nucleation theory, and empirical rules, like Ostwald's rule, should be modified to account for the role of liquid polymorphs in the nucleation process. PMID- 21322597 TI - Formation of bilayer bernal graphene: layer-by-layer epitaxy via chemical vapor deposition. AB - We report the epitaxial formation of bilayer Bernal graphene on copper foil via chemical vapor deposition. The self-limit effect of graphene growth on copper is broken through the introduction of a second growth process. The coverage of bilayer regions with Bernal stacking can be as high as 67% before further optimization. Facilitated with the transfer process to silicon/silicon oxide substrates, dual-gated graphene transistors of the as-grown bilayer Bernal graphene were fabricated, showing typical tunable transfer characteristics under varying gate voltages. The high-yield layer-by-layer epitaxy scheme will not only make this material easily accessible but reveal the fundamental mechanism of graphene growth on copper. PMID- 21322598 TI - Epitaxial graphene nucleation on C-face silicon carbide. AB - The initial stages of epitaxial graphene growth were studied by characterization of graphene formed in localized areas on C-face 6H-SiC substrates. The graphene areas were determined to lie below the level of the surrounding substrate and showed different morphologies based on size. Employing electron channeling contrast imaging, the presence of threading screw dislocations was indicated near the centers of each of these areas. After the graphene was removed, these dislocations were revealed to lie within the SiC substrate. These observations suggest that screw dislocations act as preferred nucleation sites for graphene growth on C-face SiC. PMID- 21322599 TI - Hexagonal single crystal domains of few-layer graphene on copper foils. AB - Hexagonal-shaped single crystal domains of few layer graphene (FLG) are synthesized on copper foils using atmospheric pressure chemical vapor deposition with a high methane flow. Scanning electron microscopy reveals that the graphene domains have a hexagonal shape and are randomly orientated on the copper foil. However, the sites of graphene nucleation exhibit some correlation by forming linear rows. Transmission electron microscopy is used to examine the folded edges of individual domains and reveals they are few-layer graphene consisting of approximately 5-10 layers in the central region and thinning out toward the edges of the domain. Selected area electron diffraction of individual isolated domains reveals they are single crystals with AB Bernal stacking and free from the intrinsic rotational stacking faults that are associated with turbostratic graphite. We study the time-dependent growth dynamics of the domains and show that the final continuous FLG film is polycrystalline, consisting of randomly connected single crystal domains. PMID- 21322600 TI - Single-nanowire single-mode laser. AB - We demonstrate single-mode laser emission in single nanowires. By folding a 200 nm diameter CdSe nanowire to form loop mirrors, single-mode laser emission around 738 nm wavelength is obtained with line width of 0.12 nm and low threshold. The mode selection is realized by the vernier effect of coupled cavities in the folded nanowire. In addition, the loop structure makes it possible to tune the nanowire cavity, opening an opportunity to realize a tunable single-mode nanowire laser. PMID- 21322601 TI - Localized States and resultant band bending in graphene antidot superlattices. AB - We fabricated dye sensitized graphene antidot superlattices with the purpose of elucidating the role of the localized edge state density. The fluorescence from deposited dye molecules was found to strongly quench as a function of increasing antidot filling fraction, whereas it was enhanced in unpatterned but electrically backgated samples. This contrasting behavior is strongly indicative of a built-in lateral electric field that accounts for fluorescence quenching as well as p-type doping. These findings are of great interest for light-harvesting applications that require field separation of electron-hole pairs. PMID- 21322602 TI - Vertical transfer of uniform silicon nanowire arrays via crack formation. AB - Vertical transfer of silicon nanowire (SiNW) arrays with uniform length onto adhesive substrates was realized by the assistance of creating a horizontal crack throughout SiNWs. The crack is formed by adding a water soaking step between consecutive Ag-assisted electroless etching processes of Si. The crack formation is related to the delamination, redistribution, and reattachment of the Ag film during the water soaking and subsequent wet etching steps. Moreover, the crack facilitates embedding SiNWs inside polymers. PMID- 21322603 TI - The roles of molecular structure and effective optical symmetry in evolving dipolar chromophoric building blocks to potent octopolar nonlinear optical chromophores. AB - A series of mono-, bis-, tris-, and tetrakis(porphinato)zinc(II) (PZn)-elaborated ruthenium(II) bis(terpyridine) (Ru) complexes have been synthesized in which an ethyne unit connects the macrocycle meso carbon atom to terpyridyl (tpy) 4-, 4'-, and 4''-positions. These supermolecular chromophores, based on the ruthenium(II) [5-(4'-ethynyl-(2,2';6',2''-terpyridinyl))-10,20-bis(2',6'-bis(3,3-dimethyl-1 butyloxy)phenyl)porphinato]zinc(II)-(2,2';6',2''-terpyridine)(2+) bis hexafluorophosphate (RuPZn) archetype, evince strong mixing of the PZn-based oscillator strength with ruthenium terpyridyl charge resonance bands. Potentiometric and linear absorption spectroscopic data indicate that for structures in which multiple PZn moieties are linked via ethynes to a [Ru(tpy)(2)](2+) core, little electronic coupling is manifest between PZn units, regardless of whether they are located on the same or opposite tpy ligand. Congruent with these experiments, pump-probe transient absorption studies suggest that the individual RuPZn fragments of these structures exhibit, at best, only modest excited-state electronic interactions that derive from factors other than the dipole-dipole interactions of these strong oscillators; this approximate independent character of the component RuPZn oscillators enables fabrication of nonlinear optical (NLO) multipoles with extraordinary hyperpolarizabilities. Dynamic hyperpolarizability (beta(lambda)) values and depolarization ratios (rho) were determined from hyper-Rayleigh light scattering (HRS) measurements carried out at an incident irradiation wavelength (lambda(inc)) of 1300 nm. The depolarization ratio data provide an experimental measure of chromophore optical symmetry; appropriate coupling of multiple charge-transfer oscillators produces structures having enormous averaged hyperpolarizabilities (beta(HRS) values), while evolving the effective chromophore symmetry from purely dipolar (e.g., Ru(tpy)[4-(Zn-porphyrin)ethynyl-tpy](PF(6))(2), beta(HRS) = 1280 * 10(-30) esu, rho = 3.8; Ru(tpy)[4'-(Zn-porphyrin)ethynyl-tpy](PF(6))(2), beta(HRS) = 2100 * 10(-30) esu, rho = 3.8) to octopolar (e.g., Ru[4,4''-bis(Zn-porphyrin)ethynyl tpy](2)(PF(6))(2), beta(HRS) = 1040 * 10(-30) esu, rho = 1.46) via structural motifs that possess intermediate values of the depolarization ratio. The chromophore design roadmap provided herein gives rise to octopolar supermolecules that feature by far the largest off-diagonal octopolar first hyperpolarizability tensor components ever reported, with the effectively octopolar Ru[4,4''-bis(Zn porphyrin)ethynyl-tpy](2)(PF(6))(2) possessing a beta(HRS) value at 1300 nm more than a factor of 3 larger than that determined for any chromophore having octopolar symmetry examined to date. Because NLO octopoles possess omnidirectional NLO responses while circumventing the electrostatic interactions that drive bulk-phase centrosymmetry for NLO dipoles at high chromophore concentrations, the advent of octopolar NLO chromophores having vastly superior beta(HRS) values at technologically important wavelengths will motivate new experimental approaches to achieve acentric order in both bulk-phase and thin film structures. PMID- 21322604 TI - Enhanced piezoelectricity and stretchability in energy harvesting devices fabricated from buckled PZT ribbons. AB - The development of a method for integrating highly efficient energy conversion materials onto soft, biocompatible substrates could yield breakthroughs in implantable or wearable energy harvesting systems. Of particular interest are devices which can conform to irregular, curved surfaces, and operate in vital environments that may involve both flexing and stretching modes. Previous studies have shown significant advances in the integration of highly efficient piezoelectric nanocrystals on flexible and bendable substrates. Yet, such inorganic nanomaterials are mechanically incompatible with the extreme elasticity of elastomeric substrates. Here, we present a novel strategy for overcoming these limitations, by generating wavy piezoelectric ribbons on silicone rubber. Our results show that the amplitudes in the waves accommodate order-of-magnitude increases in maximum tensile strain without fracture. Further, local probing of the buckled ribbons reveals an enhancement in the piezoelectric effect of up to 70%, thus representing the highest reported piezoelectric response on a stretchable medium. These results allow for the integration of energy conversion devices which operate in stretching mode via reversible deformations in the wavy/buckled ribbons. PMID- 21322605 TI - Realizing lateral wrap-gated nanowire FETs: controlling gate length with chemistry rather than lithography. AB - An important consideration in miniaturizing transistors is maximizing the coupling between the gate and the semiconductor channel. A nanowire with a coaxial metal gate provides optimal gate-channel coupling but has only been realized for vertically oriented nanowire transistors. We report a method for producing laterally oriented wrap-gated nanowire field-effect transistors that provides exquisite control over the gate length via a single wet etch step, eliminating the need for additional lithography beyond that required to define the source/drain contacts and gate lead. It allows the contacts and nanowire segments extending beyond the wrap-gate to be controlled independently by biasing the doped substrate, significantly improving the subthreshold electrical characteristics. Our devices provide stronger, more symmetric gating of the nanowire, operate at temperatures between 300 and 4 K, and offer new opportunities in applications ranging from studies of one-dimensional quantum transport through to chemical and biological sensing. PMID- 21322606 TI - Small hysteresis nanocarbon-based integrated circuits on flexible and transparent plastic substrate. AB - We report small hysteresis integrated circuits by introducing monolayer graphene for the electrodes and a single-walled carbon nanotube network for the channel. Small hysteresis of the device originates from a defect-free graphene surface, where hysteresis was modulated by oxidation. This uniquely combined nanocarbon material device with transparent and flexible properties shows remarkable device performance; subthreshold voltage of 220 mV decade(-1), operation voltage of less than 5 V, on/off ratio of approximately 10(4), mobility of 81 cm(2) V(-1) s(-1), transparency of 83.8% including substrate, no significant transconductance changes in 1000 times of bending test, and only 36% resistance decrease at a tensile strain of 50%. Furthermore, because of the nearly Ohmic contact nature between the graphene and carbon nanotubes, this device demonstrated a contact resistance 100 times lower and a mobility 20 times higher, when compared to an Au electrode. PMID- 21322607 TI - Excitonic fano resonance in free-standing graphene. AB - We investigate the role of electron-hole correlations in the absorption of free standing monolayer and bilayer graphene using optical transmission spectroscopy from 1.5 to 5.5 eV. Line shape analysis demonstrates that the ultraviolet region is dominated by an asymmetric Fano resonance. We attribute this to an excitonic resonance that forms near the van Hove singularity at the saddle point of the band structure and couples to the Dirac continuum. The Fano model quantitatively describes the experimental data all the way down to the infrared. In contrast, the common noninteracting particle picture cannot describe our data. These results suggest a profound connection between the absorption properties and the topology of the graphene band structure. PMID- 21322608 TI - Quinoline-annulated porphyrins. AB - Porphyrin-2,3-dione mono- and dioximes were used as starting materials for the efficient syntheses of mono- and bis-quinoline-annulated porphyrins and their corresponding N-oxides. Owing to an extended pi-system, these novel porphyrinoid chromophores show significantly red-shifted UV-vis spectra compared to the parent porphyrins. A crystal structure exemplifies the nonplanar conformation of the macrocycle. PMID- 21322609 TI - Phyteumosides A and B: new saponins with unique triterpenoid aglycons from Phyteuma orbiculare L. AB - Phyteumosides A (1) and B (2), two saponins with unprecedented triterpenoid aglycons, were isolated from the aerial parts of Phyteuma orbiculare (Campanulaceae). Their structures were elucidated by spectroscopic and chemical methods and corroborated by X-ray diffraction analyses of the aglycons obtained through enzymatic hydrolysis. The aglycon of 1 can be considered as an incompletely cyclized onoceroid or gammaceroid triterpene with two additional tetrahydropyran rings arising from oxygen bridges. Compound 2 possesses a new 17 polypodene aglycon. PMID- 21322610 TI - Probing the role of the mycosamine C2'-OH on the activity of amphotericin B. AB - A synthetic route to a mycosamine donor was designed and provided access to a set of AmB derivatives targeted to probe the effect of the C2'-OH. It was determined that the configuration of the C2'-position is inconsequential but that O methylation of this alcohol was deleterious to its mode of action. Additionally, the analog incorporating a mycosamine derivative from the enantiomeric series was devoid of activity. PMID- 21322611 TI - Laser-induced damage and recovery of plasmonically targeted human endothelial cells. AB - Laser-induced techniques that employ the surface plasmon resonances of nanoparticles have recently been introduced as an effective therapeutic tool for destroying tumor cells. Here, we adopt a low-intensity laser-induced technique to manipulate the damage and repair of a vital category of noncancerous cells, human endothelial cells. Endothelial cells construct the interior of blood vessels and play a pivotal role in angiogenesis. The degree of damage and repair of the cells is shown to be influenced by laser illumination in the presence of gold nanoparticles of different morphologies, which either target the cellular membrane or are endocytosed. A pronounced influence of the plasmonic nanoparticle laser treatment on the expression of critical angiogenic genes is shown. Our results show that plasmon-mediated mild laser treatment, combined with specific targeting of cellular membranes, enables new routes for controlling cell permeability and gene regulation in endothelial cells. PMID- 21322612 TI - Peering at a buried polymer-crystal interface: probing heterogeneous nucleation by sum frequency generation vibrational spectroscopy. AB - Sum frequency generation vibrational spectroscopy (SFG-VS) has been applied to investigate the selective crystallization of two forms of acetaminophen (ACM) on polymer surfaces. To our knowledge, this is the first account of SFG-VS being applied to study a polymer-crystal interface. SFG elucidates the molecular-level interactions governing phase selection at this buried interface, providing insight into the process of polymer-induced heteronucleation (PIHn) in solution as well as from the vapor phase. ACM heteronucleates from supersaturated aqueous solution in the metastable orthorhombic crystal form on poly(methyl methacrylate) (PMMA) surfaces, whereas the thermodynamically stable monoclinic crystal form is observed to form on poly(n-butyl methacrylate) (PBMA) surfaces. When the ACM crystals were grown by sublimation, only the monoclinic form was observed on both PMMA and PBMA. SFG-VS results indicate that hydrogen bonds are formed between PMMA C?O groups and the orthorhombic ACM crystals at the PMMA-ACM interface. At PBMA-monoclinic ACM interfaces, no hydrogen bond formation was observed. This research demonstrates that SFG-VS can be used to probe molecular interactions at polymer-crystal interfaces. Understanding the interfacial molecular interactions will ultimately provide a rational basis for improving methods for polymorph discovery and selection based on heteronucleation on polymer surfaces. PMID- 21322613 TI - High tunability of the surface-enhanced Raman scattering response with a metal multiferroic composite. AB - We demonstrate active control of the plasmonic response from Au nanostructures by the use of a novel multiferroic substrate-LuFe(2)O(4) (LFO)-to tune the surface enhanced Raman scattering (SERS) response in real time. From both experiments and numerical simulations based on the finite-difference time-domain method, a threshold field is observed, above which the optical response of the metal nanostructure can be strongly altered through changes in the dielectric properties of LFO. This offers the potential of optimizing the SERS detection sensitivity in real time as well as the unique functionality of detecting multiple species of Raman active molecules with the same template. PMID- 21322614 TI - Cell-permeable and plasma-stable peptidomimetic inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction. AB - The protein--protein interaction between the NMDA receptor and its intracellular scaffolding protein, PSD-95, is a potential target for treating ischemic brain diseases, neuropathic pain, and Alzheimer's disease. We have previously demonstrated that N-alkylated tetrapeptides are potent inhibitors of this interaction, and here, this template is exploited for the development of blood plasma-stable and cell-permeable inhibitors. Initially, we explored both the amino acid sequence of the tetrapeptide and the nature of the N-alkyl groups, which consolidated N-cyclohexylethyl-ETAV (1) as the most potent and selective compound. Next, the amide moieties of N-methylated ETAV were systematically replaced with thioamides, demonstrating that one of three amide bonds could be replaced without compromising the affinity. Subsequent optimization of the N alkyl groups and evaluation of cell permeability led to identification of N cyclohexylethyl-ETA(S)V (54) as the most potent, plasma-stable and cell-permeable inhibitor, which is a promising tool in unraveling the therapeutic potential of the PSD-95/NMDA receptor interaction. PMID- 21322615 TI - How many secondary carbocations are involved in the biosynthesis of avermitilol? AB - Quantum chemical calculations were used to assess the viability of proposed secondary carbocations as intermediates in the biosynthesis of avermitilol. One, a cyclopropylcarbinyl cation, was found to be a true minimum, while another, a simple secondary cation, was found to exist only as part of a transition structure for water capture. PMID- 21322616 TI - Controlling viscoelastic flow in microchannels with slip. AB - We show that viscoelastic flow in a microchannel under a dynamic pressure gradient dramatically changes with the value of the apparent slip. We demonstrate this by using classical hydrodynamics and the Navier boundary condition for the apparent slip. At certain driving frequencies, the flow is orders of magnitude different for systems with and without slip, implying that controlling the degree of hydrophobicity of a microchannel can lead to the control of the magnitude of the flow. We verify this for viscoelastic fluids with very different constitutive equations. Moreover, we demonstrate that flow, given a value of the apparent slip, is a non-monotonic function of the driving frequency and can be increased or reduced by orders of magnitude by slightly changing the frequency of the driving pressure gradient. Finally, we show that, for dynamic situations, slip causes and effectively thicker channel whose effective thickness depends on frequency. We have calculated relevant quantities for blood and a polymeric fluid in order to motivate experimental studies. PMID- 21322617 TI - Electronic and cytotoxic properties of 2-amino-naphtho[2,3-b]furan-4,9-diones. AB - The electronic properties of a new set of cytotoxic 2-amino-naphtho[2,3-b]furan 4,9-dione derivatives (1-8) are evaluated. The electron delocalization of these compounds is described by means of their redox potentials and solvatochromic properties. The large solvatochromism of their intramolecular electron transfer band is analyzed using the linear solvation energy relationship method. In addition, this method determined the importance of the molecular environment, quantifying the interactions that compounds (1-8) establish with their surrounding media, with the capacity of acting as hydrogen-bond acceptors (HBA) and hydrogen-bond donors (HBD) and the dipolarity/polarizability being the most significant ones. As a result, a relationship between the electronic and the cytotoxic properties of these compounds is proposed. PMID- 21322618 TI - Magnetic field effects on hydrogen abstraction of thiobenzophenone as a probe of microviscosity. AB - Hydrogen abstraction reactions of thiobenzophenone with thiophenol in solutions of varying viscosities (eta=0.29-42.0 cP) were studied by a nanosecond laser flash photolysis under magnetic fields of 0-15.5 T. In alcoholic solutions, the escaped radical yield (Y) of thiobenzophenone ketyl radical showed appreciable magnetic field effects (MFEs). The observed MFEs can be interpreted with the Deltag mechanism through the triplet radical pair. The relative escaped radical yield (R(1.7T)=Y(1.7T)/Y(0T)) decreased with increasing eta at 00.95-with four distinct structural regimes--isolated water molecules, chain-like water aggregates, bicontinuous system, and isolated ions or small ion clusters--were identified and discussed, including two different percolation limits: that of water in the ionic liquid network (around x(H(2)O)=0.8) and that of the ionic liquid in water (around x(H(2)O)=0.95). PMID- 21322620 TI - Proton NMR based investigation of the effects of temperature and NaCl on micellar properties of CHAPS. AB - The effects of temperature and NaCl on the micellization of CHAPS, a zwitterionic detergent widely used in membrane protein studies, have been investigated by NMR spectroscopy. We found that the two apparent critical micelle concentration (cmc) values of CHAPS decrease with the increase of temperature, as well as the NaCl concentration. The thermodynamic parameters derived from the temperature dependent cmc values show that the micellization process is spontaneous and exothermic, and the van der Waals interaction is likely to be the main factor for the micellization of CHAPS. The micellar hydrodynamic radii remain almost the same in a range of 100-600 mM NaCl, indicating that the aggregate states of CHAPS are not sensitive to the change of the surrounding conditions. In addition, the dependence of nuclear Overhauser effect (NOE) intensities on temperatures further demonstrates the existence of the unique staggered micellar structure of CHAPS at a concentration above the apparent second cmc, which was suggested in our previous work. Our results provide a basis for optimizing CHAPS concentration in the solubilization or stabilization of membrane proteins under nondenaturing conditions and may be helpful to understand its interaction with proteins. PMID- 21322621 TI - Self-assembly behaviors of telechelic poly(styrene-ran-sodium styrenesulfonate) with polyhedral oligomeric silsesquioxane as end groups. AB - The strong ability of polyhedral oligomeric silsesquioxane (POSS) to aggregate in nonsolvents makes it interesting to study the self-assembly behaviors of polymer POSS hybrids. Telechelic poly(styrene-ran-sodium styrenesulfonate) with POSS as the end groups was prepared via end-capping of anionic living polystyrene chains with POSS followed by a mild sulfonation. The morphology and association properties of this new amphiphilic hybrid in an aqueous solution were investigated by dynamic and static light scattering, transmission electron microscopy and atomic force microscopy. The studies reveal that the strong aggregation propensity of POSS leads to a low critical micelle concentration and induces the aggregation of micelles. Hollow supermicellar structures can be observed at a low concentration of 1 mg/mL. PMID- 21322622 TI - Vibronic spectra of jet-cooled 2-aminopurine.H2O clusters studied by UV resonant two-photon ionization spectroscopy and quantum chemical calculations. AB - For understanding the major- and minor-groove hydration patterns of DNAs and RNAs, it is important to understand the local solvation of individual nucleobases at the molecular level. We have investigated the 2-aminopurine.H(2)O monohydrate by two-color resonant two-photon ionization and UV/UV hole-burning spectroscopies, which reveal two isomers, denoted A and B. The electronic spectral shift deltanu of the S(1) <- S(0) transition relative to bare 9H-2 aminopurine (9H-2AP) is small for isomer A (-70 cm(-1)), while that of isomer B is much larger (deltanu = -889 cm(-1)). B3LYP geometry optimizations with the TZVP basis set predict four cluster isomers, of which three are doubly H-bonded, with H(2)O acting as an acceptor to a N-H or -NH2 group and as a donor to either of the pyrimidine N sites. The "sugar-edge" isomer A is calculated to be the most stable form with binding energy D(e) = 56.4 kJ/mol. Isomers B and C are H-bonded between the -NH2 group and pyrimidine moieties and are 2.5 and 6.9 kJ/mol less stable, respectively. Time-dependent (TD) B3LYP/TZVP calculations predict the adiabatic energies of the lowest (1)pipi* states of A and B in excellent agreement with the observed 0(0)(0) bands; also, the relative intensities of the A and B origin bands agree well with the calculated S(0) state relative energies. This allows unequivocal identification of the isomers. The R2PI spectra of 9H-2AP and of isomer A exhibit intense low-frequency out-of-plane overtone and combination bands, which is interpreted as a coupling of the optically excited (1)pipi* state to the lower-lying (1)npi* dark state. In contrast, these overtone and combination bands are much weaker for isomer B, implying that the (1)pipi* state of B is planar and decoupled from the (1)npi* state. These observations agree with the calculations, which predict the (1)npi* above the (1)pipi* state for isomer B but below the (1)pipi* for both 9H-2AP and isomer A. PMID- 21322623 TI - Thermodynamics and kinetics of imidazole formation from glyoxal, methylamine, and formaldehyde: a computational study. AB - Density functional theory calculations, including Poisson-Boltzmann implicit solvent and free energy corrections, are applied to study the mechanism of experimentally observed imidazole formation from the reaction of glyoxal and methylamine in solution. Our calculations suggest that a diimine species is an important intermediate in the reaction. Under acidic conditions, we find that the diimine acts as a nucleophile in attacking the carbonyl group of either formaldehyde or glyoxal to first generate an acyclic enol intermediate, which then goes on to close the ring and form imidazoles. Our results confirm that formaldehyde and, by extension, other small aldehydes are likely to be incorporated into imidazole ions in the presence of glyoxal and primary amines in clouds and aqueous aerosol. This is a new mechanism of aerosol formation by formaldehyde, the most abundant aldehyde in the atmosphere. The amount of aerosol formed will depend on the amounts of glyoxal and amines present. PMID- 21322624 TI - Poly(n-butyl methacrylate) in ionic liquids with tunable lower critical solution temperatures (LCST). AB - We describe the lower critical solution temperature (LCST)-type phase behavior of poly(n-butyl methacrylate) (PnBMA) (M =13,000 and 48,000) dissolved in 1-alkyl-3 methylimidazolium bis{(trifluoromethyl) sulfonyl}amide ionic liquids (ILs). The temperature-composition phase diagrams of these PnBMA/IL systems are strongly asymmetric with the critical composition shifted to low concentrations of PnBMA. As the molecular weight increases from 13,000 to 48,000, the critical temperature decreases by 20 degrees C, and the critical composition shifts to a lower concentration. On the basis of the LCST of PnBMA, we designed a thermosensitive poly(n-butyl methacrylate)-poly(ethylene oxide) (PnBMA-PEO) diblock copolymer that exhibits a free chain/micelle transition in an IL as the temperature increases above the lower critical micellization temperature (LCMT). Furthermore, using IL blends as solvents, both the LCST of PnBMA and the LCMT of PnBMA-PEO can be tuned over a wide range by mixing two different alkyl methylimidazolium ILs without modifying the chemical structure of the polymers. PMID- 21322625 TI - Theoretical study of isomerization and dissociation transition states of C3H5O radical isomers: ab initio characterization of the critical points and statistical transition-state theory modeling of the dynamics. AB - I use coupled-cluster theory and a modest basis set, aug-cc-pVDZ, to calculate structures and harmonic vibrational frequencies of local minima and transition states on the C(3)H(5)O potential energy surface. Accurate energies are computed using explicitly correlated coupled-cluster methods and a large basis set, cc pVQZ-F12, to approach the one-particle basis set limit. My computations characterize eight additional stable radical structures on the global potential energy surface for this system. Additionally, this study encompasses many more isomerization and dissociation pathways, both between previously known intermediates and ones first characterized here. Analysis of the transition states and statistical transition-state theory results shows that energetically small barriers connect many of the alkenol and epoxide intermediates to the straight-chain alkoxy isomers, leading to significant branching to these alkoxy radical intermediates. Facile isomerization to these alkoxy intermediates is significant because the barrier heights leading to H + acrolein and HCO + C(2)H(4) product channels are energetically accessible even at low vibrational energies. The low dissociation barrier heights and loose transition states of these pathways result in unimolecular dissociation as opposed to isomerization to a different C(3)H(5)O intermediate. PMID- 21322626 TI - Ligand exchange reaction involving Ru(III) compounds in aqueous solution: a hybrid quantum mechanical/effective fragment potential study. AB - In this work, the hybrid density functional theory/effective fragment potential (DFT/EFP) approach was applied to investigate the ligand exchange reactions [Ru(NH(3))(4)(Cl)(L)](2+)(aq)+H(2)O->[Ru(NH(3))(4)(H(2)O)(L)](3+)(aq)+Cl(-)(aq) in solution, with L= NH(3) and pyridine (Py). A procedure to generate the EFP water clusters is described. The reaction proceeds through an interchange mechanism with dissociative character, I(d), and displays a high sensitivity to the basicity of the ligand trans to the chloride. Changing the nature of the nitrogenated ligand has a drastic impact on the activation and reaction energy. When ammonia is used, the activation energy, computed at the B3LYP/cc-pVDZ/EFP level of theory is 22.7 kcal/mol, which is ~40% higher than the value of 13.4 kcal/mol computed when for L=Py. In addition, the spontaneity of the reaction changes upon changing the nature of the nitrogenated ligand. Changing the level of theory used in the QM part of the calculation from B3LYP/cc-PVDZ to MP2/cc pVTZ does not change the results appreciably, and inclusion of long-range effects by means of the polarizable continuum model has a negligible effect on the energetic of the reaction. The activation enthalpy computed at the B3LYP/cc pVDZ/EFP is in very good agreement with the experimental findings, attesting to the validity of the QM/EFP approach used in this work. PMID- 21322627 TI - Fluorine environment in bioactive glasses: ab initio molecular dynamics simulations. AB - Fluorinated bioactive glasses (FBGs) combine the antibacterial properties of fluorine with the biological activity of phosphosilicate glasses. Because their biomedical application depends on the release of fluorine, the detailed characterization of the fluorine environment in FBGs is the key to understand their properties. Car-Parrinello molecular dynamics (CPMD) simulations have been performed on a 45S5 Bioglass composition in which 10 mol % of the CaO has been replaced with CaF(2), and have allowed us to resolve some longstanding issues about the atomic structure of fluorinated bioglasses, with particular regard to the structural role of fluorine. F is coordinated almost entirely to the modifier ions Na and Ca, with a very small amount of residual Si-F bonds, whose fraction only becomes significant in the melt precursor. High temperature leads to Si-F bonds in both tetra- (SiO(3)F) and, less frequently, penta-coordinated (SiO(4)F and SiO(3)F(2)) complexes, showing that formation of these bonds through the expansion of the SiO(4) coordination shell is generally less favored. There is no evidence for preferential bonding of F to either modifier ion: almost all F atoms are coordinated to both calcium and sodium in a "mixed state", rather than exclusively to either, as had been conjectured. We discuss the consequences of these findings on the properties of fluorine-containing bioglasses. PMID- 21322628 TI - Climate and health relevant emissions from in-use Indian three-wheelers fueled by natural gas and gasoline. AB - Auto-rickshaws in India use different fuels and engine technologies, with varying emissions and implications for air quality and climate change. Chassis dynamometer emission testing was conducted on 30 in-use auto-rickshaws to quantify the impact of switching from gasoline to compressed natural gas (CNG) in spark-ignition engines. Thirteen test vehicles had two-stroke CNG engines (CNG 2S) and 17 had four-stroke CNG engines (CNG-4S), of which 11 were dual-fuel and operable on a back-up gasoline (petrol) system (PET-4S). Fuel-based emission factors were determined for gaseous pollutants (CO(2), CH(4), NO(X), THC, and CO) and fine particulate matter (PM(2.5)). Intervehicle variability was high, and for most pollutants there was no significant difference (95% confidence level) between "old" (1998-2001) and "new" (2007-2009) age-groups within a given fuel technology class. Mean fuel-based PM(2.5) emission factor (mean (95% confidence interval)) for CNG-2S (14.2 g kg(-1) (6.2-26.7)) was almost 30 times higher than for CNG-4S (0.5 g kg(-1) (0.3-0.9)) and 12 times higher than for PET-4S (1.2 g kg(-1) (0.8-1.7)). Global warming commitment associated with emissions from CNG 2S was more than twice that from CNG-4S or PET-4S, due mostly to CH(4) emissions. Comprehensive measurements and data should drive policy interventions rather than assumptions about the impacts of clean fuels. PMID- 21322629 TI - Effect of advanced aftertreatment for PM and NOx reduction on heavy-duty diesel engine ultrafine particle emissions. AB - Four heavy-duty and medium-duty diesel vehicles were tested in six different aftertreament configurations using a chassis dynamometer to characterize the occurrence of nucleation (the conversion of exhaust gases to particles upon dilution). The aftertreatment included four different diesel particulate filters and two selective catalytic reduction (SCR) devices. All DPFs reduced the emissions of solid particles by several orders of magnitude, but in certain cases the occurrence of a volatile nucleation mode could increase total particle number emissions. The occurrence of a nucleation mode could be predicted based on the level of catalyst in the aftertreatment, the prevailing temperature in the aftertreatment, and the age of the aftertreatment. The particles measured during nucleation had a high fraction of sulfate, up to 62% of reconstructed mass. Additionally the catalyst reduced the toxicity measured in chemical and cellular assays suggesting a pathway for an inverse correlation between particle number and toxicity. The results have implications for exposure to and toxicity of diesel PM. PMID- 21322630 TI - Formation of organic iodine supplied as iodide in a soil-water system in Chiba, Japan. AB - Speciation of iodine in a soil-water system was investigated to understand the mechanism of iodine mobility in surface environments. Iodine speciation in soil and pore water was determined by K-edge XANES and HPLC-ICP-MS, respectively, for samples collected at a depth of 0-12 cm in the Yoro area, Chiba, Japan. Pore water collected at a 0-6 cm depth contained 50%-60% of organic iodine bound to dissolved organic matter, with the other portion being I(-). At a 9-12 cm depth, 98% of iodine was in the form of dissolved I(-). In contrast, XANES analysis revealed that iodine in soil exists as organic iodine at all depths. Iodine mapping of soil grains was obtained using micro-XRF analysis, which also indicated that iodine is bound to organic matter. The activity of laccase, which has the ability to oxidize I(-) to I(2), was high at the surface of the soil water layer, suggesting that iodide oxidizing enzymes can promote iodine organification. The distribution coefficient of organic iodine in the soil-water system was more than 10-fold greater than that of iodide. Transformation of inorganic iodine to organic iodine plays an important role in iodine immobilization, especially in a surface soil-water system. PMID- 21322631 TI - Physical and ecological controls on freshwater floc trace metal dynamics. AB - Significantly higher concentrations of Ag, As, Cu, Co, Ni, and Pb are found in suspended floc compared to surficial bed sediments for a freshwater beach in Lake Ontario. Contrasting observed element-specific bed sediment metal partitioning patterns, floc sequestration for all elements is dominated by one substrate: amorphous oxyhydroxides. More specifically, floc metal scavenging is controlled by floc biogeochemical architecture. Floc organics, largely living microbial cells and associated exopolymeric substances (EPS), act as scaffolds for the collection and/or templating of amorphous Fe oxyhydroxides. While interactions between floc organics and amorphous Fe oxyhydroxides affected floc sorption behavior, specific element affinities and competition for these limited substrates was important for overall floc partitioning. Further, assessment of metal dynamics during stormy conditions indicated energy-regime driven shifts in floc and bed sediment partitioning that were specifically linked to the exchange of floc and bed sedimentary materials. These novel results demonstrate that the microbial nature of floc formation exerts an important control on floc metal dynamics distinguishable from surficial bed sediments and that hydrologic energy regime is an important factor to consider in overall floc metal behavior, especially in beach environments. PMID- 21322633 TI - Divergent reaction pathways of a cationic intermediate: rearrangement and cyclization of 2-substituted furyl and benzofuryl enones catalyzed by iridium(III). AB - In contrast to 2-substituted pyrrole enones, furyl and benzofuryl enones do not undergo the Nazarov electrocyclization. Instead, these furyl and benzofuryl enones exhibit unusual rearrangement sequences in the presence of catalytic amounts of [IrBr(CO)(DIM)((R)-(+)-BINAP)](SbF(6))(2) (1; DIM = diethylisopropylidene malonate) and AgSbF(6) (1:1). A 1,2-H shift followed by intramolecular Friedel-Crafts alkylation leads to synthetically valuable cyclohexanones with furanylic quaternary centers. The electrophilicity of 1 is essential for this rearrangement. PMID- 21322632 TI - Complexation of arsenite with humic acid in the presence of ferric iron. AB - In the presence of iron (Fe), dissolved organic matter (DOM) may bind considerable amounts of arsenic (As), through formation of Fe-bridged As-Fe-DOM complexes and surface complexation of As on DOM-stabilized Fe-colloids (collectively referred to as As-Fe-DOM complexation). However, direct (e.g., chromatographic and spectroscopic) evidence and fundamental kinetic and stability constants have been rarely reported for this As-Fe-DOM complexation. Using a size exclusion chromatography (SEC)-UV-inductively coupled plasma mass spectrometry (ICP-MS) technique, arsenite (As(III))-Fe-DOM complexation was investigated after adding As(III) into the priorly prepared Fe-DOM. A series of evidence, including coelution of As, Fe, and DOM from the SEC column and coretention of As, Fe, and DOM by 3 kDa MWCO centrifugal filtration membrane, demonstrated the occurrence of As(III)-Fe-DOM complexation. The kinetic data of As(III)-Fe-DOM complexation were well described by a pseudofirst order rate equation (R(2) = 0.95), with the rate constant (k') being 0.17 +/- 0.04 1/h. Stability of As(III)-Fe-DOM complexation was characterized by apparent stability constant (K(s)) derived from two-site ligand binding model, with log K(s) ranging from 4.4 +/- 0.2 to 5.6 +/- 0.4. Considering the kinetics (within hours) and stability (similar to typical metal humates) of As(III)-Fe-DOM complexation, this complexation needs to be included when evaluating As mobility in Fe and DOM rich environments. PMID- 21322634 TI - Design, synthesis, and structure-activity relationship of Trypanosoma brucei leucyl-tRNA synthetase inhibitors as antitrypanosomal agents. AB - African trypanosomiasis, caused by the proto zoal pathogen Trypanosoma brucei (T. brucei), is one of the most neglected tropical diseases that are in great need of new drugs. We report the design and synthesis of T. brucei leucyl-tRNA synthetase (TbLeuRS) inhibitors and their structure--activity relationship. Benzoxaborole was used as the core structure and C(6) was modified to achieve improved affinity based on docking results that showed further binding space at this position. Indeed, compounds with C(7) substitutions showed diminished activity due to clash with the eukaryote specific I4ae helix while substitutions at C(6) gave enhanced affinity. TbLeuRS inhibitors with IC(50) as low as 1.6 MUM were discovered, and the structure-activity relationship was discussed. The most potent enzyme inhibitors also showed excellent T. brucei parasite growth inhibition activity. This is the first time that TbLeuRS inhibitors are reported, and this study suggests that leucyl-tRNA synthetase (LeuRS) could be a potential target for antiparasitic drug development. PMID- 21322635 TI - Development of activity-based probes for cathepsin X. AB - Cathepsin X is a lysosomal cysteine protease that functions as a carboxypeptidase with broad substrate specificity. Cathepsin X was discovered only recently, and its physiological roles are still not well understood. A number of studies suggest that cathepsin X may be involved in a variety of biological processes, including cancer, aging and degenerative conditions of the brain, inflammation, and cellular communication. Here we present the synthesis and characterization of several activity-based probes (ABPs) that target active cathepsin X. These ABPs were used to label cathepsin X in complex lysates, whole cells, and in vivo. Furthermore, we have developed a method for selectively labeling and visualizing active cathepsin X in vitro and in vivo. Overall, the probes developed in this study are valuable tools for the study of cathepsin X function. PMID- 21322636 TI - Novel chemically defined approach to produce multipotent cells from terminally differentiated tissue syncytia. AB - In urodele amphibians, a critical step in limb regeneration is the cellularization and dedifferentiation of skeletal muscle. In contrast, mammalian skeletal muscle does not undergo this response to injury. We have developed a novel simple, stepwise chemical method to induce dedifferentiation and multipotency in mammalian skeletal muscle. Optimal muscle fiber cellularization was induced by the trisubstituted purine small molecule, myoseverin, compared to colchicine, nocodazole, or myoseverin B. The induction of a proliferative response in the cellulate was found to be a crucial step in the dedifferentiation process. This was achieved by down-regulation of the cyclin-dependent kinase inhibitor, p21 (CDKN 1A, CIP1). p21 was found to be a key regulator of this process, because down-regulation of the cyclin-dependent kinase inhibitors p27 (CDKN1B/KIP1) or p57 (CDKN1C/KIP2) or the tumor suppressor p53 (TP53/LFS1) failed to induce proliferation and subsequent dedifferentiation. Treatment with the small molecule reversine (2-(4-morpholinoanilino)-6-cyclohexylaminopurine) during this proliferative "window" induced the muscle cellulate to differentiate into non-muscle cell types. This lineage switching was assessed using a relatively stringent approach, based on comparative functional and phenotypic assays of cell type specific properties. This showed that our chemical method allowed the derivation of adipogenic and osteogenic cells that possessed a degree of functionality. This is the first demonstration that mammalian muscle culture can be induced to undergo cellularization, proliferation, and dedifferentiation, which is grossly similar to the key early steps in urodele limb regeneration. These results, based solely on the use of simple chemical approaches, have implications for both regenerative medicine and stem cell biology. PMID- 21322637 TI - Enantioselective organocatalytic aza-ene-type domino reaction leading to 1,4 dihydropyridines. AB - A new general methodology was developed to access highly enantiomerically enriched 1,4-dihydropyridines (DHPs) 3 via an organocatalytic asymmetric aza-ene type cascade reaction, cocatalyzed by (S)-diarylprolinol-TMS ether V and benzoic acid (BA). Both aliphatic and aryl enals 1 reacted smoothly with enaminones and beta-enamino esters 2, affording highly functionalized 1,4-DHPs 3 in high enantioselectivities and good yields. PMID- 21322638 TI - Cell-morphology profiling of a natural product library identifies bisebromoamide and miuraenamide A as actin filament stabilizers. AB - Natural products provide a rich source of biological tools, but elucidating their molecular targets remains challenging. Here we report a cell morphological profiling of a natural product library, which permitted the identification of bisebromoamide and miuraenamide A as actin filament stabilizers. Automated high content image analysis showed that these two structurally distinct marine natural products induce morphological changes in HeLa cells similar to those induced by known actin-stabilizing compounds. Bisebromoamide and miuraenamide A stabilized actin filaments in vitro, and fluorescein-conjugated bisebromoamide localized specifically to actin filaments in cells. Cell morphological profiling was also used to identify actin-stabilizing or -destabilizing natural products from marine sponge extracts, leading to the isolation of pectenotoxin-2 and lyngbyabellin C. Overall, the results demonstrate that high-content imaging of nuclei and cell shapes offers a sensitive and convenient method for detecting and isolating molecules that target actin. PMID- 21322639 TI - High-quality graphene p-n junctions via resist-free fabrication and solution based noncovalent functionalization. AB - An essential issue in graphene nanoelectronics is to engineer the carrier type and density and still preserve the unique band structure of graphene. We report the realization of high-quality graphene p-n junctions by noncovalent chemical functionalization. A generic scheme for the graphene p-n junction fabrication is established by combining the resist-free approach and spatially selective chemical modification process. The effectiveness of the chemical functionalization is systematically confirmed by surface topography and potential measurements, spatially resolved Raman spectroscopic imaging, and transport/magnetotransport measurements. The transport characteristics of graphene p-n junctions are presented with observations of high carrier mobilities, Fermi energy difference, and distinct quantum Hall plateaus. The chemical functionalization of graphene p-n junctions demonstrated in this study is believed to be a feasible scheme for modulating the doping level in graphene for future graphene-based nanoelectronics. PMID- 21322641 TI - Biflavonoids are superior to monoflavonoids in inhibiting amyloid-beta toxicity and fibrillogenesis via accumulation of nontoxic oligomer-like structures. AB - Polymerization of monomeric amyloid-beta peptides (Abeta) into soluble oligomers and insoluble fibrils is one of the major pathways triggering the pathogenesis of Alzheimer's disease (AD). Using small molecules to prevent the polymerization of Abeta peptides can, therefore, be an effective therapeutic strategy for AD. In this study, we investigate the effects of mono- and biflavonoids in Abeta42 induced toxicity and fibrillogenesis and find that the biflavonoid taiwaniaflavone (TF) effectively and specifically inhibits Abeta toxicity and fibrillogenesis. Compared to TF, the monoflavonoid apigenin (AP) is less effective and less specific. Our data show that differential effects of the mono- and biflavonoids in Abeta fibrillogenesis correlate with their varying cytoprotective efficacies. We also find that other biflavonoids, namely, 2',8'' biapigenin, amentoflavone, and sumaflavone, can also effectively inhibit Abeta toxicity and fibrillogenesis, implying that the participation of two monoflavonoids in a single biflavonoid molecule enhances their activity. Biflavonoids, while strongly inhibiting Abeta fibrillogenesis, accumulate nontoxic Abeta oligomeric structures, suggesting that these are off-pathway oligomers. Moreover, TF abrogates the toxicity of preformed Abeta oligomers and fibrils, indicating that TF and other biflavonoids may also reduce the toxicity of toxic Abeta species. Altogether, our data clearly show that biflavonoids, possibly because of the possession of two Abeta binders separated by an appropriate size linker, are likely to be promising therapeutics for suppressing Abeta toxicity. PMID- 21322642 TI - Probing the gate--voltage-dependent surface potential of individual InAs nanowires using random telegraph signals. AB - We report a novel method for probing the gate-voltage dependence of the surface potential of individual semiconductor nanowires. The statistics of electronic occupation of a single defect on the surface of the nanowire, determined from a random telegraph signal, is used as a measure for the local potential. The method is demonstrated for the case of one or two switching defects in indium arsenide (InAs) nanowire field effect transistors at temperatures T=25-77 K. Comparison with a self-consistent model shows that surface potential variation is retarded in the conducting regime due to screening by surface states with density Dss~10(12) cm(-2) eV(-1). Temperature-dependent dynamics of electron capture and emission producing the random telegraph signals are also analyzed, and multiphonon emission is identified as the process responsible for capture and emission of electrons from the surface traps. Two defects studied in detail had capture activation energies of EB~50 meV and EB~110 meV and cross sections of sigmainfinity~3*10(-19) cm2 and sigmainfinity~2*10(-17) cm2, respectively. A lattice relaxation energy of Shomega=187+/-15 meV was found for the first defect. PMID- 21322640 TI - Partitioning of synaptotagmin I C2 domains between liquid-ordered and liquid disordered inner leaflet lipid phases. AB - Synaptotagmin I is the calcium sensor in synchronous neurotransmitter release caused by fusion of synaptic vesicles with the presynaptic membrane in neurons. Synaptotagmin I interacts with acidic phospholipids, but also with soluble N ethylmaleimide-sensitive factor attachment receptors (SNAREs), at various stages in presynaptic membrane fusion. Because SNAREs can be organized into small cholesterol-dependent clusters in membranes, it is important to determine whether the C2 domains of synaptotagmin target membrane domains with different cholesterol contents. To address this question, we used a previously developed asymmetric two-phase lipid bilayer system to investigate the membrane binding and lipid phase targeting of soluble C2A and C2AB domains of synaptotagmin. We found that both domains target more disordered cholesterol-poor domains better than highly ordered cholesterol-rich domains. The selectivity is greatest (~3-fold) for C2A binding to disordered domains that are formed in the presence of 5 mol % PIP(2) and 15 mol % PS. It is smallest (~1.4-fold) for C2AB binding to disordered domains that are formed in the presence of 40 mol % PS. In the course of these experiments, we also found that C2A domains in the presence of Ca(2+) and C2AB domains in the absence of Ca(2+) are quite reliable reporters of the acidic lipid distribution between ordered and disordered lipid phases. Accordingly, PS prefers the liquid-disordered phase over the liquid-ordered phase by ~2-fold, but PIP(2) has an up to 3-fold preference for the liquid-disordered phase. PMID- 21322643 TI - Reduction of N2O and NO generation in anaerobic-aerobic (low dissolved oxygen) biological wastewater treatment process by using sludge alkaline fermentation liquid. AB - This paper reported an efficient method to significantly reduce nitrous oxide (N(2)O) and nitric oxide (NO) generation in anaerobic-aerobic (low dissolved oxygen) processes. It was found that by the use of waste-activated sludge alkaline fermentation liquid as the synthetic wastewater-carbon source, compared with the commonly used carbon source in the literature (e.g., acetic acid), the generation of N(2)O and NO was reduced by 68.7% and 50.0%, respectively, but the removal efficiencies of total phosphorus (TP) and total nitrogen (TN) were improved. Both N(2)O and NO were produced in the low dissolved oxygen (DO) stage, and the use of sludge fermentation liquid greatly reduced their generation from the denitrification. The presences of Cu(2+) and propionic acid in fermentation liquid were observed to play an important role in the reduction of N(2)O and NO generation. The analysis of the activities of denitrifying enzymes suggested that sludge fermentation liquid caused the significant decrease of both nitrite reductase activity to NO reductase activity ratio and NO reductase activity to N(2)O reductase activity ratio, which resulted in the lower generation of NO and N(2)O. Fluorescence in situ hybridization analysis indicated that the number of glycogen accumulating bacteria, which was reported to be relevant to nitrous oxide generation, in sludge fermentation liquid reactor was much lower than that in acetic acid reactor. The quantitative detection of the nosZ gene, encoding nitrous oxide reductase, showed that the use of fermentation liquid increased the number of bacteria capable of reducing N(2)O to N(2). The feasibility of using sludge fermentation liquid to reduce NO and N(2)O generation in an anaerobic-low DO process was finally confirmed for a municipal wastewater. PMID- 21322644 TI - Framework for using quantitative PCR as a nonculture based method to estimate virus infectivity. AB - Measuring the efficiency of virus disinfection with quantitative PCR (qPCR) has been criticized as inadequate due to the production of false-positive signals. Such a claim, however, presupposes an understanding of the theoretical qPCR response. Many studies have assumed that the loss in qPCR signal upon disinfection should equal the loss in infectivity, without accounting for the fact that qPCR typically assays only a fraction of the viral genome. This study aimed to develop a theoretical framework to relate viral infectivity with genome damage measured by qPCR. The framework quantified damage to the entire genome based on the qPCR amplification of smaller sections, assuming single-hit inactivation and a Poissonian distribution of damage. The framework was tested and modified using UV(254) inactivation studies with bacteriophage MS2 (culturing and qPCR of approximately half the genome). Genome regions showed heterogeneous sensitivities to UV(254) treatment, thus deviating from the assumption of Poissonian damage. We offered two modifications to account for these deviations and confirmed that the qPCR-based framework accurately estimated virus infectivity. This framework offers the potential to monitor the infectivity of viruses that remain nonculturable (norovirus). While developed for UV(254) inactivated virus, the framework should apply to any disinfection technique that causes inactivation via single genomic lesions. PMID- 21322645 TI - Maximizing the therapeutic window of an antimicrobial drug by imparting mitochondrial sequestration in human cells. AB - The number of antimicrobial agents available for use in humans is limited by the difficulty of discovering chemical agents with selective toxicity to bacterial targets. Numerous small molecule inhibitors have potential as antimicrobial agents, yet their use has been prevented by high levels of toxic cross-reactivity in human cells. For example, methotrexate (Mtx) is an effective antimetabolite that exerts its effects by inhibiting DHFR. It is a potent antibacterial when accumulated intracellularly, but toxicity in human cells limits clinical utility in infectious disease treatment. Here, we describe peptide conjugates of Mtx that are sequestered into the mitochondria of human cells (mt-Mtx). This alteration in localization of Mtx, which directs it away from its enzyme target, decreases its toxicity in human cells by a factor of 10(3). Mt-Mtx, however, maintains activity against a variety of pathogenic gram-positive organisms, including methicillin resistant Staphylococcus aureus (MRSA). The results from this proof-of-principle study describe a novel methodology for augmenting the antibacterial efficacy of drugs amenable to peptide conjugation while simultaneously decreasing their toxicity to the host organism. PMID- 21322646 TI - A dynamic covalent, luminescent metallopolymer that undergoes sol-to-gel transition on temperature rise. AB - The condensation of linear diamine and dialdehyde subcomponents around copper(I) templates in the presence of bulky trioctylphosphine ancillary ligands gave a linear, conjugated polymeric material in DMSO solution. This polymer solution was observed to undergo sol-to-gel transition as the temperature was raised to 140 degrees C, in contrast with the behavior of most gel-forming polymers, which do so upon cooling. We attribute the sol-to-gel transition to the formation of Cu(I)N(4) cross-links as the equilibria 2[Cu(I)N(2)P(2)] ? [Cu(I)N(4)] + [CuP(n)](+) + (4 - n)P favor the right-hand side at higher temperatures. The material was also observed to exhibit thermochromism and photoluminescence, with the color and intensity of both absorption and emission exhibiting temperature dependence. This material thus responds predictably to combinations of stimuli (heat, light, mechanical shear) in an interconnected way, as is required to generate complex function. PMID- 21322647 TI - Exploring the formation pathways of donor-acceptor catenanes in aqueous dynamic combinatorial libraries. AB - The discovery through dynamic combinatorial chemistry (DCC) of a new generation of donor-acceptor [2]catenanes highlights the power of DCC to access unprecedented structures. While conventional thinking has limited the scope of donor-acceptor catenanes to strictly alternating stacks of donor (D) and acceptor (A) aromatic units, DCC is demonstrated in this paper to give access to unusual DAAD, DADD, and ADAA stacks. Each of these catenanes has specific structural requirements, allowing control of their formation. On the basis of these results, and on the observation that the catenanes represent kinetic bottlenecks in the reaction pathway, we propose a mechanism that explains and predicts the structures formed. Furthermore, the spontaneous assembly of catenanes in aqueous dynamic systems gives a fundamental insight into the role played by hydrophobic effect and donor-acceptor interactions when building such complex architectures. PMID- 21322648 TI - Alterations in the mitochondrial proteome of neuroblastoma cells in response to complex 1 inhibition. AB - Increasing evidence points to mitochondrial dysfunction in Parkinson's disease (PD) associated with complex I dysfunction, but the exact pathways which lead to cell death have not been resolved. 2D-gel electrophoresis profiles of isolated mitochondria from neuroblastoma cells treated with subcytotoxic concentrations of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a well-characterized complex I inhibitor, were assessed to identify associated targets. Up to 27 differentially expressed proteins were observed, of which 16 were identified using peptide mass fingerprinting. Changes in protein levels were validated by immunoprobing 1D blots, confirming increases in heat shock cognate 71 kDa (Hsc70), 60 kDa heat shock protein (Hsp60), fumarase, glutamate oxaloacetate transaminase 2, ATP synthase subunit d, and voltage-dependent anion-channel 1 (VDAC1). Immunoprobing of 2D blots revealed isoform changes in Hsc70, Hsp60, and VDAC1. Subcytotoxic concentrations of MPTP modulated a host of mitochondrial proteins including chaperones, metabolic enzymes, oxidative phosphorylation related proteins, an inner mitochondrial protein (mitofilin), and an outer mitochondrial membrane protein (VDAC1). Early changes in chaperones suggest a regulated link between complex 1 inhibition and protein folding. VDAC1, a multifunctional protein, may have a key role in signaling between mitochondria and the rest of the cell prior to cell death. Our work provides new important information of relevance to PD. PMID- 21322649 TI - Integrated analysis of ATM mediated gene and protein expression impacting cellular metabolism. AB - A major goal of systems biology is to decipher cellular responses to genetic perturbations or environmental changes. Network integration of high-throughput data sets such as transcriptomics, proteomics, and metabolomics ("3-omics") offers a powerful tool for understanding the regulation and organization of cellular functions and biological processes. Given that the ATM (the product of the ataxia-telangiectasia mutated) gene exhibits multifaceted functions involved in complex biological networks, we attempted to analyze "3-omics" data sets by utilizing a functional pathway analysis approach. ATM-mediated gene and protein expression and metabolite products were interrogated using a model system comprised of cells genetically similar but demonstrating ATM deficiency (AT5BIVA) or ATM proficiency (ATCL8). Here, we report an unprecedented finding from the results of this integrated analysis revealing that ATM dictates purine, pyrimidine, and urea cycle pathways through the regulation of adenosine monophosphate (AMP) activated protein kinase (AMPK), a major sensor and regulator of cellular energy homeostasis. Furthermore, our results support the feasibility of applying a systems approach for identification of specific cellular networks and understanding of pathway perturbations underlying the complex A-T clinical syndrome. PMID- 21322650 TI - Advantages of tandem LC-MS for the rapid assessment of tissue-specific metabolic complexity using a pentafluorophenylpropyl stationary phase. AB - In this study, a tandem LC-MS (Waters Xevo TQ) MRM-based MS method was developed for rapid, broad profiling of hydrophilic metabolites from biological samples, in either positive or negative ion modes without the need for an ion pairing reagent, using a reversed-phase pentafluorophenylpropyl (PFPP) column. The developed method was successfully applied to analyze various biological samples from C57BL/6 mice, including urine, duodenum, liver, plasma, kidney, heart, and skeletal muscle. As result, a total 112 of hydrophilic metabolites were detected within 8 min of running time to obtain a metabolite profile of the biological samples. The analysis of this number of hydrophilic metabolites is significantly faster than previous studies. Classification separation for metabolites from different tissues was globally analyzed by PCA, PLS-DA and HCA biostatistical methods. Overall, most of the hydrophilic metabolites were found to have a "fingerprint" characteristic of tissue dependency. In general, a higher level of most metabolites was found in urine, duodenum, and kidney. Altogether, these results suggest that this method has potential application for targeted metabolomic analyzes of hydrophilic metabolites in a wide ranges of biological samples. PMID- 21322651 TI - Search for the tumor-associated proteins of oral squamous cell carcinoma collected in Taiwan using proteomics strategy. AB - Squamous cell carcinoma (SCC) accounts for more than 90% of malignant tumors of the oral cavity. In Taiwan, oral squamous cell carcinoma (OSCC) is among the most frequent malignancies, largely due to betal quid chewing. Despite the recent improvement in treatment results, the long-term outcome of OSCC generally remains poor, especially for those with advanced diseases. It is therefore desirable to identify potential biomarkers that may aid in risk stratification and perhaps the development of therapeutic targets. In this study, we exploited two-dimensional gel electrophoresis (2-DE) coupled with mass spectrometry to compare the proteome maps of 10 OSCC specimens with their adjacent nontumorous epithelia to identify differentially expressed proteins. Comparative proteomics indicated that 17 proteins were differentially expressed in OSCC with 11 up-regulated and 6 down regulated proteins. These deregulated proteins participated in cytoskeletal functions, cell signaling, antiapoptosis, angiogenesis, lipid metabolism, drug metabolism, and protein translation/turnover. They were all associated with tumor development in various cancers. Among the dys-regulated proteins, the immunoexpression of three proteins including nicotinamide N-methyltransferase, apolipoprotein AI, and 14-3-3 zeta were evaluated in 38 OSCCs of testing cohort to confirm the proteomics data. Subsequently, the expression of 14-3-3 zeta, as the most relevant to OSCC progression determined by testing cohort, was further assessed in 80 OSCCs of independent validation cohort to identify the clinical relevance of its expression. By this comprehensive study, we identified 14-3-3 zeta as the only prognosticator of local recurrence-free survival (LRFS) and also an independently predicted factor of disease-specific survival (DSS). PMID- 21322652 TI - Ab initio based surface-hopping dynamics study on ultrafast internal conversion in cyclopropanone. AB - Cyclopropanone exhibits an intriguing phenomenon that the fluorescence from the S(1) state disappears below 365 nm. This is ascribed to the ultrafast S(1) -> S(0) internal conversion process via conical intersection, which deprives opportunity of the fluorescence emission. In this work, we have used ab initio based surface hopping dynamics method to study vibrational-mode-dependent S(1) -> S(0) internal conversion of cyclopropanone. A new conical intersection between the S(1) and S(0) states is determined by the state-averaged CASSCF/cc-pVDZ calculations, which is confirmed to play a critical role in the ultrafast S(1) -> S(0) internal conversion by the nonadiabatic dynamics simulations. It is found that the internal conversion occurs more efficiently when the initial kinetic energies are distributed in the four vibrational modes related to the C?O group, especially in the C-O stretching and the O-C-C-C out-of-plane torsional modes. Meanwhile, the S(1) lifetime and the time scale of the S(1) -> S(0) internal conversion are estimated by the ab initio based dynamics simulations, which is consistent with the ultrafast S(1) -> S(0) internal conversion and provides further evidence that the ultrafast internal conversion is responsible for the fluorescence disappearance of cyclopropanone. PMID- 21322653 TI - Uncommonly high levels of 3-deoxyanthocyanidins and antioxidant capacity in the leaf sheaths of dye sorghum. AB - Extracts from leaf sheaths of farmers' varieties of dye sorghum cultivated and used in Benin as a source of biocolorings were analyzed for their anthocyanidin and phenolic contents, as well as their antioxidant capacity. The aim was to identify and quantify the types of anthocyanin and phenolic acids. The total anthocyanin content of the leaf sheaths ranged from 13.7 to 35.5 mg of cyanidin 3 glucoside equivalent/g of dry matter (DM), with an average of 27.0 mg/g. The total anthocyanin content is 90 times higher than levels usually reported in fruits and vegetables. Anthocyanin consisted essentially of apigeninidin and luteolinidin, two 3-deoxyanthocyanidins with many applications in food, beverage, and pharmaceutical industries. The apigeninidin content of the leaf sheaths was 30 times higher than that in cereal bran and ranged from 14.7 to 45.8 mg/g, with an average of 31.3 mg/g. The amount of luteolinidin ranged from 0.4 to 2.4 mg/g, with a mean of 1.2 mg/g. The total phenolic content expressed as gallic acid equivalent averaged 95.5 mg/g. The free phenolic acids identified were benzoic acid, p-coumaric acid, and o-coumaric acid at amounts of 801.4, 681.6, and 67.9 MUg/g, respectively. The leaf sheaths of dye sorghum have an antioxidant capacity [3.8-5.6 mmol of Trolox equivalent (TE)/g of DM] much higher than that reported for cereal bran and fruits and vegetables. PMID- 21322654 TI - Communication: Accurate determination of side-chain torsion angle chi1 in proteins: phenylalanine residues. AB - Quantitative side-chain torsion angle chi(1) determinations of phenylalanine residues in Desulfovibrio vulgaris flavodoxin are carried out using exclusively the correlation between the experimental vicinal coupling constants and theoretically determined Karplus equations. Karplus coefficients for nine vicinal coupling related with the torsion angle chi(1) were calculated using the B3LYP functional and basis sets of different size. Optimized chi(1) angles are in outstanding agreement with those previously reported by employing x ray and NMR measurements. PMID- 21322655 TI - Constrained active space unrestricted mean-field methods for controlling spin contamination. AB - We have recently proposed a novel approach for obtaining high-spin restricted open-shell Hartree-Fock wave functions by imposing constraints on the unrestricted Hartree-Fock (UHF) method [T. Tsuchimochi and G. E. Scuseria, J. Chem. Phys. 133, 141102 (2010)]. We here extend these ideas to the case where the constraints are released in an active space but imposed elsewhere. If the active space is properly chosen, our constrained UHF (CUHF) method greatly benefits from a controlled broken-symmetry effect while avoiding the massive spin contamination of traditional UHF. We also revisit and apply Lowdin's projection operator to CUHF and obtain multireference wave functions with moderate computational cost. We report singlet-triplet energy splittings showing that our constrained scheme outperforms fully unrestricted methods. This constrained approach can be readily used in spin density functional theory with similar favorable effects. PMID- 21322656 TI - Alkane adsorption in Na-exchanged chabazite: the influence of dispersion forces. AB - The importance of dispersion forces for the correct description of the adsorption of short alkanes in Na-exchanged and purely siliceous chabazite has been investigated at different levels of theory: (i) standard density-functional (DFT) calculations using the Perdew, Burke, and Ernzerhof (PBE) exchange-correlation functional in the generalized gradient approximation, (ii) dispersion corrections based on empirical force fields according to Grimme [J. Computat. Chem. 134, 1463 (2004)- PBE-d], (iii) calculations based on the van der Waals density functional (vdW-DF) proposed by Dion et al. [Phys. Rev. Lett. 92, 246401 (2004)], and (iv) using the random phase approximation (RPA) in combination with the adiabatic connection fluctuation-dissipation theorem (RPA-ACFDT), using wave-functions calculated at the DFT and Hartree-Fock (HF) levels. A full relaxation of the adsorbate-zeolite complex was performed at the PBE, PBE-d, and vdW-DF levels. RPA and RPA-HF energies were calculated for the optimized configurations. A critical analysis of the results shows that the most accurate description is achieved at the RPA level with HF exchange energies, while both PBE-d and vdW-DF overestimate the strength of the interaction with the acid site. PMID- 21322657 TI - The accuracy of dipole moments from spin-component scaled CC2 in ground and electronically excited states. AB - The accuracy of dipole moments calculated from wave function methods based on second-order perturbation theory is investigated in the ground and electronically excited states. Results from the approximate coupled-cluster singles-and-doubles model, CC2, Moller-Plesset perturbation theory, MP2, and the algebraic diagrammatic construction through second-order, ADC(2), are discussed together with the spin-component scaled and the scaled opposite-spin variants of these methods. The computed dipole moments show a very good correlation with data from high-resolution spectroscopy. Compared to the unscaled methods, the spin component scaling increases the accuracy of the results and improves the robustness of the calculations. An accuracy about 0.2 to 0.1 D in the ground state and about 0.3 to 0.2 D in the electronically excited states can be achieved with these approaches. PMID- 21322658 TI - Basis set construction for molecular electronic structure theory: natural orbital and Gauss-Slater basis for smooth pseudopotentials. AB - A simple yet general method for constructing basis sets for molecular electronic structure calculations is presented. These basis sets consist of atomic natural orbitals from a multiconfigurational self-consistent field calculation supplemented with primitive functions, chosen such that the asymptotics are appropriate for the potential of the system. Primitives are optimized for the homonuclear diatomic molecule to produce a balanced basis set. Two general features that facilitate this basis construction are demonstrated. First, weak coupling exists between the optimal exponents of primitives with different angular momenta. Second, the optimal primitive exponents for a chosen system depend weakly on the particular level of theory employed for optimization. The explicit case considered here is a basis set appropriate for the Burkatzki Filippi-Dolg pseudopotentials. Since these pseudopotentials are finite at nuclei and have a Coulomb tail, the recently proposed Gauss-Slater functions are the appropriate primitives. Double- and triple-zeta bases are developed for elements hydrogen through argon. These new bases offer significant gains over the corresponding Burkatzki-Filippi-Dolg bases at various levels of theory. Using a Gaussian expansion of the basis functions, these bases can be employed in any electronic structure method. Quantum Monte Carlo provides an added benefit: expansions are unnecessary since the integrals are evaluated numerically. PMID- 21322659 TI - Convergence of vibrational angular momentum terms within the Watson Hamiltonian. AB - Vibrational angular momentum terms within the Watson Hamiltonian are often considered negligible or are approximated by the zeroth order term of an expansion of the inverse of the effective moment of inertia tensor. A multimode expansion of this tensor up to second order has been used to study the impact of first and second order terms on the vibrational transitions of N(2)H(2) and HBeH(2)BeH. Comparison with experimental data is provided. The expansion of the tensor can be exploited to introduce efficient prescreening techniques. PMID- 21322660 TI - Bottom-up coarse-graining of a simple graphene model: the blob picture. AB - The coarse-graining of a simple all-atom 2D microscopic model of graphene, in terms of "blobs" described by center of mass variables, is presented. The equations of motion of the coarse-grained variables take the form of dissipative particle dynamics (DPD). The coarse-grained conservative forces and the friction of the DPD model are obtained via a bottom-up procedure from molecular dynamics (MD) simulations. The separation of timescales for blobs of 24 and 96 carbon atoms is sufficiently pronounced for the Markovian assumption, inherent to the DPD model, to provide satisfactory results. In particular, the MD velocity autocorrelation function of the blobs is well reproduced by the DPD model, provided that the effect of friction and noise is taken into account. However, DPD cross-correlations between neighbor blobs show appreciable discrepancies with respect to the MD results. Possible extensions to mend these discrepancies are briefly outlined. PMID- 21322661 TI - Treecode-based generalized Born method. AB - We have developed a treecode-based O(N log N) algorithm for the generalized Born (GB) implicit solvation model. Our treecode-based GB (tGB) is based on the GBr6 [J. Phys. Chem. B 111, 3055 (2007)], an analytical GB method with a pairwise descreening approximation for the R6 volume integral expression. The algorithm is composed of a cutoff scheme for the effective Born radii calculation, and a treecode implementation of the GB charge-charge pair interactions. Test results demonstrate that the tGB algorithm can reproduce the vdW surface based Poisson solvation energy with an average relative error less than 0.6% while providing an almost linear-scaling calculation for a representative set of 25 proteins with different sizes (from 2815 atoms to 65456 atoms). For a typical system of 10k atoms, the tGB calculation is three times faster than the direct summation as implemented in the original GBr6 model. Thus, our tGB method provides an efficient way for performing implicit solvent GB simulations of larger biomolecular systems at longer time scales. PMID- 21322662 TI - Geometric phase for collinear conical intersections. I. Geometric phase angle and vector potentials. AB - We present a method for properly treating collinear conical intersections in triatomic systems. The general vector potential (gauge theory) approach for including the geometric phase effects associated with collinear conical intersections in hyperspherical coordinates is presented. The current study develops an introductory method in the treatment of collinear conical intersections by using the phase angle method. The geometric phase angle, eta, in terms of purely internal coordinates is derived using the example of a spin aligned quartet lithium triatomic system. A numerical fit and thus an analytical form for the associated vector potentials are explicitly derived for this triatomic A(3) system. The application of this methodology to AB(2) and ABC systems is also discussed. PMID- 21322663 TI - A general set of order parameters for molecular crystals. AB - Crystallization is fundamental to many aspects of physics and chemistry in addition to being of technological relevance, for example, in the chemical, food, and pharmaceutical industries. However, the design of crystalline materials and crystallization processes is often challenging due to the many variables that can influence the process. As a part of an effort to gain a molecular-level understanding of the way molecules aggregate and organize themselves into crystal structures, in this work we present a new method to construct order parameters suitable for the study of crystallization and polymorph transformations in molecular systems. Our order parameters can be systematically defined for complex systems using information that can be obtained from simple molecular dynamics simulations of the crystals. We show how to construct the order parameters for the study of three different systems: the formation of alpha-glycine crystals in solution, the crystallization of benzene from the melt, and the polymorph transformation of terephthalic acid. Finally, we suggest how these order parameters could be used to study order-disorder transitions in molecular systems. PMID- 21322664 TI - Implementation of Lees-Edwards periodic boundary conditions for direct numerical simulations of particle dispersions under shear flow. AB - A general methodology is presented to perform direct numerical simulations of particle dispersions in a shear flow with Lees-Edwards periodic boundary conditions. The Navier-Stokes equation is solved in oblique coordinates to resolve the incompatibility of the fluid motions with the sheared geometry, and the force coupling between colloidal particles and the host fluid is imposed by using a smoothed profile method. The validity of the method is carefully examined by comparing the present numerical results with experimental viscosity data for particle dispersions in a wide range of volume fractions and shear rates including nonlinear shear-thinning regimes. PMID- 21322665 TI - Accurate and efficient algorithm for Bader charge integration. AB - We propose an efficient, accurate method to integrate the basins of attraction of a smooth function defined on a general discrete grid and apply it to the Bader charge partitioning for the electron charge density. Starting with the evolution of trajectories in space following the gradient of charge density, we derive an expression for the fraction of space neighboring each grid point that flows to its neighbors. This serves as the basis to compute the fraction of each grid volume that belongs to a basin (Bader volume) and as a weight for the discrete integration of functions over the Bader volume. Compared with other grid-based algorithms, our approach is robust, more computationally efficient with linear computational effort, accurate, and has quadratic convergence. Moreover, it is straightforward to extend to nonuniform grids, such as from a mesh-refinement approach, and can be used to both identify basins of attraction of fixed points and integrate functions over the basins. PMID- 21322666 TI - Two-dimensional replica exchange approach for peptide-peptide interactions. AB - The replica exchange molecular dynamics (REMD) method has emerged as a standard approach for simulating proteins and peptides with rugged underlying free energy landscapes. We describe an extension to the original methodology--here termed umbrella-sampling REMD (UREMD)--that offers specific advantages in simulating peptide-peptide interactions. This method is based on the use of two dimensions in the replica cascade, one in temperature as in conventional REMD, and one in an umbrella sampling coordinate between the center of mass of the two peptides that aids explicit exploration of the complete association-dissociation reaction coordinate. To mitigate the increased number of replicas required, we pursue an approach in which the temperature and umbrella dimensions are linked at only fully associated and dissociated states. Coupled with the reweighting equations, the UREMD method aids accurate calculations of normalized free energy profiles and structural or energetic measures as a function of interpeptide separation distance. We test the approach on two families of peptides: a series of designed tetrapeptides that serve as minimal models for amyloid fibril formation, and a fragment of a classic leucine zipper peptide and its mutant. The results for these systems are compared to those from conventional REMD simulations, and demonstrate good convergence properties, low statistical errors, and, for the leucine zippers, an ability to sample near-native structures. PMID- 21322667 TI - Double-hybrid density-functional theory made rigorous. AB - We provide a rigorous derivation of a class of double-hybrid approximations, combining Hartree-Fock exchange and second-order Moller-Plesset correlation with a semilocal exchange-correlation density functional. These double-hybrid approximations contain only one empirical parameter and use a density-scaled correlation energy functional. Neglecting density scaling leads to a one parameter version of the standard double-hybrid approximations. We assess the performance of these double-hybrid schemes on representative test sets of atomization energies and reaction barrier heights, and we compare to other hybrid approximations, including range-separated hybrids. Our best one-parameter double hybrid approximation, called 1DH-BLYP, roughly reproduces the two parameters of the standard B2-PLYP or B2GP-PLYP double-hybrid approximations, which shows that these methods are not only empirically close to an optimum for general chemical applications but are also theoretically supported. PMID- 21322668 TI - Direct perturbation theory in terms of energy derivatives: fourth-order relativistic corrections at the Hartree-Fock level. AB - In this work, the quantum-chemical treatment of relativistic effects by means of direct perturbation theory is extended from its lowest order, DPT2, to the next higher order, DPT4. The required theory is given in terms of energy derivatives with the DPT4 energy correction defined as the corresponding second derivative with respect to the relativistic perturbation parameter lambda(rel) = c(2) and c as the speed of light. To facilitate the implementation in standard quantum chemical program packages, a general formulation of DPT starting from a nonrelativistic Lagrangian is developed, thereby expanding both wave function and operators in terms of lambda(rel). The corresponding expressions, which incorporate in an additive manner scalar-relativistic and spin-orbit contributions, are given at the Hartree-Fock level and have been implemented in the CFOUR program package using the available analytic second-derivative techniques. The accuracy of the DPT4 corrections at the HF level is investigated by comparison with rigorous four-component calculations. Scalar-relativistic and spin-orbit contributions are analyzed individually and the importance of the various terms to those corrections is discussed. Furthermore, the basis-set dependence of the computed DPT4 corrections is investigated. PMID- 21322669 TI - Pair correlation function of soft-sphere fluids. AB - A closed-form analytic formula for the radial distribution function (RDF) or g(r) of inverse power fluids is proposed. The RDF is expressed as a sum of separate component functions, one monotonic and a series of exponentially damped oscillatory functions. Unlike previous treatments in the literature, this formula does not rely on patching different functional forms at arbitrary crossover distances. This expression, which we refer to as g(M)(r), yields the expected asymptotic behavior at large distance and reproduces the main features of the RDF generated by molecular dynamics (MD) simulations. The g(M) is applied to the soft n = 4 inverse power fluid, and it is shown that in this case seven or fewer terms are sufficient to represent accurately the MD-generated RDF over the entire fluid domain. The relative contributions of the separate terms of the g(M) as a function of density are analyzed and discussed. The key role played by the monotonic component function and two oscillatory terms is demonstrated. The origin of the crossover from the oscillatory to the monotonic behavior is shown to be the same as that recently proposed by Evans and Henderson [R. Evans and J. R. Henderson, J. Phys.: Condens. Matter 21, 474220 (2009)] for the dispersion interactions. PMID- 21322670 TI - Extended hydrodynamic approach to quantum-classical nonequilibrium evolution. I. Theory. AB - A mixed quantum-classical formulation is developed for a quantum subsystem in strong interaction with an N-particle environment, to be treated as classical in the framework of a hydrodynamic representation. Starting from the quantum Liouville equation for the N-particle distribution and the corresponding reduced single-particle distribution, exact quantum hydrodynamic equations are obtained for the momentum moments of the single-particle distribution coupled to a discretized quantum subsystem. The quantum-classical limit is subsequently taken and the resulting hierarchy of equations is further approximated by various closure schemes. These include, in particular, (i) a Grad-Hermite-type closure, (ii) a Gaussian closure at the level of a quantum-classical local Maxwellian distribution, and (iii) a dynamical density functional theory approximation by which the hydrodynamic pressure term is replaced by a free energy functional derivative. The latter limit yields a mixed quantum-classical formulation which has previously been introduced by I. Burghardt and B. Bagchi, Chem. Phys. 134, 343 (2006). PMID- 21322671 TI - Very accurate potential energy curve of the LiH molecule. AB - We present very accurate calculations of the ground-state potential energy curve (PEC) of the LiH molecule performed with all-electron explicitly correlated Gaussian functions with shifted centers. The PEC is generated with the variational method involving simultaneous optimization of all Gaussians with an approach employing the analytical first derivatives of the energy with respect to the Gaussian nonlinear parameters (i.e., the exponents and the coordinates of the shifts). The LiH internuclear distance is varied between 1.8 and 40 bohrs. The absolute accuracy of the generated PEC is estimated as not exceeding 0.3 cm(-1). The adiabatic corrections for the four LiH isotopologues, i.e., (7)LiH, (6)LiH, (7)LiD, and (6)LiD, are also calculated and added to the LiH PEC. The aforementioned PECs are then used to calculate the vibrational energies for these systems. The maximum difference between the computed and the experimental vibrational transitions is smaller than 0.9 cm(-1). The contribution of the adiabatic correction to the dissociation energy of (7)LiH molecule is 10.7 cm( 1). The magnitude of this correction shows its importance in calculating the LiH spectroscopic constants. As the estimated contribution of the nonadiabatic and relativistic effects to the ground state dissociation energy is around 0.3 cm( 1), their inclusion in the LiH PEC calculation seems to be the next most important contribution to evaluate in order to improve the accuracy achieved in this work. PMID- 21322672 TI - Dynamics of fluid mixtures in nanospaces. AB - A multicomponent extension of our recent theory of simple fluids [U. M. B. Marconi and S. Melchionna, J. Chem. Phys. 131, 014105 (2009)] is proposed to describe miscible and immiscible liquid mixtures under inhomogeneous, nonsteady conditions typical of confined fluid flows. We first derive from a microscopic level the evolution equations of the phase space distribution function of each component in terms of a set of self-consistent fields, representing both body forces and viscous forces (forces dependent on the density distributions in the fluid and on the velocity distributions). Second, we numerically solve the resulting governing equations by means of the lattice Boltzmann method, whose implementation contains novel features with respect to existing approaches. Our model incorporates hydrodynamic flow, diffusion, surface tension, and the possibility for global and local viscosity variations. We validate our model by studying the bulk viscosity dependence of the mixture on concentration, packing fraction, and size ratio. Finally, we consider inhomogeneous systems and study the dynamics of mixtures in slits of molecular thickness and relate structural and flow properties. PMID- 21322673 TI - Comparison of the experimental, semi-experimental and ab initio equilibrium structures of acetylene: influence of relativisitic effects and of the diagonal Born-Oppenheimer corrections. AB - The equilibrium structure of acetylene (also named ethyne) has been reinvestigated to resolve the small discrepancies noted between different determinations. The size of the system as well as the large amount of available experimental data provides the quite unique opportunity to check the magnitude and relevance of various contributions to equilibrium structure as well as to verify the accuracy of experimental results. With respect to pure theoretical investigation, quantum-chemical calculations at the coupled-cluster level have been employed together with extrapolation to the basis set limit, consideration of higher excitations in the cluster operator, inclusion of core correlation effects as well as relativistic and diagonal Born-Oppenheimer corrections. In particular, it is found that the extrapolation to the complete basis set limit, the inclusion of higher excitations in the electronic-correlation treatment and the relativistic corrections are of the same order of magnitude. It also appears that a basis set as large as a core-valence quintuple-zeta set is required for accurately accounting for the inner-shell correlation contribution. From a pure experimental point of view, the equilibrium structure has been determined using very accurate rotational constants recently obtained by a "global analysis" (that is to say that all non-negligible interactions are explicitly included in the Hamiltonian matrix) of rovibrational spectra. Finally, a semi-experimental equilibrium structure (where the equilibrium rotational constants are obtained from the experimental ground state rotational constants and computed rovibrational corrections) has been obtained from the available experimental ground-state rotational constants for ten isotopic species corrected for computed vibrational corrections. Such a determination led to the revision of the ground state rotational constants of two isotopologues, thus showing that structural determination is a good method to identify errors in experimental rotational constants. The three structures are found in a very good agreement, and our recommended values are r(CC) = 120.2958(7) pm and r(CH) = 106.164(1) pm. PMID- 21322674 TI - Photodissociation dynamics of H2O: effect of unstable resonances on the B(1)A1 electronic state. AB - We report a tunable vacuum ultraviolet photodissociation study of H(2)O from different unstable resonances in the B(1)A(1) electronic state, using the H-atom Rydberg tagging technique. The quantum state resolved OH product translational energy distributions and angular distributions have been measured. Experimental results illustrate, for the first time, that excitation to the different unstable resonances has very different effect on the OH(X) and OH(A) product channels. The OH(X) product rotational distributions vary only slightly, while the OH(A) product rotational distributions and state-resolved angular distributions change dramatically as the photolysis energy increases. Effect of parent rotational excitation on the OH(A) product has also been observed. Through careful simulations to the experimental spectra, OH(A)/OH(X) branching ratios have been determined at five photolysis wavelengths. The general agreement between theory and experiment in the branching ratios is good. The branching ratios for the OH(A) product from different parent rotational levels are close to the nuclear spin-statistics value, which is also consistent with the extremely low rotational temperature of the H(2)O beam in the current experiment. PMID- 21322675 TI - The C-H bond dissociation energy of furan: photoelectron spectroscopy of the furanide anion. AB - Using photoelectron spectroscopy, we interrogate the cyclic furanide anion (C(4)H(3)O(-)) to determine the electron affinity and vibrational structure of the neutral furanyl radical and the term energy of its first excited electronic state. We present the 364-nm photoelectron spectrum of the furanide anion and measure the electron affinity of the X(2)A(') ground state of the alpha-furanyl radical to be 1.853(4) eV. A Franck-Condon analysis of the well-resolved spectrum allows determination of the harmonic frequencies of three of the most active vibrational modes upon X(2)A(') <- X(1)A(') photodetachment: 855(25), 1064(25), and 1307(40) cm(-1). These modes are ring deformation vibrations, consistent with the intuitive picture of furanide anion photodetachment, where the excess electron is strongly localized on the alpha-carbon atom. In addition, the A(2)A('') excited state of the alpha-furanyl radical is observed 0.68(7) eV higher in energy than the X(2)A(') ground state. Through a thermochemical cycle involving the known gas-phase acidity of furan, the electron affinity of the furanyl radical yields the first experimental determination of the C-H(alpha) bond dissociation energy of furan (DH(298)(C(4)H(3)O-H(alpha))): 119.8(2) kcal mol(-1). PMID- 21322676 TI - On the relation between the activation energy for electron attachment reactions and the size of their thermal rate coefficients. AB - Rate coefficients k(T) for dissociative electron attachment (DEA) to molecules in many cases exhibit a more or less strong rise with increasing temperature T (the electron temperature T(e) and the molecular temperature T(G) are assumed to be in thermal equilibrium, i.e., T = T(e) = T(G)). This rise is frequently modeled by the Arrhenius equation k(T) = k(A) exp[-E(a)/(k(B)T)], and an activation energy E(a) is deduced from fits to the experimental data k(T). This behavior reflects the presence of an energy barrier for the anion on its path to the dissociated products. In a recent paper [J. Kopyra, J. Wnorowska, M. Forys, and I. Szamrej, Int. J. Mass Spectrom. 268, 60 (2007)] it was suggested that the size of the rate coefficients for DEA reactions at room temperature exhibits an exponential dependence on the activation energy, i.e., k(E(a); T ~ 300 K) = k(1) exp[ E(a)/E(0)]. More recent experimental data for molecules with high barriers [T. M. Miller, J. F. Friedman, L. C. Schaffer, and A. A. Viggiano, J. Chem. Phys. 131, 084302 (2009)] are compatible with such a correlation. We investigate the validity and the possible origin of this dependence by analyzing the results of R matrix calculations for temperature-dependent rate coefficients of exothermic DEA processes with intermediate barrier toward dissociation. These include results for model systems with systematically varied barrier height as well as results of molecule-specific calculations for CH(3)Cl, CH(3)Br, CF(3)Cl, and CH(2)Cl(2) (activation energies above 0.2 eV) involving appropriate molecular parameters. A comparison of the experimental and theoretical results for the considered class of molecules (halogenated alkanes) supports the idea that the exponential dependence of k(T = 300 K) on the activation energy reflects a general phenomenon associated with Franck-Condon factors for getting from the initial neutral vibrational levels to the dissociating final anion state in a direct DEA process. Cases are discussed for which the proposed relation does not apply. PMID- 21322677 TI - Quantum chemical assessment of the binding energy of CuO+. AB - We present a detailed theoretical investigation on the dissociation energy of CuO(+), carried out by means of coupled cluster theory, the multireference averaged coupled pair functional (MR-ACPF) approach, diffusion quantum Monte Carlo (DMC), and density functional theory (DFT). At the respective extrapolated basis set limits, most post-Hartree-Fock approaches agree within a narrow error margin on a D(e) value of 26.0 kcal mol(-1) [coupled-cluster singles and doubles level augmented by perturbative triples corrections, CCSD(T)], 25.8 kcal mol(-1) (CCSDTQ via the high accuracy extrapolated ab initio thermochemistry protocol), and 25.6 kcal mol(-1) (DMC), which is encouraging in view of the disaccording data published thus far. The configuration-interaction based MR-ACPF expansion, which includes single and double excitations only, gives a slightly lower value of 24.1 kcal mol(-1), indicating that large basis sets and triple excitation patterns are necessary ingredients for a quantitative assessment. Our best estimate for D(0) at the CCSD(T) level is 25.3 kcal mol(-1), which is somewhat lower than the latest experimental value (D(0) = 31.1 +/- 2.8 kcal mol( 1)[semicolon] reported by the Armentrout group) [Int. J. Mass Spectrom. 182/183, 99 (1999)]. These highly correlated methods are, however, computationally very demanding, and the results are therefore supplemented with those of more affordable DFT calculations. If used in combination with moderately-sized basis sets, the M05 and M06 hybrid functionals turn out to be promising candidates for studies on much larger systems containing a [CuO](+) core. PMID- 21322678 TI - Mechanically induced generation of highly reactive excited-state oxygen molecules in cluster scattering. AB - Molecular electronic excitation in (O(2))(n) clusters induced by mechanical collisions via the "chemistry with a hammer" is investigated by a combination of molecular dynamics simulations and quantum chemistry calculations. Complete active space self-consistent field augmented with triple-zeta polarizable basis set quantum chemistry calculations of a compressed (O(2))(2) cluster model in various configurations reveal the emergence of possible pathways for the generation of electronically excited singlet O(2) molecules upon cluster compression and vibrational excitation, due to electronic curve-crossing and spin orbit coupling. Extrapolation of the model (O(2))(2) results to larger clusters suggests a dramatic increase in the population of electronically excited O(2) products, and may account for the recently observed cluster-catalyzed oxidation of silicon surfaces, via singlet oxygen generation induced by cluster impact, followed by surface reaction of highly reactive singlet O(2) molecules. Extensive molecular dynamics simulations of (O(2))(n) clusters colliding onto a hot surface indeed reveal that cluster compression is sufficient under typical experimental conditions for nonadiabatic transitions to occur. This work highlights the importance of nonadiabatic effects in the "chemistry with a hammer." PMID- 21322679 TI - Photoionization of epichlorohydrin enantiomers and clusters studied with circularly polarized vacuum ultraviolet radiation. AB - The photoionization of enantiomerically pure epichlorohydrin (C(3)H(5)OCl) has been studied using linearly and circularly polarized vacuum ultraviolet synchrotron radiation. The threshold photoelectron spectrum was recorded and the first three bands assigned using molecular orbital calculations for the expected conformers, although uncertain experimental conformer populations and an anticipated breakdown in Koopmans' theorem leave some ambiguity. Measurements of the photoelectron circular dichroism (PECD) were obtained across a range of photon energies for each of these bands, using electron velocity map imaging to record the angular distributions, during which a record PECD chiral asymmetry factor of 32% was observed. A comparison with calculated PECD curves clarifies the assignment achieved using ionization energies alone and further suggests a likely relative population of the conformers. Threshold photoelectron-photoion coincidence methods were used to study the ionic fragmentation of epichlorohydrin. Fragment ion appearance energies show nonstatistical behavior with clear indications that the cationic epoxide ring is unstable and lower energy decay channels proceeding via ring breaking are generally open. Extensive neutral homochiral clusters of epichlorohydrin may be formed in supersonic molecular beam expansions seeded in Ar. Electron angular distribution measurements made in coincidence with dimer and trimer ions are used to effect an examination of the PECD associated with ionization of size-selected neutral cluster species, and these results differ clearly from PECD of the neutral monomer. The shifted ionization thresholds of the n-mers (n = 2, ..., 7) are shown to follow a simple linear relationship, but under intense beam expansion conditions the monomer deviates from this relationship, and the monomer electron spectra tail to below the expected monomer adiabatic ionization potential (IP). PECD measurements made in coincidence with monomer ions obtained under different beam expansion conditions were used to identify unambiguously a contribution from dissociative photoionization of larger clusters to the monomer parent mass ion yield above and below its adiabatic IP. PMID- 21322680 TI - Experimental and theoretical study on generalized oscillator strengths of the valence-shell electronic excitations in CF4. AB - We report an angle-resolved electron energy loss spectroscopy (EELS) study on the valence-shell electronic excitations in CF(4). Experimentally momentum-transfer dependent generalized oscillator strengths (GOSs) or GOS profiles for low-lying electronic excitations at 12.6, 13.8, and 14.8 eV are derived from EELS spectra measured at an incident electron energy of 3 keV. We also calculate GOS profiles using theoretical wave functions at the equation-of-motion coupled cluster singles and doubles level. There are good agreements between experiment and theory except for a significant discrepancy at small momentum transfer for the 1t(l) -> 3s Rydberg excitation at 12.6 eV. The experimental GOS profile for 1t(l) -> 3s exhibits a shape that is typical of a dipole allowed transition, while the excitation is formally dipole forbidden. This symmetry breaking behavior is rationally accounted for by qualitatively analyzing the nature of vibronic coupling effects. For the excitation band at 13.8 eV, a shoulder and extrema are observed in the GOS profile and are then found to be mainly due to the 2(1)T(2) transition. Furthermore, the theoretical GOS profile for the 2(1)T(2) transition exhibits a remarkable oscillatory pattern; its origin is discussed by considering multicenter interference effects. For the 14.8 eV excitation band, the predominant nondipole nature of the underlying transitions are revealed and comparisons with the theoretical calculations show that major contributions to this band come from the 4t(2) -> 3p excitation. PMID- 21322681 TI - Experimental study of the asymmetric charge transfer reaction between Ar+ ions and Fe atoms. AB - We investigate the Ar(+)-Fe asymmetric charge transfer (ACT) reaction using a combination of plasma diagnostics methods and a kinetic model of the afterglow plasma, which allow monitoring of the temporal evolution of the densities of different species. The iron vapor is created inside a discharge cell by cathode sputtering; its density is measured by atomic absorption spectroscopy. The rate coefficient of the reaction is evaluated from the emission intensity decay of Fe(+)* lines pumped by the ACT process in the He-Ar-Fe and Ar-Fe afterglow plasmas. The measurements yield a rate coefficient k = 7.6( +/- 3.0) * 10(-9) cm(3) s(-1) at T = 300 K. PMID- 21322682 TI - On the structure of the matrix isolated water trimer. AB - Infrared spectra of partially deuterated water trimers have been investigated. It is found that HDO(H(2)O)(2) has a single, bound OD stretching fundamental, (HDO)(2)H(2)O two bound OD stretches. (HDO)(3) has a single, bound OD stretch and (H(2)O)(3) has a pair of bound OH stretches. Ab initio and discrete Fourier transform (DFT) calculations predict that the water trimer has C(1) symmetry with six different, isoenergetic minima. These calculations consequently give three numerically different OD stretches for HDO(H(2)O)(2), six for (HDO)(2)H(2)O, three for (HDO)(3), and three bound OH stretches for (H(2)O)(3). The connection between the observations and the pseudorotation of the trimer is discussed with the help of Wales' pseudorotation model. It is found that pseudorotation is sufficiently fast to average the effective symmetry of the A(3) trimer to C(3h) and to eliminate the difference between the different ab initio minima for A(2)B. The only exception is (H(2)O)(3) where the splitting between the different bound OH stretches is largest. Here a doublet is observed due to incomplete averaging. DFT calculations indicate that the D-bonded form of HDO(H(2)O)(2) is between 50 and 60 cm(-1) more stable than the H-bonded form. The energy difference is determined by differences in zero point vibration energy of intermolecular librations of the two forms. Attempts to measure the energy difference indicate that the energy difference is larger, of the order of 100 cm(-1). PMID- 21322683 TI - Existence of an exceptional reaction pathway for H3(+) formation observed in collision-induced dissociation of methane ions at 1000 eV. AB - Dissociation of CH(4)(+) ions at 1000 eV induced by collision with Ar atoms was investigated by measuring the kinetic energies of the ionized fragments. At small scattering angles, including zero, H(+), H(2)(+), H(3)(+), CH(3)(+), CH(2)(+), CH(+), and C(+) fragments were observed. The attractive part of the potential in the CH(4)(+)-Ar collision system played an important role in the formation of the ionized fragments. Rainbow scattering, leading to a large scattering cross section, was shown to be responsible for the increased formation of H(3)(+). It is proposed that on collision-induced dissociation of CH(4)(+), its three hydrogen atoms, which form a triangle, simultaneously react and move together to form H(3)(+). PMID- 21322684 TI - Electron excitation of the Schumann-Runge continuum, longest band, and second band electronic states in O2. AB - We report measurements of differential and integral cross sections for electron excitation of the Schumann-Runge continuum, longest band, and second band electronic states in molecular oxygen. The energy range of the present study is 15-200 eV, with the angular range of the differential cross section (DCS) measurements from 2 to 130 degrees . A generalized oscillator strength analysis is then employed in order to derive integral cross sections (ICSs) from the corresponding DCSs, and these ICSs are compared with relevant energy and oscillator strength scaled Born cross section (BEf-scaling [Y.-K. Kim, J. Chem. Phys. 126, 064305 (2007)]) results determined as a part of this investigation. Interestingly, while the present Schumann-Runge continuum and second band ICSs were in reasonable agreement with the respective BEf-scaling results, agreement for the longest band was poor below 100 eV with a possible reason for this apparently anomalous behavior being canvassed here. Finally, where possible all present data are compared with the results from earlier measurements and calculations with the level of agreement found being very good in some cases and marginal in others. PMID- 21322685 TI - H+ versus D+ transfer from HOD+ to CO2: bond-selective chemistry and the anomalous effect of bending excitation. AB - Reactions of HOD(+) with CO(2) have been studied for HOD(+) in its ground state, and with one quantum of excitation in each of its vibrational modes: (001)- predominantly OH stretch, 0.396 eV; (010)--bend, 0.153 eV; and (100)- predominantly OD stretch, 0.293 eV. Integral cross sections and product recoil velocities were recorded for collision energies from threshold to 3 eV. The cross sections for both H(+) and D(+) transfer rise with increasing collision energy from threshold to ~1 eV, then become weakly dependent of the collision energy. All three vibrational modes enhance the total reactivity, but quite mode specifically. The H(+) transfer reaction is enhanced by OH stretch excitation, whereas OD stretch excitation has little effect. Conversely, the D(+) transfer reaction is enhanced by OD stretch excitation, while the OH stretch has little effect. Excitation of the bend strongly enhances both channels. The effects of the stretch excitations are consistent with previous studies of neutral HOD mode selective chemistry, and can be at least qualitatively understood in terms of a late barrier to product formation. The fact that bend excitation produces the largest overall enhancement is surprising, because this is the lowest energy excitation, and is not obviously connected with the reaction coordinates for either H(+) or D(+) transfer. A rationalization in terms of the effects of water distortion on the potential surface is proposed. PMID- 21322686 TI - Photodissociation of N2O: potential energy surfaces and absorption spectrum. AB - The ultraviolet photodissociation of N(2)O is studied by wave packet calculations using global three-dimensional potential energy surfaces for the two lowest (1)A' states. The incorporation of all internal degrees of freedom in the dynamics calculations is essential for a realistic treatment. The room-temperature absorption cross section is well reproduced, including the weak vibrational structures. Classical periodic orbits show that the latter can be attributed to large-amplitude NN stretch motion combined with strong excitation of the bend. Weakening of the NN bond toward the N + NO channel is the necessary prerequisite. The temperature dependence of the calculated cross section is significant, as expected for a dipole-forbidden transition of a linear molecule; but it is not as strong as observed experimentally [G. S. Selwyn and H. S. Johnston, J. Chem. Phys. 74, 3791 (1981)]. This shortcoming is due to an apparent underestimation of the (0,1,0) hot band absorption. On the other hand, the calculations yield reasonable predictions of the ratios of bending-state resolved absorption cross sections, sigma(0, 1, 0)/sigma(0, 0, 0) and sigma(0, 2, 0)/sigma(0, 0, 0), measured at 204 nm [H. Kawamata et al. J. Chem. Phys. 125, 133312 (2006)]. PMID- 21322687 TI - High resolution slit-jet infrared spectroscopy of ethynyl radical: 2Pi-2Sigma+ vibronic bands with sub-Doppler resolution. AB - High resolution infrared spectra for four (2)Pi-(2)Sigma(+) bands of jet-cooled ethynyl radical (i.e., C(2)H) in the gas phase are reported. The combination of (i) slit-jet cooling (T(rot) ~ 12 K) and (ii) sub-Doppler resolution (~ 60 MHz) permits satellite branches in each (2)Pi-(2)Sigma(+) band to be observed and resolved for the first time as well as help clarify a systematic parity misassignment from previous studies. The observed lines in each band are least squares fit to a Hamiltonian model containing rotational, spin-rotational, spin orbit, and lambda-doubling contributions for the (2)Pi state, from which we report revised excited state constants and band origins for the observed bands. Three of the four bands fit extremely well within a conventional (2)Pi model (i.e., sigma < 20 MHz), while one band exhibits a local perturbation due to an avoided crossing with a near resonant dark state. Vibronic assignments are given for the observed bands, with the dark state clearly identified as a highly excited stretch and bending overtone level X (1,2(2),0) by comparison with high level ab initio efforts. PMID- 21322688 TI - Lyman-alpha driven molecule formation on SiO2 surfaces-connection to astrochemistry on dust grains in the interstellar medium. AB - As a model for silicate dust grains in the interstellar medium, we have used high area amorphous SiO(2) as a surface on which to carry out Lyman-alpha (10.2 eV) photodecomposition of adsorbed N(2)O at 71 K and at a coverage of ~0.3 monolayer. The N(2)O molecules are adsorbed by hydrogen bonding to surface Si-OH groups. Transmission IR spectroscopy measurements permit the observation of the consumption of adsorbed N(2)O and the production of various photoproducts. It is observed that in comparison to N(2)O consumption, the relative rate of formation of the products NO(2) and N(2)O(4) made by combination reactions is enhanced significantly on the SiO(2) surface. Reactions between photogenerated radicals themselves or between radicals and parent N(2)O on the SiO(2) surface exceed the relative rates observed in the gas phase by factors of up to ~20. As the complexity of the combination product increases, its relative production rate, compared to the gas phase, increases due to the involvement of multiple surface combination elementary steps. It is proposed that the enhancement of combination reactions on the SiO(2) surface is due to the surface's ability to absorb excess energy evolved during the chemical-bond-forming events on the surface. This principle is probably significant on grain surfaces supporting photochemical processes of astrochemical interest, and indeed is expected. The cross section for adsorbed N(2)O photodecomposition on the porous SiO(2) surface is about 7 * 10(-20) cm(2) and the quantum yield for the adsorbed molecule decomposition is about 0.006, compared to a quantum yield of 1.46 in the gas phase. This decrease in photon efficiency is attributed to absorption and scattering of Lyman-alpha radiation by the SiO(2) particles. PMID- 21322689 TI - A master equation approach to the dynamics of zero electron kinetic energy (ZEKE) states and ZEKE spectroscopy. AB - We have theoretically studied important dynamic processes involved in zero electron kinetic energy (ZEKE) spectroscopy using the density matrix method with the inverse Born-Oppenheimer approximation basis sets. In ZEKE spectroscopy, the ZEKE Rydberg states are populated by laser excitation (either a one- or two photon process), which is followed by autoionizations and l-mixing due to a stray field. The discrimination field is then applied to ionize loosely bound electrons in the ZEKE states. This is followed by using the extraction field to extract electrons from the ZEKE levels which have a strength comparable to that of the extraction field. These extracted electrons are measured for the relative intensities of the ion states under investigation. The spectral positions are determined by the applied laser wavelength and modified by the extraction electric field. In this paper, all of these processes are conducted within the context of the density matrix method. The density matrix method can provide not only the dynamics of system's population and coherence (or phase) but also the rate constants of the processes involved in the ZEKE spectroscopy. Numerical examples are given to demonstrate the theoretical treatments. PMID- 21322690 TI - Paired hydrogen bonds in the hydrogen halide homodimer (HI)2. AB - The HI homodimer was found to have structural and vibrational properties unlike any other previously studied (HX)(2) system, with X = F, Cl, and Br. The infrared spectrum of (HI)(2) is also observed to be distinctly different from the other members of the series. In addition, the interaction energy of the (HI)(2) dimer has been calculated using the coupled-cluster with singles, doubles, and perturbative triples [CCSD(T)] level of theory. A four-dimensional morphed intermolecular potential has been generated and then morphed using available near infrared and submillimeter spectroscopic data recorded in supersonic jet expansions. The morphed potential is found to have a single global minimum with a symmetric structure having C(2h) symmetry. The equilibrium dissociation energy is found to be 359 cm(-1) with the geometry in Jacobi coordinates of R(e) = 4.35 A, theta(1) = 43 degrees , theta(2) = 137 degrees , and phi = 180 degrees . The infrared spectrum is characterized by pairs of excited vibrational states resulting from the coupling of the two HI stretching modes. A qualitative model using a quadratic approximation has been fitted to obtain an estimate of this coupling. Furthermore, a morphed intermolecular potential for the vibrationally excited system was also obtained that gives a quantitative estimate of the shift in the potential due to the excitation. The submillimeter analysis is consistent with a ground state having its highest probability as a paired hydrogen bond configuration with R(0) = 4.56372(1) A and an average angle theta=cos(-1)((1/2)) = 46.40(1) degrees (between the diatom center of mass/center of mass axis and direction of each component hydrogen iodide molecule). On monodeuteration, however, the ground state is predicted to undergo an anomalous structural isotope change to an L-shaped HI-DI structure with highest probability at R(0) = 4.51 A, theta(1) = 83 degrees , theta(2) = 177 degrees , and phi = 180 degrees . These results provide a test for large scale ab initio calculations and have implications for the interpretation of photoinduced chemistry and other properties of the dimer. PMID- 21322691 TI - Hyperspherical slow variable discretization method for weakly bound triatomic molecules. AB - We develop a method for calculating the bound state energies and the wave functions of weakly bound triatomic molecular systems. The method is based on the use of hyperspherical coordinates, combined with the slow variable discretization approach. The finite-element methods-discrete variable representation scheme provides an efficient means to solve the coupled-channel hyper-radial equations. Our method is applied to searching for bound states of the (20)Ne(2)H and (4)He(20)NeH triatomic molecules, using the best empirical pairwise interaction potentials. We consider not only zero total nuclear orbital momentum, J = 0, states but also J > 0 states. The (20)Ne(2)H system has been found to possess one bound state each for the J(Pi)=0(+),1(-), and 2(+) symmetries, while there exist only one bound state for the (4)He(20)NeH system in the 0(+) symmetry. We shall calculate the bound state energies and analyze the molecular structures of these species in detail. PMID- 21322692 TI - Transport coefficients for electrons in water vapor: definition, measurement, and calculation. AB - Comparison of experimental and theoretical transport data for electron swarms in water vapour over a wide range of fields provides a rigorous test of (e(-), H(2)O) scattering cross sections over a correspondingly broad range of energies. That like should be compared with like is axiomatic, but the definition of transport coefficients at high fields, when non-conservative processes are significant, has long been contentious. This paper revisits and distills the most essential aspects of the definition and calculation of transport coefficients, giving numerical results for the drift velocity and ionisation coefficient of electrons in water vapour. In particular, the relationship between the theoretically calculated bulk drift velocities of [K. F. Ness and R. E. Robson, Phys. Rev. A 38, 1446 (1988)] and the experimental "arrival time spectra" drift velocity data of Hasegawa et al. [J. Phys. D 40(8), 2495 (2007)] is established. This enables the Hasegawa et al. data to be reconciliated with the previous literature, and facilitates selection of the best (e(-), H(2)O) cross section set. PMID- 21322693 TI - Study on the carbon fragment anions produced by femtosecond laser ablation of solid C60. AB - Production of the anions (negative ions) has been observed by femtosecond laser ablation (fsLA) of solid C(60) with a time-of-flight (TOF) mass spectrometer. In contrast to C(60)(+), production of C(60)(-) due to an electron capture is found very limited because of the small electron affinity of the C(60) molecule. Narrow TOF peaks of small carbon fragment anions C(n)(-) (n <= 23) suggest instantaneous production of the fragment anions through dissociative ionization of C(60). Production of the mono-hydrogenated carbon fragment anions C(n)H(-) has been observed and also the abrupt change in the yield of C(n)H(-) has been observed at n = 10, which is attributed to the structural change of the carbon fragments from a linear chain to a monocyclic ring. The results are found similar to those obtained for the carbon fragments produced by nanosecond laser ablation (nsLA) of solid C(60), which demonstrates that the thermalization in an ablation plasma washes away any difference in the nature of carbon fragments produced by fsLA and nsLA. PMID- 21322694 TI - The infrared spectra of C2H4(+) and C2H3 trapped in solid neon. AB - When a mixture of ethylene in a large excess of neon is codeposited at 4.3 K with a beam of neon atoms that have been excited in a microwave discharge, two groups of product absorptions appear in the infrared spectrum of the deposit. Similar studies using C(2)H(4)-1-(13)C and C(2)D(4) aid in product identification. The first group of absorptions arises from a cation product which possesses two identical carbon atoms, giving the first infrared identification of two fundamentals of C(2)H(4)(+) and three of C(2)D(4)(+), as well as a tentative identification of nu(9) of C(2)H(4)(+). The positions of these absorptions are consistent with the results of density functional calculations and of earlier photoelectron studies. All of the members of the second group of product absorptions possess two inequivalent carbon atoms. They are assigned to the vinyl radical, C(2)H(3), and to C(2)D(3), in agreement with other recent infrared assignments for those species. PMID- 21322695 TI - Ab initio potential energy surface and intermolecular vibrations of the naphthalene-argon van der Waals complex. AB - The intermolecular potential energy surface (PES) of the naphthalene-argon (NpAr) complex is constructed using an ab initio method. The molecule-argon interaction energy is computed at the level of the second-order Moller-Plesset (MP2) theory combined with the augmented correlation consistent polarized valence double-zeta basis set. The analytical PES fitted to a large set of single energy values is further improved with the help of correction functions determined by calculations of the interaction energy at the coupled cluster level including single and double excitations supplemented by triple excitations performed for a limited set of intermolecular configurations. The PES determined is very flat near its four equivalent global minima of -493 cm(-1) located from both sides of the Np plane at a distance of 3.435 A and shifted from the center of Np by +/-0.43 A along its long symmetry axis. The large-amplitude motion of Ar in the complex is investigated, and dynamical consequence of a strong intermode coupling is discovered in the excited vibrational states. The theoretical results obtained allow for the reassignment of the spectral bands observed in the electronic transition S(1) <- S(0) of the NpAr complex. PMID- 21322696 TI - Ab initio potential energy surface and quantum dynamics for the H + CH4 -> H2 + CH3 reaction. AB - A new full-dimensional potential energy surface for the title reaction has been constructed using the modified Shepard interpolation scheme. Energies and derivatives were calculated using the UCCSD(T) method with aug-cc-pVTZ and 6 311++G(3df,2pd) basis sets, respectively. A total number of 30,000 data points were selected from a huge number of molecular configurations sampled by trajectory method. Quantum dynamical calculations showed that the potential energy surface is well converged for the number of data points for collision energy up to 2.5 eV. Total reaction probabilities and integral cross sections were calculated on the present surface, as well as on the ZBB3 and EG-2008 surfaces for the title reaction. Satisfactory agreements were achieved between the present and the ZBB3 potential energy surfaces, indicating we are approaching the final stage to obtain a global potential energy surface of quantitative accuracy for this benchmark polyatomic system. Our calculations also showed that the EG-2008 surface is less accurate than the present and ZBB3 surfaces, particularly in high energy region. PMID- 21322697 TI - Metastable decomposition and hydrogen migration of ethane dication produced in an intense femtosecond near-infrared laser field. AB - We investigated a formation channel of triatomic molecular hydrogen ions from ethane dication induced by irradiation of intense laser fields (800 nm, 100 fs, ~1 * 10(14) W/cm(2)) by using time of flight mass spectrometry. Hydrogen ion and molecular hydrogen ion (H,D)(n)(+) (n = 1-3) ejected from ethane dications, produced by double ionization of three types of samples, CH(3)CH(3), CD(3)CD(3), and CH(3)CD(3), were measured. All fragments were found to comprise components with a kinetic energy of ~3.5 eV originating from a two-body Coulomb explosion of ethane dications. Based on the signal intensities and the anisotropy of the ejection direction with respect to the laser polarization direction, the branching ratios, H(+):D(+) = 66:34, H(2)(+):HD(+):D(2)(+) = 63:6:31, and H(3)(+):H(2)D(+):HD(2)(+):D(3)(+) = 26:31:34:9 for the decomposition of C(2)H(3)D(3)(2+), were determined. The ratio of hydrogen molecules, H(2):HD:D(2) = 31:48:21, was also estimated from the signal intensities of the counter ion C(2)(H,D)(4)(2+). The similarity in the extent of H/D mixture in (H,D)(3)(+) with that of (H,D)(2) suggests that these two dissociation channels have a common precursor with the C(2)H(4)(2+)...H(2) complex structure, as proposed theoretically in the case of H(3)(+) ejection from allene dication [A. M. Mebel and A. D. Bandrauk, J. Chem. Phys. 129, 224311 (2008)]. In contrast, the (H,D)(2)(+) ejection path with a lower extent of H/D mixture and a large anisotropy is expected to proceed essentially via a different path with a much rapid decomposition rate. For the Coulomb explosion path of C-C bond breaking, the yield ratios of two channels, CH(3)CD(3)(2+)-> CH(3)(+) + CD(3)(+) and CH(2)D(+) + CHD(2)(+), were 81:19 and 92:8 for the perpendicular and parallel directions, respectively. This indicates that the process occurs at a rapid rate, which is comparable to hydrogen migration through the C-C bond, resulting in smaller anisotropy for the latter channel that needs H/D exchange. PMID- 21322698 TI - Density functional theory and Raman spectroscopy applied to structure and vibrational mode analysis of 1,1',3,3'-tetraethyl-5,5',6,6'-tetrachloro- benzimidazolocarbocyanine iodide and its aggregate. AB - We have measured electronic and Raman scattering spectra of 1,1',3,3'-tetraethyl 5,5',6,6'-tetrachloro-benzimidazolocarbocyanine iodide (TTBC) in various environments, and we have calculated the ground state geometric and spectroscopic properties of the TTBC cation in the gas and solution phases (e.g., bond distances, bond angles, charge distributions, and Raman vibrational frequencies) using density functional theory. Our structure calculations have shown that the ground state equilibrium structure of a cis-conformer lies ~200 cm(-1) above that of a trans-conformer and both conformers have C(2) symmetry. Calculated electronic transitions indicate that the difference between the first transitions of the two conformers is about 130 cm(-1). Raman spectral assignments of monomeric- and aggregated-TTBC cations have been aided by density functional calculations at the same level of the theory. Vibrational mode analyses of the calculated Raman spectra reveal that the observed Raman bands above 700 cm(-1) are mainly associated with the in-plane deformation of the benzimidazolo moieties, while bands below 700 cm(-1) are associated with out-of-plane deformations of the benzimidazolo moieties. We have also found that for the nonresonance excited experimental Raman spectrum of aggregated-TTBC cation, the Raman bands in the higher-frequency region are enhanced compared with those in the nonresonance spectrum of the monomeric cation. For the experimental Raman spectrum of the aggregate under resonance excitation, however, we find new Raman features below 600 cm(-1), in addition to a significantly enhanced Raman peak at 671 cm(-1) that are associated with out-of-plane distortions. Also, time dependent density functional theory calculations suggest that the experimentally observed electronic transition at ~515 nm (i.e., 2.41 eV) in the absorption spectrum of the monomeric-TTBC cation predominantly results from the pi -> pi* transition. Calculations are further interpreted as indicating that the observed shoulder in the absorption spectrum of TTBC in methanol at 494 nm (i.e., 2.51 eV) likely results from the nu(") = 0 -> nu' = 1 transition and is not due to another electronic transition of the trans-conformer-despite the fact that measured and calculated NMR results (not provided here) support the prospect that the shoulder might be attributable to the 0-0 band of the cis-conformer. PMID- 21322699 TI - Temperature-dependent structure of methyltributylammonium bis(trifluoromethylsulfonyl)amide: X ray scattering and simulations. AB - We report the combined results of computational and x ray scattering studies of amorphous methyltributylammonium bis(trifluoromethylsulfonyl)amide as a function of temperature. These studies included the temperature range for the normal isotropic liquid, a deeply supercooled liquid and the glass. The low q peaks in the range from 0.3 to 1.5 A(-1) in the structure function of this liquid can be properly accounted for by correlations between first and second nearest neighbors. The lowest q peak can be assigned to real space correlations between ions of the same charge, while the second peak arises mostly from nearest neighbors of opposite charge. Peaks at larger q values are mostly intramolecular in nature. While our simulated structure functions provide an excellent match to our experimental results and our experimental findings agree with previous studies reported for this liquid, the prior interpretation of the experimental data in terms of an interdigitated smectic A phase is not supported by our simulations. In this work, we introduce a set of general theoretical partitions of real and reciprocal space correlations that allow for unambiguous analysis of all intra- and interionic contributions to the structure function and coherent scattering intensity. We find that the intermolecular contributions to the x ray scattering intensity are dominated by the anions and cross terms between cations and anions for this ionic liquid. PMID- 21322700 TI - The chemistry of acetone at extreme conditions by density functional molecular dynamics simulations. AB - Density functional molecular dynamics simulations have been performed in the NVT ensemble (moles (N), volume (V) and temperature (T)) on a system formed by ten acetone molecules at a temperature of 2000 K and density rho = 1.322 g cm(-3). These conditions resemble closely those realized at the interface of an acetone vapor bubble in the early stages of supercompression experiments and result in an average pressure of 5 GPa. Two relevant reactive events occur during the simulation: the condensation of two acetone molecules to give hexane-2,5-dione and dihydrogen and the isomerization to the enolic propen-2-ol form. The mechanisms of these events are discussed in detail. PMID- 21322701 TI - Comparison between Einstein and Debye models for an amorphous Ni46Ti54 alloy produced by mechanical alloying investigated using extended x-ray absorption fine structure and cumulant expansion. AB - We investigated an amorphous Ni(46)Ti(54) alloy produced by mechanical alloying using extended x-ray absorption fine structure (EXAFS) technique and cumulant expansion considering Einstein and Debye models for the temperature dependence of the cumulants. Results obtained from both models were compared and very similar values were obtained. From them, we found information about the structure of the alloy besides thermal and structural disorder, anharmonicity, thermal expansion, and asymmetry of the partial distribution functions g(ij)(r). The cumulants C(1)(*), C(2)(*), and C(3)(*) also allowed us to reconstruct the g(ij)(r, T) functions from EXAFS. PMID- 21322702 TI - Structural and optical properties of liquid CO2 for pressures up to 1 TPa. AB - We report on the use of first-principles molecular dynamics calculations to examine properties of liquid carbon dioxide in the pressure-temperature range of 0-1 TPa and 200-100 000 K. The computed equations of state points are used to predict a series of shock Hugoniots with initial starting conditions that are relevant to existing and ongoing shock-wave experiments. A comparison with published measurements up to 70 GPa shows excellent agreement. We find that the liquid undergoes a gradual phase transition along the Hugoniot and have characterized this transition based on changes in bonding and structural properties as well as the conductivity and reflectivity of the fluid. PMID- 21322703 TI - Scaling of the viscosity of the Lennard-Jones chain fluid model, argon, and some normal alkanes. AB - In this work, we have tested the efficiency of two scaling approaches aiming at relating shear viscosity to a single thermodynamic quantity in dense fluids, namely the excess entropy and the thermodynamic scaling methods. Using accurate databases, we have applied these approaches first to a model fluid, the flexible Lennard-Jones chain fluid (from the monomer to the hexadecamer), then to real fluids, such as argon and normal alkanes. To enlarge noticeably the range of thermodynamics conditions for which these scaling methods are applicable, we have shown that the use of the residual viscosity instead of the total viscosity is preferable in the scaling procedures. It has been found that both approaches, using the adequate scaling, are suitable for the Lennard-Jones chain fluid model for a wide range of thermodynamic conditions whatever the chain length when scaling law exponents and prefactors are adjusted for each chain length. Furthermore, these results were found to be well respected by the corresponding real fluids. PMID- 21322704 TI - Ion-pairing dynamics of Li+ and SCN- in dimethylformamide solution: chemical exchange two-dimensional infrared spectroscopy. AB - Ultrafast two-dimensional infrared (2DIR) spectroscopy has been proven to be an exceptionally useful method to study chemical exchange processes between different vibrational chromophores under thermal equilibria. Here, we present experimental results on the thermal equilibrium ion pairing dynamics of Li(+) and SCN(-) ions in N,N-dimethylformamide. Li(+) and SCN(-) ions can form a contact ion pair (CIP). Varying the relative concentration of Li(+) in solution, we could control the equilibrium CIP and free SCN(-) concentrations. Since the CN stretch frequency of Li-SCN CIP is blue-shifted by about 16 cm(-1) from that of free SCN( ) ion, the CN stretch IR spectrum is a doublet. The temperature-dependent IR absorption spectra reveal that the CIP formation is an endothermic (0.57 kJ/mol) process and the CIP state has larger entropy by 3.12 J/(K mol) than the free ion states. Since the two ionic configurations are spectrally distinguishable, this salt solution is ideally suited for nonlinear IR spectroscopic investigations to study ion pair association and dissociation dynamics. Using polarization controlled IR pump-probe methods, we first measured the lifetimes and orientational relaxation times of these two forms of ionic configurations. The vibrational population relaxation times of both the free ion and CIP are about 32 ps. However, the orientational relaxation time of the CIP, which is ~47 ps, is significantly longer than that of the free SCN(-), which is ~7.7 ps. This clearly indicates that the effective moment of inertia of the CIP is much larger than that of the free SCN(-). Then, using chemical exchange 2DIR spectroscopy and analyzing the diagonal peak and cross-peak amplitude changes with increasing the waiting time, we determined the contact ion pair association and dissociation time constants that are found to be 165 and 190 ps, respectively. The results presented and discussed in this paper are believed to be important, not only because the ion-pairing dynamics is one of the most fundamental physical chemistry problems but also because such molecular ion-ion interactions are of critical importance in understanding Hofmeister effects on protein stability. PMID- 21322705 TI - Waterlike glass polyamorphism in a monoatomic isotropic Jagla model. AB - We perform discrete-event molecular dynamics simulations of a system of particles interacting with a spherically-symmetric (isotropic) two-scale Jagla pair potential characterized by a hard inner core, a linear repulsion at intermediate separations, and a weak attractive interaction at larger separations. This model system has been extensively studied due to its ability to reproduce many thermodynamic, dynamic, and structural anomalies of liquid water. The model is also interesting because: (i) it is very simple, being composed of isotropically interacting particles, (ii) it exhibits polyamorphism in the liquid phase, and (iii) its slow crystallization kinetics facilitate the study of glassy states. There is interest in the degree to which the known polyamorphism in glassy water may have parallels in liquid water. Motivated by parallels between the properties of the Jagla potential and those of water in the liquid state, we study the metastable phase diagram in the glass state. Specifically, we perform the computational analog of the protocols followed in the experimental studies of glassy water. We find that the Jagla potential calculations reproduce three key experimental features of glassy water: (i) the crystal-to-high-density amorphous solid (HDA) transformation upon isothermal compression, (ii) the low-density amorphous solid (LDA)-to-HDA transformation upon isothermal compression, and (iii) the HDA-to-very-high-density amorphous solid (VHDA) transformation upon isobaric annealing at high pressure. In addition, the HDA-to-LDA transformation upon isobaric heating, observed in water experiments, can only be reproduced in the Jagla model if a free surface is introduced in the simulation box. The HDA configurations obtained in cases (i) and (ii) are structurally indistinguishable, suggesting that both processes result in the same glass. With the present parametrization, the evolution of density with pressure or temperature is remarkably similar to the corresponding experimental measurements on water. Our simulations also suggest that the Jagla potential may reproduce features of the HDA-VHDA transformations observed in glassy water upon compression and decompression. Snapshots of the system during the HDA-VHDA and HDA-LDA transformations reveal a clear segregation between LDA and HDA but not between HDA and VHDA, consistent with the possibility that LDA and HDA are separated by a first order transformation as found experimentally, whereas HDA and VHDA are not. Our results demonstrate that a system of particles with simple isotropic pair interactions, a Jagla potential with two characteristic length scales, can present polyamorphism in the glass state as well as reproducing many of the distinguishing properties of liquid water. While most isotropic pair potential models crystallize readily on simulation time scales at the low temperatures investigated here, the Jagla potential is an exception, and is therefore a promising model system for the study of glass phenomenology. PMID- 21322706 TI - Two interacting particles in a spherical pore. AB - In this work we analytically evaluate, for the first time, the exact canonical partition function for two interacting spherical particles into a spherical pore. The interaction with the spherical substrate and between particles is described by an attractive square-well and a square-shoulder potential. In addition, we obtain exact expressions for both the one particle and an averaged two particle density distribution. We develop a thermodynamic approach to few-body systems by introducing a method based on thermodynamic measures [I. Urrutia, J. Chem. Phys. 134, 104503 (2010)] for nonhard interaction potentials. This analysis enables us to obtain expressions for the pressure, the surface tension, and the equivalent magnitudes for the total and Gaussian curvatures. As a by-product, we solve systems composed of two particles outside a fixed spherical obstacle. We study the low density limit for a many-body system confined to a spherical cavity and a many-body system surrounding a spherical obstacle. From this analysis we derive the exact first order dependence of the surface tension and Tolman length. Our findings show that the Tolman length goes to zero in the case of a purely hard wall spherical substrate, but contains a zero order term in density for square well and square-shoulder wall-fluid potentials. This suggests that any nonhard wall-fluid potential should produce a non-null zero order term in the Tolman length. PMID- 21322707 TI - Structural studies of water in hydrophilic and hydrophobic mesoporous silicas: an x-ray and neutron diffraction study at 297 K. AB - Water confined in a sol-gel network has been characterized by x-ray and neutron diffraction for two samples of mesoporous silica: one with a hydrophilic character (a nonmodified one) and another with a hydrophobic character (a modified one with a methylated internal pore surface). The pore size has been previously characterized [J. Jelassi et al., Phys. Chem. Chem. Phys. 134, 1039 (2010)] to have a mean pore diameter of approximately 55 A. The diffraction measurements presented in this paper have been made at room temperature [293 K] for a filling factor of 0.45, giving a mean thickness of 8-9 A for the water layer. The results show that the local order of the confined water molecules in the intermediate region of 3-6 A is significantly different from that of the bulk water and also for the two different environments. For the hydrophilic sample, the siloxyl groups at the surface modify the water structure through the effects of interfacial hydrogen-bonding, which influences the orientational configuration of local water molecules and creates a modified spatial arrangement in the pore. In the case of the hydrophobic sample, there is no specific interaction with the pore wall, which is primarily van der Waals type, and the water molecules at the interface are differently oriented to create a hydrogen-bonded network linked more directly to the rest of the water volume. In the present circumstances, the thickness of the water layer has a relatively small dimension so that the interpretation of the measured diffraction pattern is not as straightforward as for the bulk liquids, and it is necessary to consider the effects of diffraction broadening from a distributed sample volume and also the contribution from cross terms that remain after conducting a "wet-minus-dry" analysis procedure. These analytic difficulties are discussed in the context of the present measurements and compared with the work of other groups engaged in the study of water confined in different environments. The present results, again, emphasize the complexity influencing the properties of water in a confined geometry and the strong influence of surface interactions on its behavior. PMID- 21322708 TI - Strong correlations in actinide redox reactions. AB - Reduction-oxidation (redox) reactions of the redox couples An(VI)/An(V), An(V)/An(IV), and An(IV)/An(III), where An is an element in the family of early actinides (U, Np, and Pu), as well as Am(VI)/Am(V) and Am(V)/Am(III), are modeled by combining density functional theory with a generalized Anderson impurity model that accounts for the strong correlations between the 5f electrons. Diagonalization of the Anderson impurity model yields improved estimates for the redox potentials and the propensity of the actinide complexes to disproportionate. PMID- 21322709 TI - The fate of optical excitations in small polyhedral ZnS clusters: a theoretical study of the excitation and localization of electrons in Zn4S4 and Zn6S6. AB - We explore the excited state energy landscape of small polyhedral zinc sulfide clusters (Zn(4)S(4) and Zn(6)S(6)) using time-dependent density functional theory and correlated wave function based methods. We predict the optical absorption and photoluminescence spectra of the polyhedral clusters and demonstrate that, upon relaxation of the excited state, these nanostructures break symmetry and an electron and a hole localize on a small number of Zn (electron) and S (hole) centers. We further test several exchange-correlation potentials for their ability to recover the correlated wave function description of the excited state. Finally, we discuss how the degeneracy of excited states in nanostructures, such as those considered here, results in a Jahn-Teller distortion of the excited state geometry, and how numerical problems arising from this can be circumvented by starting the optimization of excited states from structures distorted along the ground state vibrational normal modes. PMID- 21322710 TI - Diluting the hydrogen bonds in viscous solutions of n-butanol with n-bromobutane: II. A comparison of rotational and translational motions. AB - Mixtures of the monohydroxy alcohol n-butanol with n-bromobutane are investigated via dielectric and nuclear magnetic resonance (NMR) techniques. Static- and pulsed-field gradient proton NMR yielded self-diffusion coefficients as a function of concentration and temperature. To monitor reorientational motions, broadband dielectric and (13)C-spin relaxation time measurements were carried out. The latter demonstrate that the structural relaxation stems from the motion of the alkyl chains. By combining data from translational diffusion coefficients with published shear viscosities, hydrodynamic radii were determined that compare favorably with the van der Waals radii of single molecules. The results for the neat alcohol and for the binary mixtures are discussed with respect to a recent transient chain model. The approach of Debye and structural relaxation times at high temperatures, identified as a general feature of monohydroxy alcohols, is also discussed within that framework. PMID- 21322711 TI - The structure of water in the hydration shell of cations from x-ray Raman and small angle x-ray scattering measurements. AB - X-ray Raman scattering (XRS) spectroscopy and small angle x-ray scattering (SAXS) are used to study water in aqueous solutions of NaCl, MgCl(2), and AlCl(3) with the particular aim to provide information about the structure of the hydration shells of the cations. The XRS spectra show that Na(+) weakens the hydrogen bonds of water molecules in its vicinity, similar to the effect of increased temperature and pressure. Mg(2+) and Al(3+), on the other hand, cause the formation of short and strong hydrogen bonds between the surrounding water molecules. The SAXS data show that Mg(2+) and Al(3+) form tightly bound hydration shells that give a large density contrast in the scattering data. From the form factors extracted from the SAXS data, we found that Mg(2+) and Al(3+) have, respectively, an equivalent of one and one and a half stable hydration shells that appear as a density contrast. In addition, we estimated that the density of water in the hydration shells of Mg(2+) and Al(3+) is, respectively, ~61% and ~71% higher than in bulk water. PMID- 21322712 TI - Sorting of brownian rods by the use of an asymmetric potential. AB - We present here a method for sorting nanometer scale brownian rods by using a switching asymmetric periodic potential. A two stage sorting process is used to isolate particles with specific dimensions, with acceptable sorting times as well as realizable potential barrier lengths. The method was tested using computer simulations. The ability to sort the nanometer scale anisotropic particles, such as gold nanorods, portends important applications in large scale data recording, photothermal surgery, and bioimaging. PMID- 21322713 TI - Structural, electronic, and dynamical properties of methane under high pressure. AB - The electronic structure and lattice dynamical properties of solid methane under high pressure have been studied based on density functional theory. We identify a cubic structure with space group of I43m below 14 GPa, the Pmn2(1) structure in the range of 14-21 GPa, and the P2(1)/c structure from 21 to 65 GPa. Our obtained Raman spectra of the P2(1)/c structure agree well with the typical Raman active modes in the available experimental data. At 65 GPa, methane undergoes a phase transition from P2(1)/c to Pnma. The structures with P2(1)/c and Pnma symmetries are insulating, and under any pressure studied methane always remains in molecular form. For Pnma phase, the orientational ordering of CH(4) molecules varies significantly at 79, 88, and 92 GPa, and by further increasing pressure the rotation of the molecules freezes and orientational ordering remains unchanged. PMID- 21322714 TI - Theory of correlated two-particle activated glassy dynamics: general formulation and heterogeneous structural relaxation in hard sphere fluids. AB - We generalize the nonlinear Langevin equation theory of activated single particle dynamics to describe the correlated motion of two tagged spherical particles in a glass- or gel-forming fluid as a function of their initial separation. The theory is built on the concept of a two-dimensional dynamic free energy surface which quantifies the forces on two particles moving in a cooperative manner. For the hard sphere fluid, above a threshold volume fraction we generically find two relaxation channels corresponding largely, but not exclusively, to a center-of mass-like displacement and a radial separation of the two tagged particles. The entropic barriers and mean first passage times are computed and found to systematically vary with volume fraction and initial particle separation; both oscillate as a function of the latter in a manner related to the equilibrium pair correlation function. A dynamic correlation length is estimated as the length scale beyond which the two-particle activated dynamics becomes uncorrelated in space and time, and is found to modestly grow with increasing mean relaxation time. The theory is also applied to a simplified model of cage escape, the elementary step of structural relaxation. Predictions for characteristic relaxation times, translation-relaxation decoupling, and stretched-exponential decay of time correlation functions are obtained. A novel mechanism for understanding why strong decoupling emerges in the activated regime, but stretched nonexponential time correlation functions do not change shape as the mean relaxation time grows, is presented and favorably compared with experiment. The theory may serve as a starting point for constructing a predictive model of multiple correlated caging and hopping (forward and backward) events of a pair of tagged particles. PMID- 21322715 TI - Modeling the early stages of self-assembly in nanophase materials. II. Role of symmetry and dimensionality. AB - We study the early stages of self-assembly of elementary building blocks of nanophase materials, considering explicitly their structure and the symmetry and the dimensionality of the reaction space. Previous work [Kozak et al., J. Chem. Phys. 134, 154701 (2007)] focused on characterizing self-assembly on small square planar templates. Here we consider larger lattices of square-planar symmetry having N = 255 sites, and both hexagonal and triangular lattices of N = 256 sites. Furthermore, to assess the consequences of a depletion zone above a basal layer (lambda = 1), we study self-assembly on an augmented diffusion space defined by lambda = 2 and lambda = 5 stacked layers having the same characteristics as the basal plane. The effective decrease in the efficiency of self-assembly of individual nanophase units when the diffusion space is expanded, by increasing the template size and/or by enlarging the depletion zone, is then quantified. The results obtained reinforce our earlier conclusion that the most significant factor influencing the kinetics of formation of a final self assembled unit is the number of reaction pathways from one or more precursor states. We draw attention to the relevance of these results to zeolite synthesis and reactions within pillared clays. PMID- 21322716 TI - Lattice-gas model of nonadditive interacting particles on nanotube bundles. AB - In the present paper, the adsorption thermodynamics of a lattice-gas model which mimics a nanoporous environment is studied by considering nonadditive interactions between the adsorbed particles. It is assumed that the energy linking a certain atom with any of its nearest neighbors strongly depends on the state of occupancy in the first coordination sphere of such an adatom. By means of Monte Carlo (MC) simulations in the grand canonical ensemble, adsorption isotherms and differential heats of adsorption were calculated. Their striking behaviors were analyzed and discussed in terms of the low temperature phases formed in the system. Finally, the results obtained from MC simulations were compared with the corresponding ones from Bragg-Williams approximation. PMID- 21322717 TI - Interface proximity effects on ionic conductivity in nanoscale oxide-ion conducting yttria stabilized zirconia: an atomistic simulation study. AB - We present an atomistic simulation study on the size dependence of dopant distribution and the influence of nanoscale film thickness on carrier transport properties of the model oxide-ion conductor yttria stabilized zirconia (YSZ). Simulated amorphization and recrystallization approach was utilized to generate YSZ films with varying thicknesses (3-9 nm) on insulating MgO substrates. The atomic trajectories generated in the molecular dynamics simulations are used to study the structural evolution of the YSZ thin films and correlate the resulting microstructure with ionic transport properties at the nanoscale. The interfacial conductivity increases by 2 orders of magnitude as the YSZ film size decreases from 9 to 3 nm owing to a decrease in activation energy barrier from 0.54 to 0.35 eV in the 1200-2000 K temperature range. Analysis of dopant distribution indicates surface enrichment, the extent of which depends on the film thickness. The mechanisms of oxygen conductivity for the various film thicknesses at the nanoscale are discussed in detail and comparisons with experimental and other modeling studies are presented where possible. The study offers insights into mesoscopic ion conduction mechanisms in low-dimensional solid oxide electrolytes. PMID- 21322718 TI - Effects of polydisperse crowders on aggregation reactions: a molecular thermodynamic analysis. AB - Intracellular crowding in biological systems is usually mimicked in in vitro experiments by adding single crowders at high volume fractions, without taking into consideration the polydispersity of the crowders in the cellular environment. Here, we develop a molecular thermodynamic formalism to examine the effects of size-polydispersity of crowders on aggregation reaction equilibria. Although the predominantly common practice so far has been to appeal to the entropic (excluded-volume) effects in describing crowding effects, we show that the internal energy (hence, the enthalpy) of the system could dramatically alter the effects, even qualitatively, particularly in the case of a mixture of crowders, depending on the changes in the covolume of the products relative to that of the reactants and on the preferential binding or exclusion of the crowders by the reactants and products. We also show that in the case of polydisperse crowders the crowders with the largest size difference dominate the overall changes in the yield of the reaction, depending on the individual concentrations of the crowders. PMID- 21322719 TI - Instability and dewetting of ultrathin solid viscoelastic films on homogeneous and heterogeneous substrates. AB - Instability and dewetting engendered by the van der Waals force in soft thin (<100 nm) linear viscoelastic solid (e.g., elastomeric gel) films on uniform and patterned surfaces are explored. Linear stability analysis shows that, although the elasticity of the film controls the onset of instability and the corresponding critical wavelength, the dominant length-scale remains invariant with the elastic modulus of the film. The unstable modes are found to be long wave, for which a nonlinear long-wave analysis and simulations are performed to uncover the dynamics and morphology of dewetting. The stored elastic energy slows down the temporal growth of instability significantly. The simulations also show that a thermodynamically stable film with zero-frequency elasticity can be made unstable in the presence of physico-chemical defects on the substrate and can follow an entirely different pathway with far fewer holes as compared to the viscous films. Further, the elastic restoring force can retard the growth of a depression adjacent to the hole-rim and thus suppress the formation of satellite holes bordering the primary holes. These findings are in contrast to the dewetting of viscoelastic liquid films where nonzero frequency elasticity accelerates the film rupture and promotes the secondary instabilities. Thus, the zero-frequency elasticity can play a major role in imposing a better-defined long range order to the dewetted structures by arresting the secondary instabilities. PMID- 21322720 TI - The interaction of hyperthermal argon atoms with CO-covered Ru(0001): scattering and collision-induced desorption. AB - Hyperthermal Ar atoms were scattered under grazing incidence (theta(i) = 60 degrees ) from a CO-saturated Ru(0001) surface held at 180 K. Collision-induced desorption involving the ejection of fast CO (~1 eV) occurs. The angularly resolved in-plane CO desorption distribution has a peak along the surface normal. However, the angular distribution varies with the fractional coverage of the surface. As the total CO coverage decreases, the instantaneous desorption maximum shifts to larger outgoing angles. The results are consistent with a CO desorption process that involves lateral interaction with neighboring molecules. Furthermore, the data indicate that the incident Ar cannot readily penetrate the saturated CO overlayer. Time-of-flight measurements of scattered Ar exhibit two components-fast and slow. The slow component is most evident when scattering from the fully covered surface. The ratio and origin of these components vary with the CO coverage. PMID- 21322721 TI - Monte Carlo simulation of nanowires of different metals and two-metal alloys. AB - Nanowires of different metals and two-metal alloys have been studied by means of canonical Monte Carlo simulations and the embedded atom method for the interatomic potentials. For nanowires of gold, a relatively stable three-atom wide chain was observed. The presence of one-atom-wide linear atomic chains is not stable in any case. For two-metal alloy nanowires, the metal with a higher surface energy tends to locate in the inner region of the nanowire. PMID- 21322722 TI - Diffusiophoresis of a nonuniformly charged sphere in an electrolyte solution. AB - The diffusiophoresis of a rigid, nonuniformly charged spherical particle in an electrolyte solution is analyzed theoretically focusing on the influences of the thickness of double layer, the surface charge distribution, the effect of electrophoresis, and the effect of double-layer polarization. We show that the nonuniform charge distribution on the particle surface yields complicated effect of double-layer polarization, leading to interesting diffusiophoretic behaviors. For example, if the sign of the middle part of the particle is different from that of its left- and right-hand parts, then depending upon the charge density and the fraction of the middle part, the particle can move either to the high concentration side or to the low-concentration side. Both the diffusiophoretic velocity and its direction can be manipulated by the distribution of the surface charge density. In particular, if the electrophoresis effect is significant, then those properties are governed by the averaged surface charge density of the particle. A dipolelike particle, where its left- (right-) hand half is negatively (positively) charged, always migrates toward the low-concentration (left-hand) side, that is, it has a negative diffusiophoretic velocity. In addition, that diffusiophoretic velocity has a negative local minimum as the thickness of double layer varies. PMID- 21322723 TI - Dimer pinning and the assignment of semiconductor-adsorbate surface structures. AB - It has been observed in scanning tunneling microscopy (STM) that the adsorption of molecules on the (001) surface of a Group IV semiconductor can lead to an asymmetric ordering of the dimers immediately adjacent to the adsorbate. This so called pinning may occur along the dimer row on only one, or both sides of the adsorbate. Here we present a straightforward methodology for predicting such pinning and illustrate this approach for several different adsorbate structures on the Si(001) surface. This approach extends earlier work by including the effects of coupling across the adsorbate as well as the nearest-neighbor interactions between the chemisorbed dimer and its adjacent dimers. The results are shown to be in excellent agreement with the room temperature experimental STM data. The examples also show how this approach can serve as a powerful tool for discriminating between alternative possible adsorbate structures on a dimerized semiconductor (001) surface, especially in cases of molecular adsorption where the STM measurements provide insufficient details of the underlying atomic structure. PMID- 21322724 TI - Methanol synthesis on ZnO(0001). III. Free energy landscapes, reaction pathways, and mechanistic insights. AB - The interplay of physical and chemical processes in the heterogeneous catalytic synthesis of methanol on the ZnO(0001) surface with oxygen vacancies is expected to give rise to a complex free energy landscape. A manifold of intermediate species and reaction pathways has been proposed over the years for the reduction of CO on this catalyst at high temperature and pressure conditions as required in the industrial process. In the present study, the underlying complex reaction network from CO to methanol is generated in the first place by using ab initio metadynamics for computational heterogeneous catalysis. After having "synthesized" the previously discussed intermediates in addition to finding novel species, mechanistic insights into this network of surface chemical reactions are obtained based on exploring the global free energy landscape, which is refined by investigating individual reaction pathways. Furthermore, the impact of homolytic adsorption and desorption of hydrogen at the required reducing gas phase conditions is probed by studying such processes using different charge states of the F-center. PMID- 21322725 TI - Depletion at solid/liquid interfaces: flowing hexadecane on functionalized surfaces. AB - We present a neutron reflectivity study on interfaces in contact with flowing hexadecane, which is known to exhibit surface slip on functionalized solid surfaces. The single crystalline silicon substrates were either chemically cleaned Si(100) or Si(100) coated by octadecyl-trichlorosilane (OTS), which resulted in different interfacial energies. The liquid was sheared in situ and changes in reflectivity profiles were compared to the static case. For the OTS surface, the temperature dependence was also recorded. For both types of interfaces, density depletion of the liquid at the interface was observed. In the case of the bare Si substrate, shear load altered the structure of the depletion layer, whereas for the OTS covered surface no effect of shear was observed. Possible links between the depletion layer and surface slip are discussed. The results show that, in contrast to water, for hexadecane the enhancement of the depletion layer with temperature and interfacial energy reduces the amount of slip. Thus a density depletion cannot be the origin of surface slip in this system. PMID- 21322726 TI - Tunnel coupled dangling bond structures on hydrogen terminated silicon surfaces. AB - We study both experimentally and theoretically the electronic behavior of dangling bonds (DBs) at a hydrogen terminated Si(100)-2*1 surface. Dangling bonds behave as quantum dots and, depending on their separation, can be tunnel coupled with each other or completely isolated. On n-type highly doped silicon, the latter have a net charge of -1e, while coupled DBs exhibit altered but predictable filling behavior derived from an interplay between interdot tunneling and Coulomb repulsion. We found good correlation between many scanning tunneling micrographs of dangling bond structures and our theoretical results of a corresponding extended Hubbard model. We also demonstrated chemical methods to prevent tunnel coupling and isolate charge on a single dangling bond. PMID- 21322727 TI - Adlayer inhomogeneity without lateral interactions: rationalizing correlation effects in CO oxidation at RuO2(110) with first-principles kinetic Monte Carlo. AB - Microkinetic modeling of surface chemical reactions still relies heavily on the mean-field based rate equation approach. This approach is expected to be most accurate for systems without appreciable lateral interactions among the adsorbed chemicals, and there in particular for the uniform adlayers resulting in poisoned regimes with predominant coverage of one species. Using first-principles kinetic Monte Carlo simulations and the CO oxidation at RuO(2)(110) as a showcase, we demonstrate that even in this limit mean-field rate equations fail to predict the catalytic activity by orders of magnitude. This deficiency is traced back to the inability to account for the vacancy pair formation that is kinetically driven by the ongoing reactions. PMID- 21322728 TI - Orientational dynamics for an amphiphilic-solvent solution. AB - In this work, we performed Monte Carlo simulations on a lattice model for spontaneous amphiphilic aggregation, in order to study the orientational and hydrogen-bonding dynamics of water on different regions inside the micellar solution. We employed an associating lattice gas model that mimics the aqueous solvent, which presents a rich phase diagram with first- and second-order transition lines. Even though this is a simplified model, it makes possible to investigate the orientational dynamics of water in an equilibrium solution of amphiphiles, as well as the influence of the different phases of the solvent in the interfacial and bulk water dynamics. By means of extensive simulations, we showed that, at high temperatures, the behavior of the orientational relaxation and hydrogen bonding of water molecules in the bulk, first, and second hydration shells are considerable different. We observe the appearance of a very slow component for water molecules in the first hydration shell of micelles when the system reaches a high-density phase, consistent with previous theoretical and experimental studies concerning biological water. Also, at high temperatures, we find that water molecules in the second hydration shell of micelles have an orientational decay similar to that of bulk water, but with a generally slower dynamics. Otherwise, at low temperatures, we have two components for the orientational relaxation of bulk water in the low density liquid phase, and only a single component in the high density liquid (HDL) phase, which reflect the symmetry properties of the different phases of the solvent model. In the very dense region of water molecules in the first hydration shell of micelles at low temperatures, we find two components for the orientational relaxation on both liquid phases, one of them much slower than that in the single component of bulk water in the HDL phase. This happens even though our model does not present any hindrance to the water rotational freedom caused by the presence of the amphiphiles. PMID- 21322729 TI - Fluctuating lattice-Boltzmann model for complex fluids. AB - We develop and test numerically a lattice-Boltzmann (LB) model for nonideal fluids that incorporates thermal fluctuations. The fluid model is a momentum conserving thermostat, for which we demonstrate how the temperature can be made equal at all length scales present in the system by having noise both locally in the stress tensor and by shaking the whole system in accord with the local temperature. The validity of the model is extended to a broad range of sound velocities. Our model features a consistent coupling scheme between the fluid and solid molecular dynamics objects, allowing us to use the LB fluid as a heat bath for solutes evolving in time without external Langevin noise added to the solute. This property expands the applicability of LB models to dense, strongly correlated systems with thermal fluctuations and potentially nonideal equations of state. Tests on the fluid itself and on static and dynamic properties of a coarse-grained polymer chain under strong hydrodynamic interactions are used to benchmark the model. The model produces results for single-chain diffusion that are in quantitative agreement with theory. PMID- 21322730 TI - Shielding effects in polymer-polymer reactions. IV. Intermolecular contact formation between star-branched molecules. AB - Pairs of star-branched molecules--taken from ensembles of athermal five-way cubic lattice chains prepared by Monte Carlo simulation--are analyzed for the relative probability of mutual contact formation between particularly specified segments i and j belonging to different chains within these pairs. These contact probabilities--termed shielding factors K(ij)--are calculated by means of exact enumeration as a function of chain length ranging from n = 8 to 256 bonds per arm, as a function of functionality (i.e., the number of arms) ranging from F = 2 to 6 arms, and as a function of segment position within the arms ranging from central to terminal segments. In addition, changes of properties that characterize the size and shape of the involved molecules while approaching and penetration are evaluated as a function of chain separation. PMID- 21322731 TI - On the importance of thermodynamic self-consistency for calculating clusterlike pair correlations in hard-core double Yukawa fluids. AB - Understanding the mechanisms of clustering in colloids, nanoparticles, and proteins is of significant interest in material science and both chemical and pharmaceutical industries. Recently, using an integral equation theory formalism, Bomont et al. [J. Chem. Phys. 132, 184508 (2010)] studied theoretically the temperature dependence, at a fixed density, of the cluster formation in systems where particles interact with a hard-core double Yukawa potential composed of a short-range attraction and a long-range repulsion. In this paper, we provide evidence that the low-q peak in the static structure factor, frequently associated with the formation of clusters, is a common behavior in systems with competing interactions. In particular, we demonstrate that, based on a thermodynamic self-consistency criterion, accurate structural functions are obtained for different choices of closure relations. Moreover, we explore the dependence of the low-q peak on the particle number density, temperature, and potential parameters. Our findings indicate that enforcing thermodynamic self consistency is the key factor to calculate both thermodynamic properties and static structure factors, including the low-q behavior, for colloidal dispersions with both attractive and repulsive interactions. Additionally, a simple analysis of the mean number of neighboring particles provides a qualitative description of some of the cluster features. PMID- 21322732 TI - Escape of polymer chains from an attractive channel under electrical force. AB - The escape of polymer chains from an attractive channel under external electrical field is studied using dynamical Monte Carlo method. Though the escaping process is nonequilibrium in nature, results show that the one-dimensional diffusion theoretical model based on the equilibrium assumption can describe the dependence of the average escaping time (tau(0)) on the polymer-channel interaction (E), the electrical field (E), the chain length (n), and the channel length (L), qualitatively. Results indicate that both E and E play very important roles in the escaping dynamics. For small E, the polymer chain moves out of the channel continuously and quickly. While for large E, the polymer chain is difficult to move out of long channels as it is trapped for a long time (tau(trap)) when the end segment is near the critical point x(C). These results are consistent with the theoretical results for the free energy profiles at small E and large E, respectively. The dependence of x(C) and tau(trap) on E and E are discussed, and specific relations are obtained. The configurational properties of polymer chain are also investigated during the escaping process. PMID- 21322733 TI - The distributions of chain lengths in a crosslinked polyisoprene network. AB - A fundament of classical rubber elasticity theory is the Gaussian chain approximation formula, P(n,r) for the probability distribution of end-to-end distances of a polymer chain composed of n beads. It is considered to provide a realistic distribution of end-to-end distances, r, provided that the length of the polymer chain is much greater than its average end-to-end distance. By considering the number of beads (n) to be the independent variable, we can use P(n,r) to construct the probability distributions of network chain lengths, for fixed r. Since the network crosslinks reduce the probability for the occurrence of longer chains, the formula must be modified by a correction factor that takes this effect into account. We find that, both the shape of the n-probability distribution, its height, and the position of the peak vary significantly with r. We provide a numerical procedure for constructing networks that respect these distributions. The algorithm was implemented in a three-dimensional, random polymer-and-node network model to construct polyisoprene networks at two common crosslink densities. Although the procedure does not constrain the density, we find that the networks constructed have densities very close to the measured bulk density. PMID- 21322734 TI - Slow dynamics in protein fluctuations revealed by time-structure based independent component analysis: the case of domain motions. AB - Protein dynamics on a long time scale was investigated using all-atom molecular dynamics (MD) simulation and time-structure based independent component analysis (tICA). We selected the lysine-, arginine-, ornithine-binding protein (LAO) as a target protein and focused on its domain motions in the open state. A MD simulation of the LAO in explicit water was performed for 600 ns, in which slow and large-amplitude domain motions of the LAO were observed. After extracting domain motions by rigid-body domain analysis, the tICA was applied to the obtained rigid-body trajectory, yielding slow modes of the LAO's domain motions in order of decreasing time scale. The slowest mode detected by the tICA represented not a closure motion described by a largest-amplitude mode determined by the principal component analysis but a twist motion with a time scale of tens of nanoseconds. The slow dynamics of the LAO were well described by only the slowest mode and were characterized by transitions between two basins. The results show that tICA is promising for describing and analyzing slow dynamics of proteins. PMID- 21322735 TI - Biomolecules under mechanical stress: a simple mechanism of complex behavior. AB - The unfolding of a biomolecule by stretching force is commonly treated theoretically as one-dimensional dynamics along the reaction coordinate coincident with the direction of pulling. Here we explore a situation, particularly relevant to complex biomolecules, when the pulling direction alone is not an adequate reaction coordinate for the unfolding or rupture process. We show that in this case the system can respond to pulling force in unusual ways. Our theory points out a remarkably simple, but largely overlooked, mechanism of the complex responses of biomolecules to force. The mechanism originates from the basic property of the transition state to change its structure under applied force. A relationship is established between a key experimental observable--force dependent lifetime--and the microscopic properties of the biomolecule in the form of an analytical solution to the problem of a force-induced molecular transition in two dimensions. The theory is applicable to biological contexts ranging from protein folding to ligand-receptor interactions. PMID- 21322737 TI - A perturbation analysis of rate theory of self-regulating genes and signaling networks. AB - A thorough kinetic analysis of the rate theory for stochastic self-regulating gene networks is presented. The chemical master equation kinetic model in terms of a coupled birth-death process is deconstructed into several simpler kinetic modules. We formulate and improve upon the rate theory of self-regulating genes in terms of perturbation theory. We propose a simple five-state scheme as a faithful caricature that elucidates the full kinetics including the "resonance phenomenon" discovered by Walczak et al. [Proc. Natl. Acad. Sci. U.S.A. 102, 18926 (2005)]. The same analysis can be readily applied to other biochemical networks such as phosphorylation signaling with fluctuating kinase activity. Generalization of the present approach can be included in multiple time-scale numerical computations for large biochemical networks. PMID- 21322736 TI - Gaussian fluctuations in tethered DNA chains. AB - In a recent work [Gao et al., Appl. Phys. Lett. 134, 113902 (2007)], we reported a novel DNA separation method by tethering DNA chains to a solid surface and then stretching the DNA chains with an electric field. The anchor is such designed that the critical force to detach a DNA chain is independent of its length. Because the stretching force is proportional to the DNA net charge, a gradual increase of the electric field leads to size-based removal of the DNA strands from the surface and thus DNA separation. Originally proposed for separation of long double-stranded DNA chains (>10 000 bps), this method has been proven useful also for short single-stranded DNA fragments (<100 bases) for which the fluctuation force induced by the solvent becomes significant. Here we show that the fluctuation force can be approximately represented by a gaussian model for tethered DNA chains. Analytical expressions have been derived to account for the dependence of the fluctuation force on the surface confinement, the polymer chain length, and the DNA tethering potential. The theoretical predictions are found to coincide with experiment. PMID- 21322738 TI - Calculation of the Helmholtz potential of an elastic strand in an external electric field. AB - We derive from statistical mechanics the Gibbs free energy of an elastic random walk chain affected by the presence of an external electric field. Intrachain charge interactions are ignored. In addition, we find two approximations of the Helmholtz potential for this system analogous to the gaussian and Cohen-Pade approximations for an elastic strand without the presence of an electric field. Our expressions agree well with exact numerical calculations of the potential in a wide range of conditions. Our analog of the gaussian approximation exhibits distortion of the monomer density due to the presence of the electric field, and our analog of the Cohen-Pade approximation additionally includes finite chain extensibility effects. The Helmholtz potential may be used in modeling the dynamics of electrophoresis experiments. PMID- 21322739 TI - Hydrophobicity within the three-dimensional Mercedes-Benz model: potential of mean force. AB - We use the three-dimensional Mercedes-Benz model for water and Monte Carlo simulations to study the structure and thermodynamics of the hydrophobic interaction. Radial distribution functions are used to classify different cases of the interaction, namely, contact configurations, solvent separated configurations, and desolvation configurations. The temperature dependence of these cases is shown to be in qualitative agreement with atomistic models of water. In particular, while the energy for the formation of contact configurations is favored by entropy, its strengthening with increasing temperature is accounted for by enthalpy. This is consistent with our simulated heat capacity. An important feature of the model is that it can be used to account for well-converged thermodynamics quantities, e.g., the heat capacity of transfer. Microscopic mechanisms for the temperature dependence of the hydrophobic interaction are discussed at the molecular level based on the conceptual simplicity of the model. PMID- 21322740 TI - Statistical mechanics of helical wormlike chain model. AB - We investigate the statistical mechanics of polymers with bending and torsional elasticity described by the helical wormlike model. Noticing that the energy function is factorizable, we provide a numerical method to solve the model using a transfer matrix formulation. The tangent-tangent and binormal-binormal correlation functions have been calculated and displayed rich profiles which are sensitive to the combination of the temperature and the equilibrium torsion. Their behaviors indicate that there is no finite temperature Lifshitz point between the disordered and helical phases. The asymptotic behavior at low temperature has been investigated theoretically and the predictions fit the numerical results very well. Our analysis could be used to understand the statics of dsDNA and other chiral polymers. PMID- 21322741 TI - Note: Deperturbation of the nu3 band of BeD2. AB - High rotational levels of the 001 (Sigma(u)) state of BeD(2) are perturbed by the nearby 03(3)0 (Phi(u)) state. Deperturbation analysis results in an experimental value for the vibrational energy of the 030 level. PMID- 21322744 TI - Retraction. PMID- 21322745 TI - Registration of CT to 3D ultrasound using near-field fiducial localization: A feasibility study. AB - OBJECTIVE: Registration of ultrasound to computed tomography (CT) images is used in several image-guided procedures, including laparoscopic surgery and radiation therapy. Conventional approaches use an external tracker calibrated to the ultrasound transducer and CT system, but several calibration steps are required. Registration can also be performed by aligning image features between modalities, but differences in feature depiction make matching difficult and initial approximate alignment is often needed. Registration using fiducials is a simpler approach but is limited by the need to implant fiducials in the anatomical region of interest so they are visible to both ultrasound and CT. This paper investigates the feasibility of using fiducials near the skin surface, and whether such fiducials can be sufficiently localized in the very near field of a 3D ultrasound transducer without significantly degrading image quality. This approach can also be used as an initialization step for feature-based registration techniques. MATERIALS AND METHODS: A stand-off pad containing fiducials (n > 3) was constructed using polyvinyl chloride and steel ball fiducials that are visible in both 3D ultrasound and CT images. Experiments on phantoms were performed to assess image quality and registration errors. Controlled variables included pad thickness and ultrasound imaging parameters. Initial tests were also conducted of a potential application in partial nephrectomy surgery. RESULTS: Image quality was degraded by an average of 6-11 13% (elevational-axial-lateral) in resolution of point targets and 5% in lesion contrast. Average fiducial localization error was 1.34 mm (axial) to 2.38 mm (lateral and elevational); average fiducial registration error (FRE) was 0.46 mm (axial), 1.08 mm (lateral) and 0.90 mm (elevational); and average total registration error (TRE) was 1.84 mm (axial), 0.89 mm (lateral) and 3.31 mm (elevational). Clinical results showed a similar FRE to that in the phantom study, but with an average TRE of 14.04 mm (over three patients). Ultimate alignment of the organ boundaries was affected mainly by motion from respiration. CONCLUSIONS: The small loss of image quality from the fiducial stand-off pad and the minimal inconvenience of using the pad at the time of the CT scan may be a worthwhile trade-off for purposes of registration since the pad provides a registration accuracy of several millimeters while still allowing subsequent feature-based registration. Future research will focus on using the registration from the fiducial stand-off pad for deformable feature-based registration of 3D ultrasound to CT for tumor localization in renal surgery. PMID- 21322746 TI - Determination of the Whiteside line on femur surface models by fitting high-order polynomial functions to cross-section profiles of the intercondylar fossa. AB - Innovative methods for morphological and functional analysis of bones have become a primary objective in the development of planning systems for total knee replacement (TKR). These methods involve the interactive identification of clinical landmarks (reference points, distances, angles, and functional axes of movement) and the determination of the optimal implant size and positioning. Among the functional axes used to estimate the correct alignment of the femoral component, the Whiteside line, namely, the anterior-posterior (AP) direction, is one of the most common. In this paper, we present a computational framework that allows automatic identification of the Whiteside line. The approach is based on geometric analysis of the saddle shape of the intercondylar fossa to extract the principal line in the AP direction. A plane parallel to the frontal plane is moved in the AP direction to obtain the 2D profiles of the intercondylar fossa. Each profile is fitted to a fifth-order polynomial curve and its maximum curvature point computed. The point set collected across all the profiles is then processed to compute the principal direction. The 2D profile-fitting and 3D line fitting residual errors were analyzed to study the relationship between the intercondylar fossa aspect and the nominal saddle surface. The method was validated using femur specimens from elderly subjects reconstructed from CT scans. The repeatability of the method was evaluated across five different femur surface resolutions. For comparison, three expert orthopaedic surgeons identified, by virtual palpation, the Whiteside line on the same 3D femur models. The repeatability (median angular error) of the Whiteside lines computed by the automated method and by manual virtual palpation, was approximately 1.0 degrees and 3.5 degrees , respectively. The angular skew error between the two axes, measured on the axial plane, averaged approximately 4.00 degrees (SD: 2.64 degrees ) with no statistical difference. The automated method therefore proved more reproducible and was in agreement with the manual method. We conclude that operator-independent methods, such the one presented in this paper, can be favorably introduced into orthopaedic surgical planning systems. PMID- 21322747 TI - Trophoblast apoptosis in human term placentas from pregnancies complicated with idiopathic intrauterine growth retardation. AB - OBJECTIVE: To investigate proliferative, apoptotic, and antiapoptotic activity of placental trophoblast in pregnancies complicated with idiopathic intrauterine growth retardation (IUGR). METHODS: Study group included data and placentas from 52 normal singleton term pregnancies with idiopathic IUGR. Records and placentas from 69 singleton pregnancies with normal fetal growth served as a control group. IUGR was defined by birth weight less than 10th percentile of standard values. Children with congenital malformations and those born with the signs of hypoxia, laboratory or clinical signs of preeclampsia or infection, children born to anemic mothers and those born from pregnancies with an increased coagulation system activity were excluded. RESULTS: There was no statistically significant difference in the cytotrophoblast proliferation index value (Z = 0.24; P = 0.553), trophoblast expression of the Bcl-2 antiapoptotic factor (Z = 0.47; P = 0.634), and trophoblast apoptotic index (Z = 0.51; P = 0.613) between the idiopathic IUGR and control group. CONCLUSION: The proliferative and apoptotic events in the trophoblast of placentas with idiopathic IUGR did not differ from physiologic ones. Study results suggest the IUGR syndrome to have no uniform etiology or even underlying pathophysiology that would determine the possible fetal risk and subsequent long-term consequences for fetal health and life. This imposes the need of a more precise definition and unambiguous distinction between the idiopathic and other forms of IUGR. PMID- 21322748 TI - Intrauterine transmission of H1N1 disease: a theory that needs evidence! AB - Three pandemics of influenza in the 20th century have been described. Unfortunately, a little is known about the effect of those pandemics on newborn infants. We are reporting our experience with newborns born to mothers proved to have H1N1 illness perinatally, who presented with sepsis-like illness at birth or shortly after, and were treated as having H1N1 disease. This study will report on the clinical features, outcome and discuss diagnosis and treatment challenges and also the possibility of intrauterine H1N1 transmission. Our cases had good neonatal outcome, H1N1 intrauterine transmission still a possibility that needs further research efforts. PMID- 21322749 TI - Megakaryocytes derived from patients with the classical form of Bernard-Soulier syndrome show no ability to extend proplatelets in vitro. PMID- 21322750 TI - Tityus discrepans scorpion venom activates platelets through GPVI and a novel Src dependent signaling pathway. AB - In humans and other mammals, Tityus discrepans (Td) scorpion envenomation produces a variety of systemic effects including respiratory distress, a generalized inflammatory reaction, modulation of blood pressure, fibrin formation, and platelet activation. For many of these effects, the venom components and underlying mechanisms are not known. In the present study, we demonstrate that Td venom (TdV) stimulates integrin alphaIIbbeta3-dependent aggregation of washed human and mouse platelets downstream of Src kinase activation. The pattern of increase in tyrosine phosphorylation induced by TdV in human platelets is similar to that induced by the collagen receptor GPVI, and includes FcR gamma-chain, Syk, and PLC gamma 2. Confirmation of GPVI activation by TdV was achieved by expression of human GPVI in chicken DT40 B cells and use of a reporter assay. To our surprise, TdV was able to activate mouse platelets deficient in the GPVI-FcR gamma-chain complex through a pathway that was also dependent on Src kinases. TdV therefore activates platelets through GPVI and a second, as yet unidentified Src kinase-dependent pathway. PMID- 21322751 TI - In vitro or in vivo expansion before adoptive T-cell therapy? PMID- 21322752 TI - Adoptive T-cell immunotherapy using T-cell receptor gene transfer: aiming at a cure for cancer. PMID- 21322755 TI - Conference scene: lessons from animal models of autoimmune diseases: from mechanisms to applications. AB - Autoimmune diseases are a group of maladies in which the patient's immune homeostasis becomes so deregulated that it mounts a destructive attack against the hosts tissues. Such diseases are characterized by an activation of autoreactive T and B cells and are associated, in some cases, with the production of pathogenic antibodies against self-molecules, culminating in inflammation and tissue damage. Target tissues can be from immune-vulnerable and immune-privileged sites. In view of the complex nature of autoimmune diseases, it is not surprising that they have long baffled immunologists, physicians and basic biomedical scientists who are struggling to combine known immunoinflammatory mechanisms into a unified general theory. The present seminar, organized by Euroscion, hosted a group of national and international scientists, affiliated to both academic and industrial research, to discuss state-of-the-art animal models for investigating pathomechanisms of autoimmune diseases, novel laboratory-based diagnostics and novel therapeutic prospects. The timely event on this important topic covered significant features of the basic pathomechanisms of autoimmune disease per se, the development of diagnostic and prognostic tests using functional biomarkers for monitoring patients and the development of targeted therapies. The absence of several prescheduled speakers allowed younger scientists, Stefan Kurten, Liliane Fossati-Jimack and Allan Holmes to shine. We are grateful for their participation. This meeting report describes key points and themes arising from this conference. PMID- 21322756 TI - Abagovomab: an anti-idiotypic CA-125 targeted immunotherapeutic agent for ovarian cancer. AB - Ovarian cancer remains the leading cause of death due to gynecologic malignancies. Most patients present with advanced disease at the time of diagnosis. Although many have a good initial response to surgical debulking and platinum-based chemotherapy, relapse is common, with the eventual development of chemotherapy resistance. Innovative treatments are needed in the remission setting to prolong the disease-free interval or prevent recurrence. Abagovomab is a murine monoclonal anti-idiotypic antibody (molecular weight: 165-175 kDa) that functionally imitates the tumor-associated antigen, CA-125. It has been shown to be well tolerated and to induce a sustained immune response in initial Phase I and II clinical trials. An ongoing, double-blind, placebo-controlled, multicenter, Phase III trial (MIMOSA) completed its double-blind period in December 2010 and will compare abagovomab maintenance therapy to placebo, which will definitively determine the efficacy of this immunotherapeutic approach in patients with ovarian cancer. PMID- 21322757 TI - L-proline-stabilized human IgG: Privigen(r) 10% for intravenous use and Hizentra(r) 20% for subcutaneous use. AB - Liquid IgG preparations are preferred over lyophilized preparations because reconstitution is not required. Formation of dimers and aggregates in liquid preparations increases adverse effects and limits the shelf life of most liquid IgG products. Improved understanding of the binding interactions in IgG dimers and aggregates led to the selection of L-proline at pH 4.8 as an excipient that would minimize their formation. CSL Behring has developed the L-proline stabilized products Privigen(r), a 10% IgG solution for intravenous use; and Hizentra(r), a 20% solution for subcutaneous use. The former has the longest shelf life of any liquid IgG in the USA--36 months, and the latter is the most concentrated IgG available. These improvements, which translate into improved convenience for pharmacies and patients, were achieved with no compromise in safety, efficacy or tolerability of the products. PMID- 21322758 TI - Effective adoptive T-cell therapy for cancer in the absence of host lymphodepletion. AB - Evaluation of: Ly LV, Sluijter M, Versluis M et al.: Peptide vaccination after T cell transfer causes massive clonal expansion, tumor eradication and manageable cytokine storm. Cancer Res. 70(21), 8339-46 (2010). Adoptive T-cell transfer (ACT) to treat cancer, autoimmunity and infectious disease holds great promise. In the cancer field, current dogma suggests that achieving a high frequency of circulating, transferred T cells is critical for therapeutic success. Achieving this high level of T-cell engraftment currently requires preconditioning of the patient. In effect, this means the eradication of the patient's own immune system, thereby creating 'space' for the adoptively transferred T cells to populate in the absence of host-cell competition. While different forms of preconditioning are employed, each carries a significant level of toxicity itself. In the paper being evaluated, Ly et al. demonstrate that the combination of ACT with vaccination using long peptides, a Toll-like receptor-7 ligand and cytokine support in the form of IL-2 can drive the expansion of adoptively transferred antigen-specific T cells in the absence of preconditioning regimens. This paper infers that reduced intensity regimens may be suitable for ACT clinical protocols. PMID- 21322759 TI - Antibody-enzyme fusion proteins for cancer therapy. AB - Advances in biomolecular technology have allowed the development of genetically fused antibody-enzymes. Antibody-enzyme fusion proteins have been used to target tumors for cancer therapy in two ways. In one system, an antibody-enzyme is pretargeted to the tumor followed by administration of an inactive prodrug that is converted to its active form by the pretargeted enzyme. This system has been described as antibody-directed enzyme prodrug therapy. The other system uses antibody-enzyme fusion proteins as direct therapeutics, where the enzyme is toxic in its own right. The key feature in this approach is that the antibody is used to internalize the toxic enzyme into the tumor cell, which activates cell-death processes. This antibody-enzyme system has been largely applied to deliver ribonucleases. This article addresses these two antibody-enzyme targeting strategies for cancer therapy from concept to (pre)clinical trials. PMID- 21322761 TI - Hymenoptera venom immunotherapy. AB - Subcutaneous venom immunotherapy is the only effective treatment for patients who experience severe hymenoptera sting-induced allergic reactions, and the treatment also improves health-related quality of life. This article examines advances in various areas of this treatment, which include the immunological mechanisms of early and long-term efficacy, indications and contraindications, selection of venom, treatment protocols, duration, risk factors for systemic reactions in untreated and treated patients as well as for relapse following cessation of treatment. Current and future strategies for improving safety and efficacy are also examined. However, although progress in the past few years has been fruitful, much remains to be accomplished. PMID- 21322760 TI - Small-molecule protein kinase inhibitors and their effects on the immune system: implications for cancer treatment. AB - Oncogenic signaling pathways have emerged as key targets for the development of small-molecule inhibitors, with several protein kinase inhibitors already in clinical use for cancer patients. In addition to their role in tumorigenesis, many of the molecules and signaling pathways targeted by these inhibitors are also important in the signaling and interaction of immune cells, such as T cells and dendritic cells. Not surprisingly, there is increasing evidence that many of these inhibitors can have a substantial impact on immune function, both stimulating and downregulating an immune response. In order to illustrate the important role of signaling molecule inhibition in the modulation of immune function, we will discuss the exemplary pathways MAPK, AKT-PI3K-mTOR and VEGF VEGFR, as well as selected small-molecule inhibitors, whose impact on immune cells has been studied more extensively. PMID- 21322762 TI - Immunotherapeutic restoration in HIV-infected individuals. AB - While the development of combined active antiretroviral therapy (cART) has dramatically improved life expectancies and quality of life in HIV-infected individuals, long-term clinical problems, such as metabolic complications, remain important constraints of life-long cART. Complete immune restoration using only cART is normally unattainable even in cases of sufficient plasma viral suppression. The need for immunologic adjuncts that complement cART remains, because while cART alone may result in the complete recovery of peripheral net CD4+ T lymphocytes, it may not affect the reservoir of HIV-infected cells. Here, we review current immunotherapies for HIV infection, with a particular emphasis on recent advances in cytokine therapies, therapeutic immunization, monoclonal antibodies, immune-modulating drugs, nanotechnology-based approaches and radioimmunotherapy. PMID- 21322763 TI - Vaccines and immunotherapeutics for the prevention and treatment of infections with West Nile virus. AB - The emergence of West Nile virus (WNV) in North America in 1999 as a cause of severe neurological disease in humans, horses and birds stimulated development of vaccines for human and veterinary use, as well as polyclonal/monoclonal antibodies and other immunomodulating compounds for use as therapeutics. Although disease incidence in North America has declined since the peak epidemics in 2002 2003, the virus has continued to be annually transmitted in the Americas and to cause periodic epidemics in Europe and the Middle East. Continued transmission of the virus with human and animal disease suggests that vaccines and therapeutics for the prevention and treatment of WNV disease could be of great benefit. This article focuses on progress in development and evaluation of vaccines and immunotherapeutics for the prevention and treatment of WNV disease in humans and animals. PMID- 21322764 TI - Therapeutic potential of vaccines for Alzheimer's disease. AB - The pathological hallmarks of Alzheimer's disease (AD) are amyloid-beta (Abeta) plaques and Tau-containing neurofibrillary tangles. Although the relationship between neuronal loss and the presence of plaques/tangles is not well understood, the prevailing Abeta hypothesis posits that excessive accumulation of conformers and assemblies of Abeta protein precedes AD-related dementia and neuronal loss. Consequently, most disease-modifying immunotherapy approaches are directed towards modulating the levels of Abeta. The first AD vaccine clinical trial (AN1792) was suspended after the patients developed meningoencephalitis. In spite of the setback, the trial provided insights to refine development second generation vaccines, which are attempting to resolve the side effects observed in the trial. This article provides an analysis of these efforts. PMID- 21322766 TI - Deterioration of hearing in a cochlear implantee with relapsing polychondritis. AB - We report on a rare case of cochlear implantation in a patient affected by relapsing polychondritis (RP), which over time induced cochlear fibrosis/ossification and deterioration of previously excellent hearing performance. The clinical course was determined by CT scan, electrophysiology, and speech perception data. We conclude that RP is a severe autoimmune connective disorder that can cause profound sensorineural hearing loss. Cochlear implantation in these patients can provide excellent performance. Continuation of therapy may improve prognosis, but relapses involving inner ear structures can determine fibrosis/ossification of the modiolus and interfere with cochlear implant use. PMID- 21322767 TI - Altered excitability of cultured chromaffin cells following exposure to multi walled carbon nanotubes. AB - We studied the effects of multi-walled carbon nanotubes (MWCNTs) on the electrophysiological properties of cultured mouse chromaffin cells, a model of spontaneously firing cells. The exposure of chromaffin cells to MWCNTs at increasing concentrations (30-263 MUg/ml) for 24 h reduced, in a dose-dependent way, both the cell membrane input resistance and the number of spontaneously active cells (from 80-52%). Active cells that survived from the toxic effects of MWCNTs exhibited more positive resting potentials, higher firing frequencies and unaltered voltage-gated Ca(2+), Na(+) and K+ current amplitudes. MWCNTs slowed down the inactivation kinetics of Ca(2+)-dependent BK channels. These electrophysiological effects were accompanied by MWCNTs internalization, as confirmed by transmission electron microscopy, indicating that most of the toxic effects derive from a dose-dependent MWCNTs-cell interaction that damages the spontaneous cell activity. PMID- 21322768 TI - Fermented milk containing Lactobacillus casei strain Shirota reduces incidence of hard or lumpy stools in healthy population. AB - The objective of the present study was to investigate the efficacy of fermented milk containing Lactobacillus casei strain Shirota (LcS) in a healthy population. Healthy subjects with Bristol Stool Form Scale (BS) score < 3.0 were randomized to fermented milk treatment for 3 weeks or non-intervention control. The primary endpoint was the proportion of subjects that produced hard or lumpy stools (HLS) >= 25% of bowel movements (H-HLS). Secondary endpoints included changes in BS score, constipation-related symptom scores and stool parameters. Efficacy was analyzed in 39 subjects. After 3 weeks of treatment the proportion of H-HLS subjects had significantly decreased from 73.7% to 36.8%, whereas in the control group the proportion had increased from 75.0% to 85.0% during the same period (P = 0.002). The BS score was significantly improved after the treatment compared with the control (P < 0.001). In conclusion, daily consumption of fermented milk containing LcS reduced the incidence of HLS. PMID- 21322769 TI - Statement of retraction. Withdrawn: HbE genotypes and fertility: a study on a Tibeto-Burmese population in Upper Assam, India. PMID- 21322770 TI - Cross-sectional study of risk factors for atherosclerosis in the Azorean population. AB - BACKGROUND: Atherosclerosis-a major cause of vascular disease, including ischemic heart disease (IHD), is a pathology that has a two-fold higher mortality rate in the Azorean Islands compared to mainland Portugal. AIM: This cross-sectional study investigated the role of genetic variation in the prevalence of atherosclerosis in this population. SUBJECTS AND METHODS: A total of 305 individuals were characterized for polymorphisms in eight susceptibility genes for atherosclerosis: ACE, PAI1, NOS3, LTA, FGB, ITGB3, PON1 and APOE. Data were analysed with respect to phenotypic characteristics such as blood pressure, lipid profile, life-style risk factors and familial history of myocardial infarction. RESULTS: In the total sample, frequencies for hypercholestrolemic, hypertensive and obese individuals were 63.6%, 39.3% and 23.3%, respectively. The genetic profile was similar to that observed in other European populations, namely in mainland Portugal. No over-representation of risk alleles was evidenced in this sample. CONCLUSIONS: One has to consider the possibility of an important non genetic influence on the high cholesterolemia present in the Azorean population. Since diet is the most important life-style risk factor for dyslipidemia, studies aiming to evaluate the dietary characteristics of this population and its impact on serum lipid levels will be of major importance. PMID- 21322771 TI - Menarcheal age in Turkey: secular trend and socio-demographic correlates. AB - BACKGROUND: Menarche is an important indicator for assessing the developmental status of pubertal girls. Despite its importance, there is no nationwide information on menarcheal age in Turkey. AIM: This paper is the first attempt to examine age at menarche for Turkey as a whole. The aim is to present the secular trend of menarcheal age and variations across different socio-demographic groups. METHODS: Data were employed from the Turkey Demographic and Health Survey, 2008. Mean menarcheal ages were estimated for birth cohorts and socio-demographic sub groups. The pace of decline in menarcheal age has been estimated using multiple linear regression analysis, controlling for year of birth and other variables. RESULTS: Mean age at menarche was estimated as 13.30 (95% CI = 13.26-13.35). It was estimated as 13.17 years (95% CI 12.95-13.38) for the youngest birth cohort (1989-1993), as opposed to 13.44 (95% CI 13.37-13.52) years for the cohort born in 1959-1968. CONCLUSION: Regression analysis indicated a decrease of 1.44 months per decade, providing evidence of a secular trend in menarcheal age in Turkey. Further results suggested childhood place of residence, education, welfare status and number of siblings to be significantly associated with menarcheal age. PMID- 21322772 TI - Predicting venous thromboembolism in hospitalized medical patients: are we there yet? PMID- 21322774 TI - Incidence of cytomegalovirus infection and disease in patients with lymphoproliferative disorders treated with alemtuzumab. AB - The aim of this study was to assess the incidence of cytomegalovirus (CMV) infection and disease in patients with hematologic malignancies treated with alemtuzumab. The outcome of CMV infection in hematologic patients treated with alemtuzumab in 19 hospitals throughout Spain was assessed retrospectively. Data were collected from the medical records of patients over a period of 6 months following initiation of alemtuzumab therapy. We studied 102 patients (89 with B cell chronic lymphocytic leukemia and 13 with other lymphoproliferative diseases, with a median age of 63 years [range 29-81 years]). Alemtuzumab was administered for a mean of 11.2 (standard deviation: 13.8) weeks, with a median total dose of 423 mg (range: 59-1440 mg). Alemtuzumab as a single agent was administered in 92.2% of patients and was associated with chemotherapy in 7.8% of cases. Prophylactic antivirals included famcyclovir (47%), acyclovir (34%), valacyclovir (14%) and valgancyclovir (5%). CMV viremia testing was performed a mean of 6.3 times (range: 1-19). The incidence of CMV infection was 38.9% (46% in patients treated with steroids and 75% in patients receiving >=1000 mg of alemtuzumab). Treatment of CMV infection included gancyclovir or valgancyclovir in 94% of cases. Viremia became negative after a median of 20 days (95% CI: 13.4-26.6). CMV disease occurred in five patients. The incidence of CMV infection in alemtuzumab treated patients was 38.9%. The incidence increased in patients treated concomitantly with steroids and in those treated with high doses of alemtuzumab, although only eight patients received 1000 mg or more, systematic monitoring of CMV viremia and early treatment of infection resulted in a favorable outcome of CMV reactivation. PMID- 21322775 TI - Iron chelation in thalassemia: time to reconsider our comfort zones. AB - Over the last 20 years, the management of thalassemia major has improved to the point where we predict that the patients' life expectancy will approach that of the normal population. These outcomes result from safer blood transfusions, the availability of three iron chelators, new imaging techniques that allow organ specific assessment of the degree of iron overload and improvement in the treatment of hepatitis. The ability to prescribe any of the three chelators, as well as their combinations, has led to a more effective reduction of the total body iron. The ability to determine the amount of iron in the liver and heart by MRI has allowed the prescription of the most appropriate chelation regime for the patient and has allowed the reconsideration of 'the comfort zones'. Thus, normalizing iron stores not only prevents new morbidities but also reverses many complications, such as cardiac failure, hypothyroidism, hypogonadism, impaired glucose tolerance and Type 2 diabetes, therefore improving survival and patients' quality of life. Furthermore, outcomes should continue to improve in the future. Starting relatively intensive chelation in younger children may prevent short stature and abnormal pubertal maturation, as well as other iron-related morbidities. In addition, further information should become available on the use of other combinations in chelation treatment, some of which have only been used in a very limited fashion so far. New safe oral chelators may also become available that may offer additional ease of use. All these advances in management do require absolute cooperation and understanding on behalf of children's parents and subsequently the adult themself. Only with such cooperation can normal long term survival be achieved as it is likely that adherence to treatment is the primary barrier to longevity. PMID- 21322776 TI - Personalizing treatment for chronic lymphocytic leukemia. AB - Over the past few years, more effective therapies have emerged in the treatment of chronic lymphocytic leukemia (CLL); these are mainly combinations of immunotherapy with fludarabine-based regimens. Despite the higher response rates obtained with these more intensive treatments, they may not always be applicable. Patients with several comorbidities have an increased toxicity with these newer therapies. Effective tools to distinguish between fit and nonfit patients and new therapeutic approaches suitable for fragile patients with CLL are therefore necessary. Moreover, there is still a subset of patients who are refractory to standard fludarabine-based treatments who continue to have very poor survival. Efforts to understand the mechanisms of resistance to treatment in order to develop new therapeutic agents for those patients are mandatory. Finally, advances in the knowledge of the pathogenesis of CLL are promoting the emergence of drugs directed to new biological targets of this disease. Consequently, trials exploring the toxicity profile and efficacy of these new therapeutic agents, alone or in combination with standard treatments, are warranted. PMID- 21322778 TI - Thalidomide, lenalidomide and bortezomib in the management of newly diagnosed multiple myeloma. AB - The field of multiple myeloma therapeutics has been an active one for many years, but perhaps no more so than in the past decade. The introduction of thalidomide, lenalidomide and bortezomib in the treatment of this disease highlights clinical advances made during this period. While these agents were initially utilized in the setting of relapsed and refactory disease, they are now part of the therapeutic armamentarium for transplant-eligible and transplant-ineligible patients with newly diagnosed multiple myeloma. The principles of management applied in the care of newly diagnosed multiple myeloma are reviewed in this article, along with the clinical studies supporting the use of thalidomide, lenalidomide and bortezomib in newly diagnosed multiple myeloma. Management of treatment-related side effects is also discussed, since it constitutes a critical element in the successful management of patients with this disease. Combination regimens utilizing thalidomide, lenalidomide and bortezomib are also highlighted, as these regimens are likely to play an increasingly important role in myeloma therapy in the future. PMID- 21322779 TI - Biology and treatment of the 5q- syndrome. AB - The 5q- syndrome is a unique subtype of myelodysplastic syndromes typified by a relatively indolent course and responsiveness to lenalidomide. Here, we review the salient biologic features of this disease. Hemizygous deletion of a segment of chromosome 5q is believed to be the disease-initiating event. Recent molecular techniques have isolated the common deleted region and characterized key candidate genes contributing to the disease phenotype. Gene-specific RNA interference strategies revealed that haplo-insufficiency for the RPS14 gene, which encodes a ribosomal protein, is a critical effector of the p53-dependent erythroid hypoplasia and apoptotic loss of erythroid precursors. Disease-specific sensitivity to lenalidomide results from the drug's inhibitory effect on two haplodeficient phosphatases, PP2Acalpha and CDC25c, which are coregulators of the G(2)/M checkpoint. Hyperphosphorylation of MDM2, as a result of inhibition of PP2A phosphatase activity, stabilizes MDM2, permitting p53 degradation and transition to G(2) arrest and clonal suppression. With the emerging data elucidating the pathogenesis of the 5q- syndrome and the success of clinical trials, a cohesive story connecting the biology and pharmacology associated with this subtype of myelodysplastic syndromes has emerged. PMID- 21322777 TI - Vaccines as consolidation therapy for myeloid leukemia. AB - Immunotherapy for myeloid leukemias remains a cornerstone in the management of this highly aggressive group of malignancies. Allogeneic (allo) stem cell transplantation (SCT), which can be curative in acute and chronic myeloid leukemias, exemplifies the success of immunotherapy for cancer management. However, because of its nonspecific immune response against normal tissue, allo SCT is associated with high rates of morbidity and mortality, secondary to graft versus-host disease, which can occur in up to 50% of allo-SCT recipients. Targeted immunotherapy using leukemia vaccines has been heavily investigated, as these vaccines elicit specific immune responses against leukemia cells while sparing normal tissue. Peptide and cellular vaccines have been developed against tumor-specific and leukemia-associated self-antigens. Although not yet considered the standard of care, leukemia vaccines continue to show promising results in the management of the myeloid leukemias. PMID- 21322780 TI - Iron overload and allogeneic hematopoietic stem-cell transplantation. AB - Iron overload is frequently observed in patients with hematologic diseases before and after allogeneic stem-cell transplantation because they usually receive multiple red blood cell transfusions. Elevated pretransplant serum ferritin levels, which are widely used as indicators of body iron status, are significantly associated with a lower overall survival rate and a higher incidence of treatment-related complications; for example, infections and hepatic veno-occlusive disease. As serum ferritin levels are affected, not only by iron loading but also by inflammation, imaging techniques to quantify tissue iron levels have been developed, for example, quantitative MRI using the transverse magnetic relaxation rate, and superconducting quantum interference devices. Iron chelators, such as deferasirox, a new oral iron-chelating agent, reduce iron load in transfusion-dependent patients. Iron-chelating therapy before and/or after transplantation is a promising strategy to improve the clinical outcomes of transplant patients with iron overload. However, further research is needed to prove the direct relationship between iron overload and adverse outcomes, as well as to determine the effects of treatment for iron overload on outcomes of allogeneic stem-cell transplantation. PMID- 21322781 TI - Pain in malignant hematology. AB - Pain is frequently experienced by patients with hematological malignancies, although it often receives little attention. Different underlying causes and mechanisms may sustain several pain syndromes in hematological malignant patients. Pain may be due to disease itself, to disease-related complications, to iatrogenic causes or may be associated with unrelated medical conditions. The management of pain in this setting requires a multidisciplinary approach, integrating analgesics and causal interventions. An accurate diagnostic assessment and the identification of the underlying causes and pathogenetic mechanisms may dictate the treatment approach. For most pain patients, the WHO's three-step analgesic scale for cancer pain relief can provide adequate relief with oral options, although difficult-to-treat pain syndromes, requiring a more complex treatment approach, may also be observed. PMID- 21322782 TI - Advances in the diagnosis and management of type 1 von Willebrand disease. AB - Von Willebrand disease (VWD) is an autosomally inherited bleeding disorder caused by a deficiency and/or abnormality of von Willebrand factor (VWF). VWF is a multimeric adhesive protein that plays an important role in primary hemostasis by promoting platelet adhesion to the subendothelium at sites of vascular injury and platelet-platelet interactions at high-shear rate conditions. Furthermore, VWF is the carrier of factor VIII, thus indirectly contributing to the coagulation process. Most cases have a partial quantitative deficiency of VWF (type 1 VWD) with variable bleeding tendency, whereas qualitative variants (type 2 VWD), due to a dysfunctional VWF, are clinically more homogeneous and account for approximately 20-30% of cases. Type 3 VWD is rare and these patients have moderate-to-severe bleeding diathesis, display a recessive pattern of inheritance and virtual absence of VWF. The diagnosis of VWD may be difficult, especially in type 1 disease, since the laboratory phenotype of the disorder is very heterogeneous and confounded by the influence on VWF levels by factors outside the VWF gene (e.g., blood group). An array of tests are usually required to characterize the several types of the disorder in order to predict the best treatment modality. Desmopressin is the treatment of choice for most patients with type 1 VWD because it corrects the the dual defects of hemostasis, that is, abnormal coagulation expressed by low levels of factor VIII and abnormal platelet adhesion expressed by the reduction of VWF. PMID- 21322783 TI - Current treatment options for primary immune thrombocytopenia. AB - Traditional treatment of primary (idiopathic) immune thrombocytopenia (ITP) predominantly consists of immune suppression and/or modulation. In addition, many treated patients develop severe adverse effects, and approximately a third of patients do not respond. Two of the newly developed thrombopoietin-receptor agonists, romiplostim and eltrombopag, are now available for the treatment of ITP. Both drugs have been shown to increase the production of platelets in a dose dependent manner, and to compensate, at least partly, for thrombocytopenia in the majority of ITP patients. The reported adverse effects are predominantly mild, although serious and long-term side effects cannot be excluded. Nevertheless, these drugs are increasingly used in the treatment of patients with thrombocytopenias. Thrombopoietin-receptor agonists do not appear to stop either the production of autoantibodies or the accelerated platelet destruction observed in ITP. Thus, the need for a specific therapy is essential, and the ultimate solution is to clarify and halt the mechanism(s) that lead to the development of ITP. PMID- 21322785 TI - Derivation of cloned human blastocysts by histone deacetylase inhibitor treatment after somatic cell nuclear transfer with beta-thalassemia fibroblasts. AB - Derivation of embryonic stem cells from patient-specific cloned blastocysts by somatic cell nuclear transfer (SCNT) holds promise for both regenerative medicine and cell-based drug discovery. However, the efficiency of blastocyst formation after human SCNT is very low. The developmental competence of SCNT embryos has been previously demonstrated in several species to be enhanced by treatment with histone deacetylase inhibitors, such as trichostatin A (TSA), to increase histone acetylation. In this study, we report that treatment of SCNT embryos with 5 nM TSA for 10 h following activation incubation increased the developmental competence of human SCNT embryos constructed from beta-thalassemia fibroblast cells. The efficiency of blastocyst formation from SCNT human embryos treated with TSA was approximately 2 times greater than that from untreated embryos. Cloned blastocysts were confirmed to be generated through SCNT by DNA and mitochondrial DNA fingerprinting analyses. Further, treatment of SCNT embryos with TSA improved the acetylation of histone H3 at lysine 9 in a manner similar to that observed in in vitro fertilized embryos. PMID- 21322790 TI - Forced Runx1 expression in human neural stem/progenitor cells transplanted to the rat dorsal root ganglion cavity results in extensive axonal growth specifically from spinal cord-derived neurospheres. AB - Cell replacement therapy holds great promise for treating a wide range of human disorders. However, ensuring the predictable differentiation of transplanted stem cells, eliminating their risk of tumor formation, and generating fully functional cells after transplantation remain major challenges in regenerative medicine. Here, we explore the potential of human neural stem/progenitor cells isolated from the embryonic forebrain (hfNSPCs) or the spinal cord (hscNSPCs) to differentiate to projection neurons when transplanted into the dorsal root ganglion cavity of adult recipient rats. To stimulate axonal growth, we transfected hfNSPC- and hscNSPC-derived neurospheres, prior to their transplantation, with a Tet-Off Runx1-overexpressing plasmid to maintain Runx1 expression in vivo after transplantation. Although pronounced cell differentiation was found in the Runx1-expressing transplants from both cell sources, we observed extensive, long-distance growth of axons exclusively from hscNSPC-derived transplants. These axons ultimately reached the dorsal root transitional zone, the boundary separating peripheral and central nervous systems. Our data show that hscNSPCs have the potential to differentiate to projection neurons with long-distance axonal outgrowth and that Runx1 overexpression is a useful approach to induce such outgrowth in specific sources of NSPCs. PMID- 21322791 TI - Metastasis to optic nerve presenting as ill-fitting prosthesis. AB - We report a rare case of metastatic adenocarcinoma of lung in anophthalmic socket, which presented as painful and difficult prosthetic wear long after an uneventful enucleation. Bulge in the socket indicated amputation neuroma, a rarity in itself; but further evaluation concealed a yet silent pulmonary mass. No case report so far describes metastatic mass in an anophthalmic socket and we describe first case of unknown lung malignancy presenting as ill-fitting prosthesis. PMID- 21322792 TI - A multi-centre case series investigating the aetiology of hypertrophic pachymeningitis with orbital inflammation. AB - INTRODUCTION: To describe our attempt in establishing a definitive diagnosis in patients with hypertrophic pachymeningitis in combination with orbital inflammatory disease and report on the outcome. MATERIALS AND METHODS: This was a retrospective case series of all patients presenting with hypertrophic pachymeningitis in association with orbital inflammation in 4 centres. Ophthalmic and neurological examination data, laboratory data, histology data, treatment plans and clinical outcome data were recorded. Patients underwent orbital/brain computed tomography and magnetic resonance imaging. RESULTS: Six patients were identified; the median age was 46.5 years. Headache was the commonest presenting symptom, followed by diplopia and reduced visual acuity. Three patients underwent orbital biopsy, 1 patient underwent dura mater biopsy, 1 patient underwent both and 1 patient underwent nasal biopsy. Four patients were diagnosed with Wegener granulomatosis and 2 patients with tuberculosis. Corticosteroid therapy was initiated in 4 patients, with steroid-sparing drugs added later. Two patients received anti-tuberculosis treatment and 1 patient was commenced on pulsed cyclophosphamide. On follow-up, 1 patient required an exenteration for a painful blind eye and 1 patient's visual acuity remained at no perception to light. One patient had complete resolution of symptoms on treatment, 1 patient had persistent reduced visual acuity and 1 patient was lost to follow-up. CONCLUSION: We postulate that the combination of orbital inflammation and pachymeningitis is strongly suggestive of Wegener granulomatosis, although it may take a number of years to confirm. Tuberculosis should also be considered. PMID- 21322793 TI - Recurrence of multiple myeloma with soft tissue plasmacytoma presenting as unilateral proptosis. AB - PURPOSE: To describe a rare case of soft tissue plasmacytoma of the orbit presenting with proptosis. RESULTS: A 57 year-old Malay lady presented with right eye proptosis of 3 weeks' duration. It was associated with pain, redness and progressive blurring of vision. The patient was diagnosed to have multiple myeloma a year previously when she was investigated for backache, and had been treated with eight cycles of Pamidronate chemotherapy. On examination visual acuity was 6/60 in the right eye with impaired optic nerve function. Severe proptosis with chemosis and complete ophthalmoplegia were found. The corneal and anterior chamber examinations were normal. Fundoscopy revealed a slightly hyperaemic disc with presence of choroidal folds infero-temporally. The left vision and eye examination findings were normal. Fine needle biopsy and MRI showed recurrence of multiple myeloma with soft tissue plasmacytoma of the extraconal region compressing the right optic nerve. She was managed with orbital radiotherapy, resulting in resolution of proptosis, but without improvement in vision. CONCLUSION: Proptosis may be an indicator of recurrence of multiple myeloma in patients thought to be in remission. PMID- 21322794 TI - Antibacterial properties of artificial eyes containing nano-sized particle silver. AB - BACKGROUND: The long-term use of an artificial eyes can lead to complications. Persistent physical stimulation and foreign body contact cause secondary infections. Secondary infection is an important complication after the placement of a artificial eyes and may be difficult to control without removing the artificial eyes. Because of these complications, patients get difficulties to wear prosthesis. Furthermore artificial eyes can change the normal bacterial flora of the patient's conjunctiva. Such postoperative infections might be overcome by improving the antimicrobial properties of the prosthesis surface. METHODS: The space in the mold previously occupied by wax was filled with polymethyl methacrylate (PMMA) resin containing silver at a concentration of 300 700 ppm (parts per million) and the prosthesis was then heat cured. Microorganisms were grown on the treated and control surfaces. We cultured for 24 hours, then counted the number of bacteria in resin compositions containing nano sized silver particles and controls (Stomacher 400((r)) POLY-BAG). RESULTS: The surface of the artificial eye containing silver grew significantly fewer Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli on in vitro bacterial cultures. The antimicrobial activity was 4.8-6.2 times stronger than for the controls. The numbers of bacteria decreased by 99.9% using the PMMA resin containing silver. CONCLUSION: The artificial eyes containing silver that were produced in this study have antibacterial activity, cause little eye discharge, and emit far-infrared rays and anions, all of which promote the ocular health of the person wearing the artificial eye. PMID- 21322795 TI - Potential and peril. PMID- 21322796 TI - Survey finds CE, IT departments view one another warily. PMID- 21322797 TI - Ask George. PMID- 21322803 TI - Robotics project: making sure heart surgery doesn't miss a beat. PMID- 21322804 TI - 80001: new era dawns for medical devices. PMID- 21322805 TI - Cybercrimes pose growing threat to medical devices. PMID- 21322806 TI - Company sees challenges, opportunities in home market. PMID- 21322807 TI - How to think like a manager. PMID- 21322808 TI - The complexities of the human-medical device interface. PMID- 21322809 TI - Standardized equipment planning process makes for smarter decisions. PMID- 21322810 TI - Sharepoint site eases information flow for clinical engineering team. PMID- 21322811 TI - Lithotripters. PMID- 21322812 TI - Tackling problems with CPMs and EKGs. PMID- 21322813 TI - Have you heard of ITIL? It's time you did. PMID- 21322814 TI - Endoscopes in your inventory: is there a disconnect? PMID- 21322815 TI - Nasal cannula, CPAP, and high-flow nasal cannula: effect of flow on temperature, humidity, pressure, and resistance. AB - BACKGROUND: Delivery of warm, humidified, supplemental oxygen via high-flow nasal cannula has several potential benefits; however, the high-flow range may not maintain humidification and temperature and in some cases may cause excessive expiratory pressure loading. OBJECTIVE: To compare the effect of flow on temperature, humidity, pressure, and resistance in nasal cannula (NC), continuous positive airway pressure (CPAP), and high-flow nasal cannula (HFNC) in a clinical setting. METHODS: The three delivery systems were tested in the nursery using each instrument's recommended specifications and flow ranges (0-3 L/min and 0-8 L/min). Flow, pressure, temperature, and humidity were measured, and resistance was calculated. RESULTS: For all devices at 0-3 L/min, there was a difference (p<0.01) in temperature (NC 35.9 degrees C > CPAP 34.5 degrees C > HFNC 34.0 degrees C), humidity (HFNC 82% > CPAP 77% > NC 57%), pressure (HFNC 22 cmH(2)O > NC 4 cmH(2)O > CPAP 3 cmH(2)O), and resistance (HFNC 636 cmH(2)O/L/sec > NC 270 cmH(2)O/L/sec > CPAP 93 cmH(2)O/L/sec) as a function of flow. For HFNC and CPAP at 0-8 L/min, there was a difference (p<0.01) in temperature (CPAP 34.5 degrees C > HFNC 34.0 degrees C) in humidity (HFNC 83 % > CPAP 76 %), pressure (HFNC 56 cmH(2)O > CPAP 14 cmH(2)O) and resistance (HFNC 783 cmH(2)O/L/sec > CPAP 280 cmH(2)O/L/sec) as a function of flow. CONCLUSIONS: Gas delivered by HFNC was more humid than NC and CPAP. However, the higher pressure and resistance delivered by the HFNC system may have clinical relevance, such as increased work of breathing, and warrants further in vivo studies. PMID- 21322816 TI - Sterilization of heat-sensitive silicone implant material by low-pressure gas plasma. AB - BACKGROUND: In recent years, plasma treatment of medical devices and implant materials has gained more and more acceptance. Inactivation of microorganisms by exposure to ultraviolet (UV) radiation produced by plasma discharges and sterilization of medical implants and instruments is one possible application of this technique. The aim of this study was to evaluate the effectiveness of this sterilization technique on silicone implant material. METHODS: Bacillus atrophaeus spores (10(6) colony-forming units [CFUs]) were sprayed on the surfaces of 12 silicone implant material samples. Four plasma sets with different gas mixtures (argon [Ar], argon-oxygen [Ar:O(2)], argon-hydrogen [Ar:H(2)] and argon-nitrogen [Ar:N(2)]) were tested for their antimicrobial properties. Post sterilization mechanical testing of the implant material was performed in order to evaluate possible plasma-induced structural damage. RESULTS: The inductively coupled low-pressure plasma technique can achieve fast and efficient sterilization of silicone implant material without adverse materials effects. All four gas mixtures led to a significant spore reduction, and no structural damage to the implant material could be observed. PMID- 21322817 TI - The case for licensing biomeds. PMID- 21322818 TI - [Characteristics and peculiarities of the course of encephalopathy in diabetes mellitus]. AB - A complex neurological and neuropsychological study of clinical signs of encephalopathy in patients with diabetes mellitus type I (DM I) was carried out. One hundred and twelve patients with different severity and compensation state of DM were examined. A comparison group included 40 patients with discirculatory encephalopathy. Clinical symptoms of encephalopathy were significantly more frequent in patients with DM I, with the presence of frequent hypoglycemias (more than once a week during the last year). The higher level of glycolized hemoglobin (by more than 6.9%) and longer duration of the disease (more than 5 years) were found in the group of patients with encephalopathy. Ultrasonic dopplerography of head and neck vessels and transcranial dopplerography support the involvement of complex vascular factors in the development of encephalopathy in DM I. The special attention is drawn to the changes in microcirculation channel that contribute to the development of encephalopathy in DM I and determine the characteristics of its clinical presentations and course compared to discirculatory encephalopathy. PMID- 21322819 TI - [The cytokine profile in the acute period of tick-borne neuroinfections in children]. AB - Clinical peculiarities and blood levels of several cytokines were studied in 199 children, aged from 1 to 15 years, in the acute period of different tick-borne infections. The mixed infection manifested itself by the more severe progression of general clinical presentations compared to monoinfections. Etiologically unspecific changes of blood concentrations of cytokines in the acute period of the disease were found. These data were associated with different clinical forms of tick-borne infections. The decrease in the interferon gamma production was associated with the most severe disease progression with focal nervous system disorders. The use of cycloferon as immune modulator in the complex therapy led to the increase in the interferon gamma level and the decrease of general clinical manifestations during tick-borne encephalitis and mixed infection. PMID- 21322820 TI - [Hereditary motor and sensory neuropathy type 4A]. AB - The first in the Russian Federation clinical cases of patients with autosomal recessive type of hereditary motor and sensory neuropathy, type 4A, (HMSN 4A) are presented. In all cases, the diagnosis has been verified using molecular-genetic methods (DNA diagnostics). An analysis of features of clinical manifestations was performed in patients, aged from 5 to 34 years, with different disease duration (from 3-to 29 years). Criteria of selection of patients for DNA diagnostics for searching mutations in the GDAP1 gene are specified. PMID- 21322821 TI - [Treatment of asthenic disorders in patients with psychoautonomic syndrome: results of a multicenter study on efficacy and safety of ladasten]. AB - The study was carried out in 28 clinical centers of Russia. The data on 728 patients with psychoautonomic syndrome (91.6% of the total sample) were available for statistical analysis. All patients suffered from asthenic disorders. The duration of treatment with ladasten in daily dose from 50 to 100 mg was 28 days. Patient's state was assessed with psychometric scales at baseline, 3, 7, 14 and 28 days of therapy and one month after the end of treatment. The percentage of responders was 76.0% on the CGI-S and 90.8% on the CGI-I. The antiasthenic effect of ladasten was seen on day 3 and remained during one month after the withdrawal of therapy. We determined clinical efficacy of ladasten in regard to anxiety depressive spectrum disorders, autonomic dystonia, sleep disorders. Ladasten therapy led to the significant increase of quality of life, which was seen not only after the end of therapy, but after the withdrawal of the drug. These results suggest the stability of the therapeutic effect achieved. Adverse effects were observed only in 3% of patients, the therapy was discontinued in 0.8%. No serious adverse effects were found. In conclusion, the efficacy of ladasten was shown in its antiasthenic, anxyolytic, autonomic nervous system stabilizing properties, the normalization of sleep-awake cycle and the increase of quality of life. Ladasten in daily dose from 50 to 100 mg is a highly effective, well tolerated and safety drug with a wide spectrum of clinical effects. Therefore, this drug could be recommended for treatment of asthenic disorders in neurological practice. PMID- 21322822 TI - [Electrophysiological correlates of efficacy of nootropic drugs in the treatment of consequences of traumatic brain injury in adolescents]. AB - To assess objectively a dynamics of brain functional state, EEG spectral power and peak latency of the P300 component of cognitive auditory evoked potentials have been analyzed in adolescents during the course of nootropic therapy of residual asthenic consequences of traumatic brain injury (ICD-10 F07.2). The study included 76 adolescents, aged 12-18 years, who have undergone severe closed head trauma with brain commotion 1/2--5 years ago. Patients have been divided into 3 groups treated during one month with cerebrolysin, piracetam or magne-B6, respectively. After the end of the nootropic therapy, 77% of patients treated with cerebrolysin as well as 50% of patients treated with piracetam and magne-B6 have demonstrated the positive dynamics of their brain functional state that manifested itself in the appearance of occipital EEG alpha rhythm or in the increase of its spectral power; in the normalization of alpha rhythm frequency; in the decrease in the spectral power of slow wave (theta and delta) EEG activity, in the amount (up to the disappearance) of paroxysmal EEG activity, in the EEG response to hyperventilation and in the shortening of the P300 peak latency. Such positive changes of neurophysiological parameters have been associated with the improvement of clinical conditions of patients and correlated significantly with the dynamics of psychometric scores of attention and memory. PMID- 21322823 TI - [Cholinergic therapy of Alzheimer's disease and its effect on health and quality of life of caregivers to the patients]. AB - To assess efficacy and safety of 4-month therapy with rivastigmine in Alzheimer's disease (AD) and to evaluate the burden of caregivers to these patients, 25 AD patients have been studied. Rivastigmine was prescribed internally and 22 patients were assigned to additional antipsychotic therapy at the admission to the hospital. The treatment duration was 16 weeks (12 weeks in the hospital and 4 weeks after the discharge). The study revealed that rivastigmine improved cognitive functions and led to the reduction of psychotic and behavioral disorders in AD patients at the moderate stage of the disease. The inclusion of rivastigmine in the complex treatment of AD patients resulted in the significant reduction in doses of necessary psychotropic drugs and in the complete withdrawal of all antipsychotic drugs in some patients. It should be specifically emphasized that the treatment with rivastigmine of patients with moderate AD and behavioral disorders led to the significant (up to 30%) reduction of the time spent for caregiving, the decrease of burden and the health improvement of caregivers that increase quality of life of both the patient and the family. PMID- 21322824 TI - [Comparative efficacy of carbamazepine, valproic acid and topiramate in symptomatic and cryptogenic occipital lobe epilepsy in children]. AB - For a retrospective observational investigation based on real clinical practice of relative efficacy of valpoic acid (VPA), carbamazepine (CBZ) and topiramate (TPM) we have selected 106 patients with age of seizure onset before 17 years with a undoubted diagnosis of symptomatic or cryptogenic occipital lobe epilepsy (OLE), who had received treatment according to ILAE recommendations, and observation time since the last treatment change was from 2 to 10 years. Patients suspicious for idiopathic epilepsies were excluded. The groups of patient receiving CBZ, VPA and TPM did not differ significantly in presenting unfavorable prognostic factors and dose regimes that allowed to conduct direct comparison of efficacy of the investigated drugs. Efficacy of VPA in children with OLE was higher compared with CBZ (69% vs 36%, p < 0.01) and TPM (69% vs 8%, p < 0.001). CBZ and TPM caused seizure aggravation more frequently than VPA (12% and 13% respectively vs 1%, p < 0.001). In case of presence of clinico electroencephalografic and MRI signs of significant organic brain damage and in patients with seizure onset under 11 years TPM was not effective. In case of focal cortical dysphasia the efficacy of CBZ was lower than VPA (20% vs 63%, p < 0.05). In MRI-negative cases VPA was most effective (79% vs 44% for CBZ, p < 0.001 and 29% for TPM, p < 0.01). Efficacy of CBZ and TPM reduces proportionally the number of previously used antiepileptic drugs (AEDs), this tendency is noted also for VPA but as a second AED it was more effective than CBZ and TPM (56% vs 15%, p < 0.01 and 14%, p < 0.05, respectively); as a first AED VPA was also most effective (82% vs 37%, p < 0.001 for CBZ and 82% vs 33%, p < 0.01 for TPM). Adverse effects were more frequent during treatment with CBZ and TPM, than VPA (21% vs 6%, p < 0.001 and 17% vs 6%, p < 0.05). PMID- 21322825 TI - [Efficacy and safety of the monotherapy with trileptal (oxcarbazepine) in children and adolescents]. AB - A prospective non-randomized non-controlled multicenter trial has been conducted. The trial included 254 children, aged from 11 months to 18 years (mean age 9.3 +/ 4.5 years), with predominantly focal forms of epilepsy treated with trileptal (oxcarbazepine). The observation period was 31 weeks. Efficacy and safety of therapy was assessed in 3 visits: screening and assignment to therapy (visit 1), the end of titration and achievement of maintenance dose (visit 2), assessment of maintenance therapy (visit 3). The percentage of patients with a positive response to the trileptal therapy (the decrease of seizure frequency by 50% and more) was 91.1%. The complete reduction of seizures was achieved in 59.4% of patients. Most of patients (95.3%) continued to receive trileptal until the end of the trial. The significant decrease (p < 0.001) of seizure frequency from visit 1 to visit 3, the reduction of epileptiform activity (p < 0.05) on the awake EEG in visit 3 were found. The mean effective dose of trileptal was 902.4 +/- 442.7 mg/day, i.e. was less than 30 mg/kg/day, daily doses did not exceed 600 mg. Adverse effects were observed in 11.2% of patients but in 40% of cases they seemed not be related to the drug. The adverse effects were from mild to moderate extent. In conclusion, trileptal as the monotherapy is effective and well tolerated in the treatment of focal epilepsies in the age groups studied. PMID- 21322826 TI - [Perspectives of the use of ginkgo biloba (memoplant) in neurological practice]. PMID- 21322827 TI - Articular cartilage in the knee: current MR imaging techniques and applications in clinical practice and research. Invited commentary. PMID- 21322828 TI - Revision of the criteria for Alzheimer's disease: A symposium. AB - The current criteria for classification of Alzheimer's disease (AD) have deficiencies that limit drug development, research, and practice. The current standard for the clinical diagnosis of AD, the National Institute of Neurological and Communicative Disorders and Stroke (now known as the National Institute of Neurological Disorders and Stroke), and the Alzheimer's Disease and Related Disorders Association (now known as the Alzheimer's Association) criteria, are nearly 25 years old and have not been revised to incorporate advances in the epidemiology and genetics of AD, studies of clinicopathologic correlations and recent studies of potential diagnostic biomarkers. In a very real sense our ability to diagnose AD with a very high level of certainty has outpaced our current diagnostic criteria. The Alzheimer's Association Research Roundtable convened a meeting in April 2009 to discuss new data and technologies that could, with further development, enable improvements in the clinical diagnosis of AD, especially in its earliest and mildest stages. This meeting reviewed the current standards for detecting and defining the clinical presentation of AD and discussed areas that could contribute to earlier and more accurate definitive clinical diagnosis. These included clinical, neuropsychological, and other performance-based assessments, genetic contributions, and biochemical and neuroimaging biomarkers that could reflect AD pathology and lead to better ascertainment of AD, mild cognitive impairment, and presymptomatic AD. PMID- 21322829 TI - [Comment to: ''Nocturia is not associated with falls among the elderly: a population study in the city of Sao Paulo'']. PMID- 21322830 TI - [Comment to: "Primary laparoscopic retroperitoneal lymph node dissection for clinical stage I nonseminomatous germ-cell testis tumor"]. PMID- 21322831 TI - Evaluation of left ventricular diastolic function with cardiac MR imaging. Invited commentary. PMID- 21322832 TI - [Comment to: "Enucleation of the prostate with 980 mm diode laser (Dilep): technique and initial results"]. PMID- 21322833 TI - [Comment to: "Renal retransplantation: risk factors and results"]. PMID- 21322834 TI - [Comment to: "Experience with sunitinib in hormone-resistant metastatic prostate cancer that is unresponsive to docetaxel"]. PMID- 21322835 TI - Megalin and androgen receptor gene expression in young and old human skeletal muscle before and after three sequential exercise bouts. AB - Androgen signaling occurs primarily via the androgen receptor. Megalin, a low density lipoprotein endocytic receptor located in various mammalian tissues, has been recently shown to facilitate sex hormone-binding globulin (SHBG) steroid complexes across cell membranes. The purpose of this investigation is to determine if the megalin gene is expressed in human skeletal muscle and if present to determine how megalin and androgen receptor mRNA expression change in response to sequential exercise bouts with respect to aging. Ten younger (age: 18 25 years) and 10 older (age: 60-75 years) men completed 3 workouts (M, W, F) each consisting of 9 sets of lower-body exercises with 10 repetitions per set at 80% 1 repetition maximum. Vastus lateralis muscle biopsies were extracted at baseline (T1), 48 hours after workout 1 (T2) and 2 (T3), and 24 hours after workout 3 (T4), and blood samples were collected before and 5 minutes after each workout. Muscle was analyzed for megalin and androgen receptor expression using gene specific primers and SYBR green chemistry, and blood was analyzed for serum testosterone, SHBG, and the free androgen index. Megalin was expressed in both young and old subjects across all time points, although no between- or within group mean differences were detected at any time point. Androgen receptor was expressed higher in young men at all time points compared to in old men (p < 0.05), and a significant correlation (p < 0.05; r = 0.506) was found between serum testosterone and androgen receptor after workout 1. Based on our data, the gene coding for megalin is expressed inside skeletal muscle, but its role, if any, in steroid cellular transport cannot be determined. This finding could lay the groundwork for more mechanistic investigations to better delineate its functional role and its potential as a therapeutic adjunct for androgen-related disorders in healthy and aged populations. PMID- 21322836 TI - Influence of muscle-tendon unit structure on rate of force development during the squat, countermovement, and drop jumps. AB - Previous research has highlighted the importance of muscle and tendon structure to stretch shortening cycle performance. However, the relationships between muscle and tendon structure to performance are highly dependent on the speed and intensity of the movement. The purpose of this study was to determine if muscle and tendon structure is associated with the rate of force development (RFD) throughout static squat jump (SJ), countermovement jump (CMJ), and drop jump (DJ; 30-cm height). Twenty-five strength- and power-trained men participated in the study. Using ultrasonography, vastus lateralis (VL) and gastrocnemius (GAS) pennation (PEN) and fascicle length (FL), and Achilles tendon (AT) thickness and length were measured. Subjects then performed SJ, CMJ, and DJ, during which RFD was calculated over time 5 distinct time intervals. During CMJs, early RFD could be predicted between 0 and 10 milliseconds by both GAS-FL (r2 = 0.213, beta = 0.461) and AT-length (r2 = 0.191, beta = 20.438). Between 10 and 30 milliseconds GAS-FL was a significant predictor of CMJ-RFD (r2 = 0.218, beta = 0.476). During DJ, initial RFD (0-10 milliseconds) could be significantly predicted by GAS-FL (r2 = 0.185, beta = 20.434), VL-PEN (r2 = 0.189, beta = 0.435), and GAS-PEN (r2 = 0.188, beta = 0.434). These findings suggest that longer ATs may have increased elasticity, which can decrease initial RFD during CMJ; thus, their use in talent identification is not recommended. The GAS fascicle length had an intensity dependent relationship with RFD, serving to positively predict RFD during early CMJs and an inverse predictor during early DJs. During DDJs, subjects with greater PEN were better able to redirected initial impact forces. Although both strength and plyometric training have been shown to increase FL, only heavy strength training has been shown to increase PEN. Thus, when a high eccentric load or multiple jumps are required, heavy strength training might be used to elicit muscular adaptations that are suited to fast force production during jumping. PMID- 21322838 TI - Genome instability: chrombling into pieces. AB - A new phenomenon in which tens to hundreds of genomic rearrangements are acquired in one step has been identified. PMID- 21322837 TI - Medulloblastoma: origins. AB - Medulloblastomas with a mutation in the Wnt pathway arise from cells that are distinct from those affected by mutations in the SHH pathway. PMID- 21322839 TI - Bad decisions for global health. PMID- 21322840 TI - Big publishers cut access to journals in poor countries. PMID- 21322841 TI - Science Media Centres go global. PMID- 21322842 TI - Discrimination against people with HIV persists in China. PMID- 21322843 TI - UK's biomedical research institute gets green light. PMID- 21322844 TI - American resurrection and the 1788 New York doctors' riot. PMID- 21322845 TI - Arthrofibrosis of the knee following anterior cruciate ligament reconstruction. PMID- 21322847 TI - [Neutral clothing is best]. PMID- 21322846 TI - Hip degenerative joint disease in a patient with medial knee pain. PMID- 21322848 TI - The costs of change. Reform expected to increase average annual spending through 2019. PMID- 21322849 TI - No place like home? Primary-care home option gets praise, questions. PMID- 21322850 TI - Deals heat up in September. PMID- 21322851 TI - Getting the data right. NQF panel seeks measures that will capture better quality data with EHRs. PMID- 21322852 TI - Commissioning. GPs and government battle for custody of white paper reforms. PMID- 21322853 TI - Pioneering publication reveals huge contrasts. PMID- 21322854 TI - David Kerr why we can't all be 5'10. PMID- 21322855 TI - Quick fixes for easing the pain. PMID- 21322856 TI - Long-term conditions. Buying a little breathing space. How personal care plans could greatly reduce chronic obstructive pulmonary disease admissions. PMID- 21322857 TI - Charles Walker, Conservative MP for Broxbourne, talks about his aim to challenge mental health stigma. PMID- 21322858 TI - Community care. PMID- 21322859 TI - Part of the Union. PMID- 21322860 TI - Problems with the recovery approach in mental health services. PMID- 21322861 TI - Change takes time, something benefits claimants are likely to become more aware of. PMID- 21322862 TI - Anxiety: falling between primary and secondary care. PMID- 21322863 TI - The NHS white paper and GP consortia offer opportunities for positive change. PMID- 21322864 TI - Breakthrough explains some of the concerns about GP consortia commissioning mental health services. PMID- 21322865 TI - GP commissioners will need to work better with independent mental health service providers. PMID- 21322866 TI - Two recent court cases have highlighted some of the implications deprivation of liberty legislation has on people with mental health problems. PMID- 21322867 TI - Peer support. PMID- 21322868 TI - Death of the service user: towards wellbeing and social inclusion. PMID- 21322869 TI - Give generously. PMID- 21322870 TI - Looking at ordinary people's tales of living with their mental illness. Interview by Alita Howe. PMID- 21322871 TI - NHS market faces closer EU attention. PMID- 21322872 TI - Phil Hammond the hardest sell. PMID- 21322873 TI - It's time to let the right ones in. PMID- 21322874 TI - Commissioning: Part one of two. The four challenges facing consortia. PMID- 21322875 TI - Rethinking EMTALA? The CMS is seeking comments on transfer rules. PMID- 21322876 TI - Face-to-face must wait. CMS delays enforcement of home health rule. PMID- 21322877 TI - 2011 Outlook. IT: set for a growth surge. PMID- 21322878 TI - 2011 Outlook. Insurers: leaner margins. PMID- 21322879 TI - 2011 Outlook. Does: more ACO, less SGR. PMID- 21322880 TI - 2011 Outlook. Legal: a large caseload. PMID- 21322881 TI - 2011 Outlook. Quality: forging a link to costs. PMID- 21322882 TI - Cost-cutting keeps profits high. Hospitals provided free services, made money in '09. PMID- 21322883 TI - Free care adds up. Hospitals' uncompensated costs up 10%. PMID- 21322884 TI - Insurers get in IT game. Data is seen as key to the success of ACOs. PMID- 21322885 TI - Same time, next year? Medicare pay fix passes with bipartisan support. PMID- 21322887 TI - Leapfrog Group 10 years later. And a few announcements from Modern Healthcare's editorial staff. PMID- 21322886 TI - 'Red flags' fix. Congress exempts docs from ID theft rule. PMID- 21322888 TI - Mid-level battle isn't lost. PMID- 21322889 TI - More on diversity in veterinary medicine. PMID- 21322890 TI - Obstacles for veterinarian-scientists. PMID- 21322891 TI - Veterinary medical education issues revisited. PMID- 21322892 TI - Horse genomics and the Dorothy Russell Havemeyer Foundation. Forward. PMID- 21322893 TI - A true witch hunt. PMID- 21322894 TI - The impact of housing rehabilitation on local neighborhoods: the case of small community development organizations. AB - Across the nation, nonprofit organizations located in poor and declining neighborhoods are promoting homeownership in the hopes that their efforts will stave off decline and contribute to neighborhood stability. A common homeownership strategy among nonprofits is to acquire boarded-up or deteriorated homes at a low price, rehabilitate them, and then sell them at an affordable price. As these programs continue, nonprofit organizations want to show quantitatively that neighborhood revitalization works-that the funds devoted to an area stabilize neighborhoods or, even more, that they initiate a surge of continued upward progress. But, unlike their larger counterparts, smaller community development organizations are usually at a disadvantage in undertaking such an evaluation. This study will help illustrate what might be done. It focuses on the case of St. Joseph's Carpenter Society (SJCS) in Camden, New Jersey and assesses the quantitative impact that SJCS has on its target neighborhoods. A three-tiered approach is adopted that ranges from a target and comparison area analysis, to regression analysis of SJCS's impact on local housing prices, and finally to an examination of the relative market performance of SJCS's houses. All told, the analysis suggests that SJCS's rehabilitation and homeownership education activities appear to have a positive influence on the neighborhoods in its target area. PMID- 21322895 TI - Do we still need cities? Evidence on rates of innovation from count data models of metropolitan statistical area patents. AB - Evidence of the importance of urban agglomeration and the offsetting effects of congestion are provided in a number of studies of productivity and wages. Little attention has been paid to this evidence in the economic growth literature, where the recent focus is on technological change. We extend the idea of agglomeration and congestion effects to the area of innovation by empirically looking for a nonlinear link between population density and patent activity. A panel data set consisting of observations on 302 USA metropolitan statistical areas (MSAs) over a 10-year period from 1990 to 1999 is utilized. Following the patent and R&D literature, models that account for the discreet nature of the dependent variable are employed. Strong evidence is found that agglomeration and congestion are important in explaining the vast differences in patent rates across US cities. The most important reason cities continue to exist, given the dramatic drop in transportation costs for physical goods over the last century, is probably related to the forces of agglomeration as they apply to knowledge spillovers. Therefore, the empirical investigation proposed here is an important part of understanding the viability of urban areas in the future. PMID- 21322896 TI - The relevance of personal characteristics in health care rationing: what the Australian public thinks and why. AB - This article examines the preferences of the general public in Australia regarding health care resource allocation. While previous studies have revealed that the public is willing to give priority to particular groups of patients based on their personal characteristics, the present article goes beyond previous efforts in attempting to explain these results. In the present study, there was strong support among respondents for giving "equal priority" to people regardless of their personal characteristics. However, respondents did reveal a preference for married patients over single, for children over adults, for carers of children and the elderly, sole breadwinners, and good community contributors. Further, they would give a lower priority to those perceived as "self-harmers" smokers, individuals with unhealthy diets, and those who rarely exercise. Variation in the answers according to broad economic and social beliefs across seven different categories ("factors") influenced the pattern of the public's attitudes towards rationing. The Principal Components Analysis (PCA) indicated that most of the items in our survey are associated with seven factors that explain or capture much of the variation. These relate to a patient's avoidance of self-harm behaviors (Safe Living), their Life Style (diet, exercise, etc.), their contribution to the community through caring for others (Caring), their talents (Gifted), their sexual behavior (Sexuality), their age and marital status (Family), and whether they are an Australian citizen or employed (Citizen). The strength of social preferences-e.g., how strongly respondents would "discriminate" against a recreational drug user or preference a person with a healthy diet-is related to the particular class of preferences. PMID- 21322897 TI - Charitable giving expenditures and the faith factor. AB - Using a permanent income hypothesis approach and an income-giving status interaction effect, a double hurdle model provides evidence of significant differences from the impact of household income and various household characteristics on both a household's likelihood of giving and its level of giving to religion, charity, education, others outside the household, and politics. An analysis of resulting income elasticity estimates revealed that households consider religious giving a necessity good at all levels of income, while other categories of giving are generally found to be luxury goods. Further, those who gave to religion were found to give more to education and charity then those not giving to religion, and higher education households were more likely to give to religion than households with less education. This analysis suggests that there may be more to religious giving behavior than has been assumed in prior studies and underscores the need for further research into the motivation for religious giving. Specifically, these findings point to an enduring, internal motivation for giving rather than an external, "What do I get for what I give," motive. PMID- 21322898 TI - Becoming a winner but staying the same: identities and consumption of lottery winners. AB - This article discusses how large lottery winnings are experienced and used by the winners. The study draws on a survey of 420 Swedish winners, which is analyzed against the background of previous research from the USA and Europe. The analyses show that winners are cautious about realizing any dreams of becoming someone else somewhere else. This result contradicts theories suggesting that identities are being liquefied by the commercially driven consumer culture in affluent Western societies. In contrast, the article concludes that winners generally try to stay much the same, but on a somewhat higher level of consumption. The critical situation that large winnings produce is generally met by an attempt to hold on to one's identity and social relations. In addition, the article shows that lump sum winners tend to save and invest large parts of their winnings, compared with winners of monthly installments who are more likely to spend on leisure and consumption. These results indicate that "wild" lump sums make winners "tame" their winnings more firmly, whereas "domesticated" monthly instalments can be spent more thoughtlessly without changing identity or becoming an unfortunate winner. PMID- 21322899 TI - Getting close to Rwandans since the genocide: studying everyday life in highly politicized research settings. AB - Research with people in highly politicized research settings illuminates the gap between the images that most African governments strive to represent and the sociopolitical realities of everyday life. This article discusses the opportunities and challenges of doing research in postgenocide Rwanda and is a useful resource for researchers contemplating their own projects under such conditions, whether in Rwanda or elsewhere. It discusses the importance of creating personal relationships and meeting people on their terms, as well as such topics as the identification of the research site, building rapport and trust with respondents, safeguarding anonymity and confidentiality, and working with local research assistants and partners. PMID- 21322900 TI - Sociopolitical crisis and the reconstruction of sustainable periurban agriculture in Abidjan, Cote d'Ivoire. AB - This article examines the effects of the post-2002 sociopolitical crisis in Abidjan, Cote d'Ivoire, on urban and peri-urban agriculture. Based on the case study of Abidjan, it argues for a conceptualization of sustainability that includes social as well as environmental dimensions and focuses on coping strategies of producers and merchants. In Abidjan, these strategies included internal migration within the city and its periphery, the use of organic fertilizers, and changes in market structure. The study illustrates how such strategies allowed producers to continue to supply produce to the market, despite the difficulties of war. PMID- 21322901 TI - Mental illness and violence. Multiple interacting factors contribute to violent behavior. PMID- 21322902 TI - Painkillers fuel growth in drug addiction. Opioid overdoses now kill more people than cocaine or heroin. PMID- 21322903 TI - Anxiety and heart disease. New research suggest there may be a link, but it's not clear why. PMID- 21322904 TI - Fish, omega-3 fatty acids, and pregnancy. PMID- 21322905 TI - My husband has attention deficit hyperactivity disorder. Someone suggested that metacognitive therapy might help him become better organized. What is that? PMID- 21322906 TI - Controlling blood sugar in diabetes: how low should you go? PMID- 21322907 TI - Penile rehabilitation after prostate cancer surgery. PMID- 21322908 TI - Unfolding bent fingers: new handiwork for bacteria. PMID- 21322909 TI - On call. Every time I open a newspaper, I seem to read about another VIP with cancer of the pancreas. It sounds like a dreadful disease. Is there some way I can be tested to see if I'm at risk? PMID- 21322910 TI - Top five habits that harm the heart. Avoiding them can help you prevent a cardiovascular apocalypse. PMID- 21322911 TI - Conversation with an expert. Plavix: what you need to know. PMID- 21322912 TI - Tiny pumps can help when heart failure advances. Left ventricular assist devices support the heart while waiting for--or in place of--a heart transplant. PMID- 21322913 TI - Ask the doctor. When someone has pneumonia, is it common for the heart rate to fluctuate wildly? PMID- 21322914 TI - Squeezing the arm to protect the heart. PMID- 21322915 TI - A pacemaker to lower blood pressure. PMID- 21322916 TI - [Recent additions to the biography of the Augsburg physician and Orient traveler Leonhard Rauwolf (1535?-1596)]. AB - The Augsburg physician Leonhard Rauwolf is known to the history of Western sciences for describing the exotic flora of the Near East in his travelogue "Aigentliche Beschreibung der Raiss [...] inn die Morgenlander" (Lauingen 1582). It has been asserted that little is known about his life before and after this journey. This paper summarizes his biography from previous biographical sketches and adds new archival findings from sources at Augsburg and Linz: Leonhard Rauwolf was the son of the Augsburg iron trader and councilman Sixt Rauwolf (1557) and his wife Agatha nee Eggelhof (1583). He had several surviving brothers, Hans (or Johann), Georg, Sixt the younger, Matthaus, Ulrich, and a sister, Agatha. Sixt and Leonhard Rauwolf's "middle class" financial situation is analyzed by means of Augsburg tax records. Professional conditions of Leonhard Rauwolf in service of three cities in Germany and Austria are verified from the sources. Four letters, written to colleagues and friends are, along with two of his letters of approbation, edited here for the first time: they illustrate his lasting strong interest in botany and his attempts to build up a professional network. Further his political fate at Augsburg is examined that was shattered by the ongoing of religious conflicts in this biconfessional town and finally caused him to remove to Linz. At last, a look is taken at his later life at Linz and the circumstances of his death which he met in Hungary during the war against the Turks. PMID- 21322917 TI - ["One makes a distinction between 2 color contrasts, the instantaneous and the afterimage". Several color theory comments by Gottfried Semper in the "style" of 1860]. AB - Gottfried Semper (1803-1879) is well-known for his work on colour schemes in architecture. The architect published several books and articles on related topics, such as polychromy in Greek and Roman edifices, mural paintings of Pompeii, and the colouring of the renaissance architecture. It has been less discussed, however, that Semper was also engaged in the contemporary discourse on colour theory as pursued in Natural Science research. The paper examines theoretical remarks on colour in Semper's publication "Der Stil" of 1860. His terminology, the modality of his explanations and his discussion of colour experiments suggest that Semper was familiar with Michel-Eugene Chevreul's theory of colour. Semper's reception of Chevreul is not surprising. The French chemist wrote one of the most important studies of colour of the nineteenth century. His famous book "De la loi du contraste simultane des couleurs" was published in Paris in 1839, where he developed some of the principles of "harmony and contrast of colours" and their application to the arts. Especially Chevreul's synthesis between theoretical consolidation and practical transformation seem to have attracted Semper's attention. PMID- 21322918 TI - ['De macula in sole observata' - a nonexistent writing by Kepler and an wrongly translated citation]. PMID- 21322919 TI - [Standardization of technical terminology]. AB - This paper analyzes the example of the publishers Oldenbourg and the publication of the 'Illustrierte Technische Worterbucher' (ITW), a multilingual dictionary which competed with a similar project that the Verein Deutscher Ingenieure (VDI) had already initiated. Its willingness to challenge the vast and well-funded VDI with this project--and to tackle the immense difficulties associated with the dictionary itself, which pioneered the standardization of technical terminology across six languages--indicates that for Oldenbourg, this project was of paramount importance to its reputation. The decision to take the challenge and publish the ITW was the starting point of Alfred Schlomann's career as well as the foundation of Oldenbourgs reputation as a premier publishing house and pioneered the standardization of technical terminology. The example shows that the publishers' decisions had been of paramount importance not only for scientists' careers and as gatekeeper of the scientific community but can also influence the development of science. PMID- 21322920 TI - ["Item as Kaiser Friedrich's foot was amputated". The leg amputation of Kaiser Friedrich III on 8 June 1493 in Linz]. AB - The article deals with the amputation of emperor Friedrich III's left leg, which took place in Linz (Upper Austria) on June 8th 1493. This is one of the most famous and best documented surgical operations of the whole Middle Ages. The article offers a study about the two most important sources, i.e., the description of the amputation by the doctor Hans Seyff (Stuttgart, Wurttembergische Landesbibliothek, Cod. med. et phys. 20 8, fol. 71V-72V) and an anonymous painting (Wien, Graphische Sammlung Albertina, Min. 22475), followed by a detailed analysis of the amputation and an overview about the different types of doctors working at Friedrich's court. PMID- 21322921 TI - [Max Mohr (1891 - 1937) - a physician in search of independence]. AB - Max Mohr (1891-1937) was a physician and one of the most successful writers during the period of the Weimar Republic (1919-1933). The biography of Max Mohr is of particular importance for the understanding of his works. Since--aside from the literary producing--his medical occupations were constitutive in his life, this article focuses on the physician Max Mohr. The pursuit of personal independence was a central theme in his life. Though working in a private practice would have enabled him to lead a civic life in Munich, Mohr--newly married in 1920--decided to move into Wolfsgrub near Rottach at Tegernsee. Mohr increasingly applied himself to his literary producing and frequently visited Berlin. In 1934, Mohr was forced to emigrate to Shanghai because of his Jewish heritage. There he quickly succeeded in building up his own practice, thus securing an economic existence. Mohr died on November 13th, 1937. PMID- 21322922 TI - [National socialism health policy and the Aachen region reflected in the "West German Observer"]. AB - The article deals with the question of medicine in the time of the Nazi regime in Germany. It focuses on the question how the media in the "Third Reich" took up the subject "medicine" in general and which aspects were notably mentioned. The footing of this research is the "Westdeutscher Beobachter" and its local edition for the region and the city of Aachen. It was a newspaper published by the regional division of the NSDAP, hence a direct repetition of the Nazi ideology can be expected. During the research it became clear that medicine was not an important subject of propaganda in this newspaper. Only a few articles were about classic Nazi medical topics like "Erbgesundheit" (racial hygiene) and even less about naturopathy. The frequency of articles containing medical issues was very inconsistent, but only in 1934 there was a mentionable number of articles mostly concerning "Erbgesundheit". In this year the racial hygiene poured in law. The main consequence was the forced sterilization of over 300,000 people. Furthermore the topic "medicine" in general seems to be a marginal factor. More popular topics like economic or foreign policy dominated the report of the "Westdeutscher Beobachter". It seems to be that the emphasis was deliberately not laid on the matter "medicine" especially eugenics--which was one of the main components of the Nazi ideology--because the regime didn't want it to become a public interest. PMID- 21322923 TI - [Characteristic of the vertical and pyramidal segment of facial nerve canal]. AB - OBJECTIVE: To study the vertical and pyramidal segment of facial nerve canal based on three-dimensional reconstruction of temporal bone CT, and provide a quantitative data for the middle ear and mastoid surgery. METHOD: Reconstruction of adult axial CT images shows the vertical and pyramidal segment of facial nerve canal. Using the Able Software 3D-DOCTOR 3.5 to show and measure the angle of the vertical and pyramidal segment of the facial nerve canal and to analyze the features and regularity based on the measured data. RESULT: According to the angle of the vertical and pyramidal segment of facial nerve canal based on the three-dimensional reconstruction model. A certain regularity has been found in the direction and the angle of different segments of the vertical and pyramidal segment of facial nerve canal. CONCLUSION: The temporal bone CT three-dimensional reconstruction can accurately show the characteristic and angle of the vertical and pyramidal segment of facial nerve canal. The characteristics and quantitative angle of the vertical and pyramidal segment of facial nerve canal from the anatomical viewpoint for clinical utility could keep the vertical and pyramidal segment of facial nerve from injury in temporal bone surgery. PMID- 21322924 TI - [Clinical evaluation of intratympanic methylprednisolone perfusion for intractable Meniere's disease]. AB - OBJECTIVE: To evaluate the clinical efficacy of the intratympanic methylprednisolone perfusion for patients of intractable Meniere's disease (MD). METHOD: Ten cases (10 ears), collected from Janu 2008 to Janu 2010, of intractable MD were studied retrospectively. The micro-catheter was placed into the tympanum of the affected ear, then methylprednisolone was imported into the tympanum once a day for 10 days. The average followed-up duration was (15. 4 +/- 5. 4) months after the perfusion. The treatment effect of vertigo, hearing loss and activity capacity was evaluated with Diagnostic Criteria for MD set by the Guiyang Meeting in 2006. The efficacy of tinnitus was analyzed by comparing the score of tinnitus handicap inventory (THI) before and after treatment. RESULT: The vertigo was absolutely controlled in 7 patients (grade A), partially controlled in 2 patients (grade B) and no efficiency in 1 patient (grade C). The 2 patients in grade B had a vertigo again in 9 months and 11 months after intratympanic perfusion, respectively, while the frequency, severity and duration of their vertigo softened obviously. Puretone threshold average (PTA) at the affected frequencies was decreased to within the level of 20 dB in one patient and was improved more than 30 dB in another one (grade A), improved 15 dB to 30 dB in 4 patients (grade B), and improved less than 15 dB in the other 4 patients. The average score of THI was 48.80 +/- 7.25 and 41.9 +/- 7.78 before and after perfusion respectively. The ability capacity of all the 10 patients after treatment was as normal (grade A), i. e. All of them could lead an independent life. There was no irreversible tympanic perforation in the operated ear and there was no other complications left. CONCLUSION: Intratympanic methylprednisolone perfusion through the micro-catheter is a safe and effective method for the intractable Meniere's disease. PMID- 21322925 TI - [The diagnosis and treatment of the simple congenital malformation of ossicular chain]. AB - OBJECTIVE: To investigate the diagnosis and treatment of the simple congenital malformation of ossicular chain. METHOD: Curative effect analysis for 4 cases of treatment of simple congenital malformation of ossicular chain were performed in our department from June 2005 to August 2009, retrospectively. 4 patients underwent middle ear exploration and ossicular chain reconstruction were followed up for 1-4 years, and air conduction threshold of speech frequency(0.5, 1.0, 2.0 kHz) were detected, 15 dB increase of which were as the standard of successful operation. RESULT: Three cases was abnormal incus, 2 cases were absence of instruction on the stapes footplates, and stapes footplates fixed, one case was absence of the incus. Hearing level had significantly improve after hearing reconstruction in 3 patients. The averaged postoperative air conduction threshold of speech frequency had 47 dB increase, bone conduction threshold have no change, while one case of hearing level without change. Tinnitus, vertigo, facial paralysis and other complications occurred were found in all the patients. CONCLUSION: The congenital conductive hearing loss without external ear malformations should be suspected of congenital malformation of ossicular chain, which could be diagnosed by tympanic exploration. Ossicular chain reconstruction can improve the hearing effectively. PMID- 21322926 TI - [Functional MRI study of auditory cortical responses in normal subjects and unilateral sensorineural hearing loss subjects]. AB - OBJECTIVE: Amplitude modulation of auditory cortical responses was evaluated with functional MRI (fMRI) in subjects of unilateral sensorineural hearing loss (USNHL) and those of normal hearing (NH). METHOD: Twenty-one subjects with USNHL and 11 with normal hearing were examined with fMRI in response to amplitude modulation tones of 500 Hz with the modulation frequency at 8 Hz. An event related design was combined with a sparse clustered volume acquisitioning paradigm in data collection in order to reduce the influence of acoustic scanner noise. SPM2 software was used for offline data analyzing. RESULT: Significant activation, including volume and intensity, were found in the temporal lobe of control subjects, and significant differences in the volume and intensity were noted between the contralateral and ipsilateral activated auditory cortexes in them, exhibiting clearly contralateral predominance. When the normal ear with unilateral sensorineural hearing loss received signals, while significant activations in bilateral auditory cortexes, greater activation in the contralateral auditory cortexes was found in the normal ear. CONCLUSION: The difference in the lateralization between the two groups suggests the plasticity of auditory cortex with unilateral sensorineural hearing loss. PMID- 21322927 TI - [A primary study of bone conduction hearing loss in adults with otitis media with effusion]. AB - OBJECTIVE: To study the bone conductive hearing loss in adults of otitis media with effusion (OME). METHOD: Fifty adults of OME treated in our hospital, from Mar. 2009 to Feb. 2010, were enrolled for analyzing bone conduction hearing loss (BCHL) before auripuncture and after auripuncture, the difference between which were compared in 51 ears. BCT of pre auripuncture 24 subjects, BCT of post auripuncture 22 subjects, and BCT recovered from OME 9 subjects compared with the contralateral ear respectively. High and extend high frequency (8, 10, 12, 16 kHz) air conduction threshold (ACT) after recover from OME was compared to the normal contralateral ear in 4 adults. RESULT: BCT improved significantly after auripuncture at the frequencies (0.5-4.0 kHz), and the improvements in 4.0 kHz are more than that in 0.5 kHz significantly (P<0.05). In the unilateral OME subjects, BCT, of post auripuncture and recovered from OME, nearly recovered to the same level as the contralateral ear in most cases. While high and extend-high frequency (8, 10, 12, 16 kHz) ACT elevated in 3 of 4 patients recovered from OME. CONCLUSION: Both effusion in middle ear and injury in inner ear could result in the elevation of BCT. Elevation of BCT at regular frequencies (0.5-4.0 kHz) is frequently associated with the effusion in middle ear, while these frequencies were insensitive in the early inner ear injury. The high and extend high frequency ACT elevation may be sensitive for the early sensorineural hearing loss. As the disease prolonged, sensorineural hearing loss of the lower frequencies (0.5-4.0 kHz) could be detected of OME patient. PMID- 21322928 TI - [Sturge-Weber syndrome (a report of one case)]. AB - OBJECTIVE: To study the etiology, clinical and pathological features, diagnose and treatment of Sturge-Weber syndrome. METHOD: The clinical data of 1 case of Sturge-Weber syndrome was analyzed retrospectively. RESULT: Sturge-Weber syndrome is sporadic neurocutaneous syndrome characterized with facial portwine stains, ocular vascular malformation. DSA can demonstrate excessive blood vessels on the leptomeninges. CONCLUSION: Sturge-Weber syndrome is a rare disease. DSA is helpful for the final diagnosis with its' clinical features. PMID- 21322929 TI - [Clinical application of facial nerve monitoring in canal wall down mastoidectomy with tympanoplasty]. AB - OBJECTIVE: To study the neuroprotective effect of facial nerve monitoring in canal wall down of mastoidectomy with tympanoplasty. METHOD: Twenty cases of chronic suppurative otitis media were performed canal wall down of mastoidectomy with tympanoplasty under general anesthesia. Facial nerve monitoring was used during surgery to locate the facial nerve. Threshold level of kinetic current and amplitude of synchronous reaction were recorded. RESULT: Seven cases with cholesteatoma were found facial nerve partial exposured in tympanic segment or mastoid segment. 13 cases had integrated facial never canal. Synchronous myopotential response of facial nerve was evoked successfully in all cases. Electroshock threshold had significant difference between facial nerve exposed group and non-exposed group (P<0.01). No facial palsy were found in all cases. CONCLUSION: Facial nerve monitoring is benefit in locating facial nerve in canal wall down of mastoidectomy with tympanoplasty and could avoid facial nerve injury during surgery. PMID- 21322930 TI - [Giant cell granuloma outside the jaw three cases and literature review]. AB - OBJECTIVE: To investigate the clinicopathological features, diagnosis and treatment of giant cell granuloma outside the jaw. METHOD: The clinical and pathological datas of 3 cases in nasopharynx, temporal bone and maxillary sinus were analyzed retrospectively. The relevant literatures were also reviewed. RESULT: The patients presented with local painless mass, part of which were aggressive. Histopathological feature was, replacement of the normal bone structure with proliferating fibrous tissue containing numerous giant cells was shown. CONCLUSION: Giant cell granuloma outside the jaw was a non-neoplastic lesion, and extremely rare. It was somewhat difficult to make a correct diagnosis. Combining the clinical data and pathological feature were more helpful to the diagnosis. Total surgical resection was an effective therapeutic method. PMID- 21322931 TI - [Analysis of prognostic factors in endoscopic surgery for juvenile nasopharyngeal angiofibroma]. AB - OBJECTIVE: Analyzing the prognostic factors in endoscopic surgery of juvenile nasopharyngeal angiofibromas (JNA). METHOD: Forty-seven records of JNA, treated with the endoscopic, from 2002 to 2008 were reviewed retrospectively. Previous surgery in other hospitals, sites involved, whether selective embolization was performed before surgery, feeding vessels, operative techniques and follow-up results were recorded. Evaluated factors include previous surgery for resection of JNA, vascular supply from carotid artery, surgery after selective embolization, involvement of cavernous bone in the root of pterygoid process, greater wing of sphenoid bone, interpterygoid fossa, infratemporal fossa and orbit. Chi-square test was used. RESULT: Operations were done under general anesthesia. The follow-up time was 12 to 87 month (median 35 month). During follow up, six patients presented recurrent lesions. Chi-square test showed that deep invasion of the cavernous bone in the root of pterygoid process was related to recurrence (P<0.05). There was no statistically significant difference between other factors and recurrence. Imaging examination showed that recurrent tumor was around the root of pterygoid process. CONCLUSION: Deep invasion of the cavernous bone in the root of pterygoid process which was related to recurrence deserve close attention before and after endoscopic surgery. PMID- 21322932 TI - [Quantitative interpretation of dexamethasone pharmacokinetics in human inner ear perilymph using computer simulations]. AB - OBJECTIVE: To study the dexamethasone pharmacokinetics of human inner ear perilymph under different drug administration using computer simulations. METHOD: The dexamethasone pharmacokinetics in guinea pigs inner ear perilymph under an intratympanic application with high-performance liquid chromatography. Dexamethasone pharmacokinetics in the guinea pigs cochlear fluid were simulated with a computer model, the Washington University Cochlear Fluids Simulator, version 1.6 and the best Simulations parameters to the experimental data could be obtain. With best Simulations parameters based on the experimental data, seven kinds application protocols were designed for human inner ear perilymph. RESULT: After an intratympanic application dose of 0.5% dexamethasone 150 ml in guinea pigs, the T(1/2K) was (2.918 +/- 0.089) h, and Cmax was (231.25 +/- 6.89) microg/L. The best Simulations parameters were that concentration of the dexamethasone 21-Phosphate disodium salt was 0.5% and the formula weight was 516, as well as drug diffusion coefficient was 0.6939 x 10(-5) cm2/s and round window permeability was 2.2 x 10(-11) cm/s while drug clearance half time was 175 minutes and scala tympaniscala vestibuli communication was 45 minutes. After an intratympanic application dose of 0.5% dexamethasone 500 mL, which the applied drug stayed in contact with the round window membrane for 15, 30, 60 and 120 minutes, the Cmax was 32.8, 64.3, 122.6 and 203.3 microg/L and the AUC was 116.5, 229.1, 423.6 and 759.2 microg/(h x L), respectively. After an intratympanic application dose of 0.5%, 1%, 2% and 4% dexamethasone 500 ml, which the applied drug stayed in contact with the round window membrane for 30 minutes respectively, the Cmax was 64.3, 127.3, 255.4 and 575.6 microg/L respectively and the AUC was 229.1, 462.8, 920.59 and 1525.2 microg/(h x L), respectively. CONCLUSION: The dexamethasone pharmacokinetics in human inner ear perilymph by computer simulations was reported. As the time contact with the round window membrane increased, the inner ear perilymph concentration of dexamethasone increased. As the concentration of dexamethasone increased, the inner ear perilymph concentration of drug increased. PMID- 21322933 TI - [Research progress on drug metabolism of flavanoids]. AB - Flavanoids are important phytochemistry compositions in foods and traditional Chinese medicines (TCM) and are mainly oxidized by CYP1A family in vivo. Some methoxyflavones could also be metabolized through demethylation. Usually, flavanoids own one or more phenolic hydroxyl group in their molecular structures, which facilitate conjugation with glucuronic acid and sulphuric acid, forming metabolites with good water-solubility to excrete. Natural flavanoids mainly exist in glycoside, and after oral ,they would be easily metabolized to aglycone by hydratase in gut microflora and then absorbed into blood. Besides, many flavanoids have strong inhibitory actions on Cytochrome P450 enzymes, which are significant mechanisms in cancer precaution and tumor inhibition. In this paper, we reviewed lots of articles and summarized metabolism characteristics of flavanoids and metabolism interaction with Cytochrome P450 enzymes. PMID- 21322934 TI - [Effect and advantage of orally taking Chinese herbal medicine for treatment of lung cancer]. AB - Lung cancer is one of the most common cancers and of the leading causes of human death worldwide. Most of patients with lung cancer are diagnosed at advanced stages as it is difficult to be detected in the early stage. Radio/chemotherapy serves as the major method for treatment of lung cancer in conventional medicine without satisfactory efficacy, but with a number of adverse effects. So, it is very popular in mainland China to employ integrated treatment of radio/chemotherapy and Chinese herbal medicine. Through analysis of the published reports in the past two decades, it was found that orally taking Chinese herbal medicine could significantly improve quality of life and body resistance, relieve clinical painfulness, reduce adverse effects of radio/chemotherapy, and prolong life-span of the patient alive with carcinoma in the body. PMID- 21322935 TI - [Correlation and path analysis on artemisinin content and yield with different agronomic traits of Artemisia annua]. AB - OBJECTIVE: To provide the basis for improving utilization of Artemisia annua germplasm resources and breeding variety, the interrelations between artemisinin content, artemisinin yield and agronomic traits of A. annua were studied. METHOD: The artemisinin content and each agronomic trait of 63 A. annua germplasm resources were measured by the visual observation and measurement methods. And the correlation analysis, regression analysis and path analysis were adopted. RESULT: The result showed that there were significant differences in the artemisinin content and yield of 63 germplasm resources from the main production region of A. annua. Correlation analysis showed that there were significantly positive correlation between leaf weight and artemisinin yield with stem and branch characters, but there were negative correlation between artemisinin content with leaf characters of A. annua plant. The artemisinin content of A. annua increased with the increasing of primary branch number, bottom secondary branch number, and bottom stem diameter, etc. On the other hand, it decreased with the increasing of top secondary branch number, secondary leaf axis length, and bottom branch diameter, etc. The artemisinin yield of A. annua increased with the increasing of artemisinin content, leaf weight, and bottom secondary branch number, etc., and decreased with the increasing of bottom branch diameter, middle secondary branch number, and stem weight, etc. Path analysis showed that the primary branch number and bottom secondary branch number had a direct positive effect on the artemisinin content of A. annua. But the top secondary branch number had a direct negative effect on the artemisinin content of A. annua. The leaf weight and artemisinin content had a direct positive effect on the artemisinin yield and the ratio of leaf/stem, branch weight and stem weight had a direct negative effect. CONCLUSION: On the breeding A. annua variety, it can take into account both high leaf yield and high artemisinin content. And it was strongly recommend that the plant with moderate plant height and crown, shortness pinnae and secondary leaf axis, less middle and top secondary branch, strong stem, higher primary branch number and bottom secondary branch number, and higher ratio leaf/stem could be selected for breeding new varieties with high leaf yield and high artemisinin content. PMID- 21322936 TI - [Comparison on botanical morphology in different populations of Changium smyrnioides]. AB - OBJECTIVE: To analyse botanical morphology in different populations and give a reference for germplasm evaluation of Changium smyrnioides. METHOD: Roots and leaves were comprehensively compared among 10 populations of Ch. smyrnioides in the main distribution area, the foliar morphology similarity coefficient was calculated, and the systematic relationships were constructed based on UPGMA method. RESULT: There was significant morphological difference among populations of Ch. smyrnioides. Plant shape was divided into the loosed-type, compacted-type and intermediated-type. Leaf split was divided into the lobated-type, parted-type and intermediate-type. Root shape was divided into spherical-type, column-type and spindle-type. Foliar morphology similarity coefficient differed significantly and ranged from 0.234 1 to 0.985 1 among 10 populations of Ch. smyrnioides. Zijinshan population was divided into a unique group when similarity coefficient was 0.37. CONCLUSION: Plant tightness, lobation depth and root shape could be used as the basis for germplasm evaluation on Ch. smyrnioides. Zijinshan population could be used as a special germplasm to be exploited. PMID- 21322937 TI - [Dynamic research of growth, N, P, K and active ingredients in Angelica dahurica var. formosana from Sichuan province]. AB - OBJECTIVE: To study the absorption and transformation of N, P, K and plant growth as well as the accumulation of active ingredients in Angelica dahurica var. formosana from Sichuan province and provide basis for rational fertilization. METHOD: Samples were collected in different growth phrases, and correlative morphological indexes, the contents and accumulations of N, P, K and active ingredients were determined. RESULT: The vegetative growth period of A. dahurica var. formosana sowed in autumn could be preliminarily divided into three phases: seedling period, aerial-part peak growth period and root peak growth period. With the development, the plant height and aerial part dry weight increased at the earlier stage, and then decreased. But the root length, root diameter, and root dry weight increased. The absorptive capacity of N, P and K varied among different developing stages. In general, the absorptive capacity of N and K was the higher than that of P. The order of total nutrition accumulation was N > P > K, the accumulation of N, P and K in aerial part decreased gradually during the growth period, while the accumulation of N, P and K in root increased gradually. The concentration of imperatorin and isoimperatorin showed decreasing-increasing decreasing-increasing trend, while the accumulation of them increased gradually. And the correlation analysis results showed that the accumulation of P and K in aerial part had positive correlation with the concentration of imperatorin in root, the accumulation of N, P and K in root had positive correlation with the concentration of isoimperatorin in root. CONCLUSION: From late April, A. dahurica var. formosana from Sichuan province entered root peak growth period and the accumulation of N, P, K, imperatorin and isoimperatorin in root increased rapidly. So the balanced application of fertilizer should be considered. PMID- 21322938 TI - [Variation of endogenous hormones in formation of microtuber of Dioscorea opposite in vitro]. AB - OBJECTIVE: Through analysis of variation and function of 5 main endogenous hormones in the formation of microtuber of Dioscorea opposite in vitro to explore the physiological and biochemical mechanism of microtuber development. METHOD: When microtubers were induced on MS + 6-BA 1.5 mg x L(-1) + NAA 1.5 mg x L(-1) + sucrose 5% medium, the endogenous hormones were isolated during different formation stages of microtubers, then purified and detected with enzyme-linked immunosorbent assays (ELISA). RESULT: The results showed that GA3 slightly decreased in initial period, rose suddenly 20 days later, and than decreased. IAA showed a dropping tendency in the total course, ABA and ZR increased in a long period, dropped at last. JA continuously rose and never dropped, GA3 and ABA and the ratio of GA3 and JA varied obviously. CONCLUSION: IAA, ABA, JA , ZR and GA3 play an important role in controlling formation of microtubers in D. opposite in vitro. PMID- 21322939 TI - [Preparation of nasal thermosensible gels of Chinese medicine Xingbi and release behavior in vitro]. AB - OBJECTIVE: To prepare the nasal thermosensible gels of Chinese medicine Xingbi and study the release mechanism. METHOD: The gels were prepared by using P407 as the gel matrix and P188 and PEG 6000 were used to adjust the gelatination temperature. The formulations were screened by the method of orthogonal test. Mathematic models were used to imitate the drug release. RESULT: 20% poloxmar 407, 2% poloxmar 188 and 2% PEG 6000 were suitable to Chinese medicine Xingbi thermosensitive gel in situ. Nasal thermosensible gels of Chinese medicine Xingbi was gelated at the temperature between 32-34 degrees C and the dissolution curves in vitro showed that the drug release could be best described by the Higuchi equation. CONCLUSION: The formulation of the nasal thermosensible gels of Chinese medicine Xingbi is reasonable and it is worth doing further research. PMID- 21322940 TI - [Determination of paeonol in rat plasma by HPLC and pharmacokinetic study]. AB - OBJECTIVE: To establish a sensitive HPLC method for determining the concentrations of paeonol in rat plasma and to evaluate its pharmacokinetic characteristics. METHOD: The paeonol from eortex Moutan was distilled by the way of water-vapor. A single i.v. dose of 4 mg x kg(-1) paeonol injection was given to 5 health rats. Paeonol was separated on a Diamonsil -C18 column with methanol water (60: 40)as mobile phase. The plasma concentrations of paeonol were determined and its pharmacokinetic parameters were calculated and evaluated by using kinetica 4.0. RESULT: The linear range of the method for paeonol was 0.204 20.4 mg x L(-1) and the determination limit was 0.204 mg x L(-1). The main pharmacokinetic parameters, such as AUC, MRT, C(max), Kel, t(1/2kel), after a single dose of paeonol injection were (111.88 +/- 14.44) mg x L(-1) x min(-1), (23.25 +/- 5.86) min, (8.99 +/- 0.84) mg x L(-1), (0.082 +/- 0.015) min(-1) and (8.73 +/- 1.54) min, respectively. CONCLUSION: The HPLC method for determining paeonol concentration in plasma is simple, rapid, sensitive and suitable for pharmacokinetic studies. PMID- 21322941 TI - [Study on HPLC fingerprinting and determine six kinds of ester-type alkaloids of Radix Aconiti lateralis praeparata slice]. AB - OBJECTIVE: To establish the HPLC fingerprint and determine six kinds of ester type alkaloids of Radix Aconiti lateralis praeparata slice. METHOD: HPLC analysis was performed on a Phenomenex Gemini C18 (4.6 mm x 250 mm, 5 microm) with 0.04 mol x L(-1) ammonium acetate (adjusted to pH 10.0 with ammonia water)and acetonitrile as mobile phase. Similarity evaluation system for chromatographic fingerprint of traditional Chinese medicine (2004 AB)was used in data analysis. RESULT: Baifupian, Heifupian from different samples were of high similarity in fingerprint, and the separation of six kinds of ester-type alkaloids was good. Huangfupian and crude aconite root showed significant difference in fingerprint, comparing with Baifupian and Heifupian. CONCLUSION: This method is simple and reliable. The HPLC fingerprint and contents of six kinds of ester-type alkaloids of Radix Aconiti lateralis praeparata slice can be used for their quality control. PMID- 21322942 TI - [Comparison of content of curdione, curcumol, germacrone and beta-elemene in different varieties of vinegar backed Rhizoma Curcuma]. AB - OBJECTIVE: To establish a HPLC method for determination of 4 components in different varieties of vinegar backed Rhizoma Curcuma. METHOD: The method was established by using an Elite Hypersil ODS2 column (4.6 mm x 250 mm, 5 microm). The mobile phase comprising acetonitrile (A) and water (B) was used to elute the targets in gradient elution mode. Flow rate and detection wavelength were set at 1 mL x min(-1) and 214 nm, respectively. The column temperature was 25 degrees C and the injection volume was 10 microL. RESULT: All calibration curves showed good linearity with r > 0.999 5. Recoveries measured at three concentrations were in the range of 97.27% - 99.27% with RSD < 3%. CONCLUSION: The validated method is simple, reliable, and successfully applied to determine the contents of the selected compounds in vinegar backed Rhizoma Curcuma. The results of the determination showed that contents of the four components in vinegar backed Curcuma wenyujin were relatively high. PMID- 21322943 TI - [Simultaneously determination of atropine sulphate, diphenhydramine hydrochloride, capsaicin and dihydrocapsaicin in pain-relieving plaster for arthritis by RP-HPLC]. AB - OBJECTIVE: To establish RP-HPLC method for determination of atropine sulphate, diphenhydramine hydrochloride, capsaicin and dihydrocapsaicin in pain-relieving plaster for arthritis. METHOD: The sample were separated on an Alltima C18 Column (4.6 mm x 250 mm, 5 microm) with the moblie phase of CH3 CN-0.1% H3 PO4. Flow rate was 1 mL x min(-1). The detective wavelength was set at 210 and 280 nm. Column temperature was 30 degrees C. RESULT: The calibration curve for atropine sulphate, diphenhydramine hydrochloride, capsaicin and dihydrocapsaicin revealed linearity in the range of 2.01-50.25, 15.08-377.00, 5.02-125.50, 5.03-125.75 mg x L(-1), respectively. The recoveries of atropine sulphate, diphenhydramine hydrochloride, capsaicin and dihydrocapsaicin were 99.00% with RSD of 0.95%, 99.89% with RSD of 1.2%, 100.1% with RSD of 1.5% and 99.51%, with RSD of 1.4%, respectively. CONCLUSION: The method is simple, rapid and accurate, which is suitable for the quality control of pain-relieving plaster for arthritis. PMID- 21322944 TI - [HPLC fingerprints of processed products from Sinapis alba]. AB - OBJECTIVE: To establish the HPLC fingerprint method and compare the changes of chemical compositions of the processed products from Sinapis alba. METHOD: The procedure of HPLC analysis was performed on a agilent TC-C18 (2) column at 35 degrees C with the acetonitrile -0.1% phosphoric acid in gradient elution as the mobile phase. The detection wavelength was set at 254 nm, and the flow rate was 1.0 mL x min(-1). The similarity evaluation system for chromatographic fingerprint of traditional Chinese medicine (Version 2004 A) was applied to analyze the similarity. RESULT: The average similarities among the processed products were over 0.96, the standard HPLC fingerprint and five main chromatographic peaks with the isolated compounds was obtained and identified. CONCLUSION: The established methods with two solvents are suitable for the HPLC fingerprints determination which elementary elucidate the scientific intensions of breaking the enzyme for glycosides. PMID- 21322945 TI - [Study on quality standard of Rhizoma Diosoreae and Rhizoma Dioscorea stir-baked with bran]. AB - OBJECTIVE: To perfect the current standard of Rhizoma Diosoreae and Rhizoma Diosoreae stir-baked with bran by improving quality standards of the two processed pieces. METHOD: The quality standards were established according to 9 batches of processed pieces, separately. The standards contains items of identification, water, total ash, acid-insoluble ash, extractives, heavy metals limit, organochlorine limit, microbial limit and assay. RESULT: The TLC of the two pieces was characteristed. The contents of acid-insoluble ash in the two pieces were increased, not more than 0.5%, 0.3%, respectively. The content limits of five kinds of heavy metals and harmful elements, two kinds of residual organochlorine pesticides and three microbial limits were increased. There were no more than 2 x 10(-7) of lead, 2 x 10(-7) of cadmium, 1 x 10(-5) of copper, 3 x 10(-7) of arsenic, 1 x 10(-7) of mercury, 1 x 10(-7) of hexachlorocyclohexane (BHC) and 1 x 10(-7) of chlorophenothane (DDT) in the two processed pieces, respectively. There were no more than 2 000 and 600 cfu x mL(-1) in the two pieces, respectively and no more than 30 MPN x 100 g(-1) and fungi can not be tested in the two pieces. The contents of allantoin in the two pieces were no more than 0.15%. CONCLUSION: This method is simple and suitable for the quality control of the two processed pieces. PMID- 21322947 TI - [Chemical constituent from fruit of Aristolochia contorta]. AB - OBJECTIVE: To study the chemical constituents of the fruit of Aristolochia contorta. METHOD: The compounds were isolated by chromatographic techniques and crystalization, the structures were elucidated by spectrum analysis. RESULT: Fifteen compounds were isolated from the dry fruit of A. contorta, which were six aristolochic acids: aristolochic acid I, aristolochic acid III a, aristolochic acid IVa, aristolochic acid II, aristolochic acid III and aristolochic acid VIIa. Three aristolactams: aristololactam I, aristololactam II and aristololactam IIIa. Three phenolic acids syringic acid, vanillic acid and p-coumaric acid. Three other type compounds: pentacosane acid, beta-sitosterol and daucossterol. CONCLUSION: Aristolochic acid III, aristolochic acid VIIa, aristololactam IIIa, and penfacosane acid were isolated from A. contorta for the first time, and compounds 4-13 were isolated from the furit of A. contorta for the first time. PMID- 21322946 TI - [Constituents of Gymnadenia conopsea]. AB - OBJECTIVE: To investigate the chemical constituents of tuber of Gymnadenia conopsea. METHOD: The constituents were isolated by using a combination of various chromatographic techniques including column chromatography over silica gel, Sephadex LH-20, and C-18, as well as reversed-phase HPLC. Structures of the isolates were identified by spectroscopic data analysis. RESULT: Thirty-four compounds were isolated. Their structures were identified as six 2 isobutyltartrate benzyl ester glucosides: coelovirin A (1), coelovirin B (2), coelovirin E (3), coelovirin D (4), dactylorhin B (5) and loroglossin (6). Three 2-isobutylmalate benzyl ester glucosides: dactylorhin A (7), dactylorhin E (8) and militarine (9). Three lignans: arctigenin (10), lappaol A (11) and lappaol F (12). Six aromatic acid (alhyde or alcohol) derivatives: 4-beta-D glucopyranosyloxyl-trans-phenylpropenoic acid (13), 4-beta-D-glucopyranosyloxyl cis-phenylpropenoic acid (14), gastrodin (15), 4-beta-D glucopyranosyloxylphenylaldehyde (16), 4-beta-D-glucopyranosyloxylbenzyl methyl ether (17), 4-beta-D-glucopyranosyloxyloxylbenzyl ethyl ether (18), and bis(4 hydroxybenzyl) ether mono 4-O-beta-D-glucopyranoside (19). Four cyclodipeptides: cyclo(L-Leu-L-Tyr) (20), cyclo(L-Leu-L-Pro) (21), cyclo(L-Val-L-Tyr) (22), and cyclo(L-Ala-D-Phe) (23). One N6-substituted andenosine: N6-(4-hydroxybenzyl) adenine riboside (24). An aromatic amide: N-trans-feruloyltyramine (25). Nine aromatic acids (or aldehyde or alcohol): 3-hydroxybenzoic acid (26), 4 hydroxyisophthalic acid (27), 4-hydroxybenzyl alcohol (28), 4-hydroxybenzyl methyl ether (29), 4-hydroxybenzylaldehyde (30), 4-hydroxybenzoic acic (31), 4 hydroxy-3-methoxybenzoic acid (32), trans-p-hydroxyphenylpropenoic acid (33), and cis-p-hydroxyphenylpropenoic acid (34). At a concentration of 1.0 x 10(-6) mol x L(-1), compounds 10-12 showed antioxidative activity inhibiting Fe(+2) -cystine induced rat liver microsomal lipid peroxidation with inhibitory rates of 53%, 59%, and 52%, respectively(positive control VE with 35% inhibition). CONCLUSION: These compounds were obtained from the genus Gymnadenia for the first time except for 5-7, 9, 15, 28-34. Compounds 10-12 possess antioxidant activity. PMID- 21322948 TI - [Determination of xanthones in Tibetan herb Jiadiranguo (Herba Haleniae)]. AB - A HPLC method was developed for simultaneous determination of 1-hydroxy-2, 3, 4, 7-trimethoxyxanthone (1), 1-hydroxy-2,3, 7- trimethoxyxanthone (2), 1-hydroxy-2, 3, 4, 5-trimethoxyxanthone (3), and 1-hydroxy-2, 3, 5- trimethoxyxanthone (4) in Halenia elliptica. The analytical column was Welchrom C18 column (4.6 mm x 250 mm, 5 microm). The mobile phase was acetonitrile- water (43:57). The detection wavelength was 265 nm. The flow rate was 1 mL x min(-1) and the column temperature was set at 40 degrees C. There was good linearity between the peak areas and concentration at the ranges of 0.414-16.6, 1.73-69.6, 5.89-117, 3.01 120.5 mg x L(-1) for 1, 2, 3 and 4 respectively. The average recoveries (n = 6) of 1, 2, 3 and 4 were 102.5%, 100.5%, 97.9% and 101.2%. Those four xanthones in thirty samples of H. elliptica. were determined by this method. The method is simple, accurate, repeatable, which could be used for the quality evaluation of H. elliptica. The total content of those four xanthones in H. elliptica should not less than 1.80% by comprehensive analysis. PMID- 21322949 TI - [Research on chromatographic fingerprint of fruits of Schisandra chinesis]. AB - OBJECTIVE: To study the chromatographic fingerprint of the fruits of Schisandra chinensis, and identify the peaks. METHOD: Analysis was performed at 30 degrees C on a Waters Symmetry C18 column (4.6 mm x 250 mm, 5 microm), eluted with acetonitrile-water gradient elution. The flow-rate was 1.0 mL x min(-1), and detection wavelength was 218 nm. The peaks in the chromatogram were identified by LC-MS. RESULT: The fingerprint of the fruits of S. chinensis was established, and fifteen peaks of lignans were identified. CONCLUSION: The method was easy, reliable and could be used as a powerful tool for the further quality control of S. chinensis. PMID- 21322950 TI - [Determination of flavones in different origin and parts of Bupleurum smithii var. parvifoliaum by UPLC-PDA]. AB - An ultra performance liquid chromatography method has been developed for determination of flavones in different origin and different parts from Bupleurum smithii var. parvifoliaum. The separation was performed at 30 degrees C on an Acquity UPLC BEH C18 column eluted with methanol and 0.1% phosphoric acid solution as mobile phases in gradient elution. The detection wavelength was set at 256 nm and the flow rate was 0.4 mL x min(-1). There flavones of rutin, quercetin and isorhamnetin were separated well, the linear calibration curves were obtained over the ranges of 0.106-1.06 microg for rutin (r = 0.999 8, n = 6), 0.004 87-0.048 7 microg for quercetin (r = 0. 999 7, n = 6), 0.022 0-0.220 microg for isorhamnetin (r = 0.999 8, n = 6). The mean recoveries of the three compounds were 99.3%, 97.8%, 98.9% with RSD of 2.4%, 3.0%, 3.2%. The result showed that the method is convenient and feasible for determination of the flavone content in B. smithii var. parvifoliaum. PMID- 21322951 TI - [Effects of HSYA on expression of bFGF protein and MMP-9 in BGC-823 transplantation tumor of nude mice]. AB - OBJECTIVE: To investigate the effects of hydroxy safflor yellow A (HSYA) on the expression of bFGF protein and MMP-9 mRNA or protein of transplantation tumor of gastric adenocarcinoma cell line BGC-823 in nude mice. METHOD: The BGC-823 cells were subcutaneously injected into the right anterior armpit of BALB/C nu/nu nude mice, and the animal model of transplantation tumor was established. The experimental groups were treated with HSYA at concentration of 0.056 and 0.028 g x L(-1) and cyclophosphamide at 2 g x L(-1), or with physiologic saline. The tumor inhibitory effect was observed, and the mRNA expression of MMP-9 of transplantation tumor was detected by real time-fluorescent quantitation PCR and the protein expression of MMP-9 and bFGF were detected by enzyme linked immunosorbent assay. RESULT: The IR in the group with HSYA at the concentration of 0.028 g x L(-1) is higher than in the group with normal sodium. After treatment with HSYA, the mRNA expression of MMP-9 has significant difference at the concentration of 0.028 g x L(-1) as compared with physiologic saline-treated group (P < 0.05), but the protein expression of MMP-9 and bFGF is obviously less than that in the physiologic saline-treated group (P < 0.05). CONCLUSION: The possible mechanism of HSYA in given concentration to antagonize tumor angiogenesis may be related with inhibiting the protein expression of MMP-9 and bFGF or the mRNA expression of MMP-9 in tumor tissue to reduce the degradation of blood vessel basilar membrane, and to restrain the migration of blood vessel and decrease the tumor vascularization. PMID- 21322952 TI - [Comparative study on metabonomics and on liver and kidney toxicity of Aristolochia fangchi and Stephania tetrandra]. AB - OBJECTIVE: Combined the blood biochemical markers, the renal histopathological changes and the metabonomics profile were investigated to study the toxicity differences between Aristolochia fangchi and Stephania tetrandra. METHOD: Ten rats were randomly selected from 70 male Wistar rats as blank control group. The remaining 60 rats were divided into three groups. The two treated groups were orally administrated by 8.1 g x kg(-1) of A. fangchi and S. tetrandra respectively and the control group by equal volume of distilled water for 4weeks. Before the administrated and every 2 weeks, urine and plasma were collected and their 1H-NMR spectra were acquired, and then subjected to data process and PCA. Blood biochemical analysis and histopathological examination were carried out. RESULT: On the 2nd weekend, the BUN of the two treated groups, the AST of A. fangchi group were all markedly higher than that of the control group (P < 0.05). Compared with the A. fangchi group, the SCr higher in the S. tetrandra group (P < 0.05). The kidney pathological changes were apparently in the two treated groups and the pathological changes in the liver apparently in the S. tetrandra group. Along with the lasting of administration to the 4th week, the BUN, ALT and AST of the two treated groups, the SCr of A. fangchi group were all significantly higher than that of the control group (P < 0.01). The renal and liver injuries in the two treated groups were all become more seriously. Comparing the A. fangchi group, the BUN, SCr and AST were all higher in the S. tetrandra group (P < 0.05). Compared with control group, the urinary concentrations of citrate, 2-oxo glutarate, taurine, hippurate, TMAO, creatine and the plasma concentrations of 3 D-hydroxybutyrate, acetone, NAC, OAC, creatinine were all changed. CONCLUSION: The A. fangchi and S. tetrandra all can induce the renal and liver lesion and its seriousness is correspondent to the lasting of administration. The liver and kidney toxicity of S. tetrandra are all more serious than the A. fangchi. PMID- 21322953 TI - [Effects and mechanisms of Simiao pill on adjuvant arthritis rats model]. AB - OBJECTIVE: To study pharmacologic actions for rheumatoid arthritis treatment and probe into the effects and mechanisms of Simiao pill on adjuvant arthritis (AA) rats. METHOD: Wistar rats, male, were randomly divided into the normal comparison group, model group, the glucosida Tripterygii TOTA group (9.45 mg x kg(-1)), the Simiao pill low dose group (1 080 mg x kg(-1)), the Simiao pill middle dose group (2 160 mg x kg(-1)) and the Simiao pill high dose group (4 320 mg x kg(-1)). Except the normal comparison group, rats in the other groups were injected Freund's complete adjuvant reagent into the rats' right etapedes to establish the AA model. Drugs were given by intragastric administration. Then paw swelling, SOD in blood serum, the spleen and and thoracic gland index, histopathology change of malleolus joint were observed. IL-1beta, IL-6 and TNF-alpha mRNA were observed by semi-quantitative reverse transcription and polymerase chain reaction(sqRT-PCR). RESULT: Simiao pill could inhibit the swelling of the rats' inflamed metapedes. Compared with the model group, each group of Simiao pill could increase SOD, decrease spleen index, advance the thoracic gland index and decrease IL-1beta, IL 6 and TNF-alpha mRNA. CONCLUSION: Simiao pill could threat AA rats and inhibit the inflammation of synovial membrane obviously. It also could relieve the degree of paw swelling, and therefore provide clinical theatment basis of RA. PMID- 21322954 TI - [Screening effective parts of combination of Astragali Radix and Angelicae Sinensis Radix (A&A) for its renoprotective effects]. AB - OBJECTIVE: The decoction of Astragali Radix and Angelicae Sinensis Radix (A&A) has shown antifibrotic effects in rats with unilateral ureteral obstruction (UUO). The aim of this study was to track the effective parts of A&A for its renoprotective effects, according to the improvement of renal function and renal tubulointerstitial damage. METHOD: A&A was sequentially extracted by using different solvents for three times and eleven different parts were gained. Wistar rats were randomly divided into Sham, UUO and the treatment groups with A&A or each part of A&A. After administration of A&A or its parts for 10 days, the levels of serum creatinin (Scr) and urea were measured. The morphological changes of kidneys were also semi-quantitatively analyzed by HE, Masson stained tissue sections, which including interstitial cell infiltration, tubular atrophy and interstitial fibrosis. RESULT: The levels of Scr, urea were significantly increased, accompanied with severe renal damage in rats with UUO. As same as A&A, the part I in the first extraction and part IC in the second extraction were all shown to decrease the levels of Scr and urea and the index of renal interstitial damage. However, the following 4 parts extracted from IC in the third extraction were shown no effect on the above indexes. CONCLUSION: The extract part I and part IC could be considered as the predominant parts of A&A for its renoprotective effects, due to their improvement of renal damage in interstitial nephropathy. PMID- 21322955 TI - [Effect of Weichang'an pill on intestinal digestion enzymes and the AQP4 concentration in proximal colon in IBS-D rats]. AB - OBJECTIVE: To investigate the influence of Weichang'an pill on the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D) in model rats. METHOD: Animal model of compound diarrhea was induced by a lactose enriched diet in the Wistar rat, combining with restraint stress. Twenty four female Wistar rats were randomly divided into normal group, model group and 60 mg x kg(-1) x d(-1) Weichang'an pill group. The rate of weight increase, the incubation period of diarrhea and the diarrhea index were observed. Then 45 female Wistar rats randomly divided into five groups: control group, model group and Weichang'an pill groups of high, medium and low doses (80, 60, 40 mg x kg(-1) x d(-1)). The indexes of thymus and spleen were calculated. The activities of LDH, MDH and disaccharidase in intestinal organization were inspected. Serum D-xylose content and the AQP4 concentration in proximal colon were detected. RESULT: After taking Weichang'an pill for 4 days, the rate of weight increase in Weichang'an pill group was higher than the model group's. While the rate of diarrhea was lower significantly. So the best cycle of taking medicine was 4 days. The indexes of thymus and spleen of model group were decreased than that of control group. And the activities of LDH, MDH and disaccharidase in intestinal organization were also decreased. But the AQP4 concentration in proximal colon was increased. Compared with the model group, the indexes of thymus and spleen increased remarkably in the group of medium doses. Meanwhile, the activities of LDH, MDH and disaccharidase increased. But the AQP4 concentration didn't change. CONCLUSION: Weichang'an pill has the effect of antidiarrhea. It can adjust the sugar's catabolism through increasing the activity of intestinal digestive ferment. PMID- 21322956 TI - [Anaphylactoid reaction induced by Qingkailing injection via basophils cells degranulation]. AB - OBJECTIVE: To observe the effects of Qingkailing injection on RBL-2H3 cell degranulation and histamine release, and discuss the possible mechanism of anaphylactoid reaction induced by Qingkailing injection. METHOD: RBL-2H3 cells were incubated with Qingkailing injection for 30 min. Then the morphological changes of cells were observed by transmission electron microscopy. Cell degranulation rate was detected by Alcian blue dye assay, Annexin V binding assay and beta-hexosaminidase assay, and cell histamine release rate was detected by ELISA. RESULT: Different concentration of Qingkailing injection can induce the typical morphological changes in RBL-2H3 cell with degranulation. The rates of degranulation and histamine release in Qingkailing injection treated cells were significantly increased and dose-dependent. CONCLUSION: RBL-2H3 cell degranulation and histamine release can be induced by single administration of Qingkailing injection, and then induced anaphylactoid reaction, which may be one of the possible mechanisms of serious adverse induced by Qingkailing injection for the first administration in clinic. PMID- 21322957 TI - [Effects of rhubarb aglycone combined with thrombolysis on brain microvascular basement membrane impairment in rats with thrombus-occluded cerebral ischemia]. AB - OBJECTIVE: To explore the protective effects of rhubarb aglycone combined with urokinase (UK) thrombolysis on brain microvascular basement membrane impairment in rats with thrombus-occluded cerebral ischemia by regulating the expression of IgG, CoLIV and LN in rats brain, by which the level of injury of brain microvascular basement membrane could be detected. METHOD: Rats were randomly divided into sham-operated, model, thrombolysis, rhubarb aglycone and combination (rhubarb aglycone combined with thrombolysis) groups. Moreover, rats in model, thrombolysis, rhubarb aglycone and combination groups were randomly divided into 3, 6, and 9 h groups respectively. Model of thrombus-occluded cerebral ischemia was duplicated by using the combination of rats' auto-thrombus with inserting the nylon thread. Rats were administrated with thrombolysis therapy through artery at 3, 6, and 9 h after cerebral ischemia. At 24 h of administration through artery, intracranial hemorrhage ratio (ICHR) and mortality of rats were observed, and then the brain of rats was taken. In the study, expression of IgG, CoLIV and LN in rats brain were measured. RESULT: Thrombolysis at 9 h of cerebral ischemia made rats mortality and BHR increase, administration of combined therapy could make them decrease. Expression of IgG level in rats brain of 9 h and 6 h model groups increased, while CoLIV and LN expression decreased significantly. In each administration 9 h group, IgG level was lower, and CoLIV and LN were higher, such changes appeared significantly in rhubarb aglycone and association groups. CONCLUSION: Brain microvascular basement membrane impairment could be caused by the therapy of delayed thrombolysis, which made the mortality and BHR increase. Rhubarb aglycone combined with the therapy of thrombolysis could perform the protective effects on brain microvascular basement membrane and then decrease the ICHR and mortality caused by thrombolysis after cerebral ischemia. PMID- 21322958 TI - [General and light microscope observation on histological changes of femoral heads between SANFH rabbit animal models and it were intervened by Osteoking]. AB - OBJECTIVE: To evaluate the histological changes on the femoral heads of the SANFH rabbit animal models and after it were intervened by Osteoking (herbs of the Yi minority in Yunnan province) using general and light microscope observation. METHOD: A total of 150 New Zealand white rabbits were randomly divided into a non treatment control group (A group, n = 24), normal rabbits with Osteoking treatment group (B group, n = 24), and the experimental group (n = 102). The experimental group was injected with escherichia coli endotoxin (10 microg x kg( 1)) into auricular vein twice by 24-hour intervals, and prednisolone (20 mg x kg( 1)) was injected into buttock three times by 24-hour intervals to make steroid induced femoral head necrosis model. At the fifth week, 48 out of 53 rabbits were equally divided into model group (C group, n = 24, models with non-treatment Osteoking) and abnormal rabbits with Osteoking treatment group (D group, n = 24). B group and D group were intragastrically administrated with Osteoking, once every two days. A group and C group were intragastrically administrated with the equal volume of saline. At 8th, 12th and 16th week after model preparation, the femoral head specimens were observed under the general and a light microscope. RESULT: Macroscopic and light microscopic analysis showed that, clear bone necrosis of femoral head was observed in the C group, and a large number of fat cell proliferation was found in the bone marrow cavity. As compared with C group, the damage level of cells in D group was milder, however, the density of bone trabecula from Osteoking treatment was high, and the ratio of bone lacuna was very low. It is also demonstrated that the surface area of bone necrosis was decreased, and the number of cells from adiposities was reduced significantly. The phenomenon of bone necrosis repaired apparently. The morphology of femoral head from A group and B group is normal. CONCLUSION: It suggested that Osteoking could effectively help repair steroid-induced femoral head necrosis in the early stage. PMID- 21322959 TI - [Absorption mechanism of tanshinone II A, cryptotanshinone, tanshinone I and tanshinones extract in rat small intestine in vivo]. AB - OBJECTIVE: To study the absorption mechanism of tanshinones in the roots of Salvia miltiorrhiza as well as the interaction between the components in the effective fraction. METHOD: The model of intestinal absorption in vivo was used and the concentrations of the tanshinones were determined by HPLC, the apparent absorption constant (K(a)) and half life of absorption (t1/2) were obtained, the other components in the extract on the absorption of the there components were also studied. RESULT: With the increase of dosage of tanshinone II A or cryptotanshinone, K(a) decreased and absorption half life t1/2 increased, the drug absorption rate constant (K(a)) had little significant effect on duodenum, Jejunum and ileum. Tanshinone I has a good absorbing in the rat small intestine. The absorption of tanshinone II A and cryptotanshinone was promoted by the other components in tanshinones extract while tanshinone I' was decreased. CONCLUSION: When the concentration increases to a certain level, the uptake of tanshinone II A and cryptotanshinone do not increase. The transport mechanism of tanshinone II A and cryptotanshinone in vivo is similar to active transport or facilitated diffusion. They could be well absorbed in general intestinal tract without specific absorption site, and the complex constituents in extract could significant effect the absorption of the pharmaceutical effective constituents. PMID- 21322960 TI - [Effect of tanshitone on prevention and treatment of retinoic acid induced osteoporosis in mice]. AB - OBJECTIVE: To observe the prevention and therapeutic effects of tanshitone (TAN) on retinoic acid induced osteoporosis in mice. METHOD: The mice osteoporosis was induced by given retinoic acid intragastrically for two weeks. The histomorphological features of bone were observed and biochemical indexes in serum (Ca, P, ALP, TRAP, E2, BGP) were determined after the mice were given TAN at the dose of 40, 80, 160 mg x kg(-1) respectly. RESULT: Tanshinone can induce high conversion of osteoporosis. The levels of P, ALP, TRAP and BGP in the TAN groups were lower than the model group, while the E2 level was higher than the model group. CONCLUSION: Tanshitone can prevent the loss bone in the experimental mice. The mechanism may be that it improves the level of estrogenic hormone and inhibits the high bone turnover. PMID- 21322962 TI - [On origin of Oviductus Ranae in Chinese Pharmacopoeia]. AB - OBJECTIVE: To discuss the problem about the origin of Oviduetus Ranae in the Chinese Pharmacopoeia according to historical documents, the researches reported recently and the author research. METHOD: Through comprehensive analysis of the documents and materials reported, the original animal sources of Oviduetus Ranae was discussed in terms of historical records, morphology, karyotype, Ag-Belt and isoenzyme electrophoresis, gene levels and so on. RESULT AND CONCLUSION: The original animal sources of Oviduetus Ranae is Rana dybowskii,its order element is an effective species in China. In order to avoid the problem of species confusion about the origin of Oviduetus Ranae, author suggests that R. dybowskii should be the original animal of Oviduetus Ranae. PMID- 21322961 TI - [Addendum and emendation of "China Medicinal Animal Fauna"]. AB - To carry out the " China Medicinal Animal Fauna" addenda and revision, with effective assessment, protection, utilization of medicinal animal resources, to promote sustainable modem research and application for medicinal animals and medical materials from animals. METHOD: Keep the original "China Medicinal Animal Fauna" characteristics and peculiarities, combined with nearly 30-year research progress of zoology and medicinal animals, and author's long-standing and rich experience. RESULT: Develop the addenda's general framework, addenda and revision contents, revision methods and technical routes of the "China Medicinal Animal Fauna". CONCLUSION: Based on the research of medicinal animal resource system, fully use of modern molecular biology and other emerging science and technology, rich the scientific connotation of medicinal material from animal, will promote the research and use of medical material from animal to a new level. PMID- 21322963 TI - [Some issues to notice in the research and quality evaluation of external preparations of traditional Chinese medicine]. AB - External preparations of traditional Chinese medicine inherits features of traditional Chinese pharmaceuticals while presenting the application of modern scientific technology in the field of medicine preparations. This paper will discuss some issues that investigators should pay attention to when they work on the preparations, such as the rationality of selecting drug dosage forms, how to select and handle drug auxiliary materials, and how to study medicinal material processing techniques. All these issues were found out during the drug evaluation cases in recent years. PMID- 21322964 TI - [Patterns of experienced and anticipated discrimination in patients with schizophremia. Italian results from the INDIGO international multisite project]. AB - AIMS: To describe patterns of experienced and anticipated discrimination in a sample of schizophrenic patients recruited in Italy in the context of the International Study of Discrimination and Stigma Outcomes (INDIGO). METHODS: Cross-sectional survey on a sample of 50 people with clinical diagnosis of schizophrenia recruited in the Italian INDIGO sites of Verona and Brescia. The 41 item interview-based Discrimination and Stigma Scale (DISC-10), which assesses how experienced and anticipated discrimination affects the life of people with schizophrenia, was used. RESULTS: The most frequently occurring areas of experienced discrimination were discrimination by family members (44%), making and keeping friends (33%), keeping (36%) and finding a job (34%), getting or keeping a driving licence (32%). Anticipated discrimination was common in applying for work, training or education (58%), looking for close relationships (50%) and doing something important (48%); 68% felt the need to conceal their diagnosis. Positive experiences were rare, and getting welfare benefits/disability pensions was the only area where participants reported being treated with advantage (34%) more commonly than with disadvantage (8%). Overall, experienced discrimination reported by Italian patients was in the intermediate position of the score range of all INDIGO sites, whereas anticipated discrimination was lower than that reported in the other countries. CONCLUSIONS: Interventions to reduce discrimination against people with schizophrenia may need to address both actual and anticipated discrimination. Targeted therapeutic strategies aiming to improve self-esteem of people with schizophrenia may be useful to facilitate their social participation and full inclusion in the community. PMID- 21322965 TI - [Adults foster family care in Italian mental health services: a survey]. PMID- 21322966 TI - [The Italian version of ISOS and RSQ, two suitable scales for investigating recovery style from psychosis]. PMID- 21322967 TI - [Operative protocol of a stepped care intervention for group and brief therapy of depression in comorbidity with physical diseases. Presentation]. PMID- 21322968 TI - [The DECO-TRE project: a model of integrated stepped-care intervention for the treatment of depression in comorbidity with physical diseases at general hospitals and in basic medicine]. PMID- 21322969 TI - Society of Pediatric Nurses Public Policy Committee position statement on disaster management for children and families. PMID- 21322970 TI - Double excitations in correlated systems: a many-body approach. AB - A coherent approach to the description of double excitations in correlated materials is presented: We derive stringent mathematical conditions on the algebraical structure of the Bethe-Salpeter and time-dependent density functional theory kernels that avoid the occurrence of spurious and nonphysical excitations. We discuss how these conditions need to be respected at any level of approximation, including the commonly used local density and static screening approximations. We propose a correlated kernel for the Bethe-Salpeter equation, and we illustrate several aspects of our approach with numerical calculations for model molecular systems. PMID- 21322971 TI - Foucault's and Arendt's "insider view" of biopolitics: a critique of Agamben. AB - This article revisits Arendt's and Foucault's converging accounts of modern (bio)politics and the entry of biological life into politics. Agamben's influential account of these ideas is rejected as a misrepresentation both because it de-historicizes biological/organic life and because it occludes the positivity of that life and thus the discursive appeal and performative force of biopolitics. Through attention to the genealogy of Arendt's and Foucault's own ideas we will see that the major point of convergence in their thinking is their insistence upon understanding biological thinking from the inside, in terms of its positivity. Agamben's assessment of modern politics is closer to Arendt's than it is to Foucault's and this marks a fascinating point of disagreement between Arendt and Foucault. Whereas Arendt sees the normalizing force of modern society as being in total opposition to individuality, Foucault posits totalization and individuation as processes of normation, which casts a light upon the relative import they place upon politics and ethics. PMID- 21322972 TI - "This war for men's minds": the birth of a human science in Cold War America. AB - The past decade has seen an explosion of work on the history of the human sciences during the Cold War. This work, however, does not engage with one of the leading human sciences of the period: linguistics. This article begins to rectify this knowledge gap by investigating the influence of linguistics and its concept of study, language, on American public, political and intellectual life during the postwar and early Cold War years. I show that language emerged in three frameworks in this period: language as tool, language as weapon, and language as knowledge. As America stepped onto the international stage, language and linguistics were at the forefront: the military poured millions of dollars into machine translation, American diplomats were required to master scores of foreign languages, and schoolchildren were exposed to language-learning on a scale never before seen in the United States. Together, I argue, language and linguistics formed a critical part of the rise of American leadership in the new world order one that provided communities as dispersed as the military, the diplomatic corps, scientists and language teachers with a powerful way of tackling the problems they faced. To date, linguistics has not been integrated into the broader framework of Cold War human sciences. In this article, I aim to bring both language, as concept, and linguistics, as discipline, into this framework. In doing so, I pave the way for future work on the history of linguistics as a human science. PMID- 21322973 TI - From Milgram to Zimbardo: the double birth of postwar psychology/psychologization. AB - Milgram's series of obedience experiments and Zimbardo's Stanford Prison Experiment are probably the two best-known psychological studies. As such, they can be understood as central to the broad process of psychologization in the postwar era. This article will consider the extent to which this process of psychologization can be understood as a simple overflow from the discipline of psychology to wider society or whether, in fact, this process is actually inextricably connected to the science of psychology as such. In so doing, the article will argue that Milgram's and Zimbardo's studies are best usefully understood as twin experiments. Milgram's paradigm of a psychology which explicitly draws its subject into the frame of its own discourse can be said to be the precondition of Zimbardo's claim that his experiment offers a window onto the crucible of human behaviour. This will be analysed by drawing on the Lacanian concepts of acting out and passage a l'acte. The question then posed is: if both Milgram and Zimbardo claim that their work has emancipatory dimensions - a claim maintained within mainstream psychology - does a close reading of the studies not then reveal that psychology is, rather, the royal road to occurrences such as Guantanamo and Abu Ghraib? The drama of a psychology which is fundamentally based on a process of psychologization is that it turns its subjects into homo sacer of psychological discourse. PMID- 21322974 TI - Shunt surgery for priapism: review of results. AB - In a review of the literature on shunt operations for priapism, 100 case reports were found. The over-all result in terms of potency is 61 per cent. In general there is little difference in outcome between the cavernosus-saphenous vein and cavernosus-spongiosum shunts. If the former surgical procedure is to be performed, a unilateral operation appears to yield better results than a bilateral one. Various causes of priapism are noted in relation to results of surgery, and the complications of shunt procedures are discussed. Equally good results are noted whether the operation is performed early or relatively late in the disease. PMID- 21322975 TI - Polycystic kidney disease: earlier diagnosis using ultrasound. AB - A unique family study is presented, representing 124 members in four generations. Sixty-four patients were studied clinically, and 31 were found to have sonographic evidence of polycystic kidney disease. Findings on intravenous urography were positive in only 15 of these 31. Ultrasound is particularly useful in younger patients in whom urinary symptoms and physical and urographic abnormalities are infrequent. The merits of early diagnosis of this disease in persons at risk are discussed. Ultrasound offers definite advantages over standard urographic and isotopic methods in the early diagnosis of polycystic kidney disease. PMID- 21322976 TI - Intraoperative nephroscopy. AB - Nephroscopy is a valuable diagnostic procedure for recognizing lesions in the renal cavity and for removal of stones. We describe a nephroscope with manipulating accessories which can be used as a combined diagnostic-operative procedure. The number of complications encountered is small. PMID- 21322977 TI - Effect of sympathomimetic drugs on canine bladder: surgical model for assessment of regional differences. AB - A surgical procedure is described in which the canine bladder was divided into body and base. The two-chambered bladder thus formed was used to assess the effect of sympathomimetic drugs in situ. Stimulation of either alpha- or beta receptors produced a change in pressure in both chambers. The bladder base showed a greater sensitivity to alpha-receptor stimulation than did the body of the bladder. No difference in sensitivity to beta-receptor stimulation was noted between body and base. PMID- 21322978 TI - Sympathetic innervation and chemical sympathectomy of canine bladder. AB - Chemical sympathectomy of the dog bladder produced by intra-aortic injection of 6 hydroxydopamine has been shown to increase the slope of the pressure/volume curve obtained by rapid fill cystometry. The volume threshold for eliciting a bladder contraction was decreased, whereas the pressure threshold did not change. Peripheral autonomic nervous elements in the bladder wall are described which are proposed as the morphologic basis for these and other such modulating influences. PMID- 21322980 TI - Ureteral rejection in isolated allograft ureter. AB - Ureteral rejection has been studied in the dog utilizing the isolated transplanted ureter technique. While on adequate immunosuppressive therapy, the allograft ureter remains functionally and histologically normal. When the drugs are discontinued, progressive destructive changes occur within the ureteral wall. As the muscle wall is destroyed the rejection process becomes irreversible. This process helps explain some of the findings seen during clinical renal transplantation. PMID- 21322979 TI - 32p-labeled thio-tepa absorption in normal rat bladders: potential guide for intravesical chemotherapy in bladder cancer. AB - Bladders of normal rats were used to evaluate the absorption of thio-tepa after intravesical instillation. Thio-tepa labeled with 32P (radioactive phosphorus) was utilized to measure drug concentrations in bladder wall, liver, and bone marrow. Thio-tepa was rapidly absorbed into the general circulation, and significant amounts of isotope were found. Thio-tepa absorption patterns in the normal rat may serve as a guide in adjusting drug dosages when thio-tepa is used intravesically in human beings for the treatment of superficial, papillary bladder tumors. PMID- 21322981 TI - Primary ureteral carcinoma. AB - A report of 22 cases of true primary transitional carcinoma of the ureter is presented. Evaluation of these cases shows that grades III and IV lesions have a poorer prognosis than grades I and II and that staging in ureteral tumors is a difficult task and unreliable for predicting survival. A conservative approach at management of low-grade lesions is suggested. PMID- 21322982 TI - Conservative management of ureteral tumor. AB - The traditional approach to transitional-cell carcinoma of the ureter has been nephroureterectomy with excision of a cuff of bladder. Evidence indicates that noninvasive transitional-cell tumor of the ureter is amenable to local resection. Five cases are presented in which transitional-cell carcinoma of the ureter was resected locally. None of the patients died from recurrence of their original tumor. It is suggested that the approach to ureteral tumor includes excisional biopsy with frozen section and reconstruction of ureteral continuity in the case of low-grade noninvasive transitional-cell tumor. PMID- 21322983 TI - Urolithiasis in children. AB - Urinary tract calculi in children are rare in the United States, with an incidence of 1 to 4 per 1000 pediatric admissions. Primary and secondary calculi are different in causation, chemical composition, and prognosis, and must be considered separately. Review of the literature in the United States and England suggests that in 60 per cent of children, as in adults, no causation will be found. Our experience with twenty-five primary and twenty-five secondary calculi in a nonendemic area, however, shows only six truly idiopathic stones. Thorough urologic and metabolic evaluation has been rewarded with an appreciable yield of metabolic or structural abnormalities. Treatment consists of standard urologic management of stones, as well as specific therapy directed at the underlying causes. PMID- 21322984 TI - Bedside sphincterometry. AB - We describe the use of a simple bedside sphinctermometer which has proved valuable and reliable in the practical evaluation and management of those patients with neurogenic bladder dysfunction. PMID- 21322985 TI - Diabetes-related need for circumcision. AB - A twelve-year retrospective study reviewing circumcision in 107 patients showed that of 94 patients with balanoposthitis 25.5 per cent had diagnosed diabetes mellitus while 3.2 per cent had unknown diabetes. In the fifty- to sixty-year-old age group, 83.3 per cent of circumcised patients had diabetes. In this age bracket there is a definite correlation of a diabetes-related need for circumcision. There is no significant histologic difference by light microscopy between prepuces in diabetic and nondiabetic patients. PMID- 21322986 TI - Chemotherapy of experimental transitional-cell carcinoma. AB - Transitional-cell carcinoma of the bladder has been induced by chronic oral administration of N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide (FANFT) in C3H/He mice, and successfully transplanted in syngeneic animals. Evaluation of the effectiveness of several chemotherapeutic agents on this tumor indicated that cyclophosphamide and cis-diammine dichloroplatinum (CACP) significantly inhibited tumor growth and prolonged the median survival time of tumor-bearing animals. When administered before formation of palpable tumors, cyclophosphamide completely prevented growth of the implants in 100 per cent of animals; when administered after the growth of larger, palpable tumors, cyclophosphamide inhibited tumor growth in all animals and produced a "cure" in 45 per cent. Combination chemotherapy with cyclophosphamide and CACP was more effective than either drug used as a single agent. Adriamycin, dactinomycin, and mitomycin C administered individually exhibited limited activity while 5-fluorouracil, CCNU (1-2 choloroethyl-3-cyclohexyl-1-nitrosourea), BCNU (1,3-bis [2-chloroethyl]-1 nitrosourea), methrotrexate, and hydroxyurea were ineffective against this tumor. The consistent growth pattern, the histologic similarity to bladder cancer in human beings, and the successful propagation in syngeneic animals, make the FANFT induced tumor a suitable model for chemotherapy of bladder carcinoma in human beings. PMID- 21322987 TI - Chemotherapy for metastatic squamous-cell carcinoma of penis: combination of vincristine and bleomycin. AB - Three patients with metastatic squamous-cell penile cancer were treated with a combination of vincristine and bleomycin. None of the tumors responded to the drug combination. All of the tumors progressed during treatment. These preliminary results suggest that the combination of vincristine and bleomycin is not efficacious for metastatic squamous-cell cancer of the penis. PMID- 21322988 TI - Strephotome. PMID- 21322989 TI - Obstructive uropathy associated with uterine prolapse. AB - Ninety-five of 252 (38 per cent) patients with uterine prolapse who had excretory urograms were evaluated to determine the presence of ureteral obstruction. Seven of the 95 (7 per cent) had evidence of hydroureteronephrosis attributable to uterine prolapse. Two patients initially had urologic complaints, and 3 of 6 patients demonstrated resolution of the hydroureteronephrosis in post-treatment urograms. The causation of the ureteral obstruction in patients with procidentia is discussed. The need for complete urologic work-up, particularly pre- and post treatment excretory urogram in patients with uterine prolapse, is emphasized. PMID- 21322990 TI - Efficacy of candicidin in benign prostatic hypertrophy. AB - Forty-three patients with benign prostatic hypertrophy with marked urinary distress, which I believed warranted surgical treatment, were selected from private practice. These patients were treated with long-term conservative therapy to determine the efficacy of candicidin for this condition. Patients receiving candicidin orally 300 mg. per day showed improved subjective symptoms in 89.3 per cent of cases compared to 18.2 per cent for patients treated by placebos. Residual urine was decreased in 85.7 per cent and flow rate was improved in more than 89 per cent of the cases. More than one third of the patients treated with candicidin showed improvement in prostate size compared to none for patients treated with placebos. Occasional gastric upset was the only adverse effect attributed to candicidin, which appears to be a safe and efficacious agent. PMID- 21322991 TI - Bilharzial (schistosomal) polypi of ureter. AB - A study of 511 patients with bilharzial ureteritis was carried out. Only 30 patients were found to have ureteral polypi, and a survey was done in reference to clinical, radiologic, cystoscopic, and pathologic aspects of this stage of the disease. A brief review is presented. PMID- 21322992 TI - Metastatic carcinoma of prostate. AB - A case is reported of a seventy-seven-year-old man with an unusual soft tissue metastasis in the pelvis from carcinoma of the prostate. PMID- 21322993 TI - Retroperitoneal fibrosis associated with retroperitoneal abscess. AB - A case of retroperitoneal fibrosis associated with retroperitoneal abscess is reported. The causation and treatment of idiopathic and nonidiopathic retroperitoneal fibrosis are discussed. PMID- 21322994 TI - Fatal air embolism following air cystometrogram. AB - A case of fatal air embolism following a routine air cystometrogram is reported. This is the first apparent complication of this type reported with air cystometrogram. PMID- 21322995 TI - Immunobiology of induced testis tumor. AB - Teratocarcinoma of the testis has been induced in the syngeneic mouse system by transplantation of embryonic genital ridges into the testes of adult mice. The regional lymph nodes of tumor-bearing animals were found to be enlarged and hyperplastic but free of tumor cells four weeks after tumor induction. The lymphocytes obtained from these lymph nodes are capable of inducing immunity against the induction of tumor when injected into a group of adult syngeneic mice. The tumor-associated antigen and in vitro cytotoxicity are being studied in our laboratory. PMID- 21322996 TI - T rosette assay: in vitro correlate of cellular immunity. AB - The T rosette assay, based on the capacity of thymus-derived lymphocytes (mediators of tumor-inhibiting immunity) to bind sheep erythrocytes in vitro, was used to quantitate percentages of T rosette-forming lymphocytes in the peripheral blood of 38 patients with urologic cancer. Results obtained using the T rosette assay yielded statistically significant direct correlations with those obtained using two other assays which have been widely employed to monitor cellular immunity: elicitation of delayed hypersensitivity to DNCB (dinitrochlorobenzene) and the proliferative response of lymphocytes to PHA (phytohemagglutinin). The findings suggest the T rosette assay provides a meaningful in vitro correlate of cellular immunity. PMID- 21322997 TI - Use of parenteral human globulin in acute, chronic, and recurrent urinary tract infections. AB - Sixty-four patients with recurrent or chronic urinary tract infections without evidence of disease demonstrated by conventional diagnostic methods underwent serum immunoglobulin studies. Only 23 were shown to have a deficiency of immune globulins, IgA, IgM, or IgG. Treatment with parenteral globulins resulted in sterile urine for the three-year follow-up period. Other urologists are urged to try this treatment under the conditions outlined. PMID- 21322998 TI - Cancer of prostate: relief of bone pain with levodopa. AB - Six patients with metastatic carcinoma of the prostate were given 250 to 500 mg. of levodopa at four-hour intervals for bone pain. Four patients showed definite improvement. Based on our observation, further trial of levodopa is recommended for relief of bone pain in patients with metastatic carcinoma of the prostate. PMID- 21322999 TI - Rotation of bladder flap for repair of vesicovaginal fistula. PMID- 21323000 TI - Vesical stabilization: useful adjunct in radical retropubic prostatectomy. PMID- 21323001 TI - Ancient Egyptian medicine: contribution to urology. AB - Most of the medical history books and articles touch only lightly on urology during the ancient Egyptian epoch. A review of those books and articles stimulated us to set forth the interesting facts presented herein about the history of urology. PMID- 21323002 TI - Fowler's solution for treatment of recurrent intraurethral condyloma acuminata. PMID- 21323003 TI - Head and neck cancer, dental implants, and dental oncology. AB - Head and neck cancer is a real presence in the dental-implant world--patients who undergo surgery, chemotherapy, and/or radiation often seek the assistance of dental-implant practitioners to restore them to better function; other patients who have had implants in place for years will return with questions regarding how their treatment will be affected by the presence of their dental implant. As oral cancer treatment modalities are rapidly changing, practitioners struggle to keep up with the literature surrounding this important subset of the dental-implant population. This month, we look at the numbers of patients suffering from oral cancers, consider the different treatment options for patients with oral cancers, and investigate the role that implants play in improving therapeutic outcomes or changing treatment course. PMID- 21323004 TI - Vascular events and invasive dental treatments linked. PMID- 21323005 TI - OIG report: adverse events still too common, 'CMS expand HAC list'. PMID- 21323006 TI - Tackling hand-off communications. PMID- 21323007 TI - Kaiser standardizes the hand-off process. PMID- 21323008 TI - Kaiser hones hand-offs from hospital to homes. PMID- 21323009 TI - What does a physician hear when you speak? PMID- 21323010 TI - CAD all over and everywhere? PMID- 21323011 TI - Accuracy of occlusal contacts for crowns with chairside CAD/CAM techniques. AB - Information from the opposing dentition is used to design and fabricate occlusal contacts with a reasonable level of accuracy for a given restoration. The dental database with the antagonist design process utilizes a bite registration to propose the construction of a virtual opposing model. The Articulation design technique utilizes a functionally generated bite registration to control both the maximum intercuspation and excursive contacts on the restoration. Correlation design technique offers the opportunity to copy the established occlusal anatomy to the preparation. Although these techniques offer a workflow to establish occlusal contacts with the Cerec system, there is a lack of quantitative data as to the accuracy achieved. Alternative techniques to control the occlusal contacts have been suggested which rely on "user customized design techniques" that recommend altered program settings, manual override of automated features in the software, or modification of the established software design programs. The purpose of this study was to measure the occlusal vertical discrepancy for various design techniques. Full crowns made using dental database with the antagonist design technique had a significantly smaller occlusal vertical discrepancy than those made with correlation. Dental Database with the Antagonist had a significantly smaller occlusal vertical discrepancy than all suggested alternative design techniques. Use of the Dental Database with Antagonist design technique provides the most accurate technique for establishing occlusal contacts with the Cerec 3D system. PMID- 21323013 TI - Color correspondence of different batches of TriLuxe CAD/CAM ceramic blocks. AB - TriLuxe ceramic blocks for chairside CAD/CAM procedures are color layered to allow natural esthetics, and only require subsequent glazing. The purpose of this study was to compare color repeatability of different batches of TriLuxe blocks. The three commercially available shades (1M2C, 2M2C, 3M2C) of TriLuxe blocks for the Cerec CAD/CAM system were examined. For each of the three colors, three different batches were tested, 5 blocks each. The measurements were made using a spectrophotometer equipped with an integrating sphere using the CIELab* colorimetric system. One-way ANOVA showed that the factor "Production Batch" was not statistically significant. Regarding deltaE, none of the 315 color comparisons (neither within the same shade, nor between specimens of the same batch, nor between specimens from different batches) exceeded the proposed deltaE = 3.3 threshold for clinical acceptability. All the different batches of the different shades of VITA TriLuxe blocks for the Cerec system showed the high degree of color correspondence necessary in industrially prefabricated CAD/CAM blocks. PMID- 21323012 TI - A patient-based model study of fixed splinting of premolars with reduced periodontal support. AB - The aim of this patient-based study was to assess the effect of fixed splinting of mandibular premolars having reduced alveolar support on load distribution in the periodontium. A patient's mandibular second premolar with considerably reduced alveolar bone height was restored using a metal-ceramic restoration splinted with the adjacent first premolar; an acceptable 3-year maintenance period was observed. A patient-based three-dimensional finite element model was constructed using the morphological measurements obtained from the diagnostic cast and radiographs. The model incorporated in vivo occlusal records and was used to analyze stress and strain in the periodontium for splinted and nonsplinted simulations. Modified models were also created to explore the effects of relative bone height on the stress and strain distributions. The maximum principal stress and strain on the periodontium of the second premolar were considerably higher before splinting than after splinting and were close to strain levels indicative of potential bone microdamage. In contrast, the stress and strain in the first premolar increased after splinting. The modified models showed that the increased vertical gap of alveolar height between the splinted teeth was another factor to increase the load in the first premolar. Since the prosthodontic procedure employed is not routinely used, the results cannot be generalized. However, it is suggested that fixed splinting can decrease the periodontal load on premolars with reduced periodontal support, but may increase the load on the splinted tooth. PMID- 21323014 TI - IPad--toy or tool? PMID- 21323015 TI - Three-dimensionally layered ceramic blocks. AB - With the aid of an innovatively structured ceramic block, it is possible to achieve results at a high esthetic level with relatively simple means. In the three-dimensionally structured Vitablocs RealLife, translucent enamel ceramic is arranged around a conically structured, opaque dentin core. The virtual restoration can be positioned freely in all three dimensions with the aid of the Cerec/inLab software. The restorations are milled fully anatomically and only minimally glazed or characterized with stains. Results that otherwise can be achieved only with much more complex layering processes are possible. PMID- 21323016 TI - The tooth fairy. PMID- 21323017 TI - PDA thanks Pennsylvania lawmakers who support dentistry. PMID- 21323018 TI - PDA, new coalition expanding oral health initiatives statewide. PMID- 21323019 TI - From freezer to frying pan. The Haiti earthquake response. PMID- 21323020 TI - Good fiscal governance and avoiding (or if that doesn't work, preparing for) an IRS audit. PMID- 21323021 TI - Fixed Income (part 2)--the yield curve. PMID- 21323022 TI - Focus on technology. PMID- 21323023 TI - Interview with Eugene S. Schneller, PhD, professor and Dean's Council of 100 Distinguished Scholars, W. P. Carey School of Business, Arizona State University. Interview by Stephen J O'Connor. PMID- 21323024 TI - Changing economics in an era of healthcare reform. PMID- 21323025 TI - Health technology assessment at the University of California-San Francisco. AB - Over the past thirty years, various efforts have been made to align the incentives of hospitals and physicians to control healthcare costs while assuring the provision of high-quality patient care. One innovative strategy used by some hospitals involves the creation of technology assessment programs to develop a more thorough and objective review process for new clinical technology. The University of California-San Francisco Medical Center has been a pioneer in this area. Its physician-led healthcare technology assessment program has been successful in changing the culture of how innovative technology is evaluated and adopted by the hospital and fostering an increased awareness among physicians of the clinical, financial, and programmatic implications of their technology decisions. We explore the operational characteristics and various effects of this program and highlight the key components to its success and opportunities for improvement in the context of its reproduction at other medical centers. PMID- 21323026 TI - Safety issues related to the electronic medical record (EMR): synthesis of the literature from the last decade, 2000-2009. AB - Healthcare is a complex industry burdened by numerous and complicated clinical and administrative transactions that require many behavioral changes by patients, clinicians, and provider organizations. While healthcare information technology (HIT) is intended to relieve some of the burden by reducing errors, several aspects of systems such as the electronic medical record (EMR) may actually increase the incidence of certain types of errors or produce new safety risks that result in harm. Healthcare leaders must appreciate the complexity surrounding EMRs and understand the safety issues in order to mandate sound EMR design, development, implementation, and use. This article seeks to inform executives, clinicians, and technology professionals what has been learned through published research on the safety of HIT systems during the last decade, focusing on computerized physician order entry (CPOE), clinical decision support systems (CDSS), and bar-coded medication administration (BCMA). PMID- 21323027 TI - Characteristics of acute care hospitals with diversity plans and translation services. AB - Hospitals provide diversity activities for a number of reasons. The authors examined community demand, resource availability, managed care, institutional pressure, and external orientation related variables that were associated with acute care hospital diversity plans and translation services. The authors used multiple logistic regression to analyze the data for 478 hospitals in the 2006 National Inpatient Sample (NIS) dataset that had available data on the racial and ethnic status of their discharges. We also used 2004 and 2006 American Hospital Association (AHA) data to measure the two dependent diversity variables and the other independent variables. We found that resource, managed care, and external orientation variables were associated with having a diversity plan and that resource, managed care, institutional, and external orientation variables were associated with providing translation services. The authors concluded that more evidence for diversity's impact, additional resources, and more institutional pressure may be needed to motivate more hospitals to provide diversity planning and translation services. PMID- 21323028 TI - Lessons of experience: Key events and lessons learned of effective chief medical officers at freestanding children's hospitals. AB - As the healthcare environment changes, physician executives who are effective leaders and agents of change are needed. Healthcare organizations that are successful at developing effective physician leaders will be at an advantage. This article examines how physician leaders develop on the job. Such knowledge and insight can be useful to healthcare systems looking to develop a new physician leadership development program or improve an existing one. This study identified that learning from other people (e.g., mentors, role models, bosses) and key events involving hardships are valuable means in developing leadership acumen for chief medical officers (CMOs) at freestanding children's hospitals. Most of the hardships CMOs reported were a result of mistakes made when they were trying to institute change. CMOs reported a disproportionately low number of learning events from developmental job assignments. This finding may indicate a lost opportunity on the part of healthcare organizations in developing leaders. The most frequent lessons learned pertained to handling relationships, interpersonal skills, and executive temperament. Skills in handling relationships and interpersonal skills were best learned through business mistakes made in dealing with others. Lessons in executive temperament, self confidence, and handling adversity were most often learned from role models and bosses. These findings indicate that physician leadership development initiatives should intentionally and systematically incorporate job assignments, role models, and mentors. PMID- 21323029 TI - An overview of selected employer requirements in the wake of health reform. PMID- 21323030 TI - What's new with phentolamine mesylate: a reversal agent for local anaesthesia? AB - Phentolamine mesylate (OraVerse), a nonselective a-adrenergic blocking drug, is the first therapeutic agent marketed for the reversal of soft-tissue anaesthesia and the associated functional deficits resulting from an intraoral submucosal injection of a local anaesthetic containing a vasoconstrictor. In clinical trials, phentolamine injected in doses of 0.2 to 0.8 mg (0.5 to 2 cartridges), as determined by patient age and volume of local anaesthetic administered, significantly hastened the return of normal soft-tissue sensation in adults and children 6 years of age and older. Median lip recovery times were reduced by 75 to 85 minutes. Functional deficits, such as drooling and difficulty in drinking, smiling, or talking--and subjects' perception of altered function or appearance- were consistently resolved by the time sensation to touch had returned to normal. Adverse effects of phentolamine injected in approved doses for reversal of local anaesthesia in patients ranging in age from 4 to 92 years were similar in incidence to those of sham injections, and no serious adverse events caused by such use were reported. The clinical use of phentolamine is viewed favorably by dentists who have administered the drug and by patients who have received it. Optimal use may require some modifications of the technique described in the package insert; cost of the agent may be influencing its widespread adoption into clinical practice. Phentolamine mesylate, in the form of OraVerse (Novalar Pharmaceuticals, San Diego, USA) represents a new therapeutic class of drugs in dentistry intended to reverse soft-tissue anaesthesia after nonsurgical dental procedures (e.g., restorative or deep scaling/root planing procedures). As shown in Figure 1, OraVerse is manufactured in 1.7 mL dental cartridges, each of which contains 0.4 mg active drug. This review describes the development of phentolamine as a dental drug, its pharmacologic characteristics, and how it may be used in clinical practice to improve patient care. PMID- 21323031 TI - Comparison between two regional anaesthesia techniques performed by inexperienced operators: the Gow-Gates block versus the Kenneth Reed block. AB - AIM: The aim was to compare the efficacy of Kenneth Reed and Gow-Gates inferior alveolar nerve blocks when performed by an inexperienced operator. METHODS: A group of 60 patients was randomised into two groups. One group had the Kenneth Reed technique used to administer an inferior alveolar nerve block whilst the other received the Gow-Gates technique. The efficacy of nerve block produced was evaluated both clinically and by electric pulp tester. MRI examination was undertaken to determine the spread of local anaesthetic. RESULTS: There were no significant differences in success rate of anaesthesia between groups. The failure rate for the Gow-Gates technique was 16.6%, whilst the failure rate for the Kenneth Reed technique was 23.3%. Time to onset was less with the Kenneth Reed technique. MRI examination showed the solution was more widely distributed after the Kenneth Reed block had been used. CONCLUSIONS: Our research has demonstrated that the Kenneth Reed technique is equally effective at producing anaesthesia of the inferior alveolar nerve. Compared with conventional techniques there is a lower incidence of positive aspiration and potential for lower morbidity as the local anaesthetic is deposited further from the neurovascular bundle than when deposited near the mandibular foramen as in most conventional Inferior Alveolar Nerve Block techniques. PMID- 21323032 TI - The safety and efficacy of using a concentrated intranasal midazolam formulation for paediatric dental sedation. AB - AIM: To add to the evidence base for safe and effective paediatric conscious sedation techniques in primary dental care. OBJECTIVE: To consider the safety and effectiveness of an alternative sedation technique for facilitating dental treatment in anxious children, thereby avoiding dental general anaesthetic. SETTING: Leagrave Dental Sedation Clinic. A primary care-based general and referral clinic for anxious patients, special care dentistry and oral surgery. SUBJECTS, MATERIALS AND METHODS: This is a prospective service evaluation of 114 selected anxious children requiring invasive dental treatment. Each child was administered 0.25 mg/kg intranasal midazolam using a concentrated 40 mg/ml midazolam (INM) in 2% lignocaine solution. MAIN OUTCOME MEASURES: Successful completion of intended dental treatment with a child who is co-operative and who meets the UK accepted definition of conscious sedation. RESULTS: 57% of the children found the administration of the new formulation acceptable. Of the 114 patients who received INM, 104 completed the treatment (91%). The 10 children who could not complete the treatment with INM were converted to intravenous sedation and treatment was completed successfully at the same appointment. During treatment there was no desaturation and only one patient desaturated briefly in the recovery area. Parents rated the technique acceptable in 76% of cases and would have the procedure repeated in 83% of cases. Parents rated this technique as having 8.3 out of 10 with only 5 parents awarding a score of less than 7 out of 10. Side effects included blurred vision, sneezing, headaches, restlessness with one patient having post-operative nausea and vomiting. CONCLUSION: In selected cases intranasal sedation provides a safe and effective alternative for dental GA in short invasive procedures limited to one or two quadrants in children. Other techniques, e.g., oral and intravenous sedation, appear to have a much higher acceptability of administration. This technique may be useful if inhalation sedation, oral sedation or intravenous sedation is considered and the child is still unco-operative, either as a technique on its own or to facilitate cannulation for intravenous sedation. It is recommended that this technique should only be used by dentists skilled in intravenous paediatric sedation with midazolam with the appropriate staff training and equipment at their disposal. PMID- 21323033 TI - Advanced paediatric conscious sedation: an alternative to dental general anaesthetic in the U.K. AB - BACKGROUND: Child dental anxiety is widespread, and it is not always possible to treat children using traditional methods such as behavioural management, local anaesthesia and even relative analgesia. In such cases a dental general anaesthetic (DGA) is the only option available to facilitate dental treatment in anxious children. AIM: This study describes an advanced conscious sedation protocol which allows invasive treatment to be carried out in anxious children. It incorporates the use of titrated intravenous midazolam and fentanyl and inhalation agents, sevoflurane and nitrous oxide/oxygen, which is administered by a Consultant Anaesthetist. The aim is to produce an evidence- based study which can offer a sedation technique as a safe and effective alternative to a DGA. STUDY DESIGN: Retrospective audit. METHOD: 267 clinical records were audited retrospectively from a specialist sedation-based clinic, for children aged 5-15 years old. The subjects all underwent invasive dental procedures with this technique between August and November 2008 as an alternative to a DGA. RESULTS: 262/267 (98%) of the subjects were treated safely and successfully and without the loss of verbal communication using this technique. This included many treatments requiring four quadrant dentistry, with both restorations and extractions as necessary being carried out in one visit. 5 subjects (2%) did not tolerate treatment and had to be referred for a DGA. No medical emergencies occurred. CONCLUSIONS: Based on the evidence for this group of patients, this advanced conscious sedation technique, offers a safe and effective alternative to DGA. This technique must be carried out in an appropriate environment by an appropriately trained and experienced team who are able to comply with the recommendations for "alternative" sedation techniques. PMID- 21323035 TI - SAAD national course in conscious sedation from the delegate's perspective. PMID- 21323034 TI - A clinician guide to patients afraid of dental injections and numbness. AB - Fears of dental injections remain a clinical problem often requiring cognitive behavioural psychology counselling and sedation in order to carry out needed dental treatment. This study, based on a national survey in Australia, compared patient concerns about numbness caused by local anaesthesia and fears of the injection itself. It also examined associations between dental fearfulness and avoidance associated with patient self-reported negative experiences and treatment need. Clinical advice on how to approach such patients is offered. Relatively high levels of dental anxiety and fear have been reported in several industrialised Western societies (McGrath & Bedi, 2004; Armfield, Spencer & Stewart, 2006; Lahti et al., 2007; Enkling, Marwinski Johren, 2006). In the U.K., almost one in three adults consider themselves to always be anxious about going to the dentist (Nuttall et al., 2001). Of concern is that this dental fear may be passed on to the children of anxious adults (Nuttall, Gilbert & Morris, 2008), leading to an inter-generational perpetuation of the problem. There is considerable evidence that dental fear is related to poorer oral health, reduced dental attendance and increased treatment stress for the attending dentist. There are many aspects of going to a dentist that might elicit feelings of apprehension, concern or anxiety in prospective patients (Liddell & Gosse, 1998; Oosterink, de Jongh & Aartman, 2008). One of the most commonly reported concerns relates to receiving injections. Indeed, fear of needles and the treatment of injection fear has been an important focus of a research in the U.K. (Boyle, Newton & Milgrom, 2010). Needle fear, in particular, is a major issue given that the delivery of local anaesthesia via injection is the central plank of pain relief techniques in dentistry (Malamed, 2009) and dentists as well as patients often avoid difficult injections as a consequence, resulting in poor pain control. A less well described anxiety of receiving dental treatment is fear of numbness associated with the dental injection (Morse & Cohen, 1983). Certainly, many dentists believe that their patients avoid local anaesthesia because of a wish to avoid the disturbing effects of numbness (Moore et al., 1998). Milgrom et al. (1997) found that fears about the numbness associated with receiving local anaesthesia significantly differentiated avoiders and non-avoiders of dental treatment. However, these concerns appeared to be much less common than those concerning the perceived pain of injections and fear of bodily injury resulting from the injection (Milgrom et al., 1997; Kaako et al., 1998). Consistent with these findings, whereas 43% of English patients asked to imagine undergoing future third molar surgery expressed concerns primarily about pain, only 6% of patients indicated concern about numbness as their worst fear (Earl, 1994). More recently, a study of Dutch people found that the feeling of numbness from the anaesthesia was rated as the 41st most feared dental stimulus out of a list of 67 possible stimuli, and that only 1.5% of the general population regarded numbness as extremely anxiety provoking (Oosterink, de Jongh & Aartman, 2008). However, it is important for a clinician to differentiate between those who dislike the sensation of temporary numbness versus those who may worry that it may never wear off. Such problem thinking can be an issue irrespective of whether a patient overcomes the fear of needles with sedation or not. A large number of patients dislike the sensation of numbness enough for manufacturers to respond with a partial antidote in alpha adrenergic receptor antagonist phentolamine mesylate (OraVerse Sanofi-Aventis, Hersh & Lindemeyer, 2010). Approval of this agent, which shortens the length of soft tissue anaesthesia after inferior alveolar block, is pending in the UK and other European countries. In other cases, dentists resort to using local anaesthetics without vasoconstrictors to shorten the period of anaesthesia (Fiset, Getz, Milgrom & Weinstein, 1989). While the association between dental fear and fear of injections has received considerable attention, the relationship between dental fear and numbness has received less attention. In particular, the nature of the associations between dental fear and avoidance and anxiety over numbness has not been studied. There has also been no research into whether or not concerns over numbness are independent of injection concerns. Finally, the association between fear of numbness and injections and dental avoidance and treatment needs has not been investigated. This study, based on survey work in Australia, aimed to compare patient concerns about numbness caused by receiving anaesthesia to that of anxiety over the receipt of needles and injections. Associations with dental fear and avoidance as well as negative experiences and treatment needs were also explored. PMID- 21323036 TI - Secretary's correspondence. PMID- 21323037 TI - A visit to Cestradent McKesson; providing inhaled sedation for dentistry since 1938. PMID- 21323038 TI - Stanley L Drummond-Jackson. Pioneer of intravenous anaesthesia in dentistry. AB - Stanley Lithgow Drummond-Jackson was born in Northumberland and qualified from Edinburgh University Dental School in 1931. Even in the early stages of his practice he devoted his energies to the problem of pain control in dentistry, publishing his first paper in 1935. In the early 20th century most dental anaesthetics were inhalational with nitrous oxide, ether, ethyl chloride and chloroform. The introduction of intravenous hexobarbitone in 1931 led to bold and enthusiastic researchers like Drummond-Jackson to pioneer its use in dental practice. He published his major work on intravenous hexobarbitone in 1952. In 1957, Drummond-Jackson and a group of colleagues formed the now well-known organisation called 'Society for the Advancement of Anaesthesia in Dentistry' or SAAD. SAAD has grown from a group of 40 to over 4000 members worldwide. In 1969, the BMJ published an article condemning Drummond-Jackson's technique of intermittent intravenous methohexitone. At his personal expense, Drummond-Jackson brought a libel action against the BMJ and authors of this paper. There were no winners as the case was settled after 38 days and earned the reputation for being the longest and most expensive libel case in the history of the London Courts. Despite this setback the founder of SAAD devoted the last days of his life in research, teaching and abolishing fear and pain in dentistry. He gained international reputation as a teacher in dental anaesthesia and was honoured with fellowships and awards. He died in 1975 at the age of 66. In the early 1900s dental anaesthesia was only inhalational with mainly nitrous oxide on one hand and ether, ethyl chloride and chloroform on the other. Induction was at times stormy and prolonged and recovery was delayed. The synthesis of barbiturates, especially intravenous hexobarbitone (1931), thiopentone (1932) and methohexitone (1959) opened new avenues for dental anaesthesia. Modern anaesthesia owes a lot to early pioneers, many of them being dentists and Drummond-Jackson was among them. PMID- 21323039 TI - DSTG annual symposium. 14 and 15 May 2010. Trinity College, Dublin. PMID- 21323040 TI - Health savings accounts and health reimbursement arrangements: assets, account balances, and rollovers, 2006-2010. AB - ASSET LEVELS GROWING: In 2010, there was $7.7 billion in health savings accounts (HSAs) and health reimbursement arrangements (HRAs), spread across 5.7 million accounts. This is up from 2006, when there were 1.2 million accounts with $835.4 million in assets, and 2009, when 5 million accounts held $7.1 billion in assets. AFTER LEVELING OFF, AVERAGE ACCOUNT BALANCE DROPS SLIGHTLY: Increases in average account balances leveled off in 2008 and 2009, and fell slightly in 2010. In 2006, account balances averaged $696. They increased to $1,320 in 2007, a 90 percent increase. Account balances averaged $1,356 in 2008 and $1,419 in 2009, 3 percent and 5 percent increases, respectively. In 2010, average account balances fell to $1,355, down 4.5 percent from the previous year. AVERAGE ROLLOVER DECLINES, WHILE TOTAL ROLLOVERS INCREASE: Despite a decline in the average rollover amount in 2010, total assets being rolled over have been increasing. $4.2 billion was rolled over in 2010, up from $4 billion in 2009. The average rollover increased from $592 in 2006 to $1,295 in 2009, and fell to $1,029 in 2010. The percentage of individuals without a rollover decreased from 23 percent in 2006 to 10 percent in 2009 and increased slightly to 13 percent in 2010. HEALTHY BEHAVIOR MEANS HIGHER ACCOUNT BALANCES AND HIGHER ROLLOVERS: Individuals who exercised, those who did not smoke, and those who were not obese had higher account balances and higher rollovers than those with less healthy behaviors. It was also found that individuals who used cost or quality information had higher account balances and higher rollovers compared with those who did not use such information. However, no relationship was found between either account balance or rollover amounts and various cost-conscious behaviors such as checking pricing before getting services or asking for generic drugs instead of brand names, among other things. DIFFERENCES IN ACCOUNT BALANCES: Men have higher account balances than women, older individuals have higher account balances than younger ones, account balances increase with household income, and education has a significant impact on account balances independent of income and other variables. DIFFERENCES IN ROLLOVER AMOUNTS: Men rolled over more money than women, and older individuals had higher rollover amounts than younger individuals. Rollover amounts increase with household income and education, and individuals with single coverage rolled over a higher amount than those with family coverage. PMID- 21323041 TI - The year for stoicism. PMID- 21323042 TI - NMC should have vetting powers, claims charity. PMID- 21323043 TI - Revised dementia strategy renews impetus for change. PMID- 21323044 TI - Urinary test not always needed. PMID- 21323045 TI - What can mental health nurses do to meet older patients' physical health needs? PMID- 21323046 TI - Environments designed to heal. AB - This article explores projects in dementia and end of life care developed as part of the Enhancing the Healing Environment programme. This nurse-led initiative, devised by charity the King's Fund in 2000, encourages staff to work in partnership with patients to improve the environment in which they deliver care. The projects discussed show how enhancing the environment results in health benefits for patients and improved quality of care. PMID- 21323047 TI - Safeguarding people's rights under the Mental Capacity Act. AB - People who lack capacity to make certain decisions have a statutory right to be represented by an independent mental capacity advocate (IMCA). However, there is concern among the organisations that provide IMCA services about the lower than expected number of referrals (instructions) by trusts in the NHS. The authors discuss possible reasons for the low instruction rate and how this could be improved. A case study of a woman with mental health problems is used to demonstrate how the role of the IMCA works in practice. PMID- 21323048 TI - Care of older people with epilepsy. AB - This article provides an overview of epileptic seizures, aetiology, diagnosis and treatment. It aims to explore relevant clinical management issues when caring for older people with epilepsy and also highlights the important role of the specialist nurse. PMID- 21323049 TI - Patient-reported outcome measures and how they are used. AB - Patient-reported outcome measures (PROMs) are increasingly being used in the NHS to inform clinical treatments and even the funding of individual healthcare providers. This article examines the background to their increasing use. It aims to provide nurses with information and advice about resources to increase their knowledge of PROMs. It outlines the importance of patient-centred outcomes, describes the different types of PROMs and their use in clinical practice. PMID- 21323050 TI - The power of three. PMID- 21323051 TI - Fight for equality still on. PMID- 21323052 TI - Safety fears as government plans to ditch statutory HCA regulation. PMID- 21323053 TI - Database reveals poor compliance with national patient safety alerts. PMID- 21323054 TI - Chronic illness scheme saves NHS 400,000 pounds in nine months. PMID- 21323055 TI - Screening system helps NMC dismiss unsuitable cases quickly. PMID- 21323056 TI - 'Embracing diversity is a source of strength to our profession'. PMID- 21323057 TI - Northern Ireland's nurses braced for cull of 1,500 posts. PMID- 21323058 TI - Meet my new sister. AB - Born male but now a confident woman, Rebecca Phillips wants to be treated with dignity. Her sister Anne Wells is an RCN convener and council member. PMID- 21323059 TI - Shaping the service to fit the person. AB - The needs of lesbian, gay, bisexual and trans people go far beyond sexual health. NHS trusts are in the process of ensuring mainstream services are meeting these needs. PMID- 21323060 TI - A major brainwave. AB - New research is shedding light on the underlying mechanisms of multiple sclerosis. New treatments may become available as a result. PMID- 21323061 TI - Explaining the role of the nurse in clinical trials. AB - In the last decade, there has been an increase in the number of clinical trials being performed in many specialties, notably in the field of cancer. Nurses are bound to encounter a patient either enquiring about clinical trials, who is currently enrolled in a clinical trial or who has had some experience of clinical trials. It is therefore useful for nurses to have a broad knowledge of what clinical trials are, the different types of trial available in the UK, and the benefits and risks associated with these trials. As many patients might be concerned about safety issues, nurses may benefit from some knowledge of the processes in place to maintain patient safety. It is therefore helpful to have an awareness and insight into the role of the clinical trial nurse. PMID- 21323062 TI - Sustainability of health promotion for people with learning disabilities. AB - AIM: To explore whether delivery of a health education programme would enable people with learning disabilities to gain knowledge about health and use it to enhance their wellbeing. METHOD: A mixed methodological approach, including questionnaires, focus groups and interviews, was used with people with learning disabilities. FINDINGS: Health education enhanced the knowledge of people with learning disabilities about their health, but this was not sustainable. Participants were unable to transfer this new information into their daily lives, and the knowledge gained did not result in demonstrable improvements in health. CONCLUSION: Healthcare professionals working with people with learning disabilities need to understand and recognise the significant influence of carers and other services. Such support systems need to be included when facilitating and enhancing health education for people with learning disabilities. PMID- 21323063 TI - Management of faecal incontinence in acutely ill patients. AB - Faecal incontinence is common in acutely ill patients, and has many predisposing factors. It is important that nursing staff understand the process of normal defecation as well as the adverse effects faecal incontinence has on patients, relatives and carers. New techniques are emerging for the management of faecal incontinence and it is important that nurses are aware of these. PMID- 21323064 TI - Carbon monoxide poisoning. PMID- 21323065 TI - Get to the point. PMID- 21323066 TI - A structure for future excellence. PMID- 21323067 TI - Embracing difference. PMID- 21323068 TI - Cutting back on sodium. Are salt substitutes the answer? PMID- 21323069 TI - Going green in the kitchen. Reducing waste. PMID- 21323070 TI - Just add fiber? PMID- 21323071 TI - Strike the spike II. Dealing with high blood glucose after meals. PMID- 21323072 TI - Denver omelet. PMID- 21323073 TI - Choosing beverages. PMID- 21323074 TI - How much do you know about caffeine? PMID- 21323075 TI - Preventing stroke. PMID- 21323076 TI - What your doctor is reading. PMID- 21323077 TI - A tribute to Jenny. PMID- 21323078 TI - Circumcisions are prejucial to boys' health. PMID- 21323079 TI - Say no to formula milk company handouts. PMID- 21323080 TI - Developing the midwife's role in public health. AB - There is widespread acceptance that health can be shaped by factors occurring as far back as infancy, and even before birth. In September 2010 the document Midwifery 2020: Delivering Expectations was launched in Edinburgh. The aim of the report was to establish the future direction for midwifery in the UK, and included specific reference to the midwife's public health role. The report notes that experiences from in utero development until eight years of age lay critical foundations for the entire life course. The report reiterates previous debate on the important contribution maternity services have in addressing health inequalities, and emphasises the importance of midwives striving to address the needs of the most vulnerable communities they serve. PMID- 21323081 TI - Keep it in the family. AB - The article will give an insight into family nursing, a fairly new role in the UK. It aims to show the writer's role transition from being a midwife to a family nurse. Family nursing is a role that supports young parents to grow socially and emotionally while helping the parents to develop a strong bond and attachment with their children. It is a licensed, structured programme, developed over 25 years in the US. The programme goals are to improve antenatal health, child health and development, and parents' economic self-sufficiency. The writer explores factors that have assisted in the role transition: skill development, supervision, behaviour change, therapeutic relationships and parenting skills. Lessons learnt from previous midwifery roles are also addressed as paramount in the role transition. PMID- 21323082 TI - Meeting the challenge of delivering high-quality breastfeeding training for all. AB - Staff training is an essential element of achieving the prestigious UNICEF UK Baby Friendly Initiative (BFI) global standard for organisations seeking to provide services that support breastfeeding. A breastfeeding self-study training programme (workbook and DVD) was developed by Health Behaviour Research Limited and delivered to healthcare staff in primary care trusts (PCTs), children's centres and their maternity units. As part of this training knowledge outcomes are measured before and after the training using the CUBA (Coventry University Breastfeeding Assessment). Interviews with participants showed that they welcomed the programme as a way of ensuring staff use evidence-based practice consistently. Self study is flexible but requires self organisation, time management against competing priorities and basic ICT skills and access. Recommendations, including the use of learning sets to encourage team learning and the production of a combined web and hard copy programme, came from the learning achieved by piloting this new programme. PMID- 21323083 TI - 'Have you had a wee yet?' Postpartum urinary retention. AB - Physiological changes in the bladder that occur during pregnancy predispose women to develop symptomatic retention of urine during the first hours to days after birth (Saultz et al 1991, Lose et al 1992). A basic definition of postpartum urinary retention (PUR) is the lack of spontaneous micturition six hours after vaginal birth or after removing an indwelling catheter (Humburg 2008). PUR after vaginal birth is a relatively common event, with the reported incidence ranging from 1.7 per cent to 17.9 per cent (Carley et al 2002, Ching-Chung et al 2002, Glavind and Bjork 2003, Yip et al 2004). When examining why PUR occurs following vaginal birth research often states that instrument-assisted birth and regional analgesia are both independently associated (MacLennan 2002, Groutz 2001,Teo et al 2007). Other common risk factors include primiparity, prolonged first and second stage, perineal damage and oxytocin use (MacLennan 2002, Glavind and Bjork 2003, Humburg 2008, Groutz et al 2001, Teo et al 2007). Unrecognised urinary retention and mismanagement may lead to recurrent urinary tract infections, upper urinary tract damage and permanent voiding difficulties (Groutz et al 2001). Humburg (2008) suggests that, overall, the lack of guidelines is one of the major problems in treating women with PUR. Careful questioning and examination from the midwife should always be performed to avoid any complication. PMID- 21323084 TI - Female bladder catheterisation: step by step. AB - Catheterisation of the female urinary bladder is performed by midwives for a range of reasons. This article outlines and the main reasons for this procedure, including during labour and after the birth. It describes the equipment needed and the procedure undertaken, summarising the aseptic technique required to minimise the risk of urinary tract infection. The use of anaesthetic gels to minimise pain and trauma is considered. The article highlights the potentially embarrassing nature of catheterisation for women and urges midwives to perform this skill with maximum dexterity and minimum fuss. PMID- 21323085 TI - Assessing and implementing approved assessment procedures. AB - In this reflection I share my experience of designing and implementing an assessment for a level three midwifery module. By sharing my experience I hope to give others an insight into the process, including the challenge of ensuring that any examination is robust enough to meet the needs of the assessment. Designing a robust assessment is crucial as ultimately any assessment on a midwifery pathway is influential in developing safe and competent midwives. PMID- 21323086 TI - The 'breathe' model of smoking cessation. AB - I challenge you to look beyond this abstract. Read the main text to discover how the use of a framework or tool to explore a study reveals so much more. The 'Breathe' study findings at first glance support the use of the 'Breathe' model of smoking cessation, yet on critiquing, using appropriate evaluation tools, this conclusion is questionable. The purpose was to measure the effectiveness of identifying pregnant smokers at booking using carbon monoxide testing and self reporting, to see if this increased the numbers engaging with specialist services and quitting for a month. The study raises many issues in relation to the identification of smokers and its impact on both engagement and cessation. It is limited by a lack of clear outcomes and dependence on an established data system. Inclusion of qualitative elements regarding women and staff views would have added depth, making it more applicable to wider service development. PMID- 21323087 TI - 'The best breastfeeding website in the world'. AB - The dramatically new UNICEF UK Baby Friendly Initiative website will launch on 9 January 2011, having been successfully piloted at the recent Baby Friendly Conference in Harrogate. One new feature will be Care Pathways, so that whether you are a parent, a health worker, or an infant feeding lead, you will be able to see and understand what good care should look like at each stage of the mother's journey. Other features of the new site will be discussion forums for health professionals to share their experiences, and video and audio-clips of mothers and health professionals sharing their stories, as well as much-improved navigation and research library. PMID- 21323088 TI - Blood tests for investigating maternal wellbeing. 4. When nausea and vomiting in pregnancy becomes pathological: hyperemesis gravidarum. AB - Nausea and vomiting in pregnancy (NVP) is commonplace, with many midwives frequently counselling women in their care. But how do midwives know when NVP becomes pathological? Although hyperemesis gravidarum (HEG) is less common, midwives must be able to recognise and differentiate between these two conditions, especially as HEG has the potential to have a detrimental effect on maternal and fetal wellbeing. The physiological impact of HEG is well documented but what often goes unacknowledged is the psychological, social, occupational and familial impact it also has on a woman's life. Knowledge about the aetiology of HEG and treatment options available is essential but a timely initial diagnosis is paramount. For this to occur the midwife must be skilled in history taking, clinical examination and utilisation of serum blood tests--specifically electrolytes and urea. An understanding of how electrolyte levels can cause pathology is vital if the midwife wishes to interpret blood tests for women with this condition. PMID- 21323089 TI - 'Miracles come every day'. PMID- 21323090 TI - Our first dinner guest. PMID- 21323092 TI - Approach to office visits for hair loss in women. PMID- 21323091 TI - Intracystic breast carcinoma: case study and review. AB - Breast carcinoma is the most common cancer in women, the second leading cause of cancer-related mortality in women, and the leading cause of death from cancer in women between the ages of 40 and 44. While cystic breast disease is the most frequent cause of benign breast masses, intracystic breast cancers are rare. We present a case of a postmenopausal woman with a large cystic breast carcinoma with its interesting radiologic and cytopathologic findings and review the literature. PMID- 21323093 TI - What's eating you? Tarantulas (Theraphosidae). PMID- 21323094 TI - What is your diagnosis. Nephrogenic systemic fibrosis. PMID- 21323095 TI - Pathologic grooming behavior: facial dermatillomania. AB - Dermatillomania is a pathologic grooming disorder characterized by repetitive, ritualistic, impulsive skin picking without an underlying dermatologic condition. It can lead to skin damage and distress and can affect patient function. This disorder has not received much attention in the literature, with few studies reporting treatment efficacy. Patients with dermatillomania typically present to primary care physicians and frequently are referred to dermatologists; only rarely do patients receive additional psychiatric consultation that may improve treatment efficacy and decrease morbidity. We provide a case report of long standing facial dermatillomania and our multimodal treatment approach. PMID- 21323096 TI - Acquired idiopathic generalized anhidrosis: case report. AB - We report a case of acquired idiopathic generalized anhidrosis (AIGA) in a 56 year-old white woman. Acquired idiopathic generalized anhidrosis is an exceedingly rare group of heterogeneous disorders that has been almost exclusively reported in young Japanese males. Our case is unique in that AlGA may be underrecognized in this patient population. PMID- 21323097 TI - Cyclosporine for SJS/TEN: a case series and review of the literature. AB - Clear guidelines for the treatment of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are lacking due to its infrequency and the absence of large controlled studies. Systemic corticosteroids and intravenous immunoglobulin (IVIG) have received considerable attention, though reports of the use of these agents have demonstrated mixed success rates in improving morbidity and mortality from SJS/TEN. We present a case series of 4 patients with SJS/TEN who rapidly responded to treatment with cyclosporin A (CsA). We discuss the proposed mechanism of action and the rationale for the use of cyclosporin based on the currently understood pathophysiologic mechanism of TEN. PMID- 21323098 TI - Nonhealing vegetating plaque on the finger: tuberculosis verrucosa cutis. AB - Tuberculosis verrucosa cutis is an uncommon form of tuberculosis that typically presents as a chronic warty plaque. It develops in individuals with moderate to high immunity to Mycobacterium tuberculosis due to inoculation of an open wound. We present the case of a Somali man born in the United Kingdom who presented with a nonhealing ulcer on the right hand of 10 years' duration. The patient was diagnosed with tuberculosis verrucosa cutis based on clinical suspicion, which was confirmed by several investigations including strongly positive results of a Mantoux test, IFN-gamma release assay, typical histology on skin biopsy, and polymerase chain reaction (PCR) analysis positive for mycobacterial DNA. Treatment with quadruple antituberculous therapy produced rapid resolution of the ulcer. This unusual condition often is overlooked in the differential diagnosis of nonhealing ulcers, yet it has an excellent prognosis with treatment. A high index of suspicion is required. PMID- 21323099 TI - Eruptive Kaposi sarcoma: an unusual presentation in an HIV-negative patient. AB - Kaposi sarcoma (KS) is an angioproliferative disease associated with human herpes virus 8 (HHV-8) infection. Four clinical variants have been described, all unified by common histopathologic features. We report a case of KS in an elderly Italian man with an unusual clinical presentation characterized by a relatively rapid onset of lesions and an unexplained low CD4 lymphocyte count. We review KS, including the 4 recognized variants, the central histopathologic findings, and various treatment options. In addition, we briefly discuss causes of CD4 lymphocytopenia, including a cursory overview of idiopathic CD4 lymphocytopenia (ICL). PMID- 21323100 TI - Unilateral eyelid angioedema with congestion of the right bulbar conjunctiva due to loxoprofen sodium. AB - Angioedema is a variant of urticaria that causes deep dermal and subcutaneous swelling. It frequently is a unilateral reaction and usually lasts for several hours but may persist for several days. We report 2 cases of angioedema that involved the right upper and lower eyelids and was associated with congestion of the right bulbar conjunctiva; the symptoms started approximately 1 to 2 hours after taking loxoprofen sodium. All of the symptoms subsided after oral corticosteroid therapy. In both cases, an oral challenge test with 60 mg of loxoprofen sodium (contained in a tablet) caused swelling of the right upper eyelid within several hours, followed by swelling of the right bulbar conjunctiva. We believe the drug reaction in both patients is angioedema. PMID- 21323101 TI - Segmental neurofibromatosis: report of 3 cases. AB - Segmental neurofibromatosis (SNF) is an uncommon variant of neurofibromatosis type 1 (NF-1) that is characterized by cafe au lait spots, freckles, and/or neurofibromas limited to a body segment. In this report we describe 3 adult patients with SNF who presented with only neurofibromas. Although 2 patients had no systemic involvement, the third patient had hypertrophic cardiomyopathy, a cardiologic abnormality that is associated with neurofibromatosis. PMID- 21323102 TI - Detection of the cancer marker CD146 expression in melanoma cells with semiconductor quantum dot label. AB - The use of highly specific and highly sensitive quantum dots immunofluorescent label is a promising approach for biomedical imaging in cancer cells. Human melanoma cell adhesion molecule CD146, overexpressed on the surface of melanoma cells, is an important target for melanoma diagnostics. We synthesized PEG-COOH capped highly fluorescent CdSe/ZnS QDs and conjugated them with streptavidin to prepare QD-SA label. Then, we used QD-SA to link with biotinylated goat anti mouse IgG and mouse anti-human CD146 to label CD146 overexpressed on live and fixed cells by FACS and Confocal microscopy. Labeling of target cells was shown to have high brightness, photostability, and specificity. Advantages of QD conjugates over FITC conjugates are discussed. The results indicate that construction based on QD-SA label, biotinylated IgG and CD146 antibody can be successfully used for detection of melanoma cells for biomedical applications. PMID- 21323103 TI - Preparation of zein nanoparticles by pH controlled nanoprecipitation. AB - Zein is a hydrophobic water insoluble plant protein and the main goal of the present study was to prepare zein nanoparticles using pH controlled nanoprecipitation method. Nanoparticle characteristics such as size, polydispersity index (PI), zeta potential, and encapsulation efficiency were studied using 6, 7-dihydroxycoumarin, as a model hydrophobic compound. Lecithin and pluronic F68 were used as stabilizers. The blank zein nanoparticles had a mean particle size of 460 nm; while coumarin loaded zein nanoparticles had a mean particle size of 365 nm. The encapsulation efficiency of coumarin loaded zein nanoparticles was 62%. The release of coumarin from zein nanoparticles was sustained in phosphate buffer (pH 7.4) for upto 9 days. Overall the results from this study demonstrate a new method for preparing drug loaded zein nanoparticles. PMID- 21323104 TI - New perspective of GABA as an inhibitor of formation of advanced lipoxidation end products: it's interaction with malondiadehyde. AB - In this research, the obtained evidences support the hypothesis that gamma aminobutyric acid (r-aminobutyric acid, GABA) can trap malondialdehyde (MDA) indirectly or directly. In vitro, reaction between GABA with fatty acid, which can be confirmed by detecting the formation and yield of MDA and the consumption of GABA, shows that GABA can trap the reactive intermediates during lipid peroxidation. Further study of the direct reaction between GABA and MDA indicated that GABA reacts readily with MDA under supraphysiological conditions to form different products. A nonfluorescent enamine (product 1) and a lipofuscin-like fluorescent 1,4-dihydropyridine (product 2) were obtained experimentally from reaction of equimolar of GABA+MDA and were detected by means of high performance liquid chromatography (HPLC) separation for the reaction mixtures at 48 h. We proposed a mechanism for the formation of these products from oxidation of polyunsaturated fatty acids (PUFA) to the reaction of GABA and MDA. The results suggest that the scavenging effects of GABA on reactive carbonyl compounds may play an important role in inhibiting the formation of advanced lipoxidation end products (ALEs), and GABA, as a potent antioxidant or additive, is a novel functional factor for nutraceuticals. PMID- 21323105 TI - Development of nanosuspension formulation for oral delivery of quercetin. AB - With the aim to enhance dissolution rate and oral bioavailability of quercetin, a poorly water-soluble drug, quercetin loaded nanosuspension (QT-NS) was fabricated by a tandem of nano-precipitation (NP) and high pressure homogenization (HPH) method. The formulation of nanosuspension was optimized by screening different stabilizers. Characterization of the original QT powder and QT-NS was carried out by transmission electron microscopy and scanning electron microscopy, X-ray diffraction (XRD) and dissolution tests. QT-NS presented a sphere-like shape under transmission electron microscopy with an average diameter of 393.5 nm and the zeta potential of -35.75 mV. XRD study suggested that QT was maintained in the state of crystalline during the fabrication process. The solubility of QT in nanosuspension was about 70-fold that of crude QT, and the dissolution of QT from QT-NS was increased as compared to that of the original QT powder. In plasma, QT NS exhibited a significant reduction of clearance rate (2 +/- 0.1 mL/min vs. 15 +/- 4 mL/min) and increase of AUC(0-infinity), (53995 +/- 4126 microg/mL x min versus 3470 +/- 110.1 microg/mL x min) compared with the control suspension. Our results showed that the developed nanosuspension formulation had a great potential as a possible formulation of the poorly water-soluble QT to enhance the bioavailability. PMID- 21323106 TI - Synthesis and characterization of nanoscale-hydroxyapatite-copper for antimicrobial activity towards bone tissue engineering applications. AB - The bacterial infection is one of the major problems associated with implant and reconstructive surgery of bone. Hence, the aim of this study was to develop biomaterials having antibacterial activity for bone tissue engineering. The hydroxyapatite nanoparticles (nHAp) improve the mechanical properties and incorporate nanotopographic features that mimic the nanostructure of natural bone. We report here for the first time the synthesis and characterization of nHAp and nHAp soaked with copper (nHAp-Cu) using SEM, AFM, FTIR and XRD. The antibacterial activity of nHAp and nHAp-Cu was determined using Gram-positive and Gram-negative bacterial strains. To have accelerated antibacterial activity, polyethylene glycol 400 (PEG 400), a synthetic biodegradable polymer was also added along with nHAp-Cu. The nHAp-Cu/PEG 400 had increased antibacterial activity towards Gram-positive than Gram-negative bacterial strains. The cytotoxicity of nHAp-Cu/PEG 400 was determined using MTT assay with rat primary osteoprogenitor cells and these biomaterials were found to be non-toxic. Hence, based on these results we suggest that the biomaterials containing nHAp-Cu/PEG 400 can be used as antibacterial materials in bone implant and bone regenerative medicine. PMID- 21323107 TI - Chondroitin sulphate decorated nanoparticulate carriers of 5-fluorouracil: development and in vitro characterization. AB - The present study investigates prospective of tailored nanoparticles as vectors to provide improved therapeutic efficacy of encapsulated anti-cancer drug 5-FU. Condritin Sulphate (CS) conjugated PLGA nanoparticles were prepared using PEG-bis amine and adipic dihydrazide as spacers and loaded with an anti-cancer drug 5-FU (CS-PEG-PLGA-FU and CS-ADH-PLGA-FU). The formulations were then compared with non CS-anchored monomethoxy(polyethylene glycol) (MPEG-PLGA-FU) nanoparticles. Nanoparticlulate systems were further characterized by FTIR, NMR, TEM studies and particle size/polydispersity index (PDI) analysis. DSC and XRD were also performed to assess the nature of 5-FU inside the nanoparticles. The nanoparticles prepared using amphiphilic block copolymer CS-PEG-PLGA were able to sustain the release of 5-FU up to 48 h whereas those of CS-ADH-PLGA and MPEG-PLGA released the drug up to 24 h. The CS-PEG-PLGA-FU nanoparticles were found to be least haemolytic when compared to free drug, CS-ADH-PLGA-FU and MPEG-PLGA-FU nanoparticles. Cytotoxicity studies were performed on MCF-7/MDA-MD 231 breast cancer cells. PLGA nanoparticles exhibited more potent cytotoxic effect on MCF 7/MDA-MD 231 cells than free doxorubicin. Further, enhanced cytotoxicity and lower hemolytic potential of CS-PEG-PLGA-FU nanoparticles suggest a potential application in cancer chemotherapy. PMID- 21323108 TI - Enhanced gene delivery using biodegradable poly(ester amine)s (PEAs) based on low molecular-weight polyethylenimine and poly(epsilon-caprolactone)-pluronic poly(epsilon-caprolactone). AB - In this paper, the poly(ester amine)s (PEAs) were successfully prepared from low molecular-weight PEI (Mn = 2000) and Poly(epsilon-caprolactone)-poly(ethylene glycol)-poly(propylene glycol)-poly(ethylene glycol)-poly(epsilon-caprolactone) (PCFC) copolymers using isophorone diisocyanate (IPDI) as cross-linker. The obtained PEAs copolymers are biodegradable and water-soluble. The PEAs/DNA complexes showed effective and stable DNA condensation with the particle size < or = 200 nm and zeta potential > or =10 mV, indicating its potential for intracellular delivery. Compared to the unmodified low-molecular-weight PEI, PEAs displayed similarly low cytotoxicity in all two cell lines (293T: Human kidney carcinoma, HUVEC: Human umbilical vein Endothelial cell) and revealed much higher transfection efficiency in 293T cell lines. Therefore these PEAs might be a novel safe and efficient polymeric gene delivery vectors. PMID- 21323109 TI - Bioimpacts of anti epidermal growth factor receptor antisense complexed with polyamidoamine dendrimers in human lung epithelial adenocarcinoma cells. AB - Lung cancer is still one of the leading causes of malignancy related deaths worldwide despite recent advances in diagnosis and therapy. Among various biomarkers detected in cancerous cells, the epidermal growth factor receptor (EGFR) plays a key role in initiation/promotion of several malignancies. Thus, a number of studies have been carried out to target this important receptor. In the present study, effects of anti-EGFR antisense (AS-ODN) nanoparticles formulated with star burst polyamidoamine (PAMAM) dendrimers on the expression of EGFR and its downstream molecules were investigated in human lung cancer A549 cells. Complexation of dendrimers with AS-ODN reduced the zeta potential of nanostructures (approximately 10 mV), but increased their size (approximately150 nm). Fluorescence microscopy revealed high transfection efficiency which was further confirmed with flow cytometry technique. Significant cell growth reduction in the treated cells was detected using MTT assay and marked downregulation of EGFR and some of its downstream signaling biomolecule (i.e., Akt kinase) were observed. Microarray profile revealed nonspecific changes in gene expression in A549 cells upon treatment with PAMAM dendrimers alone or as complexed with As-ODN, while comet assay showed no DNA damage. Based on our findings, EGFR targeting antisense is able to inhibit the growth of A549 cells via downregulation of EGFR and Akt kinase, nevertheless these nanopolyplexes can also induce nonspecific bioimpacts in target cells. PMID- 21323110 TI - Structural design and experimental analysis of a selective laser sintering system with nano-hydroxyapatite powder. AB - Hydroxyapatite (HA) is a ceramic transposition material which has been widely used for artificial bone. However, its applications are limited to a small implantation for non-bearing bone repair due to its high brittleness, low strength and poor mechanical properties. Thus, nanotechnology has been employed to improve the mechanical properties (torsion modulus, tensile strength and fatigue resistance, etc.) of HA for bone implantation. In this study, we developed a selective laser sintering system for fabrication of artificial bone with nano-HA powder. The key characteristics of this novel system is the laser with fast heating and fast cooling properties, which efficiently prevents the nanosize particles from forming micron size ones in the process of the sintering. The microstructure of the sintered nano-HA scaffolds produced in this system was investigated under Scanning Electron Microscopy (SEM). We showed that the size of nano particles were increased with the prolonged sintering time. Moreover, they are more in shape of granules instead of the original shape of needle. We suggest that the nano HA scaffolds which meet the requirements for the mechanical and biological properties of bone can be obtained by optimizing the sintering time. PMID- 21323111 TI - Lys3-bombesin conjugated to 99mTc-labelled gold nanoparticles for in vivo gastrin releasing peptide-receptor imaging. AB - The gastrin releasing peptide-receptor (GRP-r) is over-expressed in breast and prostate cancer and lymph node metastases. Lys3-bombesin is a peptide that binds with high affinity to GRP-r. The aim of this research was to prepare a multifunctional system of technetium-99m labelled gold nanoparticles conjugated to Lys3-bombesin/HYNIC-GGC and to evaluate its biological behaviour as a potential radiopharmaceutical for in vivo GRP-r imaging. METHODS: Lys3-bombesin and hydrazinonicotinamide-Gly-Gly-Cys-NH2 (HYNIC-GGC) peptides were conjugated to gold nanoparticles (AuNP, 20 nm) to prepare a multifunctional system of HYNIC-GGC AuNP-Lys3-bombesin by means of spontaneous reaction of the thiol (Cys) present in HYNIC-GGC sequence and the amine of Lys3-bombesin. The nanoconjugate was characterized by transmission electron microscopy (TEM), IR, UV-Vis, Raman, and X ray photoelectron spectroscopy (XPS). Technetium-99m labelling through the HYNIC GGC ligand was carried out using EDDA/tricine as coligands and SnCl2 as reducing agent with further size exclusion chromatography purification. Radiochemical purity was determined by size exclusion HPLC and ITLC-SG analyses. In vitro binding studies were carried out in human prostate cancer PC-3 cells (GRP-r positive cells). Biodistribution studies were accomplished in athymic mice with PC-3 induced tumours and images obtained using a micro-SPECT/CT system. RESULTS: TEM and spectroscopy techniques demonstrated that AuNPs were functionalized with HYNIC-GGC-NH2 and Lys3-bombesin through interactions with thiol groups of Cysteine and the N-terminal and epsilon-amine of Lysine respectively. Radio chromatograms showed radiochemical purity higher than 95%. 99mTc-EDDA/HYNIC-GGC AuNP-Lys3-bombesin (99mTc-AuNP-Lys3-bombesin) showed specific recognition for GRP r over-expressed in PC-3 cells. After administration of 99mTc-AuNP-Lys3-bombesin in mice the pancreas-to-blood ratio was 36 at 1 h demonstrating ability to target in vivo GRP receptor-bearing cells. In vivo micro-SPECT/CT images in mice showed an evident tumour uptake (6.39 +/- 0.83% IA/g at 1 h). CONCLUSIONS: This study demonstrated that the 99mTc-AuNP-Lys3-bombesin multifunctional system shows specific recognition for GRP-r and suitable properties to be used as a molecular imaging agent. PMID- 21323112 TI - Polymeric disinfectant nanocapsules: effect of molecular weight of poly(methyl acrylate). AB - Poly(methyl acrylate) (PMA) of various weight average molecular weights (Mw) were synthesized via the iniferter route and applied for the encapsulation of disinfectant agent (chlorhexidine digluconate; CHD) by using the controlled precipitation technique. The encapsulation efficiency of CHD-PMA nanocapsules suspended in cyclohexane increased from 70 to 100% when the Mw of PMA increased from 40 K to 550 K. After redispersing the capsules into 0.5% w/v of sodium dodecyl sulphate aqueous solution, the maximum content of CHD in the nanocapsules remained >90%. Transmission electron micrographs showed the spherical nanocapsule with continuous intact shell. PMID- 21323113 TI - Antibacterial efficacy of inhalable antibiotic-encapsulated biodegradable polymeric nanoparticles against E. coli biofilm cells. AB - Biofilm is a sessile community of bacterial cells enclosed by a self-secreted extracellular polymeric matrix that exhibit a high recalcitrance towards antibiotics. Inhaled antibiotic nanoparticles with a sustained release capability have emerged as one of the most promising anti-biofilm formulations in the fight against respiratory biofilm infections attributed to their ability to penetrate the biofilm sputum. The present work examines the antibacterial efficacies and physical characteristics of different antibiotic-loaded polymeric nanoparticle formulations. PLGA and PCL nanoparticles prepared by an emulsification-solvent evaporation method are used as the antibiotic carrier nanoparticles. Fluoroquinolone antibiotics (i.e., ciprofloxacin and levofloxacin) are selected as the antibiotic models due to their proven effectiveness against dormant bacterial cells and their ability to penetrate the biofilm matrix. The antibacterial efficacy against E. coli biofilm cells is examined in a time-kill study in which the effects of biofilm age, antibiotic exposure history, and drug removal are taken into account. Ciprofloxacin-loaded PLGA nanoparticles are identified as the most ideal formulation due to their high drug encapsulation efficiency, high antibacterial efficacy at a low dose against biofilm cells and biofilm-derived planktonic cells of E. coli. Moreover, the nanoparticulate suspension can be transformed into micro-scale dry-powder aerosols having aerodynamic characteristics ideal for inhaled delivery. PMID- 21323114 TI - Standing Out. Outpatient facility makes its presence felt on prominent Texas campus. PMID- 21323115 TI - Information flow. PMID- 21323116 TI - Cancer care concepts. Improving the treatment process through better design. PMID- 21323117 TI - Ready for tomorrow. Six critical areas of emergency power management. PMID- 21323118 TI - Flow control. Trends in hospital plumbing fixtures and fittings. PMID- 21323119 TI - CHESP's essential role in succession planning. PMID- 21323120 TI - Right the first time. ASHE's commissioning guidelines ease facility start-ups. PMID- 21323121 TI - Waste not. Developing a hospital recycling program. PMID- 21323122 TI - Reactivity of metallothioneins of frog Rana ridibunda treated by copper and zinc ions. AB - The metal-buffering and stress proteins metallothioneins (MTs) of frog are characterised by unusually high content of copper as for vertebrate animals and instability that was shown in our previous studies. They easily lost copper and especially zinc under unfavourable conditions. The aim of this study was to examine the reactivity of SH groups in the MTs from the liver of frog Rana ridibunda after the effect of Cu2+ (0.01 mg/l) and Zn2+ (0.1 mg/l) ions on the organism during 14 days. The alpha- and beta-domains of MTs with molecular weights of about 4 kDa were separated by the size-exclusion chromatography on Sephadex G-50. Unlike higher vertebrates, frogs demonstrated higher reactivity of alpha-domain than beta-domain with the Ellman's reagent (DTNB). The signs of partial oxidations in beta-domain included the creation of by-products with molecular weight about 12 kDa, low reactivity of SH-groups, and typical of -S-S bonds peculiarities of UV-spectra. The effect of both metal ions on frog provoked the elevation of SH-groups reactivity in a-domain with the appearance of by product with molecular weight of 16 kDa and its reduction in beta-domain. The incubation of MTs of control animals with 0.5 and 5.0 mM of H2O2 did not affect its chromatographic characteristics. In the frogs loaded by Cu2+ and Zn2+ the effect of 5.0 mM H2O2 on MTs provoked the release of 4 kDa product. So the alpha domain is responsible for the increased release of metals from injured MTs in frogs, whereas extremely high oxidizability of beta-domain makes its participation in the exchange of metals elusive and provokes the aggregation of MTs. PMID- 21323123 TI - Superior implicit memory: a pilot study. AB - In this pilot study, implicit memory was examined in participants selected according to their scores on the Wechsler Memory Scale-Revised. Implicit memory was explored using a word-stem completion test after 24 participants had processed texts to be remembered. Variations in priming were observed among 12 Normal and 12 Good memorizers (Verbal Memory scores >110) following presentation of target words in the context of a coherent text. One intriguing result emerged: the magnitude of the priming effect varied by group, greater among Good memorizers than Normal memorizers. PMID- 21323124 TI - Event valence and estimates of own, average person's, and randomly chosen person's risk. AB - People typically believe they have a lower likelihood of experiencing negative events and a greater likelihood of experiencing positive events than does the average person. This effect is greater for negative than positive events. It has been proposed that this is a by-product of a tendency for estimates of the average person's likelihood to increase with the size of the group concerned. If so, event valence should affect estimates of the average person's likelihood, but not estimates of one's own likelihood or estimates of the likelihood of a person selected at random. These predictions were tested for a single event using a student sample (N = 113). Results were not in accord with the proposal. An explanation in terms of motivational processes is offered instead. PMID- 21323126 TI - Moral development and perceptions of attempted suicide and physician-assisted suicide. AB - In a sample of 115 undergraduates, no association was found between a measure of moral development and the perception of attempted suicides. For the 85 women in the sample, a higher moral development score was associated with less approval of physician-assisted suicide. PMID- 21323125 TI - Traumatic stress, dissociation, and limbic irritability in patients with unipolar depression being treated with SSRIs. AB - Recent evidence suggests that stressful experiences may be related to deficits in inhibitory functions and temporo-limbic epileptic-like activity. The latter may produce psychosensory seizure-like symptoms that may also appear in nonepileptic conditions. This study assesses whether the increased presence of the seizure like symptoms in 113 unipolar depressive patients treated with SSRIs is associated with significantly more severe symptoms of depression, traumatic stress, and dissociation in comparison with 86 healthy controls. Results indicate that seizure-like symptoms in depressive patients have significant association with depression, symptoms of dissociation, and traumatic stress. This association suggests that processess generating seizure-like symptoms may be related to symptoms of depression, traumatic stress, and dissociation. PMID- 21323127 TI - Framing alters risk-taking behavior on a modified Balloon Analogue Risk Task (BART) in a sex-specific manner. AB - Framing uncertain scenarios to emphasize potential positive or negative elements influences decision making and behavior. The current experiment investigated sex differences in framing effects on risk-taking propensity in a modified version of the Balloon Analogue Risk Task (BART). Male and female undergraduates completed questionnaires on sensation seeking, impulsiveness, and risk and benefit perception prior to viewing one of three framing conditions for the BART: (1) positively-framed instructions emphasizing the ability to earn money if balloons were inflated to large size; (2) negatively framed instructions emphasizing the possibility that money could be lost if balloons were inflated to bursting; and (3) completely framed instructions noting both possible outcomes. Results revealed correlations between BART performance and impulsiveness for both sexes. Compared to positive and complete framing, negatively framed instructions decreased balloon inflation time in women but not men, indicating sex differences in response to treatments designed to alter risk-taking behavior. PMID- 21323128 TI - Predicting European suicide rates with physiological indices. AB - In a sample of 17 European nations, the prevalence of the brain parasite Toxoplasma gondii and the percentage of Finno-Ugrians in the populations were significantly associated with national suicide rates for men and women. PMID- 21323130 TI - Split-half and parallel reliabilities of the Purdue Pharmacist Directive Guidance Scale. AB - Using R and SPSS, various forms of split-half and parallel reliabilities were calculated. Robust split-half and parallel reliability coefficients for the Purdue Pharmacist Directive Guidance Scale are presented with coefficients greater than .84. PMID- 21323129 TI - The Swedish version of the parent-rated Junior Temperament and Character Inventory (J-TCI). AB - To evaluate the psychometric characteristics of the Swedish version of the Junior Temperament and Character Inventory (J-TCI), it was sent to parents of 9- and 12 yr.-old twins in Sweden. The final number of responders was 196 parents who rated 92 female and 104 male twin pairs. The inventory of one twin, randomly chosen from each pair, was included in the analyses. Reward Dependence, Persistence, and Cooperativeness were scored higher in girls; Novelty Seeking was higher in the 9 yr.-olds and Persistence in the 12-yr.-olds. Pearson's correlations showed that some dimensions were not statistically independent from each other, even if the covariance was moderate. Internal consistency (Cronbach's alpha) was satisfactory for Harm Avoidance, Novelty Seeking, Self-Directedness, and Cooperativeness (.68 .81), while it was lower in those dimensions that had fewer items. The Swedish parent version of the J-TCI shared about the same psychometric characteristics as found in international samples. PMID- 21323131 TI - Cognitive deficits presenting as psychiatric symptoms in a patient with Moyamoya disease. AB - The case of a middle-aged man who had intraventricular hemorrhages secondary to Moyamoya disease (MMD), and initially, presented with psychiatric symptoms which did not respond to treatment is described. Neuropsychological assessment showed underlying significant cognitive deficits, mostly of complex attention and speed of information processing, visuospatial and constructional abilities, verbal and nonverbal memory, and executive functions. These deficits remained stable or slightly improved in follow-up assessments. Cognitive dysfunction should be suspected in case of psychiatric or psychiatric-related symptoms in MMD patients. This case study in Greece highlights the range of preserved and impaired cognitive functions in adult MMD by means of repeated neuropsychological evaluations in which a broad range of cognitive abilities were assessed. PMID- 21323132 TI - Diagnostic utility of the PTSD Checklist in detecting ptsd in Chinese earthquake victims. AB - By using the posttraumatic stress disorder (PTSD) module of the Mini International Neuropsychiatric Interview (MINI) as the gold standard to identify PTSD, the current study investigated the diagnostic efficiency of the PTSD Checklist (PCL) as a screening questionnaire in a sample of 152 Chinese victims of the Wenchuan earthquake. The results showed that the area under the receiver operating characteristic (ROC) curve was .96 (SE = .02), and the optimally efficient cutoff score was 44. The findings provide preliminary support of the PCL as a screening questionnaire among Chinese earthquake victims. The present study may contribute to further PTSD-related research and practices in Chinese disaster settings. PMID- 21323133 TI - Family functioning of Chinese families in an impoverished neighborhood in Hong Kong. AB - Consonant with the family stress model, in this study family economic disadvantage, concomitant with cumulative family stressors, concurrently contributed to poor family functioning of 504 Chinese families in an impoverished neighborhood in Hong Kong, in which the latter factor appeared to be more pronounced. Implications were briefly discussed. PMID- 21323134 TI - Measurement of readiness to reduce driving speed: a pilot study. AB - Speeding is a preventable risky behavior that contributes to risk of accident. Readiness to change reflects an individual's recognition of and desire to change behavior. No measure to identify readiness to change has yet been validated for speeding. The Readiness to Change Questionnaire appraises readiness to change drinking behavior. The questionnaire was adapted to speeding and its psychometric properties examined. Participants (N = 112) completed the questionnaire and reported their usual driving speed. A clear component structure and acceptable internal consistency and test-retest reliability were found. Convergent validity was indicated by an association between higher readiness to change and lower driving speed. Results support the questionnaire's potential as a measure of readiness to change speeding, and advance research into the role of motivation in speeding behavior. PMID- 21323135 TI - Relationship between a history of consistent maternal employment and depression in young adults. AB - Research on the correlates of maternal employment has yielded inconsistent results. In this study, 79 male and 120 female undergraduates with mothers who had been employed from the students' infancy through their adolescence scored higher on the Beck Depression Inventory-II than those whose mothers had not been employed. This relationship between children's depressive symptoms and mothers' employment history was not evident among young adults whose mothers' employment was perceived to be financially unnecessary. PMID- 21323136 TI - Sex differences in the factor structure of a modified Sexual Experiences Questionnaire. AB - Sexual harassment has long been a problem in educational, employment, and military populations. It is unclear whether existing questionnaires used to measure sexual harassment in the U.S. military--particularly, derivatives of the Sexual Experiences Questionnaire--perform similarly in men and women. Using exploratory factor analyses in a mixed sample of active duty troops and veterans (289 men, 181 women), sex differences were found in one version's factor structure. Implications and suggestions for improving the validity of the questionnaire for men are offered. PMID- 21323137 TI - Mental health and thinking styles in Sternberg's theory: an exploratory study. AB - The relationship between thinking styles, as defined in Sternberg's theory of mental self-government, and mental health was investigated. 583 university students (362 women, 221 men; M age = 21.4 yr., SD = 0.9) in Guangzhou, P. R. China, were invited to fill out the Thinking Styles Inventory-Revised and the Symptom Checklist-90 on a voluntary basis. Results indicated that scores on six of Sternberg's 13 thinking styles were significantly correlated with the Mental Health Index. The hierarchical style (one Type I style) negatively predicted the General Severity Index beyond sex and age, whereas the judicial, anarchic, and internal styles did so positively. The specific ways in which the thinking styles and mental health scales were related to one another supported Zhang and Sternberg's (2006) claim that thinking styles are value-laden. Applications of thinking styles in enhancing mental health are discussed. PMID- 21323138 TI - Positive psychological states and anxiety: the mediating effect of proactive coping. AB - The current study examined the mediating role of proactive coping in the relationship between positive psychological states like optimism and self-esteem and trait anxiety. 204 undergraduate students completed measures of optimism, self-esteem, and trait anxiety, together with the proactive coping subscale of the Proactive Coping Inventory (PCI). Mediated effects were explored using a series of regression analyses and were confirmed through bootstrapping procedures. Results revealed that proactive coping was a partial mediator in the relationship between both optimism and self-esteem and trait anxiety. Findings indicated that proactive coping enhances a perspective on life that involves a positive attitude toward future events in the form of optimistic expectancies and enhanced feelings of self-worth. Implications of the findings for clinical practice and mental health promotion are discussed. PMID- 21323139 TI - Validation of the Psychological Work Maturity Scale in Chinese employees. AB - Psychological work maturity is an important concept in situational leadership theory. The present research revised the Psychological Work Maturity Scale for use in Chinese organizations. Three samples of full-time employees (Ns = 205, 266, and 283) from different companies and industries participated in the present study. Confirmatory factor analysis showed that a single-factor structure fit the data. The scale had acceptable reliabilities, convergent and criterion-related validities, and was shown to be an appropriate measure of psychological work maturity in Chinese employees. Maturity differences in several demographic variables were not found, but employees with longer tenure in Sample 2 scored higher on maturity, which shows that psychological work maturity may be dependent on personal development in the interaction with the varying situational factors, especially in the work domain. Implications for research and practice on psychological work maturity in China are discussed. PMID- 21323140 TI - Identity processing styles and language proficiency among Persian learners of English as a foreign language. AB - The relationship between identity processing styles and language proficiency in English as foreign language (EFL) was investigated among the Persian EFL learners. 266 Persian candidates taking part in a Ph.D. examination at Shiraz University took part. The Language Proficiency Test was used to measure language proficiency in English. The Identity Styles Inventory was used to measure normative, informational, and diffuse-avoidant identity processing styles. Relationships between normative and informational styles and language proficiency and its subscales (grammar, vocabulary, and reading) were positive and significant. Negative relationships between diffuse-avoidant style and language proficiency and its subscales (grammar, vocabulary, and reading) were observed. There were significant sex differences for diffuse-avoidant style and for vocabulary. PMID- 21323141 TI - Scoring the VIA Survey of Character. AB - The VIA Survey of Character (VIA) is a self-report inventory designed to measure and assess 24 character strengths that are linked conceptually to six fundamental "virtues"--Wisdom and Knowledge, Courage, Humanity, Justice, Temperance, and Transcendence, as developed by Peterson and Seligman in 2004. Despite its popularity, the current presentation of the VIA is not easy to score; researchers must either use a limited online scoring facility or must use outdated scoring keys. This paper presents a full description of the scoring key. PMID- 21323142 TI - Predicted and experienced affective responses to the outcome of the 2008 U.S. presidential election. AB - People typically have intense feelings about politics. Therefore, it was no surprise that the campaign and eventual election of Barack Obama were highly anticipated and emotionally charged events, making it and the emotion experienced afterward a useful situation in which to replicate prior research showing that people typically overestimate the intensity and duration of their future affective states. Consequently, it was expected that Obama supporters and McCain supporters might overestimate the intensity of their affective responses to the outcome of the election. Data showed that while McCain supporters underestimated how happy they would be following the election, Obama supporters accurately predicted how happy they would be following the election. These data provide descriptive information on the accuracy of people's predicted reactions to the 2008 U.S. presidential election. The findings are discussed in the context of the broad literature and this specific and unique event. PMID- 21323143 TI - Environmental attitude as a mediator of the relationship between psychological restoration in nature and self-reported ecological behavior. AB - Environmental attitude and ecological behavior were investigated in relation to the use of nature for psychological restoration. Specifically, with survey data from 468 German university students, the role of environmental attitude was investigated as a mediator of the restoration-behavior relationship. Assuming that positive experiences in nature can have a broad influence on environmental attitudes, the New Ecological Paradigm (NEP) scale, an attitudinal measure with broad scope, was adopted. Hierarchical regression analyses indicated partial mediation by environmental concern. The study helps to consolidate the restoration theme in the growing literature on positive motivations for ecological behavior. PMID- 21323144 TI - Resource depletion promotes automatic processing: implications for distribution of practice. AB - Recent models of cognition include two processing systems: an automatic system that relies on associative learning, intuition, and heuristics, and a controlled system that relies on deliberate consideration. Automatic processing requires fewer resources and is more likely when resources are depleted. This study showed that prolonged practice on a resource-depleting mental arithmetic task promoted automatic processing on a subsequent problem-solving task, as evidenced by faster responding and more errors. Distribution of practice effects (0, 60, 120, or 180 sec. between problems) on rigidity also disappeared when groups had equal time on resource-depleting tasks. These results suggest that distribution of practice effects is reducible to resource availability. The discussion includes implications for interpreting discrepancies in the traditional distribution of practice effect. PMID- 21323145 TI - Undergraduate psychology students' experiences of volunteering at a chronic mental health facility. AB - A volunteer program for undergraduate psychology students at a chronic mental health facility was evaluated. All 53 volunteers found the program beneficial, 96.2% reported improved understanding of psychopathology, 98.1% noted increased knowledge of the mental health care system, 86.8% reported increased interest in clinical psychology, and 47.2% felt less anxious about working with persons with mental illness as a result of the program. PMID- 21323146 TI - Effects of daylight-saving time changes on stock market volatility: a comment. AB - In a recent article in this journal, Berument, Dogan, and Onar (2010) challenged the existence of the previously documented daylight-saving effect. Kamstra, Kramer, and Levi's original finding (2000) was that average stock market returns on Mondays following time changes are economically and statistically significantly lower than typical Monday returns. Kamstra, et al. hypothesized that the effect may arise due to heightened anxiety or risk aversion on the part of market participants after they experience a 1-hr. disruption in their sleep habits, in accordance with prior findings in the psychology literature linking sleep desynchronosis with anxiety. Berument, et al. replicated the original findings using ordinary least squares estimation, but when they modeled the mean of returns using a method prone to producing biased estimates, they obtained puzzling results. The analysis here, based on standard, unbiased modeling techniques, shows that the daylight-saving effect remains intact in the U.S. PMID- 21323147 TI - Language, bilingualism, and executive functioning in early development. AB - Okanda, et al. (2010) reported new evidence concerning associations between language ability, bilingualism, and executive functioning early in development. The paper adds to a growing body of literature suggesting that bilingualism is associated with advantages in executive functioning generally, and the Dimensional Change Card Sort task in particular. However, as with all findings that hinge on between-group comparisons, there is a need to exercise caution before drawing firm conclusions about the effects of bilingualism on the development of executive control. Several lines of recent evidence are outlined that challenge key assumptions underlying the standard account of the bilingual advantage. Okanda, et al.'s findings are discussed in light of this evidence. PMID- 21323148 TI - An exploratory study of differences in emotional intelligence in U.S. and Norwegian undergraduate students. AB - The present study explored sex and cultural differences in Emotional Intelligence scores in samples from Norway (n = 297) and the United States (n = 234). Significant main effects for sex were found in overall Emotional Intelligence scores and the Empathy factor. In addition, results revealed a small but significant effect for culture in the Self-control factor, as well as support for an interaction between sex and culture in the Handling Relationships factor. The results are discussed in light of cultural differences between U.S. and Norwegian societies. PMID- 21323149 TI - Phonology and access to Chinese character meaning. AB - One of the central concerns in theories of reading skills is the role of phonology in access to word meaning. The present study focused on this issue in Chinese to examine the extent to which phonology affects Chinese character recognition. Two naming experiments were conducted with a phonologically mediated semantic priming paradigm, and the relative frequencies of semantic associates of the targets and their homophones were manipulated systematically. Analyses showed that a semantic associate produced robust priming on target naming at 57- and 250 msec. stimulus onset asynchronies, but only the low frequency homophones of high frequency semantic associates facilitated target naming at a 250-msec. stimulus onset asynchrony. These results indicate the role of phonology is neither obligatory nor efficient in access to Chinese character meaning, contradicting the key assumptions of the lexical constituency model. A revised parallel access model that emphasizes visual access to semantics is suggested as a more plausible account. PMID- 21323150 TI - Evaluation of the William S. Hall Psychiatric Institute Clinical Psychology Internship: a replication and extension. AB - This study extends three earlier investigations involving participants who completed their predoctoral clinical psychology internship at the William S. Hall Psychiatric Institute. Intern graduates (N = 37) evaluated how effectively their internship training prepared them for seven aspects of their current work as practicing psychologists. Participants also rated the relevancy of 24 different internship training experiences to their current work and how much these experiences contributed to their development as clinical psychologists. The present study, in conjunction with the three previous studies, covers most of the 40-year period since the inception of the internship program. Analysis of the current data indicates the internship has improved over time and was deemed an exceptional training experience by its graduates. Findings may be of particular interest to internship directors and faculty interested in improving their training program and those who plan to conduct a self-study to maintain their accreditation for clinical psychology internship. PMID- 21323151 TI - Psychological factors associated with poor hypertension control: differences in personality and stress between patients with controlled and uncontrolled hypertension. AB - Only one-third of patients with hypertension under pharmacological treatment achieve the recommended blood pressure goals. Psychological factors could partially account for poor hypertension control through the existence of personality traits related to treatment compliance (e.g., self-discipline, deliberation, impulsiveness), and the fact that stress and some personality traits (e.g., anxiety, depression, anger expression, Type A) are involved in the etiology of some hypertension cases. This study was aimed at examining the differences in personality and stress between patients taking antihypertensive medications with controlled and uncontrolled hypertension. Results revealed that after controlling sex, age, and traditional variables associated with poor hypertension control, the uncontrolled hypertension group showed higher scores on impulsiveness, depression, anger expression-out, and stress, with differences ranging between medium and large (Hedges' g effect size = 0.77 to 1.08). These results support the hypothesized relationship between psychological factors and poor hypertension control. PMID- 21323152 TI - Test Anxiety Scale: reliability among Ethiopian students. AB - Sarason's Test Anxiety Scale, translated into an Ethiopian language, was administered to 391 students in Grade 8 and to 422 students in preparatory school (Grades 11 and 12). In the first sample, 32 items loaded above the 0.3 criterion of acceptable item-remainder correlations and Cronbach alpha of .84. In the second sample, Cronbach alpha was .84 for the 34 items, but only 19 items had acceptable item-remainder correlations. The internal consistency reliabilities were comparable with those reported in the literature. However, the results of confirmatory factor analyses with extraction of four factors did not confirm the item loadings on factors as reported in the literature. Younger students (Grade 8) were found to have higher mean Test Anxiety than Grades 11 and 12 students. The Amharik version of the Test Anxiety Scale as a whole could be considered reliable and useful for Ethiopian students. PMID- 21323153 TI - Stability of the Spanish version of the five-item Francis Scale of Attitude toward Christianity. AB - The aim of this study was to establish test-retest reliability of a Spanish version of the Francis Scale of Attitude toward Christianity (Campo-Arias, Oviedo, & Cogollo, 2009) among adolescent students in Cartagena, Colombia. A group of ninth grade students from two public schools in Colombia (N = 157) completed the five-item scale. Cronbach's alphas were .74 and .76 in the first and second administrations, respectively. Both Pearson's rho and intra-class correlation coefficient were .69. A Spanish translation of the 5-item scale had consistent stability over four weeks. PMID- 21323154 TI - Statistical requirements for properly investigating a null hypothesis. AB - Issues involved in the evaluation of null hypotheses are discussed. The use of equivalence testing is recommended as a possible alternative to the use of simple t or F tests for evaluating a null hypothesis. When statistical power is low and larger sample sizes are not available or practical, consideration should be given to using one-tailed tests or less conservative levels for determining criterion levels of statistical significance. Effect sizes should always be reported along with significance levels, as both are needed to understand results of research. Probabilities alone are not enough and are especially problematic for very large or very small samples. Pre-existing group differences should be tested and properly accounted for when comparing independent groups on dependent variables. If confirmation of a null hypothesis is expected, potential suppressor variables should be considered. If different methods are used to select the samples to be compared, controls for social desirability bias should be implemented. When researchers deviate from these standards or appear to assume that such standards are unimportant or irrelevant, their results should be deemed less credible than when such standards are maintained and followed. Several examples of recent violations of such standards in family social science, comparing gay, lesbian, bisexual, and transgender families with heterosexual families, are provided. Regardless of their political values or expectations, researchers should strive to test null hypotheses rigorously, in accordance with the best professional standards. PMID- 21323155 TI - Romanticism as a function of age, sex, and ethnicity. AB - This study examined the association between romanticism (operationalized as mean score on the Romantic Beliefs Scale) and age, sex, and ethnicity in a large community sample (N = 436). Age was negatively correlated with romanticism scores; as age increased, romanticism scores decreased. No sex differences were found; men and women had similar, moderate scores. Although ethnicity largely was unrelated to romanticism, Asian/Pacific Islander participants were significantly more romantic than were African-American participants. PMID- 21323156 TI - The Statistical Anxiety Rating Scale: further evidence for multidimensionality. AB - The Statistical Anxiety Rating Scale has been conceptualized as multidimensional. Three of the six theoretical dimensions, Interpretation Anxiety, Test and Class Anxiety, and Fear of Asking for Help, tap anxiety about statistics; the other three dimensions, Worth of Statistics, Computation Self-concept, and Fear of Statistics Teachers, measure perceptions and attitudes toward statistics. This conceptualization of a second-order factor model consisting of two superordinate factors and six first-order factors has remained empirically untested. In 77 graduate students (15 men, 62 women; M age = 27.6 yr.) enrolled in applied statistics courses in Taiwan, a confirmatory factor analysis of two competing models based on subscale scores yielded results supporting the multidimensional construct validity of the scale. As multidimensionality was previously supported based on item scores, but not subscale scores, the findings are interpreted as partially consistent with previous research testing the theoretical factor structure of the scale. PMID- 21323157 TI - Violence risk appraisal of male and female youth, adults, and individuals. AB - Data from youth (n = 1,127), adults (n = 1,595), and individuals (N = 2,722, combined youth and adults) were followed 3 to 12 years in records to develop items to predict abuse, violence, and homicide in these 3 relevant groups for risk appraisal or safety scales. Shao's bootstrapped logistic regression yielded 14 predictors for youth (AUC = .91), 11 for adults (AUC = .99), and 13 for individuals (AUC = .96). Three regression equations were cross-validated with in bag and out-of-bag techniques. Pearson coefficients were computed with intelligence, achievement, adaptive behavior, and perception tests. Test-retest reliability was acceptable. Using case-control quasi-experimental design, this study extends probation-parole decision-making tests to infants and children as young as 3 years, with convergent and divergent validity and reliability with other tests. Sensitivity and specificity were high and minimized over- or under identification challenges in identifying potentially violent persons in the general population. PMID- 21323158 TI - Factors associated with regional bias of pfcrt (plasmodium falciparum chloroquine resistance transporter) haplotypes in Nepal. AB - Evidences of reappearance of chloroquine sensitive Plasmodium falciparum haplotypes after cessation of chloroquine in many countries provide a rationale for the search of chloroquine sensitive haplotypes in P. falciparum isolates in Nepal where the use of chloroquine for falciparum malaria treatment has been ceased since 1988. P. falciparum chloroquine resistant transporter gene (pfcrt) haplotypes were determined and the factors associated with pfcrt haplotypes in the Eastern and Central regions of Nepal were identified. Blood samples from 106 microscopy-positive falciparum malaria patients (62 from the Eastern and 44 from the Central region) were collected on filter paper. Pfcrt region covering codons 72-76 was amplified by PCR and sequenced. SVMNT haplotype was predominant in the Central region, whereas CVIET haplotype significantly more common in the Eastern region. In multivariable analysis of factors associated with CVIET haplotype, the Eastern region and parasite isolates from patients visiting India within one month are significant at 5% level of significance. These findings suggest that antimalarial pressure is different between Eastern and Central regions of Nepal and there is a need of an effective malaria control program in the border areas between India and Nepal. PMID- 21323159 TI - Directly observed therapy with primaquine to reduce the recurrence rate of plasmodium vivax infection along the Thai-Myanmar border. AB - This study was carried out from April 2005 to June 2006 to evaluate the recurrence of P. vivax malaria infection in relation to drug compliance along the Thai-Myanmar border in Ratchaburi, Thailand. Ninety-two patients with vivax malaria were sequentially assigned to 2 groups. Both groups received a standard dose of chloroquine (total dose = 2.5 g) for 3 days and primaquine (total dose = 210 mg) for 14 days. The experimental group received a full course of treatment using daily directly observed therapy (DOT) while subjects in the control group were given the medication with necessary instructions to take as self administered therapy (SAT). Patients were followed up for 3 months on Days 14, 21, 28, 60 and 90. Five of 46 patients from the SAT group had recurrence of malaria on Days 21, 44, 60, 72 and 87. Recurrence was not observed among patients in the DOT group. Survival analysis also showed significant differences between the SAT and DOT groups (p <0.05). The study suggests patient compliance with the 14-day primaquine treatment with DOT improve the outcome of .vivax malaria treatment. PMID- 21323160 TI - Species identification of intestinal microsporidia using immunofluorescence antibody assays. AB - Abstract. The species identification of Enterocytozoon bieneusi and Encephalitozoon intestinalis is only possible using transmission electron microscopy (TEM), mo lecular techniques and immunofluorescence antibody assays (IFA). In this study, 50 positive and 50 negative fecal specimens for microsporidial spores using the Weber modified trichrome (WMT) staining technique were examined using IFA-MAbs. Of the 100 specimens examined, the microsporidial spores identified by IFA-MAbs were Enterocytozoon Bieneusi 42 (75%) Encephalitozoon intestinalis 7 (12.5%) and mixed infections 7 (12.5%). The sensitivity and specificity of IFA-MAbs in detecting microsporidial spores were 98% and 86%, respectively. The agreement between the WMT staining technique and IFA-MAbs was statistically significant by Kappa statistics (K = 0.840; p < 0.001). E. bieneusi was the commonest Microsporidia species isolated from the studied population; the presence of microsporidial spores detected by IFA-MAbs should be confirmed by other methods. PMID- 21323161 TI - Efficacy of sodium metaperiodate (SMP)-ELISA for the serodiagnosis of schistosomiasis mekongi. AB - Schistosomiasis mekongi is an important public health issue in endemic countries. In this study, we evaluated an indirect immunodiagnostic ELISA method using Schistosoma mekongi soluble egg antigen. Sodium metaperiodate (SMP)-ELISA was utilized in order to remove the glycosylated epitopes responsible for false positive reactions and the results using this method were compared with those using conventional ELISA (conv-ELISA). Forty-two serum samples from schistosomiasis mekongi egg-positive patients and 100 serum samples from schistosomiasis-negative Cambodian subjects were tested using both ELISA methods. The ranges of ELISA values for positive and negative sera were distinct on SMP ELISA, but the ranges of the two groups of sera overlapped on conv-ELISA. Therefore, diagnostic criteria may be established based on the highest ELISA value on negative sera and the lowest ELISA value on positive sera. In the present study, both the sensitivity and specificity of SMP-ELISA reached 100% using the criteria in which an ELISA value > or = 0.2 was positive. PMID- 21323162 TI - Experimental infection with Paragonimus heterotremus metacercariae in laboratory animals in Manipur, India. AB - This study was aimed to find out the host-parasite relationship between Paragonimus heterotremus isolated as metacercariae from mountain crabs, Indochinamon manipurensis, in Manipur, India and laboratory animals such as puppies, albino rats, Swiss mice, guinea pigs, and rabbits, as experimental animals. The animals were fed with the metacercariae. Infected animals were sacrificed 35 to 430 days after feeding to recover worms, which were used to determine the developmental stages. Adult worms (n = 14) were recovered from 3 puppies > or = 70 days after feeding and immature worms (n = 25) were recovered from 2 other puppies 35 or 43 days after infection. The infection rate in puppies was 100%. Juvenile worms were recovered from 3 of 13 rats: 1 of 11 rats whose viscera and cavities were examined and both of two rats whose muscles were examined. Rats were not a suitable animal model for pulmonary infection with P. heterotremus. Mice, guinea pigs, and rabbits were also found to be insusceptible to pulmonary infection with P. heterotremus. PMID- 21323164 TI - Development of HAT-RAPD marker for detection of Stellantchasmus falcatus infection. AB - The trematode, Stellantchasmus falcatus, is one of the members in the Family Heterophyidae, which is reported to be an endemic fluke in northern region of Thailand. A sensitive and specific detection of this parasite is required to determine the epidemiology at larval stages. Specific primers to determine the presence of S. falcatus were investigated using high annealing temperature random amplified polymorphic DNA (HAT-RAPD) PCR, with 10 arbitrary primers to generate different polymorphic DNA profiles. Eleven parasite species were used for comparison. A 380 bp HAT-RAPD S. falcatus-specific marker was found, and was cloned and sequenced, allowing a pair of primers (St-F 5'-GGCCAACG CAATCGTCATCC 3' and St-R 5'-GCGTCGGGTTTCAGACATGG- 3') to be designed to produce a 320 bp amplicon specific for S. falcatus. It revealed no cross-reaction with any of the other tested parasite species. The S. falcatus-specific primers can be used for epidemiological monitoring and for detection in snail intermediate hosts, which serve as usefulness tools in management and epidemiological control programs. PMID- 21323163 TI - Allozyme analysis of the temporal populations of Echinostoma revolutum collected from domestic ducks in Khon Kaen Province, Thailand. AB - Four temporal populations of Echinostoma revolutum (ER1, ER2, ER3, ER4) were collected from domestic ducks in Khon Kaen Province, Thailand during February October 2008. The ER1, ER2, ER3 and ER4 were collected in February, April, June and October, respectively. The 12 enzymes encoding 15 loci were examined. Two loci were found in each of 3 enzymes, namely glucose-6-phosphate dehydrogenase (G6PD), malic enzyme (ME) and peptidase valine-leucine (PEPA). Of these, three loci, namely, G6pd-1, Me-1 and PepA-2, were polymorphic. Genotypes were assigned for the specific allelic profiles detected at these three polymorphic loci. Twenty-eight genotypes were observed in the 4 temporal populations of E. revolutum. Three genotypes, Er22, Er23 and Er25, were found in all populations. The Er6 genotype occurred had the highest frequency of all the populations. These 28 genotypes were clustered into 3 groups with genetic differences of 2-12% among the loci. A cluster of genotypes (Er1, Er3, Er9 and Er12) showed the greatest genetic difference among the genotypes (12% difference). These results show intraspecific variation exists in E. revolutum populations in domestic ducks from Khon Kaen Province, Thailand. PMID- 21323165 TI - Infection dynamics and molecular identification of metacercariae in cyprinoids from Chiang Mai and Sakon Nakhon Provinces. AB - The infection dynamics of metacercariae were assessed in cyprinoid fish (cyprinoids) from Chiang Mai and Sakon Nakhon Provinces, Thailand, during October 2008 to September 2009. The samples were collected during 3 seasons from rivers and local markets. Metacercarial infection was determined by acid-pepsin digestion and confirmed using HAT-RAPD PCR method. Thirteen and 16 species of cyprinoids were collected from Chiang Mai and Sakon Nakhon with overall prevalences of metacercarial infection of 84.5 and 47.6%, respectively. Haplorchis taichui, Haplorchoides sp, and Centrocestus caninus were found in Chiang Mai and 4 species of metacercariae: H. taichui, Haplorchoides sp, O. viverrini and an unknown trematode species in Sakon Nakhon. H. taichui and Haplorchoides sp metacercariae in 3 species of cyprinoids (Henicorhynchus siamensis, Cyclocheilichthys armatus, Amblyrhynchichthy truncatus) had the highest prevalence (100%) in Chiang Mai, while the highest prevalence (100%) of metacercaria in Sakon Nakhon was Haplorchoides sp in 1 species of cyprinoids (Cyclocheilichthys armatus). The overall prevalence from Chiang Mai Province was highest in the rainy season (95.6%), lower in the hot-dry season (88.1%) and lowest in the cool season (72.5%). In Sakon Nakhon Province the highest prevalence was in the hot-dry season (52.7%), and lower in the rainy and cool season, 44.4% and 43.5%, respectively. The HAT-RAPD profiles confirmed the identity of metacercariae and adult stage of H. taichui, Haplorchoides sp, C. caninus and O. viverrini. PMID- 21323166 TI - Seasonal variation of metacercariae in cyprinoid fish from Kwae Noi Bamroongdan Dam, Phitsanulok Province, northern Thailand. AB - Abstract. A seasonal investigation of the occurrence of metacercariae in cyprinoid fish was conducted at the Kwae Noi Bamroongdan Dam, Phitsanulok Province, northern Thailand during December 2008-August 2009. A total 361 cyprinoid fish from 10 species were examined by artificial digestion method evaluating for metacercariae. The metacercariae determined were Haplorchis taichui, Haplorchis pumilio, Haplorchoides sp and Centrocestus caninus. The prevalence of metacercariae ranged from 76.5% to 82.6%, with an intensity of infection of 23.4 to 36.6. H. taichui, Haplorchoides sp and C. caninus had the highest prevalence in the cool season, while H. pumilio was more prevalent during the hot season. The highest infection prevalence (100%) was seen in Rasbora metallicus, Barbodes gonionotus and R. metallicus. No significant differences in the type of metacercariae were found between seasons, indicating year-round infestation of cyprinoid fish. PMID- 21323167 TI - Effect of temperature on laboratory reared Anopheles dirus Peyton and Harrison and Anopheles sawadwongporni Rattanarithikul and Green. AB - Investigations have shown that female mosquitoes with a larger body size (determined by wing length) exhibit higher feeding rates and greater fecundity relative to smaller mosquitoes. In this study, Anopheles dirus and An. sawadwongporni were reared in the laboratory at two different temperatures (23 degrees C and 30 degrees C). Effects of the rearing temperature on body size, fecundity, and larval development period were examined by measuring wing length, adult body weight at emergence, the number of eggs produced and the length of time from the first to the fourth instar. Rearing temperature had a direct effect on body size, fecundity and larval development period for both species. Mosquitoes of both species reared at 23 degrees C were larger in body size, experienced prolonged development and produced a larger clutch of eggs relative to mosquitoes reared at 30 degrees C. However, there was no temperature effect on egg hatching rate and sex ratio. PMID- 21323168 TI - Survey of Anopheles mosquitoes (Diptera:Culicidae) in West Sumba District, Indonesia. AB - In August 2007, mosquitoes were collected using four different collection methods at 2 upland interior and 2 coastal villages in West Sumba District, East Nusa Tenggara Province, Indonesia. Methods included human-baited and unbaited tent and malaise traps, human-landing collections (HLC), and unbaited CDC light traps. Mosquitoes were identified to species by morphological characters and all anophelines were tested for malaria circumsporozoite protein (CSP) using an enzyme-linked immunosorbent assay (ELISA). During six trap nights, 4,174 Anopheles mosquitoes belonging to 13 species were captured and identified: An. aconitus, An. annularis, An. barbirostris, An. flavirostris, Hyrcanus Group species, An. indefinitus, An. kochi, An. leucosphyrus group, An. maculatus s.l., An. subpictus s.l., An. sundaicus s.l., An. tessellatus, and An. vagus. Of potential disease vectors, An. annularis, An. subpictus, and An. vagus were the most frequently collected species in the upland interior sites, whereas An. sundaicus, An. subpictus, and An. vagus were most commonly found along the coast. The predominant species from evening human-landing collections (mosquitoes per human) were An. subpictus and An. vagus in the upland interior and An. sundaicus along the coast. All mosquitoes were non-reactive for Plasmodium CSP. One specimen of the An. leucosphyrus group was captured from indoor HLC in Tenateke Village, an upland interior location. This finding appears to represent a new collection record for Sumba Island. PMID- 21323169 TI - Studies of phlebotomine sand fly (Diptera: Psychodidae) populations in limestone areas and caves of western Malaysia. AB - Phlebotomine sand flies were collected using CO2 baited CDC light trap in 2000 and 2001 in limestone areas and caves of western Malaysia. A total of 1,548 specimens were collected comprising 18 species from two genera: Phlebotomus (6 spp) and Sergentomyia (12 spp). Phlebotomus major major (38.9%) was the predominant species followed by Sergentomyia perturbans (20.1%), P. stantoni (15.3%) and others. Biting activity of the sand flies at the Gua Senyum caves, Gua Kota Gelanggi, Batu caves and Gua Kelam were observed using the bare leg landing catch (BLC) technique. Four Phlebotomus spp at Gua Senyum were found to bite humans with a unimodal biting peak (between 01:00 and 04:00 AM). At Gua Kota Gelanggi P. major major was observed to bite humans, but at Batu Caves and Gua Kelam no sand flies were observed to bite humans. Sergentomyia spp did not feed on humans even though high numbers were caught in light traps. The populations of phleobotomine sand flies fluctuated, with several peaks especially among P. major major which peaked in December and was low in February and August. Phlebotomus stantoni was abundant throughout 2001. Most species populations were weakly related to rainfall because they inhabited caves. PMID- 21323170 TI - Molecular typing of dengue viruses circulating on the East Coast of Peninsular Malaysia from 2005 to 2009. AB - From 2005 to 2009, the Institute for Medical Research (IMR), Kuala Lumpur, Malaysia received 488 serum and blood samples from hospitalized patients on the East Coast of Peninsular Malaysia, suspected of having dengue infection. In this study we determined the prevailing dengue serotypes using a real time polymerase chain reaction assay (RT-PCR). All 4 dengue virus serotypes were found circulating during the study period; however the predominant serotype varied. In 2005 and 2006, the predominant serotypes circulating were DENV-1 and DENV-3, in 2007, DENV-1 and DENV-2 were predominant, and in 2008 and 2009, DENV-3 was the predominant serotype. PMID- 21323171 TI - Monitoring of the h275y mutation in pandemic influenza A(H1N1) 2009 strains isolated in Malaysia. AB - Abstract. The 2009 pandemic influenza A(H1N1) infection in Malaysia was first reported in May 2009 and oseltamivir was advocated for confirmed cases in postexposure prophylaxis. However, there are cases of oseltamivir-resistance reported among H1N1-positive patients in other countries. Resistance is due to substitution of histidine by tyrosine at residue 275 (H275Y) of neuraminidase (NA). In this study, we have employed Sanger sequencing method to investigate the occurrence of mutations in NA segments of 67 pandemic 2009 A(H1N1) viral isolates from Malaysian patients that could lead to probable oseltamivir resistance. The sequencing analysis did not yield mutation at residue 275 for all 67 isolates indicating that our viral isolates belong to the wild type and do not confer resistance to oseltamivir. PMID- 21323172 TI - Noroviruses in oysters from local markets and oyster farms in southern Thailand. AB - One hundred and eighteen oyster samples collected from local markets and oyster farms in southern Thailand were examined for noroviruses (NoVs) and bacterial indicators of fecal contamination (fecal coliforms and Escherichia coli). Using a virus concentration procedure followed by RT-nested PCR, NoVs were detected in 38% of the samples. Oysters collected from oyster farms were found with NoVs at a higher detection rate (25/53 samples) than oysters from local markets (20/65 samples). Of the 45 NoV-positive oyster samples, 67% belonged to NoV genogroup I (GI), 15% to GII, and 18% to both GI and GII. DNA sequencing showed that 2 NoVs belonged to NoV GI-2 genotype. Fecal coliforms in NoV-positive oyster samples were in the range of < 3.0 to 1.5 x 10(4) most probable number (MPN)/g and 33% of NoV-positive oyster samples contained fecal coliforms within the standard acceptable level of raw shellfish (< 20 MPN/g). E. coli was found in the range of < 3.0 to 1.5 x 10(4) MPN/g and 9% of NoV-positive oyster samples were within acceptable levels of E. coli contamination (< 3 MPN/g). These findings indicate that NoV contamination in oysters obtained from both markets and oyster farms might pose a potential risk of acute gastroenteritis associated with raw oyster consumption. Examination for both fecal bacterial indicators and enteric viruses should be conducted for microbiological food safety of shellfish. PMID- 21323173 TI - DNA fingerprinting of septicemic and localized Burkholderia pseudomallei isolates from Malaysian patients. AB - We have analysed DNA fingerprinting patterns by pulsed-field gel electrophoresis (PFGE) of 52 unrelated Burkholderia pseudomallei strains isolated from septicemic and localized infections from Malaysian subjects. A total of 38 PFGE types were observed among 36 septicemic and 16 localized strains with no predominant pattern. Type 25 was seen in 2 epidemiologically related strains, suggesting human to human transmission. Twelve PFGE types were shared among 26 strains (21 septicemic and 5 localized) showing close genetic relatedness with coefficient of similarity of 0.81 to 1.0. The other 26 strains (15 septicemic and 11 localized) were unrelated as shown by the similarity coefficient of < 0.8. This study showed that our B. pseudomallei strains in Malaysia were mainly heterogenous with no predominant type both in septicemic or localized strains. PMID- 21323174 TI - Drug resistance among Mycobacterium tuberculosis isolates from private clinics and a dots center in Delhi, India. AB - The aim of this study was to ascertain the incidence of drug resistance of Mycobacterium tuberculosis isolates from patients in Delhi, India, being treated with DOTS and in private clinics, since a large proportion of patients with tuberculosis in India seek help from private healthcare sectors. Sputum samples were collected from 60 cases of tuberculosis attending a DOTS center and 42 patients from private clinics. Of these, 35 patients from the DOTS center and 12 patients from private clinics had a second sputum sample collected following two months of therapy. The isolated M. tuberculosis strains were assayed for isoniazid (INH), rifampicin (RIF), streptomycin (SM) and ethambutol (EMB) susceptibility by the proportion method. The frequencies of multidrug resistance (MDR) in the M. tuberculosis strains obtained from those treated with DOTS and in private centers were 12.7% and 5% (p > 0.5), respectively. Isolates obtained after two months of therapy showed a similar rate of MDR (12.5%) at the DOTS center, although the number of patients followed-up at the private centers was small, none of these had MDR after two months of therapy. Future studies including a larger number of patients at private centers are needed to further evaluate the prevalence of drug resistance in M. tuberculosis from private clinics. PMID- 21323175 TI - Evaluation of recombinant Lig antigen-based ELISA for detection of leptospiral antibodies in canine sera. AB - Abstract. The objectives of this study were to clone the conserved region of leptospiral immunoglobulin-like protein (lig) gene and evaluate the utility of the recombinant Lig as an ELISA antigen for detection of leptospiral antibodies in canine sera. Leptospira kirschneri serovar Grippotyposa strain Moskva V was chosen to be a target for cloning the conserved region of Lig gene. This assay was evaluated with canine sera (n = 91) that were MAT-negative (< 1:100 dilution) and sera (n = 103) that were MAT-positive (> or = 1:100 dilution) using 24 serovars. The ELISA showed a relative sensitivity as compared to MAT of 84.5% whereas the specificity was 76.9%. This assay is simple and can be routinely prepared in large amounts. It was concluded that the GST.Lig recombinant protein based ELISA could be used as a screening test for serodiagnosis of canine leptospirosis with also for confirmation of MAT-positive test results. PMID- 21323176 TI - Safety and reactogenicity of DTPa-HBV-IPV/Hib and DTPa-IPV/I-Hib vaccines in a post-marketing surveillance setting. AB - Combination vaccines have been shown to improve the timeliness of vaccination and vaccine coverage. Safety and reactogenicity of combined diphtheria-tetanus acellular pertussis-inactivated poliovirus and Haemophilus influenzae type b vaccine (DTPa-IPV/Hib, Infanrix IPV+Hib, GlaxoSmithKline Biologicals) was assessed in two clinical studies. In Study A, 2,590 subjects received DTPa IPV/Hib at 3, 4 and 5 months of age with a booster at 18 months. In Study B, 702 subjects received the same schedule but with DTPa-hepatitis B-IPV/Hib (DTPa-HBV IPV/Hib, Infanrix hexa, GlaxoSmithKline Biologicals) vaccine administered at 5 months of age. Reactogenicity was assessed for four days after each dose using diary cards. Serious adverse events (SAEs) were assessed until 24 months of age. The vaccines were well tolerated. After primary vaccination, irritability was the most frequently reported grade 3 general symptom (0.8% of doses in both studies). Fever (axillary) > 39 degrees C was infrequent (0.3% of doses in Study A; 0.5% of doses in Study B). After the booster dose, the most frequently reported grade 3 symptom was redness (5%) in Study A and pain (0.5%) in Study B. An axillary temperature > 39 degrees C was reported in 1.1% of subjects. Throughout the study period, 646 SAEs were reported, of which 6 SAEs were considered to be vaccination related. The reactogenicity and safety profile of the combined DTPa-IPV/Hib vaccine was good when used for primary and booster vaccinations in over 3,000 Singaporean infants. Substitution of DTPa-IPV/Hib with DTPa-HBV-IPV/Hib at Month 5 reduced the number of injections required at this age by one. PMID- 21323177 TI - Septicemia, meningitis, and skull osteomyelitis complicating infected cephalhematoma caused by ESBL-producing Escherichia coli. AB - An infected cephalhematoma is a rare condition in neonates. We report a case of an 18-day-old neonate who was diagnosed with an infected cephalhematoma caused by an extended spectrum beta-lactamase (ESBL)-producing Escherichia coli complicated with septicemia, meningitis, and skull osteomyelitis. He was successfully treated with meropenem and surgical incision and drainage. ESBL-producing E. coli may cause infection of a cephalhematoma in neonates. PMID- 21323178 TI - Maternal and child health in a marginalized community along the Thai-Myanmar border. AB - The objective of this study was to conduct a cross-sectional evaluation of pregnancy indicators, child growth failure, and the effect of antenatal care on birth outcomes in a marginalized community under the care of a health center in Suan Phung District, Ratchaburi Province. Health and socioeconomic data about children born in 2007 and their parents were obtained from the sub-district health center and district hospital were collected and analyzed by univariate and multivariate methods. Most of the residents in the study were Karen ethnic origin. Data was available for 152 children, of which 136 met study inclusion criteria. Health outcomes of the study population significantly different from the general Thai population included higher average parity (2.53 +/- 1.99 vs 1.735; p < 0.001), lower average birth weight (2,876.05 +/- 399.48 grams vs 3,200 grams, p < 0.001), and lower average height-for-age and weight-for-age (p < 0.001). The prevalences of stunting, underweight and wasting were higher than the general Thai population (p < 0.001). Having fewer than 4 antenatal care (ANC) visits was associated with low birth weight (unadjusted OR 4.88, 95% CI 1.13 21.05; adjusted OR 5.77, 95% CI 1.27-26.30). PMID- 21323179 TI - Medical faculty and school of health student knowledge of and behavior regarding swine flu and vaccine, in Kahramanmaras, Turkey. AB - This study was carried out to determine Medical Faculty and School of Health student knowledge of and behavior regarding swine flu and vaccine. The study was carried out at Kahramanmaras Sutcuimam University School of Health among the medical faculty and students. All 296 students of the Kahramanmaras Sutcuimam University School of Health and 76 students of the Faculty of Medicine were supposed to participate in the study. Ninety-six point one percent of the students in the study know high fever was one of the symptoms of swine flu, 91.8% said it was spread directly by sneezing or coughing and 95.5% knew washing hands with soap and water especially after coughing and sneezing, should be done to reduce the.risk of infection. Sixty-five point four percent of students knew fatigue and body aches were adverse effects of the swine flu vaccine. Only 9.6% of students received the pandemic flu vaccine. Their knowledge regarding symptoms and methods of spread was low, but regarding measures taken for prevention was high. Both swine flu knowledge and vaccine knowledge were higher in those who received the flu vaccine than in those who did not receive it. In pandemic situations, training should be given immediately to medical, midwifery and nursing students who are models for society. PMID- 21323180 TI - Dissemination of reproductive health knowledge by questions and answers through telephone hotline: a feasibility study in Myanmar. AB - This study was conducted to determine the feasibility of disseminating reproductive health (RH) information to the general public of Myanmar in a confidential, anonymous and interactive way through a telephone hotline. We carried out a cross-sectional study using a short questionnaire interview with the RH hotline callers and analyzing sample audio recordings of conversations. The hotline was advertised in print media. It was answered by trained hotline responders (medical doctors) of Department of Madical Research (Lower Myanmar) (DMR-LM). There were 743 calls during six months, from all 14 States and Divisions. Most of the calls were from Yangon, Mandalay and Bago Division. Both male (48%) and female (52%) callers used the hotline. The majority of callers (74%) were between 25 and 45 years old; 21% were young people (15-25 years old). Married people (81%) used the hotline more than singles (19%). Most of the callers (91%) had a high school to graduate education level. The most frequently asked topics were infertility (23%), birth spacing (22%), sexual problems (13%) and adolescent health, including reproductive function (12%). The anonymity of the callers, the non-judgmental attitudes of the responders and the use of media for publicity appeared to facilitate the use of the hotline by the public. More linkages with service entry points, enhancement of communication skills, sexual counselling training and use of media can improve topic coverage and utilization of the reproductive health hotline. PMID- 21323181 TI - Metabolic syndrome and its relation to chronic kidney disease in a Southeast Asian population. AB - The metabolic syndrome has been documented to increase the risk of cardiovascular disease and chronic kidney disease (CKD); however, there are few studies of this in developing countries. A total of 15,357 participants of a standardized check up, included metabolic screening, were enrolled. Metabolic syndrome was defined using criteria modified from the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) and the International Diabetes Federation (IDF). CKD was defined as a glomerular filtration rate <60 m/min per 1.73 m2. Eighty point four percent of participants were men and 2,228 (14.5%) had CKD. Metabolic syndrome was more prevalent among CKD subjects than non-CKD subjects (modified NCEP-ATP III, 30.1% vs 24.4%; p < 0.001; modified IDF 26.9% vs 23.1%; p < 0.001, respectively). Abdominal obesity, high triglycerides, high blood pressure and impaired fasting glucose were significantly associated with an increased prevalence of CKD. There was also a significant graded relationship between the number of metabolic syndrome components and the prevalence of CKD. Participants with metabolic syndrome according to the modified NCEP-ATP III and modified IDF criteria had a 1.34-fold increase in adjusted odds ratio (95% CI 1.21-1.49) and a 1.20-fold increase in adjusted odds ratio (95% CI 1.08-1.33), respectively, compared to those without metabolic syndrome. Our study demonstrated metabolic syndrome defined with modified NCEP-ATP III and modified IDF criteria was significantly associated with increased prevalence of CKD in a Southeast Asian population. PMID- 21323182 TI - Awareness and practices of self-management and influence factors among individuals with type 2 diabetes in urban community settings in Anhui Province, China. AB - This study aimed to determine the knowledge of diabetes, practices of self management (SM), and potential factors influencing patient knowledge and practices of self-management among individuals with type 2 diabetes in urban Anhui Province, China. A cross-sectional study was conducted between October and November, 2009. Three hundred sixty-five subjects with type 2 diabetes were randomly selected from three urban communities in three seperate cities. An interview was conducted to determine subject knowledge regarding diabetes, practices of self-management, and potential factors influencing this knowledge and these practices of self-management. Fewer than half of subjects (45.6%) had a basic knowledge of diabetes and 49.7% practiced adequate self-management. Significant associations were found between subject knowledge of diabetes and their education level (OR 2.096, 95% CI 1.578-2.784) and the length of disease (OR 1.307, 95% CI 1.016-1.681). Those with good self-management were influenced by greater knowledge, (OR 2.057,95% CI 1.228-3.445), strong self-efficacy in diabetes self-management (OR 1.899, CI 1.253-2.878), and household income (OR 0.537, 95% CI 0.419-0.689). Factors found by univariate analysis regarding self management included: glucose monitoring was influenced by perception of social support (p = 0.006), adherence to medication was influenced by attitude toward self-management (p < 0.001), physical activity was influenced by knowledge (p < 0.01), attitude (p < 0.01), self-efficacy (p < 0.01), and social support (p < 0.01). However, there were no factors significantly related to healthy dietary practices. Our findings show that best performance in self-management is achieved when those with type 2 diabetes have a high degree of knowledge of diabetes, positive attitudes toward diabetes, strong self-efficacy for self-management and perceptions of good social support. PMID- 21323183 TI - Hyperglycemia, glucose intolerance, hypertension and socioeconomic position in eastern Nepal. AB - Abstract. The present study was undertaken to evaluate differences between urban and rural Nepali populations in terms of hyperglycemia, socioeconomic position (SEP) and hypertension, through a community based survey in Sunsari District, eastern Nepal. Blood glucose levels were measured in participants (N = 2,006) S30 years old from urban and rural communities and were classified according to WHO criteria (1998) into normoglycemia (NGY), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and hyperglycemia (HGY). SEP was assessed by structured health interview along with anthropometric measurements and behavioral variables. Hypertension was classified per Joint National Committee (JNC-VII) criteria. Ten point three percent and 11.9% of subjects in this survey (13.3% urban and 11.0% rural) gave a family history and personal history of diabetes mellitus, respectively. Of urban participants (n = 736) with no history of diabetes 70 (9.5%) had HGY and 143 (19.4%) had glucose intolerance (IFG and IGT). Of rural participants (n = 1,270) 114 (9.0%) had HGY and 176 (13.9%) had glucose intolerance. There was an increasing trend in numbers of cases of hyperglycemia and intolerance with increasing age (chi2 198.2, p < 0.001), body mass index (BMI) (chi2 35.1, p < 0.001), SEP (chi2 48.5, p < 0.001) and hypertension (chi2 130.6, p < 0.001). Rural participants had a lower odds ratio [0.706; 95% confidence interval (CI) 0.455-1.096] of having hyperglycemia than urban participants. Individuals with medium and higher SEP had a lower odds ratio (0.878; CI 0.543-1.868) and higher odds ratio (1.405; CI 0.798-2.474), respectively, compared to individuals with lower SEP of having HGY. Both urban and rural populations are at risk for hyperglycemia and glucose intolerance. Individuals having a medium SEP had lower risk of diabetes mellitus than individuals from lower and higher SEP. PMID- 21323184 TI - Risk factors for hypertension among rural Thais. AB - A community based case-control study was conducted to determine the risk factors for hypertension among a rural population in Nakhon Ratchasima Province, Thailand. Seventy-two subjects diagnosed with hypertension (BP > or = 140/ 90 mmHg) were randomly selected. Seventy-two controls with normal blood pressure (BP < 120-80 mmHg) were also randomly selected from the same or nearest house to the subjects. Data collection was carried out in February 2010 using a structured questionnaire. Statistics used were percentages, arithmetic means, standard deviations, odds ratios (OR), adjusted odds ratios (aOR), confidence interval (95% CI) for the OR and logistic regression. After adjusting for the effect of other variables in the study, significant risk factors for hypertension were age > or = 50 years old (aOR 5.67, 95% CI 1.98-16.24), education level of primary school or lower (aOR 8.09, 95% CI 2.17-30.20), occupation of farmer or unemployed (aOR 2.88, 95% CI 1.14-7.30), body mass index 230.0 kg/m2 (aOR 7.43, 95% CI 1.68 32.87), presence of high cholesterol (aOR 11.26, 95% CI 2.55-49.75), and having mild stress to high stress (aOR 5.33, 95% CI 1.45-19.61). Forty percent of the variation in the presence of hypertension is explained by the developed model for the above risk factors. These findings are useful for health education and health promotion program development in order to prevent hypertension among rural Thai populations. PMID- 21323185 TI - Smoking behavior among adolescents in Thailand and Malaysia. AB - The objective of this study was to examine the smoking behavior among adolescents in Thailand and Malaysia. Population-based, national surveys were conducted among 1,704 adolescents between the ages of 13 and 18 from Thailand (n = 927) and Malaysia (n = 777). Respondents were selected using multistage cluster sampling. Respondents were asked to complete self-administered questionnaires. Approximately 5% of Thai and Malaysian adolescents were current smokers, while an additional 8.6% of Thai and 8.1% of Malaysian adolescents reported being beginning smokers. On average, Thai smokers reported first smoking a whole cigarette at 14.6 years old (SD = 1.9), while Malaysian smokers at age 13.9 years (SD = 2.2). More than half of Thai smokers (60.4%) reported they bought cigarettes themselves and 29.9% got cigarettes from friends. In Malaysia, most smokers (68.3%) reported they bought cigarettes themselves, only 20.7% got cigarettes from friends. Seventy-six percent of Thai adolescent smokers smoked factory-made brands as their usual brand compared to 27.7% of Malaysian adolescent smokers. Eight percent of Thai adolescents and 10% of Malaysian adolescents reported smoking hand-rolled cigarettes. Approximately half of Thais and more than 40% of Malaysian smokers reported they tried to quit smoking within the past month. The smoking prevalence of Thai adolescents is close to that of Malaysian adolescents. Factory-made cigarette consumption is an important problem in Thai adolescents and needs to be targeted. PMID- 21323186 TI - Factors related to work ability among Thai workers. AB - This study aimed to examine the factors related to work ability among small and medium enterprise (SME) workers in Thailand. The subjects consisted of 845 males and 1,163 females. They were interviewed regarding personal information, working conditions, health status, job stress and work ability. Their blood pressure, body weight and height were also measured. More than half the subjects reported high job stress. Women had higher job stress than men. The work ability index (WAI) results for managers, supervisors and operators were 42.3, 41.4 and 39.8, respectively. Job control of managers and supervisors was higher than operators. The WAI of females decreased with increasing age for those over age 45 years. Factors related to WAI were mental health, social support at work, depression and age. The results suggest job stress reduction programs should be considered to improve work ability among SME workers. PMID- 21323187 TI - Canaloplasty for pigmentary glaucoma with coexisting conjunctival lymphoma. AB - This case report presents canaloplasty as a bleb-free surgical option for lowering intraocular pressure in cases with postoperative conjunctival scarring. PMID- 21323188 TI - Bilateral Klebsiella pneumoniae (K1 serotype) endogenous endophthalmitis as the presenting sign of disseminated infection. AB - The authors report a rare presentation of bilateral Klebsiella pneumoniae endophthalmitis in an ambulatory patient without other known medical conditions. A 51-year-old Chinese woman presented with severe bilateral reduction in vision, photophobia, pain, and eyelid swelling. Hospital admission and evaluation revealed vitreous, blood, and urine cultures positive for K. pneumoniae (K1 serotype). Additional work-up revealed endocarditis, multiple liver abscesses, brain abscesses, and left lobar pneumonia. The patient underwent multiple bilateral intravitreal antibiotic injections. Ultimate visual acuity was no light perception in both eyes. K. pneumoniae endogenous endophthalmitis is a severe but potentially subclinical disease. Early diagnosis requires a high index of suspicion and recognition of risk factors including Asian ancestry and other sources of systemic infection including, most commonly, liver abscess. PMID- 21323189 TI - Bilateral fluorescein angiographic findings in unilateral Coats' disease. AB - Two patients with clinically unilateral Coats' disease were imaged with fluorescein angiography during an examination under anesthesia. Both patients were found to have abnormal retinal vasculature in their contralateral eye. These findings may represent a previously unrecognized bilateral component of Coats' disease. PMID- 21323191 TI - Assessing nurses' role in postincident review. PMID- 21323190 TI - Echographic evidence of regression of a periocular infantile capillary hemangioma treated with systemic propranolol. AB - This article documents quantitative changes in the size of a periocular capillary hemangioma using sequential echographic testing in a patient receiving off-label treatment with systemic propranolol therapy. The patient presented at 7 weeks old with a right periocular capillary hemangioma. Systemic propranolol therapy was elected. Diagnostic B-scan and quantitative A-scan echography documented the lesion size at presentation as 22.3 mm in greatest dimension. The tumor decreased in size to 20.0 mm after 21/2 weeks of treatment and 16.0 mm after 61/2 weeks of treatment. No adverse side effects have been noted. Echography is an excellent modality for documenting the regression of periocular capillary hemangiomas during treatment with systemic propranolol. PMID- 21323192 TI - Insulin omission. A troubling trend among adolescent girls. PMID- 21323194 TI - Tragedy in Arizona. There's enough blame to go around. PMID- 21323196 TI - Clip & save drug chart: drugs to treat hypertension. PMID- 21323198 TI - Childhood eye problems. PMID- 21323199 TI - Pediatric ophthalmology. PMID- 21323200 TI - A 7-year-old boy with a history of intermittent bloody diarrhea. PMID- 21323201 TI - A 17-year-old adolescent with persistent sore throat. PMID- 21323202 TI - A 6-year-old girl with a lesion on the tongue. Giant cell fibroma of tongue. PMID- 21323203 TI - Effective vision screening of young children in the pediatric office. PMID- 21323204 TI - Pediatric cataract. PMID- 21323205 TI - Amblyopia and strabismus. PMID- 21323206 TI - Treatment of bacterial conjunctivitis in children. PMID- 21323207 TI - Wisdom in old-time self-treatment. PMID- 21323208 TI - The role of the professional supervisor. PMID- 21323209 TI - Presenteeism revisited. A complete review. AB - Presenteeism is defined as employees being present at work but unable to be fully engaged in the work environment. Although presenteeism is pervasive in the workplace, the effects of the condition on employee health and productivity are less well understood. The purpose of this article is to provide a comprehensive review of the concept of presenteeism, including research and management practices. PMID- 21323211 TI - Circadian rhythm disruption. PMID- 21323212 TI - Continuing professional development: taking the broad view. PMID- 21323213 TI - Working within the guidelines: case studies. AB - Both accredited and approved continuing nursing education providers can be challenged by requirements related to using faculty who have relationships with commercial entities, or when managing commercial support or sponsorship. This column presents case studies that can be used to further an understanding of the guidelines for disclosure and for commercial support that comply with the provision of continuing nursing education activities. PMID- 21323214 TI - Using hand-held point and shoot video cameras in clinical education. AB - Clinical educators are challenged to design and implement creative instructional strategies to provide employees with optimal clinical practice learning opportunities. Using hand-held video cameras to capture patient encounters or skills demonstrations involves employees in active learning and can increase dialogue between employees and clinical educators. The video that is created also can be used for evaluation and feedback. Hands-on experiences may energize employees with different talents and styles of learning. PMID- 21323216 TI - An invitation to a conversation on quality of life in dementia. PMID- 21323220 TI - Family preparedness and end-of-life support before the death of a nursing home resident. PMID- 21323222 TI - Intramuscular cyst/ganglion in the supraspinatus. PMID- 21323223 TI - Retraction. Comparison of the mini-midvastus with the mini-medial parapatellar approach in primary TKA. PMID- 21323224 TI - Patient safety in orthopedics: are we doing enough? PMID- 21323225 TI - Isolated avulsion fracture of the fibular head: a new fixation technique using a suture anchor. PMID- 21323226 TI - Minimally invasive trauma surgery. PMID- 21323227 TI - The National Joint Registry of England and Wales. PMID- 21323228 TI - Management of necrotizing fasciitis infections. PMID- 21323229 TI - Anatomic graft placement in ACL surgery: plain radiographs are all we need. PMID- 21323231 TI - Strengths and limitations of standards of care to guide the orthopedic surgeon in VTE prevention. AB - With respect to VTE prevention, several steps can be taken by orthopedic surgeons to ensure the best standard of patient care. All patients should be assessed for VTE risk and appropriate prophylaxis should be provided. Venous thromboembolism prophylaxis guidelines, hospital protocols, and risk assessment models can guide orthopedic surgeons in making individualized decisions. In cases where guidelines offer no direct recommendations, or disagree, standardized care may need to be tempered by clinical judgment and individual patient considerations. Improved health care and better outcomes can be achieved for orthopedic surgery patients by considering VTE prophylaxis from the viewpoint of the clinical guidelines and patient-specific factors. PMID- 21323234 TI - A new beginning. PMID- 21323235 TI - Flap thickness using the moria one use-plus and moria m2 microkeratomes. PMID- 21323236 TI - Access to mental health care among older adults. AB - Many older adults experience common mental health problems that can have a negative impact on physiological health, functional status, and quality of life. Lack of access to mental health care for community-dwelling older adults is a significant problem. Busy primary care practices, few mental health professionals, inadequate problem recognition, and flaws in the health care system all contribute to restricted access to mental health care. As the population of adults 65 and older continues to grow, the need for mental health care for this group will increase. Strategies to improve access to mental health care must be targeted at the individual level, the provider level, and the system level. PMID- 21323237 TI - Polyunsaturated fatty acids. Immunomodulators in older adults. AB - The immune system tends to become less efficient as people age, and nutrition plays a significant role in older adults' immune responses. In particular, dietary fatty acids are precursors to important immune system components. Certain fatty acids, predominantly those that are polyunsaturated, also tend to decrease the risk of certain neurological diseases in older adults. This article describes the impact of dietary polyunsaturated fatty acids (PUFA) on older adults' immune system and discusses the roles of age and immune status with regard to PUFA supplements. PMID- 21323238 TI - Medication adherence and spiritual perspectives among african american older women with hypertension. A qualitative study. AB - The purpose of this qualitative study was to explore how African American older adults use spirituality to adhere to their antihypertensive medications. Data collection included in-depth individual interviews with 21 older African American women. Content analysis revealed five themes: The Lord Helps Those Who Help Themselves; Staying in the Lord for Guidance; God Is My Rock; Guardian Angels and Saints; and Brings Me Peace, Ease of Burdens, and Ability to Cope. Findings of this study suggest that spirituality is perceived as a positive resource that helps study participants adhere to their antihypertensive medication regimen. Possible faith-based interventions for nurses and other health care professionals to use with their patients are discussed. PMID- 21323239 TI - Epithelial thickness up to 26 years after radial keratotomy: three-dimensional display with Artemis very high-frequency digital ultrasound. AB - PURPOSE: To characterize the epithelial thickness profile in a population of eyes after radial keratotomy for myopia. METHODS: The epithelial thickness profile was measured in vivo by Artemis very high-frequency digital ultrasound arc-scanning (ArcScan Inc) across the central 10-mm diameter of the cornea on 14 eyes after radial keratotomy for myopia. Maps of the mean and standard deviation of epithelial thickness were plotted and compared to the epithelial thickness of a previously published population of normal untreated eyes. RESULTS: Ultrasound scanning using the Artemis was performed a mean 16.7+/-5.8 years (range: 1.6 to 26.3 years) after radial keratotomy. The mean epithelial thickness profile showed the epithelium to be thicker centrally and thinner paracentrally, which was different from the population of normal eyes. The mean thickest epithelial thickness was 78.8+/-6.0 MUm (range: 64.8 to 89.6 MUm) and the mean thinnest epithelial thickness was 43.7+/-4.3 MUm (range: 36.1 to 49.3 MUm), which were statistically significantly different from the epithelial thickness at these locations in the population of normal eyes. CONCLUSIONS: Three-dimensional thickness mapping of the epithelial thickness profile demonstrated epithelial changes that compensated in part for the central corneal flattening induced by the radial keratotomy incisions. The fact that epithelial changes were consistent across eyes from approximately 2 to 26 years after radial keratotomy suggests that epithelial changes are a permanent response to corneal curvature changes. PMID- 21323240 TI - Use of a six-dimensional eye-tracker in corneal laser refractive surgery with the SCHWIND AMARIS TotalTech laser. AB - PURPOSE: To evaluate intraoperative six-dimensional (6D) eye movements and postoperative outcomes among aberrated eyes that underwent LASIK treatments with 6D eye-tracking using the SCHWIND AMARIS platform (SCHWIND eye-tech-solutions). METHODS: Thirty-four patients (58 eyes) were enrolled in the study. Standard examinations and pre-and postoperative wavefront analyses with the Ocular Wavefront Analyzer (SCHWIND eye-tech-solutions) were performed. Treatments were planned using the Custom Ablation Manager and ablations (aspheric ablation [35 eyes] and ocular wavefront [23 eyes]) were performed using the SCHWIND AMARIS TotalTech laser. Laser in situ keratomileusis flaps were cut using the LDV femtosecond laser (Ziemer Group) in all cases. Eye movements were evaluated in terms of cyclotorsion, rolling, and axial movements. Clinical outcomes were evaluated in terms of predictability, refractive outcome, safety, wavefront aberration, and contrast sensitivity. RESULTS: Registration rate was 100% for cyclotorsion, and 90% for rolling and axial movements. Static cyclotorsion was within +/-4 degrees in 69% of eyes. Dynamic cyclotorsion was within +/-2 degrees in 72% of eyes. Z-movement was within +/-0.5 mm in 69% of eyes. At 3-month follow-up, 70% of eyes were within +/-0.25 diopters (D) of emmetropia. Mean defocus was -0.12+/-0.17 D and astigmatism was 0.15+/-0.25 D. Corrected distance visual acuity improved in 19% of eyes. CONCLUSIONS: Laser in situ keratomileusis with active compensation of 6D eye-movements with a 6D eye-tracker using the SCHWIND AMARIS is safe, predictable, and yields excellent outcomes. Refraction and higher order aberrations were reduced to subclinical values postoperatively without applying additional nomograms. PMID- 21323241 TI - Phakic intraocular lens implantation for treatment of anisometropia and amblyopia in children: 5-year follow-up. AB - PURPOSE: To evaluate the safety and efficacy during 5-year follow-up of phakic intraocular lens (PIOL) implantation to correct high anisometropia in amblyopic children who were non-compliant with traditional medical treatment including spectacles or contact lenses. METHODS: Retrospective study of 10 eyes of 10 children with high anisometropia who underwent PIOL implantation (9 with an iris supported IOL and 1 with a posterior chamber IOL). Patient age at the time of implantation ranged from 2 to 15 years. Mean preoperative spherical equivalent refraction was -10.14 +/- 6.96 diopters (D) (range: +8.00 to -18.00 D). Mean logMAR corrected distance visual acuity (CDVA) was 0.84 +/- 0.52. Postoperative data at 6, 24, and 60 months were evaluated. RESULTS: Corrected distance visual acuity improved in all children. At 24 months, logMAR CDVA was 0.39 +/- 0.35 and at 5 years was 0.36 +/- 0.38 (range for both: 0.1 to 1.0) (P=.01). Improvement of more than three logMAR lines of CDVA was achieved in all children except for one (one line improvement) who was implanted with a posterior chamber PIOL. No loss of CDVA was detected in any patient. Five years after surgery, endothelial cell count was >2000 cells/mm(2) in eight (80%) patients; for the remaining two patients, one reported frequent eye rubbing and the other suffered ocular trauma. CONCLUSIONS: Phakic IOL implantation in children with anisometropic amblyopia showed a positive long-term impact on visual acuity. PMID- 21323242 TI - Initial visual field as a predictor of recurrence and postoperative visual outcome in children with craniopharyngioma. AB - PURPOSE: The aim of this study was to investigate the significance of the initial visual field as a predictor of recurrence of craniopharyngioma and postoperative visual outcome in children with craniopharyngioma. METHODS: A retrospective analysis was performed on 27 children 15 years of age or younger with craniopharyngioma. Records of clinical features including ocular and systemic symptoms, optic disc findings, and size of the tumor were analyzed according to preoperative visual field. Postoperative visual acuities, visual fields, and recurrence rates were also evaluated. RESULTS: Preoperatively, 13 patients had a normal visual field and 14 patients had various visual field defects. The size of the tumor was not correlated with the preoperative visual field defects (P = .15). Preoperative visual field defects were associated with polyuria and polydipsia (P = .01), higher recurrence (P < .001), and poorer postoperative visual acuities (P < .001). CONCLUSION: Preoperative visual field can be a reliable clinical indicator of systemic manifestations, recurrence, and postoperative visual outcome in children with craniopharyngioma. PMID- 21323243 TI - Underacting inferior oblique muscle following myectomy or recession for unilateral inferior oblique overaction. AB - PURPOSE: To assess the incidence and investigate the functional impact of postoperative overcorrection following primary unilateral inferior oblique muscle recession and myectomy for inferior oblique overaction. METHODS: A retrospective study of 79 consecutive patients undergoing inferior oblique myectomy (43) or recession (36) with a minimum 6 months of postoperative follow-up. All underwent ocular motility examinations preoperatively and postoperatively at approximately 2 weeks and 6 months. The vertical deviation in primary position and on contralateral gaze and inferior oblique versions and ductions on contralateral elevation were analyzed. RESULTS: At 6 months, 51 patients had no inferior oblique underaction (group 1), 23 of 28 who had developed inferior oblique underaction were asymptomatic (group 2), and the remaining 5 were symptomatic (group 3). The mean preoperative hyperdeviation was 12.9 (group 1), 13.1 (group 2), and 15 (group 3) prism diopters (PD) in primary position. Postoperatively, these measured 3.8 (group 1), 3.8 (group 2), and -7.8 (group 3) PD (- indicates deviation reversal). The mean preoperative and postoperative inferior oblique versions for these three groups were +2.7, +2.2, +2.2 units and +0.9, -1.0, -1.4 units, respectively. CONCLUSION: Inferior oblique underaction was common (28 patients, 35.4%), generally mild, persistent, and usually asymptomatic 6 months following surgery. Although uncommon (5 patients, 6.3%), symptomatic inferior oblique underaction required further surgery with a successful outcome. They included 2 patients with a history of head or orbital trauma and one with masked and one with highly asymmetric bilateral inferior oblique overaction. PMID- 21323245 TI - Predictors of turnover intention in nurse faculty. AB - Turnover of nurse faculty is an increasingly important issue in nursing as the available number of qualified faculty continues to decrease. Understanding the factors that contribute to turnover is important to academic administrators to retain and recruit qualified nursing faculty. The purpose of this study was to examine predictors of turnover intention in nurse faculty working in departments and schools of nursing in Carnegie Doctoral/Research Universities-Extensive, public and private, not-for-profit institutions. The multidimensional model of organizational commitment was used to frame this study. The predictor variables explored were organizational climate, organizational commitment, work role balance, role ambiguity, and role conflict. The work roles examined were research, teaching, and service. Logistical regression was performed to examine the predictors of turnover intention. Organizational climate intimacy and disengagement, affective and continuance organizational commitment, and role ambiguity were shown to predict turnover intention in nurse faculty. PMID- 21323244 TI - Screening for retinopathy of prematurity in a tertiary hospital in Istanbul: incidence and risk factors. AB - PURPOSE: To study the incidence and risk factors of retinopathy of prematurity (ROP) in premature infants examined in a tertiary hospital in Istanbul. METHODS: Data of infants screened for ROP from April 2007 to September 2009 were retrospectively reviewed. Possible risk factors and eye examinations were recorded and analyzed using the chi-square test and univariate and multivariate regressions. RESULTS: ROP was detected in 177 (34.3%) of the 517 infants enrolled in the study; 64 had mild ROP (77.4%) and 38 had severe ROP (22.6%). The mean gestational age and birth weight of patients who were treated for ROP were 28.6 +/- 2.3 and 1,143.5 +/- 337.4, respectively. Two of these infants had a gestational age of 32 g or greater and three had a birth weight of 1,500 g or greater. The multivariate regression analyses showed gestational age, birth weight, sepsis, respiratory distress syndrome, and length of oxygen therapy as independent predictors of ROP. CONCLUSION: The incidence of ROP observed in this study was higher than that in developed countries and relatively more mature infants were affected. Criteria including gestational age of less than 34 weeks or birth weight of less than 2,000 g would have identified all infants who were at risk. PMID- 21323246 TI - Effectiveness of cultural immersion and culture classes for enhancing nursing students' transcultural self-efficacy. AB - With diversity increasing in the United States, educators are struggling to find the most effective methods to prepare nursing students to care for diverse populations. This study's purpose was to determine the impact of immersion experiences and cultural classes on nursing students' transcultural competence. A pretest-posttest, quasi-experimental design was used. Nursing students completing a 2-week to 3-week immersion experience (n = 14) completed the Transcultural Self Efficacy Tool online 1 week prior to and immediately following an immersion experience. The control group (n = 25), who were students not participating in an immersion experience, completed the instrument during the same time frame. Students who participated in an immersion experience had significantly higher posttest transcultural self-efficacy scores (p < 0.001). Compared with the control group, the students in the immersion group had significantly higher change scores (p < 0.001). In addition, the number of culture classes completed was not correlated with transcultural self-efficacy scores. Recommendations included encouraging student participation in immersion experiences to enhance transcultural competence. PMID- 21323247 TI - Cognitive tools as a scaffold for faculty during curriculum redesign. AB - During an intensive curriculum redesign process, a variety of cognitive tools were developed to support faculty. Cognitive tools served as a form of support for thinking on the individual task level and metacognitive level, as well as on the group sociocommunicative level. Using cognitive tools in collaboration with a group allowed faculty with varying levels of expertise and experience to contribute in valuable ways to social knowledge construction. Recommendations for developing and using cognitive tools in faculty workplace learning situations are included. PMID- 21323248 TI - Improving nursing students' breast cancer knowledge through a novel academic and non-profit foundation partnership. AB - The unique partnership between an affiliate of the Susan G. Komen for the Cure((c)) foundation and a school of nursing offered faculty the ability to creatively inject breast cancer content into the baccalaureate curriculum. In house breast cancer experts and external consultants developed seven breast cancer-specific educational Web-based modules to supplement a packed curriculum taught by generalists in a cost-efficient manner. Easily integrated into the baccalaureate program, these modules provided evidence-based breast cancer content to nursing students. Following completion of the modules, baccalaureate students' knowledge of breast cancer improved. PMID- 21323249 TI - Thinking beyond "the wheelchair to the car": RN-to-BSN student understanding of community and public health nursing. AB - The purpose of this study was to explore the online discussions of postlicensure nursing students taking a community health course in an RN-to-BSN program. Final discussion forums asked students to share their perceptions and understandings of the public and community health nurses' role and practice after participating in a community health clinical course. Inductive content analysis was used to assess the narratives. Analysis of the discussions yielded two categories: (1) awareness by the RNs of their individual community and the context of the public and community health nursing role, and (2) increased understanding of the patients' experience with transitions between health care settings (home-hospital-home). This research suggests a need to assess practicing RNs' professional understanding and teaching of the public and community health nurses' role if they are to facilitate effective patient transitions home and into community based settings. PMID- 21323250 TI - Changes in stress and nurse self-concept among baccalaureate nursing students. AB - This pilot study's purpose was to investigate the relationship between stress and nurse self-concept. Specifically, it examined whether enrollment in a wellness course affected stress levels and self-concept acquisition among sophomore baccalaureate nursing students (N = 52). The findings showed that early in the curriculum these students had a fairly well developed sense of professional self concept but made gains in facets of leadership and communication over the course of the semester. Students demonstrated high levels of stress that remained unchanged over the semester, regardless of self-concept acquisition. This study concluded that enrollment in a wellness course was insufficient to prepare nursing students to manage stress as they transition to professional roles, and it was possible that undergraduate education perpetuated the internalization of stress as part of a nurse's professional identity. Future studies are needed to determine effective ways to teach stress management and best design nursing curricula to reduce stressors. PMID- 21323251 TI - Nursing students' anxiety and clinical performance. AB - This study examined how mood states affect nursing students' performance on a treatment procedure consisting of a novel combination of familiar clinical steps. Thirty third-year and fourth-year nursing students were first taught the procedure and then given both an anxious-mood and a calm-mood induction in a randomly assigned counterbalanced order. Anxiety was induced by showing a video of interviews with frontline nurses and doctors during the severe acute respiratory syndrome epidemic in Hong Kong, China; calmness was induced by a video of a nursing student's pleasant orientation to a clinical placement site. Nursing students were significantly less proficient in performing the newly acquired procedure after an anxious-mood induction (focused on occupational risks) than after a calm-mood induction. Therefore, managing clinical training site anxiety among nursing students may help to optimize learning and clinical performance. PMID- 21323252 TI - Impact of double testing on student knowledge in a professional issues course. AB - Collaborative testing, allowing students to work together on the completion of an examination, is used in a wide variety of disciplines. This study examines the impact of this testing technique on knowledge of students in an undergraduate Health Care Issues, Policy and Economics course. Results indicate that although this approach does not increase student knowledge to a statistically significant level, it does increase individual student scores. This increase in examination scores may be of significance to the learner. PMID- 21323253 TI - Hmong American women crossing borders in nursing education: two case studies. AB - The Hmong population in the United States is rapidly growing. Cultural differences between this population and the American health care system lead to health disparities. These differences are exacerbated by the shortage of Hmong American nurses. The shortage may be related to difficulty in navigating the U.S. education system. The purpose of this study was to examine the perceived impact of Hmong culture on Hmong American women's nursing education. Data analysis identified four themes that were confirmed by participants: support factors, entrepreneurism, positive outcomes, and cultural expectations. On the basis of these themes, schools of nursing can positively influence Hmong American women's education by providing information sessions for their families regarding school expectations, allowing flexibility in meeting course requirements, increasing the number of Hmong and minority faculty members, and providing language assessment and support programs for English language learners. PMID- 21323254 TI - Nursing students' experiences with incivility in clinical education. AB - This qualitative study aimed to explore the experiences of nursing students as targets of incivility in clinical settings, to describe their perceptions of specific uncivil and favorable behaviors by nurses, and to examine how nursing students think schools of nursing should address incivility in clinical settings. Four focus groups were conducted comprising 21 prelicensure nursing students. Data were collected with semi-structured interviews. Uncivil behaviors fell into three themes: exclusionary, hostile or rude, and dismissive. Positive experiences occurred when students felt included by the staff nurses in patient care. Schools of nursing should prepare students through discussion. Our research suggests that incivility occurs in clinical education. Further research on a larger scale is needed to provide qualitative and generalizable findings. All health care team members, including students, should be educated about the organization's code of conduct. PMID- 21323255 TI - Effects of peer review on communication skills and learning motivation among nursing students. AB - The purpose of this study was to investigate the effects of video-based peer review on communication skills and learning motivation among nursing students. A non-equivalent control with pretest-posttest design was used. The participants were 47 sophomore nursing students taking a fundamentals of nursing course at a nursing college in Korea. Communication with a standardized patient was videotaped for evaluation. The intervention group used peer reviews to evaluate the videotaped performance; a small group of four students watched the videotape of each student and then provided feedback. The control group assessed themselves alone after watching their own videos. Communication skills and learning motivation were measured. The intervention group showed significantly higher communication skills and learning motivation after the intervention than did the control group. The findings suggest that peer review is an effective learning method for nursing students to improve their communication skills and increase their motivation to learn. PMID- 21323256 TI - Emotional connection and integration: dominant themes among undergraduate nursing students using a virtual community. AB - The use of virtual communities is an emerging pedagogical application that enhances student learning in nursing education. This study involved a sample of 40 undergraduate students enrolled in a baccalaureate nursing program using The Neighborhood as a teaching application across the curriculum. The students were followed over three successive semesters. Using the qualitative method of content analysis, student responses generated by open-ended questions were grouped and analyzed to identify major themes. Analysis of the data revealed two primary themes: (1) an emotional connection to specific characters or families, and (2) integration of characters and events into learning activities. Student feedback indicated that virtual communities provide a viable strategy for teaching nursing concepts and their application. PMID- 21323257 TI - Narrative pedagogy and art interpretation. AB - Contemporary practices in nursing education call for changes that will assist students in understanding a complex, rapidly changing world. Narrative pedagogy is an approach that offers teachers a way to actively engage students in the process of teaching and learning. The narrative approach provides ways to think critically, make connections, and ask questions to gain understanding through dialogue. The hermeneutic circle of understanding offers a way to interpret stories and discover meaning. Narratives exist in art forms that can be interpreted to evoke discussions and thinking that relate to nursing practice. Art interpretation is a way to gain access to others and acquire a deeper appreciation for multiple perspectives in the teaching-learning process. PMID- 21323258 TI - Nursing students' leadership and emotional intelligence in Turkey. AB - The purpose of this study was to determine nursing students' leadership and emotional intelligence. The study was conducted as a descriptive study in a nursing school in 2008. The sample comprised 69 junior and 85 senior nursing students and was based on voluntary participation. Data were collected through a data sheet, a leadership style questionnaire, and the Bar-On Emotional Intelligence Quotient Inventory. There were no statistically significant differences in leadership orientations and emotional intelligence between junior and senior students (p > 0.05). Although there was a significant relationship between emotional intelligence and task-oriented leadership (r = 0.427, p = 0.001), there was no significant relationship between emotional intelligence and people-oriented leadership (r = 0.076, p = 0.367). Students' emotional intelligence score was average, and their people-oriented leadership score was approximately half of the total score. It is recommended to develop strategies for improving nursing students' people-oriented leadership skills during their nursing education. PMID- 21323259 TI - Effect of ophthalmic examination procedures on the quality of spectral domain OCT images. AB - The authors compare the image quality of spectral domain optical coherence tomography (OCT) images in eyes before and after routine ophthalmic screening procedures. The study population in this prospective case series included 24 patients (45 eyes). No significant difference in OCT scan quality factor was found in the study population pre-screening and post-screening (P > .05 for the horizontal, vertical, and raster pattern scans performed in each OCT scan series). Routine ophthalmic screening procedures do not affect the quality of spectral domain OCT images. PMID- 21323260 TI - Macular hole secondary to X-linked juvenile retinoschisis. AB - The authors describe a rare case of full-thickness macular hole formation in a 10 year-old boy with X-linked juvenile retinoschisis. PMID- 21323261 TI - Macular thinning associated with unilateral optic nerve hypoplasia. AB - The authors present the case of an 8-year-old boy with a long-term diagnosis of unilateral optic nerve hypoplasia (ONH) of unknown cause in the right eye. Spectral-domain optical coherence tomography (SD-OCT) of the central macula was consistent with hypoplasia greatest in the inner retinal layers, but also involving the outer retinal layers when compared with the unaffected contralateral eye. Although ONH is commonly associated with hypoplasia of the nerve fiber and ganglion cell layers, it can also be associated with hypoplasia of other layers in the inner and outer retina, including the outer nuclear and photoreceptor inner/outer segment layers, as evidenced by SD-OCT. PMID- 21323262 TI - Successful aging: choosing wisdom over despair. AB - This article defines wisdom and despair as choices for cognitively intact older adults. Some individuals are able to integrate the conditions of old age while others respond in ways that inhibit effective integration. The conscious aging theory, as well as Erikson's developmental theory regarding achievement of integrity/wisdom, provides a theoretical basis for exploration of this topic. Constructs of personality, including self-concept, self-acceptance, destiny control, interiority, rigidity, and flexibility, are described. Finally, guidelines for nurses working with older adults who are facing this developmental stage of life are provided. PMID- 21323263 TI - Vilazodone: another novel atypical antidepressant drug. AB - This article reviews the novel atypical antidepressant drug vilazodone (Viibryd(TM)), which was approved by the U.S. Food and Drug Administration in January 2011 for the treatment of major depression. Vilazodone is a dual-acting antidepressant drug, with a primary mechanism of action of blocking the serotonin reuptake transporter together with acting as a 5-HT1A receptor partial agonist. The antidepressant efficacy of vilazodone was established in two 8-week placebo controlled studies. One long-term (52-week) open-label study has been conducted. The most common side effects are diarrhea, nausea, and headache. The drug has not been studied in pediatric patients or well studied in patients older than 65. Vilazodone is efficacious, safe, and well tolerated, but does not appear to have major efficacy advantages compared with other antidepressant drugs. However, because of its unique pharmacology and relatively benign tolerability profile, it may be a more effective alternative for patients who do not respond to or cannot tolerate currently available antidepressant drugs. PMID- 21323264 TI - Neuropsychiatric complications of traumatic brain injury. AB - Traumatic brain injury (TBI) may be defined as any extracranial mechanical force to the brain that results in any period of loss of consciousness, any loss of memory for events immediately before or after the event, or any alteration in mental status at the time of the event. The major causes are automobile accidents, falls, sporting injuries, and assaults. Many soldiers returning from combat in Afghanistan and Iraq have also experienced TBI. This article provides an overview of the neuropsychiatric complications of TBI, including impairment of consciousness, posttraumatic amnesia, cognitive disorders and dementia, posttraumatic epilepsy, aphasia, depression, mania, psychosis, anxiety disorders, personality changes, aggression, behavioral dyscontrol, fatigue/apathy, and increased risk of suicide. Discussion will focus primarily on issues affecting mental health clinicians. Because mental health providers are more involved in care of chronic issues related to TBI, these issues will be discussed in more detail, although acute neuropsychiatric complications of TBI will be briefly explained. PMID- 21323265 TI - Gender differences in the roles and functions of inpatient psychiatric nurses. AB - This study explored the difference between male and female psychiatric nurses' job performance and job satisfaction levels on an acute care inpatient unit. The amount of time male (n = 28) and female (n = 45) nurses spent on 10 specific functions and roles during a shift were observed and recorded. The nurses also self-rated the amount of time they spent on these specific functions and roles. The observed and self-rated functions were then correlated with job satisfaction. Female nurses were observed and self-rated as spending significantly more time on patient care activities, and these activities were significantly correlated with higher job satisfaction levels. Male nurses who self-rated spending more time on patient care activities had significantly lower job satisfaction scores. Findings confirm the concepts from social role theory that gender identity and expectations influence job performance in psychiatric nursing. The results offer insight for increasing job satisfaction and recruitment/retention efforts. PMID- 21323266 TI - The experiences of youth serving as caregivers for mentally ill parents: a background review of the literature. AB - Young caregivers of mentally ill parents are a vulnerable population. These vulnerabilities include risks for developmental issues, poor socialization, and poor school performance. The purpose of this background review of the literature is to explore the experiences of young caregivers of mentally ill parents and detect the gaps in the literature. The guiding research questions were: What is the experience of young caregivers of mentally ill parents? and What is the experience for those who witness or must assist their parent during a crisis? The majority of research has been conducted outside the United States, primarily in the United Kingdom, and studies have focused mostly on young caregivers of parents with physical rather than mental illness. No studies focused on young caregivers who witnessed or assisted their mentally ill parent in crisis. Information gained through this review will add to the body of knowledge for child mental health and build a case for additional research. PMID- 21323267 TI - The scleral buckling of primary rhegmatogenous retinal detachment under the surgical microscope. AB - BACKGROUND AND OBJECTIVE: To analyze the feasibility of performing scleral buckle under the surgical microscope without using the indirect ophthalmoscope. PATIENTS AND METHODS: Data came from 342 eyes of 339 patients with primary rhegmatogenous retinal detachment (RRD) that were suitable for scleral buckling. All surgeries were performed under the surgical microscope including examination and localization of retinal breaks, scleral buckling, and retinal cryotherapy. RESULTS: During intraoperative examination, additional retinal breaks were found in 39 cases. Among 36 eyes in which a retinal break was not observed pre operatively, 23 cases had retinal breaks detected during surgery. The anatomic success rate after one operation was 88.9% and the final success rate was 98.0%. CONCLUSION: Scleral buckling of RRD with equatorial or pre-equatorial breaks can be easily done under the surgical microscope, which has the merits that the surgeon's view is a clear upright image, manipulations are simple, and good surgical results can be obtained. PMID- 21323268 TI - Laser tube ligature release following aqueous shunt implantation in young children. AB - The implantation of non-valved aqueous shunting devices in children is often complicated by intraocular pressure elevation in the early postoperative period, during which time the tube is closed with a temporary suture ligature to avoid hypotony. Release of a polyglactin suture ligature using conventional laser lysis is not possible in young children in the clinic setting. The authors describe a minimally invasive technique using a portable green diode (532-nm) laser delivered through a standard endoprobe and a Hoskins laser suture lysis lens to disrupt a polyglactin suture ligature following pars plana aqueous shunt implantation in a young child. PMID- 21323269 TI - Microcoaxial torsional cataract surgery 1.8 mm versus 2.2 mm: functional and morphological assessment. AB - BACKGROUND AND OBJECTIVE: To compare functional and morphological outcomes of 1.8 mm versus 2.2-mm microincision coaxial cataract surgery (MCCS). PATIENTS AND METHODS: Thirty eyes of 30 patients that underwent MCCS were randomized to two groups: 1.8-mm MCCS (group 1: 15 eyes) and 2.2-mm MCCS (group 2: 15 eyes). RESULTS: There were no significant between-group differences in uncorrected visual acuity, best-corrected visual acuity, keratometric astigmatism, and endothelial cell count. One day postoperatively, a greater increase of corneal thickness at the incision site was observed in group 1 compared to group 2 using anterior segment optical coherence tomography with no significant differences in tunnel morphometric features and confocal microscopy showed more tunnel edema in group 1 versus group 2 that resolved in both groups. CONCLUSION: Both 1.8- and 2.2-mm torsional MCCS were safe and efficient with easy surgical maneuvers and excellent functional and morphological results; 1.8-mm MCCS induced slightly greater tunnel edema shortly after surgery that resolved in the medium term. PMID- 21323270 TI - Changes in the intraocular pressure of fellow untreated eyes following uncomplicated trabeculectomy. AB - BACKGROUND AND OBJECTIVE: Previous studies have reported changes in the intraocular pressure (IOP) of fellow eyes following unilateral trabeculectomy or selective laser trabeculoplasty. This study evaluates changes in the IOP of fellow eyes following unilateral trabeculectomy and examines correlations of findings with clinical information. PATIENTS AND METHODS: Sixty-one patients who underwent unilateral uncomplicated trabeculectomy were included. The IOP of both eyes was recorded on postoperative days 2, 3, 4, 15, 30, 60, and 90. Differences between preoperative and postoperative IOP in both eyes and correlations with clinical parameters were examined. RESULTS: The IOP of the fellow eyes was significantly reduced on the fourth postoperative day. This reduction was significantly correlated (inversely) with central corneal thickness of fellow eyes and with the level of IOP reduction to the operated eyes. CONCLUSION: The IOP of the fellow eyes remains largely unchanged during the first 3 months following trabeculectomy. However, a significant short-term reduction is noted on the fourth day, implying that unknown (possibly neurocrine) mechanisms may participate in the regulation of the IOP of fellow eyes. PMID- 21323271 TI - Protective effect of different ophthalmic viscosurgical devices on corneal endothelium during severe phacoemulsification model in rabbits. AB - BACKGROUND AND OBJECTIVE: To evaluate the protective effect of different ophthalmic viscosurgical devices (OVDs) on corneal endothelial cells against relatively severe phacoemulsification damage in a rabbit model. MATERIALS AND METHODS: Twenty-four rabbit eyes were randomly assigned to four similar groups: in three groups the aqueous humor was completely replaced by Visiol (TRB CHEMEDICA, Munchen, Germany), Biolon (Bio-Technology General Ltd., Kiryat Malachi, Israel), and Viscoat (Alcon, Puurs, Belgium) and in the control group no OVD was applied. Endothelial cell counts were performed prior to initiating the study. All eyes were exposed to continuous 5 minutes of phacoemulsification. Endothelial cell counts were repeated 4 days postoperatively. RESULTS: Viscoat showed the highest endothelial cell loss (30%), followed by Biolon (25%), Visiol (22%), and the control group (19%). None of the differences between the groups were found to be statistically significant, although they were within each group (P = .028). CONCLUSION: None of the tested OVDs demonstrated protective effect on corneal endothelial cells in comparison to the control group. This model was found to be too aggressive for the demonstration of the protective effect of different OVDs even for hard cataract. PMID- 21323272 TI - Total hip arthroplasty with ceramic-on-ceramic bearing failure from third-body wear. AB - This article describes a new mechanism of failure of a ceramic-on-ceramic total hip arthroplasty (THA) due to fretting corrosion and failure of the Morse taper. A 46-year-old man with hip osteonecrosis underwent THA in 2006. A ceramic-on ceramic, un-cemented THA with a titanium femoral component and metal-on-ceramic Morse taper was implanted. Two years postoperatively, he presented with swelling in his groin and a painless medial thigh mass. The thigh mass was diagnosed as an abscess. Incision and drainage was performed and resulted in a sinus tract that continuously drained copious amounts of seropurulent fluid. Two months later, the patient underwent irrigation, debridement, and explantation of his hip. Frozen sections showed no signs of infection. There was dramatic visible wear of the Morse taper and pieces of metal embedded in the ceramic. Permanent sections showed chronic inflammation and foreign body reaction. He subsequently underwent an uneventful re-implantation with a metal-on-highly-cross-linked-polyethylene THA. In this case, failure of the morse taper led to metal debris, which reacted with the ceramic and caused dramatic third-body wear. The thigh mass, which appeared to be an infection, proved to be a massive foreign body granuloma. Malfunction of the morse taper as reported in this case represents a possible failure mechanism of a ceramic-on-ceramic THA. PMID- 21323273 TI - Rupture of small finger flexor tendons secondary to asymptomatic nonunion of the hamate hook. AB - The incidence of fractures of the hamate hook (hamulus) has been reported to be between 2% and 4% of all carpal fractures. Untreated hamulus nonunion can cause attritional rupture of the ulnar digits' flexor digitorum profundum tendons. Rupture of flexor tendons due to nonunion of the hook of the hamate is an uncommon injury. Most surgeons treat the tendon lesion by a graft, transfer of the superficial flexor of the ring finger, or terminolateral suture of the distal stump of the deep flexor tendon of the little finger to the deep flexor tendon of the ring finger. This article reports a case of a 52-year-old right-handed man who presented with weakness of grip and loss of active flexion of both distal and proximal interphalangeal joints of the right small finger lasting 2 weeks due to grip strength while working. The clinical history and the physical examination were dissonant, and a computed tomography scan revealed a nonunion of the hamulus. Intraoperatively, the nonunion of the hamate hook was identified and the bony ossicle excised. The flexor digitorum profundus and superficialis to the small finger were both ruptured. The flexor digitorum profundus tendon was repaired with a termino-terminal suture. The patient returned to work within 3 months without restriction. Six months postoperatively, the patient had no pain and achieved full active flexion of the small finger. PMID- 21323274 TI - Arthroscopic treatment of a PCL avulsion fracture in a skeletally immature patient. AB - Posterior cruciate ligament (PCL) avulsions from the tibial attachment site in children are rare. Six cases have been reported in the English literature since 1975. Osteochondral avulsions of the PCL can be easily missed on plain radiographs in skeletally immature patients because of the rarity of these injuries and open proximal tibial physis. To properly recognize and treat the condition, careful physical examination and adequate imaging studies are crucial. Few case reports demonstrate successful surgical treatment of the injury using screw fixation. This article presents a case of a 13-year-old girl with tibial avulsion of the PCL treated by arthroscopic reduction and pull-out suture, sparing the epiphyseal plate using a posterior transseptal portal. The proximal substance of the avulsed PCL was grasped with a suture hook introduced from posterolateral to posteromedial rather than through the small, fragmented bony portion. The suture material was passed and retrieved through the bony tunnel from posterior to anterior above the epiphyseal plate. Although it has not been proven yet in terms of biomechanical benefit, we believe this alternative treatment to PCL avulsion injuries in skeletally immature patients will provide sufficient strength to maintain ligament tension during the healing process and avoid physeal injury. PMID- 21323275 TI - Anomalies of the discoid medial meniscus. AB - Anomalies associated with a discoid medial meniscus have been described. However, the clinical relevance of these anomalies has not been previously reported. Therefore, we report the clinical relevance of some of these anomalies based on our experience with a 21-year-old soldier with a 3-month history of medial right knee pain. Magnetic resonance imaging (MRI) revealed bilateral discoid medial menisci, cupping of the medial tibial plateau, and an abnormal anteroinferior transposition of the anterior horn of the meniscus. Partial meniscectomy was performed in the usual manner and the meniscus reshaped, including its anteromedial corner. PMID- 21323276 TI - Recurrent shoulder instability and arthritis treated with graft jacket resurfacing, hemiarthroplasty, and bone grafting. AB - The treatment of recurrent shoulder instability in the presence of large bony defects of the glenoid and/or the humeral head is evolving. The young patient with significant glenohumeral arthrosis presents unique challenges in terms of management. In the presence of large glenohumeral bony defects, several authors have reported poor outcomes with attempted soft tissue stabilization only. Therefore, some type of bony reconstruction is generally recommended. Glenohumeral arthrosis is a known complication of recurrent shoulder dislocation. The role of arthroplasty and glenoid resurfacing options in young patients is controversial given the demands in this group. This article presents a case of a 35-year-old patient who presented with coexisting bony defects-an engaging Hill Sachs defect and a bony Bankart defect causing recurrent shoulder instability-and post-dislocation glenohumeral arthritis with resultant pain. He underwent a humeral hemiarthroplasty, glenoid structural bone grafting, and a glenoid graft jacket. At 2-year follow-up, he reported a favorable outcome. This case represents an encouraging treatment approach for a young patient with recurrent instability caused by coexisting bony defects and significant arthrosis. PMID- 21323277 TI - Symptomatic intratendinous ganglion cyst of the patellar tendon. AB - Ganglion cysts have been previously described throughout the body, most commonly about the wrist, hand, knee, ankle, and feet. When symptomatic, they may interfere with joint mechanics, resulting in snapping, catching, and locking. Intratendinous ganglion cysts lack a synovial epithelial lining and are thought to develop from the mucoid degeneration of connective tissue caused by chronic irritation, chronic repetitive injury, and chronic ischemia. On magnetic resonance imaging, ganglion cysts originating from tendons, ligaments, tendon sheaths, menisci, or joint capsules appear as well-defined lobulated masses that follow simple or complex fluid signal intensity on all pulse sequences, with enhancing walls and internal septations on post-contrast images. There may be appreciable degeneration and partial tearing of the structure of origin, particularly if associated with tendons. On ultrasonography, they present as hypoechoic masses, with internal septations and lobulations of varying sizes, without significant vascularity on power or color Doppler sampling. A thin fluid neck extending from the structure of origin (tail sign), when present, is a reliable sign of a ganglion cyst. This article describes a sonographically guided technique to treat symptomatic ganglion cysts within the patellar tendon. Complete evacuation of the ganglion cyst, with disappearance of the tail sign, is considered the determining factor for a successful procedure. A similar technique can be used for the treatment of other symptomatic intratendinous ganglion cysts elsewhere in the body. To our knowledge, symptomatic intratendinous ganglion cysts within the patellar tendon and their treatment have not been previously reported. PMID- 21323278 TI - Hoffa fracture in a 14-year-old. AB - Coronal shear fractures of the femoral condyle (ie, Hoffa fracture) are an uncommon clinical entity typically seen in adults after higher-energy trauma. Historically poor outcomes have been reported in the literature with nonoperative treatment of these fractures. Conversely, open reduction and internal fixation of these fractures has been shown to produce good long-term clinical results in adults. These fractures appear to be even more uncommon in skeletally immature patients, with only 3 case reports documented in the literature to date. Two of the 3 cases presented as a symptomatic nonunion after initial nonoperative treatment. Herein we present a case report of a Hoffa fracture of the lateral femoral condyle in a 14-year-old boy after a wrestling injury. The fracture was treated with diagnostic arthroscopy followed by conversion to an arthrotomy for open reduction and internal fixation. Rigid fixation of the fracture was obtained with 4 headless compression screws. Twelve months postoperatively, the fracture was radiographically healed and the patient was pain free with restoration of full knee motion and return to sporting activity. The Hoffa fracture is a unique and relatively uncommon clinical entity that has a different personality than other intra-articular fractures of the knee in both adults and children. Instability of the fracture fragment can lead to a higher likelihood of nonunion with persistent pain and disability. These fractures should be treated with open reduction and internal fixation to achieve anatomic reduction with stable fixation and preservation of the blood supply to achieve early, active mobilization. We believe this optimizes the chance for good long-term functional results. PMID- 21323279 TI - Neglected patellar tendon rupture: preserve the fat pad. AB - Management of neglected patellar tendon ruptures remains a difficult therapeutic endeavor, as complications such as adhesions, proximal patellar migration, and quadriceps contracture occur. Treatment goals include restoration of extensor mechanism, both structurally and functionally, which allows active knee extension. Few cases of neglected patellar tendon rupture have been reported in the literature, however, all have used preoperative or additional intraoperative procedures to relocate the patella or to provide additional support to the reconstructed tendon. This article presents a case of a 25-year-old man whose diagnosis of patellar tendon rupture was delayed by 1 year. The patella was mobile and could be brought down to its original position manually. The patellar tendon was successfully reconstructed with autogenous semitendinosus and gracilis tendon graft. No preoperative or intraoperative traction was used on the patella. Quadriceps lengthening was not performed and no hardware was used between the patella and the tibia to augment the reconstruction. Scar tissue was not excised and was used to cover the hamstring tendons. The patient achieved a good functional result after 5 months of rehabilitation. At 14-month follow-up, the patient had returned to his pre-injury level of work with no deterioration of knee function. PMID- 21323280 TI - Bilateral, atraumatic, proximal tibiofibular joint instability. AB - Dislocation of the tibiofibular joint is rare and usually results from a traumatic event. Only 1 case of atraumatic proximal tibiofibular joint instability in a 14-year-old girl has been reported in the literature, however this condition might occur more frequently than once thought. A wide range of treatment options exist for tibiofibular dislocations. Currently, the first choice is a conservative approach, and when this fails, surgical means such as resection of the fibula head, arthrodesis, and reconstruction are considered. However, no consensus exists on the most effective treatment. This article reports a unique case of bilateral, atraumatic, proximal tibia and fibular joint instability involving a 30-year-old man with a 20-year history of pain and laxity in the right knee. The patient had no trauma to his knees; he reported 2 immediate family members with similar complaints, which suggests that this case is likely congenital. After conservative approaches proved to be ineffective, the patient underwent capsular reconstruction using free autologous gracilis tendon. At 6-month postoperative follow-up, the patient was pain free with no locking and instability. He then underwent surgery on the left knee. At 1-year follow-up after the second surgery, the patient had no symptoms or restrictions in mobility. We provide an alternative surgical approach to arthrodesis and resection for the treatment of chronic proximal tibiofibular instability. In the treatment of chronic tibiofibular instability, we believe that reconstruction of the tibiofibular joint is a safe and effective choice. PMID- 21323281 TI - Upper-extremity deep venous thrombosis following humeral shaft fracture. AB - Upper-extremity deep venous thrombosis (DVT), although not as common as its lower extremity counterpart, is a clinical entity with potentially devastating complications. Approximately 1% to 4% of all DVT cases involve the upper extremity, with 9% to 14% of these cases complicated by pulmonary embolism. Prompt diagnosis with duplex ultrasonography and subsequent anticoagulation are the gold standards for identification and treatment. The majority of these cases are secondary to medical comorbidities such as malignancy, hypercoagulable states, and indwelling catheters. Although rare, several case reports of orthopedic-related upper-extremity DVT are present in the literature. This article reports a case of upper-extremity DVT in a humeral shaft fracture treated nonoperatively. A 58-year-old man presented with right elbow pain after a fall from scaffolding. Radiographs demonstrated a distal humeral shaft fracture at the tip of a previously placed intramedullary nail. Initial treatment consisted of closed reduction in a coaptation splint. The patient re-presented 4 days later with increasing forearm pain and swelling. An ultrasound revealed an extensive thrombus of the right brachial vein. A coaptation splint was replaced and the patient was admitted to the hospital for therapeutic anticoagulation. After hematology consultation and a short hospitalization, the patient was discharged home on a 3-month course of Warfarin. The goal of treatment of upper-extremity venous thrombosis is to improve the patient's acute symptoms and prevent both pulmonary embolism and post-thrombotic syndrome. Post-thrombotic syndrome is a chronic, potentially debilitating condition that occurs in approximately 15% of upper-extremity DVT cases with symptoms consisting of pain, swelling, paresthesias, and functional limitation. PMID- 21323282 TI - A synovial osteochondroma replacing the anterior cruciate ligament at the intercondylar notch. AB - A woman presented with knee pain and locking. Pain was exacerbated at the end of the range of motion, especially during extension, with locking symptoms similar to those associated with a meniscus bucket handle tear. Ligamentous laxity was not definite. Plain radiographs showed multiple calcified loose bodies. Magnetic resonance imaging (MRI) showed a lobulated mass that was hypointense to muscle on T1-weighted sequences and hyperintense to muscle on T2-weighted sequences in the anterior cruciate ligament (ACL). Arthroscopically, multiple loose bodies were observed in the intercondylar notch and posterolateral compartment. A huge mass replaced the normal ACL and was caught in the intercondylar notch. The mass in the intercondylar notch caused loss of extension range of motion (ROM) because the piece caused a mechanical blockage. However, the loss of flexion ROM was likely caused by a loss of elasticity of the ligament rather than mechanical blockage. We resected the ACL mass, and removed the free bodies from the posterolateral corner. It was not possible to preserve the ACL fibers. Histological examination confirmed a diagnosis of osteochondromatosis. All symptoms resolved postoperatively. At 20 months postoperatively, the patient was pain free and had regained full knee motion without recurrence evidenced by follow-up MRI. However, ACL removal caused the knee instability. To date the patient has not undergone ACL reconstruction because she prefers conservative treatment and has experienced little discomfort in activities of daily living. To our knowledge, this is the first report to describe synovial osteochondromatosis wholly replacing the ACL fibers and causing mechanical blocking of both extension and flexion. PMID- 21323283 TI - The role of computed tomography in the diagnosis and management of femoral neck fractures in the geriatric patient. AB - Femoral neck fractures are common in the elderly; however, agreement on classification and treatment varies. It was hypothesized that computed tomography (CT) would increase agreement for Garden Classification and treatment plan over plain radiographs alone. This article presents results of an online survey completed by 32 respondents at a single institution. The survey was comprised of 5 elderly patients with femoral neck fractures using plain radiographs and CT images. Cases were randomly presented in 3 formats: (1) plain radiograph, (2) CT, and (3) plain radiograph and CT together. Patients were described as low-energy trauma, 65 years or older, and cleared for surgery. Garden Classification and treatment plans were queried. A single case was repeated for intraobserver reliability. Kappa was calculated for inter- and intraobserver reliability. The addition of CT and modification of the Garden Classification (nondisplaced vs displaced) improved interobserver agreement in all cases. Participants were 1.7* more likely (P=.042) to change their Modified Garden Classification when CT was added to plain radiograph compared to plain radiograph added to CT. Treatment agreement was slight to fair. Intraobserver agreement varied from slight to moderate. The rate of arthoplasty recommendations was similar across attending subspecialties; however, arthroplasty-trained surgeons were 20 to 60 times more likely to recommend total hip arthroplasty (P=.009) over hemiarthroplasty compared to nonarthroplasty-trained surgeons. The addition of CT to plain radiograph after femoral neck fracture improves Garden Classification agreement. However, treatment agreement was not impacted by CT. Factors other than improved classification agreement appeared to direct surgeons' treatment recommendations. PMID- 21323284 TI - Center edge angle measurement for hip preservation surgery: technique and caveats. AB - Anterior and lateral center edge angles have traditionally been used to determine acetabular coverage, and thereby strongly influence the decision to perform acetabular reorientation versus osteochondroplasty in patients with dysplasia and/or femoroacetabular impingement. We propose templating the center of the contained articular femoral head in aspherical hips to provide reliable assessment of acetabular coverage. Digital radiographs of 30 patients with various combinations of femoral and acetabular morphologies were evaluated using 2 methods to identify the anterior center edge angle and lateral center edge angle. The control method used an estimated femoral head center for angle apex. The study technique determined the center of the femoral head by templating the congruent aspect of the femoral head contained by the acetabulum while ignoring the increasing lateral and anterior radius associated with cam deformities. Four readers measured lateral center edge angles on anteroposterior radiographs and anterior center edge angles on false-profile radiographs. Two reads were performed by each reader using both the estimated and the templated methods for a total of 4 reads. Interobserver reliability using the proposed method compared to the standard was much improved for anterior center edge angles (intraclass correlation coefficient of 0.76 vs 0.55) as well as with lateral center edge angles (ICC of 0.80 vs 0.42). Decreased correlation was most commonly associated with abnormal sourcil morphology, posterior wall deficiency combined with calcified labra, and os acetabuli. Including the anterolateral cam deformity in identifying the center of the femoral head for measuring center edge angles leads to an underestimation of acetabular coverage, which may negatively affect hip preservation surgical decision making. PMID- 21323285 TI - The role of increased frequency of treg cells in patients with chronic osteomyelitis. AB - The aim of this study is to determine whether regulatory T cells (Treg cells) are increased in patients with chronic osteomyelitis and whether they suppress cellular immune responses to the bacteria. The frequency of circulating CD4(+)CD25(+) and CD4(+)CD25(+)FoxP3(+) T cells in 30 chronic osteomyelitis patients were compared with 30 healthy donors. Treg-depleted PBMCs from the patients were cultured together with autologous antigen, unfractioned PBMCs used as the control. The cell proliferation and production of IL-10 and IFN-gamma were compared with those of the control. The results demonstrated that frequencies of CD4(+)CD25(+) (10.85+/-2.82% vs 6.08+/-1.62%, P<.001) and CD4(+)CD25(+)FoxP3(+) T cells (2.06+/-0.83% vs 1.43%+/-0.51%, P<.001) in blood from chronic osteomyelitis patients were significantly higher than in healthy donors. The level of IL-10 (117+/-91 pg/ml vs 323+/-189 pg/ml, P<.001) in supernatants of Treg-depleted PBMCs was decreased. Cell proliferation (4489+/-11876 cpm vs 3547+/-1517 cpm, P<.05) and IFN-gamma (875+/-203 pg/ml vs 405+/-129 pg/ml, P<.001) production by CD4(+)CD25(+) T cell in response to antigen was significantly inhibited by CD4(+)CD25(+) T cells. These results indicate that specific Tregs can depress the T cell mediated immune responses to bacteria in chronic osteomyelitis, and may play an important role in the persistence of bacteria. PMID- 21323286 TI - Long-term results of bulk femoral head autograft in cementless THA for developmental hip dysplasia. AB - We evaluated the fate of bulk femoral head autograft in cementless total hip arthroplasty (THA) for developmental hip dysplasia. Of 87 hips (80 patients) studied, 37 hips (32 patients) were available for follow-up at a mean of 18.5 years (range, 15-24 years) postoperatively. The mean age of these 32 patients at the index procedure was 53.8 years (range, 40-65 years). The initial diagnosis was osteoarthritis in all 32 patients. The degree of acetabular dysplasia according to Crowe classification was type I in 18 hips (48.6%), type II in 14 (37.8%), type III in 5 (13.5%). The mean percentage of horizontal coverage of the acetabular components with graft bone was 34% (range, 25%-45%). Trabecular bridging across the graft-host interface was seen at a mean of 4 months (range, 2 6 months) postoperatively. Trabecular reorientation of the grafted bone was seen in all hips at a mean of 27 months (range, 12-36 months) postoperatively. There was no evidence of collapse and bony resorption of the grafted bone in the weight bearing portion. Acetabular component fixation was stable in all hips at final follow-up. Of the 37 hips (32 patients), 2 acetabular components required revision: 1 for a late postoperative deep infection and 1 for dissociation of the polyethylene liner. The survival rate was 94.5% (95% confidence interval, 91.3 96.5) for the acetabular component at 18.5 years of follow-up. This study found that bulk femoral head autograft in cementless THA for developmental hip dysplasia produces excellent long-term results. PMID- 21323287 TI - Comparison of dorsal and volar approaches to the proximal radius. AB - Proximal radius exposure may be acquired by either the dorsal or volar approach depending on surgical requirements. The dorsal approach is traditionally recommended for fracture fixation of the proximal radius because of theoretically improved exposure and because the dorsal aspect of the bone is the tensile surface. The posterior interosseous nerve can be visualized and protected using this approach. The volar approach is preferred for biceps repair and boasts a distal extensile approach with adequate soft tissue coverage. Impingement on the bicipital tuberosity and biceps tendon, in addition to positioning on the compression side of the bone, makes the anterior or anterolateral position for plate placement less desirable. The goal of this study was to quantify and compare in a cadaver model the area of bone exposed using both approaches. We hypothesized that equivalent exposures can be obtained and the posterior interosseous nerve can be identified with either the Thompson or Henry approach. Standard dorsal and volar approaches were performed on 10 fresh-frozen adult cadaveric upper-limb specimens. Cross-sectional area of exposure was quantified from digital photographs using software. The 2 approaches did not result in a significant difference in area exposed. Depending on case requirements, either the dorsal or volar approach will provide adequate exposure to the proximal radius. PMID- 21323288 TI - Torsional stability of uncemented femoral stems in oncologic reconstructions. AB - Modular oncology implants using uncemented fixation represent a popular reconstruction technique for limb salvage patients. Initial stability is critical to facilitate bony ingrowth of host bone into the stem of a press-fit oncologic modular rotating-hinge total knee arthroplasty (TKA). The impact of stem design on initial stability has not been defined. The goal of this study was to evaluate the initial stability of 3 different stem designs as defined by torsional load to failure. An analysis of imaging was also performed. The pilot study consisted of 5 femora in each of 3 groups based on stem design. The specimen was mounted on a multi-axis biomechanical test frame equipped with a Vicon 3D motion analysis 4 camera system (Vicon Motion Systems, Lake Forest, California) to track the relative motion between the implant and the femur. Torsional force was applied until failure. The straight-fluted stem design had the highest average torsional stiffness (18.3+/-8.2 Nm/deg) and average torque at 150 MUm of implant micromotion (23.2+/-10.6 Nm) of the 3 stem types tested.The results of this study will help to guide surgical decision making in limb salvage cases. Further investigation is warranted. PMID- 21323289 TI - Intra-articular morphine enhances analgesic efficacy of ropivacaine for knee arthroscopy in ambulatory patients. AB - The aim of this double-blind, randomized control trial was to compare the effectiveness of intra-articular ropivacaine alone or with morphine or ketoprofen for controlling pain after arthroscopic knee surgery. One hundred fifty-six patients scheduled for elective knee arthroscopy were recruited. All patients received general anesthesia and were randomly assigned to 4 groups to receive intra-articular ropivacaine 40 mg (group R), ropivacaine 24 mg plus morphine 8 mg (group R+M), ropivacaine 36 mg plus ketoprofen 100 mg (group R+K), or normal saline (group N/S). Pain, sedation, orientation, nausea, vomiting, and urine retention were recorded at 0, 1, 2, 4, 8, 12, and 24 hours postoperatively. Pain was evaluated by a 10-cm visual analog scale (VAS). When the pain was >2, a suppository of 400 mg paracetamol plus 10 mg codeine plus 50 mg caffeine was given. Results showed that at 4 hours postoperatively, pain differed significantly among the 4 groups (P<.001), with less pain recorded in the R+M group. Similarly, the number of suppositories administered postoperatively to the R+M group was significantly less (P<.001) vs the other groups. Patients who received ropivacaine and morphine or normal saline had a higher incidence of nausea and vomiting vs the other groups (P=.001 and P=.036, respectively). The combination of intra-articular ropivacaine and morphine is associated with less pain after knee arthroscopy during early recovery but with a higher incidence of nausea and vomiting. However, the addition of ketoprofen to ropivacaine provides relatively satisfactory pain relief, but with fewer side effects compared to morphine. PMID- 21323290 TI - Plaster and synthetic cast temperatures in a clinical setting: an in vivo study. AB - Previous studies have reported thermal injuries with thick cast materials and warm dip water temperatures, often much higher than is clinically applicable. The goal of this study was to assess the temperature produced in vivo by current casting techniques and materials. The study was done using clinically applicable materials and water temperatures. A single volunteer was used to test skin temperatures produced with various casting techniques. We tested several types of fiberglass and plaster of 5 or 10 layers, used soft roll of 1 or 3 layers, and used dip water temperatures of 30 degrees C and 40 degrees C. We tested 2 plaster types: Johnson & Johnson Specialist Fast Set and Specialist Extra Fast Set (New Brunswick, New Jersey). Fiberglass tested included 3M Scotchcast Poly Casting Tape and Scotchcast Plus (St Paul, Minnesota), Royce Medical Techform (Camarrillo, California), and DeBusk Classic Synthetic Tape (Powell, Tennessee). The highest temperature reached using 30 degrees C water temperature was 39 degrees C with 10 layers of 3M Scotchcast fiberglass and 1 layer of soft roll. The highest temperature reached with 40 degrees C water was 39.5 degrees C, which was reached twice: once with Johnson & Johnson Fast Set Plaster with 5 layers of plaster and 3 layers of soft roll, and once with DeBusk Classic Synthetic Casting Tape of 10 layers with 1 layer of soft roll. Under the clinically applicable conditions described in this study, using the materials we tested and with a normal vascular supply, it is unlikely that temperatures high enough to cause a burn will be produced. We caution that good clinical judgment is advised if a patient reports a cast is too hot. PMID- 21323291 TI - ACL tibial spine avulsion: mid-term outcomes and rehabilitation. AB - Tibial spine fractures are characterized by fractures at the insertion site of the anterior cruciate ligament (ACL) on the tibia and were first classified into 3 types. For displaced (type II/III) fractures, surgical treatment has included fixation with screws, sutures, or wires performed through either open or arthroscopic approaches. Optimal treatment methods remain controversial and are varied by classification type, surgeon preference, and patient age. We retrospectively studied the outcome of 22 surgically treated patients with tibial spine fractures. We analyzed factors such as age, skeletal maturity, fixation device, surgical approach, presence of comminution, loss of reduction, and rehabilitation protocol against the development of arthrofibrosis and clinical and functional outcomes. We found that age older than 18 years was a statistically significant factor for lower outcome scores. Two factors trended toward significance including; those with comminution had lower Tegner scores, and those with early range of motion returned to previous activity level more frequently. Factors found to be insignificant included surgical approach, fixation device, weight bearing, skeletal maturity, postoperative immobilization, and loss of reduction. Those with screw fixation had a higher reoperation rate due to symptomatic hardware removal. Age was the only factor that negatively impacted final functional scores. PMID- 21323292 TI - Modified retro-tubercle opening-wedge versus conventional high tibial osteotomy. AB - Despite the fact that common surgical techniques for the treatment of genu varum usually correct the malalignment in the affected knee, these methods have significant complications and cause problems in the long term. Retro-tubercle opening-wedge high tibial osteotomy is among the newer techniques for the treatment of genu varum. The goal of this study was to compare the results of retro-tubercle opening-wedge high tibial osteotomy with those of medial opening wedge osteotomy. In a randomized, controlled trial, 72 patients with varus knees who were scheduled for surgery were assigned into either the retro-tubercle opening-wedge high tibial osteotomy (n=34) or medial opening-wedge osteotomy groups (n=38). Groups were matched for age and sex. The position of the patella was compared with respect to the tuberosity and the upper tibial slope pre- and postoperatively. Patients were followed for an average of 13 months (range, 10-21 months). In the retro-tubercle opening-wedge high tibial osteotomy group, the length of the patellar tendon did not significantly differ pre- and postoperatively (P>=.5); however, in the medial opening-wedge osteotomy group, a statistically significant shortening was noted in patellar tendon postoperatively (P<=.05). Similarly, the tibial plateau inclination showed a statistically significant difference postoperatively in the medial opening-wedge osteotomy group, while the difference in the retro-tubercle opening-wedge high tibial osteotomy group did not reach statistical significance. PMID- 21323293 TI - Evaluation of scarf osteotomy for management of hallux valgus deformity. AB - Hallux valgus is a complex progressive deformity affecting the forefoot. The main pathologic anatomy concerns the first metatarsophalangeal joint, including a varus or medial deviation of the first metatarsal and pronation deformity in the longitudinal axis. The goal of this study was to evaluate a series of consecutive patients over a 2-year period after a scarf osteotomy of the first metatarsal. A scarf osteotomy was performed on 31 consecutive patients with moderate to severe hallux valgus deformity (intermetatarsal angle, 13-22 degrees ; hallux valgus angle, 20-44 degrees ). Twenty-nine women and 2 men had an average age of 57 years (range, 21-71 years) at the time of surgery. Preoperative and postoperative evaluations included standing anteroposterior and lateral radiographs, American Orthopaedic Foot and Ankle Score (AOFAS) score, physical examination, and foot pressure analysis by weight-bearing ink prints. Patients were evaluated radiographically and clinically in the initial postoperative period (<=1 month), intermediate postoperative period (2-6 months), and final follow-up (12-36 months). Twenty-eight feet were available for analysis. Five of the 28 feet had concurrent surgeries on the lesser toes for hammer-toe correction or preoperative metatarsalgia. Paired Student t test on the 28 feet showed a statistically significant improvement (P<.0001) between pre- and postoperative intermetatarsal angle, hallux valgus angle, and AOFAS score. One foot had recurrence of the hallux valgus deformity. Paired analysis of variance of the 27 feet without recurrence showed a statistically significant improvement in the pre- and postoperative parameters (P<.0001). From this subset, the multiple-comparison Student-Newman-Keuis post hoc test showed a statistically significant (P<.0001) preservation of the correction in the intermediate follow-up period to final follow-up at an average 28 months. PMID- 21323294 TI - Cementless total hip arthroplasty for the treatment of advanced tuberculosis of the hip. AB - The question of whether a total hip arthroplasty (THA) should be attempted in a patient with a current or previous tuberculosis infection continues to cause controversy. The goal of this study was to evaluate the clinical result of cementless THA for the treatment of advanced tuberculosis of the hip. Eight patients with advanced tuberculosis of the hip treated by cementless THA were retrospectively analyzed. None of the patients had draining sinus preoperatively. For patients with a confirmed preoperative diagnosis of tuberculosis and elevated C-reactive protein and erythrocyte sedimentation rate, antituberculous medication was prescribed for at least 2 weeks preoperatively. Inflamed soft tissues and destroyed bones were completely curetted out intraoperatively. All 8 patients received 1-stage cementless THA after thorough debridement. Antituberculous medications were prescribed for all patients for the first 6 months postoperatively. No patient experienced wound-healing complications. Mean Harris Hip Score was 35 (range, 30-43) preoperatively and 91 (range, 87-95) at last follow-up. At an average 46-month follow-up (range, 34-59 months), no reactivation of tuberculosis was detected. All 8 patients revealed stability by bone ingrowth on both the socket and femoral stem. Cementless THA is a safe and effective procedure for advanced tuberculosis of the hip. With thorough debridement followed by a complete course of antituberculous chemotherapy, active tuberculous infection should not be considered a contraindication for THA. PMID- 21323295 TI - Contact pressure comparison of proud osteochondral autograft plugs versus proud synthetic plugs. AB - Osteochondral autograft transfer is an accepted treatment for chondral and osteochondral defects of the knee. Synthetic plugs may eventually be used for primary treatment of defects. Currently they are largely used for osteochondral donor site backfill. Placement of osteochondral or synthetic plugs proud leads to articulating surface incongruity, increases in contact pressure, and potential for both plug and opposing surface degenerative change. We conducted a biomechanical study of human cadaver knees to determine whether differences exist in the contact pressure of osteochondral autograft plugs placed proud versus synthetic plugs placed proud. Ten human cadaveric knees were used (20 condyles). Contact pressure was measured with Tekscan sensor technology (South Boston, Massachusetts) with both static and cyclical loads (of 250 and 500 cycles) created by an MTS Bionix system (Eden Prairie, Minnesota) under the following conditions: native articular cartilage, surgically created defect (7-mm diameter), 1-mm proud osteochondral autograft, and 1-mm proud synthetic graft. Proud osteochondral autograft plugs resulted in a 21.4% increase in peak contact pressure over surrounding native articular cartilage versus a 4.9% increase with proud synthetic plugs. Synthetic plugs compressed their structure and subsided versus subchondral bone collapse with compressive load in osteochondral autograft plugs. Proud osteochondral autograft plugs have significantly higher peak contact pressures than proud synthetic plugs when placed for treatment of chondral and osteochondral defects in the knee. PMID- 21323296 TI - Platelet-rich plasma injection reduces pain in patients with recalcitrant epicondylitis. AB - Thirty patients (31 elbows) with epicondylitis unresponsive to nonsurgical treatment (including steroid injection) for >6 months received a single treatment of platelet-rich plasma injected with a peppering technique. Patients were followed using a 5-subcategory visual analog scale (VAS) for pain (0, no pain; 10, worst possible pain), modified American Shoulder and Elbow Surgeons assessment survey, and VAS for patient satisfaction (0, not at all satisfied; 10, very satisfied). Successful treatment was defined as a 25% decrease in worst pain at follow-up with no intervention after 1 year. Two patients (2 elbows) elected for surgery 1 month postinjection. Of the remaining 29 elbows followed, 28 had a 25% reduction in worst pain at >=1 follow-up visits, for an overall success rate of 90% (28 of 31 elbows). Mean scores for worst pain at baseline, 3 months, and last follow-up (patients with at least 6 months of follow-up; 25+/-14 months) were 7.2+/-1.6 (n=30 elbows), 4.0+/-2.2 (n=23), and 1.1+/-1.7 (n=26), respectively (P<.01 or less comparing follow-up scores to baseline using each patient as his or her own control). Patient satisfaction scores improved from 5.1+/-2.5 at 1 month to 9.1+/-1.9 at last follow-up (P<.01). Only 1 patient reported no improvement after 6 months. Results suggest that a single platelet rich plasma injection can improve pain and function scores, thus avoiding surgery. PMID- 21323297 TI - Diagnosis of flexible flatfoot in children: a systematic clinical approach. AB - The goal of this study was to provide measures of symptoms and signs in a consecutive case series of children with flexible flatfoot based on a systematic clinical approach. Fifty-three children (age range, 10-14 years) previously diagnosed with flexible flatfoot were evaluated by a structured interview and clinical assessment. Most patients had foot symptoms (65.3% of feet) and functional limitation (68.3%). Symptoms included a sensation of discomfort (11.3%), such as early tiredness or difficulties during prolonged standing or walking, and pain (54%), mostly located in the plantar aspect of the foot (28.7%) and the medial hindfoot (18.8%). Body mass index was positively correlated to the presence of symptoms and their severity. Even if an enlarged footprint was present in 93.1% of feet, objective assessment evidenced the presence of heel valgus only in 83% of feet. Forefoot adduction was present in 22% of feet. Jack's test provided varus correction in only 54% of feet. Internal knee rotation was the most common associated disalignment, present in 43.6% of limbs. Symptoms were significantly correlated to knee alignment, and functional limitation was correlated to heel valgus. Standing balance on 1 leg was significantly correlated to footprint grading severity. A systematic clinical approach to assess children with flexible flatfoot should always be recommended for the correct diagnosis and the associated treatment management based on symptoms, functional limitation, and foot dysfunction. Functional assessment by specific tests should be included in the examination, as evidence exists that morphology and function are not necessarily related. PMID- 21323298 TI - Care needs and functional status of older acute care patients. AB - A growing number of older adults are admitted to hospitals, and information is needed on how age-related functional decline affects nursing care needs of this population. This study compared the functional status at admission and total nursing care needs of three age groups of older inpatients. A 12-month retrospective audit was performed on the records of 225 patients in a private metropolitan hospital. The three groups of patients were matched on diagnosis. Findings revealed that older patients were significantly more dependent, had greater total nursing care needs, and were less likely to be discharged to home, indicating that in addition to medical diagnoses, age-related differences of older patients' functional status at admission and inpatient nursing care needs should be factored into staff workloads and funding of nursing care. The finding that significantly fewer of the older patients returned home must be considered when reviewing health care policy and services. PMID- 21323299 TI - Garden walking and art therapy for depression in older adults: a pilot study. AB - The purpose of this pilot study was to compare garden walking (either alone or guided) with art therapy in older adults with depression. Depression was measured using the Geriatric Depression Scale (GDS) and stories of sadness/joy. Prior to the intervention, 47% of participants had depression scores in the severe range and 53% in the mild range. At the end of the intervention, none of the participants had scores in the severe range, 89% had scores in the mild range, and 11% had scores in the normal range. Results of the GDS data using repeated measures analysis of variance indicated significant decreases in depression for all three groups from pretest to posttest. All participants, regardless of group assignment, had a lower percentage of negative-emotion word use and a higher percentage of positive-emotion word use over time. This study provides evidence for nurses wishing to guide older adults in safe, easy, and inexpensive ways to reduce depression. PMID- 21323300 TI - Toric intraocular lens misalignment inducing astigmatism after refractive surgery. AB - PURPOSE: To report the unexpected induction of astigmatism after phacoemulsification and toric intraocular lens (IOL) implantation in an eye with previous corneal refractive surgery. METHODS: Case report of a 46-year-old man with bilateral nuclear cataract and previous photorefractive keratectomy. Because corneal topography identified regular corneal astigmatism at the central optical zone, phacoemulsification and implantation of a one-piece hydrophobic acrylic toric IOL were performed. RESULTS: Unexpected induction of astigmatism occurred in the first operated eye despite proper alignment of the IOL according to the preoperative calculations using simulated K values to determine toric IOL power and alignment. A retrospective qualitative analysis of corneal topography showed mismatching of the steepest meridian, leading to an off-axis IOL. Secondary IOL rotation improved both uncorrected and corrected distance visual acuity. CONCLUSIONS: Qualitative analysis of the corneal topography is mandatory during the assessment of toric IOL alignment in eyes with previous corneal refractive surgery to identify the actual location of the steepest meridian. PMID- 21323301 TI - Artisan iris-supported phakic IOL implantation in patients with keratoconus: a review of 16 eyes. AB - PURPOSE: To evaluate the clinical outcomes of Artisan phakic intraocular lens (PIOL; Ophtec BV) implantation in patients with stable keratoconus. METHODS: In a prospective, nonrandomized case series, 14 Artisan PIOLs and 2 toric Artisan PIOLs were implanted in 13 patients (16 eyes) with stable keratoconus who had contact lens intolerance. Pre- and postoperative data were collected. RESULTS: Mean follow-up was 14.2 +/- 7.8 months. Preoperative uncorrected distance visual acuity (UDVA) was counting fingers in all patients. Mean final logMAR (Snellen equivalent) UDVA and corrected distance visual acuity (CDVA) were 0.15(20/28) +/- 0.13 and 0.11(20/26) +/- 0.10, respectively. The improvements in UDVA and CDVA were statistically significant (P<.0001 and P<.002, respectively). All patients achieved a final UDVA of 20/40 or better, and 84.6% had a final CDVA of 20/32 or better. No postoperative complications occurred except for two cases of sterile uveitis. CONCLUSIONS: Implantation of the Artisan PIOL is effective in improving visual acuity in patients with stable keratoconus. Long-term safety remains to be established as no postoperative endothelial cell counts were performed. PMID- 21323302 TI - Comparison of immersion ultrasound, partial coherence interferometry, and low coherence reflectometry for ocular biometry in cataract patients. AB - PURPOSE: To compare ocular biometry parameters measured with immersion ultrasound, partial coherence interferometry, and low coherence reflectometry in cataract patients. METHODS: Measurements of axial length and anterior chamber depth were analyzed and compared using immersion ultrasound, partial coherence interferometry, and low coherence reflectometry. Keratometry (K), flattest axis, and white-to-white measurements were compared between partial coherence interferometry and low coherence reflectometry. Seventy-eight cataract (LOCS II range: 1 to 3) eyes of 45 patients aged between 42 and 90 years were evaluated. A subanalysis as a function of cataract degree was done for axial length and anterior chamber depth between techniques. RESULTS: No statistically significant differences were noted for the study cohort or within each cataract degree among the three techniques for axial length and anterior chamber depth (P>.05, ANOVA test). Measurements between techniques were highly correlated for axial length (R=0.99) and anterior chamber depth (R=0.90 to 0.96) for all methods. Keratometry, flattest axis, and white-to-white measurements were comparable (paired t test, P>.1) and correlated well between partial coherence interferometry and low coherence reflectometry (K1 [R=0.95), K2 [R=0.97], flattest axis [R=0.95], and white-to-white [R=0.92]). CONCLUSIONS: Immersion ultrasound, partial coherence interferometry, and low coherence reflectometry provided comparable ocular biometry measurements in cataractous eyes. PMID- 21323303 TI - Management of retinal vasoproliferative tumor associated with ROP by plaque brachytherapy. AB - The authors report a secondary exudative vasoproliferative tumor of the retina associated with retinopathy of prematurity, managed by plaque radiotherapy. A 15 year-old girl with a history of mild, stable retinopathy of prematurity in both eyes noted progressively reduced visual acuity to hand motions in the left eye. Examination disclosed a vasoproliferative tumor of 10-mm base and 3.5-mm thickness with near total (macula-off) exudative retinal detachment. She was treated with iodine-125 plaque radiotherapy, giving apex dose of 40 Gy over 4 days. The tumor regressed to 1.9 mm and retinal detachment resolved 8 months following therapy. Epiretinal membrane with significant macular pucker and edema later developed and was managed with pars plana vitrectomy and membrane peeling. Visual acuity was counting fingers due to photoreceptor loss. Retinopathy of prematurity is a rare cause of vasoproliferative tumor. Iodine-125 plaque radiotherapy can lead to tumor regression and reattachment of the retina in such cases. PMID- 21323304 TI - Bell's palsy in a 3-month-old infant: recommendations for management of pediatric cases. AB - Bell's palsy is an idiopathic unilateral paresis or paralysis of the facial nerve. The authors describe a 3-month-old infant with Bell's palsy and detail the investigation and management appropriate for the pediatric age group. PMID- 21323305 TI - Congenital upper eyelid ectopic cilia. AB - Ectopic eyelid cilia is an uncommon congenital anomaly typically occuring in otherwise healthy children. It is asymptomatic, but parents may wish surgical excision for cosmetic benefits. The authors describe three cases of ectopic upper eyelid cilia, surgical intervention, and follow-up results. PMID- 21323306 TI - Optic disc contractility in morning glory disc anomaly. AB - Morning glory disc anomaly is a sporadic congenital abnormality of the optic disc that is often unilateral. These eyes possess heterotropic smooth muscle and can undergo spontaneous contraction with transient vision loss. The authors report an unusual case of contractility of a morning glory disc anomaly induced by ocular massage. PMID- 21323307 TI - Diffuse anterior retinoblastoma with undetectable retinal involvement. AB - The authors report a case of diffuse anterior retinoblastoma with ciliary body origin and no retinal involvement. This again raises a question of the cell origin of retinoblastoma. The child was treated with enucleation of the presenting eye. PMID- 21323308 TI - Protein-polymer nanoparticles for nonviral gene delivery. AB - Protein-polymer conjugates were investigated as nonviral gene delivery vectors. BSA-poly(dimethylamino) ethyl methacrylate (PDMA) nanoparticles (nBSA) were synthesized using in situ atom transfer radical polymerization (in situ ATRP) and BSA as a macroinitiator. The diameter and charge of nBSA was a function of the ATRP reaction time and ranged from 5 to 15 nm and +8.9 to +22.5, respectively. nBSA were able to condense plasmid DNA (pDNA) and form polyplexes with an average diameter of 50 nm. nBSA/pDNA polyplexes transfected cells with similar efficiencies or better as compared to linear and branched PEI. Interestingly, the nBSA particle diameter and charge did not affect pDNA complexation and transgene expression, indicating that the same gene delivery efficiency can be achieved with lower charge ratios. We believe that with the use of protein-polymer conjugates additional functionality could be introduced to polyplexes by using different protein cores and, thus, they pose an interesting alternative to the design of nonviral gene delivery vectors. PMID- 21323309 TI - Application of amine-tethered solid sorbents for direct CO2 capture from the ambient air. AB - While current carbon capture and sequestration (CCS) technologies for large point sources can help address the impact of CO(2) buildup on global climate change, these technologies can at best slow the rate of increase of the atmospheric CO(2) concentration. In contrast, the direct CO(2) capture from ambient air offers the potential to be a truly carbon negative technology. We propose here that amine based solid adsorbents have significant promise as key components of a hypothetical air capture process. Specifically, the CO(2) capture characteristics of hyperbranched aminosilica (HAS) materials are evaluated here using CO(2) mixtures that simulate ambient atmospheric concentrations (400 ppm CO(2) = "air capture") as well as more traditional conditions simulating flue gas (10% CO(2)). The air capture experiments demonstrate that the adsorption capacity of HAS adsorbents are only marginally influenced even with a significant dilution of the CO(2) concentration by a factor of 250, while capturing CO(2) reversibly without significant degradation of performance in multicyclic operation. These results suggest that solid amine-based air capture processes have the potential to be an effective approach to extracting CO(2) from the ambient air. PMID- 21323310 TI - Copper trafficking mechanism of CXXC-containing domains: insight from the pH dependence of their Cu(I) affinities. AB - Copper is trafficked to cellular destinations by homeostatic proteins that also prevent adverse reactivity of the metal. The copper metallochaperone HAH1 (human Atx1) binds Cu(I) via a CXXC motif on loop1/alpha1 of a betaalphabetabetaalphabeta ferredoxin-like structure. A similar fold constitutes each of the six metal-binding domains (MBDs) of the two P-type ATPases (Menkes and Wilson disease proteins), the destination for copper bound to HAH1. In this work we have investigated the influence of pH on copper trafficking between HAH1 and the first MBD of the Menkes protein (MNK1). Cu(I) affinities of 5.6 * 10(17) and 3.6 * 10(17) M(-1) have been determined at pH 7.0 for HAH1 and MNK1, respectively, from competition titrations with the chromophoric Cu(I) ligand bathocuproine disulfonate. The mutation of Lys60 on loop5 of HAH1 to Ala (the corresponding residue is Phe67 in MNK1) results in a 3-fold lowering of the affinity for Cu(I) at pH 7.0. The Cu(I) affinity of WT HAH1 exhibits a different pH-dependence compared to MNK1 and Lys60Ala HAH1. This arises because the pK(a) of the second Cys ligand in the CXXC motif of HAH1 is 1.5 pH units lower due to stabilization of the thiolate via a hydrogen-bonding interaction with the side chain of Lys60. The thermodynamic gradient for Cu(I) transfer between HAH1 and MNK1 depends on pH. The decrease in the pK(a) of the Cys ligand in HAH1 can also influence the kinetics of Cu(I) transfer. PMID- 21323311 TI - Millisecond dynamics in glutaredoxin during catalytic turnover is dependent on substrate binding and absent in the resting states. AB - Conformational dynamics is important for enzyme function. Which motions of enzymes determine catalytic efficiency and whether the same motions are important for all enzymes, however, are not well understood. Here we address conformational dynamics in glutaredoxin during catalytic turnover with a combination of NMR magnetization transfer, R(2) relaxation dispersion, and ligand titration experiments. Glutaredoxins catalyze a glutathione exchange reaction, forming a stable glutathinoylated enzyme intermediate. The equilibrium between the reduced state and the glutathionylated state was biochemically tuned to exchange on the millisecond time scale. The conformational changes of the protein backbone during catalysis were followed by (15)N nuclear spin relaxation dispersion experiments. A conformational transition that is well described by a two-state process with an exchange rate corresponding to the glutathione exchange rate was observed for 23 residues. Binding of reduced glutathione resulted in competitive inhibition of the reduced enzyme having kinetics similar to that of the reaction. This observation couples the motions observed during catalysis directly to substrate binding. Backbone motions on the time scale of catalytic turnover were not observed for the enzyme in the resting states, implying that alternative conformers do not accumulate to significant concentrations. These results infer that the turnover rate in glutaredoxin is governed by formation of a productive enzyme-substrate encounter complex, and that catalysis proceeds by an induced fit mechanism rather than by conformer selection driven by intrinsic conformational dynamics. PMID- 21323312 TI - Theaflavins depolymerize microtubule network through tubulin binding and cause apoptosis of cervical carcinoma HeLa cells. AB - Here we studied the antiproliferative activity of theaflavins in cervical carcinoma HeLa cells by investigating their effects on cellular microtubules and purified goat brain tubulin. Theaflavins inhibited proliferation of HeLa cells with IC(50) value of 110 +/- 2.1 MUg/mL (p = < 0.01), caused cell cycle arrest at G(2)/M phase and induced apoptosis with alteration of expression of pro- and antiapoptotic proteins. Along with these antiproliferative activities, theaflavins act as microtubule depolymerizers. Theaflavins disrupted the microtubule network accompanied by alteration of cellular morphology and also decreased the polymeric tubulin mass of the cells. The polymerization of cold treated depolymerized microtubules in HeLa cells was prevented in the presence of theaflavins. In vitro polymerization of purified tubulin into microtubules was also inhibited by theaflavins with an IC(50) value of 78 +/- 2.43 MUg/mL (P < 0.01). Thus, disruption of cellular microtubule network of HeLa cells through microtubule depolymerization may be one of the possible mechanisms of antiproliferative activity of theaflavins. PMID- 21323313 TI - Structure-based discovery of inhibitors of microsomal prostaglandin E2 synthase 1, 5-lipoxygenase and 5-lipoxygenase-activating protein: promising hits for the development of new anti-inflammatory agents. AB - Microsomal prostaglandin E(2) synthase (mPGES)-1 catalyzes the transformation of PGH(2) to PGE(2) that is involved in several pathologies like fever, pain, and inflammatory disorders. To identify novel mPGES-1 inhibitors, we used in silico screening to rapidly direct the synthesis, based on the copper-catalyzed 3 + 2 Huisgen's reaction (click chemistry), of potential inhibitors. We designed 26 new triazole-based compounds in accordance with the pocket binding requirements of human mPGES-1. Docking results, in agreement with ligand efficiency values, suggested the synthesis of 15 compounds that at least in theory were shown to be more efficient in inhibiting mPGES-1. Biological evaluation of these selected compounds has disclosed three new potential anti-inflammatory drugs: (I) compound 4 displaying selectivity for mPGES-1 with an IC(50) value of 3.2 MUM, (II) compound 20 that dually inhibits 5-lipoxygenase and mPGES-1, and (III) compound 7 apparently acting as 5-lipoxygenase-activating protein inhibitor (IC(50) = 0.4 MUM). PMID- 21323314 TI - Comprehensive studies on an overall proton transfer cycle of the ortho-green fluorescent protein chromophore. AB - Initiated by excited-state intramolecular proton transfer (ESIPT) reaction, an overall reaction cycle of 4-(2-hydroxybenzylidene)-1,2-dimethyl-1H-imidazol-5(4H) one (o-HBDI), an analogue of the core chromophore of the green fluorescent protein (GFP), has been investigated. In contrast to the native GFP core, 4-(4 hydroxybenzylidene)-1,2-dimethyl-1H-imidazol-5(4H)-one (p-HBDI), which requires hydrogen-bonding relay to accomplish proton transfer in vivo, o-HBDI possesses a seven-membered-ring intramolecular hydrogen bond and thus provides an ideal system for mimicking an intrinsic proton-transfer reaction. Upon excitation, ESIPT takes place in o-HBDI, resulting in a ~600 nm proton-transfer tautomer emission. The o-HBDI tautomer emission, resolved by fluorescence upconversion, is comprised of an instantaneous rise to a few hundred femtosecond oscillation in the early relaxation stage. Frequency analysis derived from ultrashort pulse gives two low-frequency vibrations at 115 and 236 cm(-1), corresponding to skeletal deformation motions associated with the hydrogen bond. The results further conclude that ESIPT in o-HBDI is essentially triggered by low-frequency motions and may be barrierless along the reaction coordinate. Femtosecond UV/vis transient absorption spectra also provide supplementary evidence for the structural evolution during the reaction. In CH(3)CN, an instant rise of a 530 nm transient is resolved, which then undergoes 7.8 ps decay, accompanied by the growth of a rather long-lived 580 nm transient species. It is thus concluded that following ESIPT the cis-proton transfer isomer undergoes cis-trans-isomerization. The results of viscosity-dependent dynamics are in favor of the one-bond-flip mechanism, which is in contrast to the volume-conserving isomerization behavior for cis-stilbene and p-HBDI. Further confirmation is given by the picosecond femtosecond transient IR absorption spectra, where several new and long-lived IR bands in the range of 1400-1500 cm(-1) are assigned to the phenyl in-plane breathing motions of the trans-proton transfer tautomer. Monitored by the nanosecond transient absorption, the 580 nm transient undergoes a ~7.7 MUs decay constant, accompanied by the growth of a new ~500 nm band. The latter is assigned to a deprotonated tautomer species, which then undergoes the ground-state reverse proton recombination to the original o-HBDI in ~50 MUs, achieving an overall, reversible proton transfer cycle. This assignment is unambiguously supported by pump-probe laser induced fluorescence studies. On these standpoints, a comparison of photophysical properties among o-HBDI, p-HBDI, and wild-type GFP is discussed in detail. PMID- 21323316 TI - Observation of new states of liquid crystal 8CB under nonlinear shear conditions as observed via a novel and unique rheology/small-angle X-ray scattering combination. AB - New stable states of liquid crystal 8CB could be induced by nonlinear shear conditions and observed by a newly developed rheology/X-ray scattering setup using synchrotron X-ray radiation. Nonlinear oscillatory shear created a distorted sixth order orientational structure. Even when oscillatory shear is switched off, the induced structure remains stable and can be removed only by heating the system into the isotropic state. We assume the structure to be stabilized by defects that pin the new 6-fold phase. PMID- 21323318 TI - FRED pose prediction and virtual screening accuracy. AB - Results of a previous docking study are reanalyzed and extended to include results from the docking program FRED and a detailed statistical analysis of both structure reproduction and virtual screening results. FRED is run both in a traditional docking mode and in a hybrid mode that makes use of the structure of a bound ligand in addition to the protein structure to screen molecules. This analysis shows that most docking programs are effective overall but highly inconsistent, tending to do well on one system and poorly on the next. Comparing methods, the difference in mean performance on DUD is found to be statistically significant (95% confidence) 61% of the time when using a global enrichment metric (AUC). Early enrichment metrics are found to have relatively poor statistical power, with 0.5% early enrichment only able to distinguish methods to 95% confidence 14% of the time. PMID- 21323317 TI - Surface immobilization of plasmid DNA with a cell-responsive tether for substrate mediated gene delivery. AB - The advancement of nonviral gene therapy hinges on the ability to exert highly specific spatial and temporal control of gene delivery systems to enable localized release of DNA. In this work, we have developed a system capable of promoting localized delivery of a plasmid by utilizing peptide nucleic acid (PNA) technology to bind DNA to a substrate via an enzymatically labile peptide sequence. The successful immobilization of the DNA to the model substrate as well as the specificity of the binding was confirmed with atomic force microscopy (AFM) and AFM-confocal overlay imaging. Fluorescence-based quantification revealed that surfaces treated with the conjugates had 49 +/- 22 ng of DNA/cm(2), while there were 4.2 +/- 2.1 ng of DNA/cm(2) on surfaces treated with unfunctionalized DNA. When NIH/3T3 cells were grown on the modified substrates, a significantly higher percentage of cells were transfected when the peptide tether was protease-sensitive as compared with when it was not labile. These results indicated that the peptide must be cleaved to release the DNA. In addition to providing cell-triggered release, this system decouples the properties of the complexation agent and the substrate from the method of immobilization/release to provide a model system that can be tailored to specific applications. PMID- 21323319 TI - Odd-even effects in charge transport across self-assembled monolayers. AB - This paper compares charge transport across self-assembled monolayers (SAMs) of n alkanethiols containing odd and even numbers of methylenes. Ultraflat template stripped silver (Ag(TS)) surfaces support the SAMs, while top electrodes of eutectic gallium-indium (EGaIn) contact the SAMs to form metal/SAM//oxide/EGaIn junctions. The EGaIn spontaneously reacts with ambient oxygen to form a thin (~1 nm) oxide layer. This oxide layer enables EGaIn to maintain a stable, conical shape (convenient for forming microcontacts to SAMs) while retaining the ability to deform and flow upon contacting a hard surface. Conical electrodes of EGaIn conform (at least partially) to SAMs and generate high yields of working junctions. Ga(2)O(3)/EGaIn top electrodes enable the collection of statistically significant numbers of data in convenient periods of time. The observed difference in charge transport between n-alkanethiols with odd and even numbers of methylenes--the "odd-even effect"--is statistically discernible using these junctions and demonstrates that this technique is sensitive to small differences in the structure and properties of the SAM. Alkanethiols with an even number of methylenes exhibit the expected exponential decrease in current density, J, with increasing chain length, as do alkanethiols with an odd number of methylenes. This trend disappears, however, when the two data sets are analyzed together: alkanethiols with an even number of methylenes typically show higher J than homologous alkanethiols with an odd number of methylenes. The precision of the present measurements and the statistical power of the present analysis are only sufficient to identify, with statistical confidence, the difference between an odd and even number of methylenes with respect to J, but not with respect to the tunneling decay constant, beta, or the pre-exponential factor, J(0). This paper includes a discussion of the possible origins of the odd-even effect but does not endorse a single explanation. PMID- 21323320 TI - Quantum capacitance limited vertical scaling of graphene field-effect transistor. AB - A high-quality Y2O3 dielectric layer has been grown directly on graphene and used to fabricated top-gate graphene field-effect transistors (FETs), and the thickness of the dielectric layer has been reduced continuously down to 3.9 nm with an equivalent oxide thickness (EOT) of 1.5 nm and excellent insulativity. By measuring CV characteristics of two graphene FETs with different gate oxide thicknesses, the oxide capacitance and quantum capacitance are retrieved directly from the experimental CV data without introducing any additional fitting process and parameters, yielding a relative dielectric constant of kappa=10 for Y2O3 on graphene and an oxide capacitance of about 2.28 MUF/cm2. It is found that for a rather large gate voltage range, this oxide capacitance is comparable and sometimes even larger than the quantum capacitance of graphene. Since the total gate capacitance is determined by the smaller of the oxide and quantum capacitance, our results show that not much further improvement can be gained via further vertical scaling down of the gate oxide, suggesting that Y2O3 may be the ultimate dielectric material for graphene. It is also shown that the Y2O3 gate dielectric layer with EOT of 1.5 nm may also satisfy the ultimate lateral scaling requirement on the gate length of graphene FET and be used effectively to control a graphene FET with a gate length as small as 1 nm. PMID- 21323321 TI - Excited-state intermolecular proton transfer of firefly luciferin IV. Temperature and pH dependence. AB - Time-resolved emission as well as steady-state UV-vis techniques were employed to study the photoprotolytic processes that d-luciferin, the natural substrate of the firefly luciferase, undergoes in both acidic aqueous solutions and ice. The emission spectrum of D-luciferin in a 20 mM HCl aqueous solution or higher has an additional emission band at 590 nm red-shifted with respect to the strongest emission band positioned at 530 nm of the deprotonated NRO(-*) form in a pH neutral aqueous solution. We attribute this emission band to the zwitterion form designated as (+)HNRO(-). The time-resolved emission signals show that the NRO( *) emission band at 530 nm and the zwitterion emission band at 590 are strongly quenched by a recombination process with a proton in an acidic solution and in ice. In ice, the quenching rate is 10 times faster than in the liquid state. We attribute the fast quenching rate to the high value of the proton diffusion constant in ice. PMID- 21323322 TI - Molecularly imprinted mesoporous organosilica. AB - We have prepared molecularly imprinted mesoporous organosilica (MIMO) using a semicovalent imprinting technique. A thermally reversible covalent bond was used to link a bisphenol A (BPA) imprint molecule to a functional alkoxysilane monomer at two points to generate a covalently bound imprint precursor. This precursor was incorporated into a cross-linked periodic mesoporous silica matrix via a typical acid-catalyzed, triblock copolymer-templated, sol-gel synthesis. Evidence of imprint sites buried in the pore walls was found through careful characterization of the imprinted material and its comparison to similarly prepared non-imprinted mesoporous organosilica (NIMO) and pure periodic mesoporous silica (PMS). After thermal treatment, the imprinted material (MIMO ir) removed more than 90% of appropriately sized bisphenol species from water, yet showed significantly lower binding for both smaller and larger molecules containing phenol moieties. Identically treated NIMO-ir showed much poorer retention behavior than MIMO-ir for the same bisphenol species and behaved only slightly better than PMS-ir. PMID- 21323323 TI - Metallization of branched DNA origami for nanoelectronic circuit fabrication. AB - This work examines the metallization of folded DNA, known as DNA origami, as an enabling step toward the use of such DNA as templates for nanoelectronic circuits. DNA origami, a simple and robust method for creating a wide variety of shapes and patterns, makes possible the increased complexity and flexibility needed for both the design and assembly of useful circuit templates. In addition, selective metallization of the DNA template is essential for circuit fabrication. Metallization of DNA origami presents several challenges over and above those associated with the metallization of other DNA templates such as lambda-DNA. These challenges include (1) the stability of the origami in the processes used for metallization, (2) the enhanced selectivity required to metallize small origami structures, (3) the increased difficulty of adhering small structures to the surface so that they will not be removed when subject to multiple metallization steps, and (4) the influence of excess staple strands present with the origami. This paper describes our efforts to understand and address these challenges. Specifically, the influence of experimental conditions on template stability and on the selectivity of metal deposition was investigated for small DNA origami templates. These templates were seeded with Ag and then plated with Au via an electroless deposition process. Both staple strand concentration and the concentration of ions in solution were found to have a significant impact. Selective continuous metal deposition was achieved, with an average metallized height as small as 32 nm. The shape of branched origami was also retained after metallization. These results represent important progress toward the realization of DNA-templated nanocircuits. PMID- 21323324 TI - Quantitative proteomic view on secreted, cell surface-associated, and cytoplasmic proteins of the methicillin-resistant human pathogen Staphylococcus aureus under iron-limited conditions. AB - Staphylococcus aureus is capable of colonizing and infecting humans by its arsenal of surface-exposed and secreted proteins. Iron-limited conditions in mammalian body fluids serve as a major environmental signal to bacteria to express virulence determinants. Here we present a comprehensive, gel-free, and GeLC-MS/MS-based quantitative proteome profiling of S. aureus under this infection-relevant situation. (14)N(15)N metabolic labeling and three complementing approaches were combined for relative quantitative analyses of surface-associated proteins. The surface-exposed and secreted proteome profiling approaches comprise trypsin shaving, biotinylation, and precipitation of the supernatant. By analysis of the outer subproteomic and cytoplasmic protein fraction, 1210 proteins could be identified including 221 surface-associated proteins. Thus, access was enabled to 70% of the predicted cell wall-associated proteins, 80% of the predicted sortase substrates, two/thirds of lipoproteins and more than 50% of secreted and cytoplasmic proteins. For iron-deficiency, 158 surface-associated proteins were quantified. Twenty-nine proteins were found in altered amounts showing particularly surface-exposed proteins strongly induced, such as the iron-regulated surface determinant proteins IsdA, IsdB, IsdC and IsdD as well as lipid-anchored iron compound-binding proteins. The work presents a crucial subject for understanding S. aureus pathophysiology by the use of methods that allow quantitative surface proteome profiling. PMID- 21323325 TI - Nanofabrication of broad-band antireflective surfaces using self-assembly of block copolymers. AB - We present a simple and cost-effective method for the fabrication of antireflective surfaces by self-assembly of block copolymers and subsequent plasma etching. The block copolymers create randomly oriented periodic patterns, which are further transferred into fused silica substrates. The reflection on the patterned fused silica surface is reduced to well below 1% in the ultraviolet, visible, and near-infrared ranges by exploiting subwavelength nanostructures with periodicities down to 48 nm. We show that by choosing the appropriate block copolymers and pattern transfer parameters the optical properties of the antireflective surface can be easily tuned, and the spectral measurements verify a significant reduction of the reflectivity by a factor of 10. The experiments, confirmed with simulations based on rigorous diffraction theory, also show that the tapered shape of the nanostructures gives rise to a graded index surface, resulting in a broad-band antireflective behavior. PMID- 21323326 TI - Ultrahigh density alignment of carbon nanotube arrays by dielectrophoresis. AB - We report ultrahigh density assembly of aligned single-walled carbon nanotube (SWNT) two-dimensional arrays via AC dielectrophoresis using high-quality surfactant-free and stable SWNT solutions. After optimization of frequency and trapping time, we can reproducibly control the linear density of the SWNT between prefabricated electrodes from 0.5 SWNT/MUm to more than 30 SWNT/MUm by tuning the concentration of the nanotubes in the solution. Our maximum density of 30 SWNT/MUm is the highest for aligned arrays via any solution processing technique reported so far. Further increase of SWNT concentration results in a dense array with multiple layers. We discuss how the orientation and density of the nanotubes vary with concentrations and channel lengths. Electrical measurement data show that the densely packed aligned arrays have low sheet resistances. Selective removal of metallic SWNTs via controlled electrical breakdown produced field effect transistors with high current on-off ratio. Ultrahigh density alignment reported here will have important implications in fabricating high-quality devices for digital and analog electronics. PMID- 21323327 TI - Direct observation of the beta-carotene reaction with hydroxyl radical. AB - Hydroxyl radical reacts readily with beta-carotene following submicrosecond laser photolysis of N-hydroxypyridine-2(1H)-thione (N-HPT) as a "photo-Fenton" reagent generating hydroxyl and thiyl radicals in acetonitrile:tetrahydrofuran (4:1, v/v) solution. On the basis of spectral evidence, and supported by kinetic considerations and thermodynamic calculations, a short-lived transient species, detected by time-resolved absorption spectroscopy with an absorption maximum at ~750 nm and a lifetime of ~150 ns at 25 degrees C under anaerobic conditions, is suggested to be the long-sought neutral beta-carotene radical formed by hydrogen atom abstraction. The transient spectrum is different from the spectra of the beta-carotene radical cation (~1000 nm absorption maximum with a millisecond lifetime), the beta-carotene radical adducts (~520 nm, several microsecond lifetime), the beta-carotene radical cation ion pair (~750 nm, several hundred microsecond lifetime), and the beta-carotene radical anion (~880 nm, a few tens of microsecond lifetime). In parallel, beta-carotene reacts with the thiyl radical to yield a sulfur radical adduct with absorption maximum at ~520 nm with a lifetime of 3.0 MUs. For astaxanthin and canthaxanthin, the reaction with the thiyl radical dominates and the neutral radical is hardly formed in agreement with the less reducing properties of these 4,4'-diketo carotenoids without the reactive 4,4'-hydrogens. PMID- 21323328 TI - Effect of cyclodextrins on the photophysics of three indoloquinoline derivatives: an intriguing fluorometric study. AB - Effect of cyclodextrin encapsulation on the photophysics of three indoloquinoline derivatives, namely, 5-methyl-5H-indolo[3,2-c]quinoline (MIQ), 8-chloro-5-methyl 5H-indolo[3,2-c]quinoline (CMIQ), and 2,8-dichloro-5-methyl-5H-indolo[3,2 c]quinoline (DCMIQ), has been studied using steady state and time-resolved fluorescence spectroscopy. The three compounds, which are basically cryptosanguinolentines, exist mainly in their zwitterionic forms in the excited state. Appreciable emission from the pi-pi* state can be observed on excitation of the compounds at a specific wavelength. The existence of zwitterions in the excited state leads to mutual interaction to form dimers triggered by the presence of the hydrophobic nanocavities of cyclodextrins (CDs) through Coulombic interaction. This is evidenced by steady state fluorescence measurements and treating the fluorophores with CDs of different cavity space. The photophysical behavior of the compounds gets dramatically modulated when they are treated with alpha-, beta-, and gamma-CD hosts. Presence of chloro substituent/s on the parent molecule and the extent of encapsulation by CDs of different dimensions exhibit enormous alterations in the fluorescence characteristics of the compounds. Solvation of the chromophoric moiety by water molecules deviates in character due to the guest-host interaction. Trapped water molecules inside the bigger cavity of gamma-CD seem to play a vital role in quenching the fluorescence of the zwitterions of the molecules. PMID- 21323329 TI - Angular distribution of surface-enhanced Raman scattering from individual au nanoparticle aggregates. AB - Nano-optical antennas based on plasmonic metal particles are well-known for their ability to dramatically concentrate electromagnetic energy. However, not much attention has been devoted to the directionality properties of nanoantennas. Here, we report on the angular distribution of surface-enhanced Raman scattering (SERS) emitted by isolated aggregates of gold nanoparticles. We find that most of the radiation appears at angles exceeding the critical angle of the air-glass interface supporting the aggregates, and we demonstrate that angle-resolved imaging can be used as a fast and facile method for determination of the three dimensional orientation and symmetry of the nanoantenna. PMID- 21323330 TI - A time-dependent approach to electronic transmission in model molecular junctions. AB - We present a simple method to compute the transmission coefficient of a quantum system embedded between two conducting electrodes. Starting from the solution of the time-dependent Schrodinger equation, we demonstrate the relationship between the temporal evolution of the state vector, |psi(t)>, initially localized on one electrode and the electronic transmission coefficient, T(E). We particularly emphasize the role of the oscillation frequency and the decay rate of |psi(t)> in the line shape of T(E). This method is applied to the well-known problems of the single impurity, two-site systems and the benzene ring, where it agrees with well accepted time-independent methods and gives new physical insight to the resonance and interference patterns widely observed in molecular junctions. PMID- 21323331 TI - Suppressive effects of Amarouciaxanthin A on 3T3-L1 adipocyte differentiation through down-regulation of PPARgamma and C/EBPalpha mRNA expression. AB - Fucoxanthin is converted to fucoxanthinol and amarouciaxanthin A in mice. It was previously reported that fucoxanthinol attenuated the adipogenesis of 3T3-L1 cells. However, the effects of amarouciaxanthin A on adipocyte differentiation have not been clarified. This study examined the effects of amarouciaxanthin A on 3T3-L1 adipogenesis by comparing the effects of fucoxanthinol, isofucoxanthinol, and amarouciaxanthin B. Amarouciaxanthin A significantly decreased glycerol-3 phosphate dehydrogenase (GPDH) activity, which was measured as an indicator of adipocyte differentiation. The suppressive effect of amarouciaxanthin A was stronger than that of fucoxanthinol, amarouciaxanthin B, and isofucoxanthinol. The mRNA expressions of adipocyte fatty acid-binding protein (aP2), lipoprotein lipase (LPL), and glucose-transporter 4 (Glut4) in 3T3-L1 cells were markedly down-regulated by amarouciaxanthin A compared to fucoxanthinol. Furthermore, the expression levels of peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT-enhancer-binding protein alpha (C/EBPalpha),, which are the key adipogenic transcriptional factors, were also decreased by amarouciaxanthin A during adipocyte differentiation. These results show that amarouciaxanthin A, which is a dominant metabolite of fucoxanthin in white adipose tissue, suppressed 3T3-L1 adipocyte differentiation. PMID- 21323333 TI - Swelling-induced morphology reconstruction in block copolymer nanorods: kinetics and impact of surface tension during solvent evaporation. AB - Nanoscopic domain structures of BCP nanorods can be converted into well-defined mesopore systems by swelling the BCP minority component with a selective solvent at temperatures below the bulk glass transition temperature of the nonswelling matrix. The initial stage of this process involves rapid morphology reconstruction of the nonswelling majority domains to accommodate the increased volume of the swelling minority domains caused by rapid solvent uptake. Morphology reconstruction slows down once entropic restoring forces of the swelling chains impede further uptake of swelling agent. Upon evaporation of the swelling agent, mesopores form in place of the swollen domains as the swollen minority blocks undergo entropic relaxation while intermediate nonequilibrium morphologies in the BCP nanorods are fixated by the reconstructed majority component. The surface area of mesopores developing when swollen cylindrical minority domains collapse may be minimized by the growth of Rayleigh instabilities. Depending on swelling temperature, swelling agent, and BCP architecture, BCP nanorods with one or several cylindrical channels undulated or uniform in diameter running along their long axes, linear strings of spherical cavities, and continuous mesopore systems can be obtained. PMID- 21323332 TI - Use of a high-throughput screening approach coupled with in vivo zebrafish embryo screening to develop hazard ranking for engineered nanomaterials. AB - Because of concerns about the safety of a growing number of engineered nanomaterials (ENM), it is necessary to develop high-throughput screening and in silico data transformation tools that can speed up in vitro hazard ranking. Here, we report the use of a multiparametric, automated screening assay that incorporates sublethal and lethal cellular injury responses to perform high throughput analysis of a batch of commercial metal/metal oxide nanoparticles (NP) with the inclusion of a quantum dot (QD1). The responses chosen for tracking cellular injury through automated epifluorescence microscopy included ROS production, intracellular calcium flux, mitochondrial depolarization, and plasma membrane permeability. The z-score transformed high volume data set was used to construct heat maps for in vitro hazard ranking as well as showing the similarity patterns of NPs and response parameters through the use of self-organizing maps (SOM). Among the materials analyzed, QD1 and nano-ZnO showed the most prominent lethality, while Pt, Ag, SiO2, Al2O3, and Au triggered sublethal effects but without cytotoxicity. In order to compare the in vitro with the in vivo response outcomes in zebrafish embryos, NPs were used to assess their impact on mortality rate, hatching rate, cardiac rate, and morphological defects. While QDs, ZnO, and Ag induced morphological abnormalities or interfered in embryo hatching, Pt and Ag exerted inhibitory effects on cardiac rate. Ag toxicity in zebrafish differed from the in vitro results, which is congruent with this material's designation as extremely dangerous in the environment. Interestingly, while toxicity in the initially selected QD formulation was due to a solvent (toluene), supplementary testing of additional QDs selections yielded in vitro hazard profiling that reflect the release of chalcogenides. In conclusion, the use of a high-throughput screening, in silico data handling and zebrafish testing may constitute a paradigm for rapid and integrated ENM toxicological screening. PMID- 21323334 TI - CASPT2 study of the potential energy surface of the HSO2 system. AB - The importance of the HSO(2) system in atmospheric and combustion chemistry has motivated several works dedicated to the study of associated structures and chemical reactions. Nevertheless controversy still exists in connection with the reaction SH + O(2)-> H + SO(2) and also related to the role of the HSOO isomers in the potential energy surface (PES). Here we report high-level ab initio calculation for the electronic ground state of the HSO(2) system. Energetic, geometric, and frequency properties for the major stationary states of the PES are reported at the same level of calculations: CASPT2/aug-cc-pV(T+d)Z. This study introduces three new stationary points (two saddle points and one minimum). These structures allow the connection of the skewed HSOO(s) and the HSO(2) minima defining new reaction paths for SH + O(2) -> H + SO(2) and SH + O(2) -> OH + SO. In addition, the location of the HSOO isomers in the reaction pathways have been clarified. PMID- 21323336 TI - Size and shape dependence of the photocatalytic activity of TiO2 nanocrystals: a total scattering Debye function study. AB - Nanocrystalline TiO(2) samples, prepared for smart textiles applications by the sol-gel technique in acidic or basic media, have been characterized by synchrotron X-ray powder diffraction and total scattering methods based on a fast implementation of the Debye function and original algorithms for sampling interatomic distances. Compared to the popular and widely used Rietveld-based approaches, our method is able to simultaneously model both Bragg and diffuse contributions and to quantitatively extract either sizes and size distribution information from the experimental data. The photocatalytic activity of the investigated samples is here systematically correlated to the average sizes and size distributions of anisotropically shaped coherent domains, modeled according to bivariate populations of nanocrystals grown along two normal directions. PMID- 21323335 TI - Substituent effects on electrophilic catalysis by the carbonyl group: anatomy of the rate acceleration for PLP-catalyzed deprotonation of glycine. AB - First-order rate constants, determined by (1)H NMR, are reported for deuterium exchange between solvent D(2)O and the alpha-amino carbon of glycine in the presence of increasing concentrations of carbonyl compounds (acetone, benzaldehyde, and salicylaldehyde) and at different pD and buffer concentrations. These rate data were combined with (1)H NMR data that define the position of the equilibrium for formation of imines/iminium ions from addition of glycine to the respective carbonyl compounds, to give second-order rate constants k(DO) for deprotonation of alpha-imino carbon by DO(-). The assumption that these second order rate constants lie on linear structure-reactivity correlations between log k(OL) and pK(a) was made in estimating the following pK(a)'s for deprotonation of alpha-imino carbon: pK(a) = 22, glycine-acetone iminium ion; pK(a) = 27, glycine benzaldehyde imine; pK(a) ~ 23, glycine-benzaldehyde iminium ion; and, pK(a) = 25, glycine-salicylaldehyde iminium ion. The much lower pK(a) of 17 [Toth, K.; Richard, J. P. J. Am. Chem. Soc. 2007, 129, 3013-3021] for carbon deprotonation of the adduct between 5'-deoxypyridoxal (DPL) and glycine shows that the strongly electron-withdrawing pyridinium ion is unique in driving the extended delocalization of negative charge from the alpha-iminium to the alpha-pyridinium carbon. This favors carbanion protonation at the alpha-pyridinium carbon, and catalysis of the 1,3-aza-allylic isomerization reaction that is a step in enzyme catalyzed transamination reactions. An analysis of the effect of incremental changes in structure on the activity of benzaldehyde in catalysis of deprotonation of glycine shows the carbonyl group electrophile, the 2-O(-) ring substituent and the cation pyridinium nitrogen of DPL each make a significant contribution to the catalytic activity of this cofactor analogue. The extraordinary activity of DPL in catalysis of deprotonation of alpha-amino carbon results from the summation of these three smaller effects. PMID- 21323337 TI - Carbophosphazene-supported ligand systems containing pyrazole/guanidine coordinating groups. AB - Carbophosphazene-based coordination ligands [{NC(NMe(2))}(2){NP(3,5-Me(2)Pz)(2)}] (1), [{NC(NEt)(2)}{NC(3,5-Me(2)Pz)}{NP(3,5-Me(2)Pz)(2)}] (2), [NC(3,5 Me(2)Pz)](2)[NP(3,5-Me(2)Pz)(2)] (3), [{NCCl}(2){NP(NC(NMe(2))(2))(2)}] (4), and [{NC(p-OC(5)H(4)N)}(2){NP(NC(NMe(2))(2))(2)}] (5) were synthesized and structurally characterized. In these compounds, the six-membered C(2)N(3)P ring is perfectly planar. The reaction of 1 with CuCl(2) afforded [{NC(NMe(2))}(2){NHP(O)(3,5-Me(2)Pz)}.{Cu(3,5-Me(2)PzH)(2)(Cl)}][Cl] (6). The ligand binds to Cu(II) utilizing the geminal [P(O)(3,5-Me(2)Pz)] coordinating unit. Similarly, the reaction of 2 with PdCl(2) afforded, after a metal-assisted P-N hydrolysis, [{NC(NEt)(2)}{NC(3,5-Me(2)Pz)}{NP(O)(3,5-Me(2)Pz)}.{Pd(3,5 Me(2)PzH)(Cl)}] (7). In the latter, the [P(O)(3,5-Me(2)Pz)] unit does not coordinate; in this instance, the Pd(II) is bound by a ring nitrogen atom and a carbon-tethered pyrazolyl nitrogen atom. The reaction of 3 with PdCl(2) also results in P-N bond hydrolysis affording [{NC(3,5-Me(2)Pz)(2)}{NP(O)(3,5 Me(2)Pz)}{Pd(Cl)}] (8). In contrast to 7, however, in 8, the Pd(II) elicits a nongeminal eta(3) coordination from the ligand involving two carbon-tethered pyrazolyl groups and a ring nitrogen atom. Metalated products could not be isolated in the reaction of 3 with K(2)PtCl(4). Instead, a P-O-P bridged carbodiphosphazane dimer, [{NC(3,5-Me(2)Pz)NHC(3,5-Me(2)Pz)}{NP(O)}](2) (9), was isolated as the major product. Finally, the reaction of 5 with PdCl(2) resulted in [{NC(OC(5)H(4)N)}(2){NP(NC(NMe(2))(2))(2)}.{PdCl(2)}] (10). In the latter, the exocyclic P-N bonds are quite robust and are involved in binding to the metal ion. Compounds 6-10 have been characterized by a variety of techniques including X-ray crystallography. In all of the compounds, the bond parameters of the inorganic heterocyclic rings are affected by metalation. PMID- 21323338 TI - Crystallization of calcium carbonate on chitosan substrates in the presence of regenerated silk fibroin. AB - The crystallization of calcium carbonate (CaCO3) was investigated using a mineralization system composed of a chitosan membrane and regenerated silk fibroin (RSF). Such a system may resemble the mineralization in molluscs, where chitosan is a derivative of chitin and RSF an analogue of nacreous protein. It was found that the vaterite disks generally formed on the chitosan membrane while the aragonite disks also appeared with changes of pH value or temperature of the solution. The crystallization of CaCO3 in the vicinity of the chitosan membrane was much more affected by the environment of crystallization, compared to that in bulk solution. Detailed observation from high-resolution scanning and transmission electron microscopy (HRSEM and TEM) showed that these disks consisted of nanoparticles about 20 nm in size, thus suggesting that the accumulation of hybrid CaCO3/RSF nanoparticles induced the formation of crystalline disks on the chitosan membrane. PMID- 21323339 TI - Electrochemical detection of quorum sensing signaling molecules by dual signal confirmation at microelectrode arrays. AB - n-Acyl homoserine lactones (AHLs) are produced by gram-negative bacteria to regulate gene expression in a cell density dependent manner. For instance, expression of virulence factors by pathogens such as Pseudomonas aeruginosa is induced only when a threshold concentration of AHLs is reached, which indicates that the bacterial population is big enough to promote infection. In this study, the indicator strain Agrobacterium tumefaciens NTL4 (pZLR4), which carries a beta galactosidase (beta-gal) reporter gene under the control of a quorum sensing promoter, was used to develop an electrochemical biosensor to detect AHLs using the model n-(3-oxo)-dodecanoyl-L-homoserine lactone (oxo-C12-HSL), an AHL previously detected in cystic fibrosis patients infected with P. aeruginosa. The substrate 4-aminophenyl beta-D-galactopyranoside was used to detect beta-gal activity by cyclic voltammetry. Furthermore, simultaneous monitoring of substrate consumption and p-aminophenol production by beta-gal allowed on-chip result verification by dual-signal confirmation. The sensor exhibited high reproducibility and accurately detected oxo-C12-HSL in a low picomolar to low nanomolar range in spiked liquid cultures and artificial saliva, as well as AHLs naturally released by P. aeruginosa in culture supernatants. Moreover, detection took just 2 h, required no sample pretreatment or preconcentration steps, and was easier and faster than traditional methods. PMID- 21323340 TI - Fabrication of cell chip for detection of cell cycle progression based on electrochemical method. AB - A new strategy for on-site monitoring of cell cycle progression was proposed using cell chip technology. Cell synchronization has been utilized in intensive cellular research due to the fact that cells in different phases of the cell cycle exhibit different behaviors even when exposed to the same concentrations of drugs or toxicants. However, confirmation of cell cycle arrest in research is usually dependent on fluorescence-assisted cell sorting (FACS), which is laborious, time-consuming, and expensive. In this study, we employed a cell-chip based electrochemical method to detect the cell-cycle-dependent electrochemical properties of cells. Electron transfer at the cell-electrode interface played a key role in our strategy and accurately reflected the redox activity of the cells in different phases. Rat pheochromocytoma cells were synchronized with thymidine and nocodazole, and well-defined current peaks from cells in the G1/S- and G2/M phases were significantly different as determined by differential pulse voltammetry. FACS assay and Western blot analysis were used to validate the electrochemical findings. Hence, our cell-chip-based electrochemical method can be a useful tool in determining cell cycle progression easily and economically. PMID- 21323341 TI - General strategy for performing temperature programming in high performance liquid chromatography: prediction of linear temperature gradients. AB - This paper describes how an empirical retention model is transferred from temperature-programmed gas chromatography (GC) to high temperature liquid chromatography (HT-HPLC). In order to evaluate the retention prediction, a temperature range from 50 to 180 degrees C was investigated using two test mixtures consisting of steroids and polycyclic aromatic hydrocarbons. In this temperature range, heating rates from 1.5 degrees C min(-1) up to 30 degrees C min(-1) were applied using four different high temperature stable HPLC columns with inner diameters of 1.0, 2.1, 3.0, and 4.6 mm. Temperature lag phenomena in the HPLC column as well as in the column oven are discussed, and it is shown that the linear elution strength (LES) model can be applied without any mathematical extension in order to take a temperature-dependent delay time into account. On the basis of this approximation, it is possible to perform a systematic method development using linear temperature gradients in liquid chromatography. Furthermore, it is shown that only two initial temperature gradient runs are necessary to predict the retention times of the analytes with a maximal relative error of less than 2%. PMID- 21323342 TI - Rapid determination of blood coagulation factor XIII activity using protein arrays for serodiagnosis of human plasma. AB - We developed a novel on-chip assay using protein arrays for quantitative and rapid analysis of blood coagulation factor XIII (FXIII) activity in human plasma. FXIII is activated by concerted action of thrombin and Ca(2+) and plays essential roles in hemostasis, angiogenesis, and wound healing. We fabricated protein arrays by immobilizing fibrinogen onto the 3-aminopropyltrimethoxysilane layer of well-type arrays and determined FXIII activity by analyzing biotinylated fibrinogen with Cy3-conjugated streptavidin. We determined optimal concentrations of Ca(2+), thrombin, and 5-(biotinamido)pentylamine (BAPA) for the on-chip activity assay, and the detection limit was 0.01 Lowey U/mL (9.9 pM). Using the on-chip activity assay, hepatocellular carcinoma patients (n = 24), but not hepatitis (n = 24) or liver cirrhosis patients (n = 41), had significantly lower FXIII activities (p < 0.001) than normal individuals (n = 41), indicating that FXIII activity is a possible diagnostic marker for hepatocellular carcinoma. In addition, we have successfully used this activity assay to reveal individual variations (37-57%, n = 65) in the inhibition rate of FXIII activity by isoniazid, the first-line antituberculosis agent. Thus, our optimized on-chip FXIII activity assay provides a quantitative and high-throughput approach to investigating the role(s) of FXIII in human diseases. Moreover, it has a strong potential to be applied toward FXIII-related personalized medicines. PMID- 21323343 TI - Syntheses of organic molecule-DNA hybrid structures. AB - Investigation of robust and efficient pathways to build DNA-organic molecule hybrid structures is fundamentally important to realize controlled placement of single molecules for potential applications, such as single-molecule electronic devices. Herein, we report a systematic investigation of synthetic processes for preparing organic molecule-DNA building blocks and their subsequent elongation to generate precise micrometer-sized structures. Specifically, optimal cross coupling routes were identified to enable chemical linkages between three different organic molecules, namely, polyethylene glycol (PEG), poly(p-phenylene ethynylene) (PPE), and benzenetricarboxylate, with single-stranded (ss) DNA. The resulting DNA-organic molecule hybrid building blocks were purified and characterized by both denaturing gel electrophoresis and electrospray ionization mass spectrometry (ESI-MS). The building blocks were subsequently elongated through both the DNA hybridization and ligation processes to prepare micrometer sized double-stranded (ds) DNA-organic molecule hybrid structures. The described synthetic procedures should facilitate future syntheses of various hybrid DNA based organic molecular structures. PMID- 21323344 TI - Quantification of oxidative DNA lesions in tissues of Long-Evans Cinnamon rats by capillary high-performance liquid chromatography-tandem mass spectrometry coupled with stable isotope-dilution method. AB - The purpose of our study was to develop suitable methods to quantify oxidative DNA lesions in the setting of transition metal-related diseases. Transition metal driven Fenton reactions constitute an important endogenous source of reactive oxygen species (ROS). In genetic diseases with accumulation of transition metal ions, excessive ROS production causes pathophysiological changes, including DNA damage. Wilson's disease is an autosomal recessive disorder with copper toxicosis due to deficiency of ATP7B protein needed for excreting copper into bile. The Long-Evans Cinnamon (LEC) rat bears a deletion in Atp7b gene and serves as an excellent model for hepatic Wilson's disease. We used a sensitive capillary liquid chromatography-electrospray-tandem mass spectrometry (LC-ESI-MS/MS/MS) method in conjunction with the stable isotope-dilution technique to quantify several types of oxidative DNA lesions in the liver and brain of LEC rats. These lesions included 5-formyl-2'-deoxyuridine, 5-hydroxymethyl-2'-deoxyuridine, and the 5'R and 5'S diastereomers of 8,5'-cyclo-2'-deoxyguanosine and 8,5'-cyclo-2' deoxyadenosine. Moreover, the levels of these DNA lesions in the liver and brain increased with age and correlated with age-dependent regulation of the expression of DNA repair genes in LEC rats. These results provide significant new knowledge for better understanding the implications of oxidative DNA lesions in transition metal-induced diseases, such as Wilson's disease, as well as in aging and aging related pathological conditions. PMID- 21323345 TI - Data-driven approach for metabolite relationship recovery in biological 1H NMR data sets using iterative statistical total correlation spectroscopy. AB - Statistical total correlation spectroscopy (STOCSY) is a well-established and valuable method in the elucidation of both inter- and intrametabolite correlations in NMR metabonomic data sets. Here, the STOCSY approach is extended in a novel Iterative-STOCSY (I-STOCSY) tool in which correlations are calculated initially from a driver peak of interest and subsequently for all peaks identified as correlating with a correlation coefficient greater than a set threshold. Consequently, in a single automated run, the majority of information contained in multiple STOCSY calculations from all peaks recursively correlated to the original user defined driver peak of interest are recovered. In addition, highly correlating peaks are clustered into putative structurally related sets, and the results are presented in a fully interactive plot where each set is represented by a node; node-to-node connections are plotted alongside corresponding spectral data colored by the strength of connection, thus allowing the intuitive exploration of both inter- and intrametabolite connections. The I STOCSY approach has been here applied to a (1)H NMR data set of 24 h postdose aqueous liver extracts from rats treated with the model hepatotoxin galactosamine and has been shown both to recover the previously deduced major metabolic effects of treatment and to generate new hypotheses even on this well-studied model system. I-STOCSY, thus, represents a significant advance in correlation based analysis and visualization, providing insight into inter- and intrametabolite relationships following metabolic perturbations. PMID- 21323346 TI - Detection of mercury ion by infrared fluorescent protein and its hydrogel-based paper assay. AB - Mercury is a highly hazardous and widespread pollutant with bioaccumulative properties. Novel approaches that meet the criteria of desired selectivity, high sensitivity, good biocompatibility, and low background interference in natural settings are continuously being explored. We herein describe a new strategy utilizing the combination of infrared fluorescent protein (IFP) and its chromophore as an infrared fluorescence probe for mercury ion (Hg(II)) detection. Hg(II) has been validated to have specific binding affinity to a cysteine residue (C24) of IFP, thereby inhibiting the conjugation of IFP chromophore biliverdin (BV) to C24 and "turning off" the infrared emission of IFP. The IFP/BV sensor has high selectivity toward Hg(II) among other metal ions over a broad pH range. The in vitro detection limit was determined to be less than 50 nM. As a genetically encoded probe, we demonstrate the IFP/BV sensor can serve as a tool to detect Hg(II) in living organisms or tissues. Moreover, we have exploited a protein agarose hydrogel-based paper assay to immobilize IFP for detection of Hg(II) in a portable and robust fashion. PMID- 21323347 TI - Thiostrepton maturation involving a deesterification-amidation way to process the C-terminally methylated peptide backbone. AB - Thiopeptides are a class of clinically interesting and highly modified peptide antibiotics. Their biosyntheses share a common paradigm for characteristic core formation but differ in tailoring to afford individual members. Herein we report an unusual deesterification-amidation process in thiostrepton maturation to furnish the terminal amide moiety. TsrB, serving as a carboxylesterase, catalyzes the hydrolysis of the methyl ester intermediate to provide the carboxylate intermediate, which can be converted to the amide product by an amidotransferase, TsrC. These findings revealed a C-terminal methylation of the precursor peptide, which is cryptic in thiostrepton biosynthesis but potentially common in the formation of its homologous series of thiopeptides that vary in the C-terminal form as methyl ester, carboxylate, or amide. PMID- 21323348 TI - Characterization of a glutenin-specific serine proteinase of Sunn bug Eurygaster integricepts Put. AB - Glutenin hydrolyzing proteinases (GHPs) have been purified, by affinity chromatography, from wheat seeds damaged by the Sunn bug Eurygaster integriceps (Hemiptera, Scutelleridae). A 28 kDa protein was partially sequenced by mass spectrometry and Edman degradation which showed homology to serine proteases from various insects. Three full length clones were obtained from cDNA isolated from Sunn bug salivary glands using degenerate PCR based on the sequences obtained. The cleavage site of the protease was determined using recombinant and synthetic peptides and shown to be between the consensus hexapeptide and nonapeptide repeat motifs present in the high molecular weight subunits of wheat glutenin (PGQGQQ?GYYPTSLQQ). Homology models were generated for the three proteinases identified in this study using the high resolution X-ray structure of a crayfish (Pontastacus leptodactylus) trypsin complexed with a peptide inhibitor as template (PDB accession 2F91). The novel specificity of this protease may find applications in both fundamental and applied studies. PMID- 21323349 TI - Continuous transition from 3D to 1D confinement observed during the formation of CdSe nanoplatelets. AB - We study the formation of colloidal CdSe nanoplatelets using both tansmission electron microscopy (TEM) and spectroscopic analysis. We show that the platelets form by continuous lateral extension of small (<2 nm) nanocrystal CdSe seeds. The nanoplatelet thickness is fixed by the seed dimension and remains constant during the platelet formation. The nanoplatelet lateral dimensions can be tuned using additional precursor injection. Absorption and fluorescence analysis of the CdSe nanoplatelets as they continuously extend laterally confirms a continuous transition from 3D to 1D confined nanoparticles. The formation of the CdSe platelets is found to be similar for different platelet thicknesses that we control with a precision of one CdSe monolayer. PMID- 21323351 TI - Dynamic metabonomic responses of tobacco (Nicotiana tabacum) plants to salt stress. AB - Metabolic responses are important for plant adaptation to osmotic stresses. To understand the dosage and duration dependence of salinity effects on plant metabolisms, we analyzed the metabonome of tobacco plants and its dynamic responses to salt treatments using NMR spectroscopy in combination with multivariate data analysis. Our results showed that the tobacco metabonome was dominated by 40 metabolites including organic acids/bases, amino acids, carbohydrates and choline, pyrimidine, and purine metabolites. A dynamic trajectory was clearly observable for the tobacco metabonomic responses to the dosage of salinity. Short-term low-dose salt stress (50 mM NaCl, 1 day) caused metabolic shifts toward gluconeogenesis with depletion of pyrimidine and purine metabolites. Prolonged salinity with high-dose salt (500 mM NaCl) induced progressive accumulation of osmolytes, such as proline and myo-inositol, and changes in GABA shunt. Such treatments also promoted the shikimate-mediated secondary metabolisms with enhanced biosynthesis of aromatic amino acids. Therefore, salinity caused systems alterations in widespread metabolic networks involving transamination, TCA cycle, gluconeogenesis/glycolysis, glutamate mediated proline biosynthesis, shikimate-mediated secondary metabolisms, and the metabolisms of choline, pyrimidine, and purine. These findings provided new insights for the tobacco metabolic adaptation to salinity and demonstrated the NMR-based metabonomics as a powerful approach for understanding the osmotic effects on plant biochemistry. PMID- 21323352 TI - Correcting for heat capacity and 5'-TA type terminal nearest neighbors improves prediction of DNA melting temperatures using nearest-neighbor thermodynamic models. AB - Nearest-neighbor thermodynamic (NNT) models currently provide some of the most accurate predictions of melting thermodynamics, including melting temperature (T(m)) values, for short DNA duplexes. Inherent to all existing NNT models is the assumption that DeltaH degrees and DeltaS degrees for the helix-to-coil transition are temperature invariant. Here we investigate the impact that this zero-DeltaC(p) assumption has on the accuracy of T(m) predictions for 128 DNA duplexes. Previous and new melting thermodynamic data are analyzed to establish an estimate of DeltaC(p)(bp), the heat capacity change per base pair, of 42 +/- 16 cal mol(-1) K(-1) bp(-1), as well as an optimal thermodynamic reference temperature (T(ref)) of 53 +/- 5 degrees C. These results were used to modify the unified NNT model to properly account for the temperature dependence of DeltaH degrees and DeltaS degrees and thereby extend the range over which T(m) is accurately predicted. This new approach is shown to be especially useful for duplexes that melt at a T(m) greater than 70 degrees C. Thermodynamic data collected by differential scanning calorimetry (DSC) for 16 duplexes designed to melt over a broad temperature range were used to verify the values of DeltaC(p)(bp) and T(ref) and to show that DeltaC(p)(bp) is essentially constant above 37 degrees C. Additional DSC analysis of 12 duplex sequences containing all 10 nearest neighbors allowed for errors associated with different terminal nearest neighbors to be examined and showed that duplexes containing one or more terminal 5'-TA groups are significantly more stable than predicted by the unified NNT model. A correction to improve prediction of the hybridization thermodynamics of duplexes with terminal 5'-TA groups is provided. PMID- 21323353 TI - P123-PMMA dual-templating generation and unique physicochemical properties of three-dimensionally ordered macroporous iron oxides with nanovoids in the crystalline walls. AB - Three-dimensionally (3D) ordered macroporous (3DOM) iron oxides with nanovoids in the rhombohedrally crystallized macroporous walls were fabricated by adopting the dual-templating [Pluronic P123 and poly(methyl methacrylate) (PMMA) colloidal microspheres] strategy with ferric nitrate as the metal precursor in an ethanol or ethylene glycol and methanol mixed solution and after calcination at 550 degrees C. The possible formation mechanisms of such architectured materials were discussed. The physicochemical properties of the materials were characterized by means of techniques such as XRD, TGA/DSC, FT-IR, BET, HRSEM, HRTEM/SAED, UV-vis, XPS, and H(2)-TPR. The catalytic properties of the materials were also examined using toluene oxidation as a probe reaction. It is shown that 3DOM-structured alpha-Fe(2)O(3) without nanovoids in the macroporous walls was formed in the absence of P123 during the fabrication process, whereas the dual-templating strategy gave rise to alpha-Fe(2)O(3) materials that possessed high-quality 3DOM structures with the presence of nanovoids in the polycrystalline macropore walls and higher surface areas (32-46 m(2)/g). The surfactant P123 played a key role in the generation of nanovoids within the walls of the 3DOM-architectured iron oxides. There was the presence of multivalent iron ions and adsorbed oxygen species on the surface of each sample, with the trivalent iron ion and oxygen adspecies concentrations being different from sample to sample. The dual templating fabricated iron oxide samples exhibited much better low-temperature reducibility than the bulk counterpart. The copresence of a 3DOM-structured skeleton and nanovoids in the macropore walls gave rise to a drop in the band-gap energy of iron oxide. The higher oxygen adspecies amounts, larger surface areas, better low-temperature reducibility, and unique nanovoid-containing 3DOM structures of the iron oxide materials accounted for their excellent catalytic performance in the oxidation of toluene. PMID- 21323354 TI - Molecular recognition of 4-nonylphenol on a layered silicate modified with organic functionalities. AB - A layered alkali silicate, octosilicate (Na2Si8O17), modified with the controlled amount and ratio of octadecyl and phenyl groups was synthesized to control the spatial distribution of the two functional groups and then achieve the effective and selective adsorption of 4-nonylphenol from aqueous solution. Octosilicates modified with the varied amount and ratio of the attached octadecyl/phenyl groups (0.7/0.7, 0.4/0.4, 0.3/0.3, and 0.4/1.0 groups per Si8O17 unit, respectively) were prepared by the reaction of the dodecylammonium-exchanged octosilicate with a controlled amount of octadecyltrichlorosilane and phenyltrichlorosilane sequentially. The adsorption of 4-nonylphenol from water on the four silylated octosilicates was investigated to find that the adsorption isotherm for the silylated octosilicate bearing the surface coverage with octadecyl/phenyl groups of 0.7/0.7 groups per Si8O17 unit was H-type, while the other silylated octosilicates gave S-type adsorption isotherms. The silylated octosilicate having surface coverage with octadecyl/phenyl groups of 0.7/0.7 groups per Si8O17 unit selectively adsorbed 4-nonylphenol from aqueous mixture of 4-butylphenol, 4 hexylphenol, and 4-nonylphenol. PMID- 21323355 TI - Protein sensing and cell discrimination using a sensor array based on nanomaterial-assisted chemiluminescence. AB - Cross-reactive sensor arrays, known as "chemical noses", offer an alternative to time-consuming analytical methods. Here, we report a sensor array based on nanomaterial-assisted chemiluminescence (CL) for protein sensing and cell discrimination. We have found that the CL efficiencies are improved to varied degrees for a given protein or cell line on catalytic nanomaterials. Distinct CL response patterns as "fingerprints" can be obtained on the array and then identified through linear discriminant analysis (LDA). The sensing of 12 kinds of proteins at three concentrations, as well as 12 types of human cell lines among normal, cancerous, and metastatic, has been performed. Compared with most fluorescent or colorimetric approaches which rely on the strong interaction between analytes and sensing elements, our array offers the advantage of both sensitivity and reversibility. PMID- 21323356 TI - Electrostatically directed visual fluorescence response of DNA-functionalized monolithic hydrogels for highly sensitive Hg2+ detection. AB - Hydrogels are cross-linked hydrophilic polymer networks with low optical background and high loading capacity for immobilization of biomolecules. Importantly, the property of hydrogel can be precisely controlled by changing the monomer composition. This feature, however, has not been investigated in the rational design of hydrogel-based optical sensors. We herein explore electrostatic interactions between an immobilized mercury binding DNA, a DNA staining dye (SYBR Green I), and the hydrogel backbone. A thymine-rich DNA was covalently functionalized within monolithic hydrogels containing a positive, neutral, or negative backbone. These hydrogels can be used as sensors for mercury detection since the DNA can selectively bind Hg(2+) between thymine bases inducing a hairpin structure. SYBR Green I can then bind to the hairpin to emit green fluorescence. For the neutral or negatively charged gels, addition of the dye in the absence of Hg(2+) resulted in intense yellow background fluorescence, which was attributed to SYBR Green I binding to the unfolded DNA. We found that, by introducing 20% positively charged allylamine monomer, the background fluorescence was significantly reduced. This was attributed to the repulsion between positively charged SYBR Green I by the gel matrix as well as the strong binding between the DNA and the gel backbone. The signal-to-background ratio and detection limit was, respectively, improved by 6- and 9-fold using the cationic gel instead of neutral polyacrylamide gel. This study helps understand the electrostatic interaction within hydrogels, showing that hydrogels can not only serve as a high capacity matrix for sensor immobilization but also can actively influence the interaction between involved molecules. PMID- 21323357 TI - Crystal structure, phase, and electrical conductivity of nanocrystalline W0.95Ti(0.05)O3 thin films. AB - W(0.95)Ti(0.05)O(3) films were fabricated using sputter-deposition onto Si(100) wafers in by varying the growth temperature from room temperature (RT) to 500 degrees C. X-ray diffraction (XRD), high-resolution scanning electron microscopy (SEM) coupled with energy-dispersive X-ray spectrometry (EDS), and Raman spectroscopy (RS) were performed to investigate the effect of temperature on the growth behavior, crystal structure, texturing, surface morphology, and chemical bonding of W(0.95)Ti(0.5)O(3) films. The results indicate that the effect of temperature is significant on the growth and microstructure of W(0.95)Ti(0.05)O(3) films. XRD results indicate that the effect of Ti is remarkable on the crystallization of WO(3). W(0)(.95)Ti(0.05)O(3) films grown at temperatures <300 degrees C are amorphous compared to pure WO(3) crystalline films crystallizing at 200 degrees C. Phase transformation is induced in W(0)(.95)Ti(0.05)O(3) resulting in tetragonal structure at >=300 degrees C. The structural changes were also reflected in the intensities of -W-O-W- vibrational modes in RS measurements. The SEM imaging analysis indicates that the phase transformations are accompanied by a characteristic change in surface morphology. Room temperature electrical conductivity of W(0.95)Ti(0.05)O(3) films increases from 0.63 to 27 (Omega m)(-1) with increasing temperature from RT to 400 degrees C due to improved structural order. Electrical conductivity exhibit a decrease at 500 degrees C (7.4 (Omega m)(-1)) due to disordering induced by Ti segregation, which is confirmed by XRD and RS measurements. PMID- 21323359 TI - HIV-1 IN strand transfer chelating inhibitors: a focus on metal binding. AB - Most active and selective strand transfer HIV-1 integrase (IN) inhibitors contain chelating functional groups that are crucial feature for the inhibition of the catalytic activities of the enzyme. In particular, diketo acids and their derivatives can coordinate one or two metal ions within the catalytic core of the enzyme. The present work is intended as a contribution to elucidate the mechanism of action of the HIV-IN inhibitors by studying the coordinative features of H2L1 (L-708,906), an important member of the diketo acids family of inhibitors, and H2L2, a model for S-1360, another potent IN inhibitor. Magnesium(II) and manganese(II) complexes of H2L1 and H2L2 were isolated and fully characterized in solution and in the solid state. The crystal structures of the manganese complex [Mn(HL2)2(CH3OH)2].2CH3OH were solved by X-ray diffraction analysis. Moreover, the speciation models for H2L2 with magnesium(II) and manganese(II) ions were performed and the formation constants of the complexes were measured. M(HL2)2 (M = Mg2+, Mn2+) was the most abundant species in solution at physiological pH. All the synthesized compounds were tested for their anti-IN activity, showing good results both for the ligand and the corresponding complexes. From analysis of the speciation models and of the biological data we can conclude that coordination of both metal cofactors could not be strictly necessary and that inhibitors can act as complexes and not only as free ligands. PMID- 21323358 TI - Modulating LOV domain photodynamics with a residue alteration outside the chromophore binding site. AB - Phototropins, a class of light-activated protein kinases, are essential for several blue light responses in plants and algae, including phototropism. These proteins contain two internal light, oxygen, and voltage sensitive (LOV) domains, which bind flavin chromophores and undergo a reversible photochemical formation of a cysteinyl-flavin adduct as part of the light sensing process. While the photodynamic properties of such photosensory domains are dictated by interactions between the chromophore and surrounding protein, more distant residues can play a significant role as well. Here we explore the role of the Phe434 residue in the photosensory response of the second LOV domain of Avena sativa phototropin 1 (AsLOV2), a model photochemical system for these LOV domains. Phe434 is more than 6 A from the FMN chromophore in AsLOV2; nevertheless, an F434Y point mutation is likely to change several structural features of the chromophore binding site, as we demonstrate using molecular dynamics simulations. Transient absorption signals spanning 15 decades in time were compared for wild-type AsLOV2 and the F434Y mutant, showing that the latter has significantly altered photodynamics, including (i) a faster intersystem crossing leading to triplet formation on a nanosecond time scale, (ii) biphasic formation of adduct-state kinetics on the microsecond time scale, and (iii) greatly accelerated ground-state recovery kinetics on a second time scale. We present mechanistic models that link these spectroscopic differences to changes in the configuration of the critical cysteine residue and in the chromophore's accessibility to solvent and oxygen according to MD trajectories and purging experiments. Taken together, these results demonstrate the importance of residues outside the chromophore-binding pocket in modulating LOV domain photodynamics. PMID- 21323360 TI - Effect of polymer aggregation on the open circuit voltage in organic photovoltaic cells: aggregation-induced conjugated polymer gel and its application for preventing open circuit voltage drop. AB - To investigate the structure-dependent aggregation behavior of conjugated polymers and the effect of aggregation on the device performance of conjugated polymer photovoltaic cells, new conjugated polymers (PVTT and CN-PVTT) having the same regioregularity but different intermolecular packing were prepared and characterized by means of UV-vis spectroscopy and atomic force microscopy (AFM). Photovoltaic devices were prepared with these polymers under different polymer aggregate conditions. Polymer aggregation induced by thermal annealing increases the short circuit current but provides no advantage in the overall power conversion efficiency because of a decrease in the open circuit voltage. The device fabricated from a pre-aggregated polymer suspension, acquired from ultrasonic agitation of a conjugated polymer gel, showed enhanced performance because of better phase separation and reduced recombination between polymer/PCBM. PMID- 21323361 TI - Structural properties of lithium thio-germanate thin film electrolytes grown by radio frequency sputtering. AB - In this study, lithium thio-germanate thin film electrolytes have been successfully prepared by radio frequency (RF) magnetron sputtering deposition in Ar gas atmospheres. The targets for RF sputtering were prepared by milling and pressing appropriate amounts of the melt-quenched starting materials in the nLi(2)S + GeS(2) (n = 1, 2, and 3) binary system. Approximately 1 MUm thin films were grown on Ni coated Si (Ni/Si) substrates and pressed CsI pellets using 50 W power and 25 mtorr (~3.3 Pa) Ar gas pressures to prepare samples for Raman and Infrared (IR) spectroscopy, respectively. To improve the adhesion between the silicon substrate and the thin film electrolyte, a sputtered Ni layer (~120 nm) was used. The surface morphologies and thickness of the thin films were determined by field emission scanning electron microscopy (FE-SEM). The structural properties of the starting materials, target materials, and the grown thin films were examined by X-ray diffraction (XRD), Raman, and IR spectroscopy. PMID- 21323362 TI - Computational study on the anomalous fluorescence behavior of isoflavones. AB - Isoflavones are known to show fluorescence with intensities that depend strongly on the solvent properties and exhibit Stokes' shifts as large as 1.4 eV. While some of this behavior can be explained by (excited state) deprotonation, this mechanism does not apply for all isoflavones. The aim of this study is to computationally and experimentally investigate the reasons for this anomalous behavior of neutral isoflavones, taking the daidzein molecule as a model compound. We find that the absence in fluorescence in aprotic solvents and the weak fluorescence in protic solvents can be explained by a change of order of the lowest singlet states in which a fluorescent charge-transfer state lies below the nonfluorescent locally excited state in water but not in acetonitrile. The large Stokes' shift is partly due to a significant rotation among the chromone-phenyl bond in the excited state. PMID- 21323363 TI - Borate binding to polyol-stabilized latex. AB - Borate or 4-carboxyphenylboronate anions condense with diol units on poly(glycerol monomethacrylate) stabilizer chains at the surface of polystyrene latex, increasing the latex charge density. Combining Leibler's equilibrium binding model with Ohshima's hydrogel electrophoresis model simulated the primary experimental observation: the electrophoretic mobility of this latex becomes much more negative above pH 9.5 because of borate anion binding. There is an unusual inverse relation between the electrophoretic mobility and the density of borate anions bound to the latex particles. Very high solution concentrations of borate ions and hence high ionic strengths are required to give high densities of bound borate ions. Thus, mobilities decrease in spite of increasing charge density with borate addition because of increased screening at high ionic strength. PMID- 21323364 TI - Enantioselective synthesis of axially chiral hydroxy carboxylic acid derivatives by rhodium-catalyzed [2 + 2 + 2] cycloaddition. AB - Axially chiral hydroxy carboxylic acid derivatives were successfully synthesized with high yields and ee values by the cationic rhodium(I)/axially chiral biaryl bisphosphine complex-catalyzed enantioselective [2 + 2 + 2] cycloaddition. Axially chiral hydroxy and dihydroxy carboxylic acid derivatives, bearing the aryl group at the ortho-position of the alkoxycarbonyl group, were also synthesized with high regio- and enantioselectivity. PMID- 21323365 TI - Formation and decomposition of new and unknown polar brominated disinfection byproducts during chlorination. AB - Brominated disinfection byproducts (Br-DBPs) are generally more cytotoxic and genotoxic than their chlorinated analogues. A great portion of total organic bromine in chlorinated drinking water is still unknown and may be ascribed to polar Br-DBPs. In this work, a novel approach, precursor ion scan using ultra performance liquid chromatography/electrospray ionization-triple quadrupole mass spectrometry, was adopted and further developed for selective detection and identification of polar Br-DBPs, which made it possible to reveal the whole picture of the formation and decomposition of polar Br-DBPs during chlorination. Simulated drinking water samples with chlorine contact times from 1 min to 7 d were analyzed. Many new polar aromatic and unsaturated aliphatic Br-DBPs were detected and tentatively proposed with chemical structures, of which 2,4,6 tribromophenol, 3,5-dibromo-4-hydroxybenzoic acid, 2,6-dibromo-1,4-hydroquinone, and 3,3-dibromopropenoic acid were confirmed or identified with authentic standards. It was found that various polar Br-DBPs formed and reached the maximum levels at different chlorine contact times; high molecular weight Br-DBPs might undergo decomposition to relatively low molecular weight Br-DBPs or even finally to haloacetic acids and trihalomethanes. The decomposition of newly detected intermediate Br-DBPs (including molecular ion cluster m/z 345/347/349/351, 2,4,6 tribromophenol, and 3,5-dibromo-4-hydroxybenzoic acid) during chlorination was investigated in detail. The "black box" from the input of "humic substances + bromide + chlorine" through the output of "haloacetic acids + trihalomethanes" was opened to a significant extent. PMID- 21323366 TI - Atomic structures suggest determinants of transmission barriers in mammalian prion disease. AB - Prion represents a unique class of pathogens devoid of nucleic acid. The deadly diseases transmitted by it between members of one species and, in certain instances, to members of other species present a public health concern. Transmissibility and the barriers to transmission between species have been suggested to arise from the degree to which a pathological protein conformation from an individual of one species can seed a pathological conformation in another species. However, this hypothesis has never been illustrated at an atomic level. Here we present three X-ray atomic structures of the same segment from human, mouse, and hamster PrP, which is critical for forming amyloid and confers species specificity in PrP seeding experiments. The structures reveal that different sequences encode different steric zippers and suggest that the degree of dissimilarity of these zipper structures gives rise to transmission barriers in prion disease, such as those that protect humans from acquiring bovine spongiform encephalopathy (BSE) and chronic wasting disease (CWD). PMID- 21323367 TI - A comparison of spray drying and milling in the production of amorphous dispersions of sulfathiazole/polyvinylpyrrolidone and sulfadimidine/polyvinylpyrrolidone. AB - Formulations containing amorphous active pharmaceutical ingredients (APIs) present great potential to overcome problems of limited bioavailability of poorly soluble APIs. In this paper, we directly compare for the first time spray drying and milling as methods to produce amorphous dispersions for two binary systems (poorly soluble API)/excipient: sulfathiazole (STZ)/polyvinylpyrrolidone (PVP) and sulfadimidine (SDM)/PVP. The coprocessed mixtures were characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and intrinsic dissolution tests. PXRD and DSC confirmed that homogeneous glassy solutions (mixture with a single glass transition) of STZ/PVP were obtained for 0.05 <= X(PVP) (PVP weight fraction) < 1 by spray drying and for 0.6 <= X(PVP) < 1 by milling (at 400 rpm), and homogeneous glassy solutions of SDM/PVP were obtained for 0 < X(PVP) < 1 by spray drying and for 0.7 <= X(PVP) < 1 by milling. For these amorphous composites, the value of T(g) for a particular API/PVP ratio did not depend on the processing technique used. Variation of T(g) versus concentration of PVP was monotonic for all the systems and matched values predicted by the Gordon-Taylor equation indicating that there are no strong interactions between the drugs and PVP. The fact that amorphous SDM can be obtained on spray drying but not amorphous STZ could not be anticipated from the thermodynamic driving force of crystallization, but may be due to the lower molecular mobility of amorphous SDM compared to amorphous STZ. The solubility of the crystalline APIs in PVP was determined and the activities of the two APIs were fitted to the Flory-Huggins model. Comparable values of the Flory-Huggins interaction parameter (chi) were determined for the two systems (chi = -1.8 for SDM, chi = -1.5 for STZ) indicating that the two APIs have similar miscibility with PVP. Zones of stability and instability of the amorphous dispersions as a function of composition and temperature were obtained from the Flory-Huggins theory and the Gordon-Taylor equation and were found to be comparable for the two APIs. Intrinsic dissolution studies in aqueous media revealed that dissolution rates increased in the following order: physical mix of unprocessed materials < physical mix of processed material < coprocessed materials. This last result showed that production of amorphous dispersions by co milling can significantly enhance the dissolution of poorly soluble drugs to a similar magnitude as co-spray dried systems. PMID- 21323368 TI - Synthetically directed self-assembly and enhanced surface-enhanced Raman scattering property of twinned crystalline Ag/Ag homojunction nanoparticles. AB - A synthetically directed self-assembly strategy to the aqueous-phase synthesis of twinned crystalline silver/silver homojunction nanoparticles (Ag/Ag HJNPs) is demonstrated. In the self-assembly, ethylenediamine tetraacetic acid disodium (EDTA) and solution pH values play a crucial role in the formation of Ag/Ag HJNPs while the sizes of Ag nanoparticles (NPs) in the Ag/Ag HJNPs depend on the reductant concentrations of ascorbic acid. Surface-enhanced Raman scattering (SERS) measurements indicate that the SERS intensity acquired from the Ag/Ag HJNP colloidal solution is about 200 times stronger than that obtained from isolated Ag NP colloid solution. The plasmonic and SERS behaviors of Ag/Ag HJNPs were simulated by discrete-dipole approximation (DDA) and three-dimensional finite difference time domain (3D-FDTD) methods, respectively. Theoretical calculation results disclose that surface plasmon resonance (SPR) properties of the Ag/Ag HJNPs are different from those of isolated Ag nanospheres, and their maximal SERS enhancement is about 2 orders of magnitude higher than that of isolated Ag nanospheres, which is in good agreement with the experimental results. The extra SERS enhancement can be explained by the hot spots at homojunction structures between Ag particles because of near-field coupling effect. PMID- 21323369 TI - A catalytic route to ampakines and their derivatives. AB - A catalytic domino reaction that efficiently provides access to an important class of heterocycles, the ampakines, is reported. Our approach is based on the cobalt-catalyzed hydroformylation of dihydrooxazines and allows for the facile synthesis of the pharmaceutically interesting compound CX-614 and related substances. PMID- 21323370 TI - Local and global dynamics of the G protein-coupled receptor CXCR1. AB - The local and global dynamics of the chemokine receptor CXCR1 are characterized using a combination of solution NMR and solid-state NMR experiments. In isotropic bicelles (q = 0.1), only 13% of the expected number of backbone amide resonances is observed in (1)H/(15)N HSQC solution NMR spectra of uniformly (15)N-labeled samples; extensive deuteration and the use of TROSY made little difference in the 800 MHz spectra. The limited number of observed amide signals is ascribed to mobile backbone sites and assigned to specific residues in the protein; 19 of the signals are from residues at the N-terminus and 25 from residues at the C terminus. The solution NMR spectra display no evidence of local backbone motions from residues in the transmembrane helices or interhelical loops of CXCR1. This finding is reinforced by comparisons of solid-state NMR spectra of both magnetically aligned and unoriented bilayers containing either full-length or doubly N- and C-terminal truncated CXCR1 constructs. CXCR1 undergoes rapid rotational diffusion about the normal of liquid crystalline phospholipid bilayers; reductions in the frequency span and a change to axial symmetry are observed for both carbonyl carbon and amide nitrogen chemical shift powder patterns of unoriented samples containing (13)C- and (15)N-labeled CXCR1. In contrast, when the phospholipids are in the gel phase, CXCR1 does not undergo rapid global reorientation on the 10(4) Hz time scale defined by the carbonyl carbon and amide nitrogen chemical shift powder patterns. PMID- 21323371 TI - Glycosyl sulfonium ions as storable intermediates for glycosylations. AB - Glycosyl sulfonium ions, which serve as persistent glycosyl cation equivalents, were prepared by the addition of diorganosulfides to an electrochemically generated glycosyl triflate. Low-temperature and variable-temperature NMR studies were performed to reveal the structure, stability, and reactivity of glycosyl sulfonium ions. The glycosyl sulfonium ions could be used as storable intermediates for reactions with various glycosyl acceptors including thioglycosides to give the corresponding disaccharides. PMID- 21323373 TI - Second- and third-order nonlinearities of novel push-pull azobenzene polymers. AB - In this work, the second- and third-order nonlinear optical response of spin deposited thin films of three different push-pull side chain azobenzene polymers is investigated by the second- and third-harmonic Maker fringes techniques using 30 ps laser pulses at a fundamental wavelength of 1064 nm. Measurements were carried out before and after aligning the chromophores by corona poling of the films, while different polarization configurations have been utilized. Strong dependence of the response upon the structure of the systems has been found, which is related to the different charge transfer within the molecules. The reported findings are compared with already published results. PMID- 21323372 TI - Synthesis of the cytotrienin A core via metal catalyzed C-C coupling. AB - A synthetic approach to the C17-benzene ansamycins via metal catalyzed C-C coupling is described. Key bond formations include direct iridium catalyzed carbonyl crotylation from the alcohol oxidation level followed by chelation controlled Sakurai-Seyferth dienylation to form the stereotriad, which is attached to the arene via Suzuki cross-coupling. The diene-containing carboxylic acid is prepared using rhodium catalyzed acetylene-aldehyde reductive C-C coupling mediated by gaseous hydrogen. Finally, ring-closing metathesis delivers the cytotrienin core. PMID- 21323374 TI - Highly uniform self-assembled conducting polymer/gold fibrous nanocomposites: additive-free controllable synthesis and application as efficient recyclable catalysts. AB - Uniform poly(2-aminothiophenol) nanofibers embedded with highly dispersed gold nanoparticles have been fabricated through a facile templateless one-step method. The diameter of composite nanofibers can be controlled in the range of 200-80 nm by simply tuning the speed of mechanical stirring during materials synthesis. Results from our work will provide insight into the shape-controlled synthesis of other nanomaterials by simply introducing mechanical agitation. Removal of gold nanoparticles in composite nanofibers leads to polymer nanotubes with continuous or incontinuous nanocavities depending on mechanical stirring speeds. Furthermore, morphology-dependent catalytic performances of such composites are also investigated. PMID- 21323376 TI - Graphene/silicon nanowire Schottky junction for enhanced light harvesting. AB - Schottky junction solar cells are assembled by directly coating graphene films on n-type silicon nanowire (SiNW) arrays. The graphene/SiNW junction shows enhanced light trapping and faster carrier transport compared to the graphene/planar Si structure. With chemical doping, the SiNW-based solar cells showed energy conversion efficiencies of up to 2.86% at AM1.5 condition, opening a possibility of using graphene/semiconductor nanostructures in photovoltaic application. PMID- 21323377 TI - Coumarin-based thiol chemosensor: synthesis, turn-on mechanism, and its biological application. AB - A new chemodosimetric probe (1) is reported that selectively detects thiols over other relevant biological species by the turning on of its fluorescence through a Michael type reaction. The fluorogenic process upon its reaction was revealed to be mediated by intramolecular charge transfer, as confirmed by time-dependent density functional theory calculations. The application of probe 1 to cells is also examined by confocal microscopy, and its cysteine preference was observed by an ex vivo LC-MS analysis of the cellular metabolite. PMID- 21323375 TI - In vivo optical imaging of acute cell death using a near-infrared fluorescent zinc-dipicolylamine probe. AB - Cell death is a fundamental biological process that is present in numerous disease pathologies. Fluorescent probes that detect cell death have been developed for a myriad of research applications ranging from microscopy to in vivo imaging. Here we describe a synthetic near-infrared (NIR) conjugate of zinc(II)-dipicolylamine (Zn2+-DPA) for in vivo imaging of cell death. Chemically induced in vivo models of myopathy were established using an ionphore, ethanol, or ketamine as cytotoxins. The Zn2+-DPA fluorescent probe or corresponding control was subsequently injected, and whole animal fluorescence imaging demonstrated probe uptake at the site of muscle damage, which was confirmed by ex vivo and histological analyses. Further, a comparative study with a NIR fluorescent conjugate Annexin V showed less intense uptake at the site of muscle damage and high accumulation in the bladder. The results indicate that the fluorescent Zn2+-DPA conjugate is an effective probe for in vivo cell death detection and in some cases may be an appropriate alternative to fluorescent Annexin V conjugates. PMID- 21323378 TI - Uniform hollow Lu2O3:Ln (Ln = Eu3+, Tb3+) spheres: facile synthesis and luminescent properties. AB - Uniform hollow Lu(2)O(3):Ln (Ln = Eu(3+), Tb(3+)) phosphors have been successfully prepared via a urea-assisted homogeneous precipitation method using carbon spheres as templates, followed by a subsequent calcination process. X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transformed infrared (FT-IR), thermogravimetric and differential thermal analysis (TG-DTA), photoluminescence (PL) spectra, cathodoluminescence (CL) spectra, kinetic decays, quantum yields (QY), and UV visible diffuse reflectance spectra were employed to characterize the samples. The results show that hollow Lu(2)O(3):Ln spheres can be indexed to cubic Gd(2)O(3) phase with high purity. The as-prepared hollow Lu(2)O(3):Ln phosphors are confirmed to be uniform in shape and size with diameter of about 300 nm and shell thickness of approximate 20 nm. The possible formation mechanism of evolution from the carbon spheres to the amorphous precursor and to the final hollow Lu(2)O(3):Ln microspheres has been proposed. Upon ultraviolet (UV) and low voltage electron beams excitation, the hollow Lu(2)O(3):Ln (Ln = Eu(3+), Tb(3+)) spheres exhibit bright red (Eu(3+), (5)D(0)-(7)F(2)) and green (Tb(3+), (5)D(4) (7)F(5)) luminescence, which may find potential applications in the fields of color display and biomedicine. PMID- 21323379 TI - Special issue in honor of Koji Nakanishi. PMID- 21323380 TI - DNA-functionalized nanochannels for SNP detection. AB - We have developed ultrahigh density array of functionalized nanochannels by using a block copolymer having end di-COOH group. This approach provides a facile route for direct functionalization of wall surface of the nanochannels and immobilization site for molecular recognition agents (MRAs). By using overhanging single-stranded DNA as MRAs, the DNA-functionalized nanochannels showed high resolution to detect a single-base mismatch as well as to discriminate single mismatched sequence at various locations by hybridization preference with MRAs. PMID- 21323381 TI - Controlling electric dipoles in nanodielectrics and its applications for enabling air-stable n-channel organic transistors. AB - We present a new method to manipulate the channel charge density of field-effect transistors using dipole-generating self-assembled monolayers (SAMs) with different anchor groups. Our approach maintains an ideal interface between the dipole layers and the semiconductor while changing the built-in electric potential by 0.41-0.50 V. This potential difference can be used to change effectively the electrical properties of nanoelectronic devices. We further demonstrate the application of the SAM dipoles to enable air-stable operation of n-channel organic transistors. PMID- 21323382 TI - The nature of the catalytically active species in olefin dioxygenation with PhI(OAc)2: metal or proton? AB - Evidence for the protiocatalytic nature of the diacetoxylation of alkenes using PhI(OAc)(2) as oxidant is presented. Systematic studies into the catalytic activity in the presence of proton-trapping and metal-complexing agents indicate that protons act as catalysts in the reaction. Using triflic acid as catalyst, the selectivity and reaction rate of the conversion is similar or superior to most efficient metal-based catalysts. Metal cations, such as Pd(II) and Cu(II), may interact with the oxidant in the initiation phase of the catalytic transformation; however, 1 equiv of strong acid is produced in the first cycle which then functions as the active catalyst. Based on a kinetic study as well as in situ mass spectrometry, a mechanistic cycle for the proton-catalyzed reaction, which is consistent with all experimental data presented in this work, is proposed. PMID- 21323383 TI - Synthetic studies toward A-74528. AB - A potentially biomimetic approach toward the complex polyketide A-74528 is described. It is based on highly substituted biaryl compounds, synthesized using advanced cross-coupling and condensation methodologies. PMID- 21323384 TI - Pd-catalyzed desulfitative Heck coupling with dioxygen as the terminal oxidant. AB - A Pd-catalyzed desulfitative Heck-type reaction of aromatic sulfinic acid sodium salts with various olefins is developed with O(2) as the terminal oxidant under mild conditions. The presence of phosphane ligand DPEphos in anisole can significantly enhance the reaction selectivity. PMID- 21323385 TI - Photoelectron spectroscopic study of the oxyallyl diradical. AB - The photoelectron spectrum of the oxyallyl (OXA) radical anion has been measured. The radical anion has been generated in the reaction of the atomic oxygen radical anion (O(*-)) with acetone. Three low-lying electronic states of OXA have been observed in the spectrum. Electronic structure calculations have been performed for the triplet states ((3)B(2) and (3)B(1)) of OXA and the ground doublet state ((2)A(2)) of the radical anion using density functional theory (DFT). Spectral simulations have been carried out for the triplet states based on the results of the DFT calculations. The simulation identifies a vibrational progression of the CCC bending mode of the (3)B(2) state of OXA in the lower electron binding energy (eBE) portion of the spectrum. On top of the (3)B(2) feature, however, the experimental spectrum exhibits additional photoelectron peaks whose angular distribution is distinct from that for the vibronic peaks of the (3)B(2) state. Complete active space self-consistent field (CASSCF) method and second-order perturbation theory based on the CASSCF wave function (CASPT2) have been employed to study the lowest singlet state ((1)A(1)) of OXA. The simulation based on the results of these electronic structure calculations establishes that the overlapping peaks represent the vibrational ground level of the (1)A(1) state and its vibrational progression of the CO stretching mode. The (1)A(1) state is the lowest electronic state of OXA, and the electron affinity (EA) of OXA is 1.940 +/ 0.010 eV. The (3)B(2) state is the first excited state with an electronic term energy of 55 +/- 2 meV. The widths of the vibronic peaks of the X (1)A(1) state are much broader than those of the a (3)B(2) state, implying that the (1)A(1) state is indeed a transition state. The CASSCF and CASPT2 calculations suggest that the (1)A(1) state is at a potential maximum along the nuclear coordinate representing disrotatory motion of the two methylene groups, which leads to three membered-ring formation, i.e., cyclopropanone. The simulation of b (3)B(1) OXA reproduces the higher eBE portion of the spectrum very well. The term energy of the (3)B(1) state is 0.883 +/- 0.012 eV. Photoelectron spectroscopic measurements have also been conducted for the other ion products of the O(*-) reaction with acetone. The photoelectron imaging spectrum of the acetylcarbene (AC) radical anion exhibits a broad, structureless feature, which is assigned to the X (3)A'' state of AC. The ground ((2)A'') and first excited ((2)A') states of the 1 methylvinoxy (1-MVO) radical have been observed in the photoelectron spectrum of the 1-MVO ion, and their vibronic structure has been analyzed. PMID- 21323386 TI - Naphthalimide appended rhodamine derivative: through bond energy transfer for sensing of Hg2+ ions. AB - A naphthalimide appended rhodamine based fluorescent chemosensor '1' is synthesized which undergoes through bond energy transfer in the presence of Hg(2+) ions in mixed aqueous media. PMID- 21323387 TI - Thermodynamic control of 1,3-boratropic shifts of alpha- and gamma-stannyl substituted allylboranes: hyperconjugation outweighs steric effects. AB - (E)-delta-Stannyl homoallylic alcohols are prepared by an allene hydroboration aldehyde allylboration sequence ( Chen , M. et al. J. Am. Chem. Soc. 2010 , 132, 7881 ). Key to this reaction sequence is that the kinetic allene hydroboration product, 2a, is less stable than and isomerizes to the more sterically congested alpha-stannylallylborane 3a (see abstract figure). An M06-2X density functional analysis shows that the C-Sn to boron sigma-pi hyperconjugation interaction is sufficiently stabilizing to override the steric congestion in 3a. PMID- 21323388 TI - Light-driven cytochrome p450 hydroxylations. AB - Plants are light-driven "green" factories able to synthesize more than 200,000 different bioactive natural products, many of which are high-value products used as drugs (e.g., artemisinin, taxol, and thapsigargin). In the formation of natural products, cytochrome P450 (P450) monooxygenases play a key role in catalyzing regio- and stereospecific hydroxylations that are often difficult to achieve using the approaches of chemical synthesis. P450-catalyzed monooxygenations are dependent on electron donation typically from NADPH catalyzed by NADPH-cytochrome P450 oxidoreductase (CPR). The consumption of the costly cofactor NADPH constitutes an economical obstacle for biotechnological in vitro applications of P450s. This bottleneck has been overcome by the design of an in vitro system able to carry out light-driven P450 hydroxylations using photosystem I (PSI) for light harvesting and generation of reducing equivalents necessary to drive the P450 catalytic cycle. The in vitro system is based on the use of isolated PSI and P450 membrane complexes using ferredoxin as an electron carrier. The turnover rate of the P450 in the light-driven system was 413 min(-1) compared to 228 min(-1) in the native CPR-catalyzed system. The use of light as a substitute for costly NADPH offers a new avenue for P450-mediated synthesis of complex bioactive natural products using in vitro synthetic biology approaches. PMID- 21323389 TI - Interactions between CusF and CusB identified by NMR spectroscopy and chemical cross-linking coupled to mass spectrometry. AB - The Escherichia coli periplasmic proteins CusF and CusB, as part of the CusCFBA efflux system, aid in the resistance of elevated levels of copper and silver by direct metal transfer between the metallochaperone CusF and the membrane fusion protein CusB before metal extrusion from the periplasm to the extracellular space. Although previous in vitro experiments have demonstrated highly specific interactions between CusF and CusB that are crucial for metal transfer to occur, the structural details of the interaction have not been determined. Here, the interactions between CusF and CusB are mapped through nuclear magnetic resonance (NMR) spectroscopy and chemical cross-linking coupled with high-resolution mass spectrometry to better understand how recognition and metal transfer occur between these proteins. The NMR (1)H-(15)N correlation spectra reveal that CusB interacts with the metal-binding face of CusF. In vitro chemical cross-linking with a 7.7 A homobifunctional amine-reactive cross-linker, BS(2)G, was used to capture the CusF/CusB interaction site, and mass spectral data acquired on an LTQ Orbitrap confirm the following two cross-links: CusF K31 to CusB K29 and CusF K58 to CusB K32, thus revealing that the N-terminal region of CusB interacts with the metal-binding face of CusF. The proteins transiently interact in a metal dependent fashion, and contacts between CusF and CusB are localized to regions near their respective metal-binding sites. PMID- 21323390 TI - Fabrication and characterization of laser pulled platinum microelectrodes with controlled geometry. AB - The development of a reproducible procedure for the fabrication of Pt disk-shaped microelectrodes with characteristic dimensions ranging from 50 nm to 1 MUm in diameter was carried out using a laser pulling technique. The governing physical phenomena involved in their fabrication are discussed, and the importance of adding a critical quartz thinning step in the general procedure is demonstrated. The preparation of the microelectrodes involves sealing a platinum wire inside a quartz tubing using a pipet puller, thinning the composite material (platinum/quartz assembly), and laser pulling it to obtain two microelectrodes. The resulting microelectrodes display reproducible well-controlled geometry, which is important to downstream quantitative scanning electrochemical studies and imaging. Mechanical polishing of the microelectrode is required and remains the critical step in the fabrication of nanometer size electrodes. Following production, the microelectrodes are characterized by electron microscopy, scanning electrochemical microscopy, and cyclic voltammetry. Development of these microelectrodes is motivated by their subsequent application to electrocatalysis and their potential in theoretical study because of their well-defined geometry. PMID- 21323391 TI - Role of cannabinoids in multiple sclerosis. AB - Although extracts from the cannabis plant have been used medicinally for thousands of years, it is only within the last 2 decades that our understanding of cannabinoid physiology and the provision of evidence for therapeutic benefit of cannabinoids has begun to accumulate. This review provides a background to advances in our understanding of cannabinoid receptors and the endocannabinoid system, and then considers how cannabinoids may help in the management of multiple sclerosis (MS). The relative paucity of treatments for MS-related symptoms has led to experimentation by patients with MS in a number of areas including the use of cannabis extracts. An increasing amount of evidence is now emerging to confirm anecdotal reports of symptomatic improvement, particularly for muscle stiffness and spasms, neuropathic pain and sleep and bladder disturbance, in patients with MS treated with cannabinoids. Trials evaluating a role in treating other symptoms such as tremor and nystagmus have not demonstrated any beneficial effects of cannabinoids. Safety profiles of cannabinoids seem acceptable, although a slow prolonged period of titration improves tolerability. No serious safety concerns have emerged. Methodological issues in trial design and treatment delivery are now being addressed. In addition, recent experimental evidence is beginning to suggest an effect of cannabinoids on more fundamental processes important in MS, with evidence of anti inflammation, encouragement of remyelination and neuroprotection. Trials are currently under way to test whether cannabinoids may have a longer term role in reducing disability and progression in MS, in addition to symptom amelioration, where indications are being established. PMID- 21323392 TI - Excessive daytime sleepiness in patients with Parkinson's disease. AB - Excessive daytime sleepiness (EDS) is described as inappropriate and undesirable sleepiness during waking hours and is a common non-motor symptom in Parkinson's disease, affecting up to 50% of patients. EDS has a large impact on the quality of life of Parkinson's disease patients as well as of their caregivers, in some cases even more than the motor symptoms of the disease. Drug-induced EDS is a particular problem as many dopamine agonists used for the treatment of Parkinson's disease have EDS as an adverse effect. Dopaminergic treatment may also render a subset of Parkinson's disease patients at risk for sudden-onset sleep attacks that occur without warning and can be particularly hazardous if the patient is driving. This demonstrates the need for early recognition and management not only to increase health-related quality of life but also to ensure patient safety. There are many assessment tools for EDS, including the Epworth Sleepiness Scale (ESS) and the Multiple Sleep Latency Test (MSLT), although only the Parkinson's Disease Sleep Scale (PDSS) and the SCales for Outcomes in PArkinson's Disease-Sleep (SCOPA-S) are specifically validated for Parkinson's disease. Polysomnography can be used when necessary. Management comprises non pharmacological and pharmacological approaches. Non-pharmacological approaches can be the mainstay of treatment for mild to moderate EDS. Advice on good sleep hygiene is instrumental, as pharmacological approaches have yet to provide consistent and reliable results without significant adverse effects. The efficacy of pharmacological treatment of EDS in Parkinson's disease using wakefulness promoting drugs such as modafinil remains controversial. Further areas of research are now also focusing on adenosine A(2A) receptor antagonists, sodium oxybate and caffeine to promote wakefulness. A definitive treatment for the highly prevalent drug-induced EDS has not yet been found. PMID- 21323393 TI - Managing cognitive dysfunction through the continuum of Alzheimer's disease: role of pharmacotherapy. AB - It has been shown that, during several years preceding the diagnosis of Alzheimer's disease there is a gradual cognitive decline with a continuum between the pre-dementia stage (still known as the prodromal stage but now included within the general concept of mild cognitive impairment [MCI]) and the other stages of the disease. In MCI, the use of cholinesterase inhibitors (ChEIs) is not associated with any delay in the onset of Alzheimer's disease or dementia. During the dementia stages, the three ChEIs (donepezil, galantamine and rivastigmine) are efficacious for mild to moderate Alzheimer's disease; therefore, monotherapy with a ChEI can be envisaged as initial treatment. Confirmation of the efficacy of ChEIs in the mild dementia stage is essentially based on the results from a single, randomized study carried out specifically among patients at this stage of severity. Memantine can represent an alternative to ChEIs in the moderate stage of Alzheimer's disease. At the severe stage of the disease, memantine and donepezil are currently indicated. Indeed, memantine has been approved by numerous drug regulatory agencies for use in severe stages of the disease, whereas donepezil has only been approved by the US FDA. There is currently insufficient evidence for recommending combination therapy in Alzheimer's disease. PMID- 21323394 TI - Open-label treatment with desvenlafaxine in postmenopausal women with major depressive disorder not responding to acute treatment with desvenlafaxine or escitalopram. AB - BACKGROUND: Preliminary clinical evidence indicates that menopausal status might impact on the efficacy of certain classes of antidepressants. OBJECTIVE: The aim of this study was to evaluate open-label desvenlafaxine treatment (administered as desvenlafaxine succinate) in postmenopausal women who did not achieve clinical response to acute, double-blind treatment with desvenlafaxine or escitalopram. STUDY DESIGN: This phase IIIb, multicentre study included a 6-month open-label extension phase of patients who did not respond in the initial 8-week, randomized, double-blind acute phase. PATIENTS: Postmenopausal women aged 40-70 years with a primary diagnosis of major depressive disorder were recruited. PRIMARY INTERVENTION: Non-responders to acute treatment with double-blind desvenlafaxine or escitalopram received flexible-dose, open-label desvenlafaxine 100-200 mg/day for the 6-month extension phase. MAIN OUTCOME MEASURE: The primary efficacy assessment was the 17-item Hamilton Rating Scale for Depression (HAM D(17)) total score. Secondary efficacy outcome measures were the Clinical Global Impressions-Improvement (CGI-I) and -Severity scales, Hamilton Rating Scale for Anxiety, Quick Inventory of Depressive Symptomatology-Self-Report, Visual Analogue Scale-Pain Intensity and the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary health assessments were the Changes in Sexual Functioning Questionnaire, 5-Dimension EuroQoL Index, Health State Today, Menopause Rating Scale, Sheehan Disability Scale, treatment response (>= 50% decrease in total HAM D(17) and MADRS score from acute-phase baseline and CGI-I total score <= 2), HAM D(17) remission (total score <= 7) and safety. Descriptive statistics were used to summarize outcomes. RESULTS: The efficacy analysis included 123 patients (desvenlafaxine/desvenlafaxine = 64; escitalopram/desvenlafaxine = 59). At final evaluation of the open-label extension phase, mean reductions from acute-phase baseline in HAM-D(17) total scores were -11.33 for the desvenlafaxine/desvenlafaxine group and -11.41 for the escitalopram/desvenlafaxine group. HAM-D(17) response or remission after 6 months of open-label extension phase desvenlafaxine treatment were achieved in 56-58% and 41-48% of patients, respectively. The results of the other secondary efficacy outcome measures and other definitions of treatment response were generally consistent with the primary analyses. The observed adverse events were similar to those reported during previous desvenlafaxine clinical trials. CONCLUSIONS: Postmenopausal women with major depressive disorder who did not respond to acute, double-blind treatment with escitalopram or desvenlafaxine achieved modest, continued improvement with long-term, open-label desvenlafaxine therapy. Further interpretation of these findings is limited by aspects of the study design (i.e. open-label, non-placebo-controlled) and the lack of randomized comparison groups in the extension phase, which prevents statistical assessment of the efficacy of longer term treatment with desvenlafaxine. Clinicaltrials.gov identifier: NCT00406640. PMID- 21323395 TI - Cladribine tablets: in relapsing-remitting multiple sclerosis. AB - Cladribine, an immunosuppressant that selectively reduces peripheral lymphocyte levels, has potential as an oral therapy for relapsing-remitting multiple sclerosis. An oral (tablet) formulation is being investigated in clinical trials. In the large, well designed, phase III CLARITY trial, short-course treatment with oral cladribine (cumulative dose of 3.5 or 5.25 mg/kg) resulted in a significantly greater reduction in annualized relapse rates at 96 weeks compared with placebo in patients with relapsing-remitting multiple sclerosis. Improvements in the annualized relapse rate with oral cladribine were independent of key baseline patient characteristics which included age, sex, previous treatment with disease-modifying drugs and the number of relapses in the previous 12 months. In addition, a significantly higher proportion of patients were relapse-free at 96 weeks and there were significant reductions in the risk of 3 month sustained progression of disability in cladribine recipients compared with placebo recipients. The mean numbers of brain lesions on magnetic resonance imaging were also significantly reduced with cladribine compared with placebo in the CLARITY trial. Lymphocytopenia, herpes zoster infections and neoplasms (including malignancies) were more common in cladribine than placebo recipients. PMID- 21323396 TI - Asenapine: a review of its use in the management of mania in adults with bipolar I disorder. AB - Asenapine is an atypical antipsychotic agent available in sublingual formulations (5 or 10 mg) and indicated in the US (Saphris) for the acute treatment, as monotherapy or adjunctive therapy, of manic and mixed episodes and in the EU (Sycrest) for the treatment of moderate to severe manic episodes, in adult patients with bipolar I disorder. In two large (both n = 480), well designed, 3 week trials in adult patients with bipolar I disorder, asenapine monotherapy was significantly more effective than placebo at improving mania symptoms, as assessed using the Young Mania Rating Scale total score (YMRS; primary endpoint), with significant differences between the asenapine and placebo groups occurring after 2 days of treatment. In both trials, Clinical Global Impression for Bipolar Disorder (CGI-BP) scale mania severity scores exceeded those of placebo. In one trial, response and remission rates exceeded those of placebo. In a 9-week extension study that recruited completers from the monotherapy trials, there were no significant differences between asenapine and olanzapine groups in terms in Montgomery-Asberg Depression Rating Scale (MADRS) scores, CGI-BP mania severity scores, YMRS response rates or YMRS remission rates during the extension phase. In the extension study, the efficacy of asenapine monotherapy appeared to be maintained over 40 weeks (total treatment duration of 52 weeks). In a 12-week trial of asenapine as adjunctive therapy to lithium or valproate, asenapine was more effective than placebo in improving manic symptoms, based on the difference between groups in the YMRS total score at week 3 (primary endpoint). Most adverse events associated with asenapine were of mild to moderate severity, with <7% of asenapine recipients experiencing serious adverse events (vs 7% with placebo). In a pooled analysis of the monotherapy trials, the most common adverse events (occurring in >= 5% of patients and at twice the incidence of placebo) reported during acute phase asenapine monotherapy for bipolar mania were somnolence, dizziness, extrapyramidal symptoms (EPS, other than akathisia) and increased bodyweight, which were similar in nature to those occurring during longer-term monotherapy with asenapine. EPS did not worsen in severity during longer-term asenapine monotherapy. Asenapine had minimal effects on plasma glucose, lipid and prolactin levels over both short- and longer-term treatment periods, and had little pro-arrhythmogenic potential. Further active comparator trials and longer term tolerability and safety data are required. In the meantime, asenapine is a further option for the management of manic and/or mixed symptoms in patients with bipolar I disorder and may be of particular value for patients who are at high risk for metabolic abnormalities. PMID- 21323397 TI - Pain freedom at 2 hours in migraine after telcagepant 300 mg. PMID- 21323398 TI - Maternal perceptions of factors contributing to severe under-nutrition among children in a rural African setting. AB - INTRODUCTION: In developing countries, severe undernutrition in early childhood is associated with increased mortality and morbidity, and 10-40% of hospital admissions. The current study aimed to elicit maternal perceptions of factors that contribute to severe undernutrition among children in a rural Kenyan community in order to identify appropriate and acceptable targeted interventions. METHODS: The study consisted of 10 focus group discussions (FGDs) of between eight and ten mothers each, in a rural coastal community in Kenya. A grounded theory approach was used to analyse the FGD data. RESULTS: In all FGDs 'financial constraints' was the main reason given for severe undernutrition of children. The mothers reported the additional factors of inadequate food intake, ill health, inadequate care of children, heavy workload for mothers, inadequate control of family resources by women and a lack of resources for generating income for the family. The mothers also reported their local cultural belief that severe malnutrition was due to witchcraft and the violation of sexual taboos. CONCLUSIONS: The mothers in the study community recognised multiple aetiologies for severe undernutrition. A multidisciplinary approach is needed address the range of issues raised and so combat severe undernutrition. Suggested interventions include poverty alleviation, medical education and psychosocial strategies. The content and approach of any program must address the need for variability, determined by individual and local needs, concerns, attitudes and beliefs. PMID- 21323399 TI - Acridine derivatives: a patent review (2009 - 2010). AB - INTRODUCTION: Acridines are highly important heterocyclic compounds with immense biological significance as they act as the central core of antitumor, anti protozoan, antiviral and multi-drug resistance modulating agents. The tricyclic aromatic structure of acridine is primarily responsible for its intercalation with DNA by controlling its biological profile and the substitution pattern of the molecule, which leads to several other applications. AREAS COVERED: In this review, acridine-based functional molecules and patents of acridine derivatives filed from 2009 to 2010 are discussed. The latest information about the medical importance of new acridine-based molecules is also discussed (e.g., materials with sensing and electrical/thermal properties). EXPERT OPINION: The tricyclic aromatic heterocyclic structure of acridine has a lot of potential for biological and material utilization. The versatility of fluorescent acridines could be further enhanced by introducing amino-acid chains or other polar substituents on the central moiety, which due to increased water solubility could increase their effectiveness under physiological conditions. PMID- 21323401 TI - Enteral nutrition in patients with severe traumatic brain injury: reasons for intolerance and medical management. AB - Approximately, 50% of patients with severe traumatic brain injury (TBI) exhibit intolerance to enteral nutrition (EN). This intolerance hampers the survival and rehabilitation of this subpopulation to a great extent, and poses various difficulties for clinicians due to its complex underlying mechanisms. This review discusses the possible reasons for intolerance to EN following severe TBI, current trends in medical management, as well as other related issues that are experienced by many clinicians. PMID- 21323402 TI - Assessment of visual function in idiopathic intracranial hypertension. AB - PURPOSE: Impaired visual function occurs frequently in patients with idiopathic intracranial hypertension (IIH) and may be the most seriously affected function following raised intracranial pressure. The aim of this review was to overview the methods available for the assessment of visual function in IIH. METHODS: A review of databases, including PubMed, Web of Knowledge and ocular and motility and strabismus was undertaken to identify articles relating to visual function and its assessment in IIH. RESULTS: Options for visual assessment include fundus evaluation, retinal imaging, visual field, visual acuity, contrast sensitivity, colour vision, electrodiagnostic and ocular motility evaluations. CONCLUSIONS: Many aspects of visual function assessment contribute to the monitoring of vision in patients with IIH. However, the assessment of visual field, plus fundus and retinal imaging, are particularly important in providing accurate and repeatable measurements on which to determine the progression of the condition. PMID- 21323403 TI - Large and giant petroclival meningiomas: therapeutic strategy and the choice of microsurgical approaches - report of the experience with 41 cases. AB - OBJECTIVE: To evaluate patients' clinical outcome, survival and performance status at the mild-term follow-up evaluation after optimal microsurgical resection of large and giant petroclival meningiomas (PCMs). METHODS: During a 4 year period (2004-2008), 41 patients underwent operative procedures for resection of PCMs. The tumour size was large or giant in 100% of the patients, with a mean tumour diameter of 4.4 cm. Tumours extended into adjoining regions in 26 of the patients. Six previously underwent operation or irradiation. Gross tumour resection (GTR) was accomplished in 25 (61.0%) patients, subtotal resection (STR) in 15 (36.6%) patients and partial resection in 1 (2.4%) patient. There were no operative deaths. Postoperative complications (cerebrospinal fluid leakage, quadriparesis, infections, cranial nerve palsies, etc.) were observed in 27 (65.9%) patients. Postoperative radiation or radiosurgery was administered to 6 of the 41 patients who had residual tumours. RESULTS: At the conclusion of the study, 27 (65.9%) patients were alive with radiological evidence of the residual disease, and 14 (34.1%) patients were alive without radiological evidence of the residual disease. The mean follow-up period was 35 months (range, 15-45 months). Six (14.6%; five of the STR and partially resected patients and one of the total resection patients) had recurrence; of these patients, four underwent repeat resection and two were treated with gamma knife radiosurgery. The Karnofsky Performance Scale score was 78 +/- 14 preoperatively, 80 +/- 10 at 1 year postoperatively and 81 +/- 10 at the time of the latest follow-up evaluation. Common disabilities at the time of the follow-up evaluation included diplopia, facial numbness and swallowing difficulty. Most patients developed coping mechanisms. CONCLUSIONS: The surgical strategy of large and giant PCMs should be focused on the survival and postoperative quality of life. The good surgical approach should be based on the tumour location, the growth direction, the invasion of adjacent structure, the age of the patients and the experience of neurosurgeons. Selectively pursuing an STR without radiotherapy rather than a GTR is a reasonable strategy. Moreover, microneurosurgical technique plays a key role in the level of tumour resection and preservation of nerve function. Intraoperative electrophysiological monitoring also contributes dramatically to the preservation of the nerve function. PMID- 21323404 TI - Idiopathic intracranial hypertension: lumboperitoneal shunts versus ventriculoperitoneal shunts--case series and literature review. AB - OBJECTIVES: Idiopathic intracranial hypertension (IIH) is an uncommon but important cause of headache that can lead to visual loss. This study was undertaken to review our experience in the treatment of IIH by neuronavigation assisted ventriculoperitoneal (VP) shunts with programmable valves as compared to lumboperitoneal (LP) shunts. METHODS: A retrospective chart review was conducted on 25 patients treated for IIH between 2001 and 2009. Age, sex, clinical presentation, methods of treatment and failure rates were recorded. RESULTS: Seventy-two per cent were treated initially with LP shunts. Failure rate was 11% in this group. Neuronavigation-assisted VP shunts were used to treat 28%. In this group, the failure rate was 14%. CONCLUSION: Our experience indicates that both LP shunts and VP shuts are effective in controlling all the clinical manifestations of IIH in the immediate postoperative period. Failure rates are slightly higher for VP shunts (14%) than LP shunts (11%). However, revision rates are higher with LP shunts (60%) than with VP shunts (30%). PMID- 21323405 TI - Unlocking the 'locked-in syndrome'. AB - We present a case of a 48-year-old man who was initially thought to have had a brainstem stroke and was clinically 'locked-in'. Upon investigation, a petrous apex dural atriovenous fistula was identified causing profound brainstem venous hypertension. Surgical clipping lead to complete neurological recovery. PMID- 21323406 TI - Proximal migration of a lumbo-peritoneal shunt into a cerebellar peduncle. AB - We present dramatic images of a lumbo-peritoneal (LP) shunt that has migrated into the posterior fossa. We discuss its successful revision, and review previous reports of LP shunt migration. PMID- 21323407 TI - Patient safety and image transfer between referring hospitals and neurosciences centres: an alternate best practice? PMID- 21323408 TI - Recurrent episodes of very late stent thrombosis in a patient with aspirin hypersensitivity, stent fracture and malapposition. AB - Late stent thrombosis represents a life-threatening event, usually triggered by inadequate antiplatelet therapy and promoted by multiple risk factors, such as stenting of a chronic total occlusion, overlapping stenting, an abnormal vascular response to the eluted drug, stent malapposition and stent fracture. A 57-year old man with aspirin hypersensitivity underwent successful percutaneous revascularization of a chronic total occlusion of the left anterior descending artery (LAD). He received two sirolimus-eluting stents overlapping for 2 mm and was discharged on clopidogrel and picotamide. Two years later, 15 days after clopidogrel discontinuation, he experienced an anterior ST-segment elevation myocardial infarction and underwent rescue percutaneous LAD thrombectomy after unsuccessful fibrinolysis. Coronary angiography showed fracture of the distal stent, with a 5 mm gap between the two portions, as well as severe late stent malapposition, confirmed by optical coherence tomography. Despite treatment with clopidogrel and picotamide, in the following days the patient experienced two new episodes of stent thrombosis, treated with thrombectomy and deployment of bioengineered stents. The patient underwent successful oral aspirin desensitization, with a complete in vitro inhibition of platelet function, and was discharged on aspirin, clopidogrel and warfarin, without experiencing other events at 6-month follow-up. PMID- 21323409 TI - The development of door-to-angiography time in the last 14 years for patients with acute ST-elevation myocardial infarction treated with primary coronary intervention: Determinants and outcome. Results from the MITRAplus and OPTAMI registry. AB - AIM OF THE STUDY: To examine the development of door-to-angiography time (DTA) and to evaluate the impact of door-to-angiography time in patients with ST elevation myocardial infarction (STEMI) on hospital and one-year mortality. METHODS AND RESULTS: From 1994 to 2008, 5078 patients (pts) and known DTA with acute ST-elevation myocardial infarction were enrolled into the MITRAplus and OPTAMI registry in Germany. Our data showed a reduction of the door-to- angiography time from 80 min to 64 min in the last 14 years (P < 0.001). Over 80% of patients received an angiography less than two hours after admission. The main predictor of a shorter door-to-balloon time was a hypotension with a blood pressure lower than 100 mmHg (OR 1.46, 95%CI: 1.08-1.91). Whereas a history of prior myocardial infarction (OR 0.61, 95%CI: 0.45-0.84), a previous coronary bypass grafting (OR 0.55, 95%CI: 0.33-0.91), age older than 75 years (OR 0.78, 95%CI: 0.62-0.99) and a pre-hospital delay more than three hours (OR 0.78, 95%CI: 0.66-0.93) were independent predictors for a longer of the door-to-balloon time. In the multivariate regression analysis no influence was detected of door-to angiography time on hospital or one-year mortality. CONCLUSION: The DTA decreased in the last 14 years and is actually very short in Germany. We indentified predictors of a longer door-to-angiography time in clinical practice. Given the overall short in-hospital delay, the observed door-to-angiography time did not have influence on hospital and mid term mortality. PMID- 21323410 TI - Myocardial implantation of a combination stem cell product by using a transendocardial MYOSTAR injection catheter: A technical assessment. AB - AIM: Different types of progenitor cells have been used to improve cardiac conditions after myocardial infarction (MI). Results have shown that while the infusion of a single cell type is safe and feasible, efficacy is modest. Recently, the use of a combination, rather than a single, stem cell product has emerged as an attractive option to improve cardiac outcome after a MI. Before initiating a phase II clinical trial to assess safety and efficacy after the transendocardial infusion of a combination stem cell product, a bench testing assay was designed to validate that delivery through the injection catheter is not associated with cell loss/damage. The latter is important since mesenchymal stem cells (MSC), a component of the cell product, consist of large cells expressing matrix molecules and adhesive receptors. METHODS: The cell product (a mixture of mononuclear cells and MSC) was sequentially injected through a Myostar injection catheter. Exiting fractions were assessed for cell number, viability, capability to restart cell growth and immunophenotype. RESULTS: Cell recovery and viability were high. In turn, exiting cells preserved their biological properties and immunophenotype. CONCLUSIONS: Delivery of cells through a Myostar catheter is safe and not associated with changes in cell survival and/or properties. PMID- 21323411 TI - Better outcome after cardiopulmonary resuscitation using percutaneous emergency circulatory support in non-coronary patients compared to those with myocardial infarction. AB - BACKGROUND & OBJECTIVES: Mobile heart-lung-machines applied by percutaneous cannulation are mostly used in patients suffering from acute myocardial infarction (AMI). Whether patients with non-coronary reasons for circulatory arrest benefit of percutaneous emergency circulatory support (PECS) in the same way is still unclear. METHODS: We included 22 consecutive patients who were treated by PECS during a registry period of two years. Primary study endpoint was 30-day mortality rate. RESULTS: Circulatory arrest was caused by AMI in 14 patients (64%). The remaining 8 patients suffered from cardiomyopathy/myocarditis, 4; pulmonary embolism, 2; acute pulmonary failure, 1; and tumor lysis syndrome, 1. Revascularization rate was 93% in the AMI group under PECS support. Overall survival rate was 36.4% at one month: it reached 62.5% among non-coronary patients, but only 21.4% in the AMI group (P = 0.02). Weaning was possible by direct heart transplantation in two patients. Additional two patients required implantation of a left ventricular assist device. Pumpless extracorporeal lung assist was used in one case. CONCLUSION: In this small retrospective study percutaneous emergency circulatory support provided sufficient hemodynamic stabilization in emergency situations. One fifth of AMI patients were saved by immediate restoration of circulation and causal treatment when other means of resuscitation failed. Higher survival rates were noted in non coronary patients. PMID- 21323412 TI - Biolimus-eluting biodegradable polymer-coated stent versus bare metal stent in acute ST-elevation and non-ST elevation myocardial infarction: Justification for biodegradable polymer-coated stent in acute coronary syndrome (JANICE) registry. AB - AIMS: We evaluated the efficacy and safety of a biolimus- eluting biodegradable polymer-coated stent (BES) in patients with ST-segment elevation and non ST segment elevation acute myocardial infarction (AMI). METHODS AND RESULTS: This was an observational study involving a single centre patient registry. We compared the rates of cardiac death, myocardial infarction, target vessel revascularization (TVR) and composite end point of cardiac death and myocardial infarction at 24 months in 106 patients who received BES versus 94 patients who received an otherwise similar bare metal stent (BMS) during percutaneous coronary intervention for AMI. There was no significant difference in the rate of cardiac death (0.9% versus 7.4%; P = 0.09), myocardial infarction (4.7% versus 3.2%; P = 0.69), stent thrombosis (0.9% versus 3.2%; P = 0.30) or cardiac death and myocardial infarction (5.7% versus 10.6%; P = 0.30) between the two groups. The rate of TVR was significantly higher in the BMS group (1.9% versus 8.5%; P = 0.04), with patients receiving BMS being four times more likely to require TVR. CONCLUSION: The use of BES in selected patients with AMI appears to be safe and is associated with significantly reduced rate of TVR, when compared with an otherwise similar BMS. PMID- 21323413 TI - Conceptualizing functional cognition in traumatic brain injury rehabilitation. AB - PRIMARY OBJECTIVE: To conceptualize functional cognitive constructs across the continuum of traumatic brain injury (TBI) recovery, to form the foundation for the Computer Adaptive Measure of Functional Cognition for TBI (CAMFC-TBI). BACKGROUND: TBI often has a profound impact on a survivor's ability to return to previous level of functioning and significantly reduces the overall quality of life for survivors and caregivers. Few assessments are designed to evaluate TBI's impact on cognitive functioning in everyday life. Neuropsychological tests are time consuming and may have questionable ecological validity for predicting functional outcomes. Global functional assessments contain few cognitive items and may lack psychometric rigour. Presently there is a lack of efficient, precise, ecologically valid functional cognitive measures. MAIN OUTCOME AND RESULTS: Studies that used neuropsychological and global functional assessments were reviewed to direct conceptualization of functional cognitive constructs across TBI recovery stages. An advisory panel reviewed study methodology and functional cognitive constructs development. They validated the need for the CAMFC-TBI and the six functional cognitive constructs: attention, memory, processing speed, executive functioning, social communication and emotional management. CONCLUSION: Conceptualizing functional cognitive constructs is the first step in CAMFC-TBI development. Future project stages include item pool development, qualitative testing, field-testing, psychometric analysis and computerized adaptive test programming. PMID- 21323415 TI - Source imaging of QEEG as a method to detect awareness in a person in vegetative state. AB - BACKGROUND: Assessment of awareness in patients with severe brain injury remains subjective, although patients with even limited awareness (e.g. minimal conscious state, MCS) have different prognoses and treatment than those in vegetative state (VS). Recently, task appropriate differential regional activation in VS has been reported using fMRI during mental imagery. PRIMARY OBJECTIVE: Demonstration of conscious awareness in reproducible differential EEG source localization images in a VS patient reflecting requested mental imagery was performed. METHODS: A VS patient (with re-test) and a normal control were requested to imagine singing and to mentally perform serial subtraction, while EEG was recorded. QEEG source localization was performed to identify regions of brain activation in response to tasks. RESULTS: Replicable distinctive activation of brain areas appropriate for each task was seen in the VS patient and control. Frequency spectra shifted to beta, with significant source activation in regions including the bilateral anterior cingulate, insula, left caudate and dorsolateral pre-frontal cortex to singing and the putamen, insula, left pre-frontal cortex and right temporal gyrus to subtraction by 7's. CONCLUSIONS: Results from this single case suggests the potential utility of QEEG source localization images to detect awareness in patients clinically diagnosed as being in VS. This indicates the possibility that EEG may serve as an important adjunct to the assessment of awareness in patients with disorders of consciousness in the clinical setting. PMID- 21323416 TI - Long-term outcome and health status in decompressive craniectomized patients with intractable intracranial pressure after severe brain injury. AB - OBJECTIVE: Decompressive craniectomy (DC) in severe traumatic brain injury (TBI) remains a controversial therapeutic strategy. The long-term functional recovery and health status in a sample of decompressive craniectomized TBI are reported. METHODS: Patients with TBI who underwent DC were retrospectively investigated. Patients with cerebral haemorrhage (CH) and DC were considered as control group. In all survival patients admitted to a neuro-rehabilitation setting, the modified Rankin (mRS), Glasgow Outcome scale (GOS) and Barthel Scales (BS) were administered at admission, discharge, 1 year and follow-up. The quality-of-life was evaluated with the SF-36 questionnaire at follow-up (41.1+/-16.6 months). RESULTS: Seventy (33 F, 37 M, mean age=46.8, SD=18.8) patients were enrolled: 46 (20 F, 26 M) subjects with TBI and 24 (13 F, 11 M) with CH. After surgery, 11 (23.9%) and 10 (41.6%) subjects in the TBI and CH group, respectively, died. The mean Barthel scores were 4.0 (SD=5.9), 60.9 (SD=37.5), 63.7 (SD=35.1) and 67.3 (SD=38.2) (p<0.001) and median GOS was 3, 4, 4 and 4 at admission, discharge, 1 year and follow-up, respectively, in TBI patients. Seventeen (36.9%) patients with TBI and four (16.6%) with CH made a full recovery. The SF-36 questionnaire showed significant abnormalities in all domains of health status in both groups. CONCLUSION: Craniectomized patients with TBI achieved good long-term outcome, although they experienced significant difficulties in health status. PMID- 21323417 TI - Analysis of beta-catenin expression and exon 3 mutations in pediatric sporadic aggressive fibromatosis. AB - Aggressive fibromatosis is a benign tumor with a high recurrence rate after surgical resection, particularly in children. Abnormal regulation of beta-catenin in the presence or absence of a change of genotype has been identified in adult sporadic aggressive fibromatosis. However, the status of beta-catenin expression and mutation remains unclear in pediatric patients. The present study was designed to analyze the expression and mutation status of beta-catenin in pediatric aggressive fibromatosis. B-catenin expression was analyzed by immunohistochemistry in 32 samples from pediatric patients with aggressive fibromatosis (21 recurrent cases and 11 primary-onset cases) and 15 control subjects. Somatic point mutations in beta-catenin exon 3 were identified by sequencing of polymerase chain reaction products. Nuclear expression of beta catenin was detected in 94% (30/32) of aggressive fibromatosis samples and 13% (2/15) of control samples (P < 0.001). Mutations in exon 3 of the beta-catenin gene were identified in 78% (25/32) of aggressive fibromatosis samples (19/21 recurrent cases, 6/11 primary-onset cases; P = 0.032). The primary mutation in the recurrent cases occurred at codon 45 (S45F), while codon 41 (T41A) was most frequently mutated in the primary-onset cases (P = 0.002). Abnormal expression of beta-catenin appears to occur frequently in pediatric aggressive fibromatosis. Muftations in exon 3 of the beta-catenin gene, particularly the S45F mutation, may represent risk factors for recurrence in pediatric patients and could potentially be used as prognostic factors. PMID- 21323418 TI - Pseudoactinomyces in cervical mucus. AB - Actinomyces israelii are gram-positive filamentous bacteria forming yellow sulfur granules. They are the most well known complication of intrauterine contraceptive devices (IUCD). Healthcare staff dealing with reporting cervical smears should be aware of pseudoactinomyces entity in a cervical smears and biopsies as it may raise a false alarm to the clinician and may lead to unnecessary removal of IUCD and/or medical treatment. PMID- 21323419 TI - Calcifying odontogenic cysts associated with odontomas: confocal laser scanning microscopy analysis of 13 cases. AB - The so-called calcifying odontogenic cyst (COC) represents a heterogeneous group of lesions that exhibit a variety of clinico-pathologic features. It is an uncommon lesion and represents less than 2% of all odontogenic cysts and tumors. Recently, these lesions have been reclassified as calcifying cystic odontogenic tumors (CCOT), according to the new World Health Organization (WHO) classification. CCOT are frequently found in association with, or containing areas histologically identical to, various types of odontogenic tumors, such as complex/compound odontomas. This work analyzed clinical and histological data deriving from 13 patients affected by CCOT associated with odontomas. Moreover, a confocal laser scanning microscope (CLSM) analysis was undertaken to further a better understanding of the nature of this peculiar lesion. PMID- 21323420 TI - Actin cytoskeleton reorganization correlates with cofilin nuclear expression and ultrastructural changes in cho aa8 cell line after apoptosis and mitotic catastrophe induction by doxorubicin. AB - The effect of doxorubicin on the expression of cofilin and actin in CHO AA8 cells was estimated by fluorescence and electron microscopy. The presence of cofilin and actin was observed particularly in the nuclei of cells by different modes after treatment by doxorubicin. Cells undergoing mitotic catastrophe expressed some entirely characteristic features together with overlapping elements of other types of cell death. Additionally, the authors suggest that, as defined here, reorganization of F-actin might be involved in all cell death processes. Changes in the nuclear expression of cofilin are related to F-actin cytoplasm-nuclear translocation and its intranuclear dynamic reorganization. PMID- 21323421 TI - Expression of CD1d protein in human testis showing normal and abnormal spermatogenesis. AB - CD1d is a member of CD1 family of transmembrane glycoproteins, which represent antigen-presenting molecules. Immunofluorescent staining methods were utilized to examine expression pattern of CD1d in human testicular specimens. In testis showing normal spermatogenesis, a strong CD1d cytoplasmic expression was seen the Sertoli cells, spermatogonia, and Leydig cells. A moderate expression was observed in the spermatocytes. In testes showing maturation arrest, CD1d expression was strong in the Sertoli cells and weak in spermatogonia and spermatocytes compared to testis with normal spermatogenesis. In Sertoli cell only syndrome, CD1d expression was strong in the Sertoli and Leydig cells. This preliminary study displayed testicular infertility-related changes in CD1d expression. The ultrastructural changes associated with with normal and abnormal spermatogenesis are open for further investigations. PMID- 21323422 TI - Lecithin: Cholesterol Acyltransferase (LCAT) Deficiency: renal lesions with early graft recurrence. AB - Familial lecithin:cholesterol acyltransferase (LCAT) deficiency is a rare metabolic disease with lipid deposition in several organs. The authors report a man with hypertension and proteinuria. Renal biopsy revealed glomerular changes, including peculiar thrombus-like deposits, consistent with LCAT deficiency. He was found to be compound heterozygous for two mutations of the LCAT gene. He received a kidney graft from his father. The authors also describe LCAT deficiency-related lesions in the explanted native kidneys and in biopsies at 2 days, 6 weeks, and 1 year after transplantation. The morphology of this disease is characteristic, and the diagnosis should be suspected from the ultrastructural findings. PMID- 21323423 TI - Genetic variants of Anaplasma phagocytophilum in wild caprine and cervid ungulates from the Alps in Tyrol, Austria. AB - The occurrence of genetic variants of Anaplasma phagocytophilum was studied in wild ungulates from the northern and central eastern Alps in Tyrol, Austria. For this purpose, spleen samples collected from 53 game animals during the hunting season 2008/2009 (16 roe deer [Capreolus capreolus], 10 red deer [Cervus elaphus], 16 Alpine chamois [Rupicapra r. rupicapra], 7 Alpine ibex [Capra i. ibex], and 4 European mouflons [Ovis orientalis musimon]) were analyzed. Thirty five animals originated from the Karwendel mountains, 12 from the Kaunertal area (Otztal Alps), and the remaining from other mountainous areas in Tyrol. DNA extracts were screened with a real-time polymerase chain reaction targeting the msp2 gene of A. phagocytophilum. A total of 23 (43.4%) samples, from all ungulate species studied, were A. phagocytophilum positive. As of the date of this article, A. phagocytophilum has not been reported in the Alpine ibex. The positive samples were investigated further with polymerase chain reactions for amplification of the partial 16S rRNA, groEL, and msp4 genes. Sequence analysis using forward and reverse primers revealed seven different 16S rRNA gene variants. No variant could be attributed to any particular ungulate species. The groEL gene revealed 11 different variants, which grouped in the phylogenetic analysis into two distinct clusters: one cluster contained the sequences from roe deer, whereas the sequences of the other species formed the second cluster. The msp4 gene showed a high degree of variability in the amplified part with a total of 10 different sequence types. The results show that the wild mountain ungulates were infected to a considerable extent with various variants of A. phagocytophilum. The pathogenicity of the variants and the reservoir competence of the species investigated in this study deserve further attention in future studies. PMID- 21323424 TI - An iron-superoxide dismutase antigen-based serological screening of dogs indicates their potential role in the transmission of cutaneous leishmaniasis and trypanosomiasis in Yucatan, Mexico. AB - An increasing number of studies have reported high infection rates for American cutaneous leishmaniasis in dogs, which have thus been proposed as the reservoir host. Canine leishmaniasis is widespread in different states in Mexico, where a number of Leishmania species have been isolated from dogs. In the present study, the detection of different Leishmania species is described in stray dogs from two localities, namely Tulum and Celestun on the Yucatan Peninsula (Mexico). The use of iron-superoxide dismutase excreted by the parasites as the antigen fraction and enzyme-linked immunosorbent assay and western blot tests allowed us to confirm the presence of at least three species of Leishmania (Le. mexicana, Le. braziliensis, and Le. panamensis), some of which are reported for the first time in this species. In addition to a high prevalence of Le. mexicana and Le. braziliensis, and to a lesser degree, Le. panamensis, there is a significant prevalence of Trypanosoma cruzi, suggesting that the dog may be a source of transmission of trypanosomiasis. However, a more thorough epidemiological study on the dog population, both wild as well as urban, of the Yucatan Peninsula will be required to design a control strategy for these diseases, paying particular attention to the population affected and even broadening the study to other Mexican states as well as neighboring countries. These results again confirm that iron-superoxide dismutase excreted by the different trypanosomatid species constitutes a good source of antigen for serodiagnosis in epidemiological studies. PMID- 21323425 TI - Bevacizumab and its use in epithelial ovarian cancer. AB - Bevacizumab is a monoclonal antibody that binds to VEGF, a circulating protein involved in the promotion of angiogenesis and probably tumor growth and progression. Bevacizumab has demonstrated anticancer activity in several cancers, either combined with chemotherapy or when used as a single agent, and has been approved by the US FDA as a treatment for several cancers. As VEGF has been implicated in ovarian cancer progression and ascites formation, and high levels of VEGF have been found in plasma and ascites in women with ovarian cancer, bevacizumab has been tested as an anticancer therapy in ovarian cancer. Documented single-agent activity of bevacizumab in recurrent ovarian cancer has led to combination studies with both biologic agents as well as other chemotherapy agents in both recurrent and newly diagnosed cancer. One trial in patients with recurrent, heavily pretreated ovarian cancer demonstrated a higher than predicted risk of gastrointestinal perforation, and although a lower incidence of gastrointestinal perforation has been reported in less heavily pretreated patients, patients and their physicians must be aware of this risk. Upfront studies testing the impact of adding bevacizumab to carboplatin and paclitaxel chemotherapy for the treatment of newly diagnosed cancer are currently underway, and one Phase III randomized study (Gynecologic Oncology Group study 218) was recently presented and will be discussed in this article. PMID- 21323426 TI - Recombinant chicken interferon-alpha inhibits H9N2 avian influenza virus replication in vivo by oral administration. AB - Chicken interferon-alpha (ChIFN-alpha) has been demonstrated to be an important cytokine in antiviral immunity. However, the preventive or therapeutic effect of ChIFN-alpha as an oral antiviral agent on avian influenza virus (AIV) infection has not been fully clarified in chickens systemically. In the present study, we investigated the anti-H9N2 AIV effect of ChIFN-alpha on a cohort of 7- and 33-day old specific pathogen-free (SPF) chickens by oral administration. Results showed that both the ChIFN-alpha preventive and therapeutic groups exhibited significantly reduced viral load in trachea when compared with the virus challenged control group. The therapeutic effect was better than the preventive effect on 7-day-old SPF chickens, which is opposite to 33-day-old SPF chickens. We speculated that T-dependent lymphocyte system of 33-day-old SPF chickens might be easier to be stimulated by ChIFN-alpha than that of 7-day-old SPF chickens. In addition, there was no side effect on the body weight of chickens treated with ChIFN-alpha. We also found that IFN-stimulated genes (ISGs) (2',5'-oligoadenylate synthetase and Mx1) were upregulated in groups treated by ChIFN-alpha and/or virus, indicating that these 2 ISGs not only participated in anti-AIV response in vivo but also could be induced by oral administration of ChIFN-alpha. The present study suggested that ChIFN-alpha could be used as a potential preventive and therapeutic antiviral agent against H9N2 AIV infection by oral administration. PMID- 21323427 TI - Percutaneous diode laser irradiation for lumbar discogenic pain: a clinical study. AB - The present study evaluated the efficiency of laser irradiation for treating discogenic low back pain. Discogenic low back pain is believed to result from the degeneration and disruption of outer fibers of the intervertebral disc annulus, leading to a cycle of persistent inflammation, damage to the disc matrix, and sensitization of developed annular nociceptors. We selected 11 patients as subjects on the basis of clinical findings and the results of provocative disc blockade. The patients underwent percutaneous irradiation of affected lumbar discs with a diode laser. The mean total irradiation energy per disc was 740 +/- 2.51 J, with a range of 610 to 960 J. The patients' responses were assessed with the Oswestry Disability Index (ODI) and a visual analogue scale (VAS) to determine the average level of pain. The patients' mean ODI scores at 1 day, 3 months, 6 months, 12 months, 18 months, and 24 months after laser irradiation were 18.63 +/- 11.22, 13.6 +/- 4.53, 12.5 +/- 5.5, 11.8 +/- 5.25, 10.5 +/- 2.27, and 10.5 +/- 2.27, respectively, versus a mean pre-treatment ODI score of 50.27 +/- 9.35. Their mean VAS scores at the same post-treatment intervals were 3.09 +/ 2.36, 2.4 +/- 0.97, 2.7 +/- 1.16, 2.1 +/- 0.74, 2.1 +/- 0.81, and 2.1 +/- 0.88, respectively, versus a mean pre-treatment VAS score of 7.64 +/- 1.21. The post- versus pre-treatment scores for both the ODI and VAS indicated a statistically significant clinical benefit across the full 24-month follow-up period after laser irradiation. The efficacy of laser irradiation in treating such pain may come from a thermal effect and reductions of intradiscal pressure, of the concentrations of irritant substances, and of the numbers of nociceptors in the affected region. PMID- 21323428 TI - Effects of Er:YAG laser irradiation on the microtensile bond strength to bleached enamel. AB - OBJECTIVE: The objective of this study was to evaluate the influence of different Er:YAG laser (lambda = 2.94 MUm) energy parameters on the microtensile bond strength (MUTBS) and superficial morphology of bovine enamel bleached with 16% carbamide peroxide. BACKGROUND: Laser irradiation could improve adhesion to bleached enamel surfaces. METHODS: Sixty bovine enamel blocks (7 * 3 * 3 mm(3)) were randomly assigned to six groups according to enamel preparation procedures (n = 10): G1-bleaching and Er:YAG laser irradiation with 25.52 J/cm(2) (laser A, LA); G2-bleaching and Er:YAG laser irradiation with 4.42 J/cm(2) (laser B, LB); G3-bleaching; G4-Er:YAG laser irradiation with 25.52 J/cm(2); G5-Er:YAG laser irradiation with 4.42 J/cm(2); G6-control, no treatment. G1 to G3 were bleached for 6 h during 21 days. Afterwards, enamel surfaces in all groups were slightly abraded with 600-grit SiC papers and G1, G2, G4 and G5 were irradiated according to each protocol. Enamel blocks were then restored with an etch-and-rinse adhesive system and a 4-mm thick composite buildup was made in two increments (n = 9). After 24 h, restored blocks were serially sectioned with a cross-section area of ~1 mm(2) at the bonded interface and tested in tension in a universal testing machine (1 mm/min). Failure mode was determined at a magnification of x100 using a stereomicroscope. One treated block of each group was selected for scanning electron microscopy (SEM) analysis. MUTBS data were analyzed by two-way ANOVA and no statistical differences were observed among groups. RESULTS: Mean bond strengths (SD) in MPa were: G1-30.4(6.2); G2-27.9(8.5); G3-32.3(3.9); G4 23.7(5.8); G5-29.3(6.0); G6-29.1(6.1). A large number of adhesive failures was recorded for bleached and irradiated enamel surfaces. CONCLUSIONS: Bleached enamel surfaces MUTBS values were not significantly different from those of unbleached enamel. Even though Er:YAG laser irradiation with both parameters had no influence on MUTBS for bleached and unbleached enamel, SEM analysis revealed that Er:YAG laser irradiation with 25.52 J/cm(2) should not be recommended, as enamel ablation was observed, whereas irradiation with 4.42 J/cm(2) did not promote any remarkable changes on enamel surface. PMID- 21323459 TI - Population-based worksite obesity management interventions: a qualitative case study. AB - Due to the increased prevalence of obesity and associated direct and indirect costs to employers, weight management programs have become an integral component of employer and insurer benefits plans. The programs vary in foci, scope, breadth, and implementation. The aim of this study was to explore promising employer-sponsored population-based obesity management programs. A case study that utilized a telephonic semi-structured questionnaire was conducted with small and large organizations located in different regions of the United States that had been recruited to participate. Eight employers and 1 health care advocacy coalition who met the inclusion criteria were interviewed about features of their weight management programs. The case study revealed a number of themes consistent with reports in the literature and reflecting cited best practices. Key findings include confirmation that weight management is a significant component of the wellness strategy in all participating organizations because employers are invested in population health programs and cost savings. Based upon their experience and knowledge, occupational health specialists are responsible for designing, implementing, managing, and evaluating employee health programs. Almost all employers utilize electronic media as a prominent component of wellness and disease management initiatives. Experience has shown that incentives both financial and nonmonetary-are effective motivators for employee engagement and outcomes. However, while employers report success, favorable outcomes have been difficult to quantify. PMID- 21323460 TI - Evaluation of a university-based community outreach weight management program. AB - This study tested the effectiveness of a 6-month university-based community outreach weight management program for overweight/obese adults that utilized standard guidelines from the National Heart, Lung, and Blood Institute (NHLBI). This article also provides practical observations for clinicians desirous to employ a similar program. Fifty-one overweight/obese (34.8 +/- 6.6 kg/m(2)) middle-aged (46.6 +/- 12.4 y) adults (42 females; 9 males) participated. Participants met weekly for 3 months to be weighed, to report weekly diet and physical activity (PA) data, and to receive instruction for weight management. Participants followed a self-selected dietary plan that included decreasing energy intake by ~500-1000 kcal/d and consuming a combined 5 fruits and/or vegetables (FV) daily. Participants progressed to a minimum of 150 min of PA per week, wore a pedometer, and recorded daily step counts. Additionally, there was a 3-month follow-up during which participants met monthly but continued tracking FV, PA, and pedometer counts. Body weight decreased significantly (~0.4-2.1 lbs per week; P < 0.01) during the first 3 months. Weight loss was maintained during the 3-month follow-up. Self-reported energy intake tended to increase during the first 3 months (P < 0.01). PA increased significantly (P < 0.05) beyond recommended minimums and pedometer counts increased significantly (P < 0.01). FV intake averaged below 5 per day and did not change across the study (P = 0.75). Standard treatment guidelines produce modest but consistent weight loss and improvements in PA. The NHLBI recommended approach to weight management is effective for a majority of participants and can be incorporated into a clinical program with relative ease. PMID- 21323461 TI - The after discharge care management of low income frail elderly (AD-LIFE) randomized trial: theoretical framework and study design. AB - Interdisciplinary care management is advocated for optimal care of patients with many types of chronic illnesses; however, few models exist that have been tested using randomized trials. The purpose of this report is to describe the theoretical basis for the After Discharge Management of Low Income Frail Elderly (AD-LIFE) trial, which is an ongoing 2-group randomized trial (total n = 530) to test a chronic illness management and transitional care intervention. The intervention is based on Wagner's chronic illness care model and involves comprehensive posthospitalization nurse-led interdisciplinary care management for low income frail elders with chronic illnesses, employs evidence-based protocols that were developed using the Assessing Care of Vulnerable Elders (ACOVE) guidelines, emphasizes patient activation, and integrates with community-based long-term care and other community agencies. The primary aim of the AD-LIFE trial is to test a chronic illness management intervention in vulnerable patients who are eligible for Medicare and Medicaid. This model, with its standardized, evidence-based medical and psychosocial intervention protocols, will be easily transportable to other sites interested in optimizing outcomes for chronically ill older adults. If the results of the AD-LIFE trial demonstrate the superiority of the intervention, then this data will be important for health care policy makers. PMID- 21323462 TI - Monitoring in diabetes self-management: issues and recommendations for improvement. AB - The American Association of Diabetes Educators hosted a Monitoring Symposium during which 18 invited participants considered pre-set questions regarding how diabetes education can more effectively address barriers to monitoring for people with diabetes and related conditions. This report provides a summary of the moderated discussion and highlights the key points that apply to diabetes educators and other providers involved with diabetes care. The participating thought leaders reviewed findings from published literature and participated in a moderated discussion with the aim of providing practical advice for health care practitioners regarding monitoring for people with diabetes so that the overall health of this population can be enhanced. The discussants also defined monitoring for diabetes as including that done by the clinician or laboratory, as well as self-monitoring. The discussion was distilled into key points that apply to diabetes educators and other providers involved with diabetes care. Participants developed specific recommendations for a self-monitoring behavior and monitoring framework. People with diabetes benefit from instruction and guidance about self-monitoring and decision making that is based on monitored results and informed interactions with providers. Importantly, collaboration among the entire diabetes care community is needed to ensure that monitoring is performed and utilized to its fullest advantage. Going forward, it will be critical to mitigate barriers to diabetes self-management and training and to identify linkages and partnerships to address barriers to self-monitoring. PMID- 21323463 TI - The effectiveness of a telephone-based tobacco cessation program offered as part of a worksite health promotion program. AB - Extensive research on tobacco cessation affirms the effectiveness of interventions, although the literature is more limited concerning the impact of programs designed specifically for the workplace. The present study examines the effectiveness of a telephone-based health coaching tobacco cessation program that was provided as part of worksite health promotion programs by 10 large employers. The participants were recruited based on their health risks as identified by health assessments, and the program was personalized to meet their individual needs and stages of change. The results indicate that at 12 months, health coaching program participants achieved a 32% quit rate, compared to 18% for nonparticipants. The quit rate was highest (44%) among program completers who were ready to change at baseline. These results suggest that a tobacco cessation program offered as part of a worksite health promotion program can be highly effective, especially for those who are ready to change. However, the relatively low annual participation rate may indicate that tobacco users remain among the most difficult to engage and to support in their efforts to complete programs. Therefore, implementing a variety of engagement strategies, such as policy changes, as well as social and financial incentives and penalties will most likely have a positive effect at the population level. PMID- 21323464 TI - How innovative treatment models and data use are improving diabetes care among older African American adults. AB - By 2030, the number of older adults within the United States will have doubled to approximately 71.5 million. Included in this population estimate is the relative growth in the number of older adults of racial and ethnic minority descent. Research has indicated that these individuals, specifically African Americans, have a higher incidence of diabetes than whites, as well as a higher rate of hospitalization compared to whites. This is also true for the older African American. Unfortunately, those with the greatest need for diabetes-related care are least likely to access that care. Moreover, in spite of the indication of need, it is extremely difficult to fully identify strategies that would be optimal for these older minority populations. This paper addresses strategies and techniques to fill gaps in knowledge by detailing efforts, such as the use of health information technologies and multilevel diabetes education teams, to improve the health outcomes of older adult African Americans who have diabetes. PMID- 21323465 TI - Quantitative and temporal definition of the Mla transcriptional regulon during barley-powdery mildew interactions. AB - Barley Mildew resistance locus a (Mla) is a major determinant of immunity to the powdery mildew pathogen, Blumeria graminis f. sp. hordei. Alleles of Mla encode cytoplasmic- and membrane-localized coiled-coil, nucleotide binding site, leucine rich repeat proteins that mediate resistance when complementary avirulence effectors (AVR(a)) are present in the pathogen. Presence of an appropriate AVR(a) protein triggers nuclear relocalization of MLA, in which MLA binds repressing host transcription factors. Timecourse expression profiles of plants harboring Mla1, Mla6, and Mla12 wild-type alleles versus paired loss-of-function mutants were compared to discover conserved transcriptional targets of MLA and downstream signaling cascades. Pathogen-dependent gene expression was equivalent or stronger in susceptible plants at 20 h after inoculation (HAI) and was attenuated at later timepoints, whereas resistant plants exhibited a time-dependent strengthening of the transcriptional response, increasing in both fold change and the number of genes differentially expressed. Deregulation at 20 HAI implicated 16 HAI as a crucial point in determining the future trajectory of this interaction and was interrogated by quantitative analysis. In total, 28 potential transcriptional targets of the MLA regulon were identified. These candidate targets possess a diverse set of predicted functions, suggesting that multiple pathways are required to mediate the hypersensitive reaction. PMID- 21323466 TI - Insertion sequence- and tandem repeat-based genotyping techniques for Xanthomonas citri pv. mangiferaeindicae. AB - Molecular fingerprinting techniques that have the potential to identify or subtype bacteria at the strain level are needed for improving diagnosis and understanding of the epidemiology of pathogens such as Xanthomonas citri pv. mangiferaeindicae, which causes mango bacterial canker disease. We developed a ligation-mediated polymerase chain reaction targeting the IS1595 insertion sequence as a means to differentiate pv. mangiferaeindicae from the closely related pv. anacardii (responsible for cashew bacterial spot), which has the potential to infect mango but not to cause significant disease. This technique produced weakly polymorphic fingerprints composed of ~70 amplified fragments per strain for a worldwide collection of X. citri pv. mangiferaeindicae but produced no or very weak amplification for pv. anacardii strains. Together, 12 tandem repeat markers were able to subtype X. citri pv. mangiferaeindicae at the strain level, distinguishing 231 haplotypes from a worldwide collection of 299 strains. Multilocus variable number of tandem repeats analysis (MLVA), IS1595-ligation mediated polymerase chain reaction, and amplified fragment length polymorphism showed differences in discriminatory power and were congruent in describing the diversity of this strain collection, suggesting low levels of recombination. The potential of the MLVA scheme for molecular epidemiology studies of X. citri pv. mangiferaeindicae is discussed. PMID- 21323468 TI - Fusarium head blight of cereals in Denmark: species complex and related mycotoxins. AB - Quantitative real-time polymerase chain reaction differentiating 10 Fusarium spp. and Microdochium nivale or M. majus was applied to a total of 396 grain samples of wheat, barley, triticale, oat, and rye sampled across Denmark from 2003 to 2007, along with selected samples of wheat and barley from 1957 to 2000, to determine incidence and abundance of individual Fusarium spp. The mycotoxins deoxynivalenol (DON), nivalenol, zearalenone, T-2, and HT-2 were quantified using liquid chromatography-double mass spectrometry. Major differences in the Fusarium species complex among the five cereals as well as great yearly variation were seen. Fusarium graminearum, F. culmorum, and F. avenaceum were dominant in wheat, with DON as the dominant mycotoxin. F. langsethiae, F. culmorum, and F. avenaceum were dominant in barley and oat, leading to relatively high levels of the mycotoxins T-2 and HT-2. F. graminearum, F. culmorum, and F. avenaceum dominated in triticale and rye. The nontoxigenic M. nivale/majus were present in significant amounts in all cereal species. Wheat and barley samples from 1957 to 1996 exhibited no or very low amounts of F. graminearum, indicating a recent increase of this pathogen. Biomass and mycotoxin data exhibited good correlations between Fusarium spp. and their corresponding mycotoxins under field conditions. PMID- 21323467 TI - Control of postharvest Botrytis fruit rot of strawberry by volatile organic compounds of Candida intermedia. AB - A study was conducted to identify volatile organic compounds or volatiles produced by Candida intermedia strain C410 using gas chromatography-mass spectrometry, and to determine efficacy of the volatiles of C. intermedia in suppression of conidial germination and mycelial growth of Botrytis cinerea and control of Botrytis fruit rot of strawberry. Results showed that, among 49 volatiles (esters, alcohols, alkenes, alkanes, alkynes, organic acids, ketones, and aldehydes) identified from C. intermedia cultures on yeast extract peptone dextrose agar, two compounds, 1,3,5,7-cyclooctatetraene and 3-methyl-1-butanol, were the most abundant. Synthetic chemicals of 1,3,5,7-cyclooctatetraene; 3 methyl-1-butanol; 2-nonanone; pentanoic acid, 4-methyl-, ethyl ester; 3-methyl-1 butanol, acetate; acetic acid, pentyl ester; and hexanoic acid, ethyl ester were highly inhibitory to conidial germination and mycelial growth of B. cinerea. Inhibition of conidial germination and mycelial growth of B. cinerea by volatiles of C. intermedia was also observed. Meanwhile, results showed that incidence and severity of Botrytis fruit rot of strawberry was significantly (P < 0.01) reduced by exposure of the strawberry fruit to the volatiles from C. intermedia cultures or C. intermedia-infested strawberry fruit. These results suggest that the volatiles of C. intermedia C410 are promising biofumigants for control of Botrytis fruit rot of strawberry. PMID- 21323469 TI - Multilocus sequence typing of Pseudomonas syringae sensu lato confirms previously described genomospecies and permits rapid identification of P. syringae pv. coriandricola and P. syringae pv. apii causing bacterial leaf spot on parsley. AB - Since 2002, severe leaf spotting on parsley (Petroselinum crispum) has occurred in Monterey County, CA. Either of two different pathovars of Pseudomonas syringae sensu lato were isolated from diseased leaves from eight distinct outbreaks and once from the same outbreak. Fragment analysis of DNA amplified between repetitive sequence polymerase chain reaction; 16S rDNA sequence analysis; and biochemical, physiological, and host range tests identified the pathogens as Pseudomonas syringae pv. apii and P. syringae pv. coriandricola. Koch's postulates were completed for the isolates from parsley, and host range tests with parsley isolates and pathotype strains demonstrated that P. syringae pv. apii and P. syringae pv. coriandricola cause leaf spot diseases on parsley, celery, and coriander or cilantro. In a multilocus sequence typing (MLST) approach, four housekeeping gene fragments were sequenced from 10 strains isolated from parsley and 56 pathotype strains of P. syringae. Allele sequences were uploaded to the Plant-Associated Microbes Database and a phylogenetic tree was built based on concatenated sequences. Tree topology directly corresponded to P. syringae genomospecies and P. syringae pv. apii was allocated appropriately to genomospecies 3. This is the first demonstration that MLST can accurately allocate new pathogens directly to P. syringae sensu lato genomospecies. According to MLST, P. syringae pv. coriandricola is a member of genomospecies 9, P. cannabina. In a blind test, both P. syringae pv. coriandricola and P. syringae pv. apii isolates from parsley were correctly identified to pathovar. In both cases, MLST described diversity within each pathovar that was previously unknown. PMID- 21323470 TI - Toxicity of a biodegradable microneedle implant loaded with methotrexate as a sustained release device in normal rabbit eye: a pilot study. AB - PURPOSE: Primary intraocular lymphoma is a term that refers to nonmetastatic malignant lymphoid neoplasia that arises primarily within the eye. Primary vitreo retinal lymphoma (PVRL), a subtype of primary intraocular lymphoma that comprises at least 85% of cases, provides a therapeutic challenge because of its diverse clinical presentations and variable clinical course. One of the currently available treatment options for PVRL is intravitreal injection of methotrexate. To achieve and maintain sufficient therapeutic levels of methotrexate in the eye to eradicate PVRL, the patient must undergo multiple intravitreal injections with attendant potential toxic peaks and sub-therapeutic troughs of intraocular drug concentrations. In this pilot study, we investigated the intravitreal concentration of methotrexate over time, and toxicity associated with slow sustained release of the drug from a biodegradable device containing methotrexate implanted in a deep scleral pocket of the eyes of normal rabbits. METHODOLOGY: Biodegradable microneedle implants (~8 mg) loaded with 10%wt of methotrexate were fabricated using solvent cast method. All the implants were inserted surgically in a deep lamellar scleral pocket created in each eye of 3 albino New Zealand rabbits. The left eye received a placebo implant, and the right eye received an implant loaded with methotrexate. Postoperatively, the animals were monitored regularly for complications related to the surgery, implant, or drug. The animals were sacrificed 4 weeks after the surgical implantation, and the eyes were enucleated. The eyes were studied histopathologically to look for evidence of inflammation related to the implants and toxicity related to the implant or drug. RESULTS: The biodegradable microneedle methotrexate implants were inserted successfully into deep lamellar scleral pockets of the rabbits without any intraoperative or postoperative complications. Histopathologic examination of the medicated (methotrexate implant) and nonmedicated devices (placebo) showed no evidence of drug toxicity. Also, no major differences were apparent between the eyes as well as no acute ocular inflammation or infection was evident around the implantation site. CONCLUSIONS: This sustained release implant containing methotrexate proved to be nontoxic histopathologically and well-tolerated in the eyes of normal rabbit. PMID- 21323471 TI - Protective effects of erdosteine on amikacin induced visual evoked potentials and lipid peroxidation alterations. AB - PURPOSE: We aimed at investigating the effect of erdosteine administration on amikacin induced visual evoked potentials (VEPs) alterations in rats. METHODS: For this purpose, forty male Wistar rats were divided into 4 groups: control, amikacin treated, erdosteine treated, and amikacin + erdosteine treated. Amikacin (600 mg/kg/day) was applied as a single dose of intramuscular injection for 14 days, and 10 mg/kg/day erdosteine was given by gastric gavage for the same period. We recorded all VEP components and measured plasma thiobarbituric acid reactive substance (TBARS) levels in all groups. RESULTS: Amikacin increased the latencies of all VEP components (P1, N1, P2, N2, and P3) and elevated plasma TBARS levels compared with control and erdosteine treated rats (p < 0,01). However, prolonged latencies of VEP components in amikacin treated rats returned to control levels after erdostein administration. Treatment of amikacin and erdosteine together significantly decreased plasma TBARS levels (0.05 +/- 0.018 nmol/g protein) compared with amikacin group (0.12 +/- 0.038 nmol/g protein). CONCLUSIONS: These results show that erdosteine has a protective effect on amikacin induced changes in the visual system. PMID- 21323472 TI - Influences of bone and mineral metabolism in epilepsy. AB - INTRODUCTION: Patients with epilepsy are at increased risk for metabolic bone disease, low bone mineral density and fractures. AREAS COVERED: This article reviews the predictors and mechanisms of bone loss in patients with epilepsy. It provides information regarding the basic bone biology, evidences of osteopathy with epilepsy and the potential mechanisms of its pathogenesis. This review shows that long-term use of antiepileptic drugs (AEDs) is associated with the risk of osteopathy. However, age, gender, low body mass, severity of epilepsy, co-morbid conditions, institutionalization and calcium and vitamin D deficiencies are additional and modified risk factors. AEDs may indirectly accelerate bone loss through hypovitaminosis D, hypocalcemia and hyperparathyroidism or reduce bone accrual through decreasing the levels of calcitonin, growth factors and vitamin K. Also, AEDs may directly accelerate osteoclastic (bone loss) and/or reduce osteoblastic (bone formation) activities, the main cells involved in bone remodeling. EXPERT OPINION: Understanding the basic bone biology and the pathophysiology of the disturbed bone and mineral metabolism in epilepsy will aid in identification and monitoring of patients at risk and in planning appropriate prophylactic and therapeutic measures. PMID- 21323473 TI - Emerging options in the treatment of dyslipidemias: a bright future? AB - INTRODUCTION: Hypercholesterolemia is a major risk factor for cardiovascular disease (CVD). Low-density lipoprotein cholesterol (LDL-C) reduction has been demonstrated to decrease CVD-related morbidity and mortality. However, several patients do not reach LDL-C target levels with the currently available lipid lowering agents, particularly statins. Lipid and non-lipid parameters other than LDL-C may account for the residual CVD risk after adequate LDL-C lowering with statins. AREAS COVERED: This review focuses on the efficacy and safety of emerging drugs aiming at high-density lipoprotein cholesterol (HDL-C) elevation (i.e., recombinant or plasma-derived wild-type apolipoprotein (apo) A-I, apo A-I mimetic peptides, reconstituted mutant HDL, partially delipidated HDL and cholesterol ester transfer protein inhibitors), microsomal triglyceride transfer protein inhibitors and antisense oligonucleotides. EXPERT OPINION: Several lipid modifying agents in development may potently reduce the residual CVD risk. Ongoing and future studies with clinical outcomes will clarify their efficacy in clinical practice. PMID- 21323474 TI - Combined neutral endopeptidase inhibitors. AB - INTRODUCTION: The renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathophysiology of hypertension and heart failure. ACE inhibitors, angiotensin receptor II blockers (AT-II blockers) and aldosterone antagonists have been used to tackle the RAAS in the past but combined ACE and neutral endopeptidase (NEP) inhibitors have been shown to be more potent in reducing blood and especially pulse pressure in patients with hypertension. AREAS COVERED: Different NEP inhibitors have been tested but omapatrilat is the most widely studied in the setting of hypertension, heart failure and chronic angina. We have undertaken a PubMed search on NEP with a special focus on omapatrilat and its efficacy in hypertension and heart failure. The incidence of angioedema is more frequent in patients taking combined ACE and NEP inhibitors and this has prevented these medications from finding a widespread use. Combinations of NEP inhibitors and AT-II blockers are currently being studied and have been shown to reduce the blood pressure significantly. These medications have so far not been associated with angioedema and have a great potential to be safe and effective alternatives in the near future. EXPERT OPINION: NEP inhibitors were effective in the treatment of hypertension and heart failure but the relatively high incidence of angioedema stopped their widespread use. New hope has risen with the introduction of combined NEP inhibitors and AT-II blockers and early studies are encouraging. PMID- 21323475 TI - Comparison of two different methods of fiber-optic nasal intubation: conventional method versus facilitated method (NASAL-18). AB - OBJECTIVES: As the conventional fiber-optic nasal intubation technique has several potential difficulties, we compared in this study another technique (NASAL-18) with the conventional one in attempting fiber-optic nasal intubation with a possible higher rate of success. METHODS: A randomized controlled trial was carried out at a teaching hospital. Forty-eight patients aged 25-45 years with American Society of Anesthesiologists (ASA) classes I and II undergoing elective faciomaxillary surgery were allocated to two groups of fiberscopic nasal intubation using either the NASAL-18 technique or the conventional method (control). In the NASAL-18 group, a nasal tube was gently inserted into the nasopharynx till mark 18, then a fiberscope with 41 cm length was glided over it and advanced through the nasal cavity till the glottis could be visualized. Finally the nasal tube was rolled over the fiberscope instead of one-step passage of the nasal tube after visualization of glottis in the controls. Times from the start of insertion of the fiberscope into nares till visualization of vocal cord (T1) and from here to complete intubation (T2) were recorded. These times were compared between the two groups. RESULTS: T1 values in NASAL-18 and control groups were 65.2 +/- 33.2 and 151.0 +/- 56.5 seconds, respectively (P < 0.0001). T2 durations were measured as 25.1 +/- 18.5 and 21.8 +/- 10.1 seconds in control and NASAL-18 groups, respectively (P = 0.45). The NASAL-18 group had a success rate of 83% compared to 66.7% in the control group. CONCLUSIONS: The NASAL-18 method reduces the time needed for successful fiber-optic intubation. This method can be added to the list of techniques in facilitating fiber-optic intubation. PMID- 21323476 TI - Correlations between phenolic content and antioxidant properties in twenty-four plant species of traditional ethnoveterinary use in the Mediterranean area. AB - CONTEXT: Scientific information on antioxidant properties and phenolic content of less widely used plants can be useful. Therefore, the assessment of such properties remains an interesting and useful task, particularly for finding new sources for natural antioxidants, functional foods, and nutraceuticals. OBJECTIVE: As knowledge about antioxidant properties and phenolic content of many plant species used as traditional plant remedies is limited, we determined in vitro the total antioxidant activity and the phenolic content of several plant species traditionally used for ethnoveterinary practices. MATERIALS AND METHODS: For 24 extracts (70% acetone) from wild and cultivated plant species traditionally used for health care of animals we determined the Trolox equivalent antioxidant capacity (TEAC) by the two assays 1,1-diphenyl-2-picrylhydrazyl (DPPH) and the 2,2'-azinobis (3-ethylbenzothiazoline-6-sulphonic acid) diammonium salt (ABTS). The phenolic content was determined by the Folin Ciocalteu method. RESULTS: Total phenolics, calculated as gallic acid equivalent (GAE), showed variation ranging from 3.18 (Allium sativum L. (Liliaceae)) to 147.68 (Pistacia lentiscus L. (Anacardiaceae)) mgGAE/g dry weight (DW). High TEAC values corresponded to high phenolic content, while plants with low antioxidant activity exhibited low total phenolic content. The TEAC determined through each assay and total phenolic content were positively correlated, R2 = 0.9152 and R2 = 0.8896, respectively, for DPPH and ABTS assay. DISCUSSION AND CONCLUSION: These findings suggest that phenolic content could be used as an indicator of antioxidant properties. The results of this study encourage investigations on Mediterranean plant species as sources of antioxidants. PMID- 21323477 TI - Studies on the possible mechanisms of antidiabetic activity of extract of aerial parts of Phyllanthus niruri. AB - CONTEXT/OBJECTIVES: The effects of methanol extract of aerial parts of Phyllanthus niruri L. (Euphorbiaceae), an antidiabetic herb, on glucose absorption and storage in diabetes were studied to elucidate the mechanisms of blood glucose lowering and glycemic control in diabetes. METHODS: The effect of chronic oral administration of the extract on glycemic control was evaluated in alloxan diabetic rats using blood glucose lowering and post-prandial glucose suppression activities as well as effects on hemoglobin glycation and body weight. Effects on glucose mobilization and storage were assessed using the weight and glycogen content of liver isolated from treated diabetic rats, while in vitro inhibition of alpha-amylase and alpha-glucosidase enzyme activities were used as indices of effect on glucose absorption. RESULTS: Results showed that the extract lowered blood glucose, suppressed postprandial rise in blood glucose following a glucose meal, reduced hemoglobin glycation and increased absolute and relative weights as well as glycogen content of liver in diabetic rats. Treatment with the extract also ameliorated the decrease in body weights caused by the diabetic disease. In vitro, the extract inhibited alpha-amylase (IC50: 2.15 +/- 0.1 mg/mL) and alpha-glucosidase (IC50: 0.2 +/- 0.02 mg/mL) activities. DISCUSSION AND CONCLUSION: These findings suggest that aerial parts of P. niruri may owe their blood glucose lowering properties to inhibition of glucose absorption and enhancement of glucose storage. PMID- 21323478 TI - Antiulcerogenic activity of Terminalia chebula fruit in experimentally induced ulcer in rats. AB - CONTEXT: Terminalia chebula Retz. (Combretaceae) is a medium-sized tree that grows in the wild throughout India. T. chebula has been extensively used in Ayurveda, Unani, and homoeopathic medicine. The fruit has been used as a traditional medicine for a household remedy against various human ailments. Traditionally T. chebula is used to cure chronic ulcer, gastritis, and stomach cancers. OBJECTIVE: The present study is to evaluate the antiulcer effect of hydroalcoholic (70%) extract of Terminalia chebula fruit. MATERIALS AND METHODS: Aspirin, ethanol and cold restraint stress-induced ulcer methods in rats were used for the study. The effects of the extract on gastric secretions, pH, total and free acidity using pylorus ligated methods were also evaluated. RESULTS: Animals pretreated with doses of 200 and 500 mg/kg hydroalcoholic extract showed significant reduction in lesion index, total affected area and percentage of lesion in comparison with control group (P < 0.05 and P < 0.01) in the aspirin, ethanol and cold restraint stress-induced ulcer models. Similarly extracts increased mucus production in aspirin and ethanol-induced ulcer models. At doses of 200 and 500 mg/kg of T. chebula extract showed antisecretory activity in pylorus ligated model, which lead to a reduction in the gastric juice volume, free acidity, total acidity, and significantly increased gastric pH. DISCUSSION AND CONCLUSION: These findings indicate that hydroalcoholic extract of the fruit T. chebula displays potential antiulcerogenic activity. This activity thus lends pharmacological credence to the suggested use of the plant as a natural remedy in the treatment or management of ulcer. PMID- 21323479 TI - Purification of a protein from coelomic fluid of the earthworm Eisenia foetida and evaluation of its hemolytic, antibacterial, and antitumor activities. AB - CONTEXT: Earthworm Eisenia foetida (Lumbricus rubellus), a traditional Chinese medicine, is used for treating many diseases, and its coelomic fluid has extensive biological functions. OBJECTIVE: The hemolytic, antibacterial and antitumor activities of an earthworm protein purified from coelomic fluid were investigated in vitro. MATERIALS AND METHODS: We used ultrafiltration, gel chromatography, and ion exchange chromatography in sequence to isolate and purify an earthworm protein from coelomic fluid (ECFP), and ECFP was characterized by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Hemolytic assay and antibacterial tests were applied to determine the cytolytic activity of ECFP. The MTT method was carried out to evaluate the antitumor effect of ECFP on HeLa cells and LTEP-A2 cells. RESULTS: ECFP, with molecular weight determined to be approximately 38.6 kilodaltons (KDa), was shown to possess significant hemolytic activity to chicken red blood cells (CRBC) (minimal hemolytic concentration 0.39 ug/mL). Antibacterial effect of ECFP obviously tested against Escherichia coli (minimal bactericidal concentration, MBC 180 ug/ mL) and Staphylococcus aureus (MBC 90 ug/mL) were observed. Moreover, ECFP notably inhibited the proliferation of HeLa cells (IC50 77 ug/mL) and LTEP-A2 cells (IC50 126 ug/mL) both in a time- and dose-dependent manner. DISCUSSION AND CONCLUSION: ECFP could serve as a component of the innate defense system of earthworms against foreign organisms, and thus it has potential pharmaceutical application in the future. PMID- 21323480 TI - Antioxidant capacity of hesperidin from citrus peel using electron spin resonance and cytotoxic activity against human carcinoma cell lines. AB - CONTEXT: Hesperidin is a flavonoid that has various pharmacological activities including anti-inflammatory, antimicrobial and antiviral activities. OBJECTIVE: The aim of the study is the isolation of hesperidin from the peel of Citrus sinensis L. (Rutaceae), and the evaluation of its antioxidant capacity and cytotoxicity against different human carcinoma cell lines. MATERIALS AND METHODS: In the present work, hesperidin is identified and confirmed using chromatographic and spectral analysis. To correlate between hesperidin concentration and antioxidant capacity of peel extracts, extraction was carried out using 1% HCl MeOH, MeOH, alkaline solution, the concentration of hesperidin determined qualitatively and quantitatively using high performance thin layer chromatography (HPTLC), high performance liquid chromatography (HPLC) analysis, in vitro antioxidant capacity of hesperidin and the extracts against free radical diphenylpicrylhydrazyl (DPPH*) performed using an electron spin resonance spectrophotometer (ESR). Cytotoxic assay against larynx, cervix, breast and liver carcinoma cell lines was performed. RESULTS: Hesperidin was found to be moderately active as an antioxidant agent; its capacity reached 36%. In addition, the results revealed that hesperidin exhibited pronounced anticancer activity against the selected cell lines. IC50 were 1.67, 3.33, 4.17, 4.58 ug/mL, respectively. DISCUSSION AND CONCLUSION: Orange peels are considered to be a cheap source for hesperidin which may be used in the pharmaceutical industry as a natural chemopreventive agent. Hesperidin and orange peel extract could possess antioxidant properties with a wide range of therapeutic applications. PMID- 21323481 TI - In vivo antimalarial activity of ginseng extracts. AB - CONTEXT: Novel antimalarial agents are in demand due to the emergence of multidrug resistant strains. Ginseng, a medicinal plant with antiparasitic activity, contains components that can be used to treat the tropical disease malaria. OBJECTIVE: Ginsenosides and polysaccharides are active components of ginseng. This study aimed to elucidate the ability of these compounds to inhibit the replication of Plasmodium yoelii in an attempt to determine whether the medicinal uses of ginseng are supported by pharmacological effects. New antimalarial compounds may be developed from ginsenosides and water-soluble ginseng polysaccharides (WGP). MATERIALS AND METHODS: Ginsenosides and ginseng polysaccharides were prepared from ginseng. Antimalarial activities were examined by 4-day tests and repository tests. Macrophage phagocytosis was tested in normal and malaria-bearing mice. RESULTS: Ginseng polysaccharides could inhibit residual malaria infection. After a 6-day treatment, the parasitemia reductions of WGP and acidic ginseng polysaccharide (WGPA) were 55.66% and 64.73% at 200 mg/kg/day, respectively. Ginsenosides showed significant antimalarial activity on early infection. Protopanaxadiol-type ginsenosides caused 70.97% chemosuppression at 50 mg/kg/day, higher than 52.8% of total ginsenosides at the same dose. DISCUSSION AND CONCLUSION: Protopanaxadiol-type ginsenosides have remarkably suppressive activity during early infection, while acidic ginseng polysaccharides have significant prophylactic activity against malaria by stimulating the immune system. We propose that the activity of ginsenosides is dependent upon non specific carbohydrate interactions and that the activity of ginseng polysaccharides is due to immunological modulation. Ginsenosides and ginseng polysaccharides might have a potential application in antimalarial treatments. PMID- 21323482 TI - Angiotensin-converting enzyme inhibitory activity of Viscum triflorum is host plant-dependent. AB - CONTEXT: Viscum triflorum DC. (Viscaceae) is a hemiparasitic plant used in traditional medicine on Reunion Island as a remedy to treat hypertension. OBJECTIVE: The in vitro angiotensin-converting enzyme (ACE) inhibitory activity of extracts of V. triflorum and the corresponding host plant species were examined to evaluate the use as a remedy against hypertension, and to investigate whether the host plants have an influence on the activity. MATERIALS AND METHODS: Aqueous, ethanol and acetone extracts of 24 leaf samples of V. triflorum and the corresponding host plants, representing 10 plant species, were prepared. The ACE inhibitory activities of the extracts were measured by HPLC using dansyltriglycine as substrate. RESULTS AND CONCLUSION: Water extracts of Viscum samples from only two of the 10 host plants, namely Acacia heterophylla Willd. (Fabaceae) and Sophora denudata Bory (Fabaceae), showed significant inhibitory activity, >= 50% inhibition in a concentration of 0.33 mg crude plant extract in 1 mL test solution. From the two mentioned host plant species activity was only detected in the water extract from one of the six samples of A. heterophylla. Three host species showed pronounced activity without any detection of activity in the samples of V. triflorum. The results support the traditional use provided that V. triflorum is collected from A. heterophylla or S. denudata. PMID- 21323483 TI - Pharmacological evaluation of Copaifera multijuga oil in rats. AB - CONTEXT: Copaiba oil is an oleoresin made up of resin acids and volatile compounds, and it is obtained by tapping the trunks of trees that are members of the Copaifera L. (Leguminoseae) genus and are found in tropical parts of Latin America. OBJECTIVE: This study analyzed the chemical composition of Copaifera multijuga Hayne oil and conducted preclinical trials to investigate anti inflammatory effects and any action it may have on the central nervous system (CNS) of rats. MATERIALS AND METHODS: The chemical analysis was carried out using gas chromatography with mass spectroscopy. Anti-inflammatory activity was measured by leucocytes mobilization, by chemotaxis assay in Boyden's chamber, and by pleurisy model in rats. CNS effect was determined by plus maze and open-field assays. The statistical test applied was analysis of variance (ANOVA) followed by Tukey's test or ANOVA followed by Duncan's test. RESULTS: The oil was composed of sesquiterpenes with the predominance of beta-caryophyllene (36.0%), followed by alpha-copaene (18.8%), beta-bisabolene (8.5%), and alpha-trans-bergamotene (7.0%). Data demonstrated that at 100 and 200 mg/kg doses and at a concentration of 200 MUl/ml copaiba essential oil presented anti-inflammatory effects both in vivo and in vitro based on reduced leukocyte migration to the rats' pleural cavity and to the chemotactic agent lipopolysaccharide solution, respectively. During the experiments investigating CNS effects, locomotive and exploratory activities were reduced and the animals' anxiety increased at 100 and 200 mg/kg. CONCLUSION: The results obtained suggest that copaiba oil has an interesting anti inflammatory effect and important effect on the CNS. PMID- 21323484 TI - Arabinogalactan present in the mountain celery seed extract potentiated hypolipidemic bioactivity of coexisting polyphenols in hamsters. AB - CONTEXT: Previously, we showed the essential oils (EO) of the mountain celery [Cryptotaenia japonica Hass (Umbelliferae)] seeds (MCS) to be a prominent hypolipidemic agent. OBJECTIVE: We hypothesized the aqueous extract (AE) of its seeds could also exhibit a comparable nutritional effect. MATERIALS AND METHODS: Experiments were carried out for compositional analysis, antioxidant assay, and hypolipidaemic assay with AE in hamsters. RESULTS: AE contained soluble arabinogalactan (AGal) with molecular weight (MW) 878 kDa. AE also was enriched in polyphenolics and flavonoids, reaching 30.4 and 2.20 mg/100 g, respectively. AGal consisted of eight monosaccharides (in mols %), galactose (28.75), arabinose (24.84), glucose (17.91), mannose (6.93), ribose (6.03), fucose (5.83), xylose (5.30), and rhamnose (4.41), with average MW 878 kDa. In vitro, AE showed potent ferrous chelating and DPPH scavenging effects but only moderate H2O2 scavenging capability. In hamsters, AE exhibited promising hypolipidemic bioactivity, in particular, the HDL-C and hepatic unsaturated fatty acid (UFA) biosynthesis regarding oleic, linoleic, and arachidonic acids. DISCUSSION AND CONCLUSION: The presence of AGal enhanced the hypolipidemic and antioxidative bioactivity of MCS. MCS is feasibly beneficial to the hepatic de novo UFA synthesis and the hypolipidemics as evidenced by hamster model. PMID- 21323485 TI - Shoulder surface temperature and bone scintigraphy findings in patients with rotator cuff tears. AB - BACKGROUND: Complex regional pain syndrome (CRPS) is one of the serious complications after surgical treatment of a rotator cuff tear. Both a measurement of body surface temperature and bone scintigraphy have been used as diagnostic tools for the early phase of CRPS.Unfortunately, few studies have been carried out that applied these methods to the patients after rotator cuff repair. PURPOSES: To clarify both shoulder surface temperature and bone scintigraphy findings in patients with rotator cuff tears. SUBJECTS AND METHODS: Subjects comprised patients with unilateral rotator cuff tears (five men and five women, mean age 61 years). For measurements of shoulder surface temperature, a Thermochron was attached to both shoulders. As for bone scintigraphy, intravenous injection of technetium-labelled hydroxymethylenebisphosphonic acid (99mTc HMDP)was performed, and then images were taken with a gamma camera. RESULTS: During the measurements, the changes in body surface temperature for the affected and healthy shoulders remained within the standard deviation of the reference group. The intensity of radioisotope (RI) uptake for the affected shoulder joint was significantly increased compared to that for the healthy shoulder joint (P < 0.05). CONCLUSION: RI uptake is increased in shoulders with rotator cuff tears, whereas shoulder surface temperature shows no differences on the affected and unaffected sides. PMID- 21323486 TI - Novel aspects of wet milling for the production of microsuspensions and nanosuspensions of poorly water-soluble drugs. AB - Micronization and nanoparticle production of poorly water-soluble drugs was investigated using single wet milling equipment operating in the attritor and stirred media modes. The drug particles in the median size range of 0.2?2??m were prepared by changing the milling mode and operating conditions of a Micros mill with a purpose of elucidating the dynamics of the wet milling process. It was determined that particle breakage due to mechanical stresses and aggregation due to insufficient stabilization are two competing mechanisms which together control the wet milling dynamics of the poorly water-soluble drugs. The study in the attritor mode using four different classes of stabilizers with six drugs indicated that steric stabilization worked better than electrostatic stabilization for the drugs studied. In addition, the existence of different minimum polymer concentrations for the stabilization of microsuspensions and nanosuspensions was indicated. The major role of a non-ionic polymer during the production of fine particles is its stabilization action through steric effects, and no experimental evidence was found to support the so-called Rehbinder effect. Periodic addition of the polymer as opposed to the addition of the polymer at the start of milling process was introduced as a novel processing method. This novel method of polymer addition provided effective stabilization and breakage of drug particles leading to a narrower and finer particle size distribution. Alternatively, it may allow shorter processing time and lower overall power consumption of the milling process for a desired particle size. PMID- 21323487 TI - Early development evaluation of AZD2738, a substrate for the NK receptors. AB - The purpose of this study was to investigate whether AZD2738, a dual neurokinin NK1/2 receptor antagonist, is a suitable candidate for further development with an oral immediate release solid dosage form as a possible final product. The neutral form of AZD2738 has only been isolated as amorphous material. In order to search for a solid material with improved physical and chemical stability and more suitable solid-state properties, a salt screen was performed. Mostly crystalline material of fumarate, maleate and chloride salt of AZD2738 were obtained. X-ray powder diffractometry, thermogravimetric analysis, differential scanning calorimetry and dynamic vapor sorption were used to investigate the physicochemical characteristics of the salts. Based on the physicochemical properties, the chloride salt is preferred for continued product development. The chloride salt of AZD2738 is an anhydrate, the crystallization is reproducible, the hygroscopicity is acceptable and just one polymorph was obtained. Notably is that the two obtained polymorphs of the fumarate salt of AZD2738 are monotropically related, whereas the two identified polymorphs for the maleate salt of the compound are enantiotropic. The dissolution behavior and the stability (in aqueous solutions, formulations and solid state) of the salts were also studied and found to be satisfactory, at least at pH >3. Liquid formulations should preferable be stored frozen at pH >3. PMID- 21323488 TI - Immobilization of beta-galactosidase on novel polymers having Schiff bases. AB - We have developed a strategy to immobilize beta-galactosidase as a model enzyme by using polymeric supports having Schiff bases, which were prepared from (aminomethyl)polystyrene and 2-phenlyindole-3-carboxaldehyde by condensation. beta-galactosidase was immobilized onto the new polymer supports via covalent bonds. The influence of temperature, pH, reusability, and storage capacity on the free and immobilized beta-galactosidase was investigated. Our results indicate that the (aminomethyl)polystyrene with Schiff bases is most suitable for the immobilization of beta-galactosidase. These kinds of new supports can be used for the immobilization of beta-galactosidase due to their strong storage capacity and reusability. PMID- 21323489 TI - Lesion area assessment in psoriasis patients. AB - Psoriasis is an autoimmune skin disease, afflicting skin with red plaques that are usually accompanied by silvery-white scales. Various medical treatments are used, with different impacts on the patients, but there is no definite cure for the disease. The PASI standard is employed to measure the performance of the treatments. It includes four parameters, namely area, erythema, scaliness and skin thickness. The PASI parameters are usually measured manually by physicians through subjective clinical observations which are imprecise, time consuming and in some cases lead to diverse results. This paper presents a computer-based automatic method to measure the area parameter in the PASI standard. In the proposed method, the YCbCr colour space is used to differentiate the plaques from the skin by applying an optimal threshold method. Performance evaluation results indicate that the proposed method is able to determine lesion areas with accuracy higher than 96% for 18 out of 20 cases and higher than 92% for another case. As well as high accuracy the proposed method has another advantage over previous methods: it can automatically detect plaques with silvery-white scales, plaques on hairy skins and tiny plaques, as well as simple (scale-less) plaques. PMID- 21323490 TI - Effectiveness randomized controlled trial of face to face versus Internet cognitive behaviour therapy for social phobia. AB - OBJECTIVE: To compare the effectiveness of Internet cognitive behaviour therapy (CBT) with face-to-face CBT in social phobia. METHODS: Randomized controlled trial of 75 patients with social phobia referred to an anxiety disorders clinic. A total of 37 patients participated, and post-treatment data was obtained from 25 Subjects (Ss). An intention to treat analysis was used. The same therapist (M.D.) treated both groups. RESULTS: Both groups made significant progress on symptoms and disability measures. There were no significant differences in outcome between the Internet and face-to-face groups. The total amount of therapist time required was 18 min per patient for the Internet group and 240 min per patient for the face-to-face group. CONCLUSIONS: Both forms of treatment were equally effective and this is consistent with previous findings in depression and panic disorder. The difference in clinician time required was substantial. If Internet CBT was offered as 'standard of care' the staff time saved would permit a stepped care model in which in-depth therapy for the difficult to recover patients could be provided without an increase in staff. PMID- 21323491 TI - Tailored chemotherapy doses based on toxicity in breast cancer result in similar quality of life values, irrespective of given dose levels. AB - BACKGROUND: From March 1994 to March 1998, breast cancer patients (an estimated relapse risk with 70% or more within five years with standard therapy) were randomised to treatment with tailored fluorouracil, epirubicin, and cyclophosphamide (FEC) therapy or FEC followed by marrow-supported high dose therapy in the Scandinavian Breast Group 9401 study. The aim of the present paper was to investigate differences in toxicity and eight health-related quality of life (HRQoL) variables (physical functioning, role functioning, emotional functioning, social functioning, cognitive functioning, fatigue, nausea-vomiting, and global quality of life) between women in the six dose steps used in the tailored and granulocyte colony stimulating factor supported FEC-arm at the assessment point 16 weeks after random assignment to treatment. METHODS: The European Organization and Treatment of Cancer Quality of Life Questionnaire EORTC QLQ-C30 were mailed to the patients. RESULTS: A total of 157 (87%) in the tailored FEC-group responded to the questionnaire within the time frame 16 weeks after inclusion in the study. Overall, toxicity was low, reaching grade 1-2 also in the higher dose steps. There were no overall differences between the dose steps on any of the tested HRQoL variables. Patients at dose step 4 scored statistically significantly higher on physical functioning than patients at dose step 1 (p = 0.022) and compared to those at dose step 2 (p = 0.014). Patients at dose steps -2 and -1 (combined to one group) reported statistically significantly higher mean scores on cognitive functioning than patients at dose step 1 (p = 0.022). CONCLUSION: Patients who received higher doses, based on the tailored dosing strategy, did not seem to have worse HRQoL than those who had lower doses. PMID- 21323492 TI - Comparing two versions of the Schedule for Evaluation of Individual Quality of Life in patients with advanced cancer. AB - BACKGROUND: The aim was to compare two individualized patient reported outcomes or the Schedule for the Evaluation of Individual Quality of Life - Direct Weighting (SEIQoL-DW) measuring quality of life in general, and the disease related version (SEIQoL-DR) measuring quality of life related to disease. Both instruments have been used in clinical practice settings within oncology. The instruments were compared with regard to feasibility, the areas nominated by patients as important and patients' ratings of how they were doing in these areas (Index scores). MATERIAL AND METHODS: The study included 40 patients with gastrointestinal cancer. All patients completed both versions of the instrument on a touch screen computer in relation to a medical consultation. Firstly, the participants were invited to nominate the five domains she/he currently considered to be most important in life. Secondly, they were asked to rate how they were doing in each of these domains. Finally, they were asked to quantify the relative importance of each area. Cohen's effect sizes were calculated to illuminate the clinical importance of mean value differences. RESULTS: Both instruments took less than ten minutes to complete and the procedure was considered feasible by both patients and interviewers. The proportion of patients nominating the same areas in the two versions did not differ, however, the SEIQoL DW Index score was significantly higher than the corresponding score for the SEIQoL-DR. The detected difference in the mean score measured by effect size was medium. CONCLUSION: The magnitude of the effect size of the difference in Index score imply that the two versions tap into different constructs, i.e. quality of life (QoL) versus health-related QoL (HRQL), supporting the construct validity of the two versions of the instrument. The SEIQoL-DW and the SEIQoL-DR should be considered as complementary rather than interchangeable when used in patients with cancer. PMID- 21323493 TI - ALSUntangled No. 9: Blue-green algae (Spirulina) as a treatment for ALS. PMID- 21323495 TI - Prevalence of urinary tract infection (UTI) in sequential acutely unwell children presenting in primary care: exploratory study. AB - BACKGROUND: Due to the non-specific nature of symptoms of UTI in children and low levels of urine sampling, the prevalence of UTI amongst acutely ill children in primary care is unknown. OBJECTIVES: To undertake an exploratory study of acutely ill children consulting in primary care, determine the feasibility of obtaining urine samples, and describe presenting symptoms and signs, and the proportion with UTI. DESIGN: Exploratory, observational study. SETTING: Four general practices in South Wales. SUBJECTS: A total of 99 sequential attendees with acute illness aged less than five years. MAIN OUTCOME MEASURE: UTI defined by >10(5) organisms/ml on laboratory culture of urine. RESULTS: Urine samples were obtained in 75 (76%) children. Three (4%) met microbiological criteria for UTI. GPs indicated they would not normally have obtained urine samples in any of these three children. However, all had received antibiotics for suspected alternative infections. CONCLUSION: Urine sample collection is feasible from the majority of acutely ill children in primary care, including infants. Some cases of UTI may be missed if children thought to have an alternative site of infection are excluded from urine sampling. A larger study is needed to more accurately determine the prevalence of UTI in children consulting with acute illness in primary care, and to explore which symptoms and signs might help clinicians effectively target urine sampling. PMID- 21323496 TI - Early experiences with the multidose drug dispensing system--a matter of trust? AB - OBJECTIVE: To study early experiences with multidose drug dispensing (MDD) among different groups of health personnel. DESIGN: Qualitative study based on focus group interviews. SETTING: Primary health care, Trondheim, Norway. MAIN OUTCOME: The importance of trust in the technology and in collaborating partners is actualized in the early implementation of MDD. RESULTS: GPs, home-care nurses, pharmacists, and medical secretaries trusted the new MDD technology. The quality of the GPs' medication records improved. However, health personnel, including the GPs themselves, would not always trust the medication records of the GPs. Checking the multidose bags arriving from the pharmacy was considered unnecessary in the written routines dealing with MDD. However, home-care nurses experienced errors and continued to manually check the bags. Nurses in the home-care service felt a loss of knowledge with regard to the patients' medications and in turn experienced reduced ability to give medical information to patients and to observe the effects of the drugs. The home-care services' routines for drug handling were not always trusted by the other groups of health personnel involved. CONCLUSION: Health personnel faced some challenges during the implementation of the MDD system, but most of them remained confident in the new system. Building trust has to be a process that runs in parallel with the introduction of new technology and the establishment of new routines for improving the quality in handling of medicines and to facilitate better cooperation and communication. PMID- 21323497 TI - Using patient-centred consultation when screening for depression in elderly patients: a comparative pilot study. AB - OBJECTIVE: Using validated screening instruments to detect depressive symptoms in the elderly has been recommended. The aim of this study was to compare a patient centred consultation model with the PRIME-MD screening questionnaire, using the MADRS-S as reference for detecting depressive symptoms in an elderly primary care population. DESIGN: Comparative study. SETTING: Primary care, Sweden. SUBJECTS: During an 11-month period 302 consecutive patients aged 60 and over attending a primary care centre were screened with the PRIME-MD and the Montgomery-Asberg Depression Rating Scale-Self-rated version (MADRS-S) instrument. The results were unknown to the GPs who used a structured, patient-centred consultation model comprising seven open-ended "key questions". MAIN OUTCOME MEASURES: Sensitivity, specificity, positive predictive values (PPV), and negative predictive values (NPV) were calculated for the PRIME-MD screening questionnaire and the patient centred consultation model using MADRS-S as reference for possible depression at two cut-off levels with 15% prevalence. Results. Sensitivity was lower for the consultation model than the PRIME-MD screening questionnaire: 78% and 98%, respectively. The GPs failed to identify every fifth patient using the lower cut off (MADRS-S>=13) but the number of required diagnostic interviews decreased by almost 50%: 85 versus 162, respectively. PPV was 43% and 28%, respectively. Both instruments showed high sensitivity (93%) using the higher cut-off (MADRS-S>=20) and had high NPV: 95% and 99%, respectively. CONCLUSIONS: The findings suggest that the consultation screening procedure might be as useful in everyday practice as the PRIME-MD screening questionnaire. Both screening procedures may also be useful for ruling out depressive symptoms. PMID- 21323498 TI - Primary aldosteronism among newly diagnosed and untreated hypertensive patients in a Swedish primary care area. AB - OBJECTIVE: To evaluate the prevalence of primary aldosteronism (PA) in newly diagnosed and untreated hypertensive patients in primary care using the aldosterone/renin ratio (ARR), and to assess clinical and biochemical characteristics in patients with high and normal ARR. DESIGN: Patient survey study. SETTING AND SUBJECTS: A total of 200 consecutive patients with newly diagnosed and untreated hypertension from six primary health care centres in Sweden were included. MAIN OUTCOME MEASURES: ARR was calculated from serum aldosterone and plasma renin concentrations. The cut-off level for ARR was 65. Patients with an increased ARR were considered for confirmatory testing with the fludrocortisone suppression test (FST), followed by adrenal computed tomographic radiology (CT) and adrenal venous sampling (AVS). RESULTS: Of 200 patients, 36 patients had an ARR > 65. Of these 36 patients, 11 patients had an incomplete aldosterone inhibition during FST. Three patients were diagnosed with an aldosterone producing adenoma (APA) and eight with bilateral adrenal hyperplasia (BHA). Except for moderately lower level of P-K in patients with an ARR > 65 and in patients with PA, there were no biochemical or clinical differences found among hypertensive patients with PA compared with patients without PA. CONCLUSION: Eleven of 200 evaluated patients (5.5%) were considered to have PA. The diagnosis of PA should therefore be considered in newly diagnosed hypertensive subjects and screening for the diagnosis is warranted. PMID- 21323500 TI - Pegylated-interferon-alpha(2a) in clinical practice: how to manage patients suffering from side effects. AB - INTRODUCTION: The goal of antiviral therapy in patients with chronic hepatitis C is to slow or halt the progression of fibrosis and prevent the development of cirrhosis. Accordingly, antiviral treatment is proposed for a large population of patients with chronic hepatitis. AREAS COVERED: The standard-of-care for chronic hepatitis C is the combination of pegylated IFN (PEG-IFN) and ribavirin. The use of these drugs has been correlated with a range of adverse effects, including influenza-like symptoms, hematological changes and neuropsychiatric disturbances. The effects of these adverse events associated with PEG-IFN therapy are manifold and are a major reason why patients decline or stop therapy. This review addresses the screening for adverse event risk factors and guides the patient to success with adherence strategies. EXPERT OPINION: Knowledge of the side effects correlated with PEG-IFN is very relevant for clinicians because it can allow them to arrange the best methods for treating these effects and avoid the discontinuation of antiviral treatment. Moreover, the use of new antiviral drugs will considerably shorten treatment periods reducing many of the above-described side effects and, thus, increase adherence to scheduled therapy. PMID- 21323501 TI - Modern treatment of patients at risk: still a HOPE for ACE inhibitors? AB - Indications for angiotensin-converting enzyme (ACE) inhibitors include heart failure, postmyocardial infarction, diabetes mellitus and proteinuric chronic renal disease. ACE inhibitors provided life-saving benefits in patients with heart failure or left ventricular systolic dysfunction. On the other hand, there are conflicting data regarding the ability of ACE inhibitors to reduce the incidence of cardiovascular events in patients with vascular disease and preserved left ventricular systolic function. Results of the main randomized clinical trials that evaluated the benefit of ACE inhibitors in patients with vascular disease are discussed in this editorial. In particular, the different prognostic impact of ACE inhibitors in high-risk patients with and without heart failure or preserved left ventricular systolic function is examined in detail. The possible impact of lipids and statins on the effect of ACE inhibitors is also discussed. In our opinion, the available data indicate that ACE inhibitors should continue to be used in all patients with documented coronary artery disease or different phenotypes of high vascular risk, even in a context of modern and aggressive preventive strategies. PMID- 21323502 TI - Combination lipid therapy in type 2 diabetes mellitus. AB - INTRODUCTION: A significant drop in cardiovascular risk has been seen in patients with type 2 diabetes treated with statins. However, this cardiovascular risk remains high, compared with nondiabetic individuals. This is partly due to the typical abnormalities of diabetic dyslipidemia - hypertriglyceridemia and decreased high-density lipoprotein cholesterol (HDL-C) - that are uncontrolled by statins. For this reason, combination lipid therapy may be considered in patients with type 2 diabetes. AREAS COVERED: This review presents the main reasons for a combination lipid therapy in type 2 diabetes and the effects of several drugs, including fibrates, pioglitazone, niacin and omega 3, on diabetic dyslipidemia and the prevention of cardiovascular events. The real cardiovascular benefit of fibrates in patients with type 2 diabetes is not totally clear, but they may produce a significant benefit in patients with type 2 diabetes and diabetic dyslipidemia (hypertriglyceridemia, low HDL-C). Pioglitazone, which reduces triglycerides and increases HDL-C, has been shown to reduce the risk for major cardiovascular events in type 2 diabetes. Niacin and omega 3 fatty acids have a positive effect on diabetic dyslipidemia, but warrants clinical trials to demonstrate a clear cardiovascular benefit in type 2 diabetes. EXPERT OPINION: Although combination lipid therapy seems to be useful to control diabetic dyslipidemia, the efficacy of such combined therapies on significantly reducing cardiovascular risk has still to be confirmed by additional clinical trials. PMID- 21323503 TI - Comparison of in vitro activity of ertapenem with other carbapenems against extended-spectrum beta-lactamase-producing Escherichia coli and Kleibsella species isolated in a tertiary children's hospital. AB - OBJECTIVE: The purpose of this study was to evaluate the susceptibility of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae clinical isolates to ertapenem in a tertiary pediatric care center in Turkey. DESIGN/METHODS: All isolates of ESBL-producing Enterobacteriaceae were collected from clinical specimens from children, and susceptibility tests were done using the Vitek 2 compact system. RESULTS: Ninety-nine per cent of the ESBL-producing Escherichia coli isolates were found to be susceptible to ertapenem, 99.5% to imipenem and 100% to meropenem. In the Klebsiella species, 91.5% of the isolates were susceptible to ertapenem, 99.3% to imipenem and 100% to meropenem. CONCLUSION: The results of our data, including isolates from children, showed that ertapenem had high in vitro activity against the majority of the ESBL producing E. coli and Klebsiella species, as reported in previously published studies. However, additional clinical studies are required to assess the clinical activity of ertapenem and the clinical importance of the resistant isolates. PMID- 21323504 TI - Efficacy and safety of saxagliptin in older patients with type 2 diabetes mellitus. AB - OBJECTIVE: To assess the safety and efficacy of saxagliptin (5 mg once-daily) in older patients (>=65 years of age) with inadequately controlled type 2 diabetes. RESEARCH DESIGN AND METHODS: In this retrospective subgroup analysis, data from five randomized, double-blind, placebo-controlled, multicenter, 24-week, phase 3 trials were included. The primary studies evaluated saxagliptin 5 mg once-daily (monotherapy or add-on) in patients aged 18-77 years with HbA(1c) >=7.0% (four studies) or >=7.5% (add-on to glyburide study) versus placebo. MAIN OUTCOME MEASURES: The primary efficacy endpoint of each study included in this pooled analysis was HbA(1c) change from baseline to week 24. RESULTS: In the five-study pooled population, 279 (16.6%) patients were at least 65 years old; 142 received saxagliptin 5 mg once-daily and 137 received placebo. Treatment groups were well balanced for baseline characteristics within each study. In older patients, the HbA(1c) adjusted mean change from a baseline of 8.1% was -0.73 +/- 0.16% (mean +/ SEM) with saxagliptin compared with -0.17 +/- 0.14% for placebo from a baseline of 8.0%. Adverse event rates were similar with saxagliptin 5 mg once-daily compared with placebo in older patients. CONCLUSION: The pooled subgroup analysis of saxagliptin 5 mg once-daily monotherapy and add-on therapy trials demonstrated clinically relevant and significant efficacy for reducing HbA(1c) in older (>=65 years) patients. Saxagliptin was well-tolerated in older patients with a low incidence of hypoglycemia and no weight gain. PMID- 21323505 TI - Medication persistence with long-term, specific grass pollen immunotherapy measured by prescription renewal rates. AB - OBJECTIVE: We assessed medication persistence using prescription renewal rates for grass pollen specific immunotherapy (SIT) in a representative population of patients in Germany to evaluate whether the perception of superior persistence for the subcutaneous route compared to the sublingual route could be confirmed in clinical practice. METHODS: Individual prescriptions for allergen immunotherapy were extracted from a national prescription database (INSIGHT Health) and followed over 3 years on a per-patient basis. However, patients' medical history and treatment schedules were not available for analysis. Products were identified by the national drug code (PZN number) and grouped to either subcutaneous immunotherapy (SCIT) with natural extract injections, SCIT with modified allergens (allergoids) or sublingual immunotherapy (SLIT) with natural pollen extract solutions. Persistence was defined as at least one prescription of the individual drug in the respective years. RESULTS: A total of 1409 patients started SIT in 2005 (112, 695, and 602 for natural extract SLIT, natural extract SCIT, and allergoid SCIT, respectively). In 2006, 71%, 55%, and 59% of those patients had at least one renewal prescription of natural extract SLIT, natural extract SCIT, and allergoid SCIT, respectively, as well as 51%, 34%, and 39% in 2007. In both years, persistence with natural extract SLIT was significantly higher than with natural extract SCIT (p = 0.0015 for 2006, p = 0.0003 for 2007) and allergoid SCIT (p = 0.0152 for 2006, p = 0.0111 for 2007). There were no significant differences between the two SCIT groups. CONCLUSION: Medication persistence with grass pollen SIT in a representative sample of patients in Germany was similar to published medication persistence in asthma and COPD patients. The sublingual application route shows significantly better persistency than the subcutaneous route with native allergens or allergoids. PMID- 21323506 TI - Drug delivery vehicles with improved encapsulation efficiency: taking advantage of specific drug-carrier interactions. AB - INTRODUCTION: Drug encapsulation strategies are vital for the delivery of poorly soluble, fragile or toxic compounds. Increasing a drug's encapsulation efficiency in drug carrier particles can achieve a stronger therapeutic effect along with minimized side effects. For these reasons, new encapsulation methods are developed by using new materials and various types of drug-carrier interaction. AREAS COVERED: Strategies used for drug encapsulation are discussed in this review, focusing particularly on approaches leading to high encapsulation ratios resulting from specific interactions between the drug and the carrier. In the first part, classical encapsulation by hydrophobic self-assembly, its limitations and improvements are briefly discussed. Following this, encapsulation strategies for specific drugs are reviewed, where particular kinds of interaction play a role between the drug and the encapsulating material, which can lead to dramatically increased entrapment. Such specific approaches can be utilized more generically for various classes of molecules with similar properties, with regard to their ability to participate in a given kind of interaction. EXPERT OPINION: With the focus on delivering a high drug dose precisely to the site of action, high encapsulation efficiency is the first thing to consider in drug development. Academic research shows considerable interest in specific encapsulation, and it seems to be an established trend now to design drug delivery particles to achieve the most favorable properties. The authors believe the research in this area will focus on material properties and interactions between the drug and the carrier to ensure high drug loading into particles. PMID- 21323507 TI - Is asthma associated with increased risk of injury? AB - BACKGROUND: Asthmatic patients are at higher risk of fracture and bruising due to the systemic side effects of corticosteroid medication. However, the link between asthma and injury leading to these adverse outcomes remains unclear. OBJECTIVE: This study investigated asthma and cause- and type-specific injury at the population level. METHODS: Using data from the 2001 and 2004 Australian National Health surveys (n = 52,768), the prevalence and risk of experiencing specific causes and types of injury in the past 4 weeks were assessed by logistic and Poisson regression analyses. RESULTS: A history of asthma was associated with a higher prevalence of injury for both adults and children, as well as increased risk of incurring various causes and types of injury, after accounting for the effects of confounding factors. CONCLUSIONS: The associations cannot be explained by the physiological systemic side effects of medication alone. Further research is needed to understand the underlying relationship so that an appropriate injury prevention strategy can be developed for asthma sufferers. PMID- 21323509 TI - Glutathione peroxidase activity in the blood cells of psoriatic patients correlates with their responsiveness to Efalizumab. AB - Biological treatment of psoriasis, a chronic inflammatory immune-mediated pathology of huge social impact, has become a recent revolutionizing breakthrough in the management of the disease. Apart from anti-TNF-alpha biologics, recombinant proteins-inhibitors of the T lymphocytes-antigen presenting cells interaction, Efalizumab among them, have been successfully used in the therapy of psoriasis. Serious concern regarding safety and efficacy of biologics remains because they induce numerous adverse effects and a significant number of patients are non-responders. Up-to-now, there are no biochemical or/and immunological markers of the clinical efficacy of these drugs. This study searches for immunological and redox markers of the clinical response in the group of psoriatic patients treated with Efalizumab. Clinical response to Efalizumab was assessed by Psoriasis Area and Severity Index and correlated with suppression of T-cell functions, plasma cytokines, membrane-associated polyunsaturated fatty acids (PUFAs), antioxidant enzymes and markers of oxidative stress. A 12-week Efalizumab therapy did not affect abnormal plasma levels of pro-inflammatory cytokines and lower-than-normal content of PUFAs esterified in phospholipids of red cell membranes. It did, however, suppress T-cell-mediated functions and decrease nitrites/nitrates and malonyl dialdehyde levels independently on the clinical outcome. On contrast, activities of glutathione peroxidase (GPx) and glutathione S-transferase in granulocytes were remarkably increased and catalase decreased exclusively in non-responders vs complete or partial responders. High baseline GPx in erythrocytes decreased in responders. It is concluded that clinical response to Efalizumab correlates with GPx activity in the blood cells, suggesting that high hydroperoxide levels are involved in psoriasis persistence. PMID- 21323510 TI - Plasma reactive carbonyl species: Potential risk factor for hypertension. AB - To study the role of oxidative stress in hypertension and pre-hypertension, this study analysed plasma levels of reactive carbonyl species (RCS) in 1204 Chinese Han adults. Results showed a statistically significant positive correlation (p < 0.001) between blood pressure and plasma RCS levels with or without being adjusted for covariates. Multivariate-adjusted odds ratio (OR) illustrated that, compared with the lowest quartile of plasma RCS levels, the highest quartile subjects had a 59% and a 130% increase in the risk for developing pre hypertension and hypertension, respectively. The multi-interaction analysis manifested that the underlying mechanism of the increase of hypertensive risk or pre-hypertensive risk by overweight and unhealthy lifestyles might, at least in part, be through oxidative stress. In conclusion, these findings suggest that oxidative stress, as indicated by plasma RCS levels, are not the necessary consequence of pre-hypertension or hypertension, but reliable risk factors for developing pre-hypertension or hypertension in Chinese Han adults. PMID- 21323511 TI - Thrombopoietin receptor agonists can be used temporarily with patients suffering from refractory chronic lymphocytic leukemia-associated immunologic thrombocytopenia. PMID- 21323512 TI - Akt, 14-3-3zeta, and vimentin mediate a drug-resistant invasive phenotype in diffuse large B-cell lymphoma. AB - Development of resistance to the CHOP chemotherapeutic regimen (cyclophosphamide, doxorubicin, vincristine, prednisone) remains a major cause of treatment failure and mortality in approximately 40% of patients with diffuse large B-cell lymphoma (DLBCL). We established CHOP-resistant DLBCL cells as a model system to investigate molecular mechanisms involved in multidrug resistance. Two dimensional differential in-gel (DIGE) analysis identified 10 differentially expressed proteins between CHOP-sensitive and -resistant DLBCL cells that play roles in glycolysis (triosephosphate isomerase-1, enolase-1), cytoskeletal structure (ezrin, vimentin, tubulin-specific chaperone B), purine biosynthesis (serine hydroxymethyltransferase), calcium binding (sorcin), and apoptosis (p53, 14-3-3zeta, Akt). Akt, 14-3-3zeta, and vimentin were up-regulated in CHOP resistant DLBCL cells. We showed previously that siRNA-mediated knockdown of 14-3 3zeta reversed CHOP resistance in DLBCL cells (Maxwell et al., J Biol Chem 2009;284:22379-22389). Here we show that chemical inhibition of Akt overcomes CHOP resistance in DLBCL cells. CHOP-resistant cells exhibited a five-fold greater ability to invade collagen matrices compared with CHOP-sensitive cells. Knockdown of vimentin by siRNA or withaferin A repressed the invasiveness of CHOP resistant cells in collagen matrices. Increased expressions of Akt, 14-3-3zeta, and vimentin were observed by Western blotting in primary DLBCL tissues relative to normal lymphatic tissue. The data implicate activation of an Akt-14-3-3zeta signaling pathway in promoting a multidrug-resistant phenotype associated with a vimentin-dependent invasive behavior in DLBCL cells. PMID- 21323513 TI - Predictive value of TP53 fluorescence in situ hybridization in cytogenetic subgroups of acute myeloid leukemia. AB - Acute myeloid leukemia (AML) with a complex karyotype (CK) has frequent alterations in TP53 and a very poor prognosis. We examined whether a prompt and simple fluorescence in situ hybridization (FISH) analysis for 17p13 deletion at diagnosis has a predictive value for response to therapy and overall survival in subgroups of AML. In 15 patients with a normal karyotype the TP53 FISH analysis was normal, whereas in 16 patients with CK 75% had only one copy of the TP53 allele. The deletion was also detected in 33% of six patients with monosomy or partial monosomy of chromosome 5, 7, 9, or 12. This loss of TP53 correlated significantly with a poor response to chemotherapy, and the median survival time of these patients was shorter. TP53 FISH analysis carried out at diagnosis has a predictive value with respect to chemotherapy response and can therefore facilitate a rapid decision on treatment strategies. PMID- 21323514 TI - Genetic alterations in Sezary syndrome. AB - Sezary syndrome (SS) is a rare form of cutaneous T-cell lymphoma characterized by erythroderma and the presence of Sezary cells in the skin, lymph nodes, and peripheral blood. Over the past few decades, cytogenetic and molecular cytogenetic findings have revealed many genetic alterations in patients with SS. The most frequent genetic lesions include monosomy 10, losses of 10q and 17p, gains of 8q24 and 17q, and diverse structural alterations involving these regions. Expression patterns in regions of genomic imbalance show that a large number of genes in SS are deregulated, and this might have a causative role in oncogenesis. Overall, chromosomal instability is characteristic of this lymphoma and related to a poor prognosis, but no specific abnormalities that may be directly involved in development of the disease have yet been found. PMID- 21323515 TI - Putting the E (evidence) in a new Era for myeloma. PMID- 21323516 TI - Quality of life research: adding an important dimension to the evaluation of therapeutic outcomes. PMID- 21323517 TI - Early initial therapy of advanced follicular lymphoma: the need for vigilance. PMID- 21323518 TI - Diffuse large B-cell lymphoma cycling off the main track. PMID- 21323519 TI - Biologic agent activity in chronic lymphocytic leukemia: a framework for future therapies. AB - The previous decade has witnessed remarkable advances in our understanding and treatment of chronic lymphocytic leukemia. Chemoimmunotherapy has provided patients with unprecedented remission rates and has improved survival compared to chemotherapy alone. However, the availability of targeted therapies and monoclonal antibodies argues for exploring non-cytotoxic and biologic regimens for this disease. In this article, we review available targeted and non chemotherapeutic agents for CLL, attempting to position these therapies in the treatment paradigm of CLL in the era of risk stratification as we move forward. PMID- 21323520 TI - A phase II study of bortezomib and gemcitabine in relapsed mantle cell lymphoma from the National Cancer Institute of Canada Clinical Trials Group (IND 172). AB - Bortezomib and gemcitabine have each shown activity as single agents in mantle cell lymphoma (MCL), which is incurable. The purpose of this phase II study was to determine the efficacy and safety of the previously unstudied combination of bortezomib and gemcitabine in patients with relapsed or refractory MCL. Patients were eligible if they had relapsed MCL with 1-3 prior therapies. Patients were treated with gemcitabine 1000 mg/m(2) on days 1 and 8 and bortezomib 1.0 mg/m(2) IV on days 1, 4, 8, and 11, on a 21-day schedule. Twenty-six patients were evaluable for toxicity and 25 for response. The overall response rate was 60% and the median progression free survival was 11.4 months. The main adverse effects were hematological, with 40% and 48% of patients experiencing grade 3/4 thrombocytopenia and granulocytopenia, respectively. Bortezomib and gemcitabine is an active combination in relapsed and refractory MCL with clinically meaningful results. It offers a chemotherapy backbone to which other agents, less myelosuppressive, may be added. PMID- 21323521 TI - Immunophenotypic characteristics and clinical relevance of CD56+ and CD56- extranodal nasal-type natural killer/T-cell lymphoma. AB - This study aimed to determine whether the phenotypic characteristics of the two subtypes of CD56+ and CD56- lymphoma have relevance for their clinical behavior and prognosis. The immunophenotypes of all patients were confirmed using standard criteria for CD20, CD3epsilon, CD56, cytotoxic molecules (T-cell intracellular antigen-1 [TIA-1] and granzyme B), and Ki-67, and in situ hybridization for Epstein-Barr virus (EBV)-encoded RNA (EBER). CD56 was expressed in 90 of 118 (76.3%) patients. The majority (83.3%) of patients with nasal natural killer/T cell lymphoma (NKTCL) presented with CD56+ lymphoma, whereas patients with NKTCL of the extranasal upper aerodigestive tract were more likely to have CD56- lymphoma (53.6%, p < 0.000). A lower percentage of expression of granzyme B and Ki-67 (>50%) was found in patients with CD56- lymphoma compared with those with CD56+ lymphoma (p <0.05). The clinical characteristics and prognosis were comparable between patients with CD56+ and CD56- lymphomas. The corresponding overall survival and progression-free survival rates were 74.1% and 56.7%, respectively, for patients with CD56+ lymphoma compared with 81.6% and 60.5% for those with CD56- lymphoma (p > 0.05). There was no clinical or prognostic significance in determining the two subtypes of CD56+ and CD56- NKTCL based on their immunophenotypic profiles, which has clinical implications for pathological diagnosis and insight into disease behavior. PMID- 21323522 TI - Alterations in the primary diagnosis of lymphomas pretreated with corticosteroid agents. AB - Little is known of the role of preliminary corticosteroids in clinical and morphological modifications and in difficulties in reaching a diagnosis in patients with lymphoma. We identified 31 patients who were given steroids before biopsy for primary diagnosis. We looked for the reason for steroid pretreatment, its dose, and duration. We evaluated the difficulty in reaching the primary diagnosis and whether a secondary diagnosis was made. The patients' slides were reviewed to identify secondary histological changes. Our findings suggest a variable effect of prior glucocorticoids on the clinical and histopathological alterations developing in malignant lymphomas, as well as on the complexity of the process of reaching a diagnosis. PMID- 21323523 TI - Prospective study of clinical and biological prognostic factors at diagnosis in patients with early stage B-cell chronic lymphocytic leukemia. AB - Retrospective series have reported many clinical and biological significant prognostic factors in chronic lymphocytic leukemia (CLL). We describe a prospective cohort of 135 patients with CLL homogeneously studied at diagnosis for prognostic factors. Biological variables analyzed were CD38 and ZAP-70 expression, fluorescence in situ hybridization (FISH) for 13q-, +12, 11q-, and 17p-, and conventional cytogenetics. Univariate and multivariate analysis for progression-free survival (PFS) were performed in patients with early stage (Rai 0-1) CLL. CD38 was positive in 42 (31.6%) patients and ZAP-70 in 47 (35.9%). The most frequent FISH finding was isolated 13q- in 50 (38.5%) patients, and 17p- was found in 11 (8.4%). Among 135 patients, 114 (84.4%) were Rai 0-1 at diagnosis and 39 (28.9%) presented adenopathies. With a median follow-up of 39 months, the presence of lymphadenopathy in patients with Rai 0-1 stage CLL was the only significant variable for predicting PFS in multivariate analysis (odds ratio [OR] 7, 95% confidence interval [CI] 2.2-22, p = 0.001). When only biological factors were analyzed, CD38 expression (OR 3.2, 95% CI 1.1-9.3, p = 0.03) and 17p- (OR 3.5, 95% CI 0.95-13.1, p = 0.05) correlated with worse PFS. A longer follow-up is necessary to analyze the prognostic value of these variables regarding overall survival. PMID- 21323524 TI - Pegfilgrastim to accelerate neutrophil engraftment following peripheral blood stem cell transplant and reduce the duration of neutropenia, hospitalization, and use of intravenous antibiotics: a phase II study in multiple myeloma and lymphoma and comparison with filgrastim-treated matched controls. AB - This trial was aimed to explore the efficacy of pegfilgrastim to accelerate neutrophil engraftment after stem cell autotransplant. Twenty patients with multiple myeloma and 20 with lymphoma received pegfilgrastim 6 mg on day +1. Forty cases treated with daily filgrastim starting at median day +7 (5-7), matched by age, sex, diagnosis, high-dose chemotherapy schedule, CD34 + cell dose, and prior therapy lines, were used for comparison. Median time to neutrophil engraftment was 9.5 vs. 11 days for pegfilgrastim and filgrastim, respectively (p < 0.0001). Likewise, duration of neutropenia, intravenous antibiotic use, and hospitalization favored pegfilgrastim, while platelet engraftment, transfusion requirement, and fever duration were equivalent in both groups. No grade >= 3 toxicities were observed. Patients with lymphoma performed similarly to the entire cohort, while patients with myeloma showed faster neutrophil engraftment and shorter neutropenia but not shorter hospitalization and antibiotic use. The possibility of different outcomes for lymphoma and myeloma suggests that stratification by diagnosis may be useful in future phase III studies. PMID- 21323525 TI - Allogeneic stem cell transplant in adult patients with acute myelogenous leukemia: a systematic analysis of international guidelines and recommendations. AB - In patients with acute myelogenous leukemia, published guidelines and treatment recommendations are usually the basis for starting the work-up process for allogeneic transplant. However, only consistent recommendations would allow a standardized clinical practice. We conducted a comprehensive systematic literature search to identify and evaluate the best available evidence from controlled clinical trials. In addition, recommendations given by leading organizations in the USA and Europe were analyzed. The following aspects were selected for systematic comparison: factors for risk assessment and categorization, role of type of donor, significance of allogeneic transplant in first or second complete remission and in relapse/progressive disease; and role of reduced intensity conditioning regimens. In conclusion, the recommendations for the use of allogeneic transplant given by the literature and by published guidelines are inconsistent and will need clarification. PMID- 21323526 TI - Efficient gene transfer with pseudotyped recombinant adeno-associated viral vectors into human chronic myelogenous leukemia cells. AB - Gene transfer into chronic myelogenous leukemia (CML) cells may become of relevance for overcoming therapy resistance. Single-stranded pseudotyped adeno associated viruses of serotypes 2/1 to 2/6 (ssAAV2/1-ssAAV2/6) were screened on human CML cell lines and primary cells to determine gene transfer efficiency. Additionally, double-stranded self-complementary vectors (dsAAVs) were used to determine possible second-strand synthesis limitations. On human CML cell lines, ssAAV2/2 and ssAAV2/6 were most efficient. On primary cells, ssAAV2/6 proved significantly more efficient (4.1 +/- 2.5% GFP(+) cells, p = 0.011) than the other vectors (<1%). The transduction efficiency could be significantly increased (45.5 +/- 13.4%) by using dsAAV2/6 vectors (p < 0.001 vs. ssAAV2/6). In these settings, our data suggest conversion of single- to double-stranded DNA and cell binding/entry as rate-limiting steps. Furthermore, gene transfer was observed in both late and earlier CML (progenitor) populations. For the first time, efficient AAV gene transfer into human CML cells could be shown, with the potential for future clinical application. PMID- 21323527 TI - Idiopathic cytopenia of undetermined significance and the minimal criteria for a diagnosis of myelodysplastic syndrome. AB - A bone marrow examination in a young woman with anemia and beta-thalassemia trait showed dyserythropoiesis in less than 10% of erythroblasts without other myelodysplastic changes, and cytogenetic analysis revealed trisomy of chromosome 8. Although she did not fulfill the current World Health Organization (WHO) criteria for diagnosis of a myelodysplastic syndrome, her acquired bone marrow disorder behaved as such, and she later developed acute myeloid leukemia. PMID- 21323529 TI - Impact of accelerated progression to AIDS on public health monitoring of late HIV diagnosis. AB - Some patients develop AIDS within a year of HIV infection ("accelerated progression"). Classifying such cases as late HIV diagnosis may lead to inaccurate evaluation of HIV testing efforts. We sought to determine this group's contribution to overall late diagnosis rates. To identify cases of accelerated progression (development of AIDS within 12 months of a negative HIV test), we reviewed published HIV seroconverter cohort studies and used New York City's (NYC) HIV/AIDS surveillance registry. From the literature review, three seroconverter cohort studies revealed that 1.0-3.6% of participants had accelerated progression to AIDS. Applying this frequency estimate to the number of new infections in NYC (4762) for 2006 calculated by the Centers for Diseases Control and Prevention's incidence formula, we estimated that 3.6-13.0% of 1317 NYC HIV cases who are diagnosed with AIDS within 12 months of HIV diagnosis are accelerated progressors, not persons HIV infected for many years who did not test and present with AIDS (i.e., delayed diagnosis). In addition, our analysis of the 2006 NYC surveillance registry confirmed the occurrence of accelerated progression in a population-based setting; 67 accelerated progressors were reported and 9 (13%) could be confirmed through follow-up medical record review. With increased HIV testing initiatives, the irreducible proportion of AIDS cases with accelerated progression must be considered when interpreting late diagnosis data. PMID- 21323530 TI - Psychosocial implications of HIV serostatus disclosure to youth with perinatally acquired HIV. AB - Recommendations suggest that older children and adolescents perinatally infected with HIV (PHIV+) be informed of their HIV diagnosis; however, delayed disclosure is commonly reported. This study examined the prevalence and timing of HIV disclosure to PHIV+ adolescents and the associations between the timing of disclosure and psychological functioning and other behavioral outcomes. Recruitment took place at four medical centers in New York City between December 2003 and December 2008. This sample included data from 196 PHIV+ youth and their caregivers: 50% of youth were male, 58% African American, 42% Hispanic, with a mean age of 12.71 years. According to caregiver reports, 70% of the PHIV+ youth knew their HIV diagnosis. Youths who had been told were more likely to be older; youths with a Spanish-speaking Latino caregiver and whose caregivers had a grade school education were told at an older age. Youths who had been told their HIV status were significantly less anxious than those who had not been told; there were no other differences in psychological functioning. Youths who knew their status for longer reported higher intentions to self-disclose to potential sex partners. In multivariate analyses only demographic differences associated with timing of disclosure remained. In summary, PHIV+ youth who had been told their HIV status did not show an increase of psychological problems and were more likely to have intentions to self-disclose to sexual partners. Yet, almost one third was entering puberty without important information regarding their illness. Caregivers need support to address factors impeding HIV disclosure. PMID- 21323532 TI - Randomized controlled trial of a personalized cellular phone reminder system to enhance adherence to antiretroviral therapy. AB - Adherence to antiretroviral therapy (ART) represents one of the strongest predictors of progression to AIDS, yet it is difficult for most patients to sustain high levels of adherence. This study compares the efficacy of a personalized cell phone reminder system (ARemind) in enhancing adherence to ART versus a beeper. Twenty-three HIV-infected subjects on ART with self-reported adherence less than 85% were randomized to a cellular phone (CP) or beeper (BP). CP subjects received personalized text messages daily; in contrast, BP subjects received a reminder beep at the time of dosing. Interviews were scheduled at weeks 3 and 6. Adherence to ART was measured by self-report (SR, 7-day recall), pill count (PC, past 30 days at baseline, then past 3 weeks), Medication Event Monitoring System (MEMS; cumulatively at 3 and 6 weeks), and via a composite adherence score constructed by combining MEMS, pill count, and self report. A mixed effects model adjusting for baseline adherence was used to compare adherence rates between the intervention groups at 3 and 6 weeks. Nineteen subjects completed all visits, 10 men and 9 females. The mean age was 42.7 +/- 6.5 years, 37% of subjects were Caucasian and 89% acquired HIV heterosexually. The average adherence to ART was 79% by SR and 65% by PC at baseline in both arms; over 6 weeks adherence increased and remained significantly higher in the ARemind group using multiple measures of adherence. A larger and longer prospective study is needed to confirm these findings and to better understand optimal reminder messages and user fatigue. PMID- 21323534 TI - Can Congress regulate "inactivity" (and make Americans buy health insurance)? PMID- 21323535 TI - Development of novel combination therapies. PMID- 21323536 TI - Under siege--the individual mandate for health insurance and its alternatives. PMID- 21323537 TI - Images in clinical medicine. Lingual hematoma after thrombolytic therapy. PMID- 21323533 TI - Medication adherence in children and adolescents with HIV infection: associations with behavioral impairment. AB - The impact of behavioral functioning on medication adherence in children with perinatally acquired HIV infection is not well-explored, but has important implications for intervention. This report addresses the relationship between behavioral functioning and child self-report or caregiver report of medication adherence among children and adolescents enrolled in Pediatric AIDS Clinical Trials Group Protocol 219C (conducted 2000-2007). A total of 1134 participants, aged 3-17 years, received a behavioral evaluation and adherence assessment. Complete adherence was defined as taking 100% of prescribed antiretroviral medications during three days preceding the study visit. Multivariable logistic regression models were used to evaluate associations between adherence and behavioral functioning, adjusting for potential confounders, including demographic, psychosocial, and health factors. Children demonstrated higher than expected rates of behavioral impairment (~7% expected with T > 65) in the areas of conduct problems (14%, z = 7.0, p < 0.001), learning problems (22%, z = 12.2, p < 0.001), somatic complaints (22%, z = 12.6, p < 0.001), impulsivity hyperactivity (20%, z = 11.1, p < 0.001), and hyperactivity (19%, z = 10.6, p < 0.001). Children with behavioral impairment in one or more areas had significantly increased odds of nonadherence [adjusted odds ratio (aOR) = 1.49, p = 0.04]. The odds of nonadherence were significantly higher for those with conduct problems and general hyperactivity (aOR = 2.03, p = 0.005 and aOR = 1.68, p = 0.02, respectively). Psychosocial and health factors, such as recent stressful life events and higher HIV RNA levels, were also associated with nonadherence. Knowledge of behavioral, health, and social influences affecting the child and family should guide the development of appropriate, evidence-based interventions for medication adherence. PMID- 21323538 TI - Bundled payment for ESRD--including ESAs in Medicare's dialysis package. PMID- 21323539 TI - Special treatment--the story of Medicare's ESRD entitlement. PMID- 21323541 TI - Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy. AB - BACKGROUND: Idiopathic membranous nephropathy is a major cause of the nephrotic syndrome in adults, but its etiologic basis is not fully understood. We investigated the genetic basis of biopsy-proven cases of idiopathic membranous nephropathy in a white population. METHODS: We performed independent genomewide association studies of single-nucleotide polymorphisms (SNPs) in patients with idiopathic membranous nephropathy from three populations of white ancestry (75 French, 146 Dutch, and 335 British patients). The patients were compared with racially matched control subjects; population stratification and quality controls were carried out according to standard criteria. Associations were calculated by means of a chi-square basic allele test; the threshold for significance was adjusted for multiple comparisons (with the Bonferroni method). RESULTS: In a joint analysis of data from the 556 patients studied (398 men), we identified significant alleles at two genomic loci associated with idiopathic membranous nephropathy. Chromosome 2q24 contains the gene encoding M-type phospholipase A(2) receptor (PLA(2)R1) (SNP rs4664308, P=8.6*10(-29)), previously shown to be the target of an autoimmune response. Chromosome 6p21 contains the gene encoding HLA complex class II HLA-DQ alpha chain 1 (HLA-DQA1) (SNP rs2187668, P=8.0*10(-93)). The association with HLA-DQA1 was significant in all three populations (P=1.8*10( 9), P=5.6*10(-27), and P=5.2*10(-36) in the French, Dutch, and British groups, respectively). The odds ratio for idiopathic membranous nephropathy with homozygosity for both risk alleles was 78.5 (95% confidence interval, 34.6 to 178.2). CONCLUSIONS: An HLA-DQA1 allele on chromosome 6p21 is most closely associated with idiopathic membranous nephropathy in persons of white ancestry. This allele may facilitate an autoimmune response against targets such as variants of PLA2R1. Our findings suggest a basis for understanding this disease and illuminate how adaptive immunity is regulated by HLA. PMID- 21323540 TI - Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. AB - BACKGROUND: Retinopathy of prematurity is a leading cause of childhood blindness worldwide. Peripheral retinal ablation with conventional (confluent) laser therapy is destructive, causes complications, and does not prevent all vision loss, especially in cases of retinopathy of prematurity affecting zone I of the eye. Case series in which patients were treated with vascular endothelial growth factor inhibitors suggest that these agents may be useful in treating retinopathy of prematurity. METHODS: We conducted a prospective, controlled, randomized, stratified, multicenter trial to assess intravitreal bevacizumab monotherapy for zone I or zone II posterior stage 3+ (i.e., stage 3 with plus disease) retinopathy of prematurity. Infants were randomly assigned to receive intravitreal bevacizumab (0.625 mg in 0.025 ml of solution) or conventional laser therapy, bilaterally. The primary ocular outcome was recurrence of retinopathy of prematurity in one or both eyes requiring retreatment before 54 weeks' postmenstrual age. RESULTS: We enrolled 150 infants (total sample of 300 eyes); 143 infants survived to 54 weeks' postmenstrual age, and the 7 infants who died were not included in the primary-outcome analyses. Retinopathy of prematurity recurred in 4 infants in the bevacizumab group (6 of 140 eyes [4%]) and 19 infants in the laser-therapy group (32 of 146 eyes [22%], P=0.002). A significant treatment effect was found for zone I retinopathy of prematurity (P=0.003) but not for zone II disease (P=0.27). CONCLUSIONS: Intravitreal bevacizumab monotherapy, as compared with conventional laser therapy, in infants with stage 3+ retinopathy of prematurity showed a significant benefit for zone I but not zone II disease. Development of peripheral retinal vessels continued after treatment with intravitreal bevacizumab, but conventional laser therapy led to permanent destruction of the peripheral retina. This trial was too small to assess safety. (Funded by Research to Prevent Blindness and others; ClinicalTrials.gov number, NCT00622726.). PMID- 21323542 TI - Clinical practice. Streptococcal pharyngitis. PMID- 21323544 TI - Images in clinical medicine. Differential clubbing and cyanosis. PMID- 21323543 TI - Hypoxia and inflammation. PMID- 21323545 TI - Case records of the Massachusetts General Hospital. Case 5-2011. A 65-year-old man with hematuria after treatment for prostate cancer. PMID- 21323546 TI - Bevacizumab for retinopathy of prematurity. PMID- 21323547 TI - Genes that link nephritis to autoantibodies and innate immunity. PMID- 21323548 TI - Clopidogrel with or without omeprazole in coronary disease. PMID- 21323549 TI - Clopidogrel with or without omeprazole in coronary disease. PMID- 21323551 TI - Outcomes of kidney transplantation in HIV-infected recipients. PMID- 21323552 TI - Outcomes of kidney transplantation in HIV-infected recipients. PMID- 21323554 TI - Temporal trends in rates of patient harm from medical care. PMID- 21323555 TI - Temporal trends in rates of patient harm from medical care. PMID- 21323557 TI - Opioids and deaths. PMID- 21323558 TI - Opioids and deaths. PMID- 21323559 TI - Opioids and deaths. PMID- 21323561 TI - Osteochondromas after total-body irradiation. PMID- 21323562 TI - Long-term therapy with bevacizumab in hereditary hemorrhagic telangiectasia. PMID- 21323563 TI - PLA2R autoantibodies and PLA2R glomerular deposits in membranous nephropathy. PMID- 21323564 TI - Provider perspectives on evidence-based HIV prevention interventions: barriers and facilitators to implementation. AB - Since the beginning of the HIV/AIDS epidemic, community-based organizations (CBOs) have been key players in combating this disease through grassroots prevention programs and close ties to at-risk populations. Increasingly, both funding agencies and public health institutions require that CBOs implement evidence-based HIV prevention interventions, most of which are researcher developed. However, after completing training for these evidence-based interventions (EBIs), agencies may either abandon plans to implement them or significantly modify the intervention. Based on 22 semistructured interviews with HIV prevention service providers, this article explores the barriers and facilitators to dissemination and implementation of EBIs included in the Centers for Disease Control and Prevention's (CDC) Diffusion of Effective Behavioral Interventions (DEBI) program. Results suggest that there is a tension between the need to implement interventions with fidelity and the lack of guidance on how to adapt the interventions for their constituencies and organizational contexts. Findings suggest the need for HIV prevention intervention development and dissemination that integrate community partners in all phases of research and dissemination. PMID- 21323565 TI - Prevalence and characteristics of patients with undiagnosed HIV infection in an urban emergency department. AB - The Centers for Disease Control and Prevention (CDC) recommends offering HIV testing to persons admitted to emergency departments (EDs). Whether by opt-in or opt-out, many EDs (including our own) have found a seroprevalence of 0.8-1.5% when rapid testing is offered. The true seropositivity rate is unknown. We performed a retrospective chart analysis upon all patients presenting to our ED over a 2-week period in the fall of 2007 who had serum drawn as a part of their emergency care. Demographics and clinical characteristics were linked via de identified serum, which was sent for HIV testing. Nine hundred fifty nine patients had sera available for rapid HIV testing. One hundred twenty one (13%) samples were reactive via the OraQuick((r)) test (OraSure Technologies, Bethlehem, PA), a point of care rapid antibody test. Due to concerns about the appropriateness of sera as substrate for the OraQuick((r)) technology, reactive samples were retested via standard enzyme immunoassay (EIA)/Western blot. One hundred twelve analyzable samples were retested-38 were positive and 27 of these were from patients who reported a history of HIV infection. The rate of undiagnosed HIV infection was 1.2% (11/914 potentially analyzable samples). Of all patients with HIV in our ED, 29% of them were presumably unaware of their diagnosis. In conclusion, HIV seroprevalence in our urban ED is high, and a large fraction of the patients appears to be unaware of the infection. PMID- 21323566 TI - Assessing the effectiveness of pharmacy-based adherence interventions on antiretroviral adherence in persons with HIV. AB - A key factor to the successful treatment of HIV is good adherence to antiretroviral therapy (ART). We developed a pharmacist-managed adherence clinic and designed a study to assess the impact of the adherence interventions by measuring the proportion of patients with 95% or greater adherence to ART before and after referral to the program. HIV providers referred patients with adherence problems to a pharmacist-managed adherence clinic. Interventions included scheduled clinic visits with the HIV Clinical Pharmacist and monthly refill reminders from pharmacy staff members over a 6-month period. Those aged 18-75, prescribed an ART regimen for a minimum of 3 months, and who filled their medications exclusively at the clinic pharmacy were eligible for study participation. The Proportion of Days Covered (PDC) served as a surrogate marker of overall adherence. A total of 34 patients were referred to the pharmacy clinic for adherence counseling, of whom 28 enrolled in the study. The proportion of participants with 95% or greater adherence to their ART regimen increased from 7% at baseline to 32% postintervention (p = 0.01). A subanalysis of the PDC revealed an overall increase from a baseline adherence mean of 60% to 81% postintervention (p < 0.0001). There was a notable trend toward an increase in the proportion of participants with an undetectable HIV-1 viral load (58-73%, baseline and postintervention, respectively, p = 0.10), but no statistically significant improvement in CD4 cell count. Clinical pharmacy interventions improved overall adherence to ART regimens in these patients with HIV. PMID- 21323567 TI - Interferon: current status and future prospects in cancer therapy. AB - Type I interferons (IFNs) exhibit antiproliferative activity and apoptotic effects, and regulate an immune response by activating multiple cells types, including dendritic cells, cytotoxic T cells, and natural killer cells. Most recently, a report in the literature identified dysfunctional induction of a type I IFN response in cancer stem cells--specifically, breast cancer-initiating cells, implicating this defect in progression to breast cancer. Indeed, accumulating evidence suggests that cancer stem cells/cancer-initiating cells are prevalent in leukemias and solid tumors, are resistant to chemotherapy and radiation therapy, and therefore likely contribute to tumor recurrence. IFN-beta treatment of human glioma xenografts leads to disruption of the vascular niche of glioma stem cells, in further support of a potential therapeutic effect of IFN treatment in limiting cancer stem cells. The implications are that restoring an IFN response, or enhancing an IFN response, may invoke a reduction, or elimination of both cancer stem cells and tumor cells. In this review, the clinical application of type I IFNs, mainly IFN-alphas, will be reviewed. PMID- 21323568 TI - Placental growth factor and soluble c-kit receptor dynamics characterize the cytokine signature of imatinib in prostate cancer and bone metastases. AB - To assess the hypothesis that the dynamics of plasma angiogenic and inflammatory cytokines after docetaxel chemotherapy with or without the c-kit/abl/platelet derived growth factor receptor (PDGFR) inhibitor imatinib mesylate for prostate cancer are associated with outcome, the kinetics of 17 plasma cytokines before versus after chemotherapy were assessed and associations with progression-free survival (PFS) examined. After adjusting for multiple tests, significantly different declines in placental growth factor (PIGF), soluble vascular endothelial growth factor receptor-1 (VEGFR1), VEGF, and soluble c-kit were observed with docetaxel plus imatinib (n=41) compared to docetaxel alone (n=47). Based on a piecewise linear regression model for change in concentration of each cytokine as a function of the probability of change in p-PDGFR in vivo, only the dynamics of PIGF (P<0.0001) and soluble c-kit (P<0.0001) differed with imatinib therapy. In a Bayesian log-normal regression model for PFS, a rise in human matrix metalloproteinase 9 after docetaxel alone associated with a longer PFS. Distinct plasma angiogenic cytokines are modified by imatinib and partitioned by in vivo p-PDGFR dynamics after docetaxel chemotherapy for metastatic prostate cancer. Plasma PIGF and soluble c-kit kinetics are candidate biomarkers of imatinib effect. The predictive value of human matrix metalloproteinase 9 kinetics for docetaxel efficacy requires prospective validation. PMID- 21323569 TI - Near eradication of clinically relevant concentrations of human tumor cells by interferon-activated monocytes in vitro. AB - We have previously reported that low concentrations of interferon (IFN)-activated monocytes exert near-eradicative cytocidal activity against low concentrations of several human tumor cells in vitro. In the present study, we examined 7 human tumor cell lines and 3 diploid lines in the presence or absence of 10 ng/mL IFNalpha2a and monocytes. The results confirmed strong cytocidal activity against 4 of 7 tumor lines but none against 3 diploid lines. To model larger in vivo tumors, we increased the target cell concentration and determined the concentration of IFNalpha2a and monocytes, required for cell death. We found that increasing the tumor cell concentration from 10- to 100-fold (10(5) cells/well) required an increase in the concentration of IFNs by over 100-fold and monocytes by 10-fold. High concentrations of monocytes could sometimes kill tumor or diploid cells in the absence of IFN. We may conclude that killing of high concentrations of tumor or diploid cells required high concentrations of monocytes that could sometimes kill in the absence of IFN. Thus, high concentrations of tumor cells required high concentrations of IFN and monocytes to cause near eradication of tumor cells. These findings may have clinical implications. PMID- 21323570 TI - Low-dose interferon Type I treatment is effective against H5N1 and swine-origin H1N1 influenza A viruses in vitro and in vivo. AB - The recent emergence of pandemic swine-origin influenza virus (H1N1) and the severe outbreaks of highly pathogenic avian influenza virus of the H5N1 subtype leading to death in humans is a reminder that influenza remains a frightening foe throughout the world. Besides vaccination, there is an urgent need for new antiviral strategies to protect against influenza. The innate immune response to influenza viruses involves production of interferon alpha and beta (IFN alpha/beta), which plays a crucial role in virus clearance during the initial stage of infection. We examined the effect of IFN-alpha on the replication of H5N1 and H1N1 in vitro and in vivo. A single pretreatment with low-dose IFN-alpha reduced lung virus titers up to 1.4 log(10) pfu. The antiviral effect increased after multiple pretreatments. Low-dose IFN-alpha protected mice against lethal H5N1 viral infection. Further, IFN-alpha was also effective against H1N1 in vitro and in the mouse model. These results indicate that low-dose IFN-alpha treatment leads to the induction of antiviral cytokines that are involved in the reduction of influenza virus titers in the lung. Moreover, it might be possible that a medical application during pandemic outbreak could help contain fulminant infections. PMID- 21323571 TI - Pro/anti-inflammatory cytokines in the pathogenesis of premature coronary artery disease. AB - Proinflammatory interleukin-18 (IL-18), high-sensitivity C-reactive protein (hS CRP), tumor necrosis factor-alpha (TNF-alpha), and anti-inflammatory IL-10 are involved in the pathogenesis of atherosclerosis. The aim of this study was to determine the imbalance between pro- and anti-inflammatory cytokines in premature coronary artery disease (PCAD) and their association with the degree of angiographic atherosclerotic blockade. A case-control study was carried out at the National Institute of Heart Diseases, Rawalpindi, Pakistan. Three hundred eighty-five stable coronary artery disease patients aged <45 years were screened. A total of 172 subjects participated in this study, comprising 98 PCAD patients and 74 angionegative controls. Serum IL-10, IL-18, and TNF-alpha were measured using enzyme-linked immunosorbent assay and hS-CRP was analyzed using Immulite 1000. The mean age of the patients was 40 +/- 4.23 years (69 men and 9 women). Serum IL-18, TNF-alpha, hS-CRP, and IL-18/IL-10 ratio were significantly raised in PCAD patients (P<0.01), whereas IL-10 was moderately increased (P<0.05) when compared with controls. Serum IL-18 and hS-CRP were significantly raised in patients with 86%-100% stenosis (n=57) when compared with patients with 71%-85% stenosis (n=41) (P<0.05). Serum IL-18, TNF-alpha, IL-18/IL-10 ratio, and hS-CRP significantly correlated (P<0.01) with the degree of angiographic blockade. Pro/anti-inflammatory cytokines play a vital role in the pathogenesis of PCAD and have potential to identify the degree of atherosclerosis. PMID- 21323572 TI - Tumor necrosis factor alpha and beta and interferon gamma gene polymorphisms in Turkish breast cancer patients. AB - Cytokine genes are important for researching cancer predisposition to cancers that elicit anti-tumor immune response. In this study, we investigated the association between breast cancer and tumor necrosis factor alpha (TNF-alpha) 308 (G>A), TNF-beta +252 (A>G), and interferon gamma (IFN-gamma) +874 (T>A) gene polymorphisms in a Turkish population. This study involved 204 female breast cancer patients and 204 healthy female controls. Genomic DNA was extracted from EDTA-preserved peripheral venous blood of patients and controls by a salting-out method and analyzed by polymerase chain reaction, allele-specific oligonucleotide polymerase chain reaction, and restriction fragment length polymorphism. TNF alpha -308 genotype was found to have no effect on breast cancer susceptibility. However, there were statistically significant differences between the genotype frequencies of patients and controls for TNF-beta polymorphism (p = 0.016) and the allele and genotype frequencies for the IFN-gamma polymorphism (p = 0.0312 and p = 0.001, respectively). In the composite genotype analysis, the TNF alpha/beta GAAG composite genotype (p = 0.0424), the TNF-alpha/IFN-gamma GGTT and GATT composite genotypes (p = 0.0296 and p = 0.0129, respectively), the TNF beta/IFN-gamma AGTT composite genotype (p = 0.0003), and the TNF-alpha/beta/IFN gamma GGAGTT and GAAGTT composite genotypes (p = 0.0437 and p = 0.0038, respectively) were estimated to have a protective effect against breast cancer. However, the TNF-alpha/IFN-gamma GGTA composite genotype is a risk factor for breast cancer (p = 0.0156). In conclusion, TNF-beta +252GG genotype was found more frequent in Turkish breast cancer patients than controls and IFN-gamma TA+AA genotypes were estimated to increase breast cancer risk significantly in Turkish population. PMID- 21323573 TI - Association of common variants of vascular endothelial growth factor and interleukin-18 genes with allograft survival in renal transplant recipients of North India. AB - Increased vascular endothelial growth factor (VEGF) production promotes enhanced endothelial permeability, enhanced leukocyte migration into the allograft, thereby leading to a clinically recognized rejection episode. Interleukin-18 (IL 18), a potent proinflammatory cytokine, may also be involved in mechanisms of kidney allograft rejection. The present study was, therefore, undertaken to investigate the association of functional polymorphisms in VEGF (2578C>A, 1154A>G) and IL-18 (607C>A, 137G>C) genes with risk of allograft rejection in renal transplant recipients of North India. Two hundred renal transplant recipients, 150 matched recipients-donors, and 200 unrelated healthy individuals were genotyped by amplification refractory mutation specific polymerase chain reaction and by polymerase chain reaction-restriction fragment length polymorphism. Variant allele VEGF 1154A>G (p = 0.56; odds ratio [OR] = 1.32) and variant allele (p = 0.004, OR = 1.54) and variant genotype (p = 0.007, OR = 3.26) of IL-18 607C>A, GC of IL-18 137G>C (p = 0.043, OR = 0.63) were significantly different in healthy individuals as compared with the patients with renal transplant. When 114 nonrejectors were compared with 36 rejectors (150 recipients) for association with allograft rejection, significant association was observed in heterozygous genotype of VEGF 2578C>A (p = 0.033), VEGF 1154A>G (p = 0.024). In IL-18 137G>C, CC genotype, C allele showed protective association with allograft rejection. Kaplan-Meier analysis indicated a higher mean time for first rejection episode in CA genotype carriers (31 months) as compared with AA (29 months) for VEGF 2578C>A (log p = 0.035). In VEGF, the haplotypes A-A and A-G (2578-1154) were associated with reduced risk and in IL-18 607A-137G, they were associated with high risk for allograft rejection. This observation suggests these polymorphisms are an ideal marker for prediction of pretransplant allograft outcome. PMID- 21323574 TI - Presenilin-1 polymorphisms are not relevant in susceptibility to ventricular septal defect: a case-control study. AB - Although many studies have demonstrated that presenilin-1 plays a vital role in cardiovascular system development, no data are available concerning association of polymorphisms of presenilin-1 with ventricular septal defect (VSD) in the Chinese population. The aim of this study was to evaluate the association between two single-nucleotide polymorphisms (rs1800844 and rs177415) of presenilin-1 and VSD. A total of 151 isolated VSD patients and 296 controls were included in the study. The genotype of the polymorphisms was determined by polymerase chain reaction-restriction fragment length polymorphism. Our study showed no statistically significant differences in genotype and allele frequencies between VSD and controls with any of the presenilin-1 genetic variants. These data may provide evidence that the presenilin-1 gene is not a genetic marker for VSD susceptibility in the Han Chinese population. PMID- 21323575 TI - Tumor necrosis factor alpha induces stronger cytotoxicity in ABCG2-overexpressing resistant breast cancer cells compared with their drug-sensitive parental line. AB - Tumor necrosis factor alpha (TNF-alpha) has been reported to modulate the multidrug resistance (MDR) phenotype in vitro and in vivo. Multidrug-resistant cells overexpressing the ABCB1 transporter are more susceptible to inhibition of proliferation and induction of apoptosis by TNF-alpha than their drug-sensitive counterparts. This study was aimed to investigate TNF-alpha modulatory and antiproliferative effects on drug-resistant cells overexpressing ABCG2. The effects of TNF-alpha on viability and proliferation rate of MCF-7 breast cancer cells and their ABCG2-overexpressing sublines MCF-7/mitoxantrone (MX) cells were studied using dye exclusion assay, dimethylthiazolyl-2,5-diphenyl tetrazolium bromide technique, and flow cytometric analysis of cell cycle. TNF-alpha influence on MX accumulation was investigated by flow cytometry. ABCG2 overexpressing cells were more susceptible to antiproliferative and cytotoxic effects of TNF-alpha than their parental cells. TNF-alpha increased accumulation of MX in both parental and resistant cells. Higher sensitivity of MDR cells to TNF-alpha cytotoxicity would help in characterization of its complex modulatory effects on cancer cells and benefit us in designing new approaches to overcome MDR. PMID- 21323576 TI - Nucleic acid binding behaviors and cytotoxic properties of a Ru(II) complex. AB - The interactions of complex [Ru(bpy)(2)(hnip)](2+) (1) {bpy = 2,2'-bipyridine, hnip = 2-(2-hydroxy-1-naphthyl)imidazo[4,5-f][1,10]phenanthroline} with calf thymus DNA and yeast tRNA were investigated by UV-vis spectroscopy, fluorescence spectroscopy, viscosity, equilibrium dialysis, and circular dichroism. In addition, the antitumor activities of complex 1 were evaluated with MTT method. These results indicate that the structures of DNA and RNA have significant effects on the binding behaviors of complex 1. Further, complex 1 demonstrates different antitumor activities against selected cancer cell lines in vitro. PMID- 21323577 TI - DNA intercalating studies of [Ru(bpy)2dmt]2+ with two vacant nitrogen atoms by introducing copper(II) ions. AB - A novel, yet effective method for identifying DNA-binding modes of [Ru(bpy)(2)dmt](2+) (where bpy = 2,2'-bipyridine and dmt = 2,3-dimethyl-1,4,8,9 tetra-aza-triphenylene) on an indium tin oxide electrode has been successfully developed by introducing Cu(2+) ion and ethylenediaminetetraacetic acid. The results from emission spectra and fluorescence microscopic images suggested that [Ru(bpy)(2)dmt](2+) not only associates with Cu(2+) ion in both the absence and presence of DNA but also shows strong affinity with DNA in the presence of Cu(2+). Evidence for the strong binding of [Ru(bpy)(2)dmt](2+) to DNA was determined from the interface studies using electrochemical methods. The present study suggests that a combination of photoluminescence measurement with electrochemical methods identifies the DNA-binding behavior of luminescent molecules with redox activities. [Ru(bpy)(2)dmt](2+) binds to DNA via an intercalative mode. PMID- 21323578 TI - Ubiquitously expressed hematological and neurological expressed 1 downregulates Akt-mediated GSK3beta signaling, and its knockdown results in deregulated G2/M transition in prostate cells. AB - As the molecular mechanism of beta-catenin deregulation is not well understood, and stabilized beta-catenin is known to translocate into the nucleus and activate genes for proliferation, a novel regulatory factor, hematological and neurological expressed 1 (HN1), for Akt-GSK3beta-beta-catenin axis is reported here. In our studies, HN1 gene structure was characterized. HN1 expression was found to be epidermal growth factor-responsive in PC-3 cells, and protein expression was also upregulated in PC-3 and LNCaP but not in DU145 cells. Additionally, HN1 was found to be downregulated by the specific AKT inhibitor wortmannin but not with PI3K or MAPK inhibitors, LY294002 and PD98059, respectively, in PC-3 and MCF-7 cells. Further, siRNA-mediated knockdown of HN1 resulted in considerable increase in Akt((S473)) and GSK3beta((S9),(Y216)) phosphorylations; moreover, subsequent accumulation of beta-catenin, increase in c-myc expression, and nuclear accumulation of cyclin D1 were observed in PC-3 cells. Knockdown of HN1 also resulted in prolongation of G(1) phase in cell cycle, increasing tetraploidy, presumably because of cells escaping from abnormal mitosis in PC-3 cells. Consistently, overexpression of HN1 reversed the cell cycle-specific observations, resulted in accumulation of cells in G(2)/M, and reduced the proliferation rate, which were investigated using flow cytometry and methylthiazol tetrazolium assays. As activating mutations of beta-catenin have been demonstrated in late-stage tumors, and beta-catenin stabilization was correlated with poor prognosis in previous reports, epidermal growth factor upregulated HN1 expression might have a role in deregulating the AKT GSK3beta((S9))-mediated signaling as a novel compensating mechanism. PMID- 21323579 TI - Analysis of the single-nucleotide polymorphism in the 5'UTR and part of intron I of the sheep MSTN gene. AB - The myostatin (MSTN) gene region encompassing the 5'UTR and part of intron I was sequenced in animals of two herds of Latvian Darkhead sheep to extend data on the ovine MSTN gene polymorphism and to provide information useful for local breed conservation. Two and four polymorphic loci were revealed in the 5'UTR and intron I. Four and five local haplotypes were constructed, respectively. The genotyping data obtained and that previously reported for the same genomic region were combined in one dataset for the haplotype analysis. Recombination events were detected between loci (c.-40, c.-37) in the 5'UTR and (c.373+18, c.373+101) and (c.373+101, c.373+241) in intron I. Single-nucleotide polymorphisms at c.373+249 and c.373+323 appear to be involved in the strong linkage (p < 0.01). Linkage blocks (c.373+241, c.373+243) and (c.373+241, c.373+259) were revealed at nominal (p < 0.05) level of probability. Haplotype-specific patterns of the transcription factor binding sites predicted in silico were constructed to evaluate a putative functional significance of the particular alleles and haplotypes. A nucleotide at c.373+18 was shown to influence the pre-mRNA secondary structure. DNA curvature predicted in silico for allele c.373+101C was proven experimentally. A possible impact of the particular polymorphisms on the transcription and/or splicing efficiency is discussed. PMID- 21323580 TI - Dynamic mass redistribution as a means to measure and differentiate signaling via opioid and cannabinoid receptors. AB - Classically, G protein-coupled receptor activation by a ligand has been viewed as producing a defined response such as activation of a G protein, activation or inhibition of adenylyl cyclase, or stimulation of phospholipase C and/or alteration in calcium flux. Newer concepts of ligand-directed signaling recognize that different ligands, ostensibly acting at the same receptors, may induce different downstream effects, complicating the selection of a screening assay. Dynamic mass redistribution (DMR), a label-free technology that uses light to measure ligand-induced changes in the mass of cells proximate to the biosensor, provides an integrated cellular response comprising multiple pathways and cellular events. Using DMR, signals induced by opioid or cannabinoid agonists in cells transfected with these receptors were blocked by pharmacologically appropriate receptor antagonists as well as by pertussis toxin. Differences among compounds in relative potencies at DMR versus ligand-stimulated GTPgammaS or receptor binding endpoints, suggesting functional selectivity, were observed. Preliminary evidence indicates that inhibitors of intermediate steps in the cell signaling cascade, such as receptor recycling inhibitors, mitogen-activated protein kinase kinase/p38 mitogen-activated protein kinase inhibitors, or cytoskeletal disruptors, altered or attenuated the cannabinoid-induced response. Notable is the finding that mitogen-activated protein kinase kinase 1/2 inhibitors attenuated signaling induced by the cannabinoid type 2 receptor inverse agonist AM630 but not that stimulated by the agonist CP 55,940. Thus, DMR has the potential to not only identify ligands that activate a given G protein coupled receptor, but also ascertain the signaling pathways engaged by a specific ligand, making DMR a useful tool in the identification of biased ligands, which may ultimately exhibit improved therapeutic profiles. PMID- 21323581 TI - Gastroenterology consultations in pregnancy. AB - BACKGROUND: Training in gastrointestinal (GI) disorders in pregnancy is required for all gastroenterology fellows. Nevertheless, the actual role of the gastroenterologist in the management of pregnant patients is unknown. Establishing the characteristics of GI consultations in pregnancy can help focus trainee education and prepare gastroenterologists for future practice. The purpose of this study was to determine the indications for consultations in pregnancy and the gastroenterologist's role in the evaluation and management of the pregnant patient. METHODS: A chart review was performed of all consecutive outpatient GI consultations for pregnant women at a high-volume obstetrics hospital over a 3-year period. Referring source, patient characteristics, indication(s) for consultation, diagnosis(es), change in management after consultation, and need for follow-up were recorded. RESULTS: We reviewed 370 charts. The mean age (+/-standard deviation [SD]) at referral was 28.7 years +/- 6.5, and mean weeks of gestation (+/-SD) was 21.3 +/- 8.8. Obstetrician/gynecologists requested most consultations (70.1%). New GI symptoms arising in pregnancy comprised 35.4% of consultations, and worsening of a preexisting GI disorder comprised 24.4%. The most common indications for consultation were viral hepatitis (20.2%), nausea and vomiting (18.9%), and nonspecific abdominal pain (13.5%). The most common diagnoses were acute or chronic viral hepatitis (17.8%), hyperemesis gravidarum (15.1%), gastroesophageal reflux disease (14.3%), and constipation (13.0%). Consultation changed the diagnosis in 25.1% of patients and changed management in 78.6%. Follow-up was required in 77.3% of cases during pregnancy and 37.8% postpartum. CONCLUSIONS: GI consultation in pregnancy is sought more frequently for the evaluation and management of GI disorders not unique to pregnancy than for pregnancy-unique disorders. Although GI consultation changed the diagnosis in a minority of cases, it changed management in the majority. Gastroenterologists should be familiar with the most common indications for consultation in pregnancy and be prepared to evaluate and manage pregnant women with GI disorders. PMID- 21323582 TI - Chlorhexidine and alcohol versus povidone-iodine for antisepsis in gynecological surgery. AB - BACKGROUND: Surgical site infections (SSIs) cause severe morbidity and are associated with tremendous health costs. Skin antisepsis (cleansing) with chlorhexidine and alcohol solutions has demonstrated superiority to povidone iodine in a variety of surgical interventions. Our objective was to determine if chlorhexidine and alcohol antisepsis protocol reduces the rate of SSIs in elective gynecological laparotomies compared with povidone-iodine antisepsis. METHODS: This retrospective study was carried out at the Department of Gynecology in a tertiary medical center in Tel Aviv. Patients undergoing elective gynecological laparotomies during two periods of time and who were treated with two different antisepsis protocols were included. The protocols for antisepsis were povidone-iodine 10% scrub followed by 10% povidone-iodine in 65% alcohol (n = 145) and chlorhexidine 2% followed by 70% alcohol (n = 111). The rate of SSIs as defined by the Centers for Disease Control and Prevention (CDC), and the risk factors for the occurrence of SSIs were calculated. RESULTS: Antisepsis with chlorhexidine and alcohol was associated with a reduction in the overall rate of SSIs from 14.6% to 4.5% compared with the povidone-iodine protocol (p = 0.011). The two groups of patients were similar in regard to baseline characteristics and medical history. Surgical procedures as well as the type of cut, drains, and tension suture use were similar in the two groups. Patients with SSIs tended to be older and heavier. Risk factors found to be associated with SSIs were hypertension, noninsulin-dependent diabetes mellitus (NIDDM), immunodeficiency, and the use of the povidone-iodine antisepsis protocol. CONCLUSIONS: This retrospective study demonstrates that antisepsis with chlorhexidine and alcohol was associated with a significant reduction in the rate of SSIs compared to povidone-iodine antisepsis in patients undergoing elective gynecological laparotomies. This is of extreme clinical importance, as a change in antisepsis protocol can significantly reduce the morbidity and healthcare costs associated with patients undergoing elective gynecological surgery. PMID- 21323583 TI - Violence against women and postpartum depression. AB - BACKGROUND: Violence against women (VAW), including intimate partner violence (IPV) in its various forms (sexual, physical, or stalking), and childhood violence (sexual or physical) are common and are associated with depressive symptoms. We examined the association between these violence exposures and self reported history of postpartum depression (PPD). METHODS: Women from the Kentucky Women's Health Registry (KWHR) who reported at least one live birth were included in this study. Individual IPV and child abuse histories were examined for association with self-reported history of PPD. Multivariate regression analysis estimated adjusted risk ratios (aRR) and 95% confidence intervals (95% CI), controlling for age, obstetrical history, and substance abuse history. RESULTS: The 5380 women in the KWHR reporting at least one live birth were included in this study. Of these women, 2508 (46.6%) reported a history of any VAW. A history of adult VAW was associated with a history of PPD (aRR 1.48, 95% CI 1.12-1.95). Physical IPV (aRR 1.48, 95% CI 1.12-1.95) and stalking IPV (aRR 1.39, 95% CI1.03 1.87) were individually associated with PPD. Other types of violence were not individually associated with a history of PPD. The strength of association increased with each additional type of violence experienced (aRR1.17, 95% CI 1.06 1.30). CONCLUSIONS: Adult VAW is associated with self-reported history of PPD. With an increase in the number of types of abuse experienced, this association became stronger. Our findings highlight the need for thorough VAW screening in obstetrical populations. PMID- 21323584 TI - Socioeconomic status and polycystic ovary syndrome. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a common metabolic-endocrine disorder in women and is associated with a number of metabolic morbidities. We examined the association of PCOS and its components with socioeconomic status (SES) over the life course to explore the role of the environment on the development of PCOS. METHODS: Participants included 1163 women, aged 34-39, from the Coronary Artery Risk Development in Young Adults (CARDIA) Women's Study, examined at year 16 of the CARDIA study (2001). PCOS was defined according to the 1990 National Institutes of Health (NIH) criteria. RESULTS: Logistic regression models, adjusted for age, body mass index (BMI), waist circumference, and oral contraceptive (OC) use, demonstrated a statistically significant association between those women with low parental education/high personal education and PCOS (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.4-4.4). CONCLUSIONS: Our results indicate that women who experienced low childhood SES are at increased risk of PCOS, but this risk is limited to those who have personally attained a high level of education. More research is needed to determine the childhood socioeconomic factors that might influence this risk and whether conditions associated with upward life mobility play a role or if this group of at-risk women is simply more likely to recall the symptoms that define PCOS. PMID- 21323585 TI - Type 2 iodothyronine deiodinase is expressed in human preadipocytes. AB - BACKGROUND: Type 2 iodothyronine deiodinase (D2) is an enzyme that catalyzes the production of triiodothyronine (T3) from thyroxine (T4) and plays a critical role in providing the local intracellular T3. Although D2 is highly expressed in brown adipose tissue, it was thought that D2 is hardly expressed in white adipose tissue. In the present study, we examined whether D2 is expressed in human preadipocytes, using human mesenteric and subcutaneous preadipocytes (HMPA and HSCPA, respectively). METHODS: HMPA and HSCPA were purchased and cultured in the preadipocyte medium containing 10% fetal bovine serum. We measured D2 activity and mRNA level in HMPA and HSCPA incubated with or without dibutyryl cyclic adenosine monophosphate [(Bu)2cAMP]. RESULTS: D2 activity and mRNA were detectable in human HMPA and HSCPA. The apparent Michaelis-Menten constant (K(m)) value for T4 in HMPA was 2.1 +/- 0.2 nM, and the maximum velocity (V(max)) value was 333.3 +/- 28.0 femtomols of I- released/mg protein/hour, respectively. On the other hand, the apparent K(m) value for T4 in HSCPA was 2.0 +/- 0.2 nM and the V(max) value was 91.2 +/- 8.7 femtomols of I- released/mg protein/hour, respectively. D2 activities in HMPA and HSCPA incubated with 1 mM (Bu)2cAMP for 24 hours were 7-fold (HMPA) and 3-fold (HSCPA) higher than those without (Bu)2cAMP, respectively. D2 mRNA levels in HMPA and HSCPA incubated with 1 mM (Bu)2cAMP for 3 hours were 10-fold (HMPA) and 5-fold (HSCPA) higher than those without (Bu)2cAMP, respectively. CONCLUSIONS: In the present study, we have clearly demonstrated that D2 activity and mRNA are present in the human preadipocytes from both mesenteric and subcutaneous adipose tissue. Our experiments are the first ones that identify human preadipocytes as one of the sources of T3 production. PMID- 21323586 TI - Degradation of thyroid hormone receptor beta 1: existence of stable and unstable forms. AB - BACKGROUND: The degradation of many nuclear receptors is controlled by ligand binding and mediated by the ubiquitin-proteasome pathway. However, the mechanisms implicated in thyroid hormone receptor (TR) degradation remain unclear. Our objective was to define the kinetics, mechanisms, and sub-cellular fractions involved in TRs degradation. METHODS: We used pulse-chase analyses, time-course experiments carried out in presence of cycloheximide (to inhibit new protein synthesis), and biochemical fractionation with Western blot analyses to determine the kinetics of the degradation of the TRbeta isoform, TRbeta1, in transiently transfected QBI-HEK 293A cells. RESULTS: We observed that TRbeta1 degradation is mediated by the proteasome pathway. Also, the kinetics of TRbeta1 degradation is atypical due to the co-existence of more than one TRbeta1 population, located in different cellular compartments and having different stability profiles. Moreover, TRbeta1 degradation was unaffected by a mutation in its putative PEST motif, which confers turnover of other proteins. CONCLUSION: Our findings introduce novel evidence suggesting that stable and unstable forms of TRbeta1, which might have distinct functions, co-exist in cells. PMID- 21323587 TI - "Hypoechoic triangle": a new sonographic sign or marker of advanced autoimmune thyroiditis. AB - BACKGROUND: Ultrasonography (US) changes have been noted in patients with autoimmune thyroiditis (AT). Here, we report that some patients with late stage AT have a distinctive, previously unreported finding on US that we call the "hypoechoic triangle sign" (HET). METHODS: On US, the HET sign was characterized as a well-defined area of low echogenicity, about 10 mm in diameter, between the lateral margin of one or both thyroid lobes, the medial wall of the carotid artery, and, posteriorly, the prevertebral muscles. Twenty-six patients with AT who had the HET sign (Group 1) were compared with 71 patients with AT who had normal serum thyrotropin (TSH) and free thyroid hormones levels (Group 2) and with 154 normal controls (Group 3). TSH was tested at least twice, first as part of their regular clinical care and then in follow-up. The groups were similar in terms of age, sex, and body mass index. Thyroid volume by US, TSH, free triiodothyronine, free thyroxine, antithyroid antibodies, and l-thyroxine treatment were evaluated. Sonographic gray-scale analysis and three-dimensional reconstruction of HET region were performed in five of the Group 1 patients. RESULTS: Thyroid volume was significantly smaller (p < 0.01) in Group 1 than in Groups 2 and 3 (6.9 +/- 2.18 vs. 10.4 +/- 2.1 and 9.8 +/- 2.5 mL, respectively). In Group 1, 61.5% of subjects were taking l-thyroxine for hypothyroidism; none of the Group 2 or 3 patients was taking thyroid hormone. Serum TSH was significantly higher (p < 0.01) in Group 1 versus Groups 2 and 3 (3.6 +/- 1.3 vs. 2.18 +/- 1.4 and 1.9 +/- 1.1 mIU/L, respectively). None of the Group 2 or 3 patients had the HET sign. Gray-scale US demonstrated an overlap between HET zone and the surrounding muscle tissue. CONCLUSIONS: The HET sign seems to be specific for overt thyroid failure in patients with AT as it was not noted in patients with AT not having overt thyroid failure. The incidental finding of the HET sign during cervical US examination should prompt obtaining thyroid function tests to rule out hypothyroidism. Our study provides data regarding specificity but not sensitivity of the HET sign for AT and thyroid failure because a consecutive group of AT patients with thyroid failure was not studied. In addition, the specificity of the HET sign for AT needs to be evaluated further by studying a diverse group of thyroid diseases. PMID- 21323588 TI - Aberrant expression of TfR1/CD71 in thyroid carcinomas identifies a novel potential diagnostic marker and therapeutic target. AB - BACKGROUND: Type I receptor for transferrin (TfR1/CD71) is overexpressed in several malignant tumors, but no studies are available on thyroid carcinomas. Our previous comparative analyses of the relative distribution of transferrin in benign versus papillary thyroid carcinoma (PTC) tissues highlighted a marked malignancy-associated abundance of the molecule. The aim of the present study was to evaluate whether TfR1/CD71 is also differentially expressed in benign versus malignant thyroid tissues. METHODS: Tissue samples, including benign lesions and follicular-derived carcinomas, from 241 patients and a total of 35 benign and malignant fresh specimens were assayed for TfR1/CD71 expression by reverse transcriptase-polymerase chain reaction, Western blot, and immunohistochemistry. RESULTS: We found that transcription of TfR1/CD71 gene is constitutive in thyroid epithelia, but the mRNA is differently translated in benign and malignant tissues. Western blot revealed higher levels of TfR1/CD71 protein in malignant versus benign tissues. Immunohistochemically, most carcinomas exhibited overexpression of the receptor, predominantly in the cytoplasm of neoplastic cells. The highest expression level was detected in primary and metastatic papillary carcinomas and anaplastic carcinomas, with positive results ranging from 86% to 100% of the cases. In contrast, most benign tissues were negative, with only a minority of cases showing focal and weak immunoreactivity. CONCLUSIONS: Our findings suggest that altered expression of TfR1/CD71 may be used as a marker helpful in distinguishing PTC from papillary hyperplasia and follicular variant PTC from benign follicular-patterned lesions. Additionally, the present observations support the rationale for the use of radiolabeled transferrin/transferrin analogs and/or anti-TfR1/CD71 antibodies for diagnostic and/or radiotherapeutic purposes in TfR1/CD71-expressing thyroid tumors. PMID- 21323589 TI - In thyroid fine-needle aspiration, use of bedside-prepared slides significantly increased diagnostic adequacy and specimen cellularity relative to solution-based samples. AB - BACKGROUND: In the United States, the prevalence among adults of palpable thyroid nodules is 4%-7%, of which 5%-10% may represent thyroid carcinoma. Despite the success of fine-needle aspiration in reducing the need for thyroidectomy, aspirates are inadequate to render a diagnosis in 20% of cases. Minimizing nondiagnostic samples is an important goal in improving this technique. Our objective was to determine whether bedside-prepared slides improve diagnostic adequacy over standard solution-based samples. We further sought to determine the role of needle size. METHODS: One hundred sixty-two patients were prospectively enrolled. For each, both bedside slides and standard cytology solutions were prepared; the order of preparation alternated from subject to subject. Needle size (21- or 25-gauge) also alternated from subject to subject. Slides were evaluated by pathologists blinded to needle size. The study took place in the endocrinology clinic at Boston Medical Center, the tertiary referral hospital of the Boston University School of Medicine. Key outcomes were diagnostic adequacy and specimen cellularity. RESULTS: Compared to standard solution-based samples, bedside slides provided more cellular specimens (p < 0.01) and fewer nondiagnostic samples (p = 0.016). When standard solution-based samples were used as the sole method of preparation, 21-gauge needles provided improved diagnostic adequacy. CONCLUSIONS: Bedside-prepared slides offer improved diagnostic adequacy and specimen cellularity over solution-based samples. The difference may be especially important when using smaller (25-gauge) needles to perform fine-needle aspiration. When solution-based samples are used, larger (21-gauge) needles provide more diagnostic specimens. PMID- 21323590 TI - Emerging drugs for treating skeletal muscle injury and promoting muscle repair. AB - INTRODUCTION: Musculoskeletal injuries represent a major global public health problem and muscle injury contributes significantly to the burden of disability and suffering. Drugs that can attenuate muscle trauma and/or hasten muscle repair to restore function can help reduce the economic burden and alleviate personal suffering and financial hardship. AREAS COVERED: This review provides an update on some emerging drugs with therapeutic potential for muscle injury including those that could attenuate damage or improve regeneration. Although there are few (if any) drugs in development specifically for muscle injury, there are numerous drugs in development for cardiovascular complications, such as ischemia reperfusion, that might also have efficacy for promoting regeneration after similar events in skeletal muscle. EXPERT OPINION: Drugs in development for muscle wasting or inflammatory diseases should also be considered within the context of modulating the events associated with muscle degeneration and regeneration. More rigorous pre-clinical evaluations, especially of a drug's efficacy for improving function, would help minimize false leads and hasten development of effective approaches for treating muscle damage and promoting repair after injury. PMID- 21323592 TI - Horner's syndrome as a complication of percutaneous ethanol treatment of thyroid nodule. PMID- 21323591 TI - MicroRNA dysregulation in human thyroid cells following exposure to ionizing radiation. AB - BACKGROUND: Ionizing radiation is a well-known mutagen and a risk factor for thyroid cancer. MicroRNAs (miRNAs) play an important role in the regulation of gene expression on post-transcriptional level and are dysregulated in thyroid cancer. The goal of this study was to investigate the effects of acute exposure to 1 and 10 Gy of gamma-irradiation on miRNA expression in normal human thyroid cells. METHODS: Expression of 319 miRNAs was studied in primary cultures of normal human thyroid cells 4 and 24 hours postirradiation using a miRNA expression array with further confirmation of miRNAs expression by reverse transcription-polymerase chain reaction. RESULTS: We identified 30 miRNAs that were unregulated or downregulated more than twofold after irradiation as compared to nonirradiated thyroid cells, with no significant difference found between 1 and 10 Gy of radiation. Four distinct patterns of miRNA expression change were observed: miRNAs downregulated at 4 hours and returned to normal levels at 24 hours, miRNAs upregulated at 4 hours and returned to normal levels at 24 hours, and miRNAs either upregulated or downregulated at both time points. No dysregulation of miRNAs known to occur in thyroid cancer was observed. CONCLUSIONS: Acute exposure of thyroid cells to gamma-radiation results in several specific patterns of miRNA response. It appears that alteration in miRNA expression seen 4-24 hours after irradiation has no direct association with carcinogenesis. However, it is likely to affect other cell functions, such as DNA repair. PMID- 21323593 TI - Therapeutic management of breast cancer in the elderly. AB - INTRODUCTION: Over the last few decades, the population of developed countries has aged. Breast cancer is the most common cancer among the increased numbers of older women. The choice of adjuvant treatment is particularly difficult in older women because the oncologist has to balance reduction of the risk of recurrence with patient-related comorbidities that may increase the risk of treatment related toxicity and influence patient survival. AREAS COVERED: This article describes the concept of a comprehensive geriatric assessment and reviews the current literature on biological and pathological characteristics of breast cancer in the elderly, including genomic assays recently available in the clinic. Endocrine, targeted and chemotherapy treatments both in adjuvant and metastatic setting are also covered. EXPERT OPINION: A new generation of studies aimed to re evaluate treatments in the various subtypes of breast cancer is needed. Whether this will be possible through prospective studies (especially in the adjuvant setting) is unknown. An alternative direction for further research in the elderly could be a reappraisal of old studies with carefully planned subtype analyses. Whatever the direction, the management of elderly breast-cancer patients is inherently multidisciplinary: the contribution of medical and allied health professionals is essential to the provision of optimal care. PMID- 21323596 TI - Iodine status of the U.S. population, National Health and Nutrition Examination Survey, 2005-2006 and 2007-2008. AB - BACKGROUND: This report presents urinary iodine (UI) concentrations for the general U.S. population during 2005-2006 and 2007-2008. These findings are the fourth and fifth assessments of the population since National Health and Nutrition Examination Survey (NHANES) III (1988-1994), when the median UI concentration for the population decreased from NHANES I (1971-1974). METHODS: During 2005-2006 and 2007-2008, ~ 5000 participants per year were selected to participate in NHANES. The participants were interviewed and examined. UI concentration was measured on a random one third subsample of 2649 participants, aged 6 years and older in 2005-2006, and in all participants in 2007-2008. These urine iodine concentrations are representative of the general U.S. population by age, sex, and race/ethnicity. RESULTS: (i) The median UI concentrations for the general U.S. population in 2005-2006 and 2007-2008 were 164 mg/L (95% confidence interval [CI] 154-174) and 164 mg/L (95% CI 154-173), respectively. Also, the proportions of the population with a UI concentration of < 50 mg/L during these survey periods were 9.8% +/- 1.3% and 8.8% +/- 0.4%, respectively. The median UI concentration and prevalence of >= 200 mg/L appeared to be higher in children and persons >= 70 years than in other age groups. (ii) In both surveys, children aged 6-11 years had median UI concentrations of >= 200 mg/L, and about 5% of them had a UI concentration of < 50 mg/L. (iii) All pregnant women (sample size 184) surveyed during 2005-2008 had a median UI concentration of 125 mg/L (95% CI 86 198), and 56.9% +/- 7.9% of this group had a UI concentration of < 150 mg/L. UI concentrations were lower among non-Hispanic black survey participants than non Hispanic white and Mexican-American participants. CONCLUSIONS: These findings affirm the stabilization of UI concentration and adequate iodine nutrition in the general U.S. population since 2000. However, certain groups likely do not achieve a sufficient dietary iodine intake according to the World Health Organization. The needs of these vulnerable groups and the inadequacy of their dietary iodine intake should be addressed in future efforts. PMID- 21323594 TI - Stem cells and stroke: opportunities, challenges and strategies. AB - INTRODUCTION: Stroke remains the leading cause of disability in the Western world. Despite decades of work, no clinically effective therapies exist to facilitate recovery from stroke. Stem cells may have the potential to minimize injury and promote recovery after stroke. AREAS COVERED: Transplanted stem cells have been shown in animal models to migrate to the injured region, secrete neurotrophic compounds, promote revascularization, enhance plasticity and regulate the inflammatory response, thereby minimizing injury. Endogenous neural stem cells also have a remarkable propensity to respond to injury. Under select conditions, subventricular zone progenitors may be mobilized to replace lost neurons. In response to focal infarcts, neuroblasts play important trophic roles to minimize neural injury. Importantly, these endogenous repair mechanisms may be experimentally augmented, leading to robust improvements in function. Ongoing clinical studies are now assessing the safety and feasibility of cell-based therapies for stroke. EXPERT OPINION: We outline the unique challenges and potential pitfalls in the clinical translation of stem cell research for stroke. We then detail what we believe to be the specific basic science and clinical strategies needed to overcome these challenges, fill remaining gaps in knowledge and facilitate development of clinically viable stem cell-based therapies for stroke. PMID- 21323597 TI - Urinary Iodine and Goiter Prevalence in Belarus: experience of the Belarus American cohort study of thyroid cancer and other thyroid diseases following the Chornobyl nuclear accident. AB - BACKGROUND: Because iodine deficiency can influence background rates of thyroid disease or modify radiation dose-response relationships, we compiled descriptive data on iodine status among participants in a Belarusian-American screening study who were exposed in childhood to radioiodine fallout from the Chornobyl nuclear accident. We have used the data from two consecutive screening cycles to examine whether indicators of iodine status changed before and after documented government initiatives to improve iodine intake. METHODS: Urinary iodine concentrations in spot samples and prevalence of diffuse goiter by palpation were assessed in 11,676 exposed subjects who were 18 years or younger at the time of the accident on April 26, 1986, and were screened beginning 11 years later in connection with the Belarus-American Thyroid Study. Data for the first ( January 1997-March 2001) and second (April 2001-December 2004) screening cycles, which largely correspond to time periods before and after official iodination efforts in 2000/2001, were compared for the cohort overall as well as by oblast of residence (i.e., state) and type of residency (urban/rural). RESULTS: Median urine iodine levels among cohort members increased significantly in the later period (111.5 mg/L) compared to the earlier (65.3 mg/L), with the cycle 2 level in the range defined as adequate iodine intake by the World Health Organization. During the same period, a significant decline in diffuse goiter prevalence was also observed. In both cycles, urinary iodine levels were lower in rural than in urban residents. Urinary iodine levels, but not rates of goiter, varied by oblast of residence. In both periods, adjusted median urine iodine concentrations were similar in Gomel and Minsk oblasts, where *89% of cohort members resided, and were lowest in Mogilev oblast. Yet Mogilev oblast and rural areas showed the most marked increases over time. CONCLUSIONS: Trends in urinary iodine concentrations and prevalence of diffuse goiter by palpation suggest that iodination efforts in Belarus were successful, with benefits extending to the most iodine-deficient populations. Iodine status should be considered when evaluating thyroid disease risk in radioiodine-exposed populations since it can change over time and may influence rates of disease and, possibly, dose-response relationships PMID- 21323598 TI - Urticaria and thyroid autoimmunity. AB - BACKGROUND: Chronic urticaria is a common clinical condition whose etiology, in about 75% of cases, is unknown and is therefore called chronic idiopathic urticaria (CIU). A link between CIU and autoimmune thyroid diseases was proposed several decades ago. Here we review this topic. SUMMARY: Several studies have been performed to determine if and to what degree there is an association between CIU and autoimmune thyroid diseases, particularly autoimmune thyroiditis. Many of these studies were not well controlled, however. Approximately one-fourth of CIU patients have serological evidence of thyroid autoimmunity, suggesting that these two disorders are associated. The mechanisms for the apparent association between CIU and serological evidence of thyroid autoimmunity are not clear. There are no data regarding the correlations between CIU and histological features of autoimmune thyroiditis or hypothyroidism. Despite this, there are anecdotal reports regarding L-thyroxine administration in patients with CIU. CONCLUSIONS: Screening for thyroid autoimmunity is probably useful in patients with CIU. More solid evidence, based on still lacking well-conducted controlled studies, is desirable to determine if there is a therapeutic role for L-thyroxine treatment in ameliorating the skin manifestations of urticaria. PMID- 21323599 TI - Low-normal or high-normal thyrotropin target levels during treatment of hypothyroidism: a prospective, comparative study. AB - BACKGROUND: Recent literature advocates the decrease of the upper limit of the normal thyrotropin (TSH) reference range. The objective of this study was to determine whether treated hypothyroid patients maintained within a low-normal TSH range (0.4-2.0 mIU/L) have better clinical outcomes than those maintained within a high-normal TSH range (2.0-4.0 mIU/L). METHODS: The study was performed in a thyroid outpatient clinic of a tertiary hospital. This was a prospective, interventional study. Forty-two participants with newly diagnosed overt primary hypothyroidism were paired in two groups: group 1 (n=20), low-normal target TSH; group 2 (n = 22), high-normal target TSH. Levothyroxine was initiated, and dose was adjusted to achieve and sustain the target TSH value during the study period. After the target TSH was reached, participants were evaluated every 3 months for thyroid function, serum lipid profile, resting energy expenditure (REE), body composition, and bone mineral density, for 12 months. RESULTS: Nineteen patients in group 1 and 16 in group 2 completed the study. In the whole-group analysis, total cholesterol (p = 0.01), low-density lipoprotein cholesterol (p = 0.004), and triglycerides (p < 0.001) decreased after treatment, whereas REE per kilogram of lean body mass (p = 0.001) and total fat body mass (p =0.02) increased. Group 1 patients had a significantly higher relative increase in REE (+7.1% +/- 11.3% vs. +3.6% +/- 15.1%, p = 0.02). There was no difference between the groups in the other variables. CONCLUSIONS: Despite recent trends toward lowering the upper limit of normal TSH range, the results of this 12-month study provided no substantial clinical evidence to corroborate that treatment of primary hypothyroidism should aim at maintaining TSH levels in a low-normal range PMID- 21323600 TI - Transoral robotic surgery of the vocal cord. AB - The standard endoscopic surgical approach in the management of laryngeal lesions is by the use of a laryngoscope, microscope, and laser. This requires the surgeon to work within the confines of the laryngoscope. At times, it requires repositioning of the laryngoscope and microscope to gain access to a specific area. The surgery also requires line-of-sight observation to complete the operation. The introduction of transoral robotic surgery in head and neck surgery brings the advantages of three-dimensional magnification, increased degrees of freedom with the effector arms, and an articulating distal end that mimics hand movements. To date, transoral robotic surgery of vocal cord surgery requires the use of a tracheostomy in patients. Here we report the use of a CO(2) laser fiber and the Da Vinci robotic platform (Intuitive Surgical) for the surgical management of a T1 glottic squamous cell carcinoma. PMID- 21323601 TI - Insect glutathione transferases. AB - This article is an overview of the current knowledge of insect glutathione transferases. Three major topics are discussed: the glutathione transferase contributions to insecticide resistance, the polymorphic nature of the insect glutathione transferase superfamily, and a summary of the current structure function studies on insect glutathione transferases. PMID- 21323602 TI - Regulation of the cardiac muscle ryanodine receptor by glutathione transferases. AB - Glutathione transferases (GSTs) are generally recognized for their role in phase II detoxification reactions. However, it is becoming increasingly apparent that members of the GST family also have a diverse range of other functions that are, in general, unrelated to detoxification. One such action is a specific inhibition of the cardiac isoform of the ryanodine receptor (RyR2) intracellular Ca(2+) release channel. In this review, we compare functional and physical interactions between members of the GST family, including GSTO1-1, GSTA1-1, and GSTM2-2, with RyR2 and with the skeletal isoform of the ryanodine receptor (RyR1). The active part of the muscle-specific GSTM2-2 is localized to its nonenzymatic C-terminal alpha-helical bundle, centered around alpha-helix 6. The GSTM2-2 binding site is in divergent region 3 (DR3 region) of RyR2. The sequence differences between the DR3 regions of RyR1 and RyR2 explain the specificity of the GSTs for one isoform of the protein. GSTM2-2 is one of the few known endogenous inhibitors of the cardiac RyR and is likely to be important in maintaining low RyR2 activity during diastole. We discuss interactions between a nonenzymatic member of the GST structural family, the CLIC-2 (type 2 chloride intracellular channel) protein, which inhibits both RyR1 and RyR2. The possibility that the GST and CLIC2 proteins bind to different sites on the RyR, and that different structures within the GST and CLIC proteins bind to RyR channels, is discussed. We conclude that the C-terminal part of GSTM2-2 may provide the basis of a therapeutic compound for use in cardiac disorders. PMID- 21323603 TI - Association of stem cell-related markers and survival in astrocytic gliomas. AB - To study the clinical relevance of undifferentiated tumour cells in astrocytic gliomas we employed a large tumour tissue microarray (n=283) with corresponding clinical data and analyzed the expression of Nestin and Sox-2, which mark undifferentiated stem- and progenitor cells in the normal brain. Both markers were expressed abundantly and staining of nestin significantly increased with WHO grade. Further, nestin and Sox-2 immunoreactivity was significantly associated with tumour cell proliferation and nestin expression was independently associated with poor patient survival. Our findings suggest that immature glioma cells are involved in tumour growth and tumour progression and significantly impact on patient prognosis. PMID- 21323604 TI - Is 24h nicotine equivalents a surrogate for smoke exposure based on its relationship with other biomarkers of exposure? AB - Nicotine and its 5 major metabolites (Nicotine equivalents, NE) may serve as a surrogate biomarker for smoke exposure. OBJECTIVE: To investigate the relationship between nicotine equivalents (NE) and biomarkers of exposure (BOE) to cigarette smoke. METHODS: Data from nine controlled studies in 916 adult smokers were used. BOEs to nicotine, NNK, pyrene, acrolein, benzene, 1,3 butadiene and CO were used. RESULTS: Among all the factors investigated (NE, cigarette type, age, gender, BMI and study), NE was the most statistically significant factor for all biomarker relationships. Weak to moderate relationships (0.32 <= R(2) <= 0.65) were found between NE and the BOEs. CONCLUSIONS: Based on the relationships with BOEs, NE may be considered as a surrogate biomarker of total cigarette smoke exposure. PMID- 21323605 TI - Combined measurement of PEDF, haptoglobin and tau in cerebrospinal fluid improves the diagnostic discrimination between alzheimer's disease and other dementias. AB - Using proteomic approach in cerebrospinal fluid (CSF) we identified pigment epithelium-derived factor (PEDF) and Haptoglobin (Hp) as putative markers that could discriminate between AD and other dementias. ELISA assays were developed to measure the levels of PEDF and Hp in CSF from patients with AD (AD, n=27), non-AD (NAD, n=30) and in non-demented patients (ND, n=27). The combined assessment of PEDF, Hp and Tau levels, using Iterative Marginal Optimization, improved the differential diagnosis of AD, especially in patients with moderate to severe dementia (p<0.002). This pilot study highlights the probable different contribution of oxidative mechanisms in dementia. PMID- 21323606 TI - Liposomal solubilization of new 3-hydroxy-quinolinone derivatives with promising anticancer activity: a screening method to identify maximum incorporation capacity. AB - Four new 3-hydroxy-quinolinone derivatives with promising anticancer activity could be solubilized using liposomes as vehicle to an extent that allows their in vitro and in vivo testing without use of toxic solvent(s). A screening method to identify the maximum incorporation capacity of hydrophobic drugs within liposomes was successfully applied. The compounds and lipid(s) were dissolved in methanol, and the solvent was removed by rotary evaporation. The film was resuspended with phosphate buffer (pH 7.4), and the dispersion was sonicated to reduce vesicle size. Ultracentrifugation was used to separate liposome-associated drug from free (i.e., precipitated) drug, and the amount of drug incorporated within the liposomes was quantified using high-performance liquid chromatography. All four compounds were found to be significantly incorporated within soy phosphatidylcholine (SPC) liposomes, resulting in a 200-500-fold increase in apparent solubility. Drug-to-lipid ratios in the range of 2-5 MUg/mg were obtained. Interestingly, the four quinolinone derivatives have shown different association tendencies with liposomes, probably due to the physicochemical properties of the different group bonded in position 2 of the quinolinone ring. None of the alternative lipids/lipid blends tested incorporated as much drug as SPC. Photon correlation spectroscopy analyses indicated that use of ultrasounds produced an efficient reduction in liposome size. The present approach appears suitable for incorporation capacity studies of any lipophilic drug in liposomes. PMID- 21323607 TI - Toxicological considerations for antithyroid drugs in children. AB - INTRODUCTION: Propylthiouracil (PTU), methimazole (MMI) and carbimazole are indicated for the treatment of hyperthyroidism in adult and pediatric patients. The aim of this review is to present all the relevant information regarding the use of antithyroid drugs (ATD) in pediatric thyrotoxic cases, the pediatric toxicology of ATD and the warning which has recently been issued for PTU by the FDA. AREAS COVERED: Epidemiology, diagnosis and treatment of pediatric thyrotoxicosis are all presented in this article. The authors also extensively discuss the details regarding the pharmacology, bioactivation, biodisposition, bioavailability and pharmacokinetic properties of the two main ATD (MMI and PTU). EXPERT OPINION: The FDA recently reported that use of PTU is associated with a higher risk for clinically serious or fatal liver injury compared to MMI in both adult and pediatric patients. They also found that congenital malformations were reported approximately three times more often with prenatal exposure to MMI compared with PTU and especially with the use of MMI during the first trimester of pregnancy. The authors believe that PTU should not be used in pediatric patients unless the patient is allergic to or intolerant of MMI, and there are no other treatment options available. That being said, PTU may be the treatment of choice during, and just before, the first trimester of pregnancy. PMID- 21323608 TI - Antiarrhythmic drugs for atrial fibrillation. AB - INTRODUCTION: Atrial fibrillation (AF) is associated with increased mortality and morbidity. Although stroke prevention is the only way to improve prognosis, antiarrhythmic drugs (AADs) are of primary importance both in the conversion to sinus rhythm and in the long-term control of rhythm and rate. AREAS COVERED: We searched the Cochrane Library and Medline Database for articles published in English concerning efficacy and safety of AADs in AF. Particular attention was paid to the recently published European Society of Cardiology guidelines. This review provides an overview of the currently available drugs used in AF, with a particular emphasis on their comparative efficacy and safety in different kind of patients. Recent important findings, and advantages and disadvantages of recently approved drugs such as vernakalant and dronedarone, are also discussed. EXPERT OPINION: AADs remain fundamental in the acute and long-term management of AF, to control symptoms and to reduce the negative impact of the arrhythmia on QoL. The choice of a rate- over rhythm-control strategy should be individualized and based on accurate evaluation of patient medical history and symptoms. New agents will contribute to improve treatment efficacy together with the guarantee of better safety profiles. PMID- 21323611 TI - Dioxin toxicity, aryl hydrocarbon receptor signaling, and apoptosis-persistent pollutants affect programmed cell death. AB - Exogenous ligands of the aryl hydrocarbon receptor (AhR) such as 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) and related substances are highly toxic pollutants ubiquitously present in the environment. They cause a variety of toxic effects to different organs and tissues. Among other effects, TCDD exposure to laboratory animals leads to thymus atrophy and immunosuppression on the one hand, and to tumor formation on the other. Apoptosis appears to be involved in both these toxic effects: AhR activation by TCDD was discussed to induce apoptosis of immune cells, leading to the depletion of thymocytes and ultimately immunosuppression. This mechanism could help to explain the highly immunotoxic actions of TCDD but it is nevertheless under debate whether this is the mode of action for immunosuppression by this class of chemical substances. In other cell types, especially liver cells, TCDD inhibits apoptosis induced by genotoxic treatment. In initiation-promotion studies, TCDD was shown to be a potent liver tumor promoter. Among other theories it was hypothesized that TCDD acts as a tumor promoter by preventing initiated cells from undergoing apoptosis. The exact mechanisms of apoptosis inhibition by TCDD are not fully understood, but both in vivo and in vitro studies consistently showed an involvement of the tumor suppressor p53 in this effect. Various strings of evidence have been established linking apoptosis to the detrimental effects of exogenous activation of the AhR. Within this article, studies elucidating the effects of TCDD and related substances on apoptosis signaling, be it inducing or repressing, is to be reviewed. PMID- 21323610 TI - Eritoran tetrasodium (E5564) treatment for sepsis: review of preclinical and clinical studies. AB - INTRODUCTION: Sepsis remains a leading cause of death worldwide. Despite years of extensive research, effective drugs that inhibit the pro-inflammatory effects of lipopolysaccharide (LPS) and improve outcome when added to conventional sepsis treatments are lacking. Eritoran tetrasodium (E5564) is a promising candidate therapy for sepsis belonging to a new class of such drugs which inhibit LPS induced inflammation by blocking toll-like receptor 4. AREAS COVERED: This review focuses on the rationale for the use of eritoran tetrasodium in sepsis as well as on its pharmacokinetics, pharmacodynamics, efficacy and safety. Preclinical and clinical studies from a MEDLINE/PubMed literature search in August 2010 with the search terms 'eritoran' and 'E5564' are discussed. EXPERT OPINION: Preclinical in vitro and in vivo studies of eritoran tetrasodium indicate it can limit excessive inflammatory mediator release associated with LPS and improve survival in sepsis models. While early clinical results are promising, its efficacy and safety for treating patients with sepsis are currently under investigation. Even if the ongoing Phase III clinical trial enrolling patients with severe sepsis and increased risk of death shows benefit from eritoran, questions remain and confirmatory studies would be necessary to define its clinical usage. PMID- 21323612 TI - FMS-like tyrosine kinase 3 inhibitors: a patent review. AB - INTRODUCTION: Flt3 (FMS-like tyrosine kinase 3) has been presented as a target for novel anti-leukemic drugs because Flt3 mutations have been observed in acute myeloid leukemia (AML) cells. Due to both the poor efficacy and high toxicity of current standard AML therapies, there is an unmet need for new, improved therapies. Flt3 inhibitors have great potential to address this with mutated Flt3. AREAS COVERED: This paper provides a comprehensive review of the Flt3 inhibitor patents currently available. Information from original research articles in peer-reviewed journals and current clinical developments from several resources is also described. EXPERT OPINION: Our understanding of Flt3 inhibitors has been increased by findings from recent preclinical and clinical trials. Some Flt3 inhibitors show good efficacy in AML patients, but relapse and resistance to these inhibitors are still unavoidable. To address these problems, structurally diverse inhibitors, which exhibit inhibitory activities against both wild type and mutated Flt3, should be explored. PMID- 21323613 TI - Overlap syndrome of asthma and COPD predicts low quality of life. AB - BACKGROUND: In clinical practice, patients whose airway disease shares features of both asthma and chronic obstructive pulmonary disease (COPD) remain poorly recognized. MATERIAL AND METHODS: The study population consisted of 1546 patients with a diagnosis of asthma or COPD or both. Based on patient-reported outcomes and retrospective medical record data, the study population was divided into three groups: ( 1 ) asthma only, ( 2 ) COPD only, and ( 3 ) both asthma and COPD (overlap syndrome group). We evaluated patient characteristics associated with health-related quality of life (HRQoL). RESULTS: In many respects, the overlap group fell between the asthma and COPD groups. In the overlap group, however, HRQoL was the poorest of all. In the logistic regression model, with the asthma group as the reference, both the overlap and the COPD group showed higher risk for low HRQoL [odd ratio (OR): 1.9; 95% confidence interval (CI): 1.2-3.2; and OR: 1.8, 95% CI: 1.0-3.2; respectively]. In addition, female gender, obesity, duration of disease, disability pension, and coexisting cardiovascular disease were associated with low HRQoL across the study population. CONCLUSIONS: Patients with overlapping asthma and COPD differed from those patients with asthma or COPD only. Overlap syndrome was associated with low HRQoL. PMID- 21323614 TI - Population health management in Medicare: the time is now. PMID- 21323615 TI - Avoiding randomization failure in program evaluation, with application to the Medicare Health Support program. AB - We highlight common problems in the application of random treatment assignment in large-scale program evaluation. Random assignment is the defining feature of modern experimental design, yet errors in design, implementation, and analysis often result in real-world applications not benefiting from its advantages. The errors discussed here cover the control of variability, levels of randomization, size of treatment arms, and power to detect causal effects, as well as the many problems that commonly lead to post-treatment bias. We illustrate these issues by identifying numerous serious errors in the Medicare Health Support evaluation and offering recommendations to improve the design and analysis of this and other large-scale randomized experiments. PMID- 21323616 TI - Analysis of the treatment effect of Healthways' Medicare Health Support Phase 1 Pilot on Medicare costs. AB - The objective of this analysis is to evaluate the treatment effect of Healthways' Medicare Health Support Pilot Program on total Medicare expenditures. Previous studies have analyzed the first 6 months of the program for all Medicare Health Support Organizations. The purpose of this analysis is to supplement and extend the previous work. The policy question addressed in this article is whether, on net, the intervention lowered total Medicare expenditures. The study was a retrospective analysis of data claims and membership databases. We used ordinary least squares regression techniques to estimate the effect of the intervention on total costs. We also stratified the data using risk scores calculated prior to the intervention. Our analysis found that the intervention consistently had little or no effect across the entire sample, but was associated with a statistically significant decrease in spending when the analysis concentrated on the sample that fully participated in the program. Overall, our analysis finds that total annual Medicare costs for the participating sample were 15.7% lower in 2007 ($3240) than for the control group, controlling for age, sex, race, and baseline risk. On balance, our analysis supports a conclusion that the program did successfully reduce costs for its target population. We find that Medicare expenditures were lower among enrollees in the program than they would have been without the intervention. This article shows that significant cost reductions among high-cost, chronically ill Medicare beneficiaries are possible. PMID- 21323617 TI - The impact of proactive chronic care management on hospital admissions in a German senior population. AB - An increase in chronic disease prevalence is contributing to health care cost growth and decreased quality of life in industrialized nations worldwide. Inadequate management of chronic diseases is a leading cause of hospitalizations and, thus, avoidable expenditures. In this study, we evaluated the impact of nurse-delivered care calls, the primary intervention of a proactive chronic care management (CCM) program, in a population aged 65 and older in Germany. In this analysis, hospital admission rates were evaluated among program enrollees who were diagnosed with diabetes, heart failure, coronary heart disease, or chronic obstructive pulmonary disease. The Intervention group comprised those members who participated in care calls (n=13,486), whereas the Comparison group included enrollees who did not participate in these calls (n=4,582). Changes in admission rates were calculated between the year prior to and year after program commencement. Comparative analyses were adjusted for age, sex, region of residence, and disease severity (stratification of 3 [least severe] to 1 [most severe]). Overall, a 6.0% decrease in admissions was observed among Intervention group members compared with an 18.9% increase among Comparison group members (P <= 0.0001). This decrease in admissions was driven by participants with the highest levels of risk. In addition, a dose-response relationship was observed in which admissions decreased with an increased number of care calls (P=0.0001). These results indicate that proactive CCM interventions are effective in reducing hospital admission rates in a senior population with chronic disease. PMID- 21323618 TI - A review of Healthways' Medicare Health Support program and final results for two cohorts. AB - Chronic care management programs have been shown to offer a scalable approach for improving health and reducing health care costs in commercially insured populations. Medicare Health Support (MHS) was a government-sponsored program designed to determine whether that success could be translated to a Medicare fee for-service population with complex chronic diseases. The purpose of this article is to provide an overview of MHS and its Phase I study design, and to review the officially reported outcomes of the arm of the study in which Healthways, Inc. provided program services. MHS employed a block randomized design; consent was requested after randomization and evaluation included all eligible individuals, irrespective of that consent. Healthways accepted 2 study cohorts. The first cohort included beneficiaries with diabetes and/or heart failure (Intervention, N=19,936; Control, N=9995) for a 3-year study period. The second cohort entered after 1 year and included beneficiaries with heart failure, with or without diabetes (Intervention, N=4238; Control, N=2106). Comparisons of total health care spending between the Intervention and Control groups found gross savings of $3.8 and $5.7 million for the first and second Intervention cohorts, respectively, and these savings exceeded program costs for the second cohort. Improvements in evaluated clinical measures were demonstrated in the first Intervention cohort, and overall program satisfaction was 94%. Clinical measures and satisfaction were not evaluated for the second cohort. These results indicate that Healthways successfully adapted its commercial chronic care management program for a Medicare fee-for-service population and achieved high satisfaction, improved clinical measures, and financial savings. PMID- 21323619 TI - Potential Medicare savings through prevention and risk reduction. AB - Medicare is challenged to maintain solvency as enrollment climbs because of the aging baby boomers and costs increase as a result of the substantial disease burden present among seniors. In the present study, an actuarial model was developed to determine the present cost (2008) of Medicare-covered benefits for elderly individuals, and to test the impact on cost of health risk reduction that may be possible through population health and wellness interventions. In the model, beneficiaries were categorized by risk according to health status using 3 different indices, and baseline per month and lifetime expenditures were estimated. Changes in morbidity were tested via scenarios of modified transition rates between the risk categories that might result from population health and wellness initiatives, including increases in the proportion of low-risk individuals entering Medicare, and delayed or reduced rates of upward risk transitions. The model showed that the discounted total lifetime cost of Medicare benefits was $174,018 per person, from age 65 until death. Each risk-reduction scenario was associated with both annual and lifetime cost savings, which accounted for increased longevity associated with decreased risk profiles. In conclusion, a model has been developed that can predict the impact on Medicare costs of varying levels of risk reduction in the senior population and, therefore, the potential financial benefit of population health and wellness policy initiatives directed at improving health prior to and during the years of Medicare. The model shows that there are substantial opportunities for savings through modest improvements to the health of the Medicare population. PMID- 21323620 TI - Effectiveness of health and wellness initiatives for seniors. AB - Given the increasing prevalence of obesity and lifestyle-related chronic diseases in the United States and abroad, senior wellness initiatives have emerged as a means to stem the troubling trends that threaten the well-being and the economy of many nations. Seniors are an important demographic for such programs because this age group is growing, both as a proportion of the overall population and as a contributor to health care cost escalation. The goal of senior wellness programs is to improve the overall health of seniors through a variety of approaches, including increased physical activity, better nutrition, smoking cessation, and support of other healthy behaviors. Outcome metrics of particular interest are the effects of participation in these programs on health care utilization and expenditures. This review describes several studies that demonstrate reduced inpatient admissions and health care costs, as well as improved health-related quality of life as a direct result of participation in large-scale senior wellness programs. Programs that effectively engage seniors in, and change behavior as a direct result of, participation provide strong evidence that health improvements and decreased health care expenditures can be achieved. However, solutions to the challenges of broader enrollment and sustained participation in these programs would increase the impact of their outcomes and health-related benefits. PMID- 21323621 TI - Learning from our mistakes. PMID- 21323622 TI - Differential pharmacotherapy for subgroups of fibromyalgia patients with specific consideration of 5-HT3 receptor antagonists. AB - INTRODUCTION: The fibromyalgia syndrome (FMS) has a prevalence of about 2% and is characterized by generalized musculoskeletal pain, reduced pain threshold and autonomic and functional symptoms. It is a multifactorial syndrome with four different subgroups exhibiting pathophysiological and psychiatric findings. No precise treatment strategy is currently available for the different FMS subgroups. AREAS COVERED: This article reviews the evidence for treatment options for the different FMS subgroups. EXPERT OPINION: Therapy for the first subgroup of primary FMS, with high levels of pain but no psychopathological alterations, is targeted at nociceptors expressing serotonin (5-hydroxytryptamine-3; 5-HT3) receptors with 5-HT3 receptor antagonists. The second and third subgroups are characterized by depressive syndromes with a major indication for antidepressants. The fourth subgroup with psychosomatic syndromes requires psychotherapeutic treatment. Secondary FMS is similar to the primary syndromes but is triggered by a variety of other diseases and frequently responds to 5-HT3 receptor antagonist treatment. Different classes of drug, such as pregabalin, must be tested for efficacy and tolerance. FMS treatment strategies should be tailored after the identification of individual FMS subgroups. Although several groups of drug have been studied extensively, 5-HT3 receptor antagonists are most effective in patients without psychopathological alterations. PMID- 21323623 TI - Evaluation of two HbA1c point-of-care analyzers. AB - BACKGROUND: Measurement of HbA1c is the most important parameter to assess glycemic control in diabetic patients. Different point-of-care devices for HbA1c are available. The aim of this study was to evaluate two point-of-care testing (POCT) analyzers (DCA Vantage from Siemens and Afinion from Axis-Shield). We studied the bias and precision as well as interference from carbamylated hemoglobin. METHODS: Bias of the POCT analyzers was obtained by measuring 53 blood samples from diabetic patients with a wide range of HbA1c, 4%-14% (20-130 mmol/mol), and comparing the results with those obtained by the laboratory method: HPLC HA 8160 Menarini. Precision was performed by 20 successive determinations of two samples with low 4.2% (22 mmol/mol) and high 9.5% (80 mmol/mol) HbA1c values. The possible interference from carbamylated hemoglobin was studied using 25 samples from patients with chronic renal failure. RESULTS: The means of the differences between measurements performed by each POCT analyzer and the laboratory method (95% confidence interval) were: 0.28% (p<0.005) (0.10 0.44) for DCA and 0.27% (p<0.001) (0.19-0.35) for Afinion. Correlation coefficients were: r=0.973 for DCA, and r=0.991 for Afinion. The mean bias observed by using samples from chronic renal failure patients were 0.2 (range 0.4, 0.4) for DCA and 0.2 (-0.2, 0.5) for Afinion. Imprecision results were: CV=3.1% (high HbA1c) and 2.97% (low HbA1c) for DCA, CV=1.95% (high HbA1c) and 2.66% (low HbA1c) for Afinion. CONCLUSIONS: Both POCT analyzers for HbA1c show good correlation with the laboratory method and acceptable precision. PMID- 21323624 TI - Modulated human maternal and premature neonatal erythrocyte membrane enzyme activities in relation to the mode of delivery: in vitro restoration with L carnitine. PMID- 21323625 TI - Evaluation of the Menarini/ARKRAY ADAMS A1c HA-8180V analyser for HbA1c. AB - BACKGROUND: We report an evaluation of the Menarini/ARKRAY ADAMS A1c HA-8180V analyser (HA-8180V), the fifth generation Menarini/ARKRAY ion-exchange HPLC for the measurement of HbA(1c). METHODS: We evaluated the analytical performance, the measurement of haemoglobin variants and the performance in comparison to major analytical methods. RESULTS: Within-run, between-run and total CV were 0.2%, 0.4% and 0.7% at low HbA(1c) concentrations and 0.2%, 0.2% and 0.4% at high HbA(1c) concentrations, respectively. Trueness revealed a maximum deviation of 0.8 mmol/mol (IFCC units) or 0.1% (NGSP units) over the relevant analytical range. Linearity, carry-over and linear drift were excellent. Labile-HbA(1c), carbamylated haemoglobin, icteric samples and variation in hematocrit did not affect HbA(1c) outcome. Haemoglobin variants AS, AC and F do not affect HbA(1c) outcome and are explicitly identified and correctly quantified. HbA(1c) can not be measured in samples with AE and AD, but these variants are identified correctly. In comparison to other methods used at present, the HA-8180V shows excellent performance. CONCLUSIONS: The HA-8180V performs at a high level and is fit for any clinical application. PMID- 21323626 TI - Some lessons learned from using medium scale genotyping techniques in pharmacogenetic research. PMID- 21323627 TI - Toll-like receptors (TLRs) and mannan-binding lectin (MBL): on constant alert in a hostile environment. AB - In the beginning were neither B cells nor T cells nor antibodies, but innate immune defense alone. The primary functional theme of innate immunity is the distinction between self and non-self, which is maintained by a vast number of cellular and subcellular components. In this context, the immense importance of the Toll-like receptors (TLRs) is well established. Positive (Darwinian) selection seems to be acting on the ligand-binding domains of these molecules, suggesting a selection pattern similar to that previously observed in the MHC proteins. In sharp contrast to TLRs, the biological significance of mannan binding lectin (MBL) is controversial, and, concerning humans, it has been suggested that low concentration of MBL in serum represents a selective advantage. In this mini-review, based on a doctoral thesis, evolutionary aspects of TLRs and MBL are discussed. PMID- 21323634 TI - Dexamphetamine abuse in an elderly man. PMID- 21323633 TI - Painful and involuntary multiple sclerosis. AB - INTRODUCTION: Pain, dysphagia, respiratory problems, sexual and cardiovascular dysfunctions may occur in patients with MS. AREAS COVERED: In the present review, we attempt to summarize the current knowledge on the impact pain, dysphagia, respiratory problems, sexual and cardiovascular dysfunctions have in patients with MS. EXPERT OPINION: To effectively manage MS, it is essential that these symptoms are recognized as early as possible and treated by a rehabilitative multidisciplinary approach, based on proven scientific evidence. PMID- 21323635 TI - Decisions on sick leave certifications for acute airways infections based on vignettes: a cross-sectional survey of GPs in Norway and Poland. AB - OBJECTIVE. To explore whether frequency and duration of sick-leave certification for acute airway infections differ between general practitioners (GPs) in Poland and Norway. DESIGN. Cross-sectional survey. SETTING. Educational courses for GPs. Intervention. We used a questionnaire with four vignettes presenting patients with symptoms consistent with pneumonia, sinusitis, common cold, and exacerbation of chronic obstructive pulmonary disease (COPD), respectively. For each vignette GPs were asked whether they would offer a sick-leave note, and if so, for how many days. Subjects. Convenience samples of GPs in Poland (n = 216) and Norway (n = 171). MAIN OUTCOME MEASURES. Proportion of GPs offering a sick-leave certificate. Duration of sick-leave certification. Results. In Poland 100%, 95%, 87%, and 94% of GPs would offer sick leave for pneumonia, sinusitis, common cold, and exacerbation of COPD, respectively. Corresponding figures in Norway were 97%, 83%, 60%, and 90%. Regression analysis adjusting for the GPs' sex, speciality, experience, and workload indicated that relative risks for offering sick leave (Poland versus Norway) were 1.16 (95% CI 1.07-1.26) for sinusitis and 1.50 (1.28 1.75) for common cold. Among GPs who offered sick leave for pneumonia, sinusitis, common cold, and exacerbation of COPD, mean duration was 8.9, 7.5, 5.1, and 6.9 days (Poland) versus 6.6, 4.3, 3.1, and 6.1 days (Norway), respectively. In regression analyses the differences between the Polish and Norwegian samples in duration of sick leave were statistically significant for all vignettes. A pattern of offering sick leave for three, five, seven, 10, or 14 days was observed in both countries. CONCLUSION. In the Polish sample GPs were more likely to offer sick-leave notes for sinusitis and common cold. GPs in Poland offered sick leaves of longer duration for pneumonia, sinusitis, common colds, and exacerbation of COPD compared with GPs in the Norwegian sample. PMID- 21323636 TI - Bipolar disorder susceptibility region on chromosome 3q29 not confirmed in a case control association study. AB - OBJECTIVES: We identified a bipolar disorder (BPD) susceptibility region on chromosome 3q29 in a genome-wide linkage scan (Bailer et al. 2002 (Biol Psychiatry 52: 40), NPL-score 4.09) and follow-up linkage analysis (Schosser et al. 2004 (J Psychiatr Res 38(3): 357), NPL-scores >3 with five markers). These findings were supported by further fine-mapping of this region (Schosser et al. 2007 (Eur Neuropsychopharmacol 17(6-7): 501)), finding NPL-scores >3.9 with SNPs (single nucleotide polymorphisms) spanning a region of 3.46 Mbp in BPD families. Since genetic association studies are more powerful than linkage studies for detecting susceptibility genes of small effect size, we aimed to replicate these findings in an independent case-control sample collected in London (UK) and Vienna (Austria). METHODS: A total of 51 SNPs were genotyped using Sequenom MassARRAY((r)) iPLEX Gold and tested for association in a sample of 526 cases suffering from DSM-IV and/or ICD-10 diagnosis of BPD and 691 controls. RESULTS: No genotypic and/or allelic association, as well as no haplotypic association, was found for any SNP after multiple testing correction. CONCLUSIONS: However, we cannot exclude the possibility that our sample might not have the power to detect rare variants associated with susceptibility to BPD. PMID- 21323637 TI - Nuclear envelope dynamics during plant cell division suggest common mechanisms between kingdoms. AB - Behaviour of the NE (nuclear envelope) during open mitosis has been explored extensively in metazoans, but lack of native markers has limited similar investigations in plants. In the present study, carried out using living synchronized tobacco BY-2 suspension cultures, the non-functional NE marker LBR (lamin B receptor)-GFP (green fluorescent protein) and two native, functional NE proteins, AtSUN1 [Arapidopsis thaliana SUN (Sad1/UNC84) 1] and AtSUN2, we provide evidence that the ER (endoplasmic reticulum)-retention theory for NE membranes is applicable in plants. We also observe two apparently unique plant features: location of the NE-membrane components in close proximity to chromatin throughout division, and spatially distinct reformation of the NE commencing at the chromatin surface facing the spindle poles and concluding at the surface facing the cell plate. Mobility of the proteins was investigated in the interphase NE, during NE breakdown and reformation, in the spindle membranes and the cell plate. A role for AtSUN2 in nuclear envelope breakdown is suggested. PMID- 21323639 TI - Probing the effect of MODY mutations near the co-activator-binding pocket of HNF4alpha. AB - HNF4alpha (hepatocyte nuclear factor 4alpha) is a culprit gene product for a monogenic and dominantly inherited form of diabetes, referred to as MODY (maturity onset diabetes of the young). As a member of the NR (nuclear receptor) superfamily, HNF4alpha recruits transcriptional co-activators such as SRC-1alpha (steroid receptor co-activator-1alpha) and PGC-1alpha (peroxisome-proliferator activated receptor gamma co-activator-1alpha) through the LXXLL-binding motifs for its transactivation, and our recent crystal structures of the complex provided the molecular details and the mechanistic insights into these co activator recruitments. Several mutations have been identified from the MODY patients and, among these, point mutations can be very instructive site-specific measures of protein function and structure. Thus, in the present study, we probed the functional effects of the two MODY point mutations (D206Y and M364R) found directly near the LXXLL motif-binding site by conducting a series of experiments on their structural integrity and specific functional roles such as overall transcription, ligand selectivity, target gene recognition and co-activator recruitment. While the D206Y mutation has a subtle effect, the M364R mutation significantly impaired the overall transactivation by HNF4alpha. These functional disruptions are mainly due to their reduced ability to recruit co-activators and lowered protein stability (only with M364R mutation), while their DNA-binding activities and ligand selectivities are preserved. These results confirmed our structural predictions and proved that MODY mutations are loss-of-function mutations leading to impaired beta-cell function. These findings should help target selective residues for correcting mutational defects or modulating the overall activity of HNF4alpha as a means of therapeutic intervention. PMID- 21323638 TI - Inter- and intra-molecular interactions of Arabidopsis thaliana DELLA protein RGL1. AB - The phytohormone gibberellin and the DELLA proteins act together to control key aspects of plant development. Gibberellin induces degradation of DELLA proteins by recruitment of an F-box protein using a molecular switch: a gibberellin-bound nuclear receptor interacts with the N-terminal domain of DELLA proteins, and this event primes the DELLA C-terminal domain for interaction with the F-box protein. However, the mechanism of signalling between the N- and C-terminal domains of DELLA proteins is unresolved. In the present study, we used in vivo and in vitro approaches to characterize di- and tri-partite interactions of the DELLA protein RGL1 (REPRESSOR OF GA1-3-LIKE 1) of Arabidopsis thaliana with the gibberellin receptor GID1A (GIBBERELLIC ACID-INSENSITIVE DWARF-1A) and the F-box protein SLY1 (SLEEPY1). Deuterium-exchange MS unequivocally showed that the entire N-terminal domain of RGL1 is disordered prior to interaction with the GID1A; furthermore, association/dissociation kinetics, determined by surface plasmon resonance, predicts a two-state conformational change of the RGL1 N-terminal domain upon interaction with GID1A. Additionally, competition assays with monoclonal antibodies revealed that contacts mediated by the short helix Asp-Glu-Leu-Leu of the hallmark DELLA motif are not essential for the GID1A-RGL1 N-terminal domain interaction. Finally, yeast two- and three-hybrid experiments determined that unabated communication between N- and C-terminal domains of RGL1 is required for recruitment of the F-box protein SLY1. PMID- 21323640 TI - Galactose induction of the GAL1 gene requires conditional degradation of the Mig2 repressor. AB - Skp1 an essential component of the SCF (Skp1/cullin/F-box) E3 ubiquitin ligases, which target proteins for degradation by the 26S proteasome. We generated a skp1dM mutant strain that is defective for galactose induction of the GAL1 gene and we have found that galactose-induced protein degradation of the repressor Mig2 is defective in this strain. Mig2 degradation was also abolished in cells lacking the protein kinase Snf1 and the F-box protein Das1, suggesting that Snf1 triggers galactose-induced protein degradation of Mig2 by SCFDas1. Chromatin immunoprecipitation showed that Mig2 associates with the GAL1 promoter upon the galactose-induced exit of Mig1 in skp1dM cells, but not in wild-type cells, suggesting that the conditional degradation of Mig2 is required to prevent it from binding to the GAL1 promoter under inducing conditions. A galactose-stable deletion derivative of Mig2 caused a strong Mig (multi-copy inhibition of GAL gene expression) phenotype, confirming that galactose induction of the GAL1 gene requires the degradation of the repressor Mig2. Our results shed new light on the conflicting reports about the functional role of the degradation of transcriptional activators and indicate that gene expression studies interfering with proteasome degradation should take the stabilization of potential repressors into account. PMID- 21323641 TI - Epithelial-mesenchymal transdifferentiation of renal tubular epithelial cells induced by urinary proteins requires the activation of PKC-alpha and betaI isozymes. AB - Proteinuria is a common feature for almost all glomerular diseases and reflects the severity of the glomerular lesion. The presence of a large amount of proteins in tubular fluid, however, may also contribute to the development of RIF (renal interstitial fibrosis). Endocytosis of albumin in proximal tubular cells triggers PKC (protein kinase C)-dependent generation of reactive oxygen species and secretion of chemokines. As a family including 12 isozymes, which PKC isozymes participate in RIF is still unclear. EMT (epithelial-mesenchymal transdifferentiation) of RTECs (renal tubular epithelial cells) plays a crucial role in the progress of RIF induced by proteinuria. In the present study, we investigated the role of classical PKC isozymes in the proteinuria-induced EMT of RTECs. Employing immunochemical staining, we found that PKC-alpha, -betaI and betaII were expressed in glomerulus and in RTECs in both normal and diseased renal tissues, while PKC-gamma was only expressed in podocytes in the glomerulus. Treatment of HK-2 cells with extracted urinary proteins resulted in EMT, as evidenced by morphological changes, decreased E-cadherin expression, increased alpha-SMA (alpha-smooth muscle actin) expression, as well as production of type I collagen and fibronectin. Western blot analysis of PKC isozymes in the cytosolic compared with membrane fraction revealed translocation of PKC-alpha and -betaI, but not PKC-betaII, in HK-2 cells undergoing EMT. Pretreatment with selective PKC alpha inhibitor G-6976 or PKC-beta inhibitor significantly attenuated EMT induced by urinary proteins. In summary, the present study suggested that PKC-alpha and betaI play critical roles in the EMT of RTECs in response to urinary proteins. PMID- 21323643 TI - Phosphorylation of cAMP-specific PDE4A5 (phosphodiesterase-4A5) by MK2 (MAPKAPK2) attenuates its activation through protein kinase A phosphorylation. AB - cAMP-specific PDE (phosphodiesterase) 4 isoforms underpin compartmentalized cAMP signalling in mammalian cells through targeting to specific signalling complexes. Their importance is apparent as PDE4 selective inhibitors exert profound anti inflammatory effects and act as cognitive enhancers. The p38 MAPK (mitogen activated protein kinase) signalling cascade is a key signal transduction pathway involved in the control of cellular immune, inflammatory and stress responses. In the present study, we show that PDE4A5 is phosphorylated at Ser147, within the regulatory UCR1 (ultraconserved region 1) domain conserved among PDE4 long isoforms, by MK2 (MAPK-activated protein kinase 2, also called MAPKAPK2). Phosphorylation by MK2, although not altering PDE4A5 activity, markedly attenuates PDE4A5 activation through phosphorylation by protein kinase A. This modification confers the amplification of intracellular cAMP accumulation in response to adenylate cyclase activation by attenuating a major desensitization system to cAMP. Such reprogramming of cAMP accumulation is recapitulated in wild type primary macrophages, but not MK2/3-null macrophages. Phosphorylation by MK2 also triggers a conformational change in PDE4A5 that attenuates PDE4A5 interaction with proteins whose binding involves UCR2, such as DISC1 (disrupted in schizophrenia 1) and AIP (aryl hydrocarbon receptor-interacting protein), but not the UCR2-independent interacting scaffold protein beta-arrestin. Long PDE4 isoforms thus provide a novel node for cross-talk between the cAMP and p38 MAPK signalling systems at the level of MK2. PMID- 21323642 TI - Evident and latent plasticity across the rice diterpene synthase family with potential implications for the evolution of diterpenoid metabolism in the cereals. AB - The evolution of natural product biosynthetic pathways can be envisioned to occur via a number of mechanisms. In the present study we provide evidence that latent plasticity plays a role in such metabolic evolution. In particular, rice (Oryza sativa) produces both ent- and syn-CPP (copalyl diphosphate), which are substrates for downstream diterpene synthases. In the present paper we report that several members of this enzymatic family exhibit dual reactivity with some pairing of ent-, syn- or normal CPP stereochemistry. Evident plasticity was observed, as a previously reported ent-sandaracopimaradiene synthase also converts syn-CPP into syn-labda-8(17),12E,14-triene, which can be found in planta. Notably, normal CPP is not naturally found in rice. Thus the presence of diterpene synthases that react with this non-native metabolite reveals latent enzymatic/metabolic plasticity, providing biochemical capacity for utilization of such a novel substrate (i.e. normal CPP) which may arise during evolution, the implications of which are discussed. PMID- 21323644 TI - Counter-modulation of fatty acid-induced pro-inflammatory nuclear factor kappaB signalling in rat skeletal muscle cells by AMP-activated protein kinase. AB - Sustained over-supply of saturated non-esterified 'free' fatty acids has been shown to promote skeletal muscle insulin resistance, which may be driven, in part, by an increase in inflammatory signalling within this tissue. In the present manuscript we show that exposure of L6 myotubes to palmitate, a saturated fatty acid, induces activation of the NF-kappaB (nuclear factor kappaB) pathway {based on increased IKK [IkappaB (inhibitory kappaB) kinase] phosphorylation, IkappaBalpha loss and elevated interleukin-6 mRNA expression} and that this was associated with enhanced phosphorylation/activation of p38 MAPK (mitogen activated protein kinase), JNK (c-Jun N-terminal kinase) and ERK (extracellular signal-regulated kinase) as well as impaired insulin-dependent activation of PKB (protein kinase B)/Akt and glucose transport. NF-kappaB activation by palmitate was unaffected by pharmacological inhibition of p38 MAPK or JNK, but was suppressed significantly by inhibition of MEK (MAPK/ERK kinase)/ERK signalling. The importance of ERK with respect to downstream NF-kappaB signalling was underscored by the finding that PMA, a potent ERK activator, enhanced IKK phosphorylation. Strikingly, both palmitate- and PMA-induced activation of IKK/NF kappaB were antagonized by AMPK (AMP-activated protein kinase) activators because of reduced ERK signalling. Although palmitate-induced activation of NF-kappaB was repressed by AMPK activation and by cellular overexpression of a mutated IkappaBalpha (S32A/S36A) super-repressor, this did not ameliorate the loss in insulin-stimulated PKB activation or glucose transport. Our results from the present study indicate that ERK plays a pivotal role in palmitate-induced activation of the IKK/NF-kappaB signalling axis and that AMPK can restrain the activity of this pro-inflammatory pathway. The finding that insulin resistance persists in myotubes in which NF-kappaB signalling has been repressed implies that palmitate and/or its lipid derivatives retain the capacity to impair insulin regulated events independently of the increase in inflammatory signalling. PMID- 21323645 TI - Dentinogenic capacity: immature root papilla stem cells versus mature root pulp stem cells. AB - BACKGROUND INFORMATION: Immature dental papilla stem cells and mature dental pulp stem cells are capable of performing the dentinogenesis under suitable circumstances. However, a dentinogenic comparison between immature and mature dental root stem cells remains unknown. RESULTS: iRPSCs (immature root papilla stem cells) at the root-forming stage and mRPSCs (mature root pulp stem cells) at the root-completed stage were isolated from 16-day-old and 8-week-old rat first molar roots, respectively. Growth kinetics and flow cytometry results showed that iRPSCs presented more active proliferation properties than mRPSCs. Their odontoblastic differentiation and dentinogenic potential were subsequently compared both in vitro and in vivo. iRPSCs exhibited a more potent odontoblastic differentiation than mRPSCs in vitro, as indicated by the higher levels of gene expression for dentin sialophosphoprotein and ALP (alkaline phosphatase), increased protein expression of dentin sialoprotein and runt-related transcription factor 2, decreased gene/protein expression for osterix/osteocalcin (osteogenic markers), elevated ALP activity and enhanced calcium deposition in the mineralization-inducing media. Allotransplantation results demonstrated that all iRPSCs pellets in vivo performed typical dentinogenesis, whereas mRPSCs pellets mainly produced bone-like tissues. CONCLUSION: iRPSCs presented stronger dentinogenesis but weaker osteogenesis than did mRPSCs, suggesting that the dentinogenic competence of root mesenchymal stem cells decreases, whereas their osteogenic potential the increases following the maturation of the tooth root. PMID- 21323646 TI - Adiponectin and resistin gene polymorphisms in association with their respective adipokine levels. AB - Single nucleotide polymorphisms (SNPs) at the adiponectin and resistin loci are strongly associated with hypoadiponectinemia and hyperresistinemia, which may eventually increase risk of insulin resistance, type 2 diabetes (T2DM), metabolic syndrome (MS), and cardiovascular disease. Real-time PCR was used to genotype SNPs of the adiponectin (SNP+45T>G, SNP+276G>T, SNP+639T>C, and SNP+1212A>G) and resistin (SNP-420C>G and SNP+299G>A) genes in 809 Malaysian men (208 controls, 174 MS without T2DM, 171 T2DM without MS, 256 T2DM with MS) whose ages ranged between 40 and 70 years old. The genotyping results for each SNP marker was verified by sequencing. The anthropometric clinical and metabolic parameters of subjects were recorded. None of these SNPs at the adiponectin and resistin loci were associated with T2DM and MS susceptibility in Malaysian men. SNP+45T>G, SNP+276G>T, and SNP+639T>C of the adiponectin gene did not influence circulating levels of adiponectin. However, the G-allele of SNP+1212A>G at the adiponectin locus was marginally associated (P= 0.0227) with reduced circulating adiponectin levels. SNP-420C>G (df = 2; F= 16.026; P= 1.50*10(-7) ) and SNP+299G>A (df = 2; F= 22.944; P= 2.04*10(-10) ) of the resistin gene were strongly associated with serum resistin levels. Thus, SNP-420C>G and SNP+299G>A of the resistin gene are strongly associated with the risk of hyperresistinemia in Malaysian men. PMID- 21323647 TI - The association of a single-nucleotide polymorphism of the IL-2 inducible T-cell Kinase gene with asthma. AB - Asthma manifests as TH2-dominant airway inflammation regulated by inducible T cell kinase (ITK). To investigate associations between genetic variants of the ITK gene and asthma, 31 single-nucleotide polymorphisms (SNPs) were genotyped in 303 normal controls and 498 asthmatics and the two groups were compared using logistic regression models. The functional effects of the ITK promoter SNP were assessed using pGL3 luciferase reporter systems and gel-shift assays. The minor allele-196C>T in the promoter region of the ITK gene was significantly more frequent in asthmatics than in controls. The luciferase activity of the PGL3-ITK 196T allele construct was higher than that of the -196C allele. In the gel-shift assay, -196T double-stranded oligonucleotides bound more strongly to Jurkat cell nuclear protein compared to the -196C double-stranded oligonucleotides. People with the -rare allele 196C>T may be more susceptible to asthma via transcriptional regulation of the ITK gene. PMID- 21323649 TI - Wound healing after mulesing and other options for controlling breech flystrike in Merino lambs: quantitative and semiquantitative analysis of wound healing and wound bed contraction. AB - BACKGROUND: A two-part study examined wound healing and contraction occurring after mulesing and two alternative methods of preventing breech flystrike in sheep. OBJECTIVE: To quantify wound healing using a scoring system and to assess the contractility of the wound bed of the breech after mulesing, cetrimide intradermal treatment and application of clips. METHOD: The study group of 30 mulesed, 30 cetrimide-intradermal treated, 30 control and 10 clip-treated sheep were humanely killed at six time points from 3 to 47 days after each treatment. Wound healing post treatment was assessed using a scoring system, and contractility was assessed by the quantification of myofibroblast expression. Statistical analyses allowed comparisons of temporal wound healing and contraction between treatment groups. RESULTS: Mulesing wounds healed faster in the first 11 days, but by 19 days wound healing was similar between the mulesing and cetrimide-intradermal groups. By 32 days, all three treatment groups had similar wound healing scores. There was greater myofibroblast expression in the mulesing group in the first 11 days after treatment, but by 19 days expression was similar in both the mulesing and cetrimide-intradermal groups. The clip group had significantly less myofibroblast expression from 32 days after treatment. CONCLUSION: Wound healing is initially most rapid after mulesing, but there are similar wound healing scores in the mulesing and cetrimide-intradermal treatment groups by 19 days. Both mulesing and the cetrimide-intradermal treatment induce a similar amount of wound bed contraction, with less contraction observed after application of clips. PMID- 21323651 TI - Mechanism of resistance to synthetic pyrethroids in buffalo flies in south-east Queensland. AB - Resistance to synthetic pyrethroids (SP) was first recorded in buffalo flies in Australia in 1980, associated with previous use of DDT and fenvalerate. By the 1990s, resistance was widespread. Resistance to SP in the related horn fly of the Americas is associated with kdr and super-kdr mutations in a gene encoding for a voltage-gated sodium channel. We describe 7-20-fold resistance to SP in buffalo flies from south-east Queensland, present evidence of flies that are heterozygous resistant at the kdr locus and show an increase in the frequency of the resistant allele 1 month after treatment of cattle with SP. PMID- 21323652 TI - Use of BAER to identify loss of auditory function in older horses. AB - OBJECTIVE: To use the brainstem auditory evoked response (BAER) to test the hypothesis that auditory function could be worse in older horses than in younger horses. PROCEDURE: BAER waveforms in response to click stimuli were measured in five younger horses (5-8 years) and four older horses (17-22 years). RESULTS: Compared with the younger horses, the older horses showed significantly (P < 0.02) worse BAER thresholds and significantly (P < 0.02) worse BAER wave V amplitudes to the 90 decibels above normal hearing level stimulus. These results were consistent with partial deafness in the older horse group. CONCLUSION: BAER assessment can be used to identify partial deafness in older horses. Such horses should be managed appropriately, with particular care taken in noisy environments where hearing loss could put the horse and/or its owner at risk of harm. PMID- 21323653 TI - Cutaneous asthenia in a Warmblood foal. AB - A 6-week-old Warmblood colt foal was presented for investigation of multiple haematoma formation in various locations, poor wound healing and abnormal scar formation. Based on the history and clinical presentation of hyperextensible skin with prolonged skin tenting, the foal was diagnosed with cutaneous asthenia and euthanased because of the poor prognosis. Histopathological and electron microscopic findings were inconclusive. This is the first case report of cutaneous asthenia in a Warmblood horse in Australia. Cutaneous asthenia is reviewed with particular reference to hereditary equine regional dermal asthenia and its similarities and differences to the case presented. PMID- 21323655 TI - Avian trichomoniasis: a study of lesions and relative prevalence in a variety of captive and free-living bird species as seen in an Australian avian practice. AB - BACKGROUND: Studies of avian trichomoniasis in the literature are limited to some extent, often being confined to a single bird species or group of species within a bird Order. Some incidence studies have been reported for free-living birds, and occasionally for captive birds. Very few reports describe the prevalence and types of lesions seen for a wide range of bird species, especially from a clinical perspective. METHODS: Retrospective study of avian practice records from a 10-year period. Emphasis on the types of presentations and relative prevalence of trichomoniasis in a variety of captive and free-living bird species encountered in Australian avian practice. RESULTS: The occurrence of trichomoniasis in several novel species (lorikeets, corvids and a cuckoo species), plus its distinctive presentation in southern boobook owls (Ninox boobook), is documented. CONCLUSION: Trichomoniasis should be a differential diagnosis for birds presenting with regurgitation or upper gastrointestinal abscesses, even if motile trichomonads are not found in wet preparations from crop washes or lesions. PMID- 21323656 TI - Epidemiology of recent outbreaks of infectious laryngotracheitis in poultry in Australia. AB - OBJECTIVE: Over the past 3 years, numerous outbreaks of infectious laryngotracheitis (ILT) have occurred in poultry in Australia. The objectives of this study were to identify the viral strains involved in the recent outbreaks and to determine possible epidemiological links between these outbreaks. PROCEDURE: A combination of polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analyses of several genes of the ILT virus was used to identify genetic differences in field/vaccine ILT virus isolates. In a previous study, these procedures had demonstrated five classes (1-5) in Australia. RESULTS: Analysis of 92 field ILT viruses demonstrated four new classes: 6, 7, 8 and 9. Class 6 was responsible for four outbreaks in one Victorian broiler company and demonstrated to be distinct from other Australian strains of ILT. Class 7 was the Nobilis ILT vaccine (Intervet Pty Ltd). Class 8 was responsible for the majority of the outbreaks in New South Wales and was phylogenetically close to class 7. On one occasion, classes 7 and 8 were identified in an outbreak on a Victorian farm that had used the Nobilis ILT vaccine. Class 9, also phylogenetically close to classes 7 and 8, was found only in New South Wales. The previously identified class 2 was also found to be responsible for a large number of outbreaks, mainly in Victoria. CONCLUSION: The results demonstrate that, epidemiologically, most outbreaks of ILT in New South Wales are unrelated to those in Victoria and suggest a link between classes 8 and 9 and the Nobilis ILT vaccine (class 7). PMID- 21323657 TI - Hepatotoxicosis in dogs consuming a diet of camel meat contaminated with indospicine. AB - BACKGROUND: Four dogs presented with clinical signs of severe hepatic disease after consuming a commercial camel meat diet. METHODS: Laboratory investigation revealed evidence of severe liver disease, including markedly increased serum alanine aminotransferase (ALT) activity and total bilirubin concentration, and prolonged clotting times. RESULTS: Two dogs deteriorated despite supportive therapy and were euthanased. Histologically, both livers appeared similar, with the main lesion being extensive periacinar necrosis and haemorrhage. Indospicine, a toxic amino acid of plant origin, was detected in the serum and/or plasma from all four dogs, as well as in tissues of a dog that was necropsied and in a sample of the camel meat fed to this animal. Serum biochemistry tests using blood samples collected from 15 additional dogs identified as having eaten the diet detected indospicine was in the serum of 14 and 3 had increased ALT activity. One of the latter dogs subsequently developed clinical signs of severe liver disease and was euthanased. CONCLUSION: To the authors' knowledge, this is the first published report of the detection of indospicine residues in camel meat and the occurrence of severe, sometimes fatal, liver disease in dogs that consumed this contaminated meat. PMID- 21323658 TI - Successful treatment of pulmonary aspergillosis in a cat. AB - A 7-year-old, spayed female Domestic Longhair cat was evaluated for a 6-week history of coughing. Thoracic radiography revealed a pleural effusion. Thoracic ultrasound revealed a pleural effusion and a focal lung mass. The cat underwent exploratory thoracotomy and a total left pneumonectomy was performed. Histopathology and cultures revealed fungal pneumonia and pyothorax caused by Aspergillus fumigatus. Abdominal ultrasound, repeat thoracic radiography, urinalysis with culture, and retroviral screening failed to detect evidence of systemic disease. The cat's poorly regulated diabetes mellitus is suspected to be the predisposing factor allowing a fungal pulmonary infection to become established. At 18 months after surgery the cat was still disease-free. To our knowledge this is the first reported case of successful treatment of pulmonary aspergillosis in the cat. PMID- 21323660 TI - Regulation of cytokine responses by seasonality of vitamin D status in healthy individuals. AB - The immune modulating capacity of vitamin D(3) is well-recognized. Ultra-violet (UV) exposure determines production of vitamin D(3) in vivo and varies through the course of the year, especially in temperate regions. However, it is not known whether the human innate immune response differs due to seasonality. To validate the seasonal effects of vitamin D(3) , the effect of 1,25(OH)(2) D(3) on peripheral blood mononuclear cells (PBMC) cytokine response was first determined in vitro. 1,25(OH)(2) D(3) decreased interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha release by PBMC stimulated with tripalmitoyl-S glycerylcysteine (Pam3Cys) or lipopolysaccharide (LPS). Subsequently, ex-vivo stimulation studies were performed in 15 healthy volunteers through the course of the four seasons of the year. PBMC were isolated and stimulated with Toll-like receptor (TLR)-2 and TLR-4 ligands Pam3Cys and LPS, respectively. Circulating concentrations of 25(OH)D(3) and 1,25(OH)(2) D(3) were higher during summer (P<0.05) and a down-regulation of TLR-4-mediated IL-1beta, IL-6, TNF-alpha, interferon (IFN)-gamma and IL-10 production in summer was observed compared to winter (P<0.05). The variation in cytokine response upon TLR-2 (Pam3Cys) stimulation was moderate throughout the four seasons. The repressed cytokine production during the summer months could be explained partly by the reduced cell membrane expression of TLRs. Physiological variation in vitamin D(3) status through the four seasons of the year can lead to alteration in the innate immune responses. Elevated vitamin D(3) level in vivo is associated with down-regulation of cytokine response through diminished surface expression of pattern recognition receptors. PMID- 21323661 TI - Cord blood monocyte subsets are similar to adult and show potent peptidoglycan stimulated cytokine responses. AB - Human monocytes can be divided into two major subpopulations, CD14(++) CD16(-) and CD14(+) CD16(+) cells, which are suggested to play different roles in antimicrobial responses. In neonates, characteristics and functional responses of monocyte subsets have not previously been explored, and might contribute to the qualitative difference between neonatal and adult cytokine profiles. We report that at baseline, monocyte subsets in cord blood and adult peripheral blood are present in similar frequencies, and show similar expression of CD11c, CD80/CD86, CD163 and HLA-DR. In response to the bacterial ligand peptidoglycan, cord blood monocytes had high inherent capacity for production of the early-response cytokines with levels of tumour necrosis factor and interleukin-12p70 exceeding adult levels, and also a higher phosphorylation of p38-mitogen-activated protein kinase. The CD14(+) CD16(+) cells expressed more interleukin-12p70 than CD14(++) CD16(-) cells and were present in a higher frequency in peptidoglycan-stimulated cord blood mononuclear cell cultures. Together, the behaviour of cord blood CD14(+) CD16(+) cells following peptidoglycan stimulation might indicate a qualitative difference between the neonatal antimicrobial response and that of the adult. In addition we found that serum factors in cord blood and adult sera affected cytokine production similarly, with the exception of tumour necrosis factor, regardless of the source of serum or cells. Overall, our data provide new insights into monocyte heterogeneity in cord blood and monocyte subset responses to a bacterial ligand at birth. PMID- 21323662 TI - Human IgG isotypes and activating Fcgamma receptors in the interaction of Salmonella enterica serovar Typhimurium with phagocytic cells. AB - Several classes and multiple subclasses of immunoglobulins are produced towards protein and polysaccharide antigens in response to Salmonella infection and play a key role in protection against systemic disease. The targeting of Salmonella to Fc receptors (FcR) on phagocytes is a key step in the antibody-mediated antibacterial functions of host cells. We wished to compare the relative efficiency of different human IgG subclasses, which targeted the Salmonella enterica OmpA surface protein in modulating the interaction of bacteria with human phagocytes. To this end, we developed a novel system by tagging OmpA with a foreign CD52 mimotope (TSSPSAD) and opsonizing the bacteria with a panel of humanized CD52 antibodies that share the same antigen-binding V-region, but have constant regions of different subclasses. Our data revealed that opsonization with all the IgG subclasses increases Salmonella uptake by human phagocytes. IgG3 resulted in the highest level of bacterial uptake and the highest average bacterial load per infected cell, which was closely followed by IgG1, then IgG4 and lastly IgG2. Phagocytosis mediated by IgG1, IgG3 and IgG4 had a higher dependency on FcgammaRI than FcgammaRIIA, whereas IgG2-mediated phagocytosis required FcgammaRIIA more than FcgammaRI. The results show that IgG binding to OmpA increases the uptake of Salmonella by human phagocytic cells and that the efficiency of this process depends both on the subclass of the IgG and the type of FcR that is available for antibody binding. PMID- 21323663 TI - Type 2 innate immune responses and the natural helper cell. AB - The T helper type 2 (Th2) immune response, characterized by the production of interleukin-4 (IL-4), IL-5 and IL-13, is a critical immune response against helminths invading cutaneous or mucosal sites. It also plays a critical role in the pathophysiology of allergic diseases such as asthma and allergic diarrhoea. The Th2 cytokines are induced soon after helminth infection, even before a pathogen-specific adaptive immune response is established. Recent studies have shed light on such innate Th2 cytokine production by formerly uncharacterized innate immune cells such as natural helper cells capable of producing Th2 cytokines in response to IL-25 and IL-33 independently of adaptive immune responses. These cells produce large amounts of Th2 cytokines, most notably IL-5 and IL-13, leading to eosinophilia and goblet cell hyperplasia. We discuss here the mechanisms of innate production of Th2 cytokines in host immune responses against helminth infection as well as allergic immune responses and the similarities and differences between recently identified Th2-cytokine producing cells. PMID- 21323664 TI - Neurogenesis in Alzheimer's disease. AB - It is widely acknowledged that neural stem cells generate new neurons through the process of neurogenesis in the adult brain. In mammals, adult neurogenesis occurs in two areas of the CNS: the subventricular zone and the subgranular zone of the dentate gyrus of the hippocampus. The newly generated cells display neuronal morphology, generate action potentials and receive functional synaptic inputs, their properties being equivalent to those of mature neurons. Alzheimer's disease (AD) is the widespread cause of dementia, and is an age-related, progressive and irreversible neurodegenerative disease that results in massive neuronal death and deterioration of cognitive functions. Here, we overview the relations between adult neurogenesis and AD, and try to analyse the controversies in the field. We also summarise recent data obtained in the triple transgenic model of AD that show time- and region-specific impairment of neurogenesis, which may account for the early changes in synaptic plasticity and cognitive impairments that develop prior to gross neurodegenerative alterations and that could underlie new rescue therapies. PMID- 21323665 TI - An immunohistochemical study of the distribution of nitric oxide synthase immunoreactive neurons and fibers in the reticular groove of suckling lambs. AB - The reticular groove (RG) is a specialized region of ruminant forestomach which, in suckling animals, via a vagovagal reflex, transforms itself into a tube to ensure the direct transport of milk from the esophagus to the abomasum. The nervous mechanism controlling the RG movement is not fully understood; however, at this level, the enteric nervous system (ENS) shows the highest neuronal density when compared with other forestomach compartments. Because nitric oxide is considered the putative major mediator of non-adrenergic non-cholinergic smooth muscle relaxation, the aim of the present study was to investigate the ENS of the RG of suckling lambs, both in the floor and in the lip, with particular regard to nitric oxide synthase (NOS)-immunoreactivity (-IR), by means of double immunohistochemical staining. NOS antiserum was used in association with some neurochemical markers which have been utilized by many authors in ENS. A rich innervation of fibers extended along the entire length of the RG. Proceeding distally, the number of neurons stained with a pan-neuronal marker increased; they were more numerous in the lips and lip-floor junction than in the floor itself. However, the percentage of NOS-IR neurons was the same in the proximal and distal parts. Many NOS-IR neurons often co-expressed galanin and dopamine beta-hydroxylase. Neurochemical markers, such as calbindin, calcitonin gene related peptide, IB4 and neurofilament 200 kDa, usually used to identify primary sensory neurons were not expressed in RG neurons, and the co-localization of NOS with tyrosine hydroxylase and substance P was rarely found. When compared with other districts, the RG showed some peculiar aspects, such as the lack of both neurons in the submucosal plexus and the lack of typical sensory neurons. PMID- 21323666 TI - Morphological integration between the cranial base and the face in children and adults. AB - The primary aim of the present study was to assess morphological covariation between the face and the basicranium (midline and lateral), and to evaluate patterns of integration at two specific developmental stages. A group of 71 children (6-10 years) was compared with a group of 71 adults (20-35 years). Lateral cephalometric radiographs were digitized and a total of 28 landmarks were placed on three areas; the midline cranial base, the lateral cranial base and the face. Geometric morphometric methods were applied and partial least squares analysis was used to evaluate correlation between the three shape blocks. Morphological integration was tested both with and without removing the effect of allometry. In children, mainly the midline and, to a lesser extent, the lateral cranial base were moderately correlated to the face. In adults, the correlation between the face and the midline cranial base, which ceases development earlier than the lateral base, was reduced. However, the lateral cranial base retained and even strengthened its correlation to the face. This suggests that the duration of common developmental timing is an important factor that influences integration between craniofacial structures. However, despite the apparent switch of primary roles between the cranial bases during development, the patterns of integration remained stable, thereby supporting the role of genetics over function in the establishment and development of craniofacial shape. PMID- 21323667 TI - Analysis of osteon morphotype scoring schemes for interpreting load history: evaluation in the chimpanzee femur. AB - Osteon morphotype scores (MTSs) allow for quantification of mechanically important collagen/lamellar variations between secondary osteons when viewed in circularly polarized ight (CPL). We recently modified the 6-point MTS method of Martin et al. (Martin RB, Gibson VA, Stover SM, Gibeling JC, Griffin LV (1996a) Osteonal structure in the equine third metacarpus. Bone 19, 165-71) and reported superiority of this modified method in correlating with 'tension' and 'compression' cortices of both chimpanzee proximal femoral diaphyses and diaphyses of other non-anthropoid bones that are loaded in habitual bending (Skedros et al. 2009, 2011). In these studies, the 'tension' and 'compression' cortices differed significantly in predominant collagen fiber orientation (CFO) based on weighted-mean gray levels (CFO/WMGLs) in CPL images. In chimpanzee femora, however, some osteons were difficult to score with the 6-point method; namely, 'hybrids' with peripherally bright 'hoops' and variability in alternating rings within the osteon wall. We hypothesized that some of these hybrids would be more prevalent in regions subject to torsion than bending. In this perspective the present study was aimed at expanding our 6-point scoring method (S-6-MTS) into two 12-point methods with six additional morphotypes that considered these hybrids. Three- and 4-point methods were also evaluated. We hypothesized that at least one of these other methods would out-perform the S-6-MTS in terms of accuracy, reliability, and interpreting torsion vs. bending load histories. Osteon morphotypes were quantified in CPL images from transverse sections of eight adult chimpanzee femora (neck, proximal diaphysis, mid-diaphysis), where the mid-diaphysis and base- and mid-neck locations have relatively more complex loading (e.g. torsion + bending) than the proximal diaphysis, where bending predominates. Correlation coefficients between CFO/WMGL and MTSs showed that the S-6-MTS method was either stronger or equivalent to the 12-point methods, and typically stronger than the 3- and 4-point methods for all load environments. In nearly all instances the S-6-MTS is more reliable and accurate when it is applied to cases where interpreting load history requires distinguishing habitual bending from torsion. Consequently, in studies of osteonal adaptations for these load histories the 3- and 4-point methods are not stronger correlates, and the extra time required to assign additional scores in the 12-point methods is both unnecessary and can be highly unreliable. PMID- 21323668 TI - Response to paper by J. E. McGregor and A. M. Donald, entitled ESEM imaging of dynamic biological processes: the closure of stomata pores. PMID- 21323670 TI - Application of regularized Richardson-Lucy algorithm for deconvolution of confocal microscopy images. AB - Although confocal microscopes have considerably smaller contribution of out-of focus light than widefield microscopes, the confocal images can still be enhanced mathematically if the optical and data acquisition effects are accounted for. For that, several deconvolution algorithms have been proposed. As a practical solution, maximum-likelihood algorithms with regularization have been used. However, the choice of regularization parameters is often unknown although it has considerable effect on the result of deconvolution process. The aims of this work were: to find good estimates of deconvolution parameters; and to develop an open source software package that would allow testing different deconvolution algorithms and that would be easy to use in practice. Here, Richardson-Lucy algorithm has been implemented together with the total variation regularization in an open source software package IOCBio Microscope. The influence of total variation regularization on deconvolution process is determined by one parameter. We derived a formula to estimate this regularization parameter automatically from the images as the algorithm progresses. To assess the effectiveness of this algorithm, synthetic images were composed on the basis of confocal images of rat cardiomyocytes. From the analysis of deconvolved results, we have determined under which conditions our estimation of total variation regularization parameter gives good results. The estimated total variation regularization parameter can be monitored during deconvolution process and used as a stopping criterion. An inverse relation between the optimal regularization parameter and the peak signal to-noise ratio of an image is shown. Finally, we demonstrate the use of the developed software by deconvolving images of rat cardiomyocytes with stained mitochondria and sarcolemma obtained by confocal and widefield microscopes. PMID- 21323671 TI - Anion responsive dibenzoyl-L-cystine and luminescent lanthanide soft material. AB - A mild sol-gel technique was used to incorporate terbium dibenzoyl-L-cystine complex into silica and green luminescent hybrid material was fabricated. (1)H NMR and fluorescence spectroscopy revealed the hybrids can recognize F(-) anions through hydrogen bonding formation and had no sense in binding other halide or HSO(4)(-). Furthermore, a luminescent hydrogel was successfully designed by immobilizing a terbium activated phosphor (Gd(0.1)Ce(0.9)PO(4):Tb) into molecular hydrogelator (dibenzoyl-L-cystine). The Tb(III) emission in hydrogel media gave a distinguished enhancement based on temperature increase and the function conforms to exponential equation y = 1160.6 exp(0.03x). The stability of the green luminescent gel was rather excellent and the reversibility of the gel can be recycled at least five times. PMID- 21323672 TI - Young adults talk about their problems. AB - This study aims to explore how young adults in psychotherapy and young adults in general describe their problems and how their problem formulations change over time. Two matched samples from longitudinal prospective studies were compared using thematic analysis. Semi-structured, in-depth interviews were conducted at baseline, 1.5 years after termination of psychotherapy (N=12) in the clinical sample and 3 years after baseline in the non clinical sample (N=12). Inductive thematic analysis revealed six themes: problems associated with oneself, family, intimate relationships, sense of belonging, occupation, and social roles. The psychotherapy sample was characterized by problems with oneself closely related to other problematic areas, at both pre-treatment and at follow-up 1.5 years after termination, while problematic sense of belonging was a general theme only prior to psychotherapy. However, they were less troubled by their problems after psychotherapy. Problems with oneself decreased considerably in the non-clinical sample, while problems with intimate relationships were twice as frequent at follow-up. In the psychotherapy sample, the initial experience of being passively trapped within their problems was transformed into an experience of being an active agent in their own life. However, considerable differences between the psychotherapy sample and non-clinical sample still persisted at follow-up. PMID- 21323673 TI - Encephalomyocarditis virus mortality in semi-wild bonobos (Pan panicus). AB - BACKGROUND: Fatal myocarditis from encephalomyocarditis virus (EMCV) infection has previously been identified in sporadic and epidemic forms in many species of captive non-human primates probably including one bonobo (Pan paniscus). METHODS: We investigated the deaths of two bonobos that were suspicious of EMCV using a combination of histopathology, immunohistochemistry and, for one of the two bonobos, reverse transcription PCR. RESULTS: Histopathological examination of heart tissue from the two bonobos showed changes characteristic of EMCV. Immunohistochemical studies confirmed the presence of EMCV antigen in heart tissue of both and in kidney and intestine of one of the bonobos. EMCV RNA was also isolated from the serum of the bonobo tested. CONCLUSION: Together, these findings confirm that EMCV was responsible for deaths of the two bonobos. Strict separation of bonobos in particular and captive primates in general from potential sources of EMCV contamination should be maintained to prevent mortality caused by EMCV. PMID- 21323674 TI - Blood pressure reference intervals for healthy adult chimpanzees (Pan troglodytes). AB - BACKGROUND: Cardiovascular disease is the primary cause of morbidity and mortality among captive chimpanzees. But there are no clinical definitions of normotension or hypertension in chimpanzees. METHODS: We analyzed 1 year of blood pressure (BP) data from a population of 261 healthy captive adult chimpanzees using a consistent set of criteria to ascertain health. RESULTS: Systolic BP varied by body weight. Diastolic BP varied by age. Median normotension was 126/63 mmHg, with an upper limit of 147/84 mmHg. We defined categories of pre hypertension (148/85-153/88 mmHg) and hypertension (>=154/89 mmHg). The prevalence of elevated BP was 15%. The relative risk of mortality was 2.60, compared to normotensive animals. CONCLUSIONS: We used contemporary methods from human laboratory medicine to define reliable reference intervals for chimpanzee BP. Results allow accurate diagnosis of hypertension and pre-hypertension, and demonstrate an effect of elevated BP on mortality. PMID- 21323675 TI - Pharmacokinetics of ceftiofur crystalline-free acid sterile suspension in the equine. AB - Absolute bioavailability and dose proportionality studies were performed with ceftiofur in horses. In the absolute bioavailability study, thirty animals received either an intravenous dose of ceftiofur sodium at 1.0 mg/kg or an intramuscular (i.m.) dose of ceftiofur crystalline-free acid (CCFA) at 6.6 mg/kg. In the dose proportionality study, 48 animals received daily i.m. ceftiofur sodium injections at 1.0 mg/kg for ten doses or two doses of CCFA separated by 96 h, with CCFA doses of 3.3, 6.6, or 13.2 mg/kg. Noncompartmental and mixed-effect modeling procedures were used to assess pharmacokinetics (PK). CCFA was well absorbed with a bioavailability of 100%. AUC(0-infinity) and C(max) increased in a dose-related manner following administration of the two doses of CCFA at 3.3, 6.6, and 13.2 mg/kg. The least-squares mean terminal half-life (t(1/2) ) following the tenth daily i.m. injection of ceftiofur sodium at 2.2 mg/kg was 40.8 h, but the least-squares mean t(1/2) following the second i.m. injection of CCFA at 6.6 mg/kg was 100 h. The time that plasma ceftiofur equivalent concentrations remain above a threshold concentration of 0.2 MUg/mL has been associated with efficacy, and following administration of two 6.6 mg/kg doses of CCFA, the mean time above 0.2 MUg/mL was 262 h. Simulations with the nonlinear mixed-effect PK model predicted that more than 97.5% of horses will have plasma ceftiofur equivalent concentrations >0.2 MUg/mL for 96 h after the second 6.6 mg/kg dose of CCFA. PMID- 21323676 TI - Pharmacokinetics of tilmicosin in beef cattle following intravenous and subcutaneous administration. AB - The intravenous pharmacokinetic profile of tilmicosin is yet to be achieved because of the cardiovascular effects of tilmicosin. This study summarizes two pharmacokinetic studies that provided complete pharmacokinetic profile of tilmicosin in cattle. The first study was a pharmacokinetic study of tilmicosin in beef calves dosed by i.v. infusion over 5 h. The second study was a subcutaneous (s.c.) pharmacokinetic study comparing the pharmacokinetic profile of tilmicosin in light (approximately 170 kg) and heavy (approximately 335 kg) beef cattle and comparing the labeled dose range of 10 or 20 mg/kg dose. The data from the two different studies were used to calculate bioavailability values, which support the assumption that tilmicosin is 100% bioavailable in cattle. The results from the second study showed that the weight of an animal when administered tilmicosin does not have a significant effect on exposure, but did demonstrate that doubling the dose of tilmicosin administered doubles the systemic exposure to tilmicosin. PMID- 21323677 TI - Pharmacokinetics of oxymorphone in cats. AB - This study reports the pharmacokinetics of oxymorphone in spayed female cats after intravenous administration. Six healthy adult domestic shorthair spayed female cats were used. Oxymorphone (0.1 mg/kg) was administered intravenously as a bolus. Blood samples were collected immediately prior to oxymorphone administration and at various times up to 480 min following administration. Plasma oxymorphone concentrations were determined by liquid chromatography-mass spectrometry, and plasma oxymorphone concentration-time data were fitted to compartmental models. A three-compartment model, with input in and elimination from the central compartment, best described the disposition of oxymorphone following intravenous administration. The apparent volume of distribution of the central compartment and apparent volume of distribution at steady state [mean +/- SEM (range)] and the clearance and terminal half-life [harmonic mean +/- jackknife pseudo-SD (range)] were 1.1 +/- 0.2 (0.4-1.7) L/kg, 2.5 +/- 0.4 (2.4 4.4) L/kg, 26 +/- 7 (18-38) mL/min.kg, and 96 +/- 49 (62-277) min, respectively. The disposition of oxymorphone in cats is characterized by a moderate volume of distribution and a short terminal half-life. PMID- 21323678 TI - Pharmacokinetics of amantadine in cats. AB - This study reports the pharmacokinetics of amantadine in cats, after both i.v. and oral administration. Six healthy adult domestic shorthair female cats were used. Amantadine HCl (5 mg/kg, equivalent to 4 mg/kg amantadine base) was administered either intravenously or orally in a crossover randomized design. Blood samples were collected immediately prior to amantadine administration, and at various times up to 1440 min following intravenous, or up to 2880 min following oral administration. Plasma amantadine concentrations were determined by liquid chromatography-mass spectrometry, and plasma amantadine concentration time data were fitted to compartmental models. A two-compartment model with elimination from the central compartment best described the disposition of amantadine administered intravenously in cats, and a one-compartment model best described the disposition of oral amantadine in cats. After i.v. administration, the apparent volume of distribution of the central compartment and apparent volume of distribution at steady-state [mean +/- SEM (range)], and the clearance and terminal half-life [harmonic mean +/- jackknife pseudo-SD (range)] were 1.5 +/- 0.3 (0.7-2.5) L/kg, 4.3 +/- 0.2 (3.7-5.0) L/kg, 8.2 +/- 2.1 (5.9-11.4) mL.min/kg, and 348 +/- 49 (307-465) min, respectively. Systemic availability [mean +/- SEM (range)] and terminal half-life after oral administration [harmonic mean +/- jackknife pseudo-SD (range)] were 130 +/- 11 (86-160)% and 324 +/- 41 (277-381) min, respectively. PMID- 21323679 TI - Sleep following alcohol intoxication in healthy, young adults: effects of sex and family history of alcoholism. AB - BACKGROUND: This study evaluated sex and family history of alcoholism as moderators of subjective ratings of sleepiness/sleep quality and polysomnography (PSG) following alcohol intoxication in healthy, young adults. METHODS: Ninety three healthy adults [mean age 24.4 +/- 2.7 years, 59 women, 29 subjects with a positive family history of alcoholism (FH+)] were recruited. After screening PSG, participants consumed alcohol (sex/weight adjusted dosing) to intoxication [peak breath alcohol concentration (BrAC) of 0.11 +/- 0.01 g% for men and women] or matching placebo between 20:30 and 22:00 hours. Sleep was monitored using PSG between 23:00 and 07:00 hours. Participants completed the Stanford Sleepiness Scale and Karolinska Sleepiness Scale at bedtime and on awakening and a validated post-sleep questionnaire. RESULTS: Following alcohol, total sleep time, sleep efficiency, nighttime awakenings, and wake after sleep onset were more disrupted in women than men, with no differences by family history status. Alcohol reduced sleep onset latency, sleep efficiency, and rapid eye movement sleep while increasing wakefulness and slow wave sleep across the entire night compared with placebo. Alcohol also generally increased sleep consolidation in the first half of the night, but decreased it during the second half. Sleepiness ratings were higher following alcohol, particularly in women at bedtime. Morning sleep quality ratings were lower following alcohol than placebo. CONCLUSIONS: Alcohol intoxication increases subjective sleepiness and disrupts sleep objectively more in healthy women than in men, with no differences evident by family history of alcoholism status. Evaluating moderators of alcohol effects on sleep may provide insight into the role of sleep in problem drinking. PMID- 21323680 TI - Variation in genes encoding the neuroactive steroid synthetic enzymes 5alpha reductase type 1 and 3alpha-reductase type 2 is associated with alcohol dependence. AB - BACKGROUND: Studies of alcohol effects in rodents and in vitro implicate endogenous neuroactive steroids as key mediators of alcohol effects at GABA(A) receptors. We used a case-control sample to test the association with alcohol dependence (AD) of single nucleotide polymorphisms in the genes encoding two key enzymes required for the generation of endogenous neuroactive steroids: 5alpha reductase, type I (5alpha-R), and 3alpha-hydroxysteroid dehydrogenase, type 2 (3alpha-HSD), both of which are expressed in human brain. METHODS: We focused on markers previously associated with a biological phenotype. For 5alpha-R, we examined the synonymous SRD5A1 exon 1 SNP rs248793, which has been associated with the ratio of dihydrotestosterone to testosterone. For 3alpha-HSD, we examined the nonsynonymous AKR1C3 SNP rs12529 (H5Q), which has been associated with bladder cancer. The SNPs were genotyped in a sample of 1,083 non-Hispanic Caucasians including 552 controls and 531 subjects with AD. RESULTS: The minor allele for both SNPs was more common among controls than subjects with AD: SRD5A1 rs248793 C-allele (chi(2)(1) = 7.6, p = 0.006) and AKR1C3 rs12529 G-allele (chi(2)(1) = 14.6, p = 0.0001). There was also an interaction of these alleles such that the "protective" effect of the minor allele at each marker for AD was conditional on the genotype of the second marker. CONCLUSIONS: We found evidence of an association with AD of polymorphisms in two genes encoding neuroactive steroid biosynthetic enzymes, providing indirect evidence that neuroactive steroids are important mediators of alcohol effects in humans. PMID- 21323681 TI - The neighborhood alcohol environment and at-risk drinking among African Americans. AB - BACKGROUND: Our objective was to examine whether components of the neighborhood alcohol environment-liquor store, on-premise outlet, convenience store, and supermarket densities-are positively associated with at-risk alcohol consumption among African-American drinkers. METHODS: A multilevel cross-sectional sample of 321 African-American women and men ages 21 to 65 years recruited from April 2002 to May 2003 from three community-based healthcare clinics in New Orleans, Louisiana, was studied. RESULTS: The alcohol environment had a significant impact on at-risk alcohol consumption among African-American drinkers, specifically liquor store density (adjusted OR = 3.11, 95% CI = 1.87, 11.07). Furthermore, the influence of the alcohol environment was much stronger for African-American female drinkers (adjusted OR = 6.96, 95% CI = 1.38, 35.08). CONCLUSIONS: Treatment and prevention programs should take into account the physical environment, and the concentration of outlets in minority neighborhoods must be addressed as it poses potential health risks to the residents of these neighborhoods. PMID- 21323683 TI - Molecular biology-based assessment of vitamin E-coated dialyzer effects on oxidative stress, inflammation, and vascular remodeling. AB - Cardiovascular disease represents the most common cause for the excess of morbidity and mortality found in end-stage renal disease (ESRD) and has prompted the exploration of multiple approaches to improve outcomes in these patients. Cardiovascular risk factors such as increased oxidative stress (OxSt) and inflammation are found in ESRD patients. A vitamin E-coated dialyzer using polysulfone membranes has been suggested to have positive effects on these factors. This 1-year study evaluated in 25 ESRD patients under chronic dialysis, the effects of a vitamin E-coated membrane (VitabranE ViE) "ex vivo" on mononuclear cells, OxSt, and inflammation-related biochemical and molecular biology markers using a molecular biology approach. p22(phox), heme oxygenase (HO)-1, plasminogen activator inhibitor (PAI)-1 protein level, and phosphorylated extracellular signal-regulated kinase (pERK)1/2 status were evaluated at the beginning of the study, after 6 months and after 12 months by Western blot analysis and oxidized low-density lipoprotein (OxLDL) plasma level by enzyme linked immunosorbent assay, alongside vascular remodeling assessment as measured by carotid intima-media thickness (IMT) in a subgroup of nine randomly selected patients. p22(phox), PAI-1, OxLDL, and pERK all decreased with VitabranE use, while HO-1 increased. Carotid IMT did not increase. Treatment with VitabranE significantly decreases the expression of proteins and markers relevant to OxSt and inflammation tightly associated with cardiovascular disease, and it appears highly likely that VitabranE use will provide a benefit in terms of cardiovascular protection. PMID- 21323682 TI - Rutgers alcohol problem index scores at age 18 predict alcohol dependence diagnoses 7 years later. AB - BACKGROUND: The Rutgers Alcohol Problem Index (RAPI) is widely used to assess adolescent drinking-related problems. We asked how well RAPI, administered in late adolescence, predicts alcohol diagnoses at age 25 in a 7-year follow-up. METHODS: At age 18, a population-based sample of Finnish twins completed RAPI by postal questionnaire; 597 (300 male) twins, from pairs discordant and concordant for age 18 RAPI scores, were interviewed at age 25 with the SSAGA, yielding DSM IIIR diagnoses. Polychoric correlations between RAPI and alcohol diagnoses and symptoms, the area under the response operator characteristic (ROC) curve, and the odds ratio of outcome diagnosis per unit change in adolescent RAPI were analyzed. Twin pairs discordant for both adolescent RAPI and adult diagnoses permitted within-family replications for the full sample and separately by sex. RESULTS: Nearly half the interviewed twins met diagnostic criteria for alcohol dependency (46.2%) or abuse (1.5%). Age 18 RAPI scores significantly correlated with diagnoses (0.52) and symptom counts (0.55). ROC analysis found a 74% probability that adolescent RAPI scores will be higher among those with an alcohol diagnosis at age 25 than for those without. The odds ratio of outcome alcohol diagnosis per unit increase in adolescent 18 RAPI exceeded 10.0. Within family comparisons of 117 twin pairs discordant for both age 18 RAPI and age 25 alcohol diagnoses replicated the between-family associations. In both between family and within-family analyses, RAPI was more predictive of alcohol diagnoses among females. CONCLUSIONS: Our results offer evidence, including that from informative comparisons of co-twins discordant for both predictor and outcome, that RAPI scores in late adolescence robustly predict alcohol diagnoses in early adulthood. Accordingly, our results also provide new evidence that one pathway to problem drinking in early adulthood is a direct one from problem drinking in adolescence. PMID- 21323685 TI - An odyssey in mechanical circulatory support. PMID- 21323686 TI - Cycle testing of the MagScrew total artificial heart external battery pack: update I. AB - MagScrew total artificial heart (TAH) external battery pack (EBP) cycle bench testing continued over a period of 18 months using two fresh Wilson Greatbatch lithium ion EBPs during continuous charge and discharge cycles under a simulated TAH system current requirement. The same electronic load developed for our initial testing was used to simulate the MagScrew current waveforms typically observed during nominal operation. The current load profiles for this test were modified from the ones previously described and applied to the EBP under test during a voltage-defined discharge cycle. The test ended when EBP#2 reached end of life at 1450 cycles. At that point, EBP#1 remained healthy with a capacity of 175 min until full discharge. Performance of EBP#2 was still within expected ranges. Performance of EBP#1 exceeded expectations. These differences are probably caused by slight manufacturing changes. More tests will provide additional data to define a statistical distribution to better characterize EBP performance. In conclusion, endurance performance of the EBP remained satisfactory. PMID- 21323687 TI - Stable mixed acidemia in anesthetized pigs--a model for research on biocompatibility of hemofilters under a deteriorated acid-base balance. AB - In recent years, acidosis has been of growing interest in intensive care medicine. Most animal models only provide a short-term investigation of the effects of acidosis. They are not suitable for research on interactions with extracorporeal organ support (here continuous venovenous hemofiltration, CVVH). The rationale for this study was to establish a porcine model of prolonged mixed acidemia, which is suitable for research on the interactions of acidemia and CVVH. After the induction of anesthesia in pigs (40 kg), acidemia was induced and maintained in one group with a bolus of 0.4 mol/L lactic acid followed by continuous infusion and a reduced respiratory frequency (lactic acid-group, n = 4). In another group, mixed acidemia was induced with a 0.4 mol/L acid solution (lactic and hydrochloric acid) and low tidal volume ventilation (mixed acidemia group, n = 8). To get first proof of the model's suitability to operate over an extracorporeal circuit, CVVH was additionally performed in seven pigs (mixed acidemia/CVVH-group, n = 7). The target for the pH was 7.19-7.24. The targeted pH was constantly missed in the lactic acid group, whereas it was successfully maintained for 3.5 h in four out of eight pigs of the mixed acidemia group, and in five out of seven pigs of the mixed acidemia/CVVH group. The CVVH was performed successfully for 3 h in all pigs of the respective group. The mixed acidemia model was sufficient to maintain a low pH within a narrow range for some hours and enabled research on hemofilters in vivo. PMID- 21323688 TI - Randomised clinical trial: dried plums (prunes) vs. psyllium for constipation. AB - BACKGROUND: Treatment of chronic constipation remains challenging with 50% of patients dissatisfied with current therapy. There is an unmet need for natural and safe alternatives. Dried plums (prunes) have been used traditionally for constipation but their efficacy is not known. Aim To assess and compare the effects of dried plums and psyllium in patients with chronic constipation. METHODS: Subjects were enrolled in an 8-week, single-blind, randomised cross-over study. Subjects received either dried plums (50 g b.d., fibre=6 gm/day) or psyllium (11 g b.d., fibre=6 gm/day) for 3 weeks each, in a crossover trial with a 1-week washout period. Subjects maintained a daily symptom and stool diary. Assessments included number of complete spontaneous bowel movements per week, global relief of constipation, stool consistency, straining, tolerability and taste. RESULTS: Forty constipated subjects (m/f=3/37, mean age=38 years) participated. The number of complete spontaneous bowel movements per week (primary outcome measure) and stool consistency scores improved significantly (P<0.05) with dried plums when compared to psyllium. Straining and global constipation symptoms did not differ significantly between treatments (P=N.S.). Dried plums and psyllium were rated as equally palatable and both were safe and well tolerated. CONCLUSION: Dried plums are safe, palatable and more effective than psyllium for the treatment of mild to moderate constipation, and should be considered as a first line therapy. PMID- 21323689 TI - Review article: remission rates achievable by current therapies for inflammatory bowel disease. AB - BACKGROUND: New medical therapies have improved outlook in inflammatory bowel disease but published impact on surgical rates has been modest suggesting that many patients are still not attaining remission. AIM: To review remission rates with current medical treatments for inflammatory bowel disease. METHODS: We searched MEDLINE (source PUBMED, 1966 to January, 2011). RESULTS: Induction and maintenance of remission was observed in 20% (range, 9-29.5%) and 53% (range, 36.8-59.6%) of ulcerative colitis (UC) patients treated with oral 5-ASA derivatives. Induction of remission was noted in 52% (range, 48-58%) of Crohn's disease (CD) patients and 54% of UC patients treated with steroids in population based cohorts. Maintenance of remission was reported in 71% (range, 56-95%) of CD patients on azathioprine over a 6-month to 2-year period and in 60% (range, 41.7 82.4%) in UC at 1 year or longer. Induction and maintenance of remission was noted in 39% (range, 19.3-66.7%) and 70% (range, 39-90%) of CD patients on methotrexate over a 40-week period. Induction of remission was reported in 32% (range, 25-48%), 26% (range, 18-36%) and 20% (range, 19-23%) of CD patients on infliximab, adalimumab or certolizumab pegol, respectively. The corresponding figures were 45% (range, 39-59%), 43% (range, 40-47%) and 47.9% at weeks 20-30 among initial responders. Induction of remission was observed in 33% (range, 27.5 38.8%) and 18.5% of UC patients on infliximab or adalimumab, respectively. Maintenance of remission was noted in 33% (range, 25.6-36.9%) of UC patients on infliximab at week 30. Approximately one-fifth of CD and UC patients treated with biologicals require intestinal resection after 2-5 years in referral-centre studies. CONCLUSION: In the era of biologics, the proportion of patients with inflammatory bowel disease not entering remission remains high. PMID- 21323690 TI - Individual placement and support - a model to get employed for people with mental illness - the first Swedish report of outcomes. AB - Lack of participation in the open labour market is highly prevalent for people with a mental illness across countries, and the proportion of people who get some kind of sickness benefit because of mental illness is steadily growing in Europe. Vocational rehabilitation through individual placement and support (IPS) has been shown to be effective and is evidence-based for people with severe mental illness. In Sweden, the method is used but not scientifically evaluated. The aim was to investigate vocational and nonvocational outcomes at a 1-year follow-up and the relationships between these outcomes, at two different sites in the north of Sweden. The participants were 65 men and women, mostly younger than 30 years of age and with a mental illness. Occupational situation, psychiatric symptoms, self-esteem, quality of life and psychosocial functioning were assessed. The vocational outcome during 1 year was that 25% of the participants were employed, and 14% were in education. Most of the participants moved from unemployment to work practice for a prolonged time. Participants in employment, education or work practice at follow-up showed higher satisfaction with their occupational situation than those without regular activities outside home. Among the participants in work practice, improvements in psychiatric symptoms and global functioning were identified. This attempt is the first to evaluate supported employment according to the IPS model for persons with mental illness applied in the Swedish welfare system. There is a need for a longer follow-up period to evaluate whether interventions such as further education and work practice actually will lead to real work. PMID- 21323691 TI - Flow cytometric analysis of TCR Vbeta repertoire in patients with 22q11.2 deletion syndrome. AB - In 22q11.2 deletion patients, the normal decrease in T lymphocyte counts after 1 2 years is blunted such that relatively T lymphocyte numbers increase over early childhood, probably via post-thymic expansion of peripheral lymphocytes. This may leave less T lymphocyte receptor (TCR) diversity than when derived from naive thymic emigrants. We analysed TCR Vbeta repertoire on 27 22q11.2 chromosome deletion patients. No patient had infection at sampling. CD3(+) CD4(+) recent thymic emigrants (RTEs) were identified by CD45RA and CD31 expression. TCR Vbeta repertoire was determined using four-colour flow cytometry. Patients and controls showed significant TCR Vbeta family usage differences between CD3(+) CD4(+) and CD3(+) CD4(-) T lymphocyte subpopulations. Vbeta family abnormalities (+/-3 SD of controls) were identified in 18/27 (67%) patients and 12/47 (25%) controls. In patients, the magnitude of expansions was increased, with some Vbeta families representing 37% of the cells present in the subpopulations. There was a significant increase in frequency of abnormalities in CD3(+) CD4(+) (P < 0.001) and CD3(+) CD4(-) T lymphocytes (P < 0.05) in patients. A total of 11/16 patients had an abnormal CD4(+) CD25(Bright) TCR Vbeta repertoire. There was no difference in expansions/contractions between CD4(+) CD25(Bright) and CD4(+) T lymphocyte repertoires (P = 0.575) for individual patients but significant differences in expansions/contractions between CD4(+) CD25(Bright) and CD8(+) T lymphocytes repertoires (P = 0.011). There was bias in Vbeta usage between CD3(+) CD4(+) and CD3(+) CD4(-) T lymphocyte subsets. A total of 67% patients had TCR Vbeta repertoire abnormalities, with a trend towards increased repertoire abnormalities with fewer RTEs, suggesting thymic output plays an important role in TCR repertoire diversity. There was no correlation between skewed repertoire and symptoms of infection or autoimmunity. PMID- 21323692 TI - Sphingosine 1-phosphate receptor modulator FTY720 suppresses rat experimental autoimmune prostatitis. AB - Experimental autoimmune prostatitis (EAP) is an autoimmune inflammatory disease of male sex accessory glands and is characterized by a cellular and humoral prostate-specific autoimmune response associated with inflammatory mononuclear cell (MNC) infiltration. EAP shares important clinical and immunological features with human chronic prostatitis and chronic pelvic pain syndrome. Using immunohistochemistry, we determined the pattern of pathological changes during rat EAP development, regarding the cellular responses and infiltration into the prostate gland, and therapeutic effect of FTY720, a modulator of sphingosine-1 phosphate receptors which has shown promising protective effects in animal models and clinical trials of several autoimmune diseases. Significant accumulations of total MNCs, pan-T cells and CD8(+) cells were observed in prostatic stroma as early as 11 days after autoimmune induction. However, accumulation of reactive macrophages became significant 4 days later. After reaching the maximal level at Day 16, the accumulations of all the different cell populations fell back rapidly and returned to normal level by Day 35. Suppressive FTY720 significantly reduced inflammatory infiltration of different immune cell populations and tissue disruption in prostate of EAP rats. Our results therefore suggest that FTY720 might be a potential candidate for treatment of inflammatory prostatitis. PMID- 21323693 TI - Determinants of experimental allergic responses: interactions between allergen dose, sex and age. AB - The prevalence of allergic diseases is influenced by sex and age. Although mouse models are widely used in allergy research, few experimental studies have examined the interaction effects of sex and age on allergy outcomes. Our aim was to investigate the individual and combined effects of sex and age on allergic sensitization and inflammation in two mouse models: an intraperitoneal (i.p.) and an intranasal (i.n.) sensitization model. We also investigated how the allergen immunization dose interacted with age and sex in the i.p. model. Female and male mice were immunized i.p. or i.n. with ovalbumin when 1, 6 or 20 weeks old. In both models, allergen challenges were performed by i.n. delivery. Serum antibodies, draining lymph node cytokine release and airway inflammatory responses were assessed. In the i.p. model, the antibody and cytokine levels and airway inflammation were highly influenced by immunization dose and age. The responses increased with age when using a low immunization dose, but decreased with age when using a high immunization dose. In the i.n. model, antibody production and airway tissue inflammation increased with age. Female compared with male mice generally developed more pronounced antibody and inflammatory responses. Relative to older mice, juvenile mice had augmented airway inflammation to allergen exposures. The study demonstrates that immunization dose, sex and age are highly influential on allergy outcomes. To better mimic different life stages of human allergic airway disease, murine models, therefore, require careful optimization. PMID- 21323694 TI - The impact of early viral infections and graft-versus-host disease on immune reconstitution following paediatric stem cell transplantation. AB - Viral infections and graft-versus-host disease (GVHD) render an impact on both the clinical and immunological recovery following allogeneic hematopoietic stem cell transplantation (HSCT). We studied the recuperation of the immune defence after transplant in the paediatric setting and assessed the impact of early (<100 days post-HSCT) viral [cytomegalovirus (CMV), Ebstein-Barr virus (EBV) and adenovirus] reactivations/infections and GVHD. Fifty-one paediatric recipients of HSCT were enrolled. T cell recovery was evaluated on lymphocyte subpopulations using flow cytometry and functionally by measuring T cell excision circles (TRECs) and through the analysis of T lymphocyte responses to mitogens. B cell recovery was studied by flow cytometry and functionally by ELISPOT. Acute and mild chronic GVHD allowed for a brisk recovery of both cellular and humoral immunity while moderate to severe chronic graft-versus-host disease (cGVHD) associated with a significant, tampering effect on the immunological recovery after transplant. In the former group, the early viral reactivations/infections seemingly linked with a delayed recovery of T lymphocytes and low TRECs values. Moderate to severe cGVHD appears to associate with an impaired immunological recovery after HSCT. Early viral infections linked with prolonged T cell immunodeficiency and thymic dysfunction may be indicative of the presence of subclinical GVHD. PMID- 21323695 TI - Immunogenicity and protective efficacy of a fusion protein vaccine consisting of antigen Ag85B and HspX against Mycobacterium tuberculosis infection in mice. AB - Subunit vaccines have the potential advantage to boost Mycobacterium bovis Bacillus Calmette-Guerin (BCG)-primed immunity in adults. However, most candidates are antigens highly expressed in replicating bacilli but not in dormant or persisting bacilli, which exist during Mycobacterium tuberculosis infection. We constructed M. tuberculosis fusion protein Ag85B-Mpt64(190-198) HspX (AMH) and Ag85B-Mpt64(190-198) -Mtb8.4 (AMM), which consist of Ag85B, the 190-198 peptide of Mpt64, HspX (Rv2031c) and Mtb8.4 (Rv1174c), respectively. AMH and/or AMM were mixed with adjuvants composed of dimethyl-dioctyldecyl ammonium bromide and BCG polysaccharide nucleic acid (DDA-BCG PSN) to construct subunit vaccines. Mice were immunized thrice with Ag85B, AMH and AMM vaccines and the immunogenicity of the fusion protein vaccines was determined. Then, mice were primed with BCG and boosted twice with Ag85B, AMH, AMM and AMM + AMH vaccines, respectively, followed by challenging with M. tuberculosis virulent strain H37Rv, and the immune responses and protective effects were measured. It was found that mice immunized with AMH vaccine generated high levels of antigen-specific cell mediated responses. Compared with the group injected only with BCG, the mice boosted with AMM, AMH and AMM + AMH produced higher levels of Ag85B-specific IgG1 and IgG2a and IFN-gamma-secreting T cells upon Ag85B and Mycobacterium tuberculosis purified protein derivative (PPD) stimulation. It is interesting that only mice boosted with AMM + AMH had significantly lower bacterial count in the lungs than those receiving BCG, whereas mice boosted with AMH or AMM did not. The results suggest that AMH consisting of HspX, the antigen highly expressed in dormant bacilli, could be combined with antigens from replicating bacilli to enhance BCG primed immunity so as to provide better protection against both growing and non-growing bacteria that occur during the infection process. PMID- 21323696 TI - Interleukin-4 gene polymorphisms confer Behcet's disease in Turkish population. AB - Several cytokine genes may play crucial roles in host susceptibility to Behcet's Disease (BD), because the cytokine production capacity varies among individuals and depends on the cytokine gene polymorphisms. The association of the IL-4 and IL-4Ralpha gene polymorphisms with the susceptibility to BD was investigated in this study. DNA samples were obtained from a Turkish population of 97 patients with BD and 76 healthy control subjects. All genotyping (IL-4 and IL-4Ralpha) experiments were performed using PCR sequence-specific primers. When compared with the healthy controls, the frequency of IL-4 -1098 TG and -590 CT genotypes was higher in the patients with BD. Analysis of allele frequencies showed that IL 4 -1098 G and IL-4 -590 T alleles were more common in the patients with BD when compared with healthy controls. Also, IL-4 TTC and haplotypes were found to confer BD. Interestingly, we demonstrated that IL-4Ralpha gene polymorphism seems to be associated with the Pathergy test positivity in patients with BD. Our data suggest that IL-4 gene promoter polymorphisms may affect susceptibility to BD and increase risk of developing the disease. However, in order to confirm and assess the association of IL-4 and IL-4Ralpha gene polymorphisms with the BD, large cohort studies are needed. PMID- 21323697 TI - Seventh European Workshop on Periodontology of the European Academy of Periodontology at the Parador at la Granja, Segovia, Spain. PMID- 21323698 TI - Periodontal infections: understanding the complexity--consensus of the Seventh European Workshop on Periodontology. AB - INTRODUCTION: Periodontal diseases are the pathological manifestation of the host response against the bacterial challenge from the dental biofilm at the tooth/gingival interface. The remit of this working group was to update the existing knowledge on the infectious nature of periodontal diseases. MATERIAL AND METHODS: The literature was systematically searched and critically reviewed. Four manuscripts were produced in specific topics identified as key areas to understand the importance of the microorganisms in the etio-pathogenesis of periodontal diseases. RESULTS/CONCLUSIONS: The results and conclusions of the review process are presented in the following papers, together with the group consensus statements aiming to answer the following questions: (1) Has the use of molecular methods for the characterization of the human oral microbiome changed our understanding of the role of bacteria in the pathogenesis of periodontal disease process? (2) Are the periodontal microbial complexes associated with specific cell and tissue responses? (3) How is the development of dental biofilms influenced by the host? (4) What can we learn about biofilm/host interactions from the study of inflammatory bowel disease? This consensus report provides answers to these questions with the most updated information on periodontal microbiology. PMID- 21323699 TI - Has the use of molecular methods for the characterization of the human oral microbiome changed our understanding of the role of bacteria in the pathogenesis of periodontal disease? AB - BACKGROUND: Only around half of oral bacteria can be grown in the laboratory using conventional culture methods. Molecular methods based on 16S rRNA gene sequence are now available and are being used to characterize the periodontal microbiota in its entirety. AIM: This review describes the cultural characterization of the oral and periodontal microbiotas and explores the influence of the additional data now available from culture-independent molecular analyses on current thinking on the role of bacteria in periodontitis. RESULTS: Culture-independent molecular analysis of the periodontal microbiota has shown it to be far more diverse than previously thought. A number of species including some that have yet to be cultured are as strongly associated with disease as those organisms traditionally regarded as periodontal pathogens. Sequencing of bacterial genomes has revealed a high degree of intra-specific genetic diversity. CONCLUSIONS: The use of molecular methods for the characterization of the periodontal microbiome has greatly expanded the range of bacterial species known to colonize this habitat. Understanding the interactions between the human host and its commensal bacterial community at the functional level is a priority. PMID- 21323700 TI - Periodontal microbial complexes associated with specific cell and tissue responses. AB - AIMS: In this review, we summarize data on the association between specific periodontal bacterial profiles and tissue gene/protein expression, generated from cell culture models and in vivo studies. MATERIAL AND METHODS: A PubMed search was conducted to identify publications related to the effects of periodontal microbiota on host cells/tissues. RESULTS AND CONCLUSIONS: The data indicate the presence of specific host tissue responses to particular microbial complexes, evident by differential regulation of gene or protein expression, ultimately resulting in distinct clinical phenotypes. Transcriptomic analyses showed that periodontal pathogens induce a small, "common core" of differentially regulated genes encoding for an inflammatory response, and a larger variable set of genes that may reflect pathogen-specific cellular responses. Limitations of available studies include (i) the unclear role of hundreds of subgingival species not yet investigated, (ii) the fact that in vitro studies utilizing single populations of oral cells challenged with mono-infections of planktonic bacteria may not adequately portray human periodontal diseases and (iii) the cross-sectional nature of most human studies that makes them inherently incapable of allowing temporal or causal inferences. Longitudinal studies in humans hold the potential to be superior to any model, but need to be adequately powered and controlled. PMID- 21323701 TI - How is the development of dental biofilms influenced by the host? AB - BACKGROUND: The host provides environmental conditions that support diverse communities of microorganisms on all environmentally-exposed surfaces of the body. MATERIALS AND METHODS: To review the literature to determine which properties of the host substantially influence the development of dental biofilms. RESULTS: The mouth facilitates the growth of a characteristic resident microbiota. The composition of the oral microbiota is influenced by temperature, pH, and atmosphere, as well as by the host defences and host genetics. In addition, the host supplies endogenous nutrients and a variety of surfaces for biofilm formation. In health, the resident oral microbiota forms a symbiotic relationship with the host, regulated by active host-microbe cross talk. This resident microbiota is sensitive to perturbations in the host environment, especially to changes in nutrient supply and pH, so that previously minor components of the microbiota can become more competitive (and vice versa), resulting in reorganization of biofilm community structure. CONCLUSION: The host environment dictates the composition and gene expression of the resident microbiota. Changes in oral environmental conditions can disrupt the normal symbiotic relationship between the host and its resident microbes, and increase the risk of disease. PMID- 21323702 TI - What can we learn about biofilm/host interactions from the study of inflammatory bowel disease. AB - OBJECTIVES: The aim of this review was to evaluate possible common pathogenic pathways and risk factors in inflammatory bowel disease (IBD) and periodontitis. MATERIALS AND METHODS: A MEDLINE-PubMed research was conducted. RESULTS: The pathogenesis of both diseases is multi-factorial leading to a substantial defect of the mucosal barrier, deregulation of the immune response and chronic inflammation of the mucosa. Environmental factors, particularly bacteria, are key factors in the pathogenesis of both diseases. Genetic predisposition is a key factor in the IBD pathogenesis, while a clear role of genetics in the pathogenesis of periodontitis is still unclear. The immune response in IBD is mediated by T lymphocytes as a consequence of a genetic trait associated with T cell deregulation. On the other hand, in periodontitis plasma cells and lymphocytes are the predominant cells in the chronic inflammatory lesion, with the presence of B cells being proportionally larger than T cells. CONCLUSION: IBD and periodontitis share several factors in their aetiology and pathogenesis, although they also have distinct characteristics. PMID- 21323703 TI - Host-response: understanding the cellular and molecular mechanisms of host microbial interactions--consensus of the Seventh European Workshop on Periodontology. AB - BACKGROUND: Major challenges in periodontology include understanding the pathophysiology, the interplay between various components of the host response, parallels with other diseases and identifying biomarkers of the disease. OBJECTIVES: Four reviews were compiled with the aim of better understanding: (1) the role of polymorphic nuclear leucocytes (PMNs), i.e. neutrophils; (2) the function of cytokine networks in the host response; (3) whether parallels exist with rheumatoid arthritis (RA); and (4) whether useful biomarkers currently exist to help in the management of periodontal disease. MATERIAL AND METHODS: Based on the focused questions, electronic and manual searches were conducted for human, animal and cellular studies on the above topics. RESULTS: Papers fulfilling the inclusion criteria were selected and reviews were written and reviewed and corrected before the academy meeting to produce consensus statements. CONCLUSION: The following consensus statements were produced. PMNs are important in the pathophysiology of periodontal disease but there is limited evidence on their much quoted destructive potential. Cytokine networks are enormously complex and we are really at the beginning of understanding their role in the disease process. RA has both similarities and marked differences to periodontal disease although the existing utilization of anti-cytokine therapies and other molecules in its treatment may have importance in periodontal disease therapy. Biomarkers for periodontal disease have yet to be completely defined but the ratio of receptor activator of NF-kappaB ligand to osteoprotegerin appears to be a biomarker test with utility for detecting bone destruction. PMID- 21323704 TI - How has neutrophil research improved our understanding of periodontal pathogenesis? AB - BACKGROUND: Neutrophils are the predominant cells responsible for host defence against bacterial infection. Loss of neutrophil defence, due either to deficient number or function, strongly predisposes to bacterial infections such as periodontitis. Yet, the neutrophil oxidative and proteolytic arsenal has also been implicated in perpetrating periodontal tissue damage in periodontitis. AIM: In this review, we focus on recent developments that shed light on these two aspects of neutrophil function in periodontitis. METHODS: Primary search: using PubMed search for "neutophil", "periodontal", and "periodontitis". Secondary search: using references from the articles found in the first stage. RESULTS: Early histological studies showed that infiltrating neutrophils form a wall of cells abutting the junctional epithelium in periodontal inflammatory lesions. The chronic standoff between these neutrophils and the bacterial community suggests that bacterial evasion of neutrophil clearance is a major characteristic of periodontitis. Indeed, not all functional neutrophil deficiencies increase the risk of periodontitis, an observation that points the way towards identification of particular anti-bacterial pathways essential for protection against periodontal pathogens. The net result in the majority of periodontitis patients who exhibit normal neutrophil number and function, is that neutrophils accumulate in the periodontal tissue where they are available to participate in tissue destruction. Diminished neutrophil clearance further contributes to the persistence of activated neutrophils in the periodontal tissue. CONCLUSIONS: Data on the role of neutrophils in the pathogenesis of periodontitis are mixed. Neutrophils are a critical arm of the defence against periodontitis, but bacterial evasion of the neutrophil microbicidal machinery coupled with delayed neutrophil apoptosis may transform the neutrophil from defender to perpetrator. At this stage of knowledge, attempts to induce host modulation through neutrophil suppression or activation are premature. PMID- 21323705 TI - How has research into cytokine interactions and their role in driving immune responses impacted our understanding of periodontitis? AB - OBJECTIVE: To review current knowledge on cytokine interactions and the cytokine mediated links between innate and adaptive immunity that are relevant to the pathophysiology of periodontitis. MATERIALS AND METHODS: A structured review of the literature was undertaken to identify relevant research publications using a Medline search from 1950 to September 2010. The focus of the search was on the functional role of cytokines, i.e. their actions and responses relevant to the pathogenesis of periodontal disease rather than more descriptive studies of their expression in tissues and body fluids. It was not possible to conduct a traditional systematic review with a focussed question due to the heterogeneity of published research. RESULTS: There is enormous heterogeneity in the periodontal literature in terms of experimental approaches. We have the deepest understanding of the role of the pro-inflammatory cytokines [e.g. interleukin (IL)-1beta, tumour necrosis factor-alpha, IL-6] with accumulating data on T-cell regulatory cytokines (e.g. IL-12, IL-18), chemokines and cytokines which mediate bone cell development and function (e.g. receptor activator of NF-kappaB ligand, osteoprotegerin). It is clear that there are multiple, overlapping and complex functional links between cytokines with regulatory control exerted at a number of levels and involving numerous cell types (both immune cells and resident cells in the periodontium). CONCLUSION: Cytokines appear to interact functionally in networks in the periodontium and integrate aspects of innate and adaptive immunity. However, our understanding is far from complete, particularly how molecular and cellular pathways relate to disease pathogenesis. We should adopt consistent experimental approaches to gain better insight into the totality of cytokine networks and how they drive immune responses in the periodontium. PMID- 21323706 TI - Host-derived diagnostic markers related to soft tissue destruction and bone degradation in periodontitis. AB - BACKGROUND: A major challenge in clinical periodontics is to find a reliable molecular marker of periodontal tissue destruction with high sensitivity, specificity and utility. OBJECTIVES: The aim of this systematic review is to evaluate available literature on 'the utility of molecular markers of soft and hard periodontal tissue destruction'. MATERIALS AND METHODS: Based on the focused question, 'What is the utility of molecular markers of soft and hard periodontal tissue destruction', an electronic and manual search was conducted for human studies presenting clinical data for the potential of molecular markers of tissue destruction in biofluids; gingival crevicular fluid (GCF), saliva, and serum. RESULTS: Papers fulfilling the inclusion criteria were selected. All relevant data from the selected papers were extracted and recorded in separate tables for molecules in GCF, saliva, and serum. CONCLUSION: Within the defined limits of the Problem/Population, Intervention, Comparison, Outcome, the present analysis reveals that (a) no single or combination of markers exists that can disclose periodontal tissue destruction adequately; (b) while the most fruitful source of biomarkers for periodontal destruction appears to be in molecules tightly related to bone and soft tissue destruction, this remains to be objectively demonstrated. Currently, clinical measurements are still the most reliable. PMID- 21323707 TI - What can the periodontal community learn from the pathophysiology of rheumatoid arthritis? AB - AIM: The aim of this paper is to provide a narrative review of the aetiopathogeneis and treatments of rheumatoid arthritis (RA), focusing on aspects that may share commonality with periodontitis. RESULTS: A myriad of cell types, cytokines and pathways have been investigated in both periodontitis and RA. Chronic inflammatory diseases, including RA, psoriatic arthritis, ankylosing spondylitis and periodontitis are likely to share pathogenic mechanisms of inflammation-mediated solid tissue destruction. The aetiopathogenesis of these diseases has been extensively researched over the last several decades and advances in understanding have revolutionized arthritis therapeutics. CONCLUSION: The rational, targeted inhibition of mediators in RA has provided clinically useful therapeutics and shed light on mechanisms underpinning disease pathogenesis. RA should be considered a prototypic disease revealing how understanding disease pathogenesis may transform therapeutic options and patient outcomes. PMID- 21323708 TI - Biological approaches to the development of novel periodontal therapies- consensus of the Seventh European Workshop on Periodontology. AB - BACKGROUND: Periodontitis remains a major public health issue and current management approaches have failed to impact upon the most high-risk proportion of the population and those with the most severe disease. The objective of this session was to assess if and how, current understanding of periodontitis provides the opportunity to develop new preventive and therapeutic strategies. MATERIALS AND METHODS: Based on the current understanding of the pathophysiology of periodontal diseases, the Workshop discussed the potential of antimicrobial peptides, probiotics, pro-resolving lipid mediators, and micronutritional approaches. Evidence-based position papers and expert discussions formed the basis of deliberations. RESULTS AND DISCUSSION: Current preventive and treatment approaches are only partially effective, and this appears due to the therapeutic focus remaining primarily upon biofilm management rather than embracing a pivotal role for inflammation as a driver of biofilm composition as well as tissue damage. There is a need to develop new, more effective, and efficient preventive and treatment approaches for gingivitis and periodontitis, which embrace recent advances in understanding of host modulation and inflammation resolution, as well as direct management of the microbiota. PMID- 21323709 TI - Proresolving lipid mediators: potential for prevention and treatment of periodontitis. AB - AIM: Periodontitis is an inflammatory disease initiated by microbial biofilm. The host response to the biofilm destroys the periodontium mediated by an overly robust inflammatory response in susceptible individuals. Whether the excessive host response is genetic, epigenetic or mediated by environment is unknown. New pathways of resolution of inflammation have been discovered. Resolution of inflammation is an active, agonist-mediated, programmed return to tissue homeostasis. MATERIALS AND METHODS: Various computer-based search engines were employed to identify papers relevant to resolution of inflammation. RESULTS: Recent data suggest that chronic inflammatory periodontal disease may be a failure of resolution pathways as well as overexpression of proinflammatory pathways. In this review, the biology of resolution of inflammation will be examined in normal tissues and periodontal disease. Anti-inflammatory pharmacologic agents [non-steroidal anti-inflammatory drugs (NSAIDs)] have been shown to prevent and slow the progression of periodontitis in animals and humans. However, the side effect profile of NSAIDS or other inhibitors or receptor antagonists preclude their use in periodontal therapy. CONCLUSION: The isolation and characterization of proresolving lipid mediators that are receptor agonists has opened a new area of research for potential therapeutic agents for the management of inflammatory periodontitis. PMID- 21323710 TI - Antimicrobial peptides and periodontal disease. AB - AIMS: The goal of this review is to identify the antimicrobial proteins in the oral fluids, saliva and gingival crevicular fluid and identify functional families and candidates for antibacterial treatment. RESULTS: Periodontal biofilms initiate a cascade of inflammatory and immune processes that lead to the destruction of gingival tissues and ultimately alveolar bone loss and tooth loss. Treatment of periodontal disease with conventional antibiotics does not appear to be effective in the absence of mechanical debridement. An alternative treatment may be found in antimicrobial peptides and proteins, which can be bactericidal and anti-inflammatory and block the inflammatory effects of bacterial toxins. The peptides have co-evolved with oral bacteria, which have not developed significant peptide resistance. Over 45 antibacterial proteins are found in human saliva and gingival crevicular fluid. The proteins and peptides belong to several different functional families and offer broad protection from invading microbes. Several antimicrobial peptides and proteins (AMPs) serve as templates for the development of therapeutic peptides and peptide mimetics, although to date none have demonstrated efficacy in human trials. CONCLUSIONS: Existing and newly identified AMPs may be developed for therapeutic use in periodontal disease or can serve as templates for peptide and peptide mimetics with improved therapeutic indices. PMID- 21323711 TI - Micronutritional approaches to periodontal therapy. AB - AIM: Periodontitis results from the loss of a delicate balance between microbial virulence factors and a proportionate host response. Nutritional factors have been implicated in several chronic inflammatory diseases that are associated with periodontitis. This manuscript reviews the evidence for nutritional exposures in the etiology and therapeutic management of periodontitis, and makes recommendations for daily nutritional intake for vitamin C (ascorbic acid), vitamin D, calcium, and antioxidants. RESULTS AND CONCLUSION: Periodontitis is associated with low serum/plasma micronutrient levels, which may result from dietary and/or life-style factors as well as nutrigenetic characteristics. Early evidence suggests beneficial outcomes from nutritional interventions; supporting the contention that daily intake of certain nutrients should be at the higher end of recommended daily allowances. For prevention and treatment of periodontitis daily nutrition should include sufficient antioxidants, vitamin D, and calcium. Inadequate antioxidant levels may be managed by higher intake of vegetables, berries, and fruits (e.g. kiwi fruit), or by phytonutrient supplementation. Current evidence is insufficient to support recommendations of mono-antioxidant vitamin supplements and randomised controlled double-blind intervention studies are needed to provide evidence to underpin future recommendations. Inadequate supply of vitamin D and calcium may be addressed by implementing changes in diet/life style or by supplements. PMID- 21323712 TI - Do probiotics offer opportunities to manipulate the periodontal oral microbiota? AB - BACKGROUND: As in other fields of healthcare, probiotics have been introduced for prevention and treatment of periodontal diseases. OBJECTIVE: This review was initiated to explore whether the use of probiotics can influence the periodontal microbiota and periodontal health. MATERIALS AND METHODS: Literature on the mode of action of oral probiotics was reviewed and a systematic review was performed on the microbiological and clinical effects of oral probiotics on periodontal health. RESULTS: Three animal and 11 in vivo human studies were retrieved. Six studies reported on microbiological effects whereas eight studies report on clinical effects. Seven studies were performed on healthy or gingivitis patients and four studies on periodontitis patients. Many of the retrieved studies are pilot in nature and with low quality. The high degree of heterogeneity between studies hampered analysis. CONCLUSION: Taking into consideration all limitations, the currently available data indicate an effect of probiotics on the oral microbiota and a more limited effect on clinical periodontal outcome measures. However, there is an urgent need for properly conducted clinical trials where probiotics are used as adjuncts to standard periodontal care, similar to antibiotics, using probiotic strains with, at least at an in vitro level, proven periodontal probiotic effects. PMID- 21323713 TI - Periimplant diseases: where are we now?--Consensus of the Seventh European Workshop on Periodontology. AB - BACKGROUND: Peri-implant diseases present in two forms - peri-implant mucositis and peri-implantitis. MATERIALS AND METHODS: The literature was systematically searched and critically reviewed. Four manuscripts were produced in specific topics identified as key areas to understand the microbial aetiology and the pathogenesis of peri-implant diseases and how the implant surface structure may affect pathogenesis. RESULTS: While peri-implant mucositis represents the host response of the peri-implant tissues to the bacterial challenge that is not fundamentally different from gingivitis representing the host response to the bacterial challenge in the gingiva, peri-implantitis may differ from periodontitis both in the extent and the composition of cells in the lesion as well as the progression rate. A self-limiting process with a "protective" connective tissue capsule developing appears to dominate the periodontitis lesion while such a process may occasionally be lacking in peri-implantitis lesions. Bacterial biofilm formation on implant surfaces does not differ from that on tooth surfaces, but may be influenced by surface roughness. Nevertheless there is no evidence that such differences may influence the development of peri implantitis. CONCLUSION: It was agreed that clinical and radiographic data should routinely be obtained after prosthesis installation on implants in order to establish a baseline for the diagnosis of peri-implantitis during maintenance of implant patients. PMID- 21323714 TI - Do mucositis lesions around implants differ from gingivitis lesions around teeth? AB - BACKGROUND: The purpose of this review was to compare peri-implant mucositis and gingivitis with respect to the pathogenesis aspects. SEARCH STRATEGY: An electronic search was performed up to June 2010 based on the PubMed database of the National Library of Medicine and The Cochrane Library of the Cochrane Collaboration (CENTRAL). A hand search considered the bibliography of a recently published review on the same topic (Heitz-Mayfield & Lang 2010). RESULTS: The host response to biofilms does not differ substantially at teeth or implants. The most obvious sign clinically is the development of an inflammatory lesion as a result of the bacterial challenge. Gingivitis at teeth or peri-implant mucositis at implants are precursors for more detrimental lesions, and hence have to be diagnosed properly and prevented by applying anti-infective therapy. Non-surgical interventions are usually sufficient for the treatment of both gingivitis and mucositis. CONCLUSIONS: Gingivitis and peri-implant mucositis are not fundamentally different from pathogenesis and diagnosis points of view. PMID- 21323715 TI - Are peri-implantitis lesions different from periodontitis lesions? AB - AIM: To compare histopathological characteristics of peri-implantitis and periodontitis lesions. METHODS: A search was conducted on publications up to July 2010. Studies carried out on human biopsy material and animal experiments were considered. RESULTS: While comprehensive information exists regarding histopathological characteristics of human periodontitis lesions, few studies evaluated peri-implantitis lesions in human biopsy material. Experimental peri implantitis lesions were evaluated in 10 studies and three of the studies included comparisons to experimental periodontitis. Human biopsy material: the apical extension of the inflammatory cell infiltrate (ICT) was more pronounced in peri-implantitis than in periodontitis and was in most cases located apical of the pocket epithelium. Plasma cells and lymphocytes dominated among cells in both types of lesions, whereas neutrophil granulocytes and macrophages occurred in larger proportions in peri-implantitis. EXPERIMENTAL STUDIES: placement of ligatures together with plaque formation resulted in loss of supporting tissues and large ICTs around implants and teeth. Following ligature removal, a "self limiting" process occurred in the tissues around teeth with a connective tissue capsule that separated the ICT from bone, while in peri-implant tissues the ICT extended to the bone crest. CONCLUSION: Despite similarities regarding clinical features and aetiology of peri-implantitis and periodontitis, critical histopathological differences exist between the two lesions. PMID- 21323716 TI - The characteristics of biofilms in peri-implant disease. AB - AIM: To describe the microbiota associated with peri-implant disease, with a specific emphasis on the differential diagnosis of the condition. MATERIAL AND METHODS: The potentially relevant literature was preliminarily assessed via scoping searches to find the most appropriate search terms and the most efficient Boolean search algorithm. We identified 29 reports on subjects with osseointegrated implants, with a pathological condition compatible with the definition of "peri-implant disease", and reporting microbiological data from samples taken in affected sites. RESULTS AND CONCLUSIONS: In most studies bacterial samples were obtained by methods that destroy the three-dimensional structure of the biofilm. The samples therefore describe mixtures of bacteria from unspecified districts of biofilm associated with peri-implant diseases. Analyses of such samples with various methods indicate that peri-implant disease maybe viewed as a mixed anaerobic infection. In most cases the composition of the flora is similar to the subgingival flora of chronic periodontitis that is dominated by Gram-negative bacteria. Peri-implant infections may occasionally be linked to a different microbiota, including high numbers of peptostreptococci or staphylococci. Beneficial effects of mechanical and chemical interventions to disrupt the peri-implant biofilm demonstrate that microorganisms are involved in the disease process, even if they may not always be the origin of the condition. PMID- 21323717 TI - How do implant surface characteristics influence peri-implant disease? AB - OBJECTIVES: To review the literature on how implant surface characteristics influence peri-implant disease. MATERIAL AND METHODS: A search of PubMed and The Cochrane Library of the Cochrane Collaboration (CENTRAL) as well as a hand search of articles were conducted. Publications and articles accepted for publication up to March 2010 were included. RESULTS: Thirteen studies were selected for the review. Human studies: To date, few studies have investigated if such differences occur. Limited data suggest that smooth surfaces may be less affected by peri implantitis than rough surface implants. Animal studies: In ligature-induced peri implantitis studies, no difference between surfaces has been reported. In a spontaneous progression model of peri-implantitis, there was a suggestion that the progression was more pronounced at implants with a porous anodized surface. CONCLUSION: The current review revealed that only a few studies provided data on how implant surfaces influence peri-implant disease. Based on the limited data available, there is no evidence that implant surface characteristics can have a significant effect on the initiation of peri-implantitis. PMID- 21323719 TI - Molecular-microscopical correlation in dermatopathology. PMID- 21323720 TI - Fillet of FISH. PMID- 21323721 TI - Fluorescence in situ hybridization as an ancillary method for the distinction of desmoplastic melanomas from sclerosing melanocytic nevi. AB - The histopathologic distinction of desmoplastic melanomas from sclerosing (desmoplastic) melanocytic nevi can be difficult, especially when evaluating a partial or superficial biopsy. In the study reported herein, we applied and explored the use of a novel ancillary method, a four-probe fluorescence in situ hybridization (FISH) assay targeting RREB1, MYB, Cep6 and CCND1, to this diagnostic problem. Fifteen sclerosing melanocytic nevi, including desmoplastic Spitz nevi, conventional nevi with prominent stromal sclerosis and sclerotic blue nevi, as well as 15 examples of desmoplastic melanoma, were examined. None of the sclerosing melanocytic nevi showed a level of chromosomal aberrations that met FISH criteria for melanoma. Seven of the 15 desmoplastic melanomas were 'positive' (had documented chromosomal aberrations) by FISH. Thus, a positive FISH test strongly supports the diagnosis of melanoma in this context. However, in this setting a negative FISH test is of limited diagnostic value. Our findings suggest that prior reports about the high sensitivity of the FISH test for melanoma diagnosis need to be adjusted according to melanoma subtype. PMID- 21323722 TI - Multifocal cutaneous epithelioid angiomatous nodules of the penis. AB - Cutaneous epithelioid angiomatous nodule (CEAN) represents a recently described benign vascular proliferation. We report a case affecting a 28-year-old man who presented with painful nodules on his glans penis. The patient is symptom-free 18 months after tumor excision. This is the first report of CEAN occurring on the glans penis. PMID- 21323724 TI - A comparison between jerk-cost derived from a jaw-tracking system with that from an accelerometer. AB - Jerk-cost is an inverse measure of movement smoothness and can be calculated from the first-time derivative of acceleration obtained from a tri-axial piezoelectric accelerometer (TPA), or from the third-time derivative of position obtained from a jaw-tracking device. The aims of this study were to determine, in 10 asymptomatic subjects who are chewing gum, (i) jerk-cost measures derived from displacement/time data obtained from the JAWS3D jaw-tracking device and from acceleration data obtained from a TPA used in the same jaw movement recordings, (ii) whether there was a significant relationship between jerk-cost measures derived from both devices and (iii) the degree of agreement between the two measures. Jerk-cost data were calculated in the opening phase, the closing phase, and over the full chewing cycle as the first-time derivative from acceleration obtained from the TPA, and the third-time derivative from JAWS3D for each of the X-, Y- and Z-direction series. There was a significant correlation between both measures of jerk-cost over the full chewing cycle and during jaw-opening (r = 0.65, 0.75, respectively; P < 0.001). There was no significant correlation in the closing phase (r = -0.02, P = 0.99). The Bland-Altman test showed that jerk-cost derived from the JAWS3D can differ by up to 78% below and 21% above that derived from the TPA. These results suggest that jerk-cost measures derived from a jaw tracking system cannot substitute for jerk-cost measures derived from an accelerometer. PMID- 21323725 TI - Differential expression of gastrointestinal glutathione peroxidase (GI-GPx) gene during mouse organogenesis. AB - Gastrointestinal glutathione peroxidase (GI-GPx) is an antioxidant enzyme that has been known to be restricted to the gastrointestinal tract in rodents. In an effort to determine the expression pattern of GI-GPx mRNA during organogenesis, quantitative real-time PCR and in situ hybridization for GI-GPx mRNA were conducted in whole embryos or each developing organ of mice. GI-GPx mRNA was expressed more abundantly in the extraembryonic tissues, including placenta than in embryos on embryonic days (EDs) 7.5-18.5 (P < 0.05). When compared with the expression levels of cytosolic GPx (cGPx) mRNA, GI-GPx mRNA levels were low in the embryos, but relatively high in the extraembryonic tissues (P < 0.05). According to the results of whole mount in situ hybridizations, GI-GPx mRNA was principally expressed in the ectoplacental cone, neural tube and fold, and primitive heart at EDs 7.5-8.5. At EDs 9.5-12.5, GI-GPx mRNA was abundantly expressed in nervous tissues such as the telencephalon, mesencephalon and dorsal neural tube and was also detected in the forelimb and hindlimb at EDs 10.5-12.5. In the sectioned embryos after ED 13.5, GI-GPx mRNA levels were high in the cerebral cortex, metanephric corpuscle, pancreatic ducts, surface epithelia of the skin, inner ear, and nasal conchae, gastrointestinal tract, liver, urinary bladder, airway passages of lung, and whisker follicles. These findings indicate that GI-GPx is not only spatiotemporally expressed in a variety of embryonic organs during organogenesis but also may perform a mutual compensatory role with the cGPx in the protection of embryos and extraembryonic tissues against the reactive oxygen species generated in ontogenetic periods. PMID- 21323726 TI - Early induction of interleukin-5 and peripheral eosinophilia in acute pneumonia in Japanese children infected by pandemic 2009 influenza A in the Tokyo area. AB - A novel influenza A (2009 H1N1) virus has led to a worldwide pandemic. A significant number of patients with pneumonia have been reported, although its pathogenesis remains to be elucidated. To determine its pathogenesis, we evaluated serum interleukin (IL)-5 and peripheral eosinophil counts in patients with acute pneumonia caused by the 2009 H1N1 virus. During the period from October to December 2009, 40 patients with laboratory-confirmed 2009 H1N1 pneumonia were under investigation. Their mean age at presentation was 6.8 years. The most characteristic finding was the early development of hypoxemic respiratory distress in the first 24 hr after the onset of fever. Bronchial mucous plugs included eosinophils in addition to neutrophils, even in patients without allergies. Serum IL-5 levels were elevated in 20 out of 24 patients (83%) whose samples were obtained in the first 24 hr after the onset of fever (26.5 +/- 20.1 pg/mL), independent of the presence of underlying allergies. In contrast, induction of IL-5 was not documented in sera from eight patients with laboratory confirmed 2009 H1N1 virus who developed neurological complications, but without lower respiratory infection (2.1 +/- 0.7 pg/mL, P < 0.001 vs acute pneumonia). Peripheral eosinophilia was characteristic in acute pneumonia, but not in patients without a lower respiratory infection. There was a marked difference in the induction of IL-5 in 2009 H1N1 patients who developed acute pneumonia, compared with those without a lower respiratory infection. IL-5 may play a role in the early phase of acute pneumonia caused by the 2009 H1N1 virus in Japanese children. PMID- 21323727 TI - Neonatal pulse oximetry screening: a national survey. AB - AIM: Studies suggest that universal pulse oximetry (PO) screening of all neonates before hospital discharge improves the detection rate of congenital heart disease (CHD). The aim is to survey the use of Pulse Oximetry (PO) screening in UK. METHODS: A telephone interview was conducted between late 2009 to mid-2010 of all maternity units using a standardised questionnaire. RESULTS: 209(93%) of 224 responding units did not routinely use PO. Among the 15 that performed PO, 5 measured pre and post ductal saturations, 9 measured only post-ductal saturations, and 1 measured only pre-ductal saturations. There were differences in the values used to trigger further investigation, ranging from <94% to <96% and/or difference of > 2-3% between pre and post-ductal saturations. When saturations were abnormal, 13 units performed echocardiography locally. In addition to an echocardiogram, 2 units performed chest x-ray (CXR); 2 units performed electrocardiogram (ECG) and 2 units performed both CXR and ECG. CONCLUSION: Only a minority of hospitals across the UK use PO to supplement the postnatal examination with inconsistent practice. National guidelines should be developed if PO screening is implemented with an agreed management plan if abnormal results are obtained. PMID- 21323728 TI - Comparing sleep measures of infants derived from parental reports in sleep diaries and acceleration sensors. AB - AIM: Comparing sleep measures of infants derived from two data collection methods, acceleration sensors and sleep diaries, and identify the clinical application for each data collection method. METHODS: The participants were 52 pairs of infants and mothers. Infant sleep measures were obtained through the actigraphs (Micro-mini RC, Ambulatory Monitoring Inc., Ardsley, NY, USA) and sleep diaries for over a period of 7 days. RESULTS: The results showed that the concordance in sleep measures derived from two methods showed decreases in the following order: sleep offset time [r=0.91 (p=0.00)], sleep onset time r=0.89 (p=0.00), nocturnal sleep duration [r=0.75 (p=0.00)], the number of night wakings [r=0.46 (p<0.01)] and WASO [r=0.34 (p<0.05)]. It was revealed that the accuracy of sleep diary records was affected by the sleeping place and varied throughout the study period. CONCLUSION: It was confirmed that the sleep measures indicating sleep schedule reported from the sleep diaries had high concordances compared with the data from the actigraphs. Using the sleep diary was recommended to understand behaviours when focusing on infant's daily rhythms. In terms of accuracy and stability of recording throughout the study period, understanding sleep quality and independence of sleeping places, the choice of actigraph was recommended. PMID- 21323730 TI - Applications of the multifocal electroretinogram in the detection of glaucoma. AB - Glaucoma is one of the most important eye diseases resulting in blindness worldwide. It affects the inner retina and is without signs and symptoms in the early stages, making early detection of glaucoma important for eye care professionals. Electroretinography (ERG) is an objective technique used to measure retinal electrical responses, which directly reflect retinal function. The multifocal electroretinogram (mfERG) is a relatively new tool in this area. Various modifications of the mfERG stimulation paradigms such as fast flicker, low contrast, slow sequence, global flash and luminance-modulation have been developed in recent years. Using these techniques and a better understanding of the mfERG characteristics has resulted in greater effectiveness of the mfERG in the diagnosis of glaucoma. It is likely that sensitive clinical mfERG measurement protocols for early detection of glaucomatous damage will be possible in the near future. PMID- 21323729 TI - Natural history of chronic hepatitis B REVEALed. AB - Chronic hepatitis B is a worldwide public health challenge. Knowledge of natural history of chronic hepatitis B is important for the management of the disease. A community-based prospective cohort study was carried out to evaluate the risk predictors of progression of chronic hepatitis B in Taiwan. A total of 23,820 participants were enrolled in 1991-1992 from seven townships in Taiwan. Their serum samples were collected at study entry and tested for hepatitis B surface antigen (HBsAg) and e antigen (HBeAg), antibodies against hepatitis C virus (anti HCV), alanine aminotransferase (ALT), and alpha-fetoprotein (AFP). A subcohort of 3653 male and female participants who were seropositive for HBsAg and seronegative for anti-HCV was included in the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV) study. Newly developed cases of cirrhosis and hepatocellular carcinoma (HCC) were ascertained through follow-up examination and data linkage with profiles of the National Cancer Registry, National Health Insurance Database and Death Certification System. The incidence of both HCC and cirrhosis were significantly associated with serum HBV DNA levels in a dose-response relationship from <300 (undetectable) to >=1,000,000 copies/mL. The biological gradients remained significant (P<0.001) after adjustment for age, sex, habits of cigarette smoking and alcohol drinking, HBeAg serostatus, and serum ALT level at cohort entry. A significant association with risk of cirrhosis and HCC was also observed for HBV genotype, precore G1896A mutant and basal core promoter A1762T/G1764A double mutant. Nomograms have been developed for the long-term risk prediction of cirrhosis and HCC for patients with chronic hepatitis B. Inactive carriers of HBV have an increased HCC incidence and liver-related mortality than HBsAg seronegative controls. Serum HBV DNA level at study entry is a major predictor of spontaneous seroclearance of HBeAg, HBV DNA and HBsAg. These findings may inform the effective and efficient management of chronic hepatitis B. PMID- 21323731 TI - Prevalence of diabetic retinopathy in patients with recently diagnosed diabetes mellitus. AB - BACKGROUND: The severity of diabetic retinopathy is well known to have a close association with the duration of diabetes mellitus. Patients with recently diagnosed diabetes should have adequate eye examinations to eliminate the possibility of diabetic retinopathy being present because there is no accurate means of determining the duration of the disease. The prevalence of diabetic retinopathy in type 2 diabetic patients with known duration up to one year was investigated in the present study. METHODS: A centre for diabetic retinopathy screening was set up in a community in Hong Kong. The screening procedures included history taking, visual acuity measurement, anterior ocular health assessment and retinal examination by fundus photography. Fundus photographs were taken in nine different positions of gaze through natural or dilated pupils. Using the criteria recommended by the American Optometric Association the retinopathy was graded in severity. 'Recently diagnosed diabetes mellitus' was defined as having diabetes diagnosed by a physician within the previous year. RESULTS: A total of 12,112 patients having their first visits to the centre were recruited from 2006 to 2009. Among them, 3,510 patients had recently diagnosed diabetes. The mean age of patients was 59.5 years. The prevalence of diabetic retinopathy was 18.2 per cent (639 patients) among the recently diagnosed diabetic patients. Most of the patients had mild non-proliferative diabetic retinopathy. In these 639 patients, approximately seven per cent had sight threatening retinopathy that included significant macular oedema, all of whom required monitoring. The presence of hypertension or smoking was not significantly associated with the prevalence of diabetic retinopathy in recently diagnosed diabetic patients. CONCLUSIONS: Screening for diabetic retinopathy is important for newly diagnosed diabetic patients. In Hong Kong, the prevalence of diabetic retinopathy was alarmingly high and some patients had already developed sight-threatening retinopathy that included macular oedema. Most of them had no symptoms until the retinopathy progressed and they developed macular oedema. A systematic screening program in the community is needed for early detection and to reduce blindness in diabetic patients. PMID- 21323732 TI - Constancy of the Orbscan acoustic factor to detect contact lens-induced corneal swelling. AB - PURPOSE: The aim of the present study was to compare central and peripheral corneal thickness measurements in corneas with and without contact lens (CL) induced corneal swelling, in order to establish the constancy of the Orbscan acoustic factor (AF) for reliability in detection of CL-induced corneal swelling. METHODS: Corneal thickness was measured in five corneal locations (central, superior, inferior, nasal and temporal) using both ultrasonic and Orbscan pachymetry before and after one week of high Dk (lotrafilcon A) and low Dk (etafilcon A) contact lens continuous wear (CW). Lenses were randomly fitted for CW in the right and left eyes of 20 healthy subjects to induce various amounts of corneal swelling. RESULTS: Etafilcon A contact lenses induced greater corneal swelling than the lotrafilcon A contact lenses (p < 0.05, paired Student t-test). Equal corneal swelling percentages (with and without the application of the acoustic factor) were determined from Orbscan measurements. Application of the 0.92 AF did not permit adjustment to all corneal locations. The correlations between Orbscan with and without the 0.92 AF and ultrasonic pachymetry were higher for central pachymetry (r2 > 0.88; p < 0.01) and lower for peripheral pachymetry (r2 < 0.58; p < 0.01) with similar trends in corneas with and without CL-induced swelling. CONCLUSIONS: The acoustic factor proposed by the manufacturer to obtain corneal thickness with the Orbscan compared with those from ultrasonic pachymetry was not valid for all corneal topographic positions. The AF is unnecessary when determining CL-induced corneal swelling. PMID- 21323733 TI - Ocular refractive and biometric characteristics in patients with thalassaemia major. AB - BACKGROUND: Thalassaemia major is associated with characteristic findings in craniofacial bony structures and thereby may render abnormal bony orbit and subsequently distinctive ocular biometry. The purpose of the present study was to evaluate the ocular refractive and biometric characteristics in patients with thalassaemia major. METHODS: This case-controlled study comprised 94 eyes of 47 patients with thalassaemia major and 88 eyes of 44 age- and sex-matched healthy control subjects. All participants had a complete ocular examination including slitlamp biomicroscopy, fundoscopy, ocular biometry, keratometry, refraction and analysis using Fourier transformation. RESULTS: There were no significant differences in spherical equivalent (p = 0.66) and total astigmatism (p = 0.83) between groups. Mean uncorrected vision and visual acuities (logMar) were similar (p = 0.32 and p = 0.71, respectively). Compared with controls, thalassaemic patients had a shorter axial length (23.01 +/- 0.12 [SEM] mm versus 23.46 +/- 0.12 mm, p = 0.035), thicker crystalline lens (4.01 +/- 0.11 mm versus 3.87 +/- 0.1 mm, p = 0.046) and steeper average keratometry (44.02 +/- 0.24 D versus 43.44 +/- 0.24, p = 0.03). Fifty-seven per cent of thalassaemic patients had against the-rule astigmatism (total), while 64.6 per cent of controls showed a with-the rule pattern (p < 0.05). These patterns were also found for corneal astigmatism. The magnitudes of total, corneal and lenticular astigmatism were similar among groups. Regression analysis showed significant correlation between corneal (J0 and J45) and total (J0 and J45) astigmatism. The correlations were less prominent between lenticular and total J0 and J45. The mean intraocular pressure was 14.68 +/- 0.27 mmHg and 13.3 +/- 0.26 mmHg in the thalassaemia and control groups, respectively (p < 0.001). Six eyes (12.8 per cent) of four patients in the thalassaemia group had posterior subcapsular cataract, while the condition had not been observed in controls (p = 0.049). CONCLUSIONS: Shorter axial length, thicker lens, steeper corneal curvature and more against-the-rule pattern were characteristic findings in patients with thalassaemia major. PMID- 21323734 TI - Massive cardiac fibroma. AB - Nonmyxomatous tumors of the heart are exceedingly rare in adults. We report a case of symptomatic, massive, right ventricular cardiac fibroma found in an adult. Despite multiple (preoperative) biopsies, diagnosis was made only after surgical excision. PMID- 21323735 TI - Risk of de novo hepatitis in liver recipients from hepatitis-B core antibody positive grafts - a systematic analysis. AB - SkagenMany transplant programs utilize liver grafts from hepatitis-B core antibody (HBcAb)-positive and hepatitis-B surface antigen (HBsAg)-negative donors. However, there is risk for de novo hepatitis B (DNH) in recipients of these grafts. We reviewed 26 studies reporting the rates of DNH in recipients receiving HBcAb-positive liver grafts. Four hundred and sixty-two donor-recipient pairs were included to evaluate the risk of DNH stratified by the recipient's immune status to hepatitis B and type of prophylactic therapy given, if any. The rate of DNH was highest (58%) in the stratum of hepatitis-B (HBV) naive recipients who did not receive prophylaxis. In HBV naive recipients, prophylactic therapy (lamivudine and/or hepatitis-B immunoglobulin - HBIG) reduced DNH to 11% (odds ratio [OR] = 11.1, 95% CI 4.98-25, p < 0.0001 for DNH without prophylaxis). Recipients with hepatitis-B surface antibody (HBsAb) positivity had DNH rates of 18% without prophylaxis and 0% with prophylaxis (OR = 9.2, 95% CI 1.1-83.3, p = 0.039). Recipients with both HBsAb and HBcAb positivity had DNH rates of 4% without prophylaxis and 3% with prophylaxis (p = 1.00), while recipients with HBcAb positivity alone had DNH rates of 14% without prophylaxis and 3% with prophylaxis (p = 0.21). There was no significant difference between the types of HBV prophylaxis received whether lamivudine, HBIG or both. However, in the subgroup who received HBIG alone, rates of DNH were higher after cessation of HBIG prophylaxis compared to DNH rates with indefinite HBIG (p = 0.0002). In summary, the risk of DNH is highest for HBV naive liver recipients from HBcAb positive donors. Recipients who are HBV naive as well as those recipients with isolated HBsAb positivity derive significant benefit from HBV prophylaxis after transplantation with a HBcAb-positive graft. The ideal prophylactic regimen for prevention of DNH is unclear, but based on our analysis of the literature, antivirals alone may suffice. More data are needed with the newer antivirals for hepatitis B. PMID- 21323736 TI - A health economic analysis of clinical islet transplantation. AB - Islet cell transplantation is in clinical development for type 1 diabetes. There are no data on the cost in relationship to its benefits. We performed a cost effectiveness analysis and made a comparison with standard insulin therapy, using Markov modeling and Monte Carlo simulations. The patient population was adults aged 20 yr suffering from hypoglycemia unawareness. Data were estimates from literature and clinical trials: costs were based on the situation in the United States. For insulin therapy, cumulative cost per patient during a 20-yr follow-up was $663,000, and cumulative effectiveness was 9.3 quality-adjusted life years (QALY), the average cost-effectiveness ratio being $71,000 per QALY. Islet transplantation had a cumulative cost of $519,000, a cumulative effectiveness of 10.9 QALY, and an average cost-effectiveness ratio of $47,800. During the first 10 yr, costs for transplantation were higher, but cumulative effectiveness was higher from the start onwards. In sensitivity analyses, the need for one instead of two transplants during the first year did not affect the conclusions, and islet transplantation remained cost-saving up to an initial cost of the procedure of $240,000. This exploratory evaluation shows that islet cell transplantation is more effective than standard insulin treatment, and becomes cost-saving at about 9-10 yr after transplantation. PMID- 21323737 TI - Fatigue in adult patients with primary immune thrombocytopenia. AB - BACKGROUND: Patients with primary immune thrombocytopenia (ITP) commonly describe symptoms of fatigue. However, hematologists rarely consider fatigue a manifestation of ITP. OBJECTIVES: To document the prevalence of fatigue among patients with ITP and to determine the patient characteristics that are associated with fatigue. Using a cross-sectional design, we surveyed 1871 members of the UK ITP Support Association [585 (31%) responded], and 93 patients enrolled in the Oklahoma (US) ITP Registry [68 (73%) responded] with questions about their ITP and with validated symptom assessment scales for fatigue, daytime sleepiness, and orthostatic symptoms. RESULTS: The prevalence of fatigue among both UK (39%) and US (22%) patients was significantly greater than expected compared with normal subjects (P<0.0001 and P<0.0001 respectively). In univariate analysis of the combined cohorts, fatigue was associated with a platelet count <100000/MUL, treatment with steroids, bleeding symptoms, presence of other medical conditions, daytime sleepiness, and orthostatic symptoms. Fatigue was not associated with age, gender, duration of ITP, or splenectomy status. Multivariate analysis of the combined cohorts was stratified for the presence or absence of bleeding symptoms. Among 107 patients with bleeding symptoms, fatigue was independently associated with a platelet count <100000/MUL and female gender. Among 491 patients without bleeding symptoms, fatigue was independently associated with a platelet count <30000/MUL, presence of other medical conditions, daytime sleepiness, and orthostatic symptoms. CONCLUSIONS: Fatigue is a common symptom among patients with ITP. These data provide the basis for future studies to define the clinical importance of fatigue in ITP. PMID- 21323739 TI - Multiple myeloma: interplay between osteoblastogenesis and adipogenesis. PMID- 21323738 TI - Analysis of CLLU1 expression levels before and after therapy in patients with chronic lymphocytic leukemia. AB - OBJECTIVE: Chronic lymphocytic leukemia (CLL) is incurable, but therapy leading to eradication of minimal residual disease (MRD) in CLL is associated with improved clinical outcomes. CLL upregulated gene 1 (CLLU1) is solely upregulated in CLL patient samples. We hypothesized that CLLU1 could be used to monitor for residual disease in CLL patient samples after therapy. METHODS: We examined whether the CLLU1 real-time quantitative PCR (RQ-PCR) could detect small numbers of CLL cells in mixtures of normal peripheral blood mononuclear (PBMC) cells. We then performed a retrospective analysis on time-matched cryo-preserved specimens from patients who achieved MRD-negative remissions that underwent serial marrow biopsies for evaluation of residual disease by 4-color flow cytometry. RNA from PBMC samples collected at the time of the marrow assessments was analyzed for CLLU1. Nine patients underwent a total of 46 paired blood and marrow evaluations (median 5 assessments per patient). RESULTS: CLLU1 RQ-PCR on PBMCs of healthy donors reconstituted with varying amounts of CLL cells demonstrated leukemia cells could be reliably detected with high sensitivities depending on the CLLU1 expression level. Analysis of time-matched samples assessed for CLLU1 levels in the blood by RQ-PCR and residual disease of the marrow determined by 4-color flow cytometry revealed a correlation coefficient of 0.96 (P < 0.0001). CONCLUSION: The CLLU1 RQ-PCR is a sensitive and specific assay for detecting residual CLL cells after therapy. Assessment of blood CLLU1 levels can be used as a reliable marker of tumor burden and has the potential to complement currently used techniques for MRD monitoring in patients with CLL. PMID- 21323740 TI - Autonomic nervous system in individuals with cerebral palsy: a controlled study. AB - BACKGROUND: Disturbances in homeostatic functions have been observed in individuals with cerebral palsy (CP), possibly resulting from autonomic dysfunction. Salivary flow rate and saliva composition are controlled by the autonomic nervous system, and CP individuals exhibit alterations in salivary parameters that suggest autonomic impairment. This study aimed to investigate cardiac parameters as indicative of autonomic disturbances, possibly associated with salivary changes observed in CP individuals. METHODS: Ninety individuals with CP were compared with 35 sibling volunteers with no neurological damage (CG). Twenty-four-hour ECG/Holter monitoring (SEER((r)) Light; GE Medical Systems, Milwaukee, WI, USA) and 12-lead electrocardiographic recordings were performed on the CP and control groups. Total saliva was collected, and the salivary flow rate and total protein concentration were determined. RESULTS: Cerebral palsy (CP) individuals presented a significant reduction in salivary flow rate (P < 0.01) and increased protein concentrations (P < 0.01) compared to CG. Twenty-four-hour Holter ECG analysis showed differences for high frequency (HF), low frequency (LF) and LF/HF ratio between the groups, with the CP group presenting higher HF and LF values and lower LF/HF. Electrocardiographic parameters showed a statistically significant difference for heart rate, and its correlates, and mean corrected QT interval between the groups studied (P < 0.05). Snoring was frequent among CP patients. ECG and autonomic changes were independently associated with CP. CONCLUSION: Individuals with cerebral palsy present cardiovascular changes principally manifested as disturbed sympathovagal balance. These autonomic dysfunctions could contribute to the salivary changes observed. PMID- 21323741 TI - Nuclear beta-catenin expression in basal cell adenomas of salivary gland. AB - BACKGROUND: Nuclear localization of beta-catenin is known in a wide variety of human neoplasms; however, there are few reports in basal cell adenoma of the salivary gland. Our objective was to confirm the nuclear localization of beta catenin in basal cell adenoma and to examine whether nuclear beta-catenin expression could be a useful marker in the diagnosis of basal cell adenoma. METHODS: To evaluate the nuclear localization of beta-catenin in basal cell adenomas, immunohistochemistry (IHC) and mutation analysis of CTNNB1 were performed in 22 and 21 cases, respectively. Mutation analysis of CTNNB1 in exon 3 was performed by DNA direct sequencing. In a comparative study, IHC for beta catenin was also performed in 157 other salivary gland tumors. RESULTS: Nuclear beta-catenin expression was examined in 22 basal cell adenomas; scores were 2+ in 18 cases (81.8%), 1+ in three cases (13.6%), and 0 in one case (4.5%). Expression was localized in the basaloid myoepithelial cells. CTNNB1 mutation analysis was performed in 21 basal cell adenomas; mutations, including I35T and T41P, were detected in 11/21 (52%) cases. In comparison with other salivary gland tumors, one of three basal cell adenocarcinomas showed nuclear beta-catenin expression, whereas there was no nuclear beta-catenin expression in 154 other salivary gland tumors. CONCLUSIONS: We demonstrated nuclear beta-catenin expression and activation of the CTNNB1 gene in basal cell adenoma. Although nuclear beta catenin expression may be unable to distinguish basal cell adenoma from basal cell adenocarcinoma, it should be a helpful marker in the diagnosis of basal cell adenoma. PMID- 21323742 TI - Expression of host defence peptides in the lip vermilion mucosa during early infancy. AB - Emerging resistance to antibiotics has become a major problem. Host defence peptides (HDPs), which are effector molecules of the innate immune system, show broad antimicrobial activity. Synthetic derivates are currently being investigated as new anti-infectious agents. In infants, the use of conventional antibiotics is limited to a few substances because of adverse reactions. The new HDP substances might become alternatives to conventional antibiotics, but knowledge of the physiological quantities of the HDPs in infants is essential because of a narrow therapeutic index of currently available derivates. This study compares the mRNA levels of five major HDPs between infants and adults to test the hypothesis that HDP gene expression differs between these groups. Expression profiles of human beta-defensin (hBD)-1, hBD-2 and hBD-3, psoriasin and RNase 7 were assessed in the lip vermilion mucosa of infants (n = 15) and adult controls (n = 15) using real-time polymerase chain reaction. A significantly lower expression of hBD-2 (P = 0.043), hBD-3 (P = 0.014) and psoriasin (P = 0.018) was found in infants. No difference between the groups was noted with respect to transcript levels of hBD-1 and RNase 7. In conclusion, several HDPs are expressed at lower levels in infants, but not all. The results emphasize the need to adjust the dose of agents based on the specific HDP level for the treatment of infantile infections. PMID- 21323743 TI - Expression of keratins in cutaneous epithelial tumors and related disorders- distribution and clinical significance. AB - Keratins are a highly diverse family of cytoskeletal proteins and important markers of epithelial cell differentiation. In this review, applying the new keratin nomenclature recently introduced, we summarize and discuss the distribution and significance of keratin patterns in cutaneous epithelial tumors in relation to the epithelial structures of normal human skin. The available literature data show that the analysis of keratin profiles broadens our understanding of the differentiation, nature and histogenetic origin of the various, highly singular epithelial tumors arising in the skin. Moreover, keratins may aid in histological diagnosis and, in certain instances, may be helpful for the recognition of tumor malignancy and aggressiveness. Furthermore, we briefly address the topic of keratin-related skin disorders. PMID- 21323744 TI - A new star on the H2O2rizon of wound healing? AB - A breakthrough finding has shown that hydrogen peroxide (H(2)O(2)) gradients contribute to recruit leucocytes to the wound site during the inflammatory phase of healing. It was in 1992 that NO was awarded 'molecule of the year' because of the discovery that such a tiny chemical may act as an important signalling molecule, thereby influencing research over decades. We speculate that H(2)O(2) also has the potential to have a broad impact on research over years, especially in mammalian wound healing. To justify our hypothesis, we provide evidence from the literature on (i) how H(2)O(2) gradients are created, (ii) how H(2)O(2) acts in the physiological phases of wound healing and (iii) a possible role of H(2)O(2) in bacterial defense - bacterial colonization being one of the major problems in chronic wounds. Based on this, we provide the first overview on how H(2)O(2) acts during the different wound healing phases. PMID- 21323745 TI - Cyclosporin A, but not everolimus, inhibits DNA repair mediated by calcineurin: implications for tumorigenesis under immunosuppression. AB - Unlike other immunosuppressive drugs including everolimus, cyclosporin A causes a dramatic increase of UV-induced skin cancer, a feature that is reminiscent of xeroderma pigmentosum (XP), where defective nucleotide excision repair (NER) of UV-induced DNA damage results in cutaneous carcinogenesis. The molecular basis of the clinically important differential activities of cyclosporin A and everolimus is still unclear. We measured post-UV cell survival of cyclosporin A- and everolimus-treated human fibroblasts and lymphoblasts using a cell proliferation assay (MTT). The cellular NER capacity was assessed by host cell reactivation. Using an ELISA and specific antibodies, cyclobutane pyrimidine and pyrimidine-6,4 pyrimidone photoproduct removal from the cellular genome was measured. The effect of calcineurin on NER was investigated using a calcineurin A expression vector and specific RNAi. Cyclosporin A led to a dose dependent decrease in post-UV cell survival, inhibited NER and blocked photoproduct removal. In contrast, none of these effects where seen in everolimus-treated cells. Overexpression of calcineurin A resulted in increased NER and complemented the Cyclosporin A induced reduction of NER. Downregulation of calcineurin using RNAi inhibited NER comparable to cyclosporin A-treatment. We conclude that cyclosporin A, but not everolimus, leads to an increased skin cancer risk via a calcineurin signalling dependent impairment of NER. PMID- 21323746 TI - In vivo response of GsdmA3Dfl/+ mice to topically applied anti-psoriatic agents: effects on epidermal thickness, as determined by optical coherence tomography and H&E staining. AB - This study evaluated in vivo the potential of optical coherence tomography (OCT) to determine changes in thickness of the epidermis in response to the topically applied anti-psoriatics betamethasone dipropionate (BD), salicylic acid (SA) and also fish oil (FO). GsdmA3Dfl/+ mice have an inflammatory hair loss phenotype that includes hyperproliferation and epidermal thickening, hence a potential psoriasis model. Changes in epidermal thickness were evaluated over a period of 10 days, with the mice treated with combined BD + SA, FO + SA and BD + FO + SA. The data were validated with conventional measurement using H&E staining coupled with microscopy. Initial baseline measurement revealed an average epidermal thickness of 26.92 +/- 1.17 MUm. After 10 days of treatment with BD, the average epidermal thickness was reduced by 38.8% (P = 0.0001), and inversely, treatment with FO resulted in an unexpected 105% increase (P = 0.0001) in epidermal thickness. Combined BD + FO treatment did not cause any significant change (P = 0.3755) and may further indicate opposing effects on keratinocyte proliferation. The data obtained using OCT were statistically the same as those obtained by H&E/microscopy (P = 0.4325), supporting a greater role for OCT in dermatological studies, while also allowing a reduction in the number of animals used in such studies as sacrifice at individual timepoints is not necessary. PMID- 21323747 TI - Expression of REIC/Dkk-3 in normal and hyperproliferative epidermis. AB - Dickkopf (Dkk) family members are known as Wnt modulators involved in the development, cell growth/differentiation and cancer. REIC/Dkk-3, which does not interfere with Wnt signalling, has been proposed to be a tumor suppressor gene, but its physiological function has remained unclear. In this study, we analysed the expression of REIC/Dkk-3 in normal interfollicular epidermis (IFE) and hyperproliferative epidermis. REIC/Dkk-3 was expressed in human and mouse IFE, being localized at the interface of upper spinous layer and granular layer. Skin cancer cell lines lost REIC/Dkk-3 expression as reported previously. When we analysed patient samples, REIC/Dkk-3 expression was down-regulated in the hyperproliferative epidermis including skin cancers and non-cancerous proliferative diseases. REIC/Dkk-3 expression was also suppressed in the regenerative and inflammative epidermis of model mice. These findings will certainly contribute to the extension of studies on REIC/Dkk-3. PMID- 21323749 TI - Increased cysteinyldopa plasma levels hint to melanocyte as stress sensor in psoriasis. AB - The possible role of melanocyte as a modulator of the inflammation and keratinocyte hyperproliferation in psoriasis has been hypothesised but never demonstrated on experimental basis. Aim of the present study was to assess whether plasma levels of 5-S-cysteinyldopa (CD), a metabolite reflecting melanocyte activity, undergo changes in association with psoriasis together with those of typical lipid peroxidation markers thiobarbituric acid reactive substances (TBARS). A group of 16 patients with psoriasis at different stage as indicated by the psoriasis area and severity index (PASI) were enrolled against an age and sex matched control group. Both TBARS (P<0.05) and CD (P<0.005) levels were higher than controls with statistical significance. After 1 month therapy the levels of either biomarkers decreased with respect to the starting values although with marked individual differences. CD may represent a novel and sensitive biomarker for the follow up of psoriasis and evaluation of the efficacy of therapeutic regimens beyond PASI determination. PMID- 21323748 TI - A topical Chinese herbal mixture improves epidermal permeability barrier function in normal murine skin. AB - Chinese herbal medicine (CHM) has been shown to have beneficial effects for both skin disorders with barrier abnormality and as skin care ingredients. Yet, how CHM exerts their benefits is unclear. As most, if not all, inflammatory dermatoses are accompanied by abnormal permeability barrier function, we assessed the effects of topical CHM extracts on epidermal permeability barrier function and their potential mechanisms. Topical CHM accelerated barrier recovery following acute barrier disruption. Epidermal lipid content and mRNA expression of fatty acid and ceramide synthetic enzymes increased following topical CHM treatment in addition to mRNA levels for the epidermal glucosylceramide transport protein, ATP-binding cassette A12. Likewise, CHM extract increased mRNA expression of antimicrobial peptides both in vivo and in vitro. These results demonstrate that the topical CHM extract enhances epidermal permeability barrier function, suggesting that topical CHM could provide an alternative regimen for the prevention/treatment of inflammatory dermatoses accompanied by barrier abnormalities. PMID- 21323750 TI - Decreased incidence of papillomas in mice with impaired EGFR function during multi-stage skin carcinogenesis. AB - Genetically modified mouse lines revealed that the epidermal growth factor receptor (EGFR) is essential for the development and homoeostasis of the epidermis and hair follicles. However, more detailed studies have been precluded by the shortened lifespan of Egfr knockout mice. We employed the mouse line Wa5 (carrying a point mutation resulting in the expression of a dominant negative receptor) to analyse the impact of significantly reduced EGFR signalling during multi-stage chemical skin carcinogenesis. Seven-week-old Wa5 females and control littermates received a single application of 7,12-dimethylbenz(a)anthracene followed by multiple applications of 12-O-tetradecanoylphorbol-13-acetate for 26 weeks. Wa5 mice remained free of papillomas for a longer time and developed significantly fewer tumors than control littermates. In contrast, the mean tumor size was not different between groups. The present data indicate that EGFR signalling contributes to tumor growth during multi-stage chemical carcinogenesis of the skin in mice possibly by acting as a survival factor for skin tumor cells. PMID- 21323751 TI - Jean-Claude Bystryn 1938-2010. An obituary. AB - Jean-Claude Bystryn, M.D., passed away on 19 August, 2010. Dr. Bystryn's research interests encompassed a large group of dermatologic conditions. He has earned a worldwide recognition for his innovative works on autoimmune blistering diseases, melanoma and alopecia areata. The most significant impact Dr. Bystryn's research has made is on our understanding of the mechanisms of epidermal cell detachment (acantholysis) in pemphigus and development of adequate treatment. During the last decade, he chaired the Medical Advisory Board of the International Pemphigus and Pemphigoid Foundation. Dr. Bystryn was an innovative physician-scientist whose scientific contributions will be long recalled and admired both by patients and colleagues. PMID- 21323752 TI - Determination of the correlation between stallion's age and number of sex chromosome aberrations in spermatozoa. AB - The aim of this study was a cytogenetic analysis of stallions semen to find sex chromosome aberrations and to determine if there was an association between stallion's age and aberration frequency for the sex chromosomes. Sperm samples were collected from 22 stallions of various age from 3 to 23 years. Multicolour FISH was performed on each sample, using probes for the sex chromosomes and EGFR gene, localized on 4p12 in domestic horse. A total of 26199 sperm cells were analysed (from 1 070 to 1 532 per animal). Among the analysed cells, there were 50.318% with X chromosome, 48.543% with Y chromosome and 1.139% with aberrant chromosomes. The frequency of aberrations was: sex chromosomes nullisomy (0.466%), XY aneuploidy (0.454%), XX disomy (0.146%), YY disomy (0.041%), diploidy (0.024%) and trisomy XXY (0.008%). Additionally there was a correlation between the age of an animal and the frequency of sex chromosome aberration and a significant positive correlation between age and disomy of XY, XX, YY, trisomy of XXY, autosomal disomy was seen. A Correlation between the age of a stallion and the level of nullisomy was negative. The present study demonstrated that FISH technique is a powerful method to identify sex chromosome aberrations in equine spermatozoa and might be very helpful for a breeder during a selection for the best stallion. PMID- 21323753 TI - Effects of breeding at the second oestrus or after post-weaning hormonal treatment with altrenogest on subsequent reproductive performance of primiparous sows. AB - This study investigated the effects of breeding at the second oestrus after weaning or after feeding an orally active progestagen (altrenogest) on the subsequent reproductive performance of primiparous sows. After 3 weeks of lactation, 663 weaned sows of two genotypes were allocated into three groups: G1- breeding at the first oestrus after weaning; G2--breeding at the second oestrus after weaning and G3--treatment with altrenogest for 5 days after weaning and breeding at the first oestrus after the end of the treatment. Body weight at breeding was lower in G1 and G3 than in G2 sows (p < 0.05). The interval to show oestrus was similar for G1 and G2 groups (p > 0.05) but higher (p < 0.05) than that observed in G3 group. Within genotype A, percentages of females in oestrus within 10 days were not different (p > 0.05) among groups, whereas in genotype B, more G1 and G2 sows (p < 0.05) showed oestrus than G3 sows. In both genotypes, lower farrowing rates were observed in G3 than in G1 and G2 sows (p < 0.05) and a greater litter size (p < 0.05) was observed in G2 sows. In genotype A, the number of total born piglets was similar for G1 and G3 groups (p > 0.05), whereas in genotype B, G1 sows had a greater litter size than G3 sows (p < 0.05). Body weight at weaning and at breeding was similar (p > 0.05) between farrowed and non farrowed sows in all groups. Reproductive performance is not improved in primiparous sows treated with altrenogest during 5 days after weaning. The reproductive performance of genotype B sows is compromised in Control and Altrenogest-treated sows but not in those bred at the second oestrus after mating. Breeding at the second oestrus after weaning allows primiparous sows to gain weight between weaning and service, and increases their farrowing rate and subsequent litter size. PMID- 21323754 TI - Spatial and temporal gene expression of Fn-type II and cysteine-rich secretory proteins in the reproductive tracts and ejaculated sperm of Chinese Meishan pigs. AB - Fibronectin type II and cysteine-rich secretory proteins have been well studied in the murine and human. The present study evaluated CRISP1, CRISP2, CRISP3 and Fn-type II (ELSPBP1 and pB1) gene expression patterns in ejaculated sperm and reproductive tracts of Chinese Meishan pigs from birth to day 150 of age. In ejaculated sperm, except for ELSPBP1, all others genes studied were detectable. In sexually mature boars and gilts, CRISP1 gene was expressed strongly in whole epididymides, moderate in prostate and weak in seminal vesicle. CRISP2 gene represented extensive distribution along reproductive tracts with highest abundance in testis. CRISP3 gene was expressed highly in prostate and bulbourethral gland, but weakly in testis. ELSPBP1 gene was expressed with highest abundance in cauda epididymides, moderate in corpus epididymides and weak in seminal vesicle and prostate. pB1 mRNA expression was also abundant along reproductive tracts. During the sexual development of boars after birth, these genes showed different expression patterns. CRISP1 and CRISP3 gene expression was high on day 1 and maintained until day 150, while CRISP2 expression was detectable on day 60 with high abundance and maintained until day 90 and dropped on day 150. ELSPBP1 showed low expression at birth and increased significantly on day 30 (p < 0.05) and then kept static until day 150. pB1 gene displayed moderate expression from birth to day 30 and increased significantly on day 60 (p < 0.05) and maintained at high level until day 150. Collectively, CRISP and Fn-type II genes were expressed extensively along genital tracts, and most of them showed mRNA signal in ejaculated sperm. The expression of CRISP1 and CRISP3 genes in Meishan boar was not age-dependent, while CRISP2 and pB1 gene expression was parallel with sexual development. Their unique gene expression patterns may shed light on the mechanism for the high prolificacy of Meishan pigs. PMID- 21323755 TI - Oestradiol enhances plasma growth hormone and insulin-like growth factor-I concentrations and increased the expression of their receptors mRNAs in the liver of ovariectomized cows. AB - Many metabolic hormones, growth hormone (GH), insulin-like growth factor-I (IGF I) and insulin affect ovarian functions. However, whether ovarian steroid hormones affect metabolic hormones in cattle remains unknown. This study aimed to determine the effect of sex steroids on the plasma profiles of GH, IGF-I and insulin and their receptors in the liver and adipose tissues of dairy cows. Ovariectomized cows (n = 14) were randomly divided into four groups: control group (n = 3) was treated with saline on Day 0; oestradiol (E2) group (n = 3), with saline and 1 mg oestradiol benzoate (EB) on Day 0 and 5, respectively; progesterone (P4) group (n = 4) with two CIDRs (Pfizer Inc., Tokyo, Japan) from Day 0; and E2 + P4 group (n = 4) with two CIDRs on Day 0 that were removed on Day 6 and were immediately injected with 1 mg EB. The animals were euthanized after the experiment, and liver and adipose tissues samples were quantitatively analysed using real-time PCR for the expression of mRNA for the GH (GHR), IGF-I (IGFR-I) and insulin (IR) receptor mRNAs. Oestradiol benzoate significantly increased the number of peaks (p < 0.05), pulse amplitude (p < 0.05) and area under the curve (AUC; p < 0.01) for plasma GH; moreover, it increased plasma IGF I concentration (p < 0.05), but it had no effect on the plasma insulin profile. P4 significantly decreased the AUC (p < 0.01), compared with the control group, whereas it did not affect the number of peaks and the amplitude of GH pulses. P4 + E2 did not affect the GH pulse profile. E2 increased the mRNA expression of GHR, IGFR-I and IR in the liver (p < 0.05), whereas both P4 and E2 + P4 did not change their expressions. Our results provide evidence that the metabolic and reproductive endocrine axes may regulate each other to ensure optimal reproductive and metabolic function. PMID- 21323756 TI - Effects of guaiazulene on in vitro bovine embryo production and on mRNA transcripts related to embryo quality. AB - Reactive oxygen species (ROS) are between the major contributors for the reduced rate of in vitro bovine embryo production. It is believed that they can cause abnormal meiosis of oocytes, developmental arrest or cell death of embryos. Reports on the effectiveness of various antioxidants on embryo yield are rather conflicting mainly due to the nature and the concentration of the substances used. Here we report the effects of guaiazulene--an exogenous antioxidant, without known properties that could interfere with the biological process of IVF- on embryo development and on the quality of the produced blastocysts. Bovine cumulus oocyte complexes (COCs) were aspirated from abattoir ovaries and COCs were matured in TCM199 with FCS and EGF at 39 degrees C under an atmosphere of 5% CO(2) in air, with maximum humidity. After 24 h oocytes were inseminated with frozen/thawed semen and co-incubated for further 24 h. Zygotes were cultured in groups of 25 in 25 MUl of SOF with 5% FCS at 39 degrees C under an atmosphere of 5% CO(2) , 5% O(2) in air with maximum humidity. In the first experiment the maturation medium was modified with addition of 0.1 mM of G (n = 497), or 0.01 mM of guaiazulene (n = 468), 0.05% DMSO--the guaiazulene diluent (Control(+), n = 467), and 459 oocytes were used as Control(-). In the second experiment, the culture medium was modified with the addition of 0.1 mM of guaiazulene (n = 344), 0.01 mM of guaiazulene (n = 345), 0.05% DMSO (Control(+), n = 347) and 355 were the Control(-). Blastocyst yield was recorded on days 6, 7, 8 and 9. Day 7 blastocysts from each experiment and group were snap frozen and stored for mRNA extraction. Quantification of transcripts for mRNA of genes related to metabolism (AKR1B1, PTGS2, GADPH, SLC2A5, G6PD); oxidation (GPX1); and implantation (PLAC8) was carried out by real time quantitative RT-PCR. Data for embryo development and on transcript abundance were analysed by chi(2) and anova respectively. In the first experiment no differences were found between groups in terms of cleavage rate (Control(-): 74.20%; Control(+): 74.58%; 0.01 mM: 71.61%; 0.1 mM: 71.63%) or day 9 blastocyst yield (Control(-): 28.26%; Control(+): 25.80%; 0.01 mM: 25.86%; 0.1 mM: 25.25%). In the second experiment, cleavage rate tended to be higher in 0.01 mM group than in Control(-) (77.87% vs 71.41% respectively, p = 0.07). No other differences were detected in cleavage rate (Control(+): 71.32%; 0.1mM: 72.75%) or in the overall blastocyst yield on day 9 (Control(-): 25.50%; Control(+): 26.71%; 0.01 mm: 29.58%; 0.1 mM: 25.75%). In both experiments the relative abundance of genes studied varied between groups but these differences were not statistically significant. Our results imply that oxidation has minimal effect on the in vitro embryo production. Guaiazulene, a compound possessing no biological properties other than those of a strong antioxidant, while it increased cleavage rate, it failed to improve either the blastocyst formation rate, or the quality of the produced embryos under 5% O(2) . PMID- 21323757 TI - Quantitative determination of progesterone (P4) in canine blood serum using an enzyme-linked fluorescence assay. AB - Progesterone (P4) measurement in the peripheral blood is an objective parameter for determination of reproductive functions in the bitch. This study evaluates an enzyme-linked fluorescence assay (ELFA) (Biomerieux, France) for the determination of progesterone validated for use in human. The ELFA is to be performed on the MiniVidas automated analyser which provides quantitative results within 45 min. Blood samples from a total of 27 female dogs of different breeds were used. To test the correctness of the ELFA 15 blood samples with a range of 0.3-40.0 ng/ml were compared to a radioimmunoassay (RIA) validated in the dog. The values obtained with the MiniVidas showed a high agreement (mean deviation 15%), deviations were in both directions and the correlation coefficient was 0.989. The coefficient of correlation according to Passing-Bablok test was 0.995. The intra-assay reproducibility in the MiniVidas system was tested on five samples (mean values 61.8, 6.8, 51.4, 43.7 and 1.1 ng/ml). The coefficients of variation (CV; 10-12 replicates) were 3.4%, 6.7%, 2.6%, 3.1% and 25.4%, respectively. Four serum samples (mean value 47.0, 15.1, 49.1 and 4.0 ng/ml) from different bitches were assayed singly in 10 separate series to test the inter assay variability. The corresponding CV was 2.1%, 2.2%, 3.1% and 4.3% respectively. Samples from three dogs were used to test the accuracy of the assay. These samples were diluted (1/2, 1/4, 1/8 and 1/16) with charcoal-stripped human serum (Biomerieux, France) and tested in three runs. The expected values were met in a range of 60-75%. Measurement of progesterone for the detection of ovulation as well as prediction of parturition provided meaningful results. As a conclusion the use of the MiniVidas system for determination of P4 in peripheral blood of the bitch provides rapid and reliable results. PMID- 21323758 TI - RatA (YfjG), an Escherichia coli toxin, inhibits 70S ribosome association to block translation initiation. AB - RatA (YfjG) is a toxin encoded by the ratA-ratB (yfjG-yfjF) operon on the Escherichia coli genome. Induction of RatA led to the inhibition of protein synthesis, while DNA and RNA synthesis was not affected. The stability of mRNAs was also unchanged as judged by in vivo primer extension experiments and by Northern blotting analysis. The ribosome profile of the cells overexpressing RatA showed that 70S ribosomes as well as polysomes significantly decreased with concomitant increase of 50S and 30S subunits. The addition of purified RatA to a cell-free system inhibited the formation of 70S ribosomes even in the presence of 6 mM Mg(2+) . RatA was specifically associated with 50S subunits, indicating that it binds to 50S subunits to block its association with 30S subunits leading to the inhibition of formation of 70S ribosomes. However, RatA did not cause dissociation of 70S ribosomes and its anti-association activity was blocked by paromomycin, an inhibitor for IF3, an essential initiation factor, having 21% sequence homology with RatA. Here we demonstrate that RatA is a new E. coli toxin, which effectively blocks the translation initiation step. We propose that this toxin of previously unknown function be renamed as RatA (Ribosome association toxin A). PMID- 21323759 TI - What the PDI can do for oral health. PMID- 21323760 TI - Prosthodontic education--competency and proficiency--giving away part of the farm. PMID- 21323761 TI - Effects of bond primers on bending strength and bonding of glass fibers in fiber embedded maxillofacial silicone prostheses. AB - PURPOSE: To evaluate the effect of three commonly used bond primers on the bending strength of glass fibers and their bond strength to maxillofacial silicone elastomer after 360 hours of accelerated daylight aging. MATERIALS AND METHODS: Eighty specimens were fabricated by embedding resin-impregnated fiber bundles (1.5-mm diameter, 20-mm long) into maxillofacial silicone elastomer M511 (Cosmesil). Twenty fiber bundles served as control and did not receive surface treatment with primers, whereas the remaining 60 fibers were treated with three primers (n = 20): G611 (Principality Medical), A-304 (Factor II), and A-330-Gold (Factor II). Forty specimens were dry stored at room temperature (23 +/- 1 degrees C) for 24 hours, and the remaining specimens were aged using an environmental chamber under accelerated exposure to artificial daylight for 360 hours. The aging cycle included continuous exposure to quartz-filtered visible daylight (irradiance 760 W/m(2) ) under an alternating weathering cycle (wet for 18 minutes, dry for 102 minutes). Pull-out tests were performed to evaluate bond strength between fiber bundles and silicone using a universal testing machine at 1 mm/min crosshead speed. A 3-point bending test was performed to evaluate the bending strength of the fiber bundles. One-way Analysis of Variance (ANOVA), Bonferroni post hoc test, and an independent t-test were carried out to detect statistical significances (p < 0.05). RESULTS: Mean (SD) values of maximum pull out forces (N) before aging for groups: no primer, G611, A-304, A-330-G were: 13.63 (7.45), 20.44 (2.99), 22.06 (6.69), and 57.91 (10.15), respectively. All primers increased bond strength in comparison to control specimens (p < 0.05). Primer A-330-G showed the greatest increase among all primers (p < 0.05); however, bonding degraded after aging (p < 0.05), and pull-out forces were 13.58 (2.61), 6.17 (2.89), 6.95 (2.61), and 11.72 (3.03). Maximum bending strengths of fiber bundles at baseline increased after treatment with primers and light aging in comparison with control specimens (p < 0.05), and were in the range of 917.72 to 1095.25 and 1124.06 to 1596.68 MPa at both baseline and after 360 hours aging (p < 0.05). CONCLUSIONS: The use of A-330-G primer in conjunction with silicone Cosmesil M511 produced the greatest bond strength for silicone-glass fiber surfaces at baseline; however, bond strength was significantly degraded after accelerated daylight aging. Treatment with primer and accelerated daylight aging increased bending strength of glass fibers. PMID- 21323762 TI - Silent period of masticatory cycles in dentate subjects and complete denture wearers. AB - PURPOSE: The purpose of this study was to assess, through electromyographic activity (EMG), the silent period (SP) of masseter and anterior temporal muscles in dentate subjects (DS) and complete denture wearers (CDW). MATERIALS AND METHODS: The evaluations were performed at the initial and final period of the mastication for the DS group. For the CDW group, the evaluations were performed at the initial period of mastication, with old complete dentures worn for more than 10 years (OCDW) and at the final period of the mastication with new complete dentures (NCDW), 5 months after rehabilitation. Twenty-four asymptomatic subjects (12 DS, 12 CDW) answered a questionnaire based on the Research Diagnostic Criteria for temporomandibular disorders. The CDW group answered the questionnaire before and after new denture insertion and after 5 months of rehabilitation. The SP of the muscles was recorded through EMG at the initial and final periods of mastication using artificial food (Optocal). The operator monitored 35 chewing cycles performed to grind the artificial food and selected eight open-close-clench-chewing cycles for the record. RESULTS: The SP of the muscles analyzed with new complete dentures showed no statistical difference in comparison to the old dentures. There was a statistically significant difference in the SP between the CDW and DS groups for initial and final chewing. CONCLUSION: Lowered muscular capacity and ability reduced the SP of muscles after rehabilitation with NCDWs. PMID- 21323764 TI - Primary and secondary somatosensory cortex responses to anticipation and pain: a magnetoencephalography study. AB - Several brain regions, including the primary and secondary somatosensory cortices (SI and SII, respectively), are functionally active during the pain experience. Both of these regions are thought to be involved in the sensory-discriminative processing of pain and recent evidence suggests that SI in particular may also be involved in more affective processing. In this study we used MEG to investigate the hypothesis that frequency-specific oscillatory activity may be differentially associated with the sensory and affective components of pain. In eight healthy participants (four male), MEG was recorded during a visceral pain experiment comprising baseline, anticipation, pain and post-pain phases. Pain was delivered via intraluminal oesophageal balloon distension (four stimuli at 1 Hz). Significant bilateral but asymmetrical changes in neural activity occurred in the beta-band within SI and SII. In SI, a continuous increase in neural activity occurred during the anticipation phase (20-30 Hz), which continued during the pain phase but at a lower frequency (10-15 Hz). In SII, oscillatory changes only occurred during the pain phase, predominantly in the 20-30 Hz beta band, and were coincident with the stimulus. These data provide novel evidence of functional diversity within SI, indicating a role in attentional and sensory aspects of pain processing. In SII, oscillatory changes were predominantly stimulus-related, indicating a role in encoding the characteristics of the stimulus. We therefore provide objective evidence of functional heterogeneity within SI and functional segregation between SI and SII, and suggest that the temporal and frequency dynamics within cortical regions may offer valuable insights into pain processing. PMID- 21323765 TI - A computational model of thalamocortical dysrhythmia. AB - Functional stereotactic lesions in the central lateral nucleus of the medial thalamus have proved to be an effective treatment of neurogenic pain and other neurological disorders associated with thalamocortical dysrhythmia. The mechanisms underlying patient recovery after surgery are currently being explored using quantitative electroencephalography. Here we test the hypothesis that the particular role played by the non-specific medial thalamic nuclei in thalamocortical dysrhythmia is based on the divergent connectivity between these non-specific and reticular nuclei. We built a spiking computer model of the human thalamocortical system consisting of specific, non-specific and reticular thalamic nuclei. In our simulations of the thalamocortical system, deafferentation of peripheral thalamic afferents leads to hyperpolarization and subsequent bursting in the reticular nucleus. This provides strong inhibitory feedback to both the specific and the non-specific thalamic nuclei and initiates a feedback cycle of thalamic bursts in the theta frequency range. The divergent connections between the reticular and non-specific thalamic nuclei provide synchronization of the oscillating circuits. Functional silencing of the non specific model nucleus limits reverberation and rescues the system from these oscillations. The same effect could be achieved by increasing the input to the non-specific nucleus from cortical areas. The model predicts that the invasiveness of functional neurosurgery can be reduced by targeting only deafferented areas in the medial nuclei as these are the key areas for generation and maintenance of pathological rhythms. PMID- 21323766 TI - The increased density of p38 mitogen-activated protein kinase-immunoreactive microglia in the sensorimotor cortex of aged TgCRND8 mice is associated predominantly with smaller dense-core amyloid plaques. AB - The role for phosphorylated p38 mitogen-activated protein kinase [p-p38(MAPK)] in beta-amyloid plaque deposition [a hallmark of Alzheimer's disease (AD) pathology] remains ambiguous. We combined immunohistochemistry and stereological sampling to quantify the distribution of plaques and p-p38(MAPK)-immunoreactive (IR) cells in the sensorimotor cortex of 3-, 6- and 10-month-old TgCRND8 mice. The aggressive nature of the AD-related human amyloid-beta protein precursor expressed in these mice was confirmed by the appearance of both dense-core (thioflavin-S-positive) and diffuse plaques, even in the youngest mice. p-p38(MAPK)-IR cells of the sensorimotor cortex were predominantly co-immunoreactive for the Macrophage-1 (CD11b/CD18) microglial marker. These p-p38(MAPK)-IR microglia were associated with both dense-core and diffuse plaques, but the expected age-dependent increase in the density of plaque-associated p-p38(MAPK)-IR microglia was restricted to dense-core plaques. Furthermore, the density of dense-core plaque-associated p p38(MAPK)-IR microglia was inversely correlated with the size of the core within the given plaque, which supports a role for these microglia in restricting core growth. p-p38(MAPK)-IR microglia were also observed throughout wildtype and TgCRND8 mouse cortical parenchyma, but the density of these non-plaque-associated microglia remained constant, regardless of age or genotype. We conclude that the constitutive presence of p-p38(MAPK)-IR microglia in aging mouse brain is indicative of a longitudinal role for this kinase in normal brain physiology. We suggest that this fact, as well as the fact that a pool of p-p38(MAPK)-IR microglia appears to restrict beta-amyloid plaque core development, needs to be duly considered when ascribing functions for p38(MAPK) signalling in the AD brain. PMID- 21323767 TI - Hepatocellular carcinoma without cirrhosis: think acute hepatic porphyrias and vice versa. PMID- 21323768 TI - Antiphospholipid syndrome: laboratory detection, mechanisms of action and treatment. AB - The antiphospholipid syndrome (APS) identifies a condition at increased risk of vascular occlusion and/or pregnancy complications. Patients are defined as having APS if they have at least one clinical (vascular occlusion and/or pregnancy complications) and one laboratory criterion at the same time. The laboratory criteria that define APS are repeated positivity (confirmed 12 weeks apart) for lupus anticoagulants and/or antibodies targeted against cardiolipin or beta(2) glycoprotein I immobilized on solid surfaces. Over the years, APS has attracted the interest of many medical specialties. The aim of this review is to provide an update on (i) the laboratory criteria that determine the presence of APS, (ii) how the antibodies increase the risk of vascular occlusion and foetal loss and (iii) the treatment of the related clinical events. PMID- 21323769 TI - Adenomatoid tumour of epididymis with signet ring change: a morphological curiosity. PMID- 21323770 TI - Transgenic overexpression of p23 induces spontaneous hydronephrosis in mice. AB - p23 is a cochaperone of heat shock protein 90 and also interacts functionally with numerous steroid receptors and kinases. However, the in vivo roles of p23 remain unclear. To explore its in vivo function, we generated the transgenic (TG) mice ubiquitously overexpressing p23. The p23 TG mice spontaneously developed kidney abnormalities closely resembling human hydronephrosis. Consistently, kidney functions deteriorate significantly in the p23 TG mice compared to their wild-type (WT) littermates. Furthermore, the expression of target genes for aryl hydrocarbon receptor (AhR), such as cytochrome P450, family 1, subfamily A, polypeptide 1 (Cyp1A1) and cytochrome P450, family 1, subfamily B, polypeptide 1 (Cyp1B1), were induced in the kidneys of the p23 TG mice. These results indicate that the overexpression of p23 contributes to the development of hydronephrosis through the upregulation of the AhR pathway in vivo. PMID- 21323771 TI - A small molecule with differential effects on the PTS1 and PTS2 peroxisome matrix import pathways. AB - The use of small molecules has great power to dissect biological processes. This study presents the identification and characterisation of an inhibitor of peroxisome matrix protein import. A mini-screen was carried out to identify molecules that cause alteration in peroxisome morphology, or mislocalization of a peroxisome targeted fluorescent reporter protein. A benzimidazole lead compound (LDS-003655) was identified that resulted in reduced GFP fluorescence in peroxisomes and cytosolic GFP accumulation. The effect of the compound was specific to peroxisomes as Golgi bodies, endoplasmic reticulum and the actin cytoskeleton were unaffected even at 25 MUM, whereas peroxisome import via the PTS1 pathway was compromised at 100 nM. When seedlings were grown on 25 MUM LDS 003655 they displayed morphology typical of seedlings grown in the presence of auxin, and expression of the auxin reporter DR5::GFP was induced. Analysis of a focussed library of LDS-003655 derivatives in comparison with known auxins led to the conclusion that the auxin-like activity of LDS-003655 is attributable to its in situ hydrolysis giving rise to 2,5-dichlorobenzoic acid, whereas the import inhibiting activity of LDS-003655 requires the whole molecule. None of the auxins tested had any effect on peroxisome protein import. Matrix import by the PTS2 import pathway was relatively insensitive to LDS-003655 and its active analogues, with effects only seen after prolonged incubation on high concentrations. Steady state protein levels of PEX5, the PTS1 import pathway receptor, were reduced in the presence of 100 nM LDS-003655, suggesting a possible mechanism for the import inhibition. PMID- 21323772 TI - An integrated genomic, proteomic and biochemical analysis of (+)-3-carene biosynthesis in Sitka spruce (Picea sitchensis) genotypes that are resistant or susceptible to white pine weevil. AB - Conifers are extremely long-lived plants that have evolved complex chemical defenses in the form of oleoresin terpenoids to resist attack from pathogens and herbivores. In these species, terpenoid diversity is determined by the size and composition of the terpene synthase (TPS) gene family and the single- and multi product profiles of these enzymes. The monoterpene (+)-3-carene is associated with resistance of Sitka spruce (Picea sitchensis) to white pine weevil (Pissodes strobi). We used a combined genomic, proteomic and biochemical approach to analyze the (+)-3-carene phenotype in two contrasting Sitka spruce genotypes. Resistant trees produced significantly higher levels of (+)-3-carene than susceptible trees, in which only trace amounts were detected. Biosynthesis of (+) 3-carene is controlled, at the genome level, by a small family of closely related (+)-3-carene synthase (PsTPS-3car) genes (82-95% amino acid sequence identity). Transcript profiling identified one PsTPS-3car gene (PsTPS-3car1) that is expressed in both genotypes, one gene (PsTPS-3car2) that is expressed only in resistant trees, and one gene (PsTPS-3car3) that is expressed only in susceptible trees. The PsTPS-3car2 gene was not detected in genomic DNA of susceptible trees. Target-specific selected reaction monitoring confirmed this pattern of differential expression of members of the PsTPS-3car family at the proteome level. Kinetic characterization of the recombinant PsTPS-3car enzymes identified differences in the activities of PsTPS-3car2 and PsTPS-3car3 as a factor contributing to the different (+)-3-carene profiles of resistant and susceptible trees. In conclusion, variation of the (+)-3-carene phenotype is controlled by copy number variation of PsTPS-3car genes, variation of gene and protein expression, and variation in catalytic efficiencies. PMID- 21323773 TI - Characterization of the Arabidopsis glycerophosphodiester phosphodiesterase (GDPD) family reveals a role of the plastid-localized AtGDPD1 in maintaining cellular phosphate homeostasis under phosphate starvation. AB - Glycerophosphodiester phosphodiesterase (GDPD), which hydrolyzes glycerophosphodiesters into sn-glycerol-3-phosphate (G-3-P) and the corresponding alcohols, plays an important role in various physiological processes in both prokaryotes and eukaryotes. However, little is known about the physiological significance of GDPD in plants. Here, we characterized the Arabidopsis GDPD family that can be classified into canonical GDPD (AtGDPD1-6) and GDPD-like (AtGDPDL1-7) subfamilies. In vitro analysis of enzymatic activities showed that AtGDPD1 and AtGDPDL1 hydrolyzed glycerolphosphoglycerol, glycerophosphocholine and glycerophosphoethanolamine, but the maximum activity of AtGDPD1 was much higher than that of AtGDPDL1 under our assay conditions. Analyses of gene expression patterns revealed that all AtGDPD genes except for AtGDPD4 were transcriptionally active in flowers and siliques. In addition, the gene family displayed overlapping and yet distinguishable patterns of expression in roots, leaves and stems, indicating functional redundancy as well as specificity of GDPD genes. AtGDPDs but not AtGDPDLs are up-regulated by inorganic phosphate (P(i) ) starvation. Loss-of-function of the plastid-localized AtGDPD1 leads to a significant decrease in GDPD activity, G-3-P content, P(i) content and seedling growth rate only under P(i) starvation compared with the wild type (WT). However, membrane lipid compositions in the P(i) -deprived seedlings remain unaltered between the AtGDPD1 knockout mutant and WT. Thus, we suggest that the GDPD mediated lipid metabolic pathway may be involved in release of P(i) from phospholipids during P(i) starvation. PMID- 21323774 TI - Distinct evolutionary patterns of Oryza glaberrima deciphered by genome sequencing and comparative analysis. AB - Here we present the genomic sequence of the African cultivated rice, Oryza glaberrima, and compare these data with the genome sequence of Asian cultivated rice, Oryza sativa. We obtained gene-enriched sequences of O. glaberrima that correspond to about 25% of the gene regions of the O. sativa (japonica) genome by methylation filtration and subtractive hybridization of repetitive sequences. While patterns of amino acid changes did not differ between the two species in terms of the biochemical properties, genes of O. glaberrima generally showed a larger synonymous-nonsynonymous substitution ratio, suggesting that O. glaberrima has undergone a genome-wide relaxation of purifying selection. We further investigated nucleotide substitutions around splice sites and found that eight genes of O. sativa experienced changes at splice sites after the divergence from O. glaberrima. These changes produced novel introns that partially truncated functional domains, suggesting that these newly emerged introns affect gene function. We also identified 2451 simple sequence repeats (SSRs) from the genomes of O. glaberrima and O. sativa. Although tri-nucleotide repeats were most common among the SSRs and were overrepresented in the protein-coding sequences, we found that selection against indels of tri-nucleotide repeats was relatively weak in both African and Asian rice. Our genome-wide sequencing of O. glaberrima and in depth analyses provide rice researchers not only with useful genomic resources for future breeding but also with new insights into the genomic evolution of the African and Asian rice species. PMID- 21323775 TI - Rehabilitation after spinal cord injury and the influence of the professional's support (or lack thereof). AB - AIM AND OBJECTIVES: To investigate how spinal cord injured patients struggle with their rehabilitation and how they feel that the professionals influence this process. BACKGROUND: Rehabilitation after a spinal cord injury is a long and arduous process during which the patient needs much support. Some patients lack adequate support from the professionals. This makes it pertinent to investigate the processes patients go through to get on with their lives and the influence professionals have. DESIGN: A phenomenological-hermeneutic study with a narrative approach using Ricoeur's theory. METHOD: A purposeful and consecutive sample of 12 newly injured, adult Danish-speaking patients previously living a normal life were observed 7-12 times and interviewed six or seven times over two years. RESULTS: The patients regained meaning and got on with life through resolute fighting for a meaningful life. We found three patterns of fight; the patients fought with themselves together with the professionals (pattern I). If consensus about the goals and pathway broke down and was not re-established, this fight could turn into a fight against the professionals (pattern II). This would, in turn, cause the patients to fight against themselves. A third pattern (III) was that the patients turned away, either going their own way or suppressing themselves by adapting to the professionals' views. In either case, the patients would feel being left on their own. CONCLUSION: When the patient and professionals agreed on the way forward, the patient experienced the professionals as supportive. However, if the patient's goals were not consistent with the professionals' views, the patient felt that the professionals withdrew their support. RELEVANCE TO CLINICAL PRACTICE: If the professional were able to maintain consensus with the patient, they contributed to the patient's process of regaining meaning. PMID- 21323776 TI - A review and commentary on the factors that influence expressions of sexuality by older people in care homes. AB - AIM: The aim of this paper is to review the literature on factors that influence the expression of sexuality by older people in care homes. BACKGROUND: Sexuality is an intrinsic part of what we are, however there is evidence to suggest that the sexual needs of older people are often overlooked, particularly in long-term care settings. Whilst there is information about sexuality and its expression in later life, questions remain as to how this influences and is influenced by the behaviours and experiences of residents and staff in care homes. DESIGN: A systematic search of online databases. METHOD: Databases using keyword and bibliographical searches in a specified timeframe were undertaken. Research studies ranging from 1996-2009 were selected for inclusion on the basis that they addressed issues relating to expressions of sexuality by older people in care homes. Forty articles were included in the review. FINDINGS: The review revealed a dearth of rigorous research on sexuality amongst older people in general and care home residents in particular. Issues identified in the literature were categorised into four broad thematic areas: sexuality and ageing, expression of sexuality in care homes, attitudes of staff and sexuality in dementia. CONCLUSION: There is a dearth of rigorous research on the factors influencing sexual expression by care home residents. Attitudes of staff in care homes influence their perceptions about the extent to which the expression of sexuality by residents is considered to be problematic. This, in turn influences the emotional and behavioural responses of staff to the resident. RELEVANCE TO CLINICAL PRACTICE: There is need for nurses and other care staff to gain a better understanding of and insight into late life sexuality. This involves change at an educational level but also at an organisational and cultural level in long-term care settings. PMID- 21323777 TI - The health concerns and behaviours of primigravida: comparing advanced age pregnant women with their younger counterparts. AB - AIM: This study was to describe and compare the health concerns, behaviours and anxiety of advanced age pregnant women (35 years and older) with their younger counterparts. BACKGROUND: Women have specific health concerns and behaviours during pregnancy. Delayed childbearing has an increased risk of adverse pregnancy outcomes and advanced age pregnant women may have more health concerns than younger ones. DESIGN: A cross-sectional study. METHOD: Primigravidae Chinese women aged 35 or older (n = 47) and 188 younger than aged 35 were recruited in February and March of 2005 by convenient sampling from the antenatal clinic of a regional hospital in Hong Kong to complete a questionnaire. FINDINGS: Advanced age pregnant women when compared with their counterparts were more likely to have tertiary education (42.6% vs. 28.7%) and a higher family monthly income of Hong Kong $40,001 or more (40.5% vs. 15.4%). They were more likely to be concerned the possibility of miscarriage (63.8% vs. 45.9%) and the physical demands of caring for the newborn (61.7% vs. 45.4%) but were more likely to take up healthy behaviours such as 'eating nutritious food' (100%) and avoiding 'wearing tight clothing and high-heel shoes'(100%). Advanced age women were more likely to be concerned about their 'recovery after childbirth' (63.8% vs. 42.7%), Down's syndrome (70.2% vs. 37.8%) and structural defects of their foetus (78.7% vs. 54.1%). CONCLUSION: The results of this study provide a background for improving prenatal care catering for the specific health concerns of the advanced aged and promotion of health behaviours among younger pregnant women. RELEVANCE TO CLINICAL PRACTICE: Antenatal, obstetric and community health nurses have the responsibility to provide education and support services catering to the special concerns of pregnant women at different ages. Health professionals should promote the prime time for childbearing and deliver messages regarding the potential problems associated with later childbearing at premarital counselling. PMID- 21323778 TI - The effect of music therapy on physiological signs of anxiety in patients receiving mechanical ventilatory support. AB - AIMS: The aim of this study was to investigate if relaxing music is an effective method of reducing the physiological signs of anxiety in patients receiving mechanical ventilatory support. BACKGROUND: Few studies have focused on the effect of music on physiological signs of anxiety in patients receiving mechanical ventilatory support. DESIGN: A study-case-control, experimental repeated measures design was used. METHOD: Sixty patients aged 18-70 years, receiving mechanical ventilatory support and hospitalised in the intensive care unit, were taken as a convenience sample. Participants were randomised to a control group or intervention group, who received 60 minutes of music therapy. Classical music was played to patients using media player (MP3) and headphones. Subjects had physiological signs taken immediately before the intervention and at the 30th, 60th and 90th minutes of the intervention. Physiological signs of anxiety assessed in this study were mean systolic and diastolic blood pressure, pulse rate, respiratory rate and oxygen saturation in blood measured by pulse oxymetry. Data were collected over eight months in 2006-2007. RESULTS: The music group had significantly lower respiratory rates, and systolic and diastolic blood pressure, than the control group. This decrease improved progressively in the 30th, 60th and 90th minutes of the intervention, indicating a cumulative dose effect. CONCLUSION: Music can provide an effective method of reducing potentially harmful physiological responses arising from anxiety. RELEVANCE TO CLINICAL PRACTICE: As indicated by the results of this study, music therapy can be supplied to allay anxiety in patients receiving mechanical ventilation. Nurses may include music therapy in the routine care of patients receiving mechanical ventilation. PMID- 21323779 TI - Mode of administration only has a small effect on data quality and self-reported health status and emotional distress among Swedish adolescents and young adults. AB - AIMS: The aims were to investigate potential effects of mode of administration on response rate, internal consistency, completeness of data, floor and ceiling effects and interaction effects of mode of administration, gender and age on self reported health status and emotional distress among Swedish adolescents and young adults. DESIGN: A cross-sectional comparative study. METHODS: Using a stratified quota sampling scheme, 840 adolescents and young adults (aged 13-23 years) were randomly chosen from the general population. Participants were randomised according to mode of administration, telephone interview or postal questionnaire. RESULTS: The telephone mode resulted in a higher response rate than the postal mode and fewer men than women participated in the postal mode. Mode of administration only had a small effect on self-reports. The youngest adolescents did, in some respects, respond to the modes in a reverse pattern than the older participants. CONCLUSION: The findings support the use of the SF-36 and the HADS among persons 16-23 years of age. The strengths and weaknesses of a telephone and a postal mode to collect self-report data are discussed. RELEVANCE FOR CLINICAL PRACTICE: Nurses should consider the findings of this study, e.g. when using self reports to screen for health status and emotional distress and when designing research studies. PMID- 21323780 TI - Strategies used for managing symptoms by women with fibromyalgia. AB - AIMS: The goal of this study was to describe how persons with fibromyalgia manage their lives given the multiple symptoms they experience, in particular how they use non-pharmacologic strategies, or how they incorporate these strategies along with pharmacologic agents. BACKGROUND: Persons with fibromyalgia, a widespread chronic pain condition, often suffer from considerable fatigue, sleep disturbances and morning stiffness. Medical management does not lead to a cure, and sufferers must self-manage to maintain a good quality of life. DESIGN: This qualitative descriptive study used group interview methodology. METHODS: Data were obtained from eight women with fibromyalgia. Women's mean age was 61 (range 54-81). Participants were invited to participate in a 90- minute group interview focused on symptom management. In the interview, open-ended questions allowed them to speak freely about managing multiple fibromyalgia symptoms. Content analysis by the first and second authors led to the identification of themes, which were validated by the co-authors who attended the interviews. RESULTS: Participants reported many strategies to cope with fibromyalgia symptoms and manage their lives. Main strategies included: 'pacing/planning', 'distraction techniques', 'coping with touch sensitivity', 'putting on the mask' and 'medications'. In addition, 'social support' from others with fibromyalgia and from family members was reported to be very important. CONCLUSIONS: Study findings demonstrate that women with fibromyalgia can develop strategies that enable them to cope with a life encumbered with chronic pain and fatigue. Moreover, this study confirmed effective fibromyalgia management strategies reported in other studies. Further research is needed on risks/benefits of these and other self-management strategies used by women with fibromyalgia. RELEVANCE TO CLINICAL PRACTICE: Our findings suggest that nurses should discuss the self management strategies found with persons who have fibromyalgia in the context of individual patient experiences. PMID- 21323781 TI - Work ability as a major determinant of clinical nurses' quality of life. AB - AIMS AND OBJECTIVES: To examine quality of life determinants among clinical nurses in Croatia with an emphasis on their work ability. BACKGROUND: An important personnel management challenge is to explore factors that stimulate or hinder the development of individual work ability and quality of life throughout a career. DESIGN: A cross-sectional study. METHODS: The study was performed during 2007-2008 in six randomly selected hospitals in Croatia. The self administered questionnaires included the Work Ability Index (WAI) developed by the Finnish Institute of Occupational Health, the Quality of Life questionnaire (WHOQL-BREF) developed by the World Health Organization and additional socio demographic questions. A total number of 1212 nurses completed the questionnaires, giving a response rate of 67(.) 3%. Binary logistic regression was performed to assess how socio-demographic characteristics and work ability groups predict each of the WHOQL-BREF domains. RESULTS: Having a satisfactory WAI score (WAI >= 37) was significantly the most important predictor for all quality of life domains, with the odds ratios (OR) being as follows: OR = 6(.) 8 (95% CI: 4(.) 8-9(.) 6) for the physical domain, OR = 2(.) 3 (95% CI: 1(.) 7-3(.) 1) for the psychological domain, OR = 1(.) 7 (95% CI: 1(.) 3-2(.) 4) for the social relationship domain and OR = 1(.) 7 (95% CI: 1(.) 3-2(.) 3) for the environmental domain. CONCLUSIONS: Satisfactory work ability was a major quality of life determinant in all WHOQL-BREF domains with the highest odds ratio for the physical domain. Maintaining clinical nurses' work ability is an important issue, because it is foundational for the quality of life of the workforce. RELEVANCE TO CLINICAL PRACTICE: Our study provides quantified estimates of the extent to which a satisfactory WAI score predicts a better score in physical, psychosocial, social relationships and environmental domain of nurses' quality of life. Therefore, maintaining or improving nurses' work ability remains the essential aim of hospital managers. PMID- 21323782 TI - Psychological well-being in parents of children with Angelman, Cornelia de Lange and Cri du Chat syndromes. AB - BACKGROUND: The current study focuses on mothers and fathers of children with three rare genetic syndromes that are relatively unexplored in terms of family experience: Angelman syndrome, Cornelia de Lange syndrome and Cri du Chat syndrome. METHOD: Parents of children with Angelman syndrome (n =15), Cornelia de Lange syndrome (n = 16) and Cri du Chat syndrome (n = 18), and a matched comparison group of parents of children with autism and intellectual disabilities (n = 20) completed questionnaires on both psychological distress (stress, anxiety, depression) and positive psychological functioning. RESULTS: Parents of children with Angelman syndrome consistently reported the highest levels of psychological distress, and parents of children with Cornelia de Lange syndrome the lowest, with parents of children with Cri du Chat syndrome and autism scoring between these two. Positive psychological functioning was similar across the four aetiology groups. CONCLUSIONS: Parents of children with rare genetic syndromes are at risk for high levels of stress and mental health problems. Methodological issues and the practical applications of these results are discussed. PMID- 21323783 TI - Developing voice and empowerment: the first step towards a broad consultation in research agenda setting. AB - BACKGROUND: Although people with intellectual disabilities (ID) are increasingly consulted in research, participation in research agenda setting processes is limited. This is not surprising as their voice can easily be dominated in consultations with researchers. The aim of this article is to explore the potentials of enclave deliberation as a first step towards broad consultation in research agenda setting. METHOD: The research agenda setting process followed a responsive methodology, which is characterised by a cyclical and emergent design. Two persons with ID and one parent participated in the research team. Seven persons with ID and six parents were interviewed individually. Subsequently, 10 focus groups were organised with people with ID and four focus groups with parents. Also, a questionnaire was sent to parents. RESULTS: The process towards involvement of people with ID was characterised by several steps that guided enclave deliberation. First, stories of people were collected that reflected their intimate voice. Then, a political voice was further developed through dialogue and interaction in focus groups. This process resulted in a prioritised list of nine potential topics for research. CONCLUSION: The process of developing intimate voice and political voice can be regarded as a concretisation of enclave deliberation among disempowered groups. These steps are necessary to initiate a process towards establishing a broad consultation between different stakeholders about research on ID. PMID- 21323784 TI - Why do families relinquish care? An investigation of the factors that lead to relinquishment into out-of-home respite care. AB - BACKGROUND: Families/carers relinquishing the care of family members with a disability into the care of out-of-home respite facilities is an under-researched area in the disability field. With this in mind, the aim of this study was to explore the factors that lead to families relinquishing care, the potential early indicators that families are considering relinquishment; the factors that may prevent relinquishment and the outcomes for families/carers after relinquishment occurs. METHOD: Thirty-two client files (of individuals for whom families have relinquished their care in a defined 12-month period) were reviewed for information around their relinquishment into out-of-home respite care facilities for an extended stay. Staff members involved with these families (a total of 17) were also interviewed to provide more information. RESULTS: A thematic analysis of the results found that the factors that led to relinquishment could be categorised into: (1) characteristics inherent to the individual with intellectual disability; (2) characteristics inherent to the family/carer; and (3) characteristics associated with the support context that the carer/family is currently experiencing. It was also found that families'/carers' experienced positive outcomes after relinquishment had occurred; however, feelings of guilt and mourning were initially felt. CONCLUSIONS: Extra supports (e.g. increased respite care, planning for movement of the family member into out-of-home permanent accommodation and case management) and positive interventions such as parent training were highlighted as potential strategies to achieve more lasting benefits from short-stay out-of-home respite care. PMID- 21323785 TI - Influence of irrigant, dowel type, and root-reinforcing material on fracture resistance of thin-walled endodontically treated teeth. AB - PURPOSE: Unresolved controversy exists concerning the optimum restorative material to reinforce the thin-walled roots of endodontically treated teeth to improve their fracture resistance under occlusal load. This study evaluated the effectiveness of irrigant, dowel type, and root-reinforcing material on the fracture resistance of thin-walled endodontically treated teeth. MATERIALS AND METHODS: The root canals of 140 maxillary central incisors were enlarged and equally divided into seven groups according to the canal irrigant: no irrigant (control), 5% hydrogen peroxide, 5% sodium hypochlorite, a combination of 5% hydrogen peroxide and sodium hypochlorite, 15% ethylenediaminotetraacetic acid (EDTA), 10% lactic acid, or 20% lactic acid. Within each group, root canals were lined with composite resin (PermaFlo) or glass ionomer cement (Fuji II LC). A light-transmitting plastic dowel (Luminex) was used to create space for a quartz fiber-reinforced dowel (Aestheti Post) or a titanium alloy dowel (ParaPost XH) and to cure the restorative materials. Following dowel cementation and restoration of the roots with composite core, the teeth were submitted to fracture resistance testing, and data were analyzed with 3-way ANOVA followed by Ryan-Einot-Gabriel-Welsch Multiple Range Test (alpha= 0.05). RESULTS: Fracture resistance values were significantly different among irrigants, restorative materials, and their interaction (p < 0.001); however, the dowel type was not significantly different (p= 0.51). CONCLUSIONS: Thin-walled roots that had the smear layer removed with lactic acid and that were then lined with composite resin had a higher fracture resistance. PMID- 21323786 TI - The effect of chemical surface treatments on the flexural strength of repaired acrylic denture base resin. AB - PURPOSE: To investigate the effect of the selected chemical surface treatment agents on the flexural strength of heat-polymerized acrylic resin repaired with autopolymerized acrylic resin. MATERIALS AND METHODS: Ninety heat-polymerized acrylic resin specimens (Meliodent) were prepared according to ISO1567 and randomly divided into nine groups: positive and negative control groups (groups I and II), and seven experimental groups (groups III to IX). Specimens in groups II to IX were cut in the middle and beveled 45 degrees . Group III was then treated with methyl methacrylate (the liquid part of Unifast TRAD) for 180 seconds. Group IV was treated with Rebase II adhesive according to the manufacturer's instructions. Groups V to IX were treated with methyl formate, methyl acetate, and a mixture of methyl formate-methyl acetate at various concentrations (75:25, 50:50, 25:75% v/v, respectively) for 15 seconds. They were then repaired with autopolymerized acrylic resin (Unifast TRAD). A three-point loading test was performed using a universal testing machine. One-way ANOVA and post hoc Tukey's analysis at p < 0.05 were used for statistical comparison. Failure analysis was then recorded for each specimen. The morphological changes in untreated and treated specimens were observed by scanning electron microscopy. RESULTS: The flexural strengths of groups III to IX were significantly higher than that of group II (p < 0.05). The flexural strengths of groups IV to IX showed no significant difference among them (p > 0.05). All specimens in groups V to IX showed 100% cohesive failure, while groups II, III, and IV showed cohesive failure of 10%, 60%, and 60%, respectively. From scanning electron micrographs, the application of methyl formate, methyl acetate, and a mixture of methyl formate-methyl acetate solutions on heat-polymerized acrylic resin resulted in a 3D honeycomb appearance, while specimens treated with methyl methacrylate and Rebase II adhesive developed shallow pits and small crest patterns, respectively. CONCLUSION: Treating surfaces with methyl formate, methyl acetate, and a mixture of methyl formate-methyl acetate solutions significantly enhanced the flexural strength of heat-polymerized acrylic denture base resin that had been repaired with autopolymerized acrylic resin. PMID- 21323787 TI - Prosthetic rehabilitation of postsurgical nasomaxillary hypoplasia for a patient following reconstructive surgery: a clinical report. AB - Repairs of the cleft nose, lip, and palatal deformity remain challenging endeavors for reconstructive surgeons. Postsurgical nasomaxillary hypoplasia is a common finding in patients with extensive clefts. This complex deformity has a pronounced impact on the social behavior and self image of the subject. Esthetic and functional rehabilitation of this postsurgical defect is scarcely reported in the literature. Support in the form of prostheses or stents to prevent tissue collapse is usually required in these patients following surgery. This clinical case presentation discusses the fabrication of an internal nasal stent for a cleft nose, lip, and palate patient following surgical reconstruction. Two prostheses using two prosthetic materials (Polymethyl methacrylate, flexible resin) were prepared to compare their efficacy. The final prostheses improved the patient's appearance, making the postsurgical defect less conspicuous. PMID- 21323788 TI - Soldering in prosthodontics--an overview, part I. AB - The fit of fixed multiunit dental prostheses (FDP), traditionally termed fixed partial dentures (FPDs), is an ongoing problem. Poorly fitting restorations may hasten mechanical failure, due to abutment caries or screw failure. Soldering and welding play an important role in trying to overcome misfit of fixed multiunit prostheses. The term FPD will be used to denote multiunit fixed dental prostheses in this review. This is the first of a series of articles that review the state of the art and science of soldering and welding in relation to the fit of cemented or screw-retained multiunit prostheses. A comprehensive archive of background information and scientific findings is presented. Texts in dental materials and prosthodontics were reviewed. Scientific data were drawn from the numerous laboratory studies up to and including 2009. The background, theory, terminology, and working principles, along with the applied research, are presented. This first article focuses on soldering principles and dimensional accuracy in soldering. There is some discussion and suggestions for future research and development. Soldering may improve dimensional accuracy or reduce the distortion of multiunit fixed prostheses. Many variables can affect the outcome in soldering technique. Research science has developed some helpful guidelines. Research projects are disconnected and limited in scope. PMID- 21323789 TI - A technique to achieve predictable iris positioning and symmetry in ocular and orbital prostheses. AB - An alternative technique for achieving predictable iris positioning and symmetry for ocular and orbital prostheses using a mounted graph grid is proposed. PMID- 21323790 TI - Shining D' light on chronic kidney disease: mechanisms that may underpin the cardiovascular benefit of vitamin D. AB - Hypovitaminosis D is a significant health-care burden worldwide, particularly in susceptible populations such as those with chronic kidney disease (CKD). Recent epidemiological studies have identified that both higher serum vitamin D concentrations and use of vitamin D supplements may confer a survival benefit both in terms of all-cause and cardiovascular mortality. There is potential to investigate this inexpensive therapy for the CKD population, which suffers excessive cardiovascular events, although the mechanisms explaining this link have yet to be fully elucidated. This review discusses potential mechanisms identified in the basic science literature that may provide important insights into how vitamin D may orchestrate a change in cardiovascular risk profile through such diverse mechanisms as inflammation, atherogenesis, glucose homeostasis, vascular calcification, renin-angiotensin regulation and alterations in cardiac physiology. Where available, the clinical translation of these concepts to intervention trials in the CKD population will be reviewed. PMID- 21323791 TI - Paclitaxel, ifosfamide, and nedaplatin as second-line treatment for patients with metastatic urothelial carcinoma: a phase II study of the SUOC group. AB - There is no standard second-line chemotherapy treatment for recurrent or metastatic urothelial cancer (MUC). The purpose of this phase II study was to evaluate the efficacy and toxicity of the three-drug combination of paclitaxel, ifosfamide, and nedaplatin (TIN). Patients with MUC were eligible after treatment failure with methotrexate, vinblastine, doxorubicin, and cisplatin, or gemcitabine and cisplatin. Doses for TIN therapy were paclitaxel 175 mg/m2 on day 1, ifosfamide 1500 mg/m2 on days 1-3, and nedaplatin 70 mg/m2 on day 1, every 4 weeks. Tumor response, the primary efficacy parameter, was assessed according to unidimensional measurements (Response Evaluation Criteria in Solid Tumors criteria, version 1.0). Secondary efficacy parameters were overall survival (OS) and progression-free survival (PFS). Toxicity was assessed according to the National Cancer Institute Common Toxicity Criteria, version 3.0. A total of 45 patients (13 females and 32 males) with MUC were evaluable for response and toxicity. The overall response rate was 40.0%. Median PFS time was 4.0 months (95% confidence interval [CI], 4.6-11.6). Median OS time was 8.9 months (95% CI, 10.5-18.9). Grade 3 or 4 hematologic adverse events were neutropenia (95.6%), anemia (15.6%), and thrombocytopenia (17.8%). The most common grade 3 or 4 non hematologic adverse events were anorexia (4.4%) and elevated aspartate transaminase/alanine transaminase (2.2%). No toxic death was observed. The main limitation of this study is that only 10 patients (22.2%) who were previously treated with gemcitabine and cisplatin were included. In conclusion, TIN as second-line treatment for MUC is an active regimen with a manageable toxicity profile. PMID- 21323792 TI - Fascin-1 expression correlates with repression of E-cadherin expression in hepatocellular carcinoma cells and augments their invasiveness in combination with matrix metalloproteinases. AB - Expression of fascin-1, an actin bundling protein, is a poor prognostic factor in hepatocellular carcinoma (HCC). However, its biological role in HCC cells remains unclear. Using human HCC tissues and cell lines HLE, Hep3B, and Huh7, we investigated whether fascin-1 is involved in epithelial-mesenchymal transition (EMT) and increases invasiveness, thus serving as a promoter of cancer aggressiveness. Immunohistochemical analysis revealed that fascin-1 expression in 19% of primary HCCs was associated with repression of E-cadherin expression, indicating EMT. In vitro, HLE cells showed high fascin-1 expression, loss of E cadherin, and efficient invasion through Matrigel. Knockdown of fascin-1 significantly repressed invasiveness of the HLE cells and slightly induced E cadherin expression. In contrast, Huh7 cells had low fascin-1 levels, high E cadherin expression, and were expectedly non-invasive. However, forced overexpression of fascin-1 conferred only modest invasiveness without E-cadherin repression, indicating that fascin-1 alone cannot effectively stimulate invasiveness or EMT. Furthermore, Hep3B cells were non-invasive despite high fascin-1 expression. Nevertheless, fascin-1 overexpression dramatically increased the migratory potential of Huh7 cells. We then evaluated matrix metalloproteinases (MMPs) 2 and 9 from the HCC cell lines. Significant MMP secretion was only found in HLE cells. Although MMP levels were not elevated in fascin-1-overexpressing Huh7 cells, their invasiveness was remarkably augmented by coculture with HLE cells, and was suppressed in the presence of an MMP inhibitor. In conclusion, we propose that fascin-1 primarily acts as a migration factor associated with EMT in HCC cells and facilitates their invasiveness in combination with MMPs. PMID- 21323793 TI - Autonomic nerve function in adult patients with cyclic vomiting syndrome. AB - BACKGROUND: Cyclic vomiting syndrome (CVS) in adults is a disorder characterized by recurrent and stereotypic episodes of severe nausea and vomiting separated by symptom-free periods. Autonomic dysfunction has been a postulated mechanism for the pathogenesis of this disorder in children but has not been explored in adults. METHODS: Our goals were to investigate autonomic nerve function in adult patients with CVS. The sympathetic nervous system was evaluated through postural changes in heart rate and blood pressure and sympathetic skin response in the hand and foot. The parasympathetic nervous system was tested through heart rate response to deep breathing [expiration/inspiration (E/I)], Valsalva and postural indices (30 : 15 ratio). All patients had a 4-h standard isotope labeled egg beater meal gastric emptying test (GET). KEY RESULTS: Twenty-two adult (18 female), mean age 35 +/- 11 (range 19-61 years), who met Rome III criteria for CVS were included. History of migraine headache was reported in three patients. Five (23%) had pediatric onset. Of 21 patients who completed the test, nine patients had 21 abnormalities detected in their autonomic nerve testing profile and the remaining 12 had normal autonomic function results. Orthostatic tachycardia was observed in two (mean heart rate increase 39 beats min(-1)) and a decline in blood pressure (BP) in three patients (mean BP drop 30/14 mmHg). Parasympathetic abnormalities were elicited in six patients with an abnormal response to deep breathing and E/I index <1.25. Sympathetic nerve dysfunction was reported in seven patients with absent sympathetic skin response in the foot and/or hand. Twelve (57%) of CVS group had rapid GET (<50% retention at 1 h). The frequency of abnormal autonomic nerve function was not significantly higher in rapid GET subgroup. CONCLUSIONS & INFERENCES: (i) Autonomic nerve dysfunction is common in adult CVS patients, being observed in 43% of our cohort; (ii) Sympathetic abnormalities dominate; and (iii) Rapid gastric emptying, present in 57% of patients, did not correlate with autonomic testing results. These new data provide more insight into the pathophysiology of CVS in adults and help explain the spectrum of clinical manifestations observed in this entity. PMID- 21323794 TI - Management of acute haemarthrosis in haemophilia A without inhibitors: literature review, European survey and recommendations. AB - Acute haemarthrosis is a frequent type of bleeding in individuals with haemophilia. Delayed and/or inadequate treatment can trigger a series of pathological changes within the joint, leading to a painful and disabling arthropathy. The early management of intra-articular bleeding has the potential to prevent chronic joint disease and may include a combination of factor replacement, rest, ice, rehabilitation and, in certain cases, joint aspiration. Little data are, however, available regarding the optimal management of acute haemarthrosis, especially with respect to replacement therapy and the use of adjunctive therapies (aspiration, avoidance of weight bearing and immobilization, as well as the use of anti-inflammatory medication and embolization). To provide more insight into the management of acute haemarthrosis in patients with haemophilia, a literature review was conducted. Concomitantly, current management was surveyed in 26 European haemophilia comprehensive care centres representing 15 different countries. The review highlights the need for future robust studies to better define the appropriate replacement therapy and the role of adjunctive therapies such as aspiration. The survey reveals much heterogeneity in the management of acute haemarthrosis across the EU. Within the constraints discussed, treatment recommendations are presented that reflect the literature, current practice and the clinical experience of the European Haemophilia Therapy Standardisation Board (EHTSB). PMID- 21323795 TI - Standardization of thromboelastography: a report from the TEG-ROTEM working group. AB - Laboratory evaluation of bleeding disorders has been performed with the standard clotting assays such as the PT and PTT for several decades. Our improved understanding of the process of blood coagulation has now revealed the important role played by the cellular elements such as platelets, monocytes and red blood cells. The need for a test that can assess clotting in a more 'global' manner, beyond the initiation of clot formation, has led to greater interest in assays such as thrombin generation and thromboelastography. Even though there are several publications using thromboelastography it remains a research tool as the methodology is not standardized. In an attempt to show reproducibility and consistency using thromboelastography, a group of investigators from different countries joined hands to form the TEG-ROTEM Working Group. Two studies were performed using PRP and FVIII deficient plasma and an intrinsic pathway activator. This article summarizes the results of the first international effort at standardization of thromboelastography. Both of the instruments using this technology (TEG((r)) and ROTEM((r))) were used. Nine laboratories from countries around the globe participated in this effort. The results showed a significant inter-laboratory variance with CV's greater than 10%. Although these results were not satisfactory, this has been the first effort to standardize this methodology and significant work remains to be done to improve reliability and reproducibility. These studies were performed on PRP and the results may be more reliable when preformed on whole blood samples. We believe that it is important to continue this work so that we may investigate the usefulness and potential applications of thromboelastography in the evaluation of bleeding and thrombosis. PMID- 21323796 TI - An improved, semi quantitative clot based assay for factor XIII. PMID- 21323797 TI - Acquired factor XIII inhibitor: clinical features, treatment, fibrin structure and epitope determination. AB - Acquired factor XIII (FXIII) deficiency, arising from an autoantibody against factor XIII, is a rare bleeding disorder. This autoimmune disorder most commonly occurs in the elderly. Patients who develop such acquired FXIII inhibitors may present with catastrophic bleeding events and are hard to be diagnosed with the normal general coagulation tests. Though the disease is relatively rare, it is known to cause significant mortality. In this article we briefly describe a patient who presented with extensive bleeding and a normal activated partial thromboplastin time and prothrombin time (PT), but had an acquired inhibitor to FXIII; her primary disease was systemic lupus erythematosus (SLE). Also, we will focus on the clinical features, treatment modalities, fibrin structure and epitope identification for acquired factor XIII inhibitor with a review of the literature. PMID- 21323798 TI - Pharmacoeconomic impact of obesity in severe haemophilia children on clotting factor prophylaxis in a single institution. PMID- 21323799 TI - Prevalence and risk factors of cardiovascular disease (CVD) events among patients with haemophilia: experience of a single haemophilia treatment centre in the United States (US). AB - The primary objective of the study was to examine the prevalence of cardiovascular disease (CVD) events and their known risk factors among persons with haemophilia (PWH). This cross-sectional study, covering a 5-year period, included PWH aged >=35 years who were cared for at a single haemophilia treatment centre in the United States. Medical records were extensively reviewed to collect the information about CVD events and their risk factors such as obesity, hypertension, diabetes, hypercholesterolemia and smoking. Prevalence rates were compared with national population estimates and associations between risk factors and CVD events were examined using logistic regression. The study cohort comprised 185 PWH (102 haemophilia A and 83 haemophilia B). Lifetime prevalence of a CVD event was 19.5% (36/185, 95% confidence interval [CI] 13.8-25.2%). CVD mortality was 5.4% (10/185, 95% CI 2.7-8.1). Compared with US non-Hispanic White males (NHWH), PWH had about twice the prevalence of coronary artery disease, stroke and myocardial infarction. The prevalence of CVD risk factors for PWH was similar to that for US NHWM with 39.5% of PWH exposed to two or more of these risk factors. Both hypertension and smoking were associated significantly with CVD events, with odds ratios of 4.9 and 6.3, respectively. In conclusion, this study revealed that both CVD events and its risk factors were at least equally prevalent among PWH and might have been even higher than among the US NHWM in the United States. Therefore, it is imperative to implement strategies for CVD prevention among PWH. PMID- 21323800 TI - SEMG activation patterns of thigh muscles during upright standing in haemophilic patients. AB - Although electromyography (EMG) is a common method to evaluate muscle activity, studies utilizing EMG in haemophilic patients are rare. The haemophilic arthropathy, resulting in altered afferent information is expected to cause disturbed activation and inter-muscular coordination patterns in haemophilic subjects. The aim of this study was to determine differences of selected knee muscles between haemophilic patients and non-haemophilic subjects during upright standing. Surface EMG (SEMG) amplitudes of rectus femoris, vastus medialis (VM), vastus lateralis (VL) and biceps femoris (BF) muscles of both sides were measured in 27 haemophilic patients (H) and 26 control subjects (C) while standing on an even surface. Data from both sides were pooled in C, but data of H were subdivided further according to major (H-MA) and minor (H-MI) affected joints. To normalize the data, amplitude ratios (percentage of cumulated activity) were calculated as well. Regardless of whether H-MA or H-MI was compared with C, amplitudes of all extensor muscles reached significantly higher levels in H (P < 0.05). SEMG amplitude ratios also differed between H and C. Independent of subgroup, BF showed significantly reduced activation ratios (P < 0.01). Only the ratios of VM and VL of H-MA could replicate the observed amplitude differences to C (P < 0.05). These findings show that while standing, haemophiliacs maintain the necessary stability demands through increased extensor activities and modulated coordination patterns. Although all thigh muscles of haemophiliacs are characterized by distinct atrophy, increased amplitude levels could be proved for the knee extensor muscles only. Therefore, general atrophy-related effects cannot explain these results. PMID- 21323801 TI - Sequential combined bypassing therapy is safe and effective in the treatment of unresponsive bleeding in adults and children with haemophilia and inhibitors. AB - Some 10-20% of bleeding events in haemophilia patients with high-responding inhibitors cannot be controlled with bypassing agents. However, sequential combined bypassing therapy (SCBT) has been reported to be successful in five children. To extend this observation, a survey was undertaken by the European Haemophilia Treatment Standardisation Board (EHTSB) in children and adults. Data were collected from all centres belonging to the EHTSB network by a retrospective medical record review. SCBT courses were defined as the administration of both recombinant activated factor VIIa (rFVIIa) and activated prothrombin complex concentrate (APCC) within 12 h. A web-based database was prepared to collect data on SCBT courses in a standardized and anonymous manner from patients' files. Eleven inhibitor patients underwent SCBT (nine haemophilia A; two haemophilia B). Two children had refractory knee haemarthrosis and one, an unresponsive calf haematoma. Five adults had significant bleeds following major surgery, one had lower limb compartmental syndrome and one a post-traumatic upper limb haematoma and haemarthrosis. SCBT administration alternated one APCC dose to 1-3 rFVIIa doses: dosing intervals ranged between 3 and 6 h; APCC (20-80 U kg(-1) ) was given every 8-12 h; rFVIIa (90-270 MUg kg(-1) ) was given every 3-12 h. Bleeding control was achieved in 12-24 h in all patients. SCBT was discontinued after 1-15 days. No clinical adverse events were observed, but a significant increase in D dimer levels was seen in three/five patients who were assessed. SCBT was efficacious without adverse events; nevertheless, due to potential risks, it remains a salvage treatment. A prospective clinical trial is needed to provide further evidence. PMID- 21323802 TI - Assessment of acute and persistent pain management in patients with haemophilia. AB - A descriptive survey was conducted in Region V-E of the United States to bridge the gap in available information on pain issues in the bleeding disorders population. The aim of this study was to a) determine language used by patients to describe and differentiate acute and persistent pain, b) describe pharmacological and non-pharmacological strategies utilized to control pain, c) determine the providers of pain management to this population and d) evaluate quality of life incorporating the SF-36 QOL tool. A total of 202 surveys were returned. For the purposes of this paper, it was decided to analyse only haemophilia data (n = 114). Average persistent daily pain levels were 5/10 (P < 0.001). The three most common word descriptors for both acute and persistent pain were the same - achy, throbbing and tender; the most utilized pain medications were NSAIDs and acetaminophen. Factor replacement was used for what respondents described as acute pain management 79% of the time and for persistent pain management 38% of the time. Participants described acute and persistent pain with the same pain descriptors leading to the conclusion that patients have difficulty distinguishing between acute and persistent pain. This lack of differentiation was further displayed by the use of factor replacement to treat persistent pain associated with arthritic discomfort (38%) which would be viewed as inappropriate, as well as lack of factor replacement use by 21% of respondents who identified pain as from an acute bleed. Opportunities exist to improve pain management through patient and provider-directed educational programs. PMID- 21323803 TI - Use of autologous platelet-rich clots for the prevention of local injury bleeding in patients with severe inherited mucocutaneous bleeding disorders. AB - Stopping or preventing local bleeding in patients with inherited bleeding disorders linked to abnormal platelet function is traditionally treated by transfusion of blood cell products or recombinant factor VIIa. We now report the use in such patients of autologous platelet-rich clots as an aid to preventing bleeding and to facilitating tissue regeneration at superficial sites. Two patients with von Willebrand's disease (VWD) type 2B and one patient with type I Glanzmann thrombasthenia were treated after tooth extraction and dental surgery. A fourth patient with platelet-type VWD underwent a skin biopsy. Whereas all four patients had a lifelong history of bleeding complications, the application of an autologous platelet-rich clot immediately after surgery combined with tranexamic acid intake to slow fibrinolysis prevented blood loss and resulted in rapid and normal healing. This new procedure is simple, safe and inexpensive; it provides extra security for patients with a bleeding risk undergoing dentistry or superficial surgery. PMID- 21323804 TI - EGD1 (beta-NAC) mRNA is localized in a novel cytoplasmic structure in Saccharomyces cerevisiae. AB - RNA localization is a common mechanism for recruiting proteins to specific regions of a cell, which causes cell polarization and sometimes asymmetric division. We found that EGD1 mRNA accumulates dose-dependently as a cytoplasmic granule in Saccharomyces cerevisiae. EGD1 encodes a beta-subunit of the nascent polypeptide-associated complex (NAC). NAC is a heterodimer consisting of alpha- and beta-subunits, associated with ribosomes and thought to be involved in the folding of nascent polypeptide chains. Analysis of deletion constructs showed that the localization of EGD1 mRNA requires both an upstream region and an ORF of EGD1, suggesting that the translation of Egd1p is important for localization. We also showed that Egd1p and P-body components are co-localized with EGD1 mRNA. This granule, named the EGD1 granule, has features similar to cellular inclusions containing aggregated proteins. Disruption of microtubules by treatment with a drug, benomyl, resulted in loss of the EGD1 granule. When the expression level of EGD2 encoding the alphaNAC increased, the percentage of cells showing the EGD1 granule decreased, suggesting that the granular distribution of EGD1 depends on the quantitative balance between alpha- and beta-subunits of NAC. Taken together, we propose a novel microtubule-dependent mechanism for controlling NAC through RNA localization. PMID- 21323805 TI - Advanced technologies and treatment for diabetes. Preface. PMID- 21323806 TI - Self-monitoring of blood glucose. AB - Many would argue that the introduction of modern-day diabetes management started 30 years ago with the introduction of self-monitoring of blood glucose (SMBG) at home. While that may be true, it is interesting that many of today's fundamental questions have yet to be answered. Furthermore, the technology itself continues to change, to improve and to better exist with our non-diabetes technology. For example, the first SMBG 'apps' are available now for smart-phones (iPhone), and we can expect the phones themselves to participate more directly with SMBG and diabetes management. Still, both researchers (and payors) continue to ask some fundamental questions. 1. What is the efficacy of SMBG for patients not requiring insulin therapy? 2. What is the optimum frequency of SMBG for patients who do require insulin therapy? 3. What is the role of software to assist in data management for SMBG (for both patients and clinicians)? 4. What is the cost effectiveness of SMBG for all of the different patient populations with diabetes? 5. What is the ideal chemistry which results in the least amount of interfering substances with SMBG? 6. What is an acceptable accuracy for SMBG both at home and in the hospital? The accuracy question is more important than ever since all continuous glucose monitoring (CGM) for now are calibrated with SMBG results. 7 What is the best strategy for teaching patients how best to use their SMBG data? 8. What is the best way to integrate SMBG with insulin pump therapy? 9. What is the role of SMBG with today's CGM devices? 10. What will the role of SMBG be 5-10 years from now with future CGM devices? These are just some of the questions which need more thought and study as we move into 2011. In this chapter we have selected papers that appeared in the PubMed on this topic and chose those we thought were most influential in this area. We have then addressed many of these topics although answers are far from clear for many of them. Although SMBG is not 'new' technology, much research needs to be completed before we fully understand this tool's full impact, particularly as CGM becomes more popular. PMID- 21323807 TI - Continuous glucose monitoring in 2010. AB - After the initial positive data several recent randomised controlled trials offer more firm evidence supporting the efficacy and safety of real-time continuous glucose monitoring (CGM) in type 1 diabetes (T1D). Integrating CGM with insulin pumps offers additional benefit. Improved metabolic control with significant lowering of glycated haemoglobin along with other parameters of glycaemia and without a concomitant increase in hypoglycaemia is demonstrated in all age groups, including children and adolescents. Reducing hypoglycaemia with CGM in well-controlled individuals with T1D remains to be demonstrated; however, evidence for reducing hypoglycaemia in critically ill patients seems convincing. Several important aspects of type 2 diabetes (T2D) were recently addressed by professional CGM. Adding predictive algorithms to CGM may considerably improve its efficacy and lead the way towards the closed loop. PMID- 21323808 TI - Insulin pumps. AB - The last year has seen a continued uptake of insulin pump therapy in most countries. The USA is still a leader in pump use, with probably some 40% of type 1 diabetic patients on continuous subcutaneous insulin infusion (CSII), but the large variation in usage within Europe remains, with relatively high use (> 15%) in, for example, Norway, Austria, Germany and Sweden and low use (< 5%) in Spain, the UK, Finland and Portugal. There is much speculation on the factors responsible for this variation, and the possibilities include physician attitudes to CSII and knowledge about its benefits and indications for its use (and inappropriate beliefs about dangers), the availability of reimbursement from insurance companies or funding from national health services, the availability of sufficient diabetes nurse educators and dietitians trained in pump procedures, and clear referral pathways for the pump candidate from general practitioner or general hospital to specialist pump centre. There are now several comprehensive national guidelines on CSII use (see ATTD Yearbook 2009) but more work needs to be done in unifying uptake and ensuring all those who can benefit do so. Technology developments recently include increasing use of pumps with continuous glucose monitoring (CGM) connectivity (see elsewhere in this volume) and the emergence of numerous manufacturers developing so-called 'patch pumps', often for the type 2 diabetes market. Interestingly, the evidence base for CSII in this group is not well established, and for this reason the selected papers on CSII in this section include several in this area. The use of CSII in diabetic pregnancy is a long-established practice, in spite of the lack of evidence that it is superior to multiple daily injections (MDI), and few randomised controlled trials have been done in recent years. Several papers in this field this year continue the debate about the usefulness of CSII in diabetic pregnancy and are reviewed here. It is pleasing to see more research on the psychosocial aspects of CSII during the year, both from the point of view of how psychological beliefs influence outcomes on CSII (is there a type of patient who does particularly well or poorly on CSII?) and how CSII affects psychological factors like mood, behaviour and quality of life. Quality of life is a difficult topic with doubts that the instruments always capture the aspects of quality of life important to the patient, and there have been conflicting results over the years about whether CSII alters quality of life. Patients in the clinic usually say that it does, and more evidence for quality of life improvement in pump therapy is reviewed here. PMID- 21323809 TI - Closing the loop. AB - Closed-loop algorithms can be found in every aspect of everyday modern life. Automation and control are used constantly to provide safety and to improve quality of life. Closed-loop systems and algorithms can be found in home appliances, automobiles, aviation and more. Can one imagine nowadays driving a car without ABS, cruise control or even anti-sliding control? Similar principles of automation and control can be used in the management of diabetes mellitus (DM). The idea of an algorithmic/technological way to control glycaemia is not new and has been researched for more than four decades. However, recent improvements in both glucose-sensing technology and insulin delivery together with advanced control and systems engineering made this dream of an artificial pancreas possible. The artificial pancreas may be the next big step in the treatment of DM since the use of insulin analogues. An artificial pancreas can be described as internal or external devices that use continuous glucose measurements to automatically manage exogenous insulin delivery with or without other hormones in an attempt to restore glucose regulation in individuals with DM using a control algorithm. This device as described can be internal or external; can use different types of control algorithms with bi-hormonal or uni-hormonal design; and can utilise different ways to administer them. The different designs and implementations have transitioned recently from in silico simulations to clinical evaluation stage with practical applications in mind. This may mark the beginning of a new era in diabetes management with the introduction of semi closed-loop systems that can prevent or minimise nocturnal hypoglycaemia, to hybrid systems that will manage blood glucose (BG) levels with minimal user intervention to finally fully automated systems that will take the user out of the loop. More and more clinical trials will be needed for the artificial pancreas to become a reality but initial encouraging results are proof that we are on the right track. We attempted to select recent publications that will present these current achievements in the quest for the artificial pancreas and that will inspire others to continue to progress this field of research. PMID- 21323810 TI - New insulins and insulin therapy. AB - The introduction of the so-called 'designer' insulins, the insulin analogues, has offered new opportunities in the clinical management of diabetes. Two additional new entities are close to reaching clinical practice. LinjetaTM (formally called VIAject) is not an analogue but rather a different formulation of human insulin which may give it a more rapid onset of action, potentially even faster than the currently available rapid-acting insulin analogues. DegludecTM, on the other hand, is an insulin analogue molecule with an ultra-long clinical profile derived from the soluble multi-hexamer formation, resulting in a continuous slow and stable release of insulin degludec monomers which may last longer than currently available long-acting analogues. As with any new type of drug, the safety of the 'designer' insulins has to be closely scrutinised. Last year the increased cancer risk in diabetes entered the spotlight and the potential role of insulin analogues led to controversial discussions. In spite of recent new in vitro and observational data no new conclusive evidence became available. The need for multiple well-conducted and appropriately designed prospective observational studies to follow up the effectiveness and safety of the new insulins and the new insulin treatment regimens remains. In this chapter it was our mission to chose articles published about "new insulins" over the last year that have the most important contribution for the on-going development of ultra-fast- and ultra-long acting insulin analogs and preparations and their potential side-effects, particularly cancer. This has been done by means of PubMed searches as well as a review of abstracts of the recent large international diabetes meetings such as ADA, EASD and ISPAD. PMID- 21323811 TI - New ways of insulin delivery. AB - The predominant number of papers published from the middle of 2009 to the middle of 2010 about alternative routes of insulin administration (ARIA) were still about inhaled insulin. Long-term experience with Exubera was the topic of a number of publications that are also of relevance for inhaled insulin in general. The clinical trials performed with AIR insulin by Eli Lilly were published in a supplement issue of one diabetes technology journal and most of these will be presented. A number of other publications (also one in a high ranked journal) about their inhaled insulin were from another company: MannKind. The driving force behind Technosphere insulin (TI) - which is the only one still in clinical development - is Al Mann; he has put a lot of his personal fortune in this development. We will know the opinion of the regulatory authorities about TI in the near future; however, I am personally relatively confident that the Food and Drug Administration will provide TI with market approval. The more critical question for me is: will diabetologists and patients jump on this product once it becomes commercially available? Will it become a commercial success? In view of many negative feelings in the scientific community about inhaled insulin, it might be of help that MannKind publish their studies with TI systematically. Acknowledging being a believer in this route of insulin administration myself, one has to state that Exubera and AIR insulin had not offered profound advantages in terms of pharmacokinetic (PK) and pharmacodynamic (PD) properties in comparison with subcutaneously (SC) applied regular human insulin (RHI) and rapid acting insulin analogues. The time-action profiles of these inhaled insulins were more or less comparable with that of rapid-acting insulin analogues. This is clearly different with TI which exhibits a strong metabolic effect shortly after application and a rapid decline in the metabolic effect thereafter; probably the duration of action is even too short (see postprandial glycaemic excursions with test meals in the publication by Rosenstock et al. in The Lancet (1)). In the end a number of aspects are of relevance for the success of a given product; one key aspect is clearly the price. However, for patients also practical aspects (handling, need for regular pulmonary function test etc.) are of importance. We shall have to see how creatively MannKind will handle all such questions. Until now Al Mann and his colleagues were able to manage a number of challenges during the clinical development process successfully, so one can have hopes for the market success of TI. However, it is clear that at the same time, if TI fails like Exubera did before, this will be the end for pulmonary insulin in general. Not too many original publications presenting data from clinical trials were published in the last year when it comes to oral insulin (OI), nasal insulin or transdermal insulin developments; simply none with transdermal insulin. Also at the last international congresses not many studies about ARIA were presented. At least in part this might be still a reflection of the shockwaves that the failure of Exubera has sent out to pharmaceutical companies and venture capitalists; they are quite reluctant to invest in any of these developments. However, a considerable number of reviews (in some cases more than original papers!) were published about ARIA. These reviews are listed for completeness, but in most cases are not further commented. OI is still the area of research most companies are active in; however, in some cases it is not clear how active they really are (e.g. Diabetology). Nevertheless, at least some companies are quite active and progressed in their clinical development programme close to market approval, e.g. the large Indian company Biocon is in late phase 3 with IN-105 and the small Israel-based company Oramed is in phase 2b. It appears that other interesting OI developments (e.g. Diasome) were not very active in the last year; at least they have not published new study results. It is clear that for companies that produce insulin themselves (e.g. Biocon) the costs of the good are not of such relevance as for companies that have to buy it commercially. For the latter ones a low bioavailability/biopotency compared with SC insulin administration can be a real hurdle when it comes to the price of their product. Despite some publications about nasal insulin, the overall activity with this route of insulin administration appears to be low; the same holds true for transdermal insulin. Insulin pens have gained more scientific interest in recent years, which is also reflected by an increase in publications, starting from practically nil 10 years ago to a solid number of five to 10 papers per year nowadays. Besides ARIA there are also attempts to increase the speed of insulin absorption after injection into the skin by applying it not into the SC tissue but intradermally or by heating up the skin above the SC insulin depot. Reading a number of papers that were not included in this chapter because they do not present any clinical data but are novel developments tested only in animal experiments so far, the clear message is that there is definitely not a lack of creativity/imagination amongst scientists; each year a plethora of new ideas for insulin application show up. Unfortunately not too many make it towards a full clinical development. As long as there is not a single successful product on the market that is based on a given ARIA approach, this area of research will not mature. For many patients, avoiding the need for SC injections is attractive; however, as long as no clear 'advantage' can be demonstrated, reimbursement will be difficult to achieve. Living in the time of evidence-based medicine it is clear that 'relevant' clinical advantages must be proven. The question is what is relevant. Is it just an improvement in metabolic control (= decrease in HbA1c)? Can this also mean that more patients are willing to start insulin therapy earlier than with conventional SC insulin therapy? With TI we have a product that has improved pharmacological properties (also in comparison to Exubera) for coverage of prandial insulin requirements. Subsequently, in the clinical trials performed, postprandial glycaemic excursions were lower than with SC injection of RHI or rapid-acting insulin analogues. This only in part (if at all) results in an improved metabolic control in general (= lower HbA1c) (see below). The outlook for 2011 is that there are chances that we shall have an inhaled insulin product on the market. Probably also the first OI will be submitted to the regulatory authorities for market approval or will even be available in less regulated markets. In order to select all relevant publications about new ways of insulin delivery I performed a PUBMED search and also checked the table of contents of a number of journals that publish heavily in this area of research as well references in the publications I found for additional references. Selection of the manuscripts from all publications was predominately based on the fact whether they presented data from clinical studies or not. The selected studies were critically reviewed for novelty and appropriate study design etc. In some cases also reviews about a given topic were selected if they provide relevant novel insights. PMID- 21323812 TI - Information technology in the service of diabetes prevention and treatment. AB - In the year since the first ATTD yearbook was published the field of internet and cell phone interventions has made major advances. This chapter contains clinical studies and reviews of the state-of-the-art regarding the ability of technology enabled self-management education and support to improve outcomes for patients with, or at risk for, diabetes. The reviews and papers in this chapter demonstrate increased understanding of the underlying basis for effective interventions - a prerequisite for improving the effectiveness and efficiency of these approaches. The research studies described demonstrate that internet interventions are effective for a variety of patients and for specific outcomes (e.g. diabetes self-management for teens as well as older patients, medication adherence, empowerment, psychosocial well-being, helping patients become more active, and helping patients lose weight and keep it off). As additional and more sophisticated studies are completed and the evidence base is expanded one can hope that payors will recognise their value and begin to pay for these treatments. That is what ultimately will bring effective treatments to those who need them. The associate editors' mission was to choose articles that would give the non-technology skilled reader a general overview of the field of information technology and the prevention and treatment of obesity and diabetes. Articles were selected because they either provided a significant review of the state-of the art of the field or were the results from studies that could give the reader a better understand of the benefits and challenges associated with information technology use in clinical settings. PMID- 21323813 TI - Technology and pregnancy. AB - The World Health Organisation projects that the number of diabetes-related deaths will double between the years 2005 and 2030. An important method for reducing the number of new cases of diabetes is by screening for and controlling glucose in women with gestational diabetes, the form of diabetes that afflicts up to 10% of the pregnant population. Uncontrolled gestational diabetes mellitus results in an increased risk of complications due to maternal hyperglycaemia and the resultant fetal hyperinsulinaemia. These complications include macrosomia and an increased risk of metabolic disorders including diabetes later in the child's life. Advances in the treatment of gestational diabetes have shown promising results in minimising fetal complications; they have also helped to slow the vicious cycle of women who contract gestational diabetes mellitus producing children with a high risk of developing diabetes later in life. A comprehensive literature review with an emphasis on technology has resulted in the following collection of papers relating to pregnancy and diabetes. Last year there were several technological advances in glucose monitoring. This year the applications of telemedicine in the treatment of gestational diabetes and the use of ultrasound for early detection of the disease have been at the forefront. The authors aimed to include articles that were not only relevant to the field of diabetes technology in pregnancy, but that also improved treatment and advanced understanding. The study design and results were also carefully examined in considering the articles. The selected articles contain findings that provide new techniques for diagnosing gestational diabetes mellitus as well as provide additional treatment methods for those affected by the disease. PMID- 21323814 TI - Immune intervention for type 1 diabetes mellitus. AB - The major form of type 1 diabetes (T1D) is characterised by immune-mediated pancreatic islet beta-cell destruction, and has also been called type 1A diabetes to distinguish it from idiopathic forms of islet beta-cell loss. Since the first demonstration of islet cell antibodies in 1974, the concept has been that this form of diabetes is autoimmune in nature. The commonly accepted concept is that antibodies (representing the humoral arm of the immune system) do not mediate the beta-cell destruction but rather serve as markers of that destruction, while the cellular arm of the immune system, specifically T-lymphocytes, mediate the beta cell destruction. Yet, the T-lymphocytes do not act alone. They receive help in initiating the response from antigen-presenting cells such as dendritic cells and macrophages, and appear to receive help also from B-lymphocytes. In addition, the initial immune response engenders secondary and tertiary responses - involving the whole immunological army - which collectively result in impairment of beta cell function, progressive destruction of beta-cells, and consequent development of type 1A diabetes. The process is insidious and may evolve over many years, with the overt expression of clinical symptoms becoming apparent only when most beta-cells have been destroyed. Yet, the process clearly evolves at different speeds - much more rapidly in young children, much more slowly in older individuals. And, although it has been thought that ultimately there is complete beta-cell destruction, several studies have now demonstrated some degree of persistent beta-cell function or existence (at autopsy) in long-standing T1D. A major focus of investigation in T1D is the preservation of beta-cell function (and, it is hoped, of beta-cells themselves), in the expectation that continuing endogenous insulin secretion will contribute towards better glycaemic control, reduce episodes of severe hypoglycaemia, and slow the development of complications such as retinopathy and nephropathy. Thus, there have been many studies designed to interdict the T1D disease process, mostly by altering the immune system, both during the stage of evolution of the disease and at the time of disease onset. This chapter of the Yearbook of Advanced Technology and Treatments in Diabetes reviews the key papers that have appeared in this field between July 2009 and June 2010. Articles selected were confined to studies in human beings. All immune intervention studies reported in this time frame were included. In addition, the author selected other relevant articles dealing with mechanisms, markers, triggers, and pathology of human type 1 diabetes. PMID- 21323815 TI - Exercise and diabetes. AB - Diet and exercise form the foundation of a healthy lifestyle. These are especially important for people living with diabetes mellitus, as they are the most practical non-pharmacological means by which patients may significantly improve their blood glucose levels. Exercise increases insulin sensitivity (both short and long term), lowers blood sugar levels, reduces body fat and improves cardiovascular (CV) function. Because of this, exercise offers enormous benefit to patients with diabetes. Blood glucose levels can significantly drop during and after physical activities, due to the increased utilisation of glucose as a fuel during exercise and the up-regulation of glucose transport into working muscles. Therefore, patients (especially those with type 1 diabetes) must account for the effects of exercise and adjust their medications and nutrition accordingly. Improvements in real-time continuous glucose monitoring and optimisation of basal insulin dosing may offer significant benefit to preventing hypoglycaemia in patients with type 1 diabetes who regularly exercise. Diverse exercise programmes and devices can also assist patients in monitoring their activities as well as motivating them to achieve their exercise goals. For patients with type 1 diabetes, questions such as how much, how long, how strenuous and what kind of exercise must be addressed in order for healthcare professionals to offer maximum benefit to their patients. Additionally, since patients with type 2 diabetes often have other significant co-morbidities such as obesity and CV disease, care providers must evaluate each patient's risk factors before designing an exercise programme. Several publications in the last year have addressed these issues and may serve as a valuable resource to provide safe and effective recommendations to patients and their healthcare providers. To be included in the Exercise and Diabetes chapter for the 2010 YEARBOOK, we reviewed leading peer-reviewed manuscripts that were published in the period July 2009 to June 2010. PubMed was used in the initial screening of articles. PMID- 21323816 TI - Diabetes technology and treatments in the paediatric age group. AB - Type 1 diabetes (T1D) is one of the most common chronic childhood diseases and its incidence has doubled during the last decade. The goals of intensive management of diabetes were established in 1993 by the Diabetes Control and Complications Trial (DCCT) (1). Children with T1D and their caregivers continue to face the challenge to maintain blood glucose levels in the near-normal range. It is important to prevent sustained hyperglycaemia which is associated with long term microvascular and macrovascular complications and to avoid recurrent episodes of hypoglycaemia or hyperglycaemia, especially in young children, which may have adverse effects on cognitive function and impede efforts to achieve the recommended glycaemic targets. Advances in the use of technology that may help maintain the metabolic control goals for young people with T1D were centred on continuous subcutaneous insulin infusion (CSII) (2-4), continuous glucose monitoring (CGM) (5-7), and combining both technologies into a closed-loop system (8-10). The dilemma in paediatrics of patient selection for insulin pump therapy was found to be most successful in those with more frequent self-monitoring of blood glucose (SMBG) and younger age prior to pump initiation (2). Similarly, those who used a dual-wave bolus probably paid closer attention to their management and had lower HbA1c levels (3). The advantage of using a pre-meal bolus to improve postprandial glucose levels was shown to offer another potential method to improve glycaemic control (4). SMBG is an important component of therapy in patients with diabetes, especially in the paediatric age group. Standard use of glucose meters for SMBG provides only intermittent single blood glucose levels, without giving the 'whole picture' of glucose variability during the 24 h, and especially during the night, when blood glucose levels are seldom measured. Therefore, the use of a device such as real-time continuous glucose monitoring (RT-CGM) that provides continuous glucose measurements can help patients optimise glycaemic control. These devices may have the potential to increase the proportion of patients who are able to maintain target HbA1c values, to decrease glucose excursions and to decrease the risk of severe hypoglycaemia. Previous studies in paediatric T1D patients (11,12) have demonstrated that the frequency of CGM use was significantly associated with the effect of lowering HbA1c levels. The important STAR 3 study of 485 patients (156 children) with T1D showed the benefit of sensor-augmented pump therapy over remaining on multiple daily injections (MDI) (10). The Juvenile Diabetes Research Foundation Continuous Glucose Monitoring (JDRF-CGM) studies were initially described in the 2009 Yearbook (13). Further reports of youths and adults in this study found that those with initial low HbA1c levels (< 7%) show a significant benefit from the use of CGM (5). Prolonged nocturnal hypoglycaemia was shown to continue to be a common occurrence in the entire cohort using CGM (7). Thus, there is an obvious need for closing the loop. Many patients with diabetes and especially parents of diabetic children dream about the invention of an 'artificial pancreas'. CSII and RT-CGM can be combined to form closed-loop systems. Insulin is then delivered according to RT-CGM data, as directed by a control algorithm, rather than at pre programmed rates. Few closed-loop prototypes have been developed with advanced control algorithms, such as those that are based on model predictive control (14). The group at Cambridge studied 19 young people in closed-loop systems and was able to demonstrate that exercise and diet variations could be aptly managed (9). It is expected that closed-loop studies in young people will continue to multiply in future years. T1D is characterised by immune-mediated pancreatic beta cell destruction. Thus, a major goal in the treatment of T1D in youth will be in the area of prevention. The identification of increased levels of inflammatory markers in the SEARCH study of young people with T1D may provide an important clue (15). Most of the studies countered the diabetes process by immunomodulation and/or enhancement of beta-cell proliferation and regeneration (16). An initial pilot trial of a tumour necrosis factor alpha (TNF-alpha) binding agent, Entanercept, showed benefit in preserving C-peptide production in 18 young people with newly diagnosed T1D. HbA1c levels were also lower in the treatment group (5.9% +/- 0.5% vs. 6.98% +/- 1.2%; p < 0.05) (17). Similarly, beta-cell function was shown to be preserved in children receiving the lower of two doses of ingested human recombinant interferon-alpha (hrINF-alpha) in comparison with subjects who received placebo (18). A future larger trial of both of these agents will be of interest. In this review of the literature we have tried to select recent publications that offer some insight into these issues in paediatric patients with T1D. PMID- 21323817 TI - Diabetes technology and the human factor. AB - When developing new technologies for human use the developer should take into consideration not only the efficacy and safety of the technology but also the desire and capabilities of the potential user. Any chronic disease is a challenge for both the patient and his/her caregivers. This statement is especially true in the case of patients with type 1 diabetes mellitus (T1DM) where adherence to therapy is crucial 24 hours a day 365 days a year. No vacation days are possible for the T1DM patient. It is therefore obvious why any new technology which is developed for helping patients cope with the disease should take into consideration the 'human factor' before, during and after the production process starts. There is no doubt that technology has changed the life of patients with T1DM in the last few decades, but despite the availability of new meters, new syringes, new sophisticated insulin pumps and continuous glucose sensors and communication tools, these technologies have not been well utilised by many patients. It is therefore important to understand why the technology is not always utilised and to find new ways to maximise use and benefits from the technology to as many patients as possible. The present chapter will review papers published in the last year where the patient's ability or willingness was an important factor in the success of the technology. We will try to understand why insulin pumps, glucose sensors and self-monitoring of blood glucose (SMBG) are not used enough or appropriately, whether there is a specific group that finds it more difficult than others to adopt new technologies and what can be done to overcome that issue. For this chapter we chose articles from a Public Medicine review of the literature related to human factors affecting the outcome of studies and of user acceptance of continuous glucose monitoring, insulin infusion pump therapy. We also searched the literature in the field of psychology in order to accurately define the problems that the users of technology are facing (such as adherence, quality of life, motivations, executive functioning etc.) Those articles that had the most important contributions to understanding human factors as well as those highlighting the interface between technology and psychology, were chosen for this review, with emphasis on articles that provide insight into future studies and acceptance of emerging technologies for glycemic control. PMID- 21323818 TI - Shared decision making: vision to reality. PMID- 21323819 TI - Assessing Medicare beneficiaries' strength-of-preference scores for health care options: how engaging does the elicitation technique need to be? AB - OBJECTIVE: The objective was to determine if participants' strength-of-preference scores for elective health care interventions at the end-of-life (EOL) elicited using a non-engaging technique are affected by their prior use of an engaging elicitation technique. DESIGN: Medicare beneficiaries were randomly selected from a larger survey sample. During a standardized interview, participants considered four scenarios involving a choice between a relatively less- or more-intense EOL intervention. For each scenario, participants indicated their favoured intervention, then used a 7-point Leaning Scale (LS1) to indicate how strongly they preferred their favoured intervention relative to the alternative. Next, participants engaged in a Threshold Technique (TT), which, depending on the participant's initially favoured intervention, systematically altered a particular attribute of the scenario until the participant switched preferences. Finally, they repeated the LS (LS2) to indicate how strongly they preferred their initially-favoured intervention. RESULTS: Two hundred and two participants were interviewed (189-198 were included in this study). The concordance of individual participants' LS1 and LS2 scores was assessed using Kendall tau-b correlation coefficients; scores of 0.74, 0.84, 0.85 and 0.89 for scenarios 1-4, respectively, were observed. CONCLUSION: Kendall tau-b statistics indicate a high concordance between LS scores, implying that the interposing engaging TT exercise had no significant effects on the LS2 strength-of-preference scores. Future investigators attempting to characterize the distributions of strength-of preference scores for EOL care from a large, diverse community could use non engaging elicitation methods. The potential limitations of this study require that further investigation be conducted into this methodological issue. PMID- 21323820 TI - Pictures speak louder than numbers: on communicating medical risks to immigrants with limited non-native language proficiency. AB - BACKGROUND AND OBJECTIVES: Medical risk communication has been infrequently studied in immigrants with limited non-native language proficiency, even though they may be at greatest risk of illness. In a study, we examined to what extent Polish immigrants to the UK have difficulties in understanding treatment risk reduction expressed as ratios either in their native language or in a non-native language (English). We further investigated whether this population can be aided by using visual displays to enhance comprehension. DESIGN, SETTING, AND PARTICIPANTS: A survey was conducted in the UK in spring, 2009, involving a sample of Polish immigrants (n = 96). OUTCOME MEASURES: Estimates of treatment risk reduction, confidence in estimates, and perceptions of treatment effectiveness. RESULTS: When assessing treatment risk reduction, participants often paid too much attention to the number of treated and non-treated patients who died (i.e. numerators) and insufficient attention to the overall number of treated and non-treated patients (i.e. denominators). This denominator neglect was especially noticeable when treatment risk reduction was not expressed in participants' native language. However, provision of visual aids in addition to the numerical information about risk reduction proved to be an effective method for eliminating denominator neglect. The visual aids drew participants' attention to the overall number of treated and non-treated patients and helped them to make more accurate risk estimates. CONCLUSIONS: When communicating risks to immigrants with limited non-native language proficiency, we should move beyond the simple, direct translation of health messages that are already being used with the indigenous population to messages that are more appropriate. The use of materials that include visual aids is an effective method of communicating medical risk information to immigrant populations. PMID- 21323821 TI - What does it take to have sustained use of decision aids? A programme evaluation for the Breast Cancer Initiative. AB - BACKGROUND: The Breast Cancer Initiative (BCI) was started in 2002 to disseminate breast cancer decision aids (PtDAs) to providers. METHODS: We analysed BCI programme data for 195 sites and determined the proportion of sites involved in each of five stages of dissemination and implementation of PtDAs. We conducted cross-sectional mail and telephone surveys of 79 sites with the most interest in implementation. We examined barriers associated with sustained use of the PtDAs. RESULTS: Since 2002 we attempted contact with 195 sites to join the BCI. The majority indicated interest in using PtDAs 172 of 195 (88%), 93 of 195 signed up for the BCI (48%), 57 of 195 reported distributing PtDAs to at least one patient (57%), and 46 of 195 reported sustained use (24%). We analysed data from interviews with 59 of 79 active sites (75% response rate). The majority of providers 49 of 59 (83%) had watched the PtDAs, and 46 of 59 (78%) distributed them to patients. The most common barriers were lack of a reliable way to identify patients before decisions are made (37%), a lack of time to distribute the PtDAs (22%) and having too many educational materials (15%). Sites that indicated a lack of clinician support as a barrier were significantly less likely to have sustained use compared to sites that didn't (33% vs. 74%, P = 0.02). CONCLUSIONS: Community breast cancer providers, both physicians and non physicians, express a high interest in using PtDAs with their patients. About a quarter of sites report sustained use of the PtDAs in routine care. PMID- 21323822 TI - Shared decision making or paternalism in nursing consultations? A qualitative study of primary care asthma nurses' views on sharing decisions with patients regarding inhaler device selection. AB - BACKGROUND: Although patients with asthma would like more involvement in the decision-making process, and UK government policy concerning chronic conditions supports shared decision making, it is not widely used in practice. OBJECTIVE: To investigate how nurses approach decision making in relation to inhaler choice and long-term inhaler use within a routine asthma consultation and to better understand the barriers and facilitators to shared decision making in practice. SETTING AND PARTICIPANTS: Semi-structured interviews were conducted with post registration, qualified nurses who routinely undertook asthma consultations and were registered on a respiratory course. Interviews were recorded, transcribed and analysed using the Framework approach. RESULTS: Twenty participants were interviewed. Despite holding positive views about shared decision making, limited shared decision making was reported. Opportunities for patients to share decisions were only offered in relation to inhaler device, which were based on the nurse's pre-selected recommendations. Giving patients this 'choice' was seen as key to improving adherence. DISCUSSION: There is a discrepancy between nurses' understanding of shared decision making and the depictions of shared decision making presented in the academic literature and NHS policy. In this study, shared decision making was used as a tool to support the nurses' agenda, rather than as a natural expression of equality between the nurse and patient. CONCLUSION: There is a misalignment between the goals of practice nurses and the rhetoric regarding patient empowerment. Shared decision making may therefore only be embraced if it improves patient outcomes. This study indicates attitudinal shifts and improvements in knowledge of 'shared decision-making' are needed if policy dictates are to be realised. PMID- 21323823 TI - Turning signals into meaning--'shared decision making' meets communication theory. AB - Shared decision making (SDM) is being increasingly challenged for promoting an innovative role model while adhering to an archaic approach to patient-clinician communication, both in clinical practice and the research field. Too often, SDM has been studied at the individual level, which ignores the interpersonal system between patients and physicians. We aimed to encourage debate by reflecting on the essentials of SDM in terms of epistemology. We operationalized the SDM core concept of information exchange in terms of social systems theory. An epistemological analysis of the term information refers to its inherent process character. Exchange of information thereby becomes synonymous with social sense construction, indicating that, rather than just being a vehicle, the act of communication itself is the information. We plead for the adoption of existing dyadic analytical methods such as those offered by the interpersonal paradigm. Implications of an updated concept of information for the use of SDM-evaluation methods, for SDM-goal setting, and for clinical practice of SDM are described. PMID- 21323824 TI - Do physicians' recommendations pull patients away from their preferred treatment options? AB - CONTEXT AND OBJECTIVE: Shared decision making is especially advocated for preference-sensitive decisions. We investigated whether physicians' recommendations pull patients away from their preferred treatment option when making a preference-sensitive decision. DESIGN, PARTICIPANTS AND METHODS: Inpatients (N = 102 with schizophrenia, N = 101 with multiple sclerosis) were presented with a hypothetical scenario (the choice between two drugs). They were first asked about their preferences concerning the two drugs and then they received a (fictitious) clinician's recommendation that was contrary to their preferences. Subsequently they made a final choice between the two drugs. MAIN OUTCOME MEASURES: The main outcome measure was whether the patient followed the physician's advice in the hypothetical scenario. Thereby patient's (pre recommendation) preferences served as a baseline. RESULTS: In the decision scenario, about 48% of the patients with schizophrenia and 26% of the patients with multiple sclerosis followed the advice of their physician and thus chose the treatment option that went against their initial preferences. Patients who followed their physician's advice were less satisfied with their decision than patients not following their physician's advice (schizophrenia: t = 2.61, P = 0.01; multiple sclerosis: t = 2.67, P = 0.009). DISCUSSION AND CONCLUSIONS: When sharing decisions with patients, physicians should be aware that their advice might influence patients' decisions away from their preferred treatment option. They should encourage their patients to identify their own preferences and help to find the treatment option most consistent with them. PMID- 21323825 TI - The treatment of an unusual complication associated with a HeartMate II LVAD in an adolescent. AB - The HeartMate II LVAD has provided a bridge to heart transplantation or a permanent fixture for destination therapy for patients with heart failure. LVAD infections are associated with significant morbidity even when treated with explantation, device exchange, or a salvage procedure. We present an unusual complication following the placement of the HeartMate II device in an adolescent, whereby a pocket infection resulted in a large soft tissue defect overlying and surrounding the device. The novel use of a VRAM flap was successfully used to repair the defect and salvage the device. PMID- 21323826 TI - Hypercalcemia and altered biochemical bone markers in post-bone marrow transplantation osteopetrosis: a case report and literature review. AB - Autosomal recessive osteopetrosis is a rare disorder of bone resorption defect that results in generalized sclerotic bones and bone marrow failure. Allogeneic BMT is the only treatment for cure. One of the complications following a successful BMT is hypercalcemia that is a unique complication in this group of patients. We report a three-yr-old boy with osteopetrosis who developed hypercalcemia following the successful BMT. His maximal calcium level was 13.3 mg/dL. Markedly increased both bone formation and resorption markers were demonstrated along with hypercalcemia. These findings indicated an active donor derived osteoclastic function and thus bone resorption following the successful donor engraftment in the patient. Treatment with hyperhydration, furosemide and bone resorption inhibitors, calcitonin, and bisphosphonate led to normalization of the serum calcium level. Bone resorption but not bone formation marker was persistently elevated despite having normocalcemia during a 16.5-month follow-up period. PMID- 21323827 TI - Cerebral phaeohyphomycosis caused by Bipolaris spicifera after heart transplantation. AB - Phaeohyphomycosis is an increasingly recognized cause of brain abscess in both immunocompetent and immunocompromised hosts. We report a case of cerebral phaeohyphomycosis in a 55-year-old male heart transplant recipient caused by Bipolaris spicifera. We review the literature regarding the pathogenesis, epidemiology, diagnosis, and management of infections with dematiaceous fungi. PMID- 21323828 TI - Disseminated adiaspiromycosis: case report of a liver transplant patient with human immunodeficiency infection, and literature review. AB - Disseminated adiaspiromycosis is a rare infection that is sometimes associated with immunocompromised situations. We report the case of a patient, infected with human immunodeficiency virus and receiving highly active antiretroviral therapy, who had a liver transplant for hepatocellular carcinoma. The patient presented skin and pulmonary lesions due to adiaspiromycosis during immunosuppressive therapy. A review of >60 cases in the literature shows that adiaspiromycosis is a rare infection and Emmonsia is a dimorphic fungus that is difficult to grow. It should be considered a possible diagnosis in case of fungal infection and pulmonary granulomatosis. We should be aware of emerging adiaspiromycosis in patients with risk factors of immunosuppression, particularly transplant recipients. In these patients in particular, liposomal amphotericin B therapy should be considered. PMID- 21323829 TI - Gene profiling analysis reveals the contribution of CD24 and P2Y6R to the susceptibility of young rats to Plasmodium berghei infection. AB - Our previous studies have shown that Plasmodium berghei infection induces distinct clinical, parasitological and immunological states in young susceptible rats versus adult resistant rats. This susceptibility was mainly found to be related to inadequate cellular responses. In this study we first identified the altered genes in young susceptible rats. Unexpectedly, transcriptome analysis did not reveal any alteration of effector cytokines or their receptors. At day 13 p.i., six transcripts corresponding to faim3, mesothelin, gas3 (PMP22), gas7, CD24 and P2Y6R were significantly decreased in young infected rats when compared with adult infected rats. Because CD24 and P2Y6R participate in cellular immune responses, we next evaluated their role in the course of infection. Adoptive transfer experiments showed a transient but robust participation of CD24+ cells in the control of parasitaemia. The role of P2Y6R was investigated via its specific ability to be activated by Uridine di-Phosphate (UDP). Young rats treated with UDP partially restored the expression of P2Y6R, controlled parasitaemia and survived thereafter. In conclusion, this study contributes to the discovery of novel biomarkers in young susceptible rats and suggests that the decrease in their expression could be among the reasons for the development of severe pathology in malaria. PMID- 21323831 TI - Successful bleaching of teeth with dentinogenesis imperfecta discoloration: a case report. AB - Dentinogenesis imperfecta (DI) is a hereditary condition that can cause discoloration of teeth in addition to other dental abnormalities. Patients often present to the dentist with a main goal of improving their esthetics. A myriad of treatment options have been described for this condition. This clinical report describes the management of a young adult with DI who desired improvement in dental esthetics after orthodontic treatment. As a result of his condition, the patient's dentition exhibited the classic generalized dark amber opalescence. A 14% hydrogen peroxide gel was used for bleaching of the maxillary and mandibular teeth, performed by the patient at home. The patient was followed at different intervals, and the improvement in teeth shade was significant and remained stable at 3.5 years. No adverse effects were observed. This article is the first case report in the literature describing the long-term follow-up of teeth bleaching in a patient with DI. CLINICAL SIGNIFICANCE: Teeth bleaching may be considered as the first choice of treatment in dentinogenesis imperfecta patients. If successful, it offers a simple, conservative, and economical solution to satisfy the esthetic requirements of these patients. PMID- 21323832 TI - Commentary. Successful bleaching of teeth with dentinogenesis imperfecta discoloration: a case report. PMID- 21323833 TI - Influence of esthetic dental and facial measurements on the Caucasian patients' satisfaction. AB - PURPOSE: The purpose of the present study was to investigate how some esthetic dental and facial measurements may correlate the variability of patients' ratings of their satisfaction with the maxillary anterior teeth appearance in different gender groups. MATERIALS AND METHODS: The following measurements were made on 78 Caucasian subjects: width and length of each maxillary anterior tooth, their distal gingival zenith displacements, the upper lip height, intercommisural width, maximum maxillary central incisal, and gingival display at rest and smile. All the patients rated their satisfaction with the dental appearance on the visual-analogue scale (0 meaning absolute dissatisfaction, whereas 4 indicated complete satisfaction). All the parameters have been analyzed with respect to gender. RESULTS: The majority of the esthetic dental and facial measurements were larger in men (p<0.05). The great majority of the participants were completely satisfied with their dental appearance (75% of men and 89% of women; p>0.05). In the men, the two factors of maximal maxillary incisal display at rest and intercommisural width at smile paralleled the variability of the patients' satisfaction with dental appearance by 99% (p>0.05). In women, the combination of central incisor width/length ratio, intercommisural width at rest, central incisor gingival zenith displacement, intercommisural width at smile, upper lip height, and maximum maxillary incisal display at rest paralleled the variability of the patients' satisfaction with dental appearance by 99% (p>0.05). CONCLUSIONS: Within the population tested, the results suggest that the use of esthetic dental and facial measurements may serve as an esthetic guideline and should be considered in esthetic anterior oral rehabilitation. CLINICAL SIGNIFICANCE: The information presented in this article may be useful in helping to create dental restorations with an acceptable esthetic appearance to the patient. Prior to the treatment the dentist should consider not only the size of maxillary anterior teeth but also their gingival architecture and the soft tissue surrounding the teeth. PMID- 21323834 TI - Commentary. Influence of esthetic dental and facial measurements on the Caucasian patients' satisfaction. PMID- 21323835 TI - Shade guide optimization--a novel shade arrangement principle for both ceramic and composite shade guides when identifying composite test objects. AB - STATEMENT OF PROBLEM: The most widely used shade guide for composite materials is made of ceramic and arranged according to a non-proven method. There is a need for a composite shade guide using a scientifically based arrangement principle. PURPOSE: To compare the shade tab arrangement of the Vitapan Classical shade guide and an individually made composite shade guide using both the originally proposed arrangement principle and arranged according to DeltaE2000 values with hue group division. MATERIALS AND METHODS: An individual composite shade guide made from Filtek Supreme XT body colors was compared to the Vitapan Classical shade guide. Twenty-five students matched color samples made from Filtek Supreme XT body colors using the two shade guides arranged after the two proposed principles--four shade guides in total. Age, sequence, gender, time, and number of correct matches were recorded. RESULTS: The proposed visually optimal composite shade guide was both fastest and had the highest number of correct matches. Gender was significantly associated with time used for color sampling but not regarding the number of correct shade matches. CONCLUSIONS: A composite shade guide is superior compared to the ceramic Vitapan Classical guide when using composite test objects. A rearrangement of the shade guide according to hue, subdivided according to DeltaE2000, significantly reduces the time needed to take a color sample and increases the number of correct shade matches. CLINICAL SIGNIFICANCE: Total color difference in relation to the lightest tab with hue group division is recommended as a possible and universally applicable mode of tab arrangement in dental color standards. Moreover, a shade guide made of the composite materials itself is to be preferred as both a faster and more accurate method of determining color. PMID- 21323836 TI - Commentary. Shade guide optimization--a novel shade arrangement principle for both ceramic and composite shade guides when identifying composite test objects. PMID- 21323837 TI - Surface roughness and staining susceptibility of composite resins after finishing and polishing. AB - PURPOSE: The study aims to investigate the influence of filler size and finishing systems on the surface roughness and staining of three composite resins. METHODS: Three composites, classified according to their filler size, were selected: Filtek Supreme Plus/nanofill (3M ESPE, St. Paul, MN, USA), Esthet-X/minifill (Dentsply Caulk, Milford, DE, USA), and Renamel Microfill/microfill (Cosmedent Inc., Chicago, IL, USA). Composite specimens were made in stainless steel split molds and polished with Sof-Lex (3M ESPE), Enhance+PoGo (Dentsply Caulk), or FlexiDiscs+Enamelize (Cosmedent Inc.). Finishing systems were used according to the manufacturers' instructions and polished surfaces were evaluated with a profilometer and then immersed in 2% methylene blue for 24 hours. Specimens were then prepared for spectrophotometric analysis and results were statistically analyzed by two-way analysis of variance and Tukey's test. RESULTS: No significant differences in surface roughness among the composites were found when the surfaces were treated with Enhance+PoGo. In addition, no differences were observed when the Filtek Supreme Plus composite was submitted to surface staining evaluation. In general, the composites polished with the finishing systems from the same company demonstrated lower surface roughness and staining. CONCLUSION: The results of this study recommend that composite resins could be finished and polished with finishing systems supplied by the composite's manufacturer. The surface roughness and staining of composite resins were not influenced solely by filler size. CLINICAL SIGNIFICANCE: Dentists should finish and polish composite resin with the polishing agent supplied by the same manufacturer. The smallest filler size does not necessarily result in a low surface roughness and staining susceptibility. PMID- 21323838 TI - Commentary. Surface roughness and staining susceptibility of composite resins after finishing and polishing. PMID- 21323839 TI - Antibacterial activity and physical properties of conventional glass-ionomer cements containing chlorhexidine diacetate/cetrimide mixtures. AB - STATEMENT OF THE PROBLEM: Hand excavation instruments are not as efficient as that with rotary burs in atraumatic restorative treatment (ART). PURPOSE: To evaluate the antibacterial activity (ABA), microhardness numbers (VHN), and cumulative fluoride releasing (CFR) patterns of conventional GICs (Fuji IX (FX) and Ketac Molar (KM)) containing chlorhexidine diacetate/cetrimide mixtures (2.5%/2.5%) (AB). MATERIALS AND METHODS: The powders of ABs were added to powders of FX and KM selected as experimental groups (EXPs). FX and KM were assigned as controls (CNTs). ABA against S.mutans (MS) and L.casei (LB) were examined between 1-90 days. VHN were calculated after 24 hours and CFR patterns measured between 1 30 days. Analysis of variance was used for comparison (p<0.05) RESULTS: Differences were found between EXPs regarding MS levels at days 1, 7 and 60 as well as for LB at all time periods (p<0.05). VHN decreased in EXPs compared to CNTs (p<0.05), and no differences were found between EXPs (p>0.05). CFR patterns tended to decrease in EXPs compared to the CNTs, but no differences were found between EXPs (p>0.05) CLINICAL SIGNIFICANCE These mixtures could be recommended for ART procedures to provide beneficial antibacterial effects without seriously deteriorating the physical properties of selected GICs. PMID- 21323840 TI - Commentary. Antibacterial activity and physical properties of conventional glass ionomer cements containing chlorhexidine diacetate/cetrimide mixtures. PMID- 21323841 TI - Crown margins in the esthetic zone. PMID- 21323842 TI - Critical appraisal. Power bleaching. AB - From anecdotal reports, many patients and some dentists believe that using a high concentration whitening agent and an auxiliary light source (i.e., power bleaching) provides the best whitening service available. Some believe that the light provides additional whitening. Some believe that it provides a result that cannot otherwise be obtained. Others believe that it whitens far more quickly. The present review investigates the evidence available to support or refute these claims. PMID- 21323843 TI - 2011 Brings exciting changes to the journal of midwifery & women's health. PMID- 21323844 TI - Women's prenatal concerns regarding breastfeeding: are they being addressed? AB - INTRODUCTION: This study sought to identify women's concerns regarding breastfeeding during the prenatal period and determine whether women thought that health care providers addressed these concerns. METHODS: A structured interview with both open-ended and closed-ended questions addressing the study objectives was administered to a cross-sectional sample of 130 English-speaking or Spanish speaking postpartum women at Yale-New Haven Hospital. RESULTS: When asked an open ended question regarding whether they had concerns about breastfeeding while making their decisions about feeding their infants, 81.5% of women identified at least 1 concern. Of these women, only 25.4% reported that this concern was addressed by the provider during prenatal care. When prompted with 8 common concerns regarding breastfeeding during the prenatal period, 95.4% of women identified at least 1 of these preidentified concerns. Only 17.4% of women who identified any of these 8 concerns reported that the concerns had been discussed with a provider. DISCUSSION: Women's recall of prenatal health care discussions strongly suggests that providers are not adequately addressing women's concerns about breastfeeding. PMID- 21323845 TI - Evaluation of a community intervention for promotion of safe motherhood in Eritrea. AB - INTRODUCTION: We evaluated a community-based intervention to promote safe motherhood, focusing on knowledge and behaviors that may reduce maternal mortality and birth complications. The intervention aimed to increase women's birth preparedness, knowledge of birth danger signs, use of antenatal care services, and birth at a health care facility. METHODS: Volunteers from a remote rural community in Northern Eritrea were trained to lead participatory educational sessions on safe motherhood with women and men. The evaluation used a quasiexperimental design (nonequivalent group pretest-posttest) including cross sectional surveys with postpartum women (pretest n = 466, posttest n = 378) in the intervention area and in a similar remote rural comparison area. RESULTS: Women's knowledge of birth danger signs increased significantly in the intervention area but not in the comparison area. There was a significant increase in the proportion of women who had the recommended 4 or more antenatal care visits during pregnancy in the intervention area (from 18% to 80%, P < .001), although this proportion did not change significantly in the comparison area (from 53% to 47%, P = .194). There was a greater increase in birth in a health care facility in the intervention area. DISCUSSION: Participatory sessions led by community volunteers can increase safe motherhood knowledge and encourage use of essential maternity services. PMID- 21323846 TI - Depression screening during pregnancy. AB - Depression in the antepartum period is more commonly missed by clinicians than is intimate partner violence, although more women and families suffer from this debilitating disease. Early identification and appropriate psychotherapeutic interventions significantly reduce the risk of adverse effects for the mother, infant, and family. Despite debate regarding specificity and sensitivity, 2 instruments have been predominantly referenced for use in antepartum screening: the Edinburgh Postnatal Depression Scale and the Center for Epidemiologic Studies Depression Scale. Routine screening combined with interview methods provides high reliability for predicting a risk for depression in pregnancy and postpartum. Caution should be exercised when new onset is identified or when women who were using psychotropic medications before pregnancy are being treated, because the relative risk of prenatal exposure to medication is counterbalanced by the risk of relapse of maternal psychiatric disorders. PMID- 21323847 TI - Family stories: narrative genetics and conceptions of heritability in pregnant women. AB - As our understanding of genetics has grown, and its importance has increased in clinical care, pregnancy and the fetus are often seen through a genetic lens. Clinicians who care for pregnant women are charged with explaining genetic risk and overseeing prenatal screening. For the clinician, genetics represents clearly defined application of a particular kind of scientific knowledge. Further, heritability in clinical terms is understood as purely genetic. Pregnant women themselves, however, may not give these genetic explanations the same primacy or meaning. In order to better understand the way pregnant women actually understand and explain heritability, we completed in-depth interviews with 26 pregnant women, listening as they gave weight and substance to the various factors they describe as influencing the personhood of their unborn children. Two-thirds of our respondents were Hispanic or African American. Most were recruited through programs that serve low-income women. The interviews were coded and analyzed by using categories that emerged directly from the narratives captured in the interviews and that revealed the broad, cross-cutting, overlapping parameters of women's deeply-held beliefs about heritability. These stories represent narratives of heritability that are profoundly familial and cultural. They incorporate belief in the authoritative knowledge of medicine-including any genetic information-into a complex and usually multicultural context, woven together by ancestry, household, and community. PMID- 21323848 TI - My baby, my move: examination of perceived barriers and motivating factors related to antenatal physical activity. AB - INTRODUCTION: Based on a socioecological model, the present study examined multilevel barriers and facilitators related to physical activity engagement during pregnancy in women of low socioeconomic status. METHODS: Individual and paired interviews were conducted with 25 pregnant women (aged 18-46 years, 17-40 weeks' gestation) to ask about motivational factors and to compare differences in activity level and parity. Atlas/Ti software was used to code verbatim interview transcripts by organizing codes into categories that reflect symbolic domains of meaning, relational patterns, and overarching themes. RESULTS: Perceived barriers and motivating factors differed between exercisers and nonexercisers at intrapersonal, interpersonal, and environmental levels. DISCUSSION: Future interventions should take into account key motivating multilevel factors and barriers to tailor more meaningful advice for pregnant women. PMID- 21323849 TI - Pregnancy and multiple sclerosis. AB - Multiple sclerosis (MS) is often diagnosed among women of childbearing age. This article reviews how MS affects pregnancy and provides information for health care providers who care for women with this disorder. Women with MS need to be informed regarding how the disease will affect their reproductive health. The disease itself does not usually have a negative impact on fertility or pregnancy, although some studies indicate that women with MS have a slightly increased risk for having small-for-gestational-age newborns. Some of the common MS symptoms such as fatigue, urinary frequency, constipation, and mood changes are similar to pregnancy-related symptoms. Mode of birth and anesthesia choices are similar to those for women without MS. Immunomodulatory therapy for MS needs to be discontinued before conception because most of the medications are still under investigation with regard to safety during pregnancy or have adverse effects on pregnancy. Relapse rates are increased for up to 6 months in the postpartum period. Breast feeding does not appear to increase the risk of postpartum relapses. All hormonal contraception can be used by women with MS. Some studies suggest that estrogen may have protective effects against disease progression. PMID- 21323850 TI - Influences of social norms and context on sexual decision making among adolescent women. AB - INTRODUCTION: The aim of this study was to explore women's decisions to initiate and continue sexual activity in late adolescence. METHODS: Narrative inquiry was the qualitative methodology used to research the perceptions of factors that influence the sexual decision making of women in late adolescence. Single interviews were conducted with 10 late-adolescence women between the ages of 18 and 22. Both purposive and snowball sampling were used, and recruitment ended when data saturation was achieved. RESULTS: The main findings that emerged as the story contained 3 distinct and influential components: the influence of social context provided the introduction to the story, perceptions of the expected social norm for sex and relationships formed the plot, and the narratives concluded with a discussion of how these adolescents' decision-making processes evolved in the years since coital debut. DISCUSSION: The results of this study provide evidence that adolescent sexual decision making is a multifaceted process with many layers of influence that reflect the complex world adolescents must navigate as they make decisions about their sexual behaviors. Detailed assessment of adolescent sexual activity and anticipatory guidance by health care providers will lay the foundation for risk reduction behavior and safer sexual encounters. PMID- 21323851 TI - Urban minority women's perceptions of and preferences for postpartum contraceptive counseling. AB - INTRODUCTION: Focused antenatal contraceptive counseling about postpartum contraception may reduce the risk of contraceptive nonuse and misuse, although the optimal timing, content, and communication style of such counseling remain controversial. This study used an in-depth, qualitative approach in a population of young, postpartum, urban, minority group women in order to examine women's perspectives toward the optimal provision of comprehensive contraceptive counseling. METHODS: Brief surveys and semistructured interviews were conducted with 30 consenting postpartum women. In-person, one-on-one interviews were then reviewed for themes, by using an iterative process. Qualitative analysis techniques identifying emergent themes were applied to interview data. RESULTS: In this cohort of African American (63%) and Hispanic (37%) women (median age 26 y), 73% had unplanned pregnancies. Women preferred frequent, short sessions of provider-initiated comprehensive contraceptive counseling throughout the antepartum period with reinforcement of decisions during the postpartum period. Participants valued patient-centered counseling that was inclusive of all appropriate methods and personalized to individual needs. DISCUSSION: We recommend that frequent, provider-initiated, multiple-modality discussions of appropriate postpartum contraceptive options should take place throughout pregnancy in an open, individualized manner. Further work should address the long term effects of improved patient-centered antenatal contraceptive counseling on rates of unintended pregnancy. PMID- 21323852 TI - New treatment approach for osteopenia. AB - Nearly 44 million persons in the United States have osteoporosis or osteopenia, most of whom are osteopenic. Because of sheer numbers, an increased number of fractures occur in the osteopenic group. Bone mineral density alone, based on dual energy X-ray absorptiometry scan results, is not enough to identify persons at increased risk for fracture. The World Health Organization (WHO) Working Group On Osteoporosis has developed an online tool, known as FRAX, to calculate future hip fracture probability based on individual clinical risk factors. Determining the risk of hip fracture is critical because it is the most devastating osteoporosis complication. The FRAX model was developed from population-based cohort studies in Europe, North America, Asia, and Australia. In 2008, the National Osteoporosis Foundation (NOF) adopted the WHO approach in the treatment of osteopenia. This article presents a clinical scenario to demonstrate the application of the WHO FRAX tool and the new NOF guidelines. PMID- 21323853 TI - Applying the global positioning system and google earth to evaluate the accessibility of birth services for pregnant women in northern Malawi. AB - INTRODUCTION: The objective of this study was to validate the combined use of the Global Positioning System (GPS) and Google Earth for measuring the accessibility of health care facilities for pregnant women in northern Malawi. METHODS: We used GPS and Google Earth to identify 5 major health care facilities in Mzuzu (Malawi) and the homes of 79 traditional birth attendants (TBAs). The distance and time required for each TBA to reach the nearest health care facility were measured by both GPS and by self-report of the TBAs. A convenience sample of 1138 pregnant women was interviewed about their choices of birth sites for current and previous pregnancies and the time and cost required to access health care facilities. RESULTS: The correlation coefficient between the objective measurements by GPS and subjective reports by TBAs for time required from their homes to health care facilities was 0.654 (P < .001). Among pregnant women, 45.6% reported that they could reach a health care facility within 2 hours; 23.8% reported paying more than $1 for transportation to health care facilities. For the current study, 82.6% of women intended to give birth at a health care facility. However, only 48.7% of women actually gave birth in a health care facility in a previous pregnancy, and 32.6% were assisted by TBAs. DISCUSSION: Combined GPS and Google Earth can be useful in the evaluation of accessibility of health care facilities, especially for emergency obstetric care. PMID- 21323854 TI - Acceptability and feasibility of a multiple-behavior, computer-tailored intervention for underserved pregnant women. AB - INTRODUCTION: A pilot test of a computer-tailored intervention designed to promote positive health behaviors during pregnancy among a low-income population across multiple ethnic groups was conducted. METHODS: Intervention content, based on the transtheoretical model, offered pregnant women assistance with smoking cessation, stress management, and increasing fruit and vegetable consumption. Pregnant women (N = 87) were recruited from federally qualified health centers. After completing the intervention, women answered a 16-item evaluation. RESULTS: Participants rated the program very positively, with 89.7% to 95.5% of participants agreeing or strongly agreeing with all evaluation items. For example, 95.4% of respondents reported that the program could help them be healthier, that they learned new information, and that the program was designed for pregnant women like themselves. Additionally, the majority of participants (92%) reported that they would recommend the program to a friend. There were no significant differences in the ratings based on demographic characteristics of the participants. Qualitative responses support acceptability for the program. Further, assessments before and after completion of the program indicated an increase in intention to make behavioral changes. DISCUSSION: With acceptability and feasibility confirmed, the next steps are to test efficacy and consequently to distribute the program to populations of underserved pregnant women. PMID- 21323855 TI - Intervention reduces coercion from male partners and may encourage women to leave unsafe relationships. PMID- 21323856 TI - Use of 90-day vaginal estrogen ring may improve bleeding profile in women starting dmpa. PMID- 21323857 TI - Late preterm newborns suffer significant respiratory morbidity. PMID- 21323859 TI - Smoking and women's health: tips on why and how to quit. PMID- 21323860 TI - Epigenetic inactivation of the hsa-miR-203 in haematological malignancies. AB - miR-203 is a tumour suppressor microRNA (miRNA). We studied the methylation of hsa-miR-203 in 150 samples including acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), chronic myeloid leukaemia (CML), chronic lymphocytic leukaemia (CLL) and non-Hodgkin's lymphoma (NHL) by methylation specific PCR, and miRNA expression by stem-loop RT-qPCR. hsa-miR-203 promoter was unmethylated in normal controls but homozygously methylated in two AML and four lymphoma cell lines, in which 5-Aza-2'-deoxycytidine treatment led to promoter demethylation and miR-203 re-expression. Restoration of miR-203 expression in lymphoma cells inhibited cellular proliferation and increased cell death, suggesting an inherent tumour suppressor activity. In primary samples, hsa-miR 203 methylation was absent in CML but detected in 5.0% ALL, 10.0% AML, 42.0% CLL and 38.8% of NHL (including six [60.0%] natural killer-cell, nine [40.9%] B-cell and four [23.5%] T cell NHL). Moreover, hsa-miR-203 methylation was associated with hypermethylation of hsa-miR-34a, -124a and -196b in NHL but not CLL. In CLL, hsa-miR-203 methylation was associated with a higher presenting Hb level (P = 0.033). The projected 10 year overall survival of the CLL patients was 58.2%, which was impacted by Rai stage and high-risk karyotypes but not hsa-miR-203 methylation. hsa-miR-203 was more frequently methylated in lymphoid than myeloid malignancies (P = 0.002). In conclusion, miR-203, a tumour suppressor gene, was hypermethylated in a tumour-specific manner with gene silencing. hsa-miR-203 was more frequently hypermethylated in lymphoid than myeloid malignancies. In NHL, hsa-miR-203 methylation was associated with concomitant methylation of other tumour suppressor miRNAs. The frequent hsa-miR-203 methylation in lymphoid malignancies suggested a pathogenetic role of hsa-miR-203 methylation. PMID- 21323861 TI - Crucial role of HSP90 in the Akt-dependent promotion of angiogenic-like effect of glucose-regulated protein94 (Grp94)-IgG complexes. AB - Previous observations showed that complexes of glucose-regulated protein94 (Grp94) with human IgG, both those isolated from plasma of diabetic subjects and complexes formed in vitro, displayed cytokine-like effects on human umbilical vein endothelial cells (HUVECs), including angiogenic-like transformation capacity that predicted an increased risk of vascular damage. The aim of the present work was to find an effective inhibitor of the angiogenic-like effect of Grp94-IgG complexes. Because this effect is mediated by an increased expression of matrix metalloprotease-9 (MMP-9), we tested the selective MMP-9 inhibitor, the cyclic decapeptide CTT (CTTHWGFTLC) at 5, 10 and 20 MUM. CCT failed to inhibit any morphological alteration induced by Grp94-IgG on HUVECs, on its own displaying a paradoxical angiogenic-like activity. We identified the phosphatidylinositol 3-kinase (PI3K)/Akt pathway as the specific target activated by both Grp94-IgG and CTT for sustaining the angiogenic-like transformation of HUVECs. Functioning of the PI3K/Akt pathway was crucially dependent on functional heat-shock protein (HSP)90, and both Grp94-IgG and CTT caused and increased expression of HSP90, promoting its localization to podosomes. CTT appeared to enhance the angiogenic-like effect of Grp94-IgG by increasing the rate of secretion of both HSP90 and MMP-9. By preventing the chaperoning capacity of HSP90 with the inhibitor purine-scaffold (PU)-H71 that blocked the ATP-binding site on HSP90, it was possible to inhibit the expression of Akt and secretion of HSP90 and MMP-9 induced by Grp94-IgG, thus completely reversing the angiogenic pattern. Results reveal a fundamental role of HSP90 in the PI3K/Akt pathway mediated angiogenic-like effect of Grp94-IgG, also questioning the capacity of CTT to serve as an effective inhibitor of the angiogenic effect. PMID- 21323862 TI - Medical genetics and epigenetics of telomerase. AB - Telomerase is a specialized reverse transcriptase that extends and maintains the terminal ends of chromosomes, or telomeres. Since its discovery in 1985 by Nobel Laureates Elizabeth Blackburn and Carol Greider, thousands of articles have emerged detailing its significance in telomere function and cell survival. This review provides a current assessment on the importance of telomerase regulation and relates it in terms of medical genetics. In this review, we discuss the recent findings on telomerase regulation, focusing on epigenetics and non-coding RNAs regulation of telomerase, such as microRNAs and the recently discovered telomeric-repeat containing RNA transcripts. Human genetic disorders that develop due to mutations in telomerase subunits, the role of single nucleotide polymorphisms in genes encoding telomerase components and diseases as a result of telomerase regulation going awry are also discussed. Continual investigation of the complex regulation of telomerase will further our insight into the use of controlling telomerase activity in medicine. PMID- 21323863 TI - Enhanced internalization of ErbB2 in SK-BR-3 cells with multivalent forms of an artificial ligand. AB - Targeting and down-regulation of ErbB2, a member of EGF receptor family, is regarded as one of the key aspect for cancer treatment because it is often overexpressed in breast and ovarian cancer cells. Although natural ligands for ErbB2 have not been found, unlike other ErbB receptors, EC-1, a 20-amino acid circular peptide, has been shown to bind to ErbB2 as an artificial ligand. Previously we showed EC-1 peptide did not induce the internalization of ErbB2 in SK-BR-3 cells. In this report, we designed divalent and multivalent forms of EC-1 peptide with the Fc portion of the human IgG and bionanocapsule modified with ZZ tag on its surface to improve the interaction with ErbB2. These forms showed higher affinity to ErbB2 than that of EC-1 monomer. Furthermore, prominent endosomal accumulation of ErbB2 occurred in SK-BR-3 cells when stimulated with EC Fc ligand multivalently displayed on the surface of the bionanocapsule, whereas SK-BR-3 cells as themselves displayed stringent mechanism against ErbB2 internalization without stimulation. The multivalent form of EC-1 peptide appeared to internalize ErbB2 more efficiently than divalent form did. This internalization was unaffected by the inhibition of clathrin association, but inhibited when the cholesterol was depleted which explained either caveolar or GPI-AP-early endocytic compartment (GEEC) pathway. Because of the lack of caveolin-1 expression, caveolar machinery may be lost in SK-BR-3 cell line. Therefore, it is suggested that the multivalent form of EC-1 induces the internalization of ErbB2 through the GEEC pathway. PMID- 21323864 TI - Intestinal metabolite compound K of panaxoside inhibits the growth of gastric carcinoma by augmenting apoptosis via Bid-mediated mitochondrial pathway. AB - Compound K (20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol, CK), an intestinal bacterial metabolite of panaxoside, has been shown to inhibit tumour growth in a variety of tumours. However, the mechanisms involved are largely unknown. We use human gastric carcinoma cell lines BGC823, SGC7901 and human gastric carcinoma xenograft in nude mice as models to study the mechanisms of CK in gastric cancers. We found that CK significantly inhibits the viabilities of BGC823 and SGC7901 cells in dose- and time-dependent manners. CK-induced BGC823 and SGC7901 cells apoptosis and cell cycle arrest in G2 phase by up-regulation of p21 and down-regulation of cdc2 and cyclin B1. Further studies show that CK induces apoptosis in BGC823 and SGC7901 cells mainly through mitochondria-mediated internal pathway, and that CK induces the translocation of nuclear Bid to mitochondria. Finally, we found that CK effectively inhibited the tumour formation of SGC7901 cells in nude mice. Our studies show that CK can inhibit the viabilities and induce apoptosis of human gastric carcinoma cells via Bid mediated mitochondrial pathway. PMID- 21323865 TI - Drug-induced photodermatitis in elderly nursing home residents. PMID- 21323866 TI - The validity of a structured interactive 24-hour recall in estimating energy and nutrient intakes in 15-month-old rural Malawian children. AB - This study aimed to compare the nutritional intake values among 15-month-old rural Malawian children obtained by weighed food record (WFR) with those obtained by modified 24-hour recall (mod 24-HR), and to develop algorithm for adjusting mod 24-HR values so as to predict mean intake based on WFRs. The study participants were 169 15-month-old children who participated in a clinical trial. Food consumption on one day was observed and weighed (established criterion) by a research assistant to provide the estimates of energy and nutrient intakes. On the following day, another research assistant, blinded to the direct observation, conducted the structured interactive 24-hour recall (24-HR) interview (test method). Paired t-tests and scatter-plots were used to compare intake values of the two methods. The structured interactive 24-HR method tended to overestimate energy and nutrient intakes (each P < 0.001). The regression-through-the-origin method was used to develop adjustment algorithms. Results showed that multiplying the mean energy, protein, fat, iron, zinc and vitamin A intake estimates based on the test method by 0.86, 0.80, 0.68, 0.69, 0.72 and 0.76, respectively, provides an approximation of the mean values based on WFRs. PMID- 21323867 TI - Impact of acute hypobaric hypoxia on blood flow distribution in brain. AB - AIM: Acute hypobaric hypoxia is well known to alter brain circulation and to cause neuropsychological impairment. However, very few studies have examined the regional changes occurring in the brain during acute exposure to extreme hypoxic conditions. METHODS: Regional cerebral blood flow (rCBF) response to hypoxia was investigated in six healthy subjects exposed to either normobaric normoxia or hypobaric hypoxia with ambient pressure/inspired oxygen pressure of 101/21 kPa and 50/11 kPa respectively. After 40 min at the desired pressure they were injected (99m)Tc-HMPAO and subsequently underwent single photon emission computed tomography. Regional cerebral blood flow distribution changes in the whole brain were assessed by Statistical Parametric Mapping, a well established voxel-based analysis method. RESULTS: Hypobaric hypoxia increased rCBF distribution in sensorymotor and prefrontal cortices and in central structures. PCO(2) correlated positively and SatO(2) negatively with rCBF in several temporal, parahippocampal, parietal and central structures. CONCLUSIONS: These findings underscore the specific sensitivity of the frontal lobe to acute hypobaric hypoxia and of limbic and central structures to blood gas changes emphasizing the involvement of these brain areas in acute hypoxia. PMID- 21323868 TI - Introduction and clinical evaluation of servo-controlled applanation resonance tonometry. AB - PURPOSE: In recent years, Applanation Resonance Tonometry (ART) has been suggested for intraocular pressure (IOP) measurements. The manual version of ART (ART(manual) ) has been further developed, and to improve usability, an automatic servo-controlled prototype (ART(servo) ) has been proposed. The aim of this study was to assess the limits of agreement (LoA) of ART(manual) and ART(servo) as compared with the reference method, Goldmann Applanation Tonometry (GAT). METHODS: This was a prospective single-centre study on 152 eyes from 77 subjects. It was designed according to International Standard Organization's (ISO) requirements for tonometers (ISO 2001). Intraocular pressure was measured six times/method in a standardized order. The ART technique has two available analysis procedures: a dynamic one that measures IOP during the indentation phase and a static one that causes a Goldmann-like measurement during two seconds of full applanation. The 95% LoA was defined as +/-1.96 * standard deviation of difference against GAT. RESULTS: Mean IOP for GAT was 19.1 mmHg (range: 10-37 mmHg). The 95% LoA of ART(manual) was +/-4.5 mmHg for both dynamic and static analyses. The 95% LoA of ART(servo) was +/-5.7 mmHg for dynamic and +/-4.9 mmHg for static analyses. CONCLUSIONS: This study confirms that the ART methodology is feasible. The further developed ART(manual) fulfilled the ISO standard with both the dynamic and the static analysis techniques. ART(servo) with static analysis was close to fulfilling the standard but failed to do so in the highest IOP range. ART(servo) has the potential to greatly improve usability if further development is completed. PMID- 21323870 TI - TP53 codon 72 polymorphism in patients with chronic lymphocytic leukaemia: identification of a subgroup with mutated IGHV genes and poor clinical outcome. PMID- 21323871 TI - Biological evaluation of CpG stimulation of normal human B-cells: implications for B-cell biology and cytogenetic analysis of CLL B-cells. PMID- 21323874 TI - Letter from Copenhagen. PMID- 21323875 TI - The destiny of an unacknowledged trauma: the deferred retroactive effect of apres coup in the hidden Jewish children of wartime Belgium. AB - For almost 45 years, the experience of Jewish children who were hidden during World War II was considered to be of little importance, particularly with respect to what had taken place in the concentration camps. Their very history was ignored in the many accounts of the Holocaust. It was only at the end of the 1980s that their experience began to be thought of as potentially traumatic. In this paper, the authors report on their psychoanalytical research project concerning the psychological outcomes of those experiences that had remained concealed for such an extraordinarily long latency period. The results are based on the analysis of 60 accounts and on psychoanalytically-oriented group work. The authors show that the trauma experienced by those hidden children was triggered by the retroactive effect of a deferred action [apres-coup]. PMID- 21323873 TI - Outcome of children treated with haematopoietic-stem cell transplantations from donors expressing the rare C77G variant of the PTPRC (CD45) gene. AB - The uncommon C77G polymorphism of the Protein-Tyrosine Phosphatase (PTPRC) gene (PTPRC; previously termed CD45) could confer an increased risk of immunopathology. This study compared the outcome of children following human leucocyte antigen-matched unrelated haematopoietic-stem cell transplantations (HSCT) from donors carrying (C77G cases: n = 8) or not (controls: n = 36) the PTPRC C77G polymorphism. Transmission of the PTPRC C77G polymorphism through the graft was suggested by unusual CD45RA phenotype in the donors and/or in the recipients after, but not before HSCT. Restriction-Fragment Length Polymorphism and sequencing confirmed the polymorphism. Overall survival rates were similar in C77G cases and controls (63% vs. 61%). Acute leukaemia relapse tended to be less frequent in C77G cases (0% vs. 32%; P = 0.09). Among recipients surviving >= 30 d, acute GVHD (aGVHD) >= grade 2 tended to be more frequent (100% vs. 58%; P = 0.07) and the rate of steroid-refractory or -dependant aGVHD higher (67% vs. 28%) in C77G cases. Finally, extensive chronic GVHD tended to occur more frequently (40% vs. 9%) in C77G cases. Recovery of lymphocyte subsets and virus-specific CD4 was similar in C77G cases and controls while interleukin 2 (IL2)-responses through CD3 stimulation were higher in C77G cases (P = 0.004). In conclusion, HSCT from PTPRC C77G donors could increase GVHD risk without compromising overall survival. Altered IL2-responses could be involved in this process. PMID- 21323876 TI - Trying to enter the long black branches: some technical extensions of the work of Frances Tustin for the analysis of autistic states in adults. AB - The author suggests a number of technical extensions/clinical applications of Frances Tustin's work with autistic children, which are applicable to the psychoanalysis of neurotic, borderline and psychotic adults. These are especially relevant to those individuals in whom early uncontained happenings (Bion) have been silently encapsulated through the use of secretive autosensual maneuvers related to autistic objects and shapes. Although such encapsulations may constitute obstacles to emotional and intellectual development, are consequential in both the relational and vocational spheres for many analysands and present unending challenges for their analysts, the author demonstrates ways in which it may be possible to detect and to modify these in a transference-centered analysis. A detailed process of differential diagnosis between autistic states and neurotic/narcissistic (object-related) states in adults is outlined, along with several clinical demonstrations of the handling of a variety of elemental terrors, including the 'dread of dissolution.' The idiosyncratic and perverse use of the analytic setting and of the analyst and issues of the analysand's motivations are considered and illustrated. A new model related to 'objects in the periphery' is introduced as an alternative to the more classical Kleinian models regarding certain responses and/or non-responses to transference interpretation. Issues a propos the countertransference are also taken up throughout. PMID- 21323877 TI - Psychotherapy and close-process technique. AB - The applicability and advantages of Paul Gray's concept of close-process in the practice of psychotherapy are discussed. Gray seems to have underestimated the potential and versatility of his technical approach to derivative psychotherapy procedures. Clinical vignettes are provided, describing some nodal points for intervention, and exploration of transferential, extratransferential and genetic aspects of the workable surface. Gray's methodology of intraclinical attention permits a more verifiable examination of sequences, an issue of special relevance in our age of empirical standards for the evaluation of dynamic therapies. PMID- 21323878 TI - Termination: the hidden face of analysis. AB - Although the question of analytic endings has been the subject of many contributions and round tables, it always presents a theoretical and clinical dilemma that remains unresolved by the search for more explicit criteria. The problem of the final phase is a post-Freudian development which coincides historically with the emergence of studies on the countertransference, and it presupposes prior questions concerning the goals and results of analytic treatment. The following question is posed: what is the specific psychoanalytic event of the final phase? The author begins by examining the theoretical issues linked to temporality and separation, clarifying certain clinical aspects linked to the precession of the countertransference in determining the ending, before going on to illustrate a number of indicators with a clinical vignette. He proposes that the movement which develops in analysis from the transitional relationship towards the patient's capacity to 'stand on his own two feet' in the clinical setting constitutes a crucial factor in the decision to embark on the process of termination. The conclusion opens out onto ethical issues, in view of the prior necessity for a movement to occur in the countertransference. PMID- 21323879 TI - Repression and splitting in the psychoanalytic process. AB - The authors examine the concepts of repression and splitting and their interplay during the psychoanalytic process. Initially, repression was introduced by the clinical phenomenon of resistance, leading to the formulation of the association between intrapsychic conflicts and neurotic symptoms. Later, repression was linked to normal development and to personality organization. Splitting, on the other hand, has been defined in quite diverse ways. The two main definitions are of splitting within the ego, and splitting of representations of the self, and of internal and external objects. Repression and splitting are compared developmentally, dynamically, and with respect to their relationship to psychic functioning and energic conditions. Clinical material is presented from the analysis of a patient who presented with borderline personality organization and narcissistic features. During the initial phase of analysis, splitting associated with projection, projective identification and idealization were the main defence mechanisms. As the analysis progressed and the themes of omnipotence and mourning were explored with the simultaneous working through of drive derivatives expressed in the transference, repression gained ground over the more primitive defence mechanisms. The evolution of the case showed a gradual shift from splitting to repression and the association of repression with a more advanced psychic organization. This development reflected the dynamic movement from borderline to hysterical organization in psychoanalytic nosology. PMID- 21323880 TI - 'A father is being beaten': constructions in the analysis of some male patients. AB - I will suggest that the phantasy of 'a father is being beaten' and its transformations emerges for certain male patients as a result of the work of analysis and becomes a potential appropriation of the (symbolic) father. The symbolic beating of the father takes place at the threshold between an anal sadistic organization and the oedipal situation. The phantasy of the 'father being beaten' does not necessarily mean that it is the father who is explicitly being beaten. It is a construction derived from the free associations and dreams, in the analytic encounter, reached through the work of interpretation. Detailed material of sessions of the five times a week analysis of one of my patients will be presented. This will be contrasted with material from four other analyses of male patients where the 'father being beaten' phantasy was not achieved. The common feature in all these other configurations is a foreclosure in the relationship to the father and a lack of an internalization of the paternal function as a symbolic capacity. It is my suggestion that this absence of the father in its symbolic function is then sexualized in a fusion between life and death drives. A final contrasting example is derived from Karl Abraham's classic paper detailing the analysis of a patient where one can interpret a dream as expressing 'a father is being beaten' phantasy; however the dream's repetitive nature and its links with a current dream in the analysis points out to a lack of differentiation between the sexes and an anal-sadistic organization. PMID- 21323881 TI - Finding the depressed object in the obsessional: a clinical study. AB - In this paper the author explores the clinical significance of the presence of a depressed internal object in a patient with marked obsessional features, dominating the patient's internal world and restricting relations in external life. After discussing important aspects of the contribution of Freud and later writers to the study of obsessional neurosis, the author provides clinical material that shows the patient's tormented relationship to a feared depressed object that was manifested in the transference. Developing her argument, the author suggests that if the analyst does not fully grasp the primitive anxieties of the underlying state of mind she can be prone to enter into an aggressive enactment with the patient's sadistic superego. This kind of enactment may arouse excitement and triumph in the patient, but actually confirms his doubts and fears about the capacity of his object to contain him. PMID- 21323882 TI - Helplessness and the exercise of power in the analytic session. AB - This paper describes a clinical situation in which the analyst may be provoked to become overactive if he feels that his attempts to reach his patient are frustrated. Lack of tolerance for feelings of helplessness may leave him unable to sustain a receptive stance, and he may be drawn into enactments which lead to a power struggle with his patient. I will try to describe situations where such enactments were compelling. I will also consider what enabled me to extricate myself from the activity, at least intermittently, to re-establish an analytic attitude in which understanding and containment were priorities. From time to time I was able to recognize and accept my helplessness and relinquish my attempts to reach the patient. These moments of recognition led to a shift of atmosphere in which a feeling of sadness replaced the more familiar confrontational mood. In these sadder moods the patient felt I was more available, and he too seemed more able to contemplate loss. Theoretical ideas that enabled me to recognize some of the mechanisms at play included an understanding of narcissistic mechanisms, a recognition of previous ideas of power and dominance such as Freud's Bemachtigungstrieb, and the role of dominance in the resolution of the Oedipus complex. My previous work on the dread of humiliation allowed me to be sensitive to the way helplessness can come to be associated with being looked down on and humiliated. PMID- 21323872 TI - Improvements in haemolysis and indicators of erythrocyte survival do not correlate with acute vaso-occlusive crises in patients with sickle cell disease: a phase III randomized, placebo-controlled, double-blind study of the Gardos channel blocker senicapoc (ICA-17043). AB - Red blood cell (RBC) hydration is regulated in part by the Ca(2+) -activated K(+) efflux (Gardos) channel. Senicapoc selectively blocks potassium efflux through the Gardos channel, reducing RBC dehydration and haemolysis, and increasing haemoglobin levels in sickle cell disease (SCD). This randomized, placebo controlled trial was designed to determine the safety and clinical efficacy of senicapoc in SCD patients. One hundred and forty-five patients were randomized to receive senicapoc and 144 patients to receive placebo for 52 weeks. Consistent with a previous study, patients in the senicapoc group had significantly increased haematocrit, haemoglobin, and decreased numbers of both dense erythrocytes and reticulocytes when compared to the placebo group. The unblinded Data Monitoring Committee terminated this study early due to a lack of efficacy when it determined that, despite improvements in anaemia and haemolysis, no significant improvement in the rate of sickle cell painful crises was observed in patients treated with senicapoc compared to those on placebo (0.38 vs. 0.31, respectively). Comparisons of the times to first, second and third crises between the senicapoc and placebo groups were not statistically significant. Nausea and urinary tract infections occurred more frequently in the senicapoc group than placebo. Serious adverse events were similar in the two groups. PMID- 21323883 TI - Between the quills: Schopenhauer and Freud on sadism and masochism. AB - It is a matter of common knowledge that Sigmund Freud (1856-1939) and Arthur Schopenhauer (1788-1860) shared a common worldview. Everyone familiar with the works of these two thinkers should recognize their general philosophical affinities. Both men were pessimistic about the power of human reason and attributed human behavior to powerful unconscious forces and, as a result, both were deeply skeptical about the future of human society. Drawing from previous literature, this essay compares the philosophical theory of Schopenhauer with the psychoanalytic theory of Freud. We find that, while Schopenhauer and Freud share a common philosophical orientation and diagnosed the same fundamental problems with life in civilization, they proposed some ostensibly similar, yet ultimately very different solutions. Focusing on each thinker's respective notion of sadism and masochism, this paper tries to understand and come to terms with the dimensions of this radical pessimism. PMID- 21323885 TI - On psychosomatics: the search for meaning. PMID- 21323886 TI - Psychosomatics: a current overview. AB - The term 'psychosomatic' has typically defined a series of illnesses in which somatic injury breaks out from psychic conflict not recognized as such. Currently, health is considered the only psychosomatic state of integration of mind and soma: an ideal state of integration. Somatic pathology is an effect of mind/body splitting. In the heterogeneous 'field of psychosomatics' interaction between psyche and soma ranges from classical psychosomatic illness to sporadic episodes in which the body has responded to an inability to process mental conflict. The author briefly reviews the development of psychoanalytic thought on psychosomatics in Argentina. He suggests the need to find appropriate conceptual tools to approach the mental structure underlying this pathology. He presents his ideas about the mental functioning of patients with somatization disorders. He introduces the concept of somatic event as a restitution phenomenon through which the subject attempts to re-establish self-integration and links with reality. He also offers some reflections on temporality and on changes in psychoanalytic technique with these patients. A clinical case illustrates his ideas. PMID- 21323887 TI - Psychoanalytic psychosomatics. PMID- 21323888 TI - On: the 'narcissism of minor differences'. PMID- 21323889 TI - Red cell alloimmunization in a diverse population of transfused patients with thalassaemia. AB - Red blood cell (RBC) transfusion is the primary treatment for severe forms of thalassaemia. Pre-storage screening has resulted in decreased transfusion transmitted infections, but anti-RBC antibodies remain a major problem. We report on 697 participants who had ever received transfusions. Allo- and autoantibody rates were compared with respect to splenectomy status, ethnicity, diagnosis, duration of transfusions, treatment centre, and age at transfusion initiation, together with rates before and after 1990, when leucoreduction methods were routine at thalassaemia treatment centres. Allo- and autoantibodies were reported in 115 (16.5%) and 34 (4.9%) subjects, respectively. Splenectomized patients were more likely to have alloantibodies [odds ratio (OR) = 2.528, P <= 0.0001], or autoantibodies (OR = 2.590, P = 0.0133). Alloantibodies occurred in 19 of 91 (21%) splenectomized subjects who started transfusion after 1990, and only 18 of 233 (7.7%) nonsplenectomized subjects (P < 0.001). Data from this study demonstrate that RBC antibodies continue to develop in chronically transfused thalassaemia patients at a high rate. Splenectomy preceded the development of antibodies in most cases. Increased rates of RBC sensitization among splenectomized patients is concerning and deserves further study. PMID- 21323890 TI - Allogeneic haematopoietic cell transplantation for myelofibrosis in 30 patients 60-78 years of age. AB - We analysed the results of haematopoietic cell transplantation (HCT) in 30 patients aged 60-78 (median 65) years, with primary myelofibrosis or myelofibrosis evolving from antecedent polycythaemia vera or essential thrombocythaemia. Donors were human leucocyte antigen (HLA)-identical siblings (N = 15) or unrelated individuals (N = 15). Various conditioning regimens were used, ranging from very low intensity (fludarabine plus 2 Gy total body irradiation) to high dose (busulfan plus cyclophosphamide). Stem cell sources were granulocyte colony-stimulating factor mobilized peripheral blood progenitor cells in 29 patients and marrow in one patient. Sustained engraftment was documented in 27 of 30 patients. Day -100 mortality was 13%. With a median follow-up of 22 (range 0.5 - 69) months, 3-year overall survival and progression-free survival were 45% and 40%, respectively. Currently, 13 patients are surviving. Seven patients died with disease progression at 0.5 -22 months, and 10 patients died from other causes at 1.5 -37.5 months after HCT. While the selection of older patients for transplantation was probably biased, the present results are encouraging. Motivated older patients with myelofibrosis without substantial comorbid conditions should be offered the option of allogeneic HCT. PMID- 21323891 TI - Recombinant human CD19-ligand protein as a potent anti-leukaemic agent. AB - We report the cloning and characterization of a novel 54-kDa high-mobility group (HMG)-box protein as the ligand for the human pan-B cell co-receptor CD19 (CD19 L), which interacts with the extracellular domain of CD19 in trans. CD19-L is the first CD19-specific recombinant human protein with potent anti-leukaemic activity against B-lineage acute lymphoblastic leukaemia (ALL), the most common form of childhood cancer and the second most common form of acute leukaemia in adults. Soluble recombinant CD19-L protein exhibited exquisite specificity for the extracellular domain of CD19 and strong binding to the surface of B-lineage leukaemia/lymphoma cells. Engagement of CD19 co-receptor on B-lineage ALL cells with CD19-L perturbed the CD19-associated signalling network, altering the expression levels of multiple genes directly involved in regulation of apoptosis, and triggered rapid apoptotic cell death in a CD19-specific manner. The identification of human CD19-L may lead to therapeutic innovation for B-lineage ALL and other B-lineage lymphoid malignancies as well as B-cell lymphoproliferative states and systemic autoimmunity. PMID- 21323892 TI - PPARalpha mediates the anti-inflammatory effect of simvastatin in an experimental model of zymosan-induced multiple organ failure. AB - BACKGROUND AND PURPOSE: Zymosan-induced non-septic shock is a multi-factorial pathology that involves several organs including the kidneys, liver and lungs. Its complexity and diversity presents a continuing therapeutic challenge. Given their pleiotropic effect, statins could be beneficial in non-septic shock. One of the molecular mechanisms underlying the anti-inflammatory effect of statins involves the peroxisome proliferator-activated receptor (PPAR) alpha. We used a zymosan-induced non-septic shock experimental model to investigate the role of PPARalpha in the anti-inflammatory effects of simvastatin. EXPERIMENTAL APPROACH: Effects of simvastatin (5 or 10 mg.kg(-1) i.p.) were analysed in PPARalpha knock out (KO) and PPARalpha wild type (WT) mice after zymosan or vehicle administration. Organ injury in lung, liver, kidney and intestine was evaluated by immunohistology. PPARalpha mRNA expression and nuclear factor-kappaB activation were evaluated in all experimental groups, 18 h after study onset. Cytokine levels were measured in plasma, and nitrite/nitrate in plasma and peritoneal exudate. Nitric oxide synthase, nitrotyrosine and poly ADP-ribose were localized by immunohistochemical methods. KEY RESULTS: Simvastatin significantly and dose-dependently increased the zymosan-induced expression of PPARalpha levels in all tissues analysed. It also dose-dependently reduced systemic inflammation and the organ injury induced by zymosan in lung, liver, intestine and kidney. These effects were observed in PPARalphaWT mice and in PPARalphaKO mice. CONCLUSIONS AND IMPLICATIONS: Simvastatin protected against the molecular and cellular damage caused by systemic inflammation in our experimental model. Our results also provide new information regarding the role of PPARalpha in the anti inflammatory effects of statins. PMID- 21323894 TI - Novel classes of antibiotics or more of the same? AB - The world is running out of antibiotics. Between 1940 and 1962, more than 20 new classes of antibiotics were marketed. Since then, only two new classes have reached the market. Analogue development kept pace with the emergence of resistant bacteria until 10-20 years ago. Now, not enough analogues are reaching the market to stem the tide of antibiotic resistance, particularly among gram negative bacteria. This review examines the existing systemic antibiotic pipeline in the public domain, and reveals that 27 compounds are in clinical development, of which two are new classes, both of which are in Phase I clinical trials. In view of the high attrition rate of drugs in early clinical development, particularly new classes and the current regulatory hurdles, it does not seem likely that new classes will be marketed soon. This paper suggests that, if the world is to return to a situation in which there are enough antibiotics to cope with the inevitable ongoing emergence of bacterial resistance, we need to recreate the prolific antibiotic discovery period between 1940 and 1962, which produced 20 classes that served the world well for 60 years. If another 20 classes and their analogues, particularly targeting gram-negatives could be produced soon, they might last us for the next 60 years. How can this be achieved? Only a huge effort by governments in the form of finance, legislation and providing industry with real incentives will reverse this. Industry needs to re-enter the market on a much larger scale, and academia should rebuild its antibiotic discovery infrastructure to support this effort. The alternative is Medicine without effective antibiotics. PMID- 21323893 TI - NOX1, 2, 4, 5: counting out oxidative stress. AB - For decades, oxidative stress has been discussed as a key mechanism of endothelial dysfunction and cardiovascular disease. However, attempts to validate and exploit this hypothesis clinically by supplementing antioxidants have failed. Nevertheless, this does not disprove the oxidative stress hypothesis. As a certain degree of reactive oxygen species (ROS) formation appears to be physiological and beneficial. To reduce oxidative stress therapeutically, two alternative approaches are being developed. One is the repair of key signalling components that are compromised by oxidative stress. These include uncoupled endothelial nitric oxide (NO) synthase and oxidized/heme-free NO receptor soluble guanylate cyclase. A second approach is to identify and effectively inhibit the relevant source(s) of ROS in a given disease condition. A highly likely target in this context is the family of NADPH oxidases. Animal models, including NOX knockout mice and new pharmacological inhibitors of NADPH oxidases have opened up a new era of oxidative stress research and have paved the way for new cardiovascular therapies. PMID- 21323895 TI - 20-Hydroxyeicosatetraenoic acid inhibits ATP-induced COX-2 expression via peroxisome proliferator activator receptor-alpha in vascular smooth muscle cells. AB - BACKGROUND AND PURPOSE: 20-Hydroxyeicosatetraenoic acid (20-HETE), formed from arachidonate by cytochrome P450, regulates vascular smooth muscle cell (VSMC) function. Because 20-HETE may activate peroxisome proliferator activator receptors (PPARs) and may participate in inflammatory responses, we asked whether 20-HETE may inhibit cyclooxygenase 2 (COX-2) expression by activating PPARs in VSMC. EXPERIMENTAL APPROACH: Quiescent neonatal VSMC (R22D cell line), were incubated with 20-HETE, synthetic ligands of PPARs, or inhibitors of the extracellular signal regulated kinase (ERK1/2), c-jun N-terminal kinase and the transcription factor activated protein-1 before adding ATPgammaS. mRNA and protein expression of COX-2 and the promoter luciferase activity of COX-2 and PPAR response element were determined. KEY RESULTS: Pretreatment with 20-HETE (5 10 uM) significantly inhibited ATPgammaS-induced COX-2 mRNA and protein expression in VSMC. The inhibitory effect of 20-HETE on COX-2 expression was mimicked by WY14643, a PPARalpha ligand and inhibited by MK886, a PPARalpha inhibitor or by transfection of shRNA for PPARalpha. Both 20-HETE and WY14643 significantly increased the PPAR-response element luciferase activity. Furthermore, ATPgammaS-induced activation of the COX-2 promoter containing the activated protein-1 site was also inhibited by pretreatment with 20-HETE, which was reversed by MK886 or by transfection with shRNA for PPARalpha. CONCLUSIONS AND IMPLICATIONS: The PPARalpha may mediate the inhibitory effects of 20-HETE on COX-2 expression through a negative cross-talk between PPARalpha and the COX-2 promoter. PMID- 21323896 TI - Differential reactivity of human mammary artery and saphenous vein to prostaglandin E(2) : implication for cardiovascular grafts. AB - BACKGROUND AND PURPOSE: Human internal mammary arteries (IMA) and saphenous veins (SV) are frequently used for coronary artery bypass graft surgery. Intra- and postoperatively, the bypass grafts are exposed to inflammatory conditions, under which there is a striking increase in the synthesis of prostaglandin E(2) (PGE(2) ). In this context, the physiological response of these vascular grafts to PGE(2) is highly relevant. The aim of this study was thus to characterize the PGE(2) receptor subtypes (EP(1) , EP(2) , EP(3) or EP(4) ) involved in modulation of the vascular tone in these two vessels. EXPERIMENTAL APPROACH: Rings of IMA and SV were prepared from 48 patients. The rings were mounted in organ baths for isometric recording of tension, and a pharmacological study was performed, together with associated reverse transcriptase PCR and immunohistochemistry experiments. KEY RESULTS: PGE(2) induced contractions of IMA (E(max) = 1.43 +/- 0.20 g; pEC(50) = 7.50 +/- 0.10); contractions were also observed with the EP(3) receptor agonists, sulprostone, 17-phenyl-PGE(2) , misoprostol or ONO-AE-248. In contrast, PGE(2) induced relaxation of the precontracted SV (E(max) =-0.22 +/- 0.02 g; pEC(50) = 7.14 +/- 0.09), as did the EP(4) receptor agonist, ONO-AE1-329. These results were confirmed by the use of selective EP receptor antagonists (GW627368X, L-826266, ONO-8713, SC-51322) and by molecular biology and immunostaining. CONCLUSIONS AND IMPLICATIONS: PGE(2) induced potent and opposite effects on the human vascular segments used for grafting, namely vasoconstriction of the IMA and vasodilatation of the SV via EP(3) and EP(4) receptors respectively. These observations suggest that EP(3) and EP(4) receptors could constitute therapeutic targets to increase vascular graft patency. PMID- 21323897 TI - Biotransformation of 6-thioguanine in inflammatory bowel disease patients: a comparison of oral and intravenous administration of 6-thioguanine. AB - BACKGROUND AND PURPOSE: Although 6-mercaptopurine and azathioprine are effective treatments in inflammatory bowel disease (IBD), many patients discontinue treatment because of side effects. 6-Thioguanine (6-TG) may be an alternative rescue therapy in these intolerant patients but the pharmacokinetics of 6-TG are not fully described. Here we have measured the pharmacokinetics of the biotransformation of 6-TG into the pharmacologically active metabolites, 6 thioguanine nucleotides (6-TGN), in IBD patients. EXPERIMENTAL APPROACH: In 12 patients with IBD, levels of 6-TGN and activities of thiopurine S methyltransferase, xanthine oxidase and hypoxanthine guanine-phosphoribosyl transferase were measured in a two-stage (i.v. and p.o. administration of 0.3 mg.kg(-1) 6-TG), prospective study. Median exposure of 6-TGN in red blood cells (RBC) was expressed as the ratio of the area under the curve (AUC) per mg 6-TG after i.v. dosing and that after p.o. dosing. KEY RESULTS: The median AUC per mg 6-TG was 1068 (p.o.) and 7184 (i.v.) pmol.h (8 * 10(8) RBC)(-1) . Median exposure of 6-TGN in RBC was 15% (9-28). Hypoxanthine guanine-phosphoribosyl-transferase activity correlated with peak 6-TGN and with AUC per mg (r= 0.7, P= 0.02 and r= 0.6, P= 0.03 respectively). Thiopurine S-methyltransferase activity was inversely related to AUC per mg (r=-0.8, P= 0.001), whereas that of xanthine oxidase was correlated with a lower peak 6-TGN (r=-0.7, P= 0.02). CONCLUSIONS AND IMPLICATIONS: The great variability of the AUC per mg for 6-TG observed after p.o. and i.v. administration of 6-TG, was partly explained by variability in activities of metabolizing enzymes. Exposure of 6-TGN was low in all patients. PMID- 21323898 TI - Telmisartan, ramipril and their combination improve endothelial function in different tissues in a murine model of cholesterol-induced atherosclerosis. AB - BACKGROUND AND PURPOSE: Erectile dysfunction correlates with cardiovascular disease and its common risk factors due to the development of endothelial dysfunction. Positive effects on endothelial and erectile function have been described for substances inhibiting the renin-angiotensin-system. Here, we investigated in an atherosclerosis model, whether telmisartan (angiotensin receptor blocker) and ramipril (angiotensin converting enzyme inhibitor) are equivalent or the combination of both is superior in improving endothelial function in the aorta and the corpus cavernosum and in reducing atherosclerosis. EXPERIMENTAL APPROACH: Wild-type (WT, C57/B6) and apolipoprotein-E-deficient (ApoE(-/-) ) mice were treated with a cholesterol-rich diet for 8 weeks. ApoE(-/ ) mice were supplemented with either telmisartan (20 mg.kg(-1) .day(-1) ), ramipril (2.5 mg.kg(-1) .day(-1) ) or the combination thereof. KEY RESULTS: Systolic blood pressure significantly decreased in treatment groups (P < 0.001), with significantly smaller reduction under ramipril monotherapy (P < 0.05). Endothelial function (assessed by pharmacological stimulation of aortic rings and corpus cavernosum in organ bath chambers) was impaired in ApoE(-/-) mice compared to WT animals, which was improved by all three treatments to a comparable extent (P < 0.05). Atherosclerotic lesion size in the ascending aorta and aortic sinus (P < 0.001), the amount of lipid peroxides in cavernosal and aortic tissue (P < 0.05) and free radical load (dihydroethidium-stain) (P < 0.05) were enhanced in untreated ApoE(-/-) mice in comparison to WT animals and were significantly reduced by either treatment. In penile tissue, expression of eNOS could be restored by renin-angiotensin-aldosterone system blockade. CONCLUSIONS AND IMPLICATIONS: Telmisartan and ramipril significantly improved endothelial function of aortic and cavernosal tissues in ApoE(-/-) via reduction of oxidative stress. Combination of both agents does not enhance beneficial effects significantly. PMID- 21323899 TI - Protein kinase C-independent inhibition of arterial smooth muscle K(+) channels by a diacylglycerol analogue. AB - BACKGROUND AND PURPOSE: Analogues of the endogenous diacylglycerols have been used extensively as pharmacological activators of protein kinase C (PKC). Several reports show that some of these compounds have additional effects that are independent of PKC activation, including direct block of K(+) and Ca(2+) channels. We investigated whether dioctanoyl-sn-glycerol (DiC8), a commonly used diacylglycerol analogue, blocks K(+) currents of rat mesenteric arterial smooth muscle in a PKC-independent manner. EXPERIMENTAL APPROACH: Conventional whole cell and inside-out patch clamp was used to measure the inhibition of K(+) currents of rat isolated mesenteric smooth muscle cells by DiC8 in the absence and presence of PKC inhibitor peptide. KEY RESULTS: Mesenteric artery smooth muscle K(v) currents inactivated very slowly with a time constant of about 2 s following pulses from -65 to +40 mV. Application of 1 uM DiC8 produced an approximate 40-fold increase in the apparent rate of inactivation. Pretreatment of the cells with PKC inhibitor peptide had a minimal effect on the action of DiC8, and substantial inactivation still occurred, indicating that this effect was mainly independent of PKC. We also found that DiC8 blocked BK and K(ATP) currents, and again a significant proportion of these blocks occurred independently of PKC activation. CONCLUSIONS AND IMPLICATIONS: These results show that DiC8 has a direct effect on arterial smooth muscle K(+) channels, and this precludes its use as a PKC activator when investigating PKC-mediated effects on vascular K(+) channels. PMID- 21323900 TI - The design, synthesis and pharmacological characterization of novel beta2 adrenoceptor antagonists. AB - BACKGROUND AND PURPOSE: Selective and potent antagonists for the beta(2) adrenoceptor are potentially interesting as experimental and clinical tools, and we sought to identify novel ligands with this pharmacology. EXPERIMENTAL APPROACH: A range of pharmacological assays was used to assess potency, affinity, selectivity (beta(2) -adrenoceptor vs. beta(1) -adrenoceptor) and efficacy. KEY RESULTS: Ten novel compounds were identified but none had as high affinity as the prototypical beta(2) -adrenoceptor blocker ICI-118,551, although one of the novel compounds was more selective for beta(2) -adrenoceptors. Most of the ligands were inverse agonists for beta(2) -adrenoceptor-cAMP signalling, although one (5217377) was a partial agonist and another a neutral antagonist (7929193). None of the ligands were efficacious with regard to beta(2) -adrenoceptor-beta arrestin signalling. The (2S,3S) enantiomers were identified as the most active, although unusually the racemates were the most selective for the beta(2) adrenoceptors. This was taken as evidence for some unusual enantiospecific behaviour. CONCLUSIONS AND IMPLICATIONS: In terms of improving on the pharmacology of the ligand ICI-118,551, one of the compounds was more selective (racemic JB-175), while one was a neutral antagonist (7929193), although none had as high an affinity. The results substantiate the notion that beta-blockers do more than simply inhibit receptor activation, and differences between the ligands could provide useful tools to investigate receptor biology. PMID- 21323901 TI - Significantly reduced cytochrome P450 3A4 expression and activity in liver from humans with diabetes mellitus. AB - BACKGROUND AND PURPOSE: Patients with diabetes mellitus require pharmacotherapy with numerous medications. However, the effect of diabetes on drug biotransformation is not well understood. Our goal was to investigate the effect of diabetes on liver cytochrome P450 3As, the most abundant phase I drug metabolizing enzymes in humans. EXPERIMENTAL APPROACH: Human liver microsomal fractions (HLMs) were prepared from diabetic (n= 12) and demographically matched nondiabetic (n= 12) donors, genotyped for CYP3A4*1B and CYP3A5*3 polymorphisms. Cytochrome P450 3A4, 3A5 and 2E1 mRNA expression, protein level and enzymatic activity were compared between the two groups. KEY RESULTS: Midazolam 1'- or 4 hydroxylation and testosterone 6beta-hydroxylation, catalyzed by P450 3A, were markedly reduced in diabetic HLMs, irrespective of genotype. Significantly lower P450 3A4 protein and comparable mRNA levels were observed in diabetic HLMs. In contrast, neither P450 3A5 protein level nor mRNA expression differed significantly between the two groups. Concurrently, we have observed increased P450 2E1 protein level and higher chlorzoxazone 6-hydroxylation activity in diabetic HLMs. CONCLUSIONS AND IMPLICATIONS: These studies indicate that diabetes is associated with a significant decrease in hepatic P450 3A4 enzymatic activity and protein level. This finding could be clinically relevant for diabetic patients who have additional comorbidities and are receiving multiple medications. To further characterize the effect of diabetes on P450 3A4 activity, a well-controlled clinical study in diabetic patients is warranted. PMID- 21323902 TI - Distinct tachykinin NK(1) receptor function in primate nucleus tractus solitarius neurons is dysregulated after second-hand tobacco smoke exposure. AB - BACKGROUND AND PURPOSE: Second-hand tobacco smoke (SHS) exposure in children increases the risk of asthma and sudden infant death syndrome. Epidemiological and experimental data have suggested SHS can alter neuroplasticity in the CNS, associated with substance P. We hypothesized that exposure to SHS in young primates changed the effect of substance P on the plasticity of neurons in the nucleus tractus solitarius (NTS), where airway sensory information is first processed in the CNS. EXPERIMENTAL APPROACH: Thirteen-month-old rhesus monkeys were exposed to filtered air (FA, n= 5) or SHS (n= 5) for >6 months from 50 days of their fetal age. Whole-cell patch-clamp recordings were performed on NTS neurons in brainstem slices from these animals to record the intrinsic cell excitability in the absence or presence of the NK(1) receptor antagonist, SR140333 (3 uM). KEY RESULTS: Neurons were electrophysiologically classified based on their spiking onset from a hyperpolarized membrane potential into two phenotypes: rapid-onset spiking (RS) and delayed-onset spiking (DS) types. In RS neurons, SR140333 reduced the spiking response, similarly in both FA- and SHS exposed animals. In DS neurons, SR140333 almost abolished the spiking response in FA-exposed animals, but had no effect in SHS-exposed animals. CONCLUSIONS AND IMPLICATIONS: The contribution of NK(1) receptors to cell excitability depended on firing phenotype of primate NTS neurons and was disrupted by SHS exposure, specifically in DS neurons. Our findings reveal a novel NK(1) receptor function in the primate brainstem and support the hypothesis that chronic exposure to SHS in children causes tachykinin-related neuroplastic changes in the CNS. PMID- 21323903 TI - Neuroprotective effect of the glucagon-like peptide-1 receptor agonist, synthetic exendin-4, in streptozotocin-induced diabetic rats. AB - BACKGROUND AND PURPOSE: Glucagon-like peptide-1 (GLP-1) receptors are widely expressed in neural tissues and diminish neuronal degeneration or induce neuronal differentiation. The aim of this study was to investigate the effect of the GLP-1 pathway on peripheral nerves in streptozotocin-induced diabetic rats. EXPERIMENTAL APPROACH: Diabetic and nondiabetic rats were treated with the GLP-1 receptor agonist, synthetic exendin-4 (i.p., 1 nmol.kg(-1).day(-1)) or placebo for 24 weeks, and current perception threshold values, cAMP levels and nerve fibre size in the sciatic nerve were measured. We also investigated GLP-1 receptor expression, quantitative changes in PGP9.5-positive intraepidermal nerve fibres and cleaved caspase 3-stained Schwann cells by immunohistochemistry. KEY RESULTS: GLP-1 receptor expression was detected in the sciatic nerve and skin. After exendin-4 treatment, the increase seen in current perception threshold values at 2000 and 250 Hz in diabetic rats was reduced. Also, the decrease in myelinated fibre size or axon/fibre area ratio in the sciatic nerve and the loss of intraepidermal nerve fibre in the skin of diabetic rats were ameliorated. These responses were closely associated with the attenuation of Schwann cell apoptosis and improvement in the cAMP level in exendin-4-treated diabetic rats, compared with placebo-treated animals. CONCLUSION AND IMPLICATIONS: Synthetic exendin-4 may prevent peripheral nerve degeneration induced by diabetes in an animal model, supporting the hypothesis that GLP-1 may be useful in peripheral neuropathy. The neuroprotection is probably attributable to GLP-1 receptor activation, antiapoptotic effects and restoration of cAMP content. PMID- 21323904 TI - Activation of vascular KCNQ (Kv7) potassium channels reverses spasmogen-induced constrictor responses in rat basilar artery. AB - BACKGROUND AND PURPOSE: Cerebral vasospasm is the persistent constriction of large conduit arteries in the base of the brain. This pathologically sustained contraction of the arterial myocytes has been attributed to locally elevated concentrations of vasoconstrictor agonists (spasmogens). We assessed the presence and function of KCNQ (K(v) 7) potassium channels in rat basilar artery myocytes, and determined the efficacy of K(v) 7 channel activators in relieving spasmogen induced basilar artery constriction. EXPERIMENTAL APPROACH: Expression and function of K(v) 7 channels in freshly isolated basilar artery myocytes were evaluated by reverse transcriptase polymerase chain reaction and whole-cell electrophysiological techniques. Functional responses to K(v) 7 channel modulators were studied in intact artery segments using pressure myography. KEY RESULTS: All five mammalian KCNQ subtypes (KCNQ1-5) were detected in the myocytes. K(v) currents were attributed to K(v) 7 channel activity based on their voltage dependence of activation (V(0.5) ~-34 mV), lack of inactivation, enhancement by flupirtine (a selective K(v) 7 channel activator) and inhibition by 10,10-bis(pyridin-4-ylmethyl)anthracen-9-one (XE991; a selective K(v) 7 channel blocker). XE991 depolarized the myocytes and constricted intact basilar arteries. Celecoxib, a clinically used anti-inflammatory drug, not only enhanced K(v) 7 currents but also inhibited voltage-sensitive Ca(2+) currents. In arteries pre-constricted with spasmogens, both celecoxib and flupirtine were more effective in dilating artery segments than was nimodipine, a selective L-type Ca(2+) channel blocker. CONCLUSIONS AND IMPLICATIONS: K(v) 7 channels are important determinants of basilar artery contractile status. Targeting the K(v) 7 channels using flupirtine or celecoxib could provide a novel strategy to relieve basilar artery constriction in patients with cerebral vasospasm. LINKED ARTICLES: To view two letters to the Editor regarding this article visit http://dx.doi.org/10.1111/j.1476-5381.2011.01454.x and http://dx.doi.org/10.1111/j.1476-5381.2011.01457.x. PMID- 21323905 TI - The cardioprotective efficacy of TVP1022 in a rat model of ischaemia/reperfusion. AB - BACKGROUND AND PURPOSE: Because myocardial infarction is a major cause of morbidity and mortality worldwide, protecting the heart from the ischaemia and reperfusion (I/R) damage is the focus of intense research. Based on our in vitro findings showing that TVP1022 (the S-enantiomer of rasagiline, an anti Parkinsonian drug) possesses cardioprotective effects, in the present study we investigated the hypothesis that TVP1022 can attenuate myocardial damage in an I/R model in rats. EXPERIMENTAL APPROACH: The model consisted of 30-min occlusion of the left anterior descending artery followed by 4 or 24 h reperfusion. In addition, we investigated the possible mechanisms of cardioprotection in H9c2 cells and neonatal rat ventricular myocytes (NRVM) exposed to oxidative stress induced by H(2) O(2) . KEY RESULTS: TVP1022 (20 and 40 mg.kg(-1) ) administered 5 min before reperfusion followed by an additional dose 4 h after reperfusion reduced the infarct size and attenuated the decline in ventricular function. TVP1022 also attenuated I/R-induced deterioration in cardiac mitochondrial integrity evaluated by mitochondrial swelling capacity. In vitro, using H9c2 cells and NRVM, TVP1022 attenuated both serum free- and H(2) O(2) -induced damage, preserved mitochondrial membrane potential and Bcl-2 levels, inhibited mitochondrial cytochrome c release and the increase in cleaved caspase 9 and 3 levels, and enhanced the phosphorylation of protein kinase C and glycogen synthase kinase-3beta. CONCLUSIONS AND IMPLICATIONS: TVP1022 provided cardioprotection in a model of myocardial infarction, and therefore should be considered as a novel adjunctive therapy for attenuating myocardial damage resulting from I/R injuries. PMID- 21323906 TI - Balloon catheter injury abolishes phenylephrine-induced relaxation in the rat contralateral carotid. AB - BACKGROUND AND PURPOSE: The consequences of compensatory responses to balloon catheter injury in rat carotid artery, on phenylephrine-induced relaxation and contraction in the contralateral carotid artery were studied. EXPERIMENTAL APPROACH: Relaxation and contraction concentration-response curves for phenylephrine were obtained for contralateral carotid arteries in the presence of indomethacin (COX inhibitor), SC560 (COX-1 inhibitor), SC236 (COX-2 inhibitor) or 4-hydroxytetramethyl-L-piperidine-1-oxyl (tempol; superoxide dismutase mimetic). Reactive oxygen species were measured in carotid artery endothelial cells fluorimetrically with dihydroethidium. KEY RESULTS: Phenylephrine-induced relaxation was abolished in contralateral carotid arteries from operated rats (E(max) = 0.01 +/- 0.004 g) in relation to control (E(max) = 0.18 +/- 0.005 g). Phenylephrine-induced contractions were increased in contralateral arteries (E(max) = 0.54 +/- 0.009 g) in relation to control (E(max) = 0.38 +/- 0.014 g). SC236 restored phenylephrine-induced relaxation (E(max) = 0.17 +/- 0.004 g) and contraction (E(max) = 0.34 +/- 0.018 g) in contralateral arteries. Tempol restored phenylephrine-induced relaxation (E(max) = 0.19 +/- 0.012 g) and contraction (E(max) = 0.42 +/- 0.014 g) in contralateral arteries, while apocynin did not alter either relaxation (E(max) = 0.01 +/- 0.004 g) or contraction (E(max) = 0.54 +/- 0.009 g). Dihydroethidium fluorescence was increased in contralateral samples (18 882 +/- 435 U) in relation to control (10 455 +/- 303 U). SC236 reduced the fluorescence in contralateral samples (8250 +/- 365 U). CONCLUSIONS AND IMPLICATIONS: Balloon catheter injury abolished phenylephrine induced relaxation and increased phenylephrine-induced contraction in contralateral carotid arteries, through O(2) (-) derived from COX-2. PMID- 21323909 TI - Symptom-relieving and neuroprotective effects of the phytocannabinoid Delta9-THCV in animal models of Parkinson's disease. AB - BACKGROUND AND PURPOSE: Previous findings have indicated that a cannabinoid, such as Delta(9)-THCV, which has antioxidant properties and the ability to activate CB(2) receptors but to block CB(1) , might be a promising therapy for alleviating symptoms and delaying neurodegeneration in Parkinson's disease (PD). EXPERIMENTAL APPROACH: The ability of Delta(9)-THCV to reduce motor inhibition and provide neuroprotection was investigated in rats lesioned with 6-hydroxydopamine and in mice lesioned with lipopolysaccharide (LPS). KEY RESULTS: Acute administration of Delta(9)-THCV attenuated the motor inhibition caused by 6-hydroxydopamine, presumably through changes in glutamatergic transmission. Moreover, chronic administration of Delta(9)-THCV attenuated the loss of tyrosine hydroxylase positive neurones caused by 6-hydroxydopamine in the substantia nigra, through an effect related to its antioxidant properties (it was reproduced by cannabidiol enriched botanical extract). In addition, CB(2) receptor-deficient mice responded to 6-hydroxydopamine in a similar manner to wild-type animals, and CB(2) receptors were poorly up-regulated in the rat substantia nigra in response to 6 hydroxydopamine. By contrast, the substantia nigra of mice that had been injected with LPS exhibited a greater up-regulation of CB(2) receptors. In these animals, Delta(9)-THCV also caused preservation of tyrosine hydroxylase-positive neurones. This effect probably involved CB(2) receptors as it was also elicited by the selective CB(2) receptor agonist, HU-308, and CB(2) receptor-deficient mice were more vulnerable to LPS lesions. CONCLUSIONS AND IMPLICATIONS Given its antioxidant properties and its ability to activate CB(2) but to block CB(1) receptors, Delta(9)-THCV has a promising pharmacological profile for delaying disease progression in PD and also for ameliorating parkinsonian symptoms. PMID- 21323907 TI - Endothelium-mediated control of vascular tone: COX-1 and COX-2 products. AB - Endothelium-dependent contractions contribute to endothelial dysfunction in various animal models of aging, diabetes and cardiovascular diseases. In the spontaneously hypertensive rat, the archetypal model for endothelium-dependent contractions, the production of the endothelium-derived contractile factors (EDCF) involves an increase in endothelial intracellular calcium concentration, the production of reactive oxygen species, the predominant activation of cyclooxygenase-1 (COX-1) and to a lesser extent that of COX-2, the diffusion of EDCF towards the smooth muscle cells and the subsequent stimulation of their thromboxane A2-endoperoxide TP receptors. Endothelium-dependent contractions are also observed in various models of hypertension, aging and diabetes. They generally also involve the generation of COX-1- and/or COX-2-derived products and the activation of smooth muscle TP receptors. Depending on the model, thromboxane A(2), PGH(2), PGF(2alpha), PGE(2) and paradoxically PGI(2) can all act as EDCFs. In human, the production of COX-derived EDCF is a characteristic of the aging and diseased blood vessels, with essential hypertension causing an earlier onset and an acceleration of this endothelial dysfunction. As it has been observed in animal models, COX-1, COX-2 or both isoforms can contribute to these endothelial dysfunctions. Since in most cases, the activation of TP receptors is the common downstream effector, selective antagonists of this receptor should curtail endothelial dysfunction and be of therapeutic interest in the treatment of cardiovascular disorders. PMID- 21323908 TI - Cannabinoid receptor signalling in neurodegenerative diseases: a potential role for membrane fluidity disturbance. AB - Type-1 cannabinoid receptor (CB(1)) is the most abundant G-protein-coupled receptor (GPCR) in the brain. CB(1) and its endogenous agonists, the so-called 'endocannabinoids (eCBs)', belong to an ancient neurosignalling system that plays important functions in neurodegenerative and neuroinflammatory disorders like Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. For this reason, research on the therapeutic potential of drugs modulating the endogenous tone of eCBs is very intense. Several GPCRs reside within subdomains of the plasma membranes that contain high concentrations of cholesterol: the lipid rafts. Here, the hypothesis that changes in membrane fluidity alter function of the endocannabinoid system, as well as progression of particular neurodegenerative diseases, is described. To this end, the impact of membrane cholesterol on membrane properties and hence on neurodegenerative diseases, as well as on CB(1) signalling in vitro and on CB(1) -dependent neurotransmission within the striatum, is discussed. Overall, present evidence points to the membrane environment as a critical regulator of signal transduction triggered by CB(1) , and calls for further studies aimed at better clarifying the contribution of membrane lipids to eCBs signalling. The results of these investigations might be exploited also for the development of novel therapeutics able to combat disorders associated with abnormal activity of CB(1). PMID- 21323911 TI - Clinico-immunological changes post-immunotherapy with Periplaneta americana. AB - BACKGROUND: Cockroach proteins induce allergies including asthma in predisposed individuals. Well-designed controlled studies are required to show the effect of cockroach immunotherapy (IT). This study is aimed to assess changes in clinical and immunological parameters post-IT with Periplaneta americana extract. MATERIALS AND METHODS: A double-blind, placebo-controlled trial of cockroach IT was performed for 1year in 50 patients of asthma, rhinitis or both. The efficacy of IT was assessed by change in skin reactivity and clinical parameters such as symptom/drug score, airway reactivity and immunological parameters namely IgE, IgG1 and IgG4, IL-4 and IFN-gamma by enzyme-linked immunosorbent assay and western blotting using patients' sera at baseline and after 1year of treatment. RESULTS: Immunotherapy with cockroach extract demonstrated significant improvement in clinical parameters of active group patients compared with baseline values and placebo group. Specific IgE levels showed a modest reduction, while IgG4 levels increased significantly in active IT group after 1year. IgE immunoblotting demonstrated reduction in intensity and number of specific bands, whereas IgG4 binding showed more number and distinct bands following IT. Active group patients showed correlation between increase in IgG4/IgG1 ratio and reduction in symptom score post-IT. CONCLUSIONS: Immunotherapy with cockroach extract improved clinical and immunological status of asthma and rhinitis patients. Clinical improvement in patients after IT is associated with immunological changes. PMID- 21323912 TI - Expression of melatonin in platelets of patients with aspirin-induced asthma. AB - BACKGROUND: The diffuse neuroimmunoendocrine system (DNIES) is a universal system of response, control and organism protection. Platelets are cells of DNIES producing and storing melatonin which plays an important role in the regulation of physiological processes in the human body, under normal conditions and in pathology. Our previous study has revealed a low basic melatonin production in patients with aspirin-induced asthma (AIA). It has been suggested that low daytime production of melatonin in patients with AIA is attributable to the reduction in its synthesis in platelets in this group of patients. The objective of this study was to investigate this hypothesis. MATERIALS AND METHODS: The melatonin expression in platelets has been studied by means of indirect immunofluorescence in nine patients with AIA and 14 healthy subjects. RESULTS: The results of the study have revealed that only 13.1 +/- 1.3% of platelets in patients with AIA have shown melatonin-specific luminescence, compared to 97.7 +/ 0.6% of platelets in healthy subjects (P < 0.001). No melatonin expression has been observed in the rest of platelets in patients with AIA. No significant difference between the degree of the melatonin luminescence in platelets of the patients with AIA and control group has been found. CONCLUSIONS: It can be concluded that the reduced melatonin synthesis in platelets of patients with AIA may determine a low daytime melatonin production and may lead to impairments in platelet receptors and ion channels. This results in disturbances in calcium homoeostasis, which may be a cause of platelet activation and pathological response to exogenous melatonin and acetylsalicylic acid. PMID- 21323910 TI - The dual neuroprotective-neurotoxic profile of cannabinoid drugs. AB - Extensive in vitro and in vivo studies have shown that cannabinoid drugs have neuroprotective properties and suggested that the endocannabinoid system may be involved in endogenous neuroprotective mechanisms. On the other hand, neurotoxic effects of cannabinoids in vitro and in vivo were also described. Several possible explanations for these dual, opposite effects of cannabinoids on cellular fate were suggested, and it is conceivable that various factors may determine the final outcome of the cannabinoid effect in vivo. In the current review, we focus on one of the possible reasons for the dual neuroprotective/neurotoxic effects of cannabinoids in vivo, namely, the opposite effects of low versus high doses of cannabinoids. While many studies reported neuroprotective effects of the conventional doses of cannabinoids in various experimental models for acute brain injuries, we have shown that a single administration of an extremely low dose of Delta(9) -tetrahydrocannabinol (THC) (3-4 orders of magnitude lower than the conventional doses) to mice induced long lasting mild cognitive deficits that affected various aspects of memory and learning. These findings led to the idea that this low dose of THC, which induces minor damage to the brain, may activate preconditioning and/or postconditioning mechanisms and thus will protect the brain from more severe insults. Indeed, our recent findings support this assumption and show that a pre- or a postconditioning treatment with extremely low doses of THC, several days before or after brain injury, provides effective long-term cognitive neuroprotection. The future therapeutical potential of these findings is discussed. PMID- 21323913 TI - Heart rate variability is independently associated with C-reactive protein but not with Serum amyloid A. The Cardiovascular Risk in Young Finns Study. AB - BACKGROUND: Increased levels of C-reactive protein (CRP) and serum amyloid A (SAA) are associated with an increased risk of cardiovascular disease. It is hypothesized that dysregulation of the autonomic nervous system (ANS) leads to increased inflammation via the cholinergic anti-inflammatory pathway. Heart rate variability (HRV) is a marker of ANS function. HRV has been shown to be associated with CRP levels. Currently, there are no studies addressing the relationship between HRV and SAA. DESIGN: The purpose of this study was to compare the associations between HRV, CRP and SAA in healthy young adults. CRP and SAA concentrations and short-term HRV indices [high frequency (HF), low frequency (LF), total spectral component of HRV, root mean square differences of successive R-R intervals, the standard deviation of all R-R intervals and ratio between LF and HF) were measured in 1601 men and women aged 24-39 taking part in the Cardiovascular Risk in Young Finns study. RESULTS: A significant inverse correlation (P < 0.05) between HRV indices and inflammatory markers was observed. However, in linear regression analyses, only inverse association between HRV indices and CRP levels remained significant (P < 0.05), while association between HRV indices and SAA levels was attenuated to the null (P > 0.05) after adjusting for age, sex, body mass index, cholesterol levels, leptin and other common traditional cardiovascular risk factors. CONCLUSIONS: Reduced HRV indices are independently associated with increased CRP levels, but not with SAA levels. This association supports the hypothesis that dysregulation of the ANS may lead to increased inflammation early in adulthood. PMID- 21323914 TI - The expression of nestin delineates skeletal muscle differentiation in the developing rat esophagus. AB - The muscularis externa of the developing rodent esophagus is initially composed of smooth muscle, and later replaced by skeletal muscle in a craniocaudal progression. There is growing evidence of distinct developmental origins for esophageal smooth and skeletal muscles. However, the identification of skeletal muscle progenitor cells is controversial, and the detailed cell lineage of their descendants remains elusive. In the current study, we carried out multiple labeling immunofluorescence microscopy of nestin and muscle type-specific markers to characterize the dynamic process of rat esophageal myogenesis. The results showed that nestin was transiently expressed in immature esophageal smooth muscle cells in early developing stages. After nestin was downregulated in smooth muscle cells, a distinct population of nestin-positive cells emerged as skeletal muscle precursors. They were mitotically active, and subsequently co-expressed MyoD, followed by the embryonic and later the fast type of skeletal muscle myosin heavy chain. Thus, the cell lineage of esophageal skeletal muscle differentiation was established by an immunotyping approach, which revealed that skeletal myocytes arise from a distinct lineage rather than through transdifferentiation of smooth muscle cells during rat esophageal myogenesis. PMID- 21323915 TI - Ontogenetic changes in the internal and external morphology of the ilium in modern humans. AB - Trabecular architecture forms an important structural component of bone and, depending on the loading conditions encountered during life, is organised in a systematic, bone- and species-specific manner. However, recent studies suggested that gross trabecular arrangement (e.g. density distribution), like overall bone shape, is predetermined and/or affected by factors other than loading and perhaps less plastic than commonly assumed. To explore this issue further, the present cross-sectional ontogenetic study investigated morphological changes in external bone shape in relation to changes in trabecular bundle orientation and anisotropy. Radiographs of 73 modern human ilia were assessed using radiographic and Geometric Morphometric techniques. The study confirmed the apparently strong predetermination of trabecular bundle development, i.e. prior to external loading, although loading clearly also had an effect on overall morphology. For example, the sacro-pubic bundle, which follows the path of load transmission from the auricular surface to the acetabulum, is well defined and shows relatively high levels of anisotropy from early stages of development; the situation for the ischio-iliac strut is similar. However, while the sacro-pubic strut retains a constant relationship with the external landmarks defining the joint surfaces, the ischio-iliac bundle changes its relationship with the external landmarks and becomes aligned with the iliac tubercle only during late adolescence/early adulthood. It is tentatively proposed that the rearrangement of the ischio-iliac strut may reflect a change in locomotor pattern and/or a shift in positional behavior with increasing mass after growth of external bone dimensions has slowed/ceased. PMID- 21323916 TI - The plantaris tendon and a potential role in mid-portion Achilles tendinopathy: an observational anatomical study. AB - The source of pain and the background to the pain mechanisms associated with mid portion Achilles tendinopathy have not yet been clarified. Intratendinous degenerative changes are most often addressed when present. However, it is questionable if degeneration of the tendon itself is the main cause of pain. Pain is often most prominent on the medial side, 2-7cm from the insertion onto the calcaneus. The medial location of the pain has been explained to be caused by enhanced stress on the calcaneal tendon due to hyperpronation. However, on this medial side the plantaris tendon is also located. It has been postulated that the plantaris tendon might play a role in these medially located symptoms. To our knowledge, the exact anatomy and relationship between the plantaris- and calcaneal tendon at the level of complaints have not been anatomically assessed. This was the purpose of our study. One-hundred and seven lower extremities were dissected. After opening the superficial fascia and paratendon, the plantaris tendon was bluntly released from the calcaneal tendon moving distally. The incidence of the plantaris tendon, its course, site of insertion and possible connections were documented. When with manual force the plantaris tendon could not be released, it was defined as a 'connection' with the calcaneal tendon. In all specimens a plantaris tendon was identified. Nine different sites of insertion were found, mostly medial and fan-shaped onto the calcaneus. In 11 specimens (10%) firm connections were found at the level of the calcaneal tendon mid-portion. Clinical and histological studies are needed to confirm the role of the plantaris tendon in mid-portion Achilles tendinopathy. PMID- 21323917 TI - Controversial snake relationships supported by reproductive anatomy. AB - Since the advent of molecular character sets in phylogenetic systematics our understanding of the evolutionary history of snakes has changed considerably. In some cases the novel topologies reconstructed from molecular datasets have left researchers puzzled, as no morphological feature seems to support the new relationships found. This is the case for 'Amerophidia'sensu Vidal et al. (2007; Biology of the Boas and Pythons, Eagle Mountain: Eagle Mountain Publishing; Aniliidae+ Tropidophiidae), a grouping of the Red Pipesnakes and Neotropical Dwarf Boas. We contend that in some cases the apparent lack of historical morphological support for the molecular phylogenies is due to our poor understanding of the organisms as a whole, and not the complete lack of morphological support for controversial clades. For example, we found novel evidence from reproductive anatomy that demonstrates a unique association of the oviducts and cloaca in Amerophidia. Whereas in all other female squamates the oviducts communicate directly with the cloaca, the oviducts of Aniliidae and Tropidophiidae communicate with diverticuli of the cloaca. At present this is the only unambiguous synapomorphy for the Amerophidia. We feel that confirmation of controversial molecular relationships will revolve around the investigation of non-traditional morphological characters such as reproductive anatomy. PMID- 21323919 TI - Inter- and intra-specific scaling of articular surface areas in the hominoid talus. AB - The morphology of postcranial articular surfaces is expected to reflect their weight-bearing properties, as well as the stability and mobility of the articulations to which they contribute. Previous studies have mainly confirmed earlier predictions of isometric scaling between articular surface areas and body mass; the exception to this is 'male-type', convex articular surface areas, which may scale allometrically due to differences in locomotor strategies within the analysed samples. In the present study, we used new surface scanning technology to quantify more accurately articular surface areas and to test those predictions within the talus of hominoid primates, including modern humans. Our results, contrary to predictions, suggest that there are no generalised rules of articular scaling within the talus of hominoids. Instead, we suggest that articular scaling patterns are highly context-specific, depending on the role of each articulation during locomotion, as well as taxon- and sex-specific differences in locomotion and ontogenetic growth trajectories within any given sample. While this may prove problematic for inferring body mass based on articular surface area, it also offers new opportunities of gaining substantial insights into the locomotor patterns of extinct species. PMID- 21323920 TI - Patchy bed disturbance and fish predation independently influence the distribution of stream invertebrates and algae. AB - 1. The identification of factors determining the patchy distribution of organisms in space and time is a central concern of ecology. Predation and abiotic disturbance are both well-known drivers of this patchiness, but their interplay is still poorly understood, especially for communities dominated by mobile organisms in frequently disturbed ecosystems. 2. We investigated the separate and interactive influences of bed disturbance by floods and predation by fish on the benthic community in a flood-prone stream. Electric fields excluded fish predators from half of 48 stream bed patches (area 0.49 m(2) ) with contrasting disturbance treatments. Three types of bed disturbance were created by either scouring or filling patches to a depth of 15-20 cm or by leaving the patches undisturbed, thus mimicking the mosaic of scour and fill caused by a moderate flood. Benthic invertebrates and algae were sampled repeatedly until 57 days after the disturbance. 3. Disturbance influenced all ten investigated biological response variables, whereas predation affected four variables. Averaged across time, invertebrate taxon richness and total abundance were highest in stable patches. Algal biomass and densities of five of the seven most common invertebrate taxa (most of which were highly mobile) were higher in fill than in scour patches, whereas two taxa were more abundant in scour and stable than in fill patches. Furthermore, two common invertebrate grazers were more abundant and algal biomass tended to be reduced in fish exclusion patches, suggesting a patch scale trophic cascade from fish to algae. 4. Our results highlight the importance of patchy physical disturbance for the microdistribution of mobile stream organisms and indicate a notable, but less prevalent, influence of fish predation at the patch scale in this frequently disturbed environment. Disturbance and predation treatments interacted only once, suggesting that the observed predation effects were largely independent of local bed disturbance patterns. PMID- 21323921 TI - Contrasting cascade effects of carnivores on plant fitness: a meta-analysis. AB - 1. Although carnivores indirectly improve plant fitness by decreasing herbivory, they may also decrease plant reproduction by disrupting plant-pollinator mutualism. The overall magnitude of the resulting net effect of carnivores on plant fitness and the factors responsible for the variations in strength and direction of this effect have not been explored quantitatively to date. 2. We performed a meta-analysis of 67 studies containing 163 estimates of the effects of carnivores on plant fitness and examined the relative importance of several potential sources of variation in carnivore effects. 3. Carnivores significantly increased plant fitness via suppression of herbivores and decreased fitness by consuming pollinators. The overall net effect of carnivores on plant fitness was positive (32% increase), indicating that effects via herbivores were stronger than effects via pollinators. 4. Parasitoids had stronger positive effect on plant fitness than predators. Active hunters increased plant fitness, whereas stationary predators had no significant effect, presumably because they were more prone to disrupt plant-pollinator mutualism. Carnivores with broader habitat domain had negative effects on plant fitness, whereas those with narrow habitat domain had positive effects. 5. Predator effects were positive for plants which offered rewards (e.g. extrafloral nectaries) and negative for plants which lacked any attractors. 6. This study adds new knowledge on the factors that determine the strength of terrestrial trophic cascades and highlights the importance of considering simultaneous contrasting interactions in the same study system. PMID- 21323922 TI - Experimental evidence for emergent facilitation: promoting the existence of an invertebrate predator by killing its prey. AB - 1. Recent theoretical insights have shown that predator species may help each other to persist by size-selective foraging on a shared prey. By feeding on a certain prey stage, a predator may induce a compensatory response in another stage of the same prey species, thereby favouring other predators; a phenomenon referred to as emergent facilitation. 2. To test whether emergent facilitation may occur in a natural system, we performed an enclosure experiment where we mimicked fish predation by selectively removing large zooplankton and subsequently following the response of the invertebrate predator Bythotrephes longimanus. 3. Positive responses to harvest were observed in the biomass of juvenile individuals of the dominant zooplankton Holopedium gibberum and in Bythotrephes densities. Hence, by removing large prey, we increased the biomass of small prey, i.e. stage-specific biomass overcompensation was present in the juvenile stage of Holopedium. This favoured Bythotrephes, which preferentially feed on small Holopedium. 4. We argue that the stage-specific overcompensation occurred as a result of increased per capita fecundity of adult Holopedium and as a result of competitive release following harvest. If shown to be common, emergent facilitation may be a major mechanism behind observed predator extinctions and patterns of predator invasions. PMID- 21323923 TI - Shrinking by numbers: landscape context affects the species composition but not the quantitative structure of local food webs. AB - 1. With habitat fragmentation spreading around the world, there is a pressing need to understand its impacts on local food webs. To date, few studies have examined the effects of landscape context on multiple local communities in a quantitative, spatially realistic setting. 2. To examine how the isolation of a food web affects its structure, we construct local food webs of specialist herbivores and their natural enemies on 82 individual oaks (Quercus robur) growing in different landscape contexts. 3. Across this set of webs, we find that communities in isolated habitat patches not only contained fewer species than did well-connected ones, but also differed in species composition. 4. Surprisingly, the effects observed in terms of species composition were not reflected in the quantitative interaction structure of local food webs: landscape context had no detectable effect on either the interaction evenness, linkage density, connectance, generality or vulnerability of local webs. 5. We conclude that the quantitative structure of food webs may be stable in the face of habitat fragmentation, despite clear-cut impacts on individual species. This finding offers hope-inspiring news for conservation, but should clearly be verified by empirical studies across both naturally and more recently fragmented systems. PMID- 21323924 TI - Increased hippocampal noradrenaline is a biomarker for efficacy of vagus nerve stimulation in a limbic seizure model. AB - Vagus nerve stimulation (VNS) is an effective adjunctive treatment for medically refractory epilepsy. In this study, we measured VNS-induced changes in hippocampal neurotransmitter levels and determined their potential involvement in the anticonvulsive action of VNS, to elucidate the mechanism of action responsible for the seizure suppressing effect of VNS in an animal model for limbic seizures. We used in vivo intracerebral microdialysis to measure VNS induced changes in hippocampal extracellular concentrations of noradrenaline, dopamine, serotonin and GABA in freely moving, male Wistar rats. During the same experiment, the effect of VNS on pilocarpine-induced limbic seizures was assessed using video-EEG monitoring. The involvement of VNS-induced increases in hippocampal noradrenaline in the mechanims of action of VNS was evaluated by blocking hippocampal alpha(2)-receptors. VNS produced a significant increase in hippocampal noradrenaline concentration (69 +/- 16% above baseline levels). VNS also increased the latency between pilocarpine infusion and the onset of epileptiform discharges, and reduced the duration and severity of pilocarpine induced limbic seizures. A strong positive correlation was found between the noradrenergic and anticonvulsive effects of VNS. Blockade of hippocampal alpha(2 receptors reversed the seizure-suppressing effect of VNS. VNS induces increases in extracellular hippocampal noradrenaline, which are at least partly responsible for its seizure-suppressing effect in a model for limbic seizures, and constitute a potential biomarker for the efficacy of VNS in temporal lobe epilepsy. PMID- 21323925 TI - Methylphenidate alters basal ganglia neurotensin systems through dopaminergic mechanisms: a comparison with cocaine treatment. AB - Methylphenidate (MPD) is a psychostimulant widely used to treat behavioral problems such as attention deficit hyperactivity disorder. MPD competitively inhibits the dopamine (DA) transporter. Previous studies demonstrated that stimulants of abuse, such as cocaine (COC) and methamphetamine differentially alter rat brain neurotensin (NT) systems through DA mechanisms. As NT is a neuropeptide primarily associated with the regulation of the nigrostriatal and mesolimbic DA systems, the effect of MPD on NT-like immunoreactivity (NTLI) content in several basal ganglia regions was assessed. MPD, at doses of 2.0 or 10.0 mg/kg, s.c., significantly increased the NTLI contents in dorsal striatum, substantia nigra and globus pallidus; similar increases in NTLI were observed in these areas after administration of COC (30.0 mg/kg, i.p.). No changes in NTLI occurred within the nucleus accumbens, frontal cortex and ventral tegmental area following MPD treatment. In addition, the NTLI changes in basal ganglia regions induced by MPD were prevented when D(1) (SCH 23390) or D(2) (eticlopride) receptor antagonists were coadministered with MPD. MPD treatment also increased dynorphin (DYN) levels in basal ganglia structures. These findings provide evidence that basal ganglia, but not limbic, NT systems are significantly affected by MPD through D(1) and D(2) receptor mechanisms, and these NTLI changes are similar, but not identical to those which occurred with COC administration. In addition, the MPD effects on NT systems are mechanistically distinct from the effects of methamphetamine. PMID- 21323926 TI - Tetanic failure due to decreased endogenous adenosine A(2A) tonus operating neuronal Ca(v) 1 (L-type) influx in Myasthenia gravis. AB - In healthy motor endplates, tetanic depression is overcome by tonic adenosine A(2A) -receptor-mediated facilitation of transmitter release. The A(2A) receptor operates a coordinated shift from fast-desensitizing Ca(v) 2.1 (P/Q) calcium influx to long-lasting Ca(V) 1 (L) channels on motor nerve terminals. This study aimed at investigating whether A(2A) receptors-operated Ca(2+) influx via Ca(V) 1 (L)-type channels contribute to sustain acetylcholine release evoked by 50 Hz bursts in toxin-induced Myasthenia gravis (TIMG) rats. In contrast to control animals, inhibition of [(3) H]acetylcholine (ACh) release by the Ca(V) 2.1 (P/Q) channel blocker, omega-Agatoxin IVA (100 nM), in TIMG rats had a higher magnitude than that observed with the Ca(V) 1 (L) channel blocker, nifedipine (1 MUM). Adenosine deaminase (0.5 U/mL) and the A(2A) receptor antagonist, ZM 241385 (50 nM), decreased [(3) H]ACh release by a similar amount in control rats, but their effects were smaller in magnitude in myasthenic animals. The adenosine precursor, AMP (100 MUM), increased (~40%) ACh release in both control and TIMG animals. Blockade of A(2A) , but not of A(1) , receptors prevented AMP-induced facilitation of transmitter release; nifedipine (1 MUM) mimicked the effect of the A(2A) receptor antagonist. Video-microscopy studies designed to measure real time transmitter exocytosis using the FM4-64 fluorescent dye fully supported radiochemical data. Thus, impairment of the adaptive shift from Ca(V) 2.1 (P/Q) to Ca(V) 1 (L) channels may contribute to tetanic failure in myasthenic rats. This parallels the reduction of adenosine A(2A) receptor tonus in TIMG animals, which might be restored by exogenous application of AMP. PMID- 21323927 TI - Carbon and nitrogen dynamics during forest stand development: a global synthesis. AB - Our knowledge of carbon (C) and nitrogen (N) dynamics during stand development is not only essential for evaluating the role of secondary forests in the global terrestrial C cycle, but also crucial for understanding long-term C-N interactions in terrestrial ecosystems. However, a comprehensive understanding of forest C and N dynamics over age sequence remains elusive due to the diverse results obtained across individual studies. Here, we synthesized the results of more than 100 studies to examine C and N dynamics during forest stand development. Our results showed that C accumulated in aboveground vegetation, litter and forest floor pools, while the mineral soil C pool did not exhibit significant changes in most studies. The rate of C changes declined with stand age and approached equilibrium during the later stage of stand development. The rate of N changes exhibited linear increases with that of C changes, indicating that N also accrued in various ecosystem components except mineral soil. These results demonstrate that substantial increases in C pools over age sequence are accompanied by N accretion in forest ecosystems. The concurrent C and N dynamics suggest that forest ecosystems may have an intrinsic ability to preclude progressive N limitation during stand development. PMID- 21323928 TI - Adaptation to drought in two wild tomato species: the evolution of the Asr gene family. AB - Wild tomato species are a valuable system in which to study local adaptation to drought: they grow in diverse environments ranging from mesic to extremely arid conditions. Here, we investigate the evolution of members of the Asr (ABA/water stress/ripening induced) gene family, which have been reported to be involved in the water stress response. We analysed molecular variation in the Asr gene family in populations of two closely related species, Solanum chilense and Solanum peruvianum. We concluded that Asr1 has evolved under strong purifying selection. In contrast to previous reports, we did not detect evidence for positive selection at Asr2. However, Asr4 shows patterns consistent with local adaptation in an S. chilense population that lives in an extremely dry environment. We also discovered a new member of the gene family, Asr5. Our results show that the Asr genes constitute a dynamic gene family and provide an excellent example of tandemly arrayed genes that are of importance in adaptation. Taking the potential distribution of the species into account, it appears that S. peruvianum can cope with a great variety of environmental conditions without undergoing local adaptation, whereas S. chilense undergoes local adaptation more frequently. PMID- 21323929 TI - The use of fentanyl-patch in dogs undergoing spinal surgery: plasma concentration and analgesic efficacy. AB - Objectives of this study were to evaluate plasma concentrations and analgesic efficacy of fentanyl administered transdermically in dogs undergoing spinal surgery. At the end of the surgery and before awakening, a fentanyl-patch was applied and was maintained in situ for 72 h. Blood samples were taken before the application of the patch, at 2, 4, 6, 8, 10, 12, 18, 24, 32, 40, 48, 60, and 72 h after application and then 2, 4, 6, 8, 10, and 12 h after its removal. Before each blood sampling, pain evaluation was carried out using the Glasgow pain score, appropriately modified. Plasma concentrations of fentanyl were determined using a specific immuno-enzymatic kit. In this study, the minimum analgesic plasma concentration (0.23 ng/mL) required to achieve analgesia in human and considered to apply also for dogs was reached in all animals. No animal showed pain in the range of 'intense pain'; in two cases, the level of the pain was slight or moderate. No undesired effects were found. Results suggest that the use of transdermic patches could represent a valid aid in pain therapy in small animals; in particular, it contributes to the postoperative well-being of patients undergoing major surgery. PMID- 21323930 TI - Single subcutaneous dosing of cefovecin in rhesus monkeys (Macaca mulatta): a pharmacokinetic study. AB - Cefovecin is a third-generation cephalosporin approved for antibacterial treatment with a 14-day dosing interval in dogs and cats. This antibiotic may also be useful for zoo and wildlife veterinary medicine, because of its broad spectrum and long duration of activity. The aim of the study was to determine whether cefovecin is a suitable antibiotic to prevent skin wound infection in rhesus monkeys. Therefore, the pharmacokinetics (PK) of cefovecin after a single subcutaneous injection at 8 mg/kg bodyweight in four rhesus monkeys (Macaca mulatta) and sensitivity of bacterial isolates from fresh skin wounds were determined. After administration, blood, urine, and feces were collected, and concentrations of cefovecin were determined. Further, the minimum inhibitory concentrations (MIC) for bacteria isolated from fresh skin wounds of monkeys during a health control program were determined. The mean maximum plasma concentration (C(max) ) of cefovecin was 78 MUg/mL and was achieved after 57 min. The mean apparent long elimination half-life (t1/2) was 6.6 h and excretion occurred mainly via urine. The MIC for the majority of the bacteria examined was >100 MUg/mL. The PK of cefovecin in rhesus monkeys is substantially different than for dogs and cats. Cefovecin rapidly reached C(max) which however was lower than most of the MIC levels and with a very short t1/2. Therefore, cefovecin is not recommended for treating skin wounds in rhesus monkeys. PMID- 21323931 TI - Safety evaluation and treatment affect of LY2190416, a CB-1 antagonist/inverse agonist in growing beagle dogs. AB - The objective of this study was to assess the safe use of LY2190416, a cannabinoid receptor 1 receptor antagonist/inverse agonist, for obesity management in dogs. Twenty-four clinically normal young beagle dogs were administered LY2190416 at doses of 3, 9, or 18 mg/kg or placebo, orally, once daily for 13 weeks. Food consumption and body weight were determined, and dogs were evaluated for changes in hematology, clinical chemistry, urinalysis, and serum cortisol. LY2190416 had no significant effect on hematology, clinical chemistry, urinalysis, and serum cortisol. All dogs consumed 100% of their entire daily allowance throughout the study. All dogs gained weight during the study, but treated dogs gained less than control dogs by the end of the study. During the first month, dogs exhibited a dose-dependent decrease in rate of weight gain (19.7 g/day for control dogs vs. 10.6 g/day for the 18 mg/kg dose group). LY2190416 was found to be safe at doses up to 18 mg/kg administered daily for 3 months. Results suggest that LY2190416 decreases rate of weight gain without affecting appetite or causing significant adverse health effects in normal growing dogs. Possible mechanisms for a proposed metabolic effect are discussed. PMID- 21323932 TI - Specific phage-displayed peptides discriminate different forms of neurocysticercosis by antibody detection in the serum samples. AB - Neurocysticercosis (NC), caused by Taenia solium metacestode, infects the central nervous system and is a devastating parasitic infection. Diagnosis is based on symptoms, imaging, serology and epidemiology. Current markers present variable sensitivity and specificity, frequent cross-reactions and are not able to discriminate NC clinical forms. The aim of this study was to select mimotopes of T. solium metacestode antigens that may be used in NC immunodiagnosis, specifically to discriminate between active and inactive forms. A random peptide phage display library was screened against IgY from chickens immunized with total saline extract from T. solium metacestodes and validated against 110 serum samples, classified into active NC (18), inactive NC (22), cross-reactive parasitic diseases (40) and healthy controls (30). We have successfully selected seven peptides with significant immunoreactivity to IgG of NC patients, with sensitivity ranging from 95.5% to 100% to detect the inactive form and specificity varied from 85.7% to 94.3%. One phage-displayed peptide (Cc48) can be directly used as biomarker to distinguish inactive from active forms with an accuracy of 95.7%, and this novel mimotope may also be used as an auxiliary tool to neuroimaging tests and treatment follow-up. PMID- 21323933 TI - A novel technique for chitosan microparticle preparation using a water/silicone emulsion: green tea model. AB - Many effective methods such as spray drying, coacervation, ionic gelation, solvent evaporation and sieving have been suggested for entrapping bioactive compounds into micro- or nanoparticles. However, those methods still have some limitations owing to high temperature requirement, difficulty in particle harvesting or low entrapment for uncharged molecules. In this study, a novel chitosan microparticle preparation method was developed using water-in-silicone emulsion technique with green tea extract as a model active compound. Chitosan microparticles of diameter <5 MUm were obtained from 2% chitosan solution with tripolyphosphate (TPP) solution as the hardening agent. The size and properties of the particles appeared to depend on several parameters such as TPP, emulsifier concentrations and pH. High concentration of emulsifier led to low encapsulation and particle aggregation. Entrapment efficiency of chitosan microparticles was improved with lower pH of the tripolyphosphate solution [59.94 +/- 3.97 of epigallocatechin gallate (EGCG)] while slowing release of catechins. Epigallocatechin and epicatechin were released almost completely within 2 h under acidic condition whereas EGCG and epicatechin gallate were slowly released. In neutral condition, release of catechins depended on their molecular stabilities. The stabilities of catechins loaded in chitosan microparticles were varied under various temperatures. The degradation of tea catechins increased with temperature. However, the degradation of tea catechins loaded in chitosan microparticles was less than that of free catechins. Thus, the new technique for preparing chitosan microparticles containing heat-sensitive water soluble green tea extract was successfully developed. The technique is suitable for micro encapsulation of hydrophilic compounds into chitosan microparticles with the ease of harvesting technique. PMID- 21323934 TI - Detection of Deefgea chitinilytica in freshwater ornamental fish. AB - AIM: To identify and characterize six chitinolytic bacterial strains isolated from ornamental fish. METHODS AND RESULTS: Six different isolates of Deefgea chitinilytica were detected in healthy as well as diseased ornamental fish in Germany over a period of 2 years. Bacterial strains were identified using 16S rRNA partial gene sequencing and further characterized using different biochemical microtest systems and additional standard biochemical tests. CONCLUSION: We show that commercially available biochemical microtest systems are useful for identification of D. chitinilytica, supplemented by 16S rRNA partial gene sequencing. Furthermore, this study provides new information about the occurrence of D. chitinilytica, as this is the first isolation of D. chitinilytica from animals and first described isolation in Europe. SIGNIFICANCE AND IMPACT OF THE STUDY: Deefgea chitinilytica may be isolated regularly in fish diagnostic laboratories. Therefore, accurate identification of this bacterial species is important. Involvement of D. chitinilytica in opportunistic infections of aquatic organisms cannot be excluded and has to be further investigated. PMID- 21323935 TI - Fabrication of a multi-applicable removable intraoral denture system for rodent research. AB - The objective was to engineer an inexpensive intraoral removable denture system for rodents that can be utilised in numerous oral health research applications. At the forefront is biofilm research related to Candida-associated denture stomatitis. Previously described intraoral devices are primitive and inadequate. The denture system was engineered consisting of a fixed part that is anchored to the posterior palate by orthodontic wires and acrylic resin and a removable part fitted to the anterior palate that is retained by magnets embedded in the fixed part. Both parts are custom fitted to the rodent palate by impression making and cast fabrication. Rats fitted with the intraoral denture system maintained body weight and normal activity with the device maintaining integrity and durability for upwards of 8 weeks. The denture system was used successfully to establish a working model of denture stomatitis. This newly engineered inexpensive intraoral removable denture system for rodents can be utilised in numerous oral health research applications, including denture-associated infections, biofilms and a variety of biomaterial applications. The removable portion is advantageous for longitudinal analyses and charging/discharging of biomaterials. PMID- 21323936 TI - Occupational dermatology: an evidence-based discipline? PMID- 21323938 TI - Flexural reticular pigmentation and pruritic papules in a 33-year-old woman. PMID- 21323937 TI - Evaluation of soluble CD163 as a marker of inflammation in psoriasis. AB - A reliable biomarker of disease activity in psoriasis would be helpful for management, especially if this gave early information on treatment efficacy. This study investigated whether serum levels of soluble (s)CD163 correlated with psoriasis activity as assessed by the Psoriasis Area and Severity Index (PASI). CD163, a glycoprotein molecule expressed on macrophages and dendritic cells, is cleaved from the surface of these cells in some inflammatory diseases, and sCD163 levels have been shown to correlate with disease activity in other disorders. In this study, levels of sCD163 did not correlate with PASI in the patients (P = 0.56). Five patients had moderately increased PASI (12.6-20.3) but their sCD163 levels were within the normal range. From this study, it seems that sCD163 levels do not correlate with the inflammatory process in the skin of patients with psoriasis and thus sCD163 is not likely to be a useful biomarker for this disease. PMID- 21323939 TI - A solitary oral ulcer. PMID- 21323940 TI - Unusual vulval papules. PMID- 21323941 TI - Rash and eschars in a returning traveller. PMID- 21323942 TI - Recalcitrant generalized eruption and low alkaline phosphatase: think zinc. PMID- 21323945 TI - Cluster analysis of immunohistochemical profiles delineates CK7, vimentin, S100A1 and C-kit (CD117) as an optimal panel in the differential diagnosis of renal oncocytoma from its mimics. AB - AIMS: To develop an immunohistochemical strategy for distinguishing renal oncocytoma (RO) from the eosinophilic variant of chromophobe (ChRCC), and papillary (PRCC) and clear cell (CRCC) renal cell carcinoma containing eosinophilic cytoplasm in core biopsy specimens. METHODS AND RESULTS: Cluster analysis was performed on immunohistochemical data from 21 RO, 16 ChRCC, 16 CRCC and 20 PRCC patients. A panel of CK7, C-kit, S100A1 and vimentin clustered into four groups. Cluster A (94% ChRCC) expressed C-kit and CK7 and lacked S100A1 and vimentin. Cluster B (95% RO) expressed C-kit, S100A1, focal CK7 (single or small clusters of cells) and lacked vimentin. Cluster C comprised a mixture of PRCC and CRCC with no expression of C-kit or CK7 and variable S100A1 and vimentin. PRCC with strong expression of CK7 clustered into group D. A panel of S100A1 (positive) and focal CK7 expression distinguished RO from ChRCC with 91% sensitivity and 93% specificity. A panel of vimentin (negative) and C-kit (positive) distinguished RO from CRCC with 83% sensitivity and 86% specificity and RO from PRCC with 79% sensitivity and 88% specificity. CONCLUSIONS: Hierarchical cluster analysis is an effective approach to analyse high-volume immunohistochemical data to generate an optimal panel in the differential diagnosis of oncocytoma from its mimics. PMID- 21323946 TI - CD151 expression can predict cancer progression in clear cell renal cell carcinoma. AB - AIMS: CD151 is known to be implicated in cancer progression and metastasis. The aim was to evaluate the expression of CD151 in clear cell renal cell carcinoma (CCRCC) and to assess its prognostic significance. METHODS AND RESULTS: The expression of CD151 was evaluated in 489 cases of CCRCC by immunohistochemistry. Immunoreactivity was classified into four categories (minimal, 0-10% positive cells; focal, 10-50% positive cells; diffuse moderate, >50% positive cells with moderate staining intensity; diffuse strong, >50% positive cells with strong staining). To determine the statistical significance of CD151 expression in CCRCC, all cases were divided into two groups based on their CD151 expression level: a CD151-low group (n=257; minimal and focal) and a CD151-high group (n=232; diffuse). Expression of CD151 was correlated positively with pT, pN, pM categories, pathological tumour-node-metastasis (pTNM) stage, nuclear grade, tumour size and patient's age. The CD151-high group had significantly shorter cancer-specific survival (P<0.001) and progression-free survival (P<0.001) times. Furthermore, multivariate analysis showed that CD151 expression was an independent predictor for tumour progression in patients with CCRCC (P=0.040). CONCLUSIONS: High CD151 expression is associated with advanced stage and high nuclear grade in CCRCC. CD151 is a prognostic marker for tumour progression in CCRCC patients. PMID- 21323947 TI - Identification of alternatively activated macrophages in new-onset paediatric and adult immunoglobulin A nephropathy: potential role in mesangial matrix expansion. AB - AIMS: New onset of the clinical symptoms of immunoglobulin A (IgA) nephropathy (IgAN) manifests with proliferative glomerular lesions in children, whereas adults exhibit mesangial matrix expansion and interstitial fibrosis. Alternatively, activated (M2) macrophages have been implicated in promoting tissue fibrosis in some settings. Therefore, the aim of this study was to investigate whether M2 macrophages are present in new-onset IgAN and if they are related to pathological differences between paediatric and adult disease. METHODS AND RESULTS: Biopsy specimens from paediatric (<10 years, n=14; >12 years, n=15) and adult (n=27) IgAN showed a significant infiltrate of CD68(+) macrophages. M2 macrophages, identified by CD163 or CD204 expression, were detected in glomeruli and the interstitium, being more prominent in adults versus young children. CD163(+) and CD204(+) macrophages were present in areas of fibrosis containing myofibroblasts, and double staining showed that CD163(+) cells produced the profibrotic molecule, connective tissue growth factor. In young children, total CD68(+) macrophages, but not M2 macrophages, correlated with glomerular hypercellularity. In contrast, in adults and older children, mesangial matrix expansion correlated with M2 macrophages but not with the total CD68(+) macrophage infiltrate. CONCLUSIONS: Alternatively activated M2 macrophages are present in new-onset paediatric and adult IgAN, and this population may promote the development of fibrotic lesions. PMID- 21323948 TI - Handling of radical prostatectomy specimens: total or partial embedding? AB - AIMS: Proper examination and accurate reporting of radical prostatectomy specimens (RPS) is essential in determining post-surgical treatment and predicting patient outcome. Surveys have demonstrated the absence of consensus on handling of RPS. The aim of this study was to determine whether significant information is lost when only half the horizontal tissue sections are examined. METHODS AND RESULTS: During a 1-year period, 238 RPS were sectioned into horizontal slices. Apex and basis was cut sagittally, and remaining slices were embedded in quadrants. Glass slides from every second horizontal slice were withheld. The remaining slides were evaluated microscopically, and essential pathological parameters were recorded. Subsequently, a full report was compiled, including the withheld slides. A median of 12 slides (30%) were withheld during initial assessment. In eight RPS (3.2%) the pTNM stage had to be changed; in six cases (2.6%) from pT2b to pT2c and in two cases (0.8%) from pT2c to pT3a. In one RPS (0.4%) the surgical margin status was changed. CONCLUSIONS: Only little information is lost with systematic partial embedding, overlooking features significant for the postoperative treatment in only 1.2%. Partial embedding as suggested, decreasing the laboratory workload by 30%, is concluded to be acceptable for valid histopathological assessment. PMID- 21323949 TI - In situ hybridization detection of homeobox genes reveals distinct expression patterns in oral squamous cell carcinomas. AB - AIMS: To analyse the expression of three homeobox genes (HOXA7, PITX1 and PRRX1) in oral squamous cell carcinomas (OSCC) and the relationship of such expression to certain distinct histopathological features of OSCC and in comparison to adjacent non-neoplastic epithelium (NT). METHODS AND RESULTS: Digoxigenin labelled riboprobes that are specific for each homeobox gene were generated and in situ hybridization was carried out on frozen sections. In NT samples, HOXA7 and PITX1 transcripts were found more frequently in all epithelial layers, while PRRX1 was expressed in the basal layer. With OSCC samples, expression of the three genes was associated with all histological features. However, the HOXA7 and PITX1 signals were more intense in sheets and nests and PRRX1 in small nests and isolated cells. CONCLUSION: HOXA7, PIXT1 and PRRX1 homeobox genes have different patterns of expression in OSCC depending on its histological features. PMID- 21323950 TI - Differential expression of the nuclear receptors farnesoid X receptor (FXR) and pregnane X receptor (PXR) for grading dysplasia in patients with Barrett's oesophagus. AB - AIMS: To investigate expression of nuclear receptors farnesoid X receptor (FXR) and pregnane X receptor (PXR) as a diagnostic tool to improve grading of dysplasia in Barrett's oesophagus patients. METHODS AND RESULTS: Immunostaining was analysed on a total of 192 biopsy samples of 22 Barrett's patients with no dysplasia (ND), 17 with low-grade dysplasia (LGD), 20 high-grade dysplasia (HGD) and 24 with adenocarcinoma (AC). Nuclear FXR expression was observed in 15 of 22 (68%) ND cases versus none of 19 HGD; 3 of 17 (18%); LGD; 5 of 60 (8%) patients with AC (P<0.001). FXR expression was highly specific for non-dysplastic tissue. Nuclear PXR was expressed in 16 of 20 (80%) HGD cases versus two of 16 (13%) LGD cases (PPV 89%). Upon examining adjacent tissue taken from HGD and AC patients, PXR expression was high in samples of all tissue types. CONCLUSIONS: Nuclear receptors are expressed differentially during neoplastic progression, with FXR positivity being useful to distinguish ND from dysplasia and AC. PXR nuclear expression is able to separate HGD from LGD and ND. The combination of FXR and PXR also appears to have diagnostic and possibly prognostic value, but future prospective studies are required to investigate their predictive power for neoplastic progression in Barret's oesophagus. PMID- 21323951 TI - Distinct histological features characterize primary angiosarcoma of bone. AB - AIMS: To define the histological criteria of primary angiosarcoma of bone. METHODS AND RESULTS: Forty-two angiosarcomas of bone in 23 males and 15 females were studied. Histological criteria were related to patients' outcome. Eleven patients had multifocal lesions. Lesions were located in the long and short tubular bones followed by the pelvis, spine and trunk. Tumour cells were positive for CD31 in 38 of 40, von Willebrand Factor in 21 of 35, CD34 in 15 of 38, smooth muscle actin in 22 of 36, D2-40 in 11 of 35 and keratin AE1AE3 in 27 of 39. Thirty-nine tumours showed an epithelioid phenotype. One- and 5-year survival rates were 55% and 33%, respectively. Survival analysis showed that a macronucleolus, three or more mitoses per 10 high-power field (HPF) and fewer than five eosinophilic granulocytes per 10 HPF within a tumour was associated with an even worse survival compared to the overall group. CONCLUSIONS: Because keratin positivity is seen in the majority of cases, pathologists should avoid misinterpretation as metastatic carcinoma. A macronucleolus, three or more mitoses per 10 HPF and fewer than five eosinophilic granulocytes per 10 HPF can be used to further define angiosarcoma of bone. PMID- 21323952 TI - Changes in the expression of oestrogen receptors and E-cadherin as molecular markers of progression from normal epithelium to invasive cancer in elderly patients with vulvar squamous cell carcinoma. AB - AIMS: The most common vulvar squamous cell carcinoma (conventional SCC) occurs in elderly women and develops following a human papillomavirus (HPV)-negative pathway. Because the highest incidence of conventional SCC is observed in patients with low oestrogen levels (postmenopausal women), the aim was to investigate whether hormonal factors could play a role in the development of cancer. METHODS AND RESULTS: The expression profile of oestrogen receptor alpha (ERalpha), ERbeta and progesterone receptor (PR) in a section containing both normal and tumour tissue, as well as the SCC-associated vulvar lesion, was evaluated in 34 elderly patients. Also, as recent studies have identified E cadherin as a novel transcriptional target of oestrogen signalling, the modulation of this epithelial-mesenchymal transition (EMT) marker was studied. Finally, the expression of the proliferation marker Ki67 and of the apoptotic marker p53 was assessed. Results showed that changes in both ERalpha and ERbeta expression characterize the transition from normal epithelium to cancer in patients with vulvar SCC: ERalpha was lost in cancer while ERbeta decreased, mainly showing cytoplasmic localization. A reduction in the expression of E cadherin was also observed in tumours, compared to normal epithelium. CONCLUSIONS: The data put the ER signalling pathway into the spotlight as a potentially important factor in vulvar carcinogenesis. PMID- 21323953 TI - Sox10-positive sustentacular cells in neuroendocrine carcinoma of the lung. AB - AIMS: Sustentacular cells are found in approximately half of pulmonary carcinoid tumours. However, most studies of sustentacular cells have used the less-specific antibody to the S100 protein, and any correlation between the presence of sustentacular cells and other clinicopathological factors is unclear. The aim of this study was to analyse the significance of sustentacular cells in pulmonary neuroendocrine carcinomas (NECs). METHODS AND RESULTS: A Sox10 antibody was used to investigate 113 pulmonary NECs. Sustentacular cells were observed in 66.7% of typical carcinoid (TC) and 58.3% of atypical carcinoid (AC) cases, but not in high-grade NECs. Sustentacular-rich tumours had a statistically significant correlation with peripheral locations. We found no statistical differences in age, gender, smoking history, overall survival, or the occurrence of lymph node metastasis. In all but one case, when sustentacular cells were present in the primary site, they were also present in the metastatic lymph nodes. The presence of sustentacular cells differed in morphological subtypes, with the spindle pattern being the most common subtype. CONCLUSIONS: Sox10-positive sustentacular cells were observed in carcinoid tumours but not in high-grade NECs. Sustentacular-rich carcinoid tumours did not show a correlation with the occurrence of lymph node metastasis or survival. The sustentacular cells found differed in morphological subtypes. PMID- 21323954 TI - Homo- and heterotypic cell-cell contacts in Merkel cells and Merkel cell carcinomas: heterogeneity and indications for cadherin switching. AB - AIMS: Merkel cell carcinomas (MCCs) are rare but aggressive tumours associated recently with Merkel cell polyomavirus (MCV). As development and progression of several types of carcinomas can be promoted by changes in cell adhesion proteins, the aim of this study was to examine homo- and heterotypic cell contacts of Merkel cells and MCCs. METHODS AND RESULTS: Merkel cells of healthy glabrous epidermis and 52 MCCs were analysed by double-label immunostaining, immunofluorescence and confocal microscopy. Merkel cells were connected to keratinocytes by E- and P-cadherin, desmoglein 2 and desmocollin 2. In contrast, the vast majority of MCCs (90%) contained N-cadherin, but only 67% and 65% contained E- and P-cadherin, respectively. Interestingly, P-cadherin was absent significantly more frequently in lymph node metastases than in primary tumours and by trend in more advanced clinical stages. Moreover, major subsets of MCCs synthesized desmoglein 2 and, surprisingly, tight junction proteins. No significant differences were observed upon stratification for MCV DNA, detected in 84% of tumours by real-time polymerase chain reaction. CONCLUSIONS: Assuming that MCCs originate from Merkel cells, our data indicate a switch from E- and P cadherin to N-cadherin during tumorigenesis. Whether the unexpected heterogeneity of junctional proteins can be exploited for prognostic and therapeutic purposes will need to be examined. PMID- 21323955 TI - Microfasciculation: a morphological pattern in leprosy nerve damage. AB - AIMS: To study Microfasciculation, a perineurial response found in neuropathies, emphasizing its frequency, detailed morphological characteristics and biological significance in pure neural leprosy (PNL), post-treatment leprosy neuropathy (PTLN) and non-leprosy neuropathies (NLN). METHODS AND RESULTS: Morphological characteristics of microfascicles were examined via histological staining methods, immunohistochemical expression of neural markers and transmission electronmicroscopy. The detection of microfasciculation in 18 nerve biopsy specimens [12 PNL, six PTLN but not in the NLN group, was associated strongly with perineurial damage and the presence of a multibacillary inflammatory process in the nerves, particularly in the perineurium. Immunoreactivity to anti-S100 protein, anti-neurofilament, anti-nerve growth receptor and anti-myelin basic protein immunoreactivity was found within microfascicles. Ultrastructural examination of three biopsies showed that fibroblast-perineurial cells were devoid of basement membrane despite perineurial-like NGFr immunoreactivity. Morphological evidence demonstrated that multipotent pericytes from inflammation activated microvessels could be the origin of fibroblast-perineurial cells. CONCLUSIONS: A microfasciculation pattern was found in 10% of leprosy-affected nerves. The microfascicles were composed predominantly of unmyelinated fibres and denervated Schwann cells (SCs) surrounded by fibroblast-perineurial cells. This pattern was found more frequently in leprosy nerves with acid-fast bacilli (AFB) and perineurial damage while undergoing an inflammatory process. Further experimental studies are necessary to elucidate microfascicle formation. PMID- 21323956 TI - Comparison of cadherin-17 expression between primary colorectal adenocarcinomas and their corresponding metastases: the possibility of a diagnostic marker for detecting the primary site of metastatic tumour. PMID- 21323957 TI - Comparison of dual-colour chromogenic in-situ hybridization and fluorescence in situ hybridization in the assessment of HER2 gene amplification in breast carcinoma. PMID- 21323958 TI - Primary pulmonary large B-cell lymphoma--mediastinal type? PMID- 21323959 TI - Postoperative intra-arterial methylene blue injection of colorectal cancer specimens increases the number of lymph nodes recovered. AB - AIMS: To determine the possible advantage of intra-arterial injection of methylene blue with a view to improving lymph node recovery in postoperative examination of colorectal cancer specimens. METHODS AND RESULTS: Thirty-two colorectal cancer specimens were assigned randomly to either dissection with intra-arterial methylene blue injection or to routine dissection (without methylene blue injection). Immediately postoperatively, the specimens in the staining group were injected intra-arterially with methylene blue dye. The two procedures were compared with respect to the number of lymph nodes recovered. The number of recovered lymph nodes was significantly higher in the intra-arterial methylene blue injection group than in the group investigated with routine procedures (P<0.0001). CONCLUSION: The intra-arterial methylene blue injection method is fairly easy to use postoperatively and increases significantly the number of lymph nodes recovered in colorectal cancer specimens. PMID- 21323960 TI - Immunohistochemical analysis of p53, APE1, hMSH2 and ERCC1 proteins in actinic cheilitis and lip squamous cell carcinoma. AB - AIMS: This study has compared the tissue expression of the p53 tumour suppressor protein and DNA repair proteins APE1, hMSH2 and ERCC1 in normal, dysplastic and malignant lip epithelium. METHODS AND RESULTS: Morphological analysis and immunohistochemistry were performed on archived specimens of normal lip mucosa (n=15), actinic cheilitis (AC) (n=30), and lip squamous cell carcinoma (LSCC) (n=27). AC samples were classified morphologically according to the severity of epithelial dysplasia and risk of malignant transformation. LSCC samples were morphologically staged according to WHO and invasive front grading (IFG) criteria. Differences between groups and morphological stages were determined by bivariate statistical analysis. Progressive increases in the percentage of epithelial cells expressing p53 and APE1 were associated with increases in morphological malignancy from normal lip mucosa to LSCC. There was also a significant reduction in epithelial cells expressing hMSH2 and ERCC1 proteins in the AC and LSCC groups. A higher percentage of malignant cells expressing APE1 was found in samples with an aggressive morphological IFG grade. CONCLUSIONS: Our data showed that epithelial cells from premalignant to malignant lip disease exhibited changes in the expression of p53, APE1, hMSH2 and ERCC1 proteins; these molecular change might contribute to lip carcinogenesis. PMID- 21323961 TI - Increased mucin 1 expression in recurrence and malignant transformation of salivary gland pleomorphic adenoma. AB - AIMS: Pleomorphic adenoma (PA) is the most common salivary gland tumour with a tendency to recur (RPA) and a risk of malignant transformation. Mucin 1 (MUC-1) plays a role in the progression of many tumours and may be a marker to predict RPA. The aim of this study was to evaluate MUC-1 expression in different phases of the adenoma to carcinoma sequence. METHODS AND RESULTS: Twenty-one cases of PA, 18 cases of RPA, three cases of RPA with focal transformation (TRPA) and 11 cases of carcinoma ex-pleomorphic adenoma (CXPA) were analysed immunohistochemically for MUC1 expression using an antibody to MUC1/DF3. MUC1 reactivity in RPA was stronger than that observed in PA and, in all the different carcinoma groups, MUC-1 expression was significantly higher in carcinoma than in RPA and PA. CONCLUSION: This study has confirmed that MUC-1 is related to the recurrence of PA and that this molecule is associated with malignant transformation of PA with carcinoma cells overexpressing MUC-1. PMID- 21323962 TI - HER2 status in gastro-oesophageal adenocarcinomas assessed by two rabbit monoclonal antibodies (SP3 and 4B5) and two in situ hybridization methods (FISH and SISH). AB - AIMS: HER2 gene amplification has been detected in 10-20% of gastric adenocarcinomas. In view of the recently demonstrated clinical benefit of the anti-human epidermal growth factor receptor 2 (HER2) drug trastuzumab in the treatment of advanced gastric cancer, reliable HER2 testing is of key importance. The aim of this study was to examine HER2 status in gastro-oesophageal adenocarcinomas comparing SP3 and 4B5 immunohistochemistry (IHC) with dual probe HER2 [fluorescence in situ hybridization (FISH) and silver in situ hybridization (SISH)]. METHODS AND RESULTS: IHC and SISH were carried out on biopsy specimens of 146 patients with adenocarcinomas of the oesophagus and stomach. All SP3-IHC positive cases and 91% of 4B5-IHC-positive cases were amplified. Sensitivity of SP3-IHC-positivity and 4B5-IHC-positivity for amplification was 77% and 96%, respectively. Results of FISH performed in 42 cases were identical to SISH. Amplification was heterogeneous in 73% of the adenocarcinomas; 24% of the oesophago-gastric carcinomas and 7% of distal stomach tumours were amplified. CONCLUSIONS: HER2-positivity is present in a significant proportion of oesophago gastric adenocarcinomas (24%), but at a lower rate in the distal stomach (7%). Sensitivity for amplification is higher with 4B5 IHC than with SP3. FISH and SISH yield identical results, but assessment is much easier with SISH. Our findings provide important guidance for HER2-testing in gastro-oesophageal adenocarcinomas for patients in whom anti-HER2 treatment is considered. PMID- 21323963 TI - The retinoblastoma protein/p16 INK4A pathway but not p53 is disrupted by human papillomavirus in penile squamous cell carcinoma. AB - AIMS: The pathogenesis of penile squamous cell carcinoma (PSCC) is not well understood. Human papillomavirus (HPV) may be involved in carcinogenesis, but few studies have compared cell-cycle protein expression in HPV positive and negative cancers. The aim was to determine the extent of HPV infection in different histological subtypes of PSCC and its impact on the expression of key cell-cycle proteins: p53, p21, p16(INK4A) and retinoblastoma (RB) protein. METHODS AND RESULTS: One hundred and forty-eight PSCC samples were examined immunohistochemically for RB, p16(INK4A) , p53 and p21 protein expression. One hundred and two cases were typed for HPV by PCR. HPV DNA was detected in 56% of tumours, with HPV16 present in 81%. Basaloid tumours were related strongly to HPV infection (10 of 13), while verrucous were not (three of 13). Fifty-nine per cent (38 of 64) of usual type SCCs had HPV infection. RB protein correlated negatively (P<0.0001) and p16(INK4A) (P<0.0001) and p21 (P=0.0002) correlated positively with HPV infection. p53 did not correlate with HPV infection. CONCLUSIONS: HPV infection is present in more than half of penile cancers and it is responsible for RB pathway disruption. However, no link between HPV and p53 immunodetection was found. Only basaloid and half of usual-type PSSCs correlate with HPV infection, confirming possible separate aetiologies for those tumours. PMID- 21323964 TI - p16 INK4A positivity identifies endometrial surface papillary syncitial change as a regressive feature associated with desquamation. PMID- 21323965 TI - Diagnosis of testicular carcinoma in situ '(intratubular and microinvasive)' seminoma and embryonal carcinoma using direct enzymatic alkaline phosphatase reactivity on frozen histological sections. AB - AIMS: Testis-sparing surgery might benefit quality of life, but can only be applied with histological examination for the presence of invasive germ cell tumour components, and the precursor carcinoma in situ (CIS). Currently, diagnosis is based on paraffin-embedded tissue, therefore a delay in further surgery is mainly unavoidable. The aim was to develop an intraoperative assessment technique using alkaline phosphatase as a marker. METHODS AND RESULTS: A total of 4093 snap-frozen samples and matched paraffin-embedded tissue of 1500 patients were included. Besides standard haematoxylin and eosin (H&E) staining, the direct enzymatic alkaline phosphatase reactivity (dAP) test (duration 15 min) was applied on frozen sections, while H&E and immunohistochemistry for detection of OCT3/4, alpha-fetoprotein, human chorionic gonadotrophin (hCG) and cytokeratin was performed on the paraffin-embedded slides. Endothelial cells served as control for the dAP test. Positive staining was found in all CIS (n=965), seminoma (n=1035) and embryonal carcinoma (n=584), either intratubular, microinvasive or invasive. Differentiated non-seminomas (n=1238) showed variable staining. No staining was identified in spermatocytic seminomas (n=5), testicular lymphomas (n=42), testicular rhabdomyosarcomas (n=7), Leydig cell tumours (n=31), Sertoli-cell-only nodules (n=4), (epi) dermoid cyst (n=16), normal testicular parenchyma (n=116), testicular torsion (n=32) and inflammation of the epididymis (n=19). The dAP test results matched H&E-stained parallel sections, as well paraffin-embedded tissue analysis, including immunohistochemistry. CONCLUSIONS: The dAP test is an informative, reproducible and easy tool to diagnose CIS, (intratubular and microinvasive) seminoma and embryonal carcinoma on frozen tissue sections, being of great value in the context of sparing surgery. PMID- 21323966 TI - Pathological and immunohistological findings and genetic aberrations of intestinal enteropathy-associated T cell lymphoma in Japan. AB - AIMS: To elucidate the clinicopathological findings of primary intestinal enteropathy-associated T cell lymphoma (EATL) in Japan, a non-endemic area for coeliac disease. METHODS AND RESULTS: Of the 24 cases, four (17%) had large-cell lymphoma (type I), and the remaining 20 (83%) had medium-sized lymphoma (type II). Lymphoma cells of the three type I cases were CD56-positive. Only one (4%) case showed typical CD56- and CD8-negative and CD30-positive type I EATL. In type II EATL, lymphoma cells of the 16 (80%) and 11 (55%) cases were positive for CD56 and CD8, respectively. Intramucosal tumour spreading and adjacent enteropathy like lesions were detected in 15 (71%) and 16 (76%) of 21 cases, with a severe increase of intraepithelial lymphocytes (IELs) in 12 (57%). IELs of enteropathy like lesions in five (24%) cases expressed T-bet, with no cases of CD30-positive IELs. Characteristic findings from comparative genomic hybridization of 15 cases indicated gains of 8q2 (47%), Xp (53%) and Xq (73%), but no gain of 9q3. Regarding, human leucocyte antigen (HLA) status, six cases examined did not express the DQB1*02 allele. CONCLUSIONS: Japanese EATL exhibited different histology, cytogenetic findings and HLA status from those of typical type I EATL. The rare incidence of coeliac disease may influence the tumour cell characteristics of EATL and IELs. PMID- 21323967 TI - Extensive retraction artefact predicts biochemical recurrence-free survival in prostatic carcinoma. AB - AIMS: To determine whether the presence and extent of peritumoral retraction artefact could be used to predict biochemical recurrence-free survival in prostatic carcinoma. METHODS AND RESULTS: The study included 162 consecutive patients treated by radical retropubic prostatectomy and bilateral lymphadenectomy for clinically localized prostatic carcinoma. A variable degree of retraction artefact was present in all 162 analysed tumours. The extent of retraction artefact in prostatic carcinomas ranged from 5% to 55% with a median value of 15% (interquartile range 10-25%). We found no correlation between the extent of retraction artefact in the tumours and patient's age (P=0.608), preoperative (P=0.362) and postoperative (P=0.279) Gleason score or lymph node metastases (P=0.084). In contrast, the extent of retraction artefact correlated with high preoperative prostate-specific antigen (P<0.001), short follow-up time (P<0.001), seminal vesicle invasion and/or extracapsular extension of the tumour (T3 stage tumours) (P<0.001) and positive surgical margins (P<0.001). Furthermore, extensive retraction artefact was associated with poor biochemical recurrence-free survival in both univariate (P<0.001) and multivariate analyses (P=0.013). CONCLUSION: The presence of extensive retraction artefact in prostatic carcinoma correlates with tumour characteristics signifying aggressive behaviour and indicates poor biochemical recurrence-free survival. PMID- 21323968 TI - Tumour suppressor gene TP53 mutations in atypical vascular lesions of breast skin following radiotherapy. AB - AIMS: Atypical vascular lesions (AVL) occurring at the site of radiotherapy represent an uncommon but well-documented complication in the setting of breast conserving therapy for breast carcinoma. Although the biological behaviour of AVL has been regarded as benign, it has been suggested that AVL may represent a precursor of angiosarcoma. A better understanding of the biology of AVL is essential in order to assess appropriate patient management. The aim of the present study was to investigate alterations of tumour suppressor gene TP53 in a series of radiation-induced AVL and angiosarcomas (AS). METHODS AND RESULTS: Direct sequencing analysis of the TP53 gene showed the presence of at least one variation in 10 of 12 (83.3%) AVL and in seven of eight (87.5%) AS. The most common alteration in both categories was the P72R polymorphism in exon 4. One angiosarcoma sample carried a pathogenetically relevant disruptive mutation c.592delG, a frameshift deletion in exon 6, causing a premature stop codon. CONCLUSIONS: The presence of TP53 alterations suggests that its mutational inactivation may be implicated in the pathogenesis of radiation-associated vascular proliferations. The common mutational pathway suggested by our data supports the hypothesis that AVL and AS are biologically related entities, most probably representing the extremes of a morphological continuum. PMID- 21323969 TI - Cytogenetic heterogeneity of pancreatic ductal adenocarcinomas: identification of intratumoral pathways of clonal evolution. PMID- 21323970 TI - Should we consider cancer/testis antigens NY-ESO-1, MAGE-A4 and MAGE-A1 as potential targets for immunotherapy in vulvar squamous cell carcinoma? PMID- 21323971 TI - Clear cell 'sugar' tumour of the lung with malignant histological features and melanin pigmentation--the first reported case. PMID- 21323972 TI - Incentives and barriers to lifestyle interventions for people with severe mental illness: a narrative synthesis of quantitative, qualitative and mixed methods studies. AB - AIM: To examine the evidence for incentives and barriers to lifestyle interventions for people with severe mental illness. BACKGROUND: People with severe mental illnesses, particularly those with schizophrenia, have poorer physical health than the general population with increased mortality and morbidity rates. Social and lifestyle factors are reported to contribute to this health inequality, though antipsychotic therapy poses additional risk to long term physical health. Many behavioural lifestyle interventions including smoking cessation, exercise programmes and weight-management programmes have been delivered to this population with promising results. Surprisingly little attention has been given to factors that may facilitate or prevent engagement with these interventions in this population. DATA SOURCES: Eight electronic databases were searched [1985-March 2009] along with the Cochrane Library and Google Scholar. Electronic 'hand' searches of key journals and explosion of references were undertaken. REVIEW METHODS: A narrative synthesis of qualitative, quantitative and mixed-methods studies was undertaken. RESULTS: No studies were identified that specifically explored the incentives and barriers to participation in lifestyle intervention for this population. Existing literature report some possible incentives and barriers including: illness symptoms, treatment effects, lack of support and negative staff attitudes as possible barriers; and symptom reduction, peer and staff support, knowledge, personal attributes and participation of staff as possible incentives. CONCLUSIONS: Healthcare professionals, in particular nurses, should consider issues that may hinder or encourage individuals in this clinical group to participate in lifestyle interventions if the full benefits are to be achieved. Further research is needed to explore possible incentives and barriers from the service users' own perspective. PMID- 21323973 TI - Nurses' and midwives' clinical leadership development needs: a mixed methods study. AB - AIM: This paper is a report of a descriptive study of nurses' and midwives' clinical leadership development needs. BACKGROUND: Nurses and midwives are expected to fulfil a leadership role at all levels, yet efforts to strategically support them are often unfocused. An analysis of clinical leadership development needs can provide the foundation for leadership initiatives to support staff. METHOD: A mixed methods design was used. A questionnaire was sent to 911 nurses and midwives and 22 focus groups comprising 184 participants were conducted. Data were collected between March and June 2009 across all promotional grades of nurses and midwives in Ireland. Repeated measures anova with Greenhouse-Geisser adjustment was used for post hoc pair wise comparisons of the subscale dimensions of clinical leadership. anova with Tukey's post hoc method was used for comparison between grades on each individual subscale. Thematic analysis was undertaken on the focus group data. RESULTS: Results reveal that needs related to development of the profession were the highest for all grades. The staff grade expressed a higher need in relation to 'managing clinical area', 'managing the patient care' and 'skills for clinical leadership' than managers. Qualitative analysis yielded five themes; (1) clinical leadership and leaders from a nursing and midwifery perspective; (2) quality service from a nursing and midwifery perspective; (3) clinical leaders' roles and functions; (4) capital and (5) competences for clinical leaders and leadership and the context of clinical leadership. CONCLUSION: Clinical leadership concerns quality, safety and effectiveness. Nurses and midwives are ideally placed to offer the clinical leadership that is required to ensure these patient care outcomes. Development initiatives must address the leader and leadership competencies to support staff. PMID- 21323974 TI - A qualitative descriptive study of self-management issues in people with long term intermittent urinary catheters. AB - AIM: The study was to identify and describe issues of intermittent urinary catheter users for future self-management research and/or training programmes. BACKGROUND: Limited studies were found of how people using clean intermittent catheterization manage their daily routines or troubleshoot problems. Self management research related to intermittent catheterization could lead to improved compliance with the method and better quality of life. METHOD: This qualitative descriptive study involved in-depth tape-recorded telephone interviews in 2008-2009 with 34 people in the United States of America using permanent intermittent catheterization, mostly individuals with spinal cord injury or multiple sclerosis. Recruitment was through Internet sites where individuals could link to the study website and then contact the researchers. The sample included 13 men and 21 women aged 21-72 years (mean 42 years). Content analysis for qualitative data involved iterative comparisons of transcripts, summaries and memos. Coding, key quotes and tables were developed to determine themes. FINDINGS: Six major themes were identified: Knowing the Body, Practising Intermittent Catheterization, Limited Options in Catheters and Equipment, Inaccessible Bathrooms, Hassles, and Adjustment in Making Intermittent Catheterization a Part of Life. While some persons had choices in catheters, many did not because of insurance constraints. Some individuals developed knowledge of how to balance the procedure with fluid intake and activities. CONCLUSION: The lack of acceptable bathrooms can interfere with being able to go to work, travel or be with friends and family. All using intermittent catheterization should have adequate insurance coverage when this is needed. Research into training programmes could incorporate knowledge of experienced users. PMID- 21323975 TI - Post-traumatic stress disorder symptoms among emergency nurses: their perspective and a 'tailor-made' solution. AB - AIM: The goal of this study was to identify support activities for emergency room nurses who have been exposed to traumatic events, in order to prevent post traumatic stress disorder. BACKGROUND: Emergency room nurses experience stress during traumatic events, for which they need support. It turns out that such support is insufficient, ineffective or non-existent. METHODS: This qualitative study was carried out among twelve emergency room nurses from January to May 2007. Semi-structured interviews and a focus group were conducted. Content analysis fulfilled the objectives of our research. RESULTS: The frequency of traumatic events leading to contextual exposure and exposure as a witness increases with years of experience (r=0.67 and r=0.57). The frequency of post traumatic stress disorder symptoms decreases with age (r=-0.83). The data demonstrate the importance of having a supportive social network and being able to talk things over with colleagues. The support activities considered include all types of prevention. They consist primarily of a peer support system, psycho education and emergency room simulations. CONCLUSION: A three-level complex of support activities represents a promising solution to prevent and treat post traumatic stress disorder among emergency room nurses. A further study to test its effectiveness is currently underway. PMID- 21323976 TI - Experiences of health-promoting self-care in people living with rheumatic diseases. AB - AIM: This paper is a report of a study that explores and describes the meaning of the phenomenon of health-promoting self-care as experienced by people living with rheumatic diseases. BACKGROUND: People with rheumatic diseases estimate health status as low and health belief and health status influence self-care behaviours. Several self-care behaviours are used in the efforts to mitigate the diseases. METHOD: The study had a descriptive phenomenological approach based on a reflective life-world perspective. Data were gathered in 2007 by unstructured open-ended interviews with 12 individuals living with rheumatic diseases. FINDINGS: The meaning of health-promoting self-care as experienced by people living with rheumatic diseases was that self-care takes place against a background of continual hope and belief to influence health in positive ways. Self-care was a way of life and implied being ready to understand and respond to signals from the body. Three inter-related constituents elucidated their experiences: dialogue, power struggle and choice. Self-care was experienced as dialogues with the body and with the immediate environment. In order to respond to signals from the body, power struggles were required to be entered into when fighting the diseases. Choices were required to be made and things that were beneficial for the body were prioritized. CONCLUSION: In this study, the meaning of health-promoting self-care as experienced by people living with rheumatic diseases was that self-care was a way of life. This meant to be ready to understand and respond to signals from the body. Self-care required dialogues, power struggles and choices. PMID- 21323977 TI - Access to respite breaks for families who have a relative with intellectual disabilities: a national survey. AB - AIMS: This paper reports the findings of a national study of the variations in the provision and correlates of respite breaks to families. Background. Internationally, respite breaks are a major support service to family carers, demand for which often exceeds supply for persons with an intellectual disability. Hence, the length of breaks available to families has to be rationed. Nurses are often involved in such decisions. METHOD: National data on the use of respite breaks by over 4000 families in a full calendar year (2008) were analysed to examine the variation within the Republic of Ireland on two indicators: namely the proportion of carers who had any access to breaks and the median number of days they had received. FINDINGS: Striking differences across health service areas were found on both indicators of usage. These were not solely attributable to the availability of provision but also reflected variations in the criteria local services used to allocate places. However, those persons with more severe disabilities were given priority, whereas carer characteristics were not a major influence. Contact with social workers and community nurses also increased the likelihood of carers receiving respite breaks. CONCLUSION: Intra-country comparisons of service delivery should assist planners in creating more equitable access to respite breaks and the development of more explicit eligibility criteria for their use. Nurses are well placed to lead on this. PMID- 21323978 TI - An analysis of parental roles during haematopoietic stem cell transplantation of their offspring: a qualitative and participant observational study. AB - AIM: The aim of this study was to investigate the parents' experiences and reflections on their parental role while taking care of their child. BACKGROUND: Parents of children undergoing treatment with allogeneic haematopoetic stem cell transplantation for life threatening diseases in protective isolation, experience distress related to the child's care. Parents struggle to cope with the stress related to the child's disease, treatment and survival possibilities. METHODS: During the period 2007-2009, eight participant studies and 16 in-depth interviews were performed and analysed using a theoretical ideal type construction and an interactionistic approach. RESULTS: Three ideal types of approaches were identified (1) expertise-mindedness, (2) dialogue-mindedness and (3) the approach of the socially challenged parents. Expertise-minded parents base their rationality for care and interactions on medical knowledge. It is important for dialogue-minded parents that emotions are included in the rationality for care. Being able to manage these two approaches requires emotional work in the form of both surface- and deep acting from the parents. Socially challenged parents fail to adapt to either of the two approaches since they often fail to manage the required emotional work. CONCLUSION: The three described ideal types give a new perspective on the complex interactions that occur between parents, child and staff during treatment with haematopoetic stem cell transplantation. Understanding the rationality behind the different approaches adopted by parents may assist medical staff to understand the parents' rationality for care of their child and to identify socially challenged parents who need help in managing the care of their child. PMID- 21323979 TI - Clarifying responsibility for self-management of diabetes in adolescents using insulin pumps--a qualitative study. AB - AIM: To gain insight into and generate theoretical knowledge about the processes involved when insulin pump-treated adolescents take or miss taking their bolus doses. BACKGROUND: Insulin pump treatment is considered the most physiological way to imitate the healthy body's insulin profile in adolescents with diabetes. Despite insulin pump treatment, it is hard to maintain near-normal glucose control in adolescents; one reason for this is missed bolus doses with meals. METHOD: In this qualitative interview study, the grounded theory method was chosen as a model for the collection and analysis of data. Twelve adolescents (five boys and seven girls, mean age: 14.4 years, range: 12-19 years) from different Swedish paediatric diabetes clinics, four parents and one paediatric diabetes nurse were interviewed during 2008 and 2009. Two adolescents and two parents were re-interviewed after approximately 10 months. Data from clinical visits and diabetes camps were used to verify emerging categories. FINDINGS: Responsibility in the context of taking or missing bolus doses emerged as the core category. It is elaborated and explained through three subcategories: distribution of responsibility, transfer of responsibility and clarification of responsibility. The findings describe the need to clarify the responsibility for diabetes self-management in continuous negotiations between adolescents and parents to avoid missed doses. CONCLUSION: Negotiations to clarify the responsibility for diabetes self-management must be a continuous process between adolescents and parents. Diabetes care teams can facilitate and encourage these negotiations. PMID- 21323980 TI - Changes in quality of life during biofeedback for people with puborectalis dyssynergia: generic and disease-specific measures. AB - AIM: The aim of the study was to evaluate the changes in symptoms and quality of life in people with puborectalis dyssynergia after biofeedback by using Short Form-36 and Patient Assessment of Constipation Quality of Life Questionnaire. BACKGROUND: Biofeedback is an effective treatment in clinical symptoms for puborectalis dyssynergia. However, little is known about the degree of the variation in the quality of life for these people after biofeedback. METHOD: Thirty-six people with puborectalis dyssynergia were studied between June 2006 and March 2008. A bowel symptom record, a generic quality of life measure - the Short Form-36 and a disease-specific measure - the Patient Assessment of Constipation Quality of Life Questionnaire were recorded before and after biofeedback. FINDINGS: Thirty-one people rated their satisfaction with behavioural treatment as 'major' or 'fair' and substantial symptom improvements occurred. Before treatment, seven of Short Form-36 subscales (except bodily pain) were significantly lower in people with puborectalis dyssynergia than those in healthy individuals. Following treatment, all subcategories except general health showed improvement surpassing pretreatment baseline values and equalling those for normal. The total Patient Assessment of Constipation Quality of Life Questionnaire score also dramatically improved as did all subscales. The nurses continually encouraged the participants, increased participants' motivation and got good outcomes. CONCLUSION: Patient-centred functional status outcomes measured by general and disease-specific instruments give critical data, from which to inform patient management. The nurses should give psycho-social support and increase the participants' motivation during training. PMID- 21323981 TI - A flagellin-producing Lactococcus strain: interactions with mucin and enteropathogens. AB - Bacillus cereus CH is a probiotic strain used in human nutrition whose adhesion to mucin is dependent on its surface-associated flagellin. Flagellins from the surface of several probiotic Bacillus strains were efficiently extracted with 5 M LiCl and identified by peptide fingerprinting. Based on the proteomic analysis, cloning of the gene coding for the flagellin of B. cereus CH was performed in the lactococcal vector pNZ8110 under the control of a nisin-inducible promoter. The resulting strain, Lactococcus lactis CH, produced a surface-associated flagellin after 6 h of induction with nisin. The recombinant Lactococcus strain adhered strongly to mucin-coated polystyrene plates, whilst inhibiting competitively the adhesion of the pathogens Escherichia coli LMG2092 and Salmonella enterica ssp. enterica LMG15860 to the same molecule. Strain CH could be used in further experimentation for the characterization of the molecular mechanism of action of this probiotic B. cereus CH flagellin. PMID- 21323982 TI - Identification of genes involved in the 4-aminobenzenesulfonate degradation pathway of Hydrogenophaga sp. PBC via transposon mutagenesis. AB - Genes involved in the 4-aminobenzenesulfonate (4-ABS) degradation pathway of Hydrogenophaga sp. PBC were identified using transposon mutagenesis. The screening of 10,000 mutants for incomplete 4-ABS biotransformation identified four mutants with single transposon insertion. Genes with insertions that impaired the ability to utilize 4-ABS for growth included (1) 4-sulfocatechol 1,2 dioxygenase beta-subunit (pcaH2) and 3-sulfomuconate cycloisomerase involved in the modified beta-ketoadipate pathway; (2) 4-aminobenzenesulfonate 3,4 dioxygenase component (sadA) involved in aromatic ring hydroxylation; and (3) transposase gene homolog with a putative cis-diol dehydrogenase gene located downstream. The pcaH2 mutant strain accumulated brown metabolite during growth on 4-ABS which was identified as 4-sulfocatechol through thin layer chromatography and HPLC analyses. Supplementation of wild-type sadA gene in trans restored the 4 ABS degradation ability of the sadA mutant, thus supporting the annotation of its disrupted gene. PMID- 21323983 TI - New dithiolopyrrolone antibiotics induced by adding sorbic acid to the culture medium of Saccharothrix algeriensis NRRL B-24137. AB - Dithiolopyrrolone antibiotics, produced by several microorganisms, are known for their strong antimicrobial activities. This class of antibiotics generated new interest after the discovery of their anticancer and antitumor properties. In this study, four new antibiotics were purified from the fermentation broth of Saccharothrix algeriensis NRRL B-24137 and characterized as dithiolopyrrolone derivatives. These new dithiolopyrrolone antibiotics were induced by adding sorbic acid, as precursor, at a concentration of 5 mM to the semi-synthetic medium. The analysis of the induced antibiotics was carried out by HPLC. The maximal production of the antibiotics PR2, PR8, PR9 and PR10 was 0.08+/-0.04, 0.21+/-0.04, 0.13+/-0.03 and 0.09+/-0.00 mg L(-1) , respectively, obtained after 8 days of fermentation. The chemical structures of these antibiotics were determined by (1) H- and (13) C-nuclear magnetic resonance, mass and UV-visible data. The four new dithiolopyrrolone antibiotics - PR2, PR8, PR9 and PR10 - were characterized, respectively, as crotonyl-pyrrothine, sorbyl-pyrrothine, 2-hexonyl pyrrothine and 2-methyl-3-pentenyl-pyrrothine. The minimum inhibitory concentrations of the new induced antibiotics were determined. PMID- 21323984 TI - Determination of vertical dimension of occlusion in dentate patients by cephalometric analysis--pilot study. AB - OBJECTIVES: The concept of vertical dimension of occlusion (VDO) refers to a measure in the vertical plane that establishes the relation between the maxilla and the mandible when the posterior teeth, both from the maxillary and from the mandibular arches, are occluded, regardless of whether they are natural or prosthetic, healthy or restored. This measure is subject to change, and when this occurs, it can compromise both the function and the facial aesthetics. This study proposed to develop a methodology based on cephalometric analysis by studying the 31 lateral teleradiographs of adult, dentate individuals to determine the VDO, based on bone structures that are not dependent on the presence or absence of posterior teeth. The final goal was to make this application accessible to individuals who have undergone alterations of the lower portion of the face. MATERIALS AND METHODS: The cephalometric analysis of this study, called Seraidarian-Tavano, was verified through facial angles (upper and middle angles) that, when correlated, determine the lower position of the face. RESULTS: The analysis of results showed that no statistically significant difference between the angles studied could be observed (superior angle 50.29 +/- 3.35 e median angle 49.95 +/- 3.37). In the same manner, no variation in the results regarding gender in the measure of these angles could be observed. CONCLUSION: This cephalometric analysis can be applied to determine the VDO, regardless of the presence or absence of posterior teeth. PMID- 21323985 TI - Early diastolic flow propagation velocity detects induced diastolic dysfunction during dobutamine stress echocardiography. AB - OBJECTIVE: Diastolic dysfunction precedes systolic dysfunction during the development of myocardial ischemia. Detecting diastolic dysfunction during stress test for coronary artery disease (CAD) could improve diagnostic sensitivity of the test. Flow propagation velocity (FPV) derived from color M-mode Doppler has been proposed as a sensitive marker to detect diastolic dysfunction. METHODS: The FPVs at baseline and at peak dobutamine infusion were measured using color M-mode Doppler during dobutamine stress echocardiography in 90 patients. The results are compared among the groups divided on the results of coronary angiography. RESULTS: The FPV was similar at baseline among the groups. At peak dobutamine infusion, the FPV increased significantly in the non-CAD group (from 56 +/- 19 cm/s to 66 +/- 25 cm/s), whereas it failed to increase in the groups with CAD. As a result, the peak FPV was significantly lower in the groups with CAD than in the non-CAD group. Receiver operating characteristic analysis showed that the peak FPV and DeltaFPV had good diagnostic property to detect CAD (the areas under the curves were 0.77 and 0.73, respectively). Adopting these FPV criteria, sensitivity of DSE was improved. CONCLUSION: FPV measurement during DSE detects ischemic left ventricular diastolic dysfunction. Adding the assessment of peak FPV to conventional DSE increases the sensitivity and the ability to reliably exclude CAD. PMID- 21323986 TI - Chronic mitral regurgitation: left atrial deformation analysis by two-dimensional speckle tracking echocardiography. AB - BACKGROUND: Speckle tracking echocardiography (STE) is a novel method for the angle-independent and objective quantification of myocardial deformation; it has recently evolved, enabling the quantification of longitudinal myocardial left atrial (LA) deformation dynamics. To investigate the effects of chronic mitral regurgitation (MR) on these functional atrial indices, we analyzed LA function by STE in a group of asymptomatic patients with chronic degenerative MR. METHODS: The study population included 36 patients with mild MR, 38 with moderate MR, and 42 with severe MR. 52 age-matched controls were also recruited. Global peak atrial longitudinal strain (global PALS) was measured in all subjects by averaging all atrial segments. RESULTS: Age, gender, and LV ejection fraction in all pathological groups were comparable to those in the controls. Global PALS was higher in the mild MR group (46.7 +/- 9.1%) in comparison with the controls (40.5 +/- 6.2%; P < 0.001); instead global PALS was lower in the moderate MR group (25.7 +/- 7.1%) and further reduced in the severe MR group (13.2 +/- 5.2%) in comparison with the controls (40.5 +/- 6.2%; overall P < 0.0001 by ANOVA, P < 0.05 for all pairwise comparisons). In multivariate analysis, E/Em ratio emerged as the principal independent determinant of global PALS. CONCLUSIONS: Our study provides new insight for the LA function analysis in response to different degrees of MR, showing that STE measurements of LA longitudinal strain may be considered a promising tool for the early detection of impairment of LA compliance in patients with asymptomatic chronic MR. PMID- 21323987 TI - Early right cardiac dysfunction in patients with schistosomiasis mansoni. AB - BACKGROUND: Pulmonary hypertension (PH) is a complication of schistosomiasis mansoni (SM), mainly in the hepatosplenic form. However, its prevalence is not well established. We evaluated the usefulness of Doppler echocardiographic indexes to detect right heart dysfunction in SM. METHODS: A total of 83 patients divided into two groups were studied: Group 1: 44 patients with hepatosplenic SM, and Group 2: 39 patients with hepatointestinal SM who served as controls. All patients underwent a Doppler echocardiogram. Right ventricular end-diastolic area (RVEDA), the peak systolic tricuspid annular tissue velocity (S'), right ventricular index of myocardial performance (RVIMP) and right atrial area (RAA) were measured in all patients. Tricuspid regurgitation peak velocity (TR) was measured and the pressure gradient (TG) was obtained. RESULTS: The prevalence of patients with elevated systolic pulmonary artery pressure at echocardiography was 31% in hepatosplenic patients, while no patient with the hepatointestinal form presented PH. Patients with hepatosplenic SM had larger RVEDA (10.0 +/- 2.8 vs. 8.5 +/- 1.8 cm(2) /m, P = 0.006) and RAA (9.39 [8.3-11.0] vs. 7.7 [6.9-8.4 cm(2) /m], P < 0.001). There was correlation between TG and RVIMP (r = 0.58; P < 0.001) and between TG and RAA (r = 0.36; P = 0.03) in Group 1. CONCLUSION: Larger RAA and RVEDA were found in patients with hepatosplenic SM, when compared to patients with the hepatointestinal form, which may suggest early impairment of RV function in patients with hepatosplenic SM. PMID- 21323988 TI - Left atrial appendage lipoma: an unusual location of cardiac lipomas. AB - Cardiac lipomas are benign neoplasms of the heart and accounts for 8.4% of all primary tumors. They can occur sporadically at any age with no sex preference. The tumor originates mostly in the subendocardium and subepicardium but very rarely within the myocardium. Clinically this tumor is asymptomatic and found incidentally in the vast majority of cases. On occasion large lesions can lead to mechanical obstruction and pericardial effusions if located in the epicardium. Although lipomas can occur at different atrial or ventricular locations, it was never reported at the level of the left atrial appendage (LAA). Usually a mass in the LAA represents a thrombus, however there are few case reports of LAA tumors mainly representing fibroelastomas, myxomas, hemangiomas, and malignant tumors. To our knowledge there are no reported cases of left atrial appendage lipomas (LAAL) in the medical literature. We report the first case of LAAL discovered incidentally on transesophageal echocardiogram during off pump coronary artery bypass grafting. PMID- 21323989 TI - Pancreatic challenge in the Asia Pacific region. PMID- 21323990 TI - Genetic basis of chronic pancreatitis in Asia Pacific region. AB - Chronic pancreatitis (CP) is a disease characterized by irreversible destruction and fibrosis of the parenchyma, leading to pancreatic exocrine insufficiency. In developed countries, the etiology for 60% to 70% of CP amongst male patients is alcohol and 25% are classified as idiopathic chronic pancreatitis (ICP). The genetic predisposition to CP could be an inappropriate activation of trypsinogen in the pancreas. Two common haplotypes, c.101A>G (p.N34S) and c.-215G>A, and four intronic alterations of the serine protease inhibitor Kazal type 1 (SPINK1) gene have been found to increase the risk for CP in the Asia Pacific region. Hence, SPINK1 is thought to be a candidate gene for pancreatitis. A loss-of-function alteration in chymotrypsinogen C (CTRC) gene has been shown to be associated with tropical calcific pancreatitis (TCP). Cathepsin B (CTSB) is also found to be associated with TCP. However mutations in cationic and anionic trypsinogen gene do not play an important role in causing CP in Asia Pacific region. PMID- 21323991 TI - Asian chronic pancreatitis: the common and the unique. AB - Chronic pancreatitis (CP) is a disabling condition worldwide that presents as pain, maldigestion, and diabetes. It is usually perceived as alcohol related, or classified as idiopathic otherwise. However, this is true only for Western countries. Asian CP comprises not only alcohol-related CP but also tropical pancreatitis (TP). Tropical pancreatitis is a unique entity commonly found in South Asia. It shares similar presentations with other CPs for pain and maldigestion. However, its diabetes is more ketosis resistant. Non-surgical approach like endoscopic therapy plus extracoporeal shock wave lithotripsy provides better outcome for TP than other CPs, because of its less strictured pancreatic duct that is more amenable to endoscopic stone clearance. Diagnosis of CP in Asia mainly relies on image studies such as ultrasonography +/- computed tomography (CT) scan, and non-invasive tests on fecal chymotrypsin, serum trypsin, and serum pancreatic isoamylase. Endoscopic ultrasonography and intestinal tubing tests are used mainly in some research centers. Autoimmune pancreatitis (AIP) is another CP originated from Asia in large series and subsequently being recognized in the West. AIP patients seldom present with maldigestion until the disease progresses to a very late stage and this occurs in less than one third of patients. In contrast, AIP is usually presented as pseudotumor of the pancreatic head, causing obstructive jaundice. Immunoglobulin G4 level is typically elevated in AIP and can be used as a marker for responsiveness. Without a need of surgery, steroids are the standard treatment. Those who relapse and are resistant to steroids should be placed on long-term immunosuppressive agents. PMID- 21323992 TI - Pancreatic exocrine insufficiency: diagnosis and treatment. AB - Pancreatic insufficiency is a major consequence of pancreatic diseases leading to a loss of pancreatic parenchyma, obstruction of the main pancreatic duct, decreased pancreatic stimulation, or acid-mediated inactivation of pancreatic enzymes. In addition, gastrointestinal and pancreatic surgical resections are frequent causes. Clinical manifestations include abdominal cramps, steatorrhea and malnutrition. Malnutrition, the main contributing factor of weight loss, has been related to a high morbidity and mortality secondary to an increased risk of malnutrition-related complications and cardiovascular events. Assessments of exocrine pancreatic function, such as fecal fat quantification and (13) C triglyceride breath test, are the method of choice for diagnosis. In clinical practice, high-risk patient populations include those with severe necrotizing pancreatitis, gastrointestinal and pancreatic surgery, cancer of pancreas head, and those with pancreatic calcifications. Apart from relief of maldigestion related symptoms, the main goal of pancreatic enzyme substitution therapy is to ensure a normal nutritional status. Therapy of pancreatic insufficiency is based on the oral administration of exogenous pancreatic enzymes. Restriction of fat intake, though traditionally important in conventional treatment, should be reconsidered. Enzyme substitution therapy should ideally mimic the physiological pattern of pancreatic exocrine secretion, and pancreatic enzymes in the form of enteric-coated minimicrospheres are considered as the most elaborated commercially available enzyme preparations. In general, pancreatic exocrine insufficiency in patients after surgery may be managed similarly to patients with chronic pancreatitis. This review focuses on current perspectives in diagnosis and treatment of pancreatic exocrine insufficiency and practical suggestions on its clinical management. PMID- 21323993 TI - Can myocardial strain differentiate hypertrophic from infiltrative etiology of a thickened septum? AB - OBJECTIVES: Radial systolic strain (epsilon) assessed by echocardiography has been shown to identify patterns of normal septal motion brought about by different layers, including left ventricular (LV) subendocardial (LV subendo) and mural (LV mural) layers. We aimed to use myocardial strain in assessing radial and longitudinal myocardial function in normal and thickened septum and to test if myocardial strain can differentiate hypertrophic from infiltrative cause of thickened septum. METHODS: Forty-five patients (age 61 +/- 13 years, 22 males), 13 with hypertrophic cardiomyopathy, 15 with aortic stenosis, and 17 with familial amyloid polyneuropathy, were studied and compared with 29 controls (age 61 +/- 12 years, 17 males) using 1D strain and conventional echocardiography. RESULTS: Patients had normal LV ejection fraction and stroke volume but heart rate was higher (P < 0.05) compared to controls. Septal E was reduced (-7.6 +/- 7.0% vs. -14.0 +/- 5.5%, for LV mural and -7.9 +/- 14.7% vs. -20.3 +/--7.9% for LV subendo, P < 0.001 for both layers) across LV longitudinal axis but not along its radial axis. No difference was found in any of E measurements between patient groups. A decrease in strain length by 50% increased the septal strain by more than 60% in both radial and longitudinal axes. CONCLUSION: Septal systolic strain measurements showed reduced longitudinal function but its localized nature failed to demonstrate radial disturbances in patients with pathologically thickened septum. No difference was found in systolic strain between patients according to the etiology of septal thickness. This limitation might be either technical or is explained by the maintained radial function in all patient groups. PMID- 21323994 TI - The pocket echocardiograph: a pilot study of its validation and feasibility in intubated patients. AB - BACKGROUND: The clinical use of miniaturized echocardiograph devices is expanding due to the potential to rapidly assess cardiac function in the critically ill patient. Novice echocardiographers have used the pocket echocardiograph (PE) to estimate ejection fraction in ambulatory patients, but have not evaluated intubated patients. We hypothesize that a novice echocardiographer can use PE to acquire interpretable cardiac images, and provide an accurate tool for estimating ejection fraction. METHODS: Subjects scheduled for cardiac surgery underwent blinded transesophageal echocardiography (TEE) and PE during a hemodynamically stable period after endotracheal intubation prior to incision. A single cardiology fellow acquired all PE images. The fellow and an experienced echocardiographer interpreted PE studies offline in a blinded fashion, visually estimating ejection fraction and assigning an image quality grade. Comparisons were made to the TEE study. RESULTS: Subjects (n = 22) were 81% male; age 69 +/- 9 years, and had a mean ejection fraction of 51% +/- 10.0%. Parasternal images were adequate in the vast majority of patients (77%), limited in 14%, and unacceptable in 9%, while apical (41%, 45%, and 14%) and subcostal (36%, 32%, and 32%) image quality was inferior. Ejection fraction showed fair correlation, bias, and limits of agreement for the fellow's interpretation (r = 0.50, 4.9%, +/- 20.7%), with stronger association for the experienced echocardiographer (r = 0.76, 3.3%, +/- 16.6%). CONCLUSION: A novice echocardiographer using PE can acquire interpretable images in the majority of intubated patients. Novice and expert echocardiographers can reasonably estimate ejection fraction using PE. PE may allow novice echocardiographers to rapidly assess cardiac function in intubated patients. PMID- 21323995 TI - Outcomes and survival with aortic valve replacement compared with medical therapy in patients with low-, moderate-, and severe-gradient severe aortic stenosis and normal left ventricular ejection fraction. AB - BACKGROUND: This study determined outcomes and survival with aortic valve replacement (AVR) versus medical therapy in patients with normal left ventricular ejection fraction (LVEF) with severely reduced aortic valve areas (AVA) but nonsevere mean gradients. METHODS: We identified 248 aortic stenosis (AS) patients with LVEF >= 50% and echocardiographic AVA < 1.0 cm(2). Group 1 had low gradient: <30 mmHg mean gradient; group 2 (moderate: 30 to 40 mm Hg); and group 3 (severe: >40 mm). RESULTS: There were 94, 87, and 67 patients in groups 1, 2, and 3. Incidence of death in groups 1, 2, and 3 were 55%, 39%, and 39% (P not significant). Incidence of AVR in groups 1, 2, and 3 were 23%, 53%, and 49% (P < 0.0001 for group 1 vs. 2; P = 0.0003 for group 1 vs. group 3). Incidence of AVR or death was 71%, 77%, and 76% (P not significant). AVR (hazard ratio = 0.30; 95% CI, 0.18, 0.51; P < 0.0001) and mitral annular calcification (hazard ratio = 2.33; 95% CI, 1.40, 3.88; P = 0.001) were independently associated with time to mortality. Kaplan-Meier curves for time to death did not differ significantly among the three groups. Kaplan-Meier survival curves for patients with and without AVR showed patients in all three groups who underwent AVR had significantly greater survival. CONCLUSION: Among patients with normal LVEF and AVA < 1.0 cm(2), overall survival does not differ among those with low-, moderate , or severe-aortic valve gradients. Survival is significantly improved with AVR, regardless of gradient. PMID- 21323996 TI - Potent antitumor and antineoplastic efficacy of baicalein on benzo(a)pyrene induced experimental pulmonary tumorigenesis. AB - Current study aims to evaluate the efficacy of baicalein (BE), a naturally occurring bioactive flavanoid (5,6,7-trihydroxy-flavone), at a dose of 12 mg/kg body wt in Swiss albino mice exposed to tobacco-specific carcinogen benzo(a)pyrene [B(a)P] (50 mg/kg body wt) for its ability to mitigate pulmonary adenoma formation and growth. Under coarse observation, B(a)P-administered mice, after 16 weeks, developed macroscopically detectable tumors, whereas oral treatment with BE to the lung cancer-induced mice significantly reduced tumor incidence in 16-week pre- and posttreated groups. A detailed histopathological examination of lung was conducted to determine the degree of cancer progression. Incidence of anaplasia, hyperplasia, dysplasia, severe dysplasia, and adenocarcinoma were evident in carcinogen-administrated group in 6, 10, 12, 14, and 16th weeks, respectively, whereas these anomalies were effectively reduced after pre- and posttreatment with BE. In the pretreatment group, BE significantly arrested tumor multiplicity by approximately 65% and tumor load by approximately 88%, while in the posttreatment, the compound significantly reduced the tumor multiplicity by approximately 48% and tumor load by approximately 61%. Further analysis of serum tumor markers like carcinoembryonic antigen, CK 19 fragments (CYFRA 21-1), and tissue marker enzymes like aryl hydrocarbon hydroxylase, adenosine deaminase, gamma-glutamyl transpeptidase, 5'-nucleotidase, and lactate dehydrogenase in serum and lung homogenate was carried out to substantiate the anticarcinogenic effect of BE. The overall data from our experiments suggested that BE significantly inhibited pulmonary adenoma formation and growth, thus revealing its potent antitumorigenic effect. PMID- 21323997 TI - Systemic lupus erythematosus induced by interferon beta1 therapy in a patient with multiple sclerosis. AB - Drug-induced lupus erythematosus is defined as a lupus-like syndrome temporally related to a drug exposure. We report a 34-year-old woman with multiple sclerosis who developed, while being treated with interferon beta-1a, myalgia and associated with wrist synovitis. Clinical and immunologic investigations were in favor of systemic lupus erythematosus. Interferon therapy was maintained. Under corticosteroids and antipaludeen treatment, the patient did not develop any other lupic manifestations. PMID- 21323998 TI - Cherry picking in ESRD: an ethical challenge in the era of pay for performance. AB - In poorly designed pay-for-performance schemes in which case mix adjustments are not adequate, self-interest could lead nephrologists toward cherry picking dialysis patients. Cherry picking, however, is morally problematic. First, it may manifest itself as a subtle form of covert rationing which threatens to undermine patient trust. Second, it involves shifting the burden of caring for sicker (and less financially attractive) patients to other nephrologists and dialysis units that do not practice cherry picking, creating injustices in the health care system. Finally, it treats patients as mere means through which nephrologists achieve reimbursement instead of as persons possessing dignity and deserving of respect. PMID- 21323999 TI - Do clinical outcomes in chronic hemodialysis depend on the choice of a dialyzer? AB - Nephrologists are presented with a range of choices when selecting a dialyzer for chronic hemodialysis. Dialyzers differ in the material, structure, permeability and surface area of their membrane, and how the dialyzer is sterilized. Opinions vary regarding the impact of dialyzer characteristics on patient outcomes and which, if any, of these properties to take into account when choosing a dialyzer can be confusing. In the general dialysis population, there is no compelling evidence that the choice of a membrane material from among those materials currently in clinical use has a significant impact on morbidity or mortality (although there are rare patients who will react adversely to a given dialysis membrane). Similarly, most dialyzers are capable of adequately removing small solutes, such as urea, provided they are used with an appropriate blood flow rate and treatment time to ensure delivery of a single-pool Kt/V(urea) of at least 1.25 for men and 1.65 for women. However, in some dialysis patient subpopulations, the results of randomized clinical trials suggest that use of dialyzer containing high-flux membranes confers an outcome advantage. The extent to which this advantage is realized might also depend on how the dialyzer is used, with application in convective therapies such as hemodiafiltration being superior to diffusive therapies such as hemodialysis. This possibility is currently the subject of several large clinical trials. PMID- 21324000 TI - Extracorporeal treatment of cast nephropathy. AB - Acute kidney injury (AKI) is common in patients with multiple myeloma (MM), most commonly caused by cast nephropathy resulting from precipitation of free light chains (FLC) in renal tubules. AKI may be irreversible and require dialysis and predicts a poor prognosis. Reduction in serum FLC concentration is thought to be associated with improved likelihood of kidney function recovery in MM patients with AKI. Plasma exchange (PE), by removing circulating FLC, has been used as a treatment modality to improve kidney function in MM, although its efficacy remains uncertain. Extracorporeal treatment with extended high cutoff hemodialysis (HCO-HD) has also recently been studied as a potentially more effective means of FLC removal. Both PE and HCO-HD may be beneficial in some patients, but only when used as adjuncts to successful chemotherapy. Further research is necessary to establish the specific efficacy of each of these extracorporeal methods in the treatment of cast nephropathy. PMID- 21324001 TI - Target levels for serum phosphorus and parathyroid hormone. PMID- 21324002 TI - Avoiding a cutdown--use of the transcatheter extractor in removal of tunneled dialysis catheters. AB - The purpose of our study was to evaluate the use of a transcatheter extractor (TCE) device in removing cuffed tunneled dialysis catheters without a surgical cutdown. We report eight cases where a TCE was used to successfully remove cuffed tunneled dialysis catheters through the exit site that would have otherwise required a second incision. The cuff was above the clavicle in all cases and varied 3-5 cm from the exit site. The method included inserting the device over the catheter through the exit site and engaging it over the cuff. A to-and-fro motion was then used in the same plane as the catheter to dissect the cuff from the surrounding tissue. Once the cuff was freed, the catheter was removed easily without resistance. The fibrous cuff was removed intact in all cases. We conclude that the use of this device may help avoid a cutdown and minimize trauma to the patient. It is an effective technique to remove tunneled dialysis catheters and is particularly useful in catheters with ingrown cuffs further from the exit site. PMID- 21324003 TI - Riluzole is a potent drug to protect neonatal rat hypoglossal motoneurons in vitro from excitotoxicity due to glutamate uptake block. AB - Excitotoxic damage to motoneurons is thought to be an important contribution to the pathogenesis of amyotrophic lateral sclerosis (ALS), a slowly developing degeneration of motoneurons that, in most cases of sporadic occurrence, is associated with impaired glial glutamate uptake. Riluzole is the only drug licensed for symptomatic ALS treatment and is proposed to delay disease progression. As riluzole is administered only after full ALS manifestation, it is unclear if its early use might actually prevent motoneuron damage. We explored this issue by using, as a simple in vitro model, hypoglossal motoneurons (a primary target of ALS) of the neonatal rat brainstem slice preparation exposed to excitotoxic stress due to glutamate uptake block by DL-threo-beta benzyloxyaspartate (TBOA). TBOA evoked sustained network bursting, early (1 h) enhancement of the S100B immunostaining of gray matter astrocytes, and activated the motoneuronal stress ATF-3 transcription factor; 4 h later, loss (30%) of motoneuron staining ensued and pyknosis appeared. Riluzole (5 MUM; applied 15 min after TBOA) inhibited bursting, decreased the frequency of spontaneous glutamatergic events, reversed changes in S100B immunostaining and prevented late loss of motoneuron staining. These results show that excitotoxicity induced by glutamate uptake block developed slowly, and was sensed by glia and motoneurons with delayed cell death. Our data provide novel evidence for the neuroprotective action of riluzole on motoneurons and glia when applied early after an excitotoxic stimulus. PMID- 21324004 TI - Concurrent TMS-fMRI reveals dynamic interhemispheric influences of the right parietal cortex during exogenously cued visuospatial attention. AB - We used concurrent transcranial magnetic stimulation and functional MRI (TMS fMRI) during a visuospatial cueing paradigm in humans, to study the causal role of the right angular gyrus (AG) as a source of attentional control. Our findings show that TMS over the right AG (high vs. low intensity) modulates neural responses interhemispherically, in a manner that varies dynamically with the current attentional condition. The behavioural impact of such TMS depended not only on the target hemifield but also on exogenous cue validity, facilitating spatial reorienting to invalidly cued right visual targets. On a neural level, right AG TMS had corresponding interhemispheric effects in the left AG and left retinotopic cortex, including area V1. We conclude that the direction of covert visuospatial attention can involve dynamic interplay between the right AG and remote interconnected regions of the opposite left hemisphere, whereas our findings also suggest that the right AG can influence responses in the retinotopic visual cortex. PMID- 21324005 TI - Zinc enhances long-term potentiation through P2X receptor modulation in the hippocampal CA1 region. AB - Zn2(+) is an essential ion that is stored in and co-released from glutamatergic synapses and it modulates neurotransmitter receptors involved in long-term potentiation (LTP). However, the mechanism(s) underlying Zn2(+) -induced modulation of LTP remain(s) unclear. As the purinergic P2X receptors are relevant targets for Zn2(+) action, we have studied their role in LTP modulation by Zn2(+) in the CA1 region of rat hippocampal slices. Induction of LTP in the presence of Zn2(+) revealed a biphasic effect - 5-50 MUm enhanced LTP induction, whereas 100 300 MUm Zn2(+) inhibited LTP. The involvement of a purinergic mechanism is supported by the fact that application of the P2X receptor antagonists 2',3'-O (2,4,6-trinitrophenyl) ATP (TNP-ATP) and periodate-oxidized ATP fully abolished the facilitatory effect of Zn2(+) . Notably, application of the P2X7 receptor specific antagonist Brilliant Blue G did not modify the Zn2(+) -dependent facilitation of LTP. Exogenous ATP also produced a biphasic effect - 0.1-1 MUm ATP facilitated LTP, whereas 5-10 MUm inhibited LTP. The facilitatory effect of ATP was abolished by the application of TNP-ATP and was modified in the presence of 5 MUm Zn2(+) , suggesting that P2X receptors are involved in LTP induction and that Zn2(+) leads to an increase in the affinity of P2X receptors for ATP. The latter confirms our previous results from heterologous expression systems. Collectively, our results indicate that Zn2(+) at low concentrations enhances LTP by modulating P2X receptors. Although it is not yet clear which purinergic receptor subtype(s) is responsible for these effects on LTP, the data presented here suggest that P2X4 but not P2X7 is involved. PMID- 21324006 TI - Alterations induced by chronic lead exposure on the cells of circadian pacemaker of developing rats. AB - Lead (Pb) exposure alters the temporal organization of several physiological and behavioural processes in which the suprachiasmatic nucleus (SCN) of the hypothalamus plays a fundamental role. In this study, we evaluated the effects of chronic early Pb exposure (CePbe) on the morphology, cellular density and relative optical density (OD) in the cells of the SCN of male rats. Female Wistar rats were exposed during gestation and lactation to a Pb solution containing 320 ppm of Pb acetate through drinking water. After weaning, the pups were maintained with the same drinking water until sacrificed at 90 days of age. Pb levels in the blood, hypothalamus, hippocampus and prefrontal cortex were significantly increased in the experimental group. Chronic early Pb exposure induced a significant increase in the minor and major axes and somatic area of vasoactive intestinal polypeptide (VIP)- and vasopressin (VP)-immunoreactive neurons. The density of VIP-, VP- and glial fibrillary acidic protein (GFAP)-immunoreactive cells showed a significant decrease in the experimental group. OD analysis showed a significant increase in VIP neurons of the experimental group. The results showed that CePbe induced alterations in the cells of the SCN, as evidenced by modifications in soma morphology, cellular density and OD in circadian pacemaker cells. These findings provide a morphological and cellular basis for deficits in circadian rhythms documented in Pb-exposed animals. PMID- 21324007 TI - Care recipients' and family members' perceptions of quality of older people care: a comparison of home-based care and nursing homes. AB - AIMS: To compare care recipients' and their relatives' perceptions of quality of care in nursing homes and home-based care. BACKGROUND: Older people care is increasingly being provided in community care facilities and private homes instead of hospitals. A few studies have compared care recipients' and relatives' perceptions of care quality in nursing homes as opposed to home-based care. DESIGN: Cross-sectional surveys. METHODS: Care recipients' and relatives' perceptions of quality of care were measured by questionnaire in 2003 in two older people care organisations. Quality measures were compared between care settings. Multiple regression was used to determine the predictors of overall quality ratings for each group, and possible interactions between quality measures and care settings were tested. RESULTS: Care recipients rated their opportunities for activities significantly lower in home care than in nursing homes. Relatives of care recipients in home-based care rated several aspects of care quality significantly lower than relatives of nursing home residents. No significant interaction effects regarding predictors of overall quality ratings between the care settings were found. Staff behaviour was the strongest predictor of care recipients' overall quality rating, and staff professional skills were the strongest predictor of relatives' overall quality rating. CONCLUSIONS: Compared with nursing homes, home-based older people care seems to be in greater need of development regarding staff competence, staff interaction with relatives and activities offered to older people. In both settings, nursing staff behaviour influences these stakeholders' satisfaction with care. RELEVANCE TO CLINICAL PRACTICE: These results point to a need to improve services in both care settings, but especially in home-based care. It is suggested that care recipients' preferences for social and physical activities be investigated on a regular basis in both care settings. Efforts should also be made to improve communication and interaction between family members and older people care staff, especially in home-based care. PMID- 21324008 TI - Frontiers in host-parasite ecology and evolution. PMID- 21324009 TI - Wild immunology. AB - In wild populations, individuals are regularly exposed to a wide range of pathogens. In this context, organisms must elicit and regulate effective immune responses to protect their health while avoiding immunopathology. However, most of our knowledge about the function and dynamics of immune responses comes from laboratory studies performed on inbred mice in highly controlled environments with limited exposure to infection. Natural populations, on the other hand, exhibit wide genetic and environmental diversity. We argue that now is the time for immunology to be taken into the wild. The goal of 'wild immunology' is to link immune phenotype with host fitness in natural environments. To achieve this requires relevant measures of immune responsiveness that are both applicable to the host-parasite interaction under study and robustly associated with measures of host and parasite fitness. Bringing immunology to nonmodel organisms and linking that knowledge host fitness, and ultimately population dynamics, will face difficult challenges, both technical (lack of reagents and annotated genomes) and statistical (variation among individuals and populations). However, the affordability of new genomic technologies will help immunologists, ecologists and evolutionary biologists work together to translate and test our current knowledge of immune mechanisms in natural systems. From this approach, ecologists will gain new insight into mechanisms relevant to host health and fitness, while immunologists will be given a measure of the real-world health impacts of the immune factors they study. Thus, wild immunology can be the missing link between laboratory-based immunology and human, wildlife and domesticated animal health. PMID- 21324010 TI - Digital gene expression analysis of gastrointestinal helminth resistance in Scottish blackface lambs. AB - Digital gene expression (DGE) analysis offers a route to gene discovery which by passes the need to develop bespoke arrays for nonmodel species, and is therefore a potentially valuable tool for molecular ecologists. Scottish blackface sheep, which vary in resistance to the common abomasal parasitic nematode Teladorsagia circumcincta, were trickle-infected with L3 larvae over 3 months to mimic the natural progression of infection. DGE was performed on abomasal lymph node tissue after the resolution of infection in resistant animals. Susceptible (low resistance) animals showed a large number of differentially expressed genes associated with inflammation and cell activation, but generally few differentially regulated genes in either the susceptible or the resistant group were directly involved in the adaptive immune function. Our results are consistent with the hypothesis that both resistance and susceptibility are active responses to infection and that susceptibility is associated with dysfunction in T cell differentiation and regulation. PMID- 21324011 TI - Population structure of mycobionts and photobionts of the widespread lichen Cetraria aculeata. AB - Lichens are symbioses between fungi (mycobionts) and photoautotrophic green algae or cyanobacteria (photobionts). Many lichens occupy large distributional ranges covering several climatic zones. So far, little is known about the large-scale phylogeography of lichen photobionts and their role in shaping the distributional ranges of lichens. We studied south polar, temperate and north polar populations of the widely distributed fruticose lichen Cetraria aculeata. Based on the DNA sequences from three loci for each symbiont, we compared the genetic structure of mycobionts and photobionts. Phylogenetic reconstructions and Bayesian clustering methods divided the mycobiont and photobiont data sets into three groups. An amova shows that the genetic variance of the photobiont is best explained by differentiation between temperate and polar regions and that of the mycobiont by an interaction of climatic and geographical factors. By partialling out the relative contribution of climate, geography and codispersal, we found that the most relevant factors shaping the genetic structure of the photobiont are climate and a history of codispersal. Mycobionts in the temperate region are consistently associated with a specific photobiont lineage. We therefore conclude that a photobiont switch in the past enabled C. aculeata to colonize temperate as well as polar habitats. Rare photobiont switches may increase the geographical range and ecological niche of lichen mycobionts by associating them with locally adapted photobionts in climatically different regions and, together with isolation by distance, may lead to genetic isolation between populations and thus drive the evolution of lichens. PMID- 21324012 TI - Mitochondrial and nuclear DNA sequences reveal recent divergence in morphologically indistinguishable petrels. AB - Often during the process of divergence, genetic markers will only gradually obtain the signal of isolation. Studies of recently diverged taxa utilizing both mitochondrial and nuclear data sets may therefore yield gene trees with differing levels of phylogenetic signal as a result of differences in coalescence times. However, several factors can lead to this same pattern, and it is important to distinguish between them to gain a better understanding of the process of divergence and the factors driving it. Here, we employ three nuclear intron loci in addition to the mitochondrial Cytochrome b gene to investigate the magnitude and timing of divergence between two endangered and nearly indistinguishable petrel taxa: the Galapagos (GAPE) and Hawaiian (HAPE) petrels (Pterodroma phaeopygia and P. sandwichensis). Phylogenetic analyses indicated reciprocal monophyly between these two taxa for the mitochondrial data set, but trees derived from the nuclear introns were unresolved. Coalescent analyses revealed effectively no migration between GAPE and HAPE over the last 100,000 generations and that they diverged relatively recently, approximately 550,000 years ago, coincident with a time of intense ecological change in both the Galapagos and Hawaiian archipelagoes. This indicates that recent divergence and incomplete lineage sorting are causing the difference in the strength of the phylogenetic signal of each data set, instead of insufficient variability or ongoing male biased dispersal. Further coalescent analyses show that gene flow is low even between islands within each archipelago suggesting that divergence may be continuing at a local scale. Accurately identifying recently isolated taxa is becoming increasingly important as many clearly recognizable species are already threatened by extinction. PMID- 21324013 TI - The relationship between media use in the bedroom, sleep habits and symptoms of insomnia. AB - This postal questionnaire study investigated the use of media in the bedroom and its relationships with sleep habits and symptoms of insomnia. The sample comprised 2500 individuals aged 16-40 years drawn randomly from the Norwegian national register. A total of 816 (34.0%) completed and returned the questionnaire. Respondents were asked how often they used computers, television sets, DVD players, game consoles and mobile telephones and listened to music/radio in their bedrooms. They also reported sleep habits on weekdays and at weekends/days off and symptoms of insomnia. After controlling for gender, age, anxiety and depression, the respondents who used a computer in the bedroom 'often' compared to 'rarely' rose later on weekdays and at weekends/days off, turned off the lights to go to sleep later at weekends/days off, slept more hours at weekends/days off and had a greater discrepancy between turning off the lights to go to sleep on weekdays and at weekends/days off. Respondents who used a mobile telephone in their bedrooms at night 'often' compared to 'rarely' turned off the lights to go to sleep later on weekdays and at weekends/days off, and rose later at weekends/days off. No such differences were found with the use of the other media. There were also no significant differences in symptoms of insomnia. This study indicates that the use of computers and mobile telephones in the bedroom are related to poor sleep habits, but that media use in the bedroom seems to be unrelated to symptoms of insomnia. PMID- 21324014 TI - Building a pan-European alcohol policy research competence. PMID- 21324015 TI - A new AMPHORA: an introduction to the project Alcohol Measures for Public Health Research Alliance. AB - The AMPHORA Project is a 4 years project funded by the 7th Framework Programme of the European Commission which aims to contribute with new evidence on scarcely explored or unexplored areas of alcohol consumption and alcohol-related harm in Europe. In this introductory article we describe the background of the Project and its main features. The research areas covered by AMPHORA are wide and diverse. Some of the most relevant are: an update on European epidemiological data; the definition of standard common indicators of alcohol consumption and harm; the measurement of the strength of alcohol policies; the study of contextual determinants of alcohol consumption, the analysis of the impact of marketing on youth; the availability of treatments at a European level; and two areas of harm reduction (contamination of illegal or surrogate alcohols and the reduction of harm in drinking venues). PMID- 21324016 TI - Indicators of alcohol consumption and attributable harm for monitoring and surveillance in European Union countries. AB - AIMS: Alcohol is a major risk factor for burden of disease and injury in Europe, and contributes markedly to between region differences in life expectancy. Monitoring and surveillance systems have shown to be a key factor in implementing effective policies. The aim of this paper is to propose a system of indicators for alcohol consumption and attributable harm which can be used as an over-time monitoring tool at the country level as well as for comparisons between countries. DESIGN: A systematic research in electronic data bases was conducted but most of the information was derived from ongoing international efforts to establish alcohol monitoring and surveillance systems. SETTING: European Union. PARTICIPANTS: Countries. MEASUREMENTS: Exposure to alcohol, mortality, burden of disease. FINDINGS: Adult per capita alcohol consumption, prevalence of abstention, and frequency of drinking more than 60 g pure alcohol in one occasion are proposed as a minimal set of alcohol exposure indicators, which can quickly be implemented in all EU countries. With respect to health harm indicators, the best minimal choice which can be implemented quickly in all countries of the EU would be alcohol-attributable years of life lost due to premature death. In addition, country specific indicators could be added, when alcohol places specific burden on specific diseases. CONCLUSIONS: National and European Union wide monitoring systems for alcohol exposure and attributable harm to inform public health-related policy decisions could be implemented easily. The establishement of such monitoring systems would follow the recent World Assembly resolution for a global strategy to reduce alcohol-related harm. PMID- 21324017 TI - Epidemiology and alcohol policy in Europe. AB - AIMS: To describe three aspects of the epidemiology of alcohol-attributable deaths in Europe, dose, demography and place, and to illustrate how such knowledge can better be used to inform alcohol policy formulation and implementation. DESIGN: epidemiological and population health modeling. SETTING: Europe. PARTICIPANTS: Based on country-specific aggregate statistics. MEASUREMENTS: EXPOSURE: country-specific adult per capita consumption triangulated with survey data; outcomes: mortality statistics. FINDINGS: The absolute risk of dying from an alcohol-attributable disease and injury (accounting for a protective effect for ischaemic diseases) increases with increasing daily alcohol consumption beyond 10 g alcohol per day, the first data point. Over 2/3 of all alcohol-attributable deaths occurring amongst the 20-64 year old population of the European Union (minus Cyprus and Malta) occur in the 45-64 year olds. About 25% of the difference in life expectancy between western and eastern Europe for men aged 20-64 years in 2002 can be attributed to alcohol, largely, but not exclusively, as a result of differences in heavy episodic drinking patterns. CONCLUSIONS: Any reduction in the dose of alcohol consumed, at least down to 10 g/day, will reduce the annual and lifetime risk of an alcohol related death. There is a need for alcohol policy to focus on measures in reducing alcohol consumption, throughout middle age, with immediacy of impact. Policy should strive to reduce alcohol-related health inequalities, with the specific recommendations for policy depending on the cost-effectiveness of interventions related to the epidemiological profile of the country or region under consideration. Fortunately, there are evidence-based policy options that reduce the amount of alcohol consumed and many alcohol-related harms with immediate effect, that reduce the risk of an alcohol-related death in middle age, and that would help to close the health gap between eastern and western Europe. PMID- 21324018 TI - Is contaminated unrecorded alcohol a health problem in the European Union? A review of existing and methodological outline for future studies. AB - AIMS: Some European countries with high levels of unrecorded alcohol consumption have anomalously high rates of death attributable to liver cirrhosis. Hepatotoxic compounds in illegally produced spirits may be partly responsible. Based on a review of the evidence on the chemical composition and potential harm from unrecorded alcohol, the Alcohol Measures for Public Health Research Alliance (AMPHORA) project's methodology for identifying, analysing and toxicologically evaluating such alcohols is provided. METHODS: A computer-assisted literature review concentrated on unrecorded alcohol. Additionally, we refer to our work in the capacity of governmental alcohol control authority and a number of pilot studies. RESULTS: The risk-oriented identification of substances resulted in the following compounds probably posing a public health risk in unrecorded alcohol: ethanol, methanol, acetaldehyde, higher alcohols, heavy metals, ethyl carbamate, biologically active flavourings (e.g. coumarin) and diethyl phthalate. Suggestions on a sampling strategy for identifying unrecorded alcohol that may be most prone to contamination include using probable distribution points such as local farmers and flea markets for selling surrogate alcohol (including denatured alcohol) to focusing on lower socio-economic status or alcohol-dependent individuals, and selecting home-produced fruit spirits prone to ethyl carbamate contamination. CONCLUSIONS: Standardized guidelines for the chemical and toxicological evaluation of unrecorded alcohol that will be used in a European wide sampling and are applicable globally are provided. These toxicological guidelines may also be used by alcohol control laboratories for recorded alcohol products, and form a scientific foundation for establishing legislative limits. PMID- 21324019 TI - Identifying the gap between need and intervention for alcohol use disorders in Europe. AB - AIMS: A literature review of existing research on the prevalence of alcohol use disorders (AUDs) and availability of alcohol interventions in Europe was conducted. The review also explored what is known about the gap between need and provision of alcohol interventions in Europe. METHODS: The review search strategy included: (i) descriptive studies of alcohol intervention systems in Europe; (ii) studies of alcohol service provision in Europe; and (iii) studies of prevalence of AUD and alcohol needs assessment in Europe. RESULTS: Europe has a relatively high level of alcohol consumption and the resulting disabilities are the highest in the world. Most research on implementation of alcohol interventions in Europe has been restricted to screening and brief interventions. Alcohol needs assessment methodology has been developed but has not been applied in comparative studies across countries in Europe. CONCLUSIONS: This review points to key gaps in knowledge related to alcohol interventions in Europe. There is a lack of comparative data on variations in alcohol treatment systems across European countries and there is also a lack of comparative data on the prevalence of alcohol use disorders across European countries and the relative gap between need and access to treatment. The forthcoming Alcohol Measures for Public Health Research Alliance (AMPHORA) research project work package on 'Early identification and treatment' aims to address these gaps. PMID- 21324020 TI - Environmental factors in drinking venues and alcohol-related harm: the evidence base for European intervention. AB - AIMS: Reducing alcohol-related harm in young people is a major priority across Europe. Much alcohol use and associated harm in young people occurs in public drinking environments. This review aims to identity environmental factors in drinking establishements that are associated with increased alcohol consumption and associated harm and to understand the extent of study in this area across Europe. METHODS: A systematic literature search identified studies that had explored associations between physical, staffing and social factors in drinking environments and increased alcohol use or alcohol-related harm. RESULTS: Fifty three papers were identified, covering 34 studies implemented in nine countries. Most studies had been implemented in non-European countries and many had collected data more than a decade prior to the review. The majority had used observational research techniques. Throughout the studies, a wide range of physical, staffing and social factors had been associated with higher levels of alcohol use and related harm in drinking environments. Factors that appeared particularly important in contributing to alcohol-related problems included a permissive environment, cheap alcohol availability, poor cleanliness, crowding, loud music, a focus on dancing and poor staff practice. However, findings were not always consistent across studies. CONCLUSIONS: Drinking establishments, their management and the behaviours of the young people who use them vary widely across Europe. While international research shows that environmental factors in drinking settings can have an important influence on alcohol-related harm, there is currently a scarcity of knowledge on the relevance and impacts of such factors in modern European settings. Developing this knowledge will support the implementation of strategies to create drinking environments in Europe that are less conducive to risky drinking and alcohol-related harm. PMID- 21324021 TI - Do infrastructures impact on alcohol policy making? AB - INTRODUCTION: The importance of building and strengthening effective infrastructures within the field of public health has increasingly been recognized. A wide variety of actors and structures can be identified for alcohol policy, including systems for policy development, monitoring, research and work force development, but too little is known about the complex systems of infrastructure available across European countries and their impact on alcohol policy. OBJECTIVE: This study is part of the Alcohol Measures for Public Health Research Alliance (AMPHORA) project, and aims to map existing infrastructures, but also to examine the relationship between infrastructures and alcohol policy change. METHODS: A survey of alcohol policy infrastructure and infrastructure needs at the national level will be conducted using an updated and adapted questionnaire based on the Health Promotion (HP) Source Project tool. Case studies involving in-depth interviews will be conducted for a selection of countries. Data will be analysed descriptively, mapping alcohol policy infrastructure and identifying needs to reveal any relationship between infrastructure and alcohol policy. EXPECTED RESULTS: This study can contribute to building the scientific knowledge base on this topic as well to policy development. First, the Alcohol Measures for Public Health Research Alliance will produce an extended map of alcohol policy infrastructures in a wide range of European countries. Secondly, the Alcohol Measures for Public Health Research Alliance will foster a better understanding and expand the knowledge base on the role and influence of infrastructure on alcohol policy and practice. Recommendations deriving from this study will identify the need for better utilization of existing infrastructures and for the development of new infrastructures, necessary to develop and implement effective alcohol policy from a public health perspective. PMID- 21324022 TI - Science and alcohol policy: a case study of the EU Strategy on Alcohol. AB - AIMS: To describe the extent to which the content of the European Commission's Communication on alcohol reflects public health-based scientific evidence. DESIGN: Document retrieval and content analysis. SETTING: European Union. PARTICIPANTS: Background documents leading up to the European Commission's Communication on alcohol, the Communication itself and implementation actions following the Communication. MEASUREMENTS: Documents were read and analyzed for evidence-based alcohol policy content. FINDINGS: Although the Communication acknowledges and supports existing interventions which have high evidence for effectiveness, such as enforcing blood alcohol concentration (BAC) limits for drivers, it extensively promotes other interventions which have been shown to be ineffective; for example, recommending education and persuasion strategies as a measure across all its five priority areas. Measures to influence price are mentioned only once in relation to sales in drinking venues limiting two-for-one drinks offers. Measures to control physical availability are mentioned infrequently. CONCLUSIONS: The Communication reflects the science, in that it acknowledges the significance of alcohol as a social and health determinant in Europe. However, it places more emphasis on policy actions with less evidence for effectiveness than on those with strong evidence. It also focuses its efforts more on mapping member state actions and coordinating knowledge exchange than on providing concrete recommendations for action or developing Europe-wide policy measures. This may be a compromise between the rights of Member States to develop national policy and legislation and the obligation of the European Union as a collaborative body to protect health. Furthermore, it has been suggested that the European Union's roots as a trading block emphasizes collaboration with industry stakeholders and this influences the ability to prioritize health over trade considerations. PMID- 21324023 TI - Reflections on science and the governance of alcohol policy. AB - AIMS: To consider, briefly, science's role in informing alcohol policy, and how science could help reframe the present governance of alcohol policy. DESIGN: Expression of the two project coordinators' reflections based on discussions during project meetings of the Alcohol Measures for Public Health Research Alliance (AMPHORA) project. RESULTS: Three endeavours are considered important for science's role in informing alcohol policy: modelling studies that help predict the outcomes of differing policy approaches; studying the impact of live policy changes as a powerful set of natural experiments; and, improved study of the impact of integrated, coordinated and joined up alcohol policies, as opposed to the impact of individual alcohol policy measures. Three areas where science can contribute to strengthened alcohol policy governance include: analysis of different governance architectures that might promote joined-up actions between different sectors; the design of better metrics that measure the impact of public and private sector actions on health; and, by identifying incentives that help consumers make choices on the use of alcohol that improve health. CONCLUSIONS: The impact of science on better alcohol policy governance can only happen if there is more and better dialogue between scientists and those who design alcohol policy. PMID- 21324024 TI - Older people with heart failure and general practitioners: temporal reference frameworks and implications for practice. AB - The aim of the study was to identify the time experiences of older patients and general practitioners (GPs). Secondary analysis of qualitative data collected from two longitudinal studies, one in the United Kingdom (UK) and the other in New Zealand (NZ), was carried out. The UK study involved interviews with 44 older people with heart failure and nine focus group discussions with primary health professionals during 2004-2005. The NZ study involved 79 interviews with 25 older people with heart failure and 30 telephone interviews with GPs during 2008-2009. Temporal reference frameworks function as background expectations and influence how patients and GPs experienced time and act as time controls. The key themes identified were: clock time was evident in how it structured the consultations; both patients and GPs valued needing time and for some GPs this involved creating space for emotional time. There were also tensions between needing time and wasting time; being known over time was important to both patients and GPs. For older people with heart failure improving their quality of care is essential and time is integral to this, not only the clock time and length of consultations. Identifying temporal reference frameworks provides an understanding that there are multiple times and exposes the influence of these in the lives of both the older people and GPs. PMID- 21324025 TI - Similar evolutionary potentials in an obligate ant parasite and its two host species. AB - The spatial structure of host-parasite coevolution is shaped by population structure and genetic diversity of the interacting species. We analysed these population genetic parameters in three related ant species: the parasitic slavemaking ant Protomognathus americanus and its two host species Temnothorax longispinosus and T. curvispinosus. We sampled throughout their range, genotyped ants on six to eight microsatellite loci and an MtDNA sequence and found high levels of genetic variation and strong population structure in all three species. Interestingly, the most abundant species and primary host, T. longispinosus, is characterized by less structure, but lower local genetic diversity. Generally, differences between the species were small, and we conclude that they have similar evolutionary potentials. The coevolutionary interaction between this social parasite and its hosts may therefore be less influenced by divergent evolutionary potentials, but rather by varying selection pressures. We employed different methods to quantify and compare genetic diversity and structure between species and genetic markers. We found that Jost D is well suited for these comparisons, as long as mutation rates between markers and species are similar. If this is not the case, for example, when using MtDNA and microsatellites to study sex-specific dispersal, model-based inference should be used instead of descriptive statistics (such as D or G(ST) ). Using coalescent-based methods, we indeed found that males disperse much more than females, but this sex bias in dispersal differed between species. The findings of the different approaches with regard to genetic diversity and structure were in good accordance with each other. PMID- 21324026 TI - Evidence-based guidelines for the care and maintenance of complete dentures: a publication of the American College of Prosthodontists. AB - The current rates of edentulism have been estimated to be between 7% and 69% of the adult population internationally. In the United States, while the incidence of edentulism continues to decline, rapid population growth coupled with current economic conditions suggest that edentulism and conventional denture use will continue at current or higher numbers. Unfortunately, evidence-based guidelines for the care and maintenance of removable complete denture prostheses do not exist. In 2009, the American College of Prosthodontists (ACP) formed a task force to establish evidence-based guidelines for the care and maintenance of complete dentures. The task force comprised members of the ACP, the Academy of General Dentistry, American Dental Association (ADA) Council on Scientific Affairs, the American Dental Hygienists' Association, the National Association of Dental Laboratories, and representatives from GlaxoSmithKline Consumer Healthcare. The review process included the assessment of over 300 abstracts and selection of over 100 articles meeting inclusion criteria of this review. The task force reviewed synopses of the literature and formulated 15 evidence-based guidelines for denture care and maintenance. These guidelines were reviewed by clinical experts from the participating organizations and were published in February 2011 issue of The Journal of the American Dental Association for widespread distribution to the dental community. These guidelines reflect the views of the task force. PMID- 21324027 TI - Commentary: Enhanced healing of surgical wounds of the lower leg using weekly zinc oxide compression dressings. PMID- 21324028 TI - Melanocytes and keratinocytes transfer using sandpaper technique combined with dermabrasion for stable vitiligo. AB - BACKGROUND: Surgery is currently the most successful approach for difficult cases of vitiligo. The efficacy of epidermal surface removal (dermabrasion) is near 50%, and the efficacy of grafts is 70%. OBJECTIVE: To evaluate the efficacy and safety of a combined approach using dermabrasion and grafting for unresponsive vitiligo. PATIENTS AND METHODS: Eleven patients with stable vitiligo each underwent two different procedures on different body areas: transfer of melanocytes and epidermal cells obtained using the "sandpaper method" combined with dermabrasion of the receptor area or simple dermabrasion. Micropunch testing was used to evaluate the activity of vitiligo. Only patients without activity were treated. Subjects were followed for 3 months, and digital pictures were analyzed to estimate the percentage of repigmentation. RESULTS: Transfer delivered visible results in the first month, and dermabrasion showed results in the second month. The quality of pigmentation was superior with the transfer technique, especially in the short term, although at the end of treatment, both techniques showed similar results. CONCLUSIONS: Transfer of melanocytes and keratinocytes with the sandpaper method is feasible, safe, and effective as treatment for stable vitiligo, although simple dermabrasion is as effective in the long term. PMID- 21324029 TI - Horizontal excision of in situ epidermal tumors using a flexible blade. PMID- 21324030 TI - Full-thickness triangular advancement flap for the closure of lateral upper lip defects. PMID- 21324031 TI - Repair of a medial cheek defect. PMID- 21324032 TI - Immunohistochemical evaluation of skin before and after micro-ablative fractional erbium-doped yttrium aluminum garnet laser treatment. PMID- 21324033 TI - Commentary: Herpes zoster in the distribution of the trigeminal nerve after nonablative fractional photothermolysis of the face. PMID- 21324034 TI - A rare tumor: syringocystadenocarcinoma papilliferum. PMID- 21324035 TI - Margin detection using digital dermatoscopy improves the performance of traditional surgical excision of basal cell carcinomas of the head and neck. PMID- 21324036 TI - Letter: Bleomycin dosage. PMID- 21324038 TI - Letter: A comparison study of the tensile strength of sutures used in dermatologic surgery following exposure to petrolatum. PMID- 21324039 TI - Recommendations for patient status post transcatheter closure in dermatologic and Mohs micrographic surgery. PMID- 21324040 TI - Tangential lighting aids in the identification of biopsy sites. PMID- 21324041 TI - Human cadaveric dermal matrix for management of challenging surgical defects on the scalp. AB - BACKGROUND: Biologic scaffolds have shown promise in patients unable to tolerate prolonged surgical closure or extensive wound care, but there has been little research in the field of Mohs micrographic surgery (MMS) on human cadaveric dermis in this capacity. OBJECTIVE: To evaluate the utility of human cadaveric dermis as a means of decreasing operative time, minimizing postoperative wound care, and improving aesthetic outcomes in selected patients with deep surgical defects, including those with exposed bone. METHODS: Fourteen patients (8 men, 6 women) with deep postoperative defects after MMS were treated with a cadaveric dermal allograft as part or all of their postoperative wound management. RESULTS: Allograft placement was well tolerated, with high satisfaction levels relating to minimal postoperative wound care and aesthetic outcome. Significantly shorter operative times were noted in all patients than with primary closure or grafting. CONCLUSION: In patients with significant comorbidities, inability to tolerate extended surgical repairs, or inability to perform extensive wound care, human cadaveric dermal allografts can decrease operative time and minimize wound care complexity while providing an excellent aesthetic outcome in many cases. Shorter healing times than expected were also noted in a number of patients. The authors have indicated no significant interest with commercial supporters. PMID- 21324042 TI - Hydrocolloid dressings in skin grafting for immobilization and compression. AB - BACKGROUND; Successful skin grafting requires immobilization and compression of the graft site. Traditional dressing methods such as tie-over dressings, cast splints, and elastic bandages are bulky in the joint area and can cause abrasion, maceration, and even circulatory insufficiency. OBJECTIVE: To test the effectiveness of a hydrocolloid dressing, which provides a moist wound environment, is flexible and elastic, and adheres well to skin, for securing skin grafts. MATERIALS & METHODS: A case-controlled retrospective study was conducted of 62 patients treated with skin grafts at Myongji Hospital between February 2007 and September 2009. Patients were treated with additive hydrocolloid dressing (n=31) or bolster dressing and splinting (n=31). RESULTS Treatment duration for the hydrocolloid group was significantly less than for the bolster dressing and splinting group (mean +/- standard deviation 8.32 +/- 1.82 days vs 13.55 +/- 5.30 days, p<.001). No significant differences were observed between the groups with regard to age, sex, or graft size. The hydrocolloid group included one case with complication (stitch abscess), whereas the bolster and splinting group included eight cases with complications of partial skin loss. CONCLUSIONS: Additive hydrocolloid dressing is a stable, effective method of securing skin grafts and is associated with better graft survival as measured by shorter treatment time and lower complication rate. The authors have indicated no significant interest with commercial supporters. PMID- 21324043 TI - Comparison of two surgical methods (Winograd and sleeve method) in the treatment of ingrown toenail. AB - BACKGROUND: Ingrowing toenail is one of the most common nail complaints. Although many surgical treatments are described for complicated nails, frequent recurrence of pain and postoperative disability necessitate finding an appropriate treatment. METHODS: In a clinical trial, we compared the Winograd and sleeve (gutter) surgical methods to find a simple, painless, and practical alternative. RESULTS: Of 100 patients (mean 27.8) included in the study, 50 underwent Winograd surgery and the rest the sleeve method. Postoperative infection occurred in four (8%) patients in the sleeve and three (6%) in the Winograd group. The condition reoccurred in five (10%) patients who underwent sleeve surgery and six (12%) who underwent Winograd. Recurrence rate was higher in female patients, although the difference was not statistically significant. Mean surgery duration for Winograd and sleeve methods was 15.7 minutes and 9.4 minutes, respectively, and postoperative work day loss was 2.0 weeks and 1.1 weeks, respectively. CONCLUSION: The sleeve method seems to be more practical and appropriate for patients planning to go back to work sooner and better fulfills the main characteristics for the primary treatment of choice. The authors have indicated no significant interest with commercial supporters. PMID- 21324044 TI - In-transit Merkel cell carcinoma treated with isolated limb perfusion or isolated limb infusion: a case series of 12 patients. AB - BACKGROUND: In-transit metastases of Merkel cell carcinoma (MCC) are an unusual and therapeutically challenging manifestation of the disease. Given the similarity to melanoma, in-transit MCC may be amenable to isolated regional therapy. OBJECTIVE: To present a case series of 12 patients who underwent isolated limb perfusion (ILP) or isolated limb infusion (ILI) for in-transit MCC. METHODS: A literature search was conducted using Medline and Pubmed databases for MCC, ILP, and ILI as key words. Ten cases were identified and reviewed; two cases from our hospital were also included in the series. RESULTS: Nine patients underwent ILP, and three were treated with ILI. Eleven patients had a complete clinical response, and one had a partial response. All patients avoided limb amputation. Mean follow-up was 25.3 months. Mean duration of response was 21.8 months. Four patients relapsed regionally. Two patients developed distant metastases and died of their disease. CONCLUSION: This is the largest case series of in-transit MCC treated with ILP or ILI. Both techniques appear to be a low morbidity alternative to amputation for the treatment of isolated extremity in transit MCC. ILI is less invasive than ILP and may be a more practical first-line treatment option. The authors have indicated no significant interest with commercial supporters. PMID- 21324045 TI - Feasibility and efficacy of placement of continuous sciatic perineural catheters solely under ultrasound guidance in children: a descriptive study. AB - BACKGROUND: Placement of sciatic catheters with ultrasound and stimulating catheters is known. Literature regarding catheter placements with only ultrasound is limited. We aimed to investigate the feasibility of performing continuous sciatic nerve block exclusively with ultrasound guidance and minimal equipment. METHOD: Forty ASA 1 and 2 patients aged 8 months-10 years posted for congenital talipoequinovarus surgery were included in the study. Continuous sciatic catheters were placed under ultrasound guidance with 18- gauge Tuohy needle at the infragluteal fold. Then, 0.25% of bupivacaine 0.5 ml.kg(-1) bolus was injected followed by continuous infusion later. Half the volume of the drug was injected prior to catheter insertion to improve visibility. The sciatic nerve, needle tip and shaft, catheter tip and the drug spread were visualized. The efficacy of the block intraoperatively and postoperatively was evaluated. RESULTS: The sciatic nerve, needle shaft, and tip were well visualized in all 40 patients. The catheter tip was seen in 72.5% of patients. The effect of block was complete intraoperatively and postoperatively. Clinically significant complications were absent. CONCLUSION: We conclude that in children, continuous sciatic catheters can be accurately and efficaciously placed with minimal equipment with ultrasound alone. PMID- 21324046 TI - Defining awakening from anesthesia in neonates: a consensus study. AB - BACKGROUND: A descriptive tool for determining awakening in infants is desirable to test the value of depth of anesthesia monitors. Although scales and criteria have been developed for children and infants, none has been applied to the study of anesthetised neonates. We aimed to seek consensus in a group of experts on a definition of awakening at the end of anesthesia in neonates. METHODS: We used a modified Delphi technique with an iterative process of questionnaires and anonymised feedback. Communication was conducted by email. Thirty-one consultant pediatric anesthetists in the UK and Ireland took part. Consensus was defined a priori as 80% agreement. RESULTS: The 83% of respondents agreed that defining awakening is possible. Consensus was reached on six criteria and also that a combination of these criteria must be used. As crying and attempting to cry are similar, we propose that at least two of the following five behaviors are present to consider a neonate awake after anesthesia: (i) crying or attempting to cry, (ii) vigorous limb movements, (iii) gagging on a tracheal tube, (iv) eyes open, and (v) looking around. There was also consensus that three stimuli are appropriate to test rousability in neonates awakening from anesthesia: (i) removal of skin adhesive tape, (ii) stroking/tickling the skin or gentle shaking, and (iii) pharyngeal suction. CONCLUSIONS: We propose a scale for determining awakening from anesthesia in neonates that may be used in future studies, particularly regarding electroencephalographic data and depth of anesthesia monitoring in neonates. PMID- 21324047 TI - Defining awakening from anesthesia in infants: a narrative review of published descriptions and scales of behavior. AB - OBJECTIVES: A descriptive tool or validated scale of consciousness is desirable in infants to test the value of any depth of anesthesia monitor. METHODS: We have reviewed published descriptions and scales of observed behavior that may be applicable to the study of infants during the transition from anesthesia to wakefulness. RESULTS: Potentially useful scales were found that had been developed for the assessment and study of natural sleep, neurological state, arousal, anesthesia, sedation, coma, and pain. Scales or criteria of behavior had been developed for anesthetised children, but there were no agreed definitions or criteria specifically for anesthetised infants or neonates. CONCLUSION: Criteria for awakening of infants from anesthesia need to be developed and agreed. PMID- 21324048 TI - Interventional radiology of pleural diseases. AB - Image-guided pleural procedures are important in both the diagnosis and management of pleural disease. Pleural aspiration, biopsy and drainage are all proven to be safer and more efficacious using image guidance. The aim of this article is to review common image-guided pleural techniques and the evidence base for their application in clinical practice. PMID- 21324050 TI - The role of small intestinal bacterial overgrowth in postgastrectomy patients. AB - BACKGROUND: Small intestinal bacterial overgrowth (SIBO) is expected in postgastrectomy patients; however, its role has not been clarified. This study was to estimate the prevalence of SIBO and investigate the clinical role of SIBO in postgastrectomy patients. METHODS: This prospective study involved 76 patients who underwent gastrectomy for early gastric cancer with no evidence of recurrence. An H(2)-CH(4) breath test with oral glucose challenge test was performed to diagnose SIBO and dumping syndrome. Sigstad dumping questionnaires, serum glucose, hematocrit and pulse rate were simultaneously monitored for every 30 min for 3 hours. KEY RESULTS: There were significant differences in SIBO between the postgastrectomy patients and controls (77.6%vs 6.7%, P < 0.01). Abdominal fullness or borborygmus during oral glucose load were more common in SIBO-positive than in negative patients (50.8%vs 17.6%, P = 0.03), and were the independent factors for predicting SIBO in postgastrectomy patients (P = 0.02). The prevalences of dumping syndrome and hypoglycemia after oral glucose were 35 (46.1%) and 19 (25.0%), and were not different between both groups. However, the plasma glucose was significantly lower in SIBO-positive than in SIBO-negative patients at 120 and 150 min after oral glucose load (P < 0.05). No significant differences were observed in pulse rate and hematocrit in both groups. CONCLUSIONS & INFERENCES: SIBO is common among postgastrectomy patients. It appears to be associated with postprandial intestinal symptoms and might aggravate late hypoglycemia. SIBO could be a new therapeutic target for managing intestinal symptoms in postgastrectomy patients. PMID- 21324051 TI - Can piperonyl butoxide enhance the efficacy of pyrethroids against pyrethroid resistant Aedes aegypti? AB - BACKGROUND: Pyrethroid resistance can be considered the main threat to the continued control of many mosquito vectors of disease. Piperonyl butoxide (PBO) has been used as a synergist to help increase the efficacy of certain insecticides. This enhancement stems from its ability to inhibit two major metabolic enzyme systems, P450s and non-specific esterases, and to enhance cuticular penetration of the insecticide. OBJECTIVE: To compare the mortality of a characterized resistant Aedes aegypti strain, Nha Trang, from Vietnam and the susceptible laboratory strain Bora Bora on netting with the pyrethroid deltamethrin (DM) alone and in combination with PBO. METHODS: Resistance mechanisms were characterized using molecular and bioassay techniques; standard PCR was used to test for the kdr target site mutation. Potential genes conferring metabolic resistance to DM were identified with microarray analysis using the Ae. aegypti 'detox chip'. These data were analysed alongside results from WHO susceptibility tests. P450, CYP9J32, was significantly overexpressed in the DM resistant strain compared with the susceptible Bora Bora strain. Another five genes involved with oxidative stress responses in mosquitoes were also significantly overexpressed. The Nha Trang strain was homozygous for two kdr mutations. WHO cone bioassays were used to investigate mortality with incorporated DM-treated nets with and without PBO. PBO used in combination with DM resulted in higher mortality than DM alone. CONCLUSION: Synergists may have an important role to play in the future design of vector control products in an era when alternatives to pyrethroids are scarce. PMID- 21324052 TI - Assessing the effect of different ultrasonic frequencies on bacterial viability using flow cytometry. AB - AIMS: This research investigated the effect of sonication at frequencies of 20, 40 and 580 kHz and approximately the same acoustic intensity on the viability and declumping of two micro-organisms (Escherichia coli and Klebsiella pneumonia). METHODS AND RESULTS: Two analytical methods were employed; viable plate counts (CFU ml-1) and flow cytometry to identify and quantify both live/viable and dead bacteria in the bulk liquid. Flow cytometry results for E. coli and Kl. pneumonia indicated a high sensitivity to 20 and 40 kHz frequency with a continuous decrease in the viable cells and an increase in dead cells during experiments. In contrast, results using the higher frequency of 580 kHz indicate predominantly deagglomeration of bacterial clumps rather than cell membrane disruption (Joyce et al. 2003). Results indicate a good correlation between flow cytometry and viable plate count methodology. CONCLUSIONS: Sonication has two different effects on bacteria (i) inactivation and (ii) declumping; however, the scale of these effects is dependent on intensity and frequency. Flow cytometry provides a method to distinguish between and quantify the effects through the observation of two subpopulations: (i) live/viable and (ii) dead bacterial cells. SIGNIFICANCE AND IMPACT OF THE STUDY: Treatment using power ultrasound has been shown to have a significant impact on microbial activity. This is the first time a study has compared the influence of a range of different frequencies, but at similar power settings on the survival of bacteria in phosphate buffer saline (PBS). This work is of importance for applications where ultrasound has been considered for use in industry as a means of disinfection including the treatment and pretreatment of water and also for the sterilization of liquid foods. PMID- 21324053 TI - Medium pH, carbon and nitrogen concentrations modulate the phosphate solubilization efficiency of Penicillium purpurogenum through organic acid production. AB - AIMS: To study phosphate solubilization in Penicillium purpurogenum as function of medium pH, and carbon and nitrogen concentrations. METHODS AND RESULTS: Tricalcium phosphate (CP) solubilization efficiency of P. purpurogenum was evaluated at acid or alkaline pH using different C and N sources. Glucose- and (NH(4) )(2) SO(4) -based media showed the highest P solubilization values followed by fructose. P. purpurogenum solubilizing ability was higher in cultures grown at pH 6.5 than cultures at pH 8.5. Organic acids were detected in both alkaline and neutral media, but the relative percentages of each organic acid differed. Highest P release coincided with the highest organic acids production peak, especially gluconic acid. When P. purpurogenum grew in alkaline media, the nature and concentration of organic acids changed at different N and C concentrations. A factorial categorical experimental design showed that the highest P-solubilizing activity, coinciding with the highest organic acid production, corresponded to the highest C concentration and lowest N concentration. CONCLUSIONS: The results described in the present study show that medium pH and carbon and nitrogen concentrations modulate the P solubilization efficiency of P. purpurogenum through the production of organic acids and particularly that of gluconic acid. In the P solubilization optimization studies, glucose and (NH(4) )(2) SO(4) as C and N sources allowed a higher solubilization efficiency at high pH. SIGNIFICANCE AND IMPACT OF THE STUDY: This organism is a potentially proficient soil inoculant, especially in P-poor alkaline soils where other P solubilizers fail to release soluble P. Further work is necessary to elucidate whether these results can be extrapolated to natural soil ecosystems, where different pH values are present. Penicillium purpurogenum could be used to develop a bioprocess for the manufacture of phosphatic fertilizer with phosphate calcium minerals. PMID- 21324054 TI - Can the impact of public involvement on research be evaluated? A mixed methods study. AB - BACKGROUND: Public involvement is central to health and social research policies, yet few systematic evaluations of its impact have been carried out, raising questions about the feasibility of evaluating the impact of public involvement. OBJECTIVE: To investigate whether it is feasible to evaluate the impact of public involvement on health and social research. METHODS: Mixed methods including a two-round Delphi study with pre-specified 80% consensus criterion, with follow-up interviews. UK and international panellists came from different settings, including universities, health and social care institutions and charitable organizations. They comprised researchers, members of the public, research managers, commissioners and policy makers, self-selected as having knowledge and/or experience of public involvement in health and/or social research; 124 completed both rounds of the Delphi process. A purposive sample of 14 panellists was interviewed. RESULTS: Consensus was reached that it is feasible to evaluate the impact of public involvement on 5 of 16 impact issues: identifying and prioritizing research topics, disseminating research findings and on key stakeholders. Qualitative analysis revealed the complexities of evaluating a process that is subjective and socially constructed. While many panellists believed that it is morally right to involve the public in research, they also considered that it is appropriate to evaluate the impact of public involvement. CONCLUSIONS: This study found consensus among panellists that it is feasible to evaluate the impact of public involvement on some research processes, outcomes and on key stakeholders. The value of public involvement and the importance of evaluating its impact were endorsed. PMID- 21324055 TI - Endophthalmitis as primary clinical manifestation of fatal fusariosis in an allogeneic stem cell recipient. AB - The occurrence of infections due to previously rare opportunistic pathogens is increasing despite the use of novel treatment strategies for immunocompromised patients. Here, we report the case of a patient presenting with fever, muscle pain, and bilateral endophthalmitis after allogeneic hematopoietic stem cell transplantation. Fusarium solani was isolated from peripheral blood samples and identified as the cause of gradual bilateral vision loss, despite appropriate antifungal prophylaxis, and therapy including vitrectomy and intraocular instillation of antifungal agents. The patient became comatose; basal meningitis involving both optic nerves was suspected based on magnetic resonance tomography. The patient died 8 days later due to septic multi-organ failure. Autopsy revealed that both kidneys, but no other organs, were infiltrated by Fusarium. No fungus was found in cerebral tissues or cerebrospinal fluid. Our case demonstrates some of the typical clinical features of systemic fusariosis and its potentially fatal outcome. The clinical observations reported here may help clinicians caring for immunocompromised patients to accelerate diagnosis and initiate treatment early at the onset of this fatal complication, and highlight the urgent need for interdisciplinary management of invasive fusariosis. PMID- 21324056 TI - Recombinant heptameric coatomer complexes: novel tools to study isoform-specific functions. AB - COPI (coat protein I)-coated vesicles are implicated in various transport steps within the early secretory pathway. The major structural component of the COPI coat is the heptameric complex coatomer (CM). Recently, four isoforms of CM were discovered that may help explain various transport steps in which the complex has been reported to be involved. Biochemical studies of COPI vesicles currently use CM purified from animal tissue or cultured cells, a mixture of the isoforms, impeding functional and structural studies of individual complexes. Here we report the cloning into single baculoviruses of all CM subunits including their isoforms and their combination for expression of heptameric CM isoforms in insect cells. We show that all four isoforms of recombinant CM are fully functional in an in vitro COPI vesicle biogenesis assay. These novel tools enable functional and structural studies on CM isoforms and their subcomplexes and allow studying mutants of CM. PMID- 21324057 TI - Residual vein obstruction as a predictor for recurrent thromboembolic events after a first unprovoked episode: data from the REVERSE cohort study. AB - OBJECTIVES: There is growing interest in using residual vein obstruction (RVO) to guide the duration of oral anticoagulant therapy (OAT) for unprovoked deep vein thrombosis (DVT). We sought to determine if RVO as determined by compression ultrasonography (CUS) after completion of 5-7 months of anticoagulation for unprovoked DVT is associated with an increased risk of recurrent venous thromboembolism (VTE). MATERIALS AND METHODS: This was a multicentre multinational prospective cohort study undertaken in tertiary care centers. Patients with a first 'unprovoked' major VTE were enrolled over a 4-year period and completed a mean 18-month follow-up in September 2006. All 452 patients with DVT had baseline CUS at inclusion to assess any RVO before stopping OAT at 5-7 months. During follow-up off OAT, all episodes of suspected recurrent VTE were independently adjudicated with reference to baseline imaging. RESULTS: Forty-five out of 231 patients with abnormal CUS (19.5%) had recurrent VTE during follow-up, as compared with 32 out of 220 patients with normal CUS (14.6%), and one patient had inadequate CUS. There was no significant association between an abnormal CUS at inclusion and the risk of recurrent VTE: hazard ratio 1.4 (95% confidence interval, 0.9-2.1), P=0.19. None of the different degrees of clot resolution on baseline CUS was statistically significantly associated with the risk of recurrent VTE. CONCLUSION: In our study, the presence of RVO at the time of OAT withdrawal was not associated with a statistically significant higher risk of recurrent VTE. RVO assessment may not be useful to guide duration of anticoagulation. PMID- 21324058 TI - Efficacy and safety of anticoagulants in the prevention of venous thromboembolism in patients with acute cerebral hemorrhage: a meta-analysis of controlled studies. AB - AIM: The role of anticoagulants for the prevention of venous thromboembolism in acute hemorrhagic stroke is uncertain. We performed an updated meta-analysis of studies to obtain the best estimates of the efficacy and safety of anticoagulants for the prevention of venous thromboembolism in patients with acute hemorrhagic stroke. METHODS: Using electronic and manual searches of the literature, we identified randomized and non-randomized studies comparing anticoagulants (unfractionated heparin or low-molecular-weight heparin or heparinoids) with treatments other than anticoagulants (elastic stockings, intermittent pneumatic compression or placebo) in patients with acute hemorrhagic stroke. Study outcomes included symptomatic and asymptomatic deep venous thrombosis (DVT), symptomatic and asymptomatic pulmonary embolism (PE), any hematoma enlargement or death. Risk ratios (RRs) for individual outcomes were calculated for each study and data from all studies were pooled using the Mantel-Haenszel method. RESULTS: Four studies (two randomized) involving 1000 patients with acute hemorrhagic stroke met the criteria for inclusion in this meta-analysis. Compared with other treatments, anticoagulants were associated with a significant reduction in PE (1.7% vs. 2.9%; RR, 0.37; 95% CI, 0.17-0.80; P = 0.01), a DVT rate of 4.2% compared with 3.3% (RR, 0.77; 95% CI, 0.44-1.34; P = 0.36), an increase in any hematoma enlargement (8.0% vs. 4.0%; RR, 1.42; 95% CI, 0.57-3.53; P = 0.45), and a non-significant reduction in mortality (16.1% vs. 20.9%; RR, 0.76; 95% CI, 0.57-1.03; P = 0.07). CONCLUSIONS: Our findings indicate that in patients with hemorrhagic stroke, early anticoagulation is associated with a significant reduction in PE and a non significant reduction in mortality, with the trade-off of a non-significant increase in hematoma enlargement. These results must be taken with caution and should encourage the assessment of the clinical benefit of antithrombotic prophylaxis in patients with cerebral bleeding by properly designed clinical trials. PMID- 21324059 TI - Persistently raised plasma levels of platelet-derived inflammatory mediators in HIV-infected patients during highly active anti-retroviral therapy. PMID- 21324060 TI - Expressing acid-sensing ion channel 3 in the brain alters acid-evoked currents and impairs fear conditioning. AB - Previous studies on mice with a disruption of the gene encoding acid-sensing ion channel 1a (ASIC1a) suggest that ASIC1a is required for normal fear behavior. To investigate the effects of altering the subunit composition of brain ASICs on behavior, we developed transgenic mice expressing ASIC3 via the pan-neuronal synapsin I promoter. These mice express ASIC3 in the brain, where the endogenous ASIC3 protein is not detected. We found that in ASIC3 transgenic mice, ASIC3 co immunoprecipitated with the endogenous ASIC1a protein and distributed in the same subcellular brain fractions as ASIC1a. In addition, ASIC3 significantly increased the rate of desensitization of acid-evoked currents in cultured cortical neurons. Importantly, ASIC3 reduced Pavlovian fear conditioning to both context and auditory cues. These observations suggest that ASIC3 can heteromultimerize with ASIC1a in the brain and alter the biophysical properties of the endogenous channel complex. Moreover, these data suggest that ASIC subunit composition and channel desensitization may be critical determinants for ASIC-dependent behavior. PMID- 21324061 TI - Transcriptional characteristics of Xa21-mediated defense responses in rice. AB - Bacterial blight, caused by Xanthomonas oryzae pv. oryzae (Xoo), is the most destructive bacterial disease of rice. The cloned rice gene Xa21 confers resistance to a broad spectrum of Xoo races. To identify genes involved in Xa21 mediated immunity, a whole-genome oligonucleotide microarray of rice was used to profile the expression of rice genes between incompatible interactions and mock treatments at 0, 4, 8, 24, 72 and 120 h post inoculation (hpi) or between incompatible and compatible interactions at 4 hpi, respectively. A total of 441 differentially expressed genes, designated as XDGs (Xa21 mediated differentially expressed genes), were identified. Based on their functional annotations, the XDGs were assigned to 14 categories, including defense-related, signaling, transcriptional regulators. Most of the defense-related genes belonged to the pathogenesis-related gene family, which was induced dramatically at 72 and 120 hpi. Interestingly, most signaling and transcriptional regulator genes were downregulated at 4 and 8 hpi, suggesting that negative regulation of cellular signaling may play a role in the Xa21-mediated defense response. Comparison of expression profiles between Xa21- and other R gene-mediated defense systems revealed interesting common responses. Representative XDGs with supporting evidences were also discussed. PMID- 21324062 TI - Abstracts of the 27th Annual Scientific Meeting of the Australasian College for Emergency Medicine. November 21-25, 2010. Canberra, ACT, Australia. PMID- 21324063 TI - Building the bond between teachers and learners. PMID- 21324064 TI - Feasibility of a focused ultrasound training programme for medical undergraduate students. AB - BACKGROUND: Although ultrasound is a core skill for many clinical specialties, UK medical schools are not currently required to teach this skill. The College of Emergency Medicine (CEM) has championed the use of ultrasound to answer focused clinical questions in emergency settings. We have designed and piloted an ultrasound training course for undergraduate medical students addressing one important indication: ultrasound assessment of the abdominal aorta. METHODS: Fourteen clinical students, who had no prior experience of using ultrasound, received focused ultrasound training in the form of didactic instruction, a short bedside practical workshop and self-directed learning over a 20-day period. At the end of this period, the students were assessed by a structured viva and an observed structured clinical examination (OSCE) used for accreditation by the CEM. The primary endpoint was the number of students who passed the assessment. The secondary endpoint was the accuracy of the students' anatomical measurements. RESULTS: Thirteen of the 14 (93%) students completed the training and assessment. Eight of the 13 (62%) students passed both the viva and OSCE, and were deemed to have achieved the CEM standard. The measurements by the competent students were not statistically different from those of experienced practitioners. DISCUSSION: We have shown for the first time that it is feasible to train inexperienced undergraduate students to scan the abdominal aorta to a professional standard using a focused training course. It is time for the medical education community to address whether focused ultrasound training should accompany traditional clinical skills, such as using a stethoscope, in UK medical school curricula. PMID- 21324065 TI - Teaching clinical examination using peer-assisted learning amongst graduate-entry students. AB - BACKGROUND: We ran a peer-assisted learning programme for teaching clinical examination amongst graduate-entry medical students. We had three objectives: (1) to provide a forum for using peer-assisted learning to deliver the medical schools' clinical examination curriculum using the techniques of deliberate practice; (2) to obtain feedback on the programme using the nominal group technique; (3) to use the feedback to provide a means of improving the programme in subsequent years. METHODS: The syllabus was based on the medical school's first year curriculum for clinical examination, and was drawn-up by one of the faculty members. The peer tutors were given a large degree of autonomy to run the programme as they thought best. At the end of the programme we used the nominal group technique to generate feedback. RESULTS: Final-year graduate-entry students are capable of organising a high-quality peer-assisted learning programme to teach clinical examination based on the medical school's curriculum. DISCUSSION: The nominal group technique provided an excellent method of generating structured feedback from the peer tutees, which required minimal resources and only a few hours of input from a neutral facilitator. The feedback session generated 14 specific suggestions for improving the programme in future years. These suggestions will be passed on to the peer tutors for next year, and in this way the feedback cycle is engrained in the programme. PMID- 21324066 TI - Clinical reasoning sessions: back to the patient. AB - BACKGROUND: Problem-based learning (PBL) was developed as a facilitated small group learning process based around a clinical problem. Originally designed for pre-clinical years of medical education, its application across all years poses a number of difficulties, including the risk of reducing patient contact, providing a learning process that is skewed towards an understanding of pathophysiological processes, which may not be well understood in all areas of medicine, and failing to provide exposure to clinically relevant reasoning skills. CONTEXT: Curriculum review identified dissatisfaction with PBLs in the clinical years of the Sydney Medical School's Graduate Medical Program, from both staff and students. A new model was designed and implemented in the Psychiatry and Addiction Medicine rotation, and is currently being evaluated. INNOVATION: We describe an innovative model of small-group, student-generated, case-based learning in psychiatry - clinical reasoning sessions (CRS) - led by expert facilitators. IMPLICATIONS: The CRS format returns the student to the patient, emphasises clinical assessment skills and considers treatment in the real-world context of the patient. Students practise a more sophisticated reasoning process with real patients modelled upon that of their expert tutor. This has increased student engagement compared with the previous PBL programme. PMID- 21324067 TI - Ward rounds: missed learning opportunities in diagnostic changes? AB - BACKGROUND: The introduction of the European Working Time Directive has resulted in the on-call general surgery junior doctor regularly missing consultant-led post-take ward rounds (PTWRs). This study aimed to determine the frequency with which the admission diagnosis was changed on the PTWR, and thus whether an educational opportunity for trainees is missed. METHODS: Prospective observational study of consecutive admissions to a general surgery department over a 4-week period was conducted. Patients with exacerbations of known conditions were excluded. RESULTS: Fifty-two included patients were admitted by seven general surgery juniors, and 27 per cent (14/52) of diagnoses were changed on the PTWR. There were two 'major' diagnostic changes: peritonitis and ischaemic bowel. Patients whose diagnoses were changed by the consultant were no more likely to be older (p = 0.575) or have differing white cell counts (p = 0.471), C reactive proteins (CRPs; p = 0.643) or amylase levels (p = 0.666) than those whose initial diagnosis was agreed with. Thirty-five per cent of patients (18/52) had further investigations ordered at the PTWR. These included nine ultrasound scans, four computed tomography scans, three abdominal or chest X-rays, two flexible sigmoidoscopies and one barium enema. In one case, a serum amylase was ordered. CONCLUSIONS: The rate of incorrect diagnoses by on-call surgical juniors is high, and educational feedback to these doctors is important. The PTWR represents a strong educational opportunity that is missed if admitting junior doctors are not present. These results should be taken into account for any specialty that uses junior doctors to admit patients who are then reviewed by a consultant on a PTWR. PMID- 21324068 TI - What is clinical leadership...and why is it important? AB - BACKGROUND: The 'invitation' for clinicians to participate in leadership practices, previously considered the province of the professional health service manager, is driven by a number of international policy and professional agendas. This article, the first in a short series, considers definitions and theories of clinical leadership and management, and explores leadership roles and responsibilities of the clinician in terms of levels of engagement. Recent developments in the UK's National Health Service (NHS), the largest health care organisation in the world, are used as illustrations of how theory has informed clinical leadership development. METHODS: Narrative review and discussion. RESULTS: The tensions arising from the situation of health care professionals within managed health care are described. Leadership is defined alongside its relationship to management. Key theories of leadership are considered and applications of theory to practice explored. The role and usefulness of the 'competency framework' in leadership development is debated. DISCUSSION: Health care is delivered by complex systems often involving large numbers of individuals and organisations. The effective clinician needs to understand these pathways and systems of care if they are to be able to function effectively, and must be comfortable working both within, and with, these systems for the benefit of their patients. Engaging in leading and managing systems of health care, on whatever scale - team, department, unit, hospital or health authority - is therefore a professional obligation of all clinicians. Just as leadership is argued to be necessary 'at all levels', so 'leadership development', assessment and feedback must be provided throughout the education and training of health professionals. PMID- 21324069 TI - ECLIPPx: an innovative model for reflective portfolios in life-long learning. AB - BACKGROUND: For healthcare professionals, the educational portfolio is the most widely used component of lifelong learning - a vital aspect of modern medical practice. When used effectively, portfolios provide evidence of continuous learning and promote reflective practice. But traditional portfolio models are in danger of becoming outmoded, in the face of changing expectations of healthcare provider competences today. CONTEXT: Portfolios in health care have generally focused on competencies in clinical skills. However, many other domains of professional development, such as professionalism and leadership skills, are increasingly important for doctors and health care professionals, and must be addressed in amassing evidence for training and revalidation. There is a need for modern health care learning portfolios to reflect this sea change. INNOVATION: A new model for categorising the health care portfolios of professionals is proposed. The ECLIPPx model is based on personal practice, and divides the evidence of ongoing professional learning into four categories: educational development; clinical practice; leadership, innovation and professionalism; and personal experience. IMPLICATIONS: The ECLIPPx model offers a new approach for personal reflection and longitudinal learning, one that gives flexibility to the user whilst simultaneously encompassing the many relatively new areas of competence and expertise that are now required of a modern doctor. PMID- 21324070 TI - Online role-playing for faculty development. AB - BACKGROUND: There has been a rapid growth of online teaching in the past few years, yet the implementation of role-play for formal educational activities in an online setting is growing more slowly. The use of online role-playing for the development of health professions educators is virtually un-documented in the literature. INNOVATION: In the project reported here we use role-playing as a method to motivate and increase active participation in an online web-based discussion on community-based medical education (CBME). The Foundation for Advancement of International Medical Education & Research (FAIMER((r)) ) Institute hosts virtual group discussions for fellows as part of its fellowship programmes, in order to deepen their knowledge base in health professions education and research. In June 2008, a group of seven FAIMER((r)) fellows and faculty members moderated an online discussion on CBME using an online role-play exercise with other fellows and faculty members. RESULTS: Out of a total of 102 fellows, 36 (35.3%) participated actively, which exceeded the typical percentage of list server participation. In addition, a rich discussion resulted in a comprehensive report on the goals, challenges, logistical components, role of Health Ministry policy and the possible ethical mandate of CBME in developing countries. CONCLUSION: Online role-play encouraged distributed participation among a highly diverse international group of participants, supporting the conclusion that role-playing can be used effectively with mid-career health professional faculty members in the online environment. PMID- 21324071 TI - Model construction by students within an integrated medical curriculum. AB - BACKGROUND: This paper presents our experience of running a special study module (SSM) in the second semester of the first year of our 5-year medical programme, worth 10 per cent of that semester's assessment, in which each student constructs an individually selected model illustrating a specific aspect of the teaching course. METHOD: Each student conceptualises and develops his or her model, to clarify a specific aspect of medical teaching. The use of non-traditional materials in construction is strongly encouraged. Six weeks later, each student presents their model for assessment by four first-year academic teaching staff. The student is quizzed about the concepts that he or she presents, the mode of construction and the materials used. RESULTS: The students' projects broadly cover the disciplines of physiology, biochemistry and anatomy, but are somewhat biased towards anatomy. Students spend on average about 14 hours planning and building their models, at a time when they are busy with other teaching activities. The marks awarded for the projects closely follow a normal distribution. A survey suggests that most students enjoy the exercise and feel that it has enhanced their learning and understanding. DISCUSSION: It is clear from the wide variety of different topics, models and materials that students are highly resourceful in their modelling. Creative activity does not generally play a substantial part in medical education, but is of considerable importance. The development of their models stimulates, informs and educates the constructors, and provides a teaching resource for later use in didactic teaching. PMID- 21324072 TI - Resource utilisation patterns of third-year medical students. AB - BACKGROUND: In spite of published learning objectives for generally accepted clinical competencies, little evidence-based data exist regarding how clerkship students achieve them. We queried how clerkship students' learning resource use correlates with clerkship outcomes. However, little evidence-based data exist regarding how to accomplish these goals. We queried how clerkship students' learning resource use correlates with clerkship outcomes. METHODS: We surveyed 130 students at the end of their in-patient internal medicine clerkship. Questionnaires investigated resource utilisation, study methods and knowledge acquisition goals, using 1-5 Likert scale (1 = never; 5 = always). RESULTS: Most students used UpToDate to prepare for attending physician rounds and to admit patients (64 and 67%, respectively), but not for exam preparation. Using question books for exam preparation was associated with a significant improvement in scores (77 versus 72%, p < 0.01). DISCUSSION: Students' resource utilisation varies by clinical situation and knowledge acquisition goals. Students using question books had better examination performances. PMID- 21324073 TI - Airway management and vascular access simulation during a medical student rotation. AB - BACKGROUND: Medical students electing to spend a month in anaesthesiology during their third or fourth year often experience airway management and vascular access for the first time on an actual patient. An airway management and vascular access simulation course for medical students was developed and implemented at our institution. The purpose of this study was to assess the subjective comfort level after implementing this teaching tool in medical students. METHODS: A brief didactic course on airway management and vascular access was provided to medical students on the first day of their anaesthesiology rotation. A survey was presented to the students immediately after a focused 1-hour lecture and prior to a simulation session. The pre-simulation survey was comprised of eight questions asking the medical students to rate their level of comfort with both types of procedures. The lecture was followed by a 1-hour simulation course on manikins. The medical students were asked to complete a post-simulation survey, which was comprised of the same initial eight questions. RESULTS: After participating in the didactic course and manikin simulation, the self-perceived comfort level of medical students with airway management (p < 0.0005), vascular access (p < 0.0005) and interpretation of the vascular pressure waveforms (p < 0.0005) demonstrated significant improvement. DISCUSSION: The results of this study suggest that providing medical students with a brief didactic session on airway and vascular access, including simulation on manikins, prior to the start of their encounter with actual surgical patients, can improve their comfort level in performing both procedures. PMID- 21324074 TI - Travelling educational workshops for clinical teachers: are they worthwhile? AB - BACKGROUND: The support of doctors who teach medical students in clinical settings is considered very important. In order to function as effectively as possible in their role as clinical teachers, these clinicians require educational support from faculty members. The most usual form that support takes is university staff offering face-to-face teaching on educational topics. CONTEXT: It is estimated that in the course of 1 year, and across the Faculty of Medicine at the University of Otago, there could be up to 600 clinicians actively involved in the direct support of medical students. Many of these clinicians work in locations some considerable distance from the university campus. INNOVATION: In 2009 the Medical Education Unit based at the Wellington Campus introduced a series of peripatetic face-to-face workshops for clinical teachers in several different geographical locations. Educational support of this nature is challenging to organise and potentially expensive, which begs the question: are travelling workshops worthwhile? IMPLICATIONS: Whereas the subject matter of the workshops was of interest to those who attended, of equal importance was the opportunity the workshops created to interact with colleagues in a relaxed atmosphere. In addition, the workshops were the catalyst for some clinicians to formally pursue their particular educational interests. PMID- 21324075 TI - A potential addition to continuing professional development points. PMID- 21324076 TI - Developing 'The World of Medicines' in a Nepalese medical school. PMID- 21324077 TI - Universal health care - a right for all? PMID- 21324085 TI - Art imitating life. PMID- 21324086 TI - Conventional vs. extended-cycle oral contraceptives on the quality of sexual life: comparison between two regimens containing 3 mg drospirenone and 20 ug ethinyl estradiol. AB - INTRODUCTION: Women may use new oral contraceptives (OC) having flexible extended cycle regimens with a reduced hormone-free interval. AIM: To study the changes of the quality of sexual life in users of the traditional 21/7 or extended-cycle 24/4 OC regimens both containing 3 mg drospirenone and 20 ug ethinyl estradiol. METHODS: One hundred fifteen women (age range 18-37 years) were enrolled. Fifty four women were randomly placed on traditional OC standard regimen, administered for 21 days, followed by a 7-day hormone-free interval (group A); and 61 women were placed on extended-cycle OC regimen covering 24 days of the cycle with a 4 day hormone-free interval (group B). The Short Form-36 (SF-36) validate questionnaire to assess quality of life (QoL) and the Short Personal Experience Questionnaire (SPEQ) to measure the changes of sexual behavior were administered before starting OC intake and at the 3rd and 6th cycle follow-ups. MAIN OUTCOME MEASURE: The SF-36 and the SPEQ questionnaires. RESULTS: Group A women reported QoL improvement during the 6th cycle on all the scales (P < 0.05). Group B women reported QoL improvement during the 3rd and 6th cycle (P < 0.05). Satisfaction with sexual activity, arousal, orgasm, and desire increased during the 3rd cycle in women on the group B (P < 0.05). Group A women did not report any change in all SPEQ items. At the 6th cycle, group B women reported better sexual experience than baseline in all SPEQ items (P < 0.05). All subjects who were affected by dyspareunia before OC intake reported decreased genital pain associated with intercourse at the 3rd and 6th cycle of both OC regimens (P < 0.05). CONCLUSION: Women could use OCs in a subjective flexible modality. The extended-cycle OC might produce positive effects on the quality of sexual life, enforcing the concept of tailoring an OC to a woman. PMID- 21324087 TI - Sexual functioning in male survivors of lymphoma: a systematic review (CME). AB - INTRODUCTION: The lymphomas (Hodgkin's lymphoma [HL] and non-Hodgkin's lymphoma [NHL]) are among the most common cancers affecting men under 45 years. Survival rates are now excellent, but treatment is associated with a number of side effects including sexual dysfunction with potential implications for compromised quality of life (QoL). AIMS: To address the (i) prevalence of sexual dysfunction among lymphoma survivors relative to the general population, survivors of other cancers, and in survivors of HL and NHL; and (ii) relationships between sexual functioning and disease and treatment, demographic, and psychological variables. METHODS: Inclusion criteria were quantitative studies that focused on adult male survivors of lymphoma and included a comparison group and presented results separately for HL and NHL. Standardized systematic searches were used. Information about design, sample size, age, time since diagnosis, type of treatment, comparison group, measures, and findings were extracted from eligible studies. RESULTS: Ten articles met the inclusion criteria, of which, nine included patients with HL only, and one included patients with HL or NHL. Sexual function was compromised relative to the general population, better than testicular cancer survivors, and worse than leukemia survivors. Depression was consistently associated with sexual dysfunction. There was evidence that chemotherapy, relapse, reduced testosterone levels, older age at survey, and worse physical QoL were associated with worse sexual function. CONCLUSIONS: Conclusions are limited by methodological issues including lack of utilization of standardized measures of sexual function and longitudinal research. Even so, there is evidence of sexual dysfunction among lymphoma survivors. Clinicians need to be sensitive to these issues. Future longitudinal work is necessary to determine the likelihood of recovery. PMID- 21324088 TI - Idiosyncratic heart rate response in men during sexual arousal. AB - INTRODUCTION: Heart rate, sensitive to sympathetic activation, is known to change during sexual arousal and therefore may be a useful tool for investigating psychosomatic differences between sexually functional and dysfunctional men. However, heart rate during arousal also tends to be highly variable across individual men, making its predictability based on group patterns relatively poor. AIM: We wanted to determine whether individual men show idiosyncratic heart rate patterns during sexual arousal, that is, whether they exhibit consistent patterns across similar (though not identical) stimulus situations. MAIN OUTCOME MEASURE: Agreement between heart rates under the two conditions, visual sexual stimulation (VSS) and VSS + vibrotactile (VIB), was assessed using the concordance correlation coefficient (CCC). METHODS: Thirty-eight men, 25 of whom were diagnosed with premature ejaculation (PE), were monitored for penile response and heart rate under two similar (though not identical) conditions: a 9 minute erotic video (VSS), then a 9-minute erotic video combined with vibrotactile penile stimulation (VSS + VIB). RESULTS: CCC for men with PE was 0.65; for the sexually functional comparison group, CCC was 0.82. For both groups combined, CCC was 0.71. For all groupings, the CCC was relatively high, indicating agreement in heart rate from one session to the next within individual men. CONCLUSIONS: Despite high intersubject variation in heart rate patterns, individual men show signature heart rates across similar sexual stimulus sessions. Such stereotypy helps explain previous inconsistent findings and may also serve as a marker for the effectiveness of treatments designed to improve ejaculatory control in men with PE. PMID- 21324089 TI - The role of genital nerve afferents in the physiology of the sexual response and pelvic floor function. AB - INTRODUCTION: Our understanding of genital and pelvic floor physiology is rapidly expanding. Penile erection is a neurovascular event controlled by spinal autonomic centers, the activity of which is dependent on input from supraspinal centers and the genitalia. Genital afferent stimulation excites spinal autonomic nuclei and supraspinal sexual centers of both genders. AIM: To present a detailed understanding of the functional importance of genital afferent neuroanatomy and neurophysiology. METHODS: English-written articles of diverse disciplines from 1980 to 2010 that contained information on genital anatomy, pudendal/dorsal/perineal/cavernous nerves, vibratory stimulation, reflexogenic erection, peripheral/central nervous system-mediated erectile and micturition pathways, and sexual arousal in animals and humans were reviewed. MAIN OUTCOME MEASURES: Analysis of supporting evidence for the role of genital afferents in the physiology of erectile response and pelvic floor function. RESULTS: Basic science and clinical studies support the concept that pudendal nerve circuitry serves an essential purpose for sexual behavior, erectile function, penile rigidity, ejaculation, and micturition. Males and females share a comparable pattern of genital afferent neuroanatomy and neurophysiology, and sexual and micturition reflexes are similar in both genders. Pudendal nerve branches communicate with the cavernous nerves and are nitric oxide synthase positive. Genital afferents activate multiple spinal reflexes that modulate erection and micturition. Genital sensory information is transmitted to supraspinal centers important for sexual function. CONCLUSIONS: There is expanding support for the critical role of genital afferent neurophysiology in the mechanisms of erectile function and micturition. Genital afferent stimulation is a safe and natural modality that can be harnessed to amplify autonomic and somatic activity within the penis, female genitalia, spinal cord, and higher centers via established neurological principles. Such physiological adaptive processes may be beneficial in improving sexual response, erectile function, and micturition in many disease states, including in men after radical pelvic surgery. Well-designed and executed studies in each specific population are needed to authenticate such prospects. PMID- 21324090 TI - A feasibility study comparing pharmacist and physician recommendations for sildenafil treatment. AB - INTRODUCTION: In Europe, pharmacists may be an important first point of contact for men with erectile dysfunction (ED) asking for advice and treatment. AIM: To determine if European community pharmacists could appropriately recommend suitability for supply of sildenafil 50 mg for the treatment of ED. METHODS: For this cross-sectional, observational study, the current Summary of Product Characteristics was adapted to create a study drug information sheet for use in a pharmacy setting in which, for certain patients, supply is not suitable and referral to a physician is recommended. After training and with use of a guidance questionnaire, pharmacists assessed the suitability of supply of sildenafil 50 mg for men presenting to their pharmacy. Men with self-reported ED who were not currently using a phosphodiesterase type 5 inhibitor were recruited. Within 7 days of the pharmacist-patient interaction, a physician with experience in the management of ED telephoned the subject to assess suitability. If there was discordance between the pharmacist and physician recommendations, the case was independently reassessed by a physician specialist in sexual medicine. MAIN OUTCOME MEASURES: The primary end point was the concordance rate (with 95% confidence intervals) between pharmacist and physician recommendations. Rates were weighted by country sample sizes. RESULTS: Concordance (95% confidence interval) was 0.70 (0.66-0.74) between pharmacist and physician recommendation, indicating agreement in 70% of cases, and was 0.90 (0.86-0.94) between pharmacist and physician specialist in sexual medicine. Furthermore, if the cases in which the pharmacist did not put subjects at risk (i.e., gave an acceptable recommendation) are assessed, the success rate is 83.5% (79.6-87.4%) and 92.8% (90.1-95.5%), respectively. CONCLUSION: Pharmacists were accurate in providing suitable treatment recommendation, generally not recommending sildenafil for men without ED and recommending physician assessment when there was any question about cardiovascular health, other comorbidity, or co-medication. PMID- 21324092 TI - International Index of Erectile Function (IIEF) scores generated by men or female partners correlate equally well with own satisfaction (sexual, partnership, life, and mental health). AB - INTRODUCTION: Erectile dysfunction has adverse implications for both men and their female partners. The International Index of Erectile Function (IIEF) is a widely used self-report measure. It was unclear whether scores generated by women on behalf of men are comparable to self-reports, and how IIEF scores are associated with satisfaction for both sexes in both sexual and nonsexual realms (e.g., mental health). AIMS: To examine sex differences in IIEF-5 scores generated by both sexes, and to examine associations of IIEF-5 scores with satisfaction aspects (sexual, life, own mental health, partnership) and with women's vaginal orgasm consistency (VOC). METHODS: A representative sample of Czechs (787 men and 720 women not from the same couple) aged 35-65 years completed the IIEF-5, LiSat satisfaction scale items, and provided penile-vaginal intercourse (PVI) frequency, and for women, VOC. MAIN OUTCOME MEASURES: Correlations between satisfaction measures and IIEF-5 scores separately by sex. To examine sex differences: t-test for IIEF-5 score and tests for difference of a correlation for associations of IIEF-5 with satisfaction measures. Analysis of covariance examined the association of IIEF-5 scores and VOC. Multiple regression calculated satisfaction scores from IIEF-5, PVI frequency, age, and for women: VOC. RESULTS: IIEF-5 scores generated by men and by women were similar, and similarly positively correlated with all satisfaction measures (r: 0.41-0.45 with sexual, 0.23-0.34 with other; all P < 0.001). IIEF-5 correlated positively with VOC. Multivariate analyses indicated IIEF-5 scores; PVI frequency (and for women, VOC) make independent contributions to aspects of satisfaction for both sexes. CONCLUSIONS: In this representative sample, women generated IIEF-5 scores similar to men-generated scores. For both sexes, greater IIEF-5 scores and PVI frequency (plus VOC for women) are associated with greater sexual and nonsexual satisfaction. Better erectile function was associated with greater VOC. Greater support for optimizing specifically PVI function, frequency, and quality is warranted. PMID- 21324091 TI - Patients' desire to preserve sexual activity and final decision for a nerve sparing approach: results from the MIRROR (Multicenter Italian Report on Radical Prostatectomy Outcomes and Research) Study. AB - INTRODUCTION: Preservation of sexual function after surgery represents a major issue for patients undergoing radical prostatectomy (RP). AIM: To investigate determinants of patients' desire to preserve sexual activity before RP and surgeons' final decision to perform a nerve-sparing RP (NSRP). METHODS: Overall, 2,408 prostate cancer patients, candidates to RP, from 136 urologic departments across the Italian territory were evaluated in a multicenter prospective observational study. All patients underwent RP, according to single center indications and procedures. MAIN OUTCOME MEASURES: Age, body mass index, previous benign prostatic hyperplasia history, preoperative tumor characteristics, quality of life through the Short Form Health Survey (SF-12), and the University of California Los Angeles Prostate Cancer Index (UCLA-PCI), erectile function through the International Index of Erectile Function (IIEF-5), desire to preserve sexual activity, NS operative outcomes, and surgical margins status were recorded. RESULTS: Overall, 1,667 were interested to preserve sexual activity. Age, physical component summary of SF12 (PCS-12), sexual function score of UCLA-PCI, and IIEF-5 score were the main determinants of such interest. Only 1,246 patients were suitable for a NSRP according to guidelines. Surgeons performed a non-NSRP (NNSRP) in 1,234 patients, a unilateral NSRP in 318 and a bilateral NSRP in 856. Age, bioptical Gleason score, percentage of positive cores, PCS-12, and patient's desire to preserve sexual activity were the main determinants of final decision for a NSRP. Surgeons performed a NSRP in 424 not suitable and in 121 not interested patients. Positive surgical margins in not suitable patients submitted to NSRP were not higher if compared to that obtained after NNSRP in the same subgroup. Limits include lack of oncological and functional follow-up. CONCLUSIONS: Most patients are interested to preserve sexual activity. Discrepancies exist among patients' preferences, guidelines' indications, and surgeon's final decision. PMID- 21324093 TI - Randomized comparison between laparoscopic and robot-assisted nerve-sparing radical prostatectomy. AB - INTRODUCTION: Lack of randomized controlled trials (RCTs) that compare pure laparoscopic radical prostatectomy (LRP) with robot-assisted laparoscopic radical prostatectomy (RALRP) is an important gap of the literature related to the surgical treatment of the clinically localized prostate cancer (PCa). AIM: To provide the first prospective randomized comparison on the functional and oncological outcomes of LRP and RALRP for the treatment of the clinically localized PCa. METHODS: Between 2007 and 2008, 128 consecutive male patients were randomized in two groups and treated by a single experienced surgeon with traditional LRP (Group I-64 patients) or RALRP (Group II-64 patients) in all cases with intent of bilateral intrafascial nerve sparing. MAIN OUTCOME MEASURES: Primary end point was to compare the 12 months erectile function (EF) outcomes. Complication rates, continence outcomes, and oncological results were also compared. The sample size of our study was able, with an adequate power (1-beta > 0.90), to recognize as significant large differences (above 0.30) between incidence proportions of considered outcomes. RESULTS: No statistically significant differences were observed for operating time, estimated blood loss, transfusion rate, complications, rates of positive surgical margins, rates of biochemical recurrence, continence, and time to continence. However, the 12-month evaluation of capability for intercourse (with or without phosphodiesterase type 5 inhibitors) showed a clear and significant advantage of RALRP (32% vs. 77%, P < 0.0001). Time to capability for intercourse was significantly shorter for RALRP. Rates of return to baseline International Index of Erectile Function (IIEF-6) EF domain score questionnaires (questions 1-5 and 15) (25% vs. 58%) and to IIEF-6 > 17 (38% vs. 63%) were also significantly higher for RALRP (P = 0.0002 and P = 0.008, respectively). CONCLUSIONS: Our study offers the first high-level evidence that RALRP provides significantly better EF recovery than LRP without hindering the oncologic radicality of the procedure. Larger RCTs are needed to confirm if a new gold-standard treatment in the field of RP has risen. PMID- 21324094 TI - Gepirone-ER treatment of hypoactive sexual desire disorder (HSDD) associated with depression in women. AB - INTRODUCTION: There is currently no Food and Drug Administration (FDA)-approved treatment for hypoactive sexual desire disorder (HSDD). FDA approval of products utilizing testosterone has been delayed due to possible safety concerns. Flibanserin, a 5-HT(1A) agonist, 5-HT(2) antagonist, and gepirone-ER, a 5-HT(1A) agonist, have been shown to have activity in treatment of HSDD. However, more recently, the FDA issued a non-approval letter for flibanserin. AIM: To study the effect of gepirone-ER on HSDD in women with major depressive disorder (MDD). METHODS: At baseline and post-treatment visits, a trained psychiatrist made diagnoses of HSDD based on Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) criteria. Subjects meeting criteria for HSDD were followed to observe the effect of gepirone-ER (20-80 mg/day), comparator antidepressants (fluoxetine, 20-40 mg/day or paroxetine, 10-40 mg/day), or placebo in reversing DSM-IV diagnosis. A subpopulation of women with Hamilton Depression Rating Scale (HAMD-17) entry scores of 18 or less was evaluated. Adverse events (AEs) of sexual dysfunction were also collected. MAIN OUTCOME MEASURE: Number (%) of patients who no longer met criteria for HSDD (percent resolved). RESULTS: Eight hundred seventy-five women (18-64 years of age, average 38 years old, ~80% premenopausal) entered three studies; 668 (72.5%) completed. Only 161 (18.4%) met DSM-IV criteria for HSDD. Cumulatively, 63% of gepirone-ER treated patients reversed their diagnosis of HSDD compared to 40% of placebo treated patients at end point (8 weeks) (P = 0.007). Selective serotonin reuptake inhibitor-treated patients were not different from placebo. Significant results for gepirone-ER occurred by week 2 (P = 0.0001). Patients who were mildly depressed (HAMD scores of 18 or less) also improved at week 2 (P = 0.01) and week 8 (P = 0.07). Sexual dysfunction AEs were significantly less in gepirone-ER treated patients than placebo (P = 0.013). CONCLUSIONS: Gepirone-ER may have efficacy in the treatment of HSDD among depressed and possibly nondepressed women. Efficacy occurs by week 2, and does not seem to be purely an antidepressant effect. PMID- 21324095 TI - The role of PDE5 inhibitors in penile septal scar remodeling: assessment of clinical and radiological outcomes. AB - INTRODUCTION: Effective oral medication for use in men with Peyronie's disease (PD) has been an area of interest of the medical community and lay public for decades. Isolated septal scars (ISS) without evidence of penile deformity is a relatively new clinical entity, and at present, there is paucity in the published literature regarding its treatment. Current research into the use of phosphodiesterase type 5 (PDE5) inhibitors in regulating penile erectile response has revealed an alternative role for PDE5 inhibitors in decreasing oxidative stress-associated inflammatory change as seen in PD. AIM: To examine the presence of ISS and assess the efficacy of PDE5 inhibitor use in septal scar remodeling. METHODS: Retrospective review of prospective database on all men who underwent penile Doppler ultrasound between December 2007 and December 2009. MAIN OUTCOME MEASURES: Of the 65 men with ultrasonographic-confirmed ISS, 35 men received tadalafil 2.5 mg daily over a 6-month period. The clinical outcomes between the two groups were compared using International Index of Erectile Function (IIEF)-5 score and 6 months penile Doppler ultrasound follow up. RESULTS: The mean age for the tadalafil group was 43.2 (20-65) years, similar to the control group at 44.2 (34-72) years. The length of time from onset to presentation was 22 (6 to 40) months. The majority of ultrasonographic-proven ISS was not clinically palpable and complaint of decreased penile rigidity (66%) was the predominant feature. Treatment with low-dose daily tadalafil did not result in any significant side effects (such as headache and flushing) or discontinuation. The tadalafil group reported higher IIEF-5 score (pretreatment 11/25 to post-treatment 18/25) (P < 0.01) and resolution of septal scar were recorded in 24 patients (69%) compared to three patients (10%) in the control group. CONCLUSION: Low-dose daily tadalafil is a safe and effective treatment option in septal scar remodeling. PMID- 21324096 TI - Update on corpus cavernosum smooth muscle contractile pathways in erectile function: a role for testosterone? AB - INTRODUCTION: Normal erectile function (EF) involves a coordinated relaxation of the arteries that supply the penis and the corpus cavernosum smooth muscle (CCSM), resulting in expansion of the sinusoids and increased intracavernous pressure. But the CCSM spends the majority of its time in the contracted state which is mediated by norepinephrine released from nerve endings and other vasoconstrictors like endothelins released from the endothelium. These agents cause smooth muscle myosin (SMM) phosphorylation by elevating intracellular calcium. When calcium returns to basal levels, the calcium sensitivity increases and prevents myosin dephosphorylation, which involves the RhoA/Rho-kinase (ROK) mechanism, thus maintaining force. Although mounting evidences demonstrate that androgens have a major influence on EF that is not just centrally mediated, this notion remains quite controversial. AIM: To summarize the current knowledge on CCSM contractile pathways, the role they play in modulating EF, and the influence of androgens. METHODS: The article reviews the literature and contains some previously unpublished data on CCSM contraction signaling including the role that androgens are known to play in modulating these pathways. MAIN OUTCOME MEASURES: Data from peer-reviewed publications and previously unpublished observations. RESULTS: In addition to downregulation of many pro-erectile molecular mechanisms, decreased testosterone (T) levels upregulate CCSM contractility, including hyperresponsiveness to alpha-adrenergic agonists, increased SMM phosphorylation, alteration of SMM isoform composition, activation of RhoA/ROK signaling and modulation of sphingosine-1-phosphate regulation of CCSM tone. CONCLUSIONS: Decreased T levels upregulate CCSM contractile signaling. Meanwhile, it downregulates CCSM relaxation pathways synergizing to produce erectile dysfunction (ED). Although some urologists and researchers are still skeptical of the influence of androgens on penile erection, understanding these molecular control mechanisms as well as the influence that androgens have on these pathways should provide new evidence supporting the roles of androgens in EF and enhance the discovery of novel targets for drug development to treat ED. PMID- 21324097 TI - Allelic polymorphism of human FcgammaRIIA-H/R131 receptor in American tegumentary leishmaniasis. AB - FcgammaRIIA binding to IgG subclasses with different levels of affinity is influenced by the polymorphism in the gene that encodes this receptor. The substitution of arginine (R) for histidine (H) in the 131 position defines three allelic patterns, H/H, R/R, and H/R, resulting in FcgammaRIIA-H/H131 affinity for IgG2 and higher affinity for IgG3 subclasses. Studies have shown the importance of genetic host factors in leishmaniasis and participation of FcgammaRs on the macrophage infection by amastigote forms and in the immune response to Leishmania sp. We analysed the influence of allelic diversity patterns of the receptor FcgammaRIIA on American tegumentary leishmaniasis (ATL). FcgammaRIIA-H/R131 polymorphism was determined by PCR followed by an allele-specific enzymatic digestion in 88 individuals with ATL and 98 healthy volunteer blood donors (control group). The genotypic and allelic distributions of FcgammaRIIA-H/R131 were similar among the studied groups as well in mild and severe clinical forms of ATL. Our results suggest no association between this allelic polymorphism and susceptibility or resistance to ATL, neither influencing the development of different clinical forms of this illness. PMID- 21324098 TI - Participation in pulmonary rehabilitation in routine clinical practice. AB - BACKGROUND AND AIMS: Denmark offers COPD rehabilitation to enable patients to tackle the consequences of COPD, but only a minority of the patients complete these programs. To increase the completion rate, an follow-up study was performed, to characterize COPD patients and to identify potential differences between those who complete and those who do not complete rehabilitation or do not even get a rehabilitation offer in daily clinical routine. METHODS: In- and out COPD-patients who participated in baseline tests were compared in terms of completion of rehabilitation, drop-out, and no rehabilitation offer. We obtained data on basic characteristics, co-morbidity, lung-function (FEV1), dyspnea (MRC), six-minute walkg-distance (6MWD), and quality of life (SF36). RESULTS: The source population counted 521 COPD patients of whom 256 were excluded (diagnosis withdrawn, death, moved away, long-term oxygen, severe illness). Patients who completed rehabilitation had a 15% longer 6MWD than patients not offered rehabilitation and a 10% longer 6MWD than drop-outs despite a significant lower subjective perception of physical function among completers than in the two other groups. Patients not offered rehabilitation had a slightly better lung function than the other two groups. This suggests that lower physical performance with the same (drop-outs) or even higher (not offered) lung function indicates a lower chance of completion. CONCLUSION: COPD patients who could potentially benefit most from completing rehabilitation seem to be deselected. A mere 9% completed rehabilitation within the study period and 23% ever completed. This demonstrates that the political target that 60% of COPD patients should be offered rehabilitation is still far away. PMID- 21324099 TI - Change for good. PMID- 21324100 TI - BRAF mutations in cutaneous melanoma are independently associated with age, anatomic site of the primary tumor, and the degree of solar elastosis at the primary tumor site. AB - Oncogenic BRAF mutations are more frequent in cutaneous melanoma occurring at sites with little or moderate sun-induced damage than at sites with severe cumulative solar ultraviolet (UV) damage. We studied cutaneous melanomas from geographic regions with different levels of ambient UV radiation to delineate the relative effects of cumulative UV damage, age, and anatomic site on the frequency of BRAF mutations. We show that BRAF-mutated melanomas occur in a younger age group on skin without marked solar elastosis and less frequently affect the head and neck area, compared to melanomas without BRAF mutations. The findings indicate that BRAF-mutated melanomas arise early in life at low cumulative UV doses, whereas melanomas without BRAF mutations require accumulation of high UV doses over time. The effect of anatomic site on the mutation spectrum further suggests regional differences among cutaneous melanocytes. PMID- 21324101 TI - Koebner's phenomenon in vitiligo: European position paper. AB - Koebner's phenomenon (KP) has been observed in a number of skin diseases, including vitiligo. Its clinical significance in vitiligo with respect to disease activity and course is still debatable, while its relevance for surgical techniques has been demonstrated in some reports. We present a literature review on the currently known facts about KP in vitiligo, including details of clinical, experimental, and histopathological changes. The consensus view is that there are still no methods to define and assess KP in vitiligo. A new classification is proposed to allow an evaluation of KP in daily practice or in experimental studies. However, many unanswered questions still remain after redefining KP in patients with vitiligo. Active research focusing on KP in vitiligo may not only provide unexpected clues in the pathogenesis of vitiligo but also help to tailor novel therapies against this chronic and often psychologically devastating skin disease. PMID- 21324102 TI - A zebrafish model for nevus regeneration. PMID- 21324104 TI - The first Finnish malariologist, Johan Haartman, and the discussion about malaria in 18th century Turku, Finland. AB - After the Great Northern War in 1721, Sweden ceased to be an important military power. Instead, the kingdom concentrated on developing science. Swedish research got international fame with names as Carolus Linnaeus, Pehr Wargentin and Anders Celsius. Medical research remained limited and malaria was common especially in the coastal area and along the shores of the big lakes.Already in the beginning of the 18th century Swedish physicians recommended Peruvian bark as medication and they also emphasized that bleeding or blood-letting a malaria patient was harmful. Although malaria was a common disease in the kingdom, the situation was worst in the SW-part of Finland which consisted of the town of Turku and a large archipelago in the Baltic. The farmers had no opportunity to get modern healthcare until Johan Haartman was appointed district physician in 1754. To improve the situation he wrote a medical handbook intended for both the farmers and for persons of rank. Haartman's work was first published 1759 and he discussed all the different cures and medications. His aim was to recommend the best ones and warn against the harmful. His first choice was Peruvian bark, but he knew that the farmers could not afford it. Haartman was appointed professor in medicine at the Royal Academy of Turku in 1765. The malaria situation in Finland grew worse in the 1770's and Haartman analysed the situation. He found the connection between the warm summers and the spring epidemics next year.In a later thesis, Haartman analysed the late summer/early autumn malaria epidemics in the archipelago. Althouh Haartman did not know the connection between malaria and the vector, he gave astute advice and encouraged the farmers to build their cottages in windy places away from the shallow bays in which the Anopheles females hatched. Haartman died in 1788. After his death malaria research in Turku declined. His medical handbook would not be replaced until 1844. PMID- 21324105 TI - Family and home correlates of children's physical activity in a multi-ethnic population: the cross-sectional Child Heart and Health Study in England (CHASE). AB - BACKGROUND: The influence of the family and home environment on childhood physical activity (PA) and whether this differs between ethnic groups remains uncertain. This paper investigates associations between family and home factors and childhood PA in a multi-ethnic population and explores whether associations differ between ethnic groups. METHODS: Cross-sectional study of 9-10 year-old schoolchildren, in which PA was objectively measured by Actigraph GT1 M accelerometers for <=7 days to estimate average activity counts per minute (CPM). Information on 11 family and home environmental factors were collected from questionnaires. Associations between these factors and CPM were quantified using multi-level linear regression. Interactions with ethnicity were explored using likelihood ratio tests. RESULTS: 2071 children (mean +/- SD age: 9.95 +/- 0.38 years; 47.8% male) participated, including 25% white European, 28% black African Caribbean, 24% South Asian, and 24% other ethnic origin. Family PA support and having a pet were associated with higher average CPM (adjusted mean difference: 6 (95%CI:1,10) and 13 (95%CI:3,23), respectively) while car ownership and having internet access at home were associated with lower average CPM (adjusted mean difference: -19 (95%CI:-30,-8) and -10 (95%CI:-19,0), respectively). These associations did not differ by ethnicity. Although the number of siblings showed no overall association with PA, there was some evidence of interaction with ethnicity (p for ethnicity interaction=0.04, 0.05 in a fully-adjusted model); a positive significant association with number of siblings was observed in white Europeans (per sibling CPM difference 10.3 (95% CI 1.7, 18.9)) and a positive non significant association was observed in black African-Caribbeans (per sibling CPM difference: 3.5 (-4.2, 11.2)) while a negative, non-significant association was observed in South Asians (per sibling CPM difference -6.0 (-15.5, 3.4)). CONCLUSIONS: Some family and home environmental factors have modest associations with childhood PA and these are mostly similar across different ethnic groups. This suggests that targeting these factors in an intervention to promote PA would be relevant for children in different ethnic groups. PMID- 21324106 TI - Evaluating the impact of decentralising tuberculosis microscopy services to rural township hospitals in Gansu Province, China. AB - BACKGROUND: In 2004, the Ministry of Health issued the policy of decentralising microscopy services (MCs) to one third of all township hospitals in China. The study was conducted in Gansu Province, a poor western one in China. Ganzhou was one county in Gansu Province. Ganzhou County was identified as a unique case of further decentralisation of tuberculosis (TB) treatment services in township hospitals. The study evaluated the impact of the MC policy on providers and patients in Gansu Province. The second objective was to assess the unique case of Ganzhou County compared with other counties in the province. METHODS: Both quantitative and qualitative methods were used. All 523 MCs in the province completed an institutional survey regarding their performance. Four counties were selected for in-depth investigation, where 169 TB suspects were randomly selected from the MC and county TB dispensary registers for questionnaire surveys. Informant interviews were conducted with 38 health staff at the township and county levels in the four counties. RESULTS: Gansu established MCs in 39% of its township hospitals. From January 2006 to June 2007, 8% of MCs identified more than 10 TB sputum smear positive patients while 54% did not find any. MCs identified 1546 TB sputum smear positive patients, accounting for 9% of the total in the province. The throughputs of MCs in Ganzhou County were eight times of those in other counties. Interviews identified several barriers to implement the MC policy, such as inadequate health financing, low laboratory capacity, lack of human resources, poor treatment and management capacities, and lack of supervisions from county TB dispensaries. CONCLUSION: Microscopy centre throughputs were generally low in Gansu Province, and the contribution of MCs to TB case detection was insignificant taking account the number of MCs established. As a unique case of full decentralisation of TB service, Ganzhou County presented better results. However, standards and quality of TB care needed to be improved. The MC policy needs to be reviewed in light of evidence from this study. PMID- 21324103 TI - Animal contact as a source of human non-typhoidal salmonellosis. AB - Non-typhoidal Salmonella represents an important human and animal pathogen world wide. Most human salmonellosis cases are foodborne, but each year infections are also acquired through direct or indirect animal contact in homes, veterinary clinics, zoological gardens, farm environments or other public, professional or private settings. Clinically affected animals may exhibit a higher prevalence of shedding than apparently healthy animals, but both can shed Salmonella over long periods of time. In addition, environmental contamination and indirect transmission through contaminated food and water may complicate control efforts. The public health risk varies by animal species, age group, husbandry practice and health status, and certain human subpopulations are at a heightened risk of infection due to biological or behavioral risk factors. Some serotypes such as Salmonella Dublin are adapted to individual host species, while others, for instance Salmonella Typhimurium, readily infect a broad range of host species, but the potential implications for human health are currently unclear. Basic hygiene practices and the implementation of scientifically based management strategies can efficiently mitigate the risks associated with animal contacts. However, the general public is frequently unaware of the specific disease risks involved, and high-risk behaviors are common. Here we describe the epidemiology and serotype distribution of Salmonella in a variety of host species. In addition, we review our current understanding of the public health risks associated with different types of contacts between humans and animals in public, professional or private settings, and, where appropriate, discuss potential risk mitigation strategies. PMID- 21324107 TI - Tracing the legacy of the early Hainan Islanders--a perspective from mitochondrial DNA. AB - BACKGROUND: Hainan Island is located around the conjunction of East Asia and Southeast Asia, and during the Last Glacial Maximum (LGM) was connected with the mainland. This provided an opportunity for the colonization of Hainan Island by modern human in the Upper Pleistocene. Whether the ancient dispersal left any footprints in the contemporary gene pool of Hainan islanders is debatable. RESULTS: We collected samples from 285 Li individuals and analyzed mitochondrial DNA (mtDNA) variations of hypervariable sequence I and II (HVS-I and II), as well as partial coding regions. By incorporating previously reported data, the phylogeny of Hainan islanders was reconstructed. We found that Hainan islanders showed a close relationship with the populations in mainland southern China, especially from Guangxi. Haplotype sharing analyses suggested that the recent gene flow from the mainland might play important roles in shaping the maternal pool of Hainan islanders. More importantly, haplogroups M12, M7e, and M7c1* might represent the genetic relics of the ancient population that populated this region; thus, 14 representative complete mtDNA genomes were further sequenced. CONCLUSIONS: The detailed phylogeographic analyses of haplogroups M12, M7e, and M7c1* indicated that the early peopling of Hainan Island by modern human could be traced back to the early Holocene and/or even the late Upper Pleistocene, around 7-27 kya. These results correspond to both Y-chromosome and archaeological studies. PMID- 21324108 TI - Modulation of transforming growth factor beta signalling pathway genes by transforming growth factor beta in human osteoarthritic chondrocytes: involvement of Sp1 in both early and late response cells to transforming growth factor beta. AB - INTRODUCTION: Transforming growth factor beta (TGFbeta) plays a central role in morphogenesis, growth, and cell differentiation. This cytokine is particularly important in cartilage where it regulates cell proliferation and extracellular matrix synthesis. While the action of TGFbeta on chondrocyte metabolism has been extensively catalogued, the modulation of specific genes that function as mediators of TGFbeta signalling is poorly defined. In the current study, elements of the Smad component of the TGFbeta intracellular signalling system and TGFbeta receptors were characterised in human chondrocytes upon TGFbeta1 treatment. METHODS: Human articular chondrocytes were incubated with TGFbeta1. Then, mRNA and protein levels of TGFbeta receptors and Smads were analysed by RT-PCR and western blot analysis. The role of specific protein 1 (Sp1) was investigated by gain and loss of function (inhibitor, siRNA, expression vector). RESULTS: We showed that TGFbeta1 regulates mRNA levels of its own receptors, and of Smad3 and Smad7. It modulates TGFbeta receptors post-transcriptionally by affecting their mRNA stability, but does not change the Smad-3 and Smad-7 mRNA half-life span, suggesting a potential transcriptional effect on these genes. Moreover, the transcriptional factor Sp1, which is downregulated by TGFbeta1, is involved in the repression of both TGFbeta receptors but not in the modulation of Smad3 and Smad7. Interestingly, Sp1 ectopic expression permitted also to maintain a similar expression pattern to early response to TGFbeta at 24 hours of treatment. It restored the induction of Sox9 and COL2A1 and blocked the late response (repression of aggrecan, induction of COL1A1 and COL10A1). CONCLUSIONS: These data help to better understand the negative feedback loop in the TGFbeta signalling system, and enlighten an interesting role of Sp1 to regulate TGFbeta response. PMID- 21324109 TI - Management of aplastic anemia in a woman during pregnancy: a case report. AB - INTRODUCTION: Aplastic anemia is a rare disease caused by destruction of pluripotent stem cells in bone marrow. During pregnancy it could be life threatening for both mother and child. The only causal therapy for aplastic anemia is bone marrow transplantation, which is contraindicated during pregnancy because of potential embryo toxicity. Treatment options are erythrocytes and platelet transfusions and immunosuppressive therapy. There is, however, no agreement about the optimal supportive care and treatment regime for this disorder during pregnancy. CASE PRESENTATION: A 26-year-old nulliparous Asian woman with an uneventful medical history was admitted to the hospital at 14 weeks' gestation because of excessive vomiting. Routine laboratory tests showed pancytopenia (Hb 3.5 mmol/L, leukocytes 3.5 *109/L, platelets 45 *109L). A bone marrow biopsy confirmed aplastic anemia. Methylprednisolon, cyclosporine A, packed cells and platelet transfusions were initiated. At 33 weeks she developed neutropenia (0.1 *109/L) for which oral colistin and tobramycin were given prophylactically. At 35 weeks labor was induced, during which she developed a fever of 38.2 degrees C. She gave birth spontaneously to a healthy son weighing 2415 grams, who had no signs of pancytopenia. After delivery the blood count of the patient did not recover and did not respond to medication. Eighteen weeks after delivery she died of sepsis complicated by cerebral bleeding and infarction due to severe thrombocytopenia and neutropenia, despite optimal supportive treatment. CONCLUSION: This potential life-threatening disease has a relatively good prognosis for both mother and child after optimal treatment. Transfusion during pregnancy is the first choice treatment with recommended hemoglobin levels of >5.5 mmol/L and platelet counts of >20 *109/L. Cyclosporine A seems a reasonable alternative therapy with a reported success rate in non-pregnant patients of 70% when combined with antithymocyte globuline. Our patient died 18 weeks postpartum from cerebral bleeding and infarction due to severe thrombocytopenia despite intensive supportive treatment, methylprednisolon and cyclosporine A. PMID- 21324110 TI - An unusual case of persistent groin pain after total hip arthroplasty: a case report. AB - INTRODUCTION: Arthroplasty is a well-established routine elective surgical procedure in orthopaedics. To a great extent, diagnosis, treatment and post operative rehabilitation in these patients is standardised. In a busy clinic, surgeons from time to time tend to focus their attention on common causes of joint pain, but it may lead them to overlook sinister but less common pathologies. Here we report a case of a patient with groin pain due to pre operatively undetected pelvic metastases from a pyeloureteral carcinoma who underwent total hip arthroplasty. There are several case reports which deal with primary or secondary tumours which were either discovered at the time of replacement surgery or developed at the site of prosthesis years after total hip or knee replacement. To the best of our knowledge, this is the first case report in which a metastatic cancer was missed pre-operatively and intra-operatively both by the radiologist and by the orthopaedic surgeon and should be reported so that surgeons are reminded to be careful when dealing with seemingly routine cases. CASE PRESENTATION: A 79-year-old Caucasian woman presented to the arthroplasty clinic with groin pain. Initial radiographs showed subtle bilateral abnormalities in the pelvis. Neither the radiologist nor the orthopaedic surgeon recognized it. A diagnosis of osteoarthritis of the hip was established, and she underwent total hip arthroplasty. Despite initial improvement, the patient came back with worsening hip pain three months later. Further radiological examination revealed multiple metastatic lesions throughout the pelvis due to a pyeloureteral carcinoma. CONCLUSIONS: This case report emphasizes the importance of meticulous, unbiased pre-operative assessment of patients and their radiographs, even in so called routine clinical cases. Often subtle radiological changes are classed as normal, especially if they are bilateral. Further radiological imaging should be recommended in all cases where unexplained clinical features or radiological findings are present. PMID- 21324111 TI - Tumor necrosis factor-alpha promotes survival in methotrexate-exposed macrophages by an NF-kappaB-dependent pathway. AB - INTRODUCTION: Methotrexate (MTX) induces macrophage apoptosis in vitro, but there is not much evidence for increased synovial macrophage apoptosis in MTX-treated patients. Macrophage apoptosis is reported, however, during clinical response to anti-tumor necrosis factor-alpha (TNF-alpha) treatments. This implies that TNF alpha promotes macrophage survival and suggests that TNF-alpha may protect against MTX-induced apoptosis. We, therefore, investigated this proposal and the macrophage signaling pathways underlying it. METHODS: Caspase-3 activity, annexin V binding/7-aminoactinomycin D (7-AAD) exclusion and cell-cycle analysis were used to measure steps in apoptosis of primary murine macrophages and cells of the RAW264.7 macrophage cell line that had been exposed to clinically-relevant concentrations of MTX and TNF-alpha. RESULTS: MTX induces apoptosis in primary murine macrophages at concentrations as low as 100 nM in vitro. TNF-alpha, which has a context-dependent ability to increase or to suppress apoptosis, efficiently suppresses MTX-induced macrophage apoptosis. This depends on NF-kappaB signaling, initiated through TNF Receptor Type 1 ligation. Macrophage colony stimulating factor, the primary macrophage survival and differentiation factor, does not activate NF-kappaB or protect macrophages from MTX-induced apoptosis. A weak NF kappaB activator, Receptor Activator of NF-kappaB Ligand (RANKL) is likewise ineffective. Blocking NF-kappaB in TNF-alpha-exposed macrophages allowed pro apoptotic actions of TNF-alpha to dominate, even in the absence of MTX. MTX itself does not promote apoptosis through interference with NF-kappaB signaling. CONCLUSIONS: These findings provide another mechanism by which TNF-alpha sustains macrophage numbers in inflamed tissue and identify a further point of clinical complementarity between MTX and anti-TNF-alpha treatments for rheumatoid arthritis. PMID- 21324112 TI - Effects of polymorphisms in ovine and caprine prion protein alleles on cell-free conversion. AB - In sheep polymorphisms of the prion gene (PRNP) at the codons 136, 154 and 171 strongly influence the susceptibility to scrapie and bovine spongiform encephalopathy (BSE) infections. In goats a number of other gene polymorphisms were found which are suspected to trigger similar effects. However, no strong correlation between polymorphisms and TSE susceptibility in goats has yet been obtained from epidemiological studies and only a low number of experimental challenge data are available at present. We have therefore studied the potential impact of these polymorphisms in vitro by cell-free conversion assays using mouse scrapie strain Me7. Mouse scrapie brain derived PrPSc served as seeds and eleven recombinant single mutation variants of sheep and goat PrPC as conversion targets. With this approach it was possible to assign reduced conversion efficiencies to specific polymorphisms, which are associated to low frequency in scrapie-affected goats or found only in healthy animals. Moreover, we could demonstrate a dominant-negative inhibition of prion polymorphisms associated with high susceptibility by alleles linked to low susceptibility in vitro. PMID- 21324113 TI - The impact of the genotype on the prevalence of classical scrapie at population level. AB - Total number and genotypes of animals in holdings selected for the genotype & cull option in the Compulsory Scrapie Flock Scheme (CSFS) in Great Britain were extracted from the National Scrapie Plan data warehouse. The association between various genotype-related measures and scrapie prevalence infection was tested using zero-inflated negative binomial models with the counts of positive cases as dependent variable, and country, number of flocks in the scheme, flock size, surveillance source and the following genotype-related measurements: the centered log ratios (clr) of the 15 genotypes, of the proportions of the 5 alleles at codons 136, 154 and 171, of the proportions of the 5 NSP types, and two flock susceptibility risk indicators, as explanatory variables. A total of 319341 genotyped animals from 168 holdings were included in the analysis. An increased proportion of the ARR/ARR genotype corresponded to a decrease in the number of scrapie cases. ARR/AHQ, AHQ/VRQ, ARH/VRQ and ARQ/VRQ genotypes, NSP type V, ARH, ARQ, AHQ and VRQ alleles and the low and high-susceptibility risk indicators are all associated with an increase risk in the number of scrapie cases.Regardless the management practices; the increased susceptibility that the non-ARR alleles confer on an individual could be extrapolated at the population level. Increasing prevalence of ARR allele reduces the overall risk of scrapie at population level. At genotype level, the VRQ/VRQ genotype, present a very low frequency in the study population, seems to play a residual effect in the overall risk of scrapie in a flock. PMID- 21324114 TI - PrPSc spreading patterns in the brain of sheep linked to different prion types. AB - Scrapie in sheep and goats has been known for more than 250 years and belongs nowadays to the so-called prion diseases that also include e.g. bovine spongiform encephalopathy in cattle (BSE) and Creutzfeldt-Jakob disease in humans. According to the prion hypothesis, the pathological isoform (PrPSc) of the cellular prion protein (PrPc) comprises the essential, if not exclusive, component of the transmissible agent. Currently, two types of scrapie disease are known--classical and atypical/Nor98 scrapie. In the present study we examine 24 cases of classical and 25 cases of atypical/Nor98 scrapie with the sensitive PET blot method and validate the results with conventional immunohistochemistry. The sequential detection of PrPSc aggregates in the CNS of classical scrapie sheep implies that after neuroinvasion a spread from spinal cord and obex to the cerebellum, diencephalon and frontal cortex via the rostral brainstem takes place. We categorize the spread of PrPSc into four stages: the CNS entry stage, the brainstem stage, the cruciate sulcus stage and finally the basal ganglia stage. Such a sequential development of PrPSc was not detectable upon analysis of the present atypical/Nor98 scrapie cases. PrPSc distribution in one case of atypical/Nor98 scrapie in a presumably early disease phase suggests that the spread of PrPSc aggregates starts in the di- or telencephalon. In addition to the spontaneous generation of PrPSc, an uptake of the infectious agent into the brain, that bypasses the brainstem and starts its accumulation in the thalamus, needs to be taken into consideration for atypical/Nor98 scrapie. PMID- 21324115 TI - Comparative analysis of replication characteristics of BoHV-1 subtypes in bovine respiratory and genital mucosa explants: a phylogenetic enlightenment. AB - In general, members of the Alphaherpesvirinae use the epithelium of the upper respiratory and/or genital tract as a preferential site for primary replication. Bovine herpesvirus type 1 (BoHV-1) may replicate at both sites and cause two major clinical entities designated as infectious bovine rhinotracheitis (IBR) and infectious pustular vulvovaginitis/balanoposthitis (IPV/IPB) in cattle. It has been hypothesized that subtype 1.1 invades preferentially the upper respiratory mucosa whereas subtype 1.2 favors replication at the peripheral genital tract. However, some studies are in contrast with this hypothesis. A thorough study of primary replication at both mucosae could elucidate whether or not different BoHV 1 subtypes show differences in mucosa tropism. We established bovine respiratory and genital organ cultures with emphasis on maintenance of tissue morphology and viability during in vitro culture. In a next step, bovine respiratory and genital mucosa explants of the same animals were inoculated with several BoHV-1 subtypes. A quantitative analysis of viral invasion in the mucosa was performed at 0 h, 24 h, 48 h and 72 h post inoculation (pi) by measuring plaque latitude and penetration depth underneath the basement membrane. All BoHV-1 subtypes exhibited a more profound invasion capacity in respiratory tissue compared to that in genital tissue at 24 h pi. However, at 24 h pi plaque latitude was found to be larger in genital tissue compared to respiratory tissue and this for all subtypes. These similar findings among the different subtypes take the edge off the belief of the existence of specific mucosa tropisms of different BoHV-1 subtypes. PMID- 21324117 TI - Predicting fadeout versus persistence of paratuberculosis in a dairy cattle herd for management and control purposes: a modelling study. AB - Epidemiological models enable to better understand the dynamics of infectious diseases and to assess ex-ante control strategies. For Mycobacterium avium subsp. paratuberculosis (Map), possible transmission routes have been described, but Map spread in a herd and the relative importance of the routes are currently insufficiently understood to prioritize control measures. We aim to predict early after Map introduction in a dairy cattle herd whether infection is likely to fade out or persist, when no control measures are implemented, using a modelling approach. Both vertical transmission and horizontal transmission via the ingestion of colostrum, milk, or faeces present in the contaminated environment were modelled. Calf-to-calf indirect transmission was possible. Six health states were represented: susceptible, transiently infectious, latently infected, subclinically infected, clinically affected, and resistant. The model was partially validated by comparing the simulated prevalence with field data. Housing facilities and contacts between animals were specifically considered for calves and heifers. After the introduction of one infected animal in a naive herd, fadeout occurred in 66% of the runs. When Map persisted, the prevalence of infected animals increased to 88% in 25 years. The two main transmission routes were via the farm's environment and in utero transmission. Calf-to-calf transmission was minor. Fadeout versus Map persistence could be differentiated with the number of clinically affected animals, which was rarely above one when fadeout occurred. Therefore, early detection of affected animals is crucial in preventing Map persistence in dairy herds. PMID- 21324116 TI - Staphylococcus aureus seroproteomes discriminate ruminant isolates causing mild or severe mastitis. AB - Staphylococcus aureus is a major cause of mastitis in ruminants. In ewe mastitis, symptoms range from subclinical to gangrenous mastitis. S. aureus factors or host factors contributing to the different outcomes are not completely elucidated. In this study, experimental mastitis was induced on primiparous ewes using two S. aureus strains, isolated from gangrenous (strain O11) or subclinical (strain O46) mastitis. Strains induced drastically distinct clinical symptoms when tested in ewe and mice experimental mastitis. Notably, they reproduced mild (O46) or severe (O11) mastitis in ewes. Ewe sera were used to identify staphylococcal immunoreactive proteins commonly or differentially produced during infections of variable severity and to define core and accessory seroproteomes. Such SERological Proteome Analysis (SERPA) allowed the identification of 89 immunoreactive proteins, of which only 52 (58.4%) were previously identified as immunogenic proteins in other staphylococcal infections. Among the 89 proteins identified, 74 appear to constitute the core seroproteome. Among the 15 remaining proteins defining the accessory seroproteome, 12 were specific for strain O11, 3 were specific for O46. Distribution of one protein specific for each mastitis severity was investigated in ten other strains isolated from subclinical or clinical mastitis. We report here for the first time the identification of staphylococcal immunogenic proteins common or specific to S. aureus strains responsible for mild or severe mastitis. These findings open avenues in S. aureus mastitis studies as some of these proteins, expressed in vivo, are likely to account for the success of S. aureus as a pathogen of the ruminant mammary gland. PMID- 21324118 TI - Treatment of atrial fibrillation with a dual defibrillator in heart failure patients (TRADE HF): protocol for a randomized clinical trial. AB - BACKGROUND: Heart failure(HF) and atrial fibrillation(AF) frequently coexist in the same patient and are associated with increased mortality and frequent hospitalizations. As the concomitance of AF and HF is often associated with a poor prognosis, the prompt treatment of AF in HF patients may significantly improve outcome. METHODS/DESIGN: Recent implantable cardiac resynchronization (CRT) devices allow electrical therapies to treat AF automatically. TRADE-HF (trial registration: NCT00345592; http://www.clinicaltrials.gov) is a prospective, randomized, double arm study aimed at demonstrating the efficacy of an automatic, device-based therapy for treatment of atrial tachycardia and fibrillation(AT/AF) in patients indicated for CRT. The study compares automatic electrical therapy to a traditional more usual treatment of AT/AF: the goal is to demonstrate a reduction in a combined endpoint of unplanned hospitalizations for cardiac reasons, death from cardiovascular causes or permanent AF when using automatic atrial therapy as compared to the traditional approach involving hospitalization for symptoms and in-hospital treatment of AT/AF. DISCUSSION: CRT pacemaker with the additional ability to convert AF as well as ventricular arrhythmias may play a simultaneous role in rhythm control and HF treatment. The value of the systematic implantation of CRT ICDs with the capacity to deliver atrial therapy in HF patients at risk of AF has not yet been explored. The TRADE HF study will assess in CRT patients whether a strategy based on automatic management of atrial arrhythmias might be a valuable option to reduce the number of hospital admission and to reduce the progression the arrhythmia to a permanent form. TRIAL REGISTRATION: NCT00345592. PMID- 21324119 TI - Knowledge of AIDS and HIV transmission among drug users in Rio de Janeiro, Brazil. AB - BACKGROUND: Proper knowledge of HIV transmission is not enough for people to adopt protective behaviors, but deficits in this information may increase HIV/AIDS vulnerability. OBJECTIVE: To assess drug users' knowledge of HIV/AIDS and the possible association between knowledge and HIV testing. METHODS: A Cross sectional study conducted in 2006/7 with a convenience sample of 295 illicit drug users in Rio de Janeiro, assessing knowledge on AIDS/HIV transmission and its relationship with HIV testing. Information from 108 randomly selected drug users who received an educational intervention using cards illustrating situations potentially associated with HIV transmission were assessed using Multidimensional Scaling (MDS). RESULTS: Almost 40% of drug users reported having never used condoms and more than 60% reported not using condoms under the influence of substances. Most drug users (80.6%) correctly answered that condoms make sex safer, but incorrect beliefs are still common (e.g. nearly 44% believed HIV can be transmitted through saliva and 55% reported that HIV infection can be transmitted by sharing toothbrushes), with significant differences between drug users who had and who had not been tested for HIV. MDS showed queries on vaginal/anal sex and sharing syringes/needles were classified in the same set as effective modes of HIV transmission. The event that was further away from this core of properly perceived risks referred to blood donation, perceived as risky. Other items were found to be dispersed, suggesting inchoate beliefs on transmission modes. CONCLUSIONS: Drug users have an increased HIV infection vulnerability compared to the general population, this specific population expressed relevant doubts about HIV transmission, as well as high levels of risky behavior. Moreover, the findings suggest that possessing inaccurate HIV/AIDS knowledge may be a barrier to timely HIV testing. Interventions should be tailored to such specific characteristics. PMID- 21324120 TI - How participatory is parental consent in low literacy rural settings in low income countries? Lessons learned from a community based study of infants in South India. AB - BACKGROUND: A requisite for ethical human subjects research is that participation should be informed and voluntary. Participation during the informed consent process by way of asking questions is an indicator of the extent to which consent is informed. AIMS: The aims of this study were to assess the extent to which parents providing consent for children's participation in an observational tuberculosis (TB) research study in India actively participated during the informed consent discussion, and to identify correlates of that participation. METHODS: In an observational cohort study of tuberculosis in infants in South India, field supervisors who were responsible for obtaining informed consent noted down questions asked during the informed consent discussions for 4,382 infants who were enrolled in the study. These questions were post-coded by topic. Bivariate and multivariate analysis was conducted to examine factors associated with asking at least one question during the informed consent process. RESULTS: In total, 590 out of 4,382 (13.4%) parents/guardians asked any question during the informed consent process. We found that the likelihood of parents asking questions during the informed consent process was significantly associated with education level of either parent both parents being present, and location. CONCLUSIONS: The findings have implications for planning the informed consent process in a largely rural setting with low levels of literacy. Greater effort needs to be directed towards developing simple participatory communication materials for the informed consent process. Furthermore, including both parents in a discussion about a child's participation in a research study may increase the extent to which consent is truly informed. Finally, continuing efforts need to be made to improve the communication skills of research workers with regard to explaining research processes and putting potential research participants at ease. PMID- 21324121 TI - Identifying hypermethylated CpG islands using a quantile regression model. AB - BACKGROUND: DNA methylation has been shown to play an important role in the silencing of tumor suppressor genes in various tumor types. In order to have a system-wide understanding of the methylation changes that occur in tumors, we have developed a differential methylation hybridization (DMH) protocol that can simultaneously assay the methylation status of all known CpG islands (CGIs) using microarray technologies. A large percentage of signals obtained from microarrays can be attributed to various measurable and unmeasurable confounding factors unrelated to the biological question at hand. In order to correct the bias due to noise, we first implemented a quantile regression model, with a quantile level equal to 75%, to identify hypermethylated CGIs in an earlier work. As a proof of concept, we applied this model to methylation microarray data generated from breast cancer cell lines. However, we were unsure whether 75% was the best quantile level for identifying hypermethylated CGIs. In this paper, we attempt to determine which quantile level should be used to identify hypermethylated CGIs and their associated genes. RESULTS: We introduce three statistical measurements to compare the performance of the proposed quantile regression model at different quantile levels (95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%), using known methylated genes and unmethylated housekeeping genes reported in breast cancer cell lines and ovarian cancer patients. Our results show that the quantile levels ranging from 80% to 90% are better at identifying known methylated and unmethylated genes. CONCLUSIONS: In this paper, we propose to use a quantile regression model to identify hypermethylated CGIs by incorporating probe effects to account for noise due to unmeasurable factors. Our model can efficiently identify hypermethylated CGIs in both breast and ovarian cancer data. PMID- 21324122 TI - S100A7/psoriasin expression in the human lung: unchanged in patients with COPD, but upregulated upon positive S. aureus detection. AB - BACKGROUND: Progressive airway inflammation and susceptibility to the airway colonisation and infection are characteristic for the pathophysiology of chronic obstructive pulmonary disease (COPD). Antimicrobial peptides (AMPs) are central to the function of the innate host immune response against microbial pathogens and are regulators of inflammation and immunity. S100A7/psoriasin, a recently described AMP, is an essential component of the human epithelia against invading pathogens and acts as an effector molecule of the host innate defence in the skin. We hypothesized that S100A7/psoriasin is involved in the airway mucosal immunity and differently regulated and expressed in the lung during progression of COPD. METHODS: S100A7/psoriasin gene expression was assessed in bronchial biopsies and bronchoalveolar lavage (BAL) fluid cells of healthy controls and COPD patients. Using confocal microscopy and immunohistochemistry, the protein expression of S100A7/psoriasin was investigated. RESULTS: Here, we report that S100A7/psoriasin, the major antimicrobial peptide of the human skin, is constitutively expressed in perinuclear granules of human bronchial epithelial cells and alveolar macrophages. Whereas typical activators of the innate immune response like TLR ligands and cytokines induced the upregulation of CXCL-8 mRNA and release of CXCL-8 by epithelial cells, S100A7/psoriasin mRNA expression was not modulated. To investigate a potential association of S100A7/psoriasin with COPD, S100A7/psoriasin mRNA expression was assessed in bronchial biopsies and BAL fluid cells of patients at different stages of COPD and controls. Overall, 10 healthy individuals and 34 COPD patients were enrolled in this study. We found an association of S100A7/psoriasin mRNA expression with bacterial detection in the tracheobronchial system (p = 0.0304), which was the strongest in individuals positive for with S. aureus (p = 0.0005). However, S100A7/psoriasin mRNA expression was not altered during the progression of COPD. CONCLUSIONS: S100A7/psoriasin gene expression is unchanged in the airways during COPD. The newly identified association of S100A7/psoriasin with S. aureus may provide new insights into the antimicrobial defence response of the human airways, leading to the induction of S100A7/psoriasin upon microbial challenge. PMID- 21324123 TI - Genome-wide analysis of eukaryote thaumatin-like proteins (TLPs) with an emphasis on poplar. AB - BACKGROUND: Plant inducible immunity includes the accumulation of a set of defense proteins during infection called pathogenesis-related (PR) proteins, which are grouped into families termed PR-1 to PR-17. The PR-5 family is composed of thaumatin-like proteins (TLPs), which are responsive to biotic and abiotic stress and are widely studied in plants. TLPs were also recently discovered in fungi and animals. In the poplar genome, TLPs are over-represented compared with annual species and their transcripts strongly accumulate during stress conditions. RESULTS: Our analysis of the poplar TLP family suggests that the expansion of this gene family was followed by diversification, as differences in expression patterns and predicted properties correlate with phylogeny. In particular, we identified a clade of poplar TLPs that cluster to a single 350 kb locus of chromosome I and that are up-regulated by poplar leaf rust infection. A wider phylogenetic analysis of eukaryote TLPs - including plant, animal and fungi sequences - shows that TLP gene content and diversity increased markedly during land plant evolution. Mapping the reported functions of characterized TLPs to the eukaryote phylogenetic tree showed that antifungal or glycan-lytic properties are widespread across eukaryote phylogeny, suggesting that these properties are shared by most TLPs and are likely associated with the presence of a conserved acidic cleft in their 3D structure. Also, we established an exhaustive catalog of TLPs with atypical architectures such as small-TLPs, TLP-kinases and small-TLP kinases, which have potentially developed alternative functions (such as putative receptor kinases for pathogen sensing and signaling). CONCLUSION: Our study, based on the most recent plant genome sequences, provides evidence for TLP gene family diversification during land plant evolution. We have shown that the diverse functions described for TLPs are not restricted to specific clades but seem to be universal among eukaryotes, with some exceptions likely attributable to atypical protein structures. In the perennial plant model Populus, we unravelled the TLPs likely involved in leaf rust resistance, which will provide the foundation for further functional investigations. PMID- 21324124 TI - Modified Mallampati classification as a clinical predictor of peroral esophagogastroduodenoscopy tolerance. AB - BACKGROUND: Unsedated esophagogastroduodenoscopy (EGD) is simpler and safer than sedated EGD; however, approximately 40% of patients cannot tolerate it. Early identification of patients likely to poorly tolerate unsedated EGD is valuable for improving compliance. The modified Mallampati classification (MMC) has been used to evaluate difficult tracheal intubation and laryngoscope insertion. We tried to assess the efficacy of MMC to predict the tolerance of EGD in unsedated patients. METHODS: Two hundred patients who underwent an unsedated diagnostic EGD were recruited. They were stratified according to the view of the oropharynx as either MMC class I + II (good view) or class III + IV (poor view). EGD tolerance was assessed in three ways: gag reflex by endoscopist assessment, patient satisfaction by interview, and the degree of change in vital signs. RESULTS: MMC was significantly correlated to gag reflex (P < 0.001), patient satisfaction (P = 0.028), and a change of vital signs (P = 0.024). Patients in the poor view group had a 3.87-fold increased risk of gag reflex (P < 0.001), a 1.78-fold increased risk of unsatisfaction (P = 0.067), and a 1.96-fold increased risk of a change in vital signs (P = 0.025) compared to those in the good view group. CONCLUSIONS: MMC appears to be a clinically useful predictor of EGD tolerance. Patients with poor view of oropharynx by MMC criteria may be candidates for sedated or transnasal EGD. PMID- 21324125 TI - Metabolic reconstruction of the archaeon methanogen Methanosarcina Acetivorans. AB - BACKGROUND: Methanogens are ancient organisms that are key players in the carbon cycle accounting for about one billion tones of biological methane produced annually. Methanosarcina acetivorans, with a genome size of ~5.7 mb, is the largest sequenced archaeon methanogen and unique amongst the methanogens in its biochemical characteristics. By following a systematic workflow we reconstruct a genome-scale metabolic model for M. acetivorans. This process relies on previously developed computational tools developed in our group to correct growth prediction inconsistencies with in vivo data sets and rectify topological inconsistencies in the model. RESULTS: The generated model iVS941 accounts for 941 genes, 705 reactions and 708 metabolites. The model achieves 93.3% prediction agreement with in vivo growth data across different substrates and multiple gene deletions. The model also correctly recapitulates metabolic pathway usage patterns of M. acetivorans such as the indispensability of flux through methanogenesis for growth on acetate and methanol and the unique biochemical characteristics under growth on carbon monoxide. CONCLUSIONS: Based on the size of the genome-scale metabolic reconstruction and extent of validated predictions this model represents the most comprehensive up-to-date effort to catalogue methanogenic metabolism. The reconstructed model is available in spreadsheet and SBML formats to enable dissemination. PMID- 21324126 TI - The Australian 'FORM' approach to guideline development: the quest for the perfect system. AB - BACKGROUND: Clinical practice guidelines have been defined as systematically developed statements to assist practitioner and patient decision-making about appropriate health care for specific clinical circumstances. They play an important role in guiding evidence based clinical practice. The Australian National Health and Medical Research Council has developed and pilot-tested a new framework for guideline development, the FORM approach, the role of which has yet to be further defined. METHODS: We critically review the elements of the FORM approach and compare it to other, more established methods for rating the quality of evidence and strength of recommendations. RESULTS: FORM recognizes five factors that impact the strength of a recommendation which are the evidence base, consistency, clinical impact, generalizability and applicability. Consideration of these elements leads to a four-tiered rating system represented by the letters A ("body of evidence can be trusted to guide practice") to D ("body of evidence is weak and recommendation must be applied with caution"). It builds on other existing guideline methodologies such as those developed by the Scottish Intercollegiate Guidelines Network (SIGN), the Strength of Recommendation Taxonomy (SORT) and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) groups. FORM distinguishes itself from other systems by its strong emphasis on applicability, which is separated out as its own category and relates the relevance of the body of evidence to the Australian healthcare system. CONCLUSIONS: The FORM approach offers a methodologically rigorous alternative approach to guideline development that places particular emphasis on aspects of applicability. This feature is unique and may prompt future adoption by other guidelines systems. PMID- 21324127 TI - Association of depression with treatment outcomes in Type 2 Diabetes Mellitus: a cross-sectional study from Karachi, Pakistan. AB - BACKGROUND: To assess the associations of depression with glycemic control and compliance to self-care activities in adult patients with Type 2 Diabetes Mellitus METHODS: This cross-sectional study was conducted at a tertiary-care hospital in Karachi (Aga Khan University Hospital). Equal numbers of depressed and non-depressed patients were consecutively recruited from the diabetic clinic. Information on demographic and clinical characteristics was collected in face-to face interviews and from medical records. Hospital Anxiety Depression Scale (HADS) was used to measure depression. Associations of depressed status (HADS >= 8) with poor glycemic control (Hemoglobin A1c level >= 7%) and compliance to self care activities were assessed by logistic regression analyses. RESULTS: A total of 286 patients were included in this study with a male-female ratio of 1.2:1. Mean age was 52 years and in 64.7% of them, the duration of diabetes was more than 3 years. Depressed patients were more likely to be female (adjusted odds ratio [OR] = 1.88; 95% confidence interval [95%CI] = 1.07-3.31), had a family history of diabetes (OR = 2.64; 95%CI = 1.26-5.55), and poor glycemic control (OR = 5.57; 95%CI = 2.88-10.76) compared with non-depressed patients. Depression was also associated with low compliance to self-care activities such as taking dose as advised (OR = 0.32; 95%CI = 0.14-0.73), dietary restrictions (OR = 0.45; 95%CI = 0.26-0.79) and foot care (OR = 0.38; 95%CI = 0.18-0.83). CONCLUSIONS: Adult patients with Type 2 Diabetes who have depression were more likely to have poor glycemic control and lower compliance to self-care activities, and they might need particular attention during follow-up visits. PMID- 21324128 TI - The ties that bind: an integrative framework of physician-hospital alignment. AB - BACKGROUND: Alignment between physicians and hospitals is of major importance to the health care sector. Two distinct approaches to align the medical staff with the hospital have characterized previous research. The first approach, economic integration, is rooted in the economic literature, in which alignment is realized by financial means. The second approach, noneconomic integration, represents a sociological perspective emphasizing the cooperative nature of their relationship. DISCUSSION: Empirical studies and management theory (agency theory and social exchange theory) are used to increase holistic understanding of physician hospital alignment. On the one hand, noneconomic integration is identified as a means to realize a cooperative relationship. On the other hand, economic integration is studied as a way to align financial incentives. The framework is developed around two key antecedent factors which play an important role in aligning the medical staff. First, provider financial risk bearing is identified as a driving force towards closer integration. Second, organizational trust is believed to be important in explaining the causal relation between noneconomic and economic integration. SUMMARY: Hospital financial risk bearing creates a greater need for closer cooperation with the medical staff and alignment of financial incentives. Noneconomic integration lies at the very basis of alignment. It contributes directly to alignment through the norm of reciprocity and indirectly by building trust with the medical staff, laying the foundation for alignment of financial incentives. PMID- 21324129 TI - Soybean-derived Bowman-Birk inhibitor inhibits neurotoxicity of LPS-activated macrophages. AB - BACKGROUND: Lipopolysaccharide (LPS), the major component of the outer membrane of gram-negative bacteria, can activate immune cells including macrophages. Activation of macrophages in the central nervous system (CNS) contributes to neuronal injury. Bowman-Birk inhibitor (BBI), a soybean-derived protease inhibitor, has anti-inflammatory properties. In this study, we examined whether BBI has the ability to inhibit LPS-mediated macrophage activation, reducing the release of pro-inflammatory cytokines and subsequent neurotoxicity in primary cortical neural cultures. METHODS: Mixed cortical neural cultures from rat were used as target cells for testing neurotoxicity induced by LPS-treated macrophage supernatant. Neuronal survival was measured using a cell-based ELISA method for expression of the neuronal marker MAP-2. Intracellular reactive oxygen species (ROS) production in macrophages was measured via 2', 7'-dichlorofluorescin diacetate (DCFH2DA) oxidation. Cytokine expression was determined by quantitative real-time PCR. RESULTS: LPS treatment of macrophages induced expression of proinflammatory cytokines (IL-1beta, IL-6 and TNF-alpha) and of ROS. In contrast, BBI pretreatment (1-100 MUg/ml) of macrophages significantly inhibited LPS mediated induction of these cytokines and ROS. Further, supernatant from BBI pretreated and LPS-activated macrophage cultures was found to be less cytotoxic to neurons than that from non-BBI-pretreated and LPS-activated macrophage cultures. BBI, when directly added to the neuronal cultures (1-100 MUg/ml), had no protective effect on neurons with or without LPS-activated macrophage supernatant treatment. In addition, BBI (100 MUg/ml) had no effect on N-methyl-D aspartic acid (NMDA)-mediated neurotoxicity. CONCLUSIONS: These findings demonstrate that BBI, through its anti-inflammatory properties, protects neurons from neurotoxicity mediated by activated macrophages. PMID- 21324130 TI - Long-term nucleos(t)ide analogues therapy for adults with chronic hepatitis B reduces the risk of long-term complications: a meta-analysis. AB - BACKGROUND: The effect of antiviral therapy in chronic hepatitis B (CHB) on reducing the risk of long-term complications (LTCs) remains unclear so far. To study whether long-term nucleos(t)ide analogues therapy can reduce the risk of long-term complications. METHODS: We searched MEDLINE, EMBASE, OVID, the Cochrane Central Register of Controlled Trials. Relative risks (RRs) of long-term complications with or without treatment were studied. Also subgroup analyses including the status of drug-resistance, HBeAg and pre-existing compensated cirrhosis were done using relative risks of long-term complications either with or without treatment or among nucleos(t)ide analogues treatment groups. RESULTS: Six eligible studies (3644 patients in all) were included. Data showed the incidence of long-term complications in treatment groups was induced by 74%(RR:0.26, 95% CI: 0.15-0.47) compared with no treatment. Whether drug resistant happened or not during the long-term therapy, the incidence of long term complications was still significantly induced respectively by 45%(RR: 0.55,95%CI:0.40-0.76) and 78% (RR:0.22, 95%CI: 0.13-0.36). For both different status of HBeAg and pre-existing compensated cirrhosis, there was significant lower incidence of long-term complications in treatment groups compared with no treatment, too. Moreover, among the NA treatment groups, patients with drug resistance had 2.64 times (RR:2.64, 95%CI: 1.58-4.41) higher chance of developing to long-term complications, and patients with pre-existing compensated cirrhosis also had 3.07 times (RR:3.07, 95%CI: 1.04-9.11) higher chance of developing to long-term complications. CONCLUSIONS: Long-term nucleos(t)ide analogue therapy for adults with CHB prevents or delays the development of long-term complications including decompensated cirrhosis, CHB-related death or CHB-related HCC in patients with CHB. The patients who need take antiviral drugs should receive the antiviral therapy as soon as possible. PMID- 21324131 TI - Bringing order to protein disorder through comparative genomics and genetic interactions. AB - BACKGROUND: Intrinsically disordered regions are widespread, especially in proteomes of higher eukaryotes. Recently, protein disorder has been associated with a wide variety of cellular processes and has been implicated in several human diseases. Despite its apparent functional importance, the sheer range of different roles played by protein disorder often makes its exact contribution difficult to interpret. RESULTS: We attempt to better understand the different roles of disorder using a novel analysis that leverages both comparative genomics and genetic interactions. Strikingly, we find that disorder can be partitioned into three biologically distinct phenomena: regions where disorder is conserved but with quickly evolving amino acid sequences (flexible disorder); regions of conserved disorder with also highly conserved amino acid sequences (constrained disorder); and, lastly, non-conserved disorder. Flexible disorder bears many of the characteristics commonly attributed to disorder and is associated with signaling pathways and multi-functionality. Conversely, constrained disorder has markedly different functional attributes and is involved in RNA binding and protein chaperones. Finally, non-conserved disorder lacks clear functional hallmarks based on our analysis. CONCLUSIONS: Our new perspective on protein disorder clarifies a variety of previous results by putting them into a systematic framework. Moreover, the clear and distinct functional association of flexible and constrained disorder will allow for new approaches and more specific algorithms for disorder detection in a functional context. Finally, in flexible disordered regions, we demonstrate clear evolutionary selection of protein disorder with little selection on primary structure, which has important implications for sequence-based studies of protein structure and evolution. PMID- 21324132 TI - Method to isolate polyribosomal mRNA from scarce samples such as mammalian oocytes and early embryos. AB - BACKGROUND: Although the transcriptome of minute quantities of cells can be profiled using nucleic acid amplification techniques, it remains difficult to distinguish between active and stored messenger RNA. Transcript storage occurs at specific stages of gametogenesis and is particularly important in oogenesis as stored maternal mRNA is used to sustain de novo protein synthesis during the early developmental stages until the embryonic genome gets activated. In many cases, stored mRNA can be several times more abundant than mRNA ready for translation. In order to identify active mRNA in bovine oocytes, we sought to develop a method of isolating very small amounts of polyribosome mRNA. RESULTS: The proposed method is based on mixing the extracted oocyte cytoplasm with a preparation of polyribosomes obtained from a non-homologous source (Drosophila) and using sucrose density gradient ultracentrifugation to separate the polyribosomes. It involves cross-linking the non-homologous polyribosomes and neutralizing the cross-linking agent. Using this method, we show that certain stages of oocyte maturation coincide with changes in the abundance of polyribosomal mRNA but not total RNA or poly(A). We also show that the abundance of selected sequences matched changes in the corresponding protein levels. CONCLUSIONS: We report here the successful use of a method to profile mRNA present in the polyribosomal fraction obtained from as little as 75 mammalian oocytes. Polyribosomal mRNA fractionation thus provides a new tool for studying gametogenesis and early development with better representation of the underlying physiological status. PMID- 21324133 TI - Study design and participant characteristics of a randomized controlled trial of directly administered antiretroviral therapy in opioid treatment programs. AB - BACKGROUND: HIV-infected drug users are at higher risk of non-adherence and poor treatment outcomes than HIV-infected non-drug users. Prior work from our group and others suggests that directly administered antiretroviral therapy (DAART) delivered in opioid treatment programs (OTPs) may increase rates of viral suppression. METHODS/DESIGN: We are conducting a randomized trial comparing DAART to self-administered therapy (SAT) in 5 OTPs in Baltimore, Maryland. Participants and investigators are aware of treatment assignments. The DAART intervention is 12 months. The primary outcome is HIV RNA < 50 copies/mL at 3, 6, and 12 months. To assess persistence of any study arm differences that emerge during the active intervention, we are conducting an 18-month visit (6 months after the intervention concludes). We are collecting electronic adherence data for 2 months in both study arms. Of 457 individuals screened, a total of 107 participants were enrolled, with 56 and 51 randomly assigned to DAART and SAT, respectively. Participants were predominantly African American, approximately half were women, and the median age was 47 years. Active use of cocaine and other drugs was common at baseline. HIV disease stage was advanced in most participants. The median CD4 count at enrollment was 207 cells/mm3, 66 (62%) had a history of an AIDS-defining opportunistic condition, and 21 (20%) were antiretroviral naive. CONCLUSIONS: This paper describes the rationale, methods, and baseline characteristics of subjects enrolled in a randomized clinical trial comparing DAART to SAT in opioid treatment programs. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00279110. PMID- 21324135 TI - Dose-associated changes in safety and efficacy parameters observed in a 24-week maintenance trial of olanzapine long-acting injection in patients with schizophrenia. AB - BACKGROUND: In a recently published 24-week maintenance study of olanzapine long acting injection (LAI) in schizophrenia (Kane et al., 2010), apparent dose associated changes were noted in both efficacy and safety parameters. To help clinicians balance safety and efficacy when choosing a dose of olanzapine LAI, we further studied these changes. METHODS: Outpatients with schizophrenia who had maintained stability on open-label oral olanzapine for 4 to 8 weeks were randomly assigned to "low" (150 mg/2 weeks; N = 140), "medium" (405 mg/4 weeks; N = 318), or "high" (300 mg/2 weeks; N = 141) dosages of olanzapine LAI for 24 weeks. Potential relationships between dose and several safety or efficacy measures were examined via regression analysis, the Jonckheere-Terpstra test (continuous data), or the Cochran-Armitage test (categorical data). RESULTS: Safety parameters statistically significantly related to dose were mean weight change (low: +0.67 [SD = 4.38], medium: +0.89 [SD = 3.87], high: +1.70 [SD = 4.14] kg, p = .024; effect size [ES] = 0.264 high vs. low dose), mean change in prolactin (low: -5.61 [SD = 12.49], medium: -2.76 [SD = 19.02]), high: +3.58 [SD = 33.78] MUg/L, p = .001; ES = 0.410 high vs. low dose), fasting triglycerides change from normal at baseline to high (low: 3.2%, medium: 6.0%, high: 18.9%, p = .001; NNT = 7 high vs. low dose) and fasting high-density lipoprotein cholesterol change from normal at baseline to low (low: 13.8%, medium: 19.6%, high: 30.7%, p = .019; NNT = 6 high vs. low dose). Efficacy measures significantly related to dose included Positive and Negative Syndrome Scale total score mean change (low: +2.66 [SD = 14.95], medium: -0.09 [SD = 13.47], high: -2.19 [SD = 13.11], p <.01; ES = 0.356 high vs. low dose), relapse rate (low: 16%, medium: 10%, high: 5%, p = .003; NNT = 9 high vs. low dose), all-cause discontinuation rate (low: 36%, medium: 30%, high: 24%, p = .037; NNT = 9 high vs. low dose), and rate of discontinuation due to efficacy-related reasons (low: 20%, medium: 14%, high: 6%, p <.001). Time to all-cause discontinuation (p = .035) and time to relapse (p = .005) were also significantly related to dose. CONCLUSIONS: Analyses of several safety and efficacy parameters revealed significant associations with dose of olanzapine LAI, with the highest dose generally showing greater efficacy as well as greater adverse changes in metabolic safety measures. When considering olanzapine LAI, as with all antipsychotics, it is important to carefully consider the potential benefits and risks for an individual patient. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00088491. PMID- 21324134 TI - Pregnancy-related pelvic girdle pain: an update. AB - A large number of scientists from a wide range of medical and surgical disciplines have reported on the existence and characteristics of the clinical syndrome of pelvic girdle pain during or after pregnancy. This syndrome refers to a musculoskeletal type of persistent pain localised at the anterior and/or posterior aspect of the pelvic ring. The pain may radiate across the hip joint and the thigh bones. The symptoms may begin either during the first trimester of pregnancy, at labour or even during the postpartum period. The physiological processes characterising this clinical entity remain obscure. In this review, the definition and epidemiology, as well as a proposed diagnostic algorithm and treatment options, are presented. Ongoing research is desirable to establish clear management strategies that are based on the pathophysiologic mechanisms responsible for the escalation of the syndrome's symptoms to a fraction of the population of pregnant women. PMID- 21324136 TI - Aberrant methylation of Polo-like kinase CpG islands in Plk4 heterozygous mice. AB - BACKGROUND: Hepatocellular carcinoma (HCC), one of the most common cancers world wide occurs twice as often in men compared to women. Predisposing conditions such as alcoholism, chronic viral hepatitis, aflatoxin B1 ingestion, and cirrhosis all contribute to the development of HCC. METHODS: We used a combination of methylation specific PCR and bisulfite sequencing, qReal-Time PCR (qPCR), and Western blot analysis to examine epigenetic changes for the Polo-like kinases (Plks) during the development of hepatocellular carcinoma (HCC) in Plk4 heterozygous mice and murine embryonic fibroblasts (MEFs). RESULTS: Here we report that the promoter methylation of Plk4 CpG islands increases with age, was more prevalent in males and that Plk4 epigenetic modification and subsequent downregulation of expression was associated with the development of HCC in Plk4 mutant mice. Interestingly, the opposite occurs with another Plk family member, Plk1 which was typically hypermethylated in normal liver tissue but became hypomethylated and upregulated in liver tumours. Furthermore, upon alcohol exposure murine embryonic fibroblasts exhibited increased Plk4 hypermethylation and downregulation along with increased centrosome numbers and multinucleation. CONCLUSIONS: These results suggest that aberrant Plk methylation is correlated with the development of HCC in mice. PMID- 21324137 TI - Comprehensive genetic assessment of a functional TLR9 promoter polymorphism: no replicable association with asthma or asthma-related phenotypes. AB - BACKGROUND: Prior studies suggest a role for a variant (rs5743836) in the promoter of toll-like receptor 9 (TLR9) in asthma and other inflammatory diseases. We performed detailed genetic association studies of the functional variant rs5743836 with asthma susceptibility and asthma-related phenotypes in three independent cohorts. METHODS: rs5743836 was genotyped in two family-based cohorts of children with asthma and a case-control study of adult asthmatics. Association analyses were performed using chi square, family-based and population based testing. A luciferase assay was performed to investigate whether rs5743836 genotype influences TLR9 promoter activity. RESULTS: Contrary to prior reports, rs5743836 was not associated with asthma in any of the three cohorts. Marginally significant associations were found with FEV1 and FVC (p = 0.003 and p = 0.008, respectively) in one of the family-based cohorts, but these associations were not significant after correcting for multiple comparisons. Higher promoter activity of the CC genotype was demonstrated by luciferase assay, confirming the functional importance of this variant. CONCLUSION: Although rs5743836 confers regulatory effects on TLR9 transcription, this variant does not appear to be an important asthma-susceptibility locus. PMID- 21324139 TI - Centrilobular emphysema combined with pulmonary fibrosis results in improved survival. AB - BACKGROUND: We hypothesized that, in patients with pulmonary fibrosis combined with emphysema, clinical characteristics and outcomes may differ from patients with pulmonary fibrosis without emphysema. We identified 102 patients who met established criteria for pulmonary fibrosis. The amount of emphysema (numerical score) and type of emphysema (centrilobular, paraseptal, or mixed) were characterized in each patient. Clinical characteristics, pulmonary function tests and patient survival were analysed. RESULTS: Based on the numerical emphysema score, patients were classified into those having no emphysema (n = 48), trivial emphysema (n = 26) or advanced emphysema (n = 28). Patients with advanced emphysema had a significantly higher amount of smoking in pack/years than patients with no emphysema or trivial emphysema (P < 0.0001). Median survival [1st, 3rd quartiles] of patients with advanced emphysema was 63 [36, 82] months compared to 29 [18, 49] months in patients without emphysema and 32 [19, 48] months in patients with trivial emphysema (P < 0.001). Median forced vital capacity (FVC) and total lung capacity (TLC) were higher in the advanced emphysema group compared to patients with no emphysema (P < 0.01 and P < 0.001, respectively), whereas median DLCO did not differ among groups and was overall low. Within the advanced emphysema group (n = 28), further characterization of the type of emphysema was performed and, within these subgroups of patients, survival was 75 [58, 85] months for patients with centrilobular emphysema, 75 [48, 85] months for patients with mixed centrilobular/paraseptal emphysema, and 24 [22, 35] months for patients with paraseptal emphysema (P < 0.01). Patients with advanced paraseptal emphysema had similar survival times to patients without emphysema. CONCLUSIONS: Patients with pulmonary fibrosis combined with advanced centrilobular or mixed emphysema have an improved survival compared with patients with pulmonary fibrosis without emphysema, with trivial emphysema or with advanced paraseptal emphysema. PMID- 21324138 TI - Structural and functional effects of acoustic exposure in goldfish: evidence for tonotopy in the teleost saccule. AB - BACKGROUND: Mammalian and avian auditory hair cells display tonotopic mapping of frequency along the length of the cochlea and basilar papilla. It is not known whether the auditory hair cells of fishes possess a similar tonotopic organization in the saccule, which is thought to be the primary auditory receptor in teleosts. To investigate this question, we determined the location of hair cell damage in the saccules of goldfish (Carassius auratus) following exposure to specific frequencies. Subjects were divided into six groups of six fish each (five treatment groups plus control). The treatment groups were each exposed to one of five tones: 100, 400, 800, 2000, and 4000 Hz at 176 dB re 1 MUPa root mean squared (RMS) for 48 hours. The saccules of each fish were dissected and labeled with phalloidin in order to visualize hair cell bundles. The hair cell bundles were counted at 19 specific locations in each saccule to determine the extent and location of hair cell damage. In addition to quantification of anatomical injury, hearing tests (using auditory evoked potentials) were performed on each fish immediately following sound exposure. Threshold shifts were calculated by subtracting control thresholds from post-sound exposure thresholds. RESULTS: All sound-exposed fish exhibited significant hair cell and hearing loss following sound exposure. The location of hair cell loss varied along the length of the saccule in a graded manner with the frequency of sound exposure, with lower and higher frequencies damaging the more caudal and rostral regions of the saccule, respectively. Similarly, fish exposed to lower frequency tones exhibited greater threshold shifts at lower frequencies, while high-frequency tone exposure led to hearing loss at higher frequencies. In general, both hair cell and hearing loss declined as a function of increasing frequency of exposure tone, and there was a significant linear relationship between hair cell loss and hearing loss. CONCLUSIONS: The pattern of hair cell loss as a function of exposure tone frequency and saccular rostral-caudal location is similar to the pattern of hearing loss as a function of exposure tone frequency and hearing threshold frequency. This data suggest that the frequency analysis ability of goldfish is at least partially driven by peripheral tonotopy in the saccule. PMID- 21324140 TI - Prevalence of HIV among injection drug users in Georgia. AB - BACKGROUND: Injection drug use remains a major risk factor for HIV transmission in Georgia. The study aims to characterize the prevalence of HIV among injection drug users in Georgia. METHODS: A cross-sectional, anonymous bio-behavioural survey to assess knowledge and behaviour in injection drug users in combination with laboratory testing on HIV status was conducted in five Georgian cities (Tbilisi, Gori, Telavi, Zugdidi and Batumi) in 2009. A snowball sample of 1127 eligible injection drug user participants was investigated. RESULTS: Odds of HIV exposure were increased for injection drug users of greater age, with greater duration of drug use and with a history of imprisonment or detainment (p < 0.05). CONCLUSIONS: More research is required to analyze the determinants of HIV risk in Georgian injection drug users. The imprisoned population and young injection drug users may be appropriate target groups for programmes aimed at preventing HIV transmission. PMID- 21324141 TI - P300 amplitude is insensitive to working memory load in schizophrenia. AB - BACKGROUND: Working memory (WM) tasks usually elicit a P300 ERP component, whose amplitude decreases with increasing WM load. So far, this effect has not been studied in schizophrenics (SZs), a group that is considered to have an aberrant brain connectivity and impairments in WM capacity. The aim of this study was to determine the dependency of the P300 component on WM load in a sample of SZ subjects. METHODS: We recorded 26 subjects (13 SZ patients and their matched controls) with an 80-channel electroencephalogram. Subjects performed an N-back task, a WM paradigm that manipulates the number of items to be stored in memory. RESULTS: In healthy subjects, P300 amplitude was highest in the low WM load condition, and lowest in both the attentional control condition and the high WM load condition. In contrast, SZs evidenced low P300 amplitude in all conditions. A significant between group difference in P300 amplitude was evidenced only at the low WM load condition (1 -back), being smaller in SZs. CONCLUSIONS: SZ subjects display a lower than normal P300 amplitude, which does not vary as a function of memory load. These results are consistent with a general impairment in WM capacity in these patients. PMID- 21324142 TI - Neoadjuvant imatinib in patients with locally advanced non metastatic GIST in the prospective BFR14 trial. AB - BACKGROUND: The role of surgery in the management of patients with advanced gastrointestinal stromal tumors (GIST) in the era of imatinib mesylate (IM) remains debated. We analyzed the outcome of patients with non metastatic locally advanced primary GIST treated with IM within the prospective BFR14 phase III trial. METHODS: The database of the BFR14 trial was searched for patients with no metastasis at time of inclusion. Patients treated for recurrent disease were excluded. Twenty-five of 434 patients met these criteria. RESULTS: Fifteen of 25 patients (60%) had a partial response to IM. Nine of the 25 patients (36%) underwent surgical resection of their primary tumor after a median of 7.3 months of IM treatment (range 3.4-12.0). Per protocol patients received continuous IM treatment in the post resection period, in an adjuvant setting. With a median follow-up of 53.5 months, there was a significant improvement in progression-free survival (PFS) and overall survival (OS) for patients who underwent surgical resection versus those who did not (median not reached vs 23.6 months, p = 0.0318 for PFS and median not reached vs 42.2 months, p = 0.0217 for OS). In the group of patients who underwent resection followed by IM, the 3-year PFS and OS rates were 67% and 89% respectively CONCLUSIONS: Following neoadjuvant IM for non metastatic locally advanced GIST 9 of 25 patients (36%) were selected for resection of the primary tumor. OS and PFS figures were close to those of localised intermediate or high risk GIST (70% at 5 years) in the subgroup of operated patients, while the outcome of the non-operated subgroup was similar to that of metastatic GIST. PMID- 21324143 TI - Treatment of uterine prolapse stage 2 or higher: a randomized multicenter trial comparing sacrospinous fixation with vaginal hysterectomy (SAVE U trial). AB - BACKGROUND: Pelvic organ prolapse is a common health problem, affecting up to 40% of parous women over 50 years old, with significant negative influence on quality of life. Vaginal hysterectomy is currently the leading treatment method for patients with symptomatic uterine prolapse. Several studies have shown that sacrospinous fixation in case of uterine prolapse is a safe and effective alternative to vaginal hysterectomy. However, no large randomized trials with long-term follow-up have been performed to compare efficacy and quality of life between both techniques.The SAVE U trial is designed to compare sacrospinous fixation with vaginal hysterectomy in the treatment of uterine prolapse stage 2 or higher in terms of prolapse recurrence, quality of life, complications, hospital stay, post-operative recovery and sexual functioning. METHODS/DESIGN: The SAVE U trial is a randomized controlled multi-center non-inferiority trial. The study compares sacrospinous fixation with vaginal hysterectomy in women with uterine prolapse stage 2 or higher. The primary outcome measure is recurrence of uterine prolapse defined as: uterine descent stage 2 or more assessed by pelvic organ prolapse quantification examination and prolapse complaints and/or redo surgery at 12 months follow-up. Secondary outcomes are subjective improvement in quality of life measured by generic (Short Form 36 and Euroqol 5D) and disease specific (Urogenital Distress Inventory, Defecatory Distress Inventory and Incontinence Impact Questionnaire) quality of life instruments, complications following surgery, hospital stay, post-operative recovery and sexual functioning (Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire). Analysis will be performed according to the intention to treat principle. Based on comparable recurrence rates of 3% and considering an upper-limit of 7% to be non-inferior (beta 0.2 and one sided alpha 0.025), 104 patients are needed per group. DISCUSSION: The SAVE U trial is a randomized multicenter trial that will provide evidence whether the efficacy of sacrospinous fixation is similar to vaginal hysterectomy in women with uterine prolapse stage 2 or higher. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR1866. PMID- 21324144 TI - The spatial distribution of esophageal and gastric cancer in Caspian region of Iran: an ecological analysis of diet and socio-economic influences. AB - Recent studies have suggested a systematic geographic pattern of esophageal cancer (EC) and gastric cancer (GC) incidence in the Caspian region of Iran. The aims of this study were to investigate the association between these cancers and the region's dietary and socioeconomic risk factors and to map EC and GC after adjustment for the risk factors and the removal of random and geographic variations from area specific age standardised incidence ratios (SIRs). We obtained cancer data from the Babol cancer registry from 2001 to 2005, socioeconomic indices from the Statistical Centre of Iran, and dietary patterns from the control group in a case control study conducted in the study region. Regression models were fitted to identify significant covariates, and clusters of elevated rates were identified. We found evidence of systematic clustering for EC and GC in men and women and both sexes combined. EC and GC SIRs were lower in urban areas, and were also lower in areas of high income. EC SIRs were lower in areas with higher proportions of people having unrestricted food choice and higher in areas with higher proportions of people with restricted food choice. EC and GC were associated with aggregated risk factors, including income, urbanisation, and dietary patterns. These variables represent the influence of improved lifestyle which has coincided with a decrease in upper gastrointestinal cancer frequency over recent decades but which has not necessarily been uniform throughout the region. PMID- 21324145 TI - Age at quitting smoking as a predictor of risk of cardiovascular disease incidence independent of smoking status, time since quitting and pack-years. AB - BACKGROUND: Risk prediction for CVD events has been shown to vary according to current smoking status, pack-years smoked over a lifetime, time since quitting and age at quitting. The latter two are closely and inversely related. It is not known whether the age at which one quits smoking is an additional important predictor of CVD events. The aim of this study was to determine whether the risk of CVD events varied according to age at quitting after taking into account current smoking status, lifetime pack-years smoked and time since quitting. FINDINGS: We used the Cox proportional hazards model to evaluate the risk of developing a first CVD event for a cohort of participants in the Framingham Offspring Heart Study who attended the fourth examination between ages 30 and 74 years and were free of CVD. Those who quit before the median age of 37 years had a risk of CVD incidence similar to those who were never smokers. The incorporation of age at quitting in the smoking variable resulted in better prediction than the model which had a simple current smoker/non-smoker measure and the one that incorporated both time since quitting and pack-years. These models demonstrated good discrimination, calibration and global fit. The risk among those quitting more than 5 years prior to the baseline exam and those whose age at quitting was prior to 44 years was similar to the risk among never smokers. However, the risk among those quitting less than 5 years prior to the baseline exam and those who continued to smoke until 44 years of age (or beyond) was two and a half times higher than that of never smokers. CONCLUSIONS: Age at quitting improves the prediction of risk of CVD incidence even after other smoking measures are taken into account. The clinical benefit of adding age at quitting to the model with other smoking measures may be greater than the associated costs. Thus, age at quitting should be considered in addition to smoking status, time since quitting and pack-years when counselling individuals about their cardiovascular risk. PMID- 21324147 TI - Graves' disease presenting as pseudotumor cerebri: a case report. AB - INTRODUCTION: Pseudotumor cerebri is an entity characterized by elevated intracranial pressure with normal cerebrospinal fluid and no structural abnormalities detected on brain MRI scans. Common secondary causes include endocrine pathologies. Hyperthyroidism is very rarely associated and only three case reports have been published so far. CASE PRESENTATION: We report the case of a 31-year-old Luso-African woman with clinical symptoms and laboratory confirmation of Graves' disease that presented as pseudotumor cerebri. CONCLUSION: This is a rare form of presentation of Graves' disease and a rare cause of pseudotumor cerebri. It should be remembered that hyperthyroidism is a potential cause of pseudotumor cerebri. PMID- 21324146 TI - The psychological context of quality of life: a psychometric analysis of a novel idiographic measure of bladder cancer patients' personal goals and concerns prior to surgery. AB - BACKGROUND: Over the past two decades, there has been an increasing focus on quality of life outcomes in urological diseases. Patient-reported outcomes research has relied on structured assessments that constrain interpretation of the impact of disease and treatments. In this study, we present content analysis and psychometric evaluation of the Quality of Life Appraisal Profile. Our evaluation of this measure is a prelude to a prospective comparison of quality of life outcomes of reconstructive procedures after cystectomy. METHODS: Fifty patients with bladder cancer were interviewed prior to surgery using the Quality of Life Appraisal Profile. Patients also completed the EORTC QLQ-C30 and demographics. Analysis included content coding of personal goal statements generated by the Appraisal Profile, examination of the relationship of goal attainment to content, and association of goal-based measures with QLQ-C30 scales. RESULTS: Patients reported an average of 10 personal goals, reflecting motivational themes of achievement, problem solving, avoidance of problems, maintaining desired circumstances, letting go of roles and responsibilities, acceptance of undesirable situations, and attaining milestones. 503 goal statements were coded using 40 different content categories. Progress toward goal attainment was positively correlated with relationships and activities goals, but negatively correlated with health concerns. Associations among goal measures provided evidence for construct validity. Goal content also differed according to age, gender, employment, and marital status, lending further support for construct validity. QLQ-C30 functioning and symptom scales were correlated with goal content, but not with progress toward goal attainment, suggesting that patients may calibrate progress ratings relative to their specific goals. Alternately, progress may reflect a unique aspect of quality of life untapped by more standard scales. CONCLUSIONS: The Brief Quality of Life Appraisal Profile was associated with measures of motivation, goal content and progress, as well as relationships with demographic and standard quality of life measures. This measure identifies novel concerns and issues in treating patients with bladder cancer, necessary for a more comprehensive evaluations of their health-related quality of life. PMID- 21324148 TI - Imputation strategies for missing binary outcomes in cluster randomized trials. AB - BACKGROUND: Attrition, which leads to missing data, is a common problem in cluster randomized trials (CRTs), where groups of patients rather than individuals are randomized. Standard multiple imputation (MI) strategies may not be appropriate to impute missing data from CRTs since they assume independent data. In this paper, under the assumption of missing completely at random and covariate dependent missing, we compared six MI strategies which account for the intra-cluster correlation for missing binary outcomes in CRTs with the standard imputation strategies and complete case analysis approach using a simulation study. METHOD: We considered three within-cluster and three across-cluster MI strategies for missing binary outcomes in CRTs. The three within-cluster MI strategies are logistic regression method, propensity score method, and Markov chain Monte Carlo (MCMC) method, which apply standard MI strategies within each cluster. The three across-cluster MI strategies are propensity score method, random-effects (RE) logistic regression approach, and logistic regression with cluster as a fixed effect. Based on the community hypertension assessment trial (CHAT) which has complete data, we designed a simulation study to investigate the performance of above MI strategies. RESULTS: The estimated treatment effect and its 95% confidence interval (CI) from generalized estimating equations (GEE) model based on the CHAT complete dataset are 1.14 (0.76 1.70). When 30% of binary outcome are missing completely at random, a simulation study shows that the estimated treatment effects and the corresponding 95% CIs from GEE model are 1.15 (0.76 1.75) if complete case analysis is used, 1.12 (0.72 1.73) if within-cluster MCMC method is used, 1.21 (0.80 1.81) if across-cluster RE logistic regression is used, and 1.16 (0.82 1.64) if standard logistic regression which does not account for clustering is used. CONCLUSION: When the percentage of missing data is low or intra-cluster correlation coefficient is small, different approaches for handling missing binary outcome data generate quite similar results. When the percentage of missing data is large, standard MI strategies, which do not take into account the intra-cluster correlation, underestimate the variance of the treatment effect. Within-cluster and across-cluster MI strategies (except for random effects logistic regression MI strategy), which take the intra-cluster correlation into account, seem to be more appropriate to handle the missing outcome from CRTs. Under the same imputation strategy and percentage of missingness, the estimates of the treatment effect from GEE and RE logistic regression models are similar. PMID- 21324149 TI - Characterization of statistical features for plant microRNA prediction. AB - BACKGROUND: Several tools are available to identify miRNAs from deep-sequencing data, however, only a few of them, like miRDeep, can identify novel miRNAs and are also available as a standalone application. Given the difference between plant and animal miRNAs, particularly in terms of distribution of hairpin length and the nature of complementarity with its duplex partner (or miRNA star), the underlying (statistical) features of miRDeep and other tools, using similar features, are likely to get affected. RESULTS: The potential effects on features, such as minimum free energy, stability of secondary structures, excision length, etc., were examined, and the parameters of those displaying sizable changes were estimated for plant specific miRNAs. We found most of these features acquired a new set of values or distributions for plant specific miRNAs. While the length of conserved positions (nucleus) in mature miRNAs were relatively longer in plants, the difference in distribution of minimum free energy, between real and background hairpins, was marginal. However, the choice of source (species) of background sequences was found to affect both the minimum free energy and miRNA hairpin stability. The new parameters were tested on an Illumina dataset from maize seedlings, and the results were compared with those obtained using default parameters. The newly parameterized model was found to have much improved specificity and sensitivity over its default counterpart. CONCLUSIONS: In summary, the present study reports behavior of few general and tool-specific statistical features for improving the prediction accuracy of plant miRNAs from deep-sequencing data. PMID- 21324150 TI - Efficacy of a family practice-based lifestyle intervention program to increase physical activity and reduce clinical and physiological markers of vascular health in patients with high normal blood pressure and/or high normal blood glucose (SNAC): study protocol for a randomized controlled trial. AB - BACKGROUND: Previous interventions to increase physical activity and reduce cardiovascular risk factors have been targeted at individuals with established disease; less attention has been given to intervention among individuals with high risk for disease nor has there been determination of the influence of setting in which the intervention is provided. In particular, family practice represents an ideal setting for the provision and long-term maintenance of lifestyle interventions for patients at risk (ie high-normal blood pressure or impaired glucose tolerance). METHODS/DESIGN: The Staged Nutrition and Activity Counseling (SNAC) study is a randomized clustered design clinical trial that will investigate the effectiveness and efficacy of a multi-component lifestyle intervention on cardiovascular disease risk factors and vascular function in patients at risk in primary care. Patients will be randomized by practice to either a standard of care lifestyle intervention or a behaviourally-based, matched prescriptive physical activity and diet change program. The primary goal is to increase physical activity and improve dietary intake according to Canada's Guides to Physical Activity Healthy Eating over 24 months. The primary intention to treat analysis will compare behavioral, physiological and metabolic outcomes at 6, 12 and 24 months post-randomization including estimation of incident hypertension and/or diabetes. DISCUSSION: The design features of our trial, and the practical problems (and solutions) associated with implementing these design features, particularly those that result in potential delay between recruitment, baseline data collection, randomization, intervention, and assessment will be discussed. Results of the SNAC trial will provide scientific rationale for the implementation of this lifestyle intervention in primary care. TRIAL REGISTRATION: ISRCTN: ISRCTN:42921300. PMID- 21324151 TI - Proteomic identification of OsCYP2, a rice cyclophilin that confers salt tolerance in rice (Oryza sativa L.) seedlings when overexpressed. AB - BACKGROUND: High Salinity is a major environmental stress influencing growth and development of rice. Comparative proteomic analysis of hybrid rice shoot proteins from Shanyou 10 seedlings, a salt-tolerant hybrid variety, and Liangyoupeijiu seedlings, a salt-sensitive hybrid variety, was performed to identify new components involved in salt-stress signaling. RESULTS: Phenotypic analysis of one protein that was upregulated during salt-induced stress, cyclophilin 2 (OsCYP2), indicated that OsCYP2 transgenic rice seedlings had better tolerance to salt stress than did wild-type seedlings. Interestingly, wild-type seedlings exhibited a marked reduction in maximal photochemical efficiency under salt stress, whereas no such change was observed for OsCYP2-transgenic seedlings. OsCYP2-transgenic seedlings had lower levels of lipid peroxidation products and higher activities of antioxidant enzymes than wild-type seedlings. Spatiotemporal expression analysis of OsCYP2 showed that it could be induced by salt stress in both Shanyou 10 and Liangyoupeijiu seedlings, but Shanyou 10 seedlings showed higher OsCYP2 expression levels. Moreover, circadian rhythm expression of OsCYP2 in Shanyou 10 seedlings occurred earlier than in Liangyoupeijiu seedlings. Treatment with PEG, heat, or ABA induced OsCYP2 expression in Shanyou 10 seedlings but inhibited its expression in Liangyoupeijiu seedlings. Cold stress inhibited OsCYP2 expression in Shanyou 10 and Liangyoupeijiu seedlings. In addition, OsCYP2 was strongly expressed in shoots but rarely in roots in two rice hybrid varieties. CONCLUSIONS: Together, these data suggest that OsCYP2 may act as a key regulator that controls ROS level by modulating activities of antioxidant enzymes at translation level. OsCYP2 expression is not only induced by salt stress, but also regulated by circadian rhythm. Moreover, OsCYP2 is also likely to act as a key component that is involved in signal pathways of other types of stresses-PEG, heat, cold, or ABA. PMID- 21324152 TI - Nursing heroism in the 21st Century'. AB - BACKGROUND: The Vivian Bullwinkel Oration honours the life and work of an extraordinary nurse. Given her story and that of her World War II colleagues, the topic of nursing heroism in the 21st century could not be more germane. DISCUSSION: Is heroism a legitimate part of nursing, or are nurses simply 'just doing their job' even when facing extreme personal danger? In this paper I explore the place and relevance of heroism in contemporary nursing. I propose that nursing heroism deserves a broader appreciation and that within the term lie many hidden, 'unsung' or 'unrecorded' heroisms. I also challenge the critiques of heroism that would condemn it as part of a 'militarisation' of nursing. Finally, I argue that nursing needs to be more open in celebrating our heroes and the transformative power of nursing achievements. SUMMARY: The language of heroism may sound quaint by 21st Century standards but nursing heroism is alive and well in the best of our contemporary nursing ethos and practice. PMID- 21324153 TI - Real-time forecasting of an epidemic using a discrete time stochastic model: a case study of pandemic influenza (H1N1-2009). AB - BACKGROUND: Real-time forecasting of epidemics, especially those based on a likelihood-based approach, is understudied. This study aimed to develop a simple method that can be used for the real-time epidemic forecasting. METHODS: A discrete time stochastic model, accounting for demographic stochasticity and conditional measurement, was developed and applied as a case study to the weekly incidence of pandemic influenza (H1N1-2009) in Japan. By imposing a branching process approximation and by assuming the linear growth of cases within each reporting interval, the epidemic curve is predicted using only two parameters. The uncertainty bounds of the forecasts are computed using chains of conditional offspring distributions. RESULTS: The quality of the forecasts made before the epidemic peak appears largely to depend on obtaining valid parameter estimates. The forecasts of both weekly incidence and final epidemic size greatly improved at and after the epidemic peak with all the observed data points falling within the uncertainty bounds. CONCLUSIONS: Real-time forecasting using the discrete time stochastic model with its simple computation of the uncertainty bounds was successful. Because of the simplistic model structure, the proposed model has the potential to additionally account for various types of heterogeneity, time dependent transmission dynamics and epidemiological details. The impact of such complexities on forecasting should be explored when the data become available as part of the disease surveillance. PMID- 21324154 TI - The impact of social status inconsistency on cardiovascular risk factors, myocardial infarction and stroke in the EPIC-Heidelberg cohort. AB - BACKGROUND: Social inequalities in cardiovascular diseases are well documented. Yet, the relation of social status inconsistency (having different ranks in two or more status indicators like education, occupational position or income) and medical conditions of heart or vessels is not clear. Status inconsistency (SI) is assumed to be stressful, and the association of psychosocial distress and health is well known. Therefore, we aimed to analyze the relationship between cardiovascular diseases (CVD) and status inconsistency. Another target was to assess the influence of behaviour related risk factors on this association. METHODS: 8960 men and 6070 women, aged 45-65 years, from the EPIC-Heidelberg cohort (European Prospective Investigation into Cancer and Nutrition) were included. Socio-economic status was assessed by education/vocational training and occupational position at recruitment. During a median follow-up of 8.7 years, information on CVD was collected. RESULTS: Compared to status consistent subjects, men who were in a higher occupational position than could be expected given their educational attainment had a nearly two-fold increased incidence of CVD (Odds Ratio (OR) = 1.8, 95% Confidence Interval (CI) = 1.5; 2.4, adjusted for age). Smoking behaviour and BMI differed significantly between those who had adequate occupational positions and those who did not. Yet, these lifestyle factors, as opposed to age, did not contribute to the observed differences in CVD. No association of cardiovascular diseases and status inconsistency was found for women or in cases where education exceeded occupational position. CONCLUSIONS: Status inconsistent men (occupational position > education) had a higher risk of cardiovascular diseases than status consistent men. However, harmful behaviour did not explain this relationship. PMID- 21324155 TI - Milder is better? Advantages and disadvantages of "mild" ovarian stimulation for human in vitro fertilization. AB - In the last decades, several steps have been made aiming at rendering human IVF more successful on one side, more tolerable on the other side. The "mild" ovarian stimulation approach, in which a lower-than-average dose of exogenous gonadotropins is given and gonadotropin treatment is started from day 2 to 7 of the cycle, represents a significant step toward a more patient's friendly IVF. However, a clear view of its virtues and defects is still lacking, because only a few prospective randomized trials comparing "mild" vs. conventional stimulation exist, and they do not consider some important aspects, such as, e.g., thawing cycles. This review gives a complete panorama of the "mild" stimulation philosophy, showing its advantages vs. conventional ovarian stimulation, but also discussing its disadvantages. Both patients with a normal ovarian responsiveness to exogenous gonadotropins and women with a poor ovarian reserve are considered. Overall, we conclude that the level of evidence supporting the use of "mild" stimulation protocols is still rather poor, and further, properly powered prospective studies about "mild" treatment regimens are required. PMID- 21324156 TI - Social and cultural factors underlying generational differences in overweight: a cross-sectional study among ethnic minorities in the Netherlands. AB - BACKGROUND: The prevalence of overweight appears to vary in people of first and second generation ethnic minority groups. Insight into the factors that underlie these weight differences might help in understanding the health transition that is taking place across generations following migration. We studied the role of social and cultural factors associated with generational differences in overweight among young Turkish and Moroccan men and women in the Netherlands. METHODS: Cross-sectional data were derived from the LASER-study in which information on health-related behaviour and socio-demographic factors, level of education, occupational status, acculturation (cultural orientation and social contacts), religious and migration-related factors was gathered among Turkish and Moroccan men (n = 334) and women (n = 339) aged 15-30 years. Participants were interviewed during a home visit. Overweight was defined as a Body Mass Index >= 25 kg/m2. Using logistic regression analyses, we tested whether the measured social and cultural factors could explain differences in overweight between first and second generation ethnic groups. RESULTS: Second generation women were less often overweight than first generation women (21.8% and 45.0% respectively), but this association was no longer significant when adjusting for the socioeconomic position (i.e. higher level of education) of second generation women (Odds Ratio (OR) = 0.77, 95%, Confidence Interval (CI) 0.40-1.46). In men, we observed a reversed pattern: second generation men were more often overweight than first generation men (32.7% and 27.8%). This association (OR = 1.89, 95% CI 1.09-3.24) could not be explained by the social and cultural factors because none of these factors were associated with overweight among men. CONCLUSIONS: The higher socio economic position of second generation Turkish and Moroccan women may partly account for the lower prevalence of overweight in this group compared to first generation women. Further research is necessary to elucidate whether any postulated socio-biological or other processes are relevant to the opposite pattern of overweight among men. PMID- 21324157 TI - Multi-genome identification and characterization of chlamydiae-specific type III secretion substrates: the Inc proteins. AB - BACKGROUND: Chlamydiae are obligate intracellular bacteria that multiply in a vacuolar compartment, the inclusion. Several chlamydial proteins containing a bilobal hydrophobic domain are translocated by a type III secretion (TTS) mechanism into the inclusion membrane. They form the family of Inc proteins, which is specific to this phylum. Based on their localization, Inc proteins likely play important roles in the interactions between the microbe and the host. In this paper we sought to identify and analyze, using bioinformatics tools, all putative Inc proteins in published chlamydial genomes, including an environmental species. RESULTS: Inc proteins contain at least one bilobal hydrophobic domain made of two transmembrane helices separated by a loop of less than 30 amino acids. Using bioinformatics tools we identified 537 putative Inc proteins across seven chlamydial proteomes. The amino-terminal segment of the putative Inc proteins was recognized as a functional TTS signal in 90% of the C. trachomatis and C. pneumoniae sequences tested, validating the data obtained in silico. We identified a macro domain in several putative Inc proteins, and observed that Inc proteins are enriched in segments predicted to form coiled coils. A surprisingly large proportion of the putative Inc proteins are not constitutively translocated to the inclusion membrane in culture conditions. CONCLUSIONS: The Inc proteins represent 7 to 10% of each proteome and show a great degree of sequence diversity between species. The abundance of segments with a high probability for coiled coil conformation in Inc proteins support the hypothesis that they interact with host proteins. While the large majority of Inc proteins possess a functional TTS signal, less than half may be constitutively translocated to the inclusion surface in some species. This suggests the novel finding that translocation of Inc proteins may be regulated by as-yet undetermined mechanisms. PMID- 21324158 TI - Strain-specific copy number variation in the intelectin locus on the 129 mouse chromosome 1. AB - BACKGROUND: C57BL/6J mice possess a single intelectin (Itln) gene on chromosome 1. The function of intelectins is not well understood, but roles have been postulated in insulin sensitivity, bacterial recognition, intestinal lactoferrin uptake and response to parasites and allergens. In contrast to C57BL/6J mice, there is evidence for expansion of the Itln locus in other strains and at least one additional mouse Itln gene product has been described. The aim of this study was to sequence and characterise the Itln locus in the 129S7 strain, to determine the nature of the chromosomal expansion and to inform possible future gene deletion strategies. RESULTS: Six 129S7 BAC clones were sequenced and assembled to generate 600 kbp of chromosomal sequence, including the entire Itln locus of approximately 500 kbp. The locus contained six distinct Itln genes, two CD244 genes and several Itln- and CD244-related pseudogenes. It was approximately 433 kbp larger than the corresponding C57BL/6J locus. The expansion of the Itln locus appears to have occurred through multiple duplications of a segment consisting of a full-length Itln gene, a CD244 (pseudo)gene and an Itln pseudogene fragment. Strong evidence for tissue-specific distribution of Itln variants was found, indicating that Itln duplication contributes more than a simple gene dosage effect. CONCLUSIONS: We have characterised the Itln locus in 129S7 mice to reveal six Itln genes with distinct sequence and expression characteristics. Since C57BL/6J mice possess only a single Itln gene, this is likely to contribute to functional differences between C57BL/6J and other mouse strains. PMID- 21324159 TI - Bacteremia is an independent risk factor for mortality in nosocomial pneumonia: a prospective and observational multicenter study. AB - INTRODUCTION: Since positive blood cultures are uncommon in patients with nosocomial pneumonia (NP), the responsible pathogens are usually isolated from respiratory samples. Studies on bacteremia associated with hospital-acquired pneumonia (HAP) have reported fatality rates of up to 50%. The purpose of the study is to compare risk factors, pathogens and outcomes between bacteremic nosocomial pneumonia (B-NP) and nonbacteremic nosocomial pneumonia (NB-NP) episodes. METHODS: This is a prospective, observational and multicenter study (27 intensive care units in nine European countries). Consecutive patients requiring invasive mechanical ventilation for an admission diagnosis of pneumonia or on mechanical ventilation for > 48 hours irrespective of admission diagnosis were recruited. RESULTS: A total of 2,436 patients were evaluated; 689 intubated patients presented with NP, 224 of them developed HAP and 465 developed ventilation-acquired pneumonia. Blood samples were extracted in 479 (69.5%) patients, 70 (14.6%) being positive. B-NP patients had higher Simplified Acute Physiology Score (SAPS) II score (51.5 +/- 19.8 vs. 46.6 +/- 17.5, P = 0.03) and were more frequently medical patients (77.1% vs. 60.4%, P = 0.01). Mortality in the intensive care unit was higher in B-NP patients compared with NB-NP patients (57.1% vs. 33%, P < 0.001). B-NP patients had a more prolonged mean intensive care unit length of stay after pneumonia onset than NB-NP patients (28.5 +/- 30.6 vs. 20.5 +/- 17.1 days, P = 0.03). Logistic regression analysis confirmed that medical patients (odds ratio (OR) = 5.72, 95% confidence interval (CI) = 1.93 to 16.99, P = 0.002), methicillin-resistant Staphylococcus aureus (MRSA) etiology (OR = 3.42, 95% CI = 1.57 to 5.81, P = 0.01), Acinetobacter baumannii etiology (OR = 4.78, 95% CI = 2.46 to 9.29, P < 0.001) and days of mechanical ventilation (OR = 1.02, 95% CI = 1.01 to 1.03, P < 0.001) were independently associated with B-NP episodes. Bacteremia (OR = 2.01, 95% CI = 1.22 to 3.55, P = 0.008), diagnostic category (medical patients (OR = 3.71, 95% CI = 2.01 to 6.95, P = 0.02) and surgical patients (OR = 2.32, 95% CI = 1.10 to 4.97, P = 0.03)) and higher SAPS II score (OR = 1.02, 95% CI = 1.01 to 1.03, P = 0.008) were independent risk factors for mortality. CONCLUSIONS: B-NP episodes are more frequent in patients with medical admission, MRSA and A. baumannii etiology and prolonged mechanical ventilation, and are independently associated with higher mortality rates. PMID- 21324160 TI - Phase i study of 'dose-dense' pemetrexed plus carboplatin/radiotherapy for locally advanced non-small cell lung carcinoma. AB - BACKGROUND: This phase I study investigates the feasibility of carboplatin plus dose-dense (q2-week) pemetrexed given concurrently with radiotherapy (XRT) for locally advanced and oligometastatic non-small cell lung cancer (NSCLC). METHODS: Eligible patients had Stage III or IV (oligometastatic) NSCLC. Patients received XRT to 63 Gy in standard fractionation. Patients received concurrent carboplatin (AUC = 6) during weeks 1 and 5 of XRT, and pemetrexed during weeks 1, 3, 5, and 7 of XRT. The starting dose level (level 1) of pemetrexed was 300 mg/m2. Following the finding of dose limiting toxicity (DLT) in dose level 1, an amended dose level (level 1A) continued pemetrexed at 300 mg/m2, but with involved field radiation instead of extended nodal irradiation. Consolidation consisted of carboplatin (AUC = 6) and pemetrexed (500 mg/m2) q3 weeks * 2 -3 cycles. RESULTS: Eighteen patients were enrolled. Fourteen patients are evaluable for toxicity analysis. Of the initial 6 patients treated on dose level 1, two experienced DLTs (one grade 4 sepsis, one prolonged grade 3 esophagitis). There was one DLT (grade 5 pneumonitis) in the 8 patients treated on dose level 1A. In 16 patients evaluable for response (4 with oligometastatic stage IV disease and 12 with stage III disease), the median follow-up time is 17.8 months. Thirteen of 16 patients had in field local regional response. The actuarial median survival time was 28.6 months in all patients and 34.7 months (estimated) in stage III patients. CONCLUSIONS: Concurrent carboplatin with dose-dense (q2week) pemetrexed at 300 mg/m2 with involved field XRT is feasible and encouraging in patients with locally advanced and oligometastatic NSCLC. PMID- 21324161 TI - Monitoring of clinical efficacy and in vitro sensitivity of Plasmodium vivax to chloroquine in area along Thai Myanmar border during 2009-2010. AB - BACKGROUND: In Thailand, the proportion of Plasmodium vivax infection has become equal to Plasmodium falciparum. Reports of a trend of gradual decline of in vitro sensitivity of P. vivax to chloroquine in some areas of the country, together with accumulating evidences of chloroquine resistance P. vivax in other parts of the world, emphasize the need for closely and continuously monitoring clinical efficacy in conjunction with in vitro sensitivity of P. vivax isolates. METHODS: The study was conducted at Mae Tao clinic for migrant workers, Tak Province during March 2008-August 2009. A total of 130 patients (17 Thais and 113 Burmeses; 64 males and 66 females) with mono-infection of P. vivax malaria, aged between 15-60 years and weighing more than 40 kg, were included in the study. Patients received treatment with chloroquine (2,000 mg chloroquine phosphate over three days) and the anti-relapse drug primaquine (15 mg for 14 days). In vitro sensitivity of P. vivax isolates was evaluated by schizont maturation inhibition assay. RESULTS: All patients showed satisfactory response to treatment. The cure rate was virtually 100% within the follow-up period of 42 days. Neither recurrence of P. vivax parasitaemia nor appearance of P. falciparum occurred during the investigation period. In vitro data showed a stable sensitivity of chloroquine in this area since 2006. Geometric mean and median (95% CI) values of IC50 for chloroquine were 100.1 and 134.7 (1.1-264.9) nM, respectively. CONCLUSION: In vivo results suggest that the standard regimen of chloroquine was still very effective for the treatment of blood infections with P. vivax in the Thai-Myanmar border area. In vitro sensitivity data however, raise the possibility of potential advent of resistance in the future. Regular monitoring of the chloroquine sensitivity of P. vivax is essential to facilitate the early recognition of treatment failures and to expedite the formulation of appropriate changes to the drug policy. PMID- 21324163 TI - High cell density cultivation of Escherichia coli K4 in a microfiltration bioreactor: a step towards improvement of chondroitin precursor production. AB - BACKGROUND: The bacteria Escherichia coli K4 produces a capsular polysaccharide (K4 CPS) whose backbone is similar to the non sulphated chondroitin chain. The chondroitin sulphate is one of the major components of the extra-cellular matrix of the vertebrate connective tissues and a high value molecule, widely employed as active principle in the treatment of osteoarthritis. It is usually obtained by extraction from animal tissues, but the risk of virus contaminations, as well as the scarceness of raw material, makes this productive process unsafe and unable to satisfy the growing market demand. In previous studies a new biotechnological process to produce chondroitin from Escherichia coli K4 capsular polysaccharide was investigated and a 1.4 g.L(-1) K4 CPS concentration was reached using fed batch fermentation techniques. In this work, on the trail of these results, we exploited new fermentation strategies to further improve the capsular polysaccharide production. RESULTS: The inhibitory effect of acetate on the bacterial cells growth and K4 CPS production was studied in shake flask conditions, while a new approach, that combined the optimization of the feeding profiles, the improvement of aeration conditions and the use of a microfiltration bioreactor, was investigated in three different types of fermentation processes. High polysaccharide concentrations (4.73 +/- 0.2 g.L(-1)), with corresponding average yields (0.13 +/- 0.006 gK4 CPS.gcdw(-1)), were obtained; the increase of K4 CPS titre, compared to batch and fed-batch results, was of 16-fold and 3.3 fold respectively, while average yield was almost 3.5 and 1.4 fold higher. CONCLUSION: The increase of capsular polysaccharide titre confirmed the validity of the proposed fermentation strategy and opened the way to the use of the microfiltration bioreactor for the biotechnological production of chondroitin. PMID- 21324162 TI - SDF1 in the dorsal corticospinal tract promotes CXCR4+ cell migration after spinal cord injury. AB - BACKGROUND: Stromal cell-derived factor-1 (SDF1) and its major signaling receptor, CXCR4, were initially described in the immune system; however, they are also expressed in the nervous system, including the spinal cord. After spinal cord injury, the blood brain barrier is compromised, opening the way for chemokine signaling between these two systems. These experiments clarified prior contradictory findings on normal expression of SDF1 and CXCR4 as well as examined the resulting spinal cord responses resulting from this signaling. METHODS: These experiments examined the expression and function of SDF1 and CXCR4 in the normal and injured adult mouse spinal cord primarily using CXCR4-EGFP and SDF1-EGFP transgenic reporter mice. RESULTS: In the uninjured spinal cord, SDF1 was expressed in the dorsal corticospinal tract (dCST) as well as the meninges, whereas CXCR4 was found only in ependymal cells surrounding the central canal. After spinal cord injury (SCI), the pattern of SDF1 expression did not change rostral to the lesion but it disappeared from the degenerating dCST caudally. By contrast, CXCR4 expression changed dramatically after SCI. In addition to the CXCR4+ cells in the ependymal layer, numerous CXCR4+ cells appeared in the peripheral white matter and in the dorsal white matter localized between the dorsal corticospinal tract and the gray matter rostral to the lesion site. The non-ependymal CXCR4+ cells were found to be NG2+ and CD11b+ macrophages that presumably infiltrated through the broken blood-brain barrier. One population of macrophages appeared to be migrating towards the dCST that contains SDF1 rostral to the injury but not towards the caudal dCST in which SDF1 is no longer present. A second population of the CXCR4+ macrophages was present near the SDF1 expressing meningeal cells. CONCLUSIONS: These observations suggest that attraction of CXCR4+ macrophages is part of a programmed response to injury and that modulation of the SDF1 signaling system may be important for regulating the inflammatory response after SCI. PMID- 21324164 TI - The relationship between indoleamine 2,3-dioxygenase activity and post-stroke cognitive impairment. AB - BACKGROUND: Activation of indoleamine 2,3-dioxygenase (IDO) and higher concentrations of several kynurenine metabolites have been observed post-stroke, where they have been associated with increased mortality. While lower tryptophan or a higher ratio of kynurenine/tryptophan (K/T) in peripheral blood have been associated with dementia and the severity of cognitive symptoms in Alzheimer's disease, the association between K/T ratios and post-stroke cognitive impairment (PSCI) has not been investigated. METHODS: Patients were recruited from the acute stroke unit of a general hospital within 1 month post-stroke. Assessments included the Standardized Mini-Mental State Examination (sMMSE) for cognition, the National Institutes of Health Stroke Scale (NIHSS) for stroke severity, and the Center for Epidemiological Studies-Depression Scale (CES-D) for depressive symptoms. Tryptophan and kynurenine concentrations were determined by high performance liquid chromatography. RESULTS: A total of 41 patients with ischemic stroke ([mean +/- SD] age 72.3 +/- 12.2 years, 53.7% male, sMMSE 25.6 +/- 4.1, NIHSS 7.27 +/- 5.55) were recruited. Higher K/T ratios were associated with lower post-stroke global cognition (i.e. sMMSE scores; beta = -.327, P = .037). A backward stepwise elimination linear regression (F1,40=6.15, P=.005, adjusted R2=.205) showed that the highest K/T ratio tertile (beta = -.412, P = .006) predicted lower sMMSE scores, controlling for age (beta = -.253, p = .081), with NIHSS (beta = -.027, P = 0.859), and lesion volume (beta = -.066, P = 0.659) removed from the model. In receiver operating characteristic analysis, a K/T ratio of 78.3 MUmol/mmol (top tertile) predicted significant cognitive impairment (sMMSE score <= 24) with 67% sensitivity and 86% specificity (area under the curve = 0.730, p = .022). CONCLUSIONS: These data suggest an inflammatory response characterized by IDO activation may be relevant to the development of PSCI. Since the neuroactivity of kynurenine metabolites may be amenable to pharmacotherapeutic intervention, the K/T ratio may be a clinically important biomarker. PMID- 21324165 TI - Transcription factors zeb1, twist and snai1 in breast carcinoma. AB - BACKGROUND: Epitheliomesenchymal transition (EMT) is the process where cancer cells attain fibroblastic features and are thus able to invade neighboring tissues. Transcriptional factors zeb1, snai1 and twist regulate EMT. METHODS: We used immunohistochemistry to investigate the expression of zeb1, twist and snai1 in tumor and stromal compartments by in a large set of breast carcinomas. The results were compared with estrogen and progesterone receptor status, HER2 amplification, grade, histology, TNM status and survival of the patients. RESULTS: Nuclear expression for twist was seen in the epithelial tumor cell compartment in 3.6% and for snai1 in 3.1% of the cases while zeb1 was not detected at all in these areas. In contrast, the tumor stromal compartment showed nuclear zeb1 and twist expression in 75% and 52.4% of the cases, respectively. Although rare, nuclear expression of twist in the epithelial tumor cell compartment was associated with a poor outcome of the patients (p = 0.054 log rank, p = 0.013, Breslow, p = 0.025 Tarone-Ware). Expression of snai1, or expression of zeb1 or twist in the stromal compartment did not have any prognostic significance. Furthermore, none of these factors associated with the size of the tumors, nor with the presence of axillary or distant metastases. Expression of zeb1 and twist in the stromal compartment was positively associated with a positive estrogen or progesterone receptor status of the tumors. Stromal zeb1 expression was significantly lower in ductal in situ carcinomas than in invasive carcinomas (p = 0.020). Medullary carcinomas (p = 0.017) and mucinous carcinomas (p = 0.009) had a lower stromal expression of zeb1 than ductal carcinomas. Stromal twist expression was also lower in mucinous (p = 0.017) than in ductal carcinomas. CONCLUSIONS: Expression of transcriptional factors zeb1 and twist mainly occur in the stromal compartment of breast carcinomas, possibly representing two populations of cells; EMT transformed neoplastic cells and stromal fibroblastic cells undergoing activation of zeb1 and twist due to growth factors produced by the tumor. However, epithelial expression of twist was associated with a poor prognosis, hinting at its importance in the spread of breast carcinoma. PMID- 21324166 TI - Clinical and molecular characterization of ataxia with oculomotor apraxia patients in Saudi Arabia. AB - BACKGROUND: Autosomal recessive ataxias represent a group of clinically overlapping disorders. These include ataxia with oculomotor apraxia type1 (AOA1), ataxia with oculomotor apraxia type 2 (AOA2) and ataxia-telangiectasia-like disease (ATLD). Patients are mainly characterized by cerebellar ataxia and oculomotor apraxia. Although these forms are not quite distinctive phenotypically, different genes have been linked to these disorders. Mutations in the APTX gene were reported in AOA1 patients, mutations in SETX gene were reported in patients with AOA2 and mutations in MRE11 were identified in ATLD patients. In the present study we describe in detail the clinical features and results of genetic analysis of 9 patients from 4 Saudi families with ataxia and oculomotor apraxia. METHODS: This study was conducted in the period between 2005 2010 to clinically and molecularly characterize patients with AOA phenotype. Comprehensive sequencing of all coding exons of previously reported genes related to this disorder (APTX, SETX and MRE11). RESULTS: A novel nonsense truncating mutation c.6859 C > T, R2287X in SETX gene was identified in patients from one family with AOA2. The previously reported missense mutation W210C in MRE11 gene was identified in two families with autosomal recessive ataxia and oculomotor apraxia. CONCLUSION: Mutations in APTX , SETX and MRE11 are common in patients with autosomal recessive ataxia and oculomotor apraxia. The results of the comprehensive screening of these genes in 4 Saudi families identified mutations in SETX and MRE11 genes but failed to identify mutations in APTX gene. PMID- 21324167 TI - Periodontal treatment effects on endothelial function and cardiovascular disease biomarkers in subjects with chronic periodontitis: protocol for a randomized clinical trial. AB - BACKGROUND: Periodontal disease (PD) is an infectious clinical entity characterized by the destruction of supporting tissues of the teeth as the result of a chronic inflammatory response in a susceptible host. It has been proposed that PD as subclinical infection may contribute to the etiology and to the pathogenesis of several systemic diseases including Atherosclerosis. A number of epidemiological studies link periodontal disease/edentulism as independent risk factor for acute myocardial infarction, peripheral vascular disease, and cerebrovascular disease. Moreover, new randomized controlled clinical trials have shown an improvement on cardiovascular surrogate markers (endothelial function, sICAM, hsPCR level, fibrinogen) after periodontal treatment. Nonetheless, such trials are still limited in terms of external validity, periodontal treatment strategies, CONSORT-based design and results consistency/extrapolation. The current study is designed to evaluate if periodontal treatment with scaling and root planning plus local delivered chlorhexidine improves endothelial function and other biomarkers of cardiovascular disease in subjects with moderate to severe periodontitis. METHODS/DESIGN: This randomized, single-blind clinical trial will be performed at two health centers and will include two periodontal treatment strategies. After medical/periodontal screening, a baseline endothelium dependent brachial artery flow-mediated dilatation (FMD) and other systemic surrogate markers will be obtained from all recruited subjects. Patients then will be randomized to receive either supragingival/subgingival plaque cleaning and calculus removal plus chlorhexidine (treatment group) or supragingival plaque removal only (control group). A second and third FMD will be obtained after 24 hours and 12 weeks in both treatment arms. Each group will consist of 49 patients (n = 98) and all patients will be followed-up for secondary outcomes and will be monitored through a coordinating center. The primary outcomes are FMD differences baseline, 24 hours and 3 months after treatment. The secondary outcomes are differences in C-reactive protein (hs-CRP), glucose serum levels, blood lipid profile, and HOMA index. DISCUSSION: This RCT is expected to provide more evidence on the effects of different periodontal treatment modalities on FMD values, as well as to correlate such findings with different surrogate markers of systemic inflammation with cardiovascular effects. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT00681564. PMID- 21324168 TI - Highly conserved serine residue 40 in HIV-1 p6 regulates capsid processing and virus core assembly. AB - BACKGROUND: The HIV-1 p6 Gag protein regulates the final abscission step of nascent virions from the cell membrane by the action of two late assembly (L-) domains. Although p6 is located within one of the most polymorphic regions of the HIV-1 gag gene, the 52 amino acid peptide binds at least to two cellular budding factors (Tsg101 and ALIX), is a substrate for phosphorylation, ubiquitination, and sumoylation, and mediates the incorporation of the HIV-1 accessory protein Vpr into viral particles. As expected, known functional domains mostly overlap with several conserved residues in p6. In this study, we investigated the importance of the highly conserved serine residue at position 40, which until now has not been assigned to any known function of p6. RESULTS: Consistently with previous data, we found that mutation of Ser-40 has no effect on ALIX mediated rescue of HIV-1 L-domain mutants. However, the only feasible S40F mutation that preserves the overlapping pol open reading frame (ORF) reduces virus replication in T-cell lines and in human lymphocyte tissue cultivated ex vivo. Most intriguingly, L-domain mediated virus release is not dependent on the integrity of Ser-40. However, the S40F mutation significantly reduces the specific infectivity of released virions. Further, it was observed that mutation of Ser-40 selectively interferes with the cleavage between capsid (CA) and the spacer peptide SP1 in Gag, without affecting cleavage of other Gag products. This deficiency in processing of CA, in consequence, led to an irregular morphology of the virus core and the formation of an electron dense extra core structure. Moreover, the defects induced by the S40F mutation in p6 can be rescued by the A1V mutation in SP1 that generally enhances processing of the CA-SP1 cleavage site. CONCLUSIONS: Overall, these data support a so far unrecognized function of p6 mediated by Ser-40 that occurs independently of the L-domain function, but selectively affects CA maturation and virus core formation, and consequently the infectivity of released virions. PMID- 21324169 TI - Evaluating the efficacy of sequential biologic therapies for rheumatoid arthritis patients with an inadequate response to tumor necrosis factor-alpha inhibitors. AB - INTRODUCTION: The long-term treatment of rheumatoid arthritis (RA) most often involves a sequence of different therapies. The response to therapy, disease progression and detailed knowledge of the role of different therapies along treatment pathways are key aspects to help physicians identify the best treatment strategy. Thus, understanding the effectiveness of different therapeutic sequences is of particular importance in the evaluation of long-term RA treatment strategies. The objective of this study was to systematically review and quantitatively evaluate the relationship between the clinical response to biologic treatments and the number of previous treatments with tumor necrosis factor alpha (TNF-alpha) inhibitors. METHODS: A systematic search was undertaken to identify published, peer-reviewed articles that reported clinical outcomes of biologic treatment among RA patients with an inadequate response to TNF-alpha inhibitors. Data were systematically abstracted. Efficacy rates were estimated for groups of patients who differed in the number of prior TNF-alpha inhibitors used. End points included American College of Rheumatology (ACR)-, European League Against Rheumatism (EULAR)- and Disease Activity Score 28 (DAS28)-based response criteria. RESULTS: The literature search identified 41 publications, of which 28 reported biologic treatment outcomes for RA patients with prior exposure to TNF-alpha inhibitors. Seven publications reported outcomes obtained in randomized clinical trials, while the remaining consisted of observational studies. The likelihood of responding to a subsequent biologic treatment decreased as the number of previous treatments with TNF-alpha inhibitors increased for six of the seven response criteria examined. CONCLUSIONS: For patients with prior exposure to TNF-alpha inhibitors, the likelihood of response to subsequent treatment with biologic agents declines with the increasing number of previous treatments with TNF-alpha inhibitors. PMID- 21324170 TI - Microarray profiling for differential gene expression in PMSG-hCG stimulated preovulatory ovarian follicles of Chinese Taihu and Large White sows. AB - BACKGROUND: The Chinese Taihu is one of the most prolific pig breeds in the world, which farrows at least five more piglets per litter than Western pig breeds partly due to a greater ovulation rate. Variation of ovulation rate maybe associated with the differences in the transcriptome of Chinese Taihu and Large White ovaries. In order to understand the molecular basis of the greater ovulation rate of Chinese Taihu sows, expression profiling experiments were conducted to identify differentially expressed genes in ovarian follicles at the preovulatory stage of a PMSG-hCG stimulated estrous cycle from 3 Chinese Taihu and 3 Large White cycling sows by using the Affymetrix Porcine GenechipTM. RESULTS: One hundred and thirty-three differentially expressed genes were identified between Chinese Taihu and Large White sows by using Affymetrix porcine GeneChip (p <= 0.05, Fold change >= 2 or <= 0.5). Gene Ontology (GO) analysis revealed that these genes belonged to the class of genes that participated in regulation of cellular process, regulation of biological process, biological regulation, developmental process, cell communication and signal transduction and so on. Significant differential expression of 6 genes including WNT10B and DKK2 in the WNT signaling pathway was detected. Real-time RT-PCR confirmed the expression pattern in seven of eight selected genes. A search of chromosomal location revealed that 92 differentially expressed transcripts located to the intervals of quantitative trait loci (QTLs) for reproduction traits. Furthermore, SNPs of two differentially expressed genes- BAX and BMPR1B were showed to be associated with litter size traits in Large White pigs and Chinese DIV line pigs (p <= 0.1 or p <= 0.05). CONCLUSIONS: Our study detected many genes that showed differential expression between ovary follicles of two divergent breeds of pigs. Genes involved with regulation of cellular process, regulation of biological process, in addition to several genes not previously associated with ovarian physiology or with unknown function, were differentially expressed between two breeds. The suggestive or significant associations of BAX and BMPR1B gene with litter size indicated these genetic markers had the potentials to be used in pig industry after further validation of their genetic effects. Taken together, this study reveals many potential avenues of investigation for seeking new insights into ovarian physiology and the genetic control of reproduction. PMID- 21324171 TI - Parental control and monitoring of young people's sexual behaviour in rural North Western Tanzania: implications for sexual and reproductive health interventions. AB - BACKGROUND: Parenting through control and monitoring has been found to have an effect on young people's sexual behaviour. There is a dearth of literature from sub-Saharan Africa on this subject. This paper examines parental control and monitoring and the implications of this on young people's sexual decision making in a rural setting in North-Western Tanzania. METHODS: This study employed an ethnographic research design. Data collection involved 17 focus group discussions and 46 in-depth interviews conducted with young people aged 14-24 years and parents/carers of young people within this age-group. Thematic analysis was conducted with the aid of NVIVO 7 software. RESULTS: Parents were motivated to control and monitor their children's behaviour for reasons such as social respectability and protecting them from undesirable sexual and reproductive health (SRH) outcomes. Parental control and monitoring varied by family structure, gender, schooling status, a young person's contribution to the economic running of the family and previous experience of a SRH outcome such as unplanned pregnancy. Children from single parent families reported that they received less control compared to those from both parent families. While a father's presence in the family seemed important in controlling the activities of young people, a mother's did not have a similar effect. Girls especially those still schooling received more supervision compared to boys. Young women who had already had unplanned pregnancy were not supervised as closely as those who hadn't. Parents employed various techniques to control and monitor their children's sexual activities. CONCLUSIONS: Despite parents making efforts to control and monitor their young people's sexual behaviour, they are faced with several challenges (e.g. little time spent with their children) which make it difficult for them to effectively monitor them. There is a need for interventions such as parenting skills building that might enable parents to improve their relationships with children. This would equip parents with the appropriate skills for positive guidance and monitoring of their children and avoid inappropriate parenting behaviour. As much as parents focus their attention on their school going daughters, there is a need to also remember the out-of-school young people as they are also vulnerable to adverse SRH outcomes. PMID- 21324172 TI - Process evaluation of a web-based intervention aimed at empowerment of disability benefit claimants. AB - BACKGROUND: The objective of this process evaluation study was to gain insight into the reach, compliance, appreciation, usage barriers, and users' perceived effectiveness of a web-based intervention http://www.wiagesprek.nl. This intervention was aimed at empowerment of disability claimants, prior to the assessment of disability by an insurance physician. METHODS: Reach was determined by registering claimants exposed to the study's invitation brochures, and by comparing trial participant characteristics with non-participants and nationwide claimant data. Compliance was registered by analyzing weblogs, which were automatically collected during the period of the trial. This made it possible to analyze individual use of the intervention. Appreciation, usage barriers, and users' perceived effectiveness were assessed using an online questionnaire that was sent to participants from the intervention group, 6 weeks after enrolment. RESULTS: Only 9% of the target population enrolled in the internet program. Because of selective enrolment, more females, higher educated claimants, and less ethnical minorities were reached. Compliance was ambiguous: out of the 123 participants randomized into the intervention group, a significant proportion (33%) did not use the intervention at all, while, at the same time, many participants (32%) used the intervention for more than two hours (i.e. in approximately two weeks). Overall satisfaction with the intervention was good. Claimants perceived the intervention most effective in increasing knowledge, while also a fair amount of users perceived the intervention effective in gaining right expectations or being able to communicate better with their physician. CONCLUSIONS: The uptake of the intervention http://www.wiagesprek.nl was disappointing. Specifically, the poor reach and compliance of the intervention resulted in a small proportion of the target population using the intervention as intended. Improvements in the implementation process are desirable to increase the reach and compliance and, thereby possibly, the impact of the intervention. TRIAL REGISTRATION: NTR-1414. PMID- 21324173 TI - A statistical framework for modeling gene expression using chromatin features and application to modENCODE datasets. AB - We develop a statistical framework to study the relationship between chromatin features and gene expression. This can be used to predict gene expression of protein coding genes, as well as microRNAs. We demonstrate the prediction in a variety of contexts, focusing particularly on the modENCODE worm datasets. Moreover, our framework reveals the positional contribution around genes (upstream or downstream) of distinct chromatin features to the overall prediction of expression levels. PMID- 21324174 TI - Assessment and validation of a suite of reverse transcription-quantitative PCR reference genes for analyses of density-dependent behavioural plasticity in the Australian plague locust. AB - BACKGROUND: The Australian plague locust, Chortoicetes terminifera, is among the most promising species to unravel the suites of genes underling the density dependent shift from shy and cryptic solitarious behaviour to the highly active and aggregating gregarious behaviour that is characteristic of locusts. This is because it lacks many of the major phenotypic changes in colour and morphology that accompany phase change in other locust species. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) is the most sensitive method available for determining changes in gene expression. However, to accurately monitor the expression of target genes, it is essential to select an appropriate normalization strategy to control for non-specific variation between samples. Here we identify eight potential reference genes and examine their expression stability at different rearing density treatments in neural tissue of the Australian plague locust. RESULTS: Taking advantage of the new orthologous DNA sequences available in locusts, we developed primers for genes encoding 18SrRNA, ribosomal protein L32 (RpL32), armadillo (Arm), actin 5C (Actin), succinate dehydrogenase (SDHa), glyceraldehyde-3P-dehydrogenase (GAPDH), elongation factor 1 alpha (EF1a) and annexin IX (AnnIX). The relative transcription levels of these eight genes were then analyzed in three treatment groups differing in rearing density (isolated, short- and long-term crowded), each made up of five pools of four neural tissue samples from 5th instar nymphs. SDHa and GAPDH, which are both involved in metabolic pathways, were identified as the least stable in expression levels, challenging their usefulness in normalization. Based on calculations performed with the geNorm and NormFinder programs, the best combination of two genes for normalization of gene expression data following crowding in the Australian plague locust was EF1a and Arm. We applied their use to studying a target gene that encodes a Ca2+ binding glycoprotein, SPARC, which was previously found to be up-regulated in brains of gregarious desert locusts, Schistocerca gregaria. Interestingly, expression of this gene did not vary with rearing density in the same way in brains of the two locust species. Unlike S. gregaria, there was no effect of any crowding treatment in the Australian plague locust. CONCLUSION: Arm and EF1a is the most stably expressed combination of two reference genes of the eight examined for reliable normalization of RT-qPCR assays studying density-dependent behavioural change in the Australian plague locust. Such normalization allowed us to show that C. terminifera crowding did not change the neuronal expression of the SPARC gene, a gregarious phase-specific gene identified in brains of the desert locust, S. gregaria. Such comparative results on density-dependent gene regulation provide insights into the evolution of gregarious behaviour and mass migration of locusts. The eight identified genes we evaluated are also candidates as normalization genes for use in experiments involving other Oedipodinae species, but the rank order of gene stability must necessarily be determined on a case-by-case basis. PMID- 21324175 TI - Sickness absence in musculoskeletal disorders - patients' experiences of interactions with the social insurance agency and health care. A qualitative study. AB - BACKGROUND: Sickness absence has represented a growing public health problem in many Western countries over the last decade. In Sweden disorders of the musculoskeletal system cause approximately one third of all sick leave. The Social Insurance Agency (SIA) and the health care system are important actors in handling the sickness absence process. The objective was to study how patients with personal experience of sickness absence due to musculoskeletal disorders perceived their contact with these actors and what they considered as obstructing or facilitating factors for recovery and return to work in this situation. METHODS: In-depth interviews using open-ended questions were conducted with fifteen informants (aged 33-63, 11 women), all with experience of sickness absence due to musculoskeletal disorders and purposefully recruited to represent various backgrounds as regards diagnosis, length of sick leave and return to work. The interviews were audio-recorded, transcribed verbatim and analysed using content analysis. RESULTS: The informants' perceived the interaction with the SIA and health care as ranging from coherent to fragmented. Being on sick leave was described as going through a process of adjustment in both private and working life. This process of adjustment was interactive and included not only the possibilities to adjust work demands and living conditions but also personal and emotional adjustment. The informants' experiences of fragmented interaction reflected a sense that their entire situation was not being taken into account. Coherent interaction was described as facilitating recovery and return to work, while fragmented interaction was described as obstructing this. The complex division of responsibilities within the Swedish rehabilitation system may hamper sickness absentees' possibilities of taking responsibility for their own rehabilitation. CONCLUSIONS: This study shows that people on sick leave considered the interaction with the SIA and health care as an important part of the rehabilitation process. The contact with these actors was perceived as affecting recovery and return to work. Working for a more coherent process of rehabilitation and offering professional guidance to patients on sick leave might have an empowering effect. PMID- 21324176 TI - Arsenal of plant cell wall degrading enzymes reflects host preference among plant pathogenic fungi. AB - BACKGROUND: The discovery and development of novel plant cell wall degrading enzymes is a key step towards more efficient depolymerization of polysaccharides to fermentable sugars for the production of liquid transportation biofuels and other bioproducts. The industrial fungus Trichoderma reesei is known to be highly cellulolytic and is a major industrial microbial source for commercial cellulases, xylanases and other cell wall degrading enzymes. However, enzyme prospecting research continues to identify opportunities to enhance the activity of T. reesei enzyme preparations by supplementing with enzymatic diversity from other microbes. The goal of this study was to evaluate the enzymatic potential of a broad range of plant pathogenic and non-pathogenic fungi for their ability to degrade plant biomass and isolated polysaccharides. RESULTS: Large-scale screening identified a range of hydrolytic activities among 348 unique isolates representing 156 species of plant pathogenic and non-pathogenic fungi. Hierarchical clustering was used to identify groups of species with similar hydrolytic profiles. Among moderately and highly active species, plant pathogenic species were found to be more active than non-pathogens on six of eight substrates tested, with no significant difference seen on the other two substrates. Among the pathogenic fungi, greater hydrolysis was seen when they were tested on biomass and hemicellulose derived from their host plants (commelinoid monocot or dicot). Although T. reesei has a hydrolytic profile that is highly active on cellulose and pretreated biomass, it was less active than some natural isolates of fungi when tested on xylans and untreated biomass. CONCLUSIONS: Several highly active isolates of plant pathogenic fungi were identified, particularly when tested on xylans and untreated biomass. There were statistically significant preferences for biomass type reflecting the monocot or dicot host preference of the pathogen tested. These highly active fungi are promising targets for identification and characterization of novel cell wall degrading enzymes for industrial applications. PMID- 21324177 TI - Genomewide characterization of non-polyadenylated RNAs. AB - BACKGROUND: RNAs can be physically classified into poly(A)+ or poly(A)- transcripts according to the presence or absence of a poly(A) tail at their 3' ends. Current deep sequencing approaches largely depend on the enrichment of transcripts with a poly(A) tail, and therefore offer little insight into the nature and expression of transcripts that lack poly(A) tails. RESULTS: We have used deep sequencing to explore the repertoire of both poly(A)+ and poly(A)- RNAs from HeLa cells and H9 human embryonic stem cells (hESCs). Using stringent criteria, we found that while the majority of transcripts are poly(A)+, a significant portion of transcripts are either poly(A)- or bimorphic, being found in both the poly(A)+ and poly(A)- populations. Further analyses revealed that many mRNAs may not contain classical long poly(A) tails and such messages are overrepresented in specific functional categories. In addition, we surprisingly found that a few excised introns accumulate in cells and thus constitute a new class of non-polyadenylated long non-coding RNAs. Finally, we have identified a specific subset of poly(A)- histone mRNAs, including two histone H1 variants, that are expressed in undifferentiated hESCs and are rapidly diminished upon differentiation; further, these same histone genes are induced upon reprogramming of fibroblasts to induced pluripotent stem cells. CONCLUSIONS: We offer a rich source of data that allows a deeper exploration of the poly(A)- landscape of the eukaryotic transcriptome. The approach we present here also applies to the analysis of the poly(A)- transcriptomes of other organisms. PMID- 21324178 TI - c-MYC expression sensitizes medulloblastoma cells to radio- and chemotherapy and has no impact on response in medulloblastoma patients. AB - BACKGROUND: To study whether and how c-MYC expression determines response to radio- and chemotherapy in childhood medulloblastoma (MB). METHODS: We used DAOY and UW228 human MB cells engineered to stably express different levels of c-MYC, and tested whether c-MYC expression has an effect on radio- and chemosensitivity using the colorimetric 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2 (4-sulfophenyl)-2H-tetrazolium inner salt (MTS) assay, clonogenic survival, apoptosis assays, cell cycle analysis, and western blot assessment. In an effort to validate our results, we analyzed c-MYC mRNA expression in formalin-fixed paraffin-embedded tumor samples from well-documented patients with postoperative residual tumor and compared c-MYC mRNA expression with response to radio- and chemotherapy as examined by neuroradiological imaging. RESULTS: In DAOY - and to a lesser extent in UW228 - cells expressing high levels of c-MYC, the cytotoxicity of cisplatin, and etoposide was significantly higher when compared with DAOY/UW228 cells expressing low levels of c-MYC. Irradiation- and chemotherapy-induced apoptotic cell death was enhanced in DAOY cells expressing high levels of c-MYC. The response of 62 of 66 residual tumors was evaluable and response to postoperative radio- (14 responders (CR, PR) vs. 5 non-responders (SD, PD)) or chemotherapy (23 CR/PR vs. 20 SD/PD) was assessed. c-MYC mRNA expression was similar in primary MB samples of responders and non-responders (Mann-Whitney U test, p = 0.50, ratio 0.49, 95% CI 0.008-30.0 and p = 0.67, ratio 1.8, 95% CI 0.14-23.5, respectively). CONCLUSIONS: c-MYC sensitizes MB cells to some anti-cancer treatments in vitro. As we failed to show evidence for such an effect on postoperative residual tumors when analyzed by imaging, additional investigations in xenografts and larger MB cohorts may help to define the exact function of c-MYC in modulating response to treatment. PMID- 21324179 TI - Identification of differentially expressed genes in chickens differing in muscle glycogen content and meat quality. AB - BACKGROUND: The processing ability of poultry meat is highly related to its ultimate pH, the latter being mainly determined by the amount of glycogen in the muscle at death. The genetic determinism of glycogen and related meat quality traits has been established in the chicken but the molecular mechanisms involved in variations in these traits remain to be fully described. In this study, Chicken Genome Arrays (20 K) were used to compare muscle gene expression profiles of chickens from Fat (F) and Lean (L) lines that exhibited high and low muscle glycogen content, respectively, and of individuals exhibiting extremely high (G+) or low (G-) muscle glycogen content originating from the F2 cross between the Fat and Lean lines. Real-time RT-PCR was subsequently performed to validate the differential expression of genes either selected from the microarray analysis or whose function in regulating glycogen metabolism was well known. RESULTS: Among the genes found to be expressed in chicken P. major muscle, 197 and 254 transcripts appeared to be differentially expressed on microarrays for the F vs. L and the G+ vs. G- comparisons, respectively. Some involved particularly in lipid and carbohydrate metabolism were selected for further validation studies by real-time RT-PCR. We confirmed that, as in mammals, the down-regulation of CEBPB and RGS2 coincides with a decrease in peripheral adiposity in the chicken, but these genes are also suggested to affect muscle glycogen turnover through their role in the cAMP-dependent signalling pathway. Several other genes were suggested to have roles in the regulation of glycogen storage in chicken muscle. PDK4 may act as a glycogen sensor in muscle, UGDH may compete for glycogen synthesis by using UDP-glucose for glucoronidation, and PRKAB1, PRKAG2, and PHKD may impact on glycogen turnover in muscle, through AMP-activated signalling pathways. CONCLUSIONS: This study is the first stage in the understanding of molecular mechanisms underlying variations in poultry meat quality. Large scale analyses are now required to validate the role of the genes identified and ultimately to find molecular markers that can be used for selection or to optimize rearing practices. PMID- 21324180 TI - A random effects variance shift model for detecting and accommodating outliers in meta-analysis. AB - BACKGROUND: Meta-analysis typically involves combining the estimates from independent studies in order to estimate a parameter of interest across a population of studies. However, outliers often occur even under the random effects model. The presence of such outliers could substantially alter the conclusions in a meta-analysis. This paper proposes a methodology for identifying and, if desired, downweighting studies that do not appear representative of the population they are thought to represent under the random effects model. METHODS: An outlier is taken as an observation (study result) with an inflated random effect variance. We used the likelihood ratio test statistic as an objective measure for determining whether observations have inflated variance and are therefore considered outliers. A parametric bootstrap procedure was used to obtain the sampling distribution of the likelihood ratio test statistics and to account for multiple testing. Our methods were applied to three illustrative and contrasting meta-analytic data sets. RESULTS: For the three meta-analytic data sets our methods gave robust inferences when the identified outliers were downweighted. CONCLUSIONS: The proposed methodology provides a means to identify and, if desired, downweight outliers in meta-analysis. It does not eliminate them from the analysis however and we consider the proposed approach preferable to simply removing any or all apparently outlying results. We do not however propose that our methods in any way replace or diminish the standard random effects methodology that has proved so useful, rather they are helpful when used in conjunction with the random effects model. PMID- 21324182 TI - HIS-based Kaplan-Meier plots--a single source approach for documenting and reusing routine survival information. AB - BACKGROUND: Survival or outcome information is important for clinical routine as well as for clinical research and should be collected completely, timely and precisely. This information is relevant for multiple usages including quality control, clinical trials, observational studies and epidemiological registries. However, the local hospital information system (HIS) does not support this documentation and therefore this data has to generated by paper based or spreadsheet methods which can result in redundantly documented data. Therefore we investigated, whether integrating the follow-up documentation of different departments in the HIS and reusing it for survival analysis can enable the physician to obtain survival curves in a timely manner and to avoid redundant documentation. METHODS: We analysed the current follow-up process of oncological patients in two departments (urology, haematology) with respect to different documentation forms. We developed a concept for comprehensive survival documentation based on a generic data model and implemented a follow-up form within the HIS of the University Hospital Muenster which is suitable for a secondary use of these data. We designed a query to extract the relevant data from the HIS and implemented Kaplan-Meier plots based on these data. To re-use this data sufficient data quality is needed. We measured completeness of forms with respect to all tumour cases in the clinic and completeness of documented items per form as incomplete information can bias results of the survival analysis. RESULTS: Based on the form analysis we discovered differences and concordances between both departments. We identified 52 attributes from which 13 were common (e.g. procedures and diagnosis dates) and were used for the generic data model. The electronic follow-up form was integrated in the clinical workflow. Survival data was also retrospectively entered in order to perform survival and quality analyses on a comprehensive data set. Physicians are now able to generate timely Kaplan-Meier plots on current data. We analysed 1029 follow-up forms of 965 patients with survival information between 1992 and 2010. Completeness of forms was 60.2%, completeness of items ranges between 94.3% and 98.5%. Median overall survival time was 16.4 years; median event-free survival time was 7.7 years. CONCLUSION: It is feasible to integrate survival information into routine HIS documentation such that Kaplan-Meier plots can be generated directly and in a timely manner. PMID- 21324181 TI - Testing a Dutch web-based tailored lifestyle programme among adults: a study protocol. AB - BACKGROUND: Smoking, high alcohol consumption, unhealthy eating habits and physical inactivity often lead to (chronic) diseases, such as cardiovascular diseases and cancer. Tailored online interventions have been proven to be effective in changing health behaviours. The aim of this study is to test and compare the effectiveness of two different tailoring strategies for changing lifestyle compared to a control group using a multiple health behaviour web-based approach. METHODS: In our Internet-based tailored programme, the five lifestyle behaviours of smoking, alcohol intake, fruit consumption, vegetable consumption, and physical activity are addressed. This randomized controlled trial, conducted among Dutch adults, includes two experimental groups (i.e., a sequential behaviour tailoring condition and a simultaneous behaviour tailoring condition) and a control group. People in the sequential behaviour tailoring condition obtain feedback on whether their lifestyle behaviours meet the Dutch recommendations. Using a step-by-step approach, they are stimulated to continue with a computer tailored module to change only one unhealthy behaviour first. In the course of the study, they can proceed to change a second behaviour. People in the simultaneous behaviour tailoring condition receive computer tailored feedback about all their unhealthy behaviours during their first visit as a stimulation to change all unhealthy behaviours. The experimental groups can re-visit the website and can then receive ipsative feedback (i.e., current scores are compared to previous scores in order to give feedback about potential changes). The (difference in) effectiveness of the different versions of the programme will be tested and compared to a control group, in which respondents only receive a short health risk appraisal. Programme evaluations will assess satisfaction with and appreciation and personal relevance of the intervention among the respondents. Finally, potential subgroup differences pertaining to gender, age and socioeconomic status regarding the behaviour effects and programme evaluation will be assessed. DISCUSSION: Research regarding multiple behaviour change is in its infancy. We study how to offer multiple behaviour change interventions optimally. Using these results could strengthen the effectiveness of web-based computer-tailoring lifestyle programmes. This study will yield new results about the need for differential lifestyle approaches using Internet-based expert systems and potential differences in subgroups concerning the effectiveness and appreciation. TRIAL REGISTRATION: Dutch Trial Register NTR2168. PMID- 21324183 TI - Comparison of postmenopausal endogenous sex hormones among Japanese, Japanese Brazilians, and non-Japanese Brazilians. AB - BACKGROUND: Differences in sex hormone levels among populations might contribute to the variation in breast cancer incidence across countries. Previous studies have shown higher breast cancer incidence and mortality among Japanese Brazilians than among Japanese. To clarify the difference in hormone levels among populations, we compared postmenopausal endogenous sex hormone levels among Japanese living in Japan, Japanese Brazilians living in the state of Sao Paulo, and non-Japanese Brazilians living in the state of Sao Paulo. METHODS: A cross sectional study was conducted using a control group of case-control studies in Nagano, Japan, and Sao Paulo, Brazil. Participants were postmenopausal women older than 55 years of age who provided blood samples. We measured estradiol, estrone, androstenedione, dehydroepiandrosterone sulfate (DHEAS), testosterone and free testosterone by radioimmunoassay; bioavailable estradiol by the ammonium sulfate precipitation method; and sex hormone-binding globulin (SHBG) by immunoradiometric assay. A total of 363 women were included for the present analyses, comprising 185 Japanese, 44 Japanese Brazilians and 134 non-Japanese Brazilians. RESULTS: Japanese Brazilians had significantly higher levels of estradiol, bioavailable estradiol, estrone, testosterone and free testosterone levels, and lower SHBG levels, than Japanese. Japanese Brazilians also had significantly higher levels of bioavailable estradiol, estrone and DHEAS and lower levels of SHBG and androstenedione than non-Japanese Brazilians. Levels of estradiol, testosterone and free testosterone, however, did not differ between Japanese Brazilians and non-Japanese Brazilians. These differences were observed even after adjustment for known breast cancer risk factors. We also found an increase in estrogen and androgen levels with increasing body mass index, but no association for most of the other known risk factors. CONCLUSIONS: We found higher levels of estrogens and androgens in Japanese Brazilians than in Japanese and levels similar to or higher than in non-Japanese Brazilians. Our findings may help explain the increase in the incidence and mortality rate of breast cancer among Japanese Brazilians. PMID- 21324184 TI - Effects on quality of life of weekly docetaxel-based chemotherapy in patients with locally advanced or metastatic breast cancer: results of a single-centre randomized phase 3 trial. AB - BACKGROUND: To evaluate whether weekly schedules of docetaxel-based chemotherapy were superior to 3-weekly ones in terms of quality of life in locally advanced or metastatic breast cancer. METHODS: Patients with locally advanced or metastatic breast cancer, aged <= 70 years, performance status 0-2, chemotherapy-naive for metastatic disease, were eligible. They were randomized to weekly or 3-weekly combination of docetaxel and epirubicin, if they were not treated with adjuvant anthracyclines, or docetaxel and capecitabine, if treated with adjuvant anthracyclines. Primary end-point was global quality of life change at 6-weeks, measured by EORTC QLQ-C30. With two-sided alpha 0.05 and 80% power for 35% effect size, 130 patients per arm were needed. RESULTS: From February 2004 to March 2008, 139 patients were randomized, 70 to weekly and 69 to 3-weekly arm; 129 and 89 patients filled baseline and 6-week questionnaires, respectively. Global quality of life was better in the 3-weekly arm (p = 0.03); patients treated with weekly schedules presented a significantly worsening in role functioning and financial scores (p = 0.02 and p < 0.001). Neutropenia and stomatitis were worse in the 3-weekly arm, where two toxic deaths were observed. Overall response rate was 39.1% and 33.3% in 3-weekly and weekly arms; hazard ratio of progression was 1.29 (95% CI: 0.84-1.97) and hazard ratio of death was 1.38 (95% CI: 0.82-2.30) in the weekly arm. CONCLUSIONS: In this trial, the weekly schedules of docetaxel based chemotherapy appear to be inferior to the 3-weekly one in terms of quality of life in patients with locally advanced or metastatic breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT00540800. PMID- 21324185 TI - Support vector machines-based identification of alternative splicing in Arabidopsis thaliana from whole-genome tiling arrays. AB - BACKGROUND: Alternative splicing (AS) is a process which generates several distinct mRNA isoforms from the same gene by splicing different portions out of the precursor transcript. Due to the (patho-)physiological importance of AS, a complete inventory of AS is of great interest. While this is in reach for human and mammalian model organisms, our knowledge of AS in plants has remained more incomplete. Experimental approaches for monitoring AS are either based on transcript sequencing or rely on hybridization to DNA microarrays. Among the microarray platforms facilitating the discovery of AS events, tiling arrays are well-suited for identifying intron retention, the most prevalent type of AS in plants. However, analyzing tiling array data is challenging, because of high noise levels and limited probe coverage. RESULTS: In this work, we present a novel method to detect intron retentions (IR) and exon skips (ES) from tiling arrays. While statistical tests have typically been proposed for this purpose, our method instead utilizes support vector machines (SVMs) which are appreciated for their accuracy and robustness to noise. Existing EST and cDNA sequences served for supervised training and evaluation. Analyzing a large collection of publicly available microarray and sequence data for the model plant A. thaliana, we demonstrated that our method is more accurate than existing approaches. The method was applied in a genome-wide screen which resulted in the discovery of 1,355 IR events. A comparison of these IR events to the TAIR annotation and a large set of short-read RNA-seq data showed that 830 of the predicted IR events are novel and that 525 events (39%) overlap with either the TAIR annotation or the IR events inferred from the RNA-seq data. CONCLUSIONS: The method developed in this work expands the scarce repertoire of analysis tools for the identification of alternative mRNA splicing from whole-genome tiling arrays. Our predictions are highly enriched with known AS events and complement the A. thaliana genome annotation with respect to AS. Since all predicted AS events can be precisely attributed to experimental conditions, our work provides a basis for follow-up studies focused on the elucidation of the regulatory mechanisms underlying tissue-specific and stress-dependent AS in plants. PMID- 21324186 TI - What factors are associated with recent intimate partner violence? findings from the WHO multi-country study on women's health and domestic violence. AB - BACKGROUND: Intimate partner violence (IPV) against women is a global public health and human rights concern. Despite a growing body of research into risk factors for IPV, methodological differences limit the extent to which comparisons can be made between studies. We used data from ten countries included in the WHO Multi-country Study on Women's Health and Domestic Violence to identify factors that are consistently associated with abuse across sites, in order to inform the design of IPV prevention programs. METHODS: Standardised population-based household surveys were done between 2000 and 2003. One woman aged 15-49 years was randomly selected from each sampled household. Those who had ever had a male partner were asked about their experiences of physically and sexually violent acts. We performed multivariate logistic regression to identify predictors of physical and/or sexual partner violence within the past 12 months. RESULTS: Despite wide variations in the prevalence of IPV, many factors affected IPV risk similarly across sites. Secondary education, high SES, and formal marriage offered protection, while alcohol abuse, cohabitation, young age, attitudes supportive of wife beating, having outside sexual partners, experiencing childhood abuse, growing up with domestic violence, and experiencing or perpetrating other forms of violence in adulthood, increased the risk of IPV. The strength of the association was greatest when both the woman and her partner had the risk factor. CONCLUSIONS: IPV prevention programs should increase focus on transforming gender norms and attitudes, addressing childhood abuse, and reducing harmful drinking. Development initiatives to improve access to education for girls and boys may also have an important role in violence prevention. PMID- 21324187 TI - A rebuttal to the comments on the genome order index and the Z-curve. AB - BACKGROUND: Elhaik, Graur and Josic recently commented on the genome order index (S) and the Z-curve (Elhaik et al. Biol Direct 2010, 5: 10). S is a quantity defined as S = a2 + c2 + g2 + t2, where a, c, g and t denote corresponding base frequencies. The Z-curve is a three dimensional curve that represents a DNA sequence in the manner that each can be uniquely reconstructed given the other. Elhaik et al. made 4 major claims. 1) In the previous mapping system with the regular tetrahedron, calculation of the radius of the inscribed sphere is "a mathematical error". 2) S follows an exponential distribution and is narrowly distributed with a range of (0.25 - 0.33). 3) Based on the Chargaff's second parity rule (PR2), "S is equivalent to H [Shannon entropy]" and they are derivable from each other. 4) Z-curve "suffers from over dimensionality", because based on the analysis of 235 bacterial genomes, x and y components contributed only less than 1% of the variance and therefore "would be of little use". RESULTS: 1) Elhaik et al. mistakenly neglected the parameter 4/ square root 3 when calculating the radius of the inscribed sphere. 2) The exponential distribution of S is a restatement of our previous conclusion, and the range of (0.25 - 0.33) only paraphrases the previously suggested S range (0.25 -1/3). 3) Elhaik et al. incorrectly disregard deviations from PR2 by treating the deviations as 0 altogether, reduce S and H, both having 4 variables, a, c, g and t, into functions of one single variable, a only, and apply this treatment to all DNA sequences as the basis of their "demonstration", which is therefore invalid. 4) Elhaik et al. confuse numeral smallness with biological insignificance, and disregard the distributions of purine/pyrimidine and amino/keto bases (x and y components), the variations of which, although can be less than that of GC content, contain rich information that is important and useful, such as in locating replication origins of bacterial and archaeal genomes, and in studies of gene recognition in various species. CONCLUSION: Elhaik et al. confuse S (a single number) with Z-curve (a series of 3D coordinates), which are distinct. To use S as a case study of Z-curve, by itself, is invalid. S and H are neither equivalent nor derivable from each other. The criticisms of Elhaik, Graur and Josic are wrong. PMID- 21324188 TI - The validity of using ICD-9 codes and pharmacy records to identify patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Administrative data is often used to identify patients with chronic obstructive pulmonary disease (COPD), yet the validity of this approach is unclear. We sought to develop a predictive model utilizing administrative data to accurately identify patients with COPD. METHODS: Sequential logistic regression models were constructed using 9573 patients with postbronchodilator spirometry at two Veterans Affairs medical centers (2003-2007). COPD was defined as: 1) FEV1/FVC <0.70, and 2) FEV1/FVC < lower limits of normal. Model inputs included age, outpatient or inpatient COPD-related ICD-9 codes, and the number of metered does inhalers (MDI) prescribed over the one year prior to and one year post spirometry. Model performance was assessed using standard criteria. RESULTS: 4564 of 9573 patients (47.7%) had an FEV1/FVC < 0.70. The presence of >=1 outpatient COPD visit had a sensitivity of 76% and specificity of 67%; the AUC was 0.75 (95% CI 0.74-0.76). Adding the use of albuterol MDI increased the AUC of this model to 0.76 (95% CI 0.75-0.77) while the addition of ipratropium bromide MDI increased the AUC to 0.77 (95% CI 0.76-0.78). The best performing model included: >=6 albuterol MDI, >=3 ipratropium MDI, >=1 outpatient ICD-9 code, >=1 inpatient ICD 9 code, and age, achieving an AUC of 0.79 (95% CI 0.78-0.80). CONCLUSION: Commonly used definitions of COPD in observational studies misclassify the majority of patients as having COPD. Using multiple diagnostic codes in combination with pharmacy data improves the ability to accurately identify patients with COPD. PMID- 21324189 TI - Hippocampal expression of murine TNFalpha results in attenuation of amyloid deposition in vivo. AB - Fibrillar amyloid beta (fAbeta) peptide is the major component of Abeta plaques in the brains of Alzheimer's disease (AD) patients. Inflammatory mediators have previously been proposed to be drivers of Abeta pathology in AD patients by increasing amyloidogenic processing of APP and promoting Abeta accumulation, but recent data have shown that expression of various inflammatory cytokines attenuates Abeta pathology in mouse models. In an effort to further study the role of different inflammatory cytokines on Abeta pathology in vivo, we explored the effect of murine Tumor Necrosis Factor alpha (mTNFalpha) in regulating Abeta accumulation. Recombinant adeno-associated virus serotype 1 (AAV2/1) mediated expression of mTNFalpha in the hippocampus of 4 month old APP transgenic TgCRND8 mice resulted in significant reduction in hippocampal Abeta burden. No changes in APP levels or APP processing were observed in either mTNFalpha expressing APP transgenic mice or in non-transgenic littermates. Analysis of Abeta plaque burden in mTNFalpha expressing mice showed that even after substantial reduction compared to EGFP expressing age-matched controls, the Abeta plaque burden levels of the former do not decrease to the levels of 4 month old unmanipulated mice. Taken together, our data suggests that proinflammatory cytokine expression induced robust glial activation can attenuate plaque deposition. Whether such an enhanced microglial response actually clears preexisting deposits without causing bystander neurotoxicity remains an open question. PMID- 21324190 TI - Meta-analysis of muscle transcriptome data using the MADMuscle database reveals biologically relevant gene patterns. AB - BACKGROUND: DNA microarray technology has had a great impact on muscle research and microarray gene expression data has been widely used to identify gene signatures characteristic of the studied conditions. With the rapid accumulation of muscle microarray data, it is of great interest to understand how to compare and combine data across multiple studies. Meta-analysis of transcriptome data is a valuable method to achieve it. It enables to highlight conserved gene signatures between multiple independent studies. However, using it is made difficult by the diversity of the available data: different microarray platforms, different gene nomenclature, different species studied, etc. DESCRIPTION: We have developed a system tool dedicated to muscle transcriptome data. This system comprises a collection of microarray data as well as a query tool. This latter allows the user to extract similar clusters of co-expressed genes from the database, using an input gene list. Common and relevant gene signatures can thus be searched more easily. The dedicated database consists in a large compendium of public data (more than 500 data sets) related to muscle (skeletal and heart). These studies included seven different animal species from invertebrates (Drosophila melanogaster, Caenorhabditis elegans) and vertebrates (Homo sapiens, Mus musculus, Rattus norvegicus, Canis familiaris, Gallus gallus). After a renormalization step, clusters of co-expressed genes were identified in each dataset. The lists of co-expressed genes were annotated using a unified re annotation procedure. These gene lists were compared to find significant overlaps between studies. CONCLUSIONS: Applied to this large compendium of data sets, meta analyses demonstrated that conserved patterns between species could be identified. Focusing on a specific pathology (Duchenne Muscular Dystrophy) we validated results across independent studies and revealed robust biomarkers and new pathways of interest. The meta-analyses performed with MADMuscle show the usefulness of this approach. Our method can be applied to all public transcriptome data. PMID- 21324191 TI - Mycoplasma mycoides, from "mycoides Small Colony" to "capri". A microevolutionary perspective. AB - BACKGROUND: The Mycoplasma mycoides cluster consists of five species or subspecies that are ruminant pathogens. One subspecies, Mycoplasma mycoides subspecies mycoides Small Colony (MmmSC), is the causative agent of contagious bovine pleuropneumonia. Its very close relative, Mycoplasma mycoides subsp. capri (Mmc), is a more ubiquitous pathogen in small ruminants causing mastitis, arthritis, keratitis, pneumonia and septicaemia and is also found as saprophyte in the ear canal. To understand the genetics underlying these phenotypic differences, we compared the MmmSC PG1 type strain genome, which was already available, with the genome of an Mmc field strain (95010) that was sequenced in this study. We also compared the 95010 genome with the recently published genome of another Mmc strain (GM12) to evaluate Mmc strain diversity. RESULTS: The MmmSC PG1 genome is 1,212 kbp and that of Mmc 95010 is ca. 58 kbp shorter. Most of the sequences present in PG1 but not 95010 are highly repeated Insertion Sequences (three types of IS) and large duplicated DNA fragments. The 95010 genome contains five types of IS, present in fewer copies than in PG1, and two copies of an integrative conjugative element. These mobile genetic elements have played a key role in genome plasticity, leading to inversions of large DNA fragments. Comparison of the two genomes suggested a marked decay of the PG1 genome that seems to be correlated with a greater number of IS. The repertoire of gene families encoding surface proteins is smaller in PG1. Several genes involved in polysaccharide metabolism and protein degradation are also absent from, or degraded in, PG1. CONCLUSIONS: The genome of MmmSC PG1 is larger than that of Mmc 95010, its very close relative, but has less coding capacity. This is the result of large genetic rearrangements due to mobile elements that have also led to marked gene decay. This is consistent with a non-adaptative genomic complexity theory, allowing duplications or pseudogenes to be maintained in the absence of adaptive selection that would lead to purifying selection and genome streamlining over longer evolutionary times. These findings also suggest that MmmSC only recently adapted to its bovine host. PMID- 21324192 TI - Stress response regulators identified through genome-wide transcriptome analysis of the (p)ppGpp-dependent response in Rhizobium etli. AB - BACKGROUND: The alarmone (p)ppGpp mediates a global reprogramming of gene expression upon nutrient limitation and other stresses to cope with these unfavorable conditions. Synthesis of (p)ppGpp is, in most bacteria, controlled by RelA/SpoT (Rsh) proteins. The role of (p)ppGpp has been characterized primarily in Escherichia coli and several Gram-positive bacteria. Here, we report the first in-depth analysis of the (p)ppGpp-regulon in an alpha-proteobacterium using a high-resolution tiling array to better understand the pleiotropic stress phenotype of a relA/rsh mutant. RESULTS: We compared gene expression of the Rhizobium etli wild type and rsh (previously rel) mutant during exponential and stationary phase, identifying numerous (p)ppGpp targets, including small non coding RNAs. The majority of the 834 (p)ppGpp-dependent genes were detected during stationary phase. Unexpectedly, 223 genes were expressed (p)ppGpp dependently during early exponential phase, indicating the hitherto unrecognized importance of (p)ppGpp during active growth. Furthermore, we identified two (p)ppGpp-dependent key regulators for survival during heat and oxidative stress and one regulator putatively involved in metabolic adaptation, namely extracytoplasmic function sigma factor EcfG2/PF00052, transcription factor CH00371, and serine protein kinase PrkA. CONCLUSIONS: The regulatory role of (p)ppGpp in R. etli stress adaptation is far-reaching in redirecting gene expression during all growth phases. Genome-wide transcriptome analysis of a strain deficient in a global regulator, and exhibiting a pleiotropic phenotype, enables the identification of more specific regulators that control genes associated with a subset of stress phenotypes. This work is an important step toward a full understanding of the regulatory network underlying stress responses in alpha-proteobacteria. PMID- 21324193 TI - A randomized, double-blind, placebo-controlled trial of calcium acetate on serum phosphorus concentrations in patients with advanced non-dialysis-dependent chronic kidney disease. AB - BACKGROUND: Hyperphosphatemia in patients with chronic kidney disease (CKD) contributes to secondary hyperparathyroidism, soft tissue calcification, and increased mortality risk. This trial was conducted to examine the efficacy and safety of calcium acetate in controlling serum phosphorus in pre-dialysis patients with CKD. METHODS: In this randomized, double-blind, placebo-controlled trial, 110 nondialyzed patients from 34 sites with estimated GFR < 30 mL/min/1.73 m2 and serum phosphorus > 4.5 mg/dL were randomized to calcium acetate or placebo for 12 weeks. The dose of study drugs was titrated to achieve target serum phosphorus of 2.7-4.5 mg/dL. Serum phosphorus, calcium, iPTH, bicarbonate and serum albumin were measured at baseline and every 2 weeks for the 12 week study period. The primary efficacy endpoint was serum phosphorus at 12 weeks. Secondary endpoints were to measure serum calcium and intact parathyroid hormone (iPTH) levels. RESULTS: At 12 weeks, serum phosphorus concentration was significantly lower in the calcium acetate group compared to the placebo group (4.4 +/- 1.2 mg/dL vs. 5.1 +/- 1.4 mg/dL; p = 0.04). The albumin-adjusted serum calcium concentration was significantly higher (9.5 +/- 0.8 vs. 8.8 +/- 0.8; p < 0.001) and iPTH was significantly lower in the calcium acetate group compared to placebo (150 +/- 157 vs. 351 +/- 292 pg/mL respectively; p < 0.001). At 12 weeks, the proportions of subjects who had hypocalcemia were 5.4% and 19.5% for the calcium acetate and the placebo groups, respectively, while the proportions of those with hypercalcemia were 13.5% and 0%, respectively. Adverse events did not differ between the treatment groups. CONCLUSIONS: In CKD patients not yet on dialysis, calcium acetate was effective in reducing serum phosphorus and iPTH over a 12 week period. TRIAL REGISTRATION: www.clinicaltrials.gov NCT00211978. PMID- 21324194 TI - Contraceptive methods and use by women aged 35 and over: A qualitative study of perspectives. AB - BACKGROUND: More than 30% of the pregnancies in women aged 35 and over are unintended. This paper compares perceptions about contraceptive methods and use among women with and without an unintended pregnancy after turning age 35. METHODS: Semi-structured, in-depth interviews were conducted with 17 women. They were all 35 to 49 years old, regularly menstruating, sexually active, not sterilized, not desiring a pregnancy in the near future, and at least 3 months postpartum. We purposely sampled for women who had had at least one unintended pregnancy after age 35 (n = 9) and women who did not (n = 8). We assessed partnership, views of pregnancy and motherhood, desired lifestyle, perceived advantages and disadvantages of using and obtaining currently available well known reversible contraceptives in the U.S. ''We also assessed contraceptive methods used at any time during their reproductive years, including current method use and, if appropriate, circumstances surrounding an unintended pregnancy after age 35.'' Each interview was taped and transcribed verbatim. Data were analyzed using Grounded Theory. Analysis focused on partnership, views of pregnancy, motherhood, desired lifestyle and perceived advantages and disadvantages of various reversible contraceptive methods. RESULTS: The women without an unintended pregnancy after age 35 were more likely to (1) use contraceptive methods that helped treat a medical condition, (2) consider pregnancy as dangerous, or (3) express concerns about the responsibilities of motherhood. The women who experienced an unintended pregnancy after age 35 were more likely to (1) report unstable partnerships, (2) perceive themselves at lower risk of pregnancy, or (3) report past experiences with unwanted contraceptive side effects. There was a greater likelihood a woman would choose a contraceptive method if it was perceived as easy to use, accessible, affordable and had minimal side effects. CONCLUSIONS: Women's perspective on contraceptive use after age 35 varies. Public health messages and health providers' care can help women in this age group by reviewing their fertility risks, as well as all contraceptive methods and their associated side effects. The impact of such interventions on unintended pregnancy rates in this age group should be tested in other areas of evidence-based medicine. PMID- 21324195 TI - The living microarray: a high-throughput platform for measuring transcription dynamics in single cells. AB - BACKGROUND: Current methods of measuring transcription in high-throughput have led to significant improvements in our knowledge of transcriptional regulation and Systems Biology. However, endpoint measurements obtained from methods that pool populations of cells are not amenable to studying time-dependent processes that show cell heterogeneity. RESULTS: Here we describe a high-throughput platform for measuring transcriptional changes in real time in single mammalian cells. By using reverse transfection microarrays we are able to transfect fluorescent reporter plasmids into 600 independent clusters of cells plated on a single microscope slide and image these clusters every 20 minutes. We use a fast maturing, destabilized and nuclear-localized reporter that is suitable for automated segmentation to accurately measure promoter activity in single cells. We tested this platform with synthetic drug-inducible promoters that showed robust induction over 24 hours. Automated segmentation and tracking of over 11 million cell images during this period revealed that cells display substantial heterogeneity in their responses to the applied treatment, including a large proportion of transfected cells that do not respond at all. CONCLUSIONS: The results from our single-cell analysis suggest that methods that measure average cellular responses, such as DNA microarrays, RT-PCR and chromatin immunoprecipitation, characterize a response skewed by a subset of cells in the population. Our method is scalable and readily adaptable to studying complex systems, including cell proliferation, differentiation and apoptosis. PMID- 21324196 TI - Design and implementation of the Canadian Kidney Disease Cohort Study (CKDCS): A prospective observational study of incident hemodialysis patients. AB - BACKGROUND: Many nephrology observational studies use renal registries, which have well known limitations. The Canadian Kidney Disease Cohort Study (CKDCS) is a large prospective observational study of patients commencing hemodialysis in five Canadian centers. This study focuses on delineating potentially reversible determinants of adverse outcomes that occur in patients receiving dialysis for end-stage renal disease (ESRD). METHODS/DESIGN: The CKDCS collects information on risk factors and outcomes, and stores specimens (blood, dialysate, hair and fingernails) at baseline and in long-term follow-up. Such specimens will permit measurements of biochemical markers, proteomic and genetic parameters (proteins and DNA) not measured in routine care. To avoid selection bias, all consenting incident hemodialysis patients at participating centers are enrolled, the large sample size (target of 1500 patients), large number of exposures, and high event rates will permit the exploration of multiple potential research questions. PRELIMINARY RESULTS: Data on the baseline characteristics from the first 1074 subjects showed that the average age of patients was 62 (range; 50-73) years. The leading cause of ESRD was diabetic nephropathy (41.9%), and the majority of the patients were white (80.0%). Only 18.7% of the subjects received dialysis in a satellite unit, and over 80% lived within a 50 km radius of the nearest nephrologist's practice. DISCUSSION: The prospective design, detailed clinical information, and stored biological specimens provide a wealth of information with potential to greatly enhance our understanding of risk factors for adverse outcomes in dialysis patients. The scientific value of the stored patient tissue will grow as new genetic and biochemical markers are discovered in the future. PMID- 21324197 TI - Retraction: The candidate tumor suppressor gene ECRG4 inhibits cancer cells migration and invasion in esophageal carcinoma. PMID- 21324198 TI - Circulating soluble urokinase plasminogen activator receptor is stably elevated during the first week of treatment in the intensive care unit and predicts mortality in critically ill patients. AB - INTRODUCTION: suPAR is the soluble form of the urokinase plasminogen activator receptor (uPAR), which is expressed in various immunologically active cells. High suPAR serum concentrations are suggested to reflect the activation of the immune system in circumstances of inflammation and infection, and have been associated with increased mortality in different populations of non-intensive care patients. In this study we sequentially analyzed suPAR serum concentrations within the first week of intensive care in a large cohort of well characterized intensive care unit (ICU) patients, in order to investigate potential regulatory mechanisms and evaluate the prognostic significance in critically ill patients. METHODS: A total of 273 patients (197 with sepsis, 76 without sepsis) were studied prospectively upon admission to the medical intensive care unit (ICU), on Day 3 and Day 7, and compared to 43 healthy controls. Clinical data, various laboratory parameters as well as investigational inflammatory cytokine profiles were assessed. Patients were followed for approximately one year. RESULTS: Upon admission to the ICU suPAR serum concentrations were elevated in critically ill patients as compared with healthy controls. In sepsis patients suPAR levels were higher than in non-sepsis patients (with or without systemic inflammatory response syndrome (SIRS)). During the first week after admission to the ICU serum suPAR concentrations remained stably elevated. suPAR serum concentrations measured upon admission were closely and independently correlated to various laboratory parameters, specifically biomarkers of inflammation (tumor necrosis factor (TNF), C-reactive protein (CRP)), hepatic and renal dysfunction. High suPAR levels at admission and at Day 3 were a strong independent predictor for both ICU and long-term mortality in critically ill patients. CONCLUSIONS: In sepsis and non-sepsis patients suPAR serum concentrations are increased upon admission to the ICU, likely reflecting the activation state of the immune system, and remain stably elevated in the initial course of treatment. Low suPAR levels are a positive predictor of ICU- and overall survival in critically ill patients, including sepsis and non-sepsis patients. Aside from its value as a promising new prognostic biomarker, both experimental and clinical studies are required in order to understand the specific effects and regulatory mechanisms of suPAR in SIRS and sepsis, and may reveal new therapeutic options. PMID- 21324199 TI - A statistical assessment of differences and equivalences between genetically modified and reference plant varieties. AB - BACKGROUND: Safety assessment of genetically modified organisms is currently often performed by comparative evaluation. However, natural variation of plant characteristics between commercial varieties is usually not considered explicitly in the statistical computations underlying the assessment. RESULTS: Statistical methods are described for the assessment of the difference between a genetically modified (GM) plant variety and a conventional non-GM counterpart, and for the assessment of the equivalence between the GM variety and a group of reference plant varieties which have a history of safe use. It is proposed to present the results of both difference and equivalence testing for all relevant plant characteristics simultaneously in one or a few graphs, as an aid for further interpretation in safety assessment. A procedure is suggested to derive equivalence limits from the observed results for the reference plant varieties using a specific implementation of the linear mixed model. Three different equivalence tests are defined to classify any result in one of four equivalence classes. The performance of the proposed methods is investigated by a simulation study, and the methods are illustrated on compositional data from a field study on maize grain. CONCLUSIONS: A clear distinction of practical relevance is shown between difference and equivalence testing. The proposed tests are shown to have appropriate performance characteristics by simulation, and the proposed simultaneous graphical representation of results was found to be helpful for the interpretation of results from a practical field trial data set. PMID- 21324200 TI - Active core rewarming avoids bioelectrical impedance changes in postanesthetic patients. AB - BACKGROUND: Postoperative hypothermia is a common cause of complications in patients who underwent laparoscopic cholecystectomy. Hypothermia is known to elicit electrophysiological, biochemical, and cellular alterations thus leading to changes in the active and passive membrane properties. These changes might influence the bioelectrical impedance (BI). Our aim was to determine whether the BI depends on the core temperature. METHODS: We studied 60 patients (52 female and 8 male) age 40 to 80 years with an ASA I-II classification that had undergone laparoscopic cholecystectomy under balanced inhalation anesthesia. The experimental group (n = 30) received active core rewarming during the transanesthetic and postanesthesic periods. The control group (n = 30) received passive external rewarming. The BI was recorded by using a 4-contact electrode system to collect dual sets of measurements in the deltoid muscle. The body temperature, hemodynamic variables, respiratory rate, blood-gas levels, biochemical parameters, and shivering were also measured. The Mann-Whitney unpaired t-test was used to determine the differences in shivering between each group at each measurement period. Measurements of body temperature, hemodynamics variables, respiratory rate, and BI were analyzed using the two-way repeated measures ANOVA. RESULTS: The gradual decrease in the body temperature was followed by the BI increase over time. The highest BI values (95 +/- 11 Omega) appeared when the lowest values of the temperature (35.5 +/- 0.5 degrees C) were reached. The active core rewarming kept the body temperature within the physiological range (over 36.5 degrees C). This effect was accompanied by low stable values (68 +/- 3 Omega) of BI. A significant decrease over time in the hemodynamic values, respiratory rate, and shivering was seen in the active core rewarming group when compared with the controls. The temporal course of shivering was different from those of body temperatue and BI. The control patients showed a significant increase in the serum-potassium levels, which were not seen in the active-core rewarming group. CONCLUSIONS: The BI analysis changed as a function of the changes of core temperature and independently of the shivering. In addition, our results support the beneficial use of active core rewarming to prevent accidental hypothermia. PMID- 21324201 TI - Role of dopamine D2 receptors in ischemia/reperfusion induced apoptosis of cultured neonatal rat cardiomyocytes. AB - BACKGROUND: Myocardial ischemia/reperfusion injury is the major cause of morbidity and mortality for cardiovascular diseases. Dopamine D2 receptors are expressed in cardiac tissues. However, the roles of dopamine D2 receptors in myocardial ischemia/reperfusion injury and cardiomyocyte apoptosis are unclear. Here we investigated the effects of both dopamine D2 receptors agonist (bromocriptine) and antagonist (haloperidol) on apoptosis of cultured neonatal rat ventricular myocytes induced by ischemia/reperfusion injury. METHODS: Myocardial ischemia/reperfusion injury was simulated by incubating primarily cultured neonatal rat cardiomyocytes in ischemic (hypoxic) buffer solution for 2 h. Thereafter, these cells were incubated for 24 h in normal culture medium. RESULTS: Treatment of the cardiomyocytes with 10 MUM bromocriptine significantly decreased lactate dehydrogenase activity, increased superoxide dismutase activity, and decreased malondialdehyde content in the culture medium. Bromocriptine significantly inhibited the release of cytochrome c, accumulation of [Ca2+]i, and apoptosis induced by ischemia/reperfusion injury. Bromocriptine also down-regulated the expression of caspase-3 and -9, Fas and Fas ligand, and up-regulated Bcl-2 expression. In contrast, haloperidol (10 MUM) had no significant effects on the apoptosis of cultured cardiomyocytes under the aforementioned conditions. CONCLUSIONS: These data suggest that activation of dopamine D2 receptors can inhibit apoptosis of cardiomyocytes encountered during ischemia/reperfusion damage through various pathways. PMID- 21324202 TI - Efficacy of European starling control to reduce Salmonella enterica contamination in a concentrated animal feeding operation in the Texas panhandle. AB - BACKGROUND: European starlings (Sturnus vulgaris) are an invasive bird species known to cause damage to plant and animal agriculture. New evidence suggests starlings may also contribute to the maintenance and spread of diseases within livestock facilities. Identifying and mitigating the risk pathways that contribute to disease in livestock is necessary to reduce production losses and contamination of human food products. To better understand the impact starlings have on disease transmission to cattle we assessed the efficacy of starling control as a tool to reduce Salmonella enterica within a concentrated animal feeding operation. We matched a large facility, slated for operational control using DRC-1339 (3-chloro-4-methylaniline hydrochloride, also 3-chloro p-toluidine hydrochloride, 3-chloro-4-methylaniline), with a comparable reference facility that was not controlling birds. In both facilities, we sampled cattle feed, cattle water and cattle feces for S. enterica before and after starling control operations. RESULTS: Within the starling-controlled CAFO, detections of S. enterica contamination disappeared from feed bunks and substantially declined within water troughs following starling control operations. Within the reference facility, detections of S. enterica contamination increased substantially within feed bunks and water troughs. Starling control was not observed to reduce prevalence of S. enterica in the cattle herd. Following starling control operations, herd prevalence of S. enterica increased on the reference facility but herd prevalence of S. enterica on the starling-controlled CAFO stayed at pretreatment levels. CONCLUSIONS: Within the starling-controlled facility detections of S. enterica disappeared from feed bunks and substantially declined within water troughs following control operations. Since cattle feed and water are obvious routes for the ingestion of S. enterica, starling control shows promise as a tool to help livestock producers manage disease. Yet, we do not believe starling control should be used as a stand alone tool to reduce S. enterica infections. Rather starling control could be used as part of a comprehensive disease management plan for concentrated animal feeding operations. PMID- 21324203 TI - Skill execution and sleep deprivation: effects of acute caffeine or creatine supplementation - a randomized placebo-controlled trial. AB - BACKGROUND: We investigated the effects of sleep deprivation with or without acute supplementation of caffeine or creatine on the execution of a repeated rugby passing skill. METHOD: Ten elite rugby players completed 10 trials on a simple rugby passing skill test (20 repeats per trial), following a period of familiarisation. The players had between 7-9 h sleep on 5 of these trials and between 3-5 h sleep (deprivation) on the other 5. At a time of 1.5 h before each trial, they undertook administration of either: placebo tablets, 50 or 100 mg/kg creatine, 1 or 5 mg/kg caffeine. Saliva was collected before each trial and assayed for salivary free cortisol and testosterone. RESULTS: Sleep deprivation with placebo application resulted in a significant fall in skill performance accuracy on both the dominant and non-dominant passing sides (p < 0.001). No fall in skill performance was seen with caffeine doses of 1 or 5 mg/kg, and the two doses were not significantly different in effect. Similarly, no deficit was seen with creatine administration at 50 or 100 mg/kg and the performance effects were not significantly different. Salivary testosterone was not affected by sleep deprivation, but trended higher with the 100 mg/kg creatine dose, compared to the placebo treatment (p = 0.067). Salivary cortisol was elevated (p = 0.001) with the 5 mg/kg dose of caffeine (vs. placebo). CONCLUSION: Acute sleep deprivation affects performance of a simple repeat skill in elite athletes and this was ameliorated by a single dose of either caffeine or creatine. Acute creatine use may help to alleviate decrements in skill performance in situations of sleep deprivation, such as transmeridian travel, and caffeine at low doses appears as efficacious as higher doses, at alleviating sleep deprivation deficits in athletes with a history of low caffeine use. Both options are without the side effects of higher dose caffeine use. PMID- 21324204 TI - Genetic monitoring detects an overlooked cryptic species and reveals the diversity and distribution of three invasive Rattus congeners in South Africa. AB - BACKGROUND: South Africa's long and extensive trade activity has ensured ample opportunities for exotic species introduction. Whereas the rich biodiversity of endemic southern African fauna has been the focus of many studies, invasive vertebrates are generally overlooked despite potential impacts on biodiversity, health and agriculture. Genetic monitoring of commensal rodents in South Africa which uncovered the presence of Rattus tanezumi, a South-East Asian endemic not previously known to occur in Africa, provided the impetus for expanded studies on all invasive Rattus species present. RESULTS: To this end, intensified sampling at 28 South African localities and at one site in Swaziland, identified 149 Rattus specimens. Cytochrome b gene sequencing revealed the presence of two R. tanezumi, seven Rattus rattus and five Rattus norvegicus haplotypes in south Africa. Phylogenetic results were consistent with a single, recent R. tanezumi introduction and indicated that R. norvegicus and R. rattus probably became established following at least two and three independent introductions, respectively. Intra- and inter-specific diversity was highest in informal human settlements, with all three species occurring at a single metropolitan township site. Rattus norvegicus and R. rattus each occurred sympatrically with Rattus tanezumi at one and five sites, respectively. Karyotyping of selected R. rattus and R. tanezumi individuals identified diploid numbers consistent with those reported previously for these cryptic species. Ordination of bioclimatic variables and MaxEnt ecological niche modelling confirmed that the bioclimatic niche occupied by R. tanezumi in south Africa was distinct from that occupied in its naturalised range in south-east Asia suggesting that factors other than climate may influence the distribution of this species. CONCLUSIONS: This study has highlighted the value of genetic typing for detecting cryptic invasive species, providing historical insights into introductions and for directing future sampling. The apparent ease with which a cryptic species can become established signals the need for broader implementation of genetic monitoring programmes. In addition to providing baseline data and potentially identifying high-risk introduction routes, the predictive power of ecological niche modelling is enhanced when species records are genetically verified. PMID- 21324205 TI - Epidemiology of anti-tuberculosis drug resistance in a Chinese population: current situation and challenges ahead. AB - BACKGROUND: Drug resistance has been a cause of concern for tuberculosis (TB) control in both developed and developing countries. Careful monitoring of the patterns and trends of drug resistance should remain a priority. METHODS: Strains were collected from 1824 diagnosed sputum smear positive pulmonary TB patients in Jiangsu province of China and then tested for drug susceptibility against rifampicin, isoniazid, ethambutol and streptomycin. The prevalence and patterns of drug resistance in mycobacterium tuberculosis (MTB) isolates were investigated. Multiple logistic regression analysis was performed to identify the risk factors for multidrug resistant (MDR) bacterial infection. The strength of association was estimated by odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: The drug susceptibility tests showed that 1077(59.05%) MTB strains were sensitive to all the four antibiotics and the other 747(40.95%) strains were resistant to at least one drug. The proportions of mono-drug resistance were 28.73% for isoniazid, 19.41% for rifampicin, 29.33% for streptomycin, and 13.98% for ethambutol, respectively. The prevalence of MDR-TB was 16.61%, which was significantly different between new cases (7.63%) and those with previous treatment history (33.07%). Geographical variation of drug resistance was observed, where the proportion of MDR-TB among new cases was higher in the central (9.50%) or north part (9.57%) than that in the south area (4.91%) of Jiangsu province. The age of patients was significantly associated with the risk of drug resistance (P < 0.001) and the adjusted OR (95% CI) was 1.88(1.26-2.81) for patients aged 35-44 years when compared with those 65 years or older. Patients with previous treatment history had a more than 5-fold increased risk of MDR-TB (adjusted OR: 6.14, 95% CI: 4.61-8.17), compared with those previously not having been treated. CONCLUSIONS: The high prevalence of drug resistance has been a major challenge for TB control. Prevention and control of drug-resistant TB should be emphasized by the revised DOTS (direct observed therapy, short course) program through prompt case detection, routine and quality-assured drug susceptibility test for patients at high risk of resistance, programmatic treatment with both first and second-line medicines, and systematic treatment observation, with priority for high MDR-TB settings. PMID- 21324206 TI - Down-regulation of granulocyte-macrophage colony-stimulating factor by 3C-like proteinase in transfected A549 human lung carcinoma cells. AB - BACKGROUND: Severe Acute Respiratory Syndrome (SARS) is a severe respiratory illness caused by a novel virus, the SARS coronavirus (SARS-CoV). 3C-like protease (3CLpro) of SARS-CoV plays a role in processing viral polypeptide precursors and is responsible of viral maturation. However, the function of 3CLpro in host cells remains unknown. This study investigated how the 3CLpro affected the secretion of cytokines in the gene-transfected cells. RESULTS: From immunofluorescence microscopy, the localization of c-myc tagged 3CLpro was detected both in the cytoplasm and nucleus of transfected A549 cells. Expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) was significantly decreased in 3CLpro-transfected cells by both RT-PCR and ELISA, but without changes in other cytokines, i.e., IL-1beta, IL-6, IL-8, IL12p40, TNF-alpha, and TGF-beta. Furthermore, the protein levels of NF-kB decreased in 3CLpro transfected A549 cells when compared to EGFP transfected cells. CONCLUSIONS: Our results suggest that the 3CLpro may suppress expression of GM-CSF in transfected A549 cells through down-regulation of NF-kB production. PMID- 21324207 TI - High-throughput 454 resequencing for allele discovery and recombination mapping in Plasmodium falciparum. AB - BACKGROUND: Knowledge of the origins, distribution, and inheritance of variation in the malaria parasite (Plasmodium falciparum) genome is crucial for understanding its evolution; however the 81% (A+T) genome poses challenges to high-throughput sequencing technologies. We explore the viability of the Roche 454 Genome Sequencer FLX (GS FLX) high throughput sequencing technology for both whole genome sequencing and fine-resolution characterization of genetic exchange in malaria parasites. RESULTS: We present a scheme to survey recombination in the haploid stage genomes of two sibling parasite clones, using whole genome pyrosequencing that includes a sliding window approach to predict recombination breakpoints. Whole genome shotgun (WGS) sequencing generated approximately 2 million reads, with an average read length of approximately 300 bp. De novo assembly using a combination of WGS and 3 kb paired end libraries resulted in contigs <= 34 kb. More than 8,000 of the 24,599 SNP markers identified between parents were genotyped in the progeny, resulting in a marker density of approximately 1 marker/3.3 kb and allowing for the detection of previously unrecognized crossovers (COs) and many non crossover (NCO) gene conversions throughout the genome. CONCLUSIONS: By sequencing the 23 Mb genomes of two haploid progeny clones derived from a genetic cross at more than 30* coverage, we captured high resolution information on COs, NCOs and genetic variation within the progeny genomes. This study is the first to resequence progeny clones to examine fine structure of COs and NCOs in malaria parasites. PMID- 21324208 TI - Effect of exogenous surfactants on viability and DNA synthesis in A549, immortalized mouse type II and isolated rat alveolar type II cells. AB - BACKGROUND: In mechanically ventilated preterm infants with respiratory distress syndrome (RDS), exogenous surfactant application has been demonstrated both to decrease DNA-synthesis but also and paradoxically to increase epithelial cell proliferation. However, the effect of exogenous surfactant has not been studied directly on alveolar type II cells (ATII cells), a key cell type responsible for alveolar function and repair. OBJECTIVE: The aim of this study was to investigate the effects of two commercially available surfactant preparations on ATII cell viability and DNA synthesis. METHODS: Curosurf(r) and Alveofact(r) were applied to two ATII cell lines (human A549 and mouse iMATII cells) and to primary rat ATII cells for periods of up to 24 h. Cell viability was measured using the redox indicator resazurin and DNA synthesis was measured using BrdU incorporation. RESULTS: Curosurf(r) resulted in slightly decreased cell viability in all cell culture models. However, DNA synthesis was increased in A549 and rat ATII cells but decreased in iMATII cells. Alveofact(r) exhibited the opposite effects on A549 cells and had very mild effects on the other two cell models. CONCLUSION: This study showed that commercially available exogenous surfactants used to treat preterm infants with RDS can have profound effects on cell viability and DNA synthesis. PMID- 21324209 TI - Clonal spread of antimicrobial-resistant Escherichia coli isolates among pups in two kennels. AB - Although the dog breeding industry is common in many countries, the presence of antimicrobial resistant bacteria among pups in kennels has been infrequently investigated. This study was conducted to better understand the epidemiology of antimicrobial-resistant Escherichia coli isolates from kennel pups not treated with antimicrobials. We investigated susceptibilities to 11 antimicrobials, and prevalence of extended-spectrum beta-lactamase (ESBL) in 86 faecal E. coli isolates from 43 pups in two kennels. Genetic relatedness among all isolates was assessed using pulsed-field gel electrophoresis (PFGE). Susceptibility tests revealed that 76% of the isolates were resistant to one or more of tested antimicrobials, with resistance to dihydrostreptomycin most frequently encountered (66.3%) followed by ampicillin (60.5%), trimethoprim-sulfamethoxazole (41.9%), oxytetracycline (26.7%), and chloramphenicol (26.7%). Multidrug resistance, defined as resistance against two or more classes of antimicrobials, was observed in 52 (60.5%) isolates. Three pups in one kennel harboured SHV-12 ESBL-producing isolates. A comparison between the two kennels showed that frequencies of resistance against seven antimicrobials and the variation in resistant phenotypes differed significantly. Analysis by PFGE revealed that clone sharing rates among pups of the same litters were not significantly different in both kennels (64.0% vs. 88.9%), whereas the rates among pups from different litters were significantly different between the two kennels (72.0% vs. 33.3%, P < 0.05). The pups in the two kennels had antimicrobial-resistant E. coli clones, including multidrug-resistant and ESBL-producing clones. It is likely that resistant and susceptible bacteria can clonally spread among the same and/or different litters thus affecting the resistance prevalence. PMID- 21324210 TI - District level external quality assurance (EQA) of malaria microscopy in Pakistan: pilot implementation and feasibility. AB - BACKGROUND: Prompt, quality assured laboratory diagnosis is key to effective malaria case management and control, especially since the introduction of the more expensive artemisinin combination therapy (ACT). The malaria programme and its non-government partners, on the basis of WHO recommended Lot Quality Assurance methods, have developed a district level external quality assurance (EQA) system. This study was designed to assess the feasibility, under programme conditions, of an integrated district level external quality assurance and supervision approach for malaria microscopy. DESIGN AND METHODS: A prospective study conducted over seven months period (May-November 2007). In addition to the standard WHO EQA elements, three operational innovations were introduced, with the a district laboratory supervisor: a) on site re-checking of slides, b) in ensuring uninterrupted availability of laboratory reagents and supplies at diagnostic centers, and c) supervision of administrative and technical components. The quantitative data for the study came from the service records/documents, whereas the qualitative data came from the key informant interviews. RESULTS: During the seven month period in four districts, a total of 8,118 slides were examined of which 209 (2.6%) were found positive for malaria parasites (slide positivity range between 1.6% to 6.0%). The District Laboratory Supervisors in four districts reexamined a total of 1,770 slides (22%). The proportion of slides found discordant ranged from 0.5% to 1%. The quality of smear preparation was found acceptable in 73% slides. CONCLUSIONS: A district based EQA, based on lot quality assurance methods was implemented, using context specific operational guidelines, tools and training modules, and other inputs from the malaria control programme and partners. This EQA and supervision approach was found to be feasible and acceptable to those involved. Further study is required on the microscopy quality and cost-effectiveness of adding external quality assurance and supervision to district malaria microscopy services. PMID- 21324211 TI - Selection of reference genes for gene expression studies in ultraviolet B irradiated human skin fibroblasts using quantitative real-time PCR. AB - BACKGROUND: Reference genes are frequently used to normalise mRNA levels between different samples. The expression level of these genes, however, may vary between tissues or cells and may change under certain circumstances. Cytoskeleton genes have served as multifunctional tools for experimental studies as reference genes. Our previous studies have demonstrated that the expression of vimentin, one cytoskeletal protein, was increased in ultraviolet B (UVB)-irradiated fibroblasts. Thus, we examined the expression of other cytoskeleton protein genes, ACTB (actin, beta), TUBA1A (tubulin, alpha 1a), and TUBB1 (tubulin, beta 1), in human dermal fibroblasts irradiated by UVB to determine which of these candidates were the most appropriate reference genes. RESULTS: Quantitative real time PCR followed by analysis with the NormFinder and geNorm software programmes was performed. The initial screening of the expression patterns demonstrated that the expression of VIM was suppressed after UVB irradiation at doses >=25 mJ/cm(2) and that the expression of TUBA1A was significantly reduced by UVB doses >=75 mJ/cm(2) in cultured human dermal fibroblasts. The analysis of the experimental data revealed ACTB to be the most stably expressed gene, followed by GAPDH (aglyceraldehyde-3-phosphate dehydrogenase), under these experimental conditions. By contrast, VIM was found to be the least stable gene. The combination of ACTB and TUBB1 was revealed to be the gene pair that introduced the least systematic error into the data normalisation. CONCLUSION: The data herein provide evidence that ACTB and TUBB1 are suitable reference genes in human skin fibroblasts irradiated by UVB, whereas VIM and TUBA1A are not and should therefore be excluded as reference genes in any gene expression studies involving UVB irradiated human skin fibroblasts. PMID- 21324212 TI - Studies on Escherichia coli HflKC suggest the presence of an unidentified lambda factor that influences the lysis-lysogeny switch. AB - BACKGROUND: The lysis-lysogeny decision in the temperate coliphage lambda is influenced by a number of phage proteins (CII and CIII) as well as host factors, viz. Escherichia coli HflB, HflKC and HflD. Prominent among these are the transcription factor CII and HflB, an ATP-dependent protease that degrades CII. Stabilization of CII promotes lysogeny, while its destabilization induces the lytic mode of development. All other factors that influence the lytic/lysogenic decision are known to act by their effects on the stability of CII. Deletion of hflKC has no effect on the stability of CII. However, when lambda infects DeltahflKC cells, turbid plaques are produced, indicating stabilization of CII under these conditions. RESULTS: We find that CII is stabilized in DeltahflKC cells even without infection by lambda, if CIII is present. Nevertheless, we also obtained turbid plaques when a DeltahflKC host was infected by a cIII-defective phage (lambdacIII67). This observation raises a fundamental question: does lysogeny necessarily correlate with the stabilization of CII? Our experiments indicate that CII is indeed stabilized under these conditions, implying that stabilization of CII is possible in DeltahflKC cells even in the absence of CIII, leading to lysogeny. CONCLUSION: We propose that a yet unidentified CII stabilizing factor in lambda may influence the lysis-lysogeny decision in DeltahflKC cells. PMID- 21324213 TI - Keto analogue and amino acid supplementation affects the ammonaemia response during exercise under ketogenic conditions. AB - Hyperammonaemia is related to both central and peripheral fatigue during exercise. Hyperammonaemia in response to exercise can be reduced through supplementation with either amino acids or combined keto analogues and amino acids (KAAA). In the present study, we determined the effect of short-term KAAA supplementation on ammonia production in subjects eating a low-carbohydrate diet who exercise. A total of thirteen male cyclists eating a ketogenic diet for 3 d were divided into two groups receiving either KAAA (KEx) or lactose (control group; LEx) supplements. Athletes cycled indoors for 2 h, and blood samples were obtained at rest, during exercise and over the course of 1 h during the recovery period. Exercise-induced ammonaemia increased to a maximum of 35 % in the control group, but no significant increase was observed in the supplemented group. Both groups had a significant increase (approximately 35 %) in uraemia in response to exercise. The resting urate levels of the two groups were equivalent and remained statistically unchanged in the KEx group after 90 min of exercise; an earlier increase was observed in the LEx group. Glucose levels did not change, either during the trial time or between the groups. An increase in lactate levels was observed during the first 30 min of exercise in both groups, but there was no difference between the groups. The present results suggest that the acute use of KAAA diminishes exercise-induced hyperammonaemia. PMID- 21324214 TI - Effect of a mitochondria-targeted vitamin E derivative on mitochondrial alteration and systemic oxidative stress in mice. AB - The objective of the present study was to determine whether a mitochondria targeted vitamin E derivative (MitoVit E) would affect certain mitochondrial parameters, as well as systemic oxidative stress. A total of sixty-four mice were fed a high-fat (HF) diet for 5 weeks. They were then switched to either a low-fat (LF) or a medium-fat (MF) diet, and administered orally with MitoVit E (40 mg MitoVit E/kg body weight) or drug vehicle (10 % (v/v) ethanol in 0.9 % (w/v) NaCl solution), every other day for 5 weeks. Mitochondrial ATP and H(2)O(2) production rates in both the liver and the gastrocnemius were not affected by MitoVit E administration in either LF or MF diet-fed mice. However, the number and average size of the subsarcolemmal mitochondria, but not the intermyofibrillar mitochondria, from the soleus muscle were significantly higher in the MF group receiving MitoVit E (MF-E) than in the MF group receiving vehicle only (MF-C). After the mice were switched from the HF diet to the four dietary treatments (LF C, LF-E, MF-C and MF-E), the decrease in urinary isoprostane concentration was significantly greater in the LF-E group than in the other three groups during the whole study (weeks 6-10). In addition, MitoVit E significantly increased plasma superoxide dismutase (SOD) activity in the MF diet-fed group without affecting plasma glutathione peroxidase activity or H(2)O(2) levels. Overall, these data suggest that MitoVit E affects subsarcolemmal mitochondrial density and systemic oxidative stress parameters such as plasma SOD activity and urinary isoprostane concentration. PMID- 21324215 TI - Intakes and breast-milk concentrations of essential fatty acids are low among Bangladeshi women with 24-48-month-old children. AB - Maternal fat intake and adipose reserves are major sources of PUFA during lactation. The present study examined the cross-sectional relationship between prolonged breast-feeding and maternal BMI, assessed adequacy of fat intake among lactating and non-lactating mothers of children 24-48 months of age and determined breast-milk fatty acid composition. Multi-stage sampling was used to select a representative sample of mothers from two rural districts in Bangladesh (n 474). Dietary data were collected during two non-consecutive 24 h periods via 12 h in-home daytime observations and recall. The National Cancer Institute method for episodically consumed foods was used to estimate usual intake distributions. Breast milk samples were collected from ninety-eight women, and breast-milk fatty acid methyl esters were quantified using GC. Approximately 42 % of lactating v. 26 % of non-lactating mothers were underweight (BMI < 18.5 kg/m2; P = 0.0003). The maternal diet was low in total fat (approximately 8 % of mean total energy) and food sources of PUFA, including oil and animal source foods, resulting in a low estimated mean total consumption of PUFA (5.1 g/d). Almost all women were estimated to consume less than the recommended intake levels for total fat, total PUFA, alpha-linolenic acid (ALA) and DHA. Median breast-milk linoleic acid (8.5 % weight) and ALA (0.2 %) concentrations were among the lowest reported in the literature, in contrast with arachidonic acid (0.5 %) and DHA (0.3 %) concentrations, which were mid-range. Bangladeshi women in general, and especially those who practise prolonged breast-feeding, may benefit from increased consumption of food sources of PUFA. PMID- 21324216 TI - Cost-effectiveness of targeted screening for hepatitis C in The Netherlands. AB - On account of the serious complications of hepatitis C virus (HCV) infection and the improved treatment possibilities, the need to improve HCV awareness and case finding is increasingly recognized. To optimize a future national campaign with this objective, three pilot campaigns were executed in three regions in The Netherlands. One campaign was aimed at the general population, a second (similar) campaign was extended with a support programme for primary care and a third campaign was specifically aimed at hard-drug users. Data from the pilot campaigns were used to build a mathematical model to estimate the incremental cost effectiveness ratio of the different campaigns. The campaign aimed at the general public without support for primary care did not improve case-finding and was therefore not cost-effective. The similar campaign accompanied by additional support for primary care and the campaign aimed at hard-drug users emerged as cost-effective interventions for identification of HCV carriers. PMID- 21324217 TI - Low seroprevalence of Q fever in The Netherlands prior to a series of large outbreaks. AB - The Netherlands has experienced large community outbreaks of Q fever since 2007. Sera and questionnaires containing epidemiological data from 5654 individuals were obtained in a nationwide seroprevalence survey used to evaluate the National Immunization Programme in 2006-2007. We tested these sera for IgG phase-2 antibodies against Coxiella burnetii with an ELISA to estimate the seroprevalence and to identify determinants for seropositivity before the Q fever outbreaks occurred. Overall seroprevalence was 1.5% [95% confidence interval (CI) 1.3-1.7]. Corrected for confirmation with immunofluorescence results in a subset, the estimated seroprevalence was 2.4%. Seropositivity ranged from 0.48% (95% CI 0.00 0.96) in the 0-4 years age group to 2.30% (95% CI 1.46-3.15) in the 60-79 years age group. Keeping ruminants, increasing age and being born in Turkey were independent risk factors for seropositivity. The low seroprevalence before the start of the outbreaks supports the hypothesis that The Netherlands has been confronted with a newly emerging Q fever problem since spring 2007. PMID- 21324218 TI - Diversity of the helminth community of the Pampean grassland mouse (Akodon azarae) on poultry farms in central Argentina. AB - This paper describes the helminth community of the Pampean grassland mouse (Akodon azarae) inhabiting poultry farms in central Argentina. Winter diversity (season of high rodent abundance) has been compared to spring diversity (season of low rodent abundance). Species richness was seven in both seasons: five nematodes (Syphacia carlitosi, Stilestrongylus spp., Trichuris laevitestis, Pterygodermatites (Paucipectines) azarai and Protospirura numidica criceticola) and two cestodes (adults of Cyclophyllidea and Taenia taeniaeformis hepatic cysts). No difference in richness was detected between host sexes in each season or among host age classes. However, the helminth community showed 67% similarity between winter and spring, with diversity being significantly higher in spring (H = 0.873) than in winter (H = 0.546; P < 0.0005). This could be attributed to different factors, such as host abundance, host diet or environmental factors, that affect the transmission of each species differently. On the other hand, Stilestrongylus spp. and S. carlitosi showed higher dominance and intensity in both seasons compared to their cohabiting species, P. (P.) azarai and T. laevitestis, respectively. The lower values of the latter two species may be related to a crowding effect due to their large body sizes. This is the first report of cestodes in A. azarae. The finding of T. taeniaeformis strobilocerci could be important in the epidemiology of parasitosis in domestic animals of the farms. PMID- 21324219 TI - Investigation of a large community-based outbreak of hepatitis B infection in the United Kingdom. AB - We describe the largest outbreak of hepatitis B virus infection reported to date in the UK. Between July 2001 and December 2005, 237 cases were identified in Avon, South West England. The likely route of transmission was injecting drug use in 44% (104/237) and heterosexual intercourse in 30% (71/237) of cases. A case control study in injectors showed that injecting crack cocaine [adjusted odds ratio (aOR) 23.8, 95% confidence interval (CI) 3.04-186, P<0.001] and sharing injecting paraphernalia in the year before diagnosis (aOR 16.67, 95% CI 1.78-100, P=0.010) were strongly associated with acute hepatitis B. In non-IDUs number of sexual partners and lack of consistent condom use were high compared to a national sample. We describe the control measures implemented in response to the outbreak. This outbreak has highlighted the problems associated with the low uptake from the national hepatitis B vaccination policy which targets high-risk groups, the difficulties of identifying those at risk of acquiring hepatitis B infection through heterosexual sex, and injecting crack cocaine as a risk factor for hepatitis B. PMID- 21324220 TI - A case-control study on the occurrence of Salmonella spp. in the environment of pigs. AB - The objective of this study was to compare the occurrence of Salmonella spp. found in the animal environment in pig herds with different Salmonella risks (61 herds with low seroprevalence, 81 herds with high seroprevalence) on a broad scale. The environmental samples were divided into two types: direct (n=1105) and indirect (n=1220) environmental samples. All samples were tested for Salmonella spp. via real-time polymerase chain reaction. Most of the indirect environments were more often Salmonella-positive in the high-seroprevalence herds than in the low-seroprevalence herds; significantly higher were compartment aisles [odds ratio (OR) 3.45, 95% confidence interval (CI) 1.61-7.41], driving boards (OR 3.06, 95% CI 1.38-6.92) and the central aisle of the barn (OR 3.03, 95% CI 1.35 6.83). The overall results show that especially areas in the indirect environment are the major, but mostly underestimated causes of residual Salmonella. PMID- 21324221 TI - Interpretation of the nano-electron-diffraction patterns along the five-fold axis of decahedral gold nanoparticles. AB - The transition from 10-fold to 5-fold symmetry was observed during the analysis of nanodiffraction patterns of a gold decahedral multiple twinned nanoparticle of 15 nm in diameter. The analysis shows that as the convergence of the beam is increased, the rotational symmetry of the diffraction pattern shifts from 10- to 5-fold. The 10-fold symmetry predicted by Friedel's law is lost by the asymmetric shift of the diffraction spots, an effect that becomes more noticeable as the electron beam convergence increases. Dynamical and kinematical diffraction calculations indicate this decrease in symmetry is the result of a double refraction effect coupled with the variation of the dynamical diffraction conditions arising from a varying electron beam convergence. PMID- 21324222 TI - The impact of fresh produce specifications on the Australian food and nutrition system: a case study of the north Queensland banana industry. AB - OBJECTIVE: To use the north Queensland banana industry as a case study to examine the extent to which cosmetic standards set by retailers influence the amount of edible waste generated on-farm and the effect of this on the sustainability of the Australian food and nutrition system. DESIGN: Waste audits were performed on farm at a banana packing shed to quantify the amount of fruit discarded due to cosmetic imperfections. These data, together with production records provided by the Department of Primary Industries and Fisheries and interviews with growers, were used to inform a nutritional analysis, a life cycle assessment and an economic analysis to quantify nutritional, environmental and economic impacts. SETTING: North Queensland, Australia SUBJECTS: Banana farms and packing shed.ResultBetween 10 and 30 % of the north Queensland banana crop is discarded on-farm. Of this, 78 % was found to be due to cosmetic imperfections, which equates to an industry total of 37 000 tonnes per annum. This waste represents a loss of 137 billion kilojoules with accompanying macro- and micronutrients. The life cycle assessment indicated that approximately 16 300 tonnes of carbon dioxide emissions, 11.2 gigalitres of virtual water as well as other natural resources are embodied in the waste. There is an industry-wide, economic loss of approximately $AU 26.9 million per annum. CONCLUSIONS: The majority of on-farm banana waste is caused by arbitrary cosmetic standards set by retailers, resulting in significant nutritional, environmental and economic losses. Public health nutritionists have a role to play across the entire food chain to minimize the impacts of waste on the food system. PMID- 21324223 TI - Relationship of exclusive breast-feeding to infections and growth of Tanzanian children born to HIV-infected women. AB - OBJECTIVE: We examined the relationships between exclusive breast-feeding and the risks of respiratory, diarrhoea and nutritional morbidities during the first 2 years of life among children born to women infected with HIV-1. DESIGN: We prospectively determined the incidence of respiratory illnesses, diarrhoea, fever, hospitalizations, outpatient visits and nutritional morbidities. Generalized estimating equations were used to estimate the relative risks for morbidity episodes and Cox proportional hazards models to estimate the incidence rate ratios of nutritional morbidities. SETTING: Dar es Salaam, Tanzania. SUBJECTS: The sample consisted of 666 children born to HIV-infected women. RESULTS: The 666 children were followed for 2 years. Exclusive breast-feeding was associated with lower risk for cough (rate ratio (RR) = 0.49, 95 % CI 0.41, 0.60, P < 0.0001), cough and fever (RR = 0.44, 95 % CI 0.32, 0.60, P < 0.0001) and cough and difficulty breathing or refusal to feed (RR = 0.31, 95 % CI 0.18, 0.55, P < 0.0001). Exclusive breast-feeding was also associated with lower risk of acute diarrhoea, watery diarrhoea, dysentery, fever and outpatient visits during the first 6 months of life, but showed no effect at 6-24 months of life. Exclusive breast-feeding did not significantly reduce the risks of nutritional morbidities during the first 2 years of life. CONCLUSIONS: Exclusive breast feeding is strongly associated with reductions in the risk of respiratory and diarrhoea morbidities during the first 6 months of life among children born to HIV-infected women. PMID- 21324224 TI - Adolescents in the United States can identify familiar foods at the time of consumption and when prompted with an image 14 h postprandial, but poorly estimate portions. AB - OBJECTIVE: To evaluate adolescents' abilities to identify foods and estimate the portion size of foods consumed in order to inform development of the mobile telephone food record (mpFR). DESIGN: Data were collected from two samples of adolescents (11-18 years). Adolescents in sample 1 participated in one lunch (n 63) and fifty-five of the sixty-three adolescents (87 %) returned for breakfast the next morning. Sample 2 volunteers received all meals and snacks for a 24 h period. At mealtime, sample 1 participants were asked to write down the names of the foods. Sample 2 participants identified foods in an image of their meal 10-14 h postprandial. Adolescents in sample 2 also estimated portion sizes of their breakfast foods and snacks. RESULTS: Sample 1 identified thirty of the thirty eight food items correctly, and of the misidentified foods all were identified within the correct major food group. For sample 2, eleven of the thirteen food items were identified correctly 100 % of the time. Half of the breakfast and snack foods had at least one portion size estimate within 10 % of the true amount using a variety of measurement descriptors. CONCLUSIONS: The results provide evidence that adolescents can correctly identify familiar foods and they can look at an image of their meal and identify the foods in the image up to 14.5 h postprandial. The results of the present study not only inform the development of the mpFR but also provide strong evidence of the use of digital images of eating occasions in research and clinical settings. PMID- 21324225 TI - Phr1 is required for proper retinocollicular targeting of nasal-dorsal retinal ganglion cells. AB - Precise targeting of retinal projections is required for the normal development of topographic maps in the mammalian primary visual system. During development, retinal axons project to and occupy topographically appropriate positions in the dorsal lateral geniculate nucleus (dLGN) and superior colliculus (SC). Phr1 retinal mutant mice, which display mislocalization of the ipsilateral retinogeniculate projection independent of activity and ephrin-A signaling, were found to have a more global disruption of topographic specificity of retinofugal inputs. The retinocollicular projection lacks local refinement of terminal zones and multiple ectopic termination zones originate from the dorsal-nasal (DN) retinal quadrant. Similarly, in the dLGN, the inputs originating from the contralateral DN retina are poorly refined in the Phr1 mutant. These results show that Phr1 is an essential regulator of retinal ganglion cell projection during both dLGN and SC topographic map development. PMID- 21324226 TI - The skinny on tuna fat: health implications. AB - OBJECTIVE: Dietary n-3 (omega-3) and n-6 (omega-6) PUFA have significant implications in health and disease prevention. Marine life is rich in long-chain n-3 PUFA. Children and adults in North America are reluctant fish eaters; canned tuna is a common fish in children's diets. Although a multitude of tuna products are available, their respective PUFA contents have not been well described. The aim of the present study was to compare the fatty acid (FA) profiles of different commercially available US tuna products. DESIGN: Fat and FA composition of eight products randomly selected from two US suppliers were analysed with capillary GC after lipid extraction. SETTING: Large north-eastern US grocery store chain. SUBJECTS: Canned tuna. RESULTS: Energy from fat varied from 3 to 33 % and the essential FA (EFA) linoleic acid (18 : 2n-6) and alpha-linolenic acid (18 : 3n-3) varied tenfold. DHA varied between 90 and 770 mg/serving. The n-6:n-3 ratio was 3:1-4:1 in oil-packaged products, 2:1-7:1 in packaged tuna salads and 1:3-1:7 in water-packaged products. A similar magnitude of differences was seen in the ratio between arachidonic acid (20 : 4n-6) and DHA. CONCLUSIONS: Light tuna canned in water may be a better choice of providing n-3 PUFA to individuals in a healthy population, whereas oil-packaged products may be preferable for those individuals with a need for increased EFA, such as for patients with cystic fibrosis. Awareness regarding PUFA content may aid in consumer product choices and health care provider advice. PMID- 21324227 TI - The light-induced reduction of horizontal cell receptive field size in the goldfish retina involves nitric oxide. AB - Horizontal cells of the vertebrate retina have large receptive fields as a result of extensive gap junction coupling. Increased ambient illumination reduces horizontal cell receptive field size. Using the isolated goldfish retina, we have assessed the contribution of nitric oxide to the light-dependent reduction of horizontal cell receptive field size. Horizontal cell receptive field size was assessed by comparing the responses to centered spot and annulus stimuli and from the responses to translated slit stimuli. A period of steady illumination decreased the receptive field size of horizontal cells, as did treatment with the nitric oxide donor (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium 1,2-diolate (100 MUM). Blocking the endogenous production of nitric oxide with the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester (1 mM), decreased the light-induced reduction of horizontal cell receptive field size. These findings suggest that nitric oxide is involved in light-induced reduction of horizontal cell receptive field size. PMID- 21324228 TI - Validation of self-reported folic acid use in a multiethnic population: results of the Amsterdam Born Children and their Development study. AB - OBJECTIVE: To assess folic acid supplementation rates and validate the self reporting of folic acid supplement use among pregnant women in a multiethnic cohort. DESIGN: Secondary analysis of a prospective cohort study. SETTING: Self reported folic acid supplement use in the Amsterdam Born Children and their Development study cohort was compared with serum folate concentrations using non parametric trend analysis and linear and logistic regression. SUBJECTS: A total of 4234 pregnant women of various ethnic backgrounds. RESULTS: Serum folate levels showed a significant positive linear trend as reported use of folic acid increased (P < 0.001), which was supported by linear regression (r = 0.49). Odds of having low serum folate concentration decreased with reported early start of folic acid intake. Young, multiparous or non-Western women reported less pre conception folic acid intake. Non-Western women showed lower serum folate concentrations. The overall rate of over-reporting, i.e. serum folate concentrations <=20 nmol/l while reporting the use of folic acid supplements, was 20.7 %. Women of Surinamese and Moroccan ancestry had higher odds of over reporting (OR = 2.3; 95 % CI 1.5, 3.5 and OR = 2.3; 95 % CI 1.3, 4.0, respectively). The odds for Surinamese women remained significant after adjusting for the onset of supplement use, parity and age (OR = 1.7; 95 % CI 1.1, 2.6). CONCLUSIONS: Although self-reporting is a valid method for assessing folic acid supplement use in a multiethnic population, some participants do over-report. Surinamese and possibly Moroccan women appear to over-report more often. Rates of supplementation are low, especially in non-Western women. This suggests the need for intensifying current campaigns or perhaps even additional advice to start or continue to use folic acid post-conceptionally. PMID- 21324229 TI - Perceived and objective measures of the food store environment and the association with weight and diet among low-income women in North Carolina. AB - OBJECTIVE: The present study aimed to highlight the similarities and differences between perceived and objective measures of the food store environment among low income women and the association with diet and weight. DESIGN: Cross-sectional analysis of food store environment. Store level was characterized by: (i) the availability of healthy foods in stores where participants shop, using food store audits (objective); and (ii) summary scores of self-reported perception of availability of healthy foods in stores (perceived). Neighbourhood level was characterized by: (i) the number and type of food stores within the census tract (objective); and (2) summary scores of self-reported perception of availability of healthy foods (perceived). SETTING: Six counties in North Carolina. SUBJECTS: One hundred and eighty-six low-income women. RESULTS: Individuals who lived in census tracts with a convenience store and a supercentre had higher odds of perceiving their neighbourhood high in availability of healthy foods (OR = 6.87 (95 % CI 2.61, 18.01)) than individuals with no store. Overall, as the number of healthy foods available in the store decreased, the probability of perceiving that store high in availability of healthy foods increased. Individuals with a supercentre in their census tract weighed more (2.40 (95 % CI 0.66, 4.15) kg/m2) than individuals without one. At the same time, those who lived in a census tract with a supercentre and a convenience store consumed fewer servings of fruits and vegetables (-1.22 (95 % CI -2.40, -0.04)). CONCLUSIONS: The study contributes to a growing body of research aiming to understand how the food store environment is associated with weight and diet. PMID- 21324230 TI - Folic acid awareness and intake among women in areas with high prevalence of neural tube defects in China: a cross-sectional study. AB - OBJECTIVE: To measure folic acid awareness and intake rates among women of childbearing age in certain areas of China with a high prevalence of neural tube defects (NTD). DESIGN: A cross-sectional survey was carried out utilising a nineteen-item questionnaire enquiring into individual women's knowledge of, attitude towards and practice of folic acid supplementation. SETTING: A total of 293 low-income counties in six provinces of China. SUBJECTS: Women aged 19-44 years from six provinces with a high prevalence of NTD recruited from June to August 2008. RESULTS: Among 33 025 participants, 57 % had heard of folic acid but only 15 % knew all of the core information. The intake rate was 12 %; only 8 % took the recommended dose and only 4 % of non-pregnant women took folic acid. Some women did not take folic acid because they did not know that they should take it (49 %) or they had misconceptions about it (24 %). According to logistic regression analysis, rural residence was a risk factor for folic acid awareness. Ethnicity, educational level, average annual income per person and pregnancy were the influencing factors of folic acid awareness and folic acid intake. CONCLUSIONS: Although more than half of the respondents had heard of folic acid, the intake rate was still very low in areas with a high prevalence of NTD. Thus, more efforts are needed to increase folic acid awareness and intake among women of reproductive age in these areas. PMID- 21324231 TI - Food retailer practices, attitudes and beliefs about the supply of healthy foods. AB - OBJECTIVE: Non-supermarket food retailers can be a promising channel for increasing the availability of healthy foods in underserved communities. The present paper reports on retailer practices, attitudes and beliefs about the supply of healthy foods before and after the introduction of new subsidies for healthy foods by the US Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) in October 2009. DESIGN: We designed and conducted in person standardized interviews with store owners and managers to assess perceptions of demand and profits for different foods, supply networks, barriers to stocking healthy foods and their changes following implementation of the new WIC packages. SETTING: Non-supermarket retailers in five towns of Connecticut, USA (n 68 in 2009 and n 58 in 2010). SUBJECTS: Owners and managers of WIC authorized and non-WIC convenience stores and non-chain grocery stores. RESULTS: Retailers identified customer demand as the primary factor in stocking decisions. They reported observing a significantly weaker demand for healthy foods compared with unhealthy foods, although it improved for certain foods with the new WIC subsidies. Less healthy foods were also perceived as more profitable. Supplier networks varied by product from convenient manufacturer delivery for salty snacks to self-supply for produce. WIC retailers were able to quickly adapt and supply healthy foods required under the new WIC programme guidelines. CONCLUSIONS: Retailers other than supermarkets currently perceive little demand for healthy foods, but new WIC subsidies have the power to change these perceptions. Supply barriers seem secondary in the limited offerings of healthy foods by stores and could be overcome when policy changes generate new demand for healthy foods. PMID- 21324232 TI - HIV-associated dementia in older adults: clinical and tomographic aspects. AB - BACKGROUND: Elderly adults with human immunodeficiency virus (HIV) are at greater risk of developing cognitive impairment. The purpose of this study was to describe clinical and tomographic characteristics of HIV-1 associated dementia (HIVD) in older adults. METHODS: A descriptive study was carried out involving eight HIVD patients. Seven tests were employed for cognitive assessment and transformed to whole number z-scores using appropriate normative sets. RESULTS: The average age of the patients was 71 years; seven cases described the route of HIV infection as being heterosexual; and mean schooling was 6.5 years. Six subjects were using highly active anti-retroviral therapy (HAART), with an average CD4 count of 407.8 cells/mm3. Mild dementia was detected in most cases (87.5%). Deficits on neuropsychological tests showed results similar to multi center transversal studies on HIVD. The classic HIVD triad observed in younger adults was also seen in this population: i.e. cognitive changes, psychiatric changes and motor impairment. Cortical injury shown by dyscalculia, visual spatial change and language deficits were frequent. Brain images showed cortical atrophy in all patients but was restricted to frontal lobes in five cases. CONCLUSION: The findings on brain imaging were non-specific, revealing images similar to those of the elderly brain and to HIVD in younger adults. HIVD in the elderly is a challenge and become an increasingly significant differential diagnosis for cognitive loss in old age. This dementia must be clinically suspected and image exams are useful in excluding other central disorders. Prospective studies of HIV-positive elderly people are warranted to better understand HIVD. PMID- 21324233 TI - Ultrastructural changes of sheep cumulus-oocyte complexes following different methods of vitrification. AB - To determine the ultrastructural changes of sheep cumulus-oocyte complexes (COCs) following different methods of vitrification, good quality isolated COCs (GV stage) were randomly divided into the non-vitrified control, conventional straw, cryotop and solid surface vitrification groups. In both conventional and cryotop methods, vitrified COCs were respectively loaded by conventional straws and cryotops, and then plunged directly into liquid nitrogen (LN2); whereas in the solid surface group, vitrified COCs were first loaded by cryotops and then cooled before plunging into LN2. Post-warming survivability and ultrastructural changes of healthy COCs in the cryotop group especially in comparison with the conventional group revealed better viability rate and good preservation of the ooplasm organization. However in all vitrification groups except the cryotop group, mitochondria were clumped. Solely in the conventional straw group, the mitochondria showed different densities and were extremely distended. Moreover in the latter group, plenty of large irregular connected vesicles in the ooplasm were observed and in some parts their membrane ruptured. Also, in the conventional and solid surface vitrification groups, cumulus cells projections became retracted from the zona pellucida in some parts. In conclusion, the cryotop vitrification method as compared with other methods seems to have a good post-warming survivability and shows less deleterious effects on the ultrastructure of healthy vitrified-warmed sheep COCs. PMID- 21324234 TI - Grape juice concentrate prevents oxidative DNA damage in peripheral blood cells of rats subjected to a high-cholesterol diet. AB - The goal of the present study was to investigate whether subchronic treatment with grape juice concentrate is able to protect liver and peripheral blood cells against cholesterol-induced injury in rats. The effects of the grape juice concentrate treatment on histopathological changes, immunohistochemistry for cyclo-oxygenase-2 (COX-2), and basal and oxidative DNA damage induced by H2O2 using a single-cell gel (comet) assay were evaluated. Male Wistar rats (n 18) were divided into three groups: group 1--negative control; group 2--cholesterol at 1 % (w/w) in their diet, treated for 5 weeks; group 3--cholesterol at 1 % in their chow, treated for 5 weeks, and grape juice concentrate at 222 mg/d in their drinking-water in the final week only. The results indicated that the treatment with grape juice concentrate did not show remarkable differences regarding liver tissue in group 3 compared with group 2. However, grape juice concentrate was able to decrease oxidative DNA damage induced by H2O2 in peripheral blood cells, as depicted by the tail moment results. COX-2 expression in the liver did not show statistically significant differences (P>0.05) between groups. Taken together, the present results suggest that the administration of subchronic grape juice concentrate prevents oxidative DNA damage in peripheral blood cells. PMID- 21324235 TI - Making an impact in 2011: launching The eCJP, raising standards, and reducing time to publish. PMID- 21324236 TI - Electroconvulsive therapy resurrected: its successes and promises after 75 years. PMID- 21324237 TI - What we have learned about electroconvulsive therapy and its relevance for the practising psychiatrist. AB - In this narrative review, the current knowledge base on the efficacy and the practice of electroconvulsive therapy (ECT) is reviewed, and its relevance for the practising psychiatrist is appreciated. In the past decade, several large scale studies have confirmed the significant superiority of ECT in the treatment of severe and refractory psychiatric conditions, such as major depressive disorder and bipolar disorder. However, the efficacy of ECT is not reflected in current treatment algorithms, where ECT is often reserved as a last resort. However, clinical characteristics, such as the presence of psychotic symptoms, suicidality, or catatonic signs, should prompt the clinician to consider ECT earlier in the treatment course. ECT is a safe procedure, without absolute contraindications for its use. Nevertheless, patients' fears and complaints should be acknowledged, and patients should be adequately informed about expected benefits and possible risks, such as memory problems, that are generally transient. Research focusing on further minimizing memory problems, while maintaining a superior efficacy, is ongoing. Adequate continuation treatment, either pharmacotherapy or continuation ECT, after a successful ECT course is of vital importance to maintain the benefits achieved and should be the focus of future research. PMID- 21324238 TI - How does electroconvulsive therapy work? Theories on its mechanism. AB - This article reviews 3 current theories of electroconvulsive therapy (ECT). One theory points to generalized seizures as essential for the therapeutic efficacy of ECT. Another theory highlights the normalization of neuroendocrine dysfunction in melancholic depression as a result of ECT. A third theory is based on recent findings of increased hippocampal neurogenesis and synaptogenesis in experimental animals given electroconvulsive seizures. Presently, the endocrine theory has the strongest foundation to explain the working mechanism of ECT. PMID- 21324239 TI - Incidence of diabetes in patients with schizophrenia: a population-based study. AB - OBJECTIVE: To detect the incidence of diabetes in patients with schizophrenia in Taiwan. METHODS: The National Health Research Institute provided a database of 1 million random subjects for study, from which we drew a random sample of 617 068 subjects aged 18 years and older in the year 2000. Subjects who had at least one service claim during this year, with a primary diagnosis of schizophrenia, diabetes, or with a prescription for treatment of diabetes, were identified. We compared initial diagnosis of diabetes between patients with schizophrenia and the general population in 2000. We also followed a cohort of subjects with schizophrenia from 2000 to 2005. RESULTS: The incidence of diabetes was higher in patients with schizophrenia than in the general population (1.46% and 1.12%, respectively; OR 1.47; 95% CI 1.09 to 1.97) in 2000. Compared with the general population, patients with schizophrenia showed a higher incidence of diabetes in the group aged 18 to 29 years; among females; among those with insurance of more than US$1281; among those living in the northern region; and among those residing in urban areas. The average annual incidence of diabetes in patients with schizophrenia was 1.84% from 2000 to 2005. Higher incidence of diabetes in patients with schizophrenia was associated with increased age, females, hypertension, and hyperlipidemia. CONCLUSIONS: Patients with schizophrenia had a higher incidence of diabetes for the youngest adult age group and for females than for the general population. Increased age, females, hypertension, and hyperlipidemia were risk factors of diabetes in patients with schizophrenia. PMID- 21324240 TI - Prevalence and correlates of 12-month prescription drug misuse in Alberta. AB - OBJECTIVE: We examined the prevalence and correlates of prescription drug misuse (PDM) in a population-based sample of adults from Alberta. METHODS: Data were collected from 3511 adults in Alberta aged 18 years and older in 2002 using a computer-aided telephone survey; the survey response rate was 57.4%. RESULTS: The prevalence of 12-month PDM in Alberta was 8.2% in 2002. Opiates were the most frequently misused drug class, followed by sedatives, stimulants, and tranquilizers. Current disability was particularly associated with PDM. Odds of PDM were also elevated among adult students and adults with a high school diploma relative to adults with a post-secondary degree. Past-year problem gambling, illicit drug use, and alcohol use and dependence were each associated with PDM, while past-year binge drinking and daily smoking were not. CONCLUSIONS: Findings suggest PDM was an important public health concern in Alberta in 2002. Estimates suggest prescription use and misuse have increased substantially in Canada since that time. There is an urgent need for an ongoing assessment of this evolving problem so that effective prevention and therapeutic strategies can be developed. PMID- 21324241 TI - Sexual orientation and its relation to mental disorders and suicide attempts: findings from a nationally representative sample. AB - OBJECTIVE: To compare the rates of all Axis I and II mental disorders and suicide attempts in sexual orientation minorities with rates in heterosexuals using a nationally representative sample. METHOD: Data used were from the National Epidemiologic Survey on Alcohol and Related Conditions Wave 2 (n = 34 653, response rate = 70.2%). Cross-tabulations and multivariate logistic regression analyses were performed to determine differences in rates of mental disorders and suicide attempts by sexual orientation. All analyses were stratified by sex. RESULTS: Compared with their heterosexual counterparts, lesbians and bisexual women demonstrated a 3-fold increased likelihood of substance use disorders, and gay and bisexual men showed twice the rate of anxiety disorders and schizophrenia and (or) psychotic illness, even after accounting for mental disorder comorbidity. Suicide attempts were independently associated with bisexuality, with odds 3 times higher than in heterosexuals. CONCLUSION: Findings from our study emphasize the fact that sexual orientation minorities are vulnerable to poor mental health outcomes, including suicide attempts. Clinicians need to be aware of these specific negative mental health consequences when assessing sexual orientation minorities. PMID- 21324242 TI - Psychiatric disorder in detained male adolescents as risk factor for serious recidivism. AB - OBJECTIVE: A growing body of research consistently shows that detained minors bear substantial mental health needs. However, the relation between mental disorder and criminal recidivism has largely remained unexplored. Our study examines whether psychiatric disorders increase the likelihood of recidivism after controlling for time at risk, criminal history, and the presence of other disorders. METHOD: Participants (n = 232) were detained male adolescents from all 3 youth detention centres in Flanders, Belgium, who were interviewed with the Diagnostic Interview Schedule for Children, Version IV. Two to 4 years later, information on serious recidivism was retrieved from the official judicial registration system. Serious recidivism was defined as having at least one arrest charge for violent, severe property crime, or substance-related offences. RESULTS: Serious recidivism was high, with 81% (n = 191) of the participants being rearrested. Psychiatric disorders predicted neither serious recidivism in general nor violent and severe property recidivism. However, other drug use disorder (OR 2.41; 95% CI 1.22 to 4.75) and general comorbidity (OR 2.64; 95% CI 1.40 to 4.99) were significantly predictive of substance-related recidivism. CONCLUSION: Common psychiatric disorders in detained male adolescents do not significantly increase the likelihood of subsequent arrests, with the exception that substance use disorders appear to increase the risk of later substance related recidivism. Effective treatment of these disorders may prevent detained juveniles to experience the detrimental outcomes associated with substance related crimes as adults (for example, mental illness). PMID- 21324243 TI - [Cognitive-behavioural therapy in early psychosis: an open study in a clinical setting]. AB - OBJECTIVE: Meta-analysis results confirm that cognitive-behavioural therapy in psychosis (CBTp) is efficient for persistent symptoms. However, external validity remains unexplored. CBTp in early psychosis (in the first 5 years after diagnosis) seems especially relevant, given a possible impact on long-term course. However, the few studies that experimented with CBTp with this population had poor results. They all introduced therapy during an acute psychotic phase and most of them performed a limited number of sessions. Therefore, our introductory open study aimed to evaluate the efficiency of a 25-session Australian CBTp program, introduced during a stable phase in Quebec patients with early psychosis. METHOD: The Active Cognitive Psychotherapy for Early Psychosis program was offered to 20 patients aged 14 years or older, at a rate of 1 weekly session during 6 months. RESULTS: The acceptance rate was 75%, the mean session compliance rate was 84%, and participants were satisfied with the program. Pre- and post-CBTp analyses indicated statistically significant improvements of psychotic symptomatology, which were maintained at 6-month follow-up. Self criticism improvement was also statistically significant, post-CBTp. CONCLUSION: CBTp seems to be appropriate in our clinical settings, including with adolescents. Moreover, the treatment dosage used seems to foster session compliance. PMID- 21324244 TI - [Initiation of ecstasy use in Quebec senior high school adolescents: distal and proximal predictors]. AB - OBJECTIVE: To identify distal and proximal predictors of ecstasy use initiation during adolescence. METHOD: The sample included 2162 adolescents from Quebec disadvantaged community high schools, with an annual follow-up for 5 years. Path analysis was used to predict ecstasy use initiation in secondary 5 (aged 16 to 17 years) from predictors in secondary 1 and 2 (aged 12 to 14 years) and in secondary 4 (aged 15 to 16 years). RESULTS: Secondary 5 adolescents initiating ecstasy use showed a higher risk on multiple factors, compared with nonusers. Initiation was mainly predicted by proximal risk factors related to individual use as well as peer use and deviance. Nevertheless, many proximal factors developed consistently with their corresponding distal factor (indirect link). Marijuana use was the strongest predictor of ecstasy use initiation. All things being equal, relative risk was 2.04 times higher in adolescents having used marijuana in the past year (secondary 4). CONCLUSIONS: Ecstasy use initiation in secondary 5 seems to be globally related to an externalized, rather than internalized, profile. This ecstasy use was strongly associated with other substance use and likely shares many risk factors with other substance use, specifically marijuana use. PMID- 21324245 TI - Lifestyle behaviors associated with secondary prevention of coronary heart disease among California adults. AB - INTRODUCTION: Heart disease is the leading cause of death in the United States. People diagnosed with coronary heart disease (CHD) are at an increased risk for illness and death. To reduce this risk, it is recommended that people who are diagnosed with CHD improve their health behaviors. The objective of this study was to assess the prevalence of associated lifestyle risk behaviors among California adults who have CHD. METHODS: From 2005 through 2008, the California Behavioral Risk Factor Surveillance System collected data regarding previous diagnosis of cardiovascular diseases. We used these data to generate descriptive statistics to characterize the risk behaviors among people who had been diagnosed with CHD compared with people who had not, and developed multivariate logistic models to control for confounding variables. RESULTS: Of total respondents, 5% reported previous diagnosis of CHD. Of respondents with CHD, three-quarters were not eating a healthful amount of fruits and vegetables, 66% were overweight or obese, 55% did not engage in regular physical activity, and nearly 15% were smokers. When we controlled for confounding variables, respondents who had been previously diagnosed with CHD were more likely than respondents who had not been diagnosed with CHD to be overweight or obese, to not exercise on a regular basis, and to be current smokers. CONCLUSION: Adults in California with CHD are engaging in behaviors that put them at higher risk of illness and premature death. To lower death rates due to CHD, more public health efforts should target this population. PMID- 21324246 TI - Perceptions of diabetes, barriers to disease management, and service needs: a focus group study of working adults with diabetes in Hawaii. AB - INTRODUCTION: Research about the support needs for and barriers to successful disease management of working adults with diabetes is limited. Our objective was to gain an in-depth understanding of how working adults in Hawaii perceive diabetes, barriers to disease management, and the services needed to keep people healthy and working. METHODS: From November 2008 through March 2009, we conducted focus group interviews with 74 employed adults with diabetes enrolled in the Hawaii Demonstration to Maintain Independence and Employment project. Responses to questions were analyzed within and across groups to identify recurring themes. A third layer of analysis examined themes across responses to all questions, specifically, how barriers related to identified service needs. RESULTS: Employed participants with diabetes experienced pervasive effects on their lives as a result of the disease, although they interpreted these effects positively or negatively. Barriers to disease management, such as additional health issues, social prejudice, and lack of social support, indicated a need to educate the general public about the disease. Participants identified needing social support from other people with diabetes, psychological support to address the emotional side of diabetes, and coordinated teams of specialists to address medication side effects and other health-related barriers to disease management. Many participants discussed the challenge of integrating diabetes management with work and family responsibilities and the need for monetary support. CONCLUSION: This study provides insight into how employed adults perceived their disease and what they perceived as challenges to successfully managing diabetes. The findings provide future directions for community and workplace diabetes initiatives. PMID- 21324247 TI - Facilitators and barriers to implementing a local policy to reduce sodium consumption in the County of Los Angeles government, California, 2009. AB - INTRODUCTION: This qualitative study explores facilitators and barriers to a proposed food procurement policy that would require food purchasers, distributors, and vendors of food service in the County of Los Angeles government to meet specified nutrition standards, including limits on sodium content. METHODS: We conducted 30 key informant interviews. Interviewees represented 18 organizations from the County of Los Angeles government departments that purchased, distributed, or sold food; public and private non-County entities that had previously implemented food procurement policies in their organizations; and large organizations that catered food to the County. RESULTS: Study participants reported 3 key facilitators: their organization's authority to impose nutrition standards, their organization's desire to provide nutritious food, and the opportunity to build on existing nutrition policies. Eight key barriers were identified: 1) unique features among food service settings, 2) costs and unavailability of low-sodium foods, 3) complexity of food service arrangements, 4) lack of consumer demand for low-sodium foods, 5) undesirable taste of low sodium foods, 6) preference for prepackaged products, 7) lack of knowledge and experience in operationalizing sodium standards, and 8) existing multiyear contracts that are difficult to change. Despite perceived barriers, several participants indicated that their organizations have successfully implemented nutritional standards that include limits on sodium. CONCLUSION: Developing or changing policies for procuring food represents a potentially feasible strategy for reducing sodium consumption in food service venues controlled by the County of Los Angeles. The facilitators and barriers identified here can inform the formulation, adoption, implementation, and evaluation of sodium reduction policies in other jurisdictions. PMID- 21324248 TI - The quality of school wellness policies and energy-balance behaviors of adolescent mothers. AB - INTRODUCTION: In this study, we 1) compared the quality of school wellness policies among schools participating in Moms for a Healthy Balance (BALANCE), a school- and home-based weight loss study conducted with postpartum adolescents in 27 states; and 2) assessed the relationship between policy quality with energy balance behaviors and body mass index z scores of postpartum adolescents. METHODS: As a part of BALANCE, we collected data on high-calorie food and beverage consumption, minutes spent walking, and height and weight for 647 participants. The School Wellness Policy Coding Tool was used to assess the strength and comprehensiveness of school district wellness policies from 251 schools attended by participating adolescent mothers. RESULTS: Schools averaged low scores for wellness policy comprehensiveness and strength. When compared with participants in schools with the lowest policy comprehensiveness scores, adolescent mothers in schools with the highest scores reported consuming significantly fewer daily calories from sweetened beverages while reporting higher consumption of water (P = .04 and P = .01, respectively). School wellness policy strength was associated with lower BMI z scores among adolescent mothers (P = .01). CONCLUSION: School wellness policies associated with BALANCE may be limited in their ability to promote a healthy school environment. Future studies are needed to evaluate the effect of the strength and comprehensiveness of policy language on energy balance in high-risk postpartum adolescents. Evidence from this work can provide additional guidance to federal or state government in mandating not only policy content, but also systematic evaluation. PMID- 21324249 TI - Barriers to colorectal cancer screening: physician and general population perspectives, New Mexico, 2006. AB - INTRODUCTION: Colorectal cancer (CRC) screening rates are low in New Mexico. We used statewide surveys of primary care physicians and the general population to characterize CRC screening practices and compare perceptions about screening barriers. METHODS: In 2006, we surveyed 714 primary care physicians in New Mexico about their CRC screening practices, beliefs, and perceptions of patient, provider, and system barriers. A 2004 state-specific CRC screening module for the Behavioral Risk Factor Surveillance System (BRFSS) survey asked 3,355 participants aged 50 years or older why they had not ever or had not recently completed a fecal occult blood test (FOBT) or lower endoscopy. RESULTS: The 216 physicians (30% response rate) reported offering screening to a median 80% of their average-risk patients in the past year and estimated that a median 50% were current with screening. They attributed low screening proportions mainly to patient factors (embarrassment, fear of pain, lack of insurance). However, just 51% of physician respondents used health maintenance flow sheets, and only 13% used electronic medical records to identify patients due for CRC screening. The BRFSS respondents most often reported that lack of physician discussion was responsible for not being current with screening (45% FOBT, 34% endoscopy); being asymptomatic was also often cited as an explanation for lack of screening (22% FOBT, 36% endoscopy). CONCLUSION: Physicians and adults in the general population had markedly different perspectives on barriers to CRC screening. Increasing screening may require system supports to help physicians readily identify patients due for CRC testing and interventions to educate patients about the rationale for screening. PMID- 21324250 TI - Health-related quality of life and the physical activity levels of middle-aged women, California Health Interview Survey, 2005. AB - INTRODUCTION: Several studies suggest that physical activity may improve health related quality of life. Other studies have shown that participation in physical activity differs among women of different racial/ethnic groups. This study aimed to determine whether the association between physical activity and health-related quality of life differs among women aged 40 to 64 years from different racial/ethnic groups. METHODS: We explored the association between physical activity level and health-related quality of life with descriptive statistics and multiple regression analyses adjusting for potential confounders among 11,887 women aged 40 to 64 years who identified themselves as Latinas, Asians, African Americans, or whites in the 2005 California Health Interview Survey. RESULTS: Although white women reported more regular physical activity than women of other racial/ethnic groups, Asian women reported fewer mentally and overall unhealthy days than women of other groups. Nonetheless, as physical activity increased, health-related quality of life improved only among white women (fewer physically unhealthy, mentally unhealthy, recent activity limitation, and overall unhealthy days) and among Latinas (fewer overall unhealthy days). CONCLUSION: Future studies should try to confirm if and clarify why the association between physical activity level and health-related quality of life differs among these middle-aged women of different races/ethnicities. If confirmed, this association would imply that health care professionals and those who design public health interventions may need to vary their promotion methods and messages to encourage physical activity among women of different races/ethnicities. PMID- 21324251 TI - A comparison of depression and mental distress indicators, Rhode Island Behavioral Risk Factor Surveillance System, 2006. AB - INTRODUCTION: Depression is a public health concern that warrants accurate population estimates. The patient health questionnaire 8 (PHQ-8) offers high sensitivity and specificity for assessing depression but is time-consuming to administer, answer, and score. We sought to determine whether 1 of 3 simpler instruments - the shorter PHQ-2 or 2 single questions from the health-related quality of life (HRQOL) module of the Behavioral Risk Factor Surveillance System (BRFSS) - could offer accuracy comparable to the PHQ-8. METHODS: We compared the depression and mental distress indicators of 2006 Rhode Island BRFSS data by using 4 types of analyses: 1) sensitivity and specificity estimates, 2) prevalence estimates, 3) multivariable logistic regression modeling of the relationship between each of the 4 indicators and 11 demographic and health risk variables, and 4) geographic distribution of prevalence. RESULTS: Compared with the PHQ-8, the 3 other measures have high levels of specificity but lower sensitivity. Depression prevalence estimates ranged from 8.6% to 10.3%. The adjusted odds ratios from logistic regression modeling were consistent. Each of the indicators was significantly associated with low income, being unable to work, current smoking, and having a disability. CONCLUSION: The PHQ-8 indicator is the most sensitive and specific and can assess depression severity. The HRQOL and PHQ-2 indicators are adequate to obtain population prevalence estimates if questionnaire length is limited. PMID- 21324252 TI - Dietary intake of minerals and the risk of ischemic stroke in Guangdong Province, China, 2007-2008. AB - INTRODUCTION: Previous studies have investigated the association between mineral intake and the risk of ischemic stroke, but results are inconsistent. We conducted a case-control study to ascertain the associations between intake of dietary potassium, calcium, magnesium, sodium, and iron and the ischemic stroke risk in the southern Chinese population. METHODS: Information on lifestyle and typical food consumption was obtained from 374 hospital inpatients with ischemic stroke and 464 hospital-based control patients. Added sodium from salt or soy sauce could not be reliably quantified, but participants were asked to characterize their diet as low in salt, normal, or high in salt. Logistic regression analyses were performed to assess possible associations between the effects of mineral intake and ischemic stroke risk. RESULTS: The mean weekly intakes of potassium, calcium, magnesium, and iron were lower among case patients than among control patients. Sodium was an exception. Lower stroke risk was associated with higher weekly dietary calcium or magnesium levels (adjusted odds ratio, 0.32) for the highest versus lowest category of intake, and significant dose-response relationships were seen. No significant associations were found for potassium, iron, or sodium. However, patients who consumed a salty diet were more than twice as likely as those whose diet was light in salt to experience an ischemic stroke. CONCLUSION: The findings suggest that lowering sodium intake while maintaining high levels of dietary calcium and magnesium may help prevent ischemic stroke in southern Chinese adults. PMID- 21324253 TI - Qualitative research about attributions, narratives, and support for obesity policy, 2008. AB - INTRODUCTION: Successful efforts to reduce obesity will require public policy strategies that target both individuals and external factors such as social conditions, economic circumstances, and physical environments. Public opinion data suggest that many policy changes to reduce obesity are likely to face public resistance. METHODS: We conducted 4 focus groups involving 33 adults living in or near a midsized Midwestern city in July 2008. Participants were assigned to the focus groups on the basis of self-reported political ideology. We used a semistructured discussion guide to 1) better understand public perceptions of obesity and 2) assess the promise of narratives as a strategy to stimulate meaningful discussion about obesity-related policy change. RESULTS: Participants viewed internal factors as primary causes of obesity. Despite substantial acknowledgment of external causes of obesity, many participants - particularly political conservatives - were resistant to external policy solutions for the problem. Across the political spectrum, participants responded more favorably to a short narrative emphasizing barriers to reducing adult obesity than a story emphasizing barriers to reducing childhood obesity. CONCLUSION: This study provides a deeper context for understanding public perceptions about obesity. Some types of narratives appear promising for promoting support for policy solutions to reduce obesity. PMID- 21324254 TI - Adiposity, biological markers of disease, and insulin resistance in Mexican American adolescents, 2004-2005. AB - INTRODUCTION: Rates of obesity and overweight, which frequently lead to type 2 diabetes, have increased dramatically among US children during the past 30 years. We analyzed associations between insulin resistance and other markers of disease in a sample of Mexican American adolescents from a severely disadvantaged community on the Texas-Mexico border. METHODS: We analyzed results from 325 students from 1 high school in this descriptive study. We measured height, weight, waist circumference, blood pressure, blood glucose, and lipids; calculated body mass index; and estimated insulin resistance. RESULTS: Approximately 50% of our sample (mean age, 16 y) were overweight or obese, and more participants were obese than overweight. More than 40% had high waist circumference, and 66% had elevated high-density lipoprotein cholesterol. These characteristics were already present in the youngest participants (aged 12 y). Although only 1% of participants had elevated fasting blood glucose, 27% exhibited insulin resistance and most of these were also obese. Similarly, participants with high waist circumference were more likely to exhibit insulin resistance than those with normal waist circumference. CONCLUSION: Participants in this sample had insulin resistance, a potent predictor of diabetes. Two markers, low high-density lipoprotein cholesterol and high waist circumference, were strongly linked to insulin resistance; the surrogate for central adiposity, waist circumference, exhibited strong association. We identified high levels of obesity and markers for future disease in our sample. These findings emphasize the need to address insulin resistance at least as early as adolescence to prevent adverse economic, social, and health consequences. PMID- 21324255 TI - Obesity and overweight prevalence among adolescents with disabilities. AB - INTRODUCTION: We examined overweight and obesity prevalence among adolescents with disabilities by disability type (physical vs cognitive) and demographic factors (sex, age, race/ethnicity). METHODS: Parents (N = 662) of adolescents aged 12 to 18 years with disabilities from 49 states responded to an online survey from September 2008 through March 2009. RESULTS: Prevalence of obesity among adolescents with physical and cognitive disabilities (17.5%) was significantly higher compared with that among adolescents without disabilities (13.0%). Obesity prevalence was higher among males, 18-year-olds, and youths with cognitive disabilities than among females, younger adolescents, and youths with physical disabilities. CONCLUSION: The higher prevalence of obesity among youths with disabilities compared with nondisabled youths, particularly in certain subgroups, requires further examination in future surveillance research. PMID- 21324256 TI - Diabetes self-management education in South Auckland, New Zealand, 2007-2008. AB - INTRODUCTION: Self-management education programs seek to help patients realize that they are their own principal caregivers and that health care professionals are consultants who support them in this role. The aim of this study was to evaluate a diabetes self-management education program implemented as part of a district-wide approach in South Auckland, New Zealand, which has some of the highest prevalence rates for diabetes and is one of the most ethnically diverse and deprived regions of New Zealand. METHODS: Self-management attitudes and behaviors were monitored with the use of questionnaires before and after program implementation. Clinical outcomes such as hemoglobin A1c, body mass index, and blood pressure were also tracked before the program began and 3 months after the program ended. Participant focus groups and facilitator interviews were conducted to explore perceptions of the program. RESULTS: Participants showed improvement in attitudes toward their own ability to manage their diabetes; in diet, physical activity, and foot care; and in hemoglobin A1c levels 3 months after the end of participation. Participants also reduced their sense of isolation when dealing with their diabetes. However, catering to the needs of a multiethnic community is extremely resource-intensive because of the need to provide adequate language and cultural interpretation. CONCLUSION: Self-management education can work in multiethnic, high-needs communities in New Zealand. Programs must ensure they enable the appropriate mechanisms and have appropriate resources to support the community's needs. PMID- 21324257 TI - Clinical preventive services for patients at risk for cardiovascular disease, National Ambulatory Medical Care Survey, 2005-2006. AB - INTRODUCTION: Clinical preventive services can detect diseases early, when they are most treatable, but these services may not be provided as recommended. Assessing the provision of services to patients at risk for cardiovascular disease (CVD) could help identify disparities and areas for improvement. METHODS: We used data on patient visits (n = 21,261) from the National Ambulatory Medical Care Survey, 2005-2006, and classified patients with hypertension, hyperlipidemia, obesity, or diabetes as being at risk for CVD. We assessed differences in the provision of preventive services offered to patients who were and who were not at risk for CVD. Further, for those at risk, we compared the demographic characteristics of those who had and who had not been offered services. RESULTS: Patients at risk for CVD received significantly more preventive services compared with those not at risk. For patients at risk for CVD, aspirin therapy was more likely to be recommended to those aged 65 years or older than those aged 45 to 64 years and to men than women. Cholesterol screening was more likely for men and was less likely for patients with Medicare/Medicaid or no insurance than for patients who were insured. Rates of counseling for diet and nutrition, weight reduction, and exercise were low overall, but younger patients received these services more than older patients did. CONCLUSION: Patients at risk for CVD are not all receiving the same level of preventive care, suggesting the need to clarify clinical practice guidelines and provide clinicians with education and support for more effective lifestyle counseling. PMID- 21324258 TI - Addressing the needs of the whole child: what public health can do to answer the education sector's call for a stronger partnership. AB - Although the overall level of child health in the United States remains high, public health professionals know that racial and ethnic disparities in child and adolescent health persist and that lifestyle choices related to chronic disease in adults are often established in childhood and adolescence. And yet, those health needs are not the public health sector's alone to resolve. We have natural partners among educators. Improving graduation rates is one of the most cost effective ways to reduce health disparities. This article provides strategies for how public health professionals can answer this call by educators to address the needs of the whole child. PMID- 21324259 TI - Deaf sign language users, health inequities, and public health: opportunity for social justice. PMID- 21324260 TI - An organizing framework for translation in public health: the Knowledge to Action Framework. AB - A priority for the Centers for Disease Control and Prevention (CDC) is translating scientific knowledge into action to improve the public's health. No area has a more pressing need for translation than the prevention and control of chronic diseases. Staff from CDC's National Center for Chronic Disease Prevention and Health Promotion worked across disciplines and content areas to develop an organizing framework to describe and depict the high-level processes necessary to move from discovery into action through translation of evidence-based programs, practices, or policies. The Knowledge to Action (K2A) Framework identifies 3 phases (research, translation, and institutionalization) and the decision points, interactions, and supporting structures within the phases that are necessary to move knowledge to sustainable action. Evaluation undergirds the entire K2A process. Development of the K2A Framework highlighted the importance of planning for translation, attending to supporting structures, and evaluating the public health impact of our efforts. PMID- 21324261 TI - Development of a community-based participatory colorectal cancer screening intervention to address disparities, Arkansas, 2008-2009. AB - BACKGROUND: The death rate from colorectal cancer is high and affects poor and medically underserved populations disproportionately. In the United States, health disparities are particularly acute in the Lower Mississippi River Delta region. Because many in the region have limited access to basic health care resources, they are not screened for cancer, even though screening is one of the most effective strategies to prevent colorectal cancer. Community-based participatory research is a promising approach to prevent colorectal cancer in this population. COMMUNITY CONTEXT: The Empowering Communities for Life program was implemented in 2 underserved counties in the Arkansas Lower Mississippi River Delta. The program arose from a 9-year partnership between the University of Arkansas for Medical Sciences and 9 cancer councils across Arkansas. METHODS: Empowering Communities for Life is a community-based participatory intervention designed to increase colorectal cancer screening in rural, underserved communities through fecal occult blood testing. Community and academic partners collaborated to develop research infrastructure, intervention materials and methods, and the assessment instrument. OUTCOME: Project outcomes were strengthened community-academic partnerships, certification of community partners in conducting human subjects research, development of a randomized controlled design to test the intervention's efficacy, an interactive PowerPoint presentation, an informational pamphlet, the certification of 6 lay health advisors and 22 role models to provide the intervention, and an assessment tool using an audience response system. INTERPRETATION: Lessons learned in working collaboratively with diverse groups include the importance of meeting face to face and listening. PMID- 21324262 TI - Establishing worksite wellness programs for North Carolina government employees, 2008. AB - BACKGROUND: State employee health plans sometimes provide worksite wellness programs to reduce the prevalence of chronic diseases among their members, but few offer the comprehensive range of interventions recommended by the Task Force on Community Preventive Services. COMMUNITY CONTEXT: North Carolina's State Health Plan for Teachers and State Employees provides health coverage for approximately 665,000 state employees, teachers, retirees, and dependents. Health claims indicate that the prevalence of having at least 1 chronic disease or of being obese is approximately 32% among state employees. METHODS: The State Health Plan created a partnership with North Carolina's Division of Public Health, Office of State Personnel, and other key state agencies to identify bureaucratic obstacles to providing worksite wellness programs for state employees and to develop a state policy to address them. The Division of Public Health established a model worksite program to guide development of the worksite wellness policy and pilot wellness interventions. OUTCOME: The state's first worksite wellness policy created an employee wellness infrastructure in state government and addressed administrative barriers to allow effective worksite wellness interventions. For example, the policy led to pilot implementation of a subsidized worksite weight management program. Positive results of the program helped generate legislative support to expand the weight management program throughout state government. INTERPRETATION: Strong interagency partnership is essential to guide worksite wellness policy and program development in state government. State health plans, public health agencies, and personnel agencies each play a role in that partnership. PMID- 21324263 TI - Improving fruit and vegetable consumption: use of farm-to-consumer venues among US adults. AB - Improvements to the food environment including new store development and more farm-to-consumer approaches (ie, farmers' markets, roadside stands, pick-your-own produce farms, or community-supported agriculture programs) may aid Americans in making healthier dietary choices. We analyzed data from a subset of respondents (N = 1,994) in the National Cancer Institute's Food Attitudes and Behaviors Survey, a mail survey of US adults. We determined associations between primary grocery shoppers' region and sociodemographic characteristics and frequency of purchasing fruits and vegetables in the summer from farm-to-consumer venues. A little more than one-quarter (27%) of grocery shoppers reported a frequency of at least weekly use of farm-to-consumer approaches. Older adults and respondents who live in the Northeast were most likely to shop farm-to-consumer venues at least weekly, and no differences were found by sex, race/ethnicity, education, or annual household income. These findings suggest that farm-to-consumer venues are used by many Americans and could be expanded to increase access to fruits and vegetables. PMID- 21324264 TI - Psychiatric implications of endogenous morphine: up-to-date review. AB - For over 30 years empirical studies have repeatedly demonstrated that the biosynthesis of morphine by diverse animal and human tissues occurs. Recently, the blue mussel's neural tissues and human white blood cells were used to demonstrate the de novo biosynthesis of morphine for small precursor molecules derived from the aromatic amino acid L-tyrosine. Because catecholamine precursors, i.e., L-3,4-dihydroxyphenylalanine (L-DOPA), were also found to be utilized as morphine precursors, a novel reciprocally interactive mechanism is apparent that links catecholamine and opioid pathways in the activation and inhibition of diverse tissue responses. Additionally, these observations provide new insights into morphinergic signalling that transcend analgesia and addiction. We have also linked the biological effects of nitric oxide into a common effect in endogenous morphine signalling. Given the singular importance of dopamine and morphine's interaction in the CNS, the presence and association of this signalling with nitric oxide all promises to provide novel answers for mental health phenomena, which have been lacking because of the inability in accepting the empirical endogenous morphine studies. PMID- 21324265 TI - Apolipoprotein E epsilon4-positive multiple sclerosis patients develop more gray matter and whole-brain atrophy: a 15-year disease history model based on a 4-year longitudinal study. AB - Multiple sclerosis is a disease with considerable individual variation, and genetic background plays a key role in disease susceptibility and severity. The objective of the study was to evaluate the relationship between apolipoprotein E (APOE) genotype and the evolution of different clinical and MRI parameters. We investigated a group of 150 relapsingremitting patients that completed 4-year follow-up. The mean age was 30.2 years, disease duration 56.8 months, and baseline Expanded Disability Status Scale (EDSS) 1.8. The changes in brain parenchymal volume (BPV), gray matter (GMV), white matter (WMV) and peripheral gray volume (PGMV) were measured by SIENA/X. T2-lesion volume was assessed by semi-automated methods. The mixed-effect model analysis was used to investigate evolution of clinical and MRI parameters in relation to the APOE epsilon4 genotype considering two different time models: 4-year follow-up and 15-year period from disease onset. We identified 36 APOE epsilon4-positive patients. Decline of GMV (P = 0.017), and BPV (P = 0.029) were significantly faster in APOE epsilon4-positive than in APOE epsilon4-negative patients in the 15-year model. In the 4- year model, a trend for faster decrease of GMV was found in APOE epsilon4-positive patients (P = 0.067). No differences in other MRI parameters or EDSS were found between the APOE groups. The results of the study suggest that APOE epsilon4-positive patients experience faster rate of gray matter atrophy. PMID- 21324266 TI - Isolation of granulocytes: which transcriptome do we analyse - neutrophils or eosinophils? AB - Isolation of granulocytes from blood is necessary for accurate study of changes in their expression. After gradient centrifugation, we obtain relatively pure granulocyte populations with different ratios of neutrophils and eosinophils. Unfortunately, in many studies in this field the expression results are not set according to the real variability of the granulocyte population. In many cases, the granulocyte population is marked simply as "neutrophils" and the residual population of eosinophils is not considered. Based on our recent study where we tracked the general transcription factor RNA polymerase II, we hypothesized that eosinophils are more transcriptionally active cells than neutrophils. We decided to test our hypothesis on isolated cells because its implications could change our view on many past expression analyses performed on granulocytes. In our experiments, we isolated neutrophils and eosinophils and measured their total RNA production. According to our results, eosinophils produce much more RNA than neutrophils. Therefore, relatively low numbers of highly active eosinophils can markedly affect the whole pool of granulocytic RNA. We want to emphasize that either a detailed description of the cell population or the use of a pure neutrophil population is necessary for the correct interpretation of neutrophil expression analysis results. PMID- 21324267 TI - Donepezil inhibits diisopropylfluorophosphate-induced seizures and up-regulation of synaptotagmin 4 mRNA. AB - Reversible acetylcholinesterase inhibitor donepezil displays prophylactic effects against intoxication with irreversible organophosphorous acetylcholinesterase inhibitors. We used behavioural observation of yawning and epileptic seizures, histochemical acetylcholinesterase staining, and in situ hybridization of the immediate early genes, c-fos and synaptotagmin 4 (Syt4) mRNAs in the brain, to evaluate whether donepezil could protect the brain against the effects of the organophosphate anticholinesterase, diisopropylfluorophosphate, in a rat model of intoxication. Diisopropylfluorophosphatetreated animals exhibited frequent yawning, significant inhibition of acetylcholinesterase staining and upregulation of c-fos mRNA, but not the epileptic seizures or significant change of Syt4 mRNA levels. In order to reduce the threshold for the induction of cholinergic seizures, additional groups of rats were pre-treated with LiCl 24 h before the treatment with diisopropylfluorophosphate. These rats exhibited the seizures, a significant inhibition of acetylcholinesterase staining and significant upregulation of c-fos and Syt4 mRNA levels. All the above-mentioned effects of diisopropylfluorophosphate were inhibited by donepezil pre-treatment. Donepezil pre-treatment by itself induced only a comparatively weaker inhibition of acetylcholinesterase staining and infrequent yawning. We conclude that donepezil protects the brain against diisopropylfluorophosphate-induced effects and that Syt4 mRNA upregulation may serve as a novel marker for organophosphate-induced seizures. PMID- 21324268 TI - Dynamic oxidoreductive potential of astringent retraction agents. AB - The aim of this study was to evaluate the dynamics of the cytotoxicity of gingival margin retraction astringents based on aluminium chloride, aluminium sulphate, and ferric sulphate (solutions and gels) in human fibroblasts isolated from gingiva. The cytocompatibility of ten astringent-based chemical retraction agents: Gingiva Liquid, Alustin, Racestypine, Orbat sensitive, Astringedent(r), Alustat, Hemostat, Racecord, Gel cord and ViscoStat(r), in dilutions of 1 : 10 and 1 : 20, with human gingival fibroblasts was investigated. The MTT assay was performed to determine oxidoreductive mitochondrial function after 3, 5, 10 min and 24 h of incubation. Cell viability was determined according to the chemical group, concentration, exposure time, and the clinical form of the gingival retraction agents. Ferric sulphate- based agents were the most cytotoxic, followed by aluminium chloride and aluminium sulphate. The form of the astrigents influenced cell viability. The evaluated astringents may have cytotoxic potential for gingival margin tissues under clinical conditions. PMID- 21324269 TI - Variability within the msp2 gene in populations of Anaplasma phagocythopilum. AB - Anaplasma phagocytophilum is an obligate intracellular bacterial parasite of verterbrate granulocytes. This bacterium is the aetiologic agent of human granulocytic anaplasmosis. The msp2 gene encoding major surface protein 2 is unique for Anaplasma and displays high antigenic variation. A fragment of the msp2 gene (334 bp) of A. phagocytophilum, amplified with DNA isolated from Ixodes ricinus, Syringophilidae, Capreolus capreolus and Canis lupus familiaris, was used to determine polymorphisms of Anaplasma within Polish populations. Sequence analysis of this fragment was used for observation of five different genetic variants of the bacterium within Polish sequences. The average genetic distance in Polish sequences was 0.7 % and the majority of observed substitutions had a synonymous character. High intraspecific variability observed in the msp2 gene of A. phagocytophilum is a strong proof of the high evolutionary plasticity, adaptation abilities, and abilities for fast distribution of this parasite in various environments. PMID- 21324270 TI - [Anti-tumor immunity induced by mouse lung cancer B7 vaccine]. AB - BACKGROUND: To study the cell immunity induced by lung cancer B7 vaccine, FLB2C cells. METHODS: Compared withparental lung cancer cell LA795 line, proliferation of mouse T lymphocytes stimulated by FLB2C was observed through mixed lymphocyte culture. CTLL cell MTT test was used to detect whether FLB2C stimulated T lymphocyte to secrete IL-2. After immunized with the FLB2C and LA795 cells, the CTL activity of mouse was observed in vivo. RESULTS: The spleen lymphocyte proliferation stimulated by FLB2C cells was remarkably stronger than that by LA795 . FLB2C might stimulated the T lymphocyte to secrete IL-2 in vitro, but LA795 didn't. FLB2C cell could induce CTL activity in vivo and the induced CTL killed FLB2C cells and LA795 in vitro, with the killing rate of 34% and 25.3% respectively; while LA795 induced CTL killing rate being 10.5% and 12.25% respectively (P < 0.01). CONCLUSIONS: FLB2C can stimulate T cell immunity in vivo or in vitro. The effect of FLB2C is significantly stronger than that of LA795 . The results suggest that FLB2C may be used to treat lung cancer through improving immunity. This provides immunological basis for applying FLB2C as a vaccine to clinical use. PMID- 21324271 TI - [Clinicopathological correlation of detection of regional lymph nodes micrometastasis in patients with lung cancer by reverse transcriptase-polymerase chain reaction]. AB - BACKGROUND: To analyze clinicopathological correlation of detection of lung cancer micrometastasis in regional lymph nodes (LNs) by reverse transcriptase polymerase chain reaction (RT-PCR). METHODS: Regional LNs (n=261) were obtained from 40 patients with lung cancer who underwent lobectomy. Each LN was bisected. Half of each LN was subjected to histological examination (HE) and the other half was subjected to RT-PCR amplification of CK19 mRNA. RESULTS: In 18 of 40 patients, the metastasis in regional LNs was found by both HE and RT-PCR. Of 22 N0 diseases diagnosed by HE, 6 (27%) were found to express CK19 mRNA in regional LNs. According to the results of regional LNs metastasis in 40 patients by CK19 RT-PCR, the presence of the CK19 product in LNs was related to tumor size (Chi square=5.76, P < 0.025), the presence of tumor vascular invasion (Chi square=3.88, P < 0.05), cell differentiation of the tumor (Chi-square=7.08, P < 0.01) and P-TNM stages (Chi-square=7.42, P < 0.01). In the histologically node negative patients, lymph node micrometastasis was significantly related to tumor size (P=0.038, exact test) and P-TNM stage (P=0.01, exact test). However, the results of routine histological examination did not show the above clinicopathological correlation (P > 0.05). CONCLUSIONS: The RT-PCR method is superior to routine histological examination in detecting metastasis in LNs. The micrometastasis in LNs can be detected accurately by RT-PCR. It is helpful for screening the patients in whom the early subclinical metastasis exists and disclosing the intrinsic rule of malignancy metastasis. PMID- 21324272 TI - [PCR-SSCP analysis of nm23 gene mutation in non-small cell lung cancer]. AB - BACKGROUND: To investigate the role of nm23 gene mutation in human non small cell lung cancer (NSCLC). METHODS: The mutation of nm23 gene was detected in 53 primary NSCLC tissues and 5 cases of other pulmonary benign or malignant disease tissues by PCR SSCP. RESULTS: No mutation of nm23 gene was found in all 58 specimens. CONCLUSIONS: The mutation of the nm23 gene may not effectively forebode the aggressiveness and metastatic potential of NSCLC. PMID- 21324273 TI - [Establishment and characteristics of multidrug-resistant Lewis lung cancer cell line]. AB - BACKGROUND: To establish an ADM resistant Lewis lung cancer cell line and to investigate its biological characteristics. METHODS: The multidrug-resistant cell line was gradually induced by ADM from Lewis lung cancer cell line (L3-8), its growth characteristics and cancinogenicity were observed. The fluorescent density of ADM and Rh-B in the cells were analyzed by IPP image analysis system. The ADM concentration in cells was assayed with fluorescent meter. The IC50 was evaluated by MTT assay and the drug resistant index was counted. RESULTS: The drug resistant Lewis lung cancer cell line, L3-8/ADM, which can grow in the medium containing 0.4mg/l ADM was acquired after 14 months selective culture. Its tumor generatic rate was 10/10. When the L3-8/ADM was cultured in 0.15mg/l ADM and general 1640 medium, the doubling time was 22.0h and 21.8h separately. After culturing in 4mg/l ADM and Rh-B medium, the fluorescent density ratio of L3-8/ADM and L3-8 were 2.82:1 and 2.65:1 separately. The ADM concentration of L3-8/ADM was only 64.7% of its parental, but there was no significant difference in their ADM release rate. Except for ADM, L3-8/ADM was resistant to DNR, VCR, MIT and CDDP in different degrees. CONCLUSIONS: L3-8/ADM cell is a typical MDR cell line. The cell membrane obstruction of drug infiltration might be the cause of drug resistance. This study will provide a basis for the establishment of lung cancer MDR animal model. PMID- 21324274 TI - [Expression of GLUT1 protein and its relationship with uptake of FDG in non-small cell lung cancer tissues]. AB - BACKGROUND: To investigate the expression of facilitative glucose transporter 1 (GLUT1) and its relationship with uptake of 18fluoro-2-deoxyglucose (FDG) in non small cell lung cancer (NSCLC). METHODS: Twenty-four patients with NSCLC were evaluated with 18FDG-PET examination before operation. The expression of GLUT1 was detected immunohistochemically in lung cancer and normal lung tissues, and the intensity of GLUT1 in lung cancer was assessed by computer image analysis. Correlation analysis was carried out between expression level of GLUT1 and value of SUV obtained from preoperative FDG-PET. RESULTS: Expression of GLUT1 protein was positive in 24 cases of NSCLC samples, but negative in corresponding normal tissues. A highly significant linear correlation was found between GLUT1 expression and SUV value (r= 0.86, P < 0.05). CONCLUSIONS: GLUT1 expression is quite general in NSCLC tissues, and it may play an important role in the glucose uptake of NSCLC cells. PMID- 21324275 TI - [A study on the expression of erbB4/HER4 in non-small cell lung cancer]. AB - BACKGROUND: To detect the expression of human epidermal-growth-factor receptor 4 (HER4) and elucidate the relationship between its overexpression and the clinicopathological characteristics in non-small cell lung cancer (NSCLC). METHODS: The expression of HER4 was detected in 70 cases of paraffin-embedded NSCLC tissues by immunohistochemical assay. RESULTS: HER4 were overexpressed in 91.4% of NSCLC. The overexpression of HER4 was significantly related to lymph node metastasis (P=0.007), TNM stages (P=0.011) and postoperative survival rate (P= 0.0258). CONCLUSIONS: erbB4 is one of the genes to regulate the growth of advanced NSCLC. The artificial interference with HER4 overexpression may be a good way in the treatment of advanced NSCLC. PMID- 21324276 TI - [Effect of transfection of p27(kipl) on lung cancer cells line A549]. AB - BACKGROUND: To observe the suppressive effects of exogenous p27 gene on human lung cancer cell line A549. METHODS: An adenovirus expression vector (pAd CMV p27) containing 570 bp human full-length p27 cDNA was transfected into human lung cancer cell line A549. Expression of exogenous p27 gene was detected by dot-blot hybridization and laser co-focal system. MTT was adopted to measure the effects of exogenous p27 gene on cell cycle progression and cell features of the infected A549. RESULTS: The mRNA and protein expression level of p27 was remarkably increased after transfecting with exogenous p27 gene. The apoptosis of infected A549 occurred and the progression of cell cycle was arrested in G1 phase. CONCLUSIONS: p27(kipl) gene transfer may play a therapeutic role in the treatment of lung cancer. PMID- 21324277 TI - [The relationship between microvessel density and structure in cancer tissues and prognosis in patients with non-small cell lung cancer]. AB - BACKGROUND: To explore the correlation of microvessel density (MVD) and microvessel structure (MVS) features with the patients' prognosis in non-small cell lung cancer (NSCLC). METHODS: Anti-Von Willebrand factor antibody was used to stain microvessel endothelia by means of LsAB immunohistochemical technique, then the microvessel count and structure features were observed microscopically in 49 primary NSCLC tissues. MVS pattern A had scattered microvessels with relatively integral or thick wall and with relatively regular morphology and MVS pattern B had plexiform or network like microvessels with unintegral or thin wall and with irregular morphology. RESULTS: MVD in primary NSCLC tissues was closely correlated with pTNM stage or lymph node involvement, P=0.043 and P=0.038, respectively. MVS in primary NSCLC tissues was closely correlated with the size of primary carcinoma, P=0.002. The survival of patients (23.2+/- 18.4 months) with MVD > 52/200* was significantly shorter than that of patients (35.9+/-20.9 months) with MVD < 52/200* in primary NSCLC tisssues, P=0.01. The survival of patients with MVS pattern A (39.4+/-17.2 months) was significantly longer than that of patients with MVS pattern B (23.5+/-20.3 months) in primary NSCLC tisssues, P=0.008. The survival of patients with MVD < 52/200* and MVS pattern A (42.9+/-19.3 months) was significantly longer than that of patients with MVD > 52/200* and MVS pattern B (15.7+/-16.8 months) in primary NSCLC tissues, P=0.002. CONCLUSIONS: MVD and MVS are closely associated with prognosis of NSCLC patients and might be served as parameters estimating patients' prognosis and planning assistant therapy after operation. PMID- 21324278 TI - [Study on detection of aberrant promoter hypermethylation of p16 and DAP kinase in serum DNA from patients with non-small cell lung cancer]. AB - BACKGROUND: To explore the feasibility of detection of aberrant methylaion of p16 and death-associated protein kinase gene as biological markers for the diagnosis of non-small cell lung cancer (NSCLC) patients. METHODS: The methylation of p16 and death-associated protein kinase gene in serum and primary NSCLC tumors from 30 NSCLC patients was detected by using methylation-specific PCR methods. RESULTS: Aberrant methylation of at least one gene was detected in 18 of 30 (60.0%) in NSCLC tumor tissues. In these primary tumors with methylation, 9 of 18 (50.0%) samples also was detected abnormal methylation in the matched serum samples, but not in any paired normal lung tissue and healthy control subjects. CONCLUSIONS: Detection of aberrant methylation in the serum of NSCLC patients may have implications for early diagnosis of NSCLC. PMID- 21324279 TI - [Diagnosis of occult metastasis to mediastinal lymph nodes in patients with NSCLC: detection of MUC1 mRNA by reverse transcriptase-polymerase chain reaction (RT-PCR)]. AB - BACKGROUND: To evaluate the diagnostic method of occult metastasis to mediastinal lymph nodes (MLNs) in patients with non-small cell lung cancer (NSCLC). METHODS: The mRNA expression of mucin 1(MUC1) gene, an epithelial-tissue-specific gene, was detected in dissected mediastinal lymph nodes by RT-PCR assay. Seventy-eight MLNs which had no malignant evidence on routine histopathologic examination were assessed in 19 patients with stage pN0-1 disease. Five regional lymph nodes from 5 patients with benign pulmonary diseases and 5 MLNs proved malignant by histopathology from 5 patients with NSCLC were also studied as negative and positive control respectively. RESULTS: The mRNA of MUC1 was not detected in any specimen of negative control group, whereas the mRNA was detected in all MLNs of positive control group. The mRNA in 6 out of 78 MLNs from 19 patients with pN0-1 disease was also detected, and occult metastasis was diagnosed. CONCLUSIONS: Detection of MUC1 mRNA expression might be helpful to diagnose occult metastasis in MLN in patients with lung cancer, and RT-PCR is superior to routine histopathologic examination in staging NSCLC. PMID- 21324280 TI - [Value of cardiopulmonary risk index in predicting postoperative short-term prognosis in patients with lung cancer]. AB - BACKGROUND: To determine the value of preoperative cardiopulmonary risk index (CPRI) in predicting the short-term prognosis after lung resection in patients with lung cancer. METHODS: Preoperative clinical data were used to generate a cardiac risk index (CRI) and a pulmonary risk index (PRI). And the value of cardiopulmonary risk index (CPRI) consisting of CRI and PRI in predicting postoperative prognosis was estimated in patients who underwent lung resection at Shanghai Chest Hospital in 1999. RESULTS: A total of 625 consecutive patients were studied. Postoperative complications occurred in 49 patients (7.8%), including 8 deaths within 30 days of operation. In the total group, CRI, PRI and CPRI scores ranged from 1 to 3, 0 to 5 and 1 to 7, respectively. There were 489 patients with CPRI < 4, and 136 with CPRI>=4. Using CPRI>=4 as a threshold for predicting postoperative complications, the sensitivity, specificity and accuracy rate were 75.5%, 82.8% and 82.2% respectively. CONCLUSIONS: The preoperative CPRI is one of the important indexes in predicting the short-term postoperative prognosis for patients with lung cancer. However, it can not completely predict all of postoperative risks, and should be used together with other factors. PMID- 21324281 TI - [Ifosfamide/etoposide/carboplatin chemotherapy in the treatment of patients with advanced non-small cell lung cancer]. AB - BACKGROUND: To investigate the efficacy and toxicity of ifosfamide, etoposide, and carboplatin (IEC) regimen in the treatment of patients with advanced non small cell lung cancer. METHODS: Thirty-three patients with advanced non-small cell lung cancer were treated with IEC regimen, which consisted of ifosfamide 2.0g/m2(patients with age > 70 years: 1.3g/m2), IV D1-3; etoposide 130mg/m2, IV D1-3; carboplatin 300mg/m2, IV D1, repeated every four weeks. RESULTS: Of the 33 patients, 7 cases got partial response, 24 had stable diseases, and 2 had progressive diseases, and the overall response rate was 21.2% (7/33,95% CI: 7.3% to 35.1%). The median survival and 1-year survival rate were 7.8 months (95% CI: 6.2 to 9.4 months) and 20.0%(95% CI: 6.0% to 34.0%) respectively. Main adverse effects were severe hematologic toxicities. The frequency of leukopenia,thrombocytopenia and anemia with grade III and grade IV was 51.5% (17/33), 18.2%(6/33) and 30.3%(10/33) respectively. There was significantly higher frequency of leukopenia (P=0.024) and thrombocytopenia (P=0.037) with grade III and grade IV in patients with age>=60 years than those with age < 60 years. CONCLUSIONS: IEC is an effective regimen in the treatment of patients with advanced non-small cell lung cancer. Main adverse effects are severe hematologic toxicities, which are more significant in elderly patients. It is necessary to apply G-CSF or GM-CSF protection to avoid severe myelosuppression for elderly patients. PMID- 21324282 TI - [High dose tamoxifen in the reversal treatment of multidrug resistance to EP regimen in patients with non-small cell lung cancer]. AB - BACKGROUND: To evaluate the reversal effect of high dose tamoxifen on multidrug resistance to EP regimen in patients with non-small cell lung cancer. METHODS: A total of 41 patients with NSCLC were studied, who were resistant to EP regimen and were proved to have P-gp protein overexpression. All patients were randomizedly divided into two arms. Reversal group (n=21) received oral tamoxifen 100?mg, 2 times everyday on D1-5, together with EP regimen. Control group (n=20) were only given EP regimen. RESULTS: In reversal group, complete response occurred in 1 patient, and partial response in 5; disease remained stable in 11 patients, and tumor progression occurred in 4 patients. The response rate was 28.6%(6/21). In control group, no response occurred; 9 patients had stable diseases, and the other 11 progressed. There was a significant difference in response rate between the two groups (P=0.012?1). In reversal and control groups, the median survivals were 8.4 and 4.6 months respectively (P < 0.01), and 1-year survial rates were 38.1% and 35.0% respectively. Reversal of P-gp occurred in 7 cases of reversal group (33.3%),and none in control group (P= 0.005?2) . There was no significant difference in toxicities between the two groups (P > 0.05). CONCLUSIONS: High dose tamoxifen can remarkably downregulate the expression of P gp and partially reverse the multidrug resistance to EP regimen for non-small cell lung cancer. PMID- 21324283 TI - [Study on pulmonary artery infusion following lobectomy in patients with lung cancer]. AB - BACKGROUND: To evaluate the efficacy of pulmonary artery infusion (PAI) via post catheter connecting system in patients with lung cancer after lobectomy. METHODS: Ninety patients were randomized into two groups after lobectomy and each group had 45 patients. The PAI group received chemotherapy via pulmonary artery, while the VI group received chemotherapy via peripheral vein. RESULTS: The PAI group totally received 215 cycles of chemotherapy, 4.8 cycles in average. The VI group received 195 cycles, 4.3 cycles in average. The 1-, 3-, 5-year survival rates in PAI group were 88.9%, 77.8%, 47.4% respectively, and 82.2%, 53.3%, 20.5% in VI group. And there were significant differences in the 3- and 5-year survival rates between the two groups (P < 0.05). The 3-year local recurrence rate was 12.8% for radical lobectomy patients in PAI group, and 35.0% in VI group (P < 0.05). The 1 , 3-, 5-year metastatic rates after lobectomy were 17.8%, 20.0%, 26.3% respectively in PAI group, and 15.6%, 35.6%, 51.3% respectively in VI group. And there were significant differences in the 3- and 5-year metastatic rates between the two groups (P < 0.05). CONCLUSIONS: Pulmonary artery infusion for lung cancer patients after lobectomy can reduce the post-operative recurrence and metastasis and improve the long-term survival rates. PMID- 21324284 TI - [Characteristics and clinical significance of diffusing capacity in the patients with lung cancer]. AB - BACKGROUND: To explore the characteristics and clinical significance of diffusing capacity in the patients with lung cancer. METHODS: The pulmonary diffusing capacity for carbon monoxide (DLCO) was measured with the rebreathing method in 138 patients with primary lung cancer, and 86 were performed pulmonary resection. RESULTS: There was no significant difference in DLCOrb and DLCOrbc between the groups with different histological type and degree of ventilation impairment and general type (P > 0.05). DLCOrb/VA mildly decreased in the patients whose lung ventilation function was normal. DLCOc/VA decreased in the patients with restrictive ventilation dysfunction (P < 0.01), and DLCOrb/VA decreased in the patients with obstructive and mixed ventilation dysfuncion (P < 0.05). DLCOc/VA decreased in the patients with light and obvious lung dysfunction (P < 0.05). DLCOc/VA in the patients with central lung cancer was lower than that in the peripheral ones (P < 0.01). DLCOc/VA and D LCOrb in the group with postoperative respiratory failure were lower than that in the group without respiratory failure (P < 0.05). When DLCOc/VA of less than 80% and DLCOrb/VA of less than 70% were used to predict the postoperative respiratory failure, the correct ratios of dignosis and the diagnostic indexes were high. CONCLUSIONS: The diffusing capacity decreases in the patients with lung cancer, and the main manifestation is the abnormal DLCOrb/VA and DLCOc/VA. The general type of lung cancer and the degree of pulmonary dysfunction may influence the diffusing function of the patients. DLCOc/VA of less than 80% and DLCOrb/VA of less than 70% should be selected for predicting postoperative respiratory failure. PMID- 21324285 TI - [Carcinoma of the lung and multiple primary malignant tumors]. AB - BACKGROUND: To evaluate the incidence of multiple primary malignancies combined with lung and other organs and their relationship. METHODS: All patients who consecutively treated for lung cancer from December 1964 to December 1992, were retrospectively analyzed regarding the recurrence of a synchronous primary tumor elsewhere in the body. RESULTS: Of total 1019 patients reviewed, 21 (2.1%) had associated carcinoma of other organs. In these 21 patients, the incidence of associated aerodigestive tract cancer was 71.4% (15/21) and that of other organs was 28.6% (6/21). Five patients had simultaneous cancer with the lung cancer and 16 had metachronous cancer. CONCLUSIONS: Multiple primary tumors in patients with carcinoma of the lungs is not a rare phenomenon. Surveillance programs for detection of second primary tumors should focus on these patients. PMID- 21324286 TI - [Clinical significance of tumor markers in the diagnosis of lung cancer]. AB - BACKGROUND: To determine the clinical value of serum TPA, Cyfra 21.1 and NSE in the diagnosis of lung cancer. METHODS: The serum samples of 136 patients were measured: including 15 adenocarcinomas, 39 squamous cell carcinomas, 8 small-cell lung cancers (SCLC), 34 unclassified lung cancers, and 40 benign pulmonary diseases. Serum TPA and Cyfra 21.1 were detected by ELISA and the normal value was <=0.9MUg/l and <=3.6MUg/l respectively. Serum NSE was detected by radioimmunological method and the normal value was <=20MUg/l. All data were dealed with t and Chi-square test. RESULTS: The level of TPA in each lung cancer group was significantly higher than the normal value except for that in SCLC group. The level of Cyfra 21.1 in adenocarcinoma, squamous cell carcinoma, and unclassified lung cancer groups was significantly higher than the normal value; The level of NSE in SCLC group was significantly higher than the normal value. In the benign pulmonary disease group the level of TPA was significantly higher than the normal value. TPA was sensitive for the diagnosis of lung cancer and the sensitivity was from 69.2% to 87.5%, but the specificity was low (29.3%); the specificity of Cyfra 21.1 was 97.6%, but the sensitivity was low (12.5%-35.9%); the sensitivity (75.0%) and specificity (82.9%) of NSE were high for SCLC. CONCLUSIONS: TPA shouldn't be a qualified tumor marker for lung cancer because of low specificity; the specificity of Cyfra 21.1 is higher, but the sensitivity is lower; NSE may be a satisfactory tumor marker for SCLC. PMID- 21324287 TI - Identification and management of cryptic bipolarity in patients with TRD. PMID- 21324288 TI - Biologic effects of mindfulness meditation: growing insights into neurobiologic aspects of the prevention of depression. PMID- 21324289 TI - A multicentre randomised controlled trial and economic evaluation of ion-exchange water softeners for the treatment of eczema in children: the Softened Water Eczema Trial (SWET). AB - OBJECTIVES: To determine whether installation of an ion-exchange water softener in the home could improve atopic eczema in children and, if so, to establish its likely cost and cost-effectiveness. DESIGN: An observer-blind, parallel-group randomised controlled trial of 12 weeks duration followed by a 4-week observational period. Eczema was assessed by research nurses blinded to intervention at baseline, 4 weeks, 12 weeks and 16 weeks. The primary outcome was analysed as intent-to-treat, using the randomised allocation rather than actual treatment received. A secondary per-protocol analysis excluded participants who failed to receive their allocated treatment and who were deemed to be protocol violators. SETTING: Secondary and primary care referral centres in England (UK) serving a variety of ethnic and social groups and including children living in both urban and periurban homes. PARTICIPANTS: Three hundred and thirty-six children (aged 6 months to 16 years) with moderate/severe atopic eczema, living in homes in England supplied by hard water (>= 200 mg/l calcium carbonate). INTERVENTIONS: Participants were randomised to either installation of an ion exchange water softener plus usual eczema care (group A) for 12 weeks or usual eczema care alone (group B) for 12 weeks. This was followed by a 4-week observational period, during which water softeners were switched off/removed from group A homes and installed in group B homes. Standard procedure was to soften all water in the home, but to provide mains (hard) water at a faucet-style tap in the kitchen for drinking and cooking. Participants were therefore exposed to softened water for bathing and washing of clothes, but continued to drink mains (hard) water. Usual care was defined as any treatment that the child was currently using in order to control his or her eczema. New treatment regimens used during the trial period were documented. MAIN OUTCOME MEASURES: Primary outcome was the difference between group A and group B in mean change in disease severity at 12 weeks compared with baseline, as measured using the Six Area, Six Sign Atopic Dermatitis (SASSAD) score. This is an objective severity scale completed by blinded observers (research nurses) unaware of the allocated intervention. Secondary outcomes included use of topical medications, night-time movement, patient-reported eczema severity and a number of quality of life measures. A planned subgroup analysis was conducted, based on participants with at least one mutation in the gene encoding filaggrin (a protein in the skin thought to be important for normal skin barrier function). RESULTS: Target recruitment was achieved (n = 336). The analysed population included 323 children who had complete data. The mean change in primary outcome (SASSAD) at 12 weeks was -5.0 [standard deviation (SD) 8.8] for the water softener group (group A) and -5.7 (SD 9.8) for the usual care group (group B) [mean difference 0.66, 95% confidence interval (CI) -1.37 to 2.69, p = 0.53]. The per-protocol analysis supported the main analysis, and there was no evidence that the treatment effect varied between children with and without mutations in the filaggrin gene. No between-group differences were found in the three secondary outcomes that were assessed blindly (use of topical medications; night-time movement; proportion showing reasonable, good or excellent improvement). Small, but statistically significant, differences in favour of the water softener were found in three of the secondary outcomes that were assessed by participants [Patient-Oriented Eczema Measure (POEM); well-controlled weeks (WCWs); Dermatitis Family Index (DFI)]. The results of the economic evaluation, and the uncertainty surrounding them, suggest that ion-exchange water softeners are unlikely to be a cost effective intervention for children with atopic eczema from an NHS perspective. CONCLUSIONS: Water softeners provided no additional benefit to usual care in this study population. Small, but statistically significant, differences were found in some secondary outcomes as reported by parents, but it is likely that such improvements were the result of response bias. Whether or not the wider benefits of installing a water softener in the home are sufficient to justify the purchase of a softener is something for individual householders to consider on a case-by case basis. This trial demonstrated overwhelming demand for non-pharmacological interventions for the treatment of eczema, and this is something that should be considered when prioritising future research in the field. TRIAL REGISTRATION: Current Controlled Trials ISRCTN71423189. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 15, No. 8. See the HTA programme website for further project information. Results of this trial are also published at www.plosmedicine.org. PMID- 21324290 TI - Using cervical spine clearance guidelines in a pediatric population: a survey of physician practices and opinions. AB - BACKGROUND: Unlike in adults, there are currently no standardized, validated guidelines to aid practitioners in clearing the pediatric cervical spine (C spine). Many pediatric centres in Canada have locally produced, adult-modified guidelines, but the extent to which these or other guidelines are used is unknown. OBJECTIVE: The purpose of this study was to determine if Canadian physicians are using either locally produced or adult C-spine guidelines to clear the C- spines of patients < 16 years of age. The study also characterized the common methods used by physicians to clear pediatric C-spine injuries in terms of clinical examination and radiologic imaging. METHODS: A 20-question survey was distributed to 240 Canadian pediatric emergency physicians and trauma team leaders using the Dillman Total Design Method. RESULTS: The response rate was 68%. The results showed that 61% of physicians currently use guidelines to assist in the clearance of pediatric C-spines. Of those physicians not using guidelines, 85% stated that they would use them if they were available. The clinical criteria most often used to clear pediatric C-spines were a normal neurologic examination (97%) and the absence of C-spine tenderness (95%), intoxication (94%), and distracting injuries (87%). CONCLUSIONS: Guidelines are commonly used by Canadian physicians when clearing the pediatric C-spine, yet few are validated in children. Those most commonly used are locally developed guidelines, the Canadian C-spine guidelines, or National Emergency X-Radiography Utilization Study (NEXUS) low-risk criteria. PMID- 21324291 TI - Predictors of pandemic influenza infection in adults presenting to two urban emergency departments, Toronto, 2009. AB - OBJECTIVE: Identifying features that differentiate patients with H1N1 influenza infection from those with other conditions may assist clinical decision making during waves of pandemic influenza activity. METHODS: From April 27 to June 15, 2009, nasopharyngeal swabs were obtained from all adults presenting to two urban emergency departments (EDs) with illness including fever or respiratory symptoms. H1N1 infection was detected by reverse transcriptase-polymerase chain reaction. Chart review was performed to compare cases of H1N1 influenza (n = 117) to matched controls. RESULTS: The median age of cases was 35 years versus 50 years for controls (p < .001). In those with pre-existing conditions, asthma was present in 31% of cases versus 14% of controls (OR 2.6, 95% CI 1.3-5.4). Cough (OR 7.8, 95% CI 3.2-19), fever (OR 3.0, 95% CI 1.7-5.4), headache (OR 2.0, 95% CI 1.2-3.2), and myalgias (OR 1.9, 95% CI 1.2-3.1) were significantly more common in H1N1 cases. The median white blood cell count was 5.7 * 109/mL versus 10.9 * 109/mL (p < .001). The combination of fever and cough had an OR of 5.3. Fever, cough, low white blood cell (WBC) count, and tachycardia had the highest OR at 11. The absence of both fever and cough had a negative predictive value of 99%, but this occurred in only 8% of controls. CONCLUSION: In patients presenting to the ED, the combination of fever, cough, tachycardia, and WBC count < 10 * 109/mL was suggestive of H1N1 influenza infection. However, clinical features could not reliably distinguish influenza from other acute respiratory illnesses in adult ED patients. PMID- 21324292 TI - Patient safety in emergency medical services: executive summary and recommendations from the Niagara Summit. AB - Emergency medical services (EMS) personnel care for patients in challenging and dynamic environments that may contribute to an increased risk for adverse events. However, little is known about the risks to patient safety in the EMS setting. To address this knowledge gap, we conducted a systematic review of the literature, including nonrandomized, noncontrolled studies, conducted qualitative interviews of key informants, and, with the assistance of a pan-Canadian advisory board, hosted a 1-day summit of 52 experts in the field of EMS patient safety. The intent of the summit was to review available research, discuss the issues affecting prehospital patient safety, and discuss interventions that might improve the safety of the EMS industry. The primary objective was to define the strategic goals for improving patient safety in EMS. Participants represented all geographic regions of Canada and included administrators, educators, physicians, researchers, and patient safety experts. Data were collected through electronic voting and qualitative analysis of the discussions. The group reached consensus on nine recommendations to increase awareness, reduce adverse events, and suggest research and educational directions in EMS patient safety: increasing awareness of patient safety principles, improving adverse event reporting through creating nonpunitive reporting systems, supporting paramedic clinical decision making through improved research and education, policy changes, using flexible algorithms, adopting patient safety strategies from other disciplines, increasing funding for research in patient safety, salary support for paramedic researchers, and access to graduate training in prehospital research. PMID- 21324293 TI - Emergency physicians' management of transient ischemic attack and desired sensitivity of a clinical decision rule for stroke in three countries. AB - OBJECTIVE: Four to 10% of patients with transient ischemic attack (TIA) suffer a stroke or die within 7 days. Our objectives were to determine (1) current practice for investigating and treating emergency department (ED) patients with TIA, (2) willingness to use a clinical decision rule to identify patients at high risk of impending stroke or death, and (3) the required sensitivity of this rule. METHODS: We administered a mail survey to a random sample of members of three national emergency physician associations in Australia, Canada, and the United States using a modified Dillman technique. A prenotification letter and up to three surveys were sent. RESULTS: A total of 801 responses (53.7%) from 1,493 surveys were received; 53.6% (95% CI 47.5-59.7) of emergency physicians reported routinely admitting TIA patients, ranging from 6.6% in Canada to 56.7% in the United States, and 9.9% of emergency physicians have a stroke prevention clinic, with 4.7% estimating that patients are seen within 7 days. A sensitive clinical decision rule for TIA patients would be used by 96.3% (95% CI 93.9-98.7) of emergency physicians. The median required sensitivity of this rule for stroke or death within 7 days was 97%. CONCLUSIONS: Almost half of all TIA patients are managed as outpatients, which is neither expedited nor in a dedicated stroke clinic. Emergency physicians indicate a willingness to use a highly sensitive clinical decision rule to triage TIA patients. PMID- 21324294 TI - Esophageal coin removal by emergency physicians: a continuous quality improvement project incorporating rapid sequence intubation. AB - OBJECTIVE: The objective of this study was to describe our experience removing esophageal coins from children in a tertiary care pediatric emergency department over a 4-year period. METHODS: We retrospectively reviewed a continuous quality improvement data set spanning October 1, 2004, through September 30, 2008. RESULTS: In 96 of 101 cases (95%), emergency physicians successfully retrieved the coin. The median age of the children was 19 months (interquartile range [IQR] 13-43 months; range 4 months-12.8 years). The median time to removal of coin from initiation of intubation was 8 minutes (IQR 4-14 minutes; range 1-60 minutes). Coins were extracted using forceps only in 56 cases, whereas forceps and a Foley catheter were used in the remainder. Succinylcholine and etomidate were used in almost all cases for rapid sequence intubation prior to coin removal. Complications were identified in 46 cases: minor bleeding (13), lip laceration (7), multiple attempts (5), hypoxia (3), accidental extubation (3), dental injuries (3), bradycardia (2), coin advanced (1), right main-stem bronchus intubation (1), and other (8). CONCLUSIONS: Emergency physicians successfully removed esophageal coins following rapid sequence intubation in most cases. Our approach may be considered for the management of pediatric esophageal coins, particularly in an academic pediatric emergency department. PMID- 21324295 TI - Integrating CanMEDS competencies into global health electives: an innovative elective program. AB - Globalization has opened the doors for medical students to undertake international health electives, providing an opportunity for them to gain valuable competencies and skills outside their formal curriculum. As the number of medical students embarking on these electives increases, there is a need to structure the electives with specific learning objectives and to ensure adequate educational outcomes.We describe the International Pediatric Emergency Medicine Elective (IPEME), which is a novel global health elective that brings together students from Canada and the Middle East who are selected on the basis of a competitive application process and brought to Toronto for a 4-week living and studying experience. The program was introduced in 2004 and uses four specific areas to provide its structure: pediatric emergency medicine, global health, leadership, and peace building. The elective uses core CanMEDS competencies to foster cross-cultural dialogue, networking, and cooperation and fulfills the program's aim of using health as a bridge to peace.The lessons learned from the curriculum planning and implementation process are highlighted and the impact of the program explored to help provide a framework for developing similar international electives. PMID- 21324296 TI - How do I effectively use electronic continuing medical education? PMID- 21324297 TI - Should emergency physicians use etomidate for rapid sequence intubation? PMID- 21324298 TI - Pseudoaneurysm formation following a traumatic wrist laceration. AB - Pseudoaneurysms occur secondary to partial disruption of the arterial wall. They are a commonly described complication of arterial injury, with penetrating injury and iatrogenic arterial catheterization being the most common etiologies in children. Many present weeks to months after the injury, and the initial vascular injury is often missed. The complications of pseudoaneurysm, which include thromboembolism, neurapraxia, and compartment syndrome, underscore the importance of early recognition and management. Definitive therapy consists of ultrasound guided compression or resection and possible graft interposition. We describe a case of pseudoaneurysm formation in the radial artery of an adolescent girl 6 weeks following a penetrating injury. The patient's injury was complicated by sensory and motor deficits consistent with ulnar nerve compression. This case attests to the importance of adequately ruling out arterial injury in penetrating injury and close follow-up if the history is suggestive. In addition, a high index of suspicion is warranted to facilitate imaging of a pulsatile mass to avoid confusion of a thrombosed artery with an abscess. PMID- 21324299 TI - Cough syrup psychosis. AB - Over-the-counter medications are widely accessible and used. Cough suppressant syrups contain dextromethorphan (DM), which has the potential to be abused, with resultant psychiatric symptoms. This case report describes a young woman presenting with psychotic mania secondary to DM abuse. We also describe the treatment of this toxidrome and include the results of a literature search on this topic. The recognition of cough syrup as an agent of abuse and its toxidrome is important. This will facilitate early diagnostic clarification and promote efficient treatment strategies. PMID- 21324300 TI - Penetrating craniofacial trauma from a vice clamp: case report and discussion. AB - Penetrating craniofacial trauma, although uncommon, has a high potential for death or serious morbidity from injury to vital neurovascular structures. An in situ facial foreign body, particularly if large, presents significant challenges beyond safe and timely removal. Airway management, stabilization of the object, management of increased intracranial pressure, and identification of injuries to local structures are all issues that may require addressing. We present a case of penetrating facial trauma from a vice clamp, with an in situ foreign body, that illustrates several of these challenges and provides a forum for their discussion. PMID- 21324301 TI - Asymptomatic pulmonary embolus masquerading as acute anteroseptal myocardial infarction. AB - Pulmonary embolism (PE) is an uncommon and often overlooked cause of ST-segment elevation on the electrocardiogram (ECG). Emergent echocardiography has been cited as a means to rapidly distinguish acute myocardial infarction from PE. However, both of these conditions can present with focal wall motion abnormalities. We report a case of a 51-year-old asymptomatic male who presented to our emergency department with anterior ST-segment elevation and right-heart strain on an ECG. The clinical diagnosis of ST elevation myocardial infarction was in doubt, and an echocardiogram was obtained while the patient was in the emergency department. Although a focal area of hypokinesia was observed on echocardiography, cardiac catherization did not demonstrate any evidence of acute coronary occlusion. A computed tomographic angiogram of the chest was subsequently obtained, which demonstrated evidence of submassive pulmonary emboli. Our case highlights the limited utility of emergent echocardiography in cases of ST-segment elevation. PMID- 21324302 TI - The epidemiology of human trichinellosis in China during 2004-2009. AB - The endemic foci of human trichinellosis are mainly located in southwestern China. Seroepidemiological surveys of Trichinella spiralis infection in humans were carried out in 10 out of 34 Provinces/Autonomous Regions/Municipals (P/A/M) of China during 2004-2009. The overall seroprevalence was 3.19% (3198/100,282). The highest seroprevalences were mainly located in western China: 8.43% in Yunnan, 6.37% in Inner Mongolia and 5.35% in Sichuan. The seroprevalence of Trichinella infection in humans was related to the habit of eating meat and differed among nationalities. From 2004 to 2009, 15 outbreaks of human trichinellosis, consisting of 1387 cases and four deaths, were reported in the three southwestern-most P/A of China (nine outbreaks in Yunnan, two in Sichuan and four in Tibet), where ethnic groups routinely eat raw meat. Pork is the predominant source of outbreaks of human trichinellosis in China. Out of 15 outbreaks, 12 (85.71%) were caused by eating raw or undercooked pork, and 2 (13.33%) resulted from the consumption of raw wild boar, suggesting the significance of game meat as a source of infection for human trichinellosis. An outbreak of imported trichinellosis involving 49 cases in Yunnan during December 2006 from Laos is the first recorded outbreak of imported trichinellosis in China, but the source of that outbreak could not be identified. The mandatory inspection of pork should be further strengthened in southwestern China. PMID- 21324303 TI - Analysis of the CYP21A1P pseudogene: indication of mutational diversity and CYP21A2-like and duplicated CYP21A2 genes. AB - The CYP21A1P gene downstream of the XA gene, carrying 15 deteriorated mutations, is a nonfunctional pseudogene that shares 98% nucleotide sequence homology with CYP21A2 located on chromosome 6p21.3. However, these mutations in the CYP21A1P gene are not totally involved in each individual. From our analysis of 100 healthy ethnic Chinese (i.e., Taiwanese) (n=200 chromosomes) using the polymerase chain reaction (PCR) products combined with an amplification-created restriction site (ACRS) method and DNA sequencing, we found that approximately 10% of CYP21A1P alleles (n=195 chromosomes) presented the CYP21A2 sequence; frequencies of P30, V281, Q318, and R356 in that locus were approximately 24%, 21%, 11%, and 34%, respectively, and approximately 90% of the CYP21A1P alleles had 15 mutated loci. In addition, approximately 2.5% (n=5 chromosomes) showed four haplotypes of the 3.7-kb TaqI-produced fragment of the CYP21A2-like gene and one duplicated CYP21A2 gene. We conclude that the pseudogene of the CYP21A1P mutation presents diverse variants. Moreover, the existence of the CYP21A2-like gene is more abundant than that of the duplicated CYP21A2 gene downstream of the XA gene and could not be distinguished from the CYP21A2-TNXB gene; thus, it may be misdiagnosed by previously established methods for congenital adrenal hyperplasia caused by a 21-hydroxylase deficiency. PMID- 21324304 TI - Separation of positional and geometrical fatty acid isomers as 2 nitrophenylhydrazide derivatives by high-performance liquid chromatography. AB - Previously, following derivatization to their 2-nitrophenylhydrazide (2-NPH) derivatives, fatty acid (FA) abundances have been evaluated using high performance liquid chromatography (HPLC). Although the method was sensitive, resolution was insufficient for many of the biologically important FAs. We have developed an enhanced separation of 24 FAs by use of different column temperature, stationary phase, and mobile phase gradient conditions. We applied this method to analysis of mouse skeletal muscle phospholipid and triglyceride. This further development of the chromatographic separation of 2-NPH FAs may lead to greater utility of this HPLC approach. PMID- 21324305 TI - Removal of acidic residues of the prodomain of PCSK9 increases its activity towards the LDL receptor. AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low density lipoprotein receptor (LDLR) at the cell surface and mediates intracellular degradation of the LDLR. The amino-terminus of mature PCSK9, residues 31-53 of the prodomain, has an inhibitory effect on this function of PCSK9, but the underlying mechanism is not fully understood. In this study, we have identified two highly conserved negatively charged segments (residues 32-40 and 48-50, respectively) within this part of the prodomain and performed deletions and substitutions to study their importance for degradation of the LDLRs. Deletion of the acidic residues of the longest negatively charged segment increased PCSK9's ability to degrade the LDLR by 31%, whereas a modest 8% increase was observed when these residues were mutated to uncharged amino acids. Thus, both the length and the charge of this part of the prodomain were important for its inhibitory effect. Deletion of the residues of the shorter second negatively charged segment only increased PCSK9's activity by 8%. Substitution of the amino acids of both charged segments to uncharged residues increased PCSK9's activity by 36%. These findings indicate that the inhibitory effect of residues 31-53 of the prodomain is due to the negative charge of this segment. The underlying mechanism could involve the binding of this peptide segment to positively charged structures which are important for PCSK9's activity. One possible candidate could be the histidine-rich C-terminal domain of PCSK9. PMID- 21324306 TI - Effects of pergolide mesylate on transduction efficiency of PEP-1-catalase protein. AB - The low transduction efficiency of various proteins is an obstacle to their therapeutic application. However, protein transduction domains (PTDs) are well known for a highly effective tool for exogenous protein delivery to cells. We examined the effects of pergolide mesylate (PM) on the transduction of PEP-1 catalase into HaCaT human keratinocytes and mice skin and on the anti inflammatory activity of PEP-1-catatase against 12-O-tetradecanoylphorbol-13 acetate (TPA)-induced inflammation using Western blot and histological analysis. PM enhanced the time- and dose-dependent transduction of PEP-1-catalase into HaCaT cells without affecting the cellular toxicity. In a mouse edema model, PEP 1-catalase inhibited the increased expressions of inflammatory mediators and cytokines such as cyclooxygenase-2, inducible nitric oxide synthase, interleukin 6 and -1beta, and tumor necrosis factor-alpha induced by TPA. On the other hand, PM alone failed to exert any significant anti-inflammatory effects. However, the anti-inflammatory effect of co-treatment with PEP-1-catalase and PM was more potent than that of PEP-1-catalase alone. Our results indicate that PM may enhance the delivery of PTDs fusion therapeutic proteins to target cells and tissues and has potential to increase their therapeutic effects of such drugs against various diseases. PMID- 21324307 TI - Advances in DNA methylation: 5-hydroxymethylcytosine revisited. AB - Mammalian DNA contains two modified cytosine bases; 5-methylcytosine (5mC) and 5 hydroxymethylcytosine (5hmC). Both of these have been known for decades but have received very different levels of attention in the scientific literature. 5mC has been studied extensively, and its role as an epigenetic modification involved in gene regulation, X-chromosome inactivation, genomic imprinting, long-term silencing of transposons and cancer development is well described. 5hmC, on the other hand, has only recently entered center stage when it was shown that the Ten Eleven-Translocation (TET) family of oxygenases catalyzes the conversion of 5mC to 5hmC, and that one of these enzymes, TET2, is frequently mutated in myeloid neoplasms. The formation of 5hmC can lead to demethylation of DNA, which may contribute to the dynamics of DNA methylation. 5hmC has been found in many cell types and tissues, with particularly high levels in the brain, and TET1 has been shown to be important for self-renewal and maintenance of embryonic stem cells. Future challenges include better understanding the normal molecular, cellular and physiological roles of 5hmC and TET proteins, understanding the exact roles of TET proteins in cancer development, and developing sequencing methodologies that can accurately distinguish among cytosine, 5mC and 5hmC at single-base-pair resolution. PMID- 21324308 TI - Rapid detection of the hepatitis B virus YMDD mutant using AllGloTM probes. AB - BACKGROUND: The early detection of hepatitis B virus (HBV) mutants in clinical samples is important when monitoring chronic HBV patients with lamivudine resistant mutations during lamivudine therapy. METHODS: The AllGloTM probes were designed to distinguish between wild-type (YMDD) and mutant (YVDD and YIDD) strains of HBV. The sensitivity and specificity of the assay were evaluated using a series of diluted mixtures of wild-type and mutant plasmids. This assay was compared with direct sequencing and the mutation-specific primer assay. RESULTS: Each YMDD, YVDD, and YIDD probe only detected its corresponding plasmid. Moreover, the assay correctly identified negative samples from 40 non-HBV infected patients and 100 healthy controls. The detection limit of this assay was 50 copies/ml for YVDD and YIDD. The assay could detect the mutant strains when they were present at >=10% within a mixed virus population. The assay was fully concordant with direct sequencing in 34 samples (56.7%) and partially concordant in 26 samples (43.3%), and detected more types of the HBV motif than direct sequencing. CONCLUSIONS: AllGloTM probe assay is a novel, sensitive and specific assay to detect lamivudine-related HBV mutants, therefore, may be useful for monitoring chronic HBV patients treated with lamivudine. PMID- 21324309 TI - Establishment of a new method for the detection of the affinity of antibody to hepatitis B e antigen by a routine quantitative system. AB - BACKGROUND: The commonly used quantitative analyses for specific antibodies only involve measurement of the total antibody activity, and the binding affinity is rarely analyzed. We established a method for the detection of the affinity of the antibody to hepatitis B e antigen (anti-HBe). METHODS: A method to detect anti HBe affinity was established by using a routine quantitative system (Architect Analyzer). Serum samples were collected from hepatitis B patients with anti-HBe. On the basis of the other serologic markers in the samples, patients were divided into HBsAg positive and anti-HBs positive groups. The total anti-HBe activity and anti-HBe affinity were each measured. RESULTS: The affinity of anti-HBe in the anti-HBs positive group was higher than that in the HBsAg positive group (P<0.05); conversely, the total anti-HBe activity in the anti-HBs positive group was lower than that in the HBsAg positive group (P<0.05). CONCLUSIONS: The anti HBe affinity arising from an immune response to HBV infection may vary significantly between different situations. This new approach will be suitable for determining antibody affinity in clinical laboratories. PMID- 21324310 TI - Effect of obesity on the association between ATF3 gene haplotypes and C-reactive protein level in Taiwanese. AB - OBJECTIVE: ATF3 has traditionally been related to various inflammatory processes. Our aim was to test the statistical association between variations in the ATF3 gene and levels of nine serum inflammatory markers, including C reactive protein (CRP), in a Taiwanese population using interaction analysis. METHODS: A sample population of 604 Taiwanese subjects was enrolled. Five tagging single nucleotide polymorphisms of the ATF3 gene from the Han Chinese HapMap Database were selected and genotyped. RESULTS: With or without adjustment for clinical covariates, ATF3 genotypes were found to be associated with CRP levels but not with other inflammatory marker levels. Minor alleles of 2 of the 5 ATF3 SNPs were associated with decreased CRP levels predominantly in non-obese subjects (Bonferoni P=0.018, and P=0.002 for rs11571530, and rs10475, respectively). Two haplotypes inferred from the 5 SNPs, GATTA and TACCA, were also associated with increased or decreased CRP levels, respectively, in non-obese subjects (Bonferoni P=0.012 and P=0.01, respectively) but not in obese subjects. Interaction analysis revealed interaction of obesity with an ATF3 genotype associated with a high CRP level (interaction P=0.006 for SNP rs10475). An effect of obesity on CRP level was also noted in haplotype interaction analysis (interaction P=0.019 for haplotype TACCA). CONCLUSIONS: ATF3 polymorphisms are independently associated with CRP levels in Taiwanese subjects. Further, ATF3 genotypes/haplotypes interact with obesity to set CRP levels. These findings may have implications for the prediction of atherosclerotic disease. PMID- 21324311 TI - Instability of fibroblast growth factor-23 (FGF-23): implications for clinical studies. AB - BACKGROUND: Fibroblast growth factor-23 (FGF-23) is a bone secreted hormone that regulates phosphate homeostasis and calcitriol levels. FGF-23 concentrations are elevated in chronic kidney disease (CKD), oncogenic osteomalcia and a number of rare hereditary disorders. Studies systematically evaluating the pre-analytical stability of intact FGF-23 are lacking. METHODS: The stability of FGF-23 was assessed in timed experiments using blood taken into K2-EDTA plasma specimen tubes from a group of healthy participants and from a group with mild-to-moderate CKD. We evaluated the use of aprotinin, a serine protease inhibitor, and a commercially available protease inhibitor cocktail to preserve intact FGF-23 after blood collection. FGF-23 measurements were made using both intact and C terminal assays. RESULTS: Both whole blood and separated sample studies demonstrated a rapid loss of intact FGF-23 within 2 h, while concentrations increased using the C-terminal assay. The addition of protease inhibitor cocktail stabilised FGF-23 concentrations for 4 h after blood collection. Intact and C terminal assay FGF-23 measurements showed poor correlation in both healthy and CKD cohorts. CONCLUSION: K2-EDTA plasma samples, even when promptly separated, are unsuitable for measurement of FGF-23 unless stabilised with a protease inhibitor cocktail. PMID- 21324312 TI - Anti-TNF therapy using etanercept suppresses degenerative and inflammatory changes in skeletal muscle of older SJL/J mice. AB - Limb-girdle muscular dystrophy 2B and Miyoshi myopathy are characterized by muscle fiber necrosis caused by a defect in dysferlin and inflammatory changes. SJL/J mice are deficient in dysferlin and display severe inflammatory changes, most notably the presence of cytokines, which may be related to destruction of the sarcolemma. We tested the hypothesis that tumor necrosis factor (TNF) contributes to myofibril necrosis. Administration of etanercept, an agent that blocks TNF, resulted in dose-dependent reductions in inflammatory change, necrosis, and fatty/fibrous change. These findings indicate that TNF does indeed play a role in the damage to muscle in SJL/J mice and that etanercept has the potential to reduce such damage. PMID- 21324313 TI - Inhibition of geranylgeranylation mediates sensitivity to CHOP-induced cell death of DLBCL cell lines. AB - Prenylation is a post-translational hydrophobic modification of proteins, important for their membrane localization and biological function. The use of inhibitors of prenylation has proven to be a useful tool in the activation of apoptotic pathways in tumor cell lines. Rab geranylgeranyl transferase (Rab GGT) is responsible for the prenylation of the Rab family. Overexpression of Rab GGTbeta has been identified in CHOP refractory diffuse large B cell lymphoma (DLBCL). Using a cell line-based model for CHOP resistant DLBCL, we show that treatment with simvastatin, which inhibits protein farnesylation and geranylgeranylation, sensitizes DLBCL cells to cytotoxic treatment. Treatment with the farnesyl transferase inhibitor FTI-277 or the geranylgeranyl transferase I inhibitor GGTI-298 indicates that the reduction in cell viability was restricted to inhibition of geranylgeranylation. In addition, treatment with BMS1, a combined inhibitor of farnesyl transferase and Rab GGT, resulted in a high cytostatic effect in WSU-NHL cells, demonstrated by reduced cell viability and decreased proliferation. Co-treatment of BMS1 or GGTI-298 with CHOP showed synergistic effects with regard to markers of apoptosis. We propose that inhibition of protein geranylgeranylation together with conventional cytostatic therapy is a potential novel strategy for treating patients with CHOP refractory DLBCL. PMID- 21324314 TI - Apoptotic role of TGF-beta mediated by Smad4 mitochondria translocation and cytochrome c oxidase subunit II interaction. AB - Smad4, originally isolated from the human chromosome 18q21, is a key factor in transducing the signals of the TGF-beta superfamily of growth hormones and plays a pivotal role in mediating antimitogenic and proapoptotic effects of TGF-beta, but the mechanisms by which Smad4 induces apoptosis are elusive. Here we report that Smad4 directly translocates to the mitochondria of apoptotic cells. Smad4 gene silencing by siRNA inhibits TGF-beta-induced apoptosis in Hep3B cells and UV induced apoptosis in PANC-1 cells. Cell fractionation assays demonstrated that a fraction of Smad4 translocates to mitochondria after long time TGF-beta treatment or UV exposure, during which the cells were under apoptosis. Smad4 mitochondria translocation during apoptosis was also confirmed by fluorescence observation of Smad4 colocalization with MitoTracker Red. We searched for mitochondria proteins that have physical interactions with Smad4 using yeast two-hybrid screening approach. DNA sequence analysis identified 34 positive clones, five of which encoded subunits in mitochondria complex IV, i.e., one clone encoded cytochrome c oxidase COXII, three clones encoded COXIII and one clone encoded COXVb. Strong interaction between Smad4 with COXII, an important apoptosis regulator, was verified in yeast by beta-gal activity assays and in mammalian cells by immunoprecipitation assays. Further, mitochondrial portion of cells was isolated and the interaction between COXII and Smad4 in mitochondria upon TGF-beta treatment or UV exposure was confirmed. Importantly, targeting Smad4 to mitochondria using import leader fusions enhanced TGF-beta-induced apoptosis. Collectively, the results suggest that Smad4 promote apoptosis of the cells through its mitochondrial translocation and association with mitochondria protein COXII. PMID- 21324315 TI - Prolonged cannabinoid exposure alters GABA(A) receptor mediated synaptic function in cultured hippocampal neurons. AB - Developing cannabinoid-based medication along with marijuana's recreational use makes it important to investigate molecular adaptations the endocannabinoid system undergoes following prolonged use and withdrawal. Repeated cannabinoid administration results in development of tolerance and produces withdrawal symptoms that may include seizures. Here we employed electrophysiological and immunochemical techniques to investigate the effects of prolonged CB1 receptor agonist exposure on cultured hippocampal neurons. Approximately 60% of CB1 receptors colocalize to GABAergic terminals in hippocampal cultures. Prolonged treatment with the cannabinamimetic WIN 55,212-2 (+WIN, 1 MUM, 24 h) caused profound CB1 receptor downregulation accompanied by neuronal hyperexcitability. Furthermore, prolonged +WIN treatment resulted in increased GABA release as indicated by increased mIPSC frequency, a diminished GABAergic inhibition as indicated by reduction in mIPSC amplitude and a reduction in GABA(A) channel number. Additionally, surface staining for the GABA(A) beta(2/3) receptor subunits was decreased, while no changes in staining for the presynaptic vesicular GABA transporter were observed, indicating that GABAergic terminals remained intact. These findings demonstrate that agonist-induced downregulation of the CB1 receptor in hippocampal cultures results in neuronal hyperexcitability that may be attributed, in part, to alterations in both presynaptic GABA release mechanisms and postsynaptic GABA(A) receptor function demonstrating a novel role for cannabinoid-dependent presynaptic control of neuronal transmission. PMID- 21324316 TI - Relation between startle reactivity and sucrose avidity in two rat strains bred for differential seizure susceptibility. AB - Rat strains selectively bred to be seizure-prone (Fast) versus seizure-resistant (Slow) show differing levels of anxiety, with Slow rats displaying relatively enhanced anxiety-like behaviors to aversive stimuli. Ample data has suggested that highly anxious rodents exhibit reduced avidity for sucrose and greater startle responses than rodents with relatively low anxiety levels. Thus, it was hypothesized that the Slow rats would have lower appetitive (sucrose consumption) and greater defensive (startle response) behaviors than Fast rats. Results confirmed that Slow rats consumed significantly less sucrose and exhibited greater acoustic startle responses than Fast rats. Startle response magnitude was not associated with water consumption, food consumption or body weight but was negatively correlated with sucrose consumption. These observations attest to the link between sucrose avidity and startle reactivity and further reveal that genetic selection for amygdala excitability lead to strain differences in appetitive and defensive behaviors. Thus, Fast and Slow rats may be two unique strains with which to further elucidate the genetic and neurobiological mechanisms underlying appetitive and defensive behaviors and their relation to anxiety and seizure sensitivity. PMID- 21324317 TI - Activity-dependent long-term plasticity of afferent synapses on grafted stem/progenitor cell-derived neurons. AB - Stem cell-based cell replacement therapies aiming at restoring injured or diseased brain function ultimately rely on the capability of transplanted cells to promote functional recovery. The mechanisms by which stem cell-based therapies for neurological conditions can lead to functional recovery are uncertain, but structural and functional repair appears to depend on integration of transplanted cell-derived neurons into neuronal circuitries. The nature by which stem/progenitor cell-derived neurons synaptically integrate into neuronal circuitries is largely unexplored. Here we show that transplanted GFP-labeled neuronal progenitor cells into the rat hippocampus exhibit mature neuronal morphology following 4-10 weeks. GFP-positive cells were preferentially integrated into the principal cell layers of hippocampus, particularly CA3. Patch clamp recordings from GFP-expressing cells revealed that they generated fast action potentials, and their intrinsic membrane properties were overall similar to endogenous host neurons recorded in same areas. As judged by occurrence of spontaneous excitatory postsynaptic currents (EPSCs), transplanted GFP-positive cells were synaptically integrated into the host circuitry. Comparable to host neurons, both paired-pulse depression and facilitation of afferent fiber stimulation-evoked EPSCs were observed in GFP-positive cells. Upon high-frequency stimulation, GFP-positive cells displayed post-tetanic potentiation of EPSCs, in some cases followed by long-term potentiation (LTP) lasting for more than 30 min. Our data show for the first time that transplanted neuronal progenitor cells can become functional neurons and their afferent synapses are capable of expressing activity-dependent short and long-term plasticity. These synaptic properties may facilitate host-to-graft interactions and regulate activity of the grafted cells promoting functional recovery of the diseased brain. PMID- 21324319 TI - Comparability of probable and definite autoimmune hepatitis by international diagnostic scoring criteria. AB - BACKGROUND & AIMS: The diagnostic scoring systems for autoimmune hepatitis categorize some patients as having probable disease; this designation can affect treatment strategies and recruitment to clinical studies. A retrospective study was performed to determine the bases for the classification of probable autoimmune hepatitis and its clinical importance. METHODS: The study included 185 adult patients who had been assessed at presentation for findings common to both international diagnostic scoring systems. RESULTS: Seventeen patients (9%) were graded as probable autoimmune hepatitis by the revised original scoring system, and 28 patients (15%) were similarly designated by the simplified scoring system. These patients were distinguished from those designated as definite autoimmune hepatitis by male sex, concurrent immune diseases, lower serum gamma-globulin and immunoglobulin G levels, and lower titers of autoantibody. Patients with definite or probable designations by either scoring system responded similarly to conventional corticosteroid regimens during comparable intervals of treatment. Full, partial, or nonresponses and treatment dependence were evident in all diagnostic categories with similar frequencies. Twenty-seven patients designated as probable autoimmune hepatitis by one system were designated as definite autoimmune hepatitis by the other system. CONCLUSIONS: The designation of probable autoimmune hepatitis by the international scoring systems is based on differences in clinical manifestations and does not reflect differences in the validity of the diagnosis or its treatment response. Large multicenter prospective studies are necessary to establish these observations. PMID- 21324318 TI - MicroRNA-based classification of hepatocellular carcinoma and oncogenic role of miR-517a. AB - BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a heterogeneous tumor that develops via activation of multiple pathways and molecular alterations. It has been a challenge to identify molecular classes of HCC and design treatment strategies for each specific subtype. MicroRNAs (miRNAs) are involved in HCC pathogenesis, and their expression profiles have been used to classify cancers. We analyzed miRNA expression in human HCC samples to identify molecular subclasses and oncogenic miRNAs. METHODS: We performed miRNA profiling of 89 HCC samples using a ligation-mediated amplification method. Subclasses were identified by unsupervised clustering analysis. We identified molecular features specific for each subclass using expression pattern (Affymetrix U133 2.0; Affymetrix, Santa Clara, CA), DNA change (Affymetrix STY Mapping Array), mutation (CTNNB1), and immunohistochemical (phosphor[p]-protein kinase B, p-insulin growth factor-IR, p-S6, p-epidermal growth factor receptor, beta-catenin) analyses. The roles of selected miRNAs were investigated in cell lines and in an orthotopic model of HCC. RESULTS: We identified 3 main clusters of HCCs: the wingless-type MMTV integration site (32 of 89; 36%), interferon-related (29 of 89; 33%), and proliferation (28 of 89; 31%) subclasses. A subset of patients with tumors in the proliferation subclass (8 of 89; 9%) overexpressed a family of poorly characterized miRNAs from chr19q13.42. Expression of miR-517a and miR-520c (from ch19q13.42) increased proliferation, migration, and invasion of HCC cells in vitro. MiR-517a promoted tumorigenesis and metastatic dissemination in vivo. CONCLUSIONS: We propose miRNA-based classification of 3 subclasses of HCC. Among the proliferation class, miR-517a is an oncogenic miRNA that promotes tumor progression. There is rationale for developing therapies that target miR-517a for patients with HCC. PMID- 21324320 TI - The role of ubiquitin-proteasome system in ageing. AB - Maintenance of cellular homeostasis influences ageing and it is determined by several factors, including efficient proteolysis of damaged proteins. The ubiquitin-proteasome system is the major protein degradation pathway in the cell. Specifically, the proteasome is responsible for clearance of abnormal, denatured or in general damaged proteins as well as for the regulated degradation of short lived proteins. In this review the involvement of the ubiquitin-proteasome pathway in protein degradation at different levels of cellular life is discussed in relation with ageing. Though the exact underlying mechanism is unclear, an age related decrease in proteasome activity weakens cellular capacity to remove oxidatively modified proteins and favours the development of diseases. Up regulation of proteasome activity is characteristic of muscle wasting conditions, but may not be rate limiting. Meanwhile, enhanced presence of immunoproteasomes in ageing brain and muscle tissue could reflect a persistent inflammatory defence and anti-stress mechanism. Insulin/IGF-1 signalling regulates ageing in worms, flies and mammals. The insulin/IGF-1 receptor inhibits the forkhead transcription factor, FoxO through activating a cascade of conserved kinases. Longevity increases when FoxO becomes activated in response to reduced insulin/IGF-1 signalling. The ubiquitin-proteasome system plays a major role in signal transduction associated with stress and ageing. The understanding of specific proteolytic targeting paves the way for a new generation of active molecules that may control particular steps of normal and pathological ageing. PMID- 21324321 TI - Stability and transport of cervical cytobrushes for isolation of mononuclear cells from the female genital tract. AB - Cervical cytobrushing, biopsy, or lavages have previously been used to collect mononuclear cells from the female genital tract. Compared with blood, obtaining cells from the female genital tract is more invasive and generally yields few cells for subsequent immune studies. Because of the value of including mucosal sampling in HIV vaccine trials, standardisation of methods for collection, processing, and analysis of immunity from cells derived from the female genital tract is important. The aim of this study was to assess the effect of transport conditions on the viability, recovery and antigenic responsiveness of cervical T cells. This was investigated in cervical cytobrush specimens collected from 215 chronically HIV-infected women. Cytobrushes were either processed immediately, after cryopreservation, or after 24h at 37 degrees C, 4 degrees C or room temperature. CD3(+) T cell numbers were quantified using Guava automated cell counting. Viability was assessed using Trypan and Annexin/PI staining. Intracellular cytokine staining was used to evaluate IFN-gamma responses to PMA, PHA and CEF peptides in cytobrush-derived T cells ex vivo and after delayed processing. In vitro polyclonal expansion of thawed cervical lymphocytes was conducted for 14days in the presence of anti-CD3 and IL-2. We found that CD3(+) T cell recovery and viability was similar in cytobrushes processed immediately or after 24h irrespective of the conditions at which they were maintained. Fifty percent of the CD3(+) T cells could be recovered after cryopreservation of cytobrushes and these could be polyclonally expanded in half of the cryopreserved samples. IFN-gamma production following mitogenic stimulation was similar in ex vivo and delayed processing cytobrushes. Maintaining cytobrushes at 37 degrees C prior to processing significantly improved the detection of CEF-specific T cell responses compared to ex vivo. We conclude that cervical cytobrush-derived T cells are robust and can preserve their viability, phenotype and function over 24h of mock transport. PMID- 21324322 TI - Protective action of tamoxifen on carboxyatractyloside-induced mitochondrial permeability transition. AB - AIMS: Mitochondrial permeability transition is established after massive Ca(2+) accumulation inside the matrix, in addition to an inducer. The closure of the pore can be accomplished by adenosine diphosphate and the immunosuppressant cyclosporin A. Recently, the estrogen antagonist, tamoxifen, has been introduced as an inhibitor of the opening of the permeability transition pore. However, the mechanism by which this drug inhibits pore opening is still under discussion. This work was performed with the purpose of establishing the membrane system involved in tamoxifen-induced pore closure. For this purpose, permeability transition was induced after the addition of carboxyatractyloside, which is a specific reagent that interacts with the adenine nucleotide translocase. MAIN METHODS: Permeability transition was assessed by analyzing matrix Ca(2+) release, transmembrane electric gradient, and mitochondrial swelling in aged, as well as in freshly prepared mitochondria. Also, cytochrome c content was analyzed in membrane mitochondria as well as in the supernatant. KEY FINDINGS: In freshly prepared mitochondria, tamoxifen, at the concentration of 10 MUM, totally inhibited nonspecific membrane permeability induced by 1 MUM carboxyatractyloside. In addition, tamoxifen inhibited non-specific permeability in aged mitochondria and diminished membrane fluidity. SIGNIFICANCE: Plausibly, the inhibitory effect of tamoxifen on nonspecific membrane permeability, as induced by carboxyatractyloside, should be ascribed to a diminution, of membrane fluidity by this drug. PMID- 21324323 TI - Phenotypes and circadian rhythm in utilization of formate in purine nucleotide biosynthesis de novo in adult humans. AB - AIMS: Folate coenzymes and dependent enzymes introduce one carbon units at positions 2 (C(2)) and 8 (C(8)) of the purine ring during de novo biosynthesis. Formate is one source of one-carbon units. Although much is known about lower organisms, little data exists describing formate utilization for purine biosynthesis in humans. MAIN METHODS: Mass-spectrometric analysis of urinary uric acid, the final purine catabolite, following 1.0 g oral doses of sodium [(13)C] formate was performed and detected (13)C enrichment at C(2) and C(8) separately. KEY FINDINGS: Three phenotypes were suggested. One incorporates (13)C 0.72 to 2.0% into C(2) versus only 0 to 0.07% into C(8). Another incorporates only 0 to 0.05% (13)C into C(2) or C(8). A third phenotype incorporates (13)C into C(8) (0.15%) but C(2) incorporation (0.44%) is still greater. In subjects who incorporated (13)C formate into C(2), peak enrichment occurred in voids from 8-12 h (24 h clock) suggesting a circadian rhythm. SIGNIFICANCE: Evidence that mammalian liver introduces C(8) and that C(2) is introduced in a non-hepatic site would explain our results. Our data are not similar to those in non-mammalian organisms or cells in culture and are not consistent with the hypothesis that formate from folate-dependent metabolism in mitochondria is a major one carbon source for purine biosynthesis. Timing of peak (13)C enrichment at C(2) corresponds to maximal DNA synthesis in human bone marrow. Phenotypes may explain the efficacy (or lack of) of certain anticancer and immunosuppressive drugs. PMID- 21324324 TI - Microsomal prostaglandin E synthase-1 enhances bone cancer growth and bone cancer related pain behaviors in mice. AB - AIMS: Nonsteroidal anti-inflammatory drugs are a therapeutic modality for chronic cancer pain arising from bone metastases. Chronic administration of a cyclooxygenase (COX)-2 inhibitor is effective to bone cancer-related pain. However, adverse cardiovascular effects have limited COX-2 inhibitor therapy, and elucidation of better targets for blocking prostaglandin (PG) biosynthesis is necessary. Microsomal PGE synthase-1 (mPGES-1) is an inducible enzyme that catalyzes isomerization of the endoperoxide PGH(2) to PGE(2). To investigate the validity of mPGES-1 as a therapeutic target, we evaluated bone cancer pain related behaviors in mPGES-1 knockout (PGES-1-/-) mice. MAIN METHODS: Lewis lung carcinoma cells (LLCCs) were injected into the intramedullary space of the femur of wild-type (WT) and PGES-1-/- mice. Pain-related behaviors were evaluated. KEY FINDINGS: PGES-1-/- mice exhibited reduced tumor growth in bone marrow compared to WT. The expression of pro-calcitonin gene-related peptide (CGPR) in the dorsal root ganglia of L(1-5) was significantly higher in WT mice at day 14, whereas it was unchanged in mPGES-1 mice. In the observation of pain-related behaviors, mPGES-1-/- mice exhibited significantly fewer spontaneous flinches and their onset was several days later than WT. The appearance of other pain-related behaviors in mPGES-1-/- mice was also delayed as compared to WT. LLCC-injected WT mice treated with a COX-2 inhibitor, celecoxib, exhibited similar temporal changes to mPGES1-/-. SIGNIFICANCE: The present results suggest that mPGES-1 plays a crucial role in the enhancement of bone cancer growth and bone cancer pain, and that inhibition of mPGES-1 may have clinical utility in the management of bone cancer pain. PMID- 21324325 TI - Stress induces altered CRE/CREB pathway activity and BDNF expression in the hippocampus of glucocorticoid receptor-impaired mice. AB - The gene coding for the neurotrophin Brain-Derived Neurotrophic Factor (BDNF) is a stress-responsive gene. Changes in its expression may underlie some of the pathological effects of stress-related disorders like depression. Data on the stress-induced regulation of the expression of BDNF in pathological conditions are rare because often research is conducted using healthy animals. In our experiments, we used transgenic mice with glucocorticoid receptor impaired (GR-i) expression in the hypothalamus created as a tool to study the neuroendocrine changes occurring in stress-related disorders. First, under basal condition, GR-i mice displayed lower levels of BDNF exons IX and IV and decreased CRE(BDNF) binding activity with respect to wild-type (WT) mice in the hippocampus. Then, we exposed GR-i and WT mice to an acute restraint stress (ARS) to test the hypothesis that GR-i mice display: 1] different ARS induced expression of BDNF, and 2] altered activation of signaling pathways implicated in regulating BDNF gene expression in the hippocampus with respect to WT mice. Results indicate that ARS enhanced BDNF mRNA expression mainly in the CA3 hippocampal sub-region of GR i mice in the presence of enhanced levels of pro-BDNF protein, while no effect was observed in WT mice. Moreover, ARS reduced CREB signaling and binding to the BDNF promoter in GR-i mice but enhanced signaling and binding, possibly through ERK1/2 activation, in WT mice. Thus, life-long central GR dysfunction resulted in an altered sensitivity at the transcriptional level that may underlie an impaired response to an acute psycho-physical stress. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'. PMID- 21324326 TI - Adolescent pre-exposure to ethanol or MDMA prolongs the conditioned rewarding effects of MDMA. AB - Adolescents often take ethanol (EtOH) in combination with MDMA (3,4 methylenedioxymethylamphetamine). In the present work we studied the effect of repeated intermittent adolescent pre-exposure to both drugs on the behavioral and neurochemical effects of MDMA in mice. Sixteen days after pre-treatment, the rewarding and reinstating effects of MDMA in the conditioned place preference (CPP) paradigm were evaluated, along with the levels of biogenic amines, basal motor activity and corticosterone response to different challenges. Pre-exposure to EtOH, MDMA or EtOH+MDMA did not affect the CPP induced by 10mg/kg of MDMA. However, adolescent exposure to EtOH or MDMA increased the duration of the conditioned rewarding effects of MDMA. Following extinction of the CPP, a priming dose of 5mg/kg of MDMA elicited reinstatement in all the groups, with the duration of this reinstated CPP being longer in mice pre-treated with MDMA. After reinstatement, an increase in monoamine levels was observed in mice pre-exposed to EtOH (DA, DOPAC and 5-HT in the striatum and 5-HIAA in the cortex and hippocampus) or MDMA (5-HT in the hippocampus). Basal motor activity and basal levels of corticosterone were not affected by any of these pre-treatments, but the group pre-exposed to MDMA showed higher levels of corticosterone in response to the administration of 10mg/kg of MDMA. Behavioral and hormonal effects of adolescent exposure to MDMA were reversed by co-administration of EtOH. Our results suggest that exposure to EtOH or MDMA during adolescence prolongs the rewarding properties of MDMA. PMID- 21324327 TI - Amylinergic control of food intake in lean and obese rodents. AB - Obesity develops despite a complex and seemingly well orchestrated network that controls eating, energy expenditure and ultimately body weight; many of the involved signals are derived from the gastrointestinal tract. It is assumed that this network as an entity aims at maintaining body weight and body adiposity at a relatively constant level, but the control mechanisms seem to fail at least if an individual is chronically exposed to an oversupply of food. This article summarizes recent findings about the role of amylin in the control of eating in lean and obese rodents. The article gives some short background information about the well investigated adiposity and satiating signals leptin and cholecystokinin, respectively; this will provide the framework to discuss aspects of amylin physiology and pathophysiology in the control of eating in leanness and obesity. This discussion also involves the mechanisms mediating amylin's eating inhibitory effect in the area postrema and the interactions between amylin and leptin. Further, we discuss the effect of high fat diets on amylin release and amylin action in lean and obese rats. The last part of this article raises the question whether amylin interacts with the reward system in the forebrain. PMID- 21324328 TI - Oral fatty acid signaling and intestinal lipid processing: support and supposition. AB - There is increasing recognition that specialized processes once thought to be relatively isolated to the oral cavity (e.g., taste) and intestine (e.g., nutrient absorption) are better characterized as common and continuous. This is exemplified by accumulating evidence linking oral detection of dietary fats to their intestinal processing. This review first summarizes this literature focusing on purported gustatory signaling by free fatty acid stimulation and enterocyte lipid storage and mobilization in humans. It then willfully speculates on the possible functions of this integrated system. It is proposed that it may aid absorption of fat soluble nutrients, enhance acute energy intake, sustain intestinal function during long inter-meal intervals, modulate appetite and/or detoxify ingested compounds including free fatty acids. PMID- 21324329 TI - Pharmacological investigations on adaptation in rats subjected to cold water immersion stress. AB - The present study was designed to investigate whether adaptogenic factors may be transferred from stress adapted rats to naive rats and to explore the nature of endogenous adaptogens by pharmacological modulation. The rats were subjected to cold water immersion stress by placing them individually in a tank of water (depth=15.5cm; temperature=16+/-2 degrees C) for 5min. The rats were subjected to single episode of cold water immersion stress for acute stress; while for adaptation, the rats were subjected to repeated episodes of same stressor for 5 consecutive days. The plasma of stress adapted rats was administered to naive rats before subjecting to acute stress. The stress related behavioral alterations were assessed using the actophotometer, the hole board, the open field and the social interaction tests. Acute stress with single episode of cold water immersion was associated with behavioral alterations. However, the behavioral alterations were significantly restored on subjecting repeated episodes of cold water immersion. Administration of plasma of stress adapted rats also attenuated acute stress associated behavioral alterations. Administration of naltrexone abolished the restoration of behavioral changes as a part of adaptive process in repeated stress subjected rats as well as the anti-stress effects of plasma of stress adapted rat. It may be concluded that opioids may be the potential endogenous adaptogens that tend to restore the homeostasis during repeated episodes of stress. Furthermore, the endogenous adaptogens may be transferred in the form of plasma from repeated stress subjected rats to the naive rats to confer the anti-stress properties. PMID- 21324330 TI - Consumption of cocoa flavanols results in an acute improvement in visual and cognitive functions. AB - Cocoa flavanols (CF) influence physiological processes in ways that suggest their consumption may improve aspects of neural function, and previous studies have found positive influences of CF on cognitive performance. In this preliminary study we investigated whether visual, as well as cognitive, function is influenced by an acute dose of CF in young adults. We employed a randomized, single-blinded, order counterbalanced, crossover design in which 30 healthy adults consumed both dark chocolate containing 720mg CF and a matched quantity of white chocolate, with a one week interval between testing sessions. Visual contrast sensitivity was assessed by reading numbers that became progressively more similar in luminance to their background. Motion sensitivity was assessed firstly by measuring the threshold proportion of coherently moving signal dots that could be detected against a background of random motion, and secondly by determining the minimum time required to detect motion direction in a display containing a high proportion of coherent motion. Cognitive performance was assessed using a visual spatial working memory for location task and a choice reaction time task designed to engage processes of sustained attention and inhibition. Relative to the control condition, CF improved visual contrast sensitivity and reduced the time required to detect motion direction, but had no statistically reliable effect on the minimum proportion of coherent motion that could be detected. In terms of cognitive performance, CF improved spatial memory and performance on some aspects of the choice reaction time task. As well as extending the range of cognitive tasks that are known to be influenced by CF consumption, this is the first report of acute effects of CF on the efficiency of visual function. These acute effects can be explained by increased cerebral blood flow caused by CF, although in the case of contrast sensitivity there may be an additional contribution from CF induced retinal blood flow changes. PMID- 21324331 TI - Gustatory and extragustatory functions of mammalian taste receptors. AB - An ever increasing number of reports about taste receptors in non-gustatory tissues suggest that these molecules must have additional functions apart from taste. Of the extraoral tissues expressing taste receptors, the gastrointestinal tract received particular attention since evidence is mounting that tastants after being ingested might exert important regulatory roles in digestive and metabolic processes. At present, the G protein-coupled taste receptors for sweet, umami and bitter stimuli along with taste-related signaling molecules have been investigated in various parts of the alimentary canal. While the mechanism linking the gastrointestinal activity of sweet compounds via the activation of sweet taste receptors to metabolic adjustments has been worked out in some detail, other taste receptor mediated gastrointestinal activities are less well understood. The present article summarizes current knowledge on mammalian G protein-coupled taste receptors as well as various aspects of their proposed role in gastrointestinal tissues. PMID- 21324332 TI - Time course of behavioral, physiological, and morphological changes after estradiol treatment of ovariectomized rats. AB - Previous studies showed that treatment with 17-beta-estradiol-3-benzoate (EB) reduces isoproterenol (ISOP) stimulated water intake by ovariectomized rats. This effect was observed 48h after the second of two EB injections, suggesting that the attenuation is attributable to classic EB actions to alter gene expression. However, in addition to classic, slowly-occurring, genomic effects, estrogens have more rapidly-occurring effects that may be nongenomic or 'nonclassical' genomic effects. Thus, it is possible that the EB attenuation of water intake stimulated by ISOP is genomic, nongenomic, or both. Accordingly, we measured ISOP induced water intake by OVX rats at different times after EB injections, using time points likely to indicate classic genomic effects (48h or 24h) or nonclassical genomic or nongenomic effects (90min). We also examined EB effects on body weight, uterine weight, and plasma volume and Na(+) concentration in the same animals using the same time points and EB dose. EB treatment decreased water intake stimulated by ISOP in both the 24-h and 48-h groups; however, water intake in the 90-min group was not affected by EB. Uterine weight was unchanged 90min after EB, but was increased 24h after the first injection of EB. In contrast, body weight decreased after EB, but not until 48h after the second EB injection. Finally, EB did not alter plasma Na(+) concentration or hematocrit, though plasma protein concentration increased transiently 24h after EB treatment. Taken together, these findings suggest that the behavioral, morphological, and physiological effects of EB likely are attributable to slowly-occurring, classic genomic actions of estrogens. Moreover, the time course of the observed effects varied, suggesting tissue-specific differences in estrogen receptor density or subtype, or in co-activators or co-repressors that, ultimately, determine the timing and direction of EB effects. PMID- 21324333 TI - Sex differences in high fat-induced obesity in rats: Effects of 18 methoxycoronaridine. AB - Evidence suggests that the development of diet-induced obesity in males and females might be mediated by distinct mechanisms, warranting different treatment approaches. In previous studies from this laboratory, a high sucrose diet induced excessive weight gain in female but not in male Sprague-Dawley rats, while weight gain in both sexes was similarly attenuated by the administration of a selective antagonist of alpha3beta4 nicotinic receptors, 18-methoxycoronaridine (18-MC). In the present study, assessment of high-fat induced weight gain, consummatory behavior and biochemical markers of obesity was conducted in male and female Sprague-Dawley rats and the effects of 18-MC treatment were compared in the two sexes. Male rats consuming a high-fat (HF) diet developed excessive weight gain and fat deposition compared to same same-sex controls fed with a low-fat (LF) diet. The development of obesity in these rats was attenuated by repeated administration of 18-MC (20mg/kg, i.p.), which significantly reduced their food intake without altering water intake. In contrast, female rats consuming a HF diet did not become obese and did not respond to 18-MC treatment. These results show that males and females are differentially responsive to HF-induced obesity; the 18-MC data suggest that alpha3beta4 nicotinic receptors may participate in maintaining obesity, possibly becoming a new and important target for anti obesity agents. PMID- 21324334 TI - The application of 3D representations in face recognition. AB - Most current psychological theories of face recognition suggest that faces are stored as multiple 2D views. This research aims to explore the application of 3D face representations by means of a new paradigm. Participants were required to match frontal views of faces to silhouettes of the same faces. The formats of the face stimuli were modified in different experiments to make 3D representations accessible (Experiments 1 and 2) or inaccessible (Experiment 3). Multiple 2D view based algorithms were not applicable due to the singularity of the frontal-view faces. The results disclosed the application and adaptability of 3D face representations. Participants can readily solve the tasks when the face images retain the information essential for the formation of a 3D face representations. However, the performance substantially declined when the 3D information in faces was eliminated (Experiment 3). Performance also varied between different face orientations and different participant groups. PMID- 21324335 TI - Motion psychophysics: 1985-2010. AB - This review traces progress made in the field of visual motion research from 1985 through to 2010. While it is certainly not exhaustive, it attempts to cover most of the major achievements during that period, and speculate on where the field is heading. PMID- 21324336 TI - Grasping the non-conscious: preserved grip scaling to unseen objects for immediate but not delayed grasping following a unilateral lesion to primary visual cortex. AB - Patients with damage to primary visual cortex can sometimes direct actions towards 'unseen' targets located in areas of the visual field that are deemed 'blind' on the basis of static perimetry tests. Here, we show that a patient with a complete right homonymous hemianopia after a V1 lesion remains sensitive to the width of objects presented in her blind field but only when reaching out to grasp them in 'real-time'. A subsequent fMRI experiment revealed spared extra geniculostriate pathways, which may mediate her preserved abilities. Taken together, the results support the view that visually guided movements can be mediated by pathways that do not support visual consciousness. PMID- 21324337 TI - Effects of occupational and educational changes on obesity trends in France: the results of the MONICA-France survey 1986-2006. AB - OBJECTIVE: In the past decade, the obesity prevalence in France steadily increased. In the meantime the occupational and educational status of the population improved. This study examined the impact of these changes on obesity trends in France. METHODS: In the MONICA-France surveys in 1986, 1996 and 2006, 5423 men and 5271 women (35-64 yr old) were randomly recruited from electoral rolls in three areas of France (northern, eastern and south-western). We used a logistic regression to assess the association between obesity and time and occupational/educational categories and their interactions and a counterfactual analysis to assess the contributions of occupational and educational changes to obesity trends. RESULTS: Between 1986 and 2006, the prevalence of obesity rose from 15.0% to 18.4% (p < 0.004) in men and remained stable between 15.9% and 17.2% (p = 0.72) in women. Obesity increased in all occupational categories only in men (men: p = 0.0005; women: p < 0.22) and all educational categories in both genders (p < 0.0001). The estimated contributions of occupational (educational) changes to obesity trends were -0.3% (-2.8%) in men and -1.9% (-4.6%) in women. CONCLUSION: The improvement in the French population's occupational status and educational level between 1986 and 2006 tended to reduce the impact of secular trends on the obesity prevalence. PMID- 21324338 TI - Integrative, xylE-based promoter probe vectors for use in Streptomyces. AB - Two promoter probe plasmid vectors, designated pIPP1 and pIPP2, were constructed from the existing plasmids pXE4 and pSET152. pIPP1 and 2 use the xylE gene of Pseudomonas putida as a reporter and can be transferred to streptomycetes by conjugation from Escherichia coli. The function of these plasmids as promoter probes was demonstrated in Streptomyces antibioticus and Streptomyces coelicolor using the phenoxazinone synthase and polynucleotide phosphorylase promoters from S. antibioticus. xylE activity could be detected in colonies on agar plates or via the in vitro assay for catechol dioxygenase. The integration into the S. antibioticus chromosome of the constructs containing the phsA promoter was verified by Southern blotting. The presence of the bla locus in pIPP1 allows the recovery of putative promoters by marker rescue. PMID- 21324339 TI - Sequence analysis of a group of low molecular-weight plasmids carrying multiple IS903 elements flanking a kanamycin resistance aph gene in Salmonella enterica serovars. AB - A group of low molecular-weight ColE1-like plasmids carrying the aph sequence type aph(ii) from three different Salmonella serovars were sequenced. These plasmids carry two or more copies of IS903 elements, with up to 21bp sequence differences to one another, two of which flank the aph gene. This group of plasmids did not appear to carry any known mobilization genes and instead carry three open reading frames encoding hypothetical proteins of unknown function possibly organized in an operon. The plasmid replication region (RNA I/II--rom) of this plasmid group showed extensive homology to that of pKPN2 plasmid of Klebsiella pneumoniae and pCol-let plasmid of Escherichia coli. Three of the four plasmids had identical sequences, and the fourth had an extra copy of IS903 with target duplication, suggesting a recent divergence in the different Salmonella serovars from a common ancestor. PMID- 21324340 TI - Reduction of antibody response against botulinum neurotoxin A by synthetic monomethoxypolyethylene glycol-peptide conjugates. AB - Recently, we determined the molecular locations on BoNT/A of the antigenic regions recognized by blocking Abs of cervical dystonia patients immunoresistant to BoNT/A treatment. In the present work we tested the possibility of reducing the levels of the Ab response against immunodominant antigenic sites on the heavy chain of BoNT/A in order to diminish immunoresistance caused by blocking Abs. Four antigenic regions on BoNT/A represented by peptides N8 (residues 547-565), N25 (785-803), C15 (1051-1069) and C31 (1275-1296) were tested for suppressing Ab responses against the correlate regions. The conjugates were synthesized with monomethoxypolyethylene glycol (mPEG) attached to the peptide N-termini. Tolerization with a given mPEG-peptide reduced the Ab levels against the correlate region and the antisera became less protective than antisera of untolerized controls that were immunized only with inactive BoNT/A. On days 31 and 52 in the immunization course mPEG-N8 was most effective and the antisera of tolerized mice were weaker and less protective relative to controls. Other mPEG peptides were also suppressed the Ab responses to various extents. Bleeds up to 5 months showed that tolerization can be made to persist for the entire period. The results indicated that the tolerization procedure might be potentially useful for clinical applications to immunoresistant patients. PMID- 21324341 TI - CD160: a unique activating NK cell receptor. AB - Here we discuss CD160 an essential NK cell activating receptor that remains poorly understood. CD160 receptor exhibits a number of unique structural and functional characteristics that are not common to other killer immunoglobulin like receptors that recognize major histocompatibility complex (MHC) class I molecules: (1) In addition to humans and mice, the cd160 gene is conserved in several other mammal species; (2) cd160 is located outside the NK gene complex and the Leukocyte Receptor Complex in humans; (3) CD160 expression is associated to the CD56(dim) CD16+ cytotoxic NK cell phenotype; (4) both human and mouse CD160 recognize MHC class Ia and Ib molecules; (5) unlike the other MHC class I dependent activating NK receptors, CD160 is a glycosylphosphatidylinositol anchored molecule with a single immunoglobulin-like domain, and does not bear immunoreceptor tyrosine-based activation motifs. Consequently, CD160 cannot signal by itself, requiring the recruitment of adaptor proteins. CD160 recruits phosphoinositide-3 kinase to trigger cytotoxicity and cytokine secretion; (6) specific engagement of NK CD160 receptor expressed by circulating NK cells produces proinflammatory cytokines IFN-gamma, TNF-alpha, and, most notably, IL-6 and IL-8 as well as MIP1-beta chemokine. The level of CD160-mediated IFN-gamma production is always higher than the one observed after engagement of the CD16 receptor. PMID- 21324342 TI - Insights into the B cell specific process of immunoglobulin class switch recombination. AB - Antibody maturation leads to the formation of B cell receptors (BCRs) with high affinity for antigen and the production of different Ig isotypes. The different antibody isotypes vary in activities (half-life, binding to Fc receptors, ability to activate the complement system) and tissue localization and thus are necessary for an optimal humoral response against pathogens. The molecular mechanism responsible for exchanging the Ig isotypes (IgM to IgG, IgA, or IgE) and at the same time retaining the antigen specificity and affinity is called Ig class switch recombination (CSR). In this review we discuss the molecular mechanism of CSR, with special focus on the enzyme activation induced cytidine deaminase (AID). PMID- 21324343 TI - Cytofluorimetric evaluation of N-glycolylated GM3 ganglioside expression on murine leukocytes. AB - Gangliosides are considered relevant components of lipid rafts at the plasma membrane. Antigen encounter, immunological synapse assembly and signal transduction modify lipid raft composition and distribution on immune system cells. On the contrary of other gangliosides, differential expression of the N glycolylated variant of GM3 (NGcGM3) on murine leukocytes has received limited attention. In particular, whether cell activation modulates the expression of NGcGM3 on lymphoid and myeloid cells is still unexplored. Availability of the NGcGM3 specific 14F7 MAb allows us to characterize by cytofluorimetric assays the presence of this molecule on resting and activated immune system cells. On T cells, preferential expression of NGcGM3 was detected on CD4(+) single positive thymocytes, peripheral CD4(+) lymphocytes and natural occurring regulatory T cells. In comparison with peritoneal B1 cells, reduced expression of NGcGM3 was observed in peritoneal B2 and splenic B cell subpopulations. Of note, activation of CD4(+) and NK 1.1(+) cells abrogated NGcGM3 expression while LPS-maturated DC increased the ganglioside level at the plasma membrane. Modifications on the presence of NGcGM3 mediated by cell activation did not influence the expression of the N-acetylated variant of GM3 (NAcGM3). In addition to extend previous descriptions of NGcGM3 expression on immunity cell subpopulations, this work highlights the opposite effect of cellular activation over NGcGM3 levels on lymphoid and myeloid cellular series. Obtained results complement the evaluation of a tumor-specific, non-human sialic acid containing ganglioside that has been considered an attractive target for cancer immunotherapy. PMID- 21324344 TI - Protective immunity against Chlamydia trachomatis genital infection induced by a vaccine based on the major outer membrane multi-epitope human papillomavirus major capsid protein L1. AB - The administration of an efficacious vaccine is the most effective long-term measure to control the genital tract infection caused by Chlamydia trachomatis (Ct) in humans. The current challenge for Ct vaccine development is to develop an effective delivery vehicle for induction of a high level of mucosal T and complementary B cell responses. We evaluated the immunogenicity and efficacy of a candidate vaccine comprising the major outer membrane protein (MOMP) multiepitope of Ct delivered with the human papillomavirus (HPV) major capsid protein L1 as a vehicle with adjuvant properties, in a murine model of chlamydial genital infection. A recombinant plasmid pcDNA3.1(+) containing mammalian codon optimization HPV6b L1 gene and Ct MOMP multiepitope was constructed. The Ct MOMP multiepitope containing T- and B-cell epitope-rich peptides was inserted into C terminal of HPV6b L1-coding sequence. The constructed plasmid after verified by enzyme restriction assay and DNA sequencing was transfected into COS-7 cells. Expression of the chimeric gene in COS-7 cells was confirmed by RT-PCR, Western blot analysis and immunofluorescence assay. Results revealed successful expression of the chimeric HPV6b L1/Ct MOMP multiepitope gene both at the mRNA and protein levels in transfected COS-7 cells. Intramuscular (IM) administration in mice was able to elicit not only antibodies against Ct MOMP, but also Th1 and cytotoxic T lymphocyte activity against the Ct MOMP epitopes. In addition, recipients of IM immunization of HPV6b L1/Ct MOMP multiepitope were highly resistant to infection. Altogether, the results suggested that IM delivery of HPV6b L1-MOMP multiepitope may be a suitable vaccine regimen potentially capable of inducing protective mucosal immunity against Ct infection. PMID- 21324345 TI - Basic aminopeptidase activity is an emerging biomarker in collagen-induced rheumatoid arthritis. AB - The objective of this study was to investigate the catalytic activity of basic aminopeptidase (APB) and its association with periarticular edema and circulating tumor necrosis factor (TNF)-alpha and type II collagen (CII) antibodies (AACII) in a rat model of rheumatoid arthritis (RA) induced by CII (CIA). Edema does not occur in part of CII-treated, even when AACII is higher than in control. TNF alpha is detectable only in edematous CII-treated. APB in synovial membrane is predominantly a membrane-bound activity also present in soluble form and with higher activity in edematous than in non-edematous CII-treated or control. Synovial fluid and blood plasma have lower APB in non-edematous than in edematous CII-treated or control. In peripheral blood mononuclear cells (PBMCs) the highest levels of APB are found in soluble form in control and in membrane-bound form in non-edematous CII-treated. CII treatment distinguishes two categories of rats: one with arthritic edema, high AACII, detectable TNF-alpha, high soluble and membrane-bound APB in synovial membrane and low APB in the soluble fraction of PBMCs, and another without edema and with high AACII, undetectable TNF-alpha, low APB in the synovial fluid and blood plasma and high APB in the membrane-bound fraction of PBMCs. Data suggest that APB and CIA are strongly related. PMID- 21324346 TI - Expression of antimicrobial peptides and proteins in etanercept-treated psoriasis patients. AB - Recent papers highlight the role of dysregulated expression of antimicrobial peptides and proteins (AMPs) in the pathogenesis of psoriasis. Etanercept, a blocker of the pro-inflammatory cytokine tumour necrosis factor-alpha (TNF alpha), is effective in the treatment of psoriasis. We aimed to evaluate the expression profiles of AMPs in psoriatic skin before and after a 6-week course of etanercept therapy. We included 12 psoriasis patients who underwent medium-dose etanercept treatment for 6weeks. At baseline and at the end of therapy immunohistochemistry from lesional skin was performed for psoriasin, LL-37, and human beta-defensin 2 (hBD-2). After 6-week treatment, the modified psoriasis area and severity index significantly decreased from 37.5+/-5.9 to 14+/-13.4. Lesional immunoreactivity scores of psoriasin, LL-37, and hBD-2 also significantly decreased after a 6-week course of etanercept. We have demonstrated that etanercept-induced improvement of psoriasic lesions is associated with a significant decline of AMP protein expression. PMID- 21324347 TI - beta-Endorphinergic system involvement in the inhibitory action of clonidine on induced sodium appetite. AB - In the present study, we investigated the degree to which beta-endorphin plays a role in the alpha 2-adrenergic/imidazoline receptor agonist attenuation of salt appetite. In order to evaluate whether the inhibitory action of clonidine (an alpha2-adrenergic/imidazoline receptor agonist) on induced sodium intake is mediated by the beta-endorphinergic system, we used a beta-endorphin deficient mouse line. beta-endorphin knockout (betaend(-/-)), heterozygous (betaend(+/-)) and wild-type (betaend(+/+)) mice were submitted to acute sodium depletion by a combined treatment of furosemide and low sodium diet and, 20h later, were administered with clonidine (0.5mg/kg). An hour later, the animals were subjected to a two-bottle choice test (water/2% NaCl). The results indicate that clonidine administration during the first stage of the test exerts an equivalent inhibition on sodium intake regardless of the genotype; however, in the final stage of the test, a reversal of the inhibitory response on induced sodium appetite becomes evident in the mice lacking beta-endorphin. Moreover no differences in dipsogenic response were observed between the genotypes. Considering these results and the fact that plasma half-life of clonidine at the dose administered is approximately 3h, it is possible to speculate that the inhibitory effect of clonidine on sodium appetite may be independent of beta-endorphin modulation during the first stage; however, the long-lasting inhibitory effect of clonidine may be mediated by the beta-endorphinergic system. This evidence supports the existence of adrenergic and beta-endorphinergic system interaction in the osmoregulatory response to achieve sodium balance. PMID- 21324348 TI - Propidium monoazide combined with real-time quantitative PCR underestimates heat killed Listeria innocua. AB - The combination of propidium monoazide (PMA) and quantitative real-time PCR (qPCR) significantly overestimated the fraction of viable Listeria innocua as compared to plate counts and confocal fluorescence microscopy. Our data imply that PMA-qPCR must be used with caution as an analytical tool for the differentiation between viable and dead bacteria. PMID- 21324349 TI - Behavioral, neuropsychiatric and cognitive disorders in Parkinson's disease patients with and without motor complications. AB - BACKGROUND: Parkinson's disease (PD), commonly defined as a hypokinetic movement disorder, is hampered by the appearance of motor complications (MC), including dyskinesias and motor fluctuations, and non-motor symptoms such as behavioral, neuropsychiatric and cognitive disorders, which, in the last years, are gaining increasing attention. The factors affecting MC and these non-motor symptoms are still largely unknown and their interactions are not yet fully evaluated. OBJECTIVE: To identify the presence of behavioral, neuropsychiatric and cognitive disorders in PD patients with and without MC and to evaluate their association with MC. METHODS: Consecutive PD patients received a comprehensive structured clinical evaluation including pharmacologic treatment, MC and non-motor symptoms such as reward-seeking behaviors, neuropsychiatric symptoms (depression, anxiety, psychoses and hallucinations) and dementia. RESULTS: 349 patients were included in this analysis. Patient with MC showed enhanced frequency of dementia (p < 0.001), anxiety, depression and psychoses (p < 0.01). A higher frequency of impulse control disorders was detected in patients with dyskinesias (22.2% - p < 0.001) and motor complications (12.2% - p < 0.05). Dyskinesias were significantly more present in patients with hypersexuality (p < 0.05) and compulsive shopping (p < 0.001), while they were not significantly associated with pathological gambling and binge eating. Patients with dyskinesias also had significantly higher frequency of dopamine dysregulation syndrome, hallucinations and delusions (p < 0.001), with the exception of delusional jealousy. DISCUSSION: We found a higher frequency of behavioral, neuropsychiatric and cognitive disorders in patients with MC. The lack of detection of dyskinesias in several PD patients with pathological gambling in our study represents a very interesting issue. While binge eating mainly seems to be related to the use of dopamine agonists, the significant lack of association between dyskinesias and delusional jealousy suggests the hypothesis of a possible underlying psychopathological predisposition rather than a mere pharmacologic effect in PD patients with these behavioral complications. PMID- 21324350 TI - No evidence of morphine analgesia to noxious shock in the shore crab, Carcinus maenas. AB - A number of criteria have been suggested for testing if pain occurs in animals, and these include an analgesic effect of opiates (Bateson, 1991). Morphine reduces responses to noxious stimuli in crustaceans but also reduces responsiveness in a non-pain context. Here we use a paradigm in which shore crabs receive a shock in a preferred dark shelter but not if they remain in an unpreferred light area. Analgesia should thus enhance movement to the preferred dark area because they should not experience 'pain'. However, morphine inhibits rather than enhances this movement even when no shock is given. Morphine produces a general effect of non-responsiveness rather than a specific analgesic effect and this could also explain previous studies claiming analgesia. However, we question the utility of this criterion of pain and suggest instead that behavioural criteria be employed. PMID- 21324351 TI - A novel common triplet profile for GC-rich prokaryotic genomes. PMID- 21324352 TI - Minocycline reduces glioma expansion and invasion by attenuating microglial MT1 MMP expression. AB - Glioma cells release soluble factors, which induce the expression of membrane type 1 matrix metalloprotease (MT1-MMP) in tumor associated microglia and then exploit MT1-MMP mediated matrix degradation for invasion. Here, we show that minocycline blocked the increase in MT1-MMP expression and activity in cultivated microglia stimulated with glioma conditioned medium. Glioma growth within an organotypic brain slice preparation was reduced by minocycline and this reduction depended on the presence of microglia. Glioma growth in an experimental mouse model was strongly reduced by the addition of minocycline to drinking water, compared to untreated controls. Coherently, we observed in our orthotopic glioma implantation model, that MT1-MMP was abundantly expressed in glioma associated microglia in controls, but was strongly attenuated in tumors of minocycline treated animals. Overall, our study indicates that the clinically approved antibiotic minocycline is a promising new candidate for adjuvant therapy against malignant gliomas. PMID- 21324353 TI - Class B scavenger receptor, Croquemort from kuruma shrimp Marsupenaeus japonicus: Molecular cloning and characterization. AB - The scavenger receptor, Croquemort is a member of the CD36 superfamily comprising transmembrane proteins involved in the recognition of polyanionic ligands. Various researchers have proved that members of the CD36 superfamily are involved in immunity and developmental processes. In the present study, we report a cDNA encoding the kuruma shrimp, Marsupenaeus japonicus Croquemort scavenger receptor (MjSCRBQ) obtained from a cDNA library of lymphoid organ by RACE amplification. The full-length cDNA of 2098 bp consists an open reading frame of 1596 nucleotides that translates into a 532-amino acid putative protein, with a 5' untranslated region of 323 bp and 3' UTR of 153 bp. The MjSCRBQ is constitutively expressed in gills, heart, hemolymph, hepatopancreas, intestine, lymphoid organ, muscle, nerve, and stomach and at high levels in the brain. Expression analysis in lymphoid organs of shrimp infected with white spot syndrome virus (WSSV) revealed high levels of MjSCRBQ 72 and 120 h post-infection. The MjSCRBQ contains putative functional domains including transmembrane domains and a CD36 domain. Multiple alignments of MjSCRBQ amino acid sequences showed significant identity with Drosophila melanogaster SCRBQ (31%), Salmo salar SCRBQ (29%), Homo sapiens SCRBQ (28%) and Rattus norvegicus SCRBQ (30%). In a phylogenetic analysis, MjSCRBQ was identified in the invertebrate scavenger receptor cluster. This is the first report in crustaceans of the identification and characterization of a Croquemort scavenging receptor. PMID- 21324354 TI - A novel approach for analyzing glass-transition temperature vs. composition patterns: application to pharmaceutical compound+polymer systems. AB - In medicine, polymer-based materials are commonly used as excipients of poorly water-soluble drugs. The success of the encapsulation, as well as the physicochemical stability of the products, is often reflected on their glass transition temperature (T(g)) vs. composition (w) dependencies. The shape of the T(g)(w) patterns is critically influenced by polymer's molecular mass, drug molecule's shape and molecular volume, the type and degree of shielding of hydrogen-bonding capable functional groups, as well as aspects of the preparation process. By altering mixture's T(g) the amorphous solid form of the active ingredient may be retained at ambient or body temperatures, with concomitant improvements in handling, solubility, dissolution rate and oral bioavailability. Given the importance of the problem, the glass transitions observed in pharmaceutical mixtures have been extensively analyzed, aiming to appraise the state of mixing and intermolecular interactions. Here, accumulated experimental information on related systems is re-evaluated and comparably discussed under the light of a more effective and system-inclusive T(g)(w) equation. The present analysis indicates that free volume modifications and conformational changes of the macromolecular chains dominate, over enthalpic effects of mixing, in determining thermal characteristics and crystallization inhibition/retardation. Moreover, hydrogen-bonding and ion-dipole heterocontacts--although favorable of a higher degree of mixing--appear less significant compared to the steric hindrances and the antiplasticization proffered by the higher viscosity component. PMID- 21324355 TI - Thermoresponsive polymeric radionuclide delivery system--an injectable brachytherapy. AB - Brachytherapy is of increasing popularity in clinical oncology for the local therapy of solid tumors due to high radiation doses delivered to malignant tissue while keeping the whole-body radiation burden low. Pronounced dose-dependent tumor growth reduction was achieved by single dose of injectable intratumoral brachytherapy with iodine-131-labeled thermoresponsive polymer [poly(N-isopropyl acrylamide)] in murine xenograft model (PC3 human prostate adenocarcinoma). The two doses of radionuclide were used, 2 MBq/mouse and 25 MBq/mouse. The higher dose caused gradual tumor volume reduction and 2 of 6 mice from this group were cured. The lower dose caused tumor growth retardation only. In both cases there were no signs of inflammation. The effects of both doses were statistically significant compared to untreated controls. Such injectable system should keep advantages of brachytherapy while making system administration easier and less invasive (injection instead of implantation), patient-tailored (splitting of doses into several depoes) and bioerodable. PMID- 21324356 TI - A new respirable form of rifampicin. AB - The aim of this research was to investigate a novel dry powder formulation of rifampicin (RF) that presents an improved lung deposition profile by means of a polymorphic transformation into a flake-like crystal hydrate. Rifampicin dihydrate (RFDH) was prepared by recrystallization of RF in anhydrous ethanol. A control formulation, amorphous RF (RFAM) was prepared by spray drying. The physicochemical properties of the RFDH and the RFAM were characterized. Aerosol performances of RFDH and RFAM were studied with two dry powder inhalers (DPIs), an Aerolizer and a Handihaler, using a Next Generation Impactor (NGI). The RFDH powder was successfully prepared using simple recrystallization process and had a MMAD of 2.2 MUm. The RFDH powders were characterized as having a very thin flaky structure; this unique morphology provided improved aerosolization properties with a decreased device dependency upon aerosolization. The flaky morphology of RFDH resulted in a reduced agglomeration tendency than that of spherical RFAM particles. The maximum fine particle fraction (FPF(TD)) of 68% for the RFDH was achieved with the Aerolizer device. Significant chemical degradation was not observed from the RFDH, while the RFAM showed significant chemical degradation at 9 months. The excipient-free formulation of the RFDH offers the benefit of delivering a maximum potency formulation, of the antibiotic, directly to the site of infection, the lung. PMID- 21324357 TI - Orally disintegrating mini-tablets (ODMTs)--a novel solid oral dosage form for paediatric use. AB - The new European regulations on paediatric medicines and recent WHO recommendations have induced an increased need for research into novel child appropriate dosage forms. The aim of this study was the development of orally disintegrating mini-tablets (ODMTs) as a suitable dosage form for paediatric patients. The suitability of five commercially available ready-to-use tableting excipients, Ludiflash, Parteck ODT, Pearlitol Flash, Pharmaburst 500 and Prosolv ODT, to be directly compressed into mini-tablets, with 2 mm in diameter, was examined. All of the excipients are based on co-processed mannitol. Drug-free ODMTs and ODMTs with a child-appropriate dose of hydrochlorothiazide were investigated. ODMTs could be produced with all investigated excipients. ODMTs with a sufficient crushing strength >7 N and a low friability <1% could be obtained, as well as ODMTs with a short simulated wetting test-time <5 s. ODMTs made of Ludiflash showed the best results with crushing strengths from 7.8 N up to 11.8 N and excellent simulated wetting test-times from 3.1 s to 5.0 s. For each excipient, ODMTs with accordance to the pharmacopoeial specification content uniformity could be obtained. The promising results indicate that orally disintegrating mini-tablets may serve as a novel platform technology for paediatrics in future. PMID- 21324358 TI - Identification of a cis-regulatory element that directs prothoracicotropic hormone gene expression in the silkworm Bombyx mori. AB - In the silkworm Bombyx mori and other insects, prothoracicotropic hormone (PTTH) plays a central role in controlling molting and metamorphosis by stimulating the prothoracic glands to synthesize and release the molting hormone ecdysone. Using an AcNPV (Autographa californica nucleopolyhedrovirus)-mediated transient gene transfer system, we identified a cis-regulatory element that participates in the decision to switch expression of PTTH on or off in PTTH-producing neurosecretory cells (PTPCs). The nucleotide sequence of this cis-regulatory element is similar to a cis-regulatory element that participates in direction of expression of diapause hormone-pheromone biosynthesis activating neuropeptide gene (DH-PBAN) (Shiomi et al., 2007). Furthermore, we found that B. mori Pitx (BmPitx), a bicoid like homeobox transcription factor, binds the element and activates PTTH expression. Therefore, we propose that the cell-specific expression of two neuropeptide hormone genes, PTTH and DH-PBAN, is activated by the Pitx transcription factor, which may act as a pan-activator in the insect neuroendocrine system and in vertebrate pituitary cells. PMID- 21324359 TI - Cytochrome P450 6M2 from the malaria vector Anopheles gambiae metabolizes pyrethroids: Sequential metabolism of deltamethrin revealed. AB - Resistance to pyrethroid insecticides in the malaria vector Anopheles gambiae is a major threat to malaria control programmes. Cytochome P450-mediated detoxification is an important resistance mechanism. CYP6M2 is over-expressed in wild populations of permethrin resistant A. gambiae but its role in detoxification is not clear. CYP6M2 was expressed in Escherichia coli and a structural model was produced to examine its role in pyrethroid metabolism. Both permethrin and deltamethrin were metabolized. Rates were enhanced by A. gambiae cytochrome b(5) with kinetic parameters of K(M)=11+/-1MUM and k(cat)=6.1+/-0.4 per min for permethrin (1:1 cis-trans) and K(M)=2.0+/-0.3MUM and k(cat)=1.2+/-0.1 per min for deltamethrin. Mass spectrometry and NMR analysis identified 4' hydroxy deltamethrin and hydroxymethyl deltamethrin as major and minor deltamethrin metabolites respectively. Secondary breakdown products included cyano(3-hydroxyphenyl)methyl deltamethrate and deltamethric acid. CYP6M2 was most highly transcribed in the midgut and Malpighian tubules of adult A. gambiae, consistent with a role in detoxification. Our data indicates that CYP6M2 plays an important role in metabolic resistance to pyrethroids and thus an important target for the design of new tools to combat malaria. PMID- 21324360 TI - Paradoxical function of orexin/hypocretin circuits in a mouse model of Huntington's disease. AB - Huntington's disease (HD) is a neurodegenerative disorder involving progressive motor disturbances, cognitive decline, and desynchronized sleep-wake rhythms. Recent studies revealed that restoring normal sleep-wake cycles can improve cognitive function in HD mice, suggesting that some sleep/wake systems remain operational and thus represent potential therapeutic targets for HD. Hypothalamic neurons expressing orexins/hypocretins (orexin neurons) are fundamental orchestrators of arousal in mammals, but it is unclear whether orexin circuits operate normally in HD. Here we analyzed the electrophysiology, histology, and gene expression of orexin circuits in brain slices from R6/2 mice, a transgenic model of HD with a progressive neurological phenotype. We report that in R6/2 mice, the size of an electrically distinct subpopulation of orexin neurons is reduced, as is the number of orexin-immunopositive cells in some hypothalamic regions. R6/2 orexin cells display altered glutamatergic inputs, and have an abnormal circadian profile of activity, despite normal circadian rhythmicity of the suprachiasmatic nucleus (SCN), the "master clock" of the brain. Nevertheless, even at advanced stages of HD, intrinsic firing properties of orexin cells remain normal and suppressible by serotonin, noradrenaline, and glucose. Furthermore, histaminergic neurons (key cells required for the propagation of orexin-induced arousal) also display normal responses to orexin. Together, these data suggest that the orexin system remains functional and modifiable in HD mice, although its circadian activity profile is disrupted and no longer follows that of the SCN. PMID- 21324361 TI - "Brain training" improves cognitive performance and survival in a transgenic mouse model of Huntington's disease. AB - Environmental enrichment (EE) has been shown to improve neurological function and cognitive performance in animal models of Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). We have shown recently that even when they are already living in an enriched environment, additional EE had beneficial effects in R6/2 mice. Here we examined the effects of three different enrichment paradigms on cognitive dysfunction in R6/2 mice in a longitudinal study. The EE consisted of either enforced physical exercise on the Rotarod (predominantly motor stimulation), training in a novel type of maze, the 'noughts and crosses' (OX) maze (mainly cognitive stimulation), or access to a playground, that gave the mice the opportunity for increased, self-motivated activity using running wheels and other toys in a social context (mixed EE). We designed the OX maze to test spatial memory in the R6/2 mouse while minimizing motor demands. Control mice remained in their home cages during the training period. Mice were given enrichment between 6 and 8 weeks of age, followed by cognitive (Lashley maze) and motor testing (Rotarod) between 8 and 10 weeks. Mice were then given a further period of enrichment between 10 and 12 weeks, and their behavior was re tested between 12 and 14 weeks of age. We also collected body weights and age at death from all mice. The OX maze was as sensitive for detecting learning deficits in the R6/2 mice as other types of mazes (such as the Morris water maze). Interestingly, providing cognitive stimulation via training in the OX maze produced significant improvements in subsequent cognitive performance by male, but not female, R6/2 mice in the Lashley maze task. OX maze training also significantly improved loss of body weight and survival in male R6/2 mice. These effects became apparent after as little as 2 weeks of training in the OX maze. These data suggest that there is a cognitive reserve that may be exploited in neurodegenerative disease. While brain training was not beneficial for all mice, it produced no deleterious effects, and so warrants further study in rodent models of HD. PMID- 21324362 TI - Differential regional distribution of phosphorylated tau and synapse loss in the nucleus accumbens in tauopathy model mice. AB - Tauopathies differ in terms of the brain regions that are affected. In Alzheimer's disease, basal forebrain and hippocampus are mainly involved, while frontotemporal lobar degeneration affects the frontal and temporal lobes and subcortical nuclei including striatum. Over 90% of human cases of tauopathies are sporadic, although the majority of established tau-transgenic mice have had mutations. This prompted us to establish transgenic mice expressing wild-type human tau (Tg601). Old (>14 months old) Tg601 mice displayed decreased anxiety in the elevated plus maze test and impaired place learning in the Morris water maze test. Immunoblotting of brain tissue identified that soluble tau multimer was increased with aging even though insoluble tau was not observed. In the striatum of old Tg601, the level of AT8- or AT180-positive tau was decreased compared with that of other regions, while PHF-1-positive tau levels remained equal. Phosphorylated tau-positive axonal dilations were present mainly in layers V and VI of the prefrontal cortex. Loss of synaptic dendritic spine and decreased immunohistochemical level of synaptic markers were observed in the nucleus accumbens. In vivo 2-[(18)F]fluoro-2-deoxy-d-glucose positron emission tomography analysis also showed decreased activity exclusively in the nucleus accumbens of living Tg601 mice. In Tg601 mice, the axonal transport defect in the prefrontal cortex-nucleus accumbens pathway may lead to decreased anxiety behavior. Differential distribution of hyperphosphorylated tau may cause region-specific neurodegeneration. PMID- 21324363 TI - Differential impact of diabetes and hypertension in the brain: adverse effects in white matter. AB - Humans subjected to diabetes mellitus (DM) and/or hypertension (HTN) develop cognitive decline, cerebral atrophy and white matter abnormalities, but the relative effects of DM and HTN upon myelin and axonal integrity is unknown. We studied models of Type 1 (streptozotocin-induced) and Type 2 DM (ZDF) +/- HTN (ZSF-1, SHR) in adult rats using magnetic resonance imaging (MRI) and structural and molecular techniques. Type 1 or 2 DM independently led to loss of myelin associated with changes with MRI T2 and magnetization tensor ratios throughout white matter regions. HTN's effect on myelin loss was minimal. Loss of oligodendroglia and myelin proteins was only identified in either Type 1 or Type 2 DM. Activation of the signal transduction pathways initiated by the receptor for advanced glycation end products (AGEs), RAGE, including upregulation of the signal transducer nuclear factor (NF) kappaB only occurred with DM. Diabetes is a greater contributor to white matter loss than hypertension in the rat brain, while hypertension only plays a mild additive effect upon neurodegeneration in the presence of diabetes. PMID- 21324364 TI - Adult neural precursors isolated from post mortem brain yield mostly neurons: an erythropoietin-dependent process. AB - This study was aimed at the isolation of neural precursor cells (NPCs) capable of resisting to a prolonged ischemic insult as this may occur at the site of traumatic and ischemic CNS injuries. Adult mice were anesthetized and then killed by cervical dislocation. The cadavers were maintained at room temperature or at 4 degrees C for different time periods. Post mortem neural precursors (PM-NPCs) were isolated, grown in vitro and their differentiation capability was investigated by evaluating the expression of different neuronal markers. PM-NPCs differentiate mostly in neurons, show activation of hypoxia-inducible factor-1 and MAPK, and express both erythropoietin (EPO) and its receptor (EPO-R). The exposure of PM-NPCs to neutralizing antibodies to EPO or EPO-R dramatically reduced the extent of neuronal differentiation to about 11% of total PM-NPCs. The functionality of mTOR and MAPK is also required for the expression of the neuronal phenotype by PM-NPCs. These results suggest that PM-NPCs can be isolated from animal cadaver even several hours after death and their self-renewable capability is comparable to normal neural precursors. Differently, their ability to achieve a neural phenotype is superior to that of NPCs, and this is mediated by the activation of hypoxia-induced factor 1 and EPO signaling. PM-NPCs may represent good candidates for transplantation studies in animal models of neurodegenerative diseases. PMID- 21324365 TI - Efficient expression and purification of methyltransferase in acetyl-coenzyme a synthesis pathway of the human pathogen Clostridium difficile. AB - The Wood-Ljungdahl pathway is responsible for acetyl-CoA biosynthesis and used as a major mean of generating energy for growth in some anaerobic microbes. Series of genes, from the anaerobic human pathogen Clostridium difficile, have been identified that show striking similarity to the genes involved in this pathway including methyltetrahydrofolate- and corrinoid-dependent methyltransferase. This methyltransferase plays a central role in this pathway that transfers the methyl group from methyltetrahydrofolate to a cob(I)amide center in the corrinoid iron sulfur protein. In this study, we developed two efficient expression and purification methods for methyltransferase from C. difficile for the first time with two expression vectors MBPHT-mCherry2 and pETDuet-1, respectively. Using the latter vector, more than 50mg MeTr was produced per liter Luria-Bertani broth media. The recombinant methyltransferase was well characterized by SDS-PAGE, gel filtration chromatography, enzyme assay and far-UV circular dichroism (CD). Furthermore, a highly effective approach was established for determining the methyl transfer activity of the methyltetrahydrofolate- and cobalamin-dependent methyltransferase using exogenous cobalamin as a substrate by stopped-flow method. These results will provide a solid basis for further study of the methyltransferase and the Wood-Ljungdahl pathway. PMID- 21324366 TI - Novel approach for transient protein expression in primary cultures of human dental pulp-derived cells. AB - Transfection is a powerful method for investigating variable biological functions of desired genes. However, the efficiency of transfection into primary cultures of dental pulp-derived cells (DPDC) is low. Therefore, using a recombinant vaccinia virus (vTF7-3), which contains T7 RNA polymerase, we have established a transient protein expression system in DPDCs. In this study, we used the human polymeric immunoglobulin receptor (pIgR) cDNA as a model gene. pIgR expression by the vTF7-3 expression system was confirmed by flow cytometry analysis and Western blotting. Furthermore, exogenous pIgR protein localized at the cell surface in DPDCs and formed a secretory component (SC). This suggests that exogenous pIgR protein expressed by the vTF7-3 expression system acts like endogenous pIgR protein. These results indicate the applicability of the method for cells outgrown from dental pulp tissue. In addition, as protein expression could be detected shortly after transfection (approximately 5h), this experimental system has been used intensely for experiments examining very early steps in protein exocytosis. PMID- 21324367 TI - Multi-site voxel-based morphometry--not quite there yet. AB - Voxel-based morphometry (VBM) is a widely applied method in computational neurosciences but it is currently recommended to compare only data collected at a single MRI scanner. Multi-site VBM would be a desirable approach to increase group size and, thus, statistical power. We aimed to assess if multi-site VBM is feasible on similar hardware and compare the magnitude of inter- and intra scanner differences. 18 healthy subjects were scanned in two identical 3T MRI scanners using different head coil designs, twice in scanner A and once in scanner B. 3D T1-weighted images were processed with SPM8 and FSL4.1 and compared as paired t-test (scan versus re-scan) on a voxel basis by means of a general linear model (GLM). Additionally, coefficient-of-difference (coeffD) maps were calculated for respective pairs of gray matter segmentations. We found considerable inter-scanner differences clearly exceeding a commonly used GLM significance threshold of p<0.05 (FWE corrected). The spatial pattern of detected differences was dependent on whether SPM8 or FSL4.1 was used. The inclusion of global correcting factors either aggravated (SPM8) or reduced the GLM detected differences (FSL4.1). The coeffD analysis revealed markedly higher variability within the FSL4.1 stream both for the inter- and the intra-scanner comparison. A lowered bias cutoff (30 mm FWHM) in SPM8 improved the comparability for cortical areas. Intra-scanner scan/re-scan differences were generally weaker and did not exceed a p<0.05 (FWE corrected) threshold in the GLM analysis. At 3T profound inter-scanner differences are to be expected that could severely confound an unbalanced VBM analysis. These are like related to the receive bias of the radio frequency hardware. PMID- 21324368 TI - Effect of radiolabeled metabolite elimination from the brain on the accuracy of cerebral enzyme activity estimation using positron emission tomography with substrate tracers. AB - Cerebral enzyme activity can be quantified using positron emission tomography (PET) in conjunction with a radiolabeled enzyme substrate. We investigated the relationship between the elimination rate (k(el)) of tracer metabolites from the brain and the precision of target enzyme activity estimation (k(3)). An initial simulation study indicated that the precision of k(3) estimates was highly dependent on k(el), and was characterized by several kinetic parameters including the ratio of k(el) and the efflux rate (k(2)) of authentic tracer (beta=k(el)/k(2)). The optimal tracer condition for high sensitivity was found to be beta<0.1. To verify the simulation results, we performed a PET study with a single monkey using two PET tracers, N-[(18)F]fluoroethylpiperidin-4-ylmethyl acetate ([(18)F]FEP-4MA) and N-[(11)C]methylpiperidin-4-yl acetate ([(11)C]MP4A). Both of these substrate type tracers were developed for measuring cerebral acetylcholinesterase activity. There was good retention of the radioactive metabolite of [(11)C]MP4A in the brain (k(el)=0.0036+/-0.0013 min(-1), beta=0.028), whereas that of [(18)F]FEP-4MA was eliminated from the brain (k(el)=0.012+/-0.0010 min(-1), beta=0.085). A non-linear least square analysis for simultaneous estimation of all parameters showed that the precision of the k(3) estimate for [(18)F]FEP-4MA was as high (7.4%) as that for [(11)C]MP4A (10%). These results indicate that tracers with metabolites that are eliminated from the brain at a slow rate (beta<0.1) may be useful for the quantitative measurement of target enzyme activity. PMID- 21324369 TI - Osteoarthritis year 2010 in review: non-pharmacologic therapy. AB - OBJECTIVE: To highlight seminal publications in the past year on the topic of non pharmacologic management of osteoarthritis (OA). DESIGN: A systematic search of the PUBMED and Cochrane databases from September 2009 to September 2010 was conducted to identify articles reporting on studies examining the safety or efficacy of non-pharmacologic therapies in the management of OA. Non pharmacologic therapies were those considered in the 2008 OARSI OA guidelines. Identified articles were reviewed for quality; those of highest quality and deemed to have greatest potential impact on the management of OA were summarized. RESULTS: The search identified 117 unique articles. Of these, four studies were chosen to highlight. A nested two-stage trial found that traditional Chinese acupuncture (TCA) was not superior to sham acupuncture, but that the providers' style affected both pain reduction and satisfaction with treatment, suggesting that the analgesic benefits of acupuncture may be partially mediated by the acupuncturists' behavior. A systematic review found little evidence of a significant effect for electrostimulation vs sham or no intervention on pain in knee OA. A single-blinded trial of Tai Chi vs attention controls found that 12 weeks of Tai Chi was associated with improvements in symptoms and disability in patients with knee OA. A randomized trial of early ACL reconstructive surgery and rehabilitation vs structured rehabilitation alone in subjects with acute anterior cruciate ligament tears found that, at 24 months following randomization, all study participants had improved, suggesting that a strategy of structured rehabilitation followed acute ACL injury may preclude the need for surgical reconstruction. CONCLUSIONS: High quality studies of the safety and efficacy of non-pharmacologic agents in the management of OA remain challenging due to difficulties with adequate blinding and appropriate selection of attention controls. High quality studies suggest modest, if any, benefit of many non pharmacologic therapies over attention control or placebo, but a significant impact of both over no intervention at all. PMID- 21324370 TI - Osteoarthritis year 2010 in review: pathomechanisms. AB - Osteoarthritis is characterized by progressive breakdown of articular cartilage. This review summarizes findings of the last year, which shed new light on mechanisms and factors involved in cartilage loss. Evidence is accumulating that the transcription factor hypoxia-inducible factor-2alpha (HIF-2alpha) is highly enhanced in OA cartilage and drives catabolic metalloproteinases, including the pivotal MMP-13. In addition, HIF-2alpha suppresses chondrocyte autophagy, herein promoting chondrocyte apoptosis. The crucial role of MMP-13 is further underlined by reduced OA pathology in MMP-13 deficient mice. An intriguing mechanism to drive MMP-13 production is activation of the chondrocyte discoidin domain receptor (DDR-2) receptor through interaction with denuded collagen type II. The latter might occur in a proteoglycan depleted peri-cellular matrix, where DDR-2 expression is enhanced in OA cartilage and transgenic suppression attenuates experimental OA. The initiating role of ADAMTS-5 in proteoglycan loss appears dependent on interaction with the transmembrane proteoglycan syndecan-4, since syndecan-4 deficient mice are less prone to experimental OA and display reduced ADAMTS-5 activity. Both aging and the osteoarthritis (OA) process itself induce deranged transforming growth factor-beta (TGFbeta)-receptor expression, causing a shift to dominant usage of the receptor ALK-1, in stead of ALK5 and resulting in a TGFbeta mediated catabolic pathway. ALK-1 rather than TGFbeta is a promising therapeutic target. Finally, the alarmins S100A8 and 9 have long been considered as markers of inflammatory joint destruction, but now appear to be catabolic mediators. PMID- 21324371 TI - Bone structural changes in osteoarthritis as a result of mechanoregulated bone adaptation: a modeling approach. AB - OBJECTIVE: There are strong indications that subchondral bone may play an important role in osteoarthritis (OA), making it an interesting target for medical therapies. The subchondral bone structure changes markedly during OA, and it has long been assumed that this occurs secondary to cartilage degeneration. However, for various conditions that are associated with OA, it is known that they may also induce bone structural changes in the absence of cartilage degeneration. We therefore aimed to investigate if OA bone structural changes can result from mechanoregulated bone adaptation, independent of cartilage degeneration. METHOD: With a bone adaptation model, we simulated various conditions associated with OA -without altering the articular cartilage- and we evaluated if mechanoregulated bone remodeling by itself could lead to OA-like bone structural changes. RESULTS: For each of the conditions, the predicted changes in bone structural parameters (bone fraction, trabecular thickness, trabecular number, and trabecular separation) were similar to those observed in OA. CONCLUSION: This indicates that bone adaptation in OA can be mechanoregulated with structural changes occurring independent of cartilage degeneration. PMID- 21324372 TI - Subchondral bone remodeling is related to clinical improvement after joint distraction in the treatment of ankle osteoarthritis. AB - OBJECTIVE: In osteoarthritis (OA), subchondral bone changes alter the joint's mechanical environment and potentially influence progression of cartilage degeneration. Joint distraction as a treatment for OA has been shown to provide pain relief and functional improvement through mechanisms that are not well understood. This study evaluated whether subchondral bone remodeling was associated with clinical improvement in OA patients treated with joint distraction. METHOD: Twenty-six patients with advanced post-traumatic ankle OA were treated with joint distraction for 3 months using an Ilizarov frame in a referral center. Primary outcome measure was bone density change analyzed on computed tomography (CT) scans. Longitudinal, manually segmented CT datasets for a given patient were brought into a common spatial alignment. Changes in bone density (Hounsfield Units (HU), relative to baseline) were calculated at the weight-bearing region, extending subchondrally to a depth of 8mm. Clinical outcome was assessed using the ankle OA scale. RESULTS: Baseline scans demonstrated subchondral sclerosis with local cysts. At 1 and 2 years of follow up, an overall decrease in bone density (-23% and -21%, respectively) was observed. Interestingly, density in originally low-density (cystic) areas increased. Joint distraction resulted in a decrease in pain (from 60 to 35, scale of 100) and functional deficit (from 67 to 36). Improvements in clinical outcomes were best correlated with disappearance of low-density (cystic) areas (r=0.69). CONCLUSIONS: Treatment of advanced post-traumatic ankle OA with 3 months of joint distraction resulted in bone density normalization that was associated with clinical improvement. PMID- 21324373 TI - Expression and function of the insulin receptor in normal and osteoarthritic human chondrocytes: modulation of anabolic gene expression, glucose transport and GLUT-1 content by insulin. AB - OBJECTIVE: Chondrocytes respond to insulin, but the presence and role of the specific high affinity insulin receptor (InsR) has never been demonstrated. This study determined whether human chondrocytes express the InsR and compared its abundance and function in normal and osteoarthritis (OA) human chondrocytes. DESIGN: Cartilage sections were immunostained for detection of the InsR. Non proliferating chondrocyte cultures from normal and OA human cartilage were treated with 1nM or 10nM insulin for various periods. InsR, insulin-like growth factor receptor (IGFR), aggrecan and collagen II mRNA levels were assessed by real time RT-PCR. InsR, glucose transporter (GLUT)-1, phospho-InsRbeta and phospho-Akt were evaluated by western blot and immunofluorescence. Glucose transport was measured as the uptake of [3H]-2-Deoxy-d-Glucose (2-DG). RESULTS: Chondrocytes staining positively for the InsR were scattered throughout the articular cartilage. The mRNA and protein levels of the InsR in OA chondrocytes were approximately 33% and 45%, respectively, of those found in normal chondrocytes. Insulin induced the phosphorylation of the InsRbeta subunit. Akt phosphorylation and 2-DG uptake increased more intensely in normal than OA chondrocytes. Collagen II mRNA expression increased similarly in normal and OA chondrocytes while aggrecan expression remained unchanged. The Phosphoinositol-3 Kinase (PI3K)/Akt pathway was required for both basal and insulin-induced collagen II expression. CONCLUSIONS: Human chondrocytes express functional InsR that respond to physiologic insulin concentrations. The InsR seems to be more abundant in normal than in OA chondrocytes, but these still respond to physiologic insulin concentrations, although some responses are impaired while others appear fully activated. Understanding the mechanisms that regulate the expression and function of the InsR in normal and OA chondrocytes can disclose new targets for the development of innovative therapies for OA. PMID- 21324374 TI - Role of allogeneic transplantation for FLT3/ITD acute myeloid leukemia: outcomes from 133 consecutive newly diagnosed patients from a single institution. AB - Acute myelogenous leukemia (AML) patients with FLT3/ITD mutations have an inferior survival compared to AML patients with wild-type (WT) FLT3, primarily because of an increased relapse rate. Allogeneic transplantation represents a postremission therapy that is effective at reducing the risk of relapse for many cases of poor-risk AML. Whether or not allogeneic transplantation in first complete remission (CR) can improve outcomes for patients with FLT3/ITD AML remains controversial. Our institution has adopted a policy of pursuing allogeneic transplantation, including the use of alternate donors, for FLT3/ITD AML patients in remission. As part of an instituional review board-approved study, we performed a review of the clinical data from November 1, 2004, to October 31, 2008, on all adult patients under the age of 60 presenting in consecutive fashion to the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins with newly diagnosed non-M3 AML. We followed their outcomes through August 1, 2010. During the study period, 133 previously untreated AML patients between the ages of 20 and 59 were diagnosed and received induction and consolidation therapy at our institution. Of these 133 patients, 31 (23%) harbored an FLT3/ITD mutation at diagnosis. The median overall survival (OS) from the time of diagnosis for the FLT3/ITD AML patients was compared to the OS of the entire cohort and found to be comparable (19.3 months versus 15.5 months, P = .56). Historically, OS for FLT3/ITD AML patients is significantly worse than for AML patients lacking this mutation. However, the OS for the 31 FLT3/ITD patients reported here was comparable to the 102 patients with WT FLT3 over the same 4 year time period. One difference that might have contributed to the surprising outcomes for the FLT3/ITD group is our aggressive pursuit of allogeneic bone marrow transplant (BMT) in CR1 within this group (60% of FLT3/ITD versus 17% with WT). Our single-institution study of consecutively treated AML patients supports the hypothesis that allogeneic transplant in early CR1 improves the long-term outcomes for FLT3/ITD AML. PMID- 21324375 TI - Enhanced immune response after a second dose of an AS03-adjuvanted H1N1 influenza A vaccine in patients after hematopoietic stem cell transplantation. AB - Seroconversion rates following influenza vaccination in patients with hematologic malignancies after hematopoietic stem cell transplantation (HSCT) are known to be lower compared to healthy adults. The aim of our diagnostic study was to determine the rate of seroconversion after 1 or 2 doses of a novel split virion, inactivated, AS03-adjuvanted pandemic H1N1 influenza vaccine (A/California/7/2009) in HSCT recipients (ClinicalTrials.gov Identifier: NCT01017172). Blood samples were taken before and 21 days after a first dose and 21 days after a second dose of the vaccine. Antibody (AB) titers were determined by hemagglutination inhibition assay. Seroconversion was defined by either an AB titer of <= 1:10 before and >= 1:40 after or >= 1:10 before and >= 4-fold increase in AB titer 21 days after vaccination. Seventeen patients (14 allogeneic, 3 autologous HSCT) received 1 dose and 11 of these patients 2 doses of the vaccine. The rate of seroconversion was 41.2% (95% confidence interval [CI] 18.4-67.1) after the first and 81.8% (95% CI 48.2-97.7) after the second dose. Patients who failed to seroconvert after 1 dose of the vaccine were more likely to receive any immunosuppressive agent (P = .003), but time elapsed after or type of HSCT, age, sex, or chronic graft-versus-host disease was not different when compared to patients with seroconversion. In patients with hematologic malignancies after HSCT the rate of seroconversion after a first dose of an adjuvanted H1N1 influenza A vaccine was poor, but increased after a second dose. PMID- 21324376 TI - p53 codon 271 CGT to CAT mutant fraction does not increase in nasal respiratory and olfactory epithelia of rats exposed to inhaled naphthalene. AB - A 2-year rat tumor bioassay testing whole body exposure to naphthalene (NA) vapor found a significant increase in nasal respiratory epithelial adenomas in male rats and in olfactory epithelial neuroblastomas in female rats. To obtain mechanistic insight into NA-induced nasal carcinogenesis, NA dose-response was characterized in nasal epithelium using a tumor-relevant endpoint. Specifically, levels of p53 codon 271 CGT to CAT mutation were measured in nasal respiratory and olfactory epithelium of NA-exposed male and female rats by allele-specific competitive blocker-PCR (ACB-PCR). Male and female, 8-9 week-old F344 rats (5 rats/group) were exposed to 0, 0.1, 1.0, 10, and 30ppm NA vapor for 13 weeks (6h/day, 5 days/week). The geometric mean p53 mutant fraction (MF) levels in nasal epithelium of control treatment groups ranged between 2.05 * 10(-5) and 3.05 * 10(-5). No significant dose-related changes in p53 mutant fraction (MF) were observed in the olfactory or respiratory epithelia of female rats. However, statistically significant treatment-related differences were observed in male respiratory and olfactory epithelium, with the p53 MF in the respiratory epithelium of male rats exposed to 30ppm NA significantly lower than that in controls. Further, a significant trend of decreasing p53 MF with increasing dose was observed in the male respiratory epithelium. Of the tissue types analyzed, respiratory epithelium is the most sensitive to the cytotoxic effects of NA, suggesting cytotoxicity may be responsible for the loss of p53 mutation. Because ACB-PCR has been used successfully to detect the effects of known mutagenic carcinogens, the absence of any significant increases in p53 MF associated with NA exposure adds to the weight of evidence that NA does not operate through a directly mutagenic mode of action. PMID- 21324377 TI - Evaluating the toxicity of environmental concentrations of waterborne chromium (VI) to a model teleost, Oncorhynchus mykiss: a comparative study of in vivo and in vitro. AB - Toxic effects of environmental concentrations (50, 100, and 200MUg/L) of waterborne chromium (VI) were evaluated in rainbow trout by comparison of in vitro and in vivo assays. Multiple biomarkers were measured including oxidative stress indices and antioxidant response parameters in liver and brain, as well as Na(+)-K(+)-ATPase in gill. Superoxide dismutase (SOD) and glutathione reductase (GR) activities were significantly induced (1.54-fold and 1.37-fold, respectively) in fish brain in vivo, but no significant differences were observed in any other biomarker or in vivo test group. Oxidative stress was apparent in vitro as significantly higher levels of oxidative indices, with the highest induction of TBARS and CP found in brain at 200MUg/L Cr(VI) (2.41-fold and 1.95 fold, respectively), and SOD and GR activities and reduced glutathione in brain were significantly inhibited (65%, 44%, and 36%, respectively). In vitro Na(+) K(+)-ATPase activity in gill was also significantly inhibited at concentrations of 100 and 200MUg/L (69% and 45%, respectively). Short-term exposure to environmental concentrations of Cr(VI) does not therefore evoke marked effects in fish in vivo. Based on the present results, a set of in vitro tests with tissue homogenate can be evoked more remarkable effects by the lower concentrations of Cr(VI) than in vivo, which could provide some useful information and might be a potential alternative approach for monitoring heavy metal pollution in aquatic environments. However, it needs more detailed studies in other area, such as hormonal response or genotoxicity, before these findings could be applied in the field investigation. PMID- 21324380 TI - Phylogenetic analyses of mitochondrial and nuclear data in haematophagous flies support the paraphyly of the genus Stomoxys (Diptera: Muscidae). AB - The genus Stomoxys Geoffroy (Diptera; Muscidae) contains species of parasitic flies that are of medical and economic importance. We conducted a phylogenetic analysis including 10 representative species of the genus including multiple exemplars, together with the closely related genera Prostomoxys Zumpt, Haematobosca Bezzi, and Haematobia Lepeletier & Serville. Phylogenetic relationships were inferred using maximum likelihood and Bayesian methods from DNA fragments from the cytochrome c oxidase subunit I (COI, 753bp) and cytochrome b (CytB, 587bp) mitochondrial genes, and the nuclear ribosomal internal transcribed spacer 2 (ITS2, 426bp). The combination of mitochondrial and nuclear data strongly supports the paraphyly of the genus Stomoxys because of the inclusion of Prostomoxys saegerae Zumpt. This unexpected result suggests that Prostomoxys should be renamed into Stomoxys. Also, the deep molecular divergence observed between the subspecies Stomoxys niger niger Macquart and S. niger bilineatus Grunbreg led us to propose that they should rather be considered as distinct species, in agreement with ecological data. Bayesian phylogenetic analyses support three distinct lineages within the genus Stomoxys with a strong biogeographical component. The first lineage consists solely of the divergent Asian species S. indicus Picard which appears as the sister-group to all remaining Stomoxys species. The second clade groups the strictly African species Stomoxys inornatus Grunbreg, Stomoxys transvittatus Villeneuve, Stomoxys omega Newstead, and Stomoxys pallidus Roubaud. Finally, the third clade includes both African occurring and more widespread species such as the livestock pest Stomoxys calcitrans Linnaeus. Divergence time estimates indicate that the genus Stomoxys originated in the late Oligocene around 30 million years ago, with the major lineages diversifying in the Early Miocene between 20 and 15 million years ago at a time when temperate forests developed in the Northern Hemisphere. PMID- 21324381 TI - Animal and human pathogenic Escherichia coli strains share common genetic backgrounds. AB - Escherichia coli is a versatile species encompassing both commensals of the digestive tracts of many vertebrates, including humans, and pathogenic strains causing various intra- and extraintestinal infections. Despite extensive gene flow between strains, the E. coli species has a globally clonal population structure, consisting of distinct phylogenetic groups. Little is known about the relationships between phylogenetic groups and host specificity. We therefore used multilocus sequence typing (MLST) to investigate phylogenetic relationships and evaluated the virulence gene content of 35 E. coli strains representative of the diverse diseases encountered in domestic animals. We compared these strains with a panel of 101 human pathogenic and 98 non-human and human commensal strains representative of the phylogenetic and pathovar diversity of this species. A global factorial analysis of correspondence indicated that extraintestinal infections were caused mostly by phylogenetic group B2 strains, whereas intraintestinal infections were caused mostly by phylogenetic group A/B1/E strains, with strains responsible from extraintestinal or intraintestinal infections having specific virulence factors. It was not possible to distinguish between strains of human and animal origin. A detailed phylogenetic analysis of the MLST data showed that numerous pathogenic animal and human strains are very closely related, and had a number of virulence genes in common. However, a set of specific adhesins was identified in animal non-B2 group strains of all pathotypes. In conclusion, human and animal pathogenic strains share common genetic backgrounds, but non-B2 strains of different origins seem to have different sets of adhesins that could be involved in host specificity. PMID- 21324382 TI - Reconstruction of the evolutionary dynamics of the hepatitis C virus 1b epidemic in Turkey. AB - Worldwide, 12.5% of the more than 170 million people infected by hepatitis C virus (HCV), live in Eastern Mediterranean countries. In Turkey, the prevalence of HCV infection ranges from 0.3% to 0.4% of the general population. We investigated the distribution of HCV subtype 1b in Turkey by analysing the NS5b viral genomic region, using a Bayesian coalescent-based framework and phylogeographical analysis to estimate the origin of the HCV 1b subtype epidemic and the genetic diversification of the virus in Turkey. The dataset consisted of 24 NS5b sequences obtained from patients chronically infected with HCV subtype 1b admitted to the different health districts of Ankara hospital plus the reference sequences for phylogenetic analysis. An independent dataset including the same 342-nt NS5b fragment from all over the world (203 sequences) was used to calibrate the evolutionary rate. Using the relaxed clock model, we estimated a mean evolutionary rate of 0.84 * 10(-3) sub/site/year (95% highest posterior density interval HPD 0.16-1.5 * 10(-3)). The results of the phylogeographical analysis suggested that the HCV epidemic probably originated in Greece during the first decade of 1900 and, a few years later (in the 1920s or 1930s), successfully spread to neighboring countries such as Turkey and Cyprus. The clustering of the majority of the Turkish strains in a single monophyletic group suggests the subsequent segregated circulation of the virus in the country during the years 1940-1999, which was probably due to unsafe medical parenteral procedures, with drug addiction playing a relatively negligible role. The Bayesian skyline plot (BSP) showed a growth in the number of effective infections between the 1940s and the 1990s, when the curve reached a plateau that still remains today, suggesting a partial success of improved transfusional policies. A coalescent-based approach to population dynamics can improve our understanding of the origin and spread of epidemics in a limited geographical area. PMID- 21324383 TI - Biocompatibility of magnesium phosphate minerals and their stability under physiological conditions. AB - Magnesium phosphates such as newberyite (MgHPO(4).3H(2)O) are formed in vivo and are known to be biodegradable and nontoxic after implantation. Indeed, magnesium apatites have been shown to support osteoblast differentiation and function, and bone formation can occur around metallic magnesium implants. However, very little is known regarding the precipitation and stability of magnesium phosphates in physiological environments. In order to address this, the aqueous formation of magnesium phosphate as a function of pH, temperature and ion concentration is reported. Physicochemical characterization of the precipitates was carried out; additionally, biocompatibility and gene expression of osteoblast differentiation markers for bone formation via an in vitro cell culture assay were determined. Precipitation conditions for newberyite, tribasic magnesium phosphate pentahydrate, holtedahlite, bobierrite and cattiite were determined. Under physiological conditions of pH, temperature and magnesium phosphate concentration, no precipitates were formed. However, at concentrations 10-100 times higher than physiological, magnesium phosphate precipitates of cattiite and newberyite were formed. These two minerals demonstrated biocompatibility with osteoblast cultures and induced osteoblast adhesion and differentiation. The pattern of expression of OCN and CollA1 genes in the presence of newberyite crystals was comparable to that of calcium phosphate bioceramics. In our experiments, we have shown that certain magnesium phosphate phases such as newberyite and cattiite are able to promote in vivo osteogenic activity in a similar way to calcium phosphates such as hydroxyapatite and brushite. This confirms the great potential of magnesium phosphate ceramics in the development of new biomaterials for bone regeneration. PMID- 21324384 TI - Local anaesthetic wound infiltration following paediatric appendicectomy: a randomised controlled trial: Time to stop using local anaesthetic wound infiltration following paediatric appendicectomy? AB - OBJECTIVE: This study sought to determine the efficacy of post-operative wound infiltration with local anaesthetic following paediatric appendicectomy. METHOD: In a randomised, controlled, prospective, clinical trial children aged between five and sixteen years were assigned to one of three treatment arms; infiltration of the surgical wound with bupivicaine, saline, or no infiltration. Anaesthetic and analgesic protocols were employed. Patients and observers were blinded to the treatment group. The primary end-points were post-operative pain, scored at intervals during the first twenty post-operative hours, and additional post operative analgesic requirements beyond that which was provided by a standard protocol. In addition, adverse wound outcomes were recorded. RESULTS: Eighty eight children were recruited. There were no differences in age, sex or other confounding variables between groups. There was no significant difference in mean pain scores or analgesic requirements between groups through-out the post operative period. CONCLUSION: Wound infiltration with local anaesthetic following appendicectomy in children provides no additional benefit over regular simple analgesia. Its routine use represents dogmatic practise which ought to be challenged for this patient group. PMID- 21324385 TI - Induction of hypocrellin production by Triton X-100 under submerged fermentation with Shiraia sp. SUPER-H168. AB - Hypocrellins are important photodynamic therapy compounds for cancer disease. The effect of surfactants on hypocrellin production of Shiraia sp. SUPER-H168 was evaluated under submerged fermentation condition. The production of hypocrellins could reach 780.6 mg/l with the addition of Triton X-100, confirmed by color reaction, high performance liquid chromatography, electrospray ionization mass spectrometry and nuclear magnetic resonance experiments. According to our observation, treatment of the culture at the beginning of the fermentation was most effective, and the yield of hypocrellins was much lower with the addition of Triton X-100 during the log phase and stationary phase. Shiraia sp. SUPER-H168 could not produce hypocrellin with the addition of other tested surfactants, such as Tween 40, Triton X-114 and SDS. The experimental results indicated that Shiraia sp. SUPER-H168 could not produce hypocrellins without Triton X-100 under submerged fermentation condition. PMID- 21324386 TI - High-level production of extracellular lipase by Yarrowia lipolytica mutants from methyl oleate. AB - The yeast Yarrowia lipolytica degrades efficiently low-cost hydrophobic substrates for the production of various added-value products such as lipases. To obtain yeast strains producing high levels of extracellular lipase, Y. lipolytica DSM3286 was subjected to mutation using ethyl methanesulfonate (EMS) and ultraviolet (UV) light. Twenty mutants were selected out of 1600 mutants of Y. lipolytica treated with EMS and UV based on lipase production ability on selective medium. A new industrial medium containing methyl oleate was optimized for lipase production. In the 20 L bioreactor containing new industrial medium, one UV mutant (U6) produced 356 U/mL of lipase after 24h, which is about 10.5 fold higher than that produced by the wild type strain. The properties of the mutant lipase were the same as those of the wild type: molecular weight 38 kDa, optimum temperature 37 degrees C and optimum pH 7. Furthermore, the nucleotide sequences of extracellular lipase gene (LIP2) in wild type and mutant strains were determined. Only two silent substitutions at 362 and 385 positions were observed in the ORF region of LIP2. Two single substitutions and two duplications of the T nucleotide were also detected in the promoter region. LIP2 sequence comparison of the Y. lipolytica DSM3286 and U6 strains shows good targets to effective DNA recombinant for extracellular lipase of Y. lipolytica. PMID- 21324387 TI - Guest editor's introduction. Special issue on catalytic mechanisms. PMID- 21324388 TI - Tribute to Professor Minor J. Coon. PMID- 21324389 TI - Tetrahydrobiopterin and phenylketonuria. PMID- 21324391 TI - Shunting: a better way to prevent variceal bleeding. PMID- 21324390 TI - Surgical sepsis and organ crosstalk: the role of the kidney. AB - Acute kidney injury (AKI) is a common complication of hospitalized patients, and clinical outcomes remain poor despite advances in renal replacement therapy. The accepted pathophysiology of AKI in the setting of sepsis has evolved from one of simple decreased renal blood flow to one that involves a more complex interaction of intra-glomerular microcirculatory vasodilation combined with the local release of inflammatory mediators and apoptosis. Evidence from preclinical AKI models suggests that crosstalk occurs between kidneys and other organ systems via soluble and cellular inflammatory mediators and that this involves both the innate and adaptive immune systems. These interactions are reflected by genomic changes and abnormal rates of cellular apoptosis in distant organs including the lungs, heart, gut, liver, and central nervous system. The purpose of this article is to review the influence of AKI, particularly sepsis-associated AKI, on inter organ crosstalk in the context of systemic inflammation and multiple organ failure (MOF). PMID- 21324392 TI - Simvastatin maintains osteoblastic viability while promoting differentiation by partially regulating the expressions of estrogen receptors alpha. AB - BACKGROUND: Statin is a specific inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme involved in the cholesterol synthesis pathway. In addition to their long-known efficacy for lowering cholesterol, statins have also been reported to possess anabolic effects on bone. Simvastatin is reported to increase cancellous bone volume, bone formation rate, and cancellous bone compressive strength in vivo. MATERIALS AND METHODS: In this report, the effects of simvastatin on osteoprecursor cells were evaluated. The effect on cell viability was determined by MTT assay, whereas differentiation and mineralization were examined using an alkaline phosphatase activity (ALP) test and alizarin red-S staining. Protein expressions related to bone formation, such as estrogen receptor-alpha (ER-alpha) and beta (ER-beta), were evaluated by using a Western blot analysis. To assess whether the osteoinductive effect of simvastatin occurs via estrogen receptor pathway, estrogen receptor agonist (E2) and antagonists (ICI 182,780) were applied to the cultures. RESULTS: Cultures grown in the presence of simvastatin exhibited an increased value for ALP activity and mineralization. The results of the Western blot analysis indicated that the addition of simvastatin up-regulated ER-alpha and ER-beta expression with a statistically significant difference in ER-alpha expression. Treatment of E2 led to an increase of the ALP activity and mineralization, but addition of the estrogen receptor antagonist ICI 182,780 revealed a decrease in both values. CONCLUSIONS: Based on these findings, it was concluded that simvastatin could produce positive effects on both the differentiation and mineralization of osteoprecursor cells. Our results also suggested that osteoinductive effects of simvastatin were achieved through ER pathway via the increase of ER-alpha expression. PMID- 21324393 TI - Economic and outcomes-based analysis of the care of symptomatic varicose veins. AB - OBJECTIVE: Endoluminal treatment of symptomatic varicose veins (VV) reduces or eliminates inpatient hospital stays, lowers complication rates, and increases revenue for vein care centers adopting the technique. This study compares the outcomes and economics of two treatments for VV. METHODS: Since May 2007, endovenous radiofrequency ablation (RFA) of symptomatic VV has been performed at our institution. For outcome measurements, a cohort of 100 RFA procedures (26% CEAP class C5 and C6) was compared with 100 open greater or lesser saphenous stripping and ligation procedures (SL, 18% C5 and C6). Procedures were performed between August 2002 and October 2007. The time frame was chosen to allow for a 6 mo follow-up. Patients who had adjunctive removal of secondary varicosities were included in both cohorts. Cost estimates are based on the actual total direct costs derived from the hospital's charge sheets for 20 of the 100 patients in each of the cohorts (n = 40). The actual direct costs are based on 2009-dollar values and do not include the surgeons' professional fees. RESULTS: Seventy-nine percent of the RFA therapies were performed in an outpatient clinic treatment room with the remaining 21% performed in an operating room (OR). For the SL group, all procedures were performed in the OR with 68% of patients requiring at least one night of hospital stay (average length of stay 1.2 d). The estimated direct cost of performing RFA in the treatment room was $906. This was considerably less than the estimated $4241 total direct cost for open SL followed by in-hospital observation. Outpatient open SL cost $2622, which is only slightly more than the $2533 cost for outpatient RFA performed in the OR. The use of RFA was associated with an earlier return to normal leisure activities (3.3 d versus 26 d, P < 0.05), fewer total hospital nights (3 d versus 82 d, P < 0.05), and less use of general anesthesia (16% versus 95%, P < 0.05). There were no major complications in the RFA group compared with three major complications in the SL group. CONCLUSIONS: With the introduction of endovenous techniques at our institution, there has been a significant increase in the volume of patients seeking this less invasive treatment modality. This is due largely to the ease and comfort with which patients can now be treated as well as the reduced length of stay, reduction of general anesthetic use, and the speed at which they can return to normal activities. We recommend endovenous ablation techniques as both cost-saving and patient-preferred. PMID- 21324394 TI - Improved survival with lymph node sampling in Wilms tumor. AB - OBJECTIVE: We sought to determine the impact of number of lymph nodes examined on survival for Wilms tumor (WT). METHODS: Data from the Surveillance, Epidemiology, and End Results and Florida Cancer Data System were queried for patients < 20 years of age with WT. RESULTS: Of 1805 WT patients, 1340 had lymph node (LN) data available following surgery. The mean age for the cohort was 3.3 +/- 2.8 y. Most patients were White (78%), and non-Hispanic (78%). A total of 297 patients (22%) had 0 LN sampled, while 697 (52%) had 1-5 LN, 210 (16%) had 6-10 LN, and 136 (10%) had >10 LN. Overall 5-y survival was 91%. By univariate analysis, 5-y survival was significantly lower for patients with 0 LN sampled (87% versus 91% 1 5 LN; 93% 6-10 LN; 95% >10 LN, P = 0.005). Multivariate analysis confirmed a survival advantage for patients having 1-5 LN (HR 0.600, P = 0.016), 6-10 LN (HR 0.521, P = 0.048), and >10 LN (HR 0.403, P = 0.039) compared with patients with 0 LN examined. CONCLUSION: Failure to biopsy lymph nodes for WT patients not only increases the risk of local recurrence due to understaging and inadequate adjuvant therapy, but is also an independent prognostic indicator of lower survival. PMID- 21324396 TI - p53 inhibits vascular endothelial growth factor expression in solid tumor. AB - BACKGROUND: The p53 tumor-suppressor gene is one of the most frequently mutated genes in cancers, and its mutations affect various biological actions, such as tumor growth, apoptosis, and so on. During hypoxia, p53 is stabilized by interaction with hypoxia-inducible factor-1 (HIF-1). This interaction raised the possibility for regulating HIF-1 activity by p53, which is still to be elucidated. METHODS: First, we introduced various types of the p53 mutant gene into Hep3B and evaluated the role of p53 in hypoxic responses, including vascular endothelial growth factor (VEGF) production and HIF-1 activation. Second, Hep3B vector cells and Hep3B-p53 cells were subcutaneously injected into BALB/c (nu/nu) mice, and tumor progression and the hypoxic responses were analyzed. Finally, we investigated the role of the p53 mutant genes in the level of vascularity in human pancreatic neoplasia. RESULTS: Here, we showed that expression of wild-type p53, but not null or mutated p53, significantly suppressed HIF-1 activity and production of VEGF, which mostly depends on the HIF-1beta protein level. In a tumor xenograft model, we consistently found that loss of p53 promotes VEGF production, neovascularization, and tumor progression via accumulation of HIF 1beta protein. Furthermore, in clinical pancreatic neoplasia, tumors with mutated p53 have significantly higher levels of vascularity than those with wild-type p53. CONCLUSION: These results indicate that loss of p53 contributes to neovascularization through regulation of HIF-1. PMID- 21324397 TI - Friend or foe? Linkage between hormonal response and innate immunity. PMID- 21324395 TI - TGF-beta and restenosis revisited: a Smad link. AB - Despite novel surgical therapies for the treatment of atherosclerosis, restenosis continues to be a significant impediment to the long-term success of vascular interventions. Transforming growth factor-beta (TGF-beta), a family of cytokines found to be up-regulated at sites of arterial injury, has long been implicated in restenosis; a role that has largely been attributed to TGF-beta-mediated vascular fibrosis. However, emerging data indicate that the role of TGF-beta in intimal thickening and arterial remodeling, the critical components of restenosis, is complex and multidirectional. Recent advancements have clarified the basic signaling pathway of TGF-beta, making evident the need to redefine the precise role of this family of cytokines and its primary signaling pathway, Smad, in restenosis. Unraveling TGF-beta signaling in intimal thickening and arterial remodeling will pave the way for a clearer understanding of restenosis and the development of innovative pharmacological therapies. PMID- 21324398 TI - Matrilysin expression related to radiation and microflora changes in murine bowel. AB - BACKGROUND: Matrilysin (MMP-7) elevation after radiotherapy is shown in humans. Matrilysin regulates certain cytokines and the production of bactericidal proteins when the mucosa is exposed to bacterial antigens. We investigate the effect of irradiation on matrilysin and microflora in murine bowel, after modulation with antibiotics. METHODS: Animals were divided into two different groups a radiation group (72 animals) and sham radiation group (36 animals). Animals were divided into smaller groups of six according to radiation dose (19 or 38 Gy or sham). Seven days before radiotherapy ampicillin 500 mg/kg/d was administered intramuscularly, in the antibiotic groups. An exteriorized segment of ileum was subjected to single high dose radiation (19 or 38 Gy). Samples were collected 2, 24, and 48 h and analyzed for microflora, MIP-2, TGF-beta, and MMP 7. RESULTS: The combination of antibiotics and irradiation leads to an early significant reduction of bacteria, down-regulates MIP-2, up-regulates TGF-beta and elevation of MMP-7 to levels achieved by antibiotics or irradiation alone. Lactobacilli were reduced to non-existent levels after antibiotics. CONCLUSIONS: Pretreatment with Ampicillin before irradiation and laparotomy in a murine model leads to Matrilysin over-expression as achieved by radiotherapy alone. Microfloral regulation does not affect MMP-7 stimulation after surgical or radiological trauma. Radiotherapy overrides the effect of antibiotics leading to an up-regulation of MMP-7, TGF-beta and MIP-2 expression between 24 h and 48 h. PMID- 21324399 TI - Attenuation of reperfusion-induced hepatocyte apoptosis is associated with reversed bcl-2/bax ratio in hemi-hepatic artery-preserved portal occlusion. AB - BACKGROUND: This study aimed to examine the hepatocyte apoptosis in a hepatic blood inflow occlusion rat model without hemi-hepatic arterial control and its association with the expressions of the apoptosis-regulating genes bcl-2 and bax. MATERIALS AND METHODS: Wistar rats were equally and randomly assigned to undergo sham operation (control group, n = 8), Pringle's maneuver (group PR, n = 32), hemi-hepatic occlusion (group HH, n = 32), or hemi-hepatic artery-preserved portal occlusion (group HP, n = 32). The hepatic blood inflow was interrupted for 30 min using a microvascular clip in the three experimental groups. The clips were removed to achieve hepatic reperfusion for up to 24 h. Blood samples and liver specimens were collected following reperfusion to perform pathologic examination, serum transferase assay, apoptosis analysis, and determination of bcl-2 and bax mRNA and protein expressions. RESULTS: The reperfusion-related hepatocytic injuries were more severe in the PR group than in the HH and HP groups, both pathologically and biochemically. More reperfused hepatocytes became apoptotic in the PR group than in the HH and HP groups. However, the values of the HH and HP groups were comparable in cellularity, levels of serum transferases, and apoptosis rate following reperfusion. The ratios of bcl-2/bax were reversed, which was more evident in the HH and HP groups than in the PR group. CONCLUSION: Hemi-hepatic artery-preserved portal occlusion had little effect on hepatocyte apoptosis compared with Pringle's maneuver and caused minor ischemia-reperfusion injury as shown by the reversed bcl-2/bax ratio. PMID- 21324400 TI - Transplantation of enteric cells expressing p75 in the rodent stomach. AB - BACKGROUND: Neural crest stem cells may hold potential as a cellular therapeutic to repopulate the enteric nervous system. The expression of the low-affinity nerve growth factor receptor, p75, may enrich enteric cells isolated from the neonatal rodent intestinal tract for neural crest stem cells. While these cells have shown tremendous promise in vitro, it remains to be determined whether they will survive and differentiate after in vivo transplantation. MATERIALS AND METHODS: Cells isolated from the neonatal rodent intestinal muscularis were sorted according to their degree of p75 expression. The parent, p75-high, and p75 low expressing populations were injected into the rodent stomach for 7 d in vivo. RESULTS: Cells that expressed high levels of p75 also expressed high levels of nestin. Evaluation of the parent, p75-high, and p75-low populations of cells showed 420-, 130-, and 20-fold growth, respectively, after 11 d of culture. Transplantation of these populations of cells into syngeneic rodent stomachs showed cell survival in the injection site after 7 d. Cells expressing either the neuronal marker, peripherin, or the glial marker, S100, were present in and around the injection site when the parent and the p75-high populations were transplanted. CONCLUSIONS: Enteric cells survive transplantation into the rodent stomach and induce the expression of differentiation markers in and around the injection site. Based on these results, enteric cells may hold potential as a cellular therapeutic in a variety of gastrointestinal disorders. PMID- 21324401 TI - Therapeutic potential of propagated hepatocyte transplantation in liver failure. AB - BACKGROUND: This study aimed to evaluate the therapeutic potential of intrasplenic transplantation of culture-propagated homologous hepatocytes in rats suffering from acute liver failure (ALF). METHODS: ALF was induced in dipeptidyl peptidase IV-negative (DPPIV(-)) Fischer 344 rats by totally removing the two anterior liver lobes (68% of the liver) and ligating the pedicle of the right lobe (24% of the liver). Hepatocytes isolated from DPPIV(+) Fischer 344 rats were cultured for 11 d to propagate 3-fold, and the resulting hepatocytes were dubbed "culture-propagated hepatocytes (CPHEPs)". A total of 1.5 * 10(7) cells of CPHEPs were transplanted intrasplenically before ALF induction (CPHEP group). Similarly, freshly isolated hepatocytes (FIHEPs) were transplanted as a positive control (FIHEP group), and culture medium (CM) was injected into rats as a negative control (CM group). RESULTS: The survival of the CPHEP group was comparable to that of the FIHEP group and longer than that of the CM group (P < 0.01). Both CPHEP and FIHEP transplantation improved blood parameters such as ammonia, total bilirubin, glutamic pyruvic transaminase, and glutamic oxaloacetic transaminase; transplantation also affected liver tissue parameters such as apoptosis rate and bromodeoxyuridine-labeling index. CONCLUSIONS: Transplantation of culture propagated homologous hepatocytes has a remarkable therapeutic potential for ALF in rats. PMID- 21324403 TI - The performance of laminin-containing cryogel scaffolds in neural tissue regeneration. AB - Currently, there are no effective therapies to restore lost brain neurons, although rapid progress in stem cell biology and biomaterials development provides new tools for regeneration of central nervous system. Here we describe neurogenic properties of bioactive scaffolds generated by cryogelation of dextran or gelatin linked to laminin - the main component of brain extracellular matrix. We showed that such scaffolds promoted differentiation of human cord blood derived stem cells into artificial neural tissue in vitro. Our experiments revealed that optimal range of scaffolds' pore size for neural tissue engineering was 80-100 microns. We found that scaffold seeded with undifferentiated, but not neutrally committed stem cells, gave optimal cell adhesion and proliferation in "niche"-like structures. Subsequent differentiation resulted in generation of mature 3D networks of neurons (MAP2+) and glia (S100beta+) cells. We showed that cryogel scaffolds could be transplanted into the brain tissue or organotypic hippocampal slices in a rat models. The scaffolds did not induced inflammation mediated by microglial cells (ED1-, Ox43-, Iba1-) and prevented formation of glial scar (GFAP-). Contrary, laminin-rich scaffolds attracted infiltration of host's neuroblasts (NF200+, Nestin+) indicating high neuroregeneration properties. PMID- 21324402 TI - The role of extracellular matrix composition in structure and function of bioengineered skeletal muscle. AB - One of the obstacles to the potential clinical utility of bioengineered skeletal muscle is its limited force generation capacity. Since engineered muscle, unlike most native muscle tissue, is composed of relatively short myofibers, we hypothesized that, its force production and transmission would be profoundly influenced by cell-matrix interactions. To test this hypothesis, we systematically varied the matrix protein type (collagen I/fibrin/Matrigel) and concentration in engineered, hydrogel-based neonatal rat skeletal muscle bundles and assessed the resulting tissue structure, generation of contractile force, and intracellular Ca(2+) handling. After two weeks of culture, the muscle bundles consisted of highly aligned and cross-striated myofibers and exhibited standard force-length and force-frequency relationships achieving tetanus at 40 Hz. The use of 2 mg/ml fibrin (control) yielded isometric tetanus amplitude of 1.4 +/- 0.3 mN as compared to 0.9 +/- 0.4 mN measured in collagen I-based bundles. Higher fibrin and Matrigel concentrations synergistically yielded further increase in active force generation to 2.8 +/- 0.5 mN without significantly affecting passive mechanical properties, tetanus-to-twitch ratio, and twitch kinetics. Optimized matrix composition yielded significant cellular hypertrophy (protein/DNA ratio = 11.4 +/- 4.1 vs. 6.5 +/- 1.9 MUg/MUg in control) and a prolonged Ca(2+) transient half-width (Ca(50) = 232.8 +/- 33.3 vs. 101.7 +/- 19.8 ms). The use of growth factor-reduced Matrigel, instead of standard Matrigel did not alter the obtained results suggesting enhanced cell-matrix interactions rather than growth factor supplementation as an underlying cause for the measured increase in contractile force. In summary, biomaterial-based manipulation of cell-matrix interactions represents an important target for improving contractile force generation in engineered skeletal muscle. PMID- 21324404 TI - First-trimester serum analytes, biophysical tests and the association with pathological morphometry in the placenta of pregnancies with preeclampsia and fetal growth restriction. AB - OBJECTIVE: We test the hypothesis that first-trimester serum analytes, 4-D power Doppler placental vascular indices and uterine artery Doppler (UAD) predicts abnormal placental morphometry in pregnancies with preeclampsia (PE) and fetal growth restriction (FGR). STUDY DESIGN: Maternal serum analytes (PAPP-A, hCG, ADAM12s, and PP13), bilateral UADs, and placental vascular indices were measured at 11-14 weeks in a nested-case control study within a prospective cohort of women followed from the first-trimester to delivery. Vascularization index (VI), flow index (FI), and vascularization flow index (VFI) were obtained from 4-D power Doppler histograms. Serum analytes were measured using immunofluorometric assays and values converted to multiples of the median (MoM) for gestational age. Morphometric analysis was performed on placentas from pregnancies complicated by PE (n = 13), gestational hypertension (HBP, n = 7) and FGR (defined as fetal weight <10th percentile with abnormal umbilical artery Doppler: n = 7); and 20 uncomplicated pregnancies. Two pregnancies had both FGR and PE. Each placenta was weighed and random samples taken, and fixed in formalin within 1 h of delivery. Hematoxylin & Eosin stained slides were analyzed by design-based stereology to quantify linear dimensions, surface areas and volumes of placental components. Paired t-test and ANOVA with adjustments for multiple comparisons were used. RESULTS: The surface areas of terminal and intermediate villi as well as the volume of terminal villi were significantly smaller in placentas from pregnancies complicated by FGR and PE. Compared with the control group the mean PAPP-A (MoM) was lower in the pregnancies with abnormal placenta morphometry (1.1 +/- 0.5 versus 0.7 +/- 0.5, P = 0.03). The morphometric indices were lower in those pregnancies with low PAPP-A and IUGR compared with preeclampsia. CONCLUSION: First-trimester PAPP-A levels are associated with abnormal placental morphometry at delivery in pregnancies with PE and IUGR. These findings may explain the association between adverse pregnancy outcomes and first-trimester PAPP-A. PMID- 21324405 TI - A survey of nurses in the mechanical circulatory support programs in the United States. AB - OBJECTIVE: This study aimed to examine the role of nurses working in mechanical circulatory support (MCS) programs in the United States through a description of role characteristics, including demographic information, qualifications, compensation, job preparation, work setting and responsibilities, scope of practice, contributions to patient care, and organizational outcomes. METHODS: Surveys were mailed to 189 nurses at 95 MCS programs, with a response rate of 63% (n = 119). However, 11% of respondents did not meet the inclusion criteria, and thus the final sample totaled 106 participants. RESULTS: Descriptive statistics and an analysis of contents showed many similarities among the nurses, along with some differences in work characteristics, compensation, scope of practice, and other items. CONCLUSION: The findings in this first national survey illustrate the multifaceted roles and related skill sets required of registered professional/advanced practice nurses in America's rapidly growing MCS programs. The common use of "ventricular assist device coordinator" as job title for these specialized and highly skilled nurses is incongruent with their role in these programs. PMID- 21324406 TI - Developing a shortened measure of negative thinking for use in patients with heart failure. AB - OBJECTIVE: Negative thinking is a target for treatment of depressive symptoms in patients with heart failure (HF). A brief instrument is needed to measure negative thinking in these patients. The study objective was to shorten the Crandell Cognitions Inventory (CCI) for use in patients with HF. METHODS: Baseline data from outpatients with HF (N = 179, 30% were female, age 60 +/- 13 years) were used to evaluate psychometrics of the CCI. Internal consistency reliability was measured with Cronbach's alpha construct validity with hypothesis testing. Principal components analysis was used in shortening. A separate sample of hospitalized patients with HF (N = 77, 49% were female, age 66 +/- 11 years) was used to validate the shortened CCI (CCI-SF). RESULTS: The CCI showed evidence of reliability and validity, but there was item redundancy in outpatients with HF. The 12-item CCI-SF showed good evidence of reliability and validity in inpatients with HF. CONCLUSION: The results support the reliability and validity of the CCI-SF to measure negative thinking in hospitalized patients with HF. PMID- 21324407 TI - Operational definitions of outcome indicators related to ineffective breathing patterns in children with congenital heart disease. AB - OBJECTIVE: The development of operational definitions leads to accurate assessments of health conditions. Many health indicators in the Nursing Outcomes Classification require the development of operational definitions. We sought to determine the validity of operational definitions for indicators of nursing outcomes that assess respiratory status in children with congenital heart disease. PATIENTS AND METHODS: Eight trained nurses evaluated 45 children with congenital heart disease who were aged <= 1 year and previously diagnosed with ineffective breathing patterns. The statistical analysis included median differences, intraclass correlations, and cluster analyses. RESULTS AND CONCLUSIONS: The nonuse of definitions produced inconsistencies in evaluations among evaluators. This inconsistency was not evident in the group using operational definitions. Two indicators were significant in all statistical analyses: asymmetrical chest expansion and percussed sounds. PMID- 21324408 TI - Gentian violet 1% solution in the treatment of wounds in the geriatric patient: a retrospective study. AB - To review the use of gentian violet 1% (GV) in a long-term care facility for the treatment of small, open wounds and extremity eschars of all sizes and thickness. The records of all the patients receiving topical GV therapy over a period of 1 year, from May 19, 2007 - May 19, 2008 were reviewed. The total sample was 70 patients (38 male, 32 female), average age 65.9 y.o., with 111 wounds (41 patients had >1 wound). The types of wounds were divided into 3 categories: 1) Split-thickness scabs (N = 37) limited to the epithelium, 2) full-thickness eschars and wounds with no depth <1 cm (N = 50), and 3) full-thickness eschars >1 cm located on the lower extremity (average 3.3 cm in diameter [N = 24]). All the wounds had been treated the same: topical application of GV to the wounds daily. None of the patients had any documented adverse events to the GV. Out of the 111 wounds, 103 healed completely. All wounds remained negative for cellulitis. 1) GV is a viable alternative topical agent for healing small, superficial wounds, ineffective scabs, and both small and large pressure ulcer eschars on lower extremities of geriatric patients, 2) there was very little evidence of scarring with the use of GV. PMID- 21324409 TI - Dechlorane Plus (DP) in air and plants at an electronic waste (e-waste) site in South China. AB - Air and foliage samples (Eucalyptus spp. and Pinus massoniana Lamb.) were collected from e-waste and reference sites in South China and analyzed for Dechlorane Plus (DP) and two dechlorinated DPs. DP concentrations in the air were 13.1-1794 pg/m3 for the e-waste site and 0.47-35.7 pg/m3 for the reference site, suggesting the recycling of e-waste is an important source of DP to the environment. Plant DP, with concentrations of 0.45-51.9 ng/g dry weight at the e waste site and 0.09-2.46 ng/g at the reference site, exhibited temporal patterns similar to the air DP except for pine needle at the reference site. The air-plant exchange of DP could be described with the two-compartment model. Anti-Cl11 DP was measured in most air and plant samples from the e-waste site. The ratios of anti-Cl11 DP to anti-DP in the air and plants may indicate the preferential uptake of dechlorinated DP by plant compared with DP. PMID- 21324410 TI - The deleterious consequences of privatization and outsourcing for hospital support work: the experiences of contracted-out hospital cleaners and dietary aids in Vancouver, Canada. AB - This article is based on the findings of the Hospital Support Workers Study, which includes in-depth interviews with 70 hospital housekeepers and dietary aids in Vancouver, British Columbia, Canada. As a result of provincial government legislation in 2003, all hospital-based support work in the Vancouver region was privatized and contracted out to three multinational corporations. The outsourcing of hospital support services is part of a larger global trend toward neoliberal policy reform in health care. This article presents the perceptions of hospital support workers about the consequences of contracting out on their work conditions, training, turnover rates and other issues that directly affect their quality of work and have important implications for patient health and well being. The findings suggest serious negative consequences for the health care system as a result of the privatization and contracting out of hospital support services. PMID- 21324411 TI - Association of physical violence by an intimate partner around the time of pregnancy with inadequate gestational weight gain. AB - Intimate partner violence has been previously examined in relation to a variety of pregnancy, labor and delivery outcomes. We evaluated whether women who experienced physical violence by their intimate partners around the time of pregnancy were less likely to achieve weight gain according to the US Institute of Medicine (IOM) guidelines. A cross-sectional study was conducted using the 2000-2006 Oklahoma Pregnancy Risk Assessment Monitoring Survey (PRAMS) data for post-partum women, 20 years and older. Physical violence perpetrated by an intimate partner before and/or during pregnancy was prevalent in nearly 6.5% of women. Weight gain was adequate in 38.8%, deficient in 28.4% and excessive in 32.8% of these women, respectively. After adjusting for maternal age, marital status, education, pregnancy intention, stressful life events, third-trimester use of tobacco and alcohol and gestational age at delivery, physical violence by an intimate partner around the time of pregnancy was positively but non significantly associated with excessive (but not deficient) gestational weight gain. After stratifying by age group, positive and significant associations between physical violence by an intimate partner around the time of pregnancy and inadequate gestational weight gain were observed only among women 35 years and older. With the exception of mothers >= 35 years of age, deficient and excessive gestational weight gains were not significantly related to experiences with physical violence by an intimate partner prior to delivery. Prospective cohort studies are needed to establish whether other forms of violence, including emotional and sexual abuse, can affect gestational weight gain and whether gestational weight gain can mediate the effect of physical, sexual and emotional abuse on pregnancy, labor and delivery outcomes. PMID- 21324412 TI - Reconstructing dose: a commentary on McEniry. PMID- 21324414 TI - Expression and prognostic role of pan-Ras, Raf-1, pMEK1 and pERK1/2 in patients with hepatocellular carcinoma. AB - AIMS: Ras/Raf/mitogen-activated protein kinase (MEK)/extracellular signal regulated kinase (ERK) signaling cascades play important roles in the transmission of signals involved in apoptosis. Importantly, components of these pathways are aberrantly expressed in human cancer. However, there is limited data linking clinical outcomes with the aberrant expression of this pathway. The present study analyzed the prognostic values of pan-Ras, Raf-1, phosphorylated MEK1 (pMEK1) and phosphorylated ERK1/2 (pERK1/2) in hepatocellular carcinoma (HCC). METHODS: Expression of pan-Ras, Raf-1, pMEK1 and pERK1/2 in 81 HCC patients who underwent curative resection was examined by immunohistochemical staining. Long-term survival after resection of patients according to the expression of pan-Ras, Raf-1, pMEK1 and pERK1/2 was assessed using univariate analysis and multiple Cox proportional hazards model. RESULTS: In univariate analysis, patients with Raf-1 or pMEK1 overexpression had shorter disease-free survival (DFS) (P<0.05) and poorer overall survival (OS) (P<0.05) than groups with weak-expression of Raf-1 or pMEK1, respectively. Patients with pan-Ras overexpression had poorer overall survival (OS) (P<0.05) than the group with weak expression of pan-Ras. Importantly, Raf-1 overexpression was a promising prognostic marker for poor survival according to multivariate Cox regression analysis (DFS, Hazard Ratio 1.807, P = 0.035; OS, Hazard Ratio 1.959, P = 0.044). CONCLUSIONS: Raf-1 overexpression could be considered as an independent prognostic biomarker in HCC and may predict early tumor recurrence and death for HCC patients. It can be used to stratify patients at higher risk for poor prognosis and help to select the appropriate therapeutic regime of HCC. PMID- 21324415 TI - Proximal radial drift following radial head resection. AB - BACKGROUND: Proximal radial migration is a well-documented phenomenon after radial head resection, but there have been no studies evaluating other planes of proximal radial stump drift after resection. The purpose of this study is to evaluate the anatomic position of the radial stump in relation to the capitellum after radial head resection, and determine the factors affecting this position and long-term functional outcomes. METHODS: Thirteen patients who had undergone radial head resection for a variety of injury patterns were identified and evaluated at a mean of 72 months postoperative. Each patient underwent a physical exam and outcome questionnaire evaluation (Disabilities of the Arm, Shoulder, and Hand [DASH] questionnaire, Mayo Elbow Performance Score [MEPS], and pain Visual Analog Scales [VAS] questionnaire). Anterior-posterior (AP) and lateral radiographs of the elbow were also performed. RESULTS: The proximal radius resection length was an average of 18 mm (range, 11.1-31.9) compared to the nonoperative side. The proximal radial stump was determined to have significant migration both medially (P = .01) and posteriorly (P = .002) as compared to the opposite side as determined on the AP and lateral radiographs, respectively. Greater than 2 cm of proximal radial resection was associated with greater posterior drift (P = .03). Poorer MEPS were only correlated with an initial dislocation injury pattern (P = .02). CONCLUSION: Radial head resection for fracture often leads to posterior and medial drift of the proximal radial stump, resulting in nonanatomic alignment with the capitellum. Increased resection greater than 2 cm resulted in larger amounts of drifting. Only a dislocation injury pattern was associated with worse functional outcomes. PMID- 21324416 TI - Outcomes of arthroscopic rotator cuff repairs in obese patients. AB - HYPOTHESIS: Rotator cuff tears are common orthopedic injuries and their arthroscopic treatment can be technically challenging. This study evaluated the outcomes of arthroscopic rotator cuff repairs in obese patients. We hypothesized that there would be a direct correlation between worse outcomes of arthroscopic rotator cuff repairs and increasing body mass index (BMI). MATERIALS AND METHODS: A retrospective review of patients undergoing arthroscopic rotator cuff repair by one orthopedic surgeon between 2005 and 2008 was performed. The study included 149 rotator cuff repairs. Recorded data included age, sex, BMI, size of rotator cuff tear on magnetic resonance imaging and intraoperatively, number of anchors used for repair, functional outcomes (American Shoulder and Elbow Surgeons and University of Pennsylvania scores), surgery time, total time for anesthesia, positioning, and hospital stay. Tears were classified by size. Strict inclusion and exclusion criteria were used. Surgical procedures were performed with general anesthesia, interscalene block, beach chair positioning, and a standardized operative technique. Patients followed a standard postoperative rehabilitation protocol. RESULTS: Mean patient age was 66 years. Mean follow-up was 16.3 months. Tears were classified as high grade partial (12%), small (23%), medium (29%), large (22%), and massive (14%). Patients were classified as normal weight (38%), overweight (23%), obese (20%), and morbidly obese (19%). A statistically significant correlation was found between obesity and worse functional outcomes, longer operative times, and longer length of hospital stay. DISCUSSION: This study reports new data concerning the association of BMI and early clinical outcome after arthroscopic rotator cuff repair surgery. Even though the obese group had greater limitations and lower rates of satisfaction at final follow-up than their non-obese counterparts, they still reported significant improvements from the surgery. CONCLUSION: Obesity has a negative impact on the operative time of arthroscopic rotator cuff repairs, length of hospitalization, and functional outcomes. PMID- 21324417 TI - Micromotion of plasma spray versus grit-blasted radial head prosthetic stem surfaces. AB - BACKGROUND: Initial stability of a textured surface prosthetic stem is necessary for bone in-growth. Surfaces currently used for radial head prostheses include titanium plasma spray and grit-blasted titanium. HYPOTHESIS: Plasma spray radial head prosthetic stems are less dependent than grit-blasted stems on a tight press fit. Good initial press-fit stability, with acceptable micro-motion, can be achieved with a greater range of stem sizes using a plasma spray than grit blasted surface. METHODS: Paired cadaveric radii were implanted with plasma spray or grit-blasted radial head prosthetic stems. Micromotion at the stem tip was measured under circumstances simulating eccentric loads. RESULTS: Micromotion in the plasma spray (PS) stems (49 +/- 37) MUm was not better than that in the grit blasted (GB) stems (28 +/- 10) MUm (P = .13). Micromotion of less than 100 MUm was measured in all 12 GB stems that were maximum or 1 mm less than maximum size, versus 5/6, and 4/6 PS stems, respectively. DISCUSSION: Micromotion in plasma spray prosthetic radial head stems was not better than that seen in grit-blasted stems, contrary to our initial hypothesis. CONCLUSION: Grit-blasted prosthetic radial head stems confer initial press-fit stability that is as good as, or slightly better than, corresponding plasma spray stems. Acceptable amounts of micromotion can be achieved with 2 grit-blasted stem sizes and probably with 2 plasma spray stem sizes. PMID- 21324418 TI - Trajectories of anxiety in oncology patients and family caregivers during and after radiation therapy. AB - PURPOSE: Anxiety is common in patients undergoing radiation therapy (RT) and in their family caregivers (FCs). Little is known about individual differences in anxiety trajectories during and after RT. This study aimed to identify distinct latent classes of oncology patients and their FCs based on self-reported anxiety symptoms from the beginning to four months after the completion of RT. METHOD: Using growth mixture modeling (GMM), longitudinal changes in Spielberger State Anxiety Inventory (STAI-S) scores among 167 oncology outpatients with breast, prostate, lung, or brain cancer and 85 FCs were evaluated to determine distinct anxiety symptom profiles. STAI-S scores were assessed just prior to, throughout the course of, and for four months following RT (total of 7 assessments). Baseline trait anxiety and depressive symptoms (during and after RT) were also assessed. RESULTS: The GMM analysis identified three latent classes of oncology patients and FCs with distinct trajectories of state anxiety: Low Stable (n = 93, 36.9%), Intermediate Decelerating (n = 82, 32.5%), and High (n = 77, 30.6%) classes. Younger participants, women, ethnic minorities, and those with children at home were more likely to be classified in the High anxiety class. Higher levels of trait anxiety and depressive symptoms, at the initiation of RT, were associated with being in the High anxiety class. CONCLUSIONS: Subgroups of patients and FCs with high, intermediate, and low mean levels of anxiety during and after RT were identified with GMM. Additional research is needed to better understand the heterogeneity of symptom experiences as well as comorbid symptoms in patients and FCs. PMID- 21324419 TI - Competency assessment methods - tool and processes: a survey of nurse preceptors in Ireland. AB - Determining student nurses' clinical competence is underpinned by significant challenges including a lack of reliable assessments methods and multiple factors that impact on the assessment function of preceptors. The purpose of this study was to explore preceptors' views and experiences of a competency assessment tool and process used to assess BSc student nurses' clinical competence. Data were collected using a mixed method descriptive approach that included focus groups (n=16) and a survey of preceptors (n=837) in general, mental health and intellectual disability nursing in Ireland. This paper reports the results of the preceptor survey, which yielded a response rate of 30.4%. Findings revealed that preceptors had difficulty in understanding the language used in the competency assessment document. There was a lack of continuity of the same preceptor to students over the assessment period and over half of the preceptors gave less than 30 min to the formal interview process. Preceptors more often assessed knowledge and attitudes compared to skills. Matching preceptor roster with students, standardisation of the process and a moderator system to support the integrity of competency assessment is recommended. PMID- 21324420 TI - Experimental gastrocystoplasty in rats: risk of developing ECLoma. AB - OBJECTIVE: There are no clinical reports on the risk of carcinoids in the gastric segment following gastrocystoplasty. The aim of the present study was to examine whether gastric carcinoids could develop in a rat model of gastrocystoplasty. MATERIALS AND METHODS: Rats were subjected to gastrocystoplasty in which 10% of the oxyntic part of the stomach was removed (i.e. 10% fundectomy), gastrocystoplasty with 90% fundectomy (known to induce hypergastrinemia), sham operation, or no operation, and were followed up for 6 months. Tissue specimens of bladder and stomach were analyzed by means of pathology and immunohistochemistry. RESULTS: Atrophy of gastric glands in the augmented bladders was found after gastrocystoplasty with either 10% or 90% fundectomy. Gastrocystoplasty with 90% fundectomy resulted in hyperplasia of the oxyntic mucosa, enterochromaffin-like (ECL) cell hyperplasia and ECLoma in the remnant stomach, and atrophy of the oxyntic mucosa and ECLoma in the gastric segment of the bladder. CONCLUSIONS: ECLoma could develop in the gastric segment of the bladder after gastrocystoplasty, particularly in the setting of hypergastrinemia. The tumorigenesis of ECLoma seems to follow the same pathological pathway regardless of whether the oxyntic mucosa is located in the stomach or the bladder. PMID- 21324421 TI - 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran). A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. PMID- 21324422 TI - A clone-based transcriptomics approach for the identification of genes relevant for itaconic acid production in Aspergillus. AB - Several Aspergillus species are well-known for the production of a variety of organic acids. In this study, a cloned based transcriptomics approach was used to identify genes crucial in the biosynthesis pathway for one of these acids, itaconic acid. From a number of different Aspergillus terreus controlled batch fermentations, those cultures with the largest difference in itaconic acid titer and productivity were selected for mRNA isolation. cDNAs derived from these mRNA samples were used for subsequent hybridization of glass slide arrays based on a collection of 5000 cDNA clones. A selection of 13 cDNA clones resulting in the strongest (>10-fold) differential hybridization signals were identified and subsequently the inserts of these clones were sequenced. Sequence analysis revealed the presence of in total five different gene inserts among the sequenced clones. From one of these sequences, encoding a gene of the MmgE-PrpD family, the full length coding region was shown to encode one of the crucial itaconic acid pathway enzymes cis-aconitate decarboxylase, by heterologous expression in Escherichia coli. Expression of this gene in Aspergillus niger, which is a natural citric acid producer, resulted in itaconate production. Genome analysis suggests that in A. terreus the cis-aconitate decarboxylase gene is part of an itaconate acid related gene cluster including genes encoding two pathway specific transporters and a Zinc finger protein. Interestingly, this cluster is directly linked to the large lovastatin gene cluster. PMID- 21324424 TI - [Narrow-band UV-B treatment in the early stages of mycosis fungoides]. PMID- 21324425 TI - [Prevalence of birthmarks and transient skin lesions in 1,000 Spanish newborns]. AB - BACKGROUND AND OBJECTIVES: Almost all newborn children have some sort of birthmark or transient benign skin lesion. Few studies, however, have analyzed their frequency, particularly in Spain. The aims of this study were to determine their prevalence in 1000 newborn children in the health care area of Ferrol in northwest Spain and to compare the results with those of 9 other studies with similar characteristics. PATIENTS AND METHODS: We undertook a descriptive study of 1000 newborn infants seen in the first 3 days of life at the neonatal clinic in the Department of Pediatrics, Hospital Arquitecto Marcide, Ferrol, Spain. Each infant was examined for the presence of 19 different transient benign skin lesions and 11 birthmarks. RESULTS: Birthmarks or benign skin lesions were present in 994 neonates (99.4%). Transient skin lesions were present in 99.2% and birthmarks in 72%. The 5 most prevalent lesions were sebaceous hyperplasia (75%), salmon patch (64.2%), hypertrichosis (59%), sucking calluses (54%), and palatine cysts (53.7%). CONCLUSIONS: The results of this study show that most neonates have benign skin lesions. The findings of studies to assess their frequency are influenced not only by geographic location (affecting variables such as climate, social and health care conditions, and ethnic group) but also by the timing of examination, the inclusion criteria applied, and the terminology used. PMID- 21324423 TI - MRG15 activates the cdc2 promoter via histone acetylation in human cells. AB - Chromatin remodeling is required for transcriptional activation and repression. MRG15 (MORF4L1), a chromatin modulator, is a highly conserved protein and is present in complexes containing histone acetyltransferases (HATs) as well as histone deacetylases (HDACs). Loss of expression of MRG15 in mice and Drosophila results in embryonic lethality and fibroblast and neural stem/progenitor cells cultured from Mrg15 null mouse embryos exhibit marked proliferative defects when compared with wild type cells. To determine the role of MRG15 in cell cycle progression we performed chromatin immunoprecipitation with an antibody to MRG15 on normal human fibroblasts as they entered the cell cycle from a quiescent state, and analyzed various cell cycle gene promoters. The results demonstrated a 3-fold increase in MRG15 occupancy at the cdc2 promoter during S phase of the cell cycle and a concomitant increase in acetylated histone H4. H4 lysine 12 was acetylated at 24 h post-serum stimulation while there was no change in acetylation of lysine 16. HDAC1 and 2 were decreased at this promoter during cell cycle progression. Over-expression of MRG15 in HeLa cells activated a cdc2 promoter-reporter construct in a dose-dependent manner, whereas knockdown of MRG15 resulted in decreased promoter activity. In order to implicate HAT activity, we treated cells with the HAT inhibitor anacardic acid and determined that HAT inhibition results in loss of expression of cdc2 mRNA. Further, chromatin immunoprecipitation with Tip60 localizes the protein to the same 110bp stretch of the cdc2 promoter pulled down by MRG15. Additionally, we determined that cotransfection of MRG15 with the known associated HAT Tip60 had a cooperative effect in activating the cdc2 promoter. These results suggest that MRG15 is acting in a HAT complex involving Tip60 to modify chromatin via acetylation of histone H4 at the cdc2 promoter to activate transcription. PMID- 21324426 TI - Experimental study of hybrid nematic wetting films. AB - Liquid crystal layers, with thickness less than 1 MUm, are deposited on isotropic - solid or liquid - substrates and investigated in the bulk nematic range of temperatures. The boundary conditions at interfaces are antagonist ones, therefore the layers are distorted due to nematic elasticity. These films are referred to as "hybrid nematics". The consequences are complex. First, a forbidden range of film thickness is observed, depending only on temperature. Second, the anisotropy of the elastic response gives rise to striking stripe patterns in the thicker films. This behavior is common to several members of the series of n-cyanobiphenyls deposited on oxidized silicon wafers, water and glycerol. The aim of the study is to collect data, and determine which ones find a place within a common theoretical framework. PMID- 21324427 TI - Paper surfaces functionalized by nanoparticles. AB - Nanomaterials with unique electronic, optical and catalytic properties have recently been at the forefront of research due to their tremendous range of applications. Taking gold, silver and titania nanoparticles as examples, we have reviewed the current research works on paper functionalized by these nanoparticles. The functionalization of paper with only a very small concentration of nanoparticles is able to produce devices with excellent photocatalytic, antibacterial, anti-counterfeiting, Surface Enhanced Raman Scattering (SERS) and Surface Plasmon Resonance (SPR) performances. This review presents a brief overview of the properties of gold, silver and titania nanoparticles which contribute to the major applications of nanoparticles functionalized paper. Different preparation methods of the nanoparticles functionalized paper are reviewed, focusing on their ability to control the morphology and structure of paper as well as the spatial location and adsorption state of nanoparticles which are critical in achieving their optimum applications. In addition, main applications of the nanoparticles-functionalized papers are highlighted and their critical challenges are discussed, followed by perspectives on the future direction in this research field. Whilst a few studies to date have characterized the distribution of nanoparticles on paper substrates, none have yet optimized paper as a nanoparticles' substrate. There remains a strong need to improve understanding on the optimum adsorption state of nanoparticles on paper and the heterogeneity effects of paper on the properties of these nanoparticles. PMID- 21324428 TI - In-hospital major bleeding during ST-elevation and non-ST-elevation myocardial infarction care: derivation and validation of a model from the ACTION Registry(r) GWTGTM. AB - Bleeding, a common complication of acute myocardial infarction (AMI) treatment, is associated with worse outcomes. A contemporary model for major bleeding associated with AMI treatment can stratify patients at elevated risk for bleeding and is needed to risk-adjust AMI practice and outcomes. Using the Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines (ACTION Registry-GWTG) database, an in-hospital major bleeding risk model was developed in a population of patients with ST-segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction. The model used only baseline variables and was developed (n = 72,313) and validated (n = 17,960) in patients with AMI (at 251 United States centers from January 2007 to December 2008). The 12 most statistically and clinically significant variables were incorporated into the final regression model. The calibration plots are shown, and the model discrimination is demonstrated in derivation and validation cohorts, as well as across key subgroups. The rate of major bleeding in the overall population was 10.8%. The 12 factors associated with major bleeding in the model were heart rate, baseline hemoglobin, female gender, baseline serum creatinine, age, electrocardiographic changes, heart failure or shock, diabetes, peripheral artery disease, body weight, systolic blood pressure, and home warfarin use. The risk model discriminated well in the derivation (C-statistic = 0.73) and validation (C-statistic = 0.71) cohorts. A risk score for major bleeding corresponded well with observed bleeding: very low risk (3.9%), low risk (7.3%), moderate risk (16.1%), high risk (29.0%), and very high risk (39.8%). In conclusion, the ACTION Registry-GWTG in-hospital major bleeding model stratifies risk for major bleeding using variables at presentation and enables risk-adjusted bleeding outcomes for quality improvement initiatives and clinical decision making. PMID- 21324429 TI - Relation of albuminuria to angiographically determined coronary arterial narrowing in patients with and without type 2 diabetes mellitus and stable or suspected coronary artery disease. AB - Albuminuria is associated with atherothrombotic events and all-cause mortality in patients with and without diabetes. However, it is not known whether albuminuria is associated with atherosclerosis per se in the same manner. The present study included 914 consecutive white patients who had been referred for coronary angiography for the evaluation of established or suspected stable coronary artery disease (CAD). Albuminuria was defined as a urinary albumin/creatinine ratio >= 30 MUg/mg. Microalbuminuria was defined as 30 to 300 MUg albumin/mg creatinine, and macroalbuminuria as a urinary albumin/creatinine ratio of >= 300 MUg/mg. The prevalence of stenoses of >= 50% was significantly greater in patients with albuminuria than in those with normoalbuminuria (66% vs 51%; p <0.001). Logistic regression analysis, adjusted for age, gender, diabetes, smoking, hypertension, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, C reactive protein, body mass index, estimated glomerular filtration rate, and the use of angiotensin-converting enzyme inhibitors/angiotensin II antagonists, aspirin, and statins, confirmed that albuminuria was significantly associated with stenoses >= 50% (standardized adjusted odds ratio [OR] 1.68, 95% confidence interval [CI] 1.15 to 2.44; p = 0.007). The adjusted OR was 1.54 (95% CI 1.03 to 2.30; p = 0.034) for microalbuminuria and 2.55 (95% CI 1.14 to 5.72; p = 0.023) for macroalbuminuria. This association was significant in the subgroup of patients with type 2 diabetes (OR 1.66, 95% CI 1.01 to 2.74; p = 0.045) and in those without diabetes (OR 1.42, 95% CI 1.05 to 1.92; p = 0.023). An interaction term urinary albumin/creatinine ratio*diabetes was not significant (p = 0.579). In conclusion, micro- and macroalbuminuria were strongly associated with angiographically determined coronary atherosclerosis in both patients with and those without type 2 diabetes mellitus, independent of conventional cardiovascular risk factors and the estimated glomerular filtration rate. PMID- 21324430 TI - A comparative biomechanical analysis of term fetal membranes in human and domestic species. AB - OBJECTIVE: The purpose of this study was to biomechanically characterize and compare human, porcine, equine, and ovine fetal membranes. STUDY DESIGN: Noncontact metrology was used for topographic analyses. Uniaxial tensile testing was performed to resolve specific biomechanical values. Puncture force and radial stresses were determined with biaxial puncture testing. Microstructure and surface tortuosity were analyzed histologically. RESULTS: Equine and human membranes sustained larger magnitude loading, but ovine and porcine membranes exhibited stronger material properties. Biaxial puncture validated uniaxial results; human and equine groups accommodated the largest loads but lowest stresses. Equine membranes were mostly vascularized; tortuosity was highest in porcine membranes. Species' gestation length was correlated positively with membrane thickness. CONCLUSION: The anatomy of placentation and length of species gestation show distinct relationships to membrane biomechanics. Unlike other species, human fetal membranes do not compensate for structural weakness with a thicker membrane. This finding may explain the high incidence of preterm premature rupture of membranes in humans. PMID- 21324431 TI - Prospective evaluation of insulin resistance among endometrial cancer patients. AB - OBJECTIVE: Obesity and estrogen are strong risk factors for endometrial cancer (EC). Whereas diabetes also increases the risk, little is known about related insulin resistance (IR). The purpose of this study was to determine the prevalence of IR in newly diagnosed EC patients. STUDY DESIGN: EC patients from a large, metropolitan county were prospectively enrolled from 2005 to 2008. Fasting serum was analyzed for glucose and insulin. IR was defined as a history of diabetes or a quantitative insulin sensitivity check index (QUICKI) (1/[log fasting insulin + log fasting glucose]) value of less than 0.357. RESULTS: Among 99 patients, diabetes was present in 30, and an abnormal QUICKI was found in 36 additional patients. Increased risk of IR was significantly associated with higher body mass index (P < .001), lower socioeconomic status (P = .007), and nulliparity (P = .029). CONCLUSION: IR was highly prevalent in endometrial cancer patients, including nonobese women. Better characterization of metabolic risks in addition to obesity may provide avenues for targeted cancer prevention in the future. PMID- 21324432 TI - Collection of human genomic DNA from neonates: a comparison between umbilical cord blood and buccal swabs. AB - OBJECTIVE: To compare DNA yield from neonatal umbilical cord blood and buccal swab specimens. STUDY DESIGN: Umbilical cord blood was obtained at birth in a cohort of women enrolled in a preterm labor study. If cord blood was not obtained, neonatal buccal samples were obtained using the Oragene saliva kits. DNA was extracted from all samples using the QIAamp extraction kits. DNA concentration and yield were compared between umbilical cord blood and buccal swabs. RESULTS: DNA concentrations from umbilical cord blood (n = 35) was greater than that obtained from buccal swabs (n = 20) (total sample: 209.0 +/- 110.7 ng/MUL vs 6.9 +/- 6.7 ng/MUL respectively, P < .001; partial sample: n = 30 cord blood vs n = 11 buccal, 70.0 +/- 51.4 ng/MUL vs 11.3 +/- 6.7 ng/MUL, respectively, P < .001) and produced more total DNA (total sample: 116.5 +/- 70.8 MUg vs 4.2 +/- 4.0 MUg, P < .001; partial:14.0 +/- 10.3 MUg vs 1.1 +/- 0.7 MUg, respectively, P < .001). CONCLUSION: Buccal swabs yield less neonatal DNA than umbilical cord blood specimens. PMID- 21324433 TI - Transcervical Foley catheter should be used in preference to intravaginal prostaglandins for induction of labor with an unfavorable cervix. PMID- 21324434 TI - Individual deviations in human chorionic gonadotropin concentrations during pregnancy. AB - BACKGROUND: Serum and urine human chorionic gonadotropin (hCG) vary greatly during the course of pregnancy. We investigated the cause of this variation. STUDY DESIGN: Eighty-two women provided daily urine samples during the first 6 weeks of gestation. First-void urine samples were monitored for luteinizing hormone (LH) and hCG. RESULTS: Variation was wide when pregnancy hCG anchoring to the last menstrual period (variation 677 +/- 786-fold) or to LH peak (variation 810 +/- 936-fold). When pregnancy was anchored to the day of implantation (variation 187 +/- 123-fold) variation was significantly reduced (P < .00005). Individual differences in the rate of hCG production were examined. hCG production ranged from 1.52-fold to 2.92-fold per day. Rate differences in hCG were also a major source of hCG variation. CONCLUSION: Two factors are responsible for the wide fluctuation in hCG concentrations, first dating pregnancies to the start of the last menstrual period rather than the timing of implantation and second, individual pregnancy differences in the rate of hCG production. PMID- 21324435 TI - Molecular biomarkers in endometrial hyperplasias predict cancer progression. AB - OBJECTIVE: The purpose of this study was to assess the value of the 2003 World Health Organization (WHO) and endometrial intraepithelial neoplasia (EIN) classifications, D-score, and molecular biomarkers in endometrial hyperplasia (EH) for cancer progression. STUDY DESIGN: We conducted a review of 307 endometrial hyperplasias for WHO and EIN classifications and an analysis of biomarkers, D-score, and cancer progression-free survival. RESULTS: The WHO, EIN, D-score, and many biomarkers were prognostic; 7.2% of the samples progressed to cancer. The WHO and EIN classifications correlated weakly with CK5/6 and p16. The D-score was strongest prognostically. When >1, it had the lowest false-negative progression rate of all features analyzed. COX2 negativity was the only other independent multivariate cancer progression predictor in endometrial hyperplasia, but only in cases with D-score <1. Eight of 13 cases (61%), with a combined D score of <1 and negative COX2 progressed, which contrasted with 3 of 139 of all other cases (2.8%) (P < .0001; hazard ratio, 53.0). The biomarkers did not strengthen the prognostic value of the WHO or EIN classification. CONCLUSION: Combined D-score <1 and COX2 negativity strongly predict cancer progression in endometrial hyperplasias. PMID- 21324436 TI - Alteration of masticatory muscle EMG activities during chewing after a reversible bite-raising in guinea pigs. AB - Previous studies have investigated the effects of increasing the occlusal vertical dimension (OVD) with an oral appliance on masticatory muscle EMG activity during oral behaviours in humans and animals. The present study investigated whether a short-term and reversible increase in OVD, followed by a reduction in OVD to the normal level, resulted in a time-correlated change in the EMG activities of the masseter and digastric muscles during chewing. To do this, a guinea pig model in which an increased OVD was established with natural tooth contacts was used. In the control group, in which no bite-raising treatment was applied, OVD gradually increased with a natural growth during the experimental period whilst the masseter and digastric EMG activities, burst duration, and chewing rhythm were unchanged. When the increase in OVD was established in the bite-raised group, the EMG activities of the masseter and digastric muscles were significantly increased by 88.6 and 55.2% from those before bite-raising treatment, respectively. However, during the following 11 days, the increased EMG activities of both muscles did not show changes associated with the subsequent decrease in the OVD to a normal level. The burst durations of both muscles and chewing rhythm were not significantly affected by the change in OVD during the experimental period. Within the limited recording period of the study, the return of OVD from increased to normal levels did not reverse the increased chewing related masticatory muscle EMG activity that was induced by the bite-raising treatment. PMID- 21324437 TI - Spectroscopic studies of interactions of chondroitin sulfates with cisplatin. AB - Complexation of cisplatin (CDDP) and chondroitin sulfate A (CSA) or C (CSC) has been reported to reduce the nephrotoxicity of CDDP. However the mechanism of interaction between CDDP and CSA or CSC was not known. In this study, spectroscopic analyses including NMR were carried out to examine the complexation interactions of CSA and CSC with CDDP. The time-dependent changes in the UV spectra indicate that CSA and CSC effectively complexes with CDDP in aqueous solution and that the reaction occurs subsequent to the hydrolysis of CDDP. The time-dependent change results measured by capillary electrophoresis showed that complexation of chondroitin sulfate (CS) followed first-order reaction kinetics and that the rate of CDDP hydrolysis in the complexation for both CSA and CSC was the same. These results suggested that the mechanism of complexation was a two step process with monoaqua formation proved to be the first step, which was also the reaction rate controlling step. Moreover, NMR data suggested that the carboxylic and sulfate groups of CS played an important role in its interaction with CDDP. PMID- 21324439 TI - [Application of the OSNA technique for intraoperative analysis of sentinel lymph node in breast cancer]. PMID- 21324438 TI - Full length antigen priming enhances the CTL epitope-based DNA vaccine efficacy. AB - Although CD8+ cytotoxic T lymphocyte (CTL) epitope-based DNA vaccination is valuable experience on vaccine research but many attempts are still continued to achieve acceptable protective response. To study the role of full length antigen in CTL epitope immunization, we evaluated cellular immunity of diverse patterns of complete Herpes simplex virus type 1 (HSV-1) glycoprotein B (gB) and the immunodominant CTL epitope (498-505) DNA injection in C57BL/6 mice. Optimal immune response was observed in the group immunized with the full length of gB in the first injection and CTL epitope in the second and third vaccination as assessed by lymphocyte proliferation assay (MTT), cytokine assay (ELISA) and CTL assay. B cell and spatially CD4+ T cell epitopes in full length protein might be important for appropriate priming of CTL immune response. These findings may have important implication for the improvement of CTL epitope based DNA vaccine against HSV and other pathogens. PMID- 21324440 TI - [Malignant retroperineal paraganglioma. An uncommon cause of arterial hypertension]. PMID- 21324441 TI - [Delayed diagnosis of a post-traumatic diaphragmatic hernia]. PMID- 21324442 TI - Differences in left and right carotid intima-media thickness and the associated risk factors. AB - AIM: To investigate the difference between the left and right carotid artery intima-media thickness (CIMT) with increasing age and to analyse the importance of the various risk factors associated with left and right CIMT, respectively. MATERIALS AND METHODS: Four hundred and forty-seven people were assigned into six groups based on age. CIMT and haemodynamic parameters of both carotid arteries were measured using the Quality Intima-Media Thickness (QIMT) technique. In addition, biochemical and anthropometric indices were also measured. Their associations were evaluated using simple and partial correlation analysis, adjusted for age. RESULTS: Bilateral CIMTs became thicker with age (p<0.001) and the left CIMT was significantly thicker compared with the right between the ages of 35 and 65 years (p=0.01-0.05). In addition, the right CIMT thickened 10 years later compared with the left. Partial correlation analysis showed that the right CIMT correlated better with haemodynamic parameters compared with the left CIMT, but the left CIMT showed better correlation with biochemical indices. CONCLUSION: Haemodynamic and biochemical changes had different effects on the CIMT depending on the side affected. In addition, the left CIMT was thicker than the right between the ages of 35 and 65 years old. PMID- 21324444 TI - [Acute pulmonary embolism: is necessary to stratify the risk?]. PMID- 21324443 TI - Effects of prenatal exposure to dioxin-like compounds on allergies and infections during infancy. AB - Dioxin-like compounds are endocrine disruptors. The effects of prenatal exposure to environmental levels of dioxins on immune function during infancy have not been clarified, although dioxins induce immunosuppression in offspring of animals. Moreover, human studies have not assessed the effects of gender- or congener-specific differences. The purpose of this study was to investigate the association between dioxin levels in maternal blood and the risk of infection and allergies in infancy. We examined 364 mothers and their infants enrolled in a Hokkaido Study on Environment and Children's Health between 2002 and 2005 in Sapporo, Japan. Relevant information was collected from a baseline questionnaire during pregnancy, medical records at delivery, and a follow-up questionnaire when the child was 18 months of age that assessed development of allergies and infections in infancy. Dioxin-like compound levels in maternal blood were measured with high-resolution gas chromatography/high-resolution mass spectrometry. Relatively higher levels of polychlorinated dibenzofuran were associated with a significantly increased risk of otitis media, especially among male infants (odds ratio=2.5, 95% confidence interval=1.1-5.9). Relatively higher levels of 2,3,4,7,8-pentachlorodibenzofuran were also associated with a significantly increased risk of otitis media (odds ratio=5.3, 95% confidence interval=1.5-19). However, we observed a weak association between dioxin-like compound levels and allergic symptoms in infancy. At environmental levels, prenatal exposure to dioxin-like compounds may alter immune function and increase the risk of infections in infancy, especially among males. The compound 2,3,4,7,8 pentachlorodibenzofuran may be responsible for this. PMID- 21324445 TI - Maintenance of early pregnancy without early hormone support after frozen-thawed embryo transfer in hormone replacement treatment cycles. AB - OBJECTIVE: To report two successful pregnancies after frozen-thawed ET in discontinued hormone replacement treatment cycles. DESIGN: Case report. SETTING: University hospital. PATIENT(S): Two infertile patients. INTERVENTION(S): Hormone replacement treatment for endometrial preparation and frozen-thawed ET. MAIN OUTCOME MEASURE(S): Ovarian ultrasonography, serial hormone measurements of serum E2 and P, successful pregnancy, and follow-up visit. RESULT(S): One patient discontinued both E2 and P support 2 weeks after ET. The other discontinued estrogen support on the day preceding ET. No spontaneous follicle development was observed by ultrasonography, and no increase in serum P concentration was observed. Both patients became pregnant and achieved deliveries. CONCLUSION(S): These two cases show that maintenance of pregnancy is possible without early hormone support in hormone replacement treatment cycles. PMID- 21324446 TI - At home testing: optimizing management for the infertility physician. AB - OBJECTIVE: To review and describe various over-the-counter testing products available to the infertility patient, a billion-dollar a year industry that continues to grow. DESIGN: Methodology involved a detailed Medline search of literature, use of online search engines, and focused communications with various manufacturers to determine the usefulness and validity of existing products. CONCLUSION(S): Although some home tests have been subjected to scientific scrutiny, others have not. At-home testing represents an opportunity for physicians to involve patients actively in their care. When properly used, these tests also may result in cost savings. However, physicians and consumers must understand the limitations of these tests. Many of the technologies used are innovative and, with proper evaluation and implementation, could serve as valuable adjuncts to medical practice. PMID- 21324447 TI - Lipocalin-1: a potential marker for noninvasive aneuploidy screening. AB - This study has identified the first protein, lipocalin-1, in the secretome of human blastocysts that is associated with chromosome aneuploidy. The development of a noninvasive technique to determine an embryo's developmental competence, including chromosomal constitution, by analysis of spent IVF culture medium will be a powerful tool for embryo selection in assisted reproductive technologies. PMID- 21324448 TI - Impact of submucous myoma on the severity of anemia. AB - OBJECTIVE: To analyze the impact of the diameter (myoma-phi) and the uterine cavity protruding proportion (protruding %) of the submucous myoma on serum hemoglobin (Hb) level. DESIGN: Retrospective descriptive study. SETTING: Tertiary university hospital. PATIENT(S): Two hundred fifty-nine women with a single submucous myoma. INTERVENTION(S): Transvaginal ultrasound examination and office hysteroscopy. MAIN OUTCOME MEASURE(S): Myoma-phi and protruding % were determined with transvaginal ultrasound scan and office hysteroscopy. Menorrhagic period (months) and serum Hb were recorded within 2 weeks of these examinations. RESULT(S): Serum Hb negatively correlated with myoma-phi, protruding %, and menorrhagic period. The negative association between serum Hb and protruding % was even more prominent after adjusting for myoma-phi. Multivariate regression analysis revealed that myoma-phi and protruding %, after adjusting for the confounding effect of menorrhagic period, maintained a strongly negative correlation with serum Hb level. When myoma-phi was <2 cm, however, the serum Hb levels were similar regardless of the protruding %. CONCLUSION(S): For women with a single submucous myoma, myoma-phi and protruding % can determine the serum Hb level significantly . As myoma-phi and protruding % increased, the serum Hb level decreased accordingly. PMID- 21324449 TI - Systematic review of the effectiveness and safety of assisted reproduction techniques in couples serodiscordant for human immunodeficiency virus where the man is positive. AB - OBJECTIVE: To evaluate the effectiveness and safety of assisted reproduction techniques (ART) in human immunodeficiency virus (HIV) serodiscordant couples. DESIGN: Systematic review of five databases of noncomparative open intervention and observational studies of serodiscordant couples undergoing ART, with study selection and data extraction performed independently and in duplicate. SETTING: Tertiary fertility centers. PATIENT(S): HIV serodiscordant couples where the man is HIV positive. INTERVENTION(S): Intrauterine insemination (IUI), in vitro fertilization (IVF), or intracytoplasmic injection (ICSI) performed after washed semen viral testing. MAIN OUTCOME MEASURE(S): Pregnancy rates per cycle, cumulative pregnancy, abortion rate, and HIV seroconversion in newborns or women. RESULT(S): Of the 658 abstracts retrieved, 41 were selected for review, and 17 full articles were included (3,900 IUI cycles in 1,184 couples in 11 aggregated studies and 738 ICSI/IVF cycles in 579 couples across 10 studies). The IUI and ICSI results were, respectively: pregnancy rates per cycle, 18% and 38.1%; cumulative pregnancy, 50% and 52.9%; and abortion rate, 15.6% and 20.6%. No seroconversions in women or newborns were detectable at birth or after 3 to 6 months. CONCLUSION(S): Cumulative evidence suggests that ART is safe and effective for avoiding horizontal and vertical transmission in HIV serodiscordant couples. PMID- 21324450 TI - Progesterone level and progesterone/estradiol ratio on the day of hCG administration: detrimental cutoff levels and new treatment strategy. AB - OBJECTIVE: To identify if there are certain cutoff levels for P and or the P/E(2) ratio on the day of hCG that would be defined as detrimental for occurrence of pregnancy in women with normal ovarian reserve undergoing cleavage-stage embryo transfer (ET). Secondarily, to determine if these same cutoffs might have the same potential negative effect in women undergoing blastocyst ET. DESIGN: Prospective cohort study including two randomized cohorts. SETTING: Private and university fertility centers. PARTICIPANT(S): A total of 240 women undergoing long agonist protocol with at least four grade 1 day 3 embryos. INTERVENTION(S): Women were randomized in a 1:1 ratio to undergo day 3 or day 5 embryo transfer. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate (CPR) was the primary outcome. RESULT(S): Using receiver operator characteristics, cutoffs for P and P/E(2) ratio were 1.5 ng/mL and 0.55, respectively. Patients with P <= 1.5 ng/mL and P/E(2) <= 0.55 undergoing cleavage-stage ET had higher CPR. Using multiple regression, P/E(2) ratio was the only independent predictor for pregnancy. The P and P/E(2) cutoffs were not correlated with CPR in blastocyst transfers. CONCLUSION(S): Progesterone >1.5 ng/mL and P/E(2) >0.55 affect the CPR in women undergoing cleavage-stage, but not blastocyst ET. P/E(2) ratio is the only independent prognosticator for cycle outcome in women undergoing cleavage-stage ET. PMID- 21324451 TI - Successful treatment of unresponsive thin endometrium. AB - OBJECTIVE: To assess whether inadequate, thin endometrium (<7 mm), after failure to expand with standard treatment options, will be responsive to cytokine treatment. DESIGN: Prospective cohort study of four patients. SETTING: Two independent IVF centers in New York City. PATIENT(S): Four consecutive women undergoing IVF who, after standard endometrial preparation, still demonstrated highly inadequate endometrium. INTERVENTION(S): Transvaginal endometrial perfusion with granulocyte colony-stimulating factor (G-CSF). MAIN OUTCOME MEASURE(S): Endometrial thickness on day of ET, with pregnancy as secondary endpoint. RESULT(S): We report successful endometrial expansion to at least minimal thickness of 7 mm after uterine perfusion with G-CSF in four patients previously resistant to treatment with estrogen and vasodilators. All four patients therefore reached ET, and all four also conceived, although one pregnancy required termination because of intramural, corneal ectopic location. Endometrial expansion to minimal thickness occurred within approximately 48 hours from infusion. CONCLUSION(S): Uterine perfusion with G-CSF represents a promising new tool for the currently mostly intractable problem of inadequate, thin endometrium. This treatment also deserves further investigation for its potential to improve implantation chances in association with IVF and, therefore, pregnancy rates. PMID- 21324452 TI - Aerobic exercise in women with polycystic ovary syndrome improves ovarian morphology independent of changes in body composition. AB - In a prospective study, eight women with polycystic ovary syndrome completed 16 weeks of individualized aerobic exercise training. Independent of changes in body weight and adiposity there was a statistically significant increase in aerobic fitness and insulin sensitivity and a statistically significant decrease in the total number of follicles measured by magnetic resonance imaging. PMID- 21324453 TI - Endometrial LGR7 expression during menstrual cycle. AB - In a prospective observational study, 50 healthy patients aged 18-39 years, with regular ovulatory cycle and normal hormone levels, underwent endometrial biopsy in the proliferative and secretory phase of the menstrual cycle for semiquantitative reverse-transcription polymerase chain reaction analysis of mRNA for LGR7, the classic relaxin receptor. LGR7 is constitutively expressed in human endometrium, and an increased LGR7 immunostaining is demonstrated in the secretory phase, confirming the involvement of relaxin in the physiology of endometrium and suggesting its role in implantation. PMID- 21324454 TI - CD4+CD28 null T lymphocytes are expanded in young women with polycystic ovary syndrome. AB - Women affected by polycystic ovary syndrome (PCOS) have an increased risk of cardiovascular disease. We demonstrated that women with PCOS showed an expansion of CD4(+)CD28(null) T cells, an aggressive population of T lymphocytes that has been recently associated with recurrent coronary instability and type 2 diabetes mellitus. This sheds new light on possible mechanisms responsible for the higher rate of cardiovascular disease among women with PCOS. PMID- 21324455 TI - A randomized trial of microdose leuprolide acetate protocol versus luteal phase ganirelix protocol in predicted poor responders. AB - We performed a randomized trial to compare IVF outcomes in 54 poor responder patients undergoing a microdose leuprolide acetate (LA) protocol or a GnRH antagonist protocol incorporating a luteal phase E(2) patch and GnRH antagonist in the preceding menstrual cycle. Cancellation rates, number of oocytes retrieved, clinical pregnancy rates (PR), and ongoing PRs were similar between the two groups. PMID- 21324456 TI - The steroidogenic factor-1 protein is not expressed in various forms of endometriosis but is strongly present in ovarian cortical or medullary mesenchymatous cells adjacent to endometriotic foci. AB - Steroidogenic factor-1 (SF-1) protein expression was not observed in any form of endometriosis (peritoneal, ovarian, or deep infiltrating endometriosis), which suggests that SF-1 locally produced by endometrial or stromal cells may not play a major role in the development of endometriosis. However, the strong expression of SF-1 in cortical and medullary ovarian mesenchymatous cells may be capable of creating a favorable steroidogenic environment and the development of the disease. PMID- 21324457 TI - Student nurses' career preferences for working with older people: a replicated longitudinal survey. AB - BACKGROUND: The world's populations are ageing and the need for nurses and health care workers from all disciplines to manage this phenomenon is increasing. Yet the literature and previous research undertaken by the author reveal consistently that working with older people is ranked poorly as a perceived career destination of student of nursing. OBJECTIVE: The main research objectives in this study were to (1) develop a profile of nursing career preferences and the rationale underpinning those choices and (2) compare these results with other literature to indicate if this profile is changing. DESIGN: This study uses a repeated measures design, with a non-probability sample of undergraduate Bachelor of Nursing students in the State of NSW, Australia between 2007 and 2009. RESULTS: The results show that 8% of the students began their course wanting to work with older people. Overall the ranking of 'working with older people' for commencing students was 7 out of ten. This ranking decreased throughout their course to ultimately become the least desired career choice of graduating nurses with only 3 of the 150 participants stating a desire to work with older people. Career choices, over all, divide along the lines of 'high-tech' and 'low-tech' which support the findings commonly found in the literature. It would appear that socialising factors within the education process, negative clinical experiences and the ageist bias within the broader community play an important role in these student's career choices. PMID- 21324458 TI - Association of gene variants with lipid levels in response to fenofibrate is influenced by metabolic syndrome status. AB - OBJECTIVE: Fenofibrate therapy reduces serum triglycerides (TG) and increases high-density lipoprotein-cholesterol (HDL-C) and thus addresses the atherogenic dyslipidemia associated with metabolic syndrome (MetS). Our hypothesis is that genetic factors contribute to the variability of lipid response to fenofibrate differently in subjects with MetS and without MetS. METHODS: We investigated the association in 25 candidate genes with lipid responses to a 3-weeks trial on fenofibrate in subjects with and without MetS. We employed growth curve mixed models to generate the response phenotypes to fenofibrate in TG, HDL-C, and low density lipoprotein-cholesterol (LDL-C) and examined the genetic associations accounting for family dependencies. RESULTS: After correcting for multiple testing (p<0.05) and accounting for significant differences in the association effect sizes between subjects with and without MetS (p<0.05), variants of APOA5 (rs662799) and APOE (rs429358) were associated with HDL-C and LDL-C responses in MetS subjects, while APOA4 (rs675) was associated with TG response in non-MetS subjects. There was also suggestive evidence that MetS may interact with APOA4 (p=0.017), APOA5 (p=0.06), and APOE (p=0.09) to the variation to lipid responses. CONCLUSIONS: Genetic effects that contributed to the variability of lipid responses to fenofibrate may differ in subjects with and without MetS. This research may provide guidance for more personalized and effective therapies. PMID- 21324459 TI - Abnormal plasma fibrin clot characteristics are associated with worse clinical outcome in patients with peripheral arterial disease and thromboangiitis obliterans. AB - BACKGROUND: A role of blood coagulation in the pathogenesis of peripheral arterial disease (PAD) and Buerger's disease, or thromboangiitis obliterans (TAO), remains unclear. OBJECTIVE: To test the hypothesis that PAD and TAO are associated with prothrombotic phenotype of a fibrin clot. PATIENTS AND METHODS: Ex vivo plasma fibrin clot permeability, turbidimetry and efficiency of fibrinolysis were investigated in 106 patients with PAD and 20 patients with TAO and compared with the respective control groups matched for age, sex, and cardiovascular risk factors. The progression of PAD and TAO were evaluated during follow-up of 3-7.5 years. PAD patients were characterized by lower clot permeability (-18.8%, p=0.005), shorter lag phase (-35.3%, p<0.001), higher maximum clot absorbancy (+22.4%, p<0.001), prolonged clot lysis time (+30.6%, p=0.003), and lower rate of D-dimer release from clots in the presence of recombinant tissue plasminogen activator (-16.5%, p=0.009), but twofold lower maximum D-dimer levels released from clots during lysis (p<0.001) than the controls. Similar, but more pronounced abnormalities were observed in TAO patients versus controls (all p<0.01). Seventeen PAD (16%) and 3 (15%) TAO patients were lost to follow-up. The progression observed in 47 (52.8%) PAD patients and 10 (59%) TAO patients was associated with lower clot permeability ( 14.6%, p=0.009, and -17.5%, p=0.02) and prolonged clot lysis (+11.3%, p=0.004, and +12.4%, p=0.03, respectively). CONCLUSIONS: Unfavorably altered fibrin clot properties are observed in both PAD and TAO. Denser fibrin clots with reduced susceptibility to lysis might characterize the progression of both diseases during long-term follow-up. PMID- 21324460 TI - VEGF-A-induced chemotaxis of CD16+ monocytes is decreased secondary to lower VEGFR-1 expression. AB - BACKGROUND: Monocyte recruitment into the vessel wall is a crucial initial step in vascular repair, arteriogenesis and atherogenesis. Two distinct human monocyte subpopulations can be classified according to their CD14/16 surface expression, namely CD14++CD16-monocytes (CD16-mo) and CD14+CD16+ monocytes (CD16+mo). We investigated different functional properties of the two monocyte subsets. METHODS: CD16-/CD16+mo were isolated from human blood by an immunological selection. We assessed monocyte chemokinesis, chemotaxis, adhesion and Vascular Endothelial Growth Factor (VEGF) receptor expression. Furthermore, generation of reactive oxygen species (ROS) as well as expression of antioxidant enzymes was investigated. RESULTS: Chemokinesis of CD16+mo was decreased compared to CD16-mo (p<0.01). Likewise, adhesion capacity of CD16+mo was weaker (p<0.05). CD16+mo chemotaxis towards the angiogenic ligands vascular endothelial growth factor-A (VEGF-A) and placenta growth factor-1 (PlGF-1) was reduced compared to CD16-mo. VEGFR-1 is the receptor for VEGF-A and PlGF-1 on monocytes. VEGFR-1 protein expression was lower in CD16+mo than in CD16-mo (p<0.05). The impaired VEGF-A- and PlGF-1-induced CD16+mo chemotaxis might therefore be attributed to the reduced VEGFR-1 expression. CD16+mo exhibited less spontaneous ROS production than CD16-mo. Additionally, the antioxidant enzyme manganese superoxide dismutase was expressed at higher levels in CD16+mo (p<0.05); this might partly explain the higher oxidative resistance of CD16+mo. CONCLUSION: These novel functional differences between CD16-mo and CD16+mo may predict different functional roles of both monocyte subsets in vascular repair, arteriogenesis and atherogenesis. PMID- 21324461 TI - Tumor necrosis factor-related apoptosis-inducing ligand and cardiovascular disease. PMID- 21324462 TI - A large screening of angiogenesis biomarkers and their association with neurological outcome after ischemic stroke. AB - BACKGROUND: The induction of angiogenesis after stroke may enhance neurorestorative processes. Our aim was to examine the endogenous angiogenesis balance and their association with long-term clinical outcome in ischemic stroke patients. METHODS: A total of 109 stroke subjects were included in the study. Firstly, plasma samples were obtained from control subjects (n = 26) and tPA treated stroke patients (n = 29) at baseline (within 3h of symptoms onset), 1, 2, 12, 24h after tPA treatment, at discharge and 3 months after the ischemic event. Angiogenic promoters (PDGF-AA, PDGF-BB, HGF, FGF, KGF, HB-EGF, TPO, VEGF, VEGFR 1, VEGFR-2 and SDF-1alpha) and inhibitors (endostatin, angiostatin, thrombospondin-1 and thrombospondin-2) were analyzed by Searchlight((r)) technology or ELISA. Additionally, baseline and 24h endostatin plasma level was determined in a new set of stroke patients (n = 80). Clinical parameters (NIHSS, mRS, mortality and hemorrhagic transformation events) were assessed to evaluate outcome. RESULTS: Baseline PDGF-BB, endostatin and thrombospondin-2 levels were higher in stroke patients than in controls (p < 0.05). A pro-angiogenic balance was associated with lower NIHSS scores and less intracranial hemorrhagic complications. Interestingly, a high baseline endostatin level was associated to long-term functional dependency (mRS > 2; p = 0.004). Finally, a baseline endostatin cut-off point of 184 ng/mL was an independent predictor of functional dependency at three months in the multiple logistic regression with an odds ratio of 8.9 (95% CI: 2.7-28.8; p = 0.0002). CONCLUSIONS: Our results indicate that an early pro-angiogenic balance is associated with mild short-term neurological deficit, while an acute anti-angiogenesis status determined by high endostatin plasma level predicts a worse long-term functional outcome. PMID- 21324463 TI - TRAIL attenuates the development of atherosclerosis in apolipoprotein E deficient mice. AB - TRAIL (tumour necrosis factor-related apoptosis inducing ligand) is most often reported to induce apoptosis in tumour cells. It is expressed in artery walls but its role and regulation in vascular pathologies is little studied. We aimed to measure the effect of genetic deletion of TRAIL on atherosclerosis in a mouse model. TRAIL was mainly expressed in endothelium, smooth muscle cells and macrophages within plaques. The absence of TRAIL in chow and in fat-fed mice led to greater lesion coverage in aortae (8 weeks, % area +/- SEM), n=7-8, 1.24 +/- 0.2 (no TRAIL, chow diet) vs. 0.42 +/- 0.1, p<0.01 and 3.4 +/- 0.8 (no TRAIL, Western diet) vs. 0.94 +/- 0.2, p<0.01 and larger, smooth muscle cell rich lesions at aortic roots than control mice (8 weeks, mean lesion area/total cross sectional area +/- SEM, n=7-8, 0.17 +/- 0.01 (no TRAIL, chow diet) vs. 0.135 +/- 0.006, p<0.05 and 0.36 +/- 0.03 (no TRAIL, Western diet) vs. 0.23 +/- 0.02, p<0.05) particularly at early time points. The larger early lesions appeared to be as a result of increased smooth muscle cells in lesions of TRAIL deficient, pro-atherosclerotic animals. We conclude that TRAIL attenuates plaque size at early stages of atherosclerosis. PMID- 21324465 TI - Multiphase flow modeling in centrifugal partition chromatography. AB - The separation efficiency in Centrifugal Partition Chromatography (CPC) depends on selection of a suitable biphasic solvent system (distribution ratio, selectivity factor, sample solubility) and is influenced by hydrodynamics in the chambers. Especially the stationary phase retention, the interfacial area for mass transfer and the flow pattern (backmixing) are important parameters. Their relationship with physical properties, operating parameters and chamber geometry is not completely understood and predictions are hardly possible. Experimental flow visualization is expensive and two-dimensional only. Therefore we simulated the flow pattern using a volume-of-fluid (VOF) method, which was implemented in OpenFOAM(r). For the three-dimensional simulation of a rotating FCPC(r)-chamber, gravitational centrifugal and Coriolis forces were added to the conservation equation. For experimental validation the flow pattern of different solvent systems was visualized with an optical measurement system. The amount of mobile phase in a chamber was calculated from gray scale values of videos recorded by an image processing routine in ImageJ(r). To visualize the flow of the stationary phase polyethylene particles were used to perform a qualitative particle image velocimetry (PIV) analysis. We found a good agreement between flow patterns and velocity profiles of experiments and simulations. By using the model we found that increasing the chamber depth leads to higher specific interfacial area. Additionally a circular flow in the stationary phase was identified that lowers the interfacial area because it pushes the jet of mobile phase to the chamber wall. The Coriolis force alone gives the impulse for this behavior. As a result the model is easier to handle than experiments and allows 3D prediction of hydrodynamics in the chamber. Additionally it can be used for optimizing geometry and operating parameters for given physical properties of solvent systems. PMID- 21324464 TI - Usefulness of serum tryptase level as an independent biomarker for coronary plaque instability in a Chinese population. AB - Tryptase and chymase are unique mast cell proteases that are essential in atherogenesis. This study establishes a link between serum tryptase and chymase levels and human coronary heart diseases (CHD) in a cohort of 270 subjects. Serum tryptase levels were significantly higher in patients with substantial CHD than in those without substantial CHD (substantial CHD vs. unsubstantial CHD: 7.81 +/- 0.52 ng/mL vs. 6.11 +/- 0.51 ng/mL, P=0.002). After subgrouping the substantial CHD patients into those with acute myocardial infarction (AMI) and those with unstable or stable angina pectoris (UAP or SAP), we demonstrated that serum tryptase levels were nearly doubled in AMI patients as compared with unsubstantial CHD patients (11.13 +/- 1.55 ng/mL vs. 6.11 +/- 0.51 ng/mL, P<0.01), and significantly higher than in UAP patients (7.19 +/- 0.62 ng/mL, P<0.05) or SAP patients (6.80 +/- 0.94 ng/mL, P<0.05). Although Spearman's correlation test showed that serum tryptase correlated significantly with age (P=0.014) and weakly with fasting glucose (P=0.084), total cholesterol (P=0.071), low-density lipoprotein (P=0.063), and triglyceride (P=0.058), serum tryptase levels remained significantly higher in substantial CHD patients than in unsubstantial CHD patients in a multiple linear regression test after adjusting for all these confounders (P=0.008). Serum chymase levels were also higher in AMI patients (27.64 +/- 7.57 ng/mL) or UAP patients (24.62 +/- 8.06 ng/mL) than in SAP patients (15.20 +/- 0.81 ng/mL) or unsubstantial CHD patients (16.84 +/- 0.56 ng/mL), although such differences were not statistically significant. Spearman's correlation test revealed that serum chymase levels correlated significantly only with fasting glucose levels (P=0.019), and CHD status did not affect chymase levels before and after adjusting for all confounders. Our observations suggest that serum tryptase is an independent biomarker for coronary plaque stability in this Chinese population. PMID- 21324466 TI - Selective extraction of emerging contaminants from water samples by dispersive liquid-liquid microextraction using functionalized ionic liquids. AB - Functionalized ionic liquids containing the tris(pentafluoroethyl)trifluorophosphate (FAP) anion were used as extraction solvents in dispersive liquid-liquid microextraction (DLLME) for the extraction of 14 emerging contaminants from water samples. The extraction efficiencies and selectivities were compared to those of an in situ IL DLLME method which uses an in situ metathesis reaction to exchange 1-butyl-3-methylimidazolium chloride (BMIM-Cl) to 1-butyl-3-methylimidazolium bis[(trifluoromethyl)sulfonyl]imide (BMIM-NTf(2)). Compounds containing tertiary amine functionality were extracted with high selectivity and sensitivity by the 1-(6-amino-hexyl)-1 methylpyrrolidinium tris(pentafluoroethyl)trifluorophosphate (HNH(2)MPL-FAP) IL compared to other FAP-based ILs and the BMIM-NTf(2) IL. On the other hand, polar or acidic compounds without amine groups exhibited higher enrichment factors using the BMIM-NTf(2) IL. The detection limits for the studied analytes varied from 0.1 to 55.1 MUg/L using the traditional IL DLLME method with the HNH(2)MPL FAP IL as extraction solvent, and from 0.1 to 55.8 MUg/L using in situ IL DLLME method with BMIM-Cl+LiNTf(2) as extraction solvent. A 93-fold decrease in the detection limit of caffeine was observed when using the HNH(2)MPL-FAP IL compared to that obtained using in situ IL DLLME method. Real water samples including tap water and creek water were analyzed with both IL DLLME methods and yielded recoveries ranging from 91% to 110%. PMID- 21324467 TI - Chiral separations and quantitative analysis of optical isomers on cellulose tribenzoate plates. AB - In this paper new cellulose tribenzoate/gypsum layers in the ratio up to 8/1 (w/w) were investigated for the chiral resolution of closely related aromatic ketones (e.g. tetralones and indanones), alcohols (e.g. benzhydrols) and racemates or enantiomers of other compound classes (e.g. dinitrophenyl amino acids). Among 22 investigated compounds, 16 racemates were baseline or partially resolved by eluting with methanol or 2-propanol/water mixtures on 4/1 (w/w) layers. The best results were compared with those achieved on microcrystalline cellulose triacetate plates and on cellulose tribenzoate columns. The study of structurally related solutes allowed us to increase the knowledge of the retention and resolution mechanisms on this chiral stationary phase and to highlight the role of pi-pi interactions between cellulose tribenzoate and solutes with different substituents on the aromatic ring. However, some results were unexpected and confirmed the complexity of enantioseparation mechanisms, thus evidencing the importance of experimental tests. Densitometric scan in the visible region of cellulose tribenzoate/gypsum plates after their exposure to iodine vapours allowed us to successfully perform the quantitative analysis of the investigated compounds, thus overcoming the detection problems normally encountered with this stationary phase. PMID- 21324468 TI - Properties of ionic liquids containing silver(I) or protic alkylethylenediamine cations with a bis(trifluoromethanesulfonyl)amide anion. AB - Ionic liquids of an N-alkylethylenediamine-silver(I) complex cation (alkyl=hexyl, 2-ethylhexyl, and octyl) or a protic N-alkylethylenediaminium cation (alkyl=butyl, hexyl, 2-ethylhexyl, octyl, decyl, and dodecyl) with a bis(trifluoromethanesulfonyl)amide counter anion (Ag-ILs and PILs, respectively) were prepared and their physicochemical properties were investigated. The trend of solidification decreased in the order octyl?hexyl>2-ethylhexyl for the Ag-ILs, and butyl>dodecyl>decyl>octyl>hexyl?2-ethylhexyl for the PILs. The diffusion coefficients of the cations indicated stronger intermolecular interactions in PILs than in the Ag-ILs because of hydrogen-bonding networks, and it has been revealed that the intermolecular interactions increase in the order, hexyl2 SDs below the mean) ASQ total scores were noted in 8.3% of moderate preterm infants, in 4.2% of full term infants, and in 14.9% of early preterm infants. ORs of abnormal ASQ total scores were 2.1 (95% CI, 1.3-3.4) for moderate preterm infants and 4.0 (95% CI, 2.4-6.5) for early preterm infants. Both moderate and early preterm infants had more frequent problems with fine motor, communication, and personal-social functioning compared with full-term infants. Compared with full-term infants, moderate preterm infants did not have a greater prevalence of problems with gross motor functioning and problem solving, whereas early preterms did. Socioeconomic status, small for gestational age status, and sex were associated with abnormal ASQ scores in moderate preterm infants. CONCLUSIONS: At preschool age, the prevalence of developmental delay in moderate preterm infants was 2-fold of that in full-term infants and one-half of that in early preterm infants. PMID- 21324482 TI - Is COPD associated with suicide behavior? AB - BACKGROUND: The goal of this study is to examine the relationship between chronic obstructive pulmonary disease (COPD) and suicidal ideation and suicide attempt among adults in the United States. METHODS: Data were drawn from the National Comorbidity Study-Replication (NCS-R), a household probability sample of adults ages 18 and older in the United States. RESULTS: COPD is associated with significantly increased odds of suicidal ideation and suicide attempt, compared with those without COPD. The association between COPD and suicide attempt remained statistically significant after adjusting for demographics, depression, panic disorder, substance use and nicotine dependence. The association between COPD and suicidal ideation was no longer significant after adjusting for nicotine dependence. CONCLUSIONS: Our findings provide initial evidence that there is a relationship between COPD and suicidal behavior among adults in the community. Future studies that can examine the relationship between COPD and completed suicide, as well as replication of these results, would improve our understanding of whether and to what degree COPD confers an increased vulnerability for suicide behavior. PMID- 21324483 TI - Acute panicogenic, anxiogenic and dissociative effects of carbon dioxide inhalation in patients with post-traumatic stress disorder (PTSD). AB - BACKGROUND: Increased anxiety and panic to inhalation of carbon dioxide (CO(2)) has been described in patients with anxiety disorders, especially panic disorder, compared to healthy subjects. Post-traumatic stress disorder (PTSD) has been hypothesised to resemble panic disorder and is currently classified as an anxiety disorder in DSM-IV. However, there are only very few data available about the sensitivity of patients with PTSD to CO(2). METHODS: In 10 patients with PTSD, 10 sex- and age-matched healthy subjects and 8 patients with panic disorder we assessed anxiety, panic, dissociative and PTSD symptoms before and after a single vital capacity inhalation of 35% CO(2). RESULTS: Patients with PTSD showed an increased anxiety, panic and dissociative reaction to the inhalation of 35% CO(2) compared to healthy participants. PTSD subjects' responses were indistinguishable from those of panic patients. Additionally, PTSD-typical symptoms like post traumatic flashbacks were provoked in patients with PTSD after the inhalation of CO(2). CONCLUSIONS: In our sample, PTSD was associated with an increased CO(2) reactivity, pointing to an increased susceptibility of PTSD patients to CO(2) challenge. PMID- 21324484 TI - The preventative role of curcumin on the lung inflammatory response induced by cardiopulmonary bypass in rats. AB - BACKGROUND: Acute lung injury is a frequent complication after cardiopulmonary bypass (CPB). Recent studies have reported that NF-kappaB plays an important role in the pathogenesis of post-CPB pulmonary dysfunction. Several signaling pathways, including the TLR4 pathway, induce NF-kappaB leading to an inflammatory response. We designed this study to determine whether or not curcumin inhibits TLR4 and MyD88 protein levels and ameliorates lung inflammatory injury in a rat CPB model. MATERIALS AND METHODS: Sprague-Dawley rats were randomly divided into the following five groups (n = 12): sham; control (CPB); vehicle; low-dose curcumin (L-Cur); and high-dose curcumin (H-Cur). The percutaneous beating heart CPB model of rat was established. Animals were pretreated with a single intraperitoneal injection of vehicle, L-Cur (50 mg/kg), or H-Cur (200 mg/kg) 2 h prior to CPB. Blood were sampled at various time points, then lung tissues and bronchoalveolar lavage fluid were harvested 24 h after CPB. RESULTS: CPB induced a marked increase in the concentrations of interleukin-8, tumor necrosis factor alpha, and matrix metalloproteinase-9 in plasma, bronchoalveolar lavage fluid, and lung tissues (P < 0.05 versus sham group), whereas curcumin pretreatment reduced these inflammatory markers. Curcumin had effective inhibitory effects on the expression of TLR4, MyD88, and NF-kappaB in lung tissues 24 h post-CPB (P < 0.05 versus vehicle group). Administration of curcumin remarkably decreased the lung injury score (L-Cur versus vehicle group, P = 0.024; H-Cur versus vehicle group, P = 0.013). CONCLUSIONS: Curcumin may be an alternative therapy for protecting CPB-induced lung injury by suppressing the expression of inflammatory cytokines. This anti-inflammatory effect of curcumin is partly related to the inhibition of TLR4, MyD88, and NF-kappaB. PMID- 21324485 TI - Ethyl pyruvate reduces acute lung injury via regulation of iNOS and HO-1 expression in endotoxemic rats. AB - BACKGROUND: Ethyl pyruvate (EP) has been shown to attenuate lipopolysaccharide (LPS)-induced acute lung injury (ALI). Induction of heme oxygenase-1 (HO-1) and suppression of inducible nitric oxide synthase (iNOS) expression provide cytoprotection in lung and vascular injury. The aim of this study is to evaluate whether the beneficial effect of EP on lung inflammation is related to HO-1 induction in a rat model of LPS-induced ALI. MATERIALS AND METHODS: Rats were administered LPS (30 mg/kg) by intravenous infusion for 4 h to induce ALI. EP (20, 40, and 60 mg/kg/4 h i.v. infusion) or vehicle was given 1 h after LPS initiation. RESULTS: EP 40 and 60 mg/kg attenuated plasma levels of TNF-alpha and IL-6 caused by LPS, and further increased IL-10 levels compared with the LPS group. At 6 h after LPS initiation, iNOS protein expression in lungs and plasma NO metabolite levels were markedly increased, which were reduced by EP 60 mg/kg. LPS caused a significant HO-1 induction, whereas administration of EP 60 mg/kg significantly induced higher HO-1 expression compared with the LPS group. The beneficial effects of EP on cytokines and iNOS expression were reversed by HO-1 inhibitor SnPP. EP significantly suppressed phosphorylated p38 MAPK and increased phosphorylated ERK1/2 protein levels in the lung tissue. The edema and infiltration of neutrophils into lungs was reduced by EP. CONCLUSION: EP reduced LPS-induced ALI, which may be mediated by induction of HO-1. The underlying mechanisms are associated with suppression of p38 MAPK and increase of ERK1/2 signaling pathway activation. PMID- 21324486 TI - Comparative healing of rat fascia following incision with three surgical instruments. AB - BACKGROUND: Incisional hernia and fascial dehiscence are associated with significant postoperative morbidity. Electrosurgical devices using pulsed radiofrequency energy and a novel electrode design markedly reduce thermal injury during cutting and coagulation while maintaining equal surgical performance. In this study, we examine fascial healing dynamics in a rat model following incision with a pulsed radiofrequency energy device (PRE), a conventional electrosurgical device, and a standard "cold" scalpel. We hypothesize that incisions made with the pulsed radiofrequency energy device will result in a superior fascial healing profile compared with conventional electrosurgery. MATERIALS AND METHODS: Full thickness surgical incisions were created in rat fascia using a commercially available PRE device, conventional electrosurgery, and a scalpel. Harvested fascial specimens were analyzed for burst strength testing and healing-associated histologic characteristics at d 7, 14, 21, and 42. RESULTS: PRE incisions were fully healed by 6 wk with normal tissue architecture. By all measures, wounds created by the PRE device were comparable to those made with the standard scalpel. Compared with PRE, conventional electrosurgery incisions exhibited a larger zone of tissue injury (68% greater in Coag mode, P < 0.0001; 46% greater in Cut mode, P < 0.001), an increased inflammatory response and a less favorable wound architecture. In the immediate postoperative period (1 wk), burst strength testing demonstrated that PRE fascial wounds were significantly stronger than those made by electrosurgery in Coag mode (318%, P = 0.001). CONCLUSIONS: The favorable fascial healing profile of the PRE device suggests that it is a promising new surgical technology. The early improved strength of wounds made with this device is of particular interest, as wound dehiscence is of greatest concern early in the healing process. PMID- 21324487 TI - Targeting the JNK signaling pathway potentiates the antiproliferative efficacy of rapamycin in LS174T colon cancer cells. AB - BACKGROUND: Targeting the mTOR signaling pathway with rapamycin in cancer therapy has been less successful than expected due in part to the removal of a negative feedback loop resulting in the over-activation of the PI3K/Akt signaling pathway. As the c-Jun N-terminal kinase (JNK) signaling pathway has been found to be a functional target of PI3K, we investigate the role of JNK in the anticancer efficacy of rapamycin. MATERIALS AND METHODS: The colon cancer cell line LS174T was treated with rapamycin and JNK phosphorylation was analyzed by Western Blot. Overexpression of a constitutively negative mutant of JNK in LS174T cells or treatment of LS174T cells with the JNK inhibitor SP600125 were used to determine the role of JNK in rapamycin-mediated tumor growth inhibition. RESULTS: Treatment of LS174T cells with rapamycin resulted in the phosphorylation of JNK as observed by Western Blot. The expression of a negative mutant of JNK in LS174T cells or treatment of LS174T cells with SP600125 enhanced the antiproliferative effects of rapamycin. In addition, in vivo, the antitumor activity of rapamycin was potentiated on LS174T tumor xenografts that expressed the dominant negative mutant of JNK. CONCLUSIONS: Taken together, these results show that rapamycin induced JNK phosphorylation and activation reduces the antitumor efficacy of rapamycin in LS174T cells. PMID- 21324488 TI - Single nucleotide polymorphisms in tobacco metabolism and DNA repair genes and prognosis in resected non-small-cell lung cancer. AB - BACKGROUND: If tobacco-related carcinogens are not inactivated or extruded from the cell, they can damage the DNA. Single nucleotide polymorphisms (SNPs) in genes involved in tobacco metabolism, DNA repair, and multidrug resistance have been related to lung cancer susceptibility. We examined 13 SNPs in 10 of these genes and correlated the results with time to progression (TTP) and overall survival (OS) in 71 smoker or former smoker patients with resected non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: DNA was obtained from paraffin embedded tumor. SNP analysis of the candidate genes was performed by allelic discrimination assay. Log-rank test, Kaplan-Meier plots, and Cox multivariate analysis were used to evaluate the association of TTP and survival with the SNPs evaluated. RESULTS: Patients with wild-type (wt) XPC rs2228001, wt CYP2C8 rs10509681, or non-wt NAT2 rs1799930 had a longer TTP. Patients with wt ERCC1 showed a nonsignificant trend towards longer TTP. No other relation between SNPs and TTP were observed. Patients harboring at least two unfavorable genotypes in these four genes had a shorter TTP and OS than patients with either one or no unfavorable genotypes. In the multivariate analysis, non-wt XPC rs2228001 and the presence of at least two unfavorable genotypes emerged as independent markers for shorter TTP. CONCLUSIONS: SNPs in tobacco metabolism and DNA repair genes may influence the clinical outcome of resected NSCLC. PMID- 21324489 TI - Threshold model for extremity compartment syndrome in swine. AB - BACKGROUND: Extremity compartment syndrome occurs when swelling develops within a muscle compartment to such an extent that the microvasculature is compressed and tissue perfusion is compromised. Untreated, this condition can result in widespread tissue destruction and loss of the affected limb. METHODS: Swine were subjected to diffuse muscle compression injury using a balloon catheter inserted between the anterior muscle compartment of the hind limb and the anterior face of the tibia. Balloons were inflated with saline to produce a sustained intramuscular pressure (IMP) of approximately 30 mmHg greater than mean arterial pressure. Following injury the IMP was monitored for up to 8 h. At the end of the monitoring period, the tibialis anterior muscle was collected and examined for injury. RESULTS: One animal receiving 6 h injury dislodged the implanted pressure transducers and was dropped from the data analysis. In all other limbs (n = 8) receiving 6 h injury, significant spontaneous increases in IMP were observed following injury. The tibialis anterior in all of the 6 h injury limbs also showed extensive tissue damage. In the limbs injured for 5 h (n = 10), only three showed a significant increase in IMP. The magnitude and duration of this increase closely resembled that seen following 6 h injury. Tissue damage was reduced in comparison with 6 h injury. CONCLUSIONS: The injury technique described here provides a potential useful threshold model for studying extremity compartment syndrome and the influence of related factors on the progression of this condition. PMID- 21324490 TI - Step-by-step guide for a simplified model of porcine orthotopic liver transplant. AB - BACKGROUND: Based on similar anatomy, physiology, and size to humans, pigs provide an excellent means for studying new therapies related to orthotopic liver transplant (OLT). Techniques that have been described to date, however, are unnecessarily complex and increase the likelihood of morbidity and adverse outcome. MATERIALS AND METHODS: Male outbred weanling pigs underwent OLT according to our procedure, with a short anhepatic time (<20 min) and without veno-venous bypass or vasoactive substances during the anhepatic phase. Vascular anastomoses were performed identical to the clinical setting, and a simple stented choledochocholedochostomy was created. RESULTS: The authors have performed this procedure 130 times using four transplant models: standard, whole liver (n = 10), small-for-size (n = 48), donor after cardiac death (n = 44), and donor adenoviral gene transfection (n = 28). The average cold ischemic and anhepatic times were 302 +/- 43 and 17 +/- 3 min, respectively. Hypotension was successfully treated with intravenous fluids. In all cases, the recipient survived the operation and was extubated. Survival to the end follow-up varied according to the model and was 56% (73/130) for all cases. At autopsy or euthanasia, no vascular thrombosis or outflow obstruction was found. Survival was 100% for pigs transplanted with standard, whole-liver grafts (n = 10). In this group, AST and bilirubin rose during the first 24 h after graft reperfusion, while the Quick prothrombin time (QPT) fell. By the fifth postoperative day, these parameters had returned to baseline. CONCLUSIONS: This model is straightforward and reproducible and offers surgeons and researchers the opportunity to perform OLT studies under clinically relevant conditions. PMID- 21324491 TI - Use of an ultrasonic blade facilitates muscle repair after incision injury. AB - BACKGROUND: The ultrasonic Harmonic Blade cuts and coagulates soft tissue at temperatures lower than conventional electrosurgery. This study investigated whether improved hemostatic control and reduced collateral damage in skeletal muscle incisions translates into improved myofiber regeneration, reduced fibrosis and faster muscle recovery. MATERIALS AND METHODS: Transections in the left gastrocnemius muscles of mice were made with the Harmonic Blade, and contralaterally, with either cold steel scissors or electrosurgery. Histology up to 8 wk after surgery was performed to evaluate myofiber regeneration and fibrosis. Tissue inflammation (Gr1+ neutrophils) and vascularization (CD31+ capillaries) were assessed immunohistochemically at 1 wk . RESULTS: Overall the Harmonic Blade showed significantly higher level of muscle regeneration than cold steel. Fibrosis for both the Harmonic Blade and cold steel decreased three-fold over the 8 wk period, while electrosurgery yielded significantly increasing fibrosis through wk 4 before declining. At 1 wk post-surgery the Harmonic Blade induced less inflammation than electrosurgery, and higher vascularization than electrosurgery and cold steel. CONCLUSIONS: Harmonic Blade-incised tissue showed accelerated vascularization, slight reduction of inflammation, enhanced muscle regeneration and decreased scarring, demonstrating a more effective healing process than electrosurgery. PMID- 21324492 TI - CpG ODN, Toll like receptor (TLR)-9 agonist, inhibits metastatic colon adenocarcinoma in a murine hepatic tumor model. AB - BACKGROUND: Colorectal liver metastases (mets) are often refractory to conventional therapies. CpG oligodeoxynucleotide 1826 (CpG), a Toll like receptor (TLR)-9 agonist, inhibits murine tumor growth by augmenting Th1 immunity. The impact of CpG on metastatic colon tumors is unknown. The purpose of this study was to determine the effect of CpG on the growth of hepatic colon cancer mets. METHODS: Two studies with separate control groups were performed using 40 Balb/C mice (study A, CpG 50 MUg/dose; study B, 100 MUg/dose; n = 9-11/subgroup). Tumors were induced via portal vein injection of 2 * 10(4) CT26 colon tumor cells. After surgery, the mice were randomized; test groups were given 14 daily intraperitoneal (i.p.) CpG injections (50 or 100 MUg/dose) while the control group received i.p. saline. On d 21 mice were sacrificed, the livers and spleens excised and weighed and the mets counted (reported as median +/- 95% confidence interval [CI]) and histologically assessed. RESULTS: The CpG mice had significantly fewer hepatic mets/mouse (study A, median two nodules, 95% CI, 0-3; study B, 0 nodules, 95% CI 0-0) than the control mice (study A, 6 nodules, 95% CI, 3-9, P = 0.002; Study B, 6 nodules, 95% CI, 3-9, P < 0.001). In study B, there were no mets in 9/11 CpG mice (versus 2/10 for CpG 50 MUg and 0/19 for control mice). The mean liver/spleen weights of the CpG mice in both studies were significantly greater than in control mice. Histologically, high mitotic rates were noted in control mets while fewer tumor cells and histiocytic and lymphocytic infiltrates were found in CpG livers. CONCLUSIONS: CpG inhibited liver tumor growth in this model (100 MUg/dose more than 50 MUg/dose). CpG was associated with increased liver and spleen weights not related to tumor burden. Increased lymphocytic and histiocytic infiltrates were noted in CpG-treated tumor nodules. PMID- 21324493 TI - The effect of catecholamines on hepatic artery vasospasm in small-for-size syndrome liver grafts. PMID- 21324495 TI - Antifouling strategies: history and regulation, ecological impacts and mitigation. AB - Biofouling increases drag on marine vessels resulting in higher fuel consumption and can also facilitate the transport of harmful non-indigenous species (NIS). Antifouling technologies incorporating biocides (e.g., copper and tributyltin) have been developed to prevent settlement of organisms on vessels, but their widespread use has introduced high levels of contamination into the environment and raised concerns about their toxic effects on marine communities. The recent global ban on tributyltin (1 January 2008) and increasing regulation of copper have prompted research and development of non-toxic paints. This review synthesises existing information regarding the ecological impact of biocides in a wide range of organisms and highlights directions for the management of antifouling paints. We focus particularly on representatives of the recent past (copper and tributyltin) and present (copper and 'booster') biocides. We identify knowledge gaps in antifouling research and provide recommendations relating to the regulation and phasing-out of copper. PMID- 21324494 TI - Recurrent myoglobinuria in a sporadic patient with a novel mitochondrial DNA tRNA(Ile) mutation. AB - The differential diagnosis of myoglobinuria includes multiple etiologies, such as infection, inflammation, trauma, endocrinopathies, drugs toxicity, and primary metabolic disorders. Metabolic myopathies can be due to inherited disorders of glycogen metabolism or to defects of fatty acid oxidation. Primary respiratory chain dysfunction is a rare cause of myoglobinuria, but it has been described in sporadic cases with mutations in genes encoding cytochrome b or cytochrome c oxidase (COX) subunits and in four cases with tRNA mutations. We describe a 39 year-old woman with myalgia and exercise-related recurrent myoglobinuria, who harbored a novel mitochondrial DNA mutation at nucleotide 4281 (m.4281A>G) in the tRNA-isoleucine gene. Her muscle biopsy revealed ragged-red and COX-deficient fibers. No deletions or duplication were detected by Southern blot analysis. The m.4281A>G mutation was present in the patient's muscle with a mutation load of 46% and was detected in trace amounts in urine and cheek mucosa. Single-fiber analysis revealed significantly higher levels of the mutation in COX-deficient (65%) than in normal fibers (45%). This novel mutation has to be added to the molecular causes of recurrent myoglobinuria. PMID- 21324496 TI - Lycorine induces cell death in the amitochondriate parasite, Trichomonas vaginalis, via an alternative non-apoptotic death pathway. AB - In this study, the mechanism of action of the pro-apoptotic alkaloid lycorine on an amitochondriate cell, the parasite Trichomonas vaginalis, was investigated. The cytotoxicity of lycorine against T. vaginalis was studied from 2.5 to 1000MUM and several important ultrastructural alterations were observed by electron microscopy. Lycorine arrested the T. vaginalis cell cycle, although no hallmarks of apoptosis, such as apoptotic bodies, were observed. Consequently, the underlying mechanism of action fails to completely fulfill the criteria for apoptosis. However, some similarities to paraptotic cell death were observed. PMID- 21324497 TI - Pentoxifylline induces capacitation and acrosome reaction and improves quality of motility in canine ejaculated spermatozoa. AB - To evaluate effects of different concentrations of pentoxifylline, as phosphodiesterase inhibitor, on quality of motility, capacitation and acrosome reaction, Ejaculated spermatozoa were collected from crossbred dogs. The sperm were incubated at concentrations of 0.1, 1, 10 and 100mM pentoxifylline for 2h. Conventional assessment was also made on the percentage of motility and quality of motility of spermatozoa; values were expressed as sperm motility index (SMI). Capacitation and acrosome reaction were also evaluated by chlortetracycline fluorescence staining. SMI as quality index of sperm was significantly increased in concentrations of 10 and 100mM pentoxifylline during 1 and 2h compared to control. The number of capacitated or acrosome reacted spermatozoa significantly (P<0.05) were higher than controls at high concentrations of pentoxifylline (10 and 100mM) during 1 and 2h. In conclusion, high concentration of pentoxifylline is able to induce capacitation and acrosome reaction and improves quality of motility in canine ejaculated spermatozoa. PMID- 21324498 TI - The length of BTV-8 viraemia in cattle according to infection doses and diagnostic techniques. AB - Four groups of BTV free Frisian and cross bred calves were used to determine the length of viraemia following infection with different doses of BTV-8 Italian isolate. The first group of five animals was infected with 10 TCID(50) of BTV-8, the second group of four animals with 10(3) TCID(50) and the third group, which also included four animals, was infected with 10(6) TCID(50). A placebo containing uninfected tissue culture medium was given to the four animals of the fourth group. The viraemia was evaluated by real time RT-PCR and virus isolation. In all infected groups, virus isolation was able to detect infectious virus up to 39 days post infection (dpi) while RT-PCR was positive up to 151-157dpi. Infectious dose did influence neither the length nor the pattern of BTV-8 viraemia and confirmed that real time RT-PCR remains positive although no circulating virus is detectable in the peripheral circulation. PMID- 21324499 TI - IGFR-I expression and structural analysis of the hard palatine mucosa in an ethanol-drinking rat strain (UChA and UChB). AB - The study analyzed the effects of chronic alcohol ingestion on the ultrastructure of the lining epithelium of the hard palatine mucosa of rats UChA and UChB (lines with voluntary alcohol consumption) in order to contribute to the understanding of the consequences of alcohol abuse for the morphology of the digestive system. Thirty female adult animals aged 120 days were divided into three experimental groups. (1) Ten UChA rats (genetically low ethanol consumer) with voluntary intake of 10% v/v (5.45 g/kg/day) ethanol solution and water. (2) Ten UChB (genetically high ethanol consumer) rats with voluntary intake of 10% v/v (7.16 g/kg/day) ethanol solution and water. (3) Ten Wistar rats with voluntary ad libitum water intake (control group). Both groups received Nuvital pellets ad libitum. The IGFR-I expression was intense in both experimental groups. The epithelial cells of the alcoholic rats UChA and UChB showed many alterations such as the presence of lipid droplets, altered nuclei, nuclei in corneum layer and disrupted mitochondria. It was concluded that ethanol intake induces ultrastructural lesions in the hard palatine mucosa. PMID- 21324500 TI - In vitro effects of juvenile hormone analog on wing disc morphogenesis under ecdysteroid treatment in the female-wingless bagworm moth Eumeta variegata (Insecta: Lepidoptera, Psychidae). AB - Female adults of the bagworm moth, Eumeta variegata, lack wings completely, whereas male adults of this species have functional wings. We previously found that ecdysteroid induces apoptotic events in the female wing rudiment of E. variegata in vitro, whereas the male wing discs cultured with 20-hydroxyecdysone (20E) underwent apolysis and then cell differentiation. To investigate whether juvenile hormone (JH) in involved in sex-specific cellular response to ecdysteroid during wing development between sexes of E. variegata, we tested the effects of juvenile hormone analog (JHA), methoprene, and 20E on wing disc morphogenesis between sexes in vitro. Using transmission electron microscopy (TEM), we found that both higher concentration of JHA (5 MUg/ml) and 20E (1 MUg/ml) addition induced cell death (apoptosis) in the male wing discs but not induced cell death in the female wing rudiments in vitro in E. variegata. These culture experiments clearly detected the differential responses of wing discs to JHA under ecdysteroid treatment between sexes. We propose two important hypotheses: (1) JH is not significantly involved in the suppression of the female wing rudiment morphogenesis under 20E treatment, (2) female wing rudiment has lost the ability for cell proliferation in response to the stimulus of 20E. PMID- 21324501 TI - PHEX neutralizing agent inhibits dentin formation in mouse tooth germ. AB - The mutation of phosphate-regulating gene with homologies to endopeptidases on the X-chromosome (PHEX) can lead to human X-linked hypophosphatemic rickets which displays hypo-mineralization in bone and dentin. To study its possible roles in teeth, PHEX antibody was injected into pregnant mice on E15 to explore its roles on the formation of enamel and dentin. Mallory trichrome staining results showed that arrangements of ameloblasts and odontoblasts were irregular after PHEX antibody treatment. Differentiation of odontoblasts and the formation of dentin were inhibited. Spatiotemporal distribution of PHEX protein was observed in various stages of tooth germ. Immunohistochemical results showed positive PHEX signals appeared in the inner enamel epithelium on E16 and became stronger on E18. Ameloblasts and odontoblasts showed much higher PHEX expression on P1 and P3. Expression of PHEX in odontoblasts decreased accordingly. However, enamel formation was only slightly affected. The findings proved that a decrease in PHEX expression could suppress dentin formation. PMID- 21324502 TI - The UL4 protein of equine herpesvirus 1 is not essential for replication or pathogenesis and inhibits gene expression controlled by viral and heterologous promoters. AB - Defective interfering particles (DIP) of equine herpesvirus 1 (EHV-1) inhibit standard virus replication and mediate persistent infection. The DIP genome is comprised of only three genes: UL3, UL4, and a hybrid gene composed of portions of the IR4 (EICP22) and UL5 (EICP27) genes. The hybrid gene is important for DIP interference, but the function(s) of the UL3 and UL4 genes are unknown. Here, we show that UL4 is an early gene activated solely by the immediate early protein. The UL4 protein (UL4P) was detected at 4hours post-infection, was localized throughout the nucleus and cytoplasm, and was not present in purified virions. EHV-1 lacking UL4P expression was infectious and displayed cell tropism and pathogenic properties in the mouse model similar to those of parental and revertant viruses. Reporter assays demonstrated that the UL4P has a broad inhibitory function, suggesting a potential role in establishing and/or maintaining DIP-mediated persistent infection. PMID- 21324503 TI - Arenavirus reverse genetics: new approaches for the investigation of arenavirus biology and development of antiviral strategies. AB - Several arenaviruses, chiefly Lassa virus, cause hemorrhagic fever disease in humans and pose a significant public health problem in their endemic regions. On the other hand the prototypic arenavirus LCMV is a superb workhorse for the investigation of virus-host interactions and associated disease. The development of novel antiviral strategies to combat pathogenic arenaviruses would be facilitated by a detailed understanding of the arenavirus molecular and cell biology. To this end, the development of reverse genetic systems for several arenaviruses has provided investigators with novel and powerful approaches to dissect the functions of arenavirus proteins and their interactions with host factors required to complete each of the steps of the virus life cycle, as well as to cause disease. PMID- 21324504 TI - The central repeat domain 1 of Kaposi's sarcoma-associated herpesvirus (KSHV) latency associated-nuclear antigen 1 (LANA1) prevents cis MHC class I peptide presentation. AB - KSHV LANA1, a latent protein expressed during chronic infection to maintain a viral genome, inhibits major histocompatibility complex class I (MHC I) peptide presentation in cis as a means of immune evasion. Through deletional cloning, we localized this function to the LANA1 central repeat 1 (CR1) subregion. Other CR subregions retard LANA1 translation and proteasomal processing but do not markedly inhibit LANA1 peptide processing by MHC I. Inhibition of proteasomal processing ablates LANA1 peptide presentation. Direct expression of LANA1 within the endoplasmic reticulum (ER) overcomes CR1 inhibition suggesting that CR1 acts prior to translocation of cytoplasmic peptides into the ER. By physically separating CR1 from other subdomains, we show that LANA1 evades MHC I peptide processing by a mechanism distinct from other herpesviruses including Epstein Barr virus (EBV). Although LANA1 and EBV EBNA1 are functionally similar, they appear to use different mechanisms to evade host cytotoxic T lymphocyte surveillance. PMID- 21324505 TI - Integrated analysis of water quality parameters for cost-effective faecal pollution management in river catchments. AB - In many parts of the world, microbial contamination of surface waters used for drinking, recreation, and shellfishery remains a pervasive risk to human health, especially in Less Economically Developed Countries (LEDC). However, the capacity to provide effective management strategies to break the waterborne route to human infection is often thwarted by our inability to identify the source of microbial contamination. Microbial Source Tracking (MST) has potential to improve water quality management in complex river catchments that are either routinely, or intermittently contaminated by faecal material from one or more sources, by attributing faecal loads to their human or non-human sources, and thereby supporting more rational approaches to microbial risk assessment. The River Ouse catchment in southeast England (U.K.) was used as a model with which to investigate the integration and application of a novel and simple MST approach to monitor microbial water quality over one calendar year, thereby encompassing a range of meteorological conditions. A key objective of the work was to develop simple low-cost protocols that could be easily replicated. Bacteriophages (viruses) capable of infecting a human specific strain of Bacteroides GB-124, and their correlation with presumptive Escherichia coli, were used to distinguish sources of faecal pollution. The results reported here suggest that in this river catchment the principal source of faecal pollution in most instances was non human in origin. During storm events, presumptive E. coli and presumptive intestinal enterococci levels were 1.1-1.2 logs higher than during dry weather conditions, and levels of the faecal indicator organisms (FIOs) were closely associated with increased turbidity levels (presumptive E. coli and turbidity, r = 0.43). Spatio-temporal variation in microbial water quality parameters was accounted for by three principal components (67.6%). Cluster Analysis, reduced the fourteen monitoring sites to six representative 'sentinel' sites. The correlation coefficient between presumptive E. coli and phages of Bacteroides GB 124 was very small (r = 0.05) whilst that between turbidity and suspended solids was high (r = 0.62). Variations in climate, animal and anthropogenic interferences were all, either directly or indirectly, related to faecal contamination. The findings show the importance of meteorological conditions, such as storm events, on microbial water quality, and suggest that any future increases in the frequency of storm events (associated with climate change) are likely to result in a greater incidence of FIO/pathogen loads. This low-cost approach could help to predict spatio-temporal 'hotspots' of elevated waterborne disease risk. The work also represents an important step towards integrating novel MST tools into river catchment modelling. PMID- 21324506 TI - Feasibility study of moving-fiber biofilm membrane bioreactor for wastewater treatment: process control. AB - Non-biodegradable solid wastes of non-intact membrane fibres/flatsheets and modules disposed from membrane bioreactor (MBR) plants are in a great concern for environmental impact. Estimated cumulative amount of the module solid wastes from European countries in the next five years should be larger than 1000 tons in which a proper management strategy and reuse for the disposed solid waste are urgently required. This article was aimed to propose an alternative to make uses of the non-intact membrane fibres for the aerobic biofilm supports and to study the feasibility on process operation of novel moving-fiber biofilm MBR. A system of moving-fiber biofilm membrane bioreactor was designed and evaluated experimentally, including an upflow anaerobic sludge reactor, an aerobic moving fiber biofilm reactor, and a submerged membrane filtration unit. Start-up method and operating conditions to control the biofilms growing on the moving fibers were investigated. Organic removal rates, optimum operating conditions for the system, and membrane fouling rates at various membrane aeration rates and permeate fluxes were monitored to evaluate the performance of the proposed BF-MBR process. PMID- 21324507 TI - Influence of organic matter on arsenic removal by continuous flow electrocoagulation treatment of weakly mineralized waters. AB - The aim of this study is to evaluate and understand the electrocoagulation/flocculation (ECF) process to remove arsenic from both model and natural waters with low mineral content and to compare its performances to the coagulation/flocculation (CF) process already optimized. Experiments were thus conducted with iron electrodes in the same specific treatment conditions (4<=current density (mAcm(-2))<=33) to study the influence of organic matter on arsenic removal in conditions avoiding the oxidation step usually required to improve As(III) removal. The process performance was evaluated by combining quantification of arsenic residual concentrations and speciation and dissolved organic carbon residual concentrations with zeta potential and turbidity measurements. When compared to CF, ECF presented several disadvantages: (i) lower As(V) removal yield because of the ferrous iron dissolved from the anode and the subsequent negative zeta potential of the colloidal suspension, (ii) higher residual DOC concentrations because of the fractionation of high molecular weight compounds during the treatment leading to compounds less prone to coagulate and (iii) higher residual turbidities because of the charge neutralization mechanisms involved. However, during this process, As(III) was oxidized to As(V) improving considerably its removal whatever the matrix conditions. ECF thus allowed to improve As(III) removal without applying an oxidation step that could potentially lead to the formation of toxic oxidation by-products. PMID- 21324508 TI - Effect of surfactants, dispersion and temperature on solubility and biodegradation of phenanthrene in aqueous media. AB - In the present study surfactant addition with the help of either a mechanical dispersion or a thermal treatment was applied in order to increase the solubility and the bioavailability of phenanthrene in aqueous media, and therefore to promote its biodegradation. Among four tested surfactants (Tween 80, Brij 30, sodium dodecyl sulphate and rhamnolipids), Brij 30 (0.5 gL(-1)) showed the best results allowing us to attain about 20 mgL(-1) of soluble phenanthrene. An additional thermal treatment at 60 degrees C for 24h, 200 rpm permitted to increase the solubility of phenanthrene in the presence of Brij 30 (0.5 gL(-1)) to about 30 mgL(-1). Higher dispersions of phenanthrene particles as well as the reduction of their size were obtained using Ultra-Turrax and French press. The biodegradation of phenanthrene by Pseudomonas putida was then investigated. The reduction of size of phenanthrene particles by mechanical dispersion did not influence its biodegradation, suggesting that P. putida consumed only soluble phenanthrene. The addition of Brij 30 (0.5 gL(-1)) permitted to obtain more phenanthrene metabolized. The use of Brij 30 coupled with a transitory heating of phenanthrene-containing medium at 60 degrees C led to an even more complete biodegradation. This might be a promising way to enhance biodegradation of PAHs. PMID- 21324509 TI - Stabilization of thioarsenates in iron-rich waters. AB - In recent years, thioarsenates have been shown to be important arsenic species in sulfidic, low-iron waters. Here, we show for the first time that thioarsenates also occur in iron-rich ground waters, and that all methods previously used to preserve arsenic speciation (acidification, flash-freezing, or EDTA addition) fail to preserve thioarsenates in such matrices. Laboratory studies were conducted to identify the best approach for stabilizing thioarsenates by combination and modification of the previously-applied methods. Since acidification was shown to induce conversions between thioarsenates and precipitation of arsenic-sulfide minerals, we first conducted a detailed study of thioarsenate preservation by flash-freezing. In pure water, thioarsenates were stable for 21d when the samples were flash-frozen and cryo-stored with a minimal and anoxic headspace. Increasing headspace volume and oxygen presence in the headspace were detrimental to thioarsenate stability during cryo-storage. Addition of NaOH (0.1M) or EtOH (1% V/V) counteracted these effects and stabilized thioarsenates during cryo-storage. Addition of Fe(II) to thioarsenate solutions caused immediate changes in arsenic speciation and a loss of total arsenic from solution during cryo-storage. Both effects were largely eliminated by addition of a neutral EDTA-solution, and thioarsenates were significantly stabilized during cryo-storage by this procedure. Neutralization of EDTA was required to prevent alteration of thioarsenate speciation through pH change. With the modified method (anoxic cryo-preservation by flash-freezing with minimal headspace after addition of neutralized EDTA-solution), the fractions of mono- and dithioarsenate, the two thioarsenates observed in the iron-rich ground waters, remained stable over a cryo-storage period of 11d. Further modifications are needed for the higher SH-substituted thioarsenates (tri- and tetrathioarsenate), which were not encountered in the studied iron-rich ground waters. PMID- 21324510 TI - Photocatalytic degradation of an azo dye using N-doped NaTaO3 synthesized by one step hydrothermal process. AB - N-doped NaTaO(3) compounds (NaTaO(3-)(x)N(x)) with nano-cubic morphology were successfully synthesized by one-step hydrothermal method and Methyl Orange (MO) was used as a model dye to evaluate their photocatalytic efficiency under visible light irradiation. The as-prepared NaTaO(3-)(x)N(x) samples were characterized by various techniques, such as X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM) and UV-vis diffuse reflectance spectra and GC-MS. The results indicate that NaTaO(3-)(x)N(x) displays a pure perovskite structure when the synthesis temperature is higher than 180 degrees C. Moreover, as observed by SEM images, the particles of resultant NaTaO(3-)(x)N(x) show cubic morphology with the edge length of 200 500nm, which can be easily removed by filtration after photocatalytic reaction. Doping of N increases the photocatalytic activity of NaTaO(3), and NaTaO(2.953)N(0.047) shows the highest visible-light photocatalytic activity for the degradation of MO. Based on the experiment results, a possible mechanism of the photocatalysis over NaTaO(3-)(x)N(x) and the photodegradation pathway of MO were proposed. PMID- 21324511 TI - Effects of dispersed oil exposure on the bioaccumulation of polycyclic aromatic hydrocarbons and the mortality of juvenile Liza ramada. AB - Dispersing an oil slick is considered to be an effective response to offshore oil spills. However, in nearshore areas, dispersant application is a controversial countermeasure: environmental benefits are counteracted by the toxicity of dispersant use. In our study, the actual toxicity of the dispersant response technique in the nearshore areas was evaluated through an experimental approach using juvenile Liza ramada. Fish were contaminated via the water column (i) by chemically dispersed oil, simulating dispersant application, (ii) by dispersant, as an internal control of chemical dispersion, (iii) by mechanically dispersed oil, simulating only the effect of natural mixing processes, without dispersant application, and (iv) by the water soluble fraction of oil, simulating the toxicity of an oil slick before recovery. Bioconcentrations of polycyclic aromatic hydrocarbons (PAH) and mortality were evaluated, and related to both total petroleum hydrocarbon (TPH) and polycyclic aromatic hydrocarbon (PAH) concentrations in seawater. Fish exposed to chemically dispersed oil showed both a higher bioconcentration of PAH and a higher mortality than fish exposed to either the water soluble fraction of oil or the mechanically dispersed oil. These results suggest that (i) dispersion is a more toxic response technique than containment and recovery of the oil slick; (ii) in turbulent mixing areas, dispersant application increases the environmental risk for aquatic organisms living in the water column. Even if the experimental aspects of this study compel us to be cautious with our conclusions, responders could consider these results to establish a framework for dispersant use in nearshore areas. PMID- 21324512 TI - Initial experience using microwave ablation therapy for renal tumor treatment: 18 month follow-up. AB - OBJECTIVES: To assess efficacy and morbidity of microwave ablation (MWA) for small renal tumors in an initial cohort of patients. MWA is a recently introduced thermal needle ablation treatment modality with theoretical advantages compared with radiofrequency ablation, such as greater intratumoral temperatures, lack of a grounding pad, and superior convection profile. However, experience has been limited in the human kidney. METHODS: Ten patients with a single, solid-enhancing renal tumor from June 2008 to November 2008 received laparoscopic or computed tomography-guided percutaneous MWA at a tertiary referral center with >=14 months of follow-up. MWA was performed using the Valleylab Evident, 915-MHz MWA system at 45 W with intraoperative biopsy before ablation, and peripheral fiberoptic thermometry to determine the treatment endpoints. The patients were followed up with contrast-enhanced computed tomography at 1 month, 6 months to 1 year, and annually to monitor for tumor recurrence. RESULTS: The follow-up duration for the 6 male and 4 female patients (mean tumor size 3.65 cm, range 2.0-5.5; mean age 69.8 years) was 17.9 months. The recurrence rate, defined by persistent enhancement, was 38% (3 of 8). The intraoperative and postoperative complication rate was 20% and 40%, respectively. CONCLUSIONS: MWA resulted in poor oncologic outcomes with a significant complication rate at an intermediate level of follow up. However, MWA has promising theoretical advantages and should not be discarded. Additional studies should be considered to better understand the microwave-tissue interaction and treatment endpoints for different size renal masses before widespread use. PMID- 21324513 TI - Prolonged clinical response to trabectedin in a heavily pretreated patient with advanced uterine leiomyosarcoma: a case report and literature review. PMID- 21324514 TI - Obesity in relation to endometrial cancer risk and disease characteristics in the Women's Health Initiative. AB - OBJECTIVE: Obesity increases endometrial cancer risk, yet its impact on disease stage and grade is unclear. We prospectively examined the effects of body mass index (BMI) and waist-to-hip ratio (WHR) on incidence, stage, and grade of endometrial cancer. METHODS: We studied 86937 postmenopausal women enrolled in the Women's Health Initiative. Height, weight, and waist and hip circumference were measured at baseline. Endometrial cancer cases were adjudicated by trained physicians and pathology reports were used to determine stage and grade. Cox proportional hazards models generated hazard ratios (HR) for associations between BMI and WHR and risk of endometrial cancer. Logistic regression was used to evaluate associations between BMI and WHR and disease stage and grade. RESULTS: During a mean 7.8 (standard deviation 1.6) years of follow-up, 806 women were diagnosed with endometrial cancer. Although incidence was higher among Whites, stage and grade were similar between Whites and Blacks. Elevated BMI (HR 1.76, 95% confidence interval [CI] 1.41-2.19) and WHR (HR 1.33, 95% CI 1.04-1.70) increased endometrial cancer risk when comparing women in the highest and lowest categories. No associations were observed between BMI or WHR and disease stage or grade. CONCLUSIONS: Obesity increases endometrial cancer risk independent of other factors but is not associated with stage or grade of disease. These findings support and validate previous reports. Future research should evaluate the impact of obesity on racial disparities in endometrial cancer survival. PMID- 21324515 TI - Unexpected gastrointestinal toxicity from Docetaxel/Carboplatin/Erlotinib followed by maintenance Erlotinib treatment for newly diagnosed stage III/IV ovarian cancer, primary peritoneal, or fallopian tube cancer. PMID- 21324516 TI - Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. AB - BACKGROUND: The heritable fraction of ovarian cancer exceeds that of any other common adult cancer. Most inherited cases of ovarian cancer are due to a germline mutation in BRCA1 or BRCA2. It is important to have an accurate estimate of the proportion of ovarian cancer patients who carry a mutation and the specific factors which predict the presence of a mutation. METHODS: We tested a population based series of 1342 unselected patients diagnosed with invasive ovarian cancer between 1995-1999 and 2002-2004 in Ontario, Canada, for germline mutations in BRCA1 and BRCA2. The two genes were tested in their entirety, using a range of techniques, including multiplex ligation-dependent probe amplification (MLPA). RESULTS: Among the 1342 women, 176 women carried a mutation (107 in BRCA1, 67 in BRCA2, and two in both genes) for a combined mutation frequency of 13.3%. Seven deletions were identified using MLPA (3.9% of all detected mutations). The prevalence of mutations was particularly high among women diagnosed in their forties (24.0%), in women with serous ovarian cancer (18.0%) and women of Italian (43.5%), Jewish (30.0%) or Indo-Pakistani origin (29.4%). A mutation was seen in 33.9% of women with a first-degree relative with breast or ovarian cancer and in 7.9% of women with no first-degree relative with breast or ovarian cancer. No mutation was seen in women with mucinous carcinoma. CONCLUSIONS: BRCA1 and BRCA2 mutations are common in women with invasive ovarian cancer. All women diagnosed with invasive non-mucinous ovarian cancer should be considered to be candidates for genetic testing. PMID- 21324517 TI - Wound complications after gynecologic cancer surgery. AB - OBJECTIVE: To explore clinical correlates of wound complications in high-risk women undergoing abdominal gynecologic surgery in a tertiary referral center. METHODS: Retrospective analysis of patient demographics, pre-operative and intra operative information, and outcomes was performed in a cohort of patients who underwent abdominal surgery for suspected gynecologic malignancy between 1/2005 and 6/2008. The primary outcome was wound complication within 6 weeks of surgery. Univariate and multivariate logistic regression analyses were employed. A nomogram predicting post-operative wound complications was created and validated by receiver operating characteristic (ROC) curve analysis and 10-fold cross validation. RESULTS: Median age of 373 women analyzed was 57years (range 25-88), median body mass index (BMI) 32.3kg/m(2) (range 14.0-70.7). A total of 150 patients (40%) had prior abdominal surgery; 40 (11%) had a pre-operative serum albumin <3.5g/dl; and 78 (21%) had pulmonary disease. Wound complications occurred in 125 patients (34%). In multivariate analysis wound complications were correlated with BMI of 30-39.9kg/m(2) (OR=5.62, 95% CI 2.08-15.19, p<0.0001) and BMI>=40kg/m(2) (OR=10.27, 95% CI 3.66-28.88, p<0.0001), prior abdominal surgery (OR 3.28, 95%CI1.89-5.70, p<0.0001), serum albumin<=3.5g/dl (OR 4.24, 95%CI 1.87 9.61, p=0.0005), pulmonary disease (OR 2.22, 95%CI 1.09-4.51, p=0.03), lysis of adhesions (OR 3.57, 95%CI 1.04-12.26, p=0.04), and length of surgery (OR 2.42, 95%CI 1.35-4.35, p=0.003). Risk for wound complication was lower with pelvic drain placement (OR 0.26, 95%CI 0.11-0.64, p=0.003). CONCLUSIONS: Wound complications are common in gynecologic oncology. Further studies should explore whether risk factor modification decreases complications. PMID- 21324518 TI - Meta-analysis: Circulating vitamin D and ovarian cancer risk. AB - OBJECTIVE: To review and summarize evidence from longitudinal studies on the association between circulating 25 hydroxyvitamin D (25(OH)D) and the risk of ovarian cancer (OC). METHODS: Relevant prospective cohort studies and nested case control studies were identified by systematically searching Ovid Medline, EMBASE, and ISI Web of Knowledge databases and by cross-referencing. The following data were extracted in a standardized manner from eligible studies: first author, publication year, country, study design, characteristics of the study population, duration of follow-up, OC incidence according to circulating vitamin D status and the respective relative risks, and covariates adjusted for in the analysis. Due to the heterogeneity of studies in categorizing circulating vitamin D levels, all results were recalculated for an increase of circulating 25(OH)D by 20ng/ml. Summary relative risks (RRs) were calculated using meta-analysis methods. RESULTS: Overall, ten individual-level studies were included that reported on the association between circulating vitamin D levels and OC incidence. Meta-analysis of studies on OC incidence resulted in a summary RR (95% confidence interval, CI) of 0.83 (0.63-1.08) for an increase of 25(OH)D by 20ng/ml (P=0.160). No indication for heterogeneity and publication bias was found. CONCLUSIONS: A tentative inverse association of circulating 25(OH)D with OC incidence was found, which did not reach statistical significance but which requires clarification by additional studies due to potentially high clinical and public health impact. PMID- 21324519 TI - The indoor tanning industry's double game. PMID- 21324521 TI - New insights into the treatment of persistent asthma. PMID- 21324520 TI - Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Daily inhaled corticosteroids are an effective treatment for mild persistent asthma, but some children have exacerbations even with good day-to-day control, and many discontinue treatment after becoming asymptomatic. We assessed the effectiveness of an inhaled corticosteroid (beclomethasone dipropionate) used as rescue treatment. METHODS: In this 44-week, randomised, double-blind, placebo controlled trial we enrolled children and adolescents with mild persistent asthma aged 5-18 years from five clinical centres in the USA. A computer-generated randomisation sequence, stratified by clinical centre and age group, was used to randomly assign participants to one of four treatment groups: twice daily beclomethasone with beclomethasone plus albuterol as rescue (combined group); twice daily beclomethasone with placebo plus albuterol as rescue (daily beclomethasone group); twice daily placebo with beclomethasone plus albuterol as rescue (rescue beclomethasone group); and twice daily placebo with placebo plus albuterol as rescue (placebo group). Twice daily beclomethasone treatment was one puff of beclomethasone (40 MUg per puff) or placebo given in the morning and evening. Rescue beclomethasone treatment was two puffs of beclomethasone or placebo for each two puffs of albuterol (180 MUg) needed for symptom relief. The primary outcome was time to first exacerbation that required oral corticosteroids. A secondary outcome measured linear growth. Analysis was by intention to treat. This study is registered with clinicaltrials.gov, number NCT00394329. RESULTS: 843 children and adolescents were enrolled into this trial, of whom 288 were assigned to one of four treatment groups; combined (n=71), daily beclomethasone (n=72), rescue beclomethasone (n=71), and placebo (n=74)-555 individuals were excluded during the run-in, according to predefined criteria. Compared with the placebo group (49%, 95% CI 37-61), the frequency of exacerbations was lower in the daily (28%, 18-40, p=0.03), combined (31%, 21-43, p=0.07), and rescue (35%, 24-47, p=0.07) groups. Frequency of treatment failure was 23% (95% CI 14-43) in the placebo group, compared with 5.6% (1.6-14) in the combined (p=0.012), 2.8% (0-10) in the daily (p=0.009), and 8.5% (2-15) in the rescue (p=0.024) groups. Compared with the placebo group, linear growth was 1.1 cm (SD 0.3) less in the combined and daily arms (p<0.0001), but not the rescue group (p=0.26). Only two individuals had severe adverse events; one in the daily beclomethasone group had viral meningitis and one in the combined group had bronchitis. INTERPRETATION: Children with mild persistent asthma should not be treated with rescue albuterol alone and the most effective treatment to prevent exacerbations is daily inhaled corticosteroids. Inhaled corticosteroids as rescue medication with albuterol might be an effective step-down strategy for children with well controlled, mild asthma because it is more effective at reducing exacerbations than is use of rescue albuterol alone. Use of daily inhaled corticosteroid treatment and related side-effects such as growth impairment can therefore be avoided. FUNDING: National Heart, Lung and Blood Institute. PMID- 21324522 TI - Differences in physiological response to increased seawater temperature in nearshore and offshore corals in northern Vietnam. AB - Effects of elevated seawater temperature show high spatial heterogeneity and variation within and among coral species. The objective of this study was to investigate how two coral species, Porites lutea and Galaxea fascicularis, from two high latitude reefs differently exposed to chronic disturbance, respond to elevated seawater temperatures. Corals were collected from reefs nearshore (i.e. subjected to high sediment load, higher chlorophyll alpha concentrations, turbidity etc.) and offshore (i.e. less exposed). The corals were exposed in the lab to gradually increasing temperatures (25.5-33.5 degrees C) for 72 h after which they were allowed to recover to ambient temperature (25.5 degrees C) for 24 h. Production and respiration were measured after 24, 48, 72 and 96 h. The results show that P. lutea from nearshore reefs suffered an initial decrease in gross primary production/respiration (GP/R) ratio after 24 h, after only a moderate temperature increase (+2 degrees C, from 25.5 to 27.5 degrees C), while there was no difference in GP/R ratio between heat-exposed and controls the other days, indicating that the chronic disturbance in the nearshore reef had no effect on their thermotolerance. Furthermore, P. lutea from the offshore reef showed a decrease in GP/R ratio both after 24 h and 72 h (33.5 degrees C) of exposure. In comparison, G. fascicularis showed a decrease in GP/R ratio after 48 h, 72 h and 96 h of exposure for the nearshore corals. Also, after 72 h these corals had withdrawn their polyps. There were no differences between heat-treated and controls for the offshore G. fascicularis. This implies that the chronically disturbed G. fascicularis had lower thermotolerance when exposed to a temperature increase. This study, hence, shows that the response of corals to elevated seawater temperature varies with species and environmental background history. PMID- 21324523 TI - In vivo molecular evidence of delayed titanium implant osseointegration in compromised bone. AB - Optimization of implant osseointegration in patients with reduced bone healing potential is a challenge remaining in implant dentistry. Identification of the genes that are modulated during implant osseointegration in normal versus osteopenic bone is needed to successfully address these pertinent clinical needs. The present study aimed to assess the initial and early molecular events following titanium implant installation in normal and compromised bone in a rat tibia model. Peri-implant tissue from a well-defined tissue regeneration compartment was analyzed at 2 and 7 days post-surgery for the expression of select markers of inflammation, angiogenesis, bone resorption and bone formation. Impaired bone was induced by hindlimb unloading and validated using MUCT. The essential step of angiogenesis preceding bone regeneration was evidenced for the peri-implant setting in healthy bone. Compromised bone significantly affected the angiogenesis-osteogenesis coupling in the initial phase (2 days post-surgery), with altered expressions of Vegfa and Epas1 coinciding with downregulated expressions of Col1a1, Bmp2, Bmp4, Alpl and Bglap. At 7 days post-implantation, differences between normal and compromised peri-implant bone were no longer observed. This in vivo molecular evidence of delayed implant osseointegration in compromised bone reassert modern strategies in implant development, such as surface modifications and bioengineered approaches, to improve implant osseointegration in compromised conditions. PMID- 21324524 TI - A single-monomer derived linear-like PEI-co-PEG for siRNA delivery and silencing. AB - Polyethylenimines (PEIs) are commonly used as a vehicle to deliver and protect siRNA, but the strong interaction still remains to be modulated for efficient siRNA release and silencing. Herein, a single-monomer derived linear-like PEI-co PEG (LPEI-co-PEG, P(2)) was synthesized to substantially enhance the siRNA release, but not affect the efficiency of protection. The linear-like copolymer (P(2)) was only synthesized from a single-monomer by intensive synchrotron X-ray irradiation within 5 min, randomly producing both PEI and PEG segments. The counterpart vehicle, LPEI (P(1)), was also synthesized for comparison. We found that the P(1) and P(2) were able to prevent siRNA against enzymatic degradation. Most importantly, efficient siRNA release (52%) was only observed in the siRNA/P(2) complexes and not in the siRNA/P(1) complexes (<5%), suggesting that the PEG segment may modulate the interaction between siRNA and P(2) segment. Specifically, P(2) as well as P(1) can emit photoluminescence; cancer cells exhibited a detectable photoluminescence after treatment with P(1) and P(2), indicative of their excellent transfection efficiency. Subsequently, the siGFP/P(2) complexes knocked down GFP with excellent efficiency (75%) above the siGFP/P(1) complexes (19%) and siGFP/Lipofectamine complexes (20%). Importantly, the siRNA with anti-VEGF function being associated with P(2) have been demonstrated an excellent efficiency in the suppression of tumor growth. PMID- 21324525 TI - From cell to man: evaluation of osteopontin as a possible biomarker of uranium exposure. AB - BACKGROUND: Ore workers are conventionally monitored for exposure by measuring the uranium in their urine, but specific biomarkers of kidney damage still remain to be discovered. A recent toxicogenomics study allowed us to focus on osteopontin (OSTP) normally excreted in human urine and linked to mineral metabolism. OBJECTIVES: We examined the association between osteopontin and uranium exposure both in vitro, in a human kidney cell model, and in the urine of exposed individuals. METHODS: OSTP was measured in supernatants of uranium exposed HK2 cells to establish a dose-response curve and a time course experiment. Its role was studied through a gene extinction experiment. Uranium and OSTP were then monitored in the urine of exposed nuclear fuel industry workers and a chronically exposed population. These levels were compared with those found in a non-exposed population. RESULTS: The study of HK2 cells indicated that OSTP secretion decreased after uranium exposure in a concentration and time dependent manner, but its suppression does not affect cell sensitivity to uranium. In spite of wide inter-individual variability, this parameter decreases also in human urine when urinary uranium exceeds 30 MUg/L after an acute exposure, a value considered to be critical for kidney damage. CONCLUSION: This study reports how toxicogenomics can highlight putative toxicity biomarkers in an easy to access biological fluid. The decrease of urinary osteopontin in response to uranium exposure suggests kidney damage and would thus be complementary to current markers. PMID- 21324526 TI - Ecotoxicological effects of an aged TiO2 nanocomposite measured as apoptosis in the anecic earthworm Lumbricus terrestris after exposure through water, food and soil. AB - Titanium dioxide nanoparticles seem to have a low toxicity to terrestrial organisms, though few studies are published in this area. TiO(2) used in sunscreens are nanocomposites where TiO(2) has been coated with magnesium, silica or alumina, as well as amphiphilic organics like polydimethyl siloxane (PDMS), and these coatings are modified by ageing. We assessed the ecotoxicity and propensity for bioaccumulation of an aged TiO(2) nanocomposite used in sunscreen cosmetics, and its potential effect on the frequency of apoptosis in different earthworm tissues. The earthworm Lumbricus terrestris was exposed to the TiO(2) nanocomposite for 7 days in water or 2-8 weeks in soil with the nanocomposite mixed either into food or soil at concentrations ranging from 0 to 100 mg kg(-1). Apoptosis was then measured by immunohistochemistry and Ti localized by XRF microscopy. Results showed no mortality, but an enhanced apoptotic frequency which was higher in the cuticule, intestinal epithelium and chloragogenous tissue than in the longitudinal and circular musculature. TiO(2) nanoparticles did not seem to cross the intestinal epithelium/chloragogenous matrix barrier to enter the coelomic liquid, or the cuticule barrier to reach the muscular layers. No bioaccumulation of TiO(2) nanocomposites could thus be observed. PMID- 21324527 TI - The immunostimulatory activity of phosphorothioate CpG oligonucleotides is affected by distal sequence changes. AB - CpG motifs in bacterial DNA activate innate immune cells via toll like receptor 9 (TLR9). Short synthetic oligodeoxynucleotides (ODN) containing a six base CpG motif can mimic the immunostimulatory activity of bacterial DNA. Phosphorothioate (PS) modification of the backbone of ODN makes them more resistant to nuclease degradation and consequently preferable for therapeutic use. Previous studies have shown that the sequence requirements for PS-ODN to have maximal stimulatory activity are more stringent than for normal phosphodiester (PO) ODN. Here we show small sequence changes distal to the CpG motif can affect the activity of PS-ODN whilst having no effect on the activity of PO-ODN. The addition of terminal dG residues and other minor changes to the potently immunostimulatory PS-ODN 1668S caused delayed signalling. The reduction in immunostimulatory activity of PS-ODN was associated with a delay in the activation of MAP kinases. PMID- 21324528 TI - Discovery of zebrafish (Danio rerio) interleukin-23 alpha (IL-23alpha) chain, a subunit important for the formation of IL-23, a cytokine involved in the development of Th17 cells and inflammation. AB - This paper reports the cloning and sequencing of interleukin (IL)-23 p19 subunit for the first time within a non-mammalian species, the zebrafish (Danio rerio), which was discovered using a synteny approach. In addition, amino acid sequences were for IL-23 p19 subunits were also predicted from the stickleback, Fugu and Tetraodon genomes and included in this investigation. The zebrafish IL-23 p19 cDNA consisted of a 66bp 5' UTR, a 249bp 3' UTR and a single open reading frame of 567bp giving a predicted 188 aa IL-23 p19 molecule. Multiple alignment of zebrafish IL-23 p19, with other known IL-23 p19 and IL-12 p35 amino acid sequences revealed areas of amino acid conservation, such as the presence of four predicted alpha-helixes, cysteines important for disulphide bond formation and the conservation of a tryptophan known to interact with the receptor. Amino acid homologies and phylogenetic analysis confirmed the relationship of the fish IL-23 p19 subunits with their mammalian homologues. All the teleost fish IL-23 p19 subunits were found to have 4 exons and 3 introns similar to that of human and mouse IL-23 p19 and a limited degree of synteny was found between the organisms for the regions containing the IL-23 p19 genes with only PAB-dependent poly(A) specific ribonuclease subunit 2 (PAN2) and IL-23 p19 found in the same order on human chromosome 12 and all the fish genomes looked at. Lastly using real-time PCR, constitutive expression of IL-12 p40 and IL-23 p19 was observed in the kidney, liver, gut and muscle with IL-12 p40 expression higher than IL-23 p19. As soon as an hour after stimulation with LPS, there was an increase of IL-23 p19 in zebrafish leukocytes and an increase of IL-1beta, IL-12 p40 and IL-23 p19 expression was found after infection of zebrafish for 1 or 6 days with Mycobaterium marinum strain E11. PMID- 21324529 TI - First aid actions taken by young people for mental health problems in a close friend or family member: findings from an Australian national survey of youth. AB - This study examined the first aid actions taken by young people to help someone they know and care about who was experiencing a mental health problem and the characteristics of the first aid provider (respondent) and recipient which influence these first aid actions. Participants in a national survey of Australian youth (aged 12-25 years) completed a two-year follow-up phone interview based on one of the following disorders in vignettes: depression, depression with alcohol misuse, social phobia and psychosis. Participants were asked if they knew a family member or close friend who had experienced a similar problem to the vignette character since the initial interview and those who did reported on any actions taken to help the person. Of the 2005 participants interviewed, 609 (30%) reported knowing someone with a similar problem, with depression (with or without alcohol misuse) being the most common problem. Respondent age and gender, recipient gender, and type of mental health problem, all influenced first aid actions. Findings indicate that peers are a major source of support for young people with mental health problems and underscore some important areas and subgroups of young people to target for interventions to improve young people's mental health first aid skills. PMID- 21324530 TI - Long-term maternal recall of obstetric complications in schizophrenia research. AB - Obstetric complications (OCs) are consistently implicated in the aetiology of schizophrenia. Information about OCs is often gathered retrospectively, from maternal interview. It has been suggested that mothers of people with schizophrenia may not be accurate in their recollection of obstetric events. We assessed the validity of long term maternal recall by comparing maternal ratings of OCs with those obtained from medical records in a sample of mothers of offspring affected and unaffected with psychotic illness. Obstetric records were retrieved for 30 subjects affected with psychosis and 40 of their unaffected relatives. The Lewis-Murray scale of OCs was completed by maternal interview for each subject blind to the obstetric records. There was substantial agreement between maternal recall and birth records for the summary score of "definite" OCs, birth weight, and most of the individual items rated, with the exception of antepartum haemorrhage. There were no significant differences in the validity of recall or in errors of commission by mothers for affected and unaffected offspring. These findings indicate that several complications of pregnancy and delivery are accurately recalled by mother's decades after they occurred. Furthermore, there is no indication that mothers are less accurate in recalling OCs for their affected offspring than their unaffected offspring. When comparing women with and without recall errors, we found those with recall errors to have significantly worse verbal memory than women without such errors. Assessing the cognition of participants in retrospective studies may allow future studies to increase the reliability of their data. PMID- 21324531 TI - Effects of fine structure and extended low frequencies in pediatric cochlear implant recipients. AB - OBJECTIVE: In recent years, new speech coding strategies have been developed with the aim of improving the transmission of temporal fine structure to cochlear implant recipients. This study reports on the implementation of one such strategy (fine structure processing, FSP) in children. METHODS: This was a prospective study investigating the upgrade to a new speech processor. The upgrade used a repeated measures design with an alternating order of conditions (A-B-A-B design). Twelve pre- and perilingually deaf children with MED-EL C40+ cochlear implants were enrolled in the study. Patients were upgraded from their Tempo+ speech processor, which used continuous interleaved sampling (CIS) in combination with a frequency spectrum of 200-8500 Hz, to an Opus speech processor, which used FSP with an extended frequency spectrum of 70-8500 Hz. The primary means of testing was an HSM (Hochmair, Schulz and Moser) sentence test at 65 and 80 dB in quiet. In addition, the "Mainzer Kindersprachtest" (Mainz audiometric speech test for children) was applied at 65 and 70 dB. RESULTS: When the new FSP speech processor was used together with the extended low frequency range, HSM sentence tests at 65 and 80 dB resulted in scores indicating statistically significant improvements of 7.1 and 9.9 percentage points, respectively. Scores in the "Mainzer Kindersprachtest" at 65 and 70 dB indicated statistically significant improvements of 9.3 and 6.1 percentage points, respectively. CONCLUSIONS: The present study clearly shows that children benefit from the fine structure speech coding strategy in combination with an extended frequency spectrum in the low frequencies, as is offered by the Opus speech processors. This should be taken into consideration when fitting pre- and perilingually deaf children implanted almost a decade previously. PMID- 21324532 TI - Prevalence of A1555G mitochondrial mutation in Chinese newborns and the correlation with neonatal hearing screening. AB - OBJECTIVE: To investigate the feasibility of genetic screening for deafness causative genes in the process of newborn hearing screening in China. METHODS: Total 865 newborn babies between November 2009 and March 2010 were enrolled for the simultaneous hearing and deafness causative gene screening in Tongji Hospital, Wuhan, China. Hearing screening followed a two-stage strategy with transient evoked otoacoustic emissions. Infants referred after the second-stage screening were tested by diagnostic auditory brainstem response (ABR). Genomic DNA was extracted from heel blood of newborns, and the mitochondrial 12S rRNA A1555G mutation was detected by polymerase chain reaction (PCR) based restriction fragment length polymorphism and confirmed by DNA sequencing. RESULTS: In hearing screening, 134 out of the 865 newborns (15.5%) were referred after the first stage screening and 86.6% (116/134) of them returned for the second stage. After the second-stage screening, 15 who were still referred were tested by diagnostic ABR and 3 of them failed the test. On the other hand, gene screening identified 6 of the 865 newborns (0.7%) harbored homoplasmic 12S rRNA A1555G mutation although they passed the hearing screening. CONCLUSION: It might be practical and effective to complement routine hearing screening in newborns with gene screening for the purpose of early diagnosis and discovery of the late-onset hearing loss. PMID- 21324534 TI - Detection of Helicobacter pylori in adenotonsillar tissue of children with chronic adenotonsillitis using rapid urease test, PCR and blood serology: a prospective study. AB - OBJECTIVE: Contradictory results have been reported regarding Helicobacter pylori (H. pylori) detection in adenotonsillar tissue. The aims of this study were to investigate whether adenotonsillar tissue of symptomatic children with chronic adenotonsillitis harbors the H. pylori organism, using two biopsy-based invasive methods namely; rapid urease test (RUT) and polymerase chain reaction (PCR) as well as blood serology and to compare the results obtained from each of these methods to the "gold standard". METHODS: This prospective clinical study was carried out on 20 children aged between 2 and 10 years scheduled for tonsillectomy +/- adenoidectomy in a tertiary referral center. Exclusion criteria included: use of antacids, H(2) blockers or antibiotics during the previous month before surgery and adenotonsillectomy for obstructive sleep apnea. Core biopsy samples from resected adenotonsillar tissue was tested for H. pylori detection using both RUT and PCR assay for the ureC gene. Preoperative patient venous blood samples were also tested for H. pylori IgG antibodies. As a "gold standard", examined tissue was considered to be H. pylori infected if the two biopsy specimen-based methods (RUT and PCR) yielded positive results. RESULTS: Thirty adenotonsillectomy specimens were tested (20 tonsils and 10 adenoids). RUT was positive in 16 (53.3%) specimens (12 tonsils and 4 adenoids). According to the "gold standard", 11/16 were considered false-positive, yielding this test sensitivity 100% and specificity 56%. The ureC gene sequence was detected by PCR in 5 (16.6%) specimens (3 tonsils and 2 adenoids), all of which were also positive by RUT, thus were considered H. pylori infected. Accordingly, PCR had a 100% sensitivity and specificity. Serology testing was positive for H. pylori IgG antibodies in 4/20 patients (20%), only two of them were found to have H. pylori infected adenotonsillar tissue. CONCLUSIONS: Based on our findings it seems that adenotonsillar tissue may constitute an extra-gastric reservoir for H. pylori in symptomatic children with chronic adenotonsillitis. RUT was found to be of less accuracy than PCR in H. pylori detection in an extra-gastric location, thus results of previous studies using this test alone for detection of oral H. pylori should be treated with caution. PMID- 21324535 TI - Prolonged recovery after out-patient pediatric adenotonsillectomy. AB - OBJECTIVE: To determine variables predictive of recovery room times in pediatric outpatient adenotonsillectomy. STUDY DESIGN: Retrospective case-control. METHODS: One-hundred ninety consecutive patients undergoing outpatient adenotonsillectomy at an ambulatory surgery center of a tertiary-care free standing pediatric hospital were grouped into upper and lower deciles of recovery room times. Twenty one variables were analyzed to determine which variables are predictive of prolonged recovery time. Univariate and multivariate analyses were performed. RESULTS: Of the 190 patients, mean recovery room time was 103 min (SD 53.1), 22 patients were in the lower decile (mean recovery room time of 63 +/- 6 min) and 17 patients were in the upper decile (155 +/- 40 min, P<0.0001). Of the 21 variables analyzed, post-anesthesia care unit (PACU) nursing staff was the only significant predictor of prolonged recovery room time. Compared with one PACU nurse, other nurses (N=5) predicted a longer recovery time (OR=10.8, 95% CI 2.0 59.5, P=0.0017). This association remained significant when controlling for anesthesiologist and surgeon (OR=8.8, 95% CI 1.5-50.9, P=0.0072). There were no complications in any patients. CONCLUSIONS: Recovery room times after outpatient adenotonsillectomy vary significantly (mean 103 min (SD 53.1), range 50-241 min). Of potential predictors, only the human factor (PACU nursing staff) was associated with prolonged recovery room times, independent of surgeon and anesthesiologist. Development of standardized protocols for nurses to use for discharge has the potential to increase throughput for adenotonsillectomy patients in an outpatient surgery center setting. PMID- 21324537 TI - Histamine receptors in the CNS as targets for therapeutic intervention. AB - Histamine has long been known to trigger allergic reactions and gastric acid secretion. However, it was later discovered that, in the brain, histamine regulates basic homeostatic and higher functions, including cognition, arousal, circadian and feeding rhythms. The sole source of brain histamine is neurons localized in the hypothalamic tuberomammillary nuclei. These neurons project axons to the whole brain, are organized into functionally distinct circuits influencing different brain regions and display selective control mechanisms. Although all histamine receptors (H1R, H2R, H3R and H4R) are expressed in the brain, only the H3R has become a drug target for the treatment of neurologic and psychiatric disorders, such as sleep disturbances and cognitive deficits. In this review, we discuss recent developments in the pharmacological manipulation of H3Rs and the implications for H3R-related therapies for neurological and psychiatric disorders. The legacy of Sir James Black. PMID- 21324536 TI - Impacts of environmental toxicants on male reproductive dysfunction. AB - Male infertility caused by exposure to environmental toxicants such as cadmium, mercury, bisphenol A (BPA) and dioxin is a global problem, particularly in industrialized countries. Studies in the testis and other organs have illustrated the importance of environmental toxicant-induced oxidative stress in mediating disruption to cell junctions. This, in turn, is regulated by the activation of PI3K/c-Src/FAK and MAPK signaling pathways, with the involvement of polarity proteins. This leads to reproductive dysfunction such as reduced sperm count and reduced quality of semen. In this review, we discuss how these findings can improve understanding of the modes of action of environmental toxicants in testicular dysfunction. Thus, specific inhibitors and/or antagonists against signaling molecules in these pathways may be able to 'reverse' and/or 'block' the disruptive effects of toxicant-induced damage. Additional studies comparing high level acute exposure versus low-level chronic exposure to environmental toxicants are also needed to fully elucidate the underlying molecular mechanism(s) by which these toxicants disrupt male reproductive function. PMID- 21324538 TI - Gender influence on dose saving allowed by prospective-triggered 64-slice multidetector computed tomography coronary angiography as compared with retrospective-gated mode. AB - BACKGROUND/OBJECTIVES: To assess the gender influence on radiation dose saving allowed by prospective ECG-triggered MDCT coronary angiography (P-MDCT-CA) in comparison with retrospective ECG-gated MDCT-CA (R-MDCT-CA). The influence of kilovoltage and body mass index on radiation dose and the impact of different parameters on image quality (IQ) and diagnostic confidence (DC), were also determined. METHODS: 64-slice MDCT-CA was performed in 176 patients: 66 R-MDCT-CA and 110 P-MDCT-CA. Effective dose was determined using ImpactDose software based on Monte Carlo method. Three point scales were used to assess IQ and DC on a segmental basis. RESULTS: Patients were divided into 4 groups according with the examination performed: group A (90 pts, coronary tree assessment with P-MDCT-CA); group B (55 pts, coronary tree assessment with R-MDCT-CA); group C (20 pts, bypass grafts assessment with P-MDCT-CA); and group D (11 pts, bypass grafts assessment with R-MDCT-CA). Effective dose was 68% lower for P-MDCT-CA than R MDCT-CA for coronary artery studies (Gr. A=4.7 +/- 1.69 mSv and Gr. B=14.9 +/- 4.4 mSv; p<0.05) and 63% lower for by-pass studies. Effective dose resulted significantly higher in women than in men who underwent R-MDCT-CA; conversely, no gender impact was observed on effective dose of P-MDCT-CA. As a result, dose saving with prospective gating was more pronounced in women (73%; R-MDCT-CA:16.3 mSv, P-MDCT-CA:4.5 mSv,) than in men (60%; R-MDCT-CA:12.8 mSv, P-MDCT-CA:4.8 mSv). IQ and DC of P-MDCT-CA were better or comparable than R-MDCT-CA CONCLUSIONS: P-MDCT-CA provides at least comparable IQ and DC than R-MDCT-CA with significant dose saving. This study highlights the important advantage offered by using P-MDCT-CA in female patients. PMID- 21324539 TI - A scenario tree model for the Canadian Notifiable Avian Influenza Surveillance System and its application to estimation of probability of freedom and sample size determination. AB - In 2008, Canada designed and implemented the Canadian Notifiable Avian Influenza Surveillance System (CanNAISS) with six surveillance activities in a phased-in approach. CanNAISS was a surveillance system because it had more than one surveillance activity or component in 2008: passive surveillance; pre-slaughter surveillance; and voluntary enhanced notifiable avian influenza surveillance. Our objectives were to give a short overview of two active surveillance components in CanNAISS; describe the CanNAISS scenario tree model and its application to estimation of probability of populations being free of NAI virus infection and sample size determination. Our data from the pre-slaughter surveillance component included diagnostic test results from 6296 serum samples representing 601 commercial chicken and turkey farms collected from 25 August 2008 to 29 January 2009. In addition, we included data from a sub-population of farms with high biosecurity standards: 36,164 samples from 55 farms sampled repeatedly over the 24 months study period from January 2007 to December 2008. All submissions were negative for Notifiable Avian Influenza (NAI) virus infection. We developed the CanNAISS scenario tree model, so that it will estimate the surveillance component sensitivity and the probability of a population being free of NAI at the 0.01 farm-level and 0.3 within-farm-level prevalences. We propose that a general model, such as the CanNAISS scenario tree model, may have a broader application than more detailed models that require disease specific input parameters, such as relative risk estimates. PMID- 21324540 TI - Combining bio- and chemo-catalysis: from enzymes to cells, from petroleum to biomass. AB - In the future, biomass will continue to emerge as a viable source of chemicals. The development of new industries that utilize bio-renewables provides opportunities for innovation. For example, bio- and chemo-catalysts can be combined in 'one pot' to prepare chemicals of commercial value. This has been demonstrated using isolated enzymes and whole cells for a variety of chemical transformations. The one-pot approach has been successfully adopted to convert chemicals derived from biomass, and, in our opinion, it has an important role to play in the design of a more sustainable chemical industry. To implement new one pot bio- and chemo-catalytic processes, issues of incompatibility must be overcome; the strategies for which are discussed in this opinion article. PMID- 21324541 TI - Photoacoustic imaging in cancer detection, diagnosis, and treatment guidance. AB - Imaging modalities play an important role in the clinical management of cancer, including screening, diagnosis, treatment planning and therapy monitoring. Owing to increased research efforts during the past two decades, photoacoustic imaging (a non-ionizing, noninvasive technique capable of visualizing optical absorption properties of tissue at reasonable depth, with the spatial resolution of ultrasound) has emerged. Ultrasound-guided photoacoustics is noted for its ability to provide in vivo morphological and functional information about the tumor within the surrounding tissue. With the recent advent of targeted contrast agents, photoacoustics is now also capable of in vivo molecular imaging, thus facilitating further molecular and cellular characterization of cancer. This review examines the role of photoacoustics and photoacoustic-augmented imaging techniques in comprehensive cancer detection, diagnosis and treatment guidance. PMID- 21324542 TI - A tracing tool portfolio to detect Bacillus anthracis, Clostridium botulinum and Noroviruses: bioterrorism is a food safety and security issue. PMID- 21324543 TI - Distribution and transferability of tetracycline resistance determinants in Escherichia coli isolated from meat and meat products. AB - Escherichia coli is used to assess the hygienic quality of food products and the dissemination of antimicrobial resistance. In particular, tetracycline-resistant E. coli can be chosen as an indicator of antibiotic resistant bacteria because it has a high frequency of occurrence. The purpose of this study was to investigate the distribution and transfer of tetracycline resistance determinants in meatborne E. coli. A total of 121 tetracycline-resistant E. coli isolates were collected from meat and meat products (raw meat, fish, and processed foods) from 2004 to 2006 in Korea. Among these isolates, tet(A) (52.4%) was the most frequent tetracycline resistance determinant, followed by tet(B) (41.3%), whereas tet(C) (1.7%) and tet(D) (0.8%) were less frequently identified. Two isolates (1.6%) contained two tet genes simultaneously, tet(A) and tet(B). Minimal inhibitory concentrations (MICs) to tetracycline family antibiotics, such as tetracycline, minocycline, doxycycline, oxytetracycline, and chlortetracycline were higher for isolates carrying the tet(B) gene compared to isolates carrying tet(A) (P<0.0001). Conjugation experiments were performed by the broth mating method; 119 isolates (98.3%) containing at least one of the tet genes were shown to transfer tetracycline resistance to recipient E. coli J53. Also, we observed high diversity of tetracycline-resistant E. coli isolates in meat and meat products in Korea by using XbaI pulsed-field gel electrophoresis (PFGE) typing. This study suggests that the high prevalence of tetracycline-resistant E. coli in meat may be due to the high transferability of tet determinants. PMID- 21324544 TI - Participation bias in a randomised trial of screening for lung cancer. AB - INTRODUCTION: Participation bias might affect the results and the representability of randomised controlled trials. We investigated the degree of socio-demographic and psychosocial participation bias in the Danish Lung Cancer Screening Trial (DLCST). METHODS: In DLCST the questionnaire COS-LC (Consequences of Screening in Lung Cancer) was used to measure the psychosocial aspects of screening. To investigate a difference with a comparable representative sample from the Danish population, we sent out an inclusion questionnaire to 3999 Danes in the age from 50 to 70 years randomly selected from the Central National Register. Those who completed the inclusion questionnaire and met the inclusion criteria from DLCST received the COS-LC. Those who completed the COS-LC-and thus formed a population sample comparable to DLCST - were compared to the DLCST participants on socio-demographics and psychosocial measures. RESULTS: Participation rates were high among the comparable population sample: 75.3% completed the inclusion questionnaire and 77.4% of those who were eligible completed the COS-LC. The analyses revealed differences between the DLCST participants and the comparable population sample in the following socio demographic aspects: social group, living alone, gender, age and geographical area. DLCST participants reported less negative psychosocial aspects than the comparable population sample. CONCLUSION: The present study has shown substantial socio-demographic and psychosocial participation bias in DLCST. PMID- 21324545 TI - Evaluation of saline tracer performance during electrical conductivity groundwater monitoring. AB - Saline solutions are the most commonly used hydrological tracers, because they can be easily and economically monitored by in situ instrumentation such as electrical conductivity (EC) loggers in wells or by geoelectrical measurements. Unfortunately, these low-cost techniques only provide information on the total concentration of ions in solution, i.e., they cannot resolve the ionic composition of the aqueous solution. This limitation can introduce a bias in the estimation of aquifer parameters where sorption phenomena between saline tracers and sediments become relevant. In general, only selected anions such as Cl(-) and Br(-) are recognised to be transported unretarded and they are referred to as conservative tracers or mobile anions. However, cations within the saline tracer may interact with the soil matrix through a range of processes such as ion exchange, surface complexation and via physical mass-transfer phenomena. Heterogeneous reactions with minerals or mineral surfaces may not be negligible where aquifers are composed of fine alluvial sediments. The focus of the present study was to examine and to quantify the bias between the aquifer parameters estimated during model-based interpretation of experimental data of EC measurements of saline tracer relative to the aquifer parameters found by specific measurements (i.e. via ionic chromatography, IC) of truly conservative species. To accomplish this, column displacement experiments with alluvial aquifer materials collected from the Po lowlands (Italy) were performed under water saturated conditions. The behaviour of six selected, commonly used saline tracers (i.e., LiCl, KCl, and NaCl; LiBr, KBr, and NaBr) was studied and the data analysed by inverse modelling. The results demonstrate that the use of EC as a tracer can lead to an erroneous parameterisation of the investigated porous media, if the reactions between solute and matrix are neglected. In general, errors were significant except for KCl and KBr, which is due to the weak interaction between dissolved K(+) and the sediment material. The study shows that laboratory scale pre-investigations can help with tracer selection and to optimise the concentration range targeted for in situ multilevel monitoring by unspecific geoelectrical instrumentation. PMID- 21324546 TI - Clinical, immunological and genetic features in Taiwanese patients with the phenotype of hyper-immunoglobulin E recurrent infection syndromes (HIES). AB - Hyper-immunoglobulin E recurrent infection syndromes (HIES) have distinct features, with identified associated mutations of STAT3, TYK2, and DOCK8. Among 197 Taiwanese patients with primary immunodeficiency on a referral-base of over 23 million inhabitants, STAT3 (R382W and Q469R) and DOCK8 mutations (exon 1-9 deletion) were identified in two patients each from six AD-HIES and five AR-HIES patients, respectively. Aside from decreased Th17 and memory B cells, characteristic facies and pneumatocele were not mutually exclusive regardless of STAT3 and DOCK8 mutations. One with novel DOCK8 deletion had notable cytomegalovirus retinitis, cerebral vasculitis, lead deposition, and amenorrhea. In adolescence, three AD-HIES patients without STAT3 mutation died of myocardial infarction, staphylococcus sepsis, and proteus sepsis while receiving chemotherapy for lymphoma. Close follow-up of the HIES phenotype rather than identifying genetic mutations should be the cornerstone of intervention at this juncture because of relatively lower percentage of identifying mutations in Taiwanese HIES (4/11; 36.5%). PMID- 21324547 TI - Alterations of pre-mRNA splicing in human inflammatory bowel disease. AB - Alternative pre-mRNA splicing is regarded as a pivotal mechanism for generating proteome diversity and complexity from a limited inventory of mammalian genes. Aberrant splicing has been described as a predisposing factor for a number of diseases, but very little is known about its role in chronic inflammation. In this study, we systematically screened 149 splicing factors and 145 potential intron retention events for occurrence and differential expression in inflammatory bowel diseases (IBD). As a result, we identified 47 splicing factors and 33 intron retention events that were differentially regulated in mucosal tissue of IBD patients at transcript level. Despite the fact that Crohn's disease and ulcerative colitis, two subtypes of IBD, share the expression patterns of splicing factors and intron retention events in the majority of cases, we observed significant differences. To investigate these subtype-specific changes in detail we determined the expression levels of seven splicing factors (DUSP11, HNRPAB, HNRPH3, SLU7, SFR2IP, SFPQ, SF3B14) and three intron retention events (PARC, IER3, FGD2) in a cohort of 165 patients with inflammatory diseases of the colon (120 with IBD) and 30 healthy controls by real time PCR (TaqMan). This study demonstrates the potential impact of regulated splicing factors on subsequent regulated intron retention in the pathogenesis of chronic inflammation, exemplified by IBD. PMID- 21324548 TI - Polyamine catabolism is involved in response to salt stress in soybean hypocotyls. AB - The possible relationship between polyamine catabolism mediated by copper containing amine oxidase and the elongation of soybean hypocotyls from plants exposed to NaCl has been studied. Salt treatment reduced values of all hypocotyl growth parameters. In vitro, copper-containing amine oxidase activity was up to 77-fold higher than that of polyamine oxidase. This enzyme preferred cadaverine over putrescine and it was active even under the saline condition. On the other hand, saline stress increased spermine and cadaverine levels, and the in vivo copper-containing amine oxidase activity in the elongation zone of hypocotyls. The last effect was negatively modulated by the addition of the copper-containing amine oxidase inhibitor N,N'-diaminoguanidine. In turn, plants treated with the inhibitor showed a significant reduction of reactive oxygen species in the elongation zone, even in the saline situation. In addition, plants grown in cadaverine-amended culture medium showed increased hypocotyl length either in saline or control conditions and this effect was also abolished by N,N' diaminoguanidine. Taken together, our results suggest that the activity of the copper-containing amine oxidase may be partially contributing to hypocotyl growth under saline stress, through the production of hydrogen peroxide by polyamine catabolism and reinforce the importance of polyamine catabolism and hydrogen peroxide production in the induction of salt tolerance in plants. PMID- 21324549 TI - Angiotensin II receptor blocker-induced angioedema in the oral floor and epiglottis. AB - We report the rare case of angioedema (also known as Quincke edema), which was induced by valsartan, an angiotensin II receptor blocker (ARB). ARBs are a new class of antihypertensive agent that is developed to exclude the adverse effects of angiotensin-converting enzyme inhibitors. In theory, ARBs do not contribute to the occurrence of angioedema because they do not increase the serum level of bradykinin, the responsible substance for angioedema. However, some reports of ARB-induced angioedema have recently been published. In this study, we present the forth case and the first Asian case of angioedema due to valsartan, which is one of the ARBs. Otolaryngologist should be wary of the prescribing ARB and discontinue ARBs treatment soon, if angioedema is recognized. PMID- 21324550 TI - Isolation and characterization of methicillin-resistant Staphylococcus aureus from fire stations in two northwest fire districts. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) strains were isolated and characterized from environmental surfaces of two fire stations from two independent districts in the northwestern United States. After the first sampling and before the second sampling, education was provided, additional signage was added, and changes in disinfection protocols were put in place. Nasal carriage of MRSA was determined at the second sampling. METHODS: Environmental samples were collected using SANICULT swabs and RODAC plates. Biochemical tests and 16S rRNA sequencing confirmed MRSA isolates. Antimicrobial susceptibility testing was performed, and the mecA gene, multilocus sequence typing, and SCCmec typing were determined by polymerase chain reaction, sequencing, and pulsed-field gel electrophoresis analysis. RESULTS: MRSA was isolated from 44 of 1,064 samples examined (4.1%) and included USA300 isolates. The same strains of MRSA were found in both the garage (ie, medic and fire trucks and protective clothing) and the living quarters. Nasal carriage of MRSA from one fire district was 22.5%. CONCLUSION: Community-like and hospital-like MRSA were isolated from the environmental samples. The majority of the nasal MRSA/S aureus isolates were genetically related to the environmental MRSA strains, suggesting possible transmission between personnel and the environmental surfaces. Further research is needed to verify this hypothesis. PMID- 21324551 TI - [Comment to: "Cost-Effectiveness of the combination therapy of dutasteride and tamsulosin in the treatment of benign prostatic hyperlasia in Spain"]. PMID- 21324552 TI - [Role of viral infections in immunosuppressed patients]. AB - Being a solid organ and hematopoietic stem cell transplant recipient as well as receiving chemotherapy for a malignant hematological disease clearly predispose the subject to a variety of viral infections, both common and opportunistic diseases. The patient may have acquired these infections from the community as well as from the donor organ (donor-derived infections) and/or from reactivation of an endogenous latent virus. Herpes viruses and especially the cytomegalovirus and Epstein-Barr virus are among the most common of the opportunistic viral pathogens affecting these patients, in addition to respiratory viruses. Treatment consists in antiviral drug therapies combined with the reduction in the degree of the induced immunosuppression. A review of the literature has been performed in order to update the epidemiology, pathogenesis, clinical manifestations and therapeutic approach of the viral infections in these immunocompromised patients. PMID- 21324553 TI - [Prevalence and main characteristics of urinary incontinence among institutionalized older people in Madrid (Spain)]. AB - INTRODUCTION: Urinary incontinence (UI) has been poorly studied in Spanish nursing homes. The objective is to determine the prevalence and related factors of UI in institutionalized older people in Madrid, Spain. METHODS: A probabilistic sample of 754 subjects 65 years of age and older living in public and private institutions in Madrid was randomly selected through stratified cluster sampling. Residents, caregivers and physicians were interviewed. UI was defined as any leakage in the previous 14 days. We asked about the frequency (occasional, nocturnal, frequent and total), quantity (drops or small quantities, very much), and types (urge, stress, due to cognitive impairment, and due to walking difficulty). To determine the factors associated with UI, we built logistic regression models that adjusted for age, sex, functional dependency (Barthel index) and cognitive status (Pfeiffer's test). RESULTS: The prevalence of UI was 53.6%. Of all residents 35.8% had frequent or total UI. Among those incontinent 60.1% had a very large quantity of urine loss and the most common presentation was mixed (54.1%). The most frequent type in the population was urgent UI (26.8%) followed by UI due to walking difficulty (21.4%). UI was associated (odds ratios [95% CI]) with moderate (3.51 [1.56-7.89]) and severe functional disability (44.71 [10.99-181.94]), faecal incontinence (4.97 [2.04 12.16]), stroke (4.59 [1.06-19.87]), physical restraints (4.03 [1.02-17.87]), and falls (2.10 [1.16-3.81]). The mean (95% CI) number of pads used per person per day was 3.0 (2.4-3.6). CONCLUSIONS: The prevalence of UI was somewhat higher than that of other comparable populations. Mixed forms, including functional types, were common. PMID- 21324554 TI - [Teaching sessions in primary care. Experience in health centres in an area of Madrid]. AB - Those responsible for teaching of primary care teams of Area 7 of Madrid have noted a significant disparity in the organisation of teaching sessions. Therefore, the Madrid Area 7 Commission for Teaching and Research organised an idea-sharing day. This article aims to show the different organisational forms, model sessions, the benefits of education sessions, perceived problems and suggestions for improvement. Finally there is a decalogue, which can serve as a guide for organising teaching sessions in primary care. PMID- 21324555 TI - [Fungal keratitis in an immunocompetent patient]. PMID- 21324556 TI - [Bilateral anterior uveitis and Rickettsia typhi infection]. PMID- 21324557 TI - [Management of antiretroviral drug toxicity]. AB - Highly active antiretroviral therapy (HAART)-associated toxicity has been the most important limiting factor of the doubtless efficacy of this treatment. HAART associated toxicity can have two kinds of temporal profiles; early toxicity, also known as tolerability, and long-term or chronic toxicity. Both types of toxicity are of foremost importance, not only because they represent an added co morbidity, but also because the patient often associates the starting of HAART with toxic effects. This fact has often been linked to a decrease in patient adherence to the treatment, which may eventually lead to virological failure. The appearance of long-term toxic effects is usually due to continuous, even indefinite, exposure to antiretroviral drugs. When antiretroviral drug toxicity develops, the caregiver usually has two choices; to decrease and/or reverse such toxicity. On the one hand, withdrawal of the offending agent and its substitution for another agent with a different toxicity profile, and on the other, pharmacological or non-pharmacological interventions directed at correcting the toxicity-associated problems. However, it should be kept in mind that pharmacological interventions always have the possibility of giving rise to interactions with antiretroviral drugs, eventually leading to new toxic effects. Fortunately, in the last few years, new drugs and drug families have been added to the antiretroviral armamentarium. Most of these drugs have more benign toxicity profiles than first-generation antiretroviral drugs. No doubt our best hope to decrease HAART-associated toxicity relies upon treatment with these new drugs, together with the knowledge of the genetic determinants of antiretroviral drug-associated toxicity (toxicogenetics). Hopefully, toxicogenetics will be of paramount importance in the future to design new antiretroviral regimes best fitted to a given patient, in order to personalize HAART with the objective of building up more effective and less toxic regimes. PMID- 21324559 TI - [Prevalence and determining factors of acquiring C. trachomatis infection among adolescents and young adults in Catalonia]. AB - OBJECTIVE: To determine the prevalence of Chlamydia trachomatis (C. trachomatis) and Neisseria gonorrhoeae (N. gonhorroeae) infections and the risk factors for acquiring them in individuals under 35 years-old attending sexual health clinics in Barcelona province in 2006. METHODS: Cross-sectional study of a convenience sample of 500 adolescents and young adults aged between 16 and 35 years. A total of 423 samples were analysed using real-time PCR. A standardised questionnaire was used to collect clinical, epidemiological, and behavioural data on the participants. Significant differences were analysed in the descriptive study using Pearson's ((2). The association between C. trachomatis infection and its determining factors was analysed using the Mantel-Haenszel test and a multivariate logistic regression model. RESULTS: The overall prevalence of C. trachomatis was 4%, and was significantly higher in those under 25 years of age. The overall prevalence of N. gonhorroeae was 0.2%. The independent risk factors for infection by C. trachomatis were as follows: foreign origin (OR: 3.74; CI 95%: 1.10-12.72), having had a sexual partner in the last 3 months (OR 3.91; CI 95%: 1.30-11.81), and tobacco use the last 12 months (OR: 4.99; CI 95%: 1.34 18.59). CONCLUSIONS: This is the first study performed in Catalonia that shows high prevalence of C. trachomatis in young people, thus confirming trends in the rest of Europe. Systematic monitoring of C. trachomatis infection in sentinel populations will provide valid information allowing us to assess the relevance of proposing targeted screening programs in our setting. PMID- 21324560 TI - [Encephalitis with multiple space occupying lesions in a patient with human immunodeficiency virus type 1 infection]. PMID- 21324561 TI - [Fatal Bacillus cereus sepsis and rhabdomyolysis in a patient with Hodgkin's disease]. PMID- 21324562 TI - Association of peripheral facial nerve palsy and seropositivity of HTLV 1, a case report. PMID- 21324563 TI - [Cost-effectiveness of an intervention to reduce overweight and obesity in 9-10 year-olds. The Cuenca study]. AB - OBJECTIVE: To assess the cost-effectiveness a school-based intervention designed to reduce overweight/obesity and other cardiovascular risk factors in children. METHODS: Standard cost effectiveness analysis methods and two perspectives (societal and institutional) were used. A cluster-randomized controlled trial with 10 intervention schools (691 children) and 10 control schools (718 children) was performed. Net costs were calculated by subtracting the usual after-school care cost from intervention costs. The effectiveness of the intervention was measured as the reduction in health outcomes compared with the control group. RESULTS: The intervention costs totaled 125,469.75?, representing 269.83 ?/year/child. The usual after-school care was estimated at 844,56 ?/year/child. Intervention children showed a decrease in triceps skinfold thickness (-1.25mm, 95% CI: -1.82 to -0.67; P<.001). Intervention children with body mass index (BMI) between the percentiles 25 and 75 showed a decrease in the percentage of body fat (-0.59%; 95% CI: -1.03 to -0.67; P<.001), and those with a BMI>P75 showed a decrease in triceps skinfold thickness (-1.87mm; 95%CI: -3.43 to -0.32; P<.001), and percentage of body fat (-0.67%; 95%CI: -1.32 to -0.01; P<.05). CONCLUSIONS: This type of after-school program for recreational physical activity to prevent obesity are likely to be a cost-effective use of public funds and warrant careful consideration by policy makers and program planners. PMID- 21324564 TI - [Deaf communities: patients or citizens?]. AB - The concept of disability is related to discrimination and social exclusion; that is, this issue is a socio-political question whose effects go well beyond the health of the individual. The social and human rights based model of disability points the way to fresh opportunities for action to promote the wellbeing and health of the seventy million Deaf people living in the world today. The key factors in preventing discrimination against the Deaf are recognition of their specific cultural and linguistic identity (including sign languages and Deaf culture), bilingual education, the availability of professional sign language interpreting, and access to information and communication. The present article aims to encourage greater understanding of the significance of adopting this new perspective on disability, its congruence with current national and international legislation on the rights of persons with disabilities in general and of Deaf persons in particular, and its implications in the policies and praxis due to be implemented in Spain over the next few years on enhancing the health of the Deaf community through significant examples of good practice. Examples of good practice for distinct Deaf communities include collaboration between these communities and the health sector, health training for sign language users, the inclusion of the language and culture of Deaf persons in training programs for healthcare professionals, training of Deaf specialists as future health researchers and workers, and health care services that are more accessible via different sign languages. PMID- 21324565 TI - Prevalence and correlates of skin cancer risk behaviors in Madrid (Spain). AB - OBJECTIVE: To estimate the prevalence and correlates of skin cancer-related behaviors in a representative sample of the population of the region of Madrid (Spain). METHODS: We performed a cross-sectional study based on a telephone survey. A total of 2,007 participants aged 18-64 years completed a questionnaire that included items on knowledge about the risk of skin cancer, sun exposure, the use of ultraviolet (UV) lamps and sunburn during the previous year. Logistic regression models were constructed, adjusted for gender, age, educational level and employment status. RESULTS: Sun exposure as a risk factor for skin cancer was identified by 92.3% of participants and artificial tanning by 73.6%. Knowledge of risk factors was greater among university graduates and women (P<.001). A total of 14.6% were usually exposed to the sun in the summer during the hours of maximum UV radiation, while 4.3% had used UV lamps during the previous year; the use of these lamps was more frequent among women (P<.001) and young people (P<.05). The prevalence of sunburn was 13.2% and was lower among women: odds ratio (OR) 0.68 (95% CI: 0.51-0.90); this prevalence declined with greater age (p linear trend <0.001) and was higher among students: OR 1.60 (95% CI: 1.07-2.40). CONCLUSIONS: Numerous sociodemographic factors are related to UV radiation exposure and sunburn, with young people at highest risk. UV exposure is more frequent among women, whereas sunburn is more common among men. PMID- 21324566 TI - Structure-activity relationship of 2,4,5-trioxoimidazolidines as inhibitors of thymidine phosphorylase. AB - Novel non-nucleobase-derived inhibitors of the angiogenic enzyme, thymidine phosphorylase, have been identified using molecular modelling, synthesis and biological evaluation. These inhibitors are 2,4,5-trioxoimidazolidines bearing N (substituted)phenylalkyl groups, together with, in most cases, N'-(CH(2))(n) carboxylic acid, ester or amide side chains. The best compound from this series is 3-(2,4,5-trioxo-3-phenylethyl-imidazolodin-1-yl)propionamide, with an IC(50) of 40 MUM against Escherichia coli TP. Molecular modelling suggests that this ligand, when complexed with closed-cleft human TP, would have the phenylalkyl group in the active site region normally occupied by a thymine-containing structure. PMID- 21324567 TI - Synthesis of some novel 3-(1-(1-substitutedpiperidin-4-yl)-1H-1,2,3-triazol-4-yl) 5-substituted phenyl-1,2,4-oxadiazoles as antifungal agents. AB - A novel series of 3-(1-(1-substituted piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-5 substituted phenyl-1,2,4-oxadiazoles bearing 1,2,3-triazole and piperidine ring has been synthesized in one step from amidoxime using Carbonyl diimidazole (CDI) and K(2)CO(3). All the synthesized compounds (4a-4r) are novel and evaluated for their in vitro antifungal activities. SAR for the series has been developed by comparing their MIC values with miconazole and fluconazole. Some of the compounds from the series like 4j was equipotent with miconazole against Cryptococcus neoformans whereas activities of compound 4m against Aspergillus niger and Aspergillus flavus were comparable to miconazole. Also compound 4r shows activity comparable to miconazole against Candida albicans, A. niger and A. flavus. PMID- 21324568 TI - The functional involvement of gut-expressed sweet taste receptors in glucose stimulated secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). AB - BACKGROUND & AIMS: Enteroendocrine cells are thought to directly sense nutrients via alpha-gustducin coupled taste receptors (originally identified in the oral epithelium) to modulate the secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). METHODS: We measured mRNA expression of alpha-gustducin and T1R3 along the human gut; immunohistochemistry was used to confirm co localization with GLP-1. Functional implication of sweet taste receptors in glucose-stimulated secretion of GLP-1 and PYY was determined by intragastric infusion of glucose with or without lactisole (a sweet taste receptor antagonist) in 16 healthy subjects. RESULTS: alpha-gustducin was expressed in a region specific manner (predominantly in the proximal gut and less in ileum and colon, P < 0.05). Both, T1R3 and alpha-gustducin were co-localized with GLP-1. Glucose stimulated secretions of GLP-1 (P = 0.026) and PYY (P = 0.034) were reduced by blocking sweet receptors with lactisole. CONCLUSION: Key proteins implicated in taste signaling are present in the human gut and co-localized with GLP-1 suggesting that these proteins are functionally linked to peptide secretion from enteroendocrine cells. Glucose-stimulated secretion of GLP-1 and PYY is reduced by a sweet taste antagonist, suggesting the functional involvement of gut expressed sweet taste receptors in glucose-stimulated secretion of both peptides in humans. PMID- 21324569 TI - Body composition changes over 9 years in healthy elderly subjects and impact of physical activity. AB - BACKGROUND & AIMS: Age-related changes of body composition affect health status. This study aims at clarifying body composition changes in healthy elderly subjects, and evaluating the impact of physical activity on these changes. METHODS: In 1999, 213 subjects >= 65 years recruited through advertisements underwent assessment of health state, energy expenditure by physical activity, body composition by bioimpedance analysis and body cell mass by total body potassium. In 2008, 112 of them repeated these assessments with additional determination of Barthel index, Mini Mental State Examination and Geriatric Depression Score. RESULTS: Lean tissues decreased in both genders (p < 0.05). Compared to subjects aged 65-74 years at baseline, those aged >=75 years lost more body weight (men: -3.7 +/- 5.4 vs. 0.4 +/- 5.4 kg, women: -3.6 +/- 5.5 vs. 0.3 +/- 5.2 kg, both p < 0.05), and fat-free mass (men: -3.6 +/- 3.3 vs. -0.4 +/- 2.7 kg, women: -1.8 +/- 2.3 vs. -0.1 +/- 2.5 kg, both p < 0.05). Plotting of fat free mass evolution against age at baseline showed an exponential loss of fat free mass. Increased physical activity limited lean tissue loss in men but not in women. CONCLUSION: Loss of lean tissues occurs exponentially with aging. Further research should confirm these changes in subjects over 80 years. Increasing physical activity limits fat-free mass loss in men but not women. PMID- 21324570 TI - Quercetin reduces markers of oxidative stress and inflammation in sarcoidosis. AB - BACKGROUND & AIMS: Oxidative stress and low antioxidant levels are implicated in the aetiology of sarcoidosis, an inflammatory disease. Quercetin is a potent dietary antioxidant that also displays anti-inflammatory activities. Consequently, the aim is to examine the effect of quercetin supplementation on markers of oxidative stress and inflammation in sarcoidosis. METHODS: A double blind intervention study has been conducted with two groups of non-smoking, un treated sarcoidosis patients, matched for age and gender. One group was given 4x500 mg quercetin (n = 12) orally within 24 h, the other one placebo (n = 6). Plasma malondialdehyde levels were used as marker of oxidative damage, plasma ratios of TNFalpha/IL-10 and IL-8/IL-10 as pro-inflammatory markers. RESULTS: Quercetin supplementation improved the antioxidant defence, indicated by the increased total plasma antioxidant capacity. Moreover, quercetin supplementation also reduced markers of oxidative stress and inflammation in the blood of sarcoidosis patients. The effects of quercetin supplementation appeared to be more pronounced when the levels of the oxidative stress and inflammation markers were higher at baseline. CONCLUSIONS: Sarcoidosis patients might benefit from the use of antioxidants, such as quercetin, to reduce the occurring oxidative stress as well as inflammation. The effects of long-term use of antioxidant supplementation in sarcoidosis, using e.g. quercetin, on improvement of lung function remain to be investigated. (www.clinicaltrials.gov; NCT-00402623). PMID- 21324571 TI - A review and model assessment of (32)P and (33)P uptake to biota in freshwater systems. AB - Bioaccumulation of key short-lived radionuclides such as (131)I and (32,33)P may be over-estimated since concentration ratios (CRs) are often based on values for the corresponding stable isotope which do not account for radioactive decay during uptake via the food chain. This study presents estimates for bioaccumulation of radioactive phosphorus which account for both radioactive decay and varying ambient levels of stable P in the environment. Recommended interim CR values for radioactive forms of P as a function of bioavailable stable phosphorus in the water body are presented. Values of CR are presented for three different trophic levels of the aquatic food chain; foodstuffs from all three trophic levels may potentially be consumed by humans. It is concluded that current recommended values of the CR are likely to be significantly over estimated for radioactive phosphorus in many freshwater systems, particularly lowland rivers. Further research is recommended to field-validate these models and assess their uncertainty. The relative importance of food-chain uptake and direct uptake from water are also assessed from a review of the literature. It can be concluded that food-chain uptake is the dominant accumulation pathway in fish and hence accumulation factors for radioactive phosphorus in farmed fish are likely to be significantly lower than those for wild fish. PMID- 21324572 TI - Effects of unloading bracing on knee and hip joints for patients with medial compartment knee osteoarthritis. AB - BACKGROUND: Osteoarthritis affects the whole body, thus biomechanical effects on other joints should be considered. Unloading knee braces could be effective for knee osteoarthritis, but their effects on the contralateral knee and bilateral hip joints remain unknown. This study investigated the effects of bracing on the kinematics and kinetics of involved and contralateral joints during gait. METHODS: Nineteen patients with medial compartment knee osteoarthritis were analysed. Kinematics and kinetics of the knee and hip joints in frontal and sagittal planes were measured during walking without and with bracing on the more symptomatic knee. FINDINGS: The ipsilateral hip in the braced condition showed a lower adduction angle by an average of 2.58 degrees (range, 1.05 degrees -4.16 degrees ) during 1%-49% of the stance phase, and a lower abduction moment at the second peak during the stance phase than the hip in the unbraced condition (P<0.05 and P<0.005, respectively). With bracing, the contralateral hip showed a more marked peak extension moment and lower abduction moment at the first peak (P<0.05), and the contralateral knee adduction angle increased by an average of 0.32 degrees (range, 0.21 degrees -0.45 degrees ) during 46%-55% of the stance phase (P<0.05), compared to no bracing. INTERPRETATION: Unloading bracing modified the contralateral knee adduction angle pattern at a specific time point during gait. It also affected the frontal plane on the ipsilateral hip and the frontal and sagittal planes on the contralateral hip joint. Consideration should be provided to other joints when treating knee osteoarthritis. PMID- 21324573 TI - Strange bedfellows: the Catholic Church and Brazilian National AIDS Program in the response to HIV/AIDS in Brazil. AB - The HIV epidemic has raised important tensions in the relationship between Church and State in many parts of Latin America where government policies frequently negotiate secularity with religious belief and doctrine. Brazil represents a unique country in the region due to the presence of a national religious response to HIV/AIDS articulated through the formal structures of the Catholic Church. As part of an institutional ethnography on religion and HIV/AIDS in Brazil, we conducted an extended, multi-site ethnography from October 2005 through March of 2009 to explore the relationship between the Catholic Church and the Brazilian National AIDS Program. This case study links a national, macro-level response of governmental and religious institutions with the enactment of these politics and dogmas on a local level. Shared values in solidarity and citizenship, similar organizational structures, and complex interests in forming mutually beneficial alliances were the factors that emerged as the bases for the strong partnership between the two institutions. Dichotomies of Church and State and micro and macro forces were often blurred as social actors responded to the epidemic while also upholding the ideologies of the institutions they represented. We argue that the relationship between the Catholic Church and the National AIDS Program was formalized in networks mediated through personal relationships and political opportunity structures that provided incentives for both institutions to collaborate. PMID- 21324574 TI - Young children in urban areas: links among neighborhood characteristics, weight status, outdoor play, and television watching. AB - Although research consistently demonstrates a link between residential context and physical activity for adults and adolescents, less is known about young children's physical activity. Using data from the U.S. Fragile Families and Child Wellbeing Study (N=1822, 51% male), we explored whether outdoor play and television watching were associated with children's body mass indexes (BMIs) at age five using OLS regression models, controlling for a wide array of potential confounders, including maternal BMI. We also tested whether subjective and objective neighborhood measures - socioeconomic status (from U.S. Census tract data), type of dwelling, perceived collective efficacy, and interviewer-assessed physical disorder of the immediate environment outside the home - were associated with children's activities, using negative binomial regression models. Overall, 19% of the sample were overweight (between the 85th and 95th percentiles), and 16% were obese (>= 95th percentile). Hours of outdoor play were negatively associated with BMI, and hours of television were positively associated with BMI. Moreover, a ratio of outdoor play to television time was a significant predictor of BMI. Higher maternal perceptions of neighborhood collective efficacy were associated with more hours of outdoor play, fewer hours of television viewing, and more trips to a park or playground. In addition, we found that neighborhood physical disorder was associated with both more outdoor play and more television watching. Finally, contrary to expectations, we found that children living in public housing had significantly more hours of outdoor play and watched more television, than other children. We hypothesize that poorer children may have more unstructured time, which they fill with television time but also with outdoor play time; and that children in public housing may be likely to have access to play areas on the grounds of their housing facilities. PMID- 21324575 TI - Sex differences in the treatment of patients with atrial fibrillation: population based study in a local health district. AB - Differences in the treatment of atrial fibrillation between men and women were investigated by using patients in a local health district as a reference population. The study included 688 patients (359 female) who presented with atrial fibrillation. Women were older, more frequently had heart failure, and were more often functionally dependent than men. With regards to the management of atrial fibrillation, women were prescribed digoxin more frequently than men, but underwent electrical cardioversion less often, were less frequently seen by a cardiologist, and understood less about their treatment. After stratifying the findings by age and adjusting for heart failure and the degree of functional dependence, it was observed that women aged over 85 years were prescribed digoxin more often than men, while women aged under 65 years underwent cardioversion less often than men. In conclusion, gender differences observed in the treatment of atrial fibrillation cannot be fully explained by differences in clinical characteristics between men and women in the population. PMID- 21324576 TI - Acute aortic syndrome and rheumatoid arthritis. PMID- 21324577 TI - Rotational atherectomy through radial access with a 7.5 fr sheathless guiding catheter. PMID- 21324578 TI - The influence of nonlinear intra-thoracic vascular behaviour and compression characteristics on cardiac output during CPR. AB - Clinical observations suggest that the assumption of a linear relationship between chest compression pressure and cardiac output may be oversimplified. More complex behaviour may occur when the transmural pressure is large, changing the compliances and resistances in the intra-thoracic vasculature. A fundamental understanding of these compression induced phenomena is required for improving CPR. An extensively used, lumped element computer model (model I) of the circulation was upgraded and refined to include the intrathoracic vasculature (model II). After validation, model II was extended by adding variable compliances and resistances (model III) to the vascular structures. Successively, ranges of compression pressures, frequencies, duty cycles and compression pulse shapes were applied while controlling all other parameters. Cardiac output was then compared. The nonlinearities in compliance and resistance become important, limiting factors in cardiac output, starting in our experimental series at 70 mmHg peak compression pressure, and increasing with higher pressures. This effect is reproducible for sinusoidal and trapezoidal compression forms, resulting in lower cardiac output in all experiments at high compression pressures. Duty cycle and wait time are key parameters for cardiac output. Our data strongly indicate that vascular compliance, especially the ability of vessels to collapse (and potentially the cardiac chambers), can be a central factor in the limited output generated by chest compressions. Just pushing 'harder' or 'faster' is not always better, as an 'optimal' force and frequency may exist. Overly forceful compression can limit blood flow by restricting filling or depleting volume in the cardiac chambers and central great vessels. PMID- 21324579 TI - Cyanoacrylate glue ingestion with formation of a laryngeal cast. PMID- 21324581 TI - System dynamics modeling for municipal water demand estimation in an urban region under uncertain economic impacts. AB - Accurate prediction of municipal water demand is critically important to water utilities in fast-growing urban regions for drinking water system planning, design, and water utility asset management. Achieving the desired prediction accuracy is challenging, however, because the forecasting model must simultaneously consider a variety of factors associated with climate changes, economic development, population growth and migration, and even consumer behavioral patterns. Traditional forecasting models such as multivariate regression and time series analysis, as well as advanced modeling techniques (e.g., expert systems and artificial neural networks), are often applied for either short- or long-term water demand projections, yet few can adequately manage the dynamics of a water supply system because of the limitations in modeling structures. Potential challenges also arise from a lack of long and continuous historical records of water demand and its dependent variables. The objectives of this study were to (1) thoroughly review water demand forecasting models over the past five decades, and (2) propose a new system dynamics model to reflect the intrinsic relationship between water demand and macroeconomic environment using out-of-sample estimation for long-term municipal water demand forecasts in a fast-growing urban region. This system dynamics model is based on a coupled modeling structure that takes into account the interactions among economic and social dimensions, offering a realistic platform for practical use. Practical implementation of this water demand forecasting tool was assessed by using a case study under the most recent alternate fluctuations of economic boom and downturn environments. PMID- 21324580 TI - Oxidized low-density lipoproteins in cord blood from neonates with intra-uterine growth restriction. AB - OBJECTIVE: We verified whether oxidative stress indices (oxidized low-density lipoproteins and malondialdehyde) and inflammatory biomarkers (circulating C reactive protein, interleukin-6, tumour necrosis factor-alpha, serum amyloid A and soluble intercellular vascular cell adhesion molecule) are increased in the umbilical vein of placental insufficiency induced intra-uterine growth restricted neonates. STUDY DESIGN: The prospective cohort study, involving 3 tertiary care centers, consists of 200 consecutively recruited pregnant women carrying twins. We chose the twin pregnancy model because both fetuses share the same maternal environment, thereby avoiding potential confounding factors when comparing oxidative stress and inflammation biomarkers. We analysed only twin pairs with one with intra-uterine growth restriction (N=38) defined as fetal growth<10th percentile with abnormal Doppler of the umbilical artery. Blood samples were taken at birth from the umbilical vein. Intra-pair comparisons on the biomarkers were performed using the Student paired t-test. RESULTS: We observed increased cord blood levels of oxidized low-density lipoproteins, (2.394 +/- .412 vs 1.296 +/- .204, p=.003) but not of malondialdehyde in growth restricted neonates when compared to their normal counterparts. Although indices of inflammation tended to be increased in cord blood from growth restricted newborns, the difference did not reach statistical significance. CONCLUSION: In the twin model, intra-uterine growth restriction is associated with low-density lipoprotein oxidation without apparent dysregulation of inflammation biomarkers. CONDENSATION: Increased oxidized low-density lipoproteins are observed in growth restricted twins compared to their co-twins with normal growth at birth. PMID- 21324582 TI - Evaluating the effects of alternative forest management plans under various physiographic settings using historical records as a reference. AB - Using historical General Land Office record as a reference, this study employed a landscape-scale disturbance and succession model to estimate the future cumulative effects of six alternative management plans on the tree species composition for various physiographic settings for the Mark Twain National Forest in Missouri. The results indicate that over a 200-year horizon, the relative abundance of black oak and pine species groups will decrease and the relative abundance of the white oak species group will increase, regardless of management strategy. General Land Office witness tree records provide a measure of tree species composition in the period from 1800 to 1850, prior to the large-scale influx of European settlers. Compared to the tree species composition described in the General Land Office records, the six contemporary management alternatives considered all would lead to a lower abundance of pine species, a higher abundance of red/black oak species, and a slightly higher abundance of white oak species after 200 years. Impacts of management on tree species composition varied with physiographic settings. The projected relative abundance of pine differed significantly across the five physiographic classes over the first 40 years of the simulation. In the medium term (simulation years 41-100) the projected relative pine abundance differed significantly among only four physiographic classes. In the long term (simulation years 100-200) the projected relative pine abundance differed for only one physiographic class. In contrast, differences among physiographic classes in the relative abundance of black oaks and white oaks increased over time. In general, the expected long-term differences in relative tree species abundance among six proposed alternative management plans are small compared to shifts in tree species composition that have occurred from 1850 to the present. PMID- 21324583 TI - Safety profile of robot-assisted radical prostatectomy: a standardized report of complications in 3317 patients. AB - BACKGROUND: Previous studies attempting to assess complications after robot assisted radical prostatectomy (RARP) are limited by their small numbers, short follow-up, or lack of risk factor analysis. OBJECTIVE: To document complications after RARP by strict application of standardized reporting criteria. DESIGN, SETTING, AND PARTICIPANTS: Between January 2005 and December 2009, 3317 consecutive patients underwent RARP at a tertiary referral center. Median follow up was 24.2 mo (interquartile range: 12.4-36.9). INTERVENTION: Transperitoneal RARP was performed by one of five surgeons-two experienced, three beginners. MEASUREMENTS: Complications were captured by exhaustive review of multiple datasets, including our prospective prostate cancer database, claims data, and electronic medical and institutional morbidity and mortality records, and reported according to the Martin-Donat criteria. Complications were stratified by type (medical/surgical), Clavien classification, and timing of onset. Multivariable analysis of factors predictive of complications was performed. RESULTS AND LIMITATIONS: The median hospitalization time was 1 d. There were 368 complications in 326 patients (9.8%), including a transfusion rate of 2.2%. We detected 79 medical complications in 78 patients (2.4%) and 289 surgical complications in 264 patients (8.0%). There were 242 minor (Clavien 1-2) and 126 major (Clavien 3-5) complications. Two hundred ninety-nine (81.3%) complications occurred within 30 d, 17 (4.6%) within 31-90 d, and 52 (14.1%) after 90 d from surgery. On multivariable analysis, preoperative prostate-specific antigen values and cardiac comorbidity were predictive for medical complications, whereas age, gastroesophageal reflux disease, and biopsy Gleason score were predictive of surgical complications. Limitations of this study include representing results from a single high-volume referral center and not including the learning curve of the two most experienced surgeons. CONCLUSIONS: RARP is a safe operation, with an overall complication rate of 9.8%. Most complications occurred within 30 d of surgery. PMID- 21324584 TI - Application of dithiocarbamate-modified starch for dyes removal from aqueous solutions. AB - The present study shows that the dithiocarbamate-modified starch (DTCS) is a commercially promising sorbent for the removal of anionic dyes from aqueous solutions. It is more effective than activated carbon for this purpose. At the appropriate solution pH of 4, kinetic studies indicate that the sorption of the dyes tends to follow pseudo-first-order equation. The sorption equilibrium is best described by the Langmuir-Freundlich isotherm model at 298 K. The capacities for individual dyes follow the sequence acid orange 7 > acid orange 10 > acid red 18 > acid black 1 > acid green 25, which is consistent with the inverse order of molecular size. The negative enthalpy change for the adsorption process confirms the exothermic nature of adsorption, and a free energy change confirms the spontaneity of the process. The FT-IR spectra and thermogravimetric analyses verify the sorption based on starch-NH(2)(+)CSSH?(-)O(3)S-dye electrostatic attraction. The DTCS can be regenerated from the dye loaded DTCS in a weak basic solution containing sodium sulfate. PMID- 21324585 TI - Physicochemical properties of metal-doped activated carbons and relationship with their performance in the removal of SO2 and NO. AB - Several metal-doped activated carbons (Fe, Co, Ni, V, Mn, Cu and Ce) were prepared and characterized. The results of N(2) adsorption-desorption, X-ray diffraction, and X-ray photoelectron spectroscopy indicated that some metals (Cu and Fe) were partly reduced by carbon during preparation. Activity tests for the removal of SO(2) and the selective catalytic reduction of NO with ammonia were carried out. Due to different physicochemical properties, different pathways for the SO(2) removal had been put out, i.e., catalytic oxidation, direct reaction and adsorption. This classification depended on the standard reduction potentials of metal redox pairs. Samples impregnated with V, Ce and Cu showed good activity for NO reduction by NH(3), which was also ascribed to the reduction potential values of metal redox pairs. Ce seemed to be a promising alternative to V due to the higher activity in NO reduction and the nontoxic property. A metal cation which could easily convert between the two valences seemed to be crucial to the good performance of both SO(2) and NO removal, just like V and Cu. PMID- 21324586 TI - Hazardous concentrations of selenium in soil and groundwater in North-West India. AB - Soil and groundwater samples were collected for bulk elemental analyses in particular for selenium (Se) concentrations from six agricultural sites located in states of Punjab and Haryana in North-West India. Toxic concentrations of Se (45-341 MUg L(-1)) were present in groundwater (76 m deep) of Jainpur and Barwa villages in Punjab. Selenium enrichments were also found in top soil layers (0-15 cm) of Jainpur (2.3-11.6 mg kg(-1)) and Barwa (3.1 mg kg(-1)). Mineralogical analyses confirmed silicates and phyllosilicates as main components of these soils, also reflected by the high content of SiO(2) (40-62 wt.%), Al(2)O(3) (9-21 wt.%) and K(2)O (2.2-3.2 wt.%). Prevailing intensive irrigation practices in Punjab with Se enriched groundwater may be the cause of Se accumulation in soils. Sequential extraction revealed >50% Se bioavailability in Jainpur soils. Appearance of selenite was observed in some of the batch assays with soil slurries under reducing conditions. Although safe Se concentrations were found in Hisar, Haryana, yet high levels of As, Mo and U present in groundwater indicated its unsuitability for drinking purposes. Detailed biogeochemical studies of Se in sediments or groundwater of Punjab are not available so far; intensive investigations should be started for better understanding of the problem of Se toxicity. PMID- 21324587 TI - Adsorption of diuron and dichlobenil on multiwalled carbon nanotubes as affected by lead. AB - The effect of lead on the adsorption of diuron and dichlobenil on multiwalled carbon nanotubes (MWCNTs) was investigated to explore the possible application of MWCNTs for removal of both herbicides from contaminated water. The adsorption of diuron and dichlobenil on MWCNTs at pH 6 was nonlinear and fit the Polanyi-Manes model well. The adsorption of diuron and dichlobenil was closely correlated with specific surface areas and micropore volumes of MWCNTs. An increase in oxygen content of MWCNTs with same diameters and similar surface areas decreased the adsorption of diuron and dichlobenil, while increased the adsorption of lead. Micro-Fourier transform infrared spectroscopic study indicated that hydrogen bonding is a main mechanism responsible for the adsorption of diuron or dichlobenil onto MWCNTs-O. Oxygen containing groups, mainly carboxylic groups, significantly increased the adsorption of lead through the formations of outer sphere and inner-sphere complexes, which are verified by X-ray absorption spectroscopic measurements. Oxygen containing groups and the presence of lead diminished the adsorption of diuron and dichlobenil. The suppression mechanisms of lead were ascribed to hydration and complexation of lead with carboxylic groups, which may occupy part of surface of MWCNTs-O. The large hydration shell of lead cations may intrude or shield hydrophobic and hydrophilic sites, resulting in a decreased adsorption of diuron and dichlobenil at the lead complexed moieties. PMID- 21324588 TI - Electro-scrubbing volatile organic carbons in the air stream with a gas diffusion electrode. AB - It is demonstrated that exposing the VOC air streams to the electro-scrubbing reactor with a gas diffusion electrode leads to an efficient removal of organics. The importance order of the influence factors on the electro-scrubbing reactor performance is: conductivity, voltage and air stream flow-rate. The effective conductivity and high voltages generally are beneficial to the removal process and the air flow-rate is not a significant factor compared with the other two, indicating that the reactor might have a consistently satisfying performance within a wide range of gas volumetric load. The mass transfer of both organics and oxygen in the reactor is estimated by mathematical model, and the calculation determines the concentration boundary conditions for the 2-ethoxyethyl acetate removal: if the 2-ethoxyethyl acetate concentration in the inflow air stream holds C(G,i) <= 0.7198%, the removal in the electro-scrubbing reactor is electrochemical reaction controlled; if C(G,i)>0.7198%, the controlling step will be the oxygen mass transfer from the air to the liquid in the electro-scrubbing reactor. The Apparent Current Efficiency of the electro-scrubbing reactor was also determined using COD data, which is significantly higher than some commercial metal oxide electrodes, showing that the reactor is energy efficient and has the promise for the future scale-up. PMID- 21324589 TI - Genital pain in women: Beyond interference with intercourse. PMID- 21324590 TI - Effects of coping skills training and sertraline in patients with non-cardiac chest pain: a randomized controlled study. AB - Non-cardiac chest pain (NCCP) is a common and distressing condition. Prior studies suggest that psychotropic medication or pain coping skills training (CST) may benefit NCCP patients. To our knowledge, no clinical trials have examined the separate and combined effects of CST and psychotropic medication in the management of NCCP. This randomized clinical trial examined the separate and combined effects of CST and antidepressant medication (sertraline) in participants with non-cardiac chest pain. A sample of individuals diagnosed with NCCP was randomly assigned to one of four treatments: (1) CST plus sertraline (CST+sertraline), (2) CST plus placebo (CST+placebo), (3) sertraline alone, or (4) placebo alone. Assessments of pain intensity, pain unpleasantness, anxiety, pain catastrophizing, depression, and physical disability were collected prior to treatment, and at 10- and 34-weeks following randomization. Data analyses revealed that CST and sertraline either alone or in combination significantly reduced pain intensity and pain unpleasantness. The combination of CST plus sertraline may have the greatest promise in that, when compared to placebo alone, it not only significantly reduced pain but also pain catastrophizing and anxiety. Overall, these findings support the importance of further research on the effects of CST and sertraline for non-cardiac chest pain. PMID- 21324591 TI - Antinociceptive effects of MSVIII-19, a functional antagonist of the GluK1 kainate receptor. AB - The ionotropic glutamate receptor subunit, GluK1 (GluR5), is expressed in many regions of the nervous system related to sensory transmission. Recently, a selective ligand for the GluK1 receptor, MSVIII-19 (8,9-dideoxy-neodysiherbaine), was synthesized as a derivative of dysiherbaine, a toxin isolated from the marine sponge Lendenfeldia chondrodes. MSVIII-19 potently desensitizes GluK1 receptors without channel activation, rendering it useful as a functional antagonist. Given the high selectivity for GluK1 and the proposed role for this glutamate receptor in nociception, we sought to test the analgesic potential of MSVIII-19 in a series of models of inflammatory, neuropathic, and visceral pain in mice. MSVIII 19 delivered intrathecally dose-dependently reduced formalin-induced spontaneous behaviors and reduced thermal hypersensitivity 3 hours after formalin injection and 24 hours after complete Freund's adjuvant-induced inflammation, but had no effect on mechanical sensitivity in the same models. Intrathecal MSVIII-19 significantly reduced both thermal hyperalgesia and mechanical hypersensitivity in the chronic constriction injury model of neuropathic pain, but had no effect in the acetic acid model of visceral pain. Peripheral administration of MSVIII-19 had no analgesic efficacy in any of these models. Finally, intrathecal MSVIII-19 did not alter responses in Tail-flick tests or performance on the accelerating RotaRod. These data suggest that spinal administration of MSVIII-19 reverses hypersensitivity in several models of pain in mice, supporting the clinical potential of GluK1 antagonists for the management of pain. PMID- 21324592 TI - Molecular evidence for zoonotic transmission of Giardia duodenalis among dairy farm workers in West Bengal, India. AB - No study in the past has examined the genetic diversity and zoonotic potential of Giardia duodenalis in dairy cattle in India. To assess the importance of these animals as a source of human G. duodenalis infections and determine the epidemiology of bovine giardiasis in India, fecal samples from 180 calves, heifers and adults and 51 dairy farm workers on two dairy farms in West Bengal, India were genotyped by PCR-RFLP analysis of the beta-giardin gene of G. duodenalis followed by DNA sequencing of the nested PCR products. The overall prevalence of G. duodenalis in cattle was 12.2% (22/180), the infection being more prevalent in younger calves than in adult cattle. Zoonotic G. duodenalis Assemblage A1 was identified in both calves and workers although the most prevalent genotype detected in cattle was a novel Assemblage E subgenotype. These findings clearly suggest that there is a potential risk of zoonotic transmission of G. duodenalis infections between cattle and humans on dairy farms in India. PMID- 21324593 TI - Structural and ultrastructural changes in the lungs of cats Felis catus (Linnaeus, 1758) experimentally infected with D. immitis (Leidy, 1856). AB - Clinical signs are seldom observed in feline heartworm disease, and the pathophysiological changes in the lungs of infected animals remain undefined. The goal of this study was to evaluate the structural and ultrastructural changes in the lungs of cats experimentally infected with Dirofilaria immitis. Six healthy cats were each infected with two adult heartworms by intravenous transplantation (Receptor Group, RG). The control group consisted of two uninfected animals kept under the same conditions as the RG. At 42 days after transplantation, all cats were euthanized and necropsied for worm recovery and collection of lung samples for examination by light microscopy (LM) and transmission electron microscopy. By LM, lung sections from the six infected cats exhibited bronchial and bronchiolar lesions. Alterations in all tissues of the pulmonary arteries were observed in the infected animals. In conclusion, cats infected experimentally with D. immitis developed lesions in their lungs as a consequence of arterial disease and intense interstitial pneumonia. PMID- 21324594 TI - Determination of oxidative status and apoptosis in peripheral blood of dogs with sarcoptic mange. AB - The aim of the present study was to determine the erythrocytic oxidant/antioxidant balance and apoptosis of peripheral blood leukocytes of dogs with natural Sarcoptes scabiei var. canis mite infestation. A total of twenty four clinically Sarcoptes-infested dogs were examined and used to execute the study. While another twenty four healthy dogs free of any ecto-parasite were used as controls. Peripheral blood samples were obtained from each infested only once on the day of dermatological examinations. Determination of oxidant/antioxidant balance was conceded by estimating the levels of lipid peroxides and antioxidants in erythrocytes. While, apoptosis of peripheral blood leukocytes was determined by estimating externalization of phosphatidylserine (PS) at the cell surface as well as by detection of depolarization mitochondrial membrane potential (DeltaPsim) by flow cytometry. Sarcoptes-infested dogs had revealed significantly higher (P<=0.001) contents of erythrocytic lipid peroxides in comparison with the healthy controls. Whereas the level of reduced glutathione was found to be significantly lower (P<=0.001) in Sarcoptes-infested dogs as compared to the healthy dogs. The activity of glutathione peroxidase was found to be significantly lower (P<=0.001) in Sarcoptes-infested dogs as compared to the healthy dogs. The activity of glutathione-S-transferase was also found to be significantly lower (P<=0.001) in Sarcoptes-infested dogs as compared to the healthy dogs. The dogs with sarcoptic mange had revealed significantly lower (P<=0.001) activity of superoxide dismutase in coparision with the healthy dogs. The dogs with sarcoptic mange had also revealed significantly lower (P<=0.001) activity of catalase in coparision with the healthy dogs. The percentage of apoptotic leukocytes was found to be significantly higher (P<=0.001) in Sarcoptes infested dogs as compared to the healthy controls. Sarcoptes-infested dogs had also exhibited significantly (P<=0.001) higher percentage of leukocytes with depolarized mitochondrial membrane potential in comparison with the healthy controls. It is concluded that significant alteration in oxidant/antioxidant balance and increased rate of apoptosis in peripheral leukocytes may be implicated in the pathogenesis of clinical Sarcoptes mite infestation in dogs. PMID- 21324595 TI - Heartworm disease: challenges in a changing world. PMID- 21324596 TI - Quantitative real time polymerase chain reaction assays for the sensitive detection of Besnoitia besnoiti infection in cattle. AB - Bovine besnoitiosis, an economically important disease in cattle in some countries of Africa and Asia, is emerging in Europe. The definitive host of Besnoitia besnoiti, the causative agent of bovine besnoitiosis, is unknown and the transmission of the parasite is not completely understood. Sensitive and quantitative DNA detection methods are needed to determine whether serologically positive animals are infectious and to examine the role of vectors (e.g. haematophagous insects) in the transmission of the parasite. To this end, we established two different 5'-nuclease quantitative assays to detect B. besnoiti infection in cattle and to estimate the parasite load in samples (BbRT1 and BbRT2). These PCRs are based on the sequence of the internal transcribed spacer region 1 (ITS-1) of the ribosomal RNA gene. Tests with serial dilutions of B. besnoiti genomic DNA in a buffer containing 100 ng/MUl bovine DNA revealed a detection limit of 0.01 pg genomic B. besnoiti DNA. Reliable quantification was possible in samples containing >=1 pg B. besnoiti genomic DNA with a coefficient of variation of <= 2%. To estimate the diagnostic sensitivity of the tests, skin biopsies and scrapings from the mucous membrane of the vestibulum vaginae (vaginal scrapings) were taken from cattle with clinical signs of chronic besnoitiosis. Regardless of the real time PCR assay used, 90.7% (39/43) of these animals were positive in at least one of two samples (skin or vaginal scrapings). Antibody titers, as determined by an immunofluorescent antibody test, and the threshold cycle values of the real time PCR obtained for skin samples and vaginal scrapings, were significantly correlated. The specificity of the PCRs was confirmed using genomic DNA from related parasites, including genomic DNA of Besnoitia spp., Neospora caninum, Toxoplasma gondii, Hammondia hammondi, Hammondia heydorni, Isospora spp., Sarcocystis spp., Eimeria bovis, Cryptosporidium parvum, and Trypanosoma brucei brucei. Since the sequence of the ITS-1 region of B. besnoiti is identical with that of Besnoitia species isolated from donkeys (Besnoitia bennetti), and reindeer (Besnoitia tarandi), both real time PCRs detected also DNA of these parasites. One of the B. besnoiti real time PCRs, BbRT1, but not BbRT2, cross-reacted with Besnoitia darlingi, Besnoitia oryctofelisi, and Besnoitia neotomofelis when large amounts of genomic DNA (10 ng) were used. The other B. besnoiti real time PCR assay (BbRT2) was specific for B. besnoiti, B. bennetti and B. tarandi, but did not react when 10 ng DNA of other related parasite species from the genus Besnoitia or other genera were subjected to analysis. PMID- 21324597 TI - Oocysts of Hepatozoon canis in Rhipicephalus (Boophilus) microplus collected from a naturally infected dog. AB - Canine hepatozoonosis is a tick-borne disease caused by protozoans of the genus Hepatozoon. Several tick species have been implicated as potential vectors. Therefore, extensive studies are needed to determine the 'natural' endemic cycle of this parasite. This paper presents the first report of the presence of Hepatozoon canis oocysts in Rhipicephalus (Boophilus) microplus collected from an infected dog. PMID- 21324598 TI - Fumigant toxicity of cassia and cinnamon oils and cinnamaldehyde and structurally related compounds to Dermanyssus gallinae (Acari: Dermanyssidae). AB - The toxicity of two cassia oils, four cinnamon oils and (E)-cinnamaldehyde and (E)-cinnamic acid and 34 structurally related compounds to adult Dermanyssus gallinae (De Geer) collected from a poultry house was examined using a vapour phase mortality bioassay. Results were compared with those of dichlorvos, a conventional acaricide. The cassia and cinnamon oils (cinnamon technical, cinnamon #500, cassia especial, cassia true, cinnamon bark and cinnamon green leaf) exhibited good fumigant toxicity (LD(50), 11.79-26.40 MUg cm(-3)). alpha Methyl-(E)-cinnamaldehyde (LD(50), 0.45 MUg cm(-3)) and (E)-cinnamaldehyde (0.54 MUg cm(-3)) were the most toxic compounds and the toxicity of these compounds was comparable to that of dichlorvos (0.30 MUg cm(-3)). Potent fumigant toxicity was also observed in allyl cinnamate, ethyl-alpha-cyanocinnamate, (E)-2 methoxylcinnamic acid and (Z)-2-methoxylcinnamic acid (LD(50), 0.81-0.92 MUg cm( 3)). Structure-activity relationships indicate that structural characteristics, such as types of functional groups and carbon skeleton rather than vapour pressure parameter, appear to play a role in determining toxicity. The essential oils and compounds described merit further study as potential acaricides for the control of D. gallinae populations as fumigants with contact action due to global efforts to reduce the level of highly toxic synthetic acaricides in the agricultural environment. PMID- 21324599 TI - Seroprevalence of Toxoplasma gondii and Neospora caninum infections in goats in Poland. AB - In 2007 a survey on herd-level seroprevalence of Toxoplasma gondii and Neospora caninum infections in goats in Poland was carried out. Sera were collected from all 49 breeding goat herds, scattered over the entire country, with the vast majority of them located in the western, central and northern provinces. Only adult females (>=12 months of age) were included in the study. A herd was recorded as infected if at least one seropositive female was detected. In each herd, simple random sampling was applied and sample size was determined in a way, which allowed to evaluate serological status of a herd at expected individual level seroprevalence 10% and level of confidence 95%. In total, 1060 sera were tested using two commercial indirect ELISA kits. Sera positive to N. caninum were subsequently confirmed with IFAT. The true herd-level seroprevalence was 100% for T. gondii and 9.0% for N. caninum infection. Three herds positive to T. gondii infection were randomly selected and all adult goats were tested with an ELISA. Individual-level true seroprevalence in these herds ranged from 30.2% to 100%. This is the first time that antibodies to N. caninum have been detected in goats in Poland. PMID- 21324600 TI - Genetic analysis of Anisakis typica (Nematoda: Anisakidae) from cetaceans of the northeast coast of Brazil: new data on its definitive hosts. AB - Anisakids from 5 different species of cetacean, Kogia breviceps, Peponocephala electra, Stenella clymene, Stenella longirostris and Steno bredanensis, were submitted to genetic analysis. Adults and larvae fixed in ethanol-formalin-acetic acid or in 70% ethanol for periods ranging from 10 months to 10 years were isolated from 9 cetaceans stranded on Ceara coast, Northeast Brazil. The 18S rDNA gene, ITS1, and specific Anisakis typica ITS regions were amplified by PCR. 18S rDNA and ITS1 region confirmed Anisakis sp. morphological identification but also detected the presence of Aspergillus sp. in longer preserved samples. All samples were identified as A. typica by ITS species-specific PCR. The study report three new definitive hosts of A. typica from the Brazilian Atlantic coast by genetic analysis: P. electra, K. breviceps, and S. clymene. PMID- 21324601 TI - Molecular and serological prevalence of Babesia bovis and Babesia bigemina in water buffaloes in the northeast region of Thailand. AB - Bovine babesiosis is a tick-transmitted hemoprotozoan disease that is mainly caused by Babesia bovis and Babesia bigemina and is characterized by significant morbidity and mortality worldwide. The disease is widespread in the northeastern region of Thailand, where an increasingly large part of the livestock is composed of water buffaloes. The present study was therefore conducted to investigate the epidemiological distribution of B. bovis and B. bigemina in water buffaloes in the northeastern region of Thailand. A total of 305 buffalo blood samples were randomly collected from five provinces and simultaneously analyzed by the nested PCR (nPCR) assay, ELISA, and IFAT techniques. The overall prevalence of B. bovis and B. bigemina was 11.2% and 3.6% by nPCR, 14.7% and 5.9% by ELISA, and 16.8% and 5.6% by IFAT, respectively. The high concordance between the molecular and the serological detection tests revealed the specificity and sensitivity of the diagnostic assays used for the detection of infection as well as the endemic stability status of the parasites in the surveyed areas. Statistically significant differences in the prevalence of the two infections were observed on the basis of age and location but not gender. Our data provide valuable information regarding the epidemiology of B. bovis and B. bigemina infection in water buffaloes in the northeastern region of Thailand which will likely be very beneficial for management and control programs of this disease. PMID- 21324602 TI - A modified agglutination test for the diagnosis of Besnoitia besnoiti infection. AB - Bovine besnoitiosis is caused by Besnoitia besnoiti, an obligate intracellular apicomplexan parasite. Affected animals present cutaneous and systemic manifestations and the disease may lead to considerable economic losses. Although generally associated to tropical and subtropical areas, bovine besnoitiosis is now considered an emergent disease in Europe, due to the increasing number of new cases and apparent geographical expansion. In this study we evaluated the performance of a modified agglutination test (B-MAT) in the serodiagnosis of bovine besnoitiosis in comparison to the indirect immunofluorescent-antibody test (IFAT). To establish optimal protocol conditions we used bovine sera with a known infection status for B. besnoiti infection. Positive animals (n=36) presented B. besnoiti dermal cysts and anti-B. besnoiti specific antibodies, as determined by the indirect immunofluorescence test (IFAT). Negative animals (n=103) were from non-endemic areas in Portugal and negative by the IFAT. From here, we evaluated the sensitivity and specificity of the B-MAT relative to the IFAT with a panel of sera from herds with history of bovine besnoitiosis in Portugal, Spain and France (n=402), using three serum dilutions (1:80, 1:160, 1:320). Considering the positive cut-off at 1:160 serum dilution, the B-MAT showed an almost perfect test agreement with the IFAT; (kappa=0.968; 95% CI: 0.941-0.996) with a relative sensitivity of 97.2% (95% CI: 94.1-100%) and a relative specificity of 99.3% (95% CI: 98.4-100%). As a simple and inexpensive technique the B-MAT represents a valuable tool for the diagnosis and study of the epidemiology of bovine besnoitiosis. PMID- 21324603 TI - Renal effects of Dirofilaria immitis in experimentally and naturally infected cats. AB - Canine heartworm infection has been associated with glomerular disease and proteinuria. We hypothesized that proteinuria, likely due to glomerular damage, would also be found in cats experimentally and naturally infected with Dirofilaria immitis. Two populations of cats were evaluated, including 80 that were each experimentally infected with 60 infective heartworm larvae as part of a drug safety study, and 31 that were naturally infected with D. immitis. Each had a control population with which to be compared. In the experimentally infected group, we evaluated urine from 64 cats. Ten of these cats were shown to have microalbuminuria 8 months post infection. No cat refractory to infection with larvae and no cats from the control group demonstrated microalbuminuria. All 10 microalbuminuric cats were shown to have significant proteinuria, as measured by the urine protein:creatinine ratio. There was a subtle, but significant, association between worm burden and proteinuria, and although the presence of adult heartworms was required for the development of proteinuria, both microfilaremic and amicrofilaremic cats were affected. Neither the presence of circulating heartworm antibodies and antigen nor the presence of antigenuria predicted the development of proteinuria. Both heavily infected cats (5-25 adult heartworms) and cats with worm burdens compatible with natural infections (1-4 adult heartworms) developed proteinuria, and the relative numbers of cats so affected were similar between heavily and more lightly infected cats. Naturally infected cats, for which only dipstick protein determinations were available, were shown to have a significantly greater incidence of proteinuria (90% vs 35%) than did those in an age- and gender-matched control population. Additionally, the proteinuria in heartworm-infected cats was 3- to 5-fold greater in severity. We conclude that cats infected with mature adult heartworms are at risk for developing proteinuria and that this is recognized relatively soon after infection. While heavier infections may predispose cats to developing proteinuria, this complication is seen in naturally infected cats and experimental cats with worm burdens similar to those seen in natural infections (i.e., "clinically appropriate" worm burdens). The clinical relevance of heartworm-associated proteinuria is yet to be determined. PMID- 21324604 TI - Identification and characterization of the cofactor-independent phosphoglycerate mutases of Dirofilaria immitis and its Wolbachia endosymbiont. AB - Drug treatments for heartworm disease have not changed significantly in the last decade. Due to concerns about possible drug resistance and their lower efficacy against adult worms, there is a need for the development of new antifilarial drug therapies. The recent availability of genomic sequences for the related filarial parasite Brugia malayi and its Wolbachia endosymbiont enables genome-wide searching for new drug targets. Phosphoglycerate mutase (PGM) enzymes catalyze the critical isomerization of 3-phosphoglycerate (3-PG) and 2-phosphoglycerate (2 PG) in glycolytic and gluconeogenic metabolic pathways. There are two unrelated PGM enzymes, which are structurally distinct and possess different mechanisms of action. The mammalian enzyme requires 2,3-bisphosphoglycerate as a cofactor (dependent PGM or dPGM), while the other type of PGM does not (independent PGM or iPGM). In the present study, we have determined that Dirofilaria immitis and its Wolbachia endosymbiont both possess active iPGM. We describe the molecular characterization and catalytic properties of each enzyme. Our results will facilitate the discovery of selective inhibitors of these iPGMs as potentially novel drug treatments for heartworm disease. PMID- 21324605 TI - Intensity-modulated radiotherapy versus conventional and 3D conformal radiotherapy in patients with head and neck cancer: is there a worthwhile quality of life gain? AB - BACKGROUND: Intensity-modulated radiotherapy (IMRT) is a technique that allows delivery of lower doses of radiation to normal tissue, while maintaining or increasing the tumour dose, compared with two-dimensional radiotherapy (2DRT) or three-dimensional conformal radiotherapy (3DCRT). This review of published data was undertaken to assess whether IMRT is associated with quality of life (QoL) benefits versus 2DRT and 3DCRT. DESIGN: English-language literature published between January 2005 and August 2010 was searched for studies comparing IMRT versus 2DRT or 3DCRT in head and neck cancers that included QoL evaluation. Fourteen studies (five prospective and nine retrospective) were identified, two in abstract form only. Only one study was randomised. Studies included patients with nasopharyngeal cancer only, oropharyngeal cancer only and mixed populations. RESULTS: The EORTC QLQ-C30 was the most widely used instrument, generally supplemented with the head and neck cancer module H&N35. IMRT was associated with statistically significant improvements in certain QoL domains versus 2DRT and 3DCRT, particularly those relating to xerostomia, including dry mouth, sticky saliva and eating-related domains. Improvements in global QoL were also observed in the IMRT groups in some studies. CONCLUSION: Based on the studies reviewed, patients treated with IMRT experience statistically significant improvements in several important QoL domains versus 2DRT and 3DCRT. However, studies included heterogeneous populations, different timepoints for measurements and a variety of instruments for QoL assessment. Accepting the difficulties in execution, IMRT should be compared with 3DCRT in prospective randomised studies in homogeneous patient populations, using appropriate QoL assessments and clinical end points, to establish if IMRT provides enough value for the additional resources involved. PMID- 21324606 TI - Translating addictions research into evidence-based practice: the Polaris CD outcomes management system. AB - Converting the findings from addictions studies into information actionable by (non-research) treatment programs is important to improving program outcomes. This paper describes the translation of the findings of studies on Patient Services matching, prediction of patient response to treatment (Expected Treatment Response) and prediction of dropout to provide evidence-based decision support in routine treatment. The findings of the studies and their application to the development of an outcomes management system are described. Implementation issues in a network of addictions treatment programs are discussed. The work illustrates how outcomes management systems can play an important role in translating research into practice. PMID- 21324607 TI - Motivation to change alcohol use and treatment engagement in incarcerated youth. AB - Adolescents have been reported to be less motivated to engage and remain in substance abuse treatment than adults. When they appear motivated, it is often due to external motivators such as family pressure or court mandated treatment. The purpose of this study was to determine if adolescents' motivation to change alcohol use was related to treatment engagement while incarcerated and alcohol use after release. Participants (N=114) were youth in a state correctional facility in the Northeast and included adolescents who engaged in at least monthly drinking. Motivation to change alcohol use was measured by the Alcohol Ladder (AL), and treatment engagement was measured by the Treatment Participation Questionnaire (comprised of positive and negative treatment engagement). Measures were administered at baseline, 2 months in facility follow up, and 3 months post release follow up. Analysis indicated acceptable test-retest stability (r=.388, p<=.001). The AL at 3 months post release significantly predicted quantity and frequency of alcohol use after release. The AL at baseline also significantly predicted positive and negative treatment engagement at 2 months into incarceration (i.e., 2 months in facility follow up) indicating predictive validity. These results suggest that the AL is a reliable, valid, and useful instrument for incarcerated youth. PMID- 21324608 TI - Days to treatment and early retention among patients in treatment for alcohol and drug disorders. AB - OBJECTIVES: Drug and alcohol treatment programs often have long delays between assessment and treatment admission. The study examined the impact of days to treatment admission on the probability of completing four sessions of care within an addiction treatment program implementing improvements in their admission process. METHODS: Mixed-effects logistic regression was used to test the effect of wait time on retention in care. RESULTS: Findings demonstrate a strong decrement in the probability of completing four sessions of treatment with increasing time between the clinical assessment and first treatment session. PMID- 21324609 TI - Multi-country, cross-national comparison of youth tobacco use: findings from global school-based health surveys. AB - OBJECTIVE: Describe the prevalence of current cigarette smoking and other tobacco use among 13-15year olds across 44 countries and 110 sites participating in the Global School-based Health Survey (GSHS), and compare these results with previous findings from the Global Youth Tobacco Survey. METHODS: The GSHS is conducted in countries using standardized sampling and survey methodology procedures. Smoking and other tobacco use prevalence was compiled from fact sheets available on the GSHS web site from the available 110 sites where the survey has been conducted and resulting data processed. Tobacco use prevalence rates are weighted to adjust for the probabilities of nonresponse and varying probabilities of selection. Boy to girl ratios were calculated to examine gender differences in tobacco use prevalence. RESULTS: Current smoking rates ranged widely from a low of approximately 1 in 100 students in Tajikistan and India to a high of more than 1 in 4 students in certain sites in Chile and Colombia, and more than 1 in 5 in other sites in Chile, Ecuador, Argentina, and Colombia. Other tobacco use prevalence ranged from a low of 1.0% in Hangzhou, China to a high of 43.7% in Northwest Namibia. CONCLUSION: This is the first multi-country, cross-national study of tobacco use involving GSHS data. Results provide an opportunity to examine youth tobacco use in several countries and compare results with the Global Youth Tobacco Survey (GYTS) which is a more extensive global surveillance of youth tobacco use. PMID- 21324610 TI - Dose-fractionation sensitivity of prostate cancer deduced from radiotherapy outcomes of 5,969 patients in seven international institutional datasets: alpha/beta = 1.4 (0.9-2.2) Gy. AB - PURPOSE: There are reports of a high sensitivity of prostate cancer to radiotherapy dose fractionation, and this has prompted several trials of hypofractionation schedules. It remains unclear whether hypofractionation will provide a significant therapeutic benefit in the treatment of prostate cancer, and whether there are different fractionation sensitivities for different stages of disease. In order to address this, multiple primary datasets have been collected for analysis. METHODS AND MATERIALS: Seven datasets were assembled from institutions worldwide. A total of 5969 patients were treated using external beams with or without androgen deprivation (AD). Standard fractionation (1.8-2.0 Gy per fraction) was used for 40% of the patients, and hypofractionation (2.5-6.7 Gy per fraction) for the remainder. The overall treatment time ranged from 1 to 8 weeks. Low-risk patients comprised 23% of the total, intermediate-risk 44%, and high-risk 33%. Direct analysis of the primary data for tumor control at 5 years was undertaken, using the Phoenix criterion of biochemical relapse-free survival, in order to calculate values in the linear-quadratic equation of k (natural log of the effective target cell number), alpha (dose-response slope using very low doses per fraction), and the ratio alpha/beta that characterizes dose fractionation sensitivity. RESULTS: There was no significant difference between the alpha/beta value for the three risk groups, and the value of alpha/beta for the pooled data was 1.4 (95% CI = 0.9-2.2) Gy. Androgen deprivation improved the bNED outcome index by about 5% for all risk groups, but did not affect the alpha/beta value. CONCLUSIONS: The overall alpha/beta value was consistently low, unaffected by AD deprivation, and lower than the appropriate values for late normal-tissue morbidity. Hence the fractionation sensitivity differential (tumor/normal tissue) favors the use of hypofractionated radiotherapy schedules for all risk groups, which is also very beneficial logistically in limited resource settings. PMID- 21324611 TI - Within-day temporal patterns of smoking, withdrawal symptoms, and craving. AB - We examined the temporal relationships between smoking frequency and craving and withdrawal. 351 heavy smokers (>=15 cigarettes per day) used ecological momentary assessment and electronic diaries to track smoking, craving, negative affect, arousal, restlessness, and attention disturbance in real time over 16 days. The waking day was divided into 8 2-h "bins" during which cigarette counts and mean levels of craving and withdrawal were computed. Cross-sectional analyses showed no association between restlessness and smoking, and arousal and smoking, but craving (b=0.65, p<0.01) was positively associated, and negative affect (b=-0.20, p<0.01), and attention disturbance (b=-0.24, p<0.01) were inversely associated with smoking. In prospective lagged analyses, higher craving predicted more subsequent smoking and higher smoking predicted lower craving (p's<0.01). Higher restlessness also predicted more subsequent smoking and higher smoking predicted lower restlessness (p's<0.01). Higher negative affect did not predict later smoking, but more smoking preceded lower negative affect (p<0.01). Neither attention disturbance nor arousal predicted, or were predicted by variations in smoking. In short, smoking exhibits time-lagged, reciprocal relationships with craving and restlessness, and a one-way predictive relationship with negative affect. Temporal patterns of craving and restlessness may aid in the design of smoking cessation interventions. PMID- 21324612 TI - Genomic analysis of a pneumovirus isolated from dogs with acute respiratory disease. AB - A previously unrecognized virus belonging to the subfamily Pneumovirinae and most closely related to murine pneumovirus (MPV) was identified in domestic dogs in 2 related animal shelters. Additional diagnostic testing yielded 3 new viral isolates and identified 6 additional PCR positive dogs from other USA locations indicating that its distribution is not geographically limited. Nucleotide sequences encompassing 9 of the 10 genes were compared to the only 2 available MPV strains, 15 and J3666. Several features distinguished the canine pneumovirus (CnPnV) from the murine strains. Two regions of diversity were identified in the amino-proximal region of P and the overlapping P2 ORF was only 54 amino acids (aa) compared to 137aa in MPV. The G protein had an amino-terminal cytoplasmic tail 18aa longer than in the MPV strains. The CnPnV SH protein showed the highest divergence with only 90.2% aa identity when compared to MPV strain 15. Like strain 15, the CnPnV SH ORF coded for a protein of 92aa while J3666 has a 114aa variant. Comparison of CnPnV isolates at culture passages 4 and 17 revealed 7nt differences within the 8598nt sequenced. Of note was a substitution at nt 364 in G resulting in a termination codon that would produce a truncated G protein of 122aa. Analysis of early passage and ex vivo samples showed the termination codon in G to be predominant after 6 days in culture indicating rapid selection of the mutation in A72 cells. PMID- 21324613 TI - Maternal vitamin B-12 and folate status during pregnancy and excessive infant crying. AB - BACKGROUND: The etiology of excessive infant crying is largely unknown. We hypothesize that excessive infant crying may have an early nutritional origin during fetal development. AIMS: This study is the first to explore whether (1) maternal vitamin B-12 and folate status during pregnancy are associated with excessive infant crying, and (2) whether and how maternal psychological well being during pregnancy affects these associations. STUDY DESIGN: Women were approached around the 12th pregnancy week to complete a questionnaire (n=8266) and to donate a blood sample (n=4389); vitamin B-12 and folate concentrations were determined in serum. Infant crying behavior was measured through a postpartum questionnaire (+/-3 months; n=5218). SUBJECTS: Pregnant women living in Amsterdam and their newborn child. OUTCOME MEASURES: Excessive infant crying, defined as crying >=3 h/day on average in the past week. RESULTS: Multiple logistic regression analysis was performed for 2921 (vitamin B-12) and 2622 (folate) women.Vitamin B-12 concentration (categorized into quintiles) was associated with excessive infant crying after adjustment for maternal age, parity, ethnicity, education, maternal smoking and psychological problems (OR[95%CI]: Q1=3.31[1.48-7.41]; Q2=2.50[1.08-5.77]; Q3=2.59[1.12-6.00]; Q4=2.77[1.20-6.40]; Q5=reference). Stratified analysis suggested a stronger association among women with high levels of psychological problems during pregnancy. Folate concentration was not associated with excessive infant crying. CONCLUSIONS: First evidence is provided for an early nutritional origin in excessive infant crying. A low maternal vitamin B-12 status during pregnancy could, in theory, affect infant crying behavior through two potential mechanisms: the methionine-homocysteine metabolism and/or the maturation of the sleep-wake rhythm. PMID- 21324614 TI - Stable isotopic characterization of ammonium metavanadate (NH4VO3). AB - This paper describes hydrogen ((2)H/(1)H), nitrogen ((15)N/(14)N), and oxygen ((18)O/(16)O) isotopic characterization of ammonium metavanadate (NH(4)VO(3)), a toxic industrial chemical (TIC). We analyzed nineteen high purity compounds obtained from nine suppliers, which show large ranges in trivariate stable isotope compositions, nearly 100-fold greater than analytical uncertainty. Covariation between delta(2)H and delta(15)N values indicates these ratios can be used to trace ammonia compounds, which are critical for the industrial purification of vanadyl ions and precipitation of ammonium metavanadate crystals. delta(2)H and delta(18)O plot far from the Meteoric Water Line (MWL), and suggest materials and industrial processing may lead to decoupling of H and O isotopes. We show how stable isotope characterization is a valuable forensic tool that discriminates between NH(4)VO(3) samples due to differences in source materials, modes of production, and facility location. PMID- 21324615 TI - Analysis of hydrogen peroxide field samples by HPLC/FD and HPLC/ED in DC mode. AB - The goal of this paper is to describe applications of two recently developed HPLC methods for the analysis and confirmation of the presence of hydrogen peroxide residues in field studies. The procedure utilizes two different HPLC systems, one with post-column derivatization followed by fluorescence detection (HPLC/FD), and the other with electrochemical detection (HPLC/ED). The two systems were utilized to detect hydrogen peroxide in a variety of typical forensic samples including pre- and post-blast samples, as well as a series of environmental control samples. Peroxide-based organic explosives were also examined due to their propensity to produce peroxide residues following detonation. Because samples collected from post-blast scenes are frequently shipped or stored prior to analysis, the effects of storage time, temperature and type of substrate material on the recovery of hydrogen peroxide residues were also investigated. The combined results of the study demonstrate the capability of two HPLC approaches with selective detection in the analysis and investigation of suspected incidents involving peroxide based explosives. PMID- 21324616 TI - Bioterrorism: the effects of biological decontamination on the recovery of electronic evidence. AB - The investigation of a bioterrorism event will ultimately lead to the collection of vital data from electronic devices such as computers and mobile phones. This project sought to determine the use of gamma irradiation and formaldehyde gas as effective biological decontaminants, and the effect of these methods on the recovery of electronic evidence. Electronic items were contaminated with viable spores and then exposed to both decontaminants. Log values for each matrix were calculated with flash drives recording the highest value of 566 Gy for gamma irradiation and a maximum of 50 min exposure to formaldehyde saw the effective destruction of spores. The results indicate that recovery of data varied based on the decontaminant selected, formaldehyde gas giving the most promising results, with electronic data recovered after the required exposure time. Gamma irradiation proved damaging to electronic circuitry at levels required to render the items safe. The implications to computer intelligence and forensics will be discussed based on the outcomes of these findings. PMID- 21324617 TI - Fatal intoxication due to ackee (Blighia sapida) in Suriname and French Guyana. GC-MS detection and quantification of hypoglycin-A. AB - Between 1998 and 2001 the deaths of 16 Surinamese children were recorded along the Maroni River, which forms the border between Suriname and French Guyana. After a metabolic origin was eliminated, ethnobotanical research in the field led to a hypothesis of intoxication through the ingestion of ackee. Ackee (Blighia sapida) is a large green leafy tree of West African origin. Its unripe fruit contains large quantities of two toxic molecules: hypoglycin-A and hypoglycin-B, the former being the more toxic. We have developed a GC-MS procedure allowing us to demonstrate the presence of hypoglycin-A in the gastric fluid of one of the deceased children, and to compare the content of hypoglycin-A in fruit collected on the road to Paramaribo in Suriname (5.1mg/g) with samples from Burkina Faso (8.1mg/g) and Jamaica (9.2mg/g). Field research showed the misuse of this little known plant by Maroon witch doctors. The Bushinengue witch doctors were informed about the dangers of ackee, and no new cases have been reported to date. PMID- 21324618 TI - Management of intraoral needle migration into the posterior cervical space. AB - Foreign bodies within the deep spaces of the neck pose infrequent but substantial risks involving migration, including infection, pseudoaneurysm formation, pneumothorax, hemopericardium, and embolization to the central circulation. A rare case of foreign body migration through the parapharyngeal space into the posterior cervical space is described from an intraoral needle shard. A 48-year old male presented with a right neck tenderness, referred otalgia, and intermittent neck twitching after a needle fragment was lost during an inferior alveolar nerve block. A CT scan six months after the incident revealed migration of the 2.5 cm needle posterolateral to the great vessels into the posterior cervical space. A transcervical approach led to identification and extraction of the foreign body, with resolution of symptoms. Sharp foreign bodies in the head and neck introduce an uncommon but high-impact risk of complications. Migration is often unpredictable in trajectory and time course. Early surgical removal is recommended for persistent symptoms, sustained migration, and localization to sites with critical structures. PMID- 21324619 TI - Prediction of hearing outcomes by distortion product otoacoustic emissions in patients with idiopathic sudden sensorineural hearing loss. AB - OBJECTIVE: To investigate whether distortion product otoacoustic emissions (DPOAEs) can be a prognostic indicator of hearing outcomes in patients with idiopathic sudden sensorineural hearing loss (ISSNHL). METHODS: Seventy-eight consecutive patients with ISSNHL were enrolled. DPOAEs were measured at the first hospital visit. Two primary pure tones with a frequency ratio (f2/f1) of 1.2 were used at non-equal sound pressure levels (L1/L2=80/70dB SPL). The DPOAE amplitude was measured at the 11 frequencies of 2f1-f2 with f2 varying from 593 to 6031Hz. All the patients received steroid administration in combination with hyperbaric oxygen (HBO) therapy. Hearing recovery was evaluated by the improvement in hearing compared to the unaffected contralateral ear. Correlations between the hearing improvement rate and five potential prognostic factors (the DPOAE amplitude, patient's age, days from onset to the start of treatment, initial hearing level, and presence of vertigo) were examined by simple and multiple regression analyses. RESULTS: The net DPOAE amplitude in patients with hearing improvement rate >=50% was significantly larger than that with hearing improvement rate <50% at f2 frequencies of 3031 and 4812Hz (unpaired Student's t test, p<0.05). A simple regression analysis showed that the hearing improvement rate significantly correlated with the net DPOAE amplitude at f2 frequencies of 3031 and 4812Hz, but not with that at the other f2 frequencies tested. The correlation coefficients were 0.528 and 0.522 for 3031 and 4812Hz, respectively, with p values <1*10(-6). In a multiple regression analysis, the partial correlation coefficients of the net DPOAE amplitude were 0.308 and 0.246 with p values of 0.008 and 0.036 for 3031 and 4812Hz, respectively. CONCLUSION: The significant correlation between hearing recovery and DPOAEs measured before treatment indicates that DPOAEs are a potentially useful means of predicting hearing prognosis in ISSNHL. PMID- 21324620 TI - Validity and reliability of Ability for Basic Movement Scale for Children (ABMS C) in disabled pediatric patients. AB - The objective of this pilot study was to test the validity and reliability of a new scale, the Ability for Basic Movement Scale for Children (ABMS-C). A total of 45 pediatric patients with disabilities (aged 0.1-8.8 years; 29 males, 16 females) participated in this prospective study. To prove the validity and reliability of the ABMS-C, subjects were administered the ABMS-C at a 2-week interval. In addition to the ABMS-C score, data on age, diagnosis, and results of the Gross Motor Function Classification System (GMFCS) were recorded. Spearman's rank correlation coefficient analysis showed that the ability to perform basic movements according to the scores for each item and the total scores of the ABMS C correlated significantly with the levels of the GMFCS (r=-0.628-0.784, p<0.001). The five items on the ABMS-C had appropriate internal consistency (Cronbach's alpha=0.944). Test-retest reliability analysis indicated that the "head control", "sitting", "locomotion on flat surface", "standing" and "walking" items on the ABMS-C had almost perfect reliability (kappa=0.865-1.000). This study provides evidence for the validity and reliability of the ABMS-C with regard to assessment of functional ability in disabled pediatric patients. PMID- 21324621 TI - Treatment with high intensity focused ultrasound: secrets revealed. AB - For many decades open surgery remained the only way available for local control of body tumors. In order to decrease the patients' morbidity and mortality several image guided minimally invasive procedures have been adopted. High intensity focused ultrasound (HIFU) is an extracorporeal non invasive method for tumor ablation. High intensity ultrasonic waves can be focused to a focal point resulting in lethal elevation of the temperature at the target site with consequent damage of the tumoral cells. The advances in HIFU technology during the past two decades expanded the HIFU applications to include ablation of both benign and malignant tumors with different treatment strategies being implemented for each type. The aim of this review is to introduce the reader to the details of the treatment process including pretreatment preparation, treatment planning, different ablation strategies, patients' after care as well as the follow up regimens for the most common HIFU applications. PMID- 21324622 TI - Influence of left ventricular hypertrophy on infarct size and left ventricular ejection fraction in ST-elevation myocardial infarction. AB - BACKGROUND: Left ventricular hypertrophy (LVH) predisposes to larger infarct size, which may be underestimated by the left ventricular ejection fraction (LVEF) due to supranormal systolic performance often present in patients with LVH. The aim of the study was to compare infarct size and LVEF in patients with ST-segment elevation myocardial infarction (STEMI) and increased left ventricular mass on cardiac magnetic resonance (CMR). METHODS: The study included unselected group of 52 patients (61+/-11 years, 69% male) with first STEMI who had CMR after median 5 days from the onset of the event. Left ventricular hypertrophy (LVH) was defined as left ventricular mass index exceeding 95th percentile of references values for age and gender. Infarct size was assessed with means of late gadolinium enhancement (LGE). RESULTS: LVH was found in 16 patients (31%). In comparison to the rest of the group, patients with LVH had higher absolute and relative infarct mass (p=0.002 and p=0.02, respectively). LVH was related to higher prevalence of microvascular obstruction and myocardial haemorrhage and higher number of LV segments with transmural necrosis (p=0.02, p=0.01 and p=0.01, respectively). Despite marked difference in the infarct size between both studied subgroups there was no difference in LVEF and mean number of dysfunctional LV segments. CONCLUSIONS: Patients with LVH undergoing STEMI have larger infarct size underestimated by the LV systolic performance in comparison to patients without LVH. PMID- 21324623 TI - Squamous cell cancer of hypopharynx and larynx - evaluation of metastatic nodal disease based on computed tomography perfusion studies. AB - BACKGROUND AND PURPOSE: In patients with squamous cell cancer metastatic disease in lymph nodes still remains the single most important negative predicting factor and when detected, it reduces overall 5-year survival by 50%. The aim of the study was to evaluate contrast-enhanced computed tomography (CECT) with computed tomography perfusion (CTP) examination in order to differentiate malignant from non-malignant cervical lymph nodes in patients with squamous cell cancer of hypopharynx and larynx. MATERIAL/METHODS: This was a prospective three-center study. From November 2007 until March 2010 33 consecutive patients with squamous cell cancer of the hypopharynx and 27 patients with laryngeal cancer underwent computed tomography (CT) examination followed by CTP. During first part of examination 80 ml of contrast was administered, with flow rate 1 ml/s and 100 s delay; standard head and neck examination was performed. Next, perfusion images were acquired with the coverage of 8 cm and different groups of lymph nodes were evaluated - groups II, III, IV and V. Perfusion maps for basic parameters (blood flow [BF], blood volume [BV], mean transit time [MTT] and permeability surface [PS]) were reconstructed for all patients using dedicated software. The long and short axis diameters, the density of the node before and after contrast medium administration and average values of each perfusion parameter were calculated for every node separately. Results were compared with histologic analysis of resected nodes. RESULTS: Out of the total number of 293 nodes evaluated on CECT and CTP it was possible to correlate 208 resected nodes with histologic findings. 125 of them were proven to be malignant and 83 were benign. Malignant nodes showed remarkably higher density and hyperperfusion, comparing to benign ones. The average density values in Hounsfield units (HU) for cervical nodes were: 91.9HU for metastatic comparing to 72.3 HU for non-metastatic, but this difference did not show statistical significance. The average value of BF in malignant nodes was 136.4 ml/100g/min, BV was 7.7 ml/100g, MTT was 4.4s and PS was 19.4 ml/100g/min. The average values for benign nodes were: BF was 80.7 ml/100g/min, BV was 4.7 ml/100g, MTT was 5.6s and PS was 12.8 ml/100g/min. Comparing to non-malignant nodes, malignant ones showed significantly higher BF, BV and PS values (p<0.05). CONCLUSIONS: Although CECT findings may draw our attention, pointing at abnormal morphology of the node, CTP seems to provide additional functional information regarding its possible malignancy. CTP may be useful in differentiation between malignant and benign lymph nodes, based on evaluation of the value of BF, BV and PS. PMID- 21324624 TI - High positive predictive value of CT colonography in a referral centre. AB - AIM: To assess the positive predictive value (PPV) of CTC in the clinical routine of a dedicated referral centre. MATERIAL AND METHODS: All consecutive patients referred for CTC between May 2009 and May 2010 were considered for inclusion in this study. All the patients who, following the diagnosis of a>6 mm polyp or mass at CTC, underwent a post-CTC colonoscopy within eight weeks from diagnosis were included. Per patient PPV for lesions, adenomas and advanced neoplasia was calculated. Chi-square test was used for statistical comparison, and a p value<0.05 was considered to be statistically significant. RESULTS: 516 patients were included in the study. Of them, 76 (14%) patients had at least one lesion>=6 mm on CTC. Overall, 59 (11%) patients were diagnosed at CTC with at least one polyp, 12 (2%) with a flat lesions, and 5 (1%) with a mass. Per-patient PPVs for any lesion>6 mm, neoplasia, and advanced neoplasia were 96% (95% CI: 92-100%), 68.4% (95% CI: 58-79%), and 30% (95% CI: 20-41%), respectively. PPV for neoplasia and advanced neoplasia was substantially higher for >10 mm lesions. CONCLUSION: In dedicated centers, CTC appears to be a highly specific procedure, characterized by a very low rate of false-positive results for >6 mm lesions. PMID- 21324625 TI - Prevalence of zygomatic air cell defect in adults--a retrospective panoramic radiographic analysis. AB - OBJECTIVES: This research involved retrospectively evaluating panoramic radiographs of patients from India with the intention of assessing the prevalence of Zygomatic Air Cell Defect (ZACD) and establishing its dominant location and type. METHODS: Seven thousand seven hundred and fifty-five panoramic radiographs of routine outpatients aged between 19 and 91 years were concomitantly evaluated by four investigators for estimating the prevalence and characteristics of the Zygomatic Air Cell Defect. RESULTS: The prevalence of ZACD was noted to be 1.82%, with male preponderance. Unilateralality and multilocular appearance of ZACD were the dominant patterns observed. CONCLUSION: The frequency of ZACD amongst Indian population is in harmony with most of the similar studies conducted on various geographic populations. PMID- 21324626 TI - Introduction to the special issue of "undergraduate radiology training and education". PMID- 21324627 TI - Intraductal papillary mucinous neoplasm of the pancreas: differentiate from chronic pancreatits by MR imaging. AB - PURPOSE: To evaluate the differentiating factors for intraductal papillary mucinous neoplasm of the pancreas and chronic pancreatitis as determined by MR imaging. MATERIALS AND METHODS: During a three-year period, we performed MR imaging on 33, consecutive patients with IPMN and on 41 patients with chronic pancreatitis. All IPMNs were confirmed by surgery. Two radiologists retrospectively analyzed the ductal change, the cyst shape, CBD dilatation, lymphadenopathy, and parenchymal change. The sensitivity and specificity were calculated for each MRI findings using the Chi square test. Statistically significant MR findings were further analyzed using multivariate logistic regression analysis. The diagnostic performance was evaluated according to the area under the receiver operating characteristic curve (A(z)) using specific MRI findings. Simple kappa statistics were used to evaluate the inter-observer reliability. RESULTS: Statistically specific findings for IPMN compared with those for chronic pancreatitis, were duct dilatation without stricture (specificity=95.1%, sensitivity=75.8%, p<0.0001), bulging ampulla (specificity=97.6%, sensitivity=30.3%, p<0.0001), nodule in a duct (specificity=100%, sensitivity=15.2%, p<0.0004), grape-like cyst shape (specificity=97.6%, sensitivity=78.8%, p<0.0001), and nodule in a cyst (specificity=100%, sensitivity=24.2%, p<0.0001). Statistically specific findings for chronic pancreatitis compared with those for IPMN, were duct dilatation with strictures (specificity=93.9%, sensitivity=95.1%, p<0.0001), the presence of a stone (specificity=97.0%, sensitivity=56.1%, p<0.0001), and a unilocular cyst shape (specificity=93.9%, sensitivity=34.1%, p<0.0004). Duct dilatation without stricture and a grape-like cyst shape were independently associated with the IPMN. Duct dilatation with strictures was independently associated with the chronic pancreatitis. Interobserver agreement was good to excellent for each finding (kappa=0.762-1.000). CONCLUSION: Highly specific findings for IPMN include duct dilatation without stricture, bulging ampulla, nodule in a duct, grape-like cyst shape, and nodule in a cyst. MRI is very useful for differentiating IPMN from chronic pancreatitis using these specific findings. PMID- 21324628 TI - Precolumn derivatization followed by liquid chromatographic separation and determination of tramiprosate in rat plasma by fluorescence detector: application to pharmacokinetics. AB - Alzheimer disease (AD) is characterized pathologically by extracellular amyloid deposits composed of amyloid beta (Abeta) protein. A simple and rapid method using HPLC with fluorescence detector was developed and validated for determination of tramiprosate in rat plasma. Pre-column derivatization of the deproteinized rat plasma was carried out using o-phthaldialdehyde (OPA) as a fluorescent reagent in presence of 3-mercaptopropionic acid. The liquid chromatographic separation was achieved on a Kromasil C18 column using methanol:acetonitrile: 20 mM phosphate buffer pH 7.5 (8.0:17.5:74.5 v/v/v) as a mobile phase in an isocratic elution mode. The eluents were monitored by a fluorescence detector set at 330 and 450 nm of excitation and emission wavelength respectively. Vigabatrin was used as an internal standard. The method was linear within the range 30.0-1000.0 ng/mL. Design of experiments (DOE) was used to evaluate the robustness of the method. The developed method was applied to study the pharmacokinetics of tramiprosate in rats. PMID- 21324629 TI - 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. PMID- 21324630 TI - Systematic review of guidelines on abdominal aortic aneurysm screening. AB - OBJECTIVE: Usually, physicians base their practice on guidelines, but recommendations on the same topic may vary across guidelines. Given the uncertainties regarding abdominal aortic aneurysm (AAA) screening, physicians should be able to identify systematically and transparently developed recommendations. We performed a systematic review of AAA screening guidelines to assist physicians in their choice of recommendations. METHODS: Guidelines in English published between January 1, 2003 and February 26, 2010 were retrieved using MEDLINE, CINAHL, the National Guideline Clearinghouse, the National Library for Health, the Canadian Medication Association Infobase, and the G-I-N International Guideline Library. Guidelines developed by national and international medical societies from Western countries, containing recommendations on AAA screening were included. Three reviewers independently assessed rigor of guideline development using the Appraisal of Guidelines Research and Evaluation (AGREE) instrument. Two independent reviewers performed extraction of recommendations. RESULTS: Of 2415 titles identified, seven guidelines were included in this review. Three guidelines were less rigorously developed based on AGREE scores below 40%. All seven guidelines contained a recommendation for one-time screening of elderly men by ultrasonography to select AAAs >= 5.5 cm for elective surgical repair. Four guidelines, of which three were less rigorously developed, contained disparate recommendations on screening of women and middle-aged men at elevated risk. There was no agreement on the management of smaller AAAs. CONCLUSIONS: Consensus exists across guidelines on one-time screening of elderly men to detect and treat AAAs >= 5.5 cm. For other target groups and management of small AAAs, prediction models and cost effectiveness analyses are needed to provide guidance. PMID- 21324631 TI - Clinical outcomes for hostile versus favorable aortic neck anatomy in endovascular aortic aneurysm repair using modular devices. AB - BACKGROUND: Endovascular aneurysm repair (EVAR) is not generally recommended for patients with hostile neck anatomy. This study analyzed the clinical implications of various clinical features of proximal aortic neck anatomy. METHODS: Prospectively collected data from 258 EVAR patients using modular devices were analyzed. Patients were classified as having favorable neck anatomy (FNA) or hostile neck anatomy (HNA). HNA was defined as any or all of length of <10 mm, angle of >60 degrees , diameter of >28 mm, >=50% circumferential thrombus, >=50% calcified neck, and reverse taper. Univariate, multivariate, and Kaplan-Meier analyses were used to compare early and late clinical outcomes. RESULTS: FNA was present in 37% and HNA was present in 63%. Clinical and demographic characteristics were comparable. Technical success was 99%. Mean follow-up was 22 months (range, 1-78 months). Perioperative complication rates were 3% for FNA vs 16% for HNA (P = .0027). Perioperative deaths were 0% for FNA and 3% for HNA (P = .2997). Proximal type I early endoleaks (intraoperative) occurred in 9% of FNA vs 22% for HNA (P = .0202). Intraoperative proximal aortic cuffs were used to seal endoleaks in 9% of FNA vs 22% of HNA (P = .0093). At late follow-up, abdominal aortic aneurysm expansion was noted in 6% of FNA vs 7% of HNA (P = .8509). Rates of freedom from late type I endoleaks at 1, 2, 3, and 4 years were 97%, 97%, 97%, and 90% for FNA vs 89%, 89%, 89%, and 89% for HNA (P = .1224); rates for late interventions were 95%, 90%, 90%, and 90% for FNA vs 95%, 93%, 91%, and 85% for HNA (P = .6902). Graft patency at 1, 2, and 3 years was 99%, 99%, and 99% for FNA vs 97%, 92%, and 90% for HNA (P = .0925). The survival rates were 93%, 84%, 76%, and 76% for FNA vs 88%, 82%, 74%, and 66% for HNA (P = .2631). Reverse taper was a significant predictor for early type I endoleak (odds ratio [OR], 5.25, P < .0001), reverse taper (OR, 5.95; P < .0001) and neck length (OR, 4.15; P = .0146) were for aortic cuff use; circumferential thrombus (OR, 2.44; P = .0448), and neck angle (OR, 3.38; P = .009) were for perioperative complications. CONCLUSIONS: Patients with HNA can be treated with EVAR, but with higher rates of early (intraoperative) type I endoleak and intervention. The midterm outcomes are similar to FNA. PMID- 21324632 TI - The clinical significance of circulating tumor cells in non-metastatic colorectal cancer--a review. AB - BACKGROUND: Finding a clinical tool to improve the risk stratification and identifying those colorectal cancer patients with an increased risk of recurrence is of great importance. The presence of circulating tumor cells (CTC) in peripheral blood can be a strong marker of poor prognosis in patients with metastatic disease, but the prognostic role of CTC in non-metastatic colorectal cancer is less clear. The aim of this review is to examine the possible clinical significance of circulating tumor cells in non-metastatic colorectal cancer (TNM stage I-III) with the primary focus on detection methods and prognosis. METHODS: The PubMed and Cochrane database and reference lists of relevant articles were searched for scientific literature published in English from January 2000 to June 2010. We included studies with non-metastatic colorectal cancer (TNM-stage I-III) and CTC detected pre- and/or post-operatively in peripheral blood. RESULTS: Nine studies qualified for further analyses. Detection rates of CTC in peripheral blood of patients with non-metastatic colorectal cancer varied from 4% to 57%. Seven studies applied RT-PCR and two studies used immunocytochemical methods. Seven studies found the presence of CTC to be a prognostic marker of poor disease free survival. CONCLUSION: The presence of CTC in peripheral blood is a potential marker of poor disease-free survival in patients with non-metastatic colorectal cancer. The low abundance of CTC in non-metastatic colorectal cancer requires very sensitive and specific detection methods. An international consensus on choice of detection method and markers, is warranted before incorporating CTC into risk stratification in the clinical setting. PMID- 21324633 TI - [Influence of open chest conditions on pulse pressure variations]. AB - OBJECTIVES: Pulse pressure variations are used to assess fluid responsiveness in mechanically ventilated patients. The accuracy of this index in open chest conditions remained unclear. The aim of the study was to evaluate the effect of open chest conditions on pulse pressure variations. STUDY DESIGN: Non interventional prospective study. METHODS AND PATIENTS: Twenty-eight mechanically ventilated patients scheduled for open-heart surgery were included. Pulse pressure variations, peak aortic velocity, and stroke volume were measured before and after thoracotomy with pericardotomy. Measurements were made at each step and compared. RESULTS: Neither pulse pressure variation nor peak aortic velocity and nor stroke volume variation were modified by open chest conditions (median=5% [interquartile range=6] vs 4% [6], p=NS), (20% [11] vs 17% [12], p=NS and 11% [7] vs 10% [3], p=NS) respectively. Pulse pressure variations were correlated to stroke volume before thoracotomy (r'=-0.432; p=0.02) and after thorocatomy (r'= 0.433, p=0.02). CONCLUSION: In these studied patients, preload dependancy indices were not modified by open chest conditions. Pulse pressure variations remained correlated to stroke volume even after thoracotomy. PMID- 21324634 TI - [Antibioprophylaxis in surgery and interventional medicine (adult patients). Actualization 2010]. PMID- 21324635 TI - [Lingual tonsil hypertrophy and unanticipated difficult airway management]. PMID- 21324636 TI - [Deficiency of factor V and circumcision: perioperative management. About a clinical case]. PMID- 21324637 TI - [Gas embolism: another story related to a central venous catheter withdraw]. AB - Paradoxical gas embolism is rare but life threatening complication of central venous access. In this observation, we report a paradoxical gas embolism accompanied by an acute respiratory failure and a coma following a jugular central venous access withdrawal in a liver transplanted patient. Following this observation, we discuss the prevention of gas embolism accidents and the hyperbaric oxygen therapy for its management. PMID- 21324638 TI - Coherent motion sensitivity predicts individual differences in subtraction. AB - Recent findings suggest deficits in coherent motion sensitivity, an index of visual dorsal stream functioning, in children with poor mathematical skills or dyscalculia, a specific learning disability in mathematics. We extended these data using a longitudinal design to unravel whether visual dorsal stream functioning is able to predict individual differences in subsequent specific mathematical skills, i.e., single-digit subtraction and multiplication. We measured children's sensitivity to coherent motion in kindergarten (mean age: 5 years 8 months) and evaluated their subtraction and multiplication skills in third grade (mean age 8 years 3 months). Findings revealed an association between subtraction but not multiplication performance and coherent motion sensitivity. This association remained significant even when intellectual ability and reading ability were additionally controlled for. Subtractions are typically solved by means of quantity-based procedural strategies, which reliably recruit the intraparietal sulcus. Against the background of a neural overlap between the intraparietal sulcus and visual dorsal stream functioning, we hypothesize that low-level visuospatial mechanisms might set constraints on the development of quantity representations, which are used during calculation, particularly in subtraction. PMID- 21324639 TI - Participation patterns of school-aged children with and without DCD. AB - Participation is recognized as a key to one's health and well-being and is considered to be a vital part of the development of children and youth. The purpose of this study was to examine the participation patterns of children with and without Developmental Coordination Disorder (DCD) in their out-of-school-time (OST) activities, and to see whether there is a relationship between the children's motor abilities and their choices and participation. METHODS: 50 children (5-7 years old), 25 who met diagnostic criteria of DCD and 25 without DCD, completed the Children Assessment of Participation and Enjoyment (CAPE) and were administered the Motor Assessment Battery for Children (MABC) and the Beery Buktenica Developmental Test of Visual-Motor Integration (VMI). RESULTS: A relationship was found between participation patterns and motor ability. Children with DCD had limited participation diversity in which they participated less frequently, and chose activities that were quieter and more socially isolated compared to children without DCD; there were no differences in their levels of enjoyment. CONCLUSIONS: The present study emphasizes the importance of looking at the children's participation from a broad perspective, and the many difficulties children with DCD experience in OST participation. Future studies might consider other factors (e.g., environment) while examining participation among children with DCD. PMID- 21324640 TI - The relationship between sensory processing difficulties and leisure activity preference of children with different types of ADHD. AB - Sensory processing difficulties (SPD) are prevalent among children with ADHD. Yet, the question whether different SPD characterize children with different types of ADHD has not received enough attention in the literature. The current study characterized sensory processing difficulties (SPD) of children with different types of ADHD and explored the relationship between SPD and leisure activity preference. Participants were 58 boys aged 6-10 years: 29 boys with ADHD: 15 with hyperactive-impulsive type and 14 characterized as inattentive. The controls were 29 typical peers. SPD were evaluated by The Short Sensory Profile (SSP) completed by the parents. Participants answered the preference for activities of children (PAC). According the results, SPD were manifested among children with both ADHD types. Children with both ADHD types showed significantly lower preference to participate in leisure activities than the controls. Their lower preference correlated with SPD. The findings suggest that children with different ADHD types may share common SPD, which may negatively impact their activity preference. In this study it seemed that children with ADD were more vulnerable to these impacts. SPD and participation should be considered in evaluation and intervention programs for children with ADHD in order to focus on child's abilities, needs and preferences, and enhance intervention success, child's relationships with peers and child's well-being. PMID- 21324641 TI - Early hemodynamic changes versus peak values: what is more useful to predict occurrence of dyspnea during stress echocardiography in patients with asymptomatic mitral stenosis? AB - BACKGROUND: In asymptomatic mitral stenosis (MS), the usefulness of peak exercise Doppler echocardiography (DE) values is acknowledged, but the role of values recorded during the first stage of DE remains unclear. METHODS: DE was analyzed in 48 asymptomatic patients with significant MS and revealed dyspnea in 22 patients (46%). RESULTS: MS severity and rest and peak systolic pulmonary artery pressures (SPAPs) were not different between patients who did and did not develop dyspnea. Progressions of mean gradient and relative SPAP (ratio of SPAP/baseline SPAP) were significantly greater in patients who developed dyspnea compared with those who did not (P < .01), whereas no difference was observed for absolute SPAP progression (P = .28). Onset of dyspnea was associated with a high increase of relative SPAP (>90% at 60W, OR 2.31; CI, 1.2-4.8; P = .02) but not with the 60 mm Hg peak SPAP threshold (OR 1.3; CI, 0.7-43.1; P = .40). CONCLUSION: DE reveals symptoms in 46% of patients who are considered asymptomatic. Despite similar peak values, these patients have different hemodynamic parameters during the first level of exercise compared with patients remaining asymptomatic. This may lead to the integration of early hemodynamic changes in the evaluation of exercise tolerance. PMID- 21324642 TI - Fetal predictors of urgent balloon atrial septostomy in neonates with complete transposition. AB - BACKGROUND: In complete transposition of the great vessels, a restrictive patent foramen ovale leads to inadequate circulatory mixing and severe cyanosis. Urgent balloon atrial septostomy (BAS) improves mixing and bridges neonates to surgery. Several studies have determined risk factors in utero for poor postnatal outcomes in complete transposition of the great vessels, particularly a restrictive patent foramen ovale and ductus arteriosus. In addition to these risk factors, we studied two new features, a hypermobile septum and reverse diastolic patent ductus arteriosus shunt, to determine which patients will require an urgent BAS. METHODS: We reviewed all 26 fetuses from 2001 to 2010 with complete transposition of the great vessels and closely examined the patent foramen ovale and septum primum for hypermobility, restriction, flat appearance, or redundancy. We defined hypermobility as a septum primum flap that oscillates between both atria. We also examined the ductus size and shunting pattern to evaluate whether these features contributed to urgent BAS. RESULTS: In total, 14 of 26 fetuses required urgent BAS with improved cyanosis. Nine fetuses had an urgent BAS and a hypermobile septum, and 12 fetuses had no urgent BAS or hypermobile septum. Eight fetuses had an urgent BAS and a reverse diastolic patent ductus arteriosus, and 11 fetuses had no urgent BAS or reverse diastolic patent ductus arteriosus. A hypermobile septum and reverse diastolic patent ductus arteriosus had a significant association with urgent BAS (P < .01, sensitivity = 0.64 and 0.57, specificity = 1.0 and 0.92, positive predictive value = 1.0 and 0.89, negative predictive value = 0.71 and 0.65). No fetus had a restrictive patent foramen ovale/ductus arteriosus. CONCLUSION: A hypermobile septum and reverse diastolic patent ductus arteriosus are new prenatal findings to help predict the need for an urgent BAS postnatally in patients with complete transposition of the great vessels. PMID- 21324643 TI - Changes in the textural characteristics of intima-media complex in young patients with familial hypercholesterolemia: implication for visual inspection on B-mode ultrasound. AB - BACKGROUND: To test the hypothesis that textural changes in the carotid intima media complex (IMC) on visual inspection by B-mode ultrasound are associated with early atherosclerotic involvement in patients with heterozygous familial hypercholesterolemia (FH). METHODS: 55 patients (mean age 13.4 years) were categorized into three groups according to the degree of thickness in IMC (intima media thickness [IMT]) (groups I-III) and 15 healthy controls within the same age range as the patients were assessed for first- and second-order statistics and visual scoring of textural changes in IMC (1, normal; 2, proximal interface disruption; 3, granulation). RESULTS: There was no significant difference in first-order statistics among the four groups. As for second-order statistics, groups II (moderately increased IMT) and III (markedly increased IMT) had significantly higher entropy and lower angular second moment than group I (normal IMT) and control. Likewise, groups II and III received significantly higher visual scoring than group I. Visual scoring correlated with entropy (r = 0.57) and angular second moment (r = -0.50). Multiple regression analysis identified entropy (beta = 0.52) and visual scoring (beta = 0.42) as significant determinants of IMT. CONCLUSIONS: These findings demonstrate that higher visual scoring may indicate dishomogeneity of IMC, suggesting early medial infiltration. This seems to be a simple visual marker to more effectively identify high-risk young patients with FH. PMID- 21324644 TI - The vena contracta in functional tricuspid regurgitation: a real-time three dimensional color Doppler echocardiography study. AB - BACKGROUND: The aims of this study were to evaluate the three-dimensional features and geometric determinants of the vena contracta (VC) in functional tricuspid regurgitation (TR) and to identify optimal width cutoff values for assessing functional TR severity. METHODS: Real-time three-dimensional full volume and color Doppler and two-dimensional Doppler echocardiographic images were obtained in 52 patients with various degrees of functional TR and in sinus rhythm. The tricuspid valve and right ventricle were geometrically analyzed. VC widths parallel to the septal-lateral and anteroposterior directions, VC area, and effective regurgitant orifice area (EROA) using proximal isovelocity surface area methods on real-time three dimensional color Doppler images were measured. RESULTS: The septal-lateral VC width was 0.39 +/- 0.37 cm smaller than the anteroposterior VC width (P < .001). VC widths and area were strongly correlated with EROA. The optimal cutoff values for the septal-lateral VC width, anteroposterior VC width, and VC area were 0.63 cm, 0.76 cm, and 0.37 cm(2), respectively, for moderate functional TR (EROA >=0.2 cm(2)) and were 0.84 cm, 1.26 cm, and 0.57 cm(2), respectively, for severe functional TR (EROA >=0.4 cm(2)). Multiple linear regression analyses showed that the septal leaflet tenting angle and septal-lateral annular diameter independently determined septal lateral VC width, while the anterior leaflet tenting angle and anteroposterior annular diameter independently determined the anteroposterior VC width. CONCLUSIONS: Different VC width cutoff values should be applied according to the plane of view in functional TR, because the VC cross-sectional shape is ellipsoidal with a long anteroposterior direction. VC widths are determined by annular dilation and leaflet tenting in the corresponding directions. PMID- 21324645 TI - Left ventricular outflow tract and pulmonary artery stroke distances independently predict heart failure hospitalization and mortality: the Heart and Soul Study. AB - BACKGROUND: Stroke distance of the left ventricular outflow tract (LVOT) or pulmonary artery (PA) is readily measurable by Doppler echocardiography. Stroke distance, calculated by the velocity time integral, expresses the average linear distance traveled by red blood cells during systole. We hypothesized that reduced stroke distance predicts heart failure (HF) hospitalization or mortality among ambulatory adults with stable coronary artery disease. METHODS: We compared stroke distances by lowest quartile among 990 participants in the Heart and Soul Study. We calculated hazard ratios (HRs) for events adjusted for clinical and echocardiographic parameters. RESULTS: At 5.9 +/- 1.9-year follow-up, there were 154 HF hospitalizations and 271 all-cause deaths. Among 254 participants with LVOT stroke distance in the lowest quartile (<= 18 cm), 24% developed HF hospitalization, compared with 10% of those with higher stroke distance (HR 2.7; CI, 2.0-3.8; P < .0001). This association remained after adjustment for multiple variables including medical history, heart rate, blood pressure, and left ventricular ejection fraction (HR 1.8; CI, 1.1-3.0; P = .02). Both LVOT stroke distance <= 18 cm and PA stroke distance <= 17 cm were independently associated with the combined end point of HF hospitalization and mortality (HR 1.4; CI, 1.1 1.9; P = .02). CONCLUSION: Reduced stroke distance predicts HF hospitalization and mortality independent of clinical and other echocardiographic parameters among ambulatory adults with coronary artery disease. PMID- 21324646 TI - Invalid sampling in a validation study of diagnosis codes for infection. PMID- 21324647 TI - Use of multiple-indicator multiple-causes models affirmed the factor structure of SF-36 in racially heterogeneous population groups with traumatic brain injury. PMID- 21324649 TI - Heart failure due to abnormal filling function of the heart. AB - Symptoms of heart failure can be caused by the diastolic dysfunction even in patients with normal ejection fraction, and this condition has been called diastolic heart failure. After Kitabatake and his associates first used echo Doppler to characterize the transmitral flow velocity in various disease states in 1982, there have been remarkable advances in the evaluation of diastolic function with Doppler echocardiography. Types of diastolic dysfunction can be classified into relaxation abnormality, pseudonormal, reversible restrictive physiology, and irreversible restrictive physiology. Classifying the patients into these types, in addition to the reliable estimation of left ventricular filling pressure with Doppler echocardiography, enables us to adjust treatment in individual patients and to get information about the prognosis. The main hemodynamic abnormality in patients with diastolic dysfunction is the abnormal filling function of the heart. Therefore, if we expand the scope of diastolic heart failure, patients with constrictive pericarditis can also be categorized into diastolic heart failure. The purpose of this review is to refine our knowledge in the concept of diastolic dysfunction and to update the methods used in its' evaluation. PMID- 21324650 TI - Validation of the Chinese version of the Liverpool Adverse Events Profile in patients with epilepsy. AB - The objective of the study was to validate the Chinese version of The Liverpool Adverse Events Profile (LAEP) in patients with epilepsy. The scale was translated from the English version into a Chinese version and was then back-translated to examine its accuracy. Content validity, concurrent validity, and construct validity were then used to examine the overall validity of this scale. A cross sectional design with convenience sampling was used to recruit participants from three medical centers. The LAEP Chinese version was tested with respect to validity and reliability in 357 patients with epilepsy, and another 28 patients were invited to evaluate the test-retest reliability of the scale in a 2-week interval. There was a good content validity index (CVI=1.0). Patients undergoing polytherapy had more adverse effects (chi(2)=6.10, p<0.01) and higher LAEP scores (t=-2.91, p<0.01) than patients undergoing monotherapy, indicating a good concurrent validity. Factor analysis included three factors classified by symptoms in the 22-item Chinese version of the LAEP. The total variance of these three factors was 39.3% for the scale. Internal consistency (Cronbach's alpha=0.92) and the intraclass correlation coefficient (ICC=0.80) were satisfactory. Moreover, the LAEP can be completed in a short time, is perceived as easy to complete, and there was no relevant information missing. The results indicated that the Chinese version of the LAEP yielded highly acceptable parameters of validity and reliability and can be used for measuring adverse effects of antiepileptic drugs among Chinese-speaking patients with epilepsy in Taiwan. PMID- 21324651 TI - Drawing from memory in focal epilepsy: a cognitive and neural perspective. AB - This study provides evidence of non-verbal cognitive functioning in temporal (TLE) and frontal lobe epilepsy (FLE) patients by exploring the mechanisms and neural correlates of drawing abilities. Sixty-six patients with left (n=32) or right TLE (n=34), 30 patients with left (n=18) or right FLE (n=12), and 30 healthy subjects were compared. The Drawing from Memory (DfM) test required participants to design 16 living or non-living items; the total score was the sum of all scores blindly provided by three judges who had to identify the drawings. The verbal and visual Pyramid and Palm Trees Test (PPTT), Raven Colored Progressive Matrices (Raven CPM), Cube Analysis, Token Test, Word Fluency, Card Classification, and Rey Complex Figure Test Copy trial (Rey CFC) assessed different verbal and non-verbal functions. Non-parametric statistics indicated that, with respect to controls, both TLE groups and the left FLE patients had significantly lower DfM scores. In the TLE group, hierarchical regression analyses revealed that the DfM score was predicted by the Raven CPM and PPTT scores, while, in the FLE group, it was predicted by the Rey CFC. Thus, drawing abilities may be impaired by TLE or FLE owing to different mechanisms that involve semantic or executive abilities. Implying cooperation between temporal and frontal areas that support these functions, DfM may be a sensitive index of integrity of cortical areas or neural pathways damaged by focal epilepsy. PMID- 21324652 TI - Maternal serum docosahexaenoic acid and schizophrenia spectrum disorders in adult offspring. AB - It is believed that during mid-to-late gestation, docosahexaenoic acid (DHA), an n-3 fatty acid, plays an important role in fetal and infant brain development, including neurocognitive and neuromotor functions. Deficits in several such functions have been associated with schizophrenia. Though sufficient levels of DHA appear to be important in neurodevelopment, elevated maternal DHA levels have also been associated with abnormal reproductive outcomes in both animal models and humans. Our objective was to assess whether a disturbance in maternal DHA levels, measured prospectively during pregnancy, was associated with risk of schizophrenia and other schizophrenia spectrum disorders (SSD) in adult offspring. In order to test the hypothesis that abnormal levels of DHA are associated with SSD, a case-control study nested within a large, population-based birth cohort, born from 1959 through 1967 and followed up for SSD from 1981 through 1997, was utilized. Maternal levels of both DHA and arachidonic acid (AA), an n-6 fatty acid, were analyzed in archived maternal sera from 57 cases of SSD and 95 matched controls. There was a greater than twofold increased risk of SSD among subjects exposed to maternal serum DHA in the highest tertile (OR=2.38, 95% CI=1.19, 4.76, p=0.01); no such relationship was found between AA and SSD. These findings suggest that elevated maternal DHA is associated with increased risk for the development of SSD in offspring. PMID- 21324653 TI - Enhancement of nickel elution by lipopolysaccharide-induced inflammation. AB - BACKGROUND: Implantations of metallic biomedical devices into bodies are increasing. The elution of Ni ions from these devices can lead to metal allergies. However, the molecular mechanisms of the elution have not been fully examined. Furthermore, it is not clear whether infection and inflammation affect the corrosion of metals. OBJECTIVE: We examined whether the elution of Ni from metal wires and plates was enhanced by inflammation in vivo and in vitro. METHODS: A Ni or SUS316L wire was implanted subcutaneously in the dorsum of mice. Lipopolysaccharide (LPS) was injected at the site immediately following the implantation. After 8, 24, and 72 h, the tissue around the wire was excised. RAW 264 cells were seeded on a Ni plate and incubated for 24h in medium containing LPS. The amount of Ni in the tissue or conditioned medium was determined fluorometrically. RESULTS: The release of Ni ions from the wire was significantly increased from 8 to 72 h, and further increased by LPS. LPS also enhanced the release of Ni ions by the cells, but only when they were attached to the Ni plate. Chloroquine, bafilomycin A(1) and amiloride markedly inhibited the effects of LPS. CONCLUSION: The activation of inflammatory cells on metals enhanced the elution of Ni probably via the release of protons at the interface of the cells and material. PMID- 21324654 TI - Benzo[c]phenanthridine alkaloids exhibit strong anti-proliferative activity in malignant melanoma cells regardless of their p53 status. AB - BACKGROUND: Search for new substances with antiproliferative activity towards melanoma cells is important since malignant melanoma is notoriously resistant to conventional chemotherapy. Benzo[c]phenanthridine alkaloids (BAs) are natural products with significant anti-proliferative activities, therefore they are considered as agents promising for cancer therapy. OBJECTIVES: The effects of five BAs (sanguinarine, chelerythrine, chelidonine, sanguilutine, and chelilutine) on human malignant melanoma cell lines were compared. The study focused on BAs effects on DNA, anti-apoptotic and p53 protein levels; and the involvement of p53 in cellular responses to alkaloids treatment. METHODS: Melanoma cell lines, two wild types and two with dysfunctional p53 derived from one of them were used. The mechanism of anti-proliferative and pro-apoptotic effects and the effect on DNA was investigated using MTT assay, flow cytometry, Western blot analysis, fluorescence and electron microscopy. RESULTS: All tested alkaloids exhibit strong anti-proliferative activity. CHL, CHE and SA induced apoptosis, which was probably mediated by decreasing levels of anti-apoptotic proteins (Bcl-xL, Mcl-1, XIAP) and was accompanied by mitochondrial membrane potential decrease as well as caspase-3 and PARP cleavage. Although all alkaloids caused DNA damage, which was demonstrated by induction of H2AX phosphorylation, none of the tested alkaloids stabilised p53 and their toxicity in cells with non functional p53 was comparable to wild type cells. CONCLUSION: Despite the profound similarity of BAs molecular structures, it is clear that the mechanism of cell death induction is different for each alkaloid. Our results indicate that BAs could be effective in malignant melanoma treatment, including tumours which have lost wild type p53. PMID- 21324656 TI - Clinical presentation and clinical outcomes in Chernobyl-related paediatric thyroid cancers: what do we know now? What can we expect in the future? AB - Over the last 20 years, nearly 5000 cases of differentiated thyroid cancer have been diagnosed and treated in the regions of Russia, Ukraine and Belarus in young people previously exposed to the Chernobyl radioactive fallout during childhood. At diagnosis, 60-70% of the Chernobyl-related paediatric thyroid cancers had clinically evident cervical lymph node metastases (N1) and 10-15% had distant metastases (M1). Despite early reports suggesting that the paediatric thyroid cancer cases that developed after exposure to Chernobyl fallout were particularly aggressive, it now seems that the initial presentation and early clinical course of most of these cases are very similar to both non-radiation-associated paediatric thyroid cancers and thyroid cancers that arise after exposure to external beam irradiation. Over an average clinical follow-up period of about 10 years, the disease-specific mortality rate in these paediatric thyroid cancer cases that developed after the Chernobyl accident is quite low (1% or less). As would be expected in paediatric thyroid cancer, short-term recurrence rates range from 7 to 28% in published reports (mean 17%). However, long-term studies of paediatric thyroid cancer suggest that although the 30 year disease-specific mortality rate should be about 1%, the risk of developing structural disease recurrence is nearly 30% (of which 80% are expected to be locoregional recurrences and 20% are probably new distant metastases). Projected over 30 years of follow-up, a 1% disease-specific mortality in this cohort of 5000 patients would equate to about 50 deaths directly attributable to thyroid cancer. However, a 30% recurrence rate would also mean that about 1500 patients may develop a clinically meaningful recurrence that would need to be diagnosed and treated. It is imperative that we continue to work with our colleagues in Belarus, Ukraine and Russia to ensure that this large volume of patients destined to develop clinically significant recurrences are diagnosed and treated in a timely manner. Ready access to modern disease detection tools (serum thyroglobulin, postoperative neck ultrasonography, cytology/pathology support, and radioactive iodine scanning) and treatments (surgery for recurrent disease, radioactive iodine therapy) in their major academic centres are mandatory if we expect to achieve the excellent clinical outcomes that should be seen when paediatric thyroid cancer recurrence is diagnosed early and treated appropriately. PMID- 21324655 TI - Transcranial magnetic stimulation of the ventromedial prefrontal cortex impairs theory of mind learning. AB - Imaging and lesion studies indicate that the prefrontal cortex plays a prominent role in mediating theory of mind (ToM) functioning. Particularly, the ventromedial prefrontal cortex (VMPFC) appears to be involved in mediating ToM functioning. This study utilized slow repetitive transcranial magnetic stimulation (rTMS) over the VMPFC in 13 healthy subjects in order to test whether normal functioning of the VMPFC is necessary for ToM functioning. We found that rTMS to the VMPFC, but not sham-rTMS, significantly disrupted ToM learning. Performance on a control task, not involving affective ToM functioning, was not significantly altered after applying rTMS to the VMPFC or sham-rTMS. In an additional experiment, rTMS to the vertex did not significantly affect ToM learning, confirming specificity of the VMPFC region. These findings indicate that the VMPFC is critical for intact ToM learning and shed further light on the concept and localization of ToM in particular and empathic functioning in general. PMID- 21324657 TI - Stereotactic body radiotherapy: overview of the 2010 Royal College of Radiologists' annual scientific meeting. PMID- 21324658 TI - 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neuroblastic apoptosis in the subventricular zone is caused by 1-methy-4-phenylpiridinium (MPP(+)) converted from MPTP through MAO-B. AB - Intraperitoneal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration induces apoptosis of subventricular zone (SVZ) doublecortin (Dcx) positive neural progenitor cells (migrating neuroblasts, A cells). Actually, a metabolite of MPTP, 1-methy-4-phenylpiridinium (MPP(+)), is responsible for neural progenitor cell toxicity. In the present study, to examine whether the MPTP-induced SVZ cell apoptosis is caused directly by MPP(+) metabolized through monoamine oxidase B (MAO-B), MPTP or MPP(+) was intracerebroventricularly (icv) injected into C57BL/6 mice. At Day 1 postinjection, many terminal deoxynucleotidyl transferase-mediated dUTP endlabeling (TUNEL)-positive cells were observed in the SVZ of both low (36 MUg) and high (162 MUg) dose MPTP- and MPP(+)-injected mice. The number of Dcx-positive A cells showed a significant decrease following high dose of MPTP- or MPP(+)-injection on Days 1 and 3, respectively, whereas that of EGFR-positive C cells showed no change in mice with any treatment. In addition, prior icv injection of a MAO-B inhibitor, R(-) deprenyl (deprenyl), inhibited MPTP-induced apoptosis, but not MPP(+)-induced apoptosis. MAO-B- and GFAP-double positive cells were detected in the ependyma and SVZ in all mice. It is revealed from these results that icv injection of MPTP induces apoptosis of neural progenitor cells (A cells) in the SVZ via MPP(+) toxicity. In addition, it is suggested that the conversion from MPTP to MPP(+) is caused mainly by MAO-B located in ependymal cells and GFAP-positive cells in the SVZ. PMID- 21324659 TI - New glucosidase activities identified by functional screening of a genomic DNA library from the gut microbiota of the termite Reticulitermes santonensis. AB - beta-Glucosidases are widely distributed in living organisms and play a major role in the degradation of wood, hydrolysing cellobiose or cello-oligosaccharides to glucose. Termites are among the rare animals capable of digesting wood, thanks to enzyme activities of their own and to enzymes produced by their gut microbiota. Many bacteria have been identified in the guts of lower termites, some of which possess cellulolytic or/and hemicellulolytic activity, required for digesting wood. Here, having isolated bacterial colonies from the gut of Reticulitermes santonensis, we constructed in Escherichia coli a genomic DNA library corresponding to all of the colonies obtained and screened the library for clones displaying beta-glucosidase activity. This screen revealed 8 positive clones. Sequence analysis with the BLASTX program revealed putative enzymes belonging to three glycoside hydrolase families (GH1, GH3 and GH4). Agar-plate tests and enzymatic assays revealed differences between the GH1- and GH3-type enzymes (as regards substrate specificity and regulation) and a difference in substrate specificity within the GH3 group. The substrate specificities and characteristic activities of these enzymes suggest that they may intervene in the depolymerisation of cellulose and hemicellulose. PMID- 21324660 TI - The signaling tool box for tyrosine-based costimulation of lymphocytes. AB - Triggering lymphocyte effector functions is controlled by a diverse array of immune cell coreceptors that dampen or potentiate the primary activation signal from antigen receptors. Attenuation of lymphocyte activation has been shown to be accomplished by immunoreceptor tyrosine-based inhibition motifs that upon phosphorylation recruit protein or lipid phosphatases. By contrast, a general concept of signal amplification and/or diversification is still out. However, the recent discovery of antigen receptor-intrinsic costimulation by membrane-bound immunoglobulins in class-switched memory B cells identified a consensus phosphorylation motif that can boost antigen-induced signal chains and is also employed by costimulatory receptors on T and Natural Killer cells to provide secondary signals for cellular activation. Here we define a common basis of tyrosine-based lymphocyte costimulation comprising immunoglobulin tail tyrosine (ITT)-like phosphorylation motifs and their proximal effectors, growth factor receptor-bound protein (Grb) 2 and phosphatidylinositol-3 kinase (PI3K) enzymes of class IA. PMID- 21324661 TI - Multiple use of waste catalysts with and without regeneration for waste polymer cracking. AB - Waste plastics contain a substantial number of valuable chemicals. The wastes from post-consumer as well as from industrial production can be recycled to valuable chemical feedstock, which can be used in refineries and/or petrochemical industries. This chemical recycling process is an ideal approach in recycling the waste for a better environment. Polymer cracking using a laboratory fluidized bed reactor concentrated on the used highly contaminated catalyst, E-Cat 2. Even though E-Cat 2 had low activity due to fewer acid sites, the products yielded were similar with amorphous ASA and were far better than thermal cracking. The high levels of heavy metals, namely nickel and vanadium, deposited during their lifetime as an FCC catalyst, did not greatly affect on the catalyst activity. It was also shown that E-Cat 2 could be used with and without regeneration. Although there was more deactivation when there was no regeneration step, the yield of gases (C(2)-C(7)) remained fairly constant. For the first time, these results indicate that "waste" FCC catalyst (E-Cat) is a good candidate for future feedstock recycling of polymer waste. The major benefits of using E-Cat are a low market price, the ability to tolerate reuse and regeneration capacity. PMID- 21324662 TI - Methane oxidation in landfill waste biocover soil: kinetics and sensitivity to ambient conditions. AB - Waste biocover soil was investigated as an alternative in regions with a shortage of landfill cover soil. In the work, effects of the composition, ambient conditions and nitrogen stress on CH(4) oxidation in waste biocover soil were studied. The results showed that the optimal composition of waste biocover soil as a landfill cover material for CH(4) oxidation was original pH value, 45% moisture and a particle size of <= 4mm. CH(4) oxidation rate increased rapidly over a CH(4) concentration range of 0.01-10% (v/v), and kept stable at CH(4) concentrations of 10-30% (v/v). The Michaelis-Menten model showed a good fit for the kinetic of CH(4) oxidation in landfill waste biocover soil with a maximum of 9.03 MUmol/gd.w./h. The average Q(10) was 10.6 in the batch experiments. A level of 5% of oxygen concentration was enough to sustain the activity of methanotrophs community structure in waste biocover soil. Waste biocover soil had low baseline concentrations of NH(4)(+)-N and NO(3)(-)-N. Ammonia volatilization from landfills and nitrification in landfill waste biocover soils might stimulate CH(4) consumption at concentrations below 600 mg/kg. However, the contents of NH(4)(+)-N and NO(3)(-)-N above 1200 mg/kg would inhibit CH(4) oxidation in landfill waste biocover soil. Compared with NO(3)(-)-N, NH(4)(+)-N had a greater stimulating action as nutrient at lower concentrations and inhibitory effect at higher concentrations on CH(4) oxidation in landfill waste biocover soil. PMID- 21324663 TI - Knowledge based ranking algorithm for comparative assessment of post-closure care needs of closed landfills. AB - Post-closure care (PCC) activities at landfills include cap maintenance; water quality monitoring; maintenance and monitoring of the gas collection/control system, leachate collection system, groundwater monitoring wells, and surface water management system; and general site maintenance. The objective of this study was to develop an integrated data and knowledge based decision making tool for preliminary estimation of PCC needs at closed landfills. To develop the decision making tool, 11 categories of parameters were identified as critical areas which could affect future PCC needs. Each category was further analyzed by detailed questions which could be answered with limited data and knowledge about the site, its history, location, and site specific characteristics. Depending on the existing knowledge base, a score was assigned to each question (on a scale 1 10, as 1 being the best and 10 being the worst). Each category was also assigned a weight based on its relative importance on the site conditions and PCC needs. The overall landfill score was obtained from the total weighted sum attained. Based on the overall score, landfill conditions could be categorized as critical, acceptable, or good. Critical condition indicates that the landfill may be a threat to the human health and the environment and necessary steps should be taken. Acceptable condition indicates that the landfill is currently stable and the monitoring should be continued. Good condition indicates that the landfill is stable and the monitoring activities can be reduced in the future. The knowledge base algorithm was applied to two case study landfills for preliminary assessment of PCC performance. PMID- 21324664 TI - Using self-assembled aptamers and fibrinogen-conjugated gold nanoparticles to detect DNA based on controlled thrombin activity. AB - We have developed a colorimetric probe, based on the aggregation of gold nanoparticles (Au NPs), for the detection of DNA and for the analysis of single nucleotide polymorphism (SNP); this probe functions through the modulation of the activity of thrombin (Thr) in the presence of bivalent thrombin-binding aptamers (TBAs). The bivalent TBAs were formed from TBA(27') (comprising a 27-base sequence providing TBA(27) functionality, a T(5) linker, and an 11-base sequence for hybridization) and TBA(15') (comprising a 15-base sequence providing TBA(15) functionality, a T(5) linker, and a 12-base sequence for hybridization) through their hybridization with perfectly matched DNA (DNA(pm)). The bivalent TBAs interacted specifically with thrombin, suppressing its activity toward fibrinogen modified Au NPs (Fib-Au NPs). The potency of the inhibitory effect of TBA(15') TBA(27')/DNA(pm) toward thrombin - and, thus, the degree of aggregation of the Fib-Au NPs - was highly dependent on the concentration of DNA(pm). Under the optimal conditions (50 pM thrombin, 2 nM TBA(15'), 2 nM TBA(27'), and 38 pM Fib Au NPs), the linear relationship of the response of the probe toward DNA(pm) extended from 0.1 to 2 nM, with a correlation coefficient of 0.97. The limit of detection (LOD) for DNA(pm) was 20 pM, based on a signal-to-noise ratio of 3. We also applied a corresponding TBA(15")-TBA(27")/Thr/Fib-Au NP probe to the detection of the SNP of the Arg249Ser unit in the TP53 gene, with an LOD of 32 pM. Relative to conventional molecular beacon-based and crosslinking aggregation based Au NP probes, our new approach offers higher sensitivity and higher selectivity toward DNA. PMID- 21324665 TI - A multitask biosensor for micro-volumetric detection of N-3-oxo-dodecanoyl homoserine lactone quorum sensing signal. AB - N-3-oxo-dodecanoyl-homoserine lactone (3OC(12)-HSL) is the main quorum sensing (QS) signal produced by the human pathogen Pseudomonas aeruginosa, a major cause of hard-to-treat nosocomial infections and years-lasting chronic biofilm infections in the lungs of cystic fibrosis (CF) patients. 3OC(12)-HSL-dependent QS is considered a promising target for novel anti-pseudomonads drugs. However, the screening systems employed to date for the identification of QS inhibitors (QSI) were aimed at the identification of inhibitors of 3OC(12)-HSL signaling rather than of the synthesis or the export of this molecule. Moreover, the low concentration of 3OC(12)-HSL in CF sputum has hampered large scale studies aimed at addressing the role of this molecule in the CF lung infection. Here we describe the construction and characterization of PA14-R3, a new whole-cell biosensor for the quantitative detection of 3OC(12)-HSL. PA14-R3 provides fast and direct quantification of 3OC(12)-HSL over a wide range of concentrations (from pM to MUM), and proved to be an easy-to-handle, cost-effective and reliable biosensor for high-throughput screening of 3OC(12)-HSL levels in samples of different origin, including CF sputum. Moreover, the specific features of PA14-R3 made it possible to develop and validate a novel high-throughput screening system for QSI based on the co-cultivation of PA14-R3 with the PA14 wild-type strain. With respect to previous screening systems for QSI, this approach has the advantage of being cost-effective and allowing the identification of compounds targeting, besides 3OC(12)-HSL signaling, any cellular process critical for QS response, including 3OC(12)-HSL synthesis and secretion. PMID- 21324666 TI - Construction and application of an amperometric xanthine biosensor based on zinc oxide nanoparticles-polypyrrole composite film. AB - Zinc oxide nanoparticles (ZnO-NPs) were synthesized from zinc nitrate by simple and efficient method in aqueous media at 55 degrees C without any requirement of calcinations step. A mixture of ZnO-NPs and pyrrole was eletropolymerized on Pt electrode to form a ZnO-NPs-polypyrrole (PPy) composite film. Xanthine oxidase (XOD) was immobilized onto this nanocomposite film through physiosorption. The ZnO-NPs/polypyrrole/Pt electrode was characterized by Fourier transform infrared (FTIR), cyclic voltammetry (CV), X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and electrochemical impedance spectroscopy (EIS) before and after immobilization of XOD. The XOD/ZnO NPs-PPy/Pt electrode as working electrode, Ag/AgCl as reference electrode and Pt wire as auxiliary electrode were connected through a potentiostat to construct a xanthine biosensor. The biosensor exhibited optimum response within 5s at pH 7.0, 35 degrees C and linearity from 0.8 MUM to 40 MUM for xanthine with a detection limit 0.8 MUM (S/E=3). Michaelis Menten constant (K(m)) for xanthine oxidase was 13.51 MUM and I(max) 0.071 MUA. The biosensor measured xanthine in fish meat and lost 40% of its initial activity after its 200 uses over 100 days, when stored at 4 degrees C. PMID- 21324667 TI - An electrochemical biosensor for fructosyl valine for glycosylated hemoglobin detection based on core-shell magnetic bionanoparticles modified gold electrode. AB - A high-performance amperometric fructosyl valine (FV) biosensor was developed, based on immobilization of fructosyl amino-acid oxidase (FAO) on core-shell magnetic bionanoparticles modified gold electrode. Chitosan was used to introduce amino groups onto the surface of core-shell magnetic bionanoparticles (MNPs). With FAO as an enzyme model, a new fructosyl valine biosensor was fabricated. The biosensor showed optimum response, when operated at 50 mVs(-1) in 0.1M potassium phosphate buffer, pH 7.5 and 35 degrees C. The biosensor exhibited excellent sensitivity [the detection limit is down to 0.1mM for FV], fast response time (less than 4s), wide linear range (from 0 to 2mM). Analytical recovery of added FV was 95.00-98.50%. Within batch and between batch coefficients of variation were <2.58% and <5.63%, respectively. The enzyme electrode was used 250 times over 3 months, when stored at 4 degrees C. PMID- 21324668 TI - Palladium nanoparticle/chitosan-grafted graphene nanocomposites for construction of a glucose biosensor. AB - Graphene (GR) was covalently functionalized with chitosan (CS) to improve its biocompatibility and hydrophilicity for the preparation of biosensors. The CS grafted GR (CS-GR) rendered water-soluble nanocomposites that were readily decorated with palladium nanoparticles (PdNPs) using in situ reduction. Results with TEM, SEM, FTIR, Raman and XRD revealed that CS was successfully grafted without destroying the structure of GR, and PdNPs were densely decorated on CS-GR sheets with no aggregation occurring. A novel glucose biosensor was then developed through covalently immobilizing glucose oxidase (GOD) on a glassy carbon electrode modified with the PdNPs/CS-GR nanocomposite film. Due to synergistic effect of PdNPs and GR, the PdNPs/CS-GR nanocomposite film exhibited excellent electrocatalytical activity toward H(2)O(2) and facilitated high loading of enzymes. The biosensor demonstrated high sensitivity of 31.2 MUA mM( 1)cm(-2) for glucose with a wide linear range from 1.0 MUM to 1.0mM as well as a low detection limit of 0.2 MUM (S/N=3). The low Michaelis-Menten constant (1.2mM) suggested enhanced enzyme affinity to glucose. These results indicated that PdNPs/CS-GR nanocomposites held great potential for construction of a variety of electrochemical biosensors. PMID- 21324669 TI - The simultaneous electrochemical detection of ascorbic acid, dopamine, and uric acid using graphene/size-selected Pt nanocomposites. AB - In this study, a graphene/Pt-modified glassy carbon (GC) electrode was created to simultaneously characterize ascorbic acid (AA), dopamine (DA), and uric acid (UA) levels via cyclic voltammetry (CV) and differential pulse voltammetry (DPV). During the preparation of the nanocomposite, size-selected Pt nanoparticles with a mean diameter of 1.7 nm were self-assembled onto the graphene surface. In the simultaneous detection of the three aforementioned analytes using CV, the electrochemical potential differences among the three detected peaks were 185 mV (AA to DA), 144 mV (DA to UA), and 329 mV (AA and UA), respectively. In comparison to the CV results of bare GC and graphene-modified GC electrodes, the large electrochemical potential difference that is achieved via the use of the graphene/Pt nanocomposites is essential to the distinguishing of these three analytes. An optimized adsorption of size-selected Pt colloidal nanoparticles onto the graphene surface results in a graphene/Pt nanocomposite that can provide a good platform for the routine analysis of AA, DA, and UA. PMID- 21324670 TI - Promoter proximal pausing and the control of gene expression. AB - The advent of methods for mapping the location of specific proteins across genomes is substantially enlightening our understanding of gene regulation. One recent discovery is that Pol II is concentrated at the 5' end of thousands of genes in mammalian and Drosophila cells. Before this, much research had focused on understanding how sequence-specific, DNA-binding proteins orchestrate the actions of regulators of chromatin structure and the general transcriptional machinery to control transcription initiation. The concentration of Pol II at the 5' ends of genes indicates that key steps regulating transcription occur after Pol II has associated with a gene's promoter. PMID- 21324672 TI - Epigenetic regulation and reprogramming during gamete formation in plants. AB - Plants and animals reproduce sexually via specialized, highly differentiated gametes. Yet, gamete formation drastically differs between the two kingdoms. In flowering plants, the specification of cells destined to enter meiosis occurs late in development, gametic and accessory cells are usually derived from the same meiotic product, and two distinct female gametes involved in double fertilization differentiate. This poses fascinating questions in terms of gamete development and the associated epigenetic processes. Although studies in this area remain at their infancy, it becomes clear that large-scale epigenetic reprogramming, involving RNA-directed DNA methylation, chromatin modifications, and nucleosome remodeling, contributes to the establishment of transcriptionally repressive or permissive epigenetic landscapes. Furthermore, a role for small RNAs in the regulation of transposable elements during gametogenesis is emerging. PMID- 21324671 TI - Cohesin: genomic insights into controlling gene transcription and development. AB - Over the past decade it has emerged that the cohesin protein complex, which functions in sister chromatid cohesion, chromosome segregation, and DNA repair, also regulates gene expression and development. Even minor changes in cohesin activity alter several aspects of development. Genome-wide analysis indicates that cohesin directly regulates transcription of genes involved in cell proliferation, pluripotency, and differentiation through multiple mechanisms. These mechanisms are poorly understood, but involve both partial gene repression in concert with Polycomb group proteins, and facilitating long-range looping, both between enhancers and promoters, and between CTCF protein binding sites. PMID- 21324673 TI - Branching out with DNA helicases. AB - The proper resolution of branched DNA molecules, which arise during processes such as DNA replication, DNA repair, and transcription, is critical for the maintenance of the genome. Disruption of this process can lead to genome instability and cancer progression. In this review, we describe recent progress on several interesting and biologically important enzymes that act upon different types of branched DNA substrates. PMID- 21324674 TI - Zoledronic acid preserves bone mineral density in premenopausal women who develop ovarian failure due to adjuvant chemotherapy: final results from CALGB trial 79809. AB - BACKGROUND: Chemotherapy-induced ovarian failure (CIOF) is a frequent side-effect of adjuvant chemotherapy that results in rapid bone loss. We hypothesised that zoledronic acid (ZA), a third-generation amino bisphosphonate, would prevent bone loss in premenopausal women who developed CIOF. METHODS: Women (439) were randomised to intravenous (i.v.) ZA 4 mg every 3 months for 2 years starting within 1-3 months after randomization (arm A) or 1 year after randomization (arm B, controls). CIOF was prospectively defined as >= 3 months of amenorrhoea, follicle-stimulating hormone (FSH) >= 30 MIU/ml and non-pregnant at 1 year. The primary end-point was the percentage change in bone mineral density (BMD) in the lumbar spine (LS) from baseline to 12 months in the ZA and in control groups in women who developed CIOF; the secondary end-point was BMD in LS at 3 years in all randomised women. FINDINGS: One hundred and fifty (56%) met the definition of CIOF at 1 year. Overall, grade 3 toxicities of ZA were fatigue (1%) arthralgias (21%) and pain (84%). The median percent change (interquartile range, IQR) at 1 year was +1.2% (-0.5% to +2.8%) and -6.7% (-9.7% to -2.9%) p<0.001 and at 3 years was +1.0% (-1.6% to +5.2%) and -0.5% (-3.7% to +3.2%) p=0.019 in arms A and B, respectively. INTERPRETATION: ZA every 3 months is well tolerated and prevents rapid bone loss in premenopausal women that develop CIOF. Giving ZA with rather than 1 year after the start of adjuvant chemotherapy is the preferred sequence to prevent bone loss. PMID- 21324675 TI - Activity and stability of pyrolyzed iron ethylenediaminetetraacetic acid as cathode catalyst in microbial fuel cells. AB - A low-cost and effective iron-chelated catalyst was developed as an electrocatalyst for the oxygen reduction reaction (ORR) in microbial fuel cells (MFCs). The catalyst was prepared by pyrolyzing carbon mixed iron-chelated ethylenediaminetetraacetic acid (PFeEDTA/C) in an argon atmosphere. Cyclic voltammetry measurements showed that PFeEDTA/C had a high catalytic activity for ORR. The MFC with a PFeEDTA/C cathode produced a maximum power density of 1122 mW/m(2), which was close to that with a Pt/C cathode (1166 mW/m(2)). The PFeEDTA/C was stable during an operation period of 31 days. Based on X-ray diffraction and X-ray photoelectron spectroscopy measurements, quaternary-N modified with iron might be the active site for the oxygen reduction reaction. The total cost of a PFeEDTA/C catalyst was much lower than that of a Pt catalyst. Thus, PFeEDTA/C can be a good alternative to Pt in MFC practical applications. PMID- 21324676 TI - Biofilter performance of pine nuggets and lava rock as media. AB - Wood chips and bark mulch are commonly used biofilter media because they are generally locally available and inexpensive. Nevertheless, these organic materials degrade and require replacement every 2-5 years. In this study, airflow characteristics and gas reduction efficiencies of two alternative biofilter media (pine nuggets and lava rock) with high porosity and potentially longer service lives were evaluated at three empty bed contact times (1, 3, and 5s) and two moisture levels (82% and 90% relative humidity). The lava rock had a lower pressure drop across the media and maintained higher media depth. Gas reduction efficiencies were highest for lava rock at 5s empty bed contact time and 90% humidity. The reduction efficiencies at these conditions were 56%, 88%, 87%, 25%, and 0.7% for ammonia, hydrogen sulfide, total reduced sulfur, methane and nitrous oxide, respectively. Odor reduction up to 48% was observed but was not consistent. PMID- 21324677 TI - Statistical modelling of organic matter and emerging pollutants removal in constructed wetlands. AB - Multiple regression models, clustering tree diagrams, regression trees (CHAID) and redundancy analysis (RDA) were applied to the study of the removal of organic matter and pharmaceuticals and personal care products (PPCPs) from urban wastewater by means of constructed wetlands (CWs). These four statistical analyses pointed out the importance of physico-chemical parameters, plant presence and chemical structure in the elimination of most pollutants. Temperature, pH values, dissolved oxygen concentration, redox potential and conductivity were related to the removal of the studied substances. Plant presence (Typha angustifolia and Phragmites australis) enhanced the removal of organic matter and some PPCPs. Multiple regression equations and CHAID trees provided numerical estimations of pollutant removal efficiencies in CWs. These models were validated and they could be a useful and interesting tool for the quick estimation of removal efficiencies in already working CWs and for the design of new systems which must fulfil certain quality requirements. PMID- 21324678 TI - Raman spectroscopy measurements of glucose and xylose in hydrolysate: role of corn stover pretreatment and enzyme composition. AB - The effect of corn stover pretreatment on glucose quantitation in hydrolysate using Raman spectroscopy is evaluated. Dilute sulfuric-acid pretreatment results in a 20 mg mL(-1) glucose limit of detection in hydrolysate. Soaking in aqueous ammonia pretreatment produces a 4 mg mL(-1) limit of detection. Water, ethanol or hexane extraction of corn stover reduces the spectral background that limits glucose detection in dilute acid hydrolysate. Additionally, a Raman spectroscopy multi-peak fitting method is presented to simultaneously measure glucose and xylose concentration in hydrolysate. This method yields a 6.1% average relative standard error at total saccharide concentrations above 45 mg mL(-1). When only cellulase is present, glucose and xylose yield were measured by Raman spectroscopy to be 32 +/- 4 and 7.0 +/- 0.8 mg mL(-1), respectively. When both cellulase and hemicellulase were present, xylose yield increased to 18.0 +/- 0.5 mg mL(-1). Enzymatic or colorimetric assays confirmed the validity of the Raman spectroscopy results. PMID- 21324679 TI - Microalgae bulk growth model with application to industrial scale systems. AB - The scalability of microalgae growth systems is a primary research topic in anticipation of the commercialization of microalgae-based biofuels. To date, there is little published data on the productivity of microalgae in growth systems that are scalable to commercially viable footprints. To inform the development of more detailed assessments of industrial-scale microalgae biofuel processes, this paper presents the construction and validation of a model of microalgae biomass and lipid accumulation in an outdoor, industrial-scale photobioreactor. The model incorporates a time-resolved simulation of microalgae growth and lipid accumulation based on solar irradiation, species specific characteristics, and photobioreactor geometry. The model is validated with 9 weeks of growth data from an industrially-scaled outdoor photobioreactor. Discussion focuses on the sensitivity of the model input parameters, a comparison of predicted microalgae productivity to the literature, and an analysis of the implications of this more detailed growth model on microalgae biofuels lifecycle assessment studies. PMID- 21324680 TI - Fermentation of cellobiose to ethanol by industrial Saccharomyces strains carrying the beta-glucosidase gene (BGL1) from Saccharomycopsis fibuligera. AB - Constructs carrying the Saccharomycopsis fibuligera beta-glucosidase gene (BGL1) under the control of a constitutive actin or a galactose-inducible promoter were introduced into eleven Saccharomyces strains. In ten of these recombinant strains, BGL1 expression driven by the actin promoter was between 1.6- and 18 fold higher than that obtained with the galactose-inducible promoter. Strains carrying the actin promoter yielded ethanol concentrations from cellobiose of between 0.5% and 14%, depending on their ability to accumulate Bgl1 (between 30 and 250 mU/mL) but also on their genetic background. Comparative analysis of a S. cerevisiae strain and its corresponding petite version showed similar ethanol yields, despite a 3-fold lower beta-glucosidase production of the latter, suggesting that respiratory activity could be one of the factors influencing ethanol production when using carbon sources other than glucose. This study provides a selection of strains that may be good candidates as hosts for ethanol biosynthesis from cellulosic substrates. PMID- 21324681 TI - Isatin 1,2,3-triazoles as potent inhibitors against caspase-3. AB - Sixteen disubstituted 1,2,3-triazoles were prepared using the Huisgen cycloaddition reaction and evaluated as inhibitors against caspase-3. The two most potent inhibitors were found to be (S)-1-((1-(2,3-dihydrobenzo[b][1,4]dioxin 6-yl)-1H-1,2,3-triazol-4-yl)methyl)-5-((2-(methoxymethyl)pyrrolidin-1 yl)sulfonyl)indoline-2,3-dione (7f) and (S)-1-((1-benzyl-1H-1,2,3-triazol-5 yl)methyl)-5-((2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)indoline-2,3-dione (8g) with IC(50)-values of 17 and 9 nM, respectively. Lineweaver-Burk plots revealed that these two triazoles show competitive inhibitory mechanism against caspase-3. PMID- 21324682 TI - Efficient synthesis of triazole moiety-containing nucleotide analogs and their inhibitory effects on a malic enzyme. AB - Eleven triazole moiety-containing nucleotide analogs were synthesized starting form tetra-O-acetylribose in 55-63% total yields. The synthesis involved two key steps, the lipase-mediated selective deacylation of 1-azido-2,3,5-tri-O-acetyl beta-D-ribofuranoside and the Huisgen 1,3-dipolar cycloaddition between terminal alkynes and the 1-azido ribofuranoside derivative. These analogs showed inhibitory effects against a recombinant Escherichia coli NAD-dependent malic enzyme. PMID- 21324683 TI - KDR inhibitor with the intramolecular non-bonded interaction: conformation activity relationships of novel indole-3-carboxamide derivatives. AB - We previously reported that compound 1, having a similar conformation to PTK787 (2) by forming a pseudo ring structure with an intramolecular non-bonded S-O interaction, exhibited a potent inhibitory activity against VEGFR2 tyrosine kinase (KDR). Applying the ideas of pseudo ring formations, we have designed three types of novel indole carboxamide derivatives 5-7 with an intramolecular hydrogen bonding or non-bonded S-O interaction. We describe the design and synthesis of 5-7, and also discuss the relationships of their KDR inhibitory activity and conformations that were stabilized by their intramolecular non bonded interactions. PMID- 21324684 TI - Quinolizidinone carboxylic acid selective M1 allosteric modulators: SAR in the piperidine series. AB - SAR study of the piperidine moiety in a series of quinolizidinone carboxylic acid M(1) positive allosteric modulators was examined. While the SAR was generally flat, compounds were identified with high CNS exposure to warrant additional in vivo evaluation. PMID- 21324685 TI - SAR studies on dihydropyrimidinone antibiotics. AB - There is an urgent need for the development of novel antimicrobial agents that offer effective treatment against MRSA. Using a new class of dipeptide antibiotic TAN-1057A/B as lead, we designed, synthesized and evaluated analogs of TAN 1057A/B. Several novel dihydropyrimidinone antibiotics demonstrating comparable antibiotic efficacy while possessing favorable selectivity were identified. PMID- 21324686 TI - Novel second generation analogs of eribulin. Part I: Compounds containing a lipophilic C32 side chain overcome P-glycoprotein susceptibility. AB - Eribulin mesylate (HalavenTM), a totally synthetic analog of the marine polyether macrolide halichondrin B, has recently been approved in the United States as a treatment for breast cancer. It is also currently under regulatory review in Japan and the European Union. Our continuing medicinal chemistry efforts on this scaffold have focused on oral bioavailability, brain penetration and efficacy against multidrug resistant (MDR) tumors by lowering the susceptibility of these compounds to P-glycoprotein (P-gp)-mediated drug efflux. Replacement of the 1,2 amino alcohol C32 side chain of eribulin with fragments neutral at physiologic pH led to the identification of analogs with significantly lower P-gp susceptibility. The analogs maintained low- to sub-nM potency in vitro against both sensitive and MDR cell lines. Within this series, increasing lipophilicity generally led to decreased P-gp susceptibility. In addition to potency in cell culture, these compounds showed in vivo activity in mouse xenograft models. PMID- 21324687 TI - Novel second generation analogs of eribulin. Part III: Blood-brain barrier permeability and in vivo activity in a brain tumor model. AB - Novel second generation analogs of eribulin mesylate, a tubulin agent recently approved for the treatment of breast cancer, are reported. Our recent efforts have focused on expanding the target indications for this class of compounds to other tumor types. Herein, we describe the design, synthesis and evaluation of eribulin analogs active against brain tumor cell lines in vitro and corresponding brain tumor models in mice. Attenuation of basicity of the amino group(s) in the C32 side-chain region led to compounds with lower susceptibility to P-gp mediated drug efflux, allowing these compounds to permeate through the blood-brain barrier. In preclinical in vivo studies, these compounds showed significantly higher levels in the brain and cerebrospinal fluid as compared to eribulin. In addition, analogs within this series showed antitumor activity in an orthotopic murine model of human glioblastoma. PMID- 21324688 TI - 1-((3S,4S)-4-amino-1-(4-substituted-1,3,5-triazin-2-yl) pyrrolidin-3-yl)-5,5 difluoropiperidin-2-one inhibitors of DPP-4 for the treatment of type 2 diabetes. AB - A 3-amino-4-substituted pyrrolidine series of dipeptidyl peptidase IV (DPP-4) inhibitors was rapidly developed into a candidate series by identification of a polar valerolactam replacement for the lipophilic 2,4,5-trifluorophenyl pharmacophore. The addition of a gem-difluoro substituent to the lactam improved overall DPP-4 inhibition and an efficient asymmetric route to 3,4 diaminopyrrolidines was developed. Advanced profiling of a subset of analogs identified 5o with an acceptable human DPP-4 inhibition profile based on a rat PK/PD model and a projected human dose that was suitable for clinical development. PMID- 21324689 TI - Nonsteroidal 2,3-dihydroquinoline glucocorticoid receptor agonists with reduced PEPCK activation. AB - Continuing studies based on dihydroquinoline glucocorticoid receptor agonists lead to the discovery of a series of C4-oxime analogs. Representative compounds exhibited potent transrepression activity with minimal transactivation of phosphoenolpyruvate caboxykinase (PEPCK), a key protein in the gluconeogenesis pathway. These compounds represent promising leads in identifying GR agonists with high anti-inflammatory activity and attenuated potential for glucose elevation. PMID- 21324690 TI - Synthesis and photophysical properties of new SNARF derivatives as dual emission pH sensors. AB - We report the synthesis and properties of two new seminaphthorhodafluor (SNARF) derivatives, SNARF-F and SNARF-Cl. Both these derivatives exhibit typical red shifts of absorption and fluorescence, and higher cell permeability as compared to traditional SNARF, while the pH-dependent dual-emission characteristics are well retained. In particular, the lower pK(a) (7.38) of SNARF-F makes it more suitable than traditional SNARF derivatives for intracellular applications. PMID- 21324691 TI - N-benzylimidazole carboxamides as potent, orally active stearoylCoA desaturase-1 inhibitors. AB - A potent, small molecule inhibitor with a favorable pharmacokinetic profile to allow for sustained SCD inhibition in vivo was identified. Starting from a low MW acyl guanidine (5a), identified with a RapidFire High-Throughput Mass Spectrometry (RF-MS) assay, iterative library design was used to rapidly probe the amide and tail regions of the molecule. Singleton synthesis was used to probe core changes. Biological evaluation of a SCD inhibitor (5b) included in vitro potency at SCD-1 and in vivo modulation of the plasma desaturation index (DI) in rats on a low essential fatty acid (LEFA) diet. In addition to dose-dependent decrease in DI, effects on rodent ocular tissue were noted. Therefore, in rat, these SCD inhibitors only recapitulate a portion of phenotype exhibited by the SCD-1 knockout mouse. PMID- 21324692 TI - Novel second generation analogs of eribulin. Part II: Orally available and active against resistant tumors in vivo. AB - Eribulin mesylate is a newly approved treatment for locally advanced and metastatic breast cancer. We targeted oral bioavailability and efficacy against multidrug resistant (MDR) tumors for further work. The design, synthesis and evaluation of novel amine-containing analogs of eribulin mesylate are described in this part. Attenuation of basicity of the amino group(s) in the C32 side-chain region led to compounds with low susceptibility to PgP-mediated drug efflux. These compounds were active against MDR tumor cell lines in vitro and in xenograft models in vivo, in addition to being orally bioavailable. PMID- 21324693 TI - Anti-obesity compounds in green leaves of Eucommia ulmoides. AB - The anti-hypertensive effect of Eucommia leaves has been confirmed clinically, and the study of their anti-obesity properties has advanced. However, the compounds involved in their anti-obesity effect have not been fully elucidated. In this Letter, we examined the anti-obesity effect of Eucommia green leaf extract (EGLE) divided into five fractions with high porous polystyrene gel and of the compounds isolated, geniposidic acid, asperuloside and chlorogenic acid, respectively. A metabolic syndrome-like clinical model in mice was generated by feeding a 40% high-fat diet to examine the anti-obesity effects of chronic administration of test substance. After 4 weeks, body weight, white adipose tissue weight, plasma triglyceride levels and total cholesterol levels in the model mice were significantly inhibited by the 30% MeOH fraction (containing much higher levels of asperuloside than the other fractions), and these effects were similar to those of EGLE. Chronic administration of isolated asperuloside in Eucommia leaves suppressed increases in model mouse body weight, white adipose tissue weight, plasma triglyceride levels and free fatty acids levels. These results suggest that asperuloside in Eucommia leaves has important anti-obesity effects. PMID- 21324694 TI - Antibacterial activities of imidazolium, pyrrolidinium and piperidinium salts. AB - The antibacterial activity of various types of imidazolium, pyrrolidinium and piperidinium salts with both propargyl group and alkyl and/or silylalkyl chains of different lengths, are described. Especially, the MIC (MUg/ml) of prepared each compound for Escherichia coli and other several bacteria was determined. PMID- 21324695 TI - Tumor size and survival in multicentric and multifocal breast cancer. AB - PURPOSE: Current AJCC/UICC staging of early breast cancer defines tumor stage using the largest focus, adding the suffix "(m)" to indicate multiplicity. This method may underestimate the total tumor burden in multifocal and multicentric breast cancer (MMBC). This study examines other measures of tumor size in MMBC to determine which provides the best fit in a multivariate model for survival outcomes. PATIENTS AND METHODS: This prospective cohort study used data from the Australian Capital Territory and New South Wales Breast Cancer Treatment Group database to identify 812 women with ipsilateral invasive breast cancer; 141 of these women had MMBC. The pathology slides of all women with MMBC were reviewed and all foci of invasive breast cancer were re-measured. The measures of interest were the diameter of the largest deposit, the aggregate diameter and the aggregate volume. These measures of tumor size were included with other clinicopathological features of MMBC in a multivariate analysis to assess their relationship with progression-free survival (PFS) and overall survival (OS). RESULTS: Tumor size was associated with PFS and OS in MMBC using any of the three measures; however, the diameter of the largest deposit provided the best fit in the multivariate model for OS. CONCLUSION: Tumor size is an important prognostic factor for MMBC, and the diameter of the largest deposit provides a better fit in a multivariate model for OS than aggregate diameter and aggregate volume. Therefore, tumor size in MMBC should continue to be measured using the diameter of the largest deposit. PMID- 21324696 TI - Challenges and implementation of a women's breast health initiative in rural Kashmir. AB - The purpose of this study was to explore how to successfully collect demographic, lifestyle and health behavior data, followed by an educational intervention on a culturally sensitive topic, breast cancer, in the politically fragile Kashmir Valley. Survey results of 520 women identified challenges that impact the general health of women, including literacy, hygiene and water safety, as well as a dearth of breast health and educational resources and all cancer services. The study tested culturally sensitive approaches to obtain survey data and provide appropriate breast health education for Kashmiri women at risk for breast cancer, who live within this socially and politically challenging environment. This study provides a foundation for future development of research and clinical programs to identify women at high risk and implement an active health surveillance monitoring program with a focus on breast cancer in Kashmir. PMID- 21324697 TI - Interest in cavity shaving in breast conservative treatment does not depend on lumpectomy technique. AB - In breast conserving surgery (BCS), the usefulness to perform systematic cavity shaving is actively debated. Some investigators argued that systematic cavity shaving could avoid surgical re-excision and make diagnosis of unexpected multifocality. Others argued that usefulness of cavity shaving depends on volumes of resection. In this study one hundred patients undergoing BCS with systematic cavity shaving were included. Margins less than 3 mm were considered to be insufficient. We tested clinico-pathological characteristics in order to identify predictive model of cavity margin shaving utility and we sought to determine if cavity margin shaving usefulness depends on volumes of resection. We showed that cavity shaving avoids the need for re-excision in 24% of cases as well as diagnosis of multifocality in 6% of cases. However, the clinical usefulness of cavity shaving was not related to the volumes of resection. PMID- 21324698 TI - Elderly women with breast cancer often die due to other causes regardless of primary endocrine therapy or primary surgical therapy. AB - Survival and cause of death was investigated for Primary Surgical Therapy (PST) and Primary Endocrine Therapy (PET). Of women aged >=75 years 113 patients received PET, 233 patients underwent PST. PST gave better survival, although this group was younger (p < 0.001). During follow-up the percentage of deaths due to breast cancer was similar and stable in both groups. Increased age was associated with a higher risk on death due to other causes (HR 1.11; CI 1.07-1.14), not on death due to breast cancer (HR 0.94; CI 0.87-1.01). The association of type of treatment and death due to breast cancer was not different between both groups in univariate analyses (HR 0.78; CI 0.44-1.39). In the multivariate model this non significance remained after correcting for tumor size and age (HR 0.68; CI 0.33 1.42). Treatment should not be based merely on surgical treatment. PET may be an acceptable alternative. PMID- 21324699 TI - Does lower limb preference influence gait initiation? AB - Gait initiation (GI) has been the focus of many investigations in order to determine the kinematic and kinetic parameters associated with this process. In these studies, the parameters are observed during GI with the preferential lower limb. However, none of these studies have looked at the impact on GI parameters when the start is achieved with the non-preferential limb. This investigation focused on the effects of lower limb preference on the kinematic and kinetic parameters of GI. Upon display of a visual cue, subjects stepped with preferential limb or non-preferential limb at natural speed. The duration of GI phases, the medio-lateral component of the center of mass (CM) displacement, the medio-lateral distance between the center of pressure and the CM, the step width as well as the medio-lateral impulse, were observed. When subjects started with the non-preferential limb, the bodyweight transfer was facilitated by a greater impulse during the anticipatory postural adjustment (APA) phase. Conversely, a more lateral CM displacement during the execution phase and a more lateral step in preferential start were observed. Asymmetry in frontal plane body motion was observed during weight transfer following APA, as well as during assistive control of ballistic body motion during the execution phase of the first step. In both conditions, the non-preferential limb provided the greater lateral impulse on the ground. This may have clinical relevance especially in individuals with unilateral limb dyscontrol and postural asymmetry that may require rehabilitation. PMID- 21324700 TI - The influence of correction loss in thoracolumbar fractures treated by posterior instrumentation: a minimum 7-year follow-up. AB - We retrospectively studied patients who underwent posterior pedicle screw instrumentation for thoracolumbar fractures to explore the relationship between correction loss after the operation and clinical outcome. The study included 52 patients, with a minimum postoperative follow-up of 7 years (mean of 9.8 years). From the analysis of radiological and clinical outcomes, we found that the relevant factors related to functional outcome were: (i) preoperative anterior vertebral height (AVH; regression coefficient [B]=-0.075, p=0.045); and (ii) the latest follow-up AVH (B=-0.100, p=0.043). This indicates that function is likely to be worse if the anterior vertebral column is compressed more severely at the time of injury, and that function will also be worse if the AVH is decreased at the latest follow-up. However, loss of AVH was not correlated with functional outcome. Therefore, we recommend that the AVH should be restored as much as possible by posterior instrumentation during the treatment of thoracolumbar fractures. Reducing the loss of correction to maintain the postoperative AVH is also critical to maintain the AVH at latest follow-up. PMID- 21324701 TI - Oxidation and fusion defects synergistically accelerate polyethylene failure in knee replacement. AB - We have previously reported upon a cohort of patients with premature failure of such material and postulated upon the impact of abnormally high concentrations of type 2 fusion defects whereby there is a lack of particle cohesion due to incomplete diffusion. In vivo oxidation has been purported to underscore the premature failure of polyethylene. The mechanism of such remains poorly delineated. New data has now been obtained by determining substrata oxidative profiles of 10 failed Kinemax Plus modular tibial insert analyses in conjunction with fusion defect detection. The full thickness of a series of cores was analysed using infra-red spectroscopy to identify higher levels of oxidation in loaded used material at both the articulating and non-articulating regions. A comparison was made to an unused control. Articulating, loaded, areas exhibited greater local concentrations of oxidised material and wider variation of such consistent with the higher presence of fusion defects. Subsurface analysis confirmed the presence of a major oxidative peak 2mm below the surface for all loaded areas irrespective of wear. Additionally we were able to identify a second major oxidative focus about halfway between the inferior (tibial baseplate) surface and the articulating area. We believe that the combination of high oxidation and fusion defects represents a second high stress zone consistent with the observation of tibial baseplate polyethylene dissociation and backside wear with resultant catastrophic material failure. PMID- 21324702 TI - Cofactor-type inhibitors of inosine monophosphate dehydrogenase via modular approach: targeting the pyrophosphate binding sub-domain. AB - Cofactor-type inhibitors of inosine monophosphate dehydrogenase (IMPDH) that target the nicotinamide adenine dinucleotide (NAD) binding domain of the enzyme are modular in nature. They interact with the three sub-sites of the cofactor binding domain; the nicotinamide monophosphate (NMN) binding sub-site (N sub site), the adenosine monophosphate (AMP) binding sub-site (A sub-site), and the pyrophosphate binding sub-site (P sub-site or P-groove). Mycophenolic acid (MPA) shows high affinity to the N sub-site of human IMPDH mimicking NMN binding. We found that the attachment of adenosine to the MPA through variety of linkers afforded numerous mycophenolic adenine dinucleotide (MAD) analogues that inhibit the two isoforms of the human enzyme in low nanomolar to low micromolar range. An analogue 4, in which 2-ethyladenosine is attached to the mycophenolic alcohol moiety through the difluoromethylenebis(phosphonate) linker, was found to be a potent inhibitor of hIMPDH1 (K(i)=5 nM), and one of the most potent, sub micromolar inhibitor of leukemia K562 cells proliferation (IC(50)=0.45 MUM). Compound 4 was as potent as Gleevec (IC(50)=0.56 MUM) heralded as a 'magic bullet' against chronic myelogenous leukemia (CML). MAD analogues 7 and 8 containing an extended ethylenebis(phosphonate) linkage showed low nanomolar inhibition of IMPDH and low micromolar inhibition of K562 cells proliferation. Some novel MAD analogues described herein containing linkers of different length and geometry were found to inhibit IMPDH with K(i)'s lower than 100 nM. Thus, such linkers can be used for connection of other molecular fragments with high affinity to the N- and A-sub-site of IMPDH. PMID- 21324703 TI - Synthesis and biological evaluation of imidazolo[2,1-b]benzothiazole derivatives, as potential p53 inhibitors. AB - Since activation of p53 in response to cytotoxic stress may have proapoptotic or protective effects depending on the nature of the injury, inhibitors of p53 may have therapeutic interest as modulators of chemotherapy toxicity or efficacy. In an attempt to identify novel p53 inhibitors, a quality collection of compounds structurally related to pifithrin-beta were designed and synthesized as potential inhibitors of p53. The biochemical and biological evaluations supported that compounds of the tetrahydrobenzothiazole series were inhibitors of the p53 transcriptional activity and were effective in enhancing paclitaxel-induced apoptosis. In contrast, in spite of the increased cytotoxic potency, selected compounds of the benzothiazole series were not able to modulate the transcriptional activity of p53, as indicated by lack of change of p21 expression. The therapeutic interest of the compounds of the former series in combination with taxanes was confirmed in a human tumor xenograft model. PMID- 21324704 TI - Discovery of novel (4-piperidinyl)-piperazines as potent and orally active acetyl CoA carboxylase 1/2 non-selective inhibitors: F-Boc and triF-Boc groups are acid stable bioisosteres for the Boc group. AB - Novel (4-piperidinyl)-piperazine derivatives were synthesized and evaluated as ACC1/2 non-selective inhibitors. Optimization of the substituents on the nitrogen of the piperidine ring led to the identification of the fluorine substituted tert butoxycarbonyl group. Advanced analog, 1,1,1-trifluoro-2-methylpropan-2-yl 4-{4 [(2-amino-6-methyl-1-benzothiophen-3-yl)carbonyl]piperazin-1-yl}piperidine-1 carboxylate (12c) showed potent inhibitory activities in enzyme-assay and cell based assays. Compound 12c also exhibited reduction of hepatic de novo fatty acid synthesis in rats after oral administration. PMID- 21324705 TI - Natural radioactivity and rare earth elements in feldspar samples, Central Eastern desert, Egypt. AB - The pegmatite bodies of the Eastern Desert of Egypt are widely distributed especially along the Marsa-Alam-Idfu road. The Abu Dob area covers about 150km(2) of the Arabian Nubian shield at the central part of the Eastern Desert of Egypt. Most of the pegmatite is zoned; the zonation starts with milky quartz at the core followed by alkali feldspar at the margins. The feldspars vary in color from rose to milky and in composition from K-feldspar to Na-feldspar, sometimes interactions of both types are encountered. Thirteen feldspar samples were collected from different locations in the Abu Dob area for measuring the natural radioactivity of (238)U, (232)Th and (40)K using an HPGe detector. The variation in concentration of radionuclides for the area under investigation can be classified into regions of high, medium and low natural radioactivity. The average concentration in BqKg(-1) has been observed to be from 9.5 to 183675.7BqKg(-1) for (238)U, between 6.1 and 94,314.2BqKg(-1) for (232)Th and from 0 to 7894.6BqKg(-1) for (40)K. Radium equivalent activities (Ra(eq)), dose rate (D(R)) and external hazard (H(ex)) have also been determined. In the present work, the concentration of rare earth elements are measured for two feldspar samples using two techniques, Environmental Scanning Electron microscope XIL 30 ESEM, Philips, and Inductively Coupled Plasma Mass Spectroscopy (ICP-MS). The existence of rare earth elements in this area are very high and can be used in different important industries. PMID- 21324706 TI - The study of a SPATULA-like bHLH transcription factor expressed during peach (Prunus persica) fruit development. AB - Extensive studies on the dry fruits of the model plant arabidopsis (Arabidopsis thaliana) have revealed various gene regulators of the development and dehiscence of the siliques. Peach pericarp is analogous to the valve tissues of the arabidopsis siliques. The stone (otherwise called pit) in drupes is formed through lignification of the fruit endocarp. The lignified endocarp in peach can be susceptible to split-pit formation under certain genetic as well as environmental factors. This phenomenon delays processing of the clingstone varieties of peach and causes economical losses for the peach fruit canning industry. The fruitfull (FUL) and shatterproof (SHP) genes are key MADS-box transcription protein coding factors that control fruit development and dehiscence in arabidopsis by promoting the expression of basic helix-loop-helix (bHLH) transcription factors like Spatula (SPT) and Alcatraz (ALC). Results from our previous studies on peach suggested that temporal regulation of PPERFUL and PPERSHP gene expression may be involved in the regulation of endocarp margin development. In the present study a PPERSPATULA-like (PPERSPT) gene was cloned and characterized. Comparative analysis of temporal regulation of PPERSPT gene expression during pit hardening in a resistant and a susceptible to split-pit variety, suggests that this gene adds one more component to the genes network that controls endocarp margins development in peach. Taking into consideration that no ALC-like genes have been identified in any dicot plant species outside the Brassicaceae family, where arabidopsis belongs, PPERSPT may have additional role(s) in peach that are fulfilled in arabidopsis by ALC. PMID- 21324707 TI - Tetrahydrobiopterin improves cardiac and pulmonary function after cardiopulmonary bypass. AB - OBJECTIVE: Tetrahydrobiopterin (BH4) is an important cofactor of endogenous nitric oxide synthesis. In the present preclinical study, we investigated the effects of BH4 on cardiac and pulmonary function during early reperfusion in an experimental model of cardioplegic arrest and extracorporal circulation. METHODS: Twelve anesthetized dogs underwent hypothermic cardiopulmonary bypass. After 60 min of hypothermic cardiac arrest, reperfusion was started after application of either saline vehicle (control, n = 6), or BH4 (n = 6). Left-ventricular end systolic pressure volume relationship (E(es)) was measured by a combined pressure volume conductance catheter at baseline and after 60 min of reperfusion. Left anterior descending (LAD) coronary (CBF) and pulmonary blood flow (PBF), endothelium-dependent vasodilatation to acetylcholine (ACh), endothelium independent vasodilatation to sodium nitroprusside (SNP) and alveolo-arterial O2 gradient were determined. RESULTS: The administration of BH4 led to a significantly better recovery of E(es) (given as percent of baseline: 85 +/- 22 vs 46 +/- 15%, p<0.05). CBF was also significantly higher in the BH4 group (38 +/ 5 vs 22 +/- 5 ml min-1, p<0.05). While the vasodilatatory response to SNP was similar in both groups, injection of ACh resulted in a significantly higher increase in CBF (64 +/- 12 vs 25 +/- 12%, p < 0.05) and PBF (49 +/- 15 vs 36 +/- 14%, p<0.05) in the BH4-treated animals. Alveolo-arterial O2 gradient was significantly lower after BH4 supplementation (80 +/- 15 vs 49 +/- 14 mm Hg, p < 0.05). CONCLUSIONS: Application of BH4 improves myocardial, endothelial and pulmonary function after cardiopulmonary bypass with hypothermic cardiac arrest. The observed protective effects indicate that BH4 could be a novel therapeutic option in the treatment of ischemia/reperfusion injury. PMID- 21324708 TI - Lady Windermere revisited: treatment with thoracoscopic lobectomy/segmentectomy for right middle lobe and lingular bronchiectasis associated with non-tuberculous mycobacterial disease. AB - OBJECTIVE: Lady Windermere syndrome is a well-known but poorly understood female predominant phenotype of isolated right middle lobe and lingular bronchiectasis associated with non-tuberculous mycobacterial (NTM) infection. Despite lengthy multidrug antibiotic treatment, the presence of damaged parenchymal tissue leads to symptomatic disease recurrence, often with resistant organisms. The use of surgical resection as an adjunct to medical therapy may alter this cycle, although little is known about the use of thoracoscopic lung resection in this patient population. METHODS: This is a retrospective review of a prospectively collected database of patients with pulmonary NTM disease from July 2004 to December 2009. All patients had focal bronchiectasis of the right middle lobe and lingula, treated with targeted antimicrobial therapy for several months prior to resection. RESULTS: A total of 134 patients underwent 172 operations, with 38 patients having staged bilateral resections. The cohort was predominately female (96%) and Caucasian (95%), with a mean age of 59 years (range 34-81 years). Using a thoracoscopic approach in all patients, 102 middle lobectomies and 70 lingulectomies were performed. Conversion to open thoracotomy occurred in five cases (3%). Secondary procedures were performed in 20 cases (12%). There was no operative mortality. Postoperative morbidity was noted following 12 operations (7%), primarily consisting of prolonged air leak. The mean length of stay was 3.3 days (range 1-15 days). CONCLUSIONS: Although medical therapy remains the primary treatment modality for patients with pulmonary NTM disease, the selective use of pulmonary resection may reduce the incidence of symptomatic disease recurrence. The addition of thoracoscopic resection to treatment regimens for patients with Lady Windermere syndrome can be accomplished with minimal morbidity and mortality. PMID- 21324709 TI - Photoactivation of corticosteroids in UVB-exposed skin. AB - The photodegradation of flumethasone (FM) and fluocinolone acetonide (FC) was studied in solution and in the pig skin. Both glucocorticosteroids applied to the pig skin were unstable under UVB light. The photoproducts formed in the skin were the lumi-, photolumi- and andro-derivatives for FM, the same found in vitro. Instead, FC hydroperoxide formed in solution was not found in the skin: the reactivity and oxidative ability of this photoproduct towards biological substrates (lipids, proteins) seems the reason of the lack of its detection in the ex vivo model. In fact, it demonstrated to quickly oxidize amino acids and peptides, and to react with BSA both in the dark and under irradiation. Moreover, the presence in the irradiated pig skin of the FC andro-derivative, which usually forms in H-donating environment, seems consistent with the mechanism of Norrish I fragmentation followed by H-abstraction, likely from the surrounding biological substrates. These findings indicate that photoreactivity of these compounds may take place in the skin of patients exposing themselves to sunlight and is a warning about possible skin damage as a result of that. Furthermore, photolability of these drugs in the skin might cause loss of their therapeutic activity. PMID- 21324710 TI - Photodamage of a Mn(III/IV)-oxo mixed-valence compound and photosystem II: evidence that a high-valent manganese species is responsible for UV-induced photodamage of the oxygen-evolving complex in photosystem II. AB - The Mn cluster in photosystem II (PS II) is believed to play an important role in the UV photoinhibition of green plants, but the mechanism is still not clear at a molecular level. In this work, the photochemical stability of [Mn(III)(O)(2)Mn(IV)(H(2)O)(2)(Terpy)(2)](NO(3))(3) (Terpy=2,2':6',2'' terpyridine), designated as Mn-oxo mixed-valence dimer, a well characterized functional model of the oxygen-evolving complex in PS II, was examined in aqueous solution by exposing the complex to excess light irradiation at six different wavelengths in the range of 250 to 700 nm. The photodamage of the Mn-oxo mixed valence dimer was confirmed by the decrease of its oxygen-evolution activity measured in the presence of the chemical oxidant oxone. Ultraviolet light irradiation induced a new absorption peak at around 400-440 nm of the Mn-oxo mixed-valence dimer. Visible light did not have the same effect on the Mn-oxo mixed-valence dimer. We speculate that the spectral change may be caused by conversion of the Mn(III)O(2)Mn(IV) dimer into a new structure--Mn(IV)O(2)Mn(IV). In the processes, the appearance of a 514 nm fluorescence peak was observed in the solution and may be linked to the hydration or protonation of Terpy ligand in the Mn-oxo dimer. In comparing the response of the PS II functional model compound and the PS II complex to excess light radiation, our results support the idea that UV photoinhibition is triggered at the Mn(4)Ca center of the oxygen evolution complex in PS II by forming a modified structure, possibly a Mn(IV) species, and that the reaction of Mn ions is likely the initial step. PMID- 21324711 TI - The severe sepsis bundles as processes of care: a meta-analysis. AB - OBJECTIVE: The use of the sepsis bundles in patients with severe sepsis and septic shock has been controversial in the last decade. Clinical studies have reported beneficial, as well as negative results. We conducted a meta-analysis to assess the clinical evidence and to evaluate survival effects. DATA SOURCE: Database searches (2004-current) of Medline, CINAHL, Pubmed, Cochrane, Scopus and Google scholar databases which covered full publications, abstracts from conferences and digital thesis were performed using the search terms sepsis, septic shock and/or bundles, processes of care, guidelines, early goal directed therapy, resuscitation. RESULTS: From 253 identified studies, 21 sepsis bundle original studies were selected and included 23,438 patients. The Resuscitation 6 hour Bundle pooled analysis (1819 patients) achieved the greatest survival benefit (odds ratio (OR) 2.124, 95% CI 1.701-2.651, p<0.000) with the Management 24 hour Bundle pooled analysis the lowest survival benefit (16,521 patients) (OR 1.646, 95% CI 1.036-2.614, p<0.035). Both bundles together (Complete Bundle) achieved a combined survival benefit (OR 1.744, 95% CI 1.421-2.141, p<0.000). ScvO2 and blood glucose components were analysed individually to assess their contribution to survival. CONCLUSION: The Resuscitation 6 hour bundle in the context of the patient population at hand is unlikely to do harm and is yet to be established in primary research in Australia. The Management 24 hour Bundle could not establish a strong enough survival benefit above current routine practice. The sepsis guidelines and bundles have demanded more credible process measurements and debate to induce positive changes in the intervention and treatment care of patients with severe sepsis. PMID- 21324712 TI - Histamine differentially regulates the production of Th1 and Th2 chemokines by keratinocytes through histamine H1 receptor. AB - Histamine is a biological amine that plays an important role in allergic responses. However, the involvement of histamine signaling in late allergic responses in the skin is poorly understood. Therefore, we attempted to investigate the involvement of histamine signaling in late allergic responses, especially in keratinocytes (KCs). HaCaT KCs and normal human KCs (NHKs) predominantly expressed histamine H1 receptor (H1R) and H2 receptor (H2R). Histamine suppressed tumor necrosis factor alpha (TNF-alpha)- and interferon gamma (IFN-gamma)-induced production of CC chemokine ligand 17(CCL17), a type 2 T helper (Th2) chemokine, by HaCaT KCs. It suppressed the phosphorylation of p38 mitogen-activated protein (MAP) kinase, but not that of extracellular signal regulated kinases (ERKs), and TNF-alpha- and IFN-gamma-induced nuclear factor kappaB (NFkappaB) activity. In contrast, histamine enhanced the production of CXC chemokine ligand 10 (CXCL10), a Th1 chemokine, by TNF-alpha- and IFN-gamma stimulated HaCaT KCs and NHKs. TNF-alpha- and IFN-gamma-induced CXCL10 production was upregulated by suppression of p38 MAP kinase or NF-kappaB activity, which could explain histamine involvement. We concluded that histamine suppresses CCL17 production by KCs by suppressing p38 MAP kinase and NF-kappaB activity through H1R and may act as a negative-feedback signal for existing Th2-dominant inflammation by suppressing CCL17 and enhancing CXCL10 production. PMID- 21324713 TI - Erythropoietin and hypoxia increase erythropoietin receptor and nitric oxide levels in lung microvascular endothelial cells. AB - Acute lung exposure to low oxygen results in pulmonary vasoconstriction and redistribution of blood flow. We used human microvascular endothelial cells from lung (HMVEC-L) to study the acute response to oxygen stress. We observed that hypoxia and erythropoietin (EPO) increased erythropoietin receptor (EPOR) gene expression and protein level in HMVEC-L. In addition, EPO dose- and time dependently stimulated nitric oxide (NO) production. This NO stimulation was evident despite hypoxia induced reduction of endothelial NO synthase (eNOS) gene expression. Western blot of phospho-eNOS (serine1177) and eNOS and was significantly induced by hypoxia but not after EPO treatment. However, iNOS increased at hypoxia and with EPO stimulation compared to normal oxygen tension. In accordance with our previous results of NO induction by EPO at low oxygen tension in human umbilical vein endothelial cells and bone marrow endothelial cells, these results provide further evidence in HMVEC-L for EPO regulation of NO production to modify the effects of hypoxia and cause compensatory vasoconstriction. PMID- 21324714 TI - Ketamine as a primary predictor of out-of-body experiences associated with multiple substance use. AB - Investigation of "out-of-body experiences" (OBEs) has implications for understanding both normal bodily-self integration and its vulnerabilities. Beyond reported associations between OBEs and specific brain regions, however, there have been few investigations of neurochemical systems relevant to OBEs. Ketamine, a drug used recreationally to achieve dissociative experiences, provides a real world paradigm for investigating neurochemical effects. We investigate the strength of the association of OBEs and ketamine use relative to other common drugs of abuse. Self-report data (N=192) from an online survey indicate that both lifetime frequency of ketamine use and OBEs during ketamine intoxication were more strongly related to the frequency of OBEs and related phenomena than other drugs. Moreover, the apparent effects of other drugs could largely be explained by associated ketamine use. The present results, consistent with the role of NMDA receptors in OBEs, should encourage future studies of the role of neurochemical systems in OBEs. PMID- 21324715 TI - Factors predicting complication rates after primary shoulder arthroplasty. AB - HYPOTHESIS: Shoulder arthroplasty is an effective treatment for arthritic conditions and intraarticular fractures of the proximal humerus. Treatment options include total and hemiarthroplasty of the shoulder. They hypothesis of this study was that a mandatory statewide discharge database could identify the epidemiology of primary shoulder arthroplasty, 90 day complication rates, implant survival rates, and patient and hospital characteristics associated with complications. MATERIALS AND METHODS: We identified patients undergoing primary total shoulder replacement and hemiarthroplasty between 1995 and 2005. We report rates of complications within 90 days of surgery and performed survival analysis using revision surgery as the endpoint. Logistic and proportional hazard regression models were used to estimate the effect of patient and provider factors in predicting the rates of adverse outcomes. RESULTS: During the study period, 15,288 patients underwent shoulder arthroplasty. Patients undergoing total shoulder arthroplasty and hemiarthroplasty had no statistically significant difference in the aggregate risk of 90-day complications or the risk of implant failure within the study period. Fracture patients were shown to have a higher risk of short-term complications (odds ratio, 3.2; P < .001). Implant failure rates were lower in patients with fracture, rheumatoid arthritis, increased comorbidity, and advanced age. CONCLUSION: This study reports similar rates of short-term complications and implant failure in patients undergoing total or hemiarthroplasty, an overall mortality rate of 1.3%, and a pulmonary embolism rate of 0.6%. The findings of our study indicate that the risk of short-term complications is highest in patients undergoing total or hemiarthroplasty for a fracture compared with nonfracture indications. Our results also indicate that longer-term, implant survival is largely driven by factors associated with increased activity, such as age. In patients undergoing surgery for arthritis of the shoulder, we found no difference in implant survival rates between total and hemiarthroplasty of the shoulder. PMID- 21324716 TI - Comparison of standard two-dimensional and three-dimensional corrected glenoid version measurements. AB - HYPOTHESIS: There is concern regarding the accuracy of 2-dimensional (2D) computed tomography (CT) for measuring glenoid version. Three-dimensional (3D) CT scan reconstructions can properly orient the glenoid to the plane of the scapula and have been reported to accurately measure glenoid version in cadaver models. We hypothesized that glenoid version measured by correcting 2D CT scans to the plane of the scapula by 3D reconstruction would be significantly different compared with standard 2D CT scan measurement of the glenoid in a clinical patient population. MATERIALS AND METHODS: Thirty-four patients underwent dedicated axial 2D CT scan of the shoulder with 3D reconstruction. The 2D glenoid version was measured on unmodified midglenoid axial cuts, and the 3D glenoid version measurement was corrected to be perpendicular to the plane of the scapula and then measured in the axial plane. Three observers repeated each measurement on 2 different days. RESULTS: The difference between the overall average 2D and 3D measurements was not statistically significant (P = .45). In individual scapulae, 35% of 2D measurements were 5 degrees to 10 degrees different and 12% were greater than 10 degrees different from their corresponding 3D-corrected CT measurement (P < .001 to P = .045). Reproducibility of both 2D and 3D-corrected measurements was good. DISCUSSION: Although 2D and 3D corrected methods showed a high degree of both intraobserver and interobserver reliability in this series, axial 2D images without correction were 5 to 15 degrees different than their 3D corrected counterparts in 47% of all measurements. Correcting 2D glenoid version by 3D reconstruction to the transverse plane perpendicular to the scapular body allows for an accurate assessment of glenoid version in spite of positioning differences and results in increased accuracy while maintaining high reliability. CONCLUSIONS: Owing to the variability in scapular position, the axial 2D CT scan measurement was significantly different from 3D-corrected measurement of glenoid version. Averaging the version measurements across patients did not reflect this finding. PMID- 21324717 TI - A new technique for cementation of the humeral component in elbow arthroplasty: a cadaveric study. PMID- 21324718 TI - Open or endovascular repair of aortoenteric fistulas? A multicentre comparative study. AB - OBJECTIVES: To compare aortoenteric fistula (AEF) outcome after endovascular (EV AEFR) or open repair (O-AEFR). DESIGN: Multicentre retrospective comparative study. MATERIALS/METHODS: 25 patients with AEF (24 secondary, 23 males, median age 75 years) after aortic surgery (median four years). Preoperative sepsis was evident in 19 cases. Eight patients were managed with EV-AEFR and 17 with O-AEFR. RESULTS: The two groups were comparable in preoperative characteristics. In hospital mortality after EV-AEFR was lower compared to O-AEFR (0% and 35%, respectively, p = 0.13). Similarly, morbidity after EV-AEFR was lower compared to O-AEFR (25% and 77%, respectively, p = 0.028). There was a trend for worse recurrence-free, sepsis-free, re-operation-free and AEF-related death-free rates after EV-AEFR, while the early survival advantage of EV-AEFR was lost after two years and the overall long-term survival rates (perioperative mortality included) of the two groups were similar. Preoperative sepsis had no effect on recurrence and sepsis-free rates (p = 0.94 and p = 0.92, respectively), but it was associated with worse two year overall survival (24% vs 50%, p = 0.32). On multivariate analysis, the number of symptoms (two vs one) at presentation was the single predictor of worse re-operation rates, AEF-related and overall survival. CONCLUSIONS: EV-AEFR was associated with no postoperative mortality in this study and can achieve satisfactory short and long-term results, comparable to O-AEFR. Further trials should focus on the role of EV-AEFR in patients at high risk for O-AEFR, due to shock or co-morbidities, or as a bridging procedure. PMID- 21324719 TI - An updated method for the isolation and culture of primary calf hepatocytes. AB - Primary hepatocytes are commonly used during in vitro studies, but care must be taken with isolation and culture of the cells to ensure their viability. In this study, hepatocytes were isolated from the liver (caudate process) of a newborn calf by the collagenase perfusion and digestion method. The trypan blue exclusion method was used to determine total cell number and the survival rate of hepatocytes, while hepatocyte function was assessed by measuring lactate dehydrogenase, albumin and urea in culture medium supernatants at 24, 48, 72, 96, 120, 144 and 168 h. Results showed that the number of viable cells/g of liver (wet weight) averaged 1.12*10(7) cells/g, with an average hepatocyte viability of 85.7% (range 83-92%). After 48 h of culture, the hepatocytes solidly adhered to the well culture plate and were spread in an epithelioid shape, with clear cell boundaries between the cells and biliary ductule-like structures formed which persisted for up to 10 days. Hepatocyte function was optimal at 72 h after isolation and culture. This simple and economical procedure for the isolation and culture of viable cells may be useful for in vitro bovine hepatocyte studies. PMID- 21324720 TI - Numerical simulation of NQR/NMR: Applications in quantum computing. AB - A numerical simulation program able to simulate nuclear quadrupole resonance (NQR) as well as nuclear magnetic resonance (NMR) experiments is presented, written using the Mathematica package, aiming especially applications in quantum computing. The program makes use of the interaction picture to compute the effect of the relevant nuclear spin interactions, without any assumption about the relative size of each interaction. This makes the program flexible and versatile, being useful in a wide range of experimental situations, going from NQR (at zero or under small applied magnetic field) to high-field NMR experiments. Some conditions specifically required for quantum computing applications are implemented in the program, such as the possibility of use of elliptically polarized radiofrequency and the inclusion of first- and second-order terms in the average Hamiltonian expansion. A number of examples dealing with simple NQR and quadrupole-perturbed NMR experiments are presented, along with the proposal of experiments to create quantum pseudopure states and logic gates using NQR. The program and the various application examples are freely available through the link http://www.profanderson.net/files/nmr_nqr.php. PMID- 21324721 TI - [Influence of communicating the diagnosis and the prognosis on the suffering of the terminal patient]. PMID- 21324722 TI - [Evaluation of new and emerging health technologies. Proposal for classification]. AB - AIMS: Review and develop a proposal for the classification of health technologies (HT) evaluated by the Health Technology Assessment Agencies (HTAA). DESIGN: Peer review of AETS of the previous proposed classification of HT. Analysis of their input and suggestions for amendments. Construction of a new classification. Pilot study with physicians. SETTING: Andalusian Public Health System. Spanish HTAA. PARTICIPANTS: Experts from HTAA. Tutors of family medicine residents. METHOD: HT Update classification previously made by the research team. Peer review by Spanish HTAA. Qualitative and quantitative analysis of responses. Construction of a new and pilot study based on 12 evaluation reports of the HTAA. RESULTS: We obtained 11 thematic categories that are classified into 6 major head groups: 1, prevention technology; 2, diagnostic technology; 3, therapeutic technologies; 4, diagnostic and therapeutic technologies; 5, organizational technology, and 6, knowledge management and quality of care. In the pilot there was a good concordance in the classification of 8 of the 12 reports reviewed by physicians. CONCLUSIONS: Experts agree on 11 thematic categories of HT. A new classification of HT with double entry (Nature and purpose of HT) is proposed. APPLICABILITY: According to experts, the classification of the work of the HTAA may represent a useful tool to transfer and manage knowledge. Moreover, an adequate classification of the HTAA reports would help clinicians and other potential users to locate them and this can facilitate their dissemination. PMID- 21324723 TI - Clinical impact of fluoroquinolone prophylaxis in neutropenic patients with hematological malignancies. AB - BACKGROUND: The routine use of fluoroquinolone prophylaxis in patients with neutropenia and hematological malignancies is controversial. This prophylaxis has been reported to have a positive impact in reducing infection-related mortality, but the consequent development of antibiotic resistance has become a concern. This study assessed the effect of discontinuing quinolone prophylaxis on the etiology and the resistance pattern of blood culture isolates and on the prognosis among febrile neutropenic patients receiving chemotherapy. METHODS: The results of blood cultures obtained from febrile neutropenic patients between January 2003 and June 2009 were analyzed; these results were available through a computer database set up in 2003. RESULTS: Patients receiving quinolone prophylaxis between 2003 and 2005 showed a lower incidence of Gram-negative bacteria than patients not receiving prophylaxis between 2006 and 2009 (13.5%, n=9 vs. 48.1%, n=75). Interestingly, after discontinuing prophylaxis, approximately 70% of the Gram-negative bacteria isolated were quinolone resistant, and some were extended-spectrum beta-lactamase (ESBL) producers. The frequencies of quinolone-resistant Gram-positive bacteria isolated were similar between the period of quinolone prophylaxis and the period with no prophylaxis (61.1% vs. 64.3%). In both periods, all Gram-positive isolates were sensitive to vancomycin. The infection-related mortality was comparable between patients receiving prophylaxis and those not receiving prophylaxis (1.5%, n=1 vs. 1.3%, n=2). CONCLUSIONS: These findings suggest that quinolone prophylaxis for neutropenia does not induce a significant increase in the growth of quinolone- and multidrug-resistant bacteria. Rather, discontinuing quinolone prophylaxis may induce a dramatic increase in the growth of Gram-negative bacteria, including ESBL producers. Our results suggest that the necessity for quinolone prophylaxis in neutropenic patients should be determined based on local antibiotic resistance patterns. PMID- 21324724 TI - [Predictive factors of response to anthracyclines neoadjuvant chemotherapy in breast cancer]. AB - OBJECTIVES: Anthracyclines chemotherapy remains primordial and impossible to circumvent in the treatment of breast cancer, in the adjuvant, metastatic and neoadjuvant setting. But some breast invasive tumors are resistant to anthracyclines. The neoadjuvant model is ideal to test the chemosensibility by selecting the well-responder patients and identifying the predictive factors of this response. PATIENTS AND METHODS: We report a retrospective study of 126 patients treated at our institute during 2 years (January 2003-December 2004) for a breast cancer with primary chemotherapy. All the patients received anthracyclines according to protocol AC60 (doxorubicine plus cyclophosphamide). RESULTS: The clinical objective response rate (RO) was 67 % with a complete clinical response (RC) of 11 %. We found a pathological complete response (pCR) in seven patients (5,6 %) of the 126 cases. The statistical study identifies only two clinical factors as predictive of RC and pCR: tumoral size T2-T3 and clinical nodal status N0-N1, while the SBR grading and the hormonal receptors were not correlated. DISCUSSION AND CONCLUSION: Some clinical and histological factors are recognized as predictive for the benefit of anthracyclines neoadjuvant chemotherapy, and correlated to the pCR; we discuss our results through those of the literature, by exposing the current data. PMID- 21324725 TI - [Residents in gynecology-obstetrics: are we concerned by burn out?]. PMID- 21324726 TI - Room temperature synthesis of crystalline CeO2 nanopowder: advantage of sonochemical method over conventional method. AB - In the present study, nano-sized ceria (CeO(2)) powders were prepared using conventional and sonochemically assisted precipitation method, without any stabilizers, using cerium nitrate as a starting material and sodium hydroxide as a precipitating agent. The synthesized ceria powders were characterized by XRD, TGA and SEM to determine crystallite size, % crystallinity, thermal weight loss and shape respectively. It was found that the crystallite size obtained in both the synthesis methods were below 30 nm. It was also found that sonochemical synthesis method is energy efficient method saving more than 92% of energy as compared to that utilized by the conventional synthesis method. There was also a significant reduction in the reaction duration. PMID- 21324727 TI - Strengthening access to restorative places: findings from a participatory study on engaging with nature in the promotion of health. AB - In this paper, we examine selected research findings from a community-based study on engaging with nature to promote health. Combining participatory photographic research methods with an iterative process of dialectical analysis, we explored nature-based health promotion with community citizens, practitioners, and decision-makers from various sectors to examine the complexities of connecting with natural outdoor places in local contexts. Participants identified an array of barriers to and opportunities for everyday access to restorative outdoor places. The findings suggest that inter-sectoral governance with active citizen engagement in research, decision-making, and action may be essential to develop the ecological citizenship and communal norms and strategies that promote the health of people and their shared restorative places. PMID- 21324728 TI - Evaluation of MYB promoter methylation in salivary adenoid cystic carcinoma. AB - The transcription factor MYB was recently proposed to be a promising oncogene candidate in salivary gland adenoid cystic carcinoma (ACC). However, the up regulation of MYB in ACC could not be explained solely by deletion of its 3' end. It is widely accepted that the promoter methylation status can regulate the transcription of genes, especially in human cancers. Therefore, it is important to know whether MYB promoter demethylation could explain the over-expression of MYB in ACC. By using the Methprimer program, we identified nine CpG islands in the promoter of MYB. All of these CpG islands were located within the -864 to +2082 nt region relative to the transcription start site of MYB. We then used bisulfite genomic sequencing to evaluate the methylation levels of the CpG islands of MYB in 18 primary ACC tumors, 13 normal salivary gland tissues and nine cancer cell lines. Using cell lines, we also determined the relative MYB expression levels and correlated these with the methylation levels. With bisulfite genomic sequencing, we found no detectable methylation in the CpG islands of MYB in either ACC or normal salivary gland tissues. There was a variable degree of MYB expression in the cell lines tested, but none of these cell lines demonstrated promoter methylation. Promoter hypomethylation does not appear to explain the differential expression of MYB in ACC. An alternative mechanism needs to be proposed for the transcriptional control of MYB in ACC. PMID- 21324729 TI - The evidence for the occurrence of tautomeric structures for selected aldehydes and thioaldehydes. AB - Mass spectra of selected aldehydes and thioaldehydes have been analyzed and specific fragmentation assignments have been done to keto and enol tautomers, although many peaks can be assigned to both forms (i.e. mass spectra are superimposed on one another). The enolization rate for aldehydes is generally favored by the increase in the steric effect caused by alpha substitution to the carbonyl group. The analysis of the corresponding mass spectra has allowed to establishing an acceptable correlation between selected ion abundances ratios and approximate enolization equilibrium constants (carried out by means of DFT calculations). The influence of temperature on the enol/keto selected fragments abundance ratios (for different aldehydes and thioaldehydes and for different pair of ions of the same compound whenever possible) is studied in order to estimate the enthalpy difference for the tautomeric equilibria. The results indicate that the thioketo-thioenol equilibrium can be studied by mass spectrometry and the ionization in the ion source have negligible effect on the position of that equilibrium. PMID- 21324730 TI - Vibrational analysis of 1-methyl-pyridinium-2-aldoxime and 1-methyl-pyridinium-4 aldoxime cations. AB - Pyrimidinium aldoximes are administered intravenously in cases of acute organophosphate poisoning. Since questions regarding their morphology and active conformation in the solution are still open, an effort was made to establish correspondence between their crystal state conformers and vibrational spectra, thus facilitating the future work on the assignment of bands in solution. Normal coordinate analysis including the potential energy distribution for all modes was performed for 1-methyl-pyridinium-2-aldoxime (PAM2AN) and 1-methyl-pyridinium-4 aldoxime (PAM4AN) cations (charge=+e, spin=0). Positions of infrared and Raman bands of corresponding chloride salts agree rather well with predicted values, except for modes taking part in hydrogen bonding to anions. The strength of hydrogen bonding is estimated to be of medium strength in both salts, the bonding in PAM2AN being stronger. The calculated and observed values of the characteristic stretching modes for the aldoxime moiety have been in accordance with the stronger acidity of PAM2AN structural isomer. PMID- 21324731 TI - Hydrothermal synthesis, experimental and theoretical characterization of a novel cocrystal compound in the 2:1 stoichiometric ratio containing 6-methyluracil and dipicolinic acid. AB - This paper reports the hydrothermal synthesis, experimental and theoretical studies of a novel cocrystal compound in the 2:1 stoichiometric ratio of 6 methyluracil (6mu) and dipicolinic acid (pydcH(2)) formulated as [6mu](2)[pydcH(2)] (1), for the first time. DFT calculations were performed to access the most possible geometry of the title cocrystal compound. All calculations were carried out with the B3LYP hybrid density functional level and 6-311+G(d,p) basis sets. The vibrational frequencies together with the (1)H and (13)C NMR chemical shifts have been calculated on the fully optimized geometry of 1. The theoretical results are in good agreement with the experimental and solution data. The theoretical, solution, and experimental (elemental analysis, mass spectrometry, FTIR, (1)H and (13)C NMR spectroscopies) results confirmed our proposed structure for 1 in the 2:1 stoichiometric ratio of 6mu and pydcH(2), respectively. The protonation and equilibrium constants of 6mu and pydcH(2) and constituent systems were determined by potentiometric studies and the corresponding distribution diagrams depicted. PMID- 21324732 TI - Brown diamonds from an eclogite xenolith from Udachnaya kimberlite, Yakutia, Russia. AB - We have performed petrographic and spectroscopic studies of brown diamonds from an eclogite xenolith from the Udachnaya pipe (Yakutia, Russia). Brown diamonds are randomly intermixed with colorless ones in the rock and often located at the grain boundaries of clinopyroxene and garnet. Brown diamonds can be characterized by a set of defects (H4, N2D and a line at 490.7 nm) which are absent in colorless diamonds. This set of defects is typical for plastically deformed diamonds and indicates that diamonds were likely annealed for a relatively short period after deformation had occurred. Excitation of brown colored zones with a 632.8 nm He-Ne laser produced the typical diamond band plus two additional bands at 1730 cm(-1) and 3350 cm(-1). These spectral features are not genuine Raman bands, and can be attributed to photoluminescence at ~710 nm (1.75 eV) and ~802 nm (1.54 eV). No Raman peak corresponding to graphite was observed in regions of brown coloration. Comparison with previous reports of brown diamonds from eclogites showed our eclogitic sample to have a typical structure without signs of apparent deformation. Two mechanisms with regard to diamond deformation are proposed: deformation of eclogite by external forces followed by subsequent recrystallization of silicates or, alternatively, deformation by local stress arising due to decompression and expansion of silicates during ascent of the xenolith to surface conditions. PMID- 21324733 TI - Spectral, thermal and electrochemical characterization of novel homo-dinuclear complexes [M2(H3DTPA)(H2O)6]Cl2.xH2O (M=Cr2+, Mn2+, Co2+, Ni2+ or Cu2+). AB - The title complexes were prepared and characterized employing spectral (FAB-Mass, IR, electronic, (1)H and (13)C NMR), thermal and electrochemical techniques. Analytical and FAB-Mass data suggested a homo-dinuclear stoichiometry. IR and electronic ligand field spectral studies coupled with molecular model computations have indicated a distorted octahedral geometry where the ligand coordinates as a hexadentate dianionic [H(3)DTPA](2 )(H(5)DTPA=diethylenetriaminepentaacetic acid) moiety. The electrochemical redox properties and the antibacterial activities of the compounds were also investigated. PMID- 21324734 TI - Genital ulcerations due to a cowpox virus: a misleading diagnosis of herpes. PMID- 21324735 TI - Multicenter prospective evaluation of a novel rapid immunochromatographic diagnostic kit specifically detecting influenza A H1N1 2009 virus. AB - BACKGROUND: Definitive diagnosis is crucial in reducing morbidity and mortality from pandemic influenza A H1N1 2009 (A/H1N1/2009), especially in high-risk populations. We recently developed a rapid diagnosis kit (RDK) capable of specifically detecting A/H1N1/2009. OBJECTIVES: To evaluate the diagnostic capability of the RDK in a multicenter, prospective trial. STUDY DESIGN: Samples were obtained by nasal swab from patients with suspected influenza. The diagnostic capability of the RDK was compared with that of the standard, real time reverse transcription-polymerase chain reaction (RT-PCR) method. RESULTS: Of 266 patients who met the criteria, 122 and 92 were positive for A/H1N1/2009 influenza by PCR and by the newly developed RDK, respectively. The sensitivity, specificity and positive and negative predictive values of the RDK were 73.0%, 97.9%, 96.7% and 81.0%, respectively. A/H1N1/2009 detection rates by the RDK were significantly lower in samples obtained from patients more than 3 days after onset than in samples obtained between 1 and 2 days. CONCLUSIONS: The A/H1N1/2009 specific RDK is a reliable test that can be used easily at a patient's bedside for rapid diagnosis of A/H1N1/2009. This test will be of key importance in the control of A/H1N1/2009. PMID- 21324736 TI - Cremaster muscle motor unit action potentials. AB - OBJECTIVE: Motor unit action potentials (MUAPs) of human striated cremaster muscle (CM) have not been analysed previously, so we examined the MUAPs of the CM, to learn more about the physiology of this unusual striated muscle that works mostly without voluntary control. METHODS: MUAPs of human CM were investigated in 31 normal subjects. MUAPs were elicited by either a voluntarily contraction effort or mostly by the reflex response to the tactile stimulation of the inner thigh. Concentric needle study of jitter was also performed in 10 normal subjects. RESULTS: The total number of MUAPs was 289. Approximately 40% of all MUAPs were classified as simple MUAPs (mean duration 4.7 +/- 1.7 ms), and the remainder were polyphasic potentials (mean duration 10.1 +/- 3.9 ms). In jitter study, only 29 potential pairs were obtained. There was an increase in jitter value and intermittent blocking. The mean jitter value was 81.9 +/- 56.8 MUs. The MUAPs longer than 20 ms sometimes grouped as a single long potential or as different subgroups with time intervals between them. CONCLUSION: The EMG results were similar to those obtained from patients with chronic neurogenic disorders despite the fact that the CMs studied were clinically and functionally normal in our healthy male subjects. SIGNIFICANCE: These findings suggest that the CM is an "embryogenic" striated muscle with polyneural innervation both at the muscle fibre and/or at the spinal cord level in adult males. Thus the CM has a weak cortical control but mostly excited by the cutaneous inputs. PMID- 21324737 TI - High-throughput, high-level production of PS-tag-fused single-chain Fvs by microplate-based culture. AB - In the present study, we investigated a microplate-based culture (MBC) of Escherichia coli for the high-throughput, high-level production of PS-tag-fused scFvs (scFv-PS) in insoluble form. The Overnight ExpressTM Autoinduction System (OE system) was adopted to skip the laborious induction step of the addition of IPTG. ScFv and scFv-PS began to be expressed after 6h by conventional flask culture (FLC) and by MBC when utilizing the OE system, and similar specific productivity levels were attained during cultivation. In MBC, an important factor that directly affected the production levels was rotational speed during cultivation, suggesting that the mass transfer of oxygen was rate-limiting. In a comparison of the productivity of flask cultures utilizing the 2YT-IPTG and OE systems, MBC utilizing the OE system was the highest, with approximately 1mg of insoluble scFv-PS obtained from each well under optimal conditions (1400 rpm). The results of SDS-PAGE and a cross-contamination check indicated that very similar cultivation conditions were attained in each well, without cross contamination. Thus, MBC using the OE system is very useful for the high throughput, high-level production of scFv-PS, which can be activated on the surface of hydrophilic PS plates by solid-phase refolding. Therefore, the production of a variety of specific scFv-PSs for cytokines and biomarkers will make possible the construction of sensitive and low-cost antibody microarrays, which will be very useful in clinical diagnosis and biochemical research. PMID- 21324738 TI - Effects of cytoplasmic and periplasmic chaperones on secretory production of single-chain Fv antibody in Escherichia coli. AB - The effects of cytoplasmic and periplasmic chaperones on the secretory production of an anti-bovine ribonuclease A single-chain variable fragment (scFv) 3A21 in Escherichia coli were investigated. Co-expression of a cytoplasmic chaperone, GroEL/ES, DnaK/DnaJ/GrpE, trigger factor, or SecB with 3A21 scFv affected the proportions of antigen-binding activity in the cytoplasmic soluble fraction, the periplasmic fraction, and the extracellular medium, but there was no significant difference in the total activity compared to the control without chaperone co expression. On the other hand, co-expression of a periplasmic chaperone, Skp or FkpA, with the exception of DsbC, greatly increased the binding activity in all the soluble fractions. Co-expression of both Skp and FkpA had no synergistic effect. Combinations of cytoplasmic and periplasmic chaperones decreased the productivity. In shake-flask cultures of cells co-expressing Skp or FkpA, considerable amounts of 3A21 scFv were detected in the extracellular medium by enzyme-linked immunosorbent assay (ELISA) and Western blot, and the extracellular production level of 3A21 scFv was calculated to be around 40mg/l. The binding activity of 3A21 scFv co-expressed with Skp was slightly higher than that with FkpA. These results indicate that the co-expression of periplasmic chaperones Skp and FkpA is extremely useful for the secretory production of scFvs in a culture medium using E. coli, but cytoplasmic chaperones and multiple-chaperone combinations may not be effective. PMID- 21324739 TI - Neurobehavioral function is impaired in children with all severities of sleep disordered breathing. AB - OBJECTIVE: Sleep disordered breathing (SDB) is common in children and ranges in severity from primary snoring (PS), to obstructive sleep apnea syndrome (OSAS). This study investigated everyday function (behavior, attention, executive skills) in children with varying degrees of SDB and control children with no history of SDB recruited from the community. METHODS: One hundred thirty-six children aged 7 12 were studied. Routine overnight polysomnography (PSG) classified children into 4 groups: PS (n=59), mild OSAS (n=24), moderate/severe OSAS (n=18), and controls (n=35). Behavioral function and behavioral aspects of attention and executive function were assessed using the Child Behavior Checklist (CBCL) and the Behavior Rating Inventory of Executive Function (BRIEF). RESULTS: Children with all severities of SDB had significantly higher rates of total, internalizing and externalizing behavioral problems compared to control children. Increased rates of behavioral executive dysfunction were also found across the SDB spectrum. CONCLUSION: Our findings suggest that behavioral, attention, and executive function difficulties are present in children with PS as well as OSAS. These results have implications for the treatment of milder forms of SDB, particularly PS, which is commonly viewed as benign. PMID- 21324740 TI - Non-allergic cutaneous reactions in airborne chemical sensitivity--a population based study. AB - Multiple chemical sensitivity (MCS) is characterised by adverse effects due to exposure to low levels of chemical substances. The aetiology is unknown, but chemical related respiratory symptoms have been found associated with positive patch test. The purpose of this study was to investigate the relationship between cutaneous reactions from patch testing and self-reported severity of chemical sensitivity to common airborne chemicals. A total of 3460 individuals participating in a general health examination, Health 2006, were patch tested with allergens from the European standard series and screened for chemical sensitivity with a standardised questionnaire dividing the participants into four severity groups of chemical sensitivity. Both allergic and non-allergic cutaneous reactions--defined as irritative, follicular, or doubtful allergic reactions- were analysed in relationship with severity of chemical sensitivity. Associations were controlled for the possible confounding effects of sex, age, asthma, eczema, atopic dermatitis, psychological and social factors, and smoking habits. In unadjusted analyses we found associations between allergic and non-allergic cutaneous reactions on patch testing and the two most severe groups of self reported sensitivity to airborne chemicals. When adjusting for confounding, associations were weakened, and only non-allergic cutaneous reactions were significantly associated with individuals most severely affected by inhalation of airborne chemicals (odds ratio = 2.5, p = 0.006). Our results suggest that individuals with self-reported chemical sensitivity show increased non-allergic cutaneous reactions based on day 2 readings of patch tests. PMID- 21324741 TI - The physical demands of Super 14 rugby union. AB - OBJECTIVES: The purpose of the present study was to describe the match-play demands of professional rugby union players competing in Super 14 matches during the 2008 and 2009 seasons. DESIGN: The movements of 20 players from Super 14 rugby union team during the 2008 and 2009 seasons were video recorded. METHODS: Using time-motion analysis (TMA), five players from four positional groups (front row forwards, back-row forwards, inside backs and outside backs) were assessed. RESULTS: Players covered between 4218 m and 6389 m during the games. The maximum distances covered in a game by the four groups were: front row forwards (5139 m), back row forwards, (5422 m), inside backs (6389 m) and outside backs (5489 m). The back row forwards spent the greatest amount of time in high-intensity exercise (1190 s), followed by the front row forwards (1015 s), the inside backs (876 s) and the outside backs (570 s). Average distances covered in individual sprint efforts were: front row forwards (16 m), back row forwards (14 m), inside backs (17 m) and outside backs (18 m). Work to rest ratios of 1:4, 1:4, 1:5, and 1:6 were found for the front row and back row forwards, and inside and outside backs respectively. CONCLUSION: The Super 14 competition during 2008 and 2009, have resulted in an increase in total high-intensity activities, sprint frequency, and work to rest ratios across all playing positions. For players and teams to remain competitive in Super 14 rugby, training (including recovery practices) should reflect these current demands. PMID- 21324742 TI - Physical collisions and injury in professional rugby league match-play. AB - OBJECTIVE: To document the frequency of physical collisions and incidence of contact injury in professional rugby league match-play. DESIGN: Prospective cohort study. METHODS: Video recordings of 77 National Rugby League (NRL) matches were coded for the number and type of physical collisions in which players were involved. Each match was analysed and coded for defensive (i.e. tackles, missed tackles, and ineffective tackles) and attacking collisions (i.e. tackled in possession, broken tackles, offloads, support runs, and decoy runs). Injuries that occurred as a result of a physical collision were also recorded. RESULTS: The total number of physical collisions performed per game was greatest in the wide running forwards (47 [95% CI, 42-52]), and was significantly greater (P<0.05) than the hit-up forwards (36 [95% CI, 32-40]), adjustables (29 [95% CI, 26-32]), and outside backs (24 [95% CI, 22-27]) positional groups. A total of 48 collision injuries were sustained, resulting in an overall injury incidence of 10.6 (95% CI, 7.6-13.6) per 10,000 collisions. Injuries resulting from attacking collisions were consistently higher than injuries sustained in defensive collisions. Wide running forwards had the lowest incidence of injury, and the adjustables and outside backs had the highest incidence of injury. CONCLUSIONS: These results highlight the physical demands associated with collisions and tackles in professional rugby league. Furthermore, the results of this study suggest that playing position and the type of collision sustained have a greater influence over contact injury risk in rugby league than the number of physical collisions performed. PMID- 21324743 TI - First successful pregnancy following PGD for chromosome translocation on embryos generated from in-vitro matured oocytes: a case report. AB - As far as is known, this is the first report of a successful pregnancy outcome following preimplantation genetic diagnosis for a chromosome translocation in embryos generated from in-vitro matured oocytes. A couple presented to the study clinic where the female partner was a carrier of the reciprocal chromosome translocation 46,XX,t(1;20)(p36.1;p12.2) with three consecutive pregnancy terminations due to either fetal abnormality or unbalanced translocation products detected in the conceptus. Under routine ultrasound investigation she was diagnosed with polycystic ovaries. The patient underwent an in-vitro maturation/preimplantation genetic diagnosis cycle where the immature oocytes were matured in vitro and fertilized by intracytoplasmic sperm injection. Day-3 embryos were screened for the chromosome abnormality by fluorescent in-situ hybridization. A single embryo diagnosed as chromosomally normal/balanced was transferred on day 5 and resulted in the birth of a healthy child. PMID- 21324744 TI - Male factor infertility may be associated with a low risk for tubal abnormalities. AB - This study assessed the association of an abnormal hysterosalpingography (HSG) with clinical characteristics and infertility investigation results in 1359 women who underwent HSG as part of their infertility work-up. A normal HSG result was found in 1031 tests (75.9% of all HSG tests). Significantly positive predictors of tubal occlusion on multivariate analysis were longer duration of infertility (OR 1.072, 95% CI 1.006-1.143), previous pelvic inflammatory disease (PID; OR 2.172, 95% CI 1.176-4.008), extrauterine pregnancy (EUP; OR 15.74, 95% CI 6.66 37.16) and any abdominal surgery (except Caesarean section; OR 1.503, 95% CI 1.120-2.017) and negative predictor was male factor infertility (OR 0.543, 95% CI 0.401-0.735). The presence of male factor decreased the risk of tubal abnormality from 32.4% to 15.6% (P<0.001) in women with known risk factors for tubal abnormalities (previous PID, EUP or abdominal surgery) and from 17.8% to 11.5% (P=0.01) in women at low risk for tubal abnormalities. As the risk for tubal factor is approximately 1:10 in patients with male factor infertility without other risk factors, the practice of postponing HSG until after one or two treatment cycles may be considered. PMID- 21324745 TI - Vitrification of human single pronuclear oocytes following two approaches to polar body biopsy. AB - The purpose of the present study was to investigate whether the size of the opening in the zona pellucida (ZP) of human single pronuclear (1PN) oocytes made by laser and partial zona dissection (PZD) techniques might interfere with the survival and subsequent development to blastocyst stage upon vitrification and warming. Moreover, the viability of these blastocysts was evaluated by comparing their total cell number (TCN) to the TCN of blastocysts developed from control non-vitrified zona-intact 1PN oocytes. Prior to vitrification, a total of 97 and 88 1PN oocytes were subjected to polar body biopsy using laser-assisted and PZD techniques, respectively. The size of ZP opening made by laser and PZD techniques did not interfere with survival (94.8% and 95.4%) or development to the blastocyst stage (27.8% and 26.1%). However, the TCN of laser-derived blastocysts was significantly lower than the TCN of blastocysts developed from non-vitrified control 1PN oocytes (48.7 +/- 3.4 versus 70.8 +/- 7.1, P < 0.028). The vitrification protocol used here is thus revealed to be an effective method for cryopreservation of 1PN oocytes following polar body biopsy. However, the viability of blastocysts developed from laser-treated 1PN oocytes seems to be negatively affected by this method of biopsy. PMID- 21324746 TI - The nature and origin of binucleate cells in human preimplantation embryos: relevance to placental mesenchymal dysplasia. AB - Cleavage-stage embryos often have nuclear abnormalities, one of the most common being binucleate blastomeres, which may contain two diploid or two haploid nuclei. Biopsied cells from preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS) cycles were studied to determine the relative frequency of binucleate cells with two haploid versus two diploid nuclei. The frequency of mononucleate haploid biopsied blastomeres was also recorded. In the chromosomal PGD cycles 45.2% of the biopsied binucleate cells were overall diploid and 38.7% were overall tetraploid, compared with 50.0% and 29.2% for the PGS group, respectively. Placental mesenchymal dysplasia is a rare condition associated with intrauterine growth restriction, prematurity and intrauterine death. Recent work suggests that androgenetic diploid/haploid mosaicism may be a causal mechanism. There are two possible origins of haploid nuclei, either the cell contained only one parental genome initially or they may be derived from the cytokinesis of binucleate cells with two haploid nuclei. Binucleate formation therefore may be a way of doubling up the haploid genome, to produce diploid cells of androgenetic origin as seen in placental mesenchymal dysplasia. PMID- 21324747 TI - Clinical outcome of intracytoplasmic injection of spermatozoa morphologically selected under high magnification: a prospective randomized study. AB - Recent evidence shows that the selection of spermatozoa based on the analysis of morphology under high magnification (*6000) may have a positive impact on embryo development in cases with severe male factor infertility and/or previous implantation failures. The objective of this prospective randomized study was to compare the clinical outcome of 87 intracytoplasmic morphologically selected sperm injection (IMSI) cycles with 81 conventional intracytoplasmic sperm injection (ICSI) cycles in an unselected infertile population. IMSI did not provide a significant improvement in the clinical outcome compared with ICSI although there were trends for higher implantation (28.9% versus 19.5%), clinical pregnancy (54.0% versus 44.4%) and live birth rates (43.7% versus 38.3%) in the IMSI group. However, severe male factor patients benefited from the IMSI procedure as shown by significantly higher implantation rates compared with their counterparts in the ICSI group (29.6% versus 15.2%, P=0.01). These results suggest that IMSI may improve IVF success rates in a selected group of patients with male factor infertility. New technological developments enable the real time examination of motile spermatozoa with an inverted light microscope equipped with high-power differential interference contrast optics, enhanced by digital imaging. High magnification (over *6000) provides the identification of spermatozoa with a normal nucleus and nuclear content. Intracytoplasmic injection of spermatozoa selected according to fine nuclear morphology under high magnification may improve the clinical outcome in cases with severe male factor infertility. PMID- 21324748 TI - First systematic experience of preimplantation genetic diagnosis for de-novo mutations. AB - Standard preimplantation genetic diagnosis (PGD) cannot be applied for de-novo mutations (DNM), because neither origin nor relevant haplotypes are available for testing in single cells. PGD strategies were developed for 80 families with 38 genetic disorders, determined by 33 dominant, three recessive and two X-linked DNM. All three recessive mutations were of paternal origin, while of 93 dominant mutations, 40 were paternal, 46 maternal and seven detected in affected children. The development of specific PGD strategy for each couple involved DNA analysis of the parents and affected children prior to PGD, including a mutation verification, polymorphic marker evaluation, whole and single sperm testing to establish the normal and mutant haplotypes and PGD by polar body analysis and/or embryo biopsy. Overall, 151 PGD cycles were performed for 80 families, for which a specific PGD design has been established. The application of these protocols resulted in pre-selection and transfer of 219 (1.72 per cycle) DNM-free embryos in 127 (84.1%) PGD cycles, yielding 63 (49.6%) unaffected pregnancies and birth of 59 (46.5%) healthy children, confirmed to be free of DNM. The data show feasibility of PGD for DNM, which may routinely be performed with accuracy of over 99%, using the established PGD strategy. PMID- 21324749 TI - Identification errors in the blood transfusion laboratory: a still relevant issue for patient safety. AB - Remarkable technological advances and increased awareness have both contributed to decrease substantially the uncertainty of the analytical phase, so that the manually intensive preanalytical activities currently represent the leading sources of errors in laboratory and transfusion medicine. Among preanalytical errors, misidentification and mistransfusion are still regarded as a considerable problem, posing serious risks for patient health and carrying huge expenses for the healthcare system. As such, a reliable policy of risk management should be readily implemented, developing through a multifaceted approach to prevent or limit the adverse outcomes related to transfusion reactions from blood incompatibility. This strategy encompasses root cause analysis, compliance with accreditation requirements, strict adherence to standard operating procedures, guidelines and recommendations for specimen collection, use of positive identification devices, rejection of potentially misidentified specimens, informatics data entry, query host communication, automated systems for patient identification and sample labeling and an adequate and safe environment. PMID- 21324750 TI - Evaluation of the United States pediatric urology workforce and fellowships: a series of surveys performed in 2006-2010. AB - OBJECTIVE: In the US, there has been an evolution in the practice of pediatric urology from a primary academic sub-specialty focused on reconstruction of major congenital genitorurinary abnormalities to a mixed academic and private practice that serves as the primary care giver for all pediatric urologic concerns. The estimated manpower needs were unable to be resolved, due to our inability to determine the impact of sub-specialty certification on referral patterns, along with the failure to embrace the use of physician extenders. Here, we review a series of surveys performed in 2006-2010 regarding the sub-specialty of pediatric urology. MATERIALS AND METHODS: The four surveys focused on workforce needs, appraised the financial impact of educational debt on the pediatric urology community, and evaluated concerns of the current fellows in training. RESULTS: The median financial income for a pediatric urologist, the resident's educational debt load, and a desire of the fellows to have an open dialog with the urologic community regarding the merits of the research year are revealed. CONCLUSION: We have identified that the ability to recruit fellows into our field is dependent upon a combination of factors: interest in the field, job availability in relationship to geographic locations, mentoring, concerns regarding financial/familial hardships encountered during a 2-year fellowship, and the lack of increased financial reimbursement for the extra training required. PMID- 21324752 TI - Stretch syncope: reflex vasodepressor faints easily mistaken for epilepsy. AB - The pathophysiology of stretch syncope is demonstrated through the clinical, electrophysiological, and hemodynamic findings in three patients. Fifty-seven attacks were captured by video/EEG monitoring. Simultaneous EEG, transcranial (middle cerebral artery) doppler, and continuous arterial pressure measurements were obtained for at least one typical attack of each patient. They all experienced a compulsion to precipitate their attacks. Episodes started with a stereotyped phase of stretching associated with neck torsion and breath holding, followed by a variable degree of loss of consciousness and asymmetric, recurrent facial and upper limb jerks in the more prolonged episodes. Significant sinus tachycardia coincided with the phase of stretching and was followed within 9-16 seconds by rhythmic generalized slow wave abnormalities on the EEG in attacks with impairment of consciousness. Transcranial doppler studies showed a dramatic drop in cerebral perfusion in the middle cerebral arteries during the episodes. The combination of the stereotyped semiology of the attacks, the pseudofocal myoclonic jerking, and the rhythmic generalized slow wave EEG abnormalities with the tachycardia make differential diagnosis from epilepsy challenging. PMID- 21324753 TI - Simultaneous determination of rosuvastatin and atorvastatin in human serum using RP-HPLC/UV detection: method development, validation and optimization of various experimental parameters. AB - A novel, precise, accurate and rapid isocratic reversed-phase high performance liquid chromatographic/ultraviolet (RP-HPLC/UV) method was developed, optimized and validated for simultaneous determination of rosuvastatin and atorvastatin in human serum using naproxen sodium as an internal standard. Effect of different experimental parameters and various particulate columns on the analysis of these analytes was evaluated. The method showed adequate separation for rosuvastatin and atorvastatin and best resolution was achieved with Brownlee analytical C18 column (150*4.6 mm, 5 MUm) using methanol-water (68:32, v/v; pH adjusted to 3.0 with trifluoroacetic acid) as a mobile phase at a flow rate of 1.5 ml/min and wavelength of 241 nm. The calibration curves were linear over the concentration ranges of 2.0-256 ng/ml for rosuvastatin and 3.0-384 ng/ml for atorvastatin. The lower limit of detection (LLOD) and lower limit of quantification (LLOQ) for rosuvastatin were 0.6 and 2.0 ng/ml while for atorvastatin were 1.0 and 3.0ng/ml, respectively. All the analytes were separated in less than 7.0 min. The proposed method could be applied for routine laboratory analysis of rosuvastatin and atorvastatin in human serum samples, pharmaceutical formulations, drug-drug interaction studies and pharmacokinetics studies. PMID- 21324754 TI - Intrinsic structural variability of DNA allows multiple genomic encoding for nucleosomes: comment on "Cracking the chromatin code: precise rule of nucleosome positioning" by E.N. Trifonov. PMID- 21324756 TI - The spectrum of drug-related colitides: important entities, though frequently overlooked. AB - BACKGROUND: There is at present a relative lack of knowledge concerning drug related colitides, although these may be not infrequent entities in clinical practice. AIMS: To assess the frequency and the clinical-pathological subtypes of drug-related colitides in a gastrointestinal pathology referral centre. METHODS: All charts of endoscopic biopsy samples referred for colitis in a eight-year period were reviewed. To be classified as drug related colitis, patients' charts should report the use of any drug in a two month period before colonoscopy and no other obvious cases of colitis be present. For analysis, we considered only patients taking one drug in this period. RESULTS: We found 122 cases of drug related colitis out of 3877 charts reviewed (3% of the overall colitis group). These cases were represented by microscopic colitis (50%), eosinophil rich infiltrate of the left colon (34%), ischemic colitis (11%), pseudomembranous colitis (3%), apoptotic colopathy (2%). The drugs most frequently associated with these colitides were represented by non-steroidal anti-inflammatory drugs. CONCLUSION: It is important to raise awareness concerning drug-related colitides, to avoid diagnostic errors and provide a better therapeutic approach to patients with these conditions. PMID- 21324755 TI - Tyrosinase related protein 1 (TYRP1/gp75) in human cutaneous melanoma. AB - Melanoma prognosis is based on specific pathological features at the primary lesion. In metastatic patients, the extent of lymph node involvement is also an important prognosis indicator. Many progression markers both in tissues and serum, including circulating tumor cells, have been studied and new molecular markers are awaited from high-throughput screenings to discriminate between clinical stages and predict disease progression. The present review focuses on human tyrosinase related protein 1 also known as gp75 glycoprotein (Tyrp1/gp75), a melanosomal protein involved in the pigmentary machinery of the melanocyte and often used as differentiation marker, with a special emphasis on its emerging roles in the malignant melanocyte and melanoma progression. PMID- 21324757 TI - High liver RBP4 protein content is associated with histological features in patients with genotype 1 chronic hepatitis C and with nonalcoholic steatohepatitis. AB - BACKGROUND AND AIM: To investigate the hepatic expression of retinol-binding protein-4 (RBP4) in chronic hepatitis C (CHC) and nonalcoholic steatohepatitis (NASH) patients, and its association with biochemical and histological patterns of liver damage. MATERIALS AND METHODS: Sixty-six genotype 1 CHC and 32 NASH patients were tested for hepatic RBP4 expression. Liver expression at immunostaining was scored as 0 (slight), 1 (mild), 2 (moderate), and 3 (intense). In addition, the mRNA and the quantitative protein expressions of RBP4 were tested by PCR and by western blot, respectively, in 12 NASH and 28 CHC patients. Twelve subjects undergoing elective cholecystectomy served as controls. RESULTS: Ten (31%), 16 (50%) and 6 (19%) NASH patients, and 21 (32%), 31 (47%) and 14 (21%) CHC patients had scores of 1, 2 and 3, respectively. All control subjects scored 0. In both CHC and NASH liver RBP4 scores were directly related to western blot (p=0.001 and p=0.03), not to mRNA expression (p=0.77 and p=0.40). Older age (OR, 1.07; 95%CI, 1.01-1.13), RBP4 score (4.26; 1.27-14.21) and HOMA (2.26; 1.15 4.42) were independently associated with steatosis>=10% in CHC patients. In NASH lobular inflammation (OR, 3.77; 95%CI, 1.01-24.22) and RBP4 score (4.87; 1.003 23.65) were the only risk factors for fibrosis >=2 at logistic regression analysis. CONCLUSION: Hepatic storage of RBP4, unrelated to its expression, could cause liver damage both in NASH and CHC. PMID- 21324758 TI - Cutaneous marker of an internal malignancy. PMID- 21324759 TI - Gastric screening examination using PillCam ESO 2: a pilot study. PMID- 21324760 TI - Magnetic resonance imaging of rectal volume in patients with irritable bowel syndrome. AB - BACKGROUND: Extreme stool forms (1 and 2, or 6 and 7 of the Bristol stool scale) are frequent in patients with irritable bowel syndrome and are associated with colonic transit, but it is not known whether these alterations influence rectal reservoir function. AIMS: To investigate rectal reservoir function by assessing magnetic resonance imaging reconstructions of rectal volume in healthy subjects and patients with irritable bowel syndrome, and to establish whether it varies depending on the bowel habits of the patients. METHODS: Twelve healthy subjects and 20 patients with irritable bowel syndrome (with constipation, diarrhoea, mixed or undefined bowel habit according to the Rome III criteria) underwent pelvic magnetic resonance imaging in the absence of rectal sensations. T2 sagittal images were used to calculate rectal volume by multiplying inter-slice thickness by rectal area, and summing the inter-slice volumes. RESULTS: Stool form was significantly different in the irritable bowel syndrome patients with diarrhoea or constipation, and bowel movements were more frequent in the irritable bowel syndrome patients than in the healthy subjects. Rectal volume was significantly smaller in the irritable bowel syndrome patients (27 +/- 13 mL vs. 44 +/- 21 mL; P=0.04), with no significant differences between the bowel habit sub-types. CONCLUSION: The reduced rectal volume in irritable bowel syndrome patients suggests that rectal tone is increased and that, at least in the absence of rectal sensations, the rectum is not over-distended by stools. PMID- 21324761 TI - Single site fundoplication and foregut procedures. AB - Over the past few decades, advancements in minimally invasive surgery techniques have made surgical management of gastroesophageal reflux diseases increasingly popular. More recently, the field of minimally invasive surgery has experienced a natural evolution towards a reduction in the invasiveness of surgery and even in the number of abdominal access incisions. In fact, single site/access approaches have been successfully applied to a number of common minimally invasive surgery procedures including cholecystectomy, hysterectomy, colectomy, bariatric and even anti-reflux surgery. However, there is very little published data on the application of this technique in anti-reflux surgery. We present a brief review of available data as well as a summary of our experiences with this innovative approach to minimally invasive foregut surgery. PMID- 21324762 TI - Current applications of evolving methodologies in gastroesophageal reflux disease testing. AB - Until recently catheter-based 24-h pH monitoring has been the primary methodology for the objective diagnosis of gastroesophageal reflux disease. Yet, this system has some drawbacks, such as patient discomfort, marginal sensitivity, and the inability to detect nonacid reflux. Hampered by these limitations, several new techniques have been recently introduced in clinical practice. In particular, wireless capsule pH monitoring and multichannel intraluminal impedance-pH testing have been forwarded as more sophisticated means of enhancing patient comfort during testing as well as our ability to diagnose gastroesophageal reflux disease, especially in those patients who complain of symptoms of gastroesophageal reflux disease despite adequate acid suppression therapy. The goal of this review is to compare the clinical applicability, advantages and drawbacks of catheter-based 24-h pH testing, wireless capsule pH monitoring, and multichannel intraluminal impedance-pH. PMID- 21324763 TI - Diagnostic algorithm of hepatocellular carcinoma on cirrhosis: CEUS or no CEUS, that is the problem. PMID- 21324764 TI - [Circumscript myositis ossificans]. PMID- 21324765 TI - Clinical applications of the pedicled anterolateral thigh flap in penile reconstruction. AB - BACKGROUND: Penile reconstruction remains a major challenge in plastic surgery and, over the years, a myriad of techniques has been employed to achieve a functional phalloplasty. Unfortunately, the more commonly used forearm free flaps also have significant drawbacks. The pedicled anterolateral thigh flap (ALTF) has numerous attributes, which make it a comparable, if not a better option, for penile reconstruction. METHODS: Between January 2007 and December 2009, 14 patients with partial or complete penile loss underwent reconstruction with a pedicled ALTF. The demographic data of the patients, cause of the defects, technique of reconstruction and the details about different flap parameters are presented here. RESULTS: All the 14 patients were males, and the age range was between 27 and 60 years. Nine flaps were used for total penile reconstruction and five for partial penile reconstruction. The size of the flap ranged from 5 * 4 cm to 15 * 15 cm and was based on two perforators in four cases, while a single perforator was used in the rest. The perforators were musculocutaneous in 11 and septocutaneous in three patients. Primary urethral anastomosis was performed in three cases of total phalloplasty and all cases of partial phalloplasty (n=8), while in the rest, urethral continuity was established in a second stage. All the flaps survived completely. CONCLUSIONS: We have found the pedicled ALTF to be a very versatile flap with wide range of applicability for partial as well as total phalloplasty. PMID- 21324766 TI - Extrusion of bone anchor suture following flexor digitorum profundus tendon avulsion injury repair. AB - Flexor digitorum profundus (FDP) zone I tendon avulsion injury is traditionally repaired with a pullout suture technique. More recently, bone anchor sutures have been used as a viable alternative and have largely replaced areas in hand surgery where pullout suture technique was once required. To date, there have been very few complications reported related to bone anchor suture use in FDP tendon reattachment to the bone. We report a very unusual case of extrusion of bone anchor through the nailbed, 6 years after zone I FDP tendon avulsion injury repair and a brief review of literature. PMID- 21324767 TI - An accessory bypass tract masked by the presence of atrial fibrillation in a horse. AB - Accessory bypass tracts are rarely documented in horses. Here, we present a case of an accessory bypass tract which was initially masked by the presence of atrial fibrillation. Evidence of ventricular pre-excitation was recognized after cardioversion to normal sinus rhythm and the horse was diagnosed with Wolff Parkinson-White Syndrome. In people, atrial fibrillation in the presence of an accessory bypass tract is considered dangerous due to the risk of sudden cardiac death. Although we did not consider this horse safe to ride, he continues to compete successfully and has not had recurrence of clinically significant tachyarrhythmias. PMID- 21324768 TI - Australian caseload midwifery: the exception or the rule. AB - The aim of this paper is to review the clinical outcomes of descriptive and comparative cohort studies of the Australian caseload midwifery models of care that emerged during the late 1990s and early 2000s. These models report uniformly a decrease in caesarean section operation rates when compared to local, state and national rates, irrespective of the obstetric risk of the women cared for. These outcomes are in contrast to the findings of the randomised controlled trials and comparative cohort studies of caseload midwifery conducted, predominantly in the United Kingdom, in the mid to late 1990s. The Australian studies show that caseload midwifery is a model of care that is associated with lowered rates of caesarean section operations, and other obstetric intervention rates. The absence of definitive evidence of the effect of caseload midwifery, derived from published descriptive and comparative cohort studies, underlines the need for a sufficiently powered randomised controlled trial of caseload midwifery. The randomised controlled trial of caseload midwifery being undertaken in two major teaching hospitals in Australia will provide definitive answers relating to the effect of the caseload midwifery model of care for women of all risk in the Australian context. PMID- 21324769 TI - Assessing a novel room temperature DNA storage medium for forensic biological samples. AB - The ability to properly collect, analyze and preserve biological stains is important to preserving the integrity of forensic evidence. Stabilization of intact biological evidence in cells and the DNA extracts from them is particularly important since testing is generally not performed immediately following collection. Furthermore, retesting of stored DNA samples may be needed in casework for replicate testing, confirmation of results, and to accommodate future testing with new technologies. A novel room temperature DNA storage medium, SampleMatrixTM (SM; Biomatrica, Inc., San Diego, CA), was evaluated for stabilizing and protecting samples. Human genomic DNA samples at varying amounts (0.0625-200 ng) were stored dry in SM for 1 day to 1 year under varying conditions that included a typical ambient laboratory environment and also through successive freeze-thaw cycles (3 cycles). In addition, spiking of 1-4 * SM into samples prior to analysis was performed to determine any inhibitory effects of SM. Quantification of recovered DNA following storage was determined by quantitative PCR or by agarose gel electrophoresis, and evaluation of quantitative peak height results from multiplex short tandem repeat (STR) analyses were performed to assess the efficacy of SM for preserving DNA. Results indicate no substantial differences between the quality of samples stored frozen in liquid and those samples maintained dry at ambient temperatures protected in SM. For long-term storage and the storage of low concentration samples, SM provided a significant advantage over freezer storage through higher DNA recovery. No detectable inhibition of amplification was observed at the recommended SM concentration and complete profiles were obtained from genomic DNA samples even in the presence of higher than recommended concentrations of the SM storage medium. The ability to stabilize and protect DNA from degradation at ambient temperatures for extended time periods could have tremendous impact in simplifying and improving sample storage conditions and requirements. The current work focuses on forensics analysis; however this technology is applicable to all endeavors requiring storage of DNA. PMID- 21324770 TI - Effect of different investments and mold temperatures on titanium mechanical properties. AB - PURPOSE: The aim of the present study was to evaluate commercially pure titanium (CP Ti) casting quality when a specific to titanium and a conventional phosphate bonded investments were used under different mold temperatures. For this, the evaluated parameters were surface roughness, bending strength, Vickers microhardness, casting quality by radiographies and microstructure of CP Ti. METHODS: Wax patterns (28 mm * 3 mm * 1 mm) were invested using two phosphate bonded investments: Rematitan Plus (REM), specific to titanium, and Castorit Super C (CAS), a conventional investment, fired and cooled until reaching two mold temperatures: 430 degrees C (430) and room temperature (RT). Specimens were cast from CP Ti by plasma. After casting, specimens were radiographically examined and submitted to Vickers microhardness, roughness and bending strength evaluation. Microstructure was analyzed in the center and at the surface of specimen. RESULTS: Qualitative analysis of radiographs showed that specimens which were cast using CAS-RT presented more casting porosities while the specimens which were cast with REM-430 did not present any casting porosity. No significant difference was noted among the groups in the surface roughness and Vickers microhardness data, but the bending strength of the specimens cast using CAS was greater than REM groups. The microstructure of the specimens of the different groups was similar, presenting a feather-like aspect. CONCLUSION: Casting porosities found in the specimens cast using conventional investments (CAS) and lower mold temperatures would limit their use, even mechanical properties were similar than in specimens cast using specific to titanium investment (REM) at temperatures recommended by the manufacturer. PMID- 21324771 TI - Modeling study of the light stimulation of a neuron cell with channelrhodopsin-2 mutants. AB - Channelrhodopsin-2 (ChR2) has become a widely used tool for stimulating neurons with light. Nevertheless, the underlying dynamics of the ChR2-evoked spikes are still not yet fully understood. Here, we develop a model that describes the response of ChR2-expressing neurons to light stimuli and use the model to explore the light-to-spike process. We show that an optimal stimulation yield is achieved when the optical energies are delivered in short pulses. The model allows us to theoretically examine the effects of using various types of ChR2 mutants. We show that while increasing the lifetime and shuttering speed of ChR2 have limited effect, reducing the threshold irradiance by increased conductance will eliminate adaptation and allow constant dynamic range. The model and the conclusion presented in this study can help to interpret experimental results, design illumination protocols, and seek improvement strategies in the nascent optogenetic field. PMID- 21324772 TI - Life-threatening arrhythmia verification in ICU patients using the joint cardiovascular dynamical model and a Bayesian filter. AB - In this paper, a novel nonlinear joint dynamical model is presented, which is based on a set of coupled ordinary differential equations of motion and a Gaussian mixture model representation of pulsatile cardiovascular (CV) signals. In the proposed framework, the joint interdependences of CV signals are incorporated by assuming a unique angular frequency that controls the limit cycle of the heart rate. Moreover, the time consequence of CV signals is controlled by the same phase parameter that results in the space dimensionality reduction. These joint equations together with linear assignments to observation are further used in the Kalman filter structure for estimation and tracking. Moreover, we propose a measure of signal fidelity by monitoring the covariance matrix of the innovation signals throughout the filtering procedure. Five categories of life threatening arrhythmias were verified by simultaneously tracking the signal fidelity and the polar representation of the CV signal estimations. We analyzed data from Physiobank multiparameter databases (MIMIC I and II). Performance evaluation results demonstrated that the sensitivity of the detection ranges over 93.50% and 100.00%. In particular, the addition of more CV signals improved the positive predictivity of the proposed method to 99.27% for the total arrhythmic types. The method was also used for false arrhythmia suppression issued by ICU monitors, with an overall false suppression rate reduced from 42.3% to 9.9%. In addition, false critical ECG arrhythmia alarm rates were found to be, on average, 42.3%, with individual rates varying between 16.7% and 86.5%. The results illustrate that the method can contribute to, and enhance the performance of clinical life-threatening arrhythmia detection. PMID- 21324773 TI - Trimmed-likelihood estimation for focal lesions and tissue segmentation in multisequence MRI for multiple sclerosis. AB - We present a new automatic method for segmentation of multiple sclerosis (MS) lesions in magnetic resonance images. The method performs tissue classification using a model of intensities of the normal appearing brain tissues. In order to estimate the model, a trimmed likelihood estimator is initialized with a hierarchical random approach in order to be robust to MS lesions and other outliers present in real images. The algorithm is first evaluated with simulated images to assess the importance of the robust estimator in presence of outliers. The method is then validated using clinical data in which MS lesions were delineated manually by several experts. Our method obtains an average Dice similarity coefficient (DSC) of 0.65, which is close to the average DSC obtained by raters (0.66). PMID- 21324775 TI - Testing for spatial heterogeneity in functional MRI using the multivariate general linear model. AB - Much current research in functional magnetic resonance imaging (fMRI) employs multivariate machine learning approaches (e.g., support vector machines) to detect distributed spatial patterns from the temporal fluctuations of the neural signal. The aim of many studies is not classification, however, but investigation of multivariate spatial patterns, which pattern classifiers detect only indirectly. Here we propose a direct statistical measure for the existence of distributed spatial patterns (or spatial heterogeneity) applicable to fMRI datasets. We extend the univariate general linear model (GLM), typically used in fMRI analysis, to a multivariate case. We demonstrate that contrasting maximum likelihood estimations of different restrictions on this multivariate model can be used to estimate the extent of spatial heterogeneity in fMRI data. Under asymptotic assumptions inference can be made with reference to the chi(2) distribution. The test statistic is then assessed using simulated timecourses derived from real fMRI data followed by analyzing data from a real fMRI experiment. These analyses demonstrate the utility of the proposed measure of heterogeneity as well as considerations in its application. Measuring spatial heterogeneity in fMRI has important theoretical implications in its own right and may have potential uses for better characterising neurological conditions such as stroke and Alzheimer's disease. PMID- 21324776 TI - Natural image segmentation based on tree equipartition, Bayesian flooding and region merging. AB - We propose a general purpose image segmentation framework, which involves feature extraction and classification in feature space, followed by flooding and merging in spatial domain. Region growing is based on the computed local measurements and distances from the distribution of features describing the different classes. Using the properties of the label dependent distances spatial coherence is ensured, since the image features are described globally. The distribution of the features for the different classes are obtained by block-wise unsupervised clustering based on the construction of the minimum spanning tree of the blocks' grid using the Mallows distance and the equipartition of the resulting tree. The final clustering is obtained by using the k-centroids algorithm. With high probability and under topological constraints, connected components of the maximum likelihood classification map are used to compute a map of initially labelled pixels. An efficient flooding algorithm is introduced, namely, Priority Multi-Class Flooding Algorithm (PMCFA), that assign pixels to labels using Bayesian dissimilarity criteria. A new region merging method, which incorporates boundary information, is introduced for obtaining the final segmentation map. Therefore, the merging stage is based on region features and edge localization. Segmentation results on the Berkeley benchmark data set demonstrate the effectiveness of the proposed methods. PMID- 21324774 TI - ODVBA: optimally-discriminative voxel-based analysis. AB - Gaussian smoothing of images prior to applying voxel-based statistics is an important step in voxel-based analysis and statistical parametric mapping (VBA SPM) and is used to account for registration errors, to Gaussianize the data and to integrate imaging signals from a region around each voxel. However, it has also become a limitation of VBA-SPM based methods, since it is often chosen empirically and lacks spatial adaptivity to the shape and spatial extent of the region of interest, such as a region of atrophy or functional activity. In this paper, we propose a new framework, named optimally-discriminative voxel-based analysis (ODVBA), for determining the optimal spatially adaptive smoothing of images, followed by applying voxel-based group analysis. In ODVBA, nonnegative discriminative projection is applied regionally to get the direction that best discriminates between two groups, e.g., patients and controls; this direction is equivalent to local filtering by an optimal kernel whose coefficients define the optimally discriminative direction. By considering all the neighborhoods that contain a given voxel, we then compose this information to produce the statistic for each voxel. Finally, permutation tests are used to obtain a statistical parametric map of group differences. ODVBA has been evaluated using simulated data in which the ground truth is known and with data from an Alzheimer's disease (AD) study. The experimental results have shown that the proposed ODVBA can precisely describe the shape and location of structural abnormality. PMID- 21324777 TI - Stationary probability model for bitplane image coding through local average of wavelet coefficients. AB - This paper introduces a probability model for symbols emitted by bitplane image coding engines, which is conceived from a precise characterization of the signal produced by a wavelet transform. Main insights behind the proposed model are the estimation of the magnitude of wavelet coefficients as the arithmetic mean of its neighbors' magnitude (the so-called local average), and the assumption that emitted bits are under-complete representations of the underlying signal. The local average-based probability model is introduced in the framework of JPEG2000. While the resulting system is not JPEG2000 compatible, it preserves all features of the standard. Practical benefits of our model are enhanced coding efficiency, more opportunities for parallelism, and improved spatial scalability. PMID- 21324778 TI - 3-D reconstruction of microtubules from multi-angle total internal reflection fluorescence microscopy using Bayesian framework. AB - Total internal reflection fluorescence (TIRF) microscopy excites a thin evanescent field which theoretically decays exponentially. Each TIRF image is actually the projection of a 3-D volume and hence cannot alone produce an accurate localization of structures in the z-dimension, however, it provides greatly improved axial resolution for biological samples. Multiple angle-TIRF microscopy allows controlled variation of the incident angle of the illuminating laser beam, thus generating a set of images of different penetration depths with the potential to reconstruct the 3-D volume of the sample. With the ultimate goal to quantify important biological parameters of microtubules, we present a method to reconstruct 3-D position and orientation of microtubules based on multi-angle TIRF data, as well as experimental calibration of the actual decay function of the evanescent field at each angle. We validate our method using computer simulations, by creating a phantom simulating the curvilinear characteristics of microtubules and project the artificially constructed volume into a set of TIRF image for different penetration depth. The reconstructed depth information for the phantom data is shown to be accurate and robust to noise. We apply our method to microtubule TIRF images of PtK(2) cells in vivo. By comparing microtubule curvatures of the reconstruction results and several electron microscopy (EM) images of vertically sliced sample of microtubules, we find that the curvature statistics of our reconstruction agree well with the ground truth (EM data). Quantifying the distribution of microtubule curvature reveals an interesting discovery that microtubules can buckle and form local bendings of considerably small radius of curvature which is also visually spotted on the EM images, while microtubule bendings on a larger scale generally have a much larger radius and cannot bear the stress of a large curvature. The presented method has the potential to provide a reliable tool for 3-D reconstruction and tracking of microtubules. PMID- 21324779 TI - t-Tests, F-tests and Otsu's methods for image thresholding. AB - Otsu's binarization method is one of the most popular image-thresholding methods; Student's t -test is one of the most widely-used statistical tests to compare two groups. This paper aims to stress the equivalence between Otsu's binarization method and the search for an optimal threshold that provides the largest absolute Student's t-statistic. It is then naturally demonstrated that the extension of Otsu's binarization method to multi-level thresholding is equivalent to the search for optimal thresholds that provide the largest F -statistic through one way analysis of variance (ANOVA). Furthermore, general equivalences between some parametric image-thresholding methods and the search for optimal thresholds with the largest likelihood-ratio test statistics are briefly discussed. PMID- 21324780 TI - Maintaining temporal coherence in video retargeting using mosaic-guided scaling. AB - Video retargeting from a full-resolution video to a lower resolution display will inevitably cause information loss. Content-aware video retargeting techniques have been studied to avoid critical visual information loss while resizing a video. Maintaining the spatio-temporal coherence of a retargeted video is very critical on visual quality. Camera motions and object motions, however, usually make it difficult to maintain temporal coherence using existing schemes. In this paper, we propose the use of a panoramic mosaic to guide the scaling of corresponding regions of video frames in a video shot to ensure good temporal coherence. In the proposed method, after aligning video frames in a shot to a panoramic mosaic constructed for the shot, a global scaling map for these frames is derived from the panoramic mosaic. Subsequently, the local scaling maps of individual frames are derived from the global map and is further refined according to spatial coherence constraints. Our experimental results show that the proposed method can effectively maintain temporal coherence so as to achieve good visual quality even a video contains camera motions and object motions. PMID- 21324781 TI - Composite model-based DC dithering for suppressing contour artifacts in decompressed video. AB - Because of the outstanding contribution in improving compression efficiency, block-based quantization has been widely accepted in state-of-the-art image/video coding standards. However, false contour artifacts are introduced, which result in reducing the fidelity of the decoded image/video especially in terms of subjective quality. In this paper, a block-based decontouring method is proposed to reduce the false contour artifacts in the decoded image/video by automatically dithering its direct current (DC) value according to a composite model established between gradient smoothness and block-edge smoothness. Feature points on the model with the corresponding criteria in suppressing contour artifacts are compared to show a good consistency between the model and the actual processing effects. Discrete cosine transform (DCT)-based block level contour artifacts detection mechanism ensures the blocks within the texture region are not affected by the DC dithering. Both the implementation method and the algorithm complexity are analyzed to present the feasibility in integrating the proposed method into an existing video decoder on an embedded platform or system-on-chip (SoC). Experimental results demonstrate the effectiveness of the proposed method both in terms of subjective quality and processing complexity in comparison with the previous methods. PMID- 21324782 TI - A new color filter array with optimal properties for noiseless and noisy color image acquisition. AB - Digital color cameras acquire color images by means of a sensor on which a color filter array (CFA) is overlaid. The Bayer CFA dominates the consumer market, but there has recently been a renewed interest for the design of CFAs . However, robustness to noise is often neglected in the design, though it is crucial in practice. In this paper, we present a new 2 * 3-periodic CFA which provides, by construction, the optimal tradeoff between robustness to aliasing, chrominance noise and luminance noise. Moreover, a simple and efficient linear demosaicking algorithm is described, which fully exploits the spectral properties of the CFA. Practical experiments confirm the superiority of our design, both in noiseless and noisy scenarios. PMID- 21324783 TI - Subspaces indexing model on Grassmann manifold for image search. AB - Conventional linear subspace learning methods like principal component analysis (PCA), linear discriminant analysis (LDA) derive subspaces from the whole data set. These approaches have limitations in the sense that they are linear while the data distribution we are trying to model is typically nonlinear. Moreover, these algorithms fail to incorporate local variations of the intrinsic sample distribution manifold. Therefore, these algorithms are ineffective when applied on large scale datasets. Kernel versions of these approaches can alleviate the problem to certain degree but face a serious computational challenge when data set is large, where the computing involves Eigen/QP problems of size N * N. When N is large, kernel versions are not computationally practical. To tackle the aforementioned problems and improve recognition/searching performance, especially on large scale image datasets, we propose a novel local subspace indexing model for image search termed Subspace Indexing Model on Grassmann Manifold (SIM-GM). SIM-GM partitions the global space into local patches with a hierarchical structure; the global model is, therefore, approximated by piece-wise linear local subspace models. By further applying the Grassmann manifold distance, SIM GM is able to organize localized models into a hierarchy of indexed structure, and allow fast query selection of the optimal ones for classification. Our proposed SIM-GM enjoys a number of merits: 1) it is able to deal with a large number of training samples efficiently; 2) it is a query-driven approach, i.e., it is able to return an effective local space model, so the recognition performance could be significantly improved; 3) it is a common framework, which can incorporate many learning algorithms. Theoretical analysis and extensive experimental results confirm the validity of this model. PMID- 21324784 TI - Integer computation of lossy JPEG2000 compression. AB - In this paper, an integer-based Cohen-Daubechies-Feauvea (CDF) 9/7 wavelet transform as well as an integer quantization method used in a lossy JPEG2000 compression engine is presented. The conjunction of both an integer transform and quantization step allows for a complete integer computation of lossy JPEG2000 compression. The lossy method of compression utilizes the CDF 9/7 wavelet filter, which transforms integer input pixel values into floating-point wavelet coefficients that are then quantized back into integers and finally compressed by the embedded block coding with optimal truncation tier-1 encoder. Integer computation of JPEG2000 allows a reduction in computational complexity of the wavelet transform as well as ease of implementation in embedded systems for higher computational performance. The results of the integer computation show an equivalent rate/distortion curve to the JasPer JPEG2000 compression engine, as well as a 30% reduction in computation time of the wavelet transform and a 56% reduction in computation time of the quantization processing on an average. PMID- 21324785 TI - Two efficient label-equivalence-based connected-component labeling algorithms for 3-D binary images. AB - Whenever one wants to distinguish, recognize, and/or measure objects (connected components) in binary images, labeling is required. This paper presents two efficient label-equivalence-based connected-component labeling algorithms for 3-D binary images. One is voxel based and the other is run based. For the voxel-based one, we present an efficient method of deciding the order for checking voxels in the mask. For the run-based one, instead of assigning each foreground voxel, we assign each run a provisional label. Moreover, we use run data to label foreground voxels without scanning any background voxel in the second scan. Experimental results have demonstrated that our voxel-based algorithm is efficient for 3-D binary images with complicated connected components, that our run-based one is efficient for those with simple connected components, and that both are much more efficient than conventional 3-D labeling algorithms. PMID- 21324786 TI - A Hybrid Ant Colony Optimization Algorithm for the Extended Capacitated Arc Routing Problem. AB - The capacitated arc routing problem (CARP) is representative of numerous practical applications, and in order to widen its scope, we consider an extended version of this problem that entails both total service time and fixed investment costs. We subsequently propose a hybrid ant colony optimization (ACO) algorithm (HACOA) to solve instances of the extended CARP. This approach is characterized by the exploitation of heuristic information, adaptive parameters, and local optimization techniques: Two kinds of heuristic information, arc cluster information and arc priority information, are obtained continuously from the solutions sampled to guide the subsequent optimization process. The adaptive parameters ease the burden of choosing initial values and facilitate improved and more robust results. Finally, local optimization, based on the two-opt heuristic, is employed to improve the overall performance of the proposed algorithm. The resulting HACOA is tested on four sets of benchmark problems containing a total of 87 instances with up to 140 nodes and 380 arcs. In order to evaluate the effectiveness of the proposed method, some existing capacitated arc routing heuristics are extended to cope with the extended version of this problem; the experimental results indicate that the proposed ACO method outperforms these heuristics. PMID- 21324787 TI - Training toddlers seated on mobile robots to drive indoors amidst obstacles. AB - Mobility is a causal factor in development. Children with mobility impairments may rely upon power mobility for independence and thus require advanced driving skills to function independently. Our previous studies show that while infants can learn to drive directly to a goal using conventional joysticks in several months of training, they are unable in this timeframe to acquire the advanced skill to avoid obstacles while driving. Without adequate driving training, children are unable to explore the environment safely, the consequences of which may in turn increase their risk for developmental delay. The goal of this research therefore is to train children seated on mobile robots to purposefully and safely drive indoors. In this paper, we present results where ten typically developing toddlers are trained to drive a robot within an obstacle course. We also report a case study with a toddler with spina-bifida who cannot independently walk. Using algorithms based on artificial potential fields to avoid obstacles, we create force field on the joystick that trains the children to navigate while avoiding obstacles. In this "assist-as-needed" approach, if the child steers the joystick outside a force tunnel centered on the desired direction, the driver experiences a bias force on the hand. Our results suggest that the use of a force-feedback joystick may yield faster learning than the use of a conventional joystick. PMID- 21324788 TI - [Role of traditional medicine in the health care system of the cities of sub Saharan Africa: Libreville in Gabon]. AB - Traditional medicine in Libreville is undergoing changes, despite the refusal of some actors in the modern health-care system to recognize it. It is gradually adopting the methods and techniques of modern medicine for patient management. It therefore occupies the same medical space as the modern care system, creating competition. Traditional medicine is positioning itself to deal with pathologies related to the body, thus competing with -- and annoying -- some of the actors of the modern system of care. At the same time, it lays claim to pathologies related to the spirit, thus distinguishing itself. PMID- 21324789 TI - Antecubital allergic contact dermatitis from intravenous iron infusion: a possible etiological role of nickel. PMID- 21324790 TI - Sunscreen allergy due to cinnamyl alcohol in a ketoprofen-sensitized patient. PMID- 21324791 TI - Early-stage ovarian cancer management: still a challenge. PMID- 21324792 TI - Delaying oxidation. PMID- 21324793 TI - The role of iron in tumour cell proliferation. AB - Iron has a pivotal role in homeostasis due to its participation in virtually all of the body's oxidation-reduction processes. However, iron can also be considered a double-edged weapon, as its excess may lead to an increased risk of developing cancer, presumably by the generation of reactive oxygen species, and its role as substrate to enzymes that participate in cell proliferation. Thus, iron might as well be considered a cofactor in tumour cell proliferation. In certain pathological conditions, such as haemochromatosis, hepatitis B and C virus infection, asbestosis and endometriosis, iron overload may increase the risk of cancer. By contrast, iron depletion could be considered a useful adjunct in antitumour therapy. This paper reviews the current scientific evidence behind iron's role as a protumoral agent, and the potential benefit of a state of iron depletion in patients with cancer. PMID- 21324794 TI - Stem cell and lung cancer development: blaming the Wnt, Hh and Notch signalling pathway. AB - Primary lung cancer may arise from the central (bronchial) or peripheral (bronchiolo-alveolar) compartments. However the origins of the different histological types of primary lung cancer are not well understood. Stem cells are believed to be crucial players in tumour development and there is much interest in identifying those compartments that harbour stem cells involved in lung cancer. Although the role of stem cells in carcinogenesis is not well characterised, emerging evidence is providing new insights into this process. Numerous studies have indicated that lung cancer is not a result of a sudden transforming event but a multistep process in which a sequence of molecular changes result in genetic and morphological aberrations. The exact sequence of molecular events involved in lung carcinogenesis is not yet well understood, therefore deeper knowledge of the aberrant stem cell fate signalling pathway could be crucial in the development of new drugs against the advanced setting. PMID- 21324795 TI - Monoclonal antibodies for medical oncology: a few critical perspectives. AB - Incorporation of antibodies as weapons for cancer therapy has meant a turning point in the survival, clinical and radiological response of many oncology patients. These drugs are effective, well designed missiles that either alone or in combination with chemotherapy are unavoidable weapons for breast, lung and colon cancer as well as for haematological tumours. In addition, incoming monoclonal antibodies (mAbs) and folder-like proteins will be incorporated into clinical practice in the near future. This review aims to discuss a few imminent indications of current mAbs that are used for solid tumours and to briefly introduce future mAbs to the reader. PMID- 21324796 TI - Unknown primary cancer of the head and neck: a multidisciplinary approach. AB - The management of patients with cervical lymph node metastases from an unknown primary cancer (CUP) remains a matter of controversy. Although new advanced diagnostic tools, such as positron emission tomography, have recently been introduced in oncology, the frequency of this tumour entity in clinical practice means it is still relevant. Recently introduced molecular profiling platforms may provide biological classification for the primary tissue of origin as well as insights into the pathophysiology of this clinical entity, including the characterisation of the Epstein-Barr virus and human papilloma virus genomas in the metastatic cervical nodes. Due to the lack of randomised trials, a standard therapy has not been identified yet. Although neck dissection followed by post operative radiotherapy is the most generally accepted approach, there are other curative options that can be used in some patients: neck dissection alone, nodal excision followed by post-operative radiotherapy or radiotherapy alone. A major controversy remains in the target radiation volumes that range from ipsilateral neck irradiation to prophylactic irradiation of all potential mucosal sites and both sides of the neck. Finally, the administration of concurrent chemotherapy is currently being advised for patients with adverse prognostic factors. PMID- 21324797 TI - Muscle metastasis of carcinoma. AB - Metastatic carcinoma of the soft tissue is extremely rare compared with bone metastases. An intramuscular mass is often thought to be a primary soft tissue sarcoma because intramuscular metastases are very uncommon. Any painful soft tissue mass occurring in patients with a known history of carcinoma, particularly with extensive peritumoral enhancement associated with central necrosis, is highly suspicious for skeletal muscle metastasis. A needle biopsy is necessary for proper diagnosis. It is very important to make a differential diagnosis between metastasis and primary cancer in these cases. Here we present a review of known evidence. PMID- 21324798 TI - The role of plastic surgery in sarcoma treatment. AB - INTRODUCTION: Sarcomas are low-incidence tumours, but their poor prognosis and complex treatment require the work of a multidisciplinary medical team. The Plastic Surgery Service forms part of the Sarcoma Functional Unit in our centre, performing tumour exeresis as well as immediate reconstruction. MATERIALS AND METHODS: We present a retrospective study on the experience of the Plastic Surgery Service of the Hospital Universitario de Bellvitge in the treatment of 133 sarcomas over 20 years. RESULTS: The surgical treatment was based on local radical surgery supported by primary reconstructive surgery in 42.9% of the cases, with an amputation rate in limb sarcomas of 9.7%. Radiotherapy and chemotherapy were used in the high-grade sarcomas as adjuvant treatment. The anatomical location of the head and neck was associated with the need for reconstructive procedures. Survival free from local recurrence was 84.72% at 5 years. Disease-specific survival was 81.22% at 5 years. The only prognostic factor for survival in our series was histological grade. CONCLUSIONS: Primary reconstructive surgery has a fundamental role in sarcoma treatment enabling radical surgical resection, avoiding amputations and facilitating adjuvant treatments. PMID- 21324799 TI - Cetuximab concomitant with gemcitabine and radiotherapy in advanced squamous cell carcinomas of upper aerodigestive tract: a pilot study. AB - PURPOSE: To explore the response and toxicity of advanced non-metastatic squamous cell carcinomas of upper aerodigestive tract (SCC-UADT) to a combination of cetuximab concomitant with gemcitabine and radiotherapy. METHODS: We managed patients with concomitant treatment of cetuximab (400 mg/m(2) as uploading dose, then 250 mg/m(2), IV) concomitant with gemcitabine (50 mg/m(2)) weekly for seven courses, and radiotherapy in classical fractionation until completion of 70 Gy. Primary endpoints were complete response (CR) to treatment and toxicity. We evaluated patients for toxicity on a weekly basis; evaluation of response included physical examination, endoscopy, computed tomography (CT) scan and biopsy when indicated, and was performed 6 weeks after completion of radiotherapy. Additional evaluations were done every 3 months to document disease status. Between November 2004 and November 2005, 20 patients were included. RESULTS: CR was 82.4%, overall response was 100%. Neck disease reached CR in 61.5% and partial in 38.5% of patients. The main toxicities were nausea, lymphopenia, neutropenia and mucositis. Grade 3 and 4 side effects were presented in 70.6% of patients, but mucositis, and lymphopenia without clinical repercussions, occurred in 88.2% of patients. Gastrostomy was required in 11.8% of patients to maintain nutrition. Radioepithelitis developed in 76.5%, but only three of these (23.1%) were grade III. Median overall survival was 53 months (range 6-55 months) and median progression-free survival has not yet been reached at the time of evaluation. CONCLUSIONS: Although toxicity is important, this approach has interesting activity and deserves further investigation. PMID- 21324800 TI - Radiotherapy in rectal cancer: development, adequacy and radiotherapy utilisation rate. A comparative analysis with the most frequent tumour sites. AB - INTRODUCTION: Radiotherapy is a basic weapon in the local treatment of multiple solid tumors. The radiotherapy activity has been evaluated in our centre during the past eleven years. The study focused on rectal cancer. MATERIALS AND METHODS: This is a descriptive study of all radiotherapy procedures performed between January 1998 and December 2008. It quantifies the workload of each pathology treated, the rate of irradiation and its adequacy with optimal rates of irradiation according to the best available scientific evidence. RESULTS: We quantified 9,622 external radiotherapy procedures of which 6,009 were associated with the five pathologies that involved the highest workloads. Of these, 905 were performed in rectal cancer. The workloads due to cancers of the breast, prostate, lung, gynaecological pathologies and rectal cancers were 23.2%, 11.8%, 11.6%, 6.3% and 9.3% respectively. The real "radiotherapy utilisation rates" of these pathologies were 62%, 20.2%, 34.3%, 21% and 64% respectively, while the "rates of adequacy" were 74.7%, 33.6%, 45.1%, 60% and 104.8%. CONCLUSIONS: The "radiotherapy utilisation rate" for rectal cancer was equivalent to the estimated optimum rate as defined on the basis of reference groups. The therapy utilised developed chronologically in parallel with the available scientific evidence. The radiotherapy utilisation rates for breast and prostate cancer gradually increased, with a tendency to reach optimal rates. Radiotherapy as a treatment for lung cancer was underutilised. In global terms, the rate of utilisation of radiation therapy was low, although it displayed a tendency to increase. PMID- 21324801 TI - Platinum-based adjuvant chemotherapy on moderate- and high-risk stage I and II epithelian ovarian cancer patients. Long-term single institution experience and literature review. AB - BACKGROUND: Although the optimal management of women with FIGO stages I and II epithelial ovarian cancer (EOC) is still controversial, platinum-based adjuvant chemotherapy (CT) is the mainstay of treatment. Suboptimal survival results have led to major efforts to identify prognostic factors, improve surgical staging and develop adjuvant therapies to improve patients' outcomes. PATIENTS AND METHODS: We evaluate in a retrospective study clinical efficacy and the toxicity profile of a platinum-based adjuvant CT in FIGO stages I and II EOC treated at our institution from March 1984 to December 2006. Grade I FIGO stages IA-IB were excluded from the analysis. In the first period (1984-1997), patients received a platinum-based regimen without taxanes. In the second period from 1997 onwards, patients were treated with carboplatin and paclitaxel. Four to six cycles of adjuvant CT were administered. Potential predictive factors of efficacy and the role of paclitaxel addition were also analysed. RESULTS: One hundred and fifty eight patients (60 treated with paclitaxel) met inclusion criteria and were evaluable. Median age at diagnosis was 53.7 years (range 19-81) and most patients had an Eastern Cooperative Oncology Group performance status score (ECOG) of 0-1 (91.8%); 82.9% patients had pathological stage I and 17.1% pathological stage II. With a median follow up of 8.34 years (range 4.4-11.6), 103 patients (74.1%) were free of disease and 110 of them were alive (79.1%). Median relapse-free survival (RFS) and median overall survival (OS) had not been reached at the time of the analysis. No survival difference was found between paclitaxel and carboplatin combination or non-paclitaxel-containing regimens. Statistically significant prognostic factors for better RFS in the multivariate analysis were: ECOG 0 (p=0.023; HR 0.32; 95% CI 0.17-0.57); FIGO I stage (p<0.001; HR 0.30; 95% CI 0.15 0.58); I-II histological grade (p=0.005; HR 0.38; 95% CI 0.19-0.75); mucinous histology (p=0.013; HR 0.28; 95% CI 0.13-0.53); non-surgical adherences (p<0.002, HR 0.32; 95% CI 0.15-0.54); paracolic gutters inspection (p=0.033; HR 0.50; 95% CI 0.26-0.95) and liver surface biopsies (p=0.048; HR 0.64; 95% CI 0.41 0.98).Toxicity was generally mild and non-haematologic events were the most commonly found (62.9% of the total). The most frequent haematologic toxicities were neutropenia (41.7% in all grades, 9.5% grade 3-4) and anaemia (29.1% in all grades, 3.2% grade 3-4). CONCLUSIONS: The long-term outcome of this series is comparable to the published evidence and reflects the limited activity of platinum-based CT in the adjuvant setting. The potential survival advantage of the addition of paclitaxel to carboplatin cannot be definitively answered due to the small number of patients, the limited follow-up and the retrospective nature of the study. More effective and specific treatments are clearly required, in particular for those patients with stage II and undifferentiated tumours. Quality of surgery entails prognostic value. PMID- 21324803 TI - [Cod liver oil. A natural Vitamin D for preserving health]. AB - Vitamin D deficiency is pandemic in industrialized countries due to life-style changes. Recent studies suggest that besides bone-metabolism, vitamin D plays a central role in basic cell function like multiplication, differentiation and metabolism. This may explain that low vitamin D levels represent a risk factor for several apparently different diseases such as infective, autoimmune, neurodegenerative and cardiovascular diseases, as well as diabetes, osteoporosis and cancer. Accumulating evidences suggest that an adequate intake of vitamin D may significantly decrease prevalence and clinical outcome of these diseases. Estimated reduction of the economic burden might reach about 10 percent through normalizing vitamin D levels for these diseases. However, high doses of vitamin D monotherapy needs precaution for potential adverse effects and it should be substituted with the recommended doses of vitamin D in combination with synergistic vitamin A and omega 3 fatty acids, such as cod liver oil. PMID- 21324802 TI - Hypoxia, tumour-associated macrophages, microvessel density, VEGF and matrix metalloproteinases in human gastric cancer: interaction and impact on survival. AB - INTRODUCTION: Hypoxia is a key feature of the microenvironment of cancer cells actively participating in tumour progression. Our study was aimed to evaluate the impact of hypoxia and hypoxia-associated factors on tumour progression and survival of patients with gastric cancer. MATERIAL AND METHODS: One hundred and five resected specimens were used. The level of tumour hypoxia was evaluated using (31)P NMR spectroscopy, CD68 (tumour-associated macrophages), CD34 (microvessel density, MVD) and VEGF expression, immunohistochemistry, MMP-2 and MMP-9 activity, zymography. Statistical analysis was conducted using Pearson's test, Kaplan-Meier survival analysis, log-rank test and Cox proportional hazards model. RESULTS: Intratumoral hypoxia level has been significantly correlated with VEGF expression, TAM number and total protease activity. The overall survival rate of patients with strong tumour hypoxia, high level of MVD, VEGF expression, TAM and MMP activity was significantly lower than that of the patients without the mentioned tumour characteristics. CONCLUSIONS: The hypoxia-associated signalling that is activated in tumours promotes tumour progression through the recruitment of macrophages, remodelling of extracellular matrix and neoangiogenesis. PMID- 21324804 TI - [The significance of the relationship between external/internal locus of control and adolescent substance use in behavioral medicine]. AB - Prevention and treatment of the addictions are key public health priorities in modern society. In medical practice, in relation to the biochemical processes, mapping the addiction-prone personality traits, like external/internal locus of control are getting more and more attention. Individuals with high level on internal locus of control, for example, tend to take care of their health behavior; the lack of it, on the other hand, may worsen the effectiveness of stress release which may increase the likelihood of turning to substance use. AIMS: The main goal of the present study was to investigate the relationship between adolescent substance use (both lifetime prevalence and the actual substance user status) and external/internal locus of control). METHOD: The data collection of the questionnaire survey was going on among 656 high school students in Szeged (age range between 14-21 years, mean = 16.5 years, S.D. = 1.5 years of age, 49.1% of the sample was female). Associations between indicators of substance use (as dependent variables) and scale points of external/internal locus of control (as independent variables) were assessed using odds ratios calculated by logistic regression analyses, whereas gender was used as a controlling variable. RESULTS: Among boys, scale points of external, among girls, those of internal locus of control showed higher values. External locus of control increased, whereas internal locus of control decreased the risk of substance use, however, the relative role of external/internal locus of control was different according to the type of substance use and the prevalence values. In terms of smoking, lifetime prevalence, whereas in terms of marijuana use, the actual user status was influenced. In addition, while the latter one was also affected by gender, it did not play a role at all in the previous one. CONCLUSIONS: All these findings suggest that behavioral control may play a particularly important role in prevention of adolescent substance use. For developing this, methods of cognitive therapy would be effective to be completed with autogenic relaxation training as well. PMID- 21324805 TI - [Characteristics of patient pathways in Hungary]. AB - Over the past four years, there were nearly 250 million registered visits of insured patients in outpatient services in Hungary according to the database of the National Health Insurance Fund. In the process of renewal of health care system it is extremely important to analyze the characteristics of patient pathways. With the analysis of registered visits between 2007 and 2010 the author shows that 65%-96% (average 86%) of the insured patients used the services of outpatient care in the county of their living. This figure was the lowest (65%) in Pest County, which is the service area of several providers located in Budapest. Author presents and analyses the characteristics of patient pathways in different counties of Hungary. PMID- 21324806 TI - [Verrucous carcinoma of the anal margin. The importance of adequate biopsy technique]. AB - Buschke-Lowenstein tumor (verrucous carcinoma, giant condylomata) of the anal margin is a locally invasive, destructively growing carcinoma that does not metastasize. The lesions are rare despite the increased incidence of anal condylomata and anal carcinomas. Authors report a case of a 63-year-old woman suffering from verrucous carcinoma (Buschke-Lowenstein tumor) of the anal margin. The tumor invaded the rectal sphincter and extended beyond the muscle, infiltrating the lower abdomen. Infiltration of the perivesical soft tissue caused bilateral hydronephros. Because both under- and overdiagnosis of anal cancer and precancer may lead to inappropriate treatment, it is important to perform adequate sampling for histology. Non-representative superficial biopsies may result underdiagnosis of the disease. PMID- 21324807 TI - [The governing principles of the Hungarian Constitution. Five occurrences for health]. PMID- 21324808 TI - [Franz Liszt was born 200 years ago (1811-1886)]. PMID- 21324810 TI - Visual vignette. Cavernous hemangioma. PMID- 21324811 TI - Glucagon-induced pheochromocytoma crisis. AB - OBJECTIVE: To describe a previously asymptomatic woman who developed a glucagon induced pheochromocytoma crisis during preparation for screening colonoscopy. METHODS: We present the patient's clinical features, laboratory and imaging findings, and outcome and review the related literature. RESULTS: A 76-year-old woman received glucagon to inhibit intestinal motility before routine colonoscopy. She immediately developed severe hypertension, cardiac arrhythmia, and altered mental status. Her hospital course was complicated by encephalopathy and cardiac, respiratory, renal, and hepatic failure. Computed tomography of the abdomen showed a 6.5 * 4.8-cm mass in the left adrenal gland. Biochemical testing for pheochromocytoma revealed markedly elevated plasma catecholamines and metanephrines and urinary vanillylmandelic acid and metanephrine. She underwent a successful laparoscopic left adrenalectomy. Findings from histopathologic and immunohistochemical examination of the adrenal mass were diagnostic of pheochromocytoma. CONCLUSIONS: Glucagon administration induced catecholamine release from an occult pheochromocytoma, which caused multiorgan injury. Health care providers using glucagon must consider this rare, but life-threatening, complication. PMID- 21324812 TI - Vildagliptin-induced acute pancreatitis. AB - OBJECTIVE: To describe the first reported case of acute pancreatitis in a patient receiving vildagliptin. METHODS: We present the clinical, biochemical, and radiographic findings of the study patient. RESULTS: A 61-year-old woman who presented with severe abdominal pain was found to have acute pancreatitis. This occurred 5 weeks after the commencement of vildagliptin, a dipeptidyl-peptidase 4 inhibitor, for the treatment of type 2 diabetes mellitus. The patient's pancreatic enzymes were elevated (amylase, 1205 U/L; lipase, 8846 U/L), and abdominal computed tomography demonstrated diffuse pancreatic swelling, cyst formation, and necrosis in the body of the pancreas. In the absence of an identifiable cause for the patient's pancreatitis, vildagliptin was considered a potential trigger. The patient recovered after vildagliptin therapy was ceased. CONCLUSIONS: Although incretin-based therapy effectively treats type 2 diabetes mellitus, emerging reports of acute pancreatitis in patients receiving sitagliptin and exenatide have prompted the US Food and Drug Administration to issue an alert on these drugs. This appears to be the first reported case of acute pancreatitis in a patient receiving vildagliptin, and it supports the possibility that acute pancreatitis may be a rare effect of incretin-based therapy. PMID- 21324813 TI - Parathyroid autotransplantation. AB - OBJECTIVE: To summarize the indications and techniques for parathyroid autotransplantation and to explore other aspects of the field that warrant further research and discussion. METHODS: Review of relevant literature with focus on parathyroid autotransplantation and cryopreservation. RESULTS: Parathyroid autotransplantation is an important technique used by surgeons to circumvent postoperative hypoparathyroidism. Immediate autotransplantation is used intraoperatively, most commonly in the setting of total thyroidectomy or during total parathyroidectomy in a patient with parathyroid hyperplasia. Delayed autotransplantation with cryopreservation is typically used in patients with persistent or recurrent hyperparathyroidism who require repeated cervical exploration. CONCLUSIONS: The success rate of autotransplantation in preventing postoperative hypoparathyroidism reported in the literature is highly variable and is dependent on timing, disease, and duration of tissue storage. Ultimately, surgical planning for patients with hyperparathyroidism involves finding a balance between decreasing a patient's symptoms, increasing the time of eucalcemia, and avoiding the complications of permanent hypoparathyroidism. PMID- 21324814 TI - Visual vignette. PMID- 21324815 TI - Paraneoplastic hypoglycemia-"big" deal. PMID- 21324816 TI - Positive prolactin response to bromocriptine in 2 patients with cabergoline resistant prolactinomas. AB - OBJECTIVE: To describe a positive prolactin response to bromocriptine treatment in 2 patients with cabergoline-resistant prolactinomas. METHODS: We report the patients' clinical presentations, laboratory test results, imaging findings, and clinical courses. RESULTS: Patient 1 had a 5-mm pituitary microadenoma that was initially diagnosed at age 30 years. After initial diagnosis, she was treated with transvaginal bromocriptine for 9 years and then subsequently went untreated for 2 years. After developing symptoms of amenorrhea, decreased libido, and hyperprolactinemia, oral cabergoline, 0.5 mg twice weekly, was initiated. Her prolactin concentration remained elevated at 80 ng/mL while taking cabergoline. Her prolactin concentration decreased to 13 ng/mL after her regimen was switched to bromocriptine, 5 mg daily. Patient 2 had a 17-mm pituitary macroadenoma that was initially diagnosed at age 15 years. Oral cabergoline was started at 0.5 mg twice weekly and increased to 1 mg 3 times weekly when prolactin levels continued to rise to 340 ng/mL over 18 months. After visual field defects developed, transsphenoidal surgery was performed. One year after surgery, magnetic resonance imaging showed a 6- to 7-mm pituitary adenoma, and there was a gradual rise in serum prolactin. Her serum prolactin concentration continued to rise to 212 ng/mL with increasing tumor size over 3 years. Cabergoline was discontinued and oral bromocriptine was initiated at a dosage of 10 mg daily. After 4.5 months of bromocriptine therapy, her serum prolactin concentration decreased to 133 ng/mL. However, after 2 months, the macroadenoma continued to increase in size and a visual field defect developed, so another transsphenoidal operation was performed. CONCLUSIONS: Although cabergoline is generally preferred to bromocriptine for the treatment of patients with prolactinomas because of its better tolerance profile and greater effectiveness, in patients with cabergoline resistant prolactinomas, a bromocriptine trial should be considered a safe, relatively inexpensive, and well-tolerated alternative. PMID- 21324817 TI - Surgical treatment of primary hyperparathyroidism. AB - OBJECTIVE: To review the surgical treatment options for primary hyperparathyroidism with a focus on recent refinements in minimally invasive techniques and endoscopic and video- or robot-assisted parathyroidectomy. METHODS: We review the relevant surgical treatment options for primary hyperparathyroidism. RESULTS: Parathyroidectomy is the standard therapy for patients with primary hyperparathyroidism. Advancements in imaging, including technetium Tc 99m-sestamibi single-photon emission computed tomography and ultrasonography, have improved preoperative localization, while intraoperative parathyroid hormone measurement provides a rapid test to confirm operative success. These adjuncts have enabled surgeons to perform an operation that is both safe and minimally invasive. CONCLUSIONS: The minimally invasive approach to parathyroidectomy provides comparable cure rates to conventional bilateral neck exploration with reduced operative time and improved cosmetic results. The durability, safety, and success of these procedures make them valuable options in the current and future care of patients with primary hyperparathyroidism. PMID- 21324819 TI - Visual vignette. The Hertoghe sign. PMID- 21324820 TI - Calciphylaxis due to hyperparathyroidism. AB - OBJECTIVE: To discuss when and how to workup calciphylaxis for early diagnosis and to delineate medical vs surgical management of the disease. METHODS: Review of evidence-based medical literature on calciphylaxis due to primary, secondary, and tertiary hyperparathyroidism. RESULTS: Calciphylaxis is usually associated with secondary and tertiary hyperparathyroidism. However, calciphylaxis can also be seen in the absence of chronic renal failure and has been reported in patients with primary hyperparathyroidism due to a parathyroid adenoma or carcinoma. Calciphylaxis occurs when the levels of calcium and phosphate in the blood exceed their solubility level, leading to calcium-phosphate deposits in arteries that compromise the vasculature. These ischemic changes result in plaque-like lesions that progress to painful nodules. Calciphylaxis is diagnosed on the basis of physical examination, laboratory, and histopathologic findings. When medical therapy has failed in the setting of secondary/tertiary hyperparathyroidism with calciphylaxis, parathyroidectomy is the preferred treatment. In primary hyperparathyroidism, early recognition and aggressive wound care with debridement are important in managing this condition. However, resection of the offending parathyroid gland should be strongly considered. CONCLUSIONS: When calciphylaxis is present, early detection is critical to the successful management of this condition. Although medical therapy can be effective, surgical resection of the diseased parathyroid glands can be curative and potentially life saving. A multidisciplinary approach involving early diagnosis, aggressive medical management, operative debridement, and parathyroidectomy has the best chance of improving survival in calciphylaxis. PMID- 21324821 TI - Visual vignette. PMID- 21324822 TI - Glycemic control by a glucose management service and infection rates after liver transplantation. AB - OBJECTIVE: To present an analysis of glycemic control before and after introduction of a dedicated glucose management service (GMS) and outcomes within 1 year after liver transplantation (LT). METHODS: We conducted a retrospective review of patients undergoing LT, who were treated with insulin infusions after LT, before and after introduction of a GMS. Outcome measures within 1 year after LT included graft rejection, infection, prolonged ventilation (>48 hours on a ventilator), and graft survival. A multiple logistic regression was used to examine the relationship between GMS use and outcomes. RESULTS: This study consisted of 73 (35 GMS and 38 non-GMS) organ transplant recipients. The mean perioperative blood glucose level in the GMS group was lower than in the non-GMS group: unadjusted, by 31.1 mg/dL (P = .001); adjusted for pre-insulin drip glucose, age, sex, Model for End-Stage Liver Disease (MELD) score, and type of transplant, by 23.4 mg/dL (P = .020). There were 27 rejection episodes, 48 infections, 26 episodes of prolonged ventilation, and 64 patients with graft survival at 1 year. The infection rate was lower in the GMS group than in the non GMS group: the unadjusted odds ratio was 0.28 (P = .015); when adjustments were made for pre-insulin drip glucose, pretransplant glucose, age, sex, MELD score, type of transplant, and diabetes status before transplantation, the odds ratio was 0.24 (95% confidence interval, 0.06 to 0.97; P = .045). No significant associations were noted between GMS group and rejection rates, prolonged ventilation, or graft survival. CONCLUSION: In this study of LT patients, a GMS was associated with improved glycemic control and reduced postoperative infections. Further studies investigating effects of strict glycemic control after LT are warranted. PMID- 21324823 TI - Adrenal myelolipomas in patients with congenital adrenal hyperplasia: review of the literature and a case report. AB - OBJECTIVE: To review the association between congenital adrenal hyperplasia (CAH) and adrenal myelolipomas and report a case of bilateral, giant adrenal myelolipomas in a patient with untreated CAH due to 21-hydroxylase deficiency. METHODS: We describe the patient's clinical presentation, imaging findings, and laboratory test results and review the relevant English-language literature concerning patients with both CAH and myelolipomas. RESULTS: A 45-year-old man with untreated CAH due to 21-hydroxylase deficiency presented with increasing abdominal girth and abdominal pain. Computed tomography of the abdomen demonstrated very low-density adrenal masses (22 * 11 cm on the left side and 6 * 5.5-cm on the right side) consistent with adrenal myelolipomas. The left adrenal myelolipoma was resected (24.4 * 19.0 * 9.5 cm; 2557 g). The mass was composed of mature adipose tissue with areas of hematopoietic cells of myeloid, erythroid, and megakaryocytic cell lines. Islands of adrenal cortical cells were scattered between the adipose and hematopoietic tissue. Including the present case, we identified 31 patients with both CAH and myelolipomas who have been described in the English-language literature. The details of these cases were reviewed. CONCLUSIONS: Persons with CAH may be at increased risk of developing adrenal myelolipomas, particularly if their CAH is poorly controlled. How and whether chronic exposure of the adrenal glands to high corticotropin levels increases the risk of developing myelolipomas remains a matter of speculation. PMID- 21324824 TI - Familial hyperparathyroidism due to a germline mutation of the CDC73 gene: implications for management and age-appropriate testing of relatives at risk. AB - OBJECTIVE: To discuss the implications of a young age at diagnosis in a family member with hyperparathyroidism-jaw tumor syndrome, the youngest published case to date, due to a mutation of the CDC73 gene (formerly known as HRPT2); to review this family with regard to modifications of guidelines for surveillance of hyperparathyroidism and other associated features in affected and at-risk relatives; and to discuss surgical recommendations in this syndrome. METHODS: A review of English-language publications in PubMed and a review of GeneReviews were conducted pertaining to the subject of familial hyperparathyroidism. A case is described, and the family pedigree is discussed. RESULTS: Review of the literature revealed that CDC73-related disorder has not previously been reported in patients younger than 10 years. This finding has been the basis for the recommendation for initiation of surveillance for disease manifestations at that age. Review of the family history of our current patient revealed a 7-year-old nephew with hypercalcemia attributable to primary hyperparathyroidism. CONCLUSION: Surveillance of hyperparathyroidism in affected persons and genetic testing of relatives at risk are currently recommended to start at 10 years of age. We recommend that these be conducted at a younger age, preferably 5 to 10 years before the earliest diagnosis of hyperparathyroidism within the family, and potentially at birth in families with a known mutation of the CDC73 gene, in light of the malignant potential of the disease. PMID- 21324825 TI - A stepwise approach to insulin therapy in patients with type 2 diabetes mellitus and basal insulin treatment failure. AB - OBJECTIVE: To determine whether 1 or 2 preprandial injections before the meals of greatest glycemic impact can be as effective as 3 preprandial injections in patients with type 2 diabetes mellitus and basal insulin treatment failure. METHODS: This was an open-label, parallel-group, 1:1:1 randomized study of adults with type 2 diabetes mellitus on oral antidiabetic drugs with glycated hemoglobin (A1C) levels of 8.0% or greater. After a 14-week run-in with insulin glargine, patients with an A1C level greater than 7.0% were randomly assigned to 1, 2, or 3 time(s) daily insulin glulisine for 24 weeks. Changes in A1C from randomization to study end; percentage of patients achieving an A1C level less than 7.0%; changes in A1C, fasting glucose concentrations, and weight at individual study points; and safety (adverse events and hypoglycemia) were assessed throughout the study. RESULTS: Three hundred forty-three of 631 patients (54%) completing the run-in phase with insulin glargine were randomly assigned to treatment arms. During the randomization phase, A1C reductions with insulin glulisine once or twice daily were noninferior to insulin glulisine 3 times daily (confidence intervals: -0.39 to 0.36 and -0.30 to 0.43; P>.5 for both). However, more patients met the target A1C with 3 preprandial injections (46 [46%]) than with 2 injections (34 [33%]) or 1 injection (30 [30%]). Severe hypoglycemia occurred in twice as many patients receiving 3 preprandial injections (16%) compared with those receiving 2 injections (8%) and 1 injection (7%), but these differences did not reach significance. CONCLUSION: This study provides evidence that initiation of prandial insulin in a simplified stepwise approach is an effective alternative to the current routine 3 preprandial injection basal-bolus approach. PMID- 21324826 TI - Effects of successful parathyroidectomy on metabolic cardiovascular risk factors in patients with severe primary hyperparathyroidism. AB - OBJECTIVE: To evaluate the effect of parathyroidectomy on metabolic abnormalities associated with cardiovascular disease in patients with primary hyperparathyroidism (PHPT). METHODS: Thirty-four patients with PHPT (aged 51.0 +/ 11.8 years, mean +/- standard deviation) underwent assessment before and 1 year after successful parathyroidectomy. A control group of 42 normocalcemic healthy subjects, matched for age and body mass index, was also examined at baseline. We measured serum lipids, glucose, insulin, uric acid, calcium, parathyroid hormone, C-reactive protein, and bone density. Insulin resistance index was evaluated by homeostasis model assessment, and the presence of metabolic syndrome was determined. Because of multiple tests, the level of statistical significance was set at .01. RESULTS: After parathyroidectomy, there was a decrease in diastolic blood pressure (P<.02) and in serum concentrations of uric acid (P<.04) and insulin (P<.009). No difference was observed in rates of metabolic syndrome in patients before and 1 year after parathyroidectomy (23.5% versus 17.6%; P>.46). Insulin resistance index values were also unchanged from before to after parathyroidectomy (1.3 +/- 0.9 and 1.1 +/- 0.9, respectively; P>.68). A substantial increase in spine bone density (5%; P<.05) was noted postoperatively. Multivariate logistic regression analysis, after adjustment for age and body mass index, revealed that parathyroidectomy did not lead to a significant decrease in likelihood of cardiovascular risk-odds ratio (OR), 1.82; 95% confidence interval (CI), 0.53 to 6.21 (P>.34) for the metabolic syndrome and OR, 0.82; 95% CI, 0.17 to 3.88 (P>.8) for the insulin resistance index. CONCLUSION: In this study, surgical treatment had no beneficial effect on cardiovascular risk, as assessed by the metabolic syndrome and insulin resistance markers in patients with PHPT 1 year after parathyroidectomy. PMID- 21324827 TI - Effect of environmental perchlorate on thyroid function in pregnant women from Cordoba, Argentina, and Los Angeles, California. AB - OBJECTIVE: To determine whether environmental perchlorate exposure adversely affects thyroid function in women in the first trimester of pregnancy. METHODS: First-trimester pregnant women were recruited from prenatal clinics in the Los Angeles County Hospital, Los Angeles, California, and in the Hospital Universitario de Maternidad dependent Universidad Nacional de Cordoba, Cordoba, Argentina, between 2004 and 2007. Spot urine and blood specimens were obtained during the clinic visit. Urinary perchlorate, iodine, and creatinine were measured, and thyroid function tests were performed. RESULTS: The study included 134 pregnant women from Los Angeles, California (mean gestational age +/- SD = 9.1 +/- 2.2 weeks), and 107 pregnant women from Cordoba, Argentina (mean gestational age = 10.0 +/- 2.0 weeks). Median urinary iodine values were 144 MUg/L in California and 130 MUg/L in Argentina. Urinary perchlorate levels were detectable in all women (California: median, 7.8 MUg/L [range, 0.4-284 MUg/L] and Argentina: median, 13.5 MUg/L [range, 1.1-676 MUg/L]). Serum thyroperoxidase antibodies were detectable in 21 women from California (16%) and in 17 women from Argentina (16%). Using Spearman rank correlation analyses, there was no association between urinary perchlorate concentrations and serum thyrotropin, free thyroxine index, or total triiodothyronine values, including within the subset of women with urinary iodine values less than 100 MUg/L. In multivariate analyses using the combined Argentina and California data sets and adjusting for urinary iodine concentrations, urinary creatinine, gestational age, and thyroperoxidase antibody status, urinary perchlorate was not a significant predictor of thyroid function. CONCLUSIONS: Low-level perchlorate exposure is ubiquitous, but is not associated with altered thyroid function among women in the first trimester of pregnancy. PMID- 21324828 TI - Giant pancreatic tumor with clinical characteristics of insulinoma but without common pathologic features. AB - OBJECTIVE: To report a case of a large pancreatic tumor that had clinical characteristics of an insulinoma without classic pathologic features. METHODS: We describe a 58-year-old woman who presented with a 3-month history of symptomatic hypoglycemic episodes, which were characterized by confusion. The laboratory, imaging, and pathologic findings are summarized, the current literature on giant insulinomas is reviewed, and the distinction between clinical and pathologic diagnosis of neuroendocrine tumors is discussed. RESULTS: The biochemical diagnosis of insulinoma was established with concomitant low fasting blood glucose concentrations and inappropriately high insulin levels. An abdominal computed tomographic scan revealed a mass (10 by 11.7 by 9.7 cm) in the head and body of the pancreas, which was resected. Pathologic examination revealed a massive neuroendocrine tumor (13.5 by 11 by 8 cm) without immunohistochemical evidence of insulin expression. Nevertheless, tumor resection resulted in decreased blood insulin levels and resolution of the patient's hypoglycemia. CONCLUSION: Although more than 95% of insulinomas are smaller than 3 cm, this case is unique in that the extremely large pancreatic tumor had clinical characteristics of an insulinoma but did not have the classic pathologic findings. Because of the extensive pancreatic resection, the patient is dependent on both insulin and orally administered pancreatic enzymes but remained free of symptoms and disease recurrence at 1-year follow-up. PMID- 21324829 TI - Corticotropin-independent macronodular adrenal hyperplasia associated with insulinoma. AB - OBJECTIVE: To report a case of corticotropin-independent macronodular adrenal hyperplasia (AIMAH) associated with an insulinoma. METHODS: We describe the clinical, radiographic, laboratory, and histopathologic findings of the study patient; review the current protocols for management of AIMAH; and discuss the disease etiology. RESULTS: A 64-year-old woman with multiple intradermal facial nevi experienced intermittent light-headedness, tremor, and confusion and was found to have a venous plasma glucose concentration of 52 mg/dL. Hypoglycemia and hyperinsulinemia after 18 hours of fasting suggested the presence of an insulinoma. Hepatic venous sampling for insulin after selective arterial calcium injection localized the insulinoma to the pancreatic head. The insulinoma was excised, and there was no recurrence over the 5 years the patient was in our care. During the workup for insulinoma, bilateral adrenal masses were incidentally discovered on computed tomography. Twenty-hour urinary free cortisol excretion was elevated and serum corticotropin was suppressed. Overt signs of Cushing syndrome were not present, and subsequent urinary cortisol measurements were within the reference range for several years. After 4 years, Cushing syndrome developed and bilateral adrenalectomy was performed. AIMAH was diagnosed on the basis of histopathologic findings. CONCLUSIONS: This appears to be the first reported case of AIMAH associated with an insulinoma. In the absence of other stigmata of multiple endocrine neoplasm type 1 and in the presence of multiple nevi, it may represent a novel endocrine syndrome. PMID- 21324830 TI - Virilization of a female infant by a maternal adrenocortical carcinoma. AB - OBJECTIVE: To describe a possible mechanism underlying the partial virilization of a 46, XX infant by a functional maternal adrenocortical carcinoma (ACC). METHODS: We performed immunocytochemical staining of tumor sections for luteinizing hormone (LH)/human chorionic gonadotropin (hCG) receptors. In addition, related reports in the literature are discussed. RESULTS: A previously healthy mother developed a large cortisol- and androgen-producing stage III adrenal tumor that did not interfere with conception or early morphogenesis. The tumor eluded detection until after delivery of a partially virilized 46, XX female infant with ambiguous genitalia. Immunohistochemical staining of tumor sections revealed overexpression of the LH/hCG receptor. Virilization of the genetically female fetus may have resulted from hCG-stimulated steroid secretion by the ACC. CONCLUSION: Because hypercortisolism and hyperandrogenism are associated with menstrual disturbances and spontaneous abortion, pregnancy in patients with functional adrenal tumors is uncommon. Rarely, maternal steroid excess from a functional adrenal tumor has caused 46, XX disordered sex differentiation. This unusual case demonstrates the influence of hCG on the functionality of an ACC and demonstrates the rare phenomenon of virilization of a female infant by a functional maternal adrenal tumor. PMID- 21324831 TI - Using bedtime (PM) and early morning (AM) urine cortisol/creatinine ratios to evaluate pituitary-adrenal function in an office practice. AB - OBJECTIVE: To evaluate the use of cortisol/creatinine ratios in urine specimens collected at bedtime (PM) and the following morning (AM) in a general endocrine practice as a means of assessing pituitary-adrenal function in normal volunteers, outpatients with symptoms but no clinical endocrine dysfunction, patients with Cushing syndrome, and patients with known hypopituitarism. METHODS: Double-voided PM and AM urine samples were collected from 26 healthy control subjects and 131 outpatients who had complaints of fatigue and malaise, inability to lose weight, or nonspecific concerns about potential underlying problems with their metabolism. The findings on physical examination and laboratory studies were normal in each of these outpatients. Urine was assayed for free cortisol and creatinine and expressed as ng of cortisol/mg of creatinine. Eleven patients with documented Cushing syndrome also collected urine specimens, and data for 11 patients with known hypopituitarism were also studied. RESULTS: A clear diurnal pattern of low cortisol excretion at night that increased some 7-fold in the morning (P<.0001) was reproducibly identified in healthy control subjects and those outpatients with no clinical endocrine disease. In the healthy control subjects, the mean PM urine cortisol/creatinine ratio was 15.8 (95% confidence interval [CI], 12.5 to 19.0); the mean AM cortisol/creatinine was 91.5 (95% CI, 65.0 to 118.0). The mean AM/PM ratio was 6.9, and the mean difference in AM-PM was 75.7. In the outpatients, there was no significant difference in PM, AM, AM/PM, and AM-PM values in comparison with those in healthy control subjects, and no significant difference was noted in these variables among the 3 groups of outpatients (those with fatigue, weight gain, and metabolism concerns). In 11 patients with Cushing syndrome, the mean PM urine cortisol/creatinine ratio was 127.0 (95% CI, 87.0 to 166.0), and there was loss of diurnal variation with the AM/PM ratio of 1.16 (95% CI, 0.98 to 1.35). Patients with hypopituitarism had little to no increase in AM urine cortisol/creatinine in comparison with PM urine cortisol/creatinine. CONCLUSION: Determination of PM and AM urine cortisol/creatinine ratios offers a convenient method for assessing pituitary adrenal function. PMID- 21324832 TI - Trust in the internet as a health resource among older adults: analysis of data from a nationally representative survey. AB - BACKGROUND: Distrust in the Internet as a source of health information remains common among older adults. The influence of this distrust on Internet use for health-related purposes, however, is unclear. OBJECTIVE: The objective of our study was to explore how older adults' trust in the Internet influences their online health-related activities, and to identify potential targets for improving health-related Internet resources for older adults. METHODS: Data were obtained from a nationally representative, random digit-dial telephone survey of 1450 adults 50 years of age and older in the United States. A model was developed to conceptualize the hypothesized relationships among individual characteristics, distrust, and avoidance of the Internet as a health resource. Multivariate logistic regression analyses were conducted to examine the association between trust in online health information and use of the Internet for health-related purposes. Additional multivariate logistic regression analyses were conducted to identify the key characteristics associated with trust in online health information, adding sequentially the variables hypothesized to account for distrust among older adults: sociodemographic and health characteristics, inexperience and technical difficulties with the Internet, negative feelings toward the Internet, and lack of awareness about the sources providing the health information found online. RESULTS: The mean (SD) age of the study population was 63.7 (10.6) years. Of the 823 (56.8%) Internet users, 628 (76.3%) reported using the Internet as a health resource. Trust in the Internet as a source of health information was associated with using the Internet for a number of health activities, including searching for information about a specific health condition (adjusted OR 4.43, P < .001), purchasing prescription drugs (adjusted OR 2.61, P = .03), and talking with a health care provider about information found online (adjusted OR 2.54, P = .002). Older adults (age >= 65 years) were less likely to trust the Internet as a source of health information (OR 0.63, P = .04), even after adjusting for other sociodemographic characteristics and health and function. This age effect was only slightly attenuated (adjusted OR 0.69, P = .13) after adjusting for inexperience and technical difficulties with the Internet, but it disappeared entirely (adjusted OR 0.96, P = .91) after adjusting for other hypothesized contributors to distrust (including finding the Internet confusing because it provides "too much information," and lacking awareness about the source providing health information found online). CONCLUSIONS: Website design features that clearly identify the source and credibility of information and minimize confusion may build trust among older adults and offer an opportunity to increase the utility of the Internet as a health resource for this population. PMID- 21324833 TI - Packaging and labeling of pharmaceutical products obtained from the internet. AB - BACKGROUND: For patients, the prescription container label may be the only source of instructions on how to take their medicines. In the United States, the legal requirements for a prescription label are set by federal law and state statutes. The container should be comparable to that which manufacturers use to package drug products and should preserve a product's identity, strength, quality, and purity and prevent contamination. Safety features such as a child-resistant closure should be provided. Pharmaceutical products purchased from international online pharmacies are not approved by the Food and Drug Administration (FDA) and may not meet US guidelines for labeling and packaging. OBJECTIVE: The study objective was to determine whether commonly purchased pharmaceutical products obtained from international online pharmacies are comparable to products dispensed in the United States with regard to labeling and packaging. METHODS: During March 2006 through January 2007, 41 pharmaceutical oral dosage form samples were obtained from international Internet pharmacy websites for evaluation: 18 generic simvastatin samples, 18 generic amlodipine samples, and 5 generic sildenafil samples. Contents for each package were observed and recorded and comparison of the prescription labeling and packaging of these products was made with prescription labeling and packaging requirements in the United States. RESULTS: Of the 41 drug products obtained from online pharmacies from 12 different countries, only 1 product (from Canada) would meet both labeling and packaging guidelines for products dispensed in the United States. Of those not meeting the requirements, 7 were dispensed in paper envelopes with label affixed that was either handwritten or typed and contained missing information such as name and address of dispenser, name of prescriber, name of patient, and directions for use. Another 3 products did not have a label affixed to the drug product, but information was printed on a paper document enclosed in the shipping package, while 28 products did not have labels affixed to the drug product. In all, 39 of the 41 drug products' packaging would not meet the US guidelines. Aside from the Canadian product, only 1 product from Mexico was dispensed in a container that would meet guidelines established in the United States. In total, 35 products were not dispensed in plastic vials but were dispensed in unit dose packages, paper envelopes with loose dosage forms, blister packs of drugs held together with rubber bands, or a combination of these packaging forms. CONCLUSIONS: Results suggest that labeling and packaging standards for international generic drug products are not equivalent to labeling and packaging standards in the United States. This suggests dissimilar and substandard distribution processes compared with those in the United States, which in turn presents a challenge to patient comprehension and health literacy and may affect patient adherence to drug treatment regimens. These findings have strong implications for drug product quality, patient outcomes, therapeutic effectiveness, and safety. PMID- 21324835 TI - Dual use. PMID- 21324834 TI - Research opportunities related to establishing standards for tobacco products under the Family Smoking Prevention and Tobacco Control Act. AB - INTRODUCTION: This paper was written in response to a request from the U.S. National Cancer Institute. The goal is to discuss some research directions related to establishing tobacco product standards under the Family Smoking Prevention and Tobacco Control Act, which empowers the U.S. Food and Drug Administration to regulate tobacco products. Potential research related to tobacco product ingredients, nicotine, and harmful or potentially harmful constituents of tobacco products is discussed. DISCUSSION: Ingredients, which are additives, require less attention than nicotine and harmful or potentially harmful constituents. With respect to nicotine, the threshold level in tobacco products below which dependent users will be able to freely stop using the product if they choose to do so is a very important question. Harmful and potentially harmful constituents include various toxicants and carcinogens. An updated list of 72 carcinogens in cigarette smoke is presented. A crucial question is the appropriate levels of toxicants and carcinogens in tobacco products. The use of carcinogen and toxicant biomarkers to determine these levels is discussed. CONCLUSIONS: The need to establish regulatory standards for added ingredients, nicotine, and other tobacco and tobacco smoke constituents leads to many interesting and potentially highly significant research questions, which urgently need to be addressed. PMID- 21324836 TI - Interactions between endocannabinoid and serotonergic systems in mood disorders caused by nicotine withdrawal. AB - INTRODUCTION: Endocannabinoid and serotonin systems are implicated in mechanisms underlying depression-like symptoms. Involvement of serotonin in mood disorders occurring after smoking cessation has been observed. We studied the interactions between endocannabinoid and serotonergic systems in mood and behavioral disorders caused by nicotine cessation. The effects of the endocannabinoid transport inhibitor AM404 and the cannabinoid receptor 1 antagonist AM251 in a nicotine dependent rodent model were investigated. METHODS: Dependence was induced by subcutaneous injections of nicotine (2 mg/kg, 4 injections daily) for 15 consecutive days in mice. Animals treated with AM404 or AM251 were tested for locomotor activity and abstinence signs 24 hr after nicotine withdrawal and in forced swimming test (FST) at different times: immediately after last nicotine injection (t = 0) and 15 and 30 days after nicotine withdrawal. In nicotine dependent mice treated with AM404 or AM251, expression of diencephalic serotonin receptor 1(A) (5-HT1(A)) was also measured. Effects of AM404, AM251, and WAY 100635 (5-HT(1A) receptor antagonist) in mice subjected to FST were evaluated. RESULTS: A decrease in diencephalic 5-HT(1A) levels was observed in mice previously injected with nicotine. In the same animals, AM251 caused (0.5-2 mg/kg) a significant decrease of abstinence signs and AM404 (0.5-2 mg/kg) provoked a significant dose-dependent reduction in immobility time in the FST. Either AM251 or WAY 100635 antagonized anti-immobility effects of AM404. CONCLUSIONS: Data indicate the existence of a link between serotonergic and endocannabinoid systems in the mechanisms underlying mood disorders caused by nicotine abstinence and suggest that these interactions are potential targets for pharmacological aid in smoking cessation. PMID- 21324837 TI - Association between time to first cigarette after waking up and salivary cotinine concentration. AB - INTRODUCTION: The time to first cigarette smoked after waking up appears to be a good predictor of plasma and urine cotinine levels; however, collection of blood and urine is difficult in population-based studies and may influence participation. We aimed to test whether time to first cigarette is associated with salivary cotinine. METHODS: We used data from a cross-sectional study on a representative sample of the general population of Barcelona, Spain. We gathered information on smoking by means of a questionnaire and collected saliva for cotinine analysis. Of 1,245 participants, 22.9% were daily smokers, and the final sample for analysis consisted of 210 daily smokers. RESULTS: There were significant associations between salivary cotinine and time to first cigarette, between cigarette consumption and time to first cigarette, and between salivary cotinine and cigarette consumption. Salivary cotinine had decreased as time to first cigarette increased. After adjusting for cigarette consumption and sex, there were significant differences in mean salivary cotinine according to time to first cigarette (<= 5 min: 219.2 ng/ml; 6-30 min: 175.8 ng/ml; 31-60 min: 168.5 ng/ml; >60 min: 137.2 ng/ml). All paired comparisons were significant (p < .001) except in the 6- to 30-min group versus the 31- to 60-min group (p = .701). CONCLUSIONS: After adjustment for the number of cigarettes smoked in the last 24 hr, time to first cigarette is associated with salivary cotinine concentration. PMID- 21324838 TI - Dyadic efficacy for smoking cessation: preliminary assessment of a new instrument. AB - INTRODUCTION: Smoking cessation research has demonstrated a link between social support and quitting, but interventions designed to enhance partner support have often failed. We adapted and tested a measure of dyadic efficacy to assess smokers' confidence in their abilities to work together as a team with their partners to quit smoking and cope with quitting challenges. Our goal was to establish the psychometric properties of the dyadic efficacy instrument, including its associations with cessation outcomes. METHODS: We recruited partnered smokers who called the American Cancer Society's Quitline and administered telephone interviews (N = 634, 59% female, average age = 40 years). Interviews included 8 dyadic efficacy items and a variety of sociodemographic, smoking history, and relationship variables at baseline and quit outcomes at 4 months. RESULTS: Factor analysis of the dyadic efficacy items yielded a 1-factor scale with strong internal consistency (alpha = .92). Dyadic efficacy was positively associated (p < .0001) with smoking-specific support (r = .51), relationship satisfaction (r = .44), and dyadic coping (r = .54). Dyadic efficacy was not associated with age, gender, race, relationship length, smoking quantity, or previous quit attempts. Respondents with smoking partners who were willing to quit with them had higher dyadic efficacy than those whose smoking partners were not (p < .0001). Higher baseline dyadic efficacy was predictive of 7-day point prevalence quit rates at follow-up (odds ratio = 1.25, 95% CI = 1.02-1.53). CONCLUSIONS: With further study, dyadic efficacy may enhance our understanding of the role of partner relationships in smoking cessation. PMID- 21324839 TI - Muscle fat fraction in neuromuscular disorders: dual-echo dual-flip-angle spoiled gradient-recalled MR imaging technique for quantification--a feasibility study. AB - PURPOSE: To prospectively evaluate the muscle fat fraction (MFF) measured with dual-echo dual-flip-angle spoiled gradient-recalled acquisition in the steady state (SPGR) magnetic resonance (MR) imaging technique by using muscle biopsy as the reference standard. MATERIALS AND METHODS: After ethics approval, written informed consent from all patients was obtained. Twenty-seven consecutive patients, evaluated at the Neuromuscular Disorders Center with a possible diagnosis of neuromuscular disorder, were prospectively studied with MR imaging of the lower extremities to quantify muscle fatty infiltration by means of MFF calculation. Spin-density- and T1-weighted fast SPGR in-phase and opposed-phase dual-echo sequences were performed, respectively, with 20 degrees and 80 degrees flip angles. Round regions of interest were drawn by consensus on selected MR sections corresponding to anticipated biopsy sites. These were marked on the patient's skin with a pen by using the infrared spider light of the system, and subsequent muscle biopsy was performed. MR images with regions of interest were stored on a secondary console where the MFF calculation was performed by another radiologist blinded to the biopsy results. MFFs calculated with dual-echo dual flip-angle SPGR MR imaging and biopsy were compared by using a paired t test, Pearson correlation coefficient, and Bland-Altman plots. P value of < .05 was considered to indicate a statistically significant difference. RESULTS: The mean MFFs obtained with dual-echo dual-flip-angle SPGR MR imaging and biopsy were 20.3% (range, 1.7%-45.1%) and 20.6% (range, 3%-46.1%), respectively. The mean difference, standard deviation of the difference, and t value were -0.3, 1.3, and -1.3 (P > .2), respectively. The Pearson correlation coefficient was 0.995; with the Bland-Altman method, all data points were within the +/- 2 SDs limits of agreement. CONCLUSION: The results show that dual-echo dual-flip-angle SPGR MR imaging technique provides reliable calculation of MFF, consistent with biopsy measurements. PMID- 21324840 TI - Early measurement of pulsatility and resistive indexes: correlation with long term renal transplant function. AB - PURPOSE: To correlate pulsatility index (PI) and resistive index (RI) measured at early specific intervals after transplantation with 1-year estimated glomerular filtration rate (eGFR) and death-censored transplant survival to assess the long term prognostic value of these Doppler indexes. MATERIALS AND METHODS: The local ethics committee was consulted, and no formal approval was required. This retrospective review included 178 consecutive patients (111 male, 67 female; mean age, 43.9 years +/- 13.4 [standard deviation]; age range, 16-72 years) undergoing first deceased-donor renal transplantation between 1997 and 2000. All patients were identified from a prospectively maintained database. Spectral Doppler analysis was performed within 1 week after transplantation in all patients and between 1 week and 3 months after transplantation in 124 patients. Average PI and RI were determined from measurements obtained in the upper, lower, and interpolar regions. For statistical analysis, the chi(2) test, analysis of variance, the Student t test, Kaplan-Meier survival plots, and Cox proportional hazards models were used. RESULTS: Within 1 week after transplantation, there was a significant association between PI and 1-year eGFR when analyzed as tertiles (P = .02). Between 1 week and 3 months after transplantation, there was a significant relationship between 1-year eGFR and both PI and RI when comparing the lowest and highest tertiles (47.5 mL/min/1.73 m(2) for PI <1.26 vs 32.7 mL/min/1.73 m(2) for PI >1.49 [P = .01], 42.8 mL/min/1.73 m(2) for RI <0.69 vs 32.3 mL/min/1.73 m(2) for RI >0.74 [P = .03]). Both PI and RI were independent predictors of death censored transplant survival (hazard ratio, 1.68 per unit [P < .001] and 260.4 per unit, respectively [P = .02]). CONCLUSION: PI and RI in the early posttransplantation period correlate with long-term transplant function and can potentially be used as prognostic markers to aid risk stratification for future transplant dysfunction. PMID- 21324841 TI - Magnetization transfer helps detect intestinal fibrosis in an animal model of Crohn disease. AB - PURPOSE: To determine the utility of magnetization transfer (MT) in the identification and quantification of intestinal fibrosis in a rat model of Crohn disease. MATERIALS AND METHODS: The university committee on the use and care of animals approved this study (UCUCA 08592). Lewis rats injected subserosally with peptidoglycan-polysaccharide (PG-PS) develop bowel inflammation 1 day after laparotomy (early phase) and fibrosis starting 14 days after laparotomy (late phase). The authors performed 2.0-T magnetic resonance (MR) imaging in 25 rats injected with PG-PS and 13 injected with human serum albumin (HSA) (control animals). Imaging was performed before laparotomy and on a weekly basis thereafter for up to 28 days. The MT ratio in the bowel wall was calculated. Resected cecal tissue was scored for inflammation and fibrosis. Tissue fibrosis was determined with colorimetric analysis of trichrome-stained specimens. Collagen content was measured with Western blot analysis. Statistical analyses were performed with the Student t test for continuous bivariate comparisons, the Pearson correlation for continuous variables, and the Spearman correlation for ordinal variables. RESULTS: All rats developed early inflammation, which subsided over time. Rats injected with PG-PS developed increased fibrosis in the late phase, whereas control rats did not. The mean MT ratio of rats injected with PG PS with late-phase fibrosis was higher than that in rats with early phase inflammation (P = .017). In addition, the MT ratio of rats injected with PG-PS with late-phase fibrosis was higher than that of control animals that did not develop fibrosis in the late phase (P = .0001). The MT ratio of control animals remained unchanged over time as inflammation subsided. The MT ratio in rats injected with PG-PS showed correlation with tissue fibrosis (rho = 0.63). The MT ratio showed correlation with tissue collagen (R = 0.74). The positive and negative predictive values of the MT ratio in the prediction of fibrosis were 92% (12 of 13 rats) and 83% (five of six rats), respectively. CONCLUSION: These results indicate that MT is sensitive to bowel wall fibrosis as occurs in Crohn strictures. PMID- 21324842 TI - Coronary artery calcium scoring does not add prognostic value to standard 64 section CT angiography protocol in low-risk patients suspected of having coronary artery disease. AB - PURPOSE: To evaluate the prognostic outcome of cardiac computed tomography (CT) for prediction of major adverse cardiac events (MACEs) in low-risk patients suspected of having coronary artery disease (CAD) and to explore the differential prognostic values of coronary artery calcium (CAC) scoring and coronary CT angiography. MATERIALS AND METHODS: Institutional review committee approval and informed consent were obtained. In 4338 patients who underwent 64-section CT for evaluation of suspected CAD, both CAC scoring and CT angiography were concurrently performed by using standard scanning protocols. Follow-up clinical outcome data regarding composite MACEs were procured. Multivariable Cox proportional hazards models were developed to predict MACEs. Risk-adjusted models incorporated traditional risk factors for CAC scoring and coronary CT angiography. RESULTS: During the mean follow-up of 828 days +/- 380, there were 105 MACEs, for an event rate of 3%. The presence of obstructive CAD at coronary CT angiography had independent prognostic value, which escalated according to the number of stenosed vessels (P < .001). In the receiver operating characteristic curve (ROC) analysis, the superiority of coronary CT angiography to CAC scoring was demonstrated by a significantly greater area under the ROC curve (AUC) (0.892 vs 0.810, P < .001), whereas no significant incremental value for the addition of CAC scoring to coronary CT angiography was established (AUC = 0.892 for coronary CT angiography alone vs 0.902 with addition of CAC scoring, P = .198). CONCLUSION: Coronary CT angiography is better than CAC scoring in predicting MACEs in low-risk patients suspected of having CAD. Furthermore, the current standard multisection CT protocol (coronary CT angiography combined with CAC scoring) has no incremental prognostic value compared with coronary CT angiography alone. Therefore, in terms of determining prognosis, CAC scoring may no longer need to be incorporated in the cardiac CT protocol in this population. PMID- 21324844 TI - No favour, no friends: parsing the qualifications for a journal's editor-in chief. PMID- 21324843 TI - Effectiveness of a staged US and CT protocol for the diagnosis of pediatric appendicitis: reducing radiation exposure in the age of ALARA. AB - PURPOSE: To evaluate the effectiveness of a staged ultrasonography (US) and computed tomography (CT) imaging protocol for the accurate diagnosis of suspected appendicitis in children and the opportunity for reducing the number of CT examinations and associated radiation exposure. MATERIALS AND METHODS: This retrospective study was compliant with HIPAA, and a waiver of informed consent was approved by the institutional review board. This study is a review of all imaging studies obtained in children suspected of having appendicitis between 2003 and 2008 at a suburban pediatric emergency department. A multidisciplinary staged US and CT imaging protocol for the diagnosis of appendicitis was implemented in 2003. In the staged protocol, US was performed first in patients suspected of having appendicitis; follow-up CT was recommended when US findings were equivocal. Of 1228 pediatric patients who presented to the emergency department for suspected appendicitis, 631 (287 boys, 344 girls; age range, 2 months to 18 years; median age, 10 years) were compliant with the imaging pathway. The sensitivity, specificity, negative appendectomy rate (number of appendectomies with normal pathologic findings divided by the number of surgeries performed for suspected appendicitis), missed appendicitis rate, and number of CT examinations avoided by using the staged protocol were analyzed. RESULTS: The sensitivity and specificity of the staged protocol were 98.6% and 90.6%, respectively. The negative appendectomy rate was 8.1% (19 of 235 patients), and the missed appendicitis rate was less than 0.5% (one of 631 patients). CT was avoided in 333 of the 631 patients (53%) in whom the protocol was followed and in whom the US findings were definitive. CONCLUSION: A staged US and CT imaging protocol in which US is performed first in children suspected of having acute appendicitis is highly accurate and offers the opportunity to substantially reduce radiation. PMID- 21324845 TI - Case report: probable transmission of vaccine strain of yellow fever virus to an infant via breast milk. AB - The 17D yellow fever vaccine is a live-virus vaccine that has been in use since the 1940s. The incidence of encephalitis after yellow fever vaccination among young infants is much higher than among children older than nine months of age. Until recently, avoidance of vaccination by breastfeeding women who have received yellow fever vaccine had been based on theoretical grounds only. We report the probable transmission of vaccine strain of yellow fever virus from a mother to her infant through breastfeeding. PMID- 21324846 TI - Cancer risk related to low-dose ionizing radiation from cardiac imaging in patients after acute myocardial infarction. AB - BACKGROUND: Patients exposed to low-dose ionizing radiation from cardiac imaging and therapeutic procedures after acute myocardial infarction may be at increased risk of cancer. METHODS: Using an administrative database, we selected a cohort of patients who had an acute myocardial infarction between April 1996 and March 2006 and no history of cancer. We documented all cardiac imaging and therapeutic procedures involving low-dose ionizing radiation. The primary outcome was risk of cancer. Statistical analyses were performed using a time-dependent Cox model adjusted for age, sex and exposure to low-dose ionizing radiation from noncardiac imaging to account for work-up of cancer. RESULTS: Of the 82,861 patients included in the cohort, 77% underwent at least one cardiac imaging or therapeutic procedure involving low-dose ionizing radiation in the first year after acute myocardial infarction. The cumulative exposure to radiation from cardiac procedures was 5.3 milliSieverts (mSv) per patient-year, of which 84% occurred during the first year after acute myocardial infarction. A total of 12 020 incident cancers were diagnosed during the follow-up period. There was a dose dependent relation between exposure to radiation from cardiac procedures and subsequent risk of cancer. For every 10 mSv of low-dose ionizing radiation, there was a 3% increase in the risk of age- and sex-adjusted cancer over a mean follow up period of five years (hazard ratio 1.003 per milliSievert, 95% confidence interval 1.002-1.004). INTERPRETATION: Exposure to low-dose ionizing radiation from cardiac imaging and therapeutic procedures after acute myocardial infarction is associated with an increased risk of cancer. PMID- 21324847 TI - Nursing schools to teach new ways to cope with death. PMID- 21324848 TI - Alcohol in Canada: reducing the toll through focused interventions and public health policies. PMID- 21324849 TI - Patients are harmed (again), fingers point. What's wrong? PMID- 21324850 TI - Giant cell arteritis. PMID- 21324851 TI - Radiation exposure from medical imaging: a silent harm? PMID- 21324852 TI - Dioxin scandal triggers food debate in Germany. PMID- 21324853 TI - An atypical presentation of giant cell arteritis. PMID- 21324855 TI - Superior mesenteric venous thrombosis. PMID- 21324856 TI - Physicians aplenty in Nova Scotia. PMID- 21324857 TI - Unintentional weight loss in older adults. PMID- 21324858 TI - "Obamacare" snagged in legal thicket. PMID- 21324859 TI - Sexuality of the disabled often overlooked. PMID- 21324861 TI - Best practices for noninvasive ventilation. PMID- 21324862 TI - Orthotics work in mysterious ways. PMID- 21324864 TI - Dens of inactivity. PMID- 21324865 TI - Infoway tacks towards "networked" patients. PMID- 21324866 TI - Terminal phalangeal osteosclerosis and rheumatoid arthritis. PMID- 21324868 TI - Tuberculosis in Nunavut: a century of failure. PMID- 21324869 TI - Oseltamivir-resistant pandemic H1N1 influenza. PMID- 21324867 TI - Clinical practice guidelines for the use of noninvasive positive-pressure ventilation and noninvasive continuous positive airway pressure in the acute care setting. PMID- 21324871 TI - Public health advocates push for safer sex in pornographic film industry. PMID- 21324870 TI - Maternal selenium status during early gestation and risk for preterm birth. AB - BACKGROUND: Preterm birth occurs in 5%-13% of pregnancies. It is a leading cause of perinatal mortality and morbidity and has adverse long-term consequences for the health of the child. Because of the role selenium plays in attenuating inflammation, and because low concentrations of selenium have been found in women with preeclampsia, we hypothesized that low maternal selenium status during early gestation would increase the risk of preterm birth. METHODS: White Dutch women with a singleton pregnancy (n = 1197) were followed prospectively from 12 weeks' gestation. Women with thyroid disease or type 1 diabetes were excluded. At delivery, 1129 women had complete birth-outcome data. Serum concentrations of selenium were measured during the 12th week of pregnancy. Deliveries were classified as preterm or term, and preterm births were subcategorized as iatrogenic, spontaneous or the result of premature rupture of the membranes. RESULTS: Of the 60 women (5.3%) who had a preterm birth, 21 had premature rupture of the membranes and 13 had preeclampsia. The serum selenium concentration at 12 weeks' gestation was significantly lower among women who had a preterm birth than among those who delivered at term (mean 0.96 [standard deviation (SD) 0.14] MUmol/L v. 1.02 [SD 0.13] MUmol/L; t = 2.9, p = 0.001). Women were grouped by quartile of serum selenium concentration at 12 weeks' gestation. The number of women who had a preterm birth significantly differed by quartile (chi2 = 8.01, 3 degrees of freedom], p < 0.05). Women in the lowest quartile of serum selenium had twice the risk of preterm birth as women in the upper three quartiles, even after adjustment for the occurrence of preeclampsia (adjusted odds ratio 2.18, 95% confidence interval 1.25-3.77). INTERPRETATION: Having low serum selenium at the end of the first trimester was related to preterm birth and was independent of the mother having preeclampsia. Low maternal selenium status during early gestation may increase the risk of preterm premature rupture of the membranes, which is a major cause of preterm birth. PMID- 21324872 TI - Progressive impairment of cognition and motor function: Hashimoto encephalopathy. PMID- 21324873 TI - Diagnoses and factors associated with medical evacuation and return to duty among nonmilitary personnel participating in military operations in Iraq and Afghanistan. AB - BACKGROUND: Nonmilitary personnel play an increasingly critical role in modern wars. Stark differences exist between the demographic characteristics, training and missions of military and nonmilitary members. We examined the differences in types of injury and rates of returning to duty among nonmilitary and military personnel participating in military operations in Iraq and Afghanistan. METHODS: We collected data for nonmilitary personnel medically evacuated from military operations in Iraq and Afghanistan between 2004 and 2007. We compared injury categories and return-to-duty rates in this group with previously published data for military personnel and identified factors associated with return to duty. RESULTS: Of the 2155 medically evacuated nonmilitary personnel, 74.7% did not return to duty. War-related injuries in this group accounted for 25.6% of the evacuations, the most common causes being combat-related injuries (55.4%) and musculoskeletal/spinal injuries (22.9%). Among individuals with non-war-related injuries, musculoskeletal injuries accounted for 17.8% of evacuations. Diagnoses associated with the highest return-to-duty rates in the group of nonmilitary personnel were psychiatric diagnoses (15.6%) among those with war-related injuries and noncardiac chest or abdominal pain (44.0%) among those with non-war related injuries. Compared with military personnel, nonmilitary personnel with war-related injuries were less likely to return to duty (4.4% v. 5.9%, p = 0.001) but more likely to return to duty after non-war-related injuries (32.5% v. 30.7%, p = 0.001). INTERPRETATION: Compared with military personnel, nonmilitary personnel were more likely to be evacuated with non-war-related injuries but more likely to return to duty after such injuries. For evacuations because of war related injuries, this trend was reversed. PMID- 21324874 TI - Dioxin receptor and SLUG transcription factors regulate the insulator activity of B1 SINE retrotransposons via an RNA polymerase switch. AB - Complex genomes utilize insulators and boundary elements to help define spatial and temporal gene expression patterns. We report that a genome-wide B1 SINE (Short Interspersed Nuclear Element) retrotransposon (B1-X35S) has potent intrinsic insulator activity in cultured cells and live animals. This insulation is mediated by binding of the transcription factors dioxin receptor (AHR) and SLUG (SNAI2) to consensus elements present in the SINE. Transcription of B1-X35S is required for insulation. While basal insulator activity is maintained by RNA polymerase (Pol) III transcription, AHR-induced insulation involves release of Pol III and engagement of Pol II transcription on the same strand. B1-X35S insulation is also associated with enrichment of heterochromatin marks H3K9me3 and H3K27me3 downstream of B1-X35S, an effect that varies with cell type. B1-X35S binds parylated CTCF and, consistent with a chromatin barrier activity, its positioning between two adjacent genes correlates with their differential expression in mouse tissues. Hence, B1 SINE retrotransposons represent genome wide insulators activated by transcription factors that respond to developmental, oncogenic, or toxicological stimuli. PMID- 21324875 TI - Maximum-likelihood estimation of recent shared ancestry (ERSA). AB - Accurate estimation of recent shared ancestry is important for genetics, evolution, medicine, conservation biology, and forensics. Established methods estimate kinship accurately for first-degree through third-degree relatives. We demonstrate that chromosomal segments shared by two individuals due to identity by descent (IBD) provide much additional information about shared ancestry. We developed a maximum-likelihood method for the estimation of recent shared ancestry (ERSA) from the number and lengths of IBD segments derived from high density SNP or whole-genome sequence data. We used ERSA to estimate relationships from SNP genotypes in 169 individuals from three large, well-defined human pedigrees. ERSA is accurate to within one degree of relationship for 97% of first degree through fifth-degree relatives and 80% of sixth-degree and seventh-degree relatives. We demonstrate that ERSA's statistical power approaches the maximum theoretical limit imposed by the fact that distant relatives frequently share no DNA through a common ancestor. ERSA greatly expands the range of relationships that can be estimated from genetic data and is implemented in a freely available software package. PMID- 21324876 TI - CNVnator: an approach to discover, genotype, and characterize typical and atypical CNVs from family and population genome sequencing. AB - Copy number variation (CNV) in the genome is a complex phenomenon, and not completely understood. We have developed a method, CNVnator, for CNV discovery and genotyping from read-depth (RD) analysis of personal genome sequencing. Our method is based on combining the established mean-shift approach with additional refinements (multiple-bandwidth partitioning and GC correction) to broaden the range of discovered CNVs. We calibrated CNVnator using the extensive validation performed by the 1000 Genomes Project. Because of this, we could use CNVnator for CNV discovery and genotyping in a population and characterization of atypical CNVs, such as de novo and multi-allelic events. Overall, for CNVs accessible by RD, CNVnator has high sensitivity (86%-96%), low false-discovery rate (3%-20%), high genotyping accuracy (93%-95%), and high resolution in breakpoint discovery (<200 bp in 90% of cases with high sequencing coverage). Furthermore, CNVnator is complementary in a straightforward way to split-read and read-pair approaches: It misses CNVs created by retrotransposable elements, but more than half of the validated CNVs that it identifies are not detected by split-read or read-pair. By genotyping CNVs in the CEPH, Yoruba, and Chinese-Japanese populations, we estimated that at least 11% of all CNV loci involve complex, multi-allelic events, a considerably higher estimate than reported earlier. Moreover, among these events, we observed cases with allele distribution strongly deviating from Hardy-Weinberg equilibrium, possibly implying selection on certain complex loci. Finally, by combining discovery and genotyping, we identified six potential de novo CNVs in two family trios. PMID- 21324877 TI - A novel approach identifies new differentially methylated regions (DMRs) associated with imprinted genes. AB - Imprinted genes are critical for normal human growth and neurodevelopment. They are characterized by differentially methylated regions (DMRs) of DNA that confer parent of origin-specific transcription. We developed a new strategy to identify imprinted gene-associated DMRs. Using genome-wide methylation profiling of sodium bisulfite modified DNA from normal human tissues of biparental origin, candidate DMRs were identified by selecting CpGs with methylation levels consistent with putative allelic differential methylation. In parallel, the methylation profiles of tissues of uniparental origin, i.e., paternally-derived androgenetic complete hydatidiform moles (AnCHMs), and maternally-derived mature cystic ovarian teratoma (MCT), were examined and then used to identify CpGs with parent of origin-specific DNA methylation. With this approach, we found known DMRs associated with imprinted genomic regions as well as new DMRs for known imprinted genes, NAP1L5 and ZNF597, and novel candidate imprinted genes. The paternally methylated DMR for one candidate, AXL, a receptor tyrosine kinase, was also validated in experiments with mouse embryos that demonstrated Axl was expressed preferentially from the maternal allele in a DNA methylation-dependent manner. PMID- 21324878 TI - Gene regulatory networks and the role of robustness and stochasticity in the control of gene expression. AB - In any given cell, thousands of genes are expressed and work in concert to ensure the cell's function, fitness, and survival. Each gene, in turn, must be expressed at the proper time and in the proper amounts to ensure the appropriate functional outcome. The regulation and expression of some genes are highly robust; their expression is controlled by invariable expression programs. For instance, developmental gene expression is extremely similar in a given cell type from one individual to another. The expression of other genes is more variable: Their levels are noisy and are different from cell to cell and from individual to individual. This can be highly beneficial in physiological responses to outside cues and stresses. Recent advances have enabled the analysis of differential gene expression at a systems level. Gene regulatory networks (GRNs) involving interactions between large numbers of genes and their regulators have been mapped onto graphic diagrams that are used to visualize the regulatory relationships. The further characterization of GRNs has already uncovered global principles of gene regulation. Together with synthetic network biology, such studies are starting to provide insights into the transcriptional mechanisms that cause robust versus stochastic gene expression and their relationships to phenotypic robustness and variability. Here, we discuss GRNs and their topological properties in relation to transcriptional and phenotypic outputs in development and organismal physiology. PMID- 21324879 TI - Coordinated histone modifications are associated with gene expression variation within and between species. AB - Histone modifications regulate gene expression in eukaryotes, but their effects on transcriptomes of a multicellular organism and on transcriptomic divergence between species are poorly understood. Here we present the first nucleotide resolution maps of histone acetylation, methylation, and core histone in Arabidopsis thaliana and a comprehensive analysis of these and all other available maps with gene expression data in A. thaliana, Arabidopsis arenosa, and allotetraploids. H3K9 acetylation (H3K9ac) and H3K4 trimethylation (H3K4me3) are correlated, and their distribution patterns are associated with Gene Ontology (GO) functional classifications. Highly dense and narrow distributions of these modifications near transcriptional start sites are associated with constitutive expression of genes involved in translation, whereas broad distributions toward coding regions correlate with expression variation of the genes involved in photosynthesis, carbohydrate metabolism, and defense responses. Compared to animal stem cells, dispersed distributions of H3K27me3 without bivalent H3K4me3 and H3K9ac marks correlate with developmentally repressed genes in Arabidopsis. Finally, genes affected by A. thaliana histone deacetylase 1 mutation tend to show high levels of expression variation within and between species. The data suggest that genome-wide coordinated modifications of histone acetylation and methylation provide a general mechanism for gene expression changes within and between species and in allopolyploids. PMID- 21324880 TI - Comparative methylome analysis of benign and malignant peripheral nerve sheath tumors. AB - Aberrant DNA methylation (DNAm) was first linked to cancer over 25 yr ago. Since then, many studies have associated hypermethylation of tumor suppressor genes and hypomethylation of oncogenes to the tumorigenic process. However, most of these studies have been limited to the analysis of promoters and CpG islands (CGIs). Recently, new technologies for whole-genome DNAm (methylome) analysis have been developed, enabling unbiased analysis of cancer methylomes. By using MeDIP-seq, we report a sequencing-based comparative methylome analysis of malignant peripheral nerve sheath tumors (MPNSTs), benign neurofibromas, and normal Schwann cells. Analysis of these methylomes revealed a complex landscape of DNAm alterations. In contrast to what has been reported for other tumor types, no significant global hypomethylation was observed in MPNSTs using methylome analysis by MeDIP-seq. However, a highly significant (P < 10(-100)) directional difference in DNAm was found in satellite repeats, suggesting these repeats to be the main target for hypomethylation in MPNSTs. Comparative analysis of the MPNST and Schwann cell methylomes identified 101,466 cancer-associated differentially methylated regions (cDMRs). Analysis showed these cDMRs to be significantly enriched for two satellite repeat types (SATR1 and ARLalpha) and suggests an association between aberrant DNAm of these sequences and transition from healthy cells to malignant disease. Significant enrichment of hypermethylated cDMRs in CGI shores (P < 10(-60)), non-CGI-associated promoters (P < 10(-4)) and hypomethylated cDMRs in SINE repeats (P < 10(-100)) was also identified. Integration of DNAm and gene expression data showed that the expression pattern of genes associated with CGI shore cDMRs was able to discriminate between disease phenotypes. This study establishes MeDIP-seq as an effective method to analyze cancer methylomes. PMID- 21324881 TI - Sequence-based physical mapping of complex genomes by whole genome profiling. AB - We present whole genome profiling (WGP), a novel next-generation sequencing-based physical mapping technology for construction of bacterial artificial chromosome (BAC) contigs of complex genomes, using Arabidopsis thaliana as an example. WGP leverages short read sequences derived from restriction fragments of two dimensionally pooled BAC clones to generate sequence tags. These sequence tags are assigned to individual BAC clones, followed by assembly of BAC contigs based on shared regions containing identical sequence tags. Following in silico analysis of WGP sequence tags and simulation of a map of Arabidopsis chromosome 4 and maize, a WGP map of Arabidopsis thaliana ecotype Columbia was constructed de novo using a six-genome equivalent BAC library. Validation of the WGP map using the Columbia reference sequence confirmed that 350 BAC contigs (98%) were assembled correctly, spanning 97% of the 102-Mb calculated genome coverage. We demonstrate that WGP maps can also be generated for more complex plant genomes and will serve as excellent scaffolds to anchor genetic linkage maps and integrate whole genome sequence data. PMID- 21324884 TI - Public engagement in choosing health priorities. PMID- 21324882 TI - Biome representational in silico karyotyping. AB - Metagenomic characterization of complex biomes remains challenging. Here we describe a modification of digital karyotyping-biome representational in silico karyotyping (BRISK)-as a general technique for analyzing a defined representation of all DNA present in a sample. BRISK utilizes a Type IIB DNA restriction enzyme to create a defined representation of 27-mer DNAs in a sample. Massively parallel sequencing of this representation allows for construction of high-resolution karyotypes and identification of multiple species within a biome. Application to normal human tissue demonstrated linear recovery of tags by chromosome. We apply this technique to the biome of the oral mucosa and find that greater than 25% of recovered DNA is nonhuman. DNA from 41 microbial species could be identified from oral mucosa of two subjects. Of recovered nonhuman sequences, fewer than 30% are currently annotated. We characterized seven prevalent unknown sequences by chromosome walking and find these represent novel microbial sequences including two likely derived from novel phage genomes. Application of BRISK to archival tissue from a nasopharyngeal carcinoma resulted in identification of Epstein-Barr virus infection. These results suggest that BRISK is a powerful technique for the analysis of complex microbiomes and potentially for pathogen discovery. PMID- 21324885 TI - Canada's e-health software mess: simple solution. PMID- 21324886 TI - Bones and groans. PMID- 21324887 TI - Public engagement in choosing health priorities. PMID- 21324888 TI - Obesity is associated with fatal coronary heart disease independently of traditional risk factors and deprivation. AB - BACKGROUND: The effect of body mass index (BMI) on coronary heart disease (CHD) risk is attenuated when mediators of this risk (such as diabetes, hypertension and hyperlipidaemia) are accounted for. However, there is now evidence of a differential effect of risk factors on fatal and non-fatal CHD events, with markers of inflammation more strongly associated with fatal than non-fatal events. OBJECTIVE: To describe the association with BMI separately for both fatal and non-fatal CHD risk after accounting for classical risk factors and to assess any independent effects of obesity on CHD risk. METHODS AND RESULTS: In the West of Scotland Coronary Prevention Study BMI in 6082 men (mean age 55 years) with hypercholesterolaemia, but no history of diabetes or CVD, was related to the risk of fatal and non-fatal CHD events. After excluding participants with any event in the first 2 years, 1027 non-fatal and 214 fatal CHD events occurred during 14.7 years of follow-up. A minimally adjusted model (age, sex, statin treatment) and a maximally adjusted model (including known CVD risk factors and deprivation) were compared, with BMI 25-27.4 kg/m2 as referent. The risk of non fatal events was similar across all BMI categories in both models. The risk of fatal CHD events was increased in men with BMI 30.0-39.9 kg/m2 in both the minimally adjusted model (HR = 1.75 (95% CI 1.12 to 2.74)) and the maximally adjusted model (HR = 1.60 (95% CI 1.02 to 2.53)). CONCLUSIONS: These hypothesis generating data suggest that obesity is associated with fatal, but not non-fatal, CHD after accounting for known cardiovascular risk factors and deprivation. Clinical trial registration WOSCOPS was carried out and completed before the requirement for clinical trial registration. PMID- 21324889 TI - Feasibility of a portable pedal exercise machine for reducing sedentary time in the workplace. AB - BACKGROUND: Sedentary time is independently associated with an increased risk of metabolic disease. Worksite interventions designed to decrease sedentary time may serve to improve employee health. OBJECTIVE: The purpose of this study is to test the feasibility and use of a pedal exercise machine for reducing workplace sedentary time. METHODS: Eighteen full-time employees (mean age+SD 40.2+10.7 years; 88% female) working in sedentary occupations were recruited for participation. Demographic and anthropometric data were collected at baseline and 4 weeks. Participants were provided access to a pedal exercise machine for 4 weeks at work. Use of the device was measured objectively by exercise tracking software, which monitors pedal activity and provides the user real-time feedback (eg, speed, time, distance, calories). At 4 weeks, participants completed a feasibility questionnaire. RESULTS: Participants reported sitting 83% of their working days. Participants used the pedal machines an average of 12.2+6.6 out of a possible 20 working days and pedalled an average of 23.4+20.4 min each day used. Feasibility data indicate that participants found the machines feasible for use at work. Participants also reported sedentary time at work decreased due to the machine. DISCUSSION: Findings from this study suggest that this pedal machine may be a feasible tool for reducing sedentary time while at work. These findings hold public health significance due to the growing number of sedentary jobs in the USA and the potential of the device for use in large-scale worksite health programmes. PMID- 21324890 TI - Physical activity as medicine: time to translate evidence into clinical practice. PMID- 21324891 TI - BJSM reviews: A to Z of nutritional supplements: dietary supplements, sports nutrition foods and ergogenic aids for health and performance--part 18. PMID- 21324892 TI - Modeling reveals that dynamic regulation of c-FLIP levels determines cell-to-cell distribution of CD95-mediated apoptosis. AB - The expression levels of caspase-8 inhibitory c-FLIP proteins play an important role in regulating death receptor-mediated apoptosis, as their concentration at the moment when the death-inducing signaling complex (DISC) is formed determines the outcome of the DISC signal. Experimental studies have shown that c-FLIP proteins are subject to dynamic turnover and that their stability and expression levels can be rapidly altered. Even though the influence of c-FLIP on the apoptotic behavior of a single cell has been captured in mathematical simulation studies, the effect of c-FLIP turnover and stability has not been investigated. In this study, a mathematical model of apoptosis was developed to analyze how the dynamic turnover and stability of the c-FLIP isoforms regulate apoptotic signaling for both individual cells and cell populations. Intercellular parameter and concentration distributions were used to describe the behavior of cell populations. Monte-Carlo simulations of cell populations showed that c-FLIP turnover is a key determinant of death receptor responses. The fact that the developed model simulates the state of whole cell populations makes it possible to validate it by comparison with empirical data. The proposed modeling approach can be used to further determine limiting factors in the DISC signaling process. PMID- 21324893 TI - TGF-beta regulates miR-206 and miR-29 to control myogenic differentiation through regulation of HDAC4. AB - MicroRNAs (miRs) are emerging as prominent players in the regulation of many biological processes, including myogenic commitment and skeletal muscle formation. Members of the TGF-beta family can influence the proliferation and myogenic differentiation of cells, although it is presently not clear what role miRNAs play in the TGF-beta-mediated control of myogenic differentiation. Here, we demonstrate in the myogenic C2C12 cell line, and in primary muscle cells, that miR-206 and miR-29-two miRs that act on transcriptional events implicated in muscle differentiation are down-regulated by TGF-beta. We further demonstrate that TGF-beta treatment of myogenic cells is associated with increased expression of histone deacetylase 4 (HDAC4), a key inhibitor of muscle differentiation that has been identified as a target for regulation by miR-206 and miR-29. We confirmed that increased expression of miR-206 and miR-29 resulted in the translational repression of HDAC4 in the presence or absence of TGF-beta via interaction with the HDAC4 3'-untranslated region. Importantly, we found that miR 206 and miR-29 can attenuate the inhibitory actions of TGF-beta on myogenic differentiation. Furthermore, we present evidence that the mechanism by which miR 206 and miR-29 can inhibit the TGF-beta-mediated up-regulation of HDAC4 is via the inhibition of Smad3 expression, a transducer of TGF-beta signaling. These findings identify a novel mechanism of interaction between TGF-beta and miR-206 and -29 in the regulation of myogenic differentiation through HDAC4. PMID- 21324894 TI - Nuclear protein quality is regulated by the ubiquitin-proteasome system through the activity of Ubc4 and San1 in fission yeast. AB - Eukaryotic cells monitor and maintain protein quality through a set of protein quality control (PQC) systems whose role is to minimize the harmful effects of the accumulation of aberrant proteins. Although these PQC systems have been extensively studied in the cytoplasm, nuclear PQC systems are not well understood. The present work shows the existence of a nuclear PQC system mediated by the ubiquitin-proteasome system in the fission yeast Schizosaccharomyces pombe. Asf1-30, a mutant form of the histone chaperone Asf1, was used as a model substrate for the study of the nuclear PQC. A temperature-sensitive Asf1-30 protein localized to the nucleus was selectively degraded by the ubiquitin proteasome system. The Asf1-30 mutant protein was highly ubiquitinated at higher temperatures, and it remained stable in an mts2-1 mutant, which lacks proteasome activity. The E2 enzyme Ubc4 was identified among 11 candidate proteins as the ubiquitin-conjugating enzyme in this system, and San1 was selected among 100 candidates as the ubiquitin ligase (E3) targeting Asf1-30 for degradation. San1, but not other nuclear E3s, showed specificity for the mutant nuclear Asf1-30, but did not show activity against wild-type Asf1. These data clearly showed that the aberrant nuclear protein was degraded by a defined set of E1-E2-E3 enzymes through the ubiquitin-proteasome system. The data also show, for the first time, the presence of a nuclear PQC system in fission yeast. PMID- 21324895 TI - c-Jun N-terminal kinase (JNK-1) confers protection against brief but not extended ischemia during acute myocardial infarction. AB - Brief periods of ischemia do not damage the heart and can actually protect against reperfusion injury caused by extended ischemia. It is not known what causes the transition from protection to irreversible damage as ischemia progresses. c-Jun N-terminal kinase-1 (JNK-1) is a stress-regulated kinase that is activated by reactive oxygen and thought to promote injury during severe acute myocardial infarction. Because some reports suggest that JNK-1 can also be protective, we hypothesized that the function of JNK-1 depends on the metabolic state of the heart at the time of reperfusion, a condition that changes progressively with duration of ischemia. Mice treated with JNK-1 inhibitors or transgenic mice wherein the JNK-1 gene was ablated were subjected to 5 or 20 min of ischemia followed by reperfusion. When JNK-1 was inactive, ischemia of only 5 min duration caused massive apoptosis, infarction, and negative remodeling that was equivalent to or greater than extended ischemia. Conversely, when ischemia was extended JNK-1 inactivation was protective. Mechanisms of the JNK-1 switch in function were investigated in vivo and in cultured cardiac myocytes. In vitro there was a comparable switch in the function of JNK-1 from protective when ATP levels were maintained during hypoxia to injurious when reoxygenation followed glucose and ATP depletion. Both apoptotic and necrotic death pathways were affected and responded reciprocally to JNK-1 inhibitors. JNK-1 differentially regulated Akt phosphorylation of the regulatory sites Ser-473 and Thr-450 and the catalytic Thr-308 site in vivo. The studies define a novel role for JNK-1 as a conditional survival kinase that protects the heart against brief but not protracted ischemia. PMID- 21324896 TI - p85alpha regulates osteoblast differentiation by cross-talking with the MAPK pathway. AB - Class IA phosphoinositide 3-kinase (PI3K) is involved in regulating many cellular functions including cell growth, proliferation, cell survival, and differentiation. The p85 regulatory subunit is a critical component of the PI3K signaling pathway. Mesenchymal stem cells (MSC) are multipotent cells that can be differentiated into osteoblasts (OBs), adipocytes, and chondrocytes under defined culture conditions. To determine whether p85alpha subunit of PI3K affects biological functions of MSCs, bone marrow-derived wild type (WT) and p85alpha deficient (p85alpha(-/-)) cells were employed in this study. Increased cell growth, higher proliferation rate and reduced number of senescent cells were observed in MSCs lacking p85alpha compare with WT MSCs as evaluated by CFU-F assay, thymidine incorporation assay, and beta-galactosidase staining, respectively. These functional changes are associated with the increased cell cycle, increased expression of cyclin D, cyclin E, and reduced expression of p16 and p19 in p85alpha(-/-) MSCs. In addition, a time-dependent reduction in alkaline phosphatase (ALP) activity and osteocalcin mRNA expression was observed in p85alpha(-/-) MSCs compared with WT MSCs, suggesting impaired osteoblast differentiation due to p85alpha deficiency in MSCs. The impaired p85alpha(-/-) osteoblast differentiation was associated with increased activation of Akt and MAPK. Importantly, bone morphogenic protein 2 (BMP2) was able to intensify the differentiation of osteoblasts derived from WT MSCs, whereas this process was significantly impaired as a result of p85alpha deficiency. Addition of LY294002, a PI3K inhibitor, did not alter the differentiation of osteoblasts in either genotype. However, application of PD98059, a Mek/MAPK inhibitor, significantly enhanced osteoblast differentiation in WT and p85alpha(-/-) MSCs. These results suggest that p85alpha plays an essential role in osteoblast differentiation from MSCs by repressing the activation of MAPK pathway. PMID- 21324897 TI - A Runx2/miR-3960/miR-2861 regulatory feedback loop during mouse osteoblast differentiation. AB - Our recent study showed that miR-2861 promotes osteoblast differentiation by targeting histone deacetylase 5, resulting in increased runt-related transcription factor 2 (Runx2) protein production. Here we identified another new microRNA (miRNA) (miR-3960) that played a regulatory role in osteoblast differentiation through a regulatory feedback loop with miR-2861. miR-3960 and miR-2861 were found clustered at the same loci. miR-3960 was transcribed during bone morphogenic protein 2 (BMP2)-induced osteogenesis of ST2 stromal cells. Overexpression of miR-3960 promoted BMP2-induced osteoblastogenesis. However, the inhibition of miR-3960 expression attenuated the osteoblastogenesis. Homeobox A2 (Hoxa2), a repressor of Runx2 expression, was confirmed to be a target of miR 3960. Electrophoretic mobility shift assay and chromatin immunoprecipitation experiments confirmed that Runx2 bound to the promoter of the miR-3960/miR-2861 cluster. Furthermore, overexpression of Runx2 induced miR-3960/miR-2861 transcription, and block of Runx2 expression attenuated BMP2-induced miR-3960/miR 2861 transcription. Here we report that miR-3960 and miR-2861, transcribed together from the same miRNA polycistron, both function in osteoblast differentiation through a novel Runx2/miR-3960/miR-2861 regulatory feedback loop. Our findings provide new insights into the roles of miRNAs in osteoblast differentiation. PMID- 21324898 TI - HDAC3 and HDAC7 have opposite effects on osteoclast differentiation. AB - Histone deacetylases (HDACs) are negative regulators of transcription. Endochondral bone formation including chondrocyte and osteoblast maturation is regulated by HDACs. Very little is known about the role HDACs play in osteoclast differentiation. It has been previously reported that HDAC inhibitors, trichostatin A and sodium butyrate, suppress osteoclast differentiation through multiple mechanisms. In this study, we report that suppression of HDAC3 expression similar to HDAC inhibitors inhibits osteoclast differentiation, whereas osteoclasts suppressed for HDAC7 expression had accelerated differentiation when compared with control cells. Mitf, a transcription factor, is necessary for osteoclast differentiation. We demonstrate that Mitf and HDAC7 interact in RAW 264 cells and osteoclasts. The transcriptional activity of Mitf is repressed by HDAC7. Lastly, we show that either the amino or the carboxyl terminus of HDAC7 is sufficient for transcriptional repression and that the repression of HDAC7 is insensitive to trichostatin A, indicating that HDAC7 represses Mitf at least in part by deacetylation-independent mechanism. PMID- 21324899 TI - FGFR3 heterodimerization in achondroplasia, the most common form of human dwarfism. AB - The G380R mutation in the transmembrane domain of fibroblast growth factor receptor 3 (FGFR3) causes achondroplasia, the most common form of human dwarfism. Achondroplasia is a heterozygous disorder, and thus the affected individuals express both wild-type and mutant FGFR3. Yet heterodimerization in achondroplasia has not been characterized thus far. To investigate the formation of FGFR3 heterodimers in cellular membranes, we designed an FGFR3 construct that lacks the kinase domain, and we monitored the formation of inactive heterodimers between this construct and wild-type and mutant FGFR3. The formation of the inactive heterodimers depleted the pool of full-length receptors capable of forming active homodimers and ultimately reduced their phosphorylation. By analyzing the effect of the truncated FGFR3 on full-length receptor phosphorylation, we demonstrated that FGFR3 WT/G380R heterodimers form with lower probability than wild-type FGFR3 homodimers at low ligand concentration. These results further our knowledge of FGFR3-associated bone disorders. PMID- 21324900 TI - Casein kinase 1-dependent phosphorylation of familial advanced sleep phase syndrome-associated residues controls PERIOD 2 stability. AB - The mammalian circadian clock component PERIOD2 (PER2) plays a critical role in circadian rhythm entrainment. Recently, a missense mutation at a putative phosphorylation site in hPER2, Ser-662, was identified in patients that suffer from familial advanced sleep phase syndrome (FASPS). Patients with FASPS display abnormal sleep-wake patterns characterized by a lifelong pattern of sleep onset in the early evening and offset in the early morning. Although the phosphorylation of PER2 is strongly implied from functional studies, it has not been possible to study the site-specific phosphorylation of PER2 on Ser-662, and the biochemical functions of this residue are unclear. Here, we used phospho specific antibodies to show that PER2 is phosphorylated on Ser-662 and flanking casein kinase (CK) sites in vivo. The phosphorylation of PER2 was carried out by the combined activities of casein kinase 1delta (CK1 delta) and casein kinase 1epsilon (CK1epsilon) and was antagonized by protein phosphatase 1. PER2 phosphorylation was rapidly induced in response to circadian entrainment of mammalian cell lines and occurred in both cytosolic and nuclear compartments. Importantly, we found that the pool of Ser-662-phosphorylated PER2 proteins was more stable than the pool of total PER2 molecules, implying that the FASPS phosphorylation cluster antagonizes PER2 degradation. Consistent with this idea, a Ser-662->Ala mutation that abrogated PER2 phosphorylation significantly reduced its half-life, whereas a phosphomimetic Ser-662->Asp substitution led to an elevation in half-life. Our combined findings provide new insights into PER2 regulation and the biochemical basis of FASPS. PMID- 21324901 TI - Identification of novel and distinct binding sites within tenascin-C for soluble and fibrillar fibronectin. AB - Interactions between fibronectin and tenascin-C within the extracellular matrix provide specific environmental cues that dictate tissue structure and cell function. The major binding site for fibronectin lies within the fibronectin type III-like repeats (TNfn) of tenascin-C. Here, we systematically screened TNfn domains for their ability to bind to both soluble and fibrillar fibronectin. All TNfn domains containing the TNfn3 module interact with soluble fibronectin. However, TNfn domains bind differentially to fibrillar fibronectin. This distinct binding pattern is dictated by the fibrillar conformation of FN. TNfn1-3, but not TNfn3-5, binds to immature fibronectin fibrils, and additional TNfn domains are required for binding to mature fibrils. Multiple binding sites for distinct regions of fibronectin exist within tenascin-C. TNfn domains comprise a binding site for the N-terminal 70-kDa domain of fibronectin that is freely available and a binding site for the central binding domain of fibronectin that is cryptic in full-length tenascin-C. The 70-kDa and central binding domain regions are key for fibronectin matrix assembly; accordingly, binding of several TNfn domains to these regions inhibits fibronectin fibrillogenesis. These data highlight the complexity of protein-protein binding, the importance of protein conformation on these interactions, and the implications for the physiological assembly of complex three-dimensional matrices. PMID- 21324902 TI - Small ubiquitin-related modifier ligase activity of Mms21 is required for maintenance of chromosome integrity during the unperturbed mitotic cell division cycle in Saccharomyces cerevisiae. AB - The SUMO ligase activity of Mms21/Nse2, a conserved member of the Smc5/6 complex, is required for resisting extrinsically induced genotoxic stress. We report that the Mms21 SUMO ligase activity is also required during the unchallenged mitotic cell cycle in Saccharomyces cerevisiae. SUMO ligase-defective cells were slow growing and spontaneously incurred DNA damage. These cells required caffeine sensitive Mec1 kinase-dependent checkpoint signaling for survival even in the absence of extrinsically induced genotoxic stress. SUMO ligase-defective cells were sensitive to replication stress and displayed synthetic growth defects with DNA damage checkpoint-defective mutants such as mec1, rad9, and rad24. MMS21 SUMO ligase and mediator of replication checkpoint 1 gene (MRC1) were epistatic with respect to hydroxyurea-induced replication stress or methyl methanesulfonate induced DNA damage sensitivity. Subjecting Mms21 SUMO ligase-deficient cells to transient replication stress resulted in enhancement of cell cycle progression defects such as mitotic delay and accumulation of hyperploid cells. Consistent with the spontaneous activation of the DNA damage checkpoint pathway observed in the Mms21-mediated sumoylation-deficient cells, enhanced frequency of chromosome breakage and loss was detected in these mutant cells. A mutation in the conserved cysteine 221 that is engaged in coordination of the zinc ion in Loop 2 of the Mms21 SPL-RING E3 ligase catalytic domain resulted in strong replication stress sensitivity and also conferred slow growth and Mec1 dependence to unchallenged mitotically dividing cells. Our findings establish Mms21-mediated sumoylation as a determinant of cell cycle progression and maintenance of chromosome integrity during the unperturbed mitotic cell division cycle in budding yeast. PMID- 21324903 TI - Hypotonicity-induced reduction of aquaporin-2 transcription in mpkCCD cells is independent of the tonicity responsive element, vasopressin, and cAMP. AB - The syndrome of inappropriate antidiuretic hormone secretion is characterized by excessive water uptake and hyponatremia. The extent of hyponatremia, however, is less than anticipated, which is ascribed to a defense mechanism, the vasopressin escape, and is suggested to involve a tonicity-determined down-regulation of the water channel aquaporin-2 (AQP2). The underlying mechanism, however, is poorly understood. To study this, we used the mouse cortical collecting duct (mpkCCD) cell line. MpkCCD cells, transfected with an AQP2-promoter luciferase construct showed a reduced and increased AQP2 abundance and transcription following culture in hypotonic and hypertonic medium, respectively. This depended on tonicity rather than osmolality and occurred independently of the vasopressin analog dDAVP, cAMP levels, or protein kinase A activity. Although prostaglandins and nitric oxide reduced AQP2 abundance, inhibition of their synthesis did not influence tonicity-induced AQP2 transcription. Also, cells in which the cAMP or tonicity-responsive element (CRE/TonE) in the AQP2-promoter were mutated showed a similar response to hypotonicity. Instead, the tonicity-responsive elements were pin-pointed to nucleotides -283 to -252 and -157 to -126 bp. In conclusion, our data indicate that hypotonicity reduces AQP2 abundance and transcription, which occurs independently of vasopressin, cAMP, and the known TonE and CRE in the AQP2 promoter. Increased prostaglandin and nitric oxide, as found in vivo, may contribute to reduced AQP2 in vasopressin-escape, but do not mediate the effect of hypotonicity on AQP2 transcription. Our data suggest that two novel segments ( 283 to -252 and -157 to -126 bp) in the AQP2-promoter mediate the hypotonicity induced AQP2 down-regulation during vasopressin-escape. PMID- 21324904 TI - Crystal structure and biochemical features of EfeB/YcdB from Escherichia coli O157: ASP235 plays divergent roles in different enzyme-catalyzed processes. AB - EfeB/YcdB is a member of the dye-decolorizing peroxidase (DyP) protein family. A recent study has shown that this protein can extract iron from heme without breaking the tetrapyrrole ring. We report the crystal structure of EfeB from Escherichia coli O157 bound to heme at 1.95 A resolution. The EfeB monomer contains two domains. The heme molecule is located in a large hydrophobic pocket in the C-terminal domain. A long loop connecting the two domains extensively interacts with the heme, which is a distinctive structural feature of EfeB homologues. A large tunnel formed by this loop and the beta-sheet of C-terminal domain provides a potential cofactor/substrate binding site. Biochemical data show that the production of protoporphyrin IX (PPIX) is closely related to the peroxidation activity. The mutant D235N keeps nearly the same activity of guaiacol peroxidase as the wild-type protein, whereas the corresponding mutation in the classic DyP protein family completely abolished the peroxidation activity. These results suggest that EfeB is a unique member of the DyP protein family. In addition, dramatically enhanced fluorescence excitation and emission of EfeB-PPIX was observed, implying this protein may be used as a red color fluorescence marker. PMID- 21324905 TI - Thioredoxin increases exocytosis by denitrosylating N-ethylmaleimide-sensitive factor. AB - Exocytosis involves membrane fusion between granules and the plasma membrane. Nitric oxide (NO) inhibits exocytosis by chemically modifying N-ethylmaleimide sensitive factor (NSF), a key component of the exocytic machinery. However, cells recover the ability to release messenger molecules within hours of exposure to NO through unknown mechanisms. We now identify thioredoxin (TRX1) as a denitrosylase that reverses NO inhibition of exocytosis. Endogenously synthesized NO increases S-nitrosylated NSF levels, but S-nitrosylated NSF levels decrease within 3 h after exposure to NO. We found that NO increases the interaction between TRX1 and NSF, and endogenous TRX1 removes NO from S-nitrosylated NSF. Knockdown of TRX1 increases the level of S-nitrosylated NSF, prolongs the inhibition of exocytosis, and suppresses leukocyte adhesion. Taken together, these data show that TRX1 promotes exocytosis by denitrosylating NSF. Our findings suggest that TRX1 might regulate exocytosis in a variety of physiological settings, such as vascular inflammation, thrombosis, and insulin release. PMID- 21324906 TI - Late activation of stress-activated protein kinases/c-Jun N-terminal kinases triggered by cisplatin-induced DNA damage in repair-defective cells. AB - Although stress-activated protein kinases/c-Jun N-terminal kinases (SAPK/JNK) are rapidly activated by genotoxins, the role of DNA damage in this response is not well defined. Here we show that the SEK1/MKK4-mediated dual phosphorylation of SAPK/JNK (Thr-183/Tyr-185) correlates with the level of cisplatin-DNA adducts at late times (16-24 h) after drug treatment in both human and mouse cells. Transfection of platinated plasmid DNA also caused SAPK/JNK activation. A defect in transcription-coupled nucleotide excision repair resting on a mutation in Cockayne syndrome group B protein promoted the late SAPK/JNK activation following cisplatin exposure. Signaling to SAPK/JNK was accompanied by activation of Ataxia telangiectasia mutated- and Rad3-related kinase, replication protein A, and checkpoint kinases as well as by the formation of DNA double strand breaks (DSBs). Ionizing radiation-induced DSBs did not provoke SAPK/JNK activation, and inhibition of transcription also failed to provoke this response. Late activation of SAPK/JNK stimulated by cisplatin-induced DNA lesions was reduced in the absence of specific DNA repair proteins, such as xeroderma pigmentosum protein C, pointing to an essential function of individual repair factors in DNA damage signaling to SAPK/JNK. Collectively, the data indicate that late SAPK/JNK activation is triggered by non-repaired cisplatin adducts in transcribed genes and involves replication-associated events, DSBs, tyrosine kinases, Rho GTPases, and specific repair factors. PMID- 21324908 TI - Bacterial toxin RelE mediates frequent codon-independent mRNA cleavage from the 5' end of coding regions in vivo. AB - The enzymatic activity of the RelE bacterial toxin component of the Escherichia coli RelBE toxin-antitoxin system has been extensively studied in vitro and to a lesser extent in vivo. These earlier reports revealed that 1) RelE alone does not exhibit mRNA cleavage activity, 2) RelE mediates mRNA cleavage through its association with the ribosome, 3) RelE-mediated mRNA cleavage occurs at the ribosomal A site and, 4) Cleavage of mRNA by RelE exhibits high codon specificity. More specifically, RelE exhibits a preference for the stop codons UAG and UGA and sense codons CAG and UCG in vitro. In this study, we used a comprehensive primer extension approach to map the frequency and codon specificity of RelE cleavage activity in vivo. We found extensive cleavage at the beginning of the coding region of five transcripts, ompA, lpp, ompF, rpsA, and tufA. We then mapped RelE cleavage sites across one short transcript (lpp) and two long transcripts (ompF and ompA). RelE cut all of these transcripts frequently and efficiently within the first ~100 codons, only occasionally cut beyond this point, and rarely cut at sites in proximity to the 3' end. Among 196 RelE sites in these five transcripts, there was no preference for CAG or UCG sense codons. In fact, bioinformatic analysis of the RelE cleavage sites failed to identify any sequence preferences. These results suggest a model of RelE function distinct from those proposed previously, because RelE directed frequent codon-independent mRNA cleavage coincident with the commencement of translation elongation. PMID- 21324907 TI - Docosahexaenoic acid reduces amyloid beta production via multiple pleiotropic mechanisms. AB - Alzheimer disease is characterized by accumulation of the beta-amyloid peptide (Abeta) generated by beta- and gamma-secretase processing of the amyloid precursor protein (APP). The intake of the polyunsaturated fatty acid docosahexaenoic acid (DHA) has been associated with decreased amyloid deposition and a reduced risk in Alzheimer disease in several epidemiological trials; however, the exact underlying molecular mechanism remains to be elucidated. Here, we systematically investigate the effect of DHA on amyloidogenic and nonamyloidogenic APP processing and the potential cross-links to cholesterol metabolism in vivo and in vitro. DHA reduces amyloidogenic processing by decreasing beta- and gamma-secretase activity, whereas the expression and protein levels of BACE1 and presenilin1 remain unchanged. In addition, DHA increases protein stability of alpha-secretase resulting in increased nonamyloidogenic processing. Besides the known effect of DHA to decrease cholesterol de novo synthesis, we found cholesterol distribution in plasma membrane to be altered. In the presence of DHA, cholesterol shifts from raft to non-raft domains, and this is accompanied by a shift in gamma-secretase activity and presenilin1 protein levels. Taken together, DHA directs amyloidogenic processing of APP toward nonamyloidogenic processing, effectively reducing Abeta release. DHA has a typical pleiotropic effect; DHA-mediated Abeta reduction is not the consequence of a single major mechanism but is the result of combined multiple effects. PMID- 21324910 TI - Subunit dimers of alpha-hemolysin expand the engineering toolbox for protein nanopores. AB - Staphylococcal alpha-hemolysin (alphaHL) forms a heptameric pore that features a 14-stranded transmembrane beta-barrel. We attempted to force the alphaHL pore to adopt novel stoichiometries by oligomerizing subunit dimers generated by in vitro transcription and translation of a tandem gene. However, in vitro transcription and translation also produced truncated proteins, monomers, that were preferentially incorporated into oligomers. These oligomers were shown to be functional heptamers by single-channel recording and had a similar mobility to wild-type heptamers in SDS-polyacrylamide gels. Purified full-length subunit dimers were then prepared by using His-tagged protein. Again, single-channel recording showed that oligomers made from these dimers are functional heptamers, implying that one or more subunits are excluded from the central pore. Therefore, the alphaHL pore resists all structures except those that possess seven subunits immediately surrounding the central axis. Although we were not able to change the stoichiometry of the central pore of alphaHL by the concatenation of subunits, we extended our findings to prepare pores containing one subunit dimer and five monomers and purified them by SDS-PAGE. Two half-chelating ligands were then installed at adjacent sites, one on each subunit of the dimer. Single-channel recording showed that pores formed from this construct formed complexes with divalent metal ions in a similar fashion to pores containing two half-chelating ligands on the same subunit, confirming that the oligomers had assembled with seven subunits around the central lumen. The ability to incorporate subunit dimers into alphaHL pores increases the range of structures that can be obtained from engineered protein nanopores. PMID- 21324909 TI - Globular domain of the prion protein needs to be unlocked by domain swapping to support prion protein conversion. AB - Prion diseases are fatal transmissible neurodegenerative diseases affecting many mammalian species. The normal prion protein (PrP) converts into a pathological aggregated form, PrPSc, which is enriched in the beta-sheet structure. Although the high resolution structure of the normal PrP was determined, the structure of the converted form of PrP remains inaccessible to high resolution techniques. To map the PrP conversion process we introduced disulfide bridges into different positions within the globular domain of PrP, tethering selected secondary structure elements. The majority of tethered PrP mutants exhibited increased thermodynamic stability, nevertheless, they converted efficiently. Only the disulfides that tether subdomain B1-H1-B2 to subdomain H2-H3 prevented PrP conversion in vitro and in prion-infected cell cultures. Reduction of disulfides recovered the ability of these mutants to convert, demonstrating that the separation of subdomains is an essential step in conversion. Formation of disulfide-linked proteinase K-resistant dimers in fibrils composed of a pair of single cysteine mutants supports the model based on domain-swapped dimers as the building blocks of prion fibrils. In contrast to previously proposed structural models of PrPSc suggesting conversion of large secondary structural segments, we provide evidence for the conservation of secondary structural elements of the globular domain upon PrP conversion. Previous studies already showed that dimerization is the rate-limiting step in PrP conversion. We show that separation and swapping of subdomains of the globular domain is necessary for conversion. Therefore, we propose that the domain-swapped dimer of PrP precedes amyloid formation and represents a potential target for therapeutic intervention. PMID- 21324911 TI - Polynucleotide phosphorylase activity may be modulated by metabolites in Escherichia coli. AB - RNA turnover is an essential element of cellular homeostasis and response to environmental change. Whether the ribonucleases that mediate RNA turnover can respond to cellular metabolic status is an unresolved question. Here we present evidence that the Krebs cycle metabolite citrate affects the activity of Escherichia coli polynucleotide phosphorylase (PNPase) and, conversely, that cellular metabolism is affected widely by PNPase activity. An E. coli strain that requires PNPase for viability has suppressed growth in the presence of increased citrate concentration. Transcriptome analysis reveals a PNPase-mediated response to citrate, and PNPase deletion broadly impacts on the metabolome. In vitro, citrate directly binds and modulates PNPase activity, as predicted by crystallographic data. Binding of metal-chelated citrate in the active site at physiological concentrations appears to inhibit enzyme activity. However, metal free citrate is bound at a vestigial active site, where it stimulates PNPase activity. Mutagenesis data confirmed a potential role of this vestigial site as an allosteric binding pocket that recognizes metal-free citrate. Collectively, these findings suggest that RNA degradative pathways communicate with central metabolism. This communication appears to be part of a feedback network that may contribute to global regulation of metabolism and cellular energy efficiency. PMID- 21324916 TI - Activation of peroxisome proliferator-activated receptor-alpha stimulates both differentiation and fatty acid oxidation in adipocytes. AB - Peroxisome proliferator-activated receptor-alpha (PPARalpha) is a dietary lipid sensor, whose activation results in hypolipidemic effects. In this study, we investigated whether PPARalpha activation affects energy metabolism in white adipose tissue (WAT). Activation of PPARalpha by its agonist (bezafibrate) markedly reduced adiposity in KK mice fed a high-fat diet. In 3T3-L1 adipocytes, addition of GW7647, a highly specific PPARalpha agonist, during adipocyte differentiation enhanced glycerol-3-phosphate dehydrogenase activity, insulin stimulated glucose uptake, and adipogenic gene expression. However, triglyceride accumulation was not increased by PPARalpha activation. PPARalpha activation induced expression of target genes involved in FA oxidation and stimulated FA oxidation. In WAT of KK mice treated with bezafibrate, both adipogenic and FA oxidation-related genes were significantly upregulated. These changes in mRNA expression were not observed in PPARalpha-deficient mice. Bezafibrate treatment enhanced FA oxidation in isolated adipocytes, suppressing adipocyte hypertrophy. Chromatin immunoprecipitation (ChIP) assay revealed that PPARalpha was recruited to promoter regions of both adipogenic and FA oxidation-related genes in the presence of GW7647 in 3T3-L1 adipocytes. These findings indicate that the activation of PPARalpha affects energy metabolism in adipocytes, and PPARalpha activation in WAT may contribute to the clinical effects of fibrate drugs. PMID- 21324917 TI - Primary monophasic synovial sarcoma of the pleura: diagnosis and treatment. AB - Synovial sarcomas are uncommon soft tissue malignancies that usually affect the extremities in the vicinity of large joints. The recognition of this tumor in an unexpected site, such as the pleura, is often difficult and the monophasic variant of synovial sarcoma is often mistaken for some other spindle cell tumor. In this report, we describe a very rare case of primary monophasic synovial sarcoma of the pleura treated with radical surgery. PMID- 21324918 TI - Familial aortic aneurysm and dissection due to transforming growth factor-beta receptor 2 mutation. AB - This report describes the clinical course and management of a patient with Loeys Dietz syndrome (LDS) type 2. In 2003, a 31-year-old male was diagnosed with acute aortic dissection type B; in the following six years he underwent multiple surgical and endovascular aortic procedures at different thoracic and abdominal levels secondary to progressive enlargement of both the non-dissected thoracic aorta and the false lumen distal to the left subclavian artery. LDS is characterized by arterial tortuosity and aneurysms as a result of heterozygous mutations in genes encoding transforming growth factor-beta receptor 1 and 2. Further studies are required to establish the proper surgical management. PMID- 21324919 TI - Integration of genotypic and phenotypic screening reveals molecular mediators of melanoma-stromal interaction. AB - Tumor-endothelium interactions are critical for tumor survival and metastasis. Melanomas can rapidly metastasize early in tumor progression, but the dependence of this aggressive behavior on tumor-stromal interaction is poorly understood. To probe the mechanisms involved, we developed a heterotypic coculture methodology, allowing simultaneous tracking of genomic and phenotypic changes in interacting tumor and endothelial cells in vitro. We found a dramatic rearrangement of endothelial cell networks into patterns reminiscent of vascular beds, even on plastic and glass. Multiple genes were upregulated in the process, many coding for cell surface and secreted proteins, including Neuropilin-2 (NRP2). A critical role of NRP2 in coordinated cell patterning and growth was confirmed using the coculture system. We conclude that NRP2 represents an important mediator of melanoma-endothelial interactions. Furthermore, the described methodology represents a powerful yet simple system to elucidate heterotypic intercellular interactions mediating diverse physiological and pathological processes. PMID- 21324920 TI - Protein kinase C inhibitor sotrastaurin selectively inhibits the growth of CD79 mutant diffuse large B-cell lymphomas. AB - The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) correlates with poor prognosis. The ABC subtype of DLBCL is associated with constitutive activation of the NF-kappaB pathway, and oncogenic lesions have been identified in its regulators, including CARD11/CARMA1 (caspase recruitment domain containing protein 11), A20/TNFAIP3, and CD79A/B. In this study, we offer evidence of therapeutic potential for the selective PKC (protein kinase C) inhibitor sotrastaurin (STN) in preclinical models of DLBCL. A significant fraction of ABC DLBCL cell lines exhibited strong sensitivity to STN, and we found that the molecular nature of NF-kappaB pathway lesions predicted responsiveness. CD79A/B mutations correlated with STN sensitivity, whereas CARD11 mutations rendered ABC DLBCL cell lines insensitive. Growth inhibitory effects of PKC inhibition correlated with NF-kappaB pathway inhibition and were mediated by induction of G1-phase cell-cycle arrest and/or cell death. We found that STN produced significant antitumor effects in a mouse xenograft model of CD79A/B mutated DLBCL. Collectively, our findings offer a strong rationale for the clinical evaluation of STN in ABC DLBCL patients who harbor CD79 mutations also illustrating the necessity to stratify DLBCL patients according to their genetic abnormalities. PMID- 21324921 TI - Coactivation of AKT and beta-catenin in mice rapidly induces formation of lipogenic liver tumors. AB - Obesity is a risk factor for development of certain cancers but the basis for this risk is unclear. In this study, we developed a novel mouse model that demonstrates directly how lipogenic phenotypes commonly associated with diet induced metabolic syndromes can influence hepatic cancer development. Activated AKT and beta-catenin (AKT/CAT) genes were hydrodynamically codelivered using the Sleeping Beauty transposon to initiate liver tumorigenesis. AKT/CAT and MET/CAT combination induced microscopic tumor foci by 4 weeks, whereas no tumorigenesis resulted from delivery of AKT, MET, or CAT alone. Primary AKT/CAT tumor cells were steatotic (fatty) hepatocellular adenomas which progressed to hepatocellular carcinomas (HCC) upon in vivo passage, whereas primary MET/CAT tumors emerged directly as frank HCC. Conversion of AKT/CAT tumor cells to frank HCC during passage was associated with induction of the human HCC marker alpha-fetoprotein and the stem cell marker CD133. Using hierarchical clustering and gene set enrichment analysis, we compared the primary murine AKT/CAT and MET/CAT tumors to a panel of 53 human HCCs and determined that these two mouse models could be stratified as distinct subtypes associated in humans with poor clinical prognosis. The chief molecular networks identified in primary and passaged AKT/CAT tumors were steatosis and lipid metabolic pathways, respectively. Our findings show how coactivation of the AKT and CAT pathways in hepatocytes can efficiently model development of a lipogenic tumor phenotype. Furthermore, we believe that our approach could speed the dissection of microenvironmental factors responsible for driving steatotic-neoplastic transformation to frank carcinoma, through genetic modification of existing immunodefined transgenic models. PMID- 21324922 TI - Cooperation between Pik3ca and p53 mutations in mouse mammary tumor formation. AB - PIK3CA, which codes for the p110alpha catalytic subunit of phosphatidylinositol 3 kinase, is one of the most frequently mutated genes in human breast cancer. Here, we describe a mouse model for PIK3CA-induced breast cancer by using the ROSA26 (R26) knock-in system, in which targeted Pik3ca alleles can be activated through transgenic expression of Cre recombinase. We mated Pik3ca(H1047R) and Pik3ca(wt) knock-in lines with MMTV-Cre transgenics, which express Cre in mammary epithelium. Starting at approximately 5 months of age, female R26 Pik3ca(H1047R);MMTV-Cre mice, but not control R26-Pik3ca(wt);MMTV-Cre mice, developed mammary tumors, as well as lymphoid and skin malignancies. R26 Pik3ca(H1047R);MMTV-Cre mammary tumors were typically either adenosquamous carcinoma or adenomyoepithelioma. As p53 is the most commonly mutated gene in breast cancer, we tested for genetic interaction between Pik3ca(H1047R) and p53 loss-of-function mutations in R26-Pik3ca(H1047R);p53(loxP/+);MMTV-Cre mice. This led to decreased survival of double-mutant animals, which developed lymphoma and mammary tumors with rapid kinetics. Mammary tumors that formed in p53(loxP/+);MMTV-Cre conditional mutants were either poorly differentiated adenocarcinoma or spindle cell/EMT, whereas R26-Pik3ca(H1047R);p53(loxP/+);MMTV Cre mammary tumors were mostly adenosquamous carcinoma or spindle cell/EMT indicating that double-mutant mice develop a distinct spectrum of mammary tumors. Thus, an oncogenic variant of PIK3CA implicated in multiple human breast cancer subtypes can induce a very diverse spectrum of mammary tumors in mice. Furthermore, Pik3ca(H1047R) shows cooperation with p53, which altered the specific tumors that formed. Thus, the two most frequently mutated genes in human breast cancer show cooperation in mammary tumor formation. PMID- 21324923 TI - COX-2 blockade suppresses gliomagenesis by inhibiting myeloid-derived suppressor cells. AB - Epidemiologic studies have highlighted associations between the regular use of nonsteroidal anti-inflammatory drugs (NSAID) and reduced glioma risks in humans. Most NSAIDs function as COX-2 inhibitors that prevent production of prostaglandin E2 (PGE2). Because PGE2 induces expansion of myeloid-derived suppressor cells (MDSC), we hypothesized that COX-2 blockade would suppress gliomagenesis by inhibiting MDSC development and accumulation in the tumor microenvironment (TME). In mouse models of glioma, treatment with the COX-2 inhibitors acetylsalicylic acid (ASA) or celecoxib inhibited systemic PGE2 production and delayed glioma development. ASA treatment also reduced the MDSC-attracting chemokine CCL2 (C-C motif ligand 2) in the TME along with numbers of CD11b(+)Ly6G(hi)Ly6C(lo) granulocytic MDSCs in both the bone marrow and the TME. In support of this evidence that COX-2 blockade blocked systemic development of MDSCs and their CCL2 mediated accumulation in the TME, there were defects in these processes in glioma bearing Cox2-deficient and Ccl2-deficient mice. Conversely, these mice or ASA treated wild-type mice displayed enhanced expression of CXCL10 (C-X-C motif chemokine 10) and infiltration of cytotoxic T lymphocytes (CTL) in the TME, consistent with a relief of MDSC-mediated immunosuppression. Antibody-mediated depletion of MDSCs delayed glioma growth in association with an increase in CXCL10 and CTLs in the TME, underscoring a critical role for MDSCs in glioma development. Finally, Cxcl10-deficient mice exhibited reduced CTL infiltration of tumors, establishing that CXCL10 limited this pathway of immunosuppression. Taken together, our findings show that the COX-2 pathway promotes gliomagenesis by directly supporting systemic development of MDSCs and their accumulation in the TME, where they limit CTL infiltration. PMID- 21324924 TI - Identification of a clinically relevant androgen-dependent gene signature in prostate cancer. AB - The androgen receptor (AR) is the principal target for treatment of non-organ confined prostate cancer (PCa). Androgen deprivation therapies (ADT) directed against the AR ligand-binding domain do not fully inhibit androgen-dependent signaling critical for PCa progression. Thus, information that could direct the development of more effective ADTs is desired. Systems and bioinformatics approaches suggest that considerable variation exists in the mechanisms by which AR regulates expression of effector genes, pointing to a role for secondary transcription factors. A combination of microarray and in silico analyses led us to identify a 158-gene signature that relies on AR along with the transcription factor SRF (serum response factor), representing less than 6% of androgen dependent genes. This AR-SRF signature is sufficient to distinguish microdissected benign and malignant prostate samples, and it correlates with the presence of aggressive disease and poor outcome. The AR-SRF signature described here associates more strongly with biochemical failure than other AR target gene signatures of similar size. Furthermore, it is enriched in malignant versus benign prostate tissues, compared with other signatures. To our knowledge, this profile represents the first demonstration of a distinct mechanism of androgen action with clinical relevance in PCa, offering a possible rationale to develop novel and more effective forms of ADT. PMID- 21324927 TI - Two cases of variceal haemorrhage during living-donor liver transplantation. AB - Some patients with cirrhosis experience rupture of venous varices before operation, and liver transplantation is a therapy of last resort for these patients. However, we have experienced two cases of intraoperative rupture in whom no abnormalities of the venous varices were seen on endoscopy before operation. One patient with ruptured gastrointestinal varices was treated by direct surgical ligation and the other with ruptured oesophageal gastric varices, spontaneously recovered with a Sengstaken-Blakemore tube. These cases suggest that acute variceal haemorrhage should always be considered as a possibility during living-donor liver transplantation in patients with a history of upper gastrointestinal bleeding. Careful observation of the nasogastic tube is important during clamping of the hepatic portal vein. PMID- 21324925 TI - Trastuzumab has preferential activity against breast cancers driven by HER2 homodimers. AB - In breast cancer cells with HER2 gene amplification, HER2 receptors exist on the cell surface as monomers, homodimers, and heterodimers with EGFR/HER3. The therapeutic antibody trastuzumab, an approved therapy for HER2(+) breast cancer, cannot block ligand-induced HER2 heterodimers, suggesting it cannot effectively inhibit HER2 signaling. Hence, HER2 oligomeric states may predict the odds of a clinical response to trastuzumab in HER2-driven tumors. To test this hypothesis, we generated nontransformed human MCF10A mammary epithelial cells stably expressing a chimeric HER2-FKBP molecule that could be conditionally induced to homodimerize by adding the FKBP ligand AP1510, or instead induced to heterodimerize with EGFR or HER3 by adding the heterodimer ligands EGF/TGFalpha or heregulin. AP1510, EGF, and heregulin each induced growth of MCF10A cells expressing HER2-FKBP. Trastuzumab inhibited homodimer-mediated but not heterodimer-mediated cell growth. In contrast, the HER2 antibody pertuzumab, which blocks HER2 heterodimerization, inhibited growth induced by heregulin but not AP1510. Lastly, the HER2/EGFR tyrosine kinase inhibitor lapatinib blocked both homodimer- and heterodimer-induced growth. AP1510 triggered phosphorylation of Erk1/2 but not AKT, whereas trastuzumab inhibited AP1510-induced Erk1/2 phosphorylation and Shc-HER2 homodimer binding, but not TGFalpha-induced AKT phosphorylation. Consistent with these observations, high levels of HER2 homodimers correlated with longer time to progression following trastuzumab therapy in a cohort of patients with HER2-overexpressing breast cancer. Together, our findings confirm the notion that HER2 oligomeric states regulate HER2 signaling, also arguing that trastuzumab sensitivity of homodimers may reflect their inability to activate the PI3K (phosphoinositide 3-kinase)/AKT pathway. A clinical implication of our results is that high levels of HER2 homodimers may predict a positive response to trastuzumab. PMID- 21324928 TI - Expression of the nociceptin precursor and nociceptin receptor is modulated in cancer and septic patients. AB - BACKGROUND: A role of nociceptin and its receptor (NOP) in pain and immune function has been suggested. The hypothesis was that mRNA expression of NOP and the nociceptin precursor pre-pronociceptin (pN/OFQ) in peripheral blood cells differs in end-stage cancer patients suffering from chronic pain and septic intensive care unit (ICU) patients compared with healthy controls. METHODS: Blood samples were drawn from end-stage cancer patients and septic ICU patients. Additionally, postoperative patients representing individuals with surgical stress and healthy controls were enrolled as comparative groups. NOP and pN/OFQ mRNA expression, quantified by real-time polymerase chain reaction (RT-PCR), was compared between study groups, and associated to opioid medication, pain intensities, and the inflammatory markers procalcitonin (PCT) and interleukin-6. RESULTS: NOP expression was significantly higher in cancer patients [normalized ratio, median (inter-quartile range): 10.2 (7.4/17.8)], postoperative patients [8.0 (5.3/10.2)], and ICU patients [6.6 (4.2/9.5)] compared with healthy controls [4.4 (2.7/7.0); P<0.001]. Expression of pN/OFQ was lower in cancer patients [3.8 (1.9/5.9)] and ICU patients [1.9 (1.0/2.7)] but not in postoperative patients compared with healthy controls [7.2 (6.1/9.4); P<0.001]. Increased plasma PCT was associated with decreased pN/OFQ in all patient groups. In cancer patients, no association was seen with pain scores, opioid medication or duration of analgesia, and NOP or pN/OFQ mRNA. CONCLUSIONS: NOP and pN/OFQ expression in peripheral blood cells was modulated in end-stage cancer and septic patients compared with healthy controls, whereas changes in postoperative patients were minor. The involvement of the NOP-pN/OFQ system in inflammation, impaired immune function, and pain has to be further elucidated. PMID- 21324929 TI - Analysing a family-centred preoperative intervention programme: a dismantling approach. AB - BACKGROUND: The goal of this project was to identify key effective components of ADVANCE, a family-centred preoperative intervention programme, through the use of a dismantling approach. ADVANCE was previously demonstrated to be more effective than parental presence and just as effective as midazolam in reducing children's preoperative anxiety. The total programme, however, may be difficult to implement in hospitals across the country. METHODS: Subjects in this follow-up dismantling report were 96 children aged 2-10 who were part of the original study and who underwent anaesthesia and surgery. Baseline characteristics, parental adherence to the components of ADVANCE, and child and parent anxiety were assessed. RESULTS: We found that greater parental adherence to the ADVANCE intervention was associated with lower child anxiety before surgery. The two components of ADVANCE that emerged as having a significant impact on children's anxiety were practising with the anaesthesia mask at home and parental planning and use of distraction in the preoperative holding area. In fact, not only did children experience significantly less preoperative anxiety when their parents were adherent to mask practise and use of distraction, their anxiety tended to remain stable and relatively low throughout the preoperative period. CONCLUSIONS: Shaping and exposure (i.e. practise with the anaesthesia mask) and parental use of distraction in the surgical setting are two beneficial components that could be included in preoperative preparation programmes that will be designed in the future. PMID- 21324930 TI - Experimental myocardial infarction triggers canonical Wnt signaling and endothelial-to-mesenchymal transition. AB - Despite available therapies, myocardial infarction (MI) remains a leading cause of death worldwide. Better understanding of the molecular and cellular mechanisms that regulate cardiac repair should help to improve the clinical outcome of MI patients. Using the reporter mouse line TOPGAL, we show that canonical (beta catenin-dependent) Wnt signaling is induced 4 days after experimental MI in subepicardial endothelial cells and perivascular smooth muscle actin (SMA) positive (SMA(+)) cells. At 1 week after ischemic injury, a large number of canonical-Wnt-positive cells accumulated in the infarct area during granulation tissue formation. Coincidently with canonical Wnt activation, endothelial-to mesenchymal transition (EndMT) was also triggered after MI. Using cell lineage tracing, we show that a significant portion of the canonical-Wnt-marked SMA(+) mesenchymal cells is derived from endothelial cells. Canonical Wnt signaling induces mesenchymal characteristics in cultured endothelial cells, suggesting a direct role in EndMT. In conclusion, our study demonstrates that canonical Wnt activation and EndMT are molecular and cellular responses to MI and that canonical Wnt signaling activity is a characteristic property of EndMT-derived mesenchymal cells that take part in cardiac tissue repair after MI. These findings could lead to new strategies to improve the course of cardiac repair by temporal and cell-type-specific manipulation of canonical Wnt signaling. PMID- 21324932 TI - Mouse models and the interpretation of human GWAS in type 2 diabetes and obesity. AB - Within the last 3 years, genome-wide association studies (GWAS) have had unprecedented success in identifying loci that are involved in common diseases. For example, more than 35 susceptibility loci have been identified for type 2 diabetes and 32 for obesity thus far. However, the causal gene and variant at a specific linkage disequilibrium block is often unclear. Using a combination of different mouse alleles, we can greatly facilitate the understanding of which candidate gene at a particular disease locus is associated with the disease in humans, and also provide functional analysis of variants through an allelic series, including analysis of hypomorph and hypermorph point mutations, and knockout and overexpression alleles. The phenotyping of these alleles for specific traits of interest, in combination with the functional analysis of the genetic variants, may reveal the molecular and cellular mechanism of action of these disease variants, and ultimately lead to the identification of novel therapeutic strategies for common human diseases. In this Commentary, we discuss the progress of GWAS in identifying common disease loci for metabolic disease, and the use of the mouse as a model to confirm candidate genes and provide mechanistic insights. PMID- 21324931 TI - Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer. AB - Dynamic remodeling of the extracellular matrix (ECM) is essential for development, wound healing and normal organ homeostasis. Life-threatening pathological conditions arise when ECM remodeling becomes excessive or uncontrolled. In this Perspective, we focus on how ECM remodeling contributes to fibrotic diseases and cancer, which both present challenging obstacles with respect to clinical treatment, to illustrate the importance and complexity of cell-ECM interactions in the pathogenesis of these conditions. Fibrotic diseases, which include pulmonary fibrosis, systemic sclerosis, liver cirrhosis and cardiovascular disease, account for over 45% of deaths in the developed world. ECM remodeling is also crucial for tumor malignancy and metastatic progression, which ultimately cause over 90% of deaths from cancer. Here, we discuss current methodologies and models for understanding and quantifying the impact of environmental cues provided by the ECM on disease progression, and how improving our understanding of ECM remodeling in these pathological conditions is crucial for uncovering novel therapeutic targets and treatment strategies. This can only be achieved through the use of appropriate in vitro and in vivo models to mimic disease, and with technologies that enable accurate monitoring, imaging and quantification of the ECM. PMID- 21324933 TI - Quantification of factors influencing fluorescent protein expression using RMCE to generate an allelic series in the ROSA26 locus in mice. AB - Fluorescent proteins (FPs) have great utility in identifying specific cell populations and in studying cellular dynamics in the mouse. To quantify the factors that determine both the expression and relative brightness of FPs in mouse embryonic stem cells (mESCs) and in mice, we generated eight different FP expressing ROSA26 alleles using recombinase-mediated cassette exchange (RMCE). These alleles enabled us to analyze the effects on FP expression of a translational enhancer and different 3'-intronic and/or polyadenylation sequences, as well as the relative brightness of five different FPs, without the confounding position and copy number effects that are typically associated with randomly inserted transgenes. We found that the expression of a given FP can vary threefold or more depending on the genetic features present in the allele. The optimal FP expression cassette contained both a translational enhancer sequence in the 5'-untranslated region (UTR) and an intron-containing rabbit beta-globin sequence within the 3'-UTR. The relative expressed brightness of individual FPs varied up to tenfold. Of the five different monomeric FPs tested, Citrine (YFP) was the brightest, followed by Apple, eGFP, Cerulean (CFP) and Cherry. Generation of a line of Cherry-expressing mice showed that there was a 30-fold variation of Cherry expression among different tissues and that there was a punctate expression pattern within cells of all tissues examined. This study should help investigators make better-informed design choices when expressing FPs in mESCs and mice. PMID- 21324934 TI - Controversies in cardiovascular medicine. Benefits of surgery in obstructive hypertrophic cardiomyopathy: bring septal myectomy back for European patients. AB - Hypertrophic cardiomyopathy (HCM), a heterogeneous genetic heart disease with global distribution, is an important cause of heart failure disability at any age. For 50 years, surgical septal myectomy has been the preferred and primary treatment strategy for most HCM patients with progressive, drug refractory functional limitation due to left ventricular (LV) outflow tract obstruction. With very low surgical mortality at experienced centres, septal myectomy reliably abolishes impedance to LV outflow and heart failure-related symptoms, restores quality of life, and importantly is associated with long-term survival similar to that in the general population. Nevertheless, alternatives to surgical management are necessary for selected HCM patients. For example, after a brief flirtation with dual-chamber pacing 20 years ago, percutaneous alcohol septal ablation has garnered a large measure of enthusiasm and a dedicated following in the interventional cardiology community, achieving benefits for patients, paradoxically, by virtue of producing a transmural myocardial infarct. However, an unintended consequence has been the virtual obliteration of the surgical option for HCM patients in Europe, where several robust myectomy programmes once existed. Therefore, clear differences are now evident internationally regarding management strategies for symptomatic obstructive HCM. The surgical option is now unavailable to many patients based solely on geography, including some who would likely benefit more substantially from surgical myectomy than from catheter-based alcohol ablation. It is our aspiration that this discussion will generate reconsideration and resurgence of interest in surgical septal myectomy as a treatment option for severely symptomatic obstructive HCM patients within Europe. PMID- 21324935 TI - Cardiac resynchronization therapy: from treatment to prevention. PMID- 21324936 TI - 'Reverse S' coronary sign. PMID- 21324937 TI - Quantitative volumetric analysis of conventional MRI response in recurrent glioblastoma treated with bevacizumab. AB - Although the effects of bevacizumab on magnetic resonance images (MRIs) of recurrent glioblastoma multiforme (GBM) are well documented, to our knowledge, no studies have explicitly quantified the volumetric changes resulting from initial treatment, nor have there been studies examining the ability for volumetric changes in conventional MRI to predict progression-free survival (PFS) and overall survival (OS). In the current study, we retrospectively examined volumetric changes on conventional MRI scans in 84 patients with recurrent GBM. MRIs were obtained before (mean, 11 days) and after (mean, 42 days) treatment with bevacizumab. The volume of abnormal fluid-attenuated inversion recovery (FLAIR) signal intensity, the volume of contrast enhancement, and the ratio of the 2 were quantified for each patient before and after initial treatment. Results demonstrated that initial treatment with bevacizumab resulted in a significant decrease in both the volume of abnormal FLAIR signal and the volume of contrast enhancement. Initial, residual, and change in FLAIR volume were not predictive of PFS or OS. Initial contrast-enhancing volume was predictive of PFS but not OS. The pretreatment relative nonenhancing tumor ratio, defined as the ratio of FLAIR to contrast-enhancing volume, was found to be predictive of both PFS and OS. PMID- 21324938 TI - Birthweight and mortality in adulthood: a systematic review and meta-analysis. AB - BACKGROUND: Small birth size may be associated with increased risk of cardiovascular diseases (CVD), whereas large birth size may predict increased risk of obesity and some cancers. The net effect of birth size on long-term mortality has only been assessed in individual studies, with conflicting results. METHODS: The Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines for conducting and reporting meta-analysis of observational studies were followed. We retrieved 22 studies that assessed the association between birthweight and adult mortality from all causes, CVD or cancer. The studies were systematically reviewed and those reporting hazard ratios (HRs) and 95% confidence intervals (95% CIs) per kilogram (kg) increase in birthweight were included in generic inverse variance meta-analyses. RESULTS: For all-cause mortality, 36,834 deaths were included and the results showed a 6% lower risk (adjusted HR = 0.94, 95% CI: 0.92-0.97) per kg higher birthweight for men and women combined. For cardiovascular mortality, the corresponding inverse association was stronger (HR = 0.88, 95% CI: 0.85-0.91). For cancer mortality, HR per kg higher birthweight was 1.13 (95% CI: 1.07-1.19) for men and 1.04 (95% CI: 0.98-1.10) for women (P(interaction) = 0.03). Residual confounding could not be eliminated, but is unlikely to account for the main findings. CONCLUSION: These results show an inverse but moderate association of birthweight with adult mortality from all-causes and a stronger inverse association with cardiovascular mortality. For men, higher birthweight was strongly associated with increased risk of cancer deaths. The findings suggest that birthweight can be a useful indicator of processes that influence long-term health. PMID- 21324939 TI - Explaining low mortality among US immigrants relative to native-born Americans: the role of smoking. AB - BACKGROUND: In many developed countries, immigrants live longer-that is, have lower death rates at most or all ages-than native-born residents. This article tests whether different levels of smoking-related mortality can explain part of the 'healthy immigrant effect' in the USA, as well as part of the related 'Hispanic paradox': the tendency for US Hispanics to outlive non-Hispanic Whites. METHODS: With data from vital statistics and the national census, we calculate lung cancer death rates in 2000 for four US subpopulations: foreign-born, native born, Hispanic and non-Hispanic White. We then use three different methods-the Peto-Lopez method, the Preston-Glei-Wilmoth method and a novel method developed in this article-to generate three alternative estimates of smoking-related mortality for each of the four subpopulations, extrapolating from lung cancer death rates. We then measure the contribution of smoking-related mortality to disparities in all-cause mortality. RESULTS: Taking estimates from any of the three methods, we find that smoking explains >50% of the difference in life expectancy at 50 years between foreign- and native-born men, and >70% of the difference between foreign- and native-born women; smoking explains >75% of the difference in life expectancy at 50 years between US Hispanic and non-Hispanic White men, and close to 75% of the Hispanic advantage among women. CONCLUSIONS: Low smoking-related mortality was the main reason for immigrants' and Hispanics' longevity advantage in the USA in 2000. PMID- 21324940 TI - Recent respiratory infection and risk of venous thromboembolism: case-control study through a general practice database. AB - BACKGROUND: The association between respiratory infection and risk of heart attacks and strokes is well established. However, less evidence exists for an association between respiratory infection and venous thromboembolism (VTE). In this article, we describe the associations between respiratory infection and VTE. METHODS: All cases aged >=18 years of first-time diagnosis of deep-vein thrombosis (DVT) or pulmonary embolism (PE) were identified together with single matched controls from a primary care general practice database. In addition to the matching characteristics, information was collected on other potentially important confounding factors. RESULTS: There were 457/11,557 (4.0%) DVT cases with respiratory infection in the year before the index date (73 in the preceding month) compared with 262/11,557 (2.3%) controls (24 in the preceding month). There was an increased risk of DVT in the month following infection [adjusted odds ratio (OR) = 2.64, 95% confidence interval (95% CI) 1.62-4.29] which persisted up to a year. There were 180/5162 (3.5%) PE cases with respiratory infection in the year before the index date compared with 94/5162 (1.8%) controls excluding those in the preceding month to avoid the possible misdiagnosis of early PE. There was an increased risk of PE in the 3 months following infection (adjusted OR = 2.50, 95% CI 1.33-4.72) which may have persisted up to a year. CONCLUSIONS: There are strong associations between recent respiratory infection and VTE. There should be less distinction between venous and arterial events in decisions about preventing or aborting infections, especially in high-risk patients. PMID- 21324941 TI - Trends in activity limitations: the Dutch older population between 1990 and 2007. AB - BACKGROUND: It is not clear whether recent increases in life expectancy are accompanied by a concurrent postponement of activity limitations. The objective of this study was to give best estimates of the trend in the prevalence of activity limitations among the non-institutionalized population aged 55-84 years over the period 1990-2007 in The Netherlands. METHODS: We examined self-reports on 12 measures of moderate or severe activity limitations in stair climbing, walking and getting dressed as assessed by OECD long-term disability questionnaire or Short Form-36 (SF-36) items, using original data from five population-based cross-sectional and longitudinal surveys (n = 54,847 respondents). To account for heterogeneity between surveys, we used meta-analyses to study time trends. RESULTS: Time trends of 10 out of the 12 activity limitation variables studied were stable. The prevalence of at least moderate activity limitations in stair climbing [odds ratio (OR) = 1.03)] and getting dressed (OR = 1.04) based on OECD items increased over the study period. Age- and gender-stratified time trend analyses showed consistent patterns. CONCLUSIONS: No declines were observed in the prevalence of activity limitations in the Dutch older population over the period 1990-2007. The increase in life expectancy in this period is accompanied by a stable prevalence of most activity limitations. PMID- 21324942 TI - The social context of sexual HIV prevention among female sex workers in China. PMID- 21324944 TI - Ten year revision of the brief behavioral activation treatment for depression: revised treatment manual. AB - Following from the seminal work of Ferster, Lewinsohn, and Jacobson, as well as theory and research on the Matching Law, Lejuez, Hopko, LePage, Hopko, and McNeil developed a reinforcement-based depression treatment that was brief, uncomplicated, and tied closely to behavioral theory. They called this treatment the brief behavioral activation treatment for depression (BATD), and the original manual was published in this journal. The current manuscript is a revised manual (BATD-R), reflecting key modifications that simplify and clarify key treatment elements, procedures, and treatment forms. Specific modifications include (a) greater emphasis on treatment rationale, including therapeutic alliance; (b) greater clarity regarding life areas, values, and activities; (c) simplified (and fewer) treatment forms; (d) enhanced procedural details, including troubleshooting and concept reviews; and (e) availability of a modified Daily Monitoring Form to accommodate low literacy patients. Following the presentation of the manual, the authors conclude with a discussion of the key barriers in greater depth, including strategies for addressing these barriers. PMID- 21324945 TI - Differences in the nature of body image disturbances between female obese individuals with versus without a comorbid binge eating disorder: an exploratory study including static and dynamic aspects of body image. AB - Various components of body image were measured to assess body image disturbances in patients with obesity. To overcome limitations of previous studies, a photo distortion technique and a biological motion distortion device were included to assess static and dynamic aspects of body image. Questionnaires assessed cognitive-affective aspects, bodily attitudes, and eating behavior. Patients with obesity and a binge eating disorder (OBE, n = 15) were compared with patients with obesity only (ONB; n = 15), to determine the nature of any differences in body image disturbances. Both groups had high levels of body image disturbances with cognitive-affective deficits. Binge eating disorder (BED) participants also had perceptual difficulties (static only). Both groups reported high importance of weight and shape for self-esteem. There were some significant differences between the groups suggesting that a comorbid BED causes further aggravation. Body image interventions in obesity treatment may be warranted. PMID- 21324946 TI - Investigating the similarities and differences between practitioners of second- and third-wave cognitive-behavioral therapies. AB - There has been much discussion in the literature recently regarding the conceptual and technical differences between so-called second- (e.g., Beckian cognitive therapy) and third-wave (e.g., acceptance and commitment therapy) behavioral therapies. Previous research has not addressed the potential similarities and differences among the practitioners of these types of approaches. The current study examined possible differences in the characteristics of second-wave (n = 55) and third-wave cognitive-behavioral therapists (n = 33) using an Internet-based survey. There were differences found at the technical level between the two groups. As expected, third-wave therapists reported greater use of mindfulness/acceptance techniques. Also, third-wave therapists reported greater use of exposure techniques and second-wave therapists reported greater use of cognitive restructuring and relaxation techniques. In general, third-wave clinicians were more eclectic at the technical level and demonstrated significantly greater use of family systems techniques, existential/humanistic techniques, and the total number of techniques. No significant differences were found on the attitudinal measures administered, including reliance on an intuitive thinking style, acceptance of complementary and alternative therapies and related health beliefs, or most attitudes toward evidence-based practices. The authors did not identify many differences between second-wave and third-wave therapists other than in terms of the techniques they employ. The clinical and research implications for these findings are discussed. PMID- 21324947 TI - Starting a functional assessment of depression (FAD): development of a FAD. AB - Despite abundance of treatment outcome studies, researchers have failed to identify a treatment for depression that works for all individuals. A possible solution is to individualize depression treatment. To test whether this strategy will be more effective, an assessment tied to theory of intervention is necessary. This article describes a current effort to develop a new measure of depression, the functional assessment of depression (FAD), based on behavioral assessment strategies. A factor analysis and cluster analysis were performed in an attempt to identify information provided that might prove useful in treatment planning. Future efforts to explore the incremental validity and treatment utility of the FAD are described. PMID- 21324948 TI - Risk of gestational diabetes mellitus in relation to maternal egg and cholesterol intake. AB - Higher egg and cholesterol intakes are associated with increased risk of type 2 diabetes mellitus. However, their association with gestational diabetes mellitus (GDM) has not been evaluated. The authors assessed such associations in both a prospective cohort study (1996-2008; 3,158 participants) and a case-control study (1998-2002; 185 cases, 411 controls). A food frequency questionnaire was used to assess maternal diet. Multivariable models were used to derive relative risks and 95% confidence intervals. Compared with no egg consumption, adjusted relative risks for GDM were 0.94, 1.01, 1.12, 1.54, and 2.52 for consumption of <=1, 2-3, 4-6, 7-9, and >=10 eggs/week, respectively (P for trend=0.008). Women with high egg consumption (>=7/week) had a 1.77-fold increased risk compared with women with lower consumption (95% confidence interval (CI): 1.19, 2.63). The relative risk for the highest quartile of cholesterol intake (>=294 mg/day) versus the lowest (<151 mg/day) was 2.35 (95% CI: 1.35, 4.09). In the case-control study, the adjusted odds ratio for consuming >=7 eggs/week versus <7 eggs/week was 2.65 (95% CI: 1.48, 4.72), and the odds of GDM increased with increasing cholesterol intake (P for trend=0.021). In conclusion, high egg and cholesterol intakes before and during pregnancy are associated with increased risk of GDM. PMID- 21324949 TI - Integrated genome-wide association study findings: identification of a neurodevelopmental network for attention deficit hyperactivity disorder. AB - OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a highly heritable neuropsychiatric disorder. In the present study, the authors investigated the presence of genomic convergence in the top findings of the five published genome wide association studies (GWASs) of ADHD. METHOD: The authors carried out bioinformatics pathway analyses, using the Ingenuity and BiNGO tools, as well as a systematic literature analysis of 85 genes from the five published GWASs containing single nucleotide polymorphisms associated with ADHD at a p value <0.0001. RESULTS: Findings revealed that 45 of the 85 top-ranked ADHD candidate genes encode proteins that fit into a neurodevelopmental network involved in directed neurite outgrowth. Data on copy number variations in patients with ADHD and data from animal studies provide further support for the involvement of this network in ADHD etiology. Several network proteins are also directly modulated by stimulants, the most commonly used psychopharmacological treatment for ADHD. CONCLUSIONS: The authors have identified a protein network for ADHD that contributes to our understanding of the molecular basis of the disorder. In addition, the data suggest new candidate genes for ADHD and provide clues to future research into psychopharmacological ADHD treatments. PMID- 21324951 TI - Longitudinal follow-up of bipolar disorder in women with premenstrual exacerbation: findings from STEP-BD. AB - OBJECTIVE: The impact of hormonal fluctuation during the menstrual cycle on the course of bipolar disorder is poorly understood. The authors determined the course of illness and time to relapse of bipolar disorder in prospectively followed women with premenstrual exacerbation. METHOD: Participants were 293 premenopause-age women with bipolar disorder who were followed prospectively for 1 year as part of the Systematic Treatment Enhancement Program for Bipolar Disorder. Frequency of mood episodes was compared between 191 women with premenstrual exacerbation (65.2%) and 102 women without. Among 129 women who were in recovered status at baseline, time to relapse was compared between 66 women with premenstrual exacerbation (51.2%) and 63 without. RESULTS: During follow-up, the group with premenstrual exacerbation had more episodes (primarily depressive) than did the group without, but they were not more likely to meet criteria for rapid cycling during this period. In contrast, they were more likely to report rapid cycling retrospectively. Women with premenstrual exacerbation had a shorter time to relapse and were at greater risk for relapse, but this association was not significant after adjustment for retrospectively reported rapid cycling. Women with premenstrual exacerbation had more depressive and mood elevation symptoms overall. CONCLUSIONS: Women with bipolar disorder and premenstrual exacerbation have a worse course of illness, a shorter time to relapse, and greater symptom severity, but they are not more likely to meet criteria for rapid cycling. Premenstrual exacerbation may be a clinical marker predicting a more symptomatic and relapse-prone phenotype in reproductive-age women with bipolar disorder. PMID- 21324950 TI - Maternally derived microduplications at 15q11-q13: implication of imprinted genes in psychotic illness. AB - OBJECTIVE: Rare copy number variants have been implicated in different neurodevelopmental disorders, with the same copy number variants often increasing risk of more than one of these phenotypes. In a discovery sample of 22 schizophrenia patients with an early onset of illness (10-15 years of age), the authors observed in one patient a maternally derived 15q11-q13 duplication overlapping the Prader-Willi/Angelman syndrome critical region. This prompted investigation of the role of 15q11-q13 duplications in psychotic illness. METHOD: The authors scanned 7,582 patients with schizophrenia or schizoaffective disorder and 41,370 comparison subjects without known psychiatric illness for copy number variants at 15q11-q13 and determined the parental origin of duplications using methylation-sensitive Southern hybridization analysis. RESULTS: Duplications were found in four case patients and five comparison subjects. All four case patients had maternally derived duplications (0.05%), while only three of the five comparison duplications were maternally derived (0.007%), resulting in a significant excess of maternally derived duplications in case patients (odds ratio=7.3). This excess is compatible with earlier observations that risk for psychosis in people with Prader-Willi syndrome caused by maternal uniparental disomy is much higher than in those caused by deletion of the paternal chromosome. CONCLUSIONS: These findings suggest that the presence of two maternal copies of a fragment of chromosome 15q11.2-q13.1 that overlaps with the Prader Willi/Angelman syndrome critical region may be a rare risk factor for schizophrenia and other psychoses. Given that maternal duplications of this region are among the most consistent cytogenetic observations in autism, the findings provide further support for a shared genetic etiology between autism and psychosis. PMID- 21324952 TI - Dietary and supplemental intake of one-carbon nutrients and the risk of type I and type II endometrial cancer: a prospective cohort study. AB - BACKGROUND: Type I and II endometrial cancer are biologically and clinically distinct, with type II cancers having a high frequency of p53 mutations and an association with chromosomal instability. This raises the hypothesis that one carbon nutrients (folate, methionine, and the enzymic cofactors vitamins B2, B6, and B12), which mediate chromosomal stability and DNA methylation, may be protective for type II but not type I endometrial cancer. METHODS: Using a prospective cohort of 23 356 postmenopausal women followed 20 years, we estimated the relative risks (RRs) of type I (N = 471) and II (N = 71) endometrial cancers according to intake of one-carbon nutrients, adjusting for confounders. RESULTS: No associations were observed between dietary or supplemental intake of any one carbon nutrient and risk of type I cancer. For type II cancer, positive associations were due to supplemental, rather than dietary, intake of these nutrients: supplemental folate (RR = 1.80 for >228.6 versus 0 MUg/day; P trend = 0.027) and vitamins B2 (RR = 1.94 for >1.70 versus 0 mg/day; P trend = 0.011), B6 (RR = 2.08 for >2.00 versus 0 mg/day; P trend = 0.012), and B12 (RR = 2.10 for >3.43 versus 0 MUg/day; P trend = 0.0060). CONCLUSION: Contrary to our hypothesis, use of supplements containing folate and vitamins B2, B6, and B12 was associated with an increased risk of type II endometrial cancer. PMID- 21324953 TI - Final results of the European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study: a large open-label study in diverse community settings. AB - BACKGROUND: The European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study provided sorafenib to advanced renal cell carcinoma (RCC) patients in whom previous systemic therapy had failed. The study assessed the safety and use of sorafenib for the treatment of advanced RCC in a large community-based patient population across 11 countries in Europe. PATIENTS AND METHODS: EU-ARCCS was a single-arm, open-label trial of sorafenib in advanced RCC patients. End points included safety, time to progression, progression-free survival (PFS), and disease control rate (DCR). Subgroup analyses included age, Eastern Cooperative Oncology Group performance status, histology, prior therapy, and number and sites of metastases. RESULTS: About 1159 advanced RCC patients were enrolled. Most patients (94%) experienced drug-related adverse events (AEs) of any grade, with the most common grade >=3 AEs including hand-foot skin reaction (13%), diarrhea (7%), fatigue (7%), hypertension (6%), and rash/desquamation (5%). The incidence of AEs in the subgroups was similar to that in the overall population. Median PFS was 6.6 months; DCR at >=8 and >=12 weeks was 85% and 78%, respectively. CONCLUSIONS: The sorafenib safety profile in European community-based practice settings was similar to that reported in clinical trials. The heterogeneous advanced RCC patient population in EU-ARCCS permitted assessment of sorafenib in important subpopulations of advanced RCC patients. PMID- 21324954 TI - Minimal clinically meaningful differences for the EORTC QLQ-C30 and EORTC QLQ BN20 scales in brain cancer patients. AB - BACKGROUND: We aimed to determine the smallest changes in health-related quality of life (HRQoL) scores in the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire core 30 and the Brain Cancer Module (QLQ BN20), which could be considered as clinically meaningful in brain cancer patients. MATERIALS AND METHODS: World Health Organisation performance status (PS) and mini-mental state examination (MMSE) were used as clinical anchors appropriate to related subscales to determine the minimal clinically important differences (MCIDs) in HRQoL change scores (range 0-100) in the QLQ-C30 and QLQ BN20. A threshold of 0.2 standard deviation (SD) (small effect) was used to exclude anchor-based MCID estimates considered too small to inform interpretation. RESULTS: Based on PS, our findings support the following integer estimates of the MCID for improvement and deterioration, respectively: physical (6, 9), role (14, 12), and cognitive functioning (8, 8); global health status (7, 4*), fatigue (12, 9), and motor dysfunction (4*, 5). Anchoring with MMSE, cognitive functioning MCID estimates for improvement and deterioration were (11, 2*) and for communication deficit were (9, 7). Estimates with asterisks were <0.2 SD and were excluded from our MCID range of 5-14. CONCLUSION: These estimates can help clinicians evaluate changes in HRQoL over time, assess the value of a health care intervention and can be useful in determining sample sizes in designing future clinical trials. PMID- 21324955 TI - Male pattern baldness and the risk of prostate cancer. AB - BACKGROUND: Androgens play a role in the development of both androgenic alopecia, commonly known as male pattern baldness, and prostate cancer. We set out to study if early-onset androgenic alopecia was associated with an increased risk of prostate cancer later in life. PATIENTS AND METHODS: A total of 669 subjects (388 with a history of prostate cancer and 281 without) were enrolled in this study. All subjects were asked to score their balding pattern at ages 20, 30 and 40. Statistical comparison was subsequently done between both groups of patients. RESULTS: Our study revealed that patients with prostate cancer were twice as likely to have androgenic alopecia at age 20 [odds ratio (OR) 2.01, P = 0.0285]. The pattern of hair loss was not a predictive factor for the development of cancer. There was no association between early-onset alopecia and an earlier diagnosis of prostate cancer or with the development of more aggressive tumors. CONCLUSIONS: This study shows an association between early-onset androgenic alopecia and the development of prostate cancer. Whether this population can benefit from routine prostate cancer screening or systematic use of 5-alpha reductase inhibitors as primary prevention remains to be determined. PMID- 21324956 TI - Is older colder or colder older? The association of age with body temperature in 18,630 individuals. AB - In animal studies, caloric restriction resulting in increased longevity is associated with a reduction in body temperature, which is strain specific and likely under genetic control. Small studies in humans have suggested that temperatures may be lower among elderly populations, usually attributed to loss of thermoregulation. We analyzed cross-sectional data from 18,630 white adults aged 20-98 years (mean 58.3 years) who underwent oral temperature measurement as part of a standardized health appraisal at a large U.S. health maintenance organization. Overall, women had higher mean temperatures (97.5 +/- 1.2 degrees F) than men (97.2 +/- 1.1 degrees F; p < .0001). Mean temperature decreased with age, with a difference of 0.3 degrees F between oldest and youngest groups after controlling for sex, body mass index, and white blood cell count. The results are consistent with low body temperature as a biomarker for longevity. Prospective studies are needed to confirm whether this represents a survival advantage associated with lifetime low steady state temperature. PMID- 21324957 TI - Selected risk factors associated with pulmonary tuberculosis among Saharia tribe of Madhya Pradesh, central India. AB - Tuberculosis (TB) is a major public health problem among the Saharia, a marginalized tribal group in Madhya Pradesh state, central India. However, there is no information on the risk factors associated with the development of TB disease in this community. A cross-sectional TB prevalence survey was conducted among the Saharia residing in Sheopur district of Madhya Pradesh. Information on tobacco smoking and alcohol consumption was collected from all the individuals. Persons aged >=45 years, males, smokers and alcohol consumers had higher risks of developing TB disease. There is an urgent need to develop and implement culturally appropriate awareness raising activities to target smoking and alcohol consumption to support the efforts to control TB in this community. PMID- 21324958 TI - Measurement of natural radioactivity and assessment of associated radiation hazards in soil around Baoji second coal-fired thermal power plant, China. AB - Activity concentrations of natural radionuclides (226)Ra, (232)Th and (40)K in soil around Baoji Second coal-fired thermal power plant of China were determined using gamma ray spectrometry. The mean activity concentrations of (226)Ra, (232)Th and (40)K in soil were found to be 40.3 +/- 3.5, 59.6 +/- 3.1 and 751.2 +/- 12.4 Bq kg(-1), respectively, which are all higher than the corresponding average values in Shaanxi, Chinese and world soil. The radium equivalent activity (Ra(eq)), the air absorbed dose rate (D), the annual effective dose (E), the external hazard index (H(ex)) and internal hazard index (H(in)) were evaluated and compared with the internationally reported or reference values. All the soil samples have Ra(eq) lower than the limit of 370 Bq kg(-1) and H(ex) and H(in) less than unity. The overall mean outdoor terrestrial gamma air absorbed dose rate is ~86.6 +/- 3.4 nGy h(-1) and the corresponding outdoor annual effective dose is 0.106 +/- 0.004 mSv, which is higher than the worldwide average (0.07 mSv y(-1)) for outdoor's annual effective dose. PMID- 21324959 TI - Patient radiation doses in cardiac computed tomography: comparison of published results with prospective and retrospective acquisition. AB - Prospective ECG triggering has the potential of reducing radiation exposure while maintaining diagnostic accuracy of cardiac computed tomography (CT). The aim of this study is to review patient radiation doses associated with coronary artery calcium scoring (CACS) and CT coronary angiography (CTCA) and to compare results between prospective and retrospective acquisition schemes. Patient radiation doses from CACS and CTCA were extracted from 67 relevant studies. Mean effective dose for CACS and CTCA with prospective ECG triggering is significantly lower than retrospective acquisition, 0.9+/-0.4 vs. 3.1+/-1.4 mSv, p < 0.001, and 3.4+/ 1.4 vs. 11.1+/-5.4 mSv, p < 0.001, respectively. In both cardiac CT examinations, application of dose modulation techniques result in significantly lower doses in retrospective schemes, however, even with dose modulation, retrospective acquisition is associated with significantly higher doses than prospective acquisition. The number of slices acquired per rotation and the number of X-ray sources of the CT scanner (single or dual source) do not have a significant effect on patient dose. PMID- 21324960 TI - Aortic root spontaneous echocardiographic contrast due to haemodynamic support with a percutaneous left ventricular assist device (TandemHeart). AB - Intra-procedural transoesophageal echocardiography (TEE) is useful in guiding device placement and monitoring for procedural complications in the interventional lab. We report a case of spontaneous echo contrast (SEC) formation in the aortic root immediately following initiation of haemodynamic support with a percutaneous left ventricular (LV) assist device for cardiogenic shock. With TEE guidance, assist device flow rates were adjusted, resulting in resolution of SEC. This case illustrates another potential use for intra-procedural TEE during LV assist device placement. PMID- 21324961 TI - Systemic lupus erythematosus disease activity index 2000 responder index-50: a reliable index for measuring improvement in disease activity. AB - OBJECTIVE: To test the interrater and intrarater reliability of the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) Responder Index (SRI 50), an index designed to measure >= 50% improvement in disease activity between visits in patients with systemic lupus erythematosus. METHODS: This was a multicenter, cross-sectional study with raters from Canada, the United Kingdom, and Argentina. Patient profile scenarios were derived from real adult patients. Ten rheumatologists from university and community hospitals and postdoctoral rheumatology fellows participated. An SRI-50 data retrieval form was used. Each rheumatologist scored SLEDAI-2K at the baseline visit and SRI-50 on followup visit, for the same patients, on 2 occasions 2 weeks apart. Physician global assessment (PGA) was determined on a numerical scale at baseline visit and a Likert scale on followup visit. Interrater and intrarater reliability was assessed using intraclass correlation coefficient (ICC) and kappa statistics whenever applicable. RESULTS: Forty patient profiles were created. The ICC performed on 80 patient profiles for interrater ranged from 1.00 for SLEDAI-2K and SRI-50 to 0.96 for PGA. The intrarater ICC for SLEDAI-2K, SRI-50, and PGA scores ranged from 1.00 to 0.86. Substantial agreement was determined for the interrater Likert scale, with a kappa statistic of 0.57. CONCLUSION: The SRI-50 is reliable to assess >= 50% improvement in lupus disease activity. Use of the SRI-50 data retrieval form is essential to ensure optimal performance of the SRI 50. SRI-50 can be used by both rheumatologists and trainees and performs equally well in trained as well as untrained rheumatologists. PMID- 21324962 TI - Expression of Toll-like receptors and their signaling pathways in rheumatoid synovitis. AB - OBJECTIVE: Toll-like receptors (TLR) recognizing endogenous and exogenous danger signals could play a role in rheumatoid arthritis (RA). Our aim was to describe the presence, localization, and extent of expression of TLR and their adapters. METHODS: TLR 1, 2, 3, 4, 5, 6, and 9 receptors, and myeloid differentiation primary response protein 88, Toll/interleukin receptor (TIR) domain-containing adapter protein MyD88 adapter-like, and TIR domain-containing adapter-inducing interferon/TIR-containing adapter molecule-1 adapters were analyzed in RA (n = 10) and osteoarthritis (OA; n = 5) samples using real-time polymerase chain reaction (PCR). Their colocalization with cellular markers CD68, CD15, CD3, CD4, CD8, CD20, dendritic cell lysosomal-associated membrane protein (DC-LAMP), CD123, and 5B5 was analyzed in double immunofluorescence staining. RESULTS: In RA, beta actin standardized messenger RNA of TLR 2, 3, and 9 (p < 0.001) were particularly high. TLR 5 and 6 were also elevated (p < 0.05), but TLR 1 and 4 and adapters did not differ between RA and OA. In double-staining, TLR and adapters were strongly labeled in myeloid and plasmacytoid dendritic cells (DC), moderately in CD68+ type A lining cells/macrophages, and weakly to moderately in 5B5+ type B lining cells/fibroblasts. CD3+/CD4+ and CD3+/CD8+ T cells and CD20+ B cells in perivenular areas and in lymphoid follicles were moderately TLR- and weakly adapter-positive. In OA, TLR and adapters were weakly immunolabeled in vascular, lining, and inflammatory cells. CONCLUSION: RA synovium showed abundant expression of TLR. RA synovitis tissue seems to be responsive to TLR ligands. DC, type A cells/macrophages, and type B cells/fibroblasts are, in that order from highest to lowest, equipped with TLR, suggesting a hierarchical responsiveness. In RA, danger-associated molecular patterns to TLR interactions may particularly drive DC to autoinflammatory and autoimmune cascades/synovitis. PMID- 21324963 TI - Repair of radiographic joint damage following treatment with etanercept in psoriatic arthritis is demonstrable by 3 radiographic methods. AB - OBJECTIVE: Psoriatic arthritis (PsA) is characterized by varied radiographic features. We describe a patient with PsA with severe radiographic damage that improved significantly following treatment with etanercept. The improvement was documented by several methods of radiographic assessment. METHODS: Etanercept was introduced in September 2005. Radiographs of the hands and feet were read using 3 methods: the modified Steinbrocker method, the van der Heijde (vdH) modification of the Sharp method, and the Ratingen scoring system. RESULTS: In July 2009, radiographs of the hands and feet showed improvement in erosion score and joint space narrowing, while bony proliferation remained the same [43 by modified Steinbrocker, 26 by the vdH Sharp score (12 for erosions and 14 for joint space narrowing), and 56 by the Ratingen (18 for erosion and 38 for proliferation]. CONCLUSION: The 3 radiographic methods were useful in demonstrating improvement in joint scores. The modified Steinbrocker method, which is the simplest, was able to reveal improvement in our patient. PMID- 21324964 TI - Lack of specificity of anticyclic citrullinated peptide antibodies in advanced human immunodeficiency virus infection. AB - OBJECTIVE: To determine the prevalence and specificity of anticyclic citrullinated peptide antibodies (anti-CCP) and rheumatoid factor (RF) for rheumatoid arthritis (RA) in human immunodeficiency virus (HIV) infection and to evaluate the effect of immune reconstitution on these markers. METHODS: Patients with advanced HIV infection without arthritis were enrolled. CD4+ T lymphocyte counts (CD4), anti-CCP, and RF were determined before initiating antiretroviral therapy (ART) and repeated after 6 months. Results were compared to those of healthy controls. Patients were followed for the development of RA for 1 year. RESULTS: Sixty patients and 26 controls were studied. Six-month followup results were available on 49 patients. Mean (SD) levels of anti-CCP were higher in patients with HIV compared to controls: respectively, 9.50 (11.41) versus 0.80 (1.32) units (p < 0.001). Mean (SD) levels decreased to 4.85 (8.12) units (p = 0.006) after 6 months of ART (HIV-infected group). Fifteen percent of patients initially tested positive for anti-CCP, 4% after 6 months versus no controls (p = 0.031). Forty-seven percent of patients initially tested positive for RF, 18% after 6 months versus 8% of controls (p < 0.001). Decreases in RF and anti-CCP after ART were accompanied by increased mean (SD) CD4: from 129 (56) to 278 (140) cells/mm(3) (p < 0.001). Anti-CCP and RF positivity was not associated with the development of RA. CONCLUSION: Increased titers of anti-CCP and RF occur in advanced HIV infection. Although more specific than RF, before immune reconstitution, anti-CCP is an unreliable diagnostic marker for RA and does not necessarily predict future RA. After immune reconstitution, the specificity of anti-CCP approaches that of a control group. PMID- 21324965 TI - Patient global assessment in psoriatic arthritis: a multicenter GRAPPA and OMERACT study. AB - OBJECTIVE: During OMERACT 8, delegates selected patient global assessment (PGA) of disease as a domain to be evaluated in randomized controlled trials in psoriatic arthritis (PsA). This study assessed the reliability of the PGA, measured by means of 0-100 mm visual analog scale (VAS), and the additional utility of separate VAS scales for joints (PJA) and skin (PSA). METHODS: In total, 319 consecutive patients with PsA (186 men, 133 women, mean age 51 +/- 13 yrs) were enrolled. PGA, PJA, and PSA were administered at enrolment (W0) and after 1 week (W1). Detailed clinical data, including ACR joint count, Psoriasis Area and Severity Index (PASI), and Hospital Anxiety and Depression Scale, were recorded. RESULTS: Comparison of W0 and W1 scores showed no significant variations (intraclass correlation coefficients for PGA 0.87, PJA 0.86, PSA 0.78), demonstrating the reliability of the instrument. PGA scores were not influenced by patient anxiety or depression, but were dependent on PJA and PSA (p = 0.00001). PJA was dependent on the number of swollen and tender joints (p < 0.00001). PSA scores were influenced by the extent of skin psoriasis and by hand skin involvement (p = 0.00001). Joint and skin disease were found not to correlate in terms of disease activity as evidenced by the swollen joint count compared to PASI (r = 0.11) and by the PJA compared to PSA (r = 0.38). CONCLUSION: PGA assessed by means of VAS is a reliable tool related to joint and skin disease activity. Because joint and skin disease often diverge it is suggested that in some circumstances both PJA and PSA are also assessed. PMID- 21324966 TI - Differentiation between Wegener's granulomatosis and microscopic polyangiitis by an artificial neural network and by traditional methods. AB - OBJECTIVE: To investigate the operating characteristics of the American College of Rheumatology (ACR) traditional format criteria for Wegener's granulomatosis (WG), the Sorensen criteria for WG and microscopic polyangiitis (MPA), and the Chapel Hill nomenclature for WG and MPA. Further, to develop and validate improved criteria for distinguishing WG from MPA by an artificial neural network (ANN) and by traditional approaches [classification tree (CT), logistic regression (LR)]. METHODS: All criteria were applied to 240 patients with WG and 78 patients with MPA recruited by a multicenter study. To generate new classification criteria (ANN, CT, LR), 23 clinical measurements were assessed. Validation was performed by applying the same approaches to an independent monocenter cohort of 46 patients with WG and 21 patients with MPA. RESULTS: A total of 70.8% of the patients with WG and 7.7% of the patients with MPA from the multicenter cohort fulfilled the ACR criteria for WG (accuracy 76.1%). The accuracy of the Chapel Hill criteria for WG and MPA was only 35.0% and 55.3% (Sorensen criteria: 67.2% and 92.4%). In contrast, the ANN and CT achieved an accuracy of 94.3%, based on 4 measurements (involvement of nose, sinus, ear, and pulmonary nodules), all associated with WG. LR led to an accuracy of 92.8%. Inclusion of antineutrophil cytoplasmic antibodies did not improve the allocation. Validation of methods resulted in accuracy of 91.0% (ANN and CT) and 88.1% (LR). CONCLUSION: The ACR, Sorensen, and Chapel Hill criteria did not reliably separate WG from MPA. In contrast, an appropriately trained ANN and a CT differentiated between these disorders and performed better than LR. PMID- 21324967 TI - Association of knee osteoarthritis with the accumulation of metabolic risk factors such as overweight, hypertension, dyslipidemia, and impaired glucose tolerance in Japanese men and women: the ROAD study. AB - OBJECTIVE: To clarify the association of knee osteoarthritis (KOA) with overweight (OW), hypertension (HTN), dyslipidemia (DL), and impaired glucose tolerance (IGT), which are components of metabolic syndrome (MS), in a Japanese population. METHODS: We enrolled 1690 participants (596 men, 1094 women) from the large-scale cohort study Research on Osteoarthritis Against Disability (ROAD), begun in 2005 to clarify epidemiologic features of OA in Japan. KOA was evaluated by the Kellgren-Lawrence grade, minimum joint space width (MJSW), minimum joint space area (JSA), and osteophyte area (OPA). OW, HTN, DL, and IGT were assessed using standard criteria. RESULTS: The prevalence of KOA in the total population in the age groups <= 39, 40-49, 50-59, 60-69, 70-79, and >= 80 years was 2.2%, 10.7%, 28.2%, 50.8%, 69.0%, and 80.5%, respectively. Logistic regression analyses after adjustment for age, sex, regional difference, smoking habit, alcohol consumption, physical activities, regular exercise, and history of knee injuries revealed that the OR of KOA significantly increased according to the number of MS components present (1 component: OR 1.21, 95% CI 0.88-1.68, p = 0.237; 2 components: OR 1.89, 95% CI 1.33-2.70, p < 0.001; 3 or more components: OR 2.72, 95% CI 1.77-4.18; p < 0.001). The number of MS components was inversely related to medial MSJW (beta = -0.148, R(2) = 0.21, p < 0.001), medial JSA (women only; beta = -0.096, R(2) = 0.18, p = 0.001), and positively related to OPA (beta = 0.12, R(2) = 0.11, p < 0.001). CONCLUSION: The accumulation of MS components is significantly related to presence of KOA. MS prevention may be useful to reduce cardiovascular disease and KOA risk. PMID- 21324968 TI - Systemic lupus and risk of restless legs syndrome. AB - OBJECTIVE: To determine the prevalence of restless legs syndrome (RLS) in women with systemic lupus erythematosus (SLE), and to compare this to a rheumatic disease sample without SLE. METHODS: Unselected consecutive female patients were SLE were recruited from a lupus clinic. A RLS questionnaire based on 4 criteria, validated by the International Restless Legs Syndrome Study Group, was administered during a face-to-face interview. Smoking history and height and weight data were collected. Similar methods were used to determine RLS prevalence in a comparator group of women with rheumatic diseases other than SLE. Controls were frequency-matched by age group (in 5-year age bands) to SLE subjects. Controls were otherwise unselected. RESULTS: We recruited 33 women with SLE and 32 controls. Twelve of 33 female SLE subjects scored positively for RLS (37.5%; 95% CI 22.9, 54.7) compared to 4 of 32 controls (12.5%; 95% CI 5.0, 28.1). Multivariate logistic regression showed that adjusted for age, obesity, and smoking, women with SLE were more likely to have RLS than the female controls (adjusted odds ratio 6.61, 95% CI 1.52, 28.77). In our multivariate analyses of all rheumatic patients, including SLE, the adjusted OR for obesity and RLS was 5.14 (95% CI 1.07, 24.6). CONCLUSION: These novel data indicate that RLS is more prevalent in women with SLE than in controls. Although obesity was a significant risk factor for RLS in our sample, the predictive covariates examined were limited. PMID- 21324969 TI - Amino acid export in plants: a missing link in nitrogen cycling. AB - The export of nutrients from source organs to parts of the body where they are required (e.g. sink organs) is a fundamental biological process. Export of amino acids, one of the most abundant nitrogen species in plant long-distance transport tissues (i.e. xylem and phloem), is an essential process for the proper distribution of nitrogen in the plant. Physiological studies have detected the presence of multiple amino acid export systems in plant cell membranes. Yet, surprisingly little is known about the molecular identity of amino acid exporters, partially due to the technical difficulties hampering the identification of exporter proteins. In this short review, we will summarize our current knowledge about amino acid export systems in plants. Several studies have described plant amino acid transporters capable of bi-directional, facilitative transport, reminiscent of activities identified by earlier physiological studies. Moreover, recent expansion in the number of available amino acid transporter sequences have revealed evolutionary relationships between amino acid exporters from other organisms with a number of uncharacterized plant proteins, some of which might also function as amino acid exporters. In addition, genes that may regulate export of amino acids have been discovered. Studies of these putative transporter and regulator proteins may help in understanding the elusive molecular mechanisms of amino acid export in plants. PMID- 21324970 TI - pHairyRed: a novel binary vector containing the DsRed2 reporter gene for visual selection of transgenic hairy roots. AB - We developed a new plant transformation vector, pHairyRed, for enabling high throughput, non-destructive selection of Agrobacterium rhizogenes-mediated 'hairy root' transformation. pHairyRed allows easy in planta visualization of transgenic tissue with minimal disturbance to the plant. The DsRed2 reporter gene, encoding a red fluorescent protein, was cloned to yield pHairyRed (harbouring a multiple cloning site), which was used with the highly efficient K599 A. rhizogenes strain to infect soybean (Glycine max L. Merrill) plants. DsRed2 fluorescence was easily detected in planta for the duration of a 5-week study with negligible levels of background autofluorescence. This enabled visual selection of transformed roots and subsequent excission of non-transformed roots. pHairyRed-transformed roots nodulated normally when inoculated with Bradyrhizobium japonicum. Within the nodule, DsRed2 fluorescence was plant-specific, being absent in the bacteroid dominated nodule infected zone. To test the reliability of pHairyRed as a high fidelity binary vector reporter system, the gene encoding the soybean Nod factor receptor, GmNFR1alpha, was cloned into the vector for use in a complementation study with a non-nodulating nfr1alpha mutant of soybean. Complementation was achieved and, without exception, DsRed2 fluorescence was detected in all hairy roots that successfully formed nodules (100%, n = 34). We anticipate broad application of this reporter system for the further analysis of root-related events in soybean and related legumes. PMID- 21324971 TI - Using cross-validation to evaluate predictive accuracy of survival risk classifiers based on high-dimensional data. AB - Developments in whole genome biotechnology have stimulated statistical focus on prediction methods. We review here methodology for classifying patients into survival risk groups and for using cross-validation to evaluate such classifications. Measures of discrimination for survival risk models include separation of survival curves, time-dependent ROC curves and Harrell's concordance index. For high-dimensional data applications, however, computing these measures as re-substitution statistics on the same data used for model development results in highly biased estimates. Most developments in methodology for survival risk modeling with high-dimensional data have utilized separate test data sets for model evaluation. Cross-validation has sometimes been used for optimization of tuning parameters. In many applications, however, the data available are too limited for effective division into training and test sets and consequently authors have often either reported re-substitution statistics or analyzed their data using binary classification methods in order to utilize familiar cross-validation. In this article we have tried to indicate how to utilize cross-validation for the evaluation of survival risk models; specifically how to compute cross-validated estimates of survival distributions for predicted risk groups and how to compute cross-validated time-dependent ROC curves. We have also discussed evaluation of the statistical significance of a survival risk model and evaluation of whether high-dimensional genomic data adds predictive accuracy to a model based on standard covariates alone. PMID- 21324972 TI - Health policy and systems research: defining the terrain; identifying the methods. AB - Across low- and middle-income countries on the one hand, and high-income countries on the other, there is confusion in the terminology relating to the study of health services and health systems. This commentary discusses health policy and systems research (HPSR) methods, drawing on the health services research literature and on recent work on HPSR. An earlier version of the text was written to contribute to discussions at a meeting organized by the Alliance for Health Policy and Systems Research, an agency set up in 1998 to promote and support such research in low- and middle-income countries. The paper comments on the field of HPSR methods, suggests priorities and identifies challenges facing the field of HPSR. PMID- 21324973 TI - Tissue engineering of human bladder. AB - There are a number of conditions of the bladder that can lead to loss of function. Many of these require reconstructive procedures. However, current techniques may lead to a number of complications. Replacement of bladder tissues with functionally equivalent ones created in the laboratory could improve the outcome of reconstructive surgery. A review of the literature was conducted using PubMed to identify studies that provide evidence that tissue engineering techniques may be useful in the development of alternatives to current methods of bladder reconstruction. A number of animal studies and several clinical experiences show that it is possible to reconstruct the bladder using tissues and neo-organs produced in the laboratory. Materials that could be used to create functionally equivalent urologic tissues in the laboratory, especially non autologous cells that have the potential to reject have many technical limitations. Current research suggests that the use of biomaterial-based, bladder shaped scaffolds seeded with autologous urothelial and smooth muscle cells is currently the best option for bladder tissue engineering. Further research to develop novel biomaterials and cell sources, as well as information gained from developmental biology, signal transduction studies and studies of the wound healing response would be beneficial. PMID- 21324974 TI - Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia-reperfusion-induced acute and chronic kidney injury. AB - BACKGROUND: Several studies demonstrated that mesenchymal stem cells (MSCs) reverse acute kidney injury (AKI) by a paracrine mechanism rather than by MSC transdifferentiation. We recently demonstrated that microvesicles (MVs) released from MSCs may account for this paracrine mechanism by a horizontal transfer of messenger RNA and microRNA. METHODS: MVs isolated from MSCs were injected intravenously in rats (30 MUg/rat) immediately after monolateral nephrectomy and renal artery and vein occlusion for 45 min. To evaluate the MV effects on AKI induced by ischaemia-reperfusion injury (IRI), the animals were divided into different groups: normal rats (n = 4), sham-operated rats (n = 6), IRI rats (n = 6), IRI + MV rats (n = 6), and IRI + RNase-MV rats (n = 6), and all animals were sacrificed at Day 2 after the operation. To evaluate the chronic kidney damage consequent to IRI, the rats were divided into different groups: sham-operated rats (n = 6) and IRI rats (n = 6), IRI + MV rats (n = 6), and all animal were sacrificed 6 months after the operation. RESULTS: We found that a single administration of MVs, immediately after IRI, protects rats from AKI by inhibiting apoptosis and stimulating tubular epithelial cell proliferation. The MVs also significantly reduced the impairment of renal function. Pretreatment of MVs with RNase to inactivate their RNA cargo abrogated these protective effects. Moreover, MVs by reducing the acute injury also protected from later chronic kidney disease. CONCLUSION: MVs released from MSCs protect from AKI induced by ischaemia reperfusion injury and from subsequent chronic renal damage. This suggest that MVs could be exploited as a potential new therapeutic approach. PMID- 21324975 TI - An exceptional minute tumour incidentally found in a renal biopsy. AB - Pathological analysis of renal biopsies performed to investigate a nephrological disease may exceptionally reveal incidental tumours, in addition to expected glomerular, tubulointerstitial or vascular pathology. We present the first case to date of a minute angiomyolipoma (AML), found incidentally in a renal biopsy specimen, performed in the assessment of proteinuria. AML is an uncommon kidney tumour, composed of a variable proportion of adipose tissue, spindle and epithelioid smooth muscle cells. Immunohistochemistry is mandatory for a definitive diagnosis, showing a specific perivascular epithelioid differentiation. The diagnosis of renal AML justifies the search for tuberous sclerosis-associated tumours. PMID- 21324976 TI - Alternative activation of macrophages in human peritoneum: implications for peritoneal fibrosis. AB - BACKGROUND: Depending on the cytokine microenvironment, macrophages (Mphi) can adopt a proinflammatory (M1) or a profibrotic (M2) phenotype characterized by the expression of cell surface proteins such as CD206 and CD163 and soluble factors such as CC chemokine ligand 18 (CCL18). A key role for Mphi in fibrosis has been observed in diverse organ settings. We studied the Mphi population in a human model of peritoneal dialysis in which continuous stress due to dialysis fluids and recurrent peritonitis represent a risk for peritoneal membrane dysfunction reflected as ultrafiltration failure (UFF) and peritoneal fibrosis. METHODS: We used flow cytometry and quantitative reverse transcription-polymerase chain reaction to analyse the phenotype of peritoneal effluent Mphi and tested their ability to stimulate the proliferation of human fibroblasts. Mphi from non infected patients were compared with those from patients with active peritonitis. Cytokine production was evaluated by enzyme-linked immunosorbent assay (ELISA) in spent dialysates and cell culture supernatants. RESULTS: CD206(+) and CD163(+) M2 were found within peritoneal effluents by flow cytometry analysis, with increased frequencies of CD163(+) cells during peritonitis (P = 0.003). TGFB1, MMP9 and CCL18 messenger RNA (mRNA) levels in peritoneal macrophages (pMphi) were similar to those found in M2 cells differentiated in vitro. The ability of pMphi to stimulate fibroblast proliferation correlated with CCL18 mRNA levels (r = 0.924, P = 0.016). CCL18 production by pMphi was confirmed by immunostaining of cytospin samples and ELISA. Moreover, CCL18 effluent concentrations correlated with decreased peritoneal function, which was evaluated as dialysate to plasma ratio of creatinine (r = 0.724, P < 0.0001), and were significantly higher in patients with UFF (P = 0.0025) and in those who later developed sclerosing peritonitis (P = 0.024). CONCLUSIONS: M2 may participate in human peritoneal fibrosis through the stimulation of fibroblast cell growth and CCL18 production as high concentrations of CCL18 are associated with functional deficiency and fibrosis of the peritoneal membrane. PMID- 21324977 TI - Antibiotic stability in commercial peritoneal dialysis solutions: influence of formulation, storage and duration. AB - BACKGROUND: Peritoneal dialysis (PD)-associated peritonitis is treated by administration of antibiotics mixed with the PD solution. Data on antibiotic stability for solutions in current use are limited. The aim of this study was to determine the stability of cefepime, cephazolin and ampicillin in three commercial PD solutions. METHODS: Antibiotics were added to the non-glucose compartment of the Gambro (Gambrosol(r)) and Fresenius (Balance(r)) multi compartment systems and Baxter (Dianeal(r)) single-compartment (glucose 2.5%) PD solutions in a sterile suite. Antibiotic stability over 3 weeks was determined using both a bioassay of bacterial inhibition and antibiotic concentrations. The influence on stability and sterility of storage conditions was determined. RESULTS: The bioassay demonstrated the stability of all antibiotics for 9 days at room temperature and 3 weeks when refrigerated, except ampicillin in the Gambro solution, which displayed no bioactivity after 4 days. However, a ceiling effect in bacterial inhibition at higher antibiotic concentrations limited the ability of the bioassay to detect antibiotic degradation at relevant concentrations. Antibiotic concentrations varied with time but were comparable to the bioassay and supported stability in refrigerated solutions, except ampicillin in the Gambro solution. No bacterial contamination, marked colour change or precipitation occurred. CONCLUSIONS: This study supports the stability of cephazolin and cefepime in all three PD solutions and ampicillin in only the Baxter and Fresenius PD solutions. Antibiotic stability studies should ideally be conducted prior to registration and marketing of new PD solutions. PMID- 21324978 TI - Long-term outcomes of end-stage renal disease patients admitted to the ICU. AB - BACKGROUND: End-stage renal disease (ESRD) patients admitted to the intensive care unit (ICU) have poor survival and high rates of readmission; however, little evidence exists on long-term outcomes. We set out to investigate the long-term (6 and 12 months) survival of ESRD patients admitted to the ICU and whether differential survival could be explained by dialysis modality and vascular access. METHODS: We compared the admission characteristics, outcomes and readmission rates of 619 ESRD [95 peritoneal dialysis (PD), 334 hemodialysis with a catheter (HD CVC), 190 hemodialysis with an AV fistula (HD AVF)] patients admitted to 11 ICU's in Winnipeg, Manitoba, Canada. Parametric and nonparametric tests were used as appropriate to determine differences in baseline characteristics. Multivariable Cox and logistic regression was used to assess outcomes between the groups. RESULTS: The 6- and 12-month crude survival was 62 and 52%, respectively. In a univariate model, modality and vascular access were associated with an increased hazard ratio (HR) of death [PD HR 1.60 95% confidence interval (CI) 1.20-2.13, HD CVC HR 1.55 95% CI 1.25-1.93] compared to patients on HD with an AVF. In three different multivariate adjusted models, this association persisted with HRs for death of 1.63-1.75 for PD and 1.50-1.58 for HD CVC. CONCLUSIONS: Overall long-term survival of ESRD patients after admission to the ICU is poor. Being on PD or being dialyzed with a catheter was independently associated with an increased mortality. PMID- 21324979 TI - Prevalence and correlates of sleep disturbance in systemic sclerosis--results from the UCLA scleroderma quality of life study. AB - OBJECTIVE: Rheumatologic disorders are associated with sleep disturbances. This study examines sleep disturbance correlates in patients with SSc. METHODS: Participants are 180 SSc patients in an observational study. At baseline, patients completed the Medical Outcomes Study Sleep measure (MOS-Sleep scale). In addition, patients were administered other patient-reported outcome (PRO) measures including the 36-item short form (SF-36), HAQ disability index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), Center for Epidemiologic Studies Depression (CESD) scale and a University of California at Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Questionnaire (UCLA SCTC GIT 2.0). Descriptive statistics were assessed for six scales of MOS-Sleep and the 9-item sleep problem index (SLP-9; a composite index). We computed Spearman's rank-order correlations between the MOS-Sleep scales and the HAQ-DI, FACIT-Fatigue, CESD, SSc-SCTC GIT 2.0 and SF-36 scales. In addition, we developed a regression model to assess predictors of SLP-9 scores. Covariates included demographics, physician variables of disease severity and patient-reported variables of worsening symptoms and the PRO measures. RESULTS: SSc patients reported a mean (s.d.) of 7.1 (1.73) h of sleep a night. Patients reported worse scores on four of six scales (except for snoring and sleep quantity) compared with the US general population (P < 0.001). SLP-9 was correlated with worsening pain and dyspnoea over the past 1 month, reflux scale of the UCLA SCTC GIT 2.0, CESD and FACIT-Fatigue (rho 0.26-0.56). In the stepwise multivariate regression model, the CESD, worsening dyspnoea and reflux scale were significantly associated with SLP-9 index. CONCLUSION: Sleep disturbances are common in SSc and are associated with worsening dyspnoea, depressed mood and severity of reflux symptoms. PMID- 21324980 TI - Prickle2 is localized in the postsynaptic density and interacts with PSD-95 and NMDA receptors in the brain. AB - The planar cell polarity (PCP) protein, Prickle (Pk), is conserved in invertebrates and vertebrates, and regulates cellular morphogenesis and movement. Vertebrate Pk consists of at least two family members, Pk1 and Pk2, both of which are expressed in the brain; however, their localization and function at synapses remain elusive. Here, we show that Pk2 is expressed mainly in the adult brain and is tightly associated with the postsynaptic density (PSD) fraction obtained by subcellular fractionation. In primary cultured rat hippocampal neurons, Pk2 is colocalized with PSD-95 and synaptophysin at synapses. Moreover, immunoelectron microcopy shows that Pk2 is localized at the PSD of asymmetric synapses in the hippocampal CA1 region. Biochemical assays identified that Pk2 forms a complex with PSD proteins including PSD-95 and NMDA receptor subunits via the direct binding to the C-terminal guanylate kinase domain of PSD-95. These results indicate that Pk2 is a novel PSD protein that interacts with PSD-95 and NMDA receptors through complex formations in the brain. PMID- 21324981 TI - Production of H2S by 3-mercaptopyruvate sulphurtransferase. AB - Hydrogen sulfide (H(2)S) has been established as the third gaseous signaling molecule following nitric oxide and carbon monoxide and participates in a variety of cellular functions such as modulation of neuronal transmission, endothelium dependent vasorelaxation, stimulation of angiogenesis and regulation of insulin release. Although cystathionine beta-synthase and cystathionine gamma-lyase have been regarded as the main producers of H(2)S in many tissues including brain, liver and kidney, Kimura and his colleagues have recently communicated that 3 mercaptopyruvate sulphurtransferase coupled with cysteine (aspartate) aminotransferase is responsible for the production of H(2)S in the vascular endothelium of the thoracic aorta [Shibuya et al. (2009) J. Biochem. 146, 623 626]. This finding provides a new insight into the production of the physiologically important signaling molecule. PMID- 21324982 TI - Melting of DNA-actinomycin clusters. AB - Differential methods of scanning micro-calorimetry and UV spectrophotometry were used for understanding the interaction of natural anti-tumour antibiotic actinomycin D with cluster sites of native and fragmented DNA during thermal melting. At low (micro-molar) concentrations, the actinomycin molecules penetrate into unwound regions of DNA, but not into the double helix. Moreover, they stabilize the fragmented DNA and increase a total melting point. Actinomycin D interacts with fractions of native DNA even at very low concentrations (at the antibiotic/nucleotide ratio of 1:868) and stabilizes the most loose clusters. At high concentrations, it destabilizes the double helix. PMID- 21324983 TI - What is the natural ligand of GPR55? AB - GPR55 is a seven transmembrane G protein-coupled receptor and was originally identified as a putative third cannabinoid receptor. Recently, lysophosphatidylinositol (LPI) was reported to be a GPR55 ligand. Stimulation of GPR55 by LPI activates G(12/13) and G(q/11) proteins, induces phosphorylation of the extracellular signal-regulated kinase and increases intracellular calcium concentration. Lysophospholipids are molecularly quite diverse across species and tissues. A recent report showed that the predominant fatty acyl moiety of LPI in rat brain is stearic acid followed by arachidonic acid. The biological activity of arachidonic acid-containing LPI species towards GPR55 was shown to be markedly higher than that of LPI species containing other fatty acyl groups, suggesting that 2-arachidonolyl LPI is the most likely natural ligand of GPR55. PMID- 21324984 TI - Mammalian Hippo pathway: from development to cancer and beyond. AB - The Hippo pathway was discovered as a signal transduction pathway that regulates organ size in Drosophila melanogaster. It is composed of three components: cell surface upstream regulators including cell adhesion molecules and cell polarity complexes; a kinase cascade comprising two serine-threonine kinases with regulators and adaptors; and a downstream target, a transcription coactivator. The coactivator mediates the transcription of cell proliferation-promoting and anti-apoptotic genes. The pathway negatively regulates the coactivator to restrict cell proliferation and to promote cell death. Thus, the pathway prevents tissue overgrowth and tumourigenesis. The framework of the pathway is conserved in mammals. A dysfunction of the pathway is frequently detected in human cancers and correlates with a poor prognosis. Recent works indicated that the Hippo pathway plays an important role in tissue homoeostasis through the regulation of stem cells, cell differentiation and tissue regeneration. PMID- 21324985 TI - Effects of urea and guanidine hydrochloride on the sliding movement of actin filaments with ATP hydrolysis by myosin molecules. AB - To evaluate the role of the hydration layer on the protein surface of actomyosin, we compared the effects of urea and guanidine-HCl on the sliding velocities and ATPase activities of the actin-heavy meromyosin (HMM) system. Both chemicals denature proteins, but only urea perturbs the hydration layer. Both the sliding velocity of actin filaments and actin-activated ATPase activity decreased with increasing urea concentrations. The sliding movement was completely inhibited at 1.0 M urea, while actin filaments were bound to HMM molecules fixed on the glass surface. Guanidine-HCl (0-0.05 M) drastically decreased both the sliding velocity and ATPase activation of acto-HMM complexes. Under this condition, actin filaments almost detached from HMM molecules. In contrast, the ATPase activity of HMM without actin filaments was almost independent of urea concentrations <1.0 M and guanidine-HCl concentrations <0.05 M. An increase in urea concentrations up to 2.0 M partly induced changes in the ternary structure of HMM molecules, while the actin filaments were stable in this concentration range. Hydration changes around such actomyosin complexes may alter both the stability of part of the myosin molecules, and the affinity for force transmission between actin filaments and myosin heads. PMID- 21324986 TI - When to wean. Infection more important than anaemia or allergy. PMID- 21324987 TI - Joint hypermobility syndrome. Urinary incontinence as presenting feature. PMID- 21324988 TI - Joint hypermobility syndrome. Implications for obstetric care. PMID- 21324989 TI - Gun control. Australian and US gun deaths compared. PMID- 21324991 TI - Nations with endemic malaria are urged to scrap taxes and tariffs on drugs and tests. PMID- 21324992 TI - Peer support for patients with type 2 diabetes: cluster randomised controlled trial. AB - OBJECTIVE: To test the effectiveness of peer support for patients with type 2 diabetes. DESIGN: Cluster randomised controlled. SETTING: 20 general practices in the east of the Republic of Ireland. PARTICIPANTS: 395 patients (192 in intervention group, 203 in control group) and 29 peer supporters with type 2 diabetes. INTERVENTION: All practices introduced a standardised diabetes care system. The peer support intervention ran over a two year period and contained four elements: the recruitment and training of peer supporters, nine group meetings led by peer supporters in participant's own general practice, and a retention plan for the peer supporters. MAIN OUTCOME MEASURES: HbA(1c); cholesterol concentration; systolic blood pressure; and wellbeing score. RESULTS: There was no difference between intervention and control patients at baseline. All practices and 85% (337) of patients were followed up. At two year follow-up, there were no significant differences in HbA(1c) (mean difference -0.08%, 95% confidence interval -0.35% to 0.18%), systolic blood pressure (-3.9 mm Hg, -8.9 to 1.1 mm Hg), total cholesterol concentration (-0.03 mmol/L, -0.28 to 0.22 mmol/L), or wellbeing scores (-0.7, -2.3 to 0.8). While there was a trend towards decreases in the proportion of patients with poorly controlled risk factors at follow-up, particularly for systolic blood pressure (52% (87/166) >130 mm Hg in intervention v 61% (103/169) >130 mm Hg in control), these changes were not significant. The process evaluation indicated that the intervention was generally delivered as intended, though 18% (35) of patients in the intervention group never attended any group meetings. CONCLUSIONS: A group based peer support intervention is feasible in general practice settings, but the intervention was not effective when targeted at all patients with type 2 diabetes. While there was a trend towards improvements of clinical outcomes, the results do not support the widespread adoption of peer support. Trial registration Current Controlled Trials ISRCTN42541690. PMID- 21324993 TI - In for the long haul. PMID- 21324998 TI - When to wean. Analysis article on breast feeding was misleading. PMID- 21324999 TI - Living and dying with COPD. End of life trajectories across conditions. PMID- 21325000 TI - Living and dying with COPD. What happens in neurological disease. PMID- 21325001 TI - COPD exacerbations. Anxious not to be breathless. PMID- 21325002 TI - Joint hypermobility syndrome. Psychiatric manifestations. PMID- 21325003 TI - C reactive protein and the risk of cardiovascular disease. PMID- 21325004 TI - Trends in mortality from 1965 to 2008 across the English north-south divide: comparative observational study. AB - OBJECTIVE: To compare all cause mortality between the north and south of England over four decades. DESIGN: Population wide comparative observational study of mortality. SETTING: Five northernmost and four southernmost English government office regions. POPULATION: All residents in each year from 1965 to 2008. MAIN OUTCOME MEASURES: Death rate ratios of north over south England by age band and sex, and northern excess mortality (percentage of excess deaths in north compared with south, adjusted for age and sex and examined for annual trends, using Poisson regression). RESULTS: During 1965 to 2008 the northern excess mortality remained substantial, at an average of 13.8% (95% confidence interval 13.7% to 13.9%). This geographical inequality was significantly larger for males than for females (14.9%, 14.7% to 15.0% v 12.7%, 12.6% to 12.9%, P<0.001). The inequality decreased significantly but temporarily for both sexes from the early 80s to the late 90s, followed by a steep significant increase from 2000 to 2008. Inequality varied with age, being higher for ages 0-9 years and 40-74 years and lower for ages 10-39 years and over 75 years. Time trends also varied with age. The strongest trend over time by age group was the increase among the 20-34 age group, from no significant northern excess mortality in 1965-95 to 22.2% (18.7% to 26.0%) in 1996-2008. Overall, the north experienced a fifth more premature (<75 years) deaths than the south, which was significant: a pattern that changed only by a slight increase between 1965 and 2008. CONCLUSION: Inequalities in all cause mortality in the north-south divide were severe and persistent over the four decades from 1965 to 2008. Males were affected more than females, and the variation across age groups was substantial. The increase in this inequality from 2000 to 2008 was notable and occurred despite the public policy emphasis in England over this period on reducing inequalities in health. PMID- 21325006 TI - The north-south health divide. PMID- 21325007 TI - Doctors criticise proposed changes to the undergraduate medical curriculum in India. PMID- 21325009 TI - Kidney donor is awarded L6.74m after "negligent and reckless" operation. PMID- 21325010 TI - "Harrowing accounts" show how NHS fails to meet basic standards of care of elderly people. PMID- 21325011 TI - A pneumococcal vaccine is launched in Africa to cut child deaths. PMID- 21325012 TI - Ambulatory intravenous ceftriaxone in paediatric A&E: a useful alternative to hospital admission? AB - BACKGROUND: Treatment of children with intravenous ceftriaxone on an ambulatory basis is described. This allows a child to remain at home, but also be reviewed regularly when attending the Emergency Department for antibiotics. METHODS: Indications for, and length of, treatment and laboratory parameters were recorded. Also, a survey of children's parents was undertaken to ascertain opinions regarding ambulatory treatment. RESULTS: 36 patients were treated with ambulatory ceftriaxone over 4 months. Indications included fever without focus, tonsillitis, periorbital cellulitis, urinary tract infection, petechial rash and lymphadenitis. Median duration of treatment was 2.3 days. There was no occult bacteraemia but five positive urine cultures. There was one failure of treatment with subsequent admission for alternative intravenous antibiotics. CONCLUSIONS: Parental opinion favours ambulatory treatment, with 94% of parents acknowledging they would choose it again in similar circumstances. Cost analysis favours ambulatory treatment based on predicted costs of a similar length of inpatient stay. PMID- 21325013 TI - Rationing: the loss of a concept. AB - In the literature on the subject there is a trend towards understanding the idea of rationing in healthcare very broadly, to include any form of restriction in supply. It is suggested in this paper that there are good reasons to resist this move, since it would both render the concept redundant through being trivially true and displace an earlier, egalitarian one that retains great moral significance for the supply of healthcare. The nature and significance of the narrower, egalitarian conception is set out, drawing particular attention to the fact that it marks a contrast with the idea of prioritising certain people or groups over others and to the fact that it is a form of rationing that is plausibly regarded as a morally desirable response to severe shortages. It is contrasted with the broad conception and arguments in favour of this latter are considered and rejected. PMID- 21325005 TI - Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data. AB - OBJECTIVE: To use genetic variants as unconfounded proxies of C reactive protein concentration to study its causal role in coronary heart disease. DESIGN: Mendelian randomisation meta-analysis of individual participant data from 47 epidemiological studies in 15 countries. PARTICIPANTS: 194 418 participants, including 46 557 patients with prevalent or incident coronary heart disease. Information was available on four CRP gene tagging single nucleotide polymorphisms (rs3093077, rs1205, rs1130864, rs1800947), concentration of C reactive protein, and levels of other risk factors. MAIN OUTCOME MEASURES: Risk ratios for coronary heart disease associated with genetically raised C reactive protein versus risk ratios with equivalent differences in C reactive protein concentration itself, adjusted for conventional risk factors and variability in risk factor levels within individuals. RESULTS: CRP variants were each associated with up to 30% per allele difference in concentration of C reactive protein (P<10(-34)) and were unrelated to other risk factors. Risk ratios for coronary heart disease per additional copy of an allele associated with raised C reactive protein were 0.93 (95% confidence interval 0.87 to 1.00) for rs3093077; 1.00 (0.98 to 1.02) for rs1205; 0.98 (0.96 to 1.00) for rs1130864; and 0.99 (0.94 to 1.03) for rs1800947. In a combined analysis, the risk ratio for coronary heart disease was 1.00 (0.90 to 1.13) per 1 SD higher genetically raised natural log (ln) concentration of C reactive protein. The genetic findings were discordant with the risk ratio observed for coronary heart disease of 1.33 (1.23 to 1.43) per 1 SD higher circulating ln concentration of C reactive protein in prospective studies (P=0.001 for difference). CONCLUSION: Human genetic data indicate that C reactive protein concentration itself is unlikely to be even a modest causal factor in coronary heart disease. PMID- 21325014 TI - Melanoma risk for CDKN2A mutation carriers who are relatives of population-based case carriers in Australia and the UK. AB - BACKGROUND: CDKN2A mutations confer a substantial risk of cutaneous melanoma; however, the magnitude of risk is uncertain. METHODS: The study estimated the hazard ratio (HR) and the average age specific cumulative risk (ie, penetrance) of reported melanoma for CDKN2A mutation carriers in case families using a modified segregation analysis of the first and higher degree relatives of 35 population-based cases. The study sample included 223 relatives of 13 melanoma cases diagnosed when aged 18-39 years from Melbourne, Sydney and Brisbane, Australia, and 322 relatives of 22 melanoma cases diagnosed at any age from Yorkshire, UK. RESULTS: The estimated HR for melanoma for mutation carriers relative to the general population decreased with regions of increasing ambient ultraviolet (UV) irradiance, being higher for the UK than Australia (87, 95% CI 50 to 153 vs 31, 95% CI 20 to 50, p=0.008), and across Australia, 49 (95% CI 24 to 98) for Melbourne, 44 (95% CI 22 to 88) for Sydney, and 9 (95% CI 2 to 33) for Brisbane (p=0.02). Penetrance did not differ by geographic region. It is estimated that 16% (95% CI 10% to 27%) of UK and 20% (95% CI 13% to 30%) of Australian CDKN2A mutation carriers would be diagnosed with melanoma by age 50 years, and 45% (95% CI 29% to 65%) and 52% (95% CI 37% to 69%), respectively, by age 80 years. CONCLUSIONS: Contrary to the strong association between UV radiation exposure and melanoma risk for the general population, CDKN2A mutation carriers appear to have the same cumulative risk of melanoma irrespective of the ambient UV irradiance of the region in which they live. PMID- 21325015 TI - A case-control study of risk factors for multiple sclerosis in Iran. AB - BACKGROUND: Numerous studies have assessed risk factors for multiple sclerosis (MS), although none have been conducted previously in Iran. OBJECTIVE: The objective of this study was to study lifestyle and environmental risk factors of MS in the Iranian population. METHODS: A case-control study, including 394 MS cases and 394 matched controls, was conducted in MS clinics in different Iranian cities. Information on lifestyles, environmental exposures, and past medical history was obtained from medical charts and phone interviews. RESULTS: In multivariable analysis, sunlight exposure was associated with a lower risk of MS: the odds ratio (OR) and 95% confidence interval (CI) of MS associated with a 1-h increment in daily sunlight was 0.62 (0.53-0.73). Smoking was associated with MS risk in women (OR: 6.48, 95% CI: 1.46-28.78), but not in men (OR: 0.72, 95% CI: 0.31-1.68) (p=0.002 for interaction). Finally, past history of common surgical procedures, infectious disorders, or exposure to pets and farm animals was not associated with MS risk. CONCLUSIONS: Different modifiable lifestyles, including sunlight exposure and smoking, were associated with lower MS risk in Iran. Interventions aimed at promoting smoking cessation and, more importantly, at increasing exposure to sunlight might contribute to the prevention of MS. PMID- 21325016 TI - Long-term safety profile of mitoxantrone in a French cohort of 802 multiple sclerosis patients: a 5-year prospective study. AB - BACKGROUND: From 2001, a French multicentre study was conducted prospectively in a large cohort of MS patients and annually updated up to at least 5 years after initiation of MITOX therapy. OBJECTIVE: To determine long-term safety profile of mitoxantrone (MITOX) in multiple sclerosis (MS). METHODS: Eight hundred and two patients from 12 MS centres (308 relapsing-remitting, 352 secondary progressive and 142 primary progressive) received MITOX monthly for 6 months (87%) or every 3 months (13%). Patients underwent clinical and haematologic evaluations before every MITOX infusion and every 6-12 months up to 5 years after MITOX start. Echocardiograms were performed at the start and end of MITOX and up to 5 years after. RESULTS: The cohort was followed for 5354 patient-years (mean). One out of 802 patients (0.1%) presented with acute congestive heart failure and 39 out of 794 patients (4.9%) presented with asymptomatic left ventricular ejection fraction reduction under 50% (persistent in 11 patients (28%), transient in 27 patients (69%), on the last scan at year 5 in 1 patient). Two cases of therapy related leukaemia (0.25%) were detected 20 months after MITOX start (one death and one with 8 years confirmed remission). Of the 317 women treated before the age of 45, 17.3% developed a persistent age-dependant amenorrhea. CONCLUSION: This large cohort with at least 5 years of follow-up provided good insights into the long-term safety profile of MITOX in MS. PMID- 21325018 TI - Early failure of N-methyl-D-aspartate receptors and deficient spine formation induced by reduction of regulatory heme in neurons. AB - An initial stage of many neurodegenerative processes is associated with compromised synaptic function and precedes synapse loss, neurite fragmentation, and neuronal death. We showed previously that deficiency of heme, regulating many proteins of pharmacological importance, causes neurodegeneration of primary cortical neurons via N-methyl-d-aspartate receptor (NMDAR)-dependent suppression of the extracellular signal-regulated kinase 1/2 pathway. Here, we asked whether the reduction of heme causes synaptic perturbation before neurite fragmentation in neuronal cultures and investigated molecular mechanisms of synaptic dysfunction in these cells. We showed the change in the NR2B subunit phosphorylation that correlates with compromised NMDAR function after the reduction of regulatory heme and a rapid rescue of NR2B phosphorylation and NMDAR function by exogenous heme. Electrophysiological recordings demonstrated diminished NMDAR currents and NMDAR-mediated calcium influx after 24 h of inhibition of heme synthesis. These effects were reversed by treatment with heme; however, inhibition of the Src family kinases abolished the rescue effect of heme on NMDA-evoked currents. Diminished NMDAR current and Ca(2+) influx resulted in suppressed cGMP production and impairment of spine formation. Exogenous heme exerted rescue effects on NR2B tyrosine phosphorylation and NMDA-evoked currents within minutes, suggesting direct interactions within the NMDAR complex. These synaptic changes after inhibition of heme synthesis occurred at this stage without apparent dysfunction of major hemoproteins. We conclude that regulatory heme is necessary in maintaining NR2B phosphorylation and NMDAR function. NMDAR failure occurs before neurite fragmentation and may be a causal factor in neurodegeneration; this could suggest a route for an early pharmacological intervention. PMID- 21325017 TI - Two common genetic variants near nuclear-encoded OXPHOS genes are associated with insulin secretion in vivo. AB - CONTEXT: Mitochondrial ATP production is important in the regulation of glucose stimulated insulin secretion. Genetic factors may modulate the capacity of the beta-cells to secrete insulin and thereby contribute to the risk of type 2 diabetes. OBJECTIVE: The aim of this study was to identify genetic loci in or adjacent to nuclear-encoded genes of the oxidative phosphorylation (OXPHOS) pathway that are associated with insulin secretion in vivo. DESIGN AND METHODS: To find polymorphisms associated with glucose-stimulated insulin secretion, data from a genome-wide association study (GWAS) of 1467 non-diabetic individuals, including the Diabetes Genetic Initiative (DGI), was examined. A total of 413 single nucleotide polymorphisms with a minor allele frequency >=0.05 located in or adjacent to 76 OXPHOS genes were included in the DGI GWAS. A more extensive population-based study of 4323 non-diabetics, the PPP-Botnia, was used as a replication cohort. Insulinogenic index during an oral glucose tolerance test was used as a surrogate marker of glucose-stimulated insulin secretion. Multivariate linear regression analyses were used to test genotype-phenotype associations. RESULTS: Two common variants were identified in the DGI, where the major C-allele of rs606164, adjacent to NADH dehydrogenase (ubiquinone) 1 subunit C2 (NDUFC2), and the minor G-allele of rs1323070, adjacent to cytochrome c oxidase subunit VIIa polypeptide 2 (COX7A2), showed nominal associations with decreased glucose stimulated insulin secretion (P=0.0009, respective P=0.003). These associations were replicated in PPP-Botnia (P=0.002 and P=0.05). CONCLUSION: Our study shows that genetic variation near genes involved in OXPHOS may influence glucose stimulated insulin secretion in vivo. PMID- 21325019 TI - Cadmium-induced autophagy in rat kidney: an early biomarker of subtoxic exposure. AB - Environmental exposures to cadmium (Cd) are a major cause of human toxicity. The kidney is the most sensitive organ; however, the natures of injuries and of adaptive responses have not been adequately investigated, particularly in response to environmental relevant Cd concentrations. In this study, rats received a daily ip injection of low CdCl2 dose (0.3 mg Cd/kg body mass) and killed at 1, 3, and 5 days of intoxication. Functional, ultrastructural, and biochemical observations were used to evaluate Cd effects. We show that Cd at such subtoxic doses does not affect the tubular functions nor does it induce apoptosis. Meanwhile, Cd accumulates within lysosomes of proximal convoluted tubule (PCT) cells where it triggers cell proliferation and autophagy. By developing an immunohistochemical assay, a punctate staining of light chain 3-II is prominent in Cd-intoxicated kidneys, as compared with control. We provide the evidence of a direct upregulation of autophagy by Cd using a PCT cell line. Compared with the other heavy metals, Cd is the most powerful inducer of endoplasmic reticulum stress and autophagy in PCT cells, in relation to the hypersensitivity of PCT cells. Altogether, these findings suggest that kidney cortex adapts to subtoxic Cd dose by activating autophagy, a housekeeping process that ensures the degradation of damaged proteins. Given that Cd is persistent within cytosol, it might damage proteins continuously and impair at long-term autophagy efficiency. We therefore propose the autophagy pathway as a new sensitive biomarker for renal injury even after exposure to subtoxic Cd doses. PMID- 21325020 TI - Genetic status of Asiatic black bear (Ursus thibetanus) reintroduced into South Korea based on mitochondrial DNA and microsatellite loci analysis. AB - The Asiatic black bear is one of the most endangered mammals in South Korea owing to population declines resulting from human exploitation and habitat fragmentation. To restore the black bear population in South Korea, 27 bear cubs from North Korea and Russian Far East (Primorsky Krai) were imported and released into Jirisan National Park, a reservoir of the largest wild population in South Korea, in 2004. To monitor the success of this reintroduction, the genetic diversity and population structure of the reintroduced black bears were measured using both mitochondrial and nuclear DNA markers. Mitochondrial D-loop region DNA sequences (615 bp) of 43 Japanese black bears from previous study and 14 Southeast Asian black bears in this study were employed to obtain phylogenetic inference of the reintroduced black bears. The mitochondrial phylogeny indicated Asiatic black bear populations from Russian Far East and North Korea form a single evolutionary unit distinct from populations from Japan and Southeast Asia. Mean expected heterozygosity (H(E)) across 16 microsatellite loci was 0.648 for Russian and 0.676 for North Korean populations. There was a moderate but significant level of microsatellite differentiation (F(ST) = 0.063) between black bears from the 2 source areas. In addition, genetic evidences revealed that 2 populations are represented as diverging groups, with lingering genetic admixture among individuals of 2 source populations. Relatedness analysis based on genetic markers indicated several discrepancies with the pedigree records. Implication of the phylogenetic and genetic evidences on long-term management of Asiatic black bears in South Korea is discussed. PMID- 21325021 TI - Interspecific hybridization, a matter of pioneering? Insights from Atlantic salmon and brown trout. AB - Interspecific hybridization may occur in situations of recent contact between a colonizer and a resident species, being more intense in the colonization front. Atlantic salmon Salmo salar and brown trout S. trutta have been sympatric species since their origin and they share spatial and temporal spawning niches, exhibiting low levels of bidirectional interspecific hybridization and introgression throughout their distribution range. Different causes have been identified for increased hybridization, from escapes or deliberate releases of domesticated fish to sneaking male behavior. We have examined hybridization rates and direction in different situations of advance of one of these species into a territory formerly inhabited by the other (247 samples were analyzed in northern Spain and 487 in Kerguelen Islands). In all cases, hybrids found in the colonization front were offspring of colonizer females and resident males. We hypothesize that these findings are the result of adaptive relaxed mate choice of colonizing females, regardless of the relative abundance of each species. PMID- 21325022 TI - Ireland: a fine place for multiple sclerosis research. PMID- 21325023 TI - Does Campylobacter jejuni infection elicit axonal or demyelinating Guillain-Barre syndrome, or both? PMID- 21325024 TI - Acute inflammatory neuropathies: new evidence for disease classification from Japan. PMID- 21325025 TI - Post-pruning shoot growth increases fruit abscission and reduces stem carbohydrates and yield in macadamia. AB - BACKGROUND AND AIMS: There is good evidence for deciduous trees that competition for carbohydrates from shoot growth accentuates early fruit abscission and reduces yield but the effect for evergreen trees is not well defined. Here, whole tree tip-pruning at anthesis is used to examine the effect of post-pruning shoot development on fruit abscission in the evergreen subtropical tree macadamia (Macadamia integrifolia, M. integrifolia * tetraphylla). Partial-tree tip-pruning is also used to test the localization of the effect. METHODS: In the first experiment (2005/2006), all branches on trees were tip-pruned at anthesis, some trees were allowed to re-shoot (R treatment) and shoots were removed from others (NR treatment). Fruit set and stem total non-structural carbohydrates (TNSC) over time, and yield were measured. In the second experiment (2006/2007), upper branches of trees were tip-pruned at anthesis, some trees were allowed to re shoot (R) and shoots were removed from others (NR). Fruit set and yield were measured separately for upper (pruned) and lower (unpruned) branches. KEY RESULTS: In the first experiment, R trees set far fewer fruit and had lower yield than NR trees. TNSC fell and rose in all treatments but the decline in R trees occurred earlier than in NR trees and coincided with early shoot growth and the increase in fruit abscission relative to the other treatments. In the second experiment, fruit abscission on upper branches of R trees increased relative to the other treatments but there was little difference in fruit abscission between treatments on lower branches. CONCLUSIONS: This study is the first to demonstrate an increase in fruit abscission in an evergreen tree in response to pruning. The effect appeared to be related to competition for carbohydrates between post pruning shoot growth and fruit development and was local, with shoot growth on pruned branches having no effect on fruit abscission on unpruned branches. PMID- 21325026 TI - The role of the N-terminal domain in dimerization and nucleocytoplasmic shuttling of latent STAT3. AB - STAT3 is an important transcription factor involved in immunity and cancer. In response to cytokine stimulation, STAT3 becomes phosphorylated on a single tyrosine residue. Tyrosine-phosphorylated STAT3 accumulates in the nucleus, binds to specific DNA response elements and induces gene expression. Unphosphorylated, latent STAT3 shuttles constitutively between cytoplasm and nucleus. We analysed the importance of previously identified putative nuclear localization sequences (NLS) and nuclear export sequences (NES) for nucleocytoplasmic shuttling of latent STAT3 using STAT3-deficient cells reconstituted with fluorescently labelled STAT3 mutants. Mutation of a putative NLS or NES sequence did not impair nucleocytoplasmic shuttling of latent STAT3. We were also interested in the structural requirements for dimerization of unphosphorylated STAT3 and its relevance for nucleocytoplasmic shuttling. By native gel electrophoresis and dual focus fluorescence correlation spectroscopy (2f-FCS) we identified the N-terminal domain (amino acids 1-125) to be essential for formation of unphosphorylated STAT3 dimers but not for assembly of tyrosine-phosphorylated STAT3 dimers. In resting cells, the monomeric N-terminal deletion mutant (STAT3-DeltaNT) shuttles faster between the cytoplasm and nucleus than the wild-type STAT3, indicating that dimer formation is not required for nucleocytoplasmic shuttling of latent STAT3. STAT3-DeltaNT becomes phosphorylated and dimerizes in response to interleukin-6 stimulation but, surprisingly, does not accumulate in the nucleus. These results highlight the importance of the N-terminal domain in the formation of unphosphorylated STAT3 dimers and nuclear accumulation of STAT3 upon phosphorylation. PMID- 21325027 TI - Quadriceps myopathy caused by skeletal muscle-specific ablation of beta(cyto) actin. AB - Quadriceps myopathy (QM) is a rare form of muscle disease characterized by pathological changes predominately localized to the quadriceps. Although numerous inheritance patterns have been implicated in QM, several QM patients harbor deletions in dystrophin. Two defined deletions predicted loss of functional spectrin-like repeats 17 and 18. Spectrin-like repeat 17 participates in actin filament binding, and thus we hypothesized that disruption of a dystrophin cytoplasmic actin interaction might be one of the mechanisms underlying QM. To test this hypothesis, we generated mice deficient for beta(cyto)-actin in skeletal muscles (Actb-msKO). Actb-msKO mice presented with a progressive increase in the proportion of centrally nucleated fibers in the quadriceps, an approximately 50% decrease in dystrophin protein expression without alteration in transcript levels, deficits in repeated maximal treadmill tests, and heightened sensitivity to eccentric contractions. Collectively, these results suggest that perturbing a dystrophin-beta(cyto)-actin linkage decreases dystrophin stability, which results in a QM, and implicates beta(cyto)-actin as a possible candidate gene in QM pathology. PMID- 21325028 TI - Drosophila male germline stem cells do not asymmetrically segregate chromosome strands. AB - Adult stem cells continuously supply differentiated cells throughout the life of organisms. This increases the risk of replicative senescence or neoplastic transformation due to mutations that accumulate over many rounds of DNA replication. The immortal strand hypothesis proposes that stem cells reduce the accumulation of replication-induced mutations by retaining the older template DNA strands. Other models have also been proposed in which stem cells asymmetrically segregate chromosome strands for other reasons, such as retention of epigenetic memories. Recently, the idea has emerged that the mother centrosome, which is stereotypically retained within some asymmetrically dividing stem cells, might be utilized as a means of asymmetrically segregating chromosome strands. We have tested this hypothesis in germline stem cells (GSCs) from Drosophila melanogaster testis, which undergo asymmetric divisions marked by the asymmetric segregation of centrosomes and the acquisition of distinct daughter cell fates (stem cell self-renewal versus differentiation). Using 5-bromo-2-deoxyuridine labeling combined with direct visualization of GSC-gonialblast (differentiating daughter) pairs, we directly scored the outcome of chromosome strand segregation. Our data show that, in male GSCs in the Drosophila testis, chromosome strands are not asymmetrically segregated, despite asymmetrically segregating centrosomes. Our data demonstrate that asymmetric centrosome segregation in stem cells does not necessarily lead to asymmetric chromosome strand segregation. PMID- 21325029 TI - pp32, an INHAT component, is a transcription machinery recruiter for maximal induction of IFN-stimulated genes. AB - Type I interferon (IFN) plays a crucial role in establishing the cellular antiviral state by inducing transcription of IFN-stimulated genes (ISGs). Generally, histone acetyltransferases (HATs) are positive regulators of transcription, but histone deacetylase (HDAC) activity is essential for transcriptional induction of ISGs. pp32 is known to be a key component of the inhibitor of acetyltransferase (INHAT) complex that inhibits HAT-dependent transcriptional activation. Here, we show that pp32 is involved in the positive regulation of ISG transcription. pp32 interacted with signal transducer and activator of transcription 1 (STAT1) and STAT2 in an IFN-dependent manner. pp32 was not required for tyrosine phosphorylation and nuclear translocation of STATs, but was needed for binding of transcriptional complexes with ISG promoters and, thereby, for maximal transcription activation. pp32 was found to be associated with ISG promoters in IFN-untreated cells, and its binding amount fluctuated as a function of time after IFN treatment. short interfering RNA (siRNA)-mediated knockdown of pp32 expression reduced the histone acetylation level on ISG promoters, suggesting that pp32 plays a role in ISG transcription by a function other than that of INHAT. Taking these findings together, we propose that pp32 is involved in the formation of ISG transcription initiation complexes, possibly as their recruiter. PMID- 21325031 TI - Trichoplein controls microtubule anchoring at the centrosome by binding to Odf2 and ninein. AB - The keratin cytoskeleton performs several functions in epithelial cells and provides regulated interaction sites for scaffold proteins, including trichoplein. Previously, we found that trichoplein was localized on keratin intermediate filaments and desmosomes in well-differentiated, non-dividing epithelia. Here, we report that trichoplein is widely expressed and has a major function in the correct localization of the centrosomal protein ninein in epithelial and non-epithelial cells. Immunocytochemical analysis also revealed that this protein is concentrated at the subdistal to medial zone of both mother and daughter centrioles. Trichoplein binds the centrosomal proteins Odf2 and ninein, which are localized at the distal to subdistal ends of the mother centriole. Trichoplein depletion abolished the recruitment of ninein, but not Odf2, specifically at the subdistal end. However, Odf2 depletion inhibited the recruitment of trichoplein to a mother centriole, whereas ninein depletion did not. In addition, the depletion of each molecule impaired MT anchoring at the centrosome. These results suggest that trichoplein has a crucial role in MT anchoring activity at the centrosome in proliferating cells, probably through its complex formation with Odf2 and ninein. PMID- 21325030 TI - Kindlin-2 regulates podocyte adhesion and fibronectin matrix deposition through interactions with phosphoinositides and integrins. AB - Kindlin-2 is a FERM and PH domain-containing integrin-binding protein that is emerging as an important regulator of integrin activation. How kindlin-2 functions in integrin activation, however, is not known. We report here that kindlin-2 interacts with multiple phosphoinositides, preferentially with phosphatidylinositol 3,4,5-trisphosphate. Although integrin-binding is essential for focal adhesion localization of kindlin-2, phosphoinositide-binding is not required for this process. Using biologically and clinically relevant glomerular podocytes as a model system, we show that integrin activation and dependent processes are tightly regulated by kindlin-2: depletion of kindlin-2 reduced integrin activation, matrix adhesion and fibronectin matrix deposition, whereas overexpression of kindlin-2 promoted these processes. Furthermore, we provide evidence showing that kindlin-2 is involved in phosphoinositide-3-kinase-mediated regulation of podocyte-matrix adhesion and fibronectin matrix deposition. Mechanistically, kindlin-2 promotes integrin activation and integrin-dependent processes through interacting with both integrins and phosphoinositides. TGF beta1, a mediator of progressive glomerular failure, markedly increased the level of kindlin-2 and fibronectin matrix deposition, and the latter process was reversed by depletion of kindlin-2. Our results reveal important functions of kindlin-2 in the regulation of podocyte-matrix adhesion and matrix deposition and shed new light on the mechanism whereby kindlin-2 functions in these processes. PMID- 21325032 TI - Screening breast MR imaging in women with a history of chest irradiation. AB - PURPOSE: To assess the utility of screening magnetic resonance (MR) imaging in detecting otherwise occult breast cancers in women with a history of radiation therapy to the chest. MATERIALS AND METHODS: This HIPAA-compliant study was approved by the authors' institutional review board. The need for informed consent was waived. Retrospective review of the radiology department database identified 247 screening breast MR imaging examinations performed between January 1999 and December 2008 in 91 women with a history of chest irradiation. Findings and recommendations for each breast MR study and on the most recent mammogram were reviewed. The number of cancers diagnosed, their method of detection, and tumor characteristics were examined. The exact 95% binomial proportion confidence intervals were calculated by using methods described by Clopper and Pearson. RESULTS: Biopsy was recommended for 32 suspicious lesions on 27 (11%) of 247 MR imaging studies in 21 women. Seven cancers were identified in 30 lesions sampled (23%). Biopsy was recommended in five additional patients on the basis of mammographic findings, and malignancy was detected in three. Ten cancers were detected during the study period: four detected with MR imaging alone, three with MR imaging and mammography, and three with mammography alone. The four cancers detected with MR imaging alone were invasive carcinomas. Two of three cancers detected with mammography alone were ductal carcinoma in situ (DCIS), and the third was DCIS with microinvasion. CONCLUSION: MR imaging is a useful adjunct modality to screen high-risk women with a history of chest irradiation, resulting in a 4.4% (95% confidence interval: 1.2%, 10.9%) incremental cancer detection rate; the sensitivity for detecting breast cancers by using a combination of MR imaging and mammography was higher than that for either modality alone. PMID- 21325033 TI - JPEG2000 2D and 3D reversible compressions of thin-section chest CT images: improving compressibility by increasing data redundancy outside the body region. AB - PURPOSE: To propose a preprocessing technique that increases the compressibility in reversible compressions of thin-section chest computed tomographic (CT) images and to measure the increase in compression ratio (CR) in Joint Photographic Experts Group (JPEG) 2000 two-dimensional (2D) and three-dimensional (3D) compressions. MATERIALS AND METHODS: This study had institutional review board approval, with waiver of informed patient consent. A preprocessing technique that automatically segments pixels outside the body region and replaces their values with a constant value to maximize data redundancy was developed. One hundred CT studies (50 standard-radiation dose and 50 low-radiation dose studies) were preprocessed by using the technique and then reversibly compressed by using the JPEG2000 2D and 3D compression methods. The CRs (defined as the original data size divided by the compressed data size) with and those without use of the preprocessing technique were compared by using paired t tests. The percentage increase in the CR was measured. RESULTS: The CR increased significantly (without vs with preprocessing) in JPEG2000 2D (mean CR, 2.40 vs 3.80) and 3D (mean CR, 2.61 vs 3.99) compressions for the standard-dose studies and in JPEG2000 2D (mean CR, 2.38 vs 3.36) and 3D (mean CR, 2.54 vs 3.55) compressions for the low-dose studies (P < .001 for all). The mean percentage increases in CR with preprocessing were 58.2% (95% confidence interval [CI]: 53.1%, 63.4%) and 52.4% (95% CI: 47.5%, 57.2%) in JPEG2000 2D and 3D compressions, respectively, for the standard-dose studies and 41.1% (95% CI: 38.8%, 43.4%) and 39.4% (95% CI: 37.4%, 41.7%) in JPEG2000 2D and 3D compressions, respectively, for the low-dose studies. CONCLUSION: The described preprocessing technique considerably increases CRs for reversible compressions of thin-section chest CT studies. PMID- 21325034 TI - Detection of coronary artery anomalies in infants and young children with congenital heart disease by using MR imaging. AB - PURPOSE: To evaluate the feasibility and accuracy of magnetic resonance (MR) coronary angiography for the detection of coronary artery anomalies in infants and children by using surgical findings as a reference. MATERIALS AND METHODS: The data analysis was approved by the institutional review board. One hundred children with congenital heart disease underwent MR coronary angiography while under general anesthesia (mean age +/- standard deviation, 3.9 years +/- 3; age range, 0.2-11 years). A navigator-gated, T2-prepared, three-dimensional steady state free precession whole-heart protocol (isotropic voxel size, 1.0-1.3 mm(3); mean imaging time, 4.6 minutes +/- 1.2; mean navigator efficiency, 70%; 3-mm gating window) was used after injection of gadopentetate dimeglumine. The cardiac rest period (end systole or middiastole) and acquisition window were prospectively assessed for each patient. Coronary artery image quality (score of 0 [nondiagnostic] to 4 [excellent]), vessel sharpness, and coronary artery anomalies were assessed by two observers. Surgery was performed in 58 patients, and those findings were used to define accuracy. Variables were assessed between age groups by using either analysis of variance or Kruskal-Wallis tests. RESULTS: Diagnostic image quality (score, >=1 for all coronary artery segments) was obtained in 46 of the 58 patients (79%) who underwent surgery. The origin and course of the coronary artery anatomy depicted with MR imaging was confirmed at surgery in all 46 patients-including the four (9%) with substantial coronary artery anomalies. Diagnostic-quality images were obtained in 84 of the 100 patients. The rate of success improved significantly when patients were older than 4 months (88% for patients >4 months vs 17% for patients <=4 months, P < .001). CONCLUSION: Improved whole-heart MR coronary angiography enables accurate detection of abnormal origin and course of the coronary artery system even in very young patients with congenital heart disease. PMID- 21325036 TI - Novel alleles of HLA-DQ and -DR loci show association with recurrent miscarriages among South Indian women. AB - BACKGROUND In this study, recurrent miscarriages (RMs) are defined as loss of two or more clinically detectable pregnancies before 20 weeks of gestation. HLA has been thought to play a role in RM. However, the results of earlier studies on the role of different human leucocyte antigen (HLA) genes were conflicting and inconclusive. In the present study, we investigate HLA genes (HLA-DRA, HLA-DRB1, HLA-DQA1 and HLA-DQB1) in RM couples with unknown etiology and normal couples. METHODS Blood samples from 143 RM couples and 150 control couples were analyzed, firstly to validate previously reported association studies and secondly to explore whether any novel alleles or haplotypes specific to Indian populations can be observed to be associated with RM. HLA typing was carried out by DNA sequencing. RESULTS Results suggest an association of the DQB1*03:03:02 allele with RM (odd ratio = 2.66; p(c) = 0.02; confidence interval = 1.47-4.84). Haplotypes of the DQA1 and DQB1 risk alleles also showed a significant association with RM, albeit not after Bonferroni correction for multiple comparisons. CONCLUSIONS HLA-DQB1 appears to have a strong involvement in the manifestation of RM in this population from South India. The current genetic analysis of RM and control couples not only highlights the genes exhibiting a strong etiological role but also reflects the protective nature of some HLA genes against RM. Nevertheless, most of these alleles/haplotypes were not those that are implicated in RM in other ethnic backgrounds, and hence require further validation in other populations of India, from different ethnic and/or geographic backgrounds. PMID- 21325035 TI - Quantitative imaging test approval and biomarker qualification: interrelated but distinct activities. AB - Quantitative imaging biomarkers could speed the development of new treatments for unmet medical needs and improve routine clinical care. However, it is not clear how the various regulatory and nonregulatory (eg, reimbursement) processes (often referred to as pathways) relate, nor is it clear which data need to be collected to support these different pathways most efficiently, given the time- and cost intensive nature of doing so. The purpose of this article is to describe current thinking regarding these pathways emerging from diverse stakeholders interested and active in the definition, validation, and qualification of quantitative imaging biomarkers and to propose processes to facilitate the development and use of quantitative imaging biomarkers. A flexible framework is described that may be adapted for each imaging application, providing mechanisms that can be used to develop, assess, and evaluate relevant biomarkers. From this framework, processes can be mapped that would be applicable to both imaging product development and to quantitative imaging biomarker development aimed at increasing the effectiveness and availability of quantitative imaging. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100800/-/DC1. PMID- 21325037 TI - Streptolysin O inhibits clathrin-dependent internalization of group A Streptococcus. AB - Group A Streptococcus (GAS) can be internalized by epithelial cells, including keratinocytes from human skin or pharyngeal epithelium. Internalization of GAS by epithelial cells has been postulated both to play a role in host defense and to provide a sanctuary site for GAS survival. The cholesterol-binding cytolysin streptolysin O (SLO) appears to enhance virulence in part by inhibiting GAS internalization by human keratinocytes and by disrupting the lysosomal degradation of internalized GAS. We now report that low-level production of SLO by an inducible expression system reduced GAS internalization by keratinocytes. Induced SLO expression also prevented lysosomal colocalization with intracellular bacteria and acidification of GAS-containing vacuoles. Exogenous recombinant SLO mimicked the inhibitory effect of SLO secretion on GAS entry but not that on colocalization with the lysosomal marker LAMP-1, implying that disruption of lysosomal degradation requires intracellular secretion of SLO. The internalization of SLO-negative GAS was blocked by the depletion of host cell cholesterol and by the inhibition or knocking down of the expression of clathrin or dynamin. SLO also inhibited the cellular uptake of other cargos that are internalized by clathrin-mediated uptake or by macropinocytosis. We conclude that SLO interferes with the internalization of GAS through local perturbation of the keratinocyte cell membrane and disruption of a clathrin-dependent uptake pathway. PMID- 21325038 TI - Enhanced mucosal immune responses to HIV virus-like particles containing a membrane-anchored adjuvant. AB - Previously, a modified HIV Env protein with a heterologous membrane anchor was found to be incorporated into HIV virus-like particles (VLPs) at 10-fold-higher levels than those of unmodified Env. To further improve the immunogenicity of such VLPs, membrane-anchored forms of bacterial flagellin (FliC) or a flagellin with a truncated variable region (tFliC) were constructed to be incorporated into the VLPs as adjuvants. HIV-specific immune responses induced by the resulting VLPs were determined in a guinea pig model. The VLPs induce enhanced systemic antibody responses by either systemic or mucosal vaccination and enhanced mucosal immunity by a mucosal immunization route, as demonstrated by high levels of HIV specific serum IgG and mucosal IgG and IgA. The quality of the antibody responses was also improved, as shown by enhanced neutralization capacity. VLPs incorporating FliC were more effective in inducing systemic responses, while VLPs containing tFliC were more effective in inducing mucosal IgA responses. The IgG titers in sera were found to last for at least 5 months without a significant drop. These results indicate that HIV VLPs incorporating high levels of Env and a molecular adjuvant have excellent potential for further development as a prophylactic HIV vaccine. PMID- 21325039 TI - Reversible signal binding by the Pseudomonas aeruginosa quorum-sensing signal receptor LasR. AB - Many members of the LuxR family of acyl-homoserine lactone (acyl-HSL)-dependent quorum-sensing transcriptional activators are thought to have the unusual characteristics of requiring the signal ligand during polypeptide synthesis to fold into an active conformation and of binding signal extraordinarily tightly. This is the case for the N-3-oxo-dodecanoyl-HSL-dependent Pseudomonas aeruginosa virulence regulator LasR. We present evidence that LasR can fold into an active conformation in vivo in the absence of the acyl-HSL ligand. We also present evidence indicating that in the cellular environment, LasR and N-3-oxo-dodecanoyl HSL readily dissociate. After dissociation, LasR can remain in a properly folded conformation capable of reassociating with signal. We present a new model for the folding and signal binding of LasR and other members of the family of transcription factors to which LasR belongs. Our findings have important implications concerning the cellular responses to decreased environmental concentrations of signals and have implications about potential quorum-sensing inhibition strategies. PMID- 21325040 TI - Opportunity and means: horizontal gene transfer from the human host to a bacterial pathogen. AB - The acquisition and incorporation of genetic material between nonmating species, or horizontal gene transfer (HGT), has been frequently described for phylogenetically related organisms, but far less evidence exists for HGT between highly divergent organisms. Here we report the identification and characterization of a horizontally transferred fragment of the human long interspersed nuclear element L1 to the genome of the strictly human pathogen Neisseria gonorrhoeae. A 685-bp sequence exhibiting 98 to 100% identity to copies of the human L1 element was identified adjacent to the irg4 gene in some N. gonorrhoeae genomes. The L1 fragment was observed in ~11% of the N. gonorrhoeae population sampled but was not detected in Neisseria meningitidis or commensal Neisseria isolates. In addition, N. gonorrhoeae transcripts containing the L1 sequence were detected by reverse transcription-PCR, indicating that an L1 derived gene product may be produced. The high degree of identity between human and gonococcal L1 sequences, together with the absence of L1 sequences from related Neisseria species, indicates that this HGT event occurred relatively recently in evolutionary history. The identification of L1 sequences in N. gonorrhoeae demonstrates that HGT can occur between a mammalian host and a resident bacterium, which has important implications for the coevolution of both humans and their associated microorganisms. PMID- 21325041 TI - Deletion of glycogen synthase kinase-3beta in cartilage results in up-regulation of glycogen synthase kinase-3alpha protein expression. AB - The rate of endochondral bone growth determines final height in humans and is tightly controlled. Glycogen synthase kinase-3 (GSK-3) is a negative regulator of several signaling pathways that govern bone growth, such as insulin/IGF and Wnt/beta-catenin. The two GSK-3 proteins, GSK-3alpha and GSK-3beta, display both overlapping and distinct roles in different tissues. Here we show that pharmacological inhibition of GSK-3 signaling in a mouse tibia organ culture system results in enhanced bone growth, accompanied by increased proliferation of growth plate chondrocytes and faster turnover of hypertrophic cartilage to bone. GSK-3 inhibition rescues some, but not all, effects of phosphatidylinositide 3 kinase inhibition in this system, in agreement with the antagonistic role of these two kinases in response to signals such as IGF. However, cartilage-specific deletion of the Gsk3b gene in mice has minimal effects on skeletal growth or development. Molecular analyses demonstrated that compensatory up-regulation of GSK-3alpha protein levels in cartilage is the likely cause for this lack of effect. To our knowledge, this is the first tissue in which such a compensatory mechanism is described. Thus, our study provides important new insights into both skeletal development and the biology of GSK-3 proteins. PMID- 21325042 TI - Maternal ghrelin deficiency compromises reproduction in female progeny through altered uterine developmental programming. AB - Ghrelin has a well-known role in the regulation of appetite, satiety, energy metabolism, and reproduction; however ghrelin has not been implicated in reproductive tract development. We examined the effect of ghrelin deficiency on the developmental programming of female fertility. We observed that female wild type mice born of ghrelin heterozygote dams (i.e. exposed in utero to ghrelin deficiency) had diminished fertility and produced smaller litters. We demonstrate that exposure to in utero ghrelin deficiency led to altered developmental programming of the reproductive tract. The number of ovarian follicles, corpora lutea, and embryos produced were identical in both exposed and unexposed mice. However wild-type embryos transferred to uteri of mice exposed to in utero ghrelin deficiency had a 60% reduction in the rate of embryo implantation compared with those transferred to wild-type unexposed uteri. We identified significant alterations in the uterine expression of four genes critical for implantation and a defect in uterine endometrial proliferation. Taken together, these results demonstrate that the mechanism of subfertility was abnormal endometrial function. In utero exposure to decreased levels of ghrelin led to defects in developmental programming of the uterus and subsequent subfertility in wild-type offspring. PMID- 21325043 TI - Hormonal regulation of sertoli cell micro-RNAs at spermiation. AB - Spermatogenesis is absolutely dependent on FSH and androgens; suppression of these hormones inhibits germ cell development and thus sperm production. The final release of spermatids by the Sertoli cell, a process known as spermiation, is particularly sensitive to hormone suppression. To define the molecular mechanisms that mediate FSH and androgen effects in the Sertoli cell, we investigated the expression and regulation of micro-RNAs (miRNAs), small noncoding RNAs that regulate protein translation and modify cellular responses. By array analysis, we identified 23 miRNAs up-regulated more than 2-fold after hormone suppression in vivo and in vitro in primary Sertoli cell cultures. The regulation of four of these miRNAs (miR-23b, -30c, -30d, and -690) was confirmed by quantitative RT-PCR. Bioinformatic analysis of potential targets of hormonally regulated miRNAs identified genes important for focal adhesion and regulation of the actin cytoskeleton, processes known to be intimately associated with adhesion of spermatids to Sertoli cells. Two of the identified genes, Pten, an intracellular phosphatase, and Eps15, a mediator of endocytosis, were down regulated by the withdrawal of hormones in vivo and possess miR-23b target sites in their 3'-untranslated regions. Overexpression of miR-23b in vitro resulted in decreased translation of PTEN and EPS15 protein as assessed by Western blot and luciferase analysis. We conclude that FSH and androgens act on Sertoli cells in stage VIII to control the expression of miRNAs that operate in a coordinated manner to regulate cell adhesion pathways and male fertility and that miRNA transcription is a new paradigm in the hormone dependence of spermiation. PMID- 21325044 TI - The organizational role of testicular hormones and the androgen receptor in anxiety-related behaviors and sensorimotor gating in rats. AB - Perinatal exposure to testosterone (T), which can act upon both the androgen receptor (AR) and, via aromatization of T into estrogens, upon estrogen receptors, organizes many adult behaviors in rodents. We compared behaviors in wild-type (WT) male rats and AR-deficient rats with the testicular feminization mutation (Tfm), which on the day of birth were either gonadectomized (Neo-Gdx) or sham operated. In adulthood, all rats were either gonadectomized or sham operated and implanted with T capsules to equilibrate circulating androgens. In each of four tests of behavior related to anxiety (open field, novel object exposure, light/dark box, and elevated plus maze), Neo-Gdx rats showed decreased indices of anxiety and increased activity compared with rats sham operated on the day of birth, with no differences between WT or Tfm males within treatment groups. These results indicate that testicular hormones act in development to increase adult indices of anxiety and decrease activity in males and that functional ARs are not required for this effect. Acoustic startle response was also reduced by Neo-Gdx, suggesting that postnatal testicular secretions potentiate this behavior as well. Adult corticosterone levels and sensorimotor gating, as measured by prepulse inhibition of the acoustic startle response, were increased by neonatal castration in both WT and Tfm rats. These findings indicate a role of T before adulthood in the organization of anxiety-related behaviors, activity, the hypothalamic-pituitary-adrenal axis, and sensorimotor gating in rats, all of which appears to be AR independent. PMID- 21325047 TI - Essential role for protein kinase Czeta in oleic acid-induced glucagon-like peptide-1 secretion in vivo in the rat. AB - Luminal monounsaturated long-chain fatty acids [e.g. oleic acid (OA)] increase secretion of the incretin, glucagon-like peptide-1 (GLP-1) from the ileocolonic L cell. However, it is not known whether OA ingestion causes a sufficient increase in distal luminal concentrations to directly enhance GLP-1 secretion. Furthermore, we have demonstrated that protein kinase Czeta (PKCzeta) is required for OA-induced GLP-1 secretion in vitro; however, the physiological relevance of this finding remains unknown. Therefore, we have determined luminal OA concentrations in OA-fed rats and examined the effects of direct OA stimulation on GLP-1 secretion using a novel model of intestinal-specific PKCzeta knockdown. Murine GLUTag L cells express numerous fatty acid transport proteins and take up OA in a saturable manner. Oral administration of OA increased the ileal chyme content of OA by 140-fold over 60-120 min (P < 0.05-0.01), peaking at 105 +/- 50 MUmol/g. To evaluate the direct effects of OA on GLP-1 secretion, 125 mm OA was rectally infused into the colon and terminal ileum of rats. Plasma bioactive GLP 1 increased from 20 +/- 6 to 102 +/- 21 pg/ml at 60 min (P < 0.01). However, pretreatment with ileocolonic adenoviral PKCzeta small interfering RNA resulted in a 68 +/- 8% reduction in the GLP-1 response to rectal OA (P < 0.001). The results of these studies indicate that OA levels in the rat terminal gut after oral ingestion are sufficient to induce GLP-1 secretion and that PKCzeta is necessary for the effects of OA on GLP-1 secretion in vivo. PKCzeta may therefore serve as a novel therapeutic target to enhance GLP-1 levels in patients with type 2 diabetes. PMID- 21325046 TI - Prenatal androgen exposure leads to alterations in gene and protein expression in the ovine fetal ovary. AB - Exposure of a female fetus to increased androgens in utero results in an adult phenotype reminiscent of polycystic ovary syndrome. We investigated whether prenatal androgens could directly alter the structure and function of the fetal ovary. We examined fetal ovarian cell proliferation, germ cell volume, and the expression of steroid receptors and steroidogenic enzymes. In addition, we studied the inhibitors of differentiation (Ids) and the SLIT/Roundabout developmental pathways. Female fetuses were collected from ewes treated with 100 mg testosterone propionate (TP) or vehicle control (C), twice weekly from d 60 to 70 (C = 3, TP = 6) or d 90 (C = 6, TP = 8). Female fetuses were also collected at d 70 after a single injection of TP (20 mg) or vehicle C into the fetal flank at d 60 (C = 4, TP = 8). Prenatal androgenization had no effect on fetal ovarian morphology, cell proliferation, or germ cell volume. However, there was a reduction in the expression of StAR, CYP11A, CYP17, and LHR at d 90 of gestation. There was also an increase in Id1 immunostaining at d 90 and an increase in Id3 immunostaining at d 70. Direct injection of TP into the fetus down-regulated ovarian CYP11A, estrogen receptor alpha and beta mRNA, and ROBO1 and up-regulated CYP19, androgen receptor immunostaining, and Id3 mRNA and protein. Although at d 90 prenatal androgenization does not result in structural changes of the fetal ovary, there are functional changes that may impact on ovarian development. TP has direct actions on the fetal ovary, and these may contribute to the adult ovarian phenotype in the ovine model of polycystic ovary syndrome. PMID- 21325045 TI - Minireview: estrogen receptor-initiated mechanisms causal to mammalian reproductive behaviors. AB - While estrogen-facilitated changes in gene expression constitute some of the best analyzed biochemical phenomena in the regulation of transcription, there have been at least two aspects of this topic that have led to much experimental work about estrogen actions on brain and behavior. The first task has required parsing various behavioral and neurochemical functions according to whether they depend on estrogen receptor-alpha or estrogen receptor-beta. The second task has been the formulation of how nuclear actions of estrogens comport with membrane initiated actions. With respect to these issues, applications of molecular endocrine approaches to lordosis behavior came first. Currently, the last in the chain of reproductive behaviors, maternal behavior, and an entire range of neural and cognitive functions even more complex in their determinants, must be analyzed using current molecular techniques. This minireview of estrogen actions on the chain of female reproductive behaviors highlights challenging new questions about estrogen actions on cells in the brain, questions that have important practical applications far beyond traditionally studied sex behaviors. PMID- 21325048 TI - The identification of raptor as a substrate for p44/42 MAPK. AB - The adaptor protein raptor is the functional identifier for mammalian target of rapamycin (mTOR) complex 1 (mTORC1), acting to target mTOR to specific substrates for phosphorylation and regulation. Using HPLC-electrospray ionization tandem mass spectrometry, we confirmed the phosphorylation of raptor at Ser696, Thr706, Ser721, Ser722, Ser855, Ser859, Ser863, Thr865, Ser877, Ser881, Ser883, and Ser884 and identified Tyr692, Ser699, Thr700, Ser704, Ser854, Ser857, Ser882, Ser886, Ser887, and Thr889 as new, previously unidentified raptor phosphorylation sites. Treatment of cells with insulin increased the phosphorylation of raptor at Ser696, Ser855, Ser863, and Thr865 and suppressed the phosphorylation of Ser722. Ser696 phosphorylation was insensitive to mTOR inhibition with rapamycin, whereas treatment of cells with the MAPK inhibitor PD98059 inhibited the insulin stimulated phosphorylation of raptor at Ser696. In vitro incubation of raptor with p42 MAPK significantly increased raptor phosphorylation (P < 0.01), whereas phosphorylation of a Ser696Ala mutant was decreased (P < 0.05), suggesting MAPK is capable of directly phosphorylating raptor at Ser696. Mutation of Ser696 to alanine interfered with insulin-stimulated phosphorylation of the mTOR downstream substrate p70S6 kinase. Incubation of cells with the MAPK inhibitor PD98059 and the phosphatidylinositol 3-kinase inhibitor wortmannin decreased the insulin stimulated phosphorylation of raptor, suggesting that the MAPK and phosphatidylinositol 3-kinase pathways may merge at mTORC1. PMID- 21325049 TI - Estradiol down-regulates RF-amide-related peptide (RFRP) expression in the mouse hypothalamus. AB - In most mammals, RF-amide-related peptides are synthesized in the dorsomedial hypothalamic nucleus and regulate reproduction via inhibiting GnRH neurons and, possibly, adenohypophyseal gonadotrophs. In the present study, we investigated the possibility that RFRP-synthesizing neurons are involved in estrogen feedback signaling to the reproductive axis in mice. First, we used quantitative in situ hybridization and compared the expression of prepro-RFRP mRNA of ovariectomized mice, with and without 17beta-estradiol (E2) replacement. Subcutaneous administration of E2 via silastic capsules for 4 d significantly down-regulated prepro-RFRP mRNA expression. The underlying receptor mechanism was investigated with immunohistochemistry. In ovariectomized mice, low levels of nuclear estrogen receptor (ER)-alpha immunoreactivity were detectable in 18.7 +/- 3.8% of RFRP neurons. The majority of RFRP neurons showed no ER-alpha signal, and RFRP neurons did not exhibit ER-beta immunoreactivity. Results of these studies indicate that RFRP is a negatively estradiol-regulated neurotransmitter/neuromodulator in mice. The estrogenic down-regulation of RFRP expression may contribute to estrogen feedback to the reproductive axis. The issue of whether E2 regulates RFRP neurons directly or indirectly remains open given that ER-alpha immunoreactivity is present only at low levels in a subset of these cells. PMID- 21325050 TI - Organization of two independent kisspeptin systems derived from evolutionary ancient kiss genes in the brain of zebrafish. AB - Kisspeptins are new actors in the neuroendocrine regulation of reproduction. In vertebrates, the number of kiss genes varies from none to three. Zebrafish have two kiss genes, kiss1 and kiss2, and two kiss receptors (GPR54), kiss1r and kiss2r. To provide detailed information on the organization of the kiss systems in zebrafish, antibodies were raised against the C terminus of zebrafish preproKiss1 and preproKiss2. Immunohistochemistry fully confirmed in situ hybridization data, showing that kiss1-expressing neurons are only located in the habenular nucleus, while kiss2-expressing neurons are found in the dorsal and ventral hypothalamus. Kiss1-expressing cells project only to the interpeduncular and raphe nuclei and strongly expressed the kiss1r receptor. In contrast, kiss2 expressing cells are mostly present in the dorsal and ventral hypothalamus and project widely into the subpallium, the preoptic area, the thalamus, the ventral and caudal hypothalamus, and the mesencephalon. All these regions strongly expressed the kiss2r messengers. Kiss2 fibers profusely innervate the ventral forebrain and notably made close apposition with GnRH3 neurons. Estrogen treatment of juvenile fish with estradiol causes increase in kiss2 and kiss2r expression. In the pituitary gland, no proKiss2- positive fibers were detected, while positive cells were observed in the pars intermedia. In addition to proposing a successful strategy to develop antibodies to kisspeptins, these data indicate that the kiss2 systems of zebrafish are implicated in reproductive events, while the kiss1 gene would play other functions that remain to be established. PMID- 21325051 TI - Leptin deficiency and diet-induced obesity reduce hypothalamic kisspeptin expression in mice. AB - The hormone leptin modulates a diverse range of biological functions, including energy homeostasis and reproduction. Leptin promotes GnRH function via an indirect action on forebrain neurons. We tested whether leptin deficiency or leptin resistance due to a high-fat diet (HFD) can regulate the potent reproductive neuropeptide kisspeptin. In mice with normalized levels of estradiol, leptin deficiency markedly reduced kisspeptin gene expression, particularly in the arcuate nucleus (ARC), and kisspeptin immunoreactive cell numbers in the rostral periventricular region of the third ventricle (RP3V). The HFD model was used to determine the effects of diet-induced obesity and central leptin resistance on kisspeptin cell number and gene expression. DBA/2J mice, which are prone to HFD-induced infertility, showed a marked decrease in kisspeptin expression in both the RP3V and ARC and cell numbers in the RP3V after HFD. This is the first evidence that kisspeptin can be regulated by HFD and/or increased body weight. Next we demonstrated that leptin does not signal (via signal transducer and activator of transcription 3 or 5, or mammalian target of rapamycin) directly on kisspeptin-expressing neurons in the RP3V. Lastly, in leptin receptor-deficient mice, neither GnRH nor kisspeptin neurons were activated during a preovulatory-like GnRH/LH surge induction regime, indicating that leptin's actions on GnRH may be upstream of kisspeptin neurons. These data provide evidence that leptin's effects on reproductive function are regulated by kisspeptin neurons in both the ARC and RP3V, although in the latter site the effects are likely to be indirect. PMID- 21325053 TI - The population dynamics of bacteria in physically structured habitats and the adaptive virtue of random motility. AB - Why is motility so common in bacteria? An obvious answer to this ecological and evolutionary question is that in almost all habitats, bacteria need to go someplace and particularly in the direction of food. Although the machinery required for motility and chemotaxis (acquiring and processing the information needed to direct movement toward nutrients) are functionally coupled in contemporary bacteria, they are coded for by different sets of genes. Moreover, information that resources are more abundant elsewhere in a habitat would be of no value to a bacterium unless it already had the means to get there. Thus, motility must have evolved before chemotaxis, and bacteria with flagella and other machinery for propulsion in random directions must have an advantage over bacteria relegated to moving at the whim of external forces alone. However, what are the selection pressures responsible for the evolution and maintenance of undirected motility in bacteria? Here we use a combination of mathematical modeling and experiments with Escherichia coli to generate and test a parsimonious and ecologically general hypothesis for the existence of undirected motility in bacteria: it enables bacteria to move away from each other and thereby obtain greater individual shares of resources in physically structured environments. The results of our experiments not only support this hypothesis, but are quantitatively and qualitatively consistent with the predictions of our model. PMID- 21325052 TI - Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth. AB - Although aerobic glycolysis (the Warburg effect) is a hallmark of cancer, key questions, including when, how, and why cancer cells become highly glycolytic, remain less clear. For a largely unknown regulatory mechanism, a rate-limiting glycolytic enzyme pyruvate kinase M2 (PKM2) isoform is exclusively expressed in embryonic, proliferating, and tumor cells, and plays an essential role in tumor metabolism and growth. Because the receptor tyrosine kinase/PI3K/AKT/mammalian target of rapamycin (RTK/PI3K/AKT/mTOR) signaling cascade is a frequently altered pathway in cancer, we explored its potential role in cancer metabolism. We identified mTOR as a central activator of the Warburg effect by inducing PKM2 and other glycolytic enzymes under normoxic conditions. PKM2 level was augmented in mouse kidney tumors due to deficiency of tuberous sclerosis complex 2 and consequent mTOR activation, and was reduced in human cancer cells by mTOR suppression. mTOR up-regulation of PKM2 expression was through hypoxia-inducible factor 1alpha (HIF1alpha)-mediated transcription activation, and c-Myc heterogeneous nuclear ribonucleoproteins (hnRNPs)-dependent regulation of PKM2 gene splicing. Disruption of PKM2 suppressed oncogenic mTOR-mediated tumorigenesis. Unlike normal cells, mTOR hyperactive cells were more sensitive to inhibition of mTOR or glycolysis. Dual suppression of mTOR and glycolysis synergistically blunted the proliferation and tumor development of mTOR hyperactive cells. Even though aerobic glycolysis is not required for breach of senescence for immortalization and transformation, the frequently deregulated mTOR signaling during multistep oncogenic processes could contribute to the development of the Warburg effect in many cancers. Components of the mTOR/HIF1alpha/Myc-hnRNPs/PKM2 glycolysis signaling network could be targeted for the treatment of cancer caused by an aberrant RTK/PI3K/AKT/mTOR signaling pathway. PMID- 21325054 TI - Modulation of behavioral phase changes of the migratory locust by the catecholamine metabolic pathway. AB - The migratory locust, Locusta migratoria, shows a striking phenotypic plasticity. It transitions between solitary and gregarious phases in response to population density changes. However, the molecular mechanism underlying the phase-dependent behavior changes remains elusive. Here we report a genome-wide gene expression profiling of gregarious and solitary nymphs at each stadium of the migratory locust, and we identified the most differentially expressed genes in the fourth stadium of the two phases. Bioinformatics analysis indicated that the catecholamine metabolic pathway was the most significant pathway up-regulated in the gregarious phase. We found pale, henna, and vat1, involved in dopamine biosynthesis and synaptic release, were critical target genes related to behavioral phase changes in the locusts. The roles of these genes in mediating behavioral changes in the gregarious individuals were confirmed by RNAi and pharmacological intervention. A single injection of dopamine or its agonist initiated gregarious behavior. Moreover, continuous and multiple injections of a dopamine agonist coupled with crowding resulted in more pronounced gregarious behavior. Our study thus provides insights into the relationships between genes and behavior in phase transition of this important pest species. PMID- 21325055 TI - Two ground state isoforms and a chromophore D-ring photoflip triggering extensive intramolecular changes in a canonical phytochrome. AB - Phytochrome photoreceptors mediate light responses in plants and in many microorganisms. Here we report studies using (1)H-(13)C magic-angle spinning NMR spectroscopy of the sensor module of cyanobacterial phytochrome Cph1. Two isoforms of the red-light absorbing Pr ground state are identified. Conclusive evidence that photoisomerization occurs at the C15-methine bridge leading to a beta-facial disposition of the ring D is presented. In the far-red-light absorbing Pfr state, strong hydrogen-bonding interactions of the D-ring carbonyl group to Tyr-263 and of N24 to Asp-207 hold the chromophore in a tensed conformation. Signaling is triggered when Asp-207 is released from its salt bridge to Arg-472, probably inducing conformational changes in the tongue region. A second signal route is initiated by partner swapping of the B-ring propionate between Arg-254 and Arg-222. PMID- 21325056 TI - Structural basis for nonribosomal peptide synthesis by an aminoacyl-tRNA synthetase paralog. AB - Cyclodipeptides are secondary metabolites biosynthesized by many bacteria and exhibit a wide array of biological activities. Recently, a new class of small proteins, named cyclodipeptide synthases (CDPS), which are unrelated to the typical nonribosomal peptide synthetases, was shown to generate several cyclodipeptides, using aminoacyl-tRNAs as substrates. The Mycobacterium tuberculosis CDPS, Rv2275, was found to generate cyclodityrosine through the formation of an aminoacyl-enzyme intermediate and to have a structure and oligomeric state similar to those of the class Ic aminoacyl-tRNA synthetases (aaRSs). However, the poor sequence conservation among CDPSs has raised questions about the architecture and catalytic mechanism of the identified homologs. Here we report the crystal structures of Bacillus licheniformis CDPS YvmC-Blic, in the apo form and complexed with substrate mimics, at 1.7-2.4-A resolutions. The YvmC Blic structure also exhibits similarity to the class Ic aaRSs catalytic domain. Our mutational analysis confirmed the importance of a set of residues for cyclodileucine formation among the conserved residues localized in the catalytic pocket. Our biochemical data indicated that YvmC-Blic binds tRNA and generates cyclodileucine as a monomer. We were also able to detect the presence of an aminoacyl-enzyme reaction intermediate, but not a dipeptide tRNA intermediate, whose existence was postulated for Rv2275. Instead, our results support a sequential catalytic mechanism for YvmC-Blic, with the successive attachment of two leucine residues on the enzyme via a conserved serine residue. Altogether, our findings suggest that all CDPS enzymes share a common aaRS-like architecture and a catalytic mechanism involving the formation of an enzyme-bound intermediate. PMID- 21325057 TI - Claudin-4 induction by E-protein activity in later stages of CD4/8 double positive thymocytes to increase positive selection efficiency. AB - Claudins (Clds) are crucial constituents of tight-junction strands in epithelial cells and have a central role in barrier functions. We show that Cld4 is unexpectedly expressed in normal thymic lymphocytes independently of tight junctions. The Cld4 expression was mostly confined to a portion of the CD4/CD8 double-positive (DP) cells. The proportion of Cld4(+) DP cells was markedly increased in MHC-I(-/-) II(-/-) mice but decreased in Rorgamma(-/-) mice, and Cld4(+) DP cells contained higher levels of the rearranged Tcra transcripts involving the most distal Va and Ja segments than Cld4(-) DP cells. The Cld4 expression levels were reduced in E47-deficient mice in a gene dose-dependent manner, and ChIP analysis indicated that E2A and HEB were bound to the E-box sites of the putative Cldn4 promoter region. Functionally, Cld4 showed a potent T cell receptor costimulatory activity by coligation with CD3. The Cld4 was distributed diffusely on the cell surface and associated with CD4/lck independently of CD3 in the resting thymocytes. However, Cld4 was strongly recruited to the immunological synapse on specific T-cell receptor engagement through antigen-presenting cells. In the fetal thymic organ culture, knockdown of Cldn4 resulted in the reduced generation of CD4/CD8 single-positive cells from the DP cells. These results suggest that Cld4 is induced by E-protein activity in the later stages of DP cells to increase the efficiency of positive selection, uncovering a hitherto unrecognized function of a Cld family protein. PMID- 21325058 TI - Cortisone-reductase deficiency associated with heterozygous mutations in 11beta hydroxysteroid dehydrogenase type 1. AB - In peripheral target tissues, levels of active glucocorticoid hormones are controlled by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), a dimeric enzyme that catalyzes the reduction of cortisone to cortisol within the endoplasmic reticulum. Loss of this activity results in a disorder termed cortisone reductase deficiency (CRD), typified by increased cortisol clearance and androgen excess. To date, only mutations in H6PD, which encodes an enzyme supplying cofactor for the reaction, have been identified as the cause of disease. Here we examined the HSD11B1 gene in two cases presenting with biochemical features indicative of a milder form of CRD in whom the H6PD gene was normal. Novel heterozygous mutations (R137C or K187N) were found in the coding sequence of HSD11B1. The R137C mutation disrupts salt bridges at the subunit interface of the 11beta-HSD1 dimer, whereas K187N affects a key active site residue. On expression of the mutants in bacterial and mammalian cells, activity was either abolished (K187N) or greatly reduced (R137C). Expression of either mutant in a bacterial system greatly reduced the yield of soluble protein, suggesting that both mutations interfere with subunit folding or dimer assembly. Simultaneous expression of mutant and WT 11beta-HSD1 in bacterial or mammalian cells, to simulate the heterozygous condition, indicated a marked suppressive effect of the mutants on both the yield and activity of 11beta-HSD1 dimers. Thus, these heterozygous mutations in the HSD11B1 gene have a dominant negative effect on the formation of functional dimers and explain the genetic cause of CRD in these patients. PMID- 21325060 TI - Deciphering the luteal transcriptome: potential mechanisms mediating stage specific luteolytic response of the corpus luteum to prostaglandin F2alpha. AB - The objective of this study was to identify prostaglandin F(2alpha) (PG)-induced changes in the transcriptome of bovine corpora lutea (CL) that are specific to mature, PG-responsive (day 11) CL vs. developing (day 4) CL, which do not undergo luteolysis in response to PG administration. CL were collected at 0, 4, and 24 h after PG injection on days 4 and 11 of the estrous cycle (n = 5 per day and time point), and microarray analysis was performed with GeneChip Bovine Genome Arrays. Data normalization was performed with affy package and significance testing with maanova from Bioconductor. Significance (relative to 0 h time point) was declared at fold change >2.0 or <0.5 and false discovery rate of <5%. At 4 and 24 h after PG, 221 (day 4) and 661 (day 11) and 248 (day 4) and 1,421 (day 11) regulated genes, respectively, were identified. The accentuated gene expression response in day 11 CL was accompanied by specific enrichment of PG-regulated genes in distinctive gene ontology categories (immune related and other), particularly at 24 h after injection. Specificity in putative transcription factor binding sites was observed among PG-regulated genes on day 11 vs. day 4, including a potential association of ETS transcription factors with acute PG-induced gene expression specific to day 11 CL. Temporal and PG-induced regulation of abundance of mRNA for ETS transcription factor family members linked to the stage-specific response to PG was not observed. Increased abundance of protein and/or mRNA for six PG regulated putative ETS-responsive genes was noted in day 11 but not day 4 CL. Results reveal insight into stage-specific gene expression in bovine CL in response to PG and potential transcriptional mediators of luteolysis. PMID- 21325059 TI - In vivo demonstration that alpha-synuclein oligomers are toxic. AB - The aggregation of proteins into oligomers and amyloid fibrils is characteristic of several neurodegenerative diseases, including Parkinson disease (PD). In PD, the process of aggregation of alpha-synuclein (alpha-syn) from monomers, via oligomeric intermediates, into amyloid fibrils is considered the disease causative toxic mechanism. We developed alpha-syn mutants that promote oligomer or fibril formation and tested the toxicity of these mutants by using a rat lentivirus system to investigate loss of dopaminergic neurons in the substantia nigra. The most severe dopaminergic loss in the substantia nigra is observed in animals with the alpha-syn variants that form oligomers (i.e., E57K and E35K), whereas the alpha-syn variants that form fibrils very quickly are less toxic. We show that alpha-syn oligomers are toxic in vivo and that alpha-syn oligomers might interact with and potentially disrupt membranes. PMID- 21325061 TI - A mini-review: microRNA in arthritis. AB - MicroRNA (miRNA) is a class of noncoding RNA that exhibits tissue- or developmental stage-specific expression patterns and negatively regulates gene expression. MiRNAs play an important role in human diseases, including osteoarthritis (OA) and rheumatoid arthritis (RA). OA is characterized by the progressive destruction of articular cartilage, and several miRNAs exhibit altered expression, playing a role in regulating gene expression in OA pathogenesis, especially in catabolic factors such as matrix metalloproteinases (MMP) and aggrecanases. RA is an autoimmune disease that is characterized by irreversible joint destruction due to chronic synovial inflammation. MiRNAs play an important role in inflammatory response, synovial cell proliferation, and production of MMPs in RA synovial tissues. The expression level of several miRNAs in peripheral blood mononuclear cells correlates with RA disease activity. Recently, therapeutic trials aimed at targeting miRNA in vivo have been conducted. Targeting miRNA will enable a new advanced strategy toward arthritis treatment. PMID- 21325063 TI - MicroRNA expression signature in atrial fibrillation with mitral stenosis. AB - The aim of this study was to investigate the microRNA (miRNA) signature in atrial fibrillation (AF) with mitral stenosis (MS). miRNA arrays were used to evaluate the expression signature of the right atrial appendages of healthy individuals (n=9), patients with MS and AF (n=9) and patients with MS without AF (n=4). The results were validated with qRT-PCR analysis. GOmir was used to predict the potential miRNA targets and to analyze their functions. DIANA-mirPath was used to incorporate the miRNAs into pathways. miRNA arrays revealed that 136 and 96 miRNAs were expressed at different levels in MS patients with AF and in MS patients without AF, respectively, compared with healthy controls. More importantly, 28 miRNAs were expressed differently in the MS patients with AF compared with the MS patients without AF; of these miRNAs, miR-1202 was the most dysregulated. The unsupervised hierarchical clustering analysis based on the 28 differently expressed miRNAs showed that the heat map of miRNA expression categorized two well-defined clusters that corresponded to MS with AF and MS without AF. The qRT-PCR results correlated well with the microarray data. Bioinformatic analysis indicated the potential miRNA targets and molecular pathways. This study shows that there is a distinct miRNA expression signature in AF with MS. The findings may be useful for the development of therapeutic interventions that are based on rational target selection in these patients. PMID- 21325062 TI - Chronic exposure to anabolic steroids induces the muscle expression of oxytocin and a more than fiftyfold increase in circulating oxytocin in cattle. AB - Molecular mechanisms in skeletal muscle associated with anabolic steroid treatment of cattle are unclear and we aimed to characterize transcriptional changes. Cattle were chronically exposed (68 +/- 20 days) to a steroid hormone implant containing 200 mg trenbolone acetate and 20 mg estradiol (Revalor-H). Biopsy samples from 48 cattle (half treated) from longissimus dorsi (LD) muscle under local anesthesia were collected. Gene expression levels were profiled by microarray, covering 16,944 unique bovine genes: 121 genes were differentially expressed (DE) due to the implant (99.99% posterior probability of not being false positives). Among DE genes, a decrease in expression of a number of fat metabolism-associated genes, likely reflecting the lipid storage activity of intramuscular adipocytes, was observed. The expression of IGF1 and genes related to the extracellular matrix, slow twitch fibers, and cell cycle (including SOX8, a satellite cell marker) was increased in the treated muscle. Unexpectedly, a very large 21- (microarray) to 97 (real time quantitative PCR)-fold higher expression of the mRNA encoding the neuropeptide hormone oxytocin was observed in treated muscle. We also observed an ~50-fold higher level of circulating oxytocin in the plasma of treated animals at the time of biopsy. Using a coexpression network strategy OXTR was identified as more likely than IGF1R to be a major mediator of the muscle response to Revalor-H. A re-investigation of in vivo cattle LD muscle samples during early to mid-fetal development identified a >128 fold increased expression of OXT, coincident with myofiber differentiation and fusion. We propose that oxytocin may be involved in mediating the anabolic effects of Revalor-H treatment. PMID- 21325064 TI - Role of the estrogen/estrogen-receptor-beta axis in the genomic response to pressure overload-induced hypertrophy. AB - Cardiac hypertrophy, the adaptive response of the heart to overload, is a major risk factor for heart failure and sudden death. Estrogen (E2) and estrogen receptor beta (ERbeta) offer protection against hypertrophy and in the transition to heart failure. However, the underlying pathways remain incompletely defined. We employed a publicly available microarray dataset of female wild-type (WT) and ERbeta knockout (BERKO) mice subjected to pressure overload-induced hypertrophy to perform a systematic investigation of the mechanisms involved in the protection conferred by the E2/ERbeta axis. We show that considerably more genes were modulated in response to pressure overload in BERKO mice than in WT mice. The majority of the identified candidates in BERKO mice were induced, while those in WT mice were repressed. Pathway analysis revealed a similar pattern. This study is the first to demonstrate that the lack of ERbeta led to a significant increase of inflammatory pathways. Mitochondrial bioenergetics- and oxidative stress-related pathways were also modulated. In conclusion, ERbeta acquires the role of gatekeeper of the genomic response of the heart to pressure overload induced hypertrophy. This may offer the molecular explanation for its cardioprotective role. We consider the present study to be a useful resource and that it will contribute to downstream functional analysis and to the characterization of pathways with previously unknown role in hypertrophy. PMID- 21325065 TI - Endurance athletes and type 1 diabetes. AB - OBJECTIVE: The purpose of this study was to gain insight into the current diabetes management practices of endurance athletes with type 1 diabetes and to compare these practices with the guidelines for athletes established by the American Diabetes Association (ADA). METHODS: Participants included in this descriptive study were endurance athletes aged 18 years and older with type 1 diabetes. The survey questions were based on the current clinical recommendations for endurance athletes with type 1 diabetes, as established by the ADA. A link to the questionnaire was posted on the Web site of the Diabetes Exercise and Sports Association (DESA). A total of 38 questions were included in the survey, and 91 usable surveys were received. Analysis of variance was used for several comparisons using SPSS version 17. RESULTS: Half of the clinical guidelines were followed by the participants. Among these, about 50% followed many of the guidelines "most of the time" or "almost always" and 40% followed the guidelines "sometimes" or "most of the time." Results of ANOVA showed several trends (nonsignificant) in the occurrence of low blood glucose when the guidelines were not followed. CONCLUSION: Endurance athletes with type 1 diabetes do not consistently follow the clinical guidelines for blood glucose management as recommended by the ADA. The results of this study reflect a need among athletes for diabetes management education programs that promote a better understanding of the potential negative side effects of suboptimal blood glucose control. PMID- 21325067 TI - Large-scale analysis of KIT aberrations in Chinese patients with melanoma. AB - PURPOSE: KIT aberrations were described in acral and mucosal melanomas in largely Caucasian populations. Asian populations are more prone to develop acral and mucosal than cutaneous melanomas, and may harbor a high frequency of KIT aberrations. EXPERIMENTAL DESIGN: Melanoma subtypes (n = 502) were analyzed histologically to determine melanoma subtype. Tissue samples were analyzed for mutations in exons 9, 11, 13, 17, and 18 of KIT gene in genomic DNA by PCR amplification and Sanger sequencing. The copy numbers of the KIT gene were analyzed by quantitative PCR, and protein expression levels of KIT (CD117) were determined by immunohistochemistry. RESULTS: The most common melanoma subtypes were acral (38.4%) and mucosal (33.3%) melanomas in this population. The overall incidence of somatic mutations within the KIT gene was 10.8% (54/502), and all subtypes of melanoma contained KIT mutations. Increases in KIT gene copy numbers were correlated to CD117 overexpression. The genetic mutations of KIT were unrelated to the age, gender, stage, thickness, and ulceration of primary melanomas. Importantly, the overall survival of melanoma patients with KIT mutations (P = 0.001) or with KIT aberrations (mutation plus amplification, P = 0.0002) was significantly shorter than that of patients without such alterations. CONCLUSION: In China, the prevalent melanomas are acral and mucosal melanomas. KIT mutations are detected in all melanoma subtypes. Our study suggests that increases in KIT gene copy numbers, but not KIT mutations, may be correlated to CD117 overexpression. For the first time, our study suggests that genetic KIT aberration is an adverse prognostic factor for melanoma. PMID- 21325066 TI - Riluzole enhances ionizing radiation-induced cytotoxicity in human melanoma cells that ectopically express metabotropic glutamate receptor 1 in vitro and in vivo. AB - PURPOSE: Brain metastases are a common preterminal event in patients with metastatic melanoma and require radiation therapy. Our group has previously shown that human GRM1 (hGRM1) expressing melanoma cells release excess extracellular glutamate and are growth inhibited by riluzole, an inhibitor of glutamate release. Riluzole-treated cells accumulate in G(2)/M phase of the cell cycle at 24 hours, and then undergo apoptotic cell death. We evaluated whether riluzole enhanced radiosensitivity in melanoma cells. EXPERIMENTAL DESIGN: Clonogenic assays were performed to evaluate clonogenic survival after treatment in hGRM1 expressing and nonexpressing melanoma cells. Western immunoblots were performed to confirm apoptotic cell death. A xenograft mouse model was used to validate the in vitro experiments. Tumors harvested from the xenografts were fixed and stained for apoptosis and DNA damage markers. RESULTS: In the hGRM1-positive cell lines C8161 and UACC903, riluzole enhanced the lethal effects of ionizing radiation; no difference was seen in the hGRM1-negative UACC930 cell line. C8161 cells treated with riluzole plus irradiation also showed the highest levels of the cleaved forms of PARP and caspase-3; excised C8161 xenografts showed the greatest number of apoptotic cells by immunohistochemistry (P < 0.001). On cell cycle analysis, a sequence-dependent enrichment in the G(2)/M phase was shown with the combination of riluzole and irradiation. Xenografts treated with riluzole and weekly radiation fractions showed significant growth inhibition and revealed markedly increased DNA damage. CONCLUSIONS: We have shown, in vitro and in vivo, that the combination of riluzole and ionizing radiation leads to greater cytotoxicity. These results have clinical implications for patients with brain metastases receiving whole brain radiation therapy. PMID- 21325068 TI - Copy-neutral loss of heterozygosity at the p53 locus in carcinogenesis of esophageal squamous cell carcinomas associated with p53 mutations. AB - PURPOSE: LOH at the p53 locus has been reported to be associated with esophageal squamous cell carcinogenesis. The aim of this study is to identify potential mechanisms resulting in LOH around the p53 locus in its carcinogenesis. EXPERIMENTAL DESIGN: We investigated 10 esophageal cancer cell lines and 91 surgically resected specimens, examining them for LOH at the p53 locus on chromosome 17. We examined the p53 gene by using microsatellite analysis, comparative genomic hybridization (CGH), FISH, and single-nucleotide polymorphism CGH (SNP-CGH). RESULTS: In an analysis of specimens by microsatellite markers, a close positive correlation was found between p53 mutations and LOH at the p53 locus (P < 0.01). Although four cell lines were found to be homozygous for p53 mutations, LOH at the p53 locus was not detected by CGH. Among two p53 mutant cancer cell lines and five p53 mutant/LOH cancer specimens analyzed by FISH, both the cell lines and four of the specimens exhibited no obvious copy number loss at the p53 locus. SNP-CGH analysis, which allows both determination of DNA copy number and detection of copy-neutral LOH, showed that LOHs without copy number change were caused by whole or large chromosomal alteration. CONCLUSIONS: LOH without copy number change at the p53 locus was observed in p53 mutant esophageal squamous cell carcinomas. Our data suggest that copy-neutral LOH occurring as a result of chromosomal instability might be the major mechanism for inactivation of the intact allele in esophageal squamous cell carcinogenesis associated with p53 mutation. PMID- 21325069 TI - Identification of loss of p16 expression and upregulation of MDR-1 as genetic events resulting from two novel chromosomal translocations found in a plasmablastic lymphoma of the uterus. AB - PURPOSE: To establish cell lines from the patient with plasmablastic lymphoma, who was immunologically competent including negative human immunodeficiency virus (HIV) serology, and analyze the unique chromosomal translocations seen in the cell lines in order to unveil the pathogenesis of this tumor, which had no evidence of Epstein-Barr virus involvement. EXPERIMENTAL DESIGN: Establishment of the cell lines was attempted by inoculating the patient's lymph node biopsy specimen subcutaneously to immunodeficient mice. Comparative genomic hybridization (CGH) array and FISH analysis were performed to identify breakpoints of the two chromosomal translocations. Of the 4 candidate genes identified by FISH analysis to be involved in the translocations, reverse transcription-PCR, Western blot, flow cytometry, and proliferation assay were performed to identify the exact genes involved. RESULTS: Analysis of the cell lines identified loss of p16 at the protein level by chromosomal translocation of t(9;13) and upregulation of MDR-1 by t(4;7). The cell lines expressing MDR-1 acquired resistance to chemotherapeutic agents such as cisplatin and doxorubicin, but not bortezomib. Expression of B lymphoid lineage marker genes of these cell lines was negative for paired box 5 (Pax5) or PR domain containing 1, with ZNF domain (PRDM1), but was positive for X-box binding protein 1 (Xbp1). CONCLUSIONS: We established three novel cell lines of plasmablastic lymphoma. Characterization of the unique chromosomal translocation identified loss of p16 and upregulation of MDR-1 at protein level. Expression of Xbp1(s), which is involved in the maturation of plasma cells, corresponded to the plasmablastic appearance of the tumor. These cell lines may be a useful tool to understand the pathophysiology of the disease and to develop novel treatment strategies. PMID- 21325070 TI - White paper on adoptive cell therapy for cancer with tumor-infiltrating lymphocytes: a report of the CTEP subcommittee on adoptive cell therapy. AB - Adoptive T-cell therapy (ACT) using expanded autologous tumor-infiltrating lymphocytes (TIL) and tumor antigen-specific T cell expanded from peripheral blood are complex but powerful immunotherapies directed against metastatic melanoma. A number of nonrandomized clinical trials using TIL combined with high dose interleukin-2 (IL-2) have consistently found clinical response rates of 50% or more in metastatic melanoma patients accompanied by long progression-free survival. Recent studies have also established practical methods for the expansion of TIL from melanoma tumors with high success rates. These results have set the stage for randomized phase II/III clinical trials to determine whether ACT provides benefit in stage IV melanoma. Here, we provide an overview of the current state-of-the art in T-cell-based therapies for melanoma focusing on ACT using expanded TIL and address some of the key unanswered biological and clinical questions in the field. Different phase II/III randomized clinical trial scenarios comparing the efficacy of TIL therapy to high-dose IL-2 alone are described. Finally, we provide a roadmap describing the critical steps required to test TIL therapy in a randomized multicenter setting. We suggest an approach using centralized cell expansion facilities that will receive specimens and ship expanded TIL infusion products to participating centers to ensure maximal yield and product consistency. If successful, this approach will definitively answer the question of whether ACT can enter mainstream treatment for cancer. PMID- 21325071 TI - Close and stable relationship between proliferation and a hypoxia metagene in aromatase inhibitor-treated ER-positive breast cancer. AB - PURPOSE: The majority of breast cancer patients who have estrogen receptor positive (ER(+)) tumors whose proliferation is reduced after estrogen deprivation by aromatase inhibitors (AI). This study investigates any link between proliferation and hypoxia, a major determinant of tumor biology, and defines the effect of estrogen deprivation on hypoxia-associated genes. METHODS: Genome-wide expression profiles were obtained from tumor biopsies from 81 ER(+) postmenopausal patients, before and after 2 weeks' anastrozole treatment. A hypoxia metagene was developed by identifying genes clustered with classical hypoxia-regulated genes, excluding those associated with proliferation. Proliferation was measured by Ki67 and a proliferation metagene derived from two published breast cancer data sets. RESULTS: Hypoxia and proliferation metagenes were associated at baseline (Pearson correlation coefficient, r = 0.67, P < 10( 4)) and after 2 weeks (r = 0.71, P < 10(-4)). Hypoxia metagene at baseline was associated with 2-week Ki67 (r = 0.43, P = 0.0002) and more weakly with poor 2 week Ki67 change consistent with a weak association with AI resistance. Hypoxia metagene was significantly downregulated with AI. This downregulation was significantly associated with change in the proliferation metagene and with Ki67 but, importantly, not with the substantial change in expression of classical estrogen-dependent genes. CONCLUSIONS: Hypoxia metagene is closely associated with proliferation before and after AI treatment. The downregulation of hypoxia metagene after AI therapy is most likely the result of changes in proliferation. There may be a weak effect of hypoxia metagene on de novo resistance to AIs. These findings are important to consider in coapplication of antiproliferative agents with antiangiogenic or antihypoxia agents. PMID- 21325072 TI - Sphingosine kinase-1 enhances resistance to apoptosis through activation of PI3K/Akt/NF-kappaB pathway in human non-small cell lung cancer. AB - PURPOSE: The present study was to examine the effect of sphingosine kinase-1 (SPHK1) on chemotherapeutics-induced apoptosis in non-small cell lung cancer (NSCLC) cells, which is relatively insensitive to chemotherapy, and its clinical significance in NSCLC progression. EXPERIMENTAL DESIGN: The correlation of SPHK1 expression and clinical features of NSCLC was analyzed in 218 paraffin-embedded archived NSCLC specimens by immunohistochemical analysis. The effect of SPHK1 on apoptosis induced by chemotherapeutics was examined both in vitro and in vivo, using Annexin V staining and TUNEL (terminal deoxynucleotidyl transferase mediated dUTP nick end labeling) assays. Western blotting and luciferase analysis were performed to examine the impact of SPHK1 on the PI3K/Akt/NF-kappaB signaling. RESULTS: The expression of SPHK1 was markedly increased in NSCLC and correlated with tumor progression and poor survival of patients with NSCLC. Upregulation of SPHK1 significantly inhibited doxorubicin- or docetaxel-induced apoptosis, associated with induction of antiapoptotic proteins Bcl-xl, c-IAP1, c IAP2, and TRAF1. In contrast, silencing SPHK1 expression or inhibiting SPHK1 activity with specific inhibitor, SK1-I, significantly enhanced the sensitivity of NSCLC cells to apoptosis induced by chemotherapeutics both in vitro and in vivo. Moreover, we demonstrated that upregulation of SPHK1 activated the PI3K/Akt/NF-kappaB pathway, and that inhibition of the PI3K/Akt/NF-kappaB pathway abrogated the antiapoptotic effect of SPHK1 on NSCLC cells. CONCLUSIONS: Our results suggest that SPHK1 is a potential pharmacologic target for the treatment of NSCLC and inhibition of SPHK1 expression or its kinase activity might represent a novel strategy to sensitize NSCLC to chemotherapy. PMID- 21325073 TI - Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor. AB - PURPOSE: The aim of this study was to show preclinical efficacy and clinical development potential of PKI-587, a dual phosphoinositide 3-kinase (PI3K)/mTOR inhibitor. EXPERIMENTAL DESIGN: In vitro class 1 PI3K enzyme and human tumor cell growth inhibition assays and in vivo five tumor xenograft models were used to show efficacy. RESULTS: In vitro, PKI-587 potently inhibited class I PI3Ks (IC(50) vs. PI3K-alpha = 0.4 nmol/L), PI3K-alpha mutants, and mTOR. PKI-587 inhibited growth of 50 diverse human tumor cell lines at IC(50) values of less than 100 nmol/L. PKI-587 suppressed phosphorylation of PI3K/mTOR effectors (e.g., Akt), and induced apoptosis in human tumor cell lines with elevated PI3K/mTOR signaling. MDA-MB-361 [breast; HER2(+), PIK3CA mutant (E545K)] was particularly sensitive to this effect, with cleaved PARP, an apoptosis marker, induced by 30 nmol/L PKI-587 at 4 hours. In vivo, PKI-587 inhibited tumor growth in breast (MDA MB-361, BT474), colon (HCT116), lung (H1975), and glioma (U87MG) xenograft models. In MDA-MB-361 tumors, PKI-587 (25 mg/kg, single dose i.v.) suppressed Akt phosphorylation [at threonine(T)308 and serine(S)473] for up to 36 hours, with cleaved PARP (cPARP) evident up to 18 hours. PKI-587 at 25 mg/kg (once weekly) shrank large (~1,000 mm(3)) MDA-MB-361 tumors and suppressed tumor regrowth. Tumor regression correlated with suppression of phosphorylated Akt in the MDA-MB 361 model. PKI-587 also caused regression in other tumor models, and efficacy was enhanced when given in combination with PD0325901 (MEK 1/2 inhibitor), irinotecan (topoisomerase I inhibitor), or HKI-272 (neratinib, HER2 inhibitor). CONCLUSION: Significant antitumor efficacy and a favorable pharmacokinetic/safety profile justified phase 1 clinical evaluation of PKI-587. PMID- 21325074 TI - Identification of soluble candidate biomarkers of therapeutic response to sunitinib in medullary thyroid carcinoma in preclinical models. AB - PURPOSE: Medullary thyroid carcinoma (MTC), an aggressive rare tumor due to activating mutations in the proto-oncogene RET, requires new therapeutic strategies. Sunitinib, a potent inhibitor of RET, VEGF receptor (VEGFR)-1, VEGFR 2, VEGFR-3, and platelet-derived growth factor receptor (PDGFR)alpha/beta, has been reported as clinically effective in some patients with advanced MTC. In this study, we examine molecular mechanisms of action of sunitinib and identify candidate soluble biomarkers of response. EXPERIMENTAL DESIGN: Both in vitro and in vivo assays, using the human TT RET(C634W) MTC cell line, were done to assess the activity of sunitinib. Kinetic microarray studies were used to analyze molecular pathways modified by sunitinib and to identify candidate biomarkers that were subsequently investigated in the serum of patients. RESULTS: Sunitinib displayed antiproliferative and antiangiogenic activities and inhibited RET autophosphorylation and activation of downstream signaling pathways. We showed that sunitinib treatment induced major changes in the expression of genes involved in tissue invasion and metastasis including vimentin (VIM), urokinase plasminogen (PLAU), tenascin-C (TN-C), SPARC, and CD44. Analyzing downregulated genes, we identified those encoding secreted proteins and, among them, interleukin (IL)-8 was found to be modulated in the serum of xenografted mice under sunitinib treatment. Furthermore, we demonstrated that metastatic MTC patients presented increased serum levels of IL-8 and TGF-beta2. CONCLUSIONS: Experimental models confirm the clinical efficacy of sunitinib observed in a few studies. Molecular pathways revealed by genomic signatures underline the impact of sunitinib on tissue invasion. Selected soluble candidate biomarkers could be of value for monitoring sunitinib response in metastatic MTC patients. PMID- 21325075 TI - Androgen receptor expression and breast cancer survival in postmenopausal women. AB - PURPOSE: Androgen receptor (AR) is commonly expressed in breast cancers. However, the association between tumor AR status and breast cancer survival is uncertain. Hence, we examined the association between AR status and breast cancer survival in the Nurses' Health Study (NHS). EXPERIMENTAL DESIGN: It was a prospective study of postmenopausal women enrolled in the Nurses' Health Study with stage I to III breast cancer diagnosed between 1976 and 1997 and followed from the date of diagnosis until January 1, 2008 or death. Analyses were conducted using Kaplan Meier methods and Cox proportional hazard models, to determine the association of AR status with survival outcomes adjusting for covariates. RESULTS: Among 1467 breast cancers, 78.7% were AR-positive (AR+). Among 1,164 estrogen receptor (ER) positive cases, 88.0% were AR+. AR positivity was associated with a significant reduction in breast cancer mortality (HR, 0.68; 95% CI, 0.47-0.99) and overall mortality (HR, 0.70; 95% CI, 0.53-0.91) after adjustment for covariates. In contrast, among women with ER-negative tumors (303 cases), 42.9% were AR+. There was a nonsignificant association between AR status and breast cancer death (HR, 1.59; 95% CI, 0.94-2.68). CONCLUSIONS: The association of AR status and breast cancer survival is dependent on ER status. In particular, AR expression was associated with a more favorable prognosis among women with ER-positive tumors. Thus, determination of AR status may provide additional information on prognosis for postmenopausal women with breast cancer, and provide novel opportunities for targeted therapy. PMID- 21325076 TI - Measurements of tumor cell autophagy predict invasiveness, resistance to chemotherapy, and survival in melanoma. AB - PURPOSE: Autophagy consists of lysosome-dependent degradation of cytoplasmic contents sequestered by autophagic vesicles (AV). The role of autophagy in determining tumor aggressiveness and response to therapy in melanoma was investigated in this study. EXPERIMENTAL DESIGN: Autophagy was measured in tumor biopsies obtained from metastatic melanoma patients enrolled on a phase II trial of temozolomide and sorafenib and correlated to clinical outcome. These results were compared with autophagy measurements in aggressive and indolent melanoma cells grown in two- and three-dimensional (3D) culture and as xenograft tumors. The effects of autophagy inhibition with either hydroxychloroquine or inducible shRNA (short hairpin RNA) against the autophagy gene ATG5 were assessed in three dimensional spheroids. RESULTS: Patients whose tumors had a high autophagic index were less likely to respond to treatment and had a shorter survival compared with those with a low autophagic index. Differences in autophagy were less evident in aggressive and indolent melanoma cells grown in monolayer culture. In contrast, autophagy was increased in aggressive compared with indolent melanoma xenograft tumors. This difference was recapitulated when aggressive and indolent melanoma cells were grown as spheroids. Autophagy inhibition with either hydroxychloroquine or inducible shRNA against ATG5 resulted in cell death in aggressive melanoma spheroids, and significantly augmented temozolomide-induced cell death. CONCLUSIONS: Autophagy is a potential prognostic factor and therapeutic target in melanoma. Three dimensional culture mimics the tumor microenvironment better than monolayer culture and is an appropriate model for studying therapeutic combinations involving autophagy modulators. Autophagy inhibition should be tested clinically in patients with melanoma. PMID- 21325078 TI - Age and smoke: a risky combination. PMID- 21325077 TI - Stromal LRP1 in lung adenocarcinoma predicts clinical outcome. AB - PURPOSE: LRP1 (low-density lipoprotein receptor-related protein 1) is a broadly expressed receptor that binds multiple extracellular ligands and participates in protein clearance. It is expressed in numerous cancers, but its role in lung cancer has not been characterized. Here, we investigate the relationship between LRP1 and lung cancer. EXPERIMENTAL DESIGN: LRP1 mRNA levels were determined in lung tumors from several large, multicenter studies. LRP1 protein localization was determined by immunohistochemical analysis of lung tumor microarrays. Normal fibroblasts, fibroblasts treated with the LRP1 inhibitor RAP (receptor-associated protein), and Lrp1 null fibroblasts were cocultured with 3 independent lung cancer cell lines to investigate the role of LRP1 on tumor cell proliferation. RESULTS: LRP1 mRNA levels are significantly decreased in lung tumors relative to nontumorous lung tissue. Lower expression of LRP1 in lung adenocarcinomas correlates with less favorable clinical outcome in a cohort of 439 patients. Immunohistochemical analysis shows that LRP1 is primarily expressed in stromal cells in 94/111 lung cancers, with very little protein found in cancer cells. A growth-suppressive function of mouse embryonic fibroblast (MEF) cells was observed in 3 lung cancer cell lines tested (H460, H2347, and HCC4006 cells); growth suppression was blocked by the LRP1 inhibitor RAP. Lrp1 deletion in fibroblasts reduced the ability of MEF cells to suppress tumor cell mitosis. In a validation set of adenocarcinomas, we confirmed a significant, positive correlation between both LRP1 mRNA and protein levels and favorable clinical outcomes. CONCLUSIONS: LRP1 expression is associated with improved lung cancer outcomes. Mechanistically, stromal LRP1 may non-cell autonomously suppress lung tumor cell proliferation. PMID- 21325079 TI - Obesity, metabolic abnormalities, and asthma: establishing causal links. PMID- 21325080 TI - Innate pathways shape sarcoidosis signaling: from bugs to drugs. PMID- 21325081 TI - RNA interference, RSV, and lung transplantation: a promising future for siRNA therapeutics. PMID- 21325082 TI - Streamlining the diagnostic journey for patients with tuberculosis: another step forward. PMID- 21325083 TI - Unusual left-ventricular malposition of a pulmonary artery catheter. PMID- 21325084 TI - Small airway caliber is the most important contributor of wheezing in healthy unselected newborns. PMID- 21325085 TI - Survival after bronchiolitis obliterans syndrome. PMID- 21325086 TI - Solitary bronchial squamous papilloma presenting as a plaque-like lesion in a subject with asthma. PMID- 21325090 TI - Genes that AKT to determine physiological heterogeneity in response to exercise. PMID- 21325087 TI - Effectiveness-based guidelines for the prevention of cardiovascular disease in women--2011 update: a guideline from the american heart association. PMID- 21325091 TI - Lactate: metabolic fuel or poison for racehorses? PMID- 21325092 TI - Testing for ancient admixture between closely related populations. AB - One enduring question in evolutionary biology is the extent of archaic admixture in the genomes of present-day populations. In this paper, we present a test for ancient admixture that exploits the asymmetry in the frequencies of the two nonconcordant gene trees in a three-population tree. This test was first applied to detect interbreeding between Neandertals and modern humans. We derive the analytic expectation of a test statistic, called the D statistic, which is sensitive to asymmetry under alternative demographic scenarios. We show that the D statistic is insensitive to some demographic assumptions such as ancestral population sizes and requires only the assumption that the ancestral populations were randomly mating. An important aspect of D statistics is that they can be used to detect archaic admixture even when no archaic sample is available. We explore the effect of sequencing error on the false-positive rate of the test for admixture, and we show how to estimate the proportion of archaic ancestry in the genomes of present-day populations. We also investigate a model of subdivision in ancestral populations that can result in D statistics that indicate recent admixture. PMID- 21325093 TI - Repeated unidirectional introgression of nuclear and mitochondrial DNA between four congeneric Tanganyikan cichlids. AB - With an increasing number of reported cases of hybridization and introgression, interspecific gene flow between animals has recently become a widely accepted and broadly studied phenomenon. In this study, we examine patterns of hybridization and introgression in Ophthalmotilapia spp., a genus of cichlid fish from Lake Tanganyika, using mitochondrial and nuclear DNA from all four species in the genus and including specimens from over 800 km of shoreline. These four species have very different, partially overlapping distribution ranges, thus allowing us to study in detail patterns of gene flow between sympatric and allopatric populations of the different species. We show that a significant proportion of individuals of the lake-wide distributed O. nasuta carry mitochondrial and/or nuclear DNA typical of other Ophthalmotilapia species. Strikingly, all such individuals were found in populations living in sympatry with each of the other Ophthalmotilapia species, strongly suggesting that this pattern originated by repeated and independent episodes of genetic exchange in different parts of the lake, with unidirectional introgression occurring into O. nasuta. Our analysis rejects the hypotheses that unidirectional introgression is caused by natural selection favoring heterospecific DNA, by skewed abundances of Ophthalmotilapia species or by hybridization events occurring during a putative spatial expansion in O. nasuta. Instead, cytonuclear incompatibilities or asymmetric behavioral reproductive isolation seem to have driven repeated, unidirectional introgression of nuclear and mitochondrial DNA into O. nasuta in different parts of the lake. PMID- 21325094 TI - Evolution of RNA-binding proteins in animals: insights from genome-wide analysis in the sponge Amphimedon queenslandica. AB - RNA-binding proteins (RBPs) are key players in various biological processes, most notably regulation of gene expression at the posttranscriptional level. Although many RBPs have been carefully studied in model organisms, very few studies have addressed the evolution of these proteins at the scale of the animal kingdom. We identified a large set of putative RBPs encoded by the genome of the demosponge Amphimedon queenslandica, a species representing a basal animal lineage. We compared the Amphimedon RBPs with those encoded by the genomes of two bilaterians (human and Drosophila), representatives of two other basal metazoan lineages (a placozoan and a cnidarian), a choanoflagellate (probable sister group of animals), and two fungi. We established the evolutionary history of 32 families of RBPs and found that most of the diversity of RBPs present in contemporary metazoans, including humans, was already established in the last common ancestor (LCA) of animals. This includes RBPs known to be involved in key processes in bilaterians, such as development, stem and/or germ cells properties, and noncoding RNA pathways. From this analysis, we infer that a complex toolkit of RBPs was present in the LCA of animals and that it has been recruited to perform new functions during early animal evolution, in particular in relation to the acquisition of multicellularity. PMID- 21325095 TI - Health Care Policy 2011: implications for pharmacists. AB - OBJECTIVE: The enactment of the Patient Protection and Affordable Care Act of 2010 set the stage for a new era. The 2010 Congressional election results and recent court rulings challenging the constitutionality of various provisions of the Act suggest that implementation will be anything but straightforward. The proposed changes in health insurance, along with modifications in current reimbursement models, will alter the health-care environment. It is important for pharmacists to be aware of these opportunities and the resultant changes in public expectations. It is with these considerations in mind that The Annals announces the creation of a Health Care Policy expert panel to initiate commentary and discussion regarding health-care policy issues of relevance to the pharmacy community. PMID- 21325096 TI - Authorship and characteristics of articles in pharmacy journals: changes over a 20-year interval. AB - BACKGROUND: To our knowledge, no studies have evaluated authorship patterns and characteristics of articles in pharmacy journals. OBJECTIVE: To investigate changes over a 20-year period in authorship and characteristics of articles in pharmacy journals. METHODS: All articles published in the American Journal of Health-System Pharmacy, The Annals of Pharmacotherapy, and Pharmacotherapy in 1989, 1999, and 2009 were reviewed. Data collected for each article included article type, number of authors, number of physician authors, whether any author was affiliated with a pharmaceutical company, and source of funding. RESULTS: The number of articles included was 574 in 1989, 659 in 1999, and 589 in 2009. The mean number of authors per article increased from 2.5 in 1989 to 2.8 in 1999 and 3.6 in 2009 (p<0.001). Conversely, the proportion of articles with a single author decreased from 35% in 1989 to 23% in 1999 and 11% in 2009 (p<0.001), while the proportion of multi-authored articles (>6 authors) increased from 2% in 1989 to 3% in 1999 and 9% in 2009 (p<0.001). A physician author was listed on 25% of papers in 1989, which increased to 38% in 1999 and 41% in 2009 (p<0.001). Among research articles with declared funding from industry, there was an increase over time in reported author affiliation with an industry sponsor (10% of articles in 1989, 17% in 1999, and 66% in 2009; p<0.001). CONCLUSIONS: Significant changes in authorship patterns and characteristics of articles were observed from 1989 to 2009. We found an increase in the number of authors per article over time, with fewer single-author papers now published. The explanations for the changes are likely multifactorial, including increased pressure to publish, increased research complexity, and inappropriate authorship. To prevent inappropriate author-number inflation and to preserve authorship's meaning and value, authors should adhere to the criteria for authorship from the International Committee of Medical Journal Editors. PMID- 21325097 TI - The "new" marijuana. AB - Synthetic cannabinoid-induced toxicity is increasing in frequency across the US, with more than 1057 reported cases as of August 2010. There is a paucity of literature on synthetic cannabinoid toxicity; however, there are various reports of adverse effects including tachycardia, hypertension, tachypnea, chest pain, heart palpitations, hallucinations, racing thoughts, and seizures. While reports suggest that toxic symptoms last no longer than 3-4 hours, with no residual adverse effects in many cases, there is concern about serious acute and long-term toxicities. This article reviews the development, abuse, toxicity, treatment, and legal status of synthetic cannabinoids. It is important for health-care professionals to recognize and appropriately treat synthetic cannabinoid-induced toxicity. PMID- 21325098 TI - Medical utilization and costs associated with statin adherence in Medicaid enrollees with type 2 diabetes. AB - BACKGROUND: Statin adherence is a serious problem in patients with hyperlipidemia. However, it is not clear whether statin adherence is associated with medical utilization or health-care costs. OBJECTIVE: To study statin adherence and assess associated medical utilization and health-care costs in patients with type 2 diabetes, based on a national Medicaid database. METHODS: A retrospective claims-based study was conducted using the records of patients with type 2 diabetes with comorbid hyperlipidemia who were continuously enrolled in Medicaid from January 2004 to December 2006. All data were drawn from MarketScan Medicaid Database, including inpatient, outpatient, and drug claims. The eligible patients starting statins in 2005 were followed for 1 year to measure medication use, hospitalization, outpatient visits, emergency department (ED) visits, and health-care costs based on Medicaid medical and drug claims. Adherence was measured by medication possession ratio (MPR). Multiple regression analyses were implemented to assess statin adherence-associated outcomes, including medical utilization (risks for hospitalization and ED visits), all-cause costs, and hyperlipidemia-related medical costs. RESULTS: A total of 1705 eligible patients with type 2 diabetes and hyperlipidemia were identified. The average adherence rate to statins (MPR) at 1 year was 0.61, and 37% of the patients (n=624) were adherent to statins (MPR>=0.8). Regression analyses indicated that diabetic patients who were adherent to statins showed lower risks for hospitalization (OR 0.80; 95% CI 0.636 to 0.966) and ED visits (OR 0.71; 95% CI 0.519 to 0.812) and decreased all-cause medical costs by 15% (p<0.05) and hyperlipidemia-related medical costs by 12% (p<0.05). CONCLUSIONS: Our study found high prevalence of nonadherence to statins in Medicaid patients with type 2 diabetes. Adherence to statins (MPR>=0.8) was associated with reduced medical utilization and lower medical costs. PMID- 21325099 TI - Provision of primary care to patients with chronic cough in the community pharmacy setting. AB - BACKGROUND: Community pharmacies are at the forefront of primary care providers and have an important role in the referral of patients to a medical practitioner for review when necessary. Chronic cough is a common disorder in the community and requires medical assessment. The proficiency of community pharmacy staff to refer patients with chronic cough is currently unknown. OBJECTIVE: To assess the ability of community pharmacy staff to recognize and medically refer patients with a chronic nonproductive cough. METHODS: Following ethics approval, a simulated patient study of 156 community pharmacies in Perth, Western Australia, was conducted over a 3-month period. Simulated patients presented to the pharmacy requesting treatment for a cough. The simulated patient required a referral based on a designated scenario. Demographic details, assessment questions, and advice provided were recorded by the simulated patient immediately postvisit. A logistic regression analysis was performed, with referral for medical assessment as the dependent variable. RESULTS: Of the 155 community pharmacies included in the analysis, 38% provided appropriate medical referral. Cough suppressants were provided as therapy in 72% of all visits. Predictors of medical referral were assessment of symptom duration, medical history, current medications being taken, frequency of reliever use, and the position of the pharmacy staff member conducting the consultation. A third of community pharmacies provided appropriate primary care by recommending medical referral advice to patients with chronic cough. The majority of pharmacy staff members acquired information from the patient that suggested a need for medical referral, yet did not provide referral advice. CONCLUSIONS: Appropriate medical referral is more likely when adequate assessment is undertaken and when a pharmacist is directly involved in the consultation. This highlights the need for pharmacies to ensure that processes are in place for patients to access the pharmacist. PMID- 21325100 TI - Alternatives to sodium amobarbital in the Wada test. AB - OBJECTIVE: To review the literature and identify alternatives to sodium amobarbital for use in the Wada test. DATA SOURCES: A search of PubMed (1960 October 2010) was performed using the following key words alone or in combination: Wada test, intracarotid amobarbital procedure, intracarotid, intraarterial, sodium amobarbital, methohexital, Brevital, pentobarbital, etomidate, propofol, and alternative anesthetics. References of the identified articles were reviewed for relevant information. STUDY SELECTION AND DATA EXTRACTION: All articles in English identified from the data sources were evaluated. Review included comparative, prospective, and retrospective studies along with case series and case reports. DATA SYNTHESIS: Methohexital, pentobarbital, etomidate, and propofol have all been studied as alternatives to sodium amobarbital in the Wada test. Four controlled experimental trials, 1 uncontrolled experimental trial, 6 retrospective chart reviews, and 2 case reports were reviewed. Methohexital, pentobarbital, and propofol required a second injection due to their short duration of action. Etomidate was studied as a bolus injection followed by a continuous infusion until the critical speech and memory tests were administered, which differed from the standard Wada test procedure. Patients had an increased risk of seizures with methohexital, whereas 1 patient developed transient respiratory depression immediately after receiving pentobarbital. Furthermore, propofol caused increased tone with twitching and rhythmic movements, which interfered with the completion of the Wada test for 1 patient. All authors concluded that these agents were equivalent to amobarbital for the Wada test. CONCLUSIONS: Methohexital, pentobarbital, etomidate, and propofol are viable alternatives to sodium amobarbital for use in the Wada test, but each has shortcomings. PMID- 21325101 TI - High unbound fraction of valproic acid in a hypoalbuminemic critically ill patient on renal replacement therapy. AB - OBJECTIVE: To describe a hypoalbuminemic critically ill patient with subtherapeutic total valproic acid serum concentrations but unbound valproic acid concentrations within normal limits. CASE SUMMARY: During an intensive care unit admission, a 61-year-old woman with urosepsis and multiorgan dysfunction syndrome developed tonic-clonic seizures with respiratory failure, and tracheal intubation was performed. An intravenous loading dose of valproic acid 1500 mg (25 mg/kg) was administered and therapy was continued with valproic acid 750 mg (12.5 mg/kg) twice daily. Because of progressive renal failure, continuous venovenous hemofiltration was started on day 3 of valproic acid therapy. On day 7 of valproic acid therapy, routine testing of serum valproic acid trough concentration returned as undetectable. Subsequent determinations of trough serum concentrations of total valproic acid showed values below the therapeutic range. Data from a full pharmacokinetic curve (multiple blood samples during a dosing interval) showed that the free fraction of valproic acid was >60%. Although total valproic acid concentrations were still low, the unbound concentrations were considered therapeutic. Serum albumin was 1.2 g/dL on the multiple sampling day. DISCUSSION: The patient's hypoalbuminemia probably explains the remarkably high free fraction of valproic acid. Our hypothesis is that the low albumin level was associated with high plasma clearance of valproic acid, leading to extremely low total drug concentrations. To our knowledge, this high percentage of free valproic acid has not been previously described. CONCLUSIONS: Health-care professionals should be aware of the need of early determination of both total and free fraction valproic acid serum concentrations in hypoalbuminemic critically ill patients. Increasing the dose of valproic acid purely based on total valproic acid serum concentrations in this patient population should be avoided. PMID- 21325102 TI - No effect of anticoagulant on Hb A(1c) analysis by the IFCC reference procedure. PMID- 21325103 TI - Circadian rhythm of circulating fibroblast growth factor 21 is related to diurnal changes in fatty acids in humans. AB - BACKGROUND: Fibroblast growth factor (FGF) 21 is an endocrine factor actively involved in glucose and lipid metabolism in rodents. However, little is known about its physiological function and regulation in humans. This study investigated the diurnal changes in circulating FGF21 concentrations and their association with other metabolic markers in both obese and lean individuals. METHODS: A total of 36 volunteers were assigned to 2 groups. One group received 3 standardized meals and another group was fasted for 24 h. Blood samples were drawn every 30 min throughout a 24-h period. Circulating FGF21 concentrations were measured with an in-house chemiluminescence immunoassay. The effects of fatty acids on hepatic production of FGF21 were determined by using real-time PCR. RESULTS: In both the fasting and standardized meals groups, circulating FGF21 began to rise at midnight, reaching a peak in the early morning and then declining to basal concentrations early in the afternoon. Baseline concentrations of circulating FGF21 were much higher in obese individuals than in lean individuals (P < 0.05). However, the magnitude of the nocturnal rise in circulating FGF21 was significantly blunted in obese individuals. The 24-h oscillatory pattern of circulating FGF21 resembled that of free fatty acids and cortisol, but was opposite to the patterns of insulin and glucose. Unsaturated fatty acids induced time-dependent expression of FGF21 mRNA in human hepatocytes. CONCLUSIONS: These findings support the role of FGF21 as an important metabolic regulator that integrates the circadian rhythm with energy homeostasis in humans. Diurnal rhythms of circulating FGF21 could be partly caused by the oscillation of free fatty acids. PMID- 21325104 TI - Maternal serum visfatin at 11-13 weeks of gestation in gestational diabetes mellitus. AB - BACKGROUND: Visfatin and adiponectin are produced by adipose tissue and have opposite effects on insulin resistance. Circulating concentrations of these biomarkers are altered in type 2 diabetes mellitus. We sought to examine the potential value of maternal serum visfatin and adiponectin concentrations in early pregnancy as potential biomarkers in the prediction of gestational diabetes mellitus (GDM). METHODS: This work was a case-control study of 100 women who developed GDM and 300 nondiabetic controls. Maternal serum visfatin and adiponectin were measured between 11 and 13 weeks of gestation. Regression analysis in the nondiabetic group was performed to examine the maternal characteristics affecting the serum concentrations of visfatin and adiponectin. Likelihood ratios for GDM were calculated for visfatin and adiponectin, and performance of screening was assessed by using ROC curve analysis. RESULTS: In the GDM group compared with the nondiabetic group, the median maternal serum visfatin concentration was increased (1.34 multiples of the median [MoM], interquartile range [IQR] 0.70-2.87, vs 1.00 MoM, IQR: 0.53-1.92; P = 0.004) and serum adiponectin was decreased (0.66 MoM, IQR 0.50-0.92, vs 1.01, IQR 0.70-1.29; P < 0.0001). In screening for GDM by a combination of maternal factors and serum adiponectin and visfatin, the estimated detection rate was 68.0% (95% CI 58.3 76.3%), at a false-positive rate of 10%. CONCLUSIONS: At 11-13 weeks in pregnancies that develop GDM, the serum concentration of adiponectin is decreased and visfatin is increased, and these biomarkers can be combined with maternal factors to provide effective early screening for GDM. PMID- 21325105 TI - Effect of antioxidant supplementation on insulin sensitivity in response to endurance exercise training. AB - While production of reactive oxygen and nitrogen species (RONS) is associated with some of the beneficial adaptations to regular physical exercise, it is not established whether RONS play a role in the improved insulin-stimulated glucose uptake in skeletal muscle obtained by endurance training. To assess the effect of antioxidant supplementation during endurance training on insulin-stimulated glucose uptake, 21 young healthy (age 29 +/- 1 y, BMI 25 +/- 3 kg/m(2)) men were randomly assigned to either an antioxidant [AO; 500 mg vitamin C and 400 IU vitamin E (alpha-tocopherol) daily] or a placebo (PL) group that both underwent a supervised intense endurance-training program 5 times/wk for 12 wk. A 3-h euglycemic-hyperinsulinemic clamp, a maximal oxygen consumption (Vo(2max)) and maximal power output (P(max)) test, and body composition measurements (fat mass, fat-free mass) were performed before and after the training. Muscle biopsies were obtained for determination of the concentration and activity of proteins regulating glucose metabolism. Although plasma levels of vitamin C (P < 0.05) and alpha-tocopherol (P < 0.05) increased markedly in the AO group, insulin stimulated glucose uptake increased similarly in both the AO (17.2%, P < 0.05) and the PL (18.9%, P < 0.05) group in response to training. Vo(2max) and P(max) also increased similarly in both groups (time effect, P < 0.0001 for both) as well as protein content of GLUT4, hexokinase II, and total Akt (time effect, P <= 0.05 for all). Our results indicate that administration of antioxidants during strenuous endurance training has no effect on the training-induced increase in insulin sensitivity in healthy individuals. PMID- 21325106 TI - Energy intake and adiponectin gene expression. AB - Hypoadiponectinemia and decreased adiponectin gene expression in white adipose tissue (WAT) have been well observed in obese subjects and animal models. However, the mechanism for obesity-associated hypoadiponectinemia is still largely unknown. To investigate the regulatory role of energy intake, dietary fat, and adiposity in adiponectin gene expression and blood adiponectin level, a series of feeding regimens was employed to manipulate energy intake and dietary fat in obese-prone C57BL/6, genetically obese ob/ob, obese-resistant A/J and peroxisome proliferator-activated receptor-alpha gene knockout (PPARalpha KO) mice. Adiponectin gene expression in WAT and circulating adiponectin levels were studied in these dietary intervention-treated mice. Our study showed that calorie restriction (CR) robustly increased adiponectin gene expression in epididymal fat and blood adiponectin levels in both low-fat (LF) and high-fat (HF) diet-fed C57BL/6 mice. Although HF pair-fed C57BL/6 mice received the same amount of calories as LF ad libitum-fed mice, HF diet clearly increased adiposity but showed no significant effects on adiponectin gene expression and blood adiponectin level. CR also significantly increased blood adiponectin levels in ob/ob and A/J mice. Neither CR nor HF feeding displayed any significant effect on blood adiponectin half-life in C57BL/6 mice. Interestingly, CR increased PPARalpha expression in epididymal fat of C57BL/6 mice. Low levels of blood adiponectin and adiponectin gene expression in WAT were observed in PPARalpha KO mice. PPARalpha agonist treatment increased adiponectin mRNA levels in 3T3-L1 adipocytes. Furthermore, CR failed to increase adiponectin gene expression and blood adiponectin levels in PPARalpha KO mice. Therefore, our study demonstrated that energy intake, not dietary fat, plays an important role in regulating adiponectin gene expression and blood adiponectin level. PPARalpha mediates CR enhanced adiponectin gene expression in WAT. PMID- 21325107 TI - Restoring HSP70 deficiencies improves glucose tolerance in diabetic monkeys. AB - We evaluated heat shock protein 70 (HSP70) changes in diabetes mellitus (DM) in a nonhuman primate model. To this end, two studies were conducted in DM vervet monkeys. 1) Normal control and streptozotocin-induced DM monkeys (Stz-DM) that were differentiated into moderately or poorly controlled DM by judicious insulin administration were evaluated. Liver was collected at 4, 8, 12, 16, and 20 wk after streptozotocin, exposed to ex vivo heat shock at 42 degrees C, and immunoblotted for heat shock factor 1 (HSF1), HSP70, and phosphorylated HSF1. 2) Spontaneous DM monkeys that were not pharmacologically induced were included in a crossover study of the HSP70-inducing drug geranylgeranylacetone (GGA). GGA at 20 mg/kg was given for 14 days with a 6-wk washout period. Glucose tolerance testing and plasma and muscle HSP70 were the primary outcome measurements. In Stz-DM, hyperglycemia reduced hepatic HSP70 in a dose-dependent fashion. HSF1 was increased in livers of monkeys with Stz-DM, but responses to ex vivo heat shock were impaired vs. normal monkeys. Activation of HSF1 appears to be important, because the phosphorylation change with heat stress was nearly perfectly correlated with HSP70 increases. Impaired HSF1 activation was also seen in Stz-DM after chronic hyperglycemia (>12 wk). In naturally occurring DM, increased circulating HSP70 resulted in significantly improved glucose tolerance and significant, positive trends in other measurements of insulin resistance. No change in muscle HSP70 content was observed. We conclude that increasing HSP70, potentially through targeting hyperglycemia-related deficits in HSF1 induction and activation in the liver, is a potent and viable strategy to improve glucose tolerance. PMID- 21325109 TI - Factitious ventricular tachyarrhythmia outbreak. PMID- 21325108 TI - Influence of acute alcohol ingestion on sympathetic neural responses to orthostatic stress in humans. AB - Acute alcohol consumption is reported to decrease mean arterial pressure (MAP) during orthostatic challenge, a response that may contribute to alcohol-mediated syncope. Muscle sympathetic nerve activity (MSNA) increases during orthostatic stress to help maintain MAP, yet the effects of alcohol on MSNA responses during orthostatic stress have not been determined. We hypothesized that alcohol ingestion would blunt arterial blood pressure and MSNA responses to lower body negative pressure (LBNP). MAP, MSNA, and heart rate (HR) were recorded during progressive LBNP (-5, -10, -15, -20, -30, and -40 mmHg; 3 min/stage) in 30 subjects (age 24 +/- 1 yr). After an initial progressive LBNP (pretreatment), subjects consumed either alcohol (0.8 g ethanol/kg body mass; n = 15) or placebo (n = 15), and progressive LBNP was repeated (posttreatment). Alcohol increased resting HR (59 +/- 2 to 65 +/- 2 beats/min, P < 0.05), MSNA (13 +/- 3 to 19 +/- 4 bursts/min, P < 0.05), and MSNA burst latency (1,313 +/- 16 to 1,350 +/- 17 ms, P < 0.05) compared with placebo (group * treatment interactions, P < 0.05). During progressive LBNP, a pronounced decrease in MAP was observed after alcohol but not placebo (group * time * treatment, P < 0.05). In contrast, MSNA and HR increased during all LBNP protocols, but there were no differences between trials or groups. However, alcohol altered MSNA burst latency response to progressive LBNP. In conclusion, the lack of MSNA adjustment to a larger drop in arterial blood pressure during progressive LBNP, coupled with altered sympathetic burst latency responses, suggests that alcohol blunts MSNA responses to orthostatic stress. PMID- 21325111 TI - Cost-utility of aspirin and proton pump inhibitors for primary prevention. AB - BACKGROUND: Aspirin reduces myocardial infarction but increases gastrointestinal tract (GI) bleeding. Proton pump inhibitors (PPIs) may reduce upper GI bleeding. We estimate the cost-utility of aspirin treatment with or without a PPI for coronary heart disease (CHD) prevention among men at different risks for CHD and GI bleeding. METHODS: We updated a Markov model to compare costs and outcomes of low-dose aspirin plus PPI (omeprazole, 20 mg/d), low-dose aspirin alone, or no treatment for CHD prevention. We performed lifetime analyses in men with different risks for cardiovascular events and GI bleeding. Aspirin reduced nonfatal myocardial infarction by 30%, increased total stroke by 6%, and increased GI bleeding risk 2-fold. Adding a PPI reduced upper GI bleeding by 80%. Annual aspirin cost was $13.99; the generic PPI cost was $200.00. RESULTS: In 45 year-old men with a 10-year CHD risk of 10% and 0.8 per 1000 annual GI bleeding risk, aspirin ($17,571 and 18.67 quality-adjusted life-years [QALYs]) was more effective and less costly than no treatment ($18,483 and 18.44 QALYs). Compared with aspirin alone, aspirin plus PPI ($21,037 and 18.68 QALYs) had an incremental cost per QALY of $447,077. Results were similar in 55- and 65-year-old men. The incremental cost per QALY of adding a PPI was less than $50,000 per QALY at annual GI bleeding probabilities greater than 4 to 6 per 1000. CONCLUSIONS: Treatment with aspirin for CHD prevention is less costly and more effective than no treatment in men older than 45 years with greater than 10-year, 10% CHD risks. Adding a PPI is not cost-effective for men with average GI bleeding risk but may be cost-effective for selected men at increased risk for GI bleeding. PMID- 21325112 TI - The magnitude of acute serum creatinine increase after cardiac surgery and the risk of chronic kidney disease, progression of kidney disease, and death. AB - BACKGROUND: Long-term outcomes after acute kidney injury remain poorly defined. We determined the association between the magnitude of creatinine increase after cardiac surgery and the risk of incident chronic kidney disease (CKD), CKD progression, and death. METHODS: We identified 29,388 individuals who underwent cardiac surgery at Veterans Affairs hospitals between November 1999 and September 2005. The magnitude of creatinine increase was defined by the percent change from baseline to peak creatinine levels after cardiac surgery and categorized as none (<=0%) or as class I, (1%-24%), II (25%-49%), III (50%-99%), or IV (>=100%). Cox proportional hazard models were used to examine the association between the magnitude of creatinine increase and outcomes. RESULTS: The relative hazards for outcomes increased monotonically with greater increases in creatinine levels compared with no change in creatinine levels. The relative hazards for adverse outcomes were significantly higher immediately after the creatinine increase and attenuated over time. Three months after surgery, creatinine increase classes I, II, III, and IV were associated with a greater risk of incident CKD (hazard ratios [HRs] 2.1, 4.0, 5.8, and 6.6, respectively; all P<.01), progression of CKD stage (HRs 2.5, 3.8, 4.4, and 8.0; all P<.01), and long-term mortality (HRs 1.4, 1.9, 2.8, and 5.0; all P<.01). At 5 years, the associations were lower in magnitude: incident CKD (HRs 1.4, 1.9, 2.3, and 2.3; all P<.01), CKD progression (HRs 1.5, 1.7, 1.7, and 2.4; all P<.01), and mortality (HRs 1.0, 1.2, 1.4, and 1.8; all P<.01, except class I). CONCLUSION: The magnitude of creatinine increase after cardiac surgery is associated in a graded manner with an increased risk of incident CKD, CKD progression, and mortality. PMID- 21325113 TI - The acute kidney injury to chronic kidney disease continuum: comment on "The magnitude of acute serum creatinine increase after cardiac surgery and the risk of chronic kidney disease, progression of kidney disease, and death". PMID- 21325114 TI - Effect of cardiac rehabilitation referral strategies on utilization rates: a prospective, controlled study. AB - BACKGROUND: Although cardiac rehabilitation (CR) has been shown to reduce mortality and is a recommended component in clinical practice guidelines, CR referral and utilization rates remain low. Referral strategies have been implemented to increase CR use but have yet to be compared concurrently. To determine the optimal strategy to maximize CR referral, enrollment, and participation, we evaluated 3 referral strategies compared with usual care: "automatic" only via discharge order or electronic record, health care provider liaison only, or a combined approach. METHODS: In this prospective controlled study, 2635 inpatients with coronary artery disease from 11 Ontario, Canada, hospitals using 1 of the 4 referral strategies completed a sociodemographic survey, and clinical data were extracted from medical charts. One year later, 1809 participants completed a mailed survey that assessed CR utilization. Referral strategies were compared using generalized estimating equations to control for effect of hospital. RESULTS: Adjusted analyses revealed referral strategy was significantly related to CR referral and enrollment (P<.001). Combined automatic and liaison referral resulted in the greatest CR use (odds ratio [OR], 8.41; 85.8% referral, 73.5% enrollment), followed by automatic only (OR, 3.27; 70.2% referral, 60.0% enrollment), and liaison only (OR, 3.35; 59.0% referral, 50.6% enrollment), compared with usual referral (32.2% referral, 29.0% enrollment). The degree of CR participation did not differ by referral strategy among referred participants (mean [SD] percentage of classes attended, 82.87% [27.20%]; P=.88). CONCLUSIONS: Automatic referral combined with a patient discussion can achieve among the highest rates of CR referral reported. Wider adoption of such strategies could ensure that 45% more patients being treated for cardiac disease would have access to and realize the benefits of CR. PMID- 21325115 TI - Incidence and transmission patterns of acute hepatitis C in the United States, 1982-2006. AB - BACKGROUND: Monitoring disease incidence and transmission patterns is important to characterize groups at risk for hepatitis C virus (HCV) infection. Clinical cases generally represent about 20% to 30% of all newly acquired infections. METHODS: We used sentinel surveillance to determine incidence and transmission patterns for acute hepatitis C in the United States using data from 25 years of population-based surveillance in the general community. Acute cases of hepatitis C were identified from 1982 through 2006 by a stimulated passive surveillance system in 4 to 6 US counties. Cases were defined by a discrete onset of symptoms, alanine aminotransferase (ALT) levels greater than 2.5 times the upper limit of normal (*ULN), negative findings for serologic markers for acute hepatitis A and B, and positive findings for antibody to HCV or HCV RNA. Incidence and frequency of reported risk factors were the main outcome measures. RESULTS: Of 2075 patients identified, the median age was 31 years, 91.5% had ALT values greater than 7*ULN, 77.3% were jaundiced, 22.5% were hospitalized, and 1.2% died. Incidence averaged 7.4 per 100,000 individuals (95% confidence interval [CI], 6.4 8.5 per 100,000) during 1982 to 1989 then declined averaging 0.7 per 100,000 (95% CI, 0.5-1.0 per 100,000) during 1994 to 2006. Among 1748 patients interviewed (84.2%), injection drug use (IDU) was the most commonly reported risk factor. The average number of IDU-related cases declined paralleling the decline in incidence, but the proportion of IDU-related cases rose from 31.8% (402 of 1266) during 1982 to 1989 to 45.6% (103 of 226) during 1994 to 2006. Among IDU-related cases reported during 1994 to 2006, 56 of 61 individuals (91.8%) had been in a drug treatment program and/or incarcerated. CONCLUSIONS: The incidence of acute HCV declined substantially over the 25 years of population-based surveillance. Despite declines, IDU is the most common risk factor for new HCV infection. PMID- 21325116 TI - Future directions in industry funding of continuing medical education. PMID- 21325117 TI - Atovaquone-proguanil use in early pregnancy and the risk of birth defects. PMID- 21325118 TI - Use of neuroimaging in US emergency departments. PMID- 21325119 TI - Invited commentary--Emergency department neuroimaging: are we using our heads?: Comment on "Use of neuroimaging in US emergency departments". PMID- 21325120 TI - Cardiac function in 5-year survivors of childhood cancer. PMID- 21325121 TI - Vitamin D supplementation and fracture risk. PMID- 21325122 TI - Investigating factors of decline in cognitive function or dementia. PMID- 21325123 TI - Vitamin D efficacy and safety. PMID- 21325124 TI - A key step for hospitalized elders: comment on "Early ambulation and length of stay in older adults hospitalized for acute illness". PMID- 21325125 TI - Familial Miller Fisher syndrome. AB - Miller Fisher syndrome is an acute inflammatory polyradiculoneuropathy that is generally considered a variant of Guillain-Barre syndrome and is characterized by the clinical triad of ataxia, areflexia, and ophthalmoplegia. Several reports of familial Guillain-Barre syndrome have been reported, indicating a possible underlying genetic and/or environmental predisposition to the development of Guillain-Barre syndrome. A familial association in Miller Fisher syndrome has not previously been described in the literature. We report 2 cases of Miller Fisher syndrome presenting simultaneously in siblings, with a review of recent relevant literature. PMID- 21325126 TI - Acquired opercular epilepsy with oromotor dysfunction: magnetoencephalographic analysis and efficacy of corticosteroid therapy. AB - The authors describe herein the magnetoencephalographic findings and long-term outcome of a girl with acquired opercular epilepsy with oromotor dysfunction. She presented with brief episodes of unconsciousness, tremulous movements of the upper limbs, and negative myoclonus, in addition to convulsive seizures. She also had prolonged episodes of dysarthria and oral motor dysfunction, a gradual decrease in speech output, impairment of finger movements, and deterioration in cognitive performance over several years. Her electroencephalography (EEG) recordings showed notable continuous sharp or sharp-slow discharges during sleep. Brain magnetic resonance images revealed no structural anomalies. Magnetoencephalographic analysis showed broadly distributed epileptic foci around the sylvian fissure, including a secondary source, explaining the specific prolonged neurological dysfunction. Antiepileptic drugs could control her seizures; however, they did not improve the other neurological symptoms or epileptiform discharge on EEG. Administration of low-dose prednisolone over a long period was effective for improving the neurological impairments of this patient. PMID- 21325127 TI - Seizure and encephalopathy associated with thyroid storm in children. AB - Thyroid storm with seizures is very rare in children. The authors report 3 children with thyroid storm who had a seizure in the absence of a history of neurologic disease. Acute medical management with propylthiouracil, Lugol's iodine solution, hydrocortisone, and propranolol led to a complete resolution of the symptoms. Patients with thyroid storm may be predisposed to the development of neuropsychiatric change. Early recognition and treatment of thyroid storm are essential to reduce morbidity and mortality from this disorder. PMID- 21325128 TI - Dural scalp and intracranial hemangiomas causing hydrocephalus and venous sinus thrombosis in an infant. AB - Cutaneous scalp hemangiomas may herald the presence of occult intracranial hemangiomas. A previously healthy 4-month-old girl presented with a bleeding scalp hemangioma, a bulging fontanel, and anemia. Magnetic resonance imaging (MRI) of the brain revealed hydrocephalus along with multiple intracranial hemangiomas. These lesions compressed the jugular foramina, resulting in venous sinus thrombosis involving the right transverse sinus, the left sigmoid sinus, and the torcular herophili. The patient had no family history of phakomatoses or other genetic abnormalities. A thrombophilia work-up result was unremarkable. The patient was treated with prednisolone (10 mg twice daily) and low molecular weight heparin (1 mg/kg/dose) twice daily. This treatment decreased the size of her cutaneous and intracranial hemangiomas and led to the resolution of her venous sinus thromboses and hydrocephalus. Innocuous scalp hemangioma in an infant may herald more concerning intracranial pathology, which can be treated effectively if diagnosed with appropriate imaging studies. PMID- 21325129 TI - The ERGonomics of hematopoietic stem cell self-renewal. AB - Stem cells make more of themselves by self-renewing cell divisions. In the February 1, 2011, issue of Genes & Development, Taoudi and colleagues (pp. 251 262) show an essential role for the ETS transcription factor ERG in the self renewal of embryonic hematopoietic stem cells. A model is presented in which the redundant functions of GATA2 and RUNX1 in self-renewal are under direct control of ERG. PMID- 21325130 TI - RNase E action at a distance: degradation of target mRNAs mediated by an Hfq binding small RNA in bacteria. AB - A major class of bacterial small RNAs (sRNAs), along with RNA-binding protein Hfq and endoribonuclease RNase E, acts on target mRNAs through base-pairing, leading to translational repression and rapid degradation of the mRNAs. In this issue of Genes & Development, Prevost and colleagues (pp. 385-396) demonstrate by using the well-characterized sRNA RyhB that RNase E cleavage at sites distal from the pairing region triggers degradation of target mRNAs. The study has provided an important insight into the initial events of sRNA-induced degradation of target mRNAs. PMID- 21325131 TI - Cardiac muscle regeneration: lessons from development. AB - The adult human heart is an ideal target for regenerative intervention since it does not functionally restore itself after injury yet has a modest regenerative capacity that could be enhanced by innovative therapies. Adult cardiac cells with regenerative potential share gene expression signatures with early fetal progenitors that give rise to multiple cardiac cell types, suggesting that the evolutionarily conserved regulatory networks that drive embryonic heart development might also control aspects of regeneration. Here we discuss commonalities of development and regeneration, and the application of the rich developmental biology heritage to achieve therapeutic regeneration of the human heart. PMID- 21325132 TI - JNK regulates FoxO-dependent autophagy in neurons. AB - The cJun N-terminal kinase (JNK) signal transduction pathway is implicated in the regulation of neuronal function. JNK is encoded by three genes that play partially redundant roles. Here we report the creation of mice with targeted ablation of all three Jnk genes in neurons. Compound JNK-deficient neurons are dependent on autophagy for survival. This autophagic response is caused by FoxO induced expression of Bnip3 that displaces the autophagic effector Beclin-1 from inactive Bcl-XL complexes. These data identify JNK as a potent negative regulator of FoxO-dependent autophagy in neurons. PMID- 21325133 TI - Cooperation between dE2F1 and Yki/Sd defines a distinct transcriptional program necessary to bypass cell cycle exit. AB - The Hippo signaling pathway regulates organ size homeostasis, while its inactivation leads to severe hyperplasia in flies and mammals. The transcriptional coactivator Yorkie (Yki) mediates transcriptional output of the Hippo signaling. Yki lacks a DNA-binding domain and is recruited to its target promoters as a complex with DNA-binding proteins such as Scalloped (Sd). In spite of recent progress, an open question in the field is the mechanism through which the Yki/Sd transcriptional signature is defined. Here, we report that Yki/Sd synergizes with and requires the transcription factor dE2F1 to induce a specific transcriptional program necessary to bypass the cell cycle exit. We show that Yki/Sd and dE2F1 bind directly to the promoters of the Yki/Sd-dE2F1 shared target genes and activate their expression in a strong cooperative manner. Consistently, RBF, a negative regulator of dE2F1, negates this synergy and limits the overall level of expression of the Yki/Sd-dE2F1 target genes. Significantly, dE2F1 is needed for Yki/Sd-dependent full activation of these target genes, and a de2f1 mutation strongly blocks yki-induced proliferation in vivo. Thus, the Yki transcriptional program is determined through functional interactions with other transcription factors directly at target promoters. We suggest that such functional interactions would influence Yki activity and help diversify the transcriptional output of the Hippo pathway. PMID- 21325134 TI - BLM-DNA2-RPA-MRN and EXO1-BLM-RPA-MRN constitute two DNA end resection machineries for human DNA break repair. AB - Repair of dsDNA breaks requires processing to produce 3'-terminated ssDNA. We biochemically reconstituted DNA end resection using purified human proteins: Bloom helicase (BLM); DNA2 helicase/nuclease; Exonuclease 1 (EXO1); the complex comprising MRE11, RAD50, and NBS1 (MRN); and Replication protein A (RPA). Resection occurs via two routes. In one, BLM and DNA2 physically and specifically interact to resect DNA in a process that is ATP-dependent and requires BLM helicase and DNA2 nuclease functions. RPA is essential for both DNA unwinding by BLM and enforcing 5' -> 3' resection polarity by DNA2. MRN accelerates processing by recruiting BLM to the end. In the other, EXO1 resects the DNA and is stimulated by BLM, MRN, and RPA. BLM increases the affinity of EXO1 for ends, and MRN recruits and enhances the processivity of EXO1. Our results establish two of the core machineries that initiate recombinational DNA repair in human cells. PMID- 21325135 TI - Regulation of alternative splicing by the core spliceosomal machinery. AB - Alternative splicing (AS) plays a major role in the generation of proteomic diversity and in gene regulation. However, the role of the basal splicing machinery in regulating AS remains poorly understood. Here we show that the core snRNP (small nuclear ribonucleoprotein) protein SmB/B' self-regulates its expression by promoting the inclusion of a highly conserved alternative exon in its own pre-mRNA that targets the spliced transcript for nonsense-mediated mRNA decay (NMD). Depletion of SmB/B' in human cells results in reduced levels of snRNPs and a striking reduction in the inclusion levels of hundreds of additional alternative exons, with comparatively few effects on constitutive exon splicing levels. The affected alternative exons are enriched in genes encoding RNA processing and other RNA-binding factors, and a subset of these exons also regulate gene expression by activating NMD. Our results thus demonstrate a role for the core spliceosomal machinery in controlling an exon network that appears to modulate the levels of many RNA processing factors. PMID- 21325136 TI - AphA and LuxR/HapR reciprocally control quorum sensing in vibrios. AB - Bacteria cycle between periods when they perform individual behaviors and periods when they perform group behaviors. These transitions are controlled by a cell cell communication process called quorum sensing, in which extracellular signal molecules, called autoinducers (AIs), are released, accumulate, and are synchronously detected by a group of bacteria. AI detection results in community wide changes in gene expression, enabling bacteria to collectively execute behaviors such as bioluminescence, biofilm formation, and virulence factor production. In this study, we show that the transcription factor AphA is a master regulator of quorum sensing that operates at low cell density (LCD) in Vibrio harveyi and Vibrio cholerae. In contrast, LuxR (V. harveyi)/HapR (V. cholerae) is the master regulator that operates at high cell density (HCD). At LCD, redundant small noncoding RNAs (sRNAs) activate production of AphA, and AphA and the sRNAs repress production of LuxR/HapR. Conversely, at HCD, LuxR/HapR represses aphA. This network architecture ensures maximal AphA production at LCD and maximal LuxR/HapR production at HCD. Microarray analyses reveal that 300 genes are regulated by AphA at LCD in V. harveyi, a subset of which is also controlled by LuxR. We propose that reciprocal gradients of AphA and LuxR/HapR establish the quorum-sensing LCD and HCD gene expression patterns, respectively. PMID- 21325137 TI - High dose atorvastatin decreases cellular markers of immune activation without affecting HIV-1 RNA levels: results of a double-blind randomized placebo controlled clinical trial. AB - BACKGROUND: 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) exhibit antiviral activity against human immunodeficiency virus type 1 (HIV-1) in vitro and may modulate the immune response to HIV infection. Studies evaluating the antiviral activity of statins have yielded conflicting results. METHODS: We conducted a randomized, double-blind, placebo-controlled crossover trial to investigate the effect of atorvastatin on HIV-1 RNA (primary objective) and cellular markers of immune activation (secondary objective). HIV-infected individuals not receiving antiretroviral therapy were randomized to receive either 8 weeks of atorvastatin (80 mg) or placebo daily. After a 4-6 week washout phase, participants switched treatment assignments. The study had 80% power to detect a 0.3 log(10) decrease in HIV-1 RNA level. Expression of CD38 and HLA-DR on CD4(+) and CD8(+) T cells was used to measure immune activation. RESULTS: Of 24 randomized participants, 22 completed the study. Although HIV-1 RNA level was unaffected by the intervention (-0.13 log(10) copies/mL; P = .85), atorvastatin use resulted in reductions in circulating proportions of CD4(+) HLA-DR(+) (-2.5%; P = .02), CD8(+) HLA-DR(+) (-5%; P = .006), and CD8(+) HLA-DR(+) CD38(+) T cells (-3%; P = .03). Reductions in immune activation did not correlate with declines in serum levels of low-density lipoprotein cholesterol. CONCLUSIONS: Short-term use of atorvastatin was associated with modest but statistically significant reductions in the proportion of activated T lymphocytes. PMID- 21325138 TI - Mutation of rice BC12/GDD1, which encodes a kinesin-like protein that binds to a GA biosynthesis gene promoter, leads to dwarfism with impaired cell elongation. AB - The kinesins are a family of microtubule-based motor proteins that move directionally along microtubules and are involved in many crucial cellular processes, including cell elongation in plants. Less is known about kinesins directly regulating gene transcription to affect cellular physiological processes. Here, we describe a rice (Oryza sativa) mutant, gibberellin-deficient dwarf1 (gdd1), that has a phenotype of greatly reduced length of root, stems, spikes, and seeds. This reduced length is due to decreased cell elongation and can be rescued by exogenous gibberellic acid (GA3) treatment. GDD1 was cloned by a map-based approach, was expressed constitutively, and was found to encode the kinesin-like protein BRITTLE CULM12 (BC12). Microtubule cosedimentation assays revealed that BC12/GDD1 bound to microtubules in an ATP-dependent manner. Whole genome microarray analysis revealed the expression of ent-kaurene oxidase (KO2), which encodes an enzyme involved in GA biosynthesis, was downregulated in gdd1. Electrophoretic mobility shift and chromatin immunoprecipitation assays revealed that GDD1 bound to the element ACCAACTTGAA in the KO2 promoter. In addition, GDD1 was shown to have transactivation activity. The level of endogenous GAs was reduced in gdd1, and the reorganization of cortical microtubules was altered. Therefore, BC12/GDD1, a kinesin-like protein with transcription regulation activity, mediates cell elongation by regulating the GA biosynthesis pathway in rice. PMID- 21325139 TI - Production of viable gametes without meiosis in maize deficient for an ARGONAUTE protein. AB - Apomixis is a form of asexual reproduction through seeds in angiosperms. Apomictic plants bypass meiosis and fertilization, developing offspring that are genetically identical to their mother. In a genetic screen for maize (Zea mays) mutants mimicking aspects of apomixis, we identified a dominant mutation resulting in the formation of functional unreduced gametes. The mutant shows defects in chromatin condensation during meiosis and subsequent failure to segregate chromosomes. The mutated locus codes for AGO104, a member of the ARGONAUTE family of proteins. AGO104 accumulates specifically in somatic cells surrounding the female meiocyte, suggesting a mobile signal rather than cell autonomous control. AGO104 is necessary for non-CG methylation of centromeric and knob-repeat DNA. Digital gene expression tag profiling experiments using high throughput sequencing show that AGO104 influences the transcription of many targets in the ovaries, with a strong effect on centromeric repeats. AGO104 is related to Arabidopsis thaliana AGO9, but while AGO9 acts to repress germ cell fate in somatic tissues, AGO104 acts to repress somatic fate in germ cells. Our findings show that female germ cell development in maize is dependent upon conserved small RNA pathways acting non-cell-autonomously in the ovule. Interfering with this repression leads to apomixis-like phenotypes in maize. PMID- 21325140 TI - Oxidative DNA damage bypass in Arabidopsis thaliana requires DNA polymerase lambda and proliferating cell nuclear antigen 2. AB - The oxidized base 7,8-oxoguanine (8-oxo-G) is the most common DNA lesion generated by reactive oxygen species. This lesion is highly mutagenic due to the frequent misincorporation of A opposite 8-oxo-G during DNA replication. In mammalian cells, the DNA polymerase (pol) family X enzyme DNA pol lambda catalyzes the correct incorporation of C opposite 8-oxo-G, together with the auxiliary factor proliferating cell nuclear antigen (PCNA). Here, we show that Arabidopsis thaliana DNA pol lambda, the only member of the X family in plants, is as efficient in performing error-free translesion synthesis past 8-oxo-G as its mammalian homolog. Arabidopsis, in contrast with animal cells, possesses two genes for PCNA. Using in vitro and in vivo approaches, we observed that PCNA2, but not PCNA1, physically interacts with DNA pol lambda, enhancing its fidelity and efficiency in translesion synthesis. The levels of DNA pol lambda in transgenic plantlets characterized by overexpression or silencing of Arabidopsis POLL correlate with the ability of cell extracts to perform error-free translesion synthesis. The important role of DNA pol lambda is corroborated by the observation that the promoter of POLL is activated by UV and that both overexpressing and silenced plants show altered growth phenotypes. PMID- 21325141 TI - CYP2D6 inhibition and breast cancer recurrence in a population-based study in Denmark. AB - BACKGROUND: Cytochrome P450 2D6 (CYP2D6) inhibition reduces the concentration of 4-hydroxylated tamoxifen metabolites, but the clinical relevance remains uncertain. METHODS: We conducted a large case-control study nested in the population of 11 251 women aged 35-69 years at diagnosis of stage I-III breast cancer between 1985 and 2001 on Denmark's Jutland Peninsula and registered with the Danish Breast Cancer Cooperative Group. We identified 541 recurrent or contralateral breast cancers among women with estrogen receptor-positive (ER+) disease treated with tamoxifen for at least 1 year and 300 cancers in women with ER-negative (ER-) disease never treated with tamoxifen. We matched one control subject per case patient on ER status, menopausal status, stage, calendar time, and county, genotyped the CYP2D6*4 allele to assess genetic inhibition, and ascertained prescription history to assess drug-drug inhibition. We estimated the odds ratio (OR), associating CYP2D6 inhibition with breast cancer recurrence and adjusted for potential confounding with logistic regression. To address bias from incomplete information on CYP2D6 function, we used Monte Carlo simulation to complete a record-level probabilistic bias analysis. All statistical tests were two-sided. RESULTS: The frequency of the CYP2D6*4 minor allele was 24% in case patients with ER+ tumors, 23% in case patients with ER- tumors, and 22% each in control subjects with ER+ and ER- tumors. In women with ER+ tumors, the associations of one functional allele with recurrence (OR = 0.99; 95% confidence interval = 0.76 to 1.3) and no functional allele with recurrence (OR = 1.4; 95% confidence interval = 0.84 to 2.3) were near null, as were those for women with ER- tumors. The near-null associations persisted when evaluated by intake of medications, by combining genotype with medication history, in the probabilistic bias analysis, or by restricting the analysis to women with ER expression confirmed by re-assay. CONCLUSION: The association between CYP2D6 inhibition and recurrence in tamoxifen-treated patients is likely null or small. PMID- 21325142 TI - Pitfalls in bone marrow pathology: avoiding errors in bone marrow trephine biopsy diagnosis. AB - Avoiding errors in the histological interpretation of bone marrow trephine biopsy specimens requires an unprecedented degree of collaboration between histopathologists, haematologists, specimen requesters, specimen takers, laboratory technical staff and other scientific staff. A specimen of good quality, with full, relevant clinical information is the essential starting point. This must then be processed optimally and investigated appropriately, involving immunophenotyping and molecular testing when needed. A wide range of pathologies may involve bone marrow haemopoietic and stromal components, and a systematic approach to analysing each of the components in turn is required to avoid overlooking abnormalities; correlation with bone marrow cells aspirated in parallel is particularly important. Final interpretation should be a synthesis of the histological findings with information from such haematological and other investigations, interpreted with due regard to clinical context. PMID- 21325143 TI - Pitfalls in lymphoma pathology: avoiding errors in diagnosis of lymphoid tissues. AB - The complexity involved in the histological interpretation of lymph nodes and other lymphoid tissue specimens suspected of harbouring lymphoma is underappreciated. As with other histology specimens, the quality of sections and background information are crucial but so, increasingly, is the appropriate use of immunocytochemistry and a variety of molecular analyses. Within the UK National Health Service, progressive regional centralisation is ongoing, to ensure access to specialist expertise and a full range of testing beyond traditional stains. This is to be welcomed but there remains a need to maintain skills in smaller district hospitals, to ensure lymphoma recognition in unexpected circumstances, to permit clinically useful interim diagnoses when needed urgently and to sustain training in haematopathology among junior pathologists. In this review a range of potential pitfalls in lymphoid tissue pathology is outlined, arising at all stages from specimen preparation to reporting. Knowledge of such pitfalls, some of which are common while others are rare but of vital clinical importance, should help increase confidence in lymphoma diagnosis among histopathologists. PMID- 21325144 TI - Exposure to parental and sibling smoking and the risk of smoking uptake in childhood and adolescence: a systematic review and meta-analysis. AB - BACKGROUND: There is increasing evidence that contact with other smokers, particularly in the family, is a strong determinant of risk of smoking uptake. A systematic review and meta-analysis of the magnitude of these effects is reported. METHODS: Studies were identified by searching four databases to March 2009 and proceedings from international conferences. Meta-analyses were performed using random effects, with results presented as pooled ORs with 95% CIs. RESULTS: 58 studies were included in the meta-analyses. The relative odds of uptake of smoking in children were increased significantly if at least one parent smoked (OR 1.72, 95% CI 1.59 to 1.86), more so by smoking by the mother (OR 2.19, 95% CI 1.73 to 2.79) than the father (OR 1.66, 95% CI 1.42 to 1.94), and if both parents smoked (OR 2.73, 95% CI 2.28 to 3.28). Smoking by a sibling increased the odds of smoking uptake by 2.30 (95% CI 1.85 to 2.86) and smoking by any household member by 1.92 (95% CI 1.70 to 2.16). After adjusting for overestimation of RRs it is estimated that, in England and Wales, around 17,000 young people take up smoking by the age of 15 each year as a consequence of exposure to household smoking. CONCLUSIONS: Parental and sibling smoking is a strong and significant determinant of the risk of smoking uptake by children and young people and, as such, is a major and entirely avoidable health risk. Children should be protected from exposure to smoking behaviour, especially by family members. PMID- 21325145 TI - Long-term use of thiazolidinediones and the associated risk of pneumonia or lower respiratory tract infection: systematic review and meta-analysis. AB - INTRODUCTION: The peroxisome proliferator-activated receptor-gamma agonists rosiglitazone and pioglitazone activate glucocorticoid receptors and have an immunomodulatory effect. The authors aimed to systematically determine the risk of pneumonia or lower respiratory tract infections associated with thiazolidinediones. METHODS: Systematic searches of MEDLINE, EMBASE, regulatory documents and trial registries were carried out for randomised controlled trials of thiazolidinediones with no date restrictions through March 2010. The authors selected long-term (>=1 year) randomised controlled trials of thiazolidinediones versus a placebo, metformin or sulfonylurea control for prevention or treatment of type 2 diabetes that reported on pneumonia or lower respiratory tract infection adverse events or serious adverse events (hospitalisation, disability or death). Relative risks (RRs) were estimated using a fixed-effects meta analysis, and statistical heterogeneity was assessed using the I(2) statistic. RESULTS: Thirteen trials (n=17,627, including 8163 patients receiving thiazolidinediones and 9464 patients receiving control therapy) with a duration of follow-up of 1-5.5 years were included after a detailed screening of 58 studies. Thiazolidinediones were associated with a statistically significantly increased risk for any pneumonia or lower respiratory tract infection (n=130/8163 vs 100/9464; RR 1.40; 95% CI 1.08 to 1.82; p=0.01; I(2)=0%) and serious pneumonia or lower respiratory tract infection (n=111/7391 vs 87/8692; RR 1.39; 95% CI 1.05 to 1.83; p=0.02; I(2)=0%). INTERPRETATION: Long-term thiazolidinedione use is associated with a modestly increased risk of any pneumonia or lower respiratory tract infection and serious pneumonia or lower respiratory tract infection in patients with type 2 diabetes. PMID- 21325147 TI - Uses of 'Good Laboratory Practices' by regulated industry and agencies, and the safety of bisphenol A. PMID- 21325148 TI - Adolescent blood pressure, body mass index and skin folds: sorting out the effects of early weight and length gains. AB - BACKGROUND: Although there is longstanding evidence of the short-term benefits of promoting rapid growth for young children in low-income settings, more recent studies suggest that early weight gain can also increase the risk of chronic diseases in adults. This paper attempts to separate the effects of early life weight and length/height gains on blood pressure, body mass index (BMI), sum of skin folds and subscapular/triceps skin fold ratio at 14-15 years of age. METHODS: The sample comprised 833 members of a prospective population-based birth cohort from Brazil. Conditional size (weight or height) analyses were used to express the difference between observed size at a given age and expected size based on a regression, including all previous measures of the same anthropometric index. A positive conditional weight or height indicates growing faster than expected given prior size. RESULTS: Conditional weights at all age ranges were positively associated with most outcomes; each z-score of conditional weight at 4 years was associated with an increase of 6.1 mm in the sum of skin folds (95% CI 4.5 to 7.6) in adolescence after adjustment for conditional length/height. Associations of the outcomes with conditional length/height were mostly negative or non-significant-each z-score was associated with a reduction of 2.4 mm (95% CI -3.8 to -1.1) in the sum of skin folds after adjustment for conditional weight. No associations were found with the skin fold ratio. CONCLUSION: The promotion of rapid length/height gain without excessive weight gain seems to be beneficial for long-term outcomes, but this requires confirmation from other studies. PMID- 21325149 TI - Walking on sunshine: effect of weather conditions on physical activity in older people. AB - BACKGROUND: It is unclear which weather parameters effect the motion-sensor-based measurement of physical activity in terms of walking duration in older people. METHODS: Between March 2009 and April 2010, the physical activity of 1324 German community-dwelling older people (>=65 years, 56.4% men) was recorded over 5 days using accelerometers. Multilevel linear regression analysis was used to estimate the effect of local daily weather parameters (daylight, maximum temperature, total global radiation, average precipitation, average wind speed and average humidity) on walking duration. RESULTS: Mean daily walking duration was comparable for men and women, with 104.4+/-50.7 min and 102.9+/-47.8 min, respectively. A linear relationship with walking duration was seen for all considered weather parameters. The strongest effect was found for global radiation, which involved an increase in walking duration of 16.1 min in men and 19.2 min in women between an average winter day (with about 0.8 kWh/m(2) radiation) and an average summer day (with about 6 kWh/m(2) radiation); similar patterns were found for daily maximum temperature and daylight. Furthermore, physical activity decreased significantly with increasing wind speed, precipitation and humidity. CONCLUSIONS: Studies on physical activity in community dwelling older people should consider weather conditions. PMID- 21325150 TI - SCN5A variation is associated with electrocardiographic traits in the Jackson Heart Study. AB - BACKGROUND: Understanding variation in the normal electric activity of the heart, assessed by the ECG, may provide a starting point for studies of susceptibility to serious arrhythmias such as sudden cardiac death during myocardial infarction or drug therapy. Recent genetic association studies of one ECG trait, the QT interval, have identified common variation in European-descent populations, but little is known about the genetic determinants of ECG traits in populations of African descent. METHODS AND RESULTS: To identify genetic risk factors, we have undertaken a candidate gene study of ECG traits in collaboration with the Jackson Heart Study, a longitudinal study of 5301 blacks ascertained from the Jackson, Mississippi, area. Nine quantitative ECG traits were evaluated: P, PR, QRS, QT, and QTc durations, heart rate, and P, QRS, and T axes. We genotyped 72 variations in the predominant sodium channel gene expressed in heart, SCN5A, encoding the Na(v)1.5 voltage-gated sodium channel in 4558 subjects. Both rare and common variants in this gene have previously been associated with inherited arrhythmia syndromes and variable conduction. Adjusting for age, sex, and European ancestry, we performed tests of association in 3054 unrelated participants and identified 14 significant associations (P<1.0*10(-4)), of which 13 are independent, based on linkage disequilibrium. These variants explain up to 2% of the variation in ECG traits in the Jackson Heart Study. CONCLUSIONS: These results suggest that SCN5A variation contributes to ECG trait distributions in blacks, and these same variations may be risk or protective factors associated with susceptibility to arrhythmias. PMID- 21325151 TI - Genetic variations in the alpha(2A)-adrenoreceptor are associated with blood pressure response to the agonist dexmedetomidine. AB - BACKGROUND: alpha(2A)-Adrenoceptors (alpha(2A)-ARs) have important roles in sympathetic cardiovascular regulation. Variants of ADRA2A affect gene transcription and expression and are associated with insulin release and risk for type 2 diabetes. We examined whether ADRA2A variants are also associated with cardiovascular responses to the selective alpha(2)-AR-agonist dexmedetomidine. METHODS AND RESULTS: Seventy-three healthy subjects participated in a placebo controlled, single-blind study. After 3 infusions of placebo, subjects received 3 incremental infusions of dexmedetomidine (cumulative dose, 0.4 MUg/kg). Primary outcomes were changes in systolic blood pressure (SBP) and plasma norepinephrine concentrations, measured as difference of the area-under-the-curve during placebo and dexmedetomidine infusions (DeltaAUC). We used multiple linear regression analysis to examine the associations between 9 ADRA2A tagging variants and 5 inferred haplotypes and DeltaAUC after adjustment for covariates. Homozygous carriers of rs553668 and the corresponding haplotype 4, previously associated with increased alpha(2A)-AR expression, had a 2.2-fold greater decrease in AUC(SBP) after dexmedetomidine (adjusted P=0.006); similarly, the maximum decrease in SBP was 24.7+/-8.1 mm Hg compared with 13.6+/-5.9 mm Hg in carriers of the wild-type allele (P=0.007). Carriers of haplotype 3, previously associated with reduced alpha(2A)-AR expression, had a 44% smaller decrease in AUC(SBP) (P=0.013). Haplotype information significantly improved the model predicting the decrease in SBP (P<0.001). There were similar but nonsignificant trends for diastolic blood pressure and heart rate. Genotypes were not significantly associated with norepinephrine responses. CONCLUSIONS: Common ADRA2A variants are associated with the hypotensive response to dexmedetomidine. Effects of specific variants/haplotypes in vivo are compatible with their known effects on gene expression in vitro. PMID- 21325152 TI - Letter by Kono regarding article, "Plasma bilirubin and UGT1A1*28 are not protective factors against first-time myocardial infarction in a prospective, nested case-referent setting". PMID- 21325154 TI - Letter by van Mil et al regarding, "Dynamic microRNA expression programs during cardiac differentiation of human embryonic stem cells: role for miR-499". PMID- 21325156 TI - Letter by Singh et al regarding article, "Apolipoprotein E polymorphisms and postprandial triglyceridemia before and after fenofibrate treatment in the GOLDN study". PMID- 21325158 TI - Letter by D'Alessandra et al regarding article, "Circulating microRNA-208b and microRNA-499 reflect myocardial damage in cardiovascular disease". PMID- 21325161 TI - Toward a holistic view of transcriptional regulation. PMID- 21325162 TI - Gene mutations and familial thoracic aortic aneurysms: a walk on the mild side. PMID- 21325163 TI - Genomic reflections of coronary artery disease. PMID- 21325164 TI - Psychological issues in genetic testing for inherited cardiovascular diseases. PMID- 21325165 TI - Moving beyond genome-wide association studies. PMID- 21325166 TI - Top advances in functional genomics and translational biology for 2010. PMID- 21325167 TI - Variation in APOL1 gene may contribute to high rates of kidney disease in African Americans. PMID- 21325168 TI - Exome sequencing links gene mutation in angiopoietin-like protein 3 with low density lipoprotein cholesterol. PMID- 21325169 TI - JAK2 rearrangements, including the novel SEC31A-JAK2 fusion, are recurrent in classical Hodgkin lymphoma. AB - The genetics of classical Hodgkin lymphoma (cHL) is poorly understood. The finding of a JAK2-involving t(4;9)(q21;p24) in 1 case of cHL prompted us to characterize this translocation on a molecular level and to determine the prevalence of JAK2 rearrangements in cHL. We showed that the t(4;9)(q21;p24) leads to a novel SEC31A-JAK2 fusion. Screening of 131 cHL cases identified 1 additional case with SEC31A-JAK2 and 2 additional cases with rearrangements involving JAK2. We demonstrated that SEC31A-JAK2 is oncogenic in vitro and acts as a constitutively activated tyrosine kinase that is sensitive to JAK inhibitors. In vivo, SEC31A-JAK2 was found to induce a T-lymphoblastic lymphoma or myeloid phenotype in a murine bone marrow transplantation model. Altogether, we identified SEC31A-JAK2 as a chromosomal aberration characteristic for cHL and provide evidence that JAK2 rearrangements occur in a minority of cHL cases. Given the proven oncogenic potential of this novel fusion, our studies provide new insights into the pathogenesis of cHL and indicate that in at least some cases, constitutive activation of the JAK/STAT pathway is caused by JAK2 rearrangements. The finding that SEC31A-JAK2 responds to JAK inhibitors indicates that patients with cHL and JAK2 rearrangements may benefit from targeted therapies. PMID- 21325170 TI - Radioimmunotherapy-based conditioning for hematopoietic cell transplantation in children with malignant and nonmalignant diseases. AB - Targeted irradiation of the bone marrow with radiolabeled monoclonal antibodies (radioimmunotherapy) represents a novel therapeutic approach with both myeloablative and antileukemic potential. In an open-label, single-center pilot study, 30 pediatric and adolescent patients undergoing hematopoietic cell transplantation for malignant (n = 16) and nonmalignant (n = 14) disorders received treatment with a 90Y-labeled anti-CD66 monoclonal antibody. Patients with a high risk of relapse (n = 7) received additional treatment with standard conditioning based on either total body irradiation or busulfan to intensify the antileukemic effect. In patients with comorbidities (n = 23), radioimmunotherapy was combined with a reduced-intensity conditioning regimen to reduce systemic toxicity. Preferential irradiation of the bone marrow was achieved in all patients. Nonrelapse mortality was 4 (13%) of 30 patients. In patients with malignant diseases, the probabilities of overall and disease-free survival at 2 years were 0.69 (95% confidence interval 0.37-0.87) and 0.46 (95% confidence interval 0.19-0.70), respectively. In patients with nonmalignant diseases, the probability of both overall and disease-free survival at 2 years was 0.94 (95% confidence interval 0.63-0.99). This pilot study demonstrates that radioimmunotherapy is effective in achieving myeloablation with low additional toxicity when used in combination with standard or reduced-intensity conditioning in young patients. PMID- 21325171 TI - Working Party proposal for a revised classification system of renal dysfunction in patients with cirrhosis. AB - OBJECTIVES: To propose an improvement on the current classification of renal dysfunction in cirrhosis. Clinicians caring for patients with cirrhosis recognize that the development of renal dysfunction is associated with significant morbidity and mortality. While most cases of renal dysfunction in cirrhosis are functional in nature, developed as a result of changes in haemodynamics, cardiac function, and renal auto-regulation, there is an increasing number of patients with cirrhosis and structural changes in their kidney as a cause of renal dysfunction. Therefore, there is a need for a newer classification to include both functional and structural renal diseases. DESIGN: A working party consisting of specialists from multiple disciplines conducted literature search and developed summary statements, incorporating the renal dysfunction classification used in nephrology. These were discussed and revised to produce this proposal. SETTING: Multi-disciplinary international meeting. PATIENTS: None. INTERVENTIONS: Literature search using keywords of cirrhosis, renal dysfunction, acute kidney injury (AKI), chronic kidney injury (CKD), and hepatorenal syndrome. RESULTS: Acute kidney injury will include all causes of acute deterioration of renal function as indicated by an increase in serum creatinine of >50% from baseline, or a rise in serum creatinine of >= 26.4 umol/L (>= 0.3 mg/dL) in < 48 hours. Chronic renal disease will be defined as an estimated glomerular filtration rate (GFR) of < 60 ml/min calculated using the Modification of Diet in Renal Disease 6 (MDRD6) formula, recognising that the MDRD6 formula is not perfect for the cirrhotic patients and this may change as improved means of estimating GFR becomes available. Acute on chronic kidney disease will be defined as AKI superimposed on existing chronic renal disease using the above definitions for AKI and CKD. CONCLUSIONS: Accepting this new classification will allow studies into the epidemiology, incidence, prevalence, natural history and the development of new treatments for these subtypes of renal dysfunction in cirrhosis. PMID- 21325172 TI - Easy dye application at surveillance colonoscopy: modified use of a washing pump. PMID- 21325173 TI - Pancreas divisum as a predisposing factor for chronic and recurrent idiopathic pancreatitis: initial in vivo survey. AB - BACKGROUND: It is a controversial issue whether pancreas divisum (PD) induces pancreatitis. All previous studies have investigated this issue based on endoscopic procedures, which inevitably involve a selection bias. OBJECTIVES: To determine the unbiased prevalence rate of PD in a community population and to investigate the effect of PD on idiopathic pancreatitis using a non-invasive magnetic resonance (MR) technique. DESIGN: Cross-sectional study. PATIENTS: The study enrolled 504 subjects from the community who participated in the medical check-up programme and 46 patients with idiopathic pancreatitis (8 acute, 23 chronic, 15 recurrent) extracted from 70,122 consecutive MR studies performed at an academic tertiary care hospital. INTERVENTIONS: All subjects underwent magnetic resonance (MR) scanning and medical examination. MAIN OUTCOME MEASURES: Statistical comparison between subjects from the community and patients with idiopathic pancreatitis was made for the rate of PD (and its subtypes: classical PD, PD with absent ventral duct, and incomplete PD), MR findings, and clinical features. RESULTS: Multiple logistic regression analysis revealed PD as a significant factor that induces pancreatitis (OR 23.4; p<0.0001). The PD rate was significantly higher for all/chronic/recurrent idiopathic pancreatitis patients (35%/43%/33%; p<0.001 for all) than for subjects in the community group (2.6%), but was not higher for acute pancreatitis (13%; p=0.357). All PD subtypes were indicated to induce idiopathic pancreatitis but showed different associations with each onset type of pancreatitis. CONCLUSIONS: This is the first study to describe the prevalence of PD and PD subtypes in a community population and their association with idiopathic pancreatitis in vivo based on the findings of non invasive MR and with minimal selection bias. It is concluded that PD should be considered a predisposing factor for chronic and recurrent pancreatitis. PMID- 21325175 TI - The cover. The Lewis chessmen. PMID- 21325176 TI - A piece of my mind. The pavilion. PMID- 21325177 TI - Scientists probe oxytocin therapy for social deficits in autism, schizophrenia. PMID- 21325178 TI - Guideline cites appropriateness criteria for performing tonsillectomy in children. PMID- 21325179 TI - Study: Few advocacy groups disclose grants from drug companies. PMID- 21325180 TI - Preventing falls in acute care hospitals. PMID- 21325181 TI - Docosahexaenoic acid supplementation and Alzheimer disease. PMID- 21325182 TI - Cognitive and functional impairment after severe sepsis. PMID- 21325183 TI - Thirty-day readmission rates for Medicare beneficiaries by race and site of care. AB - CONTEXT: Understanding whether and why there are racial disparities in readmissions has implications for efforts to reduce readmissions. OBJECTIVE: To determine whether black patients have higher odds of readmission than white patients and whether these disparities are related to where black patients receive care. DESIGN: Using national Medicare data, we examined 30-day readmissions after hospitalization for acute myocardial infarction (MI), congestive heart failure (CHF), and pneumonia. We categorized hospitals in the top decile of proportion of black patients as minority-serving. We determined the odds of readmission for black patients compared with white patients at minority serving vs non-minority-serving hospitals. SETTING AND PARTICIPANTS: Medicare Provider Analysis Review files of more than 3.1 million Medicare fee-for-service recipients who were discharged from US hospitals in 2006-2008. MAIN OUTCOME MEASURE: Risk-adjusted odds of 30-day readmission. RESULTS: Overall, black patients had higher readmission rates than white patients (24.8% vs 22.6%, odds ratio [OR], 1.13; 95% confidence interval [CI], 1.11-1.14; P < .001); patients from minority-serving hospitals had higher readmission rates than those from non minority-serving hospitals (25.5% vs 22.0%, OR, 1.23; 95% CI, 1.20-1.27; P < .001). Among patients with acute MI and using white patients from non-minority serving hospitals as the reference group (readmission rate 20.9%), black patients from minority-serving hospitals had the highest readmission rate (26.4%; OR, 1.35; 95% CI, 1.28-1.42), while white patients from minority-serving hospitals had a 24.6% readmission rate (OR, 1.23; 95% CI, 1.18-1.29) and black patients from non-minority-serving hospitals had a 23.3% readmission rate (OR, 1.20; 95% CI, 1.16-1.23; P < .001 for each); patterns were similar for CHF and pneumonia. The results were unchanged after adjusting for hospital characteristics including markers of caring for poor patients. CONCLUSION: Among elderly Medicare recipients, black patients were more likely to be readmitted after hospitalization for 3 common conditions, a gap that was related to both race and to the site where care was received. PMID- 21325184 TI - Hospital utilization and characteristics of patients experiencing recurrent readmissions within children's hospitals. AB - CONTEXT: Early hospital readmission is emerging as an indicator of care quality. Some children with chronic illnesses may be readmitted on a recurrent basis, but there are limited data describing their rehospitalization patterns and impact. OBJECTIVES: To describe the inpatient resource utilization, clinical characteristics, and admission reasons of patients recurrently readmitted to children's hospitals. DESIGN, SETTING, AND PATIENTS: Retrospective cohort analysis of 317,643 patients (n = 579,504 admissions) admitted to 37 US children's hospitals in 2003 with follow-up through 2008. MAIN OUTCOME MEASURE: Maximum number of readmissions experienced by each child within any 365-day interval during the 5-year follow-up period. RESULTS: In the sample, 69,294 patients (21.8%) experienced at least 1 readmission within 365 days of a prior admission. Within a 365-day interval, 9237 patients (2.9%) experienced 4 or more readmissions; time between admissions was a median 37 days (interquartile range [IQR], 21-63). These patients accounted for 18.8% (109,155 admissions) of all admissions and 23.2% ($3.4 billion) of total inpatient charges for the study cohort during the entire follow-up period. Tests for trend indicated that as the number of readmissions increased from 0 to 4 or more, the prevalences increased for a complex chronic condition (from 22.3% [n = 55,382/248,349] to 89.0% [n = 8225/9237]; P < .001), technology assistance (from 5.3% [n = 13,163] to 52.6% [n = 4859]; P < .001), public insurance use (from 40.9% [n = 101,575] to 56.3% [n = 5202]; P < .001), and non-Hispanic black race (from 21.8% [n = 54,140] to 34.4% [n = 3181]; P < .001); and the prevalence decreased for readmissions associated with an ambulatory care-sensitive condition (from 23.1% [62,847/272,065] to 14.0% [15,282/109,155], P < .001). Of patients readmitted 4 or more times in a 365-day interval, 2633 (28.5%) were rehospitalized for a problem in the same organ system across all admissions during the interval. CONCLUSIONS: Among a group of pediatric hospitals, 18.8% of admissions and 23.2% of inpatient charges were accounted for by the 2.9% of patients with frequent recurrent admissions. Many of these patients were rehospitalized recurrently for a problem in the same organ system. PMID- 21325185 TI - Serum bilirubin and risk of respiratory disease and death. AB - CONTEXT: Serum total bilirubin levels in healthy patients reflect genetic and environmental factors that could influence the risk of developing respiratory disease. OBJECTIVE: To examine the relationship between bilirubin levels and respiratory disease. DESIGN, SETTING, AND PARTICIPANTS: Cohort study among 504,206 adults from a UK primary care research database (the Health Improvement Network) with serum bilirubin levels recorded but no evidence of hepatobiliary or hemolytic disease. Data were recorded between January 1988 and December 2008. MAIN OUTCOME MEASURES: Incidence of chronic obstructive pulmonary disease (COPD), lung cancer, and all-cause mortality. RESULTS: Median bilirubin levels were 0.64 mg/dL (interquartile range, 0.47-0.88 mg/dL) in men and 0.53 mg/dL (interquartile range, 0.41-0.70 mg/dL) in women. There were 1341 cases of lung cancer, 5863 cases of COPD, and 23,103 deaths, with incidence rates of 2.5, 11.9, and 42.5 per 10,000 person-years, respectively. The incidence of lung cancer per 10,000 person years in men was 5.0 (95% confidence interval [CI], 4.2-6.0) in the first decile category of bilirubin compared with 3.0 (95% CI, 2.3-3.8) in the fifth decile. The corresponding incidences for COPD in men were 19.5 (95% CI,17.7-21.4) and 14.4 (95% CI, 12.7-16.2). The mortality rates per 10,000 person-years in men were 51.3 (95% CI, 48.5-54.2) in the first decile category compared with 38.1 (95% CI, 35.5-40.8) in the fifth decile. The associations were similar for women. After adjusting for other important health indicators, regression estimates for incidence rate of lung cancer per 0.1-mg/dL increase in bilirubin level were an 8% decrease (95% CI, 5%-11%) for men and an 11% decrease (95% CI, 7%-14%) for women. The regression estimate for COPD in men per 0.1-mg/dL increase in bilirubin level was a 6% decrease (95% CI, 5%-7%) and for mortality in men was a 3% decrease (95% CI, 2%-3%) after accounting for other health indicators. The results for COPD and mortality in women were very similar. CONCLUSION: Among patients with normal-range bilirubin levels in primary care practices, relatively higher levels of bilirubin were associated with a lower risk of respiratory disease and all-cause mortality. PMID- 21325186 TI - Finances in the older patient with cognitive impairment: "He didn't want me to take over". AB - Financial capacity can be defined as the ability to independently manage one's financial affairs in a manner consistent with personal self-interest. Financial capacity is essential for an individual to function independently in society; however, Alzheimer disease and other progressive dementias eventually lead to a complete loss of financial capacity. Many patients with cognitive impairment and their families seek guidance from their primary care clinician for help with financial impairment, yet most clinicians do not understand their role or know how to help. We review the prevalence and impact of diminished financial capacity in older adults with cognitive impairment. We also articulate the role of the primary care clinician, which includes (1) educating older adult patients and their families about the need for advance financial planning; (2) recognizing signs of possible impaired financial capacity; (3) assessing financial impairments in cognitively impaired adults; (4) recommending interventions to help patients maintain financial independence; and (5) knowing when and to whom to make medical and legal referrals. Clearly delineating the clinician's role regarding identification of financial impairment could establish for patients and families effective financial protections and limit the economic, psychological, and legal hardships of financial incapacity on patients with dementia and their families. PMID- 21325187 TI - Damage prevention and control for financial incapacity. PMID- 21325188 TI - Sudden acceleration of diabetes quality measures. PMID- 21325189 TI - How many "me-too" drugs is too many? PMID- 21325190 TI - A historical perspective on clinical trials innovation and leadership: where have the academics gone? PMID- 21325191 TI - Minding the gap between efforts to reduce readmissions and disparities. PMID- 21325193 TI - JAMA patient page. Deep brain stimulation. PMID- 21325194 TI - Contrast staining outside the sirolimus-eluting stent leading to coronary aneurysm formation: a case of very late stent thrombosis associated with hypersensitivity reaction. PMID- 21325197 TI - Don't judge a book by its cover: don't judge stenosis severity solely by intravascular ultrasound. PMID- 21325196 TI - Cell therapy for critical limb ischemia: moving forward one step at a time. PMID- 21325198 TI - Optimal use of thienopyridines in non-ST-elevation acute coronary syndrome following CURRENT-OASIS 7. PMID- 21325200 TI - Percutaneous tricuspid valve implantation in a Fontan patient with congestive heart failure and protein-losing enteropathy. PMID- 21325199 TI - Vascular smooth muscle cell proliferation in restenosis. PMID- 21325201 TI - Focus issue: conquering the data mountain. AB - High-throughput technologies have enabled a rapid increase in the acquisition of data regarding cellular regulation, such as protein-protein interactions, gene expression profiling, proteomic analyses of changes in protein abundance, and global analyses of posttranslational modifications. The challenge now is for the community to devise adequate standards for assessing reliability and annotation, facilities for storage, mechanisms for sharing, and tools for visualization and analysis. In conjunction with Science (http://www.sciencemag.org/special/data), this issue of Science Signaling tackles some of the key issues related to the data deluge faced by cell signaling researchers. PMID- 21325202 TI - Setting the standards for signal transduction research. AB - Major advances in high-throughput technology platforms, coupled with increasingly sophisticated computational methods for systematic data analysis, have provided scientists with tools to better understand the complexity of signaling networks. In this era of massive and diverse data collection, standardization efforts that streamline data gathering, analysis, storage, and sharing are becoming a necessity. Here, we give an overview of current technologies to study signal transduction. We argue that along with the opportunities the new technologies open, their heterogeneous nature poses critical challenges for data handling that are further increased when data are to be integrated in mathematical models. Efficient standardization through markup languages and data annotation is a sine qua non condition for a systems-level analysis of signaling processes. It remains to be seen the extent to which and the speed at which the emerging standardization efforts will be embraced by the signaling community. PMID- 21325203 TI - Effective representation and storage of mass spectrometry-based proteomic data sets for the scientific community. AB - Mass spectrometry-based proteomics has emerged as a technology of choice for global analysis of cell signaling networks. However, reporting and sharing of MS data are often haphazard, limiting the usefulness of proteomics to the signaling community. We argue that raw data should always be provided with proteomics studies together with detailed peptide and protein identification and quantification information. Statistical criteria for peptide identification and their posttranslational modifications have largely been established for individual projects. However, the current practice of indiscriminately incorporating these individual results into databases such as UniProt is problematic. Because of the vast differences in underlying data quality, we advocate a differentiated annotation of data by level of reliability. Requirements for the reporting of quantitative data are being developed, but there are few mechanisms for community-wide sharing of these data. PMID- 21325204 TI - The potential cost of high-throughput proteomics. AB - Improvements in speed and mass accuracy of mass spectrometers revolutionized proteomics, with high-throughput proteomics enabling the profiling of complete proteomes and thousands of posttranslational modification sites. The limits of high-throughput proteomics are constantly pushed to new frontiers, and mass spectrometry-based proteomics may eventually permit the analysis of protein expression profiles in less than a day. Increased data acquisition speed has led to a dramatic increase in the total number of tandem mass spectrometry (MS/MS) spectra, such that millions of MS/MS spectra are now acquired in a given set of analyses. Many of these spectra are insufficiently validated; instead, statistical tools are commonly used to estimate false-positive or false-discovery rates for these data sets. Many laboratories may not realize the costs associated with using these widely available, but minimally validated, data sets. The costs associated with use of these data can include missed opportunities for biological insight, the pollution of databases with increasing numbers of false-positive identifications, and time spent by biologists investigating false leads, resulting in a lack of faith in proteomics data. Improved strategies for data validation need to be implemented, along with a change in the culture of high throughput proteomics, linking proteomics closer to biology. PMID- 21325205 TI - Integrating multiple types of data for signaling research: challenges and opportunities. AB - New technologies promise to provide unprecedented amounts of information that can build a foundation for creating predictive models of cell signaling pathways. To be useful, however, this information must be integrated into a coherent framework. In addition, the sheer volume of data gathered from the new technologies requires computational approaches for its analysis. Unfortunately, there are many barriers to data integration and analysis, mostly because of a lack of adequate data standards and their inconsistent use by scientists. However, solving the fundamental issues of data sharing will enable the investigation of entirely new areas of cell signaling research. PMID- 21325206 TI - Visual representation of scientific information. AB - Great technological advances have enabled researchers to generate an enormous amount of data. Data analysis is replacing data generation as the rate-limiting step in scientific research. With this wealth of information, we have an opportunity to understand the molecular causes of human diseases. However, the unprecedented scale, resolution, and variety of data pose new analytical challenges. Visual representation of data offers insights that can lead to new understanding, whether the purpose is analysis or communication. This presentation shows how art, design, and traditional illustration can enable scientific discovery. Examples will be drawn from the Broad Institute's Data Visualization Initiative, aimed at establishing processes for creating informative visualization models. PMID- 21325207 TI - MUC1-C oncoprotein promotes STAT3 activation in an autoinductive regulatory loop. AB - Signal transducer and activator of transcription 3 (STAT3) is activated in human breast cancer and other malignancies. Mucin 1 (MUC1) is a heterodimeric cell surface glycoprotein that is overexpressed in human carcinomas and, like STAT3, promotes cell survival and induces transformation. We found that in breast cancer cells, the MUC1 carboxyl-terminal receptor subunit (MUC1-C) associates with the gp130-Janus-activated kinase 1 (JAK1)-STAT3 complex. The MUC1-C cytoplasmic domain interacted directly with JAK1 and STAT3, and MUC1-C was necessary for JAK1 mediated STAT3 activation. In turn, MUC1-C and activated STAT3 occupied the promoter of MUC1, and MUC1-C contributed to STAT3-mediated activation of MUC1 transcription. The MUC1-C inhibitor GO-201 blocked the MUC1-C interaction with STAT3, thereby decreasing MUC1-C and STAT3 occupancy on the MUC1 and STAT3 promoters and activation of STAT3 target genes, including MUC1 itself. These findings indicate that MUC1-C promotes STAT3 activation and that MUC1-C and STAT3 function in an autoinductive loop that may play a role in cancer cell survival. PMID- 21325208 TI - Luminal esophageal temperature monitoring with a deflectable esophageal temperature probe and intracardiac echocardiography may reduce esophageal injury during atrial fibrillation ablation procedures: results of a pilot study. AB - BACKGROUND: Luminal esophageal temperature (LET) monitoring is one strategy to minimize esophageal injury during atrial fibrillation ablation procedures. However, esophageal ulceration and fistulas have been reported despite adequate LET monitoring. The objective of this study was to assess a novel approach to LET monitoring with a deflectable LET probe on the rate of esophageal injury in patients undergoing atrial fibrillation ablation. METHODS AND RESULTS: Forty-five consecutive patients undergoing an atrial fibrillation ablation procedure followed by esophageal endoscopy were included in this prospective observational pilot study. LET monitoring was performed with a 7F deflectable ablation catheter that was positioned as close as possible to the site of left atrial ablation using the deflectable component of the catheter guided by visualization of its position on intracardiac echocardiography. Ablation in the posterior left atrial was limited to 25 W and terminated when the LET increased 2 degrees C from baseline. Endoscopy was performed 1 to 2 days after the procedure. All patients had at least 1 LET elevation >2 degrees C necessitating cessation of ablation. Deflection of the LET probe was needed to accurately measure LET in 5% of patients when ablating near the left pulmonary veins, whereas deflection of the LET probe was necessary in 88% of patients when ablating near the right pulmonary veins. The average maximum increase in LET was 2.5+/-1.5 degrees C. No patients had esophageal thermal injury on follow-up endoscopy. CONCLUSIONS: A strategy of optimal LET probe placement using a deflectable LET probe and intracardiac echocardiography guidance, combined with cessation of radiofrequency ablation with a 2 degrees C rise in LET, may reduce esophageal thermal injury during left atrial ablation procedures. PMID- 21325210 TI - Teaching points with 3-dimensional mapping of cardiac arrhythmia: mechanism of arrhythmia and accounting for the cycle length. PMID- 21325209 TI - Predictors of short-term complications after implantable cardioverter defibrillator replacement: results from the Ontario ICD Database. AB - BACKGROUND: Complications after implantable cardioverter-defibrillator (ICD) replacement are often clinically devastating, particularly when infection or reoperation occurs. Identifying factors contributing to complications may permit identification of high-risk individuals that warrant incremental monitoring and therapy to attenuate risk. In addition, replacement may be a discretionary decision in the context of an advisory or borderline device performance and patient, device, and implanter factors that predict adverse outcome may assist in clinical decision-making. METHODS AND RESULTS: In a prospective, multicenter, population-based registry of all ICD patients at 18 centers in Ontario, Canada, we examined 45-day complication and all-cause mortality rates from February 2007 to August 2009 in patients undergoing ICD generator replacement. Complications were determined longitudinally and were categorized as major or minor. ICD replacement was performed in 1081 of 5176 patients (20.8%) undergoing ICD implantation (age, 64.3+/-12.7 years; 78.5% men). In patients undergoing ICD replacement, 47 patients (4.3%) had a complication within 45 days, with 47 major complications in 28 patients (2.6%), most commonly infection (n=23), lead revision (n=35), electrical storm (n=14), and pulmonary edema (n=13). Minor complications occurred in 2.3% of patients, most commonly incisional infection (n=10) and pocket hematoma (n=10). On multivariable analysis, risk factors associated with major complications were Canadian Cardiovascular Society angina class (adjusted hazard ratio [HR], 3.70 for class 2 to 4 versus 0 to 1; P=0.027) and multiple previous procedures on the pocket (adjusted HR, 3.35 for >1 versus 1; P=0.058). Risk factors associated with any complication were the use of antiarrhythmic therapy (adjusted HR, 6.29; P=0.001), implanter volume (adjusted HR 10.4 for <60/y versus >120/y, P=0.026), and Canadian Cardiovascular Society angina class (adjusted HR, 3.00 for class 2 to 4 versus 0 to 1; P=0.031). In a Cox model with a time-dependent variable of major complication within 45 days after replacement, major complications after ICD replacement were associated with an increased risk of mortality at 45, 90, and 180 days (adjusted HR, 9.61, 12.69, and 6.41, respectively; P=0.002 to 0.039). CONCLUSIONS: Risk factors associated with complications after ICD replacement include the presence of angina, antiarrhythmic therapy, increased number of previous procedures, and low implanter volume. Major complications may be associated with increased risk of subsequent mortality. PMID- 21325212 TI - Pleomorphic ventricular tachycardia and risk for sudden cardiac death. PMID- 21325213 TI - Using floating atrial electrodes to combat the rising tide of inappropriate defibrillator therapies. PMID- 21325214 TI - Wolff-Parkinson-White syndrome and isoproterenol testing in children: a valid adjunct to predict risk? PMID- 21325215 TI - Ablation of ventricular tachycardia in chronic chagasic cardiomyopathy with giant basal aneurysm: Carto sound, CT, and MRI merge. PMID- 21325216 TI - Left ventricular perforation during cooled-tip radiofrequency ablation for ischemic ventricular tachycardia. PMID- 21325217 TI - T cell costimulation blockade and organ transplantation: a change of philosophy for transplant immunologists? PMID- 21325218 TI - Pillars article: long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature. 1996. 381: 434-438. 1996. PMID- 21325219 TI - Functional characteristics of the high affinity IgG receptor, FcgammaRI. AB - IgG FcRs are important mediators of immunity and play a key role during Ab-based immunotherapy. Within the leukocyte IgG receptor family, only FcgammaRI is capable of IgG binding with high affinity. FcgammaRI exists as a complex of a ligand binding alpha-chain and an FcR gamma-chain. The receptors' alpha-chain can, furthermore, elicit several functions independent of the ITAM-bearing FcR gamma-chain. Functional implications of high-affinity IgG binding and mechanisms underlying FcR gamma-chain-independent signaling remain unclear to this day. In this paper, we provide an overview of past literature on FcgammaRI and address the implications of recently described interactions between cytosolic proteins and the FcgammaRI alpha-chain, as well as cytokine-enhanced FcgammaRI immune complex binding. Furthermore, an analysis of potential polymorphisms within the FCGR1A gene is provided. PMID- 21325220 TI - Why the phylogenetic regression appears robust to tree misspecification. AB - The phylogenetic comparative method uses estimates of evolutionary relationships to explicitly model the covariance structure of interspecific data. By accounting for common ancestry, the coevolution between 2 or more traits, as a response to one another or to environmental variables, can be studied without confounding similarities due to identity by descent. Because the true phylogeny is unknowable, an estimate must be used, introducing a source of error into phylogenetic comparative analysis that can be difficult to quantify. This manuscript aims to elucidate how tree misspecification is propagated through a comparative analysis. I focus on the phylogenetic regression under a Brownian motion model of evolution and consider the effect of local phylogenetic perturbations on the regression fit. Motivated by Felsenstein's method of independent contrasts, I derive a matrix square root of the phylogenetic covariance matrix that has an obvious phylogenetic interpretation. I use this result to transform the perturbed phylogenetic regression model into an ordinary linear regression in which one interpretable point has been affected. The simplicity of this formulation allows the contributions of data and phylogeny to be disentangled when studying the effect of tree misspecification. Consequentially, I find that branch length misspecification can be easily explained in terms of the reweighting of contrast scores between subtrees. An analytical consideration of this and other perturbations helps to explain why the phylogenetic regression appears generally to be robust to tree misspecification, and I am able to identify conditions under which the regression may not yield robust results. I discuss why soft polytomies do not meet these problematic conditions, leading to the conclusion that unresolved bifurcations should have only modest effects on the regression fit. PMID- 21325221 TI - Housing and egg safety review ignores best available science on Salmonella risk. PMID- 21325223 TI - Characterization of gas emissions from a Mediterranean broiler farm. AB - Gas emissions from broiler production have been the subject of intensive research. However, little experimental information exists for farms under the particular management and environmental conditions of the European Mediterranean area. In this study, ammonia, carbon dioxide, methane, and nitrous oxide concentrations and emissions were measured in a commercial broiler farm located in Spain. Gas concentrations were measured using a photoacoustic gas monitor, whereas the ventilation flow was evaluated by controlling the operation status of each fan. Two rearing periods were studied, one in summer and one in winter. All gas emissions increased with bird age. Ammonia emission rates averaged 19.7 and 18.1 mg/h per bird in the summer and winter, respectively, and increased with indoor temperature (r(2) = 0.51 in summer; r(2) = 0.42 in winter). Average CO(2) emission rates were 3.84 and 4.06 g/h per bird, CH(4) emission was 0.44 and 1.87 mg/h per bird, and N(2)O emission was 1.74 and 2.13 mg/h per bird in summer and winter, respectively. A sinusoidal daily variation pattern was observed in all emissions except for CH(4). These patterns were characterized in terms of time of maximum emission and amplitude of the daily variation. PMID- 21325224 TI - Production performance and nitrogen flow of Shaver White layers housed in enriched or conventional cage systems. AB - Despite the large number of studies examining the impact of cage systems on Ca and P nutrition, data are limited on the N balance of hens when housed under different systems. To this end, an experiment was conducted to assess N balance, manure characteristics, and indices of the performance of laying hens housed in 2 distinct caging systems. A total of 4,836 commercial Shaver White hens were housed in either enriched (EC) or conventional (CC) cages (average floor space per bird of 643 and 468 cm(2), respectively) under semicontrolled environmental conditions. Enriched cages provided hens with a curtained nesting area, scratch pad, and perches. Birds in both systems were phase fed similar layer diets for 11 periods (4 wk each). Data, expressed on a hen basis, were analyzed as repeated measures using the mixed model procedure of SAS. Lower feed disappearance (P < 0.01; 92.5 vs. 95.0 +/- 0.6 g/d, DM basis) and manure output (P < 0.01; 79.8 vs. 91.3 +/- 1.2 g/d, as-is basis, and 27.0 vs. 28.1 +/- 0.2 g/d, DM basis) were observed in birds housed in EC compared with CC, respectively. Manure DM was 34.1 and 31.0 +/- 0.3% for EC and CC, respectively. Egg production, feed conversion ratio, BW, egg weight, and egg mass were not significantly different between the 2 systems. Overall egg N output decreased with age for both cage systems and was not significantly different between the systems. Although no difference was observed in the overall manure N excretion (1.94 and 1.96 +/- 0.02 g/d for EC and CC, respectively), hens housed in CC had a significantly (P < 0.05) higher N balance compared with those in the EC system (85.0 vs. 30.2 +/- 13.6 mg/d, respectively), which could potentially be explained by a higher (P < 0.05) manure N excretion in the EC at the later stages of production. The current data provide estimates of the efficiency of N utilization in laying hens housed under different housing conditions. PMID- 21325225 TI - Examinations on the prevalence of footpad lesions and breast skin lesions in British United Turkeys Big 6 fattening turkeys in Germany. Part I: prevalence of footpad lesions. AB - The present study demonstrates the prevalence of footpad lesions in turkeys and their level of expression in both live birds and in carcasses. In clinical investigations of 11,860 turkeys (5,740 males, 6,120 females) of the strain British United Turkeys Big 6, individuals of all the observed flocks showed alterations to the plantar skin. In general, the degree and severity of skin alterations were higher in the 16th week of life than in the 6th or 11th week of life. Epithelial necrosis, however, was already apparent in about 45% of individuals in the 6th week of life. At this point, deep lesions on the footpad surface were still rare findings. In the 11th week of life, such skin changes were apparent in 14.7% of males and 25.7% of hens. In general, the feet of male turkeys were less affected by footpad damage than those of females in the subsequent fattening period. In hens, the prevalence of lesions of the footpads at wk 16 of age was 60.0%, almost twice as high as in males of the same age group (33.8%). A comparison of the findings from the right and left feet showed that the state of the 2 extremities was correlated (Spearman correlation: r = 0.830). During the visual inspection of 16,200 slaughtered turkeys (7,800 males, 8,400 hens), almost all carcasses studied showed alterations to the footpad skin. Only 2.1% of males and 0.6% of females were without lesions. The most frequently observed lesions measured up to 2 cm in diameter (males: 59.2%; hens: 57.7%). Pronounced skin lesions of the footpad (males: 21.1%; females: 29.5%) and necrosis of the superficial epithelium (males: 17.5%; females: 12.1%) were less common. Foot abscesses were diagnosed only sporadically (males: 0.1%; females: 0.1%). PMID- 21325226 TI - Effect of lactic acid bacteria probiotic culture for the treatment of Salmonella enterica serovar Heidelberg in neonatal broiler chickens and turkey poults. AB - In the present study, a series of experiments was conducted to evaluate the ability of a commercial probiotic culture (FloraMax, IVS-Wynco LLC, Springdale, AR) to reduce Salmonella enterica serovar Heidelberg (SH) in chicks and turkey poults. In experiments 1 and 2, chicks were randomly assigned to treatment groups and then challenged via oral gavage with SH. Chicks were treated 1 h following SH challenge with the probiotic culture via oral gavage. At 24 and 72 h posttreatment, cecal tonsils and ceca were collected for recovery and enumeration of enteric Salmonella Heidelberg, respectively. In experiment 3, day-of-hatch turkeys were randomly assigned to treatment groups and then challenged via oral gavage with SH. Poults were treated 1 h following challenge with the probiotic via oral gavage. At 24 and 72 h post probiotic treatment, cecal tonsils and ceca were collected for recovery and enumeration of enteric SH, respectively. The probiotic culture significantly reduced the incidence of SH in cecal tonsils at both time points in chicks in both experiments (P < 0.05). These data demonstrate that administration of probiotic 1 h post SH challenge significantly reduced the incidence of SH recovery from cecal tonsils of chicks compared with controls 24 and 72 h following treatment. Similarly, probiotic treatment resulted in significant reductions in the concentrations of SH within the ceca in both experiments. Although similar significant results were observed at both 24 and 72 h in experiment 3, it was clear that poults were more susceptible to SH colonization than chicks. Overall, a Lactobacillus-based probiotic significantly reduced Salmonella enterica serovar Heidelberg in chicks and turkey poults. PMID- 21325227 TI - Effects of dietary polyphenol-rich grape products on intestinal microflora and gut morphology in broiler chicks. AB - Grapes have high amounts of phenolic compounds, which can modulate the gut activity as well as modify the structure and function of the gastrointestinal tract. The microbiological activity of avoparcin, grape pomace concentrate, and grape seed extract was evaluated in an in vitro study. An in vivo experiment was also conducted to study the effect of the inclusion of grape pomace concentrate and grape seed extract in the diet of broiler chicks on performance, intestinal microflora (by cultured and terminal restriction fragment length polymorphism methodology), and gut morphology at 21 d of age. Dietary treatments included an antibiotic-free diet (CON), a positive control (AVP; 50 mg/kg of avoparcin), and antibiotic-free diets containing grape pomace concentrate (GPC; 60 g/kg) or grape seed extract (GSE; 7.2 g/kg). Performance was not affected by dietary treatment except in the case of birds fed the GSE diet, which showed decreased weight gain. In the ileal content, birds fed CON and GSE diets had the highest populations of Lactobacillus. Compared with the CON diet, the AVP, GPC, and GSE diets increased the populations of Enterococcus and decreased the counts of Clostridium in the ileal content. In the cecal digesta, birds fed GPC and GSE diets had higher populations of Escherichia coli, Lactobacillus, Enterococcus, and Clostridium than birds in any other treatment group. Animals fed GPC and GSE diets showed a higher biodiversity degree than those fed control diets. The frequency of detection of several potential phenol-degrading bacteria as well as unidentified and uncultured organisms was increased in animals fed GPC and GSE diets. Birds fed the CON diet had longer villi and deeper crypt depth than birds in any other treatment group. The highest villi height:crypt depth ratio corresponded to birds fed GPC and AVP diets and the lowest to those fed CON and GSE diets. In conclusion, dietary polyphenol-rich grape products modify the gut morphology and intestinal microflora and increase the biodiversity degree of intestinal bacteria in broiler chicks. PMID- 21325228 TI - Comparison of corn-based and Canadian pearl millet-based diets on performance, digestibility, villus morphology, and digestive microbial populations in broiler chickens. AB - A study was undertaken to examine the effects of partially or totally replacing corn with pearl millet in broiler diets on growth performance, jejunal digesta viscosity, and histomorphological parameters, ileal CP digestibility, and cecal microbial populations. Two hundred 1-d-old male Ross 508 broilers were randomly assigned to 1 of 5 isonitrogenous and isocaloric dietary treatments (8 cage replicates; 5 birds/cage) and grown over a 42-d experimental period. Dietary treatments included a standard corn-soybean meal diet and one in which the total amount of grain (corn + pearl millet) consisted of 25, 50, 75, or 100% pearl millet. All diets contained chromic oxide (0.4%) as an indigestible marker. Body weight and feed intake were recorded weekly throughout 42 d. At d 14, 28, and 42, 8 birds/treatment (1 bird/cage) were killed for sample collection and analysis. In comparison with corn, pearl millet grain contained higher CP (14.48 vs. 7.35%, on a DM basis) but slightly lower ME (3,093 vs. 3,355 kcal/kg, on a DM basis). Total replacement of corn by pearl millet significantly (P < 0.05) improved BW and feed conversion. Moreover, in comparison with the standard diet, feeding broilers pearl millet-based diets had no detrimental effects on digesta viscosity, villus height, villus width, and villus surface area of the jejunum. Ileal CP digestibility and cecal concentrations of Escherichia coli, lactobacilli, and bifidobacteria were also similar between birds fed corn and pearl millet. It was concluded that substituting corn for pearl millet in broiler diets can improve production responses without causing any adverse effects on nutrient digestibility or bird health. PMID- 21325229 TI - Influence of whole corn feeding on the performance, digestive tract development, and nutrient retention of geese. AB - The objective of the current study was to investigate the influence of including whole corn (WC) in goose diets on the performance, digestive tract development, and nutrient retention. A total of 112 Yangzhou geese, 7 d old and with similar BW, were distributed into 8 pens of 14 birds/pen (7 male, 7 female). Each treatment was represented by 4 replicates. Geese were fed corn-soybean-based diets containing 640 g (8-28 d) and 615 g (29-70 d) of corn/kg of diet from 8 to 70 d of age, and 2 particle sizes of corn grains were used: ground corn (GC) and WC. During the period from 8 to 49 d, daily feed intake (P < 0.05) and daily weight gain (P = 0.054) of WC-fed birds tended to be lower than that of GC-fed birds. However, WC diet tended to improve (P = 0.07) G:F from 50 to 70 d of age. Higher relative weights of the gizzard (P < 0.05) at 28, 49, and 70 d, proventriculus at 49 d, and duodenum at 28 and 70 d of age were observed in birds fed the WC diet compared with those fed the GC diet. Intestinal wall thickness in the jejunum and crypt depth and intestinal wall thickness in the ileum were greater (P < 0.05) in WC-fed birds at 28 d of age. Villus height and intestinal wall thickness in the duodenum and villus height in the jejunum were greater in birds fed the WC diet compared with those fed the GC diet at 70 d of age, and birds fed the WC diet had a greater (P < 0.05) intestinal wall thickness, villus height, and crypt depth measurements in the ileum compared with those fed the GC diet. The retention ratio of CP and neutral detergent fiber were higher (P < 0.05) in birds fed the WC diet than in those fed the GC diet. Overall, no negative effect was observed in birds fed the WC diet compared with those maintained on the GC diet. PMID- 21325230 TI - Effects of protein level and digestibility on the growth and carcass characteristics of broiler chickens. AB - A study was conducted to evaluate the effects of dietary protein level and protein digestibility on the growth performance and carcass characteristics of broilers from 1 to 35 d of age. Broiler chickens (n = 320) were fed 4 different ideal protein-balanced, isocaloric diets in a 2 * 2 factorial design with 2 levels of protein [high protein (HiPro; 20 and 18% or 200 and 180 g/kg) and low protein (LoPro; 18 and 16% or 180 and 160 g/kg) on d 1 to 14 and d 15 to 35, respectively] and 2 levels of protein digestibility [high digestibility (HiDig) and low digestibility (LoDig); approximately 85% and 80% CP digestibility, respectively]. The HiDig diets were formulated using soybean meal and fishmeal, whereas the LoDig diets used wheat distillers dried grains with solubles and meat and bone meal as the primary protein sources. The standardized ileal digestibility (SID) values of the wheat distillers dried grains with solubles and meat and bone meal (56.5 and 72.0% SID for lysine, respectively) were measured before the experiment to improve the accuracy of the diet formulations. During the starter phase, the interaction was significant for ADG; birds fed the LoPro LoDig diet grew slower than birds fed the other 3 diets (P < 0.05). During the grower phase, the interaction was significant for ADFI; birds fed the LoPro-LoDig diet had the lowest ADFI compared with those fed the other 3 diets. The interaction between protein level and digestibility was significant for the SID of most of the AA and was significantly higher for birds fed the HiPro-HiDig diet compared with those fed the other 3 diets. Total breast meat yield was significantly higher in birds fed the HiPro diets than in those fed the LoPro diets, whereas birds fed the HiDig diets had significantly more abdominal fat than those fed the LoDig diets. The results suggest that low-protein diets can support growth performance equal to high-protein diets when highly digestible ingredients are used. However, maximum breast meat yield requires a high-protein diet and is not affected by ingredient digestibility. PMID- 21325231 TI - Phytase supplementation improved growth performance and bone characteristics in broilers fed varying levels of dietary calcium. AB - An experiment was conducted to investigate the effect of dietary Ca level on the efficacy of phytase. A total of 288 male Ross * Ross 708 broilers with initial and final BW of 37 and 705 g, respectively, were used in brooder batteries from 0 to 21 d posthatch. Each treatment had 8 replications with 6 broilers/replicate pen. All diets were corn-soybean meal based and formulated to contain 1.26% total Lys. The treatments were positive control with 0.45% nonphytate P and 1% Ca and a negative control with 0.20% nonphytate P with 0.67, 1.00, or 1.33% Ca fed with or without 500 phytase units of Optiphos (Escherichia coli-derived phytase; JBS United Inc., Sheridan, IN). Increasing Ca from 0.67 to 1.33% linearly decreased (P <= 0.003) ADG, ADFI, bone breaking strength, bone weight, tibia ash weight, and percentage tibia ash; however, quadratic effects were found for ADFI, G:F, percentage tibia ash, and mortality (P <= 0.09). Phytase supplementation increased (P < 0.001) ADG, ADFI, bone breaking strength, bone weight, ash weight, and percentage tibia ash and decreased (P = 0.054) mortality. The increase in ADG, ADFI, bone weight, ash weight, and percentage tibia ash (P <= 0.026) and decrease in mortality (phytase * Ca linear; P = 0.058) from phytase supplementation was greater in broilers fed the higher levels of Ca. Calcium utilization was linearly decreased (P < 0.002) with increasing Ca. Phosphorus digestibility and utilization were increased with increasing levels of Ca (P <= 0.002); however, P utilization decreased at 1% Ca and increased at 1.33% (quadratic; P < 0.070). Phytase supplementation increased Ca utilization (P < 0.024), P digestibility (P < 0.001), and P utilization (P < 0.029). However, the increase in P digestibility (phytase * Ca; P < 0.021) was greater at the lower levels of Ca whereas P utilization (phytase * Ca; P < 0.001) was greater at 1.33% Ca with phytase supplementation. The results of this research indicate that dietary Ca level, within the ranges used in this experiment, does not negatively affect the efficacy of phytase. PMID- 21325232 TI - Isolation and characterization of duck embryonic neural stem and progenitor cells. AB - Both embryonic and adult neural stem cells (NSC) of rodents and humans have been isolated and cultured in vitro to date, and they are thought to have tremendous clinical promise in restoring the diseased or injured central nervous system. However, there are few counterpart reports on neural stem cells from birds. This study explored the isolation and culture system of duck neural stem and progenitor cells (NSPC) and investigated their major biological properties. Cells from the dorsal ventricular ridges of 10- to 13-d embryos were isolated, cultured, and purified by using a neurosphere assay. Growth kinetics and karyotype were analyzed. The differentiation potential of NSPC was detected by immunofluorescence. Apoptosis and acetylation level of histone 4 lysine 12 (H4K12) were assessed. Results indicated that the nestin-positive neurospheres derived from duck embryos were able to self-renew and differentiate into neurons, astrocytes, and oligodendrocytes, and were prone to be transfected with exogenous genes. Karyotype analysis showed that 95% (38 out of 40) of cells of the population were diploid. Apoptosis detection indicated that the apoptotic rate was elevated with increasing passage number and culture time. The cells were highly acetylated and exhibited typical NSPC properties. Efficiently transfected with fluorescent genes, they were available for gene therapy and suitable for research on intracellular distribution of proteins of interest. PMID- 21325233 TI - Regulation of anion transport across the uterine epithelium of Gallus domesticus. AB - For egg shell production, cations, primarily Ca(2+), and anions, primarily HCO(3)(-), must be secreted across the uterine epithelium. Because alterations of HCO(3)(-) transport influence Ca(2+) secretion, the present study was performed to gain insight into the regulation of anion transport (i.e., chloride and HCO(3)(-) transport) across the egg shell gland of the domestic chicken. To this purpose, unstripped uterus epithelia were mounted in modified Ussing chambers and electrogenic [i.e., short circuit current (I(sc))] and electroneutral anion transport were measured. Stimulating adenylate cyclases by forskolin, thereby enhancing the intracellular cyclic adenosine monophosphate( )(cAMP) concentration, evoked 2 patterns of I(sc) responses. Under HCO(3)(-)-buffered conditions, some of the tissues (3/8) showed an increase of I(sc), whereas in others (5/8) a decrease of I(sc) was observed in the presence of the drug. The I(sc) increase existed in HCO(3)(-) secretion because under HCO(3)(-)-free conditions forskolin stimulated only an I(sc) decrease. In addition, methazolamide, a blocker of carboanhydrases, significantly reduced baseline I(sc). The forskolin-induced decrease of I(sc) presented a Cl(-) absorption. In the absence of HCO(3)(-), forskolin yielded only an I(sc) decrease and the transepithelial flux of (36)Cl(-) was reduced. In the presence of mucosal 5-nitro 2-(3-phenylpropylamino) benzoic acid, a nonselective blocker of chloride channels, forskolin-induced I(sc) decrease was inhibited. In addition to cAMP, the regulatory influence of neurons or prostaglandins on baseline I(sc) and anion transport was investigated. Neither tetrodotoxin, a blocker of neuronal Na(+) conductances, electrical field stimulation, nor indomethacin, a blocker of cyclooxygenases, influenced the baseline I(sc) or anion transport. In summary, these data show effects of forskolin (i.e., cAMP) on anion transport across the egg shell gland of the domestic chicken: HCO(3)(-) secretion (supporting Ca(2+) mineralizing of the egg shell) and Cl(-) absorption. Neurons or prostaglandins did not influence the anion transport. PMID- 21325234 TI - High eggshell temperatures during incubation decrease growth performance and increase the incidence of ascites in broiler chickens. AB - High eggshell temperatures (EST; >=38.9 degrees C) during the second half of incubation are known to decrease the body and organ development of broiler hatchlings. In particular, relative heart weights are decreased by a high EST, and this may increase the incidence of metabolic disorders that are associated with cardiovascular development, such as ascites. The current study investigated the effects of a high EST on chick quality, subsequent performance, and the incidence of ascites later in life. Eggs were incubated at a normal (37.8 degrees C) or high (38.9 degrees C) EST from d 7 of incubation onward. After hatching, the chickens were housed per EST in pens, and a normal or cold temperature schedule was applied during the grow-out period. Hatchability, hatchling quality, BW, feed conversion ratio, total mortality, mortality associated with ascites, slaughter characteristics, and ascites susceptibility at 6 wk of age were evaluated. Except for total ventricle weight, no interaction was found between EST and the grow-out temperature. Hatchability was comparable between the EST treatments, but the percentage of second-grade chickens was 0.7% higher at the high EST. Yolk-free body mass was 3.0 g lower, and heart weights were 26% lower at hatch in the high compared with the normal EST treatment. Body weight continued to be less during the grow-out period after the high EST incubation. However, breast meat yield was 1.0% higher in the high than in the normal EST. Feed conversion ratio did not differ between EST treatments. Total mortality was 4.1% higher and mortality associated with ascites was 3.8% higher in the high compared with the normal EST treatment. The ratio between the right and total ventricle was 1.1% higher in the high compared with the normal EST treatment at slaughter age. In conclusion, a high EST from d 7 of incubation onward decreased hatchling quality and growth performance, but increased breast meat yield. Furthermore, high EST incubation increased the incidence of ascites, which may be related to the reduced heart development at hatch. PMID- 21325235 TI - Improvement of cold resistance and performance of broilers by acute cold exposure during late embryogenesis. AB - The aim of this study was to fine-tune previous acute cold exposure treatments of broiler embryos during late embryogenesis to improve lifelong cold resistance and performance. Six hundred Cobb hatching eggs were incubated under standard conditions and then exposed to 3 treatments: control; cold treatment in which embryos were exposed to 15 degrees C for 30 min on d 18 and 19 of incubation (30 * 2); and cold treatment similar to 30 * 2 but with 60-min exposures (60 * 2). Egg shell temperature (T(egg)) and heart rate (HR) were monitored pre- and posttreatment. Upon hatching, hatchability, body weight, and body temperature were recorded. From 14 to 35 d of age, three quarters of the chickens in each treatment were raised under ascites-inducing conditions (AIC) and the remaining birds were raised under standard brooding conditions (SBC). The T(egg) and HR decreased significantly in response to increased exposure time on d 18 of incubation. On d 19 of incubation, before the second cold exposure, the 30 * 2 group showed greater T(egg) and HR than the controls, and during the second exposure they maintained these parameters better than the 60 * 2 embryos. No treatment effect on hatchability was observed. At 35 d of age ascites incidence among 30 * 2 chickens under AIC was significantly less than that among the controls (P < 0.01), and body weight of these chickens under either SBC or AIC was significantly higher than that of the controls. Under SBC relative breast muscle weight was significantly higher in 60 * 2 chickens, whereas the relative heart weight was higher in both cold-treated groups than in the controls. It can be concluded that repeated short acute cold exposures during late embryogenesis significantly reduced ascites incidence and improved growth rate under either SBC or AIC. These results may be related to a prenatal epigenetic adaptation of the thermoregulatory and cardiovascular systems to low ambient temperature. PMID- 21325236 TI - Calcitonin receptor bindings in the hen hypothalamus before and after oviposition. AB - To demonstrate the presence of a receptor for calcitonin (CT) in the hen hypothalamus and to determine when CT acts on this tissue during the oviposition cycle, bindings of (125)I labeled CT in the plasma membrane fraction of the hen hypothalamus were measured by radioligand binding assay. The specific CT binding component in the plasma membrane fraction of the hypothalamus containing the preoptic area (HPOA) possessed properties of a receptor: binding specificity to CT, saturable binding, high affinity, and limited capacity. As for the median eminence area, no specific binding component was found in the present study. Therefore, the binding component for CT in the plasma membrane fraction of HPOA is likely to be a receptor for CT. In laying hens, the binding affinity of CT receptor increased at 30 min before oviposition and the binding capacity was decreased at 30 min before oviposition but not changed in nonlaying hens during a 24-h period. These results suggest that the action of CT on the hen HPOA may increase 30 min before oviposition. PMID- 21325237 TI - Comparison of effects of hypoxia on glutathione and activities of related enzymes in livers of Tibet chicken and Silky chicken. AB - The Tibet chicken originates from the Qinghai-Tibet Plateau and has adapted well to hypoxia, whereas the Silky chicken is a lowland chicken breed from an area with an altitude of 750 m. The objective of the present study was to investigate whether differences exist in glutathione and related metabolism between the Tibet chicken and the Silky chicken when birds were housed in a normoxic or hypoxic chamber for 20 h. Activities of glutathione peroxidase, glutathione S transferase, and glutathione reductase and levels of glutathione were determined spectrophotometrically. Under normoxia conditions and moderate hypoxia (14% oxygen concentration) conditions, no differences were found in levels of total glutathione, reduced glutathione (GSH), disulfide-oxidized glutathione (GSSG), the GSH:GSSG ratio, and activities of glutathione peroxidase and glutathione S transferase between the Tibet chicken and the Silky chicken. Under extreme hypoxia conditions (14% oxygen concentration for 14 h and then 10.5% oxygen concentration for 6 h), values for the GSH content, the GSH:GSSG ratio, and the activity of glutathione reductase in the liver of the Tibet chicken were higher than those of the Silky chicken. The results indicate that the Tibet chicken responded better than the Silky chicken to oxidative stress in extreme hypoxia through glutathione enzymes of detoxification. This work provides reference for future studies on the association of glutathione metabolism with the adaptation to hypoxia. PMID- 21325238 TI - Influence of rearing system on growth performance, carcass traits, and meat quality of Yangzhou geese. AB - An experiment was conducted using a total of 540 one-day-old Yangzhou geese to study the effect of rearing system on growth performance, carcass traits, and meat quality of male and female Yangzhou geese. The birds were divided into homogeneous groups according to initial BW and sex. The male and female geese were raised in separate pens under 5 different treatments, with 3 replicate pens of 18 male or 18 female geese per pen for each treatment. This experiment included 2 stages, with geese at 1 to 28 d of age (the first stage) and 29 to 70 d of age (the second stage). The 5 different treatments were 1) system A (geese raised on a wire floor), 2) system B (geese raised on the floor), 3) system C (geese raised on the floor and transferred to to a wire floor), 4) system D (geese raised on a wire floor and transferred to the floor), and 5) system E (geese raised on the floor and transferred to a free range). Results showed that feed conversion rate, BW, and BW gain were significantly affected by rearing system and sex (P < 0.05). For carcass yield, results suggested that eviscerated carcass yield and heart yield were affected by rearing system (P < 0.05) but not by sex (P > 0.05). Differences between sexes, but not rearing systems, were observed for only breast yield, thigh yield, and liver yield (P < 0.05). Rearing system and sex had a remarkable effect (P < 0.05) on subcutaneous fat thickness, abdominal fat yield, and gizzard yield. The nutrient composition (water, protein, and fat), water-holding capacity, shear force, and pH of the pectoralis major muscle were not affected (P > 0.05) by the rearing system, and only water, protein, and pH of the meat were affected by sex (P < 0.05). This study indicates that rearing system A, in which Yangzhou geese were raised on a wire floor, improved growth performance but had little effect on meat quality, implying that the use of rearing system A, using a wire floor, might be feasible and effective for Yangzhou geese. PMID- 21325239 TI - Validation of a real-time polymerase chain reaction assay for the detection of Salmonella in crops of broiler chickens. AB - Salmonella is one of the frequent causes of bacterial foodborne diseases with major public health impact in industrialized countries. Food-producing animals, in particular poultry, are major sources of human salmonellosis. Salmonella is normally found in the gastrointestinal tract of animals and can contaminate the carcass during the slaughtering process. In poultry, crops are also colonized by this pathogen. Crops are more likely to get ruptured during evisceration and contaminate the carcass and therefore present a health risk to consumers. Reducing Salmonella colonization in crops could decrease carcass contamination and is considered a potential preharvest critical control point in poultry production. Furthermore, rapid and reliable diagnostic methods to detect Salmonella are needed to monitor crop colonization to help ensure food safety. However, detection of Salmonella by bacteriological methods is time consuming and labor intensive and is not suitable for routine screening of a large number of samples. Therefore, this study was undertaken to validate a real-time PCR (RPCR) assay for the detection of Salmonella spp. in crop samples of broiler chickens. In total, 997 crop samples (35 spiked, 962 field) were processed by both RPCR and culture. The RPCR correctly identified all spiked crop samples. Out of 962 field crop samples, 100 tested positive by RPCR and 88 tested positive by culture for Salmonella, giving a sample level prevalence of 10.4 % (95% CI: 8.54 to 12.50%) and 9.1% (95% CI: 7.40 to 11.15%), respectively. The agreement beyond chance between RPCR and culture was 92% (P < 0.001) and 100% (P < 0.001) for field and spiked samples, respectively. Compared with culture, the sensitivity and specificity of RPCR were 98.86 and 98.51% for field samples and 100 and 100% for spiked samples, respectively. Where bacterial speciation is required, only the positive samples would be cultured. Therefore, RPCR can be used as a good screening tool for Salmonella spp. in crops by eliminating the time-consuming and labor-intensive culture of negative samples. PMID- 21325240 TI - Effect of dietary garlic powder on layer performance, fecal bacterial load, and egg quality. AB - This study was conducted to investigate the potential of garlic powder (GP) in improving production efficiency, egg quality, and gut health of laying hens. A total of seventy-two 30-wk-old Dekalb white strain hens were used. The live weight of the hens ranged between 1.71 and 2.12 kg. Hens were randomly allotted into 3 dietary treatment groups in a complete randomized design experiment. The 3 dietary treatments were control (no garlic addition) and 3 and 5% GP additions to a basal diet on weight:weight ratio basis. Egg production and feed consumption were recorded daily, and hen BW and internal quality of fresh eggs were assessed weekly. Fecal samples were assessed for total bacterial load. The results from this study revealed significant (P < 0.05) increases of 0.81 mm in albumen height and 2.71 Haugh units of fresh eggs at 3% GP addition. Egg and albumen weights increased significantly (P < 0.05) by 2.06 and 1.84 g, respectively, at 5% GP over the control treatment. Egg production decreased significantly at 5% GP following a decrease in feed consumption. Similarly, log bacterial count in feces showed a dose-dependent reduction as dietary GP increased. Organoleptic evaluation of eggs from treatment birds revealed a strong garlic flavor in eggs from 5% GP group compared with the control and 3% GP groups. Results of this study suggest that dietary GP improved egg weight and albumen quality with a strong garlic flavor at high dietary levels. PMID- 21325241 TI - Marination properties and sensory evaluation of breast fillets from air-chilled and immersion-chilled broiler carcasses. AB - The purpose of this study was to evaluate the effect of carcass chilling methods on marination properties, tenderness, sensory attributes, and consumer acceptance of broiler breast fillets. A total of 120 broilers were slaughtered at 6 wk of age. Carcasses were either immersion chilled (in a 2-stage prechill-chill system; IC) or air chilled (AC) and then deboned at 3 h postmortem to allow sufficient chilling time for the AC carcasses. Fillets were tumble marinated in a 16.5% solution (0.75% salt and 0.45% phosphate, final concentration) at 24 h postmortem for 30 min. Weight change attributable to chilling of the ready-to-cook carcasses, marination pickup, marination retention, cook loss, and total loss of raw fillets was measured. Instrumental tenderness of cooked fillets was measured using the Meullenet-Owens razor shear method. Fillets were also evaluated by a consumer sensory panel (n = 72) for texture, flavor, and juiciness, including overall acceptance. During the chilling process, the IC birds had a significantly greater percentage of weight change in the ready-to-cook carcass (3.94%) than did the AC birds (-2.02%). Although carcasses had weight changes caused by the chilling method, chilling method did not affect marination properties, as indicated by no significant differences between treatments in marination pickup and marination retention. However, significant differences were observed in cook loss and total loss in marinated breast fillets, with lower losses in the AC method, whereas nonmarinated fillets from the 2 chilling methods demonstrated similar cook losses and total losses. Tenderness was not affected by chilling method (IC and AC), based on instrumental Meullenet-Owens razor shear values of marinated and nonmarinated breast fillets. Results of consumer testing followed similar trends, showing no significant differences in overall acceptance, texture, and flavor attributes between IC and AC broiler breast fillets regardless of the chilling method. When marinating breast fillets, air chilling had a yield advantage over immersion chilling, as evidenced by the lower cook loss in breast fillets. PMID- 21325242 TI - Influence of dietary nano elemental selenium on growth performance, tissue selenium distribution, meat quality, and glutathione peroxidase activity in Guangxi Yellow chicken. AB - This experiment was designed to investigate the effect of feed supplementation with nano elemental Se (Nano-Se) on growth performance, tissue Se distribution, meat quality, and glutathione peroxidase (GSH-Px) activity in Guangxi Yellow chicken. Four treatments (control, T-1, T-2, and T-3 treatment groups) with 3 replicates of 30 chickens each were carried out. Diets for the control, T-1, T-2, and T-3 groups consisted of the basal diet supplemented with, respectively, 0.00, 0.10, 0.30, and 0.50 mg/kg of Nano-Se. Improved final BW, daily BW gain (DWG), feed conversion ratios, and survival rate (P < 0.05) were observed in the groups supplemented with Nano-Se as compared with the control groups after 90 d of feeding. The groups that received Nano-Se showed higher (P < 0.05) hepatic and muscle Se contents, drip loss percentage, inosine 5'-monophosphate content, and GSH-Px activities in the serum and liver than that did the control groups. For the T-2 and T-3 groups, a significant difference (P < 0.05) was observed in final BW, DWG, muscle Se content, breast drip loss, and GSH-Px activities in the serum and liver compared with the T-1 group. However, no significant differences were observed in final BW, DWG, and GSH-Px activities in the serum and liver between the T-2 and T-3 groups. It could be concluded from this study that supplementing diets with 0.30 mg/kg of Nano-Se for was effective in increasing the growth performance and feed conversion ratios of chickens, the Se content of tissues, and the quality of the meat. PMID- 21325243 TI - Moisture content, processing yield, and surface color of broiler carcasses chilled by water, air, or evaporative air. AB - This study was conducted to investigate the effects of water chilling (WC), air chilling (AC), and evaporative air chilling (EAC) on the moisture content, processing yield, surface color, and visual appearance of broiler carcasses. For the WC treatment, 1 group of birds was hard scalded and submersed into ice slush, whereas for AC, 1 group of birds was soft scalded and exposed to blowing air (1.0 m/s at 0 degrees C) and for EAC, or 1 group of birds was soft scalded and exposed to blowing air and a cold water spray (every 5 min). During chilling, carcass temperature was reduced most effectively by WC (55 min), followed by EAC (120 min) and AC (155 min). After chilling, both WC and EAC carcasses picked up moisture at 4.6 and 1.0% of their weights, respectively, whereas AC carcasses lost 1.5% of their weight. On cutting at 5 h postmortem, WC carcasses showed the highest (2.5%), EAC showed the second highest (0.4%), and AC showed the least (0.3%) moisture loss. After 24 h of storage, almost 83% of the absorbed water in the WC carcass parts was released as purge, whereas EAC and AC carcasses maintained weights close to the prechilled weights. In an instrumental color evaluation and a visual evaluation by panelists, AC carcasses showed a darker appearance, a more yellow color, and more surface discoloration compared with WC or EAC carcasses. PMID- 21325244 TI - Breast meat quality and consumer sensory properties of broiler carcasses chilled by water, air, or evaporative air. AB - Three poultry chilling methods, namely, water chilling (WC), air chilling (AC), and evaporative air chilling (EAC), were compared to evaluate their effects on broiler breast meat quality and consumer sensory characteristics. A total of 189 birds were processed with 1 of the 3 chilling methods. One-third of the birds were hard scalded (57.7 degrees C, 120 s) and subjected to WC (an ice slurry immersion at 0 degrees C). The remaining birds were soft scalded (50 degrees C, 220 s) and randomly assigned to either AC (blowing air, 1.0 m/s) or EAC (blowing air plus each carcass sprayed with 0.5 L of 0.4 degrees C water) in a chilling room (0.9 +/- 0.4 degrees C). Water chilling reduced the carcass temperature most efficiently (57 min), whereas AC and EAC were the least (125 min) and intermediate (93 min) in efficiency, respectively. No significant difference was found among the chilling methods in moisture content, cooking yield, and shear force of deskinned breast fillets stored overnight. However, the pH (5.6) of 24-h stored fillets was higher in WC fillets than in AC (5.5) and EAC (5.5) fillets. For the surface color of skinless breasts, WC carcasses showed a higher Commission Internationale de l'Eclairage (CIE) L* value than AC or EAC carcasses, whereas AC carcasses exhibited more redness (higher CIE a*) and yellowness (higher CIE b*) than the other 2 chilling methods. When raw breast meat was made into cooked gels, no significant difference was observed in cooking loss, moisture content, shear stress, and shear strain, regardless of the chilling method. In consumer sensory evaluations, AC breasts had a higher juiciness score than did WC and EAC breasts, but no significant difference was found for flavor, texture, and overall acceptability. PMID- 21325245 TI - Melamine residues in eggs of laying hens exposed to melamine-contaminated feed. AB - An experiment was carried out to determine melamine residual levels in eggs by feeding laying hens 200 or 1,000 mg of melamine/kg of diet. Each diet was offered in 3 replicate cages (10 laying hens/cage) from d 1 to 29, followed by a 9-d feeding of a withdrawal diet that contained no melamine. Two eggs were collected from each replicate cage each day for the determination of residual melamine levels after 1 d of feeding. The feeding of melamine resulted in a fast accumulation of melamine in eggs within 3 to 4 d, then maintained 2.00 to 3.88 mg/kg for 200 mg of melamine/kg of diet and 11.09 to 16.46 mg/kg for 1,000 mg of melamine/kg of diet. A withdrawal period of 4.0 d for 1,000 mg of melamine/kg of diet was required based on tolerance values established by the World Health Organization and no withdrawal period was required for 200 mg of melamine/kg of diet. PMID- 21325246 TI - Comparison of logistic and neural network models to fit to the egg production curve of White Leghorn hens. AB - Neural networks are capable of modeling any complex function and can be used in the poultry and animal production areas. The aim of this study was to investigate the possibility of using neural networks on an egg production data set and fitting models to the egg production curve by applying 2 approaches, one using a nonlinear logistic model and the other using 2 artificial neural network models [multilayer perceptron (MLP) and radial basis function]. Two data sets from 2 generations of a White Leghorn strain that had been selected mainly for egg production were used. In the first data set, the mean weekly egg-laying rate was ascertained over a 54-wk egg production period. This data set was used to adjust and test the logistic model and to train and test the neural networks. The second data set, covering 52 wk of egg production, was used to validate the models. The mean absolute deviation, mean square error, and R(2) were used to evaluate the fit of the models. The MLP neural network had the best fit in the test and validation phases. The advantage of using neural networks is that they can be fitted to any kind of data set and do not require model assumptions such as those required in the nonlinear methodology. The results confirm that MLP neural networks can be used as an alternative tool to fit to egg production. The benefits of the MLP are the great flexibility and their lack of a priori assumptions when estimating a noisy nonlinear model. PMID- 21325247 TI - Blood donor well-being: a primary responsibility of blood collection agencies. AB - Current FDA regulations and AABB standards do not adequately protect the well being of blood donors. Several practices have adverse consequences for donors, including: elevated incidence of donation related reactions and injuries, iron deficiency anemia in premenopausal women, and inadequate counseling of donors to obtain medical follow-up for health risks identified during pre-donation health screening. These practices can be improved without impacting negatively on the national blood supply. In addition to revising current blood collection operations, blood centers should explore the feasibility of establishing expanded donor health screening programs and determining their effectiveness in improving donor health, donor recruitment, and donor retention. PMID- 21325248 TI - Diagnostic value of imprint cytology during image-guided core biopsy in improving breast health care. AB - The aim of this study was to investigate the accuracy of imprint cytology (IC) of breast core biopsy under ultrasound guidance and to assess the value of a rapid on-site preliminary diagnosis of breast lesions. A total of 437 breast core needle biopsies under ultrasound guidance with touch imprint cytology, histology, and final diagnosis were reviewed. These cases were collected from archived files at our institution. Of 437 core biopsies, IC classified 241 (55%) as benign; 22 (5%) as probably benign; 28 (6%) as probably malignant; 107 (25%) as malignant; and 39 (9%) as inadequate for IC diagnosis. Histological classifications for the 437 cases were: 285 (65%) benign; 132 (30%) malignant; 16 (4%) atypical hyperplasia; and 4 (1%) inadequate specimen. The overall sensitivity and specificity indices of IC were 95% and 96%, respectively, for benign and probably benign lesions vs malignant and probably malignant breast lesions. The overall positive and negative predictive values were 91% and 97%, respectively. The overall accuracy was 95% (379 of 398 cases, excluding specimens inadequate for IC diagnosis). IC of ultrasound-guided core needle biopsy provides a rapid and reliable preliminary diagnosis for breast lesions; it also serves as a means to verify the adequacy of biopsy specimens and to optimize the biopsy procedure. Use of IC may reduce anxiety in patients with benign lesions and expedite the diagnosis and assessment of treatment options in patients with breast cancer. PMID- 21325249 TI - Role of macrophage migration inhibitory factor in glucocorticoid release and glucocorticoid receptor function in rats. AB - Experimental evidence indicates that macrophage migration inhibitory factor (MIF) plays a pathological role in the development of glucocorticoid resistance in sepsis patients. However, the impact of MIF on glucocorticoid release and the functions of the glucocorticoid receptor (GR) have not been studied extensively. In this study, exogenous administration of recombinant mouse macrophage migration inhibitory factor (rMIF), at a dose close to the levels found in the blood of sepsis patients, significantly enhanced serum corticosterone concentration but neither altered circulatory function nor stimulated nitric oxide (NO) release in rats. Incubation of cultured rat cardiomyocytes with 10 ng/ml and 20 ng/ml of rMIF did not cause changes in GR protein expression compared to control values but significantly decreased the expression of heat shock protein 90. GR specific binding activity was significantly inhibited by incubation of rat hepatocytes with 20 ng/ml rMIF alone or with 100 MUmol/L L-NAME (a NO synthase inhibitor), and no significant difference was found between the two groups. These results suggest that elevated MIF levels in sepsis patients, at least in part, play an important role in the development of glucocorticoid resistance and that the NO signaling pathway is not involved in this pathological process. PMID- 21325250 TI - Evaluation of performance including influence by interfering substances of the Innovance D-dimer assay on the Sysmex coagulation analyzer. AB - D-dimer is formed during activation of the coagulation system and is commonly assayed in order to diagnose disseminated intravascular coagulation, deep vein thrombosis, and pulmonary embolism. Enzyme-linked immunosorbent assay has been validated as the reference method, but it is a time-consuming procedure. The objective of this study was to evaluate a new immunoturbidimetric, particle enhanced, Innovance((r)) D-dimer immunoassay. A total of 129 plasma samples from apparently healthy individuals and 298 samples from patients were collected for linearity, precision, and correlation studies. Testing the precision of low- and high-controls yielded CV values of 2.08% and 1.76%, respectively. The central 95% non-parametric reference interval estimated from healthy controls was 0.093-0.68 mg/L Fibrinogen Equivalent Units (FEU; median, 0.26 mg/L FEU). Comparison analysis yielded acceptable correlation with the STA Liatest((r)) D-dimer assay (R(2) = 0.9471). At a cut-off level of <0.5 mg/L FEU, the sensitivity and specificity indices of the Innovance D-dimer assay were 99.7% and 89.1%, respectively. Thus the Innovance D-dimer method showed acceptable precision and linearity, and the assay results showed acceptable correlation with the STA Liatest D-dimer method. The Innovance method was relatively unaffected by potential interfering substances such as bilirubin and hemoglobin. In conclusion, the Innovance D-dimer assay is suitable for monitoring D-dimer concentrations in various clinical conditions and should be useful in clinical laboratories. PMID- 21325251 TI - Erythropoietin prevents secondary brain injury induced by cortical lesion in mice: possible involvement of Nrf2 signaling pathway. AB - Erythropoietin (EPO) has demonstrated neuroprotective effects against traumatic brain injury (TBI), but the underlying mechanisms remain unclear. The signaling pathway of an antioxidant transcription factor, nuclear factor erythroid 2 related factor 2 (Nrf2), has been shown in our previous studies to play an important role in protecting mice from TBI-induced secondary brain injury. The present study explored the effect of recombinant human erythropoietin (rhEPO) on cerebral activation of the Nrf2 signaling pathway and secondary brain injury in mice after TBI. Adult male ICR mice were randomly divided into three groups: (1) Sham group; (2) TBI group; and (3) TBI+rhEPO group (n = 12 per group). Closed head injury was performed using Hall's weight-dropping method. rhEPO was administered at a dose of 5,000 IU/kg at 30 min after TBI. Brain samples were extracted at 24 hr after the trauma. The treatment with rhEPO markedly up regulated the mRNA expression and activities of Nrf2 and its downstream cytoprotective enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1). Administration of rhEPO also significantly ameliorated the secondary brain injury, as shown by decreased severity of neurological deficit, brain edema, and cortical apoptosis. In summary, post-TBI rhEPO administration induces Nrf2-mediated cytoprotective responses in the injured brain, and this may be a mechanism whereby rhEPO improves the outcome following TBI. PMID- 21325252 TI - A novel capillary electrophoresis-based multiplex PCR assay for detection of respiratory pathogens. AB - The field of infectious disease testing has recently experienced rapid expansion in the number of multiplexed PCR-based assays available for detecting respiratory pathogens. This study provides a preliminary evaluation of a multiplex assay from Seegene that uses capillary electrophoresis as the detection platform for viral and bacterial respiratory pathogens. We compared this technology to a real-time PCR assay for 3 viral targets. Thirty respiratory samples were collected that had previously tested positive for either Flu A, Flu B, or RSV (ten of each). The Seegene assay detected 9/10 Flu A samples, 9/10 Flu B, and 10/10 RSV, for a total detection rate of 93%. The two samples that were undetected by the Seegene assay both generated late-crossing thresholds on the real-time platform, consistent with low viral loads. The Seeplex assay provides a promising alternative for multiplex respiratory testing. PMID- 21325253 TI - Time-kill synergy tests of tigecycline combined with imipenem, amikacin, and ciprofloxacin against clinical isolates of multidrug-resistant Klebsiella pneumoniae and Escherichia coli. AB - This study evaluated the activity of tigecycline combined with imipenem, amikacin, and ciprofloxacin against clinical isolates of multidrug-resistant Klebsiella pneumoniae and Escherichia coli co-producing extended-spectrum beta lactamases and acquired AmpC beta-lactamases. Broth microdilution tests were performed for cefotaxime, ceftazidime, cefepime, imipenem, amikacin, ciprofloxacin, and tigecycline. Time-kill synergy studies were tested for tigecycline plus imipenem, tigecycline plus amikacin, and tigecycline plus ciprofloxacin. Imipenem (MIC(90) = 1 MUg/ml for both K. pneumoniae and E. coli) and tigecycline (MIC(90) = 2 MUg/ml for K. pneumoniae and 1 MUg/ml for E. coli) were the most potent agents. Combination studies with tigecycline plus imipenem resulted in synergy against 18 K. pneumoniae and 3 E. coli isolates; tigecycline plus amikacin yielded synergy against 8 K. pneumoniae and 3 E. coli isolates; tigecycline plus ciprofloxacin yielded synergy against 7 K. pneumoniae and 2 E. coli isolates. No antagonism was observed with any combination. In the present study, imipenem, amikacin, and ciprofloxacin led to indifferent and some synergistic effects in combination with tigecycline, and none of them demonstrated antagonistic effects. PMID- 21325254 TI - Multiplex ligation-dependent probe amplification assay for diagnosis of congenital adrenal hyperplasia. AB - Mutations in the CYP21A2 gene encoding the 21-hydroxylase enzyme account for >90% of congenital adrenal hyperplasia (CAH) cases. Approximately 20% of mutant alleles carrying large deletion/duplication have also been reported. Herein, we describe the use of the multiplex ligation-dependent probe amplification (MLPA) method for convenient and rapid detection of deletions/duplications in the CYP21A2 gene. We used MLPA to analyze the gene dose of CYP21A2 MLPA in 13 Korean patients who previously underwent direct sequencing for the molecular diagnosis of CAH. The MLPA assays identified 5 patients with CYP21A2 deletions; all 5 patients carried a single mutant allele peak in sequence analysis. These results demonstrate the diagnostic usefulness of MLPA to detect CYP21A2 deletions/duplications for diagnosis of CAH. PMID- 21325255 TI - Comparison of HPV genotyping assays and Hybrid Capture 2 for detection of high risk HPV in cervical specimens. AB - High-risk types of human papillomavirus (HR-HPV) are among the primary causes of cervical cancers. Hybrid Capture 2 (HC-II) (Digene, Gaithersburg, MD), which detects 13 HR-HPVs as a group, is the only HPV assay approved to date by the United States Food and Drug Administration. In Korea, several HPV genotyping assays are commercially available, including HPV RFMP (GeneMatrix Co., Seoul), HPVDNACHIP (Biomedlab Co., Seoul), and MyHPV Chip (Mygene Co., Seoul). We compared the results of these assays with those of HC-II. Among 553 residual samples of liquid-based Pap tests, a total of 435 (78.7%) were available for HPV assays. They were classified into four cytologic categories: normal, atypical squamous cells of undetermined significance (ASCUS), low-grade cervical squamous intraepithelial lesions (LSIL), and high grade SIL or carcinoma (HSIL+). Among these samples, 23.0%, 40.6%, 82.5%, 93.8% were HR-HPV positive by HC-II, respectively; 6.6%, 18.1%, 44.4%, 84.4%, by HPV RFMP, respectively; 5.7%, 24.5%, 54.0%, 84.4%, by HPVDNACHIP, respectively; and 6.6%, 11.6%, 42.9%, 84.4%, by MyHPV, respectively. Compared with HC-II, the concordance rates and kappa values were 70.6% and 0.421 for HPV RFMP; 75.4% and 0.514 for HPVDNACHIP; and 67.8% and 0.367 for MyHPV. The concordance rates and kappa values between genotyping assays were 85.1% and 0.644 for HPV RFMP and HPVDNACHIP; 83.4% and 0.574 for HPV RFMP and MyHPV Chip; and 82.8% and 0.579 for HPVDNACHIP and MyHPV Chip. In conclusion, compared with HC-II test, the genotyping tests showed more than fair concordance but lower sensitivity in the detection of HR-HPVs, limiting their usefulness as HR-HPV screening tools. PMID- 21325256 TI - Epidermal growth factor receptor positivity in angiomyolipoma contiguous to renal cell carcinoma: report of two cases with immunohistochemical analysis. AB - Renal cell carcinoma (RCC) and angiomyolipoma (AML), usually unassociated, have occasionally been reported to coexist in the same person, usually in patients with tuberous sclerosis. We report two patients without tuberous sclerosis whose nephrectomy specimens contained renal cell carcinoma directly contiguous to AML in the same kidney. When immunohistochemical staining for epidermal growth factor receptor (EGFR) was performed on the RCCs, an interesting observation was made. The contiguous AMLs demonstrated strong positivity for EGFR, a feature not observed in isolated AMLs. The significance of this finding is unclear. Paracrine regulation may exist between these two closely adjacent tumors leading to synchronous high expression of EGFR in the AML adjacent to RCC, which may in turn affect the biologic behavior of these AMLs, compared to AMLs not associated with RCC. PMID- 21325257 TI - Plasma cell neoplasm in conjunction with glioblastoma of the conus medullaris. AB - We report a plasma cell neoplasm in conjunction with a glioblastoma multiforme (GBM) of the conus medullaris in a 42-year-old man. Glioblastoma is a World Health Organization (WHO) grade IV neoplasm that requires surgical intervention, radiation, and possibly chemotherapy. Astrocytomas of the spinal cord are rare neoplasms, with intramedullary glioblastomas comprising only 1% to 3%. Plasma cell neoplasms result from monoclonal proliferation of mature B cells; they have been reported as a primary malignancy with gliomas arising after treatment. Secondary plasma cell neoplasms arising within glioblastomas have not previously been described. However, there have been reports of glioblastomas related to other plasma cell and hematopoietic diseases such as Waldenstrom's macroglobulinemia and myeloid sarcomas. PMID- 21325258 TI - Acute myeloid leukemia with complex hypodiploidy and loss of heterozygosity of 17p in a boy with Fanconi anemia. AB - Fanconi anemia (FA) is a congenital bone marrow failure syndrome in association with increased susceptibility to malignancy. We report the first in-depth description of a boy with FA who developed acute myeloid leukemia with complex hypodiploidy karyotype after successful stem cell transplantation. Of note, the leukemic cells consistently showed loss of heterozygosity (LOH) of the short arm of chromosome 17 (17p), which harbors the TP53 tumor suppressor gene. The complex hypodiploidy karyotype of the leukemic cells with LOH for 17p may represent a unique karyotypic profile that reflects genomic instability and thereby confers poor prognosis. PMID- 21325259 TI - A novel three-way Ph variant t(8;9;22) in adult acute lymphoblastic leukemia. AB - Although three-way Philadelphia (Ph) variant translocation has been uncommonly (3~8%) reported in chronic myeloid leukemia (CML), it has been even more rarely described in acute leukemias (ALs). When we reviewed the Mitelman database and the literature, we found about 595 three-way Ph variant cases; among these, only 39 three-way Ph variant translocations in AL were documented. Here, we report a novel three-way Ph variant case of t(8;9;22) in adult acute lymphoblastic leukemia (ALL). Based on bone marrow morphology, chromosome fluorescent in situ hybridization (FISH), reverse transcriptase-polymerase chain reaction (RT-PCR), and flow cytometrry, this patient was diagnosed with B lymphoblastic leukemia/lymphoma associated with both t(8;9;22) (q21;q34;q11.2) and BCR/ABL1 rearrangement (e1a2 type). Because of the rarity of reported AL patients with three-way Ph variant, further studies on their prognosis and treatment response to imatinib mesylate are necessary. PMID- 21325260 TI - Therapy-related myelodysplastic syndrome/acute myeloid leukemia with del(7)(q22) in a patient with de novo AML. AB - A 55-year-old Korean woman was initially diagnosed with acute myelomonocytic leukemia (AML). After induction chemotherapy was performed using cytarabine, idarubicin, and G-CSF, complete remission (CR) was subsequently achieved following reinduction chemotherapy using the same chemotherapeutic agents. Thirty six months after the initial CR, an increase in immature cells (up to 12.0%) was observed in the patient's bone marrow. Because chromosome analysis revealed a karyotype of 46,XX,del(7)(q22) in all of the analyzed cells, the patient was diagnosed with therapy-related myelodysplastic syndrome (t-MDS). Although the patient subsequently received chemotherapy and G-CSF for neutropenia, t-MDS rapidly progressed after 3 months to therapy-related acute myeloid leukemia (t AML). Although very rare, de novo AML can progress to a secondary MDS/AML with del(7q) after chemotherapy with cytarabine, idarubicin, and G-CSF. Further investigation into the role of genes located in 7q22 may provide more information about the mechanisms of leukemogenesis. PMID- 21325261 TI - Mutations of ACADS gene associated with short-chain acyl-coenzyme A dehydrogenase deficiency. AB - Short-chain acyl-coenzyme A dehydrogenase deficiency (SCADD) is an autosomal recessive disorder of mitochondrial fatty acid oxidation associated with mutations in the ACADS gene (Acyl-CoA Dehydrogenase, Short-chain, OMIM #606885). SCADD is a heterogeneous condition that has been associated with various clinical phenotypes ranging from fetal metabolic decompensation in infancy to asymptomatic individuals. Here, the first Korean neonate diagnosed with SCADD by biochemical and genetic findings is reported. The patient has remained asymptomatic by avoiding hypoglycemia. An increased concentration of butylcarnitine was detected on newborn screening. Subsequent urine organic acid analysis showed increased urinary excretion of ethylmalonic acid. To confirm the presence of the genetic abnormality, all the coding exons of the ACADS gene and flanking introns were amplified by the polymerase chain reaction (PCR). Sequence analysis of the ACADS gene revealed novel homozygous missence mutations, c. 1031A>G (p.E344G) in exon 9. In summary, the first Korean patient with confirmed SCADD by genetic analysis is reported with novel mutation. PMID- 21325262 TI - A heparin binding site Arg79Cys missense mutation in the SERPINC1 gene in a Korean patient with hereditary antithrombin deficiency. AB - We describe a case of heparin binding site Arg79Cys mutation in the gene encoding antithrombin, SERPINC1, in a Korean patient with hereditary antithrombin (AT) deficiency. The patient was a 34-year-old Korean man who presented with deep vein thrombosis (DVT) in his right leg without precipitating factors. On outpatient evaluation, coagulation tests without anticoagulation revealed a decreased AT III activity level at 48%, but normal AT III antigen level at 103%, indicating type II AT deficiency. Family studies revealed that his father (62 years of age) had decreased AT activity (48%) but had normal AT antigen levels (116%), indicating that the proband had a paternally inherited type II AT deficiency. Direct sequencing of the SERPINC1 gene in the patient and his father revealed a heterozygotic missense mutation, a cytosine to thymine substitution at nucleotide position 235 in exon 2 of the SERPINC1 gene (p.Arg79Cys). To our knowledge, this is the first report of Arg79Cys heterozygote mutation in family members with venous thromboembolism. PMID- 21325263 TI - A novel mutation in the MECP2 gene in a Korean patient with Rett syndrome. AB - Rett syndrome (RTT) is a severe X-linked dominant neurodevelopmental disorder. Mutations in the MECP2 gene on chromosome Xq28 have been shown to be the cause of RTT. Using DNA samples from a RTT patient and her parents, we sequenced three exons and flanking intron regions of the MECP2 gene using the polymerase chain reaction. Sequencing of the MECP2 gene in the proband revealed a novel 41-base pair deletion in exon 4 (c.1152_1192del41). This mutation resulted in premature termination of the 487 amino acid protein at the 390th codon, predicting a partial loss of the C-terminal domain. We did not observe this mutation in either parent of the RTT patient, but further studies are needed to evaluate the possibility of germline mosaicism. PMID- 21325264 TI - Much overlooked causes of lung cancer. PMID- 21325265 TI - Remote communication through solute carriers and ATP binding cassette drug transporter pathways: an update on the remote sensing and signaling hypothesis. AB - Recent data from knockouts, human disease, and transport studies suggest that solute carrier (SLC) and ATP binding cassette (ABC) multispecific "drug" transporters maintain effective organ and body fluid concentrations of key nutrients, signaling molecules, and antioxidants. These processes involve transcellular movement of solutes across epithelial barriers and fluid compartments (e.g., blood, cerebrospinal fluid, urine, bile) via "matching" or homologous sets of SLC (e.g., SLC21, SLC22, SLC47) and ABC transporters. As described in the "Remote Sensing and Signaling Hypothesis" (Biochem Biophys Res Commun 323:429-436, 2004; Biochem Biophys Res Commun 351:872-876, 2006; J Biol Chem 282:23841-23853, 2007; Nat Clin Pract Nephrol 3:443-448, 2007; Mol Pharmacol 76:481-490, 2009), highly regulated transporter networks with overlapping substrate preferences are involved in sensing and signaling to maintain homeostasis in response to environmental changes (e.g., substrate imbalance and injury). They function in parallel with (and interact with) the endocrine and autonomic systems. Uric acid (urate), carnitine, prostaglandins, conjugated sex steroids, cGMP, odorants, and enterobiome metabolites are discussed here as examples. Xenobiotics hitchhike on endogenous carrier systems, sometimes leading to toxicity and side effects. By regulation of the expression and/or function of various remote organ multispecific transporters after injury, the overall transport capacity of the remote organ to handle endogenous toxins, metabolites, and signaling molecules may change, aiding in recovery. Moreover, these transporters may play a role in communication between organisms. The specific cellular components involved in sensing and altering transporter abundance or functionality depend upon the metabolite in question and probably involve different types of sensors as well as epigenetic regulation. PMID- 21325266 TI - Antisense RNA protects mRNA from RNase E degradation by RNA-RNA duplex formation during phage infection. AB - The ecologically important cyanobacterium Prochlorococcus possesses the smallest genome among oxyphototrophs, with a reduced suite of protein regulators and a disproportionately high number of regulatory RNAs. Many of these are asRNAs, raising the question whether they modulate gene expression through the protection of mRNA from RNase E degradation. To address this question, we produced recombinant RNase E from Prochlorococcus sp. MED4, which functions optimally at 12 mM Mg(2+), pH 9 and 35 degrees C. RNase E cleavage assays were performed with this recombinant protein to assess enzyme activity in the presence of single- or double-stranded RNA substrates. We found that extraordinarily long asRNAs of 3.5 and 7 kb protect a set of mRNAs from RNase E degradation that accumulate during phage infection. These asRNA-mRNA duplex formations mask single-stranded recognition sites of RNase E, leading to increased stability of the mRNAs. Such interactions directly modulate RNA stability and provide an explanation for enhanced transcript abundance of certain mRNAs during phage infection. Protection from RNase E-triggered RNA decay may constitute a hitherto unknown regulatory function of bacterial cis-asRNAs, impacting gene expression. PMID- 21325267 TI - A highly conserved protein of unknown function in Sinorhizobium meliloti affects sRNA regulation similar to Hfq. AB - The SMc01113/YbeY protein, belonging to the UPF0054 family, is highly conserved in nearly every bacterium. However, the function of these proteins still remains elusive. Our results show that SMc01113/YbeY proteins share structural similarities with the MID domain of the Argonaute (AGO) proteins, and might similarly bind to a small-RNA (sRNA) seed, making a special interaction with the phosphate on the 5'-side of the seed, suggesting they may form a component of the bacterial sRNA pathway. Indeed, eliminating SMc01113/YbeY expression in Sinorhizobium meliloti produces symbiotic and physiological phenotypes strikingly similar to those of the hfq mutant. Hfq, an RNA chaperone, is central to bacterial sRNA-pathway. We evaluated the expression of 13 target genes in the smc01113 and hfq mutants. Further, we predicted the sRNAs that may potentially target these genes, and evaluated the accumulation of nine sRNAs in WT and smc01113 and hfq mutants. Similar to hfq, smc01113 regulates the accumulation of sRNAs as well as the target mRNAs. AGOs are central components of the eukaryotic sRNA machinery and conceptual parallels between the prokaryotic and eukaryotic sRNA pathways have long been drawn. Our study provides the first line of evidence for such conceptual parallels. Furthermore, our investigation gives insights into the sRNA-mediated regulation of stress adaptation in S. meliloti. PMID- 21325268 TI - Commentary: Family assessment in pediatric psychology. PMID- 21325269 TI - A case study: Acceptance and commitment therapy for pediatric sickle cell disease. AB - OBJECTIVE: Sickle cell disease (SCD) negatively impacts patients' functioning and quality of life. Acceptance and Commitment Therapy (ACT) promotes acceptance of difficult sensations, emotions, and thoughts when doing so facilitates living a values-based life. This study describes ACT for improving functioning and quality of life for an adolescent with SCD and his parents. METHODS: A 16-year old with SCD and his parents attended an eight-session ACT program. Process (adolescent psychological flexibility, parent acceptance) and outcome (adolescent social anxiety, pain, functioning, quality of life; parent distress) measures were conducted prior to and following treatment and at 3-month follow-up. RESULTS AND CONCLUSIONS: Improvements were evident, especially at follow-up. Process measures suggest adolescent psychological flexibility and parent acceptance might explain positive effects. Anecdotal comments support these findings and provide additional evidence that ACT might effectively promote functioning and quality of life in adolescents with chronic diseases. PMID- 21325270 TI - A task shifting approach to primary mental health care for adults in South Africa: human resource requirements and costs for rural settings. AB - BACKGROUND A recent situational analysis suggests that post-apartheid South Africa has made some gains with respect to the decentralization and integration of mental health into primary health care. However, service gaps within and between provinces remain, with rural areas particularly underserved. Aim This study aims to calculate and cost a hypothetical human resource mix required to populate a framework for district adult mental health services. This framework embraces the concept of task shifting, where dedicated low cost mental health workers at the community and clinic levels supplement integrated care. METHOD The expected number and cost of human resources was based on: (a) assumptions of service provision derived from existing services in a sub-district demonstration site and a literature review of evidence-based packages of care in low- and middle-income countries; and (b) assumptions of service needs derived from other studies. RESULTS For a nominal population of 100 000, minimal service coverage estimates of 50% for schizophrenia, bipolar affective disorder, major depressive disorder and 30% for post-traumatic stress disorder and maternal depression would require that the primary health care staffing package include one post for a mental health counsellor or equivalent and 7.2 community mental health worker posts. The cost of these personnel amounts to L28 457 per 100 000 population. This cost can be offset by a reduction in the number of other specialist and non specialist health personnel required to close service gaps at primary care level. CONCLUSION The adoption of the concept of task shifting can substantially reduce the expected number of health care providers otherwise needed to close mental health service gaps at primary health care level in South Africa at minimal cost and may serve as a model for other middle-income countries. PMID- 21325271 TI - Oxidized low density lipoprotein induces bone morphogenetic protein-2 in coronary artery endothelial cells via Toll-like receptors 2 and 4. AB - Vascular calcification is a common complication in atherosclerosis. Bone morphogenetic protein-2 (BMP-2) plays an important role in atherosclerotic vascular calcification. The aim of this study was to determine the effect of oxidized low density lipoprotein (oxLDL) on BMP-2 protein expression in human coronary artery endothelial cells (CAECs), the roles of Toll-like receptor (TLR) 2 and TLR4 in oxLDL-induced BMP-2 expression, and the signaling pathways involved. Human CAECs were stimulated with oxLDL. The roles of TLR2 and TLR4 in oxLDL-induced BMP-2 expression were determined by pretreatment with neutralizing antibody, siRNA, and overexpression. Stimulation with oxLDL increased cellular BMP-2 protein levels in a dose-dependent manner (40-160 MUg/ml). Pretreatment with neutralizing antibodies against TLR2 and TLR4 or silencing of these two receptors reduced oxLDL-induced BMP-2 expression. Overexpression of TLR2 and TLR4 enhanced the cellular BMP-2 response to oxLDL. Furthermore, oxLDL was co localized with TLR2 and TLR4. BMP-2 expression was associated with activation of nuclear factor-kappaB (NF-kappaB), p38 mitogen-activated protein kinase (MAPK), and extracellular signal-regulated kinase (ERK)1/2. Inhibition of NF-kappaB and ERK1/2 reduced BMP-2 expression whereas inhibition of p38 MAPK had no effect. In conclusion, oxLDL induces BMP-2 expression through TLR2 and TLR4 in human CAECs. The NF-kappaB and ERK1/2 pathways are involved in the signaling mechanism. These findings underscore an important role for TLR2 and TLR4 in mediating the BMP-2 response to oxLDL in human CAECs and indicate that these two immunoreceptors contribute to the mechanisms underlying atherosclerotic vascular calcification. PMID- 21325272 TI - Natural loss-of-function mutation of myeloid differentiation protein 88 disrupts its ability to form Myddosomes. AB - Myeloid differentiation protein 88 (MyD88) is a key signaling adapter in Toll like receptor (TLR) signaling. MyD88 is also one of the most polymorphic adapter proteins. We screened the reported nonsynonymous coding mutations in MyD88 to identify variants with altered function. In reporter assays, a death domain variant, S34Y, was found to be inactive. Importantly, in reconstituted macrophage like cell lines derived from knock-out mice, MyD88 S34Y was severely compromised in its ability to respond to all MyD88-dependent TLR ligands. Unlike wild-type MyD88, S34Y is unable to form distinct foci in the cells but is present diffused in the cytoplasm. We observed that IRAK4 co-localizes with MyD88 in these aggregates, and thus these foci appear to be "Myddosomes." The MyD88 S34Y loss-of function mutant demonstrates how proper cellular localization of MyD88 to the Myddosome is a feature required for MyD88 function. PMID- 21325273 TI - VentX trans-activates p53 and p16ink4a to regulate cellular senescence. AB - Cell senescence is a process of irreversible arrest of cell proliferation and plays an important role in tumor suppression. Recent studies showed that Wnt inhibition is a trigger of cellular senescence. Using methods of reverse genetics, we recently identified VentX, a human homolog of the vertebrate Xenopus Vent family of homeobox genes, as a novel Wnt repressor and a putative tumor suppressor in lymphocytic leukemia. Here, we show that VentX is a direct transcriptional activator of p53-p21 and p16ink4a-Rb tumor suppression pathways. Ectopic expression of VentX in cancer cells caused an irreversible cell cycle arrest with a typical senescence-like phenotype. Conversely, inhibition of VentX expression by RNA interference ameliorated chemotherapeutic agent-induced senescence in lymphocytic leukemia cells. The results of our study further reveal the mechanisms underlying tumor suppression function of VentX and suggest a role of VentX as a potential target in cancer prevention and treatment. PMID- 21325274 TI - Functional implications of an intermeshing cogwheel-like interaction between TolC and MacA in the action of macrolide-specific efflux pump MacAB-TolC. AB - Macrolide-specific efflux pump MacAB-TolC has been identified in diverse gram negative bacteria including Escherichia coli. The inner membrane transporter MacB requires the outer membrane factor TolC and the periplasmic adaptor protein MacA to form a functional tripartite complex. In this study, we used a chimeric protein containing the tip region of the TolC alpha-barrel to investigate the role of the TolC alpha-barrel tip region with regard to its interaction with MacA. The chimeric protein formed a stable complex with MacA, and the complex formation was abolished by substitution at the functionally essential residues located at the MacA alpha-helical tip region. Electron microscopic study delineated that this complex was made by tip-to-tip interaction between the tip regions of the alpha-barrels of TolC and MacA, which correlated well with the TolC and MacA complex calculated by molecular dynamics. Taken together, our results demonstrate that the MacA hexamer interacts with TolC in a tip-to-tip manner, and implies the manner by which MacA induces opening of the TolC channel. PMID- 21325275 TI - Type VI secretion system in Pseudomonas aeruginosa: secretion and multimerization of VgrG proteins. AB - Pseudomonas aeruginosa is a Gram-negative bacterium causing chronic infections in cystic fibrosis patients. Such infections are associated with an active type VI secretion system (T6SS), which consists of about 15 conserved components, including the AAA+ ATPase, ClpV. The T6SS secretes two categories of proteins, VgrG and Hcp. Hcp is structurally similar to a phage tail tube component, whereas VgrG proteins show similarity to the puncturing device at the tip of the phage tube. In P. aeruginosa, three T6SSs are known. The expression of H1-T6SS genes is controlled by the RetS sensor. Here, 10 vgrG genes were identified in the PAO1 genome, among which three are co-regulated with H1-T6SS, namely vgrG1a/b/c. Whereas VgrG1a and VgrG1c were secreted in a ClpV1-dependent manner, secretion of VgrG1b was ClpV1-independent. We show that VgrG1a and VgrG1c form multimers, which confirmed the VgrG model predicting trimers similar to the tail spike. We demonstrate that Hcp1 secretion requires either VgrG1a or VgrG1c, which may act independently to puncture the bacterial envelope and give Hcp1 access to the surface. VgrG1b is not required for Hcp1 secretion. Thus, VgrG1b does not require H1-T6SS for secretion nor does H1-T6SS require VgrG1b for its function. Finally, we show that VgrG proteins are required for secretion of a genuine H1-T6SS substrate, Tse3. Our results demonstrate that VgrG proteins are not only secreted components but are essential for secretion of other T6SS substrates. Overall, we emphasize variability in behavior of three P. aeruginosa VgrGs, suggesting that, although very similar, distinct VgrGs achieve specific functions. PMID- 21325277 TI - Selective activation of the transcription factor NFAT1 by calcium microdomains near Ca2+ release-activated Ca2+ (CRAC) channels. AB - NFATs are a family of Ca(2+)-dependent transcription factors that play a central role in the morphogenesis, development, and physiological activities of numerous distinct cell types and organ systems. Here, we visualize NFAT1 movement in and out of the nucleus in response to transient activation of store-operated Ca(2+) release-activated Ca(2+) (CRAC) channels in nonexcitable cells. We show that NFAT migration is exquisitely sensitive to Ca(2+) microdomains near open CRAC channels. Another Ca(2+)-permeable ion channel (TRPC3) was ineffective in driving NFAT1 to the nucleus. NFAT1 movement is temporally dissociated from the time course of the Ca(2+) signal and remains within the nucleus for 10 times longer than the duration of the trigger Ca(2+) signal. Kinetic analyses of each step linking CRAC channel activation to NFAT1 nuclear residency reveals that the rate limiting step is transcription factor exit from the nucleus. The slow deactivation of NFAT provides a mechanism whereby Ca(2+)-dependent responses can be sustained despite the termination of the initial Ca(2+) signal and helps explain how gene expression in nonexcitable cells can continue after the primary stimulus has been removed. PMID- 21325276 TI - Combination treatment with HER-2 and VEGF peptide mimics induces potent anti tumor and anti-angiogenic responses in vitro and in vivo. AB - HER-2 is a member of the EGF receptor family and is overexpressed in 20-30% of breast cancers. HER-2 overexpression causes increased expression of VEGF at both the RNA and protein levels. HER-2 and VEGF are therefore considered good targets for cancer treatment, which has led to the development of two humanized monoclonal antibodies (mAb) pertuzumab and bevacizumab. Although passive immunotherapy with these Abs are approved for treatment of advanced breast cancer, a number of concerns exist. Treatment is expensive, has a limited duration of action, and is usually accompanied by serious side effects. We hypothesized that therapy with conformational peptide mimics aimed at blocking receptor-ligand interaction is potentially safer with little toxicity, cheaper with a longer half-life, and has greater penetrating abilities than mAbs. We designed and synthesized peptides based on the binding of HER-2 with pertuzumab and VEGF with VEGFR2. We show that treatment with the peptide mimics induces potent anti-tumor responses in vitro as determined by cell viability, proliferation, and HER2 phosphorylation assays. We also demonstrate in a transplantable BALB/c mouse tumor model that treatment with the peptide mimics resulted in a greater delay in tumor growth and development. Similarly, treatment with the peptide mimics inhibited angiogenesis in vivo as assessed by a Matrigel plug assay. To address the problem of degradability of L-amino acid peptides in vivo, we synthesized the retro-inverso D-peptide mimics that resulted in higher efficacy in treatment. Our study shows that combination treatment with HER-2 and VEGF peptide mimics provides greater efficacy than individual treatments. PMID- 21325278 TI - Genetic and neutralization sensitivity of diverse HIV-1 env clones from chronically infected patients in China. AB - As HIV-1 continues to spread in China from traditional high risk populations to the general public, its genetic makeup has become increasingly complex. However, the impact of these genetic changes on the biological and neutralization sensitivity of the virus is unknown. The current study aims to characterize the genetic, biological, and neutralization sensitivity of HIV-1 identified in China between 2004 and 2007. Based on a total of 107 full-length envelope genes obtained directly from the infected patients, we found that those viruses fell into three major genetic groups: CRF01_AE, subtype B', and subtype C/CRF07_BC/CRF08_BC/B'C. Pseudotyped viruses built upon the viable env genes have demonstrated their substantial variability in mediating viral entry and in sensitivity to neutralization by subtype-specific plasma pools and broadly neutralizing monoclonal antibodies (bnmAb). Many viruses are resistant to one or more bnmAb, including those known to have high potency against diverse viruses from outside China. Sequence and structural analysis has revealed several mechanisms by which these resistant viruses escape recognition from bnmAb. We believe that these results will help us to better understand the impact of genetic diversity on the neutralizing sensitivity of the viruses and to facilitate the design of immunogens capable of eliciting antibodies with potency and breadth similar to those of bnmAb. PMID- 21325279 TI - Functional reconstitution of an atypical G protein heterotrimer and regulator of G protein signaling protein (RGS1) from Arabidopsis thaliana. AB - It has long been known that animal heterotrimeric Galphabetagamma proteins are activated by cell-surface receptors that promote GTP binding to the Galpha subunit and dissociation of the heterotrimer. In contrast, the Galpha protein from Arabidopsis thaliana (AtGPA1) can activate itself without a receptor or other exchange factor. It is unknown how AtGPA1 is regulated by Gbetagamma and the RGS (regulator of G protein signaling) protein AtRGS1, which is comprised of an RGS domain fused to a receptor-like domain. To better understand the cycle of G protein activation and inactivation in plants, we purified and reconstituted AtGPA1, full-length AtRGS1, and two putative Gbetagamma dimers. We show that the Arabidopsis Galpha protein binds to its cognate Gbetagamma dimer directly and in a nucleotide-dependent manner. Although animal Gbetagamma dimers inhibit GTP binding to the Galpha subunit, AtGPA1 retains fast activation in the presence of its cognate Gbetagamma dimer. We show further that the full-length AtRGS1 protein accelerates GTP hydrolysis and thereby counteracts the fast nucleotide exchange rate of AtGPA1. Finally, we show that AtGPA1 is less stable in complex with GDP than in complex with GTP or the Gbetagamma dimer. Molecular dynamics simulations and biophysical studies reveal that altered stability is likely due to increased dynamic motion in the N-terminal alpha-helix and Switch II of AtGPA1. Thus, despite profound differences in the mechanisms of activation, the Arabidopsis G protein is readily inactivated by its cognate RGS protein and forms a stable, GDP bound, heterotrimeric complex similar to that found in animals. PMID- 21325280 TI - Allosteric modulation of hormone release from thyroxine and corticosteroid binding globulins. AB - The release of hormones from thyroxine-binding globulin (TBG) and corticosteroid binding globulin (CBG) is regulated by movement of the reactive center loop in and out of the beta-sheet A of the molecule. To investigate how these changes are transmitted to the hormone-binding site, we developed a sensitive assay using a synthesized thyroxine fluorophore and solved the crystal structures of reactive loop cleaved TBG together with its complexes with thyroxine, the thyroxine fluorophores, furosemide, and mefenamic acid. Cleavage of the reactive loop results in its complete insertion into the beta-sheet A and a substantial but incomplete decrease in binding affinity in both TBG and CBG. We show here that the direct interaction between residue Thr(342) of the reactive loop and Tyr(241) of the hormone binding site contributes to thyroxine binding and release following reactive loop insertion. However, a much larger effect occurs allosterically due to stretching of the connecting loop to the top of the D helix (hD), as confirmed in TBG with shortening of the loop by three residues, making it insensitive to the S-to-R transition. The transmission of the changes in the hD loop to the binding pocket is seen to involve coherent movements in the s2/3B loop linked to the hD loop by Lys(243), which is, in turn, linked to the s4/5B loop, flanking the thyroxine-binding site, by Arg(378). Overall, the coordinated movements of the reactive loop, hD, and the hormone binding site allow the allosteric regulation of hormone release, as with the modulation demonstrated here in response to changes in temperature. PMID- 21325281 TI - Epigenetic regulation of the IL-13-induced human eotaxin-3 gene by CREB-binding protein-mediated histone 3 acetylation. AB - The etiology of a variety of chronic inflammatory disorders has been attributed to the interaction of genetic and environmental factors. Herein, we identified a link between epigenetic regulation and IL-13-driven eotaxin-3 in the pathogenesis of chronic allergic inflammation. We first demonstrated that the cAMP-responsive element (CRE) site in the eotaxin-3 promoter affects IL-13-induced eotaxin-3 promoter activity. Furthermore, the CRE-binding protein-binding protein (CBP), a histone acetyltransferase, induced base-line and IL-13-induced eotaxin-3 promoter activity. Additionally, IL-13 treatment promoted global histone 3 acetylation as well as the formation of a complex containing CBP and STAT6 and the subsequent acetylation of histone 3 at the eotaxin-3 promoter. CBP gene silencing decreased IL-13-induced transcription of eotaxin-3. Conversely, inhibition of histone deacetylation increased IL-13-induced eotaxin-3 production. Clinical studies demonstrated markedly increased global acetylation of histone 3 in the inflamed tissue of patients with allergic inflammation. Collectively, these results identify an epigenetic mechanism involving CBP and chromatin remodeling in regulating IL-13-induced chemokine transcription. PMID- 21325282 TI - Crystal Structure of the cis-Dimer of Nectin-1: implications for the architecture of cell-cell junctions. AB - In multicellular organisms, cells are interconnected by cell adhesion molecules. Nectins are immunoglobulin (Ig)-like cell adhesion molecules that mediate homotypic and heterotypic cell-cell adhesion, playing key roles in tissue organization. To mediate cell-cell adhesion, nectin molecules dimerize in cis on the surface of the same cell, followed by trans-dimerization of the cis-dimers between the neighboring cells. Previous cell biological studies deduced that the first Ig-like domain of nectin and the second Ig-like domain are involved in trans-dimerization and cis-dimerization, respectively. However, to understand better the steps involved in nectin adhesion, the structural basis for the dimerization of nectin must be determined. In this study, we determined the first crystal structure of the entire extracellular region of nectin-1. In the crystal, nectin-1 formed a V-shaped homophilic dimer through the first Ig-like domain. Structure-based site-directed mutagenesis of the first Ig-like domain identified four essential residues that are involved in the homophilic dimerization. Upon mutating the four residues, nectin-1 significantly decreased cis-dimerization on the surface of cultured cells and abolished the homophilic and heterophilic adhesion activities. These results indicate that, in contrast with the previous notion, our structure represents a cis-dimer. Thus, our findings clearly reveal the structural basis for the cis-dimerization of nectins through the first Ig like domains. PMID- 21325284 TI - CTCF and BORIS regulate Rb2/p130 gene transcription: a novel mechanism and a new paradigm for understanding the biology of lung cancer. AB - Although innumerable investigations regarding the biology of lung cancer have been carried out, many aspects thereof remain to be addressed, including the role played by the retinoblastoma-related protein Rb2/p130 during the evolution of this disease. Here we report novel findings on the mechanisms that control Rb2/p130 gene expression in lung fibroblasts and characterize the effects of Rb2/p130 deregulation on the proliferative features of lung cancer cells. We revealed for the first time that in lung fibroblasts the expression of Rb2/p130 gene is directly controlled by the chromatin insulator CCCTC-binding factor, CTCF, which by binding to the Rb2/p130 gene promoter induces, and/or maintains, a specific local chromatin organization that in turn governs the transcriptional activity of Rb2/p130 gene. However, in lung cancer cells the activity of CTCF in controlling Rb2/p130 gene expression is impaired by BORIS, a CTCF-paralogue, which by binding to the Rb2/p130 gene could trigger changes in the chromatin asset established by CTCF, thereby affecting CTCF regulatory activity on Rb2/p130 transcription. These studies not only provide essential basic insights into the molecular mechanisms that control Rb2/p130 gene expression in lung cancer, but also offer a potential paradigm for the actions of other activators and/or corepressors, such as CTCF and BORIS, that could be crucial in explaining how alterations in the mechanism regulating Rb2/p130 gene expression may accelerate the progression of lung tumors, or favor the onset of recurrence after cancer treatment. PMID- 21325285 TI - Role of phytosterols in lipid-lowering: current perspectives. AB - The cholesterol-lowering effect of plant sterols was first discovered in the early 1950s. However, it is only recently that plant sterols have become clinically important, when advances in food-technology have made it possible to combine sterols with a variety of food products including margarines, yogurts, fruit juices and cereal bars. We review the clinical trial evidence of lipid lowering efficacy of plant sterols and discuss their implications in routine clinical practice. To generate the evidence we searched the Pubmed database for English language literature, using relevant keywords and medical subject heading (MeSH) terms, and extracted the findings from recently published studies and meta analyses on this topic. Our findings suggest that the short-term use of food supplements rich in plant sterols is a safe and effective strategy; to maximize the benefits of dietary and lifestyle therapy, either with or without statin therapy, among majority of dyslipidemic patients with need for additional lipid lowering. PMID- 21325287 TI - Preclinical evaluation of telomerase-specific oncolytic virotherapy for human bone and soft tissue sarcomas. AB - PURPOSE: Tumor-specific replication-selective oncolytic virotherapy is a promising antitumor therapy for induction of cell death in tumor cells but not of normal cells. We previously developed an oncolytic adenovirus, OBP-301, that kills human epithelial malignant cells in a telomerase-dependent manner. Recent evidence suggests that nonepithelial malignant cells, which have low telomerase activity, maintain telomere length through alternative lengthening of telomeres (ALT). However, it remains unclear whether OBP-301 is cytopathic for nonepithelial malignant cells. Here, we evaluated the antitumor effect of OBP-301 on human bone and soft tissue sarcoma cells. EXPERIMENTAL DESIGN: The cytopathic activity of OBP-301, coxsackie and adenovirus receptor (CAR) expression, and telomerase activity were examined in 10 bone (OST, U2OS, HOS, HuO9, MNNG/HOS, SaOS-2, NOS-2, NOS-10, NDCS-1, and OUMS-27) and in 4 soft tissue (CCS, NMS-2, SYO 1, and NMFH-1) sarcoma cell lines. OBP-301 antitumor effects were assessed using orthotopic tumor xenograft models. The fiber-modified OBP-301 (termed OBP-405) was used to confirm an antitumor effect on OBP-301-resistant sarcomas. RESULTS: OBP-301 was cytopathic for 12 sarcoma cell lines but not for the non-CAR expressing OUMS-27 and NMFH-1 cells. Sensitivity to OBP-301 was dependent on CAR expression and not on telomerase activity. ALT-type sarcomas were also sensitive to OBP-301 because of upregulation of human telomerase reverse transcriptase (hTERT) mRNA following virus infection. Intratumoral injection of OBP-301 significantly suppressed the growth of OST and SYO-1 tumors. Furthermore, fiber modified OBP-405 showed antitumor effects on OBP-301-resistant OUMS-27 and NMFH-1 cells. CONCLUSIONS: A telomerase-specific oncolytic adenovirus is a promising antitumor reagent for the treatment of bone and soft tissue sarcomas. PMID- 21325288 TI - Reduced p21(WAF1/CIP1) via alteration of p53-DDX3 pathway is associated with poor relapse-free survival in early-stage human papillomavirus-associated lung cancer. AB - PURPOSE: DDX3 alteration has been shown to participate in hepatocellular tumorigenesis via p21(WAF1/CIP1) (p21) deregulation. We observed that DDX3 and p21 expression in lung tumors was negatively associated with E6 expression. Therefore, the aim of this study was to clarify whether deregulation of p21 by DDX3 via an E6-inactivated p53 pathway would enhance tumor progression in HPV associated lung cancers. EXPERIMENTAL DESIGN: Real-time PCR, luciferase assays, immunoprecipitation, and chromatin immunoprecipitation (ChIP) were performed to determine whether DDX3 was regulated by p53 to synergistically enhance p21 transcriptional activity. Cell proliferation was examined by cell counting and colony formation assays. DDX3 and p21 expression were evaluated in 138 lung tumors by real-time PCR and immunohistochemistry. The prognostic value of p21 expression on relapse-free survival (RFS) was analyzed by Kaplan-Meier analysis. RESULTS: Real-time PCR, luciferase assays, and ChIP assays indicated that three putative p53 binding sites, located at -1,080/-1,070, -695/-685, and -283/-273 on the DDX3 promoter, were required for DDX3 transcription. DDX3 deregulation by the E6-inactivated p53 pathway could promote cell proliferation and the ability to form colonies via reduced Sp1 binding activity on the p21 promoter. Among tumors, p21 expression was positively associated with DDX3 expression and negatively related with E6 expression, particularly in early-stage (I + II) tumors. Interestingly, low p21 expression was associated with a poor RFS in early-stage lung cancer. CONCLUSION: The reduction of p21 by the alteration of the p53-DDX3 pathway plays an essential role in early-stage HPV-associated lung tumorigenesis and is correlated with poor RFS of lung cancer patients. PMID- 21325289 TI - Array-based comparative genomic hybridization identifies CDK4 and FOXM1 alterations as independent predictors of survival in malignant peripheral nerve sheath tumor. AB - PURPOSE: Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas with variable patient survival and few known prognostically relevant genomic biomarkers. To identify survival-associated genomic biomarkers, we performed high-resolution array-based comparative genomic hybridization (aCGH) on a large set of MPNSTs. EXPERIMENTAL DESIGN: Candidate gene alterations identified by aCGH in 38 MPNSTs were validated at the DNA, RNA, and protein levels on these same tumors and an independent set of 87 MPNST specimens. RESULTS: aCGH revealed highly complex copy number alterations, including both previously reported and completely novel loci. Four regions of copy number gain were associated with poor patient survival. Candidate genes in these regions include SOX5 (12p12.1), NOL1 and MLF2 (12p13.31), FOXM1 and FKBP1 (12p13.33), and CDK4 and TSPAN31 (12q14.1). Alterations of these candidate genes and several others of interest (ERBB2, MYC and TP53) were confirmed by at least 1 complementary methodology, including DNA and mRNA quantitative real-time PCR, mRNA expression profiling, and tissue microarray-based fluorescence in situ hybridization and immunohistochemistry. Multivariate analysis showed that CDK4 gain/amplification and increased FOXM1 protein expression were the most significant independent predictors for poor survival in MPNST patients (P < 0.05). CONCLUSIONS: Our study provides new and independently confirmed candidate genes that could serve as genomic biomarkers for overall survival in MPNST patients. PMID- 21325290 TI - The progression from MGUS to smoldering myeloma and eventually to multiple myeloma involves a clonal expansion of genetically abnormal plasma cells. AB - PURPOSE: Genetic aberrations detected in multiple myeloma (MM) have also been reported in the premalignant conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM). Our aim was to investigate in depth the level of clonal heterogeneity of recurrent genetic abnormalities in these conditions. EXPERIMENTAL DESIGN: Immunoglobulin heavy chain (IGH) translocations, 13q14 and 17p13 deletions, and 1q21 gains using FISH were evaluated in 90 MGUS, 102 high-risk SMM, and 373 MM. To this end, we not only purified plasma cells (PC) for the FISH analysis (purity > 90%), but subsequently, we examined the correlation between the proportion of PC with cytogenetic changes and the number of clonal PC present in the same sample, as measured by multiparametric flow cytometry. RESULTS: We observed a significant difference between the proportion of clonal PC with specific genetic abnormalities in MGUS compared with SMM and in SMM compared with MM. Thus, the median proportion of PC with IGH translocations globally considered, t(11;14) and 13q deletions was significantly lower in MGUS than in SMM, and in SMM than in MM [IGH translocations: 34% vs. 57% vs. 76%; t(11;14): 38% vs. 61% vs. 81%; and 13q deletion: 37% vs. 61% vs. 74% in MGUS, SMM, and MM, respectively]. For t(4;14), the difference was significant in the comparison between MGUS/SMM and MM and for 1q between MGUS and SMM/MM. CONCLUSIONS: This study demonstrates that the progression from MGUS to SMM, and eventually to MM, involves a clonal expansion of genetically abnormal PC. PMID- 21325291 TI - A polymorphism in the cytidine deaminase promoter predicts severe capecitabine induced hand-foot syndrome. AB - PURPOSE: Hand-foot syndrome (HFS) is one of the most relevant dose-limiting adverse effects of capecitabine, an oral prodrug of 5-fluorouracil used in the standard treatment of breast and colorectal cancer. We investigated the association between grade 3 HFS and genetic variations in genes involved in capecitabine metabolism. EXPERIMENTAL DESIGN: We genotyped a total of 13 polymorphisms in the carboxylesterase 2 (CES2) gene, the cytidine deaminase (CDD) gene, the thymidine phosphorylase (TP) gene, the thymidylate synthase (TS) gene, and the dihydropyrimidine dehydrogenase (DPD) gene in 130 patients treated with capecitabine. We correlated these polymorphisms with susceptibility to HFS. RESULTS: We found an association of HFS appearance with rs532545 located in the promoter region of CDD (OR = 2.02, 95% CI = 1.02-3.99, P = 0.039). Because we found no association between the rs532545 genotype and CDD mRNA expression in Epstein-Barr virus lymphoblastoid cells, we explored additional genetic variations across the CDD promoter. We found an insertion, rs3215400, in linkage disequilibrium with rs532545 (D' = 0.92), which was more clearly associated with HFS (OR = 0.51, 95% CI = 0.27-0.95, P = 0.028) in patients and with total CDD gene expression (P = 0.004) in lymphoblastoid cells. In silico analysis suggested that this insertion might create a binding site for the transcriptional regulator E2F. Using a SNaPshot assay in lymphoblastoid cells, we observed a 5.7-fold increased allele-specific mRNA expression from the deleted allele. CONCLUSIONS: The deleted allele of rs3215400 shows an increased allele-specific expression and is significantly associated with an increased risk of capecitabine-induced HFS. PMID- 21325292 TI - Rapid diagnosis of medulloblastoma molecular subgroups. AB - PURPOSE: Microarray studies indicate medulloblastoma comprises distinct molecular disease subgroups, which offer potential for improved clinical management. EXPERIMENTAL DESIGN: Minimal mRNA expression signatures diagnostic for the Wnt/Wingless (WNT) and Sonic Hedgehog (SHH) subgroups were developed, validated, and used to assign subgroup affiliation in 173 tumors from four independent cohorts, alongside a systematic investigation of subgroup clinical and molecular characteristics. RESULTS: WNT tumors [12% (21/173)] were diagnosed >5 years of age (peak, 10 years), displayed classic histology, CTNNB1 mutation (19/20), and associated chromosome 6 loss, and have previously been associated with favorable prognosis. SHH cases [24% (42/173)] predominated in infants (<3 years) and showed an age-dependent relationship to desmoplastic/nodular pathology; all infant desmoplastic/nodular cases (previously associated with a good outcome) were SHH positive, but these relationships broke down in noninfants. PTCH1 mutations were common [34% (11/32)], but PTCH1 exon1c hypermethylation, chromosome 9q and REN (KCTD11) genetic loss were not SHH associated, and SMO or SUFU mutation, PTCH1 exon1a or SUFU hypermethylation did not play a role, indicating novel activating mechanisms in the majority of SHH cases. SHH tumors were associated with an absence of COL1A2 methylation. WNT/SHH-independent medulloblastomas [64% (110/173)] showed all histologies, peaked at 3 and 6 years, and were exclusively associated with chromosome 17p loss. CONCLUSIONS: Medulloblastoma subgroups are characterized by distinct genomic, epigenomic and clinicopathologic features, and clinical outcomes. Validated array-independent gene expression assays for the rapid assessment of subgroup affiliation in small biopsies provide a basis for their routine clinical application, in strategies including molecular disease risk stratification and delivery of targeted therapeutics. PMID- 21325295 TI - Natural killer cells are scarce in colorectal carcinoma tissue despite high levels of chemokines and cytokines. AB - PURPOSE: Tumor infiltrating T lymphocytes in colorectal cancer (CRC) have prognostic impact, but the role of natural killer (NK) cells in CRC tissue is unclear. The contribution of intratumoral cytokines and chemokines in shaping the composition of the inflammatory lymphocytic infiltrate is also unclear. EXPERIMENTAL DESIGN: In this study, localization and densities of NK and T cells within primary CRC, CRC liver metastases, adenomas, and normal tissues were analyzed on whole tissue sections from 112 patients. In a subset of these patients, the most important 50 cytokines and chemokines were quantified in paired serum, primary CRC and adjacent mucosa samples and in CRC liver metastases and correlated with NK and T-cell infiltration, respectively. RESULTS: The various compartments displayed characteristic differences like significantly higher chemokine concentrations in CRC tissue. Most importantly, despite high local chemokine levels, NK cells were generally scarce within CRC tumor tissues, independent of human leukocyte antigen (HLA) class I expression. Adjacent normal mucosa contained normal levels of NK cells. In contrast, corresponding T-cell numbers varied substantially and were positively correlated with higher chemokine levels. CONCLUSIONS: Our findings indicate a distinct regulation of NK cells versus T cells in the CRC tumor microenvironment. NK-cell migration into CRC tumor tissue is obviously impaired early during tumor development by mechanisms that do not affect T-cell infiltration. PMID- 21325296 TI - ICER evokes Dusp1-p38 pathway enhancing chemotherapy sensitivity in myeloid leukemia. AB - PURPOSE: The inducible cyclic adenosine monophosphate (cAMP) early repressor (ICER) is found downregulated in acute myeloid leukemia (AML), failing to control cAMP response element binding protein (CREB) transcriptional activity, recently demonstrated to mediate AML progression. We aimed to characterize ICER's role in drug sensitivity by treating myeloid cell lines and primary AML with chemotherapics. EXPERIMENTAL DESIGN: The effects on CREB target genes induced by ICER restoration and drug treatment were studied by quantitative real-time PCR (qRT-PCR) and western blot. Cell cycle and apoptosis analysis were performed. Possible ICER-evoked pathways were investigated in vitro. The mechanism involved in enhanced drug sensitivity was described in primary AML cultures by silencing ICER main target genes. RESULTS: AML cell lines reduced cell growth and enhanced apoptotic behavior after chemotherapy treatment if ICER was expressed. A significantly lowered expression of CREB target genes involved in cell cycle control (CyA1, B1, D1), and in the mitogen-activated protein kinase signaling pathway (ERK, AKT, DUSP1/4), was found after Etoposide treatment. The dual specificity phosphatases DUSP1 and DUSP4, directly repressed by ICER, activated the p38 pathway, which triggered enhanced caspase-dependent apoptosis. The silencing of DUSP1/4 in HL60 confirmed the same enhanced drug sensitivity induced by ICER. Primary AML cultures, silenced for DUSP1 as well as restored of ICER expression, showed DUSP1 downregulation and p38 activation. CONCLUSION: ICER mediates chemotherapy anticancer activity through DUSP1-p38 pathway activation and drives the cell program from survival to apoptosis. ICER restoration or DUSP1 inhibition might be possible strategies to sensitize AML cancer cells to conventional chemotherapy and to inhibit tumor growth. PMID- 21325294 TI - Principles and current strategies for targeting autophagy for cancer treatment. AB - Autophagy is an evolutionarily conserved, intracellular self-defense mechanism in which organelles and proteins are sequestered into autophagic vesicles that are subsequently degraded through fusion with lysosomes. Cells, thereby, prevent the toxic accumulation of damaged or unnecessary components, but also recycle these components to sustain metabolic homoeostasis. Heightened autophagy is a mechanism of resistance for cancer cells faced with metabolic and therapeutic stress, revealing opportunities for exploitation as a therapeutic target in cancer. We summarize recent developments in the field of autophagy and cancer and build upon the results presented at the Cancer Therapy Evaluation Program (CTEP) Early Drug Development meeting in March 2010. Herein, we describe our current understanding of the core components of the autophagy machinery and the functional relevance of autophagy within the tumor microenvironment, and we outline how this knowledge has informed preclinical investigations combining the autophagy inhibitor hydroxychloroquine (HCQ) with chemotherapy, targeted therapy, and immunotherapy. Finally, we describe ongoing clinical trials involving HCQ as a first generation autophagy inhibitor, as well as strategies for the development of novel, more potent, and specific inhibitors of autophagy. PMID- 21325297 TI - A multilocus technique for risk evaluation of patients with neuroblastoma. AB - PURPOSE: Precise and comprehensive analysis of neuroblastoma genetics is essential for accurate risk evaluation and only pangenomic/multilocus approaches fulfill the present-day requirements. We present the establishment and validation of the PCR-based multiplex ligation-dependent probe amplification (MLPA) technique for neuroblastoma. EXPERIMENTAL DESIGN: A neuroblastoma-specific MLPA kit was designed by the SIOP Europe Neuroblastoma Biology Committee in cooperation with MRC-Holland. The contained target sequences cover 19 chromosomal arms and reference loci. Validation was performed by single locus and pangenomic techniques (n = 174). Dilution experiments for determination of minimal tumor cell percentage were performed and testing of reproducibility was checked by interlaboratory testing (n = 15). Further 156 neuroblastomas were used for establishing the amplification cutoff level. RESULTS: The MLPA technique was tested in 310 neuroblastomas and 8 neuroblastoma cell lines (including validation and amplification cutoff level testing). Intertechnique validation showed a high concordance rate (99.5%). Interlaboratory MLPA testing (kappa = 0.95, P < 0.01) revealed 7 discrepant of 1,490 results (0.5%). Validation by pangenomic techniques showed a single discordance of 190 consensus results (0.5%). The test results led to formulation of interpretation standards and to a kit revision. The minimal tumor cell percentage was fixed at 60%. CONCLUSIONS: The recently designed neuroblastoma-specific MLPA kit covers all chromosomal regions demanded by the International Neuroblastoma Risk Group for therapy stratification and includes all hitherto described genetic loci of prognostic interest for future studies and can be modified or extended at any time. Moreover, the technique is cost effective, reliable, and robust with a high interlaboratory and intertechnique concordance. PMID- 21325298 TI - Serum biomarker panels for the detection of pancreatic cancer. AB - PURPOSE: Serum-biomarker based screening for pancreatic cancer could greatly improve survival in appropriately targeted high-risk populations. EXPERIMENTAL DESIGN: Eighty-three circulating proteins were analyzed in sera of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC, n = 333), benign pancreatic conditions (n = 144), and healthy control individuals (n = 227). Samples from each group were split randomly into training and blinded validation sets prior to analysis. A Metropolis algorithm with Monte Carlo simulation (MMC) was used to identify discriminatory biomarker panels in the training set. Identified panels were evaluated in the validation set and in patients diagnosed with colon (n = 33), lung (n = 62), and breast (n = 108) cancers. RESULTS: Several robust profiles of protein alterations were present in sera of PDAC patients compared to the Healthy and Benign groups. In the training set (n = 160 PDAC, 74 Benign, 107 Healthy), the panel of CA 19-9, ICAM-1, and OPG discriminated PDAC patients from Healthy controls with a sensitivity/specificity (SN/SP) of 88/90%, while the panel of CA 19-9, CEA, and TIMP-1 discriminated PDAC patients from Benign subjects with an SN/SP of 76/90%. In an independent validation set (n = 173 PDAC, 70 Benign, 120 Healthy), the panel of CA 19-9, ICAM 1 and OPG demonstrated an SN/SP of 78/94% while the panel of CA19-9, CEA, and TIMP-1 demonstrated an SN/SP of 71/89%. The CA19-9, ICAM-1, OPG panel is selective for PDAC and does not recognize breast (SP = 100%), lung (SP = 97%), or colon (SP = 97%) cancer. CONCLUSIONS: The PDAC-specific biomarker panels identified in this investigation warrant additional clinical validation to determine their role in screening targeted high-risk populations. PMID- 21325299 TI - Identifying dispersed epigenomic domains from ChIP-Seq data. AB - MOTIVATION: Post-translational modifications to histones have several well known associations with regulation of gene expression. While some modifications appear concentrated narrowly, covering promoters or enhancers, others are dispersed as epigenomic domains. These domains mark contiguous regions sharing an epigenomic property, such as actively transcribed or poised genes, or heterochromatically silenced regions. While high-throughput methods like ChIP-Seq have led to a flood of high-quality data about these epigenomic domains, there remain important analysis problems that are not adequately solved by current analysis tools. RESULTS: We present the RSEG method for identifying epigenomic domains from ChIP Seq data for histone modifications. In contrast with other methods emphasizing the locations of 'peaks' in read density profiles, our method identifies the boundaries of domains. RSEG is also able to incorporate a control sample and find genomic regions with differential histone modifications between two samples. AVAILABILITY: RSEG, including source code and documentation, is freely available at http://smithlab.cmb.usc.edu/histone/rseg/. PMID- 21325300 TI - Automated workflows for accurate mass-based putative metabolite identification in LC/MS-derived metabolomic datasets. AB - MOTIVATION: The study of metabolites (metabolomics) is increasingly being applied to investigate microbial, plant, environmental and mammalian systems. One of the limiting factors is that of chemically identifying metabolites from mass spectrometric signals present in complex datasets. RESULTS: Three workflows have been developed to allow for the rapid, automated and high-throughput annotation and putative metabolite identification of electrospray LC-MS-derived metabolomic datasets. The collection of workflows are defined as PUTMEDID_LCMS and perform feature annotation, matching of accurate m/z to the accurate mass of neutral molecules and associated molecular formula and matching of the molecular formulae to a reference file of metabolites. The software is independent of the instrument and data pre-processing applied. The number of false positives is reduced by eliminating the inaccurate matching of many artifact, isotope, multiply charged and complex adduct peaks through complex interrogation of experimental data. AVAILABILITY: The workflows, standard operating procedure and further information are publicly available at http://www.mcisb.org/resources/putmedid.html. CONTACT: warwick.dunn@manchester.ac.uk. PMID- 21325301 TI - Annotating genes and genomes with DNA sequences extracted from biomedical articles. AB - MOTIVATION: Increasing rates of publication and DNA sequencing make the problem of finding relevant articles for a particular gene or genomic region more challenging than ever. Existing text-mining approaches focus on finding gene names or identifiers in English text. These are often not unique and do not identify the exact genomic location of a study. RESULTS: Here, we report the results of a novel text-mining approach that extracts DNA sequences from biomedical articles and automatically maps them to genomic databases. We find that ~20% of open access articles in PubMed central (PMC) have extractable DNA sequences that can be accurately mapped to the correct gene (91%) and genome (96%). We illustrate the utility of data extracted by text2genome from more than 150 000 PMC articles for the interpretation of ChIP-seq data and the design of quantitative reverse transcriptase (RT)-PCR experiments. CONCLUSION: Our approach links articles to genes and organisms without relying on gene names or identifiers. It also produces genome annotation tracks of the biomedical literature, thereby allowing researchers to use the power of modern genome browsers to access and analyze publications in the context of genomic data. AVAILABILITY AND IMPLEMENTATION: Source code is available under a BSD license from http://sourceforge.net/projects/text2genome/ and results can be browsed and downloaded at http://text2genome.org. PMID- 21325302 TI - Proteomics to go: Proteomatic enables the user-friendly creation of versatile MS/MS data evaluation workflows. AB - We present Proteomatic, an operating system independent and user-friendly platform that enables the construction and execution of MS/MS data evaluation pipelines using free and commercial software. Required external programs such as for peptide identification are downloaded automatically in the case of free software. Due to a strict separation of functionality and presentation, and support for multiple scripting languages, new processing steps can be added easily. AVAILABILITY AND IMPLEMENTATION: Proteomatic is implemented in C++/Qt, scripts are implemented in Ruby, Python and PHP. All source code is released under the LGPL. Source code and installers for Windows, Mac OS X, and Linux are freely available at http://www.proteomatic.org. CONTACT: michael.specht@uni muenster.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21325303 TI - The effects of feedback loops on disease comorbidity in human signaling networks. AB - MOTIVATION: In general, diseases are more likely to be comorbid if they share associated genes or molecular interactions in a cellular process. However, there are still a number of pairs of diseases which show relatively high comorbidity but do not share any associated genes or interactions. This observation raises the need for a novel factor which can explain the underlying mechanism of comorbidity. We here consider a feedback loop (FBL) structure ubiquitously found in the human cell signaling network as a key motif to explain the comorbidity phenomenon, since it is well known to have effects on network dynamics. RESULTS: For every pair of diseases, we examined its comorbidity and length of all FBLs involved by the disease-associated genes in the human cell signaling network. We found that there is a negative relationship between comorbidity and length of involved FBLs. This indicates that a disease pair is more likely to comorbid if they are connected with FBLs of shorter length. We additionally showed that such a negative relationship is more obvious when the number of positive involved FBLs is larger than that of negative involved FBLs. Moreover, we observed that the negative relationship between comorbidity and length of involved FBLs holds especially for disease pairs that do not share any disease-associated genes. Finally, we proved all these results through intensive simulations, based on a Boolean network model. CONTACT: kwonyk@ulsan.ac.kr SUPPLEMENTARY INFORMATION: Supplementary data are available at BioInformatics online. PMID- 21325304 TI - Olfaction-based anthropophily in a mosquito-specialist predator. AB - Evarcha culicivora is an unusual salticid spider because it feeds indirectly on vertebrate blood by choosing blood-carrying mosquitoes as preferred prey. Its preferred mosquitoes are Anopheles, the genus to which all human malaria vectors belong. Here, we show that human odour, which is known to be salient to malaria vectors, is also salient to the adults and juveniles of E. culicivora. Test spiders spent more time in the vicinity of a source of human odour (previously worn socks) when the alternative was unworn socks. PMID- 21325305 TI - Female bonobos use copulation calls as social signals. AB - During mating events, females of many primate species produce loud and distinct vocalizations known as 'copulation calls'. The adaptive significance of these signals is considered to be in promoting the caller's direct reproductive success. Here, we investigated copulation calling in bonobos (Pan paniscus), a species in which females produce these vocalizations during sexual interactions with partners of both sexes. Females were more likely to call when mating with males than with females. We also observed a positive relationship between the likelihood of calling and partner rank, regardless of partner sex. Sexual activity generally increased with swelling size (an indicator of reproductive state) and, during their peak swelling, females called more with male than with female partners. Female bonobos are unusual among the non-human primates in terms of their heightened socio-sexuality. Our results suggest that in this species, copulation calls have undergone an evolutionary transition from a purely reproductive to a more general social function, reflecting the intrinsic evolutionary links between vocal behaviour and social cognition. PMID- 21325306 TI - Understanding testosterone variation in a tropical lek-breeding bird. AB - Male reproductive coalitions, in which males cooperate to attract females, are a rare strategy among vertebrates. While some studies have investigated ultimate aspects of these relationships, little is known about the mechanistic role that hormones play in modulating cooperative behaviours. Here, we examined male testosterone variation in a tropical lekking bird, the wire-tailed manakin (Pipra filicauda), which exhibits cooperative male-male display coalitions. We found that testosterone levels in territorial males were comparable to those of temperate breeding birds, a surprising result given their environmental, social and reproductive dynamics. In addition, social status rather than plumage was a strong predictor of testosterone variation. Territorial males had significantly higher testosterone levels than did two other plumage classes of floater males, who do not hold territories. We hypothesize that testosterone variation plays an important role in the establishment of male dominance hierarchies (competition), while concurrently facilitating stable display partnerships (cooperation). PMID- 21325307 TI - Ecosystem approach to inland fisheries: research needs and implementation strategies. AB - Inland fisheries are a vital component in the livelihoods and food security of people throughout the world, as well as contributing huge recreational and economic benefits. These valuable assets are jeopardized by lack of research based understanding of the impacts of fisheries on inland ecosystems, and similarly the impact of human activities associated with inland waters on fisheries and aquatic biodiversity. To explore this topic, an international workshop was organized in order to examine strategies to incorporate fisheries into ecosystem approaches for management of inland waters. To achieve this goal, a new research agenda is needed that focuses on: quantifying the ecosystem services provided by fresh waters; quantifying the economic, social and nutritional benefits of inland fisheries; improving assessments designed to evaluate fisheries exploitation potential; and examining feedbacks between fisheries, ecosystem productivity and aquatic biodiversity. Accomplishing these objectives will require merging natural and social science approaches to address coupled social-ecological system dynamics. PMID- 21325308 TI - Coevolving parasites enhance the diversity-decreasing effect of dispersal. AB - High dispersal rates between patches in spatially structured populations can impede diversification and homogenize diversity. These homogenizing effects of dispersal are likely to be enhanced by coevolving parasites that impose strong selection on hosts for resistance. However, the interactive effects of dispersal and parasites on host diversification have never been tested. We used spatially structured, experimental populations of the bacterium Pseudomonas fluorescens, cultured with or without the phage SBW25F2 under three levels of dispersal (none, localized or global), and quantified diversity in terms of evolved bacterial colony morphologies after approximately 100 bacterial generations. We demonstrate that higher levels of colony morphology richness evolved in the presence of phage, and that dispersal reduced diversity most strongly in the presence of phage. Thus, our results suggest that, while parasites can drive host diversification, host populations coevolving with parasites are more prone to homogenization through dispersal. PMID- 21325309 TI - Synergy between social and private information increases foraging efficiency in ants. AB - Insect societies integrate many information sources to organize collective activities such as foraging. Many ants use trail pheromones to guide foragers to food sources, but foragers can also use memories to find familiar locations of stable food sources. Route memories are often more accurate than trail pheromones in guiding ants, and are often followed in preference to trail pheromones when the two conflict. Why then does the system expend effort in producing and acquiring seemingly redundant and low-quality information, such as trail pheromones, when route memory is available? Here we show that, in the ant Lasius niger, trail pheromones and route memory act synergistically during foraging; increasing walking speed and straightness by 25 and 30 per cent, respectively, and maintaining trail pheromone deposition, but only when used together. Our results demonstrate a previously undescribed major role of trail pheromones: to complement memory by allowing higher confidence in route memory. This highlights the importance of multiple interacting information sources in the efficient running of complex adaptive systems. PMID- 21325310 TI - On the vapour trail of an atmospheric imprint in insects. AB - Terrestrial arthropods, at constant risk from desiccation, are highly sensitive to atmospheric temperature and humidity. A physiological marker of these abiotic conditions could highlight phenotypic adaptations, indicate niche partitioning, and predict responses to climate change for a group representing three-quarters of the Earth's animal species. We show that the (18)O composition of insect haemolymph is such a measure, providing a dynamic and quantitatively predictable signal for respiratory gas exchange and inputs from atmospheric humidity. Using American cockroaches (Periplaneta americana) under defined experimental conditions, we show that insects respiring at low humidity demonstrate the expected enrichment in the (18)O composition of haemolymph because of evaporation. At high humidity, however, diffusional influx of atmospheric water vapour into the animal forces haemolymph to become depleted in (18)O. Additionally, using cockroaches sampled from natural habitats, we show that the haemolymph (18)O signature is transferred to the organic material of the insect's exoskeleton. Insect cuticle, therefore, exhibits the mean atmospheric conditions surrounding the animals prior to moulting. This discovery will help to define the climatic tolerances of species and their habitat preferences, and offers a means of quantifying the balance between niche partitioning and 'neutral' processes in shaping complex tropical forest communities. PMID- 21325311 TI - Yolk androgen deposition without an energetic cost for female rockhopper penguins: a compensatory strategy to accelerate brood reduction? AB - Whether androgen deposition in eggs is physiologically costly for female birds has remained a crucial but unsolved question, despite a broad use of this assumption in functional studies. We tested whether females depositing high androgen concentrations experienced higher mass losses than females depositing low androgen concentrations. Analysing female body mass change during egg formation in rockhopper penguins (Eudyptes chrysocome chrysocome), we observed no energetic cost to androgen deposition. Nevertheless, lighter females laid eggs with higher yolk androgen concentrations. This relationship existed only for the second-laid egg (B-egg), but not for the first-laid egg (A-egg). Since the B-egg is usually the first to hatch and the only one to produce a fledging chick, we hypothesize that differential yolk androgen deposition may be an adaptive strategy for females to affect brood reduction. PMID- 21325312 TI - 'Canis empathicus'? A proposal on dogs' capacity to empathize with humans. AB - Empathy has long attracted the attention of philosophers and psychologists, and more recently, of evolutionary biologists. Interestingly, studies suggest that empathy is a phylogenetically continuous phenomenon, ranging across animals from automatic emotional activation in response to the emotions of others, to perspective-taking that becomes increasingly complex with increasing brain size. Although suggestions have been made that the domestic dog may have the capacity to empathize with humans, no discussion has yet addressed the topic, nor have experimental routes been proposed to further explore the level of emotional and cognitive processing underlying dogs' seemingly empathic behaviour towards humans. In this opinion piece, we begin by contextualizing our topic of interest within the larger body of literature on empathy. Thereafter we: (i) outline the reasons for why we believe dogs may be capable of empathizing with humans, perhaps even at some level beyond emotional contagion; (ii) review available evidence both pro and against our opinion; and (iii) propose routes for future studies to accurately address the topic. Also, we consider the use of dogs to further explore open questions regarding empathy in humans. PMID- 21325313 TI - Nanogel surface coatings for improved single-molecule imaging substrates. AB - Surfaces that resist protein adsorption are important for many bioanalytical applications. Bovine serum albumin (BSA) coatings and multi-arm poly(ethylene glycol) (PEG) coatings display low levels of non-specific protein adsorption and have enabled highly quantitative single-molecule (SM) protein studies. Recently, a method was developed for coating a glass with PEG-BSA nanogels, a promising hybrid of these two low-background coatings. We characterized the nanogel coating to determine its suitability for SM protein experiments. SM adsorption counting revealed that nanogel-coated surfaces exhibit lower protein adsorption than covalently coupled BSA surfaces and monolayers of multi-arm PEG, so this surface displays one of the lowest degrees of protein adsorption yet observed. Additionally, the nanogel coating was resistant to DNA adsorption, underscoring the utility of the coating across a variety of SM experiments. The nanogel coating was found to be compatible with surfactants, whereas the BSA coating was not. Finally, applying the coating to a real-world study, we found that single ligand molecules could be tethered to this surface and detected with high sensitivity and specificity by a digital immunoassay. These results suggest that PEG-BSA nanogel coatings will be highly useful for the SM analysis of proteins. PMID- 21325314 TI - Modelling the spread of infectious salmon anaemia among salmon farms based on seaway distances between farms and genetic relationships between infectious salmon anaemia virus isolates. AB - Infectious salmon anaemia (ISA) is an important infectious disease in Atlantic salmon farming causing recurrent epidemic outbreaks worldwide. The focus of this paper is on tracing the spread of ISA among Norwegian salmon farms. To trace transmission pathways for the ISA virus (ISAV), we use phylogenetic relationships between virus isolates in combination with space-time data on disease occurrences. The rate of ISA infection of salmon farms is modelled stochastically, where seaway distances between farms and genetic distances between ISAV isolates from infected farms play prominent roles. The model was fitted to data covering all cohorts of farmed salmon and the history of all farms with ISA between 2003 and summer 2009. Both seaway and genetic distances were significantly associated with the rate of ISA infection. The fitted model predicts that the risk of infection from a neighbourhood infectious farm decreases with increasing seaway distance between the two farms. Furthermore, for a given infected farm with a given ISAV genotype, the source of infection is significantly more likely to be ISAV of a small genetic distance than of moderate or large genetic distances. Nearly half of the farms with ISA in the investigated period are predicted to have been infected by an infectious farm in their neighbourhood, whereas the remaining half of the infected farms had unknown sources. For many of the neighbourhood infected farms, it was possible to point out one or a few infectious farms as the most probable sources of infection. This makes it possible to map probable infection pathways. PMID- 21325315 TI - A highly distributed Bragg stack with unique geometry provides effective camouflage for Loliginid squid eyes. AB - Cephalopods possess a sophisticated array of mechanisms to achieve camouflage in dynamic underwater environments. While active mechanisms such as chromatophore patterning and body posturing are well known, passive mechanisms such as manipulating light with highly evolved reflectors may also play an important role. To explore the contribution of passive mechanisms to cephalopod camouflage, we investigated the optical and biochemical properties of the silver layer covering the eye of the California fishery squid, Loligo opalescens. We discovered a novel nested-spindle geometry whose correlated structure effectively emulates a randomly distributed Bragg reflector (DBR), with a range of spatial frequencies resulting in broadband visible reflectance, making it a nearly ideal passive camouflage material for the depth at which these animals live. We used the transfer-matrix method of optical modelling to investigate specular reflection from the spindle structures, demonstrating that a DBR with widely distributed thickness variations of high refractive index elements is sufficient to yield broadband reflectance over visible wavelengths, and that unlike DBRs with one or a few spatial frequencies, this broadband reflectance occurs from a wide range of viewing angles. The spindle shape of the cells may facilitate self assembly of a random DBR to achieve smooth spatial distributions in refractive indices. This design lends itself to technological imitation to achieve a DBR with wide range of smoothly varying layer thicknesses in a facile, inexpensive manner. PMID- 21325316 TI - Scanning ion conductance microscopy: a convergent high-resolution technology for multi-parametric analysis of living cardiovascular cells. AB - Cardiovascular diseases are complex pathologies that include alterations of various cell functions at the levels of intact tissue, single cells and subcellular signalling compartments. Conventional techniques to study these processes are extremely divergent and rely on a combination of individual methods, which usually provide spatially and temporally limited information on single parameters of interest. This review describes scanning ion conductance microscopy (SICM) as a novel versatile technique capable of simultaneously reporting various structural and functional parameters at nanometre resolution in living cardiovascular cells at the level of the whole tissue, single cells and at the subcellular level, to investigate the mechanisms of cardiovascular disease. SICM is a multimodal imaging technology that allows concurrent and dynamic analysis of membrane morphology and various functional parameters (cell volume, membrane potentials, cellular contraction, single ion-channel currents and some parameters of intracellular signalling) in intact living cardiovascular cells and tissues with nanometre resolution at different levels of organization (tissue, cellular and subcellular levels). Using this technique, we showed that at the tissue level, cell orientation in the inner and outer aortic arch distinguishes atheroprone and atheroprotected regions. At the cellular level, heart failure leads to a pronounced loss of T-tubules in cardiac myocytes accompanied by a reduction in Z-groove ratio. We also demonstrated the capability of SICM to measure the entire cell volume as an index of cellular hypertrophy. This method can be further combined with fluorescence to simultaneously measure cardiomyocyte contraction and intracellular calcium transients or to map subcellular localization of membrane receptors coupled to cyclic adenosine monophosphate production. The SICM pipette can be used for patch-clamp recordings of membrane potential and single channel currents. In conclusion, SICM provides a highly informative multimodal imaging platform for functional analysis of the mechanisms of cardiovascular diseases, which should facilitate identification of novel therapeutic strategies. PMID- 21325317 TI - Modelling behavioural contagion. AB - The last decade has seen much work on quantitative understanding of human behaviour, with online social interaction offering the possibility of more precise measurement of behavioural phenomena than was previously possible. A parsimonious model is proposed that incorporates several observed features of behavioural contagion not seen in existing epidemic model schemes, leading to metastable behavioural dynamics. PMID- 21325318 TI - Surface plasmon resonance imaging detection of silver nanoparticle-tagged immunoglobulin. AB - The detection sensitivity of silver nanoparticle (AgNP)-tagged goat immunoglobulin G (gIgG) microarrays was investigated by studying surface plasmon resonance (SPR) images captured in the visible wavelength range with the help of a Kretchmann-configured optical coupling set-up. The functionalization of anti gIgG molecules on the AgNP surface was studied using transmission electron microscopy, photon correlation measurements and UV-visible absorption spectroscopy. A value of 1.3*10(7) M(-1) was obtained for the antibody-antigen binding constant by monitoring the binding events at a particular resonance wavelength. The detection limit of this SPR imaging instrument is 6.66 nM of gIgG achieved through signal enhancement by a factor of larger than 4 owing to nanoparticle tagging with the antibody. PMID- 21325319 TI - Evidence of strategic periodicities in collective conflict dynamics. AB - We analyse the timescales of conflict decision-making in a primate society. We present evidence for multiple, periodic timescales associated with social decision-making and behavioural patterns. We demonstrate the existence of periodicities that are not directly coupled to environmental cycles or known ultraridian mechanisms. Among specific biological and socially defined demographic classes, periodicities span timescales between hours and days. Our results indicate that these periodicities are not driven by exogenous or internal regularities but are instead driven by strategic responses to social interaction patterns. Analyses also reveal that a class of individuals, playing a critical functional role, policing, have a signature timescale of the order of 1 h. We propose a classification of behavioural timescales analogous to those of the nervous system, with high frequency, or alpha-scale, behaviour occurring on hour long scales, through to multi-hour, or beta-scale, behaviour, and, finally gamma periodicities observed on a timescale of days. PMID- 21325320 TI - Biomimicry in textiles: past, present and potential. An overview. AB - The natural world around us provides excellent examples of functional systems built with a handful of materials. Throughout the millennia, nature has evolved to adapt and develop highly sophisticated methods to solve problems. There are numerous examples of functional surfaces, fibrous structures, structural colours, self-healing, thermal insulation, etc., which offer important lessons for the textile products of the future. This paper provides a general overview of the potential of bioinspired textile structures by highlighting a few specific examples of pertinent, inherently sustainable biological systems. Biomimetic research is a rapidly growing field and its true potential in the development of new and sustainable textiles can only be realized through interdisciplinary research rooted in a holistic understanding of nature. PMID- 21325321 TI - Ignoring the challenge? Male black redstarts (Phoenicurus ochruros) do not increase testosterone levels during territorial conflicts but they do so in response to gonadotropin-releasing hormone. AB - Competition elevates plasma testosterone in a wide variety of vertebrates, including humans. The 'challenge hypothesis' proposes that seasonal peaks in testosterone during breeding are caused by social challenges from other males. However, during experimentally induced male-male conflicts, testosterone increases only in a minority of songbird species tested so far. Why is this so? Comparative evidence suggests that species with a short breeding season may not elevate testosterone levels during territory defence. These species may even be limited in their physiological capability to increase testosterone levels, which can be tested by injecting birds with gonadotropin-releasing hormone (GnRH). We studied two populations of black redstarts that differ in breeding altitude, morphology and the length of their breeding season. Unexpectedly, males of neither population increased testosterone in response to a simulated territorial intrusion, but injections with GnRH resulted in a major elevation of testosterone. Thus, black redstarts would have been capable of mounting a testosterone response during the male-male challenge. Our data show, for the first time, that the absence of an androgen response to male-male challenges is not owing to physiological limitations to increase testosterone. Furthermore, in contrast to comparative evidence between species, populations of black redstarts with a long breeding season do not show the expected elevation in testosterone during male-male challenges. PMID- 21325322 TI - Scaling up ideals to freedom: are densities of red knots across western Europe consistent with ideal free distribution? AB - Local studies have shown that the distribution of red knots Calidris canutus across intertidal mudflats is consistent with the predictions of an ideal distribution, but not a free distribution. Here, we scale up the study of feeding distributions to their entire wintering area in western Europe. Densities of red knots were compared among seven wintering sites in The Netherlands, UK and France, where the available mollusc food stocks were also measured and from where diets were known. We tested between three different distribution models that respectively assumed (i) a uniform distribution of red knots over all areas, (ii) a uniform distribution across all suitable habitat (based on threshold densities of harvestable mollusc prey), and (iii) an ideal and free distribution (IFD) across all suitable habitats. Red knots were not homogeneously distributed across the different European wintering areas, also not when considering suitable habitats only. Their distribution was best explained by the IFD model, suggesting that the birds are exposed to interference and have good knowledge about their resource landscape at the spatial scale of NW Europe, and that the costs of movement between estuaries, at least when averaged over a whole winter, are negligible. PMID- 21325323 TI - Ultra-fast underwater suction traps. AB - Carnivorous aquatic Utricularia species catch small prey animals using millimetre sized underwater suction traps, which have fascinated scientists since Darwin's early work on carnivorous plants. Suction takes place after mechanical triggering and is owing to a release of stored elastic energy in the trap body accompanied by a very fast opening and closing of a trapdoor, which otherwise closes the trap entrance watertight. The exceptional trapping speed--far above human visual perception--impeded profound investigations until now. Using high-speed video imaging and special microscopy techniques, we obtained fully time-resolved recordings of the door movement. We found that this unique trapping mechanism conducts suction in less than a millisecond and therefore ranks among the fastest plant movements known. Fluid acceleration reaches very high values, leaving little chance for prey animals to escape. We discovered that the door deformation is morphologically predetermined, and actually performs a buckling/unbuckling process, including a complete trapdoor curvature inversion. This process, which we predict using dynamical simulations and simple theoretical models, is highly reproducible: the traps are autonomously repetitive as they fire spontaneously after 5-20 h and reset actively to their ready-to-catch condition. PMID- 21325324 TI - Sea to sky: impacts of residual salmon-derived nutrients on estuarine breeding bird communities. AB - Pacific salmon (Oncorhynchus spp.) returning to streams around the North Pacific Rim provide a nutrient subsidy to these ecosystems. While many species of animals feed directly on salmon carcasses each autumn, salmon-derived nutrients can also be stored in coastal habitats throughout the year. The effects of this storage legacy on vertebrates in other seasons are not well understood, especially in estuaries, which can receive a large portion of post-spawning salmon nutrients. We examine the effects of residual salmon-derived nutrients, forest habitats and landscape features on summer breeding birds in estuary forests. We compared models containing environmental variables and combined chum (Oncorhynchus keta) and pink (Oncorhynchus gorbuscha) salmon biomass to test predictions concerning bird density and diversity. We discovered that total bird, insectivore, golden crowned kinglet and Pacific wren densities and Shannon's diversity in the summer were strongly predicted by salmon biomass in the autumn. For most metrics, this relationship approaches an asymptote beyond 40 000 kg of salmon biomass. Foliage height diversity, watershed catchment area and estuary area were also important predictors of avian communities. Our study suggests that the legacy of salmon nutrients influences breeding bird density and diversity in estuaries that vary across a wide gradient of spawning salmon biomass. PMID- 21325325 TI - Identification of a gene associated with avian migratory behaviour. AB - Bird migration is one of the most spectacular and best-studied phenomena in behavioural biology. Yet, while the patterns of variation in migratory behaviour and its ecological causes have been intensively studied, its genetic, physiological and neurological control remains poorly understood. The lack of knowledge of the molecular basis of migration is currently not only limiting our insight into the proximate control of migration, but also into its evolution. We investigated polymorphisms in the exons of six candidate genes for key behavioural traits potentially linked to migration, which had previously been identified in several bird species, and eight control loci in 14 populations of blackcaps (Sylvia atricapilla), representing the whole range of geographical variation in migration patterns found in this species, with the aim of identifying genes controlling variation in migration. We found a consistent association between a microsatellite polymorphism and migratory behaviour only at one candidate locus: the ADCYAP1 gene. This polymorphism explained about 2.6 per cent of the variation in migratory tendency among populations, and 2.7-3.5% of variation in migratory restlessness among individuals within two independent populations. In all tests, longer alleles were associated with higher migratory activity. The consistency of results among different populations and levels of analysis suggests that ADCYAP1 is one of the genes controlling the expression of migratory behaviour. Moreover, the multiple described functions of the gene product indicate that this gene might act at multiple levels modifying the shift between migratory and non-migratory states. PMID- 21325326 TI - Impact of the experimental removal of lizards on Lyme disease risk. AB - The distribution of vector meals in the host community is an important element of understanding and predicting vector-borne disease risk. Lizards (such as the western fence lizard; Sceloporus occidentalis) play a unique role in Lyme disease ecology in the far-western United States. Lizards rather than mammals serve as the blood meal hosts for a large fraction of larval and nymphal western black legged ticks (Ixodes pacificus--the vector for Lyme disease in that region) but are not competent reservoirs for the pathogen, Borrelia burgdorferi. Prior studies have suggested that the net effect of lizards is to reduce risk of human exposure to Lyme disease, a hypothesis that we tested experimentally. Following experimental removal of lizards, we documented incomplete host switching by larval ticks (5.19%) from lizards to other hosts. Larval tick burdens increased on woodrats, a competent reservoir, but not on deer mice, a less competent pathogen reservoir. However, most larvae failed to find an alternate host. This resulted in significantly lower densities of nymphal ticks the following year. Unexpectedly, the removal of reservoir-incompetent lizards did not cause an increase in nymphal tick infection prevalence. The net result of lizard removal was a decrease in the density of infected nymphal ticks, and therefore a decreased risk to humans of Lyme disease. Our results indicate that an incompetent reservoir for a pathogen may, in fact, increase disease risk through the maintenance of higher vector density and therefore, higher density of infected vectors. PMID- 21325327 TI - Food web structure and biocontrol in a four-trophic level system across a landscape complexity gradient. AB - Decline in landscape complexity owing to agricultural intensification may affect biodiversity, food web complexity and associated ecological processes such as biological control, but such relationships are poorly understood. Here, we analysed food webs of cereal aphids, their primary parasitoids and hyperparasitoids in 18 agricultural landscapes differing in structural complexity (42-93% arable land). Despite little variation in the richness of each trophic group, we found considerable changes in trophic link properties across the landscape complexity gradient. Unexpectedly, aphid-parasitoid food webs exhibited a lower complexity (lower linkage density, interaction diversity and generality) in structurally complex landscapes, which was related to the dominance of one aphid species in complex landscapes. Nevertheless, primary parasitism, as well as hyperparasitism, was higher in complex landscapes, with primary parasitism reaching levels for potentially successful biological control. In conclusion, landscape complexity appeared to foster higher parasitism rates, but simpler food webs, thereby casting doubt on the general importance of food web complexity for ecosystem functioning. PMID- 21325328 TI - Connectivity dominates larval replenishment in a coastal reef fish metapopulation. AB - Direct estimates of larval retention and connectivity are essential to understand the structure and dynamics of marine metapopulations, and optimize the size and spacing of reserves within networks of marine-protected areas (MPAs). For coral reef fishes, while there are some empirical estimates of self-recruitment at isolated populations, exchange among sub-populations has been rarely quantified. Here, we used microsatellite DNA markers and a likelihood-based parentage analysis to assess the relative magnitude of self-recruitment and exchange among eight geographically distinct sub-populations of the panda clownfish Amphiprion polymnus along 30 km of coastline near Port Moresby, Papua New Guinea. In addition, we used an assignment/exclusion test to identify immigrants arriving from genetically distinct sources. Overall, 82 per cent of the juveniles were immigrants while 18 per cent were progeny of parents genotyped in our focal metapopulation. Of the immigrants, only 6 per cent were likely to be genetically distinct from the focal metapopulation, suggesting most of the connectivity is among sub-populations from a rather homogeneous genetic pool. Of the 18 per cent that were progeny of known adults, two-thirds dispersed among the eight sub populations and only one-third settled back into natal sub-populations. Comparison of our data with previous studies suggested that variation in dispersal distances is likely to be influenced by the geographical setting and spacing of sub-populations. PMID- 21325329 TI - A trade-off between current and future sex allocation revealed by maternal energy budget in a small mammal. AB - Sex-allocation theories generally assume differential fitness costs of raising sons and daughters. Yet, experimental confirmation of such costs is scarce and potential mechanisms are rarely addressed. While the most universal measure of physiological costs is energy expenditure, only one study has related the maternal energy budget to experimentally controlled offspring sex. Here, we experimentally test this in the bank vole (Myodes glareolus) by simultaneously manipulating the litter's size and sex ratio immediately after birth. Two weeks after manipulation, when mothers were at the peak of lactation and were pregnant with concurrent litters, we assessed their energy budget. We found that maternal food consumption and daily energy expenditure increased with the size of the litters being lactated. Importantly, the effects of offspring sex on energy budget depended on the characteristics of the simultaneously gestating litters. Specifically, the mothers nursing all-male litters and concurrently pregnant with male-biased litters had the highest energy expenditure. These had consequences for the next generation, as size of female offspring from the concurrent pregnancy of these mothers was compromised. Our study attests a higher cost of sons, consequently leading to a lower investment in them, and reveals the significance of offspring sex in moulding the trade-off between current and future maternal investment. PMID- 21325330 TI - Structural support, not insulation, is the primary driver for avian cup-shaped nest design. AB - The nest micro-environment is a widely studied area of avian biology, however, the contribution of nest conductance (the inverse of insulation) to the energetics of the incubating adult and offspring has largely been overlooked. Surface-specific thermal conductance (W degrees C(-1) cm(-2)) has been related to nest dimensions, wall porosity, height above-ground and altitude, but the most relevant measure is total conductance (G, W degrees C(-1)). This study is the first to analyse conductance allometrically with adult body mass (M, g), according to the form G = aM(b). We propose three alternative hypotheses to explain the scaling of conductance. The exponent may emerge from: heat loss scaling (M(0.48)) in which G scales with the same exponent as thermal conductance of the adult bird, isometric scaling (M(0.33)) in which nest shape is held constant as parent mass increases, and structural scaling (M(0.25)) in which nests are designed to support a given adult mass. Data from 213 cup-shaped nests, from 36 Australian species weighing 8-360 g, show conductance is proportional to M(0.25). This allometric exponent is significantly different from those expected for heat loss and isometric scaling and confirms the hypothesis that structural support for the eggs and incubating parent is the primary factor driving nest design. PMID- 21325331 TI - Learning to count begins in infancy: evidence from 18 month olds' visual preferences. AB - We used a preferential looking paradigm to evaluate infants' preferences for correct versus incorrect counting. Infants viewed a video depicting six fish. In the correct counting sequence, a hand pointed to each fish in turn, accompanied by verbal counting up to six. In the incorrect counting sequence, the hand moved between two of the six fish while there was still verbal counting to six, thereby violating the one-to-one correspondence principle of correct counting. Experiment 1 showed that Australian 18 month olds, but not 15 month olds, significantly preferred to watch the correct counting sequence. In experiment 2, Australian infants' preference for correct counting disappeared when the count words were replaced by beeps or by Japanese count words. In experiment 3, Japanese 18 month olds significantly preferred the correct counting video only when counting was in Japanese. These results show that infants start to acquire the abstract principles governing correct counting prior to producing any counting behaviour. PMID- 21325333 TI - Unified effects of aggregation reveal larger prey groups take longer to find. AB - Previous work has suggested that larger groups of prey are more conspicuous to predators. However, this ignores that prey populations are finite. As groups get larger they become fewer, hence the encounter rate between predator and prey decreases with prey aggregation. Here, we present a two-dimensional model based on visual angle to unify these encounter and conspicuousness effects of aggregation. With experimental support using three-spined sticklebacks (Gasterosteus aculeatus L.), searching for chironomid larvae, we demonstrate that the increase in visual angle with increasing group size is outweighed by its corresponding decrease as the groups become fewer and thus further away from the searching predator. The net effect is that prey are found with more difficulty when they aggregate, giving an additional anti-predatory benefit to group living rather than a cost. PMID- 21325332 TI - Weak conspecific feedbacks and exotic dominance in a species-rich savannah. AB - Whether dominance drives species loss can depend on the power of conspecific self limitation as dominant populations expand; these limitations can stabilize competitive imbalances that might otherwise cause displacement. We quantify the relative strength of conspecific and heterospecific soil feedbacks in an exotic dominated savannah, using greenhouse trials and field surveys to test whether dominants are less self-suppressed, highly suppressive of others or both. Soil feedbacks can impact plant abundance, including invasion, but their implications for coexistence in invader-dominated systems are unclear. We found that conspecific feedbacks were significantly more negative than heterospecific ones for all species including the dominant invaders; even the rarest natives performed significantly better in the soils of other species. The strength of these negative feedbacks, however, was approximately 50 per cent stronger for natives and matched their field abundance--the most self-limited natives were rare and narrowly distributed. These results suggest that exotics dominate by interacting with natives carrying heavier conspecific feedback burdens, without cultivating either negative heterospecific effects that suppress natives or positive ones that accelerate their own expansion. These feedbacks, however, could contribute to coexistence because all species were self-limited in their own soils. Although the net impact of this feedback stabilization will probably interact with other factors (e.g. herbivory), soil feedbacks may thus contribute to invader dominance without necessarily being detrimental to species richness. PMID- 21325334 TI - War as a moral imperative (not just practical politics by other means). AB - We present findings from one survey and five experiments carried out in the USA, Nigeria and the Middle East showing that judgements about the use of deadly intergroup violence are strikingly insensitive to quantitative indicators of success, or to perceptions of their efficacy. By demonstrating that judgements about the use of war are bounded by rules of deontological reasoning and parochial commitment, these findings may have implications for understanding the trajectory of violent political conflicts. Further, these findings are compatible with theorizing that links the evolution of within-group altruism to intergroup violence. PMID- 21325335 TI - The effects of maxillary protraction and its long-term stability--a clinical trial in Chinese adolescents. AB - The purpose of this study was to evaluate the effect of reverse pull headgear (RPHG) in the treatment of Class III malocclusions in the late mixed and early permanent dentition and its long-term stability at the time when facial growth was close to completion. The treatment group comprised 22 subjects (12 males and 10 females, mean age: 11.38 +/- 0.69 years). The control group included 17 subjects (7 males and 10 females, mean age: 11.54 +/- 1.07 years). The mean RPHG treatment time was 1.5 +/- 0.95 years and the observation time for the control group was 1.75 +/- 0.83 years. For each subject, lateral cephalograms were obtained before (T1) and after (T2) treatment or observation. These cephalograms were traced and analyzed and the differences between T1 and T2 values were examined with paired t-tests. Of the 22 treated cases, 10 patients were followed up until at the mean age of 16.18 years (T3). Since there was no relapse in anterior crossbite, the long-term effects of RPHG were evaluated by measuring the maxillary and mandibular skeletal changes. The follow-up patients were divided into two groups based on the change in ANB: a stable group (decrease in ANB < 2 degrees) and an unstable group (decrease in ANB > 2 degrees). The skeletal effects of RPHG in treating Class III anomalies just before or at the beginning of the pubertal growth spurt include protraction of the maxilla and dentition and inhibition of forward growth of the mandible. With regard to the long-term change, a slight alteration in the position of the maxilla and in the position and growth direction of the mandible resulted in a slight decrease in ANB in the stable group. The slight retrusion in the maxilla, combined with the significant protrusion in the mandible and the more horizontal mandibular growth direction, resulted in a decrease in ANB in the unstable group. This indicated that the maxilla remained relatively stable and that the unstable factor was continuing mandibular growth during the pubertal and post-pubertal period. For patients with an excessive mandible, orthopaedic therapy should start at the beginning of pubertal growth and orthodontic fixed appliance should follow immediately after RPHG so that mandibular growth in the sagittal direction during puberty or even after pubertal growth may be effectively inhibited. PMID- 21325337 TI - Rapid characterization of sugar-binding specificity by in-solution proximity binding with photosensitizers. AB - Cell-surface carbohydrates are known to participate in many important physiological and pathological activities by interacting with their corresponding proteins or receptors. Although several methods have been developed for studying carbohydrate-protein interactions, one major problem originates from the weak bindings of carbohydrates/proteins that are often lost during repeating wash steps. Herein, we established a homogeneous solution carbohydrate array in which polyacrylamide-based glycans are used for offering a multivalent environment. The method requires no wash step and can be carried out in a high-throughput manner. We characterized the carbohydrate-binding specificities of 11 lectins and 7 antibodies, the majority of which displayed the binding patterns in consistence with previous reports. These results demonstrate that our developed solution carbohydrate array provides a useful alternative that is better than or comparable with the current available methods. PMID- 21325336 TI - PGC-1 coactivators in the control of energy metabolism. AB - Chronic disruption of energy balance, where energy intake exceeds expenditure, is a major risk factor for the development of metabolic syndrome. The latter is characterized by a constellation of symptoms including obesity, dyslipidemia, insulin resistance, hypertension, and non-alcoholic fatty liver disease. Altered expression of genes involved in glucose and lipid metabolism as well as mitochondrial oxidative phosphorylation has been implicated in the pathogenesis of these disorders. The peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family of transcriptional coactivators is emerging as a hub linking nutritional and hormonal signals and energy metabolism. PGC-1alpha and PGC-1beta are highly responsive to environmental cues and coordinate metabolic gene programs through interaction with transcription factors and chromatin remodeling proteins. PGC-1alpha has been implicated in the pathogenic conditions including obesity, type 2 diabetes, neurodegeneration, and cardiomyopathy, whereas PGC-1beta plays an important role in plasma lipoprotein homeostasis and serves as a hepatic target for niacin, a potent hypotriglyceridemic drug. Here, we review recent advances in the identification of physiological and pathophysiological contexts involving PGC-1 coactivators, and also discuss their implications for therapeutic development. PMID- 21325338 TI - Genetic analysis of the O-antigen gene clusters of Yersinia pseudotuberculosis O:6 and O:7. AB - Among the 21 O-polysaccharide (OPS) O-antigen-based serotypes described for Yersinia pseudotuberculosis, those of O:6 and O:7 are unusual in that both contain colitose (4-keto-3,6-dideoxy-d-mannose or 4-keto-3,6-dideoxy-l-xylo hexose), which has not otherwise been reported for this species, and the O:6 OPS also contains yersiniose A (4-C[(R)-1-hydroxyethyl]-3,6-dideoxy-d-xylo-hexose), another unusual dideoxyhexose sugar. In Y. pseudotuberculosis, the genes for OPS synthesis generally cluster together between the hemH and gsk loci. Here, we present the sequences of the OPS gene clusters of Y. pseudotuberculosis O:6 and O:7, and the location of the genes required for synthesis of these OPSs, except that there is still ambiguity regarding allocation of some of the glycosyltransferase functions. The O:6 and O:7 gene clusters have much in common with each other, but differ substantially from the group of 13 gene clusters already sequenced, which share several features and sequence similarities. We also present a possible sequence of events for the derivation of the O:6 and O:7 gene clusters from the most closely related set of 13 sequenced previously. PMID- 21325339 TI - Ceramide glucosyltransferase of the nematode Caenorhabditis elegans is involved in oocyte formation and in early embryonic cell division. AB - Ceramide glucosyltransferase (Ugcg) [uridine diphosphate (UDP)-glucose:N acylsphingosine D-glucosyltransferase or UDP-glucose ceramide glucosyltransferase (GlcT): EC 2.4.1.80] catalyzes formation of glucosylceramide (GlcCer) from ceramide and UDP-glucose. There is only one Ugcg gene in the mouse genome, which is essential in embryogenesis and brain development. The nematode Caenorhabditis elegans has three Ugcg genes (cgt-1, cgt-2 and cgt-3), and double RNAi of the cgt 1 and cgt-3 genes results in lethality at the L1 larval stage. In this study, we isolated knockout worms for the three genes and characterized the gene functions. Each gene product showed active enzymatic activity when expressed in GM95 cells deficient in glycosphingolipids (GSLs). When each gene function was disrupted, the brood size of the animal markedly decreased, and abnormal oocytes and multinucleated embryos were formed. The CGT-3 protein had the highest Ugcg activity, and knockout of its gene resulted in the severest phenotype. When cgt-3 RNAi was performed on rrf-1 worms lacking somatic RNAi machinery but with intact germline RNAi machinery, a number of abnormal oocytes and multinucleated eggs were observed, although the somatic phenotype, i.e., L1 lethal effects of cgt 1/cgt-3 RNAi, was completely suppressed. Cell surface expression of GSLs and sphingomyelin, which are important components of membrane domains, was affected in the RNAi-treated embryos. In the embryos, an abnormality in cytokinesis was also observed. From these results, we concluded that the Ugcg gene is indispensable in the germline and that an ample supply of GlcCer is needed for oocytes and fertilized eggs to maintain normal membranes and to proceed through the normal cell cycle. PMID- 21325340 TI - Phylogenetic relationships among arecoid palms (Arecaceae: Arecoideae). AB - BACKGROUND AND AIMS: The Arecoideae is the largest and most diverse of the five subfamilies of palms (Arecaceae/Palmae), containing >50 % of the species in the family. Despite its importance, phylogenetic relationships among Arecoideae are poorly understood. Here the most densely sampled phylogenetic analysis of Arecoideae available to date is presented. The results are used to test the current classification of the subfamily and to identify priority areas for future research. METHODS: DNA sequence data for the low-copy nuclear genes PRK and RPB2 were collected from 190 palm species, covering 103 (96 %) genera of Arecoideae. The data were analysed using the parsimony ratchet, maximum likelihood, and both likelihood and parsimony bootstrapping. KEY RESULTS AND CONCLUSIONS: Despite the recovery of paralogues and pseudogenes in a small number of taxa, PRK and RPB2 were both highly informative, producing well-resolved phylogenetic trees with many nodes well supported by bootstrap analyses. Simultaneous analyses of the combined data sets provided additional resolution and support. Two areas of incongruence between PRK and RPB2 were strongly supported by the bootstrap relating to the placement of tribes Chamaedoreeae, Iriarteeae and Reinhardtieae; the causes of this incongruence remain uncertain. The current classification within Arecoideae was strongly supported by the present data. Of the 14 tribes and 14 sub-tribes in the classification, only five sub-tribes from tribe Areceae (Basseliniinae, Linospadicinae, Oncospermatinae, Rhopalostylidinae and Verschaffeltiinae) failed to receive support. Three major higher level clades were strongly supported: (1) the RRC clade (Roystoneeae, Reinhardtieae and Cocoseae), (2) the POS clade (Podococceae, Oranieae and Sclerospermeae) and (3) the core arecoid clade (Areceae, Euterpeae, Geonomateae, Leopoldinieae, Manicarieae and Pelagodoxeae). However, new data sources are required to elucidate ambiguities that remain in phylogenetic relationships among and within the major groups of Arecoideae, as well as within the Areceae, the largest tribe in the palm family. PMID- 21325341 TI - Obesity and weight management in the elderly. AB - Our population is ageing, and obesity is increasing in the elderly bringing massive and rapidly changing burdens of ill health related to increased body weights and fat as well as the main drivers of poor diet and inactivity. Overweight and obesity, and a static body mass index (BMI) commonly conceal sarcopenia (gain in body fat but loss of muscle mass and functional capacity) in older people, aggravated by inactivity. A systematic computerized literature search using an iterative manipulation process of the keywords: obesity, elderly, weight loss. The following databases were accessed on 20 October 2010: Medline, Cochrane Collaboration, Ovid and Scholar Google. A large number of clinical consequences of overweight and obesity are particularly problematic for elderly individuals, including type 2 diabetes mellitus, arthritis, urinary incontinence and depression. The observation that the BMI value associated with the lowest relative mortality is slightly higher in older than in younger adults has often been misinterpreted that obesity is not as harmful in the elderly. BMI may be a less appropriate index in the elderly. All the medical consequences of obesity are multi-factorial but all are alleviated by modest, achievable weight loss (5 10 kg) with an evidence-based maintenance strategy. Since sarcopenic obesity is common in the elderly, a combination of exercise and modest calorie restriction appears to be the optimal method of reducing fat mass and preserving muscle mass. Reduction in polypharmacy is a valuable target for weight management. Age is not an obstacle to weight management interventions using moderate calorie restriction and exercise, and the currently licensed drug orlistat appears to have no age related hazards. Overall balance of clinical outcomes has not been evaluated. In older people the risks from bariatric surgery outweigh benefits. Obesity, and specifically sarcopenic obesity, should also be prevented not only from younger age, but also during major life transitions including retirement, to improve better health outcomes and quality of life in later years, with a focus on those in 'obese families', where the main increases in obesity are located. Randomized controlled trials to determine health benefits and risks from long-term weight management in obese elderly are necessary. PMID- 21325342 TI - Acute myocardial infarction complication diagnosed by three-dimensional echocardiography. AB - Transthoracic echocardiography is the modality of choice for the bedside diagnosis of acute myocardial infarction mechanical complications. We report the case of a ventricular septal rupture occurring soon after inferior myocardial infarction, revascularized by primary angioplasty. This challenging diagnosis was elucidated by 3D-echocardiography as 2D-imaging was not conclusive. This case demonstrates the importance of 3D-echocardiography in a cardiac intensive care setting. It provided additional information to 2D-echocardiography by identifying and locating post-acute myocardial infarction (AMI) septal rupture with implications for planning surgery. PMID- 21325344 TI - Typical atrioventricular nodal re-entrant tachycardia: still many obscure points. PMID- 21325343 TI - Change in 25-hydroxyvitamin D and physical performance in older adults. AB - BACKGROUND: Vitamin D deficiency is common among older adults and is associated with poor physical performance; however, studies examining longitudinal changes in 25-hydroxyvitamin D (25[OH]D) and physical performance are lacking. We examined the association between 25(OH)D and physical performance over 12 months in older adults participating in the Lifestyle Interventions and Independence for Elders Pilot (LIFE-P), a multicenter physical activity intervention trial. METHODS: Plasma 25(OH)D and physical performance, assessed by the short physical performance battery (SPPB) and 400-m walk test, were measured at baseline, 6 month, and 12-month follow-up in community-dwelling adults aged 70-89 years at risk for disability (n = 368). Mixed models were used to examine the association between 25(OH)D and physical performance adjusting for demographics, intervention group, season, body mass index, and physical activity. RESULTS: One half of the participants were vitamin D deficient (25[OH]D < 20 ng/mL) at baseline. In cross sectional analyses, vitamin D deficiency was associated with lower SPPB scores and slower 400-m walk speeds (mean difference [SE]: 0.35 [0.16], p = .03 and 0.04 [0.02] m/s, p = .01, respectively). Although baseline 25(OH)D status was not significantly associated with change in physical performance over 12 months, individuals who were vitamin D deficient at baseline but no longer deficient at follow-up had significant improvements in SPPB scores (mean difference [SE]: 0.55 [0.22], p = .01) compared with those whose 25(OH)D status remained the same. CONCLUSION: Increases in 25(OH)D to greater than or equal to 20 ng/mL were associated with clinically significant improvements in physical performance among older adults. PMID- 21325345 TI - The incidence and risk factors for new onset atrial fibrillation in the PROSPER study. AB - AIMS: Atrial fibrillation/flutter (AF) is the most common arrhythmia in older people. It associates with reduced exercise capacity, increased risk of stroke, and mortality. We aimed to determine retrospectively whether pravastatin reduces the incidence of AF and whether any electrocardiographic measures or clinical conditions might be risk factors for its development. METHODS AND RESULTS: The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) was a randomized, double-blind controlled trial that recruited 5804 individuals aged 70 82 years with a history of, or risk factors for, vascular disease. A total of 2891 were allocated to pravastatin and 2913 to placebo; mean follow-up was 3.2 years. Electrocardiograms (ECGs), which were recorded at baseline, annually thereafter, and at run-out, were processed by computer and reviewed manually. In all, 264 of 2912 (9.1%) of the placebo group and 283 of 2888 (9.8%) of the pravastatin-treated group developed AF [hazard ratio 1.08 (0.92,1.28), P= 0.35)]. Multivariate analysis showed that PR and QTc intervals, age, left ventricular hypertrophy, and ST-T abnormalities were related to development of AF after adjustment for many variables including alcohol consumption, which itself was univariately predictive of developing AF. Previous myocardial infarction on the ECG was not a risk factor. A history of vascular disease was strongly linked with developing AF but not diabetes and hypertension. CONCLUSION: Pravastatin does not reduce the incidence of AF in older people at risk of vascular disease, at least in the short-medium term. Risk factors for AF include older age, prolongation of PR or QTc intervals, left ventricular hypertrophy, and ST-T abnormalities on the ECG. PMID- 21325346 TI - Performance of an implantable automatic atrial fibrillation detection device: impact of software adjustments and relevance of manual episode analysis. AB - AIMS: Implantable loop recorders (ILRs) with specific atrial fibrillation (AF) detection algorithms (ILR-AF) have been developed for continuous AF monitoring. We sought to analyse the clinical value of a new AF monitoring device and to compare it to serial 7-day Holter. METHODS AND RESULTS: Sixty-four consecutive patients suffering from paroxysmal AF were included in this prospective analysis and received an ILR-AF. Manual electrogram analysis was performed for each automatically detected episode and each was categorized into one of three possible diagnoses: 'no AF', 'definite AF', and 'possible AF' (non-diagnostic). Analysis was performed separately before and after a software upgrade that was introduced during the course of the study. A subgroup of patients (51 of 64) underwent AF catheter ablation with subsequent serial 7-day Holter in comparison with the ILR-AF. A total of 333 interrogations were performed (203 before and 130 after software upgrade). The number of patients with AF misdetection was significantly reduced from 72 to 44% following the software upgrade (P = 0.001). The number of patients with non-diagnostic interrogations went from 38 to 16% (P = 0.001). Compared with serial 7-day Holter, the ILR-AF had a tendency to detect a higher number of patients with AF recurrences (31 vs. 24%; P = 0.125). CONCLUSIONS: The rate of AF detection on ILR-AF may be higher compared with standard AF monitoring. However, false-positive AF recordings hamper the clinical value. Developments in device technology and device handling are necessary to minimize non-diagnostic interrogations. PMID- 21325347 TI - Perforating vein fistula is superior to forearm fistula in elderly haemodialysis patients with diabetes and arterial hypertension. AB - BACKGROUND: Access-related problems are one of the major causes of morbidity in elderly patients with chronic kidney disease. The aim of this study was to assess potential risks and benefits in elderly patients comparing forearm arteriovenous fistula (AVF) and perforating vein AVF below the elbow for primary vascular access. METHODS: A retrospective comparison of elderly patients (65.7 +/- 9.3 years, 70.4% male patients, 36.2% late referral) undergoing primary vascular access surgery using forearm AVF (n = 50) and perforating vein AVF (n = 55) was performed over a 2-year period, including a multivariate analysis of potential risk factors and benefits of primary patency (PP = intervention-free access survival) and secondary patency (SP = access survival until abandonment). RESULTS: Patency rates after 24 months were significantly higher in patients with perforating vein AVF (PP + SP: 78.2%) compared to forearm AVF (PP: 62%, SP: 56%, P = 0.04). Presence of diabetes mellitus in patients with forearm AVF was associated with a decreased PP [odds ratio (OR): 3.6, 95% confidence interval (CI): 0.9-13.8] and SP (OR: 4.8, 95% CI: 1.3-17.9), and arterial hypertension was associated with a lower PP (OR: 6.7, 95% CI: 0.8-53.9), whereas the presence of hyperparathyroidism was associated with higher PP and SP (OR: 0.2, 95% CI: 0.1 0.7). In contrast, PP and SP in patients with perforating vein AVF were not influenced by comorbidities. CONCLUSIONS: Perforating vein AVF is superior to forearm AVF in elderly patients with diabetes and arterial hypertension due to the proximal fistula location, probably caused by an improved artery distensibility during fistula maturation. PMID- 21325348 TI - Anaemia and resistance to erythropoiesis-stimulating agents as prognostic factors in haemodialysis patients: results from the RISCAVID study. AB - BACKGROUND: Resistance to erythropoiesis-stimulating agents (ESAs) is often associated with chronic inflammation. Here, we investigated how anaemia, ESA resistance and the plasma levels of biological markers of inflammation could influence all-cause and cardiovascular disease morbidity and mortality. METHODS: Seven hundred and fifty-three haemodialysis (HD) patients (mean age 66 +/- 14.2 years, mean dialytic age 70 +/- 77 months and diabetes 18.8%) were enrolled and followed-up for 36 months. Demographic, clinical and laboratory data, co morbidity conditions, administered drugs, all-cause mortality and fatal/non-fatal cardiovascular (CV) events were recorded. We measured ESA resistance index, C reactive protein (CRP) and interleukin-6 (IL-6). RESULTS: Six hundred and fifty one patients (86.4%) received ESAs. Patients with haemoglobin level <11 g/dL (n = 225) showed increased risk of CV [relative risk (RR) 1.415, 95% confidence interval (CI) 1.046-1.914] and overall mortality (RR 1.897, 95% CI 1.423-2.530) versus patients with haemoglobin levels >11 g/dL. ESA resistance values categorized into quartiles (Quartile I <5.6, Quartile II 5.7-9.6, Quartile III 9.7-15.4 and Quartile IV >15.4) correlated with all-cause mortality and fatal/non fatal CV events (RR 1.97, 95% CI 1.392-2.786; RR 1.619, 95% CI 1.123-2.332, respectively). Furthermore, albumin was significantly reduced versus reference patients and correlated with all-cause mortality and CV events; CRP levels were higher in hyporesponders (Quartile IV) (P < 0.001) and predicted all-cause mortality and CV events. IL-6 but not CRP was a strong predictor of ESA resistance. CONCLUSIONS: ESA responsiveness can be considered a strong prognostic factor in HD patients and seems to be tightly related to protein-energy wasting and inflammation. PMID- 21325349 TI - Iron and vascular calcification. Is there a link? AB - Iron deficiency is frequently seen in patients with end-stage renal disease, particularly in those treated by dialysis, this is because of an impairment in gastrointestinal absorption and ongoing blood losses or alternatively, due to an impaired capacity to mobilize iron from its stores, called functional iron deficiency. Therefore, these patients may require intravenous iron to sustain adequate treatment with erythropoietin-stimulating agents. Aside from this, they are also prone to vascular calcification, which has been reported a major contributing factor in the development of cardiovascular disease and the increased mortality associated herewith. Several factors and mechanisms underlying the development of vascular calcification in chronic kidney diseased patients have been put forward during recent years. In view of the ability of iron to exert direct toxic effects and to induce oxidative stress on the one hand versus its essential role in various cellular processes on the other hand, the possible role of iron in the development of vascular calcification should be considered. PMID- 21325350 TI - Glutathione peroxidase, superoxide dismutase and catalase genotypes and activities and the progression of chronic kidney disease. AB - BACKGROUND: Oxidative stress has been linked to the progression of disease, including chronic kidney disease (CKD). The aim of the present study was to determine the association between single-nucleotide polymorphisms (SNPs) of the antioxidant enzymes, superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase and their activities and the progression of CKD. METHODS: This is a prospective cohort study of 185 CKD patients (Stages 2-4), followed for up to 12 months. All patients were genotyped for SNPs of SOD (SOD Ala16Val), GPx (GPx Pro197Leu) and catalase (C-262T). The rate of change over the study period of estimated glomerular filtration rate (eGFR), plasma and red blood cell (RBC) GPx, RBC SOD and RBC catalase activities were determined. RESULTS: CKD patients with the SOD Ala/Val and Val/Val genotypes had a significantly greater eGFR decline compared to those with the Ala/Ala genotype (Ala/Val compared with Ala/Ala odds ratio (OR) 0.35, 95% CI 0.19 to 0.64, P = 0.001; Val/Val compared with Ala/Ala OR 0.25, 95% CI 0.10 to 0.65, P = 0.005). The progression of CKD was not associated with SNPs of the GPx or catalase genes studied but there was a direct relationship between the rate of change of plasma GPx activity and the rate of change of eGFR over 12 months (P = 0.025). CONCLUSION: CKD patients with the SOD Ala/Val and Val/Val genotypes have a greater decline in kidney function than those with the Ala/Ala genotype. PMID- 21325351 TI - Effects of comorbid and demographic factors on dialysis modality choice and related patient survival in Europe. AB - BACKGROUND: The mean age of patients starting dialysis increased over the years, as has the proportion of patients with diabetes mellitus, ischaemic heart disease, peripheral vascular disease (PVD), cerebrovascular disease (CD) and malignancy. We assessed dialysis modality choice within subgroups of patients with these comorbidities and in different age categories and subsequently evaluated the association between modality choice and patient survival in these subgroups. METHODS: Seven European renal registries participating in the ERA-EDTA Registry provided data from 15,828 incident peritoneal dialysis (PD) and haemodialysis (HD) patients (1998-2006) with available comorbidity data. The likelihood to receive PD rather than HD was assessed with logistic regression and 3-year survival on PD versus HD was evaluated using Cox regression. RESULTS: Besides large international variations in the likelihood to receive PD, we found that elderly patients and patients with PVD, CD, malignancy and multiple comorbidities were significantly less likely to receive PD than HD. Overall patients starting on PD had survival benefits [adjusted hazard ratio (HR(adj)) 0.82 (0.75-0.90)], especially patients without comorbidity [HR(adj) 0.65 (0.53 0.80)] or those with malignancy [HR(adj) 0.73 (0.56-0.94)]. In males, survival benefits of PD were independent of diabetic status. Conversely, diabetic females tended to have increased mortality risk on PD [HR(adj) 1.16 (0.93-1.44)], especially if they were >70 years [HR(adj) 1.55 (1.15-2.08)]. CONCLUSIONS: In general, modality choice was consistent with expected survival. However, elderly patients, non-diabetic patients and those with malignancy were less likely to receive PD, even though they had decreased mortality risk on PD. Also, although a survival benefit of PD was found for male patients without comorbidity, HD was just as likely to be the chosen dialysis modality as was PD for these patients. PMID- 21325352 TI - Introduction of the CKD-EPI equation to estimate glomerular filtration rate in a Caucasian population. AB - BACKGROUND: Chronic kidney disease (CKD) is defined as the presence of kidney damage, albuminuria or a reduction in glomerular filtration rate (GFR). A GFR <60 mL/min/1.73 m(2) alone is sufficient to diagnose CKD Stages III-V. Recently, the new chronic kidney disease epidemiology collaboration (CKD-EPI) equation was introduced. It has been suggested to result in higher estimated glomerular filtration rates (eGFRs) than the Modification of Diet in Renal Disease (MDRD(4)) formula. Here, we assess consequences of introducing the CKD-EPI equation in a West European Caucasian population. METHODS: Data were obtained from 6097 Caucasian participants of the Nijmegen Biomedical Study (2823 males and 3274 females). Serum creatinine values were determined using the Jaffe method, calibrated against mass spectrometry and were used to calculate eGFR(MDRD4) and eGFR(CKD-EPI). Demographic data, health status and information on medication use for all participants was obtained with a postal questionnaire. RESULTS: The introduction of the CKD-EPI equation changed the curve of eGFR by age, with higher values in the younger age groups and a steeper decline of eGFR with ageing. As a consequence, younger people were more often classified to a higher GFR stage and older people, especially males, to a lower GFR stage. CONCLUSIONS: In comparison with the MDRD(4) formula, the CKD-EPI equation leads to higher estimates of GFR in young people and lower estimates in the elderly. On a population level, this may lead to higher estimates of kidney function. However, in routine clinical practice where the population is predominantly elderly, the opposite may be true. The introduction of eGFR(CKD-EPI) necessitates reconsidering the definition of CKD. We suggest introducing age-dependent threshold values and/or the use of urinary albumin excretion to improve risk stratification. PMID- 21325353 TI - Rituximab for the treatment of Churg-Strauss syndrome with renal involvement. AB - INTRODUCTION: Churg-Strauss syndrome (CSS) is a small vessel systemic vasculitis associated with asthma and eosinophilia that causes glomerulonephritis (GN) in ~25% of patients. Rituximab (RTX) is a chimeric anti-CD20 monoclonal antibody that depletes B cells and is effective in numerous autoimmune diseases including antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. We aim to evaluate the safety and efficacy of RTX in inducing remission of renal disease activity in patients with CSS. METHODS: We conducted a single-center, open-label pilot study using RTX (375 mg/m(2)/week * 4) for induction of remission in CSS patients with renal involvement [defined as having >25% dysmorphic red cells, red blood cell casts or pauci-immune GN on biopsy]. Written informed consent was obtained from all individuals. Patients were eligible if they were untreated, had failed glucocorticoid therapy or had failed glucocorticoid dose reductions because of disease relapses. The primary outcome was remission of renal disease activity defined as stability or improvement of creatinine clearance, absence of active urinary sediment and reduction of the glucocorticoid dose to <50% of the average dose received over 3 months before enrollment or <10 mg/day (whichever is smaller) at 6 months. Patients were followed up for 1 year. RESULTS: Only three patients (two females; ages 54, 55 and 65) were enrolled. All patients had positive myeloperoxidase-ANCA and renal involvement. Two patients had biopsy proven pauci-immune crescentic GN. All achieved the primary end point of renal remission within the first 3 months and remained in renal remission during the year following RTX treatment. One patient experienced a nonrenal relapse (eye and joint involvement) at 6 months coinciding with the reconstitution of CD19+ cells and eosinophilia. He was retreated with RTX and achieved remission within 6 weeks. No major adverse effects were recorded. CONCLUSIONS: In this pilot study, RTX was safe and successful in controlling renal disease activity in three patients with CSS. This agent deserves further study in CSS. PMID- 21325354 TI - Increased IGF-1 in muscle modulates the phenotype of severe SMA mice. AB - Spinal muscular atrophy (SMA) is an inherited motor neuron disease caused by the mutation of the survival motor neuron 1 (SMN1) gene and deficiency of the SMN protein. Severe SMA mice have abnormal motor function and small, immature myofibers early in development suggesting that SMN protein deficiency results in retarded muscle growth. Insulin-like growth factor 1 (IGF-1) stimulates myoblast proliferation, induces myogenic differentiation and generates myocyte hypertrophy in vitro and in vivo. We hypothesized that increased expression of IGF-1 specifically in skeletal muscle would attenuate disease features of SMADelta7 mice. SMADelta7 mice overexpressing a local isoform of IGF-1 (mIGF-1) in muscle showed enlarged myofibers and a 40% increase in median survival compared with mIGF-1-negative SMA littermates (median survival = 14 versus 10 days, respectively, log-rank P = 0.025). Surprisingly, this was not associated with a significant improvement in motor behavior. Treatment of both mIGF-1(NEG) and mIGF 1(POS) SMA mice with the histone deacetylase inhibitor, trichostatin A (TSA), resulted in a further extension of survival and improved motor behavior, but the combination of mIGF-1 and TSA treatment was not synergistic. These results show that increased mIGF-1 expression restricted to muscle can modulate the phenotype of SMA mice indicating that therapeutics targeted to muscle alone should not be discounted as potential disease-modifying therapies in SMA. IGF-1 may warrant further investigation in mild SMA animal models and perhaps SMA patients. PMID- 21325355 TI - Renal granular cell tumour (Abrikossoff tumour): case report and review of the literature. AB - A 52-year-old female was referred to our institute for an incidental renal mass. A homogenously enhancing mass was detected on multidetector CT (MDCT) imaging. Histologically, the tumour was consistent with granular cell tumour (GCT). GCT is a benign tumour that often involves the skin and subcutaneous tissue. Rarely has it been reported to involve the genitourinary system. Here we present the first reported case of GCT with renal involvement along with its MDCT imaging features. The authors also present a review of the literature along with a review of typical MDCT imaging features of enhancing renal masses with emphasis given to renal cell carcinoma and its varying subtypes. PMID- 21325356 TI - A case of lobular carcinoma in situ presenting as a solid mass. AB - A patient presented with a 2 cm lump in the lower outer quadrant of the left breast. Mammogram and ultrasonography showed a solid mass with a microlobulated contour, partially irregular border and microcalcifications. MRI showed an irregular mass with early enhancement and high signal intensity, and the late phase image demonstrated a partial washout pattern. These findings suggest that the tumour was a malignant invasive carcinoma. Non-invasive ductal carcinoma was diagnosed after a fine needle aspiration and core needle biopsy followed by a partial breast excision and sentinel lymph node (SLN) biopsy. A pathological examination of the lesion displayed characteristic small monomorphic cells, solid proliferation and massive distension within the lobular unit. The tumour was immunohistochemically negative for E-cadherin and pure lobular carcinoma in situ (LCIS) was diagnosed. Pure LCIS is very rare and there have been no previous reports of pure LCIS forming a solid mass. PMID- 21325357 TI - CT and ultrasound findings of metanephric adenoma: a report of two cases and literature review. AB - Metanephric adenoma (MA) of the kidney is an uncommon benign epithelial tumour that can present at any age. The histology of the lesion is well established, but imaging findings have been described in only a few cases. We report the CT and ultrasound appearance of MA in two females to increase the awareness of this entity among radiologists. Its recognition may facilitate nephron-sparing surgery. PMID- 21325358 TI - Pituicytoma: case report and literature review. AB - Pituicytoma is a rare primary tumour of the neurohypophysis or infundibulum, which masquerades as a pituitary adenoma. We present a pituicytoma case in a 45 year-old female presenting as a focal lesion of the neurohypophysis. This case report reviews the clinical, neuroimaging and histopathological features of this rare tumour in order to understand it better. PMID- 21325359 TI - Constrictive pericarditis presenting with an outpouching of the right ventricle free wall simulating an aneurysmal dilatation. AB - We present a case of constrictive pericarditis resulting in an outpouching of the right ventricular free wall, simulating a right ventricular free wall aneurysm. The present case is, to the best of our knowledge, the first reported right ventricular free wall aneurysm-like outpouching adjacent to surrounding regions of thickened pericardium in a patient with constrictive pericarditis. PMID- 21325360 TI - A case of tracheal varices: an unusual but important cause of mural nodules in the trachea. AB - Tracheal varices (TV) are uncommon but can be an important source of massive or recurrent haemoptysis. We present a case of TV in a 32-year-old patient with a history of Glenn-Fontan surgery, for congenital tricuspid atresia, and portal hypertension owing to cardiac cirrhosis. We discuss TV presenting as tracheal nodules in the presence of extensive mediastinal collateral circulation. PMID- 21325361 TI - FDG-PET/CT-guided biopsy of bone metastases sets a new course in patient management after extensive imaging and multiple futile biopsies. AB - A 73-year-old man with a history of prostate and bladder carcinoma and persistent back pain was diagnosed by MRI with multiple vertebral metastases including a compression fracture of T7. He received radiotherapy for pain relief and for vertebral instability with incipient spinal stenosis, but additional targeted systemic therapy was intended. Therefore, multiple attempts at minimally invasive and open biopsies for histological characterisation of the bone metastases were performed, but failed to provide a conclusive specimen, although CT, MRI and bone scintigraphy were used for biopsy planning. Only histopathological analysis of an (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT-guided additional biopsy at a site with high metabolic activity yielded the final diagnosis of bone metastases of a neuroendocrine small cell cancer of unknown origin; hence, the patient had a third malignancy requiring a different therapy regimen and diagnostic work-up. PMID- 21325362 TI - The use of central venous catheters for intravenous contrast injection for CT examinations. AB - The use of intravenous (i.v.) contrast media in CT examinations is often of great value in improving diagnostic accuracy. The preferable route of administration is via a peripheral i.v. cannula, with powered injectors allowing reliable delivery of rapid flow rates. However, many patients with a pre-existing central venous access device may have difficult peripheral access and there is a temptation to use the central device for delivery of contrast media. This review summarises the available evidence for the safe and effective use of these devices to assist the radiologist in balancing the relative risks and benefits of their use for contrast medium injection. PMID- 21325363 TI - Comparison of diamond-like carbon-coated nitinol stents with or without polyethylene glycol grafting and uncoated nitinol stents in a canine iliac artery model. AB - OBJECTIVE: Neointimal hyperplasia is a major complication of endovascular stent placement with consequent in-stent restenosis or occlusion. Improvements in the biocompatibility of stent designs could reduce stent-associated thrombosis and in stent restenosis. We hypothesised that the use of a diamond-like carbon (DLC) coated nitinol stent or a polyethylene glycol (PEG)-DLC-coated nitinol stent could reduce the formation of neointimal hyperplasia, thereby improving stent patency with improved biocompatibility. METHODS: A total of 24 stents were implanted, under general anaesthesia, into the iliac arteries of six dogs (four stents in each dog) using the carotid artery approach. The experimental study dogs were divided into three groups: the uncoated nitinol stent group (n = 8), the DLC-nitinol stent group (n = 8) and the PEG-DLC-nitinol stent group (n = 8). RESULTS: The mean percentage of neointimal hyperplasia was significantly less in the DLC-nitinol stent group (26.7+/-7.6%) than in the nitinol stent group (40.0+/ 20.3%) (p = 0.021). However, the mean percentage of neointimal hyperplasia was significantly greater in the PEG-DLC-nitinol stent group (58.7+/-24.7%) than in the nitinol stent group (40.0+/-20.3%) (p = 0.01). CONCLUSION: Our findings indicate that DLC-coated nitinol stents might induce less neointimal hyperplasia than conventional nitinol stents following implantation in a canine iliac artery model; however, the DLC-coated nitinol stent surface when reformed with PEG induces more neointimal hyperplasia than either a conventional or DLC-coated nitinol stent. PMID- 21325364 TI - Accuracy of multislice CT angiography for the assessment of in-stent restenoses in the iliac arteries at reduced dose: a phantom study. AB - OBJECTIVE: We investigated the potential of low-dose CT angiography for accurate assessment of in-stent restenoses (ISRs) of the iliac artery. METHOD: A Rando anthropomorphic phantom (Alderson Research Labs, Stanford, CA), custom-made wax simulating hyperplastic tissue and a nitinol stent were used to simulate a patient with clinically relevant iliac artery ISRs. The cylindrical lumen was filled with a solution of iodine contrast medium diluted in saline, representing a patient's blood during CT angiography. The phantom was subjected to standard- and low-dose angiographic exposures using a modern multidetector (MD) CT scanner. The percentage of ISR was determined using the profile along a line normal to the lumen axis on reconstructed images of 2 and 5 mm slice thickness. Percentage ISRs derived using the standard- and low-dose protocols were compared. In a preliminary study, seven patients with stents were subjected to standard- and low dose MDCT angiography during follow-up. The resulting images were assessed and compared by two experienced radiologists. RESULTS: The accuracy in measuring the percentage ISR was found to be better than 12% for all simulated stenoses. The differences between percentage ISRs measured on images obtained at 120 kVp/160 mAs and 80 kVp/80 mAs were below 6%. Patient image sets acquired using low exposure factors were judged to be of satisfactory diagnostic quality. The assessment of ISR did not differ significantly between image sets acquired using the standard factors and those acquired using the low-exposure factors, although the mean reduction in patient effective dose was 48%. CONCLUSION: A reduction in exposure factors during MDCT angiography of the iliac artery is possible without affecting the accuracy in the determination of ISRs. PMID- 21325365 TI - The lumbar sedimentation sign: spinal MRI findings in patients with subarachnoid haemorrhage with no demonstrable intracranial aneurysm. AB - We present a new MRI finding within the lumbar spine in a series of six patients admitted with CT proven subarachnoid haemorrhage (SAH) where cerebral angiography demonstrated no aneurysm and who had not had a lumbar puncture. A retrospective audit of 130 patients presenting to a regional neurosciences centre over a 13 month period with a suspected diagnosis of SAH was performed. Seven patients with proven SAH underwent MRI of the lumbar spine during the same admission. In six of these patients layering of haemorrhagic blood products was demonstrated within the lumbosacral spine. The process is analogous to the previously ubiquitous bedside erythrocyte sedimentation rate assay and has has been termed the "lumbar sedimentation" sign. This finding has not previously been reported in the literature in relation to SAH. While this is a small unselected group it may provide a useful adjunct in the diagnosis of SAH. PMID- 21325366 TI - Beware the cardiac shadow! PMID- 21325367 TI - Letter to the editor: Contrasting radiological presentation of disease burden in an immunocompetent H1N1 positive patient. PMID- 21325368 TI - Heterochromatin: the hidden epigenetic geography of the Y chromosome. PMID- 21325369 TI - Efficiency as a function of MEQ-CWT for large area germanium detectors using LLNL phantom. AB - The lung counting system at Kalpakkam, India, used for the estimation of transuranics deposited in the lungs of occupational workers, consists of an array of three large area germanium detectors fixed in a single assembly. The efficiency calibration for low energy photons was carried out using 241Am and 232Th lung sets of Lawrence Livermore National Laboratory phantom. The muscle equivalent chest wall thickness (MEQ-CWT) was derived for the three energies 59.5, 75.95 (average energy of 232Th) and 238.9 keV for the series of overlay plates made of different adipose mass ratios. Efficiency as a function of MEQ-CWT was calculated for individual detectors for the three energies. Variation of MEQ CWT from 16 to 40 mm resulted in an efficiency variation of around 40 % for all the three energies. The array efficiency for different MEQ-CWT ranged from 1.4*10 3 to 3.2*10-3, 1.5*10-3 to 3.3*10-3 and 1.1*10-3 to 2.3*10-3 for 59.5, 75.95 and 238.9 keV, respectively. In the energy response, efficiency was observed to be maximum for 75.95 keV compared with 59.5 and 238.9 keV. PMID- 21325370 TI - Irish clinicians' views of interventions for children with autistic spectrum disorders. AB - The current study investigated clinicians' perspectives on the effectiveness of interventions designed to support the development of children with autistic spectrum disorders (ASDs). Researchers developed a semi-structured interview which was administered to 11 clinicians involved in the assessment and treatment of ASDs (5 = clinical psychologists, 6 = psychiatrists). Content analysis of qualitative data revealed that Irish clinicians typically endorse an eclectic approach to treatment, combining facets of different methods of interventions in a complementary fashion. The process that clinicians engaged in when evaluating modes of treatment was assessed. Significant variation was observed in how clinicians merge clinical experience with empirical evidence. Challenges which clinicians face in assessing individuals on the autistic spectrum, such as the proliferation of misinformation on interventions, as well as the role of parents in treatment, were also discussed within the interviews. The implications of the findings for understanding the process of selecting interventions for children with ASDs are discussed. PMID- 21325371 TI - Visual/verbal-analytic reasoning bias as a function of self-reported autistic like traits: a study of typically developing individuals solving Raven's Advanced Progressive Matrices. AB - People with autism spectrum condition (ASC) perform well on Raven's matrices, a test which loads highly on the general factor in intelligence. However, the mechanisms supporting enhanced performance on the test are poorly understood. Evidence is accumulating that milder variants of the ASC phenotype are present in typically developing individuals, and that those who are further along the autistic-like trait spectrum show similar patterns of abilities and impairments as people with clinically diagnosed ASC. We investigated whether self-reported autistic-like traits in a university student sample, assessed using the Autism Spectrum Quotient (AQ; Baron-Cohen, Wheelwright, Skinner, et al., 2001), predict performance on Raven's Advanced Progressive Matrices. We found that reporting poorer social skills but better attention switching predicted a higher Advanced matrices score overall. DeShon, Chan, and Weissbein (1995) classified Advanced matrices items as requiring a visuospatial, or a verbal-analytic strategy. We hypothesised that higher AQ scores would predict better performance on visuospatial items than on verbal-analytic items. This prediction was confirmed. These results are consistent with the continuum view and can be explained by the enhanced perceptual functioning theory of performance peaks in ASC. The results also confirm a new prediction about Raven's Advanced Progressive Matrices performance in people with ASC. PMID- 21325372 TI - Epigenetics of thyroid cancer and novel therapeutic targets. AB - An increasing body of evidence suggests that epigenetic changes (DNA methylation, remodeling and post-translational modification of chromatin) play important roles in thyroid tumorigenesis, as a result of their effects on tumor-cell differentiation and proliferation. Epigenetic silencing of various thyroid specific genes has been detected in thyroid tumors. These changes can diminish the tumor's ability to concentrate radioiodine, which dramatically reduces treatment options. Epigenetic changes in tumor-promoting and tumor-suppressor genes also contribute to the dysregulation of thyrocyte growth and other aspects of tumorigenesis, such as apoptosis, motility and invasiveness. We provide a brief overview of the mechanisms underlying epigenetic regulation of gene expression and the current methods used to investigate it. This is followed by a review of the principal epigenetic alterations detected in thyroid cancer cells, epigenetic strategies for treating thyroid cancers and data from preclinical and clinical studies (some still underway) on the use in this setting of demethylating agents and histone deacetylase inhibitors. PMID- 21325373 TI - Dexamethasone alters the expression of genes related to the growth of skeletal muscle in chickens (Gallus gallus domesticus). AB - Glucocorticoids (GCs) are involved in the muscle wasting caused by trauma, inactivity, and stress. In the present study, three experiments were conducted to investigate the effect of GCs on the expression of genes related to muscle development in chickens. Broilers at 7 or 35 days of age were subjected to dexamethasone (DEX) treatment (2 mg/kg body mass (BM)) for 3 or 7 days. The expression levels of genes such as IGF1, IGF1 receptor, MSTN, WW domain containing E3 ubiquitin (UB) protein ligase 1, myogenic determining factor, and myogenic factor 5 were measured. The results showed that BM gain was significantly suppressed by DEX treatment. The plasma level of insulin was increased (P<0.05) by DEX treatment at feeding, whereas IGF1 was decreased (P<0.05). The expression of genes in the IGF1, myostatin, and UB-proteasome (UBP) pathways were altered by DEX treatment in age- and exposure time-related ways. These results suggest that GCs suppress IGF1 and upregulate myostatin and/or activated myostatin and the UBP pathway, which might be the source of the effect of GCs on muscle development. PMID- 21325376 TI - Global initiative launches to speed up the discovery of new drugs. PMID- 21325377 TI - Advocacy and concerted action are needed to tackle rising rates of malnutrition. PMID- 21325378 TI - A boy with a painful arm. PMID- 21325380 TI - Explaining the unexplainable. PMID- 21325382 TI - Global HPV vaccination. PMID- 21325383 TI - Medicine and the Media. How useful are lifetime risks of disease? PMID- 21325384 TI - Statins for primary prevention of cardiovascular disease. PMID- 21325386 TI - Type 1 diabetes in children. PMID- 21325387 TI - Glucagon-like peptide-1 analogues for type 2 diabetes. PMID- 21325388 TI - Hypoglycaemia. PMID- 21325389 TI - The other Twitter revolution: how social media are helping to monitor the NHS reforms. PMID- 21325390 TI - Circumcision in boys and girls: why the double standard? PMID- 21325391 TI - Absence of up-regulation for a proliferation-inducing ligand in Sjogren's sialadenitis lesions. AB - OBJECTIVE: To determine whether a proliferation-inducing ligand (APRIL) has a role in the survival of plasma cells infiltrating salivary glands from SS patients. METHODS: We performed immunological staining for APRIL in minor salivary glands from SS with a pair of antibodies specifically recognizing APRIL producing cells and secreted APRIL. RESULTS: Despite high leucocyte infiltration, APRIL-producing cells, identified as neutrophils, were rare in SS salivary glands. Keratinocytes from the adjacent oral epithelium also produced APRIL, but we never detected significant levels of secreted APRIL in SS salivary glands. We obtained similar results with B-cell lymphomas associated with SS. In fact, there was no significant difference in APRIL production and the level of secreted APRIL in these pathological samples compared with normal corresponding tissues. CONCLUSION: The combined observation that APRIL production is not up-regulated in lesions from SS patients, and that secreted APRIL is not retained in these lesions, indicates that plasma cells frequently present in SS lesions may not rely on APRIL for survival, as they do in other rheumatic diseases. PMID- 21325392 TI - Use of reclassification for assessment of improved prediction: an empirical evaluation. AB - BACKGROUND: An increasing number of studies evaluate the ability of predictors to change risk stratification and alter medical decisions, i.e. reclassification performance. We examined the reported design and analysis of recent studies of reclassification and the robustness of their claims for improved reclassification. METHODS: Two independent investigators searched PubMed and citations to the article that introduced the currently most popular reclassification metric (net reclassification index, NRI) to identify studies performing reclassification analysis (January 2006-January 2010). We focused on articles that included any analyses comparing the performance of a baseline predictive model vs the baseline model plus some additional predictor for a prospectively assessed outcome. We recorded information on the baseline model used, outcomes assessed, choice of risk thresholds and features of reclassification analyses. RESULTS: Of 58 baseline models used in 51 eligible papers, only 14 (24%) were previously described, used as described and had same outcomes as originally intended. Calibration was examined in 53% of the studies. Sixteen studies (31%) provided a reference for the choice of risk thresholds and only six used the previously proposed categories or justified the use of alternative thresholds. Only 14 studies (27%) stated that the chosen risk thresholds had different therapeutic intervention implications. NRI was calculated in 38 studies and was smaller in studies with adequately referenced or justified risk thresholds vs others (P < 0.0001). CONCLUSIONS: Reclassification studies would benefit from more rigorous methodological standards; otherwise claims for improved reclassification may remain spurious. PMID- 21325393 TI - Constipation during and after the civil war in Sri Lanka: a paediatric study. AB - Constipation is a common childhood disease. It is associated with exposure to stressful events. Sri Lanka was involved in three decades of civil war causing significant emotional stress. This study assessed the prevalence of childhood constipation during and after war. Data were collected from 10- to 16-year olds in five randomly selected schools, in three provinces (two schools from Eastern province), using a validated, self-administered questionnaire. Constipation was diagnosed using Rome III criteria. Phase I was conducted during the war to liberate Eastern province from separatist groups. Phase II was conducted 2 years after the war in same schools. During Phase I, prevalence of constipation was significantly higher in Eastern province (18.1%) compared with Western (14.2%) and Southern (12.6%) provinces (p = 0.009). Constipation was significantly lower in Eastern province in Phase II (10%) compared with Phase I (p < 0.0001). This study highlights the possible link between devastating emotional effects of civil war and childhood constipation. PMID- 21325394 TI - Retinal detachment repair by vitrectomy: simplified formulae to estimate the risk of failure. AB - AIM: Devise simplified formulae, using preoperative clinical data, to give risk estimates of (1) failure and (2) proliferative vitreoretinpathy (PVR) following primary retinal detachment repair by vitrectomy. METHODS: 641 patients were analysed as part of an RCT investigating use of 5-fluorouracil and low-molecular weight heparin. Treatment status had no effect on success rates and did not therefore form part of the analyses. Preoperative risk factors for surgical failure and for PVR within 6 months of retinal detachment surgery were identified, and a multiple variable logistic regression model developed. Further analyses were performed to devise a simple points system to produce risk estimates of failure. RESULTS: Three risk factors were related to failure previous lens extraction (p=0.046), grade C PVR (p=0.039) and extent of detachment (p<0.001). Three risk factors were also related to failure due to PVR vitreous haemorrhage (p=0.088), grade C PVR (p=0.044) and extent of detachment (p<0.001). There was good agreement between risk estimates produced by the points system and those calculated directly using a multivariate regression model. The points-system model gave an area under the receiver operating characteristic curve of 0.658. The receiver operating characteristic curve for the PVR model gave an area under the curve of 0.8399 suggesting greater diagnostic value. CONCLUSIONS: A simple points system may be used as a clinical guide to identify patients at higher risk of failure following retinal detachment repair by vitrectomy. This may help clinicians select appropriate surgical approaches and stratify cases in research and surgical training. PMID- 21325395 TI - Mutation spectrum of fork-head transcriptional factor gene (FOXL2) in Indian Blepharophimosis Ptosis Epicanthus Inversus Syndrome (BPES) patients. AB - AIM: The fork-head transcription factor gene (FOXL2) gene has been implicated in Blepharophimosis Ptosis Epicanthus Inversus Syndrome (BPES) type I and type II. The authors aimed to evaluate the involvement of FOXL2 in familial and sporadic cases of BPES in an Indian cohort. METHODS: The present cohort comprised clinically well-characterised BPES cases that included six affected families, two sporadic cases and 60 unaffected normal controls. The 5' untranslated and coding region of FOXL2 was screened by resequencing and confirmed by restriction digestion. Further, genotype-phenotype correlations were done to understand the implications of the observed mutation. RESULTS: Six mutations were observed in eight cases (87.5%). These included a novel deletion (c.860delC), three previously reported duplications (c.663-692dup 30, c.672-701dup30 and c.843 859dup17), a frame shift (c.804dupC) and a homozygous missense mutation (p.E69K). The p.E69k mutation was seen in both heterozygous and homozygous form in a large four-generational family, and disease severity was found to be directly linked to the allelic dosage. Two SNPs (c.501C->T, c.536C->G) were also noted. An unusual coexistence of polycystic ovarian disease (PCOD) with BPES was also seen in one of the families. DISCUSSION: Mutations in the region downstream of the fork-head domain were predominantly responsible for BPES among Indian patients. PMID- 21325396 TI - Soluble vascular endothelial growth factor receptor (VEGFR)-2 in macular oedema- a mechanism for regulating angiogenesis? PMID- 21325397 TI - Quality improvement in developing nations. PMID- 21325398 TI - Insulin-induced oxidative stress up-regulates heme oxygenase-1 via diverse signaling cascades in the C2 skeletal myoblast cell line. AB - Impaired insulin sensitivity (insulin resistance) is a common denominator in many metabolic disorders, exerting pleiotropic effects on skeletal muscle, liver, and adipose tissue function. Heme oxygenase-1 (HOX-1), the rate-limiting enzyme in heme catabolism, has recently been shown to confer an antidiabetic effect while regulating cellular redox-buffering capacity. Therefore, in the present study, we probed into the mechanisms underlying the effect of insulin on HOX-1 in C2 skeletal myoblasts. Hence, insulin was found to suppress C2 myoblasts viability via stimulation of oxidative stress, with HOX-1 counteracting this action. Insulin induced HOX-1 expression in a time- and dose-dependent manner, an effect attenuated by selective inhibitors of ERK1/2 (PD98059), Src (4-amino-5-(4 chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d] pyrimidine), and c-Jun terminal kinases 1 and 2 (SP600125) pathways. Furthermore, nuclear factor-kappaB role in insulin induced HOX-1 up-regulation was verified, with ERK1/2, Src, and c-Jun terminal kinases 1 and 2 mediating p65-nuclear factor-kappaB subunit phosphorylation. Overall, our novel findings highlight for the first time the transduction mechanisms mediating HOX-1 induction in insulin-treated C2 myoblasts. This effect was established to be cell type specific because insulin failed to promote HOX-1 expression in HepG2 hepatoma cells. Deciphering the signaling networks involved in insulin-stimulated HOX-1 up-regulation is of prominent significance because it may potentially contribute to elucidation of the mechanisms involved in associated metabolic pathologies. PMID- 21325399 TI - Chromatin everywhere. PMID- 21325400 TI - Chromatin structure of pluripotent stem cells and induced pluripotent stem cells. AB - Pluripotent embryonic stem (ES) cells are specialized cells with a dynamic chromatin structure, which is intimately connected with their pluripotency and physiology. In recent years somatic cells have been reprogrammed to a pluripotent state through over-expression of a defined set of transcription factors. These cells, known as induced pluripotent stem (iPS) cells, recapitulate ES cell properties and can be differentiated to apparently all cell lineages, making iPS cells a suitable replacement for ES cells in future regenerative medicine. Chromatin modifiers play a key function in establishing and maintaining pluripotency, therefore, elucidating the mechanisms controlling chromatin structure in both ES and iPS cells is of utmost importance to understanding their properties and harnessing their therapeutic potential. In this review, we discuss recent studies that provide a genome-wide view of the chromatin structure signature in ES cells and iPS cells and that highlight the central role of histone modifiers and chromatin remodelers in pluripotency maintenance and induction. PMID- 21325401 TI - Adaptation of subtype a human immunodeficiency virus type 1 envelope to pig tailed macaque cells. AB - The relevance of simian/human immunodeficiency virus (SHIV) infection of macaques to HIV-1 infection in humans depends on how closely SHIVs mimic HIV-1 transmission, pathogenesis, and diversity. Circulating HIV-1 strains are predominantly subtypes C and A and overwhelmingly require CCR5 for entry, yet most SHIVs incorporate CXCR4-using subtype B envelopes (Envs). While pathogenic subtype C-based SHIVs have been constructed, the subtype A-based SHIVs (SHIV-As) constructed to date have been unable to replicate in macaque cells. To understand the barriers to SHIV-A replication in macaque cells, HIVA(Q23)/SIV(vif) was constructed by engineering a CCR5-tropic subtype A provirus to express SIV vif, which counters the macaque APOBEC3G restriction. HIVA(Q23)/SIV(vif) replicated poorly in pig-tailed macaque (Ptm) lymphocytes, but viruses were adapted to Ptm lymphocytes. Two independent mutations in gp120, G312V (V3 loop) and A204E (C2 region), were identified that increased peak virus levels by >100-fold. Introduction of G312V and A204E to multiple subtype A Envs and substitution of G312 and A204 with other residues increased entry into Ptm cells by 10- to 100 fold. G312V and A204E Env variants continued to require CCR5 for entry but were up to 50- and 200-fold more sensitive to neutralization by IgG1b12 and soluble CD4 and had a 5- to 50-fold increase in their ability to utilize Ptm CD4 compared to their wild-type counterparts. These findings identify the inefficient use of Ptm CD4 as an unappreciated restriction to subtype A HIV-1 replication in Ptm cells and reveal amino acid changes to gp120 that can overcome this barrier. PMID- 21325402 TI - Recombinant adenovirus serotype 26 (Ad26) and Ad35 vaccine vectors bypass immunity to Ad5 and protect nonhuman primates against ebolavirus challenge. AB - The use of adenoviruses (Ad) as vaccine vectors against a variety of pathogens has demonstrated their capacity to elicit strong antibody and cell-mediated immune responses. Adenovirus serotype C vectors, such as Ad serotype 5 (Ad5), expressing Ebolavirus (EBOV) glycoprotein (GP), protect completely after a single inoculation at a dose of 10(10) viral particles. However, the clinical application of a vaccine based on Ad5 vectors may be hampered, since impairment of Ad5 vaccine efficacy has been demonstrated for humans and nonhuman primates with high levels of preexisting immunity to the vector. Ad26 and Ad35 segregate genetically from Ad5 and exhibit lower seroprevalence in humans, making them attractive vaccine vector alternatives. In the series of studies presented, we show that Ad26 and Ad35 vectors generate robust antigen-specific cell-mediated and humoral immune responses against EBOV GP and that Ad5 immune status does not affect the generation of GP-specific immune responses by these vaccines. We demonstrate partial protection against EBOV by a single-shot Ad26 vaccine and complete protection when this vaccine is boosted by Ad35 1 month later. Increases in efficacy are paralleled by substantial increases in T- and B-cell responses to EBOV GP. These results suggest that Ad26 and Ad35 vectors warrant further development as candidate vaccines for EBOV. PMID- 21325403 TI - Hepatitis C patient-derived glycoproteins exhibit marked differences in susceptibility to serum neutralizing antibodies: genetic subtype defines antigenic but not neutralization serotype. AB - Neutralizing antibodies have a role in controlling hepatitis C virus (HCV) infection. A successful vaccine will need to elicit potently neutralizing antibodies that are capable of preventing the infection of genetically diverse viral isolates. However, the specificity of the neutralizing antibody response in natural HCV infection still is poorly understood. To address this, we examined the reactivity of polyclonal antibodies isolated from chronic HCV infection to the diverse patient-isolated HCV envelope glycoproteins E1 and E2 (E1E2), and we also examined the potential to neutralize the entry of pseudoparticles bearing these diverse E1E2 proteins. The genetic type of the infection was found to determine the pattern of the antibody recognition of these E1E2 proteins, with the greatest reactivity to homologous E1E2 proteins. This relationship was strongest when the component of the antibody response directed only to linear epitopes was analyzed. In contrast, the neutralization serotype did not correlate with genotype. Instead, serum-derived antibodies displayed a range of neutralization breadth and potency, while different E1E2 glycoproteins displayed different sensitivities to neutralization, such that these could be divided broadly into neutralization-sensitive and -resistant phenotypes. An important additional observation was that entry mediated by some E1E2 proteins was enhanced in the presence of some of the polyclonal antibody fractions isolated during chronic infection. These data highlight the need to use diverse E1E2 isolates, which represent extremes of neutralization sensitivity, when screening antibodies for therapeutic potential and for testing antibodies generated following immunization as part of vaccine development. PMID- 21325404 TI - Specific regulation of the chemokine response to viral hemorrhagic septicemia virus at the entry site. AB - The fin bases constitute the main portal of rhabdovirus entry into rainbow trout (Oncorhynchus mykiss), and replication in this first site strongly conditions the outcome of the infection. In this context, we studied the chemokine response elicited in this area in response to viral hemorrhagic septicemia virus (VHSV), a rhabdovirus. Among all the rainbow trout chemokine genes studied, only the transcription levels of CK10 and CK12 were significantly upregulated in response to VHSV. As the virus had previously been shown to elicit a much stronger chemokine response in internal organs, we compared the effect of VHSV on the gills, another mucosal site which does not constitute the main site of viral entry or rhabdoviral replication. In this case, a significantly stronger chemokine response was triggered, with CK1, CK3, CK9, and CK11 being upregulated in response to VHSV and CK10 and CK12 being down-modulated by the virus. We then conducted further experiments to understand how these different chemokine responses of mucosal tissues could correlate with their capacity to support VHSV replication. No viral replication was detected in the gills, while at the fin bases, only the skin and the muscle were actively supporting viral replication. Within the skin, viral replication took place in the dermis, while viral replication was blocked within epidermal cells at some point before protein translation. The different susceptibilities of the different skin layers to VHSV correlated with the effect that VHSV has on their capacity to secrete chemotactic factors. Altogether, these results suggest a VHSV interference mechanism on the early chemokine response at its active replication sites within mucosal tissues, a possible key process that may facilitate viral entry. PMID- 21325405 TI - Regulation of foamy virus protease activity by viral RNA: a novel and unique mechanism among retroviruses. AB - Foamy viruses (FVs) synthesize the Pol precursor protein from a specific transcript. Thus, in contrast to what was found for orthoretroviruses, e.g., human immunodeficiency virus, no Gag-Pol precursor protein is synthesized. Foamy viral Pol consists of a protease (PR) domain, a reverse transcriptase domain, and an integrase domain and is processed into a mature protease-reverse transcriptase (PR-RT) fusion protein and the integrase. Protease activity has to be strictly regulated in order to avoid premature Gag and Pol processing before virus assembly. We have demonstrated recently that FV protease is an inactive monomer with a very weak dimerization tendency and postulated protease activation through dimerization. Here, we identify a specific protease-activating RNA motif (PARM) located in the pol region of viral RNA which stimulates PR activity in vitro and in vivo, revealing a novel and unique mechanism of retroviral protease activation. This mechanism is strikingly different to that of orthoretroviruses, where the protease can be activated even in the absence of viral RNA during the assembly of virus-like particles. Although it has been shown that the integrase domain is important for Pol uptake, activation of the foamy virus protease is integrase independent. We show that at least two foamy virus PR-RT molecules bind to the PARM and only RNAs containing the PARM result in significant activation of the protease. DNA harboring the PARM is not capable of protease activation. Structure determination of the PARM by selective 2' hydroxyl acylation analyzed by primer extension (SHAPE) revealed a distinct RNA folding, important for protease activation and thus virus maturation. PMID- 21325406 TI - Structural features of the Seneca Valley virus internal ribosome entry site (IRES) element: a picornavirus with a pestivirus-like IRES. AB - The RNA genome of Seneca Valley virus (SVV), a recently identified picornavirus, contains an internal ribosome entry site (IRES) element which has structural and functional similarity to that from classical swine fever virus (CSFV) and hepatitis C virus, members of the Flaviviridae. The SVV IRES has an absolute requirement for the presence of a short region of virus-coding sequence to allow it to function either in cells or in rabbit reticulocyte lysate. The IRES activity does not require the translation initiation factor eIF4A or intact eIF4G. The predicted secondary structure indicates that the SVV IRES is more closely related to the CSFV IRES, including the presence of a bipartite IIId domain. Mutagenesis of the SVV IRES, coupled to functional assays, support the core elements of the IRES structure model, but surprisingly, deletion of the conserved IIId(2) domain had no effect on IRES activity, including 40S and eIF3 binding. This is the first example of a picornavirus IRES that is most closely related to the CSFV IRES and suggests the possibility of multiple, independent recombination events between the genomes of the Picornaviridae and Flaviviridae to give rise to similar IRES elements. PMID- 21325407 TI - The unique transmembrane hairpin of flavivirus fusion protein E is essential for membrane fusion. AB - The fusion of enveloped viruses with cellular membranes is mediated by proteins that are anchored in the lipid bilayer of the virus and capable of triggered conformational changes necessary for driving fusion. The flavivirus envelope protein E is the only known viral fusion protein with a double membrane anchor, consisting of two antiparallel transmembrane helices (TM1 and TM2). TM1 functions as a stop-transfer sequence and TM2 as an internal signal sequence for the first nonstructural protein during polyprotein processing. The possible role of this peculiar C-terminal helical hairpin in membrane fusion has not been investigated so far. We addressed this question by studying TM mutants of tick-borne encephalitis virus (TBEV) recombinant subviral particles (RSPs), an established model system for flavivirus membrane fusion. The engineered mutations included the deletion of TM2, the replacement of both TM domains (TMDs) by those of the related Japanese encephalitis virus (JEV), and the use of chimeric TBEV-JEV membrane anchors. Using these mutant RSPs, we provide evidence that TM2 is not just a remnant of polyprotein processing but, together with TM1, plays an active role in fusion. None of the TM mutations, including the deletion of TM2, affected early steps of the fusion process, but TM interactions apparently contribute to the stability of the postfusion E trimer and the completion of the merger of the membranes. Our data provide evidence for both intratrimer and intertrimer interactions mediated by the TMDs of E and thus extend the existing models of flavivirus membrane fusion. PMID- 21325408 TI - Impact of amino acid mutations in PB2, PB1-F2, and NS1 on the replication and pathogenicity of pandemic (H1N1) 2009 influenza viruses. AB - Here, we assessed the effects of PB1-F2 and NS1 mutations known to increase the pathogenicity of influenza viruses on the replication and pathogenicity in mice of pandemic (H1N1) 2009 influenza viruses. We also characterized viruses possessing a PB1-F2 mutation that was recently identified in pandemic (H1N1) 2009 influenza virus isolates, with and without simultaneous mutations in PB2 and NS1. Our results suggest that some NS1 mutations and the newly identified PB1-F2 mutation have the potential to increase the replication and/or pathogenicity of pandemic (H1N1) 2009 influenza viruses. PMID- 21325409 TI - The Epstein-Barr virus BRRF1 protein, Na, induces lytic infection in a TRAF2- and p53-dependent manner. AB - The Epstein-Barr virus (EBV) BRRF1 lytic gene product (Na) is encoded within the same immediate-early region as the BZLF1 (Z) and BRLF1(R) gene products, but its role during EBV infection has not been well defined. We previously showed that Na cooperates with the R protein to induce lytic gene expression in latently infected EBV-positive 293 cells, and in some EBV-negative cell lines it can activate the Z promoter in reporter gene assays. Here we show that overexpression of Na alone is sufficient to induce lytic gene expression in several different latently infected epithelial cell lines (Hone-Akata, CNE2-Akata, and AGS-Akata), while knockdown of endogenous Na expression reduces lytic gene expression. Consistent with its ability to interact with tumor necrosis factor receptor associated factor 2 (TRAF2) in a yeast two-hybrid assay, we demonstrate that Na interacts with TRAF2 in cells. Furthermore, we show that TRAF2 is required for Na induction of lytic gene expression, that Na induces Jun N-terminal protein kinase (JNK) activation in a TRAF2-dependent manner, and that a JNK inhibitor abolishes the ability of Na to disrupt viral latency. Additionally, we show that Na and the tumor suppressor protein p53 cooperate to induce lytic gene expression in epithelial cells (including the C666-1 nasopharyngeal carcinoma cell line), although Na does not appear to affect p53 function. Together these data suggest that Na plays an important role in regulating the switch between latent and lytic infection in epithelial cells and that this effect requires both the TRAF2 and p53 cellular proteins. PMID- 21325410 TI - Herpes simplex virus 2 microRNA miR-H6 is a novel latency-associated transcript associated microRNA, but reduction of its expression does not influence the establishment of viral latency or the recurrence phenotype. AB - The herpes simplex virus 2 (HSV-2) viral microRNA (miRNA) designated miR-H6 is located upstream of the latency-associated transcript (LAT) promoter region on the strand opposite the LAT. Deletion of the LAT promoter and part of LAT exon 1 abolished HSV-2 miR-H6 expression in acutely and latently infected guinea pig dorsal root ganglia (DRG), suggesting that this region is needed both for the expression of LAT-encoded miRNAs and for miR-H6 expression in vivo. Relative to cells infected with a viral rescuant, miR-H6 expression was significantly reduced in cells infected with a mutant HSV-2 virus, NotPolyA, with an insertion of a simian virus (SV40) polyadenylation signal sequence between the LAT promoter and miR-H6 sequences. In addition, expression of miR-H6, but not LAT or viral DNA, was significantly reduced in both mouse trigeminal ganglia (TG) and guinea pig DRG latently infected with the NotPolyA mutant. Guinea pigs infected with NotPolyA experienced reduced neurological complications of acute infection relative to those infected with the rescuant, but the recurrence phenotype of the NotPolyA mutant was similar to those of its rescuant and wild-type HSV-2, indicating that reduction of miR-H6 expression is not by itself able to alter the establishment of latency for the wild-type virus or the recurrence phenotype. Furthermore, the mutation in NotPolyA did not affect the propensity of wild-type HSV-2 to establish latency in neurons positive for subtype marker KH10. In contrast to published reports regarding its HSV-1 homolog, HSV-2 miR-H6 did not affect ICP4 expression in transfected or infected cells. We hypothesize that viral miRNAs associated with LAT expression are likely to work collectively, contributing to the phenotype attributed to the LAT. PMID- 21325411 TI - Immunotypes of a quaternary site of HIV-1 vulnerability and their recognition by antibodies. AB - HIV-1 is neutralized by a class of antibodies that preferentially recognize a site formed on the assembled viral spike. Such quaternary structure-specific antibodies have diverse neutralization breadths, with antibodies PG16 and PG9 able to neutralize 70 to 80% of circulating HIV-1 isolates while antibody 2909 is specific for strain SF162. We show that alteration between a rare lysine and a common N-linked glycan at position 160 of HIV-1 gp120 is primarily responsible for toggling between 2909 and PG16/PG9 neutralization sensitivity. Quaternary structure-specific antibodies appear to target antigenic variants of the same epitope, with neutralization breadth determined by the prevalence of recognized variants among circulating isolates. PMID- 21325412 TI - The C-terminal nsP1a protein of human astrovirus is a phosphoprotein that interacts with the viral polymerase. AB - Human astrovirus nonstructural C-terminal nsP1a protein (nsP1a/4) colocalizes with the endoplasmic reticulum and viral RNA. It has been suggested that nsP1a/4 protein is involved in the RNA replication process in endoplasmic reticulum derived intracellular membranes. A hypervariable region (HVR) is contained in the nsP1a/4 protein, and different replicative patterns can be distinguished depending on its variability. In the present work, both the astrovirus RNA dependent RNA polymerase and four types (IV, V, VI, and XII) of nsP1a/4 proteins have been cloned and expressed in the baculovirus system to analyze their interactions. Different isoforms of each of the nsP1a/4 proteins exist: a nonphosphorylated isoform and different phosphorylated isoforms. While the polymerase accumulates as a monomer, the nsP1a/4 proteins accumulate as oligomers. The oligomerization domain of nsP1a/4-V is mapped between residues 176 and 209. For all studied genotypes, oligomers mainly contain the nonphosphorylated isoform. When RNA polymerase is coexpressed with nsP1a/4 proteins, they interact, likely forming heterodimers. The polymerase binding region has been mapped in the nsP1a/4-V protein between residues 88 and 176. Phosphorylated isoforms of nsP1a/4 type VI show a stronger interactive pattern with the polymerase than the nonphosphorylated isoform. This difference is not observed in genotypes IV and V, suggesting a role of the HVR in modulating the interaction of the nsP1a/4 protein with the polymerase through phosphorylation/dephosphorylation of some critical residues. PMID- 21325413 TI - Unmasking the active helicase conformation of nonstructural protein 3 from hepatitis C virus. AB - The nonstructural protein 3 (NS3) helicase/protease is an important component of the hepatitis C virus (HCV) replication complex. We hypothesized that a specific beta-strand tethers the C terminus of the helicase domain to the protease domain, thereby maintaining HCV NS3 in a compact conformation that differs from the extended conformations observed for other Flaviviridae NS3 enzymes. To test this hypothesis, we removed the beta-strand and explored the structural and functional attributes of the truncated NS3 protein (NS3DeltaC7). Limited proteolysis, hydrodynamic, and kinetic measurements indicate that NS3DeltaC7 adopts an extended conformation that contrasts with the compact form of the wild-type (WT) protein. The extended conformation of NS3DeltaC7 allows the protein to quickly form functional complexes with RNA unwinding substrates. We also show that the unwinding activity of NS3DeltaC7 is independent of the substrate 3'-overhang length, implying that a monomeric form of the protein promotes efficient unwinding. Our findings indicate that an open, extended conformation of NS3 is required for helicase activity and represents the biologically relevant conformation of the protein during viral replication. PMID- 21325414 TI - Internal initiation is responsible for synthesis of Wuhan nodavirus subgenomic RNA. AB - Nodaviruses are small nonenveloped spherical viruses with a bipartite genome of RNAs. In nodaviruses, subgenomic RNA3 (sgRNA3) plays a critical role in viral replication and survival, as it coordinates the replication of two viral genomic RNAs (RNA1 and RNA2) and encodes protein B2, which is a potent RNA-silencing inhibitor. Despite its importance, the molecular mechanism of nodaviral sgRNA3 synthesis is still poorly understood. Here, we propose that sgRNA3 of Wuhan nodavirus (WhNV) is internally initiated from a promoter on the negative template of genomic RNA1. Serial deletion and mutation analyses further revealed that the core promoter of WhNV sgRNA3 is between nucleotide positions -22 and +6 of its transcription start site. Besides, a stem-loop structure of WhNV sgRNA3 was computationally predicted upstream of sgRNA3's transcription start site. Both the secondary structure and the primary sequence were determined to be required for promoter activity. Furthermore, our results show that the synthesis of WhNV sgRNA3 is counterregulated by the replication of WhNV genomic RNA2, which encodes a viral capsid precursor protein. And this sgRNA3 synthesis is also able to trans activate the replication of RNA2. Altogether, findings in this study indicate that there is a newly discovered internal initiation model for the synthesis of nodaviral sgRNA. PMID- 21325415 TI - Severe restriction of xenotropic murine leukemia virus-related virus replication and spread in cultured human peripheral blood mononuclear cells. AB - Xenotropic murine leukemia virus-related virus (XMRV) is a gammaretrovirus recently isolated from human prostate cancer and peripheral blood mononuclear cells (PBMCs) of patients with chronic fatigue syndrome (CFS). We and others have shown that host restriction factors APOBEC3G (A3G) and APOBEC3F (A3F), which are expressed in human PBMCs, inhibit XMRV in transient-transfection assays involving a single cycle of viral replication. However, the recovery of infectious XMRV from human PBMCs suggested that XMRV can replicate in these cells despite the expression of APOBEC3 proteins. To determine whether XMRV can replicate and spread in cultured PBMCs even though it can be inhibited by A3G/A3F, we infected phytohemagglutinin-activated human PBMCs and A3G/A3F-positive and -negative cell lines (CEM and CEM-SS, respectively) with different amounts of XMRV and monitored virus production by using quantitative real-time PCR. We found that XMRV efficiently replicated in CEM-SS cells and viral production increased by >4,000 fold, but there was only a modest increase in viral production from CEM cells (<14-fold) and a decrease in activated PBMCs, indicating little or no replication and spread of XMRV. However, infectious XMRV could be recovered from the infected PBMCs by cocultivation with a canine indicator cell line, and we observed hypermutation of XMRV genomes in PBMCs. Thus, PBMCs can potentially act as a source of infectious XMRV for spread to cells that express low levels of host restriction factors. Overall, these results suggest that hypermutation of XMRV in human PBMCs constitutes one of the blocks to replication and spread of XMRV. Furthermore, hypermutation of XMRV proviruses at GG dinucleotides may be a useful and reliable indicator of human PBMC infection. PMID- 21325416 TI - Infection, viral dissemination, and antibody responses of rhesus macaques exposed to the human gammaretrovirus XMRV. AB - Xenotropic murine leukemia-related virus (XMRV) was identified in association with human prostate cancer and chronic fatigue syndrome. To examine the infection potential, kinetics, and tissue distribution of XMRV in an animal model, we inoculated five macaques with XMRV intravenously. XMRV established a persistent, chronic disseminated infection, with low transient viremia and provirus in blood lymphocytes during acute infection. Although undetectable in blood after about a month, XMRV viremia was reactivated at 9 months, confirming the chronicity of the infection. Furthermore, XMRV Gag was detected in tissues throughout, with wide dissemination throughout the period of monitoring. Surprisingly, XMRV infection showed organ-specific cell tropism, infecting CD4 T cells in lymphoid organs including the gastrointestinal lamina propria, alveolar macrophages in lung, and epithelial/interstitial cells in other organs, including the reproductive tract. Of note, in spite of the intravenous inoculation, extensive XMRV replication was noted in prostate during acute but not chronic infection even though infected cells were still detectable by fluorescence in situ hybridization (FISH) in prostate at 5 and 9 months postinfection. Marked lymphocyte activation occurred immediately postinfection, but antigen-specific cellular responses were undetectable. Antibody responses were elicited and boosted upon reexposure, but titers decreased rapidly, suggesting low antigen stimulation over time. Our findings establish a nonhuman primate model to study XMRV replication/dissemination, transmission, pathogenesis, immune responses, and potential future therapies. PMID- 21325417 TI - Consistent inhibition of HIV-1 replication in CD4+ T cells by acyclovir without detection of human herpesviruses. AB - Acyclovir, a nucleoside analog, is thought to be specific for the human herpesviruses because it requires a virally encoded enzyme to phosphorylate it to acyclovir monophosphate. Recently, acyclovir triphosphate was shown to be a direct inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. Here, we showed that acyclovir is an inhibitor of HIV-1 replication in CD4(+) T cells from cord blood that have undetectable levels of the eight human herpesviruses. Additionally, acyclovir phosphates were detected by reverse-phase-high performance liquid chromatography (RP-HPLC) and quantified in a primer extension assay from cord blood. The data support acyclovir as an inhibitor of HIV-1 replication in herpesvirus-negative cells. PMID- 21325418 TI - Distinct severe acute respiratory syndrome coronavirus-induced acute lung injury pathways in two different nonhuman primate species. AB - Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), caused by influenza A virus H5N1 and severe acute respiratory syndrome coronavirus (SARS CoV), supposedly depend on activation of the oxidative-stress machinery that is coupled with innate immunity, resulting in a strong proinflammatory host response. Inflammatory cytokines, such as interleukin 1beta (IL-1beta), IL-8, and IL-6, play a major role in mediating and amplifying ALI/ARDS by stimulating chemotaxis and activation of neutrophils. To obtain further insight into the pathogenesis of SARS-CoV-associated ALI, we compared SARS-CoV infections in two different nonhuman primate species, cynomolgus macaques and African green monkeys. Viral titers in the upper and lower respiratory tract were not significantly different in SARS-CoV-infected macaques and African green monkeys. Inflammatory cytokines that play a major role in mediating and amplifying ALI/ARDS or have neutrophil chemoattractant activity, such as IL-6, IL-8, CXCL1, and CXCL2, were, however, induced only in macaques. In contrast, other proinflammatory cytokines and chemokines, including osteopontin and CCL3, were upregulated in the lungs of African green monkeys to a significantly greater extent than in macaques. Because African green monkeys developed more severe ALI than macaques, with hyaline membrane formation, some of these differentially expressed proinflammatory genes may be critically involved in development of the observed pathological changes. Induction of distinct proinflammatory genes after SARS-CoV infection in different nonhuman primate species needs to be taken into account when analyzing outcomes of intervention strategies in these species. PMID- 21325419 TI - Early induction of autophagy in human fibroblasts after infection with human cytomegalovirus or herpes simplex virus 1. AB - The infection of human fetal foreskin fibroblasts (HFFF2) with human cytomegalovirus (HCMV) resulted in the induction of autophagy. This was demonstrated by the increased lipidation of microtubule-associated protein 1 light chain 3 (LC3), a hallmark of autophagy, and by the visualization of characteristic vesicles within infected cells. The response was detected first at 2 h postinfection and persisted for at least 3 days. De novo protein synthesis was not required for the effect, since HCMV that was irradiated with UV light also elicited the response, and furthermore the continuous presence of cycloheximide did not prevent induction. Infection with herpes simplex virus type 1 (HSV-1) under conditions that inhibited viral gene expression provoked autophagy, whereas UV-irradiated respiratory syncytial virus did not. The induction of autophagy occurred when cells were infected with HCMV or HSV-1 that was gradient purified, but HCMV dense bodies and HSV-1 light particles, each of which lack nucleocapsids and genomes, were inactive. The depletion of regulatory proteins Atg5 and Atg7, which are required for autophagy, reduced LC3 modification in response to infection but did not result in any detectable difference in viral or cellular gene expression at early times after infection. The electroporation of DNA into HFFF2 cultures induced the lipidation of LC3 but double-stranded RNA did not, even though both agents stimulated an innate immune response. The results show a novel, early cellular response to the presence of the incoming virion and additionally demonstrate that autophagy can be induced by the presence of foreign DNA within cells. PMID- 21325420 TI - Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response. AB - The spike (S) protein of the severe acute respiratory syndrome coronavirus (SARS CoV) can be proteolytically activated by cathepsins B and L upon viral uptake into target cell endosomes. In contrast, it is largely unknown whether host cell proteases located in the secretory pathway of infected cells and/or on the surface of target cells can cleave SARS S. We along with others could previously show that the type II transmembrane protease TMPRSS2 activates the influenza virus hemagglutinin and the human metapneumovirus F protein by cleavage. Here, we assessed whether SARS S is proteolytically processed by TMPRSS2. Western blot analysis revealed that SARS S was cleaved into several fragments upon coexpression of TMPRSS2 (cis-cleavage) and upon contact between SARS S-expressing cells and TMPRSS2-positive cells (trans-cleavage). cis-cleavage resulted in release of SARS S fragments into the cellular supernatant and in inhibition of antibody-mediated neutralization, most likely because SARS S fragments function as antibody decoys. trans-cleavage activated SARS S on effector cells for fusion with target cells and allowed efficient SARS S-driven viral entry into targets treated with a lysosomotropic agent or a cathepsin inhibitor. Finally, ACE2, the cellular receptor for SARS-CoV, and TMPRSS2 were found to be coexpressed by type II pneumocytes, which represent important viral target cells, suggesting that SARS S is cleaved by TMPRSS2 in the lung of SARS-CoV-infected individuals. In summary, we show that TMPRSS2 might promote viral spread and pathogenesis by diminishing viral recognition by neutralizing antibodies and by activating SARS S for cell-cell and virus-cell fusion. PMID- 21325421 TI - On the role of the SP1 domain in HIV-1 particle assembly: a molecular switch? AB - Expression of a retroviral protein, Gag, in mammalian cells is sufficient for assembly of immature virus-like particles (VLPs). VLP assembly is mediated largely by interactions between the capsid (CA) domains of Gag molecules but is facilitated by binding of the nucleocapsid (NC) domain to nucleic acid. We have investigated the role of SP1, a spacer between CA and NC in HIV-1 Gag, in VLP assembly. Mutational analysis showed that even subtle changes in the first 4 residues of SP1 destroy the ability of Gag to assemble correctly, frequently leading to formation of tubes or other misassembled structures rather than proper VLPs. We also studied the conformation of the CA-SP1 junction region in solution, using both molecular dynamics simulations and circular dichroism. Consonant with nuclear magnetic resonance (NMR) studies from other laboratories, we found that SP1 is nearly unstructured in aqueous solution but undergoes a concerted change to an alpha-helical conformation when the polarity of the environment is reduced by addition of dimethyl sulfoxide (DMSO), trifluoroethanol, or ethanol. Remarkably, such a coil-to-helix transition is also recapitulated in an aqueous medium at high peptide concentrations. The exquisite sensitivity of SP1 to mutational changes and its ability to undergo a concentration-dependent structural transition raise the possibility that SP1 could act as a molecular switch to prime HIV-1 Gag for VLP assembly. We suggest that changes in the local environment of SP1 when Gag oligomerizes on nucleic acid might trigger this switch. PMID- 21325422 TI - Genome structure of caulobacter phage phiCb5. AB - The complete genome sequence of caulobacter phage phiCb5 has been determined, and four open reading frames (ORFs) have been identified and characterized. As for related phages, the ORFs code for maturation, coat, replicase, and lysis proteins, but unlike other Leviviridae members, the lysis protein gene of phiCb5 entirely overlaps with the replicase in a different reading frame. The lysis protein of phiCb5 is about two times longer than that of the distantly related MS2 phage and presumably contains two transmembrane helices. Analysis of the proposed genome secondary structure revealed a stable 5' stem-loop, similar to other phages, and a substantially shorter 3' untranslated region (UTR) structure with only three stem-loops. PMID- 21325423 TI - Vesicular stomatitis virus-based H5N1 avian influenza vaccines induce potent cross-clade neutralizing antibodies in rhesus macaques. AB - We analyzed the ability of a vaccine vector based on vesicular stomatitis virus (VSV) to induce a neutralizing antibody (NAb) response to avian influenza viruses (AIVs) in rhesus macaques. Animals vaccinated with vectors expressing either strain A/Hong Kong/156/1997 or strain A/Vietnam/1203/2004 H5 hemagglutinin (HA) were able to generate robust NAb responses. The ability of the vectors to induce NAbs against homologous and heterologous AIVs after a single dose was dependent upon the HA antigen incorporated into the VSV vaccine. The vectors expressing strain A/Vietnam/1203/2004 H5 HA were superior to those expressing strain A/Hong Kong/156/1997 HA at inducing cross-clade NAbs. PMID- 21325424 TI - Marburg virus VP40 antagonizes interferon signaling in a species-specific manner. AB - Marburgviruses are zoonotic pathogens that cause lethal hemorrhagic fever in humans and nonhuman primates. However, they do not cause lethal disease in immunocompetent mice unless they are adapted to this species. The adaptation process can therefore provide insight into the specific virus-host interactions that determine virulence. In primate cells, the Lake Victoria marburgvirus Musoke strain (MARV) VP40 matrix protein antagonizes alpha/beta interferon (IFN alpha/beta) and IFN-gamma signaling by inhibiting the activation of the cellular tyrosine kinase Jak1. Here, VP40 from the Ravn strain (RAVV VP40)-from a distinct Marburg virus clade-is demonstrated to also inhibit IFN signaling in human cells. However, neither MARV nor RAVV VP40 effectively inhibited IFN-signaling in mouse cells, as assessed by assays of the antiviral effects of IFN-alpha/beta and the IFN-alpha/beta-induced phosphorylation of Jak1, STAT1, and STAT2. In contrast, the VP40 from a mouse-adapted RAVV (maRAVV) did inhibit IFN signaling. Effective Jak1 inhibition correlated with the species from which the cells were derived and did not depend upon whether Jak1 was of human or mouse origin. Of the seven amino acid changes that accumulated in VP40 during mouse adaptation, two (V57A and T165A) are sufficient to allow efficient IFN signaling antagonism by RAVV VP40 in mouse cells. The same two changes also confer efficient IFN antagonist function upon MARV VP40 in mouse cells. The mouse-adaptive changes did not affect the budding of RAVV VP40 in mouse cells, suggesting that this second major function of VP40 did not undergo adaptation. These data identify an apparent determinant of RAVV host range and virulence and define specific genetic determinants of this function. PMID- 21325425 TI - Upregulation of insulin-like growth factor binding protein 3 in astrocytes of transgenic mice that express Borna disease virus phosphoprotein. AB - In a previous study, we demonstrated that transgenic mice that express Borna disease virus (BDV) phosphoprotein (P) in astrocytes show striking neurobehavioral abnormalities resembling those in BDV-infected animals. To understand the molecular disturbances induced by the expression of P in astrocytes, we performed microarray analysis with cultured astroglial cells transiently expressing P. We showed that expression of insulin-like growth factor binding protein 3 mRNA increases not only in P-expressing cultured cells but also in astrocytes from the cerebella of P transgenic mice (P-Tg). Furthermore, we demonstrated that insulin-like growth factor signaling is disturbed in the P-Tg cerebellum, a factor that might be involved in the increased vulnerability of Purkinje cell neurons in the brain. PMID- 21325426 TI - Korean deaf adolescents' awareness of thematic and taxonomic relations among ordinary concepts represented by pictures and written words. AB - Individuals' relative awareness of thematic and taxonomic relations is influenced by factors such as language and background knowledge. Relatively weak in Korean language skills and also having relatively limited social opportunities, Korean deaf adolescents might be different from hearing adolescents in how they make decisions in taxonomically and thematically associated entities represented by pictures and words. Experiment 1 indicated that deaf adolescents had longer reaction times than hearing adolescents in a forced-choice decision-making task. Both deaf and hearing adolescents had shorter reaction times and higher accuracies with pictures than with words, but deaf adolescents' differences were bigger than those of hearing adolescents. Experiment 2 further showed that deaf adolescents had lower accuracies than hearing adolescents in a priming task of living-nonliving categorization. Both deaf and hearing adolescents had shorter reaction times with taxonomic than with thematic categories, but deaf adolescents' difference was bigger than that of hearing adolescents. In conclusion, Korean deaf adolescents were aware of thematic and taxonomic relations less than hearing adolescents in general. They were more likely than hearing adolescents to show the advantage of pictures over words in their performance in conceptual activities and to prefer taxonomic to thematic associations for written words in Experiment 2. PMID- 21325427 TI - Association between focal erosions and generalised bone loss in psoriatic arthritis. PMID- 21325428 TI - Variable expression and treatment of PAPA syndrome. PMID- 21325429 TI - Modulation of cystatin A expression in human airway epithelium related to genotype, smoking, COPD, and lung cancer. AB - The cathepsin inhibitor Cystatin A (CSTA) has antiapoptotic properties linked with neoplastic changes in squamous cell epithelium, where it has been proposed as a diagnostic and prognostic marker of lung cancer. Notably, cystatin A is upregulated in dysplastic epithelium, prompting us to hypothesize that it might be modulated in chronic obstructive pulmonary disease (COPD), a small airway epithelial (SAE) disorder that is a risk factor for non-small cell lung cancer (NSCLC) in a subset of smokers. Here we report that genetic variation, smoking, and COPD can all elevate levels of CSTA expression in lung small airway epithelia, with still further upregulation in squamous cell carcinoma (SCC), an NSCLC subtype. We examined SAE gene expression in 178 individuals, including healthy nonsmokers (n = 60), healthy smokers (n = 82), and COPD smokers (n = 36), with corresponding large airway epithelium (LAE) data included in a subset of subjects (n = 52). Blood DNA was genotyped by SNP microarray. Twelve SNPs upstream of the CSTA gene were found to associate with its expression in SAE. Levels were higher in COPD smokers than in healthy smokers, who, in turn, had higher levels than nonsmokers. CSTA gene expression in LAE was also smoking responsive. Using publicly available NSCLC expression data we also found that CSTA was upregulated in SCC versus LAE and downregulated in adenocarcinoma versus smoke-exposed SAE. All phenotypes were associated with different proportional expression of CSTA to cathepsins. Our findings establish that genetic variability, smoking, and COPD all influence CSTA expression, as does SCC, supporting the concept that CSTA may make pivotal contributions to NSCLC pathogenesis in both early and late stages of disease development. PMID- 21325430 TI - Evaluation of the effects of 20 nonsynonymous single nucleotide polymorphisms of CYP2C19 on S-mephenytoin 4'-hydroxylation and omeprazole 5'-hydroxylation. AB - CYP2C19 is a highly polymorphic enzyme that affects the metabolism of a wide range of therapeutic drugs. Almost all the identified alleles of CYP2C19 are derived from nonsynonymous single nucleotide polymorphisms (nsSNPs). The objective of this study was to functionally characterize 20 nsSNPs of CYP2C19, distributed throughout the entire coding region, most of which have not been thoroughly characterized. cDNAs of these variants were constructed and expressed in yeast cells. All variants had similar levels of apoprotein and holoprotein expression, except for CYP2C19.16 and D360N, which had significantly lower holoprotein levels than the wild-type (WT) CYP2C19 enzyme, and CYP2C19.5B, which showed only apoprotein. The activity of the CYP2C19 variants was investigated using two substrates, S-mephenytoin and omeprazole, and six different kinetic parameters were measured. CYP2C19.5B, CYP2C19.6, and CYP2C19.8 were found to be catalytically inactive. The entire dataset of the remaining 17 variants, together with the WT, was analyzed by multivariate analysis. This analysis indicated that CYP2C19.9, CYP2C19.10, CYP2C19.16, CYP2C19.18, CYP2C19.19, A161P, W212C, and D360N were substantially altered in catalytic properties in comparison with the WT, with each of these variants exhibiting either dramatically decreased catalytic activities or higher K(m) values. These results not only generally confirmed the function of previously reported variants but also identified additional reduced-function variants. These findings will greatly extend our understanding of CYP2C19 genetic polymorphisms in humans as well as facilitate the structure-function study of the CYP2C19 protein. PMID- 21325431 TI - Novel cytochrome P450-mediated ring opening of the 1,3,4-oxadiazole in setileuton, a 5-lipoxygenase inhibitor. AB - Setileuton [4-(4-fluorophenyl)-7-[({5-[(1S)-1-hydroxy-1-(trifluoromethyl)propyl] 1,3,4-oxadiazol-2-yl}amino)methyl]-2H-1-benzopyran-2-one] is a selective inhibitor of the 5-lipoxygenase enzyme, which is under investigation for the treatment of asthma and atherosclerosis. During the development of setileuton, a metabolite (M5) was identified in incubations with rat, dog, and human liver microsomes that represented the addition of 18 Da to the 1,3,4-oxadiazole portion of the molecule. Based on mass spectral data, a ring opened structure was proposed and confirmed through comparison with a synthetic standard. The metabolic ring opening was examined in vitro in rat liver microsomes and was determined to be mediated by cytochrome P450s (P450s). Upon examination of the specific P450s involved using cDNA-expressed rat P450s, it was shown that CYP1A2 likely was the major isoform contributing to the formation of M5. Studies using stable labeled molecular oxygen and water demonstrated that the oxygen was incorporated from molecular oxygen, rather than water, and confirmed that the metabolic formation was oxidative. An alternative, comparatively slow pathway of chemical hydrolysis also was identified and described. Three potential mechanisms for the two-step metabolic ring opening of the 1,3,4-oxadizole are proposed. PMID- 21325432 TI - Organic anion transporter 3 mediates the efflux transport of an amphipathic organic anion, dehydroepiandrosterone sulfate, across the blood-brain barrier in mice. AB - The present study investigated the efflux transport systems of organic anions across the blood-brain barrier (BBB) using dehydroepiandrosterone sulfate (DHEAS) as a probe. The elimination of DHEAS from the brain after microinjection into the cerebral cortex was characterized in wild-type mice and mice with deficiency of well characterized organic anion transporters, organic anion-transporting polypeptide 1a4 (Oatp1a4)/Slco1a4 and organic anion transporter 3 (Oat3)/Slc22a8, at the BBB. The saturable efflux of DHEAS from the brain was completely inhibited by probenecid, benzylpenicillin, and estrone-3-sulfate and moderately inhibited by taurocholate and p-aminohippurate (50-57%). Uptake of DHEAS and estrone-3 sulfate was greater in murine Oat3 cRNA-injected oocytes than that in water injected oocytes. Efflux of these compounds from the brain was significantly delayed in Oat3(-/-) mice compared with that in wild-type mice, indicating that indeed Oat3 is functionally important in vivo. Furthermore, probenecid and taurocholate inhibited DHEAS efflux completely in Oat3(-/-) mice. Contrary to the past report in rats that suggested involvement of Oatp1a4, specific uptake of DHEAS and estrone-3-sulfate by murine Oatp1a4 was not detected in vitro, and efflux of both compounds from the brain was not altered in Oatp1a4(-/-) mice. There was no significant difference in the uptake of DHEAS by brain slices prepared from wild-type, Oatp1a4(-/-), and Oat3(-/-) mice. Taken together, these results suggest that Oat3 plays a significant role in the efflux of steroid conjugates across the BBB in mice and that the BBB also expresses other unknown organic anion transporters for the efflux of DHEAS. Transport mechanisms of organic anions at the BBB are far more diverse than they were assumed to be. PMID- 21325433 TI - Deletion of the GluA1 AMPA receptor subunit alters the expression of short-term memory. AB - Deletion of the GluA1 AMPA receptor subunit selectively impairs short-term memory for spatial locations. We further investigated this deficit by examining memory for discrete nonspatial visual stimuli in an operant chamber. Unconditioned suppression of magazine responding to visual stimuli was measured in wild-type and GluA1 knockout mice. Wild-type mice showed less suppression to a stimulus that had been presented recently than to a stimulus that had not. GluA1 knockout mice, however, showed greater suppression to a recent stimulus than to a nonrecent stimulus. Thus, GluA1 is not necessary for encoding, but affects the way that short-term memory is expressed. PMID- 21325434 TI - Repeatedly reactivated memories become more resistant to hippocampal damage. AB - We examined whether repeated reactivations of a context memory would prevent the typical amnesic effects of post-training damage to the hippocampus (HPC). Rats were given a single contextual fear-conditioning session followed by 10 reactivations, involving a brief return to the conditioning context (no shock). Subsequently, the rats received sham or complete lesions of the HPC. When tested for retention, the HPC rats that experienced the reactivations froze significantly more than nonreactivation HPC rats and did not significantly differ from their respective control group. These findings suggest that memory reactivations contribute to long-term memories becoming independent of the HPC. PMID- 21325436 TI - Weaknesses in using quasi-quantitative food-frequency questionnaire data to link habitual intake of flavonoids to hypertension incidence. PMID- 21325435 TI - Requirement of dopamine signaling in the amygdala and striatum for learning and maintenance of a conditioned avoidance response. AB - Two-way active avoidance (2WAA) involves learning Pavlovian (association of a sound cue with a foot shock) and instrumental (shock avoidance) contingencies. To identify regions where dopamine (DA) is involved in mediating 2WAA, we restored DA signaling in specific brain areas of dopamine-deficient (DD) mice by local reactivation of conditionally inactivated Th genes using viral gene therapy. Among all targeted areas--prefrontal cortex (PFC), amygdala, ventral striatum, dorsal striatum, and whole striatum--only restoration of DA signaling to both the whole striatum together with the amygdala enabled DD mice to acquire 2WAA. However, after prolonged overtraining during which DD mice had DA synthesis systemically reconstituted pharmacologically with L-3,4-dihydroxyphenylalanine (L Dopa), DA signaling in the striatum alone was sufficient to maintain 2WAA, whereas DA signaling in the PFC together with the amygdala was insufficient to maintain 2WAA. Our results indicate that learning 2WAA requires DA signaling in both the amygdala and the entire striatum; however, after sufficient training, DA signaling in the striatum alone can maintain the learned avoidance behavior. PMID- 21325437 TI - Prediction of postprandial glycemia and insulinemia in lean, young, healthy adults: glycemic load compared with carbohydrate content alone. AB - BACKGROUND: Dietary glycemic load (GL; defined as the mathematical product of the glycemic index and carbohydrate content) is increasingly used in nutritional epidemiology. Its ability to predict postprandial glycemia and insulinemia for a wide range of foods or mixed meals is unclear. OBJECTIVE: Our objective was to assess the degree of association between calculated GL and observed glucose and insulin responses in healthy subjects consuming isoenergetic portions of single foods and mixed meals. DESIGN: In study 1, groups of healthy subjects consumed 1000-kJ portions of 121 single foods in 10 food categories. In study 2, healthy subjects consumed 2000-kJ servings of 13 mixed meals. Foods and meals varied widely in macronutrient content, fiber, and GL. Glycemia and insulinemia were quantified as area under the curve relative to a reference food (= 100). RESULTS: Among the single foods, GL was a more powerful predictor of postprandial glycemia and insulinemia than was the available carbohydrate content, explaining 85% and 59% of the observed variation, respectively (P < 0.001). Similarly, for mixed meals, GL was also the strongest predictor of postprandial glucose and insulin responses, explaining 58% (P = 0.003) and 46% (P = 0.01) of the variation, respectively. Carbohydrate content alone predicted the glucose and insulin responses to single foods (P < 0.001) but not to mixed meals. CONCLUSION: These findings provide the first large-scale, systematic evidence of the physiologic validity and superiority of dietary GL over carbohydrate content alone to estimate postprandial glycemia and insulin demand in healthy individuals. This trial was registered at ANZCTR.org as ACTRN12610000484044. PMID- 21325438 TI - Sensing of energy and nutrients by AMP-activated protein kinase. AB - AMP-activated protein kinase (AMPK) is a cellular energy sensor that exists in almost all eukaryotes. Genetic studies in lower eukaryotes suggest that the ancestral role of AMPK was in response to starvation for a carbon source and that AMPK is involved in life-span extension in response to caloric restriction. In mammals, AMPK is activated by an increasing cellular AMP:ATP ratio (which signifies a decrease in energy) caused by metabolic stresses that interfere with ATP production (eg, hypoxia) or that accelerate ATP consumption (eg, muscle contraction). Because glucose deprivation can increase the AMP:ATP ratio, AMPK can also act as a glucose sensor. AMPK activation occurs by a dual mechanism that involves allosteric activation and phosphorylation by upstream kinases. Once activated, AMPK switches on catabolic pathways that generate ATP (eg, the uptake and oxidation of glucose and fatty acids and mitochondrial biogenesis) while switching off ATP-consuming, anabolic pathways (eg, the synthesis of lipids, glucose, glycogen, and proteins). In addition to the acute effects via direct phosphorylation of metabolic enzymes, AMPK has longer-term effects by regulating transcription. These features make AMPK an ideal drug target in the treatment of metabolic disorders such as insulin resistance and type 2 diabetes. The antidiabetic drug metformin (which is derived from an herbal remedy) works in part by activating AMPK, whereas many xenobiotics or "nutraceuticals," including resveratrol, quercetin, and berberine, are also AMPK activators. Most of these agents activate AMPK because they inhibit mitochondrial function. PMID- 21325439 TI - Fundamental misunderstanding of the relation between energy density (kcal/g) and energy cost ($/kcal). PMID- 21325440 TI - The expression level of ecto-NTP diphosphohydrolase1/CD39 modulates exocytotic and ischemic release of neurotransmitters in a cellular model of sympathetic neurons. AB - Once released, norepinephrine is removed from cardiac synapses via reuptake into sympathetic nerves, whereas transmitter ATP is catabolized by ecto-NTP diphosphohydrolase 1 (E-NTPDase1)/CD39, an ecto-ATPase. Because ATP is known to modulate neurotransmitter release at prejunctional sites, we questioned whether this action may be ultimately controlled by the expression of E-NTPDase1/CD39 at sympathetic nerve terminals. Accordingly, we silenced E-NTPDase1/CD39 expression in nerve growth factor-differentiated PC12 cells, a cellular model of sympathetic neuron, in which dopamine is the predominant catecholamine. We report that E NTPDase1/CD39 deletion markedly increases depolarization-induced exocytosis of ATP and dopamine and increases ATP-induced dopamine release. Moreover, overexpression of E-NTPDase1/CD39 resulted in enhanced removal of exogenous ATP, a marked decrease in exocytosis of ATP and dopamine, and a large decrease in ATP induced dopamine release. Administration of a recombinant form of E-NTPDase1/CD39 reproduced the effects of E-NTPDase1/CD39 overexpression. Exposure of PC12 cells to simulated ischemia elicited a release of ATP and dopamine that was markedly increased in E-NTPDase1/CD39-silenced cells and decreased in E-NTPDase1/CD39 overexpressing cells. Therefore, transmitter ATP acts in an autocrine manner to promote its own release and that of dopamine, an action that is controlled by the level of E-NTPDase1/CD39 expression. Because ATP availability greatly increases in myocardial ischemia, recombinant E-NTPDase1/CD39 therapeutically used may offer a novel approach to reduce cardiac dysfunctions caused by excessive catecholamine release. PMID- 21325441 TI - Reducing the late sodium current improves cardiac function during sodium pump inhibition by ouabain. AB - Inhibition by cardiac glycosides of Na(+), K(+)-ATPase reduces sodium efflux from myocytes and may lead to Na(+) and Ca(2+) overload and detrimental effects on mechanical function, energy metabolism, and electrical activity. We hypothesized that inhibition of sodium persistent inward current (late I(Na)) would reduce ouabain's effect to cause cellular Na(+) loading and its detrimental metabolic (decrease of ATP) and functional (arrhythmias, contracture) effects. Therefore, we determined effects of ouabain on concentrations of intracellular sodium (Na(+)(i)) and high-energy phosphates using (23)Na and (31)P NMR, the amplitude of late I(Na) using the whole-cell patch-clamp technique, and contractility and electrical activity of guinea pig isolated hearts, papillary muscles, and ventricular myocytes in the absence and presence of inhibitors of late I(Na). Ouabain (1-1.3 MUM) increased Na(+)(i) and late I(Na) of guinea pig isolated hearts and myocytes by 3.7- and 4.2-fold, respectively. The late I(Na) inhibitors ranolazine and tetrodotoxin significantly reduced ouabain-stimulated increases in Na(+)(i) and late I(Na). Reductions of ATP and phosphocreatine contents and increased diastolic tension in ouabain-treated hearts were also markedly attenuated by ranolazine. Furthermore, the ouabain-induced increase of late I(Na) was also attenuated by the Ca(2+)-calmodulin-dependent kinase I inhibitors KN-93 [N-[2-[[[3-(4-chlorophenyl)-2-propenyl]methylamino]methyl]phenyl]-N-(2 hydroxyethyl)-4-methoxybenzenesulphonamide] and autocamide-2 related inhibitory peptide, but not by KN-92 [2-[N-(4'-methoxybenzenesulfonyl)]amino-N-(4' chlorophenyl)-2-propenyl-N-methylbenzylamine phosphate]. We conclude that ouabain induced Na(+) and Ca(2+) overload is ameliorated by the inhibition of late I(Na). PMID- 21325442 TI - The relation between the names and designations of syphilis in the 16th century and its clinical gravity. PMID- 21325443 TI - Increased HIV testing and reduced undiagnosed infection among gay men in Scotland, 2005-8: support for the opt-out testing policy? AB - OBJECTIVE: To examine changes in HIV testing and undiagnosed infection among men who have sex with men in Scotland between 2005 and 2008. METHODS: Self-completed questionnaires and Orasure oral fluid collection kits were distributed to men visiting the commercial gay scene in Glasgow and Edinburgh. RESULTS: Questionnaires and oral fluid specimens were provided by 1350 men (51.6% response rate) in 2005 and 1277 (59.7% response rate) in 2008. 2572 men were eligible for inclusion in the analyses. Recent HIV testing increased from 33.2% in 2005 to 48.3% in 2008 (p<0.001). HIV prevalence was comparable in 2005 and 2008 (4.4% and 4.6%, respectively). Among HIV-positive men, there was a reduction in undiagnosed infection between 2005 and 2008 from 41.7% to 26.3% (p=0.08). Undiagnosed HIV did not differ between men who were and were not tested in the past year. In 2008, only four (26.7%) HIV-positive men tested in the past 6 months were undiagnosed, compared with 11 (42.3%) HIV-positive men who had not tested (p=0.03). CONCLUSION: There was a substantial increase in recent HIV testing between 2005 and 2008. Although there was a concurrent (non-significant) reduction in undiagnosed HIV, there was no difference in undiagnosed infection between men who had and had not tested recently. However, lower proportions of undiagnosed infection among the most recent HIV-positive testers suggest frequent testing could play a role in reducing undiagnosed HIV and should remain central to HIV prevention efforts. PMID- 21325444 TI - Outcome of advanced NSCLC patients harboring sensitizing EGFR mutations randomized to EGFR tyrosine kinase inhibitors or chemotherapy as first-line treatment: a meta-analysis. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are effective as first-line treatment of advanced non-small-cell lung cancer patients with EGFR mutations (EGFR-M+). PATIENTS AND METHODS: We conducted a literature-based meta-analysis to quantify the magnitude of benefit with upfront EGFR TKI in EGFR-M+ patients. Meta-regression and sensitivity analyses were also carried out to identify additional predictors of outcome and to assess the influence of trial design. RESULTS: Five trials (805 patients) were identified (three trials prospectively enrolling EGFR-M+ patients and two retrospective analyses of EGFR-M+ patients). TKI significantly increased progression-free survival (PFS) [hazard ratio (HR) 0.45, 95% confidence interval (CI) 0.36-0.58, P < 0.0001] and overall response rate (ORR) (HR 2.08, 95% CI 1.75 2.46, P < 0.0001)] over chemotherapy, while significantly decreasing neutropenia. No significant difference was observed in overall survival. The rate of exon-19 mutations, female gender, and nonsmoking status were identified as additional predictors of outcome at meta-regression analysis. A significant interaction with trial design was found for both PFS (P = 0.028) and ORR (P = 0.008), suggesting a larger advantage for patients treated within prospective trials. CONCLUSIONS: In EGFR-M+ patients, first-line TKI increase both PFS and ORR by ~25%, while significantly decreasing toxicity. The role of additional predictive factors and the influence of trial design on the magnitude of the observed benefit warrant further investigation. PMID- 21325445 TI - Long-term results of International Breast Cancer Study Group Trial VIII: adjuvant chemotherapy plus goserelin compared with either therapy alone for premenopausal patients with node-negative breast cancer. AB - BACKGROUND: The International Breast Cancer Study Group Trial VIII compared long term efficacy of endocrine therapy (goserelin), chemotherapy [cyclophosphamide, methotrexate and fluorouracil (CMF)], and chemoendocrine therapy (CMF followed by goserelin) for pre/perimenopausal women with lymph-node-negative breast cancer. PATIENTS AND METHODS: From 1990 to 1999, 1063 patients were randomized to receive (i) goserelin for 24 months (n = 346), (ii) six courses of 'classical' CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy (n = 360), or (iii) six courses of CMF plus 18 months goserelin (CMF-> goserelin; n = 357). Tumors were classified as estrogen receptor (ER) negative (19%), ER positive (80%), or ER unknown (1%); 19% of patients were younger than 40. Median follow-up was 12.1 years. RESULTS: For the ER-positive cohort, sequential therapy provided a statistically significant benefit in disease-free survival (DFS) (12-year DFS = 77%) compared with CMF alone (69%) and goserelin alone (68%) (P = 0.04 for each comparison), due largely to the effect in younger patients. Patients with ER negative tumors whose treatment included CMF had similar DFS (12-year DFS CMF = 67%; 12-year DFS CMF-> goserelin = 69%) compared with goserelin alone (12-year DFS = 61%, P= NS). CONCLUSIONS: For pre/perimenopausal women with lymph-node negative ER-positive breast cancer, CMF followed by goserelin improved DFS in comparison with either modality alone. The improvement was the most pronounced in those aged below 40, suggesting an endocrine effect of prolonged CMF-induced amenorrhea. PMID- 21325446 TI - Incidental versus symptomatic venous thrombosis in cancer: a prospective observational study of 340 consecutive patients. AB - BACKGROUND: The clinical significance of incidental venous thrombosis (IVT) is uncertain. The objective of this study was to compare the clinical characteristics and the outcome of cancer patients with IVT with those of patients with symptomatic venous thrombosis (SVT). PATIENTS AND METHODS: Prospective observational study enrolling consecutive cancer patients newly diagnosed with venous thromboembolism (May 2006-April 2009). Diagnosis of IVT was based on vascular filling defects in scheduled computed tomography scans in the absence of clinical symptoms. Anticoagulant therapy was routinely prescribed regardless of SVT or IVT. RESULTS: IVT was diagnosed in 94 out of 340 (28%) patients. Patients with IVT were older (63.7 +/- 10.5 versus 60.8 +/- 10.5 years, P = 0.035), more frequently had metastatic cancer (82% versus 65%, P = 0.01) and were less likely to be receiving chemotherapy at the time of the thrombotic event (53% versus 67%, P = 0.018). Mean follow-up was 477 days. A lower risk of venous rethromboses was observed in patients with IVT (log-rank P = 0.043), with no differences in major bleeding and overall survival compared with SVT patients. CONCLUSIONS: A high proportion of venous thrombotic events in cancer patients are diagnosed incidentally during scheduled imaging. Prospective controlled trials evaluating the optimal therapy in this setting are required. PMID- 21325447 TI - What the specific tools of geriatrics and oncology can tell us about the role and status of geriatricians in a pilot geriatric oncology program. AB - BACKGROUND: Pilot Oncogeriatric Coordination Units (UPCOGs) were created by the French National Cancer Institute (INCA) in order to implement routine geriatric assessment of all cancer patients over 75 years of age. This article examines the role of geriatric and oncologic tools in the organization of medical oncogeriatric activities, focusing on the role and place of geriatricians. METHODS: We conducted a qualitative sociological survey in the West Paris Oncogeriatric Program (POGOP), one of the Pilot Oncogeriatric Coordination Units (UPCOGs) recently created in France. Various qualitative methods were used including a review of the literature, participative observational surveys, and semidirective interviews with medical staff managing elderly cancer patients. RESULTS: The results show that the way in which geriatric assessment procedures are implemented confirms the role of the geriatrician in the diagnosis and prevention of vulnerabilities and fragility at the time of initial diagnosis and medical decision making. Nevertheless, the articulation of these different working methods gives rise to various organizational configurations. CONCLUSIONS: The POGOP has largely contributed to clarifying medical activity in oncogeriatrics: identification of physicians, definition of shared goals, initiation, and structuring of new partnerships. Nevertheless, the geriatrician's tools, expertise, and know-how are often perceived ambiguously. PMID- 21325448 TI - Cancer-related fatigue: a practical review. AB - Fatigue is an exceedingly common often treatable problem in cancer patients that profoundly affects all aspects of quality of life. Prevalence estimates have ranged from 50% to 90% of cancer patients overall. After addressing reversible or treatable contributing factors, such as hypothyroidism, anemia, sleep disturbance, pain, emotional distress, climacterium, medication adverse events, metabolic disturbances, or organ dysfunction such as heart failure, myopathy, and pulmonary fibrosis, patients may be screened with a brief fatigue self-assessment tool. All cancer patients should be screened regularly for fatigue. Those with moderate or severe fatigue may benefit from both pharmacologic and nonpharmacologic interventions, while mild fatigue that does not interfere with quality of life can be treated with nonpharmacologic measures alone. Physicians often have insufficient knowledge about fatigue and its treatments or underestimate the impact of fatigue on quality of life, while patients may consider it an unavoidable and untreatable side-effect and fear that reporting it may incite a change toward less aggressive cancer treatment. A practical review may therefore be useful to health care professionals in order to avoid the common barriers to its treatment that exist on the sides of both physicians and patients. PMID- 21325449 TI - Epidermal growth factor receptor as a biomarker for cervical cancer. AB - This review focuses on the different modes of expression of the epidermal growth factor receptor (EGFR). All methods used to assess EGFR expression are critically analyzed and insights into the use of inhibitors of EGFR for treatment of cervical cancer are discussed. Currently, expression of EGFR as a biomarker for prognosis or for treatment of cervical cancer is not defined for clinical use. PMID- 21325450 TI - RINF (CXXC5) is overexpressed in solid tumors and is an unfavorable prognostic factor in breast cancer. AB - BACKGROUND: We have previously described the essential role of the retinoid inducible nuclear factor (RINF) during differentiation of hematopoietic cells and suggested its putative involvement in myeloid leukemia and preleukemia. Here, we have investigated whether this gene could have a deregulated expression in malignant tissues compared with their normal tissues of origin and if this potential deregulation could be associated with important clinicopathological parameters. PATIENTS AND METHODS: RINF messenger RNA expression was examined in biopsies from locally advanced breast tumors, metastatic malignant melanomas, and papillary thyroid carcinomas and compared with their paired or nonpaired normal reference samples. Further, the prognostic role of RINF expression was evaluated in locally advanced breast cancer. RESULTS: RINF expression was significantly higher in all tumor forms (primary breast, and thyroid cancers and metastatic melanomas) as compared with normal control tissues (P < 0.001 for each comparison). Importantly, high levels of RINF expression correlated to a poor overall survival in breast cancer (P = 0.013). This finding was confirmed in three independent public microarray datasets (P = 0.043, n = 234; P = 0.016, n = 69; P = 0.001, n = 196) and was independent of tamoxifen therapy. Notably, high levels of RINF was strongly associated with TP53 wild-type status (P = 0.002) possibly indicating that high levels of RINF could substitute for TP53 mutations as an oncogenic mechanism during the malignant development of some cases of breast cancer. CONCLUSIONS: Our data indicate that (i) RINF overexpression is associated with the malignant phenotype in solid tumors and (ii) RINF overexpression represents an independent molecular marker for poor prognosis in breast tumors. PMID- 21325451 TI - A phase I pharmacokinetic and pharmacodynamic study of AT7519, a cyclin-dependent kinase inhibitor in patients with refractory solid tumors. AB - BACKGROUND: AT7519 is an inhibitor of multiple cyclin-dependent kinases (CDKs). Based on potent antitumor activity in preclinical models, a first-in-human clinical trial in refractory solid tumors investigated its safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD). PATIENTS AND METHODS: AT7519 was administered in a '3 + 3' dose- escalation scheme on 5 consecutive days every 3 weeks to patients with advanced, refractory solid tumors. Samples to monitor AT7519 PK and PD were obtained. RESULTS: Twenty-eight patients were treated at seven dose levels (1.8-40 mg/m(2)/day). At 40 mg/m(2)/day, one patient developed hypotension and ST segment elevation. At 34 mg/m(2)/day, dose-limiting toxic effects (DLTs) were QTc prolongation with one death (grade 5), fatigue (grade 4) and mucositis (grade 3). Electrocardiogram review suggested a dose-dependent increase in QTc and recruitment was discontinued without establishing a maximum tolerated dose. Four patients exhibited stable disease for >6 months and one had a prolonged partial response. PK profile revealed modest interpatient variation with linear exposure at increasing doses. Inhibition of markers of CDK activity was observed across the dose range and manifested in antiproliferative activity at a dose of 28 mg/m(2). CONCLUSION: AT7519 elicited clinical and PD activity resulting from CDK inhibition at doses below the appearance of DLT of QTc prolongation. PMID- 21325452 TI - Identification, localization and expression of LPXRFamide peptides, and melatonin dependent induction of their precursor mRNA in the newt brain. AB - The existence of RFamide peptides with a C-terminal LPXRFamide (X=L or Q) motif has been identified in the brain of various vertebrate species. However, the presence of LPXRFamide peptides in the urodele brain is not yet known. In this study, we cloned a cDNA encoding the precursor of LPXRFamide peptides from the newt brain by a combination of 3' and 5' rapid amplification of cDNA ends. The deduced LPXRFamide peptide precursor consisted of 233 amino acid residues, encoding four putative LPXRFamide peptides. All the peptide sequences were flanked by a glycine C-terminal amidation signal and basic amino acid on each end as an endoproteolytic site. Mass spectrometric analyses detected a nonapeptide, two decapeptides and an octapeptide produced from the precursor polypeptide in the brain as endogenous ligands. In situ hybridization further revealed the cellular localization of newt LPXRFamide (nLPXRFa) precursor mRNA in the suprachiasmatic nucleus (SCN) in the newt hypothalamus. Immunocytochemistry showed a cluster of cell bodies restricted to the SCN and their terminals in the median eminence. To understand the regulatory mechanism of nLPXRFa peptide expression, we further analyzed the effect of melatonin on the expression of nLPXRFa precursor mRNA. Melatonin administration to newts increased the expression of nLPXRFa precursor mRNA in the diencephalon. These results indicate that the urodele hypothalamus possesses LPXRFamide peptides and the expression of LPXRFamide peptides is regulated by melatonin. The localization of nLPXRFa peptides further suggests that these peptides may be involved in the regulation of pituitary hormone release in newts. PMID- 21325453 TI - Chromogranin a measurement for assessing the selectivity of adrenal venous sampling in primary aldosteronism. AB - CONTEXT: The assessment of selectivity of blood sampling is a fundamental step for a proper interpretation of the results of adrenal vein sampling (AVS), which is a "must" for identifying the surgically curable subtypes of primary aldosteronism. However, uncertainties remain on how to best achieve this goal. OBJECTIVE: The aim of the study was to investigate whether chromogranin A (ChA) is tonically released in adrenal vein blood and might be used to assess the selectivity of AVS. DESIGN AND METHODS: In consecutive patients undergoing AVS, we compared the plasma cortisol and ChA levels in the adrenal veins and infrarenal inferior vena cava blood. We then calculated and compared the selectivity index based on cortisol with that based on ChA. RESULTS: Thirteen patients had cortisol and ChA levels assessed simultaneously. Besides the expected step-up of cortisol, they showed a step-up of ChA levels between the inferior vena cava and blood from either adrenal vein. The selectivity index determined with ChA was weakly correlated with that calculated with cortisol; the former was much smaller (3- and 4- fold on the right and left side, respectively) than the latter. This translated into a proportional error at Bland-Altman plot between selectivity indexes. Accordingly, only 53% of AVS were bilaterally selective using the selectivity index determined with ChA, as compared to 84% with selectivity index determined with cortisol (P = 0.0001). CONCLUSIONS: These findings indicate that ChA is tonically released by the adrenal gland but do not support the usefulness of using ChA instead of cortisol for assessing the selectivity of blood sampling during AVS, perhaps with the exception of aldosterone-producing tumors that cosecrete cortisol. PMID- 21325455 TI - Place of cabergoline in acromegaly: a meta-analysis. AB - CONTEXT: Cabergoline is widely considered to be poorly effective in acromegaly. OBJECTIVE: The aim of this study was to obtain a more accurate picture of the efficacy of cabergoline in acromegaly, both alone and in combination with somatostatin analogs. DESIGN: We systematically reviewed all trials of cabergoline therapy for acromegaly published up to 2009 in four databases (PubMed, Pascal, Embase, and Google Scholar). We identified 15 studies (11 prospective) with a total of 237 patients; none were randomized or placebo controlled. A meta-analysis was conducted on individual data (n = 227). RESULTS: Cabergoline was used alone in nine studies. Fifty-one (34%) of the 149 patients achieved normal IGF-I levels. In multivariate analysis, the decline in IGF-I was related to the baseline IGF-I concentration (beta = 1.16; P <0.001), treatment duration (beta = 0.28; P < 0.001), and baseline prolactin concentration (beta = 0.18; P = 0.01), and with a trend toward a relation with the cabergoline dose (beta = 0.38; P =0.07). In five studies, cabergoline was added to ongoing somatostatin analog treatment that had failed to normalize IGF-I. Forty patients (52%) achieved normal IGF-I levels. The change in IGF-I was significantly related to the baseline IGF-I level (beta = 0.74; P < 0.001) but not to the dose of cabergoline, the duration of treatment, or the baseline prolactin concentration. CONCLUSION: This meta-analysis suggests that cabergoline single-agent therapy normalizes IGF-I levels in one third of patients with acromegaly. When a somatostatin analog fails to control acromegaly, cabergoline adjunction normalizes IGF-I in about 50% of cases. This effect may occur even in patients with normoprolactinemia. PMID- 21325454 TI - Activation of the receptor for advanced glycation end products system in women with severe preeclampsia. AB - CONTEXT: Activation of the receptor for advanced glycation end products (RAGE) mediates cellular injury. Soluble forms of RAGE [soluble RAGE (sRAGE), endogenous secretory (esRAGE)] bind RAGE ligands, thereby preventing downstream signaling and damage. OBJECTIVES: The objective of the study was to characterize the changes in maternal serum, amniotic fluid, and cord blood soluble receptor for advanced glycation end products (sRAGE) during physiological gestation and to provide insight into mechanisms responsible for RAGE activation in preeclampsia. DESIGN AND SETTINGS: This was a cross-sectional study at a tertiary university hospital. PATIENTS: We studied 135 women in the following groups: nonpregnant controls (n = 16), healthy pregnant controls (n = 68), pregnant women with chronic hypertension (n = 13), or pregnant women with severe preeclampsia (sPE; n = 38). INTERVENTIONS AND MAIN OUTCOME MEASURES: sRAGE and esRAGE levels were evaluated in vivo by ELISA in maternal serum, amniotic fluid, and cord blood and in vitro after stimulation of the amniochorion and placental explants with lipopolysaccharide or xanthine/xanthine oxidase. Placenta and amniochorion were immunostained for RAGE. Real-time quantitative PCR measured RAGE mRNA. RESULTS: Pregnant women had significantly decreased serum sRAGE compared with nonpregnant subjects (P < 0.001). sPE women had higher serum and amniotic fluid sRAGE and esRAGE relative to those expected for gestational age (P < 0.001). Cord blood sRAGE remained unaffected by sPE. RAGE immunoreactivity and mRNA expression appeared elevated in the amniochorion of sPE women. Xanthine/xanthine oxidase (but not lipopolysaccharide) significantly up-regulated the release of sRAGE (P < 0.001) in the amniochorion explant system. CONCLUSIONS: Fetal membranes are a rich source of sRAGE. Elevated maternal serum and amniotic fluid sRAGE and esRAGE, paralleled by increased RAGE expression in the amniochorion, suggest activation of this system in sPE. PMID- 21325456 TI - Vitamin D and hyperparathyroidism in obesity. AB - BACKGROUND: Low vitamin D status and hyperparathyroidism occur in obesity and may be involved in pathogenesis of obesity-associated comorbid conditions. AIMS: Our aims were to determine in obesity whether there was vitamin D insufficiency, assessed by serum 25-hydroxyvitamin D (s25D) and serum PTH (sPTH) and whether it related to comorbid conditions. METHODS: We conducted a case-control study of 48 women having bariatric surgery and 50 healthy women frequency matched for race, age, year, and season of study. Height, weight, s25D, sPTH, serum 1,25 dihydroxyvitamin D (s1,25D), serum bone alkaline phosphatase, serum cross-linked N-telopeptides of type 1 collagen, and serum calcium, phosphate, creatinine, glucose, and insulin were measured, and comorbid conditions were documented from patient files. RESULTS: Weight (140 vs. 76 kg, P < 0.001), sPTH (44.4 vs. 25.6 pg/ml, P < 0.001), s1,25D (39 vs. 24 pg/ml, P < 0.001), serum bone alkaline phosphatase (19 vs. 12 ng/ml, P < 0.001), serum cross-linked N-telopeptides of type 1 collagen (9.6 vs. 7.9 nm bone collagen equivalents, P = 0.007), serum phosphate (3.45 vs. 3.24 mg/dl, P = 0.043), and serum creatinine (1.05 vs. 0.87 mg/dl, P < 0.001) were higher, and s25D (16 vs. 23 ng/ml, P <.001) was lower in bariatric-surgery women than control women. s25D was lower in bariatric-surgery women than controls in summer (17 vs. 26 ng/ml, P < 0.0001) but not winter (15 vs. 18 ng/ml, P > 0.2). Multiple regression analysis demonstrated that weight predicted s25D (P < 0.001) and sPTH (P = 0.001), but s25D did not predict sPTH or the presence of comorbid conditions except for osteoarthritis. CONCLUSION: Women having bariatric surgery had lower s25D and higher sPTH. The major determinant of s25D and sPTH was weight. Hyperparathyroidism in obesity did not indicate vitamin D insufficiency. Low s25D was not associated with comorbid conditions, apart from osteoarthritis. PMID- 21325457 TI - Contributions of cardiorespiratory fitness and visceral adiposity to six-year changes in cardiometabolic risk markers in apparently healthy men and women. AB - CONTEXT: Both excess visceral adipose tissue (VAT) and low cardiorespiratory fitness (CRF) levels are associated with a deteriorated cardiometabolic risk profile. OBJECTIVE: The aim of the study was to examine the respective contributions of changes in VAT accumulation vs. changes in CRF to 6-yr longitudinal changes in cardiometabolic risk markers. DESIGN, SETTINGS, AND PARTICIPANTS: We conducted a prospective, population-based study with an average follow-up of 5.9 +/- 0.8 yr. We followed 132 middle-aged participants from the Quebec Family Study (mean age, 35.3 +/- 13.9 yr). VAT was measured by computed tomography, whereas the level of CRF was assessed by a submaximal physical working capacity test at baseline and at follow-up. A complete cardiometabolic risk profile, including systolic and diastolic blood pressure, fasting glucose and insulin levels, C-reactive protein (n = 72), as well as a standard lipoprotein-lipid profile, was obtained at baseline and at follow-up. MAIN OUTCOME MEASURES: We measured changes in CRF, VAT, and cardiometabolic risk profile over 6 yr. RESULTS: After adjusting for age and sex, 6-yr changes in VAT were negatively correlated with changes in CRF (r = -0.38; P < 0.001). In a multivariate model that included age, sex, changes in VAT, changes in CRF, as well as baseline levels of the above cardiometabolic risk factors, 6-yr changes in VAT were the most important predictor of the change in the metabolic syndrome score (R(2) = 13.2%; P < 0.001). Adding 6-yr changes in CRF levels significantly improved the predictability of the model (R(2) = 19.7%; P = 0.002). CONCLUSIONS: Changes in both VAT and CRF levels observed over 6 yr are associated with changes in parameters of the lipoprotein-lipid profile, glucose-insulin homeostasis, and inflammatory markers. Thus, maintaining a low level of VAT and a high level of CRF are important targets for maintenance of cardiometabolic health. PMID- 21325458 TI - Pretreatment serum anti-mullerian hormone predicts long-term ovarian function and bone mass after chemotherapy for early breast cancer. AB - CONTEXT: Administration of chemotherapy to premenopausal women shortens their reproductive lifespan by depleting nonrenewable oocytes. Preservation of fertility is a priority for many such women, and identification of women at risk of infertility is therefore important. However, age is the only patient characteristic currently recognized to be predictive of long-term ovarian function after chemotherapy. OBJECTIVE: Our objective was to assess markers of ovarian reserve and age as long-term predictors of ovarian function after chemotherapy. DESIGN AND SETTING: We conducted a prospective, longitudinal study at a university hospital and research institute. PATIENTS: Patients included women who were premenopausal at the time of diagnosis of early breast cancer. MAIN OUTCOME MEASURES: Ovarian function was assessed at 5 yr follow-up in relation to pretreatment hormonal and ultrasound markers of ovarian reserve. RESULTS: Forty-two women received (neo-)adjuvant chemotherapy. Continuing menses 4-5 yr after diagnosis closely reflected ovarian activity as assessed by a range of serum markers, including estradiol, inhibin B, FSH, and anti-mullerian hormone (AMH). Pretreatment serum AMH, FSH, antral follicle count, and age predicted late ovarian activity by univariate analysis. However, only AMH was predictive in a multivariate logistic regression (odds ratio = 13.0; 95% confidence interval = 2.5-66.7); 0.71 ng/ml gave peak likelihood ratio of 7.0 with 54% sensitivity and 92% specificity. Bone mineral density fell over the 4-5 yr after diagnosis with greater loss in women with lower ovarian activity. Higher pretreatment AMH was associated with lower bone mineral density at both lumbar spine and hip at 5 yr (P < 0.02). CONCLUSION: Measurement of AMH at cancer diagnosis predicts long-term ovarian function after chemotherapy. Use of this in clinical practice may allow better prediction of chemotherapy-related risk to future fertility. PMID- 21325459 TI - Vitamin D deficiency is associated with depletion of circulating endothelial progenitor cells and endothelial dysfunction in patients with type 2 diabetes. AB - CONTEXT: Vitamin D (Vit-D) deficiency is associated with type 2 diabetes mellitus (DM) and endothelial dysfunction. The relationship of Vit-D deficiency with circulating endothelial progenitor cells and endothelial dysfunction in type 2 DM patients nonetheless remains unclear. OBJECTIVE: We aimed to investigate the cross-sectional association of Vit-D status with brachial flow-mediated dilation (FMD) and circulating endothelial progenitor cell (EPC) numbers in type 2 DM patients. DESIGN, SETTING, AND PARTICIPANTS: We conducted a cross-sectional study of 280 patients (59% male, aged 68 +/- 10 yr) with type 2 DM recruited in outpatient clinics during the winter period. MAIN OUTCOME MEASURE: We measured serum 25-hydroxyvitamin D [25(OH)D] by an ELISA kit, circulating CD34+/kinase insert domain-containing receptor (KDR)+ and CD133+/KDR+ EPCs by flow cytometry and brachial artery FMD by vascular ultrasound, respectively. RESULTS: The mean serum 25(OH)D concentration was 25.00 +/- 9.17 ng/ml, and 34.3% of patients had Vit-D deficiency [25(OH)D < 20 ng/ml]. Serum 25(OH)D concentration had a significant correlation with hemoglobin A1c level [B = -0.018, 95% confidence interval (CI) -0.035 to -0.002, P = 0.032]. Patients with Vit-D deficiency status had significantly lower brachial FMD (mean difference -1.43%, 95% CI -2.31 to 0.55, P = 0.001) and CD133+/KDR+EPC counts (mean difference -0.12%, 95% CI -0.21 to -0.019, P = 0.022) than those with sufficient Vit-D status after adjustment for age, sex, and cardiovascular risk factors, including hemoglobin A1c levels. CONCLUSIONS: Our results demonstrate that serum 25(OH)D status was significantly associated with brachial artery FMD and circulating CD133+/KDR+EPCs. This suggests that Vit-D deficiency might contribute to depletion of EPCs and endothelial dysfunction in patients with type 2 DM. PMID- 21325460 TI - Current thyroglobulin autoantibody (TgAb) assays often fail to detect interfering TgAb that can result in the reporting of falsely low/undetectable serum Tg IMA values for patients with differentiated thyroid cancer. AB - CONTEXT: Specimens have thyroglobulin antibody (TgAb) measured prior to thyroglobulin (Tg) testing because the qualitative TgAb status (positive or negative) determines risk for Tg assay interference, and the quantitative TgAb concentration serves as a surrogate tumor marker for differentiated thyroid cancer. OBJECTIVE: This study assessed the reliability of four TgAb methods to detect interfering TgAb [as judged from abnormally low Tg immunometric assay (IMA) to Tg RIA ratios] and determine whether between-method conversion factors might prevent a change in method from disrupting TgAb monitoring. METHODS: Sera from selected and unselected TgAb-negative and TgAb-positive differentiated thyroid cancer patients had serum Tg measured by both IMA and RIA and TgAb measured by a reference method and three additional methods. RESULTS: The Tg IMA and Tg RIA values were concordant when TgAb was absent. Tg IMA to Tg RIA ratios below 75% were considered to indicate TgAb interference. Manufacturer-recommended cutoffs were set in the detectable range, and when used to determine the presence of TgAb misclassified many specimens displaying Tg interference as TgAb negative. False-negative misclassifications were virtually eliminated for two of four methods by using the analytical sensitivity (AS) as the detection limit for TgAb. Relationships between values for different specimens were too variable to establish between-method conversion factors. CONCLUSIONS: Many specimens with interfering TgAb were misclassified as TgAb negative using manufacturer recommended cutoffs. It is recommended that assay AS limits be used to detect TgAb to minimize false-negative misclassifications. However, for two of four assays, AS limits failed to detect interfering TgAb in 20-30% of cases. TgAb methods were too qualitatively and quantitatively variable to establish conversion factors that would allow a change in method without disrupting serial TgAb monitoring. PMID- 21325461 TI - Effects of physiological variations in circulating insulin levels on bone turnover in humans. AB - CONTEXT: Recent studies in mice have demonstrated that insulin signaling in osteoblasts stimulates bone formation and reduces osteoprotegerin production; the latter results in an increase in bone resorption, which then leads to the release of undercarboxylated osteocalcin from bone. Undercarboxylated osteocalcin, in turn, enhances insulin sensitivity. OBJECTIVE: The objective of the study was to test whether physiological changes in insulin levels regulate bone metabolism in humans. DESIGN: This investigation was an analysis of samples from a prospective study. SETTING: The study was conducted at a clinical research unit. PARTICIPANTS AND INTERVENTIONS: Fourteen subjects underwent a 7-h stepped insulin infusion accompanied by a glucose clamp and somatostatin infusion along with replacement infusions of GH and glucagon, thus isolating possible effects of insulin on bone. Insulin was infused at rates achieving low (~150 pmol/liter), intermediate (~350 pmol/liter), or high (~700 pmol/liter) plasma insulin levels. MAIN OUTCOME MEASURES: Bone turnover markers, undercarboxylated osteocalcin, and osteoprotegerin levels at the end of the low, intermediate, and high dose insulin infusions were measured. RESULTS: Values for the outcome measures at the end of the intermediate- and high-dose insulin infusions were no different from values at the end of the low-dose insulin infusion. However, measures of insulin sensitivity (glucose infusion and disappearance rates) correlated positively with C-terminal telopeptide of type I collagen levels. CONCLUSIONS: Acute changes in insulin levels, as occur during meals, do not regulate bone turnover, undercarboxylated osteocalcin, or osteoprotegerin levels. However, the correlation of measures of insulin sensitivity with bone resorption suggests the need for further studies in humans on the possible regulation of bone metabolism by insulin. PMID- 21325462 TI - High prevalence of RAS mutations in RET-negative sporadic medullary thyroid carcinomas. AB - CONTEXT: Sporadic medullary thyroid carcinomas (MTC) frequently harbor mutations in the RET protooncogene. We have earlier reported a series of 51 sporadic MTC with 64.7% of RET-positive and 35.3% of RET-negative cases. OBJECTIVE: In the present study, we investigated the possible involvement of RAS and BRAF protooncogenes in the development of sporadic RET-negative MTC. PATIENTS AND DESIGN: We performed PCR amplification and sequencing analysis of the three mutational hotspots (codons 12, 13, and 61) of the H-, K-, and N-RAS genes, and of the mutational hotspot (codon 600) and exon 11 of the BRAF gene in 65 sporadic MTC, of which 40 were RET positive and 25 were RET negative. RESULTS: Somatic H RAS and K-RAS mutations were detected in 14 of 25 (56.0%) and three of 25 (12.0%) of RET-negative sporadic MTC, respectively. On the other hand, only one of 40 (2.5%) RET-positive sporadic MTC had a RAS mutation, namely in H-RAS. One of the H-RAS mutations was novel (c.32_37dupCCGGCG). No mutations of N-RAS or BRAF were detected in all assessed tumor samples. CONCLUSIONS: Overall, our results showed that RAS mutations were present in 68.0% (17 of 25) of the RET-negative MTC and in only 2.5% of the RET-positive MTC (P < 0.0001), suggesting that activation of the protooncogenes RAS and RET represents alternative genetic events in sporadic MTC tumorigenesis. PMID- 21325464 TI - Up-regulation of PPAR-gamma mRNA expression in the liver of obese patients: an additional reinforcing lipogenic mechanism to SREBP-1c induction. AB - INTRODUCTION: Triglyceride accumulation in the liver is an early feature in the development of nonalcoholic fatty liver disease (NAFLD) associated with human obesity, which is a multifactorial syndrome and whose underlying mechanisms are beginning to be understood. OBJECTIVES: Liver peroxisome proliferator-activated receptor-gamma (PPAR-gamma) mRNA expression was measured as a signaling mechanism related to steatosis in obese patients with NAFLD. METHODS: Liver PPAR-gamma and sterol receptor element-binding protein 1c (SREBP-1c) mRNA (real-time RT-PCR), serum total adiponectin (RIA), and high molecular weight (HMW)-adiponectin (ELISA) levels, and insulin resistance (IR) evolution (homeostasis model assessment-IR) were determined in 22 obese NAFLD patients (16 with steatosis and six with steatohepatitis) who underwent subtotal gastrectomy with gastrojejunal anastomosis in Roux-en-Y and 16 nonobese subjects who underwent laparoscopic cholecystectomy (controls). RESULTS: Liver PPAR-gamma mRNA levels were 112 and 188% higher (P < 0.05) than control values in obese patients with steatosis and steatohepatitis, respectively, who also exhibited 70 and 62% increases in those of SREBP-1c, concomitantly with IR and lower levels of serum total adiponectin and HMW-adiponectin (P < 0.05). Liver PPAR-gamma expression showed positive associations with SREBP-1c mRNA levels (r = 0.86; P < 0.0001), serum insulin levels (r = 0.39; P < 0.01), and homeostasis model assessment-IR (r = 0.60; P < 0.0001), and negative correlations with total adiponectin (r = -0.37; P < 0.01) and HMW-adiponectin (r = -0.51; P < 0.001) levels in serum. CONCLUSIONS: PPAR gamma is up-regulated in the liver of obese patients with NAFLD, representing an additional reinforcing lipogenic mechanism to SREBP-1c induction in the development of hepatic steatosis. PMID- 21325463 TI - Habitual levels of vigorous, but not moderate or light, physical activity is positively related to cortical bone mass in adolescents. AB - CONTEXT: The intensity of habitual physical activity (PA) needed to affect skeletal development in childhood is currently unclear. OBJECTIVE: To examine associations between light PA, moderate PA, and vigorous PA (as assessed by accelerometry), and tibial cortical bone mass (BMC(C)) as measured by peripheral quantitative computed tomography. DESIGN/SETTING: Cross-sectional analysis based on the Avon Longitudinal Study of Parents and Children. PARTICIPANTS: A total of 1748 boys and girls (mean age 15.5 yr) participated in the study. OUTCOME MEASURES: We measured BMC(C), cortical bone mineral density, periosteal circumference, and endosteal circumference by tibial peripheral quantitative computed tomography. RESULTS: Multivariable models, adjusted for height and other activity levels, indicated vigorous PA was positively related to BMC(C) (P = 0.0001). There was little evidence of a relationship with light PA or moderate PA (both P >= 0.7). In path analyses, the relationship between vigorous PA and BMC(C) [0.082 (95% confidence interval [CI]: 0.037, 0.128), P = 0.0004] (SD change per doubling of vigorous PA) was minimally attenuated by adjusting for body composition [0.070 (95% CI: 0.026, 0.115), P = 0.002]. In analyses adjusted for body composition, the relationship between vigorous PA and BMC(C) was explained by the periosteal circumference pathway [0.043 (95% CI: 0.004, 0.082), P = 0.03] and the endosteal circumference adjusted for periosteal circumference pathway [0.031 (95% CI: 0.011, 0.050), P = 0.002], while there was little contribution from the cortical bone mineral density pathway (P = 0.3). CONCLUSIONS: Vigorous day-to-day PA is associated with indices of BMC(C) and geometry in adolescents, whereas light or moderate PA has no detectable association. Therefore, promoting PA in childhood is unlikely to benefit skeletal development unless high-impact activities are also increased. PMID- 21325465 TI - The effect of soy phytoestrogen supplementation on thyroid status and cardiovascular risk markers in patients with subclinical hypothyroidism: a randomized, double-blind, crossover study. AB - CONTEXT: There is concern whether soy phytoestrogens may affect thyroid function. If true, soy phytoestrogens may be expected to have a greater impact in subjects with subclinical hypothyroidism. OBJECTIVE: The primary aim was to determine the effect of soy phytoestrogen supplementation on thyroid function, with a secondary aim of assessing the effects on cardiovascular risk indices in patients with subclinical hypothyroidism. DESIGN AND SETTING: We conducted a randomized, double blind, crossover study in a tertiary care setting. PARTICIPANTS: Sixty patients with subclinical hypothyroidism participated in the study. INTERVENTION: Patients were randomly assigned to either low-dose phytoestrogen (30 g soy protein with 2 mg phytoestrogens, representative of a Western diet) or high-dose phytoestrogen (30 g soy protein with 16 mg phytoestrogens, representative of a vegetarian diet) supplementation for 8 wk, then crossed over after an 8-wk washout period. MAIN OUTCOME MEASURES: The primary outcome was progression to overt hypothyroidism, with secondary outcome measures of blood pressure, insulin resistance, lipids, and highly sensitive C-reactive protein (hsCRP). RESULTS: Six female patients in the study progressed into overt hypothyroidism with a standardized rate ratio of 3.6 (95% confidence interval, 1.9, 6.2) after 16-mg phytoestrogen supplementation. Both systolic and diastolic blood pressure decreased with 16 mg phytoestrogens, whereas systolic pressure alone decreased with 2 mg phytoestrogens. Insulin resistance (homeostasis model assessment of insulin resistance, 3.5 +/- 0.09 vs. 2.6 +/- 0.08; P < 0.02) and hsCRP (4.9 +/- 0.04 vs. 3.9 +/- 0.03; P < 0.01) decreased with 16 mg phytoestrogens. Lipid profile remained unchanged. CONCLUSION: There is a 3-fold increased risk of developing overt hypothyroidism with dietary supplementation of 16 mg soy phytoestrogens with subclinical hypothyroidism. However, 16-mg soy phytoestrogen supplementation significantly reduces the insulin resistance, hsCRP, and blood pressure in these patients. PMID- 21325467 TI - Symptomatic atherosclerotic occlusive disease of all supra-aortic arch vessels treated with total aortic arch rerouting. AB - We present an uncommon case of symptomatic atherosclerotic occlusive disease of all supra-aortic arch vessels and its surgical treatment by total aortic arch rerouting after endarteriectomy of all target vessels. PMID- 21325466 TI - Drospirenone/ethinyl estradiol versus rosiglitazone treatment in overweight adolescents with polycystic ovary syndrome: comparison of metabolic, hormonal, and cardiovascular risk factors. AB - CONTEXT: Adolescents with polycystic ovary syndrome (PCOS) have insulin resistance and higher rates of the metabolic syndrome. OBJECTIVE: Our objective was to compare the effects of 6 months treatment with drospirenone/ethinyl estradiol (EE) (3 mg/30 MUg) vs. rosiglitazone (4 mg) daily on the hormonal and cardiometabolic profiles of overweight/obese adolescents with PCOS. DESIGN: We conducted a randomized, double-blinded, parallel clinical trial in an academic hospital, with n = 46 patients. OUTCOME MEASURES: The primary outcome measure was insulin sensitivity, hepatic with [6,6-(2)H(2)]glucose and peripheral with a 3-h hyperinsulinemic-euglycemic clamp. Other outcome measures included plasma androgen profile and response to ACTH stimulation, glucose and insulin response to oral glucose tolerance test, insulin secretion with a 2-h hyperglycemic clamp, fasting lipid profile, inflammatory markers, intima media thickness, aortic pulse wave velocity, body composition by dual-energy x-ray absorptiometry, and abdominal adiposity by computed tomography scan. RESULTS: Drospirenone/EE resulted in greater reductions in androgenemia. Neither treatment led to change in weight or body mass index, but rosiglitazone led to a significant decrease in visceral adiposity. Compared with drospirenone/EE, treatment with rosiglitazone improved hepatic and peripheral insulin sensitivity and lowered fasting and stimulated insulin levels during the oral glucose tolerance test. Treatment with drospirenone/EE was associated with elevations in total cholesterol, high sensitivity C-reactive protein and leptin concentrations, whereas treatment with rosiglitazone led to lower triglycerides and higher adiponectin concentrations. Neither treatment affected intima media thickness or pulse wave velocity. CONCLUSIONS: In overweight/obese adolescents with PCOS, 6 months treatment with rosiglitazone was superior to drospirenone/EE in improving the cardiometabolic risk profile, and effective but inferior in attenuating hyperandrogenemia. Additional studies are needed to test insulin sensitizers in the treatment of the reproductive and cardiometabolic aspects of PCOS. PMID- 21325468 TI - Mesenteric ischemia in a patient with an acute aortic dissection type A. One-step repair of the aortic and visceral lesions. Role of laparoscopy for timely diagnosis and treatment. AB - Organ malperfusion is a serious complication of acute aortic dissection type A. Increased awareness of this complication and the availability of better diagnostic tools may improve the survival rate for these patients. Here, we discuss the potential role of laparoscopy in the setting of an acute dissecting aneurysm complicated by mesenteric ischemia. PMID- 21325469 TI - What is the best treatment for malignant pleural effusions? AB - A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was whether chemical pleurodesis is superior to catheter drainage or pleuroperitoneal shunts (PPS) in the management of patients with pleural effusions. Overall 161 papers were found using the reported search, of which 14 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results are tabulated. We conclude that chemical pleurodesis is superior to chronic catheter drainage and PPS in terms survival length and mortality rates but in patients with trapped lung syndrome chronic intrapleural catheter placement is indicated. Six studies reported patient outcomes after treatment with chemical pleurodesis. They report high success rates (89.4%) and low mortality rates (2%) without any need to convert to open thoracotomy. Mean hospital stay of 2.33 days, complication rates of 16.5% and mean survival length of 23.8 +/- 16.3 months were observed. Five studies managed malignant pleural effusions (MPEs) using chronic indwelling catheters. They reported mean survival length of 126 days. Symptomatic relief was achieved in 94.2% of patients. There was a significant reduction in the Medical Research Council dyspnoea score (3.0-1.9, P < 0.001) and despite complication rates of 22%, comparable mortality rates (7.5%) were observed. Even in patients with trapped lung syndrome, mean survival length was 125 days with symptomatic improvement being achieved in 90.9% of patients. Three studies treated MPEs using PPSs. Mean hospital stay was 6.2 days (range 2-26) with a mean survival length of 11 months. Pleurodesis success rates varied from 57.1% to 95% with a complication rate of 14.8%. PPSs were shown to produce lower success rates (57.1% vs. 92.3%), shorter survival lengths (4.3 +/- 1.9 vs. 6.7 +/- 2.1 months) and higher complication rates (14.3% vs. 2.8%) than talc pleurodesis. Overall, chemical pleurodesis is the optimal treatment option for MPE with use of chronic intrapleural catheters reserved in cases where talc pleurodesis is not possible. PMID- 21325470 TI - A novel HESX1 splice mutation causes isolated GH deficiency by interfering with mRNA processing. AB - OBJECTIVE: Mutations in HESX1 represent a rare cause of GH deficiency (GHD) associated with a broad spectrum of other anomalies. We searched for causative mutations in a cohort of 244 Italian patients affected by combined and isolated GHD (IGHD). METHODS: The HESX1 gene-coding region and exon-intron boundaries were screened by denaturing HPLC scanning. RESULTS: A novel mutation adjacent to the invariant donor splice site of intron 2 (c.357+3G>A) was identified at the heterozygous state in an IGHD patient. The in vitro and in vivo mRNA analysis of the wild-type HESX1 allele revealed the presence of the whole cDNA and two isoforms lacking exon 2 and exons 2-3 respectively. The mutant HESX1 allele yielded only two splicing products, the whole cDNA and the cDNA missing exons 2 3, whereas the mRNA lacking exon 2 was absent. An in vitro assay demonstrated that the exon 2-deleted mRNA, predicting a prematurely truncated protein, is subjected to nonsense-mediated mRNA decay (NMD). CONCLUSIONS: The c.357+3G>A mutation prevents the generation of one of the alternative isoforms normally produced by the wild-type allele, predicting a truncated HESX1 protein. The mutation is likely to cause IGHD in the heterozygous patient by interfering with the downregulation of HESX1 expression mediated by alternative splicing and NMD. Our results open new insight into the mechanism of HESX1 regulation suggesting that the coupling of alternative splicing and NMD might play a fundamental role in directing the HESX1 expression, and that the alteration of this process might lead to severe consequences. PMID- 21325471 TI - Metabolic syndrome and the effect of testosterone treatment in young men with congenital hypogonadotropic hypogonadism. AB - OBJECTIVE: The relationship between metabolic syndrome (MS) and hypogonadism has always been investigated in study groups confounded with aging, obesity or chronic metabolic disorders. So far, there has been no data about the presence of MS in young hypogonadal patients. Also, there is controversial data about the metabolic effects of testosterone replacement therapy. We investigated the frequency of MS in treatment-naive, young men with congenital hypogonadal hypogonadism (CHH). We also searched for the effect of testosterone replacement on the metabolic profiles of this specific patient group. DESIGN: Retrospective analysis. METHODS: A total of 332 patients (age 21.68 +/- 2.09 years) were enrolled. The control group included 395 age- and body mass index (BMI)-matched healthy young men (age 21.39 +/- 1.49 years). Standard regimen of testosterone esters (250 mg/3 weeks) was given to 208 patients. RESULTS: MS was more prevalent in CHH (P<0.001) according to healthy controls. The patients had higher arterial blood pressure, waist circumference (WC), triglyceride (P<0.001 for all), fasting glucose (P=0.02), fasting insulin (P=0.004), homeostatic model assessment of insulin resistance (HOMA-IR) (P=0.002) and lower high density lipoprotein (HDL) cholesterol (P<0.001) levels. After 5.63+/-2.6 months of testosterone treatment, the BMI, WC (P<0.001 for both), systolic blood pressure (P=0.002) and triglyceride level (P=0.04) were increased and the total and HDL cholesterol levels were decreased (P=0.02 and P<0.001 respectively). CONCLUSIONS: This study shows increased prevalence of MS and unfavorable effects of testosterone replacement in young patients with CHH. Long-term follow-up studies are warranted to investigate the cardiovascular safety of testosterone treatment in this specific population. PMID- 21325472 TI - Lessons from MATRICS. PMID- 21325473 TI - The volume of nipple aspirate fluid is not affected by 6 months of treatment with soy foods in premenopausal women. AB - Based on the hypothesis that soy food consumption may influence breast tissue activity, we examined its effect on the production of nipple aspirate fluid (NAF), a possible indicator of breast cancer risk. Of 310 premenopausal women screened, 112 (36%) produced at least 10 MUL of NAF, the minimum for study participation. In a crossover design, we randomized 96 women to 2 groups who, in reverse order, consumed a high-soy diet with 2 soy servings/d (1 serving = 177 mL soy milk, 126 g tofu, or 23 g soy nuts) and a low-soy diet with <3 servings/wk of soy for 6 mo each separated by a 1-mo washout period. During each diet period, 3 NAF samples were obtained (baseline and 3 and 6 mo) using a FirstCyte Aspirator and 4 urine samples (baseline and 1, 3, and 6 mo) were analyzed for isoflavonoids by liquid chromatography tandem MS. Adherence to the study protocol according to 24-h dietary recalls and urinary isoflavonoid excretion was high. The drop-out rate was 15% (n = 14); 82 women completed the intervention. The 2 groups produced similar mean NAF volumes at baseline (P = 0.95) but differed in age and previous soy intake and in their response to the intervention (P = 0.03). In both groups, NAF volume decreased during the first 3 mo of the high-soy diet period and returned to baseline at 6 mo, but there was no effect of the high-soy diet on NAF volume (P = 0.50 for diet; P-interaction = 0.21 for diet with time). Contrary to an earlier report, soy foods in amounts consumed by Asians did not increase breast tissue activity as assessed by NAF volume. PMID- 21325474 TI - Nonbreast-fed HIV-1-exposed Burkinabe infants have low energy intake between 6 and 11 months of age despite free access to infant food aid. AB - In a WHO-coordinated, mother-to-child HIV transmission (MTCT) prevention trial in Burkina Faso, HIV-1-infected mothers were advised to either stop breast-feeding by 6 mo or totally avoid it. Participants were provided with cereal-based, infant fortified mix (IFM) from 6 to 12 mo postpartum along with infant feeding counseling. Our objective was to describe nonbreast-fed infants' food consumption and adequacy of nutrient intake. A 1-d weighed food record and one 24-h dietary recall were performed in 68 nonbreast-fed, non-HIV-infected 6- to 11-mo-old infants. Mean food energy density and feeding frequency were satisfactory in 6-8 mo olds [0.8 +/- 0.2 kcal/g (3.3 +/- 0.9 kJ/g) and 7.2 +/- 1.6 times/d] and in 9 11 mo olds [0.9 +/- 0.2 kcal/g (3.6 +/- 0.8 kJ/g) and 7.7 +/- 2.1 times/d]. Median energy intake was 523 kcal [range: 82-1053 (2187 kJ, range: 345-4401)] in 6-8- and 811 kcal [range: 34-1543 (3392 kJ, range: 144-6452)] in 9-11-mo-old infants, respectively. Approximately 75% of their energy intake was provided by subsidized foods (milk that mothers obtained from support networks and IFM). One half of the infants had intakes < 80 kcal/kg (<334 kJ/kg) on the day of the survey, mainly because IFM and milk were consumed in amounts that were too low. Thus, coverage of energy needs required a diet with sufficient amounts of both IFM and milk in these vulnerable infants. These findings argue for the development of adequate, sustainable infant fortified foods and their rapid integration into MTCT prevention services. They also lend support to the recent revision of WHO infant feeding guidance for future MTCT prevention programming that recommends breast-feeding up to 12 mo postpartum (under cover of antiretroviral prophylaxis) as the safest feeding option for infants of HIV infected mothers. PMID- 21325475 TI - 20-year trends in Filipino women's weight reflect substantial secular and age effects. AB - Increasing obesity in low- and middle-income countries is well documented in cross-sectional studies. However, few longitudinal studies identify factors that influence individual weight gain patterns over time in relation to the major social and economic changes that now characterize these settings. This study uses data from adult Filipino women participating in the Cebu Longitudinal Health and Nutrition Survey from 1983 to 2005. A sample of 3005 women contributed 1-8 observations each. Longitudinal mixed effects models identified how age and secular weight trends related to underlying effects of urbanization and changing household socioeconomic status (SES) and to proximate individual effects of reproductive history, diet, and occupational physical activity. The 23-y secular trend in weight amounted to nearly 10 kg. Younger women gained more weight than older women (12.4 kg in those < 20 y old in 1983 vs. 4.9 kg in those > 35 y). Periods of more rapid weight gain corresponded to periods of rapid increase in SES and urbanization. Weight was positively related to energy intake, percentage of calories from protein, and more sedentary occupations, but negatively related to months pregnant and lactating and postmenopausal status. These effects all varied with age and over time. The trends contributed to a 6-fold increase in prevalence of overweight and an increasing number of women who have or are likely to develop obesity-related metabolic diseases. The trends are highly relevant for health policy and preventive health measures in the Philippines and other countries now facing the dual burden of over- and undernutrition. PMID- 21325476 TI - Selected dietary flavonoids are associated with markers of inflammation and endothelial dysfunction in U.S. women. AB - Flavonoids show antiinflammatory effects in vitro and human intervention studies have suggested beneficial effects of flavonoid-rich foods on biomarkers of inflammation and endothelial function. In the present study, we assessed the relationship between flavonoid intake and biomarkers of inflammation and endothelial dysfunction in a cross-sectional study of participants from the Nurses' Health Study cohort. Intake of 6 flavonoid subclasses (flavonols, flavones, flavanones, flavan-3-ols, anthocyanidins, and polymeric flavonoids) was assessed using a FFQ administered in 1990. Also, the main food sources of these flavonoids were examined. Blood samples were collected in 1989-1990 and plasma C reactive protein (CRP), IL-6, IL-18, soluble tumor necrosis factor receptor-2 (sTNF-R2), soluble intercellular adhesion molecule-1, soluble vascular adhesion molecule-1 (sVCAM-1), and E-selectin were measured in 1194-1598 women. The multivariate-adjusted geometric mean of plasma IL-8 were lower for women in the highest intake quintile of flavones, flavanones, and total flavonoids compared with those in the lowest quintiles by 9% (Q1: 264 ng/L, Q5: 241 ng/L; P-trend = 0.019), 11% (Q1: 273 ng/L, Q5: 244 ng/L; P-trend = 0.011), and 8% (Q1: 276 ng/L, Q5: 55 ng/L; P-trend = 0.034), respectively. The multivariate-adjusted geometric mean for women in the highest intake quintile of flavonol compared with those in the lowest quintile was 4% lower for sVCAM-1 (Q1: 578 MUg/L, Q5: 557 MUg/L; P trend = 0.012). Among flavonoid-rich foods, higher intake of grapefruit was significantly associated with lower concentrations of CRP and sTNF-R2. In summary, higher intakes of selected flavonoid subclasses were associated with modestly lower concentrations of inflammatory biomarkers. In particular, flavonoids typically found in citrus fruits were modestly associated with lower plasma IL-18 concentrations. PMID- 21325477 TI - Single cell detection of latent cytomegalovirus reactivation in host tissue. AB - The molecular mechanisms leading to reactivation of latent cytomegalovirus are not well understood. To study reactivation, the few cells in an organ tissue that give rise to reactivated virus need to be identified, ideally at the earliest possible time point in the process. To this end, mouse cytomegalovirus (MCMV) reporter mutants were designed to simultaneously express the red fluorescent protein mCherry and the secreted Gaussia luciferase (Gluc). Whereas Gluc can serve to assess infection at the level of individual mice by measuring luminescence in blood samples or by in vivo imaging, mCherry fluorescence offers the advatage of detection of infection at the single cell level. To visualize cells in which MCMV was being reactivated, precision-cut lung slices (PCLS) that preserve tissue microanatomy were prepared from the lungs of latently infected mice. By day 3 of cultivation of the PCLS, reactivation was revealed by Gluc expression, preceding the detection of infectious virus by approximately 4 days. Reactivation events in PCLS could be identified when they were still confined to single cells. Notably, using fractalkine receptor-GFP reporter mice, we never observed reactivation originating from CX3CR1(+) monocytes or pulmonary dendritic cells derived therefrom. Furthermore, latent viral genome in the lungs was not enriched in sorted bone-marrow-derived cells expressing CD11b. Taken together, these complementary approaches suggest that CD11b(+) and CX3CR1(+) subsets of the myeloid differentiation lineage are not the main reservoirs and cellular sites of MCMV latency and reactivation in the lungs. PMID- 21325478 TI - Helicoverpa armigera nucleopolyhedrovirus occlusion-derived virus-associated protein, HA100, affects oral infectivity in vivo but not virus replication in vitro. AB - ORF100 (ha100) of Helicoverpa armigera nucleopolyhedrovirus (HearNPV) has been reported as one of the unique genes of group II alphabaculoviruses encoding a protein located in the occlusion-derived virus (ODV) envelope and nucleocapsid. The protein consists of 510 aa with a predicted mass of 58.1 kDa and is a homologue of poly(ADP-ribose) glycohydrolase in eukaryotes. Western blot analysis detected a 60 kDa band in HearNPV-infected HzAM1 cells starting at 18 h post infection. Transient expression of GFP-fused HA100 in HzAM1 cells resulted in cytoplasmic localization of the protein, but after superinfection with HearNPV, GFP-fused HA100 was localized in the nucleus. To study the function of HA100 further, an ha100-null virus was constructed using bacmid technology. Viral one step growth curve analyses showed that the ha100-null virus had similar budded virus production kinetics to that of the parental virus. Electron microscopy revealed that deletion of HA100 did not alter the morphology of ODVs or occlusion bodies (OBs). However, bioassays in larvae showed that the 50 % lethal concentration (LC(50)) value of HA100-null OBs was significantly higher than that of parental OBs; the median lethal time (LT(50)) of ha100-null OBs was about 24 h later than control virus. These results indicate that HA100 is not essential for virus replication in vitro. However, it significantly affects the oral infectivity of OBs in host insects, suggesting that the association HA100 with the ODV contributes to the infectivity of OBs in vivo. PMID- 21325479 TI - ICP27 protein of Marek's disease virus interacts with SR proteins and inhibits the splicing of cellular telomerase chTERT and viral vIL8 transcripts. AB - All herpesviruses have a post-transcriptional regulatory protein that prevents precursor mRNA splicing and leads to the shutting off of host protein synthesis. The ICP27 protein of herpes simplex virus 1 (HSV-1) is the prototype of these proteins. Marek's disease virus (MDV-1), an alphaherpesvirus that induces lymphoma in birds, also has an ICP27 protein that is produced in lytic MDV-1 infected cells. We characterized this protein. We demonstrated ICP27 production in latently infected MSB-1 cells, but only on MDV-1 reactivation. ICP27 was found predominantly in specific structures within the nucleus. The ICP27 of MDV-1 colocalized and interacted with SR proteins. We demonstrated inhibitory effects of MDV-1 ICP27 on the splicing of both the viral vIL8 and cellular chTERT (telomerase reverse transcriptase) genes. Thus, the ICP27 of MDV-1 plays a similar role to the ICP27 of HSV-1 and may be involved in MDV-1 replication and the development of Marek's disease. PMID- 21325480 TI - Hepatitis B virus X protein overcomes all-trans retinoic acid-induced cellular senescence by downregulating levels of p16 and p21 via DNA methylation. AB - Despite current molecular evidence suggesting that hepatitis B virus (HBV) X protein (HBx) plays an important role during HBV-mediated hepatocarcinogenesis, the detailed mechanism is still controversial. Here, it was shown that HBx overcomes cellular senescence provoked by all-trans retinoic acid (ATRA) in HepG2 cells, as demonstrated by the impaired induction of irreversible G(1) arrest and senescence-associated beta-galactosidase activity by ATRA in the presence of HBx. The anti-senescence effect of HBx was also observed in another human hepatoma cell line, Hep3B, but not in Huh-7 cells in which the p16 and p21 proteins are absent. In addition, HBx suppressed ATRA-mediated induction of p16 and p21 in HepG2 cells via promoter hypermethylation, resulting in inactivation of retinoblastoma protein. Furthermore, the ability of HBx to overcome ATRA-induced cellular senescence almost completely disappeared when the levels of p16 and p21 in the HBx-expressing cells became similar to those in the control cells by complementation in the former by exogenous expression, knockdown of their expression in the latter using specific small interfering RNA or treatment with a DNA methylation inhibitor, 5-Aza-2'-deoxycytidine. These results suggest that HBx executes its potential by downregulating levels of p16 and p21 via DNA methylation. As cellular senescence is a tumour-suppression process, the present study provides a new strategy by which HBV promotes hepatocarcinogenesis. PMID- 21325481 TI - Aguacate virus, a new antigenic complex of the genus Phlebovirus (family Bunyaviridae). AB - Genomic and antigenic characterization of Aguacate virus, a tentative species of the genus Phlebovirus, and three other unclassified viruses, Armero virus, Durania virus and Ixcanal virus, demonstrate a close relationship to one another. They are distinct from the other nine recognized species within the genus Phlebovirus. We propose to designate them as a new (tenth) serogroup or species (Aguacate virus) within the genus. The four viruses were all isolated from phlebotomine sandflies (Lutzomyia sp.) collected in Central and South America. Aguacate virus appears to be a natural reassortant and serves as one more example of the high frequency of reassortment in this genus. PMID- 21325483 TI - Differential inhibition of dengue virus infection in mammalian and mosquito cells by iota-carrageenan. AB - The antiviral activity against dengue virus-2 (DENV-2) of carrageenans reported here has shown a differential susceptibility of C6/36 HT and Vero cells, taken as models of mosquito and mammalian cells, depending on the structural class of polysaccharides: all polysaccharides blocked DENV-2 infection in monkey Vero cells, but only iota-carrageenans were virus inhibitors in mosquito cells. However, iota-carrageenans were less effective in mosquito cells in comparison with mammalian cells with effective concentration 50 % (EC(50)) values in C6/36 HT cells 4.9-17.5-fold higher than in Vero cells, as determined by virus yield reduction assay. The mode of action of iota-carrageenan in both cell types was strikingly different: in Vero cells the inhibitory activity was exerted only at the initiation of the cycle, affecting virion binding, whereas in mosquito cells DENV-2 adsorption was not affected and comparable levels of inhibition were obtained if the compound was added to cells together with the virus, after 8 h of infection or by cell pre-treatment before infection. Furthermore, iota carrageenans induced a subtle alteration in mosquito cells, detected by cell proliferation and protein synthesis analyses, suggesting that a probable cellular target may be responsible for the refractory state of mosquito cells to DENV-2 infection produced by this class of polysulfates. The failure of iota-carrageenan to block DENV-2 adsorption to mosquito cells appeared to be related to the low presence of adequate heparan sulfate (HS) in C6/36 HT cell surface and is indicative of a differential participation of HS residues for DENV-2 entry in both types of cells. PMID- 21325482 TI - Infection with human coronavirus NL63 enhances streptococcal adherence to epithelial cells. AB - Understanding the mechanisms of augmented bacterial pathogenicity in post-viral infections is the first step in the development of an effective therapy. This study assessed the effect of human coronavirus NL63 (HCoV-NL63) on the adherence of bacterial pathogens associated with respiratory tract illnesses. It was shown that HCoV-NL63 infection resulted in an increased adherence of Streptococcus pneumoniae to virus-infected cell lines and fully differentiated primary human airway epithelium cultures. The enhanced binding of bacteria correlated with an increased expression level of the platelet-activating factor receptor (PAF-R), but detailed evaluation of the bacterium-PAF-R interaction revealed a limited relevance of this process. PMID- 21325484 TI - Measles virotherapy in a mouse model of adult T-cell leukaemia/lymphoma. AB - Adult T-cell leukaemia/lymphoma (ATL) is a highly aggressive CD4(+) T-cell malignancy caused by human T-cell leukaemia virus type 1. Measles virus (MV) oncolytic therapy has been reported to be efficient in reducing tumour burden in subcutaneous xenograft models of lymphoproliferative disorders such as myeloma, B cell lymphoma and cutaneous T-cell lymphoma, but its potential to reduce tumour burden in disseminated lymphoproliferative disorders such as ATL remains to be determined. In this study, MV oncolytic therapy was evaluated in the MET 1/NOD/SCID xenograft mouse model of ATL. Treatment with the vaccine-related strain MV-NSE led to a significant reduction in tumour burden. In mice with a high tumour burden, therapy with MV-NSE significantly increased survival beyond any other single treatment tested previously using this model. Interestingly, signs of morbidity (cachexia) in mice treated with MV were not directly associated with tumour burden, but were correlated with the secretion of interleukin-6 by MET-1 cells and host cells. The results suggest that MV therapy could be a promising therapy for generalized lymphoproliferative disease. PMID- 21325485 TI - Development and evaluation of a latex agglutination test for the serodiagnosis of paracoccidioidomycosis. AB - Paracoccidioidomycosis (PCM) is the most prevalent systemic mycosis in Latin America. It is caused by the dimorphic fungus Paracoccidioides brasiliensis. The immunodiffusion (ID) test is one of the most widely used techniques for PCM serologic diagnosis due to the simplicity and low costs of its execution. However, it requires trained and qualified people to execute it. The purpose of this study was to evaluate a latex particle agglutination (LA) test for the detection of anti-P. brasiliensis antibodies by using pooled crude exoantigens from the fungus. Fifty-one serum samples obtained from patients with PCM were tested. Positivity was observed in 84% (43/51) of these patients, and the agglutination patterns varied from small clumps with a cloudy background to large clumps with a clear background. The antibody titer reactivity ranged from 1:2 to 1:64. Cross-reactivity was observed in sera from patients with aspergillosis, histoplasmosis, and nonfungal disease. Serum samples obtained from healthy donors were not reactive. The sensitivity and specificity of the LA test were 84% and 81%, respectively. When comparing the LA test with the double-immunodiffusion test, we found an agreement of 92%. Further work is needed to improve the performance of the LA assay before it can be proposed as a reliable diagnostic tool, mainly in laboratories with little infrastructure. PMID- 21325486 TI - Nasal immunity to staphylococcal toxic shock is controlled by the nasopharynx associated lymphoid tissue. AB - The nasopharynx-associated lymphoid tissue (NALT) of humans and other mammals is associated with immunity against airborne infections, though it is generally considered to be a secondary component of the mucosa-associated lymphoid system. We found that protective immunity to a virulence factor of nasal mucosa colonizing Staphylococcus aureus, staphylococcal enterotoxin B (SEB), requires a functional NALT. We examined the role of NALT using intranasal (IN) vaccination with a recombinant SEB vaccine (rSEBv) combined with an adjuvant in a mouse model of SEB-induced toxic shock. The rSEBv was rapidly internalized by NALT cells at the mucosal barrier, and transport into NALT was accelerated by inclusion of a Toll-like receptor 4 (TLR4) agonist. Vaccine-induced germinal centers of B cells formed within NALT, accompanied by elevated levels of IgA(+) and IgG(+) cells, and these were further increased by TLR4 activation. The NALT was the site of specific anti-rSEBv IgA and IgG production but was also influenced by intraperitoneal (IP) inoculation and perhaps other isolated lymphoid follicles observed within the nasal cavity. Vaccination by the IN route generated robust levels of anti-rSEBv IgA in saliva, nasal secretions, and blood compared to much lower levels after IP vaccination. IN vaccination also induced secretion of anti rSEBv IgG in the blood and nasal secretions. Significantly, the efficacy of IN vaccination was dependent on NALT, as surgical removal resulted in greater sensitivity to IN challenge with wild-type SEB. Thus, protective immunity to SEB within the nasal sinuses was elicited by responses originating in NALT. PMID- 21325487 TI - Torque teno virus viremia load size in patients with selected congenital defects of innate immunity. AB - Plasma loads of torque teno virus (TTV) among individuals differ extensively beginning early in life, suggesting a role for innate immunity. Here, congenital mannose-binding lectin deficiencies, but not deficiencies in respiratory ciliary function, correlated with increased TTV loads. Notably, however, the presence of either disorder was associated with particularly high TTV loads. PMID- 21325488 TI - Fast, antigen-saving multiplex immunoassay to determine levels and avidity of mouse serum antibodies to pertussis, diphtheria, and tetanus antigens. AB - To enhance preclinical evaluation of serological immune responses to the individual diphtheria, tetanus, and pertussis (DTP) components of DTP combination vaccines, a fast hexavalent bead-based method was developed. This multiplex immunoassay (MIA) can simultaneously determine levels of specific mouse serum IgG antibodies to P antigens P.69 pertactin (P.69 Prn), filamentous hemagglutinin (FHA), pertussis toxin (Ptx), and combined fimbria type 2 and 3 antigens (Fim2/3) and to diphtheria toxin (Dtx) and tetanus toxin (TT) in a single well. The mouse DTP MIA was shown to be specific and sensitive and to correlate with the six single in-house enzyme-linked immunosorbent assays (ELISAs) for all antigens. Moreover, the MIA was expanded to include avidity measurements of DTP antigens in a multivalent manner. The sensitivities of the mouse DTP avidity MIA per antigen were comparable to those of the six individual in-house avidity ELISAs, and good correlations between IgG concentrations obtained by both methods for all antigens tested were shown. The regular and avidity mouse DTP MIAs were reproducible, with good intra- and interassay coefficients of variability (CV) for all antigens. Finally, the usefulness of the assay was demonstrated in a longitudinal study of the development and avidity maturation of specific IgG antibodies in mice having received different DTP vaccines. We conclude that the hexaplex mouse DTP MIA is a specific, sensitive, and high-throughput alternative for ELISA to investigate the quantity and quality of serological responses to DTP antigens in preclinical vaccine studies. PMID- 21325489 TI - Modulation of plasmid DNA vaccine antigen clearance by caspase 12 RNA interference potentiates vaccination. AB - The magnitude of the immune responses elicited by plasmid DNA vaccines might be limited, in part, by the duration of vaccine antigen expression in vivo. To explore strategies for improving plasmid DNA vaccine efficacy, we studied the apoptotic process in myocytes of mice vaccinated intramuscularly. We found that after vaccination, the proapoptotic protein caspase 12 (Casp12) was upregulated in myocytes coincident with the loss of vaccine antigen expression. To harness this observation to improve plasmid DNA vaccine efficacy, we used RNA interference technology, coadministering plasmid DNA expressing a short hairpin RNA (shRNA) of Casp12 with plasmid DNA vaccine constructs. This treatment with shRNA Casp12, administered twice within the first 10 days following vaccine administration, increased antigen expression 7-fold, the antigen-specific CD8(+) T cell immune response 6-fold, and antigen-specific antibody production 5-fold. This study demonstrates the critical role for Casp12 in plasmid DNA vaccine induced immune responses and shows that increased antigen expression mediated by down-modulation of Casp12 can be used to potentiate vaccine efficacy. PMID- 21325490 TI - Increased cell-mediated immune responses in patients with recurrent herpes simplex virus type 2 meningitis. AB - The clinical picture of herpes simplex virus type 2 (HSV-2) infection includes genital blisters and less frequently meningitis, and some individuals suffer from recurrent episodes of these manifestations. We hypothesized that adaptive and/or innate immune functional deficiencies may be a major contributing factor in susceptibility to recurrent HSV-2 meningitis. Ten patients with recurrent HSV-2 meningitis were studied during clinical remission. For comparison, 10 patients with recurrent genital HSV infections as well as 21 HSV-seropositive and 19 HSV seronegative healthy blood donors were included. HSV-specific T cell blasting and cytokine secretion were evaluated in whole blood cultures. HSV-2-induced NK cell gamma interferon production, dendritic cell Toll-like receptor (TLR) expression, and TLR agonist-induced alpha interferon secretion were analyzed. Patients with recurrent HSV-2 meningitis had elevated T cell blasting and Th1 and Th2 cytokine production in response to HSV antigens compared to those of patients with recurrent genital infections. A somewhat increased NK cell response, increased dendritic cell expression of TLR3 and -9, and increased TLR-induced alpha interferon responses were also noted. Contrary to our expectation, recurrent HSV 2 meningitis patients have increased HSV-specific adaptive and innate immune responses, raising the possibility of immune-mediated pathology in the development of recurrent HSV2 meningitis. PMID- 21325494 TI - Molecular mechanisms of angiotensin II stimulation on aquaporin-2 expression and trafficking. AB - ANG II plays a major role in renal water and sodium regulation. In the immortalized mouse renal collecting duct principal cells (mpkCCD(cl4)) cell line, we treated cells with ANG II and examined aquaporin-2 (AQP2) protein expression, trafficking, and mRNA levels, by immunoblotting, immunofluorescence, and RT-PCR. After 24-h incubation, ANG II-induced AQP2 protein expression was observed at the concentration of 10(-10) M and increased in a dose-dependent manner. ANG II (10( 7) M) increased AQP2 protein expression and mRNA levels at 0.5, 1, 2, 6, and 24 h. Immunofluorescence studies showed that ANG II increased the apical membrane targeting of AQP2 from 30 min to 6 h. Next, the signaling pathways underlying the ANG II-induced AQP2 expression were investigated. The PKC inhibitor Ro 31-8220 (5 * 10(-6) M) and the PKA inhibitor H89 (10(-5) M) blocked ANG II-induced AQP2 expression, respectively. Calmodulin inhibitor W-7 markedly reduced ANG II- and/or dDAVP-stimulated AQP2 expression. ANG II (10(-9) M) and/or dDAVP (10(-10) M) stimulated AQP2 protein levels and cAMP accumulation, which was completely blocked by pretreatment with the vasopressin V2 receptor (V2R) antagonist SR121463B (10(-8) M). Pretreatment with the angiotensin AT(1) receptor (AT1R) antagonist losartan (3 * 10(-6) M) blocked ANG II (10(-9) M)-stimulated AQP2 protein expression and cAMP accumulation, and partially blocked dDAVP (10(-10) M) and dDAVP+ANG II-induced AQP2 protein expression and cAMP accumulation. In conclusion, ANG II regulates AQP2 protein, trafficking, and gene expression in renal collecting duct principal cells. ANG II-induced AQP2 expression involves cAMP, PKC, PKA, and calmodulin signaling pathways via V2 and AT(1) receptors. PMID- 21325495 TI - Assessing vesicoureteral reflux in live inbred mice via ultrasound with a microbubble contrast agent. AB - Vesicoureteral reflux (VUR) is a common pediatric anomaly linked to renal scarring and hypertension. Although there are many mouse VUR models, cystograms have previously only been performed in euthanized animals, thus preventing serial assessments for VUR in the same animal and not delineating "live" physiology. Our purpose was to develop a live murine cystogram assay that could be used serially to track reflux. We injected microbubbles via transurethral catheters into bladders of C57BL6/J and C3H/HeJ inbred mouse strains that are known to have low and high VUR rates, respectively. We performed ultrasound to visualize microbubbles in the renal pelvis to determine feasibility of the procedure. We then repeated the microbubble ultrasound using a transducer allowing for visualization of both kidneys and ureters simultaneously and for 3 dimensional (3D) reconstruction. We then performed "euthanized" cystograms on all mice for comparison. C3H/HeJ mice had a strong and persistent microbubble signal in the renal pelvis and ureters bilaterally with low-contrast infusion volumes (<100 MUl) and similarly showed bilateral reflux by euthanized cystograms. With larger infused volumes (>=150 MUl), C57BL6/J mice had small volumes of microbubbles in the renal pelvis that cleared quickly and did not show reflux on euthanized cystograms. Thus, using animal models of known VUR, we demonstrate the utility of contrast-enhanced ultrasound to visualize reflux in live mice. PMID- 21325496 TI - Cdk2-dependent phosphorylation of p21 regulates the role of Cdk2 in cisplatin cytotoxicity. AB - Cisplatin cytotoxicity is dependent on cyclin-dependent kinase 2 (Cdk2) activity in vivo and in vitro. We found that an 18-kDa protein identified by mass spectrometry as p21(WAF1/Cip1) was phosphorylated by Cdk2 starting 12 h after cisplatin exposure. The analysis showed it was phosphorylated at serine 78, a site not previously identified. The adenoviral transduction of p21 before cisplatin exposure protects from cytotoxicity by inhibiting Cdk2. Although cisplatin causes induction of endogenous p21, the protection is inefficient. We hypothesized that phosphorylation of p21 at serine 78 could affect its role as a Cdk inhibitor, and thereby lessen its ability to protect from cisplatin cytotoxicity. To investigate the effect of serine 78 phosphorylation on p21 activity, we replaced serine 78 with aspartic acid, creating the phosphomimic p21(S78D). Mutant p21(S78D) was an inefficient inhibitor of Cdk2 and was inefficient at protecting TKPTS cells from cisplatin-induced cell death. We conclude that phosphorylation of p21 by Cdk2 limits the effectiveness of p21 to inhibit Cdk2, which is the mechanism for continued cisplatin cytotoxicity even after the induction of a protective protein. PMID- 21325497 TI - Cannabinoid receptor 1 mediates high glucose-induced apoptosis via endoplasmic reticulum stress in primary cultured rat mesangial cells. AB - The endocannabinoid system in animals and humans is involved in the onset of diverse diseases, including obesity and diabetic nephropathy, which is a major end-stage renal disease characterized by high glucose (HG)-induced apoptosis of mesangial cells. Endocannabinoids induce physiological and behavioral effects by activating two specific receptors, cannabinoid receptor 1 (CB(1)R) and cannabinoid receptor 2 (CB(2)R). However, the pathophysiology of CB(1)R in diabetic nephropathy has not been elucidated. We investigated the effects of HG on CB(1)R expression and its signaling pathways in primary cultured rat mesangial cells. HG significantly increased CB(1)R mRNA and protein levels in a time dependent manner and induced CB(1)R internalization. NF-kappaB and cPLA(2) were involved in the HG-induced increase in CB(1)R levels. Using a CB(1)R antagonist (AM251) and CB(1) siRNA transfection, we showed that HG-induced CB(1)R is linked to apoptosis. Specifically, HG inhibited the expression of GRP78, but induced increases in endoplasmic reticulum (ER) stress proteins, including phosphorylated (p)-protein kinase-like ER-associated kinase, p-eukaryotic initiation factor 2alpha, p-activating transcription factor-4, and C/EBP homologous protein. In addition, HG increased the Bax/Bcl-2 ratio and increased the amounts of cleaved poly(ADP-ribose) polymerase and caspase-3. These apoptotic effects were prevented by AM251 and by the downregulation of CB(1)R expression by small interfering RNA. We propose a mechanism by which blockade of CB(1)R attenuates HG-induced apoptosis in rat mesangial cells. Our findings suggest that blockade of CB(1)R may be a potential therapy in diabetic nephropathy. PMID- 21325498 TI - Toward an understanding of hypertension resistance. PMID- 21325499 TI - Bradykinin acutely inhibits activity of the epithelial Na+ channel in mammalian aldosterone-sensitive distal nephron. AB - Activation of the renal kallikrein-kinin system results in natriuresis and diuresis, suggesting its possible role in renal tubular sodium transport regulation. Here, we used patch-clamp electrophysiology to directly assess the effects of bradykinin (BK) on the epithelial Na(+) channel (ENaC) activity in freshly isolated split-opened murine aldosterone-sensitive distal nephrons (ASDNs). BK acutely inhibits ENaC activity by reducing channel open probability (P(o)) in a dose-dependent and reversible manner. Inhibition of B2 receptors with icatibant (HOE-140) abolished BK actions on ENaC. In contrast, activation of B1 receptors with the selective agonist Lys-des-Arg(9)-BK failed to reproduce BK actions on ENaC. This is consistent with B2 receptors playing a critical role in mediating BK signaling to ENaC. BK has little effect on ENaC P(o) when G(q/11) was inhibited with Gp antagonist 2A. Moreover, inhibition of phospholipase C (PLC) with U73122, but not saturation of cellular cAMP levels with the membrane permeable nonhydrolysable cAMP analog 8-cpt-cAMP, prevents BK actions on ENaC activity. This argues that BK stimulates B2 receptors with subsequent activation of G(q/11)-PLC signaling cascade to acutely inhibit ENaC activity. Activation of BK signaling acutely depletes apical PI(4,5)P(2) levels. However, inhibition of Ca(2+) pump SERCA of the endoplasmic reticulum with thapsigargin does not prevent BK signaling to ENaC. Furthermore, caffeine, while producing a similar rise in [Ca(2+)](i) as in response to BK stimulation, fails to recapitulate BK actions on ENaC. Therefore, we concluded that BK acutely inhibits ENaC P(o) in mammalian ASDN via stimulation of B2 receptors and following depletion of PI(4,5)P(2), but not increases in [Ca(2+)](i). PMID- 21325500 TI - Increased renal dopamine and acute renal adaptation to a high-phosphate diet. AB - The current experiments explore the role of dopamine in facilitating the acute increase in renal phosphate excretion in response to a high-phosphate diet. Compared with a low-phosphate (0.1%) diet for 24 h, mice fed a high-phosphate (1.2%) diet had significantly higher rates of phosphate excretion in the urine associated with a two- to threefold increase in the dopamine content of the kidney and in the urinary excretion of dopamine. Animals fed a high-phosphate diet had a significant increase in the abundance and activity of renal DOPA (l dihydroxyphenylalanine) decarboxylase and significant reductions in renalase, monoamine oxidase A, and monoamine oxidase B. The activity of protein kinase A and protein kinase C, markers of activation of renal dopamine receptors, were significantly higher in animals fed a high-phosphate vs. a low-phosphate diet. Treatment of rats with carbidopa, an inhibitor of DOPA decarboxylase, impaired adaptation to a high-phosphate diet. These experiments indicate that the rapid adaptation to a high-phosphate diet involves alterations in key enzymes involved in dopamine synthesis and degradation, resulting in increased renal dopamine content and activation of the signaling cascade used by dopamine to inhibit the renal tubular reabsorption of phosphate. PMID- 21325501 TI - Unwrapping the ventral stream. PMID- 21325502 TI - Role for Reelin in neurotransmitter release. AB - The extracellular matrix molecule Reelin is known to control neuronal migration during development. Recent evidence suggests that it also plays a role in the maturation of postsynaptic dendrites and spines as well as in synaptic plasticity. Here, we aimed to address the question whether Reelin plays a role in presynaptic structural organization and function. Quantitative electron microscopic analysis of the number of presynaptic boutons in the stratum radiatum of hippocampal region CA1 did not reveal differences between wild-type animals and Reelin-deficient reeler mutant mice. However, additional detailed analysis showed that the number of presynaptic vesicles was significantly increased in CA1 synapses of reeler mutants. To test the hypothesis that vesicle fusion is altered in reeler, we studied proteins known to control transmitter release. SNAP25, a protein of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, was found to be significantly reduced in reeler mutants, whereas other SNARE complex proteins remained unaltered. Addition of recombinant Reelin to organotypic slice cultures of reeler hippocampi substantially rescued not only SNAP25 protein expression levels but also the number of vesicles per bouton area indicating a role for Reelin in presynaptic functions. Next, we analyzed paired-pulse facilitation, a presynaptic mechanism associated with transmitter release, and observed a significant decrease at CA1 synapses of reeler mutants when compared with wild-type animals. Together, these novel findings suggest a role for Reelin in modulating presynaptic release mechanisms. PMID- 21325503 TI - Inhibition of the plasma membrane Ca2+ pump by CD44 receptor activation of tyrosine kinases increases the action potential afterhyperpolarization in sensory neurons. AB - The cytoplasmic Ca(2+) clearance rate affects neuronal excitability, plasticity, and synaptic transmission. Here, we examined the modulation of the plasma membrane Ca(2+) ATPase (PMCA) by tyrosine kinases. In rat sensory neurons grown in culture, the PMCA was under tonic inhibition by a member of the Src family of tyrosine kinases (SFKs). Ca(2+) clearance accelerated in the presence of selective tyrosine kinase inhibitors. Tonic inhibition of the PMCA was attenuated in cells expressing a dominant-negative construct or shRNA directed to message for the SFKs Lck or Fyn, but not Src. SFKs did not appear to phosphorylate the PMCA directly but instead activated focal adhesion kinase (FAK). Expression of constitutively active FAK enhanced and dominant-negative or shRNA knockdown of FAK attenuated tonic inhibition. Antisense knockdown of PMCA isoform 4 removed tonic inhibition of Ca(2+) clearance, indicating that FAK acts on PMCA4. The hyaluronan receptor CD44 activates SFK-FAK signaling cascades and is expressed in sensory neurons. Treating neurons with a CD44-blocking antibody or short hyaluronan oligosaccharides, which are produced during injury and displace macromolecular hyaluronan from CD44, attenuated tonic PMCA inhibition. Ca(2+) activated K(+) channels mediate a slow afterhyperpolarization in sensory neurons that was inhibited by tyrosine kinase inhibitors and enhanced by knockdown of PMCA4. Thus, we describe a novel kinase cascade in sensory neurons that enables the extracellular matrix to alter Ca(2+) signals by modulating PMCA-mediated Ca(2+) clearance. This signaling pathway may influence the excitability of sensory neurons following injury. PMID- 21325504 TI - Frizzled3 is required for neurogenesis and target innervation during sympathetic nervous system development. AB - The sympathetic nervous system has served as an amenable model system to investigate molecular mechanisms underlying developmental processes in the nervous system. While much attention has been focused on neurotrophic factors controlling survival and connectivity of postmitotic sympathetic neurons, relatively little is known about signaling mechanisms regulating development of sympathetic neuroblasts. Here, we report that Frizzled3 (Fz3), a member of the Wnt receptor family, is essential for maintenance of dividing sympathetic neuroblasts. In Fz3(-/-) mice, sympathetic neuroblasts exhibit decreased proliferation and premature cell cycle exit. Fz3(-/-) sympathetic neuroblasts also undergo enhanced apoptosis, which could not be rescued by eliminating the proapoptotic factor, Bax. These deficits result in reduced generation of sympathetic neurons and pronounced decreases in the size of sympathetic chain ganglia. Furthermore, the axons of sympathetic neurons that persist in Fz3(-/-) ganglia are able to extend out of sympathetic ganglia toward distal targets, but fail to fully innervate final peripheral targets. The cell cycle exit, but not target innervation, defects in Fz3(-/-) mice are phenocopied in mice with conditional ablation of beta-catenin, a component of canonical Wnt signaling, in sympathetic precursors. Sympathetic ganglia and innervation of target tissues appeared normal in mice lacking a core planar cell polarity (PCP) component, Vangl2. Together, our results suggest distinct roles for Fz3 during sympathetic neuron development; Fz3 acts at early developmental stages to maintain a pool of dividing sympathetic precursors, likely via activation of beta-catenin, and Fz3 functions at later stages to promote innervation of final peripheral targets by postmitotic sympathetic neurons. PMID- 21325505 TI - Longitudinal near-infrared imaging of myelination. AB - Myelination is one of the fundamental biological processes in the development of vertebrate nervous system. Disturbance of myelination is found to be associated with progression in many neurological diseases such as multiple sclerosis. Tremendous efforts have been made to develop novel therapeutic agents that prevent demyelination and/or promote remyelination. These efforts need to be accompanied by the development of imaging tools that permit direct quantification of myelination in vivo. In this work, we describe a novel near-infrared fluorescence imaging technique that is capable of direct quantification of myelination in vivo. This technique is developed based on a near-infrared fluorescent probe, 3,3'-diethylthiatricarbocyanine iodide (DBT) that readily enters the brain and specifically binds to myelinated fibers. In vivo imaging studies were first conducted in two animal models of hypermyelination and hypomyelination followed by longitudinal studies in the cuprizone-induced demyelination/remyelination mouse model. Quantitative analysis suggests that DBT is a sensitive and specific imaging probe of myelination, which complements other current myelin-imaging modalities and is of low cost. PMID- 21325506 TI - Spontaneous electrical activity in the human fetal cortex in vitro. AB - Our knowledge about the developing human cerebral cortex is based on the analysis of fixed postmortem material. Here we use electrical recordings from unfixed human postmortem tissue to characterize the synaptic physiology and spontaneous network activity of pioneer cortical neurons ("subplate neurons"). Our electrophysiological experiments show that functional glutamate or GABA ionotropic receptors are expressed on human subplate (SP) neurons as early as 20 gestational weeks. Extracellular (synaptic) stimulations evoked postsynaptic potentials in a very small fraction of SP neurons, suggesting that functional synaptic contacts are rare at midgestation. Although synaptic inputs were scarce, we regularly observed spontaneous (unprovoked) electrical activity among human SP neurons, comprised of sustained plateau depolarizations and bursts of action potential firing, which resembled cortical UP and DOWN states in the adult neocortex. Plateau depolarizations and bursts of action potential firing are thought to depend on the mature morphology and physiology of adult cortical network. However, our current data reveal that similar cortical rhythm is generated by a very immature ensemble of human fetal neurons. In the relative absence of sensory inputs, as in development in utero, or in slow-wave sleep (i.e., throughout the entire lifespan), the spontaneous slow oscillatory pattern (UP and DOWN states) is a fundamental aspect of human cortical physiology. PMID- 21325507 TI - Reaction time correlations during eye-hand coordination: behavior and modeling. AB - During coordinated eye-hand movements, saccade reaction times (SRTs) and reach reaction times (RRTs) are correlated in humans and monkeys. Reaction times (RTs) measure the degree of movement preparation and can correlate with movement speed and accuracy. However, RTs can also reflect effector nonspecific influences, such as motivation and arousal. We use a combination of behavioral psychophysics and computational modeling to identify plausible mechanisms for correlations in SRTs and RRTs. To disambiguate nonspecific mechanisms from mechanisms specific to movement coordination, we introduce a dual-task paradigm in which a reach and a saccade are cued with a stimulus onset asynchrony (SOA). We then develop several variants of integrate-to-threshold models of RT, which postulate that responses are initiated when the neural activity encoding effector-specific movement preparation reaches a threshold. The integrator models formalize hypotheses about RT correlations and make predictions for how each RT should vary with SOA. To test these hypotheses, we trained three monkeys to perform the eye-hand SOA task and analyzed their SRTs and RRTs. In all three subjects, RT correlations decreased with increasing SOA duration. Additionally, mean SRT decreased with decreasing SOA, revealing facilitation of saccades with simultaneous reaches, as predicted by the model. These results are not consistent with the predictions of the models with common modulation or common input but are compatible with the predictions of a model with mutual excitation between two effector-specific integrators. We propose that RT correlations are not simply attributable to motivation and arousal and are a signature of coordination. PMID- 21325509 TI - Frequency-dependent recruitment of fast amino acid and slow neuropeptide neurotransmitter release controls gonadotropin-releasing hormone neuron excitability. AB - The anteroventral periventricular nucleus (AVPV) is thought to play a key role in regulating the excitability of gonadotropin-releasing hormone (GnRH) neurons that control fertility. Using an angled, parahorizontal brain slice preparation we have undertaken a series of electrophysiological experiments to examine how the AVPV controls GnRH neurons in adult male and female mice. More than half (59%) of GnRH neurons located in the rostral preoptic area were found to receive monosynaptic inputs from the AVPV in a sex-dependent manner. AVPV stimulation frequencies <1 Hz generated short-latency action potentials in GnRH neurons with GABA and glutamate mediating >90% of the evoked fast synaptic currents. The AVPV GABA input was dominant and found to excite or inhibit GnRH neurons in a cell dependent manner. Increasing the AVPV stimulation frequency to 5-10 Hz resulted in the appearance of additional poststimulus inhibitory as well as delayed excitatory responses in GnRH neurons that were independent of ionotropic amino acid receptors. The inhibition observed immediately following the end of the stimulation period was mediated partly by GABA(B) receptors, while the delayed activation was mediated by the neuropeptide kisspeptin. The latter response was essentially absent in Gpr54 knock-out mice and abolished by a Gpr54 antagonist. Together, these studies show that AVPV neurons provide direct amino acid and neuropeptidergic inputs to GnRH neurons. Low-frequency activation generates predominant GABA/glutamate release with higher frequency activation recruiting release of kisspeptin. This frequency-dependent release of amino acid and neuropeptide neurotransmitters greatly expands the range of AVPV control of GnRH neuron excitability. PMID- 21325508 TI - Dorsal radial glial cells have the potential to generate cortical interneurons in human but not in mouse brain. AB - Radial glial (RG) cells, in the neocortical ventricular/subventricular zone (VZ/SVZ), generate cortical projection neurons both in rodents and humans, but whether they can also generate cortical interneurons is not clear. We demonstrated both on cryosections and in cell cultures that in the human VZ/SVZ, cells can be double labeled with RG markers and calretinin (CalR) and GABA, markers that suggest interneuronal lineage. We examined in more detail the cell fate of human RG cells isolated from the VZ/SVZ at midterm. After 24 h, no CalR(+) or GABA(+) cells were seen in cultures, whereas 5-10% cells expressed Nkx2.1 and Dlx, two ventral transcription factors. CalR(+) and GABA(+) cells were apparent for the first time after 3 d in vitro, and their number increased in subsequent days, consistent with the gradual transition of RG cells into CalR(+) or GABA(+) cells. Indeed, the progeny of genetically labeled RG cells could be immunolabeled with antibodies to CalR and GABA or ventral transcription factors (Nkx2.1(+), Dlx(+)). In contrast to humans, in the embryonic mouse, similar experiments showed that only RG cells isolated from the subpallium (ganglionic eminence) generate CalR(+) or GABA(+) cells, whereas this was not the case with RG cells isolated from the pallium. These findings support the idea that human, but not mouse, dorsal RG cells have the potential to generate various subtypes of neocortical interneurons. Multiple progenitors and sites of cortical interneuron origin in human might be an evolutionary adaptation underlying brain expansion and the increased complexity of cortical circuitry in humans. PMID- 21325510 TI - Stereological estimate of the total number of neurons in spinal segment D9 of the red-eared turtle. AB - The red-eared turtle is an important animal model for investigating the neural activity in the spinal circuit that generates motor behavior. However, basic anatomical features, including the number of neurons in the spinal segments involved, are unknown. In the present study, we estimate the total number of neurons in segment D9 of the spinal cord in the red-eared turtle (Trachemys scripta elegans) using stereological cell counting methods. In transverse spinal cord sections stained with modified Giemsa, motoneurons (MNs), interneurons (INs), and non-neuronal cells were distinguished according to location and morphology. Each cell type was then counted separately using an optical disector with the cell nucleus as counting item. The number of cells in segment D9 was as follows (mean +/- SE): MNs, 2049 +/- 74; INs, 16,135 +/- 316; non-neuronal cells, 47,504 +/- 478 (n = 6). These results provide the first estimate of the total number of neurons in a spinal segment in a terrestrial vertebrate based on unbiased stereological methods and an upper bound on the number of neurons involved in segmental sensorimotor activity. These findings also form a crucial quantitative foundation for integrating electrophysiological data into mathematical circuit models. PMID- 21325511 TI - The relationship between duration of initial alcohol exposure and persistence of molecular tolerance is markedly nonlinear. AB - The neuronal calcium- and voltage-activated BK potassium channel is modulated by ethanol, and plays a role in behavioral tolerance in vertebrates and invertebrates. We examine the influence of temporal parameters of alcohol exposure on the characteristics of BK molecular tolerance in the ventral striatum, an important component of brain reward circuitry. BK channels in striatal neurons of C57BL/6J mice exhibited molecular tolerance whose duration was a function of exposure time. After 6 h exposure to 20 mm (0.09 mg%) ethanol, alcohol sensitivity was suppressed beyond 24 h after withdrawal, while after a 1 or 3 h exposure, sensitivity had significantly recovered after 4 h. This temporally controlled transition to persistent molecular tolerance parallels changes in BK channel isoform profile. After withdrawal from 6 h, but not 3 h alcohol exposure, mRNA levels of the alcohol-insensitive STREX (stress axis regulated exon) splice variant were increased. Moreover, the biophysical properties of BK channels during withdrawal from 6 h exposure were altered, and match the properties of STREX channels exogenously expressed in HEK 293 cells. Our results suggest a temporally triggered shift in BK isoform identity. Once activated, the transition does not require the continued presence of alcohol. We next determined whether the results obtained using cultured striatal neurons could be observed in acutely dissociated striatal neurons, after alcohol administration in the living mouse. The results were in remarkable agreement with the striatal culture data, showing persistent molecular tolerance after injections producing 6 h of intoxication, but not after injections producing only 3 h of intoxication. PMID- 21325512 TI - WRP/srGAP3 facilitates the initiation of spine development by an inverse F-BAR domain, and its loss impairs long-term memory. AB - The WAVE-associated Rac GAP, WRP, is thought to regulate key aspects of synapse development and function and may be linked to mental retardation in humans. WRP contains a newly described inverse F-BAR (IF-BAR) domain of unknown function. Our studies show that this domain senses/facilitates outward protrusions analogous to filopodia and that the molecular basis for this is likely explained by a convex lipid-binding surface on the WRP IF-BAR domain. In dendrites the IF-BAR domain of WRP forms a bud on the shaft from which precursors to spines emerge. Loss of WRP in vivo and in vitro results in reduced density of spines. In vivo this is primarily a loss of mushroom-shaped spines. Developmentally, WRP function is critical at the onset of spinogenesis, when dendritic filopodia are prevalent. Finally, because WRP is implicated in mental retardation, behaviors of WRP heterozygous and null mice have been evaluated. Results from these studies confirm that loss of WRP is linked to impaired learning and memory. PMID- 21325513 TI - Routing the flow of sensory signals using plastic responses to bursts and isolated spikes: experiment and theory. AB - Processing complex sensory environments efficiently requires a diverse array of neural coding strategies. Neural codes relying on specific temporal patterning of action potentials may offer advantages over using solely spike rate codes. In particular, stimulus-dependent burst firing may carry additional information that isolated spikes do not. We use the well characterized electrosensory system of weakly electric fish to address how stimulus-dependent burst firing can determine the flow of information in feedforward neural circuits with different forms of short-term synaptic plasticity. Pyramidal cells in the electrosensory lateral line lobe burst in response to low-frequency, local (prey) signals. We show that the ability of pyramidal cells to code for local signals in the presence of additional high-frequency, global (communication) stimuli is uncompromised, while burst firing is reduced. We developed a bursting neuron model to understand how these effects, in particular noise-induced burst suppression, arise from interplay between incoming sensory signals and intrinsic neuronal dynamics. Finally, we examined how postsynaptic target populations preferentially respond to one of the two sensory mixtures (local vs local plus global) depending on whether the populations are in receipt of facilitating or depressing synapses. This form of feedforward neural architecture may allow for efficient information flow in the same neural pathway via either isolated or burst spikes, where the mechanisms by which stimuli are encoded are adaptable and sensitive to a diverse array of stimulus and contextual mixtures. PMID- 21325514 TI - Neural correlates of instrumental contingency learning: differential effects of action-reward conjunction and disjunction. AB - Contingency theories of goal-directed action propose that experienced disjunctions between an action and its specific consequences, as well as conjunctions between these events, contribute to encoding the action-outcome association. Although considerable behavioral research in rats and humans has provided evidence for this proposal, relatively little is known about the neural processes that contribute to the two components of the contingency calculation. Specifically, while recent findings suggest that the influence of action-outcome conjunctions on goal-directed learning is mediated by a circuit involving ventromedial prefrontal, medial orbitofrontal cortex, and dorsomedial striatum, the neural processes that mediate the influence of experienced disjunctions between these events are unknown. Here we show differential responses to probabilities of conjunctive and disjunctive reward deliveries in the ventromedial prefrontal cortex, the dorsomedial striatum, and the inferior frontal gyrus. Importantly, activity in the inferior parietal lobule and the left middle frontal gyrus varied with a formal integration of the two reward probabilities, DeltaP, as did response rates and explicit judgments of the causal efficacy of the action. PMID- 21325515 TI - Dopaminergic projections from midbrain to primary motor cortex mediate motor skill learning. AB - The primary motor cortex (M1) of the rat contains dopaminergic terminals. The origin of this dopaminergic projection and its functional role for movement are obscure. Other areas of cortex receive dopaminergic projections from the ventral tegmental area (VTA) of the midbrain, and these projections are involved in learning phenomena. We therefore hypothesized that M1 receives a dopaminergic projection from VTA and that this projection mediates the learning of a motor skill by inducing cellular plasticity events in M1. Retrograde tracing from M1 of Long-Evans rats in conjunction with tyrosine hydroxylase immunohistochemistry identified dopaminergic cell bodies in VTA. Electrical stimulation of VTA induced expression of the immediate-early gene c-fos in M1, which was blocked by intracortical injections of D(1) and D(2) antagonists. Destroying VTA dopaminergic neurons prevented the improvements in forelimb reaching seen in controls during daily training. Learning recovered on administration of levodopa into the M1 of VTA-lesioned animals. Lesioning VTA did not affect performance of an already learned skill, hence, left movement execution intact. These findings provide evidence that dopaminergic terminals in M1 originate in VTA, contribute to M1 plasticity, and are necessary for successful motor skill learning. Because VTA dopaminergic neurons are known to signal rewards, the VTA-to-M1 projection is a candidate for relaying reward information that could directly support the encoding of a motor skill within M1. PMID- 21325516 TI - Recurrent processing in V1/V2 contributes to categorization of natural scenes. AB - Humans are able to categorize complex natural scenes very rapidly and effortlessly, which has led to an assumption that such ultra-rapid categorization is driven by feedforward activation of ventral brain areas. However, recent accounts of visual perception stress the role of recurrent interactions that start rapidly after the activation of V1. To study whether or not recurrent processes play a causal role in categorization, we applied fMRI-guided transcranial magnetic stimulation on early visual cortex (V1/V2) and lateral occipital cortex (LO) while the participants categorized natural images as containing animals or not. The results showed that V1/V2 contributed to categorization speed and to subjective perception during a long activity period before and after the contribution of LO had started. This pattern of results suggests that recurrent interactions in visual cortex between areas along the ventral stream and striate cortex play a causal role in categorization and perception of natural scenes. PMID- 21325517 TI - Olivocochlear efferent control in sound localization and experience-dependent learning. AB - Efferent auditory pathways have been implicated in sound localization and its plasticity. We examined the role of the olivocochlear system (OC) in horizontal sound localization by the ferret and in localization learning following unilateral earplugging. Under anesthesia, adult ferrets underwent olivocochlear bundle section at the floor of the fourth ventricle, either at the midline or laterally (left). Lesioned and control animals were trained to localize 1 s and 40 ms amplitude-roved broadband noise stimuli from one of 12 loudspeakers. Neither type of lesion affected normal localization accuracy. All ferrets then received a left earplug and were tested and trained over 10 d. The plug profoundly disrupted localization. Ferrets in the control and lateral lesion groups improved significantly during subsequent training on the 1 s stimulus. No improvement (learning) occurred in the midline lesion group. Markedly poorer performance and failure to learn was observed with the 40 ms stimulus in all groups. Plug removal resulted in a rapid resumption of normal localization in all animals. Insertion of a subsequent plug in the right ear produced similar results to left earplugging. Learning in the lateral lesion group was independent of the side of the lesion relative to the earplug. Lesions in all reported cases were verified histologically. The results suggest the OC system is not needed for accurate localization, but that it is involved in relearning localization during unilateral conductive hearing loss. PMID- 21325518 TI - Gamma-band activity as a signature for cross-modal priming of auditory object recognition by active haptic exploration. AB - When visual sensory information is restricted, we often rely on haptic and auditory information to recognize objects. Here we examined how haptic exploration of familiar objects affects neural processing of subsequently presented sounds of objects. Recent studies indicated that oscillatory responses, in particular in the gamma band (30-100 Hz), reflect cross-modal processing, but it is not clear which cortical networks are involved. In this high-density EEG study, we measured gamma-band activity (GBA) in humans performing a haptic-to auditory priming paradigm. Haptic stimuli served as primes, and sounds of objects as targets. Haptic and auditory stimuli were either semantically congruent or incongruent, and participants were asked to categorize the objects represented by the sounds. Response times were shorter for semantically congruent compared with semantically incongruent inputs. This haptic-to-auditory priming effect was associated with enhanced total power GBA (250-350 ms) for semantically congruent inputs and additional effects of semantic congruency on evoked GBA (50-100 ms). Source reconstruction of total GBA using linear beamforming revealed effects of semantic congruency in the left lateral temporal lobe, possibly reflecting matching of information across modalities. For semantically incongruent inputs, total GBA was enhanced in middle frontal cortices, possibly indicating the processing or detection of conflicting information. Our findings demonstrate that semantic priming by haptic object exploration affects processing of auditory inputs in the lateral temporal lobe and suggest an important role of oscillatory activity for multisensory processing. PMID- 21325519 TI - Tau-induced defects in synaptic plasticity, learning, and memory are reversible in transgenic mice after switching off the toxic Tau mutant. AB - This report describes the behavioral and electrophysiological analysis of regulatable transgenic mice expressing mutant repeat domains of human Tau (Tau(RD)). Mice were generated to express Tau(RD) in two forms, differing in their propensity for beta-structure and thus in their tendency for aggregation ("pro-aggregant" or "anti-aggregant") (Mocanu et al., 2008). Only pro-aggregant mice show pronounced changes typical for Tau pathology in Alzheimer's disease (aggregation, missorting, hyperphosphorylation, synaptic and neuronal loss), indicating that the beta-propensity and hence the ability to aggregate is a key factor in the disease. We now tested the mice with regard to neuromotor parameters, behavior, learning and memory, and synaptic plasticity and correlated this with histological and biochemical parameters in different stages of switching Tau(RD) on or off. The mice are normal in neuromotor tests. However, pro-aggregant Tau(RD) mice are strongly impaired in memory and show pronounced loss of long-term potentiation (LTP), suggesting that Tau aggregation specifically perturbs these brain functions. Remarkably, when the expression of human pro-aggregant Tau(RD) is switched on for ~ 10 months and off for ~ 4 months, memory and LTP recover, whereas aggregates decrease moderately and change their composition from mixed human plus mouse Tau to mouse Tau only. Neuronal loss persists, but synapses are partially rescued. This argues that continuous presence of amyloidogenic pro-aggregant Tau(RD) constitutes the main toxic insult for memory and LTP, rather than the aggregates as such. PMID- 21325520 TI - Cross-sensory modulation of primary sensory cortex is developmentally regulated by early sensory experience. AB - The presence of cross-sensory influences on neuronal responses in primary sensory cortex has been observed previously using several different methods. To test this idea in rat S1 barrel cortex, we hypothesized that auditory stimuli combined with whisker stimulation ("cross-sensory" stimuli) may modify response levels to whisker stimulation. Since the brain has been shown to have a remarkable capacity to be modified by early postnatal sensory activity, manipulating postnatal sensory experiences would be predicted to alter the degree of cross-sensory interactions. To test these ideas, we raised rats with or without whisker deprivation and with or without postnatal exposure to repeated auditory clicks. We recorded extracellular responses under urethane anesthesia from barrel cortex neurons in response to principal whisker stimulation alone, to auditory click stimulation alone, or to a cross-sensory stimulus. The responses were compared statistically across different stimulus conditions and across different rearing groups. Barrel neurons did not generate action potentials in response to auditory click stimuli alone in any rearing group. However, in cross-sensory stimulus conditions the response magnitude was facilitated in the 0-15 ms post-whisker stimulus epoch in all rearing conditions, whereas modulation of response magnitude in a later 15-30 ms post-whisker-stimulus epoch was significantly different in each rearing condition. The most significant cross-sensory effect occurred in rats that were simultaneously whisker deprived and click reared. We conclude that there is a modulatory type of cross-sensory auditory influence on normal S1 barrel cortex, which can be enhanced by early postnatal experiences. PMID- 21325521 TI - Functional nicotinic acetylcholine receptors containing alpha6 subunits are on GABAergic neuronal boutons adherent to ventral tegmental area dopamine neurons. AB - Diverse nicotinic acetylcholine receptor (nAChR) subtypes containing different subunit combinations can be placed on nerve terminals or soma/dendrites in the ventral tegmental area (VTA). nAChR alpha6 subunit message is abundant in the VTA, but alpha6*-nAChR cellular localization, function, pharmacology, and roles in cholinergic modulation of dopaminergic (DA) neurons within the VTA are not well understood. Here, we report evidence for alpha6beta2*-nAChR expression on GABA neuronal boutons terminating on VTA DA neurons. alpha-Conotoxin (alpha-Ctx) MII labeling coupled with immunocytochemical staining localizes putative alpha6* nAChRs to presynaptic GABAergic boutons on acutely dissociated, rat VTA DA neurons. Functionally, acetylcholine (ACh) induces increases in the frequency of bicuculline-, picrotoxin-, and 4-aminopyridine-sensitive miniature IPSCs (mIPSCs) mediated by GABA(A) receptors. These increases are abolished by alpha6*-nAChR selective alpha-Ctx MII or alpha-Ctx PIA (1 nm) but not by alpha7 (10 nm methyllycaconitine) or alpha4* (1 MUm dihydro-beta-erythroidine)-nAChR-selective antagonists. ACh also fails to increase mIPSC frequency in VTA DA neurons prepared from nAChR beta2 knock-out mice. Moreover, ACh induces an alpha-Ctx PIA sensitive elevation in intraterminal Ca(2+) in synaptosomes prepared from the rat VTA. Subchronic exposure to 500 nm nicotine reduces ACh-induced GABA release onto the VTA DA neurons, as does 10 d of systemic nicotine exposure. Collectively, these results indicate that alpha6beta2*-nAChRs are located on presynaptic GABAergic boutons within the VTA and modulate GABA release onto DA neurons. These presynaptic alpha6beta2*-nAChRs likely play important roles in nicotinic modulation of DA neuronal activity. PMID- 21325523 TI - Sleep contributes to the strengthening of some memories over others, depending on hippocampal activity at learning. AB - Memory consolidation benefits from sleep. In addition to strengthening some memory traces, another crucial, albeit overlooked, function of memory is to erase irrelevant information. Directed forgetting is an experimental approach consisting in presenting "to be remembered" and "to be forgotten" information that allows selectively decreasing or increasing the strength of individual memory traces according to the instruction provided at learning. This paradigm was used in combination with functional MRI to determine, in humans, what specifically triggers at encoding sleep-dependent compared with time-dependent consolidation. Our data indicate that relevant items that subjects strived to memorize are consolidated during sleep to a greater extent than items that participants did not intend to learn. This process appears to depend on a differential activation of the hippocampus at encoding, which acts as a signal for the offline reprocessing of relevant memories during postlearning sleep episodes. PMID- 21325522 TI - Origin and determination of inhibitory cell lineages in the vertebrate retina. AB - Multipotent progenitors in the vertebrate retina often generate clonally related mixtures of excitatory and inhibitory neurons. The postmitotically expressed transcription factor, Ptf1a, is essential for all inhibitory fates in the zebrafish retina, including three types of horizontal and 28 types of amacrine cell. Here, we show that specific types of inhibitory neurons arise from the cell autonomous influence of Ptf1a in the daughters of fate-restricted progenitors, such as Ath5 or Vsx1/2-expressing progenitors, and that in the absence of Ptf1a, cells that would have become these specific inhibitory subtypes revert to the histogenetically appropriate excitatory subtypes of the same lineage. Altered proportions of amacrine subtypes respecified by the misexpression of Ptf1a in the Ath5 lineage suggest that Ath5-expressing progenitors are biased, favoring the generation of some subtypes more than others. Yet the full array of inhibitory cell subtypes in Ath5 mutants implies the existence of Ath5-independent factors involved in inhibitory cell specification. We also show that an extrinsic negative feedback on the expression of Ptf1a provides a control mechanism by which the number of any and all types of inhibitory cells in the retina can be regulated in this lineage-dependent way. PMID- 21325524 TI - Parietal area VIP causally influences heading perception during pursuit eye movements. AB - The ventral intraparietal area (VIP) of the macaque monkey brain is a multimodal area with visual, vestibular, somatosensory, and eye movement-related responses. The visual responses are strongly directional, and VIP neurons respond well to complex optic flow patterns similar to those found during self-motion. To test the hypothesis that visual responses in VIP directly contribute to the perception of self-motion direction, we used electrical microstimulation to perturb activity in VIP while animals performed a two-alternative heading discrimination task. Microstimulation systematically biased monkeys' choices in a direction consistent with neuronal preferences at the stimulation site, and these effects were larger while the animal was making smooth pursuit eye movements. From these results, we conclude that VIP is causally involved in the perception of self-motion from visual cues and that this involvement is gated by ongoing motor behavior. PMID- 21325525 TI - It's about time: how input timing is used and not used to create emergent properties in the auditory system. AB - The hypothesis for directional selectivity of frequency modulations (FMs) invokes a mechanism with an honored tradition in sensory neurobiology, the relative timing of excitation and inhibition. The proposal is that the timing disparity is created by asymmetrical locations of excitatory tuning and inhibitory sidebands. Thus, cells in which the inhibitory sidebands are tuned to frequencies lower than the excitatory tuning are selective for downward sweeping FMs, because frequencies first generate excitation followed by inhibition. Upward sweeping FMs, in contrast, first evoke inhibition that either leads or is coincident with the excitation and prevents discharges. Here we evaluated FM directional selectivity with in vivo whole-cell recordings from the inferior colliculus of awake bats. From the whole-cell recordings, we derived synaptic conductance waveforms evoked by downward and upward FMs. We then tested the effects of shifting inhibition relative to excitation in a model and found that latency shifts had only minor effects on EPSP amplitudes that were often <1.0 mV/ms shift. However, when the PSPs peaked close to spike threshold, even small changes in latency could cause some cells to fire more strongly to a particular FM direction and thus change its directional selectivity. Furthermore, the effect of shifting inhibition depended strongly on initial latency differences and the shapes of the conductance waveforms. We conclude that "timing" is more than latency differences between excitation and inhibition, and response selectivity depends on a complex interaction between the timing, the shapes, and magnitudes of the excitatory and inhibitory conductances and spike threshold. PMID- 21325526 TI - Short- and long-lasting consequences of in vivo nicotine treatment on hippocampal excitability. AB - The potential for relapse following cessation of drug use can last for years, implying the induction of stable changes in neural circuitry. In hippocampal slices from rats treated with nicotine for 1 week, withdrawal from nicotine in vivo produces an increase in CA1 pyramidal cell excitability that persists up to 9 months. Immediately upon drug cessation, the enhanced excitability depends on input from regions upstream of CA1, while the long-term excitability change (> 4 weeks) is expressed as an increase in the intrinsic excitability of CA1 neurons. Re-exposure to nicotine in vitro restores hippocampal function to control levels via activation of high-affinity nicotinic acetylcholine receptors after 1 d of withdrawal, but not at times >4 weeks. Thus, nicotine in vivo first induces homeostatic adaptations followed by other more robust neural changes. These mechanisms may contribute to hippocampal localized cue-motivated reinstatement of drug-seeking and/or cognitive deficits observed during withdrawal. PMID- 21325527 TI - Emergence of learned categorical representations within an auditory forebrain circuit. AB - Many learned behaviors are thought to require the activity of high-level neurons that represent categories of complex signals, such as familiar faces or native speech sounds. How these complex, experience-dependent neural responses emerge within the brain's circuitry is not well understood. The caudomedial mesopallium (CMM), a secondary auditory region in the songbird brain, contains neurons that respond to specific combinations of song components and respond preferentially to the songs that birds have learned to recognize. Here, we examine the transformation of these learned responses across a broader forebrain circuit that includes the caudolateral mesopallium (CLM), an auditory region that provides input to CMM. We recorded extracellular single-unit activity in CLM and CMM in European starlings trained to recognize sets of conspecific songs and compared multiple encoding properties of neurons between these regions. We find that the responses of CMM neurons are more selective between song components, convey more information about song components, and are more variable over repeated components than the responses of CLM neurons. While learning enhances neural encoding of song components in both regions, CMM neurons encode more information about the learned categories associated with songs than do CLM neurons. Collectively, these data suggest that CLM and CMM are part of a functional sensory hierarchy that is modified by learning to yield representations of natural vocal signals that are increasingly informative with respect to behavior. PMID- 21325528 TI - Large-scale calcium waves traveling through astrocytic networks in vivo. AB - Macroscopic changes in cerebral blood flow, such as those captured by functional imaging of the brain, require highly organized, large-scale dynamics of astrocytes, glial cells that interact with both neuronal and cerebrovascular networks. However, astrocyte activity has been studied mainly at the level of individual cells, and information regarding their collective behavior is lacking. In this work, we monitored calcium activity simultaneously from hundreds of mouse hippocampal astrocytes in vivo and found that almost all astrocytes participated en masse in regenerative waves that propagated from cell to cell (referred to here as "glissandi"). Glissandi emerged depending on the neuronal activity and accompanied a reduction in infraslow fluctuations of local field potentials and a decrease in the flow of red blood cells. This novel phenomenon was heretofore overlooked, probably because of the high vulnerability of astrocytes to light damage; glissandi occurred only when observed at much lower laser intensities than previously used. PMID- 21325529 TI - Presenilin-1 regulates neural progenitor cell differentiation in the adult brain. AB - Presenilin-1 (PS1) is the catalytic core of the aspartyl protease gamma secretase. Previous genetic studies using germ-line deletion of PS1 and conditional knock-out mice demonstrated that PS1 plays an essential role in neuronal differentiation during neural development, but it remained unclear whether PS1 plays a similar role in neurogenesis in the adult brain. Here we show that neural progenitor cells infected with lentiviral vectors-expressing short interfering RNA (siRNA) for the exclusive knockdown of PS1 in the neurogenic microenvironments, exhibit a dramatic enhancement of cell differentiation. Infected cells differentiated into neurons, astrocytes and oligodendrocytes, suggesting that multipotentiality of neural progenitor cells is not affected by reduced levels of PS1. Neurosphere cultures treated with gamma-secretase inhibitors exhibit a similar phenotype of enhanced cell differentiation, suggesting that PS1 function in neural progenitor cells is gamma-secretase dependent. Neurospheres infected with lentiviral vectors expressing siRNA for the targeting of PS1 differentiated even in the presence of the proliferation factors epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF), suggesting that PS1 dominates EFG and bFGF signaling pathways. Reduction of PS1 expression in neural progenitor cells was accompanied by a decrease in EGF receptor and beta-catenin expression level, suggesting that they are downstream essential transducers of PS1 signaling in adult neural progenitor cells. These findings suggest a physiological role for PS1 in adult neurogenesis, and a potential target for the manipulation of neural progenitor cell differentiation. PMID- 21325530 TI - Memory, visual discrimination performance, and the human hippocampus. AB - We evaluated recent proposals that the hippocampus supports certain kinds of visual discrimination performance, for example, when spatial processing is required and the stimuli have a high degree of feature overlap. Patients with circumscribed hippocampal lesions tried to discriminate between images of similar faces or images of similar scenes. In one condition, elements of the stimulus display repeated from trial to trial, and in another condition every trial was unique. In the repeated condition for both faces and scenes, controls gradually improved their performance across testing. In the trial-unique condition, no improvement occurred. The patients were impaired for both faces and scenes in the repeated condition where controls could benefit from learning. However, the patients were fully intact in the trial-unique condition. The results suggest that previous reports of impaired discrimination performance after medial temporal lobe damage may reflect impaired learning rather than impaired visual perception. The findings support the fundamental idea that memory is a distinct cerebral function separable from other perceptual and cognitive abilities. PMID- 21325531 TI - Functional reorganization of the brain in humans following spinal cord injury: evidence for underlying changes in cortical anatomy. AB - Loss of somatosensory drive results in functional reorganization of the primary somatosensory cortex (SI). While the phenomenon of functional cortical reorganization is well established, it remains unknown whether in humans, functional reorganization results from changes in brain anatomy, or simply reflects an unmasking of already existing dormant synapses. In 20 subjects with complete thoracic spinal cord injuries (SCIs) and 23 controls, we used functional and structural magnetic resonance imaging to determine whether SI reorganization was associated with changes in SI anatomy. SCI resulted in a significant SI reorganization, with the little finger representation moving medially toward the lower body representation (i.e., area of sensory loss). Furthermore, although SCI was associated with gray matter volume loss in the lower body representation, this loss was minimized as reorganization increased. That is, the greater the medial shift in little finger representation, the greater the gray matter preservation in the lower body representation. In addition, in the region of greatest SI reorganization (little finger), fractional anisotropy was correlated with SI reorganization. That is, as SI reorganization increased, the extent of aligned structures decreased. Finally, although thalamocortical fibers remained unchanged, the ease and direction of water movement within the little finger representation was altered, being directed more toward the midline in SCI subjects. These data show that SI reorganization following SCI is associated with changes in SI anatomy and provide compelling evidence that SI reorganization in humans results from the growth of new lateral connections, and not simply from the unmasking of already existing lateral connections. PMID- 21325532 TI - Ovarian hormone deficiency reduces intrinsic excitability and abolishes acute estrogen sensitivity in hippocampal CA1 pyramidal neurons. AB - Premature and uncompensated loss of ovarian hormones following ovariectomy (OVX) elevates the risks of cognitive impairment and dementia. These risks are prevented with estrogen (E(2))-containing hormone replacement therapy initiated shortly following OVX but not after substantial delay. Currently, the cellular bases underlying these clinical findings are unknown. At the cellular level, intrinsic membrane properties regulate the efficiency of synaptic inputs to initiate output action potentials (APs), thereby affecting neuronal communication, hence cognitive processing. This study tested the hypothesis that in CA1 pyramidal neurons, intrinsic membrane properties and their acute regulation by E(2) require ovarian hormones for maintenance. Whole-cell current clamp recordings were performed on neurons from ~ 7-month-old OVX rats that experienced either short-term (10 d, control OVX) or long-term (5 months, OVX(LT)) ovarian hormone deficiency. The results reveal that long-term hormone deficiency reduced intrinsic membrane excitability (IE) as measured by the number of evoked APs and firing duration for a given current injection. This was accompanied by AP broadening, an increased slow afterhyperpolarization (sAHP), and faster accumulation of Na(V) channel inactivation during repetitive firing. In the control OVX neurons, E(2) acutely increased IE and reduced the sAHP. In contrast, acute regulation of IE by E(2) was absent in the OVX(LT) neurons. Since the degree of IE of hippocampal pyramidal neurons is positively related with hippocampus-dependent learning ability, and modulation of IE is observed following successful learning, these findings provide a framework for understanding hormone deficiency-related cognitive impairment and the critical window for therapy initiation. PMID- 21325533 TI - Endogenous GABA levels in the pontine reticular formation are greater during wakefulness than during rapid eye movement sleep. AB - Studies using drugs that increase or decrease GABAergic transmission suggest that GABA in the pontine reticular formation (PRF) promotes wakefulness and inhibits rapid eye movement (REM) sleep. Cholinergic transmission in the PRF promotes REM sleep, and levels of endogenous acetylcholine (ACh) in the PRF are significantly greater during REM sleep than during wakefulness or non-REM (NREM) sleep. No previous studies have determined whether levels of endogenous GABA in the PRF vary as a function of sleep and wakefulness. This study tested the hypothesis that GABA levels in cat PRF are greatest during wakefulness and lowest during REM sleep. Extracellular GABA levels were measured during wakefulness, NREM sleep, REM sleep, and the REM sleep-like state (REM(Neo)) caused by microinjecting neostigmine into the PRF. GABA levels varied significantly as a function of sleep and wakefulness, and decreased significantly below waking levels during REM sleep (-42%) and REM(Neo) (-63%). The decrease in GABA levels during NREM sleep (22% below waking levels) was not statistically significant. Compared with NREM sleep, GABA levels decreased significantly during REM sleep (-27%) and REM(Neo) (-52%). Comparisons of REM sleep and REM(Neo) revealed no differences in GABA levels or cortical EEG power. GABA levels did not vary significantly as a function of dialysis site within the PRF. The inverse relationship between changes in PRF levels of GABA and ACh during REM sleep indicates that low GABAergic tone combined with high cholinergic tone in the PRF contributes to the generation of REM sleep. PMID- 21325534 TI - Simultaneous acquisition of multiple auditory-motor transformations in speech. AB - The brain easily generates the movement that is needed in a given situation. Yet surprisingly, the results of experimental studies suggest that it is difficult to acquire more than one skill at a time. To do so, it has generally been necessary to link the required movement to arbitrary cues. In the present study, we show that speech motor learning provides an informative model for the acquisition of multiple sensorimotor skills. During training, subjects were required to repeat aloud individual words in random order while auditory feedback was altered in real-time in different ways for the different words. We found that subjects can quite readily and simultaneously modify their speech movements to correct for these different auditory transformations. This multiple learning occurs effortlessly without explicit cues and without any apparent awareness of the perturbation. The ability to simultaneously learn several different auditory motor transformations is consistent with the idea that, in speech motor learning, the brain acquires instance-specific memories. The results support the hypothesis that speech motor learning is fundamentally local. PMID- 21325535 TI - Dissociating the effect of noise on sensory processing and overall decision difficulty. AB - It has been proposed that perceptual decision making involves a task-difficulty component, which detects perceptual uncertainty and guides allocation of attentional resources. It is thought to take place immediately after the early extraction of sensory information and is specifically reflected in a positive component of the event related potentials, peaking at ~ 220 ms after stimulus onset. However, in the previous research, neural processes associated with the monitoring of overall task difficulty were confounded by those associated with the increased sensory processing demands as a result of adding noise to the stimuli. Here we dissociated the effect of phase noise on sensory processing and overall decision difficulty using a face gender categorization task. Task difficulty was manipulated either by adding noise to the stimuli or by adjusting the female/male characteristics of the face images. We found that it is the presence of noise and not the increased overall task difficulty that affects the electrophysiological responses in the first 300 ms following stimulus onset in humans. Furthermore, we also showed that processing of phase-randomized as compared to intact faces is associated with increased fMRI responses in the lateral occipital cortex. These results revealed that noise-induced modulation of the early electrophysiological responses reflects increased visual cortical processing demands and thus failed to provide support for a task-difficulty component taking place between the early sensory processing and the later sensory accumulation stages of perceptual decision making. PMID- 21325536 TI - Wnt5a is a transcriptional target of Dlx homeogenes and promotes differentiation of interneuron progenitors in vitro and in vivo. AB - During brain development, neurogenesis, migration, and differentiation of neural progenitor cells are regulated by an interplay between intrinsic genetic programs and extrinsic cues. The Dlx homeogene transcription factors have been proposed to directly control the genesis and maturation of GABAergic interneurons of the olfactory bulb (OB), subpallium, and cortex. Here we provide evidence that Dlx genes promote differentiation of olfactory interneurons via the signaling molecule Wnt5a. Dlx2 and Dlx5 interact with homeodomain binding sequences within the Wnt5a locus and activate its transcription. Exogenously provided Wnt5a promotes GABAergic differentiation in dissociated OB neurons and in organ-type brain cultures. Finally, we show that the Dlx-mutant environment is unfavorable for GABA differentiation, in vivo and in vitro. We conclude that Dlx genes favor interneuron differentiation also in a non-cell-autonomous fashion, via expression of Wnt5a. PMID- 21325537 TI - Taxol facilitates axon regeneration in the mature CNS. AB - Mature retinal ganglion cells (RGCs) cannot normally regenerate axons into the injured optic nerve but can do so after lens injury. Astrocyte-derived ciliary neurotrophic factor and leukemia inhibitory factor have been identified as essential key factors mediating this effect. However, the outcome of this regeneration is still limited by inhibitors associated with the CNS myelin and the glial scar. The current study demonstrates that Taxol markedly enhanced neurite extension of mature RGCs and PC12 cells by stabilization of microtubules and desensitized axons toward myelin and chondroitin sulfate proteoglycan (CSPG) inhibition in vitro without reducing RhoA activation. In vivo, the local application of Taxol at the injury site of the optic nerve of rats enabled axons to regenerate beyond the lesion site but did not affect the intrinsic regenerative state of RGCs. Furthermore, Taxol treatment markedly increased lens injury-mediated axon regeneration in vivo, delayed glial scar formation, suppressed CSPG expression, and transiently reduced the infiltration of macrophages at the injury site. Thus, microtubule-stabilizing compounds such as Taxol might be promising candidates as adjuvant drugs in the treatment of CNS injuries particularly when combined with interventions stimulating the intrinsic regenerative state of neurons. PMID- 21325538 TI - Ventral striatum and orbitofrontal cortex are both required for model-based, but not model-free, reinforcement learning. AB - In many cases, learning is thought to be driven by differences between the value of rewards we expect and rewards we actually receive. Yet learning can also occur when the identity of the reward we receive is not as expected, even if its value remains unchanged. Learning from changes in reward identity implies access to an internal model of the environment, from which information about the identity of the expected reward can be derived. As a result, such learning is not easily accounted for by model-free reinforcement learning theories such as temporal difference reinforcement learning (TDRL), which predicate learning on changes in reward value, but not identity. Here, we used unblocking procedures to assess learning driven by value- versus identity-based prediction errors. Rats were trained to associate distinct visual cues with different food quantities and identities. These cues were subsequently presented in compound with novel auditory cues and the reward quantity or identity was selectively changed. Unblocking was assessed by presenting the auditory cues alone in a probe test. Consistent with neural implementations of TDRL models, we found that the ventral striatum was necessary for learning in response to changes in reward value. However, this area, along with orbitofrontal cortex, was also required for learning driven by changes in reward identity. This observation requires that existing models of TDRL in the ventral striatum be modified to include information about the specific features of expected outcomes derived from model based representations, and that the role of orbitofrontal cortex in these models be clearly delineated. PMID- 21325539 TI - Hippocampal neurons encode different episodes in an overlapping sequence of odors task. AB - Recent theoretical models of hippocampal function suggest that the hippocampus plays a critical role in the memory for the overlapping sequences of events that comprise episodic memory. Consistent with this idea, the firing of hippocampal "place cells" have been shown to represent not only location, but also the context or episode in which the location occurs. Thus, hippocampal neurons fire differently in the same location depending on the particular journey or sequence of places in which the subject is traveling. Further, recent work in rats has shown that hippocampal lesions impair memory for sequences of odors and the ability to disambiguate overlapping sequences of odors. We therefore recorded the activity of hippocampal complex-spike cells during a disambiguation of odor sequences task in which the two sequences shared three common odors. Consistent with data from spatial memory tasks, we found that 26 of 44 complex-spike cells fired differentially in the periods before, or during the presentation of the ambiguous odors depending on the sequence in which the odors were presented. This finding further supports the idea that the hippocampus is critical for episodic memory, and extends the physiological evidence to suggest that the hippocampal neurons play a broader role representing sequences of both spatial and nonspatial information. PMID- 21325540 TI - Dynamic causal modeling of subcortical connectivity of language. AB - Subcortical-cortical interactions in the language network were investigated using dynamic causal modeling of magnetoencephalographic data recorded during auditory comprehension. Participants heard sentences that either were correct or contained violations. Sentences containing violations had syntactic or prosodic violations or both. We show that a hidden source, modeling magnetically silent deep nuclei, is required to explain the data best. This is in line with recent brain imaging studies and intracranial recordings suggesting an involvement of subcortical structures in language processing. Here, the processing of syntactic and prosodic violations elicited a global increase in the amplitude of evoked responses, both at the cortical and subcortical levels. As estimated by Bayesian model averaging, this was accompanied by various changes in cortical-cortical and subcortical cortical connectivity. The most consistent findings in relation to violations were a decrease of reentrant inputs to Heschl's gyrus (HG) and of transcallosal lateral connections. These results suggest that in conditions where one hemisphere detects a violation, possibly via fast thalamocortical (HG) loops, the intercallosal connectivity is reduced to allow independent processing of syntax (left hemisphere) and of prosody (right hemisphere). This study is the first demonstration in cognitive neuroscience that subcortical-cortical loops can be empirically investigated using noninvasive electrophysiological recordings. PMID- 21325541 TI - Simultaneous detection and identification of Aspergillus and mucorales species in tissues collected from patients with fungal rhinosinusitis. AB - Rapid detection and differentiation of Aspergillus and Mucorales species in fungal rhinosinusitis diagnosis are desirable, since the clinical management and prognosis associated with the two taxa are fundamentally different. We describe an assay based on a combination of broad-range PCR amplification and reverse line blot hybridization (PCR/RLB) to detect and differentiate the pathogens causing fungal rhinosinusitis, which include five Aspergillus species (A. fumigatus, A. flavus, A. niger, A. terreus, and A. nidulans) and seven Mucorales species (Mucor heimalis, Mucor racemosus, Mucor cercinelloidea, Rhizopus arrhizus, Rhizopus microsporus, Rhizomucor pusillus, and Absidia corymbifera). The assay was validated with 98 well-characterized clinical isolates and 41 clinical tissue specimens. PCR/RLB showed high sensitivity and specificity, with 100% correct identifications of 98 clinical isolates and no cross-hybridization between the species-specific probes. Results for five control isolates, Candida albicans, Fusarium solani, Scedosporium apiospermum, Penicillium marneffei, and Exophiala verrucosa, were negative as judged by PCR/RLB. The analytical sensitivity of PCR/RLB was found to be 1.8 * 10(-3) ng/MUl by 10-fold serial dilution of Aspergillus genomic DNA. The assay identified 35 of 41 (85.4%) clinical specimens, exhibiting a higher sensitivity than fungal culture (22 of 41; 53.7%) and direct sequencing (18 of 41; 43.9%). PCR/RLB similarly showed high specificity, with correct identification 16 of 18 specimens detected by internal transcribed spacer (ITS) sequencing and 16 of 22 detected by fungal culture, but it also has the additional advantage of being able to detect mixed infection in a single clinical specimen. The PCR/RLB assay thus provides a rapid and reliable option for laboratory diagnosis of fungal rhinosinusitis. PMID- 21325542 TI - International external quality assurance for laboratory identification and typing of Streptococcus agalactiae (Group B streptococci). AB - We report the results from the first international multicenter external quality assessment (EQA) studies for molecular and serological typing of group B streptococcus (GBS) strains as part of DEVANI (Design of a Vaccine against Neonatal Infections), a pan-European program. A questionnaire-based surveillance was undertaken among eight laboratories participating in DEVANI and six laboratories not participating in DEVANI from 13 countries in order to assess their current microbiological procedures for GBS screening, diagnosis, and typing. GBS strains from three EQA distributions were characterized using molecular and serological methods based on GBS capsular polysaccharide typing. Participants were asked to test the first distribution using their current serotyping and genotyping methods. The Strep-B-Latex agglutination method was the most widely used method, with a typeability value of >90%. A multiplex PCR assay for GBS capsular gene typing was also used by 2 of 14 centers, which achieved a typeability value of 93%; this assay detected only 9 of 10 GBS capsular polysaccharide genes. From the second and third EQA studies, standardized protocols were prepared for serological and molecular typing of GBS strains based on the Strep-B-Latex agglutination method and a novel multiplex PCR assay that detected all 10 GBS capsular types (Ia to IX). These standardized protocols are being used by many European laboratories, and as the use of these methods increases, it is imperative to continuously improve and assess laboratory performance and offer training to any laboratories that have technical difficulties. PMID- 21325544 TI - Automated extraction and amplification for direct detection of Mycobacterium tuberculosis complex in various clinical samples. PMID- 21325545 TI - First cases of microsporidiosis in transplant recipients in Spain and review of the literature. AB - Microsporidia are currently considered emerging pathogens responsible for life threatening infections in organ transplant recipients. Here, we describe the first cases of intestinal microsporidiosis by Enterocytozoon bieneusi genotype D in two non-HIV-infected renal transplant recipients from Spain. Previously reported cases of microsporidiosis in organ transplant recipients have also been reviewed, highlighting the necessity of considering organ transplant recipients a risk group for microsporidiosis. A systematic search for these parasites is recommended in cases of persistent diarrhea and in the differential diagnosis of other syndromes, such as chronic fever of unknown etiology. PMID- 21325546 TI - Evaluation of the Abbott RealTime CT/NG assay in comparison to the Roche Cobas Amplicor CT/NG assay. AB - Several commercial methods exist for the molecular detection of Chlamydia trachomatis and Neisseria gonorrhoeae in clinical samples. Here we evaluated the performance characteristics of the newly FDA-cleared Abbott RealTime CT/NG assay (where "CT" stands for Chlamydia trachomatis and "NG" stands for Neisseria gonorrhoeae) that uses the automated m2000 molecular platform. Results were compared to those of the Roche Cobas Amplicor CT/NG assay. A total of 926 cervical swab, 45 female urine, 6 male urethral swab, and 407 male urine specimens from 1,384 patients were examined. After resolving all Roche N. gonorrhoeae-positive results with two additional real-time PCR assays, we found that the agreement between the assays was excellent. For urine samples, there was 99.6% positive agreement and 97.7% negative agreement for C. trachomatis, and for male urine samples, there was 100% positive agreement and 99.7% negative agreement for N. gonorrhoeae. For cervical swab samples, there was 98.8% positive agreement and 98.5% negative agreement for C. trachomatis, and there was 96.6% positive agreement and 99.8% negative agreement for N. gonorrhoeae. In limiting dilution analyses, we found that the Abbot assay was more sensitive than the Roche assay for both C. trachomatis and N. gonorrhoeae. In addition, there appeared to be an enhanced ability of the Abbott assay to detect dual infections, especially in the presence of large amounts of N. gonorrhoeae and small amounts of C. trachomatis organisms. In summary, we conclude that the Abbott RealTime CT/NG assay is an accurate and automated new addition to the available testing options for C. trachomatis and N. gonorrhoeae. PMID- 21325547 TI - Evaluation of a DNA microarray (Check-MDR CT102) for rapid detection of TEM, SHV, and CTX-M extended-spectrum beta-lactamases and of KPC, OXA-48, VIM, IMP, and NDM 1 carbapenemases. AB - The Check-MDR CT102 microarray, aimed at identifying bacteria producing extended spectrum beta-lactamase (ESBL) (SHV, TEM, and CTX-M) and carbapenemase (KPC, OXA 48, VIM, IMP, and NDM-1), was evaluated on a total of 144 Gram-negative strains expressing various beta-lactamases. The sensitivity and specificity were 100% for most tested genes, suggesting that this assay allows accurate identification of common ESBL and carbapenemase producers from bacterial cultures. PMID- 21325543 TI - Molecular phylogeny of Coxsackievirus A16 in Shenzhen, China, from 2005 to 2009. AB - Phylogenetic analysis of a Coxsackievirus A16 (CA16) sequence from Shenzhen, China, and other Chinese and international CA16 sequences revealed a pattern of endemic cocirculation of strains of clusters B2a and B2b within subtype B2 viruses. Amino acid evolution and nucleotide variation in the VP1 region were slight for 5 years. PMID- 21325548 TI - First characterization of CTX-M-15-producing Escherichia coli ST131 and ST405 clones causing community-onset infections in South America. AB - CTX-M-15-producing Escherichia coli has emerged worldwide as an important pathogen associated with community-onset infections, but in South America reports are scarce. We document the presence of CTX-M-15-producing E. coli of the international ST131 and ST405 clones in Colombia and present the first molecular characterization of these isolates in South America. PMID- 21325549 TI - Complete genome sequence of a Yersinia enterocolitica "Old World" (3/O:9) strain and comparison with the "New World" (1B/O:8) strain. AB - Yersinia enterocolitica is a heterogeneous bacterial species with a wide range of animal reservoirs through which human intestinal illness can be facilitated. In contrast to the epidemiological pattern observed in the United States, infections in China present a pattern similar to those in European countries and Japan, wherein "Old World" strains (biotypes 2 to 5) are prevalent. To gain insights into the evolution of Y. enterocolitica and pathogenic properties toward human hosts, we sequenced the genome of a biotype 3 strain, 105.5R(r) (O:9), obtained from a Chinese patient. Comparative genome sequence analysis with strain 8081 (1B/O:8) revealed new insights into Y. enterocolitica. Both strains have more than 14% specific genes. In strain 105.5R(r), putative virulence factors were found in strain-specific genomic pathogenicity islands that comprised a novel type III secretion system and rtx-like genes. Many of the loci representing ancestral clusters, which are believed to contribute to enteric survival and pathogenesis, are present in strain 105.5R(r) but lost in strain 8081. Insertion elements in 105.5R(r) have a pattern distinct from those in strain 8081 and were exclusively located in a strain-specific region. In summary, our comparative genome analysis indicates that these two strains may have attained their pathogenicity by completely separate evolutionary events, and the 105.5R(r) strain, a representative of the Old World biogroup, lies in a branch of Y. enterocolitica that is distinct from the "New World" 8081 strain. PMID- 21325550 TI - Clinical significance of Propionibacterium acnes recovered from blood cultures: analysis of 524 episodes. AB - Of 522 patients with Propionibacterium acnes bacteremia (PAB), 18 (3.5%) had clinically significant PAB. Of these 18 patients, 10 (55.6%) had hospital acquired bacteremia and 6 (33.3%) had undergone invasive procedures before development of PAB. One patient with a ventricular septal defect presented with infective endocarditis. After the exclusion of 1 patient whose outcome was not available, the overall mortality rate was 5.9% (1/17). PMID- 21325551 TI - Development of a real-time PCR assay for detecting and quantifying human bocavirus 2. AB - Human bocavirus 2 (HBoV2) is a parvovirus that has been recently identified in stool samples from children. Any association between the virus and clinical disease is unclear. A rapid, reliable diagnostic method is necessary to address this issue. In this study, we developed a sensitive and specific HBoV2 quantitative real-time PCR assay that targets the HBoV2 NP-1 gene, based on the TaqMan method. The assay could reproducibly detect 10 copies of a recombinant DNA plasmid containing a partial region of the HBoV2 genome, with a dynamic range of 8 log units (10(1) to 10(8) copies). A clinical evaluation detected HBoV2 in 85 (24.6%) of 345 children with gastroenteritis, with viral loads ranging from 1.67 * 10(2) to 4.27 * 10(9) copies per ml of stool specimen. PMID- 21325552 TI - Rapid genotyping of human papillomavirus by post-PCR array-based hybridization techniques. AB - Kinetic hybridization measurements on a microarray are expected to become a valuable tool for genotyping applications. A method has been developed that enables kinetic hybridization measurements of PCR products on a low-density microarray. This is accomplished by pumping a solution containing PCR products up and down through a porous microarray substrate. After every pumping cycle, the fluorescently labeled PCR products hybridized to capture probes immobilized on the solid surface of the porous microarray substrate are measured. By this method, both binding curves and high-resolution melting curves are obtained instead of the single endpoint hybridization intensities as with commonly used post-PCR array-based hybridization techniques. We used 20 subtypes of the human papillomavirus (HPV) as a model system to test our detection method and blindly analyzed 216 clinical samples. We compared our microarray flowthrough method with a reference method, PCR followed by a reverse line blot (RLB). Real-time hybridization measurements followed by high-resolution melting curves of low concentrations of fluorescently labeled HPV targets on a microarray were successfully carried out without any additional chemical signal amplification. The results of our new method were in good agreement (93%, with a kappa coefficient of kappa = 0.88 [95% CI, 0.81 to 0.94]) with the RLB results. All discrepant samples were analyzed by a third method, enzyme immunoassay (EIA). Furthermore, in a number of cases, we were able to identify false-positive samples by making use of the information contained in the kinetic binding and melting curves. This clearly demonstrates the added value of the use of kinetic measurements and high-resolution melting curves, especially for highly homologous targets. PMID- 21325553 TI - Comparison of clinical performance of Abbott RealTime High Risk HPV test with that of hybrid capture 2 assay in a screening setting. AB - Randomized trials have produced sound evidence about the efficacy of screening with human papillomavirus (HPV) DNA tests in reducing cervical cancer incidence and mortality. We evaluated the clinical performance and reproducibility of the Abbott RealTime High Risk (HR) HPV test compared with that of the HR hybrid capture 2 (HC2) assay as assessed by a noninferiority score test. A random sample of 998 cervical specimens (914 specimens of cervical intraepithelial neoplasia less severe than grade 2 [=CIN2]), collected in the Florence and Catania cervical Cancer Screening Programs from women aged 25 to 64 and already tested by HR HC2, were retested with the Abbott RealTime HR HPV test. Absolute specificity was 92.3% (95% confidence interval [CI], 90.4 to 94.0) and 92.6% (95% CI, 90.7 to 94.2) for the Abbott RealTime HR HPV test and the HR HC2, respectively. Absolute sensitivity was 96.4% (95% CI, 89.9 to 99.3) and 97.6% (95% CI, 91.7 to 99.7) for the Abbott RealTime HR HPV test and the HR HC2, respectively. The noninferiority score test revealed that the clinical sensitivity and specificity of the Abbott RealTime HR HPV test were not inferior (P = 0.004 and 0.009, respectively) to those of HR HC2. Overall agreement between the two assays was 96.5%, with a k value of 0.86 (CI 95%, 0.82 to 0.91). We evaluated the intralaboratory reproducibility by retesting 521 samples at least 4 weeks after the first test; the crude agreement between the first and second test was 98.5%, with an overall k value of 0.97 (CI 95%, 0.95 to 0.99). This test fully satisfies the requirements of a primary cervical cancer screening test. This assay differentiates between HPV16, HPV18, and non-HPV16/18 types in every specimen, but how to use this information in a screening setting still is unclear. PMID- 21325554 TI - Fecal leukocytes in children infected with diarrheagenic Escherichia coli. AB - The purpose of this study was to determine the presence and quantity of fecal leukocytes in children infected with diarrheagenic Escherichia coli and to compare these levels between diarrhea and control cases. We analyzed 1,474 stool samples from 935 diarrhea episodes and 539 from healthy controls of a cohort study of children younger than 2 years of age in Lima, Peru. Stools were analyzed for common enteric pathogens, and diarrheagenic E. coli isolates were studied by a multiplex real-time PCR. Stool smears were stained with methylene blue and read by a blinded observer to determine the number of polymorphonuclear leukocytes per high-power field (L/hpf). Fecal leukocytes at >10 L/hpf were present in 11.8% (110/935) of all diarrheal episodes versus 1.1% (6/539) in controls (P < 0.001). Among stool samples with diarrheagenic E. coli as the only pathogen isolated (excluding coinfection), fecal leukocytes at >10 L/hpf were present in 8.5% (18/212) of diarrhea versus 1.3% (2/157) of control samples (P < 0.01). Ninety five percent of 99 diarrheagenic E. coli diarrhea samples were positive for fecal lactoferrin. Adjusting for the presence of blood in stools, age, sex, undernutrition, and breastfeeding, enterotoxigenic E. coli (ETEC) isolation as a single pathogen, excluding coinfections, was highly associated with the presence of fecal leukocytes (>10 L/hpf) with an odds ratio (OR) of 4.1 (95% confidence interval [CI], 1.08 to 15.51; P < 0.05). Although diarrheagenic E. coli was isolated with similar frequencies in diarrhea and control samples, clearly it was associated with a more inflammatory response during symptomatic infection; however, in general, these pathogens elicited a mild inflammatory response. PMID- 21325556 TI - Characterization of 2009 pandemic influenza A (H1N1) virus specimens with a positive hemagglutinin 1 signal in the Luminex xTAG respiratory viral panel assay. AB - This retrospective review analyzed Luminex xTAG respiratory viral panel (RVP) results for 2009 pandemic influenza A (H1N1) virus specimens. Comparing median fluorescence intensity (MFI) signals for the influenza A virus and hemagglutinin 1 (H1) reactions for specimens with very low positive (MFI < 1,000) or "no-call" H1 results reliably distinguished 2009 H1N1 from seasonal virus. PMID- 21325555 TI - Clinical and laboratory characteristics of invasive infections due to methicillin resistant Staphylococcus aureus isolates demonstrating a vancomycin MIC of 2 micrograms per milliliter: lack of effect of heteroresistant vancomycin intermediate S. aureus phenotype. AB - We describe clinical and laboratory characteristics of invasive methicillin resistant Staphylococcus aureus (MRSA) infections with vancomycin MICs of 2 MUg/ml and compare heteroresistant-intermediate S. aureus (hVISA) to non-hVISA. Health care-associated community-onset infections were the most common and resulted in frequent complications and relapses. hVISA-infected patients were more likely to have been hospitalized in the year prior to MRSA culture. PMID- 21325557 TI - Development and validation of a multiplex PCR for detection of Scedosporium spp. in respiratory tract specimens from patients with cystic fibrosis. AB - The emergence of Scedosporium infections in diverse groups of individuals, which are often treatment refractory, warrants timely and accurate laboratory diagnosis. Species- or group-specific primers based on internal transcribed spacer (ITS) sequence polymorphisms were designed for Scedosporium aurantiacum, Scedosporium dehoogii, Scedosporium prolificans, Pseudallescheria boydii species complex (former clade 5)/Pseudallescheria apiosperma (formerly classified as S. apiospermum sensu lato) and Pseudallescheria minutispora. Primers for S. aurantiacum, S. prolificans, and P. boydii species complex/P. apiosperma were incorporated into a multiplex PCR assay for the detection and identification of the three major clinically important Scedosporium species and validated using sputum specimens collected from patients seen at a major Australian cystic fibrosis clinic. The multiplex PCR assay showed 100% specificity in identifying the three major clinically relevant Scedosporium species from pure culture. When evaluated using DNA extracts from sputa, sensitivity and specificity of the multiplex PCR assay were 62.1% and 97.2%, respectively. This highly species specific multiplex PCR assay offers a rapid and simple method of detection of the most clinically important Scedosporium species in respiratory tract specimens. PMID- 21325558 TI - New Delhi metallo-beta-lactamase (NDM-1)-producing Klebsiella pneumoniae: case report and laboratory detection strategies. AB - The spread of antimicrobial resistance among Enterobacteriaceae is a significant clinical threat. We report the first case of an Enterobacteriaceae strain harboring the NDM-1 metallo-beta-lactamase in a pediatric patient in the United States. We describe strategies for the detection of this novel resistance mechanism encountered in an isolate of Klebsiella pneumoniae. PMID- 21325559 TI - Preferential deletion events in the direct repeat locus of Mycobacterium tuberculosis. AB - The "Harlingen" IS6110 restriction fragment length polymorphism (RFLP) cluster has linked over 100 tuberculosis cases in The Netherlands since 1993. Four Mycobacterium tuberculosis isolates that were epidemiologically linked to this cluster had different spoligotype patterns, as well as slightly divergent IS6110 profiles, compared to the majority of the isolates. Sequencing of the direct repeat (DR) locus revealed sequence polymorphisms at the putative deletion sites. These deletion footprints provided evidence for independent deletions of the central region of the DR locus in three isolates, while the different genotype of the fourth isolate was explained by transmission. Our finding suggests that convergent deletions in the DR locus occur frequently. However, deletion footprints are not suitable to detect convergent deletions in the DR because they seem to be exceptional. Deletion footprints in the DR were not described previously, and we did not observe them in any public M. tuberculosis complex sequences. We conclude that preferential deletions in the DR loci of closely related strains are usually an unnoted event that interferes with clustering of closely related strains. PMID- 21325560 TI - Reevaluating and optimizing polyomavirus BK and JC real-time PCR assays to detect rare sequence polymorphisms. AB - PCR-based molecular assays have a central role in polyomavirus diagnostics. To assure optimal performance, target sequences should be regularly updated according to newly available sequences. The aim of this study was to review our in-house polyomavirus BK (BKV) and JC (JCV) real-time PCR assays. Database analysis revealed variations in the BKV target region which might affect the assay performance, while no significant changes were found in the JCV target region. We compared two degenerate versions of our BKV primers which accommodated at least 95% of all published genetic variants. Dilutions of cloned viral genomic DNA and probit analysis indicated an analytical sensitivity of the updated BKV assay of 4.15 copies/reaction and that of the JCV assay was 3.37 copies/reaction. The specificity was assessed by testing JCV- and BKV-positive samples that showed no cross-reactivity. The performance of the original and updated BKV assay was compared in 101 urine and 200 plasma samples submitted to our routine diagnostic laboratory revealed similar quantitative results. We conclude that our JCV and updated BKV real-time PCR assays are robust and detect rare variants possibly encountered in the clinical routine. PMID- 21325561 TI - Transmission of methicillin-resistant Staphylococcus aureus between human and hamster. AB - Transmission of methicillin-resistant Staphylococcus aureus (MRSA) between humans and animals is increasingly recognized. We newly document that the transmission of MRSA between human and hamster is possible. PMID- 21325562 TI - Genotypes and characteristics of clustering and drug susceptibility of Mycobacterium tuberculosis isolates collected in Heilongjiang Province, China. AB - For the last decade China has occupied second place, after India, among the top five countries with high burdens of tuberculosis (TB). Heilongjiang Province is located in northeastern China. The prevalence of drug-resistant TB in Heilongjiang Province is higher than the average level in China. To determine the transmission characteristics of Mycobacterium tuberculosis strains isolated in this area and their genetic relationships, especially among the Beijing family strains, we investigated their genotypes. From May 2007 to October 2008, 200 M. tuberculosis isolates from patients presenting pulmonary TB were analyzed by molecular typing using PCR-based methods: spacer-oligonucleotide typing (spoligotyping), Beijing family-specific PCR (detection of the deletion of region of difference 105 [RD105]), and mycobacterial interspersed repetitive-unit variable-number tandem-repeat (MIRU-VNTR) analysis. Different combinations of MIRU-VNTR loci were evaluated to define the genotypes and clustering characteristics of the local strains. We found that Beijing family strains represented 89.5% of the isolates studied. However, the rates of multidrug resistant (MDR) M. tuberculosis among Beijing and non-Beijing family strains were not statistically different. The 15-locus set is considered the optimal MIRU-VNTR locus combination for analyzing the M. tuberculosis strains epidemic in this area, while the 10-locus set is an ideal set for first-line molecular typing. We found that the clustering rate of all the M. tuberculosis isolates analyzed was 10.0% using the 15-locus set typing. We conclude that the Beijing family genotype is predominant and that highly epidemic TB and MDR TB are less likely associated with the active transmission of M. tuberculosis in the study area. PMID- 21325563 TI - Reduction of ovarian and oviductal cancers in calorie-restricted laying chickens. AB - Epithelial ovarian cancer (OVAC) remains a highly lethal malignancy. It is a leading cause of cancer deaths among women in the United States causing more deaths than all other gynecologic malignancies combined. The pathogenesis of OVAC is not completely understood, but the process of repeated ovulation is believed to lead to genetic damage in the ovarian epithelium. As part of a prospective trial designed to evaluate OVAC chemopreventive strategies using the chicken model, caloric restriction (55% less energy) was used to inhibit ovulation in groups of hens receiving chemopreventives, thereby minimizing the impact of ovulation on the incidence of reproductive tract cancer. A separate group of chickens was maintained concurrently in the same environment, and managed similarly, except that caloric intake was not restricted. Among birds not receiving chemopreventive agents, we compared caloric versus noncaloric restricted birds to determine the relations between calorie restriction and risk of developing adenocarcinoma of the reproductive tract. Mortality in the calorie restricted group was almost half that of those on full feed. Calorie-restricted chickens maintained body weights averaging 1.423 kg compared with the full-fed birds at 1.892 kg. Ovulation rate varied with the full-fed group producing 64% more eggs than the calorie-restricted group. Total reproductive cancers occurred in 57 (33.3%) birds for the full-fed group and 26 (10.3%) birds for the calorie restricted group. On the basis of histopathology, 45 (26.3%) birds in the full fed group had ovarian adenocarcinoma compared with 16 (6.3%) birds in the calorie restricted group. Calorie restriction in laying hens resulted in a near five-fold reduction in OVAC. PMID- 21325564 TI - Weight gain is associated with an increased risk of prostate cancer recurrence after prostatectomy in the PSA era. AB - Although obesity at the time of prostatectomy has been associated with prostate cancer recurrence, it is unknown whether obesity before or after surgery, or weight change from the years prior to surgery to after surgery is associated with recurrence. Thus, we examined the influence of obesity and weight change on recurrence after prostatectomy. We conducted a retrospective cohort study of 1,337 men with clinically localized prostate cancer who underwent prostatectomy performed during 1993-2006 by the same surgeon. Men self-reported weight and physical activity at 5 years before and 1 year after surgery on a survey during follow-up. Mean follow-up was 7.3 years. We estimated multivariable-adjusted HRs of prostate cancer recurrence comparing obesity at 5 years before and at 1 year after surgery with normal weight, and a gain of more than 2.2 kg from 5 years before to 1 year after surgery with stable weight. During 9,797 person years of follow-up, 102 men recurred. Compared with men who had stable weight, those whose weight increased by more than 2.2 kg had twice the recurrence risk (HR = 1.94; 95% CI, 1.14-3.32) after taking into account age, pathologic stage and grade, and other characteristics. The HR of recurrence was 1.20 (95% CI, 0.64-2.23) and 1.72 (95% CI, 0.94-3.14) comparing obesity at 5 years before and at 1 year after surgery, respectively, with normal weight. Physical activity (>= 5 h/wk) did not attenuate risk in men who gained more than 2.2 kg. By avoiding weight gain, men with prostate cancer may both prevent recurrence and improve overall well-being. PMID- 21325565 TI - High levels of bioplastic are produced in fertile transplastomic tobacco plants engineered with a synthetic operon for the production of polyhydroxybutyrate. AB - An optimized genetic construct for plastid transformation of tobacco (Nicotiana tabacum) for the production of the renewable, biodegradable plastic polyhydroxybutyrate (PHB) was designed using an operon extension strategy. Bacterial genes encoding the PHB pathway enzymes were selected for use in this construct based on their similarity to the codon usage and GC content of the tobacco plastome. Regulatory elements with limited homology to the host plastome yet known to yield high levels of plastidial recombinant protein production were used to enhance the expression of the transgenes. A partial transcriptional unit, containing genes of the PHB pathway and a selectable marker gene encoding spectinomycin resistance, was flanked at the 5' end by the host plant's psbA coding sequence and at the 3' end by the host plant's 3' psbA untranslated region. This design allowed insertion of the transgenes into the plastome as an extension of the psbA operon, rendering the addition of a promoter to drive the expression of the transgenes unnecessary. Transformation of the optimized construct into tobacco and subsequent spectinomycin selection of transgenic plants yielded T0 plants that were capable of producing up to 18.8% dry weight PHB in samples of leaf tissue. These plants were fertile and produced viable seed. T1 plants producing up to 17.3% dry weight PHB in samples of leaf tissue and 8.8% dry weight PHB in the total biomass of the plant were also isolated. PMID- 21325566 TI - Regulation of solute flux through plasmodesmata in the root meristem. AB - Plasmodesmata permit solutes to move between cells nonspecifically and without having to cross a membrane. This symplastic connectivity, while straightforward to observe using fluorescent tracers, has proven difficult to quantify. We use fluorescence recovery after photobleaching, combined with a mathematical model of symplastic diffusion, to assay plasmodesmata-mediated permeability in the Arabidopsis (Arabidopsis thaliana) root meristem in wild-type and transgenic lines, and under selected chemical treatments. The permeability measured for the wild type is nearly 10-times greater than previously reported. Plamodesmal permeability remains constant in seedlings treated with auxin (30 mM indoleacetic acid for 2 and 24 h; 100 nm indoleacetic acid for 2 h); however, permeability is diminished in two lines previously reported to have impaired plasmodesmal function as well as in wild-type seedlings treated for 24 h with 0.6 mM tryptophan. Moreover, plasmodesmal permeability is strongly altered by applied hydrogen peroxide within 2 h of treatment, being approximately doubled at a low concentration (0.6 mM) and nearly eliminated at a higher one (6 mM). These results reveal that the plasmodesmata in the root meristem carry a substantial flux of small molecules and that this flux is subject to rapid regulation. PMID- 21325567 TI - iTRAQ analysis reveals mechanisms of growth defects due to excess zinc in Arabidopsis. AB - The micronutrient zinc is essential for all living organisms, but it is toxic at high concentrations. Here, to understand the effects of excess zinc on plant cells, we performed an iTRAQ (for isobaric tags for relative and absolute quantification)-based quantitative proteomics approach to analyze microsomal proteins from Arabidopsis (Arabidopsis thaliana) roots. Our approach was sensitive enough to identify 521 proteins, including several membrane proteins. Among them, IRT1, an iron and zinc transporter, and FRO2, a ferric-chelate reductase, increased greatly in response to excess zinc. The expression of these two genes has been previously reported to increase under iron-deficient conditions. Indeed, the concentration of iron was significantly decreased in roots and shoots under excess zinc. Also, seven subunits of the vacuolar H(+) ATPase (V-ATPase), a proton pump on the tonoplast and endosome, were identified, and three of them decreased significantly in response to excess zinc. In addition, excess zinc in the wild type decreased V-ATPase activity and length of roots and cells to levels comparable to those of the untreated de-etiolated3-1 mutant, which bears a mutation in V-ATPase subunit C. Interestingly, excess zinc led to the formation of branched and abnormally shaped root hairs, a phenotype that correlates with decreased levels of proteins of several root hair-defective mutants. Our results point out mechanisms of growth defects caused by excess zinc in which cross talk between iron and zinc homeostasis and V-ATPase activity might play a central role. PMID- 21325570 TI - Proposals for change in orthopaedic education: recommendations from an orthopaedic residency directors' peer forum. PMID- 21325568 TI - Expression of antibody fragments with a controlled N-glycosylation pattern and induction of endoplasmic reticulum-derived vesicles in seeds of Arabidopsis. AB - Intracellular trafficking and subcellular deposition are critical factors influencing the accumulation and posttranslational modifications of proteins. In seeds, these processes are not yet fully understood. In this study, we set out to investigate the intracellular transport, final destination, N-glycosylation status, and stability of the fusion of recombinant single-chain variable fragments to the crystallizing fragment of an antibody (scFv-Fc) of two antiviral monoclonal antibodies (2G12 and HA78). The scFv-Fcs were expressed in Arabidopsis (Arabidopsis thaliana) seeds and leaves both as secretory molecules and tagged with an endoplasmic reticulum (ER) retention signal. We demonstrate differential proteolytic degradation of scFv-Fcs in leaves versus seeds, with higher degradation in the latter organ. In seeds, we show that secretory versions of HA78 scFv-Fcs are targeted to the extracellular space but are deposited in newly formed ER-derived vesicles upon KDEL tagging. These results are in accordance with the obtained N-glycosylation profiles: complex-type and ER-typical oligomannosidic N-glycans, respectively. HA78 scFv-Fcs, expressed in seeds of an Arabidopsis glycosylation mutant lacking plant-specific N-glycans, exhibit custom made human-type N-glycosylation. In contrast, 2G12 scFv-Fcs carry exclusively ER typical oligomannosidic N-glycans and were deposited in newly formed ER-derived vesicles irrespective of the targeting signals. HA78 scFv-Fcs exhibited efficient virus neutralization activity, while 2G12 scFv-Fcs were inactive. We demonstrate the efficient generation of scFv-Fcs with a controlled N-glycosylation pattern. However, our results also reveal aberrant subcellular deposition and, as a consequence, unexpected N-glycosylation profiles. Our attempts to elucidate intracellular protein transport in seeds contributes to a better understanding of this basic cell biological mechanism and is a step toward the versatile use of Arabidopsis seeds as an alternative expression platform for pharmaceutically relevant proteins. PMID- 21325571 TI - The rising incidence of acromioplasty. PMID- 21325573 TI - Comparison of a standard and a gender-specific posterior cruciate-substituting high-flexion knee prosthesis. A prospective, randomized, short-term outcome study. PMID- 21325575 TI - Relationship of neural axis level of injury to motor recovery and health-related quality of life in patients with a thoracolumbar spinal injury. PMID- 21325577 TI - Transepiphyseal replacement of the anterior cruciate ligament in skeletally immature patients: a preliminary report. PMID- 21325579 TI - Outcomes of an anatomic posterolateral knee reconstruction. PMID- 21325580 TI - Commentary on an article by Gaetano J. Scuderi, MD, et al.: "Identification of a novel fibronectin-aggrecan complex in the synovial fluid of knees with painful meniscal injury". PMID- 21325581 TI - Commentary on an article by Harry K.W. Kim, MD, MSc, FRCSC, et al.: "How much varus is optimal with proximal femoral osteotomy to preserve the femoral head in Legg-Calve-Perthes disease?". PMID- 21325583 TI - Preoperative alcohol screening scores: association with complications in men undergoing total joint arthroplasty. AB - BACKGROUND: The risks associated with preoperative alcohol misuse by patients before undergoing total joint arthroplasty are not well known, yet alcohol misuse by surgical patients is common and has been linked to an increased risk of complications after other procedures. The purpose of this study was to evaluate the association between a patient's preoperative standardized alcohol-misuse screening score and his or her risk of complications after total joint arthroplasty. METHODS: The Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) is an alcohol-misuse screening instrument administered annually to all patients receiving care through the Veterans Health Administration (VHA). The scores range from 0 to 12, with higher scores signifying greater and more frequent consumption. In a study of 185 male patients who had alcohol screening scores recorded in the year preceding surgery at a Palo Alto VHA facility, and who reported at least some alcohol use, we estimated the association between preoperative screening scores and the number of surgical complications in an age and comorbidity-adjusted regression analyses. RESULTS: Of the 185 patients reporting at least some drinking in the year before their total joint replacement, 17% (thirty-two) had an alcohol screening score suggestive of alcohol misuse; six of those thirty-two patients had one complication, four had two complications, and two had three complications. The screening scores were significantly related to the number of complications in a negative binomial regression analysis (exp[beta] = 1.29, p = 0.035), which demonstrated a 29% increase in the expected number of complications with every additional point of the screening score above 1, although with wide confidence intervals for the higher scores. CONCLUSIONS: Complications following total joint arthroplasty were significantly related to alcohol misuse in this group of male patients treated at a VHA facility. The AUDIT-C has three simple questions that can be incorporated into a preoperative evaluation and can alert the treatment team to patients with increased postoperative risk. Preoperative screening for alcohol misuse, and perhaps preoperative counseling or referral to treatment for heavy drinkers, may be indicated for patients who are to undergo total joint arthroplasty. PMID- 21325584 TI - Identification of a novel fibronectin-aggrecan complex in the synovial fluid of knees with painful meniscal injury. AB - BACKGROUND: Molecular biomarkers associated with knee pain may be useful as diagnostic modalities, prognostic indicators, and surrogate end points for therapeutic trials. The present study describes a novel complex of fibronectin and aggrecan that is present in the affected knee of patients with pain and meniscal abnormality. METHODS: The present prospective study included thirty patients with knee pain, mechanical symptoms, and magnetic resonance imaging findings that were positive for a meniscal tear who chose arthroscopic partial meniscectomy after unsuccessful nonoperative management. Synovial fluid was aspirated at the time of surgery and was assayed for the fibronectin-aggrecan complex with use of a heterogeneous enzyme-linked immunosorbent assay (ELISA). The results were compared with knee aspirates from ten asymptomatic volunteers with no pain who underwent magnetic resonance imaging of the knee. RESULTS: The mean optical density (and standard deviation) of the fibronectin-aggrecan complex was significantly greater in synovial fluid from knees undergoing arthroscopic surgery as compared with fluid from asymptomatic controls (13.29 +/- 8.48 compared with 0.03 +/- 0.09; p < 0.001). The mean age in the study group was significantly greater than in control group (46.0 +/- 12.6 compared with 38.5 +/- 6.0 years; p = 0.02), but controlling for age did not affect the results. Post hoc, an optical density cutoff value of 0.3 distinguished the study group from the control group with 100% accuracy. CONCLUSIONS: A novel fibronectin-aggrecan complex is present in the synovial fluid of painful knees with meniscal abnormality. The fibronectin-aggrecan complex may prove to be useful as a clinical biomarker or therapeutic target. Further research is warranted to correlate functional outcome after surgery with the fibronectin-aggrecan complex and other cartilage biomarkers. PMID- 21325585 TI - How much varus is optimal with proximal femoral osteotomy to preserve the femoral head in Legg-Calve-Perthes disease? AB - BACKGROUND: Although proximal femoral varus osteotomy is an established operative treatment for Legg-Calve-Perthes disease, there is a lack of data on how much varus at the osteotomy is optimal for preserving the spherical shape of the femoral head. The purpose of this study was to determine if there is a correlation between the amount of varus used and the Stulberg radiographic outcome at maturity and to determine if the varus angulation improved over time. METHODS: The database and the radiographs of fifty-two patients treated with proximal femoral varus osteotomy from a multicenter prospective study were analyzed. The neck-shaft angles were measured before the operation, after the operation, and at the time of final follow-up, and the amount of varus placed was correlated with the Stulberg outcome at skeletal maturity. Spearman correlations and logistic regression were used for statistical analysis. RESULTS: All patients were six years of age or older at the time of diagnosis (mean 8.0 +/- 1.4 years), and all were skeletally mature at the time of follow-up (mean age [and standard deviation] at the time of follow-up, 16.5 +/- 2.0 years). The mean neck-shaft angle was 138 degrees +/- 7 degrees preoperatively and 115 degrees +/- 11 degrees postoperatively with a mean varus change of 23 degrees +/- 10 degrees . No significant correlation was observed between the postoperative neck-shaft angle at maturity and the Stulberg outcome (r = -0.15, p = 0.17) and between the amount of varus placed and the Stulberg outcome (r = 0.14, p = 0.36). However, when the lateral pillar groups were analyzed separately with use of logistic regression, a significant relationship was observed for the lateral pillar group B (p = 0.025), with a higher postoperative neck-shaft angle having a greater probability of being associated with a Stulberg class-I or II outcome. At maturity, the mean neck-shaft angle had improved from 115 degrees +/- 11 degrees following the initial surgery to 124 degrees +/- 8 degrees . However, nineteen (37%) of the fifty-two patients showed no improvement (defined as a change of >5 degrees ) and fifteen (29%) of the fifty-two patients had an overriding greater trochanter. CONCLUSIONS: Contrary to the conventional belief, greater varus angulation does not necessarily produce better preservation of the femoral head following proximal femoral varus osteotomy. Given the results, our recommendation is to achieve 10 degrees to 15 degrees of varus correction when performing proximal femoral varus osteotomy on hips that are in the early stages of Legg Calve-Perthes disease. PMID- 21325586 TI - Osteoporosis as a risk factor for distal radial fractures: a case-control study. AB - BACKGROUND: Distal radial fractures occur earlier in life than hip and spinal fractures and may be the first sign of osteoporosis. The aims of this case control study were to compare the prevalence of osteopenia and osteoporosis between female and male patients with low-energy distal radial fractures and matched controls and to investigate whether observed differences in bone mineral density between patients and controls could be explained by potential confounders. METHODS: Six hundred and sixty-four female and eighty-five male patients who sustained a distal radial fracture, and 554 female and fifty-four male controls, were included in the study. All distal radial fractures were radiographically confirmed. Bone mineral density was assessed with use of dual x ray absorptiometry at the femoral neck, total hip (femoral neck, trochanter, and intertrochanteric area), and lumbar spine (L2-L4). A self-administered questionnaire provided information on health and lifestyle factors. RESULTS: The prevalence of osteoporosis was 34% in female patients and 10% in female controls. The corresponding values were 17% in male patients and 13% in male controls. In the age group of fifty to fifty-nine years, 18% of female patients and 5% of female controls had osteoporosis. In the age group of sixty to sixty-nine years, the corresponding values were 25% and 7%, respectively. In adjusted conditional logistic regression analyses, osteopenia and osteoporosis were significantly associated with distal radial fractures in women. Osteoporosis was significantly associated with distal radial fractures in men. CONCLUSIONS: The prevalence of osteoporosis in patients with distal radial fractures is high compared with that in control subjects, and osteoporosis is a risk factor for distal radial fractures in both women and men. Thus, patients of both sexes with an age of fifty years or older who have a distal radial fracture should be evaluated with bone densitometry for the possible treatment of osteoporosis. PMID- 21325587 TI - Total ankle replacement in patients with gouty arthritis. AB - BACKGROUND: Gout is the most common cause of inflammatory arthritis in men and older women. The purpose of this review was to assess prosthetic component stability, postoperative pain relief, functional outcome, and quality of life of patients with gouty ankle arthritis who were treated with total ankle replacement. METHODS: Sixteen patients (nineteen ankles) with chronic gout and a mean age (and standard deviation) of 65.2 +/- 5.5 years were treated with a non constrained three-component total ankle arthroplasty because of painful ankle arthritis. The average duration of follow-up was 5.1 +/- 2.5 years. Component stability was assessed with use of weight-bearing radiographs. Clinical outcomes were analyzed with use of a visual analogue scale (VAS) for pain, a 36-item short form health survey (SF-36), and the American Orthopaedic Foot & Ankle Society (AOFAS) hindfoot score. RESULTS: There were no intraoperative complications. In one patient, both arthroplasties were revised 4.7 years postoperatively because of painful prosthetic loosening. The average VAS score for pain decreased significantly from 7.5 +/- 1.8 (range, 5 to 10) to 1.2 +/- 1.3 (range, 0 to 3) (p < 0.001). All eight categories of the SF-36 score showed significant improvement (all p < 0.001). The average AOFAS hindfoot score increased significantly from 38 +/- 15 (range, 15 to 77) preoperatively to 75 +/- 13 (range, 54 to 92) postoperatively (p < 0.001). CONCLUSIONS: Total ankle replacement in patients with painful gouty ankle arthritis is associated with a low risk of intraoperative and postoperative complications and leads to significant pain relief, high patient satisfaction, and good functional results. PMID- 21325588 TI - Acetabular reconstruction with impaction bone-grafting and a cemented cup in patients younger than fifty years old: a concise follow-up, at twenty to twenty eight years, of a previous report. AB - In a previous report, we presented our results of forty-two acetabular reconstructions, performed with use of impaction bone-grafting and a cemented polyethylene cup, in thirty-seven patients who were younger than fifty years and had a minimum of fifteen years of follow-up. The present update study shows the results after twenty to twenty-eight years. Eight additional cups had to be revised--four because of aseptic loosening, three because of wear, and one during a revision of the stem. Three additional cups were considered loose on radiographs. Survivorship of the acetabular reconstructions, with an end point of revision for any reason, was 73% after twenty years and 52% after twenty-five years. With revision for aseptic loosening as the end point, survival was 85% after twenty years and 77% after twenty-five years; for signs of loosening on radiographs, survival was 71% at twenty years and 62% at twenty-five years. In conclusion, our previous results have declined but the technique of using impacted morselized bone graft and a cemented cup is useful for the purpose of restoring bone stock in young patients whose acetabular defects require primary or revision total hip arthroplasty. PMID- 21325589 TI - Effect of ACL transection on internal tibial rotation in an in vitro simulated pivot landing. AB - BACKGROUND: The amount of resistance provided by the ACL (anterior cruciate ligament) to axial tibial rotation remains controversial. The goal of this study was to test the primary hypotheses that ACL transection would not significantly affect tibial rotation under the large impulsive loads associated with a simulated pivot landing but would increase anterior tibial translation. METHODS: Twelve cadaveric knees (mean age of donors [and standard deviation] at the time of death, 65.0 +/- 10.5 years) were mounted in a custom testing apparatus to simulate a single-leg pivot landing. A compound impulsive load was applied to the distal part of the tibia with compression (~800 N), flexion moment (~40 N-m), and axial tibial torque (~17 N-m) in the presence of five trans-knee muscle forces. A differential variable reluctance transducer mounted on the anteromedial aspect of the ACL measured relative strain. With the knee initially in 15 degrees of flexion, and after five combined compression and flexion moment (baseline) loading trials, six trials were conducted with the addition of either internal or external tibial torque (internal or external loading), and then six baseline trials were performed. The ACL was then sectioned, six baseline trials were repeated, and then six trials of either the internal or the external loading condition, whichever had initially resulted in the larger relative ACL strain, were carried out. Tibiofemoral kinematics were measured optoelectronically. The results were analyzed with a nonparametric Wilcoxon signed-rank test. RESULTS: Following ACL transection, the increase in the normalized internal tibial rotation was significant but small (0.7 degrees /N-m +/- 0.3 degrees /N-m to 0.8 degrees /N-m +/- 0.3 degrees /N-m, p = 0.012), while anterior tibial translation increased significantly (3.8 +/- 2.9 to 7.0 +/- 2.9 mm, p = 0.017). CONCLUSIONS: ACL transection leads to a small increase in internal tibial rotation, equivalent to a 13% decrease in the dynamic rotational resistance, under the large forces associated with a simulated pivot landing, but it leads to a significant increase in anterior tibial translation. PMID- 21325591 TI - A preoperative smoking cessation intervention increases postoperative quit rates and may reduce postoperative morbidity. PMID- 21325590 TI - Effect of short-duration low-magnitude cyclic loading versus immobilization on tendon-bone healing after ACL reconstruction in a rat model. AB - BACKGROUND: Successful anterior cruciate ligament reconstruction with use of soft tissue grafts requires healing between tendon and bone. Little is known about the effect of mechanical load on the cellular and molecular cascade of tendon-to-bone healing. Understanding these mechanical influences has critical implications for postoperative rehabilitation following anterior cruciate ligament reconstruction. The purpose of this study was to test the hypothesis that, compared with perioperative immobilization, short-duration low-magnitude cyclic axial loading would result in impaired tendon-to-bone healing after anterior cruciate ligament reconstruction in a rat model. METHODS: Fifty-two male Sprague-Dawley rats underwent anterior cruciate ligament reconstruction with use of a flexor digitorum longus autograft. The patellar tendon, capsule, and ligamentous structures were circumferentially released, and an external fixator parallel to the anterior cruciate ligament graft was placed across the knee. Mechanical loading, consisting of cyclic displacement of the femur and tibia constrained to axial translation parallel to the graft, was applied daily. The rats were randomly assigned to immobilization or daily loading, for fourteen or twenty eight days. Biomechanical, micro-computed tomographic, and histomorphometric analysis was performed on the bone-tendon-bone complexes. RESULTS: The load measured across the knees during cyclic displacement increased over time (p < 0.05). Load-to-failure testing of the isolated femur-anterior cruciate ligament graft-tibia specimens revealed no significant differences between groups at two or four weeks. By two weeks postoperatively, a greater number of ED1+ inflammatory macrophages (phagocytic cells involved in the initial injury response) were seen at the tendon-bone interface after loading in the cyclically loaded group than in the immobilized group (p = 0.01). Compared with the baseline values, the number of trabeculae was significantly lower after loading for four weeks (p = 0.02). CONCLUSIONS: Short-duration low-magnitude cyclic axial loading of the anterior cruciate ligament graft in the postoperative period is not detrimental to the strength of the healing tendon-bone interface but appears to be associated with greater inflammation and less bone formation in the tunnel in this rat model. PMID- 21325592 TI - Rehabilitation and early anterior cruciate ligament reconstruction was not better than rehabilitation and delayed reconstruction. PMID- 21325593 TI - A gender-specific prosthesis was similar to a standard prosthesis in women having total knee replacement. PMID- 21325594 TI - Modifiable risk factors for surgical site infection. PMID- 21325595 TI - What's new in foot and ankle surgery. AB - This update summarizes recent research pertaining to the subspecialty of orthopaedic foot and ankle surgery that was published or presented between August 2009 and July 2010. The sources of these studies include The Journal of Bone and Joint Surgery (American and British Volumes), Foot & Ankle International, and the proceedings of Specialty Day at the annual meeting of the American Academy of Orthopaedic Surgeons (AAOS), held on March 13, 2010, in New Orleans, Louisiana, and the summer meeting of the American Orthopaedic Foot & Ankle Society (AOFAS), held on July 7 through 10, 2010, in National Harbor, Maryland. PMID- 21325596 TI - Myelodysplasia and leukemia of Fanconi anemia are associated with a specific pattern of genomic abnormalities that includes cryptic RUNX1/AML1 lesions. AB - Fanconi anemia (FA) is a genetic condition associated with bone marrow (BM) failure, myelodysplasia (MDS), and acute myeloid leukemia (AML). We studied 57 FA patients with hypoplastic or aplastic anemia (n = 20), MDS (n = 18), AML (n = 11), or no BM abnormality (n = 8). BM samples were analyzed by karyotype, high density DNA arrays with respect to paired fibroblasts, and by selected oncogene sequencing. A specific pattern of chromosomal abnormalities was found in MDS/AML, which included 1q+ (44.8%), 3q+ (41.4%), -7/7q (17.2%), and 11q- (13.8%). Moreover, cryptic RUNX1/AML1 lesions (translocations, deletions, or mutations) were observed for the first time in FA (20.7%). Rare mutations of NRAS, FLT3-ITD, MLL-PTD, ERG amplification, and ZFP36L2-PRDM16 translocation, but no TP53, TET2, CBL, NPM1, and CEBPalpha mutations were found. Frequent homozygosity regions were related not to somatic copy-neutral loss of heterozygosity but to consanguinity, suggesting that homologous recombination is not a common progression mechanism in FA. Importantly, the RUNX1 and other chromosomal/genomic lesions were found at the MDS/AML stages, except for 1q+, which was found at all stages. These data have implications for staging and therapeutic managing in FA patients, and also to analyze the mechanisms of clonal evolution and oncogenesis in a background of genomic instability and BM failure. PMID- 21325598 TI - The incidence, risk factors, and outcome of transfusion-related acute lung injury in a cohort of cardiac surgery patients: a prospective nested case-control study. AB - Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion related morbidity and mortality. Both antibodies and bioactive lipids that have accumulated during storage of blood have been implicated in TRALI pathogenesis. In a single-center, nested, case-control study, patients were prospectively observed for onset of TRALI according to the consensus definition. Of 668 patients, 16 patients (2.4%) developed TRALI. Patient-related risk factors for onset of TRALI were age and time on the cardiopulmonary bypass. Transfusion related risk factors were total amount of blood products (odds ratio [OR] = 1.2; 95% confidence interval [CI], 1.03-1.44), number of red blood cells stored more than 14 days (OR = 1.6; 95% CI, 1.04-2.37), total amount of plasma (OR = 1.2; 95% CI, 1.03-1.44), presence of antibodies in donor plasma (OR = 8.8; 95% CI, 1.8 44), and total amount of transfused bioactive lipids (OR = 1.0; 95% CI, 1.00 1.07). When adjusted for patient risk factors, only the presence of antibodies in the associated blood products remained a risk factor for TRALI (OR = 14.2; 95% CI, 1.5-132). In-hospital mortality of TRALI was 13% compared with 0% and 3% in transfused and nontransfused patients, respectively (P < .05). In conclusion, the incidence of TRALI is high in cardiac surgery patients and associated with adverse outcome. Our results suggest that cardiac surgery patients may benefit from exclusion of blood products containing HLA/HNA antibodies. PMID- 21325597 TI - Gene expression profiling of peripheral blood mononuclear cells from children with active hemophagocytic lymphohistiocytosis. AB - Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, genetically heterogeneous autosomal recessive immune disorder that results when the critical regulatory pathways that mediate immune defense mechanisms and the natural termination of immune/inflammatory responses are disrupted or overwhelmed. To advance the understanding of FHL, we performed gene expression profiling of peripheral blood mononuclear cells from 11 children with untreated FHL. Total RNA was isolated and gene expression levels were determined using microarray analysis. Comparisons between patients with FHL and normal pediatric controls (n = 30) identified 915 down-regulated and 550 up-regulated genes with more than or equal to 2.5-fold difference in expression (P <= .05). The expression of genes associated with natural killer cell functions, innate and adaptive immune responses, proapoptotic proteins, and B- and T-cell differentiation were down regulated in patients with FHL. Genes associated with the canonical pathways of interleukin-6 (IL-6), IL-10 IL-1, IL-8, TREM1, LXR/RXR activation, and PPAR signaling and genes encoding of antiapoptotic proteins were overexpressed in patients with FHL. This first study of genome-wide expression profiling in children with FHL demonstrates the complexity of gene expression patterns, which underlie the immunobiology of FHL. PMID- 21325599 TI - Treosulfan-based conditioning regimens for hematopoietic stem cell transplantation in children with primary immunodeficiency: United Kingdom experience. AB - Children with primary immunodeficiency diseases, particularly those less than 1 year of age, experience significant toxicity after hematopoietic stem cell transplantation, with busulfan- or melphalan-based conditioning. Treosulfan causes less veno-occlusive disease than busulfan and does not require pharmacokinetic monitoring. We report its use in 70 children. Children received 42 g/m(2) or 36 g/m(2) with cyclophosphamide 200 mg/kg (n = 30) or fludarabine 150 mg/m(2) (n = 40), with alemtuzumab in most. Median age at transplantation was 8.5 months (range, 1.2-175 months); 46 (66%) patients were 12 months of age or younger. Donors were as follows: matched sibling donor, 8; matched family donor, 13; haploidentical, 4; and unrelated, 45. Median follow-up was 19 months (range, 1-47 months). Overall survival was 81%, equivalent in those age less or greater than 1 year. Skin toxicity was common. Veno-occlusive disease occurred twice with cyclophosphamide. Eighteen patients (26%) had graft-versus-host disease, and only 7 (10%) greater than grade 2. Two patients rejected; 24 of 42 more than 1 year after transplantation had 100% donor chimerism. The remainder had stable mixed chimerism. T-cell chimerism was significantly better with fludarabine. Long-term follow-up is required, but in combination with fludarabine, treosulfan is a good choice of conditioning for hematopoietic stem cell transplantation in primary immunodeficiency disease. PMID- 21325600 TI - Type of skin eruption is an independent prognostic indicator for adult T-cell leukemia/lymphoma. AB - Cutaneous involvement is seen in ~ 50% of adult T-cell leukemia/lymphoma (ATLL) patients. We investigated the association between skin eruption type and prognosis in 119 ATLL patients. ATLL eruptions were categorized into patch (6.7%), plaque (26.9%), multipapular (19.3%), nodulotumoral (38.7%), erythrodermic (4.2%), and purpuric (4.2%) types. When the T stage of the tumor node-metastasis-blood (TNMB) classification of mycosis fungoides/Sezary syndrome was applied to ATLL staging, 16.0% were T1, 17.7% T2, 38.7% T3, and 4.2% T4, and the remaining 23.5% were of the multipapular and purpuric types. For the patch type, the mean survival time (median survival time could not be estimated) was 188.4 months. The median survival times (in months) for the remaining types were as follows: plaque, 114.9; multipapular, 17.3; nodulotumoral, 17.3; erythrodermic, 3.0; and purpuric, 4.4. Kaplan-Meier curves of overall survival showed that the erythrodermic type had the poorest prognosis, followed by the nodulotumoral and multipapular types. The patch and plaque types were associated with better survival rates. Multivariate analysis demonstrated that the hazard ratios of the erythrodermic and nodulotumoral types were significantly higher than that of the patch type, and that the eruption type is an independent prognostic factor for ATLL. The overall survival was worse as the T stage became more advanced: the multipapular type and T2 were comparable, and the purpuric type had a significantly poorer prognosis than T1. PMID- 21325601 TI - Serum amyloid A overrides Treg anergy via monocyte-dependent and Treg-intrinsic, SOCS3-associated pathways. AB - The acute phase protein serum amyloid A (SAA) has been well characterized as an indicator of inflammation. Nevertheless, its functions in pro versus anti inflammatory processes remain obscure. Here we provide unexpected evidences that SAA induces the proliferation of the tolerogenic subset of regulatory T cells (T(reg)). Intriguingly, SAA reverses T(reg) anergy via its interaction with monocytes to activate distinct mitogenic pathways in T(reg) but not effector T cells. This selective responsiveness of T(reg) correlates with their diminished expression of SOCS3 and is antagonized by T(reg)-specific induction of this regulator of cytokine signaling. Collectively, these evidences suggest a novel anti-inflammatory role of SAA in the induction of a micro-environment that supports T(reg) expansion at sites of infection or tissue injury, likely to curb (auto)-inflammatory responses. PMID- 21325602 TI - The role of vanin-1 and oxidative stress-related pathways in distinguishing acute and chronic pediatric ITP. AB - Pediatric immune thrombocytopenia (ITP) is usually self-limited. However, approximately 20% of children develop chronic ITP, which can be associated with significant morbidity because of long-term immunosuppression and splenectomy in refractory cases. To explore the molecular mechanism of chronic ITP compared with acute ITP, we studied 63 pediatric patients with ITP. Gene expression analysis of whole blood revealed distinct signatures for acute and chronic ITP. Oxidative stress-related pathways were among the most significant chronic ITP-associated pathways. Overexpression of VNN1, an oxidative stress sensor in epithelial cells, was most strongly associated with progression to chronic ITP. Studies of normal persons demonstrated VNN1 expression in a variety of blood cells. Exposure of blood mononuclear cells to oxidative stress inducers elicited dramatic up regulation of VNN1 and down-regulation of PPARgamma, indicating a role for VNN1 as a peripheral blood oxidative stress sensor. Assessment of redox state by tandem mass spectrometry demonstrated statistically significant lower glutathione ratios in patients with ITP versus healthy controls; lower glutathione ratios were also seen in untreated patients with ITP compared with recently treated patients. Our work demonstrates distinct patterns of gene expression in acute and chronic ITP and implicates oxidative stress pathways in the pathogenesis of chronic pediatric ITP. PMID- 21325603 TI - Catalytic domain modification and viral gene delivery of activated factor VII confers hemostasis at reduced expression levels and vector doses in vivo. AB - Catalytic domain variants of activated factor VII (FVIIa) with enhanced hemostatic properties are highly attractive for the treatment of bleeding disorders via gene-based therapy. To explore this in a hemophilic mouse model, we characterized 2 variants of murine activated FVII (mFVIIa-VEAY and mFVIIa-DVQ) with modified catalytic domains, based on recombinant human FVIIa (rhFVIIa) variants. Using purified recombinant proteins, we showed that murine FVIIa (mFVIIa) and variants had comparable binding to human and murine tissue factor (TF) and exhibited similar extrinsic coagulant activity. In vitro in the absence of TF, the variants showed a 6- to 17-fold enhanced proteolytic and coagulant activity relative to mFVIIa, but increased inactivation by antithrombin. Gene delivery of mFVIIa-VEAY resulted in long-term, effective hemostasis at 5-fold lower expression levels relative to mFVIIa in hemophilia A mice or in hemophilia B mice with inhibitors to factor IX. However, expression of mFVIIa-VEAY at 14 fold higher than therapeutic levels resulted in a progressive mortality to 70% within 6 weeks after gene delivery. These results are the first demonstration of the hemostatic efficacy of continuous expression, in the presence or absence of inhibitors, of a high-activity gene-based FVIIa variant in an animal model of hemophilia. PMID- 21325604 TI - The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. AB - Immune thrombocytopenia (ITP) is commonly encountered in clinical practice. In 1996 the American Society of Hematology published a landmark guidance paper designed to assist clinicians in the management of this disorder. Since 1996 there have been numerous advances in the management of both adult and pediatric ITP. These changes mandated an update in the guidelines. This guideline uses a rigorous, evidence-based approach to the location, interpretation, and presentation of the available evidence. We have endeavored to identify, abstract, and present all available methodologically rigorous data informing the treatment of ITP. We provide evidence-based treatment recommendations using the GRADE system in those areas in which such evidence exists. We do not provide evidence in those areas in which evidence is lacking, or is of lower quality--interested readers are referred to a number of recent, consensus-based recommendations for expert opinion in these clinical areas. Our review identified the need for additional studies in many key areas of the therapy of ITP such as comparative studies of "front-line" therapy for ITP, the management of serious bleeding in patients with ITP, and studies that will provide guidance about which therapy should be used as salvage therapy for patients after failure of a first-line intervention. PMID- 21325605 TI - The final split: the regulation of anther dehiscence. AB - Controlling male fertility is an important goal for plant reproduction and selective breeding. Hybrid vigour results in superior growth rates and increased yields of hybrids compared with inbred lines; however, hybrid generation is costly and time consuming. A better understanding of anther development and pollen release will provide effective mechanisms for the control of male fertility and for hybrid generation. Male sterility is associated not only with the lack of viable pollen, but also with the failure of pollen release. In such instances a failure of anther dehiscence has the advantage that viable pollen is produced, which can be used for subsequent rescue of fertility. Anther dehiscence is a multistage process involving localized cellular differentiation and degeneration, combined with changes to the structure and water status of the anther to facilitate complete opening and pollen release. After microspore release the anther endothecium undergoes expansion and deposition of ligno cellulosic secondary thickening. The septum separating the two locules is then enzymatically lysed and undergoes a programmed cell death-like breakdown. The stomium subsequently splits as a consequence of the stresses associated with pollen swelling and anther dehydration. The physical constraints imposed by the thickening in the endothecium limit expansion, placing additional stress on the anther, so as it dehydrates it opens and the pollen is released. Jasmonic acid has been shown to be a critical signal for dehiscence, although other hormones, particularly auxin, are also involved. The key regulators and physical constraints of anther dehiscence are discussed. PMID- 21325606 TI - Development of structural and biochemical characteristics of C(4) photosynthesis in two types of Kranz anatomy in genus Suaeda (family Chenopodiaceae). AB - Genus Suaeda (family Chenopodiaceae, subfamily Suaedoideae) has two structural types of Kranz anatomy consisting of a single compound Kranz unit enclosing vascular tissue. One, represented by Suaeda taxifolia, has mesophyll (M) and bundle sheath (BS) cells distributed around the leaf periphery. The second, represented by Suaeda eltonica, has M and BS surrounding vascular bundles in the central plane. In both, structural and biochemical development of C(4) occurs basipetally, as observed by analysis of the maturation gradient on longitudinal leaf sections. This progression in development was also observed in mid-sections of young, intermediate, and mature leaves in both species, with three clear stages: (i) monomorphic chloroplasts in the two cell types in younger tissue with immunolocalization and in situ hybridization showing ribulose bisphosphate carboxylase oxygenase (Rubisco) preferentially localized in BS chloroplasts, and increasing in parallel with the establishment of Kranz anatomy; (ii) vacuolization and selective organelle positioning in BS cells, with occurrence of phosphoenolpyruvate carboxylase (PEPC) and immunolocalization showing that it is preferentially in M cells; (iii) establishment of chloroplast dimorphism and mitochondrial differentiation in mature tissue and full expression of C(4) biochemistry including pyruvate, Pi dikinase (PPDK) and NAD-malic enzyme (NAD ME). Accumulation of rbcL mRNA preceded its peptide expression, occurring prior to organelle positioning and differentiation. During development there was sequential expression and increase in levels of Rubisco and PEPC followed by NAD ME and PPDK, and an increase in the (13)C/(12)C isotope composition of leaves to values characteristic of C(4) photosynthesis. The findings indicate that these two forms of NAD-ME type C(4) photosynthesis evolved in parallel within the subfamily with similar ontogenetic programmes. PMID- 21325607 TI - Was the Devonian radiation of large predatory fish a consequence of rising atmospheric oxygen concentration? PMID- 21325608 TI - Systems-level analysis of microbial community organization through combinatorial labeling and spectral imaging. AB - Microbes in nature frequently function as members of complex multitaxon communities, but the structural organization of these communities at the micrometer level is poorly understood because of limitations in labeling and imaging technology. We report here a combinatorial labeling strategy coupled with spectral image acquisition and analysis that greatly expands the number of fluorescent signatures distinguishable in a single image. As an imaging proof of principle, we first demonstrated visualization of Escherichia coli labeled by fluorescence in situ hybridization (FISH) with 28 different binary combinations of eight fluorophores. As a biological proof of principle, we then applied this Combinatorial Labeling and Spectral Imaging FISH (CLASI-FISH) strategy using genus- and family-specific probes to visualize simultaneously and differentiate 15 different phylotypes in an artificial mixture of laboratory-grown microbes. We then illustrated the utility of our method for the structural analysis of a natural microbial community, namely, human dental plaque, a microbial biofilm. We demonstrate that 15 taxa in the plaque community can be imaged simultaneously and analyzed and that this community was dominated by early colonizers, including species of Streptococcus, Prevotella, Actinomyces, and Veillonella. Proximity analysis was used to determine the frequency of inter- and intrataxon cell-to cell associations which revealed statistically significant intertaxon pairings. Cells of the genera Prevotella and Actinomyces showed the most interspecies associations, suggesting a central role for these genera in establishing and maintaining biofilm complexity. The results provide an initial systems-level structural analysis of biofilm organization. PMID- 21325610 TI - Seeing a molecular machine self-renew. PMID- 21325613 TI - Mapping backbone and side-chain interactions in the transition state of a coupled protein folding and binding reaction. AB - Understanding the mechanism of protein folding requires a detailed knowledge of the structural properties of the barriers separating unfolded from native conformations. The S-peptide from ribonuclease S forms its alpha-helical structure only upon binding to the folded S-protein. We characterized the transition state for this binding-induced folding reaction at high resolution by determining the effect of site-specific backbone thioxylation and side-chain modifications on the kinetics and thermodynamics of the reaction, which allows us to monitor formation of backbone hydrogen bonds and side-chain interactions in the transition state. The experiments reveal that alpha-helical structure in the S-peptide is absent in the transition state of binding. Recognition between the unfolded S-peptide and the S-protein is mediated by loosely packed hydrophobic side-chain interactions in two well defined regions on the S-peptide. Close packing and helix formation occurs rapidly after binding. Introducing hydrophobic residues at positions outside the recognition region can drastically slow down association. PMID- 21325614 TI - Thinking outside the box: fostering innovation and non-hypothesis-driven research at NIH. AB - The National Institutes of Health (NIH) has long been known as an institution that supports biomedical advances through hypothesis-driven research. Another aspect of NIH, however, has received comparatively little attention and may be critical to advancing translational science beyond its current limitations. Specifically, this aspect of NIH focuses on supporting innovation through the development of high-risk technologies that have the potential to empower research. PMID- 21325615 TI - Comment on "Multidimensional results reporting to participants in genomic studies: getting it right". AB - Bookman et al. write to correct the impression given in the Commentary by Kohane and Taylor that the recommendations of the National Heart, Lung, and Blood Institute (NHLBI) Working Group "Reporting Genetic Results in Research Studies" included advice to return genetic information to research subjects only in cases where there is a proven or preventative intervention for the identified disorder. In fact, the report does recommend that genetic information be returned to subjects when there is an intervention available, but it does not recommend against giving this kind of information to subjects if there is no available intervention. PMID- 21325616 TI - For placebo effects in medicine, seeing is believing. AB - The gold standard for determining the efficacy of biomedical therapies is the detection of a significant difference between the therapeutic effects of an active pharmacological agent or procedure and a matched inert placebo in a randomized controlled trial. Detecting this difference has become a challenge for medicine, especially for outcomes that are based on patient self-rated scales. Yet factors that contribute to placebo responses have received scant attention. In this issue of Science Translational Medicine, Bingel et al. report on an example of how noninvasive whole-brain imaging contributes to our understanding of brain-based placebo effects. Here we highlight ways in which neuroimaging is catalyzing a revolution in society's perspective of placebo effects by providing a compelling visualization of how brain activities that reflect a person's thoughts, feelings, and past experiences can enhance or antagonize his or her response to a medical treatment. PMID- 21325617 TI - Growth hormone receptor deficiency is associated with a major reduction in pro aging signaling, cancer, and diabetes in humans. AB - Mutations in growth signaling pathways extend life span, as well as protect against age-dependent DNA damage in yeast and decrease insulin resistance and cancer in mice. To test their effect in humans, we monitored for 22 years Ecuadorian individuals who carry mutations in the growth hormone receptor (GHR) gene that lead to severe GHR and IGF-1 (insulin-like growth factor-1) deficiencies. We combined this information with surveys to identify the cause and age of death for individuals in this community who died before this period. The individuals with GHR deficiency exhibited only one nonlethal malignancy and no cases of diabetes, in contrast to a prevalence of 17% for cancer and 5% for diabetes in control subjects. A possible explanation for the very low incidence of cancer was suggested by in vitro studies: Serum from subjects with GHR deficiency reduced DNA breaks but increased apoptosis in human mammary epithelial cells treated with hydrogen peroxide. Serum from GHR-deficient subjects also caused reduced expression of RAS, PKA (protein kinase A), and TOR (target of rapamycin) and up-regulation of SOD2 (superoxide dismutase 2) in treated cells, changes that promote cellular protection and life-span extension in model organisms. We also observed reduced insulin concentrations (1.4 MUU/ml versus 4.4 MUU/ml in unaffected relatives) and a very low HOMA-IR (homeostatic model assessment-insulin resistance) index (0.34 versus 0.96 in unaffected relatives) in individuals with GHR deficiency, indicating higher insulin sensitivity, which could explain the absence of diabetes in these subjects. These results provide evidence for a role of evolutionarily conserved pathways in the control of aging and disease burden in humans. PMID- 21325618 TI - The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. AB - Evidence from behavioral and self-reported data suggests that the patients' beliefs and expectations can shape both therapeutic and adverse effects of any given drug. We investigated how divergent expectancies alter the analgesic efficacy of a potent opioid in healthy volunteers by using brain imaging. The effect of a fixed concentration of the MU-opioid agonist remifentanil on constant heat pain was assessed under three experimental conditions using a within-subject design: with no expectation of analgesia, with expectancy of a positive analgesic effect, and with negative expectancy of analgesia (that is, expectation of hyperalgesia or exacerbation of pain). We used functional magnetic resonance imaging to record brain activity to corroborate the effects of expectations on the analgesic efficacy of the opioid and to elucidate the underlying neural mechanisms. Positive treatment expectancy substantially enhanced (doubled) the analgesic benefit of remifentanil. In contrast, negative treatment expectancy abolished remifentanil analgesia. These subjective effects were substantiated by significant changes in the neural activity in brain regions involved with the coding of pain intensity. The positive expectancy effects were associated with activity in the endogenous pain modulatory system, and the negative expectancy effects with activity in the hippocampus. On the basis of subjective and objective evidence, we contend that an individual's expectation of a drug's effect critically influences its therapeutic efficacy and that regulatory brain mechanisms differ as a function of expectancy. We propose that it may be necessary to integrate patients' beliefs and expectations into drug treatment regimes alongside traditional considerations in order to optimize treatment outcomes. PMID- 21325619 TI - A meningococcal factor H binding protein mutant that eliminates factor H binding enhances protective antibody responses to vaccination. AB - Certain pathogens recruit host complement inhibitors such as factor H (fH) to evade the immune system. Microbial complement inhibitor-binding molecules can be promising vaccine targets by eliciting Abs that neutralize this microbial defense mechanism. One such Ag, meningococcal factor H-binding protein (fHbp), was used in clinical trials before the protein was discovered to bind fH. The potential effect of fH binding on vaccine immunogenicity had not been assessed in experimental animals because fHbp binds human fH specifically. In this study, we developed a human fH transgenic mouse model. Transgenic mice immunized with fHbp vaccine had 4- to 8-fold lower serum bactericidal Ab responses than those of control mice whose native fH did not bind the vaccine. In contrast, Ab responses were unimpaired in transgenic mice immunized with a control meningococcal group C polysaccharide-protein conjugate vaccine. In transgenic mice, immunization with an fH nonbinding mutant of fHbp elicited Abs with higher bactericidal activity than that of fHbp vaccination itself. Abs elicited by the mutant fHbp more effectively blocked fH binding to wild-type fHbp than Abs elicited by fHbp that bound fH. Thus, a mutant fHbp vaccine that does not bind fH but that retains immunogenicity is predicted to be superior in humans to an fHbp vaccine that binds human fH. In the case of mutant fHbp vaccination, the resultant Ab responses may be directed more at epitopes in or near the fH binding site, which result in greater complement-mediated serum bactericidal activity; these epitopes may be obscured when human fH is bound to the wild-type fHbp vaccine. PMID- 21325620 TI - TCR bias of in vivo expanded T cells in pancreatic islets and spleen at the onset in human type 1 diabetes. AB - Autoreactive T cells, responsible for the destruction of pancreatic beta cells in type 1 diabetes, are known to have a skewed TCR repertoire in the NOD mouse. To define the autoreactive T cell repertoire in human diabetes, we searched for intraislet monoclonal expansions from a recent onset in human pancreas to then trace them down to the patient's peripheral blood and spleen. Islet infiltration was diverse, but five monoclonal TCR beta-chain variable expansions were detected for Vbeta1, Vbeta7, Vbeta11, Vbeta17, and Vbeta22 families. To identify any sequence bias in the TCRs from intrapancreatic T cells, we analyzed 139 different CDR3 sequences. We observed amino acid preferences in the NDN region that suggested a skewed TCR repertoire within infiltrating T cells. The monoclonal expanded TCR sequences contained amino acid combinations that fit the observed bias. Using these CDR3 sequences as a marker, we traced some of these expansions in the spleen. There, we identified a Vbeta22 monoclonal expansion with identical CDR3 sequence to that found in the islets within a polyclonal TCR beta-chain variable repertoire. The same Vbeta22 TCR was detected in the patient's PBMCs, making a cross talk between the pancreas and spleen that was reflected in peripheral blood evident. No other pancreatic monoclonal expansions were found in peripheral blood or the spleen, suggesting that the Vbeta22 clone may have expanded or accumulated in situ by an autoantigen present in both the spleen and pancreas. Thus, the patient's spleen might be contributing to disease perpetuation by expanding or retaining some autoreactive T cells. PMID- 21325621 TI - Ocular neovascularization caused by herpes simplex virus type 1 infection results from breakdown of binding between vascular endothelial growth factor A and its soluble receptor. AB - The normal cornea is transparent, which is essential for normal vision, and although the angiogenic factor vascular endothelial growth factor A (VEGF-A) is present in the cornea, its angiogenic activity is impeded by being bound to a soluble form of the VEGF receptor-1 (sVR-1). This report investigates the effect on the balance between VEGF-A and sVR-1 that occurs after ocular infection with HSV, which causes prominent neovascularization, an essential step in the pathogenesis of the vision-impairing lesion, stromal keratitis. We demonstrate that HSV-1 infection causes increased production of VEGF-A but reduces sVR-1 levels, resulting in an imbalance of VEGF-A and sVR-1 levels in ocular tissues. Moreover, the sVR-1 protein made was degraded by the metalloproteinase (MMP) enzymes MMP-2, -7, and -9 produced by infiltrating inflammatory cells that were principally neutrophils. Inhibition of neutrophils, inhibition of sVR-1 breakdown with the MMP inhibitor marimastat, and the provision of exogenous recombinant sVR 1 protein all resulted in reduced angiogenesis. Our results make the novel observation that ocular neovascularization resulting from HSV infection involves a change in the balance between VEGF-A and its soluble inhibitory receptor. Future therapies aimed to increase the production and activity of sVR-1 protein could benefit the management of stromal keratitis, an important cause of human blindness. PMID- 21325622 TI - Damage-associated molecular pattern S100A9 increases bactericidal activity of human neutrophils by enhancing phagocytosis. AB - The damage-associated molecular-pattern S100A9 is found at inflammatory sites in infections and various autoimmune diseases. It is released at very high concentrations in the extracellular milieu by activated neutrophils and monocytes in response to various agents. This proinflammatory protein is found in infected mucosae and tissue abscesses where it acts notably as a potent neutrophil activator. In this study, we examined the role of S100A9 in the control of infections. S100A9 was found to increase human neutrophil bactericidal activity toward Escherichia coli. Although S100A9 induced the accumulation of reactive oxygen species over time through the activation of NADPH oxidase, its antimicrobial activity was mediated mainly by enhancing the efficiency of neutrophil phagocytosis. Interestingly, S100A9 did not act by increasing cell surface expression of CD16, CD32, or CD64 in neutrophils, indicating that its biological effect in FcR-mediated phagocytosis is independent of upregulation of FcgammaR levels. However, S100A9-induced phagocytic activity required the phosphorylation of Erk1/2, Akt, and Syk. Taken together, our results demonstrate that S100A9 stimulates neutrophil microbicidal activity by promoting phagocytosis. PMID- 21325623 TI - Cutting edge: mast cells regulate disease severity in a relapsing-remitting model of multiple sclerosis. AB - Mast cells (MCs) exert a significant pathologic influence on disease severity in C57BL/6 (B6) strain-dependent experimental allergic encephalomyelitis (EAE), a model of primary progressive multiple sclerosis (MS). However, relapsing remitting MS, which is modeled in SJL mice, is the more prevalent form. Given genetically determined heterogeneity in numbers and responsiveness of MCs from various strains of mice, we asked whether these cells also influence this more clinically relevant MS model using SJL-Kit(W/W-v) mice. Similar to the commercially available WBB6F(1)-Kit(W/W-v) mice, SJL-Kit(W/W-v) mice are MC deficient, anemic, and neutropenic and have normal T cell compartments. They exhibit significantly reduced disease severity, but retain the relapsing remitting course, a phenotype reversed by selective MC reconstitution. These data confirm that MC influence is not confined to an isolated model of EAE and reveal a new system to study the effects of MC heterogeneity on relapsing-remitting EAE and other SJL strain-specific diseases. PMID- 21325624 TI - Loss of desmocollin-2 confers a tumorigenic phenotype to colonic epithelial cells through activation of Akt/beta-catenin signaling. AB - Desmocollin-2 (Dsc2) and desmoglein-2 (Dsg2) are transmembrane cell adhesion proteins of desmosomes. Reduced expression of Dsc2 has been reported in colorectal carcinomas, suggesting that Dsc2 may play a role in the development and/or progression of colorectal cancer. However, no studies have examined the mechanistic contribution of Dsc2 deficiency to tumorigenesis. Here we report that loss of Dsc2 promotes cell proliferation and enables tumor growth in vivo through the activation of Akt/beta-catenin signaling. Inhibition of Akt prevented the increase in beta-catenin-dependent transcription and proliferation following Dsc2 knockdown and attenuated the in vivo growth of Dsc2-deficient cells. Taken together, our results provide evidence that loss of Dsc2 contributes to the growth of colorectal cancer cells and highlight a novel mechanism by which the desmosomal cadherins regulate beta-catenin signaling. PMID- 21325625 TI - Vacuolization of mucolipidosis type II mouse exocrine gland cells represents accumulation of autolysosomes. AB - We previously reported that mice deficient in UDP-GlcNAc:lysosomal enzyme GlcNAc 1-phosphotransferase (mucolipidosis type II or Gnptab -/- mice), the enzyme that initiates the addition of the mannose 6-phosphate lysosomal sorting signal on acid hydrolases, exhibited extensive vacuolization of their exocrine gland cells, while the liver, brain, and muscle appeared grossly unaffected. Similar pathological findings were observed in several exocrine glands of patients with mucolipidosis II. To understand the basis for this cell type-specific abnormality, we analyzed these tissues in Gnptab -/- mice using a combined immunoelectron microscopy and biochemical approach. We demonstrate that the vacuoles in the exocrine glands are enlarged autolysosomes containing undigested cytoplasmic material that accumulate secondary to deficient lysosomal function. Surprisingly, the acid hydrolase levels in these tissues ranged from normal to modestly decreased, in contrast to skin fibroblasts, which accumulate enlarged lysosomes and/or autolysosomes also but exhibit very low levels of acid hydrolases. We propose that the lysosomal defect in the exocrine cells is caused by the combination of increased secretion of the acid hydrolases via the constitutive pathway along with their entrapment in secretory granules. Taken together, our results provide new insights into the mechanisms of the tissue specific abnormalities seen in mucolipidosis type II. PMID- 21325626 TI - Regulation of mitochondrial morphology by APC/CCdh1-mediated control of Drp1 stability. AB - Homeostatic maintenance of cellular mitochondria requires a dynamic balance between fission and fusion, and controlled changes in morphology are important for processes such as apoptosis and cellular division. Interphase mitochondria have been described as an interconnected network that fragments as cells enter mitosis, and this mitotic mitochondrial fragmentation is known to be regulated by the dynamin-related GTPase Drp1 (dynamin-related protein 1), a key component of the mitochondrial division machinery. Loss of Drp1 function and the subsequent failure of mitochondrial division during mitosis lead to incomplete cytokinesis and the unequal distribution of mitochondria into daughter cells. During mitotic exit and interphase, the mitochondrial network reforms. Here we demonstrate that changes in mitochondrial dynamics as cells exit mitosis are driven in part through ubiquitylation of Drp1, catalyzed by the APC/C(Cdh1) (anaphase-promoting complex/cyclosome and its coactivator Cdh1) E3 ubiquitin ligase complex. Importantly, inhibition of Cdh1-mediated Drp1 ubiquitylation and proteasomal degradation during interphase prevents the normal G1 phase regrowth of mitochondrial networks following cell division. PMID- 21325627 TI - Subunit organization and Rab interactions of Vps-C protein complexes that control endolysosomal membrane traffic. AB - Traffic through late endolysosomal compartments is regulated by sequential signaling of small G proteins of the Rab5 and Rab7 families. The Saccharomyces cerevisiae Vps-C protein complexes CORVET (class C core vacuole/endosome tethering complex) and HOPS (homotypic fusion and protein transport) interact with endolysosomal Rabs to coordinate their signaling activities. To better understand these large and intricate complexes, we performed interaction surveys to assemble domain-level interaction topologies for the eight Vps-C subunits. We identified numerous intersubunit interactions and up to six Rab-binding sites. Functional modules coordinate the major Rab interactions within CORVET and HOPS. The CORVET-specific subunits, Vps3 and Vps8, form a subcomplex and physically and genetically interact with the Rab5 orthologue Vps21. The HOPS-specific subunits, Vps39 and Vps41, also form a subcomplex. Both subunits bind the Rab7 orthologue Ypt7, but with distinct nucleotide specificities. The in vivo functions of four RING-like domains within Vps-C subunits were analyzed and shown to have distinct functions in endolysosomal transport. Finally, we show that the CORVET- and HOPS specific subunits Vps3 and Vps39 bind the Vps-C core through a common region within the Vps11 C-terminal domain (CTD). Biochemical and genetic experiments demonstrate the importance of these regions, revealing the Vps11 CTD as a key integrator of Vps-C complex assembly, Rab signaling, and endosomal and lysosomal traffic. PMID- 21325628 TI - Filamin depletion blocks endoplasmic spreading and destabilizes force-bearing adhesions. AB - Cell motility is an essential process that depends on a coherent, cross-linked actin cytoskeleton that physically coordinates the actions of numerous structural and signaling molecules. The actin cross-linking protein, filamin (Fln), has been implicated in the support of three-dimensional cortical actin networks capable of both maintaining cellular integrity and withstanding large forces. Although numerous studies have examined cells lacking one of the multiple Fln isoforms, compensatory mechanisms can mask novel phenotypes only observable by further Fln depletion. Indeed, shRNA-mediated knockdown of FlnA in FlnB(-/-) mouse embryonic fibroblasts (MEFs) causes a novel endoplasmic spreading deficiency as detected by endoplasmic reticulum markers. Microtubule (MT) extension rates are also decreased but not by peripheral actin flow, because this is also decreased in the Fln-depleted system. Additionally, Fln-depleted MEFs exhibit decreased adhesion stability that appears in increased ruffling of the cell edge, reduced adhesion size, transient traction forces, and decreased stress fibers. FlnA(-/-) MEFs, but not FlnB(-/-) MEFs, also show a moderate defect in endoplasm spreading, characterized by initial extension followed by abrupt retractions and stress fiber fracture. FlnA localizes to actin linkages surrounding the endoplasm, adhesions, and stress fibers. Thus we suggest that Flns have a major role in the maintenance of actin-based mechanical linkages that enable endoplasmic spreading and MT extension as well as sustained traction forces and mature focal adhesions. PMID- 21325629 TI - Hairless is a cofactor for Runt-dependent transcriptional regulation. AB - Runt is a vital transcriptional regulator in the developmental pathway responsible for segmentation in the Drosophila embryo. Runt activates or represses transcription in a manner that is dependent on both cellular context and the specific downstream target. Here we identify Hairless (H) as a Runt interacting molecule that functions during segmentation. We find that H is important for maintenance of engrailed (en) repression as was previously demonstrated for Groucho (Gro), Rpd3, and CtBP. H also contributes to the Runt dependent repression of sloppy-paired-1 (slp1), a role that is not shared with these other corepressors. We further find distinct roles for these different corepressors in the regulation of other Runt targets in the early Drosophila embryo. These findings, coupled with observations on the distinct functional requirements for Runt in regulating these several different targets, indicate that Runt-dependent regulation in the Drosophila blastoderm embryo relies on unique, target-gene-specific molecular interactions. PMID- 21325630 TI - The Ndc80 complex uses a tripartite attachment point to couple microtubule depolymerization to chromosome movement. AB - In kinetochores, the Ndc80 complex couples the energy in a depolymerizing microtubule to perform the work of moving chromosomes. The complex directly binds microtubules using an unstructured, positively charged N-terminal tail located on Hec1/Ndc80. Hec1/Ndc80 also contains a calponin homology domain (CHD) that increases its affinity for microtubules in vitro, yet whether it is required in cells and how the tail and CHD work together are critical unanswered questions. Human kinetochores containing Hec1/Ndc80 with point mutations in the CHD fail to align chromosomes or form productive microtubule attachments. Kinetochore architecture and spindle checkpoint protein recruitment are unaffected in these mutants, and the loss of CHD function cannot be rescued by removing Aurora B sites from the tail. The interaction between the Hec1/Ndc80 CHD and a microtubule is facilitated by positively charged amino acids on two separate regions of the CHD, and both are required for kinetochores to make stable attachments to microtubules. Chromosome congression in cells also requires positive charge on the Hec1 tail to facilitate microtubule contact. In vitro binding data suggest that charge on the tail regulates attachment by directly increasing microtubule affinity as well as driving cooperative binding of the CHD. These data argue that in vertebrates there is a tripartite attachment point facilitating the interaction between Hec1/Ndc80 and microtubules. We discuss how such a complex microtubule-binding interface may facilitate the coupling of depolymerization to chromosome movement. PMID- 21325631 TI - Mitotic progression becomes irreversible in prometaphase and collapses when Wee1 and Cdc25 are inhibited. AB - Mitosis requires precise coordination of multiple global reorganizations of the nucleus and cytoplasm. Cyclin-dependent kinase 1 (Cdk1) is the primary upstream kinase that directs mitotic progression by phosphorylation of a large number of substrate proteins. Cdk1 activation reaches the peak level due to positive feedback mechanisms. By inhibiting Cdk chemically, we showed that, in prometaphase, when Cdk1 substrates approach the peak of their phosphorylation, cells become capable of proper M-to-G1 transition. We interfered with the molecular components of the Cdk1-activating feedback system through use of chemical inhibitors of Wee1 and Myt1 kinases and Cdc25 phosphatases. Inhibition of Wee1 and Myt1 at the end of the S phase led to rapid Cdk1 activation and morphologically normal mitotic entry, even in the absence of G2. Dampening Cdc25 phosphatases simultaneously with Wee1 and Myt1 inhibition prevented Cdk1/cyclin B kinase activation and full substrate phosphorylation and induced a mitotic "collapse," a terminal state characterized by the dephosphorylation of mitotic substrates without cyclin B proteolysis. This was blocked by the PP1/PP2A phosphatase inhibitor, okadaic acid. These findings suggest that the positive feedback in Cdk activation serves to overcome the activity of Cdk-opposing phosphatases and thus sustains forward progression in mitosis. PMID- 21325632 TI - MYADM regulates Rac1 targeting to ordered membranes required for cell spreading and migration. AB - Membrane organization into condensed domains or rafts provides molecular platforms for selective recruitment of proteins. Cell migration is a general process that requires spatiotemporal targeting of Rac1 to membrane rafts. The protein machinery responsible for making rafts competent to recruit Rac1 remains elusive. Some members of the MAL family of proteins are involved in specialized processes dependent on this type of membrane. Because condensed membrane domains are a general feature of the plasma membrane of all mammalian cells, we hypothesized that MAL family members with ubiquitous expression and plasma membrane distribution could be involved in the organization of membranes for cell migration. We show that myeloid-associated differentiation marker (MYADM), a protein with unique features within the MAL family, colocalizes with Rac1 in membrane protrusions at the cell surface and distributes in condensed membranes. MYADM knockdown (KD) cells had altered membrane condensation and showed deficient incorporation of Rac1 to membrane raft fractions and, similar to Rac1 KD cells, exhibited reduced cell spreading and migration. Results of rescue-of-function experiments by expression of MYADM or active Rac1L61 in cells knocked down for Rac1 or MYADM, respectively, are consistent with the idea that MYADM and Rac1 act on parallel pathways that lead to similar functional outcomes. PMID- 21325633 TI - Synthetic triterpenoid CDDO prevents the progression and metastasis of prostate cancer in TRAMP mice by inhibiting survival signaling. AB - In an extension of our previous studies showing potent antitumorigenic activity of synthetic triterpenoids of oleanolic acid against prostate cancer cell lines, we examined the efficacy of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) in preventing the development and/or progression of prostate cancer in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Data show that oral gavage with CDDO (10 MUmol/kg) for 20 weeks resulted in inhibition of the progression of preneoplastic lesions in the dorsolateral prostate and ventral prostate to adenocarcinoma without toxicity. CDDO also inhibited metastasis of tumor to the distant organs. Treatment with CDDO significantly inhibited cell proliferation, reduced the density of blood vessels and promoted apoptosis in the prostatic tissue. Further, Akt, NF-kappaB and NF-kappaB regulated Bcl-2, Bcl-xL, survivin and cIAP1 appear to be the molecular targets of CDDO for inhibiting the progression of prostate cancer in TRAMP mice. Thus, these studies show for the first time the potential of CDDO for chemoprevention of human prostate cancer. PMID- 21325635 TI - Overexpressed PAK4 promotes proliferation, migration and invasion of choriocarcinoma. AB - Gestational trophoblastic disease (GTD) includes frankly malignant choriocarcinoma (CCA) and placental site trophoblastic tumor and potentially malignant hydatidiform mole. p21-Activated kinase (PAK) 4 promotes cell motility. This study investigated the role of PAK4 in the pathogenesis of GTD. PAK4 messenger RNA and protein expressions in clinical samples and cell lines of normal placentas and GTD were determined by quantitative real-time polymerase chain reaction and western blot, respectively. The effects of human chorionic gonadotropin (hCG) and phosphoinositide 3 kinase (PI3K) on the expression and activation of PAK4 were investigated by treating CCA JEG3 and JAR cells with anti hCG antibody and PI3K inhibitor, respectively. The effects of PAK4 on CCA cell proliferation, migration and invasion were assessed by corresponding functional assays. We demonstrated overexpression of PAK4 in GTD and CCA cell lines at both RNA and protein level. hCG is one of the upstream regulators of PAK4 expression, whereas activation of PAK4 is PI3K/PKB dependent in JEG3 and JAR cells. Significant correlation was found between PAK4 expression and proliferation index minichromosome maintenance complex component 7 (P = 0.007). In JEG3 and JAR cells, stably transfected PAK4 increased proliferation, migration and invasion, whereas small interfering RNA knockdown of PAK4 decreased proliferation, migration and invasion along with downregulated CDK6 and membrane-type 1 matrix metalloproteinase (MT1-MMP) and upregulated p16. We further found PAK4-mediated transcription of MT1-MMP in CCA cells by luciferase reporter assay. Our results demonstrated for the first time that overexpressed PAK4 was involved in the pathogenesis of GTD, promoting proliferation and enhancing cell migration and invasion in CCA cells. PMID- 21325634 TI - Curcumin suppresses proliferation and induces apoptosis in human biliary cancer cells through modulation of multiple cell signaling pathways. AB - Cholangiocarcinoma (CCA) is a tumor with poor prognosis that is resistant to all currently available treatments. Whether curcumin, a nutraceutical derived from turmeric (Curcuma longa), has potential therapeutic activity against human CCA was investigated using three CCA cell lines (KKU100, KKU-M156 and KKU-M213). Examination of mitochondrial dehydrogenase activity, phosphatidylserine externalization, esterase staining, caspase activation and poly-adenosine diphosphate ribose polymerase cleavage demonstrated that curcumin inhibited proliferation of and induced apoptosis in these biliary cancer cells. Colony formation assay confirmed the growth-inhibitory effect of curcumin on CCA cells. When examined for the mechanism, curcumin was found to activate multiple cell signaling pathways in these cells. First, all CCA cells exhibited constitutively active nuclear factor (NF)-kappaB, and treatment with curcumin abolished this activation as indicated by DNA binding, nuclear translocation and p65 phosphorylation. Second, curcumin suppressed activation of signal transducer and activator of transcription-3 as indicated by decreased phosphorylation at both tyrosine(705) and serine(727) and inhibition of janus kinase-1 phosphorylation. Third, curcumin induced expression of peroxisome proliferator-activated receptor gamma. Fourth, curcumin upregulated death receptors, DR4 and DR5. Fifth, curcumin suppressed the Akt activation pathway. Sixth, curcumin inhibited expression of cell survival proteins such as B-cell lymphoma-2, B-cell leukemia protein xL, X linked inhibitor of apoptosis protein, c-FLIP, cellular inhibitor of apoptosis protein (cIAP)-1, cIAP-2 and survivin and proteins linked to cell proliferation, such as cyclin D1 and c-Myc. Seventh, the growth inhibitory effect of curcumin was enhanced in the IkappaB kinase-deficient cells, the enzyme required for nuclear factor-kappaB activation. Overall, our results indicate that curcumin mediates its antiproliferative and apoptotic effects through activation of multiple cell signaling pathways, and thus, its activity against CCA should be further investigated. PMID- 21325636 TI - A disintegrin and metalloprotease 10 activity sheds the ectodomain of the amyloid precursor-like protein 2 and regulates protein expression in proximal tubule cells. AB - A disintegrin and metalloprotease 10 (ADAM10) is a zinc protease that mediates ectodomain shedding of numerous receptors including Notch and members of the amyloid precursor protein family (APP, APLP1, and APLP2). Ectodomain shedding frequently activates a process called regulated intramembrane proteolysis (RIP) that links cellular events with gene regulation. To characterize ADAM10 in kidney and in opossum kidney proximal tubule (OKP) cells, we performed indirect immunofluorescence microscopy and immunoblotting of renal membrane fractions using specific antibodies. These studies show that ADAM10 and APLP2 are coexpressed in the proximal tubule and in OKP cells. To study the role of ADAM10 activity in the proximal tubule, we stably overexpressed wild-type ADAM10 or an inactive mutant ADAM10 in OKP cells. We found a direct correlation between the amount of active ADAM10 expressed and 1) the amount of APLP2 ectodomain shed into the culture supernatant and 2) the amount of Na(+)/H(+) exchanger 3 (NHE3) and megalin mRNA and protein expressed compared with control proteins. To establish a link between ADAM10-mediated shedding of APLP2 and the effect on NHE3 and megalin mRNA expression we performed RNA interference experiments using APLP2-specific short hairpin RNA (shRNA) in OKP cells. Cells expressing the APLP2 shRNA showed >80% knock down of APLP2 protein and mRNA as well as 60-70% reduction in NHE3 protein and mRNA. Levels of megalin and Na-K-ATPase protein and mRNA were not changed. These studies show 1) ADAM10 and APLP2 are expressed in proximal tubule cells and, 2) ADAM10 activity has a pronounced effect on expression of specific brush-border proteins. We postulate that ADAM10 and APLP2 may represent elements of a here-to-fore unknown signaling pathway in proximal tubule that link events at the brush border with control of gene expression. PMID- 21325637 TI - PDGF-induced vascular smooth muscle cell proliferation is associated with dysregulation of insulin receptor substrates. AB - In vascular smooth muscle cells (VSMCs), platelet-derived growth factor (PDGF) plays a major role in inducing phenotypic switching from contractile to proliferative state. Importantly, VSMC phenotypic switching is also determined by the phosphorylation state/expression levels of insulin receptor substrate (IRS), an intermediary signaling component that is shared by insulin and IGF-I. To date, the roles of PDGF-induced key proliferative signaling components including Akt, p70S6kinase, and ERK1/2 on the serine phosphorylation/expression of IRS-1 and IRS 2 isoforms remain unclear in VSMCs. We hypothesize that PDGF-induced VSMC proliferation is associated with dysregulation of insulin receptor substrates. Using human aortic VSMCs, we demonstrate that prolonged PDGF treatment led to sustained increases in the phosphorylation of protein kinases such as Akt, p70S6kinase, and ERK1/2, which mediate VSMC proliferation. In addition, PDGF enhanced IRS-1/IRS-2 serine phosphorylation and downregulated IRS-2 expression in a time- and concentration-dependent manner. Notably, phosphoinositide 3-kinase (PI 3-kinase) inhibitor (PI-103) and mammalian target of rapamycin inhibitor (rapamycin), which abolished PDGF-induced Akt and p70S6kinase phosphorylation, respectively, blocked PDGF-induced IRS-1 serine phosphorylation and IRS-2 downregulation. In contrast, MEK1/ERK inhibitor (U0126) failed to block PDGF induced IRS-1 serine phosphorylation and IRS-2 downregulation. PDGF-induced IRS-2 downregulation was prevented by lactacystin, an inhibitor of proteasomal degradation. Functionally, PDGF-mediated IRS-1/IRS-2 dysregulation resulted in the attenuation of insulin-induced IRS-1/IRS-2-associated PI 3-kinase activity. Pharmacological inhibition of PDGF receptor tyrosine kinase with imatinib prevented IRS-1/IRS-2 dysregulation and restored insulin receptor signaling. In conclusion, strategies to inhibit PDGF receptors would not only inhibit neointimal growth but may provide new therapeutic options to prevent dysregulated insulin receptor signaling in VSMCs in nondiabetic and diabetic states. PMID- 21325638 TI - KCa1.1 channel contributes to cell excitability in unmyelinated but not myelinated rat vagal afferents. AB - High conductance calcium-activated potassium (BK(Ca)) channels can modulate cell excitability and neurotransmitter release at synaptic and afferent terminals. BK(Ca) channels are present in primary afferents of most, if not, all internal organs and are an intriguing target for pharmacological manipulation of visceral sensation. Our laboratory has a long-standing interest in the neurophysiological differences between myelinated and unmyelinated visceral afferent function. Here, we seek to determine whether there is a differential distribution of BK(Ca) channels in myelinated and unmyelinated vagal afferents. Immunocytochemistry studies with double staining for the BK-type K(Ca)1.1 channel protein and isolectin B4 (IB4), a reliable marker of unmyelinated peripheral afferents, reveal a pattern of IB4 labeling that strongly correlates with the expression of the K(Ca)1.1 channel protein. Measures of cell size and immunostaining intensity for K(Ca)1.1 and IB4 cluster into two statistically distinct (P < 0.05) populations of cells. Smaller diameter neurons most often presented with strong IB4 labeling and are presumed to be unmyelinated (n = 1,390) vagal afferents. Larger diameter neurons most often lacked or exhibited a very weak IB4 labeling and are presumed to be myelinated (n = 58) vagal afferents. Complimentary electrophysiological studies reveal that the BK(Ca) channel blockers charybdotoxin (ChTX) and iberiotoxin (IbTX) bring about a comparable elevation in excitability and action potential widening in unmyelinated neurons but had no effect on the excitability of myelinated vagal afferents. This study is the first to demonstrate using combined immunohistochemical and electrophysiological techniques that K(Ca)1.1 channels are uniquely expressed in unmyelinated C-type vagal afferents and do not contribute to the dynamic discharge characteristics of myelinated A-type vagal afferents. This unique functional distribution of BK-type K(Ca) channels may provide an opportunity for afferent selective pharmacological intervention across a wide range of visceral pathophysiologies, particularly those with a reflexogenic etiology and pain. PMID- 21325641 TI - MAPKs and NF-kappaB differentially regulate cytokine expression in the diaphragm in response to resistive breathing: the role of oxidative stress. AB - Inspiratory resistive breathing (IRB) induces cytokine expression in the diaphragm. The mechanism of this cytokine induction remains elusive. The roles of MAPKs and NF-kappaB and the impact of oxidative stress in IRB-induced cytokine upregulation in the diaphragm were studied. Wistar rats were subjected to IRB (50% of maximal inspiratory pressure) via a two-way nonrebreathing valve for 1, 3, or 6 h. Additional groups of rats subjected to IRB for 6 h were randomly assigned to receive either solvent or N-acetyl-cysteine (NAC) or inhibitors of NF kappaB (BAY-11-7082), ERK1/2 (PD98059), and P38 MAPK (SB203580) to study the effect of oxidative stress, NF-kappaB, and MAPKs in IRB-induced cytokine upregulation in the diaphragm. Quietly breathing animals served as controls. IRB upregulated cytokine (IL-6, TNF-alpha, IL-10, IL-2, IL-1beta) protein levels in the diaphragm and resulted in increased activation of MAPKs (P38, ERK1/2) and NF kappaB. Inhibition of NF-kappaB and ERK1/2 blunted the upregulation of all cytokines except that of IL-6, which was further increased. P38 inhibition attenuated all cytokine (including IL-6) upregulation. Both P38 and ERK1/2 inhibition decreased NF-kappaB/p65 subunit phosphorylation. NAC pretreatment blunted IRB-induced cytokine upregulation in the diaphragm and resulted in decreased ERK1/2, P38, and NF-kappaB/p65 phosphorylation. In conclusion, IRB induced cytokine upregulation in the diaphragm is under the regulatory control of MAPKs and NF-kappaB. IL-6 is regulated differently from all other cytokines through a P38-dependent and NF-kappaB independent pathway. Oxidative stress is a stimulus for IRB-induced cytokine upregulation in the diaphragm. PMID- 21325639 TI - Pnck induces ligand-independent EGFR degradation by probable perturbation of the Hsp90 chaperone complex. AB - We have recently described a novel role for pregnancy-upregulated non-ubiquitous calmodulin kinase (Pnck) in the induction of ligand-independent epidermal growth factor receptor (EGFR) degradation (Deb TB, Coticchia CM, Barndt R, Zuo H, Dickson RB, and Johnson MD. Am J Physiol Cell Physiol 295: C365-C377, 2008). In the current communication, we explore the probable mechanism by which Pnck induces ligand-independent EGFR degradation. Pnck-induced EGFR degradation is calcium/calmodulin independent and is regulated by cell density, with the highest EGFR degradation observed at low cell density. Pnck is a novel heat shock protein 90 (Hsp90) client protein that can be co-immunoprecipitated with Hsp90. Treatment of Pnck-overexpressing cells with the pharmacologic Hsp90 inhibitor geldanamycin results in enhanced EGFR degradation, and destruction of Pnck. In cells in which Pnck is inducing EGFR degradation, we observed that Hsp90 exhibits reduced electrophoretic mobility, and through mass spectrometric analysis of immunopurified Hsp90 protein we demonstrated enhanced phosphorylation at threonine 89 and 616 (in both Hsp90-alpha and -beta) and serine 391 (in Hsp90 alpha). Kinase-active Pnck protein is degraded by the proteasome, concurrent with EGFR degradation. A Pnck mutant (T171A) protein with suppressed kinase activity induced EGFR degradation to essentially the same level as wild-type (WT) Pnck, suggesting that Pnck kinase activity is not required for the induction of EGFR degradation. Although EGFR is degraded, overexpression of WT Pnck paradoxically promoted cellular proliferation, whereas cells expressing mutant Pnck (T171A) were growth inhibited. WT Pnck promoted S to G(2) transition, but cells expressing the mutant exhibited higher residency time in S phase. Basal MAP kinase activity was inhibited by WT Pnck but not by mutant T171A Pnck protein. Cyclin-dependent kinase (Cdk) inhibitor p21/Cip-1/Waf-1 was transcriptionally suppressed downstream to MAP kinase inhibition by WT Pnck, but not the mutant protein. Collectively, these data suggest that 1) Pnck induces ligand-independent EGFR degradation most likely through perturbation of Hsp90 chaperone activity due to Hsp90 phosphorylation, 2) EGFR degradation is coupled to proteasomal degradation of Pnck, and 3) modulation of basal MAP kinase activity, p21/Cip 1/Waf-1 expression, and cellular growth by Pnck is independent of Pnck-induced ligand-independent EGFR degradation. PMID- 21325640 TI - Age-related impairment of T cell-induced skeletal muscle precursor cell function. AB - Sarcopenia is the age-associated loss of skeletal muscle mass and strength. Recent evidence suggests that an age-associated loss of muscle precursor cell (MPC) functionality contributes to sarcopenia. The objectives of the present study were to examine the influence of activated T cells on MPCs and determine whether an age-related defect in this signaling occurs. MPCs were collected from the gastrocnemius and plantaris of 3-mo-old (young) and 32-mo-old (old) animals. Splenic T cells were harvested using anti-CD3 Dynabead isolation. T cells were activated for 48 h with costimulation of 100 IU/ml interleukin-2 (IL-2) and 5 MUg/ml of anti-CD28. Costimulation increased 5-bromo-2'-deoxyuridine incorporation of T cells from 13.4 +/- 4.6% in control to 64.8 +/- 6.0% in costimulated cells. Additionally, T cell cytokines increased proliferation on MPCs isolated from young muscle by 24.0 +/- 5.7%, whereas there was no effect on MPCs isolated from aged muscle. T cell cytokines were also found to be a chemoattractant. T cells were able to promote migration of MPCs isolated from young muscle; however, MPCs isolated from aged muscle did not respond to the T cell-released chemokines. Conversely, whereas T cell-released cytokines did not affect myogenesis of MPCs isolated from young animals, there was a decrease in MPCs isolated from old animals. These data suggest that T cells may play a critical role in mediating MPC function. Furthermore, aging may alter T cell induced MPC function. These findings have implications for developing strategies aimed at increasing MPC migration and proliferation leading to an improved regenerative capacity of aged skeletal muscle. PMID- 21325642 TI - A single prior bout of exercise protects against palmitate-induced insulin resistance despite an increase in total ceramide content. AB - Ceramide accumulation has been implicated in the impairment of insulin-stimulated glucose transport in skeletal muscle following saturated fatty acid (FA) exposure. Importantly, a single bout of exercise can protect against acute lipid induced insulin resistance. The mechanism by which exercise protects against lipid-induced insulin resistance is not completely known but may occur through a redirection of FA toward triacylglycerol (TAG) and away from ceramide and diacylglycerol (DAG). Therefore, in the current study, an in vitro preparation was used to examine whether a prior bout of exercise could confer protection against palmitate-induced insulin resistance and whether the pharmacological [50 MUM fumonisin B(1) (FB1)] inhibition of ceramide synthesis in the presence of palmitate could mimic the protective effect of exercise. Soleus muscle of sedentary (SED), exercised (EX), and SED in the presence of FB1 (SED+FB1) were incubated with or without 2 mM palmitate for 4 h. This 2-mM palmitate exposure impaired insulin-stimulated glucose transport (-28%, P < 0.01) and significantly increased ceramide, DAG, and TAG accumulation in the SED group (P < 0.05). A single prior bout of exercise prevented the detrimental effects of palmitate on insulin signaling and caused a partial redistribution of FA toward TAG (P < 0.05). However, the net increase in ceramide content in response to palmitate exposure in the EX group was not different compared with SED, despite the maintenance of insulin sensitivity. The incubation of soleus from SED rats with FB1 (SED+FB1) prevented the detrimental effects of palmitate and caused a redirection of FA toward TAG accumulation (P < 0.05). Therefore, this research suggests that although inhibiting ceramide accumulation can prevent the detrimental effects of palmitate, a single prior bout of exercise appears to protect against palmitate-induced insulin resistance, which may be independent of changes in ceramide content. PMID- 21325643 TI - High-end arteriolar resistance limits uterine artery blood flow and restricts fetal growth in preeclampsia and gestational hypertension at high altitude. AB - The reduction in infant birth weight and increased frequency of preeclampsia (PE) in high-altitude residents have been attributed to greater placental hypoxia, smaller uterine artery (UA) diameter, and lower UA blood flow (Q(UA)). This cross sectional case-control study determined UA, common iliac (CI), and external iliac (EI) arterial blood flow in Andeans residing at 3,600-4,100 m, who were either nonpregnant (NP, n = 23), or experiencing normotensive pregnancies (NORM; n = 155), preeclampsia (PE, n = 20), or gestational hypertension (GH, n = 12). Pregnancy enlarged UA diameter to ~0.62 cm in all groups, but indices of end arteriolar vascular resistance were higher in PE or GH than in NORM. Q(UA) was lower in early-onset (<=34 wk) PE or GH than in NORM, but was normal in late onset (>34 wk) illness. Left Q(UA) was consistently greater than right in NORM, but the pattern reversed in PE. Although Q(CI) and Q(EI) were higher in PE and GH than NORM, the fraction of Q(CI) distributed to the UA was reduced 2- to 3-fold. Women with early-onset PE delivered preterm, and 43% had stillborn small for gestational age (SGA) babies. Those with GH and late-onset PE delivered at term but had higher frequencies of SGA babies (GH=50%, PE=46% vs. NORM=15%, both P < 0.01). Birth weight was strongly associated with reduced Q(UA) (R(2) = 0.80, P < 0.01), as were disease severity and adverse fetal outcomes. We concluded that high end-arteriolar resistance, not smaller UA diameter, limited Q(UA) and restricted fetal growth in PE and GH. These are, to our knowledge, the first quantitative measurements of Q(UA) and pelvic blood flow in early- vs. late-onset PE in high-altitude residents. PMID- 21325644 TI - Exercise-induced regulation of muscular Na+-K+ pump, FXYD1, and NHE1 mRNA and protein expression: importance of training status, intensity, and muscle type. AB - It is investigated if exercise-induced mRNA changes cause similar protein expression changes of Na(+)-K(+) pump isoforms (alpha(1), alpha(2), beta(1), beta(2)), FXYD1, and Na(+)/K(+) exchanger (NHE1) in rat skeletal muscle. Expression was evaluated (n = 8 per group) in soleus and extensor digutorum longus after 1 day, 3 days, and 3 wk (5 sessions/wk) of either sprint (4 * 3-min sprint + 1-min rest) or endurance (20 min) running. Two hours after exercise on day 1, no change in protein expression was apparent in either training group or muscle, whereas sprint exercise increased the mRNA of soleus alpha(2) (4.9 +/- 0.8-fold; P < 0.05), beta(2) (13.2 +/- 4.4-fold; P < 0.001), and NHE1 (12.0 +/- 3.1-fold; P < 0.01). Two hours after sprint exercise, protein expression normalized to control samples was higher on day 3 than day 1 for soleus alpha(1) (41 +/- 18% increase vs. 15 +/- 8% reduction; P < 0.05), alpha(2) (64 +/- 35% increase vs. 37 +/- 12% reduction; P < 0.05), beta(1) (17 +/- 21% increase vs. 14 +/- 29% reduction; P < 0.05), and FXYD1 (35 +/- 16% increase vs. 13 +/- 10% reduction; P < 0.05). In contrast, on day 3, soleus alpha(1) (0.1 +/- 0.1-fold; P < 0.001), alpha(2) (0.2 +/- 0.1-fold; P < 0.001), beta(1) (0.4 +/- 0.1-fold; P < 0.05), and beta(2)-mRNA (2.9 +/- 1.7-fold; P < 0.001) expression was lower than after exercise on day 1. After 3 wk of training, no change in protein expression relative to control existed. In conclusion, increased expression of Na(+)-K(+) pump subunits, FXYD1 and NHE1 after 3 days exercise training does not appear to be an effect of increased constitutive mRNA levels. Importantly, sprint exercise can reduce mRNA expression concomitant with increased protein expression. PMID- 21325645 TI - Effects of maturation and acidosis on the chaos-like complexity of the neural respiratory output in the isolated brainstem of the tadpole, Rana esculenta. AB - Human ventilation at rest exhibits mathematical chaos-like complexity that can be described as long-term unpredictability mediated (in whole or in part) by some low-dimensional nonlinear deterministic process. Although various physiological and pathological situations can affect respiratory complexity, the underlying mechanisms remain incompletely elucidated. If such chaos-like complexity is an intrinsic property of central respiratory generators, it should appear or increase when these structures mature or are stimulated. To test this hypothesis, we employed the isolated tadpole brainstem model [Rana (Pelophylax) esculenta] and recorded the neural respiratory output (buccal and lung rhythms) of pre- (n = 8) and postmetamorphic tadpoles (n = 8), at physiologic (7.8) and acidic pH (7.4). We analyzed the root mean square of the cranial nerve V or VII neurograms. Development and acidosis had no effect on buccal period. Lung frequency increased with development (P < 0.0001). It also increased with acidosis, but in postmetamorphic tadpoles only (P < 0.05). The noise-titration technique evidenced low-dimensional nonlinearities in all the postmetamorphic brainstems, at both pH. Chaos-like complexity, assessed through the noise limit, increased from pH 7.8 to pH 7.4 (P < 0.01). In contrast, linear models best fitted the ventilatory rhythm in all but one of the premetamorphic preparations at pH 7.8 (P < 0.005 vs. postmetamorphic) and in four at pH 7.4 (not significant vs. postmetamorphic). Therefore, in a lower vertebrate model, the brainstem respiratory central rhythm generator accounts for ventilatory chaos-like complexity, especially in the postmetamorphic stage and at low pH. According to the ventilatory generators homology theory, this may also be the case in mammals. PMID- 21325646 TI - Neuronostatin acts in brain to biphasically increase mean arterial pressure through sympatho-activation followed by vasopressin secretion: the role of melanocortin receptors. AB - Neuronostatin is a recently described neuropeptide that is derived from the somatostatin preprohormone. We have shown previously that neuronostatin led to a biphasic, dose-related increase in mean arterial pressure when injected into the lateral cerebroventricle of adult, male rats. Because neuronostatin depolarized both magnocellular and parvocellular, paraventricular nucleus neurons in hypothalamic slice preparations, we hypothesized that neuronostatin elevated mean arterial pressure first by stimulating sympathetic nervous system activity followed by the release of a pressor hormone, specifically vasopressin. We found that the first phase of neuronostatin-induced increase in mean arterial pressure was reversed by pretreatment with phentolamine, indicating that phase 1 was, indeed, due to an increase in sympathetic activity. We also found that centrally injected neuronostatin led to a dose-related increase in vasopressin secretion in a time course consistent with the peak of the second phase. Furthermore, the second phase of arterial pressure elevation was reversed by pretreatment with a vasopressin 1 receptor antagonist, indicating that phase 2 was likely due to an increase in vasopressin secretion. We previously have shown that the anorexigenic and antidipsogenic effects of neuronostatin were reversed by pretreatment with the melanocortin 3/4 receptor antagonist, SHU9119, so we evaluated the ability of SHU9119 to reverse the effects of neuronostatin on MAP and vasopressin secretion. We found that SHU9119 abrogated the second phase of neuronostatin-induced increase in MAP and neuronostatin-induced vasopressin secretion, indicating that neuronostatin acts through the central melanocortin system to increase vasopressin release, ultimately leading to an elevation in MAP. PMID- 21325647 TI - Effect of protein source in diets fed during gestation and lactation on food intake regulation in male offspring of Wistar rats. AB - We hypothesized that protein source in the nutritionally adequate AIN-93G diets fed during gestation, lactation, and weaning influences food intake (FI) regulation in male offspring of Wistar rats. Pregnant rats were fed the recommended casein-based (C) or soy protein-based (S) diet during gestation (experiment 1) or during gestation and lactation (experiment 2). Pups (n = 12 per group) weaned to C or S diets were followed for 9 wk (experiment 1) or 14 wk (experiment 2). At termination, body weight was 5.4% and 9.4% higher, respectively, in offspring of dams fed the S diet. Altered FI regulation was shown by failure of devazepide (a CCK-A receptor blocker) to block FI reduction after protein preloads in offspring of S diet-fed dams, whereas it had a strong effect on offspring of C diet-fed dams (P < 0.005). Similarly, naloxone (an opioid receptor blocker) blocked FI reduction more after casein than after soy protein preloads (P < 0.01). In experiment 2, offspring of dams fed the S diet had higher hypothalamic gene expression of agouti related protein at weaning (P < 0.05), and higher FI was found throughout postweaning (P < 0.0001). FI reduction after protein preloads at week 7 and after glucose preloads at week 13 was greater in offspring of C diet-fed dams (P < 0.05). Plasma insulin at weaning and insulin, ghrelin, and glucagon-like peptide-1 at week 15 were higher in offspring of S diet-fed dams (all P < 0.05). In conclusion, nutritionally complete C and S diets consumed during gestation and lactation differ in their effects on body weight and FI regulation in the offspring. Extending the diet from gestation alone to throughout gestation and lactation exaggerated the adverse effects of the S diet. However, the diet consumed postweaning had little effect on the outcome. PMID- 21325648 TI - Localized beta-adrenergic receptor blockade does not affect sweating during exercise. AB - The purpose of the current study was to determine the effect of a locally administered nonselective beta-adrenergic antagonist on sweat gland function during exercise. Systemically administered propranolol has been reported to increase, decrease, or not alter sweat production during exercise. To eliminate the confounding systemic effects associated with orally administered propranolol, we used iontophoresis to deliver it to the eccrine sweat glands within a localized area on one forearm prior to exercise. This allowed for determination of the direct effect of beta-adrenergic receptor blockade on sweating during exercise. Subjects (n = 14) reported to the laboratory (23 +/- 1 degrees C, 35 +/ 3% relative humidity) after having refrained from exercise for >=12 h. Propranolol (1% solution) was administered to a 5-cm(2) area of the flexor surface of one forearm via iontophoresis (1.5 mA) for 5 min. A saline solution was administered to the opposing arm via iontophoresis. Each subject then exercised on a motor-driven treadmill at 75% of their age-predicted maximal heart rate for 20 min, while sweat rate was measured simultaneously in both forearms. Immediately after cessation of exercise, the number of active sweat glands was measured by application of iodine-impregnated paper to each forearm. The sweat rate for the control and propranolol-treated forearm was 0.62 +/- 41 and 0.60 +/- 0.44 (SD) mg.cm(-2).min(-1), respectively (P = 0.86). The density of active sweat glands for the control and propranolol-treated forearm was 130 +/- 6 and 134 +/- 5 (SD) glands/cm(2), respectively, (P = 0.33). End-exercise skin temperature was 32.9 +/- 0.2 and 33.1 +/- 0.3 degrees C for the control and propranolol-treated forearm, respectively (P = 0.51). Results of the current study show that when propranolol is administered locally, thus eliminating the potential confounding systemic effects of the drug, it does not directly affect sweating during the initial stages of high-intensity exercise in young, healthy subjects. PMID- 21325649 TI - Neuronal suppressor of cytokine signaling-3 deficiency enhances hypothalamic leptin-dependent phosphatidylinositol 3-kinase signaling. AB - Suppressor of cytokine signaling-3 (SOCS3) is thought to be involved in the development of central leptin resistance and obesity by inhibiting STAT3 pathway. Because phosphatidylinositol 3-kinase (PI3K) pathway plays an important role in transducing leptin action in the hypothalamus, we examined whether SOCS3 exerted an inhibition on this pathway. We first determined whether leptin sensitivity in the hypothalamic PI3K pathway was increased in brain-specific Socs3-deficient (NesKO) mice. In NesKO mice, hypothalamic insulin receptor substrate-1 (IRS1) associated PI3K activity was significantly increased at 30 min and remained elevated up to 2 h after leptin intraperitoneal injection, but in wild-type (WT) littermates, the significant increase was only at 30 min. Hypothalamic p-STAT3 levels were increased up to 5 h in NesKO as opposed to 2 h in WT mice. In food restricted WT mice with reduced body weight, leptin increased hypothalamic PI3K activity only at 30 min, and p-STAT3 levels at 30-120 min postinjection. These results suggest increased leptin sensitivity in both PI3K and STAT3 pathways in the hypothalamus of NesKO mice, which was not due to a lean phenotype. In the next experiment with a clonal hypothalamic neuronal cell line expressing proopiomelanocortin, we observed that whereas leptin significantly increased IRS1 associated PI3K activity and p-JAK2 levels in cells transfected with control vector, it failed to do so in SOCS3-overexpressed cells. Altogether, these results imply a SOCS3 inhibition of the PI3K pathway of leptin signaling in the hypothalamus, which may be one of the mechanisms behind the development of central leptin resistance and obesity. PMID- 21325650 TI - Maturation of sleep homeostasis in developing rats: a role for preoptic area neurons. AB - The present study evaluated the hypothesis that developmental changes in hypothalamic sleep-regulatory neuronal circuits contribute to the maturation of sleep homeostasis in rats during the fourth postnatal week. In a longitudinal study, we quantified electrographic measures of sleep during baseline and in response to sleep deprivation (SD) on postnatal days 21/29 (P21/29) and P22/30 (experiment 1). During 24-h baseline recordings on P21, total sleep time (TST) during the light and dark phases did not differ significantly. On P29, TST during the light phase was significantly higher than during the dark phase. Mean duration of non-rapid-eye-movement (NREM) sleep bouts was significantly longer on P29 vs. P21, indicating improved sleep consolidation. On both P22 and P30, rats exhibited increased NREM sleep amounts and NREM electroencephalogram delta power during recovery sleep (RS) compared with baseline. Increased NREM sleep bout length during RS was observed only on P30. In experiment 2, we quantified activity of GABAergic neurons in median preoptic nucleus (MnPN) and ventrolateral preoptic area (VLPO) during SD and RS in separate groups of P22 and P30 rats using c-Fos and glutamic acid decarboxylase (GAD) immunohistochemistry. In P22 rats, numbers of Fos(+)GAD(+) neurons in VLPO did not differ among experimental conditions. In P30 rats, Fos(+)GAD(+) counts in VLPO were elevated during RS. MnPN neuronal activity was state-dependent in P22 rats, but Fos(+)GAD(+) cell counts were higher in P30 rats. These findings support the hypothesis that functional emergence of preoptic sleep-regulatory neurons contributes to the maturation of sleep homeostasis in the developing rat brain. PMID- 21325651 TI - Classification of primary progressive aphasia and its variants. AB - This article provides a classification of primary progressive aphasia (PPA) and its 3 main variants to improve the uniformity of case reporting and the reliability of research results. Criteria for the 3 variants of PPA- nonfluent/agrammatic, semantic, and logopenic--were developed by an international group of PPA investigators who convened on 3 occasions to operationalize earlier published clinical descriptions for PPA subtypes. Patients are first diagnosed with PPA and are then divided into clinical variants based on specific speech and language features characteristic of each subtype. Classification can then be further specified as "imaging-supported" if the expected pattern of atrophy is found and "with definite pathology" if pathologic or genetic data are available. The working recommendations are presented in lists of features, and suggested assessment tasks are also provided. These recommendations have been widely agreed upon by a large group of experts and should be used to ensure consistency of PPA classification in future studies. Future collaborations will collect prospective data to identify relationships between each of these syndromes and specific biomarkers for a more detailed understanding of clinicopathologic correlations. PMID- 21325652 TI - Cerebrovascular risk factors and preclinical memory decline in healthy APOE epsilon4 homozygotes. AB - OBJECTIVE: To characterize the effects of cerebrovascular (CV) risk factors on preclinical memory decline in cognitively normal individuals at 3 levels of genetic risk for Alzheimer disease (AD) based on APOE genotype. METHODS: We performed longitudinal neuropsychological testing on an APOE epsilon4 enriched cohort, ages 21-97. The long-term memory (LTM) score of the Auditory Verbal Learning Test (AVLT) was the primary outcome measure. Any of 4 CV risk factors (CVany), including hypercholesterolemia (CHOL), prior cigarette use (CIG), diabetes mellitus (DM), and hypertension (HTN), was treated as a dichotomized variable. We estimated the longitudinal effect of age using statistical models that simultaneously modeled the cross-sectional and longitudinal effects of age on AVLT LTM by APOE genotype, CVany, and the interaction between the two. RESULTS: A total of 74 APOE epsilon4 homozygotes (HMZ), 239 epsilon4 heterozygotes (HTZ), and 494 epsilon4 noncarriers were included. APOE epsilon4 carrier status showed a significant quadratic effect with age-related LTM decline in all models as previously reported. CVany was associated with further longitudinal AVLT LTM decline in APOE epsilon4 carriers (p=0.02), but had no effect in noncarriers. When epsilon4 HTZ and HMZ were considered separately, there was a striking effect in HMZ (p<0.001) but not in HTZ. In exploratory analyses, significant deleterious effects were found for CIG (p=0.001), DM (p=0.03), and HTN (p=0.05) in APOE epsilon4 carriers only that remained significant only for CIG after correction for multiple comparisons. CONCLUSION: CV risk factors influence age-related memory decline in APOE epsilon4 HMZ. PMID- 21325654 TI - The taxonomy of primary progressive aphasia: it walks and quacks like a duck ... but which duck? PMID- 21325653 TI - Amyloid PET imaging in patients with mild cognitive impairment: a 2-year follow up study. AB - BACKGROUND: Patients with amnestic mild cognitive impairment (MCI) have greater risk of conversion to Alzheimer disease (AD). Increased brain amyloid burden in AD and MCI has been demonstrated with PET using [(11)C] Pittsburgh compound B (PiB) as a tracer. OBJECTIVE: To evaluate change in beta-amyloid deposition in with MCI during 2-year follow-up. METHODS: Patients with MCI and controls were studied with [(11)C] PiB PET, MRI, and neuropsychometry at baseline and these investigations were repeated in patients with MCI after follow-up. RESULTS: Those patients with MCI converting to AD during follow-up had greater [(11)C] PiB retention in the posterior cingulate (p=0.020), in the lateral frontal cortex (p=0.006), in the temporal cortex (p=0.022), in the putamen (p=0.041), and in the caudate nucleus (p=0.025) as compared to nonconverters. In converters, there was no significant change in [(11)C] PiB uptake, whereas an increase was seen as compared to baseline in nonconverters in the anterior and posterior cingulate, temporal and parietal cortices, and putamen. Hippocampal atrophy was greater in converters at baseline than in nonconverters, but increased significantly in both groups during follow-up. CONCLUSIONS: Hippocampal atrophy and amyloid deposition seem to dissociate during the evolution of MCI, the atrophy increasing clearly and [(11)C] PiB retention changing modestly when conversion to AD occurs. Longer follow-up is needed to determine whether nonconverters would convert to AD later, which would suggest accelerated [(11)C] PiB retention preceding clinical conversion. PMID- 21325656 TI - Coexistence of late gadolinium enhancement due to myocardial infarction and hypertrophic cardiomyopathy. PMID- 21325655 TI - Biotinylated probe isolation of targeted gene region improves detection of T790M epidermal growth factor receptor mutation via peptide nucleic acid-enriched real time PCR. AB - BACKGROUND: The presence of the EGFR (epidermal growth factor receptor) T790M mutation in tumor tissue or body fluids from patients treated with EGFR tyrosine kinase inhibitors may indicate the onset of resistance to treatment. It is important to identify this mutation as early as possible so that treatment can be modified accordingly or potential side effects of further treatment can be avoided. This requirement calls for high detection sensitivity. Peptide nucleic acids (PNAs) are used as PCR clamps to inhibit amplification of wild-type DNA during PCR cycling, thereby enriching for rare mutations such as T790M. We describe a modification that improves the detection limit of PNA-clamp methods by at least 20-fold. METHODS: We enriched the target by exposing genomic DNA to an EGFR exon 20-specific biotinylated oligonucleotide, followed by binding to streptavidin beads. We then prepared serial dilutions of the isolated target DNA containing the T790M mutation by mixing with wild-type DNA and then performed PNA clamp-based, real-time TaqMan PCR. For comparison, we performed PNA clamp-based PCR directly on genomic DNA. RESULTS: Whereas the detection limit for PNA clamp based PCR performed directly on genomic DNA is 1 mutant allele in 1000 wild-type alleles, conducting the assay with biotinylated oligonucleotide-enriched target DNA improved the detection limit to 1 mutant allele in 40,000 wild-type alleles. A possible explanation for the improvement in detection is that biotin-based target isolation efficiently eliminates wild-type DNA; therefore, fewer erroneous amplifications of wild-type DNA can occur early during the PCR. CONCLUSIONS: Combining target molecule isolation via a biotinylated probe with PNA-enriched TaqMan real-time PCR provides a major improvement for detecting the EGFR T790M resistance mutation. PMID- 21325658 TI - Process support for risk mitigation: a case study of variability and resilience in vascular surgery. AB - OBJECTIVE: To inform the design of IT support, the authors explored the characteristics and sources of process variability in a surgical care process that transcends multiple institutions and professional boundaries. SETTING: A case study of the care process in the Abdominal Aortic Aneurysm surveillance programme of three hospitals in Norway. DESIGN: Observational study of encounters between patients and surgeons accompanied by semistructured interviews of patients and key health personnel. RESULTS: Four process variety dimensions were identified. The captured process variations were further classified into intended and unintended variations according to the cause of the variations. Our main findings, however, suggest that the care process is best understood as systematised analysis and mitigation of risk. Even if major variations accommodated for the flexibility needed to achieve particular clinical aims and/or to satisfy patient preferences, other variations reflected healthcare actors' responses to risks arising from a lack of resilience in the existing system. On this basis, the authors outlined suggestions for a resilience-based approach by including awareness in workflow as well as feedback loops for adaptive learning. The authors suggest that IT process support should be designed to prevent process breakdowns with patient dropouts as well as to sustain risk mitigating performance. CONCLUSION: Process variation was in part induced by systemised risk mitigation. IT-based process support for monitoring processes such as that studied here should aim to ensure resilience and further mitigate risk to enhance patient safety. PMID- 21325659 TI - Can we save money by improving quality? PMID- 21325660 TI - The Mississippi categorisation of post-traumatic amnesia is better than the Russell classification. PMID- 21325661 TI - Neurologists' understanding and management of conversion disorder. AB - BACKGROUND: Conversion disorder is largely managed by neurologists, for whom it presents great challenges to understanding and management. This study aimed to quantify these challenges, examining how neurologists understand conversion disorder, and what they tell their patients. METHODS: A postal survey of all consultant neurologists in the UK registered with the Association of British Neurologists. RESULTS: 349 of 591 practising consultant neurologists completed the survey. They saw conversion disorder commonly. While they endorsed psychological models for conversion, they diagnosed it according to features of the clinical presentation, most importantly inconsistency and abnormal illness behaviour. Most of the respondents saw feigning as entangled with conversion disorder, with a minority seeing one as a variant of the other. They were quite willing to discuss psychological factors as long as the patient was receptive but were generally unwilling to discuss feigning even though they saw it as their responsibility. Those who favoured models in terms of feigning were older, while younger, female neurologists preferred psychological models, believed conversion would one day be understood neurologically and found communicating with their conversion patients easier than it had been in the past. DISCUSSION: Neurologists accept psychological models for conversion disorder but do not employ them in their diagnosis; they do not see conversion as clearly different from feigning. This may be changing as younger, female neurologists endorse psychological views more clearly and find it easier to discuss with their patients. PMID- 21325663 TI - Lung function decline in relation to mould and dampness in the home: the longitudinal European Community Respiratory Health Survey ECRHS II. AB - BACKGROUND: There are few longitudinal studies that have examined the association of lung function decline with indoor mould and dampness. Lung function decline in relation to dampness and mould in the home has studied in adults over a 9 year period. METHODS: Spirometry was performed twice in participants in the European Respiratory Health Survey (ECRHS I and II) who were initially examined aged 20-45 years, in 1990-1995 and 9 years later (n=6443). Information on their current home was collected twice by interview. Dampness (water damage or damp spots) and indoor mould, ever and in the last 12 months, were assessed. A dampness score and a mould score were calculated. In addition, 3118 homes at 22 centres were inspected directly at follow-up for the presence of dampness and mould. RESULTS: Dampness and mould were common. Overall, 50.1% reported any dampness and 41.3% any indoor mould in either ECRHS I or ECRHS II. Women with dampness at home had an additional decline in forced expiratory volume in 1 s (FEV(1)) of -2.25 ml/year (95% CI -4.25 to -0.25), with a significant trend in increased lung function decline in relation to the dampness score (p=0.03). The association in women was significant when excluding those with asthma at baseline. Observed damp spots in the bedroom was associated with a significant additional decline in FEV(1) of -7.43 ml/year (95% CI -13.11 to 1.74) in women. CONCLUSION: Dampness and indoor mould growth is common in dwellings, and the presence of damp is a risk factor for lung function decline, especially in women. PMID- 21325664 TI - U.K. immigrant screening is inversely related to regional tuberculosis burden. PMID- 21325665 TI - Rethinking TB screening: politics, practicalities and the press. PMID- 21325666 TI - Apolipoprotein CIII: 42 years old and even more interesting. PMID- 21325667 TI - Getting physical with the aortic valve. PMID- 21325668 TI - Update on venous thromboembolism: risk factors, mechanisms, and treatments. PMID- 21325669 TI - The role of thrombolysis in the clinical management of deep vein thrombosis. AB - The cornerstones of current management of deep vein thrombosis (DVT) are the routine use of anticoagulant therapy, graduated elastic compression stockings, and early ambulation. Thrombolytic therapy was previously reserved only for patients with life-, limb-, or organ-threatening complications. However, the postthrombotic syndrome has been increasingly recognized as a frequent and serious long-term complication of DVT. In parallel, endovascular thrombolytic methods have evolved considerably in recent years, prompting discussion and controversy as to whether they should be more liberally used. In some centers, pharmacomechanical catheter-directed thrombolysis is now routinely used in the treatment of acute iliofemoral DVT. Randomized trials are currently under way to determine when the use of pharmacomechanical catheter-directed thrombolysis is appropriate in patients presenting with acute proximal DVT. PMID- 21325670 TI - Hypercoagulability and hypofibrinolysis and risk of deep vein thrombosis and splanchnic vein thrombosis: similarities and differences. AB - In this review, we provide an overview of the risk factors for venous thromboembolism, focusing on hypercoagulability and hypofibrinolysis. In the first part of this review, we discuss the risk factors for commonly occurring venous thrombosis, in particular deep vein thrombosis and pulmonary embolism. In the second part, we provide an overview of the risk factors for the Budd-Chiari syndrome and portal vein thrombosis. These are rare, life-threatening forms of venous thromboembolism located in the splanchnic veins. There are many similarities in the risk profiles of patients with common venous thrombosis and splanchnic vein thrombosis. Inherited thrombophilia and hypofibrinolysis increase the risk of both common venous thrombosis and splanchnic vein thrombosis. However, there are also apparent differences. Myeloproliferative neoplasms and paroxysmal nocturnal hemoglobinuria have a remarkably high frequency in patients with thrombosis at these unusual sites but are rarely seen in patients with common venous thrombosis. There are also clear differences in the underlying risk factors for Budd-Chiari syndrome and for portal vein thrombosis, suggesting site specificity of thrombosis even within the splanchnic venous system. These clear differences in underlying risk factors provide leads for further research on the site specificity of venous thrombosis and the development of thrombosis at these distinct sites. PMID- 21325671 TI - Molecular mechanisms affecting fibrin structure and stability. AB - Fibrin structure and stability have been linked to many thrombotic diseases, including venous thromboembolism. Analysis of the molecular mechanisms that affect fibrin structure and stability became possible when the crystal structure of fibrinogen was solved. Biochemical studies of natural and recombinant variant fibrinogens have examined the interactions that mediate the conversion of soluble fibrinogen to the insoluble fibrin network. These studies identified intermolecular interactions that control fibrin structure, although some critical events remain ambiguous. Studies show that fibrin structure modulates the enzymatic lysis of the fibrin network, so the molecular mechanisms that control structure also control stability. Studies show that the mechanical stability of the fibrin clot depends on the properties of the fibrin monomer, leading investigators to explore the molecular basis of the monomer's mechanical properties. The work summarized here provides insights that might allow the development of pharmaceuticals and treatments to modulate fibrin structure and stability in vivo and thereby prevent or limit thrombotic disease. PMID- 21325672 TI - Computational approaches to studying thrombus development. AB - In addition to descriptive biological models, many computational models have been developed for hemostasis/thrombosis that provide quantitative characterization of thrombus development. Simulations using computational models that have been developed for coagulation reactions, platelet activation, and fibrinogen assembly have been shown to be in close agreement with experimental data. Models of processes involved in hemostasis/thrombosis are being integrated to simulate the development of the thrombus simultaneously in time and space. Further development of computational approaches can provide quantitative insights leading to predictions that are not obvious from qualitative biological models. PMID- 21325674 TI - The concise argument. PMID- 21325673 TI - Leukocytes and the natural history of deep vein thrombosis: current concepts and future directions. AB - Observational studies have shown that inflammatory cells accumulate within the thrombus and surrounding vein wall during the natural history of venous thrombosis. More recent studies have begun to unravel the mechanisms that regulate this interaction and have confirmed that thrombosis and inflammation are intimately linked. This review outlines our current knowledge of the complex relationship between inflammatory cell activity and venous thrombosis and highlights new areas of research in this field. A better understanding of this relationship could lead to the development of novel therapeutic targets that inhibit thrombus formation or promote its resolution. PMID- 21325675 TI - Moral enhancement and pro-social behaviour. PMID- 21325676 TI - Using computer simulations to determine the limitations of dynamic clamp stimuli applied at the soma in mimicking distributed conductance sources. AB - In previous studies we used the technique of dynamic clamp to study how temporal modulation of inhibitory and excitatory inputs control the frequency and precise timing of spikes in neurons of the deep cerebellar nuclei (DCN). Although this technique is now widely used, it is limited to interpreting conductance inputs as being location independent; i.e., all inputs that are biologically distributed across the dendritic tree are applied to the soma. We used computer simulations of a morphologically realistic model of DCN neurons to compare the effects of purely somatic vs. distributed dendritic inputs in this cell type. We applied the same conductance stimuli used in our published experiments to the model. To simulate variability in neuronal responses to repeated stimuli, we added a somatic white current noise to reproduce subthreshold fluctuations in the membrane potential. We were able to replicate our dynamic clamp results with respect to spike rates and spike precision for different patterns of background synaptic activity. We found only minor differences in the spike pattern generation between focal or distributed input in this cell type even when strong inhibitory or excitatory bursts were applied. However, the location dependence of dynamic clamp stimuli is likely to be different for each cell type examined, and the simulation approach developed in the present study will allow a careful assessment of location dependence in all cell types. PMID- 21325677 TI - Comprehensive mapping of whisker-evoked responses reveals broad, sharply tuned thalamocortical input to layer 4 of barrel cortex. AB - Cortical neurons are organized in columns, distinguishable by their physiological properties and input-output organization. Columns are thought to be the fundamental information-processing modules of the cortex. The barrel cortex of rats and mice is an attractive model system for the study of cortical columns, because each column is defined by a layer 4 (L4) structure called a barrel, which can be clearly visualized. A great deal of information has been collected regarding the connectivity of neurons in barrel cortex, but the nature of the input to a given L4 barrel remains unclear. We measured this input by making comprehensive maps of whisker-evoked activity in L4 of rat barrel cortex using recordings of multiunit activity and current source density analysis of local field potential recordings of animals under light isoflurane anesthesia. We found that a large number of whiskers evoked a detectable response in each barrel (mean of 13 suprathreshold, 18 subthreshold) even after cortical activity was abolished by application of muscimol, a GABA(A) agonist. We confirmed these findings with intracellular recordings and single-unit extracellular recordings in vivo. This constitutes the first direct confirmation of the hypothesis that subcortical mechanisms mediate a substantial multiwhisker input to a given cortical barrel. PMID- 21325678 TI - Receptor saturation controls short-term synaptic plasticity at corticothalamic synapses. AB - Glutamatergic synapses of layer 6 corticothalamic (CT) neurons form a major excitatory input onto thalamic relay cells, allowing neocortex to continuously control sensory information processing in thalamic circuits. CT synapses display both short- and long-term forms of use-dependent synaptic enhancement, mediated at least in part by increases in the probability of transmitter release. At some synapses, such increases in release probability are accompanied by a higher degree of multivesicular release (MVR) and larger glutamate transients at individual release sites, resulting in the saturation of postsynaptic receptors. The extent to which MVR and postsynaptic saturation interact and control short term plasticity at CT synapses is not known. Here we examined two distinct presynaptic forms of short-term enhancement, facilitation and augmentation, at CT synapses contacting relay neurons in the ventrobasal nucleus of the mouse thalamus. We found that, in the presence of the low-affinity antagonist gamma-D glutamylglycine, to relieve postsynaptic DL-alpha-amino-3-hydroxy-5-methylisox azole-propionic acid (AMPA) receptor saturation, the magnitude of facilitation and augmentation increased. Whereas receptor saturation was prominent for both AMPA and N-methyl-D-aspartate receptors, desensitization of AMPA receptors did not significantly alter short-term plasticity. Our results suggest that at CT synapses the activity-dependent increase in synaptic strength is controlled by postsynaptic receptor saturation. PMID- 21325679 TI - Binaural processing by the gecko auditory periphery. AB - Lizards have highly directional ears, owing to strong acoustical coupling of the eardrums and almost perfect sound transmission from the contralateral ear. To investigate the neural processing of this remarkable tympanic directionality, we combined biophysical measurements of eardrum motion in the Tokay gecko with neurophysiological recordings from the auditory nerve. Laser vibrometry shows that their ear is a two-input system with approximately unity interaural transmission gain at the peak frequency (~ 1.6 kHz). Median interaural delays are 260 MUs, almost three times larger than predicted from gecko head size, suggesting interaural transmission may be boosted by resonances in the large, open mouth cavity (Vossen et al. 2010). Auditory nerve recordings are sensitive to both interaural time differences (ITD) and interaural level differences (ILD), reflecting the acoustical interactions of direct and indirect sound components at the eardrum. Best ITD and click delays match interaural transmission delays, with a range of 200-500 MUs. Inserting a mold in the mouth cavity blocks ITD and ILD sensitivity. Thus the neural response accurately reflects tympanic directionality, and most neurons in the auditory pathway should be directional. PMID- 21325680 TI - Contributors to excess antagonist activity during movement in children with secondary dystonia due to cerebral palsy. AB - Children with secondary dystonia due to cerebral palsy exhibit abnormal upper extremity postures and slow voluntary movement. However, the interaction between abnormal postures and abnormal movement in dystonia is still unclear. Some mechanisms by which postures are maintained in dystonia include stretch reflexes, overflow of muscle activation to other muscles, and direct coactivation of antagonist muscles. This study explored the independent contributions of each of these postural mechanisms to abnormal biceps brachii (antagonist) activity during elbow extension, which slows movement. A linear model of biceps activation as a function of velocity-dependent reflexes, triceps-dependent overflow, and direct drive to the biceps was fitted to experimental data from 11 children and young adults with secondary dystonia due to cerebral palsy and 11 age-matched control subjects. Subjects performed elbow extension movements against each of four levels of resistance without perturbations or in each of two perturbation conditions. Results show that biceps activity in children with dystonia consists of significant contributions of reflex activation, overflow from triceps, and direct muscular drive. Additionally, stretch reflexes during movement are shown to be elevated at three latencies after stretch. These findings suggest that there are postural mechanisms involved in stabilizing the elbow along its slow trajectory during movement and provide a quantitative basis for the selection of treatments targeting specific impairments in children with secondary dystonia due to cerebral palsy. PMID- 21325681 TI - Space coding by gamma oscillations in the barn owl optic tectum. AB - Gamma-band (25-140 Hz) oscillations of the local field potential (LFP) are evoked by sensory stimuli in the mammalian forebrain and may be strongly modulated in amplitude when animals attend to these stimuli. The optic tectum (OT) is a midbrain structure known to contribute to multimodal sensory processing, gaze control, and attention. We found that presentation of spatially localized stimuli, either visual or auditory, evoked robust gamma oscillations with distinctive properties in the superficial (visual) layers and in the deep (multimodal) layers of the owl's OT. Across layers, gamma power was tuned sharply for stimulus location and represented space topographically. In the superficial layers, induced LFP power peaked strongly in the low-gamma band (25-90 Hz) and increased gradually with visual contrast across a wide range of contrasts. Spikes recorded in these layers included presumptive axonal (input) spikes that encoded stimulus properties nearly identically with gamma oscillations and were tightly phase locked with the oscillations, suggesting that they contribute to the LFP oscillations. In the deep layers, induced LFP power was distributed across the low and high (90-140 Hz) gamma-bands and tended to reach its maximum value at relatively low visual contrasts. In these layers, gamma power was more sharply tuned for stimulus location, on average, than were somatic spike rates, and somatic spikes synchronized with gamma oscillations. Such gamma synchronized discharges of deep-layer neurons could provide a high-resolution temporal code for signaling the location of salient sensory stimuli. PMID- 21325683 TI - Impaired prehension is associated with lesions of the superior and inferior hand representation within the human cerebellum. AB - Impairment of patients with cerebellar disease in prehension is well recognized. So far specific localizations within the human cerebellum associated with the impairment have rarely been assessed. To address this question we performed voxel based lesion symptom mapping (VLSM) in patients with chronic focal cerebellar lesions in relation to specific deficits in prehensile movements. Patients with stroke within the posterior inferior cerebellar artery territory (n = 13) or the superior cerebellar artery (SCA) territory (n = 7) and corresponding control subjects were included in the study. Participants reached out, grasped, and lifted an object with either the left or right hand and with fast or normal movement speed. Both kinematic and grip-force parameters were recorded. Magnetic resonance imaging anatomical scans of the cerebellum were acquired, and lesions were marked as regions of interest. For VLSM analysis, a nonparametric test (Brunner-Munzel) was applied. Cerebellar patients showed clear abnormalities in hand transport (impaired movement speed and straightness) and, to a lesser degree, in hand shaping (increased finger touch latencies) while grip function was preserved. Deficits were most prominent in patients with SCA lesions and for ipsilesional, fast movements. Disorders in hand transport may be more difficult to compensate than deficits in hand shaping and grip-force control in chronic focal lesions of the cerebellum because of higher demands on predictive control of interaction torques. Lesions of the superior cerebellar cortex (lobules IV, V, VI) were associated with slower hand transport, whereas lesions of both superior (lobules VI, V, VI) and inferior cerebellar cortex (lobules VII, VIII) were associated with impaired movement straightness. These findings show that both the superior and inferior hand representations within the cerebellum contribute to hand transport during prehensile movements; however, they may have a different functional role. PMID- 21325682 TI - Synchronization between the end stages of the dorsal and the ventral visual stream. AB - The end stage areas of the ventral (IT) and the dorsal (AIP) visual streams encode the shape of disparity-defined three-dimensional (3D) surfaces. Recent anatomical tracer studies have found direct reciprocal connections between the 3D shape selective areas in IT and AIP. Whether these anatomical connections are used to facilitate 3D-shape perception is still unknown. We simultaneously recorded multi-unit activity (MUA) and local field potentials in IT and AIP while monkeys discriminated between concave and convex 3D shapes and measured the degree to which the activity in IT and AIP synchronized during the task. We observed strong beta-band synchronization between IT and AIP preceding stimulus onset that decreased shortly after stimulus onset and became modulated by stereo signal strength and stimulus contrast during the later portion of the stimulus period. The beta-coherence modulation was unrelated to task-difficulty, regionally specific, and dependent on the MUA selectivity of the pairs of sites under study. The beta-spike-field coherence in AIP predicted the upcoming choice of the monkey. Several convergent lines of evidence suggested AIP as the primary source of the AIP-IT synchronized activity. The synchronized beta activity seemed to occur during perceptual anticipation and when the system has stabilized to a particular perceptual state but not during active visual processing. Our findings demonstrate for the first time that synchronized activity exists between the end stages of the dorsal and ventral stream during 3D-shape discrimination. PMID- 21325684 TI - Separability of stimulus parameter encoding by on-off directionally selective rabbit retinal ganglion cells. AB - The ganglion cell output of the retina constitutes a bottleneck in sensory processing in that ganglion cells must encode multiple stimulus parameters in their responses. Here we investigate encoding strategies of On-Off directionally selective retinal ganglion cells (On-Off DS RGCs) in rabbits, a class of cells dedicated to representing motion. The exquisite axial discrimination of these cells to preferred vs. null direction motion is well documented: it is invariant with respect to speed, contrast, spatial configuration, spatial frequency, and motion extent. However, these cells have broad direction tuning curves and their responses also vary as a function of other parameters such as speed and contrast. In this study, we examined whether the variation in responses across multiple stimulus parameters is systematic, that is the same for all cells, and separable, such that the response to a stimulus is a product of the effects of each stimulus parameter alone. We extracellularly recorded single On-Off DS RGCs in a superfused eyecup preparation while stimulating them with moving bars. We found that spike count responses of these cells scaled as independent functions of direction, speed, and luminance. Moreover, the speed and luminance functions were common across the whole sample of cells. Based on these findings, we developed a model that accurately predicted responses of On-Off DS RGCs as products of separable functions of direction, speed, and luminance (r = 0.98; P < 0.0001). Such a multiplicatively separable encoding strategy may simplify the decoding of these cells' outputs by the higher visual centers. PMID- 21325685 TI - Transient bold activity locked to perceptual reversals of auditory streaming in human auditory cortex and inferior colliculus. AB - Our auditory system separates and tracks temporally interleaved sound sources by organizing them into distinct auditory streams. This streaming phenomenon is partly determined by physical stimulus properties but additionally depends on the internal state of the listener. As a consequence, streaming perception is often bistable and reversals between one- and two-stream percepts may occur spontaneously or be induced by a change of the stimulus. Here, we used functional MRI to investigate perceptual reversals in streaming based on interaural time differences (ITD) that produce a lateralized stimulus perception. Listeners were continuously presented with two interleaved streams, which slowly moved apart and together again. This paradigm produced longer intervals between reversals than stationary bistable stimuli but preserved temporal independence between perceptual reversals and physical stimulus transitions. Results showed prominent transient activity synchronized with the perceptual reversals in and around the auditory cortex. Sustained activity in the auditory cortex was observed during intervals where the DeltaITD could potentially produce streaming, similar to previous studies. A localizer-based analysis additionally revealed transient activity time locked to perceptual reversals in the inferior colliculus. These data suggest that neural activity associated with streaming reversals is not limited to the thalamo-cortical system but involves early binaural processing in the auditory midbrain, already. PMID- 21325686 TI - Deletion of Dlx1 results in reduced glutamatergic input to hippocampal interneurons. AB - Dlx transcription factors are important in the differentiation of GABAergic interneurons. In mice lacking Dlx1, early steps in interneuron development appear normal. Beginning at ~ 1 mo of age, primarily dendrite-innervating interneuron subtypes begin to undergo apoptosis in Dlx1(-/-) mice; this is accompanied by a reduction in GABAergic transmission and late-onset epilepsy. The reported reduction of synaptic inhibition is greater than might be expected given that interneuron loss is relatively modest in Dlx1(-/-) mice. Here we report that voltage-clamp recordings of CA1 interneurons in hippocampal slices prepared from Dlx1(-/-) animals older than postnatal day 30 (>P30) revealed a significant reduction in excitatory postsynaptic current (EPSC) amplitude. No changes in EPSCs onto interneurons were observed in cells recorded from younger animals (P9 12). Current-clamp recordings from interneurons at these early postnatal ages showed that interneurons in Dlx1(-/-) mutants were immature and more excitable, although membrane properties normalized by P30. Terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling, caspase-3, and NeuN staining did not reveal frank cell damage or loss in area CA3 of hippocampal sections from adult Dlx1(-/-) mice. Delayed interneuron maturation may lead to interneuron hyperexcitability, followed by a compensatory reduction in the strength of excitatory transmission onto interneurons. This reduced excitation onto surviving interneurons, coupled with the loss of a significant fraction of GABAergic inputs to excitatory neurons starting at P30, may underlie cortical dysrhythmia and seizures previously observed in adult Dlx1(-/-) mice. PMID- 21325687 TI - Synaptic transmission and plasticity are modulated by nonmuscle myosin II at the neuromuscular junction of Drosophila. AB - The synaptic vesicle population in a nerve terminal is traditionally divided into subpopulations according to physiological criteria; the readily releasable pool (RRP), the recycling pool, and the reserve pool. It is recognized that the RRP subserves synaptic transmission evoked by low-frequency neural activity and that the recycling and reserve populations are called on to supply vesicles as neural activity increases. Here we investigated the contribution of nonmuscle myosin II (NMMII) to synaptic transmission with emphasis on the role a motor protein could play in the supply of vesicles. We used Drosophila genetics to manipulate NMMII and assessed synaptic transmission at the larval neuromuscular junction. We observed a positive correlation between synaptic strength at low-frequency stimulation and NMMII expression: reducing NMMII reduced the evoked response, while increasing NMMII increased the evoked response. Further, we found that NMMII contributed to the spontaneous release of vesicles differentially from evoked release, suggesting differential contribution to these two release mechanisms. By measuring synaptic responses under conditions of differing external calcium concentration in saline, we found that NMMII is important for normal synaptic transmission under high-frequency stimulation. This research identifies diverse functions for NMMII in synaptic transmission and suggests that this motor protein is an active contributor to the physiology of synaptic vesicle recruitment. PMID- 21325689 TI - Glycolytic enzyme activity is essential for domestic cat (Felis catus) and cheetah (Acinonyx jubatus) sperm motility and viability in a sugar-free medium. AB - We have previously reported a lack of glucose uptake in domestic cat and cheetah spermatozoa, despite observing that these cells produce lactate at rates that correlate positively with sperm function. To elucidate the role of glycolysis in felid sperm energy production, we conducted a comparative study in the domestic cat and cheetah, with the hypothesis that sperm motility and viability are maintained in both species in the absence of glycolytic metabolism and are fueled by endogenous substrates. Washed ejaculates were incubated in chemically defined medium in the presence/absence of glucose and pyruvate. A second set of ejaculates was exposed to a chemical inhibitor of either lactate dehydrogenase (sodium oxamate) or glyceraldehyde-3-phosphate dehydrogenase (alpha chlorohydrin). Sperm function (motility and acrosomal integrity) and lactate production were assessed, and a subset of spermatozoa was assayed for intracellular glycogen. In both the cat and cheetah, sperm function was maintained without exogenous substrates and following lactate dehydrogenase inhibition. Lactate production occurred in the absence of exogenous hexoses, but only if pyruvate was present. Intracellular glycogen was not detected in spermatozoa from either species. Unexpectedly, glycolytic inhibition by alpha chlorohydrin resulted in an immediate decline in sperm motility, particularly in the domestic cat. Collectively, our findings reveal an essential role of the glycolytic pathway in felid spermatozoa that is unrelated to hexose metabolism or lactate formation. Instead, glycolytic enzyme activity could be required for the metabolism of endogenous lipid-derived glycerol, with fatty acid oxidation providing the primary energy source in felid spermatozoa. PMID- 21325688 TI - Gastric and pyloric motor pattern control by a modulatory projection neuron in the intact crab Cancer pagurus. AB - Neuronal release of modulatory substances provides motor pattern generating circuits with a high degree of flexibility. In vitro studies have characterized the actions of modulatory projection neurons in great detail in the stomatogastric nervous system, a model system for neuromodulatory influences on central pattern generators. Less is known about the activities and actions of modulatory neurons in fully functional and richly modulated network settings, i.e., in intact animals. It is also unknown whether their activities contribute to the motor patterns in different behavioral conditions. Here, we show for the first time the activity and effects of the well-characterized modulatory projection neuron 1 (MCN1) in vivo and compare them to in vitro conditions. MCN1 was always spontaneously active, typically in a rhythmic fashion with its firing being interrupted by ascending inhibitions from the pyloric motor circuit. Its activity contributed to pyloric motor activity, because 1) the cycle period of the motor pattern correlated with MCN1 firing frequency and 2) stimulating MCN1 shortened the cycle period while 3) lesioning of the MCN1 axon reduced motor activity. In addition, gastric mill motor activity was elicited for the duration of the stimulation. Chemosensory stimulation of the antennae moved MCN1 away from baseline activity by increasing its firing frequency. Following this increase, a gastric mill rhythm was elicited and the pyloric cycle period decreased. Lesioning the MCN1 axon prevented these effects. Thus modulatory projection neurons such as MCN1 can control the motor output in vivo, and they participate in the processing of exteroceptive sensory information in behaviorally relevant conditions. PMID- 21325690 TI - The influence of genetic and environmental factors on the etiology of the human umbilical cord: the East Flanders prospective twin survey. AB - The umbilical cord is vulnerable to a number of insults that may alter cord morphology, diminish cord flow, and ultimately compromise fetal nutrition. Thus, an investigation of the underlying mechanisms of the development of cord morphology and possible pathologies associated with it may provide insight regarding fetal growth in the intrauterine environment and have an impact on later development of the child. To our knowledge, this study, which included 11,980 twins, is the first to report the relative contribution of genes and environment in the development of the cord. Umbilical cord length, insertion, knots, twisting, and number of vessels were examined by trained midwives at birth. Means and percentages of cord characteristics by twin zygosity/chorionicity and gender were calculated. ANOVA and chi-square tests were performed to calculate discordance in cord morphology between dizygotic (DZ), monozygotic monochorionic (MZMC), and monozygotic dichorionic (MZDC) twins. Univariate genetic models were fit to the umbilical cord characteristics to investigate the genetic and environmental influences on umbilical cord morphology. Mainly nonshared environmental but also genetic factors influence umbilical cord morphology. In MZMC male and female twins, a peripheral/marginal cord insertion was significantly (P < 0.01) more prevalent compared to MZDC and DZ male and female twins, respectively. In MZMC male twins, clockwise twisting was significantly (P = 0.02) less frequent compared to DZ twins. Environmental and genetic factors influence cord morphology and pathology. Twin members can experience environmental influences that are not shared between them even in that very early stage of in utero life. PMID- 21325691 TI - Cigarette smoke increases progesterone receptor and homeobox A10 expression in human endometrium and endometrial cells: a potential role in the decreased prevalence of endometrial pathology in smokers. AB - Cigarette smoking has long been tied to a multitude of poor health outcomes; however, in reproductive biology, smoking has shown several unintuitive findings. Smoking is associated with significantly decreased rates of endometriosis and endometrial cancer. Here, we show that treatment with cigarette smoke extract leads to increased mRNA and protein expression of homeobox A10 (HOXA10) and progesterone receptor (PGR) as well as more rapid decidualization of endometrial stromal cells in vitro. In vivo, mice exposed to cigarette smoke similarly showed increased expression of HOXA10 and PGR in the endometrium. Both HOXA10 and PGR drive endometrial differentiation and are suppressed in endometrial tumors and in endometriosis. The increased expression found upon exposure to cigarette smoke may provide a protective effect, mediating the decreased incidence of endometrial disease among smokers. This mechanism contrasts with the accepted paradigm that the effects of smoking on the uterus are secondary to ovarian alterations rather than direct effects on endometrium as demonstrated here. PMID- 21325692 TI - Rat blastocyst-derived stem cells are precursors of embryonic and extraembryonic lineages. AB - Despite recent advances in the derivation of rat embryonic stem cells, clear comprehension of the timing and mechanisms underlying rat early embryo lineage selection is lacking. We have previously shown the in vivo contribution of rat embryonic stem-like cells exclusively to developing extraembryonic tissues. To elucidate possible mechanisms governing the in vitro and in vivo behaviors of these rat blastocyst-derived stem cells, we evaluated their developmental capacity by using several approaches. Molecular marker analysis demonstrated the expression profile of genes characterizing not only pluripotency but also extraembryonic endoderm and trophoblast. In vitro differentiation through embryoid body formation showed in vitro pluripotent capacity through differentiation into derivatives of all three embryonic germ layers. Following either blastocyst injection, diploid or tetraploid aggregation, and embryo transfer, these rat blastocyst-derived stem cells also demonstrated in vivo multipotency through contribution to multiple developmentally distinct extraembryonic lineages. Features of phenotypic heterogeneity were revealed following examination of cell line morphology and culture behavior, as well as quantitative analysis of marker expression in discrete undifferentiated and differentiated populations of cells by flow cytometry. We demonstrate for the first time that stem cells derived from the rat blastocyst have the ability to contribute to the embryonic and extraembryonic lineages. Together, these results provide a valuable new model for rat stem cell biology and for the elucidation of early lineage selection in the embryo. PMID- 21325693 TI - Perception of multi-stable dot lattices in the visual periphery: an effect of internal positional noise. AB - Dot lattices are very simple multi-stable images where the dots can be perceived as being grouped in different ways. The probabilities of grouping along different orientations as dependent on inter-dot distances along these orientations can be predicted by a simple quantitative model. L. Bleumers, P. De Graef, K. Verfaillie, and J. Wagemans (2008) found that for peripheral presentation, this model should be combined with random guesses on a proportion of trials. The present study shows that the probability of random responses decreases with decreasing ambiguity of lattices and is different for bi-stable and tri-stable lattices. With central presentation, similar effects can be produced by adding positional noise to the dots. The results suggest that different levels of internal positional noise might explain the differences between peripheral and central proximity grouping. PMID- 21325694 TI - Arterial and venous thrombosis: more in common than previously thought. PMID- 21325695 TI - Vaccination of the immune-compromised patients with focus on patients with autoimmune-inflammatory diseases. AB - Among immunocompromised patients morbidity and mortality due to vaccine preventable infections is high. Although vaccination seems indicated, controversy exists about which vaccines should be offered, at what moment, and to whom. Guidelines are needed as the number of immunocompromised individuals increases due to the wider use of immunosuppressive drugs and, in particular, because since the introduction of biological agents, the spectrum of immunosuppressive drugs is rapidly expanding. In this review we will highlight controversies about vaccination in immunocompromised patients and will discuss indications for the several vaccines available to prevent infectious diseases with the focus on patients with autoimmune-inflammatory diseases. PMID- 21325696 TI - An overview of the current diagnosis and recent developments in neuroendocrine tumours of the gastroenteropancreatic tract: the diagnostic approach. AB - Neuroendocrine tumours of the gastroenteropancreatic tract (GEP-NETs) comprise a group of very heterogeneous neoplasms, which are considered 'rare diseases'. Epidemiological studies on the incidence of GEP-NETs worldwide have reported a remarkable increase in the detection of these tumours. In a recent study, based on pathology reports (PALGA) to investigate the incidence of pancreatic and duodenal neuroendocrine tumours in the Netherlands from 1991 until 2009, we also noticed a significant increase in the incidence of these tumours. In particular, the incidence of non-functioning neuroendocrine tumours had significantly increased over this period. Remarkably, a substantial discrepancy was observed between the numbers of neuroendocrine tumours diagnosed in the clinical as opposed to the pathological setting, emphasising that these tumours provide a real diagnostic challenge. To improve the diagnosis of GEP -NET s, we advocate that these complex neoplasms should receive more specialised attention. In this mini-review we provide an overview of the current diagnostic approach to GEP NETs, and add the recent developments in establishing the diagnosis of these tumours, in order to increase knowledge and awareness of GEP-NETs among clinicians and pathologists. Early detection in order to prevent morbidity from GEP-NETs is advocated. PMID- 21325697 TI - Therapy in pneumonia: what is beyond antibiotics? AB - Community-acquired pneumonia (CAP) is a common and serious disease with significant mortality, morbidity and associated healthcare costs. Severity of pneumonia is related to the extent of the inflammatory response. Primary goal in the treatment of pneumonia is starting adequate antibiotic therapy as soon as possible. However, antimicrobial resistance among the most common bacteria causing pneumonia is increasing. For those two reasons, extended inflammatory response and increasing antibiotic resistance, it is interesting to look at adjunctive non-antibiotic therapeutic strategies aimed at modulation of the inflammatory response or at the micro-organism itself. In this review, we discuss the current knowledge regarding these therapies and their possible role in the future. PMID- 21325698 TI - Risk factors of arterial cardiovascular complications in patients with prior venous thromboembolism. AB - BACKGROUND: The effect of cardiovascular risk factors (CVRs) and thrombophilic defects on the risk of arterial cardiovascular complications in patients with prior venous thromboembolism (VTE) is unclear. OBJECTIVE: We investigated whether the risk of arterial cardiovascular complications is increased after VTE and whether CVRs and thrombophilic defects influence this risk. METHODS: Subjects were selected from three family cohorts of probands with VTE or arterial cardiovascular complication before the age of 50 and thrombophilic defects (i.e. hyperhomocysteinaemia, prothrombin G20210A or elevated FVIII). For this analysis, probands with arterial cardiovascular complications before inclusion and their relatives as well as relatives without the studied thrombophilic defects were excluded. We calculated the incidence of arterial cardiovascular complications (e.g. myocardial infarction, ischaemic stroke, transient ischaemic attack or peripheral arterial disease) in subjects with and without VTE and adjusted the relative risk for at least one CVR, two or more thrombophilic defects and quintiles of a propensity score (considering risk factors conditional to VTE history). RESULTS: 861 subjects were included, of whom 399 had experienced VTE before inclusion. Twelve arterial cardiovascular complications occurred in subjects with and nine in subjects without VTE history. Hence the annual incidence was 1.0 (95% CI 0.5 to 1.7) and 0.7 (0.3 to 1.2) in subjects with and without VTE (RR 1.5, 0.6 to 3.6). Adjusting for possible confounders did not change this relative risk. CONCLUSION: The mildly elevated risk of arterial cardiovascular complications in patients with prior VTE appears to be independent of cardiovascular risk factors and thrombophilic defects. PMID- 21325699 TI - Pneumococcal aortitis: an insidious diagnosis. AB - A patient with Streptococcus pneumoniae aortitis is presented. Because of nonspecific symptoms (fever and back pain) there was a long diagnostic delay. In addition, the aortitis was located near the renal arteries which severely hampered early surgical treatment. Although emergency surgery was performed when aortic rupture occurred, the patient did not survive. Infectious arteritis of large vessels is a diagnosis often made late and associated with high mortality. PMID- 21325700 TI - Life-threatening hypokalaemic paralysis associated with distal renal tubular acidosis. AB - A 56-year-old woman developed acute respiratory failure requiring mechanical ventilation due to acute hypokalaemic paralysis. There was no gastrointestinal potassium loss nor was she taking diuretics. Additional analyses revealed a normal anion gap metabolic acidosis with a positive urine anion gap. An acid-load test revealed a renal urine acidification defect, leading to the diagnosis of distal renal tubular acidosis. Normalisation of serum potassium level was established with oral bicarbonate supplementation and temporary potassium supplementation. PMID- 21325701 TI - Hoarseness due to a thyroid mass. Symptomatic thyroid schwannoma. PMID- 21325702 TI - Skin lesions depicting a systemic disease. Weber-Christian disease. PMID- 21325703 TI - Treatment of acute hepatitis C virus infection in HIV+ patients: Dutch recommendations for management. AB - With a rising incidence of acute hepatitis C virus (HCV) infection in patients coinfected with the human immunodeficiency virus (HIV), there is a need for evidence-based treatment recommendations. There are no randomised trials available and published studies differ with respect to design, patient characteristics and number of patients included, making a comparison between studies difficult. However, it is critical to standardise treatment for this group of patients in order to optimise the outcome of therapy. The Dutch Society for HIV Physicians proposed to write recommendations for the treatment of acute HCV in HIV -coinfected patients. Combination therapy with pegylated interferon alpha and ribavirin is the preferred regimen initiated preferably within 12 weeks after the diagnosis of acute HCV. A treatment duration of 24 weeks is recommended in case of a favourable virological response (either achievement of a rapid virological response or a > 2 log10 decrease plus undetectable HCV-RNA at week 12). In all other patients prolonging the duration of therapy to 48 weeks should be considered. PMID- 21325704 TI - Red-cell casts despite a negative urine dipstick analysis in a patient with Crohn's disease. PMID- 21325705 TI - Vitamin D might reduce some vascular risk factors and, consequently, risk of dementia. PMID- 21325706 TI - Recent developments in the use of gamma-H2AX as a quantitative DNA double-strand break biomarker. AB - The past year has seen considerable developments in the use of the DNA double strand breaks (DSBs) to evaluate genome alterations in cells undergoing a variety of genotoxic stresses in vitro and in vivo. When the gamma-H2AX foci which mark the DSBs are stained, individual breaks are detectible, making the assay suitable for situations requiring great sensitivity. While the methods for the detection of gamma-H2AX foci are still evolving, particularly for in vivo detection, the basic assay has proven to be useful in several diverse areas of research. We will highlight recent developments of the assay in four areas: radiation biodosimetry, the evaluation or validation of new cancer drugs in clinical studies, chronic inflammation, and environmental genotoxicity. PMID- 21325707 TI - Improved total variation-based CT image reconstruction applied to clinical data. AB - In computed tomography there are different situations where reconstruction has to be performed with limited raw data. In the past few years it has been shown that algorithms which are based on compressed sensing theory are able to handle incomplete datasets quite well. As a cost function these algorithms use the l(1) norm of the image after it has been transformed by a sparsifying transformation. This yields to an inequality-constrained convex optimization problem. Due to the large size of the optimization problem some heuristic optimization algorithms have been proposed in the past few years. The most popular way is optimizing the raw data and sparsity cost functions separately in an alternating manner. In this paper we will follow this strategy and present a new method to adapt these optimization steps. Compared to existing methods which perform similarly, the proposed method needs no a priori knowledge about the raw data consistency. It is ensured that the algorithm converges to the lowest possible value of the raw data cost function, while holding the sparsity constraint at a low value. This is achieved by transferring the step-size determination of both optimization procedures into the raw data domain, where they are adapted to each other. To evaluate the algorithm, we process measured clinical datasets. To cover a wide field of possible applications, we focus on the problems of angular undersampling, data lost due to metal implants, limited view angle tomography and interior tomography. In all cases the presented method reaches convergence within less than 25 iteration steps, while using a constant set of algorithm control parameters. The image artifacts caused by incomplete raw data are mostly removed without introducing new effects like staircasing. All scenarios are compared to an existing implementation of the ASD-POCS algorithm, which realizes the step size adaption in a different way. Additional prior information as proposed by the PICCS algorithm can be incorporated easily into the optimization process. PMID- 21325708 TI - A dosimetric system for quantitative cell irradiation experiments with laser accelerated protons. AB - An integrated dosimetry and cell irradiation system (IDOCIS) with laser accelerated proton beams was developed, characterized, calibrated and successfully used for systematic in vitro experiments. Due to the broad exponentially shaped energy spectrum, the low-energy range of the protons (<20 MeV) and the high pulse dose, the absolute dosimetry for this beam quality is challenging. Therefore, a dedicated Faraday cup is used as an energy and dose rate independent absolute dosimeter that has been calibrated consistently with three independent methods. A transmission ionization chamber providing online relative dose information is cross-calibrated against the Faraday cup. Providing both online and absolute dose information, the IDOCIS allows for quantitative dosimetric and radiobiological studies at current low-energy laser-accelerated proton beams. Finally, first dosimetric characterizations of a laser-accelerated proton beam with the IDOCIS are presented. PMID- 21325710 TI - Influence of hydrogen on thermally induced phase separation in GeO/SiO2 multilayers. AB - The influence of the annealing atmosphere on the temperature induced phase separation of Ge oxide in GeO(x)/SiO(2) multilayers (x~1), leading to size controlled growth of Ge nanocrystals, is explored by means of x-ray absorption spectroscopy at the Ge K-edge. Ge sub-oxides contained in the as-deposited multilayers diminish with increasing annealing temperature, showing complete phase separation at approximately 450 degrees C using inert N(2) ambient. The use of reducing H(2) in the annealing atmosphere influences the phase separation even at an early stage of the disproportionation. In particular, the temperature regime where the phase separation occurs is lowered by at least 50 degrees C. At temperatures above 400 degrees C the sublayer composition, and thus the density of the Ge nanocrystals, can be altered by making use of the reduction of GeO(2) by H(2). PMID- 21325709 TI - Low-dose megavoltage cone-beam CT imaging using thick, segmented scintillators. AB - Megavoltage, cone-beam computed tomography (MV CBCT) employing an electronic portal imaging device (EPID) is a highly promising technique for providing soft tissue visualization in image-guided radiotherapy. However, current EPIDs based on active matrix flat-panel imagers (AMFPIs), which are regarded as the gold standard for portal imaging and referred to as conventional MV AMFPIs, require high radiation doses to achieve this goal due to poor x-ray detection efficiency (~2% at 6 MV). To overcome this limitation, the incorporation of thick, segmented, crystalline scintillators, as a replacement for the phosphor screens used in these AMFPIs, has been shown to significantly improve the detective quantum efficiency (DQE) performance, leading to improved image quality for projection imaging at low dose. Toward the realization of practical AMFPIs capable of low dose, soft-tissue visualization using MV CBCT imaging, two prototype AMFPIs incorporating segmented scintillators with ~11 mm thick CsI:Tl and Bi(4)Ge(3)O(12) (BGO) crystals were evaluated. Each scintillator consists of 120 * 60 crystalline elements separated by reflective septal walls, with an element-to-element pitch of 1.016 mm. The prototypes were evaluated using a bench top CBCT system, allowing the acquisition of 180 projection, 360 degrees tomographic scans with a 6 MV radiotherapy photon beam. Reconstructed images of a spatial resolution phantom, as well as of a water-equivalent phantom, embedded with tissue equivalent objects having electron densities (relative to water) varying from ~0.28 to ~1.70, were obtained down to one beam pulse per projection image, corresponding to a scan dose of ~4 cGy--a dose similar to that required for a single portal image obtained from a conventional MV AMFPI. By virtue of their significantly improved DQE, the prototypes provided low contrast visualization, allowing clear delineation of an object with an electron density difference of ~2.76%. Results of contrast, noise and contrast-to-noise ratio are presented as a function of dose and compared to those from a conventional MV AMFPI. PMID- 21325711 TI - Nanomechanical coupling enables detection and imaging of 5 nm superparamagnetic particles in liquid. AB - We demonstrate that a force microscope operated in a bimodal mode enables the imaging and detection of superparamagnetic particles down to 5 nm. The bimodal method exploits the nanomechanical coupling of the excited modes to enhance the sensitivity of the higher mode to detect changes in material properties. The coupling requires the presence of nonlinear forces. Remarkably, bimodal operation enables us to identify changes of slowly varying forces (quasi-linear) in the presence of a stronger nonlinear force. Thus, unambiguous identification of single apoferritin (non-magnetic) and ferritin (magnetic) molecules in air and liquid is accomplished. PMID- 21325712 TI - Controlling the interparticle distance in a 2D molecule-nanoparticle network. AB - Mechanically controllable break junctions allow for an impressive level of control over the distance between two electrodes, but lack stability at room temperature. On the other hand, two-dimensional (2D) networks of nanoparticles bridged by molecules form a stable device structure for investigating molecular conductance properties. Here, we combine both techniques to create a robust platform for molecular charge transport with control over the inter-electrode distance on the picometer scale. The resistance change due to bending of our structures is dependent on the molecular species present between the nanoparticles. PMID- 21325713 TI - Synthesis of dense, single-crystalline CrO2 nanowire arrays using AAO template assisted chemical vapor deposition. AB - High-density, vertically aligned CrO(2) nanowire arrays were obtained via atmospheric-pressure CVD assisted by AAO templates. The CrO(2) nanowire arrays show remarkably enhanced coercivity compared with CrO(2) films or bulk. It was found that the length of the nanowires is greatly influenced by the pore diameter of the AAO template used. The growth mechanism and the pore size dependence of the CrO(2) nanowire arrays are discussed. The present method provides a useful approach for the synthesis of CrO(2) nanowire arrays. Such highly ordered nanowire arrays within an AAO template may have important applications in ultrahigh-density perpendicular magnetic recording devices and the mass production of spintronic nanodevices. PMID- 21325714 TI - Electrical properties of conductive Ge nanocrystal thin films fabricated by low temperature in situ growth. AB - Thin films composed of Ge nanocrystals embedded in an amorphous SiO(2) matrix (Ge NC TFs) were prepared using a low temperature in situ growth method. Unexpected high p-type conductivity was observed in the intrinsic Ge-NC TFs. Unintentional doping from shallow dopants was excluded as a candidate mechanism of hole generation. Instead, the p-type characteristic was attributed to surface state induced hole accumulation in NCs, and the hole conduction was found to be a thermally activated process involving charge hopping from one NC to its nearest neighbor. Theoretical analysis has shown that the density of surface states in Ge NCs is sufficient to induce adequate holes for measured conductivity. The film conductivity can be improved significantly by post-growth rapid thermal annealing and this effect is explained by a simple thermodynamic model. The impact of impurities on the conduction properties was also studied. Neither compensation nor enhancement in conduction was observed in the Sb- and Ga-doped Ge-NC TFs, respectively. This could be attributed to the fact that these impurities are no longer shallow dopants in NCs and are much less likely to be effectively activated. Finally, the photovoltaic effect of heterojunction diodes employing such Ge-NC TFs was characterized in order to demonstrate its functionality in device implementation. PMID- 21325715 TI - Carbon nanotube films as a platform to transduce molecular recognition events in metalloporphyrins. AB - Porphyrins have been widely used for many years as functional materials for chemical sensors. Their outstanding chemical features are balanced by some restrictions in terms of transduction techniques. In particular, porphyrin layers are barely conductive, with the consequence that the fabrication of porphyrin based chemiresistors is not possible, except in few rare cases. On the other hand, carbon nanotubes (CNTs) have superior electric properties ranging from metallic to semiconductor in character. Although the conductivity of CNTs is very sensitive to adsorbed molecules, it should be considered that the adsorption onto carbon structures is also scarcely selective and cannot be modified unless other molecular recognition systems are coupled with the CNTs. Following this approach, in this paper we investigated the sensing properties of hybrid CNT-porphyrin films to explore the possibility of transducing the adsorption events occurring in a porphyrin layer into resistance changes of the CNT layers. The results obtained indicate that the presence of the porphyrin films increases the sensitivity of the electric resistance of the CNTs to the concentration of volatile compounds. This enhancement is probably due to the catalytic effect of the metalloporphyrin in conveying the charge transfer from the adsorbate molecule to the CNTs substrate. This property of metalloporphyrins may introduce a further differentiation between porphyrin based sensors that could be positively utilized in sensor array configurations. PMID- 21325717 TI - Verification of structural and electrostatic properties obtained by the use of different pseudoatom databases. AB - The existing pseudoatom databases (ELMAM, Invariom, UBDB and ELMAM2) enable structure refinement to be performed with the use of aspherical scattering factors computed from the transferable aspherical atom model (TAAM) as an alternative to independent atom model refinement. In addition, electrostatic properties can be estimated with the help of the databases. The quality of the structural and electrostatic properties obtained from the individual databases was tested. On the basis of a 100 K high-resolution single-crystal X-ray diffraction experiment on L-His-L-Ala dihydrate and 23 K high-resolution data for L-Ala [Destro & Marsh (1988). J. Phys. Chem. 92, 966-973], the structural properties, electron-density distributions and molecular electrostatic potentials obtained from different TAAMs were compared to each other and to reference models. Experimental multipolar models and theoretical models refined against theoretical structure factors computed from periodic density functional theory (DFT) calculations were compared to the TAAMs in order to determine which model best describes the crystal-field effect. Unperturbed wavefunctions based on the MP2 and DFT calculations and properties obtained directly from these were used as a reference to judge how properly the databases reproduce the properties of isolated molecules. For Gly-L-His dihydrate, D,L-His and the above-mentioned two crystal structures, deviations of the molecular dipole moments and Coulombic intermolecular interaction energies from the reference values were examined. Root mean-square deviations (RMSDs) and correlation coefficients were used as a quantitative measure of the quality of the analysed properties. TAAM refinements reproduce X-H bond lengths optimized in theoretical periodic calculations. Structural properties obtained from different database models are similar to each other. The anisotropic displacement parameters from TAAMs are similar to the results of experimental multipolar refinement; differences are about 0.5 and 2.5% for high-resolution and low-resolution data, respectively. Differences in dipole moment magnitudes calculated from database models are about 5%, and directions differ by up to 30 degrees . The values of electrostatic interaction energies estimated from the individual TAAMs differ greatly from each other and from the reference values. RMSDs are about 9-15 and 22-33 kJ mol(-1) for UBDB and the other database models, respectively. PMID- 21325716 TI - Structure-factor analysis of femtosecond microdiffraction patterns from protein nanocrystals. AB - A complete set of structure factors has been extracted from hundreds of thousands of femtosecond single-shot X-ray microdiffraction patterns taken from randomly oriented nanocrystals. The method of Monte Carlo integration over crystallite size and orientation was applied to experimental data from Photosystem I nanocrystals. This arrives at structure factors from many partial reflections without prior knowledge of the particle-size distribution. The data were collected at the Linac Coherent Light Source (the first hard-X-ray laser user facility), to which was fitted a hydrated protein nanocrystal injector jet, according to the method of serial crystallography. The data are single 'still' diffraction snapshots, each from a different nanocrystal with sizes ranging between 100 nm and 2 um, so the angular width of Bragg peaks was dominated by crystal-size effects. These results were compared with single-crystal data recorded from large crystals of Photosystem I at the Advanced Light Source and the quality of the data was found to be similar. The implications for improving the efficiency of data collection by allowing the use of very small crystals, for radiation-damage reduction and for time-resolved diffraction studies at room temperature are discussed. PMID- 21325718 TI - Interference fringes in multiple Bragg-Laue mode. AB - Interference fringes in multiple Bragg-Laue mode have been measured from the lateral surface of an Si plane-parallel crystal by changing the distance L between the incident point of X-rays and the crystal edge for two sample crystals with different thicknesses H. The period of the interference fringes becomes large when the distance L becomes large or the thickness H becomes small. When the ratio L/H is larger than 15, a shorter period of oscillation appears in addition to the interference fringes. These variations are explained by considering the beams in multiple Bragg-Laue modes based on the dynamical theory of diffraction. When L/H is less than 15, the measured fringes are well reproduced by taking account of interference between beams in the Bragg-Laue and the Bragg-Bragg-Laue modes. The short period of the oscillations observed for L/H > 15 is reproduced by adding the intensities of the beams in higher-order Bragg Laue mode. The interference fringes calculated by taking the visibility into account show good agreement with the measured ones. PMID- 21325719 TI - Importance of the consideration of anharmonic motion in charge-density studies: a comparison of variable-temperature studies on two explosives, RDX and HMX. AB - Extremely accurate X-ray data were obtained for the explosive RDX (hexahydro 1,3,5-trinitro-1,3,5-triazine) at three different temperatures (20, 120 and 298 K). Collected reflections were integrated using the latest version of the program VIIPP which uses separate Kalpha(1)/Kalpha(2) contributions to the profile fitting during integration. For each temperature both anharmonic and harmonic descriptions of the atomic thermal motion were utilized in the model refinements along with the multipole expansion of the electron density. H atoms were refined anisotropically and agree well with a previous neutron study. Topological analysis [Bader (1990). Atoms in Molecules: A Quantum Theory. The International Series of Monographs of Chemistry, edited by J. Halpern & M. L. H. Green. Oxford: Clarendon Press] of the attained electron density followed. For 1,3,5,7 tetranitro-1,3,5,7-tetraazacyclooctane (HMX), old data collected at 20 and 120 K were re-integrated with the new version of VIIPP and refined in the same manner as for RDX. In both cases theoretical structure factors were also calculated based on the 20 K structures, and employed in comparison multipole refinements for the atoms at rest. Limiting the refinement to a harmonic model of the atomic displacements may result in a biased and erroneous electron density, especially when atomic vibrations are significant (as in RDX) and at temperatures higher than obtained by using liquid helium. Given the similarity of the two compounds the effects of anharmonic motion are strikingly more severe in the case of RDX. Our study reinforces the conclusion of Meindl et al. [Acta Cryst. (2010), A66, 362-371] that in certain cases it is necessary to include anharmonic term(s) of the probability density function (or temperature factor) in order to obtain a meaningful electron density suitable for topological analysis, even for compact (high-density) light-atom structures. For RDX it was observed that the oxygen lone-pair concentrations of electrons are located close to perpendicular to the N O bond vectors, which is typical for explosive materials. Conjugation of the electron density in the -N-NO(2) fragment has been established based on the topological bond orders. Nine moderately strong hydrogen bonds and nine N-N, O-N and O-O bonding interactions were found and described. The RDX molecular electronic energy per mole is 4.02-4.04 a.u., very close to the reported value for HMX. PMID- 21325720 TI - Form, symmetry and packing of biomacromolecules. III. Antigenic, receptor and contact binding sites in picornaviruses. AB - The relation between serotype differentiation and crystallographic symmetry, revealed by the contact fingerprint diagrams investigated in Part II [Janner (2010). Acta Cryst. A66, 312-326] for the human rhinovirus, is extended to the Picornaviridae family. The approach, outlined in Part I [Janner (2010). Acta Cryst. A66, 301-311] and Part II for biomacromolecules packed in a crystal and based on concepts such as packing lattice, kissing points and crystal-packing parameters, can directly be applied to the picornaviruses. In particular, the contact fingerprint diagrams of 20 different virus strains have been derived. In these cases, as for the rhinovirus, these diagrams are serotype/strain specific, justifying the name fingerprint. The molecular basis for the serotype variability, and the associated conservation requirements, is usually analysed by considering antigenic sites, where capsid residues bind with antibodies, and receptor sites, where other residues bind with molecular receptors of the host cell membrane. Both the antigenic variation and the receptor conservation allow repeated infection of the host cells of the given animals. The graphical description of these sites is usually done by footprints and roadmap diagrams, mapping properties of the capsid surface and using the icosahedral symmetry of the capsid. The alternative fingerprint diagrammatic description, based on the crystal symmetry, adopted in Part II for the contact sites, where a capsid is bound to the next one in the crystal packing, is extended to the antigenic and receptor binding sites. Again, the antigenic/receptor fingerprints are specific, at least for the nine picornaviruses investigated so far, despite the more than a factor of ten larger coarse graining with respect to the corresponding footprint and roadmap diagrams. The latter are based on a grid spacing of about 2 A, whereas the spacing implied by the packing-lattice approximation adopted in fingerprints varies typically from 20 to 50 A. The fingerprint diagrams are accordingly simpler (because approximated), but nevertheless still serotype specific, despite the complex character of the interactions involved. PMID- 21325721 TI - Long-term results of the S.M.A.R.T. Control(TM) stent for superficial femoral artery lesions, J-SMART registry. AB - BACKGROUND: The use of a stent in the treatment of lesions of the superficial femoral artery (SFA) remains controversial. Although some reports have suggested that use of a nitinol stent in conjunction with aggressive medical management is effective for long SFA lesions, few long-term, large-scale studies have been done. METHODS AND RESULTS: A retrospective analysis was conducted of data from a multicenter study in which the S.M.A.R.T. Control(TM) stent was used for treatment of de novo SFA lesions. A total of 528 lesions in 432 patients were included. Mean patient age was 72.5+/-9.1 years; mean stent length was 15.7+/ 8.1cm; 259 lesions (49%) were classified as C/D according to the TransAtlantic Inter-Society Consensus (TASC) II classification. Primary and secondary patency at 4 years was 66% and 87%, respectively. No cilostazol administration (41% re stenosis group vs. 29% no-restenosis group, P<0.01), female gender (42% vs. 26%, P<0.01), younger age (70.7+/-9.3 years vs. 72.9+/-9.0 years, P<0.05), and chronic total occlusion (CTO; 72% vs. 52%, P<0.01) were independent predictors of re stenosis. CONCLUSIONS: The S.M.A.R.T. Control(TM) stent provided good long-term durability in the treatment of SFA lesions, and no cilostazol administration, female gender, younger age and CTO were associated with re-stenosis. PMID- 21325722 TI - Lipocalin-type prostaglandin D synthase is associated with coronary vasospasm and vasomotor reactivity in response to acetylcholine. AB - BACKGROUND: Lipocalin-type prostaglandin D synthase (L-PGDS) catalyzes the biosynthesis of PGD(2), which acts as an anticoagulant, vasodilator, and inflammatory mediator. We examined the serum L-PGDS level, coronary macro- and microvasomotor functions, and their relationship in patients with chest pain and angiographically normal coronary arteries. METHODS AND RESULTS: The study included 96 patients who underwent diagnostic coronary angiography and had angiographically normal coronary arteries. Blood flow of the left anterior descending coronary artery (LAD) was analyzed by Doppler guidewire examination. Serum L-PGDS level was determined by ELISA. Infusion of acetylcholine (ACh) induced vasospasm of the LAD in all patients with vasospastic angina (VSA) (n=45), but in none of the patients without VSA (n=51). There were no significant differences in the baseline clinical characteristics of the nonVSA and VSA groups, except for the frequency of smoking. Serum L-PGDS level in the VSA group was significantly higher than that in the nonVSA group (77.1+/-4.4 vs. 63.9+/-2.5 ug/dl, P<0.01). Significant negative correlations were observed between the degree of LAD vasomotion in response to ACh and serum L-PGDS level (3 ug/min: r= 0.33; 10 ug/min: r=-0.35; 30 ug/min: r=-0.33, P<0.01). CONCLUSIONS: The L-PGDS level was elevated in patients with VSA and was associated with epicardial coronary vasomotion in response to ACh. PMID- 21325723 TI - Repeated intracoronary infusion of peripheral blood stem cells with G-CSF in patients with refractory ischemic heart failure--a pilot study. AB - BACKGROUND: Recent investigations have suggested the clinical efficacy of granulocyte colony-stimulating factor (G-CSF) infusion alone or in combination with a single dose delivery of peripheral blood stem cells (PBSC) infusion in patients with myocardial infarction (MI) and congestive heart failure (HF). The current study tested the feasibility and effect of repeated intracoronary infusions PBSC and the mobilization of G-CSF in patients with refractory HF after MI. METHODS AND RESULTS: Patients with recent large MI and a lower left ventricular ejection fraction (LVEF) were enrolled into one of the following 3 groups: Group R (n=15) received repeated intracoronary infusion of PBSC and one dose of G-CSF; Group S (n=15) received a single infusion of PBSC and a G-CSF dose; and Group C (n=15) received neither PBSC nor a G-CSF dose. Cardiac performance was evaluated by echocardiography and single photon-emission computed tomography (SPECT). All the patients underwent 12-month follow-up. LVEF in Group R (47.00+/-4.90%) was significantly higher than that in Group S (44.40+/-3.87%, P<0.01) and Group C (40.80+/-3.41%, P<0.01). Similarly, the improvement of myocardial perfusion assessed by SPECT in Group R was more than that in Group S (P=0.012) and Group C (P<0.01). Neither death nor new MI occurred. CONCLUSIONS: Repeated intracoronary infusions of PBSC plus mobilization of G-CSF might be an optional effective strategy for treating patients with refractory HF after recent large MI. PMID- 21325724 TI - Impact of low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio on long-term outcome in patients undergoing percutaneous coronary intervention. AB - BACKGROUND: Several studies have demonstrated that the low-density lipoprotein cholesterol/high-denisty lipoprotein-cholesterol (LDL-C/HDL-C) ratio is an excellent predictor of cardiovascular disease. The aim of the present study was to determine whether the LDL-C/HDL-C ratio would affect outcome in patients after percutaneous coronary intervention (PCI). METHODS AND RESULTS: Six-hundred-eighty seven participants who underwent successful PCI for acute coronary syndromes or stable angina were enrolled. They were divided into 3 groups on the basis of the LDL-C/HDL-C ratio recorded 6 months after PCI: those with LDL-C/HDL-C<=1.5 (n=125); 1.52 (n=357). In the 3 groups, the incidence of major adverse cardiac events (MACE) was measured during the 5 years after baseline evaluation. MACE was defined as cardiac death, non-fatal myocardial infarction, new lesions, and restenosis. The median follow-up duration was 33 months. Kaplan-Meier analysis demonstrated that patients with LDL-C/HDL C<=1.5 had a significantly lower incidence of MACE after PCI than patients with 1.52.0 (P<0.001). In addition, Cox proportional hazards analysis indicated that the LDL-C/HDL-C ratio was correlated with the incidence of MACE (HR=1.39, 95% confidence interval: 1.20 1.61, P<0.001). CONCLUSIONS: The LDL-C/HDL-C ratio had an impact on long-term outcome in patients undergoing PCI. PMID- 21325726 TI - Role of peroxisome proliferator-activated receptor-gamma in atherosclerosis: an update. AB - Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a member of the ligand-activated nuclear receptor family. Thiazolidinediones, such as rosiglitazone and pioglitazone, are synthetic agonists selective for PPARgamma and have been used in the clinical treatment of type 2 diabetes. However, beyond the metabolic effects on glycemic control, PPARgamma and its ligands also have profound effects on cardiovascular biological and pathophysiological processes. As cardiovascular diseases are closely associated with insulin resistance, and the major cause of death and complications of type 2 diabetes, a comprehensive understanding of the cardiovascular roles of this receptor is critical for the rational application of the existing agonists and the future development of therapeutic modulators. Therefore, this review will focus on the recent advances regarding the cardiovascular functions of PPARgamma and its recognized effects on major cardiovascular diseases, in particular, atherosclerosis and associated processes. PMID- 21325727 TI - Non-responders to cardiac resynchronization therapy: the magnitude of the problem and the issues. AB - A variable proportion of cardiac resynchronization therapy (CRT) patients do not benefit from treatment (termed 'non-responders'). The problem of non-response to CRT might become increasingly important, because it is anticipated that larger groups of heart failure patients are indicated to the therapy. This article will discuss the definition of response to CRT, the parameters related to response to CRT, and finally whether response to CRT might be predicted. The effort to improve patient selection in order to maximize human and financial resource utilization has fallen short so far. It is, however, conceivable that rather than the identification of a 'universally' applicable cut-off value, risk strata-in which inclusion of method for determination of left ventricular volumes, etiology, QRS duration and morphology, etc-might better serve the goal of defining non-responders. Potentially simple clinical scores might help in refining outcome and by doing so, allow to more precisely measure response to CRT in daily practice in the individual patient at the time of CRT implantation. Although sophisticated cardiac imaging modalities have been intensively utilized for improving patient outcome, it seems that many mechanical dyssynchrony measures suffer from technical limitations and from difficult interpretation of the complex signals, which lack reproducibility outside highly specialized laboratories. PMID- 21325728 TI - Factors associated with tuberculosis as an AIDS-defining disease in an immigration setting. AB - BACKGROUND: Immigration can affect the evolution of TB as an AIDS-defining disease (AIDS-TB). METHODS: The Barcelona AIDS register for 1994-2005 was analyzed, and the global characteristics of AIDS-TB and AIDS-non-TB cases were compared. The Mantel-Haenszel test was used in the trend analysis, and logistic regression was used in the multivariate analysis. RESULTS: Of the 3600 cases studied, 1130 had both AIDS and TB. A declining trend in AIDS-TB rates was observed in both sexes among both immigrants and native residents. The percentage of AIDS-TB was significantly higher among immigrants (P = 0.02). The number of cases among immigrants remained constant over the period of study, but decreased among native residents. The sociodemographic and immunological characteristics associated with TB were male sex, age younger than 36 years, inner city residence, a record of incarceration, greater than 200 CD4+ T-cells/mm(3), injecting drug use, heterosexual sex, and immigration from Latin America, the Caribbean, or sub-Saharan Africa. CONCLUSIONS: The incidence of TB as an AIDS defining disease decreased in Barcelona during a recent 10-year period in both native and immigrant populations. However, immigrants remain a high-risk group for AIDS-TB and should be targeted for surveillance and control of both diseases. PMID- 21325729 TI - Three critical issues to consider before implementing a new genome-cohort study in Japan. PMID- 21325730 TI - Cohort profile: the ages 2003 cohort study in Aichi, Japan. AB - BACKGROUND: The longevity of Japanese is thought to be associated with psychosocial factors such as sense of coherence, social support, and social capital. However, the actual factors responsible and the extent of their contribution to individual health status are not known. METHODS: The Aichi Gerontological Evaluation Study (AGES) 2003 Cohort Study is a prospective cohort study of community-dwelling, activities of daily living-independent people aged 65 or older living in 6 municipalities in Chita peninsula, Aichi Prefecture, Japan. Information on psychosocial factors and other individual- and community level factors was collected in the second half of 2003 using a baseline questionnaire. Vital status and physical and cognitive decline have been followed using data derived from long-term care insurance certification. Geographical information on the study participants was also obtained. RESULTS: A total of 13 310 (6508 men; 6802 women) study participants were registered in the study. For an interim report, we followed the cohort for 48 months, yielding 24 753 person years of observation among men and 26 456 person-years among women. CONCLUSIONS: The AGES 2003 Cohort Study provides useful evidence for research in social epidemiology, gerontology, and health services. PMID- 21325731 TI - Association between dietary pattern and serum C-reactive protein in Japanese men and women. AB - BACKGROUND: Dietary pattern may influence the risks of cardiovascular disease, atherosclerosis, type 2 diabetes, and metabolic syndrome through its effects on inflammation. We evaluated the association between dietary pattern and serum high sensitivity C-reactive protein (hs-CRP) in a Japanese population. METHODS: In this cross-sectional analysis, we used baseline data from 3905 men and 5640 women (age 40-69 years) who participated in a population-based cohort study between November 2005 and December 2007. Participants with possible inflammation-related diseases, current analgesic use, high hs-CRP levels (>=3000 ng/mL) or extreme dietary energy intake were excluded. We used 46 items from a validated short food frequency questionnaire and examined major dietary patterns by factor analysis. RESULTS: We identified 5 dietary patterns: healthy (high in vegetables and fruit), Western (high in meat and fried foods), seafood (high in shellfish, squid, fish, etc.), bread (high in bread and low in rice), and dessert (high in confections and fruit). After adjustment for age, alcohol use, smoking, physical activity, and body mass index, hs-CRP levels in men were inversely associated with the healthy, bread, and dessert patterns (P-trend: 0.01, 0.06, and <0.01, respectively) and positively associated with the seafood pattern (P-trend = 0.02). In women, hs-CRP levels were inversely associated with the healthy pattern (P-trend = 0.06) and positively associated with the Western pattern (P-trend = 0.06). CONCLUSIONS: The healthy dietary pattern may be associated with suppressed inflammation in Japanese men and women, independently of body mass index and other factors. The sex-specific associations of hs-CRP with other dietary patterns (eg, the seafood pattern) require further study. PMID- 21325732 TI - An association between long-term exposure to ambient air pollution and mortality from lung cancer and respiratory diseases in Japan. AB - BACKGROUND: Evidence for a link between long-term exposure to air pollution and lung cancer is limited to Western populations. In this prospective cohort study, we examined this association in a Japanese population. METHODS: The study comprised 63 520 participants living in 6 areas in 3 Japanese prefectures who were enrolled between 1983 and 1985. Exposure to particulate matter less than 2.5 um in aerodynamic diameter (PM(2.5)), sulfur dioxide (SO(2)), and nitrogen dioxide (NO(2)) was assessed using data from monitoring stations located in or nearby each area. The Cox proportional hazards model was used to calculate the hazard ratios associated with the average concentrations of these air pollutants. RESULTS: The 10-year average concentrations of PM(2.5), SO(2), and NO(2) before recruitment (1974-1983) were 16.8 to 41.9 ug/m(3), 2.4 to 19.0 ppb, and 1.2 to 33.7 ppb, respectively (inter-area range). During an average follow-up of 8.7 years, there were 6687 deaths, including 518 deaths from lung cancer. The hazard ratios for lung cancer mortality associated with a 10-unit increase in PM(2.5) (ug/m(3)), SO(2) (ppb), and NO(2) (ppb) were 1.24 (95% confidence interval: 1.12 1.37), 1.26 (1.07-1.48), and 1.17 (1.10-1.26), respectively, after adjustment for tobacco smoking and other confounding factors. In addition, a significant increase in risk was observed for male smokers and female never smokers. Respiratory diseases, particularly pneumonia, were also significantly associated with all the air pollutants. CONCLUSIONS: Long-term exposure to air pollution is associated with lung cancer and respiratory diseases in Japan. PMID- 21325733 TI - Prevalence of mental disorders and suicidal thoughts among community-dwelling elderly adults 3 years after the niigata-chuetsu earthquake. AB - BACKGROUND: Japan is located in an area prone to natural disasters, and major earthquakes have occurred recently in rural areas where the proportion of elderly adults is high. Although elderly persons are vulnerable members of communities at a time of disaster, the prevalence of mental disorders among this population has yet to be reported in Japan. This study aimed to determine the prevalence of mental disorders and suicidal thoughts among community-dwelling elderly persons 3 years after an earthquake and to identify risk factors associated with their quality of life (QOL). METHODS: Face-to-face interviews were conducted with 496 community-dwelling persons aged 65 years or older in areas of Japan where 2 major earthquakes had occurred during a 3-year period. The main outcome was diagnosis of a mental disorder or suicidality. RESULTS: During the 3-year period after the earthquake, 1.6% of men and 5.5% of women had received a diagnosis of major depression. There were no cases of posttraumatic stress disorder. Women were more likely than men to report suicidality (7.8% vs 3.8%, P = 0.075). CONCLUSIONS: The prevalence of mental disorders was lower than that reported in previous studies. Despite the low prevalence of mental disorders, the percentage of community dwelling elderly persons with subclinical mental health symptoms was high. The results indicate that appropriate public health and medical interventions are warranted after a natural disaster. PMID- 21325734 TI - Perceptions of psychosocial hazards, work-related stress and workplace priority risks in developing countries. AB - OBJECTIVES: During the last few decades, major global developments in the world of work include an international trend to shift production to developing countries, with wide variations in working conditions and exposure to traditional and emerging occupational risks, such as psychosocial risks. The latter have rarely been addressed or explored in developing and economically-emerging country contexts while we find an abundant body of research from industrialized countries. The research presented, which is part of a larger study, explored the perception of multi-disciplinary experts from different regions, as defined by the World Health Organization (WHO), of the nature of psychosocial hazards, and work-related stress, as well as their views on workplace priorities that require urgent attention. METHODS: Semi-structured interviews were conducted with 29 experts from developing countries which were subjected to thematic analysis. A two-tiered Delphi survey was completed by 74 experts in the first round with 53 of these experts completing the survey in the second round. RESULTS: Psychosocial hazards and work-related stress were mostly seen as interchangeable in terms of source and effect and all participants perceived them as concern to their workforce. Through the interviews and the Delphi surveys they allude to our contemporary understanding of psychosocial risks. Workplace risks of priority differed by region but primarily work-related stress, injury and accident prevention, and substance abuse and risk behaviors were reported to require urgent attention. CONCLUSIONS: The current lack of awareness and research in the area of psychosocial risks and work-related stress hampers action in developing countries. International experts should support the exchange of information and the development of interventions in workplaces in developing countries with a view to integrating these emerging risks into comprehensive occupational health and safety policy frameworks to make such approaches more effective. PMID- 21325735 TI - The development of the European framework for psychosocial risk management: PRIMA EF. AB - AIM: This paper presents the development process of the European framework for psychosocial risk management (PRIMA-EF). It also summarises and discusses key findings of research conducted through this policy-orientated research programme. OBJECTIVES: This paper presents an overview of the development process of PRIMA EF. The background, methods and outcomes are described and discussed. The paper summarises the key findings of PRIMA-EF and concludes by a discussion of the merit of PRIMA-EF in the area of psychosocial risk management and its intended use. PRIMA-EF has been built on a review, critical assessment, reconciliation and harmonisation of existing European approaches for the management of psychosocial risks and the promotion of mental health at the workplace. The framework has been built from a theoretical analysis of the risk management process, identifying its key elements in logic and philosophy, strategy and procedures, areas and types of measurement, and from a subsequent analysis of European risk management approaches. It is meant to accommodate all existing psychosocial risk management approaches across Europe. It also provides a model and key indicators that relate to the psychosocial risk management process both at the enterprise and macro levels. METHOD: Experts, researchers, social partners, key European and international organisations and networks were involved throughout the development of PRIMA-EF. A number of methods were applied including literature, case study and policy reviews, interviews, surveys, focus groups and workshops. The scientific findings have been used to develop user-friendly tools for use at the enterprise and policy levels such as guidelines, indicators, guidance sheets, inventories and web-based tools. CONCLUSIONS: PRIMA-EF is intended as a framework for harmonizing practice and current methods in the area of psychosocial risk management. It can also be used as a guidance tool for the development of further methods both in Europe and internationally as it can provide a benchmark for validation of new methods. A number of priorities have been identified on the basis of PRIMA-EF for the future of psychosocial risk management and the promotion of mental health at workplace in Europe. PMID- 21325736 TI - Job stress and mental health of permanent and fixed-term workers measured by effort-reward imbalance model, depressive complaints, and clinic utilization. AB - OBJECTIVES: The number of workers with precarious employment has increased globally; however, few studies have used validated measures to investigate the relationship of job status to stress and mental health. Thus, we conducted a study to compare differential job stress experienced by permanent and fixed-term workers using an effort-reward imbalance (ERI) model questionnaire, and by evaluating depressive complaints and clinic utilization. METHODS: Subjects were permanent or fixed-term male workers at a Japanese research institute (n=756). Baseline data on job stress and depressive complaints were collected in 2007. We followed up with the same population over a 1-year period to assess their utilization of the company clinic for mental health concerns. RESULTS: The ERI ratio was higher among permanent workers than among fixed-term workers. More permanent workers presented with more than two depressive complaints, which is the standard used for the diagnosis of depression. ERI scores indicated that the effort component of permanent work was associated with distress, whereas distress in fixed-term work was related to job promotion and job insecurity. Moreover, over the one-year follow-up period, fixed-term workers visited the on-site clinic for mental concerns 4.04 times more often than permanent workers even after adjusting for age, lifestyle, ERI, and depressive complaints. CONCLUSIONS: These contrasting findings reflect the differential workloads and working conditions encountered by permanent and fixed-term workers. The occupational setting where employment status was intermingled, may have contributed to the high numbers of mental health-related issues experienced by workers with different employment status. PMID- 21325737 TI - Benzene induces cytotoxicity without metabolic activation. AB - OBJECTIVES: Benzene has been consistently associated with hematological disorders, including acute myeloid leukemia and aplastic anemia, but the mechanisms causing these disorders are still unclear. Various metabolites of benzene lead to toxicity through the production of reactive oxygen species (ROS), the inhibition of topoisomerase and DNA damage. However, benzene itself is considered to have no mutagenic or cytotoxic activity. In this study, we investigated the effects of benzene itself on a human myeloid cell line with or without benzene metabolizing enzyme inhibitors. METHODS: A human myeloid cell line, HL-60, was exposed to benzene with or without cytochrome P450 2E1 or myeloperoxidase inhibitor. Cytotoxicity was evaluated in terms of global DNA methylation levels, induction of apoptosis, and ROS production. RESULTS: Benzene did not change global DNA methylation levels. However, benzene itself increased the levels of apoptosis and ROS. This cytotoxicity did not change with the addition of benzene metabolizing enzyme inhibitors. Benzene itself increased the mRNA levels of oxidative stress-related genes and transcription factors of activator protein-1. CONCLUSIONS: Benzene did not influence global DNA methylation in HL-60 cells, but had cytotoxic effects and changed gene expression levels. To elucidate the mechanisms of benzene toxicity, benzene itself as well as benzene metabolites must be investigated. PMID- 21325738 TI - Procedure for bovine ICSI, not sperm freeze-drying, impairs the function of the microtubule-organizing center. AB - This study was designed to investigate whether freeze-dried (FD) bull spermatozoa maintained the function of the microtubule-organizing center (MTOC) after rehydration and intracytoplasmic sperm injection (ICSI). In a preliminary attempt, the cleavage and blastocyst formation rates in FD-ICSI zygotes (36 and 1%, respectively) were found to be considerably lower than those in control ICSI zygotes (67 and 21%, respectively) or in IVF zygotes (78 and 43%, respectively). An alkaline comet assay indicated that the DNA fragmentation index (length of comet tail % DNA liberated) was not significantly different between fresh and FD spermatozoa. In the main experiment, formation of sperm-asters in the FD-ICSI oocytes 7 h postinsemination occurred at a similar rate when compared with the control ICSI oocytes (41 vs. 49%). Among the oocytes exhibiting sperm aster formation, the extent of microtubule network assembly was comparable between the FD-ICSI and control ICSI groups. However, the MTOC of the ICSI oocytes was not as functional as that of IVF oocytes in terms of the aster formation rate (97%) and the fluorescent intensity of the microtubule network (2.0 folds). These results suggest that the freeze-drying process per se had no adverse effect on maintaining the MTOC function in bull spermatozoa. PMID- 21325739 TI - Basal levels and GnRH-induced responses of peripheral testosterone and estrogen in Holstein bulls with poor semen quality. AB - The present study investigated the basal levels and GnRH-induced responses of peripheral testosterone and estrogen in Holstein bulls with poor semen quality. On the basis of semen parameters, bulls (n=5) having poor semen quality were selected as experimental bulls, and good semen quality bulls (n=4) were used as control bulls. Both groups were treated intramuscularly once with GnRH (250 ug of fertirelin acetate). Blood samples were collected at -1 day (d), -30 min and 0 h (treatment) followed by every 30 min for 5 h and 1, 3 and 5 d post-GnRH treatment (PGT), and LH, testosterone and estradiol-17beta (E(2)) concentrations were measured. The pretreatment concentrations were used as basal levels. The percentage increments based on the 0-h levels were calculated per bull for each sampling time until 5 h PGT, and differences were compared between the experimental and control groups. The PGT concentrations of testosterone and basal and PGT concentrations of E(2) were significantly lower in the experimental group. The testosterone increment in the experimental group was delayed and significantly lower from 1 to 5 h PGT than those in the control group. It can be suggested that bulls with poor semen quality have delayed and lower GnRH-induced testosterone response and may also have lower estrogen levels. PMID- 21325740 TI - The effects of manipulation medium, culture system and recipient cytoplast on in vitro development of intraspecies and intergeneric felid embryos. AB - The aim of this study was to investigate if reconstructed felid embryos obtained by intraspecies or intergeneric cloning can develop in vitro. Fibroblast cells (f) from a domestic cat (DCf), marbled cat (MCf) and bovine (Bf) were used as donor cells, and oocytes (o) from domestic cats (DCo) and bovine (Bo) were used as recipient cytoplasts. There were two intraspecies (donor cell + recipient cytoplast: DCf + DCo and Bf + Bo) and three intergeneric (MCf + DCo, DCf + Bo and MCf + Bo) cloning groups in the study. In Experiment 1, the effects of manipulation media, modified TCM-199 (199H) or Emcare holding medium (EHM), on in vitro development of DCf + DCo embryos were investigated. The blastocyst formation rate (BFR) of the embryos manipulated in EHM (33.3%) was higher (P<0.05) compared with those manipulated in 199H (18.1%). In Experiment 2, DCf + DCo and MCf + DCo embryos were cocultured with or without domestic cat oviductal epithelium cells. Irrespective of coculture, the same BFR was obtained for DCf + DCo embryos (44.4 vs. 38.0%), while MCf + DCo embryos could not develop beyond the morula stage. In experiment 3, although the development of MCf + DCo and DCf + Bo embryos was arrested at the morula stage, 8.6% of MCf + Bo embryos were able to develop to the blastocyst stage. These results demonstrated that EHM was superior to 199H as an embryo manipulation medium and that the DCo and Bo could support the early embryonic development of intergeneric cloned marbled cat embryos up to the morula stage. However, postimplantation development still needs to be investigated. PMID- 21325741 TI - A case of recovery from canine destructive cholangitis in a Miniature Dachshund. AB - A 7-year-old Miniature Dachshund presented with severe chronic jaundice and elevated liver enzymes. Destructive cholangitis was diagnosed according to histopathological findings of remarkable ductopenia with inflammatory infiltrates and fibrosis in the portal areas. Supportive therapy with prednisolone, high-dose ursodeoxycholic acid, human placental extract and antibiotics was tried, and the patient showed recovery of clinical signs 3 months after diagnosis. A second liver biopsy was performed about 1 year after initial diagnosis, and bile duct restoration was confirmed with continuous inflammation around portal areas and inside the lobules. Although we could not determine which treatment was effective in this case, destructive cholangitis in dogs may be recoverable with long-term supportive therapies. PMID- 21325742 TI - Nesfatin-1 enhances glucose-induced insulin secretion by promoting Ca(2+) influx through L-type channels in mouse islet beta-cells. AB - Nucleobindin-2 (NUCB2)-derived nesfatin-1 located in the brain has been implicated in the satiety and control of energy metabolism. Nesfatin-1 is also produced in the periphery and present in the plasma. It has recently been reported that NUCB2/nesfatin-1 is localized in pancreatic islet beta-cells in mice and rats and released from islets. However, its function in islets remains largely unknown. This study examined direct effects of nesfatin-1 on insulin release from pancreatic islets and on cytosolic Ca(2+) concentration ([Ca(2+)](i)) in single beta-cells from ICR mice. In the presence of 8.3 mmol/L glucose, nesfatin-1 at 10(-10)-10(-9) mol/L tended to increase and at 10(-8) mol/L increased insulin release from isolated islets, while at 2.8 mmol/L glucose nesfatin-1 had no effect. Furthermore, nesfatin-1 at 10(-10)-10(-8) mol/L increased [Ca(2+)](i) in single beta-cells in the presence of 8.3 but not 2.8 mmol/L glucose. The nesfatin-1-induced [Ca(2+)](i) increase and insulin release were inhibited by removal of extracellular Ca(2+) and by addition of nitrendipine, a blocker of voltage-dependent L-type Ca(2+) channels. Unexpectedly, the [Ca(2+)](i) responses to nesfatin-1 were unaltered by inhibitors of protein kinase A (PKA) and phospholipase A(2) (PLA(2)). These results indicate that nesfain-1 potentiates glucose-induced insulin secretion by promoting Ca(2+) influx through L-type Ca(2+) channels independently of PKA and PLA(2) in mouse islet beta-cells. PMID- 21325743 TI - Cell proliferation in visceral organs induced by ventromedial hypothalamic (VMH) lesions: Development of electrical VMH lesions in mice and resulting pathophysiological profiles. AB - We have found that ventromedial hypothalamic (VMH) lesions produced by electrocoagulation induce cell proliferation in visceral organs through vagal hyperactivity, and also stimulate regeneration of partially resected liver in rats. To facilitate identification of proliferative and/or regenerative factors at the gene level, we developed electrical production of VMH lesions in mice, for which more genetic information is available compared to rats, and examined the pathophysiological profiles in these mice. Using ddy mice, we produced VMH lesions with reference to the previously reported method in rats. We then examined the pathophysiological profiles of the VMH-lesioned mice. Electrical VMH lesions in mice were produced using the following coordinates: 1.6 mm posterior to the bregma, anteriorly; 0.5 mm lateral to the midsagittal line, transversely; and 0.2 mm above the base of the skull, vertically, with 1 mA of current intensity and 10 s duration. The VMH-lesioned mice showed similar metabolic characteristics to those of VMH-lesioned rats, including body weight gain, increased food intake, increased percentage body fat, and elevated serum insulin and leptin. However, there were some differences in short period of hyperphagia, and in normal serum lipids compared to those of VMH-lesioned rats. The mice showed a similar cell proliferation in visceral organs, including stomach, small intestine, liver, and, exocrine and endocrine pancreas. In conclusion, procedures for development of VMH lesions in mice by electrocoagulation were developed and the VMH-lesioned mice showed pathophysiological profiles similar to those of VMH lesioned rats, particularly in cell proliferation in visceral organs. These findings have not been observed previously in gold thioglucose-induced VMH lesioned mice. This model may be a new tool for identifying factors involved in cell proliferation or regeneration in visceral organs. PMID- 21325744 TI - Adipose tissue-targeted 11beta-hydroxysteroid dehydrogenase type 1 inhibitor protects against diet-induced obesity. AB - Current pharmacological treatments for obesity and metabolic syndrome have various limitations. Recently, adipose tissue 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) has been proposed as a novel therapeutic target for the treatment of obesity and metabolic syndrome. Nevertheless, there is no adipose tissue-targeted 11beta-HSD1 inhibitor available now. We sought to develop a new 11beta-HSD1 pharmacological inhibitor that homes specifically to the white adipose tissue and aimed to investigate whether adipose tissue-targeted 11beta HSD1 inhibitor might decrease body weight gain and improve glucose tolerance in diet-induced obesity mice. BVT.2733, an 11beta-HSD1 selective inhibitor was connected with a peptide CKGGRAKDC that homes to white fat vasculature. CKGGRAKDC BVT.2733 (T-BVT) or an equimolar mixture of CKGGRAKDC and BVT.2733 (NT-BVT) was given to diet-induced obesity mice for two weeks through subcutaneous injection. T-BVT decreased body weight gain, improved glucose tolerance and decreased adipocyte size compared with vehicle treated mice. In adipose tissue T-BVT administration significantly increased adiponectin, vaspin mRNA levels; In liver T-BVT administration decreased the mRNA level of phosphoenolpyruvate carboxykinase (PEPCK), increased the mRNA levels of mitochondrial carnitine palmi toyltransferase-I (mCPT-I) and peroxisome proliferator-activated receptoralpha(PPARalpha). No significant differences in adipocyte size and hepatic gene expression were observed after treatment with NT-BVT compared with vehicle treated mice, though NT-BVT also decreased body weight gain, improved glucose tolerance, and increased uncoupling protein-2 (UCP-2) mRNA levels in muscle. These results suggest that an adipose tissue-targeted pharmacological inhibitor of 11beta-HSD1 may prove to be a new approach for the treatment of obesity and metabolic syndrome. PMID- 21325745 TI - The effect of weight loss and treatment with metformin on serum vaspin levels in women with polycystic ovary syndrome. AB - Many patients with polycystic ovary syndrome (PCOS) have insulin resistance, obesity (mostly visceral) and glucose intolerance, conditions associated with abnormalities in the production of vaspin, a novel adipokine that appears to preserve insulin sensitivity and glucose tolerance. The aim of the study was to assess serum vaspin levels in PCOS and the effects on vaspin levels of metformin or of weight loss. We studied 79 patients with PCOS and 50 healthy female volunteers. Normal weight patients with PCOS (n=25) were treated with metformin 850 mg bid for 6 months. Overweight/obese patients with PCOS (n=54) were prescribed a normal-protein, energy-restricted diet for 6 months; half of them were also given orlistat 120 mg tid and the rest were given sibutramine 10 mg qd. At baseline and after 6 months, serum vaspin levels and anthropometric, metabolic and hormonal features of PCOS were determined. Overall, patients with PCOS had higher vaspin levels than controls (p=0.021). Normal weight patients with PCOS had higher vaspin levels than normal weight controls (p=0.043). Vaspin levels were non-significantly higher in overweight/obese patients with PCOS than in overweight/obese controls. In normal weight patients with PCOS, metformin reduced vaspin levels non-significantly. In overweight/obese patients with PCOS, diet plus orlistat or sibutramine did not affect vaspin levels. Vaspin levels were independently correlated with body mass index in women with PCOS (p=0.001) and with waist circumference in controls (p=0.015). In conclusion, serum vaspin levels are elevated in PCOS but neither a small weight loss nor metformin affect vaspin levels significantly. PMID- 21325746 TI - Hypopituitarism in a patient with transsphenoidal cephalocele: longitudinal changes in endocrinological abnormalities. AB - We report a 21-year-old man with severe fatigue due to hypopituitarism. At the age of 6 years, he was diagnosed with short stature due to a GH deficiency accompanied by a sphenoid cystic lesion. Laboratory findings and provocative tests for pituitary hormone function revealed ACTH, LH, FSH, TSH, and GH deficiency. Computed tomography and magnetic resonance imaging revealed transsphenoidal cephalocele due to a defect in the floor of the sella turcica. At 6 years, he only had severe GH deficiency and poor response of LH to LHRH. Hypothalamic-pituitary dysfunction and pituitary herniation have progressed subsequently; we observed a longitudinal progression of hypothalamic-pituitary dysfunction caused by transsphenoidal cephalocele. This dysfunction requires the selection of a treatment that will not aggravate the condition further. PMID- 21325747 TI - Yoso-tama-no-kakehashi; the first Japanese guidebook on raising rats. AB - During the 18th century, raising the "nezumi" rodent became so prevalent in Japan that two guidebooks were published on the topic. The first guidebook was entitled Yoso-tama-no-kakehashi (1775) and the second was entitled Chinganso-date-gusa (1787). It remains unclear in these texts whether the term nezumi was used to refer to the rat (Rattus norvegicus) or the mouse (Mus musculus). In this review, I explore Yoso-tama-no-kakehashi (English translation: A bridge to obtaining novel jewel-like nezumi). It was written by the owner of "Shunpo-do" and comprises two volumes; the first is 34 pages in length and the second is 14 pages. It introduces the nezumi and then provides details on novel varieties and the methods that were used to raise them. The nezumi dwells in peoples' homes. It is noteworthy that the "norako" species is classified in the same group as the nezumi. The norako is smaller than the nezumi. Its alias is "hatsuka-nezumi", a term which is still used in Japan today when referring to the mouse. This indicates that when the guidebook was written people distinguished the rat from the mouse by identifying the rat using the word nezumi and the mouse using the word norako. Moreover, I recently confirmed that the rat varieties which are introduced in Yoso-tama-no-kakehashi, such as "white", "spotted", "black bear like", "deer-spotted", and "cracked-mark", can be found in modern laboratory rats. Taken together, it is very likely that the term nezumi is used to refer to the rat in Yoso-tama-no-kakehashi and that this was indeed a guidebook on the rat. PMID- 21325748 TI - Lipid mediators in life science. AB - "Lipid mediators" represent a class of bioactive lipids that are produced locally through specific biosynthetic pathways in response to extracellular stimuli. They are exported extracellularly, bind to their cognate G protein-coupled receptors (GPCRs) to transmit signals to target cells, and are then sequestered rapidly through specific enzymatic or non-enzymatic processes. Because of these properties, lipid mediators can be regarded as local hormones or autacoids. Unlike proteins, whose information can be readily obtained from the genome, we cannot directly read out the information of lipids from the genome since they are not genome-encoded. However, we can indirectly follow up the dynamics and functions of lipid mediators by manipulating the genes encoding a particular set of proteins that are essential for their biosynthesis (enzymes), transport (transporters), and signal transduction (receptors). Lipid mediators are involved in many physiological processes, and their dysregulations have been often linked to various diseases such as inflammation, infertility, atherosclerosis, ischemia, metabolic syndrome, and cancer. In this article, I will give an overview of the basic knowledge of various lipid mediators, and then provide an example of how research using mice, gene-manipulated for a lipid mediator-biosynthetic enzyme, contributes to life science and clinical applications. PMID- 21325749 TI - Study on establishment of congenic strains and screening of characteristics in IRS-2 deficient mice to support translational research on type 2 diabetes. AB - In research into type 2 diabetes, diet-based approaches, i.e., nutritional intake, are important approaches for therapeutic research. We would like to make the following two proposals from the standpoint of laboratory animal science for reproducible animal studies using type 2 diabetes mouse models. These include congenic strains of diabetes mouse models and improvement of diets used in daily care and management. In this research, the Irs2homo-knockout mouse with both impaired glucose tolerance and insulin resistance, and thus type 2 diabetes, was established as a congenic strain. The effect of the genetic background on the onset of diabetes was examined. Next, we discussed which diets are appropriate for general care and management of mouse models in which the pathophysiology is controlled by nutritional conditions. Therefore, we prepared diets by converting the current Japanese and US diets to mice and adjusting the diet contents accordingly. We compared the insulin signals such as those of the liver, pancreas and white fat. We were thus able to establish an evaluation system closer to diabetes in the current population. Using this data as an example, we should consider the quality and ordinary diet of animals as important factors in animal experiments. PMID- 21325750 TI - Influence of platinum nanoparticles orally administered to rats evaluated by systemic gene expression profiling. AB - Platinum is recognized as a harmless metal and is widely used in many industrial products. Recent studies have proposed that platinum in the form of nanoparticles has antioxidant properties, suggesting potential uses for platinum nanoparticles as additives in foods and cosmetics, with direct exposure consequences for humans. However, the influence of platinum nanoparticles on humans has not been sufficiently evaluated, thus far. Therefore, to investigate the influence of platinum nanoparticles on a living body, we comprehensively examined the expression profiles of genes obtained from 25 organs and tissues of rats after oral administration of platinum nanoparticles by gavage. Comparative analysis revealed that the expression levels of 18 genes were altered in 12 organs and tissues after the administration (approximately 0.17% of all the genes examined). Of the tissues examined, those of the glandular stomach, which were most directly exposed to the orally administered platinum nanoparticles, showed altered expression levels of genes associated with inflammation. In subcutaneous adipose tissue, the expression levels of genes whose products exhibited ATPase activity were altered. Real-time reverse transcription polymerase chain reaction (real time RT-PCR) analysis confirmed the alteration in the expression levels of these genes in these 2 different tissues. Our findings indicate that orally administered platinum nanoparticles do not have a marked effect on systemic gene expression levels, except on a small number of genes expressed in rat tissues, including peripheral tissues indirectly exposed to the orally administered nanoparticles. PMID- 21325751 TI - Effect of short period vasectomy on FSH, LH, inhibin and testosterone secretions, and sperm motility in adult male rats. AB - The present study was undertaken to clarify changes in secretions of FSH, LH, inhibin and testosterone, and sperm motility after bilateral vasectomy in adult male rats. Bilateral vasectomy was created surgically (treated group) and intact rats were used as control (control group). On days 3, 5, 7, 14, 30, 60, and 90 after surgery, plasma concentrations of FSH, LH, inhibin, and testosterone were measured by radioimmunoassay, and sperm motility characteristics were measured by computer-assisted sperm analysis (CASA). The results show that weights of epididymides significantly increased in vasectomized rats as compared to control rats. Histologically, damage to spermatogenesis was observed in vasectomized rats. Multinucleated giant cells were observed in the lumen of some seminiferous tubules, and there were degenerative spermatids in the epididymides of vasectomized rats. Plasma levels of LH, FSH, and testosterone only decreased on day 3 after vasectomy; however, plasma levels of ir-inhibin significantly increased on day 3 after vasectomy. In addition, the sperm motility parameters, straight-line velocity, curvilinear velocity, deviation of the sperm head from the mean trajectory and the maximum amplitude of lateral head displacement were decreased from day 60 after vasectomy. These results suggest that vasectomy reduces sperm motility starting from day 60 after vasectomy, and early bilateral vasectomy does not strongly affect the endocrine function of the testis, though it may result in damage to spermatogenesis in vasectomized rats. PMID- 21325752 TI - Kyoto rhino rats derived by ENU mutagenesis undergo congenital hair loss and exhibit focal glomerulosclerosis. AB - N-ethyl-N-nitrosourea (ENU) mutagenesis is an important tool for studying gene function and establishing human disease models. Here, we report the characterization of a novel hairless mutant rat strain that carries a recessive mutation called Kyoto rhino (krh), which was created by ENU-mutagenesis. We produced a F344-krh strain through inbreeding without backcrossing to F344 rats. The krh/krh rats lost their coat hair by eight weeks of age. They also developed wrinkled skin, cystic hair canals and long curved nails by four months of age. Markedly dilated hair follicles that contained keratin debris were observed during histological analysis of the skin. The krh locus was mapped near the hairless (Hr) gene on chromosome 15. Sequence analysis revealed a nonsense mutation (c. 1238 C>A, p. S413X) in the Hr gene. The truncated HR protein was deduced to lack a zinc-finger domain and repression domains. In aged Hr(krh)/Hr(krh) rats, focal glomerulosclerosis (FGS) was observed in which collapsed glomeruli contained protein exudates in Bowman's capsule. Mesangial matrices that had proliferated in segments and foot processes that were fused in podocytes were also observed. The Hr(krh)/Hr(krh) rats also suffered from significant proteinuria. Given its breeding history, the F344-Hr(krh) strain may harbor ENU-induced mutation(s) that underlie FGS in addition to having the Hr(krh) mutation. The F344-Hr(krh) rat is a useful model of skin disease and may provide a new model system for the examination of the pathogenesis of FGS. PMID- 21325753 TI - Triplex PCR for the simultaneous detection of Pseudomonas aeruginosa, Helicobacter hepaticus, and Salmonella typhimurium. AB - The accurate and economical diagnosis of pathogenic bacteria is necessary for the microbiological control of laboratory animals. In this study, we developed a triplex PCR method for the direct detection of three common gastroenteric bacteria, Pseudomonas aeruginosa, Helicobacter hepaticus, and Salmonella typhimurium. Targets were specifically amplified by conventional PCR assay using a genomic fragment from P. aeruginosa, 16S ribosomal RNA from H. hepaticus, and the invA gene from S. typhimurium. To investigate the specificity of our primers, they were tested against purified DNA from many other bacterial species. There were no amplification products from other bacteria. Under optimized conditions, the triplex assay simultaneously yielded a 726-bp product from P. aeruginosa, a 417-bp product from H. hepaticus, and a 246-bp product from S. typhimurium. The detection limits of this assay in pure culture were 10 pg for P. aeruginosa, and 0.1 pg for H. hepaticus and S. typhimurium. All three bacteria were successfully detected in the liver, cecum, and feces of experimentally infected mice. This method is a useful and convenient assay that allows the simultaneous identification of bacterial pathogens in mice. Our triplex method will be used to improve quality control in the detection of pathogenic bacterial infections in laboratory animal facilities. PMID- 21325754 TI - Identification of a novel point mutation of mouse Atp2b2 induced by N-ethyl-N nitrosourea mutagenesis. AB - N-ethyl-N-nitrosourea (ENU)-induced mutagenesis is an important approach in the study of gene function and the establishment of human disease models. Here we report an ENU-induced mutation, Elfin, as a mouse model with hearing loss. Homozygous mutants were deaf and displayed severe ataxia, while heterozygous mice had a significant hearing loss. Histological analysis of the inner ear revealed that Elfin had progressive degeneration of the organ of Corti, spiral ganglion cells and an absence of otoconia in the vestibular system. The new mutation was mapped to chromosome 6 between microsatellite markers D6Mit39 and D6Mit254, where the Ca(2+)-ATPase type 2 (Atp2b2) gene resides. Sequence analysis revealed a unique T-to-A transition mutation at amino acid 655 resulting in Ile-to-Asn substitution. These results for the Elfin mutant confirm the role of ATP2B2 in balance, hearing and formation of otoconia and suggest it may serve as a new model of human hereditary hearing loss. PMID- 21325756 TI - Aquaporin-1 expression in canine peripheral erythrocytes and its relation to cell volume. AB - To evaluate the relationship between aquaporin-1 (AQP1) expression and the cell volume of red blood cells (RBCs), canine peripheral RBCs were separated according to specific gravity, and expression of the AQP1 protein on the membrane of RBCs was compared using anti-dog AQP1 polypeptide serum. Western blot analysis indicated that there was no significant difference in AQP1 expression between large and small cell fractions. In addition, the AQP1 expression of inherited high K/low Na RBCs which are known to be 20% larger than normal RBCs, was comparable to that of normal RBCs. These results suggest that AQP1, the major water channel in RBCs, does not determine the cell volume of peripheral canine RBCs. PMID- 21325755 TI - Influence of internal fixator stiffness on murine fracture healing: two types of fracture healing lead to two distinct cellular events and FGF-2 expressions. AB - This study aimed to clarify the relationship between the mechanical environment at the fracture site and endogenous fibroblast growth factor-2 (FGF-2). We compared two types of fracture healing with different callus formations and cellular events using MouseFix(TM) plate fixation systems for murine fracture models. Left femoral fractures were induced in 72 ten-week-old mice and then fixed with a flexible (Group F) or rigid (Group R) Mouse Fix(TM) plate. Mice were sacrificed on days 3, 5, 7, 10, 14, and 21. The callus volumes were measured by 3D micro-CT and tissues were histologically stained with hematoxylin & eosin or safranin-O. Sections from days 3, 5, and 7 were immunostained for FGF-2 and Proliferating Cell Nuclear Antigen (PCNA). The callus in Group F was significantly larger than that in Group R. The rigid plate allowed bone union without a marked external callus or chondrogenesis. The flexible plate formed a large external callus as a result of endochondral ossification. Fibroblastic cells in the granulation tissue on days 5 and 7 in Group F showed marked FGF-2 expression compared with Group R. Fibroblastic cells showed ongoing proliferation in granulation tissue in group F, as indicated by PCNA expression, which explained the relative granulation tissue increase in group F. There were major differences in early phase endogenous FGF-2 expression between these two fracture healing processes, due to different mechanical environments. PMID- 21325757 TI - Elevated serum levels of resistin, leptin, and adiponectin are associated with C reactive protein and also other clinical conditions in rheumatoid arthritis. AB - OBJECTIVE: Body fat is an important source of hormones and cytokines (adipokines) that not only regulate the energy balance, but also regulate the inflammatory and immune responses. This study investigated the association of clinical conditions with serum levels of adipokines in patients with rheumatoid arthritis. METHODS: Serum levels of resistin, leptin, and adiponectin were measured by enzyme-linked immunosorbent assay in 141 patients (110 women) who fulfilled the 1987 revised criteria of the American Rheumatism Association for the diagnosis of rheumatoid arthritis and in 146 normal controls (124 women). Then the correlations between adipokine levels and clinical parameters were evaluated. RESULTS: The serum resistin level did not differ between the patients and controls. However, serum leptin levels were significantly higher in male and female rheumatoid arthritis patients than in the corresponding controls, while the serum adiponectin level was significantly higher in female patients than in female controls. Multivariate analysis revealed that predictors of an elevated resistin level were female sex and C-reactive protein (CRP), while the leptin level was related to the body mass index and CRP. Predictors of an elevated adiponectin level were the use of prednisolone and CRP, however, CRP was negatively associated with adiponectin in patients with rheumatoid arthritis. CONCLUSION: The serum levels of resistin and leptin were positively associated with CRP level in patients with rheumatoid arthritis, suggesting that these adipokines may act as pro-inflammatory cytokines in this disease. The serum adiponectin level was elevated in the patients, however, it was negatively associated with CRP level. In addition, the serum levels of resistin, leptin, and adiponectin were also associated with female sex, BMI and the use of prednisolone, respectively. PMID- 21325758 TI - Ubiquitin-positive pneumocytes and inclusion bodies are present in secondary organizing pneumonia. AB - OBJECTIVE: We previously reported that various types of interstitial pneumonia (IP) patterns contain intracytoplasmic eosinophilic inclusions or Mallory bodies (inclusions) that are ubiquitin positive (Ub+). In the present study, we examined tissues with the organizing pneumonia pattern (OP) to determine if they contain inclusions and Ub+ pneumocytes using lobectomized specimens. METHODS: Tissues from 34 patients with secondary OP, which appeared in 33 carcinomas and 1 pulmonary abscess, were histologically evaluated for the type of intraluminal granulation tissue and the presence of erosions and inclusions. Granulation tissues were classified into polypoid, mural and occluded subtypes according to Basset's criteria and scored. RESULTS: Inclusions were noted in 5.9% of the secondary OP cases with light microscope. Ub+ pneumocytes were detected after immunostaining and all inclusions were Ub+. Ub+ pneumocytes (inclusions) were noted in 14.7% of the secondary OP cases. OP contained pneumocyte erosions and inflammatory cell infiltration without a significant difference in the Ub+ and Ub subgroups. Although there was no significant difference in the polypoid type of granulation tissue between the Ub+ and Ub- negative (Ub-) subgroups, the Ub+ subgroup had significant increases (p<0.05) in the mural-occluded type of granulation tissue (Ub+: 1.76+/-0.64, n=5 vs. Ub-: 0.72+/-0.87, n=29) as compared to the Ub- subgroup. CONCLUSION: Some patients with secondary OP had Ub+ inclusions as pneumocyte injury. PMID- 21325759 TI - Clinical features of lymphangioleiomyomatosis complicated by renal angiomyolipomas. AB - OBJECTIVE: Renal angiomyolipomas (R-AMLs) are major complications of lymphangioleiomyomatosis (LAM). The objective of this study was to better understand the influence of R-AMLs in patients with LAM on the prognosis and other clinical factors related to respiration, and to investigate the management of R-AMLs in patients with LAM. PATIENTS AND METHODS: We retrospectively investigated the clinical features of 7 patients with LAM [4 were TSC (Tuberous sclerosis complex)-LAM and 3 were S (sporadic)-LAM] complicated by R-AMLs admitted to our hospital from 1997 to 2008. RESULTS: All patients were females and the mean age at diagnosis of LAM was 40.7 years (31.7 years for TSC-LAM and 52.7 years for S-LAM). Although 5 patients had symptoms related to R-AMLs, only 1 patient experienced symptoms related to R-AMLs at the time of diagnosis. Five patients had bilateral and 2 patients had unilateral R-AMLs. R-AMLs ruptured in 4 cases (3 patients were TSC-LAM) including 2 patients in whom they ruptured bilaterally, and who underwent bilateral nephrectomy. In 1 case, unilateral R AMLs grew larger and appeared on the other side during the follow-up period. CONCLUSION: Although only rare cases of LAM show symptoms related to R-AMLs initially, R-AMLs are a notable complication. To avoid nephrectomy, R-AMLs should be diagnosed when they are small and should be followed up carefully by periodic echograms or CT scans. PMID- 21325760 TI - Prognosis of medical treatment for Japanese patients with carotid stenosis. AB - PURPOSE: This study was designed to determine whether, among Japanese patients receiving medical treatment for carotid stenosis, symptomatic carotid stenosis was more strongly associated with subsequent neurological events than asymptomatic carotid stenosis. METHODS: We consecutively registered Japanese patients with carotid stenosis of 50% or more as evaluated by digital subtraction angiography who were treated medically. We reviewed medical records regarding previous neurological events as well as other stroke risk factors and underlying diseases at admission. We monitored the occurrence and date of stroke and death after the first evaluation. We also attempted to obtain information from patients or their family members by means of a questionnaire or telephone survey. RESULTS: Among 67 patients with carotid stenosis of 50% or more who were treated medically, follow-up was completed in 62 subjects (56 men, 6 women; median age, 72 years; mean follow-up period, 37.3 months). The number of patients with subsequent stroke with symptomatic carotid stenosis was five, while that with asymptomatic stenosis was four. A significantly higher rate of subsequent stroke was observed in patients with symptomatic carotid stenosis compared with those with asymptomatic stenosis (p=0.012). Cox proportional hazards model indicated that symptomatic carotid stenosis was significantly correlated with future neurologic events (p=0.019). CONCLUSION: In a Japanese population with carotid stenosis treated medically, symptomatic carotid stenosis is associated with future stroke more frequently than asymptomatic carotid stenosis. PMID- 21325761 TI - Segmental copy number loss of SFMBT1 gene in elderly individuals with ventriculomegaly: a community-based study. AB - OBJECTIVE: Idiopathic normal pressure hydrocephalus (iNPH) is clinically important as a treatable gait disturbance or preventable dementia by shunt operation. We have recently reported that approximately 1.5% of the elderly living in a Japanese community showed ventriculomegaly with features of iNPH on MRI (VIM), which may represent a preclinical stage of iNPH. The purpose of the present study was to identify a possible genetic change in VIM subjects. METHODS: Eight subjects with VIM and 10 healthy individuals were examined for copy number variations (CNV) with a CNV-targeted whole-genome oligonucleotide microarray (Agilent 400 K CNV array). Another panel of 100 healthy Japanese individuals was screened for CNV by whole-genome using the deCODE-Illumina CNV 370 K chip. Immunohistochemical examination of the human brain was performed using an avidin biotin-peroxidase complex method. RESULTS: Among several genetic changes observed, a copy number loss within the SFMBT1 gene was seen in half of the VIM cases (4 of 8 cases), that was rare among the Japanese control subjects (0/10 by Agilent 400 K CNV array or 1/100 by deCODE/Illumina CNV 370 K chip). Immunohistochemical examination of the human brain revealed that the SFMBT1 protein was localized mainly in the arterial walls, the ependymal cells, and the epithelium of the choroid plexus, all of which play a crucial role in the CSF circulation. CONCLUSION: A segmental copy number loss of the SFMBT1 gene may be involved in the pathological process in some individuals with VIM/iNPH. PMID- 21325762 TI - Clinical and radiological features of acute-onset diffuse interstitial lung diseases in patients with rheumatoid arthritis receiving treatment with biological agents: importance of Pneumocystis pneumonia in Japan revealed by a multicenter study. AB - OBJECTIVE: Acute-onset diffuse interstitial lung disease (AoDILD) in patients with rheumatoid arthritis (RA) has been a serious concern, especially for those under treatment with biological agents which may affect the presentation and outcome of AoDILD, including Pneumocystis pneumonia (PCP). Therefore, we conducted a retrospective, multi-center study of AoDILD in RA patients receiving biological agents. METHODS: Patients who developed AoDILD while receiving biological agents (infliximab, etanercept, adalimumab and tocilizumab) were enrolled in the study. Definite PCP was defined as patients who showed either P. jirovecii organisms in their respiratory samples by microscopic examination, or positive tests for both P. jirovicii DNA-PCR with respiratory samples and an elevated serum 1,3-beta-D-glucan level above the cut-off value. Probable PCP was defined as either a positive test for P. jirovicii PCR or an elevated serum beta D-glucan level. Chest HRCT findings were evaluated and scored by two board certified radiologists. RESULTS: The final diagnoses for 26 patients examined were definite PCP for 13 patients, probable PCP for 11, and methotrexate associated pneumonitis in 2 patients. Definite and probable PCP cases were clinically indistinguishable. Generalized, diffuse ground-glass opacity (GGO) is the characteristic HRCT finding in patients with definite or probable PCP, which was different from our previous findings in RA patients, mostly without biologics, showing GGO distributed in a panlobular or multilobular manner. The clinical outcome was favorable by treatment with trimethoprim-sulfamethoxazole and glucocorticoids. CONCLUSION: The possibility of PCP should be intensively investigated in RA patients developing AoDILD while receiving biological agents. PMID- 21325763 TI - A case of adult autoimmune hepatitis with histological features of giant cell hepatitis. AB - Giant cell hepatitis is rare in adult patients. This form of hepatitis shows fast progression to cirrhosis. A 65-year-old woman was admitted to our hospital with jaundice. She was negative for hepatitis virus markers and positive for antinuclear antibodies. We diagnosed her as autoimmune hepatitis. Liver biopsy findings revealed typical features of interface hepatitis and giant cell hepatitis. Giant cells were positive for keratin 8/18, but not for keratin 19, keratin 7 or Ki-67. These results suggest that giant cell formation is associated with the fusion of matured hepatocytes rather than the active proliferation of immature cells. PMID- 21325764 TI - A case of primary biliary cirrhosis which developed eight years after diagnosis of systemic lupus erythematosus. AB - A 29-year-old Japanese female was diagnosed with systemic lupus erythematosus (SLE) at the age of 21 and went into remission after administration of prednisolone. Although no liver dysfunction had been observed upon diagnosis of SLE or during follow-up, an increase of hepatobiliary enzyme levels was seen eight years after the diagnosis of SLE. Antimitochondrial antibodies were positive. Cell infiltration around intrahepatic bile ducts and granuloma formation were observed in the liver. Therefore, she was diagnosed with primary biliary cirrhosis (PBC). Administration of ursodeoxycholic acid resulted in normalization of hepatobiliary enzyme levels. Development of PBC after SLE is extremely rare. PMID- 21325765 TI - Long fish tapeworm in the intestine: an in situ observation by capsule endoscopy. AB - We present the case of a patient who was referred to our hospital after she reported having passed a long, whitish object per rectum. Accordingly, capsule endoscopy was performed using the PillCam((r)) SB video capsule. A tapeworm of the species Diphyllobothrium nihonkaiense was detected; it appeared to be freely floating and unfolded in the jejunum and sometimes tangled or irregularly folded in the ileum. The stretching of the strobila by strong peristalsis in the ileum may have resulted in the separation of the caudal portion of the strobila, which descended into the colon and was eventually passed per rectum. PMID- 21325766 TI - Severe hypercalcemia associated with hepatocellular carcinoma secreting intact parathyroid hormone: a case report. AB - Here we describe a 73-year-old woman with hypercalcemia caused by a hepatocellular carcinoma (HCC) secreting intact parathyroid hormone (iPTH). Serum tumor markers and dynamic CT findings indicated a diagnosis of HCC. The source of the elevated serum iPTH was not obvious. Transarterial chemoembolization (TACE) was effective against the HCC, and the serum iPTH level fell to within the normal range, suggesting a correlation between the carcinoma and the iPTH. About 2 months later, the tumor had grown and the serum calcium level increased leading to physical deterioration and death. This clinical course suggested that HCC can ectopically secrete iPTH. PMID- 21325767 TI - Development of Cushing's syndrome during effective chemotherapy for small cell lung cancer. AB - Paraneoplastic Cushing's syndrome caused by ectopic adrenocorticotropin (ACTH) production has been reported. However, most cases of this syndrome are diagnosed before first-line chemotherapy or at the time of disease recurrence. Here, we present a 53-year-old man who gradually developed the symptoms of Cushing's syndrome during effective chemotherapy for small cell lung cancer. His symptoms were controlled using mitotane, but his primary cancer progressed and he died 5 months after the start of chemotherapy. This very rare case of Cushing's syndrome associated with small cell lung cancer during effective chemotherapy is presented here. PMID- 21325768 TI - Late postprandial hypoglycemia due to bioactive insulin dissociation from autoantibody leading to unconsciousness in a patient with insulin autoimmune syndrome. AB - We report here the case of an 83-year-old man who was treated for unconsciousness and hypoglycemia (39 mg/dL) accompanied by marked elevation of serum immunoreactive insulin (IRI) (4,760 uIU/mL). We diagnosed his condition as insulin autoimmune syndrome (IAS, Hirata disease) because of a high insulin autoantibody (IAA) titer (>90%: bound/total) and no history of exogenous insulin administration. Reactive hypoglycemia occurred due to immediate association followed by dissociation between insulin and insulin autoantibodies after glucose or food intake. An alpha-glucosidase inhibitor in combination with frequent small meals reduced the postprandial hyperglycemia (glucose spike) and ameliorated the reactive hypoglycemia. PMID- 21325769 TI - Malignant vaginal melanoma with metastases to the papilla of Vater in a dialysis patient: a case report. AB - Malignant vaginal melanoma is an extremely rare clinical condition, with less than 150 cases reported to date. A dialysis patient had primary vaginal melanoma with metastases to the papilla of Vater. Gastroduodenoscopy revealed a polypoid tumor. Histological findings revealed vimentin, S-100 protein, HMB45, MelanA positive sarcoma-like cells. This staining pattern indicated that this tumor was a malignant melanoma of the papilla. Analysis of an autopsy specimen of the papilla of Vater revealed metastasis from the primary vaginal melanoma. Metastasis of a malignant tumor to the gastrointestinal tract, especially to the papilla, is uncommon. Melanoma should be considered in the differential diagnosis of primary gastrointestinal tract malignancy. PMID- 21325770 TI - Pneumocystis jirovecii pneumonia and alveolar hemorrhage in a pregnant woman with human T cell lymphotropic virus type-1 infection. AB - Acute lung injury during pregnancy results in morbidity and mortality in both the mother and the fetus. Pneumocystis jirovecii pneumonia (PCP) is a rare disease but may occur in pregnant immune-suppressed women. Here, we describe a case of acute lung injury due to PCP and alveolar hemorrhage in a pregnant woman who was a human T lymphotropic virus type-1 (HTLV-1) carrier. PCP should be considered in the differential diagnosis of pulmonary complications during pregnancy in HTLV-1 endemic areas. PMID- 21325771 TI - Latex anaphylaxis caused by a Swan-Ganz catheter. AB - A 78-year-old woman visited the division of cardiovascular disease in our hospital. She underwent a cardiac catheter examination, and a Swan-Ganz catheter was inserted. Several minutes later, she developed anaphylactic shock. She had no past history of latex allergy, but did have a banana allergy. Skin prick tests showed a positive reaction to an extract of latex gloves and an extract of the balloon of a Swan-Ganz catheter. Anaphylactic shock caused by the latex balloon of a Swan-Ganz catheter was diagnosed. It is necessary to pay attention to not only latex allergy but also fruit allergies with a cross-reactivity to latex. PMID- 21325772 TI - A case of SLE presenting stroke-like symptoms. AB - We report a 50-year-old woman with systemic lupus erythematosus (SLE) who developed stroke-like symptoms, including disturbance of consciousness and severe left hemiparesis. Despite the stroke-like symptoms, MR imaging showed quite atypical findings for stroke; broad high-intensity areas in the right fronto parietal lobes on diffusion-weighted images were shown mainly as iso-intensity areas on the ADC map, without any findings of stenosis of the cerebral large arteries. The cerebral blood flow in these areas was significantly decreased, as evaluated by single photon emission computed tomography. The present case suggests that small vessel vasculopathies localized in the unilateral hemisphere could cause "stroke-like" symptoms in SLE. PMID- 21325773 TI - Amitriptyline and lorazepam improved catatonia and occipital hypoperfusion in a patient with DLB. AB - A 76-year-old woman presented with catatonia, refusal to eat due to delusion, and visual hallucination. Single photon emission computed tomography showed remarkable occipital hypoperfusion and frontal hyperperfusion. (123)I metaiodobenzyl guanidine myocardial scintigraphy revealed decreased uptake. She was diagnosed as probable dementia with Lewy bodies (DLB). Intravenous or oral L dopa had no effect on catatonia. Amitriptyline and lorazepam improved catatonia and visual hallucination. Cerebral blood flow of the frontal and occipital lobes seemed to be normalized. Occipital hypoperfusion is one of the features of DLB. Although the mechanism of perfusion abnormality in DLB remains to be clarified, our case suggested that it might be reversible. PMID- 21325774 TI - MRI findings of occipital seizures in non-ketotic hyperglycemia. PMID- 21325775 TI - A novel apolipoprotein E mutation, ApoE Osaka (Arg158 Pro), in a dyslipidemic patient with lipoprotein glomerulopathy. AB - Lipoprotein glomerulopathy (LPG) is a rare disease characterized by the presence of thrombuslike deposition in markedly dilated glomerular capillaries and is often accompanied by an increased serum apolipoprotein E (apoE) level. Several gene mutations of apoE have been reported to be associated with LPG. In the current study, we report an LPG patient with a novel apoE mutation, apoE Osaka. The patient was a 45-year-old man who was hospitalized due to nephrotic syndrome. Light and electron microscopic observations of renal biopsy clearly showed characteristic findings of LPG, including lamellate thrombi in the lumen of dilated glomerular capillaries. His apoE phenotype was apoE3/2 and he had mild dyslipidemia with a mid-band on polyacrylamide gel electrophoresis. It is intriguing that the serum apoE level was within normal limits. We determined the sequence of the apoE gene using direct sequencing of the polymerase chain reaction (PCR) products. ApoE gene analysis showed a nucleotide substitution of G to C at codon 158 of exon 4. This mutation denoted an amino acid substitution of arginine residue for the proline residue at position 158 of apoE. The result of PCR associated with restriction fragment length polymorphism analysis also suggested that this mutation is heterozygous. It is possible that apoE Osaka mutation causes a conformational change of apoE protein and affects the interaction between abnormal apoE-containing lipoproteins and the endothelial cells of glomerular capillaries. The precise mechanism of LPG related with apoE Osaka, however, remains to be elucidated. PMID- 21325776 TI - Impact of polyunsaturated fatty acids on oxidized low density lipoprotein-induced U937 cell apoptosis. AB - AIM: Dietary supplements in polyunsaturated fatty acids (PUFA), particularly omega-3, are well known for their beneficial effects in preventing cardiovascular diseases (CVD). The aim of this study was to determine the role of PUFA on the modulation of apoptosis induced by hypochlorous acidoxidized LDL (HOCl-oxLDL) in U937 cells. METHODS: We tested the effect of monocyte cell line U937 supplementation with eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (ARA) or oleic acid (OA) on the modulation of HOCl-oxLDL-induced apoptosis. RESULTS: First, we showed the incorporation of fatty acids in the cellular membrane in U937 cells. Then, we showed that both EPA and ARA exerted a pro-apoptotic effect through the intrinsic mitochondrial apoptotic pathway including the dissipation of mitochondrial membrane potential followed by cardiolipin depletion, the downstream activation of caspase-3 and the increase in DNA fragmentation. The pro-apoptotic effect of EPA or ARA was completely blocked in U937/Bcl-2 cells. CONCLUSIONS: A new mechanism of dietary supplements in PUFA with likely consequences in apoptosis could be suggested through the mitochondrial pathway in monocytes. PMID- 21325777 TI - Associations of psychological distress with metabolic syndrome among Japanese urban residents. AB - AIMS: To examine and evaluate the association between psychological distress and metabolic syndrome (MetS). METHODS: Between 2005 and 2006, 1,613 men and women aged 30-79 participated in annual health examinations at Takarazuka City Health Promotion Center in Takarazuka, Japan. Psychological stress was assessed with the General Health Questionnaire (GHQ) and MetS was evaluated using three criteria based on those of the Japanese Society of Internal Medicine as the Japanese counterpart of the third report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Cholesterol in Adults (NCEP/ATPIII) and the International Diabetes Federation (IDF). RESULTS: The mean depression score after adjustment for age, smoking, alcohol intake and serum total cholesterol levels was higher for men with than without MetS as defined by Japanese criteria as well as for men with than without fasting glucose >= 110 mg/dL. Multivariable-adjusted, odds ratio associated with increments of one standard deviation in the depression score was 1.48 (1.19-1.84) for MetS, and anxiety and depression scores were 1.32 (1.08-1.61) and 1.24 (1.03-1.50) for fasting glucose >= 110 mg/dL, respectively. Similar trends were observed for the depression score and MetS as defined by NCEP/ATPIII and IDF. For women, somatic symptoms, anxiety, and depression were not associated with MetS and its components. CONCLUSIONS: Depressive symptoms are considered to be associated with MetS and, more specifically, glucose abnormality among urban Japanese men. PMID- 21325778 TI - Occupational exposure of dentists to extremely-low-frequency magnetic field. AB - OBJECTIVE: To compare occupational exposure to extremely-low-frequency magnetic field (ELF-MF) between dentists practicing in dental clinics and those employed in hospitals. METHODS: Thirty-two dentists who worked at clinics (n=15) and 33 dentists employed at hospital dental departments (n=7) voluntarily provided their informed consent to participate in this measurement study. The study dentists were requested to wear an ELF-MF dosimeter for some 3 h at work to determine their personal exposure. Spot measurements taken at a number of locations in each dental office were used to indicate the work environment exposure level. Additionally, ELF-MF emitted from common dental equipment was also measured. All measurements were performed with EMDEX Lite meters. RESULTS: The average environmental exposure to ELF-MF is higher in clinic dental offices than in hospital dental departments (0.55 vs. 0.15 uT, p=0.008). Personal dosimetry showed that on average, clinic dentists spent 35.71 and 19.39% of their time at exposures above 0.3 and 0.4 uT at work, respectively. The corresponding figures for hospital dentists were 19.61 and 13.92%. Additionally, ELF-MF was greater than 0.4 uT at 30 cm from all selected equipment, but the ELF-MF generally diminished as the distance from dental equipment increased. Uultraviolet air sterilization system produced 3 times as much ELF-MF as other dental equipment. CONCLUSIONS: This study suggests the possibility of over-exposure of dentists to power frequency ELF-MF. Additionally, certain dental equipment may produce ELF-MF levels greater than 0.4 uT in areas where dentists usually work when treating patients. PMID- 21325779 TI - Indium chloride-induced micronuclei in in vivo and in vitro experimental systems. AB - OBJECTIVES: The aim of this study was to investigate the genotoxic effects of indium trichloride (InCl(3).4H(2)O; InCl(3)) using the in vivo bone marrow micronucleus test and the in vitro CHL/IU cell micronucleus test. METHOD: BALB/c mice were administered a single intraperitoneal (i.p.) injection of InCl (3) at a dose 0.625, 1.25, 2.5, 5, or 10 mg/kg b.w. The frequency of micronuclei, the ratio of polychromatic erythrocytes to normochromatic erythrocytes (P/N ratio) and body weight gain were determined 24 h after administration of the InCl(3). In the in vitro micronucleus test, CHL/IU cells were treated continuously for 24, 48, or 72 h in the absence of S9mix (the continuous treatment method) and/or for 6 h with or without S9 mix followed by an 18, 42 or 66 h recovery time (the short time treatment method). The frequency of micronuclei was determined at the end of each culture period. RESULTS: The frequency of micronuclei induced by InCl(3) increased in the in vivo erythroblast-erythrocyte micronucleus test using BALB/c mice at doses of 2.5 and 5 mg/kg b.w. The P/N ratio, a marker of bone marrow toxicity, decreased significantly following the injection of InCl(3). Body weight gain was also inhibited by InCl(3). InCl(3) induced micronuclei in the CHL/IU cell micronucleus test in both the continuous treatment method and the short time treatment method, both with and without S9mix. CONCLUSIONS: These results suggest that InCl(3) has a genotoxic effect on mammalian cells both in vivo and in vitro. PMID- 21325780 TI - Alleviating effects of AS1892802, a Rho kinase inhibitor, on osteoarthritic disorders in rodents. AB - The effects of AS1892802, a selective Rho-associated coiled coil kinase (ROCK) inhibitor, on knee cartilage damage and pain behavior were examined in a rat model of osteoarthritis (OA). Monoiodoacetate (MIA) was intraarticularly injected into the right knee joints of rats. ROCK I and II mRNA levels increased in knee joints of MIA-injected rats. Our newly synthesized ROCK inhibitor, AS1892802, was injected into the ipsilateral knee or administered p.o. for 3 weeks. The compound dose-dependently and significantly inhibited of cartilage damage in the tibial plateau in a dose-dependent manner and decreased the weight distribution deficit associated with MIA injection. In addition, the compound also inhibited bradykinin induced pain responses in normal rats. In vitro, the compound could induce chondrocyte differentiation in a chondrogenic cell line and significantly inhibited IL-1beta- or bradykinin-induced prostaglandin E(2) production in a synovial cell line. AS1892802 prevents cartilage damage induced by MIA and has analgesic effects in rat pain models, suggesting that AS1892802 may be clinically useful for the treatment of OA.[Supplementary Figure: available only at http://dx.doi.org/10.1254/jphs.10319FP]. PMID- 21325781 TI - A negative correlation between expression profiles of runt-related transcription factor-2 and cystine/glutamate antiporter xCT subunit in ovariectomized mouse bone. AB - We have previously demonstrated that glutamate (Glu) suppresses cellular proliferation toward self-renewal through a mechanism associated with the depletion of intracellular GSH after promoting the retrograde operation of the bidirectional cystine/Glu antiporter in undifferentiated osteoblastic MC3T3-E1 cells. In this study, we investigated the expression profile of the xCT subunit of the antiporter as well as the master regulator of osteoblastogenesis runt related transcription factor-2 (Runx2) in ovariectomized mouse bone. In spinal columns isolated 28 days after ovariectomy, a marked reduction was seen with the intensity of Von Kossa staining used as an index of ossification. In femurs of these ovariectomized mice, a significant decrease was seen in mRNA and protein levels of Runx2 along with increased expression of both mRNA and the corresponding protein for the xCT subunit. To evaluate the possible role of the antiporter in osteoblastogenesis, stable transfectants were established with the xCT subunit toward the culture with osteoblastic differentiation inducers in MC3T3-E1 cells. In stable xCT transfectants cultured under differentiation conditions, marked decreases were seen in nodule formation, Ca(2+) accumulation, and osteoblastic marker gene expression, in addition to downregulation of both mRNA and the corresponding protein for Runx2. Runx2 promoter activity was markedly stimulated in MC3T3-E1 cells transfected with a responsive promoter plasmid after the culture under differentiation conditions, while transient and stable transfection with xCT expression vector invariably prevented the stimulation through an activator protein-1 site. These results suggest that Runx2 expression would be negatively regulated by the cystine/glutamate antiporter expressed by osteoblastic cells at the level of gene transactivation. PMID- 21325782 TI - Presence of HBV-DNA in cord blood is associated with spontaneous preterm birth in pregnant women with HBeAg-negative chronic hepatitis B virus infection. AB - Spontaneous preterm birth is the leading cause of perinatal morbidity and mortality. In this study the spontaneous preterm birth rates in a group of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus (HBV)-infected pregnant women without known risk factors for preterm delivery as well as the role of maternal laboratory data and hepatitis B surface antigen/HBV deoxyribonucleic acid (HBV-DNA) in cord blood in respect to preterm labour were evaluated. 138 consecutive HBeAg-negative chronic HBV-infected pregnant women were evaluated during the perinatal period. Serum HBV-DNA was determined by using the Cobas Amplicor HBV Test in both maternal and cord blood samples. 102 women were finally evaluated (36 were excluded) and 15 of them (14.7%) had spontaneous preterm birth. A significant association between spontaneous preterm birth and HBV-DNA in cord blood was observed (p = 0.007). HBV-DNA positivity in cord blood was significantly associated with maternal HBV-DNA levels (p = 0.002). The relative risk of HBV-DNA in cord blood was 6.43 times higher among women with serum HBV-DNA >=10,000 copies/ml and lymphocyte count <1,500 compared to those with all the other combinations of both parameters (p = 0.001). In conclusion, the presence of HBV-DNA in cord blood is significantly associated with spontaneous preterm birth in chronic HBV-infected pregnant women. Women with HBV DNA >=10,000 copies/ml and lymphocyte count <1,500 during the perinatal period have a higher probability of HBV-DNA in their cord blood. PMID- 21325783 TI - Plasmacytoid urothelial carcinoma of the bladder: a rare malignancy. AB - In 2004, the WHO recognized the plasmacytoid subtype as a distinct variant of vesical malignancy. We present a case of plasmacytoid urothelial carcinoma of the bladder treated with radical surgery and adjuvant chemotherapy, thus achieving long-term survival. A 70-year-old woman presented with persistent dysuria and underwent cystoscopy which revealed the presence of diffuse deformity, involving the right lateral vesical wall. Histology revealed the presence of muscle invasive urothelial carcinoma of the plasmacytoid variant. The patient subsequently underwent radical cystectomy and orthotopic ileal neobladder substitution, as well as adjuvant chemotherapy. At 36 months of follow-up, the patient is free of local recurrence and metastases, while her voiding function is well preserved. Bladder plasmacytoid urothelial carcinoma is considered a rare tumor, with unique microscopic and immunohistochemical features. The ideal therapeutic approach is debatable, but the combination of radical surgery and chemotherapy should constitute the mainstay of management. PMID- 21325785 TI - Characteristics and outcome and the omphalocele circumference/abdominal circumference ratio in prenatally diagnosed fetal omphalocele. AB - OBJECTIVE: To evaluate the outcome of fetuses with prenatally diagnosed omphalocele and to investigate the predictive value of the omphalocele circumference/abdominal circumference (OC/AC) ratio - a measure for the relative size of the omphalocele. MATERIALS AND METHODS: This study includes all fetuses prenatally diagnosed with omphalocele at our centre between 1995 and 2007. Medical records and footage of ultrasound examinations were reviewed. Omphalocele was classified in four groups: isolated, chromosomal, syndromic, and multiple anomalies. RESULTS: Eighty-eight cases were identified: 21 (24%) were isolated and 67 had additional structural anomalies. Of the 44 fetuses (50%) with chromosomal anomalies, 2 had omphalocele as a solitary finding. Fifty-three pregnancies (60%) were terminated because of the size of the lesion or associated structural or chromosomal anomalies. Twenty-one cases resulted in a live birth, of which 17 were vaginal deliveries (81%, all uncomplicated) including 3 cases of giant omphalocele (>=5 cm). The OC/AC ratio was found predictive for herniation of the liver, respiratory insufficiency and type of surgical reconstruction. Currently, 12/88 fetuses (14%) are alive and well, including 2 infants with multiple anomalies. CONCLUSION: Identification of omphalocele should arouse suspicion of genetic abnormalities, even in cases that appear isolated. The OC/AC ratio may influence counselling regarding the postnatal course. PMID- 21325784 TI - Hepatitis B virus core protein variations differ in tumor and adjacent nontumor tissues from patients with hepatocellular carcinoma. AB - OBJECTIVES: To characterize the mutation pattern of a hepatitis B virus (HBV) core protein (HBcAg) derived from hepatocellular carcinoma (HCC) and adjacent nontumor tissues. METHODS: HBV core gene fragments (nt. 1901-2365) were amplified from 98 HBV-related HCC tissues and 33 adjacent nontumor tissues. The deduced amino acids (AAs) of the core gene were aligned with the prototype sequences of HBV genotypes B and C. RESULTS: In total, there were 54 positions that showed polymorphism at the deduced AA level. The mutations were predominantly located in three major (codons 83-87, 95-104 and 130-135) and three minor (codons 21-38, 59 63 and 151-155) mutation-clustering regions (MCRs). The substitution rate in MCRs was significantly higher than in mutation-devoid regions (p < 0.001). The most frequently occurring mutations in rank were codon P130T (38.8%), I97L (37.8%) and S87G (23.5%). In addition, there were 7 patients that showed internal deletions in the middle of HBcAg with sizes ranging from 34 to 59 AAs. Unexpectedly, the core genes isolated from tumor tissues had fewer mutations compared with those isolated from adjacent nontumor tissues from the same patients (p < 0.05). CONCLUSIONS: Accumulation of naturally occurring mutations in certain restricted segments of HBcAg may be related to the development of HCC. PMID- 21325786 TI - Amino acid substitution in HCV core region and genetic variation near the IL28B gene affect viral dynamics during telaprevir, peginterferon and ribavirin treatment. AB - OBJECTIVES: Genetic variation near the IL28B gene and substitution of aa 70 and 91 in the core region of HCV-1b are useful as predictors of treatment efficacy to telaprevir/pegylated interferon (PEG-IFN)/ribavirin, but its impact on viral dynamics is not clear. METHODS: This study investigated predictive factors of viral dynamics during 12- or 24-week regimen of triple therapy in 80 Japanese adults infected with HCV-1b. RESULTS: After 24 h of commencement of treatment, the proportion of patients with Arg70 and Leu91 substitutions in the core region who showed >=3.0 log drop in HCV RNA level was significantly higher than that of patients with Gln70 (His70) and/or Met91. At 8 and 12 weeks, HCV RNA loss rate of patients with rs8099917 genotype TT near IL28B gene was significantly higher than that of patients with non-TT. Multivariate analysis identified substitution of aa 70 and 91 as a predictor of >=3.0 log fall in HCV RNA level at 24 h (Arg70 and Leu91) and SVR (Arg70), and rs8099917 (TT) as a predictor of HCV RNA loss at 12 weeks and SVR. CONCLUSIONS: This study identified genetic variation near IL28B gene and aa substitution of the core region as predictors of viral dynamics during triple therapy. PMID- 21325787 TI - Techniques in pediatric surgery: congenital hyperinsulinism. AB - For surgery in congenital hyperinsulinism (CHI), a distinct surgical strategy and technique is required for focal, diffuse and atypical CHI. In focal CHI, a confined, localized and parenchyma-sparing resection which is guided by the PET CT is always indicated in order to cure the patient. In diffuse CHI, however, the results of surgical therapy are unpredictable and cure is an exception. Therefore, a strong tendency exists nowadays that medical therapy should be preferred in diffuse CHI. In atypical CHI the situation is more complex: if the focal lesion or the segmental mosaic are not too extensive, cure by resection should be possible. But care must be taken in atypical cases not to resect too much of the gland in order not to induce diabetes. PMID- 21325788 TI - Early signs of cardiac failure: a clue for parvovirus infection screening in the first trimester? AB - Parvovirus B19 is a small single-stranded DNA virus and a potent inhibitor of erythropoiesis due to its cytotoxicity to erythroid progenitor cells. Although adult disease is generally mild, fetal parvovirus B19 infection can cause spontaneous abortion in early pregnancy and aplastic anemia, nonimmune hydrops fetalis and in utero fetal demise. The prevalence of parvovirus B19 maternal infection during pregnancy is about 1-2%. The vertical transmission occurs in 10 35%, being highest in the first and second trimesters. The risk of adverse fetal outcome is 10%. In contrast to the second or third trimester, in pregnancies affected by increased nuchal translucency (NT) in the late first trimester, the prevalence of maternal infection was not higher than in the general population. We report a case of first-trimester parvovirus B19 infection with increased NT and reversed a-wave in the ductus venosus (DV) at 11 weeks, with fetal demise 2 weeks later. PMID- 21325789 TI - Immediate effect on overactive bladder symptoms following administration of imidafenacin. AB - INTRODUCTION: One of the factors influencing the treatment compliance of patients with overactive bladder (OAB) symptoms is thought to be the time to reach clinical effectiveness after administering drugs. We investigated the immediate effect of imidafenacin on OAB symptoms. PATIENTS AND METHODS: Imidafenacin (0.1 mg) was administered. OAB symptom scores (OABSS) were evaluated before administration, and at 2 and 4 weeks after administration. The subjective efficacy in patients was examined by recording daily changes for 2 weeks. RESULTS: Twenty patients were evaluated for efficacy using OABSS and uroflowmetry with postvoid residual volume. Nineteen patients completely recorded daily changes in subjective efficacy. The mean total OABSS decreased gradually during 2 weeks after administration. Patients reported the drug's efficacy to begin 3 days after the commencement of administration. Urinary flow and postvoid residual volume did not change after administration. CONCLUSION: The subjective efficacy of imidafenacin was observed from 3 days after the commencement of administration. PMID- 21325790 TI - Vitamin D receptor genetic polymorphisms and the risk of urolithiasis: a meta analysis. AB - OBJECTIVE: Genetic variants of vitamin D receptor (VDR) were implicated in urolithiasis susceptibility in several case-control studies. However, these studies so far have provided conflicting results. In order to investigate the potential relationship, a meta-analysis was conducted. METHODS: Eligible studies were retrieved via both computerized searches and review of references. The relation of VDR polymorphisms to urolithiasis was quantified on ApaI, BsmI, FokI and TaqI separately. Stratified analyses on regional characteristics and stone composition were also performed. Estimates of OR with 95% CI were summarized using the fixed- or random-effect models as appropriate. RESULTS: A total of 17 studies were included in our analysis. There was no evidence showing significant associations between ApaI and BsmI polymorphisms and urolithiasis risk in overall estimates. However, f allele and ff+Ff genotype in the dominant model of FokI were related with an increase of urolithiasis risk. TaqI also presented with increased urolithiasis risk with t allele and tt+Tt genotype in the dominant model. CONCLUSION: Our meta-analysis indicated VDR polymorphisms could be potential biomarkers for urolithiasis susceptibility. PMID- 21325791 TI - Experimental infection of goats with tick-borne encephalitis virus and the possibilities to prevent virus transmission by raw goat milk. AB - OBJECTIVES: The aim of this work was to study the tick-borne encephalitis virus (TBEV) infection of goats and the possibilities to prevent human milk-borne infections either by immunizing animals or the heat treatment of milk. METHODS: An experiment was conducted with 20 milking goats. Ten goats (half of them immunized) were challenged with live TBEV and 10 were left uninfected. Clinical signs and body temperatures of the animals were recorded and milk samples were collected daily. The presence of viral RNA and infectious virions in milk were detected by RT-PCR and intracerebral inoculation of suckling mice, respectively. Milk samples containing infectious virions were subjected to various heat treatment conditions and retested afterwards to assess the effect on infectivity. RESULTS: The infected goats did not show any clinical signs or fever compared to uninfected ones. Infectious virions were detected for 8-19 days from the milk samples (genome for 3-18 days by PCR) of infected goats. Immunized goats did not shed the virus. After heat treatment of the milk, the inoculated mice survived. CONCLUSIONS: Goats shed the virus with their milk without showing any symptoms. Human milk-borne infections can be avoided both by immunizing goats and boiling/pasteurizing infected milk. PMID- 21325793 TI - Analysis of sexually dimorphic expression of genes at early gonadogenesis of pejerrey Odontesthes bonariensis using a heterologous microarray. AB - The process of morphological development of a differentiated gonad from an undifferentiated primordium is a very important step of gonadogenesis. Studies on sexually dimorphic gene expression are important to increase our understanding of this process and to investigate how environmental factors such as temperature can regulate gonadal development. The aim of this study was to identify putative genes involved in sex differentiation in pejerrey (Odontesthes bonariensis) reared at male- and female-producing temperatures (MPT and FPT, respectively) using a microarray heterologous from the medaka (Oryzias latipes), a closely phylogenetic species. Genes related to numerous processes presented higher expression at MPT, including those involved in muscular contraction, metabolic pathways, developmental processes, and reproduction. Genes induced by FPT were classified under the gene ontology terms of response to stimulus, transport and proteolysis. From genes selected for validation, at MPT ndrg3 expression was observed in the somatic cells, whereas pen-2 was detected in germ cells in the caudal portion of the gonads, where no apoptotic signals were observed. Finally, hsp90 was highly expressed in somatic cells of the gonads at the FPT. The results suggest that the interplay of pro-apoptotic and anti-apoptotic genes is important during the masculinization process and for the prevention of sterility following exposure to warm temperatures. PMID- 21325792 TI - Sex differences in the cerebellum and frontal cortex: roles of estrogen receptor alpha and sex chromosome genes. AB - Most neurobehavioral diseases are sexually dimorphic in their incidence, and sex differences in the brain may be key for understanding and treating these diseases. Calbindin (Calb) D28K is used as a biomarker for the well-studied sexually dimorphic nucleus, a hypothalamic structure that is larger in males than in females. In the current study weanling C56BL/6J mice were used to examine sex differences in the Calb protein and message focusing on regions outside of the hypothalamus. A robust sex difference was found in Calb in the frontal cortex (FC) and cerebellum (CB; specifically in Purkinje cells); mRNA and protein were higher in females than in males. Using 2 mouse lines, i.e. one with a complete deletion of estrogen receptor alpha (ERalpha) and the other with uncoupled gonads and sex chromosomes, we probed the mechanisms that underlie sexual dimorphisms. In the FC, deletion of ERalpha reduced Calb1 mRNA in females compared to males. In addition, females with XY sex chromosomes had levels of Calb1 equal to those of males. Thus, both ERalpha and the sex chromosome complement regulate Calb1 in the FC. In the CB, ERalpha knockout mice of both sexes had reduced Calb1 mRNA, yet sex differences were retained. However, the sex chromosome complement, regardless of gonadal sex, dictated Calb1 mRNA levels. Mice with XX chromosomes had significantly greater Calb1 than did XY mice. This is the first study demonstrating that sex chromosome genes are a driving force producing sex differences in the CB and FC, which are neuoranatomical regions involved in many normal functions and in neurobehavioral diseases. PMID- 21325794 TI - Multiprobe fluorescence in situ hybridization (UroVysion) for the detection of urothelial carcinoma - FISHing for the right catch. AB - Urinary cytology has a well-established role in the detection and monitoring of urothelial carcinoma. The main strength of cytology is the high specificity for high-grade urothelial carcinoma and carcinoma in situ, but it has a low sensitivity for low-grade, non-invasive tumors. There are several other limitations of cytology. Cytology of the upper urinary tract and after intravesical therapy with bacillus Calmette-Guerin is notoriously difficult to interpret. In addition, there is a poorly defined but commonly used category of atypical cytology of uncertain significance. The UroVysion multiprobe fluorescence in situ hybridization has emerged as a helpful tool to address these limitations. It consists of fluorescently labeled DNA probes to detect increased copy numbers (polysomy) of the chromosomes 3, 7 and 17 and deletion of 9p21, the site of the P16 tumor suppressor gene. Multiple studies have shown that fluorescence in situ hybridization in voided urine and washing specimens can help in patient management due to its superior sensitivity over cytology in different situations. It can be particularly useful to clarify equivocal cytological findings. However, some aspects remain to be further addressed including cost efficiency, optimal cut-off values and the true performance under real-life conditions. PMID- 21325795 TI - Papillary thyroid carcinoma: an easy fine needle aspiration biopsy diagnosis? AB - OBJECTIVE: To analyze reasons for unclear or missed diagnoses in fine needle aspiration biopsy (FNAB) of papillary thyroid carcinoma (PTC). STUDY DESIGN: Among 35,000 thyroid FNAB diagnoses made during 1989-2009, 135 PTC FNAB diagnoses were divided into 3 categories by expressed probability. A group of 10 cases with histologic PTC diagnosis not mentioned in our previous FNAB sample was also analyzed. RESULTS: Of the 75 PTC FNAB diagnoses, 71 were confirmed; the remaining 4 were hyperplastic goiters. In the group of 45 cases with PTC, in which FNAB diagnosis was the next most probable differential diagnosis, 23 were confirmed. In the group of 15 cases, in which the PTC FNAB diagnosis was considered the less probable differential diagnosis, 3 PTCs were found. The other cases in both groups were usually histologically diagnosed as lymphocytic thyroiditis. In the group of 10 cases with histologic PTC diagnosis, 6 were evaluated as suspicious for (other) malignancy, 3 were diagnosed as hyperplasia with oncocytes and 1 as low cellularity; sample reaspiration was recommended. CONCLUSION: FNAB diagnosis of PTC is not always possible, with success rate influenced by lesion type and size, accompanying diagnoses, representativeness of cytology sample and experience of the cytopathologist. PMID- 21325796 TI - The efficacy of fine needle aspiration cytology in the preoperative evaluation of parakeratotic odontogenic keratocysts. AB - OBJECTIVE: To assess the performance of fine needle aspiration cytology (FNAC) in preoperative diagnosis of parakeratotic odontogenic keratocyst. STUDY DESIGN: Twenty-three cases of odontogenic keratocyst which were evaluated with FNAC prior to enucleation were included in the study. Aspiration smears were stained with Papanicolaou and hematoxylin-eosin stain. Results obtained from FNAC were compared with histopathologic data obtained from the excisional biopsies. RESULTS: Keratotic cell clusters with or without inflammation were identified in all the cytologic smears. No dysplastic changes were seen. The evaluation of the excisional biopsies revealed cystic epithelium which is characterized by palisaded basal cells, a corrugated surface with a lumen containing keratin debris. Two of the cases which revealed satellite cysts were not associated with Gorlin-Goltz syndrome due to the absence of other findings. CONCLUSION: Parakeratotic odontogenic keratocyst can be substantially diagnosed preoperatively utilizing FNAC with a careful evaluation. PMID- 21325797 TI - Fine needle aspiration cytology in lesions of the nose, nasal cavity and paranasal sinuses. AB - OBJECTIVE: To assess the spectrum of lesions in the sinonasal region diagnosed on FNAC. STUDY DESIGN: This is a retrospective audit of sinonasal lesions diagnosed on FNAC over a period of 12 years (1998-2009). RESULTS: Out of a total of 79,851 FNACs, 158 (0.2%) were from the sinonasal region. FNAC was non-diagnostic in 20 (12.6%) cases. Infective/inflammatory lesions comprised of 30 (19%) cases including non-specific inflammation (19), fungal infection (7), tuberculosis (2), actinomycosis (1) and filariasis (1). Benign cysts (24; 15.2%) included epidermal inclusion cysts, mucocele and aneurysmal bone cyst. Benign bone tumors (4) comprised of giant cell tumor, fibrous dysplasia, chondroma, and osteoblastoma. Other benign tumors included lipoma (6), hemangioma (5), schwannoma (2), meningioma (1), pleomorphic adenoma (1), sebaceous adenoma (1) and other skin adnexal tumors (3). Malignant epithelial tumors (24; 15.2%) included squamous cell carcinoma (10), basal cell carcinoma (5), poorly differentiated carcinoma (4) and metastatic carcinoma (5). Two cases of chordoma and one case each of dermatofibrosarcoma pertuberance and hemangiopericytoma were seen. Sarcomas included sarcoma, not otherwise specified (4), rhabdomyosarcoma (3), osteosarcoma (2), chondrosarcoma (2), leiomyosarcoma (1), malignant fibrous histiocytoma (1), fibrosarcoma (1) and malignant peripheral nerve sheath tumor (1). There were cases of malignant small round cell tumor (11), non-Hodgkin lymphoma (3), plasmacytoma (2) and malignant melanoma (2). CONCLUSION: A variety of non neoplastic and neoplastic conditions can involve the sinonasal region. FNAC is a reliable diagnostic procedure in a good number of cases, especially in the light of clinico-radiological data. PMID- 21325798 TI - S100P and XIAP expression in pancreatic ductal adenocarcinoma: potential novel biomarkers as a diagnostic adjunct to fine needle aspiration cytology. AB - OBJECTIVE: The usefulness of 2 novel biomarkers in pancreatic surgical and cytological specimens that could reliably differentiate non-neoplastic pancreatic duct and benign gut epithelium from pancreatic ductal adenocarcinoma (PDA) was evaluated. STUDY DESIGN: A total of 14 pancreatic resection specimens (RSs), 23 endoscopic ultrasound-guided fine needle aspirations (EUS-FNAs) of PDA and 8 benign pancreatic EUS-FNAs were selected. Twelve of 14 RSs had corresponding EUS FNAs with cell blocks (CBs). Non-neoplastic pancreatic tissue, including chronic pancreatitis, was evaluated in all RSs. Immunohistochemical stains for S100P and X-linked inhibitor of apoptosis protein (XIAP) were performed on tissue and CB sections. Staining intensity (0 no staining; 1+ weak; 2+ moderate; 3+ strong) and proportion of positive cells (less than 10% negative; 1+ 10-25%; 2+ 26-75%; 3+ greater than 75%) were assessed. Positive staining was defined as >=10% cells with at least 1+ intensity. RESULTS: The sensitivity and specificity of S100P and XIAP immunoreactivity for a diagnosis of PDA in RSs were both 100%. In contrast, the sensitivity and specificity in EUS-FNA CBs of S100P were 78.2 and 87.5% and of XIAP 82.6 and 50.0%, respectively. The combined sensitivity of S100P and XIAP was 100% in 12 RSs and 83.3% in the corresponding EUS-FNA CBs. CONCLUSION: Two novel biomarkers have very high sensitivity and specificity in the diagnosis of PDA in RSs. S100P has slightly lower sensitivity and higher specificity of PDA than XIAP in EUS-FNA specimens. We recommend using both biomarkers as cytological diagnostic adjuncts, especially in difficult cases of well-differentiated PDA versus reactive ductal epithelium. PMID- 21325799 TI - Diagnostic role of p63 immunostaining in fine needle aspiration cytology of different breast lesions. AB - OBJECTIVE: To evaluate the potential diagnostic role of the myoepithelial marker p63 in fine needle aspiration cytology (FNAC) of breast in comparison to other diagnostic tools. STUDY DESIGN: A total of 49 FNAC of breast were assessed according to clinical, mammographic, cytological findings, and p63 immunostaining on FNAC. The strength of agreement with final histological diagnosis (FHD) was measured by kappa test. RESULTS: p63 was positive in myoepithelial cells of 75% (9/12) of benign cases and negative in 89% (33/37) of the malignant cases with strong agreement with the FHD (p < 0.0001, kappa = 0.63). All the malignant positive cases showed variable degrees of in situ component. Only one malignant case (1/37, 0.03%) showed few p63 positive neoplastic cells in FNAC. Combined FNAC and p63 staining (with <25% cutoff point) to diagnose malignancy showed 100% sensitivity, 75% specificity, 92% positive predictive value, 100% negative predictive value, and 94% diagnostic accuracy. Most of the cytologically suspicious cases (7/9, 78%) showed negative p63 staining results, and all these suspicious cases (100%) proved to be malignant by the FHD. There was poor agreement between diagnosis according to positive background naked nuclei (NN) and the FHD (kappa = 0.24 and p < 0.0001); however, presence of more than 74% positive NN is strongly suggestive of fibroadenoma. CONCLUSION: p63 immunostaining with a cutoff value of <25% to diagnose malignancy is a highly sensitive and specific myoepithelial marker which is recommended as an adjuvant tool to FNAC of breast in suspicious cases. PMID- 21325800 TI - Discordance between cytology and biopsy histology of the cervix: what to consider and what to do. AB - OBJECTIVE: Since cytology is the examination utilized for the screening of cervical cancer, it is important to determine its correlation with histologic examination, the gold standard in the diagnosis of cervical disease. STUDY DESIGN: A retrospective evaluation was made of 431 patients who presented with colposcopic indication for cervical biopsy between 2003 and 2007. RESULTS: In 90.8% (289/318) of the patients, cytology showing cervical intraepithelial neoplasia (CIN) was confirmed as CIN in the histology of the cervix, while 62.8% (71/113) of patients with normal cytology had a confirmation of a normal histology (kappa = 0.558). CONCLUSION: Cytology demonstrated a sensitivity and specificity of 87.3 and 71.0%, respectively. The agreement between cervical cytology and histology, considering the presence of CIN, was moderate. Correlations between accuracy and errors of cytology are discussed with therapeutic emphasis. PMID- 21325801 TI - Switching from neural networks (PAPNET) to the Imager (Hologic) for computer assisted screening. AB - OBJECTIVE: The large set of ThinPrep slides prepared in the Leiden Cytology and Pathology Laboratory is exploited for calculating the impact of the transition from PAPNET neural network scanning to the Imager technology. STUDY DESIGN: All cervical samples were suspended and fixed in the coagulant fixative BoonFix. We compared 57,541 ThinPrep slides which were scanned by PAPNET and 64,273 ThinPrep slides processed with the Imager: 99,157 cases originated from the Dutch population screening program of asymptomatic women (screenees) and the remaining 22,657 samples were of symptomatic women. In the PAPNET series, 23% were diagnosed by additional light microscopy; in the Imager method, all slides were studied light microscopically. The cytoscores (positive cytology per 1,000 samples) were calculated for normal, atypical squamous cells of undetermined significance (ASC-US), cervical intraepithelial neoplasia (CIN) grades I-II, and for CIN III+. The odds ratios (ORs) for the positive cytoscores were assessed for both the screenees and the symptomatic women. RESULTS: The cytoscores, per 1,000 cases, for ASC-US varied from 17.77 to 40.59, for CIN I-II from 7.17 to 33.35, and for CIN III+ from 2.81 to 8.8. These 6 cytoscores were higher for symptomatic women than for screenees. We observe significantly elevated ORs for the Imager for ASC-US (1.26 and 1.23), CIN I-II (1.45) and for CIN III+ (1.58 and 1.45). These 3 ORs are higher for screenees than for symptomatic women. CONCLUSION: The Imager technology is more efficacious, particularly for handling screenee slides. PMID- 21325802 TI - Reflex high risk HPV testing in atypical squamous cells, cannot exclude high grade intraepithelial lesion: a large institution's experience with the significance of this often ordered test. AB - OBJECTIVE: Cervical cytology specimens diagnosed with ASC-H consist of squamous cells with equivocal cytology for high-grade dysplastic lesions. We reviewed our cases of ASC-H with reflex HPV testing to evaluate this patient population. STUDY DESIGN: We retrospectively identified patients with ASC-H in Pap smears over a 3 year period. Reflex high-risk (HR) HPV DNA testing was performed by request. Follow-up results and smear characteristics were evaluated. RESULTS: HR HPV DNA testing was positive in 60 of 82 (73%) cases tested. The risk of high grade cervical intraepithelial neoplasia (CIN) on follow-up after a positive HPV test with ASC-H is 68.3%. The risk of high grade CIN after a negative HPV test with ASC-H is 58.3%. High grade CIN lesions were found in 20% HPV-negative patients. The cellularity of atypical cells in Pap smears was not helpful in analyzing differences in HPV-positive and HPV-negative ASC-H. CONCLUSION: The risk of high grade dysplasia after an ASC-H Pap diagnosis was high irrespective of the reflex HPV test results in our patient population. Therefore, our findings support the continued utilization of the current ASCCP guidelines of colposcopy and caution when utilizing reflex HR HPV testing in the colposcopy triage ASC-H patients. PMID- 21325803 TI - Cytological characteristics of pulmonary pleomorphic and giant cell carcinomas. AB - OBJECTIVE: To establish cytological features of pulmonary pleomorphic carcinoma (PC) or giant cell carcinoma (GC), we evaluated the cytological characteristics of these tumors using a multidisciplinary approach. STUDY DESIGN: Samples from 13 surgically resected and histologically confirmed PC or GC patients were collected from our institutes. Eight cases without prior chemotherapy before surgery were selected, and cytological features were analyzed. RESULTS: The background contained numerous lymphocytes and neutrophils. The tumor cells were arranged in flat loose clusters, but some were in fascicles. The shape of the tumor cell was spindle or pleomorphic, and the sizes of the tumor cells varied by more than 5 fold. The tumor cells had an abundant, thick and well-demarcated cytoplasm. The location of the nucleus was centrifugal, and the nucleus was oval or irregularly shaped. Multinucleated giant cells were frequently observed. The size of the nucleus was more than 5 times that of normal lymphocytes, and its size also varied by more than 5-fold. The nuclear membrane was thin, and nuclear chromatin was coarsely granular, while the nucleolus was single and round. CONCLUSION: PC or GC has characteristic cytological features, however, spindle cells tended to be hardly observed in cytological specimens in some cases. PMID- 21325805 TI - Distinction of intestinal and diffuse types of gastric adenocarcinoma on brush cytology. AB - OBJECTIVE: To distinguish between the intestinal and diffuse types of gastric adenocarcinoma on brush cytology (BC). STUDY DESIGN: Brushing smears and biopsy samples obtained at endoscopic examination from 32 patients with clinically or radiologically suspected gastric malignancy were included in the study. Cytologic smears were examined by 2 cytopathologists, using predetermined criteria to arrive at a consensus diagnosis. A meticulous attempt was made to distinguish between the 2 types of gastric adenocarcinoma. Cytologic diagnoses were correlated with the histologic diagnoses. RESULTS: Twenty-one cases (65.6%) were concordant between BC and endoscopic biopsy (EB) with respect to sub-typing. Two (6.2%) cases reported as 'poorly differentiated adenocarcinoma' on BC turned out to be 'diffuse type'. Three cases (9.4%) reported as 'diffuse type' on BC were 'intestinal type' on EB. Two of these discordant cases had intestinal metaplasia on BC, which should have suggested 'intestinal type' of adenocarcinoma on BC. Three cases (9.4%) were false positive. On review, 2 of these false-positive cases showed cytologically convincing malignant cells, the third case was misinterpreted as diffuse type of adenocarcinoma due to reactive glandular cells entangled in the mucoid background. Three (9.4%) EB were non-representative with only superficial mucosa; BC diagnosis in these 3 cases was intestinal type of adenocarcinoma. CONCLUSION: Although, overlapping cytomorphology between the intestinal and diffuse types of gastric adenocarcinoma can cause diagnostic problem; with a meticulous cytomorphologic approach, it is possible to accurately distinguish between the 2 types in a considerable number of cases. PMID- 21325804 TI - Enhancer of zeste homologue 2 expression in breast carcinoma smears in relationship with p53, Ki-67 and other prognostic parameters. AB - BACKGROUND: The polycomb group protein enhancer of zeste homologue 2 (EZH 2) has been reported as a marker of aggressive breast cancer. The aim of this study was to investigate the correlation between the expression of EZH 2 with p53 and Ki-67 expression and other clinicopathological parameters in primary breast carcinomas in order to determine the role of the above marker as a prognosticator of tumor aggressiveness and patient outcome. PATIENTS AND METHODS: One hundred primary operable breast cancer patients were investigated in order to identify the expression of EZH 2, Ki-67 and p53 in imprint smears immunocytochemically. The prevalence of expression of these markers was then correlated with clinicopathological parameters. Follow-up was available for all patients. RESULTS: EZH 2 was expressed in 64% of the cases and correlated with higher levels of p53 (relative risk = 3.00, p < 0.0001) and Ki-67 (relative risk = 3.25, p < 0.0001). Malignant cells showed immunoreactivity for all markers in the nucleus. Univariate analysis revealed a strong association between EZH 2 protein expression and tumor grade and size, lymph node metastasis, and HER-2 and estrogen and progesterone receptor status. Multivariable statistical analysis revealed that lymph node metastasis was the main predictor for EZH 2 expression. Decreased patient survival was also significantly associated with EZH 2 expression (p < 0.0001). CONCLUSIONS: EZH 2 expression may be a marker of poor prognosis in breast carcinoma patients and has been suggested as a candidate for targeted therapy. PMID- 21325806 TI - Is conventional urinary cytology still reliable for diagnosis of primary bladder carcinoma? Accuracy based on data linkage of a consecutive clinical series and cancer registry. AB - OBJECTIVE: Reported urine cytology accuracy, particular sensitivity, is highly variable. We evaluated the accuracy of urinary cytology for primary bladder cancer using population data linkage to provide valid estimates. STUDY DESIGN: Consecutive cytology tests processed through a major service between January 2000 and December 2004 were linked to a regional population cancer registry (allowing outcome ascertainment). Sensitivity and specificity were calculated using different thresholds, based on standardized reporting categories (C1 = negative, C2 = reactive, C3 = atypical, C4 = suspicious, C5 = malignant, Cx = inadequate). RESULTS: Cancer registry matching of 2,594 tests revealed 130 incident bladder cancers, of which 97 occurred within 12 months of cytology and were included in calculating accuracy. Sensitivity (C3-C5 considered positive) ranged between 40.2 and 42.3%, and specificity was 93.7-94.1%. If C3 results are counted as negative, sensitivity estimates reduced to 24.7-26.0%. The positive predictive value of a C3, C4 or C5 report was 11.7, 39.2, and 66.6%, respectively. High tumor grade was associated with significantly higher sensitivity compared to low and intermediate grades combined (p = 0.02). CONCLUSION: Urine cytology is highly specific but has intermediate sensitivity, indicating that it has a role in adjunct diagnosis, but not in screening for primary bladder cancer. C3 results should be considered 'positive' and further investigated, and all positive results should prompt further intervention. PMID- 21325807 TI - Cytomorphometric analysis and assessment of periodic acid Schiff positivity of exfoliated cells from apparently normal buccal mucosa of type 2 diabetic patients. AB - BACKGROUND: In recent years, important advances have been made in the diagnosis of diabetes mellitus, and new strategies have been put forward for its treatment. The purpose of this study was to analyze the cytomorphometric changes and glycogen content in exfoliated cells of oral mucosa as an adjunct in the diagnosis of diabetes mellitus. METHOD: The smears were taken from buccal mucosa of 30 type 2 diabetes mellitus patients (study group) and 30 healthy individuals (control group). One smear was stained with rapid Papanicolaou stain and the other with periodic acid Schiff stain (PAS). In Papanicolaou stain smears, the nuclear area, cytoplasmic area and cytoplasmic to nuclear ratio were evaluated from 50 cells in each smear using Image analysis software (Q Win Standard, LeicaTM) and a research microscope (DM 2500, Leica). PAS-stained smears were analyzed for the presence of glycogen in exfoliated cells. RESULTS: The results showed that the mean nuclear area was significantly higher (p < 0.001) in the study group whereas the mean cytoplasmic area did not exhibit a statistically significant difference (p > 0.001). The mean cytoplasmic to nuclear ratio was significantly lower in the study group (p < 0.001). There was a significant increase in the count of PAS-positive exfoliated cells of the study group as compared with the control group (p < 0.001). CONCLUSION: The results associated with clinical observations suggest that type 2 diabetes mellitus can produce morphologic and functional alterations in oral epithelial cells, detectable by microscopic and cytomorphometric analysis using exfoliative cytology which can be used in the diagnosis of the disease. PMID- 21325808 TI - Morphometric assessments for the prognostic evaluation of human gliomas. AB - BACKGROUND AND AIM: To correlate stereological parameters to the WHO morphological classification of brain tumours and to address the prognostic value of the different parameters. METHODS AND MATERIALS: A quantitative analysis of 50 astrocytomas was performed by an image analysis system. At least 450 nuclei were counted and measured in every sample. The ANOVA 1-way test and Newman-Keuls modification were used for statistical evaluation. RESULTS: The morphometric data showed significant differences between the tumour grades. We found the nuclear volume and form factor to be parameters of the degree of 'nuclear atypia' from low- to high-grade gliomas. When malignancy was increased, the mean values of nuclear orientation were found to be elevated. CONCLUSIONS: The results of our study underline the usefulness of morphometric techniques in tumour research. These techniques seem to be an important tool for grading gliomas and also for practical therapeutic purposes. PMID- 21325809 TI - Ultrafast papanicolaou stain modified for developing countries: efficacy and pitfalls. AB - OBJECTIVE: To study the efficacy of the ultrafast Papanicolaou (UFP) staining technique for immediate cytologic diagnosis, to check specimen adequacy during radiologically guided fine needle aspiration cytology (FNAC) procedures and to objectively assess the quality of UFP stain and factors affecting it. STUDY DESIGN: Serial and random samples of cytologic material from 347 patients during a 2-year period were divided in 3 groups. Group I included 238 outpatient FNACs, group II included 59 radiologically guided FNACs, and group III included 50 cases of intraoperative cytology. After staining air-dried smears with UFP stain, immediate diagnosis was given. In group II, material adequacy was also conveyed to the radiologist. RESULTS: Overall diagnosis was possible in 297 (85.6%) cases. Only 8 (2.3%) cases could not be diagnosed due to staining difficulties. The overall concordance rate was 98%. Seventy-five percent of cases showed 'excellent' and 'good' morphology, allowing easy diagnosis. In 25% of 'fair' cases diagnosis was still possible, although with some difficulties. Factors affecting the quality of staining are discussed. CONCLUSION: The UFP staining technique is an accurate and reliable method for rapid cytology reporting. It significantly reduces total turn around time of the test result, thereby having the potential to be cost-effective, both for the patient and the hospital. PMID- 21325810 TI - Repeat processing of residual ThinPrep Pap tests: sampling of the vial may not be invariably homogeneous. AB - OBJECTIVE: To re-evaluate the reproducibility of additional slides prepared from residual cervical ThinPrep (TP) samples. STUDY DESIGN: Sixty paired specimens (conventional smears and direct-to-vial TP) were studied. Up to 10 additional slides were prepared from each TP vial. All slides were reviewed for adequacy of material, presence of abnormal cells and presence of normal flora or other pathogens. The additional TP slides were further evaluated for the presence of diagnostic elements which were not found on the conventional smear and primary TP slide. RESULTS: Abnormal cells found on the primary TP slide were also identified on all additional slides in 48/50 cases (96%) with squamous cell lesions. The distribution of material on TP slides was evaluated as homogenous in 51 cases (85%) and as non-homogenous in 9 (15%). Using the primary slides (conventional smear and TP) as a reference, additional diagnostic cells upgrading the cytologic diagnosis were found on the repeat slides in 7 cases (11.7%) and fungi consistent with Candida in 3 (5%). CONCLUSION: Repeat processing of residual cervical TP samples may not be an invariably reproducible procedure and the first slide may not be necessarily representative of the specimen as a whole. Nevertheless, both primary and repeat TP slides seem to be extremely effective in detecting a lesion (regardless of grade) in abnormal cases. The exact impact of non-homogeneous sampling of the vial on the diagnostic accuracy of the TP method should be further investigated. PMID- 21325811 TI - Agreement between methods for diagnosing HPV-induced anal lesions in women with cervical neoplasia. AB - OBJECTIVE: To evaluate agreement between 3 methods for screening anal intraepithelial lesions: anal cytology, anoscopy and human papillomavirus (HPV) detection by PCR. STUDY DESIGN: This prospective, cross-sectional study screened 324 women with cervical neoplasia for anal neoplasia. Agreement between methods was calculated using the kappa coefficient. RESULTS: Of 324 anal cytologies performed, 31.5% (n = 102) were found to be abnormal: low-grade anal lesions were detected in 19.1% (n = 62) of cases, high-grade lesions in 3.1% (n = 10) and atypical squamous cells of undetermined significance in 9.3% (n = 30). With respect to the biopsies, 25.7% (n = 20) were positive, consisting of 7 cases of HPV infection, 5 anal intraepithelial neoplasia (AIN) grade 1, 6 AIN grade 2, and 2 AIN grade 3. Twenty-one samples (6.5%) were inadequate for HPV analysis. Of the 303 adequate samples, 84.2% (n = 255) tested positive for HPV. Agreement between cytology and anoscopy was fair (kappa = 0.31). Agreement between PCR for HPV and cytology was slight (kappa = 0.08) and no agreement was found between PCR for HPV and anoscopy (kappa = 0.00). CONCLUSION: Agreement between the different methods of diagnosing HPV-induced anal lesions is slight to fair; however, anal cytology permits identification of cases in which lesions are present, allowing them to be referred for anoscopy and biopsy. PMID- 21325812 TI - Herpesviridae viral infections following rituximab combined chemotherapy in patients with diffuse large B-cell lymphoma. AB - BACKGROUND: Herpesviridae viral infections (HVIs) are particularly common in patients with hematologic malignancies after undergoing hematopoietic stem cell transplantation or receiving chemotherapy. However, there have been few reports on the incidence and risk factors of HVIs in diffuse large B-cell lymphoma (DLBL) patients treated with rituximab combined chemotherapy. METHODS: We analyzed 270 patients who were newly diagnosed with DLBL. All of the patients had received rituximab combined chemotherapy between June 2004 and April 2010. RESULTS: Twenty nine patients (10.7%) developed HVI a median of 5.57 months (range 0.37-30.03) after initial chemotherapy. The estimated cumulative incidence rates of HVIs were 8.3 and 12.8% at 1 and 3 years, respectively, in all patients. Independent risk factors for HVIs were a high international prognostic index risk [p = 0.017, hazard ratio (HR) 2.633, 95% confidence interval (CI) 1.185-5.850], neutropenic fever (p = 0.023, HR 2.476, 95% CI 1.134-5.406) and a high cumulative dose of steroids (p = 0.023, HR 2.921, 95% CI 1.162-7.346). CONCLUSION: A high international prognostic index risk, neutropenic fever and a high cumulative dose of steroids appear to be risk factors for HVI in DLBL patients who are undergoing rituximab combined chemotherapy. PMID- 21325813 TI - Acute myeloid leukemia with a RUNX1-RUNX1T1 t(1;21;8)(q21;q22;q22) novel variant: a case report and review of the literature. AB - Variants of t(8;21)(q22;q22) account for approximately 3% of all t(8;21) in acute myeloid leukemia (AML). We report a 63-year-old female patient with AML, who showed a 3-way novel variant of t(8;21), t(1;21;8)(q21;q22;q22). She presented with gastric discomfort and splenomegaly, and her complete blood count was: white blood cell count 7.96 * 10(9)/l, with 7% blasts; hemoglobin 8.3 g/dl, and platelets 66 * 10(9)/l. Her bone marrow showed increased blasts (32.5%) with a basophilic cytoplasm, salmon-pink granules and Auer rods. Cytogenetic analysis revealed a karyotype of 46,XX,t(1;21;8)(q21;q22;q22), and fluorescence in situ hybridization confirmed a RUNX1-RUNX1T1 fusion signal on the derivative chromosome 8. After induction chemotherapy, the patient achieved complete remission and has been stable for 6 months. To the best of our knowledge, this is the first report on the novel variant of t(8;21) involving the breakpoint 1q21 and the third case with a translocation among chromosomes 1, 21 and 8. Although the clinical relevance of variant t(8;21) is still unclear, a review of 24 such cases in the literature does not imply a poorer prognosis of variant t(8;21) than of the classic t(8;21). PMID- 21325814 TI - Trajectories in the spinal cord and the mediolateral spread in the cerebellar cortex of spinocerebellar fibers from the unilateral lumbosacral enlargement in the chicken. AB - Spinocerebellar (SC) neurons in the lumbosacral enlargement (LSE) give rise mainly to crossed fibers and generally terminate in parasagittal bands in the granular layer of the chicken cerebellar cortex. However, parasagittal bands for mossy fiber terminals have not always been clear in some cerebellar folia. The present study aimed at (1) observing the course in the spinal cord of the spinocerebellar tracts (SCTs), (2) confirming whether SC fibers originating from the unilateral LSE terminate in parasagittal bands, and (3) elucidating the relationship between the ventral and lateral funicular parts of the SCTs in the cervical enlargement (CE) using anterograde and retrograde labeling methods. The SCTs were located in the medial part of the ventral funiculi in spinal segment (SS) 27, the full width of the ventral funiculi in SS 22, the lateral and ventral funiculi in SS 14 and in the lateral funiculi from SS 10 rostralward. Projection areas in the cerebellar cortex of SC fibers were studied following unilateral injections of WGA-HRP into the LSE. As a result, SC fibers from the LSE terminated bilaterally in parasagittal bands of folia II-VI and IXc. Labeled terminals in the injected side were similar in number to those in the other side in folia II-IV and IXc and more than those in the other side in folia V and VI. Following ablation of the left (contralateral) lateral funiculus of the CE, the same tracer was injected into the right (ipsilateral) LSE or into the anterior or posterior cerebellar lobe. As a result, anterogradely labeled SC fibers passing through the ventral funiculus in the CE mainly terminated in the contralateral cerebellar cortex in folia II, III and IV, and in the ipsilateral cerebellar cortex in folia V, VI and IX. Following ablation of the unilateral lateral funiculus, retrogradely labeled neurons in the contralateral LSE were found in all SC neuron groups showing marked reduction in number. Thus, the ventral and lateral funicular parts of the SCTs in the CE were not pathways for specific SC neuron groups but different in projection areas. PMID- 21325815 TI - Sex differences in the dorsolateral telencephalon correlate with home range size in blenniid fish. AB - Blenniid fish exhibit a polygynandric mating system with parental care restricted to males. Nest-holder males defend a breeding territory centered on their nest, usually a crevice or hole in a rocky substrate, to which they attract females to spawn. Females, on the other hand, must search for nests in order to spawn and usually are the choosy sex, producing several sequential egg batches and broods during the breeding season. Therefore, male blennies are more site-attached than females. This situation offers an opportunity to investigate potential neural correlates of intraspecific differences in selective pressures for different spatial abilities in these species. Since the dorsolateral telencephalon has been considered a teleost homologue of the mammalian hippocampus, we predicted that the spatial abilities required for females to locate and return accurately to nests of males may have produced a sex difference in the size of the telencephalic nuclei involved in spatial abilities, biased towards females. To test this hypothesis, we assessed the home ranges and measured the size of the dorsolateral telencephalon of both sexes during the breeding season in two blenniid species, the shanny (Lipophrys pholis) and the Azorean rock-pool blenny (Parablennius parvicornis). We chose these two species because they differ in the degree of chemical communication they use, and this could also lead to differences in telencephalic areas. As predicted, in both species females present considerably larger home ranges paralleled by larger dorsolateral ventral telencephalic nuclei (DLv) than males. Other telencephalic nuclei that were measured did not show any sex difference in size. These results suggest that the DLv is involved in spatial abilities in blenniid fish and that sexual selection may be promoting this divergence as already described for mammals and birds. PMID- 21325816 TI - In vitro developed spontaneously contracting cardiomyocytes from rainbow trout as a model system for human heart research. AB - BACKGROUND/AIMS: Cellular models are an interesting tool to study human heart diseases. To date, research groups mainly focus on mouse models, but important murine physiology is different from human characteristics. Recently, scientists found that the electrophysiology of fish cardiomyocytes largely resembles that of humans. So far, cardiomyocyte models were generated using differentiation medium, were stimulated electrically or, when contracting spontaneously, only did so over a short time period. We established an in vitro spontaneously, long-term beating heart model generated from rainbow trout, with the potential to be used as a new human heart model system because of its electrophysiology. METHODS: Spontaneously contracting 3D cell layers from rainbow trout were generated in vitro and analyzed using PCR and immunochemistry. Further, electrophysiology was measured via intra - and extracellular recordings. RESULTS: Contracting cardiomyogenic aggregates were generated without differentiation medium and were beating autonomously for more than one month. Electrophysiological measurements exhibit that the action potential properties of fish cardiomyocytes in part resemble the characteristics of human cardiomyocytes. The sensitivity of the beating cell aggregates to drugs could also be confirmed. CONCLUSION: Spontaneously contracting cardiomyogenic cell aggregates from rainbow trout generated in vitro are suitable for human heart research and pharmacology. PMID- 21325818 TI - Tanshinone IIA prevented brain iron dyshomeostasis in cerebral ischemic rats. AB - BACKGROUND: Tanshinone IIA is a lipid-soluble compound extracted from Chinese herb Danshen which was commonly used in the treatment of cerebrovascular diseases. Brain iron homeostasis is very essential for normal physiological functions of neurons, and brain iron accumulation contributes to many neurological disorders. The present study was aimed to determine whether Tanshinone IIA protects against cerebral ischemic injury via maintaining brain iron homeostasis. METHODS: Wistar Rats were orally administered with Tanshinone IIA (4, 20 and 100 mg/kg/d) for one week, and then subjected to cerebral ischemia by middle cerebral artery occlusion (MCAO) for 2 h. In vitro, cultured neurons were pretreated with Tanshinone IIA (2, 10 and 50 uM) for one week, and then exposed to hypoxia for 24 h. Brain iron content was determined by Flame Atomic Absorption Spectrophotometer and intracellular free iron level was measured by laser scanning Confocal microscopy. Expression levels of iron transport proteins including DMT1, TfR, Fpn1 and Heph were assessed by Western blot technique. RESULTS: Tanshinone IIA pretreatment resulted in a significant reduction of cerebral infarct volume in MCAO rats. Compared with control rats, cerebral ischemia considerably augmented total iron content in the brain of MCAO rats, which was also effectively restricted by Tanshinone IIA pretreatment. MCAO rats exhibited the increased expression of iron influx proteins DMT1 and TfR, and the decreased expression of iron efflux proteins Fpn1 and Heph compared with control rats, which was responsible for elevated iron content in the ischemic brain. Tanshinone IIA pretreatment prevented the dysregulation of these four iron transport proteins and maintained brain iron homeostasis. In vitro studies also confirmed that Tanshinone IIA alleviated the hypoxia-induced decline of cell viability and the overload of intracellular free iron level in neurons through downregulating the expression of DMT1 and TfR, and upregulating the expression of Fpn1 and Heph. CONCLUSION: Tanshinone IIA protected brain tissues against ischemic and hypoxic damage in vivo and in vitro by mediating brain iron homeostasis which was associated with the downregulation of DMT1 and TfR, and the upregulation of Fpn1 and Heph. These results provide new insights into molecular mechanisms of ischemia-induced brain iron abnormalities and suggest maintaining brain iron homeostasis may be a novel therapeutic strategy for ischemic cerebrovascular diseases. PMID- 21325817 TI - Myocardial reperfusion injury: reactive oxygen species vs. NHE-1 reactivation. AB - BACKGROUND/AIMS: Flow restoration to ischemic myocardium reduces infarct size (IS), but it also promotes reperfusion injury. A burst of reactive oxygen species (ROS) and/or NHE-1 reactivation were proposed to explain this injury. Our study was aimed to shed light on this unresolved issue. METHODS: Regional infarction (40 min-ischemia/2 hs-reperfusion) was induced in isolated and perfused rat hearts. Maximal doses of N-(2-mercaptopropionyl)-glycine (MPG 2mmol/L, ROS scavenger), cariporide (10MUmol/L, NHE-1 inhibitor), or sildenafil (1MUmol/L, phosphodiesterase5A inhibitor) were applied at reperfusion onset. Their effects on IS, myocardial concentration of thiobarbituric acid reactive substances (TBARS), ERK1/2, p90(RSK), and NHE-1 phosphorylation were analyzed. RESULTS: All treatments decreased IS ~ 50% vs. control. No further protection was obtained by combining cariporide or MPG with sildenafil. Myocardial TBARS increased after infarction and were decreased by MPG or cariporide, but unaffected by sildenafil. In line with the fact that ROS induce MAPK-mediated NHE-1 activation, myocardial infarction increased ERK1/2, p90(RSK), and NHE-1 phosphorylation. MPG and cariporide cancelled these effects. Sildenafil did not reduce the phosphorylated ERK1/2-p90(RSK) levels but blunted NHE-1 phosphorylation suggesting a direct dephosphorylating action. CONCLUSIONS: 1) Reperfusion injury would result from ROS-triggered MAPK-mediated NHE-1 phosphorylation (and reactivation) during reperfusion; 2) sildenafil protects the myocardium by favouring NHE-1 dephosphorylation and bypassing ROS generation. PMID- 21325819 TI - Effect of a chronic cholesterol-rich diet on vascular structure and oxidative stress in LDLR-/- mice. AB - AIMS: There is conflicting evidence regarding the relationship between hypercholesterolemia and oxidative stress in vessels. To test the potential relationship, a mouse model of hypercholesterolemia was used. METHODS: Low density lipoprotein receptor-deficient (LDLR(-/-)) and control (C57Bl/6) mice were fed a normal or (1.25%) high-cholesterol (HC) diet for 8 weeks, and the incidence of this chronic diet was evaluated on the degree of vascular oxidative stress and vascular structure (collagen content and lipid infiltration expressed in arbitrary units: AU=%/mm(2)). RESULTS: Animals treated with the HC diet presented an increase in lipid infiltration (0.35+/-0.13 vs. 1.7+/-0.18 control and 1.04+/-0.16 vs. 1.84+/-0.23 LDLR(-/-), AU p<0.05) associated with higher collagen content (control: 2.13+/-0.40 vs. 3.46+/-0.36 and LDLR(-/-): 2.37+/-0.36 vs. 3.79+/-0.60; AU p<0.05 red Sirius staining). Interestingly, ROS production in the aorta was only increased in the LDLR(-/-) +cholesterol group (0.17+/-0.04 and 0.16+/-0.05 in the control groups, 0.14+/-0.02 vs. 0.34+/-0.06 in the LDLR(-/-) groups, p<0.05). C57Bl/6 and LDLR(-/-) mice presented altered vascular structure associated with the rich cholesterol diet, which was not necessarily associated with increased oxidative stress. CONCLUSION: These findings highlight the complex interrelation between oxidative stress and lipid metabolism in the circulatory tract. PMID- 21325820 TI - AMID mediates adenosine-induced caspase-independent HuH-7 cell apoptosis. AB - BACKGROUND/AIMS: The mechanism underlying extracellular adenosine-induced caspase independent apoptosis in HuH-7 human hepatoma cells is not fully understood. The present study investigated the role for apoptosis-inducing factor (AIF) homologous mitochondrion-associated inducer of death (AMID) in the pathway. METHODS: To see the implication of AMID in adenosine-induced HuH-7 cell apoptosis, real-time reverse transcription-polymerase chain reaction (RT-PCR), immunofluorescent cytochemistry, time-laps GFP monitoring, cell cycle analysis, flow cytometry, Western blotting, cell viability assay, and TUNEL staining were carried out. RESULTS: Adenosine upregulated AMID expression in HuH-7 cells, and translocated AMID from the cytosol into the nucleus. Adenosine induced HuH-7 cell apoptosis, and the effect was further enhanced by overexpressing AMID. Adenosine induced HuH-7 cell apoptosis, alternatively, was inhibited by knocking-down AMID. CONCLUSION: The results of the present study provide evidence for AMID as a critical factor for adenosine-induced caspase-independent HuH-7 cell apoptosis. PMID- 21325821 TI - The NFKB pathway inhibitors Bay 11-7082 and parthenolide induce programmed cell death in anucleated Erythrocytes. AB - The preclinical compounds Bay 11-7082 and parthenolide trigger apoptosis, an effect contributing to their antiinflammatory action. The substances interfere with the activation and nuclear translocation of nuclear factor NFkappaB, by inhibiting NFkappaB directly (parthenolide) or by interfering with the inactivation of the NFkappaB inhibitory protein IkappaB-alpha (Bay 11-7082). Beyond that, the substances may be effective in part by nongenomic effects. Similar to apoptosis of nucleated cells, erythrocytes may undergo apoptosis-like cell death (eryptosis) characterized by cell membrane scrambling with phosphatidylserine exposure, and cell shrinkage. Thus, erythrocytes allow the study of nongenomic mechanisms contributing to suicidal cell death, e.g. Ca(2+) leakage or glutathione depletion. The present study utilized Western blotting to search for NFkappaB and IkappaB-alpha expression in erythrocytes, FACS analysis to determine cytosolic Ca(2+) (Fluo3 fluorescence), phosphatidylserine exposure (annexin V binding), and cell volume (forward scatter), as well as an enzymatic method to determine glutathione levels. As a result, both NFkappaB and IkappaB alpha are expressed in erythrocytes. Targeting the NFkappaB pathway by Bay 11 7082 (IC(50) ~ 10 MUM) and parthenolide (IC(50) ~ 30 MUM) triggered suicidal erythrocyte death as shown by annexin V binding and decrease of forward scatter. Bay 11-7082 treatment further increased intracellular Ca(2+) and led to depletion of reduced glutathione. The effects of Bay 11-7082 and parthenolide on annexin V binding could be fully reversed by the antioxidant N-acetylcysteine. In conclusion, the pharmacological inhibitors of NFkappaB, Bay 11-7082 and parthenolide, interfere with the survival of erythrocytes involving mechanisms other than disruption of NFkappaB-dependent gene expression. PMID- 21325822 TI - Mechanisms of platelet-activating factor-induced enhancement of VEGF expression. AB - It has been previously reported that platelet-activating factor (PAF) induces the expression of vascular endothelial growth factor (VEGF) via the downregulation of p53 activity. In this study, we attempted to characterize the mechanism by which p53 activity negatively regulates PAF-induced VEGF expression. PAF increased luciferase activity as well as VEGF mRNA expression in human non-small cell lung cancer cell line H1299 transfected with VEGF luciferase reporter plasmid (VEGF Luc). Cotransfection of the cells with wt p53, but not mutant p53, effected a blockage of PAF-induced VEGF mRNA expression. The ChIP assay revealed that p53 did not bind to the VEGF promoter. Transfection of Egr-1 or Sp-1 expression vector increased VEGF luciferase activity in VEGF-Luc-transfected cells, and this was inhibited by transfection with wt p53. The results of the Immunoprecipitation and immunoblot analysis showed that p53 binds to Egr-1 and Sp-1. Additionally, our electrophoretic mobility shift assay demonstrated that PAF induced the mobilization of Egr-1 and Sp-1 to the nucleus, and this activity was inhibited by transfection with wt p53. These data indicate that PAF inhibits protein complexes between p53 and Egr-1/Sp-1 via the downregulation of p53 levels, thus increasing the free form levels of Egr-1 and Sp-1, ultimately resulting in the transcriptional activation of VEGF. PMID- 21325823 TI - Angiotensin II induces the expression of c-reactive protein via MAPK-dependent signal pathway in U937 macrophages. AB - Atherosclerosis is an inflammatory disease in the vessel wall. As an inflammatory molecule, C-reactive protein (CRP) participates in all stages of atherosclerotic process. Although angiotensin II (Ang II) can stimulate the vascular cells to produce CRP, it is unknown whether Ang II induces CRP expression in macrophages. The present study was to observe effect of Ang II on CRP production and the related signal pathway in U937 macrophages so as to provide more evidence for the proinflammatory action of Ang II. The results showed that Ang II significantly increased mRNA and protein expression of CRP in U937 macrophages in time- and concentration-dependent manners. AT(1) receptor blocker losartan blocked Ang II induced CRP expression in mRNA and protein levels in U937 macrophages. Losartan and complex II inhibitor TIFA decreased Ang II -stimulated reactive oxygen species (ROS) generation, and antioxidant NAC completely abolished Ang II induced CRP expression in U937 macrophages. The further study indicated that losartan, NAC, MEK1/2 inhibitor PD98059, p38MAPK inhibitor SB203580 obviously inhibited ERK1/2 and p38MAPK phosphorylation, and PD98059, SB203580 and NF-kappaB inhibitor PDTC reduced Ang II -induced mRNA and protein expression of CRP in U937 macrophages. These demonstrate that Ang II is capable of inducing CRP generation in macrophages via AT(1)-ROS-ERK1/2/p38MAPK-NF-kappaB signal pathway, which contributes to better understanding of the proinflammatory and proatherosclerotic actions of Ang II. PMID- 21325824 TI - Adenosine activates AMPK to phosphorylate Bcl-XL responsible for mitochondrial damage and DIABLO release in HuH-7 cells. AB - BACKGROUND/AIMS: Accumulating evidence has pointed to AMP-activated protein kinase (AMPK) as an inducer of apoptosis in a variety of cancer cells. The present study aimed at understanding AMPK signals for adenosine-induced HuH-7 cell apoptosis. METHODS: Cell viability, AMPK activity, mitochondrial membrane potentials, phosphorylation of Bcl-X(L), in situ DIABLO mobilizations, and caspase-3 activity were monitored in HuH-7 cells. Plasmid DNAs for DIABLO-GFP, mutant Bcl-X(L), dominant negative mutant AMPKalpha2 and the siRNAs to silence the AMPKalpha1 or AMPKalpha2 targeted gene were constructed and transfected. RESULTS: Adenosine or the AMPK activator AICAR induced apoptosis in HuH-7 cells, and no synergistic effect was obtained with co-treatment. Adenosine activated AMPK, to phosphorylate Bcl-X(L). Adenosine or AICAR disrupted mitochondrial membrane potentials, and the effect was inhibited by knocking-down AMPKalpha1 and/or AMPKalpha2, expressing dominant negative mutant AMPKalpha2 or mutant Bcl X(L) lacking Ser/Thr phosphorylation sites. AICAR stimulated DIABLO release from the mitochondria, and the release was suppressed by expressing the mutant Bcl X(L). AICAR activated caspase-3, which was also inhibited by expressing the mutant Bcl-X(L). CONCLUSION: Adenosine activates AMPK, to disrupt mitochondrial membrane potentials through Bcl-X(L) phosphorylation, allowing DIABLO release from the mitochondria, as a factor for caspase-3 activation to induce HuH-7 cell apoptosis. PMID- 21325825 TI - Substrate-dependent interference of carbonic anhydrases with the glutamine transporter SNAT3-induced conductance. AB - The glutamine transporter SNAT3 (SLC38A3), which also transports asparagine and histidine, exchanges sodium for protons, and displays a non-stoichiometrical conductance, which is suppressed by the catalytic activity of carbonic anhydrase II (CAII). In this study, we show that this conductance of rat SNAT3, expressed in Xenopus oocytes, is also suppressed following co-expression with CAI, CAIII, CAIV, and CAII-H64A (mutant with impaired intramolecular H(+) shuttling). All CA isoforms and the CAII mutant displayed catalytic activity in intact oocytes, although in vitro studies had reported only very low catalytic activity of CAIII and CAII-H64A. The CA-mediated suppression of conductance was only observed, however, when glutamine, but not when asparagine, was the substrate. We hypothesized that this substrate specificity of the CA action might be due to the different ion selectivity induced by the different amino acid substrates, which induce currents carried by sodium and/or protons. The ion selectivity and conductance was dependent on both pH and extracellular sodium concentration for glutamine and asparagine; however the sodium dependence of the conductance, when asparagine was the substrate, was significantly greater at higher sodium concentrations, which might explain the difference in the sensitivity of the conductance to CAs. Given the presence of CAs in most cells, substrate sensing of SNAT3 would be indicated by different membrane potential changes. PMID- 21325826 TI - Differentially expressed protein profile of renal tubule cell stimulated by elevated uric acid using SILAC coupled to LC-MS. AB - BACKGROUND/AIMS: Hyperuricemia could lead to serious renal disease. It will advance our understanding of the mechanism of this disease to study the differentially expressed protein in renal tubular epithelial cells stimulated by elevated uric acid. METHODS: We used SILAC coupled to LC-MS to study differentially expressed protein profile and to analysis the functional status of renal tubular epithelial cells stimulated by 600MUM uric acid, and to investigate the potential biology function. The MS results were analyzed by online platform and further confirmed by western blotting. RESULTS: 789 differentially expressed proteins were identified, of which 42 proteins and 49 proteins were related with cell proliferation and cell apoptosis, respectively. Pathway analysis showed that MAPK signaling pathway was a key pathway related to the function of these proteins. In addition, prohibitin-2 was identified to be related to renal cell transdifferentiation stimulated by elevated uric acid. CONCLUSION: This work provides an overview of protein expression changes in HK-2 cells treated with elevated uric acid and will contribute to further study of cell apoptosis and fibrosis in renal disease patients. PMID- 21325827 TI - Expression of the Lactobacillus plantarum surface layer MIMP protein protected NCM460 epithelial cells from enteroinvasive Escherichia coli infection. AB - Our previous studies demonstrated that the micro integral membrane protein (MIMP) located within the integral membrane protein of Lactobacillus plantarum CGMCC 1258 protected the intestinal barrier from injury. To further analyze the protective effects conferred to intestinal epithelial cells by MIMP, we established transient MIMP-expressing NCM460 cells (NCM460/MIMP) as a means of assessing their susceptibility to infection. We constructed a recombinant eukaryotic expression vector using pcDNA3.1(-) and the MIMP gene. The recombinant vector was then transduced into NCM460 cells and the anti-infective properties of the transient MIMP-expressing NCM460/MIMP cells assessed. Flow cytometric analysis revealed that 82.16% +/-12.22% of NCM460/MIMP cells expressed MIMP and Western blot analysis confirmed high levels of MIMP expression. Attachment assays showed that the ability of enteropathogenic Escherichia coli (EPEC) to attach to NCM460/MIMP cells decreased significantly compared to adhesion observed to NCM460 cells. Western blot and quantitative RT-PCR showed that the expression levels of tight junction (TJ) proteins, including claudin-1, occludin, JAM-1 and ZO-1 in NCM460/MIMP cells infected with EPEC were similar to levels observed in uninfected NCM460 cells. Fluorescence further showed that NCM460/MIMP cells had significantly higher TJ protein staining intensity ocompared to NCM460 cells and transmission electron microscopy indicated that TJ structure was unchanged in NCM460/MIMP cells infected with EPEC compared to NCM460 cells after EPEC infection. Expression levels of PKC-eta and phosphorylated occludin were also higher after EPEC infection in NCM460/MIMP cells compared to expression levels in EPEC-infected NCM460 cells. These data demonstrated that NCM460/MIMP cells possessed EPEC anti-infective properties related to the activation of protein kinase C-eta and occludin phosphorylation. PMID- 21325828 TI - Differential role for ERK2 in anoxia-induced activation of transcription and translation of Hsp70 in NIH 3T3 cells. AB - Hsp70 has the ability to enhance the recovery of stressed cells by its ability to catalyze the reassembly of damaged proteins. Such a chaperoning function is essential for the Hsp70-mediated protection against anoxic stress that causes protein denaturation. We have studied induction of both transcription and translation of Hsp70 during recovery from chemical anoxia and the role of the extracellular signal regulated kinase ERK2 in this induction of Hsp70. 10 mM azide for 30 minutes (chemical anoxia) significantly inhibited the activity of ERK2 (measured as phospho-ERK) but the ERK-2 activity is rapidly increased in a MEK-independen manner, when azide is washed out of the cells. Chemical anoxia and overnight recovery induced Hsp70 expression (analyzed by Western blotting) and this was inhibited by actinomycin D as well as by cycloheximide showing that induction of both translation and transcription was involved. Inhibition of the MAP kinase p38, which was transiently activated during chemical anoxia, had no effect on the increase in Hsp70 expression whereas an inhibitor of reactive oxygen species and inhibition of the phosphatase PP1 and PP2a inhibited the increase in Hsp70 expression. Inhibition of ERK2 by the MEK inhibitor PD98059 resulted in strong inhibition of Hsp70 protein expression and simultaneous stimulation of hsp70 transcription. PMID- 21325829 TI - Transgenic overexpression of heart-specific adenine nucleotide translocase 1 positively affects contractile function in cardiomyocytes. AB - BACKGROUND/AIMS: The adenine nucleotide translocase (ANT) exchanges ATP and ADP over the inner mitochondrial membrane, supplying the cells with energy. Interestingly, myocardial ANT1 overexpression preserves cardiac structure and function under pathophysiological conditions. To ascertain whether the contractile system is directly affected by increased ANT1 expression, we analyzed cell morphology, contraction and relaxation parameters of ANT1 transgenic (ANT1 TG) cardiomyocytes, myofibrillar protein expression, and Ca(2+) handling in ANT1 TG rat hearts. RESULTS: ANT1-TG cardiomyoycytes displayed an elevation in cell volume (52.6 +/- 12.0%; p<0.0001) in comparison to wildtype (WT) cells. Concurrently, contractile function in ANT1-TG cells was significantly increased, measured by a decline in time to peak contraction (TTP) and RT50, the time from peak contraction to 50% relaxation, during stimulation with 0.5, 1, and 2 Hz. Quantification of myofibrillar proteins exhibited a marked increase in total cardiac myosin heavy chain (51.8 +/- 12.8%) (p<0.03), beta myosin heavy chain (22.9 +/- 5.0%; p<0.03), actin (23.8 +/- 8.8%; p<0.05), and troponin I (51.5 +/- 13.7%; p<0.01). Regarding intracellular Ca(2+) handling, ANT1-TGs revealed a significant elevation in sarcoplasmic reticulum (SR) Ca(2+) ATPase (SERCA2a) protein level (22.2 +/- 4.7%; p<0.01) associated with increased Ca(2+) uptake into the SR (34%; p<0.01). Moreover, the plasmalemmal Ca(2+) ATPase (PMCA) indicated advanced protein expression (23.8 +/- 4.8%; p<0.01), whereas the protein amount of the Na(+)/Ca(2+) exchanger was not altered in ANT1 overexpressing hearts. CONCLUSION: These data reveal a close association of elevated mitochondrial ATP/ADP transportation via ANT1 with increased contractile function. Furthermore, the ANT1-TGs exhibit an elevation in SR Ca(2+) transport that contributes to increased cardiac work, which may protect the heart under pathophysiological conditions. PMID- 21325831 TI - Regulation of serotonin transport in human platelets by tyrosine kinase Syk. AB - Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter involved in the regulation of numerous neuro-physiological processes. The circulating level of 5 HT is regulated by the membrane transporter SERT present both in the presynaptic nerve terminals and blood platelets. 5-HT transport is a process tightly regulated by a variety of factors including protein phosphorylation. Aim of this study was to ascertain if also the SERT Tyr-phosphorylation mediated by Syk kinase concurs to the regulation of SERT activity. Indeed we found that 5-HT uptake decreased upon platelet exposure to piceatannol or Syk-inhibitor II, two structurally unrelated inhibitors of the tyrosine-kinase Syk. Tyr-phosphorylation of anti-SERT-immuno-stained proteins in membrane extracts and in anti-SERT-immuno precipitates, decreased upon platelet treatment with piceatannol, in parallel with a reduction of Syk-activity. Syk was immuno-revealed in the anti-SERT immuno precipitates, which displayed a piceatannol-sensitive kinase activity towards SERT itself and the Syk-substrate alpha-sinuclein. Syk inhibitors also caused a decrease of the monensin-induced 5-HT-efflux from platelets and of imipramine binding to them. It is concluded that, in addition to the phosphorylation of SERT mediated by various other kinases, also that catalyzed by Syk might play an important role in the 5-HT transport, likely favoring the transporter conformation exposing the neurotransmitter binding sites. PMID- 21325830 TI - ASIC-like currents in freshly isolated cerebral artery smooth muscle cells are inhibited by endogenous oxidase activity. AB - BACKGROUND/AIMS: The aim of this study was to determine if VSMC ASIC-like currents are regulated by oxidative state. METHODS: We used whole-cell patch clamp of isolated mouse cerebral VSMCs to determine if 1) reducing agents, such as DTT and GSH, and 2) inhibition of endogenous oxidase activity from NADPH and Xanthine oxidases potentiate active currents and activate electrically silent currents. RESULTS: Pretreatment with 2 mM DTT or GSH, increased the mean peak amplitude of ASIC-like currents evoked by pH 6.0 from 0.4 +/- 0.1 to 14.9 +/- 3.6 pA/pF, and from 0.9 +/- 0.3 to 11.3 +/- 2.4 pA/pF, respectively. Pretreatment with apocynin, a NADPH oxidase inhibitor, mimics the effect of the reducing agents, with the mean peak current amplitude increased from 0.9 +/- 0.5 to 7.0 +/ 2.6 pA/pF and from 0.5 +/- 0.2 to 26.4 +/- 6.8 pA/pF by 50 and 200 MUM apocynin, respectively. Pretreatment with allopurinol, a xanthine oxidase inhibitor, also potentiates the VSMC ASIC-like activity. CONCLUSION: These findings suggest that VSMC ASIC-like channels are regulated by oxidative state and may be inhibited by basal endogenous oxidative sources such as NADPH and xanthine oxidase. PMID- 21325832 TI - alpha, beta-DCP-LA selectively activates PKC-epsilon and stimulates neurotransmitter release with the highest potency among 4 diastereomers. AB - BACKGROUND/AIMS: We have been probing bioactivities of 8-[2-(2-pentyl cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA), a linoleic acid derivative with cyclopropane rings instead of cis-double bonds, using a racemic modification. Racemic DCP-LA contains possible 4 diastereomers. We, therefore, separately synthesized DCP-LA diastereomers such as alpha alpha-, alpha, beta-, beta,alpha-, and beta, beta-DCP-LA and assessed the effects of each diastereomer on protein kinase C (PKC) activity and transmitter release. METHODS: PKC activity under the cell-free conditions and in PC-12 cells, and glutamate, dopamine, and serotonin released from rat brain slices were assayed with a high performance liquid chromatography (HPLC) system. RESULTS: Of 4 diastereomers alpha, beta-DCP LA selectively and directly activated PKC-e, with the highest potency. alpha beta DCP-LA stimulated release of glutamate, dopamine, and serotonin from rat hippocampal, striatal, and hypothalamic slices, respectively, under the control of PKC, possibly PKC-e, and alpha7 nicotinic ACh receptors, with the highest potency among 4 diastereomers. CONCLUSION: alpha, beta-DCP-LA serves as a selective and direct activator of PKC-e, to stimulate transmitter release by targeting alpha7 nicotinic ACh receptors. This suggests that alpha, beta-DCP-LA could be developed as a promising drug for treatment of not only dementia but neurodegenerative diseases and psychiatric disorders due to reduction/deficiency of neurotransmitters. PMID- 21325833 TI - Expression of PITX2 homeodomain transcription factor during rat gonadal development in a sexually dimorphic manner. AB - PITX2, a multifunctional Paired-like homeodomain transcription factor, plays obligatory role during development of organs like heart, brain and pituitary. It regulates differentiation of vascular smooth muscle cells and hematopoietic stem cells. Although we earlier reported the Pitx2/PITX2 expression in gonad, but the expression pattern of its different isoforms in mammalian gonads especially during development is still not known. As PITX2 participates in the development of multiple organs and different homeobox genes have been shown to control gonadal functions, we wanted to investigate the role of PITX2 in gonadal development and its function. The objective of our study was to know the expression profile of different Pitx2/PITX2 isoforms and its localization throughout the development of gonads. Here we show the temporal and spatial expression pattern of Pitx2/PITX2 and its localization throughout the embryonic and postnatal stages of rat gonads. Pitx2/PITX2 expression profile reveals the differential and dimorphic expression pattern of its two isoforms PITX2B2 and Cbeta throughout the embryonic development stages and also in the postnatal stages, where it becomes more prominent. This is the first report where PITX2 homeodomain transcription factor shows isoform-specific sexually dimorphic expression. In addition, PITX2 localization was found in the embryonic ovarian primordial germ cell clusters and germ cells inside the testicular cords and also in somatic cells. In adults, ovarian granulosa and theca cells as well as germ cells inside the seminiferous tubules in testis express PITX2. All the evidences suggest that the differential expression of PITX2 might be associated with sex specific embryonic and postnatal gonadal development and the physiological processes. PMID- 21325834 TI - Na+-H+ exchanger regulatory factor 1 (NHERF1) PDZ scaffold binds an internal binding site in the scavenger receptor megalin. AB - The scavenger receptor megalin binds to albumin in the microvilli of the renal proximal tubule, and transports the ligand to the intravillar cleft for processing by endocytosis. Albumin endocytosis in the proximal tubule is regulated by protein complexes containing a number of transmembrane and accessory proteins including PDZ scaffolds such as NHERF1 and NHERF2. PDZ scaffold proteins bind to class I PDZ binding motifs (S/T-X-Phi) in the extreme C-terminus of targets. Megalin contains a functional PDZ binding motif (SDV) in its distal terminus, however a potential interaction with the NHERF proteins has not been investigated. As megalin associates with NHE3 in the microvilli and NHE3 is tethered to the intravillar cleft via its interaction with NHERF1, we investigated if there is a direct interaction between megalin and NHERF1 in renal proximal tubule cells. Using confocal microscopy we determined that megalin and NHERF1 co-localise in the apical region in proximal tubule cells. Immunoprecipitation experiments performed using rat kidney lysate indicated that megalin bound NHERF1 in vivo. Using fusion proteins and peptides, we determined that PDZ2 of NHERF1 bound to megalin and that this interaction was via the C terminus of megalin directly and in the absence of any accessory protein. We next investigated which domain in megalin was regulating this interaction. Using GST fusion proteins we determined that the loss of the most distal C-terminus of megalin containing the PDZ binding motif (SDV) did not alter its ability to bind to NHERF1. Significantly, we then identified an internal NHERF binding domain in the C-terminus of megalin. Using peptide studies we were able to demonstrate that NHERF1 bound to an internal PDZ binding motif in megalin and that a loss of a single threonine residue abolished the interaction between megalin and NHERF1. Finally, in proximal tubule cells, silencing NHERF1 increased megalin expression. Therefore, we have identified a novel protein interaction in proximal tubule cells and specifically identified a new internal PDZ binding motif in the C terminus of megalin. PMID- 21325835 TI - Anatomical and physiological basis of topical therapy of the mucosa. AB - The mucosa as a nonkeratinized epithelium covering body surfaces has widely differing anatomical and physiological properties depending on the organ system involved (gastrointestinal, respiratory, urinary, genital, ocular). In general, the mucosae close to the skin are more permeable to exogenous substances, more prone to irritant reactivity, and they have a unique microbial ecology which is qualitatively and quantitatively different from that of the adjacent keratinized epithelium. Clinical presentations of exogenous dermatoses in mucosae appear different from those of the skin. These specific properties of mucosae have to be considered in the development and application of topical agents, cosmetics and consumer products. PMID- 21325836 TI - Morphology and physiological changes of genital skin and mucosa. AB - The morphology and physiology of both the vulva and vagina undergo characteristic age-related changes over a lifetime. At birth, these tissues exhibit the effects of residual maternal estrogens. During puberty, the vulva and vagina mature under the influence of adrenal and gonadal steroid hormones. During the reproductive years, the vagina responds to ovarian steroid hormone cycling, and both tissues adapt to the needs of pregnancy and delivery. Following menopause, the vulva and vagina atrophy. A rise in the prevalence of incontinence among older women increases the risk of vulvar and perineal dermatitis. This chapter covers the morphology and physiology of the genital area from infancy to old age. PMID- 21325837 TI - Nasal drug delivery in humans. AB - Intranasal administration is an attractive option for local and systemic delivery of many therapeutic agents. The nasal mucosa is--compared to other mucosae- easily accessible. Intranasal drug administration is noninvasive, essentially painless and particularly suited for children. Application can be performed easily by patients or by physicians in emergency settings. Intranasal drug delivery offers a rapid onset of therapeutic effects (local or systemic). Nasal application circumvents gastrointestinal degradation and hepatic first-pass metabolism of the drug. The drug, the vehicle and the application device form an undividable triad. Its selection is therefore essential for the successful development of effective nasal products. This paper discusses the feasibility and potential of intranasal administration. A series of questions regarding (a) the intended use (therapeutic considerations), (b) the drug, (c) the vehicle and (d) the application device (pharmaceutical considerations) are addressed with a view to their impact on the development of products for nasal application. Current and future trends and perspectives are discussed. PMID- 21325838 TI - Antimicrobial topical agents used in the vagina. AB - Vaginally applied antimicrobial agents are widely used in the vagina in women with lower genital tract infections. An 'antimicrobial' is a general term that refers to a group of drugs that are effective against bacteria, fungi, viruses and protozoa. Topical treatments can be prescribed for a wide variety of vaginal infections. Many bacterial infections, such as bacterial vaginosis, desquamative inflammatory vaginitis or, as some European authors call it, aerobic vaginitis as well as infection with Staphylococcus aureus or group A streptococci, may be treated in this way. Candida vulvovaginitis is a fungal infection that is very amenable to topical treatment. The most common viral infections which can be treated with topical medications are condylomata acuminata and herpes simplex. The most often encountered protozoal vaginitis, which is caused by Trichomonas vaginalis, may be susceptible to topical medications, although this infection is treated systemically. This chapter covers the wide variety of commonly used topical antimicrobial agents for these diseases and focuses on the individual therapeutic agents and their clinical efficacy. In addition, potential difficulties that can occur in practice, as well as the usage of these medications in the special setting of pregnancy, are described in this chapter. PMID- 21325839 TI - Topical therapy for mucosal yeast infections. AB - Mucosal yeast infection is best understood as a consequence of compromised mucosal cell-mediated and innate immunity. Defense against oral candidiasis is dominantly cell mediated. The innate immune system may play the main role in regulating vulvovaginal yeast infection. Conditions that compromise cell-mediated immunity such as leukemia, severe illness and HIV infection must be considered as predisposing factors for recurrent oral candidiasis. Compromise of vaginal innate immunity due to mucosal allergy or due to a genetic defect such as mannose binding lectin deficiency contributes to chronic vulvovaginal yeast infection. Treatment of cofactors must be considered in order to achieve control in recurrent mucosal yeast infection. PMID- 21325840 TI - Anti-inflammatory treatment. AB - Inflammatory mucosal disorders are treated conventionally with potent or superpotent topical corticosteroids. For more than 20 years, topical cyclosporine has been used in the management of oral mucous membrane affections. Recently other topically applied calcineurin inhibitors, namely tacrolimus and pimecrolimus, expanded the armamentarium for the treatment of inflammatory mucosal diseases. This chapter places its main emphasis on the efficacy and safety of topical calcineurin inhibitors in the management of different oral and genital conditions, including anogenital lichen sclerosus (LS), oral and genital lichen planus, plasma cell balanitis and vulvitis, mucous membrane pemphigoid and pemphigus vulgaris, all conditions having usually a protracted course, requiring long-lasting treatment. There is current evidence for the effectiveness of both pimecrolimus and tacrolimus in the topical treatment of inflammatory oral mucosal diseases and genital dermatoses, especially oral lichen planus and genital LS. PMID- 21325841 TI - Topical antineoplastic agents in the treatment of mucocutaneous diseases. AB - Topical antineoplastic agents have a well-established role in the treatment of several dermatological conditions. Their use in the treatment of mucosal skin disease also has gained increasing recognition. Topical 5-fluorouracil (5-FU), an antimetabolite, and imiquimod, an immunomodulatory agent with antitumor properties, are the two principal topical antineoplastic agents used in the treatment of mucocutaneous diseases. Although the vast majority of their mucosal uses are currently not approved by the Federal Drug Administration, there are numerous case series, open-label studies and randomized controlled trials supporting their uses in the treatment of mucocutaneous diseases. Both topical 5 FU and imiquimod have been successfully utilized in the treatment of a wide range of mucosal diseases, including actinic cheilitis, Bowen's disease of the anal and vulvar mucosa, and genital and perianal condyloma. Reports of their uses in the treatment of mucocutaneous diseases indicate that these agents can be safely administered, though adverse effects such as local inflammation may be augmented when these agents are applied to mucosal surfaces. Additionally, locally acting intralesional chemotherapeutic agents, such as bleomycin and interferon, have well-defined applications in the treatment of mucosal skin diseases such as condyloma acuminata. As further studies are conducted, these topical and intralesional neoplastic agents, in addition to emerging agents that are in various stages of development, such as Toll-like receptor 9 agonists and ingenol mebutate, may play an increasingly important role in the future treatment of mucocutaneous diseases. PMID- 21325842 TI - Diaper area and disposable diapers. AB - Since the 1960s, cloth diapers have been replaced by disposable diapers. The evolution of healthier skin in the diaper area has been demonstrated in parallel to that of disposable diapers. The improvements of disposable diapers--fit, dryness, comfort--have been based on the understanding of factors playing a role in the development of diaper dermatitis. PMID- 21325843 TI - Products used on female genital mucosa. AB - A wide variety of products are used by women in the genital area and, therefore, come into contact with the genital mucosa. The largest category of such products would be those used for cleanliness and odor control, such as soaps and body washes, douches, premoistened wipes and towelettes, dusting powder and deodorant sprays. A second large category of products are those intended to absorb fluids, such as products used for menstrual protection (tampons, pads and panty liners) and incontinence protection. Lubricants and moisturizers, and aesthetic products (hair removal products and dyes) are also fairly common. In addition, over the counter medications are now available for the treatment of fungal infections. This chapter briefly discusses the products women use on or around the genital area, the perceived or real benefits, and the potential health effects of these products. PMID- 21325844 TI - Emollients on the genital area. AB - Emollients are known to lubricate, moisturize and soothe the skin. Prior to their incorporation into feminine hygiene pads, thorough premarket toxicological testing is conducted to evaluate their safety and effectiveness via in-use clinical settings. Product testing has been conducted on various body sites proven previously to be valid and reliable, such as the arm and popliteal fossa and, more recently, the genital area. Several clinical studies have confirmed the safety and efficacy of emollient-containing feminine hygiene products, which have also been shown to provide dermatological benefits in the genital area. PMID- 21325845 TI - Oral care. AB - Adequate dental and oral hygiene may become a challenge for all users and especially for elderly people and young children because of their limited motor skills. The same holds true for patients undergoing/recovering from chemo /radiotherapy with accompanying sensitive mucosal conditions. Poor dental hygiene can result in tooth decay, gingivitis, periodontitis, tooth loss, bad breath (halitosis), fungal infection and gum diseases. The use of a toothbrush is the most important measure for oral hygiene. Toothbrushes with soft bristles operated carefully by hand or via an electric device help to remove plaque and to avoid mucosal trauma. A handlebar with a grip cover can be helpful for manually disabled patients or for those with reduced motor skills. In case of oral hygiene at the bedside or of patients during/after chemo-/radiotherapy a gauze pad can be helpful for gently cleaning the teeth, gums and tongue. The use of fluoride toothpaste is imperative for the daily oral hygiene. Detergents such as sodium lauryl sulphate improve the cleaning action but may also dehydrate and irritate the mucous membrane. The use of products containing detergents and flavouring agents (peppermint, menthol, cinnamon) should therefore be avoided by bedridden patients or those with dry mouth and sensitive mucosa. Aids for suitable interdental cleaning, such as dental floss, interdental brushes or dental sticks, are often complicated to operate. Their correct use should be instructed by healthcare professionals. To support dental care, additional fluoridation with a fluoride gel or rinse can be useful. Products further containing antiseptics such as chlorhexidine or triclosan reduce the quantity of bacteria in the mouth. For patients undergoing or having undergone radio-/chemotherapy, a mouthwash that concomitantly moisturizes the oral mucosa is advisable. PMID- 21325846 TI - Assessing the dermal safety of products intended for genital mucosal exposure. AB - Manufacturers employ a stepwise approach to ensure the skin safety and compatibility of consumer products that are intended for contact with mucosal skin. The properties of the ingredients are evaluated fully, along with any available safety and skin compatibility information, to eliminate any chemicals that may be strong contact sensitizers or irritants. Contact sensitization potential is evaluated by applying a quantitative exposure assessment to each ingredient or component to determine if the extent of the expected exposure is likely to pose any risk of contact sensitization. Likely exposures are calculated using the manufacturer's unique knowledge of the intended product matrix, consumer usage patterns and measurements of particular exposure variables. If adequate safety assurance cannot be provided, further testing may be conducted. The skin compatibility and irritation potential of each ingredient is evaluated using existing test data, and experience from other products containing the same or a structurally similar ingredient. Once a finished product or formulation is developed, another round of assessments is conducted to ensure that no unexpected matrix effects negatively impact the skin compatibility profile. This may include clinical testing protocols involving single and multiple patch tests, and extended use testing, with visual and/or instrumental assessments. This approach to ensuring the skin safety of products has been used successfully for many decades, and adverse skin reactions to modern products are rare. The challenge for the future is to develop test protocols that will discriminate between products that are very similar in their favorable skin compatibility profile. Options to meet this challenge include testing protocols that will: (1) further exaggerate exposure conditions, such as the behind-the-knee protocol, (2) increase the sensitivity of scoring for irritant effects, such as with the use of instrumentation, and (3) quantitatively measuring additional endpoints, such as subjective sensory effects. PMID- 21325847 TI - Can the behind-the-knee clinical test be used to evaluate the mechanical and chemical irritation potential for products intended for contact with mucous membranes? AB - BACKGROUND: The behind-the-knee (BTK) clinical test system is being used increasingly to replace in-use clinical studies in the evaluation of potential irritation effects of consumer products. The objectives of these studies were to determine if the BTK test could adequately evaluate the potential to cause irritation for feminine protection products intended for mucous membrane contact, and confirm that the BTK test would not underestimate the irritant potential that may occur when products such as tampons come into contact with mucous membranes. MATERIALS AND METHODS: Two identical tampon products were tested in in-use and BTK clinical studies. In the BTK clinical test, sites were scored daily 30-60 min after sample removal (PM scores with no recovery) and prior to application of the next sample (after 18 h of recovery). In the in-use clinical study, 6 sites (labia minora, introitus, lower and middle vaginal walls, upper vagina and cervix) were graded separately for erythema using colposcopy after use of each product for an entire menstrual cycle. RESULTS: In the in-use clinical study, the labia minora were most susceptible to irritation effects with mean erythema scores (+/- SE) of 0.36 (+/- 0.05) and 0.50 (+/- 0.06) for the experimental and control products, respectively. All other sites produced a mean erythema <=0.26. In the BTK clinical test, the postbaseline averages for erythema for the experimental and control products were 0.19 (+/- 0.04) and 0.20 (+/- 0.04) for the AM scores (with recovery), and 1. 25 (+/- 0.05) and 1. 27 (+/- 0.06) for the PM scores (no recovery). CONCLUSIONS: Preliminary results showed that the BTK clinical test may be used to evaluate potential irritation effects of products that contact mucous membranes. In a first comparison of 2 tampon products in both the in-use and BTK clinical studies, the BTK protocol produced erythema reactions at the test sites that were similar to or severer than those observed on mucosal sites in the in-use study. Overall, the BTK clinical test showed a higher sensitivity, rapid turnaround time, higher flexibility and easier implementation. Thus, making the BTK clinical test a more useful tool for both safety testing and claim support. PMID- 21325848 TI - Contact sensitization in the anal and genital area. AB - We analysed the patch test results in 1,374 patients suffering from dermatoses in the anogenital area (n = 561 genital dermatoses, n = 470 anal dermatoses, n = 343 anogenital dermatoses) patch tested in 44 dermatological departments of the Information Network of Departments of Dermatology from 2004 to 2008. All other patients patch tested during this time period without anogenital dermatoses formed the control group (n = 49, 142). Of the total study group, 662 (48.2%) patients were male. 179 (13%) had a past or present atopic dermatitis. The vast majority of the patients was older than 40 years (n = 989, 72%). Suspected allergen sources were first of all topical medicaments, followed by cosmetics, cleansing agents, clothes, rubber products, systemic medicaments and disinfectants. Allergic contact dermatitis was diagnosed in 409 (29.8%) of the tested patients. Patients with anogenital dermatoses were sensitized mainly to active agents of topical medicaments, in particular bufexamac (5.3%). Sensitization pattern and sensitization rates observed in patients with genital and anal involvement differed significantly. Patients with anal disease had significantly higher sensitization rates for bufexamac (9.4 vs. 1.1%), fragrance mix I (8.7 vs. 4.2%) and II (4.5 vs. 2.6%), propolis (5.4 vs. 1.9%) and methyldibromoglutaronitrile (6.3 vs. 4.1%). Patients with chronic anal dermatoses seem to have a higher risk to develop sensitizations to topically applied products and drugs than patients with genital dermatoses. Recommended patch test series (German Contact Dermatitis Research Group) are standard series, local anaesthetics series, topical antibiotics, antimycotics, steroids, ointment bases and preservative series as well as the patients' own products. PMID- 21325849 TI - Perceptions of sensitive skin of the genital area. AB - BACKGROUND: People with sensitive skin vary in the signs and symptoms they experience, and in the degree of sensitivity at different anatomical sites. The goal of this study is to determine patterns of perceived sensitivity of the skin of the genital area using an epidemiological approach among a general population. METHODS: Questionnaires designed to evaluate perceptions of sensitive skin in general and at specific anatomical sites (face, body and genital area) were given to 1,039 people. Questions included perceptions of sensitive skin in general and at 3 specific anatomical sites (the face, the body and the genital area). In addition, responders were asked about reactions to certain products and environmental factors. RESULTS: Over half of the responders (56.3%) perceived that the skin of the genital area was sensitive. A significantly higher percentage of African-Americans perceived their genital skin as sensitive compared to Caucasians (66.4 and 54.2%, respectively; p = 0.0096). A significantly higher number of Caucasian females claimed sensitive genital skin compared to Caucasian males (57.0 and 37.3%, respectively; p < 0.0001). In women, the perception of sensitive skin of the genital area is dependent on age and increases in older subjects. Perceived sensitive skin in general, or sensitive skin of the face or body, was not dependent on ethnicity, gender or age. The factor most strongly associated with sensitive genital skin was rough fabrics. CONCLUSIONS: The pattern of responses among different ethnicities, genders and age groups for perceived sensitive genital skin differs from that at the other anatomical sites evaluated in the study. Increasing our understanding in perceived sensitive skin in the genital area is needed. PMID- 21325850 TI - New irritation test method: behind the knee and mucosa. AB - The epithelium of the lower genital tract, a highly sensitive sensory area where a host of sexual, reproductive and health functions are performed, is a unique anatomical site. It is very responsive to both internal and external stimuli, with a reactive area function of returning to an asymptomatic resting state. Commercial products intended for use in this area must be demonstrated to have minimal inflammatory responses. To determine this, the potential response of the lower genital tract epithelium to such products has to be evaluated. Direct assessment of the vagina is limited, because of its interior location. Behind-the knee testing offers many advantages. The test products can be compared to commercial products approved by the Food and Drug Administration at the same time, and the use of cross-polarization light permits subsurface evaluation of the extent of inflammation, a more exact measure than surface recording alone. PMID- 21325851 TI - Noninvasive detection of coronary artery stenoses with contrast-enhanced whole heart coronary magnetic resonance angiography at 3.0 T. AB - PURPOSE: To prospectively evaluate the accuracy of contrast-enhanced whole-heart coronary magnetic resonance angiography (CMRA) at 3.0 T, with the use of sublingual nitroglycerin and abdominal banding, for assessing significant stenosis (>=50% lumen diameter reduction) in patients with suspected coronary disease, using conventional coronary artery angiography as the reference standard. METHODS: We prospectively studied 71 consecutive patients with suspected coronary artery disease scheduled for conventional coronary angiography. Contrast-enhanced whole-heart CMRA was performed after sublingual nitroglycerin with an abdominal banding rolled tightly along the side of the ribs. The diagnostic performance of CMRA for the detection of significant lesions was compared with that of quantitative coronary angiography. RESULTS: The acquisition of CMRA was completed in 67 of 71 patients, with an average imaging time of 9.6 +/- 3.2 min. The average navigator efficiency was 48%. The sensitivity, specificity as well as positive and negative predictive values of whole-heart CMRA for the detection of significant lesions on a segment-by-segment analysis were 91.4, 85.8, 48.7 and 98.5%, respectively, and in a patient-based analysis 94.6, 86.7, 89.7 and 92.9%, respectively. CONCLUSIONS: Contrast-enhanced whole-heart CMRA with 3.0 T optimized by using sublingual nitroglycerin and abdominal banding methods permits reliable detection of significant obstructive coronary artery disease in patients with suspected coronary disease. PMID- 21325852 TI - Small-scale cannabis growers in Denmark and Finland. AB - AIMS: To compare domestic cannabis cultivation in Denmark and Finland to describe national characteristics in small-scale cannabis growing. DESIGN: A Web survey conducted among small-scale cannabis growers in Denmark (June to November 2008) and Finland (May to June 2009). PARTICIPANTS: Current cannabis growers (Denmark, 401; Finland, 1,054). MEASUREMENTS: Comparisons in regard to social background, growing history, practices, purposes and motives of growing, and perceptions of risks. FINDINGS: Cannabis was cultivated primarily for own use, but sharing with friends and avoiding criminal circles also were significant motives for growing. Finnish growers prioritized indoor cultivation, whereas the Danes were more in favor of open-air plantations. Risks of getting caught by the police were observed to be greater in Finland. Growing for medical purposes was twice as prevalent in Finland as in Denmark. CONCLUSIONS: Cannabis growing is a stronger and more novel phenomenon in Finland than in Denmark, but both countries have been influenced by international trends. Finnish and Danish small-scale cannabis cultivators can be considered to be ideologically oriented lifestyle growers. Differences in the magnitude of the phenomenon may reflect differences in the availability and quality of cannabis in national drug markets. The Internet had promoted the spreading of the trend. PMID- 21325853 TI - Low incidence of asymptomatic contrast-enhancing brain lesions in Japanese patients with multiple sclerosis. AB - BACKGROUND: The number of contrast-enhancing brain lesions is used as an endpoint in multiple sclerosis (MS) clinical trials. However, the incidence of asymptomatic contrast-enhancing brain lesions (AEBLs) in Japanese patients with MS has not been determined. OBJECTIVE: To describe the number of AEBLs per scan in Japanese patients with relapsing-remitting MS (RRMS). METHODS: We reviewed the medical records of 23 Japanese patients with RRMS who showed (1) a stable or improving condition for at least 30 days before a magnetic resonance imaging (MRI) examination and (2) at least one relapse in the preceding year or two relapses in the preceding 2 years. RESULTS: The percentage of patients with AEBLs was 39.1% (9/23 patients) and the number of AEBLs per scan was 0.37. CONCLUSIONS: The results suggest that the disease activity shown by brain MRI was lower in Japanese patients with MS compared with that in Caucasian patients. PMID- 21325854 TI - Transient global amnesia: seven years of experience with diffusion-weighted imaging in an emergency department. AB - BACKGROUND/AIMS: Hippocampal lesions on diffusion-weighted imaging (DWI) are commonly described in transient global amnesia (TGA). We evaluated the utility of DWI and the presence of hippocampal lesions in the diagnosis of TGA. METHODS: A total of 203 TGA episodes were diagnosed at our emergency department from January 2003 to May 2010. DWI (5-mm slice thickness) was performed using a 1.5 T scanner. Patients were divided into 2 groups based on the presence of hippocampal lesions on DWI: DWI- and DWI+. The clinical characteristics and the time interval from development of amnesia to magnetic resonance imaging (MRI) were compared. RESULTS: 16 patients had hippocampal lesions on DWI. The DWI- and DWI+ groups had similar clinical characteristics. The overall median time interval from amnesia to MRI was 6 h, and this interval was significantly longer for the DWI+ group than the DWI- group [9 h (IQR 6.5-25) vs. 5 h (IQR 4-9), p = 0.002]. CONCLUSION: DWI has a low diagnostic yield when performed early in the course of TGA. Positive findings can confirm the diagnosis, but in negative results, careful interpretation is required, including the time interval from amnesia to MRI. PMID- 21325855 TI - Restricted left gyrus rectus hemorrhage with unusual frontal syndrome presentation. PMID- 21325856 TI - Apolipoprotein alleles and the response to interferon-beta-1b in multiple sclerosis. AB - BACKGROUND: Results for the e4/e2 alleles of the ApoE gene as markers of susceptibility, clinical and radiological progression, and cognitive deterioration in patients with multiple sclerosis (MS) are contradictory. AIM: The usefulness of these markers in predicting the response to interferon-beta-1b (IFNbeta-1b) was evaluated. MATERIAL AND METHODS: 95 patients with relapsing remitting MS treated with IFNbeta-1b (mean follow-up 7.44 years) were studied. We correlated the e4 and e2 alleles with the time to the first relapse or to a 1 point worsening on the Expanded Disability Status Scale, time to moderate disability, progression index, and treatment discontinuation due to inefficacy. RESULTS: We found no association between the e4 allele and any of the variables. The e2 allele was associated with increased time to moderate disability. CONCLUSION: The e4 allele of ApoE has no prognostic value for the response to IFNbeta-1b. The e2 allele delayed the progression of disability in our MS patient cohort. PMID- 21325857 TI - Congenital diaphragmatic hernia: one name for various diseases. PMID- 21325858 TI - Fetal surgery for congenital diaphragmatic hernia is back from never gone. AB - Over half of the cases of congenital diaphragmatic hernia are picked up prenatally. Prenatal assessment aims to rule out associated anomalies and to make an individual prognosis. Prediction of outcome is based on measurements of lung size and vasculature as well as on liver herniation. A subset of fetuses likely to die in the postnatal period is eligible for a fetal intervention that can promote lung growth. Two randomized trials have shown that fetal surgery using open anatomical repair or tracheal occlusion via hysterostomy has no benefit. Since then, a percutaneous fetoscopic technique has been introduced, which has been shown to be safe and seems to improve survival when compared to historical controls. Rupture of the fetal membranes and early delivery, nevertheless, remain an issue, but are less likely as compared to earlier experience. Improved outcomes are confirmed in two other studies published in this issue of Fetal Diagnosis and Therapy. This paper summarizes the experimental and clinical history of fetal surgery for congenital diaphragmatic hernia. It stresses the need for another randomized trial. This trial started in Europe and patients should be asked whether they would like to participate. PMID- 21325859 TI - Actual outcome in infants with congenital diaphragmatic hernia: the role of a standardized postnatal treatment protocol. AB - BACKGROUND: Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly with a high rate of mortality and morbidity. OBJECTIVE: Our aim was to determine a possible effect of standardized treatment on outcome in infants with CDH. METHODS: All prenatally diagnosed patients with unilateral CDH born alive between January 2006 and December 2009 at the Erasmus MC or the University Hospital Mannheim were eligible for inclusion. Patients who underwent a fetal tracheal occlusion were excluded. From November 1, 2007, all CDH patients were treated according to a standardized treatment protocol. Patients were divided into two chronological groups according to their date of birth: without standardized treatment (group 1, Jan 2006-Oct 2007) and with standardized treatment (group 2, Nov 2007-Dec 2009). Outcome measures were mortality by day 28, bronchopulmonary dysplasia (BPD), defined as oxygen dependency at day 28, and need for extracorporeal membrane oxygenation (ECMO) therapy. Uni- and multivariate analyses were performed. RESULTS: 167 patients were included. By day 28, 18% of the infants had died. Of the patients who were alive at day 28, 49% had BPD. An ECMO procedure was performed in 31% of the patients. Overall mortality for all included patients was 22%. In group 1, overall mortality was 33% and in group 2 overall mortality was 12% (p = 0.004). A standardized treatment protocol was independently associated with a reduced risk for mortality by day 28 (OR 0.28, 95% CI 0.11-0.68). Higher observed-to-expected lung-to-head ratios were independently associated with a lower risk for mortality by day 28 (OR 0.97, 95% CI 0.95-0.99), BPD (OR 0.97, 95% CI 0.94-0.98) and need for ECMO (OR 0.98, 95% CI 0.96-0.99). An intrathoracic position of the liver was independently associated with an increased risk for BPD (OR 3.12, 95% CI 1.41-6.90) and need for ECMO therapy (OR 3.25, 95% CI 1.54-6.88). CONCLUSION: Survival rates in patients with CDH increased significantly after the implementation of a standardized treatment protocol. PMID- 21325860 TI - Fetoscopic endotracheal occlusion for severe isolated diaphragmatic hernia: initial experience from a single clinic in Brazil. AB - OBJECTIVE: To report on the initial experience in a single Brazilian university clinic of the use of fetoscopic endotracheal occlusion (FETO) to treat severe isolated congenital diaphragmatic hernia (CDH). METHODS: The inclusion criteria for FETO for this prospective study were isolated CDH and intrathoracic herniation of the liver, as well as the lung area to head circumference ratio (LHR) <1.0. The main variables evaluated were LHR and observed to expected (o/e) LHR before and after FETO, gestational age (GA) at FETO, reversal of tracheal occlusion (TO), and birth and discharge of a living child from the hospital. RESULTS: Among 8 isolated left-sided CDH cases with normal karyotypes, the median LHR and o/e LHR before FETO were 0.7 (range: 0.6-0.9) and 0.27 (range: 0.22 0.32), respectively. The median LHR and o/e LHR after FETO were 1.2 (range: 0.9 1.8) and 0.45 (0.31-0.67), respectively. The median GA at FETO, reversal of TO and birth were 26.8 (range: 26-29), 32.5 (range: 31.0-34.0) and 37 weeks (range: 35-37), respectively. Neonatal survival at the time of hospital discharge was 50% (4/8). CONCLUSION: FETO is feasible at our institution and may help to improve postnatal survival of children with severe CDH in developing countries. PMID- 21325861 TI - Tracheal occlusion works. PMID- 21325862 TI - Tooth size variation related to age in Amboseli baboons. AB - We measured the molar size from a single population of wild baboons from Amboseli (Kenya), both females (n=57) and males (n=50). All the females were of known age; the males represented a mix of known-age individuals (n=31) and individuals with ages estimated to within 2 years (n=19). The results showed a significant reduction in the mesiodistal length of teeth in both sexes as a function of age. Overall patterns of age-related change in tooth size did not change whether we included or excluded the individuals of estimated age, but patterns of statistical significance changed as a result of changed sample sizes. Our results demonstrate that tooth length is directly related to age due to interproximal wearing caused by M2 and M3 compression loads. Dental studies in primates, including both fossil and extant species, are mostly based on specimens obtained from osteological collections of varying origins, for which the age at death of each individual in the sample is not known. Researchers should take into account the phenomenon of interproximal attrition leading to reduced tooth size when measuring tooth length for ondontometric purposes. PMID- 21325863 TI - Single- and multi-locus association tests incorporating phenotype heterogeneity. AB - Taking disease subtypes into account when testing for an association between genetic factors and disease risk may help to identify specific aetiologic pathways. One way to assess a genetic association, whilst accounting for heterogeneity, is to use polytomous regression. This approach only allows heterogeneity to be considered in terms of a single categorical variable. In this article, we describe an alternative and novel test of association which incorporates multivariate measures of categorical and continuous heterogeneity. We describe both a single-SNP and a global multi-SNP test and use simulated data to demonstrate the power of the tests when genetic effects differ across disease subtypes. Applying the tests to the study of genetic variation in the oestrogen metabolic pathway and its association with breast cancer risk and prognosticators strengthened our understanding that the modulation of aromatase activity can influence the occurrence of tumours, and their grade and size, in postmenopausal women. PMID- 21325864 TI - Association tests for X-chromosomal markers--a comparison of different test statistics. AB - OBJECTIVE: Genome-wide association studies have successfully elucidated the genetic background of complex diseases, but X chromosomal data have usually not been analyzed. A reason for this is that there is no consensus approach for the analysis taking into account the specific features of X chromosomal data. This contribution evaluates test statistics proposed for X chromosomal markers regarding type I error frequencies and power. METHODS: We performed extensive simulation studies covering a wide range of different settings. Besides characteristics of the general population, we investigated sex-balanced or unbalanced sampling procedures as well as sex-specific effect sizes, allele frequencies and prevalence. Finally, we applied the test statistics to an association data set on Crohn's disease. RESULTS: Simulation results imply that in addition to standard quality control, sex-specific allele frequencies should be checked to control for type I errors. Furthermore, we observed distinct differences in power between test statistics which are determined by sampling design and sex specificity of effect sizes. Analysis of the Crohn's disease data detects two previously unknown genetic regions on the X chromosome. CONCLUSION: Although no test is uniformly most powerful under all settings, recommendations are offered as to which test performs best under certain conditions. PMID- 21325865 TI - Short stature due to SHOX deficiency: genotype, phenotype, and therapy. AB - SHOX deficiency is a frequent cause of short stature. The short stature homeobox containing gene resides in the telomeric PAR1 region on the short arm of both sex chromosomes and escapes X inactivation. For this review, abstracts of 207 publications presented by PubMed for the search term 'SHOX' were screened. Heterozygote SHOX mutations (80% deletions) were detected in 2-15% of individuals with formerly idiopathic short stature, in 50-90% of individuals with Leri-Weill dyschondrosteosis, and in almost 100% of girls with Turner syndrome. Mutational analysis is primarily performed by MLPA analysis followed by gene sequencing if necessary. SHOX is a nuclear protein that binds to DNA and acts as a transcriptional activator. Orthologs are present in many vertebrates but not in rodents. Gene expression starting as early as 33 days postconception in humans is predominant in the mid portion of the buds and in the first and second pharyngeal arches. In the growth plate, hypertrophic chondrocytes express SHOX where it seems to have antiproliferative potency. The penetrance of SHOX deficiency is high, but its clinical expression is very variable becoming more pronounced with age and being more severe in females. Growth failure starts early during the first years of life and the height deficit present at preschool age seems not to deteriorate further. The mean adult height is -2.2 SDS. Auxological analysis of the body proportions (mesomelia), the presence of minor abnormalities, and the search for subtle radiographic signs are important keys to the diagnosis which has to be confirmed by genetic analysis. The growth-promoting effect of GH therapy approved for individuals with SHOX mutations seems to be equal to the effect seen in Turner syndrome. PMID- 21325866 TI - Negative anti-C1q antibody titers may influence therapeutic decisions and reduce the number of renal biopsies in systemic lupus erythematosus. AB - In a cross-sectional study involving 62 patients with systemic lupus erythematosus (SLE), we found that patients with biopsy-proven lupus nephritis (LN) had higher titers of anti-C1q antibodies than active SLE without nephritis patients. Anti-C1q was associated with a negative predictive value of 94.59%, a positive predictive value of 52%, a sensitivity of 86.66% and a specificity of 74.47% for the diagnosis of LN. We conclude that high titers of anti-C1q antibodies are strongly associated with the presence of active LN, and the negative predictive value of this test for diagnosing LN is very high; therefore, it can influence therapeutic decisions and reduce the number of renal biopsies in patients with SLE. PMID- 21325867 TI - Daily sodium intake in chronic kidney disease patients during nephrology clinic follow-up: an observational study with 24-hour urine sodium measurement. AB - OBJECTIVE: To determine daily sodium intake in 'real practice' in a large group of chronic kidney disease (CKD) patients who were under regular follow-up in a nephrology clinic. METHODS: A total of 373 consecutive outpatients with CKD stages 1-5 (not on dialysis; men: 52.3%, mean age: 51.6 +/- 15.4 years) were included in the study. All patients had at least 3 or more nephrology visits and received information on reducing their sodium intake. Data for systolic and diastolic blood pressure, number of antihypertensive medications and 2 consecutive 24-hour urinary sodium levels were obtained from the patients' medical records. RESULTS: The mean 24-hour urinary sodium levels of 2 consecutive urine samples were 168.8 +/- 70.3 and 169.3 +/- 67.4 mEq/day (p > 0.05). Only 14.7% of the patients had a sodium excretion <100 mmol/day. There was no difference in daily sodium intake from stages 1 to 4, but it was significantly lower in stage 5 (126.6 +/- 60.5 mEq/day, p < 0.05). No relation was found between 24-hour urinary sodium output, number of antihypertensives or thiazide use. CONCLUSIONS: This study showed that almost 85% of CKD patients under regular nephrologic care were consuming more sodium than the recommended level. More robust measures should be devised to increase patient and physician compliance with reducing sodium intake in CKD. PMID- 21325868 TI - Uraemia progression in chronic kidney disease stages 3-5 is not constant. AB - INTRODUCTION: Chronic kidney disease (CKD) is a progressive disease leading to loss of glomerular filtration rate (DeltaGFR, measured in ml/min/1.73 m(2)/year). DeltaGFR is usually assumed to be constant, but the hyperfiltration theory suggests that it accelerates in severe uraemia. A retrospective analysis of estimated GFR (eGFR) calculated from the Modification of Diet in Renal Disease equation was performed to evaluate whether DeltaGFR is constant or accelerating. METHODS: 1,441 patients attending a nephrology clinic over a 21-year period, with an initial eGFR <60 ml/min/1.73 m(2) and an observation period >=2 years, were included. eGFR was calculated from all creatinine measurements. 420 patients developed end-stage renal disease (ESRD). First- and second-order polynomial regression analysis of eGFR against time was performed for each patient individually. Patients had accelerating uraemia progression if the second-order term coefficient was negative. RESULTS: The initial eGFR was 30.8 +/-15.1 ml/min/1.73 m(2). The second-order coefficient was median -0.15 ml/min/1.73 m(2)/year(2) (interquartile range -0.92, +0.34). Significantly more patients had an accelerating loss (62%, p < 0.001). Acceleration was mainly seen when eGFR was <30 ml/min. DeltaGFR was mean 1.47 +/- 4.5 ml/min/1.73 m(2)/year (male 1.67, female 1.22). ESRD patients lost 5.4 +/- 5.4 ml/min/year/1.73 m(2) during the last year before ESRD. Accelerating loss was seen for all diagnoses except polycystic disease. Diagnoses with higher DeltaGFR were polycystic renal disease (3.3 ml/min/1.73 m(2)/year), hypertensive nephropathy (2.1 ml/min/1.73 m(2)/year) and diabetic nephropathy (2.6 ml/min/ 1.73 m(2)/year). There was no evidence of improvement in overall uraemia progression during the period of observation. CONCLUSIONS: Uraemia progression in CKD stages 3-5 is not linear, but shows an accelerating trend. This suggests that hyperfiltration mechanisms play a role in CKD progression. ESRD cannot thus be predicted from previous DeltaGFR alone. PMID- 21325869 TI - Relationship between biochemical markers and radial cortical bone changes in hemodialysis patients. AB - BACKGROUND/AIM: Bone loss in patients with osteoporosis may be predicted by the elevation of biochemical markers of bone turnover. Therefore, we studied the relationship between biochemical markers, including parathyroid hormone (PTH), and the 2-year change in radial cortical bone in patients under chronic hemodialysis. METHODS: Tartrate-resistant acid phosphatase-5b (TRACP-5b), bone specific alkaline phosphatase, whole PTH, and total intact PTH were measured in 53 patients under maintenance hemodialysis. Additionally, radial cortical bone mineral density (BMD) and relative cortical area (RCA) were measured by peripheral quantitative computed tomography 2 years apart. RESULTS: In all patients, BMD decreased by 2.5% and RCA decreased by 5.8% during 2 years. TRACP 5b levels significantly correlated with decreased RCA in all and female patients, but not with decreased BMD. Bone-specific alkaline phosphatase correlated with decreased BMD in all patients and with decreased RCA in all and female patients. Whole PTH did not correlate with decreased RCA or BMD. Total intact PTH significantly correlated with decreased BMD in all and male patients and with decreased RCA in all and female patients. In stepwise multiple regression analysis, TRACP-5b and total intact PTH were selected as explanatory variables for decreased RCA and decreased BMD, respectively. CONCLUSION: These results suggest that TRACP-5b and total intact PTH are powerful markers to predict radial cortical bone loss in hemodialysis patients. PMID- 21325870 TI - Metformin: the safest hypoglycaemic agent in chronic kidney disease? AB - Metformin is the first-line oral agent in the treatment of type 2 diabetes and has many established benefits, including the reduction of macrovascular complications of diabetes. Its prescription in patients with renal impairment is limited by concerns relating to the theoretical risk of lactic acidosis, a fear which is perpetuated by numerous case reports in which it is implicated. Critical review of this literature calls into question the validity of these claims, with metformin usually acting as an 'innocent bystander' in acutely unwell patients with conditions well recognised to precipitate lactic acidosis such as sepsis or hypovolaemia. In fact, the evidence supports the safe use of appropriate doses of metformin in patients with chronic stable renal impairment, and highlights the important possible greater risks of the alternatives, most notably severe hypoglycaemia in patients taking sulphonylureas and/or insulin and fluid retention in patients taking a thiazolidinedione. Other traditional contraindications to metformin use such as heart failure are also being re evaluated, as the benefits of metformin in these patients are increasingly recognised. Physicians should weigh this evidence carefully before deciding to withdraw metformin therapy in their patients with stable chronic kidney disease. PMID- 21325871 TI - Hypovitaminosis D is associated with systemic inflammation and concentric myocardial geometric pattern in hemodialysis patients with low iPTH levels. AB - BACKGROUND: Vitamin D [25(OH)D] deficiency is a cardiovascular risk factor in the hemodialysis (HD) population. The aim of this study was to identify hypovitaminosis D in HD patients without signs of hyperparathyroidism and to analyze its association to inflammation and echocardiographic alterations. METHODS: Patients on HD with iPTH <300 pg/ml not receiving vitamin D therapy were recruited. Hypovitaminosis D was defined as 25(OH)D <30 ng/ml. High-sensitivity C reactive protein, interleukin-6 and serum albumin were used as inflammation markers. Echocardiograms were performed in an interdialytic mid-week day. RESULTS: Sixty-one patients (mean age of 56 +/- 15 years, 52% males, 93% Caucasians, 31% diabetic) were included, and 75% presented hypovitaminosis D. Inflammation was more prevalent among those with hypovitaminosis D, and these patients presented higher relative wall thickness (0.48 +/- 0.11 vs. 0.42 +/- 0.10 mm; p = 0.05) and lower left ventricular diastolic (49.8 +/- 6.2 vs. 54.7 +/ 5.8 mm; p = 0.013) and systolic (31.9 +/- 5.7 vs. 36.8 +/- 7.2 mm; p = 0.012) diameters. CONCLUSIONS: Hypovitaminosis D is associated with inflammation and concentric geometric pattern of the left ventricle, even in the absence of high iPTH levels. Vitamin D repletion (aiming to reduce cardiovascular complications) should also be considered in HD patients with normal or low iPTH levels. PMID- 21325872 TI - Photodynamic therapy for variant central serous chorioretinopathy: efficacy and side effects. AB - BACKGROUND: Retinal pigment epithelial detachment (PED) is a recognised associated finding in central serous chorioretinopathy (CSC). We report our experience in treating patients using photodynamic therapy (PDT) in a variant of chronic CSC that presents with only an isolated PED. We present long-term follow up data and novel observations on the pattern of retinal pigment epithelium (RPE) changes seen after treatment. METHODS: Retrospective case series. RESULTS AND DISCUSSION: CSC with subfoveal PED can be associated with a poor visual prognosis especially when the PED becomes chronic. PDT has been used to treat typical CSC with good outcomes. Three eyes in 3 patients were successfully treated with PDT, using the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy protocol. However, marked RPE disturbance was observed after treatment directly overlying the areas of brisk choroidal hyperpermeability. PMID- 21325873 TI - Vitreous and aqueous penetration of orally and topically administered moxifloxacin. AB - AIM: It was the aim of this study to compare the pharmacokinetics of moxifloxacin (MFLX) hydrochloride in rabbits after topical and oral administration. METHODS: Three 50-MUl applications of MFLX (0.5%) topical ophthalmic solution were instilled into the cul-de-sac of New Zealand white rabbits at 15-min intervals. Aqueous and vitreous samples were collected and analyzed 30-240 min after the final instillation. Assays were performed using high-performance liquid chromatography. MFLX (16 mg/kg of body weight) was administered orally. Drug concentrations in aqueous, vitreous and serum samples, collected at 30-360 min after administration, were determined using high-performance liquid chromatography. RESULTS: After topical administration, the maximum concentrations of MFLX in the aqueous and vitreous samples were 10.2 +/- 1.6 MUg/ml (30 min; n = 6) and 0.10 +/- 0.03 MUg/ml (30 min; n = 6), respectively. After oral administration, the maximum concentrations in the aqueous, vitreous and serum samples were 0.9 +/- 0.3 MUg/ml (120 min; n = 6), 0.7 +/- 0.2 MUg/ml (240 min; n = 6) and 1.6 +/- 0.9 MUg/ml (120 min; n = 6), respectively. The percentages of serum MFLX concentration in the aqueous and vitreous samples after oral administration were 55.2 and 41.7%, respectively. CONCLUSIONS: The aqueous concentration of MFLX was about 10-fold higher after topical than after oral administration. However, intravitreal MFLX concentrations after oral administration were about 7-fold higher than those after topical administration. The MFLX concentrations in the aqueous humor following oral administration exceeded the minimum inhibitory concentration for 90% of the bacteria involved in ocular infection. PMID- 21325874 TI - Human lens transmission of blue light: a comparison of autofluorescence-based and direct spectral transmission determination. AB - PURPOSE: Direct measurement of the transmission of light through the human lens is not possible in vivo unless invasive techniques are used. In the current study, a reliable in vivo estimate of the transmission of blue light through the lens was assessed by comparing an indirect and noninvasive method based on autofluorescence measurements with a direct method. METHODS: Total transmission of blue light was measured in human donor lenses using a direct method applicable only in vitro and compared with transmittance estimates made by an in vivo applicable autofluorescence technique. RESULTS: Human lens transmission of blue light decreases with age by 0.7-0.8% per year at 480 nm. The comparison of methods showed that the autofluorescence-based method correlated significantly with the direct measurements (R = 0.83, p < 0.001) and acceptable agreement between the two methods was found. DISCUSSION: In conclusion, the human lens transmittance of blue light can be measured reliably in vivo. This enables the possibility to correct for retinal light intensities when studying the mechanisms of the circadian rhythm in clinical studies and related disorders and in addition when working with clinical and experimental methods affected by retinal blue light intensities. PMID- 21325875 TI - An assessment of the human nail plate pH. AB - PURPOSE OF STUDY: To measure the pH of the surface of healthy nail plates. PROCEDURES: The surface pH of human fingernails and big toenails was measured in vivo using a skin pH meter. The influence of washing, anatomical site (fingers/toes), side (left/right), digit (digits 1-5) and gender was determined. The pH of the nail interior was also measured. RESULTS: The pH of the nail plate surface was around 5, with toenails having a significantly higher pH than fingernails. Immediately after hand washing, the nail surface pH increased significantly, from pH 5.1 +/- 0.4 to 5.3 +/- 0.5. However, this was not sustained with time, and the pH returned to prewashing levels within 20 min. Gender had an influence on unwashed, but not washed, nail plate pH. The pH of the nail plate interior was lower than that of its surface. CONCLUSIONS: It was possible to measure nail plate pH, and baseline values are provided. PMID- 21325876 TI - Caspase-3 joins the p53 interactome. PMID- 21325877 TI - Maternal characteristics that predict a preference for mandatory adolescent HPV vaccination. AB - Adolescent human papillomavirus (HPV) vaccination uptake, as a means of cervical cancer prevention, remains suboptimal with significant racial disparity. A survey study of mothers already engaging in their own cancer screening, at a predominantly black urban site and a predominantly white suburban site, finds that a majority of mothers surveyed support hypothetical mandates for adolescent HPV vaccination three years after the introduction of these vaccines. Enactment of state laws may represent an efficient means to improve HPV vaccination in adolescent daughters of these mothers. Nevertheless, in a sizable minority, maternal perceptions of the HPV vaccine may hinder adherence to these vaccination laws. In these women, tailored interventions directed at these perceptions may be required. PMID- 21325878 TI - Cell biology and medicine at the crossroads. PMID- 21325879 TI - Direct and indirect effects of the pRb tumor suppressor on autophagy. AB - Autophagy, an intracellular degradation pathway involved in cell survival or demise, is tightly controlled by complex regulatory mechanisms. A link between the Rb tumor suppressor and autophagy is now emerging. pRb plays a critical role in cell cycle progression and survival as well as the differentiation of certain cell types. Recently, we have reported that during skeletal myogenesis, Rb deficient myoblasts fuse to form short myotubes that quickly degenerate. Myotube degeneration was associated with increased autophagic flux and inhibition of autophagy rescued the defect leading to long, twitching myotubes. We propose that Rb-loss sensitizes cells to autophagy via direct and indirect mechanisms and we discuss how these might affect cancer progression and response to chemotherapy. PMID- 21325880 TI - Induction of autophagy by drug-resistant esophageal cancer cells promotes their survival and recovery following treatment with chemotherapeutics. AB - We investigated the cell-death mechanisms induced in esophageal cancer cells in response to the chemotherapeutic drugs, 5-fluorouracil (5-FU) and cisplatin. Chemosensitive cell lines exhibited apoptosis whereas chemoresistant populations exhibited autophagy and a morphology resembling type II programmed cell death (PCD). Cell populations that respond with autophagy are more resistant and will recover following withdrawal of the chemotherapeutic agents. Specific inhibition of early autophagy induction with siRNA targeted to Beclin 1 and ATG7 significantly enhanced the effect of 5-FU and reduced the recovery of drug treated cells. Pharmacological inhibitors of autophagy were evaluated for their ability to improve chemotherapeutic effect. The PtdIns 3-kinase inhibitor 3 methyladenine did not enhance the cytotoxicity of 5-FU. Disruption of lysosomal activity with bafilomycin A 1 or chloroquine caused extensive vesicular accumulation but did not improve chemotherapeutic effect. These observations suggest that an autophagic response to chemotherapy is a survival mechanism that promotes chemoresistance and recovery and that selective inhibition of autophagy regulators has the potential to improve chemotherapeutic regimes. Currently available indirect inhibitors of autophagy are, however, ineffective at modulating chemosensitivity in these esophageal cancer cell lines. PMID- 21325881 TI - p62, Ref(2)P and ubiquitinated proteins are conserved markers of neuronal aging, aggregate formation and progressive autophagic defects. AB - Suppression of macroautophagy, due to mutations or through processes linked to aging, results in the accumulation of cytoplasmic substrates that are normally eliminated by the pathway. This is a significant problem in long-lived cells like neurons, where pathway defects can result in the accumulation of aggregates containing ubiquitinated proteins. The p62/Ref(2)P family of proteins is involved in the autophagic clearance of cytoplasmic protein bodies or sequestosomes. These unique structures are closely associated with protein inclusions containing ubiquitin as well as key components of the autophagy pathway. In this study we show that detergent fractionation followed by western blot analysis of insoluble ubiquitinated proteins (IUP), mammalian p62 and its Drosophila homologue, Ref(2)P can be used to quantitatively assess the activity level of aggregate clearance (aggrephagy) in complex tissues. Using this technique we show that genetic or age dependent changes that modify the long-term enhancement or suppression of aggrephagy can be identified. Moreover, using the Drosophila model system this method can be used to establish autophagy-dependent protein clearance profiles that are occurring under a wide range of physiological conditions including developmental, fasting and altered metabolic pathways. This technique can also be used to examine proteopathies that are associated with human disorders such as frontotemporal dementia, Huntington and Alzheimer disease. Our findings indicate that measuring IUP profiles together with an assessment of p62/Ref(2)P proteins can be used as a screening or diagnostic tool to characterize genetic and age dependent factors that alter the long-term function of autophagy and the clearance of protein aggregates occurring within complex tissues and cells. PMID- 21325882 TI - KAPping PML nuclear body number. PMID- 21325883 TI - Filamin A stimulates cdc25C function and promotes entry into mitosis. AB - The activity of the dual specificity phosphatase cdc25C is required for mitotic progression though the mechanisms by which cdc25C is activated prior to mitosis in human cells remain unclear. The data presented herein show that the actin binding protein Filamin A forms a complex with cdc25C in vivo and binds preferentially to the mitotic form of cdc25C. Co-expression of Filamin A with cdc25C results in an increase in PCC induced by cdc25C, while knocking down Filamin A expression reduces the levels of PCC induced by cdc25C overexpression. Further, only a Filamin A fragment that forms a complex with both cdc25C and cyclin B1 and retains the dimerization domain can stimulate the ability of cdc25C to induce PCC. These results suggest that Filamin A provides a platform for the assembly of the cyclin B1-cdk1- cdc25C complex resulting in cdk1 activation and mitotic progression. PMID- 21325886 TI - A Janus molecule provides a rational reshape to a multi-functional drug. PMID- 21325884 TI - Mip1 associates with both the Mps1 kinase and actin, and is required for cell cortex stability and anaphase spindle positioning. AB - The Mps1 family of protein kinases contributes to cell cycle control by regulating multiple microtubule cytoskeleton activities. We have uncovered a new Mps1 substrate that provides a novel link between Mps1 and the actin cytoskeleton. We have identified a conserved human Mps1 (hMps1) interacting protein we have termed Mps1 interacting protein-1 (Mip1). Mip1 defines an uncharacterized family of conserved proteins that contain coiled-coil and calponin homology domains. We demonstrate that Mip1 is a phosphoprotein that interacts with hMps1 in vitro and in vivo and is a hMps1 substrate. Mip1 exhibits dynamic localization during the cell cycle; Mip1 localizes to the actin cytoskeleton during interphase, the spindle in early mitosis, and the cleavage furrow during cytokinesis. Mip1 function is required to ensure proper spindle positioning at the onset of anaphase after cells begin furrow ingression. Cells depleted of Mip1 exhibit aberrant mitotic actin filament organization, excessive membrane blebbing, dramatic spindle rocking, and chromosome distribution errors during early cytokinesis producing high numbers of binucleate cells. Our data indicate that Mip1 is a newly recognized component of the actin cytoskeleton that interacts with hMps1 and that it is essential to ensure proper segregation of the genome during cell cleavage. PMID- 21325885 TI - Three independent mechanisms for arrest in G2 after ionizing radiation. AB - Cell cycle checkpoints ensure that eukaryotic cells do not enter mitosis after ionizing irradiation (IR). The G(2)-arrest after IR is the result of activation of multiple signalling pathways, the contributions of which vary with time after irradiation. We have studied the time evolution of the IR-induced G(2)-arrest in human B-lymphocyte cancer cell lines, as well as the molecular mechanisms responsible for the arrest. Cells that were in G(2) phase at the time of irradiation experienced a transient arrest that blocked entry into mitosis at 0-2 hours after IR (0.5 or 4 Gy). Activation of ATM and CHEK2 occurred at the same time as this early arrest and was, like the arrest, abrogated by the ATM inhibitor KU-55933. A late, permanent and ATM-independent arrest (>=6 hours after IR) of cells that were in G(2)/S/G(1) at the time of irradiation (4 Gy) was inactivated by caffeine. This late G(2)-arrest could not be explained by down regulation of genes with functions in G(2)/mitosis (e.g. PLK1, CCNB1/2), since the down-regulation was transient and not accompanied by reduced protein levels. However, the persistent phosphorylation of CHEK1 after 4 Gy suggested a role for CHEK1 in the late arrest, consistent with the abrogation of the arrest in CHEK1 depleted cells. TP53 was not necessary for the late G(2)-arrest, but mediated an intermediate arrest (2-10 hours after IR) independently of ATM and CHEK1. In conclusion, the IR-induced arrest in G(2) is mediated by ATM immediately after irradiation, with TP53 for independent and transient back-up, while CHEK1 is necessary for the late arrest. PMID- 21325887 TI - Ionizing radiation-induced TAp63alpha phosphorylation at C-terminal S/TQ motifs requires the N-terminal transactivation (TA) domain. AB - TAp63alpha, a homolog of p53 and one of six alternatively spliced p63 isoforms, is a critical mediator of the ionizing radiation (IR)-induced DNA damage response in female germ cells and also tumor suppression in somatic cells. The DeltaNp63alpha isoform, lacking the N-terminal transactivation (TA) domain, is associated with oncogenic potential. The mechanism of p63 functional regulation is not well understood. TAp63alpha is phosphorylated by ionizing radiation (IR) induced DNA damage and gene transactivation is likely to be involved. Based on information gleaned from studies on p53, we explored the possibility that TAp63alpha S/TQ sites may be phosphorylated by IR-induced DNA damage. Our findings show a wortmanin-sensitive kinase phosphorylates TAp63alpha at C terminal Ser-Gln and Thr-Gln (S/TQ) sites but not N-terminal S/TQ sites. DeltaNp63alpha, lacking the TA domain, and TAp63gamma, lacking C-terminal domains, including S/TQ sites, fail to undergo IR-induced phosphorylation. We propose a model for TA domain-dependent C-terminal phosphorylation drawing from previously described self-inactivating intramolecular interaction between N terminal TA domain and C-terminal Transactivation Inhibitory Domain (TID) of TAp63alpha. A specific topology adopted only by TAp63alpha, but not possible for DeltaNp63alpha or TAp63gamma, may lead to TAp63alpha-specific kinase recruitment, phosphorylation and self-inactivation release. TID-lacking TAp63gamma, like p53, is constitutively active and thus may forgo phosphorylation-dependent activation. Thus, p53 is regulated by protein stabilization and TAp63alpha by protein activation but both appear to involve S/TQ phosphorylation. The difference in phosphorylation potential of TAp63alpha and DeltaNp63alpha may in part help explain why the two similar isoforms have diametrically opposite tumor suppression and oncogene functions, respectively. PMID- 21325888 TI - Low insulin content of large islet population is present in situ and in isolated islets. AB - The existence of morphologically distinct populations of islets in the pancreas was described over 60 years ago. Unfortunately, little attention has been paid to possible functional differences between islet subpopulations until recently. We demonstrated that one population, the small islets, were superior to large islets in a number of functional aspects. However, that work did not determine whether these differences were inherent, or whether they arose because of the challenge of isolation procedures. Nor, were there data to explain the differences in insulin secretion. We utilized immunohistochemistry, immunofluorescence, ELISA, and transmission electron microscopy to compare the unique characteristics found in isolated rat islet populations in situ and after isolation. Insulin secretion of small isolated islets was significantly higher compared to large islets, which correlated with higher insulin content/area in small islets (in situ), a higher density of insulin secretory granules, and greater insulin content/volume in isolated islets. Specifically, the core b-cells of the large islets contained less insulin/cell with a lower insulin granule density than peripheral b-cells. When insulin secretion was normalized for total insulin content, large and small islets released the same percentage of total insulin. Small islets had a higher density of cells/area than large islets in vitro and in situ. The data provide a possible explanation for the inferior insulin secretion from large islets, as they have a lower total cell density and the b-cells of the core contain less insulin/cell. PMID- 21325889 TI - Oxidative and nitrosative signaling in plants: two branches in the same tree? AB - Reactive oxygen species (ROS) and reactive nitrogen species (RNS) constitute key features underpinning the dynamic nature of cell signaling systems in plants. Despite their importance in many aspects of cell biology, our understanding of oxidative and especially of nitrosative signaling and their regulation remains poorly understood. Early reports have established that ROS and RNS coordinately regulate plant defense responses to biotic stress. In addition, evidence has accumulated demonstrating that there is a strong cross-talk between oxidative and nitrosative signaling upon abiotic stress conditions. The goal of this mini review is to provide latest findings showing how both ROS and RNS comprise a coordinated oxidative and nitrosative signaling network that modulates cellular responses in response to environmental stimuli. PMID- 21325890 TI - Linking oncogenes to invasion in thyroid cancer. PMID- 21325891 TI - Aurora kinases and spindle assembly: variations on a common theme? AB - The Aurora A (AurA) serine/threonine kinase controls multiple aspects of cell division and plays a key role in centrosome maturation and bipolar spindle assembly. The pleiotropic functions of AurA depend on its interaction with several cofactors, the best known of which is TPX2. TPX2 targets AurA to spindle microtubules (MTs) and activates it, both allosterically and by protecting the activation loop (T-loop) of the kinase domain from dephosphorylation. Although several factors have been implicated in the regulation of AurA at centrosomes, the underlying mechanism has remained elusive, and the existence of a distinct centrosome-specific AurA activator has been proposed. Our recent study has identified this activator as Cep192/Spd-2, one of the key factors in centrosome biogenesis. Cep192 targets AurA to centrosomes, where it promotes its activation by a novel, oligomerization-dependent mechanism characterized by extensive T-loop phosphorylation and high kinase activity. This process is key to the function of centrosomes as microtubule-organizing centers. Here, our findings are discussed in the context of other recent studies on the Aurora kinases, with an emphasis on their role in spindle assembly. The collected evidence suggests that the 'hot spots' of MT nucleation, centrosomes and kinetochores, rely on the oligomerization-mediated mechanism of activation of AurA and AurB, respectively. PMID- 21325892 TI - Further insights into the mechanism of hypoxia-induced NFkappaB. [corrected]. AB - The cellular response to hypoxia relies on the activation of a specific transcriptional program. Although, most of the attention is focused on the transcription factor HIF, other transcription factors are also activated in hypoxia. We have recently described the mechanism for hypoxia induced NFkappaB. We have demonstrated the crucial dependency on the IKK complex as well as in the upstream IKK kinase TAK1. TAK1 and IKK activation is dependent upon the calcium calmodulin kinase, CaMK2 and requires Ubc13 as the E2 ubiquitin conjugation enzyme. We report a role for XIAP as the possible E3-ubiquitin ligase for this system. Interestingly, hypoxia induced IKK mediated phosphorylation of IkappaBalpha, does not lead to degradation. Hypoxia prevents IkappaBalpha de sumoylation of Sumo-2/3 chains on critical lysine residues, normally required for K-48 linked polyubiquitination. Our results define a novel pathway regulating NFkappaB activation. PMID- 21325894 TI - The integral role of mTOR in lipid metabolism. PMID- 21325893 TI - Comparative transcriptional pathway bioinformatic analysis of dietary restriction, Sir2, p53 and resveratrol life span extension in Drosophila. AB - A multiple comparison approach using whole genome transcriptional arrays was used to identify genes and pathways involved in calorie restriction/dietary restriction (DR) life span extension in Drosophila. Starting with a gene centric analysis comparing the changes in common between DR and two DR related molecular genetic life span extending manipulations, Sir2 and p53, lead to a molecular confirmation of Sir2 and p53's similarity with DR and the identification of a small set of commonly regulated genes. One of the identified upregulated genes, takeout, known to be involved in feeding and starvation behavior, and to have sequence homology with Juvenile Hormone (JH) binding protein, was shown to directly extend life span when specifically overexpressed. Here we show that a pathway centric approach can be used to identify shared physiological pathways between DR and Sir2, p53 and resveratrol life span extending interventions. The set of physiological pathways in common among these life span extending interventions provides an initial step toward defining molecular genetic and physiological changes important in life span extension. The large overlap in shared pathways between DR, Sir2, p53 and resveratrol provide strong molecular evidence supporting the genetic studies linking these specific life span extending interventions. PMID- 21325895 TI - An ending is a new beginning: transcription termination supports re-initiation. PMID- 21325896 TI - G1/S transcription and the DNA synthesis checkpoint: common regulatory mechanisms. AB - When DNA replication is challenged, cells activate a DNA-synthesis checkpoint blocking cell cycle progression until they are able to overcome the replication defects. In fission yeast, Cds1 is the effector kinase of this checkpoint, inhibiting M phase entry through inactivation of the phosphatase Cdc25, stabilizing stalled replication forks to prevent deleterious DNA structures and triggering transcriptional activation of S-phase genes. The MBF complex controls the transcription of genes required for the S phase and Yox1, a homeodomain containing protein, binds and represses MBF-dependent transcription at the end of S phase in a cell cycle-regulated manner. Interestingly, when the DNA synthesis checkpoint is activated, Yox1 is phosphorylated by Cds1 resulting in the abrogation of its binding to MBF. As a consequence, MBF-dependent transcription is maintained active until cells are able to overcome the replication challenge. Thus, Yox1 couples normal cell cycle regulation and the DNA synthesis checkpoint in a single transcriptional complex. PMID- 21325897 TI - Tracking BAX once its trigger is pulled. PMID- 21325899 TI - Massive transfusion: assessing higher plasma: blood ratios and earlier plasma administration. PMID- 21325898 TI - Abiotic stress and the plant circadian clock. AB - In this review, we focus on the interaction between the circadian clock of higher plants to that of metabolic and physiological processes that coordinate growth and performance under a predictable, albeit changing environment. In this, the phytochrome and cryptochrome photoreceptors have shown to be important, but not essential for oscillator control under diurnal cycles of light and dark. From this foundation, we will examine how emerging findings have firmly linked the circadian clock, as a central mediator in the coordination of metabolism, to maintain homeostasis. This occurs by oscillator synchronization of global transcription, which leads to a dynamic control of a host of physiological processes. These include the determination of the levels of primary and secondary metabolites, and the anticipation of future environmental stresses, such as mid day drought and midnight coldness. Interestingly, metabolic and stress cues themselves appear to feedback on oscillator function. In such a way, the circadian clock of plants and abiotic-stress tolerance appear to be firmly interconnected processes. PMID- 21325900 TI - Effective management of postoperative nausea and vomiting: let us practise what we preach! PMID- 21325901 TI - Antishivering effects of two different doses of intrathecal meperidine in caesarean section: a prospective randomised blinded study. AB - BACKGROUND AND OBJECTIVE: Shivering causes various adverse disturbances and interferes with monitoring. The optimal dose of intrathecal meperidine to prevent shivering without producing other side-effects remains unknown. This prospective randomised double-blinded study was conducted to compare the antishivering effects of two different doses of intrathecal meperidine. METHODS: Seventy two parturients, scheduled for elective caesarean section under spinal anaesthesia, were enrolled in three different groups. Spinal anaesthesia consisted of bupivacaine 0.5% (10 mg) for the control group (M0), and the same dose of bupivacaine with meperidine 12.5 or 25 mg for the experimental groups (M1, M2). Blood pressure, heart rate, skin and core temperatures, sensory level, capnometry, pulse oximetry, Apgar scores, shivering intensity and intrathecal opioid-related side-effects were evaluated and recorded by a blinded observer. Data were analysed using analysis of variance, chi2 test, Kruskal-Wallis H-test and Mann-Whitney U-test. A P value less than 0.05 was considered to be significant. RESULTS: Shivering was more intense in group M0 than in groups M1 and M2 with P values of 0.003 and less than 0.001, respectively. The intensity of shivering was comparable in groups M1 and M2. As regards the incidence of significant shivering, it was found to be highest in M0 (4/24 ~16.7%) in comparison with M1 (0/24) and M2 (0/24) (P = 0.03). Nausea and vomiting occurred more frequently with higher doses of meperidine (P < 0.001 and P = 0.003, respectively). Other complications were comparable. CONCLUSION: The use of intrathecal meperidine for caesarean section during spinal anaesthesia for the prevention of shivering cannot be recommended as its use is associated with increased incidence of nausea and vomiting. PMID- 21325902 TI - Effect of an intravenous bolus of phenylephrine or ephedrine on skin blood flow during spinal anaesthesia: a randomised, double-blind, controlled study. PMID- 21325903 TI - The future of nursing and holistic care. PMID- 21325905 TI - Using recent Institute of Medicine recommendations to expand our horizons: a call to courage. PMID- 21325906 TI - The experience of persons with allergic respiratory symptoms: practicing yoga as a self-healing modality. AB - The purpose of this study was to describe the experience of persons with allergic respiratory symptoms who practice yoga as a self-healing modality. Fifteen participants were interviewed. Using the content analysis method, 5 themes emerged from the data: perceived positive effects, powerful and harmonious inner energy, mindfulness and self-awareness, understanding self and others, and promoting and achieving a state of balance and harmony. These findings foster the value of knowing the experience of persons who practice yoga as an intervention in holistic nursing. PMID- 21325907 TI - Spousal support experiences of rural women living with chronic illness. AB - From an examination of the spousal support experiences of rural women with chronic conditions who participated in a research-based, online support intervention, indications were that health care providers must recognize the need for and provide appropriate support/information related to the emotional, psychosocial, sexual, and relational impacts of chronic illness. PMID- 21325908 TI - The medicinal qualities of Moringa oleifera. AB - Moringa oleifera is an ancient tree that is historically known to possess numerous medicinal qualities. The purpose of this article is to familiarize nurses with the use of Moringa oleifera in traditional medicine, present the findings of evidence-based studies, and provide implications for clinical practice and further research. PMID- 21325909 TI - Successful holistic management of type 2 diabetes with depression: a very personal story. AB - We used illness narrative methods to evaluate the retrospective illness story of a bereaved woman who has recovered from type 2 diabetes and depression with comorbid hypertension, hyperlipidemia, vertigo, and obesity. Her spoken illness story was obtained with a single interview question: What happened? Our findings show that the patient searched for and found personal meaning in her illness. The finding of meaning in her illness appears to have supported her efforts to adopt more positive health beliefs and health behaviors. Although she received excellent health care throughout her illness, she attributes her return to good health to spiritual growth. We discuss the practice implications of this patient's illness story for clinicians who seek new insights into patients who have complex illness stories. PMID- 21325910 TI - Acupressure and physical stress among high school students. AB - Acupressure has been found to be effective in a number of conditions. This study aims at determining the effectiveness of acupressure on physical stress among high school students. A quasi-experimental pretest/posttest control group design was used. Statistical analysis of data revealed that acupressure was effective in reducing physical stress among students within the study group (Z = -5.803, P < .001) and among students between the 2 study groups (Z = -7.409, P < .001). PMID- 21325911 TI - Research in review: the role of herbal medicine in women's health. PMID- 21325915 TI - Applicability of a change of direction ability field test in soccer assistant referees. AB - The aim of this study was to examine the applicability of a test for change of direction ability (10-8-8-10 test, involving line and sideward sprinting, 36 m) in elite-level soccer assistant referees (ARs). One hundred AR of the first second and third Italian Championships (ARA-B and ARC, n = 50, respectively) performed the 10-8-8-10 on 3 separate occasions. Twenty AR authorities scored test relevance (1-5 scale, from trivial to very large) for logical validity using a questionnaire. Construct validity was examined comparing ARA-B and ARC for the 10-8-8-10 performance. Short-term reliability was assessed testing a random selection of ARs (n = 64) over 3 separate occasions every other day. Performance in the 10-8-8-10 test was assumed as total coverage time using telemetric photocells. Results showed that the 10-8-8-10 test was perceived as possessing from large (n = 4/20) to very-large (n = 16/20) relevance to AR physical match performance. No significant performance difference was found between competitive levels (p = 0.57). Area under the curve (= 0.49; p = 0.87) showed no significant sensitivity of 10-8-8-10 in detecting competitive-level difference. The intraclass correlation coefficient (n = 64) and typical error of measurement (test 2 vs. 3) values were 0.90 (p < 0.0001) and 0.18 seconds, respectively. This study showed that the 10-8-8-10 test possesses logical validity, good reliability, and it is independent of the competitive level. As such, this original investigation represents the first step in the identification and assessment of a valid and reliable AR change of direction test. Given the strength of our findings, governing bodies should look to integrate the 10-8-8-10 test into the fitness test protocols devised for ARs, with scores >= 9.67 being considered as a starting point for the empirical validation of minimum selection criteria for elite-level ARs. PMID- 21325916 TI - Percent body fat prediction equations: external validity and race/ethnicity. PMID- 21325918 TI - "Critical power": time to abandon. PMID- 21325920 TI - Influencing melanoma prevention. PMID- 21325921 TI - Uric acid and gout. PMID- 21325924 TI - Subacute bacterial endocarditis: making the diagnosis. AB - The presentation of endocarditis varies from patient to patient, making it a difficult infection to diagnose correctly. While some patients will develop symptoms acutely over days, it may take weeks or months for symptoms to develop as in the case of subacute bacterial endocarditis. PMID- 21325925 TI - Closing the immunization gap. AB - Current vaccination rates are falling with a new group of unimmunized children. Since some parents are unaware of the diseases and potential health threats, many are often influenced by the media and myths, choosing to delay or avoid vaccinations. NP providers must be prepared to confront these myths with facts to help parents make informed decisions. Vaccine-preventable diseases, popular myths, and evidence-based research findings are reviewed in this manuscript. PMID- 21325926 TI - Vitamin D deficiency & cardiovascular disease. AB - Evolving data indicate that vitamin D deficiency is associated with an increased risk of cardiovascular disease (CVD). The purpose of this article is to increase NPs' awareness of the link between vitamin D deficiency and CVD, and to assist with recommendations for screening and treatment in at-risk patients. PMID- 21325928 TI - Open posterior reduction and stabilization of a C1 burst fracture using mono axial screws. PMID- 21325929 TI - Electromyographic analysis of paravertebral muscles in patients with idiopathic scoliosis. PMID- 21325930 TI - Posterior vertebral column resection in severe spinal deformities: a total of 102 cases. PMID- 21325931 TI - Calcitonin treatment in lumbar spinal stenosis: a meta-analysis. PMID- 21325932 TI - Architectural analysis of human abdominal wall muscles: implications for mechanical function. PMID- 21325933 TI - Biomechanical comparison of three different types of C7 fixation techniques. PMID- 21325934 TI - Does fusion status correlate with patient outcomes in lumbar spinal fusion? PMID- 21325935 TI - Utilization of breast conserving therapy in stages 0, I, and II breast cancer patients in New Jersey: an American College of Surgeons National Cancer Data Base (NCDB) analysis. AB - BACKGROUND: The purpose of the study was to determine the use of breast conservation surgery (BCS) followed by whole breast irradiation [BCS+radiation therapy (RT)] in stages 0, I, and II breast cancer patients treated in New Jersey using the National Cancer Database. MATERIALS AND METHODS: A retrospective analysis was conducted using the data from 13 hospitals in New Jersey certified by the American College of Surgeons Commission on Cancer and members of the Cancer Institute of New Jersey's Network affiliates. Subjects with a first primary malignancy of the breast (stages 0, I, and II) treated from 2000 to 2006 were included in the analysis. RESULTS: A total of 11,146 patients with stage 0 (n=2843), stage I (n=4757), and stage II (n=3546) were treated for their breast cancer. Of stage 0, I, and II patients, 72% (n=2053), 73% (n=3482), and 53% (n=1865) received BCS, respectively. Of these patients, 40% (n=826), 67.6% (n=2353), and 63% (n=1177) received adjuvant RT after BCS for their stages 0, I, and II, respectively. Use of BCS+RT was equivalent across racial groups and all ages, except patients above 70 years of age (61% <40 y, 57% 40 to 49 y, 60% 50 to 59 y, 65% 60 to 69 y, and 51% >70 y). CONCLUSIONS: These data report an underutilization of RT after BCS in patients with stage 0 breast cancer treated across 13 hospitals in New Jersey. The Commission on Cancer's Rapid Quality Reporting System may be one method of identifying groups of patients not receiving care according to evidence-based guidelines. PMID- 21325936 TI - Herpesviridae viral infections after chemotherapy without antiviral prophylaxis in patients with malignant lymphoma: incidence and risk factors. AB - OBJECTIVES: The herpesviridae family includes, among others, herpes simplex virus, varicella zoster virus, Epstein-Barr virus, and cytomegalovirus. Herpesviridae viral infections (HVIs) can lead to serious complications in lymphoma patients undergoing chemotherapy. There is no consensus on the dose and duration of antiviral prophylaxis in these patients. We retrospectively analyzed the incidence and risk factors for HVI in lymphoma patients undergoing chemotherapy. METHODS: We reviewed the records of 266 patients who were newly diagnosed with lymphoma and received chemotherapy without acyclovir prophylaxis between June 1996 and August 2009. RESULTS: The cumulative incidence rate of HVI was 20.16% for 5 years from the start of chemotherapy. Independent predictive factors for HVI in lymphoma patients were: female sex [hazard ratio (HR) 2.394; 95% confidence interval (CI): 1.245-4.607; P=0.009], cumulative dose of steroids per body surface area of at least 2500 mg/m(2) (HR 7.717; 95% CI: 3.814-18.703; P<0.001), and history of neutropenic fever (HR 0.297; 95% CI: 0.150-0.588; P<0.001). CONCLUSIONS: Female sex, high dose of steroids per body surface area, and neutropenic fever were risk factors for HVI in patients with lymphoma undergoing chemotherapy without acyclovir prophylaxis. PMID- 21325937 TI - Adjuvant chemoradiotherapy after curative resection for extrahepatic bile duct cancer: a long-term single center experience. AB - OBJECTIVES: To analyze the outcome of adjuvant chemoradiotherapy for patients with extrahepatic bile duct (EHBD) cancer, and to identify the prognostic factors for these patients. METHODS: Between January 1995 and December 2002, 86 patients with adenocarcinoma of EHBD underwent curative resection followed by adjuvant chemoradiotherapy. There were 59 male and 27 female patients, and median age was 59 years (range, 34 to 73 y). Postoperative radiotherapy was delivered to tumor bed and regional lymph nodes up to 40 Gy at 2 Gy/fraction with a 2-week planned rest. Intravenous 5-fluorouracil (500 mg/m(2)/d) was given on day 1 to 3 of each split course. The median follow-up period was 83 months for survivors. RESULTS: Forty-eight patients failed the treatment: locoregional recurrence in 20, distant metastasis in 38, and both locoregional and distant relapses in 10 patients. Five year locoregional relapse-free survival rate was 70.3%. On multivariate analysis, resection margin status was the only significant prognosticator (P=0.0299). Five year distant metastasis-free survival rate was 53.6%. Three or more involved lymph nodes had an adverse impact on distant metastasis-free survival (P=0.0334). Five-year overall survival rate was 44.7%, and poorly differentiated tumor was associated with inferior overall survival (P=0.0297). CONCLUSIONS: Adjuvant chemoradiotherapy after curative resection can achieve a long-term survival in patients with EHBD cancer. Resection margin status, number of involved lymph nodes, and histologic differentiation are associated with locoregional relapse, distant metastasis, and overall survival, respectively. Distant metastasis was the major pattern of failure, possibly due to the increased locoregional control by use of adjuvant chemoradiotherapy. Intensification of systemic treatment is warranted. PMID- 21325938 TI - The role of genotype in 104 cases of diffuse large B-cell lymphoma primary of breast. AB - OBJECTIVES: To analyze the role of genotype in patients with diffuse large B-cell lymphoma primary of breast (DLBCL-PB) treated with chemotherapy or immunochemotherapy. METHODS: We carried out a retrospective analysis in 104 patients with DLBCL-PB who were treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or immunochemotherapy: R-CHOP (adding rituximab) and also carried out an analysis of genotype, studied with immunohistochemistry, as a prognostic factor. RESULTS: Seventy-seven percent of patients showed the non-GCB (germinal center B) genotype. Patients treated with CHOP had a complete response of 70%; actuarial curves at 5 years showed that disease-free survival was 66 % and overall survival was 52% and that it was not statistically different than patients treated with R-CHOP: 78%, 61%, and 53%, respectively. When genotype was analyzed to assess the impact in prognosis, no statistical differences were observed. Patients treated with R-CHOP and non-GCB genotype have a complete response of 77%, disease-free survival of 56%, and overall survival of 66% that were not statistically different than patients with GCB: 80%, 60%, and 60% respectively, (P: 0.81, 0.5, and 0.66, respectively). CONCLUSIONS: We confirm that the non-GCB genotype is most frequent in DLBCL-PB, but the addition of rituximab did not improve outcome in primary breast lymphoma with non-GCB phenotype. PMID- 21325939 TI - Efficacy and tolerability of long-acting octreotide in the treatment of thymic tumors: results of a pilot trial. AB - OBJECTIVES: Octreotide is a somatostatin analog, long-acting formulations of which have been used experimentally for the treatment of patients with invasive tumors and/or residual disease after conventional therapies. The objective of this retrospective study was to evaluate the efficacy of long-acting octreotide (Sandostatin LAR) for the treatment of thymic tumors, with a primary efficacy end point of progression-free survival. METHODS: Between 1994 and 2010, 44 patients with thymic malignancies were evaluated. Twenty-seven patients underwent an OctreoScan, and 12 OctreoScan-positive patients were treated with long-acting octreotide at a dose of 20 mg, given as an intramuscular injection, every 2 weeks. RESULTS: Treatment with long-acting octreotide gave the following results: 3 cases of partial response (25%), 5 cases of stable disease (42%), and 4 cases of progressive disease (33%), with an average progression-free survival of 8 months (range, 3 to 21). Treatment compliance and tolerability were good for all evaluated patients. CONCLUSIONS: The results of this study confirm the somatostatin receptor as a valid target for the treatment of thymic malignancies. Overall, therapy with long-acting somatostatin analogs seems to be safe and effective. PMID- 21325940 TI - Thyroid transcription factor-1 in primary CNS tumors. AB - In diagnostic pathology thyroid transcription factor-1 (TTF-1) is used as a relatively specific and sensitive diagnostic marker of thyroid and lung adenocarcinomas and lung carcinoids but has also been demonstrated in minor proportions of carcinomas from other organs as well as nonepithelial neoplasms. Two antibody clones are widely used for TTF-1 demonstration, 8G7G3/1 and SPT24, the latter being the most sensitive. Few studies have addressed the occurrence of TTF-1 in central nervous system (CNS) tumors with highly divergent results, a major reason for which seems to be use of different clones. Based on multitissue blocks we analyzed the TTF-1 expression in a series of 155 CNS tumors comparing antibody clones 8G7G3/1 and SPT24 in optimized protocols on the Benchmark Ultra stainer. With clone SPT24 TTF-1 staining was observed in 13 cases (8%). Among astrodendroglial and oligodendroglial tumors, TTF-1 expression was found in 10 of 56 grades III to IV tumors (18%), as opposed to 0 of 47 grades I to II tumors (0%). The TTF-1 expression in positive tumors was generally weak to moderate and focal (mean histoscore 28, range: 2 to 120). TTF-1 positivity was inversely correlated to the expression of nestin. Among 52 other CNS tumors, TTF-1 expression was found in 1 of 3 central neurocytoma (the only CNS tumor with a moderate, diffuse staining), 1 of 18 ependymal tumors, and 1 of 5 choroid plexus tumors, whereas 4 pineal tumors, 11 meningiomas, 8 embryonal tumors, and 4 mixed neuronal-glial tumors all were negative. None of the 155 tumors stained with the 8G7G3/1 antibody clone. TTF-1 expression in primary brain tumors should be taken into consideration when interpreting brain tumors of uncertain origin. PMID- 21325941 TI - Comparison of 2 monoclonal TTF-1 antibodies. PMID- 21325942 TI - The cincinnati procedure: technique and outcomes of combined living-related conjunctival limbal allografts and keratolimbal allografts in severe ocular surface failure. AB - PURPOSE: To explain our preferred technique and evaluate the success of ocular surface transplantation using a combined living-related conjunctival limbal allograft (lr-CLAL) and keratolimbal allograft (KLAL) in patients with severe ocular surface failure and conjunctival deficiency. METHODS: Retrospective study of all patients undergoing combined lr-CLAL/KLAL at the Cincinnati Eye Institute/University of Cincinnati. Patients were retrospectively analyzed for demographics, immunosuppression exposure, ocular surface stability, and need for keratoplasty. Snellen best-corrected visual acuity was evaluated preoperatively and at final visit. RESULTS: Nineteen patients (24 eyes) underwent combined lr CLAL/KLAL. Mean follow-up was 43.4 months (range: 12.2 to 125.5 months). At the last recorded visit, the ocular surface was stable in 54.2% (13 of 24), improved in 33.3% (8 of 24), and failed in 12.5% (3 of 24) of eyes. 79.2% (19 of 24) of patients underwent staged keratoplasty. For the primary keratoplasty, 73.7% (14 of 19) of patients underwent penetrating keratoplasty, 21.1% of patients underwent Boston type I keratoprosthesis, and 5.2% of patients underwent deep anterior lamellar keratoplasty; 57.9% of patients required repeat keratoplasty. Preoperative best-corrected visual acuity was 20/400 or worse in 87.5% (21 of 24); 75% (18 of 24) of eyes had improvement in visual acuity at the last follow up with 70.8% of patients (17 of 24) achieving 20/125 vision or better. Of patients with a Boston keratoprosthesis, 90.0% (9 of 10) had an improvement in vision with 70.0% achieving 20/125 vision or better at the last follow-up. CONCLUSIONS: Ocular surface transplantation with a combined lr-CLAL/KLAL and staged keratoplasty is an effective procedure to improve visual acuity in patients with severe ocular surface disease and conjunctival deficiency. Keratoprosthesis after limbal stem cell transplantation is an alternative to penetrating or lamellar keratoplasty in this patient population. PMID- 21325943 TI - Genetics of occupational asthma. AB - PURPOSE OF REVIEW: To discuss gene association studies conducted in workers diagnosed with occupational asthma. RECENT FINDINGS: Human leukocyte antigen studies conducted in European workers have defined major histocompatibility complex class II alleles and haplotypes associated with diisocyanate asthma. Recently, certain glutathione S-transferase genotypes (e.g. the GSTM1 null genotype) and N-acetyltransferase genotypes associated with slow acetylation phenotypes have been reported to be associated with diisocyanate asthma. Genotype combinations of IL-4 receptor-alpha and CD14 single nucleotide polymorphisms (SNPs) were significantly associated with diisocyanate asthma, but only in workers exposed to hexamethylene diisocyanate. A recent genome-wide association study (GWAS) conducted in Korea identified several SNPs of the alpha-T-catenin gene that were significantly associated with diisocyanate asthma. SUMMARY: Although candidate gene association studies have yet to identify reliable predictors of occupational asthma, future investigations including GWAS studies may identify high-risk genotypes allowing identification of workers at risk. PMID- 21325944 TI - Occupational lower airway disease in relation to World Trade Center inhalation exposure. AB - PURPOSE OF REVIEW: To summarize the knowledge about the occupational lower airway diseases that seem related to exposures at the World Trade Center disaster site. RECENT FINDINGS: Those diseases have been characterized as irritant-induced asthma, chronic nonspecific bronchitis, chronic bronchiolitis/small airway disease, and aggravated preexistent chronic obstructive lung disease (most frequently chronic obstructive pulmonary disease, but also asthma), with the expected overlapping features among them. One remarkable characteristic of the irritant-induced asthma observed among these workers was the slow onset of symptoms and long delay in clinical diagnoses. SUMMARY: Longitudinal studies suggest that both the incidence and the associated functional decline of these predominantly obstructive lung diseases stabilized several years ago, but longer follow-up is clearly necessary. PMID- 21325945 TI - Role of innate immunity in the development of allergy and asthma. AB - PURPOSE OF REVIEW: Asthma is essentially a developmental disease, in which the normal growth and development of the respiratory and immune systems are affected by environmental exposures acting on underlying genetic predispositions. The purpose of this review is to examine the role of innate immunity in the lungs in the development of allergy and asthma. RECENT FINDINGS: Both the innate and adaptive arms of the immune system are immature at birth and undergo prolonged periods of postnatal maturation. As such, they are vulnerable to adverse environmental exposures, both before and after birth. Both genetic predispositions and environmentally induced epigenetic changes in gene expression are likely to contribute to the risk of asthma; however, the relative contributions are unclear. Increasing interest is focused on deficient innate responses of the respiratory epithelium to viral infections and how these may increase the risk of asthma. However, definitive proof that these are primary and not secondary effects is lacking. Although most research has concentrated on the role of respiratory viral infections in increasing the asthma risk, the recent suggestion that the lung has a resident bacteriome and potentially important viral-bacterial interactions in the lungs broadens research scope in this area. SUMMARY: Classic risk factors for asthma include a family history of asthma and allergies, early and persistent allergic sensitization and viral lower respiratory infections in early life. However, these factors do not fully explain the risk. Perhaps, the resident pulmonary microbiome and the immune response that this generates during respiratory viral infections will provide the 'missing link' in the epidemiology. PMID- 21325946 TI - Reduction of exposure in the management of occupational asthma. AB - PURPOSE OF REVIEW: The management of immunologically mediated occupational asthma may be difficult in clinical practice since complete avoidance of exposure to the sensitizing agent is associated with a substantial adverse socio-economic impact. The purpose of this review was to critically analyze the available information on the effectiveness of reducing exposure as an alternative to complete avoidance. RECENT FINDINGS: Short-term exposure studies showed that respiratory protective devices can reduce bronchial responses to sensitizing agents in patients with occupational asthma, but do not provide complete protection. Recent systematic reviews of long-term follow-up studies of workers with occupational asthma indicated that reduction of exposure to the causal agent is associated with a lower likelihood of improvement in asthma symptoms and a higher risk of worsening of symptoms and nonspecific bronchial hyper-responsiveness. There are insufficient data to compare the socio-economic consequences related to both of these management options. SUMMARY: Available data indicate that a reduction of exposure to the agents causing occupational asthma cannot be routinely recommended as an alternative to complete avoidance. However, due to the methodological weaknesses of the published studies, further investigations are required to determine the evidence-based cost-effectiveness of the occupational asthma management strategies. PMID- 21325947 TI - Determining perceived sound quality in a simulated hearing aid using the international speech test signal. AB - OBJECTIVES: Based on speech segments from female talkers of different languages, the International Speech Test Signal (ISTS) has speech-like acoustic properties but is not intelligible. This study investigated whether sound quality ratings for the ISTS are similar to ratings obtained for linguistically meaningful speech. DESIGN: A simulated hearing aid was used to process the ISTS for a variety of noise, nonlinear, linear, and combined nonlinear and linear processing conditions. The sound quality of the test conditions was rated by both normal hearing and hearing-impaired (HI) listeners. Listeners' ratings were then modeled using the Hearing Aid Sound Quality Index (HASQI). RESULTS: The HASQI predictions indicated how closely the ISTS sound quality ratings were to listener ratings of American English. In the normal-hearing group, correlations between HASQI predictions and listener ratings were 0.90 for nonlinear processing, 0.78 for linear processing, and 0.88 for combined processing. In the HI group, correlations between HASQI predictions and listener ratings were 0.96 for nonlinear processing, 0.94 for linear processing, and 0.96 for combined processing. CONCLUSIONS: Since the ISTS is intended for use with hearing aids, the accuracy of the HASQI predictions for the HI listeners reinforces the validity of using this signal for hearing aid sound quality ratings and predictions. PMID- 21325948 TI - Global analysis of disease-related DNA sequence variation in 10 healthy individuals: implications for whole genome-based clinical diagnostics. AB - BACKGROUND: Understanding how sequence variants within healthy genomes are distributed with respect to ethnicity and disease-implicated genes is an essential first step toward establishing baselines for personalized genomic medicine. METHODS: In this study, we present an analysis of 10 genomes from healthy individuals of various ethnicities, produced using six different sequencing technologies. In total, these genomes contain more than 34 million single-nucleotide variants. RESULTS: We have analyzed these variants from a clinical perspective, assaying the influence of sequencing technology and ethnicity on prognosis. We have also examined the utility of OMIM and the disease gene literature for determining the impact of rare, personal variants on an individual's health. CONCLUSIONS: Our analyses demonstrate that clinical prognoses are complicated by sequencing platform-specific errors and ethnicity. We show that disease-causing alleles are globally distributed along ethnic lines, with alleles known to be disease causing in Eurasians being significantly more likely to be homozygous in Africans. PMID- 21325950 TI - Risk factors for sessile serrated adenomas. AB - BACKGROUND: Although sessile serrated adenomas (SSAs) may represent a separate and important pathway for colorectal cancer (CRC), little is known about the risk factors for these lesions. Molecular abnormalities such as BRAF have been observed in SSA and smokers. Our hypothesis is that smoking may be associated with these lesions. METHODS: All patients diagnosed with an SSA from January 2007 to September 2010 were identified retrospectively based on a pathology database query. There were 2 sets of controls. One group had no adenomas, whereas another group had tubular adenomas. These groups were randomly identified from 2007 to 2010. Data collected included age, sex, ethnicity, height, weight, family history of CRC, diabetes mellitus, use of aspirin, statins, and calcium, and serum trigylcerides and cholesterol. We defined smokers as those patients who smoked at least 20 pack-years. RESULTS: We identified 90 patients with an SSA of any size, 90 patients with tubular adenomas, and 200 controls with no adenomas. Of the 90 SSAs, 42 were 6 mm or larger and 19 of them were >=1 cm. Most of the SSAs was flat (76/90; 84.4%). After multivariate analyses, smokers with at least 20 pack year exposure were found to have an increased risk [adjusted odds ratio (OR)=7.31; 95% confidence interval (CI), 3.92-13.63] of having any SSAs, SSAs >=6 mm (adjusted OR=7.77; 95% CI, 3.48-17.35), and large SSAs (adjusted OR=10.20; 95% CI, 3.31-31.41) compared with nonsmokers. We also observed this relationship when comparing patients with SSAs to those with tubular adenomas. CONCLUSIONS: Our data suggest that smoking at least 20 pack-years is strongly associated with any and large SSAs. In addition, diabetes mellitus and obesity seem to be associated with SSAs as well. Our data has implications for CRC screening. PMID- 21325952 TI - Portopulmonary hypertension. AB - The development of pulmonary arterial hypertension in the setting of portal hypertension is known as portopulmonary hypertension. Portal hypertension is thought to predispose patients to disturbances in the homeostatic regulation of numerous neurohumoral and vasoactive mediators that induce the development of pulmonary arterial hypertension. Portopulmonary hypertension is pathologically indistinguishable from idiopathic pulmonary arterial hypertension and is characterized by the development of vasoconstriction, vascular remodeling, and thrombosis within the pulmonary vasculature. Although described in patients with both cirrhotic and noncirrhotic portal hypertension, portopulmonary hypertension is most prevalent among patients with end-stage liver disease, and its severity seems to be independent of the etiology or severity of liver disease. All liver transplant candidates must be screened for the presence of portopulmonary hypertension because of the high perioperative mortality risk of liver transplantation associated with this condition. Primary screening for portopulmonary hypertension consists of Doppler-estimated pulmonary artery systolic pressure measurement during echocardiography. However, the diagnosis of portopulmonary hypertension is based on unique hemodynamic criteria as determined by right heart catheterization. Untreated portopulmonary hypertension portends a poor prognosis, and the efficacy of current treatment modalities is limited. At present, the primary goals of therapy are to provide symptomatic relief, prolong survival, and improve pulmonary hemodynamics to facilitate safe and successful liver transplantation. PMID- 21325951 TI - Fatty acid synthase expression in Barrett's esophagus: implications for carcinogenesis. AB - GOALS: To investigate the relationship between fatty acid synthase (FASN) expression and the clinicopathological characteristics of Barrett's esophagus and its carcinogenesis. BACKGROUND: FASN, a key enzyme of the fatty acid biosynthetic pathway, is overexpressed not only in various types of cancer, but also in premalignant conditions. Therefore, FASN overexpression is considered to be indicative of a possible premalignant stage. STUDY: Patients (N=354) with endoscopically and histologically proven Barrett's esophagus were enrolled. Mucin phenotyping of Barrett's esophagus, expression of FASN and COX-2, cellular proliferation, and apoptosis were evaluated immunohistochemically in biopsy samples, and factors influencing FASN expression were determined by multivariate logistic regression analysis. To evaluate if gastric reflux induces FASN expression, esophageal adenocarcinoma cells were treated with bile acid and low pH, and the effect of a FASN inhibitor on cell proliferation was assessed. RESULTS: Expression of FASN protein was observed in 52.2% of patients with Barrett's esophagus by immunohistochemistry; this expression pattern was retained in esophageal adenocarcinoma. Intestinal mucin phenotype, COX-2, increased stromal angiogenesis, and elevated proliferating cell nuclear antigen index were confirmed to be positive independent factors for FASN expression. In the esophageal adenocarcinoma cell line SEG-1, FASN mRNA was induced by bile acid with low pH. Cell proliferation was strongly suppressed by the FASN inhibitor C75. CONCLUSIONS: FASN is strongly expressed in the intestinal mucin phenotype of Barrett's esophagus, in which Barrett's glandular cells display elevated cellular proliferation, angiogenesis, and COX-2 expression. Exposure of the lower esophagus to bile acid with low pH may induce FASN in Barrett's esophagus. PMID- 21325953 TI - Lynch syndrome and MYH-associated polyposis: review and testing strategy. AB - Individuals with Lynch syndrome have an increased risk for colorectal cancer, endometrial cancer, and other associated cancers such as gastric cancer, ovarian cancer, urothelial cancers, hepatobiliary tract cancer, brain cancer, cancer of the small intestine, pancreatic cancer, and particular skin cancers. Lynch syndrome caused by defects in DNA mismatch repair genes, and diagnostic testing for Lynch syndrome begins with microsatellite instability and immunohistochemical analysis on the tumor specimen followed by germline genetic testing and possibly further studies on the tumor. MYH-associated polyposis syndrome is a recently characterized, autosomal recessive, polyposis syndrome caused by biallelic mutations in the MYH gene. Individuals carrying 2 copies of the mutation have a significantly increased risk of polyposis, colorectal cancer, upper gastrointestinal polyps and additional features commonly seen in familial adenomatous polyposis syndrome. Genetic testing for MYH mutation is complicated by the phenotypic overlap of MYH-associated polyposis with other colorectal cancer syndromes. This study serves to clarify the best testing approach. PMID- 21325949 TI - Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: a worldwide collaborative project. AB - PURPOSE: To achieve clinical validation of cutoff values for newborn screening by tandem mass spectrometry through a worldwide collaborative effort. METHODS: Cumulative percentiles of amino acids and acylcarnitines in dried blood spots of approximately 25-30 million normal newborns and 10,742 deidentified true positive cases are compared to assign clinical significance, which is achieved when the median of a disorder range is, and usually markedly outside, either the 99th or the 1st percentile of the normal population. The cutoff target ranges of analytes and ratios are then defined as the interval between selected percentiles of the two populations. When overlaps occur, adjustments are made to maximize sensitivity and specificity taking all available factors into consideration. RESULTS: As of December 1, 2010, 130 sites in 45 countries have uploaded a total of 25,114 percentile data points, 565,232 analyte results of true positive cases with 64 conditions, and 5,341 cutoff values. The average rate of submission of true positive cases between December 1, 2008, and December 1, 2010, was 5.1 cases/day. This cumulative evidence generated 91 high and 23 low cutoff target ranges. The overall proportion of cutoff values within the respective target range was 42% (2,269/5,341). CONCLUSION: An unprecedented level of cooperation and collaboration has allowed the objective definition of cutoff target ranges for 114 markers to be applied to newborn screening of rare metabolic disorders. PMID- 21325954 TI - 5-HT2A receptor gene polymorphisms and irritable bowel syndrome. AB - GOALS: The aim of the study was to investigate the potential association between single nucleotide polymorphisms of the 5-HT2A receptor gene and susceptibility to irritable bowel syndrome (IBS) in the Greek population. BACKGROUND: Serotonin [5 hydroxytryptamine (5-HT)] is the main mediator involved in the pathophysiology of IBS. Thus, genes implicated in 5-HT metabolism are good candidates for susceptibility to IBS. Two single nucleotide polymorphisms -1438 (G/A) and 102 (C/T) in the 5-HT2A receptor gene have been associated with the pathophysiology of IBS. STUDY: One hundred twenty-four patients with IBS diagnosed according to the Rome III criteria and 238 healthy individuals were included in the study. The -1438 (G/A) and 102 (C/T) in the 5-HT2A receptor gene polymorphisms have been studied using the polymerase chain reaction based restriction fragment length polymorphism method. RESULTS: A genotype association was found between A allele and AA genotype of the -1438 (G/A) polymorphism and IBS (P=0.0037 and P=0.0064, respectively). Concerning the 102 (C/T) polymorphism, no significant association was found. CONCLUSIONS: This study suggests that the carriers of A allele of the 1438 (G/A) polymorphism of the 5-HT2A receptor gene have a high risk of IBS. PMID- 21325955 TI - Tuberculous mastitis in systemic lupus erythematosus: a report of 2 cases. PMID- 21325956 TI - Use of ultrasound guidance in an inaugural acute gout of the hip joint: apropos of a West African case. PMID- 21325957 TI - Acroosteolysis in systemic lupus erythematosus. PMID- 21325958 TI - Saline breast implant fluid collection and reactive arthritis in a patient with streptococcal toxic shock syndrome. AB - Streptococcal toxic shock syndrome is a potentially lethal condition with an increasing incidence over the last 30 years. We present the case of a 55-year-old patient with signs and symptoms of streptococcal toxic shock syndrome. This patient's presentation was unique in that it was followed by an accumulation of fluid at her breast implant in addition to a polyarticular reactive arthritis. We propose that the patient's reactive arthritis is consistent with the diagnosis of post-streptococcal reactive arthritis, a variant of acute rheumatic fever, which similarly to its variant is immunologically driven. We hypothesize that the fluid collection around the patient's breast implant was triggered by her infection and was also immunologically mediated. PMID- 21325959 TI - Susac syndrome and pregnancy: disease management. AB - Susac syndrome (SS) consists of a triad of vision loss, hearing loss, and encephalopathy due to autoimmune-mediated vascular endothelial injury. Herein we describe a 25-year-old previously healthy woman who presented at 20 weeks' gestation with symptoms of confusion, difficulty walking, and vision and hearing loss. She had branch-retinal artery occlusions on funduscopic examination, and sensorineural hearing loss. Additionally, non-contrast enhanced brain magnetic resonance imaging showed multiple white matter and callosal lesions consistent with ischemia. She was treated initially with aspirin, corticosteroids, and intravenous immunoglobulin with early improvement, although recurrent disease was treated with cyclophosphamide and rituximab after induction of premature delivery (at 35 weeks' gestation) to spare the fetus possible toxicity. We additionally discuss a general overview of SS, what is known about pregnancy and this disease, and issues regarding diagnostic and treatment approaches for SS during pregnancy. PMID- 21325960 TI - Colitis associated with active systemic lupus erythematosus successfully treated with rituximab. AB - Intestinal vasculitis is a serious and often underrecognized complication of systemic lupus erythematosus (SLE) usually managed with high-dose corticosteroids. We report a case of corticosteroid refractory colitis (likely due to intestinal vasculitis) that achieved remission with a single cycle of high dose rituximab. This has not previously been described to our knowledge. A 46 year-old woman with SLE presented with 1-week history of bloody diarrhea, abdominal pain, worsening joint pains, fatigue, and mouth ulcers. There was evidence of increased SLE activity with low C4, raised anti-double-stranded DNA antibody, leukopenia, and anemia. Colonoscopy showed active pancolitis (confirmed histologically). A diagnosis of acute colitis associated with active SLE was made, and she received intravenous methylprednisolone 1 g daily for 3 days followed by 60 mg oral prednisolone daily. She continued to have symptomatic colitis with worsening anemia requiring frequent blood transfusions. She then received 2 doses of rituximab 1 g (750 mg/m(2)) 2 weeks apart that led to improvement in colitis symptoms and SLE disease activity over the next 4 weeks. A repeat colonoscopy (and histology) confirmed good resolution of colitis. Six months later, she continued to be in remission with low-dose prednisolone. Intestinal vasculitis should be considered as a possible cause of acute abdominal pain in SLE as early recognition and treatment can improve long-term survival. Rituximab can be an effective alternative for patients refractory to conventional treatment. PMID- 21325961 TI - Autoimmune clustering: sweet syndrome, Hashimoto thyroiditis, and psoriasis. AB - Acute febrile neutrophilic dermatosis (AFND; Sweet syndrome) is characterized by a constellation of symptoms and findings: fever, neutrophilia, and tender erythematous skin lesions that typically show an upper dermal infiltrate of mature neutrophils. Whereas some cases are idiopathic, others have been associated with a variety of disorders. In this report, we describe the occurrence of AFND with chronic lymphocytic thyroiditis (Hashimoto thyroiditis) and preexisting psoriasis. This is the first case report of the association of chronic lymphocytic thyroiditis with AFND from the United States and only the third reported in the world's literature. Because the coexistence of these disorders is rare, an underlying common pathogenic mechanism is a possibility. We postulate this to be CD4(+) T-cell dysfunction. PMID- 21325962 TI - Chorea in systemic lupus erythematosus. AB - BACKGROUND: Chorea is recognized as one of the neurologic manifestations of systemic lupus erythematosus (SLE). Most reports show an association between chorea and antiphospholipid (aPL) antibodies in SLE patients. OBJECTIVES: The objective of this study was to describe the association of aPL antibodies with lupus chorea and its possible role in the pathogenesis of chorea. METHODS: We made a retrospective review of all cases of lupus chorea between 1989 and 2007 in a tertiary care center in Mexico City. RESULTS: We found 7 episodes of chorea in 5 patients with SLE. In 2 patients (3 episodes), chorea was associated with cerebral ischemia; one of these cases had positive anticardiolipin (aCL) immunoglobulin G (IgG) antibodies, whereas the other was diagnosed as having vascular lipohyalinosis as the probable cause of cerebral ischemia. In 3 patients (4 episodes), an immune-mediated mechanism was suspected; these cases had negative aPL at the onset of chorea, but IgM aCL antibodies became positive later. CONCLUSIONS: In most episodes, chorea seems to be immunologically mediated and was associated with a later appearance of IgM aCL antibodies. Chorea in patients with lupus may also be caused by cerebral ischemia, and in some cases, it may be associated with IgG aCL antibodies. PMID- 21325963 TI - Effects of lifestyle physical activity in adults with fibromyalgia: results at follow-up. AB - BACKGROUND: In a 12-week randomized controlled trial of the effects of lifestyle physical activity (LPA) on symptoms and function among adults with fibromyalgia, we found that LPA participants increased their average daily step count by 54%, improved their self-reported functioning by 18%, and reduced their pain by 35%. OBJECTIVES: The objective of the study was to evaluate the intermediate (6 months) and long-term (12 months) effects of the LPA intervention on outcomes. METHODS: Participants completed follow-up assessments of physical activity, pain, fibromyalgia-related function, fatigue, depression, number of tender points, 6 minute walk test, and perceived improvement at 6 and 12 months after intervention. RESULTS: Of the 73 participants who completed the 12-week trial, 53 (73%) completed both the 6- and 12-month follow-up. Although the LPA participants reported greater perceived improvement at each follow-up, they did not differ from controls on pain, physical activity, tenderness, fatigue, depression, or the 6-minute walk test. Self-reported functioning declined markedly at follow-up for the LPA participants. CONCLUSIONS: Although participants reported greater perceived improvement at each assessment, the beneficial effects of LPA on physical activity, function, and pain found after the 12-week intervention were not sustained over time. This recidivism is seen in studies of activity and exercise in nearly any condition, and innovative methods that may prevent this are a focus of future studies. PMID- 21325964 TI - Incidence and prevalence of systemic sclerosis in a healthcare plan in Buenos Aires. AB - BACKGROUND: Systemic sclerosis (scleroderma) is an infrequent disease. Data on incidence and prevalence are scarce and conflictive. There are no such data in Latin America or in Argentina in particular. OBJECTIVES: We undertook to examine the incidence and prevalence of systemic sclerosis in the prepaid health maintenance organization of our hospital, in the city of Buenos Aires. METHODS: Members of the plan between 1999 and 2004 were followed up for incident cases, and prevalence was calculated at the end of the period. RESULTS: A total of 98,642 persons were followed up for a total of 32,9534 person-years. Density of incidence overall was 21.2 per million person-years (95% confidence interval [CI], 5.4-37). Density of incidence for diffuse disease was 6.1 per million person-years (95% CI, 2.3-14.5), and for limited disease, it was 15.2 per million person-years (95% CI, 2-28). Prevalence was 296 per million people (95% CI, 193 434); females, 477 per million people (95% CI, 309-704); and males, 28 per million people (95% CI, 7-157). Prevalence for diffuse disease was 57 per million people (95% CI, 18-133), and for limited disease, it was 240 per million people (95% CI, 148-365). CONCLUSIONS: Despite potential biases, these data are in agreement with others from different parts of the world and the first obtained in Argentina and, to our knowledge, in Latin America. PMID- 21325965 TI - Protracted rheumatic manifestations in travelers. AB - BACKGROUND: Travel returnees may complain of protracted rheumatic symptoms, but there are sparse data regarding their causes. We aimed to describe travelers returning with new rheumatic symptoms. METHODS: We conducted a retrospective analysis of Israeli travelers who were referred to the Sheba Medical Center from January 2005 to January 2010 with prolonged (>4 weeks) nontraumatic arthralgia or arthritis. RESULTS: During 5 years, 14 patients (7 men and 7 women) with posttravel arthritis/arthralgia were seen. A total of 5 patients were diagnosed with reactive arthritis, and 9 were diagnosed with rheumatic symptoms related to infection with Alphaviruses: Chikungunya virus or Ross River virus. Some disability remained for several months in most cases, but only 1 case of reactive arthritis eventually evolved to a chronic spondyloarthropathy. CONCLUSIONS: Travel-related arthritis may persist even several months after the exposure. Assessing patients' travel history may help in the evaluation of some cases with rheumatic manifestations. Their prognosis may be better than that of autoimmune arthritides. PMID- 21325966 TI - Sense of coherence as a predictor of quality of life in adolescents with congenital heart defects: a register-based 1-year follow-up study. AB - OBJECTIVE: Sense of coherence (SOC) is a resource for health and quality of life (QoL) in adults. The aim of this investigation was to prospectively evaluate the association between SOC and QoL in adolescents with congenital heart defects (CHDs). METHODS: This is an observational study among 770 adolescents aged 14 to 17 years from a national CHD register. SOC was measured at baseline with the SOC L9 questionnaire. QoL was measured at baseline and at a follow-up 12 months later. For this, we used the KINDL-R (revidierter KINDer Lebensqualitatsfragebogen) questionnaire to evaluate overall well-being and 6 subscales (physical well-being, psychological well-being, self-esteem, family related well-being, friend-related well-being, and school-related well-being). The association between SOC and QoL both in terms of overall well-being and the KINDL-R subscales was evaluated in multilevel linear models. Fully adjusted models accounted for age, gender, behavioral factors, and medical and socioeconomic status. RESULTS: Overall well-being, self-esteem, and school related well-being were significantly higher at follow-up than at baseline. SOC (median: 50 [range: 16-63] points) was positively associated with overall well being and all KINDL-R subscales at baseline. In overall well-being and the KINDL R subscales (except in psychological well-being), significant negative interaction terms were observed for SOC at baseline and time to follow-up. However, the associations between SOC at baseline and overall well-being and all KINDL-R subscales at follow-up remained significant even in fully adjusted models. CONCLUSION: SOC is an independent predictor of QoL in adolescents with CHD. In psychological well-being, this prediction remains stable, whereas in total well-being and all other QoL subdimensions, its strength as such wanes over the course of a year but does not entirely dissipate. Further studies should evaluate whether interventions designed to increase SOC in children with CHD would also improve their QoL. PMID- 21325967 TI - A modified healthy steps model to improve resident training in behavioral and developmental care. AB - OBJECTIVE: To assess whether implementing a modified Healthy Steps (HS) for young children program in residency clinics could improve resident education and their perception of the quality of care provided for common behavioral and developmental (B/D) issues. METHODS: Residents and faculty blinded to study intent were surveyed to assess perceptions of resident preparedness and the quality of behavioral and developmental (B/D) care at 4 pediatric residency training sites in North Carolina. Initially, Program 1 (with an established HS program) was compared with 3 sites without established programs at baseline (Programs 2, 3, and 4), and then the results before and after implementation at Programs 2 to 4 were compared. RESULTS: Initially, subjects at Program 1 were more likely than those at Programs 2 to 4 to rate residents as "well" or "very well" prepared to provide B/D care (63% vs 20% respectively, 95% confidence interval of the difference, 25-61%) and more likely to rate the overall quality of B/D care at their clinic as "high" or "extremely high" (94% and 47% respectively, 95% confidence interval for the difference, 34-59%). After implementation of HS at Programs 2 to 4, the mean percentage of subjects rating residents as "well" or "very well" prepared and the ratings of the care provided increased dramatically. CONCLUSION: A modified HS model focusing on resident B/D education substantially increased attending and resident ratings of residents' preparedness to deliver B/D care and increased the ratings of the quality of B/D care provided. PMID- 21325969 TI - Use of in vivo gene expression of isolated bone marrow mesenchymal stromal cells to study the pathophysiology of osteoporosis in patients with severe thalassemia. AB - We compared osteoblast differentiation gene expressions in the isolated CD105 mesenchymal stromal cells from bone marrow in 10 patients with severe thalassemia and 12 normal donor controls. The fold expressions of osteoblast differentiation genes of CD105 cells from patients with thalassemia were lower than those of normal donors but increased after being cultured in Dulbecco's modified Eagle's medium with 10% fetal calf serum. Moreover, the fold expressions of these genes of CD105 cells from normal donors when cultured with 10% pooled serum of patients with thalassemia were lower than when cultured with 10% pooled serum of normal donors. We have also presented the evidence of reversible suppressed expression of these genes in CD105cells from patients with thalassemia when cultured in pooled serum of normal donors. Moreover, healthy donor CD105 cells exhibited lower expression of these genes when cultured in pooled serum of patients with thalassemia compared with pooled serum of normal donors indicating the existence of circulating factors in thalassemic serum impairing the differentiation of mesenchymal stromal cells to osteoblasts. PMID- 21325970 TI - White matter integrity and core cognitive function in children diagnosed with sickle cell disease. AB - Children diagnosed with sickle cell disease (SCD) have an increased risk of stroke, often associated with white matter damage and neurocognitive morbidity. Growing evidence suggests that subtle changes in white matter integrity, which do not pass the threshold to be visible on a clinical magnetic resonance image and classified as stroke, may contribute to decreased cognitive performance. We used archived diffusion-weighted imaging and neurocognitive assessment data to identify associations between microstructural changes in normal-appearing white matter and cognitive performance in children with SCD. Study participants included 10 healthy children and 15 pediatric SCD patients (5 with identified lesions and 10 without lesion). After excluding lesioned tissue from analyses, we detected significant increases in apparent diffusion coefficient across the brains of patients in comparison with control children, suggesting compromise to the structure of normal-appearing white matter. Deficits in working memory and processing speed were also apparent in patients. Increased apparent diffusion coefficient and deficiencies in processing speed were again detected in a subanalysis including only the patients without lesion. Correlation analyses evidenced associations between the microstructure of the right frontal lobe and cerebellum, and processing speed. This outcome suggests a relationship between tissue integrity and cognitive morbidity in SCD patients. PMID- 21325968 TI - Epidemiology and clinical long-term outcome of childhood aplastic anemia in Korea for 15 years: retrospective study of the Korean Society of Pediatric Hematology Oncology (KSPHO). AB - PURPOSE: Aplastic anemia (AA) is a rare hematologic disease characterized by pancytopenia and hypocellular marrow. The Korean Society of Pediatric Hematology Oncology investigated retrospectively the incidence, survival, and transfusion independency according to treatment strategies in AA. METHODS: All the questionnaires were sent to members for medical records. We collected and analyzed 702 available data. RESULTS: The male and female ratio was 1.2, and the median age at diagnosis was 9.3 years. The annual incidence of Korean children with AA was 5.16 per million per year. Constitutional anemia was diagnosed in 44 children. In acquired AA, causes were identified in 39 children. Severe AA (SAA) at initial diagnosis was more common than nonsevere AA. The overall survival was 47.8% with supportive care, 68.1% with immunosuppressive therapy (IST), and 81.8% with hematopoietic stem cell transplantation. In IST, response rate was 65.7%, and relapse rate after response was 54.4% within a median of 23.0 months. The factors with overall survival were severity of disease in supportive care, severity and response in IST, donor type, graft failure, and posttransplant events in hematopoietic stem cell transplantation. CONCLUSIONS: Long-term outcome in AA was dependent on treatment strategies. These Korean results may help research and prospective international clinical trials for childhood AA. PMID- 21325971 TI - Low depressive symptom and mental distress scores in adult long-term survivors of childhood acute lymphoblastic leukemia. AB - Childhood cancer survivors are thought to be at risk of psychological difficulties. We examined the prevalence of depressive symptoms and mental well being in adult long-term survivors of childhood acute lymphoblastic leukemia (ALL) at a mean age of 20 years after the cessation of therapy. Depressive symptoms were assessed with Beck Depression Inventory (BDI-21) and mental distress with General Health Questionnaire (GHQ-12) among 73 ALL survivors and 146 healthy controls. The ALL survivors obtained significantly lower BDI scores (P=0.046) compared with the controls, indicating less depressive symptoms among the ALL survivors. BDI scores indicated a significantly less frequent moderate or severe depression in the ALL survivors compared with the controls (P=0.039). BDI scores indicated no depression in 80.8% of the ALL survivors and 73.3% of the control group. The female ALL survivors obtained lower BDI scores than did the female controls (P=0.005). No difference was found in GHQ-12 scores between the survivors and the controls. Survivors of ALL reported fewer depressive symptoms and equal mental well-being compared with healthy controls. Our findings support the idea that childhood leukemia survivors' subjective experience of well-being is possibly affected by repressive adaptive style. PMID- 21325972 TI - BK-virus-associated hemorrhagic cystitis in children after hematopoietic stem cell transplantation. AB - BACKGROUND: BK-virus-induced hemorrhagic cystitis (BK-HC) is a serious complication in children undergoing hematopoietic stem cell transplantation (HSCT). Data of BK-HC in children undergoing HSCT are still limited. AIM OF THE STUDY: To describe the epidemiology, clinical course, and outcome of children with BK-HC after HSCT. MATERIALS AND METHODS: The medical records of all children aged 0 to 20 years, who underwent HSCT at Schneider Children's Medical Center between 2000 and 2008 and were diagnosed with BK-HC, were reviewed for demographic, clinical, and microbiological data. Patients in whom BK-HC had developed were compared with patients in whom it did not. RESULTS: Seventeen children (5.3%) acquired BK-HC at 10 to 180 days after HSCT (mean, 57 d); 9 had grade 3 to 4 disease. Bleeding lasted for 4 to 42 days (mean, 14). All patients but 1, who died of unrelated causes, recovered. Follow-up ranged from 6 to 91 months (mean, 35 months). Acute myeloid leukemia, use of cyclophosphamide in the conditioning regimen, unrelated donor, and older age were associated with the development of hemorrhagic cystitis (HC). CONCLUSIONS: The incidence of BK-HC in children after HSCT is relatively low. Its rate of successful resolution is very high. Further prospective studies are required to determine optimal therapy. PMID- 21325973 TI - Higher doses of CD34+ PBPC are associated with a rapid acquisition of full donor chimerism and lower risk of relapse after allogeneic transplantation in pediatric patients with hematological malignancies. AB - We conducted a retrospective study assessing the predictive value of early full donor chimerism status for relapse after allogeneic peripheral blood progenitor cell transplantation in 40 children aged between 1 and 16 years (median 8) with leukemia. The only variable that had a significant influence on chimerism status in either univariate or multivariate analysis was the number of CD34 cells infused. We found that the patients who were in complete donor chimerism by day +30 had a lower probability of relapse than those who were not (14% +/- 6% versus 54% +/- 15%; HR, 5.24; 95% confidence interval, 2.10-43.63; P = 0.003). Mixed chimerism by day +30, absence of chronic GvHD, and advanced disease at transplantation were significant risk factors for relapse in our patients. Children who presented early complete chimerism had a probability of developing chronic graft versus host disease significantly higher than patients with mixed chimerism (P = 0.04). Therefore, the analysis of chimerism kinetic in children undergoing peripheral blood progenitor cell transplantation would permit an early identification of patients at risk of relapse and patients with high risk of developing chronic graft versus host disease. PMID- 21325974 TI - Phase II trial of S-1 as second-line therapy in patients with advanced non-small cell lung cancer. AB - PURPOSE: Currently available agents for the treatment of advanced stage non-small cell lung cancer (NSCLC) have limited efficacy. S-1 is a novel formulation of oral fluoropyrimidine shown to be tolerable and active in patients with NSCLC in Japan. We conducted a multicenter phase II study in previously treated patients with NSCLC to evaluate the efficacy of single-agent S-1 in a predominantly non Asian population. PATIENTS AND METHODS: Patients with advanced NSCLC and previously treated with only one line of chemotherapy received oral S-1 at 30 mg/m every 12 hours for 14 consecutive days followed by a 7-day rest until meeting discontinuation criteria. The primary end point was to evaluate the overall response rate. RESULTS: Fifty-seven patients were accrued from 21 centers across the United States. Overall response rates and stable disease according to independent review were 7.1% and 48.2%, respectively, with a disease control rate of 55.3%. Progression-free survival was 2.9 months, median overall survival 7.3 months, and 1-year survival 31.6%. There were no significant differences in survival according to histologic subtype. The treatment was well tolerated, with the most common treatment-related side effects being nausea (54%) and diarrhea (49%). CONCLUSION: Single-agent S-1 is well tolerated and has activity comparable with the other agents approved for use in recurrent/relapsed NSCLC. PMID- 21325975 TI - How well does the new lung cancer staging system predict for local/regional recurrence after surgery?: A comparison of the TNM 6 and 7 systems. AB - INTRODUCTION: To evaluate how well the tumor, node, metastasis (TNM) 6 and TNM 7 staging systems predict rates of local/regional recurrence (LRR) after surgery alone for non-small cell lung cancer. METHODS: All patients who underwent surgery for non-small cell lung cancer at Duke between 1995 and 2005 were reviewed. Those undergoing sublobar resections, with positive margins or involvement of the chest wall, or those who received any chemotherapy or radiation therapy (RT) were excluded. Disease recurrence at the surgical margin, or within ipsilateral hilar and/or mediastinal lymph nodes, was considered as a LRR. Stage was assigned based on both TNM 6 and TNM 7. Rates of LRR were estimated using the Kaplan-Meier method. A Cox regression analysis evaluated the hazard ratio of LRR by stage within TNM 6 and TNM 7. RESULTS: A total of 709 patients were eligible for the analysis. Median follow-up was 32 months. For all patients, the 5-year actuarial risk of LRR was 23%. Conversion from TNM 6 to TNM 7 resulted in 21% stage migration (upstaging in 13%; downstaging in 8%). Five-year rates of LRR for stages IA, IB, IIA, IIB, and IIIA disease using TNM 6 were 16%, 26%, 43%, 35%, and 40%, respectively. Using TNM 7, corresponding rates were 16%, 23%, 37%, 39%, and 30%, respectively. The hazard ratios for LRR were statistically different for IA and IB in both TNM 6 and 7 but were also different for IB and IIA in TNM 7. CONCLUSIONS: LRR risk increases monotonically for stages IA to IIB in the new TNM 7 system. This information might be valuable when designing future studies of postoperative RT. PMID- 21325976 TI - A prospective radiological study of thin-section computed tomography to predict pathological noninvasiveness in peripheral clinical IA lung cancer (Japan Clinical Oncology Group 0201). AB - PURPOSE: Pathological noninvasiveness needs to be precisely predicted in preoperative radiological examinations of patients with early lung cancer for the application of limited surgery. PATIENTS AND METHODS: Patients with clinical T1N0M0 peripheral lung cancer were recruited. Radiological findings of the main tumor were evaluated as to ground-glass opacity with thin-section computed tomography. The primary end point was specificity, i.e., the proportion of patients with radiologically diagnosed invasive lung cancer to patients with pathologically diagnosed invasive lung cancer. The precision-based planned sample size was 450. We expected that the lower limit of the 95% confidence interval (CI) for specificity should be satisfied in >=97% of patients. RESULTS: We enrolled 811 patients from 31 institutions between December 2002 and May 2004. The primary end point was evaluated in 545 patients. The specificity and sensitivity for the diagnosis of pathologically diagnosed invasive cancer were 96.4% (161/167, 95% CI: 92.3-98.7%) and 30.4% (115/378, 95% CI: 25.8-35.3%), respectively, i.e., a negative result. Nevertheless, the specificity for lung adenocarcinoma <=2.0 cm with <=0.25 consolidation to the maximum tumor diameter was 98.7% (95% CI: 93.2-100.0%), and this criterion could be used to radiologically define early adenocarcinoma of the lung. CONCLUSIONS: Although our predetermined criterion for specificity was not statistically confirmed, radiological diagnosis of noninvasive lung cancer with a thin-section computed tomography scan corresponded well with pathological invasiveness. Radiological noninvasive peripheral lung adenocarcinoma could be defined as an adenocarcinoma <=2.0 cm with <=0.25 consolidation. PMID- 21325977 TI - Influence of cigarette smoking on histological subtypes of stage I lung adenocarcinoma. AB - BACKGROUND: The purpose of this study was to examine the association between cigarette smoking and histological subtypes of lung adenocarcinoma. METHODS: We reviewed a total of 320 consecutive patients with stage I adenocarcinoma who underwent complete resections with systematic node dissections from January 2004 to December 2006 at the National Cancer Center Hospital East. RESULTS: A statistically significant difference was observed in recurrence-free probabilities between never smokers and ever smokers (3-year recurrence-free probabilities of 95.6% and 88.6%, respectively, p = 0.034). Among adenocarcinoma histological subtypes, only a solid component was significantly more frequent in ever smokers than in never smokers (p < 0.001). Among patients with solid components, significantly more cases had lymphatic permeation (p = 0.007), intratumoral vascular invasion (p < 0.001), and visceral pleural invasion (p < 0.001). Multivariate analysis revealed that ever-smoking history was the only statistically significant independent clinical predictor for a solid component (p < 0.001). Among ever smokers, smoking extent in pack-years of patients with solid components was significantly greater than that of those without solid components (p < 0.001). With respect to predominant subtypes, smoking extent in pack-years of patients with predominantly solid adenocarcinomas was significantly greater than that of patients with predominantly bronchioloalveolar carcinoma, papillary, or acinar adenocarcinomas (all p < 0.001). CONCLUSION: A greater smoking extent was associated with the presence of adenocarcinoma solid components, which may have more aggressive biological features resulting in poorer outcomes. PMID- 21325978 TI - Soy isoflavones augment radiation effect by inhibiting APE1/Ref-1 DNA repair activity in non-small cell lung cancer. AB - INTRODUCTION: Soy isoflavones sensitize cancer cells to radiation both in vitro and in vivo. To improve the effect of radiotherapy for non-small cell lung cancer, we assessed the potential of using a complementary approach with soy isoflavones. METHODS: Human A549 non-small cell lung cancer cells were treated with soy isoflavones, radiation, or both and tested for cell growth. DNA double strand breaks (DSBs) were detected by immunostaining for gamma-H2AX foci. Expressions of gamma-H2AX, HIF-1alpha, and APE1/Ref-1 were assessed by Western blots. DNA-binding activities of HIF-1alpha and NF-kappaB transcription factors were analyzed by electrophoretic mobility shift assay. RESULTS: Soy isoflavones increased A549 cell killing induced by radiation. Multiple gamma-H2AX foci were detectable at 1 hour after radiation but decreased at 24 hours after radiation. Soy isoflavones also caused DNA DSBs, but gamma-H2AX foci increased over time. Soy isoflavones and radiation caused an increase in gamma-H2AX foci, which persisted at 24 hours, indicating both increased DNA damage and inhibition of repair. Soy isoflavones inhibited the radiation-induced activity of the DNA repair/redox enzyme APE1/Ref-1 and the transcription factors NF-kappaB and HIF 1alpha. E3330, which inhibits the redox activity of APE1/Ref-1, did not alter the repair of radiation-induced DSBs. Methoxyamine, which inhibits APE1/Ref-1 DNA repair activity, partly blocked the decrease in radiation-induced DSBs at 24 hours, suggesting partial mitigation of radiation-induced DNA repair akin to the effect of soy combined with radiation, in agreement with cytotoxic assays. CONCLUSIONS: Inhibition of APE1/Ref-1 DNA repair activity by soy could be involved in the mechanism by which soy alters DNA repair and leads to cell killing. PMID- 21325979 TI - Inhibition of JAK2 signaling by TG101209 enhances radiotherapy in lung cancer models. AB - INTRODUCTION: Persistent STAT3 activation contributes to lung carcinogenesis. Survivin, one of STAT3-regulated genes, is antiapoptotic and confers cancer radioresistance. METHODS: We tested whether TG101209, a small-molecule inhibitor of JAK2 (a STAT3-activating tyrosine kinase), affected survivin expression and sensitized lung cancer to radiation. We investigated whether inhibition of JAK2 signaling with TG101209 can be used to reduce survivin expression and enhance radiosensitivity of lung cancer cells in vitro and tumor growth delay in vivo. JAK2 downstream signaling, including PI3-K/Akt and Ras/MAPK/ERK pathways, was also explored. RESULTS: TG101209 inhibited STAT3 activation and survivin expression and sensitized HCC2429 (dose enhancement ratio = 1.34, p = 0.002) and H460 (dose enhancement ratio = 1.09, p = 0.006) cells to radiation in clonogenic assays. Radiation promoted phospho-Akt and phospho-ERK in H460 cells, while their levels were unchanged in HCC2429. After treatment with TG101209, phospho-ERK protein levels were reduced in both HCC2429 and H460 cells. HCC2429 cells transfected with KRAS-12V mutant were more resistant to radiation- and TG101209 induced apoptosis than wild-type control cells. In vivo, addition of TG101209 to radiation in lung xenografts produced a significant tumor growth delay (>10 days) compared with radiation alone and was well tolerated. Immunohistochemistry staining of tumor sections showed that TG101209 increased apoptosis and decreased cell proliferation and vascular density, suggesting that TG101209 also has antiangiogenic effects. CONCLUSIONS: TG101209 enhanced the effects of radiation in lung cancer in vitro and in vivo. This study suggests the potential utility of selecting lung cancer patients according to KRAS mutation status for future clinical trials testing combination of TG101209 and radiotherapy. PMID- 21325980 TI - The C-terminus of Hsp70-interacting protein promotes Met receptor degradation. AB - INTRODUCTION: The tyrosine kinase Met receptor regulates a complex array of cellular behaviors known collectively as invasive growth. Although essential for normal development and wound repair, this pathway is frequently deregulated in tumors to promote their growth, motility, and invasion. Accordingly, Met is overexpressed in a variety of human tumors, and this aberrant expression correlates with a poor patient prognosis. Previous studies have shown that Met receptor levels are governed in part by Cbl-mediated ubiquitination and degradation, and the uncoupling of Met from this pathway promotes its transforming activity. METHODS: Here, we describe a novel mechanism of Met degradation in Non Small Cell Lung Cancer Cells and HeLa cells using western blot, immunocytochemistry, immunoprecipitation assay, invasion assay, cell viability assay and in vivo tumor growth model. RESULTS: Met receptor interacted with the C-terminus of heat shock protein 70-interacting protein (CHIP), leading to proteasomal degradation of the receptor in vitro. In addition, CHIP overexpression destabilized endogenous Met receptor in lung cancer cells, whereas CHIP knockdown increased Met receptor expression, indicating an essential role for CHIP in the regulation of Met degradation. CHIP overexpression inhibited Met mediated lung cancer cell growth and invasion. Finally, we confirmed these results by tumor xenograft model. CONCLUSION: Based on these findings, we conclude that CHIP is a suppressor of Met function, serving to regulate cellular receptor levels by promoting Met receptor degradation. PMID- 21325981 TI - Selecting patients with extensive-stage small cell lung cancer for prophylactic cranial irradiation by predicting brain metastases. AB - INTRODUCTION: Prophylactic cranial irradiation has recently been reported to improve overall survival and quality of life in patients with extensive-stage small cell lung cancer. The generalizability of this treatment to an unselected population with extensive-stage small cell lung cancer is not clear, as the incidence of brain metastases is variably reported in the literature, ranging from 25 to 60%. METHODS: We completed a retrospective review of 130 consecutive patients with extensive-stage small cell lung cancer seen in consultation between January 1, 2004, and December 31, 2006. Our primary objective was to determine the incidence of brain metastases and to establish significant factors that were predictive of developing brain metastases, using both univariate and multivariate regression analysis. RESULTS: The median patient age was 68.0 years, and the median survival time was 25.6 weeks. The majority of patients (84.9%) received systemic therapy. Twenty-nine patients (22.3%) presented with brain metastases while an additional 21 patients (20.8%) developed brain metastases over their lifetime. Response to chemotherapy was a predictor of brain metastases using univariate (odds ratio [OR] 5.28, p = 0.03) and multivariate analysis (OR 5.49, p = 0.04). Weight loss more than 5 kg predicted for freedom from the development of brain metastases using univariate (OR 0.20, p = 0.01) and multivariate analysis (OR 0.69, p = 0.03). CONCLUSIONS: 20.8% of patients developed brain metastases after their initial presentation. This incidence is lower than that previously reported and may suggest that prophylactic cranial irradiation should be targeted to patients at highest risk. Response to chemotherapy and less than 5 kg baseline weight loss were independent predictors of future brain metastases. PMID- 21325982 TI - Palliation and pleurodesis in malignant pleural effusion: the role for tunneled pleural catheters. AB - INTRODUCTION: Despite increasing use of tunneled pleural catheters (TPCs), their efficacy as a definitive procedure for achieving palliation or spontaneous pleurodesis (SP) in the management of malignant pleural effusion (MPE) remains unclear. In the largest TPC series to date, we evaluate the efficacy for palliation and review the rate and predictors of SP. METHODS: Retrospective review of 418 TPCs (355 patients) over 2 years (September 2007-September 2009) was performed. Palliation was deemed successful when the patient did not require any other subsequent effusion-directed drainage procedure. SP was defined as satisfying the following criteria: (a) TPC removal without need for further effusion-directed intervention during the patient's lifespan and (b) no evidence of effusion reaccumulation by clinical and radiographic evidence at 1-month postremoval follow-up. RESULTS: After TPC placement, no subsequent effusion directed procedure was required for 380 of 418 (91%). SP was achieved after only 26% of TPCs (110 of 418), in which the median time to catheter removal was 44 days. Neither demographics nor primary tumor type predicted SP. In patients selected for TPC placement in the operating room, SP occurred in 36% (39 of 107), with 45% in loculated MPE (13 of 29, p = 0.014). Complications occurred after 20 TPCs (4.8%), with none occurring after bedside placement. CONCLUSION: TPC placement is safe and provides durable palliation, most often obviating the need for subsequent procedures in MPE patients. TPC, however, remains suboptimal at achieving pleurodesis. PMID- 21325983 TI - Evaluation of the three-dimensional deformities in scoliosis surgery with computed tomography: efficacy and relationship with clinical outcomes. AB - STUDY DESIGN: Prospective radiological and clinical study with scoliosis patients. OBJECTIVE: To determine the pre- and postoperative differences in the three-dimensional (3D) parameters and relationships with the outcome in scoliosis surgery. SUMMARY OF BACKGROUND DATA: Despite a proven important role of the 3D deformities in scoliosis, it is warranted to confirm the efficacy of these measurements, which carry a cost burden and radiation hazard. METHODS: Fifty adolescent idiopathic scoliosis patients who underwent correction surgery were enrolled in this study. Pre- and postoperative whole spine radiographs and computed tomography were performed. The vertebral rotation (VR), rib hump index (RH), sternal shift (SS) on computed tomography were measured at the level of the apex in each patient. In addition, the patients described the SRS 30 (scoliosis research society 30) and ODI (owestry disability index) score. And, the differences in the parameter and the relationships between the radiological and clinical outcomes were analyzed. RESULTS: There was significant decrease in the coronal curvature, RH, and SS after surgery (P < 0.0001). In addition, the VR decreased postoperatively but that was not significant (P = 0.236). There were significant relationships between the parameters in the coronal curvature, VR, RH, and SS, pre- and postoperatively (P < 0.05). However, regarding the pre- and postoperative differences, only the changes in the SS were related to changes in the coronal curvature (P = 0.006). In addition, there were significant relationships between the parameters and outcomes. The changes in ODI were related to changes in the coronal curvature, VR, RH, and SS (P < 0.0001, P = 0.039, P < 0.0001, P = 0.019, respectively). However, the changes in the SRS was only related to the changes in SS (P < 0.0001). CONCLUSION: There were significant correlations between the VR, RH, and SS with the coronal curvature, pre- and postoperatively. In addition, there were significant correlations between the 3D deformities and outcomes. Computed tomography based measurements of 3D deformities can provide useful information in planning, and predicting the outcome of corrective surgery. PMID- 21325984 TI - Agmatine-reduced collagen scar area accompanied with surface righting reflex recovery after complete transection spinal cord injury. AB - STUDY DESIGN: Intended to investigate whether agmatine treatment reduces collagen scar area in mice subjected to spinal cord injury (SCI). OBJECTIVE: The purpose of the present study is to demonstrate the protective effect of agmatine on complete transection SCI mice. SUMMARY OF BACK GROUND DATA: The deposition of collagen that occurs at the lesion site, during the SCI, was well known. Agmatine has been reported to exert neuroprotective effect in various stress models including central nervous system injuries. In the present investigation, we hypothesized that agmatine treatment could rescue the mice subjected to SCI. METHODS: Complete SCI was made at the T9 level. Agmatine was dissolved in normal saline (100 mg/kg, Sigma, St. Louis, MO) and given intraperitoneally 5 minutes after complete transection daily for 4 weeks (agmatine-treated mice, n = 30). Controls received normal saline in the same manner (experimental control, n = 30). Surface righting reflex test, expression of bone morphogenetic protein-7 (BMP-7), TGFbeta-2 (transforming growth factor beta-2), and collagen scar area were measured and the results were compared with Mann-Whitney U test using SAS. RESULTS: Agmatine treatment improved the surface righting reflex of mice at 4 weeks after SCI (P = 0.030). The collagen scar, physical barrier to axon regeneration, was noticeably diminished by agmatine treatment at 4 weeks after SCI (P = 0.001). The expression of BMP-7, which is considered both neuroprotective and neuroregenerative, was increased in agmatine treatment group compared with experimental control group in the early stages after SCI (P = 0.015 at 1 day after SCI; P = 0.010 at 3 days; P = 0.035 at 1 week; P = 0.826 at 2 weeks). The expression of TGFbeta-2 correlated with the deposition of the collagen matrix at the lesion site was decreased with agmatine treatment at 1 and 2 weeks after SCI (P = 0.001 at 1 week; P = 0.002 at 2 weeks). Survival rate was found to be higher in agmatine treatment group than in the experimental control group for 4 weeks after SCI (P = 0.076). CONCLUSION: These results suggest that agmatine treatment could support neuroregeneration by reducing the collagen scar area through decreasing the expression of TGFbeta-2 and increasing the expression of BMP-7 after SCI. Especially, the improved surface righting reflex of agmatine treated group proposes that agmatine treatment have the potency to facilitate functional recovery after SCI. However, the drug (agmatine) warrants further investigation in higher mammals. PMID- 21325985 TI - A comparison of three types of postoperative pain control after posterior lumbar spinal surgery. AB - STUDY DESIGN: Retrospective, nonrandomized, comparative study. OBJECTIVE: This study compared the early postoperative analgesic effects and the postoperative nausea and vomiting (PONV) associated with three methods of pain control after posterior lumbar spinal surgery. SUMMARY OF BACKGROUND DATA: The use of opioids for postoperative pain control is common after spinal surgery; however, PONV is the most frequently encountered side effect, and it is yet to be overcome. The effectiveness of the use of an absorbable low-dose morphine-soaked microfibrillar collagen hemostatic sponge placed on the surface of the dural sac (epidural MMCHS) was compared to patient-controlled analgesia (PCA) and intermittent intramuscular bolus injection of meperidine for postoperative pain control after spine surgery. METHODS: One hundred sixty-five patients who underwent short segment posterior lumbar spinal decompression and fusion surgery between January 2007 and July 2007 in the orthopedic department of a medical center were enrolled. For postoperative pain control, 40 patients received epidural MMCHS, 48 patients received PCA, and 77 patients received meperidine injection. Patient ratings of pain intensity (visual analog scale score from 0 [no pain] to 10 [most severe pain]), nausea (from 0 [no nausea] to 5 [severe nausea]), and vomiting (from 0 [no vomiting] to 5 [severe vomiting]) were recorded at 4 hours postoperation and on postoperative days 1, 2, and 3. RESULTS: The analgesic effect was enhanced significantly in both epidural MMCHS group and the PCA group as compared with the meperidine group on postoperative days 1 and 2 (P < 0.05). On postoperative days 1, 2, and 3, PONV was more severe in the PCA group than in the other two groups (P < 0.05). The side effects of epidural MMCHS were nausea (25%), pruritus (12.5%), vomiting (5%), and hypotension (2.5%). CONCLUSION: A single low-dose epidural MMCHS is effective for postoperative pain control and minimizes the occurrence of PONV after posterior lumbar spinal surgery. PMID- 21325986 TI - Biomechanical evaluation of a novel fenestrated pedicle screw augmented with bone cement in osteoporotic spines. AB - STUDY DESIGN: Comparative biomechanical study was conducted in osteoporotic human cadaveric spines. OBJECTIVE: Determine the influence of the volume of polymethyl methacrylate injected through a fenestrated pedicle screw on the pullout strength and on the ability to safely remove the implant. SUMMARY OF BACKGROUND DATA: Pedicle screw fixation in the osteoporotic spine can be improved by the addition of bone cement. Various injection techniques have been used. While improvement has been shown for the pullout strength, the optimal volume of cement to inject has not been previously studied. METHODS: Seven osteoporotic spines were instrumented with a standard and a fenestrated pedicle screw augmented with polymethyl methacrylate at each level (T7-L5). Three volumes of bone cement were randomly injected and stratified to the thoracic (0.5 cc, 1.0 cc, and 1.5 cc) and lumbar spine (1.5 cc, 2.0 cc, and 2.5 cc). Axial pullout strength and removal torque of the pedicle screws were quantified. RESULTS: The pullout strength of the fenestrated screw was normalized with respect to its contralateral control. Student paired t tests were conducted and a statistically significant increase was noted for 1.0 cc (186 +/- 45%) and 1.5 cc (158 +/- 46%) in the thoracic spine and for 1.5 cc (264 +/- 193%), 2.0 cc (221 +/- 93%), and 2.5 cc (198 +/- 42%) in the lumbar spine. There was no significant difference with higher volumes of cement. The median removal torque was 0.34 Nm for the standard and 1.83 Nm for the augmented screws. When the augmented implants were removed, the bone cement sheared completely off at the fenestrations in 15 of the 17 cases. CONCLUSION: Significant increases in pullout strength can be accomplished by injecting a limited quantity of bone cement through a fenestrated screw while minimizing the risks associated with higher volume. The majority of implants were removed without damaging the vertebra as the bone cement sheared off at the fenestrations. PMID- 21325987 TI - Low-intensity pulsed ultrasound enhances posterior spinal fusion implanted with mesenchymal stem cells-calcium phosphate composite without bone grafting. AB - STUDY DESIGN: Experimental study on the effect of low-intensity pulsed ultrasound (LIPUS) on rabbit spinal fusion with mesenchymal stem cell (MSC)-derived osteogenic cells and bioceramic composite. OBJECTIVE: To investigate the efficacy of LIPUS in enhancing fusion rate and bone formation with porous tricalcium phosphate (TCP) bioceramic scaffold impregnated with MSCs without any bone grafts. SUMMARY OF BACKGROUND DATA: The goal of spinal fusion in the corrective spinal surgery for spinal deformities is to achieve solid bony fusion between selected vertebral segments. Previous studies with bone morphogenetic proteins and genetically manipulated materials revealed significant difficulties in actual clinical application. Alternative such as LIPUS has been shown to be effective in enhancing healing of fracture and nonunion clinically. Its potential for enhancing spinal fusion warrants further in-depth study. METHODS: Posterolateral intertransverse processes spinal fusion at the L5 and L6 levels were evaluated in New Zealand white rabbit model. The animals were divided into three groups with (A) TCP alone, (B) TCP with differentiated MSCs, and (C) TCP with differentiated MSCs and LIPUS treatment. At week 7 postoperation, manual palpation, peripheral quantitative computed tomography, and histomorphometric assessments were performed. RESULTS: At week 7 postoperation, a statistically significant increase in clinical fusion by manual palpation was observed in group C animals treated with LIPUS (86%) in comparing with groups A (0%) and B (14%) without LIPUS. With peripheral quantitative computed tomographic analysis, the bone volume of group C fusion mass was significantly larger than the other two groups. Group C fusion also had better osteointegration length between host bone and implanted composite and more new bone formed in the TCP implants. Importantly, all the group C animals had osteochondral bridging--early stage of bony fusion histologically. Endochondral ossification was observed at the junction between the cartilaginous and osseous tissues at the intertransverse processes area. Quantitative analysis showed that the fusion mass in group C had significantly smaller gap and larger area of cartilaginous tissue between the transverse processes. CONCLUSION: The present study showed that the combination of synthetic biomaterials, autologous differentiated MSCs, and LIPUS could promote clinical fusion in rabbit posterior spinal fusion model. The mechanism was likely to be mediated through better osteointegration between the host bone and implanted materials and enhanced endochondral ossification at the fusion site. PMID- 21325988 TI - Dysphagia following cervical spine surgery with anterior instrumentation: evidence from fluoroscopic swallow studies. AB - STUDY DESIGN: Retrospective review. OBJECTIVE: The purpose of this study was to evaluate alterations in objective swallowing parameters in patients reporting dysphagia after anterior cervical-spine surgery. SUMMARY OF BACKGROUND DATA: Dysphagia is increasingly recognized as a potential complication of anterior surgical approaches to the cervical spine. Retraction pressure on the esophagus that alters blood flow, edema of the pharynx, and laryngeal nerve injury are among factors implicated. There has been little investigation of the biomechanics of swallowing in a large cohort of patients reporting postoperative dysphagia. METHODS: The fluoroscopic swallow studies of all persons reporting dysphagia after anterior c-spine surgery between January 1, 2000, and December 31, 2008, were retrospectively reviewed. The dysphagic cohort was divided into early (<2 months postsurgery) and late (>2 months) groups. Aspiration and completeness of epiglottic inversion were noted. Objective measures of pharyngeal wall thickness, upper esophageal sphincter opening, hyoid displacement, pharyngeal constriction, and pharyngeal transit time were abstracted and compared to the same parameters in age and sex-matched normal control subjects. Analysis of variance was used for statistical comparison of objective measures across groups. RESULTS: Sixty-seven patients were identified. Significant differences were identified between control subjects and both patient groups, as well as between the 2 patient groups, for most objective measures considered. Instances of aspiration were identified in 50% of patients in the early postoperative group, reduced to 18% in the later group. Significantly increased pharyngeal wall thickness and poor epiglottic inversion were characteristic of both c-spine groups. CONCLUSION: Significant alterations in swallowing mechanics can accompany c-spine surgery with anterior plating. A number of these changes improve over time, leaving patients with relatively minor impairment; however, some appear to be long-lasting. Education and dysphagia therapy can be useful treatment adjuncts. PMID- 21325989 TI - Scoliosis research society morbidity and mortality of adult scoliosis surgery. AB - STUDY DESIGN: A retrospective review. OBJECTIVE: To obtain an assessment of complication incidence using the largest known database of adult scoliosis and to determine whether the rate of complication depends on various clinical parameters. SUMMARY OF BACKGROUND DATA: The Scoliosis Research Society (SRS) morbidity and mortality database has previously been used to assess complication rates in adolescents undergoing scoliosis correction. To better understand complications in adults, degenerative and idiopathic adult scoliosis (AS) cases were studied. METHODS: The SRS morbidity and mortality database was queried to identify cases of AS from 2004 to 2007. Complications were identified and analyzed on the basis of patient type of scoliosis (degenerative vs. adult idiopathic), age, use of osteotomy, revision surgery status, and surgical approach. Age was stratified into less than or equal to 60 and greater than 60. Surgical approach was stratified into anterior only, posterior only, and combined anterior/posterior. RESULTS: A total of 4980 cases of AS were submitted from 2004 to 2007. There were 521 patients with complications (10.5%), and a total of 669 complications (13.4%). The most common complications were dural tear 142 (2.9%), superficial wound infection 46 (0.9%), deep wound infection 73 (1.5%), implant complication 80 (1.6%), acute neurological deficits 49 (1.0%), delayed neurological deficits 41 (0.5%), epidural hematoma 12 (0.2%), wound hematoma 22 (0.4%), pulmonary embolus 12 (0.2%), and deep venous thrombosis 9 (0.2%). There were 17 deaths (0.3%). There were 2555 patients with degenerative and 2425 patients with adult idiopathic scoliosis. Complication rates in these two groups were not significantly different (11.0% and 9.9%, respectively, P = 0.20). Age was not associated with complication rate (P = 0.32). Significantly higher complication rates were identified in osteotomies, revision surgery, and/or combined anterior-posterior surgery (P = 0.0006, 0.006, and 0.03, respectively). CONCLUSIONS: The overall complication rate for AS treatment is 13.4%. Complication rate is significantly higher when osteotomies, revision procedures, and combined anterior/posterior approaches are used. Complication rate is not influenced by scoliosis type or age. PMID- 21325990 TI - Blood serum antibody analysis and long-term follow-up of patients treated with recombinant human bone morphogenetic protein-2 in the lumbar spine. AB - STUDY DESIGN: Prospective, longitudinal cohort study. OBJECTIVE: To examine the incidence of bone morphogenetic protein (BMP)-2 antibody formation in lumbar spine applications and to determine the clinical significance of an antibody response. SUMMARY OF BACKGROUND DATA: Immune responses can affect the safety and efficacy profile of recombinant proteins. Type, incidence, and time course of antibody formation were evaluated in clinical studies investigating recombinant human bone morphogenetic protein (rhBMP)-2 in spinal arthrodesis. METHODS: Analysis of antibody formation to BMP-2, bovine collagen, and human collagen was performed after three prospective clinical studies investigating rhBMP-2 in single-level lumbar spinal arthrodesis. Two studies investigated rhBMP-2 applied to an absorbable collagen sponge at 1.5 mg/cm3 in lumbar interbody fusion (n=449); one study investigated rhBMP-2 applied to a ceramic and collagen compression-resistant matrix at 2.0 mg/cm3 in instrumented posterolateral fusion (n=239). Control patients received iliac crest bone graft (n=360). Two validated enzyme-linked immunosorbent assays were used to test for BMP-2 antibodies. Neutralizing antibodies were assessed using a cell bioassay. The incidence of antibodies to bovine and human collagen was determined. Radiographic and clinical outcome data were assessed to determine whether antibodies were correlated to patient outcomes. RESULTS: BMP-2 antibody rates ranged from 0.8% to 6.4% in rhBMP 2 patients and from 0% to 2.3% in control patients. Formation of BMP-2 antibodies peaked within the first 3 months and returned toward baseline values by 12 months. No neutralizing antibodies were detected. Bovine collagen antibody rates ranged from 12.7% to 18.8% in the rhBMP-2 patients and from 12.9% to 21.2% in the control patients. No antibodies to human collagen were detected. Adverse event rates were similar in antibody-positive and antibody-negative patients. BMP-2 antibodies did not affect bridging bone rates. CONCLUSION: Formation of anti-BMP 2 antibodies was low and transient. No neutralizing antibodies were observed. Formation of antibodies did not affect fusion success or appear to have clinical sequelae. PMID- 21325991 TI - Necrotizing fasciitis in patients with spinal cord injury: an analysis of 25 patients. AB - STUDY DESIGN: Retrospective chart review. OBJECTIVE: The aim of this study was to analyze the correlation between necrotizing fasciitis (NF) and pressure ulcers, as well as the mortality, and complication rate, in patients with spinal cord injury (SCI). SUMMARY OF BACKGROUND DATA: Pressure ulcers represent a challenging problem, especially in immobilized patients. Necrotizing soft tissue infections arising from decubitus ulcers in patients with SCIs have been reported. METHODS: Twenty-five SCI patients with NF treated between April 2000 and December 2009 were included in the study. All patients were analyzed in regard to the number of surgical debridements, length of hospital stay, and laboratory, microbiological, and histological assessments. Information about age, sex, preexisting conditions, anatomical localization, and etiology of the NF were acquired from the patients' medical records. RESULTS: There were 19 paraplegic and 6 tetraplegic patients with a median age of 47 years. In 18 cases, NF developed in the setting of pressure sores. Grade 4 pressure sores were identified in 15 cases and grade 3 pressure sores in 3 cases. The incidence of developing NF is significantly higher in patients with fourth-grade pressure sores than in those with a lower-grade lesion (odds ratio = 2.91; 95% confidence interval, 1.29-6.56). The mean laboratory risk indicator for NF score was 6.6 upon admission. The most common bacteria were streptococci. During the hospital stay, six patients developed sepsis and two died because of septic multiorgan failure. CONCLUSION: Patients with grade 3 and 4 pressure sores had a significantly increased risk of developing NF. The current investigators recommend that close clinical and laboratory monitoring of all patients with grade 3 or 4 pressure sores is appropriate so that any early clinical signs of NF can be recognized and evaluated for early and aggressive treatment. PMID- 21325992 TI - Biological and biomechanical effects of fibrin injection into porcine intervertebral discs. AB - STUDY DESIGN: Surgically denucleated porcine intervertebral discs (IVD) were injected with BIOSTAT BIOLOGX Fibrin Sealant (FS), and the in vivo effects were assessed over time by histological, biochemical, and mechanical criteria. OBJECTIVE: The objectives were to test whether the intradiscal injection of FS stimulates disc healing. SUMMARY OF BACKGROUND DATA: Disc avascularity prevents the deposition of a provisional fibrin scaffold that typically facilitates soft tissue repair. Poor disc wound healing leads to disc damage accumulation and chronic inflammation characterized by overproduction of proinflammatory cytokines and proteolytic enzymes. METHODS: Four lumbar IVDs from each of 31 Yucatan minipigs were randomized to untreated controls; degenerative injury (nucleotomy); and nucleotomy plus FS injection. Animals were killed at 1, 2, 3, 6, and 12 weeks postsurgery. IVDs were harvested to quantify (1) architecture using morphological and histological grading; (2) proteoglycan composition using DMMB assay; (3) cytokine content using ELISA; and (4) mechanical properties using quantitative pressure/volume testing. RESULTS: There was progressive invasion of annular tissue into the nucleus of nucleotomy discs and concomitant reduction in proteoglycan content. By contrast, FS supplementation inhibited nuclear fibrosis and facilitated proteoglycan content recovery over time. FS discs synthesized significantly less TNF-alpha than degenerate discs (66% vs. 226%, P < 0.05) and had upregulation of IL-4 (310% vs. 166%) and TGF-beta (400% vs. 117%) at 2 to 3 weeks posttreatment. At the third week postsurgery, the denucleated discs were less stiff than controls (pressure modulus 779.9 psi vs. 2754.8 psi; P < 0.05) and failed at lower pressures (250.5 psi vs. 492.5 psi; P < 0.05). The stiffness and leakage pressure of the FS-treated discs recovered to control values after 6 and 12 weeks, respectively. CONCLUSION: FS facilitated structural, compositional, and mechanical repair of the surgically damaged IVD. These FS-derived benefits are likely due to its conductive scaffold properties and metabolically active constituents such as thrombin, factor XIII, and aprotinin acetate. PMID- 21325993 TI - No association of kidney graft loss with human leukocyte antigen antibodies detected exclusively by sensitive Luminex single-antigen testing: a Collaborative Transplant Study report. AB - BACKGROUND: It is unclear whether kidney transplant recipients with preformed donor-specific human leukocyte antigen (HLA) antibodies (DSA) detectable only in the highly sensitive Luminex single-antigen (LSA) assay are at an increased risk of graft failure. METHODS: We studied 3148 patients who received a deceased donor kidney graft between 1996 and 2008 and were enrolled in the prospective serum project of the Collaborative Transplant Study. There were 118 patients with graft loss during the first 3 years after transplantation on whom recipient and donor DNA was available for complete HLA typing. We compared the incidence of LSA detected DSA in these patients with graft failure and matched controls with functioning grafts. All patients were found negative in the less-sensitive complement-dependent lymphocytotoxicity and enzyme-linked immunosorbent assays. RESULTS: When mean fluorescence intensity (MFI) of greater than or equal to 1000 was used as a cutoff for Luminex positivity, 118 patients with graft loss did not show a higher incidence of DSA against HLA-A, -B, -C, -DRB1/3/4/5, -DQA1, -DQB1, DPA1, or -DPB1 antigens than 118 matched controls without graft loss (for all loci P not significant). The incidence of strong DSA (MFI >=2000 or MFI >=3000) detected only by LSA was low (for all loci between 0% and 5%) and did not identify unacceptable antigens that were relevant for graft loss within the first 3 years after transplantation. CONCLUSION: We conclude that, given currently practiced crossmatch procedures and immunosuppressive regimens, exclusion of donor organs carrying "unacceptable" HLA based exclusively on sensitive LSA antibody testing is not justified. PMID- 21325994 TI - The importance of tissue factor expression by porcine NICC in triggering IBMIR in the xenograft setting. AB - BACKGROUND: In islet transplantation, tissue factor (TF) has been reported to be involved in triggering the instant blood-mediated inflammatory reaction (IBMIR), which causes early massive loss of islets transplanted intraportally. TF is synthesized and secreted by several cell sources including islets and inflammatory cells such as neutrophils, monocytes, and platelets. In this study, we investigated whether xenografts-mediated IBMIR could be inhibited by selectively inhibiting TF production by islets using small interfering RNA (siRNA)-mediated TF gene knockdown. METHODS: Porcine neonatal islet cell clusters (NICC) were transfected with siRNA specific for TF or a nonspecific siRNA. TF gene and protein expression were analyzed by real-time polymerase chain reaction and fluorescence-activated cell sorting, respectively. The effect of TF knockdown on IBMIR was evaluated using an in vitro tubing loop model of human blood-NICC interactions. RESULTS: TF siRNA transfection of NICC resulted in reduced TF gene and protein expression. TF siRNA transfected NICC showed a significant reduction in the formation of blood clots, platelet activation, thrombin generation, and complement activation after exposure to human ABO compatible blood in vitro. In addition, there was reduced neutrophil infiltration within blood clots containing TF siRNA transfected NICC. CONCLUSIONS: TF expression on porcine NICC is an important initiator of IBMIR in islet xenotransplantation. This study identifies porcine TF as a potential target for inhibiting this response. PMID- 21325995 TI - Tenofovir therapy in hepatitis B virus-positive solid-organ transplant recipients. AB - BACKGROUND: Tenofovir therapy has been found to be efficient in treating hepatitis B virus (HBV) in nontransplant patients. However, in the setting of solid-organ transplantation, the efficacy of tenofovir has not been tested. The aim of this pilot study was to assess the clinical and biologic response and tolerance to tenofovir therapy in HBV-positive organ transplant recipients. METHODS: Seven patients, three kidney, three liver, and one cardiac transplant recipients, with chronic HBV infection were partial responders to adefovir (n=7), lamivudine (n=7), or entecavir (n=5) therapy. Consequently, they were placed on tenofovir therapy (245 mg daily, which was adapted to renal function) alone (n=4) or in combination with lamivudine (n=3). Tenofovir therapy was assessed at 1, 3, 6, and 12 months postinitiation or at the last follow-up. RESULTS: HBV DNA viral load (4.16 [2.03-5.56] log10 copies/mL at baseline) became significantly decreased to 3.15 (1.08-5.17), 2.88 (1.3-4.3), 3.53 (1.3-5.75), 3.33 (1.3-7.57), and 2.31 (1.3-4.81) log copies/mL at 1, 3, 6, and 12 months posttenofovir initiation and at last follow-up, respectively (P=0.02). Three patients were HBV DNA negative at the last follow-up. Liver enzyme levels did not change significantly throughout the follow-up period. Clinical and biologic tolerance was excellent. CONCLUSIONS: Even though HBV DNA clearance was not achieved in all patients, the results of this pilot study are encouraging and demonstrate that tenofovir therapy is safe and efficacious in treating HBV-positive organ transplant patients. However, a larger trial is needed to confirm these preliminary results. PMID- 21325996 TI - Age, exclusion criteria, and generalizability of randomized trials enrolling kidney transplant recipients. AB - BACKGROUND: The proportion of elderly (>=65 years) kidney transplant recipients (KTRs) doubled in the United States from 1999 to 2008. Given higher mortality, more medication side effects, and less rejection among elderly KTRs, optimal care of these patients may require tailored decisions about transplant therapeutics. It is unknown whether participants in transplant clinical trials-which generate the best evidence for patient care-are representative of the aging population of KTRs. METHODS: Using PubMed, we identified randomized trials involving KTRs from 1999 to 2008 and determined age-exclusion criteria and the mean age of participants. The mean age of these trial participants was compared with the mean age of the overall population of incident KTRs in the United States. RESULTS: The 87,222 participants in 573 trials were significantly younger than the US KTR population (P<0.05). This age discrepancy worsened over the study period (during the years 2006 to 2008, the mean age was 45 years for trial participants versus 50 years for US KTRs, P<0.05). Thirty percent of trials had an exclusion criterion based on older age, and 16% excluded recipients aged 65 years or older. In multivariable regression, immunosuppression trials (P<0.01) and trials in higher impact journals (P=0.03) were more likely to exclude the elderly, but there was no significant difference in exclusion of elderly patients based on a trial's geographic location. CONCLUSIONS: Trial participants are younger than KTRs in the United States and many trials exclude older patients. Transplant investigators should make strong efforts to recruit patients across the total age spectrum. PMID- 21325997 TI - Migration of cells from the yolk sac to hematopoietic tissues after in utero transplantation of early and mid gestation canine fetuses. AB - BACKGROUND: In utero hematopoietic cell transplantation offers a means of early intervention for the treatment of diseases before birth. Delivery of cells to the yolk sac is a minimally invasive approach that results in low levels of chimerism. However, there is little information on the optimal doses, timing of delivery, and migration of transplanted cells from the yolk sac into the fetus. METHODS: Varying cell doses of mesenchymal stromal cells or bone marrow mononuclear cells labeled with fluorescent supraparamagnetic iron oxide nanoparticles and a fluorescent intracellular dye, 5- and 6-([(4 chloromethyl)benzoyl]-amino) tetramethylrhodamine, were transplanted under ultrasound guidance to the yolk sacs of day 25 or day 35 canine fetuses. Ex vivo whole body fluorescence imaging and microscopy of tissue sections were correlated with the presence of iron oxide in injected and control fetuses. RESULTS: Day 25 and day 35 recipients showed similar survival rates after injection of cells into yolk sacs, although increased fetal morality was associated with cell doses greater than 10 cells/kg to day 25 fetuses. The fluorescence and iron oxide signals were predominantly localized to the abdominal regions, with no fluorescence visible in yolk sacs. Microscopy of tissues revealed colocalization of fluorophore with iron oxide in donor cells detected in the fetal livers and bone marrow of recipients 7 and 17 days after receiving mesenchymal stromal cells or bone marrow mononuclear cells. CONCLUSIONS: These studies demonstrated that cells injected into the yolk sacs of early gestation canine fetuses migrate to recipient hematopoietic tissues. Thus, yolk sac injection offers a safe and effective approach for engraftment of cells to fetal hematopoietic tissues. PMID- 21325998 TI - Integrated strategies for the successful management of breakthrough cancer pain. AB - PURPOSE OF REVIEW: To highlight the significant impact breakthrough cancer pain (BTcP) can have on patients' quality of life and to discuss potential management strategies that could improve pain control in clinical practice as well as effective strategies to manage risk. RECENT FINDINGS: BTcP can place a significant physical, psychological and economic burden on patients. Despite advances in the management of cancer pain, through the application of modern, evidence-based, multimodality management and the availability of new treatment options, recent European surveys have indicated that the diagnosis and treatment of BTcP is still suboptimal. A general lack of consensus on its definition alongside poor recognition and inadequate assessment may often lead to undertreatment and poor patient outcomes. Fentanyl preparations that have been developed and licensed specifically for the treatment of BTcP have been shown to work more rapidly and be preferred by patients to traditional rescue medication, such as normal-release oral opioids. SUMMARY: Optimizing the management of BTcP requires an integrated approach, including independent assessment and better use of available treatments while taking into consideration risk management strategies, which will ultimately lead to improved outcomes and quality of life for patients. PMID- 21325999 TI - Transdermal opioids for cancer pain. AB - PURPOSE OF REVIEW: Cancer patients with moderate-to-severe pain require opioids for analgesia. Whereas early guidelines recommend oral morphine as the 'drug of choice', newer synthetic opioids can be given by a reliable and effective nonoral transdermal route. We examine the mode of action of transdermal patches and we review the evidence on two drugs, which are currently available in this formulation - buprenorphine and fentanyl - covering physicochemical characteristics and pharmacokinetics of the patches, clinical efficacy data and adverse effects. RECENT FINDINGS: Both buprenorphine and fentanyl possess ideal characteristics for transdermal delivery, being small molecules with high lipophilicity. Studies of buprenorphine patches show benefits but there is poor randomized controlled trial evidence comparing them with oral opioids. Fentanyl patches have been used for longer and have a larger body of evidence supporting their use, with data to suggest improved pain relief and reduced opioid side effects compared with sustained release oral morphine. Patients who have used both oral morphine and transdermal fentanyl express a preference for the patch drug. SUMMARY: Transdermal buprenorphine and fentanyl are now established for moderate-to-severe cancer pain. There is still a need for further comparative studies with other opioids, especially for buprenorphine. PMID- 21326000 TI - Manipulating the consequential effect: an alternative approach to reducing pelvic radiation disease other than dose reduction. PMID- 21326001 TI - Nutritional support for malnourished patients with cancer. AB - PURPOSE OF REVIEW: Cancer and its treatments frequently have a negative impact on the weight and nutritional status of patients. Weight loss is associated with reduced survival and poorer outcomes of treatment but is not well characterized and frequently confused with cachexia, which may complicate the interpretation of studies of nutritional support. The aims of this review were to examine the impact of cancer on nutritional status and to review the role of simple oral nutritional interventions and novel agents. RECENT FINDINGS: The terms weight loss, malnutrition and cachexia refer to different entities and new definitions have recently been proposed that take account of the role of the underlying inflammatory processes. Oral nutritional interventions are widely recommended for malnourished cancer patients, but the evidence for their benefits to clinical, nutritional and patient-centred outcomes is limited. Meta-analysis has highlighted the variability in response to simple nutritional interventions of different cohorts of cancer patients and suggested that improvements in nutritional endpoints and aspects of quality of life may be achieved in some patients. Recent research has largely focused on treatments aiming to modulate the inflammatory processes associated with cachexia, but to date has not identified a single treatment with clear efficacy. SUMMARY: Studies characterizing the potential for nutritional support in combination with anti inflammatory agents in defined patient groups are defined to advance the evidence base in this area. PMID- 21326002 TI - Systematic review: quality of life after treatment for upper gastrointestinal cancer. AB - PURPOSE OF REVIEW: The aim of this systematic review is to scrutinize and summarize the design, conduct and reporting standards of articles recently published describing health-related quality of life (HRQL) outcomes of treatment of upper gastrointestinal cancer. RECENT FINDINGS: Some 2312 abstracts were published between January and July 2009 and initial elimination of papers reduced this number to 22 articles. Of these, 17 were judged to have robust HRQL methodology, but a further seven were excluded due to a high risk of bias in the study design. Ten articles (four randomized trials) were finally included in the review. Studies in curative treatments for oesophagogastric cancer show that surgery and chemoradiation therapy has a major short-term detrimental effect on HRQL, but recovery occurs within 6 months in long-term survivors but those not achieving a survival benefit report very poor HRQL. In advanced oesophageal cancer, 18 mm self-expandable metal stents and nonstent therapies lead to better short-term HRQL scores than nonexpandable stents and are the recommended standard of care. A small survival advantage and improved HRQL is conferred by adjuvant and palliative gemcitabine chemotherapy in patients with pancreatic cancer. SUMMARY: This review identified few well-designed studies that also included a robust assessment of HRQL. High-quality trials with reliable HRQL methods are required for outcomes to inform health policy and clinical decision-making. PMID- 21326003 TI - The significance of altered gastrointestinal permeability in cancer patients. AB - PURPOSE OF REVIEW: The diagnosis and assessment of severity of intestinal mucosal damage in cancer patients treated by anticancer therapy still rely mostly on anamnestic data. We review here studies reporting on the use of intestinal permeability measurements in cancer patients before and during treatment. RECENT FINDINGS: The concept of intestinal permeability is based on differential permeability of intestinal mucosa to molecular markers, including monosaccharides and disaccharides, along the crypt-villus axis. Cytotoxic drugs and/or radiation impair replacement of intestinal epithelia and induce flattening of the villi, leading to increased exposure of luminal contents to crypts and increased disaccharide absorption. Increased disaccharide/monosaccharide ratio and decreased xylose absorption have been described in patients treated by radiotherapy as well as different cytotoxic or targeted agents across a spectrum of malignant disorders. Intestinal permeability changes correlated with clinical manifestations, including diarrhea, mucositis, neutropenic enterocolitis and systemic infections. The measurement of intestinal permeability has also been used as a surrogate end-point in interventional studies. SUMMARY: Intestinal permeability testing using nonmetabolized sugars may represent a tool for noninvasive objective assessment of intestinal toxicity of anticancer therapy. PMID- 21326004 TI - Surgical management of bowel obstruction in gynaecological malignancies. AB - PURPOSE OF REVIEW: Bowel obstruction in gynaecological malignancies continues to present clinical challenges and a multidisciplinary approach to discuss management is crucial. Surgery, usually with palliative intent, is associated with significant morbidity and mortality. There is an absence of level 1 evidence and national guidelines, and only limited quality-of-life data. RECENT FINDINGS: Acute bowel obstruction in gynaecological cancer patients is rare and surgery is associated with a higher morbidity and mortality rate. Less commonly, emergency bowel obstruction cases will have had radiotherapy or recent chemotherapy, which also increases surgical morbidity and mortality. However, most often, bowel obstruction in irradiated gynaecological cancer patients is not due to cancer. Ovarian cancer is the most common malignancy. Caution is needed in those EOC patients with ascites, short treatment-free interval, acute abdomen and chemoresistance. Comorbidities are frequent. The decision for surgery should be made on an individual basis. Palliative care input is important early in patient management as for most patients the surgical goal is palliation and not cure. There is still a paucity of published data on quality-of-life assessments. SUMMARY: There is a need to identify those patients who may benefit from palliative surgical intervention and those who will not. Ideally, agreed national guidelines should be produced and regularly reviewed. PMID- 21326007 TI - Antihypertensive therapy for patients with obstructive sleep apnea. AB - PURPOSE OF REVIEW: Patients with obstructive sleep apnea (OSA) often have hypertension that is difficult to control. We review the causes of OSA hypertension and evidence supporting specific therapies. RECENT FINDINGS: Sleep apnea commonly accompanies the metabolic syndrome and renal insufficiency. Apneas stimulate atrial natriuretic peptide release and sympathetic nerve activity, which persists throughout the daytime. The combination of increased sympathetic nerve activity and a nocturnal diuresis help explain reports that beta-1 antagonists lower blood pressure more than thiazide diuretics in OSA. The angiotensin-converting enzyme (ACE) inhibitors and angiotensin II blocking drugs have been equally effective in some studies. Patients with treatment-resistant hypertension usually have OSA and have had a good antihypertensive response to spironolactone. SUMMARY: Although most elderly hypertensives respond to diuretics and calcium channel blockers, patients with OSA responded to beta-1 adrenergic blockers, ACE inhibitors, and angiotensin II blocking drugs. The response to a second drug is not known. However, many patients with OSA remain hypertensive on three antihypertensive agents, in which case the addition of spironolactone has been effective. It is reasonable to prescribe shorter acting antihypertensive drugs at night to treat nocturnal hypertension. PMID- 21326008 TI - Current world literature. PMID- 21326009 TI - Acral soft tissue tumors: a review. AB - Acral soft tissue tumors may present significant diagnostic challenges both for the pathologist and the clinician. This review discusses the most common benign and malignant entities that characteristically present in an acral location. Clinical, histologic, and immunohistochemical features are discussed along with prognosis and differential diagnosis. PMID- 21326010 TI - Differential diagnosis of renal tumors with papillary architecture. AB - Papillary renal cell carcinoma is the second most common malignant renal epithelial tumor and constitutes approximately 15% of renal cell tumors. However, papillary architecture is neither unique to papillary renal cell carcinoma, nor do all papillary renal cell carcinomas show exclusive papillary histology. Many of the nonpapillary renal cell carcinomas with papillary architecture have been recognized only recently. Distinction of these from papillary renal cell carcinoma is essential, as biologic behavior and potential therapeutic options are distinct in many such tumors. Close attention to the cytologic and growth pattern characteristics will allow us to arrive at the proper diagnosis in most cases, although sometimes immunohistochemistry and rarely genetic evaluation may be needed. PMID- 21326011 TI - Practical immunohistochemistry in hematopathology: a review of useful antibodies for diagnosis. AB - This review article offers some useful panels of immunohistochemical stains and discusses their use in determining a hematopathology diagnosis. As a comprehensive review of the vast array of hematolymphoid malignancies is beyond the scope of this study, the suggestions are based on broad morphologic categories such as follicular proliferations, paracortical expansions, diffuse small-cell infiltrates, diffuse large-cell infiltrates, and Hodgkin-like infiltrates. The review article also discusses the most common hematolymphoid malignancies and their immunohistochemical profiles, and how to use immunophenotyping to differentiate them from other entities. Common diagnostic pitfalls and misconceptions about certain antibodies will also be discussed. New antibodies, such as SOX11, will also be explored in the context of specific disease entities for which they may be of use. PMID- 21326012 TI - The medical mystery of Napoleon Bonaparte: an interdisciplinary expose. AB - Napoleon Bonaparte (1769 to 1821) is one of the most studied historical figures in European history. Not surprisingly, amongst the many mysteries still surrounding his person is the cause of his death, and particularly the suspicion that he was poisoned, continue to intrigue medical historians. After the defeat of the Napoleonic Army at the battle of Waterloo in 1815, Napoleon was exiled to the small island of Saint Helena in the South Atlantic, where he died 6 years later. Although his personal physician, Dr Francois Carlo Antommarchi, stated in his autopsy report that stomach cancer was the cause of death, this diagnosis was challenged in 1961 by the finding of an elevated arsenic concentration in one of Napoleon's hair samples. At that time it was suggested that Napoleon had been poisoned by one of his companions in exile who was allegedly supported by the British Government. Since then Napoleon's cause of death continues to be a topic of debate. The aim of this review is to use a multidisciplinary approach to provide a systematic and critical assessment of Napoleon's cause of death. PMID- 21326013 TI - Prostate cancer staging and grading at radical prostatectomy over time. AB - Prostate-specific antigen (PSA) testing has been associated with a sharp increase in prostate cancer (PCA) detection after its introduction in the late 1980s. Since its launch and its implementation as diagnostic test in 1994, temporal patterns in patients' age and serum PSA level at presentation have changed, with younger patients being diagnosed at lower PSA cutoff levels. Many studies suggest that PSA screening has resulted in a profound downward migration in clinical and pathologic stage of newly diagnosed PCA, although the effect has slowed in the most recent years. The impact on tumor grading is less clear. Histologic grading of PCA, based on the Gleason system, is predictive of the biological behavior and prognosis of the tumor. If tumor progresses from low grade to high grade, the early detection would lead to a higher percentage of low-grade disease diagnosed over time. However, published data suggest that tumor grade shifts have occurred over time and are unlikely to be attributable to changes in tumor biology, but rather to changes in practice with respect to Gleason grading. This review will address PCA staging and grading trends from the pre-PSA era to the present time with emphasis on the potential role played by changes in clinical and pathologic practice. PMID- 21326014 TI - Diagnostic approach and prognostic factors of cancers. AB - When one follows a systematic approach to make a diagnosis of a malignant lesion, it is relatively easy to render a correct cancer diagnosis in most cases during routine daily practice. The first step is to recognize whether or not the specimen contains a lesion and then to determine whether the lesion is neoplastic or non-neoplastic. As a neoplasm is a clonal proliferation, neoplastic conditions are consisted of a single cell type, whereas non-neoplastic conditions consist of multiple different cell types. After determining that a lesion is neoplastic, the next step is to decide whether the neoplasm is of an epithelial origin or mesenchymal origin. The main differences between epithelial tumors and mesenchymal tumors include: (1) The tumor cells in epithelial tumors are oval round to polygonal, but in mesenchymal tumors, the tumor cells are in general spindle-shaped; (2) Epithelial tumors generally form tumor cell nests, but mesenchymal tumors are arranged diffusely in sheets, without forming tumor cell nests; (3) In epithelial tumors, desmoplastic stroma is well formed in between tumor cell nests, but in mesenchymal tumors there is no desmoplastic stroma; and lastly, (4) feeding vessels open in the stroma in epithelial tumors but open directly between tumor cells in mesenchymal tumors. After this, we can decide whether the tumor is benign or malignant. The differences between benign and malignant tumors include; (1) differentiation, (2) growth rate, (3) growth pattern, and (4) metastasis. A benign tumor is well differentiated, grows slowly, shows expansile growth with encapsulation and does not metastasize. In contrast, a malignant tumor is often poorly differentiated, grows rapidly with many mitoses, shows invasive growth with no capsule and frequently metastasizes. In general, malignant tumors show high cellularity, tumor necrosis and nuclear alterations, which include nuclear enlargement with a high nuclear/cytoplasmic ratio, hyperchromatism, pleomorphism, prominent nucleoli, and frequent mitoses. The final step is to classify the type of tumor based on the cellular differentiation and gross and microscopic growth pattern based on the light microscopic examination of hematoxylin and eosin stained slides. For the correct identification of the tumor, immunostaining, molecular diagnostic tools, or possibly electron microscopic evaluation may be required. After making a diagnosis of malignancy, one should then consider the relevant prognostic factors. The 2 well-known prognostic factors (category I prognostic factors) important in almost all tumors include stage and grade. Therefore, information for regarding stage and grade should be included in the pathology report. PMID- 21326015 TI - Metabolic syndrome and the non-neoplastic kidney. PMID- 21326016 TI - Spontaneous complete regression in merkel cell carcinoma after biopsy. PMID- 21326019 TI - Neurourologic and structural determinants of incontinence: a major pressure ulcer risk factor. PMID- 21326022 TI - Can you pass the surgical dressing ordering and documentation test? PMID- 21326023 TI - Retrospective comparison of diabetic foot ulcer and venous stasis ulcer healing outcome between a dermal repair scaffold (PriMatrix) and a bilayered living cell therapy (Apligraf). AB - OBJECTIVE: The goal of this study was to review clinical experience in treating diabetic and venous stasis wounds with Apligraf or PriMatrix. METHODS: A total of 40 diabetic foot ulcers and 28 venous stasis ulcers were treated with either PriMatrix or Apligraf for number of days open and for number of days for complete healing between the 2 treatments. CONCLUSIONS: Although both treatments were highly effective, the study results of 68 ulcers in 48 patients demonstrated that patients treated with PriMatrix healed faster than patients treated with Apligraf despite larger wound sizes. PMID- 21326024 TI - Incontinence and incontinence-associated dermatitis. AB - Incontinence is a prevalent problem and can lead to many complications. Both urinary and fecal incontinence can result in tissue breakdown, now commonly referred to as incontinence-associated dermatitis. This article addresses the types of incontinence, its etiology and pathophysiology, assessment, prevention and treatment, and the latest research. PMID- 21326026 TI - Lower-extremity wound checklist. PMID- 21326028 TI - "Will you be there with me?" The human connection in oncology nursing care. PMID- 21326027 TI - Deliberating over mastectomy: survival and social roles. AB - BACKGROUND: Most studies based on a woman's decision regarding breast cancer treatments have focused on surgical treatment preference and related factors. Few studies have been carried out to identify the concerns associated with coming to terms with a mastectomy and cancer diagnosis among women eligible for a mastectomy only. OBJECTIVE: The aim of this study was to explore Taiwanese women's experience about facing a mastectomy and to determine their deliberations before agreeing to a recommended mastectomy. METHODS: Ten women who had undergone a mastectomy participated, with 3 undergoing individual interviews and 7 participating in a focus group. Findings during the interviews guided the focus group. RESULTS: Content analysis revealed 4 themes through the women's narratives of the decision-making experience when a mastectomy was recommended. These included (a) surviving is a priority, (b) fulfilling responsibility, (c) coming to terms with postsurgery alternatives, and (d) making arrangements. CONCLUSION: The experience surrounding the decision to undergo a mastectomy among Taiwanese women may be complicated by survival concerns, the meanings of the breast, and a feeling of an uncontrolled daily life. Cultural beliefs ensured that women were fulfilling their expected social roles and always thinking about significant others first. IMPLICATIONS FOR PRACTICE: Recognizing women's private concerns with sensitivity and supporting women to balance their own needs and assigned social responsibilities are important considerations for women undergoing a mastectomy. Developing cultural competency is necessary for nurses working in communities with diverse ethnoculture people. PMID- 21326029 TI - Intention, needs, and expectations of cancer patients participating in clinical trials. AB - BACKGROUND: Clinical trials provide information for developing new treatment strategies, enhancing cancer knowledge, and improving trial effectiveness. However, factors related to patients' participation in clinical trials have not been explored in Taiwan. OBJECTIVES: This study explored cancer patients' willingness to participate in clinical trials and motivational factors, barriers, needs, expectations, and other factors influencing their decision making. METHODS: In this cross-sectional study, information was collected using structured questionnaires with cancer patients from an academic medical center. RESULTS: Among 184 cancer patients sampled, most (87.5%) were willing to participate in a clinical trial. Their attitude toward participating in clinical trials was positive (average motivational score = 59.09; highest scoring item was "chance of cure"). Participants had a slight barrier level for participating in clinical trials (average barrier score = 21.51; highest scoring item was "concern over adverse effects of drugs used in clinical trials"). They had strong needs for clinical trial participation (average need factors score = 59.24; highest scoring need item was "supply of clinical trial-related information by medical personnel, including study purpose, adverse effects, effectiveness, and notices"). Participants had expectations of clinical trial participation (average expectations score = 66.58; highest scoring item was "nonrecurrence of tumor"). Factors predicting participation in clinical trials included medical issues and subjective viewpoint. CONCLUSIONS: These study results can help clinical researchers understand cancer patients' willingness to participate in clinical trials and other influencing factors. IMPLICATIONS FOR PRACTICE: Clinical research nurses can use this information in discussions with cancer patients and important stakeholders to help eligible patients better understand clinical trials to make informed decisions about participation. PMID- 21326030 TI - "Once you're 82 going on 83, surviving has a different meaning": older breast cancer survivors reflect on cancer survivorship. AB - BACKGROUND: Because the concept of cancer survivorship (CS) has become widely popularized, it is tempting to assume that all individuals treated for cancer will personally identify with the public term. This is the first investigation about the meaning of the taken-for-granted concept from the perspective of a group of older survivors. OBJECTIVES: How women 70 years or older who recently completed treatment for primary, early-stage breast cancer relate to concepts such as "cancer survivor" and "cancer survivorship." METHOD: Data were collected and analyzed using constructivist grounded theory. RESULTS: The majority of the 18 women, 70 to 94 years of age, did not self-identify as cancer survivors or identify with the phases of CS. Some had never heard of CS. Instead of perceiving CS as a discrete concept, the women used comparisons and self-judgments to contemplate how much they deserved the title, how they compared with real cancer survivors, and how they can be certain that they are cancer-free. CONCLUSIONS: Although the benefits of identifying as a cancer survivor may be self-evident to health care providers and researchers, the women did not simply accept the generic concept as part of their well-established personal identities. Cancer survivorship was an ambiguous concept that predated the women's cancer experience. IMPLICATIONS FOR PRACTICE: The generic title of cancer survivor is here to stay because it is useful to advocates, consumers, providers, and researchers alike. However, "survivors" will be best served by providers and researchers who are aware that the concept is not organic but is learned from outside sources. PMID- 21326031 TI - Visual inspection with acetic acid in cervical cancer screening. AB - BACKGROUND: Visual inspection with acetic acid (VIA) is an attractive screening method for early-phase cervical cancer in underdeveloped countries. OBJECTIVE: This study addressed the validity of VIA in cervical cancer screening by comparing results with colposcopy findings. METHODS: Of 350 women screened at the Ege University clinic using the Papanicolaou test, colposcopy and VIA were used additionally to screen 50 of these women. Colposcopy, VIA, and Papanicolaou test results were compared. A sociodemographic data questionnaire and a VIA questionnaire were used. RESULTS: When VIA findings were compared with Papanicolaou test findings, the sensitivity of VIA was 82.14%, specificity was 50.00%, positive predictive value (PPV) was 67.64%, and negative predictive value (NPV) was 68.75%. When the method of VIA was compared with colposcopy, VIA had a sensitivity of 85.29%, specificity of 68.75%, PPV of 85.29%, and NPV of 68.75%. CONCLUSIONS: In the screening of cervical cancer, the sensitivity of VIA was high, whereas the corresponding specificity was only at an acceptable level. The PPV and NPV of VIA were found to be high. In other words, the validity of VIA during early-phase screening is high in terms of sensitivity and acceptable for specificity and predictive values. IMPLICATIONS FOR PRACTICE: Visual inspection with acetic acid is an acceptable screening method for cervical cancer and seems to be an efficient and cost-effective method to detect high-level dysplasia. PMID- 21326032 TI - True to our methods, true to ourselves. PMID- 21326033 TI - Quantitative determination of estrogen receptor, progesterone receptor, and HER2 mRNA in formalin-fixed paraffin-embedded tissue--a new option for predictive biomarker assessment in breast cancer. AB - The development of optimized therapy strategies against malignant tumors is critically dependent on the assessment of tissue-based biomarkers in routine diagnostic tissue samples. We investigated a novel, fully automated, and xylene free method for RNA isolation and biomarker determination using formalin-fixed paraffin-embedded (FFPE) tissue. The aim was to show that this approach is feasible and gives results that are comparable to the current gold standards. Expression of the breast cancer biomarkers ESR1, PGR, and HER2 was measured in a total of 501 FFPE tissue samples from 167 breast carcinomas, which had been stored for up to 21 years. Total RNA was extracted from tissue sections and biomarker expression was measured by kinetic RT-PCR (RT-kPCR). The results of the new method were compared with immunohistochemistry as the current gold standard.RNA was successfully isolated from all samples, with a mean yield of 1.4 MUg/sample and fragment lengths of at least 150 bp in 99% of samples. RT-kPCR analysis of ESR1, PGR, and HER2 was possible in all samples. Comparing RT-kPCR results with standard IHC, we found a good concordance for ESR1 (agreement: 98.4%), PGR (84.4%), and HER2 (89.8%). We observed a low section-to-section variability of kPCR results for all 3 biomarkers (root of mean squared errors: 0.2 to 0.5 Ct values). The new approach is a reliable high-throughput instrument for standardized testing of biomarkers in clinical routine and for research studies on archived FFPE material up to 21 years old. For the assessment of ESR1, PGR, and HER2 the results are comparable to the current gold-standard. PMID- 21326034 TI - Validation of the multiplex ligation-dependent probe amplification (MLPA) technique for the determination of HER2 gene amplification in breast cancer. AB - BACKGROUND: Multiplex ligation-dependent probe amplification (MLPA) is a polymerase chain reaction-based assay that can assess HER2 gene copy number relative to control genes. DESIGN: Institutional ethics board approval was obtained. Using commercially available kits, 208 consecutive invasive breast cancers undergoing routine in situ hybridization testing (chromogenic in situ hybridization and fluorescence in situ hybridization) were also tested independently by MLPA. The American Society of Clinical Oncology/College of American Pathologists guidelines were applied for the reporting of ISH results. In accordance with earlier studies, MLPA results were reported as amplified when the HER2 gene copy number per cell was >= 4.0. RESULTS: At the conclusion of all ISH testing 25 of 208 cases (12.0%) were regarded as amplified, 182 (87.5%) as nonamplified, and 1 case (0.5%) as undetermined owing to insufficient tissue. This case is excluded from further analysis. Of the 182 cases categorized as not amplified by ISH, all were also negative by MLPA. Of the 25 cases amplified by ISH, 23 (92.0%) were amplified by MLPA, but the 2 remaining ISH-amplified cases were negative by MLPA. Using ISH as the reference test, MLPA has the following diagnostic indices: sensitivity 92.0%, specificity 100%, positive predictive value 100%, negative predictive value 98.9%, and overall accuracy 99.0%. CONCLUSIONS: The high level of concordance between MLPA and ISH results, exceeding the American Society of Clinical Oncology requirements for validation of a new test, supports the use of MLPA for assessment of HER2-amplification. These results merit further consideration of MLPA as a possible alternative or additional platform for HER2 testing. PMID- 21326035 TI - Molecular diagnosis of sentinel lymph nodes for breast cancer: one step ahead for standardization. AB - Sentinel node (SN) pathologic analysis shows great limitations related to reproducibility and challenges pathologists with respect to methodology and standardization. Recently, a new, highly specific and sensitive molecular procedure has been developed, based on cytokeratin 19 messenger RNA amplification, which allows for fast and effective intraoperative evaluation of the SN. Our aim in this study was to compare 2 arms for intraoperative evaluation: one study arm with 478 cases in which an exhaustive histopathologic procedure was performed and the other study arm with 211 cases that were analyzed using the new molecular method. Our results indicate that both methods similarly distinguish between benign and malignant lymph nodes but the type of metastasis is better defined and stratified by the molecular method. We conclude that the molecular method should be recommended for SN diagnosis because besides its high sensitivity, specificity, and operating room adequacy, it may allow for standardization for SN evaluation. PMID- 21326036 TI - The activated targets of mTOR signaling pathway are characteristic for PDGFRA mutant and wild-type rather than KIT mutant GISTs. AB - The therapy for gastrointestinal stromal tumors (GISTs) has been revolutionized by tyrosin kinase inhibitors. Clinicopathologic studies have been conducted to assess therapeutical responses in cases with KIT and platelet-derived growth factor receptor alpha (PDGFRA) gene mutations. Cell culture data suggest that Akt/mammalian target of rapamycin (mTOR) kinase signaling may be important in GIST. The aim of our study was to determine the activity of the mTOR pathway in a larger series of GISTs (108 different cases) with different exon mutation types. The KIT and/or PDGFRA mutation status of 108 GIST patients was analyzed by direct DNA sequencing. Immunohistochemistry was performed on tissue microarrays using antibodies for phospho-p70S6 kinase, phospho-4EBP1, and phospho-S6, which are downstream target proteins of mTOR. DNA sequencing identified 73 cases with mutations of KIT and 12 cases with PDGFRA mutations. Wild-type receptors were present in 23 cases. KIT exon mutations were accompanied by the activation of the mTOR pathway in 28 of 73 (38.4%) cases, whereas PDGFRA mutant GISTs showed activation in 10 of 12 (83.3%) cases. Wild-type cases were accompanied by mTOR activation in 17 of 23 (73.9%) cases. Our results indicate that the activation of the mTOR pathway is not a general hallmark of GIST with KIT mutations. However, mTOR signaling seems to be activated in PDGFRA mutants and in wild-type cases, which suggests that mTOR or upstream mTOR inhibitors may be therapeutically useful in primary resistant GISTs and confirms earlier data that mTOR is a crucial survival pathway in resistant GISTs. PMID- 21326037 TI - MPL mutation profile in JAK2 mutation-negative patients with myeloproliferative disorders. AB - Mutations in the thrombopoietin receptor gene (myeloproliferative leukemia, MPL) have been reported in patients with JAK2 V617F-negative chronic myeloproliferative disorders (MPDs). We evaluated the prevalence of MPL mutations relative to JAK2 mutations in patients with suspected MPDs. A total of 2790 patient samples submitted for JAK2 mutation analysis were tested using real-time polymerase chain reaction and bidirectional sequencing of plasma RNA. JAK2 V617F negative samples were tested for JAK2 exons 12 to 14 mutations, and those with negative results were then tested for mutations in MPL exons 10 and 11. Of the 2790 patients, 529 (18.96%) had V617F, 12 (0.43%) had small insertions or deletions in exon 12, and 7 (0.25%) had other JAK2 mutations in exons 12 to 14. Of the 2242 JAK2 mutation-negative patients, 68 (3.03%) had MPL mutations. W515L was the predominant MPL mutation (n=46; 68%), and 10 (15%) patients had other W515 variants. The remaining MPL mutations (n=12, 17%) were detected at other locations in exons 10 and 11 and included 3 insertion/deletion mutations. The S505N mutation, associated with familial MPD, was detected in 3 patients. Overall, for every 100 V617F mutations in patients with suspected MPDs, there were 12.9 MPL mutations, 2.3 JAK2 exon 12 mutations, and 1.3 JAK2 exons 13 to 14 mutations. These findings suggest that MPL mutation screening should be performed before JAK2 exons 12 to 14 testing in JAK2 V617F-negative patients with suspected MPDs. PMID- 21326038 TI - Detection of allelic status of 1p and 19q by microsatellite-based PCR versus FISH: limitations and advantages in application to patient management. AB - Combined loss of chromosome arms 1p and 19q in oligodendroglial tumors has become a powerful predictor of prognosis and treatment response, and hence clinical testing for their detection is widely used nowadays. Polymerase chain reaction (PCR)-based loss of heterozygosity (LOH) analysis and fluorescence in-situ hybridization (FISH) are the 2 important relatively common clinical molecular diagnostic techniques used for this purpose and they have their unique advantages and limitations. The preference of methodology used depends on local expertise and existing laboratory capabilities. However, there is no consensus on which methodologic approach has a better potential. The objective of the study was to compare the accuracy, reliability, and feasibility of FISH and PCR in detecting the 1p and 19q LOH status. Using the PCR-based method, a LOH analysis was performed on 30 oligodendrogliomas and 10 glioblastomas using fresh-frozen tissue and peripheral blood as control. A FISH assay using paraffin blocks was performed on all the cases. Concordance for 1p and 19q was found in 92.5% (37 of 40) and 82.5% (33 of 40) cases, respectively. The relative advantages and limitations of both the techniques are analyzed and discussed. The main issue pertains to the use of the best technique in large clinical trials whose results are translated to patient care services. Unless the technique used is correct, the results of clinical trials and their correlations may be somewhat questionable. PMID- 21326039 TI - Effect of unexpected sequence interruptions to conventional PCR and repeat primed PCR in myotonic dystrophy type 1 testing. AB - Myotonic dystrophy type 1 (DM1) is caused by expansion of the CTG trinucleotide repeat in the DMPK gene. Our study focuses on the effect of recently described unusual sequence interruptions inside the CTG tract on conventional polymerase chain reaction (PCR) and triplet repeat primed PCR (TP-PCR) amplifications, which are the methods now widely used in molecular testing for DM1. For molecular characterization of the CTG repeat tract, we used conventional fluorescent PCR with bidirectional labeling and both forward and reverse direction TP-PCR. Though the results of the methods are still unambiguous for most alleles, mistyping and false results may occur in the typing of some unordinary alleles carrying sequence interruptions. The presence of these interruptions may lead not only to altered TP-PCR profiles, as can be expected, but also to abnormal electrophoretic mobility of complementary strands produced by conventional amplification of such alleles. Our findings suggest that the simultaneous combination of bidirectionally labeled conventional PCR with TP-PCR performed in both directions may be necessary for increasing the reliability and accuracy of the TP-PCR-based assay for DM1 testing. PMID- 21326040 TI - Nucleic acid quality preservation by an alcohol-based fixative: comparison with frozen tumors in a routine pathology setting. AB - Pathologic diagnosis requires tissue fixation for histologic and immunohistologic analysis, and formalin is routinely used for this. The disadvantage of this fixative is its inability to preserve nucleic acids. Pathologic tumor diagnosis requires extensive molecular analyses, for which formalin fixation may be not adequate. Recently, an alcohol-based fixative (molecular fixative, MF) was described that allows nucleic acid preservation as well as histologic and immunohistologic studies. Moreover, the MF fixation processing system (Xpress) is fast and is well adapted to a routine process. We evaluated RNA and DNA quality within 1 month and after 1 year for 10 breast carcinomas and 20 sarcomas fixed in MF in comparison with the corresponding frozen tumors. The quality of DNA extracted from the MF-fixed tissue was similar to that extracted from the frozen tumors. The quality of RNA extracted from the MF-fixed tissue was lower than that of frozen tumors; nevertheless, a majority of RNA integrity number (RIN) values were greater than 7. Gene expression quantification by real-time polymerase chain reaction gave comparable results between tumors fixed with MF and frozen tumors. Tissue fixation at 4 degrees C with the MF improved the RNA quality measured by the RIN value. However, after storage for 1 year at room temperature, although DNA quality was preserved, RNA extracted from tissues fixed with the MF was degraded. Tissue fixation with the MF is an important improvement for molecular pathologic diagnosis, enabling a combination of routine pathologic diagnoses and current molecular diagnoses if they are carried out near the processing time. PMID- 21326041 TI - The clinical aspects of mirror therapy in rehabilitation: a systematic review of the literature. AB - The objective of this study was to evaluate the clinical aspects of mirror therapy (MT) interventions after stroke, phantom limb pain and complex regional pain syndrome. A systematic literature search of the Cochrane Database of controlled trials, PubMed/MEDLINE, CINAHL, EMBASE, PsycINFO, PEDro, RehabTrials and Rehadat, was made by two investigators independently (A.S.R. and M.J.). No restrictions were made regarding study design and type or localization of stroke, complex regional pain syndrome and amputation. Only studies that had MT given as a long-term treatment were included. Two authors (A.S.R. and S.M.B.) independently assessed studies for eligibility and risk of bias by using the Amsterdam-Maastricht Consensus List. Ten randomized trials, seven patient series and four single-case studies were included. The studies were heterogeneous regarding design, size, conditions studied and outcome measures. Methodological quality varied; only a few studies were of high quality. Important clinical aspects, such as assessment of possible side effects, were only insufficiently addressed. For stroke there is a moderate quality of evidence that MT as an additional intervention improves recovery of arm function, and a low quality of evidence regarding lower limb function and pain after stroke. The quality of evidence in patients with complex regional pain syndrome and phantom limb pain is also low. Firm conclusions could not be drawn. Little is known about which patients are likely to benefit most from MT, and how MT should preferably be applied. Future studies with clear descriptions of intervention protocols should focus on standardized outcome measures and systematically register adverse effects. PMID- 21326042 TI - Using data from Multidimensional Pain Inventory subscales to assess functioning in pain rehabilitation. AB - The aim of this study was to examine whether Multidimensional Pain Inventory (MPI) subscale score changes can be used for monitoring interdisciplinary cognitive behavioural pain rehabilitation programmes, using the Psychological General Well-Being (PGWB) index as an independent variable of rehabilitation outcome. Data from 434 consecutively referred patients disabled by chronic pain were analysed. The intervention was a 4-week interdisciplinary pain rehabilitation group programme (5 h/day), based on biopsychosocial and cognitive behavioural principles. Mean PGWB total scores improved after rehabilitation (P<0.0001) with clinically relevant effect sizes for patients with 'dysfunctional' and 'interpersonally distressed' MPI profiles. Substantial correlations (r=0.7-0.3; P<0.001) were found between the changes in PGWB total scores and four of the MPI subscale scores. These were combined into a composite variable ['pain severity', 'interference', 'life control' (given reversed scores) and 'affective distress'], and were labelled as the Pain Rehabilitation Index. The subscales, 'support' and 'general activity level', were omitted, as changes were ambiguous with respect to functioning. 'Dysfunctional' and 'interpersonally distressed' profile patients showed a marked improvement in Pain Rehabilitation Index after rehabilitation (effect sizes of 0.77 and 0.43; P<0.0001, respectively). Conversely, the 'adaptive copers' may have deteriorated somewhat (effect size -0.28; P=0.036). We propose that scores from four MPI subscales are integrated and the difference pre-post rehabilitation is used to indicate composite rehabilitation outcomes, making it possible to interpret all included MPI subscales in the same direction. Psychometric evaluation of the index is warranted. PMID- 21326043 TI - "Mask up" to control infectious diseases. PMID- 21326049 TI - How can you achieve clinical excellence by sitting in a wheelchair? PMID- 21326052 TI - Under the apple tree. PMID- 21326055 TI - Hot or cold? Treating cellulitis. PMID- 21326056 TI - Tapping incretin-based therapy for type 2 diabetes. PMID- 21326057 TI - Thinking of going back to school? Just do it! PMID- 21326058 TI - "Smart" infusion pumps are selectively intelligent. PMID- 21326059 TI - Multimodal approaches to pain management. PMID- 21326061 TI - Blood cultures: 5 steps to doing it right. PMID- 21326063 TI - Administering medications for Parkinson disease on time. PMID- 21326064 TI - Epiglottitis. PMID- 21326065 TI - Will conventional local anesthetics soon be replaced by neurotoxins? PMID- 21326066 TI - Intravenous lidocaine infusions as alternative to epidural analgesia: quite not there... PMID- 21326067 TI - Intravenous lidocaine is as effective as epidural bupivacaine in reducing ileus duration, hospital stay, and pain after open colon resection: "second best" compared with "second best" results in equality. PMID- 21326068 TI - Notes on recreation of a simple, inexpensive model for the practice of ultrasound guided regional anesthesia technique. PMID- 21326069 TI - Ultrasound signs in pneumothorax. PMID- 21326071 TI - Ultrasound detection of epidural catheters in pediatric patients. PMID- 21326073 TI - Superficial cervical plexus neuropathy with chronic pain after superficial cervical plexus block and interscalene catheter placement. PMID- 21326074 TI - What's new in SHOCK, March 2011? PMID- 21326076 TI - The contribution of HIV-discordant relationships to new HIV infections in Rakai, Uganda. AB - We determined HIV infections in the Rakai cohort before (82/9434) and after (131/13082) the availability of antiretroviral therapy (ART). The proportions of total HIV infections pre-ART and post-ART were 18.3% and 13.7%, respectively, among identifiable HIV-discordant couples, 23.2% and 26.0%, respectively, in concordant HIV-negative couples, 29.3% and 17.6% in married persons with unknown partner status, and 29.3% and 42.7% in the unmarried. Voluntary counseling and testing targeting discordant couples is unlikely to have a substantial impact in this setting. PMID- 21326075 TI - Emerging integrase inhibitor resistance mutations in raltegravir-treated HIV-1 infected patients with low-level viremia. AB - BACKGROUND: The emergence of integrase strand-transfer inhibitor (INSTI) resistance-associated mutations was examined in patients with low-level viremia after switching from enfuvirtide to raltegravir in the ANRS 138-Easier trial. METHODS: Integrase genes of plasma virus from raltegravir-treated patients in the Easier trial with low-level viremia (50-500 copies/ml) were sequenced to determine INSTI resistance-associated mutations. Baseline viral load, baseline and nadir CD4 cell count, antiretroviral treatment, genotypic susceptibility score, level of viremia and degree of treatment adherence during the study period were also analyzed. RESULTS: Forty-nine patients experienced at least one episode of low-level viremia while receiving raltegravir; integrase genotyping was successful in samples from 39 individuals (80%). Among them, three [7.7%, 95% confidence interval (CI) 1.6-20.9%] had significant INSTI resistance mutations consisting of N155H in two and P145S in one. Absence of these mutations from proviral DNA at baseline suggested selection of INSTI resistance during episodes of low-level viremia. No specific factors significantly associated with emergence of INSTI resistance mutations during low-level viremia were identified. CONCLUSION: Emergence of INSTI resistance mutations can occur during episodes of low-level viremia in patients receiving raltegravir-containing regimens. PMID- 21326077 TI - Concomitant Castleman's disease and sarcoidosis. AB - Castleman's disease (CD) is an atypical lymphoproliferative disorder characterized by hyperplasia of lymphoid tissue that may develop at a single site or throughout the body. This disorder has frequently been associated with several systemic syndromes, including human immunodeficiency virus infection, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS) syndrome and various connective tissue diseases. However, there have been no previously reported cases of concomitant sarcoidosis and CD. In this report, the authors describe a young woman with an enlarging neck mass, biopsy of which showed histopathological features consistent with the hyaline vascular type of CD along with the presence of non-necrotizing granulomas and was deemed unresectable due to encasement of vital neural and vascular structures. Further studies revealed hypermetabolic generalized lymphadenopathy with pulmonary perilymphatic nodules. Bronchoscopic investigations demonstrated the presence of non-necrotizing granulomas within the lung parenchyma and mediastinal lymph nodes, a CD4(+) T-lymphocyte predominant bronchoalveolar lavage and an elevated CD4/CD8 ratio consistent with a concomitant diagnosis of sarcoidosis. Institution of immunosuppression with prednisone and methotrexate led to reduction in size of the neck mass that allowed radical curative resection of the CD. PMID- 21326078 TI - Unusual cause of postrenal biopsy anuria in a renal transplant patient. AB - Arteriovenous fistula (AVF) is an uncommon but well-known complication of percutaneous renal biopsy. Most postbiopsy AVFs are asymptomatic and regress spontaneously; however, some AVFs result in hypertension, hematuria and renal insufficiency. Transplant renal artery stenosis (TRAS) is a potentially curable cause of posttransplant arterial hypertension, allograft dysfunction and graft loss. Whether postbiopsy AVF superimposed on TRAS also regresses spontaneously is unknown. The authors present a case of acute renal failure in a 56-year-old male renal allograft recipient with the combination of postbiopsy AVF and TRAS. At first, the authors performed percutaneous angioplasty with stent implantation for the TRAS, but the AVF gradually enlarged. Eighteen months later, the patient began to experience hypertension, and his serum creatinine level increased; he received transcatheter arterial embolization therapy for enlarged AVF, and his renal function returned to baseline level. PMID- 21326079 TI - Effects of angiotensin receptor blocker on phenotypic alterations of podocytes in early diabetic nephropathy. AB - BACKGROUND: Emerging evidence suggests that podocyte injury is a crucial event in the stage of diabetic nephropathy (DN), a process in which angiotensin II is implicated. In this study, the authors investigated the influence of irbesartan, an angiotensin receptor blocker, on the phenotypic alterations of podocytes in experimental DN. METHODS: DN was induced by combination of high-sucrose, high-fat diet and intraperitoneal injection of low dose of streptozotocin (35 mg/kg) in spontaneously hypertensive rats. Diabetic rats were treated with irbesartan (50 mg/kg/d) by gavage for 8 weeks. Nondiabetic normotensive Wistar-Kyoto rats, which have the same genetic background as spontaneously hypertensive rat, were used as controls. The renal histological changes were investigated by light and electron microscopy. The epithelial marker of nephrin and mesenchymal marker of desmin were detected by real-time reverse transcriptase-polymerase chain reaction and Western blotting. RESULTS: Compared with controls, diabetic rats were associated with mesangial matrix deposition, thickening of glomerular basement membrane, albuminuria, loss of podocytes and effacement of foot processes. Furthermore, the expression of nephrin was significantly reduced whereas desmin was increased. Irbesartan treatment not only lowered blood pressure and albuminuria but also attenuated podocyte loss, maintenance of nephrin expression and inhibition of desmin expression. CONCLUSIONS: This study demonstrates that early irbesartan intervention attenuates the podocyte damage and ameliorates phenotypic alterations of podocytes, which provides a novel insight for the early application of angiotensin receptor blocker to prevent the development of DN. PMID- 21326080 TI - Personalized pharmacotherapy for treatment approaches focused at primary insomnia. AB - The treatment of primary insomnia may be complex and clinically challenging. A comprehensive multidimensional evaluation with a thorough history and physical examination coupled with appropriate testing/imaging will facilitate development of a working diagnosis. Optimal treatment strategies of challenging cases typically involve interdisciplinary team approaches (including a sleep medicine specialist) providing multimodal approaches to treatment, including nonpharmacologic and pharmacologic strategies. A stepped care approach to treatment may serve as a useful guide for health care providers unfamiliar with sleep disturbance issues. Treatment plans based on sound medical judgment, clinical insight, and a thorough and global understanding of particular patient's comorbid conditions may lead to optimal patient-specific/patient-focused/patient centered personalized care. PMID- 21326081 TI - A National Cancer Clinical Trials Network: recommendations from the Institute of Medicine. AB - Oncology has become one of the most active areas of drug discovery, with >800 cancer therapeutics in development. This not only presents an unprecedented opportunity to improve the outcome for patients with cancer but also requires an effective and efficient clinical trials network to generate the evidence necessary for regulatory approval and optimal integration of new treatments into clinical care. The Clinical Trials Cooperative Group Program supported by the National Cancer Institute has been instrumental in establishing standards of care in oncology over the last 50 years, but it currently faces numerous challenges that threaten its ability to undertake the large-scale, multi-institutional trials that advance patient care. The Institute of Medicine recently appointed a consensus study committee to assess the organization and operation of the Cooperative Group Program and recommend ways to improve the quality of cancer clinical trials conducted by the Groups and others. The committee developed a set of recommendations, summarized here, that aim to improve the speed and efficiency of trials; incorporate innovative science and trial design; improve prioritization, selection, and support of trials; and increase participation by patients and physicians. PMID- 21326082 TI - Evaluation of efficacy and tolerability of glimepiride and metformin combination: a multicentric study in patients with type-2 diabetes mellitus, uncontrolled on monotherapy with sulfonylurea or metformin. AB - The objectives of this study were to evaluate the efficacy and tolerability of glimepiride plus extended release metformin (MET) on glycemic control in patients with type-2 diabetes mellitus uncontrolled on monotherapy with sulfonylurea or MET. This was a prospective, open-labeled, multicentric study over 12 weeks. Patients who were diagnosed with type-2 diabetes and were uncontrolled on monotherapy with single oral hypoglycemic agents such as glimepiride or MET and characterized by glycosylated hemoglobin (HbA1c) >=7% and <=10% and fasting plasma glucose (FPG) >= 140 mg/dL were enrolled in this study. Treatment regimen was started at 1 mg of glimepiride plus 500 mg of MET once a day and was titrated to next dose level depending on the clinician's judgment, not exceeding a total daily dose of 8 mg of glimepiride and 2000 mg of MET. After 12-weektreatment, glimepiride plus MET combination showed improvement in metabolic control as assessed by changes in HbA1c, FPG, and post prandial glucose (PPG). Primary efficacy parameter, HbA1c, was significantly reduced to (7.65 +/- 1.70) at the end of the treatment from the baseline value (8.35 +/- 0.93) (P < 0.001). Of the patients, 65.79% showed >=0.5% reduction in HbA1c and or HbA1c <7% at the end of the therapy. FPG and PPG were significantly reduced at the end of the therapy as compared with baseline values (P < 0.001). Moreover, the lipid profile was also improved during the treatment period. The addition of glimepiride to MET is an effective treatment for patients inadequately controlled on sulfonylurea or Met alone. A combination of glimepiride with MET achieves good glycemic control with better tolerability profile. PMID- 21326083 TI - Clinical overview of fibromyalgia. AB - Fibromyalgia (FM) is a complex disorder that affects up to 5% of the general population worldwide, more frequently in women than in men. In addition to chronic widespread pain, patients with FM usually experience other characteristic symptoms, including fatigue, disturbed sleep, stiffness, reduced functioning, dyscognition, and depressed mood. Many patients also have comorbid conditions such as depression, irritable bowel syndrome, temporomandibular disorder, or migraine. Although the etiology of FM remains unclear, evidence suggests that biologic, genetic, and environmental factors are involved. The variability of symptoms and the frequency of comorbidities among patients with FM make this a difficult disorder to diagnose. Diagnosis may be further complicated by the stigmatization of this disorder among treatment providers, the health insurance industry, and the general population. Treating chronic pain disorders such as FM can be time consuming and costly, and other issues such as polypharmacy, treatment adherence, and access to treatment often need to be addressed. The aim of this article is to provide physicians with a general overview of FM, including a brief review of the pathophysiology that explains the biologic and genetic bases of this disorder. Also included is a synopsis of new diagnostic criteria and other useful diagnostic tools and a discussion of various treatment challenges and strategies. PMID- 21326084 TI - Clopidogrel use and short-term mortality after peptic ulcer bleeding: a population-based cohort study. AB - Clopidogrel therapy increases bleeding risk, but whether it influences short-term mortality after peptic ulcer bleeding (PUB) is unknown. The objective was to examine whether clopidogrel use at the time of PUB increases 30-day mortality. We conducted this cohort study in northern Denmark (population 1.7 million). We used the Danish National Patient Registry, covering all hospitals, to identify all patients with a first-ever inpatient diagnosis of endoscopically or surgically confirmed PUB between 1998 and 2008 and their comorbidities. From the prescription database in the region, we ascertained the use of clopidogrel at the time of admission (current use) or before admission (former use) and use of concurrent medications. We obtained mortality data from the Danish Civil Registration System. We used regression modeling to compute mortality rate ratios (MRRs) with 95% confidence intervals (CIs), controlling for potential confounders. We identified 6951 patients with bleeding peptic ulcers. At admission, 122 (1.8%) were current users of clopidogrel, 143 (2.1%) were former users, and 6686 (96.2%) were nonusers. Thirty-day mortality was 5.7% for current users, 7.0% for former users, and 8.0% for nonusers. The adjusted 30-day MRR was reduced in both current and former users, compared with nonusers (MRR = 0.72, 95% CI 0.34, 1.52 and MRR = 0.71, 95% CI 0.38, 1.32, respectively). There was no notable modification of the association within gender or age strata. Although the use of clopidogrel increases the risk of PUB, former use and current use of clopidogrel were not associated with increased short-term mortality after admission for this condition. PMID- 21326085 TI - Allergy to lactated ringer solution-an unusual case presentation. AB - Allergic reactions may be noted by an anesthesiologist during various stages of anesthesia that include induction, maintenance, and post anesthesia care. The incidence of allergic reactions is most common in the perioperative period as a result of various drugs being used concomitantly. It is of paramount importance that an allergic reaction be rapidly diagnosed and adequately treated, because anaphylaxis and acute allergic reactions can occur within minutes in a sensitized individual and can be fatal. Here, we report a case of allergic reaction encountered during induction of anesthesia, after administration of intravenous infusion using lactated Ringer solution. PMID- 21326086 TI - Levodopa treatment of late onset extrapyramidal movements in a child after high voltage electrocution. AB - We present the case of a 12-year-old girl with abnormal extrapyramidal movements associated with basal ganglia lesions after electrical injury. After her injury, our patient initially did well and recovered from acute cardiovascular and hemodynamic instability, and the results of her neurological examination, head computed tomography scan, and electroencephalogram were normal on discharge from hospital. Two weeks after discharge, she developed extrapyramidal movements, and head magnetic resonance imaging showed areas of bilateral, symmetrical enhanced associated with signal intensity in the basal ganglia, hypoxic encephalopathy, and cerebral edema that may have occurred secondary to the cardiopulmonary arrest that she suffered immediately after her accident. The symptoms disappeared after low dose levodopa was instituted and have not recurred during the 15 months of treatment. Injury and death from electric current, although rare, are not uncommon and occur mostly as a result of accidental contact with a live wire. This is the first case report documenting the use of levodopa for extrapyramidal movements secondary to high-tension electrocution. PMID- 21326087 TI - Modulation of toll-like receptors by insulin. AB - Toll-like receptors (TLRs) are first-line molecules for initiating the innate immune responses and mediating functional activation in immune effector cells. A family of 10 functional human TLRs altogether can recognize the ligands that do not exist in the host and initiate the inflammatory cascades. This triggers the production of inflammatory cytokines, chemokines, and interferons. Overactivation of innate immunity might lead to immune-mediated inflammatory disorders. Besides that, TLRs are currently viewed as active participants in the cross-communication between immunity and metabolic health. Recent data directly implicate the activation of inflammatory pathways in the pathogenesis of type 1 and type 2 diabetes, atherosclerosis, obesity, and also cancer. The following approaches to develop new TLR drugs have been undertaken: generating TLR agonists/antagonists, creating monoclonal antibody to TLRs, blocking the key molecules in the signaling pathways, down-modulating TLR signaling. In this article, we briefly review the involvement of TLRs in diseases associated with metabolic alterations, underscoring the modulation of TLRs by insulin. PMID- 21326088 TI - The seven bridges of Konigsberg. PMID- 21326089 TI - New perioperative cervical injury: medical and legal implications for patients and anesthesia providers. PMID- 21326090 TI - Cervical spinal cord, root, and bony spine injuries: a closed claims analysis. AB - BACKGROUND: The aim of this study was to characterize cervical cord, root, and bony spine claims in the American Society of Anesthesiologists Closed Claims database to formulate hypotheses regarding mechanisms of injury. METHODS: All general anesthesia claims (1970-2007) in the Closed Claims database were searched to identify cervical injuries. Three independent teams, each consisting of an anesthesiologist and neurosurgeon, used a standardized review form to extract data from claim summaries and judge probable contributors to injury. RESULTS: Cervical injury claims (n = 48; mean +/- SD age 47 +/- 15 yr; 73% male) comprised less than 1% of all general anesthesia claims. When compared with other general anesthesia claims (19%), cervical injury claims were more often permanent and disabling (69%; P < 0.001). In addition, cord injuries (n = 37) were more severe than root and/or bony spine injuries (n = 10; P < 0.001), typically resulting in quadriplegia. Although anatomic abnormalities (e.g., cervical stenosis) were often present, cord injuries usually occurred in the absence of traumatic injury (81%) or cervical spine instability (76%). Cord injury occurred with cervical spine (65%) and noncervical spine (35%) procedures. Twenty-four percent of cord injuries were associated with the sitting position. Probable contributors to cord injury included anatomic abnormalities (81%), direct surgical complications (24% [38%, cervical spine procedures]), preprocedural symptomatic cord injury (19%), intraoperative head/neck position (19%), and airway management (11%). CONCLUSION: Most cervical cord injuries occurred in the absence of traumatic injury, instability, and airway difficulties. Cervical spine procedures and/or sitting procedures appear to predominate. In the absence of instability, cervical spondylosis was the most common factor associated with cord injury. PMID- 21326092 TI - A novel chromosomal aberration in a child with suspected Juberg-Hayward syndrome. PMID- 21326091 TI - Delaying blood transfusion in experimental acute anemia with a perfluorocarbon emulsion. AB - BACKGROUND: To avoid unnecessary blood transfusions, physiologic transfusion triggers, rather than exclusively hemoglobin-based transfusion triggers, have been suggested. The objective of this study was to determine systemic and microvascular effects of using a perfluorocarbon-based oxygen carrier (PFCOC) to maintain perfusion and oxygenation during extreme anemia. METHODS: The hamster (weight, 55-65 g) window chamber model was used. Two isovolemic hemodilution steps were performed using hydroxyethyl starch, 10%, at normoxic conditions to a hematocrit of 19% (hemoglobin, 5.5 g/dl), the point at which the transfusion trigger was reached. Two additional hemodilution exchanges using the PFCOC (Oxycyte) and increasing the fraction of inspired oxygen to 1.0 were performed to reduce the hematocrit to 11% (hemoglobin, 3.8 g/dl) and 6% (hemoglobin, 2.0 g/dl), respectively. No control group was used in the study because this concentration of hemodilution is lethal with conventional plasma expanders. Systemic parameters, microvascular perfusion, functional capillary density, and oxygen tensions across the microvascular network were measured. RESULTS: At 6% hematocrit, the PFCOC maintained mean arterial pressure, cardiac output, systemic oxygen delivery, and oxygen consumption. As hematocrit was decreased from 11% to 6%, functional capillary density, calculated microvascular oxygen delivery, and oxygen consumption decreased; and the oxygen extraction ratio was close to 100%. Peripheral tissue oxygenation was not predicted by systemic oxygenation. CONCLUSIONS: The PFCOC, in conjunction with hyperoxia, was able to sustain organ function and partially provide systemic oxygenation during extreme anemia during the observation period. The PFCOC can work as a bridge until erythrocytes are available for transfusion or when additional oxygen is required, despite the possible limitations in peripheral tissue oxygenation. PMID- 21326093 TI - Growth retardation, developmental delay and dysmorphic features in a girl with a partial duplication of Xq. PMID- 21326095 TI - Acute-on-chronic liver failure: concept, natural history, and prognosis. AB - PURPOSE OF REVIEW: A population of patients with previously compensated cirrhosis will develop acute deterioration resulting in multiorgan failure and high short term mortality. Complications of cirrhosis frequently culminate in admissions to the ICU. This review advances the concept of acute-on-chronic liver failure as a distinct clinical entity. RECENT FINDINGS: Recently, the American Association for the Study of Liver Disease and the European Association for the Study of the Liver created a research consortium to advance the state of the science of acute on-chronic liver failure. The goal of this consortium is aimed at improving outcomes, identification of a subset of patients with cirrhosis at high risk for deterioration, and the inciting events that lead to this deterioration. Liver transplant remains the only curative option for advanced cirrhosis; however, the limited number of available organs necessitates innovations in the care of advanced liver disease. Liver replacement therapies have not as yet demonstrated reduction in mortality, but have demonstrated improvements in other measures. Large-scale prospective studies of cirrhosis are required. SUMMARY: Acute-on chronic liver failure may be a distinct clinical entity with a potential for reversibility when identified early and managed with aggressive critical care support. PMID- 21326094 TI - Should mechanical ventilation be guided by esophageal pressure measurements? AB - PURPOSE OF REVIEW: Despite the well recognized role of mechanical ventilation in lung injury, appropriate surrogate markers to guide titration of ventilator settings remain elusive. One would like to strike a balance between protecting aerated units from overdistension while recruiting unstable units, thereby reducing tissue damage associated with their cyclic recruitment and derecruitment. To do so requires some estimate of the topographical distribution of parenchymal stress and strain. RECENT FINDINGS: Recent studies have highlighted the importance of chest wall recoil and its effect on pleural pressure (Ppl) in determining lung stress. Although esophageal pressure (Pes) has traditionally been used to measure the average Ppl in normal upright patients, in recumbent acute lung injury/acute respiratory distress syndrome patients Pes based estimates of Ppl are subject to untestable assumptions. Nevertheless, Pes measurements in recumbent patients with injured lungs strongly suggest that Ppl over dependent parts of the lung can exceed airway pressure by substantial amounts. Moreover, results of a pilot study in which Pes was used to titrate positive end-expiratory pressure (PEEP) suggest clinical benefit. SUMMARY: Notwithstanding its theoretical limitations, esophageal manometry has shown promise in PEEP titration and deserves further evaluation in a larger trial on patients with injured lungs. PMID- 21326096 TI - Acute-on-chronic liver failure: the heart and systemic hemodynamics. AB - PURPOSE OF REVIEW: Circulatory abnormalities in cirrhosis include hyperdynamic circulation and cirrhotic cardiomyopathy. The extent of circulatory abnormalities is further exaggerated in acute-on-chronic liver failure (ACLF). The mechanism remains unclear and management also needs to be evaluated. RECENT FINDINGS: The predominant mechanism of ACLF is thought to be a systemic inflammatory reaction. Cardiovascular-active factors such as tumor necrosis factor and nitric oxide are increased and cortisol is decreased; the former further dilates the vasculature and the latter decreases the sensitivity to vasoconstrictors. The exaggerated vasodilatation further decreases the cardiac afterload. However, no study has yet demonstrated the benefit of vasodilators/vasoconstrictors in the management of ACLF. Standard medical treatment in this setting is associated with high mortality. Patients treated with molecular adsorbent recirculating system (MARS) had improved serum levels of inflammatory mediators such as tumor necrosis factor alpha and interleukin-6, but this was not associated with improved survival. Liver transplantation eventually reverses the cardiovascular abnormalities. SUMMARY: Circulatory abnormalities are exaggerated in ACLF. The predominant mechanism is a systemic inflammatory reaction. Modalities such as MARS improve serum markers of inflammation, but not survival. Liver transplantation is the definitive treatment of the cardiovascular abnormalities of ACLF. PMID- 21326097 TI - Peripheral immune cells in the pathology of traumatic brain injury? AB - PURPOSE OF REVIEW: This review will consider the reasons why the inhibition of leucocyte recruitment after traumatic brain injury has not been demonstrated but should remain an area of active interest. RECENT FINDINGS: Focal lesions to the brain display a characteristic inflammatory response with infiltration of peripheral immune cells after injury. These cells are believed to be important because they contain and release a multitude of inflammatory mediators associated with increased tissue injury. Furthermore a large body of evidence from ischaemic injuries suggests that inhibition of leucocyte recruitment can reduce injury and improve outcome. However, therapeutic efficacy has not been demonstrated in clinical trials and for traumatic injuries the results are less convincing. SUMMARY: A greater appreciation of the timing of assessment, leucocyte subsets and the extended inflammatory response will be discussed. PMID- 21326098 TI - Inflammation, high-density lipoprotein and cardiovascular dysfunction. AB - PURPOSE OF REVIEW: This review describes the evidence that supports the hypothesis that high-density lipoprotein (HDL) is atheroprotective due to its antiinflammatory effects and benefits on vascular health. RECENT FINDINGS: Recent investigations have shown that HDL may inhibit atherosclerosis by promoting healthy endothelial function and by limiting or inhibiting the activation of macrophage and other immune cells. Receptors for HDL clearly regulate immune system function as well as cellular stress. Recent studies also suggest that participation of HDL in the process of reverse cholesterol transport may inhibit growth factor and cytokine receptor signaling by depleting cholesterol from lipid rafts. However, inflammation can also be associated with circulating dysfunctional HDL, which often possesses both prooxidative and proinflammatory properties. SUMMARY: These studies suggest that HDL-based therapeutics have potential in treating both acute and chronic conditions associated with inflammation. These studies also reveal several other pathways that may be targeted for therapeutic drug development. PMID- 21326099 TI - Update on infectious complications following lung transplantation. AB - PURPOSE OF REVIEW: Lung transplantation is an important therapeutic treatment for many patients with life-threatening pulmonary diseases; however, long-term survival is still relatively limited compared with other solid organ transplants. Over the last year, several articles have been published helping to increase our knowledge of infections in lung transplant recipients. In particular, important new information has been published recently regarding cytomegalovirus (CMV) and fungal infections following lung transplantation. RECENT FINDINGS: Recent studies indicate prolonged (>=12 months) antiviral prophylaxis for CMV after lung transplant may be beneficial in high-risk transplant recipients. Epidemiologic studies show invasive fungal infections are increasingly being recognized following solid organ transplantation, particularly with Aspergillus and Candida species. Pulmonary infections with CMV and Aspergillus are likely contributors to the development of bronchiolitis obliterans syndrome (BOS). SUMMARY: Lung transplantation has many potential posttransplant complications with infection being a major contributor. More information has become available regarding CMV prophylaxis, CMV treatment, pulmonary fungal infection epidemiology, and the role of both CMV and Aspergillus on the development of BOS, which helps toward the goal of increasing long-term survival in lung transplant recipients. PMID- 21326100 TI - What is new in the prevention of ventilator-associated pneumonia? AB - PURPOSE OF REVIEW: Ventilator-associated pneumonia (VAP) remains a frequent and severe complication in endotracheally intubated patients. Strict adherence to preventive measures reduces the risk of VAP. The objective of this paper is to review what has come forward in recent years in the nonpharmacological prevention of VAP. RECENT FINDINGS: It seems advantageous to implement care bundles rather than single prevention measures. A solid basis of knowledge seems necessary to facilitate implementation and maintain a high adherence level. Continuous educational efforts have a beneficial effect on attitude toward VAP. Intermittent subglottic secretions drainage, continuous lateral rotation therapy, and polyurethane cuffed endotracheal tubes decrease the risk of pneumonia. In an in vitro setting, an endotracheal tube with a taper-shaped cuff appears to better prevent fluid leakage compared to cylindrical polyurethane or polyvinylchloride cuffed tubes. Cuff pressure control by means of an automatic device and multimodality chest physiotherapy need further investigation, as do some aspects of oral hygiene. SUMMARY: New devices and strategies have been developed to prevent VAP. Some of these are promising but need further study. In addition, more attention is being given to factors that might facilitate the implementation process and the challenge of achieving high adherence rates. PMID- 21326101 TI - Is a maximum Revised Trauma Score a safe triage tool for Helicopter Emergency Medical Services cancellations? AB - INTRODUCTION: The Revised Trauma Score is used worldwide in the prehospital setting and provides a snapshot of patient's physiological state. Several studies have shown that the reliability of the RTS is high in trauma outcomes. In the Netherlands, Helicopter Emergency Medical Services (HEMS) are mostly used for delivery of specialized trauma teams on-scene and occasionally for patient transportation. In our trauma system, the Emergency Medical Services crew performs triage after arrival on-scene and cancels the HEMS-dispatch if deemed unnecessary. In this study we assessed the ability of a maximum on-scene Revised Trauma Score (RTS=12) to be used as a triage tool for HEMS cancellation. METHODS: All patients with a maximum on-scene RTS after blunt trauma (with or without receiving HEMS care) who were presented in the trauma resuscitation room of two Level-1 trauma centers during a period of 6 months, were included. Information concerning prehospital and in-hospital vital parameters, severity and localization of the injuries, and the in-hospital course were analyzed. Major trauma patients were classified using the following parameters: Injury Severity Score of at least 16, emergency intervention, Intensive Care Unit admission, and in-hospital death. RESULTS: Four-hundred and forty blunt trauma patients having a maximum RTS were included between 1 July and 31 December 2006. Eighty patients received on-scene HEMS care. Almost 16% of the total population concerned major trauma patients, of which only 25 (36%) received HEMS care. In 17 patients (3.9%), the RTS deteriorated during transportation. Major trauma patients sustained more injuries to the chest, abdomen, and lower extremities. CONCLUSION: The RTS alone is not a reliable triage tool for HEMS cancellations in our trauma system and will lead to a considerable rate of undertriage with one in every six cancellations being incorrect. Other criteria based on patient's vital signs, combined with anatomical and mechanism of injury parameters should be developed to safely minimize triage errors. PMID- 21326102 TI - Do we routinely need cranial computed tomography for mild head injuries in Turkey? AB - The objectives of this study were to determine the role of clinical parameters in detecting intracranial injury and to find out whether cranial computed tomography (CT) is routinely needed for mild head injury (MHI) in Turkey. This retrospective study was conducted by reviewing the records of patients with MHI who underwent cranial CT in our emergency department. We carried out multiple logistic regression analysis, and odds ratios with 95% confidence intervals were calculated by using SPSS 15.0. This study included 923 patients. Positive cranial CT findings were determined in 17 patients (1.8%) and six of them (0.6%) underwent surgery. Statistically significant correlations were found among headache, presence of clinical findings of skull fracture, focal neurological deficit and positive cranial CT findings. Although the incidence of the intracranial lesions, especially those requiring surgery, is low in MHI, the liberal use of CT scanning in MHI seems to be justified in countries such as Turkey. PMID- 21326103 TI - Unplanned return visit to emergency department: a descriptive study from a tertiary care hospital in a low-income country. AB - The objective of this study was to determine the incidence, causes, and factors associated with unplanned return visits to emergency department of a tertiary care centre in a low-income country. We conducted a retrospective chart review of all patients who had unplanned returned visit to our emergency department within 48 h of their initial visit during a 1-year study period. The incidence of unplanned revisits is 2%. Two-thirds (69%) of these patients were adults. The most common presenting complaint was fever (29%). During return visits 55% of patients required admission. On multivariable logistic regression model; fever, triage categories 1 and 2, and patients leaving against medical advice were the independent risk factors for revisits requiring admission. Infectious diseases are the leading cause of return visits in our setting. PMID- 21326104 TI - Cardiac fibroblasts in cell culture systems: myofibroblasts all along? AB - The cytoarchitecture of the working myocardium is characterized by densely packed cardiomyocytes that are embedded in a three-dimensional network of numerous fibroblasts. Although the importance of cardiac fibroblasts in maintaining an orderly structured extracellular matrix is well recognized, less is known about their potential paracrine and electrotonic interactions with cardiomyocytes. This is partly the result of the complex intermingling of both cell types in vivo that tends to preclude a direct investigation of heterocellular crosstalk. It is for that reason that most of our present knowledge regarding stromal-parenchymal cell interactions is based on culture systems that permit direct access to either cell type. An often disregarded feature of such studies is that cardiac fibroblasts in standard two-dimensional cell culture have a pronounced tendency to undergo a phenotype switch to myofibroblasts. This cell type typically appears in injured hearts where it contributes importantly to fibrotic remodeling. The present review focuses on recent insights into electrical and paracrine crosstalk between myofibroblasts and cardiomyocytes while acknowledging that a comprehensive understanding of stromal-parenchymal cell interactions will depend on future methodological developments that permit retaining the fibroblast phenotype in cell culture systems and that will, most importantly, allow direct investigations of heterocellular crosstalk in intact tissue. PMID- 21326106 TI - Acute hypoxia stimulates intracellular peroxynitrite formation associated with pulmonary artery smooth muscle cell proliferation. AB - There is separate evidence for peroxynitrite formation and hypoxia-induced cell proliferation in several models of hypoxic pulmonary hypertension. We therefore hypothesized that the stimulation of pulmonary artery smooth muscle cells (PASMCs) proliferation by hypoxia is due to peroxynitrite formation. The effect of hypoxia alone and in combination with <= 0.2 MUM peroxynitrite on PASMCs was investigated in explants from bovine lungs grown in 1%, 5%, or 10% oxygen for 24 hours with or without peroxynitrite. At 0.1% fetal bovine serum, DNA synthesis of PASMCs (assessed by 3H thymidine incorporation) was increased by transient exposure to 0.2 MUM peroxynitrite (by 158% +/- 14%, P < 0.01) or to 24 hours of hypoxia (5% oxygen) (by 221% +/- 17%, P < 0.01). Results were similar at 2.5% fetal bovine serum. Treatment of PASMCs with 0.2 MUM peroxynitrite or 5% O2 hypoxia caused a significant increase in nitrotyrosine formation to a similar extent and intensity. The proliferative response to 0.2 MUM peroxynitrite or to the combination of peroxynitrite plus 5% O2 was similar to the effect of 5% O2 alone and was abolished by simultaneous treatment with peroxynitrite scavenger ebselen (5 MUM). Our present data indicate that hypoxia can initiate peroxynitrite-induced proliferative events and suggest a mechanism for the vascular hypertrophy associated with pulmonary hypertension. PMID- 21326105 TI - Vasodilation in response to the GPR30 agonist G-1 is not different from estradiol in the mRen2.Lewis female rat. AB - Our studies in the mRen2.Lewis female rat, an angiotensin II- and estrogen dependent model of hypertension, revealed that chronic activation of estrogen receptor GPR30 markedly reduces blood pressure in ovariectomized females. The present studies measured acute vasodilation to the selective GPR30 agonist G-1 and 17-beta-estradiol (10(-9)-10(-5.5) M) in isolated aortic rings and mesenteric arteries from intact mRen2.Lewis females. Maximal relaxation was greater in mesenteric vessels versus the aorta for both G-1 (47% +/- 8% vs 80% +/- 5% of phenylephrine preconstriction, P < 0.001) and estradiol (42% +/- 7% vs 83% +/- 4% of phenylephrine preconstriction, P < 0.001). The GPR30 antagonist G15 attenuated the response to both estradiol and G-1. Removal of the endothelium or pretreatment with Nitro-L-arginine methyl ester (L-NAME) partially attenuated vasorelaxation. Responses were not altered in mesenteric vessels from ovariectomized females. Immunohistochemical analysis revealed GPR30 expression in mesenteric endothelial and smooth muscle cells, and smooth muscle expression was confirmed in cultured cells. We conclude that estradiol-induced relaxation in conduit and resistance vessels from mRen2.Lewis females may be mediated by the novel estrogen receptor GPR30. The direct vasodilatory response of G-1 in resistance vessels presents one mechanism for the reduction in blood pressure induced by chronic G-1 administration. PMID- 21326107 TI - Effect of olprinone, a phosphodiesterase III inhibitor, on balance of cerebral oxygen supply and demand during cardiopulmonary bypass. AB - Neuropsychological dysfunction with cardiopulmonary bypass (CPB) may be facilitated by inadequate cerebral oxygen balance during CPB. Olprinone, a phosphodiesterase III inhibitor, augments cerebral blood flow by a direct vasodilator effect on cerebral arteries. We conducted the present randomized study in patients undergoing cardiac surgery with CPB to investigate whether olprinone improved the balance of cerebral oxygen supply and demand during the rewarming period of CPB. After anesthesia, a 5.5 F fiberoptic oximeter catheter was inserted into the right jugular bulb retrogradely for monitoring the jugular venous oxyhemoglobin saturation (SjO2), and a probe of transcranial near-infrared spectroscopy was placed over the forehead for monitoring the bilateral regional cerebral oxygen saturation (rSO2). Patients were randomly assigned to 3 groups, and olprinone was administered at 0, 0.2, or 0.4 MUg.kg(-1).min(-1) after establishment of hypothermic CPB. Olprinone significantly prevented the reduction of the SjO2 at 5 and 10 minutes after the start of rewarming, although it did not alter rSO2. Furthermore, there was a minor reduction of the bilateral rSO2 at low doses of olprinone (0.2 MUg.kg(-1).min(-1)). We conclude that olprinone prevents the decrease of the SjO2 at the rewarming period and improves the balance of cerebral oxygen supply and demand during the rewarming period of CPB. In addition, a future extended study may be required to elucidate the effect of low dose of olprinone. PMID- 21326108 TI - Contribution of nitric oxide in big endothelin-1-induced cardioprotective effects on ischemia/reperfusion injury in rat hearts. AB - We have recently shown that an appropriate amount of exogenous big endothelin-1 (ET-1) has beneficial effects on ischemia-/reperfusion-induced norepinephrine overflow and cardiac dysfunction in rat hearts and that these effects occur through a conversion to ET-1 by endothelin-converting enzyme and following stimulation of ETB receptor. In this study, we examined the possible involvement of nitric oxide (NO) in the big ET-1-induced cardioprotective effects. According to the Langendorff technique, isolated rat hearts were subjected to 40-minute global ischemia followed by 30-minute reperfusion. Exogenous big ET-1 (0.3 nM) significantly increased NOx (NO2/NO3) level in the coronary effluent after onset of reperfusion. This effect was markedly attenuated by treatment with SM-19712 (selective endothelin-converting enzyme inhibitor), A-192621 (selective ETB receptor antagonist), or NG-nitro-l-arginine (nonselective NO synthase inhibitor), respectively. In addition, N-nitro-l-arginine blunted big ET-1 induced suppression of norepinephrine overflow and improvement of cardiac dysfunction after ischemia/reperfusion. These findings suggest that NO produced by ETB receptor activation plays an important role in exogenous big ET-1-induced actions. PMID- 21326109 TI - Antibody to granulocyte macrophage colony-stimulating factor reduces the number of activated tissue macrophages and improves left ventricular function after myocardial infarction in a rat coronary artery ligation model. AB - Granulocyte macrophage colony-stimulating factor (GM-CSF) promotes infarct expansion and inappropriate collagen synthesis in a myocardial infarction (MI). This study was designed to determine if treatment with anti-GM-CSF will inhibit macrophage migration, preserve function, and limit left ventricular (LV) remodeling in the rat coronary artery ligation model. Treatment with a monoclonal antibody to GM-CSF (5 mg/kg) was initiated 24 hours before coronary artery ligation and continued every 3 days for 3 weeks. Left coronary arteries of rats were ligated, animals were recovered, and cardiac function was evaluated 3 weeks postligation. Tissue samples were processed for histochemistry. Anti-GM-CSF treatment increased LV ejection fraction (37 +/- 3% vs 47 +/- 5%) and decreased LV end systolic diameter (0.75 +/- 0.12 vs 0.59 +/- 0.05 cm) with no changes in LV systolic pressure (109 +/- 4 vs 104 +/- 5 mm Hg), LV end diastolic pressure (22 +/- 4 vs 21 +/- 2 mm Hg), LV end diastolic diameter (0.96 +/- 0.04 vs 0.92 +/ 0.05 cm), or the time constant of LV relaxation tau (25.4 +/- +2.4 vs 22.7 +/- 1.4 milliseconds) (P < 0.05). Significantly lower numbers of tissue macrophages and significant reductions in infarct size were found in the myocardium of antibody-treated animals (81 +/- 21.24 vs 195 +/- 31.7 positive cells per 0.105 mm, compared with controls. These findings suggest that inhibition of macrophage migration may be beneficial in the treatment of heart failure after MI. PMID- 21326111 TI - The effect of selective antihypertensive drugs on the vascular remodeling associated hypertension: insights from a profilin1 transgenic mouse model. AB - Hypertension represents a major risk factor for cardiovascular diseases. We have developed a novel transgenic mouse model by overexpressing the cDNA of human profilin1 in the blood vessels of transgenic mice, which led to vascular hypertrophy and hypertension. We assessed the effects of losartan, amlodipine, or atenolol on vascular hypertrophy-associated hypertension, by treating the profilin1 transgenic mice for 4 weeks. Our myograph results showed improvement in the contraction response toward phenylephrine and in the relaxation response toward acetylcholine and sodium nitrite in losartan- and amlodipine-treated profilin1 mice. Western blot analyses using mesenteric arteries of losartan- and amlodipine-treated profilin1 mice showed significant decreases in their signaling, respectively, as follows: the expression of alpha1 integrin (104% and 93%) and beta1 integrin (116% and 109%); p-ERK1/2 (149% and 130%) and p-JNK (171% and 137%); the phospho-myosin light chain 20 (117% and 150%); and the ROCKII expression (125% and 180%). Conversely, there were significant increases in the endothelial nitric oxide synthase expression (82% and 80%) and activation (p endothelial nitric oxide synthase) (78% and 76%). On the other hand, atenolol treated profilin1 mice showed no significant change in all measured parameters. In conclusion, the profilin1 gene may represent a new therapeutic target in the treatment of vascular hypertrophy-associated hypertension. PMID- 21326110 TI - Angiotensin-(1-7) blockade attenuates captopril- or hydralazine-induced cardiovascular protection in spontaneously hypertensive rats treated with NG nitro-L-arginine methyl ester. AB - We assessed the contribution of angiotensin-(1-7) [Ang-(1-7)] to captopril induced cardiovascular protection in spontaneously hypertensive rats (SHRs) chronically treated with the nitric oxide synthesis inhibitor NG-nitro-L-arginine methyl ester (SHR-l). NG-nitro-L-arginine methyl ester (80 mg/L) administration for 3 weeks increased mean arterial pressure (MAP) from 196 +/- 6 to 229 +/- 3 mm Hg (P < 0.05). Treatment of SHR-l with Ang-(1-7) antagonist [d-Ala7]-Ang-(1-7) (A779; 744 MUg.kg(-1).d(-1) ip) further elevated MAP to 253 +/- 6 mm Hg (P < 0.05 vs SHR-l or SHR). Moreover, A779 treatment attenuated the reduction in MAP and proteinuria by either captopril (300 mg/L in drinking water) or hydralazine (1.5 mg.kg(-1).d(-1) ip). In isolated perfused hearts, the recovery of left ventricular function from global ischemia was enhanced by captopril or hydralazine treatment and was exacerbated with A779. The Ang-(1-7) antagonist attenuated the beneficial effects of captopril and hydralazine on cardiac function. Recovery from global ischemia was also improved in isolated SHR-l hearts acutely perfused with captopril during both the perfusion and reperfusion periods. The acute administration of A779 reduced the beneficial actions of captopril to improve recovery after ischemia. We conclude that during periods of reduced nitric oxide availability, endogenous Ang-(1-7) plays a protective role in effectively buffering the increase in blood pressure and renal injury and the recovery from cardiac ischemia. Moreover, Ang-(1-7) contributes to the blood pressure lowering and tissue protective actions of captopril and hydralazine in a model of severe hypertension and end-organ damage. PMID- 21326112 TI - Presence of Erdheim-Chester disease and Langerhans cell histiocytosis in the same patient: a report of 2 cases. AB - The histiocytic disorders Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD), can both present with multisystem involvement, with the central nervous system and the bone, skin, neuroendocrine, cardiac, respiratory, and gastrointestinal systems potentially affected. The 2 entities occasionally can be difficult to distinguish. Both rarely affect the orbit and the central nervous system, and although there are rare reports of patients with coexistent LCH and ECD, there are no reported cases of the 2 diseases that involve both the orbital and neuroendocrine systems. We report 2 such cases, and review the literature of cases of LCH and ECD occurring in the same patient. The presentation of LCH and ECD in certain patients suggests a possible abnormality in the common CD34 progenitor cell. The coexistence of the 2 disease states should be suspected in patients with atypical presentations of either disorder. PMID- 21326113 TI - Attitudes toward urinary incontinence among community nurses and community dwelling older people. AB - PURPOSE: The purpose of this study was to describe attitudes toward urinary incontinence among nurses and community-dwelling older people. SUBJECTS AND SETTING: Random samples of 100 community-dwelling persons older than 60 years and 100 nurses practicing in community health service centers were invited to participate in the study set in Shanghai, People's Republic of China. DESIGN: A descriptive cross-sectional design was used to gather self-report data for this study. INSTRUMENTS: The UI Attitude Scale (UIAS) was used to measure attitudes toward UI. RESULTS: The response rate was 100% for all groups. Most respondents indicated that family support was important in dealing with UI (98% nurses, 83% older people), and UI is preventable (63% nurses, 56% older people). Nurses were more likely to perceive that UI can be effectively treated (92% vs 76% older people, P = .002), managed (91% vs 76% older people, P = .004) and hinders social interactions (88% vs 73% older people, P = .007) than community-dwelling adults. Older persons were more likely to perceive UI as shameful (32% vs 6% nurses, P = .000), their own fault (44% vs 4% nurse, P = .000), and frustrating to be taken care of (54% vs 15% nurses, P = .000). Older persons with UI were more unwilling to talk about incontinence(45% vs 17% nurses, P .000), and more often considered UI not serious enough to warrant treatment (29% vs 2% nurses, P = .000). CONCLUSION: The findings indicated a greater need for community education program on UI among community nurses and older people in China. Strategies to alter attitudes toward UI should be explored. PMID- 21326114 TI - The effects of a multi-intervention incontinence care program on clinical, economic, and environmental outcomes. AB - PURPOSE: The aim of the study was to assess the effects of a multi-intervention program consisting of use of new absorbent products, a structured skin care regimen, and nursing advice on clinical (incontinence-associated dermatitis [IAD]), economic, and environmental outcomes. SUBJECTS AND SETTING: The study setting was a nursing home in northern Italy. Sixty-three patients with urinary incontinence participated, including 46 women and 17 men. Their average was 84.0 +/- 9.1 years (mean +/- SD). Thirty-five participants were entirely dependent on others for activities of daily living, such as bathing or dressing. DESIGN: Single-group, pre-/postintervention study. METHODS: The multi-intervention program was implemented in 3 phases: (1) initial assessment of incontinence care (phase 0, baseline measurement), (2) introduction of new absorbent products for incontinence and a structured skin care regimen (phase 1), and (3) introduction of advice provided by continence nurses (phase 2). RESULTS: All 63 subjects were found to have IAD at baseline.When compared to baseline measurement, the relative risk of IAD following implementation of phase 1 (new absorbent products and structured skin care regimen) was 0.24 (95% confidence interval [CI], 0.16-0.35). Adding advice from continence nurses during this final phase (2) of the study further diminished the relative risk of IAD to 0.15 (95% CI, 0.04-0.59). In addition,the relative risk of IAD was 0.03 (95% CI 0.01-0.12) when the complete intervention (new absorbent products, structured skin care regimen, and continence nurse advice) was compared to baseline measurement. Baseline evaluation revealed that incontinent residents used an average of 5.19 absorbent products,at a mean cost of ? 1.79 per day. Following introduction of the multi intervention program, the mean number of absorbent products consumed per day was 2.02 per incontinent patient, at a mean cost of ? 0.97 per day. In addition to these clinical and economic outcomes, implementation of the multi-intervention program reduced the daily production of waste generated by the nursing home from 33 to 11 kg/d. CONCLUSIONS: Results of this study suggest that a multi intervention program, including introduction of new absorbent products, a structured skin hygiene program, and advice from continence nurses, reduce the relative risk of IAD, absorbent product use, and generation of waste materials. PMID- 21326115 TI - The effect of 2 different care products on incontinence-associated dermatitis in patients with fecal incontinence. AB - PURPOSE: We compared the effects of 2 devices used to contain fecal incontinence- a perianal pouch and adult containment brief--on the incidence of incontinence associated dermatitis (IAD). DESIGN: Randomized controlled trial. SUBJECTS AND SETTING: The sample was drawn from patients hospitalized in the neurology and neurosurgery wards of a large university hospital in Turkey. Thirty bedridden subjects with fecal incontinence and indwelling urinary catheters participated in the study. Subjects were randomly allocated to treatment with a perianal pouch (n = 15) or adult containment brief (n = 15). METHODS: Routine hygiene was completed once daily and repeated whenever the perineal area was found to be soiled.Perineal skin integrity was evaluated daily during skin care. Data were collected using a Patient Identification Form, a Patient Observation Form, and a Perineal Skin Integrity Assessment Form. RESULTS: The mean number of products used on a daily basis by patients with a perianal pouch was 5.80, as compared to 5.46 by patients with adult incontinence briefs. IAD occurred in 66.7%of patients in the perianal pouch group and in 100% of subjects managed by containment briefs, a statistically significant difference (chi2 = 6.0, P = 0.04). The onset of IAD occurred later in subjects allocated to management with a perianal pouch than inpatients using adult containment briefs (U = 30.500, P = 0.011). IAD involved an average of 1.8 areas among patients managed with a perianal pouch, as compared to 2.3 areas in patients managed with adult containment briefs (P = NS). CONCLUSION: Management of bedridden patients with fecal incontinence with a perianal pouch reduced the incidence of IAD and delayed to time to onset when compared to management with adult containment briefs. We recommend use of perianal pouches for prevention of IAD in bedridden patients with fecal incontinence. PMID- 21326116 TI - Adapting pressure ulcer prevention for use in home health care. AB - PURPOSE: Clinical practice guidelines on pressure ulcer (PU)prevention have been written primarily for inpatient settings,but we currently lack data as to how these guidelines have been adapted for use in home health care. The purpose of this study was to delineate interventions and activities used to prevent PU in home health care. DESIGN: Focus group study using text analysis. SUBJECTS: A focus group was conducted with 9 certified wound care nurses who practiced in home health care at least 50% of the time. Most of the participants had 10 or more years of home health experience and 5 or more years of wound care experience. METHODS: The single 75-minute focus group was convened by teleconference and audiotaped. A semistructured moderator's guide was used to lead the discussion. Transcribed data were analyzed using standard text analysis. Preliminary results were distributed to focus group participants for review, comment, or clarification, and refined as needed. RESULTS: Certified wound care nurse participants used an array of interventions, including those recommended by clinical practice guidelines, to prevent PU in home health patients.However, specific activities differed from those performed in hospitals and nursing homes. Interventions unique to homehealth care included (1) assessment of patients' economic and insured status to determine implementation options, (2) assessment of caregiving resources and caregivers' ability to manage PU prevention, and (3) collaboration with community resources and health care vendors to obtain needed prevention materials and supplies. CONCLUSION: Findings provide insight into guideline adaptation in home health care and suggest that PU prevention in the homehealth care setting is more complex than that in hospitals and nursing homes and requires significant skills in communication and collaboration. PMID- 21326117 TI - Decreasing pressure ulcer risk during hospital procedures: a rapid process improvement workshop. AB - A 300-bed acute care community hospital used a 2-day "Rapid Process Improvement Workshop" to identify factors contributing to facility-acquired pressure ulcers (PU). The Rapid Process Improvement Workshop included key stakeholders from all procedural areas providing inpatient services and used standard components of rapid process improvement: data analysis, process flow charting, factor identification, and action plan development.On day 1, the discovery process revealed increased PU risk related to prolonged immobility when transporting patients for procedures, during imaging studies, and during the perioperative period. On day 2, action plans were developed that included communication of PU risk or presence of an ulcer,measures to shorten procedure times when clinically appropriate, implementation of prevention techniques during procedures, and recommendations for mattress upgrades. In addition, educational programs about PU prevention were developed, schedules for presentations were established, and an online power point presentation was completed and placed in a learning management system module. Finally, our nursing department amended a hospital wide handoff communication tool to include skin status and PU risk level. This tool is used in all patient handoff situations, including nonnursing departments such as radiology. Patients deemed at risk for ulcers were provided "Braden Risk" armbands to enhance interdepartmental awareness. PMID- 21326118 TI - Undetectable antimullerian hormone levels and recovery of chemotherapy-induced ovarian failure in women with breast cancer on an oral aromatase inhibitor. AB - OBJECTIVE: Knowledge of the menopause status of a woman with breast cancer is important for good clinical practice. Long-lasting amenorrhea is frequent in this population, often for reasons other than definitive menopause. Antiestrogens like tamoxifen or oral aromatase inhibitors (AIs) may reactivate the ovary causing vaginal bleeding, menstruation, pregnancy, and unopposed endometrial stimulation. In contrast to tamoxifen, AIs are not active against breast cancer in the presence of functional ovaries. Antimullerian hormone (AMH) is a potential marker of residual ovarian function that can predict not only the onset of menopause but also chemotherapy-induced amenorrhea (CIA) and fertility. We assess the value of AMH in women who recovered from CIA on an AI. METHODS: This is a series of six women with clinical and biochemical evidence of ovarian recovery during AI treatment. All six were premenopausal at breast cancer diagnosis and developed CIA. AMH, follicle-stimulating hormone, and estradiol levels were measured when patients developed clinical signs of ovarian recovery and/or when a gynecological procedure showed evidence of this. RESULTS: In all six AI-treated women, AMH levels were undetectable despite clinical, biochemical, or pathological evidence of ovarian reactivation after a long period of amenorrhea and sensitive biochemical markers indicating definitive menopause status. CONCLUSIONS: Repeated biochemical monitoring of ovarian function remains important in women with breast cancer undergoing AI treatment because ovarian function can recover, AIs are not active with functional ovaries, and amenorrhea does not, by itself, confirm definitive menopause. Undetectable AMH levels do not exclude residual ovarian function in women with breast cancer on an AI. PMID- 21326119 TI - Concordance between self-reported and sternal skin conductance measures of hot flushes in symptomatic perimenopausal and postmenopausal women: a systematic review. AB - OBJECTIVE: Sternal skin conductance is considered the gold standard in hot flush and night sweat measurement, but results sometimes differ from women's own self reports. To date, there has been no systematic review of concordance between sternal skin conductance and self-report measures. An exploratory meta-analysis was conducted to quantify concordance between these measures and to explore the reasons for discordance between them. METHODS: A search of Medline, EMBASE, Web of Science, and PsychInfo from inception to December 2009 was conducted. Studies that measured self-reported hot flushes and/or night sweats and sternal skin conductance concurrently in symptomatic perimenopausal and postmenopausal women were retained for data extraction. Studies were included if data on concordance between the two measures were available. RESULTS: Concordance rates overall were 29%, but variability between studies was too broad to identify a single typical concordance rate. However, concordance rates for ambulatory monitoring were more homogeneous and also had a 29% concordance rate. Nonambulatory studies tended to result in more concordant hot flushes (54%) than ambulatory studies did, and night sweats tended to be under-reported more often than over-reported (46% and 22%, respectively). CONCLUSIONS: Concordance rates were typically lower than early reports of sternal skin conductance measures but were highly variable between studies. Possible measurement error and study conditions might partly explain the discordance and variation in study findings, but further exploration of the effects of symptom perception is warranted. Use of both measures concurrently is likely to achieve more reliable and valid measurement of hot flushes and night sweats than either measure alone. PMID- 21326120 TI - The relationship of subjective sleep quality and cardiac autonomic nervous system in postmenopausal women with insomnia under auricular acupressure. AB - OBJECTIVE: The aim of this study is to examine the relationship between the changes in self-reported sleep symptoms and cardiac sympathovagal activity among women with postmenopausal insomnia (PI) who received auricular acupressure (AA) therapy. METHODS: A pretest/posttest study design was conducted at Taipei Veterans General Hospital, Taiwan, from August 2008 to July 2009. Forty-five women (mean +/- SD age, 56.2 +/- 5.4 years) with PI (4.9 +/- 3.5 years of insomnia) received an AA therapy course on five auricular points every night before going to sleep for 4 weeks. Heart rate variability (HRV), the Chinese version of the Pittsburgh Sleep Quality Index, and the Menopause Rating Scale were measured before and after AA treatment. RESULTS: The total sleep duration and sleep efficiency were increased, and the sleep latency was shortened significantly (P < 0.01) after AA therapy. The total Menopause Rating Scale and somatovegetative subscale scores were reduced significantly (P < 0.05) after the intervention. A greater percentage change in Pittsburgh Sleep Quality Index was moderately correlated with both a lower percentage change in high-frequency power of HRV (r = -0.660, P < 0.001) and a greater percentage change in normalized low frequency power (nLF) of HRV (r = 0.599, P < 0.001). An elevation of high frequency power and a reduction of nLF of HRV were observed in the responder group, whereas a raise in nLF of HRV was noted in the nonresponder group. CONCLUSIONS: This study suggests that AA intervention leads to more cardiac parasympathetic and less cardiac sympathetic activity, which contributes to the improvement of PI. PMID- 21326122 TI - PET/CT with 3'-deoxy-3'-[18F]fluorothymidine for lung cancer patients receiving carbon-ion radiotherapy. AB - OBJECTIVE: The aim of this study was to investigate the clinical value of 3' deoxy-3'-[F]fluorothymidine-positron emission tomography/computed tomography (FLT PET/CT) for lung cancer patients receiving carbon-ion radiotherapy. METHODS: Twenty consecutive patients with lung cancer underwent FLT-PET/CT before and after carbon-ion radiotherapy. Fifty minutes after intravenous injection of approximately 300 MBq of FLT, PET/CT data were acquired. Maximal standardized uptake value of the tumor was measured, from which the reduction rate of tumor FLT uptake was calculated. After treatment, the patients were followed (17-42 months for survivors) for the development of recurrence and survival. RESULTS: Primary responses to carbon-ion radiotherapy were partial in 13 patients, stable disease in six patients, and nonevaluable in one patient. Although tumor FLT uptake significantly decreased after treatment (P < 0.001), the presence of radiation pneumonitis hampered its precise evaluation. During the follow-up period, nine patients developed recurrence, and seven patients died including two deaths from other causes. Pretreatment FLT uptake of patients who developed recurrence and who died of lung cancer were significantly higher than that of patients who did not (P = 0.008 and 0.007, respectively). Kaplan-Meier analysis using a cut-off value also supported the prognostic value of pre-carbon-ion radiotherapy FLT-PET/CT. CONCLUSION: This investigation suggests that FLT-PET/CT is feasible in evaluating lung cancer patients undergoing carbon-ion radiotherapy. The presence of radiation pneumonitis can influence tumor FLT uptake and needs special attention. Pre-carbon-ion radiotherapy FLT-PET/CT seems to have a prognostic value and may contribute to decision-making on the treatment strategy. PMID- 21326121 TI - A cross-sectional and 10-year prospective study of postmenopausal estrogen therapy and blood pressure, renal function, and albuminuria: the Rancho Bernardo Study. AB - OBJECTIVE: Blood pressure, urine albumin-to-creatinine ratio, and estimated glomerular filtration rate (GFR) are highly correlated conditions. The longitudinal effect of exposure to postmenopausal estrogen therapy on these traits studied together has not been reported. METHODS: This was a cross sectional study of 1,044 older postmenopausal community-dwelling women from the Rancho Bernardo Study (1992-1996); 443 women were reevaluated ~ 10 years later (2002-2005). We determined the cross-sectional and prospective association of baseline postmenopausal estrogen therapy and blood pressure, urine albumin-to creatinine ratio, GFR, and the odds of categorical hypertension (physician diagnosis, medication, or blood pressure >= 140/>= 90 mm Hg), chronic kidney disease (GFR <= 60 mL/min per 1.73 m2), and albuminuria (urine albumin-to creatinine ratio >= 25 mg/g). RESULTS: At baseline, the mean age was 68.3 years for current estrogen users, 75.4 years for past users, and 74.3 years for never users. In the cross-sectional analyses, current users had lower diastolic blood pressure and lower odds of having chronic kidney disease, independent of covariates. In the ~ 10-year follow-up, comparisons between never, past, and current estrogen use (91% continuous use since baseline), the mean diastolic blood pressure declined over time in current users, whereas systolic blood pressure increased among never users. Urine albumin-to-creatinine ratio also increased in never users and decreased in current users; GFR did not differ by estrogen use. CONCLUSIONS: In cross-sectional analyses, estrogen users had better GFR and blood pressure than nonusers did, but the 10-year follow-up showed improved blood pressure and decreased urine albumin-to-creatinine ratio among mostly long-term current users, without differences in GFR by estrogen use. This study suggests no association of GFR with 10 years of continuous estrogen use and an inverse association with albuminuria. PMID- 21326123 TI - Use of [18F]fluorodeoxyglucose and the ATLAS small animal PET scanner to examine cerebral functional activation by whisker stimulation in unanesthetized rats. AB - PURPOSE: Stroking the whiskers of a rat is known to increase cerebral blood flow and glucose utilization in the somatosensory cortex. We sought to determine whether this activation could be detected with small animal PET and 2-[F]fluoro-2 deoxyglucose ([F]FDG). METHODS: Awake rats were coinjected with [F]FDG and [C]deoxyglucose ([C]DG), and during the uptake of the tracers, five, 10, or 15 whiskers on one side of the face were continuously stimulated. At the end of uptake, the animal was killed and imaged with the Advanced Technology Laboratory Animal Scanner small animal PET scanner. Carbon-14 autoradiography was then performed on brain sections obtained from each animal, and increases in tracer uptake in the somatosensory cortex were compared with those determined with PET. RESULTS: Both methods showed increases in [F]FDG and [C]DG uptake in the somatosensory cortex in response to the stimulation of as few as five whiskers. However, the magnitude of activation determined from the PET images was less than that from autoradiography due to the lower spatial resolution of the PET scanner. CONCLUSION: Advanced Technology Laboratory Animal Scanner small animal PET imaging with [F]FDG can be used to assess neuronal functional activity in vivo. PMID- 21326124 TI - Diagnostic value of 18F-FDG-PET/CT in indeterminate infiltrative hepatic lesions in an endemic area of viral hepatitis. AB - BACKGROUND AND AIM: Infiltrative hepatic lesions in conventional imaging modalities are a continuing diagnostic challenge in clinical practice, especially in an endemic area of viral hepatitis. The purpose of this study isto prospectively assess the role of F-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography/computed tomography (PET/CT) in indeterminate infiltrative hepatic lesions seen in conventional CT or magnetic resonance imaging (MRI). METHODS: Dual-phase FDG-PET/CT was performed on35consecutive patients with indeterminate infiltrative hepatic lesions in CT or MRI. The variables analyzed included visual score and maximum standardized uptakevalue. Final diagnosis was histopathology orclinicalfollow-up for at least 12 months. RESULTS: Malignancy was proven in 28 patients and there were benign strictures in seven patients. Sensitivity, specificity, and overall diagnostic accuracy of FDG-PET/CT using visual score were 85.7% (24/28), 71.4% (5/7), and 82.9% (29/35). Early and delayed maximum standardized uptake values were significantly higher in infiltrative hepatic malignancies than in benign lesions. Furthermore, PET/CT detected 13 unexpected distant metastatic foci notseen in other imaging studies. Thirteen patients (37.1%)had the plans of clinical treatment altered by FDG PET/CT alone. CONCLUSION: FDG-PET/CT can help to clarify the diagnosis of indeterminate infiltrative hepatic lesions in CT or MRI. Inthis patient population, FDG-PET/CT may hold promisein the detection of unsuspected occult metastases, facilitating decision making and treatment planning. PMID- 21326125 TI - Signet cell adenocarcinoma of the rectum metastatic to the orbit. AB - A 24-year-old man developed abdominal carcinomatosis from signet cell carcinoma of the rectum. His only distal metastasis involved the superior orbit. Orbital pathology showed signet cells with a characteristic immunopathologic pattern. No hereditary syndrome was found. The authors identified only 5 cases in the literature describing colorectal adenocarcinoma metastatic to the orbit, with 2 showing histopathology. The authors believe that this rare case represents the first illustrating bona fide signet cell colorectal cancer involving the orbit. PMID- 21326126 TI - Clinical and pathologic eyelid alterations in a patient with Darier disease. AB - Darier disease (DD) is a rare autosomal dominant dermatosis that has infrequent ocular manifestations, especially those involving the eyelids. The authors describe a patient with long-standing DD who presented with both classic and unique clinical findings. Eyelid biopsy samples studied with electron microscopy demonstrated histopathological changes consistent with DD. The authors postulate how clinical findings not previously reported as "classic" to DD may be associated. To the authors' knowledge, electron micrographs detailing changes associated with DD have not been published for eyelid tissue. PMID- 21326127 TI - Single-suture brow lift in VII palsy. PMID- 21326128 TI - Indications for orbital imaging by the oculoplastic surgeon. AB - OBJECTIVE: To determine the indications for ordering orbital imaging and the indications for ordering CT versus MRI by oculoplastic surgeons and to assess the correlation between surgeon's clinical indications for imaging and the radiologist's diagnosis. DESIGN: Retrospective review of imaging requisitions and radiology reports. PARTICIPANTS: Patients of 4 oculoplastic surgeons who required CT or MRI scans. METHODS: Imaging requisitions and radiology reports of patients from 4 oculoplastic surgeons were reviewed to determine the indication for ordering a CT or MRI scan between March 2006 and March 2009. The indications were then compared with the radiologist's diagnosis. RESULTS: A total of 735 patients were included: 449 (61.1%) female and 286 (38.9%) male, with an average age of 50.1 years and an age range of 7 months to 93 years. Of these patients, a total of 632 CT and 223 MRI scans were ordered, 135 of which were follow-up scans. CONCLUSIONS: The most common indication for CT scan was thyroid disease, followed by orbital tumors and then inflammatory disease, while the most common indication for MRI scan was orbital tumors, followed by inflammatory disease and then thyroid disease. CT scans were more commonly ordered than MRI, largely for trauma and to rule out orbital foreign body. PMID- 21326129 TI - Tenon recession: a novel adjunct to improve outcome in the treatment of large angle strabismus in thyroid eye disease. AB - PURPOSE: Treatment of large-angle strabismus in thyroid eye disease has historically suffered from low success rates. The authors report a novel technique that adds Tenon recession without conjunctival recession to standard extraocular muscle surgery. METHODS: Twenty-six patients with thyroid eye disease associated strabismus with preoperative deviations of >= 25 prism diopters in horizontal or vertical deviations underwent strabismus surgery. The amount of recession for a given muscle was determined by a combined analysis of the preoperative versions, deviation in primary gaze and in gaze opposite the restricted muscle, and intraoperative forced duction testing. Before conjunctival closure, the underlying Tenon layer and associated orbital tissues were recessed and allowed to retract posteriorally. The overlying conjunctiva was subsequently reapproximated to its anatomic position without tension. RESULTS: The average preoperative measurements for horizontal and vertical deviations were 39.2 +/- 13.4 and 45.0 +/- 18.9 prism diopters, respectively. Average postoperative measurements for horizontal and vertical deviations were 3.2 +/- 6.0 and 11.1 +/- 11.9 prism diopters, respectively. Overall, 22 of 26 patients (84.6%) were within 10 prism diopters of intended correction postoperatively and achieved binocular fusion with or without the use of prisms for both distance and near vision. Four had residual deviations that required reoperation, all of which successfully produced binocular vision without the use of prisms. CONCLUSIONS: In the authors' experience, Tenon recession improves outcomes in surgery for large-angle strabismus in thyroid eye disease. PMID- 21326130 TI - Recurrent infarction of sphenoid bone with subperiosteal collection in a child with sickle cell disease. AB - Infarction of the orbital bone in patients with sickle cell disease is very rare. The authors report a young boy who presented twice with marked acute proptosis and eyelid swelling of the right eye resulting from infarction in the greater wing of the sphenoid bone accompanied by an orbital subperiosteal collection. The time interval between the 2 attacks was 3 years. PMID- 21326131 TI - Surgical technique: modified lateral tarsorrhaphy. AB - PURPOSE: The signs of thyroid eye disease include proptosis, eyelid retraction, and exposure of the ocular surface, resulting in a symptomatic and unsatisfactory aesthetic appearance. A number of surgical techniques have been proposed to treat the eyelid sequelae of thyroid eye disease, which vary in both complexity and potential complications; the authors propose a novel technique for correcting inferolateral scleral show. This technique is proposed for cases of mild inferior scleral show (2 mm or less). METHODS: This retrospective consecutive case series includes 7 eyes of 5 patients from 2003 to 2006. All patients underwent surgery by a single surgeon at Moorfields Eye Hospital, London, UK. The surgical technique is composed of 3 principal steps: 1) marking of intended lateral tarsorrhaphy, 2) gray line split and anterior lamella excision, and 3) suturing of upper and lower limbs of lateral canthal tendon/lateral ends of tarsal pates) and canthal angle reformation. RESULTS: Seven eyes of 5 patients underwent the procedure; all patients were women, and their mean age was 49.6 years (range 29 67). Mean inferior scleral show was reduced from 2.0 mm preoperatively (range 1.5 2.5) to 0.3 mm postoperatively (range 0.0-0.5) at 49-month follow up. There were no complications related to the surgical technique, and all patients were satisfied with the postoperative result. One patient with proptosis measuring 24 mm required 2-wall orbital decompression 20 months later. CONCLUSIONS: Patient selection is important for the effective use of the modified tarsorrhaphy technique and should be reserved for those with 2 mm or less of inferior scleral show. Two principal factors to be considered before this eyelid surgery and the use of a box suture in reformation of the lateral canthal angle are discussed. Although a number of surgical procedures are available to manage eyelid malposition secondary to thyroid eye disease, they vary in complexity and severity of complications. The modified tarsorrhaphy technique was effective in the treatment of a specific group of patients who had undergone previous orbital and eyelid surgery for thyroid eye disease. PMID- 21326132 TI - Drug resistance prevalence in human immunodeficiency virus type 1 infected pediatric populations in Honduras and El Salvador during 1989-2009. AB - BACKGROUND: Emergence of viral resistance is a major obstacle for antiretroviral treatment (ART) effectiveness. Human immunodeficiency virus type-1 (HIV-1) variants and drug-resistance mutations were identified in naive and antiretroviral drug-experienced children with virologic failure, in Honduras and El Salvador. METHODS: Dried blood spots (DBS) from 80 individuals (54 from Honduras, 26 from El Salvador) infected during their childhood between 1989 and 2009 were collected in 2009. The HIV pol region was amplified and sequenced to identify antiretroviral-resistant mutations according to the 2009 International AIDS Society. The genotypic drug resistance interpretation was performed using the Stanford algorithm. HIV-1 variants were characterized by phylogenetic analysis and subtyping tools. RESULTS: HIV-1 protease and reverse transcription sequences were obtained from DBS specimens in 71 and 66 patients, respectively, of the 80 patients. All children were native Central Americans carrying subtype B, with a mean age of 9 years, most were male (65%), perinatally infected (96%), with moderate/severe AIDS symptoms (70%), and receiving first line ART at the time of sequencing (65%). Diagnostic delay was frequently observed. Infected children from Honduras presented longer ART experience and clinical outcomes, and more frequent severe symptoms. Resistant variants infected 1 of 11 naive children from El Salvador but none of the perinatally infected naive children from Honduras. Resistance was higher among ART-exposed individuals in both countries and similar for protease inhibitors (16%), nucleoside reverse transcription inhibitors (44%-52%), and nonnucleoside reverse-transcription inhibitors (66.7%). One in 10 pretreated children in each country was infected with resistant viruses to the 3 drug families. CONCLUSIONS: Our data support the need for continued surveillance of resistance patterns using DBS at national levels among naive and pretreated children to optimize the ART regimens. PMID- 21326133 TI - Estimation of the basic reproduction number of enterovirus 71 and coxsackievirus A16 in hand, foot, and mouth disease outbreaks. AB - BACKGROUND: Coxsackievirus A16 (Cox A16) and enterovirus 71 (EV71) are common pathogens causing hand, foot, and mouth disease (HFMD) in pediatric population. Little is known about the basic reproductive number (R0) for these enteroviruses. METHODS: We estimated the R0 of EV71 and of Cox A16 from laboratory-confirmed HFMD outbreaks reported to the Department of Health, from 2004 to 2009. We derived a mathematical model and calculated R0 based on the cumulative number of cases at the initial growth phase of the outbreaks, as determined by the epidemic curves. We tested the association of R0 with settings and sizes of the institution and total number of persons affected. RESULTS: We analyzed 34 outbreaks, 27 caused by Cox A16 and 7 caused by EV71. Assuming the incubation period to be 5 days, the median R0 of EV71 was 5.48 with an interquartile range of 4.20 to 6.51, whereas the median R0 of Cox A16 was 2.50 with an interquartile range of 1.96 to 3.67. The R0 of EV71 was significantly higher than that of CoxA16, P = 0.002; and sensitivity analysis showed the same results. The R0 was not associated with outbreak settings, sizes of the institutions, or number of persons affected. CONCLUSIONS: The R0 for EV71 and for Cox A16 was determined using a model which showed that the R0 for EV71 was higher than that of Cox A16. This finding helps better understand the transmission dynamics of HFMD outbreaks and formulate public health measures for controlling the disease. PMID- 21326134 TI - Causes of death in pediatric patients vertically infected by the human immunodeficiency virus type 1 in Madrid, Spain, from 1982 to mid-2009. AB - BACKGROUND: Effective therapies have increased life expectancy of human immunodeficiency virus (HIV)-infected pediatric patients. We investigated the underlying causes of death, mortality, and acquired immune deficiency syndrome (AIDS) rates in HIV-infected pediatric patients in Madrid, Spain. METHODS: We studied a multicenter cohort of 478 HIV-infected pediatric patients in Madrid. Mortality and AIDS incidence rates, causes of death, CD4 T-cell, and HIV RNA were analyzed during calendar periods (CPs): pre-HAART (highly active antiretroviral therapy) (CP1: 1982-1996) and post-HAART era (CP2: 1997-2009). RESULTS: During 5690 person-years of follow-up 157 (32.8%) deaths occurred. Median age at death increased (CP1: 3.2 years [1.0-6.3] vs. CP2: 7.7 years [3.1-11.4]; P < 0.01). Mortality and AIDS rates decreased 10.6-fold (95% confidence intervals [CI]: 6.9 16.7) and 6.9-fold (95% CI: 5.0-9.6), respectively, between CPs. Nevertheless, mortality was 10.4-fold (95% CI: 5.8-18.8; P < 0.001) higher than in age-similar general population in late-CP2. In all, 169 causes of death were reported. Multiple causes were reported in 16 of 151 (10.6%) patients. In 81.1% (137/169), the causes were AIDS-defining, 11.8% (20/169) HIV-related, and 7.1% (12/169) non HIV-related. Infections were the leading causes (60.8%, 101/166); from 1999 to 2007 the risk of death from infections was 115.9 times (95% CI: 42.0-265.8; P < 0.001) higher than in the age-similar general population. Comorbidity was reported in 66.9% (101/151) of patients. Median HIV-1 RNA at death decreased (CP1: 5.9 [5.0-6.3]; CP2: 5.3 [4.2-5.8]; P < 0.01). CONCLUSIONS: Despite decline in mortality and AIDS rates, it is important to monitor all causes of death as prolonged survival might allow underlying comorbidity to become more clinically relevant. PMID- 21326135 TI - Etiology of meningitis among patients admitted to a tertiary referral hospital in Botswana. AB - This retrospective review evaluated records of cerebrospinal fluid samples between 2000 and 2008 at Princess Marina Hospital in Gaborone, Botswana. Of the 7501 cerebrospinal fluid samples reviewed, Streptococcus pneumoniae (n = 125) and Haemophilus influenzae (n = 60) were the most common bacteria cultured. There were also 1018 cryptococcal and 44 tuberculous meningitis cases. Antimicrobial susceptibilities are described. Public health interventions could decrease the burden of meningitis in Botswana. PMID- 21326136 TI - Effectiveness of serogroup C meningococcal conjugate vaccine: a 7-year follow-up in Quebec, Canada. AB - BACKGROUND: A mass immunization campaign was implemented in 2001 to control a serogroup C meningococcal disease outbreak, and a newly licensed serogroup C meningococcal conjugate vaccine (C-MCV) was used. In 2002, 1 C-MCV dose was routinely offered to children 12 months of age. OBJECTIVE: To assess the epidemiologic effect of the campaign and C-MCV effectiveness during a 7-year period according to age at vaccination and delay since vaccine administration. METHODS: Cases of invasive meningococcal infection reported to public health authorities and the reference laboratory during the period 1990 to 2008 were obtained to calculate year- and age-specific incidence rates. Multiple sources were used to ascertain the immunization status of cases. Immunization registry data were used to estimate age-specific C-MCV uptake rates in different birth cohorts. Vaccine effectiveness was estimated by Mantel-Haenszel method and logistic regression models. RESULTS: After mass immunization campaign, meningococcal C disease incidence decreased markedly not only in highly vaccinated but also in poorly vaccinated and nonvaccinated birth cohorts. Overall vaccine effectiveness was 87.4% (95% CI: 75.4%-94.2%) with lower protection in children vaccinated <2 years of age and waning of protection of higher magnitude in this age group. CONCLUSION: Results support the current Canadian recommendation to provide booster vaccination for adolescents. PMID- 21326137 TI - Laparoscopic donor nephrectomy does not compromise outcomes for pediatric transplant recipients. AB - BACKGROUND: Despite the apparent safety of laparoscopic kidney procurement (laparoscopic donor nephrectomy [LDN]) in adults, doubts have persisted about its use in pediatric recipients, following the publication of a United Network for Organ Sharing analysis, which suggested that rejection rates were higher after LDN when compared with open procurement (open donor nephrectomy [ODN]) for children. The aim of this study was to determine whether acute rejection rates, and graft and patient survival, were worse after LDN for pediatric recipients. The analysis included both short and medium term outcomes. METHODS: The UK Transplant Registry, a validated database with mandatory reporting, was interrogated from 2000 to 2007 for outcomes of pediatric recipients. A total of 306 recipients were identified, 119 of which had LDN. RESULTS: Acute rejection was higher in the ODN group, compared with LDN (40.6% vs. 24.3% P=0.007). Graft survival at 1 year (99.2% vs. 94.3% P=0.03) and 3 years (99.2% vs 91.4%, P=0.01) was worse after ODN. There were more deaths after ODN (4 vs. 0), but this did not reach statistical significance. Cox proportional hazards modeling showed that the negative effect of ODN on graft survival was reduced when adjusted for acute rejection. CONCLUSIONS: LDN seems to be safe for pediatric recipients in both the short and longer terms. PMID- 21326139 TI - Prognostic significance of interleukin-7 receptor-alpha gene polymorphisms in allogeneic stem-cell transplantation: a confirmatory study. AB - BACKGROUND: Interleukin-7 (IL-7) is a hematopoietic cytokine essential for T-cell development in the thymus and for the maintenance of peripheral T cells. A previous study of single nucleotide polymorphisms in the exons of IL-7 receptor alpha-chain (IL-7Ralpha) in a Danish cohort of patients undergoing allogeneic stem-cell transplantation (SCT) identified donor genotype GG at rs1494555 as a risk factor for treatment-related mortality (TRM) after SCT. METHODS: In this validation study, 116 British and French SCT patients and their donors were investigated by sequence-specific primer polymerase chain reaction. RESULTS: Both donor rs1494555GG genotype and the tightly coupled rs1494558TT genotype were significantly associated with grade 3 to 4 acute graft versus host disease. Although both genotypes tended to be associated with increased TRM, this did not translate into altered overall survival. CONCLUSION: The present data indicate that the IL-7 pathway is associated with alloreactivity in SCT, which is in line with the previously observed association between IL-7Ralpha single nucleotide polymorphisms and TRM. PMID- 21326138 TI - Effect of obesity on the outcome of kidney transplantation: a 20-year follow-up. AB - BACKGROUND: Cardiovascular disease is both a major threat to the life expectancy of kidney transplant recipients and an important determinant of late allograft loss. Obesity is an important risk factor for cardiovascular disease. METHODS: We investigated the relation between both pretransplant and 1-year posttransplant body mass index (BMI) with patient and renal graft survival in a cohort of 1810 adult patients. Sixty-one percent of all patients were men; median age (interquartile range [IQR]) was 46 years (35-56 years); median (IQR) pretransplant BMI was 23.0 kg/m (20.8-25.6 kg/m); 1 year after transplantation, the median (IQR) BMI had increased 1.6 kg/m (0.3-3.2 kg/m) and median (IQR) follow-up time was 8.3 years (5.3-12.0 years). We categorized BMI as follows: less than or equal to 20, more than 20 to less than or equal to 25 (normal), more than 25 to less than or equal to 30, and more than 30 (obesity) kg/m. RESULTS: Using a Cox proportional hazards model, after adjustment for cardiovascular risk factors, the relative risks (95% confidence intervals) of death and death censored graft failure during all follow-up for pretransplant obesity compared with normal BMI were 1.22 (0.86-1.74) and 1.34 (1.02-1.77), respectively; for obesity 1 year after transplantation compared with normal BMI, it was 1.39 (1.05 1.86) and 1.39 (1.10-1.74), respectively; and for change in BMI (per 5 kg/m increment) during the first year after transplantation, it was 1.23 (1.01-1.50) and 1.18 (1.01-1.38), respectively. CONCLUSIONS: One year posttransplant BMI and BMI increment are more strongly related to death and graft failure than pretransplant BMI among kidney transplant recipients. Patients with BMI more than 30 kg/m compared with a normal BMI have approximately 20% to 40% higher risk for death and graft failure. PMID- 21326140 TI - DNA libraries for the construction of phage libraries: statistical and structural requirements and synthetic methods. AB - Peptide-based molecular probes identified by bacteriophage (phage) display technology expand the peptide repertoire for in vivo diagnosis and therapy of cancer. Numerous peptides that bind cancer-associated antigens have been discovered by panning phage libraries. However, until now only few of the peptides selected by phage display have entered clinical applications. The success of phage derived peptides essentially depends on the quality of the library screened. This review summarizes the methods to achieve highly homogenous libraries that cover a maximal sequence space. Biochemical and chemical strategies for the synthesis of DNA libraries and the techniques for their integration into the viral genome are discussed in detail. A focus is set on the methods that enable the exclusion of disturbing sequences. In addition, the parameters that define the variability, the minimal numbers of copies per library and the use of alternating panning cycles to avoid the loss of selected hits are evaluated. PMID- 21326141 TI - Peppermint oil decreases the production of virulence-associated exoproteins by Staphylococcus aureus. AB - The present study aimed to evaluate the antimicrobial activity of peppermint oil against Staphylococcus aureus, and further investigate the influence of peppermint oil on S. aureus virulence-related exoprotein production. The data show that peppermint oil, which contained high contents of menthone, isomenthone, neomenthol, menthol, and menthyl acetate, was active against S. aureus with minimal inhibitory concentrations (MICs) ranging from 64-256 ug/mL, and the production of S. aureus exotoxins was decreased by subinhibitory concentrations of peppermint oil in a dose-dependent manner. The findings suggest that peppermint oil may potentially be used to aid in the treatment of S. aureus infections. PMID- 21326142 TI - The influence of comonomer on ethylene/alpha-olefin copolymers prepared using [bis(N-(3-tert butylsalicylidene)anilinato)] titanium (IV) dichloride complex. AB - We describe the synthesis of [bis(N-(3-tert-butylsalicylidene)anilinato)] titanium (IV) dichloride (Ti-FI complex) and examine the effects of comonomer (feed concentration and type) on its catalytic performance and properties of the resulting polymers. Ethylene/1-hexene and ethylene/1-octene copolymers were prepared through copolymerization using Ti-FI catalyst, activated by MAO cocatalyst at 323 K and 50 psi ethylene pressure at various initial comonomer concentrations. The obtained copolymers were characterized by DSC, GPC and 13C NMR. The results indicate that Ti-FI complex performs as a high potential catalyst, as evidenced by high activity and high molecular weight and uniform molecular weight distribution of its products. Nevertheless, the bulky structure of FI catalyst seems to hinder the insertion of alpha-olefin comonomer, contributing to the pretty low comonomer incorporation into the polymer chain. The catalytic activity was enhanced with the comonomer feed concentration, but the molecular weight and melting temperature decreased. By comparison both sets of catalytic systems, namely ethylene/1-hexene and ethylene/1-octene copolymerization, the first one afforded better activity by reason of easier insertion of short chain comonomer. Although 1-hexene copolymers also exhibited higher molecular weight than 1-octene, no significant difference in both melting temperature and crystallinity can be noticed between these comonomers. PMID- 21326143 TI - Maintenance therapy for B-chronic lymphocytic leukemia. AB - Although modern treatment options for B-chronic lymphocytic leukemia (CLL) produce high response rates, virtually all patients relapse, presumably due to the persistence of minimal residual disease (MRD). Novel approaches that maintain response and therefore delay growth of MRD may ultimately improve survival outcomes. In CLL, any type of continued therapy must be not only well tolerated but also convenient to ensure compliance. There has been some exploration of rituximab as maintenance therapy in CLL; however, given its limited clinical activity as a single agent, other options need to be studied. One such agent is the immunomodulatory drug lenalidomide, which has demonstrated clinical activity both in patients with relapsed or refractory CLL and in the frontline setting. Other attractive agents being explored in the maintenance setting include epigallocatechin gallate, curcumin, and the citrus pectin-derived galectin-3 inhibitor GCS-100. These naturally occurring compounds are well tolerated, and they inhibit survival signals in the microenvironment necessary for tumor development, making them well suited for evaluation as maintenance therapy for CLL. PMID- 21326144 TI - Clinical development of kinase inhibitors for the treatment of differentiated thyroid cancer. AB - The incidence of thyroid cancer is growing at a rapid rate, with the majority of cases being differentiated thyroid cancers. Although a significant number of patients with localized disease are cured, a paucity of effective therapies currently exists for patients with recurrent and/or metastatic disease. The translational bridging of critical biologic insights into the pathogenesis of thyroid cancer and the clinical development of specific kinase inhibitors that disrupt these oncogenic pathways has led to exciting progress in clinical thyroid cancer research. This review will present the scientific rationale and clinical trial data gathered to date with kinase inhibitors in differentiated thyroid cancers. PMID- 21326145 TI - New strategies to prevent and manage bone complications in cancer. PMID- 21326146 TI - Chemotherapy regimens in metastatic breast cancer. PMID- 21326147 TI - The hypercoagulability of intravenous immunoglobulin. PMID- 21326148 TI - Omacetaxine: the FDA decision. PMID- 21326149 TI - A 51-year-old man with rapidly progressive metastatic sarcomatoid renal cell carcinoma: an apparent complete clinical response to second-line therapy with sunitinib and low-dose interferon-alpha. PMID- 21326150 TI - Review: therapy for kidney cancer with a sarcomatoid component. PMID- 21326151 TI - Updates in the treatment of neuroblastoma. PMID- 21326152 TI - Advances in CML: The role of allogeneic hematopoietic stem cell transplantation. PMID- 21326153 TI - PARP inhibition outside of BRCA mutation carriers. PMID- 21326154 TI - Abiraterone in prostate cancer. PMID- 21326155 TI - Future directions for antiplatelet drugs. PMID- 21326156 TI - Adjuvant therapy for stage II and III colon cancer. PMID- 21326157 TI - Umbilical cord blood transplantation. AB - Umbilical cord blood transplantation (CBT) has been widely used as an alternative source of hematopoietic cell support for stem cell transplant patients. CBT offers several advantages over traditional stem cell sources, such as immediate availability, absence of risk for donors, lower risk of acute graft-versus-host disease, and a less stringent requirement for human leukocyte antigen matching. Recent studies suggest that CBT is a safe and effective strategy for adult patients lacking a suitable related or unrelated donor. However, delayed engraftment and delayed immune reconstitution are significant clinical problems. Novel strategies, such as the use of multiple donors, cotransplantation with accessory cells, ex vivo expansion of cord blood hematopoietic progenitor cells, graft manipulation to improve T-cell recovery, and pharmacologic interventions to restore early thymopoiesis, hold promise to enhance engraftment and immune reconstitution after CBT. These approaches may significantly increase the quality and availability of cord blood for transplantation. PMID- 21326158 TI - Successful treatment of amegakaryocytic thrombocytopenia with eltrombopag in a patient with systemic lupus erythematosus (SLE). PMID- 21326159 TI - Acquired amegakaryocytic thrombocytopenia: potential role of thrombopoietin receptor agonists. PMID- 21326160 TI - Importance of circulating tumor cells in diagnosis, prognosis, and treatment selection. PMID- 21326161 TI - Positive blood cultures. PMID- 21326162 TI - Improving the therapeutic index of IL-2. PMID- 21326163 TI - Chemoimmunotherapy in chronic lymphocytic leukemia. PMID- 21326164 TI - Importance of accurate HER2 testing in patients with metastatic breast cancer. PMID- 21326166 TI - Novel agents for the treatment of chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Currently, the most effective treatment for CLL consists of a combination of fludarabine, cyclophosphamide, and rituximab. Although this approach has encouraging results, patients with CLL eventually relapse and require additional therapies. Many of the current therapeutic regimens for CLL are myelotoxic, immunosuppressive, and associated with infectious complications. Targeted therapies can often minimize these complications. The US Food and Drug Administration has recently approved 2 agents, bendamustine and ofatumumab, for the treatment of CLL. Emerging therapies ranging from new monoclonal antibodies to small molecules that interfere with vital pathways in signal transduction and cell cycle regulation are currently being developed. This article will focus on novel agents in earlier development phases for CLL, including the immunomodulator lenalidomide; monoclonal antibodies, such as lumiliximab, GA-101, and small molecule immunopharmaceuticals; BCL-2 inhibitors, such as oblimersen, obatoclax, and ABT-263; and protein kinase inhibitors, such as flavopiridol, spleen tyrosine kinase inhibitors, and phosphatidylinositol 3-kinase inhibitors. PMID- 21326167 TI - Soft tissue sarcoma mimicking eosinophilic leukemia. PMID- 21326168 TI - Review: eosinophils and eosinophilic leukemia. PMID- 21326169 TI - Ex vivo culture of patient tissue & examination of gene delivery. AB - This video describes the use of patient tissue as an ex vivo model for the study of gene delivery. Fresh patient tissue obtained at the time of surgery is sliced and maintained in culture. The ex vivo model system allows for the physical delivery of genes into intact patient tissue and gene expression is analysed by bioluminescence imaging using the IVIS detection system. The bioluminescent detection system demonstrates rapid and accurate quantification of gene expression within individual slices without the need for tissue sacrifice. This slice tissue culture system may be used in a variety of tissue types including normal and malignant tissue and allows us to study the effects of the heterogeneous nature of intact tissue and the high degree of variability between individual patients. This model system could be used in certain situations as an alternative to animal models and as a complementary preclinical mode prior to entering clinical trial. PMID- 21326170 TI - Chronic potassium depletion increases adrenal progesterone production that is necessary for efficient renal retention of potassium. AB - Modern dietary habits are characterized by high-sodium and low-potassium intakes, each of which was correlated with a higher risk for hypertension. In this study, we examined whether long-term variations in the intake of sodium and potassium induce lasting changes in the plasma concentration of circulating steroids by developing a mathematical model of steroidogenesis in mice. One finding of this model was that mice increase their plasma progesterone levels specifically in response to potassium depletion. This prediction was confirmed by measurements in both male mice and men. Further investigation showed that progesterone regulates renal potassium handling both in males and females under potassium restriction, independent of its role in reproduction. The increase in progesterone production by male mice was time dependent and correlated with decreased urinary potassium content. The progesterone-dependent ability to efficiently retain potassium was because of an RU486 (a progesterone receptor antagonist)-sensitive stimulation of the colonic hydrogen, potassium-ATPase (known as the non-gastric or hydrogen, potassium-ATPase type 2) in the kidney. Thus, in males, a specific progesterone concentration profile induced by chronic potassium restriction regulates potassium balance. PMID- 21326171 TI - Aberrant glycosylation of IgA1 is inherited in both pediatric IgA nephropathy and Henoch-Schonlein purpura nephritis. AB - Serum galactose-deficient immunoglobulin A1 (Gd-IgA1) is an inherited risk factor for adult IgA nephropathy (IgAN). In this paper, we determined the heritability of serum Gd-IgA1 levels in children with IgAN and Henoch-Schonlein purpura nephritis (HSPN), two disorders with clinical phenotypes sharing common pathogenic mechanisms. Serum Gd-IgA1 concentrations were quantified using a Helix aspersa-lectin-based enzyme-linked immunosorbent assay. As a group, 34 children with either disorder (20 with HSPN and 14 with IgAN) had significantly higher Gd IgA1 levels compared with 51 age- and ethnicity-matched pediatric controls. Serum levels of Gd-IgA1 were also elevated in a large fraction of 54 first-degree relatives of pediatric IgAN and HSPN patients compared with 141 unrelated healthy adult controls. A unilineal transmission of the trait was found in 17, bilineal transmission in 1, and sporadic occurrence in 5 of 23 families when both parents and the patient were analyzed. There was a significant age-, gender-, and household-adjusted heritability of serum galactose-deficient IgA1 estimated at 76% in pediatric IgAN and at 64% in HSPN patients. Thus, serum galactose deficient IgA1 levels are highly inherited in pediatric patients with IgAN and HSPN, providing support for another shared pathogenic link between these disorders. PMID- 21326172 TI - Myosin drives autophagy in a pathway linking Atg1 to Atg9. PMID- 21326173 TI - Retinoblastoma protein goes green: the role of RBR in Arabidopsis meiosis. PMID- 21326174 TI - AMPK and autophagy get connected. PMID- 21326176 TI - Sick worms help elucidate viral infections. PMID- 21326177 TI - Raise a glass to vascular health. PMID- 21326180 TI - Miscommunication involving 'standard care'. PMID- 21326181 TI - Miscommunication involving 'standard care'. Response to protocol review scenario: revise protocol form. PMID- 21326182 TI - Miscommunication involving 'standard care'. Response to protocol review scenario: specify all medications. PMID- 21326183 TI - Miscommunication involving 'standard care'. Response to protocol review scenario: a word from OLAW. PMID- 21326184 TI - Miscommunication involving 'standard care'. Response to protocol review scenario: describe in detail. PMID- 21326185 TI - Enlarged mouse preputial glands. PMID- 21326187 TI - Urolithiasis and cystotomy in the rabbit. AB - Cystotomy is a surgical incision into the urinary bladder, which may be required for removal of calculi, diagnosis of tumors or refractory urinary tract infections, or repair of ectopic ureters and ruptured bladders. This column describes the indications and techniques for cystotomy in the rabbit. PMID- 21326188 TI - Flushing induction chambers used for rodent anesthesia to reduce waste anesthetic gas. AB - Anesthetic induction chambers used for medical research are a substantial source of waste anesthetic gas (WAG). Ideally, any generated waste gas should be actively vented away from personnel operating the chamber by either a ventilated hood or snorkel. Unfortunately, the ideal environment for anesthetizing rodents is not always available. In an effort to create a safer environment, the authors designed a system to reduce WAG. This system is portable, can be adapted to different precision vaporizing anesthetic systems and fits in a variety of physical locations. The system flushes anesthetic gas out of an induction chamber before operators open the chamber. To ensure that the system was adequately flushing the anesthetic gas, the authors measured WAG concentration in the environment above the induction chamber and directly behind the vent of an activated charcoal filter. They also compared the efficiency of the filters in vertical and horizontal positions. Finally, they measured the recovery time for mice and rats after flushing the anesthetic gas from an induction chamber. The results show that flushing the induction chamber was an inexpensive and effective method for reducing WAG accumulation in the air surrounding the chamber. PMID- 21326189 TI - Analgesic effects of tramadol, carprofen or multimodal analgesia in rats undergoing ventral laparotomy. AB - In this study, the authors evaluated the analgesic efficacy of tramadol (an opioid-like analgesic), carprofen (a nonsteroidal anti-inflammatory drug) and a combination of both drugs (multimodal therapy) in a rat laparotomy model. The authors randomly assigned rats to undergo either surgery (abdominal laparotomy with visceral manipulation and anesthesia) or anesthesia only. Rats in each group were treated with tramadol (12.5 mg per kg body weight), carprofen (5 mg per kg body weight), a combination of tramadol and carprofen (12.5 mg per kg body weight and 5 mg per kg body weight, respectively) or saline (anesthesia control group only; 5 mg per kg body weight). The authors administered analgesia 10 min before anesthesia, 4 h after surgery or (for the rats that received anesthesia only) anesthesia and 24 h after surgery or anesthesia. They measured locomotor activity, running wheel activity, feed and water consumption, body weight and fecal corticosterone concentration of each animal before and after surgery. Clinical observations were made after surgery or anesthesia to evaluate signs of pain and distress. The authors found that carprofen, tramadol and a combination of carprofen and tramadol were all acceptable analgesia regimens for a rat laparotomy model. PMID- 21326190 TI - Promoting biomedical research. PMID- 21326191 TI - Continuous, but not intermittent, antipsychotic drug delivery intensifies the pursuit of reward cues. AB - Chronic exposure to antipsychotic medications can persistently change brain dopamine systems. Most studies on the functional significance of these neural changes have focused on motor behavior and few have addressed how long-term antipsychotic treatment might influence dopamine-mediated reward function. We asked, therefore, whether a clinically relevant antipsychotic treatment regimen would alter the incentive motivational properties of a reward cue. We assessed the ability of a Pavlovian-conditioned stimulus to function as a conditioned reward, as well as to elicit approach behavior in rats treated with haloperidol, either continuously (achieved via subcutaneous osmotic minipump) or intermittently (achieved via daily subcutaneous injections). Continuous, but not intermittent, treatment enhanced the ability of amphetamine to potentiate the conditioned reinforcing effects of a cue associated with water. This effect was not related to differences in the ability to attribute predictive value to a conditioned stimulus (as measured by conditioned approach behavior), but was potentially linked to the development of behavioral supersensitivity to amphetamine and to augmented amphetamine-induced immediate early-gene expression (c-fos and Nur77) in dorsal striatopallidal and striatonigral cells. By enhancing the ability of reward cues to control behavior and by intensifying dopamine mediated striatopallidal and striatonigral cell activity, standard (ie, continuous) antipsychotic treatment regimens might exacerbate drug-seeking and drug-taking behavior in schizophrenia. Achieving regular but transiently high antipsychotic levels in the brain (as modeled in the intermittent condition) might be a viable option to prevent these changes. This possibility should be explored in the clinic. PMID- 21326192 TI - Child MU-opioid receptor gene variant influences parent-child relations. AB - Variation in the MU-opioid receptor gene has been associated with early social behavior in mice and rhesus macaques. The current study tested whether the functional OPRM1 A118G predicted various indices of social relations in children. The sample included 226 subjects of self-reported European ancestry (44% female; mean age 13.6, SD=2.2) who were part of a larger representative study of children aged 9-17 years in rural North Carolina. Multiple aspects of recent (past 3 months) parent-child relationship were assessed using the Child and Adolescent Psychiatric Assessment. Parent problems were coded based upon a lifetime history of mental health problems, substance abuse, or criminality. Child genotype interacted with parent behavior such that there were no genotype differences for those with low levels of parent problems; however, when a history of parent problems was reported, the G allele carriers had more enjoyment of parent-child interactions (mean ratio (MR)=3.5, 95% CI=1.6, 8.0) and fewer arguments (MR=3.1, 95% CI=1.1, 8.9). These findings suggest a role for the OPRM1 gene in the genetic architecture of social relations in humans. In summary, a variant in the MU opioid receptor gene (118G) was associated with improved parent-child relations, but only in the context of a significant disruption in parental functioning. PMID- 21326193 TI - Group II metabotropic glutamate receptor agonist ameliorates MK801-induced dysfunction of NMDA receptors via the Akt/GSK-3beta pathway in adult rat prefrontal cortex. AB - Pharmacological intervention targeting mGluRs has emerged as a potential treatment for schizophrenia, whereas the mechanisms involved remain elusive. We explored the antipsychotic effects of an mGluR2/3 agonist in the MK-801 model of schizophrenia in the rat prefrontal cortex. We found that the mGluR2/3 agonist LY379268 effectively recovered the disrupted expression of NMDA receptors induced by MK-801 administration. This effect was attributable to the direct regulatory action of LY379268 on NMDA receptors via activation of the Akt/GSK-3beta signaling pathway. As occurs with the antipsychotic drug clozapine, acute treatment with LY379268 significantly increased the expression and phosphorylation of NMDA receptors, as well as Akt and GSK-3beta. Physiologically, LY379268 significantly enhanced NMDA-induced current in prefrontal neurons and a GSK-3beta inhibitor occluded this effect. In contrast to the widely proposed mechanism of modulating presynaptic glutamate release, our results strongly argue that mGluR2/3 agonists modulate the function of NMDA receptors through postsynaptic actions and reverse the MK-801-induced NMDA dysfunction via the Akt/GSK-3beta pathway. This study provides novel evidence for postsynaptic mechanisms of mGluR2/3 in regulation of NMDA receptors and presents useful insights into the mechanistic actions of mGluR2/3 agonists as potential antipsychotic agents for treating schizophrenia. PMID- 21326194 TI - Pharmacological blockade of 5-HT7 receptors as a putative fast acting antidepressant strategy. AB - Current antidepressants still display unsatisfactory efficacy and a delayed onset of therapeutic action. Here we show that the pharmacological blockade of serotonin 7 (5-HT(7)) receptors produced a faster antidepressant-like response than the commonly prescribed antidepressant fluoxetine. In the rat, the selective 5-HT(7) receptor antagonist SB-269970 counteracted the anxiogenic-like effect of fluoxetine in the open field and exerted an antidepressant-like effect in the forced swim test. In vivo, 5-HT(7) receptors negatively regulate the firing activity of dorsal raphe 5-HT neurons and become desensitized after long-term administration of fluoxetine. In contrast with fluoxetine, a 1-week treatment with SB-269970 did not alter 5-HT firing activity but desensitized cell body 5-HT autoreceptors, enhanced the hippocampal cell proliferation, and counteracted the depressive-like behavior in olfactory bulbectomized rats. Finally, unlike fluoxetine, early-life administration of SB-269970, did not induce anxious/depressive-like behaviors in adulthood. Together, these findings indicate that the 5-HT(7) receptor antagonists may represent a new class of antidepressants with faster therapeutic action. PMID- 21326195 TI - Chronic high-fat diet drives postnatal epigenetic regulation of MU-opioid receptor in the brain. AB - Opioid system dysregulation has been observed in both genetic and high-fat diet (HFD)-induced models of obesity. An understanding of the molecular mechanisms of MOR transcriptional regulation, particularly within an in vivo context, is lacking. Using a diet-induced model of obesity (DIO), mice were fed a high-fat diet (60% calories from fat) from weaning to >18 weeks of age. Compared with mice fed the control diet, DIO mice had a decreased preference for sucrose. MOR mRNA expression was decreased in reward-related circuitry (ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC)) but not the hypothalamus, important in the homeostatic regulation of feeding. DNA methylation is an epigenetic modification that links environmental exposures to altered gene expression. We found a significant increase in DNA methylation in the MOR promoter region within the reward-related brain regions. Methyl CpG-binding protein 2 (MeCP2) can bind methylated DNA and repress transcription, and DIO mice showed increased binding of MeCP2 to the MOR promoter in reward-related regions of the brain. Finally, using ChIP assays we examined H3K9 methylation (inactive chromatin) and H3 acetylation (active chromatin) within the MOR promoter region and found increased H3K9 methylation and decreased H3 acetylation. These data are the first to identify DNA methylation, MeCP2 recruitment, and chromatin remodeling as mechanisms leading to transcriptional repression of MOR in the brains of mice fed a high-fat diet. PMID- 21326196 TI - Human Ecstasy use is associated with increased cortical excitability: an fMRI study. AB - The serotonergic neurotoxin, 3,4-methylenedioxymethamphetamine (MDMA/Ecstasy), is a highly popular recreational drug. Human recreational MDMA users have neurocognitive and neuropsychiatric impairments, and human neuroimaging data are consistent with animal reports of serotonin neurotoxicity. However, functional neuroimaging studies have not found consistent effects of MDMA on brain neurophysiology in human users. Several lines of evidence suggest that studying MDMA effects in visual system might reveal the general cortical and subcortical neurophysiological consequences of MDMA use. We used 3 T functional magnetic resonance imaging during visual stimulation to compare visual system lateral geniculate nucleus (LGN) and Brodmann Area (BA) 17 and BA 18 activation in 20 long abstinent (479.95+/-580.65 days) MDMA users and 20 non-MDMA user controls. Lifetime quantity of MDMA use was strongly positively correlated with blood oxygenation level-dependent (BOLD) signal intensity in bilateral LGN (r(s)=0.59; p=0.007), BA 17 (r(s)=0.50; p=0.027), and BA 18 (r(s)=0.48; p=0.031), and with the spatial extent of activation in BA 17 (r(s)=0.059; p=0.007) and BA 18 (r(s)=0.55; p=0.013). There were no between-group differences in brain activation in any region, but the heaviest MDMA users showed a significantly greater spatial extent of activation than controls in BA 17 (p=0.031) and BA 18 (p=0.049). These results suggest that human recreational MDMA use may be associated with a long lasting increase in cortical excitability, possibly through loss of serotonin input to cortical and subcortical regions. When considered in the context of previous results, cortical hyper-excitability may be a biomarker for MDMA-induced serotonin neurotoxicity. PMID- 21326197 TI - Transcutaneous immunization as preventative and therapeutic regimens to protect against experimental otitis media due to nontypeable Haemophilus influenzae. AB - We have developed three nontypeable Haemophilus influenzae (NTHI) adhesin-derived immunogens that are significantly efficacious against experimental otitis media (OM) due to NTHI when delivered parenterally. We now expanded our preventative immunization strategies to include transcutaneous immunization (TCI) as a less invasive, but potentially equally efficacious, regimen to prevent OM due to NTHI. Additionally, we examined the potential of TCI as a therapeutic immunization regimen to resolve ongoing experimental OM. Preventative immunization with NTHI outer membrane protein (OMP) P5- and type IV pilus-targeted immunogens, delivered with the adjuvant LT(R192G-L211A), induced significantly earlier clearance of NTHI from the nasopharynges and middle ears of challenged chinchillas compared with receipt of immunogen or adjuvant alone. Moreover, therapeutic immunization resulted in significant resolution of established NTHI biofilms from the middle ear space of animals compared with controls. These data advocate TCI with the adhesin-directed immunogens as an efficacious regimen for prevention and resolution of experimental NTHI-induced OM. PMID- 21326198 TI - Cancer biology: Role of nuclear PTEN revealed. PMID- 21326199 TI - HTRA proteases: regulated proteolysis in protein quality control. AB - Controlled proteolysis underlies a vast diversity of protective and regulatory processes that are of key importance to cell fate. The unique molecular architecture of the widely conserved high temperature requirement A (HTRA) proteases has evolved to mediate critical aspects of ATP-independent protein quality control. The simple combination of a classic Ser protease domain and a carboxy-terminal peptide-binding domain produces cellular factors of remarkable structural and functional plasticity that allow cells to rapidly respond to the presence of misfolded or mislocalized polypeptides. PMID- 21326200 TI - Moving into the cell: single-molecule studies of molecular motors in complex environments. AB - Much has been learned in the past decades about molecular force generation. Single-molecule techniques, such as atomic force microscopy, single-molecule fluorescence microscopy and optical tweezers, have been key in resolving the mechanisms behind the power strokes, 'processive' steps and forces of cytoskeletal motors. However, it remains unclear how single force generators are integrated into composite mechanical machines in cells to generate complex functions such as mitosis, locomotion, intracellular transport or mechanical sensory transduction. Using dynamic single-molecule techniques to track, manipulate and probe cytoskeletal motor proteins will be crucial in providing new insights. PMID- 21326201 TI - Submillimetre galaxies reside in dark matter haloes with masses greater than 3 * 10(11) solar masses. AB - The extragalactic background light at far-infrared wavelengths comes from optically faint, dusty, star-forming galaxies in the Universe with star formation rates of a few hundred solar masses per year. These faint, submillimetre galaxies are challenging to study individually because of the relatively poor spatial resolution of far-infrared telescopes. Instead, their average properties can be studied using statistics such as the angular power spectrum of the background intensity variations. A previous attempt at measuring this power spectrum resulted in the suggestion that the clustering amplitude is below the level computed with a simple ansatz based on a halo model. Here we report excess clustering over the linear prediction at arcminute angular scales in the power spectrum of brightness fluctuations at 250, 350 and 500 MUm. From this excess, we find that submillimetre galaxies are located in dark matter haloes with a minimum mass, M(min), such that log(10)[M(min)/M(?)] = 11.5(+0.7)(-0.2) at 350 MUm, where M(?) is the solar mass. This minimum dark matter halo mass corresponds to the most efficient mass scale for star formation in the Universe, and is lower than that predicted by semi-analytical models for galaxy formation. PMID- 21326202 TI - Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. AB - Inflammatory mechanisms influence tumorigenesis and metastatic progression even in cancers whose aetiology does not involve pre-existing inflammation or infection, such as breast and prostate cancers. For instance, prostate cancer metastasis is associated with the infiltration of lymphocytes into advanced tumours and the upregulation of two tumour-necrosis-factor family members: receptor activator of nuclear factor-kappaB (RANK) ligand (RANKL) and lymphotoxin. But the source of RANKL and its role in metastasis have not been established. RANKL and its receptor RANK control the proliferation of mammary lobuloalveolar cells during pregnancy through inhibitor of nuclear factor-kappaB (IkappaB) kinase-alpha (IKK-alpha), a protein kinase that is needed for the self renewal of mammary cancer progenitors and for prostate cancer metastasis. We therefore examined whether RANKL, RANK and IKK-alpha are also involved in mammary/breast cancer metastasis. Indeed, RANK signalling in mammary carcinoma cells that overexpress the proto-oncogene Erbb2 (also known as Neu), which is frequently amplified in metastatic human breast cancers, was important for pulmonary metastasis. Metastatic spread of Erbb2-transformed carcinoma cells also required CD4(+)CD25(+) T cells, whose major pro-metastatic function was RANKL production. Most RANKL-producing T cells expressed forkhead box P3 (FOXP3), a transcription factor produced by regulatory T cells, and were located next to smooth muscle actin (SMA)(+) stromal cells in mouse and human breast cancers. The dependence of pulmonary metastasis on T cells was replaceable by exogenous RANKL, which also stimulated pulmonary metastasis of RANK(+) human breast cancer cells. These results are consistent with the adverse impact of tumour-infiltrating CD4(+) or FOXP3(+) T cells on human breast cancer prognosis and suggest that the targeting of RANKL-RANK can be used in conjunction with the therapeutic elimination of primary breast tumours to prevent recurrent metastatic disease. PMID- 21326204 TI - Consequences of climate change on the tree of life in Europe. AB - Many species are projected to become vulnerable to twenty-first-century climate changes, with consequent effects on the tree of life. If losses were not randomly distributed across the tree of life, climate change could lead to a disproportionate loss of evolutionary history. Here we estimate the consequences of climate change on the phylogenetic diversities of plant, bird and mammal assemblages across Europe. Using a consensus across ensembles of forecasts for 2020, 2050 and 2080 and high-resolution phylogenetic trees, we show that species vulnerability to climate change clusters weakly across phylogenies. Such phylogenetic signal in species vulnerabilities does not lead to higher loss of evolutionary history than expected with a model of random extinctions. This is because vulnerable species have neither fewer nor closer relatives than the remaining clades. Reductions in phylogenetic diversity will be greater in southern Europe, and gains are expected in regions of high latitude or altitude. However, losses will not be offset by gains and the tree of life faces a trend towards homogenization across the continent. PMID- 21326203 TI - Intrinsic transition of embryonic stem-cell differentiation into neural progenitors. AB - The neural fate is generally considered to be the intrinsic direction of embryonic stem (ES) cell differentiation. However, little is known about the intracellular mechanism that leads undifferentiated cells to adopt the neural fate in the absence of extrinsic inductive signals. Here we show that the zinc finger nuclear protein Zfp521 is essential and sufficient for driving the intrinsic neural differentiation of mouse ES cells. In the absence of the neural differentiation inhibitor BMP4, strong Zfp521 expression is intrinsically induced in differentiating ES cells. Forced expression of Zfp521 enables the neural conversion of ES cells even in the presence of BMP4. Conversely, in differentiation culture, Zfp521-depleted ES cells do not undergo neural conversion but tend to halt at the epiblast state. Zfp521 directly activates early neural genes by working with the co-activator p300. Thus, the transition of ES cell differentiation from the epiblast state into neuroectodermal progenitors specifically depends on the cell-intrinsic expression and activator function of Zfp521. PMID- 21326205 TI - Preadipocytes of type 2 diabetes subjects display an intrinsic gene expression profile of decreased differentiation capacity. AB - OBJECTIVE: Insulin resistance and type 2 diabetes mellitus (T2DM) are associated with increased adipocyte size, altered secretory pattern and decreased differentiation of preadipocytes. In this study, we identified the underlying molecular processes in preadipocytes of T2DM patients, a characteristic for the development of T2DM. DESIGN AND PARTICIPANTS: Preadipocyte cell cultures were prepared from subcutaneous fat biopsies of seven T2DM patients (age 53 +/- 12 years; body mass index (BMI) 34 +/- 5 kg m(-2)) and nine control subjects (age 51 +/- 12 years; BMI 30 +/- 3 kg m(-2)). Microarray analysis was used to identify altered processes between the T2DM and control preadipocytes. RESULTS: Gene expression profiling showed changed expression of transcription regulators involved in adipogenesis and in extracellular matrix remodeling, actin cytoskeleton and integrin signaling genes, which indicated decreased capacity to differentiate. Additionally, genes involved in insulin signaling and lipid metabolism were downregulated, and inflammation/apoptosis was upregulated in T2DM preadipocytes. CONCLUSION: Decreased expression of genes involved in differentiation can provide a molecular basis for the reduced adipogenesis of preadipocytes of T2DM subjects, leading to reduced formation of adipocytes in subcutaneous fat depots, and ultimately leading to ectopic fat storage. PMID- 21326206 TI - Dutch versus English advantage in the epidemic of central and generalised obesity is not shared by ethnic minority groups: comparative secondary analysis of cross sectional data. AB - BACKGROUND: Ethnic minority groups in Western European countries tend to have higher levels of overweight than the majority populations for reasons that are poorly understood. Investigating relative differences between countries could enable an investigation of the importance of national context in determining these inequalities. OBJECTIVE: To explore: (1) whether Indian and African origin populations in England and the Netherlands are similarly disadvantaged compared with the White populations in terms of the prevalence of overweight and central obesity; (2) whether the previously known Dutch advantage of relatively low overweight prevalence is also observed in Dutch ethnic minority groups and (3) the contribution of health behaviour and socio-economic position to the differences observed. METHODS: Secondary analyses of population-based studies of 16 406 participants from England and the Netherlands. Prevalence ratios were estimated using regression models. RESULTS: Except for African men, ethnic minority groups in both countries had higher rates of overweight and central obesity than their White counterparts. However, the Dutch minority groups were relatively more disadvantaged than English minority groups as compared with the majority populations. The Dutch advantage of the low prevalence of obesity was only seen in White men and women and African men. In contrast, English-Indian (prevalence ratio=0.87, 95% confidence interval (CI): 0.81-0.93) and English Caribbean (prevalence ratio=0.82, 95% CI: 0.76-0.89) women were less centrally obese than their Dutch equivalents. The Dutch-Indian men were very similar to the English-Indian men. The contribution of health behaviour and socio-economic position to the observed differences were small. CONCLUSION: Contrary to the patterns in White groups, the Dutch ethnic minority women were more obese than their English equivalents. More work is needed to identify factors that may contribute to these observed differences. PMID- 21326207 TI - Lifelong doubling of mortality in men entering adult life as obese. AB - BACKGROUND: The association between obesity in adults and excess morbidity and mortality is well established, but the impact of being obese in early adulthood on health throughout adult life needs elucidation. We investigated the all-cause mortality until 80 years of age in men starting adult life as obese. METHODS: Among 362,200 Danish young men, examined for military service between 1943 and 1977, all obese (defined as body mass index (BMI >= 31.0 kg m(-2)), and, as controls, a random 1% sample of the remaining population were identified. A total of 1862 obese, corresponding to all men above the 99.5 percentile in this population, and 3476 controls were included, at a median age of 19 years (range: 18-25 years of age). They were followed until 2007 and Cox regression models were used to estimate the mortality in the obese relative to the controls. In addition, two reference groups were used: normal weight men (BMI: 18.5-24.9 kg m( 2)) and the men with the lowest mortality in this cohort (BMI: 22.0-24.9 kg m( 2)). RESULTS: During the 65 years of follow-up, 1191 men died. At all ages from 18 to 80 years, the mortality in the obese was twice that of the controls (hazard ratio (HR): 2.10; 95% confidence interval (CI): 1.84-2.39). The median survival proportion (0.5) was reached about 8 years earlier in the obese than in either of the reference groups. Relative to the normal weight and men with the lowest mortality HRs of 2.14 (95% CI: 1.86-2.45) and 2.38 (95% CI: 2.00-2.85), respectively, were estimated for the obese. Neither year of birth nor education significantly influenced the excess mortality. CONCLUSION: Men entering adult life as obese experience a lifelong doubling of mortality, a finding that strongly supports the continued need to avoid beginning adult life as obese. PMID- 21326208 TI - Investigations of the human endocannabinoid system in two subcutaneous adipose tissue depots in lean subjects and in obese subjects before and after weight loss. AB - CONTEXT: Endocannabinoids (ECs) have a role in obesity by affecting appetite and through peripheral effects. Obesity is associated with a dysregulation of the endocannabinoid system (ECS). OBJECTIVE: We aimed to determine the ECS in subcutaneous adipose tissue (AT) in obese subject and investigate the influence of diet-induced weight loss on this system. DESIGN: The obese study participants underwent a 12 weeks diet regimen resulting in 10-12% weight loss. All study participants underwent fasting blood samples and AT biopsies from abdomen and gluteal region, the obese subjects both before and after weight loss. SETTING AND PARTICIPANTS: A total of 21 healthy obese individuals (10 men/11 women, age 39.5 +/- 1.6 years, body mass index (BMI): 37.5 +/- 0.8 kg m(-2)) and 21 age- and gender-matched lean subjects (BMI: 23.8 +/- 0.4 kg m(-2)) were studied. MAIN OUTCOME MEASURES: The activity of ECS in AT was determined by measuring arachidonoyl glycerol (2-AG) and N-arachidonoylethanolamine/anandamide in AT by mass spectrometry and gene expressions of enzymes and receptors involved in the ECS. RESULTS: The EC, 2-AG was reduced in obese individuals in the gluteal AT depot (P<0.01). Moreover, 2-AG increased in both depots in the obese subjects following weight loss (P<0.05). The gene expression of the CB1 was either not affected by the obese state (in the gluteal AT depot) or reduced (in the abdominal depot, P<0.05) and significantly affected by weight loss. The expression of the degrading enzymes FAAH, FAAH2, MGL and MGL2 was differently affected by obesity, AT depot and weight loss. CONCLUSION: We found reduced levels of 2-AG in subcutaneous AT in obesity, which increased after weight loss. In abdominal AT, the low CB1 expression was normalised after weight loss, whereas in gluteal AT the CB1 expression was reduced after weight loss. These findings support the concept of a dysregulated ECS in AT in association with obesity. PMID- 21326209 TI - Child and adolescent fast-food choice and the influence of calorie labeling: a natural experiment. AB - OBJECTIVE: Obesity is an enormous public health problem and children have been particularly highlighted for intervention. Of notable concern is the fast-food consumption of children . However, we know very little about how children or their parents make fast-food choices, including how they respond to mandatory calorie labeling. We examined children's and adolescents' fast-food choice and the influence of calorie labels in low-income communities in New York City (NYC) and in a comparison city (Newark, NJ). DESIGN: Natural experiment: Survey and receipt data were collected from low-income areas in NYC, and Newark, NJ (as a comparison city), before and after mandatory labeling began in NYC. Study restaurants included four of the largest chains located in NYC and Newark: McDonald's, Burger King, Wendy's and Kentucky Fried Chicken. SUBJECTS: A total of 349 children and adolescents aged 1-17 years, who visited the restaurants with their parents (69%) or alone (31%) before or after labeling was introduced. In total, 90% were from racial or ethnic minority groups. RESULTS: We found no statistically significant differences in calories purchased before and after labeling; many adolescents reported noticing calorie labels after their introduction (57% in NYC) and a few considered the information when ordering (9%). Approximately 35% of adolescents ate fast food six or more times per week and 72% of adolescents reported that taste was the most important factor in their meal selection. Adolescents in our sample reported that parents have some influence on their meal selection. CONCLUSIONS: Adolescents in low-income communities notice calorie information at similar rates as adults, although they report being slightly less responsive to it than adults. We did not find evidence that labeling influenced adolescent food choice or parental food choices for children in this population. PMID- 21326210 TI - The Arabidopsis peptide kiss of death is an inducer of programmed cell death. AB - Programmed cell death (PCD) has a key role in defence and development of all multicellular organisms. In plants, there is a large gap in our knowledge of the molecular machinery involved at the various stages of PCD, especially the early steps. Here, we identify kiss of death (KOD) encoding a 25-amino-acid peptide that activates a PCD pathway in Arabidopsis thaliana. Two mutant alleles of KOD exhibited a reduced PCD of the suspensor, a single file of cells that support embryo development, and a reduced PCD of root hairs after a 55 degrees C heat shock. KOD expression was found to be inducible by biotic and abiotic stresses. Furthermore, KOD expression was sufficient to cause death in leaves or seedlings and to activate caspase-like activities. In addition, KOD-induced PCD required light in leaves and was repressed by the PCD-suppressor genes AtBax inhibitor 1 and p35. KOD expression resulted in depolarization of the mitochondrial membrane, placing KOD above mitochondria dysfunction, an early step in plant PCD. A KOD?GFP fusion, however, localized in the cytosol of cells and not mitochondria. PMID- 21326211 TI - The SUMO system controls nucleolar partitioning of a novel mammalian ribosome biogenesis complex. AB - Ribosome biogenesis is a tightly controlled pathway that requires an intricate spatial and temporal interplay of protein networks. Most structural rRNA components are generated in the nucleolus and assembled into pre-ribosomal particles, which are transferred for further maturation to the nucleoplasm and cytoplasm. In metazoa, few regulatory components for these processes have been characterized. Previous work revealed a critical role for the SUMO-specific protease SENP3 in the nucleolar steps of ribosome biogenesis. We biochemically purified a SENP3-associated complex comprising PELP1, TEX10 and WDR18, and demonstrate that this complex is involved in maturation and nucleolar release of the large ribosomal subunit. We identified PELP1 and the PELP1-associated factor LAS1L as SENP3-sensitive targets of SUMO, and provide evidence that balanced SUMO conjugation/deconjugation determines the nucleolar partitioning of this complex. This defines the PELP1-TEX10-WDR18 complex as a regulator of ribosome biogenesis and suggests that its SUMO-controlled distribution coordinates the rate of ribosome formation. These findings contribute to the basic understanding of mammalian ribosome biogenesis and shed new light on the role of SUMO in this process. PMID- 21326212 TI - TIM23-mediated insertion of transmembrane alpha-helices into the mitochondrial inner membrane. AB - While overall hydrophobicity is generally recognized as the main characteristic of transmembrane (TM) alpha-helices, the only membrane system for which there are detailed quantitative data on how different amino acids contribute to the overall efficiency of membrane insertion is the endoplasmic reticulum (ER) of eukaryotic cells. Here, we provide comparable data for TIM23-mediated membrane protein insertion into the inner mitochondrial membrane of yeast cells. We find that hydrophobicity and the location of polar and aromatic residues are strong determinants of membrane insertion. These results parallel what has been found previously for the ER. However, we see striking differences between the effects elicited by charged residues flanking the TM segments when comparing the mitochondrial inner membrane and the ER, pointing to an unanticipated difference between the two insertion systems. PMID- 21326213 TI - The mitochondrial fission factor dynamin-related protein 1 modulates T-cell receptor signalling at the immune synapse. AB - During antigen-specific T-cell activation, mitochondria mobilize towards the vicinity of the immune synapse. We show here that the mitochondrial fission factor dynamin-related protein 1 (Drp1) docks at mitochondria, regulating their positioning and activity near the actin-rich ring of the peripheral supramolecular activation cluster (pSMAC) of the immune synapse. Mitochondrial redistribution in response to T-cell receptor engagement was abolished by Drp1 silencing, expression of the phosphomimetic mutant Drp1S637D and the Drp1 specific inhibitor mdivi-1. Moreover, Drp1 knockdown enhanced mitochondrial depolarization and T-cell receptor signal strength, but decreased myosin phosphorylation, ATP production and T-cell receptor assembly at the central supramolecular activation cluster (cSMAC). Our results indicate that Drp1 dependent mitochondrial positioning and activity controls T-cell activation by fuelling central supramolecular activation cluster assembly at the immune synapse. PMID- 21326214 TI - Evidence that metabolism and chromosome copy number control mutually exclusive cell fates in Bacillus subtilis. AB - Bacillus subtilis chooses between matrix production and spore formation, which are both controlled by the regulator Spo0A~P. We report that metabolism and chromosome copy number dictate which fate is adopted. Conditions that favour low Spo0A~P levels promote matrix production, whereas conditions favouring high levels trigger sporulation. Spo0A~P directs the synthesis of SinI, an antirepressor for the SinR repressor of matrix genes. The regulatory region of sinI contains an activator site that Spo0A~P binds strongly and operators that bind Spo0A~P weakly. Evidence shows that low Spo0A~P levels turn sinI ON and high levels turn sinI OFF and instead switch sporulation ON. Cells in which sinI and sinR were transplanted from their normal position near the chromosome replication terminus to positions near the origin and cells that harboured an extra copy of the genes were blocked in matrix production. Thus, matrix gene expression is sensitive to the number of copies of sinI and sinR. Because cells at the start of sporulation have two chromosomes and matrix-producing cells one, chromosome copy number could contribute to cell-fate determination. PMID- 21326215 TI - CD28 costimulation Impairs the efficacy of a redirected t-cell antitumor attack in the presence of regulatory t cells which can be overcome by preventing Lck activation. AB - Adoptive T-cell transfer showed promising efficacy in recent trials raising interest in T cells with redirected specificity against tumors. T cells were engineered with a chimeric antigen receptor (CAR) with predefined binding and CD3zeta signaling to initiate T-cell activation. CD28 costimulation provided by a CD28-CD3zeta signaling CAR moreover improved T cell activation and persistence; however, it failed to meet the expectations with respect to mounting attacks against solid tumors infiltrated with regulatory T (Treg) cells. We revealed that a CD28 CAR-redirected T-cell attack is accompanied by higher numbers of Treg cells infiltrating the tumor and is less efficient against cancer cells in presence of Treg cells than a CD3zeta CAR T-cell attack. Deletion of the lck binding moiety in the CD28 CAR endodomain, however, improved redirected anti tumor activity in presence of Treg cells without impairing interferon-gamma (IFN gamma) secretion, proliferation, and cytolysis. CD28 modification abrogated interleukin-2 (IL-2) induction upon CAR engagement which in turn is no longer available to sustain Treg cell persistence. CARs with the modified CD28 endodomain thereby expedite the implementation of adoptive T-cell therapy in patients with a variety of cancer types that are heavily infiltrated by Treg cells. PMID- 21326216 TI - Efficacy of a combined intracerebral and systemic gene delivery approach for the treatment of a severe lysosomal storage disorder. AB - Multiple sulfatase deficiency (MSD), a severe autosomal recessive disease is caused by mutations in the sulfatase modifying factor 1 gene (Sumf1). We have previously shown that in the Sumf1 knockout mouse model (Sumf1(-/-)) sulfatase activities are completely absent and, similarly to MSD patients, this mouse model displays growth retardation and early mortality. The severity of the phenotype makes MSD unsuitable to be treated by enzyme replacement or bone marrow transplantation, hence the importance of testing the efficacy of novel treatment strategies. Here we show that recombinant adeno-associated virus serotype 9 (rAAV9) vector injected into the cerebral ventricles of neonatal mice resulted in efficient and widespread transduction of the brain parenchyma. In addition, we compared a combined, intracerebral ventricles and systemic, administration of an rAAV9 vector encoding SUMF1 gene to the single administrations-either directly in brain, or systemic alone -in MSD mice. The combined treatment resulted in the global activation of sulfatases, near-complete clearance of glycosaminoglycans (GAGs) and decrease of inflammation in both the central nervous system (CNS) and visceral organs. Furthermore, behavioral abilities were improved by the combined treatment. These results underscore that the "combined" mode of rAAV9 vector administration is an efficient option for the treatment of severe whole-body disorders. PMID- 21326217 TI - Gene therapeutic approach using mutation-adapted U1 snRNA to correct a RPGR splice defect in patient-derived cells. AB - Retinitis pigmentosa (RP) is a disease that primarily affects the peripheral retina and ultimately causes visual impairment. X-chromosomal forms of RP are frequently caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. We show that the novel splice donor site (SDS) mutation c.1245+3A>T in intron 10 of RPGR cosegregates with RP in a five-generation Caucasian family. The mutation causes in-frame skipping of exon 10 from RPGR transcripts in patient derived primary fibroblasts. To correct the splice defect, we developed a gene therapeutic approach using mutation-adapted U1 small nuclear RNA (U1). U1 is required for SDS recognition of pre-mRNAs and initiates the splice process. The mutation described herein interferes with the recognition of the SDS by U1. To overcome the deleterious effects of the mutation, we generated four U1 isoforms with increasing complementarity to the SDS. Lentiviral particles were used to transduce patient-derived fibroblasts with these U1 variants. Full complementarity of U1 corrects the splice defect partially and increases recognition of the mutant SDS. The therapeutic effect is U1-concentration dependent as we show for endogenously expressed RPGR transcripts in patient derived cells. U1-based gene therapeutic approaches constitute promising technologies to treat SDS mutations in inherited diseases including X-linked RP. PMID- 21326218 TI - Long-term regulation of genetically modified primary hematopoietic cells in dogs. AB - We report long-term results from a large animal model of in vivo selection. Nine years ago, we transplanted two dogs (E900 and E958) with autologous marrow CD34(+) cells that had been transduced with a gammaretrovirus vector encoding a conditionally activatable derivative of the thrombopoietin receptor. Receptor activation through administration of a chemical inducer of dimerization (CID) (AP20187 or AP1903) confers a growth advantage. We previously reported responses to two 30-day intravenous (i.v.) courses of AP20187 administered within the first 8 months post-transplantation. We now report responses to 5-day subcutaneous (s.c.) courses of AP20187 or AP1903 at months 14, 90, and 93 (E900), or month 18 (E958), after transplantation. Long-term monitoring showed no rise in transduced cells in the absence of drug. Retroviral insertion site analysis showed that 4 of 6 (E958) and 5 of 12 (E900) transduced hematopoietic cell clones persisted lifelong. Both dogs were euthanized for reasons unrelated to the gene therapy treatment at 8 years 11 months (E958) and 11 years 1 month (E900) of age. Three clones from E900 remained detectable in each of two secondary recipients, one of which was treated with, and responded to, AP1903. Our results demonstrate the feasibility of safely regulating genetically engineered hematopoietic cells over many years. PMID- 21326219 TI - Gene editing of human embryonic stem cells via an engineered baculoviral vector carrying zinc-finger nucleases. AB - Human embryonic stem (hES) cells are renewable cell sources that have potential applications in regenerative medicine. The development of technologies to produce permanent and site-specific genome modifications is in demand to achieve future medical implementation of hES cells. We report herein that a baculoviral vector (BV) system carrying zinc-finger nucleases (ZFNs) can successfully modify the hES cell genome. BV-mediated transient expression of ZFNs specifically disrupted the CCR5 locus in transduced cells and the modified cells exhibited resistance to HIV 1 transduction. To convert the BV to a gene targeting vector, a DNA donor template and ZFNs were incorporated into the vector. These hybrid vectors yielded permanent site-specific gene addition in both immortalized human cell lines (10%) and hES cells (5%). Modified hES cells were both karyotypically normal and pluripotent. These results suggest that this baculoviral delivery system can be engineered for site-specific genetic manipulation in hES cells. PMID- 21326220 TI - Effects of branched-chain amino acids supplementation in patients with cirrhosis and a previous episode of hepatic encephalopathy: a randomized study. AB - OBJECTIVES: Protein intake impacts on nutritional status and may determine the recurrence of hepatic encephalopathy (HE). A low-protein diet has been considered the standard treatment after an episode of HE, while branched-chain amino acids (BCAA) have been shown to improve minimal HE. We performed a study to investigate the long-term effects of supplementing a protein-controlled diet with BCAA. METHODS: A randomized, double-blind, multicenter study that included 116 patients with cirrhosis and a previous episode of HE was conducted in four tertiary care hospitals. All patients received a standard diet of 35 kcal/kg per day and 0.7 g of proteins/kg per day and a supplement of 30 g of BCAA (BCAA group) or maltodextrin (MDX group) during 56 weeks. RESULTS: The actuarial risk of remaining free of HE did not differ between groups (BCAA=47%, MDX=34%, P=0.274), but patients in the BCAA group exhibited a better outcome on two neuropsychological tests and an increase in the mid-arm muscle circumference. Recurrence was associated with low plasma albumin at baseline and a decrease in sodium and an increase in creatinine during follow-up. Patients with recurrence of HE exhibited a lack of improvement in global cognitive function. CONCLUSIONS: Diet supplementation with BCAA after an episode of HE does not decrease recurrence of HE. However, supplementation with BCAA improves minimal HE and muscle mass. Identification of risk factors for recurrence of HE may allow the development of new preventive therapies that could decrease the neuropsychological sequelae of repeated episodes of HE. PMID- 21326221 TI - Performance of a risk index for advanced proximal colorectal neoplasia among a racially/ethnically diverse patient population (risk index for advanced proximal neoplasia). AB - OBJECTIVES: Tailoring the use of screening colonoscopy based on the risk of advanced proximal neoplasia (APN) has been advocated as a strategy for reducing demand and optimizing effectiveness. A 7-point index based on age, sex, and distal findings at sigmoidoscopy has been proposed that stratifies individuals into low, intermediate, and high-risk categories. The aim of this cross-sectional analysis was to determine the validity of this index, which was originally derived and validated among mostly whites, for black and Hispanic patients. METHODS: Data, including age, sex, colonoscopic findings, and pathology, were collected retrospectively from 1,481 white, 1,329 black, and 689 Hispanic asymptomatic, average-risk patients undergoing screening colonoscopy between 2000 and 2005. Cumulative scores ranging from 0 to 7 were derived for each subject and categorized as low, intermediate, or high risk. Rates of APN were assessed for each risk category after stratification by race/ethnicity. Index performance was assessed using the C-statistic and compared across the three racial groups. RESULTS: Rates of APN among patients categorized as low, intermediate, or high risk increased from 1.0 to 2.8 to 3.7% for whites, 1.0 to 2.2 to 4.2% for blacks, and 0.6 to 1.9 to 3.7% for Hispanics. The index performed similarly for all three groups, but showed limited ability to discriminate low from intermediate-risk patients, with C-statistic values of 0.62 for whites, 0.63 for blacks, and 0.68 for Hispanics. CONCLUSIONS: A risk index based on age, sex, and distal endoscopic findings has limited ability to discriminate low from intermediate-risk white, black, and Hispanic patients for APN. PMID- 21326222 TI - Mucosal gene expression of cell adhesion molecules, chemokines, and chemokine receptors in patients with inflammatory bowel disease before and after infliximab treatment. AB - OBJECTIVES: Inflammatory bowel disease (IBD) is characterized by a continuous influx of leukocytes into the gut wall. This migration is regulated by cell adhesion molecules (CAMs), and selective antimigration therapies have been developed. This study investigated the effect of infliximab therapy on the mucosal gene expression of CAMs in IBD. METHODS: Mucosal gene expression of 69 leukocyte/endothelial CAMs and E-cadherin was investigated in 61 IBD patients before and after first infliximab infusion and in 12 normal controls, using Affymetrix gene expression microarrays. Quantitative reverse transcriptase-PCR (qRT-PCR), immunohistochemistry, and western blotting were used to confirm the microarray data. RESULTS: When compared with control colons, the colonic mucosal gene expression of most leukocyte/endothelial adhesion molecules was upregulated and E-cadherin gene expression was downregulated in active colonic IBD (IBDc) before therapy, with no significant colonic gene expression differences between ulcerative colitis and colonic Crohn's disease. Infliximab therapy restored the upregulations of leukocyte CAMs in IBDc responders to infliximab that paralleled the disappearance of the inflammatory cells from the colonic lamina propria. Also, the colonic gene expression of endothelial CAMs and of most chemokines/chemokine receptors returned to normal after therapy in IBDc responders, and only CCL20 and CXCL1-2 expression remained increased after therapy in IBDc responders vs. control colons. When compared with control ileums, the ileal gene expression of MADCAM1, THY1, PECAM1, CCL28, CXCL1, -2, -5, -6, and -11, and IL8 was increased and CD58 expression was decreased in active ileal Crohn's disease (CDi) before therapy, and none of the genes remained dysregulated after therapy in CDi responders vs. control ileums. This microarray study identified a number of interesting targets for antiadhesion therapy including PECAM1, IL8, and CCL20, besides the currently studied alpha4beta7 integrin MADCAM1 axis. CONCLUSIONS: Our data demonstrate that many leukocyte/endothelial CAMs and chemokines/chemokine receptors are upregulated in inflamed IBD mucosa. Controlling the inflammation with infliximab restores most of these dysregulations in IBD. These results show that at least part of the mechanism of anti-tumor necrosis factor-alpha therapy goes through downregulation of certain adhesion molecules. PMID- 21326223 TI - Methylation of NEUROG1 in serum is a sensitive marker for the detection of early colorectal cancer. AB - OBJECTIVES: Colorectal cancer is the third most common cancer and a major cause of cancer-related deaths. Early detection of colonic lesions can reduce the incidence and mortality of colorectal cancer. Colonoscopy is the screening test for colorectal cancer with the highest efficacy, but its acceptance in the general public is rather low. To identify suitable tumor-derived markers that could detect colorectal cancer in blood samples, we analyzed the methylation status of a panel of genes in sera of affected patients. METHODS: Using methylation-specific quantitative PCR, we analyzed the methylation of ten marker genes in sera of healthy individuals and patients with colorectal cancer. RESULTS: Only HLTF, HPP1/TPEF, and NEUROG1 DNA methylation was detectable in at least 50% of patients with colorectal cancers. Whereas HLTF and HPP1/TPEF preferentially detected advanced and metastasized colorectal cancers, NEUROG1 methylation was detectable in UICC stages I-IV at a similar rate. Compared with other methylation markers, such as ALX4, SEPT9, and vimentin, NEUROG1 shows a higher sensitivity for colorectal cancer at UICC stages I and II. At a specificity of 91%, NEUROG1 reached a sensitivity of 61% (confidence interval, 50.4-70.6%) for the detection of colorectal cancers. Furthermore, detection of NEUROG1 methylation was independent of age and gender. CONCLUSIONS: Methylation of the NEUROG1 gene is frequently found in sera of patients with colorectal cancers independent of tumor stage. The quantitative detection of NEUROG1 DNA methylation in serum is a suitable approach for the non-invasive screening for asymptomatic colorectal cancer. PMID- 21326224 TI - Association between visual gaze patterns and adenoma detection rate during colonoscopy: a preliminary investigation. AB - OBJECTIVES: Eye gaze tracking (EGT) technology follows a person's gaze and records the resulting visual gaze pattern (VGP). Adenoma detection rate (ADR) is a validated measure of colonoscopy quality. Higher ADRs are associated with prolonged withdrawal times and other endoscopic maneuvers that allow a better visualization of the mucosa; however, the influence of VGP has yet to be explored. We aim to quantify the VGP for endoscopists observing colonoscopy videos and describe the association between VGP and ADR. Furthermore, we will evaluate the relationship between VGP and the endoscopists' years of experience. METHODS: Eleven endoscopists watched three videos while their VGP was recorded. The videos corresponded to 3 min of three different colonoscopy withdrawals. We divided the screen into a 3 * 3 grid of nine segments: eight peripheral and one central. We compared percent of gaze time (GT) in the central vs. peripheral segments using a paired t-test. VGP with ADR and years of practice were evaluated using Pearson's test. RESULTS: Subjects spent more GT in the screen's central segment (65 vs. 33%, P<0.001). ADR was significantly associated with increased percentage of central GT (r = 0.67, P = 0.024) and increased mean GT in the central segment (r = 0.70, P = 0.017). There was negative correlation between endoscopists' years of practice and the percentage of central GT (r = -0.67, P = 0.025), but no correlation between years of practice and percentage of peripheral GT (r = 0.24, P = 0.47). CONCLUSIONS: This reveals an association between a centrally focused VGP and ADR. Future steps include confirming in a larger sample and exploring if VGP can retrain low ADR endoscopists to perform higher quality colonoscopies. PMID- 21326226 TI - Mechanism for spectral break in cosmic ray proton spectrum of supernova remnant W44. AB - Recent observations of supernova remnant W44 by the Fermi spacecraft observatory support the idea that the bulk of galactic cosmic rays is accelerated in such remnants by a Fermi mechanism, also known as diffusive shock acceleration. However, the W44 expands into weakly ionized dense gas, and so a significant revision of the mechanism is required. Here, we provide the necessary modifications and demonstrate that strong ion-neutral collisions in the remnant surrounding lead to the steepening of the energy spectrum of accelerated particles by exactly one power. The spectral break is caused by Alfven wave evanescence leading to the fractional particle losses. The gamma-ray spectrum generated in collisions of the accelerated protons with the ambient gas is calculated and successfully fitted to the Fermi Observatory data. The parent proton spectrum is best represented by a classical test particle power law ?E( 2), steepening to E(-3) at E(br)~7 GeV due to deteriorated particle confinement. PMID- 21326225 TI - Flammable biomes dominated by eucalypts originated at the Cretaceous-Palaeogene boundary. AB - Fire is a major modifier of communities, but the evolutionary origins of its prevalent role in shaping current biomes are uncertain. Australia is among the most fire-prone continents, with most of the landmass occupied by the fire dependent sclerophyll and savanna biomes. In contrast to biomes with similar climates in other continents, Australia has a tree flora dominated by a single genus, Eucalyptus, and related Myrtaceae. A unique mechanism in Myrtaceae for enduring and recovering from fire damage likely resulted in this dominance. Here, we find a conserved phylogenetic relationship between post-fire resprouting (epicormic) anatomy and biome evolution, dating from 60 to 62 Ma, in the earliest Palaeogene. Thus, fire-dependent communities likely existed 50 million years earlier than previously thought. We predict that epicormic resprouting could make eucalypt forests and woodlands an excellent long-term carbon bank for reducing atmospheric CO(2) compared with biomes with similar fire regimes in other continents. PMID- 21326227 TI - Vibrational dynamics and surface structure of amorphous selenium. AB - In contrast to crystalline solids in which structural order governs dynamics and thermodynamics, the lack of long-range periodicity in amorphous materials is responsible for several anomalies. Although the relation between these anomalies and the 'bulk structure' is generally understood, the surface structure and the corresponding vibrational spectrum of amorphous solids is practically an unexplored theme. In this study, we resolve the differences in vibrational dynamics and atomic structure between bulk and surface (top 5 nm) atoms of amorphous selenium. We combine experimental (grazing incidence inelastic X-ray scattering) and computational (ab initio and semiempirical molecular orbital theoretical calculations) methods to scrutinize a variety of possible structural models. We find that a high concentration of particular types of 'coordination defects' in the surface layer is responsible for the observed differences. Resolving the structure of amorphous surfaces is, for example, important for understanding nanoparticles' properties where the surface-to-bulk ratio has a crucial role. PMID- 21326228 TI - New silica clathrate minerals that are isostructural with natural gas hydrates. AB - Silica clathrate compounds (clathrasils) and clathrate hydrates are structurally analogous because both materials have framework structures with cage-like voids occupied by guest species. The following three structural types of clathrate hydrates are recognized in nature: cubic structure I (sI); cubic structure II (sII); and hexagonal structure H (sH). In contrast, only one naturally occurring silica clathrate mineral, melanophlogite (sI-type framework), has been found to date. Here, we report the discovery of two new silica clathrate minerals that are isostructural with sII and sH hydrates and contain hydrocarbon gases. Geological and mineralogical observations show that these silica clathrate minerals are traces of low-temperature hydrothermal systems at convergent plate margins, which are the sources of thermogenic natural gas hydrates. Given the widespread occurrence of submarine hydrocarbon seeps, silica clathrate minerals are likely to be found in a wide range of marine sediments. PMID- 21326229 TI - Structural basis for the recognition and cleavage of histone H3 by cathepsin L. AB - Proteolysis of eukaryotic histone tails has emerged as an important factor in the modulation of cell-cycle progression and cellular differentiation. The recruitment of lysosomal cathepsin L to the nucleus where it mediates proteolysis of the mouse histone H3 tail has been described recently. Here, we report the three-dimensional crystal structures of a mature, inactive mutant of human cathepsin L alone and in complex with a peptide derived from histone H3. Canonical substrate-cathepsin L interactions are observed in the complex between the protease and the histone H3 peptide. Systematic analysis of the impact of posttranslational modifications at histone H3 on substrate selectivity suggests cathepsin L to be highly accommodating of all modified peptides. This is the first report of cathepsin L-histone H3 interaction and the first structural description of cathepsin L in complex with a substrate. PMID- 21326230 TI - Interconnect-free parallel logic circuits in a single mechanical resonator. AB - In conventional computers, wiring between transistors is required to enable the execution of Boolean logic functions. This has resulted in processors in which billions of transistors are physically interconnected, which limits integration densities, gives rise to huge power consumption and restricts processing speeds. A method to eliminate wiring amongst transistors by condensing Boolean logic into a single active element is thus highly desirable. Here, we demonstrate a novel logic architecture using only a single electromechanical parametric resonator into which multiple channels of binary information are encoded as mechanical oscillations at different frequencies. The parametric resonator can mix these channels, resulting in new mechanical oscillation states that enable the construction of AND, OR and XOR logic gates as well as multibit logic circuits. Moreover, the mechanical logic gates and circuits can be executed simultaneously, giving rise to the prospect of a parallel logic processor in just a single mechanical resonator. PMID- 21326231 TI - I(h)-mediated depolarization enhances the temporal precision of neuronal integration. AB - Feed-forward inhibition mediated by ionotropic GABA(A) receptors contributes to the temporal precision of neuronal signal integration. These receptors exert their inhibitory effect by shunting excitatory currents and by hyperpolarizing neurons. The relative roles of these mechanisms in neuronal computations are, however, incompletely understood. In this study, we show that by depolarizing the resting membrane potential relative to the reversal potential for GABA(A) receptors, the hyperpolarization-activated mixed cation current (I(h)) maintains a voltage gradient for fast synaptic inhibition in hippocampal pyramidal cells. Pharmacological or genetic ablation of I(h) broadens the depolarizing phase of afferent synaptic waveforms by hyperpolarizing the resting membrane potential. This increases the integration time window for action potential generation. These results indicate that the hyperpolarizing component of GABA(A) receptor-mediated inhibition has an important role in maintaining the temporal fidelity of coincidence detection and suggest a previously unrecognized mechanism by which I(h) modulates information processing in the hippocampus. PMID- 21326232 TI - Soil clay content underlies prion infection odds. AB - Environmental factors-especially soil properties-have been suggested as potentially important in the transmission of infectious prion diseases. Because binding to montmorillonite (an aluminosilicate clay mineral) or clay-enriched soils had been shown to enhance experimental prion transmissibility, we hypothesized that prion transmission among mule deer might also be enhanced in ranges with relatively high soil clay content. In this study, we report apparent influences of soil clay content on the odds of prion infection in free-ranging deer. Analysis of data from prion-infected deer herds in northern Colorado, USA, revealed that a 1% increase in the clay-sized particle content in soils within the approximate home range of an individual deer increased its odds of infection by up to 8.9%. Our findings suggest that soil clay content and related environmental properties deserve greater attention in assessing risks of prion disease outbreaks and prospects for their control in both natural and production settings. PMID- 21326233 TI - Gipc3 mutations associated with audiogenic seizures and sensorineural hearing loss in mouse and human. AB - Sensorineural hearing loss affects the quality of life and communication of millions of people, but the underlying molecular mechanisms remain elusive. Here, we identify mutations in Gipc3 underlying progressive sensorineural hearing loss (age-related hearing loss 5, ahl5) and audiogenic seizures (juvenile audiogenic monogenic seizure 1, jams1) in mice and autosomal recessive deafness DFNB15 and DFNB95 in humans. Gipc3 localizes to inner ear sensory hair cells and spiral ganglion. A missense mutation in the PDZ domain has an attenuating effect on mechanotransduction and the acquisition of mature inner hair cell potassium currents. Magnitude and temporal progression of wave I amplitude of afferent neurons correlate with susceptibility and resistance to audiogenic seizures. The Gipc3(343A) allele disrupts the structure of the stereocilia bundle and affects long-term function of auditory hair cells and spiral ganglion neurons. Our study suggests a pivotal role of Gipc3 in acoustic signal acquisition and propagation in cochlear hair cells. PMID- 21326235 TI - Antisense expression increases gene expression variability and locus interdependency. AB - Genome-wide transcription profiling has revealed extensive expression of non coding RNAs antisense to genes, yet their functions, if any, remain to be understood. In this study, we perform a systematic analysis of sense-antisense expression in response to genetic and environmental changes in yeast. We find that antisense expression is associated with genes of larger expression variability. This is characterized by more 'switching off' at low levels of expression for genes with antisense compared to genes without, yet similar expression at maximal induction. By disrupting antisense transcription, we demonstrate that antisense expression confers an on-off switch on gene regulation for the SUR7 gene. Consistent with this, genes that must respond in a switch-like manner, such as stress-response and environment-specific genes, are enriched for antisense expression. In addition, our data provide evidence that antisense expression initiated from bidirectional promoters enables the spreading of regulatory signals from one locus to neighbouring genes. These results indicate a general regulatory effect of antisense expression on sense genes and emphasize the importance of antisense-initiating regions downstream of genes in models of gene regulation. PMID- 21326236 TI - Towards the prediction of protein interaction partners using physical docking. AB - Deciphering the whole network of protein interactions for a given proteome ('interactome') is the goal of many experimental and computational efforts in Systems Biology. Separately the prediction of the structure of protein complexes by docking methods is a well-established scientific area. To date, docking programs have not been used to predict interaction partners. We provide a proof of principle for such an approach. Using a set of protein complexes representing known interactors in their unbound form, we show that a standard docking program can distinguish the true interactors from a background of 922 non-redundant potential interactors. We additionally show that true interactions can be distinguished from non-likely interacting proteins within the same structural family. Our approach may be put in the context of the proposed 'funnel-energy model'; the docking algorithm may not find the native complex, but it distinguishes binding partners because of the higher probability of favourable models compared with a collection of non-binders. The potential exists to develop this proof of principle into new approaches for predicting interaction partners and reconstructing biological networks. PMID- 21326237 TI - Infrared spectroscopy with multivariate analysis to interrogate endometrial tissue: a novel and objective diagnostic approach. AB - BACKGROUND: Endometrial cancer is the most common gynaecological malignancy in the United Kingdom. Diagnosis currently involves subjective expert interpretation of highly processed tissue, primarily using microscopy. Previous work has shown that infrared (IR) spectroscopy can be used to distinguish between benign and malignant cells in a variety of tissue types. METHODS: Tissue was obtained from 76 patients undergoing hysterectomy, 36 had endometrial cancer. Slivers of endometrial tissue (tumour and tumour-adjacent tissue if present) were dissected and placed in fixative solution. Before analysis, tissues were thinly sliced, washed, mounted on low-E slides and desiccated; 10 IR spectra were obtained per slice by attenuated total reflection Fourier-transform IR (ATR-FTIR) spectroscopy. Derived data was subjected to principal component analysis followed by linear discriminant analysis. Post-spectroscopy analyses, tissue sections were haematoxylin and eosin-stained to provide histological verification. RESULTS: Using this approach, it is possible to distinguish benign from malignant endometrial tissue, and various subtypes of both. Cluster vector plots of benign (verified post-spectroscopy to be free of identifiable pathology) vs malignant tissue indicate the importance of the lipid and secondary protein structure (Amide I and Amide II) regions of the spectrum. CONCLUSION: These findings point towards the possibility of a simple objective test for endometrial cancer using ATR-FTIR spectroscopy. This would facilitate earlier diagnosis and so reduce the morbidity and mortality associated with this disease. PMID- 21326238 TI - Abrogated expression of DEC1 during oesophageal squamous cell carcinoma progression is age- and family history-related and significantly associated with lymph node metastasis. AB - BACKGROUND: Oesophageal squamous cell carcinoma (SCC) causes the highest number of cancer deaths in some regions of Northern China. Previously, we narrowed down a critical region at 9q33-34, identified to be associated with tumour-suppressive function of deleted in oesophageal cancer 1 (DEC1) in oesophageal SCC. METHODS: We generated DEC1 antibody and constructed tissue microarrays (TMAs) utilising tissue specimens from Henan, a high-risk region for oesophageal SCC, to investigate the importance of DEC1 expression in this cancer. RESULTS: Tissue microarray immunohistochemical staining reveals significant loss of DEC1 from hyperplasia, to tumour, and to lymph node metastasis. In addition, the loss of DEC1 in tumour is age-dependent. Interestingly, there is significant abrogation of DEC1 expression in patients with a family history of oesophageal SCC. Deleted in oesophageal cancer 1 localises to both the cytoplasm and nucleus. The vesicular pattern of DEC1 in the cytoplasm appears to localise at the Golgi and Golgi-endoplasmic reticulum intermediate compartment. CONCLUSION: This is the first TMA study to suggest a clinical association of DEC1 in lymph node metastatic oesophageal SCC, early onset oesophageal SCC and familial oesophageal SCC development. Subcellular localisation of DEC1 and its expression in oesophageal SCC tissues provide important insight for further deciphering the molecular mechanism of DEC1 in oesophageal SCC development. PMID- 21326239 TI - Auxological changes in UK survivors of childhood acute lymphoblastic leukaemia treated without cranial irradiation. AB - BACKGROUND: As most children with acute lymphoblastic leukaemia (ALL) achieve long-term survival, minimising late effects of treatment is a priority. Acute lymphoblastic leukaemia survivors treated historically with protocols including cranial irradiation demonstrate increased weight gain. METHODS: We retrospectively studied all 134 patients treated on the MRC/UKALL97 protocol (without cranial irradiation as standard therapy) at a single centre, with 77 inclusions. Height-, weight- and body mass index (BMI) standard-deviation scores (SDS) were recorded at diagnosis and annually until 3 years out (YO) from end of treatment (EoT); changes across time were explored using a univariate model (significance P <= 0.001 to account for multiple comparisons). RESULTS: Whole group height SDS was lower from 1 year into treatment until 2 YO, whereas weight- and BMI-SDS remained higher until 3 YO. In females, height-SDS was lower until EoT, but higher weight- and BMI-SDS persisted until 3 YO. In males, height-SDS was lower at EoT and at 2 YO; differences in BMI-SDS had resolved by 2 YO. By WHO criteria, more patients were overweight or obese at 3 YO than at diagnosis (P=0.01). CONCLUSION: Survivors of childhood ALL, particularly females, exhibit adverse changes in height-, weight- and BMI-SDS, which arise during treatment and persist into follow-up. Patients should be supported with appropriate dietary and lifestyle advice during ALL treatment and follow-up, which may minimise these changes and reduce associated long-term morbidity. PMID- 21326234 TI - Effector diversification within compartments of the Leptosphaeria maculans genome affected by Repeat-Induced Point mutations. AB - Fungi are of primary ecological, biotechnological and economic importance. Many fundamental biological processes that are shared by animals and fungi are studied in fungi due to their experimental tractability. Many fungi are pathogens or mutualists and are model systems to analyse effector genes and their mechanisms of diversification. In this study, we report the genome sequence of the phytopathogenic ascomycete Leptosphaeria maculans and characterize its repertoire of protein effectors. The L. maculans genome has an unusual bipartite structure with alternating distinct guanine and cytosine-equilibrated and adenine and thymine (AT)-rich blocks of homogenous nucleotide composition. The AT-rich blocks comprise one-third of the genome and contain effector genes and families of transposable elements, both of which are affected by repeat-induced point mutation, a fungal-specific genome defence mechanism. This genomic environment for effectors promotes rapid sequence diversification and underpins the evolutionary potential of the fungus to adapt rapidly to novel host-derived constraints. PMID- 21326241 TI - Glioma cells showing IDH1 mutation cannot be propagated in standard cell culture conditions. AB - BACKGROUND: It has recently been reported by several sources that original (i.e., present in vivo) glioma cell phenotypes or genotypes cannot be maintained in vitro. For example, glioblastoma cell lines presenting EGFR amplification cannot be established. METHODS AND RESULTS: IDH1 sequencing and loss of heterozygosity analysis was performed for 15 surgery samples of astrocytoma and early and late passages of cells derived from those and for 11 archival samples. We were not able to culture tumour cells presenting IDH1 mutations originating from currently proceeded 10 tumours; the same results were observed in 7 samples of archival material. CONCLUSION: The IDH1 mutation is expected to be almost mutually exclusive with EGFR amplification, so glioma cells with IDH1 mutations seem to represent a new group of tumour cells, which cannot be readily analysed in vitro because of their elimination. The reasons for this intriguing phenomenon should be investigated since its understanding can help to define a new therapeutic approach based on simulating in vivo conditions, responsible for tumour cells elimination in vitro. Moreover, a new model for culturing glioma cells in vitro should be designed since the current one does not provide conditions corresponding to in vivo growth. PMID- 21326240 TI - Downregulation of cell surface CA125/MUC16 induces epithelial-to-mesenchymal transition and restores EGFR signalling in NIH:OVCAR3 ovarian carcinoma cells. AB - BACKGROUND: Epithelial ovarian cancer (EOC) cells are prone to metastasise throughout the peritoneal cavity. The epithelial-to-mesenchymal transition (EMT) is a necessary step towards metastatic tumour progression. CA125/MUC16 mucin is a high-molecular-weight glycoprotein overexpressed in the majority of serous carcinomas, suggesting a possible role in the pathogenesis of these cancers. METHODS: The role of CA125/MUC16 in EMT was investigated using single-chain antibody-mediated knockdown of cell surface CA125/MUC16 in overexpressing EOC NIH:OVCAR3 cells. RESULTS: CA125/MUC16 knockdown was associated with morphological alterations along with decreased surface expression of epithelial markers (E-cadherin, cytokeratin-18) and increased expression of mesenchymal markers (N-cadherin, vimentin). Co-immunoprecipitation experiments revealed that CA125/MUC16 binds to E-cadherin and beta-catenin complexes. The in vitro studies showed disruption of cell-cell junctions, enhanced motility, migration and invasiveness in CA125/MUC16 knockdown cells. Enhanced epidermal growth factor receptor (EGFR) activation was observed in CA125/MUC16 knockdown cells along with increased Akt and ERK1/2 phosphorylation, which are downstream effectors of EGFR, and increased MMP-2 and MMP-9 expression and activities. Epidermal growth factor receptor inhibition strongly inhibited the motility of CA125/MUC16 knockdown cells. CONCLUSIONS: Our findings suggest that CA125/MUC16 plays a role in EMT, presumably through its interaction with E-cadherin and beta-catenin complexes and by modulating EGFR and its downstream signalling pathway in NIH:OVCAR3 cells. PMID- 21326242 TI - Different miRNA signatures of oral and pharyngeal squamous cell carcinomas: a prospective translational study. AB - BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs, which regulate mRNA translation/decay, and may serve as biomarkers. We characterised the expression of miRNAs in clinically sampled oral and pharyngeal squamous cell carcinoma (OSCC and PSCC) and described the influence of human papilloma virus (HPV). METHODS: Biopsies obtained from 51 patients with OSCC/PSCC and 40 control patients were used for microarray analysis. The results were correlated to clinical data and HPV status. Supervised learning by support vector machines was employed to generate a diagnostic miRNA signature. RESULTS: One hundred and fourteen miRNAs were differentially expressed between OSCC and normal oral epithelium, with the downregulation of miR-375 and upregulation of miR-31 as the most significant aberrations. Pharyngeal squamous cell carcinoma exhibited 38 differentially expressed miRNAs compared with normal pharyngeal epithelium. Differences in the miRNA expression pattern of both normal epithelium and SCC were observed between the oral cavity compared with the pharynx. Human papilloma virus infection revealed perturbations of 21 miRNAs, most significantly in miR-127-3p and miR363. A molecular classifier including 61 miRNAs was generated for OSCC with an accuracy of 93%. CONCLUSION: MicroRNAs may serve as useful biomarkers in OSCC and PSCC. The influence of HPV on miRNA may provide a mechanism for the distinct clinical behaviour of HPV-infected tumours. PMID- 21326243 TI - A phase I study of the safety and tolerability of olaparib (AZD2281, KU0059436) and dacarbazine in patients with advanced solid tumours. AB - BACKGROUND: Poly adenosine diphosphate (ADP)-ribose polymerase (PARP) is essential in cellular processing of DNA damage via the base excision repair pathway (BER). The PARP inhibition can be directly cytotoxic to tumour cells and augments the anti-tumour effects of DNA-damaging agents. This study evaluated the optimally tolerated dose of olaparib (4-(3--4-fluorophenyl) methyl-1(2H)-one; AZD2281, KU0059436), a potent PARP inhibitor, with dacarbazine and assessed safety, toxicity, clinical pharmacokinetics and efficacy of combination treatment. PATIENTS AND METHODS: Patients with advanced cancer received olaparib (20-200 mg PO) on days 1-7 with dacarbazine (600-800 mg m(-2) IV) on day 1 (cycle 2, day 2) of a 21-day cycle. An expansion cohort of chemonaive melanoma patients was treated at an optimally tolerated dose. The BER enzyme, methylpurine-DNA glycosylase and its substrate 7-methylguanine were quantified in peripheral blood mononuclear cells. RESULTS: The optimal combination to proceed to phase II was defined as 100 mg bd olaparib with 600 mg m(-2) dacarbazine. Dose-limiting toxicities were neutropaenia and thrombocytopaenia. There were two partial responses, both in patients with melanoma. CONCLUSION: This study defined a tolerable dose of olaparib in combination with dacarbazine, but there were no responses in chemonaive melanoma patients, demonstrating no clinical advantage over single-agent dacarbazine at these doses. PMID- 21326244 TI - Patient and tumour characteristics, management, and age-specific survival in women with breast cancer in the East of England. AB - BACKGROUND: Breast cancer relative survival (BCRS), which compares the observed survival of women with breast cancer with the expected survival of women for the whole population of the same age, time period, and geographical region, tends to be poorer in older women, but the reasons for this are not clear. We examined the influence of patient and tumour characteristics, and treatment on BCRS to see whether these could explain the age-specific effect. METHODS: Data for 14,048 female breast cancer patients diagnosed from 1999 to 2007, aged 50 years or over were obtained from the Eastern Cancer Registration and Information Centre. We estimated relative 5- and 10-year survival for patients in four age groups (50 69, 70-74, 75-79, and 80+ years). We also modelled relative excess mortality (REM) rate using Poisson regression adjusting for patient characteristics and treatment. The REMs derived from these models quantify the extent to which the hazard of death differs from the hazard in the reference category, after taking into account the background risk of death in the general population. We compared the results with those obtained for breast cancer-specific mortality, analysed using multivariate Cox regression. RESULTS: Median follow-up time was 4.7 years. Relative 5-year survival was 89, 81, 76, and 70% for patients aged 50-69, 70-74, 75-79, and 80+ years, respectively. Corresponding relative 10-year survival was 84, 77, 67, and 66%. Unadjusted REM was 1.93, 2.74, and 3.88 for patients aged 70 74, 75-79, and 80+ years, respectively, (50-69 years as reference). The equivalent hazard ratios from the Cox model were 1.88, 2.45, and 3.81. These were attenuated after adjusting for confounders (REM - 1.49, 1.36, and 1.23; Cox - 1.47, 1.50, and 1.76). CONCLUSION: We confirmed poorer BCRS in older women in our region. This was partially explained by known prognostic factors. Further research is needed to determine whether biological differences or suboptimal management can explain the residual excess mortality. PMID- 21326245 TI - Psychological impact and acceptability of magnetic resonance imaging and X-ray mammography: the MARIBS Study. AB - BACKGROUND: As part of the Magnetic Resonance Imaging for Breast Screening (MARIBS), Study women with a family history of breast cancer were assessed psychologically to determine the relative psychological impact and acceptability of annual screening using magnetic resonance imaging (MRI) and conventional X-ray mammography (XRM). METHODS: Women were assessed psychologically at baseline (4 weeks before MRI and XRM), immediately before, and immediately after, both MRI and XRM, and at follow-up (6 weeks after the scans). RESULTS: Overall, both procedures were found to be acceptable with high levels of satisfaction (MRI, 96.3% and XRM, 97.7%; NS) and low levels of psychological morbidity throughout, particularly at 6-week follow-up. Low levels of self-reported distress were reported for both procedures (MRI, 13.5% and XRM, 7.8%), although MRI was more distressing (P=0.005). Similarly, higher anticipatory anxiety was reported before MRI than before XRM (P=0.003). Relative to XRM, MRI-related distress was more likely to persist at 6 weeks after the scans in the form of intrusive MRI-related thoughts (P=0.006) and total MRI-related distress (P=0.014). More women stated that they intended to return for XRM (96.3%) than for MRI (88%; P<0.0005). These effects were most marked for the first year of screening, although they were also statistically significant in subsequent years. CONCLUSION: Given the proven benefits of MRI in screening for breast cancer in this population, these data point to the urgent need to provide timely information and support to women undergoing MRI. PMID- 21326249 TI - Genetics of local adaptation in salmonid fishes. PMID- 21326246 TI - Phase II study of S-1 combined with oxaliplatin as therapy for patients with metastatic biliary tract cancer: influence of the CYP2A6 polymorphism on pharmacokinetics and clinical activity. AB - BACKGROUND: Advanced biliary cancer is often treated with fluoropyrimidine-based chemotherapy. In this study, we evaluated the efficacy and tolerability of a combination of S-1, an oral fluoropyrimidine prodrug, and oxaliplatin in patients with metastatic biliary cancer. METHODS: Patients with histologically confirmed metastatic biliary cancer and no history of radiotherapy or chemotherapy were enrolled. Oxaliplatin was administered intravenously (130 mg m(-2)), followed by 14-day administration of oral S-1 (40 mg m(-2) twice daily) with a subsequent 7 day rest period every 21 days. Pharmacokinetic analysis of S-1 was performed at cycle 1. Patients were genotyped for CYP2A6 polymorphisms ((*)1, (*)4, (*)7, (*)9 or (*)10), and pharmacokinetic and clinical parameters compared according to the CYP2A6 genotype. RESULTS: In total, 49 patients were evaluated, who received a median of four cycles. The overall response rate was 24.5%. Median progression free and overall survival was 3.7 and 8.7 months, respectively. The most common haematological grade 3 out of 4 toxicity was neutropenia (14%), while non hematological grade 3 out of 4 toxicities included anorexia (14%), nausea (12%), asthenia (10%), vomiting (10%), and diarrhoea (4%). Biotransformation of S-1 (AUC(0-24 h) of 5-fluorouracil/AUC(0-24 h) of tegafur) was 1.85-fold higher for the *1/*1 group than for the other groups (90% confidence interval 1.37-2.49). Diarrhoea (P=0.0740), neutropenia (P=0.396), and clinical efficacy (response rate, P=0.583; PFS, P=0.916) were not significantly associated with CYP2A6 genotype, despite differences in 5-FU exposure. CONCLUSION: The combination of S 1 and oxaliplatin appears to be active and well tolerated in patients with metastatic biliary cancer, and thus is feasible as a therapeutic modality. CYP2A6 genotypes are associated with differences in the biotransformation of S-1. However, the impact of the CYP2A6 polymorphism on variations in clinical efficacy or toxicity requires further evaluation. PMID- 21326250 TI - 3,6,7-Tri-epi-invictolide, a diastereomer of queen recognition pheromone, and its analog from a marine-derived actinomycete. PMID- 21326251 TI - Bacteriostatic versus bactericidal activity of ciprofloxacin in Escherichia coli assessed by flow cytometry using a novel far-red dye. AB - As common microbiological methods for the assessment of bacteriostatic or bactericidal activities are very time-consuming, in this work we describe that the use of a novel far-red fluorescent stain, Vybrant DyeCycle Ruby (DCR) for the flow cytometric analysis of fluoroquinolone (ciprofloxacin) bacteriostatic and bactericidal activities in Escherichia coli proved to be specific for bacterial DNA and, after ciprofloxacin exposure, DNA distribution analysis was achieved using a 7.5 MUM DCR concentration to stain 5 * 105 ethanol-fixed bacterial cells. The analysis of the bacterial DNA histograms obtained from the ciprofloxacin concentrations tested, enabled the distinction between ciprofloxacin bacteriostatic and bactericidal activities. PMID- 21326252 TI - A new anti-MRSA antibiotic complex, WAP-8294A II. Structure characterization of minor components by ESI LCMS and MS/MS. AB - The anti-MRSA antibiotic, WAP-8294A, was isolated from the fermentation broth of Lysobacter sp. The major component, WAP-8294A2, is composed of 1 mol of Gly, L Leu, L-Glu, D-Asn, D-Trp, D-threo-beta-hydroxyasparagine, N-Me-D-Phe and N-Me-L Val, and 2 mol of L-Ser, D-Orn and D-3-hydroxy-7-Me-octanoic acid. The structure of the WAP-8294A2 was mainly determined as a cyclic depsipeptide by 2D NMR experiments. However, it was difficult to use the NMR experiment to determine the minor components, A1, A4 and Ax13, isolated in small amounts. In the present study, ESI MS/MS was applied to the structure elucidation of these minor components. The structures of these minor components were determined on the basis of the fragmentation pattern of the product ions of WAP-8294A2 in the ESI MS/MS. As a result, it was confirmed that A1 and A4 had the same amino acid sequence as A2, while A1 and A4 had the 3-OH-octanoic acid and 3-OH-8-Me-nonanoic acid, respectively, in the place of the 3-OH-7-Me-octanoic acid in A2. In the structure of Ax13, it was found that Gly of A2 was changed to beta-Ala of Ax13. PMID- 21326253 TI - New angucycline C-glycosides from Streptomyces sp. RI33. AB - In the course of our screening program for anticancer agents from natural sources, five new angucyclines, JBIR-90 (1), -116 (2), -91 (3), -92 (4) and -93 (5), were isolated from the fermentation broth of Streptomyces sp. RI33. The structures of 1-5 were elucidated on the basis of 1D and 2D NMR spectroscopy and MS analyses. Compounds 2-4 showed cytotoxic activities against malignant pleural mesothelioma cells at IC(50) values of 20-50 MUM. PMID- 21326254 TI - NMR study of peplomycin in aqueous solution. Assignment of resonances by means of two-dimensional spectroscopy. AB - 1H-NMR spectra of peplomycin (PEP) recorded at 400 and, for the first time, 900 MHz at 2 degrees C were examined. All the spin systems in the PEP molecule were identified through 2D NMR spectroscopy. The use of NMR spectroscopy allowed the unambiguous assignment of 62 protons, generating 47 non-exchangeable and 15 exchangeable signals. The analysis of the signals observed in 2D-NOE spectra indicates that PEP exhibits an extended conformation at 2 degrees C. A comparison between the solution conformation of apo-PEP and the solution structure of HOO-Co(III)-PEP indicates that the overall structure of apo-PEP is extended in solution, but exhibiting a conformation of the bithiazole (B) sulfonium (S) unit similar to that of HOO-Co(III)-PEP. The present investigation represents the initial stage of an NMR study of the solution conformation and dynamics of PEP, its derivatives, its metal complexes and the interactions of metallo-PEPs with their target DNA. PMID- 21326256 TI - Pharmacogenomics at the tipping point: challenges and opportunities. PMID- 21326260 TI - What to expect from the Pharmacogenomics Research Network. PMID- 21326261 TI - Ethical issues in developing pharmacogenetic research partnerships with American Indigenous communities. AB - Pharmacogenetic research offers the potential to improve the safety and efficacy of drug prescribing. Assuring that the benefits of this research reach indigenous and other medically underserved people is an important justice concern. First, however, a legacy of mistrust, derived from traditional research practices that disempower communities, must be overcome. Linking pharmacogenetic research to collaborative, power-sharing research partnerships provides a valuable opportunity to develop new and positive precedents for genetic research in indigenous communities. PMID- 21326262 TI - Physician barriers to incorporating pharmacogenetic treatment strategies for nicotine dependence into clinical practice. AB - Advances in genomics research may improve health outcomes by tailoring treatment according to patients' genetic profiles. The treatment of nicotine dependence, in particular, may soon encompass pharmacogenetic treatment models. Realizing the benefits of such treatment strategies may depend on physicians' preparedness to incorporate genetic testing into clinical practice. This article describes barriers to clinical integration of pharmacogenetic treatments that will need to be addressed to realize the benefits of individualized smoking-cessation treatment. PMID- 21326263 TI - Pharmacogenomics: "noninferiority" is sufficient for initial implementation. AB - Recent clinical annotation of a whole-genome sequence suggests that pharmacogenomics (PGx) may be ready for clinical implementation now. This conclusion rests on the recognition that PGx has greatly mitigated risks as compared with using genomics for assessment of disease risk. Failure to recognize these differences can produce unrealistic cost-benefit scenarios and impractical standards of evidence. In many cases, pharmacogenetic tests need only reach reasonable expectations of noninferiority (compared with current prescribing practices) to merit use. PMID- 21326267 TI - Thrombotic distal middle cerebral artery occlusion produced by topical FeCl(3) application: a novel model suitable for intravital microscopy and thrombolysis studies. AB - Intravital or multiphoton microscopy and laser-speckle imaging have become popular because they allow live monitoring of several processes during cerebral ischemia. Available rodent models have limitations for these experiments; e.g., filament occlusion of the proximal middle cerebral artery (MCA) is difficult to perform under a microscope, whereas distal occlusion methods may damage the MCA and the peri-arterial cortex. We found that placement of a 10% FeCl(3)-soaked filter paper strip (0.3 * 1 mm(2)) on the duramater over the trunk of the distal MCA through a cranial window for 3 minutes induced intraarterial thrombus without damaging the peri-arterial cortex in the mouse. This caused a rapid regional cerebral blood flow decrease within 10 minutes and total occlusion of the MCA segment under the filter paper in 17+/-2 minutes, which resulted in a typical cortical infarct of 27+/-4 mm(3) at 24 hours and moderate sensorimotor deficits. There was no significant hemispheric swelling or hemorrhage or mortality at 24 hours. Reperfusion was obtained in half of the mice with tissue plasminogen activator, which allowed live monitoring of clot lysis along with restoration of tissue perfusion and MCA flow. In conclusion, this relatively simple and noninvasive stroke model is easy to perform under a microscope, making it suitable for live imaging and thrombolysis studies. PMID- 21326268 TI - Serum 25-hydroxy-vitamin D and ionised calcium in relation to lung function and allergen skin tests. AB - BACKGROUND: Evidence suggests that higher levels of vitamin D and calcium are associated with greater lung function and that vitamin D is inversely associated with atopic sensitisation. It is unknown whether the associations of vitamin D and calcium with lung function are independent of each other or mediated by atopic sensitisation. OBJECTIVE: To study the associations of 25-hydroxyvitamin D (25(OH)D) and ionised calcium levels with lung function and specific allergen sensitisation in adolescents (12-19 years) and adults (20-59 years) and to assess whether the associations with lung function are due to altered atopic sensitisation. METHODS: This is a cross-sectional analysis of the data from the third National Health and Nutrition Examination Survey. RESULTS: The 25(OH)D levels were positively associated with forced vital capacity in adolescents (0.035 (95% confidence interval (CI): 0.007-0.064) s.d.; s.d. in model adjusted for multiple confounders). This association and the previously reported association between higher serum levels of 25(OH)D and better lung function in adults were independent of serum calcium levels, which were not associated with lung function. In adults, calcium was associated with sensitisation to grass allergens (odds ratio per s.d., 1.17 (95% CI: 1.03-1.32), 1.15 (95% CI: 1.01 1.31) and 1.18 (95% CI: 1.06-1.32) for white oak, Bermuda grass and short ragweed, respectively) and peanut odds ratio 1.21 (95% CI: 1.02-1.43) after adjusting for age, gender and race/ethnicity, but these associations attenuated towards the null after adjusting for additional confounders. The associations were independent of 25(OH)D levels, which were not associated with allergen sensitisation. CONCLUSIONS: Circulating levels of 25(OH)D are positively associated with lung function and this does not seem to be driven by allergen sensitisation or influenced by calcium levels. PMID- 21326269 TI - Beverage-specific alcohol intake and bone loss in older men and women: a longitudinal study. AB - BACKGROUND/OBJECTIVES: There is inconsistent evidence regarding the association between moderate alcohol consumption and bone mineral density (BMD). The aim of this study was to describe the associations between total and beverage-specific alcohol intake and bone loss in older men and women. SUBJECT/METHODS: A total of 862 randomly selected subjects (mean age 63 years, range 51-81, 51% men) were studied at baseline and 2 years later. BMD was assessed by dual-energy X-ray absorptiometry. Beverage specific and total alcohol intake was assessed by food frequency questionnaire. Falls risk was determined using the short form Physiological Profile Assessment. Incident fractures were ascertained by questionnaire. RESULTS: Total alcohol intake in men positively predicted change in BMD at the lumbar spine and hip (beta=0.008% and 0.006% per year per gram, P<0.05) after adjustment for confounders, but there was no significant association between alcohol intake and change in BMD in women. Lumbar spine BMD at baseline was negatively associated with frequency of spirits/liquor drinking in men (beta=-0.01 g/cm(2) per category, P=0.045) and was positively associated with frequency of beer drinking (low alcohol) in women (beta=0.034 g/cm(2) per category, P=0.002). Change in lumbar spine BMD was positively associated with the frequency of red wine drinking in men (beta=0.08% per year per class, P=0.046). Neither beverage-specific nor total alcohol intake was associated with falls risk or fracture. CONCLUSIONS: Alcohol intake especially red wine might prevent bone loss in older men but not women, whereas low-alcohol beer may be protective in women and spirits/liquor may be deleterious in men. PMID- 21326270 TI - Study to investigate the potential of probiotics in children attending school. AB - BACKGROUND/OBJECTIVES: To determine if consumption of yogurt containing a high dose of probiotic (1*10(10) colony-forming unit per 100 ml), Bifidobacterium animalis subsp. lactis (B. lactis), decreases absences in children 2-4 years attending daycare/school centers. SUBJECTS/METHODS: We conducted a double blinded, randomized, placebo-controlled, allocation concealment clinical trial in the Washington, DC area. Our active intervention was a strawberry yogurt-based drink supplemented with B. lactis BB-12. The placebo was indistinguishable from the active drink, differing only in absence of the probiotic BB-12. RESULTS: A total of 172 children between the ages of 2 and 4 from the Washington, DC area were enrolled. The primary outcome, missed days of school because of illness per 100 days, was similar in both the active (2.54 days absent/100 school days) and control groups (2.42 days absent/100 school days) (P=0.873). CONCLUSIONS: The probiotic-containing yogurt-based beverage studied did not decrease absences because of illnesses in daycare/school for healthy children ages 2-4 years. PMID- 21326271 TI - Divergent anti-inflammatory effects of different oil acute consumption on healthy individuals. AB - BACKGROUND/OBJECTIVES: Inter-cellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and tumor necrosis factor-alpha (TNF-alpha), are implicated in atherogenesis. In addition, several types of oil as part of different types of diet are associated with the initiation of atherosclerosis and consequently with the risk of cardiovascular disease. However, the exact role of oil consumption on vascular inflammation remains unknown. In this parallel study, we assessed the acute effects of extra virgin olive oil, soy oil, corn oil and cod liver oil on circulating soluble(s) forms of adhesion molecules and TNF alpha. SUBJECTS/METHODS: In all, 67 healthy volunteers were randomized to receive 50 ml of oil. Soluble forms of VCAM-1, ICAM-1 and TNF-alpha were measured by enzyme-linked immunosorbent assay at baseline and at 3 h post oil consumption. RESULTS: All types of oil had no significant effect on soluble VCAM-1 levels (P=nonsignificant (NS) for all). On the contrary, all oil types decreased ICAM-1 levels (P<0.01). Olive oil (P<0.05), soy oil and cod liver oil (P<0.01 for both) reduced TNF-alpha levels significantly, in contrast to corn oil, which induced a nonsignificant decrease (P=NS). Moreover, there was a significant correlation between the absolute change in ICAM-1 and TNF-alpha levels (rho=0.379, P<0.05), but not between the absolute changes in VCAM-1 and TNF-alpha levels (rho=0.019, P=NS). CONCLUSIONS: Acute consumption of all types of oil decreased significantly ICAM-1 levels. In addition, olive oil, soy oil and cod liver oil decreased significantly TNF-alpha levels. Moreover, the absolute change in TNF-alpha levels was correlated with the absolute change in ICAM-1 levels. These findings indicate that acute consumption of specific types of oil is associated with specific significant anti-inflammatory effects. PMID- 21326272 TI - Influence of the recall period on a beverage-specific weekly drinking measure for alcohol intake. AB - BACKGROUND/OBJECTIVES: Our knowledge of the association between alcohol intake and alcohol-related health outcomes depends, to a large extent, on the validity and reliability of self-reported alcohol intake. Weekly drinking measures are frequently used in epidemiological surveys, but it has been shown that respondents have problems in correctly reporting intake for a full week. The aim of this study is to investigate whether a beverage-specific question implies better recall and, thereby, eliminates or diminishes the previously reported association between the recall period and the self-reported weekly alcohol intake. SUBJECTS/METHODS: The data is derived from the Danish Health Interview Survey 2005, which is based on a region-stratified random sample of 21,832 Danish citizens aged >=16 years (response rate: 67%). The data were collected via face to-face interviews. RESULTS: A beverage-specific question on alcohol intake on each day during the last week did not alter the strong association between the recall period and self-reported alcohol intake. However, the overall self reported alcohol intake increased substantially when using the beverage-specific question instead of asking for the overall alcohol intake on each day. Moreover, the analyses indicated that interviews on Sundays should be avoided if the purpose is to assess alcohol intake for the previous day (Saturdays). CONCLUSIONS: It seems problematic to recall alcohol intake even when the recall period is as short as 1 week. Weekly drinking measures should primarily be used when the main aim of the study is to assess the average volume of alcohol intake in a specific population. PMID- 21326273 TI - Architects at the bacterial surface - sortases and the assembly of pili with isopeptide bonds. AB - The cell wall envelope of Gram-positive bacteria can be thought of as a surface organelle for the assembly of macromolecular structures that enable the unique lifestyle of each microorganism. Sortases - enzymes that cleave the sorting signals of secreted proteins to form isopeptide (amide) bonds between the secreted proteins and peptidoglycan or polypeptides - function as the principal architects of the bacterial surface. Acting alone or with other sortase enzymes, sortase construction leads to the anchoring of surface proteins at specific sites in the envelope or to the assembly of pili, which are fibrous structures formed from many protein subunits. The catalysis of intermolecular isopeptide bonds between pilin subunits is intertwined with the assembly of intramolecular isopeptide bonds within pilin subunits. Together, these isopeptide bonds endow these sortase products with adhesive properties and resistance to host proteases. PMID- 21326274 TI - Expanding fungal pathogenesis: Cryptococcus breaks out of the opportunistic box. AB - Cryptococcus neoformans is generally considered to be an opportunistic fungal pathogen because of its tendency to infect immunocompromised individuals, particularly those infected with HIV. However, this view has been challenged by the recent discovery of specialized interactions between the fungus and its mammalian hosts, and by the emergence of the related species Cryptococcus gattii as a primary pathogen of immunocompetent populations. In this Review, we highlight features of cryptococcal pathogens that reveal their adaptation to the mammalian environment. These features include not only remarkably sophisticated interactions with phagocytic cells to promote intracellular survival, dissemination to the central nervous system and escape, but also surprising morphological and genomic adaptations such as the formation of polyploid giant cells in the lung. PMID- 21326276 TI - Importance of feedback loops between soil inorganic nitrogen and microbial communities in the heterotrophic soil respiration response to global warming. PMID- 21326275 TI - Towards a point-of-care test for active tuberculosis: obstacles and opportunities. AB - Limited access to diagnostic services and the poor performance of current tests result in a failure to detect millions of tuberculosis cases each year. An accurate test that could be used at the point of care to allow faster initiation of treatment would decrease death rates and could reduce disease transmission. Previous attempts to develop such a test have failed, and success will require the marriage of biomarkers that are highly predictive for the disease with innovative technology that is reliable and affordable. Here, we review the status of research into point-of-care tests for active tuberculosis and discuss barriers to the development of such diagnostic tests. PMID- 21326277 TI - The potential of synthetic biology: a view from the European Academies Science Advisory Council. PMID- 21326278 TI - Pharmacotherapy: GLP-1 analogues and insulin: sound the wedding bells? PMID- 21326279 TI - Pituitary tumors: cabergoline versus bromocriptine: a meta-analysis? PMID- 21326280 TI - Metopic and sagittal synostosis in Greig cephalopolysyndactyly syndrome: five cases with intragenic mutations or complete deletions of GLI3. AB - Greig cephalopolysyndactyly syndrome (GCPS) is a multiple congenital malformation characterised by limb and craniofacial anomalies, caused by heterozygous mutation or deletion of GLI3. We report four boys and a girl who were presented with trigonocephaly due to metopic synostosis, in association with pre- and post-axial polydactyly and cutaneous syndactyly of hands and feet. Two cases had additional sagittal synostosis. None had a family history of similar features. In all five children, the diagnosis of GCPS was confirmed by molecular analysis of GLI3 (two had intragenic mutations and three had complete gene deletions detected on array comparative genomic hybridisation), thus highlighting the importance of trigonocephaly or overt metopic or sagittal synostosis as a distinct presenting feature of GCPS. These observations confirm and extend a recently proposed association of intragenic GLI3 mutations with metopic synostosis; moreover, the three individuals with complete deletion of GLI3 were previously considered to have Carpenter syndrome, highlighting an important source of diagnostic confusion. PMID- 21326281 TI - Isolated hypogonadotropic hypogonadism with SOX2 mutation and anophthalmia/microphthalmia in offspring. AB - Isolated hypogonadotropic hypogonadism (IHH) is a genetically heterogeneous condition in which patients frequently require assisted reproduction to achieve fertility. In patients with IHH who are otherwise well, no particular increased risk of congenital anomalies in the resultant offspring has been highlighted. Heterozygous mutations in SOX2 are the commonest single-gene cause of anophthalmia/microphthalmia (A/M) and sometimes result in pituitary abnormalities. We report a family with a novel frameshift mutation in the SOX2 transactivation domain, p.Gly280AlafsX91, resulting in bilateral anophthalmia and subtle endocrinological abnormalities in a male sibling, and unilateral microphthalmia in a female sibling. The mutation is present in their mother who has IHH, but has no eye disorders or other anomalies. She underwent assisted reproduction to achieve fertility. This report has important implications for the evaluation of patients with IHH, particularly in the setting of planned infertility treatment. PMID- 21326282 TI - Clinical utility gene card for: renal coloboma (Papillorenal) syndrome. PMID- 21326283 TI - Differential secretion of the mutated protein is a major component affecting phenotypic severity in CRLF1-associated disorders. AB - Crisponi syndrome (CS) and cold-induced sweating syndrome type 1 (CISS1) are disorders caused by mutations in CRLF1. The two syndromes share clinical characteristics, such as dysmorphic features, muscle contractions, scoliosis and cold-induced sweating, with CS patients showing a severe clinical course in infancy involving hyperthermia, associated with death in most cases in the first years of life. To evaluate a potential genotype/phenotype correlation and whether CS and CISS1 represent two allelic diseases or manifestations at different ages of the same disorder, we carried out a detailed clinical analysis of 19 patients carrying mutations in CRLF1. We studied the functional significance of the mutations found in CRLF1, providing evidence that phenotypic severity of the two disorders mainly depends on altered kinetics of secretion of the mutated CRLF1 protein. On the basis of these findings, we believe that the two syndromes, CS and CISS1, represent manifestations of the same disorder, with different degrees of severity. We suggest renaming the two genetic entities CS and CISS1 with the broader term of Sohar-Crisponi syndrome. PMID- 21326284 TI - Multiple independent variants in 6q21-22 associated with susceptibility to celiac disease in the Dutch, Finnish and Hungarian populations. AB - Celiac disease is an inflammatory enteropathy caused by intolerance to gluten. Previous linkage studies in the Dutch, Finnish and Hungarian populations have revealed a locus on chromosome 6q21-22 conferring susceptibility to celiac disease. This locus has previously been implicated in susceptibility to other autoimmune diseases such as Crohn's disease and type 1 diabetes. We performed fine mapping on 446 independent individuals with celiac disease and 641 controls of Dutch origin, testing 872 tagging SNPs in a 22 Mb region of chromosome 6. The 12 most promising SNPs were followed up in 2071 individuals from 284 Finnish and 357 Hungarian celiac disease families to identify risk variants in this region. Multiple markers in the region were significantly associated with celiac disease in the Dutch material. Two SNPs, rs9391227 and rs4946111, were significantly associated with celiac disease in the Finnish population. The association to rs9391227 represents the strongest association signal found in the Finnish (P = 0.003, OR 0.66) as well as the combined Dutch, Finnish and Hungarian populations (P = 3.6 * 10(-5), OR 0.76). The rs9391227 is situated downstream of the HECT domain and ankyrin repeat containing, E3 ubiquitin protein ligase 1 (HACE1) gene and is contained within a region of strong linkage disequilibrium enclosing HACE1. Two additional, independent, susceptibility variants in the 6q21-22 region were also found in a meta-analysis of the three populations. The 6q21-22 region was confirmed as a celiac disease susceptibility locus and harbors multiple independent associations, some of which may implicate ubiquitin-pathways in celiac disease susceptibility. PMID- 21326285 TI - De novo MECP2 duplication in two females with random X-inactivation and moderate mental retardation. AB - Xq28 duplications including MECP2 are a well-known cause of severe mental retardation in males with seizures, muscular hypotonia, progressive spasticity, poor speech and recurrent infections that often lead to early death. Female carriers usually show a normal intellectual performance due to skewed X inactivation (XCI). We report on two female patients with a de novo MECP2 duplication associated with moderate mental retardation. In both patients, the de novo duplication occurred on the paternal allele, and both patients show a random XCI, which can be assumed as the triggering factor for the phenotype. Furthermore, we describe the phenotype that might be restricted to unspecific mild-to -moderate mental retardation with neurological features in early adulthood. PMID- 21326286 TI - Pericentric inversion of chromosome 18 in parents leading to a phenotypically normal child with segmental uniparental disomy 18. AB - In this study, we report a familial inversion of chromosome 18, inv(18)(p11.31q21.33), in both members of a consanguineous couple. Their first child had inherited one balanced pericentric inversion along with a recombinant chromosome 18 resulting in dup(18q)/del(18p), and had mild dysmorphic features in the absence of mental and developmental retardation. The second child had received two recombinant chromosomes 18, from the mother a derivative chromosome 18 with dup(18p)/del(18q) and from the father a derivative chromosome 18 with dup(18q)/del(18p). The aberration was prenatally detected; however, as the two opposite aneuploidies were thought to compensate each other, the family decided to carry on with the pregnancy, knowing that uniparental disomy for the segments outside the inversion could have an adverse influence on the development of the child. Uniparental disomy was confirmed by SNP arrays. The child, who has been followed up until the age of 20 months, is healthy and normal. It seems to be the first reported case with two opposite recombinant chromosomes that compensate each other and lead to segmental uniparental disomy for two segments on the chromosome, one maternal and the other paternal. PMID- 21326287 TI - Parents' and children's communication about genetic risk: a qualitative study, learning from families' experiences. AB - Little is known about how parents explain to their children their risk of inheriting a gene that may cause disease in the child or in the child's future progeny. This study explored how genetic risk information is shared between family members and the factors affecting it, to ascertain the implications for children, young people and their parents to inform future service development and provision. A volunteer group of parents, children (8-11 years) and young people (12+ years) in families affected by or at risk of one of six inherited genetic conditions was interviewed. The semi-structured interviews explored the roles of family members, the language used and the self-reported psychological outcomes in a discussion on genetic risk information. The findings were analysed using grounded theory. A total of 33 families participated, which included 79 individuals. Parents often found discussing genetic risk information very difficult and emotionally painful. Discussions were not usually planned and often a major event prompted parents to finally explain genetic risks to their children; however, children usually preferred to learn about the genetic condition gradually throughout childhood. Parents identified a number of challenges they faced related to talking to children, and many thought health professionals should provide more advice to assist them in providing developmentally appropriate information. We therefore conclude that greater emphasis is required in supporting parents and children in discussing genetic risk information throughout their child's development. Open communication about genetic risks throughout childhood seemed to help children and parents cope better and come to terms with the implications of the genetic condition. PMID- 21326288 TI - The value and benefits of the International Conference on Harmonisation to drug regulatory authorities: advancing harmonization for better public health. AB - The International Conference on Harmonisation (ICH) is an unparalleled undertaking, which has brought together drug regulatory authorities and pharmaceutical trade associations from Europe, Japan, and the United States, to discuss the scientific and technical aspects of medical product registration. Launched in 1990, the value and benefits of ICH to regulators are being realized. ICH has harmonized submission requirements and created a harmonized submission format that is relieving both companies and regulatory authorities of the burdens of assembling and reviewing separate submissions for each region. As more countries embrace ICH guidelines, we anticipate additional benefits, including the promotion of good review practices and, ultimately, a common regulatory language that will facilitate further interactions among global drug regulatory authorities. PMID- 21326289 TI - Validation and predictive performance assessment of clinical trial simulation models. PMID- 21326290 TI - The placebo response is part of good medicine. PMID- 21326291 TI - Clinical trials of antidepressants: "enrichment strategies". PMID- 21326292 TI - Epidermal keratinocytes from light vs. dark skin exhibit differential degradation of melanosomes. AB - Modification of skin complexion coloration has traditionally been accomplished by interruption or attenuation of melanogenesis and/or melanosome transfer. Post transfer modification of pigmented melanosomes provides an attractive and distinct avenue of modulating skin pigmentation. The processing of melanosomes during keratinocyte (KC) terminal differentiation and the degradative variability observed between light and dark skin (LS and DS) remains enigmatic. To evaluate this, we developed a model system to investigate the loss of fluorescently labeled and isolated melanosomes by cultured human KCs. The extent of melanosome loss has been qualitatively assessed using transmission electron microscopy and indirect immunofluorescence with confocal microscopy, and quantitatively assessed using flow cytometry analysis. Results show that melanosomes are incorporated into the cytoplasm of both light and dark keratinocytes (LKCs and DKCs) and trafficked to a perinuclear region. Within 48 hours, confocal microscopy images suggest that LKCs display accelerated melanosome loss. This time-dependent decrease in carboxyfluorescein diacetate (CFDA) fluorescence was then quantitatively analyzed using flow cytometry. Consistent with the results of the confocal analysis, over a 48-hour time frame, LKCs appear to lose melanosomes more efficiently than DKCs. These experiments show that melanosomes are more rapidly lost in KCs derived from LS as opposed to DS. PMID- 21326293 TI - Erythropoietic uroporphyria associated with myeloid malignancy is likely distinct from autosomal recessive congenital erythropoietic porphyria. PMID- 21326294 TI - Skin-depigmenting agent monobenzone induces potent T-cell autoimmunity toward pigmented cells by tyrosinase haptenation and melanosome autophagy. AB - In this study, we report the previously unknown mechanism of inducing robust anti melanoma immunity by the vitiligo-inducing compound monobenzone. We show monobenzone to increase melanocyte and melanoma cell immunogenicity by forming quinone-haptens to the tyrosinase protein and by inducing the release of tyrosinase- and melanoma antigen recognized by T cells-1 (MART-1)-containing CD63+ exosomes following melanosome oxidative stress induction. Monobenzone further augments the processing and shedding of melanocyte-differentiation antigens by inducing melanosome autophagy and enhanced tyrosinase ubiquitination, ultimately activating dendritic cells, which induced cytotoxic human melanoma reactive T cells. These T cells effectively eradicate melanoma in vivo, as we have reported previously. Monobenzone thereby represents a promising and readily applicable compound for immunotherapy in melanoma patients. PMID- 21326295 TI - Genome-wide analysis identifies a quantitative trait locus in the MHC class II region associated with generalized vitiligo age of onset. AB - Generalized vitiligo is a common autoimmune disease in which acquired patchy depigmentation of skin, hair, and mucous membranes results from loss of melanocytes from involved areas. Previous genetic analyses have focused on vitiligo susceptibility, and have identified a number of genes involved in disease risk. Age of onset of generalized vitiligo also involves a substantial genetic component, but has not previously been studied systematically. In this study, we report a genome-wide association study of vitiligo age of onset in 1,339 generalized vitiligo patients, with replication in an independent cohort of 677 cases. We identified a quantitative trait locus for vitiligo age of onset in the major histocompatibility complex (MHC) class II region, located near c6orf10 BTNL2 (rs7758128; P=8.14 * 10(-11)), a region that is also associated with generalized vitiligo susceptibility. In contrast, there was no association of vitiligo age of onset with any other MHC or non-MHC loci that are associated with vitiligo susceptibility. These findings highlight the differing roles played by genes involved in vitiligo susceptibility versus vitiligo age of onset, and illustrate that genome-wide analyses can be used to identify genes involved in quantitative aspects of disease natural history, as well as disease susceptibility per se. PMID- 21326296 TI - BRAF exon 15 T1799A mutation is common in melanocytic nevi, but less prevalent in cutaneous malignant melanoma, in Chinese Han. AB - Frequent somatic mutations of BRAF (v-raf murine sarcoma viral oncogene homolog B) exon T1799A, which are implicated in the initial events of promutagenic cellular proliferation, are detected in both malignant melanomas (MM) and melanocytic nevi (MN). Most of the data regarding BRAF exon T1799A mutation have been from Caucasian cohorts, and a comprehensive screening of a homogeneous population is lacking. A total of 379 cases of MN and 195 cases of MM were collected from Chinese Han living in three geographical regions in China, i.e., northeast, southwest, and northwest China. BRAF exon T1799A mutation was detected by PCR and sequencing from microdissected tumors. In all, 59.8% cases of MN harbored BRAF exon T1799A mutation. Samples from regions with high UV exposure had higher detection rates than regions with lower UV exposure (73.5, 67.0, and 38.9%, respectively; chi(2) = 31.674, P = 1.59E-7). There were no differences in mutation rates between congenital and acquired MN; however, acquired MN with advanced age of onset had a higher mutation rate than those with younger age of onset (chi(2) = 13.23, P = 0.02). In all, 15.0% cases of MM harbored the BRAF mutation. The mutation rate in MM was not affected by region, histological type, gender, pattern of UV exposure, and age. The study suggests that the mutation is not necessarily associated with malignant transformation. PMID- 21326297 TI - Filaggrin null mutations are not a protective factor for acne vulgaris. PMID- 21326298 TI - Keratin 14-null cells as a model to test the efficacy of gene therapy approaches in epithelial cells. AB - Skin fragility disorders caused by keratin mutations are incurable, and a better understanding of their etiology is needed to find new ways to improve and treat these conditions. The best-studied skin fragility disorder is epidermolysis bullosa simplex (EBS), an autosomal dominant condition caused by mutations in keratin 5 (K5) or K14. To analyze disease mechanisms and develop gene therapy strategies, we have used keratinocyte cell lines derived from EBS patients as model systems. Here, we describe two cell lines established from EBS patients with K14-null mutations. We analyze the responses of these cells to stress assays previously shown to discriminate between wild-type and keratin-mutant keratinocytes, to directly evaluate the efficacy of rescuing K14-null cells by supplementation with wild-type K14 complementary DNA (cDNA). The K14-null cells show elevated levels of stress correlating with reduced normal keratin function. By transfecting wild-type K14 into these cells, we demonstrate "proof of principle" that an add-back approach can significantly rescue the normal keratinocyte behavior profile. These K14-null cell lines provide a disease model for studying the effects of keratin ablation in EBS patients and to test the efficacy of gene add-back and other therapy approaches in keratinocytes. PMID- 21326299 TI - Fibronectin potentiates topical erythropoietin-induced wound repair in diabetic mice. AB - Diabetes mellitus disrupts all phases of the wound repair cascade and leads to development of chronic wounds. We previously showed that topical erythropoietin (EPO) can promote wound repair in diabetic rats. Fibronectin (FN) has a critical role throughout the process of wound healing, yet it is deficient in wound tissues of diabetic patients. Therefore, we investigated the effect of topical treatment of both EPO and FN (EPO/FN) on wound repair in diabetic mice. Full thickness excisional skin wounds in diabetic and nondiabetic mice were treated with a cream containing vehicle, EPO, FN, or EPO/FN. We assessed the rate of wound closure, angiogenesis, apoptosis, and expression of inflammatory cytokines, endothelial nitric oxide synthase (eNOS) and beta1-integrin, in the wound tissues. We also investigated the effect of EPO, FN, and EPO/FN on human dermal microvascular endothelial cells and fibroblasts cultured on fibrin-coated plates, or in high glucose concentrations. EPO/FN treatment significantly increased the rate of wound closure and this effect was associated with increased angiogenesis, increased eNOS and beta1-integrin expression, and reduced expression of inflammatory cytokines and apoptosis. Our findings show that EPO and FN have an additive effect on wound repair in diabetic mice. PMID- 21326300 TI - A large mutational study in pachyonychia congenita. AB - Pachyonychia congenita (PC) is a rare autosomal dominant skin disorder characterized predominantly by nail dystrophy and painful palmoplantar keratoderma. Additional clinical features include oral leukokeratosis, follicular keratosis, and cysts (steatocysts and pilosebaceous cysts). PC is due to heterozygous mutations in one of four keratin genes, namely, KRT6A, KRT6B, KRT16, or KRT17. Here, we report genetic analysis of 90 new families with PC in which we identified mutations in KRT6A, KRT6B, KRT16, or KRT17, thereby confirming their clinical diagnosis. A total of 21 previously unreported and 22 known mutations were found. Approximately half of the kindreds had mutations in KRT6A (52%), 28% had mutations in KRT16, 17% in KRT17, and 3% of families had mutations in KRT6B. Most of the mutations were heterozygous missense or small in-frame insertion/deletion mutations occurring within one of the helix boundary motif regions of the keratin polypeptide. More unusual mutations included heterozygous splice site mutations, nonsense mutations, and a 1-bp insertion mutation, leading to a frameshift and premature termination codon. This study, together with previously reported mutations, identifies mutation hotspot codons that may be useful in the development of personalized medicine for PC. PMID- 21326301 TI - Additive value of standard ECG for the risk prediction of hypertensive disorders during pregnancy. AB - Prediction of hypertensive complications during pregnancy remains limited, especially in healthy and initially normotensive women. We conducted a prospective screening study for hypertensive complications in pregnant women. We studied 221 nulliparous healthy and normotensive women with singleton pregnancies whose first routine visit was carried out before the twelfth week of gestation. We tested several demographic, clinical and laboratory variables as predictors of a composite pool of prespecified events, including gestational hypertension, preeclampsia or eclampsia. We analyzed the potential additive role of ECG in the identification of women at increased risk of hypertensive disorders. Mean age at entry was 30 years. During pregnancy, there were 28 prespecified events (22 women with gestational hypertension, 5 with preeclampsia and 1 with eclampsia). In univariate analyses, blood pressure (BP), weight, body mass index (BMI) and left atrial (LA) abnormality detected by ECG in lead V(1) showed an association with the risk of hypertensive disorders (all P<0.05). In a multivariable analysis, only mean BP (OR: 3.08, 95% confidence interval (CI): 1.61-5.92; P=0.001 for each 10 mm Hg increase) and LA abnormality in lead V(1) (OR: 4.35, 95% CI: 1.84-10.31; P=0.001) were independent predictors of hypertensive disorders. The final model discriminated well between women who developed hypertensive disorders and women who remained normotensive (AUC=0.75; 95% CI: 0.67-0.84; P<0.0001). This study suggests that standard ECG is valuable to refine risk stratification for hypertensive disorders in initially normotensive pregnant women. LA abnormality, easily detected by simple visual inspection of the traditional ECG, and mean arterial pressure (MAP), allows a rapid and effective risk stratification for hypertensive disorders. PMID- 21326302 TI - Programmed hypertension in rats treated with a NF-kappaB inhibitor during nephrogenesis: renal mechanisms. AB - Suppression of the renin-angiotensin system (RAS) during murine lactation causes progressive renal injury, indicating a physiological action of angiotensin II on nephrogenesis. The nuclear factor NF-kappaB system is one of the main intracellular mediators of angiotensin II. We investigated whether inhibition of this system with pyrrolidine dithiocarbamate (PDTC) during rat nephrogenesis would lead to similar hypertension and renal injury as observed with RAS suppressors. Immediately after delivery, 32 Munich-Wistar dams, each nursing 6 male pups, were divided into 2 groups: C, untreated, and PDTC, receiving PDTC, 280 mg kg(-1) day(-1) orally, during 21 days. After weaning, the offspring were followed until 10 months of age without treatment. Adult rats that received neonatal PDTC exhibited stable hypertension and myocardial injury, without albuminuria. To gain additional insight into this process, the renal expression of RAS components and sodium transporters were determined by quantitative real time PCR (qRT-PCR) at 3 and 10 months of life. Renal renin and angiotensinogen were upregulated at 3 and downregulated at 10 months of age, suggesting a role for early local RAS activation. Likewise, there was early upregulation of the proximal sodium/glucose and sodium/bicarbonate transporters, which abated later in life, suggesting that additional factors sustained hypertension in the long run. The conclusions drawn from the findings were as follows: (1) an intact NF kappaB system during nephrogenesis may be essential to normal renal and cardiovascular function in adult life; (2) neonatal PDTC represents a new model of hypertension, lacking overt structural injury or functional impairment of the kidneys; and (3) hypertension in this model seems associated with early temporary activation of renal RAS and sodium transporters. PMID- 21326303 TI - A common polymorphism of CYP4A11 is associated with blood pressure in a Chinese population. AB - Variants of the human CYP4A11, which belongs to the cytochrome P450, family 4, have been reported to be associated with hypertension in general populations. However, data in the Chinese population are limited. This study sought to assess the effect of CYP4A11 on the prevalence of hypertension and blood pressure in a Chinese population. Three tagging single nucleotide polymorphisms, rs9332982, rs4660980 and rs3890011, were genotyped in 1734 community-based participants. Individuals with secondary hypertension were excluded. Sex-pooled and sex specific analysis for genotype-phenotype association were both conducted. We found rs9332982 T allele was nominally associated with higher prevalence of hypertension in women after adjustment for covariates (OR: 1.38, 95%CI: 1.06 1.81, P = 0.0183). The significance did not retain after Bonferroni correction. In blood pressure analysis restricted to normotensive individuals, rs4660980 was associated with both systolic (beta = -3.17, P = 0.0011) and diastolic blood pressure (beta = -1.75, P = 0.0010) in men. A common variant on CYP4A11 was associated with blood pressure in a Chinese population. Future studies are needed to confirm our findings. PMID- 21326304 TI - Unexpected occurrence of adrenal Cushing's syndrome in a patient with systemic lupus erythematosus. PMID- 21326305 TI - Lifetime risk of stroke and impact of hypertension: estimates from the adult health study in Hiroshima and Nagasaki. AB - Very few reports have been published on lifetime risk (LTR) of stroke by blood pressure (BP) group. This study included participants in the Radiation Effects Research Foundation Adult Health Study who have been followed up by biennial health examinations since 1958. We calculated the LTR of stroke for various BP based groups among 7847 subjects who had not been diagnosed with stroke before the index age of 55 years using cumulative incidence analysis adjusting for competing risks. By 2003, 868 subjects had suffered stroke (512 (58.9%) were women and 542 (62.4%) experienced ischemic stroke). BP was a significant factor in determining risk of stroke for men and women, with distributions of cumulative risk for stroke significantly different across BP groups. The LTR of all-stroke for normotension (systolic BP/diastolic BP < 120/80 mm Hg), prehypertension (120 139/80-89 mm Hg), stage 1 hypertension (140-159/90-99 mm Hg) and stage 2 hypertension (> 160/100 mm Hg) were 13.8-16.9-25.8-25.8% in men and 16.0-19.9 24.0-30.5% in women, respectively (P < 0.001 among BP groups in both sexes). The estimates did not differ significantly (P = 0.16) between normotensive and prehypertensive subjects. One in five Japanese atomic bomb survivor subjects experienced stroke over their lifetime from the age of 55 years. Long-term stroke risks were elevated in those with hypertension (> 140/90 mm Hg) at any of the index ages of 45, 55, 65 and 75 years. PMID- 21326306 TI - Detection of global DNA methylation and paternally imprinted H19 gene methylation in preeclamptic placentas. AB - Preeclampsia (PE) is a severe hypertensive disorder associated with pregnancy; despite substantial research effort in the past several years, the etiology of PE is still unclear. The role of epigenetic factors in the etiology of PE, including DNA methylation, has been poorly characterized. In the present study, we investigated global DNA methylation as well as DNA methylation of the paternally imprinted H19 gene in preeclamptic placentas. Using 5-methylcytosine immunohistochemistry and Alu and LINE-1 repeat pyrosequencing, we found that the global DNA methylation level and the DNA (cytosine-5) methyltransferase 1 mRNA level were significantly higher in the early-onset preeclamptic placentas when compared with the normal controls. Data from methylation-sensitive high resolution melting demonstrated hypermethylation of the promoter region of the H19 gene, and results of real-time PCR showed decreased mRNA expression of H19 gene in the early-onset preeclamptic placentas as compared with the normal controls. Our results suggest that abnormal DNA methylation during placentation might be involved in the pathophysiology of PE, especially early-onset preeclampsia. PMID- 21326307 TI - Relationship of home blood pressure with target-organ damage in children and adolescents. AB - The objective of this study was to compare home blood pressure (HBP) vs. ambulatory (ABP) and clinic (CBP) measurements in terms of their association with target-organ damage in children and adolescents. A total of 81 children and adolescents (mean age 13 +/- 3 years, 53 boys) referred for elevated CBP had measurements of CBP (1 visit), HBP (6 days) and ABP (24-h). Seventy-six participants were also assessed with carotid-femoral pulse wave velocity (PWV) and 54 with echocardiography. Average CBP was 122.1 +/- 15.1/71 +/- 12.9 mm Hg (systolic/diastolic), HBP 121.3 +/- 11.5/69.4 +/- 6.6 mm Hg and 24-h ABP 118.9 +/ 12/66.6 +/- 6.1 mm Hg. Left ventricular mass (LVM) was correlated with systolic blood pressure (BP) (coefficient r = 0.55/0.54/0.45 for 24-h/daytime/nighttime ABP, 0.53 for HBP and 0.41 for CBP; all P< 0.01). No significant correlations were found for diastolic BP. PWV was also significantly correlated with systolic BP (r = 0.52/0.50/0.48 for 24-h/daytime/nighttime ABP, 0.50 for HBP and 0.47 for CBP; all P < 0.01). Only diastolic ABP and HBP were significantly correlated with PWV (r = 0.30 and 0.28, respectively, P<0.05). In multivariate stepwise regression analysis (with age, gender, body mass index [BMI], clinic, home and 24 h ambulatory systolic/diastolic BP and pulse pressure, clinic, home and 24-h heart rate as independent variables), PWV was best predicted by systolic HBP (R(2) = 0.22, beta +/- s.e. = 0.06 +/- 0.01), whereas LVM was determined (R(2) = 0.67) by 24-h pulse pressure (beta = 1.21 +/- 0.41), age (beta = 2.93 +/- 1.32), 24-h heart rate (beta = -1.27 +/- 0.41) and BMI (beta = 1.78 +/- 0.70). These data suggest that, in children and adolescents, ABP as well as HBP measurements appear to be superior to the conventional CBP measurements in predicting the presence of subclinical end-organ damage. PMID- 21326308 TI - Angiotensin-converting enzyme inhibition and fibrinolytic balance. PMID- 21326309 TI - De novo 19q13.42 duplications involving NLRP gene cluster in a patient with systemic-onset juvenile idiopathic arthritis. AB - Systemic-onset juvenile idiopathic arthritis (s-JIA) is a rare inflammatory disease classified as a subtype of chronic childhood arthritis, manifested by spiking fever, erythematous skin rash, pericarditis and hepatosplenomegaly. The genetic background underlying s-JIA remains poorly understood. To detect disease related copy number variations (CNVs), we performed single-nucleotide polymorphism array analysis in 50 patients with s-JIA. We detected many CNVs, but most of them were inherited from either of normal-phenotype parents. However, in one patient, we could identify two de novo microduplications at 19q13.42 with the size of 77 and 622 kb, separated by a 109-kb segment of normal copy number. The duplications encompass NLRP family (NLRP2, NLRP9 and NLRP11) as well as IL11 and HSPBP1, all of which have an important role in inflammatory pathways. These genes may significantly contribute to the pathogenesis of s-JIA. PMID- 21326310 TI - Mitochondrial DNA and Y-chromosomal stratification in Iran: relationship between Iran and the Arabian Peninsula. AB - Modern day Iran is strategically located in the tri-continental corridor uniting Africa, Europe and Asia. Several ethnic groups belonging to distinct religions, speaking different languages and claiming divergent ancestries inhabit the region, generating a potentially diverse genetic reservoir. In addition, past pre historical and historical events such as the out-of-Africa migrations, the Neolithic expansion from the Fertile Crescent, the Indo-Aryan treks from the Central Asian steppes, the westward Mongol expansions and the Muslim invasions may have chiseled their genetic fingerprints within the genealogical substrata of the Persians. On the other hand, the Iranian perimeter is bounded by the Zagros and Albrez mountain ranges, and the Dasht-e Kavir and Dash-e Lut deserts, which may have restricted gene flow from neighboring regions. By utilizing high resolution mitochondrial DNA (mtDNA) markers and reanalyzing our previously published Y-chromosomal data, we have found a previously unexplored, genetic connection between Iranian populations and the Arabian Peninsula, likely the result of both ancient and recent gene flow. Furthermore, the regional distribution of mtDNA haplogroups J, I, U2 and U7 also provides evidence of barriers to gene flow posed by the two major Iranian deserts and the Zagros mountain range. PMID- 21326311 TI - Genome-wide association study identifies genetic variants influencing F-cell levels in sickle-cell patients. AB - Fetal hemoglobin (HbF) level has emerged as an important prognostic factor in sickle-cell disease (SCD) and can be measured by the proportion of HbF-containing erythrocytes (F-cells). Recently, BCL11A (zinc-finger protein) was identified as a regulator of HbF, and the strongest association signals were observed either directly for rs766432 or for correlated single-nucleotide polymorphisms (SNPs). To identify additional independently associated genetic variants, we performed a genome-wide association study (GWAS) on the proportion of F-cells in individuals of African ancestry with SCD from the Silent Infarct Transfusion (SIT) Trial cohort. Our study not only confirms the association of rs766432 (P-value <3.32 * 10(-13)), but also identifies an independent novel intronic SNP, rs7606173, associated with F-cells (P-value <1.81 * 10(-15)). The F-cell variances explained independently by these two SNPs are ~13% (rs7606173) and ~11% (rs766432), whereas, together they explain ~16%. Additionally, in men, we identify a novel locus on chromosome 17, glucagon-like peptide-2 receptor (GLP2R), associated with F-cell regulation (rs12103880; P-value <3.41 * 10(-8)). GLP2R encodes a G protein coupled receptor and involved in proliferative and anti-apoptotic cellular responses. These findings highlight the importance of denser genetic screens and suggest further exploration of the BCL11A and GLP2R loci to gain additional insight into HbF/F-cell regulation. PMID- 21326312 TI - Hypospadias associated with hypertelorism, the mildest phenotype of Opitz syndrome. AB - Hypospadias is a common congenital malformation in boys in which the urethral meatus opens on the underside of the penis. It is considered a complex disorder with several genes involved and the molecular etiology is just beginning to be revealed. As more than 85% of Opitz G/BBB syndrome (OS) patients with MID1 mutations are manifested with hypospadias, we have investigated the association between the MID1 gene and hypospadias. DNA from 114 hypospadias cases was analyzed with direct sequencing of the MID1 gene. Genotyping analysis was performed for the single-nucleotide polymorphism (SNP) c.1230G>A in 370 individuals with varying degrees of hypospadias and compared with 759 healthy controls. We identified one nonsense mutation c.712G>T (p.E238X), one missense mutation c.1679A>G (p.K560R) and two synonymous variants c.1230G>A (p.S410S) and c.1284T>G (p.V428V). We also detected a significant difference in the rare allele frequency of SNP c.1230G>A in hypospadias patients as compared with controls (P=0.016). Our finding suggests that hypospadias associated with hypertelorism is the mildest phenotype in OS caused by MID1 mutations. PMID- 21326313 TI - Proposal of pharmacogenetics-based warfarin dosing algorithm in Korean patients. AB - Warfarin is a commonly prescribed anticoagulant drug for the prevention of thromboembolic disorders. We investigated the contribution of genetic variations of four genes and clinical factors to warfarin dose requirement and provided a warfarin-dosing algorithm based on genetic and clinical variables in Korean patients. We recruited 564 Korean patients on stable anticoagulation. Single nucleotide polymorphisms (SNPs) for the VKORC1, CYP2C9, CYP4F2 and GGCX were analyzed. Using multiple regression analysis, we developed a model to predict the warfarin requirement. The SNPs of VKORC1, CYP2C9, CYP4F2 and GGCX showed significant correlation with warfarin dose. Patients with the 3730AA genotype received significantly higher doses of warfarin than those with the 3730GG (P=0.0001). For CYP2C9, the highest maintenance dose was observed in the patients with wild-type genotype compared with the variant allele carriers (P<0.0001). The multiple regression model including age, gender, body surface area (BSA), international normalized ratio (INR) and four genetic polymorphisms accounted for 35% of total variations in warfarin dose (R(2)=0.3499; P<0.0001). This study shows that age, gender, BSA, INR and VKORC1, CYP2C9 and CYP4F2 polymorphism affect warfarin dose requirements in Koreans. Translation of this knowledge into clinical guidelines for warfarin prescription may contribute to improve the efficacy and safety of warfarin treatment for Korean patients. PMID- 21326314 TI - Molecular diagnosis and clinical onset of Charcot-Marie-Tooth disease in Japan. AB - To study the genetic background of Japanese Charcot-Marie-Tooth disease (CMT) patients, we analyzed qualitative and quantitative changes in the disease-causing genes mainly by denaturing high performance liquid chromatography and multiplex ligation-dependent probe analysis in 227 patients with demyelinating CMT and 127 patients with axonal CMT. In demyelinating CMT, we identified 53 patients with PMP22 duplication, 10 patients with PMP22 mutations, 20 patients with MPZ mutations, eight patients with NEFL mutations, 19 patients with GJB1 mutations, one patient with EGR2 mutation, five patients with PRX mutations and no mutations in 111 patients. In axonal CMT, we found 14 patients with MFN2 mutations, one patient with GARS mutation, five patients with MPZ mutations, one patient with GDAP1 mutation, six patients with GJB1 mutations and no mutations in 100 patients. Most of the patients carrying PMP22, MPZ, NEFL, PRX and MFN2 mutations showed early onset, whereas half of the patients carrying PMP22 duplication and all patients with GJB1 or MPZ mutations showing axonal phenotype were adult onset. Our data showed that a low prevalence of PMP22 duplication and high frequency of an unknown cause are features of Japanese CMT. Low prevalence of PMP22 duplication is likely associated with the mild symptoms due to genetic and/or epigenetic modifying factors. PMID- 21326315 TI - Mini-review series: focus on chemokines. PMID- 21326317 TI - Sequencing of TNFAIP3 and association of variants with multiple autoimmune diseases. AB - The TNFAIP3 locus at 6q23, encoding A20, has been associated with multiple autoimmune diseases (AIDs). In this study, we sequence the coding portions of the gene to identify contributing causal polymorphisms that may explain some of the observed associations. A collection of 123 individuals from the Multiple Autoimmune Disease Genetics Consortium (MADGC) collection, each with multiple AIDs (mean=2.2 confirmed diagnoses), and 397 unrelated healthy controls were used for initial sequencing. A total of 32 polymorphisms were identified in the sequencing experiments, including 16 novel and 11 coding variants. Association testing in the entire MADGC collection (1,008 Caucasians with one or more AIDs and 770 unaffected family controls) revealed association of a novel intronic insertion-deletion polymorphism with rheumatoid arthritis (RA) (odds ratio (OR)=2.48, P=0.041). Genotyping of the most common coding polymorphism, rs2230926, in the MADGC collection and additional control individuals revealed a significant association with Sjogren's syndrome (OR=3.38, P=0.038), Crohn's disease (OR=2.25, P=0.041), psoriasis (OR=0.037, P=0.036) and RA (OR=1.9, P=0.025). Finally, haplotype and additional testing of polymorphisms revealed that cases were enriched for 5' and 3' untranslated region variants (one-sided P value=0.04), but not specifically for common (>2% minor allele frequency), rare, exonic, intronic, non-synonymous or synonymous variants. PMID- 21326316 TI - Interferon-inducible gene 202b controls CD8(+) T cell-mediated suppression in anti-DNA Ig peptide-treated (NZB * NZW) F1 lupus mice. AB - Administration of an artificial peptide (pConsensus) based on anti-DNA IgG sequences that contain major histocompatibility complex class I and class II T cell determinants, induces immune tolerance in NZB/NZW F1 female (BWF1) mice. To understand the molecular basis of CD8(+) Ti-mediated suppression, we previously performed microarray analysis to identify genes that were differentially expressed following tolerance induction with pCons. CD8(+) T cells from mice tolerized with pCons showed more than two-fold increase in Ifi202b mRNA, an interferon inducible gene, versus cells from untolerized mice. Ifi202b expression increased through weeks 1-4 after tolerization and then decreased, reapproaching baseline levels at 6 weeks. In vitro polyclonal activation of tolerized CD8(+) T cells significantly increased Ifi202b mRNA expression. Importantly, silencing of Ifi202b abrogated the suppressive capacity of CD8(+) Ti cells. This was associated with decreased expression of Foxp3, and decreased gene and protein expression of transforming growth factor (TGF)beta and interleukin-2 (IL-2), but not of interferon (IFN)-gamma, IL-10, or IL-17. Silencing of another IFN-induced gene upregulated in tolerized CD8(+) T cells, IFNAR1, had no effect on the ability of CD8(+) T cells to suppress autoantibody production. Our findings indicate a potential role for Ifi202b in the suppressive capacity of peptide induced regulatory CD8(+) Ti cells through effects on the expression of Foxp3 and the synthesis of TGFbeta. PMID- 21326318 TI - DNA methylation dysregulates and silences the HLA-DQ locus by altering chromatin architecture. AB - The major histocompatibility complex class II (MHC-II) locus encodes a cluster of highly polymorphic genes HLA-DR, -DQ and -DP that are co-expressed in mature B lymphocytes. Two cell lines were established over 30 years ago from a patient diagnosed with acute lymphocytic leukemia. Laz221 represented the leukemic cells of the patient; whereas Laz388 represented the normal B cells of the patient. Although Laz388 expressed both HLA-DR and HLA-DQ surface and gene products, Laz221 expressed only HLA-DR genes. The discordant expression of HLA-DR and HLA DQ genes was due to epigenetic silencing of the HLA-DQ region CCCTC transcription factor (CTCF)-binding insulators that separate the MHC-II sub-regions by DNA methylation. These epigenetic modifications resulted in the loss of binding of the insulator protein CTCF to the HLA-DQ flanking insulator regions and the MHC II-specific transcription factors to the HLA-DQ promoter regions. These events led to the inability of the HLA-DQ promoter regions to interact with flanking insulators that control HLA-DQ expression. Inhibition of DNA methylation by treatment with 5'-deoxyazacytidine reversed each of these changes and restored expression of the HLA-DQ locus. These results highlight the consequence of disrupting an insulator within the MHC-II region and may be a normal developmental mechanism or one used by tumor cells to escape immune surveillance. PMID- 21326319 TI - Identification and characterization of Cri1, a locus controlling mortality during Citrobacter rodentium infection in mice. AB - Infection of inbred mouse strains with Citrobacter rodentium represents an ideal model to reveal the genetic factors controlling host resistance to noninvasive enteric bacterial pathogens. We have chosen a positional cloning approach to identify putative gene(s) that control the known difference in survival between resistant C57BL/6J and susceptible C3H/HeJ and C3H/HeOuJ mice. Our work has identified one major locus within proximal chromosome 15 that is responsible for the marked susceptibility of both C3H strains, and we formally exclude Tlr4 from control of survival to this pathogen. We have named this new host resistance locus Cri1 (Citrobacter rodentium infection 1). The Cri1 genetic interval currently spans ~16 Mb and it confers survival to the infection in a recessive manner. Transfer of the Cri1 locus from the surviving B6 mice into a congenic mouse with a C3Ou genetic background confirms its overall chromosomal localization and its highly significant effect on host survival. The C3Ou.B6-Cri1 mice thus produced have also enabled us to dissociate the control of mouse survival from the control of bacterial load early in the infection as well as from control of colonic hyperplasia. PMID- 21326320 TI - The human G1m1 allotype associates with CD4+ T-cell responsiveness to a highly conserved IgG1 constant region peptide and confers an asparaginyl endopeptidase cleavage site. AB - The human G1m1 allotype comprises two amino acids, D12 and L14, in the CH3 domain of IGHG1. Although the G1m1 allotype is prevalent in human populations, ~40% of Caucasiods are homozygous for the nG1m1 allotype corresponding to E12 and M14. Peptides derived from the G1m1 region were tested for their ability to induce CD4+ T-cell proliferative responses in vitro. A peptide immediately downstream from the G1m1 sequence was recognized by CD4+ T cells in a large percentage of donors (peptide CH315-29). CD4+ T-cell proliferative responses to CH315-29 were found at an increased frequency in nG1m1 homozygous donors. Homozygous nG1m1 donors possessing the HLA-DRB1*07 allele displayed the highest magnitudes of proliferation. CD4+ T cells from donors homozygous for nG1m1 proliferated to G1m1 carrying Fc-fragment proteins, whereas CD4+ T cells from G1m1 homozygous donors did not. The G1m1 sequence creates an enzymatic cleavage site for asparaginyl endopeptidase in vitro. Proteolytic activity at D12 may allow the presentation of the CH315-29 peptide, which in turn may result in the establishment of tolerance to this peptide in G1m1-positive donors. Homozygous nG1m1 patients may be more likely to develop CD4+ T-cell-mediated immune responses to therapeutic antibodies carrying the G1m1 allotype. PMID- 21326321 TI - Two missense variants in UHRF1BP1 are independently associated with systemic lupus erythematosus in Hong Kong Chinese. AB - UHRF1BP1 encodes a highly conserved protein with unknown function. Previously, a coding variant in this gene was found to be associated with systemic lupus erythematosus (SLE) in populations of European ancestry (rs11755393, R454Q, P=2.22 x 10-8, odds ratio=1.17). In this study, by a combination of genome-wide study and replication involving a total of 1230 patients and 3144 controls, we confirmed the association of this coding variant to SLE in Hong Kong Chinese. We also identified another coding variant in this gene that independently contributes to SLE susceptibility (rs13205210, M1098T, P=4.44 x 10-9, odds ratio=1.49). Cross-population confirmation establishes the involvement of this locus in SLE and indicates that distinct alleles are contributing to disease susceptibility. PMID- 21326322 TI - Nucleating actin for invasion. AB - The invasion of cancer cells into the surrounding tissue is a prerequisite and initial step in metastasis, which is the leading cause of death from cancer. Invasive cell migration requires the formation of various structures, such as invadopodia and pseudopodia, which require actin assembly that is regulated by specialized actin nucleation factors. There is a large variety of different actin nucleators in human cells, such as formins, spire and Arp2/3-regulating proteins, and the list is likely to grow. Studies of the mechanisms of various actin nucleation factors that are involved in cancer cell function may ultimately provide new treatments for invasive and metastatic disease. PMID- 21326323 TI - Novel roles for Slits and netrins: axon guidance cues as anticancer targets? AB - Over the past few years, several genes, proteins and signalling pathways that are required for embryogenesis have been shown to regulate tumour development and progression by playing a major part in overriding antitumour safeguard mechanisms. These include axon guidance cues, such as Netrins and Slits. Netrin 1 and members of the Slit family are secreted extracellular matrix proteins that bind to deleted in colorectal cancer (DCC) and UNC5 receptors, and roundabout receptors (Robos), respectively. Their expression is deregulated in a large proportion of human cancers, suggesting that they could be tumour suppressor genes or oncogenes. Moreover, recent data suggest that these ligand-receptor pairs could be promising targets for personalized anticancer therapies. PMID- 21326325 TI - Molecular targets of phytochemicals for cancer prevention. AB - Although successful for a limited number of tumour types, the efficacy of cancer therapies, especially for late-stage disease, remains poor overall. Many have argued that this could be avoided by focusing on cancer prevention, which has now entered the arena of targeted therapies. During the process of identifying preventive agents, dietary phytochemicals, which are thought to be safe for human use, have emerged as modulators of key cellular signalling pathways. The task now is to understand how these chemicals perturb these pathways by modelling their interactions with their target proteins. PMID- 21326324 TI - Can corruption of chromosome cohesion create a conduit to cancer? AB - Cohesin is a conserved multisubunit protein complex with diverse cellular roles, making key contributions to the coordination of chromosome segregation, the DNA damage response and chromatin regulation by epigenetic mechanisms. Much has been learned in recent years about the roles of cohesin in a physiological context, whereas its potential and emerging role in tumour initiation and/or progression has received relatively little attention. In this Opinion article we examine how cohesin deregulation could contribute to cancer development on the basis of its physiological roles. PMID- 21326326 TI - The forgotten fallopian tube. PMID- 21326328 TI - Adherence therapy for medication non-compliant patients with hypertension: a randomised controlled trial. AB - The objective of this study is to establish the efficacy of adherence therapy (AT) compared with treatment as usual (TAU) in reducing blood pressure (BP) in non-compliant hypertensive patients. This study was designed as a parallel-group single-blind randomised controlled trial. The study was carried out at three general hospital outpatient clinics in Jordan. A total of 136 non-compliant hypertensive patients with a mean baseline BP of 164.5 mm Hg (s.d. 10.0) over 102.2 mm Hg (s.d. 7.0) participated in the study. 7 weekly 20-min sessions of AT in addition to TAU. The main outcome of this study is systolic blood pressure (SBP) at 11-weeks follow-up. In all, 68 patients received TAU and 68 AT. Intention-to-treat analysis included all participants randomised. AT lowered SBP by -23.11 mm Hg (95% CI: -25.85, -20.36) and diastolic BP (DBP) by -15.18 mm Hg (95% CI: -17.55, -12.80) at 11 weeks compared with TAU. Adherence (measured by pill counting) was also improved in the AT group by 37% at 11 weeks compared with TAU. No significant adverse events were reported. AT increases adherence to medication for hypertension which then leads to a clinically important reduction in BP. PMID- 21326329 TI - Treatment of experimental autoimmune encephalomyelitis in SJL/J mice with a replicative HSV-1 vector expressing interleukin-5. AB - Experimental autoimmune encephalomyelitis (EAE) is an autoimmune inflammation of the central nervous system and is used as the experimental model of multiple sclerosis (MS). The exact mechanism behind the disease is still unknown, but interleukin (IL)-17 expressing T cells are thought to mediate the disease. Toll like receptors (TLRs) are known to have a role in the innate immune response against pathogens, and several TLRs have also a role in the disease course of EAE. Here, we show that treatment with a herpes simplex virus type 1 vector expressing the Th2 cytokine IL-5 ameliorates EAE and decreases the numbers of infiltrating lymphocytes in the brain. The effect involves downregulation of TLR 2, 3 and 9 mRNA expression and upregulation of type I interferons (IFNs) in brains during onset of disease. The elevated expression of type I IFNs was also observed during recovery. PMID- 21326330 TI - Schwann cell targeting via intrasciatic injection of AAV8 as gene therapy strategy for peripheral nerve regeneration. AB - Efficient transduction of the peripheral nervous system (PNS) is required for gene therapy of acquired and inherited neuropathies, neuromuscular diseases and for pain treatment. We have characterized the tropism and transduction efficiency of different adeno-associated vectors (AAV) pseudotypes after sciatic nerve injection in the mouse. Among the pseudotypes tested, AAV2/1 transduced both Schwann cells and neurons, AAV2/2 infected only sensory neurons and AAV2/8 preferentially transduced Schwann cells. AAV2/8 expression in the sciatic nerve was detected up to 10 weeks after administration, the latest time point analyzed. The injected mice developed neutralizing antibodies against all AAVs tested; the titers were higher against AAV2/1 than AAV2/2 and were the lowest for AAV2/8, correlating with a higher transgene expression overtime. AAV2/8 coding for ciliary neurotrophic factor (CNTF) led to an upregulation of P0 and PMP22 myelin proteins, four weeks after transduction of injured sciatic nerves. Importantly, CNTF-transduced mice showed a significant increase in both GAP43 expression in sensory neurons, a marker of axonal regeneration, and the compound muscle action potential. These results prove the utility of AAV8 as a gene therapy vector for Schwann cells to treat myelin disorders or to improve nerve regeneration. PMID- 21326331 TI - Efficient and stable transduction of dopaminergic neurons in rat substantia nigra by rAAV 2/1, 2/2, 2/5, 2/6.2, 2/7, 2/8 and 2/9. AB - Dysfunction of the nigrostriatal system is the major cause of Parkinson's disease (PD). This brain region is therefore an important target for gene delivery aiming at disease modeling and gene therapy. Recombinant adeno-associated viral (rAAV) vectors have been developed as efficient vehicles for gene transfer into the central nervous system. Recently, several serotypes have been described, with varying tropism for brain transduction. In light of the further development of a viral vector-mediated rat model for PD, we performed a comprehensive comparison of the transduction and tropism for dopaminergic neurons (DNs) in the adult Wistar rat substantia nigra (SN) of seven rAAV vector serotypes (rAAV 2/1, 2/2, 2/5, 2/6.2, 2/7, 2/8 and 2/9). All vectors were normalized by titer and volume, and stereotactically injected into the SN. Gene expression was assessed non invasively and quantitatively in vivo by bioluminescence imaging at 2 and 5 weeks after injection, and was found to be stable over time. Immunohistochemistry at 6 weeks following injection revealed the most widespread enhanced green fluorescence protein expression and the highest number of positive nigral cells using rAAV 2/7, 2/9 and 2/1. The area transduced by rAAV 2/8 was smaller, but nevertheless almost equal numbers of nigral cells were targeted. Detailed confocal analysis revealed that serotype 2/7, 2/9, 2/1 and 2/8 transduced at least 70% of the DNs. In conclusion, these results show that various rAAV serotypes efficiently transduce nigral DNs, but significant differences in transgene expression pattern and level were observed. PMID- 21326332 TI - Temporal factors in school closure policy for mitigating the spread of influenza. AB - Is school closure effective in mitigating influenza outbreaks? For Singapore, we developed an individual-based simulation model using real-life contact data. We evaluated the impacts of temporal factors - trigger threshold and duration - on the effectiveness of school closure as a mitigation policy. We found an upper bound of the duration of school closure, where further extension beyond which will not bring additional benefits to suppressing the attack rate and peak incidence. For school closure with a relatively short duration (< 6 weeks), it is more effective to start closure after a relatively longer delay from the first day of infection; if the duration of school closure is long (>6 weeks), however, it is better to start it as early as reasonable. Our studies reveal the critical importance of timing in school closure, especially in cost-cautious situations. Our studies also demonstrate the great potential of a properly developed individual-based simulation model in evaluating various disease control policies. PMID- 21326333 TI - Social security and mortality: the role of income support policies and population health in the United States. AB - Social Security is the most important and effective income support program ever introduced in the United States, alleviating the burden of poverty for millions of elderly Americans. We explored the possible role of Social Security in reducing mortality among the elderly. In support of this hypothesis, we found that declines in mortality among the elderly exceeded those among younger age groups following the initial implementation of Social Security in 1940, and also in the periods following marked improvements in Social Security benefits via legislation and indexing of benefits that occurred between the mid-1960s and the early 1970s. A better understanding of the link between Social Security and health status among the elderly would add a significant and missing dimension to the public discourse over the future of Social Security, and the potential role of income support programs in reducing health-related socioeconomic disparities and improving population health. PMID- 21326334 TI - Response of Prochlorococcus ecotypes to co-culture with diverse marine bacteria. AB - Interactions between microorganisms shape microbial ecosystems. Systematic studies of mixed microbes in co-culture have revealed widespread potential for growth inhibition among marine heterotrophic bacteria, but similar synoptic studies have not been done with autotroph/heterotroph pairs, nor have precise descriptions of the temporal evolution of interactions been attempted in a high throughput system. Here, we describe patterns in the outcome of pair-wise co cultures between two ecologically distinct, yet closely related, strains of the marine cyanobacterium Prochlorococcus and hundreds of heterotrophic marine bacteria. Co-culture with the collection of heterotrophic strains influenced the growth of Prochlorococcus strain MIT9313 much more than that of strain MED4, reflected both in the number of different types of interactions and in the magnitude of the effect of co-culture on various culture parameters. Enhancing interactions, where the presence of heterotrophic bacteria caused Prochlorococcus to grow faster and reach a higher final culture chlorophyll fluorescence, were much more common than antagonistic ones, and for a selected number of cases were shown to be mediated by diffusible compounds. In contrast, for one case at least, temporary inhibition of Prochlorococcus MIT9313 appeared to require close cellular proximity. Bacterial strains whose 16S gene sequences differed by 1-2% tended to have similar effects on MIT9313, suggesting that the patterns of inhibition and enhancement in co-culture observed here are due to phylogenetically cohesive traits of these heterotrophs. PMID- 21326335 TI - Prey bacteria shape the community structure of their predators. AB - Although predator-prey interactions among higher organisms have been studied extensively, only few examples are known for microbes other than protists and viruses. Among the bacteria, the most studied obligate predators are the Bdellovibrio and like organisms (BALOs) that prey on many other bacteria. In the macroscopical world, both predator and prey influence the population size of the other's community, and may have a role in selection. However, selective pressures among prey and predatory bacteria have been rarely investigated. In this study, Bacteriovorax, a predator within the group of BALOs, in environmental waters were fed two prey bacteria, Vibrio vulnificus and Vibrio parahaemolyticus. The two prey species yielded distinct Bacteriovorax populations, evidence that selective pressures shaped the predator community and diversity. The results of laboratory experiments confirmed the differential predation of Bacteriovorax phylotypes on the two bacteria species. Not only did Bacteriovorax Cluster IX exhibit the versatility to be the exclusive efficient predator on Vibrio vulnificus, thereby, behaving as a specialist, but was also able to prey with similar efficiency on Vibrio parahaemolyticus, indicative of a generalist. Therefore, we proposed a designation of versatilist for this predator. This initiative should provide a basis for further efforts to characterize the predatory patterns of bacterial predators. The results of this study have revealed impacts of the prey on Bacteriovorax predation and in structuring the predator community, and advanced understanding of predation behavior in the microbial world. PMID- 21326336 TI - RNA-seq reveals cooperative metabolic interactions between two termite-gut spirochete species in co-culture. AB - The hindguts of wood-feeding termites typically contain hundreds of microbial species. Together with their insect host, these gut microbes degrade lignocellulose into usable catabolites. Although past research revealed many facets of the stepwise flow of metabolites in this scheme, not much is known about the breadth of interactions occurring between termite-gut microbes. Most of these microbes are thought to depend on, and to have co-speciated with, their host and each other for millions of years. In this study, we explored the interactions of two spirochetes previously isolated from the very same termite species. As hydrogen (H(2)) is the central free intermediate in termite-gut lignocellulose digestion, we focused on interactions between two closely related termite-gut spirochetes possessing complementary H(2) physiologies: one produces H(2), while the other consumes it. In vitro, these two Treponema species markedly enhanced each other's growth. RNA sequencing resolved the transcriptomes of these two closely related organisms, revealing that co-cultivation causes comprehensive changes in global gene expression. The expression of well over a 100 genes in each species was changed >twofold, with over a dozen changed >10-fold. Several changes implicating synergistic cross-feeding of known metabolites were validated in vitro. Additionally, certain activities beneficial to the host were preferentially expressed during consortial growth. However, the majority of changes in gene expression are not yet understandable, but indicate a broad, comprehensive and mutualistic interaction between these closely related, co resident gut symbionts. The results suggest that staggeringly intricate networks of metabolic and gene interactions drive lignocellulose degradation and co evolution of termite gut microbiota. PMID- 21326337 TI - Autotrophic growth of nitrifying community in an agricultural soil. AB - The two-step nitrification process is an integral part of the global nitrogen cycle, and it is accomplished by distinctly different nitrifiers. By combining DNA-based stable isotope probing (SIP) and high-throughput pyrosequencing, we present the molecular evidence for autotrophic growth of ammonia-oxidizing bacteria (AOB), ammonia-oxidizing archaea (AOA) and nitrite-oxidizing bacteria (NOB) in agricultural soil upon ammonium fertilization. Time-course incubation of SIP microcosms indicated that the amoA genes of AOB was increasingly labeled by (13)CO(2) after incubation for 3, 7 and 28 days during active nitrification, whereas labeling of the AOA amoA gene was detected to a much lesser extent only after a 28-day incubation. Phylogenetic analysis of the (13)C-labeled amoA and 16S rRNA genes revealed that the Nitrosospira cluster 3-like sequences dominate the active AOB community and that active AOA is affiliated with the moderately thermophilic Nitrososphaera gargensis from a hot spring. The higher relative frequency of Nitrospira-like NOB in the (13)C-labeled DNA suggests that it may be more actively involved in nitrite oxidation than Nitrobacter-like NOB. Furthermore, the acetylene inhibition technique showed that (13)CO(2) assimilation by AOB, AOA and NOB occurs only when ammonia oxidation is not blocked, which provides strong hints for the chemolithoautotrophy of nitrifying community in complex soil environments. These results show that the microbial community of AOB and NOB dominates the nitrification process in the agricultural soil tested. PMID- 21326338 TI - The effect of adrenalectomy on the cardiac response to subacute fetal anemia. AB - The mechanisms that stimulate fetal heart growth during anemia are unknown. To examine the hypothesis that adrenal hormones contribute to this process, we determined the effects of adrenalectomy (Adx) on heart growth and the activation of cardiac mitogen-activated protein kinases (MAPKs) in the presence and absence of fetal anemia. To identify mechanisms contributing to the initiation of cardiac growth, the duration of anemia was limited to a period shorter than that previously described to result in increased cardiac mass. Four groups of fetal sheep were studied (Adx-Anemic, Adx-Control, Intact-Anemic, Intact-Control). Anemia was created by daily controlled hemorrhage for 5 days; hearts were collected for analysis at 133 d gestation (term 145 d). Cardiomyocyte morphometry, immunohistochemistry for Ki-67 (proliferation marker), and Western blotting for protein levels of MAPKs and proliferating cell nuclear antigen (PCNA) were performed. Blood pressure, heart rate, heart weight-to-body weight ratio, and cardiomyocyte length and width remained similar among groups throughout the study. PCNA levels in the Adx-Anemic group were twice as high as in any other group (both ventricles, p < 0.05). Levels of phosphorylated extracellular signal-regulated kinase (ERK) were ~60% higher in the Intact-Anemic and Adx-Anemic groups, compared with the Intact-Control and Adx-Control groups (p < 0.02). These results suggest that adrenal hormones may attenuate fetal cardiomyocyte proliferation in response to anemia (as evidenced by the increased PCNA in Adx-Anemic fetuses) and that phosphorylation of myocardial ERK results from fetal anemia, irrespective of the status of the fetal adrenal gland. PMID- 21326339 TI - The nitric oxide-cGMP signaling pathway plays a significant role in tolerance to the analgesic effect of morphine. AB - Although the phenomenon of opioid tolerance has been widely investigated, neither opioid nor nonopioid mechanisms are completely understood. The aim of the present study was to investigate the role of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway in the development of morphine-induced analgesia tolerance. The study was carried out on male Wistar albino rats (weighing 180-210 g; n = 126). To develop morphine tolerance, animals were given morphine (50 mg/kg; s.c.) once daily for 3 days. After the last dose of morphine was injected on day 4, morphine tolerance was evaluated. The analgesic effects of 3-(5' hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), BAY 41-2272, S-nitroso-N acetylpenicillamine (SNAP), N(G)-nitro-L-arginine methyl ester (L-NAME), and morphine were considered at 15 or 30 min intervals (0, 15, 30, 60, 90, and 120 min) by tail-flick and hot-plate analgesia tests (n = 6 in each study group). The results showed that YC-1 and BAY 41-2272, a NO-independent activator of soluble guanylate cyclase (sGC), significantly increased the development and expression of morphine tolerance, and L-NAME, a NO synthase (NOS) inhibitor, significantly decreased the development of morphine tolerance. In conclusion, these data demonstrate that the nitric oxide-cGMP signal pathway plays a pivotal role in developing tolerance to the analgesic effect of morphine. PMID- 21326340 TI - Increased nitric oxide production in platelets from severe chronic renal failure patients. AB - Nitric oxide (NO) production occurs through oxidation of the amino acid L arginine by NO synthase (NOS). NO inhibits platelet activation by increasing the levels of cyclic guanosine monophosphate (cGMP), thus maintaining vascular homeostasis. Our group previously demonstrated (da Silva et al. 2005) an enhancement of the L-arginine-NO-cGMP pathway in platelets taken from chronic renal failure (CRF) patients on haemodialysis associated with reduced platelet aggregation. We investigate the platelet L-arginine-NO-cGMP pathway, platelet function, and inflammation from patients in CRF on conservative treatment. A total of 42 CRF patients and 42 controls (creatinine clearance = 27 +/- 3 vs. 93 +/- 1 mL per min per 1.73 m2, respectively) participated in this study. NOS activity and expression and cGMP concentration were measured in platelets. Platelet aggregation induced by collagen or ADP was evaluated and plasma levels of fibrinogen were determined by the Clauss method. A marked increase in basal NOS activity was seen in undialysed CRF patients compared with controls, accompanied by an elevation of fibrinogen plasma levels. There were no differences in expression of NOS and in cGMP levels. In this context, platelet aggregation was not affected. We provide the first evidence of increased intraplatelet NO biosynthesis in undialysed CRF patients, which can be an early marker of future haemostatic abnormalities during dialysis treatment. PMID- 21326341 TI - Effect of celecoxib on the antihypertensive effect of losartan in a rat model of renovascular hypertension. AB - Certain nonsteroidal anti-inflammatory drugs have been reported to elevate blood pressure in some hypertensive patients, who are either untreated or treated with antihypertensive agents. This study was undertaken to determine the effect of a selective cyclooxygenase-2 (COX-2) inhibitor, celecoxib, on the antihypertensive effects of the angiotensin II type 1 receptor (AT1) antagonist, losartan potassium. We studied the effect of oral treatment with losartan (30 mg/kg), celecoxib (3 mg/kg), and their combination on the mean arterial blood pressure (MAP), plasma renin activity (PRA), and plasma prostaglandin E2 (PGE2) in male Sprague-Dawley rats with renovascular hypertension (RVH) induced by partial subdiaphragmatic aortic constriction. Treatment was continued for 7 days after aortic coarctation. Aortic coarctation led to significant increases in the MAP, PRA, and plasma PGE2. In RVH rats, losartan treatment caused a significant decrease of MAP with a significant increase in both plasma PGE2 and PRA. Celecoxib caused a nonsignificant change in MAP with a significant decrease in the raised levels of plasma PGE2 and PRA. Concomitant administration of celecoxib and losartan did not significantly affect the lowering effect of losartan on MAP with a subsequent significant decrease in the plasma PGE2 and PRA in RVH rats. Therefore, celecoxib could be used in renin-dependent hypertensive patients who receive losartan, without fear of a rise in their blood pressure. PMID- 21326342 TI - Changes in adiponectin expression in acute myocardial infarction rats and the significance of bisoprolol intervention. AB - The aims of this study were to explore the changes in expression of myocardial adiponectin (APN), changes in serum APN, and the significance of bisoprolol intervention in acute myocardial infarction (AMI) rats. An AMI rat model was established for the purposes of this study and was used for analysis of serum APN as determined by ELISA. Changes in expression of myocardial APN mRNA and APN protein in AMI rats were determined via reverse transcriptase (RT)-PCR and immunohistochemistry. Serum APN concentration and APN protein expression of the myocardium decreased significantly in the AMI groups compared with the sham operation group, with the lowest serum APN and APN protein expression on day 7 after AMI. On days 7 and 10 after AMI, the expression of myocardial APN mRNA in the AMI groups decreased significantly compared with the sham operation group. However, the APN mRNA increased on day 10 compared with that on day 7. Notably, there was an increase in levels of serum APN and myocardial APN expression after bisoprolol intervention. The expression of myocardial APN and serum APN decreased in AMI rats. APN may be an important protective factor against AMI. Bisoprolol can also protect against AMI because it increases APN expression. PMID- 21326343 TI - Time course in calpain activity and autolysis in slow and fast skeletal muscle during clenbuterol treatment. AB - Calpains are Ca2+ cysteine proteases that have been proposed to be involved in the cytoskeletal remodeling and wasting of skeletal muscle. Cumulative evidence also suggests that beta2-agonists can lead to skeletal muscle hypertrophy through a mechanism probably related to calcium-dependent proteolytic enzyme. The aim of our study was to monitor calpain activity as a function of clenbuterol treatment in both slow and fast phenotype rat muscles. For this purpose, for 21 days we followed the time course of the calpain activity and of the ubiquitous calpain 1 and 2 autolysis, as well as muscle remodeling in the extensor digitorum longus (EDL) and soleus muscles of male Wistar rats treated daily with clenbuterol (4 mg.kg-1). A slow to fast fiber shift was observed in both the EDL and soleus muscles after 9 days of treatment, while hypertrophy was observed only in EDL after 9 days of treatment. Soleus muscle but not EDL muscle underwent an early apoptonecrosis phase characterized by hematoxylin and eosin staining. Total calpain activity was increased in both the EDL and soleus muscles of rats treated with clenbuterol. Moreover, calpain 1 autolysis increased significantly after 14 days in the EDL, but not in the soleus. Calpain 2 autolysis increased significantly in both muscles 6 hours after the first clenbuterol injection, indicating that clenbuterol-induced calpain 2 autolysis occurred earlier than calpain 1 autolysis. Together, these data suggest a preferential involvement of calpain 2 autolysis compared with calpain 1 autolysis in the mechanisms underlying the clenbuterol-induced skeletal muscle remodeling. PMID- 21326344 TI - Central mechanism underlying pressor and bradycardic effect of intracerebroventricularly injected arachidonic acid. AB - The aim of the current study was to determine the central cyclooxygenase (COX) pathway and central thromboxane signaling in the cardiovascular effects evoked by arachidonic acid (AA). As a main control for the study, different doses of AA (75, 150, or 300 ug) were administered intracerebroventricularly (i.c.v.). Centrally injected AA dose- and time-dependently increased mean arterial pressure and decreased heart rate in conscious normotensive Sprague-Dawley rats. The maximal cardiovascular effects of AA were observed at min 10 of the injection and lasted almost 30 min. To investigate the central mechanism of the AA-induced cardiovascular effect in conscious normotensive animals, pretreatment with nonselective COX inhibitor indomethacin (200 ug; i.c.v.), thromboxane A2 (TXA2) synthesis inhibitor furegrelate (250 or 500 ug; i.c.v.), or TXA2 receptor antagonist SQ-29548 (8 or 16 ug; i.c.v.) was carried out 15 min before AA (150 ug; i.c.v.) injection. While indomethacin completely prevented the pressor and bradycardic responses to AA, furegrelate and SQ-29548 attenuated these effects in part in awake normotensive rats. In conclusion, these findings suggest that the pressor and bradycardic cardiovascular effects of centrally injected AA are dependent on COX activity being totally central and the TXA2 signaling pathway being subsequently central, at least in part. PMID- 21326345 TI - Bethanechol and N-acetylcysteine mimic feeding signals and reverse insulin resistance in fasted and sucrose-induced diabetic rats. AB - Meal-induced insulin sensitization (MIS) is explained by the HISS (hepatic insulin sensitizing substance) hypothesis. In the presence of two "feeding signals," a pulse of insulin results in the release of HISS from the liver. HISS acts selectively on skeletal muscle and doubles the response to insulin. HISS is not released in the fasted state or in the sucrose-supplemented diabetes model. We tested the hypothesis that provision of both feeding signals allows insulin to cause HISS release in both the normal fasted and the diabetic model. The dynamic response to insulin (50 mU/kg over 5 min) was quantified using the rapid insulin sensitivity test (RIST). Gastric injection of a liquid test meal or i.v. administration of N-acetylcysteine in 24 h fasted rats raised hepatic glutathione to a similar degree (by 46%-47%). Hepatic denervation in fed rats eliminated the parasympathetic signal and eliminated MIS, and bethanechol completely restored MIS. Both compounds administered together allowed insulin to stimulate HISS release in 24 h fasted rats and in a diabetic model (9-week, 35% liquid sucrose supplement). Neither was effective alone. Both "feeding signals" are necessary and sufficient for insulin to stimulate HISS release. PMID- 21326348 TI - The polymicrobial nature of airway infections in cystic fibrosis: Cangene Gold Medal Lecture. AB - Microbial communities characterize the airways of cystic fibrosis (CF) patients. Members of these diverse and dynamic communities can be thought of as pathogens, benign commensals, or synergens--organisms not considered pathogens in the traditional sense but with the capacity to alter the pathogenesis of the community through microbe-microbe or polymicrobe-host interactions. Very few bacterial pathogens have been implicated as clinically relevant in CF; however, the CF airway microbiome can be a reservoir of previously unrecognized but clinically relevant organisms. A combination of culture-dependent and culture independent approaches provides a more comprehensive perspective of CF microbiology than either approach alone. Here we review these concepts, highlight the future challenges for CF microbiology, and discuss the implications for the management of CF airway infections. We suggest that the success of treatment interventions for chronic CF lung disease will rely on the context of the microbes within microbial communities. The microbiology of CF airways may serve as a model to investigate the emergent properties of other clinically relevant microbial communities in the human body. PMID- 21326346 TI - Apoptosis-inducing factor contributes to epithelial cell apoptosis induced by enteropathogenic Escherichia coli. AB - The mechanisms by which enteropathogenic Escherichia coli (EPEC) causes intestinal epithelial cell apoptosis remain unclear. We tested the hypothesis that apoptosis-inducing factor (AIF) is involved in apoptosis induced by EPEC. Infection of intestinal epithelial cells in vitro with EPEC led to the mitochondrial and cytosolic accumulation of AIF. This effect was partially dependent on caspase activity. Knockdown of AIF with siRNA blocked cellular apoptosis in response to EPEC infection, as assessed by poly(ADP-ribose) polymerase cleavage and oligonucleosome formation. Taken together, these data suggest that caspase-dependent mobilization of AIF contributes to EPEC-induced epithelial cell apoptosis. PMID- 21326349 TI - Screening for lectin-like protein-producing microorganisms based on cell surface proteins. AB - A method for screening lectin-producing microorganisms was developed. The presence of lectin on microbial cell surfaces was used as an index for their selective isolation. The lectin-producing microorganisms adhered to sugar modified agarose beads and were selectively eluted with specific saccharide solutions. Spin columns were an effective tool for excluding non-lectin producers. Eighty-seven percent of the microorganisms that were eluted from the beads showed hemagglutination. The results of sequence analysis indicated that some of the eluted microorganisms have not been previously identified as lectin producing microorganisms. PMID- 21326350 TI - Characterization of intronic structures and alternative splicing in Phytophthora sojae by comparative analysis of expressed sequence tags and genomic sequences. AB - The oomycetes, a distinct phylogenetic lineage of fungus-like microorganisms, are heterokonts (stramenopiles) belonging to the supergroup Chromalveolata. Although the complete genomic sequences of a number of oomycetes have been reported, little information regarding the introns therein is available. Here, we investigated the introns of Phytophthora sojae, a pathogen that causes soybean root and stem rot, by a comparative analysis of genomic sequences and expressed sequence tags. A total of 4013 introns were identified, of which 96.6% contained canonical splice sites. The P. sojae genome possessed features distinct from other organisms at 5' splice sites, polypyrimidine tracts, branch sites, and 3' splice sites. Diverse repeating sequences, ranging from 2 to 10 nucleotides in length, were found at more than half of the intron-exon boundaries. Furthermore, 122 genes underwent alternative splicing. These data indicate that P. sojae has unique splicing mechanisms, and recognition of those mechanisms may lead to more accurate predictions of the location of introns in P. sojae and even other oomycete species. PMID- 21326351 TI - Composition of the bacterial biota in slime developed in two machines at a Canadian paper mill. AB - During the process of papermaking by pulp and paper plants, a thick and viscous deposits, termed slime, is quickly formed around the paper machines, which can affect the papermaking process. In this study, we explored the composition of the bacterial biota in slime that developed on shower pipes from 2 machines at a Canadian paper mill. Firstly, the composition was assessed for 12 months by DNA profiling with polymerase chain reaction coupled with denaturing gradient gel electrophoresis. Except for short periods (2-3 months), clustered analyses showed that the bacterial composition of the slime varied substantially over the year, with less than 50% similarity between the denaturing gradient gel electrophoresis profiles. Secondly, the screening of 16S rRNA gene libraries derived from 2 slime samples showed that the most abundant bacteria were related to 6 lineages, including Chloroflexi, candidate division OP10, Clostridiales, Bacillales, Burkholderiales, and the genus Deinococcus. Finally, the proportion of 8 bacterial lineages, such as Deinococcus sp., Meiothermus sp., and Chloroflexi, was determined by the Catalyzed Reporter Deposition-Fluorescence In Situ Hybridization in 2 slime samples. The results showed a high proportion of Chloroflexi, Tepidimonas spp., and Schlegelella spp. in the slime samples. PMID- 21326352 TI - Application of a nifH microarray to assess the impact of environmental factors on free-living diazotrophs in a glacier forefield. AB - Glacier forefield environments are exposed to extreme and fluctuating climatic and nutritional conditions. The high diversity of free-living diazotrophic communities found in these environments indicates that nitrogen fixers are able to efficiently cope with such conditions. In this study, a nifH microarray was used to monitor changes in diazotrophic populations in the field over a season, in the presence or absence of plants and in 2 glacier forefields characterized by a different bedrock type (siliceous or calcareous), as well as at different temperatures (10 degrees C, 15 degrees C) and under different nitrogen fertilization regimes (0, 10, 40 kg N.ha(-1).year(-1)) in laboratory systems. Population structures responded highly dynamically to environmental changes. Plant presence had the strongest impact, which decreased toward the end of the season and with high amounts of nitrogen fertilization. Temperature and nitrogen fertilization increases indirectly affected diazotrophic communities through their positive impact on plant growth. These results indicate strong carbon limitation in young glacier forefield soils. Phylotypes related to the genus Methylocystis strongly responded to environmental variations. These methanotrophic microorganisms, which are able to retrieve nitrogen and carbon from the atmospheric pool, are particularly adapted to the extreme nutritional conditions found in glacier forefields. PMID- 21326353 TI - Genetic diversity of picoeukaryotes in eight lakes differing in trophic status. AB - The genetic diversity of picoeukaryotes (0.2-5.0 um) was investigated in 8 lakes differing in trophic status in Nanjing, China. Denaturing gradient gel electrophoresis (DGGE) and cloning and sequencing of 18S rRNA genes were applied to analyze the picoeukaryotic communities. DGGE analysis showed that among the 8 lakes, the diversity of picoeukaryotes was greatest in the mesotrophic Lake Nan (24 bands) and least in the oligotrophic Lake Qian (12 bands). Cluster analysis of DGGE profiles revealed that the 8 lakes were grouped into 2 distinct clusters. Cluster 1 contained lakes Mochou, Zixia, Huashen, Nan, Pipa, and Qian, while cluster 2 contained lakes Xuanwu and Baijia. Clone libraries were constructed from the mesotrophic Lake Xuanwu and the oligotrophic Lake Zixia, and the 2 libraries were compared using the program LIBSHUFF. This analysis indicated that the picoeukaryotic community composition differed significantly between the 2 lakes (p = 0.001). A total of 25 operational taxonomic units were detected; 18 (62 clones) were related to known eukaryotic groups, while 7 (30 clones) were not affiliated with any known eukaryotic group. Alveolates and stramenopiles were the dominant groups in Lake Xuanwu, while alveolates and chlorophyta predominated in Lake Zixia. Multivariate statistical analysis indicated that the differences in the picoeukaryotic community composition of the 8 lakes might be related to trophic status and top-down regulation by metazooplankton. PMID- 21326354 TI - Lactobacillus casei as a probiotic in malnourished Giardia lamblia-infected mice: a biochemical and histopathological study. AB - The study describes the in vivo activity of Lactobacillus casei in malnourished Giardia lamblia-infected BALB/c mice. By experimentation, it was found that daily administration of the probiotic 7 days before inoculation with Giardia trophozoites in malnourished mice efficiently reduced both the severity and duration of giardiasis. More specifically, excretion of Giardia cysts and trophozoites counts were reduced, while faecal lactobacilli counts increased significantly in probiotic-fed malnourished mice, compared with control mice. Interestingly, it was also observed that oral feeding of the probiotic to malnourished mice abrogated all the anthropometric and biochemical anomalies. Histologically, morphological and cellular alteration of microvillus membrane integrity revealed that probiotic administration ameliorated the mucosal damage in malnourished, probiotic-inoculated, Giardia-infected mice compared with the severe microvillus atrophy, oedematous and vacuolated epithelial cells, and ileitis in malnourished Giardia-infected mice. The results clearly show the antigiardial effect of the probiotic in vivo by modulating the gut cells to inhibit the colonization and multiplication of Giardia trophozoites, thus reducing the severity and duration of murine giardiasis. PMID- 21326355 TI - Comparative evaluation of a chromogenic agar medium-PCR protocol with a conventional method for isolation of Vibrio parahaemolyticus strains from environmental and clinical samples. AB - Screening for pathogenic Vibrio parahaemolyticus has become routine in certain areas associated with food-borne outbreaks. This study is an evaluation of the CHROMagar Vibrio (CV) medium-PCR protocol and the conventional method (TCBS (thiosulfate-citrate-bile salts-sucrose) agar plus biochemical and Wagatsuma agar tests) for detection of V. parahaemolyticus in shrimp, water, sediment, and stool samples collected for biosurveillance in an endemic area of northwestern Mexico. A total of 131 environmental and clinical samples were evaluated. The CV medium PCR protocol showed a significantly improved ability (P < 0.05) to isolate and detect V. parahaemolyticus, identifying isolates of this bacteria missed by the conventional method. Although some other bacteria, distinct from pathogenic V. parahaemolyticus, produced violet colonies similar to that of V. parahaemolyticus on CV medium, we were able to detect a superior number of samples of V. parahaemolyticus with the CV medium-PCR protocol than with the conventional method. The Kanagawa phenomenon is routinely determined on Wagatsuma agar for the diagnosis of V. parahaemolyticus (pathogenic) positive for thermostable direct hemolysin (TDH) in developing countries. In our results, Wagatsuma agar showed low sensitivity (65.4% at 24 h and 75.6% at 48 h) and specificity (52.4% at 48 h) for identifying V. parahaemolyticus positive for TDH. Overall, our data support the use of the CV medium-PCR protocol in place of the conventional method (TCBS biochemical tests-Wagatsuma agar) for detection of pathogenic V. parahaemolyticus, both in terms of effectiveness and cost efficiency. PMID- 21326356 TI - Prevalence of putative virulence markers in Campylobacter jejuni and Campylobacter coli isolated from hospitalized children, raw chicken, and raw beef in Tehran, Iran. AB - The incidence of the virulence-associated genes cdtA, cdtB, cdtC, cadF, dnaJ, racR, and pldA has been investigated in Campylobacter jejuni and Campylobacter coli collected from raw chicken and beef from retailers in Tehran, Iran, and from hospitalized children (age, <=14 years) suffering from diarrhea. Campylobacter spp. were collectively identified by morphological and biochemical methods. Campylobacter jejuni and C. coli were discriminated from other Campylobacter spp. by amplification of a specific conserved fragment of the 16S rRNA gene. The distinction between C. jejuni and C. coli was subsequently made by molecular determination of the presence of the hipO gene in C. jejuni or the ask gene in C. coli. Fragments of the studied virulence-associated genes, cdtA, cdtB, cdtC, cadF, racR, dnaJ, and pldA, were amplified by PCR and subjected to horizontal gel electrophoresis. A total of 71 isolates of C. jejuni and 24 isolates of C. coli from meat were analyzed, while the numbers of isolates from the hospitalized children were 28 and 9, respectively. The unequal distribution of C. jejuni and C. coli in the samples has also been reported in other studies. Statistical analyses by the use of the two-tailed Fisher's exact test of the occurrence of the virulence genes in the isolates of different origins showed that the occurrence of the dnaJ gene was consistently significantly higher in all C. jejuni isolates than in C. coli. The occurrence of the other virulence markers did not differ significantly between species in the majority of the isolates. The PCR results also showed that the occurrence of the virulence markers in the analyzed isolates was much lower than in other studies, which may be caused by a divergent genomic pool of our isolates in comparison with others. PMID- 21326357 TI - A putative twin-arginine translocation system in the phytopathogenic bacterium Xylella fastidiosa. AB - The twin-arginine translocation (Tat) pathway of the xylem-limited phytopathogenic bacterium Xylella fastidiosa strain 9a5c, responsible for citrus variegated chlorosis, was explored. The presence of tatA, tatB, and tatC in the X. fastidiosa genome together with a list of proteins harboring 2 consecutive arginines in their signal peptides suggested the presence of a Tat pathway. The functional Tat dependence of X. fastidiosa OpgD was examined. Native or mutated signal peptides were fused to the beta-lactamase. Expression of fusion with intact signal peptides mediated high resistance to ampicillin in Escherichia coli tat+ but not in the E. coli tat null mutant. The replacement of the 2 arginines by 2 lysines prevented the export of beta-lactamase in E. coli tat+, demonstrating that X. fastidiosa OpgD carries a signal peptide capable of engaging the E. coli Tat machinery. RT-PCR analysis revealed that the tat genes are transcribed as a single operon. tatA, tatB, and tatC genes were cloned. Complementation assays in E. coli devoid of all Tat or TatC components were unsuccessful, whereas X. fastidiosa Tat components led to a functional Tat translocase in E. coli TatB-deficient strain. Additional experiments implicated that X. fastidiosa TatB component could form a functional heterologous complex with the E. coli TatC component. PMID- 21326358 TI - MeCP2: structure and function. AB - Despite a vast body of literature linking chromatin structure to regulation of gene expression, the role of architectural proteins in higher order chromatin transitions required for transcription activation and repression has remained an under-studied field. To demonstrate the current knowledge of the role of such proteins, we have focused our attention on the methylated DNA binding and chromatin-associated protein MeCP2. Structural studies using chromatin assembled in vitro have revealed that MeCP2 can associate with nucleosomes in an N-terminus dependent manner and efficiently condense nucleosome arrays. The present review attempts to match MeCP2 structural domains, or lack thereof, and specific chromatin features needed for the proper recruitment of MeCP2 to its multiple functions as either activator or repressor. We specifically focused on MeCP2's role in Rett syndrome, a neurological disorder associated with specific MeCP2 mutations. PMID- 21326359 TI - WSTF does it all: a multifunctional protein in transcription, repair, and replication. AB - Williams syndrome transcription factor (WSTF) has emerged as an incredibly versatile nuclear protein. WSTF and the ATP-dependent chromatin remodeling complexes in which it exists, WINAC, WICH, and B-WICH, have been studied in a variety of organisms. This research has revealed roles for WSTF in a number of diverse molecular events. WSTF function includes chromatin assembly, RNA polymerase I and III gene regulation, vitamin D metabolism, and DNA repair. In addition to functioning as a subunit of several ATP-dependent chromatin remodeling complexes, WSTF binds specifically to acetylated histones and is itself a histone kinase as well as a target of phosphorylation. This review will describe the three known WSTF-containing complexes and discuss their various roles as well as mechanisms of regulating WSTF activity. PMID- 21326360 TI - Nucleosome distribution and linker DNA: connecting nuclear function to dynamic chromatin structure. AB - Genetic information in eukaryotes is managed by strategic hierarchical organization of chromatin structure. Primary chromatin structure describes an unfolded nucleosomal array, often referred to as "beads on a string". Chromatin is compacted by the nonlinear rearrangement of nucleosomes to form stable secondary chromatin structures. Chromatin conformational transitions between primary and secondary structures are mediated by both nucleosome-stacking interactions and the intervening linker DNA. Chromatin model system studies find that the topography of secondary structures is sensitive to the spacing of nucleosomes within an array. Understanding the relationship between nucleosome spacing and higher order chromatin structure will likely yield important insights into the dynamic nature of secondary chromatin structure as it occurs in vivo. Genome-wide nucleosome mapping studies find the distance between nucleosomes varies, and regions of uniformly spaced nucleosomes are often interrupted by regions of nonuniform spacing. This type of organization is found at a subset of actively transcribed genes in which a nucleosome-depleted region near the transcription start site is directly adjacent to uniformly spaced nucleosomes in the coding region. Here, we evaluate secondary chromatin structure and discuss the structural and functional implications of variable nucleosome distributions in different organisms and at gene regulatory junctions. PMID- 21326362 TI - Heterochromatin and the DNA damage response: the need to relax. AB - Higher order chromatin structure has an impact on all nuclear functions, including the DNA damage response. Over the past several years, it has become increasingly clear that heterochromatin and euchromatin represent separate entities with respect to both damage sensitivity and repair. The chromatin compaction present in heterochromatin helps to protect this DNA from damage; however, when lesions do occur, the compaction restricts the ability of DNA damage response proteins to access the site, as evidenced by its ability to block the expansion of H2AX phosphorylation. As such, DNA damage in heterochromatin is refractory to repair, which requires the surrounding chromatin structure to be decondensed. In the case of DNA double-strand breaks, this relaxation is at least partially mediated by the ATM kinase phosphorylating and inhibiting the function of the transcriptional repressor KAP1. This review will focus on the functions of KAP1 and other proteins involved in the maintenance or restriction of heterochromatin, including HP1 and TIP60, in the DNA damage response. As heterochromatin is important for maintaining genomic stability, cells must maintain a delicate balance between allowing repair factors access to these regions and ensuring that these regions retain their organization to prevent increased DNA damage and chromosomal mutations. PMID- 21326361 TI - Structure of the H1 C-terminal domain and function in chromatin condensation. AB - Linker histones are multifunctional proteins that are involved in a myriad of processes ranging from stabilizing the folding and condensation of chromatin to playing a direct role in regulating gene expression. However, how this class of enigmatic proteins binds in chromatin and accomplishes these functions remains unclear. Here we review data regarding the H1 structure and function in chromatin, with special emphasis on the C-terminal domain (CTD), which typically encompasses approximately half of the mass of the linker histone and includes a large excess of positively charged residues. Owing to its amino acid composition, the CTD was previously proposed to function in chromatin as an unstructured polycation. However, structural studies have shown that the CTD adopts detectable secondary structure when interacting with DNA and macromolecular crowding agents. We describe classic and recent experiments defining the function of this domain in chromatin folding and emerging data indicating that the function of this protein may be linked to intrinsic disorder. PMID- 21326363 TI - Activation and function of immediate-early genes in the nervous system. AB - Immediate-early genes have important roles in processes such as brain development, learning, and responses to drug abuse. Further, immediate-early genes play an essential role in cellular responses that contribute to long-term neuronal plasticity. Neuronal plasticity is a characteristic of the nervous system that is not limited to the first stages of brain development but persists in adulthood and seems to be an inherent feature of everyday brain function. The plasticity refers to the neuron's capability of showing short- or long-lasting phenotypic changes in response to different stimuli and cellular scenarios. In this review, we focus on the immediate-early genes encoding transcription factors (AP-1 and Egr) that are relevant for neuronal responses. Our current understanding of the mechanisms involved in the induction of the immediate-early genes is presented. PMID- 21326365 TI - In silico identification and characterization of microRNAs and their putative target genes in Solanaceae plants. AB - MicroRNAs (miRNAs) are a class of small, single-stranded, noncoding RNAs ranging from 19 to 25 nucleotides. The miRNA control various cellular functions by negatively regulating gene expression at the post-transcriptional level. The miRNA regulation over their target genes has a central role in regulating plant growth and development; however, only a few reports have been published on the function of miRNAs in the family Solanaceae. We identified Solanaceae miRNAs and their target genes by analyzing expressed sequence tag (EST) data from five different Solanaceae species. A comprehensive bioinformatic analysis of EST data of Solanaceae species revealed the presence of at least 11 miRNAs and 54 target genes in pepper (Capsicum annuum L.), 22 miRNAs and 221 target genes in potato (Solanum tuberosum L.), 12 miRNAs and 417 target genes in tomato (Solanum lycopersicum L.), 46 miRNAs and 60 target genes in tobacco (Nicotiana tabacum L.), and 7 miRNAs and 28 target genes in Nicotiana benthamiana. The identified Solanaceae miRNAs and their target genes were deposited in the SolmiRNA database, which is freely available for academic research only at http://genepool.kribb.re.kr/SolmiRNA. Our data indicate that the Solanaceae family has both conserved and specific miRNAs and that their target genes may play important roles in growth and development of Solanaceae plants. PMID- 21326366 TI - Comparative transcriptome analysis of yeast strains carrying slt2, rlm1, and pop2 deletions. AB - The function of the genes SLT2 (encoding the Mpk1 protein), RLM1, and POP2 have previously been related to several stress responses in yeasts. DNA arrays have been used to identify differences among the transcriptomes of a Saccharomyces cerevisiae wild type strain and its derivative Deltaslt2, Deltarlm1, and Deltapop2 mutants. Correspondence analyses indicate that the vast majority of genes that show lower expression in Deltarlm1 also show lower expression in Deltaslt2. In contrast, there is little overlap between the results of the transcriptome analyses of the Deltapop2 strain and the Deltaslt2 or Deltarlm1 strains. The DNA array data were validated by reverse Northern blotting and chromatin immunoprecipitation (ChIp). ChIp assays demonstrate Rlm1p binding to specific regions of the promoters of two genes that show expression differences between the Deltarlm1 mutant and wild type strains. Interestingly, RLM1 deletion decreases the transcription of SLT2, encoding the Mpk1p kinase that phosphorylates Rlm1p, suggesting a feedback control in the signal transduction pathway. Also, deletion of RLM1 causes a decrease in the mRNA level of KDX1, which is paralogous to SLT2. In contrast, deletion of POP2 is accompanied by an increase of both SLT2 and KDX1 levels. We show that SLT2 mRNA increase in the Deltapop2 strain is due to a decrease in RNA turnover, consistent with the expected loss of RNA-deadenylase activity in this strain. PMID- 21326367 TI - Mitogenomic and microsatellite variation in descendants of the founder population of Newfoundland: high genetic diversity in an historically isolated population. AB - The island of Newfoundland, the first of England's overseas colonies, was settled from the 17th century onward by restricted numbers of English, Irish, and French immigrants, in small "outport" communities that have maintained geographic, religious, and linguistic isolation to the latest generations. To measure the extent of modification and loss of genetic variation through founder effect, drift, and inbreeding in this historically isolated population, we analyzed the complete mitochondrial DNA (mtDNA) genomes and 14 microsatellite loci from each of 27 individuals with matrilineal ancestries extending to the colonial period. Every individual has a unique mtDNA genome sequence. All but one of these genomes are assignable to one of five major (H,J,K,T, and U) or minor (I) European haplogroups. The possibility of homoplasy at single nucleotide polymorphism (SNP) sites that define subtypes within the H haplogroup is discussed. Observed haplogroup proportions do not differ significantly from those of western Europeans or between English and Irish Newfoundlanders. The exceptional individual is a member of haplogroup A2, who appears to be the descendant of a Mi'kmaq First Nations mother and a French father, a common marriage pattern in the early settlement of Newfoundland. Microsatellite diversity is high (HE = 0.763), unstructured with respect to mtDNA haplotype or ethnicity, and there is no evidence of linkage disequilibrium. There is a small but significant degree of inbreeding (FIS = 0.0174). Collection of whole mtDNA genome data was facilitated by the use of microarray sequencing, and we describe a simple algorithm that is 99.67% efficient for sequence recovery. PMID- 21326368 TI - Analysis of allelic differential expression in the human genome using allele specific serial analysis of gene expression tags. AB - Recent reports have demonstrated that a significant proportion of human genes display allelic differential expression (ADE). ADE is associated with phenotypic variability and may contribute to complex genetic diseases. Here, we present a computational analysis of ADE using allele-specific serial analysis of gene expression (SAGE) tags representing 1295 human genes. We identified 472 genes for which unequal representation (>3-fold) of allele-specific SAGE tags was observed in at least one SAGE library, suggesting the occurrence of ADE. For 235 out of these 472 genes, the difference in the expression level between both allele specific SAGE tags was statistically significant (p < 0.05). Eleven candidate genes were then subjected to experimental validation and ADE was confirmed for 8 out of these 11 genes. Our results suggest that at least 25% of the human genes display ADE and that allele-specific SAGE tags can be efficiently used for the identification of such genes. PMID- 21326369 TI - A high-density genetic linkage map of a black spruce (Picea mariana) * red spruce (Picea rubens) interspecific hybrid. AB - Genetic maps provide an important genomic resource of basic and applied significance. Spruce (Picea) has a very large genome size (between 0.85 * 1010 and 2.4 * 1010 bp; 8.5-24.0 pg/1C, a mean of 17.7 pg/1C ). We have constructed a near-saturated genetic linkage map for an interspecific backcross (BC1) hybrid of black spruce (BS; Picea mariana (Mill.) B.S.P.) and red spruce (RS; Picea rubens Sarg.), using selectively amplified microsatellite polymorphic loci (SAMPL) markers. A total of 2284 SAMPL markers were resolved using 31 SAMPL-MseI selective nucleotide primer combinations. Of these, 1216 SAMPL markers showing Mendelian segregation were mapped, whereas 1068 (46.8%) SAMPL fragments showed segregation distortion at alpha = 0.05. Maternal, paternal, and consensus maps consistently coalesced into 12 linkage groups, corresponding to the haploid chromosome number (1n = 1x = 12) of 12 in the genus Picea. The maternal BS map consisted of 814 markers distributed over 12 linkage groups, covering 1670 cM, with a mean map distance of 2.1 cM between adjacent markers. The paternal BS * RS map consisted of 773 markers distributed over 12 linkage groups, covering 1563 cM, with a mean map distance of 2.0 cM between adjacent markers. The consensus interspecific hybrid BC1 map consisted of 1216 markers distributed over 12 linkage groups, covering 1865 cM (98% genome coverage), with a mean map distance of 1.5 cM between adjacent markers. The genetic map reported here provides an important genomic resource in Picea, Pinaceae, and conifers. PMID- 21326370 TI - Substitution pattern of the CArG element in human and mouse genomes. AB - cis-Elements CArG bound by serum response factor (SRF) are presently being intensively studied, but little is known about the substitution pattern of functional CArG elements. Here, we have performed the first evolutionary analysis of CArGome in the human and mouse genome through bioinformatic methods and statistical tests. We calculated the substitution rate at each site of the functional CArG elements. The results showed that the core sites of the functional CArG elements evolved faster than did the background DNA, indicating that these sites were likely to evolve under positive selection. Moreover, a strong TATA "motif" was evident in the core region within the functional CArG elements in both human and mouse promoters. This motif could probably be a major contribution to the formation of the spatial structure, which was important for CArG-SRF recognition. Thus, the study further revealed the sequence character and substitution pattern of CArG elements and provided useful information for the study of the SRF-binding efficiencies of CArG promoters in functional assays. PMID- 21326371 TI - High-density fluorescence in situ hybridization signal detection on barley (Hordeum vulgare L.) chromosomes with improved probe screening and reprobing procedures. AB - The barley (Hordeum vulgare L.) genome was screened to identify sequences that could be used for fluorescence in situ hybridization (FISH). From 2000 transformed bacterium colonies carrying barley clones, 56 colonies were selected on the basis of the patterns that their PCR products produced when subjected to agarose gel electrophoresis. Among them, 42 (75%) exhibited fluorescent signals on barley chromosomes after in situ hybridization using the directly labeled PCR products. Sequencing revealed seven clones, pHv-365, pHv-177, pHv-1112, pHv-689, pHv-1476, pHv-1889, and pHv-1972, to be newly identified FISH-positive sequences. The remainder possess previously described sequences such as 5S, GAA microsatellite, centromere repeats, HVT01, and pHvMWG2315 (324 bp repeat). It is shown here that a combination of five probes, which produce strong signals on barley chromosomes, pHv-38 (5S), pHv-365, pHv-961 (HVT01), GAA, and TAG microsatellites, offer unequivocal recognition of each chromosome. The combination of three probes, i.e., pHv-1123 (barley 324 bp repeat), GAA, and TAG, decorated entire chromosomes with fine dotted signals and was useful for detecting the break points of aberrant chromosomes. The signals' distributions of pHv-177, pHv-1112, and TAG were highly polymorphic. An improved reprobing procedure and its usefulness are also discussed. PMID- 21326372 TI - A survey of Penstemon's genome size. AB - Penstemon is the largest genus in North America with more than 270 reported species. However, little is known about its genome size. This information may be useful in developing hybrids for landscape use and for gaining insight into its current taxonomy. Using flow cytometry, we estimated the genome size of approximately 40% of the genus (115 accessions from 105 different species). Genome sizes for both reported and probable diploids range from P. dissectus 2C = 0.94 pg (1C = 462 Mbp) to P. pachyphyllus var. mucronatus 2C = 1.88 pg (1C = 919 Mbp), and the polyploids range from P. attenuatus var. attenuatus 2C = 2.35 pg (1C = 1148 Mbp) to P. digitalis 2C = 6.45 pg (1C = 3152 Mbp). Chromosome counts were done for ten previously published and four previously unreported Penstemon species (P. dissectus, P. navajoa, P. caespitosus var. desertipicti, and P. ramaleyi). These counts were compiled with all previously published chromosome data and compared with the flow cytometry results. Ploidy within this study ranged from diploid to dodecaploid. These data were compared and contrasted with the current taxonomy of Penstemon and previously published internal transcribed spacer and chloroplast DNA phylogenetic work. Based on genome size and previous studies, reassigning P. montanus to the subgenus Penstemon and P. personatus to the subgenus Dasanthera, would better reflect the phylogeny of the genus. Furthermore, our data concur with previous studies suggesting that the subgenus Habroanthus be included in the subgenus Penstemon. The DNA content of subgenus Penstemon exhibits high plasticity and spans a sixfold increase from the smallest to the largest genome (P. linarioides subsp. sileri and P. digitalis, respectively). Our study found flow cytometry to be useful in species identification and verification. PMID- 21326373 TI - A peripheral governor regulates muscle contraction. AB - Active skeletal muscles are capable of keeping the global [adenosine triphosphate (ATP)] reasonably constant during exercise, whether it is mild exercise, activating a few motor units, or all-out exercise using a substantial mass of muscle. This could only be accomplished if there were regulatory processes in place not only to replenish ATP as quickly as possible, but also to modulate the rate of ATP use when that rate threatens to exceed the rate of ATP replenishment, a situation that could lead to metabolic catastrophe. This paper proposes that there is a regulatory process or "peripheral governor" that can modulate activation of muscle to avoid metabolic catastrophe. A peripheral governor, working at the cellular level, should be able to reduce the cellular rate of ATP hydrolysis associated with muscle contraction by attenuating activation. This would necessarily cause something we call peripheral fatigue (i.e., reduced contractile response to a given stimulation). There is no doubt that peripheral fatigue occurs. It has been demonstrated in isolated muscles, in muscles in situ with no central nervous system input, and in intact human subjects performing voluntary exercise with small muscle groups or doing whole-body exercise. The regulation of muscle activation is achieved in at least 3 ways (decreasing membrane excitability, inhibiting Ca2+ release through ryanodine receptors, and decreasing the availability of Ca2+ in the sarcoplasmic reticulum), making this a highly redundant control system. The peripheral governor attenuates cellular activation to reduce the metabolic demand, thereby preserving ATP and the integrity of the cell. PMID- 21326374 TI - Fat adaptation in well-trained athletes: effects on cell metabolism. AB - The performance of prolonged (>90 min), continuous, endurance exercise is limited by endogenous carbohydrate (CHO) stores. Accordingly, for many decades, sports nutritionists and exercise physiologists have proposed a number of diet-training strategies that have the potential to increase fatty acid availability and rates of lipid oxidation and thereby attenuate the rate of glycogen utilization during exercise. Because the acute ingestion of exogenous substrates (primarily CHO) during exercise has little effect on the rates of muscle glycogenolysis, recent studies have focused on short-term (<1-2 weeks) diet-training interventions that increase endogenous substrate stores (i.e., muscle glycogen and lipids) and alter patterns of substrate utilization during exercise. One such strategy is "fat adaptation", an intervention in which well-trained endurance athletes consume a high-fat, low-CHO diet for up to 2 weeks while undertaking their normal training and then immediately follow this by CHO restoration (consuming a high-CHO diet and tapering for 1-3 days before a major endurance event). Compared with an isoenergetic CHO diet for the same intervention period, this "dietary periodization" protocol increases the rate of whole-body and muscle fat oxidation while attenuating the rate of muscle glycogenolysis during submaximal exercise. Of note is that these metabolic perturbations favouring the oxidation of fat persist even in the face of restored endogenous CHO stores and increased exogenous CHO availability. Here we review the current knowledge of some of the potential mechanisms by which skeletal muscle sustains high rates of fat oxidation in the face of high exogenous and endogenous CHO availability. PMID- 21326375 TI - Time to move beyond a brainless exercise physiology: the evidence for complex regulation of human exercise performance. AB - In 1923, Nobel Laureate A.V. Hill proposed that maximal exercise performance is limited by the development of anaerobiosis in the exercising skeletal muscles. Variants of this theory have dominated teaching in the exercise sciences ever since, but 90 years later there is little biological evidence to support Hill's belief, and much that disproves it. The cardinal weakness of the Hill model is that it allows no role for the brain in the regulation of exercise performance. As a result, it is unable to explain at least 6 common phenomena, including (i) differential pacing strategies for different exercise durations; (ii) the end spurt; (iii) the presence of fatigue even though homeostasis is maintained; (iv) fewer than 100% of the muscle fibers have been recruited in the exercising limbs; (v) the evidence that a range of interventions that act exclusively on the brain can modify exercise performance; and (vi) the finding that the rating of perceived exertion is a function of the relative exercise duration rather than the exercise intensity. Here I argue that the central governor model (CGM) is better able to explain these phenomena. In the CGM, exercise is seen as a behaviour that is regulated by complex systems in the central nervous system specifically to ensure that exercise terminates before there is a catastrophic biological failure. The complexity of this regulation cannot be appreciated if the body is studied as a collection of disconnected components, as is the usual approach in the modern exercise sciences. PMID- 21326376 TI - New Canadian physical activity guidelines. AB - The Canadian Society for Exercise Physiology (CSEP), in cooperation with ParticipACTION and other stakeholders, and with support from the Public Health Agency of Canada (PHAC), has developed the new Canadian Physical Activity Guidelines for Children (aged 5-11 years), Youth (aged 12-17 years), Adults (aged 18-64 years), and Older Adults (aged >=65 years). The new guidelines include a preamble to provide context and specific guidelines for each age group. The entire guideline development process was guided by the Appraisal of Guidelines for Research Evaluation (AGREE) II instrument, which is the international standard for clinical practice guideline development. Thus, the guidelines have gone through a rigorous and transparent developmental process; we based the recommendations herein on evidence from 3 systematic reviews, and the final guidelines benefitted from an extensive online and in-person consultation process with hundreds of stakeholders and key informants, both domestic and international. Since 2006, the products of our efforts resulted in the completion of 21 peer-reviewed journal articles (including 5 systematic reviews) that collectively guided this work. The process that Canadian researchers undertook to update the national physical activity guidelines represents the most current synthesis, interpretation, and application of the scientific evidence to date. PMID- 21326378 TI - Canadian sedentary behaviour guidelines for children and youth. AB - The Canadian Society for Exercise Physiology (CSEP), in partnership with the Healthy Active Living and Obesity Research Group (HALO) at the Children's Hospital of Eastern Ontario Research Institute, and in collaboration with ParticipACTION, and others, has developed the Canadian Sedentary Behaviour Guidelines for Children (aged 5-11 years) and Youth (aged 12-17 years). The guidelines include a preamble to provide context, followed by the specific recommendations for sedentary behaviour. The entire development process was guided by the Appraisal of Guidelines for Research Evaluation (AGREE) II instrument, which is the international standard for clinical practice guideline development. Thus, the guidelines have gone through a rigorous and transparent developmental process and the recommendations are based on evidence from a systematic review and interpretation of the research evidence. The final guidelines benefitted from an extensive online consultation process with 230 domestic and international stakeholders and key informants. The final guideline recommendations state that for health benefits, children (aged 5-11 years) and youth (aged 12-17 years) should minimize the time that they spend being sedentary each day. This may be achieved by (i) limiting recreational screen time to no more than 2 h per day - lower levels are associated with additional health benefits; and (ii) limiting sedentary (motorized) transport, extended sitting time, and time spent indoors throughout the day. These are the first evidence based Canadian Sedentary Behaviour Guidelines for Children and Youth and provide important and timely recommendations for the advancement of public health based on a systematic synthesis, interpretation, and application of the current scientific evidence. PMID- 21326380 TI - Adiposity and aerobic fitness are associated with metabolic disease risk in children. AB - To examine the relative association of physical activity, cardiorespiratroy fitness (CRF), and adiposity with risk for metabolic disease in prepubescent children. Forty-six prepubescent children (age, 9.4 +/- 1.7 years; 24 males) were assessed for adiposity (%fat) via dual-energy X-ray absorptiometry, CRF with a peak graded exercise test, and physical activity using pedometers. Metabolic disease risk was assessed by a composite score of the following factors: waist circumference (WC), mean arterial pressure (MAP), triacylglycerol (TAG), total cholesterol to high-density lipoprotein cholesterol ratio (TC/HDL-C ratio), glucose, and insulin. Adiposity was correlated with metabolic disease risk score, as well as homeostasis model assessment of insulin resistance (HOMA-IR), TAG, TC/HDL-C ratio, WC, insulin, and MAP (r range = 0.33 to 0.95, all p < 0.05). Physical activity was negatively associated with metabolic disease risk score, as well as HOMA-IR, TAG, WC, insulin, and MAP (r range = -0.32 to -0.49, all p < 0.05). CRF was inversely associated with metabolic disease risk score and HOMA IR, TAG, TC/HDL-C ratio, WC, insulin, and MAP (r range = -0.32 to -0.63, all p < 0.05). Compared across fitness-physical activity and fatness groups, the low-fit high-fat and the low-activity-high-fat groups had higher metabolic risk scores than both low-fat groups. Regression analyses revealed sexual maturity (beta = 0.27, p = 0.044) and %fat (beta = 0.49, p = 0.005) were the only independent predictors of metabolic disease risk score, explaining 4.7% and 9.5% of the variance, respectively. Adiposity appears to be an influential factor for metabolic disease risk in prepubescent children, and fitness is protective against metabolic disease risk in the presence of high levels of adiposity. PMID- 21326381 TI - Exercise-induced protection of bone marrow cells following exposure to radiation. AB - The hormetic effects of exercise training have previously been shown to enhance cellular protection against oxidative stress. Therefore, adaptations to exercise training may attenuate the harmful effects of radiation induced by oxidative stress. Flow cytometric analysis of genotoxicity (gammaH2AX foci and micronucleated reticulocytes (MN-RET)) and cytotoxicity (apoptosis and percentage of reticulocytes) were conducted on bone marrow cells isolated from acutely exercised (Acute EX), exercise-trained (EX), and sedentary (SED) mice following 1 and 2 Gy radiation challenges in vitro. Acute EX increased the percentage of cells with activated caspase-3 and -7 (32%, p < 0.001) and gammaH2AX foci formation in response to 2 Gy radiation challenge (10%, p < 0.05). Exercise training significantly attenuated gammaH2AX foci formation and MN-RET production in response to 1 Gy radiation challenge (18%, p < 0.05 and 22%, p < 0.05, respectively). Exercise training also significantly reduced basal percentages of cells with activated caspase-3 and -7 and in response to radiation in bone marrow cells (11%, p < 0.05). These results suggest that oxidative stress caused by acute exercise induces an adaptive response responsible for the radioprotective effects of exercise training. PMID- 21326382 TI - Gender differences in whole-body fat oxidation kinetics during exercise. AB - Discrepancies appear in studies comparing fat oxidation between men and women. Therefore, this study aimed to quantitatively describe and compare whole-body fat oxidation kinetics between genders during exercise, using a sinusoidal (SIN) model. Twelve men and 11 women matched for age, body mass index, and aerobic fitness (maximal oxygen uptake and maximal power output per kilogram of fat-free mass (FFM)) performed submaximal incremental tests (Incr) with 5-min stages and a 7.5% maximal power output increment on a cycle ergometer. Fat oxidation rates were determined using indirect calorimetry, and plotted as a function of exercise intensity. The SIN model, which includes 3 independent variables (dilatation, symmetry, translation) that account for the main quantitative characteristics of kinetics, was used to mathematically describe fat oxidation kinetics and to determine the intensity (Fatmax) eliciting the maximal fat oxidation (MFO). During Incr, women exhibited greater fat oxidation rates from 35% to 85% maximal oxygen uptake, MFO (6.6 +/- 0.9 vs. 4.5 +/- 0.3 mg.kg FFM-1.min-1), and Fatmax (58.1% +/- 1.9% vs. 50.0% +/- 2.7% maximal oxygen uptake) than men (p < 0.05). While men and women showed similar global shapes of fat oxidation kinetics in terms of dilatation and symmetry (p > 0.05), the fat oxidation curve tended to be shifted toward higher exercise intensities in women (rightward translation, p = 0.08). These results support the idea that women have a greater reliance on fat oxidation than men during submaximal exercise, but also indicate that this greater fat oxidation is shifted toward higher exercise intensities in women than in men. PMID- 21326383 TI - Myogenic mRNA markers in young and old human skeletal muscle prior to and following sequential exercise bouts. AB - This study examined how multiple bouts of conventional resistance training affected the mRNA expression of transcripts and a protein associated with satellite cell activity in human skeletal muscle. Ten younger men (means +/- SE; age, 21.0 +/- 0.5 years; body mass, 82.3 +/- 4.2 kg; height, 178.4 +/- 2.2 cm; percent body fat, 15.4% +/- 2.9%) and 10 older men (age, 66.4 +/- 1.6 years; body mass, 94.2 +/- 3.7 kg; height, 180.9 +/- 2.2 cm; percent body fat, 27.4% +/- 1.8%) completed 3 lower-body workouts (Monday, Wednesday, Friday; 9 sets of 10 repetitions at 80% 1 repetition maximum). Vastus lateralis muscle biopsies were collected prior to intervention (T1), 48 h following workout 1 (T2), 48 h following workout 2 (T3), and 24 h following workout 3 (T4). Real-time reverse transcription-polymerase chain reaction was performed to assess genes of interest, and muscle proliferating cell nuclear antigen (PCNA) was assessed using Western blotting. The CYCLIN D1 gene was expressed more highly in the older vs. younger men (p < 0.05), whereas the expression of all other genes and muscle PCNA were similar between age groups. MYOD mRNA expression increased at T2 (p < 0.05) and MHCEMB gene expression modestly increased (p < 0.05) at T4 relative to baseline expression values in the younger men. Baseline elevations in CYCLIN D1 mRNA expression in older persons may indicate that a compensatory expression of this transcript is occurring in an attempt to retain the muscle's proliferative potential. Increases in MYOD and MHCEMB indicate that 1 week of conventional resistance exercise may i crease myogenic activity, including satellite cell proliferation and differentiation, respectively, in younger men. PMID- 21326384 TI - Regional and relative adiposity patterns in relation to carbohydrate and lipid metabolism in men with spinal cord injury. AB - This study examined the relationship among regional and relative adipose tissue distribution, glucose, and lipid metabolism in men with spinal cord injury (SCI). After overnight fasting, 32 individuals with motor complete tetraplegia (Tetra) (n = 7) and paraplegia (Para) (n = 25) underwent resting energy expenditure and measurement of serum lipid profile, followed by an oral glucose tolerance test to measure plasma glucose and plasma insulin concentrations. Regional fat mass (FM) and fat-free mass were quantified using dual-energy X-ray absorptiometry. Relative adipose tissue was calculated as the ratio of leg FM/trunk FM, leg FM/whole-body FM, and trunk FM/whole-body FM. Individuals with Tetra have greater leg FM/trunk FM (45%) and leg FM/body FM (26%) and lower trunk FM/body FM (29%) ratios than individuals with Para (p < 0.05). Glucose area under the curve (AUC) was positively related to leg FM (r = 0.34, p = 0.05) but not to trunk or body FM. Strong negative relationships were noted between the ratio of trunk FM to body FM and glucose AUC (r = -0.38, p = 0.03) and low-density lipoprotein cholesterol (LDL-C) (r = -0.45, p = 0.001). Whole-body FM was negatively related to high-density lipoprotein cholesterol (r = -0.49, p = 0.007) after controlling for percentage of trunk FM. Both leg and trunk FM may play a pivotal role in determining the metabolic profile in individuals with SCI. Relative to whole-body FM and leg FM, trunk FM may induce a protective effect on glucose homeostasis and the LDL-C profile. PMID- 21326385 TI - Energy expenditure characteristics of weight lifting: 2 sets to fatigue. AB - We investigated the work performed and energy expenditure characteristics within and among 2 sets of the bench press at 70%, 80%, and 90% of 1 repetition maximum (1RM). For both sets fatigue was the end point. We asked: do multiple sets affect subsequent work output along with aerobic, anaerobic, and excess postexercise oxygen consumption (EPOC) contributions? Ten males participated. Work was significantly less for the 2nd set within the 70% and 80% protocols, but not the 90% protocol. Anaerobic (glycolytic) energy expenditure was less for the 2nd set within all protocols. However, within all protocols, the work / energy expenditure ratio was not different between sets. Overall work was significantly different among protocols, becoming less as the weight lifted was increased: 70%, 637.1 +/- 122.4 J; 80%, 512.4 +/- 93.4 J; 90%, 324.7 +/- 92.6 J (p < 0.001). EPOC was not different among protocols after the 1st set, 2nd set, or combined overall. Moreover, the overall EPOC did not correlate with overall work performed (r = 0.31, p = 0.11). EPOC overall did correlate with aerobic (r = 0.68, p < 0.001) and anaerobic (r = 0.65, p < 0.001) energy expenditures. In terms of a work / energy expenditure ratio, the least amount of completed work at 90% 1RM required greater energy expenditure as compared with 70% and 80% because of an EPOC that is similar for all. As more work is completed (i.e., lower weight, more repetitions), aerobic and anaerobic exercise energy expenditures appear to increase accordingly, yet absolute EPOC remains essentially unchanged, contributing less to the overall energy expenditure. PMID- 21326386 TI - NF-kappaB activation in organs from STZ-treated rats. AB - Nuclear factor kappa B (NF-kappaB) is a ubiquitously expressed transcription factor comprised of various subunits (p50 (NF-kappaB1), p52 (NF-kappaB2), p65 (RelA), RelB, and c-Rel). Activation of certain NF-kappaB subunits appears to foster an inflammatory state that may promote the development of disease. Thus characterizing the specific NF-kappaB subunits may provide insight into the pathogenesis of certain diseases. The purpose of this study was to determine if 1 month of a diabetic state, induced by streptozotocin (STZ) treatment, alters the constitutive level of NF-kappaB activation, its subunit composition, or the content of NF-kappaB-related proteins in rodent liver, kidney, spleen, and heart. Diabetes was induced in male Sprague-Dawley rats by a single tail vein injection of STZ (55 mg.kg-1 body weight). After 30 days, the heart, liver, spleen, and kidney were assessed for NF-kappaB activation and subunit composition with electrophoretic mobility shift assay (EMSA), and p50 and p65 subunit content was assessed with Western blotting. In diabetic animals, the constitutive level of NF kappaB activation was reduced in liver, but was unchanged in kidney, spleen, and heart. EMSA supershifts showed the predominant subunit in the activated NF-kappaB complexes from both diabetic and control animals to be p50, although the p65 subunit was detected in NF-kappaB complexes from diabetic hearts. The content of p50 was unaltered in all diabetic tissues examined, whereas the content of p65 was increased only in hearts from diabetic animals. These findings support the idea that a diabetic state may induce specific changes in NF-kappaB subunit composition in certain tissues. PMID- 21326387 TI - The extent of aerobic system activation during continuous and interval exercise protocols in young adolescents and men. AB - This study assessed the extent of aerobic system activation in young adolescents and men during heavy continuous (HC), short-interval (SI), and long-interval (LI) aerobic exercise protocols, and compared this response between the 2 age groups in the 3 protocols. Ten young adolescents (aged 13.2 +/- 0.3 years) and 10 men (aged 21.0 +/- 1.6 years) completed a maximal incremental test, an HC exercise protocol (83% of maximal aerobic velocity; MAV), an SI exercise protocol (30 s at 110% MAV with 30 s at 50%), and an LI exercise protocol (3 min at 95% MAV with 3 min at 35%). Oxygen consumption and heart rate were measured continuously, and blood samples were obtained for lactate determination. Men completed more runs and distance in the SI protocol (p < 0.05) than adolescents; however, there were no age differences in the number of LI runs and in the duration of HC protocol. In both age groups, more time was spent above 90% and 95% of maximal oxygen consumption (p < 0.05), and a higher percentage of maximal oxygen consumption was reached in the LI compared with the HC and SI protocols, with no differences between the HC and SI protocols. Although within each protocol the percentage of maximal oxygen consumption achieved and time spent above 90% and 95% of maximal oxygen consumption was not different between age groups, the time spent at 80% maximal oxygen consumption was longer for adolescents than men in the HC protocol, and longer for men than boys in the SI protocol (p < 0.05). In conclusion, all protocols elicited high levels of aerobic activation in both age groups. The LI protocol taxed the aerobic system at 90%-100% of maximal oxygen consumption for a longer time when compared with the HC and SI protocols in young adolescents and in men. However, differences were observed between groups in taxing the aerobic system at 80% maximal oxygen consumption: in young adolescents, the HC protocol allowed longer running time than the LI and SI protocols, while in men there were no differences among protocols. PMID- 21326388 TI - Association between exercise hemodynamics and changes in local vascular function following acute exercise. AB - Skeletal muscle contractions are associated with physical stimuli that act upon muscle vasculature, including increased shear stress and blood pressure. It is unclear if acute dynamic exercise alters local vascular function. The purpose of this study was to examine the role of exercise hemodynamics on the effects of acute exercise on vascular function, as evaluated by brachial artery flow mediated dilation (FMD). Healthy individuals (n = 14; age, 18-34 years) performed 30 min of handgrip exercise at fast and slow contractions. Blood pressure during exercise was measured using a Vasotrac system (Medwave Inc.), while shear rate during exercise and FMD at rest and after 30 min of recovery from exercise were measured in the brachial artery of the active arm using Doppler ultrasound. Estimated contractile work was correlated with blood pressure (r = 0.61, p < 0.01) and retrograde shear rate (r = -0.78, p < 0.01). As a result, blood pressure was higher (p < 0.05) and oscillatory shear index was lower (p < 0.05) during slow as compared with fast contractions. On average, FMD was unchanged following fast contractions (5.4 +/- 3.4%dilation to 6.1 +/- 3.8%dilation; p = 0.19), but significantly reduced following slow contractions (6.9 +/- 4.2%dilation to 3.6 +/- 2.5%dilation; p = 0.01). Within slow contractions, subgroup analysis revealed blood pressure to associate with the change in FMD; such that individuals with mean blood pressure >100 mm Hg (range, 102-139 mm Hg) during exercise had larger decreases in FMD than individuals with lower exercise blood pressure. These results indicate that impaired local vascular function following acute exercise with high contractile activity is associated with blood pressure stimuli in healthy individuals. PMID- 21326389 TI - Estimated fluid and sodium balance and drink preferences in elite male junior players during an ice hockey game. AB - Research in many sports suggests that losing ~2% of body mass (BM) through sweating impairs athletic performance, although this has not been tested in ice hockey players. This study investigated pregame hydration, and on-ice sweat loss, fluid intake, and sodium (Na+) balance of elite male junior players during an ice hockey game. Twenty-four players (2 goalies, 7 defensemen, 15 forwards) volunteered to participate in the study (age, 18.3 +/- 0.3 years; weight, 86.5 +/ 1.6 kg; height, 184.1 +/- 1.3 cm). Players were weighed pre- and postgame, fluid and sodium intake were monitored throughout the game, and fluid and Na+ balance were determined within the time between BM measurements. Sweat Na+ loss was calculated based on sweat loss and sweat [Na+] determined from sweat-patch analysis on the same players during an intense practice. Players arrived at the rink in a euhydrated state and drank 0.6 +/- 0.1 L of fluid before the game. Mean playing time for the forwards was 18:85 +/- 1:15 min:s and playing time for the defense was 24:00 +/- 2:46 min:s. Sweat loss was 3.2 +/- 0.2 L and exceeded net fluid intake (2.1 +/- 0.1 L). Mean BM loss was 1.3% +/- 0.3%, with 8/24 players losing between 1.8% to 4.3% BM. Players preferred to drink water and a carbohydrate electrolyte solution before the game and during intermissions, while only water was consumed during each period. Practice mean forehead sweat [Na+] was 74 mmol.L-1. Estimated sweat Na+ losses of 3.1 +/- 0.4 g (~8 g NaCl) coupled with low Na+ intake of 0.8 +/- 0.2 g (~2 g NaCl) resulted in a significant Na+ deficit by the end of the game. This study demonstrated that despite abundant opportunities to hydrate during a hockey game, one-third of the players did not drink enough fluid to prevent sweat losses of 2% BM or higher. Losing 2% BM has been associated with decreases in athletic performance. PMID- 21326390 TI - How to test maximal oxygen uptake: a study on timing and testing procedure of a supramaximal verification test. AB - Verification tests are becoming increasingly common for confirming maximal oxygen uptake (VO2 max) attainment. Yet, timing and testing procedures vary between working groups. The aims of this study were to investigate whether verification tests can be performed after an incremental test or should be performed on a separate day, and whether VO2 max can still be determined within the first testing session in subjects not satisfying the verification criterion. Forty subjects (age, 24 +/- 4 years; VO2 max, 50 +/- 7 mL.min-1.kg-1) performed a maximal incremental treadmill test and, 10 min afterwards, a verification test (VerifDay1) at 110% of maximal velocity (vmax). The verification criterion was a VerifDay1 peak oxygen uptake (VO2 peak) <=5.5% higher than the incremental test value. Subjects not achieving the verification criterion performed another verification test at 115% vmax (VerifDay1') 10 min later, trying to confirm VerifDay1 VO2 peak as VO2 max. All other subjects exclusively repeated VerifDay1 on a separate day (VerifDay2). Of the 40 subjects, 6 did not satisfy the verification criterion. In 4 of them, attainment of VO2 max was confirmed by VerifDay1'. VO2 peak was equivalent between VerifDay1 and VerifDay2 (3722 +/- 991 mL.min-1 vs. 3752 +/- 995 mL.min-1, p = 0.56), whereas time to exhaustion was significantly longer in VerifDay2 (2:06 +/- 0:22 min:s vs. 2:42 +/- 0:38 min:s, p < 0.001, n = 34). The verification test VO2 peak does not seem to be affected by a preceding maximal incremental test. Incremental and verification tests can therefore be performed within the same testing session. In individuals not achieving the verification criterion, VO2 max can be determined by means of a subsequent, more intense verification test in most but not all cases. PMID- 21326391 TI - Changes in calcium status in aged rats fed Lactobacillus GG and Bifidobacterium lactis and oligofructose-enriched inulin. AB - In this study we hypothesized that an increase in numbers of beneficial bacteria in the large intestine can affect calcium (Ca) status in the elderly. Adult and aged rats were fed a diet with or without synbiotics for 21 days. Synbiotics increased the numbers of lactobacilli and bifidobacteria in large intestine in both adult and aged rats. The plasma Ca concentration was significantly increased while osteocalcin concentration was significantly decreased only in aged rats fed synbiotics. PMID- 21326392 TI - A comprehensive evaluation of motion sensor step-counting error. AB - The purpose of this study was to conduct a comprehensive evaluation of the effect that walking speed, gender, leg length, motion sensor tilt angle, brand, and placement have on motion sensor step-counting error. Fifty-nine participants performed treadmill walking trials at 6 speeds while wearing 5 motion sensor brands placed on the anterior (Digiwalker, DW; Walk4Life, WFL; New Lifestyles, NL; Omron, OM), midaxillary (DW; WFL; NL; ActiGraph, AG), and posterior (DW, WFL, NL) aspects of the waistline. The anterior-placed NL and midaxillary-placed AG were the most accurate motion sensors. Motion sensor step-count error tended to decrease at faster walking speeds, with lesser tilt angles, and with an anterior waistline placement. Gender and leg length had no effect on motion sensor step count error. We conclude that the NL and AG yielded the most accurate step counts at a range of walking speeds in individuals with different physical characteristics. PMID- 21326394 TI - The Maori Affairs Select Committee Inquiry and the road to a smokefree Aotearoa. PMID- 21326395 TI - The B4School Check--addressing the new morbidity in child health. PMID- 21326396 TI - Has the time come for a universal varicella (chicken pox) vaccination in New Zealand? PMID- 21326397 TI - The role of sociocultural factors in obesity aetiology in Pacific adolescents and their parents: a mixed-methods study in Auckland, New Zealand. AB - AIM: To explore sociocultural factors that may promote or prevent obesity in Pacific communities in New Zealand. Specific objectives were to describe the behaviours, beliefs and values of Pacific adolescents and their parents, related to food consumption and physical activity and to examine the patterns among obese and non-obese Pacific adolescents and their parents. METHODS: A self-completion questionnaire was administered to 2495 Pacific students who participated in the New Zealand arm of the Obesity Prevention In Communities (OPIC) project, with quantitative comparisons between 782 obese and 814 healthy weight students. Sixty eight people (33 adolescents and 35 parents) from 30 Pacific households were interviewed in the qualitative phase of the study. RESULTS: Healthy eating and higher levels of physical activity were related to parental presence at home, parental occupational type (non-shift) and better health education and experience. Obese adolescents held the same attitudes, beliefs and values about food and physical activity as their healthy-weight counterparts, but these factors were not protective for obesity-risk. CONCLUSION: This study indicates that social status and environmental factors related to poverty affect the health promoting behaviours of Pacific communities in New Zealand. To address obesity in Pacific youth, specific macro-environmental changes are recommended including food pricing control policies to mitigate healthy food costs, revising sustained employment hour policies, making changes to school food and physical activity environments. PMID- 21326398 TI - Body image and body change strategies among Tongan adolescents in Tonga and New Zealand. AB - AIM: The aim of this study was to evaluate the body image and body change strategies of adolescents from Tonga, and Tongans who are resident New Zealand. METHOD: In total, 598 Tongans from Tonga and 388 Tongans from New Zealand completed measures of body image, body change strategies and messages about their body. RESULTS: Tongans in Tonga were more likely to receive positive messages about a larger body from adults at school, church and the media, and losing weight from the media. They were also more likely to adopt strategies to lose weight, increase weight and increase muscles. CONCLUSION: The large body ideal appears to be still valued in Tonga, whereas Tongans also want to lose weight because of media messages to achieve a healthy body weight. PMID- 21326399 TI - Improving school readiness with the Before School Check: early experience in Hawke's Bay. AB - AIM: The New Zealand Ministry of Health's Before-School Check (B4SC) aims to identify those 4-year-old children with health, developmental or behavioural problems likely to impact on their education so these can be remediated before school entry. This evaluation aims to demonstrate the outcomes of the first 10 months of the B4SC programme in Hawke's Bay and the lessons learnt. METHODS: The B4SC was implemented in Hawke's Bay using an intersectoral, collaborative approach including all major stakeholders, led by the Hawke's Bay Primary Health Organisation (HBPHO). Local clinical practice and referral processes were established by a Clinical Advisory Group. Eighty-four practice nurses, Well Child/Tamariki Ora nurses and independent practitioners have been trained in group and individual settings. All referrals come through a clinical nurse leader to an intersectoral triage group. RESULTS: In the 10 months since the first training the nurses have assessed 1848 out of 2180 or 84% of the cohort, including 75% of children in quintile 5. Referrals average 55% and have been of high quality with 74% accepted, 14% already known, and only 8% declined at triage. CONCLUSION: The intersectoral Clinical Advisory Group has been critical to the success of the programme, as it has achieved engagement and commitment from all stakeholders to the clinical processes and referral pathways. Training nurses with existing community health skills, relationships with families and strong community networks has led to high rates of children seen from the most deprived quintile. The training and the referral pathway, via the Clinical Nurse Leader to an intersectoral triage group, have led to high quality referrals and a low rate of referrals declined. PMID- 21326400 TI - Gestational diabetes mellitus in Tonga: insights from healthcare professionals and women who experienced gestational diabetes mellitus. AB - AIM: To gain contextual insights from Tongan healthcare professionals and women who had developed gestational diabetes mellitus (GDM). METHOD: Qualitative, individual, semi-structured, face-to-face interviews were conducted during 2006 with 11 women who had developed GDM in the previous 12 months and 10 health professionals who worked in the GDM/diabetes area in Tonga. RESULTS: Due to funding issues glucose supplies were often scarce which precluded universal screening. GDM management which focused on encouraging behavioural change to diet and physical activity were reported to be effective in managing GDM in Tonga. Changes to physical activity levels were difficult because of 'laziness' (the participant's words). Preventative screening was perceived to be a foreign idea in Tonga which negatively influenced post-partum screening and monitoring. CONCLUSION: GDM was reportedly well-managed through lifestyle interventions. 'Laziness', identified as a contributing factor to obesity and physical inactivity needs to be considered within a broader context of complex social and economic changes in Tonga. There are clear challenges to shift attitudes towards preventative screening in Tonga and for screening supplies to be adequately funded. Lifestyle intervention targeted towards modifiable risk factors of obesity and physical activity for GDM and Type 2 diabetes need to extend into the postpartum period. PMID- 21326401 TI - Maori challenges and crown responsibilities: Maori policymaker ideas on smokefree policy options. AB - AIM: To determine obstacles/opportunities within policy processes, for smokefree interventions appropriate to Maori. In particular, to explore Maori policymakers' ideas on how to achieve progress on smokefree homes, cars and community property. METHODS: Documents and interviews with 16 senior Maori officials and Members of Parliament, and nine interviews in two case studies, were used to explore Maori policymakers' ideas for (i) Progress, within relevant policy processes, on smoking in homes, cars and community property; (ii) Particular interventions that the interviewees felt were most and least effective, practical, sustainable, politically feasible or desirable in some way; (iii) The context, and obstacles and opportunities for such interventions. The case studies were of a Maori health service and a group of Maori District Health Board managers. RESULTS: Several key themes emerged from the research including, (i) children as drivers for change, (ii) strong national and local indigenous leadership needed for change, (iii) delivering smokefree messages as part of wider healthy living approaches, (iv) targeting of the messages for greatest impact for Maori, (v) need for a Maori approach, not a general approach, (vi) central and local government having a significant role in the prevention of tobacco harm, (vii) ideas on how tobacco tax revenue should be spent on tobacco control, and (viii) the rights of children to smokefree environments. CONCLUSIONS: Results indicate that indigenous specific approaches and indigenous leadership are critical for Maori tobacco-free advances. Harnessing indigenous values and principles related to health, family and children was the preferred method of these Maori policymakers for delivering social marketing messages. PMID- 21326402 TI - Association of parent and best friend smoking with stage of adolescent tobacco smoking. AB - OBJECTIVE: Compare the effect of parental and best friend smoking across the stages of adolescent smoking, from being a never smoker susceptible to smoking, to being a daily smoker METHOD: National cross-sectional annual survey (2002-2006 combined) of 157,637 Year 10 students aged 14 and 15 years who answered an anonymous self-administered questionnaire. RESULTS: The effects of smoking by parents and best friend varied with stage of adolescent tobacco smoking. Attributable risk calculations showed that parental and best friend smoking explained only 6.3% of susceptibility to smoking among never smokers, and 21.7% of non-smoking students who had ever experimented with cigarettes. The attributable risk for parental and best friend smoking progressively increased with smoking frequency, up to 78.7% for daily smoking. The effect of best friend smoking was stronger than parental smoking, although there was a synergistic effect of both variables on the risk of daily smoking. CONCLUSION: Smoking by best friend and parents are strongly associated with current smoking by adolescents, but unrelated to susceptibility to smoke among those who are non smokers. PMID- 21326403 TI - SIDS-related knowledge and infant care practices among Maori mothers. AB - AIM: Maori have high SIDS rates and relevant information is needed to craft appropriate prevention strategies. The aim of the study was to determine what Maori mothers know about SIDS prevention, and to determine their SIDS-related child care practices. METHODS: Maori mothers who gave birth in the Counties Manukau District Health Board area were surveyed about their SIDS related knowledge, and infant care practices and their reasons for using and their concerns about these practices. Results were compared with a similar 2005 survey of a largely European sample. RESULTS: Knowledge of Maori mothers about SIDS prevention was much lower than for European mothers. More Maori infants slept prone and Maori mothers stopped breastfeeding significantly earlier. Although co sleeping rates were similar, bedsharing increased to 65% for some part of the night. In addition, more than half of the Maori mothers had smoked in pregnancy and 21% of them were sharing a bed with their infant. Potentially unsafe soft objects such as rolled blankets or pillows were used by a third of mothers to help maintain the sleep position. CONCLUSIONS: Maori mothers have a poorer knowledge of SIDS prevention practices. The high rate of maternal smoking, the early cessation of breastfeeding, and co-sleeping where there was smoking in pregnancy were also areas of concern. Appropriate health promotion measures need to be developed for the high-risk Maori community. PMID- 21326404 TI - Preventing cardiovascular disease: a review of the effectiveness of identifying the people with familial hypercholesterolaemia in New Zealand. AB - AIM: To identify the diagnostic and treatment rates for familial hypercholesterolaemia (FH) in New Zealand. METHODS: The FH data held by Canterbury Health Laboratories and the Canterbury District Health Board lipid clinic was examined to give an indication of the level of identification and treatment of FH in both Canterbury and New Zealand. RESULTS: Between 2004-08, 588 people, out of a possible 10,500 affected people, who presented with a pre treatment cholesterol =8.0 mmol/L, lipid stigmata or a strong family history of cardiovascular disease (CVD), were tested for low density lipoprotein (LDLR) and apolipoprotein B (APOB) mutations. Mutations were identified in 76 cases (13%). 353 relatives were screened and 159 (45%) were found to have FH. This data suggests that less than 20% of the affected people in Canterbury have been diagnosed and less than 2.2% nationally. CONCLUSION: FH diagnostic services in New Zealand appear significantly underdeveloped thereby denying affected people the opportunity of early treatment to reduce the risk of premature cardiovascular events. Cascade screening is shown to be a cost effective and efficient approach to identifying people with FH. PMID- 21326405 TI - Moving forward with healthcare prioritisation. PMID- 21326406 TI - Love bites--an unusual cause of blunt internal carotid artery injury. PMID- 21326407 TI - A case of oesophageal varices and portal hypertension in an HIV-positive patient with no evidence of cirrhosis. AB - We present a case of portal hypertension and variceal bleeding in the absence of cirrhosis, in an HIV-positive patient on long-term antiretroviral treatment with didanosine. We believe this to be the first such case identified in New Zealand (NZ). PMID- 21326408 TI - Medical image. A medical emergency following chicken pox. PMID- 21326409 TI - Medical image. Aortic aneurysm in a girl with Takayasu's arteritis. PMID- 21326410 TI - Poorer mental health in many New Zealand smokers: national survey data from the ITC Project. PMID- 21326411 TI - A response to the article "task manager: an innovative approach to improving hospital communication after hours". PMID- 21326412 TI - Spectral-domain differential interference contrast microscopy. AB - We present a fiber-optic low-coherence imaging technique, termed spectral-domain differential interference contrast microscopy (SD-DIC), for quantitative DIC imaging of both reflective surfaces and transparent biological specimens. SD-DIC combines the common-path nature of a Nomarski DIC interferometer with the high sensitivity of spectral-domain low-coherence interferometry to obtain high resolution, quantitative measurements of optical pathlength gradients from a single point on the sample. Full-field imaging can be achieved by scanning the sample. A reflected-light SD-DIC system was demonstrated using a USAF resolution target as the phase object. Live cardiomyocytes were also imaged, achieving a resolution of 36 pm for pathlength gradient measurements. The dynamics of cardiomyocyte contraction were recorded with high sensitivity at selected sites on the cells. PMID- 21326413 TI - Wavefront sensing with critical sampling. AB - Different types of nonredundant sampling patterns are shown to guarantee completeness of the basis formed by the sampled partial derivatives of Zernike polynomials, commonly used to reconstruct the wavefront from its slopes (wavefront sensing). In the ideal noise-free case, this enables one to recover double the number of modes J than sampling points I (critical sampling J=2I). With real data, noise amplification makes the optimal number of modes lower I4.44 V/MUm is observed. The electro-optical properties of the BPLC Fresnel lens are analyzed and discussed. PMID- 21326437 TI - Spectral and temporal changes of optical pulses propagating through time-varying linear media. AB - We present universal formulas for the spectral and temporal output optical fields from a linear traveling-wave medium whose refractive index changes during its propagation within the medium. These formulas agree with known changes in central wavelength and energy that are associated with adiabatic wavelength conversion (AWC). Moreover, they reveal new changes to the optical pulses that have not been noticed, such as pulse compression and spectral broadening. Most significantly, we find that AWC alters the pulse power, pulse chirp, and pulse delay. All of these effects depend on whether the central wavelength is blueshifted or redshifted, the first sign of asymmetry to be reported for AWC. These findings impact the applications of AWC to optical signal processing in microphotonic and nanophotonic structures as well as in lightwave systems. PMID- 21326438 TI - Ionization penalty in nonlinear Raman neuroimaging. AB - Light-assisted ionization accompanying coherent anti-Stokes Raman scattering (CARS) of ultrashort laser pulses in brain tissue is shown to manifest itself in a detectable blueshift of the anti-Stokes signal. This blueshift can serve as an indicator of ionization processes in CARS-based neuroimaging. PMID- 21326439 TI - High-resolution microwave frequency transfer over an 86-km-long optical fiber network using a mode-locked laser. AB - We demonstrate the transfer of an ultrastable microwave frequency by transmitting a 30-nm-wide optical frequency comb from a mode-locked laser over 86 km of installed optical fiber. The pulse train is returned to the transmitter via the same fiber for compensation of environmentally induced optical path length changes. The fractional transfer stability measured at the remote end reaches 4*10(-17) after 1600 s, corresponding to a timing jitter of 64 fs. PMID- 21326440 TI - Magnetically tunable surface plasmon resonance based on a composite consisting of noble metal nanoparticles and a ferromagnetic thin film. AB - We demonstrate magnetically tunable surface plasmon resonance based on a composite consisting of noble metal nanoparticles and ferromagnetic thin film. We found that both the frequency and linewidth of the localized surface plasmon resonance can be manipulated by applying an external magnetic field. The underlying mechanism is attributed to the variation of the dielectric constant in the ferromagnetic thin film resulting from the change of magnetization. Our result shown here paves an alternative route for manipulation of the characteristics of the surface plasmon resonance, which may serve as a new design concept for the development of magneto-optical devices. PMID- 21326441 TI - Scattering-induced changes in the temporal coherence length and the pulse duration of a partially coherent plane-wave pulse. AB - The scattering of a partially coherent plane-wave pulse on a Gaussian-correlated, quasi-homogeneous random medium is investigated. The analytical expressions for the temporal coherence length and the pulse duration of the scattered field are derived. We demonstrate that the scattering-induced changes in the temporal coherence length and the pulse duration may be used to determine the correlation function of the scattering potential of the medium. PMID- 21326442 TI - Sagnac interferometer with adaptive nonlinear detection. AB - We present a Sagnac interferometer that uses a nonlinear adaptive medium for detection. The nonlinearity of the medium being characterized by a finite response time, the detection has a finite frequency bandwidth determining two operational regimes: at low variation rate of the rotation speed the interferometer operates in the slow-light regime, providing a direct measurement of the angular acceleration. For high variation rate of the rotation speed the amplitude of the alternating component of the Sagnac phase shift is instead detected, with the continuous and low-frequency components filtered out by the adaptive nonlinear process in the medium. PMID- 21326443 TI - Coherent beam combination of narrow-linewidth 1.5 MUm fiber amplifiers in a long pulse regime. AB - We report what we believe to be the first experimental demonstration of coherent beam combining of two fiber amplifiers in a 100 ns pulse regime using a signal leak between the pulses. Pulses of ~100 W stimulated-Brillouin-scattering limited peak power are combined with 95% efficiency, a residual phase error of lambda/27, and no significant beam quality degradation. PMID- 21326444 TI - Dynamic phase evaluation in sparse-sampled temporal speckle pattern sequence. AB - The rapid progress of modern manufacturing technology has posed stringent requirements for inspecting techniques for vibration characterization and dynamic testing. Because of its simplicity, accuracy, and whole-field character, speckle interferometry has served as one of the major techniques for dynamic measurement, where normally a dense-sampled temporal speckle sequence is captured for phase retrieval using Fourier or wavelet transforms. In this Letter, a method is proposed for phase evaluation of sparse-sampled speckle patterns when the sampling rate is lower than two points per temporal cycle. Dynamic experiments using a high-speed camera demonstrated the effectiveness of the proposed method for complicated wrapped phase retrieval in electronic/digital speckle pattern interferometry. PMID- 21326445 TI - Efficient spectral conversion and temporal compression of femtosecond pulses in SF6. AB - An uniquely high conversion efficiency of fundamental radiation from a Ti:sapphire laser to a supercontinuum is achieved through filamentary propagation in sulfur hexafluoride (SF6) to generate a uniform over-octave spectrum. Two different parts of the supercontinuum, firstly around the fundamental wavelength of 800 nm and secondly within the newly generated frequency range around 550 nm, are shown to be compressible down to minimal pulse duration of about 10 fs demonstrating a potential of the method for single-cycle pulses generation. PMID- 21326446 TI - Skew-faceted elliptical reflector. AB - A light patch created by an illumination optical element often requires having a specific shape and illuminance distribution. This Letter presents a modification of Oliker's elliptical faceted reflector that can work with a very large field of view and provide the required uniformity across a specified target area. PMID- 21326447 TI - Composition-dependent photosensitivity in As-S glasses induced by bandgap light: structural origin by Raman scattering. AB - Massive photoinduced short- and medium-range structural changes (photopolymerization) in As-S glasses are induced by near-bandgap light and studied by Raman scattering. Structural changes involve bond restructuring in sulfur-rich nanodomains of these nanoscale-phase-separated glasses. The spectral dependence of the photopolymerization effect demonstrates that various wavelengths can be used to optically change the structure of As-S glasses. The immense structural changes are relevant to recent findings about the role of bandgap light illumination for fabricating channel waveguides in noncrystalline arsenic sulfides. PMID- 21326448 TI - Enhanced angular tolerance of resonant waveguide grating reflectors. AB - We introduce an approach to enhance the angular tolerance of resonant waveguide gratings by stacking two resonant structures on top of each other. It is shown that reflectivities close to unity can be retrieved over the entire angular spectrum by a double T-shaped grating configuration. Although a combination of silicon as the high-index and diamond as the low-index material is considered, the principles of our new approach can also be used to realize monolithic silicon structures with similar properties. We illustrate that the functionality of the device can be understood by a decomposition into separated elements. Our approach might have compelling applications as new diffractive-reflective optical components with low-coating thermal noise in the field of high-precision metrology. PMID- 21326449 TI - All-passive phase locking of a compact Er:fiber laser system. AB - A passively phase-locked laser source based on compact femtosecond Er:fiber technology is introduced. The carrier-envelope offset frequency is set to zero via difference frequency generation between a soliton at a wavelength of 2 MUm and a dispersive wave at 860 nm generated in the same highly nonlinear fiber. This process results in a broadband output centered at 1.55 MUm. Subsequently, the 40 MHz pulse train seeds a second Er:fiber amplifier, which boosts the pulse energy up to 8 nJ at a duration of 125 fs. Excellent phase stability is demonstrated via f-to-2f spectral interferometry. PMID- 21326450 TI - Goos-Hanchen and Imbert-Fedorov shifts of a nondiffracting Bessel beam. AB - Goos-Hanchen (GH) and Imbert-Fedorov (IF) shifts are diffractive corrections to geometric optics that have been extensively studied for a Gaussian beam that is reflected or transmitted by a dielectric interface. Propagating in free space before and after reflection or transmission, such a Gaussian beam spreads due to diffraction. We address here the question of how the GH and IF shifts behave for a "nondiffracting" Bessel beam. PMID- 21326451 TI - Compensation of dispersion-induced power fading for highly linear radio-over fiber link using carrier phase-shifted double sideband modulation. AB - A carrier phase-shifted (CPS) double sideband (DSB) modulation technique in radio over-fiber (RoF) system is proposed and experimentally demonstrated. By tuning the biases in a single-drive dual parallel Mach-Zehnder modulator (SD-DPMZM), the optical carrier in the DSB spectrum acquires additional phase shift. The transmittance response of a dispersive RoF link is thus being controlled and shifted in the frequency domain. Experiments successfully turned the maximum transmission frequency to 10 GHz and 15 GHz for both 25 and 39 km fiber links. This is also a highly linear scheme, of which a spurious-free dynamic range (SFDR) of 111.3 dB.Hz2/3 is experimentally obtained. PMID- 21326452 TI - Efficient green-light generation by proton-exchanged periodically poled MgO:LiNbO3 ridge waveguide. AB - Efficient cw 532 nm green-light generation is demonstrated using a periodically poled MgO:LiNbO3 ridge waveguide prepared by a process that combines annealed proton exchange and precise dicing. Performance of waveguides with different widths has been investigated. The 6-MUm-wide, 1.6-cm-long uncoated ridge waveguide has achieved a green output power of 127 mW under a coupled fundamental light power of 250 mW. The highest conversion efficiency achieved is 53%. PMID- 21326453 TI - On-chip parametric amplification with 26.5 dB gain at telecommunication wavelengths using CMOS-compatible hydrogenated amorphous silicon waveguides. AB - We present what we believe to be the first study of parametric amplification in hydrogenated amorphous silicon waveguides. Broadband on/off amplification up to 26.5 dB at telecom wavelength is reported. Measured nonlinear parameter is 770 W( ) m(-1), nonlinear absorption 28 W(-1) m(-1), bandgap 1.61 eV. PMID- 21326454 TI - Large-aperture focusing of high-energy x rays with a rolled polyimide film. AB - We describe a point-focusing x-ray lens made of a rolled polyimide film with etched prisms. The resulting lens is a cylinder with a large number of prisms forming an internal conic structure. The method allows for the manufacturing of lenses with large apertures and short focal lengths, for energies up to at least 100 keV. In order to evaluate the concept, we have hand-rolled a few lenses and evaluated them at a synchrotron source. The measured performance of the prototype is promising, and deviations from the theoretical limits are quantitatively explained. PMID- 21326455 TI - Intensity measurement bend sensors based on periodically tapered soft glass fibers. AB - We demonstrate a technique for tapering periodically an all-solid soft glass fiber, consisting of two types of lead silicate glasses, by the use of a focused CO(2) laser beam and investigate the bend sensing applications of the periodically tapered soft glass fiber. Such a soft glass fiber with periodic microtapers could be used to develop promising bend sensors with a sensitivity of -27.75 MUW/m(-1) by means of measuring the bend-induced change of light intensity. The proposed bend sensor exhibits a very low measurement error of down to +/-1%. PMID- 21326456 TI - Detection of saturated absorption spectroscopy at high sensitivity with displaced crossovers. AB - We present an unconventional experimental approach for detecting saturated absorption spectroscopy. Using this approach, crossover peaks are displaced, leaving out peaks corresponding to an atom's natural resonant frequencies. Sensitivity of detection can also be enhanced. Consequently, the spectrum could reflect the energy structure of atoms more explicitly. Without harmful influence from crossovers, the locking range of the error signal is significantly increased and the symmetry of the dispersion line shape is perfectly preserved, so reliability of frequency stabilization can be improved. PMID- 21326457 TI - Holographic Fabry-Perot spectrometer. AB - We propose a spectrum analyzer based on the properties of a hologram recorded with the field transmitted by a Fabry-Perot etalon. The spectral response of this holographic Fabry-Perot spectrometer (HFPS) is analytically investigated in the paraxial approximation and compared with a conventional Fabry-Perot etalon of similar characteristics. We demonstrate that the resolving power is twice increased and the free spectral range (FSR) is reduced to one-half. The proposed spectrometer could improve the operational performance of the etalon because it can exhibit high efficiency and it would be insensible to environmental conditions such as temperature and vibrations. Our analysis also extends to another variant of the HFPS based on holographic multiplexing of the transmitted field of a Fabry-Perot etalon. This device increases the FSR, keeping the same HFPS performance. PMID- 21326458 TI - Microstructural and microspectral characterization of a vertically aligned liquid crystal display panel. AB - The microstructural and microspectral characteristics of a vertically aligned liquid crystal display (VA-LCD) panel were obtained noninvasively for the first time. With 1 MUm axial and 2 MUm transversal resolutions, the cell gap profile beneath the patterned thin-film transistor of the VA-LCD panel can clearly be resolved. The thicknesses of the multiple thin-film layers and the embedded defects can also be unveiled. As far as spectral response is concerned, the light transmittance at the layer boundaries can be estimated from the measured reflectance, which is crucial information for the design of a highly transmissive panel. The color shift of the VA-LCD panel due to fabrication error was evaluated. PMID- 21326459 TI - High-resolution transparent x-ray beam location and imaging. AB - We present a high-resolution in situ imaging and localization method of energetic particle beams. Recording of the scattered radiation from a thin featureless foil, placed in the path of the beam, and taken with a pinhole or coded aperture camera arrangement magnifies beam movements at the sensor. At the same time, a magnified image of the beam is available with an exceptional signal-to-noise ratio. We show measurement results of the level of precision that can be achieved and compare them to theoretical limits based on the signal-to-noise levels. PMID- 21326460 TI - Multiple narrow bandpass optical filters based on one-dimensional rugate photonic structures of two periodicities. AB - A theoretical analysis of a design of multiple narrow bandpass filters based on one-dimensional (1D) rugate photonic structures with a period jump defect is presented. The optical properties, including transmittance and energy density distributions, are numerically calculated using the propagation matrix method. Our results show that multiple resonance transmission modes are produced when the period jump defect is introduced into the 1D rugate film. Both blueshift and redshift of the stop band of the rugate structure and wavelengths of resonant modes are observed, depending on the change of period jump. The number, the wavelengths, the band intervals, and the intensities of multiple resonance transmission modes are tunable by adjusting structure parameters of the rugate structure. Experimental feasibility of the proposed multiple narrow bandpass optical filters using the technique of glancing angle deposition is also discussed. PMID- 21326461 TI - 10% Yb3+-Lu2O3 ceramic laser with 74% efficiency. AB - We demonstrate laser oscillation at 1080 nm with more than 16 W of output power and with an optical-to-optical slope efficiency of up to 74% using a 10% Yb3+ doped Lu2O3 ceramic made by hot pressing. This represents the highest output power and efficiency obtained for a Yb3+ doped Lu2O3 ceramic and demonstrates the feasibility for power scaling. PMID- 21326462 TI - A continuous wave SrMoO4 Raman laser. AB - We demonstrate a cw, laser diode-pumped Nd:GdVO4/SrMoO4 crystalline Raman laser. First Stokes laser output at 1173.5 nm of 2.18 W was achieved with a diode-to first Stokes efficiency of 8.7%. With intracavity frequency doubling in LiB3O5, 3.1 W of cw yellow emission at 586.8 nm was obtained with a 12.4% diode-to-yellow efficiency. The experimental results show that SrMoO4 is an excellent stimulated Raman scattering gain material for high-power cw near-IR Stokes and yellow lasers. PMID- 21326463 TI - Temperature-dependent photoluminescence properties of Sr2CeO4:Eu3+ and its modification for use in fluorescence thermometry. AB - The efficient red material Sr2CeO4:Eu3+ (SCOE) has been studied as a potential thermographic phosphor for application in the single-color fluorescence thermometry technique. The temperature-dependent photoluminescence spectra and the integrated emission intensity of SCOE at different temperatures indicate that this red-light-emitting phosphor is extremely sensitive to ambient temperature. On this basis, we designed another three red materials as potential thermographic phosphors that have higher brightness and temperature sensitivity than SCOE, by means of adding Li+, Na+, and K+ ions into the lattice. PMID- 21326464 TI - Equalization-enhanced phase noise induced timing jitter. AB - In electronic digital signal processing based optical communication systems, digital equalization for chromatic dispersion interacts with local oscillator phase noise to produce equalization-enhanced phase noise (EEPN). In addition to both phase and intensity noises, EEPN also induces timing jitter to the equalized signal. For a 100 Gbit/s quadrature-phase-shift keying signal with laser linewidth of 300 kHz, the timing jitter is up to 20% of the symbol interval for a transmission distance of 1500 km. PMID- 21326465 TI - Nonlinear polarization bistability in optical nanowires. AB - Using the full vectorial nonlinear Schrodinger equations that describe nonlinear processes in isotropic optical nanowires, we show that there exist structural anisotropic nonlinearities that lead to unstable polarization states that exhibit periodic bistable behavior. We analyze and solve the nonlinear equations for continuous waves by means of a Lagrangian formulation and show that the system has bistable states and also kink solitons that are limiting forms of the bistable states. PMID- 21326466 TI - Design methodology for compact photonic-crystal-based wavelength division multiplexers. AB - We present an extremely compact wavelength division multiplexer design, as well as a general framework for designing and optimizing frequency selective devices embedded in photonic crystals satisfying arbitrary design constraints. Our method is based on the Dirichlet-to-Neumman simulation method and uses low rank updates to the system to efficiently scan through many device designs. PMID- 21326467 TI - Multiple wavelength reflectance microscopy to study the multiphysical behavior of microelectromechanical systems. AB - In order to characterize surface chemomechanical phenomena driving microelectromechanical systems behavior, we propose herein a method to simultaneously obtain a full kinematic field describing the surface displacement and a map of its chemical modification from optical measurements. Using a microscope, reflected intensity fields are recorded for two different illumination wavelengths. Decoupling the wavelength-independent and -dependent contributions to the measured relative intensity changes then yields the sought fields. This method is applied to the investigation of the electroelastic coupling, providing images of both the local surface electrical charge density and the device deformation field. PMID- 21326468 TI - JCAHO & Me. PMID- 21326469 TI - Thoracic aortic endograft collapse after endovascular treatment of a traumatic pseudoaneurysm. AB - Aortic endograft placement is evolving into the standard of care for treatment of patients with anatomically suitable thoracic aortic aneurysms. Application of this technique and these devices in other thoracic aortic pathology, such as traumatic pseudoaneurysms, symptomatic type B aortic dissections, penetrating ulcers, and even mycotic aneurysms, appears to be promising. We report a case in which a stent graft was used to treat a post-traumatic pseudoaneurysm of the thoracic aorta. The case was complicated by delayed collapse of the endograft, which led to hypoperfusion of the extremities, kidneys, and intestines. Reestablishment of endograft patency and distal reperfusion was achieved by placement of two balloon-expandable stents within the endograft. Potential factors leading to the development of this complication are discussed. PMID- 21326470 TI - Acute renal failure associated with percutaneous mechanical thrombectomy for iliocaval venous thrombosis. AB - Mechanical thrombectomy devices are increasingly being used in selected patients with acute venous thromboembolic disease to rapidly decrease thrombus burden and establish venous patency. Hemolysis and hemoglobinuria secondary to red blood cell fragmentation is known to occur after the use of these devices. In this article we describe a case in which a 16-year-old female patient developed acute renal failure after use of a mechanical thrombectomy device for treatment of symptomatic iliocaval venous thrombosis. PMID- 21326471 TI - Embolization of a traumatic uterine arteriovenous malformation. AB - Uterine arteriovenous malformation (AVM) is a rare but potentially life threatening source of bleeding. A high index of suspicion and accurate diagnosis of the condition in a timely manor are essential because instrumentation that is often used for other sources of uterine bleeding can lead to massive hemorrhage. Although angiography remains the gold standard for diagnosis, ultrasound (US) and magnetic resonance imaging (MRI) are the modalities of choice for the evaluation of a suspected AVM. US and MRI cannot only accurately define a uterine AVM, but they also have the ability to assess the extent of pelvic involvement noninvasively. The definitive treatment of uterine AVM is hysterectomy. However, most women diagnosed with the condition are of childbearing age. Transcatheter uterine artery embolization offers a safe and effective alternative to surgery, with the major advantage of retaining childbearing capacity. PMID- 21326472 TI - Saline Mobilization of the Colon during Percutaneous Renal Cryoablation. AB - A 62-year-old woman with a history of multiple abdominal surgeries underwent computed tomography-guided percutaneous renal cryoablation for a 1.5-cm enhancing left renal mass. We describe the technique of salinoma formation to displace the colon away from the tumor to avoid colonic injury during cryoablation. PMID- 21326473 TI - Indirect Complication of AV Graft Thrombectomy-Thrombolysis Secondary to Previously Attempted Placement of a Temporary Hemodialysis Catheter. AB - Common interventional procedures on frequently encountered patients may wrongly place one on a track that deals with the task at hand while not assessing the global patient. Nowhere is this more problematic than in the dialysis population where in the course of achieving and maintaining vascular access, the interventionist becomes exceedingly familiar with each patient and his or her particular clinical history. Unfortunately, events that may have occurred in the past few hours may rarely be overlooked. We present a case of patient mortality as an indirect result of an upper extremity polytetrafluoroethylene graft thrombectomy-thrombolysis procedure that followed attempted nontunneled catheter placement via the groin. PMID- 21326475 TI - Caval Penetration with Retroperitoneal Hemorrhage Following Placement of an Inferior Vena Cava (IVC) Filter. AB - Placement of inferior vena cava (IVC) filters is an increasingly common request at our institution. The rise in utilization of caval filtration is probably multifactorial and includes pulmonary embolism (PE) prophylaxis most notably in the setting of trauma, the approval and widespread use of temporary/removable filters, and the perceived low complication rates associated with new generation filter designs. We present a unique case of IVC penetration by a new generation filter that resulted in a retroperitoneal hemorrhage in a fully anticoagulated patient. PMID- 21326474 TI - Acute compartment syndrome related to stent-graft exclusion of a popliteal arterial aneurysm. AB - The purpose of this morbidity and mortality case report is to discuss a characteristic of the Viabahn (W.L. Gore, Newark, DE) stent-graft deployment as well as a complication related to wire trauma during endovascular exclusion of a popliteal artery aneurysm. We encountered a phenomenon not described in the literature during deployment of a Viabahn stent graft. This necessitated further wire purchase, which resulted in perforation of a branch vessel within the calf. The rapid recognition of the clinical findings and prompt diagnosis of compartment syndrome was essential to early intervention, which prevented further complication and permanent sequelae. PMID- 21326476 TI - Vascular complications associated with percutaneous biliary drainage: a report of three cases. AB - Percutaneous biliary drainage is a common interventional radiology procedure. It is usually performed in the setting of biliary obstruction, benign or malignant, after endoscopic approach failed or is technically not possible. Percutaneous biliary drainage has a relatively low complication rate, and most complications that occur are usually self-limited. Major complications, however, can occur. In this article, we report three major hemorrhagic complications and their management. They include hemorrhage secondary to fistula formation and pseudoaneurysm formation occurring several days to weeks subsequent to the initial drain placement. PMID- 21326478 TI - Delayed presentation of rupture after venous angioplasty. AB - Venous rupture is an uncommon complication resulting from dialysis graft interventions. We present a case in which contrast extravasation recurred following an initially successful balloon tamponade. The rupture site could not be negotiated with a guidewire to provide endovascular treatment, necessitating balloon occlusion of the graft. PMID- 21326477 TI - Two cases of major hemorrhage secondary to transjugular liver biopsy. AB - Transjugular liver biopsy is an essential procedure in the armamentarium of the interventional radiologist for patients who otherwise are unable to undergo percutaneous liver biopsy. Multiple conditions exist that necessitate the transjugular approach for biopsy, including acquired coagulopathy, congenital blood disorders, or requirement for measurements of hepatic venous and/or wedged hepatic vein pressures. The safety and efficacy of transjugular liver biopsy is well established, with many studies citing extremely low rates of complication with high rates of technical success. Nonetheless, transjugular liver biopsy is not without complications. The most often reported complication is asymptomatic capsular perforation; however occasionally, major hemorrhagic complications and even death have been reported. We describe two major hemorrhagic complications that manifested several days after the procedure and required emergent intervention. PMID- 21326479 TI - Single-session treatment of portal vein thrombosis using combined pharmacomechanical thrombolysis. AB - A patient with portal hypertension developed thrombosis of her transjugular intrahepatic portosystemic shunt (TIPS) and the portal vein. The Trellis device (Bacchus Vascular, Santa Clara, CA) was used to achieve rapid lysis of the portal vein thrombus and help restore portal and TIPS patency in a single session. PMID- 21326480 TI - Longitudinal stent fracture and migration of a stent fragment complicating treatment of hepatic vein stenosis after orthotopic liver transplantation. AB - We report a case of inferior vena cava (IVC) stent placement complicated by longitudinal stent fracture and migration of a stent fragment to the right pulmonary artery 2 years after initial placement. During attempted stenting of a hepatic venous anastomotic stenosis following orthotopic liver transplantation, a Palmaz P308 stent (Cordis International, Miami, FL) migrated and was redeployed into the IVC. Two years later, the patient had recurrent ascites and liver failure. Chest radiograph showed the Palmaz P308 stent had fractured longitudinally with a fragment in the right interlobular pulmonary artery. Half of the stent remained in the IVC. Mild stenosis was noted in the IVC where the stent was deployed. Overdilation of stents may be associated with stent fracture and should be performed with caution. PMID- 21326481 TI - Use of the viabil covered stent in the treatment of a benign biliary stricture with the subsequent development of acute pancreatitis. AB - The use of bare metal stents for benign biliary strictures is typically avoided due to historically poor long-term patency. Thus, in patients who are not surgical candidates, the management of benign biliary strictures can be a frustrating process. This article describes a patient who developed a common bile duct stricture following a complex endovascular thoracoabdominal aneurysm repair. The stricture was treated with the placement of a covered metallic biliary stent; a procedure complicated by the development of acute pancreatitis. PMID- 21326482 TI - Portal vein pseudoaneurysm with portoenteric fistula: an unusual cause for massive gastrointestinal hemorrhage. AB - Pancreaticoduodenectomy (Whipple's procedure) is a commonly performed procedure for the treatment of pancreatic malignancies. Postoperative bleeding from adjacent arteries is a well-established complication of this procedure. This article describes an unusual case of massive gastrointestinal bleeding following pancreaticoduodenectomy due to the development of a portal vein pseudoaneurysm with a portoenteric fistula. The diagnosis was confirmed with multidetector computed tomography angiography; the different endovascular treatment options are discussed. PMID- 21326483 TI - Iatrogenic Ureteral Injury during Translumbar Embolization of a Type II Endoleak. AB - The persistence of flow within an aneurysm sac remains the so-called Achilles heel of endovascular aortic aneurysm repair. The management of type II endoleaks remains controversial, although aneurysm sac expansion is an accepted indication for intervention. The present case describes a patient with a type II endoleak following endovascular repair of an abdominal aortic aneurysm treated by translumbar embolization. The procedure was complicated by iatrogenic injury to the left ureter and nontarget embolization resulting in acute ureteral obstruction. PMID- 21326484 TI - Embolization of pulmonary arteriovenous malformations. PMID- 21326485 TI - Filter migration to right heart. PMID- 21326486 TI - Diagnostic radiology for interventional radiologists. PMID- 21326487 TI - Use of the Interlock Fibered IDC Occlusion System in Clinical Practice. AB - The use of coils in embolotherapy has been extensively described. Many different types of coils are commercially available for use. In 2006, the Interlock Fibered IDC Occlusion System (Boston Scientific, Natick, MA) was introduced to clinical practice. In this article, embolotherapy with coils in general is discussed, and the use of the Interlock coils in particular is described in different clinical scenarios. PMID- 21326488 TI - Plaque Excision in Management of Lower Extremity Peripheral Arterial Disease with the SilverHawk Atherectomy Catheter. AB - Atherectomy, the removal of plaque from diseased vessels, is theoretically appealing with respect to various procedures used for revascularization of lower extremity vessels. Instead of damaging the native vessel by pushing aside plaque with a balloon or stent, the plaque is removed. Many atherectomy devices have been designed in attempts to achieve this goal. The SilverHawk device is the latest percutaneous device employing this treatment strategy. We discuss patient selection, technical considerations, and strategies for both above and below the knee revascularization, as well as pitfalls in each location based on our experience with over 200 patients. PMID- 21326489 TI - Venous thromboembolic disease: the use of "optional" inferior vena cava filters. AB - Approximately 140,000 to 200,000 patients die as a result of pulmonary embolism in the United States each year. If the diagnosis is made and therapy initiated, the mortality rate drops to 8%. Vena cava filters play a role in the management of patients with thromboembolic disease. Deployment of "optional" filters is changing practice paradigms. PMID- 21326490 TI - Expanding use of embolic protection devices. AB - Embolic protection devices were initially developed for the treatment of saphenous vein aorto-coronary bypass graft stenosis due to the significant risk of atheroembolism, and their use is well accepted. The use of these devices for carotid arterial interventions is also well accepted due to the significant consequences of embolization in the cerebral circulation. The use of these devices is extending to other vascular beds to include the renal arteries and lower extremities. We review the basic principles of these devices and their uses in various vascular beds based on our own experience as well as that in the literature. PMID- 21326491 TI - Ultrasound-Enhanced Thrombolysis: EKOS EndoWave Infusion Catheter System. AB - The purpose of the EKOS EndoWave Infusion Catheter System is to enhance catheter directed thrombolysis by accelerating the fibrinolytic process with the application of ultrasound. Improving the efficiency of the thrombolytic process reduces the treatment time and total lytic dose delivered, thereby lowering the overall cost of therapy and the risk of an associated bleeding complication. PMID- 21326492 TI - Neurointervention for the peripheral radiologist: tips and tricks. AB - Interventional neuroradiology is a high-risk, high-yield field with small margins for catastrophic errors. A wider range of complex vascular disorders of the brain, spine, head, and neck are now treatable with new endovascular technology. This article describes new tools and techniques in this ever-expanding field. PMID- 21326493 TI - Radioembolization of yttrium-90 microspheres for hepatic malignancy. AB - The liver represents a frequent site for primary and secondary neoplasia. Cytoreductive techniques positively influence the outcome of disease progression in these patients. Transhepatic arterial radioembolotherapy utilizing yttrium-90 microspheres represents a recently available in situ therapy that has shown encouraging results in the treatment of these patients. Harnessing the skills of many different specialties, such as interventional radiology, surgical oncology, medical oncology, nuclear medicine, radiation oncology, medical physics, and radiation safety, brings invaluable expertise to the treatment process for a safe and effective radioembolization treatment program. PMID- 21326494 TI - Novel devices for wound closure in interventional radiology. AB - Wound closure issues are not as common in the field of interventional radiology when compared with other surgical fields, such as plastic surgery or dermatology. A common exception to this rule involves the placement and removal of chest wall vascular ports. This article reviews newer wound closure devices such as skin adhesives and closure film. PMID- 21326495 TI - Carbon dioxide angiography. PMID- 21326496 TI - Iatrogenic post-catheterization pseudoaneurysm. PMID- 21326497 TI - Macroergonomics. PMID- 21326498 TI - Treatment of hemodialysis graft pseudoaneurysms with stent grafts: institutional experience and review of the literature. AB - Hemodialysis access grafts are an important component of the treatment of patients with renal failure. Because access sites are limited, maximizing graft lifespan is of major importance to dialysis patients. Pseudoaneurysm formation is a rare, but important complication potentially limiting the longevity of dialysis grafts. With rapidly advancing technology, placement of stent grafts in patients with end-stage renal disease is an important step in prolonging the life of the graft. We conducted a review of the literature regarding stent-graft use for hemodialysis access. In addition, we looked at our experience utilizing the Viabahn((r)) (W. L. Gore & Associates, Newark, DE) stent graft in pseudoaneurysm repair. Our patients achieved primary patency of their grafts for 1, 5, and 9 months, respectively. No complications related to stent-graft implementation have been encountered in six stent-graft implants over the course of 29 months. PMID- 21326499 TI - Dialysis access in europe and north america: are we on the same path? AB - Large differences in dialysis access exist between Europe, Canada, and the United States, even after adjustment for patient characteristics. Vascular access care is characterized by similar issues, but with a different magnitude. Obesity, type 2 diabetes, and peripheral vascular disease, independent predictors of central venous catheter use, are growing problems globally, which could lead to more difficulties in native arteriovenous fistula placement and survival. Creation of dedicated dialysis access teams, including a vascular access coordinator, is a fundamental step in improving vascular access care; however, it might not be sufficient. The possibility that factors other than patient characteristics and surgical skills are important in determining outcomes is likely; it might explain apparent contradictions of end-stage renal disease (ESRD) practices (kidney transplant, peritoneal dialysis, patterns of vascular access use in hemodialysis), where some countries excel in one area and score poorly in another. We are on the same path, but we have a long way to go. PMID- 21326500 TI - A review of evolving dialysis catheter technologies. AB - Dialysis catheters continue to play a vital role in the delivery of hemodialysis to patients for both temporary vascular access, serving as a bridge to permanent access, and for long-term access for patients with end-stage renal disease (ESRD). During the past decade, there has been an emergence of technological advancements in the design of dialysis catheters in an attempt to reduce catheter malfunction, decrease infection rates, and improve their long-term efficiency. New improvements in catheter design are aimed at translating into improved catheter performance. This review article summarizes some of the novel catheter designs developed within the last decade. PMID- 21326501 TI - Central venous obstruction management. AB - A major challenge in the management of hemodialysis patients is central venous stenosis and obstruction. Placement of central venous catheters has been shown to result in a high incidence of central venous stenosis or obstruction. There has been extensive literature on the treatment of this important and prevalent problem. Treatment options include percutaneous balloon angioplasty and bare metal stents. Unfortunately, all the available treatment options have variable rates of patency, requiring repeated intervention. More recently, covered stents have been mentioned in the literature for the treatment of central venous stenosis and obstruction. There is very little data to date, and further randomized controlled trials will be needed to compare the efficacy of percutaneous balloon angioplasty, bare metal stents, and covered stents. It appears prevention of this difficult problem is paramount, by limiting use of central venous catheters. PMID- 21326502 TI - The KDOQI 2006 Vascular Access Update and Fistula First Program Synopsis. AB - The optimal care of patients with end stage renal disease on hemodialysis involves a multidisciplinary approach involving nephrologists, vascular surgeons, transplant surgeons and interventional radiologists. A collaborative effort by these groups of physicians was used to create the KDOQI guidelines and the Fistula First program, which have served as the template for the management of dialysis patients. This article will briefly review the recent updates for vascular access in the KDOQI guidelines and summarize the highlights of the Fistula First program. PMID- 21326503 TI - Distal revascularization and interval ligation: a primer for the vascular and interventional radiologist. AB - Dialysis-associated steal syndrome is a clinically significant complication associated with the creation of dialysis grafts or fistulae. The distal revascularization and interval ligation (DRIL) procedure is a surgical procedure, which has been used to treat patients with hand ischemia secondary to arterial "steal" from dialysis accesses. This article will review the dialysis-associated steal syndrome and the history, anatomy, and clinical results of the DRIL procedure. PMID- 21326504 TI - Surveillance of hemodialysis vascular access. AB - A mature, functional arteriovenous (AV) access is the lifeline for a hemodialysis (HD) patient as it provides sufficient enough blood flow for adequate dialysis. As the chronic kidney disease (CKD) and end-stage renal disease (ESRD) population is expanding, and because of the well-recognized hazardous complications of dialysis catheters, the projected placement and use of AV accesses for HD is on the rise. Although a superior access than catheters, AV accesses are not without complications. The primary complication that causes AV accesses to fail is stenosis with subsequent thrombosis. Surveying for stenosis can be performed in a variety of ways. Clinical monitoring, measuring flow, determining pressure, and measuring recirculation are all methods that show promise. In addition, stenosis can be directly visualized, through noninvasive techniques such as color duplex imaging, or through minimally invasive venography. Each method of screening has its advantages and disadvantages, and several studies exist which attempt to answer the question of which test is the most useful. Ultimately, to maintain the functionality of the access for the HD patient, a team approach becomes imperative. The collaboration and cooperation of the patient, nephrologist, dialysis nurse and technician, vascular access coordinator, interventionalist, and vascular surgeon is necessary to preserve this lifeline. PMID- 21326505 TI - Catheter-related bloodstream infections. AB - Tunneled, cuffed, double-lumen catheters are commonly used for long-term venous access in hemodialysis patients. Complications of these catheters, including catheter-related infection, are a major cause of morbidity and resource utilization in the hemodialysis population. Treatment of catheter-related bloodstream infections includes the use of antibiotics and evaluation of the need for catheter removal or exchange. Measures to prevent catheter-related infections include use of an aseptic technique and antiseptic cleaning solution, elimination of Staphylococcus aureus nasal carriage, topical exit site application of antibiotics, use of antibiotic lock solutions, and use of catheters and cuffs coated or impregnated with antimicrobial or antiseptic agents. This review article will provide an update on the prevalence, diagnosis, treatment, and prevention of catheter-related infections in the hemodialysis population. PMID- 21326506 TI - Optimizing arteriovenous fistula maturation. AB - Autogenous arteriovenous fistulas are the preferred vascular access in patients undergoing hemodialysis. Increasing fistula prevalence depends on increasing fistula placement, improving the maturation of fistula that fail to mature and enhancing the long-term patency of mature fistula. Percutaneous methods for optimizing arteriovenous fistula maturation will be reviewed. PMID- 21326507 TI - Renal ostial angioplasty and stenting. Part 2: pitfalls and complications. PMID- 21326508 TI - Compartment syndrome following external iliac artery stenting and lower extremity thrombolysis. PMID- 21326509 TI - On Chaos: Codes and the RSNA. PMID- 21326510 TI - Which Arteries Are Expendable? The Practice and Pitfalls of Embolization throughout the Body. AB - This article outlines general concepts of, and strategies for, therapeutic embolization throughout the body, touching on all major arterial distributions. Clinical scenarios that allow or prevent safe embolization of vessels are presented. Specific agents are recommended where appropriate, as are alternate approaches when embolization is not an option. Pre-embolization precautions and adjunctive measures are described in high-risk areas. PMID- 21326511 TI - An overview of embolic agents. AB - Therapeutic embolization is a common procedure in interventional radiology. A wide variety of agents are available, and each has its own place and use. Additionally, many new agents have appeared on the market in the past several years. The aim of this review article is to give a brief description of available agents, guide appropriate selection, and familiarize the reader regarding appropriate use and limitations. PMID- 21326513 TI - Embolotherapy in the management of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) ranks fifth in frequency of cancers worldwide. The incidence of HCC in the United States is rising, primarily due to the number of patients who were infected by hepatitis in the 1960s and 1970s coupled with the rising migrant population from Asia, where hepatitis is widely prevalent. Up to 80% of the patients present with multicentric HCC and advanced liver disease or comorbidities that restrict the option of resection or liver transplantation. The dual blood supply (arterial and portal) to the liver with predominantly arterial supply to the tumor has made embolotherapy a cornerstone in the management of inoperable HCC. The techniques have become refined not only due to the development of microcatheter angiographic capabilities, but also in the ability to deliver a wide variety of therapeutic agents to these tumors. This article reviews the fundamental principles of bland embolization, chemoembolization, and radioembolization in the management of HCC. PMID- 21326512 TI - Imaging and percutaneous treatment of vascular anomalies. AB - Vascular anomalies are an extensive group of malformations of the arterial, venous, and lymphatic systems, either in isolation or, more often, in combination. Although mostly congenital, they can occasionally be acquired as well. They present a challenge both for workup and therapy. This article attempts to describe some of their main anomalies, their workup, and their therapies, with the goal of increasing the comfort level of endovascular therapists. PMID- 21326514 TI - Preoperative portal venous and hepatic arterial embolization of tumor. AB - Although the goal of embolization is usually to create therapeutic ischemia or hemostasis without surgery, the rationale for preoperative embolotherapy is different in several respects. First, the aim is to prepare patients for definitive surgical resection rather than cure or palliation, and, thus, the goals and expectations are limited and defined by close communication between the interventionalist and the surgeon. Second, when considering segmental resection, the normal liver should be protected from procedural damage. Third, the search for extrahepatic disease is crucial for these patients because resection is typically abandoned in favor of alternative therapies for patients with systemic disease. Finally, intraoperative ultrasound should always be considered to survey the future liver remnant for unsuspected small tumors and allow ablation of these lesions to maximize the success of partial hepatectomy. This article describes preoperative hepatic arterial and portal venous embolization in patients with or without cirrhosis complicated by tumors judged eligible for surgical resection or orthotopic liver transplantation (OLT). Each type of embolization will be reviewed in terms of indications and contraindications, technique, and complications. Finally, the outcomes will be evaluated in terms of morbidity, mortality, and tumor recurrence rates. PMID- 21326515 TI - Uterine artery embolization: a safe and effective, minimally invasive, uterine sparing treatment option for symptomatic fibroids. AB - Leiomyomas (or fibroids) are exceedingly common lesions. The indications to initiate treatment are based on the symptoms that can arise from their presence. In general, medical therapy should be considered the first line of treatment. Currently, the treatment of fibroids is in evolution. Since uterine artery embolization (UAE) was first described by Ravina et al in 1995, it has been shown to be a safe, efficacious, and cost-effective alternative to traditional surgical options, with data from long-term studies now available. Appropriate patient evaluation and selection are vital; the ideal candidate is one who is premenopausal, has symptomatic fibroids resistant to medical therapy, no longer desires fertility, and wishes to maintain her uterus. Uterine artery embolization is primarily an angiographic procedure, but periprocedural clinical management is critical for patient satisfaction. This article discusses the various embolic materials that are commonly used and available for UAE; understanding the technical nuances is critical for long-term success. PMID- 21326516 TI - Gonadal vein embolization: treatment of varicocele and pelvic congestion syndrome. AB - Therapeutic embolization of the gonadal veins is performed on male and female patients for different clinical situations using similar techniques. The testicular varicocele is a common clinical problem associated with pain and reduced fertility rates. In women, chronic pelvic pain can be attributed to pelvic congestion syndrome, which is said to result from retrograde flow in incompetent ovarian veins. Both of these clinical problems respond well to gonadal vein embolization. In this article, we review the clinical evaluation, diagnostic workup, and technical aspects of percutaneous intervention of gonadal vein embolization. The supporting literature is also reviewed. PMID- 21326517 TI - Visceral trauma: principles of management and role of embolotherapy. AB - Interventional radiology for the treatment of traumatic visceral hemorrhage has emerged as an important adjunct to modern trauma care. This article outlines the general surgical concepts of the acute care of trauma patients as a guideline for catheter-based therapy. Specific considerations are presented for embolizing visceral injuries in the liver, spleen, and kidney. Expected outcomes and follow up are reviewed. PMID- 21326518 TI - Transcatheter embolization in the treatment of hemorrhage in pelvic trauma. AB - Massive hemorrhage related to pelvic trauma is relatively rare, but when it occurs rapid triage to therapeutic intervention is essential for survival. Traditional surgical repairs had limited success. Anatomic and clinical studies indicate that arterial hemorrhage is often identified in patients with hemodynamic instability that do not respond to initial resuscitation. Transcatheter angiography directly identifies arterial injury, and embolization can control retroperitoneal arterial hemorrhage. Stent-graft technology extends the scope of interventional therapy to include rapid and definitive repair of nonexpendable artery injury. Successful management requires coordination between multiple services and the continuation of resuscitative procedures in the angiography suite. PMID- 21326519 TI - Embolization in the head and neck. AB - In this article, we review current practices in therapeutic embolization of the head and neck. Major applications including vascular malformations, highly vascular tumors, trauma, and other sources of hemorrhage are discussed. We emphasize the importance of a thorough knowledge of head and neck vascular anatomy, especially of potential connections to critical territories not intended for embolization. The choice of embolic agent and its effect on safety and efficacy of treatment are presented. PMID- 21326521 TI - Absolute alcohol embolization of sporadic angiomyolipoma. AB - Angiomyolipoma is a benign hamartoma. Seventy percent of angiomyolipomas occur sporadically in the general population and the remainder are associated with a syndrome. Of patients with tuberous sclerosis, 60 to 80% have an angiomyolipoma. Sporadic angiomyolipomas tend to be single and occur in an older age group. In tuberous sclerosis, the lesions are usually bilateral and multiple. Therapy is indicated when there are symptoms or when the lesion is greater than 4 cm. Criteria for further embolization include growth of the lesion by 2 cm at annual follow-up computed tomography and presentation with acute hemorrhage. We describe a case of a sporadic asymptomatic angiomyolipoma treated with absolute alcohol embolization. PMID- 21326520 TI - Bronchial artery embolization for hemoptysis. AB - Bronchial artery bleeding is the most common cause of life-threatening hemoptysis. The most common underlying etiologies include tuberculosis, bronchiectasis, aspergillosis, and cystic fibrosis. Bronchial artery embolization is an important treatment for significant hemoptysis, given its high early success rate and relatively low risk compared with alternative medical and surgical treatments. In this article, the relevant anatomy and pathophysiology leading to bronchial artery bleeding is discussed, including the roles of parenchymal lung diseases and of collateral and aberrant vessels. The indications for treatment, success rate, and complication rate for bronchial artery embolization are reviewed. Preprocedure clinical stabilization and evaluation, including the roles of radiographs, bronchoscopy, and computed tomography examination are evaluated. Details of technique, including the published variety of approaches, and an emphasis on avoidance of nontarget embolization of important mediastinal structures and of the anterior spinal artery are discussed. PMID- 21326522 TI - CTA Runoff. PMID- 21326523 TI - Embolization iatrogenic hemorrhage after paracentesis. PMID- 21326524 TI - Making Seminars Better through Popular Literature. PMID- 21326525 TI - Complications after endovascular aneurysm repair. AB - Endovascular aneurysm repair (EVAR) has become an established technique for the treatment of many infrarenal aortic aneurysms. Although EVAR is obviously less invasive than open surgical repair, it is not free of complications. These can potentially result in severe morbidity or even mortality, stressing the need for an early detection and subsequent treatment. In this review article, the pathophysiology, diagnosis, and treatment of the most common complications of EVAR, with the exception of endoleaks, are described. PMID- 21326526 TI - Imaging Surveillance following Endovascular Aneurysm Repair. AB - Endoleaks are unique complications of endovascular aneurysm repair (EVAR) that necessitate lifelong imaging surveillance for the patient. Several imaging modalities may be used to monitor the patient for endoleaks and other complications related to the stent graft. At present, computed tomographic angiography remains the gold standard for the detection of endoleaks. Other modalities that can be used to detect endoleaks include magnetic resonance, ultrasonography, nuclear medicine techniques, and pressure monitoring. In addition, follow-up imaging with digital subtraction angiography is important for endoleak classification and to guide decisions regarding therapy. In this article, we review the classification of endoleaks and discuss the different imaging strategies available for post-EVAR surveillance. PMID- 21326527 TI - Endovascular repair of the thoracic aorta. AB - The emergence of endovascular repair of the thoracic aorta (TEVAR) quickly followed the development of technology for the exclusion of infrarenal abdominal aortic aneurysms. Stent grafts comprised of metal struts covered with fabric made of Dacron/polyester or polytetrafluoroethylene were developed for the purpose of achieving an adequate seal at the proximal and distal aspects of thoracic aneurysms, thus excluding sac flow. The recognition of the decreased morbidity of this approach compared with open repair was readily apparent, as it avoided left thoracotomy, aortic cross-clamping, and left heart bypass. Since then, TEVAR is increasingly being used for other aortic pathologies such as complicated type B dissection, traumatic aortic transection, and aneurysmal disease extending into the arch or visceral segment, requiring debranching procedures. PMID- 21326528 TI - Emergent aortic endovascular stent grafts for ruptured aortoiliac aneurysms. AB - A ruptured abdominal aortic aneurysm is an emergency anywhere in the world. Physician expertise and clinical status of the patient drive the treatment modalities in the majority of cases. Independent of treatment choice, the goal of therapy is to stabilize the patient as quickly as possible in a manner that establishes maximum survival and minimum morbidity and provides a long-lasting, durable result. Endovascular aortic repair has become an acceptable alternative to open surgical repair in a subset of patients presenting with ruptured aortoiliac aneurysms. Patient selection, physician preference, institutional experience, and availability of appropriate equipment make up a majority of factors influencing treatment choices. Once the decision has been made to treat the patient via endovascular techniques, then experience, planning, and the ability to improvise solutions "on the fly" become vital components to the success of the procedure. Two separate cases, requiring intraprocedural improvisation, are presented followed by a review of the literature. PMID- 21326529 TI - Management of Endoleaks following Endovascular Aneurysm Repair. AB - Endovascular aneurysm repair (EVAR) has emerged as a viable alternative to open repair for abdominal aortic aneurysms. Endoleaks are a complication unique to EVAR and can occur in up to 25% of patients. In this article, the management of endoleaks following EVAR will be discussed. PMID- 21326530 TI - Devices used for endovascular aneurysm repair: past, present, and future. AB - Since its first implementation in patients in 1991, endovascular aneurysm repair for abdominal aortic aneurysms has gained wide acceptance and availability. This development has been fueled in great part by advances in stent-graft design and by a variety of devices for various anatomic features. This commentary will summarize some of these endograft developments and indicate the path forward for novel endoprostheses. PMID- 21326531 TI - Preprocedural planning for endovascular stent-graft placement. AB - Endovascular stent grafts have become a viable treatment for aortic thoracic and abdominal aneurysms in both elective and emergent situations. Computed tomographic (CT) angiography is the primary tool for determining eligibility for this procedure. This article discuses the preprocedural evaluation of an endovascular stent candidate. Evaluation begins with identification of the aneurysm pathology and its relationship to treatment efficacy. The radiologist must evaluate the aneurysm geometry for compatibility with stent hardware. Aneurysm features that suggest a contraindication must be recognized. Procedures that involve a combination of endovascular stenting and surgical revascularization are discussed so that the reader understands the limits of stent eligibility. Vascular access for stent placement must also be evaluated for the ability to accommodate stent delivery. The radiologist also must be familiar with CT imaging protocols and alternative methods of imaging that can evaluate stent feasibility. The utility of three-dimensional processing is discussed. PMID- 21326532 TI - Endovascular repair of aortic disease: a venture capital perspective. AB - Endovascular devices for the treatment of abdominal and thoracic aortic disease are poised to become the next $1 billion medical device market. A shift from open repair to endovascular repair, advances in technology, screening initiatives, and new indications are driving this growth. Although billion-dollar medical device markets are rare, this field is fraught with risk and uncertainty for startups and their venture capital investors. Technological hurdles, daunting clinical and regulatory timelines, market adoption issues, and entrenched competitors pose significant barriers to successful new venture creation. In fact, the number of aortic endografts that have failed to reach commercialization or have been pulled from the market exceeds the number of Food and Drug Administration-approved endografts in the United States. This article will shed some light on the venture capital mind-set and decision-making paradigm in the context of aortic disease. PMID- 21326533 TI - Current status of percutaneous endografting. AB - Significant advances in the technology and techniques in the field of endovascular thoracic and abdominal aortic aneurysm repair have been made since its introduction in the early 1990s. The low incidence of periprocedural complications combined with comparable early outcomes to open surgery have made the endovascular treatment option the first choice of therapy in patients whose aortic anatomy is suitable for endografting. All currently available endografts for aortic aneurysm repair have delivery systems at least 21-French in outer diameter and have traditionally been inserted via surgical cutdowns. More recently, attempts to validate a totally percutaneous approach to the placement of these devices have been introduced by utilizing suture-mediated closure devices. This article will provide an overview of suture-mediated closure devices, our experience with the off-label application of suture-mediated devices for percutaneous closure of arterial access sites during endovascular aneurysm repair, and a review of the literature on this topic. PMID- 21326534 TI - Renal ostial angioplasty and stenting. Part 1: the routine procedure. PMID- 21326535 TI - "Ex vacuo" pneumothorax. PMID- 21326536 TI - To sleep or not to sleep. PMID- 21326537 TI - Office evaluation of leg pain. AB - A successful office evaluation of a patient who presents with leg pain encompasses several factors and treatment decisions. Of course, the first goal of the evaluation is to determine the etiology of the leg pain. Following this, a complete history and physical examination is mandatory. Frequently at this point, additional imaging studies will become necessary. It is only at this point can various treatment options be explored. Clearly, the office evaluation of a patient with leg pain needs to be comprehensive. In addition, the initial evaluation establishes a relationship with the patient, one that will need to continue for some time even if a successful intervention is performed. PMID- 21326538 TI - The evaluation of lower-extremity ulcers. AB - Lower-limb ulceration is prevalent in Western countries. There are many different types of ulcers with several causes. The most prevalent are those due to vascular disease, of which venous is the most common, accounting for over two-thirds of all types of ulcers. There are also many other causes for ulceration such as malignancy, infections, and skin, drug-induced, and autoimmune diseases. The ulcers have different characteristics, which may be differentiated by the history and clinical examination of the patients. However, objective documentation for the ulcer etiology is necessary prior to instigating treatment. The methods for diagnosing the causes for the ulcers include plethysmography, ultrasound, angiography, computer tomography, magnetic resonance imaging, and skin biopsy. All these tests should be used in conjunction with the clinical presentation of the patient. They should be performed in a cost-effective manner to avoid delays in diagnosis and reduce costs and usage of resources. PMID- 21326539 TI - Endovascular management of aortoiliac occlusive disease. AB - Patients with aortoiliac occlusive disease (AIOD) may be asymptomatic or may have intermittent claudication or critical limb ischemia. Treatment options for AIOD include management of risk factors, endovascular intervention, and/or surgical revascularization. PMID- 21326540 TI - Endovascular treatment of femoral-popliteal disease. AB - Available and improved options for the treatment of femoral-popliteal disease have increased over the last decade. Even though most patients suffering from claudication due to femoral-popliteal disease are treated with aggressive medical and noninvasive methods, patients with limb-threatening disease and severely lifestyle-limiting symptoms are treated with invasive treatments, which include endovascular treatment options. Unfortunately, the unique forces involved in this vascular segment have challenged the long-term patency and clinical effectiveness of these treatments. The purpose of this brief review is to discuss treatment strategies and options for patients with femoral-popliteal disease. Included in this discussion will be the review of data from recent published studies and late breaking trials as it pertains to certain treatment strategies. PMID- 21326541 TI - Tibial intervention for critical limb ischemia. AB - Diagnosis and treatment of critical limb ischemia (CLI) is increasingly important as the average age of the world population and the incidence of diabetes and metabolic syndrome increases. Fortunately, most patients will not progress to this stage of peripheral arterial disease, yet if left untreated, there is a high risk of future cardiovascular events. At the point of ischemic rest pain or tissue loss, there are significant implications for morbidity and mortality. There is a high prevalence of multisegment occlusive disease in the CLI patient with the infrapopliteal vessels frequently involved. Revascularization of the affected limb is of utmost importance as the prospects of wound healing and relief of ischemic rest pain are poor without reestablishing continuous flow to the distal extremity. With the advent of endovascular devices designed to treat this vexing problem, the ability to successfully treat this difficult patient population with less procedural morbidity has been greatly enhanced. PMID- 21326542 TI - Carotid artery stenting: what you need to know. AB - Carotid stenting has become an accepted alternative in patients with carotid stenosis. The purpose of this article is to review the relevant trials, describe the different devices available for stenting, the devices for cerebral protection, as well as describe techniques and tricks for successful carotid artery stenting. Understanding how to appropriately preoperatively evaluate patients and intra- and postoperative procedures, carotid artery stenting can be a safe procedure. PMID- 21326544 TI - Chronic mesenteric ischemia: diagnosis and treatment. AB - Chronic mesenteric ischemia is a rare condition, generally characterized by postprandial abdominal pain. Although chronic mesenteric ischemia accounts for only a small percentage of all mesenteric ischemic events, it can have significant clinical consequences. There are multiple etiologies; however, the most common cause is atherosclerosis. The diagnosis of chronic mesenteric ischemia requires a high clinical index of suspicion. An imaging study can confirm the presence of a stenosis or occlusion involving the mesenteric vessels in patients who are suspected of having chronic mesenteric ischemia. The diagnosis is usually late in its course due to the slow progression of disease and the abundance of mesenteric collaterals. Because of the extensive collateral network, usually at least two of the three visceral vessels need to be affected before patients develop symptoms. Treatment is necessary to avoid progression to bowel ischemia and infarction. Once a diagnosis of chronic mesenteric ischemia is made, treatment options include open surgical revascularization and endovascular revascularization. PMID- 21326545 TI - Embolization agents-which one should be used when? Part 1: large-vessel embolization. PMID- 21326543 TI - The current state of endovascular therapy in the evaluation and management of renovascular disease. AB - Hypertension is the most common reason for physician office visits among nonpregnant adults in the United States; up to one-third of Americans over the age of 18 have been diagnosed with hypertension. Patients with physiologically significant renal artery stenosis often go unnoticed because hypertension can often be well controlled with antihypertensive medications. As a result, screening for renovascular causes of hypertension is rarely done. However, the likelihood of renovascular disease increases in patients with acute, severe, or refractory hypertension and should be explored in patients who fall into these categories. Renovascular disease is a crucial consideration in the management of hypertension due to its increasing incidence and its potential for reversibility. Although renovascular disease accounts for less than 1% of patients with mild hypertension, it is estimated that between 10 and 45% of white patients with severe or malignant hypertension have renal artery stenosis (RAS). In this population, diagnosing and treating RAS can have a profound and long-lasting effect on the treatment of hypertension. PMID- 21326546 TI - Hemorrhage after transjugular liver biopsy requiring embolization. PMID- 21326547 TI - Babe ruth and interventional radiology. PMID- 21326548 TI - Liver anatomy: microcirculation of the liver. AB - Comprehension of the structural and functional characteristics of the hepatic microcirculation can help improve the design, planning, and practice of imaging guided treatment for hepatic tumors and for portal vein embolization (PVE). The hepatic microcirculation derives dual blood supply from the portal vein and the hepatic artery. The terminal portal venules directly connect to the hepatic sinusoids, but the terminal hepatic arterioles connect to arterioportal communications before entering the sinusoids: the peribiliary plexus, the terminal arteriosinus twigs, the vasa vasorum on the portal vein, and the direct arterioportal anastomosis. These communications play important roles in the balance of blood perfusion to the liver parenchyma and in controlling the blood supply to hepatic tumors and the anticipated remnant liver (in cases of PVE). At the microcirculatory level, various embolic agents present different distribution patterns. To further our understanding, iodized oil has been found to pass into the portal vein after hepatic arterial administration through the peribiliary plexus and subsequently traverses the sinusoids to enter the lungs and then the systemic circulation. Ultimately, a thorough knowledge of the host environment at the microcirculatory level is essential in developing strategies for both tumor treatment and for inducing liver regeneration. PMID- 21326549 TI - Portal vein normal anatomy and variants: implication for liver surgery and portal vein embolization. AB - The normal anatomy of the portal vein is defined as a division of the main portal vein into two branches-the left (supplying segments II, III, and IV) and right portal veins; the right dividing secondarily into two branches-the anterior (supplying segments V and VIII) and the posterior (supplying segments VI and VII) portal veins. Variants are frequent and account for 20 to 35% of the population. The most frequent variants are portal trifurcation with division of the main portal vein into the left, right anterior, and posterior branches, and the early origin of the right posterior branch directly from the portal vein. The presence of portal vein variants increases the risk of bile duct hilar anatomical variation. These variants must be diagnosed before complex hepatectomy, split or living donor transplantation, and before complex interventional procedures such as portal vein embolization. The purpose of this article is to review normal and variant portal venous anatomy and their implications for liver surgery and preoperative portal vein embolization. PMID- 21326551 TI - Standardized liver volumetry for portal vein embolization. AB - Major and extended hepatic resections are being performed with increasing frequency as morbidity and mortality rates after major hepatectomies have declined and definitions of resectability have expanded for primary and metastatic hepatic malignancies. Systematic assessment of the anticipated functional remnant liver is essential before major hepatic resection to avoid postoperative hepatic insufficiency and its attendant sequelae. The volume of the future liver remnant (FLR) correlates with FLR function and postoperative outcome. This article describes the rationale for FLR measurement, methods of measuring FLR volume, and standardization to the total estimated liver volume. The indications for portal vein embolization based on standardized liver volumetry are summarized. PMID- 21326550 TI - Liver regeneration and the atrophy-hypertrophy complex. AB - The atrophy-hypertrophy complex (AHC) refers to the controlled restoration of liver parenchyma following hepatocyte loss. Different types of injury (e.g., toxins, ischemia/reperfusion, biliary obstruction, and resection) elicit the same hypertrophic response in the remnant liver. The AHC involves complex anatomical, histological, cellular, and molecular processes. The signals responsible for these processes are both intrinsic and extrinsic to the liver and involve both physical and molecular events. In patients in whom resection of large liver malignancies would result in an inadequate functional liver remnant, preoperative portal vein embolization may increase the remnant liver sufficiently to permit aggressive resections. Through continued basic science research, the cellular mechanisms of the AHC may be maximized to permit curative resections in patients with potentially prohibitive liver function. PMID- 21326552 TI - Strategies for resection using portal vein embolization: hepatocellular carcinoma and hilar cholangiocarcinoma. AB - Preoperative portal vein embolization (PVE) is increasingly used to optimize the volume and function of the future liver remnant (FLR) and to reduce the risk for complications of major hepatectomy for hepatocellular carcinoma (HCC) or hilar cholangiocarcinoma (CCA). In patients with HCC who are candidates for extended hepatectomy and in patients with HCC and well-compensated cirrhosis who are being considered for major hepatectomy, FLR volumetry is routinely performed, and PVE is employed in selected cases to optimize the volume and function of the FLR prior to surgery. Similarly, in patients with hilar CCA who are candidates for extended hepatectomy, careful preoperative preparation using biliary drainage, FLR volumetry, and PVE optimizes the volume and function of the FLR prior to surgery. Appropriate use of PVE has led to improved postoperative outcomes after major hepatectomy for these diseases and oncological outcomes similar to those in patients who undergo resection without PVE. Specific indications for PVE are being clarified. FLR volumetry is necessary for proper selection of patients for PVE. Analysis of the degree of hypertrophy of the FLR after PVE (a dynamic test of liver regeneration) complements analysis of the pre-PVE FLR volume (a static test). Together, FLR degree of hypertrophy and FLR volume are the best predictors of outcome after major hepatectomy in an individual patient, regardless of the degree of underlying liver disease. This article synthesizes the literature on the approach to patients with HCC and CCA who are candidates for major hepatectomy. The rationale and indications for FLR volumetry and PVE and outcomes following PVE and major hepatectomy for HCC and CCA are discussed. PMID- 21326554 TI - Percutaneous transhepatic portal vein embolization: rationale, technique, and outcomes. AB - Portal vein embolization (PVE) is used to induce preoperative liver hypertrophy in patients with anticipated marginal future liver remnant (FLR) volumes who are otherwise potential candidates for resection. PVE can be performed utilizing the transhepatic contralateral and ipsilateral approaches. The transhepatic contralateral approach is the most commonly used technique worldwide, largely owing to its technical ease. However, the contralateral approach risks injuring the FLR, thereby compromising the planned surgical resection. The transhepatic ipsilateral approach offers a potentially safer alternative because the complications associated with this approach affect only the hepatic lobe that will be resected and are usually not serious enough to preclude surgery. This article discusses PVE using the transhepatic ipsilateral and contralateral approaches, including patient selection criteria, anatomical and technical considerations, and patient complications and outcomes. PMID- 21326553 TI - Strategies for resection using portal vein embolization: metastatic liver cancer. AB - The oncological landscape is constantly changing with the development of new curatively intended therapeutic strategies. More and more, liver metastases are amenable to resection following the progress achieved as a result of new oncological concepts (i.e., treat detectable disease with surgery and ablative therapies and treat the remaining nondetectable disease with efficient chemotherapy) as well as improved chemotherapeutic and ablation techniques. One of the major limitations to extending the indications for liver resection is the volume of the future remnant liver (FRL). To overcome these limitations, portal vein embolization (PVE) has played a key role in obtaining preoperative hypertrophy of the FRL and thus has reduced postoperative morbidity and mortality. Interestingly, thermal ablation of multiple bilateral liver metastases makes it difficult to predict the volume of parenchyma scheduled for ablation. Furthermore, prolonged chemotherapy impairs liver parenchyma function, which has a negative impact on liver hypertrophy. In the future, both volumetric and functional assessment of the FRL will be used to determine whether PVE is necessary before hepatectomy in individual patients and new strategies (e.g., PVE used alone or combined with other treatments; timing of PVE may vary) will be based on these principles. This article presents various current strategies for the use of PVE in patients with metastatic liver cancer. PMID- 21326555 TI - Sequential transcatheter arterial chemoembolization and portal vein embolization for hepatocellular carcinoma: the university of Tokyo experience. AB - When undertaking portal vein embolization (PVE) in patients with hepatocellular carcinoma (HCC), the following possibilities should be considered: (1) failure to induce hypertrophy of the nonembolized segments due to the underlying liver disease, (2) acceleration of tumor growth by occlusion of the portal venous flow because HCC is a hypervascular tumor fed exclusively by hepatic arterial flow, and (3) poor efficacy of PVE due to the presence of arterioportal shunts frequently observed in cases of liver cirrhosis and HCC. With these in mind, we performed sequential transcatheter arterial chemoembolization (TACE) and PVE in 45 patients with HCC undergoing major liver resection. This double preparation was well tolerated, enhanced the hypertrophy process in the nonembolized segments, and suppressed the tumor growth during the preparation period. Furthermore, PVE also functioned as a preoperative test to select patients for major liver resection. Sequential TACE and PVE is an effective preoperative intervention in patients with HCC scheduled for major liver resection. PMID- 21326556 TI - Sequential arterial and portal vein embolization in patients with cirrhosis and hepatocellular carcinoma: the hospital beaujon experience. AB - When feasible, hepatic resection is the treatment of choice for large hepatocellular carcinoma (HCC). Because HCC is often developed on chronic liver disease, which is known to have limited regeneration capacity, major hepatic resections are often contraindicated. Portal vein embolization (PVE) has been introduced to extend the indications for major hepatic resection and to increase the safety of the surgical procedure. However, hypertrophy after PVE is often less than in normal liver. It has been suggested that preoperative sequential arterial embolization and PVE have a strong anticancer effect and could increase the rate of hypertrophy more than PVE alone. In our experience, sequential arterial embolization and PVE effectively increase the future liver remnant and induce a high rate of complete tumor necrosis. This combined procedure should broaden the indication for major resection in chronic liver disease. PMID- 21326558 TI - Transjugular intrahepatic portosystemic shunt. PMID- 21326557 TI - Chemotherapy and its effect on liver hypertrophy: implications for portal vein embolization and resection. AB - Liver resection remains the gold standard treatment for colorectal liver metastases (CRLM). The improvement of the efficacy of chemotherapy has resulted in an increase of CRLM candidates for curative resection, including a significant proposition of patients initially deemed unresectable. The safety of liver resection has increased by taking advantage of regenerative capacities of the liver with preoperative portal vein embolization (PVE) and two-stage strategies. However, chemotherapy regimens including new drugs such as oxaliplatin and irinotecan may induce pathologic changes of the nontumorous liver parenchyma that could increase the risk of liver resection, and the impact of chemotherapy on the nontumorous liver parenchyma may limit tolerance of these resections. Preoperative portal obstruction, including PVE, which aimed to hypertrophy the future remnant liver, can be adversely affected by this chemotherapy. The aim of this article is to describe the impact of chemotherapy on nontumorous liver parenchyma and to evaluate the impact of chemotherapy on the regenerative capacities of the liver, especially after PVE. PMID- 21326559 TI - Early Mortality after TIPS in a Liver Transplant Recipient. PMID- 21326560 TI - Louisville or bust. PMID- 21326561 TI - Mesenteric vasculature and collateral pathways. AB - The arterial and venous circulation of the bowel is complex and is characterized by marked redundancy of multiple interconnecting branches, which provides a rich blood supply to aid in the digestive process and also serves to protect the bowel from potential ischemia or infarction. As a result of this circulatory pattern, anatomic variants and extensive collateral pathways are common. A thorough knowledge of both the arterial and venous mesenteric circulation, including normal, variant, and collateral anatomy, is necessary for the appropriate evaluation and management of the various disease processes that may affect the vascular supply of the gastrointestinal system. PMID- 21326562 TI - Mesenteric ischemia. AB - Mesenteric ischemia is classified as either acute or chronic. The former is a life-threatening emergency in which a sudden reduction in intestinal blood flow may ultimately result in bowel infarction. The most common causes are arterial embolism, arterial thrombosis, nonocclusive mesenteric ischemia, and mesenteric venous thrombosis. A high index of suspicion, early diagnosis and rapid intervention are necessary so that normal mesenteric perfusion is restored before fatal bowel infarction can occur. Chronic mesenteric ischemia is usually caused by stenotic or occlusive disease involving the proximal segments of the mesenteric arterial supply to the bowel, usually as a result of atherosclerosis. Intestinal angina is the classic presentation, defined as recurrent postprandial abdominal pain that subsides in 1 to 2 hours, with associated weight loss and aversion to food. When combined with the clinical presentation, physical examination, and laboratory data, imaging plays a key role in the diagnosis of either acute or chronic mesenteric ischemia. Recognition of pertinent imaging findings and various treatment options may aid in preventing the serious and possibly fatal sequelae that may occur in cases of mesenteric ischemia. PMID- 21326563 TI - Arterial interventions in gastrointestinal bleeding. AB - The diagnosis and management of gastrointestinal (GI) bleeding are complicated. A multitude of pathologic processes results in GI bleeding, and often, the bleeding is intermittent in nature. Of the available diagnostic tools, angiography has been the gold standard. Management of patients requires a multidisciplinary approach involving gastroenterologists, interventional radiologists, and surgeons. Therapeutic arterial interventions include pharmacologic control with the use of intraarterial vasopressin, embolization with temporary and permanent embolizing materials, and catheter-induced vasospasm. PMID- 21326564 TI - Visceral artery aneurysms: diagnosis and percutaneous management. AB - Visceral artery aneurysms (VAAs) and visceral artery pseudoaneurysms (VAPAs) frequently present as life-threatening emergencies. VAAs are now being diagnosed with increasing frequency, related to routine use of magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound. Both surgery as well as endovascular techniques are well established in their management. Endovascular management includes transarterial deployment of coils, N-butyl cyanoacrylate, or stent grafts. Direct percutaneous embolization of visceral aneurysms and pseudoaneurysms may also be performed. Special attention to aneurysmal etiology congenital, atherosclerotic, infectious, and inflammatory is outlined. Advances in endovascular management with various aneurysmal isolation techniques are discussed. It is concluded that percutaneous endovascular management, now offers a safe and effective alternative to conventional surgery with lower procedural morbidity and mortality and high technical success rates. PMID- 21326565 TI - Visceral arteriography in trauma. AB - The nonoperative management including endovascular treatment of traumatic injuries to most abdominal solid viscera is increasingly gaining acceptance as treatment of choice in a select group of patients. The indications, techniques, and principles of endovascular management of hepatic, splenic, and renal injuries are discussed in this review. PMID- 21326566 TI - Inferior pancreaticoduodenal artery aneurysms in association with celiac stenosis/occlusion. AB - Inferior pancreaticoduodenal artery aneurysms in association with celiac stenosis or occlusion are well described in the literature. These aneurysms are true aneurysms and develop as a result of increased flow through the pancreaticoduodenal arcades in the presence of hemodynamically significant stenosis of the celiac axis or common hepatic artery. Aneurysms may be multiple and rarely associated with aneurysms in other collateral pathways-such as the dorsal pancreatic artery or the arc of Buhler. These aneurysms may be incidentally detected or patients may present with abdominal pain or shock secondary to rupture of the aneurysms. Treatment options include surgical resection and transcatheter embolization; current literature favors the latter option. Treatment of celiac axis stenosis may be recommended in addition to treating the aneurysms; however, no formal guidelines exist on this recommendation. PMID- 21326567 TI - Segmental arterial mediolysis. AB - Segmental arterial mediolysis (SAM) is a nonatherosclerotic, noninflammatory arteriopathy, which is characterized by dissecting aneurysms resulting from lysis of the outer media of the arterial wall. The most common presentation is abdominal pain and hemorrhage in the elderly. Computed tomography (CT) and angiography imaging findings overlap with various vasculitides and include segmental changes of aneurysm and stenosis. A key distinguishing feature is the presence of dissections, the principle morphologic expression of SAM. Differentiation and exclusion of an inflammatory arteritis is crucial in appropriate management, as immunosuppressants generally used for treatment of vasculitis may be ineffective or even worsen the vasculopathy. Although the disease can be self-limiting without treatment or with conservative medical therapy, the acute process carries a 50% mortality rate and may necessitate urgent surgical and/or endovascular therapy. Prompt recognition and diagnosis are therefore of utmost importance in appropriate management of this rare entity. PMID- 21326568 TI - Visceral Artery Interventions in Takayasu's Arteritis. AB - Takayasu's arteritis is an idiopathic chronic inflammatory disease affecting the aorta, its major branches and the pulmonary arteries. It leads to stenosis, occlusion, dilatation, and aneurysm formation in the involved vessels. Visceral arterial involvement occurs in 11 to 68% cases. Steno-obstructive lesions are most commonly seen and are usually symptomatic. Dilative and aneurismal lesions are uncommon and, when present, are usually clinically silent. Renal arteries are most commonly involved (24 to 68%), resulting in renovascular hypertension, whereas mesenteric arterial involvement is seen in 11 to 28% cases and is usually clinically silent. The assessment of disease activity is of utmost importance in its management as revascularization is best performed in the inactive phase. The disease activity can be assessed by clinical, biochemical, or radiological markers. The primary objectives of treatment include the control of disease activity by drug therapy, pharmacologic control of blood pressure (BP), supportive management and revascularization (surgical or endovascular) of the symptomatic ischemic territory. Surgical treatment is challenging due to the diffuse nature of the disease and involvement of adjacent aortic walls. It has a high incidence of anastomotic aneurysm formation (12 to 14%) and graft failure (20 to 40%) over time. Endovascular therapy (usually in the form of balloon angioplasty) has specific technical and procedural issues, but is safe and effective in the control of hypertension with success rates ranging between 80 to 96%. The overall complication rates are low. The cumulative 5-year patency rate for the management of renal artery stenosis is 67%. The use of stents is usually restricted as a bailout to treat obstructive dissection after angioplasty, due to a variety of reasons as their use may adversely affect the long-term outcome of treatment. Angioplasty is less effective in relieving obstruction in the mesenteric arteries and the outcomes are also infrequently reported. PMID- 21326569 TI - Arterial interventions for renovascular hypertension. AB - Renovascular hypertension is a major cause of secondary hypertension. It affects relatively younger patients. The unifying pathology is renal artery stenosis. The most common cause is atherosclerosis accounting for about 90% of cases with fibromuscular dysplasia being the second most common cause. Both of these are amenable to percutaneous interventional therapy. With the advent of new medical therapies, the control of blood pressure has improved significantly. In well selected patients, renal arterial intervention has a good outcome. The intervention includes renal angioplasty and stenting. In this article, the authors review the role of percutaneous intervention and the techniques involved with renal angioplasty and stenting for the treatment of renovascular hypertension. PMID- 21326570 TI - Renal vascular lesions: diagnosis and endovascular management. AB - Renal vascular abnormalities included in this review are renal artery aneurysms (RAA) and renal arteriovenous malformations (AVM). The clinical presentation, diagnosis, and principles of management with emphasis on endovascular techniques are discussed. PMID- 21326571 TI - Embolization of nonliver visceral tumors. AB - Catheter-directed embolization of visceral tumors, with the exception of the liver, has received limited attention in the literature. The visceral arterial anatomy can be complex and its understanding is critical for procedure planning and limiting complications. Embolization of splenic neoplasms is exceedingly rare. Preoperative embolization for adrenal, renal, and gut tumors plays an important role in select patients. Embolization has been used successfully in the treatment of pancreatic insulinomas and in limited cases of unresectable pancreatic adenocarcinomas. Embolization of bleeding visceral tumors can be accomplished with a high likelihood of success. PMID- 21326572 TI - Transarterial chemoembolization for hepatocellular carcinoma. PMID- 21326573 TI - Axillary vein rupture after angioplasty. AB - Venous rupture is an uncommon complication resulting from dialysis graft interventions. The authors describe a case of axillary vein rupture following angioplasty necessitating placement of a covered stent for the control of hemorrhage. PMID- 21326574 TI - The 4 A's. PMID- 21326575 TI - Obstetric and gynecologic emergencies: a review of indications and interventional techniques. AB - There are many interventional techniques that can be used to aid the obstetrician or gynecologist in caring for their patients in the acute setting. Embolization can be life saving in the case of postpartum hemorrhage. Bleeding related to cervical cancer or the threat of bleeding from cervical ectopic pregnancy is amenable to embolization as is hemorrhage related to uterine arteriovenous malformations. Postpartum women are also at a uniquely high risk for deep vein thrombosis and pulmonary emboli and may benefit from consultation and treatment by an interventional radiologist. The goal of this article is to discuss the valuable role that the interventional radiologist plays in the treatment of these obstetric and gynecologic conditions. PMID- 21326576 TI - Vascular malformations involving the female pelvis. AB - Vascular malformations (VM) are classified by flow characteristics and channel content. They can involve any organ and tissue plane, and occur in focal and diffuse forms. Slow-flow vascular malformations (venous and lymphatic malformations) are typically treated by sclerotherapy, whereas fast-flow lesions (arteriovenous malformations) are managed with embolizations. Some VMs, such as VMs of the rectum or uterus, are best dealt with surgically. This review will present a summary of the conditions, their imaging features, and some useful endovascular therapeutic techniques. PMID- 21326577 TI - Pelvic congestion syndrome: diagnosis and treatment. AB - The diagnosis of pelvic congestion syndrome (PCS) continues to challenge all physicians involved especially those in such specialties as anesthesia, gastroenterology, general surgery, obstetrics and gynecology, and interventional radiology. When other pelvic pathology is ruled out, an interventional radiologist may be consulted for additional evaluation and treatment of PCS. A heightened awareness and clinical suspicion for the specific symptomatology and associated findings may bring about a more rapid progression toward treatment. For most interventional radiologists who treat PCS patients, magnetic resonance imaging/MR venography (MRI/MRV), diagnostic venogram, and embolotherapy are at the center of diagnosis and treatment of PCS. PMID- 21326578 TI - Uterine artery embolization for treatment of symptomatic fibroids. AB - Over the past decade, uterine artery embolization (UAE) has become a popular alternative treatment for women with symptomatic fibroids who desire uterine preservation and/or the avoidance of surgical intervention. In this article, the history of UAE, preprocedure patient evaluation and patient selection, procedure technique, and expected UAE outcomes are reviewed. PMID- 21326579 TI - Uterine Artery Embolization in the Management of Symptomatic Uterine Fibroids: An Overview of Complications and Follow-up. AB - Uterine artery embolization (UAE) evolved as a treatment for symptomatic uterine fibroids in the early 1990s, after initially being used as a temporizing measure prior to hysterectomy or myomectomy. Since that time, over 100,000 UAEs have been performed. Technical success rates have been quoted ranging from 94 to 99%. The overall incidence of major complications associated with the procedure is low, the majority of which can be prevented. Knowledge of the potential complications and the measures that can be taken to avoid these complications is essential. Furthermore, because UAE is a relatively new procedure, no standardized recommendations for patient follow-up exist. Common practice for patient follow up includes both clinic visits at increasing time intervals postprocedure, as well as telephone follow-up, and imaging follow-up when necessary. As symptomatic improvement is subjective, some institutions have developed standardized questionnaires to better assess patient improvement postprocedure. Aggressive pain control is a crucial component of follow-up, as uncontrolled pain can result in readmission and patient dissatisfaction. PMID- 21326580 TI - Uterine artery embolization for the treatment of adenomyosis. AB - Adenomyosis is a benign uterine disorder that causes menorrhagia and dysmenorrhea. Although it was once considered a contraindication to uterine artery embolization, several authors have examined whether adenomyosis can be treated with uterine artery embolization. This article reviews the pathophysiology of adenomyosis, its imaging characteristics, as well as recent studies evaluating the efficacy of uterine artery embolization for treatment of adenomyosis. PMID- 21326581 TI - Magnetic resonance-guided focused ultrasound for uterine fibroids. AB - Uterine fibroids are an important problem for women of reproductive age. Although hysterectomy has been the traditional treatment for fibroids, many women are interested in a less invasive therapy. Magnetic resonance-guided focused ultrasound (MRgFUS) is a new technique for treating a variety of solid tumors. It has been tested and approved by the U.S. Food & Drug Administration (FDA) for the treatment of uterine fibroids. The procedure is completely noninvasive. It is performed as an outpatient procedure and the patient can resume her normal activities the day following the procedure. Techniques of treatment of uterine fibroids are still being refined, but significant progress has been made in understanding some of the challenges for this new technology. Some fibroids are more responsive to the focused ultrasound; some fibroids are more resistant. Not all women are candidates for this procedure. Absolute contraindications include bowel that is in the path of the ultrasound beam, or surgical scars in the beam pathway. The procedure of MRgFUS is feasible, safe and becoming increasingly popular. Questions still remain particularly the use of this technique for patients desiring fertility, and what will be the long-term results. PMID- 21326582 TI - Radiofrequency ablation as a treatment strategy for liver metastases from breast cancer. AB - The American Cancer Society estimates that in 2007, 178,000 women in the United States will be diagnosed, and that 40,000 women will die from breast cancer. Metastatic breast cancer is a systemic disease, uncommonly involving an isolated organ. Liver metastases from breast cancer occur in ~50% of the patients who develop breast cancer metastases and are associated with a poor outcome. Hepatic metastasectomy as an adjuvant treatment even in patients with stable extrahepatic disease has been shown to impart a significant survival advantage over chemotherapy alone. In the treatment of hepatocellular carcinoma (HCC) and colorectal liver metastases (CRLM), radiofrequency ablation (RFA) has been shown to be a safe, minimally invasive treatment option with low morbidity and short hospital stay that is more readily repeatable than resection. The data supporting RFA of breast cancer liver metastases (BCLM) is currently limited to small, retrospective series that, like hepatic resection, have demonstrated adjuvant RFA improves survival compared with chemotherapy alone. This review will examine the rationale, indications, supportive data, and complications of RFA in the treatment of BCLM. PMID- 21326584 TI - Fallopian tube catheterization. AB - The delicate fallopian tube is the anatomic pathway to human reproduction. Simple, inexpensive tools and techniques allow radiologists to access this structure for promoting, and preventing pregnancy. Results from centers worldwide have shown that catheter recanalization is possible in ~90% of women with proximal tubal occlusion using basic angiographic techniques familiar to all interventional radiologists. The American Society for Reproductive Medicine has recommended that patients in whom the hysterosalpingogram (HSG) demonstrates proximal tubal occlusion undergo fallopian tube catheterization with selective salpingography prior to more invasive and more costly infertility treatments. The pregnancy rate following fallopian tube recanalization is as high as 60% when the unblocked tubes are found to be normal and there is no history of tubal disease. In a population where the cause of infertility is less well-defined, tubal catheterization may not only help women conceive, but may also help to better define the underlying tubal abnormality. In the prevention of unwanted pregnancy, numerous materials and devices have been tested for blocking fallopian tubes. The ESSURE coil (Conceptus, Inc., Mountain View, CA) was FDA approved in 2002 for tubal sterilization by hysteroscopic placement. In some locales, radiologists are being asked to assist with this procedure or to place the coils fluoroscopically through fallopian tube catheterization. PMID- 21326583 TI - Osteoporotic vertebral compression fractures and vertebral augmentation. AB - Vertebral fractures account for ~27% of all osteoporotic fractures in both men and women. The economic burden is substantial and growing: osteoporosis is expected to affect 14 million people by the year 2020. There is substantial morbidity associated with osteoporotic vertebral compression fractures (VCFs) including decreased quality of life, reduced pulmonary function, and increased mortality. Relatively recent additions to the treatment armamentarium include vertebral augmentation using vertebroplasty and kyphoplasty. Numerous retrospective and case studies demonstrate short-term efficacy and low complication rates of vertebroplasty and kyphoplasty in the treatment of osteoporotic VCFs, but controlled trials are needed for validation. The pathophysiology, risk factors, consequences, characteristics, and imaging of osteoporotic VCFs are presented in detail along with a discussion of treatment options and patient selection. Vertebral augmentation is comprehensively reviewed, including the technical aspects of the procedures, contraindications, complications, and clinical outcomes. PMID- 21326585 TI - Tunneled central venous catheter insertion. PMID- 21326586 TI - Iatrogenic flow limiting arterial dissection. PMID- 21326587 TI - The customer is always right. PMID- 21326588 TI - Palliative radiation therapy in the management of brain metastases, spinal cord compression, and bone metastases. AB - Radiation therapy plays an important role in both curative and palliative cancer treatment. Palliative radiation therapy is given to alleviate symptoms, restore function, relieve suffering caused by cancer, and improve quality of life. Pain relief, control of bleeding or ulceration, prevention of impending compression or obstruction from tumor, and shrinkage of tumor masses causing symptoms are indications for palliative radiotherapy. Palliative radiotherapy is a very effective tool in alleviating pain symptoms and generally well tolerated. Common fractionation schemes are 8 Gy delivered in one fraction and 30 Gy delivered in 10 fractions. This article discusses general principles of administering palliative radiation therapy. Site-specific treatment is addressed, divided into palliative radiotherapy for brain metastases, spinal cord compression, and bone metastases. In each of these areas, we discuss presentation, management, and therapeutic strategies. PMID- 21326589 TI - Palliative Care for Interventional Radiology: An Oncologist's Perspective. AB - Palliative care is an approach to care that seeks to improve the quality of life of patients and families facing problems due to life-threatening malignancies. Interventional radiology offers diagnostic, therapeutic, and palliative procedures that provide tangible benefits to oncology patients. A comprehensive evaluation and goals of care discussion will facilitate appropriate treatment recommendations from interventionalists. We describe a framework, with suggested questions for patients, which will enhance the level of communication between interventionalists and oncology patients. PMID- 21326590 TI - Endovascular therapy for palliative care of cancer patients. AB - Interventional radiology procedures often play an integral role in the diagnosis and treatment of patients with cancer. In the latter stages of cancer treatment, palliative care therapies may be sought for improvement in the quality of remaining life for oncology patients. Increased awareness among interventionalists and referring oncologists regarding minimally invasive treatments for palliation is desirable to provide additional options for patients. In particular, endovascular therapies can provide control of symptoms and complications related to incurable malignancies. PMID- 21326591 TI - Palliative nonvascular interventions. AB - Interventional radiologists are often called on to help with quality of life issues in end-stage cancer patients. Many times, the discomfort can be directly associated to the tumor mass itself, but in other instances, tumors can cause secondary obstruction of normal structures that can lead to patient distress. As with most palliative care patients, their medical conditions are not conducive to major surgery; therefore minimally invasive techniques are ideal for the treatment of these conditions. The following discussion addresses the various nonvascular interventions available to these patients, including the indications and limitations of these procedures. PMID- 21326592 TI - Percutaneous management of malignant fluid collections. AB - The development of a pleural effusion or ascites in patients with underlying malignancy typically heralds end-stage disease and often results in a significant reduction in the patient&'s quality of life. The goal of treatment is the safe and effective palliation of symptoms with minimal inconvenience to the patient. Malignant fluid collections in the chest and abdomen are amenable to percutaneous management with either intermittent thoracentesis or paracentesis or by placement of temporary or permanent drainage catheters. PMID- 21326593 TI - Vertebroplasty and kyphoplasty for the palliation of pain. AB - Vertebroplasty and kyphoplasty are percutaneous techniques developed over the past 20 years to treat vertebral hemangiomas, osteoporotic compression fractures, and osteolytic tumors of the spine. In carefully selected patients, these procedures have led to the cessation or significant reduction in pain in 80 to 90% of patients. In this article, we review the indications and contraindications of these procedures, appropriate patient selection and evaluation, the technique, outcomes, and the potential complications of this form of therapy when performed for the alleviation of pain for osteolytic tumors of the spine. PMID- 21326594 TI - Palliative interventions for pain in cancer patients. AB - Pain is a debilitating problem that is common to most patients with cancer at some time during the course of their disease. Conventional therapies such as opiate analgesics and radiation therapy provide suboptimal and limited relief. Novel image-guided interventions have made a significant impact in the management of this difficult problem. This article reviews some of the most promising image guided techniques for relieving bone and visceral pain in patients suffering from cancer. PMID- 21326595 TI - Minimizing occupational exposure to biohazards. PMID- 21326596 TI - Pulseless Electrical Activity Arrest after SVC Dilation. PMID- 21326598 TI - Running worms: C. elegans self-sorting by electrotaxis. AB - The nematode C. elegans displays complex dynamical behaviors that are commonly used to identify relevant phenotypes. Although its maintenance is straightforward, sorting large populations of worms when looking for a behavioral phenotype is difficult, time consuming and hardly quantitative when done manually. Interestingly, when submitted to a moderate electric field, worms move steadily along straight trajectories. Here, we report an inexpensive method to measure worms crawling velocities and sort them within a few minutes by taking advantage of their electrotactic skills. This method allows to quantitatively measure the effect of mutations and aging on worm's crawling velocity. We also show that worms with different locomotory phenotypes can be spatially sorted, fast worms traveling away from slow ones. Group of nematodes with comparable locomotory fitness could then be isolated for further analysis. C. elegans is a growing model for neurodegenerative diseases and using electrotaxis for self sorting can improve the high-throughput search of therapeutic bio-molecules. PMID- 21326597 TI - Proteome analyses of cellular proteins in methicillin-resistant Staphylococcus aureus treated with rhodomyrtone, a novel antibiotic candidate. AB - The ethanolic extract from Rhodomyrtus tomentosa leaf exhibited good antibacterial activities against both methicillin-resistant Staphylococcus aureus (MRSA) and S. aureus ATCC 29213. Its minimal inhibitory concentration (MIC) values ranged from 31.25-62.5 ug/ml, and the minimal bactericidal concentration (MBC) was 250 ug/ml. Rhodomyrtone, an acylphloroglucinol derivative, was 62.5-125 times more potent at inhibiting the bacteria than the ethanolic extract, the MIC and MBC values were 0.5 ug/ml and 2 ug/ml, respectively. To provide insights into antibacterial mechanisms involved, the effects of rhodomyrtone on cellular protein expression of MRSA have been investigated using proteomic approaches. Proteome analyses revealed that rhodomyrtone at subinhibitory concentration (0.174 ug/ml) affected the expression of several major functional classes of whole cell proteins in MRSA. The identified proteins involve in cell wall biosynthesis and cell division, protein degradation, stress response and oxidative stress, cell surface antigen and virulence factor, and various metabolic pathways such as amino acid, carbohydrate, energy, lipid, and nucleotide metabolism. Transmission electron micrographs confirmed the effects of rhodomyrtone on morphological and ultrastructural alterations in the treated bacterial cells. Biological processes in cell wall biosynthesis and cell division were interrupted. Prominent changes including alterations in cell wall, abnormal septum formation, cellular disintegration, and cell lysis were observed. Unusual size and shape of staphylococcal cells were obviously noted in the treated MRSA. These pioneer findings on proteomic profiling and phenotypic features of rhodomyrtone-treated MRSA may resolve its antimicrobial mechanisms which could lead to the development of a new effective regimen for the treatment of MRSA infections. PMID- 21326599 TI - Detection of epileptogenic cortical malformations with surface-based MRI morphometry. AB - Magnetic resonance imaging has revolutionized the detection of structural abnormalities in patients with epilepsy. However, many focal abnormalities remain undetected in routine visual inspection. Here we use an automated, surface-based method for quantifying morphometric features related to epileptogenic cortical malformations to detect abnormal cortical thickness and blurred gray-white matter boundaries. Using MRI morphometry at 3T with surface-based spherical averaging techniques that precisely align anatomical structures between individual brains, we compared single patients with known lesions to a large normal control group to detect clusters of abnormal cortical thickness, gray-white matter contrast, local gyrification, sulcal depth, jacobian distance and curvature. To assess the effects of threshold and smoothing on detection sensitivity and specificity, we systematically varied these parameters with different thresholds and smoothing levels. To test the effectiveness of the technique to detect lesions of epileptogenic character, we compared the detected structural abnormalities to expert-tracings, intracranial EEG, pathology and surgical outcome in a homogeneous patient sample. With optimal parameters and by combining thickness and GWC, the surface-based detection method identified 92% of cortical lesions (sensitivity) with few false positives (96% specificity), successfully discriminating patients from controls 94% of the time. The detected structural abnormalities were related to the seizure onset zones, abnormal histology and positive outcome in all surgical patients. However, the method failed to adequately describe lesion extent in most cases. Automated surface-based MRI morphometry, if used with optimized parameters, may be a valuable additional clinical tool to improve the detection of subtle or previously occult malformations and therefore could improve identification of patients with intractable focal epilepsy who may benefit from surgery. PMID- 21326600 TI - Ultra-rapid categorization of fourier-spectrum equalized natural images: macaques and humans perform similarly. AB - BACKGROUND: Comparative studies of cognitive processes find similarities between humans and apes but also monkeys. Even high-level processes, like the ability to categorize classes of object from any natural scene under ultra-rapid time constraints, seem to be present in rhesus macaque monkeys (despite a smaller brain and the lack of language and a cultural background). An interesting and still open question concerns the degree to which the same images are treated with the same efficacy by humans and monkeys when a low level cue, the spatial frequency content, is controlled. METHODOLOGY/PRINCIPAL FINDINGS: We used a set of natural images equalized in Fourier spectrum and asked whether it is still possible to categorize them as containing an animal and at what speed. One rhesus macaque monkey performed a forced-choice saccadic task with a good accuracy (67.5% and 76% for new and familiar images respectively) although performance was lower than with non-equalized images. Importantly, the minimum reaction time was still very fast (100 ms). We compared the performances of human subjects with the same setup and the same set of (new) images. Overall mean performance of humans was also lower than with original images (64% correct) but the minimum reaction time was still short (140 ms). CONCLUSION: Performances on individual images (% correct but not reaction times) for both humans and the monkey were significantly correlated suggesting that both species use similar features to perform the task. A similar advantage for full-face images was seen for both species. The results also suggest that local low spatial frequency information could be important, a finding that fits the theory that fast categorization relies on a rapid feedforward magnocellular signal. PMID- 21326601 TI - Genetic variation in spatio-temporal confined USA300 community-associated MRSA isolates: a shift from clonal dispersion to genetic evolution? AB - INTRODUCTION: Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) are increasingly isolated, with USA300-0114 being the predominant clone in the USA. Comparative whole genome sequencing of USA300 isolates collected in 2002, 2003 and 2005 showed a limited number of single nucleotide polymorphisms and regions of difference. This suggests that USA300 has undergone rapid clonal expansion without great genomic diversification. However, whole genome comparison of CA-MRSA has been limited to isolates belonging to USA300. The aim of this study was to compare the genetic repertoire of different CA-MRSA clones with that of HA-MRSA from the USA and Europe through comparative genomic hybridization (CGH) to identify genetic clues that may explain the successful and rapid emergence of CA-MRSA. MATERIALS AND METHODS: Hierarchical clustering based on CGH of 48 MRSA isolates from the community and nosocomial infections from Europe and the USA revealed dispersed clustering of the 19 CA-MRSA isolates. This means that these 19 CA-MRSA isolates do not share a unique genetic make-up. Only the PVL genes were commonly present in all CA-MRSA isolates. However, 10 genes were variably present among 14 USA300 isolates. Most of these genes were present on mobile elements. CONCLUSION: The genetic variation present among the 14 USA300 isolates is remarkable considering the fact that the isolates were recovered within one month and originated from a confined geographic area, suggesting continuous evolution of this clone. PMID- 21326602 TI - Optimization based tumor classification from microarray gene expression data. AB - BACKGROUND: An important use of data obtained from microarray measurements is the classification of tumor types with respect to genes that are either up or down regulated in specific cancer types. A number of algorithms have been proposed to obtain such classifications. These algorithms usually require parameter optimization to obtain accurate results depending on the type of data. Additionally, it is highly critical to find an optimal set of markers among those up or down regulated genes that can be clinically utilized to build assays for the diagnosis or to follow progression of specific cancer types. In this paper, we employ a mixed integer programming based classification algorithm named hyper box enclosure method (HBE) for the classification of some cancer types with a minimal set of predictor genes. This optimization based method which is a user friendly and efficient classifier may allow the clinicians to diagnose and follow progression of certain cancer types. METHODOLOGY/PRINCIPAL FINDINGS: We apply HBE algorithm to some well known data sets such as leukemia, prostate cancer, diffuse large B-cell lymphoma (DLBCL), small round blue cell tumors (SRBCT) to find some predictor genes that can be utilized for diagnosis and prognosis in a robust manner with a high accuracy. Our approach does not require any modification or parameter optimization for each data set. Additionally, information gain attribute evaluator, relief attribute evaluator and correlation-based feature selection methods are employed for the gene selection. The results are compared with those from other studies and biological roles of selected genes in corresponding cancer type are described. CONCLUSIONS/SIGNIFICANCE: The performance of our algorithm overall was better than the other algorithms reported in the literature and classifiers found in WEKA data-mining package. Since it does not require a parameter optimization and it performs consistently very high prediction rate on different type of data sets, HBE method is an effective and consistent tool for cancer type prediction with a small number of gene markers. PMID- 21326603 TI - Changes in brain size during the menstrual cycle. AB - BACKGROUND: There is increasing evidence for hormone-dependent modification of function and behavior during the menstrual cycle, but little is known about associated short-term structural alterations of the brain. Preliminary studies suggest that a hormone-dependent decline in brain volume occurs in postmenopausal, or women receiving antiestrogens, long term. Advances in serial MR-volumetry have allowed for the accurate detection of small volume changes of the brain. Recently, activity-induced short-term structural plasticity of the brain was demonstrated, challenging the view that the brain is as rigid as formerly believed. METHODOLOGY/PRINCIPAL FINDINGS: We used MR-volumetry to investigate short-term brain volume changes across the menstrual cycle in women or a parallel 4 week period in men, respectively. We found a significant grey matter volume peak and CSF loss at the time of ovulation in females. This volume peak did not correlate with estradiol or progesterone hormone levels. Men did not show any significant brain volume alterations. CONCLUSIONS/SIGNIFICANCE: These data give evidence of short-term hormone-dependent structural brain changes during the menstrual cycle, which need to be correlated with functional states and have to be considered in structure-associated functional brain research. PMID- 21326604 TI - Adaptive avoidance of reef noise. AB - Auditory information is widely used throughout the animal kingdom in both terrestrial and aquatic environments. Some marine species are dependent on reefs for adult survival and reproduction, and are known to use reef noise to guide orientation towards suitable habitat. Many others that forage in food-rich inshore waters would, however, benefit from avoiding the high density of predators resident on reefs, but nothing is known about whether acoustic cues are used in this context. By analysing a sample of nearly 700,000 crustaceans, caught during experimental playbacks in light traps in the Great Barrier Reef lagoon, we demonstrate an auditory capability in a broad suite of previously neglected taxa, and provide the first evidence in any marine organisms that reef noise can act as a deterrent. In contrast to the larvae of species that require reef habitat for future success, which showed an attraction to broadcasted reef noise, taxa with a pelagic or nocturnally emergent lifestyle actively avoided it. Our results suggest that a far greater range of invertebrate taxa than previously thought can respond to acoustic cues, emphasising yet further the potential negative impact of globally increasing levels of underwater anthropogenic noise. PMID- 21326605 TI - A one-dimensional continuum elastic model for membrane-embedded gramicidin dimer dissociation. AB - Membrane elastic properties, which are subject to alteration by compounds such as cholesterol, lipid metabolites and other amphiphiles, as well as pharmaceuticals, can have important effects on membrane proteins. A useful tool for measuring some of these effects is the gramicidin A channels, which are formed by transmembrane dimerization of non-conducting subunits that reside in each bilayer leaflet. The length of the conducting channels is less than the bilayer thickness, meaning that channel formation is associated with a local bilayer deformation. Electrophysiological studies have shown that the dimer becomes increasingly destabilized as the hydrophobic mismatch between the channel and the host bilayer increases. That is, the bilayer imposes a disjoining force on the channel, which grows larger with increasing hydrophobic mismatch. The energetic analysis of the channel-bilayer coupling is usually pursued assuming that each subunit, as well as the subunit-subunit interface, is rigid. Here we relax the latter assumption and explore how the bilayer junction responds to changes in this disjoining force using a simple one-dimensional energetic model, which reproduces key features of the bilayer regulation of gramicidin channel lifetimes. PMID- 21326606 TI - dPORE-miRNA: polymorphic regulation of microRNA genes. AB - BACKGROUND: MicroRNAs (miRNAs) are short non-coding RNA molecules that act as post-transcriptional regulators and affect the regulation of protein-coding genes. Mostly transcribed by PolII, miRNA genes are regulated at the transcriptional level similarly to protein-coding genes. In this study we focus on human miRNAs. These miRNAs are involved in a variety of pathways and can affect many diseases. Our interest is on possible deregulation of the transcription initiation of the miRNA encoding genes, which is facilitated by variations in the genomic sequence of transcriptional control regions (promoters). METHODOLOGY: Our aim is to provide an online resource to facilitate the investigation of the potential effects of single nucleotide polymorphisms (SNPs) on miRNA gene regulation. We analyzed SNPs overlapped with predicted transcription factor binding sites (TFBSs) in promoters of miRNA genes. We also accounted for the creation of novel TFBSs due to polymorphisms not present in the reference genome. The resulting changes in the original TFBSs and potential creation of new TFBSs were incorporated into the Dragon Database of Polymorphic Regulation of miRNA genes (dPORE-miRNA). CONCLUSIONS: The dPORE-miRNA database enables researchers to explore potential effects of SNPs on the regulation of miRNAs. dPORE-miRNA can be interrogated with regards to: a/miRNAs (their targets, or involvement in diseases, or biological pathways), b/SNPs, or c/transcription factors. dPORE-miRNA can be accessed at http://cbrc.kaust.edu.sa/dpore and http://apps.sanbi.ac.za/dpore/. Its use is free for academic and non-profit users. PMID- 21326607 TI - Evidence for the role of horizontal transfer in generating pVT1, a large mosaic conjugative plasmid from the clam pathogen, Vibrio tapetis. AB - The marine bacterium Vibrio tapetis is the causative agent of the brown ring disease, which affects the clam Ruditapes philippinarum and causes heavy economic losses in North of Europe and in Eastern Asia. Further characterization of V. tapetis isolates showed that all the investigated strains harbored at least one large plasmid. We determined the sequence of the 82,266 bp plasmid pVT1 from the CECT4600(T) reference strain and analyzed its genetic content. pVT1 is a mosaic plasmid closely related to several conjugative plasmids isolated from Vibrio vulnificus strains and was shown to be itself conjugative in Vibrios. In addition, it contains DNA regions that have similarity with several other plasmids from marine bacteria (Vibrio sp., Shewanella sp., Listonella anguillarum and Photobacterium profundum). pVT1 contains a number of mobile elements, including twelve Insertion Sequences or inactivated IS genes and an RS1 phage element related to the CTXphi phage of V. cholerae. The genetic organization of pVT1 underscores an important role of horizontal gene transfer through conjugative plasmid shuffling and transposition events in the acquisition of new genetic resources and in generating the pVT1 modular organization. In addition, pVT1 presents a copy number of 9, relatively high for a conjugative plasmid, and appears to belong to a new type of replicon, which may be specific to Vibrionaceae and Shewanelleacae. PMID- 21326608 TI - Prolyl isomerase pin1 protects mice from endotoxin shock. AB - BACKGROUND: Prolyl isomerase Pin1 may be involved in innate immunity against microbial infection, but the mechanism how Pin1 controls the innate immunity is poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: Injection of lipopolysaccharide (LPS) into the mice induces inflammatory pulmonary disorder and sometimes the serious damages lead to death. Comparing to the wild-type (WT) mice, the Pin1-/- mice showed more serious damages in lung and the lower survival rate after the LPS injection. We compared the levels of typical inflammatory cytokines. Pin1-/- mice overreacted to the LPS injection to produce inflammatory cytokines, especially IL-6 more than WT mice. We showed that Pin1 binds phosphorylated PU.1 and they localize together in a nucleus. These results suggest that Pin1 controls the transcriptional activity of PU.1 and suppresses overreaction of macrophage that causes serious damages in lung. CONCLUSIONS/SIGNIFICANCE: Pin1 may protect the mice from serious inflammation by LPS injection by attenuating the increase of IL-6 transcription of the mouse macrophages. PMID- 21326609 TI - Analysis of two novel midgut-specific promoters driving transgene expression in Anopheles stephensi mosquitoes. AB - BACKGROUND: Tissue-specific promoters controlling the expression of transgenes in Anopheles mosquitoes represent a valuable tool both for studying the interaction between these malaria vectors and the Plasmodium parasites they transmit and for novel malaria control strategies based on developing Plasmodium-refractory mosquitoes by expressing anti-parasitic genes. With this aim we have studied the promoter regions of two genes from the most important malaria vector, Anopheles gambiae, whose expression is strongly induced upon blood feeding. RESULTS: We analysed the A. gambiae Antryp1 and G12 genes, which we have shown to be midgut specific and maximally expressed at 24 hours post-bloodmeal (PBM). Antryp1, required for bloodmeal digestion, encodes one member of a family of 7 trypsin genes. The G12 gene, of unknown function, was previously identified in our laboratory in a screen for genes induced in response to a bloodmeal. We fused 1.1 kb of the upstream regions containing the putative promoter of these genes to reporter genes and transformed these into the Indian malaria vector A. stephensi to see if we could recapitulate the expression pattern of the endogenous genes. Both the Antryp1 and G12 upstream regions were able to drive female-predominant, midgut-specific expression in transgenic mosquitoes. Expression of the Antryp1 driven reporter in transgenic A. stephensi lines was low, undetectable by northern blot analysis, and failed to fully match the induction kinetics of the endogenous Antryp1 gene in A. gambiae. This incomplete conservation of expression suggests either subtle differences in the transcriptional machinery between A. stephensi and A. gambiae or that the upstream region chosen lacked all the control elements. In contrast, the G12 upstream region was able to faithfully reproduce the expression profile of the endogenous A. gambiae gene, showing female midgut specificity in the adult mosquito and massive induction PBM, peaking at 24 hours. CONCLUSIONS: Our studies on two putative blood-meal induced, midgut-specific promoters validate the use of G12 upstream regulatory regions to drive targeted transgene expression coinciding spatially and temporally with pre sporogonic stages of Plasmodium parasites in the mosquito, offering the possibility of manipulating vector competence or performing functional studies on vector-parasite interactions. PMID- 21326610 TI - Isolation of bacterial ribosomes with monolith chromatography. AB - We report the development of a rapid chromatographic method for the isolation of bacterial ribosomes from crude cell lysates in less than ten minutes. Our separation is based on the use of strong anion exchange monolithic columns. Using a simple stepwise elution program we were able to purify ribosomes whose composition is comparable to those isolated by sucrose gradient ultracentrifugation, as confirmed by quantitative proteomic analysis (iTRAQ). The speed and simplicity of this approach could accelerate the study of many different aspects of ribosomal biology. PMID- 21326611 TI - Transient responses to NOTCH and TLX1/HOX11 inhibition in T-cell acute lymphoblastic leukemia/lymphoma. AB - To improve the treatment strategies of T-cell acute lymphoblastic leukemia/lymphoma (T-ALL), further efforts are needed to identify therapeutic targets. Dysregulated expression of HOX-type transcription factors occurs in 30 40% of cases of T-ALL. TLX1/HOX11 is the prototypical HOX-type transcription factor. TLX1 may be an attractive therapeutic target because mice that are deficient in TLX1 are healthy. To test this possibility, we developed a conditional doxycycline-regulated mouse model of TLX1-initiated T-ALL. TLX1 induced T-ALL after ~5-7 months with penetrance of 15-60%. Similar to human TLX1 type T-ALLs, the TLX1-induced tumors were arrested at the cortical stage of T cell development and acquired activating NOTCH1 mutations. Inhibition of NOTCH signaling abrogated growth of cell lines derived from the TLX1-induced tumors. NOTCH inhibition also transiently delayed leukemia progression in vivo. Suppression of TLX1 expression slowed the growth of TLX1 tumor cell lines. Suppression of TLX1 in vivo also transiently delayed leukemia progression. We have shown that TLX1 functions as a T-cell oncogene that is active during both the induction and the maintenance phases of leukemia. However, the effect of suppressing NOTCH or TLX1 was transient. The tumors eventually "escaped" from inhibition. These data imply that the biological pathways and gene sets impacted by TLX1 and NOTCH have largely lost their importance in the fully established tumor. They have been supplanted by stronger oncogenic pathways. Although TLX1 or NOTCH inhibitors may not be effective as single agents, they may still contribute to combination therapy for TLX1-driven acute leukemia. PMID- 21326612 TI - Ventromedial prefrontal cortex activation is associated with memory formation for predictable rewards. AB - During reinforcement learning, dopamine release shifts from the moment of reward consumption to the time point when the reward can be predicted. Previous studies provide consistent evidence that reward-predicting cues enhance long-term memory (LTM) formation of these items via dopaminergic projections to the ventral striatum. However, it is less clear whether memory for items that do not precede a reward but are directly associated with reward consumption is also facilitated. Here, we investigated this question in an fMRI paradigm in which LTM for reward predicting and neutral cues was compared to LTM for items presented during consumption of reliably predictable as compared to less predictable rewards. We observed activation of the ventral striatum and enhanced memory formation during reward anticipation. During processing of less predictable as compared to reliably predictable rewards, the ventral striatum was activated as well, but items associated with less predictable outcomes were remembered worse than items associated with reliably predictable outcomes. Processing of reliably predictable rewards activated the ventromedial prefrontal cortex (vmPFC), and vmPFC BOLD responses were associated with successful memory formation of these items. Taken together, these findings show that consumption of reliably predictable rewards facilitates LTM formation and is associated with activation of the vmPFC. PMID- 21326613 TI - Two-component system RgfA/C activates the fbsB gene encoding major fibrinogen binding protein in highly virulent CC17 clone group B Streptococcus. AB - Group B streptococcus (GBS) strains with the highest ability to bind to human fibrinogen belong to the highly invasive clonal complex (CC) 17. To investigate the fibrinogen-binding mechanisms of CC17 strains, we determined the prevalence of fibrinogen-binding genes (fbsA and fbsB), and fbs regulator genes (rogB encoding an fbsA activator, rovS encoding an fbsA repressor and rgf encoding a two-component system [TCS] whose role on fbs genes was not determined yet) in a collection of 134 strains representing the major CCs of the species. We showed that specific gene combinations were related to particular CCs; only CC17 strains contained the fbsA, fbsB, and rgf genes combination. Non polar rgfAC deletion mutants of three CC17 serotype III strains were constructed. They showed a 3.2- to 5.1-fold increase of fbsA transcripts, a 4.8- to 6.7-fold decrease of fbsB transcripts, and a 52% to 68% decreased fibrinogen-binding ability, demonstrating that the RgfA/RgfC TCS inhibits the fbsA gene and activates the fbsB gene. The relative contribution of the two fbs genes in fibrinogen-binding ability was determined by constructing isogenic fbsA, fbsB, deletion mutants of the three CC17 strains. The ability to bind to fibrinogen was reduced by 49% to 57% in DeltafbsA mutants, and by 78% to 80% in DeltafbsB mutants, suggesting that FbsB protein plays a greater role in the fibrinogen-binding ability of CC17 strains. Moreover, the relative transcription level of fbsB gene was 9.2- to 12.7-fold higher than that of fbsA gene for the three wild type strains. Fibrinogen-binding ability could be restored by plasmid-mediated expression of rgfAC, fbsA, and fbsB genes in the corresponding deletion mutants. Thus, our results demonstrate that a specific combination of fbs genes and fbs regulator genes account for the high fibrinogen-binding ability of CC17 strains that may participate to their enhanced invasiveness for neonates as compared to strains of other CCs. PMID- 21326614 TI - 2-hydroxyglutarate production, but not dominant negative function, is conferred by glioma-derived NADP-dependent isocitrate dehydrogenase mutations. AB - BACKGROUND: Gliomas frequently contain mutations in the cytoplasmic NADP(+) dependent isocitrate dehydrogenase (IDH1) or the mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDH2). Several different amino acid substitutions recur at either IDH1 R132 or IDH2 R172 in glioma patients. Genetic evidence indicates that these mutations share a common gain of function, but it is unclear whether the shared function is dominant negative activity, neomorphic production of (R)-2 hydroxyglutarate (2HG), or both. METHODOLOGY/PRINCIPAL FINDINGS: We show by coprecipitation that five cancer-derived IDH1 R132 mutants bind IDH1-WT but that three cancer-derived IDH2 R172 mutants exert minimal binding to IDH2-WT. None of the mutants dominant-negatively lower isocitrate dehydrogenase activity at physiological (40 uM) isocitrate concentrations in mammalian cell lysates. In contrast to this, all of these mutants confer 10- to 100-fold higher 2HG production to cells, and glioma tissues containing IDH1 R132 or IDH2 R172 mutations contain high levels of 2HG compared to glioma tissues without IDH mutations (54.4 vs. 0.1 mg 2HG/g protein). CONCLUSIONS: Binding to, or dominant inhibition of, WT IDH1 or IDH2 is not a shared feature of the IDH1 and IDH2 mutations, and thus is not likely to be important in cancer. The fact that the gain of the enzymatic activity to produce 2HG is a shared feature of the IDH1 and IDH2 mutations suggests that this is an important function for these mutants in driving cancer pathogenesis. PMID- 21326615 TI - Endogenous retinoic acid activity in principal cells and intercalated cells of mouse collecting duct system. AB - BACKGROUND: Retinoic acid is the bioactive derivative of vitamin A, which plays an indispensible role in kidney development by activating retinoic acid receptors. Although the location, concentration and roles of endogenous retinoic acid in post-natal kidneys are poorly defined, there is accumulating evidence linking post-natal vitamin A deficiency to impaired renal concentrating and acidifying capacity associated with increased susceptibility to urolithiasis, renal inflammation and scarring. The aim of this study is to examine the presence and the detailed localization of endogenous retinoic acid activity in neonatal, young and adult mouse kidneys, to establish a fundamental ground for further research into potential target genes, as well as physiological and pathophysiological roles of endogenous retinoic acid in the post-natal kidneys. METHODOLOGY/PRINCIPAL FINDINGS: RARE-hsp68-lacZ transgenic mice were employed as a reporter for endogenous retinoic acid activity that was determined by X-gal assay and immunostaining of the reporter gene product, beta-galactosidase. Double immunostaining was performed for beta-galactosidase and markers of kidney tubules to localize retinoic acid activity. Distinct pattern of retinoic acid activity was observed in kidneys, which is higher in neonatal and 1- to 3-week-old mice than that in 5- and 8-week-old mice. The activity was present specifically in the principal cells and the intercalated cells of the collecting duct system in all age groups, but was absent from the glomeruli, proximal tubules, thin limbs of Henle's loop and distal tubules. CONCLUSIONS/SIGNIFICANCE: Endogenous retinoic acid activity exists in principal cells and intercalated cells of the mouse collecting duct system after birth and persists into adulthood. This observation provides novel insights into potential roles for endogenous retinoic acid beyond nephrogenesis and warrants further studies to investigate target genes and functions of endogenous retinoic acid in the kidney after birth, particularly in the collecting duct system. PMID- 21326616 TI - Current Research in Crohn's Disease and Ulcerative Colitis: Highlights from the 2010 ACG Meeting. PMID- 21326617 TI - The role of rhythmic neural synchronization in rest and task conditions. AB - Rhythmic neural synchronization is found throughout the brain during many different tasks and even at rest. Beyond their underlying mechanisms, the question of their role is still controversial. Modeling can bring insight on this difficult question. We review here our recent modeling results concerning this issue in different situations. During rest, we show how local rhythmic synchrony can induce a spatiotemporally organized spontaneous activity at the brain level. Then, we show how rhythmic synchrony decreases reaction time in attention and enhances the strength and speed of information transfer between different groups of neurons. Finally, we show that when rhythmic synchrony creates firing phases, the learning with spike timing-dependent plasticity of repeatedly presented input patterns is greatly enhanced. PMID- 21326618 TI - Flexible decisions and chess expertise. PMID- 21326619 TI - Life Cycle, Morphology, Ontogenesis, and Phylogeny of Bromeliothrix metopoides nov. gen., nov. spec., a Peculiar Ciliate (Protista, Colpodea) from Tank Bromeliads (Bromeliaceae). AB - Bromeliothrix metopoides was discovered in tank bromeliads from Central and South America. Pure cultures could be established in various media stimulating growth of its food, i.e. bacteria and heterotrophic flagellates of the genus Polytomella. The new ciliate was investigated in the light- and scanning electron microscope, with various silver impregnation techniques, and with molecular methods, using the small-subunit rDNA. The morphology and its changes during the life cycle are documented by 167 figures and a detailed morphometry. Bromeliothrix metopoides is about 27-55 * 22-36 MUm in size and has a complex life cycle with Metopus-shaped, bacteriophagous theronts and trophonts (microstomes) and obovate, flagellate-feeding macrostomes having a large, triangular oral apparatus. The thin-walled resting cysts of the theronts and trophonts are uniquely ellipsoidal, while the thick-walled cyst of the macrostome morph is globular. Reproduction occurs in freely motile condition either by binary fission or polytomy, producing a unique, motile "division chain" composed of four globular offspring, of which the central ones are connected by a curious, plug-like holdfast. Division is associated with a complete reorganization of the parental oral and somatic infraciliature. Stomatogenesis is merotelokinetal as in other members of the order Colpodida. The right polykinetid is generated by the rightmost postoral kinety, while the left polykinetid is produced by the two left postoral kineties and five left side kineties. The division in freely motile condition resembles the Exocolpodidae Foissner et al., 2002, to which Bromeliothrix is tentatively assigned, differing from Exocolpoda mainly by the formation of a macrostome morph and a division chain. Bromeliothrix has a ciliary and silverline pattern typical for members of the family Colpodidae. This matches the molecular classification which, however, hardly reflects the outstanding division and life cycle, suggesting some decoupling of morphological and molecular evolution. The specific morphological and ontogenetic traits of Bromeliothrix are interpreted as adaptations to the highly competitive habitat, favouring r-selected life strategies. Bromeliothrix metopoides is widespread in various tank bromeliads and can be easily cultivated in a wide variety of limnetic and terrestrial media. Thus, it remains obscure why this ciliate is restricted to tank bromeliads, i.e. did not occur in about 2,000 soil and freshwater samples investigated globally, including some 100 samples from Central and South America. PMID- 21326620 TI - Interventions Aimed at Improving Child Language by Improving Maternal Responsivity. AB - Maternal responsivity, or the ways in which mothers provide for, interact with, and respond to their children, helps to shape their children's development, including language development. In this chapter, we describe maternal responsivity as a multilevel construct with different measures appropriate for each level. Molar responsivity refers to aspects of interaction style such as affect that can best be measured with rating scales. Molecular responsivity refers to contingent maternal behaviors that occur in response to child behaviors; and are best reflected by the frequencies of occurrence of these contingent behaviors. Results of many studies have demonstrated that both molar and molecular responsivity are related to important child outcomes such as language development. Children of more responsive mothers tend to have better outcomes. Based on these findings, interventions aimed at improving maternal responsivity and thereby child language outcomes have been developed and investigated through a number of studies. Results have shown positive outcomes for maternal responsivity and lesser secondary benefits to child language outcomes. Some of the qualities that appear associated with better outcomes include timing the interventions to co-occur with specific developments in child behaviors, teaching over a span of approximately 10-12 sessions, and designing lessons to be culturally sensitive to individual families. PMID- 21326621 TI - Increasing Communication in Children With Concurrent Vision and Hearing Loss. AB - Nine children with complex communication needs and concurrent vision and hearing losses participated in an intervention program aimed at increasing intentional prelinguistic communication. The intervention constituted a pilot, descriptive study of an adapted version of prelinguistic milieu teaching, hence referred to as A-PMT. In A-PMT, natural gestures and vocalizations were targeted in child focused, one-on-one activities conducted by a member of the project staff. Adaptations included using more physical prompts than in other forms of PMT and using means other than directed eye gaze to determine directionality of gestures. All nine participants increased their rates of initiated, intentional communication substantially during the course of intervention; in addition, each participant acquired new forms of natural gestures. Results were limited primarily to requests (as opposed to other communication functions). Discussion centers on how to promote more generalized communication developments in future implementations of the program. PMID- 21326622 TI - Linking of Glycine Receptor Transmembrane Segments Three and Four Allows Assignment of Intrasubunit-Facing Residues. AB - Glycine receptors (GlyRs) are pentameric ligand-gated ion channels that mediate inhibitory neurotransmission in the brain and spinal cord and are targets of alcohols and anesthetics. The transmembrane (TM) domain of GlyR subunits is composed of four alpha-helical segments (TM1-4), but there are conflicting data about the orientation of TM3 and TM4 and, therefore, also the proximity of residues (e.g., A288) that are important for alcohol and anesthetic effects. In the present study, we investigated the proximity of A288 in TM3 to residues in TM4 from M404 to K411. We generated eight double mutant GlyRs (A288C/M404C, A288C/F405C, A288C/Y406C, A288C/W407C, A288C/I408C, A288C/I409C, A288C/Y410C, and A288C/K411C), as well as the corresponding single mutants, and expressed them in Xenopus laevis oocytes. To measure glycine responses, we used two-electrode voltage clamp electrophysiology. We built homology models of the GlyR using structures of the nicotinic acetylcholine receptor (nAChR) and a prokaryotic ion channel (Gloeobacter violaceus, GLIC) as templates, and asked which model best fit our experimental data. Application of the cross-linking reagent HgCl(2) in the closed state produced a leftward shift in the glycine concentration-response curves of the A288C/W407C and A288C/Y410C mutants, suggesting they are able to form cross-links. In addition, when HgCl(2) was coapplied with glycine, responses were changed in the A288C/Y406C, A288C/I409C, and A288C/Y410C double mutants, suggesting that agonist-induced rotation of TM4 allows A288C/Y406C and A288C/I409C to cross-link. These results are consistent with a model of GlyR, based on nAChR, in which A288, Y406, W407, I409, and Y410 face into a four helical bundle. PMID- 21326623 TI - Aggressive management of tibial osteomyelitis shows good functional outcomes. AB - BACKGROUND: Severe open tibial fractures can be successfully treated acutely with a combined orthopedic and plastic surgery approach, but a proportion will go on to develop chronic osteomyelitis. For the past 6 years, an aggressive approach of bone and soft tissue debridement followed by skeletal reconstruction and vascularized tissue transfer has been pursued by the orthopedic and plastic surgery teams at Liverpool Hospital. We present the results of our patient series. METHODS: All patients treated for chronic osteomyelitis by combined skeletal stabilization, debridement, and flap coverage between January 2000 and July 2006 were included. Clinical record review was combined with patient interviews and questionnaires. Outcome measures included fracture union, stable soft tissue coverage, freedom from infection, mobility, return to work/sport, and pain. RESULTS: Twelve patients were followed up after a mean of 4.2 years. Patients had undergone a mean of 8.4 procedures prior to treatment, and a mean of 2.5 procedures as part of their treatment. We achieved fracture union, stable soft tissue coverage, and eradicated infection in all patients. All patients were walking, 10 unaided, and 80% had returned to work. All but one patient involved in sport at the time of injury had returned to sport. Two patients had mild pain when walking long distances only. CONCLUSION: Skeletal stabilization, debridement, and flap coverage is costly and complex surgery. However, in our series, these interventions resulted in eradication of infection and good clinical outcomes in most cases, providing an alternative to both amputation and long-term antibiotic therapy. PMID- 21326624 TI - Single-stage full-thickness scalp reconstruction using acellular dermal matrix and skin graft. AB - Full-thickness scalp defects with exposed calvarium pose a reconstructive challenge, particularly in patients with extensive comorbidities. A single-stage acellular dermal matrix and split-thickness skin graft reconstruction represents a simple and valuable surgical approach to achieving durable scalp coverage without requiring a donor-site or prolonged treatment. Reconstruction of full thickness scalp defects with exposed calvarium is a difficult problem that generally requires local or free flap reconstruction. However, patients with significant medical comorbidities present a further challenge given the risks of a major surgical procedure. Simple skin graft directly onto bone frequently fails and does not provide durable coverage, while combined artificial skin substitute and split-thickness skin graft approach involves a prolonged treatment period with multiple-staged procedures. Herein, we present a case of an 82-year-old female patient with complex medical comorbidities with a large scalp defect and calvarial exposure following Moh's surgery. She was successfully treated with a single-stage acellular dermal matrix and a STSG reconstruction. Her treatment period was effectively shortened, and she had an excellent clinical outcome. PMID- 21326625 TI - Cecal varices presenting as anemia: case report and review of the literature. AB - Since the original description of colonic varices in 1954 [N Engl J Med 1954;250:434-438], fewer than 100 cases have been reported in the literature. Particularly, even fewer cases of cecal varices have been reported. More than 75% of these cases have been due to portal hypertension. Our objective is to contribute a rare case with an uncommon presentation to the medical literature. We present the case of a 53-year-old male with hepatitis C and hepatitis B liver cirrhosis who presented for outpatient colonoscopy. The indication for colonoscopy was bright red blood per rectum and iron deficiency anemia. A significant amount of varices were noted in the cecum and proximal ascending colon. No endoscopic evidence of colonic bleeding was noted. This is the first reported case of cecal varices not presenting with massive lower gastrointestinal bleeding. PMID- 21326626 TI - Incidence and impact of baseline electrolyte abnormalities in patients admitted with chemotherapy induced febrile neutropenia. AB - BACKGROUND: Febrile neutropenia (FN) and myelosupression remain a challenging oncologic medical emergency and dose limiting toxicity associated with chemotherapy for cancers. Various factors are known to affect the outcomes for patients diagnosed with FN. Electrolyte abnormalities have commonly been observed, but the real incidence and their impact has been only scarcely studied in literature. METHODS: This was a prospective, observational study. A total of two hundred and fifteen (215) patients admitted between January 2007 and August 2008 were included. Analysis of data was made using SPSS version16.0.Toxicity profile was graded according to CTC version 3.0. RESULTS: Almost equal number of FN was observed in both solid tumors and hematological cancers with almost equal gender distribution. Of all 83.5% patients demonstrated some electrolyte abnormalities. All grades combined, hypokalemia was seen in 48% of patients, with 51.4% having grade I, 33.3% grade III and 15.2% G IV (life threatening) hypokalemia. Hyponatremia of all grades was seen in 67.9% patients, of them 60.3% had Grade I, 33.3% grade III and 0.7% patients had grade IV hyponatremia. Hypomagnesaemia (70 patients assessed) was seen in 54.3% patient, 94.7% having grade I decline. Average length of stay for patients who received IV electrolyte replacement was 6.3 days compared to 4.9 days in those who did not. Out of 90 patients who required special care unit 75 had electrolyte abnormalities, of 15 patients who expired 13 had electrolyte abnormalities CONCLUSION: This analysis, which is first of its kind, suggests that decline in electrolyte levels is frequently observed in patients presenting with FN. These abnormalities can have independent negative impact on the outcome for such patients. Special attention should be paid to electrolyte imbalance right from the outset. PMID- 21326627 TI - miR-21 Expression in Pregnancy-Associated Breast Cancer: A Possible Marker of Poor Prognosis. AB - AIMS: microRNAs (miRNAs) are a class of small noncoding RNAs that can act as key modulators in tumorigenesis-related genes. Specifically, it has been suggested that miR-21 overexpression plays a role in the development and progression of breast cancer. So far, the role of miRNAs in pregnancy-associated breast cancer (PABC) has not been investigated. METHODS AND RESULTS: We evaluated miR-21 expression by quantitative RT-PCR in 35 patients, 25 with PABC and 10 control breast cancer cases not pregnancy-associated with similar clinicopathological features. We then analyzed protein expression for PTEN, BCL2 and PDCD4 as miR-21 target genes by IHC, and finally correlated the results with patients' clinicopathological features.Significant overexpression of miR-21 in PABC tumors compared to normal adjacent tissue was found. Overexpression of miR-21 was frequently found in high grade tumors with loss of hormone receptor expression and was significantly associated with positive lymph nodes (p=0.025). In PABC patients, PTEN, BCL2 and PDCD4 target protein expression was decreased in 80%, 76% and 40% respectively. CONCLUSION: Our study supports the involvement of miR 21 in breast cancer progression and metastasis formation in PABC implying a role of this miRNA as a marker for poor prognosis in PABC patients. PMID- 21326628 TI - Patients with localised prostate cancer (t1 - t2) show improved overall long-term survival compared to the normal population. AB - BACKGROUND: Little information is available on the long-term outcomes of patients with localised prostate cancer. OBJECTIVE: To examine the long-term survival of patients with localised prostate gland carcinoma T1 - T2, N0, M0 (UICC stage I and II) compared to the normal population. DESIGN: Retrospective cohort. SETTING: Regensburg, Germany. PARTICIPANTS: Data on 2121 patients with histologically confirmed, localised prostate cancer diagnosed between 1998 and 2007 were extracted from the cancer registry of the tumour centre in Regensburg, Germany. MEASUREMENTS: Overall survival rate in the patient cohort was estimated and compared to the expected survival rate of a comparable group in the general population derived from the official life-tables of Germany stratified by age, sex and calendar year. RESULTS: Ten years after diagnosis, patients with stage I and II localised prostate gland carcinoma had an approximately 10% increase in survival compared to the normal male population (Relative Survival = 110.7%, 95% CI 106.6 - 114.8%). LIMITATIONS: We did not examine the effect of cancer treatment or cancer aggressiveness on the overall survival of patients. We did not assess the incidence of subsequent non-primary cancers in our patient population or how this incidence affects the patients' follow-up care and survival. CONCLUSIONS: Patients with stage I+II localised prostate gland carcinoma have improved survival compared with the normal male population. This finding cannot be explained solely by the administration of prostate carcinoma treatments, suggesting that men who participate in PSA screening may have better overall health behaviors and care than men who do not participate in screening. Future research should examine how treatment choice, especially an "active surveillance" approach to care, affects survival in these patients more than ten years after diagnosis. PMID- 21326629 TI - Phase I Dose Escalation Study of Sodium Stibogluconate (SSG), a Protein Tyrosine Phosphatase Inhibitor, Combined with Interferon Alpha for Patients with Solid Tumors. AB - PURPOSE: Sodium stibogluconate (SSG), a small molecule inhibitor of protein tyrosine phosphatases, combined with IFN-alpha-2b (IFN-alpha) inhibited solid tumor cell line growth in vitro. We conducted a phase I clinical trial with SSG plus IFN-alpha in advanced cancer patients to assess tolerance, maximum tolerated dose (MTD) and immune system effects. EXPERIMENTAL DESIGN: SSG was administered intravenously alone for five days of week 1, cycle 1 (21 days per cycle) and together with IFN-alpha 2b s (3 million units sc TIW) in week 2, and after a rest during week 3, on a 2-week on/1-week off cycle. SSG dose levels were 400, 600, 900, 1125, and 1350 mg/m(2). RESULTS: Twenty-four patients were studied. Common toxicities included asymptomatic elevated serum lipase, thrombocytopenia, fatigue, fever, chills and anemia. The dose-limiting toxicities (DLT) were hypokalemia, thrombocytopenia, fatigue, pancreatitis and skin rash. The MTD was 900 mg/m(2 )SSG and IFN-alpha, 3 million units TIW. At this dose, patients had a significantly lower number of regulatory T cells (T(R )Cells) (p = 0.012), myeloid dendritic cells (mDC) (p = 0.028); higher percentage of natural killer (NK) cells that synthesized perforin (p = 0.046) and of plasmacytoid dendritic cells (pDC) that secreted IFN-alpha (p = 0.018) in response to activation through toll-like receptor (TLR) 7 and TLR 8 by CL097, the highly water-soluble derivative of the imidazoquinoline compound R848. CONCLUSIONS: SSG in combination with IFN-alpha 2b was well tolerated and augmented cellular immune parameters. PMID- 21326630 TI - Chemical synthesis and biological activities of 3-alkyl pyridinium polymeric analogues of marine toxins. AB - Two new large poly-1,3-dodecylpyridinium salts, APS12 and APS12-2 of 12.5- and 14.7-kDa size, respectively, were synthesised and tested for their pore-forming and transfection capabilities in HEK 293 and undifferentiated mouse ES cells using patch-clamp recording, Ca(2+) imaging and flow cytometry. Polymerisation reactions were enhanced by microwaves, and the product sizes were controlled by altering the irradiation time. This method can also be applied to obtain polymers with variable linking chains as shown by the preparation of poly-(1,3 octylpyridinium) salt of 11.9-kDa size. Molecular weights of the final products were determined using ESIMS analysis, which also indicated the products to be amongst the largest macro-cycles ever recorded, up to a 900-membered ring. Anti bacterial, haemolytic and anti-acetylcholinesterase activities were also reported for the two dodecyl pyridinium polymers. These biological activities are characteristic to the structurally related marine toxin, poly-APS. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12154 010-0036-4) contains supplementary material, which is available to authorized users. PMID- 21326631 TI - A random-effects model for group-level analysis of diffuse optical brain imaging. AB - Diffuse optical imaging is a non-invasive technique for measuring changes in blood oxygenation in the brain. This technique is based on the temporally and spatially resolved recording of optical absorption in tissue within the near infrared range of light. Optical imaging can be used to study functional brain activity similar to functional MRI. However, group level comparisons of brain activity from diffuse optical data are difficult due to registration of optical sensors between subjects. In addition, optical signals are sensitive to inter subject differences in cranial anatomy and the specific arrangement of optical sensors relative to the underlying functional region. These factors can give rise to partial volume errors and loss of sensitivity and therefore must be accounted for in combining data from multiple subjects. In this work, we describe an image reconstruction approach using a parametric Bayesian model that simultaneously reconstructs group-level images of brain activity in the context of a random effects analysis. Using this model, we demonstrate that localization accuracy and the statistical effects size of group-level reconstructions can be improved when compared to individualized reconstructions. In this model, we use the Restricted Maximum Likelihood (ReML) method to optimize a Bayesian random-effects model. PMID- 21326633 TI - Sub-wavelength infrared imaging of lipids. AB - Infrared absorption spectroscopy of lipid layers was performed by combining optics and scanning probe microscopy. This experimental approach enables sub diffraction IR imaging with a spatial resolution on the nanometer scale of 1, 2 dioleoyl-sn-glycero-3-phosphocholine lipid layers. PMID- 21326632 TI - The structural origin of second harmonic generation in fascia. AB - Fascia tissue is rich in collagen type I proteins and can be imaged by second harmonic generation (SHG) microscopy. While identifying the overall alignment of the collagen fibrils is evident from those images, the tridimensional structural origin for the observation of SHG signal is more complex than it apparently seems. Those images reveal that the noncentrosymmetric (piezoelectric) structures are distributed heterogeneously on spatial dimensions inferior to the resolution provided by the nonlinear optical microscope (sub-micron). Using piezoresponse force microscopy (PFM), we show that an individual collagen fibril has a noncentrosymmetric structural organization. Fibrils are found to be arranged in nano-domains where the anisotropic axis is preserved along the fibrillar axis, while across the collagen sheets, the phase of the second order nonlinear susceptibility is changing by 180 degrees between adjacent nano-domains. This complex architecture of noncentrosymmetric nano-domains governs the coherent addition of 2omega light within the focal volume and the observed features in the SHG images taken in fascia. PMID- 21326634 TI - A study on tetrahedron-based inhomogeneous Monte Carlo optical simulation. AB - Monte Carlo (MC) simulation is widely recognized as a gold standard in biophotonics for its high accuracy. Here we analyze several issues associated with tetrahedron-based optical Monte Carlo simulation in the context of TIM-OS, MMCM, MCML, and CUDAMCML in terms of accuracy and efficiency. Our results show that TIM-OS has significant better performance in the complex geometry cases and has comparable performance with CUDAMCML in the multi-layered tissue model. PMID- 21326635 TI - Contrast improvement of terahertz images of thin histopathologic sections. AB - We present terahertz images of 10 MUm thick histopathologic sections obtained in reflection geometry with a time-domain spectrometer, and demonstrate improved contrast for sections measured in paraffin with water. Automated segmentation is applied to the complex refractive index data to generate clustered terahertz images distinguishing cancer from healthy tissues. The degree of classification of pixels is then evaluated using registered visible microscope images. Principal component analysis and propagation simulations are employed to investigate the origin and the gain of image contrast. PMID- 21326636 TI - Flexible hollow optical fiber bundle for infrared thermal imaging. AB - A flexible and coherent bundle of hollow optical fibers was fabricated for infrared thermal imaging. For acquisition of thermal images, differences in the transmission efficiency among the fibers were numerically compensated to obtain high temperature resolution of 1 degrees C for measuring body temperature. In a lens system with 10-fold magnification and hollow fibers of 320-MUm inner diameter, the spatial resolution is around 3 mm. The hollow-fiber bundle enables observation of the surface temperature of inner organs and blood flow of the surfaces when the bundle is introduced into the human body with an endoscope. PMID- 21326637 TI - Two-photon excited hemoglobin fluorescence. AB - We discovered that hemoglobin emits high energy Soret fluorescence when two photon excited by the visible femtosecond light sources. The unique spectral and temporal characteristics of hemoglobin fluorescence were measured by using a time resolved spectroscopic detection system. The high energy Soret fluorescence of hemoglobin shows the spectral peak at 438 nm with extremely short lifetime. This discovery enables two-photon excitation fluorescence microscopy to become a potentially powerful tool for in vivo label-free imaging of blood cells and vessels. PMID- 21326638 TI - High speed multiphoton axial scanning through an optical fiber in a remotely scanned temporal focusing setup. AB - Simultaneous spatial and temporal focusing is used to acquire high speed (200Hz), chemically specific axial scans of mouse skin through a single-mode fiber. The temporal focus is remotely scanned by modulating the group delay dispersion (GDD) at the proximal end of the fiber. No moving parts or electronics are required at the distal end. A novel GDD modulation technique is implemented using a piezo bimorph mirror in a folded grating pair to achieve a large GDD tuning range at high speed. PMID- 21326639 TI - Prospective evaluation of a portable depth-sensitive optical spectroscopy device to identify oral neoplasia. AB - A portable, depth-sensitive clinical spectroscopy device for noninvasive early diagnosis of oral cancer is described. We carried out a pilot study to evaluate the ability of the device to identify oral neoplasia using a previously developed diagnostic algorithm. A total of 79 oral sites in 33 subjects, including 28 patients with oral lesions and 5 healthy volunteers, were measured and analyzed. Measurements of 54 nonkeratinized oral sites yielded an area under the receiver operating characteristic curve of 0.90. Measurements of 25 keratinized oral sites yielded an area under the receiver operating characteristic curve of 0.83. PMID- 21326640 TI - Temporal changes of human cone photoreceptors observed in vivo with SLO/OCT. AB - In this study we use our previously introduced scanning laser ophthalmoscope (SLO) / transverse scanning optical coherence tomography (TS-OCT) instrument to investigate long term changes in cone photoreceptors. The instrument is capable to provide 3D information of the human cone photoreceptors with negligible eye motion artifacts due to an implemented 3D motion correction on a cellular level. This allows for an in vivo investigation of exactly the same location on the retina with cellular resolution over several days. Temporal changes in the backscattered intensity are observed and quantified within the junction between inner and outer segments of cone photoreceptors, the cone outer segments, the end tips of cone photoreceptors and the retinal pigment epithelium. Furthermore, the length of individual cone outer segments is measured and observed over time. We show, to the best of our knowledge for the first time, that bright reflection spots which are located within the outer segment of cone photoreceptors change their position when observed over extended time periods. The average measured bright reflection spot motion speed corresponds well to the expected cone growth speed. We believe that this observation can be associated with the first direct in vivo imaging of the cone renewal process. PMID- 21326641 TI - Remote focusing for programmable multi-layer differential multiphoton microscopy. AB - We present the application of remote focusing to multiphoton laser scanning microscopy and utilize this technology to demonstrate simultaneous, programmable multi-layer imaging. Remote focusing is used to independently control the axial location of multiple focal planes that can be simultaneously imaged with single element detection. This facilitates volumetric multiphoton imaging in scattering specimens and can be practically scaled to a large number of focal planes. Further, it is demonstrated that the remote focusing control can be synchronized with the lateral scan directions, enabling imaging in orthogonal scan planes. PMID- 21326642 TI - Monitoring blood flow responses during topical ALA-PDT. AB - Photodynamic therapy (PDT) using topical 5-aminolevulinic acid (ALA) is currently used as a clinical treatment for nonmelanoma skin cancers. In order to optimize PDT treatment, vascular disruption early in treatment must be identified and prevented. We present blood flow responses to topical ALA-PDT in a preclinical model and basal cell carcinoma patients assessed by diffuse correlation spectroscopy (DCS). Our results show that ALA-PDT induced early blood flow changes and these changes were irradiance dependent. It is clear that there exists considerable variation in the blood flow responses in patients from lesion to lesion. Monitoring blood flow parameter may be useful for assessing ALA-PDT response and planning. PMID- 21326643 TI - In-vivo two-photon imaging of the honey bee antennal lobe. AB - Due to the honey bee's importance as a simple neural model, there is a great need for new functional imaging modalities. Herein we report on the development and new findings of a combined two-photon microscope with a synchronized odor stimulus platform for in-vivo functional and morphological imaging of the honey bee's olfactory system focusing on its primary centers, the antennal lobes (ALs). Our imaging platform allows for simultaneously obtaining both morphological measurements of the AL's functional units, the glomeruli, and in-vivo calcium recording of their neural activities. By applying external odor stimuli to the bee's antennae, we were able to record the characteristic glomerular odor response maps. Compared to previous works where conventional fluorescence microscopy was used, our approach has been demonstrated to offer all the advantages of multi-photon imaging, providing substantial enhancement in both spatial and temporal resolutions while minimizing photo-damages. In addition, compared to previous full-field microscopy calcium recordings, a four-fold improvement in the functional signal has been achieved. Finally, the multi-photon associated extended penetration depth allows for functional imaging of profound glomeruli. PMID- 21326644 TI - Images of photoreceptors in living primate eyes using adaptive optics two-photon ophthalmoscopy. AB - In vivo two-photon imaging through the pupil of the primate eye has the potential to become a useful tool for functional imaging of the retina. Two-photon excited fluorescence images of the macaque cone mosaic were obtained using a fluorescence adaptive optics scanning laser ophthalmoscope, overcoming the challenges of a low numerical aperture, imperfect optics of the eye, high required light levels, and eye motion. Although the specific fluorophores are as yet unknown, strong in vivo intrinsic fluorescence allowed images of the cone mosaic. Imaging intact ex vivo retina revealed that the strongest two-photon excited fluorescence signal comes from the cone inner segments. The fluorescence response increased following light stimulation, which could provide a functional measure of the effects of light on photoreceptors. PMID- 21326645 TI - Imaging carious dental tissues with multiphoton fluorescence lifetime imaging microscopy. AB - In this study, multiphoton excitation was utilized to image normal and carious dental tissues noninvasively. Unique structures in dental tissues were identified using the available multimodality (second harmonic, autofluorescence, and fluorescence lifetime analysis) without labeling. The collagen in dentin exhibits a strong second harmonic response. Both dentin and enamel emit strong autofluorescence that reveals in detail morphological features (such as dentinal tubules and enamel rods) and, despite their very similar spectral profiles, can be differentiated by lifetime analysis. Specifically, the carious dental tissue exhibits a greatly reduced autofluorescence lifetime, which result is consistent with the degree of demineralization, determined by micro-computed tomography. Our findings suggest that two-photon excited fluorescence lifetime imaging may be a promising tool for diagnosing and monitoring dental caries. PMID- 21326646 TI - Optical vortices generated by a PANDA ring resonator for drug trapping and delivery applications. AB - We propose a novel drug delivery system (DDS) by using a PANDA ring resonator to form, transmit and receive the microscopic volume by controlling some suitable ring parameters. The optical vortices (gradient optical field/well) can be generated and used to form the trapping tool in the same way as the optical tweezers. The microscopic volume (drug) can be trapped and moved (transported) dynamically within the wavelength router or network. In principle, the trapping force is formed by the combination between the gradient field and scattering photons, which has been reviewed. The advantage of the proposed system is that a transmitter and receiver can be formed within the same system, which is called transceiver, in which the use of such a system for microscopic volume (drug volume) trapping and transportation (delivery) can be realized. PMID- 21326647 TI - Improved bioluminescence and fluorescence reconstruction algorithms using diffuse optical tomography, normalized data, and optimized selection of the permissible source region. AB - Reconstruction algorithms are presented for two-step solutions of the bioluminescence tomography (BLT) and the fluorescence tomography (FT) problems. In the first step, a continuous wave (cw) diffuse optical tomography (DOT) algorithm is used to reconstruct the tissue optical properties assuming known anatomical information provided by x-ray computed tomography or other methods. Minimization problems are formed based on L1 norm objective functions, where normalized values for the light fluence rates and the corresponding Green's functions are used. Then an iterative minimization solution shrinks the permissible regions where the sources are allowed by selecting points with higher probability to contribute to the source distribution. Throughout this process the permissible region shrinks from the entire object to just a few points. The optimum reconstructed bioluminescence and fluorescence distributions are chosen to be the results of the iteration corresponding to the permissible region where the objective function has its global minimum This provides efficient BLT and FT reconstruction algorithms without the need for a priori information about the bioluminescence sources or the fluorophore concentration. Multiple small sources and large distributed sources can be reconstructed with good accuracy for the location and the total source power for BLT and the total number of fluorophore molecules for the FT. For non-uniform distributed sources, the size and magnitude become degenerate due to the degrees of freedom available for possible solutions. However, increasing the number of data points by increasing the number of excitation sources can improve the accuracy of reconstruction for non-uniform fluorophore distributions. PMID- 21326648 TI - A cylindrical zoom lens unit for adjustable optical sectioning in light sheet microscopy. AB - Light sheet microscopy became a powerful tool in life sciences. Often, however, the sheet geometry is fixed, whereas it would be advantageous to adjust the sheet geometry to specimens of different dimensions. Therefore we developed an afocal cylindrical zoom lens system comprising only 5 lenses and a total system length of less than 160 mm. Two movable optical elements were directly coupled, so that the zoom factor could be adjusted from 1x to 6.3x by a single motor. Using two different illumination objectives we achieved a light sheet thickness ranging from 2.4 um to 36 um corresponding to lateral fields of 54 um to 12.3 mm, respectively. Polytene chromosomes of salivary gland cell nuclei of C.tentans larvae were imaged in vivo to demonstrate the advantages in image contrast by imaging with different light sheet dimensions. PMID- 21326649 TI - Fluorescence time-resolved imaging system embedded in an ultrasound prostate probe. AB - Ultrasound imaging (US) of the prostate has a low specificity to distinguish tumors from the surrounding tissues. This limitation leads to systematic biopsies. Fluorescent diffuse optical imaging may represent an innovative approach to guide biopsies to tumors marked with high specificity contrast agents and therefore enable an early detection of prostate cancer. This article describes a time-resolved optical system embedded in a transrectal US probe, as well as the fluorescence reconstruction method and its performance. Optical measurements were performed using a pulsed laser, optical fibers and a time resolved detection system. A novel fast reconstruction method was derived and used to locate a 45 uL ICG fluorescent inclusion at a concentration of 10 uM, in a liquid prostate phantom. Very high location accuracy (0.15 cm) was achieved after reconstruction, for different positions of the inclusion, in the three directions of space. The repeatability, tested with ten sequential measurements, was of the same order of magnitude. Influence of the input parameters (optical properties and lifetime) is presented. These results confirm the feasibility of using optical imaging for prostate guided biopsies. PMID- 21326650 TI - The societal costs of insomnia. AB - OBJECTIVE: Insomnia can be broadly defined as difficulty initiating or maintaining sleep, or sleep that is not refreshing or of poor quality with negative effect on daytime function. Insomnia can be a primary condition or comorbid to an underlying disorder. Subjective measures of insomnia used in population studies, usually based on complaints of unsatisfactory sleep, put the prevalence at about 10%. Insomnia is more common in the elderly and in women, and is often associated with medical and psychiatric disorders. This review examines the measures used to assess quality of sleep (QOS) and daytime functioning and the impact of insomnia on society using these measures. METHODS: Literature searches were performed to identify all studies of insomnia (primary and comorbid) in adults (aged 18-64 years) and the elderly (aged >= 65 years) with baseline and/or outcomes relating to QOS or daytime functioning. The impact of poor QOS on quality of life (QOL), psychomotor and cognitive skills, health care resource utilization, and other societal effects was examined. RESULTS: Although definitions and measurement scales used to assess sleep quality vary widely, it is clear that the societal consequences of insomnia are substantial and include impaired QOL and increased health care utilization. The impact of poor QOS and impaired daytime functioning common in insomnia can lead to indirect effects such as lower work productivity, increased sick leave, and a higher rate of motor vehicle crashes. CONCLUSIONS: Insomnia is associated with substantial direct and indirect costs to society. It is almost impossible to separate the costs associated with primary and comorbid insomnia. More studies are required which control for the severity of any primary disorder to accurately evaluate the costs of comorbid insomnia. Development of standardized diagnostic and assessment scales will enable more accurate quantification of the true societal burden of insomnia and will contribute to greater understanding of this disorder. PMID- 21326651 TI - Clinical outcomes of long-acting injectable risperidone in patients with schizophrenia: six-month follow-up from the Electronic Schizophrenia Treatment Adherence Registry in Latin America. AB - BACKGROUND: Risperidone long-acting injection (RLAI) has been shown to be efficacious, improve compliance, and increase long-term retention rate on therapy. The aim of this work was to determine the effect of RLAI on clinical outcome and hospitalization rate in patients with schizophrenia or schizoaffective disorder enrolled in the electronic Schizophrenia Treatment Adherence Registry in Latin America. METHODS: Data were collected at baseline, retrospectively for the 12 months prior to baseline, and prospectively every three months for 24 months. Hospitalization prior to therapy was assessed by a retrospective chart review. Efficacy and functioning were evaluated using Clinical Global Impression of Illness Severity (CGI-S), Personal and Social Performance (PSP), and Global Assessment of Functioning (GAF) scores. Relapse and treatment were also registered. RESULTS: Patients were recruited in Mexico (n = 53), Brazil (n = 11), and Colombia (n = 15). Sixty-five percent (n = 52) were male, and mean age was 32.9 years. Patients were classified as having schizophrenia (n = 73) or schizoaffective disorder (n = 6). The mean dose of RLAI at six months was 34.1 mg (standard deviation = 10.2 mg). The percentage of hospitalized patients before treatment was 28.2% and 5.1% at six months after initiating RLAI (P < 0.001). Significant changes were registered on CGI-S, GAF, and PSP scores. CONCLUSIONS: RLAI was associated with an improvement in clinical symptoms and functioning, and a greater reduction in hospitalization. PMID- 21326652 TI - Evidence to practice: treatment of anxiety in individuals with autism spectrum disorders. AB - CLINICAL QUESTION: What treatment improves social interactions and reduces reports of anxiety symptoms in individuals with autism spectrum disorders (ASD) and a co-occurring anxiety disorder? RESULTS: Systematic reviews and randomized clinical trials suggest that cognitive behavior therapy in tandem with direct instruction of social skills using applied behavior analysis intervention components may be effective for treating anxiety in individuals with high functioning ASD. For individuals with ASD, an anxiety disorder, and an intellectual disability, systematic desensitization may be effective. IMPLEMENTATION: Intervention should emphasize teaching social skills. Reinforcers (ie, rewards based upon the client's interests) should be used to encourage participation in therapy. Treatment should incorporate visual aides and family involvement. Intervention components involving abstract concepts, visualization, and discussions of emotions are less useful given difficulties in abstract reasoning and communication inherent to ASD. PMID- 21326653 TI - Treatment of attention deficit hyperactivity disorder with monoamine amino acid precursors and organic cation transporter assay interpretation. AB - BACKGROUND: This paper documents a retrospective pilot study of a novel approach for treating attention deficit hyperactivity disorder (ADHD) with amino acid precursors of serotonin and dopamine in conjunction with urinary monoamine assays subjected to organic cation transporter (OCT) functional status determination. The goal of this research was to document the findings and related considerations of a retrospective chart review study designed to identify issues and areas of concern that will define parameters for a prospective controlled study. METHODS: This study included 85 patients, aged 4-18 years, who were treated with a novel amino acid precursor protocol. Their clinical course during the first 8-10 weeks of treatment was analyzed retrospectively. The study team consisted of PhD clinical psychologists, individuals compiling clinical data from records, and a statistician. The patients had been treated with a predefined protocol for administering amino acid precursors of serotonin and dopamine, along with OCT assay interpretation as indicated. RESULTS: In total, 67% of participants achieved significant improvement with only amino acid precursors of serotonin and dopamine. In patients who achieved no significant relief of symptoms with only amino acid precursors, OCT assay interpretation was utilized. In this subgroup, 30.3% achieved significant relief following two or three urine assays and dosage changes as recommended by the assay results. The total percentage of patients showing significant improvement was 77%. CONCLUSION: The efficacy of this novel protocol appears superior to some ADHD prescription drugs, and therefore indicates a need for further studies to verify this observation. The findings of this study justify initiation of further prospective controlled studies in order to evaluate more formally the observed benefits of this novel approach in the treatment of ADHD. PMID- 21326654 TI - Anemia and 90-day mortality in COPD patients requiring invasive mechanical ventilation. AB - BACKGROUND: There are data to suggest that anemia is associated with increased mortality in patients with chronic obstructive pulmonary disease (COPD). In contrast, critically ill patients with low hemoglobin levels (4.3-5.5 mmol/L, 7.0 9.0 g/dL) in general do not appear to have a worsened clinical outcome. The effects of anemia in critically ill patients with COPD remain to be clarified. We examined the association between anemia (hemoglobin <7.4 mmol/L, <12.0 g/dL) and 90-day mortality in COPD patients with acute respiratory failure treated with invasive mechanical ventilation in a single-institution follow-up study. METHOD: We identified all COPD patients at our institution (n = 222) admitted for the first time to the intensive care unit (ICU) requiring invasive mechanical ventilation in 1994-2004. Data on patient characteristics (eg, hemoglobin, pH, blood transfusions, and Charlson Comorbidity Index), and mortality were obtained from population-based clinical and administrative registries and medical records. We used Cox's regression analysis to estimate mortality rate ratios (MRR) in COPD patients with and without anemia. RESULTS: A total of 42 (18%) COPD patients were anemic at time of initiating invasive mechanical ventilation. The overall 90-day mortality among anemic COPD patients was 57.1% versus 25% in nonanemic patients. The corresponding adjusted 90-day MRR was 2.6 (95% confidence interval 1.5-4.5). Restricting analyses to patients not treated with blood transfusions during their intensive care unit stay did not materially change the MRR. CONCLUSION: We found anemia to be associated with increased mortality among COPD patients with acute respiratory failure requiring invasive mechanical ventilation. PMID- 21326655 TI - Birth outcome in women with breast cancer, cutaneous malignant melanoma, or Hodgkin's disease: a review. AB - BACKGROUND: Data on birth outcome in women diagnosed with cancer before, during, or shortly after pregnancy are very sparse. The purpose of this review was to summarize the existing epidemiologic evidence of the adverse effect of breast cancer, cutaneous malignant melanoma, and Hodgkin's disease on birth outcome. METHODS: The MEDLINE database was used to review the literature systematically. Studies that examined the following outcomes were included: preterm birth, low birth weight, low birth weight at term, stillbirths, congenital abnormalities, male proportion of newborns, and mean birth weight. Studies were grouped according to whether the woman had been diagnosed with the specific cancer before, during, or shortly after pregnancy. RESULTS: Few data exist on birth outcome in women with breast cancer, melanoma, or Hodgkin's disease. The overall results from the limited number of studies, which included a comparison group for birth outcome, were reassuring. However, for women diagnosed with breast cancer before pregnancy, the only 2 studies that included comparison groups for birth outcome had conflicting results regarding the risk of preterm birth and congenital abnormalities. Furthermore, a recent cohort study of birth outcome in women who were diagnosed with Hodgkin's disease before pregnancy indicated a slightly increased risk of congenital abnormalities among the newborns. CONCLUSION: Overall, the existing studies offer reassuring results concerning the risks of adverse birth outcome for women diagnosed with breast cancer, melanoma, or Hodgkin's disease before, during or shortly after pregnancy. A limitation of most studies was the imprecise risk estimates caused by the small number of adverse birth outcomes and the lack of results stratified by treatment. Therefore, international collaboration is necessary in the future, to obtain more precise risk estimates for adverse birth outcomes, and to allow stratified analyses according to, for example, treatment. PMID- 21326656 TI - Tuberculosis mortality in HIV-infected individuals: a cross-national systematic assessment. AB - OBJECTIVE: Tuberculosis (TB) is a leading cause of death in human immunodeficiency virus (HIV)-positive individuals. We sought to compare mortality rates in TB/HIV co-infected individuals globally and by country/territory. DESIGN: We conducted a cross-national systematic assessment. METHODS: TB mortality rates in HIV-positive and HIV-negative individuals were obtained from the World Health Organization (WHO) Stop TB department for 212 recognized countries/territories in the years 2006-2008. Multivariate linear regression determined the impact of health care resource and economic variables on our outcome variable, and TB mortality rates. RESULTS: In 2008, an estimated 13 TB/HIV deaths occurred per 100,000 population globally with the African region having the highest death rate ([AFRH] >=4% adult HIV-infection rate) at 86 per 100,000 individuals. The next highest rates were for the Eastern European Region (EEUR) and the Latin American Region (LAMR) at 4 and 3 respectively per 100,000 population. African countries' HIV-positive TB mortality rates were 29.9 times higher than non-African countries (95% confidence interval [CI]: 16.8-53.4). Every US$100 of government per capita health expenditure was associated with a 33% (95% CI: 24%-42%) decrease in TB/HIV mortality rates. The multivariate model also accounted for calendar year and did not include highly active antiretroviral therapy (HAART) coverage. CONCLUSIONS: Our results indicate that while the AFRH has the highest TB/HIV death rates, countries in EEUR and LAMR also have elevated mortality rates. Increasing health expenditure directed towards universal HAART access may reduce mortality from both diseases. PMID- 21326658 TI - "My two cents". PMID- 21326657 TI - Change in the prevalence of obesity and use of health care in Denmark: an observational study. AB - PURPOSE: The purpose of this study was to examine the influence of the increasing prevalence of obesity on the development of health care utilization in Denmark in the period 1987-2005. PATIENTS AND METHODS: From a random sample of adult Danes (19,142 women and 18,335 men) who participated in the Danish Health Interview Surveys in 1987, 1994, 2000, and 2005, self-reported data on type of health care utilization within the previous 3 months and on height and weight were obtained. RESULTS: Adjusted odds ratios (ORs) showed that an increased use of health care among obese men compared with those of normal weight was pronounced and significant for those aged 45-64 years, whereas it was weaker and borderline significant for those aged 25-44 and 65+ years. Among obese men, there was an increasing use of health care until 2005. Among women, there was also an increased use of health care among the obese women in comparison with the normal weight women. An increase in the use of health care was found among obese women during 1987-2000, followed by a leveling of utilization during 2000-2005. CONCLUSIONS: In conclusion, this study showed that the increase in health care utilization in Denmark could, in part, be attributed to an increase in prevalence of obesity and to an increase in health care utilization among obese men in particular. PMID- 21326659 TI - Introduction to clinical interventional radiology. AB - Within 10 years of Dr. Sven Seldinger's introduction of needle replacement of a catheter in 1953, Dr. Charles Dotter, at the University of Oregon Health Sciences, began to use catheters as surgical instruments. Dr. Dotter said, "The angiographer who enters into the treatment of arterial obstructive disease can now play a key role, if he is prepared and willing to serve as a true clinician, not just as a skilled catheter mechanic. He must accept the responsibility for the direct care of patients before and after the procedure; now see them as patients, not just as blocked arteries." On this prediction time has shown Dr. Dotter to be exactly right. We are on the verge of tremendous growth in peripheral vascular interventions, particularly in the arterial arena. There are several forces within and outside radiology that presaged this transition that will be explored in this issue. But it is clear that all of radiology, not just interventionalists, have finally heeded Dotter's message. In 2004, the American College of Radiology published a "white paper" on interventional radiology clinical practice. The white paper outlined the features and resource needs of interventional radiologists for providing patient care. In this issue we will explore the reasons why in 2004 there is no other way to practice interventional radiology than to practice as a clinical doctor. PMID- 21326660 TI - The evolution of interventional radiology. AB - Interventional radiology was once considered "angiography," or in some hospitals, "special procedures." Angiographers usually did not perform evaluation and management services. In 1963, Dr. Charles T. Dotter recognized the potential of catheters to be used in performing intravascular surgery. By the mid-1980s a wide array of therapeutic interventions and devices had been developed. The emergence of interventional radiology as a dedicated specialty, where interventionalists practice solely interventional radiology, has been a tremendous boost to referrals for therapeutic interventions. However, the possibility for change depends on the practice environment in which interventionalists work. This may serve as a note of caution to young interventionalists just out of fellowship; they have the most to lose if a practice doesn't support interventional clinical practice over the long haul in terms of time and resources. PMID- 21326661 TI - Clinical interventional radiology: parallels with the evolution of general surgery. AB - Parallels between the evolution of surgery into an accepted clinical specialty and changes in the practice of interventional radiology (IR) have been drawn. Technical advances have mandated a change in the role of interventional radiologists from diagnostic radiologist to that of the treating physician. The development of "modern" IR is an accelerated repetition of the evolution of "modern" clinical surgery. The resistance or delay of some to accept IR as a clinical specialty is a duplication of the resistance to accept surgery as a clinical specialty by medicine in general. It is clearly time to understand that the benefits the interventional radiologist brings to the patient far exceed his ability to synthesize imaging data with catheter skills. Those of us who have accepted this can take some comfort in the fact that we now tread a path already proven in its destination. PMID- 21326662 TI - Tracking changes in the practice of interventional radiology. AB - The Society of Interventional Radiology survey in 2000 to 2001 reported what appeared to be favorable results. However, closer scrutiny provides more information. The Society of Interventional Radiology's strategic plan calls for 80% of interventional radiologists to be clinical practitioners by the year 2006. Recent American College of Radiology practice guidelines support this goal. Interventionalists need to decide whether they are going to provide clinical care and those who chose to take on the clinical practice model will most likely be successful. PMID- 21326663 TI - Critical appraisal of the technical practice model for interventional radiology. AB - It is clear that interventional radiology contributes substantially to the status of radiology departments in the hospital as well as in the community. Experience has shown that clinical management is the key to well-reimbursed procedure volume and increased referrals for those services. Additionally, it allows the opportunity for interventionalists to participate in technological changes that we can envision right now, which could have significant impact on the management of numerous diseases. If treatment is "clearly indicated," then the interventionalist has an obligation to present that opinion to the patient and to implement that care if the patient desires. Interventional radiologists have recognized that clinical care requires service to the patient first and foremost. PMID- 21326664 TI - Hallmarks of a clinical practice. AB - The American College of Radiology recently ratified a practice guideline on interventional clinical practice that includes very specific details about what constitutes a clinical practice for interventional radiology as well as interventional neuroradiology. Several "benchmarks" were developed. These "benchmarks" are felt to be important in the Society of Interventional Radiology strategic plan. Interventionalists need to establish themselves as disease process or organ system experts to succeed in obtaining clinical referrals. Interventionalists who don't take the initiative to obtain patients and populate their schedules with interesting, well-reimbursed procedures will be relegated to performing mundane services. PMID- 21326665 TI - The potential for interventional radiologists of peripheral arterial disease. AB - It is unfortunate that in the peripheral arena surgeons often get the first referral for patients with peripheral arterial disease. Interventionalists should present themselves as vascular specialists to the referring community. Peripheral vascular disease in the future will be primarily an interventional specialty. Endovascular interventions are safe for people with claudication and interventionalists should offer them. If interventionalists provide comprehensive care and thoughtfully enter a market with the will to compete, it is very likely that they will succeed. PMID- 21326666 TI - Setting up a medical clinical office. AB - The lack of clinical office space is the biggest Achilles' heel of interventional radiology and establishing an office eliminates that weakness immediately. Many interventionalists practice within a hospital setting; however, setting up a clinical office outside the hospital offers more flexibility. There are several reasons why interventionalists who set up clinical practices will succeed well into the future. Also, the American Board of Medical Specialties offers the fully trained interventional radiologist board certification in interventional disease management. PMID- 21326667 TI - Transitioning to a clinical practice model in your local environment. AB - Once the clinical practice model is established, transitioning is fairly easy. Office staff such as schedulers and nurse practitioners should understand that all elective therapeutic interventions are to be booked only by interventional radiologists once the interventionalist has done a thorough diagnostic evaluation, including a history and physical in an office environment. To optimize the interventionalist's workload and efficiency, some triaging of patients in the clinical office is necessary. Also, noninvasive testing will need to be made available in the clinical office. PMID- 21326668 TI - Marketing the interventional clinical practice to the referring community and to patients. AB - If interventionalists are able to set up clinical practices and promote themselves along service lines, especially peripheral arterial disease, it is likely that they will have some market share and that market share will grow as new devices and technologies become available. The key to success will be changing the impression of the referring community that interventional radiologists are technical specialists and don't see patients. Marketing experts tell us that several impressions are required for a concept to stick with the target audience. One of the most important points that an interventionalist can make to establish themselves as a clinical specialty is high-quality work and effective communications. PMID- 21326669 TI - The interventional radiology clinic: what you need to know. AB - It is increasingly recognized that clinical management in interventional radiology is necessary. To effectively participate in such management requires patient management infrastructure. The cornerstone of this effort is the clinical office. PMID- 21326670 TI - Business plans. AB - The business strategy for establishing a clinical office involves three key components: fundamental change from the traditional technical model in processes for accepting referrals; establishment of a high-quality clinical operation; and changing the perception of interventionalist radiology among the referring community and the public. The costs and revenues used to derive profit and loss statements will vary considerably across regions and practice set-ups. Some of the considerations are outlined in this article, but it will be up to interventionalists and their business managers to make these factors conform to their individual practices and locations. PMID- 21326671 TI - Varicose vein management: considerations for the diagnostic radiology group practice. AB - The purpose of this brief article is to suggest some specific considerations that diagnostic radiology groups must make prior to embarking upon a varicose veins practice component. There are many excellent sources for further information, including the Web sites and practice management components of organizations such as the Society of Interventional Radiology, American College of Phlebology, International Vein Congress, and Union Internationale Phlebologie, all of which also hold excellent meetings or sections. Major points addressed in the article will include business plans, physician and group requirements, physical space and equipment requirements, and personnel issues. Though vein practice is clearly a major undertaking, the nature of varicose venous disease is such that there is a serendipitous overlap between the skill sets of the interventional radiologists and those required of the treating phlebologist. Consequently, with the proper motivation, self-education, and ongoing training, the addition of a varicose vein practice component can be extremely gratifying and rewarding for the physician, his radiology group, and most importantly the patients whom they serve. PMID- 21326672 TI - Case studies in clinical practice development. AB - By asking identical questions of several successful practitioners of clinical interventional radiology, a snapshot of the current and future status of interventional radiology as a clinical discipline is presented. PMID- 21326673 TI - Mushroom gastrostomy. PMID- 21326674 TI - Broken, inflated angioplasty balloon on a wire. PMID- 21326675 TI - Academics versus Private Practice. PMID- 21326676 TI - A guide to antibiotics for the interventional radiologist. AB - Antibiotics are among the most common pharmaceutical agents used by the interventional radiologist. This article updates some of the practical aspects of the use of antibiotics in interventional radiological practice and provides some general guidelines with respect to indications for and selection of antibiotics. In particular, the objectives of this article are to review the basic pharmacology of the common antibiotic agents, the interventional radiological procedures in which prophylactic antibiotics are usually administered, the specific antimicrobial agents recommended for prophylaxis before common interventional radiological procedures, the appropriate antibiotics for patients allergic to penicillins, and the indications for antibiotic prophylaxis to prevent bacterial endocarditis. PMID- 21326677 TI - Use of antiplatelet inhibitors in peripheral vascular interventions. AB - In the past decade, a tremendous amount of information has been gathered about platelet function and its impact on percutaneous vascular interventions. Strategies for prevention of platelet aggregation have moved beyond aspirin administration. Powerful oral antiplatelet agents such as ticlopidine (Ticlid) and clopidogrel (Plavix) have been developed to prevent platelet aggregation and thrombosis. The discovery of the glycoprotein IIb/IIIa receptor, which is responsible for platelet aggregation, has led to the development of receptor antagonists. These drugs include abciximab (ReoPro), eptifibatide (Integrilin), and tirofiban (Aggrastat). Several large studies have demonstrated that these drugs can improve outcomes in coronary interventions. Because most of the data regarding antiplatelet agents in percutaneous interventions comes from studies of coronary interventions, knowledge of these studies is necessary before using the antiplatelet drugs in peripheral vascular interventions. This article reviews the use of these agents in percutaneous coronary artery interventions and discusses their potential use in peripheral interventions. PMID- 21326678 TI - Percutaneous interventions in the coagulopathic patient. AB - Interventional procedures in patients with coagulopathies carry a perceived risk of increased bleeding and complications. Acquired and inherited deficiencies of blood-clotting factors, thrombocytopenia and platelet dysfunction, and effect of anticoagulation are common problems encountered by practicing clinical interventional radiologists. In this article we review common coagulopathies, available data on percutaneous procedures in coagulopathic patients, and recommendations for periprocedure treatment. PMID- 21326680 TI - Contrast-induced nephropathy: what we know, what we think we know, and what we don't know. AB - Contrast-induced nephropathy is a common but poorly understood problem. A large body of literature devoted to the subject is replete with contradictions and conflicting reports. The purpose of this article is to summarize our current understanding of the problem by reviewing some of the best studies done to date. Recommendations based on the current literature are also provided. PMID- 21326681 TI - Sedation and analgesia in interventional radiology. AB - Complex medical procedures requiring the administration of sedation and analgesia are frequently performed in sites outside the operating room. In particular, interventional radiologists must understand basic principles of sedation and analgesia to direct nurses or nurse practitioners to provide adequate conscious sedation. The purpose of this article is to review basic principles of sedation, pharmacologic agents used for sedation and analgesia, practice guidelines, monitoring, and management of common hemodynamic problems encountered during sedation. PMID- 21326679 TI - Heparin in interventional radiology: a therapy in evolution. AB - Interventional radiology techniques made possible by the antithrombotic properties of heparin have revolutionized treatment for a myriad of disorders. Newer low-molecular-weight heparins (LMWHs) offer several advantages over unfractionated heparin (UFH), especially in chronic settings. They are increasing in popularity for use during vascular procedures. However, LMWH shares limitations with UFH such as heterogeneity, nonspecificity, and induction of thrombocytopenia. These drawbacks have led to a search for the next generation of antithrombotic agents. Homogeneous drugs targeting specific coagulation cascade molecules are now available. The number of alternative anticoagulant drug combinations presents clinicians with a confusing array of choices. The strengths and weaknesses of UFH, LMWH, and direct antithrombin agents are presented. The promising future of LMWH and hirudins is discussed. PMID- 21326682 TI - Differentiating pharmacologic agents used in catheter-directed thrombolysis. AB - The use of catheter-directed thrombolysis is a proven treatment for arterial ischemia, deep vein thrombosis, and severe pulmonary embolism. For arterial ischemia, thrombolysis has resulted in improved amputation-free survival and fewer subsequent surgeries to reestablish blood flow to the ischemic limb. The management of patients with thromboembolic diseases is complex, and the multiple thrombolytic drugs available to choose from compound this complexity. Although some believe the available thrombolytic agents are interchangeable, real biochemical differences exist that may prove otherwise. This article describes these pharmacologic differences and how they may affect the clinical practice of catheter-directed thrombolysis. PMID- 21326683 TI - Pharmaceuticals for Intra-arterial Therapy. AB - Clinical pharmacology may be defined as the branch of medicine concerned with the therapeutic agents used in the prevention, treatment, and control of disease. Pharmaceuticals are the specific agents used to combat disease. Hence, many of the agents used by the interventionalist may be considered pharmaceuticals. Safe and effective use of these therapeutics requires understanding of vascular anatomy and disease pathology, proper technique, and knowledge of the therapeutic agents. This article reviews many of the agents available and some that are on the horizon. The future of transarterial therapies is bright and holds many promises. PMID- 21326684 TI - Superselective embolization of colonic bleeding. PMID- 21326685 TI - Iatrogenic Renal Dissection during Renal Artery Stenting. PMID- 21326686 TI - Advice to Fellows and Residents (with Apologies to Mark Twain). PMID- 21326687 TI - Lower extremity venous anatomy. AB - The lower extremity venous system includes the superficial, deep, and perforating veins. The antegrade flow of blood within these veins is ensured by a system of muscular venous pumps and bicuspid valves. Dysfunction of the system may result from degeneration of the vein wall, post-thrombotic valvular damage, chronic venous obstruction, or dysfunction of the muscular pumps. Although chronic venous disease often receives less attention than arterial disease, it includes an array of manifestations resulting from a complex interaction of anatomy and hemodynamic failure. A thorough understanding of the highly variable venous anatomy is essential to understanding the underlying pathophysiology as well as in directing treatment. PMID- 21326688 TI - Venous pathophysiology. AB - Chronic venous insufficiency and varicose veins are among the most prevalent medical problems in the adult population. Historically, our understanding of venous reflux disease focused upon the anatomical mechanisms of valvular incompetence. More recent investigations into the cellular and molecular aspects of venous insufficiency have shown that the disease is a complex multifactorial process reflecting both systemic abnormalities of connective tissue synthesis and cellular inflammatory reaction. New minimally invasive endovenous treatments for primary lower extremity venous insufficiency have spurred growing clinical interest in this disease. The intent of this review article is to discuss the prevalence, epidemiological risk factors, and current theories of the pathophysiology of primary venous insufficiency. PMID- 21326689 TI - Sequelae of untreated venous insufficiency. AB - Untreated venous insufficiency results not only in a gradual loss of cosmesis but also in variety of complications including persistent pain and discomfort, hemorrhage, superficial thrombophlebitis, and progressive skin changes that may ultimately lead to ulceration. In rare instances, chronic soft tissue changes may lead to stiffness of the ankle joint, fixed plantar flexion, and periostitis. This article reviews the variety of complications caused by venous insufficiency. PMID- 21326690 TI - Chronic venous insufficiency: clinical assessment and patient selection. AB - Chronic venous insufficiency is a complex condition, with widely varied clinical manifestations, etiologies, and underlying pathophysiology. An orderly workup is mandatory to assess the nature of a patient's underlying venous disease. This begins in the office setting with a careful medical history, physical examination, and bedside diagnostic tests. These are augmented by confirmatory diagnostic testing, including duplex ultrasonography, venography, plethysmography, and ambulatory venous pressure measurement. Based upon the results of these examinations, the patient's venous disease can be classified according to standardized classification schemes, which in turn leads to the selection of an appropriate treatment strategy. This article outlines the steps in the clinical assessment and classification of patients with chronic venous insufficiency. PMID- 21326691 TI - Imaging of venous insufficiency. AB - Duplex ultrasonography (DUS) is an essential part of the evaluation of patients with most forms of superficial venous insufficiency. DUS has also become an important tool in directing and assessing the results of a variety of minimally invasive treatments of this disease. In this article, we review the salient aspects of performing an adequate DUS evaluation and the utility of this technique in guiding treatment. PMID- 21326692 TI - Varicose vein surgery. AB - The treatment of superficial venous disease and chronic venous insufficiency continues to evolve, and the interest in venous disease has matched that in arterial disease in vascular medicine. A better understanding of venous anatomy and pathophysiology and the development of newer, more efficient diagnostic technology have allowed clinicians to utilize minimally invasive techniques in the treatment of varicose veins. These techniques have reduced recurrence and improved overall quality of life (postoperative pain and bruising) following these procedures. This article provides an overview of basic venous surgical anatomy and pathophysiology, along with several older and newer surgical options in the treatment of superficial venous disease. Advantages and disadvantages of each approach are briefly discussed so that the reader may gain better understanding of the options available in the treatment of chronic venous insufficiency. PMID- 21326693 TI - Percutaneous options for acute deep vein thrombosis. AB - Anticoagulant therapy is associated with poor late limb outcomes in many patients with deep vein thrombosis (DVT). Because systemic thrombolysis and surgical thrombectomy have inherent limitations, image-guided percutaneous thrombus removal is currently favored. Pharmacologic thrombolysis is effective in removing thrombus, but long-term benefit has not been conclusively demonstrated and major bleeding rates appear to be higher than those observed with anticoagulation alone. Percutaneous mechanical thrombectomy is limited as a stand-alone DVT treatment method by inability to clear large thrombosed veins completely and by pulmonary embolism. Pharmacomechanical thrombolysis represents the most promising currently available method to treat DVT. Randomized trials with long-term follow up are needed to determine the appropriate indications for these procedures. In the meantime, a highly individualized approach to selection of patients is recommended, taking into account the chronicity and anatomic extent of DVT, the presence of circulatory compromise, the patient's bleeding risk profile, life expectancy, and anticipated activity level. PMID- 21326694 TI - Endovenous thermal ablation of the saphenous vein. AB - Endovenous saphenous vein obliteration in the form of radiofrequency or laser therapies has quickly ascended to a position of prime importance in the treatment of reflux within the superficial venous system. The technical aspects of these procedures, as well as their decreased morbidity when compared with saphenous vein stripping, make them highly appealing to both practitioners and patients alike. Less bruising, less pain, and less postoperative recovery are associated with these endovenous techniques than with the historical "gold standard" of saphenous vein stripping. Efficacy exceeds that of sclerotherapy, the other nonsurgical option. These improvements have led to greater acceptance by patients and consequently greater patient demand for endovenous ablation procedures. Practitioners should therefore become well versed in the techniques of performing these procedures safely and effectively for patients. PMID- 21326695 TI - Injection sclerotherapy. AB - Injection sclerotherapy is an important primary and adjunctive therapy in the spectrum of care for superficial venous insufficiency. This article briefly reviews the history of the procedure, agents used, technique, and outcomes. The place of injection sclerotherapy in the treatment of superficial venous disease is discussed. PMID- 21326696 TI - Ambulatory phlebectomy. AB - Approximately 2400 years ago, Hippocrates performed the first phlebotomy to treat a varix. Since that time, modifications to the removal of varicose vein have evolved. It was Dr. Muller, a Swiss dermatologist, who reinvented and refined the technique of ambulatory phlebectomy. Although this technique was adopted slowly, it is now considered the standard method for treating varicose veins. The procedure is performed on an ambulatory patient under local anesthesia with little, if any, recovery time. After approximately a 2-mm puncture or incision made by an 18-gauge needle or a 15-degree ophthalmic blade, a small hook-like instrument coupled with fine clamps is employed to extract the varix. A dry sterile compression dressing and or class 2 stocking is applied. Significant complications are rare. PMID- 21326697 TI - Percutaneous therapy for deep vein reflux. AB - At present, there are no widely accepted surgical or percutaneous treatment options for chronic venous insufficiency of the deep venous system. The small intestinal submucosa square stent bicuspid venous valve (BVV) has shown the most promising results of artificial venous valves developed to date. In experimental long-term studies in sheep jugular veins, 88% of implanted valves exhibited good function; 12% had decreased function related to valve tilting, of which only 4% had partial thrombosis. BVVs were also placed in three patients and have remained patent without thrombosis or other complications since 2002. At present, 3 years after BVV placement, symptoms in two patients are decreased. Proper sizing and proper placement of the valves were critical to their function. To eliminate occasional tilting of the original BVV, a second-generation BVV has been developed and tested. PMID- 21326698 TI - Developing an interventional radiology varicose vein practice. AB - A varicose vein or phlebology practice can be incorporated into an outpatient interventional radiology practice with some proper planning. For an established interventional radiology clinic practice, the barriers to entry into such a phlebology practice are actually fairly low. A critical component in this process is establishing a business plan. An intact business plan can provide the proper foundation for any business venture, including a successful phlebology practice. Key steps in any business plan include an evaluation of the proposed venture, proper planning, organization, implementation, and periodic review. In this article, I describe how an active varicose vein practice was established in our outpatient radiology office in Charlotte, North Carolina, as well as highlight several important features that could, and probably should be, incorporated into any phlebology practice. PMID- 21326699 TI - Chest port insertion. PMID- 21326700 TI - Subcutaneous chest port infection. PMID- 21326702 TI - What's in a Name? PMID- 21326701 TI - On "mushroom gastrostomy" (semin intervent radiol 2005;22:61-63). PMID- 21326703 TI - Role of emergency transjugular intrahepatic portosystemic shunts. AB - Transjugular intrahepatic portosystemic shunts (TIPS) is a highly effective treatment for bleeding esophageal varices, with control of the bleeding in over 90% of the patients. TIPS is recommended as "rescue" treatment if primary hemostasis cannot be obtained with endoscopic and pharmacological therapy, or if uncontrollable early rebleeding occurs within 48 hours. TIPS is also a very effective technique for patients presenting with severe refractory bleeding gastric and ectopic varices, cases where endoscopic techniques are less effective. Emergency TIPS should be considered early in patients with refractory variceal bleeding once medical treatment and sclerotherapy fail, before the clinical condition worsens. Every effort should be made to stabilize the patient before TIPS, including the use of tamponade tubes and aggressive correction of coagulopathy. Patients with acute variceal bleeding with a Child-Pugh score > 12, Apache score II > 18 points, hemodynamically unstable, receiving vasopressors and coagulopathy, and/or bilirrubin > 6 mg/dL have a high risk of early death after TIPS. Expedite liver transplantation after emergency TIPS should be considered for high-risk patients. PMID- 21326704 TI - The evaluation of the patient undergoing an elective transjugular intrahepatic portosystemic shunt procedure. AB - In its early stages, the transjugular intrahepatic portosystemic shunt (TIPS) was utilized as a lifesaving procedure to treat uncontrollable esophageal variceal bleeding. Most of the initial cases were performed in an emergency situation in the worst possible conditions. The experience gained over the past 15 years has established TIPS as an important therapeutic option in the management of patients with complications of portal hypertension such as variceal bleeding or refractory ascites who do not respond to medical therapy. In current medical practice, 80 to 90% of TIPS procedures are performed in an elective or semielective fashion and only a small percentage of cases are now performed on an emergency basis. The experience gained has demonstrated that certain patients do not benefit from a TIPS procedure and furthermore, their baseline condition may even worsen after a TIPS. This article reviews the most important aspects of the clinical evaluation of patients undergoing an elective TIPS procedure. PMID- 21326705 TI - Hepatic perfusion and hemodynamic effects of transjugular intrahepatic portosystemic shunts. AB - The liver depends on a dual blood supply from the hepatic artery and the portal vein. The normal liver receives 70% portal flow and 30% hepatic arterial flow, with most arterial blood feeding the biliary tree. As cirrhosis robs the liver of its regenerative capacity, the portal flow decreases and intrahepatic portosystemic shunting increases with a variable increase in arterial flow across arterioportal shunts. This compensation mechanism attempts to reperfuse remaining sinusoids. Transjugular intrahepatic portosystemic shunts (TIPS) or surgical portosystemic shunts may acutely diminish portal perfusion further, leading to hepatic failure. Small-diameter TIPS or surgical shunts reduce the incidence of complications by preserving nutritive portal flow. Although the inverse relationship of arterial and portal flow is physiologically valid, there is individual variation in the ability to substitute one blood supply for another. This variability may result from anatomic or functional factors influencing the flow across arterioportal shunts. Hepatic perfusion curves derived from enhanced imaging studies can subtype cirrhotic patients into favorable versus unfavorable perfusion patterns. Patients with high arterial flow to the liver or patients with retained portal-type flow curves have better survival and morbidity compared with those patients with unfavorable flow manifest by diminished arterial-type curves on hepatic perfusion analysis. PMID- 21326706 TI - Transjugular intrahepatic portosystemic shunt in the management of refractory ascites. AB - The purpose of this article is to describe the pathophysiological basis for the use of transjugular intrahepatic portosystemic shunt (TIPS) in patients with cirrhosis and refractory ascites, the short- and long-term hemodynamic, biochemical, and hormonal changes after TIPS, and the results of controlled trials of TIPS in cirrhotic patients with refractory ascites. TIPS placement is associated with normalization of sinusoidal pressure and a significant improvement in urinary sodium excretion that correlates with suppression of plasma renin activity (indicative of an improvement in effective arterial blood volume). Although effective in preventing the recurrence of ascites, the efficacy of TIPS is offset by an increase in the incidence of severe hepatic encephalopathy, a high incidence of shunt dysfunction, and a higher cost without an overall survival benefit, which should be reevaluated in light of polytetrafluoroethylene-covered stents. TIPS placement is currently indicated in seleceted cirrhotic patients with refractory ascites who require more than two to three large-volume paracenteses per month. PMID- 21326708 TI - The difficult transjugular intrahepatic portosystemic shunt: alternative techniques and "tips" to successful shunt creation. AB - The transjugular intrahepatic portosystemic shunt (TIPS) is one of the most complex procedures performed by interventional radiologists. Most of these procedures are straightforward and may be successfully completed within 2 hours. In some cases, TIPS creation may be extremely difficult, for example in situations such as: variant anatomy, portal vein thrombosis, hepatic vein thrombosis, or preexisting TIPS. In this article we describe some maneuvers that may be attempted in cases where creation of the shunt proves to be difficult. PMID- 21326707 TI - Should stent-grafts replace bare stents for primary transjugular intrahepatic portosystemic shunts? AB - Transjugular intrahepatic portosystemic shunt (TIPS) creation using bare stents is a second-line treatment for complications of portal hypertension due in part to the relatively high number of reinterventions and the occurrence of new or worsened encephalopathy. Initially, custom-made stent-grafts were used for TIPS revision in cases of biliary fistulae. Subsequently, custom stent-grafts were used for de novo TIPS creation. With the introduction of the VIATORR((r)) TIPS endoprosthesis a dedicated stent-graft became available for TIPS creation and revision. The VIATORR((r)) demonstrated its efficacy and superiority to uncovered stents in retrospective analyses, case-matched analyses, and randomized studies. The improved patency of stent-grafts has led many to requestion the role of TIPS as a second-line therapy. Currently, randomized trials are warranted to redefine the role of TIPS in the treatment of complications of portal hypertension. PMID- 21326709 TI - Transjugular intrahepatic portosystemic shunts in patients with hepatic malignancy. AB - Since its first clinical application in 1988, the transjugular intrahepatic portosystemic shunt (TIPS) has emerged as a safe and effective means of managing patients with morbid portal hypertension. Despite the considerable body of literature on TIPS, portal decompression in patients with malignancy has not been sufficiently examined. These patients typically experience sequelae of portal hypertension that requires palliation. The purpose of this article is to review the reported experience with TIPS in patients with malignancy. PMID- 21326710 TI - Reduced stents and stent-grafts for the management of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt creation. AB - Hepatic encephalopathy (HE) is a common complication encountered by patients after transjugular intrahepatic portosystemic shunt (TIPS) creation. Although most patients respond well to conservative medical therapy, up to 7% of patients do not and require more invasive therapeutic approaches. One option is emergent liver transplantation; however, most patients are not suitable candidates. During the past decade, various percutaneous techniques have been described that alter the hemodynamics through the TIPS by occluding it with coils or balloons or by reducing its diameter using constrained stents or stent-grafts. These endovascular techniques have produced symptomatic improvement in many patients with refractory HE, with either complete resolution or substantial reduction of HE symptoms that can be controlled with additional medical therapy. Unfortunately, despite all attempts, some patients remain incapacitated and ultimately die. Further research is necessary to improve our understanding of HE after TIPS creation so that less invasive and safer procedures can be developed to treat this difficult clinical problem. PMID- 21326711 TI - Transjugular intrahepatic portosystemic shunts in liver transplant recipients: technical considerations and review of the literature. AB - Transjugular intrahepatic portosystemic shunt (TIPS) is an accepted therapeutic option for the treatment of complications of portal hypertension, such as refractory variceal bleeding, refractory ascites, refractory hepatic hydrothorax and Budd-Chiari syndrome, in cirrhotic livers. However, portal hypertension is uncommon after liver transplantation, and when it occurs, it has been related to hepatic vein outflow obstruction, small liver donor size, rejection, or recurrence of the original disease. There are few reports in the literature addressing TIPS experience in liver transplant patients. This review will address the published experience of TIPS procedures in liver transplant patients, including indications, technical issues, complications, and outcomes. PMID- 21326712 TI - Tandem wire angioplasty. PMID- 21326714 TI - On judging book covers. PMID- 21326713 TI - Renal Artery Occlusion Due to Angiotensin-Converting Enzyme Inhibition and Reintervention for in-Stent Stenosis. PMID- 21326715 TI - Current imaging strategies of primary and secondary neoplasms of the liver. AB - This article details the diagnosis and imaging of primary and secondary neoplasms of the liver. Benign conditions that can mimic malignancy are also discussed, such as focal nodular hyperplasia and adenoma. Considerable attention is given to hepatoma, which is the most common primary hepatic tumor in the United States. The roles of magnetic resonance imaging, computed tomography, and ultrasound are evaluated, with recommendations for their effective use. Pitfalls in imaging related to posttreatment changes and unusual patterns of metastatic disease are illustrated. PMID- 21326716 TI - Patient selection for surgical management of primary and metastatic liver cancers: current perspectives. AB - The surgical management of liver malignancies remains a mainstay in the treatment of such patients, and has benefited from dramatic advancements over the last two decades. Improvements in surgical technique, better understanding of hepatic anatomy, and improvement in anesthesiological supportive care has resulted in a decline in perioperative morbidity and operative mortality. Proper patient selection for surgical and nonsurgical treatment currently employs a multidisciplinary approach in our institution. This review will focus on the surgical treatment options for both primary and secondary liver cancers. PMID- 21326717 TI - Positron emission tomography for staging and assessment of tumor response of hepatic malignancies. AB - (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is a useful functional imaging method that complements conventional anatomic imaging modalities for screening patients with colorectal hepatic metastases and hepatocellular cancer to determine their suitability for interventional procedures. FDG PET is more sensitive in detecting colorectal cancer than hepatocellular cancer (~90% versus ~50%). The likelihood of detecting hepatic malignancy with FDG PET rapidly diminishes for lesions smaller than 1 cm. The greatest value of FDG PET in these patients is in excluding extrahepatic disease that might lead to early recurrence after interventional therapy. Promising results have been reported with FDG PET that may show residual (local) or recurrent disease before conventional imaging methods in patients receiving interventional therapy. For patients with colorectal hepatic metastases, many investigators believe that patients with PET evidence of recurrent hepatic disease should receive additional treatment even when there is no confirmatory evidence present on other methodologies. For patients with hepatocellular cancer no conclusions regarding the value of FDG PET for assessment of response to interventional therapy can be reached as there is almost no published data. PMID- 21326718 TI - Combining local and regional therapeutic modalities to treat hepatic malignancies. AB - Hepatocellular carcinoma and metastatic colon cancer have proven to be challenging problems in oncology today. Currently multiple treatment options are available for treating patients with these diseases, and for this reason, a multimodality and multidisciplinary approach is needed to optimize the effectiveness of treatment. Local ablation techniques along with intra-arterial therapy may be complementary and therefore increase survival in patients being treated for hepatocellular carcinoma and metastatic colon cancer. With proper patient selection, further improvement in treatment outcomes can be achieved when these techniques are combined with surgical resection and multidrug systemic chemotherapy. Therefore, it is imperative that interventional radiologists work closely with our colleagues in other medical and surgical specialties to provide our patients with the best possible treatment options. PMID- 21326719 TI - The treatment of primary and metastatic hepatic neoplasms using percutaneous cryotherapy. AB - Cryotherapy has been used clinically in the treatment of metastatic liver malignancies since the 1980s. Rapid freezing to sub-zero temperatures promotes ice formation in the extracellular space and the exit of intracellular water. Cellular death is the result of dehydration, protein denaturation, and microcirculatory failure. Cryotherapy probes use nitrogen or argon gas as a coolant and the development of the ice ball can be monitored using ultrasound, computed tomography, or magnetic resonance imaging. Traditionally, cryotherapy has been performed during laparoscopy or laparotomy, using intraoperative ultrasound for image guidance. A decrease in cryoprobe size (from ~24 Fr to ~15 gauge) in conjunction with experience gained in open cryosurgical treatment has allowed the development of minimally invasive percutaneous approaches. In this review, we describe the use of cryotherapy for treatment of primary or secondary liver neoplasms using a percutaneous approach. PMID- 21326721 TI - Yttrium-90 radioembolization of hepatocellular carcinoma and metastatic disease to the liver. AB - Yttrium-90 ((90)Y) radioembolization is a catheter-based therapy that delivers internal radiation to hepatic tumors in the form of microspheres. (90)Y can be delivered to the hepatic tumor as either a constituent of a glass microsphere, TheraSphere((r)), or as a biocompatible resin-based microsphere, SIR Spheres((r)). Once embedded within the tumor microcirculation, these microspheres emit beta-radiation at therapeutic levels. While the technical aspects of radioembolization are quite complex, the collective clinical experience presented in the literature supports the use of (90)Y radioembolization for unresectable hepatic malignancies. PMID- 21326720 TI - Epidemiology of primary and secondary liver cancers. AB - Primary liver cancer is the sixth most common cancer worldwide with a wide geographic distribution. The incidence of primary liver cancer is increasing and there is still a higher prevalence in developing countries. Early recognition remains an obstacle and lack of it results in poor outcomes for hepatocellular carcinoma (HCC), the most prevalent primary liver cancer, and cholangiocarcinoma. The most common risk factors associated with HCC are hepatitis B and chronic hepatitis C infections, alcohol use, smoking, and aflatoxin exposure. Emerging risk factors such as obesity might play an important role in the future because of the increasing prevalence of this condition. PMID- 21326722 TI - Percutaneous radiofrequency thermal ablation of primary and metastatic hepatic tumors: current concepts and review of the literature. AB - The liver is a common site for primary malignancy and hematogenous metastasis. Although surgical resection of primary or metastatic hepatic tumors is generally regarded as first-line therapy, the majority of patients with hepatic malignancy have disease that is not amenable to surgical resection because of tumor location, poor hepatic reserve, or medical comorbidities. This has led to significant interest in the development of nonsurgical image-guided therapies, including radiofrequency ablation (RFA). RFA is appealing as a minimally invasive therapy that may be performed on an outpatient basis. It enables ablation of an area 3 to 5 cm in diameter, with relatively low morbidity and mortality rates. The results concerning the use of percutaneous RFA in the treatment of hepatocellular carcinoma, colorectal metastases, and other hepatic metastases are reviewed in this article. Clinical and technical considerations and complications are also discussed. PMID- 21326723 TI - Emerging local ablation techniques. AB - Local ablation technologies for hepatic malignancy have developed rapidly in the past decade, with advances in several percutaneous or externally delivered treatment methods including radiofrequency ablation, microwave ablation, laser ablation, and high-intensity focused ultrasound. Research has focused on increasing the size of the ablation zone and minimizing heat-sink effects. More recent developments include improvements in treatment planning and navigation with integration of several imaging modalities, as well as automated delivery of the ablation through robotics. These improvements will allow increased consistency in treatment delivery and will facilitate translation to the community setting. Combination therapies with multimodality guidance are on the cutting edge of image-guided, minimally invasive cancer therapies. Local ablation is being combined with regional therapies, such as arterial chemoembolization and local activation of systemically administered drugs, with promising results. Potential combinations with local ablation also include external radiation therapy and antitumor immune modulation. Image-guided oncology is emerging as an important part of the interventional radiology practice, thanks in part to the innovation and imaging background that lies at the roots of our discipline. PMID- 21326725 TI - Catheter drainage: seldinger technique. PMID- 21326726 TI - Great Vessel Laceration during Central Venous Catheter Insertion. PMID- 21326724 TI - Chemotherapy and other systemic therapies for hepatocellular carcinoma and liver metastases. AB - For hepatocellular carcinoma (HCC) that has advanced to the point that it is no longer amenable to local therapies, systemic therapy can be considered in select patients who have a good performance status. No systemic therapy has been clearly shown to improve overall survival compared with supportive care alone, although cancer-related symptoms can sometimes be palliated with therapy and some objective responses are seen. Systemic therapies for HCC include chemotherapy, both intravenous and infused via the hepatic artery, as well as hormonal therapy, immunotherapy, and targeted biologic agents. Colorectal, pancreatic, breast, and lung cancer are some of the most common tumors that metastasize to the liver. Response rates and effect on overall survival as a result of systemic therapy for liver metastases vary widely depending on primary tumor site. Targeted biologic agents are being integrated into standard treatment regimens for all of these cancer types, with variable effects on survival and other outcomes for all affected patients including those with liver metastases. PMID- 21326727 TI - On-call radiology. PMID- 21326728 TI - Hilar biliary obstruction: malignant masquerades. AB - Biliary obstruction at the hepatic hilus is most often due to malignancy. Clinically, it can be very difficult to differentiate malignant from benign obstruction when a mass lesion is not evident on cross-sectional imaging. In this article, we describe three cases of benign biliary obstruction due to so-called malignant masquerades to familiarize the reader with the clinical, radiographic, and pathological features of these uncommon but important entities. PMID- 21326729 TI - Subintimal stent graft reconstruction of an infrarenal aortic occlusion. AB - The traditional approach to revascularization in aortoiliac disease is surgical. Endovascular treatment techniques for revascularization have emerged in recent years and have resulted in less invasive options for management of vascular disease. In this article, we describe a novel approach to endovascular stent graft reconstruction of a heavily calcified infrarenal aortic occlusion. The interventional management of aortic occlusions is subsequently discussed. PMID- 21326730 TI - Retrieval of a wall-embedded recovery inferior vena cava filter using rigid bronchoscopy forceps. AB - Optional inferior vena cava (IVC) filters are an attractive option to help prevent pulmonary embolism because these filters can be retrieved when the risk for thromboembolic events has passed. Retrieval of IVC filters can be difficult if the filter tilts and its tip becomes embedded into the wall of the IVC. A case is presented in which rigid bronchoscopy forceps were used to retrieve a filter that had become embedded in the wall of the IVC. PMID- 21326731 TI - The use of paired optionally retrievable gunther tulip filters in trauma patients with anatomical variants. AB - Inferior vena cava (IVC) filtration is commonly performed to protect against pulmonary embolism in acutely injured patients with contraindications for anticoagulation therapy. Increasingly, optionally retrievable IVC filters are utilized, particularly in younger patients with longer life expectancies. There are well-described anatomical variants that preclude the typical infrarenal deployment of IVC filters. We describe three cases in which trauma patients with congenital anomalies required temporary prophylaxis with IVC filters. One patient had a duplication of the IVC requiring filter deployment in each IVC limb. The second patient had a low inserting accessory left renal vein, and a third patient had a megacava. Both of these patients required filter deployment in each common iliac vein. In each case, a pair of optionally retrievable Gunther Tulip filters was deployed and subsequently retrieved. PMID- 21326732 TI - Endovascular therapy of superior gluteal artery aneurysms: case report and review of literature. AB - We report two cases of superior gluteal artery aneurysms successfully treated with coil embolization and review treatment options for these lesions. Our experience in the treatment of three total aneurysms, two likely post-traumatic in etiology and one mycotic, suggests that endovascular therapy is an effective alternative to open surgery when treating superior gluteal artery aneurysms. PMID- 21326733 TI - Occlusion of a rapidly expanding hemodialysis graft pseudoaneurysm with placement of a stent graft. AB - We describe a 44-year-old man with end-stage renal disease who underwent insertion of a stent graft to repair a hemodialysis graft pseudoaneurysm. The indication for stent graft placement was an acute and rapidly enlarging intragraft pseudoaneurysm. The patient experienced no complications following the procedure, but he presented with two graft occlusions within the 2 months following the procedure. PMID- 21326734 TI - Embolization of a Recurrent Type 2 Endoleak Using the Liquid Embolic n-Butyl Cyanoacrylate. AB - Endovascular aneurysm repair (EVAR) has become an accepted alternative to open aortic aneurysm repair. Endoleaks are one of the most common complications of EVAR and can result in aneurysm enlargement and rupture. When embolization of type 2 endoleaks is needed, a transarterial or translumbar approach may be used. Metal coils are often utilized, but liquid agents have also been used for embolization. This case report involves endoleak embolization using metallic coils along with the liquid embolic agent n-butyl cyanoacrylate (n-BCA). PMID- 21326735 TI - A case of pancreatic islet cell transplantation in a patient with situs ambiguous: anatomical and radiological considerations. AB - Pancreatic islet cell transplantation is an evolving treatment of severe, refractory type 1 diabetes that has been gaining more use, particularly after one year rates of insulin independence post-transplantation were found to approach 80% under the Edmonton protocol. Islet cell transplantation involves percutaneous delivery of harvested allogeneic beta cells into the portal venous circulation for implantation into the liver. We present the case of a 35-year-old woman with type 1 diabetes and situs ambiguous with left isomerism and resultant variant anatomy of her portal venous anatomy who underwent islet cell transplantation, which, to our knowledge, has not been previously reported. PMID- 21326736 TI - Covered stent treatment of carotid blowout syndrome. AB - Carotid artery blowout is a devastating complication of head and neck malignancy, irradiation, and trauma. New endovascular therapies of acute carotid artery rupture involve stent-directed, carotid-sparing treatment strategies. We report a case of successful covered stent treatment of carotid artery hemorrhage in the setting of head and neck cancer and review the literature describing the use of this therapeutic method. Evaluation of 19 recently reported cases of covered stent treatment of carotid artery blowout due to head and neck cancer and presenting with sentinel or acute hemorrhage demonstrates that this method is a fast and effective means of controlling bleeding, with a technical success rate of ~95%. A significant early recurrent hemorrhage rate raises concern regarding the short-term safety and efficacy of this therapy, however, and suggests that stent graft treatment of carotid artery rupture due to head and neck malignancy is best suited as a temporizing measure before more definitive therapy. PMID- 21326737 TI - Splenic artery embolization and balloon occlusion retrograde alcohol embolization in a patient with bleeding gastric varices. AB - We present a patient with a large spontaneous splenorenal shunt secondary to isolated splenic vein thrombosis who developed severe bleeding from fundal gastric varices. The patient was managed emergently with splenic artery embolization and balloon occlusion retrograde embolization of the varices with alcohol. We discuss the clinical presentation, embolization techniques, and a potential complication of the use of alcohol for this purpose. PMID- 21326738 TI - Tibial recanalization with excimer laser angioplasty. AB - We report a case of chronic critical limb ischemia (CLI) due to occlusive tibial artery disease that we treated with an excimer laser with good clinical results. The current status of laser technology in the treatment of infrainguinal arterial disease is reviewed, and our approach to the use of this device in these challenging patients is presented. Data that indicate the value of this modality in the treatment of patients with CLI are discussed. PMID- 21326739 TI - Utility of percutaneous treatment in spontaneous renal artery dissection: case report and review of the literature. AB - Spontaneous renal artery dissection (SRAD) is a relatively rare entity that has been described in several case reports and small series in the medical literature. The condition is best diagnosed with angiography, with renal ischemia or infarction a common complication. Conservative medical management, surgical intervention, and percutaneous intervention are all discussed in the current literature. However, there is no consensus on which treatment option provides the best clinical outcome. Percutaneous stent placement has only recently been considered as an option for treatment of SRAD. This case report reviews the course of an otherwise healthy patient with a solitary right kidney who had SRAD complicated by renal infarction and was treated by percutaneous renal artery stent placement. Subsequently, we discuss and review the literature on SRAD treatment. PMID- 21326740 TI - Embolization of postsurgical obturator artery pseudoaneurysm. AB - The anatomy of the obturator artery in the pelvis makes this vessel and its branches prone to iatrogenic injury during pelvic surgery. We present a postoperative obturator artery pseudoaneurysm treated by transcatheter embolization. Normal and variant obturator vascular anatomy, as well as pathology related to traumatic injury of this vessel, are subsequently discussed. PMID- 21326741 TI - Treatment of an acute common iliac artery occlusion with mechanical thrombectomy and stenting. AB - We report a case of acute lower extremity ischemia caused by occlusion of the right common iliac artery (CIA), which we treated with mechanical thrombectomy followed by stent placement. The current role of mechanical thrombectomy in the treatment of acute limb ischemia is discussed. Considerations in primary stenting for acute arterial occlusions are presented. We briefly review the role of computed tomographic angiography (CTA) in the evaluation of patients with acute limb ischemia. PMID- 21326742 TI - Interventional management of arc of buhler aneurysm. AB - The Arc of Buhler (AOB) represents a persistence of the ventral anastomosis between the superior mesenteric artery (SMA) and the celiac arterial systems. The exact incidence of the AOB is not known, but it is believed to be <= 4%. Aneurysms of this rare anomaly are even more uncommon. We report a case of an aneurysm of the AOB with an intact pancreaticoduodenal artery arcade (PDAA) and near occlusive celiac origin stenosis. Stenoses or occlusions of the celiac origin have been reported in association with AOB aneurysms, as well as in patients with PDAA aneurysms. Transcatheter embolization (TCE) was successfully performed, thereby excluding the AOB aneurysm while preserving flow through the PDAA. To our knowledge, this is the first report of successful percutaneous treatment of an AOB aneurysm. The pathophysiology and management AOB and PDAA aneurysms are reviewed. Review of the literature suggests that TCE, when feasible, is at least as effective as conventional surgery in patients with PDAA aneurysms, but with lower morbidity and mortality. Based on this data and our experience, we believe that TCE should be the initial treatment of choice in patients with PDAA or AOB aneurysms. PMID- 21326743 TI - Acute Pericardial Effusion during Endovascular Intervention for Superior Vena Cava Syndrome: Case Series and Review. AB - We describe three cases of acute pericardial effusion during endovascular treatment of superior vena cava (SVC) syndrome, one of which resulted in fatal pericardial tamponade. SVC syndrome results from impaired venous return from the head and upper extremities to the right atrium. Malignancy and catheter-induced SVC stenosis accounts for the majority of cases of SVC syndrome. Endovascular therapy is the treatment of choice for SVC syndrome due to its rapid relief of symptoms and low morbidity. Acute pericardial effusion and pericardial tamponade may result from inadvertent extraluminal traversal of the SVC in the so-called danger zone above the right atrium, as well as secondary to dissection of wires in a location where fascial planes have been altered by neoplasia or inflammation. PMID- 21326744 TI - Endovascular embolization of large hepatic arteriovenous fistulas. AB - Treatment of hepatic artery to portal vein fistulas (HAPFs) has shifted in the past two decades from surgical resection of the involved liver to embolization. A uniform technique for percutaneous intervention has not been established because the approach is influenced by the size, location, and number of feeding arteries. We report two cases of HAPFs treated with embolization at our institution. Different outcomes in these two patients illustrate several fundamental principles in the treatment of HAPFs. PMID- 21326745 TI - Transcatheter alcohol embolization of an aldosteronoma. AB - Successful transcatheter arterial embolization of symptomatic adrenal aldosteronoma in a 56-year-old woman with hypertension and hypokalemia is described. The presentation, diagnosis, and treatment of aldosterone-producing tumors are subsequently discussed. PMID- 21326746 TI - Budd-Chiari syndrome: hepatic venous web outflow obstruction treated by percutaneous placement of hepatic vein stent. AB - Budd-Chiari syndrome (BCS) denotes a heterogeneous group of diseases characterized by hepatic venous outflow obstruction at the level of the hepatic veins or inferior vena cava resulting in portal hypertension. Traditional approach to treatment of BCS involves systemic thrombolysis and surgical portosystemic shunt or transjugular intrahepatic portosystemic shunt in progressive cases of BCS or as a bridge to transplantation. Recently, an increasing number of successful reports of BCS therapy have involved endovascular techniques, including angioplasty and stent placement. The present report illustrates successful percutaneous recanalization of complete hepatic vein occlusion by angioplasty and stent implantation in a patient with membranous obstruction. PMID- 21326747 TI - Lymphangiography: a case study. AB - Lymphatic leak is a rare but well-described complication of a multitude of surgeries, whose sequela may potentially be life threatening. For cases refractory to conservative management, surgical therapy has been the mainstay of treatment. Although radiology has always played a contributory role in the diagnosis of lymphatic leaks with lymphoscintigraphy and lymphangiography, minimally invasive management of lymphatic leaks by interventional radiologists has only been described in the last decade. We present a case of percutaneous disruption of the cisterna chyli to treat a lymphatic leak of the thoracic duct. PMID- 21326748 TI - Renal artery embolization: application and success in patients with renal cell carcinoma and angiomyolipoma. AB - Renal artery embolization is a procedure primarily performed by interventional radiologists that can be utilized for treatment of renal tumors, both malignant and benign. It has many applications, including pretreatment of renal cell carcinomas prior to planned resection to decrease hemorrhagic complications intraoperatively, treatment of malignant renal tumor in patients who are not deemed suitable surgical candidates, as well as treatment of benign renal tumors and their potential hemorrhagic complications. There are many different techniques. We describe how the procedure is approached at the University of Florida-Gainesville and provide examples of two cases, a renal cell carcinoma and an angiomyolipoma, treated at our institution with transcatheter embolotherapy. PMID- 21326749 TI - Management of ureteroiliac artery fistula. AB - We present a case of ureteroiliac artery fistula in a patient with a history of malignant extrinsic ureteral obstruction and prior pelvic radiation therapy. Successful angiographic diagnosis and endovascular treatment were performed in this patient. High index of suspicion is critical to diagnosis of this condition. PMID- 21326750 TI - Pulmonary artery pseudoaneurysm: etiology, presentation, diagnosis, and treatment. AB - Pulmonary artery pseudoaneurysms (PAPs) are uncommon but associated with high mortality. Left untreated, lesions can enlarge, rupture, and lead to exsanguination and death. Presentations range from life-threatening hemorrhage to silent lesions that enlarge for days, months, or years. Because abnormalities on imaging studies can lead to early diagnosis and treatment and embolization is the treatment of choice, the radiologist can contribute to both timely diagnosis and treatment of PAPs. Pseudoaneurysms due to penetrating trauma, blunt trauma, bacterial endocarditis, and complications related to pulmonary artery catheters and right heart catheterization are presented. Three were treated by embolization. PMID- 21326751 TI - Interventional management of renal vascular origin hematuria. AB - Several renal vascular pathological processes have been associated with hematuria. These include renal artery aneurysm (RAA), fibromuscular dysplasia (FMD), renal nutcracker syndrome (RNS), renal arteriovenous malformation, renal vasculitis, and renal artery or vein thrombosis. We present an unusual case of hematuria in a patient eventually diagnosed with RAA, FMD, and RNS. Percutaneous therapy, including endovascular coiling, percutaneous transluminal angioplasty, and stent placement were used to address the underlying pathology. The differential diagnosis, pathophysiology, and surgical and interventional management of these renal vascular disorders are reviewed. PMID- 21326752 TI - Prophylactic angioplasty of failing hemodialysis shunts. PMID- 21326753 TI - Iatrogenic Marginal Artery Dissection during Superselective Microcoil Embolization for Colonic Bleeding. PMID- 21326754 TI - Tools, techniques, and cats. PMID- 21326755 TI - Complications of hepatic chemoembolization. AB - Transarterial hepatic chemoembolization continues to evolve as an integral therapy for unresectable primary and secondary liver tumors. Despite relatively low morbidity, major complications may be seen. This article provides an overview of the spectrum of vascular and nonvascular complications related to this therapy. PMID- 21326757 TI - Complications of uterine fibroid embolization. AB - Uterine fibroid embolization (UFE) is an increasingly popular, minimally invasive treatment option for women with symptomatic fibroid disease. UFE therapy in qualified hands is an effective, well-tolerated procedure that offers relief of fibroid symptoms with a low risk of complications. In the acute postprocedural period, immediate complications may relate to vascular access, thromboembolic events, infection, and pain management. Reported major complications include but are not limited to pulmonary embolus, uterine ischemia, necrosis, sepsis, and death. Non-life-threatening complications include altered ovarian and sexual function, subcutaneous tissue necrosis, expulsion of fibroid tissue, and treatment failure. Awareness of the known complications of UFE may allow more rapid diagnosis and effective therapeutic responses to complications when they occur. PMID- 21326758 TI - Complications of inferior vena caval filters. AB - Inferior vena caval filters have been shown to be effective in the prevention of pulmonary embolism, with low morbidity and mortality associated with their implantation. Awareness of potential complications can further decrease the risk of filter placement and lead to early detection and management of complications to improve clinical outcomes. The purpose of this article is to review the procedure-related and delayed complications associated with inferior vena caval filters. PMID- 21326756 TI - Complications of embolization. AB - Embolization is a remarkably versatile procedure used in nearly all vascular and nonvascular systems to treat a wide range of pathology. The published literature is rich with studies demonstrating the enormous therapeutic potential offered by embolization procedures, and the possibilities continue to expand with the advent of new embolization agents and techniques. Unfortunately, with this variety and innovation comes a wide spectrum of potential complications, not always easy to classify and summarize, associated with embolization. This article reviews the procedures and associated complications of arterial and venous embolization procedures, organized by vascular distribution. PMID- 21326759 TI - Treatment of complications following endovascular repair of abdominal aortic aneurysms. AB - Endovascular aneurysm repair (EVAR) is an important treatment option for abdominal aortic aneurysms, with lower perioperative morbidity and mortality rates than open surgical aneurysm repair. However, EVAR is associated with several unique complications that are not encountered with surgical repair such as endoleaks, graft migration, and renal artery occlusion. Preservation of the morbidity and mortality advantages of EVAR relies on the successful treatment of these complications by minimally invasive, endovascular approaches. Some of the techniques used to treat EVAR complications include balloon dilation and stenting, deployment of additional stent-graft pieces, coil embolization, and thrombolysis. Although the employment of these endovascular salvage techniques is common, data regarding their intermediate- to long-term efficacy is sparse, and further studies are needed to determine their efficacy in preventing conversion to open aneurysm repair and aneurysm rupture. PMID- 21326760 TI - Transjugular intrahepatic portosystemic shunt-related complications and practical solutions. AB - Despite the clinical complexity of patients with severe liver disease and the technical demands associated with the creation of a transjugular intrahepatic portosystemic shunt (TIPS), the major complication rate of this procedure is less than 5%. Delayed recognition and treatment of complications related to TIPS can have life-threatening consequences. This article provides an overview of the spectrum of periprocedural and delayed complications related to the performance of TIPS and offers the reader pearls for both avoiding and managing those complications. PMID- 21326761 TI - Complications of radiofrequency ablation of neoplasms. AB - Radiofrequency ablation (RFA) is one of several techniques currently available to the interventional radiologist for direct local destruction of neoplastic tissue. At the present time RFA is among the most widely used and investigated of local therapies and has shown promise in oncological therapy for a variety of tissue types and anatomic locations, the latter including liver, kidney, bone, lung, and adrenal gland. This review will discuss risks of RFA, including methods to anticipate, avoid, ameliorate, or treat complications that may occur as a result of RFA. PMID- 21326762 TI - Complications of percutaneous chest biopsy. AB - Percutaneous lung biopsy is one of the most common procedures performed in radiology departments and the minimally invasive gold standard for the histopathologic investigation of lung masses. Compared with other percutaneous biopsy procedures, lung biopsy carries a higher risk of potential complications, including occasional reports of death. Radiologists should be able to quickly recognize complications, provide required acute care, manage the patient to complete resolution, and obtain a consultation from colleagues in surgery and medicine when indicated. To this end, standing protocols for the performance of lung biopsy and the management of complications such as pneumothorax should be in place prior to performing percutaneous lung biopsy. PMID- 21326763 TI - Complications of percutaneous fluid drainage. AB - Percutaneous abscess drainage is one of the most common and rewarding procedures performed by interventional radiologists. Technical success is immediately apparent by aspiration of purulent contents and is nearly always achieved, with rates exceeding 90% in most literature studies. Clinical success is typical even for many abscesses colonized with multidrug-resistant organisms. In patients presenting with sepsis, this procedure offers an immediate and minimally invasive solution to a life-threatening condition, often resulting in defervescence and restoration of hemodynamic stability within 1 to 2 days. Although complications of abscess drainage are uncommon, radiologists should be able to recognize and treat all adverse sequelae discussed in this article. PMID- 21326764 TI - Percutaneous nephrostomy. PMID- 21326765 TI - Embolization of an iatrogenic renal arteriovenous fistula. PMID- 21326766 TI - "What is Best in Life, Conan?". PMID- 21326767 TI - On-call treatment of acute gastrointestinal hemorrhage. AB - Urgent treatment of gastrointestinal bleeding is multidisciplinary and often variable by institution. In general, medical management is the first-line therapy for both upper and lower gastrointestinal hemorrhage. In severe upper gastrointestinal hemorrhage, endoscopy is performed prior to other interventions as it is often both diagnostic and therapeutic. Embolization is performed for refractory arterial bleeding. Transjugular portosystemic shunt insertion may be performed to treat refractory variceal bleeding although its use at night is controversial. The treatment algorithm for lower gastrointestinal bleeding is less clear but in general, severe bleeding is handled in the interventional suite by superselective embolization and less severe bleeding is initially treated by endoscopy after an 8- to 12-hour bowel prep. This article will summarize the current approach in my hospital for treating patients with acute gastrointestinal hemorrhage. PMID- 21326768 TI - Bronchial artery embolization for treatment of life-threatening hemoptysis. AB - Massive hemoptysis is an emergent and life-threatening condition with a broad range of underlying causes. Fortunately, massive hemoptysis accounts for a minority of cases of hemoptysis, ~5%. Unlike hemorrhage in other areas of the body, the primary cause of death from pulmonary hemorrhage is most commonly asphyxiation rather than exsanguination. Given the limited capacity for the lung to preserve oxygen transfer in the setting of massive hemoptysis, a rapid and effective method for controlling hemorrhage is essential to minimize death in patients demonstrating respiratory compromise. Since its introduction in 1973, bronchial artery embolization has proven to be a safe and effective tool for the treatment of massive hemoptysis and is now considered the treatment of choice, with initial success rates ranging from 77 to 94%. The long-term control rate of hemoptysis ranges from 70 to 85% and is largely a function of the degree of inflammation and the natural progression of the underlying disease. This article reviews the current literature on bronchial artery embolization for the treatment of massive hemoptysis. PMID- 21326769 TI - Inferior vena cava filters. AB - Venous thromboembolism (VTE) remains a common disease with significant clinical impact upon our patients. Diagnostic challenges occur because of the nonspecific nature of the presenting symptoms. The advent of multidetector computed tomography, methods to stratify patients into VTE risks (low, intermediate, high) along with serological assays (D-dimers), have helped direct patients through proper workup and into conclusive diagnosis. In most cases, standard medical therapy for VTE is anticoagulation therapy (OAT). In situations where standard OAT is either contraindicated or complications result from that therapy, insertion of inferior vena cava (IVC) filters is considered. Recent reports suggest that although IVC filters are able to prevent pulmonary emboli (PE) in the short and intermediate term, there appear to be long-term consequences including excess recurrent deep venous thombosis (DVT and IVC/filter occlusions). Recognition of the time sequence of IVC filter benefits and complications has encouraged development of optional IVC filters, which can be left in place indefinitely or removed usually before certain time constraints. This article will attempt to address the timing of IVC filter placements to protect patients from significant PE. PMID- 21326770 TI - Transcatheter arterial embolotherapy: a therapeutic alternative in obstetrics and gynecologic emergencies. AB - Transcatheter arterial embolization has become a major treatment modality in a variety of clinical applications, including management of bleeding related to a broad spectrum of obstetric and gynecologic disorders. Embolotherapy has a well documented role in the management of pelvic and genital tract hemorrhage in the postpartum and postoperative/postcesarean setting. It is also an integral part in the treatment armamentarium of abdominal and cervical ectopic pregnancy, arteriovenous malformation, and gynecologic neoplasms, including more recently, uterine leiomyomata. Based on experiences accumulated over the past decades, embolotherapy has been proven to be highly effective with success rate in the 90 to 100% range in the appropriate clinical settings. It provides visualization of the bleeding site and enables targeted, minimally invasive therapy to achieve hemostasis, which allows preservation of the uterus and hence fertility. In hospitals where experienced personnel and technology is available, transcatheter arterial embolization should be considered in the emergent management of obstetric and gynecologic hemorrhage, particularly when local and conservative measures fail to attain hemostasis. PMID- 21326771 TI - Percutaneous management of biliary emergencies. AB - Most biliary emergencies can be classified as either infectious or obstructive. Infectious complications include acute cholecystitis and cholangitis. Many of these can be treated either surgically or endoscopically, but in some instances, less-invasive percutaneous techniques can be utilized to successfully treat these conditions. Obstructive complications, especially in the setting of liver transplant, can be serious if not treated quickly. Percutaneous drainage is sometimes the only acceptable treatment alternative for these patients. PMID- 21326772 TI - Catheter-directed thrombolysis for acute limb ischemia. AB - Acute limb ischemia is a potentially life-threatening clinical event. Thrombosis in situ, bypass graft thrombosis, and embolic occlusion are the three major precipitating events leading to acute limb ischemia. Management of acute ischemia depends on the clinical status of the affected limb and patient comorbidities. Catheter-directed thrombolysis (CDT) is the treatment of choice for patients with relatively mild acute limb ischemia (Rutherford categories I and IIa) with no contraindications to thrombolytic therapy. Patients with severe acute limb ischemia (Rutherford category IIb) need emergent revascularization. CDT should be considered, nonetheless, if the relative risks compared with primary operation are favorable. CDT is a life- and limb-saving treatment for many patients despite limitations of efficacy and associated complications. This article is a review of the etiology of acute arterial occlusion; clinical triage of patients presenting with acute limb ischemia; catheter guide wire techniques, pharmacological agents, and devices in current use for CDT; as well as the outcomes of CDT. PMID- 21326774 TI - Unconventional venous access techniques. AB - For patients dependent on permanent venous catheters for survival, the progressive loss of venous access sites should prompt a systematic approach to alternative sites and techniques to maximize patient survival and minimize complications. Interventional radiologists should be familiar with the appropriate use of both conventional and unconventional types of venous access and their associated risks. This article discusses the use of venous access sites available as alternatives to occluded internal jugular veins, including the subclavian veins, the femoral veins, the inferior vena cava, and the hepatic veins. In addition, unconventional techniques for venous access are reviewed, including recannulization of occluded neck and chest veins, catheterization of small thyrocervical veins, and sharp recannulization of occluded central veins. PMID- 21326773 TI - The role of interventional radiology in trauma. AB - Since the development of angiography and transcatheter techniques, interventional radiology has played an important role in the management of trauma patients. The ability to treat life-threatening hemorrhage with transcatheter embolization has spared countless patients the morbidity of surgery. Advances in cross-sectional imaging and increases in understanding of which patients will best benefit from embolization promise to further refine the interventional radiologist's role. As the applications of transcatheter therapy broaden to include embolization of unstable patients with solid organ injuries and endovascular repair of major arterial injuries, the interventional radiologist must be increasingly prepared to provide prompt, efficient, and high-quality service. PMID- 21326775 TI - Emergency percutaneous nephrostomy. AB - The primary indication for the urgent percutaneous nephrostomy is to relieve an obstructed and infected renal collecting system (pyonephrosis). Percutaneous nephrostomy catheter placement is a safe procedure with a high technical success rate. This article will discuss all aspects regarding the emergent placement of nephrostomy catheters, including the indications, techniques, results, and complications. Differences between emergent and nonemergent placement of percutaneous nephrostomy catheters will also be addressed. PMID- 21326776 TI - Islet cell transplantation. PMID- 21326777 TI - Inferior vena cava filter malposition in a paraspinal vein. PMID- 21326778 TI - Top 5 Reasons Why You Can't Blame Interventional Radiologists for Neglecting Clinical Duties for So Long. PMID- 21326779 TI - Coding issues for interventional radiology: get paid for what you do! AB - As interventional radiology continues to evolve into a true clinical practice, more time will be spent on the clinical decision process; this time is reimbursable in the form of evaluation and management (E&M) services. Once assumed to be an inherent part of the procedure itself, we know many procedures now do not include follow-up E&M components. Unfortunately, E&M coding is somewhat complex and requires rigorous documentation. Below is a discussion of the fundamentals of E&M services, general principles of documentation, and the mechanics of coverage and reimbursement. PMID- 21326780 TI - The Basics of Interventional Radiology Management in a Large Radiology Group: A Bird's-Eye View. AB - Through nearly 6 decades of growth we have enjoyed and suffered under many different types of management structures. From these experiences we have become believers in a central committee structure that advances our agenda with hospital administrators and third-party payers. The best way to illustrate what we think is a winning solution is by describing our present management system. Herein we describe what we do and what works for our large radiology group as well as our interventional practice. Although this structure works well for our large medical group, it will likely work equally well for a smaller medical group. PMID- 21326781 TI - Lessons learned on how to protect an interventional radiologist against malpractice claims. AB - Unfortunately, the risk of lawsuit is high for the interventional radiologist, especially for the one who assumes a more active clinical role in the care of patients. The importance of assuming this guardianship role in patient care is paramount to building an active referral base for reasons given in several accompanying articles in this issue. Because of added malpractice risks, it is important to fully understand the risks of this clinical role and how to protect yourself from potential lawsuits. This article discusses in depth steps, which can be taken to lessen the risk of a lawsuit, and steps to help effectively defend against a frivolous claim. PMID- 21326782 TI - Paperwork for the busy interventionalist: the basic six. AB - Communication and patient care go hand in hand. Unfortunately, due to time constraints direct verbal communication with health care providers in every instance is not practical; it is also inefficient. Documentation is mandated by the Joint Commission on Accreditation of Healthcare Organizations and hospital bylaws. It reduces ambiguity and actually speeds communication between physician and hospital staff. Standard paperwork is recommended in most cases. Forms for patient admission, history and physical examination, daily patient rounds, preprocedural orders, consent form, discharge summary, and discharge orders allow the busy interventionalist to multitask with reasonable efficiency and fewer mistakes. PMID- 21326783 TI - Using midlevel providers in interventional radiology. AB - Developing and implementing clinical services, including consultations, rounds, and clinic, is time-consuming, and for the interventional radiologist this means time away from the interventional laboratory. Using a team approach to providing clinical services is logical, and the midlevel provider is a perfect fit for an interventional radiology team. Midlevel providers can be grouped into two categories, advanced practice nurses (APNs) and physician's assistants (PAs). Under the umbrella of APN are several specialties including the nurse practitioner (NP), clinical nurse specialist (CNS), certified nurse midwife, and certified nurse anesthetist. The midlevel providers that are particularly suited for interventional radiology are the NPs, CNSs, and PAs. This article discusses midlevel providers in-depth including skills, limitations, and expenses. PMID- 21326784 TI - Establishing surveillance clinics: the road to success. AB - Interventional radiology interacts with all medical disciplines and historically has not had a patient base of its own. The specialty has depended upon referrals for procedures (often complex) and not referrals for the global management of the disease process or patient. Because of this, when referrers develop catheter based skills, referrals to interventional radiology drop and competition for primary care physician referrals increase; a double strike. To compete, interventional radiology needs to offer clinical services to the primary care physician. One way to compete is by establishing particular disease surveillance programs. Below we discuss in detail the process of establishing surveillance clinics, which one worked for us, and the expected outcomes of these clinics. PMID- 21326785 TI - Outpatient care of the interventional radiology patient. AB - The current trend among interventional radiologists is to be actively involved in the pre- and post-procedure care that surrounds many of our procedures. For this to occur, defined office space that is set up in such a way that is conducive to outpatient consultation and post-procedure visits is required. In addition, appropriate support staff such as midlevel providers (including nurse practitioners and physician assistants) and a receptionist are needed to make the entire system work. Finally, dedicated time to focus on direct patient care is mandatory. Equally important is understanding the processes that occur in the background of a typical procedural encounter, including generating referrals, obtaining insurance pre-authorization, managing medical records, and communicating with referring physicians, all of which are expected to take place when managing patients in an outpatient setting. When these components are in place, it becomes possible for an interventionalist to successfully develop an outpatient office and to meet the expectation that patients will be seen before and after procedures by the practitioner performing that procedure. PMID- 21326786 TI - Interventional radiology and the hospitalist: an opportunity for collaboration. AB - Since 1999, the number of hospitalists in the United States has grown from 1500 to 15,000. In addition to this 10-fold increase in individuals, hospitalists are also expanding their clinical reach through increased involvement in consultative and comanagement clinical care, quality improvement, and hospital administration. Interventional radiologists are likely to have more interaction with hospitalists. With a thorough understanding of each other's roles, hospitalists and interventional radiologists have an opportunity to build collaborative relationships of mutual benefit. PMID- 21326787 TI - Clinical care of patients undergoing uterine artery embolization. AB - Uterine artery embolization (UAE) is a relatively recent, safe, and minimally invasive procedure for women experiencing symptomatic fibroids. This process of percutaneous occlusion of blood vessels to disrupt blood flow will consequently impede nourishment to the uterine fibroids and cause infarction. To have proper patient treatment to optimize overall clinical success, guidelines should be rigorously followed. This article will delineate a suitable patient care process for UAE in which subsequent interventional radiologists can employ. PMID- 21326788 TI - Inferior vena cava filter insertion. PMID- 21326789 TI - Superior vena cava syndrome. PMID- 21326790 TI - The top 10 things I learned on clinical interventional radiology rounds. PMID- 21326791 TI - ALS and Pop Music. PMID- 21326792 TI - Aortic development and anomalies. AB - Development of the aorta takes place during the third week of gestation. It is a complex process that can lead to a variety of congenital variants and pathological anomalies. In diagnostic and interventional radiology, knowledge of aortic abnormalities and variant branching sequence is crucially important. This article gives a systematic overview of anatomical variability of the aorta. PMID- 21326794 TI - Endovascular treatment of thoracic dissection. AB - Type A aortic dissection remains fatal if untreated. Although classical medical therapy for type B dissection is considered the therapy of choice in uncomplicated cases, the paradigm is changing as greater experience is accrued with endovascular treatments and technical advances improve the long-term outlook. Diagnosis is also becoming more sophisticated, allowing greater appreciation of the anatomy of dissections and improving the knowledge base as their natural history is assessed. PMID- 21326793 TI - Endovascular management of coarctation of the aorta. AB - Untreated thoracic aortic coarctation leads to early death predominantly because of hypertension and its cardiovascular sequelae. Surgical treatment has been available for > 50 years and has improved hypertension and survival. More recently, endovascular techniques have offered a minimally invasive alternative to traditional open repair. Early and intermediate results suggest angioplasty and stenting have an important role in the management of aortic coarctation, particularly in adults and older children. PMID- 21326795 TI - Thoracic aortic and great vessel trauma and its management. AB - Interventional radiologists (IRs) now play a major role in the management of thoracic aortic and great vessel trauma. The recent availability of a wide range of stent grafts able to treat vessels from 3 to 46 mm in diameter is clearly a significant contributor to this change. Stent grafts can now treat the majority of incomplete aortic injuries with much lower morbidity and mortality than open surgery. Short- to medium-term follow-up is encouraging, but the long-term durability is unknown, and close monitoring of these patients must continue. In great vessel trauma, stent grafts are a useful adjunct to balloon tamponade, embolization, and bare stents. As a result, a wide range of head neck and upper limb vascular injuries can be managed with less local trauma, blood loss, and physiological stress. The increased involvement of IR in the management of vascular trauma is not simply the result of technological advances. IRs have increasingly made themselves available to carry out these emergency procedures. IRs should assist in the development of trauma protocols and management algorithms that involve endovascular expertise early in the assessment of the major trauma patient. PMID- 21326796 TI - Endovascular treatment of atherosclerotic and other thoracic aortic aneurysms. AB - The incidence of thoracic aortic aneurysms (TAAs) is increasing with the present rate of occurrence at 10.9 cases per 100,000 people per year. The estimated 5 year risk of rupture of a TAA with a diameter between 4 and 5.9 cm is 16%, but it rises to 31% for aneurysms >= 6 cm. Despite increasing awareness of the importance of early diagnosis and treatment options, there are no clear guidelines available at the time of writing. Nor is there any clear evidence for specific pharmacological treatment able to resolve or delay the disease progression. Endovascular treatment (EVT), proposed as an alternative to surgery, has been considered a therapeutic innovation, especially because it is minimally invasive, which allows treatment even in high surgical risk patients. Vascular imaging is crucial for patient selection, endoprosthesis choice, and planning of the treatment because not all aneurysms are suitable. Early and midterm results are encouraging, but long-term results are necessary to definitively assess reliability of stent-graft materials and improvement in patient survival. In the choice between surgical or endovascular repair of TAAs, many factors must be considered, including the clinical situation, comorbidities, anatomy, choice of equipment, and last, but not less important, experience of the clinical team. PMID- 21326797 TI - The Current Status of AAA Stent Grafting. AB - It is now 16 years since the endovascular treatment of abdominal aortic aneurysm (AAA) was first described. It is probably true to say that, with current device technology, > 50% of all patients with an infrarenal aneurysm can be treated with an endograft. Endografting has become an important tool in the treatment of AAA. There are many reasons for this success. Rapid technical development followed the initial "homemade" devices, allowing easy accurate insertion. In early cohort series it was always the case that the operative mortality of endografting in AAA was lower than surgical treatment. In addition, postoperative management was easier and hospital stay was shorter after an endograft. No evidence indicated that quality of life improved after the perioperative period, however, and it was unclear whether the reduction in intensive hospital care requirement justified the considerable extra costs for an endovascular device. Despite these shortcomings, early widespread public awareness pushed endograft treatment forward. Patients started to ask for this new treatment option. But long-term outcome data then, and to some extent today, are still lacking. PMID- 21326798 TI - Fenestrated aortic stent grafts. AB - Fenestrated stent grafts have been developed to offer an endovascular treatment option to those patients with abdominal aortic aneurysms whose infrarenal necks are anatomically unsuitable for endovascular repair with standard infrarenal devices. The ability to have customized fenestrations that will preserve flow to essential visceral arteries allows proximal seal and fixation to be achieved at and above the renal level. This article discusses patient selection, stent-graft design, and the importance of accurate planning. Deployment techniques along with complications and their avoidance are considered. The published midterm results are reviewed and appear to justify the continued use and evaluation of this technique as an alternative to open surgical repair in high-risk patients with infrarenal necks unsuitable for standard endovascular repair. PMID- 21326800 TI - Carotid intervention 2: technical considerations. AB - Carotid angioplasty and stenting (CAS) is an evolving technique for treating patients with carotid occlusive disease. However, technical and clinical outcomes are closely related to the knowledge and experience of the interventionalist, and procedural mistakes often lead to serious neurological complications. This article discusses the preinterventional workup of a patient selected for CAS, the different steps of a CAS procedure, the potential complications, how to avoid them, and once they occur how to intervene. Finally, a short overview of the follow-up is given. PMID- 21326799 TI - Carotid intervention 1: who should be treated? AB - Stroke is a major cause of morbidity and mortality in the modern world. Carotid artery atheromatous disease is responsible for a significant number of these events. The effects of carotid artery disease may be prevented by appropriate treatment. All patients with known atheromatous disease should be treated with medical therapy. Despite this, some patients remain at high risk of stroke, which may be reduced by the selective use of additional therapies such as carotid endarterectomy or carotid stenting. Patients who have had recent neurological symptoms, attributable to their carotid disease, may benefit most from these additional treatments, particularly if the treatment is performed soon after the event. The operation needs to be performed with low complication rates. Some groups of patients who have been free of neurological symptoms may also benefit from these additional therapies, but these patients have a much lower inherent risk of stroke, and so the potential benefits are less. In such circumstances it is even more important that the operations are performed with minimal morbidity. Patients undergoing coronary artery bypass grafts, who also have carotid disease, are at elevated risk of stroke, and it is common practice to treat both conditions. There is no strong data to support this practice. PMID- 21326801 TI - Carotid intervention 3: the evidence for cerebral protection. AB - Carotid stenting is a safe alternative option to conventional carotid endarterectomy in the treatment of carotid artery stenosis in patients considered poor candidates for surgery or who choose not to have open surgery. During the stenting procedure, however, distal embolization may occur with neurological sequelae. To reduce the incidence of this, several cerebral-protection devices (CPDs) have been developed. Different types of CPDs are now commercially available: distal occlusion balloons, distal filters, and proximal protection devices with or without reversal of flow. But complications can occur with their use and are usually associated with an inability to cross the lesion, failure to capture the emboli, vasospasm, and vessel wall injury. Because protection devices are currently the focus of interest by manufacturers and physicians, several trials are going on worldwide to analyze the characteristics of each of them and to evaluate their efficacy in reducing the rate of distal embolization. PMID- 21326802 TI - Carotid interventions above and below the bulb. AB - Atherosclerotic occlusive lesions of the common carotid artery (CCA), the internal carotid artery (ICA), and the intracranial branches are amenable to angioplasty and stenting. Non atheromatous occlusive lesions caused by fibromuscular dysplasia, arteritis, or trauma may also be treated by image guided intervention in selected patients. Aneurysmal lesions of the CCA, ICA and the intracranial branches of degenerative, mycotic or traumatic etiologies, as well as carotid cavernous fistulae are mostly best treated by embolization. Technological developments continuously expand the indications of interventional treatment in these vascular territories. PMID- 21326803 TI - Subclavian and vertebral arterial interventions. AB - Endovascular treatment of supra-aortic atherosclerotic arterial stenoses and occlusions using percutaneous transluminal angioplasty (PTA) and stent placement is an accepted first-choice procedure. Technical success, primary success, and midterm patency after PTA and stent placement for the treatment of stenosed or obstructed brachiocephalic arteries are promising and complication rates are low. Permanent miniaturization and device improvement makes treatment of atherosclerotic obstructive disease by endovascular means in brachial and cephalic arteries a safe procedure showing promising midterm patency rates. PMID- 21326804 TI - Percutaneous biliary drainage. PMID- 21326805 TI - Pneumothorax treated by small-bore chest tube. PMID- 21326806 TI - Constitutive activation with overexpression of the mTORC2-phospholipase D1 pathway in uterine leiomyosarcoma and STUMP: morphoproteomic analysis with therapeutic implications. AB - The mammalian target of rapamycin (mTOR) is centrally involved in growth, survival and metabolism. In cancer, mTOR is frequently hyperactivated and is a clinically validated target for therapy and drug development. Biologically, mTOR acts as the catalytic subunit of two functionally distinct complexes, called mTOR complex 1 (mTORC1) which is predominantly cytoplasmic in subcellular localization and mTOR complex 2 (mTORC2) which is both cytoplasmic and nuclear. mTORC1 is sensitive to the selective inhibitor rapamycin. By contrast, mTORC2 is relatively resistant to rapamycin. Moreover, its putative downstream effector, Akt phosphorylated on serine 473 represents a signal transduction pathway for tumor survival. Phospholipase D (PLD) and its product, phosphatidic acid (PA) have been implicated as an activator of mTOR signaling, including the direct phosphorylative activation of p70S6K atthreonine 389. The latter promotes cell cycle progression. In this study, we investigated the activation status and subcellular localization of mTOR and the relative expression of PLD1, as well as their downstream effectors in a spectrum of uterine smooth muscle tumors using normal myometria as controls. The results show significant activation with overexpression of phosphorylated mTORC2 complex in uterine leiomyosarcoma (ULMS) and smooth muscle tumors of uncertain malignant potential (STUMP) as evidenced by nuclear localization of p-mTOR (Ser 2448) in ULMS>STUMP>uterine leiomyoma and normal myometria (p<0.05) and with overexpression of PLD1(p<0.05). Cor relatively, there are overexpressions of nuclear p-Akt (Ser 473) and nuclear p p70S6K (Thr 389) in ULMS and STUMP (p<0.05). The activation with overexpression of components of the mTORC2-PLD1 pathway in ULMS and to a lesser degree in STUMP provides insight into their tumorigenic mechanisms. Thus the development of therapies designed to target mTORC2 and PLD1 activity may be beneficial in treating ULMS. PMID- 21326807 TI - Anaplastic lymphoma kinase-positive diffuse large B-cell lymphoma presenting as an isolated nasopharyngeal mass: a case report and review of literature. AB - Anaplastic lymphoma kinase (ALK)-positive diffuse large B-cell lymphoma is a rare and distinct variant of diffuse large B-cell lymphoma with characteristic morphologic, immunophenotypic, and cytogenetic features. We report a case of ALK positive diffuse large B-cell lymphoma in a 44-year-old male with progressively worsening unilateral nasal congestion and obstruction secondary to a nasopharyngeal mass. Radiologically, the mass was showed to extend to orophanrynx from nasopharynx. Histologically, the tumor cells exhibited plasmablastic morphology with expression of Bob-1, CD4, CD10, CD45, CD56, CD138, EMA, MUM1, Oct 2, and kappa immunoglobulin light chain, but negative for CD20, CD30, CD79a, PAX 5, and lambda. More importantly, the neoplastic cells showed positive immunoreactivity for ALK with exclusive cytoplasmic granular staining pattern. This case represented the second reported ALK-positive diffuse large B-cell lymphoma in the nasopharyngeal region. PMID- 21326808 TI - NPM-ALK and the JunB transcription factor regulate the expression of cytotoxic molecules in ALK-positive, anaplastic large cell lymphoma. AB - Anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma (ALK+ ALCL) is an aggressive non-Hodgkin lymphoma of T/null immunophenotype that is most prevalent in children and young adults. The normal cellular counterpart of this malignancy is presumed to be the cytotoxic T lymphocyte (CTL), and this presumption is partly based on the observation that these tumour cells often express cytotoxic granules containing Granzyme B (GzB) and Perforin. Chromosomal translocations involving the gene encoding for the ALK tyrosine kinase are also characteristic of ALK+ ALCL, and the resulting fusion proteins (e.g. NPM-ALK) initiate signalling events important in ALK+ ALCL pathogenesis. These events include the elevated expression of JunB; an AP-1 family transcription factor that promotes ALK+ ALCL proliferation. In this report we demonstrate that JunB is a direct transcriptional activator of GzB and that GzB transcription is also promoted by NPM-ALK. We found that Perforin expression was not regulated by JunB, but was promoted by NPM-ALK in some cell lines and inhibited by it in others. In conclusion, our study makes the novel observation that signalling through NPM-ALK and JunB affect the expression of cytotoxic molecules in ALK+ ALCL. Moreover, these findings demonstrate the expression of GzB and Perforin in this lymphoma is not solely due its presumed CTL origin, but that oncogenic signalling is actively influencing the expression of these proteins. PMID- 21326809 TI - TDP-43 in aging and Alzheimer's disease - a review. AB - Transactive response DNA-binding protein of 43 kDa (TDP-43), an RNA and DNA binding protein involved in transcriptional repression, RNA splicing and RNA metabolism during the stress response, is the major component of neuronal inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions, now referred to as FTLD-TDP. While initially thought to be relatively specific to ALS and FTLD-TDP, TDP-43 pathology has now been detected in a number of other neurodegenerative diseases, many associated with tau pathology, including Guam Parkinson dementia complex and Alzheimer's disease (AD). TDP-43 pathology is detected in 25% to 50% of AD cases, especially those with more severe clinical phenotype and greater Alzheimer type pathology, as well as AD cases with hippocampal sclerosis (HS). HS is characterized by selective neuronal loss affecting CA1 sector of the hippocampus, and most cases of HS, with or without AD, have TDP-43 pathology. Whether TDP-43 pathology is merely an incidental finding in AD or actually contributing to the more severe clinical phenotype remains unresolved. Presence of TDP-43 in normal elderly, who are at increased risk for AD, would strengthen the argument that it is not merely a secondary or incidental finding in end stage AD. Limited studies suggest that TDP-43 pathology is infrequent in neurologically normal elderly (3% or less). We provide an overview of what is known about TDP-43 in AD, normal aging and in other disorders and suggest that TDP-43 proteinopathies be considered in two classes - primary and secondary. PMID- 21326810 TI - Transcriptional profiling and genotyping of degraded nucleic acids from autopsy tissue samples after prolonged formalin fixation times. AB - BACKGROUND: Samples used for genotyping and transcription studies are obtained and conserved in very specific conditions. The possibility to use autopsy tissue samples, which contain nucleic acids of very poor quality, would open new possibilities for genetic studies. METHODS: We have used liver tissue samples from autopsy cases to (i) determine its quality; (ii) study gene expression of 13 genes involved in different cell processes, before and after cDNA pre amplification (quantitative reverse transcriptase polymerase chain reaction); and (iii) analyze the presence of 2 common polymorphisms of relevance for illness (ACE I/D genotype by PCR amplification, and TNF-alpha promoter gene polymorphism, by DNA sequencing). RESULTS: Samples were grouped according to different buffered formalin fixation times (group 1, <15 days; group 2, 60-90 days; group 3, 150-180 days; group 4, 240-270 days). Nucleic acids showed a time-dependent degradation. The expression of 13 genes could be studied in all cases from groups 1 and 2, only 7 from group 3 and none from group 4. cDNA preamplification allowed the study of all genes in all samples. DNA genotyping for ACE and TNF-alpha promoter region was possible in all cases. CONCLUSIONS: We conclude that nucleic acids extracted from autopsy specimens after prolonged periods of time in formalin were of sufficient quality to study gene expression and genotyping using currently available methodology and cDNA pre-amplification. PMID- 21326811 TI - Neonatal exposure to fluoxetine and fluvoxamine alteres spine density in mouse hippocampal CA1 pyramidal neurons. AB - Some women in childbearing ages take selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and fluvoxamine for treating psychiatric symptoms. However, these compounds may cause some side effects to their children. It has been identified that early life exposure to SSRIs increased the chance of developing mood disorders and the biological basis is still unclear. Here, we studied the effects of neonatal exposure to SSRIs on neuronal morphology. We used GFP-transgenic mice to investigate the acute and long-lasting effects of early life exposure to SSRIs on dendritic spine density of CA1 neurons. We found that 18-day drug applications of fluoxetine and fluvoxamine significantly reduced spine density of basal dendrites at postnatal day 22 (P22), but only fluvoxamine caused a reduction of spine density of apical dendrites. Interestingly, compared with the control group, the spine densities of basal dendrites after fluoxetine and fluvoxamine exposure and the spine density of apical dendrites after fluoxetine exposure increased in adult mice at the age of P90. We also observed impaired locomotor activity in adult mice after exposure to SSRIs. Our findings demonstrated that neonatal exposure to SSRIs was capable of influencing the morphological plasticity of excitatory synapses. It raised the caution for clinical use of SSRIs. PMID- 21326812 TI - Large and round tumor nuclei in osteosarcoma: good clinical outcome. AB - Osteosarcoma is the most frequent primary malignant bone tumor. Distinct histological features are distinguishable based on the morphology of the tumor. Differences in nuclei size and shape are often observed in osteosarcoma reflecting its broad histopathological heterogeneity. This study explores the relevance of two nuclear parameters in osteosarcoma: large area and round shape. Computerized nuclear morphometry was performed in 56 conventional osteosarcoma preoperative biopsies. The mean patient follow-up time was 35.1 months. Based on the nuclear area, no significant difference (P = 0.09) in overall survival between patients with large (> 42.5 MUm(2)) and small (< 42.5 MUm(2)) tumor nuclei was found. However, when cases with large and round nuclei were analyzed jointly (> 42.5 MUm(2) and coefficient of nuclear roundness > 0.7), these two parameters together were likely to be a predictive factor (P = 0.05). Osteosarcoma patients with large and round tumor nuclei had a better outcome than patients with small and polymorphic (ovoid or spindle-shaped) nuclei. In this study, nuclear morphometry proved to be a useful tool to shed light on the biology of osteosarcoma showing that some morphometric parameters can be easily applied to help identifying patients with a good prognosis. PMID- 21326813 TI - D2-40: an additional marker for myoepithelial cells of breast and the precaution in interpreting tumor lymphovascular invasion. AB - D2-40 is a recently available mouse monoclonal antibody specific for human podoplanin and has been used in identifying lymphovascular invasion (LVI) of tumors. Although its expression has been evaluated in other tissues, its use as a marker for myoepithelial cells (MEC) of breast has not been studied. To explore its expression in the MEC of breast, paraffin-embedded tissue blocks from 48 patients with breast diseases were selected to include usual ductal hyperplasia (UDH, 41 cases), atypical ductal hyperplasia (ADH, 4 cases) and ductal carcinoma in situ (DCIS, 17 cases). Normal breast parenchyma and invasive carcinoma coexisting in the tissue sections were also included in the study. Immunohistochemistry for D2-40, calponin and p63 was performed and the staining patterns were reviewed and compared. D2-40 immunohistochemical staining is positive in the cytoplasm of MEC in UDH, ADH, and the majority of DCIS. The staining pattern of D2-40 is comparable with that of calponin, however D2-40 staining of MEC is weaker than that of calponin and with less background. In addition, myoepithelial cells and myofibroblasts at the edge of retraction spaces of DCIS are also stained by D2-40 that could be misinterpreted as tumor LVI. In conclusion, D2-40 immunohistochemistry reliably identifies the MEC of breast in a variety of lesions in a pattern similar to that of calponin and p63, and can be used as an additional MEC marker. Caution should be exercised when interpreting the staining of cells surrounding DCIS and carcinoma with retraction artifact. PMID- 21326814 TI - Hairy cell leukemia and variant in Taiwan: report of a variant case and literature review. AB - Hairy cell leukemia (HCL) is characterized by leukemic cells with abundant "hairy" cytoplasm, strong cytoplasmic positivity for tartrate-resistant acid phosphatase (TRAP), characteristic immunophenotype and sensitivity to treatment with purine nucleoside analogs. HCL-variant (HCL-v) encompasses chronic B-cell leukemias resembling classical HCL but exhibiting variant cytomorphology, variant immunophenotype and resistance to conventional HCL therapy. We present the case of a 67-year-old Taiwanese male with HCL-v who had leukocytosis and splenomegaly. His hairy leukemic cells were weakly positive for TRAP and expressed CDllc and CD103 but not CD25. He received oral chemotherapy with chlorambucil and in complete hematological remission in 9 months but relapsed 2 months later. Literature review revealed 9 cases of HCL and 3 cases of HCL-v including current case from Taiwan. All patients were adults with splenomegaly. The HCL patients had a significantly higher frequency of leukopenia (p = 0.024) and monocytopenia (p = 0.008) and a lower frequency of leukocytosis (p = 0.018) than HCL-v patients. All 8 HCL patients responded favorably to 2-chlorodeoxyadenosine with or without splenectomy. The 3 HCL-v patients had leukocytosis and received chemotherapy with variable outcome. HCL and HCL-v are rare in Taiwan and their pathological and immunophenotypical features were not fully characterized. A multimodality approach incorporating hematological findings, cytomorphology, histopathology, cytochemistry, complete immunophenotyping and clinical features is needed to identify and characterize such cases in Taiwan. PMID- 21326815 TI - The importance of fine needle aspiration in conjunction with radiologic examination in the evaluation of granular cell tumor presenting as a thyroid mass: a case report. AB - Granular cell tumor presenting as a thyroid mass is very rare. It may arise from the thyroid gland or from the tissues/organs adjacent to the thyroid gland. It may cytologically mimick other common thyroid tumors. The accurate evaluation of these tumors may be important for management. We describe a granular cell tumor arising from the tissue adjacent to the thyroid gland and with multiple organ/tissue involvement in a 27-year-old woman with an initial presentation of a thyroid mass. The diagnosis was made by fine needle aspiration and immunocytochemial stains in conjunction with radiological examination. To our knowledge, there is no previous report of such cases in the literature and the importance of fine needle aspiration in conjunction with radiologic examination in the evaluation of granular cell tumor presenting as a thyroid mass has not been well addressed. PMID- 21326816 TI - Invasive pleomorphic lobular carcinoma, negative for ER, PR and Her/2neu--a case report. AB - Pleomorphic variant of lobular carcinoma is a recently described variant of invasive lobular carcinoma. It is reported to be positive for estrogen receptors and progesterone receptors and over express Her2/neu in most cases. We present here a case of invasive variant of pleomorphic lobular carcinoma with coexisting classic and pleomorphic variants of lobular carcinoma in situ along with focal ductal carcinoma in situ. The immunohistochemical results on hormone receptors and high molecular weight cytokeratins in all the above components of the tumor are presented. The invasive tumor was negative for estrogen receptors, progesterone receptors and Her2/neu. Most foci of lobular carcinoma in situ showed morphogenic heterogeneity and a corresponding heterogeneous staining for hormone receptors. The high molecular weight cytokeratins (CK5/6 and CK 903) were non contributory in establishing diagnosis. PMID- 21326817 TI - Carcinosarcoma of female urethra with melanocytic differentiation. AB - Carcinosarcoma arising from the female urethra is rare. We report an unusual case of urethral carcinosarcoma from a female patient with melanocytic differentiation. The tumor consists of a high-grade papillary serous carcinoma with psammoma bodies and a mesenchymal component with area of heterologous (cartilaginous) element. More interestingly, there are epithelioid tumor cells containing melanin pigment. On immunohistochemical stains, the epithelioid tumor cells are positive for S100, HMB45 and Mart-1, but negative for cytokeratin. This case represents an unusual carcinosarcoma with areas of melanocytic differentiation. Such rare tumors have been occasionally reported in the breast, uterus, kidney, and lung. These cases demonstrate the capacity of tumor cells to differentiate into divergent elements, supporting the concept of pluripotent tumor stem cells. PMID- 21326818 TI - Angiolipomatous mesenchymal hamartoma (angiolipomatosis) of the sigmoid mesocolon. AB - BACKGROUND: Primary mesenteric tumors are exceedingly rare and may thus pose a diagnostic challenge. They encompass both benign and malignant neoplasms as well as reactive and idiopathic tumefactive fibroinflammatory lesions. METHOD AND RESULTS: A 70-year-old man who was diagnosed with sigmoid colon cancer was found to have a large non-homogeneous predominantly fatty retroperitoneal soft tissue mass on computerized tomography (CT) scan. The mass was attached to the aorta and have encased the inferior mesenteric artery and extended into the sigmoid mesocolon. Histological examination of the mass showed ill-defined lipoma-like mature fatty tissue traversed by paucicellular fibrous septa entrapping small nerves and containing remarkably increased venous blood vessels reminiscent of soft tissue angiomatosis without evidence of malignancy. The histological features were consistent with an angiolipomatous hamartomatous mesenchymal proliferation. CONCLUSIONS: Angiolipomatous hamartoma might be histogenetically related to soft tissue angiomatosis. To our knowledge, this case represents the first well documented lesion of this type at this location and must be distinguished from other fat-containing masses, particularly angiomyolipoma, sclerosing mesenteritis and mesenteric liposarcoma. PMID- 21326819 TI - Perspective on the metazoan nuclear pore complex. AB - Fusing the inner and outer membranes of the nucleus, the nuclear pore complex (NPC) forms a selective portal which serves as the sole gateway of the nucleus. These aqueous translocation channels allow free diffusion of small molecules and ions, as well as receptor-mediated transport of large macromolecules. Over the last several years major progress has been made in both structural determination of individual nucleopurins (Nups) and their complexes by X-ray crystallography and in structural analysis of the entire assembly by means of cryo-electron tomography. By combining cryo-electron tomography with advanced image processing techniques, the metazoan NPC structure from Xenopus oocytes was resolved to medium resolution, revealing novel details. Here, we discuss new features of the Xenopus NPC and consider future perspectives that will eventually allow resolution of the structure and function of NPCs with high accuracy. PMID- 21326821 TI - GANP enhances the efficiency of mRNA nuclear export in mammalian cells. AB - Nuclear export of mRNPs is mediated by transport factors such as NXF1 that bind mRNPs and mediate their translocation through the central channel of nuclear pores (NPC) using transient interactions with FG-nucleoporins. A number of nuclear factors enhance the efficiency of this process by concentrating mRNPs at the nuclear face of the pores. Although this enhancement has been explored mainly with the yeast TREX-2 complex, recent work has indicated that mammalian cells employ GANP (Germinal-centre Associated Nuclear Protein) for efficient mRNP nuclear export and for efficient recruitment of NXF1-containing mRNPs to NPCs. GANP is constructed from several domains that show local homology to FG nucleoporins, the yeast mRNA export factor Sac3p and the mammalian MCM3 acetyltransferase. Whereas yeast TREX-2 is located primarily at nuclear pores, some GANP is located in the nuclear interior in addition to that found at the pores. GANP depletion inhibits bulk mRNA export, resulting in retention of mRNPs and NXF1 in punctate foci within the nucleoplasm, consistent with GANP's being an integral component of the mammalian mRNA export machinery. Here, we discuss the model for GANP function presented in our recent paper and its implications for the mechanism of mRNA export in mammalian cells. PMID- 21326820 TI - Integrating complex functions: coordination of nuclear pore complex assembly and membrane expansion of the nuclear envelope requires a family of integral membrane proteins. AB - The nuclear envelope harbors numerous large proteinaceous channels, the nuclear pore complexes (NPCs), through which macromolecular exchange between the cytosol and the nucleoplasm occurs. This double-membrane nuclear envelope is continuous with the endoplasmic reticulum and thus functionally connected to such diverse processes as vesicular transport, protein maturation and lipid synthesis. Recent results obtained from studies in Saccharomyces cerevisiae indicate that assembly of the nuclear pore complex is functionally dependent upon maintenance of lipid homeostasis of the ER membrane. Previous work from one of our laboratories has revealed that an integral membrane protein Apq12 is important for the assembly of functional nuclear pores. Cells lacking APQ12 are viable but cannot grow at low temperatures, have aberrant NPCs and a defect in mRNA export. Remarkably, these defects in NPC assembly can be overcome by supplementing cells with a membrane fluidizing agent, benzyl alcohol, suggesting that Apq12 impacts the flexibility of the nuclear membrane, possibly by adjusting its lipid composition when cells are shifted to a reduced temperature. Our new study now expands these findings and reveals that an essential membrane protein, Brr6, shares at least partially overlapping functions with Apq12 and is also required for assembly of functional NPCs. A third nuclear envelope membrane protein, Brl1, is related to Brr6, and is also required for NPC assembly. Because maintenance of membrane homeostasis is essential for cellular survival, the fact that these three proteins are conserved in fungi that undergo closed mitoses, but are not found in metazoans or plants, may indicate that their functions are performed by proteins unrelated at the primary sequence level to Brr6, Brl1 and Apq12 in cells that disassemble their nuclear envelopes during mitosis. PMID- 21326822 TI - Multiple novel functions of lamina associated polypeptide 2alpha in striated muscle. AB - Lamina-associated polypeptide 2alpha (LAP2alpha) is a nucleoplasmic protein that interacts with A-type lamins and the retinoblastoma protein (pRb) and affects pRb mediated cell cycle regulation and chromatin organization. Mutations in lamin A/C and LAP2alpha cause late onset striated muscle diseases, but the molecular mechanisms are poorly understood. We have recently reported on the striated muscle phenotype of LAP2alpha-deficient mice, revealing new unexpected roles of LAP2alpha. Loss of LAP2alpha in skeletal muscle caused an upregulated stem cell type gene expression in muscle satellite cell progeny and their delayed myogenic differentiation in vitro. In vivo, the myofiber-associated muscle stem cell pool was increased. In addition, absence of LAP2alpha promoted muscle remodeling towards fast myofiber types in the soleus muscle of old animals. In cardiac tissue, deletion of LAP2alpha caused systolic dysfunction in young mice with an increased susceptibility for fibrosis in old animals. The functional impairment in the heart was accompanied by a deregulation of major cardiac transcription factors, GATA4 and MEF2c and activation of compensatory pathways, including the downregulation of beta-adrenergic receptor signaling.Here we discuss potential functions of LAP2alpha in striated muscle at molecular level and how loss of these functions may cause the diverse muscle phenotypes. We propose that LAP2alpha serves as a transcriptional co-regulator, which controls muscle specific gene expression during muscle regeneration, muscle remodeling and stress response. PMID- 21326823 TI - A role for DNA sequence in controlling the spatial organization of the genome. AB - Recruitment of genes to the nuclear periphery upon transcriptional activation is a common phenomenon in Saccharomyces cerevisiae. We have recently identified DNA elements called gene recruitment sequences (GRSs) in the promoters of genes that are recruited to the nuclear periphery. These elements are necessary for peripheral targeting of genes. GRSs also function as DNA zip codes: they are sufficient to target an ectopic locus to the nuclear periphery. Targeting promotes full transcription and involves the interaction of promoters with the Nuclear Pore Complex (NPC). GRSs are widespread across the yeast genome, and are enriched in the promoters of genes induced by protein folding stress. Here, we place these observations in the context of the more global topic of genome organization and speculate about how the position of genes impacts their expression. PMID- 21326824 TI - Binding properties and dynamic localization of an alternative isoform of the cap binding complex subunit CBP20. AB - The nuclear cap-binding complex (CBC) is a heterodimer composed of CBP20 and CBP80 subunits and has roles in the biogenesis of messenger RNAs (mRNAs), small nuclear RNAs (snRNAs) and microRNAs. CBP20 is a phylogenetically conserved protein that interacts with the 7-methyl guanosine (m7G) cap added to the 5' end of all RNA polymerase II transcripts. CBP80 ensures high affinity binding of the cap by CBP20 and provides a platform for interactions with other factors. Here we characterize an alternative splice variant of CBP20, termed CBP20S. The CBP20S transcript has an in-frame deletion, leading to the translation of a protein lacking most of the RNA recognition motif (RRM). We show that CBP20S is conserved among mammalian species and is expressed in human cell lines and bone marrow cells. Unlike the full-length CBP20, CBP20S does not bind CBP80 or the m7G cap. Nevertheless, CBP20S does bind mRNA, is localized to an active transcription site and redistributed to nucleolar caps upon transcription inhibition. Our results suggest that this novel form CBP20S plays a role in transcription and/or RNA processing independent of CBP80 or the cap. PMID- 21326825 TI - Transportin 3 and importin alpha are required for effective nuclear import of HIV 1 integrase in virus-infected cells. AB - Unlike other retroviruses, human immunodeficiency virus type-1 (HIV-1) can infect terminally differentiated cells, due to the ability of its pre-integration complex (PIC) to translocate via the host nuclear pore complex (NPC). The PIC Nuclear import has been suggested to be mediated by the viral integrase protein (IN), via either the importin alpha or transportin 3 (TNPO3/transportin-SR2) pathways.We show that in virus-infected cells, IN interacts with both importin alpha and TNPO3, simultaneously or separately, suggesting a multiple use of nuclear import pathways. Disruption of either the IN-importin alpha or IN-TNPO3 complexes in virus-infected cells by specific cell-permeable-peptides resulted in inhibition of IN and viral cDNA nuclear import. Here we show that peptides which disrupt either one of these complexes block virus infection, indicating involvement of both pathways in efficient viral replication. Formation of IN importin alpha and IN-TNPO3 complexes has also been observed in IN-transfected cultured cells. Using specific peptides, we demonstrate that in transfected cells but not in virus infected cells the importin alpha pathway overrides that of TNPO3. The IN-importin alpha and IN-TNPO3 complexes were not observed in virus infected Rev-expressing cells, indicating the Rev protein's ability to disrupt both complexes.Our work suggests that IN nuclear import requires the involvement of both importin alpha and TNPO3. The ability to inhibit nuclear import of the IN DNA complex and consequently, virus infection by peptides that interrupt IN's interaction with either importin alpha or TNPO3 indicates that for efficient infection, nuclear import of IN should be mediated by both nuclear-import receptors. PMID- 21326826 TI - Blocking protein farnesylation improves nuclear shape abnormalities in keratinocytes of mice expressing the prelamin A variant in Hutchinson-Gilford progeria syndrome. AB - Hutchinson-Gilford progeria syndrome (HGPS) is an accelerated aging disorder caused by mutations in LMNA leading to expression of a truncated prelamin A variant termed progerin. Whereas a farnesylated polypeptide is normally removed from the carboxyl-terminus of prelamin A during endoproteolytic processing to lamin A, progerin lacks the cleavage site and remains farnesylated. Cultured cells from human subjects with HGPS and genetically modified mice expressing progerin have nuclear morphological abnormalities, which are reversed by inhibitors of protein farnesylation. In addition, treatment with protein farnesyltransferase inhibitors improves whole animal phenotypes in mouse models of HGPS. However, improvement in nuclear morphology in tissues after treatment of animals has not been demonstrated. We therefore treated transgenic mice that express progerin in epidermis with the protein farnesyltransferase inhibitor FTI 276 or a combination of pravastatin and zoledronate to determine if they reversed nuclear morphological abnormalities in tissue. Immunofluorescence microscopy and "blinded" electron microscopic analysis demonstrated that systemic administration of FTI-276 or pravastatin plus zoledronate significantly improved nuclear morphological abnormalities in keratinocytes of transgenic mice. These results show that pharmacological blockade of protein prenylation reverses nuclear morphological abnormalities that occur in HGPS in vivo. They further suggest that skin biopsy may be useful to determine if protein farnesylation inhibitors are exerting effects in subjects with HGPS in clinical trials. PMID- 21326827 TI - Estrogen fueled, nuclear kiss: did it move for you? AB - A paper appearing in late 2008,1 attracted considerable attention with its description of a dramatic juxtaposition of two estrogen responsive genes on different chromosomes within 15-60 minutes of adding estradiol. These results challenged a growing consensus of limited chromosome mobility within interphase nuclei, while raising questions of whether a hitherto unknown molecular mechanism might exist to move chromosomes long distances within the nucleus. These results also raised the fascinating question of how two genes on widely separated chromosomes might find each other over such a short time span. Now, a more recent paper reports no such long-range interaction or chromosome movements in the same cell types under what appear to be well replicated conditions, forcing a reexamination of the prior results. PMID- 21326828 TI - "Compact" nuclear domains: reconsidering the nucleolus. AB - The nucleolus is among the most striking cell components when viewed by phase contrast microscopy and yet, recent studies have revealed it to possess a lower molecular density than anticipated. A new report demonstrates that the nucleolus accommodates the assembly of a virus, this amidst building ribosomes and performing other host cell functions. PMID- 21326829 TI - Engineering organisms for industrial fuel production. AB - Volatile fuel costs, the need to reduce greenhouse gas emissions and fuel security concerns are driving efforts to produce sustainable renewable fuels and chemicals. Petroleum comes from sunlight, CO(2) and water converted via a biological intermediate into fuel over a several million year timescale. It stands to reason that using biology to short-circuit this time cycle offers an attractive alternative--but only with relevant products at or below market prices. The state of the art of biological engineering over the past five years has progressed to allow for market needs to drive innovation rather than trying to adapt existing approaches to the market. This report describes two innovations using synthetic biology to dis-intermediate fuel production. LS9 is developing a means to convert biological intermediates such as cellulosic hydrolysates into drop-in hydrocarbon product replacements such as diesel. Joule Unlimited is pioneering approaches to eliminate feedstock dependency by efficiently capturing sunlight, CO(2) and water to produce fuels and chemicals. The innovations behind these companies are built with the market in mind, focused on low cost biosynthesis of existing products of the petroleum industry. Through successful deployment of technologies such as those behind LS9 and Joule Unlimited, alternative sources of petroleum products will mitigate many of the issues faced with our petroleum-based economy. PMID- 21326830 TI - Synthetic biology: a foundation for multi-scale molecular biology. AB - The field of synthetic biology has made rapid progress in a number of areas including method development, novel applications and community building. In seeking to make biology "engineerable," synthetic biology is increasing the accessibility of biological research to researchers of all experience levels and backgrounds. One of the underlying strengths of synthetic biology is that it may establish the framework for a rigorous bottom-up approach to studying biology starting at the DNA level. Building upon the existing framework established largely by the Registry of Standard Biological Parts, careful consideration of future goals may lead to integrated multi- scale approaches to biology. Here we describe some of the current challenges that need to be addressed or considered in detail to continue the development of synthetic biology. Specifically, discussion on the areas of elucidating biological principles, computational methods and experimental construction methodologies are presented. PMID- 21326831 TI - Lactococcus lactis as an adjuvant and delivery vehicle of antigens against pneumococcal respiratory infections. AB - Most studies of Lactococcus lactis as delivery vehicles of pneumococcal antigens are focused on the effectiveness of mucosal recombinant vaccines against Streptococcus pneumoniae in animal models. At present, there are three types of pneumococcal vaccines: capsular polysaccharide pneumococcal vaccines (PPV), protein-polysaccharide conjugate pneumococcal vaccines (PCV) and protein-based pneumococcal vaccines (PBPV). Only PPV and PCV have been licensed. These vaccines, however, do not represent a definitive solution. Novel, safe and inexpensive vaccines are necessary, especially in developing countries. Probiotic microorganisms such as lactic acid bacteria (LAB) are an interesting alternative for their use as vehicles in pneumococcal vaccines due to their GRAS (Generally Recognized As Safe) status. Thus, the adjuvanticity of Lactococcus lactis by itself represents added value over the use of other bacteria, a question dealt with in this review. In addition, the expression of different pneumococcal antigens as well as the use of oral and nasal mucosal routes of administration of lactococcal vaccines is considered. The advantages of nasal live vaccines are evident; nonetheless, oral vaccines can be a good alternative when the adequate dose is used. Another point addressed here is the use of live versus inactivated vaccines. In this sense, few researchers have focused on inactivated strains to be used as vaccines against pneumoccoccus. The immunogenicity of live vaccines is better than the one afforded by inactivated ones; however, the probiotic inactivated vaccine combination has improved this matter considerably. The progress made so far in the protective immune response induced by recombinant vaccines, the successful trials in animal models and the safety considerations of their application in humans suggest that the use of recombinant vaccines represents a good short-term option in the control of pneumococcal diseases. PMID- 21326832 TI - The Bacterial Ghost platform system: production and applications. AB - The Bacterial Ghost (BG) platform technology is an innovative system for vaccine, drug or active substance delivery and for technical applications in white biotechnology. BGs are cell envelopes derived from Gram-negative bacteria. BGs are devoid of all cytoplasmic content but have a preserved cellular morphology including all cell surface structures. Using BGs as delivery vehicles for subunit or DNA-vaccines the particle structure and surface properties of BGs are targeting the carrier itself to primary antigen-presenting cells. Furthermore, BGs exhibit intrinsic adjuvant properties and trigger an enhanced humoral and cellular immune response to the target antigen. Multiple antigens of the native BG envelope and recombinant protein or DNA antigens can be combined in a single type of BG. Antigens can be presented on the inner or outer membrane of the BG as well as in the periplasm that is sealed during BG formation. Drugs or supplements can also be loaded to the internal lumen or periplasmic space of the carrier. BGs are produced by batch fermentation with subsequent product recovery and purification via tangential flow filtration. For safety reasons all residual bacterial DNA is inactivated during the BG production process by the use of staphylococcal nuclease A and/or the treatment with beta-propiolactone. After purification BGs can be stored long-term at ambient room temperature as lyophilized product. The production cycle from the inoculation of the pre-culture to the purified BG concentrate ready for lyophilization does not take longer than a day and thus meets modern criteria of rapid vaccine production rather than keeping large stocks of vaccines. The broad spectrum of possible applications in combination with the comparably low production costs make the BG platform technology a safe and sophisticated product for the targeted delivery of vaccines and active agents as well as carrier of immobilized enzymes for applications in white biotechnology. PMID- 21326833 TI - Rapid generation of random mutant libraries. AB - A simple and efficient method utilizing in vivo recombination to create recombinant libraries incorporating the products of PCR amplification is described. This will be especially useful for generating large pools of randomly mutagenized clones after error-prone PCR mutagenesis. Here we investigate various parameters to optimize this approach and we demonstrate that as little as 1 pmole of PCR fragment can generate a library with greater than 104 clones in a single transformation without ligation. PMID- 21326835 TI - Investigating the importance of charged residues in lantibiotics. AB - Lantibiotics are antimicrobial peptides which can have a broad spectrum activity against many Gram positive pathogens. Many of these peptides contain charged amino acids which may be of critical importance with respect to antimicrobial activity. We have recently carried out an in-depth bioengineering based investigation of the importance of charged residues in a representative two peptide lantibiotic, lacticin 3147, and here we discuss the significance of these findings in the context of other lantibiotics and cationic antimicrobial peptides. PMID- 21326834 TI - Transgenic organisms expressing genes from Bacillus thuringiensis to combat insect pests. AB - Various subspecies (ssp.) of Bacillus thuringiensis (Bt) are considered the best agents known so far to control insects, being highly specific and safe, easily mass produced and with long shelf life.1 The para-crystalline body that is produced during sporulation in the exosporium includes polypeptides named delta endotoxins, each killing a specific set of insects. The different entomopathogenic toxins of various Bt ssp. can be manipulated genetically in an educated way to construct more efficient transgenic bacteria or plants that express combinations of toxin genes to control pests.2 Joint research projects in our respective laboratories during the last decade demonstrate what can be done by implementing certain ideas using molecular biology with Bt ssp. israelensis (Bti) as a model system. Here, we describe our progress achieved with Gram negative bacterial species, including cyanobacteria, and some preliminary experiments to form transgenic plants, mainly to control mosquitoes (Diptera), but also a particular Lepidopteran and Coleopteran pest species. In addition, a system is described by which environment-damaging genes can be removed from the recombinants thus alleviating procedures for obtaining permits to release them in nature. PMID- 21326836 TI - Improving yield of industrial biomass propagation by increasing the Trx2p dosage. AB - The beneficial effect of improving yeast redox response by increasing thioredoxin levels has been shown. Decreased lipid and protein oxidation is reflected in an increased biomass yield. In addition, increased redox defenses like glutathione and ROS scavenging enzymes are observed. Furthermore, the wine produced with the modified strain presented more aromatic compounds than the control strain, and its organoleptic properties increased. Here, we hypothesize that reduced glycolytic enzyme carbonylation can increase not only the glycolytic flux but also, and consequently, the biomass yield in the industrial biomass propagation process. The commercial use of the thioredoxin bioengineered yeast as an antioxidant dietetic supplement is also discussed. PMID- 21326837 TI - Gene knockdown by ihpRNA-triggering in the ectomycorrhizal basidiomycete fungus Laccaria bicolor. AB - Ectomycorrhiza (ECM) is a mutualistic association between fungi and the roots of the vast majority of trees. These include numerous ecologically and economically relevant species and the participating fungal symbionts are predominantly filamentous basidiomycetes. In natural ecosystems the plant nutrient uptake from soil takes place via the extraradical mycelia of these ECM mycosimbionts as a trade for plant photosyntates. The symbiotic phase in the life cycle of ECM basidiomycetes is the dikaryotic hyphae. Therefore, studies on symbiotic relevant gene functions require the inactivation of both gene copies in these dikaryotic fungi. RNA silencing is a eukaryotic sequence homology-dependent degradation of target RNAs which is believed to have evolved as a protection mechanism against invading nucleic acids. In different eukaryotic organisms, including fungi, the RNA silencing pathway can be artificially triggered to target and degrade gene transcripts of interest, resulting in gene knock-down. Most importantly, RNA silencing can act at the cytosolic level affecting mRNAs originating from several gene copies and different nuclei thus offering an efficient means of altering gene expression in dikaryotic organisms. Therefore, the pHg/pSILBAgamma silencing vector was constructed for efficient RNA silencing triggering in the model mycorrhizal fungus Laccaria bicolor. This cloning vector carries the Agaricus bisporus gpdII-promoter, two multiple cloning sites separated by a L. bicolor nitrate reductase intron and the Aspergillus nidulans trpC terminator. pSILBAgamma allows an easy two-step PCR-cloning of hairpin sequences to be expressed in basidiomycetes. With one further cloning step into pHg, a pCAMBIA1300-based binary vector carrying a hygromycin resistance cassette, makes the pHg/pSILBAgamma plasmid compatible with Agrobacterium-mediated transformation. The pHg/pSILBAgamma-system results in predominantly single integrations of RNA silencing triggering T-DNAs in the fungal genome and the integration sites of the transgenes can be resolved by plasmid rescue. Besides the optimized use in L. bicolor, general consideration was taken to build a vector system with maximum compatibility with other homobasidiomycetes and different transformation techniques. PMID- 21326838 TI - Microbial renewable feedstock utilization: a substrate-oriented approach. AB - Increasingly lignocellulosic biomass hydrolysates are used as the feedstock for industrial fermentations. These biomass hydrolysates consist of complex mixtures of different fermentable sugars, but also contain inhibitors and salts that affect the performance of the product-generating microbes. The performance of six industrially relevant microorganisms, i.e., two bacteria (Escherichia coli and Corynebacterium glutamicum), two yeasts (Saccharomyces cerevisiae and Pichia stipitis) and two fungi (Aspergillus niger and Trichoderma reesei) were compared for their ability to utilize and grow on different feedstock hydrolysates (corn stover, wheat straw, sugar cane bagasse and willow wood). Moreover, the ability of the selected hosts to utilize waste glycerol from the biodiesel industry was evaluated. P. stipitis and A. niger were found to be the most versatile and C. glutamicum, and S. cerevisiae were shown to be the least adapted to renewable feedstocks. Clear differences in the utilization of the more abundant carbon sources in these feedstocks were observed between the different species. Moreover, in a species-specific way the production of various metabolites, in particular polyols, alcohols and organic acids was observed during fermentation. Based on the results obtained we conclude that a substrate-oriented instead of the more commonly used product oriented approach towards the selection of a microbial production host will avoid the requirement for extensive metabolic engineering. Instead of introducing multiple substrate utilization and detoxification routes to efficiently utilize lignocellulosic hydrolysates only one biosynthesis route forming the product of interest has to be engineered. PMID- 21326839 TI - BT-engineered bugs versus insect pests. PMID- 21326840 TI - Mixed vascular occlusion in a patient with interferon-associated retinopathy. AB - Interferon (INF)-associated retinopathy occurs in 15-64% of INF-treated patients, transforming this complication into a significant risk for visual impairment. This retinopathy has been described as an ocular complication with a variable clinical course, usually benign and asymptomatic. The most common findings are hemorrhages and cotton wool spots. Atypical ocular side effects include branch or central retinal artery occlusion, central retinal vein occlusion, anterior ischemic optic neuropathy, optic disc edema, neovascular glaucoma and vitreous hemorrhage. Some case series suggest that in most cases the clinical course of the disease is benign, asymptomatic and without long-term consequences and therefore do not recommend any specific treatment; they only recommend the discontinuation of INF in patients with severe manifestations or risk factors such as hypertension or diabetes mellitus. The case reported here presents an atypical manifestation of INF-associated retinopathy consisting of a mixed retinal vascular occlusion (arterial and venous), associated with severe occlusive inflammatory microangiopathy with extensive retinal damage by ischemia and a torpid clinical course despite suspension of treatment. These varieties of occlusive vascular events have not yet been found simultaneously in the literature and neither with an unfavorable clinical course. Although the clinical course of INF-associated retinopathy in most cases is asymptomatic, there may be complications with risk to vision, which is less common. The magnitude and severity of the consequences associated with INF therapy are to be determined in prospective further studies. PMID- 21326841 TI - Towards controlling trachoma in ghana. PMID- 21326842 TI - Prevalence of active trachoma two years after control activities. AB - BACKGROUND: Following an epidemiological assessment to map out the endemicity of trachoma in Ghana, Trachoma control interventions were put in place in two districts in Upper West and three in Northern Regions in the year 2001. The control activities were based on the WHO recommended strategy of SAFE. After two years of intervention, a study was undertaken to determine the impact of the control activities. METHODS: A simple random selection of compounds was done. Trained and standardized ophthalmic nurses examined children aged 1 to 10 years for dirty faces and signs of active trachoma. Community members were interviewed to ascertain availability of potable water and latrines. RESULTS: A total of 9,288 children aged 1-10 years were examined in 2003. Overall TF/TI prevalence for Upper West was 5.6% and for Northern Region was 3.5%. In 2000, 6,241 children aged 1-10 years were examined. The overall prevalence of TF/TI for baseline was 15.0% for Upper West and 9.1% for Northern Region. The prevalence of TF/TI showed significant reduction (p-value <0.001) in all five districts and overall in the two regions. CONCLUSION: Trachoma control activities over a two-year period in two regions in Ghana had led to significant reduction in the prevalence of active disease. Integrated surveillance and active monitoring will help early detection of active disease. PMID- 21326843 TI - Evaluation of oral and extra-oral factors predisposing to delusional halitosis. AB - OBJECTIVE: This study evaluated the role of patients' associated oral and extra oral factors, as well as previous dental treatment, as possible predisposing (triggering) factors in the development delusional halitosis. METHOD: Forty-six patients diagnosed of delusional halitosis, over a consecutive period of 2 years (2003-2004) were selected for this study. Diagnosis was based on: use of standard halitosis questionnaire (to confirm the presence of psychological component) modified to obtain data on oral and extra-oral factors, as well as previous dental treatment linked by patients as cause of oral malodour; clinical assessment without objective evidence of oral malodour; absence of reliable third party to confirm patients' claim of oral malodour; and screening with sulphur monitor (RH-17 Series Halimeter, Interscan, Chatsworth, CA) that was within normal range (80-140ppb). RESULTS: All the 46 patients studied had normal halimeter measurement and no reliable third party to confirm the patients' claim of oral malodour. Twenty-four (52.2%) patients had associated possible predisposing factors. The most common associated factors were bitter taste (25.0%), oral deposits (20.8%), carious tooth (16.7%) and previous tooth extraction (16.7%). Associated factors were divided into oral, extra-oral and dental treatment. Patients' associated oral factors were significantly correlated as predisposing factors for delusional halitosis (p<0.01) CONCLUSION: This study shows significant correlation of patients' associated oral factors as the triggering event, which could predispose those individuals who may have underlying psychosomatic tendencies to developing delusional halitosis. PMID- 21326844 TI - Perceived quality of healthcare delivery in a rural district of ghana. AB - OBJECTIVE: The study aimed at finding out clients' perceptions of the quality of healthcare delivery at the district level in rural Ghana, using the Komenda-Edina Eguafo-Abrem District as a case study. DESIGN: 803 patients were purposively selected and interviewed after visits to health facilities using a pretested questionnaire, while focus group discussions were held in 13 communities. The study was done between October 2003 and August 2004. RESULTS: The majority of respondents (70%) were females. The mean expected maximum waiting time for seeking medical help was 1 hr. About 98% said they were asked to explain their problem. However, lower proportions, 74%, 43% and 46% were physically examined, told what was wrong, or given advice about their illness, respectively. About 90% of the respondents were satisfied or very satisfied with the care given during their visit to the health facility. The participants perceived poor attitude of some health workers, long waiting times, high cost of services, inadequate staff, policy of payment for health services, frequent referrals to hospitals, and lack of ambulances at facilities as being detrimental to effective delivery of quality healthcare. CONCLUSIONS: The study found that generally the quality of healthcare delivery was perceived to be high for most of the indicators used. There were, however, some concerns that patients were not told the diagnosis or informed about the management of their illness. These need to be addressed. The level of satisfaction with quality of healthcare was high. PMID- 21326845 TI - Predictors of post operative bleeding and blood transfusion in cardiac surgery. AB - INTRODUCTION: In spite of the recent advances in heart surgery, patients undergoing cardiac surgery with cardiopulmonary bypass are at risk of developing significant post-operative bleeding and substantial blood requirements. OBJECTIVE: To evaluate the impact of some perioperative predictors of post operative bleeding, and blood transfusion after heart surgery and offer suggestions on preventive measures. DESIGN AND METHODS: A prospective analytical study. The perioperative factors studied were haemoglobin level, international normalised ratio (INR), platelet count, and total bypass time. Eighty-seven consecutive patients who underwent heart surgery in the year 2004 were selected. Each patient had laboratory work up which included full blood count, clotting profile, kidney and liver function tests. The total blood loss within the first twenty-four hours and the total units of blood transfused before the patient was discharged were also recorded. RESULTS: Pre-operative haemoglobin was significant in determining the total units of blood received by a patient. Increasing total bypass time caused a significant increase in the percentage reduction of the pre operative platelet count (p <0.004). However even though there was an increasing trend of post-operative bleeding with increase in total bypass time, this was not significant from the analysis (p<0.069). The percentage reduction in platelet count and immediate postoperative platelet count were significant predictors of postoperative bleeding (p <0 .009) and (p <0.003) respectively. CONCLUSION: Pre operative haemoglobin, percentage reduction in the platelet count after cardiopulmonary bypass and immediate postoperative platelet count are significant predictors of postoperative bleeding and blood requirements. PMID- 21326847 TI - Child health: past, present and future challenges. PMID- 21326846 TI - Inhibition of vascular response in inflammation by crude aqueous extract of the root bark of zanthoxylum xanthoxyloides. AB - BACKGROUND: The root bark extract of Zanthoxylum xanthozyloides is used in folklore medicine in Ghana and Nigeria to treat inflammation. A previous pharmacological study confirmed the anti-inflammatory activity of the extract. OBJECTIVE: To study the effect of the extract on vascular response in inflammation. METHOD: The extract was obtained by Soxhlet extraction and rotatory evaporation, followed by freeze-drying. Groups of rats (with carrageenin-induced paw inflammation) and mice (with xylene-induced pinna inflammation) were, respectively, assigned randomly to treatment groups. The animals were given three different treatments orally: 0.9% saline (control), the extract (400mg/kg and 800mg/kg for mice; 1000mg/kg, 2000 mg/kg, and 4000mg/kg for rats), and indomethacin (5mg/kg and 10mg/kg for mice; 10mg/kg, 20mg/kg, and 40mg/kg for rats). In another set of experiment, each treatment group received phenylephrine subcutaneously (30ug/kg for rats and 20ug/kg for mice) in addition to the specified treatment aforementioned. In both sets of experiments, each group of rats was rotated through the entire treatment groups such that each animal served as control as well as received all the treatments. Analysis of variance was used as the statistical test. RESULTS: The extract and indomethacin both caused dose dependent reduction in the carrageenin-induced increase in paw volume in rats and also reduced xylene-induced increase in blood flow in mice pinna arteries. Phenylephrine enhanced the decrease in capillary permeability and vasodilatation caused by low dose extract but not that caused by high dose extract or both low and high dose indomethacin. CONCLUSION: The extract reduced vasodilatation and decreased capillary permeability in inflammation. PMID- 21326848 TI - Impalement injuries of the chest. AB - Impalement injuries of the chest are uncommon in civilian practice with few reports in the literature. We report three cases of thoracic impalement seen over a 5 year period with unusual underlying mechanisms. In two of the cases, the impalement was obvious; in the third, the impalement was concealed having occurred 5 months earlier. In Case 1, the underlying mechanism was a high-speed road traffic accident. The patient was impaled by a metallic square pipe piled by the roadside. In Case 2, the gun-housing of a locally-made rifle gave way as it was fired and allowed a reverse ejection of the barrel during recoil that impaled the hunter's chest. In Case 3, a domestic assault with an old umbrella caused an impalement injury as one of the umbrella spokes broke off, penetrated and lodged in the left chest going unnoticed for 5 months. Persistent chest pain and haemoptysis led to a request for chest radiographic examination upon which the foreign body was discovered. Massive haemoptysis brought the patient to emergency thoracotomy. All three patients underwent thoracotomy with a successful outcome. PMID- 21326849 TI - Melanotic neuroectodermal tumour of infancy (progonoma) treated by radical maxillary surgery. AB - Two cases of melanotic neuroectodermal tumour of infancy (MNTI), otherwise known as melanotic progonoma, both arising from the maxilla are presented here. The two infants both presented within three months of each other and though clinically Burkitt's lymphoma was stated as a possible diagnosis, the correct diagnosis was made on biopsy specimens. Radical surgery consisting of wide resection of the tumour with margins of healthy tissue via hemi-maxillectomy was performed in each case as an initial method of treatment. At follow up four months later, both infants appeared clinically well. One infant was then lost to follow up thereafter but the other was reviewed three years later, and apart from slight facial asymmetry, there was no evidence of tumour recurrence. PMID- 21326850 TI - Cardiomegaly in ghana: an autopsy study. PMID- 21326851 TI - Beyond mistrust: tweaking the doctor-employer relationship. PMID- 21326852 TI - Recurring measles epidemic in Vietnam 2005-2009: implication for strengthened control strategies. AB - BACKGROUND: Measles remains a serious vaccine preventable cause of mortality in developing nations. Vietnam is aiming to achieve the level of immunity required to eliminate measles by maintaining a high coverage of routine first vaccinations in infants, routine second vaccinations at school entry and supplementary local campaigns in high-risk areas. Regular outbreaks of measles are reported, during 2005-2009. METHODS: National measles case-based surveillance data collected during 2005-June 2009 was analyzed to assess the epidemiological trend and risk factors associated with measles outbreak in Vietnam. RESULTS: Of the 36,282 measles suspected cases reported nationwide, only 7,086 cases were confirmed through laboratory examination. Although cyclical outbreaks occurred between 2005 and 2009, there was no definite trend in measles outbreaks during these periods. Overall, 2438 of measles confirmed cases were among children <=5 years and 3068 cases were among people >=16 years. The distribution with respect to gender skewed towards male (3667 cases) significant difference was not observed (P= 0.1693). Unsurprisingly, 4493 of the confirmed cases had no history of vaccination (X(2) <0.01). The northern and highland regions were identified as the main endemic foci and the spatial distribution changed with time. The occurrence of cases, in a considerable proportion of vaccinated population, is not only a reflection of the high vaccination coverage in Vietnam but also portrays a possibility of less than 100% vaccine efficacy. More so, in order to prevent measles in adults, high-risk groups must be identified and catch-up for selected groups selected. CONCLUSIONS: This study therefore reinforces the need for continued improvement of surveillance system and to probe into the possible role of changes in age-distribution of cases if the effective control of measles is to be achieved. PMID- 21326854 TI - Laparoscopy-assisted resection of tailgut cysts: report of a case. AB - Tailgut cysts, or retrorectal cystic hamartomas, are rare congenital developmental lesions, most commonly located in the retrorectal space, and are more common in women. We present a case of retrorectal tailgut cyst managed using a laparoscopic approach. A 36-year-old woman presented with incidentally detected retrorectal tumors during evaluation for a gallbladder polyp. Her past medical history revealed that she had undergone cesarean section twice. The tumor marker CA 19-9 level was 42.52 U/ml. CT of the pelvis with contrast and pelvic MRI revealed a 3.9 * 3.3 cm well-defined, homogeneous cystic mass in the right presacral area, and a 2.5 * 1.5 cm cystic mass in the precoccygeal space. The patient underwent laparoscopic exploration with a preoperative diagnosis of tailgut cysts based on radiological findings. The operative time was 90 min including 30 min of subsequent laparoscopic cholecystectomy without placement of additional trocars. The surgical specimens consisted of two fragments of fibrofatty tissues, unilocular cystic masses. The final pathologic diagnosis was tailgut cysts with no evidence of malignancy. Postoperative recovery was uneventful, and the patient was discharged after 3 days. In conclusion, surgical resection is recommended in the management of retrorectal tailgut cyst to establish a definite diagnosis and to rule out malignancy. The laparoscopic approach is a feasible and safe option. PMID- 21326853 TI - The myoepithelial cell layer may serve as a potential trigger factor for different outcomes of stage-matched invasive lobular and ductal breast cancers. AB - Invasive lobular cancer (ILC) tends to be significantly larger in size with significantly more positive lymph nodes, whereas ILC has a significantly more favorable outcome, compared to stage-matched invasive ductal carcinoma (IDC). The mechanism accounting for such differences remains elusive. Based on morphological, immunohistochemical, and molecular studies of over 1,000 cases of human breast cancers, we hypothesize that the differences may result from the structural and/or functional differences of their surrounding myoepithelial cell layers, which dictate lobular and ductal tumor cells to follow different pathways of invasion or metastasis. The background, rationale, supportive data, and implications of our hypothesis are presented and discussed. PMID- 21326855 TI - A case of long partial response to combination therapy of bevacizumab and capecitabine for liver metastases of rectal cancer. AB - A 69-year-old female visited our department with a diagnosis of rectosigmoid cancer and multiple hepatic metastases (stage IV). Abdominal CT revealed multiple metastatic lesions in the bilateral lobes of the liver. The primary lesion was considered to be resectable, and high anterior resection of the rectum was performed. After the operation, 6 courses of therapy with bevacizumab (BV) and modified FOLFOX6 were performed. CT showed a partial response, and tumor marker levels became normal. After a total of 11 courses of this therapy, grade 3 peripheral neuropathy developed, and the therapy was changed to BV and capecitabine (Cape). After 6 courses of this therapy, CT showed the maintenance of partial response, and tumor marker levels were also within the normal range. BV and Cape therapy may be useful not only for reducing peripheral neuropathy, but also as a maintenance therapy in patients requiring the suspension of oxaliplatin administration due to peripheral neuropathy. PMID- 21326856 TI - A large portal vein: a rare finding of recent portal vein thrombosis. AB - Acute portal vein thrombosis (PVT) is rarely encountered by clinicians. The most common manifestation of acute PVT is sudden onset of abdominal pain. A computed tomography scan without contrast often shows a high-density material in the portal vein. After injection of contrast agents, absence of luminal enhancement and enlargement of the obstructed portal vein are shown. In this case report, we demonstrated a rare computed tomography finding in which the diameter of the main portal vein was enormously distended to 3-fold that of the aorta in a patient with recent PVT. Despite thrombolysis and anticoagulation were immediately given, portal venous recanalization was not achieved in the patient. After 5 years, variceal bleeding and ascites occurred and liver function had persistently deteriorated. Finally, he died of progressive liver failure. Considering this case, we suggest that an early decision for invasive interventional treatment might be necessary to both increase the rate of portal venous recanalization and improve prognosis, as anticoagulation and thrombolysis therapy failed to recanalize recent PVT. PMID- 21326857 TI - Survival following Treatment of Aortoesophageal Fistula with Dual Esophageal and Aortic Intervention. AB - Aortoesophageal fistulas are a rare but commonly fatal complication of esophageal cancer. Reports of successfully managed cases are few, with high mortality and morbidity usually resulting from failure to control the initial massive haemodynamic insult. We report the case of a 47-year-old Caucasian man with recently diagnosed advanced esophageal cancer who suffered an episode of massive haematemesis. Emergency gastroscopy revealed an arterial bleeding point in the proximal esophagus. A self-expanding metal esophageal stent was placed to achieve initial partial haemostasis. CT angiography confirmed an aortoesophageal fistula. An endoluminal stent device was thus inserted within the thoracic aorta stabilising the bleeding point. The patient subsequently made an uneventful recovery and was discharged on long-term antibiotics for palliative care. He survived for 2 months at home before dying of disseminated malignancy. The successful use of esophageal stenting as a means of achieving haemostasis, allowing time for endovascular intervention, is as yet a relatively unexplored area of management of this rare condition. PMID- 21326858 TI - Development of pseudomembranous colitis four months after initiation of rifampicin. AB - Pseudomembranous colitis (PMC) may develop with long-term antibiotic administration, but is rarely reported to be caused by antitubercular agents. We present a case of PMC that occurred 120 days after starting rifampicin. A 74-year old man was diagnosed with pulmonary tuberculosis and started on a standard HERZ regimen (isoniazid, ethambutol, rifampicin, pyrazinamide). After 4 months of HERZ, he presented with frequent bloody, mucoid, jelly-like diarrhea and lower abdominal pain. Sigmoidoscopy revealed multiple whitish plaques with edematous mucosa that were compatible with PMC. Biopsies from these lesions showed ulcer related necrotic and granulation tissue. We stopped antitubercular treatment and started the patient on oral metronidazole. His symptoms completely resolved within 2 weeks. Antitubercular treatment was restarted by replacing rifampicin with levofloxacin. The patient did not present with diarrhea or bloody stool throughout the rest of treatment. PMID- 21326859 TI - Does phenytoin improve the healing of gastrointestinal fistulas? AB - Pancreatic fistulas are among the most devastating complications after pancreatic surgery. Their subsequent development can be lethal. We report two cases of pancreatic fistulas treated with phenytoin. Fistula tract healing consists of several processes, including cell migration and the formation of a new extracellular matrix. Multiple studies have shown that phenytoin can promote wound healing and induce faster fibrosis. We postulate that such a positive effect can be used to enhance fibrosis of the pancreatic fistula tract. We treated two patients who had developed high-output pancreatic fistulas after pancreatic surgery. The first underwent hand-assisted laparoscopic pancreatic necrosectomy and developed two high-output pancreatic fistulas and a colocutaneous fistula. The second occurred post Whipple surgery. Both were given oral phenytoin after failure to respond to other measures. In conclusion, oral phenytoin may have a positive effect in the treatment of fistulas. Prospective studies are needed to indicate this possible effect of phenytoin on fistula healing. PMID- 21326860 TI - Identification of novel susceptibility Loci for kawasaki disease in a Han chinese population by a genome-wide association study. AB - Kawasaki disease (KD) is an acute systemic vasculitis syndrome that primarily affects infants and young children. Its etiology is unknown; however, epidemiological findings suggest that genetic predisposition underlies disease susceptibility. Taiwan has the third-highest incidence of KD in the world, after Japan and Korea. To investigate novel mechanisms that might predispose individuals to KD, we conducted a genome-wide association study (GWAS) in 250 KD patients and 446 controls in a Han Chinese population residing in Taiwan, and further validated our findings in an independent Han Chinese cohort of 208 cases and 366 controls. The most strongly associated single-nucleotide polymorphisms (SNPs) detected in the joint analysis corresponded to three novel loci. Among these KD-associated SNPs three were close to the COPB2 (coatomer protein complex beta-2 subunit) gene: rs1873668 (p = 9.52*10-5), rs4243399 (p = 9.93*10-5), and rs16849083 (p = 9.93*10-5). We also identified a SNP in the intronic region of the ERAP1 (endoplasmic reticulum amino peptidase 1) gene (rs149481, p(best) = 4.61*10-5). Six SNPs (rs17113284, rs8005468, rs10129255, rs2007467, rs10150241, and rs12590667) clustered in an area containing immunoglobulin heavy chain variable regions genes, with p(best)-values between 2.08*10-5 and 8.93*10-6, were also identified. This is the first KD GWAS performed in a Han Chinese population. The novel KD candidates we identified have been implicated in T cell receptor signaling, regulation of proinflammatory cytokines, as well as antibody-mediated immune responses. These findings may lead to a better understanding of the underlying molecular pathogenesis of KD. PMID- 21326861 TI - Dynamics of molecular evolution and phylogeography of Barley yellow dwarf virus PAV. AB - Barley yellow dwarf virus (BYDV) species PAV occurs frequently in irrigated wheat fields worldwide and can be efficiently transmitted by aphids. Isolates of BYDV PAV from different countries show great divergence both in genomic sequences and pathogenicity. Despite its economical importance, the genetic structure of natural BYDV-PAV populations, as well as of the mechanisms maintaining its high diversity, remain poorly explored. In this study, we investigate the dynamics of BYDV-PAV genome evolution utilizing time-structured data sets of complete genomic sequences from 58 isolates from different hosts obtained worldwide. First, we observed that BYDV-PAV exhibits a high frequency of homologous recombination. Second, our analysis revealed that BYDV-PAV genome evolves under purifying selection and at a substitution rate similar to other RNA viruses (3.158*10(-4) nucleotide substitutions/site/year). Phylogeography analyses show that the diversification of BYDV-PAV can be explained by local geographic adaptation as well as by host-driven adaptation. These results increase our understanding of the diversity, molecular evolutionary characteristics and epidemiological properties of an economically important plant RNA virus. PMID- 21326862 TI - Transplanted human amniotic membrane-derived mesenchymal stem cells ameliorate carbon tetrachloride-induced liver cirrhosis in mouse. AB - BACKGROUND: Human amniotic membrane-derived mesenchymal stem cells (hAMCs) have the potential to reduce heart and lung fibrosis, but whether could reduce liver fibrosis remains largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: Hepatic cirrhosis model was established by infusion of CCl4 (1 ml/kg body weight twice a week for 8 weeks) in immunocompetent C57Bl/6J mice. hAMCs, isolated from term delivered placenta, were infused into the spleen at 4 weeks after mice were challenged with CCl4. Control mice received only saline infusion. Animals were sacrificed at 4 weeks post-transplantation. Blood analysis was performed to evaluate alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Histological analysis of the livers for fibrosis, hepatic stellate cells activation, hepatocyte apoptosis, proliferation and senescence were performed. The donor cell engraftment was assessed using immunofluorescence and polymerase chain reaction. The areas of hepatic fibrosis were reduced (6.2%+/-2.1 vs. control 9.6%+/-1.7, p<0.05) and liver function parameters (ALT 539.6+/-545.1 U/dl, AST 589.7+/-342.8 U/dl,vs. control ALT 139.1+/-138.3 U/dl, p<0.05 and AST 212.3+/-110.7 U/dl, p<0.01) were markedly ameliorated in the hAMCs group compared to control group. The transplantation of hAMCs into liver-fibrotic mice suppressed activation of hepatic stellate cells, decreased hepatocyte apoptosis and promoted liver regeneration. More interesting, hepatocyte senescence was depressed significantly in hAMCs group compared to control group. Immunofluorescence and polymerase chain reaction revealed that hAMCs engraftment into host livers and expressed the hepatocyte-specific markers, human albumin and alpha-fetoproteinran. CONCLUSIONS/SIGNIFICANCE: The transplantation of hAMCs significantly decreased the fibrosis formation and progression of CCl4-induced cirrhosis, providing a new approach for the treatment of fibrotic liver disease. PMID- 21326863 TI - SIMPLE/LITAF expression induces the translocation of the ubiquitin ligase itch towards the lysosomal compartments. AB - LITAF is a small cellular protein with an unknown function. The C-terminus of LITAF contains a highly conserved domain termed the SIMPLE-like domain (SLD), while the N-terminus contains two PPXY motifs that mediate protein-protein interactions with WW-domain containing proteins. LITAF also harbors two endosome/lysosome targeting sequences at its C-terminus, but there has been conflicting reports regarding its intracellular localization. Here, we demonstrate that LITAF is localized to the late endosome/lysosomal compartment in a variety of cell lines. We also show that Itch, a WW-domain containing protein, and LITAF strongly interact and that this interaction depends on the two PPXY motifs in the N-terminus of LITAF. Interestingly, co-expression of LITAF with Itch induces major changes in Itch intracellular localization, bringing Itch from the trans-Golgi network to lysosomes. We show that this re-localization is dependent upon the interaction with the PPXY sequences of LITAF, since disruption of these binding motifs completely abrogates Itch re-localization. PMID- 21326864 TI - Chemogenomic analysis of G-protein coupled receptors and their ligands deciphers locks and keys governing diverse aspects of signalling. AB - Understanding the molecular mechanism of signalling in the important super-family of G-protein-coupled receptors (GPCRs) is causally related to questions of how and where these receptors can be activated or inhibited. In this context, it is of great interest to unravel the common molecular features of GPCRs as well as those related to an active or inactive state or to subtype specific G-protein coupling. In our underlying chemogenomics study, we analyse for the first time the statistical link between the properties of G-protein-coupled receptors and GPCR ligands. The technique of mutual information (MI) is able to reveal statistical inter-dependence between variations in amino acid residues on the one hand and variations in ligand molecular descriptors on the other. Although this MI analysis uses novel information that differs from the results of known site directed mutagenesis studies or published GPCR crystal structures, the method is capable of identifying the well-known common ligand binding region of GPCRs between the upper part of the seven transmembrane helices and the second extracellular loop. The analysis shows amino acid positions that are sensitive to either stimulating (agonistic) or inhibitory (antagonistic) ligand effects or both. It appears that amino acid positions for antagonistic and agonistic effects are both concentrated around the extracellular region, but selective agonistic effects are cumulated between transmembrane helices (TMHs) 2, 3, and ECL2, while selective residues for antagonistic effects are located at the top of helices 5 and 6. Above all, the MI analysis provides detailed indications about amino acids located in the transmembrane region of these receptors that determine G-protein signalling pathway preferences. PMID- 21326866 TI - Characterizing genetic diversity of contemporary pacific chickens using mitochondrial DNA analyses. AB - BACKGROUND: Mitochondrial DNA (mtDNA) hypervariable region (HVR) sequences of prehistoric Polynesian chicken samples reflect dispersal of two haplogroups--D and E--by the settlers of the Pacific. The distribution of these chicken haplogroups has been used as an indicator of human movement. Recent analyses suggested similarities between prehistoric Pacific and South American chicken samples, perhaps reflecting prehistoric Polynesian introduction of the chicken into South America. These analyses have been heavily debated. The current distribution of the D and E lineages among contemporary chicken populations in the Western Pacific is unclear, but might ultimately help to inform debates about the movements of humans that carried them. OBJECTIVES: We sought to characterize contemporary mtDNA diversity among chickens in two of the earliest settled archipelagos of Remote Oceania, the Marianas and Vanuatu. METHODS: We generated HVR sequences for 43 chickens from four islands in Vanuatu, and for 5 chickens from Guam in the Marianas. RESULTS: Forty samples from Vanuatu and three from Guam were assigned to haplogroup D, supporting this as a Pacific chicken haplogroup that persists in the Western Pacific. Two haplogroup E lineages were observed in Guam and two in Vanuatu. Of the E lineages in Vanuatu, one was identical to prehistoric Vanuatu and Polynesian samples and the other differed by one polymorphism. Contrary to our expectations, we observed few globally distributed domesticate lineages not associated with Pacific chicken dispersal. This might suggest less European introgression of chickens into Vanuatu than expected. If so, the E lineages might represent lineages maintained from ancient Pacific chicken introductions. The Vanuatu sample might thus provide an opportunity to distinguish between maintained ancestral Pacific chicken lineages and replacement by global domesticates through genomic analyses, which could resolve questions of contemporary haplogroup E chicken relationships and inform interpretations of debated sequences from archaeological samples. PMID- 21326865 TI - A signature of maternal anti-fetal rejection in spontaneous preterm birth: chronic chorioamnionitis, anti-human leukocyte antigen antibodies, and C4d. AB - BACKGROUND: Chronic chorioamnionitis is found in more than one-third of spontaneous preterm births. Chronic chorioamnionitis and villitis of unknown etiology represent maternal anti-fetal cellular rejection. Antibody-mediated rejection is another type of transplantation rejection. We investigated whether there was evidence for antibody-mediated rejection against the fetus in spontaneous preterm birth. METHODS AND FINDINGS: This cross-sectional study included women with (1) normal pregnancy and term delivery (n = 140) and (2) spontaneous preterm delivery (n = 140). We analyzed maternal and fetal sera for panel-reactive anti-HLA class I and class II antibodies, and determined C4d deposition on umbilical vein endothelium by immunohistochemistry. Maternal anti HLA class I seropositivity in spontaneous preterm births was higher than in normal term births (48.6% vs. 32.1%, p = 0.005). Chronic chorioamnionitis was associated with a higher maternal anti-HLA class I seropositivity (p<0.01), significant in preterm and term birth. Villitis of unknown etiology was associated with increased maternal and fetal anti-HLA class I and II seropositivity (p<0.05, for each). Fetal anti-HLA seropositivity was closely related to maternal anti-HLA seropositivity in both groups (p<0.01, for each). C4d deposition on umbilical vein endothelium was more frequent in preterm labor than term labor (77.1% vs. 11.4%, p<0.001). Logistic regression analysis revealed that chronic chorioamnionitis (OR = 6.10, 95% CI 1.29-28.83), maternal anti-HLA class I seropositivity (OR = 5.90, 95% CI 1.60-21.83), and C4d deposition on umbilical vein endothelium (OR = 36.19, 95% CI 11.42-114.66) were associated with preterm labor and delivery. CONCLUSIONS: A major subset of spontaneous preterm births has a signature of maternal anti-fetal cellular and antibody-mediated rejections with links to fetal graft-versus-host disease and alloimmune reactions. PMID- 21326867 TI - SOD2 deficient erythroid cells up-regulate transferrin receptor and down-regulate mitochondrial biogenesis and metabolism. AB - BACKGROUND: Mice irradiated and reconstituted with hematopoietic cells lacking manganese superoxide dismutase (SOD2) show a persistent hemolytic anemia similar to human sideroblastic anemia (SA), including characteristic intra-mitochondrial iron deposition. SA is primarily an acquired, clonal marrow disorder occurring in individuals over 60 years of age with uncertain etiology. METHODOLOGY/PRINCIPAL FINDINGS: To define early events in the pathogenesis of this murine model of SA, we compared erythroid differentiation of Sod2-/- and normal bone marrow cells using flow cytometry and gene expression profiling of erythroblasts. The predominant transcriptional differences observed include widespread down regulation of mitochondrial metabolic pathways and mitochondrial biogenesis. Multiple nuclear encoded subunits of complexes I-IV of the electron transport chain, ATP synthase (complex V), TCA cycle and mitochondrial ribosomal proteins were coordinately down-regulated in Sod2-/- erythroblasts. Despite iron accumulation within mitochondria, we found increased expression of transferrin receptor, Tfrc, at both the transcript and protein level in SOD2 deficient cells, suggesting deregulation of iron delivery. Interestingly, there was decreased expression of ABCb7, the gene responsible for X-linked hereditary SA with ataxia, a component required for iron-sulfur cluster biogenesis. CONCLUSIONS/SIGNIFICANCE: These results indicate that in erythroblasts, mitochondrial oxidative stress reduces expression of multiple nuclear genes encoding components of the respiratory chain, TCA cycle and mitochondrial protein synthesis. An additional target of particular relevance for SA is iron:sulfur cluster biosynthesis. By decreasing transcription of components of cluster synthesis machinery, both iron utilization and regulation of iron uptake are impacted, contributing to the sideroblastic phenotype. PMID- 21326868 TI - An objective scatter index based on double-pass retinal images of a point source to classify cataracts. AB - PURPOSE: To propose a new objective scatter index (OSI) based in the analysis of double-pass images of a point source to rank and classify cataract patients. This classification scheme is compared with a current subjective system. METHODS: We selected a population including a group of normal young eyes as control and patients diagnosed with cataract (grades NO2, NO3 and NO4) according to the Lens Opacities Classification System (LOCS III). For each eye, we recorded double-pass retinal images of a point source. In each patient, we determined an objective scatter index (OSI) as the ratio of the intensity at an eccentric location in the image and the central part. This index provides information on the relevant forward scatter affecting vision. Since the double-pass retinal images are affected by both ocular aberrations and intraocular scattering, an analysis was performed to show the ranges of contributions of aberrations to the OSI. RESULTS: We used the OSI values to classify each eye according to the degree of scatter. The young normal eyes of the control group had OSI values below 1, while the OSI for subjects in LOCS grade II were around 1 to 2. The use of the objective index showed some of the weakness of subjective classification schemes. In particular, several subjects initially classified independently as grade NO2 or NO3 had similar OSI values, and in some cases even higher than subjects classified as grade NO4. A new classification scheme based in OSI is proposed. CONCLUSIONS: We introduced an objective index based in the analysis of double-pass retinal images to classify cataract patients. The method is robust and fully based in objective measurements; i.e., not depending on subjective decisions. This procedure could be used in combination with standard current methods to improve cataract patient surgery scheduling. PMID- 21326869 TI - Phenotypic overlap between MMP-13 and the plasminogen activation system during wound healing in mice. AB - BACKGROUND: Proteolytic degradation of extracellular matrix is a crucial step in the healing of incisional skin wounds. Thus, healing of skin wounds is delayed by either plasminogen-deficiency or by treatment with the broad-spectrum metalloproteinase (MP) inhibitor Galardin alone, while the two perturbations combined completely prevent wound healing. Both urokinase-type plasminogen activator and several matrix metallo proteinases (MMPs), such as MMP-3, -9 and 13, are expressed in the leading-edge keratinocytes of skin wounds, which may account for this phenotypic overlap between these classes of proteases. METHODOLOGY: To further test that hypothesis we generated Mmp13;Plau and Mmp13;Plg double-deficient mice in a cross between Mmp13- and Plau-deficient mice as well as Mmp13- and Plg-deficient mice. These mice were examined for normal physiology in a large cohort study and in a well-characterized skin wound healing model, in which we made incisional 20 mm-long full-thickness skin wounds. PRINCIPAL FINDINGS: While mice that are deficient in Mmp13 have a mean healing time indistinguishable to wild-type mice, wound healing in both Plau- and Plg deficient mice is significantly delayed. Histological analysis of healed wounds revealed a significant increase in keratin 10/14 immunoreactive layers of kerationcytes in the skin surface in Mmp13;Plau double-deficient mice. Furthermore, we observe, by immunohistological analysis, an aberrant angiogenic pattern during wound healing induced by Plau-deficiency, which has not previously been described. CONCLUSIONS: We demonstrate a phenotypic overlap, defined as an additional delay in wound healing in the double-deficient mice compared to the individual single-deficient mice, between MMP-13 and the plasminogen activation system in the process of wound healing, but not during gestation and in postnatal development. Thus, a dual targeting of uPA and MMP-13 might be a possible future strategy in designing therapies aimed at tissue repair or other pathological processes, such as cancer invasion, where proteolytic degradation is a hallmark. PMID- 21326871 TI - Targeting vascular NADPH oxidase 1 blocks tumor angiogenesis through a PPARalpha mediated mechanism. AB - Reactive oxygen species, ROS, are regulators of endothelial cell migration, proliferation and survival, events critically involved in angiogenesis. Different isoforms of ROS-generating NOX enzymes are expressed in the vasculature and provide distinct signaling cues through differential localization and activation. We show that mice deficient in NOX1, but not NOX2 or NOX4, have impaired angiogenesis. NOX1 expression and activity is increased in primary mouse and human endothelial cells upon angiogenic stimulation. NOX1 silencing decreases endothelial cell migration and tube-like structure formation, through the inhibition of PPARalpha, a regulator of NF-kappaB. Administration of a novel NOX specific inhibitor reduced angiogenesis and tumor growth in vivo in a PPARalpha dependent manner. In conclusion, vascular NOX1 is a critical mediator of angiogenesis and an attractive target for anti-angiogenic therapies. PMID- 21326872 TI - PKCdelta sensitizes neuroblastoma cells to L-buthionine-sulfoximine and etoposide inducing reactive oxygen species overproduction and DNA damage. AB - Neuroblastoma is a type of pediatric cancer. The sensitivity of neuroblastoma (NB) cancer cells to chemotherapy and radiation is inhibited by the presence of antioxidants, such as glutathione (GSH), which is crucial in counteracting the endogenous production of reactive oxygen species (ROS). We have previously demonstrated that cells depleted of GSH undergo apoptosis via oxidative stress and Protein kinase C (PKC) delta activation. In the present study, we transfected PKCdelta in NB cells resistant to oxidative death induced by L-buthionine-S,R sulfoximine (BSO), a GSH-depleting agent. Cell responses, in terms of ROS production, apoptosis and DNA damage were evaluated. Moreover, PKCdelta activation was monitored by analyzing the phosphorylation status of threonine 505 residue, carrying out PKC activity assay and investigating the subcellular localization of the kinase. The cell responses obtained in BSO-resistant cells were also compared with those obtained in BSO-sensitive cells subjected to the same experimental protocol. Our results demonstrate, for the first time, that PKCdelta induces DNA oxidation and ROS overproduction leading to apoptosis of BSO resistant NB cells and potentiates the cytotoxic effects induced by BSO in sensitive cells. Moreover, PKCdelta overexpression enhances the sensitivity of NB cells to etoposide, a well-characterised drug, commonly used in neuroblastoma therapy. Altogether our data provide evidence of a pro-oxidant role of PKCdelta that might be exploited to design new therapeutic strategies aimed at selective killing of cancer cells and overcoming drug resistance. However, it becomes evident that a more detailed understanding of ROS-mediated signaling in cancer cells is necessary for the development of redox-modulated therapeutic approaches. PMID- 21326873 TI - Capturing the context of maternal deaths from verbal autopsies: a reliability study of the maternal data extraction tool (M-DET). AB - BACKGROUND: The availability of quality data to inform policy is essential to reduce maternal deaths. To characterize maternal deaths in settings without complete vital registration systems, we designed and assessed the inter-rater reliability of a tool to systematically extract data and characterize the events that precede a nationally representative sample of maternal deaths in India. METHOD/PRINCIPAL FINDINGS: Of 1017 nationally representative pregnancy-related deaths, which occurred between 2001 and 2003, we randomly selected 105 reports. Two independent coders used the maternal data extraction tool (questions with coding guidelines) to collect information on antenatal care access, final pregnancy outcome; planned place of birth and care provider; community consultation, transport, admission, hospital referral; and verification of cause of death assignment. Kappa estimated inter-rater agreement was calculated and classified as poor (K<=0.4), moderate (K = 0.4<=0.6), substantial (K = 0.6<= 0.8) and high (K>0.8) using the criteria from Landis & Koch. The data extraction tool had high agreement for gestational age, pregnancy outcome, transport, death en route and admission to hospital; substantial agreement for receipt of antenatal care, planned place of birth, readmission and referral to higher level hospital, and whether or not death occurred in the intrapartum period; moderate to substantial agreement for classification of deaths as direct or indirect obstetric deaths or incidental deaths; moderate agreement for classification of community healthcare consultation and total number of healthcare contacts; and poor agreement for the classification of deaths as sudden deaths and other/unknown cause of death. The ability of the tool to identify the most responsible-person in labour varied from moderate agreement to high agreement. CONCLUSIONS: This data extraction tool achieved good inter-rater reliability and can be used to collect data on events surrounding maternal deaths and for verification/improvement of underlying cause of death. PMID- 21326874 TI - Autoantibodies to endothelial cell surface ATP synthase, the endogenous receptor for hsp60, might play a pathogenic role in vasculatides. AB - BACKGROUND: Heat shock protein (hsp) 60 that provides "danger signal" binds to the surface of resting endothelial cells (EC) but its receptor has not yet been characterized. In mitochondria, hsp60 specifically associates with adenosine triphosphate (ATP) synthase. We therefore examined the possible interaction between hsp60 and ATP synthase on EC surface. METHODOLOGY/PRINCIPAL FINDINGS: Using Far Western blot approach, co-immunoprecipitation studies and surface plasmon resonance analyses, we demonstrated that hsp60 binds to the beta-subunit of ATP synthase. As a cell surface-expressed molecule, ATP synthase is potentially targeted by anti-EC-antibodies (AECAs) found in the sera of patients suffering vasculitides. Based on enzyme-linked immunosorbent assay and Western blotting techniques with F1-ATP synthase as substrate, we established the presence of anti-ATP synthase antibodies at higher frequency in patients with primary vasculitides (group I) compared with secondary vasculitides (group II). Anti-ATP synthase reactivity from group I patients was restricted to the beta subunit of ATP synthase, whereas those from group II was directed to the alpha-, beta- and gamma-subunits. Cell surface ATP synthase regulates intracellular pH (pHi). In low extracellular pH medium, we detected abnormal decreased of EC pHi in the presence of anti-ATP synthase antibodies, irrespective of their fine reactivities. Interestingly, soluble hsp60 abrogated the anti-ATP synthase induced pHi down-regulation. CONCLUSIONS/SIGNIFICANCE: Our results indicate that ATP synthase is targeted by AECAs on the surface of EC that induce intracellular acidification. Such pathogenic effect in vasculitides can be modulated by hsp60 binding on ATP synthase which preserves ATP synthase activity. PMID- 21326875 TI - Increasing protein at the expense of carbohydrate in the diet down-regulates glucose utilization as glucose sparing effect in rats. AB - High protein (HP) diet could serve as a good strategy against obesity, provoking the changes in energy metabolic pathways. However, those modifications differ during a dietary adaptation. To better understand the mechanisms involved in effect of high protein diet (HP) on limiting adiposity in rats we studied in parallel the gene expression of enzymes involved in protein and energy metabolism and the profiles of nutrients oxidation. Eighty male Wistar rats were fed a normal protein diet (NP, 14% of protein) for one week, then either maintained on NP diet or assigned to a HP diet (50% of protein) for 1, 3, 6 and 14 days. mRNA levels of genes involved in carbohydrate and lipid metabolism were measured in liver, adipose tissues, kidney and muscles by real time PCR. Energy expenditure (EE) and substrate oxidation were measured by indirect calorimetry. Liver glycogen and plasma glucose and hormones were assayed. In liver, HP feeding 1) decreased mRNA encoding glycolysis enzymes (GK, L-PK) and lipogenesis enzymes(ACC, FAS), 2) increased mRNA encoding gluconeogenesis enzymes (PEPCK), 3) first lowered, then restored mRNA encoding glycogen synthesis enzyme (GS), 4) did not change mRNA encoding beta-oxidation enzymes (CPT1, ACOX1, betaHAD). Few changes were seen in other organs. In parallel, indirect calorimetry confirmed that following HP feeding, glucose oxidation was reduced and fat oxidation was stable, except during the 1(st) day of adaptation where lipid oxidation was increased. Finally, this study showed that plasma insulin was lowered and hepatic glucose uptake was decreased. Taken together, these results demonstrate that following HP feeding, CHO utilization was increased above the increase in carbohydrate intake while lipogenesis was decreased thus giving a potential explanation for the fat lowering effect of HP diets. PMID- 21326876 TI - Comprehensive small animal imaging strategies on a clinical 3 T dedicated head MR scanner; adapted methods and sequence protocols in CNS pathologies. AB - BACKGROUND: Small animal models of human diseases are an indispensable aspect of pre-clinical research. Being dynamic, most pathologies demand extensive longitudinal monitoring to understand disease mechanisms, drug efficacy and side effects. These considerations often demand the concomitant development of monitoring systems with sufficient temporal and spatial resolution. METHODOLOGY AND RESULTS: This study attempts to configure and optimize a clinical 3 Tesla magnetic resonance scanner to facilitate imaging of small animal central nervous system pathologies. The hardware of the scanner was complemented by a custom built, 4-channel phased array coil system. Extensive modification of standard sequence protocols was carried out based on tissue relaxometric calculations. Proton density differences between the gray and white matter of the rodent spinal cord along with transverse relaxation due to magnetic susceptibility differences at the cortex and striatum of both rats and mice demonstrated statistically significant differences. The employed parallel imaging reconstruction algorithms had distinct properties dependent on the sequence type and in the presence of the contrast agent. The attempt to morphologically phenotype a normal healthy rat brain in multiple planes delineated a number of anatomical regions, and all the clinically relevant sequels following acute cerebral ischemia could be adequately characterized. Changes in blood-brain-barrier permeability following ischemia reperfusion were also apparent at a later time. Typical characteristics of intra cerebral haemorrhage at acute and chronic stages were also visualized up to one month. Two models of rodent spinal cord injury were adequately characterized and closely mimicked the results of histological studies. In the employed rodent animal handling system a mouse model of glioblastoma was also studied with unequivocal results. CONCLUSIONS: The implemented customizations including extensive sequence protocol modifications resulted in images of high diagnostic quality. These results prove that lack of dedicated animal scanners shouldn't discourage conventional small animal imaging studies. PMID- 21326877 TI - Antibodies to a full-length VAR2CSA immunogen are broadly strain-transcendent but do not cross-inhibit different placental-type parasite isolates. AB - The high molecular weight, multidomain VAR2CSA protein mediating adhesion of Plasmodium falciparum-infected erythrocytes in the placenta is the leading candidate for a pregnancy malaria vaccine. However, it has been difficult so far to generate strong and consistent adhesion blocking antibody responses against most single-domain VAR2CSA immunogens. Recent advances in expression of the full length recombinant protein showed it binds with much greater specificity and affinity to chondroitin sulphate A (CSA) than individual VAR2CSA domains. This raises the possibility that a specific CSA binding pocket(s) is formed in the full length antigen and could be an important target for vaccine development. In this study, we compared the immunogenicity of a full-length VAR2CSA recombinant protein containing all six Duffy binding-like (DBL) domains to that of a three domain construct (DBL4-6) in mice and rabbits. Animals immunized with either immunogen acquired antibodies reacting with several VAR2CSA individual domains by ELISA, but antibody responses against the highly conserved DBL4 domain were weaker in animals immunized with full-length DBL1-6 recombinant protein compared to DBL4-6 recombinant protein. Both immunogens induced cross-reactive antibodies to several heterologous CSA-binding parasite lines expressing different VAR2CSA orthologues. However, antibodies that inhibited adhesion of parasites to CSA were only elicited in rabbits immunized with full-length immunogen and inhibition was restricted to the homologous CSA-binding parasite. These findings demonstrate that partial and full-length VAR2CSA immunogens induce cross-reactive antibodies, but inhibitory antibody responses to full-length immunogen were highly allele specific and variable between animal species. PMID- 21326878 TI - The effect of risk perception on the 2009 H1N1 pandemic influenza dynamics. AB - BACKGROUND: The 2009 H1N1 pandemic influenza dynamics in Italy was characterized by a notable pattern: as it emerged from the analysis of influenza-like illness data, after an initial period (September-mid-October 2009) characterized by a slow exponential increase in the weekly incidence, a sudden and sharp increase of the growth rate was observed by mid-October. The aim here is to understand whether spontaneous behavioral changes in the population could be responsible for such a pattern of epidemic spread. METHODOLOGY/PRINCIPAL FINDINGS: In order to face this issue, a mathematical model of influenza transmission, accounting for spontaneous behavioral changes driven by cost/benefit considerations on the perceived risk of infection, is proposed and validated against empirical epidemiological data. The performed investigation revealed that an initial overestimation of the risk of infection in the general population, possibly induced by the high concern for the emergence of a new influenza pandemic, results in a pattern of spread compliant with the observed one. This finding is also supported by the analysis of antiviral drugs purchase over the epidemic period. Moreover, by assuming a generation time of 2.5 days, the initially diffuse misperception of the risk of infection led to a relatively low value of the reproductive number , which increased to in the subsequent phase of the pandemic. CONCLUSIONS/SIGNIFICANCE: This study highlights that spontaneous behavioral changes in the population, not accounted by the large majority of influenza transmission models, can not be neglected to correctly inform public health decisions. In fact, individual choices can drastically affect the epidemic spread, by altering timing, dynamics and overall number of cases. PMID- 21326879 TI - A generic system for the expression and purification of soluble and stable influenza neuraminidase. AB - The influenza surface glycoprotein neuraminidase (NA) is essential for the efficient spread of the virus. Antiviral drugs such as Tamiflu (oseltamivir) and Relenza (zanamivir) that inhibit NA enzyme activity have been shown to be effective in the treatment of influenza infections. The recent 'swine flu' pandemic and world-wide emergence of Tamiflu-resistant seasonal human influenza A(H1N1) H(274)Y have highlighted the need for the ongoing development of new anti virals, efficient production of vaccine proteins and novel diagnostic tools. Each of these goals could benefit from the production of large quantities of highly pure and stable NA. This publication describes a generic expression system for NAs in a baculovirus Expression Vector System (BEVS) that is capable of expressing milligram amounts of recombinant NA. To construct NAs with increased stability, the natural influenza NA stalk was replaced by two different artificial tetramerization domains that drive the formation of catalytically active NA homotetramers: GCN4-pLI from yeast or the Tetrabrachion tetramerization domain from Staphylothermus marinus. Both recombinant NAs are secreted as FLAG tagged proteins to allow for rapid and simple purification. The Tetrabrachion based NA showed good solubility, increased stability and biochemical properties closer to the original viral NA than the GCN4-pLI based construct. The expressed quantities and high quality of the purified recombinant NA suggest that this expression system is capable of producing recombinant NA for a broad range of applications including high-throughput drug screening, protein crystallisation, or vaccine development. PMID- 21326881 TI - A complete skull of an early cretaceous sauropod and the evolution of advanced titanosaurians. AB - Advanced titanosaurian sauropods, such as nemegtosaurids and saltasaurids, were diverse and one of the most important groups of herbivores in the terrestrial biotas of the Late Cretaceous. However, little is known about their rise and diversification prior to the Late Cretaceous. Furthermore, the evolution of their highly-modified skull anatomy has been largely hindered by the scarcity of well preserved cranial remains. A new sauropod dinosaur from the Early Cretaceous of Brazil represents the earliest advanced titanosaurian known to date, demonstrating that the initial diversification of advanced titanosaurians was well under way at least 30 million years before their known radiation in the latest Cretaceous. The new taxon also preserves the most complete skull among titanosaurians, further revealing that their low and elongated diplodocid-like skull morphology appeared much earlier than previously thought. PMID- 21326882 TI - Implications of CTL-mediated killing of HIV-infected cells during the non productive stage of infection. AB - Patients infected with HIV exhibit orders of magnitude differences in their set point levels of the plasma viral load. As to what extent this variation is due to differences in the efficacy of the cytotoxic T lymphocyte (CTL) response in these patients is unclear. Several studies have shown that HIV-infected CD4+ T cells also present viral epitopes that are recognized by CTLs before the productive stage of infection, i.e., during the intracellular eclipse phase before the infected cell starts to produce new viral particles. Here, we use mathematical modeling to investigate the potential impact of early killing of HIV-infected cells on viral replication. We suggest that the majority of CTL-mediated killing could occur during the viral eclipse phase, and that the killing of virus producing cells could be substantially lower at later stages due to MHC-I-down regulation. Such a mechanism is in agreement with several experimental observations that include CD8+ T cell depletion and antiretroviral drug treatment. This indicates a potentially important role of CTL-mediated killing during the non-productive stage of HIV-infected cells. PMID- 21326883 TI - Recurrent indigestion in a young adult. AB - Bochdalek hernias (BHs) arise due to congenital diaphragmatic defect and can result in gross displacement of abdominal tissues into the thorax. Although they are uncommon in occurrence, they usually present as serious respiratory distress in infants. In the adult population, they are asymptomatic and only detected incidentally. In this report, we present the case of a 26-year-old male who acutely presented with severe epigastric pain radiating to the back and deranged vital signs as a result of incorrect previous diagnoses. A large left diaphragmatic hernia containing his pancreatic tail, spleen, stomach and other intra-abdominal organs was confirmed by CT scan, together occupying a third of the hemithorax. Although not common, diagnostics of BHs should be considered in patients presenting with acute abdomen. A plain chest X-ray displaying diminished left diaphragmatic outline or signs of mediastinal shift should raise suspicion. Previous normal chest X-ray can be deceptive and does not rule out a diaphragmatic hernia. Herein, we also review the literature for previously reported acute presentation of 11 similar cases in adults and highlight the value of including BH as one of the differential diagnoses. PMID- 21326884 TI - Genome stability control by checkpoint regulation of tRNA gene transcription. AB - The RNA polymerase III pre-initiation complex (PIC) assembled on yeast tRNA genes naturally causes replication fork pausing that contributes to genome instability. Mechanistic coupling of the fork pausing activity of tRNA genes to replication has long been considered likely, but only recently demonstrated. In contrast to the expectation that this coupling might occur by a passive mechanism such as direct disruption of transcription factor-DNA complexes by a component of the replisome, it turns out that disassembly of the RNA polymerase III PIC is actively controlled by the replication stress checkpoint signal transduction pathway. This advance supports a new model in which checkpoint-dependent disassembly of the transcription machinery at tRNA genes is a vital component of an overall system of genome stability control that also targets replication and DNA repair proteins. PMID- 21326885 TI - New insights into the role of TFIIB in transcription initiation. AB - The general transcription factor TFIIB plays essential, but as yet unclear, roles in transcription initiation by RNA polymerase II. We recently found that phosphorylation of TFIIB is required for productive transcription. We discuss the implications of this work for the functions of TFIIB in promoter escape and gene loop formation. PMID- 21326886 TI - General transcription factors and subunits of RNA polymerase III: Paralogs for promoter- and cell type-specific transcription in multicellular eukaryotes. AB - In the course of evolution of multi-cellular eukaryotes, paralogs of general transcription factors and RNA polymerase subunits emerged. Paralogs of transcription factors and of the RPC32 subunit of RNA polymerase III play important roles in cell type- and promoter-specific transcription. Here we discuss their respective functions. PMID- 21326887 TI - Polymerase trafficking: A role for transcription factors in preventing replication fork arrest. AB - Replication forks and transcription complexes often collide, which can result in mutagenesis and chromosomal rearrangements. Recent studies of E. coli demonstrate a role for transcription factors in reducing conflicts between replication and transcription. These findings suggest that transcription regulators preserve genome integrity by preventing replication fork arrest. PMID- 21326888 TI - Promoting transcription of chromosome ends. AB - We recently identified CpG island promoters driving transcription of human telomeric repeat-containing RNA (TERRA). This discovery has shaped a new concept in telomere biology, where TERRA promoters and downstream telomeric sequences constitute autonomous genic units. PMID- 21326889 TI - ZBED6: The birth of a new transcription factor in the common ancestor of placental mammals. AB - A DNA transposon integrated into -the genome of a primitive mammal some 200 million years ago and, millions of years later, it evolved an essential function in the common ancestor of all placental mammals. This protein, now named ZBED6, was recently discovered because a mutation disrupting one of its binding sites, in an intron of the IGF2 gene, makes pigs grow more muscle. These findings have revealed a new mechanism for regulating muscle growth as well as a novel transcription factor that appears to be of major importance for transcriptional regulation in placental mammals. PMID- 21326890 TI - Non-redundant functions of the protein isoforms arising from alternative splicing of the VEGF-A pre-mRNA. AB - The different protein isoforms generated from the vascular endothelial growth factor-A (VEGF-A) gene, an essential regulator of blood vessel formation, differ in biochemical property and functional activity. Despite the relevance of VEGF-A for both normal and pathologic angiogenesis, our understanding of the molecular mechanisms governing alternative splicing of its pre-mRNA is still in its infancy. PMID- 21326891 TI - Revealing developmental networks by comparative transcriptomics. AB - Metazoan development relies upon the precise control of the genome's expression. This enables different cells in the animal to have different properties, despite having the same genetic material, and different animals to have different morphologies despite sharing developmental genes. However, near-identical organisms may have different overall genomic content, suggesting that the mechanisms by which evolution of the phenotype proceeds on a global level are not well understood. We review here recent works that have discovered a tremendous amount of variation between the developmental transcriptomes of both closely and distantly related organisms. It is evident that the evolution of regulatory programs occurs at a rapid rate comparable to that of other genomic processes. Distinguishing the selective pressures on each regulatory element will thus be crucial towards understanding its functional relevance. We propose that such a comparative approach is most suited to the identification of unifying principles in cell fate specification and differentiation in the animal embryo. PMID- 21326892 TI - Serious complications in gene-expression studies with stress perturbation: An example of UV-exposed p53-mutant mouse embryonic fibroblasts. AB - Reanalysis of our UV study of p53-mutant mouse embryonic fibroblasts revealed an intriguing orchestration of massive transcriptome responses. However, close scrutiny of the data uncovered an affected mRNA/rRNA ratio, effectively inhibiting valid data analysis. UV-dose range-finding showed low-dose UV specific and high-dose stress-related responses, which represent a plea for UV dose range finding in experimental design. PMID- 21326893 TI - The interaction between bacterial transcription factors and RNA polymerase during the transition from initiation to elongation. AB - There are three stages of transcription: initiation, elongation and termination, and traditionally there has been a clear distinction between the stages. The specificity factor sigma is completely released from bacterial RNA polymerase after initiation, and then recycled for another round of transcription. Elongation factors then associate with the polymerase followed by termination factors (where necessary). These factors dissociate prior to initiation of a new round of transcription. However, there is growing evidence suggesting that sigma factors can be retained in the elongation complex. The structure of bacterial RNAP in complex with an essential elongation factor NusA has recently been published, which suggested rather than competing for the major sigma binding site, NusA binds to a discrete region on RNAP. A model was proposed to help explain the way in which both factors could be associated with RNAP during the transition from transcription initiation to elongation. PMID- 21326894 TI - Keeping up to speed with the transcription termination factor Rho motor. AB - In bacteria, a subset of transcription termination events requires the participation of the transcription termination factor Rho. Rho is a homo hexameric, ring-shaped, motor protein that uses the energy derived from its RNA dependent ATPase activity to directionally unwind RNA and RNA-DNA helices and to dissociate transcription elongation complexes. Despite a wealth of structural, biochemical and genetic data, the molecular mechanisms used by Rho to carry out its biological functions remain poorly understood. Here, we briefly discuss the most recent findings on Rho mechanisms and function and highlight important questions that remain to be addressed. PMID- 21326895 TI - Illuminating transcription pathways using fluorescent reporter genes and yeast functional genomics. AB - Technological advances have enabled researchers to probe gene regulatory pathways on an unprecedented scale. Here, we summarize our recent work that exploits a systematic screening approach in the budding yeast to discover regulators of a promoter of interest. We discuss future applications of our approach based on emerging themes in the literature. PMID- 21326896 TI - Yin Yang 1: a multifaceted protein beyond a transcription factor. AB - As a transcription factor, Yin Yang 1 (YY1) regulates the transcription of a dazzling list of genes and the number of its targets still mounts. Recent studies revealed that YY1 possesses functions independent of its DNA binding activity and its regulatory role in tumorigenesis has started to emerge. PMID- 21326897 TI - Mechanism of histone survival during transcription by RNA polymerase II. AB - This work is related to and stems from our recent NSMB paper, "Mechanism of chromatin remodeling and recovery during passage of RNA polymerase II" (December 2009). Synopsis. Recent genomic studies from many laboratories have suggested that nucleosomes are not displaced from moderately transcribed genes. Furthermore, histones H3/H4 carrying the primary epigenetic marks are not displaced or exchanged (in contrast to H2A/H2B histones) during moderate transcription by RNA polymerase II (Pol II) in vivo. These exciting observations suggest that the large molecule of Pol II passes through chromatin structure without even transient displacement of H3/H4 histones. The most recent analysis of the RNA polymerase II (Pol II)-type mechanism of chromatin remodeling in vitro (described in our NSMB 2009 paper) suggests that nucleosome survival is tightly coupled with formation of a novel intermediate: a very small intranucleosomal DNA loop (O-loop) containing transcribing Pol II. In the submitted manuscript we critically evaluate one of the key predictions of this model: the lack of even transient displacement of histones H3/H4 during Pol II transcription in vitro. The data suggest that, indeed, histones H3/H4 are not displaced during Pol II transcription in vitro. These studies are directly connected with the observation in vivo on the lack of exchange of histones H3/H4 during Pol II transcription. PMID- 21326899 TI - Transcription-coupled repair and apoptosis provide specific protection against transcription-associated mutagenesis by ultraviolet light. AB - Recent data reveal that gene transcription affects genome stability in mammalian cells. For example, transcription of DNA that is damaged by the most prevalent exogenous genotoxin, UV light, induces nucleotide substitutions and chromosomal instability, collectively called UV-induced transcription-associated mutations (UV-TAM). An important class of UV-TAM consists of nucleotide transitions that are caused by deamination of cytosine-containing photolesions to uracil, presumably occurring at stalled transcription complexes. Transcription-associated deletions and recombinational events after UV exposure may be triggered by collisions of replication forks with stalled transcription complexes. In this Point-of-View we propose that mammalian cells possess two tailored mechanisms to prevent UV-TAM in dermal stem cells. First, the transcription-coupled nucleotide excision repair (TCR) pathway removes lesions at transcribed DNA strands, forming the primary barrier against the mutagenic consequences of transcription at a damaged template. Second, when TCR is absent or when the capacity of TCR is exceeded, persistently stalled transcription complexes induce apoptosis, averting the generation of mutant cells following replication. We hypothesize that TCR and the apoptotic response in conjunction reduce the risk of skin carcinogenesis. PMID- 21326898 TI - Modulation of RNA polymerase activity through the trigger loop folding. AB - Folding of the trigger loop of RNA polymerase promotes nucleotide addition through creating a closed, catalytically competent conformation of the active center. Here, we discuss the impact of adjacent RNA polymerase elements, including the F loop and the jaw domain, as well as external regulatory factors on the trigger loop folding and catalysis. PMID- 21326900 TI - Transcription and replication: breaking the rules of the road causes genomic instability. AB - Replication and transcription machineries progress at high speed on the same DNA template, which inevitably causes traffic accidents. Problems are not only caused by frontal collisions between polymerases, but also by cotranscriptional R-loops. These RNA-DNA hybrids induce genomic instability by blocking fork progression and could be implicated in the development of cancer. PMID- 21326901 TI - Molecular basis of transcription initiation in Archaea. AB - Compared with eukaryotes, the archaeal transcription initiation machinery commonly known as the Pre-Initiation Complex-is relatively simple. The archaeal PIC consists of the TFIIB ortholog TFB, TBP, and an 11-subunit RNA polymerase (RNAP). The relatively small size of the entire archaeal PIC makes it amenable to structural analysis. Using purified RNAP, TFB, and TBP from the thermophile Pyrococcus furiosus, we assembled the biochemically active PIC at 65oC. The intact archaeal PIC was isolated by implementing a cross-linking technique followed by size-exclusion chromatography, and the structure of this 440 kDa assembly was determined using electron microscopy and single-particle reconstruction techniques. Combining difference maps with crystal structure docking of various sub-domains, TBP and TFB were localized within the macromolecular PIC. TBP/TFB assemble near the large RpoB subunit and the RpoD/L "foot" domain behind the RNAP central cleft. This location mimics that of yeast TBP and TFIIB in complex with yeast RNAP II. Collectively, these results define the structural organization of the archaeal transcription machinery and suggest a conserved core PIC architecture. PMID- 21326903 TI - Transcriptional interference by RNA polymerase pausing and dislodgement of transcription factors. AB - Transcriptional interference is the in cis suppression of one transcriptional process by another. Mathematical modeling shows that promoter occlusion by elongating RNA polymerases cannot produce strong interference. Interference may instead be generated by (1) dislodgement of slow-to-assemble pre-initiation complexes and transcription factors and (2) prolonged occlusion by paused RNA polymerases. PMID- 21326902 TI - Crosstalk between phosphorylation and multi-site arginine/lysine methylation in C/EBPs. AB - C/EBPs are implied in an amazing number of cellular functions: C/EBPs regulate tissue and cell type specific gene expression, proliferation, and differentiation control. C/EBPs assist in energy metabolism, female reproduction, innate immunity, inflammation, senescence, and the development of neoplasms. How can C/EBPs fulfill so many functions? Here we discuss that C/EBPs are extensively modified by methylation of arginine and lysine side chains and that regulated methylation profoundly affects the activity of C/EBPs. PMID- 21326904 TI - CarD: a new RNA polymerase modulator in mycobacteria. AB - Mycobacteria CarD is an essential RNAP binding protein that regulates many transcripts including rRNA. This article will review our present state of knowledge regarding CarD and compare the known functions of CarD with other RNAP binding proteins in E. coli, emphasizing how this information can guide future investigations. PMID- 21326905 TI - Dual roles of lineage restricted transcription factors: the case of MITF in melanocytes. AB - Microphthalmia-associated Transcription Factor, MITF, is a master regulator of melanocyte development, differentiation, migration, and survival.(1) A broad collection of studies have indicated that MITF directly regulates the transcription of genes involved in pigmentation, which are selective to the melanocyte lineage. In addition, MITF controls expression of genes which are expressed in multiple cell lineages, and may also play differential roles in activating vs. maintaining gene expression patterns. In this Point of View article, we discuss lineage restricted transcription factor activation of both tissue-specific and ubiquitously expressed genes using melanocytes and MITF as a model system that may eventually provide insights into such processes in multiple cell lineages. PMID- 21326906 TI - Genomic approaches for the discovery of CFTR regulatory elements. AB - Non-coding regions of the human genome contain vast regulatory potential that contributes to the coordination of gene expression. Indeed, regulatory elements can reside large genomic distances from the promoters of genes they control. Here we describe approaches recently used to identify functional elements within the complex CFTR locus. PMID- 21326907 TI - Mediator and post-recruitment regulation of RNA polymerase II. AB - The human Mediator complex interacts extensively with the RNA polymerase II (Pol II) enzyme and recent data from our lab suggest activator-induced structural shifts within Mediator trigger activation of stalled Pol II. These results are discussed together with other recent findings regarding post-recruitment regulation of Pol II. PMID- 21326908 TI - Mitochondrial transcription: how does it end? AB - The structure of the mitochondrial transcription termination factor (MTERF1) provides novel insight into the mechanism of binding, recognition of the termination sequence and the conformational changes involved in mediating termination. Besides its functional implications, this structure provides a framework to understand the consequences of numerous diseases associated with mitochondrial DNA mutations. PMID- 21326910 TI - Fixing the model for transcription: the DNA moves, not the polymerase. AB - The traditional model for transcription sees active polymerases tracking along their templates. An alternative (controversial) model has active enzymes immobilized in "factories." Recent evidence supports the idea that the DNA moves, not the polymerase, and points to alternative explanations of how regulatory motifs like enhancers and silencers work. PMID- 21326909 TI - New discoveries linking transcription to DNA repair and damage tolerance pathways. AB - In Escherichia coli, the transcription elongation factor NusA is associated with all elongating RNA polymerases where it functions in transcription termination and antitermination. Here, we review our recent results implicating NusA in the recruitment of DNA repair and damage tolerance mechanisms to sites of stalled transcription complexes. PMID- 21326912 TI - Humor me. PMID- 21326911 TI - B2 RNA represses TFIIH phosphorylation of RNA polymerase II. AB - Mouse B2 RNA represses RNA polymerase II (Pol II) transcription during the cellular heat shock response. B2 RNA binds Pol II, enters complexes at promoters, and keeps the polymerase from engaging the DNA. Here we show that phosphorylation of Ser5 residues in the Pol II carboxy terminal domain (CTD) decreases after heat shock at the promoter of the repressed actin gene in mouse cells, despite the continued presence of Cdk7 and cyclin H. Biochemical assays revealed that B2 RNA, when present with Pol II in promoter-bound complexes, specifically represses CTD phosphorylation by TFIIH. PMID- 21326913 TI - Compatible solutes: A listerial passe-partout? AB - Recently we reported a role for compatible solute uptake in mediating bile tolerance and increased gastrointestinal persistence in the foodborne pathogen Listeria monocytogenes.1 Herein, we review the evolution in our understanding of how these low molecular weight molecules contribute to growth and survival of the pathogen both inside and outside the body, and how this stress survival mechanism may ultimately be used to target and kill the pathogen. PMID- 21326914 TI - Adherent-invasive Escherichia coli target the epithelial barrier. AB - Involvement of intestinal microbes in the pathogenesis of chronic inflammatory bowel diseases (IBD, including Crohn disease and ulcerative colitis) is well established. However, the mechanisms by which bacteria lead to intestinal injury in IBD remain unclear and are the focus of current research. Using adherent invasive Escherichia coli (AIEC) strain LF82, which is linked to Crohn disease, we recently demonstrated the ability of these intestinal microbes to disrupt the integrity of epithelial cells in an in vitro cell model. This disruption provides the bacteria a capacity to penetrate into and beyond the epithelial monolayer, replicate in cells, disseminate within the host, and induce a chronic immune response. These findings provide a link between microbes related to IBD, disruption of the intestinal epithelial cell barrier, and disease pathogenesis.In this addendum, we provide a synopsis on current data concerning the role of AIEC in the pathogenesis of intestinal inflammation, summarise our recent findings, and highlight the central role of the epithelium in mucosal defence. We also discuss, in more detail, the potential implications of our findings and present ideas for future studies and targets for intervention. PMID- 21326916 TI - PKA-mediated phosphorylation of EPEC-Tir at serine residues 434 and 463: A novel pathway in regulating Rac1 GTPase function. AB - Type-III or type-IV secretion systems of many Gram-negative bacterial pathogens inject effector proteins into host cells that modulate cellular functions in their favour. A preferred target of these effectors is the actin-cytoskeleton as shown by studies using the gastric pathogens Helicobacter pylori (H. pylori) and enteropathogenic Escherichia coli (EPEC). We recently developed a co-infection approach to study effector protein function and molecular mechanisms by which they highjack cellular signalling cascades. This is exemplified by our observation that EPEC profoundly blocks H. pylori-induced epithelial cell scattering and elongation, a disease-related event requiring the activity of small Rho GTPase Rac1. While this suppressive effect is dependent on the effector protein Tir and the outer-membrane protein Intimin, it unexpectedly revealed evidence for Tir-signalling independent of phosphorylation of Tir at tyrosine residues 454 and 474. Instead, our studies revealed a previously unidentified function for protein kinase A (PKA)-mediated phosphorylation of Tir at serine residues 434 and 463. We demonstrated that EPEC infection activates PKA for Tir phosphorylation. Activated PKA then phosphorylates Rac1 at its serine residue 71 associated with reduced GTP-load and inhibited cell elongation. Phosphorylation of Rho GTPases such as Rac1 might be an interesting novel strategy in microbial pathogenesis. PMID- 21326915 TI - Comparing the microbiota of the cystic fibrosis lung and human gut. PMID- 21326917 TI - Intertwinement of stress response regulons in Bifidobacterium breve UCC2003. AB - Bifidobacteria constitute an important component of the microbiota of the gastrointestinal tract of humans and other mammals. Various bifidobacterial strains are commercially exploited because of their perceived beneficial role in the maintenance of gut homeostasis. We have determined the response of B. breve UCC2003, a Gram-positive bacterium originally isolated from the nursling stool of a breast-fed infant, to several stresses (heat, osmotic, solvent) using transcriptomics, classical techniques and in silico analysis, as well as the transcriptional response of B. breve UCC2003 to oxidative stresses caused by the exposure to diamide, peroxide and environmental oxygen. Integration of these results allowed the formulation of a model for an interacting regulatory network for stress response in B. breve UCC2003, where HspR controls SOS response and the ClgR regulon, which in turn regulates and is regulated by HrcA. This model of an interacting regulatory network is believed to represent the paradigm for stress adaptation in bifidobacteria. PMID- 21326918 TI - Induction of a regulatory B cell population in experimental allergic encephalomyelitis by alteration of the gut commensal microflora. AB - We have recently shown that alteration of the gut commensal microbiota with antibiotics can modify the susceptibility to autoimmune demyelinating processes of the central nervous system. Treatment of mice with a broad spectrum of antibiotics not only induced significant changes in the regulatory T cell populations of the gut associated lymphoid tissues (GALT) and peripheral lymphoid organs but reduced the susceptibility to EAE, the most widely used animal model for human multiple sclerosis. Here, we show further that oral antibiotic treatment of EAE mice induced a CD5(+)B cell subpopulation that conferred protection against the disease. Protection was associated with an enhanced frequency of CD5(+)B cells in distal lymphoid sites such as cervical LN. In vitro stimulation with LPS increased the production of IL-10 by splenic CD5(+)B cells. Adoptive transfer of CD5(+)B cells from antibiotic treated mice reduced significantly the severity of EAE by shifting the immune responses from Th1/Th17 towards anti-inflammatory Th2-type responses. Our results demonstrate that this specific B cell population appears to be involved in the immune regulation of autoimmunity, in particular this experimental demyelinating disease of the central nervous system by gut commensal microflora. PMID- 21326919 TI - The many roads traveled by Helicobacter pylori to NFkappaB activation. AB - Many of the pathologies linked to Helicobacter pylori are caused by the ability of the bacteria to induce chronic inflammation in the stomach of the host. One of the major transcription factors that regulate inflammation is NFkappaB, which is constitutively activated in many cancers including some gastric cancers. H. pylori has been shown to activate NFkappaB using several different bacterial components and host signaling pathways in cell-type and strain-specific ways. Our recent studies demonstrate that H. pylori utilizes its virulence factor CagA to target signaling molecule TAK1 for the activation of NFkappaB. In this article, we will summarize our findings together with other recent progress in the H. pylori-mediated activation of NFkappaB and discuss the role of CagA and TAK1 in the H. pylori-mediated activation of NFkappaB and gastric diseases. PMID- 21326920 TI - The bacterial virulence factor NleA's involvement in intestinal tight junction disruption during enteropathogenic E. coli infection is independent of its putative PDZ binding domain. AB - Enteropathogenic Escherichia coli (EPEC) is an enteric pathogen able to cause severe diarrhea. Once adhered to the small intestine, EPEC disrupts tight junctions that are important for intestinal barrier function. This disruption is dependent on the bacterial type III secretion system, as well as the translocated effectors EspF and Map. Recently we have shown that a third type III translocated bacterial effector protein, NleA, is also involved in tight junction disruption during EPEC infection. NleA has a predicted PDZ-binding domain at its C-terminus which is proposed to be involved in protein interactions with PDZ domain containing proteins. Since several PDZ-domain-containing proteins localize to tight junctions, we hypothesized that the PDZ-binding domain of NleA might be important for its role in tight junction disruption. However, here we show that a molecular variant of NleA lacking the PDZ-binding domain behaves indistinguishably from the wild-type protein with respect to disruption of tight junctions. PMID- 21326921 TI - Development of a novel oral vaccine against Mycobacterium avium paratuberculosis and Johne disease: a patho-biotechnological approach. AB - Mycobacterium avium subsp. paratuberculosis (MAP) is the etiological agent of Johne disease, a granulomatous enteritis of cattle and other domesticated and wild ruminant species. Johne disease is prevalent worldwide and has a significant impact on the global agricultural economy. Current vaccines against Johne are insufficient in stemming its spread, and associated side-effects prevent their widespread use in control programs. Effective and safe vaccine strategies are needed. The main purpose of this paper is to propose and evaluate the development of a novel oral subunit-vaccine using a patho-biotechnological approach. This novel strategy, which harnesses patho-genetic elements from the intracellular pathogen Listeria monocytogenes, may provide a realistic route towards developing an effective next generation subunit vaccine against Johne disease and paratuberculosis. PMID- 21326922 TI - Metabolic engineering of Saccharomyces cerevisiae for lactose/whey fermentation. AB - Lactose is an interesting carbon source for the production of several bio products by fermentation, primarily because it is the major component of cheese whey, the main by-product of dairy activities. However, the microorganism more widely used in industrial fermentation processes, the yeast Saccharomyces cerevisiae, does not have a lactose metabolization system. Therefore, several metabolic engineering approaches have been used to construct lactose-consuming S. cerevisiae strains, particularly involving the expression of the lactose genes of the phylogenetically related yeast Kluyveromyces lactis, but also the lactose genes from Escherichia coli and Aspergillus niger, as reviewed here. Due to the existing large amounts of whey, the production of bio-ethanol from lactose by engineered S. cerevisiae has been considered as a possible route for whey surplus. Emphasis is given in the present review on strain improvement for lactose-to-ethanol bioprocesses, namely flocculent yeast strains for continuous high-cell-density systems with enhanced ethanol productivity. PMID- 21326923 TI - Bioengineered bugs expressing oligosaccharide receptor mimics: toxin-binding probiotics for treatment and prevention of enteric infections. AB - Many microbial pathogens recognize oligosaccharides displayed on the surface of host cells as receptors for toxins and adhesins. These ligand-receptor interactions are critical for disease pathogenesis, making them promising targets for novel anti-infectives. One strategy with particular utility against enteric infections involves expression of molecular mimics of host oligosaccharides on the surface of harmless bacteria capable of surviving in the gut. This can be achieved in Gram-negative bacteria by manipulating the outer core region of the lipopolysaccharide (LPS) through expression of cloned heterologous glycosyltransferases. The resultant chimeric LPS molecules are incorporated into the outer membrane by the normal assembly route and presented as a closely packed 2-D array of receptor mimics. Several such "designer probiotics" have been constructed, and these bind bacterial toxins in the gut lumen with very high avidity, blocking their uptake by host cells and thereby preventing disease. PMID- 21326924 TI - Microbial-based therapy of cancer: current progress and future prospects. AB - The use of bacteria in the regression of certain forms of cancer has been recognized for more than a century. Much effort, therefore, has been spent over the years in developing wild-type or modified bacterial strains to treat cancer. However, their use at the dose required for therapeutic efficacy has always been associated with toxicity problems and other deleterious effects. Recently, the old idea of using bacteria in the treatment of cancer has attracted considerable interest and new genetically engineered attenuated strains as well as microbial compounds that might have specific anticancer activity without side effects are being evaluated for their ability to act as new anticancer agents. This involves the use of attenuated bacterial strains and expressing foreign genes that encode the ability to convert non-toxic prodrugs to cytotoxic drugs. Novel strategies also include the use of bacterial products such as proteins, enzymes, immunotoxins and secondary metabolites, which specifically target cancer cells and cause tumor regression through growth inhibition, cell cycle arrest or apoptosis induction. In this review we describe the current knowledge and discuss the future directions regarding the use of bacteria or their products, in cancer therapy. PMID- 21326925 TI - Homologous expression of aspartokinase (ask) gene in Streptomyces clavuligerus and its hom-deleted mutant: effects on cephamycin C production. AB - In this study, the effect of homologous multiple copies of the ask gene, which encodes aspartokinase catalyzing the first step of the aspartate pathway, on cephamycin C biosynthesis in S. clavuligerus NRRL 3585 and its hom mutant was investigated. The intracellular pool levels of aspartate pathway amino acids accorded well with the Ask activity levels in TB3585 and AK39. When compared with the control strain carrying vector alone without any gene insert, amplification of the ask gene in the wild strain resulted in a maximum of 3.1- and 3.3-fold increase in specific, 1.7- and 1.9-fold increase in volumetric cephamycin C production when grown in trypticase soy broth (TSB) and a modified chemically defined medium (mCDM), respectively. However, expression of multicopy ask gene in a hom-deleted background significantly decreased cephamycin C yields when the cells were grown in either TSB or mCDM, most probably due to physiological disturbance resulting from enzyme overexpression and high copy number plasmid burden in an auxotrophic host, respectively. PMID- 21326926 TI - Genetically modified Pseudomonas biosensing biodegraders to detect PCB and chlorobenzoate bioavailability and biodegradation in contaminated soils. AB - Whole cell microbial biosensors offer excellent possibilities for assaying the complex nature of the bioavailable and bioaccessible fraction of pollutants in contaminated soils, which currently cannot be easily addressed. This paper describes the application and evaluation of three microbial biosensor strains designed to detect the bioavailability and biodegradation of PCBs (and end products) in contaminated soils and sediments. Polychlorinated biphenyls (PCBs) are considered to be one of the most wide spread, hazardous and persistent pollutants. Herein we describe that there was a positive correlation between the PCB levels within the samples and the percentage of biosensor cells that were expressing their reporter gene; gfp. Immobilisation of the biosensors in calcium alginate beads allowed easy and accurate detection of the biosensor strains in contaminated soil and sludge samples. The biosensors also showed that PCB degradation activity was occurring at a much greater level in Pea inoculated planted soil compared to inoculated unplanted soil indicating rhizoremediation (the removal of pollutants by plant root associated microbes) shows considerable promise as a solution for removing organic xenobiotics from the environment. PMID- 21326927 TI - Bioremediation of soluble heavy metals with recombinant Caulobacter crescentus. AB - To achieve one-step separation of heavy metal ions from contaminated water, we have developed a novel bioremediation technology based on self-immobilization of the Caulobacter crescentus recombinant strain JS4022/p723-6H, which overexpresses hexahistidine peptide on the surface of the bacterial cells and serves as a whole cell adsorbent for dissolved heavy metals. Biofilms formed by JS4022/p723-6H are effective at retaining cadmium from bacterial growth media or environmental water samples. Here we provide additional experiment data discussing the application potential of this new technology. Supplementation of calcium to the growth media produced robust JS4022/p723-6H cells by alleviating their sensitivity to chelators. After growth in the presence of 0.3% CaCl(2).2H(2)O, double the amount of JS4022/p723-6H cells survived the treatment with 2 mM EDTA. Free cells of JS4022/p723-6H effectively sequestered 51% of the total cadmium from a Lake Erie water sample at pH 5.4, compared to 37% retrieved by the control strain. Similar levels of adsorption were observed at pH 4.2 as well. Cells of JS4022/p723-6H were tolerant of acid treatment for 90 min at pH >=1.1 or 120 min at pH >=2.5, which provides an avenue for the convenient regeneration of the bacterial cells metal-binding capacity with acidic solutions. Designs of possible bioreactors and an operation system are also presented. PMID- 21326928 TI - Engineering of a psychrophilic bacterium for the bioremediation of aromatic compounds. AB - Microbial degradation of aromatic hydrocarbons has been studied with the aim of developing applications for the removal of toxic compounds. Efforts have been directed toward the genetic manipulation of mesophilic bacteria to improve their ability to degrade pollutants, even though many pollution problems occur in sea waters and in effluents of industrial processes which are characterized by low temperatures. From these considerations the idea of engineering a psychrophilic microorganism for the oxidation of aromatic compounds was developed.In a previous paper it was demonstrated that the recombinant Antarctic Pseudoalteromonas haloplanktis TAC125 (PhTAC/tou) expressing a toluene-o-xylene monooxygenase (ToMO) is able to convert several aromatic compounds into corresponding catechols. In our work we improved the metabolic capability of PhTAC/tou cells by combining action of recombinant ToMO enzyme with that of the endogenous P. haloplanktis TAC125 laccase-like protein. This strategy allowed conferring new and specific degradative capabilities to a bacterium isolated from an unpolluted environment; indeed engineered PhTAC/tou cells are able to grow on aromatic compounds as sole carbon and energy sources. Our approach demonstrates the possibility to use the engineered psychrophilic bacterium for the bioremediation of chemically contaminated marine environments and/or cold effluents. PMID- 21326929 TI - Powerful workhorses for antimicrobial peptide expression and characterization. AB - Discovery of antimicrobial peptides (AMP) is to a large extent based on screening of fractions of natural samples in bacterial growth inhibition assays. However, the use of bacteria is not limited to screening for antimicrobial substances. In later steps, bioengineered "bugs" can be applied to both production and characterization of AMPs. Here we describe the idea to use genetically modified Escherichia coli strains for both these purposes. This approach allowed us to investigate SpStrongylocins 1 and 2 from the purple sea urchin Strongylocentrotus purpuratus only based on sequence information from a cDNA library and without previous direct isolation or chemical synthesis of these peptides. The recombinant peptides are proved active against all bacterial strains tested. An assay based on a recombinant E. coli sensor strain expressing insect luciferase, revealed that SpStrongylocins are not interfering with membrane integrity and are therefore likely to have intracellular targets. PMID- 21326930 TI - Efficient Agrobacterium-based transient expression system for the production of biopharmaceuticals in plants. AB - We have recently described an efficient transient expression system mediated by Agrobacterium tumefaciens for the production of HIV-1 Nef protein in Nicotiana benthamiana plants. In order to enhance the yield of recombinant protein we assayed the effect of three gene-silencing viral suppressor proteins (P25 of Potato Virus X, P19 of Artichoke Mottled Crinckle virus and Tomato Bushy Stunt virus) on Nef expression levels. Results demonstrated that AMCV-P19 gave the highest Nef yield (1.3% of total soluble protein) and that this effect was correlated to a remarkable decrease of Nef-specific small interfering RNAs (siRNAs) indicating an effective modulation of RNA silencing mechanisms. Here we report additional data on the production of different heterologous proteins including human immunoglobulin heavy and light chains and a virus coat protein that demonstrate the robustness of this co-agroinfiltration expression system boosted by the AMCV-P19 gene-silencing suppressor. PMID- 21326931 TI - The monoclonal myth. AB - Most researchers confidently assume that transformation of recombinant plasmid libraries into microbial hosts followed by outgrowth of isolated colonies results in a "one cell-one mutant gene-one protein variant" paradigm. Indeed, this assumption is supported by the overwhelming majority of published studies employing bacterial expression hosts. In stark contrast, we recently reported on Saccharomyces cerevisiae libraries containing unexpectedly high frequencies of cells harboring heterogeneous mixtures of plasmids, so called Multiple Vector Transformants (MVT). Intriguingly, we observed that yeast MVT persist as a significant proportion of populations for multiple generations. MVT can lead to misidentification of isolated mutants loss of functionally enhanced clones, and unwitting propagation of false positives derived from contaminating control sequences. Such experimental complications can have devastating outcomes in the context of protein engineering by combinatorial library screening. Herein, we demonstrate that the phenomenon of MVT is not restricted to vectors bearing the CEN/ARSH origin of replication, but may be an even greater concern when using high copy 2 um plasmids. To mitigate the risks associated with MVT, we have developed an optimized sequencing procedure that facilitates rapid and reliable identification of MVT among clones of interest. In our experience, MVT and their associated risks can be virtually eliminated by employing extended liquid outgrowths of transformed populations and archiving sequence-verified, monoclonal, mutant genes from cell-templated PCR amplicons. PMID- 21326932 TI - Probiotics and pharmabiotics: alternative medicine or an evidence-based alternative? AB - That commensal bacteria play an important role in human health is beyond doubt, and it is now widely accepted that humans function as super organisms, whose collective metabolic potential exceeds the sum of our individual eukaryotic and prokaryotic components. However, while it is has been established that the prokaryotic component of the human superorganism is amenable to manipulation by chemotherapeutic, dietary or microbial interventions, the significance of such alterations in terms of human health or well being is less well established. Prebiotics (non- digestible food ingredients that stimulate the growth and/or activity of bacteria in the digestive system) and probiotics (live microorganisms that when administered in adequate amounts, confer a health benefit on the host) are often bracketed among 'alternative' approaches to influencing human health, such as homeopathy, naturopathy, acupuncture and hypnotherapy. Others believe that prebiotics and probiotics have proven their effectiveness in properly conducted, clinically controlled human trials and therefore can be considered as evidence-based alternatives or adjuncts to conventional medicines. My journey from a position of total skepticism to 'reluctant convert' is the basis of this article, which should not be considered in any sense as a review of the literature but simply a personal account of this transition. While I am not bent on converting other doubters, I will recount some of the thought processes and evidence that has helped to form my current opinion. PMID- 21326933 TI - A short story about a big magic bug. AB - Bacillus megaterium, the "big beast," is a Gram-positive bacterium with a size of 4 * 1.5 um. During the last years, it became more and more popular in the field of biotechnology for its recombinant protein production capacity. For the purpose of intra- as well as extracellular protein synthesis several vectors were constructed and commercialized (MoBiTec GmbH, Germany). On the basis of two compatible vectors, a T7 RNA polymerase driven protein production system was established. Vectors for chromosomal integration enable the direct manipulation of the genome. The vitamin B(12) biosynthesis of B. megaterium served as a model for the systematic development of a production strain using these tools. For this purpose, the overexpression of chromosomal and plasmid encoded genes and operons, the synthesis of anti-sense RNA for gene silencing, the removal of inhibitory regulatory elements in combination with the utilization of strong promoters, directed protein design, and the recombinant production of B(12) binding proteins to overcome feedback inhibition were successfully employed. For further system biotechnology based optimization strategies the genome sequence will provide a closer look into genomic capacities of B. megaterium. DNA arrays are available. Proteome, fluxome and metabolome analyses are possible. All data can be integrated by using a novel bioinformatics platform. Finally, the size of the "big beast" B. megaterium invites for cell biology research projects. All these features provide a solid basis for challenging biotechnological approaches. PMID- 21326934 TI - Bioengineered viral vectors for targeting and killing prostate cancer cells. AB - Enabling the transduction of therapeutic gene expression exclusively in diseased sites is the key to developing more effective treatments for advanced prostate cancer using viral-based therapy. While prostate cancers that express high levels of HER-2 are resistant to the killing effects of trastuzumab, they can be targeted for selective gene expression and destruction by lentiviruses with envelope proteins engineered to bind to this therapeutic antibody. More importantly, after intravenous injection, this trastuzumab-bound lentivirus is able to target castration-resistant prostate tumor xenografts, albeit with low efficiency. This proof of principle opens up multiple possibilities for the prevention and treatment of prostate cancer using a viral-based therapy. However, to be safe and more effective, the viral vectors must target prostate cancer cells more selectively and efficiently. A higher degree of specificity and efficiency of cancer cell targeting can be achieved by engineering viral vectors to bind to a specific cell surface marker and by controlling the expression of the therapeutic payload at transcriptional level, with a tissue-specific promoter, and at the translational level, with a regulatory sequences inserted into either the 5'UTR or 3'UTR regions of the therapeutic gene(s). The latter would be designed to ensure that translation of this mRNA occurs exclusively in malignant cells. Furthermore, in order to obtain a potent anti-tumor effect, viral vectors would be engineered to express pro-apoptotic genes, intra-cellar antibodies/nucleotide aptamers to block critical proteins, or siRNAs to knockdown essential cellular mRNAs. Alternatively, controlled expression of an essential viral gene would restore replication competence to the virus and enable selective oncolysis of tumor cells. Successful delivery of such bioengineered viruses may provide a more effective way to treat advanced prostate cancer. PMID- 21326935 TI - Bacterial supersystem for alginate import/metabolism and its environmental and bioenergy applications. AB - Distinct from most alginate-assimilating bacteria that secrete polysaccharide lyases extracellularly, a gram-negative bacterium, Sphingomonas sp. A1 (strain A1), can directly incorporate alginate into its cytoplasm, without degradation, through a "superchannel" consisting of a mouth-like pit on the cell surface, periplasmic binding proteins, and a cytoplasmic membrane-bound ATP-binding cassette transporter. Flagellin homologues function as cell surface alginate receptors essential for expressing the superchannel. Cytoplasmic alginate lyases with different substrate specificities and action modes degrade the polysaccharide to its constituent monosaccharides. The resultant monosaccharides, alpha-keto acids, are converted to a reduced form by NADPH-dependent reductase, and are finally metabolized in the TCA cycle. Transplantation of the strain A1 superchannel to xenobiotic-degrading sphingomonads enhances bioremediation through the propagation of bacteria with an elevated transport activity. Furthermore, strain A1 cells transformed with Zymomonas mobilis genes for pyruvate decarboxylase and alcohol dehydrogenase II produce considerable amounts of biofuel ethanol from alginate when grown statically. PMID- 21326936 TI - Recombinant BCG as a vaccine vehicle to protect against tuberculosis. AB - Mycobacterium bovis Bacille Calmette Guerin (BCG) was first administered to humans in 1921 and has subsequently been delivered to an estimated 3 billion individuals, with a low incidence of serious complications. The vaccine is immunogenic and is stable and cheap to produce. Additionally, the vaccine can be engineered to express foreign molecules in a functional form, and this has driven the development of BCG as a recombinant vector to protect against infectious diseases and malignancies such as cancer. However, it is now clear that the existing BCG vaccine has proved insufficient to control the spread of tuberculosis, and a major focus of tuberculosis vaccine development programs is the construction and testing of modified forms of BCG. This review summarizes the strategies employed to develop recombinant forms of BCG and describes the potential of these vaccines to stimulate protective immunity and protect against Mycobacterium tuberculosis infection. PMID- 21326938 TI - Improving the sensitivity of bacterial bioreporters for heavy metals. AB - Whole-cell bacterial bioreporters represent a convenient testing method for quantifying the bioavailability of contaminants in environmental samples. Despite the fact that several bioreporters have been constructed for measuring heavy metals, their application to environmental samples has remained minimal. The major drawbacks of the available bioreporters include a lack of sensitivity and specificity. Here, we report an improvement in the limit of detection of bacterial bioreporters by interfering with the natural metal homeostasis system of the host bacterium. The limit of detection of a Pseudomonas putida KT2440 based Zn/Cd/Pb-biosensor was improved by a factor of up to 45 by disrupting four main efflux transporters for Zn/Cd/Pb and thereby causing the metals to accumulate in the cell. The specificity of the bioreporter could be modified by changing the sensor element. A Zn-specific bioreporter was achieved by using the promoter of the cadA1 gene from P. putida as a sensor element. The constructed transporter-deficient P. putida reporter strain detected Zn(2+) concentrations about 50 times lower than that possible with other available Zn-bioreporters. The achieved detection limits were significantly below the permitted limit values for Zn and Pb in water and in soil, allowing for reliable detection of heavy metals in the environment. PMID- 21326937 TI - Recombinant organisms for production of industrial products. AB - A revolution in industrial microbiology was sparked by the discoveries of ther double-stranded structure of DNA and the development of recombinant DNA technology. Traditional industrial microbiology was merged with molecular biology to yield improved recombinant processes for the industrial production of primary and secondary metabolites, protein biopharmaceuticals and industrial enzymes. Novel genetic techniques such as metabolic engineering, combinatorial biosynthesis and molecular breeding techniques and their modifications are contributing greatly to the development of improved industrial processes. In addition, functional genomics, proteomics and metabolomics are being exploited for the discovery of novel valuable small molecules for medicine as well as enzymes for catalysis. The sequencing of industrial microbal genomes is being carried out which bodes well for future process improvement and discovery of new industrial products. PMID- 21326939 TI - Myristoylation negative msbB-mutants of probiotic E. coli Nissle 1917 retain tumor specific colonization properties but show less side effects in immunocompetent mice. AB - Specific colonization of solid tumors by bacteria opens the way to novel approaches in both tumor diagnosis and therapy. However, even non-pathogenic bacteria induce responses by the immune system, which could be devastating for a tumor bearing patient. As such effects are caused e.g., by the lipid A moiety of the lipopolysaccharide, a msbB-mutant of the probiotic E. coli Nissle 1917 strain was investigated. Bacteria of the mutant strain did not show any growth defects in culture media when compared to wild-type E. coli Nissle 1917 but were unable to myristoylate lipid A, had less toxic effects on immunocompetent BALB/c mice, and were still able to specifically colonize tumors. Therefore, the modification of lipid A could result in bacterial strains that might be better suited for diagnosis and therapy of tumors than the corresponding wild-type strains, even if those are not considered pathogenic or are of probiotic background. PMID- 21326940 TI - Bacteria as tumor therapeutics? PMID- 21326941 TI - Cross-system excision of chaperone-mediated proteolysis in chaperone-assisted recombinant protein production. AB - Main Escherichia coli cytosolic chaperones such as DnaK are key components of the control quality network designed to minimize the prevalence of polypeptides with aberrant conformations. This is achieved by both favoring refolding activities but also stimulating proteolytic degradation of folding reluctant species. This last activity is responsible for the decrease of the proteolytic stability of recombinant proteins when co-produced along with DnaK, where an increase in solubility might be associated to a decrease in protein yield. However, when DnaK and its co-chaperone DnaJ are co-produced in cultured insect cells or whole insect larvae (and expectedly, in other heterologous hosts), only positive, folding-related effects of these chaperones are observed, in absence of proteolysis-mediated reduction of recombinant protein yield. PMID- 21326942 TI - Strategies for enhancing bioluminescent bacterial sensor performance by promoter region manipulation. AB - Genetically engineered microbial reporter strains are based upon the fusion of an inducible sensing element upstream of a reporting element, so that the construct emits a dose-dependent signal when exposed to the inducing compound(s) or stress factor(s). In this communication we described several general approaches undertaken in order to enhance the sensing performance of such promoter::reporter fusions. Significant improvements in detection sensitivity, response kinetics and signal intensity were achieved by modification of the length of the promoter containing DNA fragment, by random or site-directed mutagenesis and by promoter duplication. The general nature of these genetics manipulations makes them applicable to other types of promoter::reporter fusions. PMID- 21326943 TI - Nurturing the genome: A-type lamins preserve genomic stability. AB - A-type lamins provide a scaffold for tethering chromatin and protein complexes regulating nuclear structure and function. Interest in lamins increased after mutations in the LMNA gene were found to be associated with a variety of human disorders termed laminopathies. These include muscular dystrophy, cardiomyopathy, lipodystrophy, peripheral neuropathy and premature aging syndromes such as progeria. In addition, altered expression of A-type lamins is emerging as a contributing factor to tumorigenesis. How different alterations in a gene that is ubiquitously expressed can cause such an array of systemic as well as tissue specific diseases remains an enigma. Several lines of evidence indicate that mutant forms of A-type lamins impact on genome function and integrity. A current model suggests that genomic instability plays a major part in the pathophysiology of some lamin-related diseases. However, this model remains to be fully investigated. Here we discuss recent studies revealing novel functions for A-type lamins in the maintenance of telomeres and in the DNA damage response (DDR) pathway. These findings have shed some light onto the putative molecular mechanisms by which alterations in A-type lamins induce genomic instability and contribute to disease. PMID- 21326944 TI - Nuclear pore complex during neuronal degeneration: cracking the last barrier! AB - In eukaryotic cells, the exchange of molecules between the genetic material within the nucleus and the cytosol occurs through the Nuclear Pore Complex (NPC), which is a large membrane-embedded assembly composed by multiple proteins named nucleoporins arranged around an aqueous channel. The bi-directional passive diffusion and the active transport of factors across the nuclear envelope are responsible for a variety of biological processes and they are controlled respectively by the size of the pore and the interaction between nucleoporins and karyopherins. Thus, it is not surprising that most of the degenerative programs induce cellular stress by altering the NPC composition or the binding between nucleoporins and docking factors. This facilitates the access of nuclear DNA to pro-death factors, amplify the detrimental cascade and finally play a role in the disassembly of the nuclear structure. Recently, we have shown that during calcium mediated neuronal degeneration NPC components can be degraded with consequent increase of NPC channel permeability. Moreover, we proved that these changes occurred much earlier than the final disassembly of the nuclear envelope and they are mediated by calcium overload. Is the increase of NPC leakiness the executioner of the excitotoxic process or simply a final event of a cell condemned to death? Here we speculate the consequence of the nucleoporin loss, the alteration of nucleocytoplasmic transport and their contribution to neuronal demise. PMID- 21326945 TI - Unloading RNAs in the cytoplasm: an "importin" task. AB - The nuclear cap-binding complex (CBC), a heterodimer comprised of a 20 kDa subunit (CBP20) and an 80 kDa regulatory subunit (CBP80), binds to nascent RNA polymerase II transcripts and is important throughout different aspects of RNA metabolism. In a recent publication, using a combination of X-ray crystallographic information, mutagenesis studies, small-angle scattering experiments, analytical ultracentrifugation and in vivo assays, we presented evidence that importin-alpha and importin-beta, two nucleocytoplasmic transport proteins, play key roles in regulating the binding of capped RNA by the CBC in cells. A model for how complexes between CBC and the importins cycle in and out of the nucleus and direct the proper positional binding and release of capped RNA is presented here and is discussed in light of recent publications. PMID- 21326946 TI - Characterization of the membrane-coating Nup84 complex: paradigm for the nuclear pore complex structure. AB - Nuclear pore complexes (NPCs) function as selective gates for nucleocytoplasmic transport. Although the NPC was discovered more than half a century ago, our knowledge of NPC components in atomic detail has exploded only over the past few years. Recent structural, biochemical, and in vivo studies of NPC components, in particular the membrane-coating heptameric Nup84 complex, have shed light onto the NPC architecture as well as onto its dynamic nature. Striking similarities were revealed between the components of the NPC and of coat protein complexes in the endocytic and secretory pathways, supporting their common evolutionary origin in a progenitor protocoatomer. Here, we summarize these findings and discuss emerging concepts that underlie the molecular architecture and the dynamics of the NPC. We conclude that the uncovered principles are not limited to the NPC, but are likely to extend to other macromolecular assemblies. PMID- 21326947 TI - The fate of irreparable DNA double-strand breaks and eroded telomeres at the nuclear periphery. PMID- 21326948 TI - Maf1 regulation: a model of signal transduction inside the nucleus. AB - RNA polymerase III (Pol III) is responsible for the synthesis of 5S ribosomal RNA (rRNA) and transfer RNAs (tRNAs) essential for protein synthesis and cell growth. Pol III is tightly controlled by growth signals such as nutrients and deregulation of Pol III-dependent transcription can lead to oncogenic transformation. In response to extracellular stimuli, the target of rapamycin complex 1 (TORC1) regulates Pol III activity through Maf1, a key conserved Pol III repressor. Recent studies have unraveled intricate mechanisms by which Maf1 activity is controlled at multiple levels, including nuclear transport and phoshorylation at specific chromatin loci. These studies suggest an emerging mode of gene regulation by extracellular signals inside the nucleus. PMID- 21326949 TI - The cellular response to DNA damage: a focus on MDC1 and its interacting proteins. AB - The DNA damage response (DDR) is comprised of a network of proteins that respond to DNA damage. Mediator of DNA Damage Checkpoint 1 (MDC1) plays an early and important role in the DDR. Recent data show that MDC1 binds multiple proteins that participate in various aspects of the DDR, positioning it at the core of the DDR. Furthermore, interactions with non-DDR proteins were also revealed, suggesting novel roles for MDC1.In this review we provide a comprehensive overview of all known MDC1-binding proteins and discuss their role. We present these binding partners according to their function, thereby providing the reader with a detailed and updated overview of the cellular response to DNA damage. We discuss more recent findings in detail and conclude by presenting the challenges the field faces in the future. PMID- 21326950 TI - Dosage effect of zero to three functional LBR-genes in vivo and in vitro. AB - The Lamin B receptor (LBR) is a pivotal architectural protein in the nuclear envelope. Mutations in the Lamin B receptor lead to nuclear hyposegmentation (Pelger-Huet anomaly). We have exactly quantified the nuclear lobulation in neutrophils from individuals with 0, 1, 2 and 3 functional copies of the lamin B receptor gene and analyzed the effect of different mutation types. Our data demonstrate that there is a highly significant gene-dosage effect between the gene copy number and the nuclear segmentation index of neutrophils. This finding is paralleled by a dose-dependent increase in LBR protein and staining intensity of the nuclear membrane in corresponding lymphoblastoid cell lines, which demonstrates a significant correlation on the protein level as well. We further show that LBR expression continually increases during granulopoiesis in vitro from human precursor cells with ovoid nuclei to multi-segmented neutrophil nuclei 11 days later, indicating relevance for regular human granulopoiesis. Altogether, LBR is a unique model that will allow the systematic study of gene-dosage effects and of modifying endogeneous and exogeneous factors on granulopoiesis. PMID- 21326951 TI - Nucleocytoplasmic shuttling of HIV-1 integrase is controlled by the viral Rev protein. AB - In the current study we show that the Rev protein of Human Immunodeficiency Virus type 1 (HIV-1) inhibits nuclear import and mediates nuclear export of the HIV-1 integrase (IN) protein, which catalyzes integration of the viral cDNA. Interaction between IN and Rev in virus infected cells, resulting in the formation of a Rev-IN complex, has been previously described by us. Here we show that nuclear import of the IN, is inhibited by early expressed Rev. No nuclear import of IN was observed when Rev-overexpressing cells were infected by wild type HIV-1. Similarly, no translocation of IN into nuclei was observed in the presence of Rev-derived peptides. On the other hand, massive nuclear import was observed following infection by a DeltaRev virus or in the presence of peptides that promote dissociation of the Rev-IN complex. Our results show that IN is only transiently present within the nuclei of infected cells. Treatment of infected cells with leptomycin B caused nuclear retention of the Rev-IN complex. Removal of the leptomycin from these treated cells resulted in nuclear export of both Rev and IN. On the other hand, disruption of the nuclear located Rev-IN complex resulted in export of only the Rev protein indicating Rev-mediated nuclear export of IN. Our results suggest the involvement of Rev in regulating the integration process by limiting the number of integration events per cell despite the presence of numerous copies of viral cDNA. PMID- 21326952 TI - The traffic of proteins between nucleolar organizer regions and prenucleolar bodies governs the assembly of the nucleolus at exit of mitosis. AB - The building of nuclear bodies after mitosis is a coordinated event crucial for nuclear organization and function. The nucleolus is assembled during early G(1) phase. Here, two periods (early G1a and early G1b) have been defined. During these periods, the nucleolar compartments (DFC, GC) corresponding to different steps of ribosome biogenesis are progressively assembled. In telophase, rDNA transcription is first activated and PNBs (reservoirs of nucleolar processing proteins) are formed. The traffic of the processing proteins between incipient nucleoli and PNBs was analyzed using photoactivation. We demonstrate that the DFC protein fibrillarin passes from one incipient nucleolus to other nucleoli but not to PNBs, and that the GC proteins, B23/NPM and Nop52, shuttle between PNBs and incipient nucleoli. This difference in traffic suggests a way of regulating assembly first of DFC and then of GC. The time of residency of GC proteins is high in incipient nucleoli compared to interphase nuclei, it decreases in LMB treated early G1a cells impairing the assembly of GC. Because the assembly of the nucleolus and that of the Cajal body at the exit from mitosis are both sensitive to CRM1 activity, we discuss the fact that assembly of GC and/or its interaction with DFC in early G1a depends on shuttling between PNBs and NORs in a manner dependent on Cajal body assembly. PMID- 21326953 TI - Segment-orientated analysis of two-dimensional strain and strain rate as assessed by velocity vector imaging in patients with acute myocardial infarction. AB - AIMS: Strain rate imaging techniques have been proposed for the detection of ischemic or viable myocardium in coronary artery disease, which is still a challenge in clinical cardiology. This retrospective comparative study analyzed regional left ventricular function and scaring with two-dimensional strain (2DS) in the first 4 to 10 days after acute anterior myocardial infarction (AMI). METHODS AND RESULTS: The study population consisted of 32 AMI patients with an LAD occlusion and successful reperfusion. The assessment of peak systolic 2DS and peak systolic strain rate (SR) was performed segment-oriented with the angle independent speckle tracking algorithm Velocity Vector Imaging (VVI). The infarcted, adjacent and non-infarcted segments were revealed by late enhancement MRI (LE-MRI), which was used as reference for the comparison with 2DS. The infarcted segments showed a significant decrease of tissue velocities, 2DS and SR in comparison to the non-affected segments. CONCLUSION: 2DS and SR as assessed by VVI seem to be a suitable approach for echocardiographic quantification of global and regional myocardial function as well as a promising tool for multimodal risk stratification after anterior AMI. PMID- 21326954 TI - The influence of hyperbaric oxygen treatment on the healing of experimental defects filled with different bone graft substitutes. AB - To assess potential effects of hyperbaric oxygen (HBOT) on artificial bone grafts, beta - Tricalcium phosphate (beta-TCP) and calcium phosphate coated bovine bone (CPCBB) substitutes were applied to standard bone defects in rat tibiae. The control defects were left empty. Half of the animals received 60 minutes of 2.4 atmosphere absolute (ATA) of HBOT. Rats were sacrificed at one, two and four weeks. Bone healing was assessed histologically and histomorphometrically using light microscopy. The periosteum over the bone defects was examined ultrastructurally. Cardiac blood was collected to determine the serum osteocalcin levels. The HBOT increased new bone formation in the unfilled controls and beta-TCP groups and significantly decreased cartilage matrix and fibrous tissue formations in all groups. Active osteoblasts and highly organized collagen fibrils were prominent in the periosteum of beta-TCP and control groups. Serum osteocalcin levels also increased with HBOT. The healing of defects filled with CPCBB was similar to the controls and it did not respond to HBOT. These findings suggested that the HBOT had beneficial effects on the healing of unfilled bone defects and those filled with beta-TCP bone substitute but not with CPCBB, indicating a material-specific influence pattern of HBOT. PMID- 21326955 TI - High dose astaxanthin lowers blood pressure and increases insulin sensitivity in rats: are these effects interdependent? AB - The present investigation in Sprague-Dawley rats (SD) was designed to examine effects of astaxanthin (Asta) at different doses on elevated blood pressure (BP) and glucose-insulin perturbations produced by heavy sucrose ingestion. We also examined effects of Asta on BP during restraint stress. SD were divided into six groups each containing eight rats. All SD ate a basic diet of ground regular rat chow with sucrose added at 30% w/w. The Control group received only the basic diet containing added sucrose, while the other five groups each received the same diet with added test material: captopril, (30 mg/Kg), pioglitazone (15.0 mg/Kg), low Asta (25 mg/Kg), medium Asta (50 mg/kg) or high Asta (100 mg/Kg). Many tests were carried out to examine the mechanisms behind the effects of Asta on BP (serum ACE activity, losartan challenge, and LNAME challenge) and the glucose insulin system (glucose tolerance, HOMA measurement, and insulin challenge). In SD, a relatively low dose of Asta decreased SBP, but produced no major changes in the glucose-insulin system simulating results from a previous study using Zucker Fatty Rats. Increasing the dose of Asta resulted in both a lowering of elevated systolic BP and enhanced insulin sensitivity determined by many different estimations. BP lowering was consistent with changes in the renin-angiotensin (RAS) and nitric oxide (NO) systems. At the examined doses of each, captopril lowered BP in SD without influencing glucose-insulin metabolism, whereas pioglitazone favorably affected glucose-insulin metabolism while showing essentially no effects on BP. Accordingly, Asta beneficially affects both sucrose induced elevations of BP and insulin resistance at relatively high doses in SD. Also, Asta at higher doses lessens restraint stress, whereas, captopril and pioglitazone did not at the doses examined, even though they influenced the BP and glucose-insulin systems respectively. PMID- 21326956 TI - Relationship between anti-CCP antibodies and oxidant and anti-oxidant activity in patients with rheumatoid arthritis. AB - OBJECTIVE/AIM: A new group of autoantibodies in Rheumatoid Arthritis (RA), the anti-cyclic citrullinated peptide (anti-CCP) antibodies directed to citrulline containing proteins, which are of value for the severity of RA. Up to date, the relationship between anti-CCP antibodies and oxidant, anti-oxidant activity in patients with RA has not been elucidated in the previous studies. In this study we aimed to investigate the effect of anti-CCP antibodies in the circulation on whole blood, serum and synovial fluid oxidant and anti-oxidant activity in patients with RA. MATERIALS AND METHODS: RA patients with anti-CCP (+) (n=25) and anti-CCP (-) (n=24) were recruited into the study. All patients had a positive rheumatoid factor (RF). The patients who were under treatment with only non steroidal antiinflammatory drugs (NSAID) at the study time included in the study. Catalase (CAT), Glutathione peroxidase (GSHPx), Myeloperoxidase (MPO) activities and the levels of Malondialdehyde (MDA) were measured in whole blood, serum and synovial fluid in both groups. RESULTS: There were no significant differences in terms of the mean whole blood and serum antioxidative activity (CAT, GSHpx) and the mean blood and serum MDA and MPO values (oxidative activity), between the patients with anti-CCP(+) and those with anti-CCP(-). There was increased synovial oxidant activity (MDA and MPO levels) (p<0.05) in anti-CCP(+) RA patients with or without ESR negativity when compared with anti-CCP(-) RA patients. There was positive correlation between anti-CCP antibody levels and synovial MDA and MPO levels (r=0.435, p<0.05, r=0.563, p<0.05 respectively) in anti-CCP (+) group. CONCLUSIONS: In conclusion, anti-CCP antibody positivity seems to be associated with increased synovial fluid oxidant activity (increased MDA and MPO levels) in patients with RA. These conclusions need to be validated in a larger controlled study population. PMID- 21326957 TI - The value of serum biomarkers (Bc1, Bc2, Bc3) in the diagnosis of early breast cancer. AB - BACKGROUND: Surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF) is an approach to biomarker discovery that combines chromatography and mass spectrometry. We aimed to consider the efficacy of Bc1, Bc2, and Bc3 serum biomarkers on early detection of breast cancer (BC) in this study. STUDY DESIGN: In this prospective study, 91 patients who were admitted to our hospital between January 2007 and July 2008 were included. Serum samples from 91 women were stored at -80 degrees C until use. The cancer group included 27 cases of BC. The benign breast disease group included 24 women with benign breast diseases and control group 37 age-matched apparently healthy women. The data obtained for these three groups of patients was worked out for each serum biomarker (Bc1, Bc2, and Bc3) by using SELDI-TOF individually and compared with each other separately and evaluated statistically. RESULTS: Bc2 possesses the highest individual diagnostic power. Bc2 was statistically significant in comparison between the malignant disease group, control group and benign disease group. Bc1 was statistically significant in the malignant disease group compared to control group as well as in the benign disease group compared to control group. Thus Bc1, rather than showing malignant progression, it shows tumoral progression or inflammatory process. Bc3 was found upregulated in all malignant cases; however, it was not statistically significant compared to the benign disease group or the control group. CONCLUSIONS: It has been shown that Bc2 profiles might be useful in clinical practice to improve BC diagnosis. However none of the proteomics reach reasonable AUC values for the discrimination of the BC. Additional confirmation in larger and similarly-designed prospective studies is needed to consider of the efficacy of Bc1 and Bc2 in early diagnosis of the BC. PMID- 21326959 TI - Total immunoglobulin G and IgG1 subclass levels specific for the MSP-1(19) of Plasmodium falciparum are different in individuals with either processing inhibitory, blocking or neutral antibodies. AB - BACKGROUND: Some MSP-1(19) specific antibodies that inhibit merozoite invasion also inhibit the secondary processing of MSP-1. However the binding of these inhibitory antibodies can be blocked by another group of antibodies, called blocking antibodies, which recognize adjacent or overlapping epitopes, but themselves have no effect on either MSP-1 processing or merozoite invasion. These antibodies have been reported to be present in individuals living in a malaria endemic area. METHODS: Blood samples were obtained from children shown to have processing inhibitory, blocking, and neutral antibodies in a previous study. Enzyme linked immunosorbent assay (ELISA), was used to determine the total IgG, IgM and IgG subtypes. RESULTS: There was a significant difference in anti-MSP 1(19) IgG, while there was no significant difference in the anti-MSP-1(19) IgM. Only anti MSP-1(19) IgG1, amongst the IgG subtypes was significantly different between the groups. CONCLUSION: This study shows that antibodies against MSP-1 are different not only in specificity and function but also in the amount of total IgG and IgG subtype produced. PMID- 21326960 TI - In vitro susceptibility of Plasmodium falciparum to monodesethylamodiaquine, quinine, mefloquine and halofantrine in Abidjan (Cote d'Ivoire). AB - BACKGROUND: Malaria is the primary cause of hospitalization in Cote d'Ivoire. Early treatment is one of the strategies to control this illness. However, the spread of resistance of Plasmodium falciparum to antimalarial drugs can seriously compromise this strategy. OBJECTIVES: The aim of this study was to assess the in vitro susceptibility of P. falciparum to monodesethylamodiaquine and aminoalcohols in Abidjan (Cote d'Ivoire). METHODS: We assessed the in vitro susceptibility of isolates collected from patients with uncomplicated malaria by using the WHO optical microtest technique. RESULTS: The proportions of resistance to monodesethylamodiaquine, mefloquine and halofantrine were 12.5%, 15.6% and 25.9%, respectively. For quinine, none of isolates showed evidence of in vitro resistance. However, two isolates (6.1%) had IC(50) values above 300 nM. The IC(50) of each drug was positively and significantly correlated to that of the other three drugs, and the correlation was higher between halofantrine and mefloquine. CONCLUSIONS: Our results showed that the in vitro chloroquine resistance reported in previous studies has been extended to other antimalarial drugs investigated in this study except for quinine. Therefore, it is necessary to implement a long-term monitoring system of antimalarial drug resistance. PMID- 21326961 TI - Awareness and use of insecticide-treated bed nets among children attending outpatient clinic at UNTH, Enugu - the need for an effective mobilization process. AB - BACKGROUND: The promotion of insecticide-treated net (ITN) can be a key approach towards the reduction of morbidity and mortality from malaria. OBJECTIVE: To determine the proportion of mothers using insecticide treated nets for their children and reasons for nonuse. STUDY DESIGN: Prospective hospital-based study. METHOD: Consecutive mothers attending the children's out patient clinic of UNTH, Ituku-Ozalla, Enugu, whose children presented with fever without localizing focus were interviewed with the aid of an open-ended structured questionnaire. RESULTS: Awareness of ITN was found in 184 (80%) of the 230 mothers interviewed, while only 48 (26.1%) use it for their children. There was statistically significant difference in terms of ITN awareness between the highly educated mothers and those with lower educational qualification (p = 0.000) but, in terms of ITN usage, there was no significant difference between the two groups (p = 0.40). Socio economic class did not influence the use of ITN (p = 0.153). A greater number; 56 (41.2%) have no reason for non-use. Reasons for nonuse include use of windows and door nets 22 (16.2%) and not convenient to spread 18 (13.2%). CONCLUSION: There was a high awareness of ITN, which did not influence usage. PMID- 21326962 TI - Barriers to use of antiretroviral drugs in Rakai district of Uganda. AB - BACKGROUND: About 75% of people living with HIV/AIDS (PHAs) who need antiretroviral therapy have no access to these drugs in low-income countries. OBJECTIVE: To investigate the barriers to use of ART in Rakai district of Uganda. METHODS: We interviewed 38 key informants and 384 PHAs. Data was collected on: education/mobilization for ART, sources of information for ART, beliefs regarding ART, social support, use of alternative medicine, stigma/discrimination towards PHAs, distance to ART centres, transport costs to ART centres, waiting time, and on suggestions as how to improve the use of ART. RESULTS: The major barriers mentioned regarding use of ART included: inadequate mobilization, long waiting time at ART treatment centres, high cost of transport to reach ART centres, stigma/discrimination towards PHAs and inadequate number of health workers to attend to PHAs. CONCLUSIONS: Access to antiretroviral therapy could be ameliorated by: improving community education using innovative approaches such as through music, dance and videos, increasing the number of providers who are able to provide ART as through engagement of non health professionals in ART care, bringing ART nearer to where people live and instituting measures aimed at reducing stigma/discrimination such as through involvement of PHAs in demystisfying HIV/AIDS. PMID- 21326963 TI - Respiratory symptoms and ventilatory function tests in Nigerians with HIV infection. AB - BACKGROUND: The impact of the human immunodeficiency virus (HIV) infection on the respiratory system of Africans has been little studied. This study aimed to determine the pattern of respiratory symptoms and ventilatory functions in HIV infected Nigerians. METHODS: In this cross sectional study, Respiratory symptoms frequency, Forced vital capacity (FVC), Forced expiratory volume in one second (FEV(1)), FEV(1)/FVC ratio, Forced expiratory flow between 25% and 75% of FVC, were determined in 100 HIV positive subjects and compared with values in 100 HIV negative controls. RESULTS: HIV positive patients had significantly more respiratory symptoms and lower ventilatory function tests values compared to the matched controls (p<0.05). HIV patients with at least one respiratory symptom and those with CD4 count less than 200 cells/ul had lower ventilatory function values than their counterparts. 32% of the HIV patients had restrictive ventilatory functional impairment. (p<0.05). Using regression analysis, factors like HIV status, CD4 count and presence of respiratory symptoms were found to be associated with impairment in ventilatory functions. CONCLUSIONS: HIV infected patients had more frequent respiratory symptoms and lower ventilatory function values. Further lung function studies and CT scanning in HIV positive patients especially in those with respiratory symptoms are indicated. PMID- 21326965 TI - Serum protein electrophoresis: any role in monitoring for antiretroviral therapy? AB - BACKGROUND: Developing world are always looking for monitoring tools during reagent shortage and equipments troubles which are very frequent. The aim of this study was to evaluate Serum Protein Electrophoresis (SPE) as a marker for assessing HIV treatment response. METHODS: A cross-sectional study was conducted with 220 participants in four distinct groups: Symptomatic HIV positive patients [specifically those on antiretroviral treatment (ART) versus those not on ART] asymptomatic HIV positive patients, and healthy blood donors. Five serum protein fractions (Albumin, Alpha-1, Alpha-2, Beta, and Gamma) were compared between these groups after measuring the density of the fractions. RESULTS: Concentration of gamma globulin was lowest among healthy blood donors, intermediate and comparable among asymptomatic HIV positive and symptomatic HIV positive on ART and highest among untreated symptomatic HIV positive. Concentration of gamma globulin was inversely correlated with the disease stage (p < 0.001). CONCLUSION: In this study, conducted in a setting where the burden of infectious diseases is high, the density of gamma globulin and albumin fractions were significantly associated with HIV status, and among HIV positive patients, with stage of HIV disease and ART. These results suggest that the feasibility of using SPE for monitoring the response of ART in low resource settings should be further explored. PMID- 21326966 TI - Lipid profile in HIV/AIDS patients in Nigeria. AB - INTRODUCTION: Alterations of serum lipid profiles have been reported widely among Human Immuno deficiency Virus (HIV) positive patients on Highly Active Anti Retroviral Therapy (HAART). However, there are few data on serum lipid profile among treatment naive HIV positive patients in our environment. OBJECTIVES: To describe the pattern of lipid profile among treatment naive HIV positive patients and changes following HAART initiation. METHODS: One hundred and thirty HIV positive patients seen in HIV center in an urban area in Nigeria and 44 matched individuals were recruited. Data were collected on socio demographic characters, baseline lipid profiles and CD4 count. Values of lipid parameters were retrieved after 12 months on HAART. RESULTS: The mean Low density lipoprotein(LDL) was 2.26+ 0.9 mmol/l among the test group compared with 0.96+0.39 mmol/L among the control, p value=0.000. The mean High density lipoprotein (HDL) was also significantly lower, 0.8+0.6 mmol/L reaching a dyslipidemic level, in the HIV positive group than the control, p value = 0.00. Tuberculosis/HIV co infected patients had a significantly elevated mean LDL, p=0.002. CONCLUSION: Abnormality of serum lipid is common among treatment naive HIV patients seen in Nigeria. The NNRTI regimen is associated with elevation of HDL and some stabilization of TC and TG. PMID- 21326967 TI - Sexual behavior of medical students: A single institutional survey. AB - OBJECTIVE: We investigated the sexual practices of medical students as they are positioned to serve as peer educators in the fight against HIV/AIDS. METHODS: This was a cross sectional study, where self- administered questionnaires were distributed to consenting 4(th) to 6(th) year medical students in Jos, Nigeria with a view of elucidating information regarding sexual practices and condom utilization. Safe sex practice was defined as the use of condoms and being in a monogamous relationship. RESULTS: Of a total of 400 questionnaires distributed, 365 respondents (249 males and 116 females) had adequate data for analysis. A large proportion (62%) of our students have never had sex before and less than 30% of them are sexually active. Only 6.1% had multiple sexual partners and homosexuality was uncommon (1.9%). Condom utilization amongst the sexually active was high (65%) and similar among male and female students (71.3% vs. 51.9% respectively, p = 0.08). CONCLUSION: There exists safe sexual practice among medical students in our setting. This group could be recruited as peer educators in the war against HIV/AIDS. PMID- 21326968 TI - Academic performance of school children with behavioural disorders in Uyo, Nigeria. AB - INTRODUCTION: Behavioural disorders can have a negative influence on the academic performance of school children. There are no similiar published is no known studies in Nigeria. OBJECTIVE: To compare the academic performance of primary school children with behavioural disorders with that of their controls. METHODS: A total of 132 primary school pupils aged 6-12 years with behavioural disorders using Rutter scale for teachers (Scale B(2)) and their matched-controls were selected. Their academic performance was assessed and compared using the overall scores achieved in the first and second term examinations in the 2005/2006 academic sessions, as well as the scores in individual subjects. Number of days absent from school was documented. RESULTS: While 26.5% and 12.9% pupils with behavioural disorders had high and poor academic performance respectively, 38.6% and 9.1% pupils without such disorders had high and poor performances respectively. The difference in the ooverall academic performance was statistically significant (p=0.04). The mean scores of the pupils with behavioural disorders on four core subjects compared well with those of the controls. Pupils with antisocial behaviour underachieved more than others. School absence rate had no significant influence on their performance. CONCLUSION: Behavioural disorders are associated with poor academic performance in school children in Uyo. PMID- 21326969 TI - Risk factors for contracting anthrax in Kuwirirana ward, Gokwe North, Zimbabwe. AB - BACKGROUND: A report of an anthrax outbreak was received at Gokwe district hospital from the Veterinary department on the 23(rd) January 2007. This study was therefore conducted to determine risk factors for contracting anthrax amongst residents of Kuwirirana ward. METHODS: We conducted a 1:1 unmatched case control study. A case was any person in Kuwirirana ward who developed a disease which manifested by itching of the affected area, followed by a painful lesion which became papular, then vesiculated and eventually developed into a depressed black eschar from 12 January to 20 February 2007. A control was a person resident of Kuwirirana ward without such diagnosis during the same period. RESULTS: Thirty seven cases and 37 controls were interviewed. On univariate analysis, eating contaminated meat (OR = 7.7, 95% CI 2-29.8), belonging to a household with cattle deaths (OR= 9.7, 95% CI 2.9-33), assisting with skinning anthrax infected carcasses (OR= 5.4(95% CI 1.7-17), assisting with meat preparation for drying (OR = 5(95%CI 1.9-13.9), assisting with cutting contaminated meat (OR = 4.8(95% CI 1.7-13.2), having cuts or wounds during skinning (OR = 19.5, 95% CI 2.4-159) and belonging to a village with cattle deaths (OR = 6.5(95%CI 1.3-32) were significantly associated with anthrax. CONCLUSION: Anthrax in Kuwirirana resulted from contact with and consumption of anthrax infected carcasses. We recommend that the district hold regular zoonotic committee meetings and conduct awareness campaign for the community and carry out annual cattle vaccinations. PMID- 21326970 TI - Comparison of Pulmonary TB DOTS clinic medication before and after the introduction of daily DOTS treatment and attitudes of treatment defaulters in the Western Division of the Gambia. AB - BACKGROUND: Over a third of the world's population is infected with the tuberculin bacteria. In 1993 WHO launched the DOTS-strategy to enhance treatment compliance. Despite Gambia's adaption in 1985 it falls below WHO target of 85% cure rate. The defaulter rate was 14% in 2001, which reached 16% in the urban areas of the Western Division in 2003. OBJECTIVES: This study aimed to compare TB treatment and outcomes before and after the introduction of daily directly observed therapy (DOTS) medication and the perceptions/attitudes of defaulters in the Western Division of the Gambia. METHODS: The study employed a mixed study design; a quantitative cross sectional study that reviewed the clinic records of pulmonary TB patients before and after the introduction of daily TB-DOTS medication and an in-depth interview of defaulters on the daily medication. The study was conducted at the Brikama TB-clinic in Gambia, located at the main hospital of Brikama serving all satellite villages. It registers on average 110/100 000 new smear-positive pulmonary TB-cases per annum. The quantitative arm compared clinic-based records of TB-DOTS medication before and after the introduction of daily medication. The qualitative arm explored the perceptions of daily medication defaulters. RESULTS: There was no statistically significant difference between the treatment outcomes of the two medication policies. However patients were less likely to have had three sputum tests reviewed in the daily medication period (22% v 72% Odds Ratio 6.2 (p <0.001). However, they reported that daily medication with its fixed-dose combination was more convenient. CONCLUSION: Patients' full compliance with daily medication was hindered by socio economic factors. The daily medication with its increased workload undermines the proper implementation of fundamental DOTS-elements, particularly follow up and sputum review. PMID- 21326971 TI - Indoor air mycoflora of residential dwellings in Jos metropolis. AB - BACKGROUND: The quality of air in the environment where one lives or works can have potential effects on human health. There are strong indications that in many parts of the world, our homes, schools and workplaces are heavily contaminated with air-borne molds and other biological contaminants. OBJECTIVES: This study was carried out to assess the level of fungal contamination of indoor air, health related experiences of residents, and the prevalent fungi species in the homes. METHODS: The investigation was done between May 2005 and January 2006, using structured questionnaires and the agar plate exposure. 150 houses from 14 locations were examined. RESULTS: 380 fungi belonging to 10 species were isolated, Chaetomium globosum (17%), Aspergillus fumigatus (14%), Stachybotrys alternans (14%) and Alternaria alternata (14%) being the predominant isolates. CONCLUSION: The indoor air quality of residential dwellings in Jos is poor. Rate of isolation of fungi was not significantly different in the wet and dry periods of the year and residential density affected the occurrence of fungal contaminants. Residents are displeased with fungal presence in their homes and the associated health implications. There is need for proper attention to the quality of the indoor environment. PMID- 21326972 TI - Prevalence of left ventricular diastolic dysfunction in newly diagnosed Nigerians with systemic hypertension: a pulsed wave Doppler echocardiographic study. AB - BACKGROUND: Systemic hypertension is a common cause of left ventricular diastolic dysfunction. However, its prevalence in Nigerians with untreated systemic hypertension is unknown. OBJECTIVE: To determine the prevalence of left ventricular diastolic dysfunction in newly diagnosed Nigerians with systemic hypertension using Doppler transmitral inflow and pulmonary venous flow velocities. METHODS: Two-dimensional echocardiography including Doppler was performed on 150 newly diagnosed cases of systemic hypertension and 150 normotensive controls. They were divided into hypertensives without left ventricular hypertrophy and those with left ventricular hypertrophy based on echocardiographically determined left ventricular mass index. Pulsed Doppler transmitral inflow and the pulmonary venous flow waves were used to categorise the patterns of diastolic dysfunction. RESULTS: The hypertensives and the normotensive controls were comparable in their baseline characteristics. The E/A ratio differed significantly between hypertensives with and without left ventricular hypertrophy and controls (1.00+0.30, 1.04+/-0.42, 1.33+/-0.27, p < 0.001). Left ventricular diastolic dysfunction occurred in 62% of systemic hypertension and 11.3% of the controls. Impaired relaxation was the commonest pattern (84.9%) of diastolic dysfunction. CONCLUSION: Our study showed that left ventricular diastolic dysfunction is prevalent in Nigerians with newly diagnosed systemic hypertension and effort should be made to routinely screen for them. PMID- 21326973 TI - Mobile phone ownership among Nigerians with diabetes. AB - BACKGROUND: A survey was undertaken to determine the number of individuals who have access to Mobile phones among those attending our Diabetes clinic in order to explore whether this could replace or become an adjunct to street home address as contact information. METHOD: An observer-based questionnaire was administered to capture parameters of interest at the weekly diabetes clinic in order to answer the survey question RESULTS: 130 individuals aged 15-80 years who attended the clinic in the month of May 2008 were surveyed. Eighty nine (89) patients had active Mobile phone and lines while 70.8% of these were females. Strikingly, 37% percent of the study populations were from across states boundaries and other geographic areas but majority reside in Ilorin metropolis where the facility is based. CONCLUSION: The results indicate that over two thirds of those with diabetes attending the clinic had active Mobile phone line and this could be used as an adjunct to or replace street address as a contact particular between patients and their professional care givers. PMID- 21326974 TI - Chronic lymphocytic leukaemia: a-twenty-years experience and problems in Ile-Ife, South-Western Nigeria. AB - AIM: To investigate the usefulness of some clinical and laboratory parameters in assessing the prognosis and survival of CLL in a resource-limited setting. METHODS: Between September 1986 and March 2007, 79 consecutive patients were retrospectively studied. Diagnosis was based on clinical and haematological findings. RESULTS: A total of 79 patients, aged 30 to 81 (median = 60) years were managed. There were 34 males and 45 females (ratio = 0.8:1). About 86.1% were aged above 50 years. Massive splenomegaly and hepatomegaly were recorded in 70.9% and 29.1% of patients, respectively. More than 63% presented in stage C. Anaemia was recorded in 74.7%. Haematocrit correlated negatively with WBC but positively with platelet count. The spleen correlated positively with liver. The overall survival at 2 years was 70.2%. Logistic regression showed that younger age, male sex, higher haematocrit, and lower platelet count improved survival, while lower WBC, moderate hepatomegaly and splenomegaly conferred survival advantage. CONCLUSION: It could be concluded that massive splenomegaly is a common finding in the majority of our patients. Non availability of immunophenotyping facility is a major constraint. PMID- 21326975 TI - Microbiological quality and safety of cooking butter in Beni-Suef governorate Egypt. AB - BACKGROUND: Cooking butter is one of the most popular types of fat consumed in Egyptian houses. It is produced in villages by rural women that are usually using their traditional knowledge during manufacturing. OBJECTIVE: To study the rate of contamination and hygienic quality of cooking butter METHODS: A total of 60 random samples of cooking butter, were collected from different farmers' houses in different villages, Beni-Suef Governorate, Egypt. Cooking butter samples were examined for psychrotrophic bacteria, total coliforms, faecal coliforms and molds and yeasts counts. Additionally examination for the presence of pathogenic bacteria like E.coli, S.aureus and Ps.aeruginosa were also performed. RESULTS: The microbiological examination revealed that 100, 100, 36.7, 31.7, 31.7 and 23.3% of the examined samples were contaminated by psychrotrophic bacteria, molds and yeasts, coliforms, faecal coliforms, E.coli and S.aureus, respectively. None of the examined cooking butter samples contained Ps.aeruginosa. The means values of sodium chloride and titratable acidity were 0.57 +/- 0.05 % and 0.20 +/- 0.013%, respectively. CONCLUSION: The present study showed that cooking butter is produced under unhygienic condition and without good manufacturing practice. The Public health significance and suggestive control measures are discussed. PMID- 21326976 TI - Chemoprophylaxis with doxycycline in suspected epidemic of leptospirosis during floods: does this really work? PMID- 21326977 TI - The tobacco industry tactics-a challenge for tobacco control in low and middle income countries. PMID- 21326978 TI - Reporting statistics in clinical trials published in Indian journals: a survey. AB - OBJECTIVES: Clinical trials are having very important place in the hierarchy of evidence based medicine. It has been observed that current methods of use and reporting of statistics of clinical trials are responsible for errors in the interpretation of results. So we decided to evaluate clinical trials published in three Indian journals of 2007 and 2008 to analyse statistical issues which may affect the interpretation of results. SETTINGS AND DESIGN: Retrospective observational study MATERIALS AND METHODS: We analyzed all the clinical trials (46) published in Indian pediatrics, Indian journal of pharmacology, journal of postgraduate medicine and of 2007-2008. RESULTS: We found that median number of end points reported in clinical trials was 4 and median number of end points which were used for testing of significance was also 4. (21) 45% of trials reported repeated measurement. 18 (39%) trials had three or more than three treatment groups. median number of test of significance was 15. post hoc subgroup analysis was done in 19% (9) of trials. P value was the sole criteria for interpretation of results in most of the trials, confidence interval was calculated in 11 (23%) trials. Baseline comparison between the study groups was done in 41 (89%) trials. in all cases comparison was done by statistical tests. Exact sample size was calculated in 18 (39%) trials. CONCLUSION: There are great chances of having error during the interpretation of results of these trials was because of multiple treatment groups, repeated measurements of endpoints, multiple tests of significance, over reliability on P value and less use of confidence interval. Statistical methods available for reducing chances of errors should be used and result should be interpreted accordingly. PMID- 21326979 TI - Autoimmune liver disease in a Nigerian woman. AB - Autoimmune liver diseases are chronic liver disease with similar clinical features to viral and non-autoimmune liver disorders but with distinct sero autoimmunologic features. In developed countries, it accounts for about 20% of all liver transplantations in the USA. Most studies on liver disease in Nigeria centred on viral or alcohol aetiology with complete absence of data on autoimmune liver disease.We here report a case of a young woman with autoimmune hepatitis for the first time in Nigeria. The patient presented with features of chronic liver disease of neither viral nor alcoholic aetiology. The diagnosis was based on the presence of hypergammaglobulinaemia and auto-antibodies in the serum.We concluded that physicians should always bear in mind the possibility of autoimmune hepatitis in patients with features of chronic liver disease, especially when the viral markers are negative and there is no history of significant alcohol consumption. PMID- 21326981 TI - Ramadan: a different side of the emergencies? PMID- 21326980 TI - Neurosyphilis masquerading as hemiparesis and Jacksonian epilepsy in an HIV positive patient: a case report. AB - BACKGROUND: Neurosyphilis is a common but often missed disease worldwide, mainly because it has many manifestations making its diagnosis difficult. It is often missed among HIV patients as the search for other co-infections such as toxoplasmosis often overshadows its consideration. OBJECTIVES: To describe one of our cases of neurosyphilis in HIV, raise awareness about the reality of neurosyphilis in Africa and share our experiences in diagnosis and management of the disease. METHODS: A 40 year old, HIV positive female was admitted with a 2 month history of left sided facial and limb weakness followed by delirium, aphasia and Jacksonian epilepsy. She underwent clinical and laboratory evaluation. RESULTS: On examination she had a maculo-papular rash and left sided paresis. Rapid Plasma Reagin(RPR) was reactive(titre 1:16). Treponema Pallidum Haemoaggluttination Assay(TPHA) was also reactive. Cerebrospinal fluid (CSF) analysis revealed: protein 56 mg per dl, glucose 71 mg per dl, cells 14 per high power field (predominantly lymphocytes). The VDRL on the CSF was positive. The CD4 cell count was 320 per ml. She was treated with intravenous penicillin G, 4 mega-units 6 hourly for 14 days, with a very good response. CONCLUSION: Neurosyphilis still occurs in Uganda. It should be considered in all patients with neurological/ophthalmic illness, including those with HIV. Most cases respond well to intravenous penicillin G. PMID- 21326982 TI - The clinical efficacy of cryptolepis sanguinolenta in the treatment of malaria. PMID- 21326983 TI - Treatment of falciparum malaria with a tea-bag formulation of cryptolepis sanguinolenta root. PMID- 21326984 TI - Clinical efficacy of a tea-bag formulation of cryptolepis sanguinolenta root in the treatment of acute uncomplicated falciparum malaria. AB - OBJECTIVE: To evaluate the clinical efficacy and safety of a tea bag formulation of the root of C. sanguinolenta DESIGN: This is a prospective descriptive open trial. SETTING: Patients were recruited from Korle-Bu, Mamprobi and Dansoman Polyclinics. SUBJECTS: Forty-four subjects with uncomplicated malaria were recruited for the study. METHOD: Patients presented with clinical symptoms of malaria. Laboratory investigations conducted included malaria parasite counts, haematological indices and biochemical tests which were obtained before, during and after a 5-day treatment period, up to Day 28 posttreatment. All patients in the study were symptomatic with significant parasitaemia. Patients were given one teabag three times a day, that is, morning, noon and night, for five days of treatment. RESULTS: Fifty percent of the patients were cleared of their P. falciparum parasitaemia by 72 hours, and all by Day 7. Presenting symptoms of fever, chills, nausea and vomiting cleared rapidly, all by Day 3, but resolution of haematological and biochemical abnormalities associated with malaria was generally slow, a feature seen in malaria post-treatment. The overall cure rate was 93.5% due to two cases of recrudescence on Days 21 and 28. The laboratory findings did not suggest any toxicity. CONCLUSION: On the basis of fever clearance and disappearance of parasitaemia by Day 7, the formulation has been shown to be non-toxic and highly effective in the treatment of acute uncomplicated malaria. PMID- 21326985 TI - Presentation of retinoblastoma at a paediatric eye clinic in ghana. AB - BACKGROUND: Retinobalstoma, the commonest childhood malignant intraocular tumour, is usually diagnosed early with over 90% survival rate in developed countries. In developing countries, the diagnosis is late resulting in less than 50% survival. OBJECTIVE: To determine retinoblastoma stages at presentation and patients' outcomes. DESIGN: Retrospective case series. METHODS: The clinical and histopathological records of children with retinoblastoma seen from May 2004 to December 2005 were studied. Data was analysed for mode of presentation, laterality, clinical staging using Reese-Ellsworth (R-E) classification, histopathological high risk features (HHRF) for metastasis, and patient outcome. SETTING: Ophthalmology Unit, Korle-Bu Teaching Hospital, Ghana. RESULTS: Twenty three patients presented with retinoblastoma over the period. Males were 12(52.2%). The age range from 1 to 84 months, mean 36.3(+/-22.15) and median (36 months). Nineteen (82.6%) had unilateral and 4(17.4%) bilateral disease. The common clinical presentations were leukocoria in 20(87.0%), proptosis 8(34.8%), strabismus 5(21.7%) and red eye 5(21.7%). The clinical features were commensurate with R-E stage V in 20(87.0%) patients, 2(8.7%) with orbital recurrence and 1(4.3%) with post-enucleation anophthalmos. HHRFs were present in 9(75%) enucleated eyes with invasion of optic nerve as the commonest site (7/9). The patients were followed up for 1 day to 19 months. Eight abandoned treatment, 2 were discharged for palliative treatment, 2 out of 5 with metastasis died and 6 had no metastases at their last visit. Common sites for metastasis were the bone marrow, brain and orbit. CONCLUSION: Majority of the patients presented with advanced disease manifesting as leukocoria, proptosis, RE stages V disease and poor outcome. PMID- 21326986 TI - Airway and respiratory complications in children undergoing cleft lip and palate repair. AB - OBJECTIVES: Anatomical abnormalities associated with cleft lip and palate increase the risk of airway complications. The aim of this study was to determine the incidence of intra-operative airway and respiratory complications during cleft lip and palate repair and identify risk factors. DESIGN: Observational study in which fifty consecutive patients undergoing cleft lip or/ and palate repair (CL, CP, CLP) were prospectively studied in a teaching hospital in Nigeria. Anaesthesia was achieved by the inhalational or intravenous route. Tracheal intubation was performed under deep inhalational anaesthesia or muscle relaxation. All patients were ventilated. Demographic data, airway and respiratory complications were documented. RESULTS: The mean age of the patients was 26.62+/- 4.71(SEM) months (median 11.50). Nineteen airway complications occurred in 16 patients (incidence - 38%) as failed and difficult intubation (2% respectively) which only occurred in CP surgeries, Tube disconnection (6%), Tube compression (2%), Accidental extubation (2%) and Desaturation (14%). Laryngeal spasm (6%) and Bronchospasm (4%) occurred in surgeries for CP repair only. Some patients had more than one complication. Complications occurred in 38.4% of patients having CP repair, 15.8% having CL repair and 50% having CLP repair (p=0.185). This was not influenced by weight nor age group (p = 0.076 and 0.400 respectively). CONCLUSION: Cleft repair had a high incidence of airway/ respiratory complications. More complications occurred with CP surgery. There is a need to ensure adequately skilled personnel and appropriate monitoring to minimise morbidity. PMID- 21326987 TI - Prevalence of genital Chlamydia and gonococcal infections in at risk women in the kumasi metropolis, ghana. AB - OBJECTIVE: To study the prevalence of genital chlamydia and gonococcal infections in women at risk of acquiring sexually transmitted infections in the Kumasi metropolis, Ghana. DESIGN: Structured interviews and clinical examination of participants and obtaining vaginal swabs to test for gonorrhoea and chlamydia infections. PARTICIPANTS: Women aged between 18-35 years (inclusive) with a history of having at least 3 sexual acts per week and having had at least 2 sex partners in the previous 3 months and were willing to be part of the study. RESULTS: One thousand and seventy (1070) women participated in the study. Genital chlamydia infection was found in 4.8% of participants whilst gonococcal infection was found in 0.9% of participants. CONCLUSION: The prevalence of genital chlamydia and gonococcal infections was low in these at-risk women. The prevalence is also lower than reported in other female populations in the country. PMID- 21326988 TI - Presentation patterns of primary open angle glaucomas in north eastern ghana. AB - INTRODUCTION: Previous reports have indicated that open angle glaucoma is a major problem in the Upper East region of Ghana. Such reports have shown high prevalence among young patients under the age of 40 years. None has given enough details on the burden, pattern of distribution and extent of changes in the optic nerve head and intraocular pressures. This study aims at addressing these issues in order to highlight the situation. METHODS: Retrospective case series involving review of clinical records of all first-time attendants diagnosed with glaucoma at the Bawku Hospital between October 2003 and December 2005. Case definitions and diagnostic criteria were made to conform as much as possible to the ISGEO and EGS recommendations. Data analysis was done using the Epi-Info software. RESULTS: Records of 891 eyes of 446 patients were reviewed. Median age was 56 years with 23.6% below 40 years. POAG was diagnosed in 98.4% with 8.3% manifesting the NTG variant. One third (34.1%) of all the patients reported bilaterally blind while half were uniocularly blind. Nearly a third (70.2%) had CDRs>0.8 while more than half (54.9%) had CDRs measured at unity. Males were twice as many as females (65.5% and 34.5% respectively) but blindness sequelae among the latter was twice as much and this was statistically significant (p=0.0008;chi2 test) CONCLUSION: late presentation of open angle glaucoma cases is a major problem in this part of Ghana. We recommend a more aggressive approach to tackle the disease and reduce its blindness sequelae. PMID- 21326989 TI - Diagnosis of tuberculosis in ghana: the role of laboratory training. AB - OBJECTIVES: The laboratory is considered the cornerstone of tuberculosis (TB) control programme. International review of Ghana's programme in the late nineties identified the laboratory services as the weakest component. Sputum smear microscopy (SSM) being the main method of diagnosing pulmonary TB in Ghana, the training objectives were to: (i) strengthen the knowledge and skills of laboratory personnel on SSM (ii) impart necessary techniques in biosafety and (iii) introduce a Quality Assurance (QA) system in order to strengthen SSM services. METHODS: Personnel were selected for training during a nationwide situation analysis of SSM centres in 2000/2001. Four training sessions on SSM/QA were held between 2001/2004. RESULTS: A total of 80 personnel were trained: 10 regional TB coordinators and 70 laboratory personnel. The participants upon return to their respective regions also organized training within their districts. This approach resulted in another 100 district TB coordinators and 200 laboratory personnel being trained. Improvement in smear preparation, staining and reading ability of the participants were observed during the post-test and subsequent visit to their respective laboratories. The training has led to strengthening of TB laboratory services in the country and has contributed to increase in case detection from 10,745 in 2000 to 11,827 in 2004 and 14,022 in 2008. It was observed during the post-training follow-up and quarterly supervision visits that morale of the personnel was high. CONCLUSION: Continuous training and re-training of laboratory personnel on SSM and QA at regular intervals do play an important role for effective and efficient TB control programme. PMID- 21326990 TI - Special position for the anaesthetic management of a patient with giant neck and back masses. AB - A neck mass is a risk factor for difficult airway during induction of anaesthesia particularly when accompanied with a giant back mass which limits positioning of the patient in the supine position. We report the management of a young woman with known recurrent neurofibroma scheduled for resection of her giant neck and back masses. Unfortunately, her dorsal thoracic mass was too huge to allow adoption of the supine position for induction of anaesthesia. In order to achieve a suitable supine position which is fundamental during airway management, we created a hole in the operating table to fit her giant back mass. Exhibition of this special operating table may help to achieve a suitable position and ease airway management which is not possible with routine tables in cases with giant posterior masses. PMID- 21326991 TI - Left thoracic kidney: a rare finding at intravenous urography. AB - Thoracic kidney is a rare type of renal ectopia. Patients with thoracic kidneys are usually asymptomatic and the condition is usually discovered incidentally during radiological evaluation for other conditions or during thoracic surgery. An intravenous urography done for a thirty-eight year old man referred on account of a seemingly small right kidney on an abdominal ultrasound scan, showed a normal right kidney and a left thoracic kidney. Thoracic kidney is a rare but an important cause of a thoracic 'mass' or 'elevated hemi diaphragm'. It should be considered in the evaluation of such patients to prevent unnecessary surgical interventions and image guided biopsies. PMID- 21326992 TI - Current Status of HIV/AIDS Treatment, Care and Support Services in Ghana. PMID- 21326993 TI - Care of patients on anti-retroviral therapy in kumasi metropolis. AB - OBJECTIVE: To assess the characteristics of a cross-section of HIV infected persons receiving treatment from the Antiretroviral Therapy (ART) clinic in Komfo Anokye Teaching Hospital (KATH), Kumasi and highlight perspectives related to taking their treatment. DESIGN: Using a structured questionnaire, sociodemographic characteristics and information related to taking ART were elicited from a random sample of 227 persons living with HIV (PLHIV) accessing ART in Kumasi in 2007. Health workers at the ART clinic were also given self administered questionnaires to obtain their perspectives on the clinic. RESULTS: Of those sampled, the majority (79.7%) were women and a third (34.8%) were unemployed. More than 95% of the study participants were on the recommended three drug antiretroviral therapy and most of the study participants, (80.6%) said they had never missed a dose of their drugs since starting treatment. About half of the respondents (51%) said the cost of the treatment was not affordable. Seven out of ten (73.6%) waited 3 hours at the clinic before being attended to. On an average clinic day, the number of patients the health workers attended to ranged from 30 to 100. CONCLUSION: PLHIV accessing ART in Komfo Anokye Teaching Hospital were found to be managed as per national HIV treatment guidelines. Inability to afford the cost of treatment and service providers being overwhelmed by the large number of patients patronizing the clinic may have implications for patients taking ART as prescribed and the quality of care. PMID- 21326994 TI - Confocal scanning laser tomography of the optic nerve head of glaucoma patients: inter-correlation of disc parameters. AB - OBJECTIVE: To evaluate the scanning laser tomography characteristics of the optic nerve head in patients with primary open angle (POAG) glaucoma using the Heidelberg retina tomography (HRT II). DESIGN: A clinic-based retrospective study. PARTICIPANTS: A total of 84 eyes of 42 POAG patients with good quality HRT II Images were studied at Charles Nicolle Hospital University department of Ophthalmology out-patient clinic, Tunis. METHODS: Characteristics of optic disc pattern of glaucoma patients were documented using the HRT II. Association of disc area with the other HRT parameters and inter-eye difference in the HRT parameters were assessed using simple and multiple regression analysis. MAIN OUT COME MEASURES: Disc area, cup area, rim area, cup-to-disc area ratio, cup volume, rim volume, mean cup depth, maximum cup depth and mean retinal nerve fibre layer thickness. RESULTS: Twenty-seven males and 15 females were studied. The mean age of glaucoma patients was 48.9+/-2.7 years. The mean disc area, cup area, cup-to disc area ratio and rim area were 2.19+/-0.46 (range, 1.23 - 3.16mm2), 0.95+/ 0.94 (range 0.08 - 2.15), 0.42+/-0.21(range 0.004-0.92), 1.25+/- 0.46 (range 0.18 2.64) respectively. Disc area was positively correlated to the cup area (p=0.001), rim area (p=0.001), cup to disc area ratio (p=0.03), and mean cup depth (p=0.02).The glaucoma diagnosis score was strongly correlated with the rim area (p< 0.001), cup area (p< 0.001), mean cup depth (p< 0.001) and cup disc area ratio (p< 0.001). Absolute inter eye parameter between the two eyes were positively correlated with disc area (p< 0.05). CONCLUSIONS: There was a significant correlation of the parameters between the two eyes and between the disc area and some other HRT parameters. PMID- 21326995 TI - Plasma homocysteine as a risk factor for strokes in ghanaian adults. AB - BACKGROUND: Stroke is an increasing problem in Ghana and the West African sub region. New and modifiable risk factors for stroke have gained prominence in the last decade but have not been adequately researched in West Africa. METHOD: This was a case-control study with plasma Homocysteine (Hcy) as an independent risk factor for stroke. 80 consecutive stroke patients with 80 age-sex matched controls were venesected in the fasting state for assay of Hcy and other biochemical parameters. RESULTS: Mean Hcy level in stroke cases of 40.7 +/- 9.5umol/l was significantly higher than 16.8 +/- 10.6umol/l in controls [p<0.0001]. There was a significant association of hyperHcy with stroke [chi(2); p<0.0001]. OR of stroke calculated for quartiles of Hcy, demonstrated an increase in OR of 1.37 (25(th) percentile) to an OR of 3.80 (75(th) percentile). CONCLUSIONS: Hcy was elevated in patients with stroke and should be considered as a modifiable risk factor for stroke in Ghanaian adults. PMID- 21326996 TI - Effects of the intake of natural cocoa powder on some biochemical and haematological indices in the rat. AB - BACKGROUND: Natural cocoa and cocoa products are increasingly attracting the attention of many investigators and the general public because of their potential nutritional and medicinal properties and other claims. OBJECTIVE: This study sought to evaluate the effect the consumption of natural cocoa powder has on some biochemical and hematological indices in the rat, as a way of establishing the biochemical basis for some of the claims made for the consumption of cocoa and its products. METHODS: Male Wistar albino rats were fed natural cocoa powder in an aqueous suspension for 48 days, Biochemical and haematological indices were then determined from blood samples. RESULTS: The treatment had no significant effect on ALT, AST, ALP, uric acid, total protein, haemoglobin and haematocrit levels. However, there were significant reductions in the total cholesterol level (2.52 +/- 0.07 mmol/L) versus (1.88 +/- 0.23 mmol/L), LDL - cholesterol level (1.09 +/- 0.03 m mol/L) versus (0.74 +/- 0.06 m mol/L), and in triglyceride level (1.28 +/- 0.15 m mol/L) versus (1.08 +/- 0.04 m mol/L) after treatment (p <0.05). The results further indicated significant increases in white blood cell (7.53 +/- 0.19 * 10(3)/mm(3)) versus (10.40 +/- 1.66 * 10(3)/mm(3)) and platelet counts (379+/- 112.0* 10(3)/mm(3)) versus (583.8+/-11.4* 10(3)/mm(3)). CONCLUSION: The administration of natural cocoa powder to rats caused significant reductions in total serum cholesterol levels, LDL-cholesterol levels and triglycerides with a significant increase in white blood cell counts. PMID- 21326997 TI - Evaluation of cataract surgery outcome in Western Nigeria. AB - OBJECTIVE: To evaluate the baseline visual outcome of cataract surgeries and improve on these towards achieving one of the objectives of vision 2020. DESIGN: A retrospective study. SETTING: Hospital-based, utilizing 3 eye centres in Osun State, Nigeria between January 2000 and December 2002. METHODS: Records of 283 hospital-elective-cataract-surgeries only of all ages in 3 centres were evaluated. RESULTS: Mean age was 62.2 years. Fifty-eight 58% were blind before while only 6.3% remained blind post op. With best correction, visual outcome was good in 47.5%, moderate in 37.6% and poor in 15%. The commonest co-morbidity was glaucoma 33 (71.7%). The most common intra operative complications were vitreous loss 61 (27.35%) and posterior capsular rupture (6.28%). Capsular opacity (6.28%) was commonest post operatively with significantly poor visual outcome (chi(2)= 51.46, p-value = <0.05). Causes of poor visual outcome were uncorrected refractive error (59.37%), co-morbidity (24.22%), and surgery related complications (16.41%). Visual outcome was significantly better with IOL or prescribed glasses (chi(2)=19.66, p-value <0.05) and better still with ECCE +IOL (chi(2)=8.46, p-value <0.05). Poor visual outcome was significantly associated with co-morbidity (chi(2) = 23.88, p-value <0.05), surgical complications (chi(2)= 51.46, p-value = <0.05). CONCLUSION: The baseline cataract visual outcome was poor due to delay in correction of refractive error, comorbidities, and surgical complications. Good outcome could be attained by routinely ensuring different methods of adequate postoperative visual rehabilitation. Skills acquisition, availability of adequate equipments, establishment of a good records system to achieve effective evaluation and monitoring of outcome cannot be over emphasized. PMID- 21326998 TI - Clinical genetics: ghanaian gratitude for british and hungarian contributions: a personalized historical perspective. PMID- 21326999 TI - An unusual fracture of the mandible. AB - A rare case of horizontal fracture of mandibular symphysis caused by a sharp matchet cut is presented. Under local anaesthesia with sedation, the fracture site was exposed through the sutured laceration on the left submandibular region. The fracture was adequately reduced and fixed with two circum-mandibular wires. Healing was uneventful, but postoperative radiograph after six weeks revealed a bony defect in the anterior part of the lower border of the mandible, resulting from shifting of the fractured segment posteriorly during healing. Complete recovery of left lower lip sensation was found 4 months postoperatively. PMID- 21327000 TI - Broad ligament haematoma following a snake bite. AB - Haematomas in various body organs have been reported following snake bites. We report the case of a post-menopausal woman who presented with a broad ligament haematoma diagnosed two days after a viper bite which required blood transfusion and laparotomy. This rare possibility should be considered in the differential diagnosis of a woman presenting with a lower abdominal or pelvic mass, anaemia and a bleeding diathesis after a snake bite. PMID- 21327001 TI - Time to develop capacity to diagnose drug resistant tuberculosis. PMID- 21327002 TI - High Frequency of First-Line Anti-Tuberculosis Drug Resistance among Persons with Chronic Pulmonary Tuberculosis at a Teaching Hospital Chest Clinic. AB - INTRODUCTION: The burden of MDR-TB is unknown in areas that do not have drug susceptibility testing (DST), but its frequency is expected to be higher in previously treated cases. Where DST is not available the WHO recommended standardized retreatment (Category II) regimen is given to previously treated TB patients OBJECTIVE: To evaluate the frequency and pattern of drug resistance of Mycobacterium tuberculosis isolated from patients with chronic smear positive pulmonary tuberculosis. METHOD: We conducted a retrospective review of mycobacterial cultures and drug susceptibility testing (DST) performed on sputum samples collected, between January 2005 and September 2006, from 40 patients with pulmonary TB who had failed at least one standard retreatment regimen. Clinical data was extracted from patients' case notes. RESULTS: M. tuberculosis was recovered from 28 (70%) of the 40 patients. Of the 28 culture positive cases, 10 (36%) had resistance to at least rifampicin and isoniazid (multi-drug resistant TB), 22 (79%) isolates had resistance to streptomycin and 13 (46%) to ethambutol. Of the patients with a positive culture, only one (3.6%) had a fully susceptible organism. Of the 10 patients with MDR TB, 7 had received two or more retreatment courses. CONCLUSION: The frequency of drug resistant TB was high among patients who failed at least one course of category II therapy. Effective combination regimens based on DST is necessary in patients who remain smear positive on the standardized retreatment regimen. PMID- 21327003 TI - Reasons given by pregnant women for late initiation of antenatal care in the niger delta, Nigeria. AB - BACKGROUND: Many studies show that the vast majority of Nigerian women register for antenatal care late and that the determinants may differ from those found in developed countries. OBJECTIVE: To determine the reasons for late booking among women presenting at the antenatal clinic of a major tertiary hospital in the Niger Delta, Nigeria DESIGN: A cross sectional questionnaire based survey. SETTING: A large tertiary hospital in the Niger delta, Nigeria PARTICIPANTS: Pregnant women registering for antenatal care after 14 weeks gestation. RESULTS: The majority of respondents were aged 20-39 years (97.1%), quarters were primigravidae and 25 % of the women belonged to the upper socioeconomic class. Seventy three point six percent booked in the second trimester and 26.4% in the third trimester. Of the women who had given birth before, 80% had booked late in at least one previous pregnancy. More than three-fifth of the women (65.6%) booked late due to ignorance or misconceptions of the purpose of, and right time to commence antenatal care. CONCLUSION: The findings of this study suggest that most women book late because of a belief that there are no advantages in booking for antenatal care in the first three months of pregnancy. This seems to be because antenatal care is viewed primarily as curative rather than preventive in the study population. Research is needed to determine the best approaches for health education programmes to correct the misconceptions about antenatal care. PMID- 21327004 TI - Resistance-mediating polymorphisms of Plasmodium falciparum among isolates from children with severe malaria in kumasi, ghana. AB - BACKGROUND: Antimalarial drug resistance has been a major contributor to the failure of the battle against malaria in many developing countries. The P. falciparum genes, pfcrt and pfmdr-1, have been implicated in chloroquine resistance. The objective of this study was to determine the presence of mutant alleles of these chloroquine resistance genes among isolates of P. falciparum from children presenting with severe malaria in Ghana. METHODS: Venous blood samples were taken from patients, and plasma chloroquine levels measured. P. falciparum chromosomal DNA was isolated from the blood samples, and subjected to PCR, restriction digestion and sequencing. Resulting data were analysed using the STATA statistical software. RESULTS: Of 140 children recruited into the study, 109 (77.9%) had detectable pre-treatment chloroquine levels. PCR and restriction digestion analysis of the pfcrt gene indicated that 124 (88.6%) had the mutant T76 gene, and that this correlated with higher chloroquine levels. Sequence analysis of these showed consistent genetic sequences for chloroquine resistant and sensitive parasites with respect to Pfcrt codons 72 through 76.The Pfcrt T76 mutation was found in 88.4% of isolates having the Pfmdr-1Y86 mutation. The Pfmdr 1 Y86 mutation was found in 67.6% of isolates having the Pfcrt T76 mutation. CONCLUSION: The study affirms Pfcrt as a better chloroquine resistance marker. Both mutations are independently selected by chloroquine levels and that one mutation (Y86) might modify/increase the effect of the other (T76). This study also depicts the much-overlooked antimalarial drug resistance situation in the area and emphasizes the need for a proper treatment strategy. PMID- 21327005 TI - Clinic visits and cervical cancer screening in accra. AB - OBJECTIVE: To determine the factors that increase the chances of a woman in Accra having a Pap smear and whether women who have recently visited clinics have higher chances of having had Pap smears. DESIGN: A cross-sectional study METHODS: A representative sample of women in Accra, Ghana was interviewed and the clinical and demographic factors influencing cervical cancer screening was assessed. RESULTS: Out of 1193 women with complete data, only 25 (2.1%) had ever had a Pap smear performed though 171 (14.3%) had their last outpatient clinic visit for either a gynaecological consultation or a regular check up. Simple logistic regression showed that a high educational level, high socioeconomic status and a history over the past month of postmenopausal or intermenstrual bleeding significantly increased the odds of ever having a pap smear. Neither monthly income nor last clinic visit for a gynaecological consultation or regular check up increased the odds of having a pap smear. Multiple logistic regression showed that a high educational level and experiencing postmenopausal or intermenstrual bleeding were the most important determinants of ever having a Pap smear. CONCLUSION: While we wait for a national program for cervical cancer screening, there is a need for clinicians to put more individual effort into ensuring that asymptomatic women are screened for cervical cancer. PMID- 21327006 TI - Body Mass Index, Weight Gain during Pregnancy and Obstetric Outcomes. AB - OBJECTIVES: To find out the effects of pregnancy weight gain in different body mass index (BMI) groups on maternal and neonatal outcomes in women delivering singletons at term. DESIGN: Retrospective analysis of clinical records of patients attending antenatal clinics and delivering in hospital from January 1st 1992 to December 31st 2009. SETTING: A private specialist hospital. METHODS: The records of patients starting antenatal care in the first trimester, attending at least four clinics and delivering singletons from 37 completed weeks up to 42 weeks gestation were analysed. Patients' booking gestational age, height, weight and obstetric and neonatal outcomes at delivery were noted. RESULTS: The total number of deliveries was 2,391 out of which 1755 (72.4%) were analysed. The overweight and obese group compared to the normal were significantly older, shorter, weighed more at booking and gained more weight during pregnancy. The overweight or obese were significantly more likely to have induction of labour and be delivered by caesarean section compared to the normal. Maternal and neonatal outcomes which were more significant in the overweight and obese were macrosomia, stillbirth, perineal trauma, post-partum haemorrhage and retained placenta. CONCLUSIONS: Most deliveries in the two BMI groups resulted in normal weight babies. Overweight and Obesity is associated with significantly increased incidence of adverse maternal and neonatal outcomes. It is recommended that further studies involving larger samples comparable to those done in western countries are carried out. PMID- 21327007 TI - Is routine human papillomavirus vaccination an option for ghana? AB - Cervical cancer remains an important public health problem in developing countries where over 80% of the global burden occurs annually but screening has been ineffective. In a polygamous country like Ghana with a high incidence of cervical cancer but no national screening program, the Human Papilloma Virus (HPV) vaccine presents a unique opportunity to reduce the burden of HPV infection and cervical cancer in Ghanaian women. The evidence so far indicates that the vaccines are safe and efficacious. Although routine HPV vaccination of girls raises several religious, political, socioeconomic and ethical challenges, the emphasis of this paper will be on addressing the ethical challenges using the principles of autonomy, beneficence, non-maleficence and justice as a framework. Parental autonomy can be preserved with judicious exemptions for those who decline the vaccine on religious and philosophical grounds. This promotes public health without trampling parental authority. Routine HPV vaccination confers several benefits to individuals and society by preventing HPV infection. Instead of causing harm; it reduces harm by preventing the development of about 70% of cervical cancers and removing the negative physical and psychological impact of a cervical cancer diagnosis. It also has the potential to reduce the disparities in cervical cancer rates and its cost effectiveness will ensure considerable cost savings in terms of the money spent on diagnosis and treatment. Consequently, the HPV vaccine is an important public health landmark and achievement in women's health that must be heralded, especially in developing countries where the bulk of the disease and death occur. PMID- 21327008 TI - Congenital malaria in newborn twins. AB - Malaria during first few months of life may be due to transplacental transfer of parasitized maternal erythrocytes. The most common clinical features of congenital malaria are fever, anaemia and splenomegaly. Other signs and symptoms include hepatosplenomegaly, jaundice, regurgitation, loose stools, and poor feeding. A 28 year old woman (G2P1A), with 36 weeks gestation, reported to a health facility in Sunyani on 22(nd) February 2009 with history of labour pains, without fever. According to the mother, even though she did not sleep in insecticide treated bed net during her pregnancy, she took all the recommended drugs of sulfadoxine/ pyrimethamine-intermittent preventive treatment for malaria. She delivered twins on the same day. The mother and the twins developed fever on the same day. A laboratory investigation on the three of them was positive for malaria parasites. The three were successfully treated with quinine. Congenital malaria is real and it is therefore recommended that babies born to mothers with malaria should be screened for congenital malaria. PMID- 21327009 TI - Non-puerperal uterine inversion: a case report. AB - Non-puerperal uterine inversion is rare. A 42-year old woman presented with lower abdominal pain, offensive vaginal discharge and a huge protruding mass per vaginum. A clinical diagnosis of non-puerperal uterine inversion was made and she successfully underwent vaginal hysterectomy. A high index of suspicion is required to make a prompt diagnosis. PMID- 21327010 TI - Cost of health care delivery in ghana. PMID- 21327011 TI - Estimating the cost of healthcare delivery in three hospitals in southern ghana. AB - OBJECTIVE: The cost burden (called full cost) of providing health services at a referral, a district and a mission hospital in Ghana were determined. METHODS: Standard cost-finding and cost analysis tools recommended by World Health Organization are used to analyse 2002 and 2003 hospital data. Full cost centre costs were computed by taking into account cash and non-cash expenses and allocating overhead costs to intermediate and final patient care centres. FINDINGS: The full costs of running the mission hospital in 2002 and 2003 were US$600,295 and US$758,647 respectively; for the district hospital, the respective costs were US$496,240 and US$487,537; and for the referral hospital, the respective costs were US$1,160,535 and US$1,394,321. Of these, overhead costs ranged between 20% and 42%, while salaries made up between 45% and 60%. Based on healthcare utilization data, in 2003 the estimated cost per outpatient attendance was US$ 2.25 at the mission hospital, US$ 4.51 at the district hospital and US$8.5 at the referral hospital; inpatient day costs were US$ 6.05, US$ 9.95 and US$18.8 at the respective hospitals. User fees charged at service delivery points were generally below cost. However, some service delivery points have the potential to recover their costs. CONCLUSION: Salaries are the major cost component of the three hospitals. Overhead costs constitute an important part of hospital costs and must be noted in efforts to recover costs. Cost structures are different at different types of hospitals. Unit costs at service delivery points can be estimated and projected into the future. PMID- 21327012 TI - Case control study to determine the factors associated with leprosy in the sene district, brong ahafo region of ghana. AB - INTRODUCTION: There are currently an estimated 10-12 million cases of leprosy in the world. In Sene District of the Brong Ahafo Region of Ghana the prevalence of leprosy is 2.4/10,000 of the population. Most of these cases are children, indicating that new infections are still occurring in the communities. OBJECTIVES: To identify factors associated with leprosy in the Sene District in order to implement an effective strategy to eliminate leprosy from the district. DESIGN: Case-control study. METHOD: The cases were selected from a register of active leprosy cases. Controls were matched for age, and sex. For every one case identified two controls were selected. RESULTS: Of the twenty four cases identified, eighteen (75%) were paucibacillary and six (25%) were multibacillary leprosy. Most of the leprosy lesions were found on the trunk (25%) and upper limbs (37.5%). 13(54.2%) of the cases were under twenty years old. From the study, contact with someone with leprosy in the same house is associated with having leprosy. (OR -3.4 95%CI 1.09-10.8 p=0.017). Not having BCG vaccination is associated with having leprosy (OR 11 95%CI 2.12-76.17)p=0.0005). CONCLUSION: The findings confirm that close contact with a patient with leprosy facilitates transmission of M. leprae. To reduce leprosy in the Sene District there is the need to increase BCG vaccination coverage in children and ensure that all contacts of cases are thoroughly screened for the disease and treated. Health workers in the district need to be trained to identify leprosy lesions. PMID- 21327013 TI - A two-year review of uterine rupture in a regional hospital. AB - BACKGROUND: Uterine rupture causes high maternal and neonatal mortality in many rural setting in the world. Further studies might provide specific interventions to reduce the high prevalence. OBJECTIVE: To determine the frequency, causes, clinical presentation, management and outcome of uterine rupture SETTING: Department of Obstetrics and Gynaecology, Upper West Regional Hospital, Wa, Ghana. DESIGN: Retrospective descriptive study. METHOD: A descriptive study of cases of ruptured uterus in the Regional Hospital from 1st January, 2007 to 31st December 2008 was done. A structured questionnaire was developed to collate data from various registers for analysis. RESULTS: Total deliveries were 5085 with 4172(82%) spontaneous vaginal delivery and 911(17.9%) caesarean sections. Uterine rupture occurred in 41 cases for a ratio of 1:124 Grand multipara with five or more deliveries represented 41.5% while those with two prior successful deliveries represented 31.7%. The mean parity was 3.8 (SD 2.3) under antenatal care, 85.4% had at least four visits. Severe anaemia 28(68.3%) and abdominal tenderness 27(65.8%) were the most frequent clinical presentation while the use of local herbal concoction with suspected uterotonic activity 24(58.5%), fetopelvic disproportion 4 (9.8%) and malpresentation 5(12.1%) were the most significant causes. Major complications were: neonatal deaths 34(82.9%), maternal mortality 4(9.8%) and wound infections 15 (36.6%). Subtotal hysterectomy 10(24.4%) and total hysterectomy 18(43.8%) were preferred to uterine repair 12(23.3%) and 87.8% required at least two units of blood transfusion. CONCLUSION: skilled attendance with accessible emergency obstetric care and focused antenatal care are key elements for the prevention and management of uterine rupture. PMID- 21327014 TI - Penetrating abdominal injuries in adults seen at two teaching hospitals in ghana. AB - BACKGROUND: The incidence of penetrating abdominal injuries (PAI) has increased in the West African sub-region. OBJECTIVE: To determine the pattern and management outcome of penetrating abdominal injuries (PAI) in the two main teaching hospitals in Ghana. STUDY DESIGN: A prospective and retrospective descriptive study. SETTING: Komfo Anokye Teaching Hospital (KATH), Kumasi and Korle-Bu Teaching Hospital (KBTH), Accra. METHODS: Relevant details of all adult patients admitted with penetrating abdominal injuries over a 11-year period were recorded at KATH and KBTH in Accra. The study in KATH was prospective pro forma based and that in the KBTH was a retrospective case review of all penetrating abdominal injuries. RESULTS: There were 411 patients, mostly men (M: F-8:1). The peak age of patients was 20-29 years, 164 patients (39.9%). Abdominal stab wound injuries accounted for 251 (61.1%). Three hundred and thirty - one patients (80.5%) had an emergency laparotomy. Twelve patients required 16 emergency thoracotomies. The small bowel (23.2%), stomach (12.9%), colon (10.2%), the liver (10.0%), were the most commonly injured organs. In 92 patients (29.0%) no significant intra-abdominal injury was detected at laparotomy CONCLUSION: Stab wounds are the main penetrating abdominal injuries seen mostly among young male adults in Ghana. Management was by a mandatory laparotomy after clinical assessment. The overall mortality was 4.4%. Selective non-operative management of abdominal stab wounds is possible. PMID- 21327015 TI - Permanent complete heart block following surgical correction of congenital heart disease. AB - BACKGROUND: The risk of complete heart block (CHB) from congenital heart repairs in Ghana is unknown. This information is important for referring physicians and in pre-operative counselling of patients and facilitates the process of obtaining informed consent for such repairs. OBJECTIVES: This study was undertaken to determine the incidence of permanent post-operative CHB requiring pacemaker implantation; and the post-operative problems related to the pacemaker. DESIGN: Retrospective study design. SETTING: The National Cardiothoracic Centre (NCTC), Korle-Bu Teaching Hospital, Accra, Ghana. METHOD: Review of all patients who had intra-cardiac repair of congenital heart disease known to predispose to post operative complete heart block from January 1993 to December 2008 was carried out with computation of the frequency of complete heart block according to the intra operative diagnoses. RESULTS: Six out of 242 patients (2.5%) developed permanent post-operative CHB. All underwent closure of a large perimembranous ventricular septal defect (VSD) either as an isolated defect (2 of 151 or 1.3%) or in the setting of conotruncal anomalies (4 of 73 or 5.5%). The dominant parental concern relating to the implanted device was the financial implications of future multiple surgeries to replace a depleted pulse generator. CONCLUSION: Permanent post-operative complete heart block occurred in 1.3% of patients undergoing VSD repair and 5.5% of those undergoing repair of conotruncal anomalies (Fallot's tetralogy). The dominant anatomic risk factor was a large perimembranous VSD as an isolated defect or as part of a conotruncal anomaly. Permanent pacemaker implantation in this setting is attended by a low morbidity. PMID- 21327016 TI - The zoonotic implications of pentastomiasis in the royal python (python regius). AB - Pentastomes are worm-like endoparasites of the phylum Pentastomida found principally in the respiratory tract of reptiles, birds, and mammals. They cause a zoonotic disease known as pentastomiasis in humans and other mammals. The autopsy of a Nigerian royal python (Python regius) revealed two yellowish-white parasites in the lungs, tissue necrosis and inflammatory lesions. The parasite was confirmed to be Armillifer spp (Pentastomid); this is the first recorded case of pentastomiasis in the royal python (Python regius) in Nigeria. This report may be an alert of the possibility of on-going zoonotic transmission of pentastomiasis from snake to man, especially in the sub-urban/rural areas of Nigeria and other West African countries where people consume snake meat. PMID- 21327017 TI - Early surgical repair of penile fractures. AB - OBJECTIVES: To present our experience with diagnosis and surgical management of penile fracture PATIENTS AND METHODS: We present six cases of penile fracture managed at our unit between 2003 and 2008. The diagnosis was based on clinical presentation and physical examination. The treatment was surgical in all cases with Subcoronal circumferential degloving incision, evacuation of hematoma and reconstruction of the rupture with absorbable suture. RESULTS: The clinical diagnosis of penile fracture was accurate in all six cases. All patients had a successful outcome, with preservation of erectile function CONCLUSION: Penile fracture is a clinical diagnosis and immediate surgical repair offers complete recovery of sexual function. PMID- 21327018 TI - A case report of intracranial vertebral-basilar artery hypoplasia presenting with episodic dizziness. AB - Basilar artery hypoplasia (BAH) is usually accompanied with unilateral vertebral artery hypoplasia (VAH); however, BAH with bilateral VAHs composing vertebral basilar artery hypoplasia (VBAH) is indeed a rare curiosity. A 61-year-old woman presented with episodic dizziness for ten years. It accompanied with headache, bilateral tinnitus and blurred vision. Time-of-flight magnetic resonance angiogram with T2 true fast imaging in steady state precession confirmed the VBAH, rather than a stenosis. Symptoms subsided after daily oral aspirin and life style change has been recommended for three months. The following one year was uneventful, and hearing improved. Finally, we conclude that the episodic dizziness with sensori-neural hearing impairment might attribute to the VBAH. It appears that life-style change was the main therapy and the antiplatelet was simply a supplementary one. PMID- 21327019 TI - What is black and white and a puzzle all over? PMID- 21327020 TI - CX3CR1 is critical for Salmonella-induced migration of dendritic cells into the intestinal lumen. PMID- 21327021 TI - Effects of a gluten-free diet on gut microbiota and immune function in healthy adult humans. AB - Diet is a major environmental factor influencing gut microbiota diversity and functionality, which might be relevant to subjects following dietary therapies. Celiac disease (CD) is an enteropathy caused by an aberrant immune response to cereal gluten proteins and the only therapy is the adherence to a gluten-free diet (GFD). In this context, a preliminary study was conducted to establish whether the GFD in itself could modify the composition and immune properties of the gut microbiota. The trial included 10 healthy subjects (30.3 years-old), which were submitted to a GFD over one month. Analysis of fecal microbiota and dietary intake indicated that numbers of healthy gut bacteria decreased, while numbers of unhealthy bacteria increased parallel to reductions in the intake of polysaccharides after following the GFD. Fecal samples of subjects under a GFD, which represent an altered microbiota, also exerted lower immune stimulatory effects on peripheral blood mononuclear cells than those of subjects on a regular gluten-containing diet. This addendum presents further discussion on the rationale behind these findings, limitations of the study and possible consequences of dietary counselling in the care process of celiac disease patients. PMID- 21327024 TI - Developmental biology of gut-probiotic interaction. AB - While our current knowledge of probiotic interaction in the developing gut remains poorly understood, emerging science is providing greater biological insight into their mechanism of action and therapeutic potential for human disease. Given their beneficial effects, probiotics remain promising agents in neonatal gastrointestinal disorders. Probiotics may restore or supply essential bacterial strains needed for gut maturation and homeostasis, particularly in hosts where this process has been disrupted. Here we highlight the unique characteristics of developing intestinal epithelia with a focus on gut development and colonization as well as the inflammatory propensity of immature epithelia. Additionally, we review potential mechanisms of beneficial probiotic interaction with immature intestinal epithelia including immunomodulation, upregulation of cytoprotective genes, prevention and regulation of apoptosis and maintenance of barrier function. Improved knowledge of gut-probiotic interaction in developing epithelia will allow for a better understanding of how probiotics exert their beneficial effects and help guide their therapeutic use. PMID- 21327026 TI - Eating in, eating out. PMID- 21327025 TI - Probiotics and ileitis: could augmentation of TNF/NFkappaB activity be the answer? AB - Probiotics have gained tremendous popularity amongst individuals searching for alternative and "natural" means to promote intestinal health. It has been suggested that the probiotic formulation VSL#3 promotes several aspects of intestinal health including attenuation of inflammatory bowel diseases (IBD). Although a definitive mechanism of action has not been clearly identified, it is generally accepted that probiotics suppress development of chronic inflammation by inhibiting activation of various inflammatory signaling pathways. This concept however needs to be revisited in light of a recent publication by Pagnini et al. showing that VSL#3 prevents development of ileitis through activation of NFkappaB and production of the prototypical inflammatory cytokine TNFalpha. PMID- 21327023 TI - Safety assessment of probiotics for human use. AB - The safety of probiotics is tied to their intended use, which includes consideration of potential vulnerability of the consumer or patient, dose and duration of consumption, and both the manner and frequency of administration. Unique to probiotics is that they are alive when administered, and unlike other food or drug ingredients, possess the potential for infectivity or in situ toxin production. Since numerous types of microbes are used as probiotics, safety is also intricately tied to the nature of the specific microbe being used. The presence of transferable antibiotic resistance genes, which comprises a theoretical risk of transfer to a less innocuous member of the gut microbial community, must also be considered. Genetic stability of the probiotic over time, deleterious metabolic activities, and the potential for pathogenicity or toxicogenicity must be assessed depending on the characteristics of the genus and species of the microbe being used. Immunological effects must be considered, especially in certain vulnerable populations, including infants with undeveloped immune function. A few reports about negative probiotic effects have surfaced, the significance of which would be better understood with more complete understanding of the mechanisms of probiotic interaction with the host and colonizing microbes. Use of readily available and low cost genomic sequencing technologies to assure the absence of genes of concern is advisable for candidate probiotic strains. The field of probiotic safety is characterized by the scarcity of studies specifically designed to assess safety contrasted with the long history of safe use of many of these microbes in foods. PMID- 21327027 TI - Proinflammatory fecal mRNA and childhood bacterial enteric infections. AB - INTRODUCTION: Assessment of specific mRNAs in human samples is useful in characterizing disease. However, mRNA in human stool has been understudied. RESULTS: Compared to controls, infected stools showed increased transcripts of IL 1beta, IL-8 and calprotectin. mRNA and protein concentrations correlated for IL 8, but not for calprotectin. DISCUSSION: Stool mRNA quantification offers a potentially useful, noninvasive way to assess inflammation in the gastrointestinal tract, and may be more sensitive than EIA. METHODS: We purified fecal RNA from 46 children infected with Campylobacter jejuni, Escherichia coli O157:H7, Salmonella spp. or Shigella sonnei and 26 controls and compared the proportions of IL-1beta, IL-8, osteoprotegerin and calprotectin mRNA between groups using qRT-PCR. We determined the concentrations of calprotectin, IL-8 and osteoprotegerin by enzyme immunoassays in cognate specimens. PMID- 21327028 TI - The role of the immune system in regulating the microbiota. AB - A diverse population of bacteria, archaea and fungi, collectively known as the microbiota, abounds within the gastrointestinal tract of the mammalian host. This microbial population makes many important contributions to host physiology through inter-kingdom signalling and by providing nutrients that have both local and systemic effects. In a healthy state the overall host-microbial interaction is symbiotic; however, a growing number of diseases have been associated with a dysregulated microbiota. To avoid these consequences, the host exerts substantial effort to maintain proper regulation of the microbiota with respect to localization and composition. Although important to maintaining microbial balance, the host immune response can also be the cause of a disrupted microbiota, contributing to disease severity. Here, we discuss the role of the host in both maintaining and disrupting a balanced gastrointestinal microbiota. PMID- 21327029 TI - Immune responses to gut microbiota-commensals and pathogens. AB - The mammalian alimentary tract harbors hundreds of species of commensal microorganisms that intimately interact with the host immune system. Within the gut, the immune system actively reacts with potentially pathogenic microbes, while simultaneously remaining ignorant towards the vast majority of non pathogenic microbiota. The disruption of this delicate balance results in inflammatory bowel diseases. In this review, we describe the recent advances in our understanding of how host-microbiota interactions shape the immune system and how they affect the responses against pathogenic bacteria. PMID- 21327030 TI - Clostridium difficile infection: An overview of the disease and its pathogenesis, epidemiology and interventions. AB - Clostridium difficile infection (CDI) is the primary cause of antibiotic associated diarrhea and is a significant nosocomial disease. In the past ten years, variant toxin-producing strains of C. difficile have emerged, that have been associated with severe disease as well as outbreaks worldwide. This review summarizes current information on C. difficile pathogenesis and disease, and highlights interventions used to combat single and recurrent episodes of CDI. PMID- 21327031 TI - Guide to designing, conducting, publishing and communicating results of clinical studies involving probiotic applications in human participants. AB - The heterogeneity of human clinical trials to assess the effectiveness of probiotics presents challenges regarding interpretation and comparison. Evidence obtained from clinical trials among a population with a disease or specific risk factors may not be generalizable to healthy individuals. The evaluation of interventions in healthy persons requires careful selection of outcomes due to the absence of health indicators and the low incidence of preventable conditions. Given the tremendous resources invested in such trials, development of consistent approaches to assessing the effectiveness of probiotics would be beneficial. Furthermore, the reporting, presentation and communication of results may also affect the validity of the scientific evidence obtained from a trial. This review outlines the challenges associated with the design, implementation, data analysis and interpretation of clinical trials in humans involving probiotics. Best practices related to their design are offered along with recommendations for enhanced collaboration to advance research in this emerging field. PMID- 21327033 TI - In-depth genetic analysis of Clostridium difficile PCR-ribotype 027 strains reveals high genome fluidity including point mutations and inversions. AB - Previously, we demonstrated that the recently evolved PCR-ribotype 027 hypervirulent Clostridium difficile strain (R20291) has acquired five genetic regions compared to the historic 027 counterpart strain (CD196), that may in part explain phenotypic traits relating to survival, antimicrobial resistance and virulence. Closer scrutiny of the three genome sequences reveals that, in addition to gene gain/loss, point mutations and inversions appear to have accumulated. Inversions are located upstream of potential coding sequences and could affect expression of these. C. difficile has a highly fluid genome with multiple mechanisms to modify its genetic content and is continuing to evolve in our hospitals influenced by environmental changes and human activity. PMID- 21327032 TI - Mucin-bacterial interactions in the human oral cavity and digestive tract. AB - Mucins are a family of heavily glycosylated proteins that are the major organic components of the mucus layer, the protective layer covering the epithelial cells in many human and animal organs, including the entire gastro-intestinal tract. Microbes that can associate with mucins benefit from this interaction since they can get available nutrients, experience physico-chemical protection and adhere, resulting in increased residence time. Mucin-degrading microorganisms, which often are found in consortia, have not been extensively characterized as mucins are high molecular weight glycoproteins that are hard to study because of their size, complexity and heterogeneity. The purpose of this review is to discuss how advances in mucus and mucin research, and insight in the microbial ecology promoted our understanding of mucin degradation. Recent insight is presented in mucin structure and organization, the microorganisms known to use mucin as growth substrate, with a specific attention on Akkermansia muciniphila, and the molecular basis of microbial mucin degradation owing to availability of genome sequences. PMID- 21327034 TI - Evaluating the latest high-throughput molecular techniques for the exploration of microbial gut communities. AB - The human gut microbiota has become the subject of an increasing amount of attention, due to an emerging understanding of its role in maintaining health throughout our lives. Since only a small proportion of the gut bacteria can be quantified using traditional plate culturing methods, culture-independent approaches are required for determining the structure of complex microbial communities. To avoid cloning bias and low phylotype coverage that affects amplicon cloning and sequencing strategies, high-throughput methods such as phylogenetic arrays and massively parallel sequencing are now being used to find more than just the most abundant taxa, at significantly lower costs and higher speeds. The target for these methods is the 16S ribosomal RNA gene that is present in all prokaryotes. Since the gene is too long to be sequenced using high throughput methods, regions of high variability (from V1-V9) are selected for amplification and either direct sequencing, or hybridization against phylogenetic microarrays. In our recent study,1 we compared sequencing of amplified V4 and V6 regions using 454 FLX Pyrosequencing2 with the HITChip, an oligonucleotide microarray for taxonomic profiling of human intestinal tract communities based on concatenations of known V1 and V6 regions.3 We found good correlations between the phylogenetic classifications stemming from the two technologies, especially at lower-order ranks (phylum, class, order, and to a lesser extent, family), which indicates high robustness of both approaches. However, the V6 regions proved to be much less suitable for taxonomic classification than the V4 region, probably due to this region simply being too variable. Although this study was, to our knowledge, the deepest sequencing of single gastrointestinal samples reported to date, the microbial richness levels had still not leveled out, with up to 1,800 unique phylotypes detected in one community. Encouragingly for studies with lower sequencing coverage per sample, we also noticed that a fifth of the sequencing depth (40,000 as opposed to 200,000 reads) was sufficient for capturing a majority of microbial diversity within a sample. PMID- 21327035 TI - The DamX protein of Escherichia coli and Salmonella enterica. AB - We recently showed that disruption of damX causes bile sensitivity in Salmonella enterica. The damX gene is part of an operon that contains genes with heterogeneous functions: DNA adenine methylation, biosynthesis of aromatic compounds, carbohydrate metabolism, and tRNA charging. The damX gene encodes a protein with a predicted size of 46 kDa. In Salmonella, DamX is found in the inner membrane of both dividing and non-dividing cells. The DamX protein contains a peptidoglycan-binding SPOR domain, and accumulates in the E. coli septal ring. E. coli mutants lacking DamX are bile-sensitive like their Salmonella counterparts. PMID- 21327036 TI - Tossed salads. PMID- 21327037 TI - How can probiotics and prebiotics impact mucosal immunity? AB - The study of probiotics and prebiotics is an expanding field of interest and scientific research that has resulted in insights related to the host immune response. Recent advances have naturally led to key questions. What are the specific probiotic components that mediate immunomodulation? Can we extrapolate the results of in vitro studies in animal and human trials? Which biomarkers and immune parameters should be measured in probiotic and prebiotic intervention studies? These questions were part of a discussion entitled "How Can Probiotics and Prebiotics Impact Mucosal Immunity" at the 2009 Annual Meeting of the International Scientific Association for Probiotics and Prebiotics (ISAPP). This review highlights recent knowledge about the modulation of mucosal immunity by probiotics and prebiotics, as well as considerations for measuring their effects on mucosal immunity. A list of biomarkers and immune parameters to be measured in human clinical trials is included. PMID- 21327038 TI - The interaction of gut microbes with host ABC transporters. AB - ATP binding cassette (ABC) transporters are increasingly recognized for their ability to modulate the absorption, distribution, metabolism, secretion and toxicity of xenobiotics. In addition to their essential function in drug resistance, there is also emerging evidence documenting the important role ABC transporters play in tissue defense. In this respect, the gastrointestinal tract represents a critical vanguard of defense against oral exposure of drugs while at the same time functions as a physical barrier between the lumenal contents (including bacteria) and the intestinal epithelium. Given emerging evidence suggesting that multidrug resistance protein (MDR) plays an important role in host-bacterial interactions in the gastrointestinal tract, this review will discuss the interplay between MDR of the intestinal epithelial cell barrier and gut microbes in health and disease. In particular, we will explore host-microbe interactions involving three apically restricted ABC transporters of the intestinal epithelium; P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2) and cystic fibrosis transmembrane regulator (CFTR). PMID- 21327039 TI - 'Nodophagy': New crossroads in Crohn disease pathogenesis. AB - Autophagy is a homeostatic pathway that processes and recycles damaged organelles and other cytoplasmic contents. While studies have implicated autophagy in the immune response to infection, the understanding of how the autophagic machinery specifically targets intracellular pathogens has remained elusive. Two recent studies have uncovered an autophagy-mediated immune response to bacteria through their detection by Nod receptors. In particular, Nod1 and Nod2 recruit the autophagic protein ATG16L1 to the plasma membrane at the bacterial entry site to promote an autophagy-dependent elimination of bacteria. In addition, Nod2 and ATG16L1 synergize to initiate an adaptive immune response to bacterial invasion by enhancing major histocompatibility complex (MHC) class II antigen presentation. These findings link two Crohn disease-associated susceptibility genes and reveal that cells expressing the risk-associated variants of ATG16L1 are defective in autophagy-mediated bacterial handling and antigen presentation. This could lead to bacterial persistence and contribute to the pathogenesis of the disease. PMID- 21327040 TI - Enteric pathogens and gut function: Role of cytokines and STATs. AB - The gut harbors the largest immune system in the body. The mucosa is considered to be the initial site of interaction with commensal and pathogenic organisms; therefore, it is the first line of defense against the pathogens. In response to the invasion of various pathogens, naive CD4(+) cells differentiate into subsets of T helper (Th) cells that are characterized by different cytokine profiles. Cytokines bind to cell surface receptors on both immune and non-immune cells leading to activation of JAK-STAT signaling pathway and influence gut function by upregulating the expression of specific target genes. This review considers the roles of cytokines and receptor-mediated activation of STATs on pathogen-induced changes in gut function. The focus on STAT4 and STAT6 is because of their requirement for the full development of Th1 and Th2 cytokine profiles. PMID- 21327041 TI - Helicobacter pylori directs tolerogenic programming of dendritic cells. AB - Our laboratory has shown that Helicobacter pylori infection in mice triggers an increase in the number of subepithelial lamina propria CD11c(+) dendritic cells with luminal projections. The physical characteristic of these cells is consistent with their ability to traverse epithelial tight junctions as reported by Maria Recigno.3 Gastric CD103(+) dendritic cells, which are known to induce mucosal regulatory T cells, were also increased in number, raising the question whether H. pylori infection induces a regulatory T cell-skewed response by way of a bacteria-dendritic cell interaction. In fact, bone marrow-derived dendritic cells underwent tolerogenic programming, skewing the balance between effector and regulatory T cell responses towards regulatory T cell differentiation in a transforming growth factor-beta- and interleukin-10-dependent manner. Depletion of regulatory T cell numbers augmented H. pylori-specific effector helper T cell responses, which correlated with a lower degree of H. pylori colonization. These results suggest H. pylori is capable of inducing a regulatory T cell-skewed response that limits the host's ability to eradicate the bacteria, allowing the H. pylori infection to persist. To better understand the mechanism of H. pylori tolerogenic programming we compared the differential expressions of 34 genes critical for dendritic cell function in bone marrow-derived dendritic cells pulsed with live H. pylori or other Gram-negative bacteria (e.g., Escherichia coli, Acinetobacter lwoffii). Our data imply that H. pylori targets the Toll-like receptor 2 pathway to induce a regulatory T cell-skewed response. In addition, we show that H. pylori-pulsed dendritic cells are capable of inducing the conversion of naive T cells to regulatory T cells. These observations are evidence of a unique tolerogenic program in dendritic cells that involves active editing of the immune response by H. pylori, favoring its persistence in the gastric mucosa. PMID- 21327042 TI - Structural insight into Helicobacter pylori DNA replication initiation. AB - While increasing knowledge is accumulating about the molecular mechanisms allowing the human pathogen Helicobacter pylori to survive and to subvert host defenses, much less is known about fundamental aspects of its biology, including DNA replication. We have studied the initiation step of chromosome replication of H. pylori and particularly the interaction between the initiator protein DnaA and its recently identified regulator HobA. This work has recently culminated in the determination of the crystal structure of the domains I and II of DnaA (DnaA(I II)) in complex with HobA. By combining the structure with a variety of biochemical experiments we show that a tetramer of HobA can accommodate up to four DnaA molecules organized in a particular conformation within the complex. Mutations of the HobA interface that impaired the binding with DnaA were designed and proved to be lethal once introduced into H. pylori. These features suggest that HobA provides a molecular scaffold onto which regular oligomers of DnaA can assemble. The HobA-promoted oligomerization of DnaA could have a determinant role in the formation of the open complex. We propose a speculative model of HobA dependent DnaA oligomerization leading to DNA unwinding. More generally, the parallel we draw with Escherichia coli DnaA and DiaA (HobA-like E. coli protein) will direct new studies that will contribute to the understanding of bacterial DNA replication. PMID- 21327043 TI - Probiotic manipulation of the gastrointestinal microbiota. AB - In a recent publication we examined whether high abundance of a probiotic species, Lactobacillus casei subsp. rhamnosus GG (LGG), impacted the overall composition of the gastrointestinal (GI) microbiota of six-month-old infants at high risk for asthma development. Profound GI microbiota restructuring and the establishment of significantly more even and putatively, functionally redundant consortia were characteristic of high LGG abundance. Here we discuss, in the context of more recently published data, support for the hypothesis that the beneficial effect of probiotic supplementation on human health lies in the formation of a stable and resilient gut ecosystem enriched for species that exert a concerted beneficial effect on the host immune system via direct and indirect mechanisms. PMID- 21327044 TI - Interaction of FkpA, a peptidyl-prolyl cis/trans isomerase with EspP autotransporter protein. AB - The serine protease autotransporters of Enterobacteriaceae (SPATEs) represent a large class of proteases with contributions to virulence. They are synthesized with a C-terminal domain that forms a beta-barrel pore in the outer membrane implicated in translocation of the N-terminal 'passenger' domain across the outer membrane. The most recent model for autotransporter secretion comprises entry to the periplasm via the Sec apparatus, followed by the insertion of the C-terminus into the outer membrane as a beta-barrel protein and accompanied by translocation of the passenger domain to the bacterial cell surface, all of this with the assistance of the Bam complex insertase/foldase and periplasmic chaperone proteins. We have recently observed direct involvement of periplasmic chaperones in the biogenesis of EspP, a prototypical autotransporter protein produced by Escherichia coli O157:H7. Using molecular and biophysical approaches we demonstrated for the first time, direct protein-protein interactions between the periplasmic SurA and DegP chaperones and either the EspP-beta or EspP passenger domains. Such chaperone interactions took place on conserved aromatic residues on the SPATE family. In this report, we now demonstrate direct binding of the periplasmic chaperone FkpA to the EspP passanger domain in Surface Plasmon Resonance experiments with relatively high affinity. We also provide evidence of interaction between the SurA and Skp chaperones with the Bam. These findings in conjunction with newly published data support the role of chaperones in preventing misfolding of AT passenger domains before translocation throughout the Bam complex. PMID- 21327045 TI - Long-term treatment of NZB mice with anti-CD4 results in wasting disease, lymphoid atrophy and chronic diarrhea. AB - In this paper, we have shown that long-term treatment of NZB mice with anti-CD4 antibody results in four major pathological effects: firstly the development of a severe wasting disease; secondly lymphoid atrophy of the thymus, spleen, mesenteric lymph node and Peyers patches (PP); thirdly, severe chronic ulcerative colitis and fourthly a neutrophilia with neutrophil infiltration in the spleen, liver and mesenteric lymph nodes. At the same time, mice subjected to anti-CD4 treatment showed a reduction in the microbial diversity in ileal walls and contents, as well as in colonic contents, together with overgrowth of E. coli in the intestinal lumen and wall. In addition, there was the appearance of large numbers of spiral shaped bacteria on the mucosal surface often associated with colonic ulceration. PMID- 21327046 TI - Why are levels of maternal microchimerism higher in type 1 diabetes pancreas? AB - Maternal microchimerism (MMc) results from transfer of maternal cells to the fetus in pregnancy. These cells have been shown to persist into adulthood in healthy individuals and an increased frequency of MMc has been associated with autoimmune disease. Female (presumed maternal) islet beta cells have recently been identified at higher levels in pancreas from a child with T1D compared to three controls. There was, however, no evidence that these cells were the targets of autoimmune attack. The aim of this study was to analyze well-characterized T1D pancreases encompassing a spectrum in age at diagnosis, and duration of diabetes, for the presence of maternal microchimerism compared to control pancreases.Pancreas samples were available from six males with T1D and four male controls. Fluorescent-labeled probes were used to detect X and Y chromosomes. At least 1,000 cells, usually 4,000-8,000 cells underwent confocal imaging for each pancreas. The frequency of MMc was higher in T1D pancreases (range 0.31-0.80%, mean 0.58%) than in controls (0.24-0.50%, mean 0.38%) (p = 0.05). Intriguingly, clusters of 2-3 MMc were occasionally found in the pancreases, particularly T1D pancreases, suggesting replication of these cells. Concomitant FISH and immunofluorescence staining for insulin or CD45 was performed to phenotype cells of maternal origin. Insulin positive and insulin negative MMc were identified indicating that MMc contribute to the exocrine and endocrine compartments. No CD45 positive MMc were observed. These data confirm the presence of maternal cells in human pancreas and support previous observations that levels of MMc are higher in T1D pancreas compared to controls. MMc do not appear to be immune effector cells and those that stain positive for insulin within intact islets in T1D tissue appear healthy with no evidence that they are the focus of immune attack. This study adds support to the hypothesis that maternal stem cells have the capacity to cross the placental barrier and differentiate into both endocrine and exocrine cells but more detailed characterization of MMc in the pancreas is required. PMID- 21327047 TI - Fetal microchimerism persists at high levels in c-kit stem cells in sensitized mothers. AB - We previously showed that fetal and maternal exposure to non-inherited maternal antigens (NIMA) during gestation and nursing resulted in lifelong tolerance to NIMA in some offspring. This NIMA-specific tolerance was mediated by regulatory T cells (Tregs) and was correlated with the level of multi-lineage maternal microchimerism (Mc) indicating a causative link between Mc and Treg development. To determine if transfer of fetal cells into mothers resulted in a similar tolerance to fetal cells, we used qPCR to detect rare fetal derived cells and a delayed type hypersensitivity (DTH) assay to detect fetal alloantigen-specific effector and regulatory T cells in mothers. We found that 5/8 B6 mothers of H2(b/d) offspring were sensitized to the alloantigens H2(d) and HY, indicating a dominance of alloantigen-specific effector T cells. Though these sensitized mothers did not have detectable fetal Mc (FMc) in any of the organs tested, they had very high levels of fetus-derived c-kit(+) stem cells in their bone marrow. The remaining 3/8 B6 mothers that were not sensitized to the fetal antigens had detectable FMc found mostly in heart, lungs and liver, and in 2/3, we could detect alloantigen-specific regulatory T cells. This data indicates that, as in NIMA-specific tolerance, tolerance in multiparous females to inherited paternal antigens (IPA) expressed by the fetus is associated with the presence of fetal Mc in differentiated cell subsets. Surprisingly, robust lin(-)c-kit(+) bone marrow cell fetal Mc can occur in sensitized mothers. This suggests a continuous source of allospecific priming, coupled with active elimination of mature IPA-expressing lin(+) cells by effector T cells of the maternal host. PMID- 21327048 TI - Cells from a vanished twin as a source of microchimerism 40 years later. AB - We report the case of a 40-year-old man diagnosed with a scleroderma-like disease. Clinical similarities with graft versus host disease prompted initial testing for chimerism employing fluorescence in situ hybridization (FISH). Female cells were observed within peripheral blood mononuclear cells from the patient.Because maternal cells have been detected in healthy immunologically competent adults and patients with autoimmune conditions, we hypothesized that these cells were of maternal origin. Contrary to our expectations, HLA-specific quantitative PCR (QPCR) ruled out maternal microchimerism. However, HLA-specific QPCR testing was positive for the paternal HLA haplotype that the patient did not inherit. We reasoned that the most likely origin of chimerism with non-inherited paternal HLA alleles was from an unrecognized "vanished" twin. The patient had never received a blood transfusion.This report suggests that cells from a vanished twin are a possible source of chimerism. The frequency of chimerism from this source is not yet known and whether the scleroderma-like disease observed in the patient is anecdotal or implies a potential association with autoimmune disease remains to be elucidated. PMID- 21327049 TI - Regulation of the earliest immune response to in utero hematopoietic cellular transplantation. AB - In Utero Hematopoietic Cellular Transplantation (IUHCT) is a promising intervention to treat a wide range of congenital disease. Through the presentation of donor cells to the immature immune system, mixed hematopoietic chimerism and donor-specific tolerance can be achieved. However, the failure of engraftment in prenatal recipients in which no immunodeficiency exists suggests the existence of a fetal immune barrier to transplantation. Although the possible barriers include effectors of the adaptive and innate immune system, our recent findings and ongoing investigations indicate that the barrier most likely resides in the developing NK cells. A chimerism level above a certain threshold during NK cell development is necessary to overcome rejection. Clinically, this transplantation barrier might also exist in early human fetal NK cells. Understanding the fetal immune barrier to allotransplantation is essential in advancing clinical application of IUHCT. Herein, we provide a short summary and new evidence for the earliest immune response to prenatal transplantation. PMID- 21327050 TI - Stable mixed double donor chimerism: Absence of war doesn't necessarily mean peace. AB - Double cord blood transplantation has successfully been introduced to remedy the obstacle of a limited stem cell dose in a single cord blood graft. After a short initial period, the sustained hematopoiesis is derived almost exclusively from one of the donated units. In a recent publication in Clinical and Experimental Immunology we investigated two rare individuals in which both cord blood units co existed for more than two years after transplantation. PMID- 21327051 TI - Migration of microchimeric fetal cells into maternal circulation before placenta formation. AB - Fetal cell microchimerism is defined as the persistence of pluripotent fetal cells in the maternal body long after delivery. The exact process by which fetal cells cross the placental barrier and enter maternal circulation is still being investigated. We reported that fetal cells persist only in the maternal bone marrow and may give rise to subpopulations with the ability to differentiate into the tissue-specific mature cells within injured maternal organs. Moreover, most of the fetal cells enter the maternal circulation during the early stages of pregnancy. These results indicate that the fetal cells with a multilineage potential, which were detected in a variety of maternal organs during pregnancy did not pass through the placental barrier; rather, they were derived from the fetal cells that entered maternal circulation early after implantation, and sustained their population long after delivery. PMID- 21327052 TI - Novel diagnostics in renal transplantation. AB - Renal transplantation is the treatment of choice for many patients with end stage renal disease. While significant progress has been achieved in short-term outcomes, long-term graft survival has only marginally improved. More than 50% of transplanted kidneys from deceased donors fail within ten years; and from living donors, within 12 years. A lack of clinical tools to accurately monitor the allograft is a major causative factor in this lack of progress. This paper discusses newly available methods used to assess allograft status with emphasis on the role of circulating chimerism in renal transplantation as a diagnostic indicator for rejection and injury. PMID- 21327053 TI - The story of Mycoplasma mycoides JCVI-syn1.0: the forty million dollar microbe. PMID- 21327054 TI - Biologic TNFalpha-inhibitors that cross the human blood-brain barrier. AB - Tumor necrosis factor (TNF)alpha inhibitors (TNFI) are a major class of biologic therapeutics, and include decoy receptor and monoclonal antibody (MAb) therapeutics that block TNFalpha action. TNFalpha is a pro-inflammatory cytokine in brain disease, such as stroke, brain or spinal cord injury, or Alzheimer disease. However, the biologic TNFIs cannot be developed for the brain, because these large molecules do not cross the blood-brain barrier (BBB). Brain penetrating forms of TNFalpha decoy receptors or anti-TNFalpha antibody therapeutics can be re-engineered as IgG fusion proteins with a BBB molecular Trojan horse, such as the mAb against the human insulin receptor (HIR). The HIRMAb undergoes receptor-mediated transport across the BBB via the endogenous insulin receptor, and carries into brain the fused biologic TNFI. A fusion protein of the HIRMAb and the type II TNF receptor (TNFR) extracellular domain, designated the HIRMAb-TNFR fusion protein, has been engineered and expressed in stably transfected Chinese hamster ovary (CHO) cells. The HIRMAb-TNFR fusion protein binds both the HIR and TNFalpha with low nM affinity. The HIRMAb cross reacts with the Rhesus monkey insulin receptor, and the HIRMAb-TNFR is rapidly, and selectively, taken up by primate brain at concentrations that inhibit TNFalpha. In addition, a fusion protein of the HIRMAb and a therapeutic single chain Fv (ScFv) antibody has been engineered and also expressed in stably transfected CHO cells. The BBB molecular Trojan horse platform technology allows for the engineering of brain-penetrating recombinant proteins as new biologic therapeutics for the human brain. PMID- 21327055 TI - Live, attenuated strains of Listeria and Salmonella as vaccine vectors in cancer treatment. AB - Live, attenuated strains of many bacteria that synthesize and secrete foreign antigens are being developed as vaccines for a number of infectious diseases and cancer. Bacterial-based vaccines provide a number of advantages over other antigen delivery strategies including low cost of production, the absence of animal products, genetic stability and safety. In addition, bacterial vaccines delivering a tumor-associated antigen (TAA) stimulate innate immunity and also activate both arms of the adaptive immune system by which they exert efficacious anti-tumor effects. Listeria monocytogenes and several strains of Salmonella have been most extensively studied for this purpose. A number of attenuated strains have been generated and used to deliver antigens associated with infectious diseases and cancer. Although both bacteria are intracellular, the immune responses invoked by Listeria and Salmonella are different due to their sub cellular locations. Upon entering antigen-presenting cells by phagocytosis, Listeria is capable of escaping from the phagosomal compartment and thus has direct access to the cell cytosol. Proteins delivered by this vector behave as endogenous antigens, are presented on the cell surface in the context of MHC class I molecules, and generate strong cell-mediated immune responses. In contrast, proteins delivered by Salmonella, which lacks a phagosomal escape mechanism, are treated as exogenous antigens and presented by MHC class II molecules resulting predominantly in Th2 type immune responses. This fundamental disparity between the life cycles of the two vectors accounts for their differential application as antigen delivery vehicles. The present paper includes a review of the most recent advances in the development of these two bacterial vectors for treatment of cancer. Similarities and differences between the two vectors are discussed. PMID- 21327056 TI - Exploitation of prokaryotic expression systems based on the salicylate-dependent control circuit encompassing nahR/P(sal)::xylS2 for biotechnological applications. AB - Expression vectors appear to be an indispensable tool for both biological studies and biotechnological applications. Controlling gene overexpression becomes a critical issue when protein production is desired. In addition to several aspects regarding toxicity or plasmid instability, tight control of gene expression is an essential factor in biotechnological processes. Thus, the search for better controlled circuits is an important issue among biotechnologists. Traditionally, expression systems involve a single regulatory protein operating over a target promoter. However, these circuits are limited on their induction ratios (e.g., by their restriction in the maximal expression capacity, by their leakiness under non-induced conditions). Due to these limitations, regulatory cascades, which are far more efficient, are necessary for biotechnological applications. Thus, regulatory circuits with two modules operating in cascade offer a significant advantage. In this review, we describe the regulatory cascade based on two salicylate-responsive transcriptional regulators of Pseudomonas putida (nahR/P(sal)::xylS2), its properties, and contribution to a tighter control over heterologous gene expression in different applications.Nowadays, heterologous expression has been proven to be an indispensable tool for tackling basic biological questions, as well as for developing biotechnological applications. As the nature of the protein of interest becomes more complex, biotechnologists find that a tight control of gene expression is a key factor which conditions the success of the downstream purification process, as well as the interpretation of the results in other type of studies. Fortunately, different expression systems can be found in the market, each of them with their own pros and cons. In this review we discuss the exploitation of prokaryotic expression systems based on a promising expression system, the salicylate-dependent control circuit encompassing nahR/P(sal)::xylS2, as well as some of the improvements that have been done on this system to exploit it more efficiently in the context of both biotechnological applications and basic research. PMID- 21327057 TI - Heterologous laccase production and its role in industrial applications. AB - Laccases are blue multicopper oxidases, catalyzing the oxidation of an array of aromatic substrates concomitantly with the reduction of molecular oxygen to water. These enzymes are implicated in a variety of biological activities. Most of the laccases studied thus far are of fungal origin. The large range of substrates oxidized by laccases has raised interest in using them within different industrial fields, such as pulp delignification, textile dye bleaching, and bioremediation. Laccases secreted from native sources are usually not suitable for large-scale purposes, mainly due to low production yields and high cost of preparation/purification procedures. Heterologous expression may provide higher enzyme yields and may permit to produce laccases with desired properties (such as different substrate specificities, or improved stabilities) for industrial applications. This review surveys researches on heterologous laccase expression focusing on the pivotal role played by recombinant systems towards the development of robust tools for greening modern industry. PMID- 21327058 TI - Oligonucleotide recombination: a hidden treasure. AB - In Swingle et al. we demonstrate that it is possible to use recombineering to direct a variety of changes in wild-type bacterial cells without the addition of phage-encoded proteins. This discovery is potentially applicable to biological engineering in a wide variety of bacterial species. Here we describe key features of oligo recombination as it is currently understood, and propose strategies for expanding the utility of oligo recombination for bioengineering. PMID- 21327059 TI - Immunization trials with an avian chlamydial MOMP gene recombinant adenovirus. AB - Chicks were inoculated with a live vector vaccine of avian chlamydial MOMP gene recombinant adenovirus to evaluate efficacy, safety and viability of the vaccine. Five batches of the recombinant adenovirus vaccines, which were prepared using the 22nd generation avian chlamydial MOMP gene recombinant adenovirus cultured in HEK293 cells, were used to vaccinate 7 days-old chicks negative for chlamydial antibody. The recombinant adenovirus vaccine was shown to be both safe and effective in inducing specific immunity in vaccinated chicks. PMID- 21327060 TI - Computer-aided design of biological circuits using TinkerCell. AB - Synthetic biology is an engineering discipline that builds on modeling practices from systems biology and wet-lab techniques from genetic engineering. As synthetic biology advances, efficient procedures will be developed that will allow a synthetic biologist to design, analyze, and build biological networks. In this idealized pipeline, computer-aided design (CAD) is a necessary component. The role of a CAD application would be to allow efficient transition from a general design to a final product. TinkerCell is a design tool for serving this purpose in synthetic biology. In TinkerCell, users build biological networks using biological parts and modules. The network can be analyzed using one of several functions provided by TinkerCell or custom programs from third-party sources. Since best practices for modeling and constructing synthetic biology networks have not yet been established, TinkerCell is designed as a flexible and extensible application that can adjust itself to changes in the field. PMID- 21327061 TI - Combating chlamydiosis. PMID- 21327062 TI - The use of Listeria monocytogenes as a DNA delivery vector for cancer gene therapy. AB - Listeria monocytogenes is an intracellular pathogen that lyses the phagosomal vacuole of infected cells, proliferates in the host cell cytoplasm and can actively enter adjacent cells. The pathogen is therefore well suited to exploitation as a vector for the delivery of DNA to target cells as the lifecycle favors cellular targeting with vector amplification and the potential for cell-to cell spread. We have recently demonstrated DNA transfer by L. monocytogenes in growing tumors in murine models. Our approach exploited an ampicillin sensitive stain of L. monocytogenes which can be lysed through systemic administration of ampicillin to facilitate release of plasmid DNA for expression by infected mammalian cells. Here, we discuss the implications of this technology and the potential for future improvements of the system. PMID- 21327063 TI - Overexpression and purification of halophilic proteins in Haloferax volcanii. AB - Halophilic enzymes function optimally at high salt concentrations and are active at low water availability. Such conditions are encountered at elevated concentrations of solutes such as salts and sugars, and at high concentrations of organic solvents. However, expression in heterologous hosts such as Escherichia coli can cause problems, since halophilic proteins typically misfold and aggregate in conditions of low ionic strength. We have harnessed the sophisticated genetic tools available for the haloarchaeon Haloferax volcanii, to develop a system for the overexpression and purification of halophilic proteins under native conditions. PMID- 21327064 TI - Redox driven metabolic tuning: carbon source and aeration affect synthesis of poly(3-hydroxybutyrate) in Escherichia coli. AB - Growth and polymer synthesis were studied in a recombinant E. coli strain carrying phaBAC and phaP of Azotobacter sp. strain FA8 using different carbon sources and oxygen availability conditions. The results obtained with glucose or glycerol were completely different, demonstrating that the metabolic routes leading to the synthesis of the polymer when using glycerol do not respond to environmental conditions such as oxygen availability in the same way as they do when other substrates, such as glucose, are used. When cells were grown in a bioreactor using glucose the amount of polymer accumulated at low aeration was reduced by half when compared to high aeration, while glycerol cultures produced at low aeration almost twice the amount of polymer synthesized at the higher aeration condition. The synthesis of other metabolic products, such as ethanol, lactate, formate and acetate, were also affected by both the carbon source used and aeration conditions. In glucose cultures, lactate and formate production increased in low agitation compared to high agitation, while poly(3 hydroxybutyrate) synthesis decreased. In glycerol cultures, the amount of acids produced also increased when agitation was lowered, but carbon flow was mostly redirected towards ethanol and poly(3-hydroxybutyrate). These results indicated that carbon partitioning differed depending on both carbon source and oxygen availability, and that aeration conditions had different effects on the synthesis of the polymer and other metabolic products when glucose or glycerol were used. PMID- 21327065 TI - A place for everything: chromosomal integration of large constructs. AB - We have developed an easy, reliable two-step method for the insertion of large DNA fragments into any desired location in the E. coli chromosome. The method is based on the recombineering of a small (~1.3 kbp) "Landing Pad" into the chromosome at the insertion site, to which the large construct is subsequently delivered via I-SceI endonuclease excision from a donor plasmid. To demonstrate the power of this method, we here show the insertion of a fragment containing the entire lac operon (~9 kbp) into four predefined novel locations in the E. coli chromosome, a feat not possible with existing technologies. In addition, the chromosomal breaks induced by landing pad excision provide sufficient selective pressure that positive selection by antibiotics is unnecessary, making precise, exact insertion without extraneous sequence possible. PMID- 21327066 TI - The intricacy of nuclear membrane dynamics during nucleophagy. AB - The cell nucleus is an organelle bounded by a double-membrane which undergoes drastic reorganization during major cellular events such as cell division and apoptosis. Maintenance of proper nuclear structure, function and dynamics is central to organelle vitality. Over recent years growing evidence has shown that parts of the nucleus can be specifically degraded by an autophagic process termed nucleophagy. The process is best described in the yeast, Saccharomyces cerevisiae, where piecemeal microautophagy of the nucleus or nucleophagy (micronucleophagy) requires direct interaction of the nuclear membrane with that of the vacuole (the yeast lytic compartment). Here, we review the process of nucleophagy in the context of nuclear membrane dynamics, and examine the evidence for autophagic degradation of the nucleus in mammalian cells. Finally, we discuss the importance of nucleophagy as a 'housecleaning' mechanism for the nucleus under both normal and disease conditions. PMID- 21327067 TI - The ins and outs of nuclear re-export of retrogradely transported tRNAs in Saccharomyces cerevisiae. AB - In Saccharomyces cerevisiae intron-containing pre-tRNAs are exported from the nucleus to the cytoplasm for removal of the introns, and the spliced tRNAs are returned to the nucleus for reasons that are not understood. The re-imported spliced tRNAs are then subjected to aminoacylation in the nucleolus to ensure that they are functional prior to re-export to the cytoplasm. Previous studies have shown that re-imported spliced tRNAs and mature tRNAs made entirely in the nucleus from intronless precursors are retained in the nucleus of S. cerevisiae in response to glucose, amino acid, nitrogen or inorganic phosphate deprivation. Contrary to these studies, we recently reported that starvation of S. cerevisiae of amino acids or nitrogen results in nuclear accumulation of re-imported spliced tRNAs, but not tRNAs made from intronless precursors. This finding suggests that separate pathways are used for nuclear export of retrogradely transported spliced tRNAs and tRNAs made from intronless pre-tRNAs. In addition, the data support the conclusion that the nuclear re-export pathway for retrogradely transported spliced tRNAs, but not the pathway responsible for nuclear export of tRNAs derived from intronless precursors is regulated during amino acid or nitrogen starvation. This regulation appears to occur at a step after the re-imported spliced tRNAs have undergone aminoacylation quality assurance and, in part, involves the TORC1 signalling pathway. Moreover, it was established that Utp9p is an intranuclear component that only facilitates nuclear re-export of retrogradely transported spliced tRNAs by the beta-karyopherin Msn5p. Utp9p acts in concert with Utp8p, a key player in nuclear tRNA export in S. cerevisiae, to translocate aminoacylated re-imported spliced tRNAs from the nucleolus to Msn5p and assist with formation of the Msn5p-tRNA-Gsp1p-GTP export complex. This pathway, however, is not the only one responsible for nuclear re-export of retrogradely transported spliced tRNAs. PMID- 21327068 TI - Space shuttling in the cell: nucleocytoplasmic transport and microtubule organization during the cell cycle. AB - Microtubules form a multifunctional filamentous structure essential for the cell. In interphase, microtubules form networks in the cytoplasm and play pivotal roles in cell polarity and intracellular transport of various biomolecules. In mitosis, microtubules dramatically change their morphology to assemble the mitotic spindle, thereby pulling the chromosomes toward the spindle poles. One long standing question is how microtubules are reorganized upon mitotic entry. Yeast cells undergo closed mitosis, in which the nuclear envelope persists, whereas higher eukaryotes undergo open mitosis, in which the nuclear envelope breaks down. Microtubule reorganization must be controlled by selective localization of microtubule-assembly factors. Recent findings in fission yeast indicate that several microtubule-associated proteins (MAPs) shuttle between the cytoplasm and the nucleus through regulation by Ran GTPase, the universal organizer of nucleocytoplasmic transport. Furthermore, the synergistic interplay of Ran and cyclin-dependent kinase (CDK) induces the critical spatiotemporal shift of modes in microtubule assembly from cytoplasmic arrays to nuclear spindles. A MAP complex Alp7/TACC-Alp14/TOG undergoes nucleocytoplasmic shuttling in interphase, whereas it is retained in the mitotic nucleus through a decrease of its nuclear export by CDK. Our understanding of how microtubules are reorganized during the cell cycle is beginning to emerge. PMID- 21327069 TI - Traffic control at the nuclear pore. AB - The proper communication between organelles is essential for many aspects of eukaryotic life. The coordination of nuclear and cytoplasmic activities in particular is of pivotal importance and depends on transport in and out of the nucleus. The material which translocates through nuclear pores is diverse; it includes numerous proteins, RNAs and large ribonucleoprotein complexes like ribosomal subunits. To ensure the correct nucleocytoplasmic distribution of these components, appropriate mechanisms have to be in place which control traffic across the nuclear envelope. A growing number of studies support the notion that transport through nuclear pore complexes is intimately linked to cell physiology. As such, it has become evident that changes in the cellular environment, either by externally applied stress, aging or disease, alter nuclear traffic. Due to the progress made in the past few years, we are now beginning to understand these processes at the molecular level. Thus, the concept emerges that stress or disease conditions correlate with signaling events which aim at the nuclear transport apparatus. Here, we summarize results from recent publications that provide evidence for the hypothesis that changes in cell physiology modulate nuclear traffic by targeting multiple transport factors. We propose that this traffic control is at least in part mediated by specific signaling events. PMID- 21327070 TI - SMARCAL1 and replication stress: an explanation for SIOD? AB - The SNF2 family of ATPases acts in the context of chromatin to regulate transcription, replication, repair and recombination. Defects in SNF2 genes cause many human diseases. For example, mutations in SMARCAL1 (also named HARP) cause Schimke immuno-osseous dysplasia (SIOD); a multi-system disorder characterized by growth defects, immune deficiencies, renal failure and other complex phenotypes. Several groups including ours recently identified SMARCAL1 as a replication stress response protein. Importantly, SMARCAL1 localizes to stalled replication forks and this localization of SMARCAL1 activity prevents DNA damage accumulation during DNA replication. We determined that SIOD-related SMARCAL1 mutants could not prevent replication-associated DNA damage in cells in which endogenous SMARCAL1 was silenced, establishing the first link between SIOD and a defect in a specific biological activity. Here, we also report that cells from patients with SIOD exhibit elevated levels of DNA damage that can be rescued by re-introduction of wild-type SMARCAL1. Our data suggest that loss of SMARCAL1 function in patients may cause DNA replication-associated genome instability that contributes to the pleiotropic phenotypes of SIOD. PMID- 21327071 TI - A transmembrane inner nuclear membrane protein in the mitotic spindle. AB - We have recently characterized a novel transmembrane protein of the inner nuclear membrane of mammalian cells. The protein has two very interesting features. First, despite being an integral membrane protein it is able to concentrate in the membranes colocalizing with the mitotic spindle in metaphase and anaphase. Hence, the protein was named Samp1, Spindle associated membrane protein 1. Secondly, it displays a functional connection to centrosomes. This article discusses various aspects of Samp1 in relation to possible cellular function(s). PMID- 21327072 TI - Extra views on RNA-dependent DNA methylation and MBD6-dependent heterochromatin formation in nucleolar dominance. AB - Nucleolar dominance is a widespread epigenetic phenomenon, describing the preferential silencing of ribosomal RNA (rRNA) genes inherited from one progenitor of an interspecific hybrid, independent of maternal or paternal effects. In the allotetraploid hybrid plant species Arabidopsis suecica, A. thaliana-derived rRNA genes are silenced whereas the A. arenosa-derived rRNA genes are transcribed. We reported previously on an RNAi-based screen of DNA methyltransferases, methylcytosine binding proteins and RNA-dependent DNA methylation pathway proteins that identified specific activities required for the establishment or enforcement of nucleolar dominance. Here we present additional molecular and cell biological evidence that siRNA-directed cytosine methylation and the methylcytosine binding protein MBD6 bring about large-scale chromosomal effects on rRNA gene loci subjected to nucleolar dominance in A. suecica. PMID- 21327073 TI - A newly discovered role of telomeres in an ancient organism. AB - Trypanosoma brucei expresses Variant Surface Glycoprotein (VSG) genes in a strictly monoallelic fashion in its mammalian hosts, and the regulation of this important virulence mechanism has been the research focus for decades. Telomere position effect (TPE), an epigenetic phenomenon, has been proposed to play a critical role in VSG regulation, yet no telomeric protein was identified whose disruption led to VSG derepression. We recently identified tbRAP1 as an intrinsic component of the T. brucei telomere complex and a major regulator for silencing VSG expression sites (ESs). Knockdown of tbRAP1 led to derepression of all ES linked VSGs but not VSGs located elsewhere, and resulted in stronger derepression of telomere-proximal genes than telomere-distal genes. This tapered silencing pattern further argues that telomere integrity plays a key role in tbRAP1 dependent silencing and for the first time provides direct evidence indicating that telomeres are important for VSG expression regulation. Whether chromatin remodeling is important for tbRAP1-mediated silencing as in classical TPE will also be discussed. PMID- 21327074 TI - Direct actin binding to A- and B-type lamin tails and actin filament bundling by the lamin A tail. AB - Nuclear intermediate filament networks formed by A- and B-type lamins are major components of the nucleoskeleton. Lamins have growing links to human physiology and disease including Emery-Dreifuss muscular dystrophy (EDMD), lipodystrophy, cardiomyopathy, neuropathy, cerebellar disorders and segmental accelerated 'aging' syndromes. How lamins interact with other nucleoskeletal components, and even the identities of these other components, are open questions. Previous studies suggested lamins might bind actin. We report that the recombinant C terminal tail domain of human A- and B-type lamins binds directly to purified actin in high-speed pelleting assays. This interaction maps to a conserved Actin Binding site (AB-1) comprising lamin A residues 461-536 in the Ig-fold domain, which are 54% identical in lamin B1. Two EDMD-causing missense mutations (R527P and L530P) in lamin A that are predicted to disrupt the Ig-fold, each reduced F actin binding by ~66%, whereas the surface-exposed lipodystrophy-causing R482Q mutation had no significant effect. The lamin A tail was unique among lamins in having a second actin-binding site (AB-2). This second site was mapped to lamin A tail residues 564-608, based on actin-binding results for the lamin C tail and internal deletions in the lamin A tail that cause Hutchinson-Gilford Progeria Syndrome (Delta35, Delta50) or restrictive dermopathy (Delta90). Supporting the presence of two actin-binding sites, recombinant precursor (unmodified) and mature lamin A tails (not C or B1 tails) each bundled F-actin in vitro: furthermore F-actin bundling was reduced 25-40% by the R527P, L530P, Delta35 and Delta50 mutations, and was abolished by Delta90. Unexpectedly, the mature lamin A tail bound F-actin significantly more efficiently than did the prelamin A tail; this suggested unmodified residues 647-664, unique to prelamin A, might auto inhibit binding to actin (and potentially other partners). These biochemical results suggest direct mechanisms by which lamins, particularly lamin A, might impact the concentration of free actin in the nucleus or pathways including transcription, nuclear export, chromatin remodeling, chromatin movement and nuclear assembly that require nuclear myosin 1c and polymerizable actin. PMID- 21327075 TI - Dynamic properties of meiosis-specific lamin C2 and its impact on nuclear envelope integrity. AB - A hallmark of meiosis is the precise pairing and the stable physical connection (synapsis) of the homologous chromosomes. These processes are essential prerequisite for their proper segregation. Pairing of the homologs during meiotic prophase I critically depends on characteristic movements of chromosomes. These movements, in turn, require attachment of meiotic telomeres to the nuclear envelope and their subsequent dynamic repositioning. Dynamic repositioning of meiotic telomeres goes along with profound structural reorganization of the nuclear envelope. The short A-type lamin C2 is thought to play a critical role in this process due to its specific expression during meiotic prophase I and the unique localization surrounding telomere attachments. Consistent with this notion, here we provide compelling evidence that meiosis-specific lamin C2 features a significantly increased mobility compared to somatic lamins as revealed by photobleaching techniques. We show that this property can be clearly ascribed to the lack of the N-terminal head and the significantly shorter alpha helical coil domain. Moreover, expression of lamin C2 in somatic cells induces nuclear deformations and alters the distribution of the endogenous nuclear envelope proteins lamin B1, LAP2, SUN1 and SUN2. Together, our data define lamin C2 as a "natural lamin deletion mutant" that confers unique properties to the nuclear envelope which would be essential for dynamic telomere repositioning during meiotic prophase I. PMID- 21327076 TI - 4D chromatin dynamics in cycling cells: Theodor Boveri's hypotheses revisited. AB - This live cell study of chromatin dynamics in four dimensions (space and time) in cycling human cells provides direct evidence for three hypotheses first proposed by Theodor Boveri in seminal studies of fixed blastomeres from Parascaris equorum embryos: (I) Chromosome territory (CT) arrangements are stably maintained during interphase. (II) Chromosome proximity patterns change profoundly during prometaphase. (III) Similar CT proximity patterns in pairs of daughter nuclei reflect symmetrical chromosomal movements during anaphase and telophase, but differ substantially from the arrangement in mother cell nucleus. Hypothesis I could be confirmed for the majority of interphase cells. A minority, however, showed complex, rotational movements of CT assemblies with large-scale changes of CT proximity patterns, while radial nuclear arrangements were maintained. A new model of chromatin dynamics is proposed. It suggests that long-range DNA-DNA interactions in cell nuclei may depend on a combination of rotational CT movements and locally constrained chromatin movements. PMID- 21327077 TI - Phosphorylation of nucleoporins: signal transduction-mediated regulation of their interaction with nuclear transport receptors. AB - The nuclear pore complex (NPC) is composed of ~30 unique proteins, collectively referred to as nucleoporins or Nups. While metazoan Nups are known to be phosphorylated during mitosis to cause disassembly of the NPC, what is less clear is whether Nups are phosphorylated and regulated by extracellular stimuli in interphase cells. Our multi-step phosphoproteomic approach revealed a number of physiologically relevant extracellular signal-regulated kinase (ERK) targets, including Nups containing FG repeats (FG Nups) that provide binding sites for nuclear transport receptors (NTRs) during the NPC passage. The phosphorylation of FG Nups by ERK does not affect the overall architecture of the NPC but directly inhibits their interactions with NTRs and regulates the permeability barrier properties of the NPC. Such regulation at the levels of transport machinery is expected to have a broad impact on cellular physiology through the spatiotemporal control of signaling events. Until recently, many studies have focused on cellular signaling-mediated phosphorylation of individual cargo proteins, such as transcription factors. An understanding of the effects of signaling pathways on nucleocytoplasmic transport machinery is only beginning to emerge. PMID- 21327078 TI - Membrane-coating lattice scaffolds in the nuclear pore and vesicle coats: commonalities, differences, challenges. AB - The nuclear pore complex (NPC) regulates all traffic between the cytoplasm and the nucleus. It is a large protein assembly composed of multiple copies of ~30 nucleoporins (nups). Structural studies of the NPC have been limited by its considerable size and complexity. Progress toward understanding the structure of this nanomachine has benefited from its modular nature, which allows for this 40 60 MDa assembly to be broken down into subcomplexes that can be studied individually. While recent work by both crystallographers and electron microscopists has greatly enhanced our model of the NPC, the resolution gap between crystal and EM structures remains too large to confidently place individual proteins within the context of the fully assembled NPC. In an effort to arrive at a veritable model of the NPC, we solved the structure of several scaffold nups and defined the ancestral coatomer element (ACE1) common to a set of nucleoporins and COPII vesicle coat proteins. Subsequently, we proposed a lattice-like model of the NPC, analogous to the COPII lattice, in which ACE1 proteins form the edge elements and beta-propellers form the vertex elements. Here, we review our recent studies, speculate on how interactions between subcomplexes of the NPC are mediated, and outline the steps and challenges that lay ahead on the path to understanding this enormous assembly in molecular detail. PMID- 21327079 TI - The danger of "multi-tasking": LBR out of control. AB - The nuclear envelope (NE) is a barrier that separates nuclear from cytoplasmic processes. It is composed of an inner and outer nuclear membrane (INM, ONM), separated by the perinuclear space (PNS). The ONM is contiguous with the endoplasmic reticulum (ER), and thus, the lumen of the NE and that of the ER constitute one compartment. The lamin B receptor (LBR) is a NE protein that has a central structural role as a linker of the INM, the lamina and chromatin, and a less well characterized functional role as a sterol reductase. In a recent study, we reported that the forced expression of mutant variants of LBR in some cell types induces a separation of the INM from the outer nuclear envelope concomitantly with a separation of ER membranes, whereas in other cells no separation is observed. In this extra view, we speculate about the mechanism that leads to this fundamental disruption of NE and ER structure. Our observations furthermore raise the question to what extent LBR contributes to the establishment or maintenance of the ER and PNS luminal compartment, and how a single mutant protein can so drastically interfere with its regular organization. PMID- 21327080 TI - The mechanisms regulating the subcellular localization of AID. AB - Activation induced deaminase (AID) is a unique enzyme that directly introduces mutations in the immunoglobulin genes to generate antibody diversity during the humoral immune response. Since this mutator enzyme poses a measurable risk of off target mutation, which can be deleterious or transforming for a cell, several regulatory mechanisms exist to control its activity. At least three of these mechanisms affect AID subcellular localization. It was recently found that AID is actively imported into the nucleus, most likely through importin-alpha/beta recognizing a structural nuclear localization signal. However, AID is largely excluded from the nucleus in steady state thanks to two mechanisms. In addition to nuclear export through the exportin CRM1, a mechanism retaining AID in the cytoplasm exists. Cytoplasmic retention hinders the passive diffusion of AID into the nucleus playing an important role in the nuclear exclusion of AID. Subcellular localization of AID also determines its stability. The regulation of the nuclear fraction of AID by these many mechanisms has functional implications for antibody diversification. PMID- 21327081 TI - Nucleoporin MOS7/Nup88 contributes to plant immunity and nuclear accumulation of defense regulators. AB - Controlled nucleocytoplasmic trafficking is an important feature for fine-tuning signaling pathways in eukaryotic organisms. Nuclear pore complexes (NPCs) composed of nucleoporin proteins (Nups) are essential for the exchange of macromolecules across the nuclear envelope. A recent genetic screen in our laboratory identified a partial loss-of-function mutation in Arabidopsis MOS7/Nup88 that causes defects in basal immunity, Resistance (R) protein-mediated defense and systemic acquired resistance. In Drosophila and mammalian cells, exportin-mediated nuclear export of activated Rel/NFkappaB transcription factors is enhanced in nup88 mutants resulting in immune response failure. Consistent with Nup88 promoting nuclear retention of NFkappaB, our functional analyses revealed that MOS7/Nup88 is required for appropriate nuclear accumulation of the autoactivated R protein snc1, as well as the key immune regulators EDS1 and NPR1. These results suggest that controlling the nuclear concentrations of specific immune regulators is fundamental for defining defense outputs. PMID- 21327082 TI - The perinuclear actin cap in health and disease. AB - We recently demonstrated the existence of a previously uncharacterized subset of actomyosin fibers that form the perinuclear actin cap, a cytoskeletal structure that tightly wraps around the nucleus of a wide range of somatic cells. Fibers in the actin cap are distinct from well-characterized, conventional actin fibers at the basal and dorsal surfaces of adherent cells in their subcellular location, internal organization, dynamics, ability to generate contractile forces, response to cytoskeletal pharmacological treatments, response to biochemical stimuli, regulation by components of the linkers of nucleoskeleton and cytoskeleton (LINC) complexes, and response to disease-associated mutations in LMNA, the gene that encodes for the nuclear lamin component lamin A/C. The perinuclear actin cap precisely shapes the nucleus in interphase cells. The perinuclear actin cap may also be a mediator of microenvironment mechanosensing and mechanotransduction, as well as a regulator of cell motility, polarization and differentiation. PMID- 21327083 TI - Intranuclear membranes induced by lipidated proteins are derived from the nuclear envelope. AB - Association of nuclear lamins with the inner nuclear membrane (INM) is mediated by lipid modifications: either by C-terminal isoprenylation or N-terminal myristoylation. Overexpression of lamins or other lipidated nuclear proteins induces the formation of intranuclear membrane-like arrays. Lamin-induced intranuclear array formation has been observed in Xenopus oocytes as well as in mammalian tissue culture cells. With the use of a membrane-specific fluorescence dye we show here that these arrays are made up of typical lipid membranes. While continuity between these intranuclear membranes and the INM has not been observed so far the presence of integral as well as luminal marker proteins of the endoplasmic reticulum (ER) indicates that these membranes are derived from the nuclear membrane/ER compartment. Earlier studies demonstrated that overexpression of integral membrane proteins of the INM can induce formation of intranuclear membranes, which bud from the INM. Integral membrane proteins reach the INM via the pore membranes while lipidated proteins are imported into the nucleoplasm via the classical NLS pathway where they interact with the INM via their lipid moieties. Together with the previously published data our results show that the formation of intranuclear membranes follows similar routes irrespective of whether the proteins triggering membrane formation are integral membrane or lipidated proteins. PMID- 21327084 TI - Mutations causing Greenberg dysplasia but not Pelger anomaly uncouple enzymatic from structural functions of a nuclear membrane protein. AB - The lamin B receptor (LBR) is an inner nuclear membrane protein with a structural function interacting with chromatin and lamins, and an enzymatic function as a sterol reductase. Heterozygous LBR mutations cause nuclear hyposegmentation in neutrophils (Pelger anomaly), while homozygous mutations cause prenatal death with skeletal defects and abnormal sterol metabolism (Greenberg dysplasia). It has remained unclear whether the lethality in Greenberg dysplasia is due to cholesterol defects or altered nuclear morphology.To answer this question we characterized two LBR missense mutations and showed that they cause Greenberg dysplasia. Both mutations affect residues that are evolutionary conserved among sterol reductases. In contrast to wildtype LBR, both mutations failed to rescue C14 sterol reductase deficient yeast, indicating an enzymatic defect. We found no Pelger anomaly in the carrier parent excluding marked effects on nuclear structure. We studied Lbr in mouse embryos and demonstrate expression in skin and the developing skeletal system consistent with sites of histological changes in Greenberg dysplasia. Unexpectedly we found in disease-relevant cell types not only nuclear but also cytoplasmatic LBR localization. The cytoplasmatic LBR staining co-localized with ER-markers and is thus consistent with the sites of endogeneous sterol synthesis. We conclude that LBR missense mutations can abolish sterol reductase activity, causing lethal Greenberg dysplasia but not Pelger anomaly. The findings separate the metabolic from the structural function and indicate that the sterol reductase activity is essential for human intrauterine development. PMID- 21327085 TI - SR and SR-related proteins redistribute to segregated fibrillar components of nucleoli in a response to DNA damage. AB - Pre-mRNA splicing factors are often redistributed to nucleoli in response to physiological conditions and cell stimuli. In telophase nuclei, serine-arginine rich (SR) proteins, which usually reside in nuclear speckles, localize transiently to active ribosomal DNA (rDNA) transcription sites called nucleolar organizing region-associated patches (NAPs). Here, we show that ultraviolet light and DNA damaging chemicals induce the redistribution of SR and SR-related proteins to areas around nucleolar fibrillar components in interphase nuclei that are similar to, but distinct from, NAPs, and these areas have been termed DNA damage-induced NAPs (d-NAPs). In vivo labeling of nascent RNA distinguished d NAPs from NAPs in that d-NAPs were observed even after full rDNA transcriptional arrest as a result of DNA damage. Studies under a variety of conditions revealed that d-NAP formation requires both RNA polymerase II-dependent transcriptional arrest and nucleolar segregation, in particular, the disorganization of the granular nucleolar components. Despite the redistribution of SR proteins, splicing factor-enriched nuclear speckles were not disrupted because other nuclear speckle components, such as nuclear poly(A) RNA and the U5-116K protein, remained in DNA-damaged cells. These data suggest that the selective redistribution of splicing factors contributes to the regulation of specific genes via RNA metabolism. Finally, we demonstrate that a change in alternative splicing of apoptosis-related genes is coordinated with the occurrence of d-NAPs. Our results reveal a novel response to DNA damage that involves the dynamic redistribution of splicing factors to nucleoli. PMID- 21327086 TI - The function of spliceosome components in open mitosis. AB - Spatial separation of eukaryotic cells into the nuclear and cytoplasmic compartment permits uncoupling of DNA transcription from translation of mRNAs and allows cells to modify newly transcribed pre mRNAs extensively. Intronic sequences (introns), which interrupt the coding elements (exons), are excised ("spliced") from pre-mRNAs in the nucleus to yield mature mRNAs. This not only enables alternative splicing as an important source of proteome diversity, but splicing is also an essential process in all eukaryotes and knock-out or knock down of splicing factors frequently results in defective cell proliferation and cell division. However, higher eukaryotes progress through cell division only after breakdown of the nucleus ("open mitosis"). Open mitosis suppresses basic nuclear functions such as transcription and splicing, but allows separate, mitotic functions of nuclear proteins in cell division. Mitotic defects arising after loss-of-function of splicing proteins therefore could be an indirect consequence of compromised splicing in the closed nucleus of the preceding interphase or reflect a direct contribution of splicing proteins to open mitosis. Although experiments to directly distinguish between these two alternatives have not been reported, indirect evidence exists for either hypotheses. In this review, we survey published data supporting an indirect function of splicing in open mitosis or arguing for a direct function of spliceosomal proteins in cell division. PMID- 21327087 TI - Mapping of protein- and chromatin-interactions at the nuclear lamina. AB - The nuclear envelope and the lamina define the nuclear periphery and are implicated in many nuclear processes including chromatin organization, transcription and DNA replication. Mutations in lamin A proteins, major components of the lamina, interfere with these functions and cause a set of phenotypically diverse diseases referred to as laminopathies. The phenotypic diversity of laminopathies is thought to be the result of alterations in specific protein- and chromatin interactions due to lamin A mutations. Systematic identification of lamin A-protein and -chromatin interactions will be critical to uncover the molecular etiology of laminopathies. Here we summarize and critically discuss recent technology to analyze lamina-protein and-chromatin interactions. PMID- 21327088 TI - The 53BP1-EXPAND1 connection in chromatin structure regulation. AB - The mammalian interphase chromatin responds to DNA damages by altering the compactness of its architecture, thereby permitting local access of DNA repair machineries. Adding to the cellular strategies of chromatin remodeling following DNA damage, our recent work identified the 53BP1-EXPAND1 module in promoting chromatin dynamics in response to DNA double-strand breaks. Endowed with a nucleosome-binding PWWP domain, EXPAND1 tethers to the chromatin where it is involved in maintaining basal chromatin accessibility in unperturbed cells. Interestingly, through its direct interaction with the DNA damage mediator protein 53BP1, EXPAND1 accumulates at the damage-modified chromatin and triggers its further decondensation. These observations, together with the fact that EXPAND 1 promotes cell survival following DNA damage, suggest that the chromatin bound factor may facilitate DNA repair by regulating the organization of chromatin structure. PMID- 21327089 TI - Permeating the nuclear pore complex. AB - The extensive and multifaceted traffic between nucleus and cytoplasm is handled by a single type of macromolecular assembly called the nuclear pore complex (NPC). While being readily accessible to ions and metabolites, the NPC imposes stringent selectivity on the passage of proteins and RNA, tightly regulating their traffic between the two major cellular compartments. Here we discuss how shuttling carriers, which mediate the transport of macromolecules through NPCs, cross its permeability barrier. We also discuss the co-existence of receptor mediated macromolecular transport with the passive diffusion of small molecules in the context of the various models suggested for the permeability barrier of the NPC. Finally, we speculate on how nuclear transport receptors negotiate the dependence of their NPC-permeating abilities on hydrophobic interactions with the necessity of avoiding these promiscuous interactions in the cytoplasm and nucleus. PMID- 21327090 TI - Nuclear envelope attachment is not necessary for telomere function in fission yeast. AB - Inner nuclear membrane (INM) proteins can be important for positioning chromosomes within the nucleus. Little is known about INM proteins in the fission yeast Schizossacharomayces pombe. Telomeres are the most obvious chromosomal sites that are anchored to the nuclear envelope in this organism. A group of proteins that tether telomeres to the spindle-pole body (SPB) during meiotic prophase, such as Bqt1, Bqt2 and Sad1, has been identified previously, but proteins for anchoring telomeres to the nuclear envelope in vegetative cells have not been identified until recently. A recent report demonstrates that Bqt3 and Bqt4 are INM proteins that affect nuclear positioning of telomeres in vegetative cells, and consequently affect the telomere clustering in meiotic prophase. Interestingly, in the absence of Bqt4, telomeres are separated from the nuclear envelope but telomere silencing and telomere length are properly regulated. An important implication of these results is that the functional integrity of telomeres is maintained independently of their connection to the nuclear envelope. PMID- 21327091 TI - Cytosol-dependent membrane fusion in ER, nuclear envelope and nuclear pore assembly: biological implications. AB - Endoplasmic reticulum and nuclear envelope rearrangements after mitosis are often studied in the reconstitution system based on Xenopus egg extract. In our recent work we partially replaced the membrane vesicles in the reconstitution mix with protein-free liposomes to explore the relative contributions of cytosolic and transmembrane proteins. Here we discuss our finding that cytosolic proteins mediate fusion between membranes lacking functional transmembrane proteins and the role of membrane fusion in endoplasmic reticulum and nuclear envelope reorganization. Cytosol-dependent liposome fusion has allowed us to restore, without adding transmembrane nucleoporins, functionality of nuclear pores, their spatial distribution and chromatin decondensation in nuclei formed at insufficient amounts of membrane material and characterized by only partial decondensation of chromatin and lack of nuclear transport. Both the mechanisms and the biological implications of the discovered coupling between spatial distribution of nuclear pores, chromatin decondensation and nuclear transport are discussed. PMID- 21327093 TI - Reversal of age-dependent nuclear morphology by inhibition of prenylation does not affect lifespan in Caenorhabditis elegans. AB - Fibroblasts derived from Hutchinson-Gilford progeria syndrome (HGPS) patients and dermal cells derived from healthy old humans in culture display age-dependent progressive changes in nuclear architecture due to accumulation of farnesylated lamin A. Treating human HGPS cells or mice expressing farnesylated lamin A with farnesyl transferase inhibitors (FTIs) reverses nuclear phenotypes and extends lifespan. Aging adult Caenorhabditis elegans show changes in nuclear architecture resembling those seen in HGPS fibroblasts, as well as a decline in motility, phenotypes which are also inhibited by the FTI gliotoxin. However, it was not clear whether these effects were due to loss of farnesylation or to side effects of this drug. Here, we used a different FTI, manumycin or downregulated polyprenyl synthetase with RNAi to test the roles of farnesylation in C. elegans aging. Our results show that the age-dependent changes in nuclear morphology depend on farnesylation. We also demonstrate that inhibition of farnesylation does not affect motility or lifespan, suggesting that the effects of blocking protein prenylation on nuclear morphology could be separated from their effects on motility and lifespan. These results provide further understanding of the role of lamin and farnesylation in the normal aging process and in HGPS. PMID- 21327092 TI - On the right track: following the nucleo-cytoplasmic path of an mRNA. AB - The transcription machinery in the eukaryotic nucleus generates messenger RNA molecules that translocate through the nucleoplasm, anchor to a nuclear pore, and find their way out into the cytoplasm. The dynamic aspects of these steps in the expression pathway were examined in order to understand the kinetic time-frames of gene activation and message dissemination. Utilizing live-cell imaging and tracking of single mRNPs containing different sized mRNAs and varying numbers of introns and exons, it was possible to quantify the temporal and spatial characteristics of the nucleoplasmic travels of mRNPs as well as the kinetics of translocation through the nuclear pore. PMID- 21327094 TI - An in vitro model for Pelger-Huet anomaly: stable knockdown of lamin B receptor in HL-60 cells. AB - The principal human blood granulocyte (neutrophil) possesses a lobulated and deformable nucleus, important to facilitate rapid egress from blood vessels as these cells migrate to sites of bacterial or fungal infection. This unusual nuclear shape is a product of elevated levels of an integral membrane protein of the nuclear envelope lamin B receptor (LBR) and of decreased amounts of lamin A/C. In humans, a genetic deficiency of LBR produces Pelger-Huet anomaly, resulting in blood neutrophils that exhibit hypolobulated nuclei with redistributed heterochromatin. Structural changes in nuclear architecture occur during granulopoiesis within bone marrow. The exact mechanisms of this nuclear shape change and of heterochromatin redistribution remain largely unknown. As a tool to facilitate analysis of these mechanisms, a stable LBR knockdown subline of HL-60 cells was established. During in vitro granulopoiesis induced with retinoic acid, the LBR knockdown cells retain an ovoid shaped nucleus with reduced levels of lamin A/C; while, the parent cells develop highly lobulated nuclei. In contrast, macrophage forms induced in LBR knockdown cells by in vitro treatment with phorbol ester were indistinguishable from the parent cells, judged by both nuclear shape and attached cell morphology. The capability of differentiation of LBR knockdown HL-60 cells should facilitate a detailed analysis of the molecular relationship between LBR levels, granulocyte nuclear shape and heterochromatin distribution. PMID- 21327096 TI - An Olympian protozoan. AB - Ciliated protozoa of the genus Tetrahymena have provided a uniquely enabling platform for monumental discoveries in the molecular biology of the nucleus. PMID- 21327095 TI - Identification of differential protein interactors of lamin A and progerin. AB - The nuclear lamina is an interconnected meshwork of intermediate filament proteins underlying the nuclear envelope. The lamina is an important regulator of nuclear structural integrity as well as nuclear processes, including transcription, DNA replication and chromatin remodeling. The major components of the lamina are A- and B-type lamins. Mutations in lamins impair lamina functions and cause a set of highly tissue-specific diseases collectively referred to as laminopathies. The phenotypic diversity amongst laminopathies is hypothesized to be caused by mutations affecting specific protein interactions, possibly in a tissue-specific manner. Current technologies to identify interaction partners of lamin A and its mutants are hampered by the insoluble nature of lamina components. To overcome the limitations of current technologies, we developed and applied a novel, unbiased approach to identify lamin A-interacting proteins. This approach involves expression of the high-affinity OneSTrEP-tag, precipitation of lamin-protein complexes after reversible protein cross-linking and subsequent protein identification by mass spectrometry. We used this approach to identify in mouse embryonic fibroblasts and cardiac myocyte NklTAg cell lines proteins that interact with lamin A and its mutant isoform progerin, which causes the premature aging disorder Hutchinson-Gilford progeria syndrome (HGPS). We identified a total of 313 lamina-interacting proteins, including several novel lamin A interactors, and we characterize a set of 35 proteins which preferentially interact with lamin A or progerin. PMID- 21327097 TI - DNA-dependent cohesin cleavage by separase. AB - Eukaryotic genomes are organized into chromosomes. In order to maintain genomic stability during cell proliferation, a series of elaborate processes is employed to ensure that chromosomes are duplicated and segregated equally into daughter cells. Sister chromatid cohesion, a tight association of duplicated sister chromatids, allows their attachment to the opposite centrosomes. Sister chromatid cohesion depends on the cohesin complex, a proteinaceous ring that entraps the chromatids together. At the metaphase-to-anaphase transition, a protease called separase is activated and completely dissolves the cohesion by cleaving SCC1, a subunit of the cohesin complex. As one of the key executors of anaphase, separase is regulated temporally and spatially by often redundant mechanisms. A recent study revealed that chromosomal DNA is required as a cofactor for the cleavage of cohesin to occur. This DNA dependence is the underlying biochemical mechanism that allows separase to selectively cleave only the chromosome-associated cohesin. We propose that the chromosomal DNA dependent cohesin cleavage by separase is a component of a regulatory pathway that cells utilize to protect the bulk of cohesin. This intact cohesin becomes immediately available in G(1) to resume its other function-regulation of gene transcription by means of chromatin insulation. PMID- 21327098 TI - Nuclear positional control of HIV transcription in 4D. AB - Retroviruses integrate their genome into the chromatin of the host cell and are subject to the same control mechanisms governing transcription in the nucleus. There is increasing evidence that the spatial position of a gene within the nucleus in time affects its activity. Therefore it becomes important to study the chromatin environment in space and time of the HIV-1 provirus, particularly in cells where a tight transcriptional control allows the virus to hide away from antiviral treatment and immune response. We recently showed that the HIV-1 provirus is found at the nuclear periphery of latently infected lymphocytes associated in trans with centromeric heterochromatin. After induction of transcription, this association was lost, although the location of the transcribing provirus remained peripheral. Our results reveal a novel mechanism of transcriptional silencing involved in HIV-1 post-transcriptional latency and open wider perspectives for the general organization of chromatin in the nucleus. PMID- 21327099 TI - Sem1: a versatile "molecular glue"? AB - The evolutionary conserved protein Sem1/Dss1 is a bona fide subunit of the regulatory particle (RP) of the proteasome and in mammalian cells stabilizes the tumor suppressor protein BRCA2. A recent study from our laboratory has revealed an unexpected non- proteasomal role of Sem1 in mRNA export. We found that Sem1, independent of the RP, is a functional component of the nuclear pore associated TREX-2 complex that is directly involved in the dynamic relocalization of a subset of DNA loci to the nuclear periphery. Like other components of TREX-2, Sem1 is required for proper nuclear export of mRNAs, transcription elongation and preventing transcription-associated genomic instability. Strikingly, Sem1 associates with a third multi-subunit protein complex namely the COP9 signalosome, which is involved in de-neddylation. We propose that Sem1 is a versatile protein that regulates the functional integrity of multiple protein complexes involved in diverse biological pathways. PMID- 21327100 TI - The nuclear pore complex: a new dynamic in HIV-1 replication. AB - The ability to traverse an intact nuclear envelope and productively infect non dividing cells is a salient feature of human immunodeficiency virus type 1 (HIV 1) and other lentiviruses, but the viral factors and mechanism of nuclear entry have not been defined. We have recently reported a functional role for the nucleoporin NUP153 in the nuclear import of the HIV-1 preintegration complex (PIC). Our findings suggest that HIV-1 sub-viral particles gain access to the nucleus by interacting directly with the nuclear pore complex (NPC) via the binding of PIC-associated integrase (IN) to the C-terminal domain of NUP153. This article discusses how NPC conformation and constitution might influence nuclear import of the PIC, and the subsequent integration of the viral cDNA into actively transcribed genes. PMID- 21327101 TI - It takes two: communication between homologous alleles preserves genomic stability during V(D)J recombination. AB - Chromosome pairing is involved in X chromosome inactivation, a classic instance of monoallelic gene expression. Antigen receptor genes are also monoallelically expressed ("allelically excluded") by B and T lymphocytes, and we asked whether pairing contributed to the regulation of V(D)J recombination at these loci. We found that homologous immunoglobulin (Ig) alleles pair up during recombination. Homologous Ig pairing is substantially reduced in the absence of the RAG1/RAG2 recombinase, but a transgene expressing an active site RAG1 mutant (which binds but does not cleave DNA) rescues pairing in Rag1(-/-) developing B cells. RAG mediated cleavage on one allele induces the other allele to relocate to pericentromeric heterochromatin (PCH), likely to ensure that only one allele is cut at a time. This relocation to PCH requires the DNA damage sensor ATM (ataxia telengiectasia mutated). In the absence of ATM, repositioning at PCH is diminished and the incidence of cleavage on both alleles is significantly increased. ATM appears to be activated by the introduction of a double-strand break on one allele to act in trans on the uncleaved allele, repositioning or maintaining it at PCH, to prevent bi-allelic recombination and chromosomal translocations. PMID- 21327102 TI - D4Z4 as a prototype of CTCF and lamins-dependent insulator in human cells. AB - Using cellular models that mimic the organizations of the subtelomeric 4q35 locus found in patients affected with Facio-Scapulo-Humeral Dystrophy (FSHD) and in healthy individuals, we recently investigated the biological function of the D4Z4 macrosatellite in this subtelomeric context.We demonstrated that D4Z4 acts as a CTCF and A-type lamins dependent insulator element exhibiting both enhancer- blocking and barrier activities, and displaces a telomere towards the nuclear periphery. This peripheral positioning activity lies within a short sequence that interacts with CTCF and A-type lamins. Depletion in either of these two proteins suppresses these perinuclear activities, revealing the existence of a subtelomeric sequence that is sufficient to position an adjacent telomere to the nuclear periphery. We discuss here the biological implications of these results in the light of our current knowledge in related fields and the potential implication of other CTCF and A-type lamins insulators in the light of human pathologies. PMID- 21327103 TI - Chromosome conformation by crosslinking: polymer physics matters. AB - The genetic information is encoded on double-stranded DNA, a long linear polymer chain. Among the central themes of Nucleus will be the advancement of our understanding of how those chains are folded so that they fit into the cell nucleus, and at the same time their information can be read off efficiently. In fact, a quantitative description of the structure of the folded genome is one of the most challenging problems in structural biology, and poses a much more formidable problem than-for instance-the folding of a protein. There are three main reasons for this: first, the genomic DNA is by orders of magnitude the largest biomolecule in the cell; second, it cannot be defined by a single spatial structure because of its flexibility; and third, even if the 'fold' of the genome were more or less defined in any one cell, variations among individual cells may be very large, for the same reasons of flexibility. PMID- 21327104 TI - LINC complexes in health and disease. AB - The cell nucleus communicates with the rest of the cell via nucleo/cytoplasmic transport of proteins and RNA through the nuclear pores. Direct mechanical links between the nucleus and the cytoplasm have recently emerged in the form of LINC (Linkers of the nucleoskeleton to the cytoskeleton) protein complexes. A LINC complex consists of four components. At its core are an inner nuclear membrane (INM) transmembrane protein and an outer nuclear membrane (ONM) transmembrane protein which physically interact with each other in the lumen of the NE. The INM LINC component interacts on the nucleoplasmic side with either the lamina or with an INM-associated protein. The ONM LINC component on the other hand contacts on the cytoplasmatic side a component of the cytoskeleton. This review highlights the components of LINC complexes and their emerging roles in mechanotransduction, nuclear migration, chromosome positioning, signaling, meiosis, cytoskeletal organization and human disease. PMID- 21327105 TI - Lamin B receptor: multi-tasking at the nuclear envelope. AB - Lamin B receptor (LBR) is an integral membrane protein of the interphase nuclear envelope (NE). The N-terminal end resides in the nucleoplasm, binding to lamin B and heterochromatin, with the interactions disrupted during mitosis. The C terminal end resides within the inner nuclear membrane, retreating with the ER away from condensing chromosomes during mitotic NE breakdown. Some of these properties are interpretable in terms of our current structural knowledge of LBR, but many of the structural features remain unknown. LBR apparently has an evolutionary history which brought together at least two ancient conserved structural domains (i.e., Tudor and sterol reductase). This convergence may have occurred with the emergence of the chordates and echinoderms. It is not clear what survival values have maintained LBR structure during evolution. But it seems likely that roles in post-mitotic nuclear reformation, interphase NE growth and compartmentalization of nuclear architecture might have provided some evolutionary advantage to preservation of the LBR gene. PMID- 21327106 TI - The nucleoporin Nup153 affects spindle checkpoint activity due to an association with Mad1. AB - The nucleoporin Nup153 is known to play pivotal roles in nuclear import and export in interphase cells and as the cell transitions into mitosis, Nup153 is involved in nuclear envelope breakdown. In this study, we demonstrate that the interaction of Nup153 with the spindle assembly checkpoint protein Mad1 is important in the regulation of the spindle checkpoint. Overexpression of human Nup153 in HeLa cells leads to the appearance of multinucleated cells and induces the formation of multipolar spindles. Importantly, it causes inactivation of the spindle checkpoint due to hypophosphorylation of Mad1. Depletion of Nup153 using RNA interference results in the decline of Mad1 at nuclear pores during interphase and more significantly causes a delayed dissociation of Mad1 from kinetochores in metaphase and an increase in the number of unresolved midbodies. In the absence of Nup153 the spindle checkpoint remains active. In vitro studies indicate direct binding of Mad1 to the N-terminal domain of Nup153. Importantly, Nup153 binding to Mad1 affects Mad1's phosphorylation status, but not its ability to interact with Mad2. Our data suggest that Nup153 levels regulate the localization of Mad1 during the metaphase/anaphase transition thereby affecting its phoshorylation status and in turn spindle checkpoint activity and mitotic exit. PMID- 21327107 TI - Molecular characterization of Xenopus lamin LIV reveals differences in the lamin composition of sperms in amphibians and mammals. AB - Lamins are nuclear intermediate filament proteins. They are involved in most nuclear activities and are essential for retaining the mechano-elastic properties of the nucleus. Somatic cells of vertebrates express lamins A, B1 and B2 while lamin LIII, a major component of the amphibian oocyte lamina is absent in mammals. The organization of the lamina of germ cells differs significantly from that of somatic cells. Mammalian spermatogenic cells express two short lamins, C2 and B3, that are splice isoforms of lamin A and B2, respectively. Here we identify the previously described Xenopus lamin LIV as splice variant of the lamin LIII gene. LIV contains 40 extra residues in coil 2A of the rod domain, which results in altered assembly properties. Xenopus lamin LIV and mammalian B3 assemble into short structures rather than into long IF-like filaments. Expression of lamin LIV is restricted to male germ cells suggesting that it might be the functional equivalent of mammalian lamin B3. We provide evidence that lamins C2 and B3 are restricted to the mammalian lineage and describe the lamin composition of Xenopus sperm. Our results show that the evolution of germ cell specific lamins followed separate and distinctly different paths in amphibians and mammals. PMID- 21327108 TI - Dynamic control of Cajal body number during zebrafish embryogenesis. AB - The Cajal body (CB) is an evolutionarily conserved nuclear subcompartment, enriched in components of the RNA processing machinery. The composition and dynamics of CBs in cells of living organisms is not well understood. Here we establish the zebrafish embryo as a model system to investigate the properties of CBs during rapid growth and cell division, taking advantage of the ease of live cell imaging. We show that zebrafish embryo CBs contain coilin and multiple components of the pre-mRNA splicing machinery. Histone mRNA 3' end processing factors, present in CBs in some systems, were instead concentrated in a distinct nuclear body. CBs were present in embryos before and after activation of zygotic gene expression, indicating a maternal contribution of CB components. During the first 24 hours of development, embryonic cells displayed up to 30 CBs per nucleus; these dispersed prior to mitosis and reassembled within minutes upon daughter cell nucleus formation. Following zygotic genome activation, snRNP biogenesis was required for CB assembly and maintenance, suggesting a self assembly process that determines CB numbers in embryos. Differentiation into muscle, neurons and epidermis was associated with the achievement of a steady state number of 2 CBs per nucleus. We propose that CB number is regulated during development to respond to the demands of gene expression in a rapidly growing embryo. PMID- 21327110 TI - Exciting times for gastrointestinal microbiology. PMID- 21327111 TI - Fascinating science, compelling cause. PMID- 21327109 TI - Novel domains in the hnRNP G/RBMX protein with distinct roles in RNA binding and targeting nascent transcripts. AB - The heterogenous nuclear ribonucleoprotein G (hnRNP G) controls the alternative splicing of several pre-mRNas. While hnRNP G displays an amino terminal RNA recognition motif (RRM), we find that this motif is paradoxically not implicated in the recruitment of hnRNP G to nascent transcripts in amphibian oocytes. In fact, a deletion analysis revealed that targeting of hnRNP G to active transcription units depends on another domain, centrally positioned, and consisting of residues 186-236. We show that this domain acts autonomously and thus is named NTD for nascent transcripts targeting domain. Furthermore, using an RNA probe previously characterized in vitro as an RNA that interacts specifically with hnRNP G, we demonstrate a new auxiliary RNA binding domain (RBD). It corresponds to a short region of 58 residues positioned at the carboxyl terminal end of the protein, which recognizes an RNA motif predicted to adopt an hairpin structure. The fact that the NTD acts independently from both the RRM and the RBD strongly suggests that the initial recruitment of hnRNP G to nascent pre-mRNAs is independent of its sequence-specific RNA binding properties. Together, these findings highlight the modular organization of hnRNP G and offer new insights into its multifunctional roles. PMID- 21327112 TI - Infectious diarrhea: Cellular and molecular mechanisms. AB - Diarrhea caused by enteric infections is a major factor in morbidity and mortality worldwide. An estimated 2-4 billion episodes of infectious diarrhea occur each year and are especially prevalent in infants. This review highlights the cellular and molecular mechanisms underlying diarrhea associated with the three classes of infectious agents, i.e., bacteria, viruses and parasites. Several bacterial pathogens have been chosen as model organisms, including Vibrio cholerae as a classical example of secretory diarrhea, Clostridium difficile and Shigella species as agents of inflammatory diarrhea and selected strains of pathogenic Escherichia coli (E. coli) to discuss the recent advances in alteration of epithelial ion absorption. Many of the recent studies addressing epithelial ion transport and barrier function have been carried out using viruses and parasites. Here, we focus on the rapidly developing field of viral diarrhea including rotavirus, norovirus and astrovirus infections. Finally we discuss Giardia lamblia and Entamoeba histolytica as examples of parasitic diarrhea. Parasites have a greater complexity than the other pathogens and are capable of creating molecules similar to those produced by the host, such as serotonin and PGE(2). The underlying mechanisms of infectious diarrhea discussed include alterations in ion transport and tight junctions as well as the virulence factors, which alter these processes either through direct effects or indirectly through inflammation and neurotransmitters. PMID- 21327113 TI - Good fences make good neighbors: Gastrointestinal mucosal structure. AB - The gastrointestinal lumen is home to over 400 species of microorganisms. The composition of this microbial community varies along the length of the gastrointestinal tract as a function of regional epithelial secretory activity as well as diet and other defined and undefined determinants. Improved understanding of the factors that impact luminal microbial populations and development of means to modulate gut microbes for therapeutic benefit hold great promise. The gastrointestinal epithelium, which regulates interactions between microbes and the mammalian host, is the topic of this review. PMID- 21327114 TI - Salmonella SPI-1-mediated neutrophil recruitment during enteric colitis is associated with reduction and alteration in intestinal microbiota. AB - Gastrointestinal infections involve an interactive tripartite relationship between the invading pathogen, the host, and the host's resident intestinal microbiota. To characterize the host inflammatory response and microbiota alterations during enteric salmonellosis, C57BL/6 mice were pre-treated with a low dose of streptomycin (LD model) and then infected with S. typhimurium strains, including mutants in the two Type III secretion systems, SPI-1 and SPI-2 (invAmut and ssaRmut, respectively). Cecal colonization and inflammation in the LD model were evaluated to assess infection success and progression, and compared to the traditional high dose (HD) model. Perturbations to the microbial community in the LD model were assessed via evaluation of total microbial numbers, the proportion of intestinal gamma-Proteobacteria and tRFLP analysis. In the LD model, consistently high colonization by the parental strain (WT) and invAmut S. typhimurium was associated with significant intestinal pathology. However, microbial community profiles were more similar both in numbers and composition between mice infected with the mutant strains, than with the WT strain. Consequently, significant infection-induced inflammation did not always produce similar microbiota perturbations. Large numbers of luminal neutrophils were observed in the ceca of WT-infected, but not in invAmut or ssaRmut infected mice. Neutrophils were thus implicated as a potential mediator of microbiota perturbations during WT enteric salmonellosis. These studies offer a new model of S. typhimurium-induced intestinal disease that retains the three participants of the disease process and further defines the role of virulence factors, the host microbiota, and inflammation in S. typhimurium-induced intestinal disease. PMID- 21327115 TI - Targeting of whole killed bacteria to gastrointestinal M-cells induces humoral immunity in the female reproductive tract. AB - Recently, we demonstrated that oral delivery of whole killed bacteria, when agglutinated by an M-cell targeting lectin, resulted in an enhanced systemic and mucosal antibody response, as well as a protective immunity, against the gut pathogens Helicobacter pylori and Campylobacter jejuni. Importantly, this protection was achieved without the addition of exogenous adjuvant. Here, in this addendum, we extend this initial study by reporting on the vaginal antibody response induced by these vaccinations. These data show that the targeting of M cells within the gastrointestinal tract also induces the secretion of antigen specific antibodies (IgG and IgA) at a distal mucosal site, namely the vaginal mucosa. This observation raises the possibility that oral delivery of a whole, killed bacteria vaccine that target intestinal M-cells could potentially provide a strategy for inducing protective immunity against pathogenic bacteria that infect mucosal sites outside the gastrointestinal tract. PMID- 21327116 TI - Bacterial catabolism of nonulosonic (sialic) acid and fitness in the gut. AB - The term nonulosonic acid or sialic acid encompasses a varied group of nine carbon amino sugars widely distributed among mammals and higher metazoans. Among bacteria, the ability to synthesize sialic acid was first examined in a small number of human pathogenic species that deposit sialic acid on their outer surface. New phylogenomic data suggest that the ability to synthesize sialic acid and sialic acid-like compounds is not a novel bacterial innovation but a much more widespread ancient trait. In contrast, the genes required for the catabolism of sialic acid are found only among pathogenic and commensal bacterial species. This ability to utilize sialic acid as a carbon source is correlated with bacterial virulence, especially, in the sialic acid rich environment of the gut. In this article, we present the most recent findings in sialobiology with a focus on sialic acid catabolism. PMID- 21327117 TI - The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. AB - We have recently shown that the colon is protected by an inner mucus layer that efficiently separates the bacteria in the outer mucus from the epithelial cells. The inner mucus is impervious for bacteria and built by a network formed by the MUC2 mucin. Lack or defects in this inner mucus layer allow bacteria to reach the epithelia, something that triggers colon inflammation. PMID- 21327118 TI - Microbial regulation of SAA3 expression in mouse colon and adipose tissue. AB - Recently, we demonstrated that colonic and adipose expression of SAA3 was modulated by the gut microbiota and Toll-like receptor signaling in mice. We observed that SAA3 was expressed by colonic epithelial cells and that its expression was induced in a murine colonocyte cell line following lipopolysaccharide stimulation and nuclear NFkappaB translocation. In this addendum, we extend this initial study and suggest that SAA3 (1) resembles human SAA1 both in amino acid homology and tissue distribution, (2) appears to have autocrine or paracrine effects rather than endocrine, and (3) binds to bacteria within the gastrointestinal tract. Although speculative, these observations raise the possibility that SAA3 may promote local inflammation in adipose tissue that affects insulin signaling and also function as an antimicrobial agent in the colon. PMID- 21327119 TI - Cross-talk between iron homeostasis and intestinal inflammation. AB - Recent publications from my laboratory have highlighted the important influence of altered iron homeostasis on the inflammatory response to intestinal bacteria. Here, I provide commentary on one of those papers, "Selective modulation of TLR4 activated inflammatory responses by altered iron homeostasis in mice", which was published in the Journal of Clinical Investigation in November, 2009. It describes experiments that point to a previously unappreciated role for intracellular iron in the regulation of Toll-like receptor 4 signaling, and also demonstrates the potential therapeutic application of this information in a novel anti-inflammatory strategy based on manipulating iron balance. Our findings indicate that further investigation of the cross-talk between iron homeostasis and inflammation will yield new insights into the pathogenesis of chronic inflammatory diseases and may suggest new treatment approaches for these conditions. PMID- 21327120 TI - Salmonella's iron armor for battling the host and its microbiota. AB - Most Salmonella enterica serotypes are associated with acute intestinal inflammation and diarrhea in humans. While the mechanisms triggering intestinal inflammation are well studied, relatively little is known about how the pathogen benefits from causing disease. Recent work has provided first insights into the genetic design that enables S. enterica to benefit from the host response by outgrowing the microbiota in the gut. The pathogen gained an edge over its competitors by acquiring genes conferring resistance against antimicrobials, such as lipocalin-2, that are encountered in the intestinal lumen only during inflammation. This strategy enables the pathogen to exploit host responses to gain a competitive advantage over other microbes during its growth in the inflamed gut. PMID- 21327122 TI - Bioengineered bugs, drugs and contentious issues in patenting. AB - Bioengineered bugs, as is the scope of this journal, have great potential in various practical applications. A corollary to bringing useful products to the market is that such products need protection from copying by other people or businesses. Such government-sponsored protections are legally enforced through a patent, copyright or trademark/trade secret system commonly known as intellectual property rights. A condition for obtaining a patent is that the invention must not be disclosed to public either through seminars, informal public disclosures or publications in journals, although in the United States, there is a one year grace period that is allowed to obtain a patent after public disclosure. This article describes my personal experience in obtaining a patent in 1980 on a genetically manipulated bacterium designed for oil spill cleanup. This patent application went through a series of court cases that finally ended up in the Supreme Court of the United States. I also mention a similar contentious legal issue that is on the horizon and that the readers of Bioengineered Bugs should be aware of. Finally, I have taken the opportunity to describe my current efforts to bring to the market some unique potential multi-disease-targeting candidate drugs from Pseudomonas aeruginosa and gonococci/meningococci that, if found non-toxic and efficacious in humans, will revolutionize the drug industry. To ensure their marketability, we are trying to develop a patent portfolio that will ensure that they will be legally protected and such protections will be broad-based and enforceable. PMID- 21327123 TI - Recombinant bacteriophage lysins as antibacterials. AB - With the increasing worldwide prevalence of antibiotic resistant bacteria, bacteriophage endolysins (lysins) represent a very promising novel alternative class of antibacterial in the fight against infectious disease. Lysins are phage encoded peptidoglycan hydrolases which, when applied exogenously (as purified recombinant proteins) to Gram-positive bacteria, bring about rapid lysis and death of the bacterial cell. A number of studies have recently demonstrated the strong potential of these enzymes in human and veterinary medicine to control and treat pathogens on mucosal surfaces and in systemic infections. They also have potential in diagnostics and detection, bio-defence, elimination of food pathogens and control of phytopathogens. This review discusses the extensive research on recombinant bacteriophage lysins in the context of antibacterials, and looks forward to future development and potential. PMID- 21327124 TI - Receptor mimicry as novel therapeutic treatment for biothreat agents. AB - The specter of intentional release of pathogenic microbes and their toxins is a real threat. This article reviews the literature on adhesins of biothreat agents, their interactions with oligosaccharides and the potential for anti-adhesion compounds as an alternative to conventional therapeutics. The minimal binding structure of ricin has been well characterised and offers the best candidate for successful anti-adhesion therapy based on the Galbeta1-4GlcNAc structure. The botulinum toxin serotypes A-F bind to a low number of gangliosides (GT1b, GQ1b, GD1a and GD1b) hence it should be possible to determine the minimal structure for binding. The minimal disaccharide sequence of GalNAcbeta1-4Gal found in the gangliosides asialo-GM1 and asialo-GM2 is required for adhesion for many respiratory pathogens. Although a number of adhesins have been identified in bacterial biothreat agents such as Yersinia pestis, Bacillus anthracis, Francisella tularensis, Brucella species and Burkholderia pseudomallei, specific information regarding their in vivo expression during pneumonic infection is lacking. Limited oligosaccharide inhibition studies indicate the potential of GalNAcbeta1-4Gal, GalNAcbeta-3Gal and the hydrophobic compound, para-nitrophenol as starting points for the rational design of generic anti-adhesion compounds. A cocktail of multivalent oligosaccharides based on the minimal binding structures of identified adhesins would offer the best candidates for anti-adhesion therapy. PMID- 21327126 TI - Optimal epitope composition after antigen screening using a live bacterial delivery vector: application to TRP-2. AB - Immunotherapeutic approaches, based on the generation of tumor-specific cytotoxic T-lymphocytes (CTL), are currently emerging as promising strategies of anti-tumor therapy. The potential use of attenuated bacteria as engineered vectors for vaccine development offers several advantages, including the stimulation of innate immunity. We developed an attenuated live bacterial vector using the type III secretion system (TTSS) of Pseudomonas aeruginosa to deliver in vivo tumor antigens. Using an inducible and rapid expression plasmid, vaccination with several antigens of different length and epitope composition, including TRp-2, gp100 and MUC18, was evaluated against glioma tumor cells. We observed similar CTL immunity and T-cell receptor (TCR) repertoire diversity with the vaccines, TRP2(125-243), TRP2L(125-376) and TRP2S(291-376). However, only immunization with TRP2L(125-376) induced significant anti-tumor immunity. Taken together, our data indicate the importance of the epitopes composition and/or peptide length of these peptides for inducing cytotoxic T-lymphocyte (CTL) mediated immunity. Characteristics that consistently improved anti-tumor immunity include: long peptides with immunodominant and cryptic CD8(+) epitopes, and strong CD4(+) Th epitopes. Our bacterial vector is versatile, easy-to-use and quick to produce. This vector is suitable for rapid screening and evaluation of antigens of varying length and epitope composition. PMID- 21327127 TI - In vivo persistence and protective efficacy of the bacille Calmette Guerin vaccine overexpressing the HspX latency antigen. AB - New strategies to control infection with Mycobacterium tuberculosis, the causative agent of tuberculosis, are urgently required, particularly in areas where acquired immunodeficiencies are prevalent. In this report we have determined if modification of the current tuberculosis vaccine, Mycobacterium bovis BCG, to constitutively express the mycobacterial HspX latency antigen altered its protective effect against challenge with virulent M. tuberculosis. Overexpression of M. tuberculosis HspX in BCG caused reduced growth in aerated cultures compared to control BCG, but growth under limited oxygen availability was not markedly altered. Upon infection of mice, BCG:HspX displayed tissue specific attenuation compared to control BCG, with reduced growth within the lung and liver but not the spleen. Both BCG:HspX and control BCG protected mice against aerosol M. tuberculosis challenge to a similar extent, however, immunodeficient mice infected with BCG:HspX survived significantly longer than mice infected with the control BCG strain. Therefore, altering the in vivo persistence of BCG by overexpression of HspX may be one important step towards developing a new tuberculosis vaccine with an improved safety profile and suitable protective efficacy against M. tuberculosis infection. PMID- 21327125 TI - Bacillus thuringiensis: a genomics and proteomics perspective. AB - Bacillus thuringiensis (Bt) is a unique bacterium in that it shares a common place with a number of chemical compounds which are used commercially to control insects important to agriculture and public health. Although other bacteria, including B. popilliae and B. sphaericus, are used as microbial insecticides, their spectrum of insecticidal activity is quite limited compared to Bt. Importantly, Bt is safe for humans and is the most widely used environmentally compatible biopesticide worldwide. Furthermore, insecticidal Bt genes have been incorporated into several major crops, rendering them insect resistant, and thus providing a model for genetic engineering in agriculture.This review highlights what the authors consider the most relevant issues and topics pertaining to the genomics and proteomics of Bt. At least one of the authors (L.A.B.) has spent most of his professional life studying different aspects of this bacterium with the goal in mind of determining the mechanism(s) by which it kills insects. The other authors have a much shorter experience with Bt but their intellect and personal insight have greatly enriched our understanding of what makes Bt distinctive in the microbial world. Obviously, there is personal interest and bias reflected in this article notwithstanding oversight of a number of published studies. This review contains some material not published elsewhere although several ideas and concepts were developed from a broad base of scientific literature up to 2010. PMID- 21327128 TI - Efficacy of a Lactococcus lactis DeltapyrG vaccine delivery platform expressing chromosomally integrated hly from Listeria monocytogenes. AB - Listeria monocytogenes is a significant food-borne pathogen and the causative agent of listeriosis, a disease which manifests as meningitis in immunocompromised adults or infection of the fetus and miscarriage in pregnant women. We have previously used Lactococcus lactis, a GRAS (Generally Regarded As Safe) organism, as a vaccine vector against listeriosis by engineering plasmid mediated expression of the immunodominant antigen from L. monocytogenes, listeriolysin O (LLO). However, the environmental release of an engineered vaccine vector carrying a replicating plasmid during clinical usage may raise safety concerns. Here we describe the integration of the LLO gene (hly) into the L. lactis chromosome through homologous double crossover to allow stable expression, in order to avoid the use of antibiotic selection markers and to eliminate the requirement for a plasmid-based system. The approach was designed to simultaneously eliminate the pyrG gene encoding the CTP synthase which is responsible for converting UTP to CTP in a unique step in the de novo pyrimidine synthesis in L. lactis. This gene was targeted in order to restrict bacterial replication outside of the host (biological containment). The resulting cytidine auxotroph was able to secrete LLO constitutively and could elicit LLO(91-99) specific CD8(+) T lymphocytes in the murine infection model. Moreover, protection against lethal challenge with L. monocytogenes was accomplished after intraperitoneal (IP) vaccination with the constructed strain. The implications for the use of cytidine auxotropy in biological containment are discussed. PMID- 21327129 TI - Biocontainment strategies for live lactic acid bacteria vaccine vectors. AB - Stability is an important issue when engineering bacteria for use as live vaccine vectors. For the majority of live bacterial vaccines, the antigen-encoding gene is either plasmid located or integrated into the chromosome. Regardless, several safety concerns can be raised for both instances. One concern when using plasmid encoded antigens is the transfer of antibiotic resistance markers. Alternatively, for chromosomal integrated antigens however, the concern focuses on the spread and possible release of genetically-modified microorganisms (GMM) into the environment, which is problematic. Their recombinant nature calls for a proper bio-containment strategy to be implemented or in place before any realistic attempt at releasing a live bacterial vaccine. No examples of human bacterial vaccines causing problems among animals have been found in the literature but the possibility exists and has to be both tested and evaluated before release of a live bacterial vaccine. The ideal GMM for use in humans should therefore contain the minimal amount of foreign DNA and must not include an antibiotic resistance marker. Furthermore, the possibilities of transgene horizontal transfer must be minimized, and GMM lethality for biocontainment should be achieved in an unconfined environment. PMID- 21327131 TI - Epilepsy in rural Ugandan children: seizure pattern, age of onset and associated findings. AB - INTRODUCTION: Much information on childhood epilepsy in sub Saharan Africa is hospital based. A survey was considered necessary before integrating epilepsy management into a Ugandan community programme. METHOD: Using an 'outreach' method, children with recurrent seizures were offered assessment at 19 sites in Rukungiri District. A brief history and neurological and developmental assessment was carried out on each child. A clinical diagnosis of epilepsy, including seizure type, was given to 440 of 618 children <18 years with 178 exclusions. RESULTS: The age-specific prevalence of epilepsy in children < 15 years was 2.040/00 (95% CI 1.940/00 to 2.24 0/00) based on 395 cases in an <15 years population of 193,126. Percentage distribution by seizure type was:-generalised tonic-clonic (53%), complex partial seizures CPS (27%), simple partial and miscellaneous seizures (6% each), with some diagnostic overlap between seizure types. Cerebral palsy, evident or evolving, was most strongly associated with CPS. A positive perinatal or infantile history was noted in 12 and 6% respectively, and 50.2% of seizures began in infancy. CONCLUSIONS: The prevalence of epilepsy is similar in Gambian children. The high contribution from early onset CPS, resembles Kenyan reports of malaria-associated CPS, suggesting a causal association with malaria. PMID- 21327132 TI - Tuberculosis in rural Uganda. AB - BACKGROUND: St Francis Hospital, a health facility in the rural district of Mayuge, Uganda. OBJECTIVES: To evaluate the presentation, course and outcome of patients with tuberculosis hospitalized to receive the intensive phase of treatment. METHOD: Observational analytical study of all patients admitted during June 2002-March 2005. RESULTS: There were 680 patients. Their median age was 31 years (range 2-75); 364 (54 %) were male. There were 564 (83 %) new patients; 60 (9 %) defaulters; 35 (5 %) relapses; 14 (2 %) transfers; four chronic patients; and three treatment failures. Three hundred and thirteen patients (58 %) had moderate or severe malnutrition on admission. Among 102 patients tested for the human immunodeficiency virus, 68 (67 %) were positive. At the end of hospitalization 593 patients (87 %) were to be followed-up at St Francis Hospital or were transferred to another health facility, 31 (5 %) had absconded and 56 (8 %) had died. CONCLUSION: The severely limited resources of our patients and the human immunodeficiency virus co-infection are likely factors contributing to their late presentation and the severity of the disease. It is doubtful that in our setting tuberculosis can be effectively controlled without addressing and correcting these factors. PMID- 21327133 TI - Risk factors for indoor air pollution in rural households in Mauche division, Molo district, Kenya. AB - BACKGROUND: Exposure to indoor air pollution may be responsible for nearly 2 million per year deaths in developing countries. In Kenya, it is among the factors linked to high morbidity, especially in children aged below five years. OBJECTIVES: The survey was conducted in 2005 in 350 rural households to identify household factors that are likely to enhance indoor air pollution. METHODS: Questionnaire, continuous and spot observations were used to collect data on household characteristics, type of primary building in homestead, number of rooms, type of ventilation present and type of fuel used by the household. RESULTS: State of housing and type of fuel used were found to be likely risk factors for indoor air pollution. Fifty two point six percent of those interviewed live in mud walled houses with iron sheet roofs. Ninety one percent live in either single or two roomed houses. Ventilation is provided both by small windows and a space left in between the wall and roof. Thirty seven percent of observed houses have no windows. In all households, fuel wood is used for cooking. CONCLUSION: State of housing and fuel used in sampled households encourage indoor air pollution, which has been associated with various diseases. PMID- 21327134 TI - Electocardiographic findings in adult Nigerians with sickle cell anaemia. AB - BACKGROUND: Cardiovascular system abnormalities are common causes of morbidity and mortality in sickle cell anaemia. OBJECTIVES: The study aims at determining the pattern of electrocardiographic changes in adult Nigerian sickle cell anaemia patients. METHODS: A descriptive cross sectional study was done on sixty sickle cell anaemia patients seen at the adult sickle cell clinic of University of Nigeria Teaching Hospital (UNTH) Enugu, and sixty age and sex matched normal controls. All the subjects had clinical evaluation as well as electrocardiographic examination. RESULTS: The mean heart rate, P-wave duration, P-wave dispersion, PR interval, QRS duration, QRS dispersion, QTc interval and QTc dispersion were significantly higher in the patients than in the control group. Electrocardiographic abnormalities identified by this study were: left ventricular hypertrophy (75%; 1.7%), left atrial enlargement (40%; 0%), biventricular hypertrophy (11%; 0), ST-segment elevation (10%; 0%) and increased P-wave and QTc dispersions. ST segment elevation was found more in patients with moderate and severe anaemia (P= 0.02, Spearman correlation r= 0.342; P= 0.007), CONCLUSION: Sickle cell anaemia is associated with significant electrocardiographic abnormalities. Further prospective studies are recommended to evaluate the prognostic significance of the electrocardiographic intervals dispersion on the long term disease outcome in sickle cell anaemia. PMID- 21327135 TI - Morphology of human myocardial bridges and association with coronary artery disease. AB - BACKGROUND: The functional significance of myocardial bridging remains controversial. The bridge morphology and structure of the tunneled vessels may modify its ultimate clinical effects. OBJECTIVE: To describe the morphological characteristics of myocardial bridges and their influence on coronary histology. DESIGN: A descriptive cross-sectional study. METHODS: One hundred and nine formalin-fixed adult hearts were evaluated by dissection for these data: prevalence, site, lengths and depths of myocardial bridges. Vessel segments proximal and distal to the bridged portion were also processed for histology and stained to elaborate smooth muscle, collagen and elastic fibers. Stereology was also employed to compare the relative sizes of the tunica intima and the vessel wall to lumen ratios. RESULTS: Myocardial bridges were found in 40.4% of the hearts, most commonly in the left anterior descending artery (LAD). The average length of the bridges was 22.66 +11.94 mm while the depth was 1.83+ 0.98mm, with only 11% being long (34.87mm - 50mm) and 9% of them being deep (3.46mm - 5.00mm). The tunica intima was thickest proximal to and thinnest under the myocardial bridge. The intima of the proximal segment was also more elastic. An elaborate perivascular 'cushion' of adipose tissue intervened between the intramural coronary and the surrounding myocardium. CONCLUSIONS: Most myocardial bridges are superficial and short. Tunica intima under myocardial bridges is spared from "atherogenesis". The thick perivascular space around the bridged segment may protect it from extreme compression. PMID- 21327136 TI - Atherogenic index of plasma as useful predictor of cardiovascular risk among postmenopausal women in Enugu, Nigeria. AB - BACKGROUND: Menopausal health in our environment has received little attention. As an independent risk factor for dyslipidaemia, the degree and pattern of derangement, though difficult to assess may adversely affect the cardiovascular health of our women. OBJECTIVES: To estimate the serum lipid profile and the atherogenic index of plasma in normal post menopausal women. METHODS: This is a cross sectional study involving 80 apparently healthy women voluntarily recruited from staff of the University of Nigeria and the Teaching Hospital (UNTH) located in Enugu. They include 50 postmenopausal subjects aged between 50 and 70 years and 30 premenopausal controls aged between 25 and 49 years. Total cholesterol (TC), and the various subfractions; high density lipoprotein cholesterol (HDL-C), very low density lipoprotein cholesterol (VLDL-C), low density lipoprotein cholesterol (LDL-C) and triglycerides (TG) were determined. Atherogenic index of plasma (AIP); log (TG/HDL-C) was calculated. RESULTS: There were statistically significant increases (P< 0.0001) in TC, TG, LDL-C, VLDL-C and AIP but a statistically significant decrease (P<0.0001) in HDL-C in postmenopausal women when compared with the premenopausal subjects. Except HDL-C that showed insignificant reduction, there were statistically significant derangement of other lipid subfractions as the duration of menopause increased. CONCLUSION: Menopause, no doubt alters lipid profile. A triglyceride based index (AIP) can significantly add value when assessing the risk of developing atherosclerosis in Nigeria. PMID- 21327137 TI - Patent medicine vendors, community pharmacists and STI management in Abuja, Nigeria. AB - BACKGROUND: Increasingly, literature indicates that Patent Medicine Vendors (PMVs) and Community Pharmacists (CPs) provide sexual reproductive health services and products to their young patrons. OBJECTIVES: This study explored the validity of literature claims, principally from CPs and PMVs perspective in Abuja, Nigeria. METHODS: Participants were recruited with convenience sampling based on their willingness to participate in the study and our judgement of their professional competence. They were administered a semi-structured questionnaire, which was modelled after McCracken's long interview. We empirically assessed the validity of CPs and PMVs opinions with an exit interview of seven consenting patrons. Interviews were audio taped, transcribed verbatim and subjected to iterative thematic analysis. RESULTS: Participants' accounts and our observations indicate that PMVs and CPs serve young people's sexual reproductive healthcare needs in Abuja. CPs and PMVs provide young people with a seamless and non judgemental access to contraceptives, sexual health advice and post-sexual risk exposure care. CONCLUSION: The study corroborates literature claims that CPs and PMVs provide sexual reproductive health advice, services and products to young people. However, participants contend that the current pharmacy practice laws in Nigeria constrain the scope and quality of services that young unmarried people require. Because it is unlikely that Nigeria will reinvigorate her primary healthcare system soon, we call for the formal co-option of CPs and PMVs into the sexual reproductive health management system to standardize and improve services. PMID- 21327138 TI - Pattern of death in a Nigerian teaching hospital; 3-decade analysis. AB - BACKGROUND: In developing countries such as Nigeria, limited resources require that health priorities be selected wisely and death-related research is clearly warranted. The aim of this study is to provide a comprehensive report on the various causes of death in our center from 1978 to 2006. METHODS: This was a descriptive, retrospective study of all deaths recorded at the Obafemi Awolowo University Teaching Hospitals Complex (OAUTHC), Ile - Ife, Osun State in Southwest Nigeria from 1978 to 2006. RESULT: A total number of 9,947 deaths were recorded during the study period and there were 6,277 male deaths (63.1%) and 3,670 female deaths (36.9%) with a female to male ratio of 1:1.5. The age ranged from birth to 100 years with a median of 25 years. Infection (2,594 patients; 26.1%) was the most common cause of death and this was followed closely by trauma death (2,028 patients; 20.4%) and neonatal death (1,074 patients; 10.8%). Death from infectious disease and trauma reduced from 1,048 and 1,441 in the first decade (1977 - 1986) to 478 and 133 in the last decade respectively. While death from neoplasia increased from 112 in the first decade to 354 in the last decade of the study period. CONCLUSION: Our study shows that death from infectious disease in the present decade has reduced to almost half that was recorded in first decade. Similarly death from trauma has also reduced compared to the first decade of the study. Death from neoplasia is however higher in the last decade. PMID- 21327139 TI - Self-destruction by multiple methods during a single episode: a case study and review of the literature. AB - BACKGROUND: Although the prevalence of suicide in the world is not clear, however, the reported rates of suicides are consistently higher among men tan women regardless of age group. METHODS: A case employing multiple methods during a brief time of self-destructive behavior is presented. A 44-year-old postmaster who was under criminal investigation by his head office for embezzlement, leaped down a high river cliff and drowned after an initial attempt to commit suicide by hanging from the bridge over the river. The autopsy and scene investigations were both employed and very helpful. RESULTS: Three different methods of suicide were apparent in this instance: hanging, leaping down the cliff and drowning as was evidenced by the autopsy and positive diatom test. The complexity of this case was the planned protection against the failure of one method employed to commit suicide. The methods used were all highly lethal ones. There was neither history of previous suicide attempts nor psychiatric disorder. CONCLUSION: Although the cause of death may appear clear at autopsy in cases of self-destruction by multiple highly lethal methods during a single episode, scene investigation is important for the forensic pathologist to understand the whole story of the case and determine the manner and actual cause of death. Scene investigation and autopsy is emphasized as part of the whole postmortem investigation of death in cases of unusual suicide using multiple methods of self-destruction. PMID- 21327140 TI - Antidiabetic and haematinic effects of Parquetina nigrescens on alloxan induced type-1 diabetes and normocytic normochromic anaemia in Wistar rats. AB - BACKGROUND: The plant, Parquetina nigrescens is used in folklore medicine to treat diabetes mellitus and its complications in several parts of West Africa. OBJECTIVE: To determine the effect of Parquetina nigrescens extract on fasting blood glucose in alloxan-induced diabetic rats. METHODS: The blood glucose levels, complete blood count, erythrocyte indices and osmotic fragility, body and organ weights were evaluated. RESULTS: Diabetic rats treated with the extract showed significant (P<0.01) reduction of the blood glucose to levels comparable to that of the non-diabetic control and those treated with chlorpropamide (standard drug). Similarly, there was significant (P<0.01) reduction in the complete blood count in the diabetic rats. DISCUSSION: The anaemia, leucopenia and thrombocytopenia associated with the diabetes were corrected in the animals treated with the extract and chlorpropamide. The extract also reduced the erythrocyte osmotic fragility, body and organ weights. Parquetina nigrescens demonstrated antidiabetic property by reducing the elevated blood glucose in alloxan treated rats which is comparable to animals that received the standard drug. CONCLUSION: Paraquetina nigrescens stabilized the erythrocyte membrane, decreased the body weight probably by lowering lipogenesis. However, the mechanism underlying the antidiabetic and haematinic properties of Parquetina nigrescens remains to be elucidated. PMID- 21327141 TI - Ameliorative effects of Cnidoscolus aconitifolius on alloxan toxicity in Wistar rats. AB - BACKGROUND: Diabetes has been associated with several complications occasioned by oxidative stress. Thus, in treatment of the condition, these complications must also be taken into consideration. This study evaluates the effect of Cnidoscolus aconitifolius complications of diabetes induced by alloxan, on haematology and sperm morphometry using the Wistar rats. METHODS: Diabetes was induced in 25 rats using alloxan. The diabetic rats were then divided into five groups B-F consisting of five rats per group. Groups C-E were administered with 100 mg/kg, 500 mg/kg and 1000 mg/kg of ethanolic leaves extract of Cnidoscolus aconitifolius, respectively, for four weeks post treatment with alloxan, while group F received Chlorpropamide (Diabenes(r), Pfizer). The diabetic rats in group B were not treated while group A served as the non diabetic control. RESULT: Following treatment with alloxan, there was anaemia, thrombocytopenia and leucopenia, while the sperm count, motility and live/dead ratio were significantly reduced. Sperm morphological abnormalities and erythrocyte osmotic fragility also increased significantly. Following treatment of alloxan treated rats with the extract, there were significant increases in the PCV, RBC, Hb, WBC, MCV and the platelet values. Erythrocyte osmotic fragility, sperm count, motility and live/dead ratio also improved significantly. CONCLUSION: Cnidoscolus aconitifolius extract was found to ameliorate the effects of alloxan induced diabetes on the haematology but not on the abnormal sperm morphometry in rats. PMID- 21327142 TI - Does general surgery clerkship make a future career in surgery more appealing to medical students? AB - BACKGROUND: Medical students' decreasing interest in surgical careers has raised much concern. This report is to ascertain the influence of surgical clerkship on the perceptions of medical students on prospects of a future career interest in surgery. METHODS: A cross sectional study, involving final year medical students. Information concerning their interest in a surgical career, what they thought of surgery before and after general surgery clerkship was obtained. RESULTS: A total of 120 medical students participated in the study. The age range was 24 - 36 years (mean 27+2). There were 87 (72.5%) males and 33(27.5%) females. Ten students (8.0%) were interested in surgery before their last surgery clerkship, 18 (15%) Obstetric and Gynaecology, 92(76.6%) others. Those that developed interest in surgery following the clerkship increased to 33 (27.5%) (P<0.001), 34 (28.3%) Obstetric & Gynecology, while other specialties reduced to 53 (44.2%). One hundred and one (84.2%) (M = 71, F = 30) students believe they had identified a role model or a mentor during the clerkship, either a consultant or a resident. Eighty eight (73.3%) (M = 62, F = 26) student who liked and loved surgery at the end of the clerkship identified surgical mentors during their time. CONCLUSION: General surgical clerkship has influence on future career in surgery among medical students. Focused and effective mentoring by faculty as well as early exposure of students to positive role models should help to reverse negative impressions held by students. PMID- 21327143 TI - Progress in dracunculiasis eradication in Oyo state, South-west Nigeria: a case study. AB - BACKGROUND: Dracunculiasis currently occurs in only 5 countries, Nigeria inclusive. OBJECTIVE: To study the prevalence and management of the guinea worm disease at the threshold of its eradication in Oyo state. METHODS: KAP questionnaires were administered to head of households and cyclopoid copepods in domestic water sources were identified and checked for infection. Prevalence of infection in the study population was monitored and reasons for continued transmission in the area ascertained. RESULTS: Fifty three cases were reported in study area in 2004 and 2005 but no cases in 2006. Five hundred head of households were interviewed in ten villages. 43.9% believe the disease is in the blood and further probing shows that 54.6% believe infection is due to inherited susceptibility. 1.8% used antibiotics for treatment while 37.1% used herbs. Boreholes, wells, treatment of ponds with AbateTM, filter distribution and health education were interventions in place. Un-infected Halicyclops korodiensis and Africyclops curticornis were recovered from ponds. CONCLUSION: Ignorance especially belief in inherited susceptibility, lack of sustained safe water sources and influx of infected immigrant farmers are major variables responsible for the continued presence of the disease in the state. PMID- 21327144 TI - Cervical Klippel-Feil syndrome predisposing an elderly African man to central cord myelopathy following minor trauma. AB - An otherwise-healthy, active 83-year-old Nigerian man developed reversible central cord myelopathy from a mild fall on a level surface. Cervical spine magnetic resonance imaging (MRI) revealed C5, 6, and 7 block vertebrae and marked disc extrusions only at the immediately adjoining upper and lower non-fused segments of the cervical spine. There was no spinal canal stenosis otherwise. We think that the unique presentation of this case of Klippel-Feil syndrome further supports the impression that following fusion (congenital or acquired) of one segment of the spinal column, hypermobility of the non-fused adjoining segments may strongly predispose to more disc extrusions. PMID- 21327145 TI - Deportation of trophoblastic emboli to maternal lung: A source of cell-free DNA in maternal blood? AB - During human pregnancy there is a continuous transport of numerous syncytiotrophoblastic cells from the intervillous space of the placenta into the maternal lung. There these cells undergo apoptosis and the fetal nuclear DNA is liberated within the pulmonary capillaries to become cffDNA in the maternal serum. We have examined the sections of lungs of 11 pregnant women (from 8 weeks to term gestation) who had come to the Medical Examiner's Offices after their traumatic demise. We then identified the deported, embolized trophoblastic cells in pulmonary capillaries and attempted to show them to contain hCG immunohistochemically but were unable to do this. We also determined their apoptotic profiles by TUNEL reaction. PMID- 21327146 TI - The voices of Chimerism. PMID- 21327147 TI - Maternal and fetal microchimerism in granulocytes. AB - Cell trafficking during pregnancy may result in durable microchimerism, both fetal microchimerism in the mother and maternal microchimerism in her children. Whether microchimerism is continuously replenished has not been well-described. To address this question, we isolated granulocytes, cells with relatively short half-lives, from peripheral blood of healthy women. CD66b-positive cells were isolated by fluorescence activated cell sorting and a panel of polymorphism specific quantitative pCR assays was employed to investigate fetal and maternal microchimerism. Overall 33% (10/30) of study subjects had at least one source of microchimerism in CD66b(+) cells. Interestingly, maternal microchimerism was more common than fetal microchimerism, 40% vs. 15%, respectively (p = 0.05) and was present at higher levels (p = 0.03). The identification of maternal and fetal origin CD66b(+) cells is strong evidence for an active microchimeric hematopoietic stem and progenitor cell niche. Furthermore, microchimeric CD66b(+) cells could have an impact on innate and adaptive immune responses. PMID- 21327148 TI - How microchimerism can impart HLA susceptibility in patients with rheumatoid arthritis. AB - Rheumatoid arthritis, a chronic inflammatory joint disease, is strongly associated with HLA-DRB1*01 and *04 alleles that have in common similar 5-amino acid motifs in the third hypervariable region of DRB1 (QKRAA, QRRAA, RRRAA), the so called shared epitope (SE). Most patients with RA carry 1 or 2 doses of the SE, with particular genetic combinations at higher risk. In recent work we provided evidence that patients who lack HLA-DRB1*01 and/or *04 alleles can acquire RA susceptibility through fetal, maternal or iatrogenic microchimerism. We also discuss how Mc carrying HLA-DRB1*04 alleles is more likely to be present in the peripheral blood of RA patients compared to Mc carrying HLA-DRB1*01 alleles. We further analyze our results in light of the hierarchy for RA risk with different combinations of the SE. How Mc could contribute to RA susceptibility and whether it also contributes to the hierarchy of risk observed with particular combinations of SE-containing alleles is certainly the beginning of an intriguing story and may offer hope for future therapeutic and/or preventative interventions. PMID- 21327149 TI - Combining Treg therapy with mixed chimerism: Getting the best of both worlds. AB - Deliberate establishment of donor-specific immunologic tolerance is considered to be the "Holy Grail" in transplantation medicine, but clinical tolerance protocols for routine organ transplantation are still an unmet need. Mixed hematopoietic chimerism is an attractive tolerance strategy with considerable potential. Recent pilot trials provide proof-of-principle that mixed chimerism can induce tolerance in renal transplant recipients. Routine clinical translation, however, is impeded by the side effects of the cytotoxic recipient conditioning necessary for the transient engraftment of HLA-mismatched BM. In murine studies recently published in The American Journal of Transplantation, we demonstrated that the therapeutic application of polyclonal recipient regulatory T cells (Tregs) leads to engraftment of practicable doses of fully allogeneic BM and to donor-specific tolerance without any cytotoxic conditioning, thereby eliminating a major impediment for the clinical translation of the mixed chimerism strategy in the experimental setting. The background and the implications of these findings are discussed. PMID- 21327150 TI - Long-term feto-maternal microchimerism revisited: Microchimerism and tolerance in hematopoietic stem cell transplantation. AB - Bidirectional fetal-maternal cell traffic during pregnancy gives rise to stable persistence of minute amounts of allogeneic cells both in the mother and in her offspring, a phenomenon called long-term fetal or maternal microchimerism. Over the past decade, increasing attention has been devoted to elucidating the biological relevance of such reciprocal microchimerism, unveiling its conflicting roles in either immune sensitization or tolerance induction against fetal or maternal alloantigens. Recent studies in mice and humans have highlighted the significance of fetal-maternal microchimerism in the induction and maintenance of CD4(+)CD25(+) and CD8(+) T regulatory cells that counterbalance the immune responses to fetal or maternal antigens mediated by T effector cells. Consistent with these observations, T-cell-replete hematopoietic stem cell transplantation between mutually microchimeric mothers and their HLA-haploidentical offspring has been shown to be feasible, although the degree of microchimerism-associated tolerance appears to substantially differ among the cases. Since in vitro or trans-vivo assays to detect antigen-specific tolerance in the context of the T regulator versus T effector balance are now available, future clinical studies incorporating these tests into the criteria for donor selection are warranted to more precisely define the relevance of fetal-maternal microchimerism in allotolerance and immune homeostasis after hematopoietic stem cell transplantation. PMID- 21327151 TI - The pendulum swings: Tolerance versus priming to NIMA. AB - Fetal and/or perinatal exposure to noninherited maternal antigens (NIMA) has been reported to induce NIMA-specific tolerance. This tolerant state is highly beneficial in transplantation settings; enhanced graft acceptance has been observed when transplanted tissues express NIMA. Reduction in severe graft-vs host disease has also been noted when bone marrow grafts originate from donors exposed to NIMA in early life. However, there is emerging evidence that exposure to NIMA can alternatively lead to specific priming. The processes regulating tolerance versus priming to NIMA are poorly understood and probably multifactorial. Based on studies in both humans and mice, we propose that both the quality and the quantity of NIMA exposure will be found to be key determinants of these opposing outcomes. PMID- 21327152 TI - Breast milk and transplantation tolerance. AB - Recent experimental and clinical studies suggest that exposure of the fetus to noninherited maternal antigens (NIMAs) during pregnancy has an impact on allogeneic transplantations performed later in life. We have reported that NIMA exposure by breastfeeding further potentiates the tolerogenic NIMA effect mediated by in utero NIMA exposure during pregnancy in mice of allogeneic hematopoietic stem cell transplantation (HSCT). Breastfeeding generates Foxp3(+) regulatory T cells that suppress anti-maternal immunity and persist until adulthood. These results reveal a previously unknown impact of breastfeeding on the outcome of allogeneic HSCT. PMID- 21327153 TI - Epigenetic approaches for the detection of fetal DNA in maternal plasma. AB - The presence of fetal DNA in the plasma of pregnant women has opened up new possibilities for noninvasive prenatal diagnosis. Over the past decades, different types of fetal markers have been developed, initially based on discriminative genetic markers such as male-specific signals or paternally inherited polymorphisms, and gradually evolved to the detection of fetal-specific transcripts or epigenetic signatures. This development has extended the coverage of the application of cell-free fetal DNA to essentially all pregnancies, regardless of the gender of the fetus or its polymorphic status. In this review, we present an overview of the development of noninvasive prenatal diagnosis through epigenetics. We introduce the basis of how fetal DNA could be detected from a large background of maternal DNA in maternal plasma based on fetal specific DNA methylation patterns. We evaluate the methodologies involved and discuss the factors that affect the robustness of the detection. We review the progress in adopting fetal epigenetic markers for noninvasive prenatal assessment of fetal chromosomal aneuploidies and pregnancy-associated disorders. We conclude with comments on the future directions regarding the search for new fetal epigenetic markers and the clinical implementation of epigenetic approaches for noninvasive prenatal diagnosis. PMID- 21327154 TI - Double unit cord blood transplantation: Who wins-and why do we care? AB - Double unit cord blood transplantation (DUCBT) has emerged as a successful strategy to improve engraftment and decrease transplant related mortality in adults and large children undergoing cord transplantation. In the vast majority of cases, one unit emerges as the sole source of long term hematopoiesis in the recipient following DUCBT. No factors have been identified that reliably predict which unit will emerge as the dominant unit, and limited studies have examined the mechanism underlying the observation. In a recent publication in Blood, we provide the first compelling data that effector CD8(+) T cells play a critical role in the dominant unit actively rejecting the losing unit. Our findings provide an important first step in understanding the interactions following DUCBT, and provide insights that might be used to optimize graft versus leukemia effect and cord unit selection as well as better understand mechanisms of tolerance. PMID- 21327155 TI - Transcriptional regulation underlying recovery from a DNA damage-induced arrest. AB - When the DNA of a cell is damaged, cell cycle progression is arrested and cell cycle-specific transcription is inhibited. However, cell cycle-specific transcription is required for eventual recovery from the DNA damage-induced arrest. Here we discuss recent findings that demonstrate how transcription is fine-tuned during the DNA damage response and how this controls the capacity to recover from a DNA damage arrest in G(2) phase. PMID- 21327156 TI - Transcriptional regulation of the human telomerase reverse transcriptase: new insights. AB - hTERT and NFAT were thought until recently to belong to separate metabolic compartments. The involvement of NFAT in the induction of hTERT transcription suggested by hTERT expression variations during lymphocyte stimulation and immunosuppressive treatments explains the link between hTERT expression and cell stimulation and offers new insights for therapeutic developments. PMID- 21327157 TI - Transcription factors controlling stomatal movements and drought tolerance. AB - In the last years some efforts in the characterization of transcription factors involved in stomatal movements in plants have been undertaken. These findings provide new insights into the molecular mechanisms that plants adopt to cope with abiotic stress and offer new strategies to improve plant drought tolerance. PMID- 21327158 TI - SIRT6: a master epigenetic gatekeeper of glucose metabolism. AB - Sirtuins are the mammalian homologs of the yeast histone deacetylase Sir2. In recent years, an ever-expanding picture has emerged indicating that these proteins (SIRT1-7) play broad functions in cellular stress resistance, genomic stability, energy metabolism, aging and tumorigenesis. Among members of this family, SIRT6 appears to have particular significance in regulating metabolism, DNA repair and lifespan. In this context, new research from our lab has established SIRT6 as a key regulator of glucose homeostasis. In this Point of View article, we will first highlight our recent findings, and then provide an in depth discussion of their implications in cancer and aging. PMID- 21327160 TI - The Rad23 ubiquitin receptor, the proteasome and functional specificity in transcriptional control. AB - The proteasome has been implicated in transcriptional control in a bewildering number of ways, and many questions remain about how functional selectivity is conferred to its action. Here we discuss transcriptional roles for the ubiquitin receptor Rad23 and posit that such receptors may be key players dictating proteasome transcriptional specificity. PMID- 21327159 TI - CDK8: a positive regulator of transcription. AB - CDK8 belongs to a group of cyclin-dependent kinases involved in transcriptional regulation from yeast to mammals. CDK8 associates with the Mediator complex, but functions outside of Mediator are also likely. Historically, CDK8 has been described mostly as a transcriptional repressor, but a growing body of research provides unequivocal evidence for various roles of CDK8 in gene activation. Several transcriptional programs of biomedical importance employ CDK8 as a co activator, including the p53 network, the Wnt/beta-catenin pathway, the serum response network, and those governed by SMADs and the thyroid hormone receptor, thus highlighting the importance of further investigation into this enigmatic transcriptional regulator. PMID- 21327161 TI - Coordination of glucose and glutamine utilization by an expanded Myc network. AB - Glucose and glutamine are the most abundant circulating nutrients and support the growth and proliferation of all cells, in particular rapidly growing and dividing cancer cells. Several recent studies implicate an expanded Myc network in how cells sense and utilize both glucose and glutamine. These studies reveal an unappreciated coordination between glycolysis and glutaminolysis, potentially providing new targets for therapeutic intervention in cancer. PMID- 21327162 TI - The impact of transcriptional cycling on gene regulation. AB - Research of the past decade showed that transcriptional regulation could be a highly dynamic and cyclical process. Many transcription factors and their co regulators cyclically associate with a periodicity of 30-75 min with regulatory chromatin regions resulting in dynamically changing chromatin marks and cyclical activities of RNA polymerase II in mRNA synthesis. PMID- 21327163 TI - Characterization of Xpr (Xpct) reveals instability but no effects on X-chromosome pairing or Xist expression. AB - X-chromosome inactivation balances X-chromosome dosages in male and female mammals by transcriptionally repressing one X in the female sex. Proper counting and the mutually exclusive choice of active X and inactive X have been hypothesized to involve X-chromosome crosstalk via homologous chromosome pairing. Transient pairing of two female Xs requires noncoding Tsix and Xite. A recent study suggested a new pairing element (Xpr), located ~200 kb upstream of Xist, in the Xpct region. Xpr is proposed to induce pairing and activate Xist expression. Here, we further characterize Xpr and find that the Xpr sequence is unstable when introduced as transgenes into male ES cells. Xpr transgenes show an unusual tendency to disperse throughout the nucleus. However, we observe neither pairing between Xpr alleles nor ectopic Xist expression. In the absence of Tsix, Xpr does not induce inter-allelic Xic interactions. Female ES cells carrying Xpr transgenes are more stable. Nonetheless, pairing also does not seem to occur in female cells. We conclude that, while Xpr contains unusual properties, it most likely does not serve as a pairing or counting element. Differences in statistical methods and controls may explain some of the discrepancies. PMID- 21327164 TI - A time-calibrated species-level phylogeny of bats (Chiroptera, Mammalia). AB - Despite their obvious utility, detailed species-level phylogenies are lacking for many groups, including several major mammalian lineages such as bats. Here we provide a cytochrome b genealogy of over 50% of bat species (648 terminal taxa). Based on prior analyzes of related mammal groups, cytb emerges as a particularly reliable phylogenetic marker, and given that our results are broadly congruent with prior knowledge, the phylogeny should be a useful tool for comparative analyzes. Nevertheless, we stress that a single-gene analysis of such a large and old group cannot be interpreted as more than a crude estimate of the bat species tree. Analysis of the full dataset supports the traditional division of bats into macro- and microchiroptera, but not the recently proposed division into Yinpterochiroptera and Yangochiroptera. However, our results only weakly reject the former and strongly support the latter group, and furthermore, a time calibrated analysis of a pruned dataset where most included taxa have the entire 1140bp cytb sequence finds monophyletic Yinpterochiroptera. Most bat families and many higher level groups are supported, however, relationships among families are in general weakly supported, as are many of the deeper nodes of the tree. The exceptions are in most cases apparently due to the misplacement of species with little available data, while in a few cases the results suggest putative problems with current classification, such as the non-monophyly of Mormoopidae. We provide this phylogenetic hypothesis, and an analysis of divergence times, as tools for evolutionary and ecological studies that will be useful until more inclusive studies using multiple loci become available. PMID- 21327165 TI - Hal: an automated pipeline for phylogenetic analyses of genomic data. AB - The rapid increase in genomic and genome-scale data is resulting in unprecedented levels of discrete sequence data available for phylogenetic analyses. Major analytical impasses exist, however, prior to analyzing these data with existing phylogenetic software. Obstacles include the management of large data sets without standardized naming conventions, identification and filtering of orthologous clusters of proteins or genes, and the assembly of alignments of orthologous sequence data into individual and concatenated super alignments. Here we report the production of an automated pipeline, Hal that produces multiple alignments and trees from genomic data. These alignments can be produced by a choice of four alignment programs and analyzed by a variety of phylogenetic programs. In short, the Hal pipeline connects the programs BLASTP, MCL, user specified alignment programs, GBlocks, ProtTest and user specified phylogenetic programs to produce species trees. The script is available at sourceforge (http://sourceforge.net/projects/bio-hal/). The results from an example analysis of Kingdom Fungi are briefly discussed. PMID- 21327166 TI - MSM 2010 Theme Monograph Psychopharmacology Today. PMID- 21327167 TI - Psychopharmacology Today: Where are We and Where Do We Go From Here? AB - Since the 1950s we have had the same three neurotransmitters to work with to treat depression, one transmitter for psychoses, three for anxiety. We have developed newer drugs that are more tolerable, but we have not developed drugs that are better in efficacy. The last 50-60 years should be considered the decades that allowed us to treat a greater number of patients with safer and more tolerable drugs. We have also decreased stigma and allowed primary care clinicians to become more comfortable treating the mentally ill. We clearly treat more patients than before, and sometimes are now accused of over-prescribing wantonly as our drugs are safer. Without any clear blockbuster new drug ready to be added to our armamentarium, what can we do as psychopharmacologists today, and tomorrow, to obtain better results? This introductory manuscript will attempt to provide an overview of ideas so that an adept, well-rounded clinician might be able to obtain better outcomes despite using neurotransmitter pharmacodynamics that have been around since the 1950s. Finally, I will comment on the psychotropic pipeline, which may be added to our armamentarium in the future. PMID- 21327168 TI - Modern Medicine: Towards Prevention, Cure, Well-being and Longevity. AB - Modern medicine has done much in the fields of infectious diseases and emergencies to aid cure. In most other fields, it is mostly control that it aims for, which is another name for palliation. Pharmacology, psychopharmacology included, is mostly directed towards such control and palliation too. The thrust, both of clinicians and research, must now turn decisively towards prevention and cure. Also, longevity with well-being is modern medicine's other big challenge. Advances in vaccines for hypertension, diabetes, cancers etc, deserve attention; as also, the role of meditation, yoga, spirituality etc in preventing disease at various levels. Studies on longevity, life style changes and healthy centenarians deserve special scrutiny to find what aids longevity with wellbeing. A close look at complementary and alternative medicine is needed to find any suitable models they may have, cutting aside their big talk and/or hostility towards mainstream medical care. Medicine is a manifestation of the human eros, and should not become a means of its thanatos. It must realise its true potential, so that eros prevails, and thanatos prevails only ultimately, not prematurely. PMID- 21327169 TI - The geriatric population and psychiatric medication. AB - With improvement in medical services in the last few years, there has been a constant rise in the geriatric population throughout the world, more so in the developing countries. The elderly are highly prone to develop psychiatric disorders, probably because of age related changes in the brain, concomitant physical disorders, as well as increased stress in later life. Psychiatric disorders in this population may have a different presentation than in other groups and some of psychopathologies might be mistaken for normal age related changes by an unwary clinician. Therefore the need of the day is to train psychiatrists and physicians to better recognize and manage mental disorders in this age group. PMID- 21327170 TI - Weight-gain in psychiatric treatment: risks, implications, and strategies for prevention and management. AB - Weight-gain in psychiatric populations is a common clinical challenge. Many patients suffering from mental disorders, when exposed to psychotropic medications, gain significant weight with or without other side-effects. In addition to reducing the patients' willingness to comply with treatment, this weight-gain may create added psychological or physiological problems that need to be addressed. Thus, it is critical that clinicians take precautions to monitor and control weight-gain and take into account and treat all problems facing an individual. In this review, we examine some of the key issues surrounding weight gain in individuals suffering from mental disorders for contemporary practitioners in community clinics. We describe some factors known to make certain patients more susceptible to treatment-induced weight-gain and mechanisms implicated in this process. We also highlight a few psychological and pharmacological interventions that have proven effective in weight management. Importantly, we provide critical steps for management and prevention of weight gain and related issues in the clinical practice of psychopharmacology. PMID- 21327172 TI - Lactating mother and psychotropic drugs. AB - Usage of psychotropics during pregnancy and lactation has always been a topic of debate and controversy. The debate stems from the potential adverse effects on the growing fetus or infants due to the transfer of psychotropic drugs through placenta or breast milk of mothers receiving them; and the problem of discontinuing psychotropics in lactating mother considering chances of relapse. However, most of the psychotropics are found to be relatively safe when used cautiously during the lactation phase. This article describes available data on the use of psychotropics in lactating mothers, in particular, in relation to the safety profile of infants. PMID- 21327171 TI - The pharmacotherapy of alcohol dependence: a state of the art review. AB - The psychopharmacology of alcohol dependence is today poised at interesting crossroads. Three major drugs Naltrexone, Disulfiram and Acamprosate have been tried and tested in various trials and have many meta-analyses each to support them. While Naltrexone may reduce craving, Acamprosate scores on cost effectiveness worldwide with Disulfiram being an alcohol deterrent drug. Studies support, refute and criticize the use of each of these drugs. Combining one or more of them is also a trend seen. The most important factor in efficacy has been the combination of psychosocial treatment with medication. Studies from the early 1970s to date have been reviewed and the findings presented in a manner useful for the busy clinician to judge the best pharmacological option in the management of alcohol dependence. The role of depot disulfiram, naltrexone, and medications like Topiramate and SSRIs under research for alcohol dependence, are also addressed. PMID- 21327173 TI - The noncompliant patient in psychiatry: the case for and against covert/surreptitious medication. AB - Nonadherence to treatment continues to be one of psychiatry's greatest challenges. To improve adherence and thus improve the care of patients, clinicians and patients' family members sometimes resort to hiding medication in food or drink, a practice referred to as covert/ surreptitious medication. The practice of covert drug administration in food and beverages is well known in the treatment of psychiatrically ill world-wide but no prevalence rates exist. Covert medication may seem like a minor matter, but it touches on legal and ethical issues of a patient's competence, autonomy, and insight. Medicating patients without their knowledge is not justifiable solely as a shortcut for institutions or families wishing to calm a troublesome patient and thus alleviate some of the burdens of care giving. The paramount principle is ensuring the well-being of a patient who lacks the competence to give informed consent. Ethically, covert/surreptitious administration can be seen as a breach of trust by the doctor or by family members who administer the drugs. Covert medication contravenes contemporary ethical practice. Legally, treatment without consent is permissible only where common law or statute provides such authority. The practice of covert administration of medication is not specifically covered in the mental health legislation in developing countries. Many of the current dilemmas in this area have come to public attention because of two important developments in medical ethics and the law - the increasing importance accorded to respect for autonomy and loss of the parens patriae jurisdiction of the courts [parens patriae means 'parent of the country'; it permitted a court to consent or refuse treatment on behalf of an 'incapacity', or alternatively to appoint a guardian with such powers]. PMID- 21327174 TI - Overlap of autism and seizures: understanding cognitive comorbidity. AB - This article introduces the concept of 'cognitive comorbidity,' which lays emphasis on common cognitive deficits that cut across different disorders. The concept is illustrated with the help of two commonly reported overlapping conditions (autism and epilepsy). It is further explained by concentrating on two important cognitive processes of facial emotional recognition and emotional memory, shown to be compromised in both conditions; and their underlying neural substrates. Cognitive comorbidity is then contrasted with 'comorbidity,' a term which is more commonly used for describing cognitive disorders. The paper closes by providing directions for rehabilitative and theoretical efforts that could be inspired by the newly introduced concept. PMID- 21327175 TI - Of sophists and spin-doctors: industry-sponsored ghostwriting and the crisis of academic medicine. AB - Ghostwriting for medical journals has become a major, but largely invisible, factor contributing to the problem of credibility in academic medicine. In this paper I argue that the pharmaceutical marketing objectives and use of medical communication firms in the production of ghostwritten articles constitute a new form of sophistry. After identifying three distinct types of medical ghostwriting, I survey the known cases of ghostwriting in the literature and explain the harm done to academic medicine and to patients. Finally, I outline steps to address the problem and restore the integrity of the medical literature. PMID- 21327176 TI - Recurrent Ascending Colon Cancer Manifesting as Inferior Vena cava Thrombus. AB - We report an extremely rare case of recurrent ascending colon cancer manifesting as inferior vena cava (IVC) thrombus. A 77-year-old woman previously diagnosed with ascending colon cancer underwent right hemicolectomy with lymph node dissection. Though the tumor invaded the retroperitoneum and involved the right ovarian artery and vein, curative operation was performed. The patient took 5-FU p.o. Two and a half years later, tumor thrombus in the IVC extending into the right atrium was incidentally found and diagnosed as recurrence of colon cancer by biopsy. RF-induced hyperthermia using 5-FU and CDDP i.v. was immediately performed, but she died after 6 months because of multiple liver and pulmonary metastases. In treating colon cancers invading the retroperitoneum, it should be recalled that some cases recur as tumor thrombus in the IVC and that close follow up is therefore necessary. PMID- 21327177 TI - Amelanotic esophageal malignant melanoma: case report and short review of the literature. AB - Malignant melanoma in the esophagus is a rare condition which has been described only occasionally in case reports or in larger series of patients with esophageal disease. We describe here the very rare case of a patient who presented initially with a 2-month history of dysphagia and weight loss which led to the endoscopic diagnosis of an unclear lesion in the distal esophagus. Biopsies were taken revealing positive immunohistochemical staining against HMB-45. As there were no signs of skin melanoma and there was an absence of pigmentation, a diagnosis of primary amelanotic malignant melanoma was made. Primary staging of the lesion was completed with computed tomography (CT), which revealed a locally advanced tumor with lymph node metastases at the lesser curvature of the stomach and celiac trunk. As there is still a lack of potential protocols for multimodal neoadjuvant treatment for this rare tumor entity, a palliative abdominothoracic esophagectomy with systemic lymphadenectomy and intrathoracic anastomosis was carried out. Due to an intraoperative R2 situation, clip marking was performed to allow postoperative radiotherapy. Two months postoperatively, the planning CT scan for radiotherapy revealed progression of the retroperitoneal tumor mass, which was enclosing the celiac trunk, renal vein, and superior mesenteric artery. Multiple new liver and lung metastases were also found. During the following weeks, the patient developed acute renal failure and was admitted for dialysis, and the planned radiotherapy was deferred. At the end of May 2007, 4 months after the primary diagnosis, the patient died due to acute renal failure. PMID- 21327178 TI - Antiretroviral therapy-associated acute motor and sensory axonal neuropathy. AB - Guillain-Barre syndrome (GBS) has been reported in HIV-infected patients in association with the immune reconstitution syndrome whose symptoms can be mimicked by highly active antiretroviral therapy (HAART)-mediated mitochondrial toxicity. We report a case of a 17-year-old, HIV-infected patient on HAART with a normal CD4 count and undetectable viral load, presenting with acute lower extremity weakness associated with lactatemia. Electromyography/nerve conduction studies revealed absent sensory potentials and decreased compound muscle action potentials, consistent with a diagnosis of acute motor and sensory axonal neuropathy. Lactatemia resolved following cessation of HAART; however, neurological deficits minimally improved over several months in spite of immune modulatory therapy. This case highlights the potential association between HAART, mitochondrial toxicity and acute axonal neuropathies in HIV-infected patients, distinct from the immune reconstitution syndrome. PMID- 21327179 TI - A Young Man with Anti-NMDAR Encephalitis following Guillain-Barre Syndrome. AB - A 19-year-old man developed rapidly progressive muscle weakness and dysesthesia in the extremities, and dyspnea after a flu-like episode. Nerve conduction studies showed reduced motor nerve conduction velocities with conduction block, and sensory nerve action potentials could not be evoked. The patient was diagnosed as having Guillain-Barre syndrome (GBS), and was treated with 2 cycles of intravenous immunoglobulin (IVIg) therapy and was assisted by mechanical ventilation. During the recovery course of the illness, he experienced several attacks of psychomotor agitation from the 37th hospital day, and generalized tonic convulsive seizures suddenly developed on the 42nd hospital day. Brain MRI showed high-intensity lesions in the bilateral thalamus and medial temporal lobes. The convulsions were controlled by continuous thiopental infusion (until the 50th hospital day) and mechanical ventilation (until the 84th hospital day). Intravenous methylprednisolone pulse therapy (1,000 mg/day) for 3 days followed by dexamethasone (16 mg/day) was added. After relief of convulsive seizures, prominent orolingual dyskinesia appeared, and on MRI marked atrophy of the bilateral medial temporal lobes was seen. Anti-N-methyl-D-aspartate receptor (NMDAR) antibodies in serum and cerebrospinal fluid were positive on the 92nd hospital day. Anti-NMDAR encephalitis usually affects young females but a small number of male cases with this disease have been reported. Our male patient was unique in having GBS, a post-infectious autoimmune disease, as a preceding disease, suggesting that anti-NMDAR encephalitis itself is caused by a parainfectious autoimmune mechanism. PMID- 21327180 TI - Idiopathic Parkinson's disease, osteoporosis, and hip fractures: a case report. AB - Patients with chronic idiopathic Parkinson's disease are at a high risk for fractures, particularly of the hip. The causes may be multifactorial, including poor balance and other forms of neurological dysfunction. Osteopenia and osteoporosis leading to decreased bone mass are common in these patients. We report a case of a male patient with a long-standing history of Parkinson's disease on chronic high-dose carbidopa-levodopa who suffered a hip fracture. The relationship of Parkinson's disease and carbidopa-levodopa use with osteopenia and hip fractures is discussed, emphasizing the crucial need for prevention in this patient population along with medical and surgical treatment. PMID- 21327181 TI - Obsessive-compulsive behavior disappearing after left capsular genu infarction. AB - This case report describes a 74-year-old woman with obsessive-compulsive behaviors that disappeared following a left capsular genu infarction. The patient's capsular genu infarction likely resulted in thalamocortical disconnection in the cortico-basal ganglia-thalamocortical loop, which may have caused the disappearance of her obsessive-compulsive symptoms. The fact that anterior capsulotomy has been demonstrated to be effective for treating refractory obsessive-compulsive disorder further supports this hypothesis. PMID- 21327186 TI - Alkyne-mediated domino hydroformylation/double cyclization: mechanistic insight and synthesis of (+/-)-tashiromine. AB - A novel domino reaction, alkyne-mediated domino hydroformylation/double cyclization, has been developed for rapid preparation of indolizidine type alkaloids. DFT calculations were applied for rationales of reactivity and selectivity. A concise synthesis of tashiromine as the application of the methodology is also reported. PMID- 21327187 TI - Rapidly disassembling nanomicelles with disulfide-linked PEG shells for glutathione-mediated intracellular drug delivery. AB - The synthesis and biological efficacy of novel nanomicelles that rapidly disassemble and release their encapsulated payload intracellularly under tumor relevant glutathione (GSH) levels are reported. The unique design includes a PEG sheddable shell and poly(epsilon-benzyloxycarbonyl-l-lysine) core with a redox sensitive disulfide linkage. PMID- 21327188 TI - Role of surface ligands in optical properties of colloidal CdSe/CdS quantum dots. AB - In order to study the role of surface ligands in determining optical properties of colloidal quantum dots (QDs), we have selectively fabricated and studied CdSe/CdS core-shell QDs with strongly confined electron and hole states attached with commonly used surface ligands. Optical properties, viz. absorption and fluorescence of these QDs, are characterized from which salient changes have been observed for different ligand substitutions which, through theoretical analysis, can be associated with electronic structure properties of the QD-ligand composite systems, in particular localization of wave functions of electrons and holes in the QDs and the band matching of the HOMO-LUMO gap of the ligands. The findings can be utilized to facilitate the understanding and optimization of properties of QD biomarkers with functionalizing surface ligands for targeting cellular objects. PMID- 21327189 TI - Tracking cellular metabolomics in lipoapoptosis- and steatosis-developing liver cells. AB - Palmitate (PA) is known to induce reactive oxygen species (ROS) formation and apoptosis in liver cells, whereas concurrent treatment of oleate (OA) with PA predominately induces steatosis without ROS in liver cells. We previously reported that PA treatment induces the decoupling of glycolysis and tricarboxylic acid cycle (TCA cycle) fluxes, but OA co-treatment restored most metabolic fluxes to their control levels. However, the mechanisms by which metabolites are linked to metabolic fluxes and subsequent lipoapoptotic or steatotic phenotypes remain unclear. To determine the link, we used GC-MS-based polar and non-polar metabolic profiling in lipoapoptosis- or steatosis-developing H4IIEC3 hepatoma cells, to examine the metabolome at different time points after treatment with either PA alone (PA cells) or both PA and OA (PA/OA cells). Metabolic profiles revealed various changes in metabolite levels for TCA cycle intermediates, pentose phosphate pathway (PPP) intermediates, and energy storage metabolites between PA and PA/OA cells. For example, adenosine was markedly increased only in PA cells, whereas gluconate was increased in PA/OA cells. To assess the interaction among these metabolites, the metabolite-to-metabolite correlations were calculated and correlation networks were visualized. These correlation networks demonstrate that a dissociation among PPP metabolites was introduced in PA-treated cells, and this dissociation was restored in PA/OA-treated cells. Thus, our data suggest that abnormal PPP fluxes, in addition to increased adenosine levels, might be related to the decoupling of glycolysis and the resulting lipoapoptotic phenotype. PMID- 21327190 TI - A metabolomics and proteomics study of the adaptation of Staphylococcus aureus to glucose starvation. AB - As a versatile pathogen Staphylococcus aureus can cause various disease patterns, which are influenced by strain specific virulence factor repertoires but also by S. aureus physiological adaptation capacity. Here, we present metabolomic descriptions of S. aureus central metabolic pathways and demonstrate the potential for combined metabolomics- and proteomics-based approaches for the basic research of this important pathogen. This study provides a time-resolved picture of more than 500 proteins and 94 metabolites during the transition from exponential growth to glucose starvation. Under glucose excess, cells exhibited higher levels of proteins involved in glycolysis and protein-synthesis, whereas entry into the stationary phase triggered an increase of enzymes of TCC and gluconeogenesis. These alterations in levels of metabolic enzymes were paralleled by more pronounced changes in the concentrations of associated metabolites, in particular, intermediates of the glycolysis and several amino acids. PMID- 21327191 TI - Metals in neurodegenerative disease. PMID- 21327192 TI - Remarkably reactive dihydroindoloindoles via palladium-catalysed dearomatisation. AB - Palladium-catalysed dearomatisation reactions allow access to a previously unknown class of indoloindole heterocycle: 5,10b-dihydroindolo[2,3-b]indoles. The highly reactive nature of these compounds is demonstrated by their facile reactions with water and with hydride, alkyl, aryl and allyl-based organometallic nucleophiles. PMID- 21327193 TI - Photoinitiated ambient temperature copper-catalyzed atom transfer radical addition (ATRA) and cyclization (ATRC) reactions in the presence of free-radical diazo initiator (AIBN). AB - The use of UV light in copper-catalyzed atom transfer radical addition (ATRA) and cyclization (ATRC) reactions of various (poly)halogenated compounds to highly active alkenes in the presence of AIBN is reported. Radicals generated from photodecomposition of AIBN efficiently regenerated the copper(I) complex at ambient temperature enabling ATRA of CCl(4) and CBr(4) with catalyst loadings as low as 0.05 mol-%. The desired monoadduct was obtained in lower yields in the ATRA of less active halogenated compounds, which was mostly due to incomplete alkene conversions. Ambient temperature ATRA of CCl(4) to various 1,6-dienes followed by sequential ATRC was also performed in the presence of UV light using [Cu(II)(TPMA)Cl][Cl] complex and AIBN. High yields of the 5-exo-trig cyclic product were obtained for all dienes with preferential formation of the cis isomer. PMID- 21327194 TI - Iron-catalyzed direct amination of azoles using formamides or amines as nitrogen sources in air. AB - A new iron-catalyzed, direct C-H amination of azoles at C2 has been developed by using formamides or amines as nitrogen sources. Imidazole is the only additive in the catalyst system and oxygen in air is employed during the transformation process. PMID- 21327199 TI - Synthesis of heterosegment-junctioned hybrid nanotubes of polythiophene and heterometallic nanoparticles by sequential template-based electropolymerization. AB - New heterosegment-junctioned hybrid nanotubes of polythiophene and heterometallic nanoparticles (Pd, Au NPs) have been synthesized by sequential electropolymerization of terthiophene-modified Pd and Au NPs in a nanoporous template. PMID- 21327200 TI - Chemical synthesis of bacterial lipoteichoic acids: an insight on its biological significance. AB - During infections caused by Gram-negative bacteria, lipopolysaccharide (LPS, endotoxin) has a dominant role leading to fulminant pro-inflammatory reactions in the host. As there is no LPS in Gram-positive bacteria, other microbial cell wall components have been identified to be the causative agent for the pro inflammatory activity since also Gram-positive bacterial infections lead to comparable clinical symptoms and reactions. On search for the "Gram-positive endotoxin" a widely accepted hypothesis has been raised in that the lipoteichoic acids (LTAs) serve as pathogen-associated molecular patterns (PAMPs) during Gram positive sepsis, although the amount necessary for a pro-inflammatory in vitro response is several orders of magnitude higher than that for LPS. Therefore, LTA cannot be considered to be "the (endo)toxin of Gram-positive bacteria". Although LPS and LTA show structural relatedness (amphiphilic, negatively charged glycophospholipids), they are structurally quite different from each other and one might expect that they are also recognized by different receptors of the innate immune system, the so called toll-like receptors 4 and 2 (TLR4 and TLR2), respectively. Based on their chemical structure, the LTAs were classified into four types (type I-IV) of which we have carefully investigated the LTA of Staphylococcus aureus (type I), Lactococcus garvieae (type II) and Streptococcus pneumoniae (type IV). Hence, these LTAs have been synthesized in our group and biologically evaluated with respect to their potency to activate cytokines in transiently TLR2/CD14-transfected human endothelial kidney cells (HEK 293) or human macrophages and whole blood cells. Although LTA of type I and IV are structurally quite different, especially in their hydrophilic moiety, they originally were believed to interact with the same receptor (TLR2). Hence, the chemical syntheses leading to structurally defined, non-contaminated stimuli have a major impact on the outcome and interpretation of these biological studies of the innate immune system. With this material, it became evident that synthetic LTA from S. aureus and S. pneumoniae are not recognized by TLR2. Instead, another receptor of the innate immune system, the lectin pathway of the complement, known since many years to interact with LTA in quite a specific way, has gained increasing attractivity. With the help of synthetic LTA we obtained first evidences that this receptor is indeed the pathogen recognition receptor (PRR) for LTA. PMID- 21327201 TI - Microscopic origins of electron and hole stability in ZnO. AB - We present a fundamental method to assess the doping limits of hetero-polar materials; applied to the case of ZnO, we show clearly that electrons are stable and holes are unstable under the limits of thermodynamic control. PMID- 21327202 TI - A helix-forming alphabetagamma-chimeric peptide with catalytic activity: a hybrid peptide ligase. AB - We describe the catalytic activity of the first chimeric ligase containing a foldameric sequence of beta- and gamma-amino acids. The chimeric backbone provides for the spatial arrangement of all functional groups involved in the formation of the catalytic site to allow efficient catalysis to take place. Our finding indicates significant progress in the field of functionally active artificial motifs. PMID- 21327203 TI - An ab initio study of electrochemical vs. electromechanical properties: the case of CO adsorbed on a Pt(111) surface. AB - We have studied electrochemical vibrational and energy properties of CO/Pt(111) in the framework of periodic density functional theory (DFT) calculations. We have used a modified version of the previously developed Filhol-Neurock method to correct the unphysical contributions arising from homogeneous background countercharge in the case of thick metallic slabs. The stability of different CO adsorption sites on Pt(111) (Top, Bridge, Hcp, Fcc) has been studied at constant electric field. The energies are dominated by the surface dipole interaction with the external electric field: a strong positive electric field favors the surfaces with the lower dipole moment (that correspond to the ones with the lower coordination). The Stark tuning slope of the CO stretching frequency for a Top site was calculated for different surface coverages in very good agreement with both experimental and other theoretical results. Finally, we have performed an analysis of the origin of Stark shifts showing that the total Stark effect can be split into two competing components. The first one corresponds to the direct effect of charging on the C-O chemical bond: it is referred as an electrochemical effect. The second is the consequence of the surface dipole interaction with the applied electric field that modifies the C-O distance, inducing a change of the C O force constant because of C-O bond anharmonicity: it is referred as the electromechanical effect. In the CO/Pt(111) case, the dominant contribution is electromechanical. The electrochemical contribution is very small because the electronic system involved in the surface charging is mostly non-bonding as analyzed by looking at the surface Fukui function. PMID- 21327204 TI - Simulation and measurement of complete dye sensitised solar cells: including the influence of trapping, electrolyte, oxidised dyes and light intensity on steady state and transient device behaviour. AB - A numerical model of the dye sensitised solar cell (DSSC) is used to assess the importance of different loss pathways under various operational conditions. Based on our current understanding, the simulation describes the processes of injection, regeneration, recombination and transport of electrons, oxidised dye molecules and electrolyte within complete devices to give both time dependent and independent descriptions of performance. The results indicate that the flux of electrons lost from the nanocrystalline TiO(2) film is typically at least twice as large under conditions equivalent to 1 sun relative to dark conditions at matched TiO(2) charge concentration. This is in agreement with experimental observations (Barnes et al. Phys. Chem. Chem. Phys. [DOI: 10.1039/c0cp01855d]). The simulated difference in recombination flux is shown to be due to variation in the concentration profile of electron accepting species in the TiO(2) pores between light and dark conditions and to recombination to oxidised dyes in the light. The model is able to easily incorporate non-ideal behaviour of a cell such as the variation of open circuit potential with light intensity and non-first order recombination of conduction band electrons. The time dependent simulations, described by the multiple trapping model of electron transport and recombination, show good agreement with both small and large transient photocurrent and photovoltage measurements at open circuit, including photovoltage rise measurements. The simulation of photovoltage rise also suggests the possibility of assessing the interfacial resistance between the TiO(2) and substrate. When cells with a short diffusion length relative to film thickness were modelled, the simulated small perturbation photocurrent transients at short circuit (but not open circuit) yielded significantly higher effective diffusion coefficients than expected from the mean concentration of electrons and the electrolyte in the cell. This implies that transient measurements can overestimate the electron diffusion length in cells which have a low collection efficiency. The model should provide a useful general framework for exploring new cell descriptions, architectures and other factors influencing device performance. PMID- 21327205 TI - Mechanism of enhancement in absorbance of vibrational bands of adsorbates at a metal mesh with subwavelength hole arrays. AB - We have investigated the mechanism of enhanced absorption intensities of vibrational bands of adsorbates on copper meshes with subwavelength holes by measuring and simulating temporal profiles of infrared pulses transmitted through the meshes. As reported previously [Williams et al., J. Phys. Chem. B, 2003, 107, 11871], the absorption intensities of CH stretching bands of alkanethiolate adsorbed on the mesh increase substantially with decreasing hole size. The enhancements of absorption intensities are associated with temporal delays of infrared pulses transmitted through the mesh. Finite difference time domain calculations reproduce the observed pulse delays as a function of hole size. These facts indicate that the delays of transmitted pulses are not caused by coupling of infrared radiation to surface plasmon polaritons propagating on the front and rear surfaces of the mesh, but they are caused by the reduction in group velocity owing to coupling to waveguide modes of mesh holes. Consequently, the strong enhancements of the absorption intensities are attributed to adsorbates inside the holes rather than to those on the mesh surfaces that have been proposed previously. PMID- 21327206 TI - Beyond the Butler-Volmer equation. Curved Tafel slopes from steady-state current voltage curves. AB - We report the discovery and analysis of curved Tafel slopes from the electrochemical reduction of hexamminecobalt(III) under steady-state conditions. In order to confirm the existence of the curvature, random assemblies of carbon microelectrodes (RAMTM electrodes) were employed to obtain experimental data over more than three orders of magnitude, without significant double layer charging currents and without ohmic distortion. Since the rate-determining step in the reduction reaction is electron transfer, and no ligand substitution reactions occur on the timescale of experiments, the curvature of the Tafel plot is attributed to the dependence of the symmetry factor on electrode potential. PMID- 21327207 TI - Cationic recognition by tert-butylcalix[4]arene-functionalized nanoprobes. AB - A nanoparticle-based strategy has been demonstrated using structurally-tailored tert-butylcalixarenes immobilized on gold nanoparticles to tune the guest access to the calixarene cone cavity for cationic recognition. This strategy exploits the interparticle charge-induced aggregation upon selective capture of metal cations into the nanoparticle-immobilized tert-butylcalixarenes, which produces calorimetric changes for the detection. A possible pathway for the binding of M(n+) into the t-BCA structure and the interparticle interaction is proposed for the formation of an electric double layer inducing the interparticle association responsible for the red-shifted surface plasmon resonance band of the nanoparticles. The value of this class of calorimetric nanoprobes will be in the area of designing advanced host-guest probes using a variety of calixarene ligands for ionic recognition in a simplistic detection format. PMID- 21327208 TI - Influence of disorder-to-order transition on lattice thermal expansion and oxide ion conductivity in (Ca(x)Gd(1-x))(2)(Zr(1-x)M(x))2O7 pyrochlore solid solutions. AB - The effect of simultaneous substitutions of Ca at A site and Nb or Ta at B site in pyrochlore-type solid solutions: (Ca(x)Gd(1-x))(2)(Zr(1-x)M(x))(2)O(7) (x = 0.1, 0.2, 0.3, 0.4, 0.5 and M = Nb or Ta) were studied by powder X-ray diffraction (XRD), FT NIR Raman spectroscopic techniques and transmission electron microscopy. The solid solutions were prepared by the conventional high temperature ceramic route. The XRD results and Rietveld analysis revealed that the defect fluorite structure of Gd(2)Zr(2)O(7) progressively changed to a more ordered pyrochlore phase by simultaneous substitutions at A and B sites. Raman spectroscopy reveals the progressive ordering in the anion sublattice with simultaneous doping. High-resolution images and selected-area electron diffraction patterns obtained from TEM confirms the XRD and Raman spectroscopic results. High-temperature XRD studies show that the lattice expansion coefficient in these pyrochlore oxides is of the order of 10(-6) K(-1). Lattice thermal expansion coefficient increases with increase of disorder in pyrochlore oxides, and hence the variation of thermal expansion coefficient with composition is also a good indicator of disordering in pyrochlore-type oxides. The ionic conducting properties of the samples were characterised by impedance spectroscopy, and it was found that Nb-doped compositions show a considerable change in conductivity near the phase boundary of disordered pyrochlore and defect fluorite phases. PMID- 21327209 TI - Continuous monitoring of NO in flue gas based on wavelet decomposition. AB - In this paper, a new algorithm for nitric oxide (NO) measurement based on multi scale wavelet decomposition is proposed. The algorithm uses one-dimensional discrete multi-scale wavelet decomposition to analyze the transmission spectrum of flue gas. Through the different scales of decomposition, the relation between the absorption characteristics of NO gas and the reconstruction of wavelet coefficients is found. The DB9 wavelet can obtain the most obvious absorption characteristics of the NO gas. After calibration, the algorithm is used to measure the concentration of the mixture of NO and SO(2). The results show that the algorithm is efficient towards SO(2) absorption interference with a full scale error less than +/- 0.4% in laboratory conditions. The algorithm was then applied to field measurements with an overall standard deviation of 8.37 mg m( 3), which is better than 18.92 mg m(-3) determined by the least squares method. Under the interference of desulfurization, the full-scale measurement errors are less than +/- 2%. In addition, the algorithm avoids using the reference spectrum, thereby reducing the aging of the light source effectively. It has strong anti interference capability, good durability, and practicality in the continuous monitoring of NO. PMID- 21327210 TI - Distribution and partitioning of aliphatic hydrocarbons and polycyclic aromatic hydrocarbons between water, suspended particulate matter, and sediment in harbours of the West coastal of the Gulf of Tunis (Tunisia). AB - Harbours of La Goulette, Rades and Sidi Bou Said are considered as the principal largest and most important port in the Gulf of Tunis characterised by a direct influence of different activities (sailing, industry and fishing) to the Mediterranean Sea. Due to their social and economic impact, a comprehensive assessment of the spatial distribution and partitioning of 24 polycyclic aromatic hydrocarbons (PAHs) and 18 aliphatic hydrocarbons (AHs) in summer and in winter among overlying water, suspended particulate matter (SPM) and surface sediments is essential. Distribution of hydrophobic organic contaminants in abiotic compartments is important for describing their transfer and fate in aquatic ecosystems and to identify the potential danger due to mobilization of contaminants produced by managing of the same sediments. Total organic carbon (TOC) contents range between 4.3% and 6.5%, with an average value of 5.9% in summer, and between 2.3% and 9.6%, with an average value of 6.1% in winter. The average concentrations of SigmaPAH in winter and in summer were respectively 703.1 ng L-1 and 378.4 ng L-1 in seawater, 4599.1 ng g-1 and 3114 ng g-1 in SPM, and 1507.6 ng g-1 dw (dry weight) and 1294.6 ng g-1 dw in surface sediment. For SigmaAH the average concentrations in winter and in summer were respectively 701 ng L-1 and 741.7 ng L-1 in seawater, 6743.5 ng g-1 and 6282.9 ng g-1 in SPM, and 4971.3 ng g-1 and 4588.1 ng g-1 in surface sediment. Higher PAH and AH concentrations were observed in SPM than in surface sediment. SPM and water were dominated by PAH with low molecular weight, while for sediment low and high molecular weight PAHs were present. PAH and AH fingerprint ratios, such as pristane to phytane (Pr/Ph), phenanthrene to anthracene (Phe/An) and fluoranthene to pyrene (Fl/Py), suggest that hydrocarbons in all harbours may originate from both pyrolytic and petrogenic sources derived from discharge of untreated sewage and wastewater or from direct input by ship traffic in the area. The results showed significant difference (ANOVA, p < 0.05) for hydrocarbon mean concentrations between all harbours studied and between different matrixes. PMID- 21327211 TI - Holographic optical tweezers and their relevance to lab on chip devices. AB - During the last decade, optical tweezers have been transformed by the combined availability of spatial light modulators and the speed of low-cost computing to drive them. Holographic optical tweezers can trap and move many objects simultaneously and their compatibility with other optical techniques, particularly microscopy, means that they are highly appropriate to lab-on-chip systems to enable optical manipulation, actuation and sensing. PMID- 21327212 TI - Synthesis and evaluation of xylopyranoside derivatives as "decoy acceptors" of human beta-1,4-galactosyltransferase 7. AB - Proteoglycans (PGs), including heparan sulfate forms, are important regulators of tumor progression. In the PGs biosynthetic process, the core protein is synthesized on a ribosomal template and the sugar chains are assembled post translationally, one sugar at a time, starting with the linkage of xylose to a serine residue of the core protein and followed by galactosidation of the xylosylprotein. Hydrophobic xylopyranosides have been previously shown to prime heparan sulfate synthesis, a property that was required to cause growth inhibition of tumor cells. To know if the antiproliferative activity of synthetic xylopyranosides is related to their ability to act as "decoy acceptors" of xylosylprotein 4-beta-galactosyltransferase, we have heterologously expressed the catalytic domain of the human beta-1,4-GalT 7 and studied the ability of a variety of synthetic xylopyranoside derivatives to act as substrates or inhibitors of the recombinant enzyme. PMID- 21327213 TI - Electrospinning-derived Tb2(WO4)3:Eu(3+) nanowires: energy transfer and tunable luminescence properties. AB - One-dimensional Tb(2)(WO(4))(3) and Tb(2)(WO(4))(3):Eu(3+) nanowires have been prepared by a combination method of sol-gel process and electrospinning. X-Ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), photoluminescence (PL), low voltage cathodoluminescence (CL) and time-resolved emission spectra as well as kinetic decays were used to characterize the resulting samples. The as-obtained precursor samples present fiber-like morphology with uniform size, and Tb(2)(WO(4))(3) and Tb(2)(WO(4))(3):Eu(3+) nanowires were formed after annealing. Under ultraviolet excitation and low-voltage electron beams excitation into WO(4)(2-) and the f-f transition of Tb(3+), the Tb(2)(WO(4))(3) samples show the characteristic emission of Tb(3+) corresponding to (5)D(4)-(7)F(6, 5, 4, 3) transitions due to an efficient energy transfer from WO(4)(2-) to Tb(3+), while Tb(2)(WO(4))(3):Eu(3+) samples mainly exhibit the characteristic emission of Eu(3+) corresponding to (5)D(0)-(7)F(0, 1, 2) transitions due to an energy transfer occurs from WO(4)(2-) and Tb(3+) to Eu(3+). The increase of Eu(3+) concentration leads to the increase of the energy transfer efficiency from Tb(3+) to Eu(3+). The PL color of Tb(2)(WO(4))(3):x mol% Eu(3+) phosphors can be tuned from green to red easily by changing the doping concentration (x) of Eu(3+), making the materials have potential applications in fluorescent lamps and color display fields. PMID- 21327214 TI - Synthesis of fluorinated pseudopeptides: metal mediated reversal of stereochemistry in diastereoselective addition of organometallic reagents to N (tert-butanesulfinyl)-alpha-fluoroenimines. AB - The addition reaction of organometallic reagents to N-(tert-butanesulfinyl)-alpha fluoroenimines was studied. Depending of the nature of the organometallic species (Grignard reagents or zincate complexes), we were able to control the configuration of the newly created stereogenic centers in high yields with good to high diastereomeric ratios. The chiral beta-fluoro allylamines are key synthons toward the synthesis of fluorinated pseudopeptides bearing a fluoroolefin moiety as a peptide bond mimic. PMID- 21327215 TI - Green oxidations of furans--initiated by molecular oxygen--that give key natural product motifs. AB - In this article, we explore how changes in the positioning of pendant hydroxyl functionalities in the photooxygenation substrate dramatically alter the course of furan oxidations that are initiated by singlet oxygen; and, how these different reactivities can be harnessed through cascade reaction sequences to access, rapidly and effectively, a broad range of important natural product motifs. PMID- 21327216 TI - Formation and regulation of fullerene-incorporation in liposomes under the phase transition temperature. AB - The fullerene-exchange reaction from a cyclodextrin cavity to liposomes represents one of the best methods to prepare lipid membrane-incorporated [70]fullerenes (C(70)). The C(70)-exchange reaction occurred completely at temperatures above the phase transition temperature (T(m)) of the liposomes; however, lowering the temperature to below the T(m) led to C(70) aggregation outside the liposomes. This observation has limited the development of more functional LMIC(70) using a variety of liposome compositions. In this paper, this reaction was found to occur efficiently by the addition of small amounts of lipids bearing a pi-moiety. The pi-moieties act as a gate when hydrophobic C(70) migrates into the hydrophilic liposome surface. Therefore, the pi-moieties should exist in the polar head groups of the lipids and the C(70)-exchange reaction can be controlled by pH. PMID- 21327217 TI - A pellet-type optical nanomaterial of silica-based naphthalimide-DPA-Cu(II) complexes: recyclable fluorescence detection of pyrophosphate. AB - A pellet-type nanomaterial prepared from a mesoporous silica-immobilized naphthalimide-DPA-Cu(II) complex (MSIND-Cu) is investigated as a selective fluorescent chemosensor for PPi detection with a large "off-on" fluorescence change, low detection limit, short response time and a broad pH test range. PMID- 21327218 TI - Selective incorporation of functional dicarboxylates into zinc metal-organic frameworks. AB - Zinc(II) nitrate reacts with different ratios of 1,4-benzenedicarboxylic acid (H(2)bdc) and 2-halo-1,4-benzenedicarboxylic acid (H(2)bdc-X, X = Br or I) to give [Zn(4)O(bdc)(3-x)(bdc-X)(x)], in which preferential incorporation of bdc is observed. The selective incorporation is related to crystal growth rates, and the proportion of incorporated bdc-X rises with increasing reaction time. PMID- 21327219 TI - The role of long-lived oxygen precursors on AuM alloys (M = Ni, Pd, Pt) in CO oxidation. AB - Gold alloys have been reported to be active in very low temperature oxidation of CO. The reasons for the better performance of AuNi with respect to Ni(111) surfaces were reported recently by indicating an active role of gold. Our results show that for this alloy, the CO oxidation molecular channel is responsible for the low temperature performance but the remaining oxygen on the surface is tightly bound and the process is not catalytic at low to room temperatures. The contribution from the associative path is also improved for the rest of the series: AuPd and AuPt. Only in the latter case, an important reduction of the light-off temperature of the catalytic path is observed. PMID- 21327220 TI - Fabrication and characterization of buckypaper-based nanostructured electrodes as a novel material for biofuel cell applications. AB - The fabrication process of buckypapers (BPs) made from stable suspensions of as received or functionalized multi-walled carbon nanotubes (MWCNTs) with high purity (97.5 wt%, Baytubes), their characterization and their utilization towards novel biofuel cell electrode applications are reported. The BPs can vary in thickness between 1 MUm and 200 MUm, are mechanically robust, flexible, stable in solvents, possess high meso-porosities as well as high apparent electrical conductivities of up to 2500 S m(-1). Potentiodynamic measurements of biocathodes based on bilirubin oxidase (BOD)-decorated BPs for the oxygen reduction reaction (ORR) in neutral media (phosphate buffer solution) containing glucose indicate that BP electrodes based on functionalized MWCNTs (fBPs) perform better than BP electrodes of as-received MWCNTs and have high potential as an effective electrode material in biofuel cells and biosensors. PMID- 21327221 TI - Proton-induced reactivities of ruthenium azido complexes: the first example of boron-carbon bond formation by methylene insertion into a B-H bond. AB - Whereas the reaction of Tp(PhCN)(PPh(3))Ru-N(3) {Tp = HB(pz)(3), pz = pyrazolyl} with CH(3)I in CH(2)Cl(2) led to the cationic ruthenium methyleneimine complex [Tp(PPh(3))(PhCN)Ru(NH=CH(2))]I, the analogous reaction with HCl gave rise to the ruthenium chloride complex containing a methyl tris(pyrazolyl)borate ligand (Me)Tp(PPh(3))(PhCN)RuCl, as a result of the highly unusual methylene insertion into a B-H bond of the Tp ligand. PMID- 21327222 TI - Tuning of the excitation wavelength from UV to visible region in Eu(3+)-beta diketonate complexes: comparison of theoretical and experimental photophysical properties. AB - A novel class of efficient visible light sensitized antenna complexes of Eu(3+) based on the use of a series of highly conjugated beta-diketonates, namely, 1-(1 phenyl)-3-(2-fluoryl) propanedione, 1-(2-naphthyl)-3-(2-fluoryl)propanedione, 1 (4-biphenyl)-3-(2-fluoryl) propanedione, and 2,2'-bis(di-p-tolylphosphino)-1,1' binaphthyl oxide as an ancillary ligand has been designed, synthesized, characterized and their photophysical properties investigated. The coordination geometries of the typical Eu(3+) complexes were calculated using the Sparkle/PM3 model. Photophysical properties of europium complexes benefit from adequate protection of the metal by the rigid phosphine oxide ligand against non-radiative deactivation and efficient ligand-to-metal energy transfer exceeding 50% as compared to precursor samples. The replacement of the phenyl group with the naphthyl or biphenyl groups in the 3-position of the fluoryl based beta diketonate ligand remarkably extends the excitation window of the corresponding Eu(3+) complexes towards the visible region (up to 500 nm). The highly conjugated beta-diketonate ligands sensitize efficiently the luminescence of Eu(3+) ions with quantum yields ranging from 19 to 43 % in the solid state, which is among the highest reported for a visible sensitized Eu(3+)complex. The theoretical quantum efficiencies from the Sparkle/PM3 structures are in good agreement with the experimental values, clearly attesting to the efficacy of the theoretical models. PMID- 21327223 TI - A catalyst-free and facile route to periodically ordered and c-axis aligned ZnO nanorod arrays on diverse substrates. AB - In this work we present a method for the deposition of periodically ordered, c axis aligned ZnO nanorod arrays. By using chemical bath deposited films in conjunction with silica templating through nanosphere monolayers, masks suitable for high temperature deposition are created. A vapour phase transport technique is then used to deposit ordered arrays, quickly and inexpensively in a manner ideal for low cost, scalable and reproducible growth on a diverse range of substrates. PMID- 21327224 TI - Alkoxyl- and carbon-centered radicals as primary agents for degrading non phenolic lignin-substructure model compounds. AB - Lignin degradation by white-rot fungi proceeds via free radical reaction catalyzed by oxidative enzymes and metabolites. Basidiomycetes called selective white-rot fungi degrade both phenolic and non-phenolic lignin substructures without penetration of extracellular enzymes into the cell wall. Extracellular lipid peroxidation has been proposed as a possible ligninolytic mechanism, and radical species degrading the recalcitrant non-phenolic lignin substructures have been discussed. Reactions between the non-phenolic lignin model compounds and radicals produced from azo compounds in air have previously been analysed, and peroxyl radical (PR) is postulated to be responsible for lignin degradation (Kapich et al., FEBS Lett., 1999, 461, 115-119). However, because the thermolysis of azo compounds in air generates both a carbon-centred radical (CR) and a peroxyl radical (PR), we re-examined the reactivity of the three radicals alkoxyl radical (AR), CR and PR towards non-phenolic monomeric and dimeric lignin model compounds. The dimeric lignin model compound is degraded by CR produced by reaction of 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH), which under N(2) atmosphere cleaves the alpha-beta bond in 1-(4-ethoxy-3-methoxyphenyl)-2-(2 methoxyphenoxy)-1,3-propanediol to yield 4-ethoxy-3-methoxybenzaldehyde. However, it is not degraded by the PR produced by reaction of Ce(4+)/tert-BuOOH. In addition, it is degraded by AR produced by reaction of Ti(3+)/tert-BuOOH. PR and AR are generated in the presence and absence of veratryl alcohol, respectively. Rapid-flow ESR analysis of the radical species demonstrates that AR but not PR reacts with the lignin model compound. Thus, AR and CR are primary agents for the degradation of non-phenolic lignin substructures. PMID- 21327225 TI - A stereoselective, Sm(II)-mediated approach to decorated cis-hydrindanes: synthetic studies on faurinone and pleuromutilin. AB - The cis-hydrindane motif is found in a number of natural products that display important biological activity. A flexible, stereoselective approach to the framework has been developed that features highly diastereoselective, SmI(2) mediated cyclisations. The strategy has been exploited in the first synthesis of the proposed structure of faurinone and an approach to the skeleton of the antibacterial natural product, pleuromutilin. PMID- 21327226 TI - Structure and magnetism of new hybrid cobalt hydroxide materials built from decorated brucite layers. AB - The structure, synthesis and magnetic properties of three new complex cobalt hydroxyl oxalates are presented, showing a modification of the 2-D double layer hydroxide structure. Co(12)(OH)(18)(ox)(3)(pip) [ox = oxalate, C(2)O(4)(2-); pip = piperazine, C(4)N(2)H(10)] (1), is essentially built from brucite-like layers with a one ninth depletion of the octahedral sites and a preservation of a trigonal crystallographic symmetry. ACo(28)(OH)(43)(ox)(6)Br(2)(H(2)O)(2) [A = Na (2), K (3)] are similarly composed of a brucite-like layer with three nineteenths depletion of octahedral sites, again preserving a trigonal symmetry. Both 2 and 3 show a small degree of structural disorder within the framework. All of these compounds have alternating layers of a mineral-like metal hydroxide structure and a metal oxalate coordination network, with the depletion in the hydroxyl layers being templated by the coordination network. Magnetic studies of 1 reveal a metamagnetic character, with the onset of an antiferromagnetic phase below T(c) = 23.5 K (H = 0 G), and a first order antiferromagnet to metamagnet transition at H(c) = 500-1000 G (T = 20-6 K). Compound 3 shows a more conventional ferrimagnetic ordering below 33(+/-1) K with a small coercive field of 107(+/-5) G at 10 K. PMID- 21327227 TI - Development of a sampling method for the simultaneous monitoring of straight chain alkanes, straight-chain saturated carbonyl compounds and monoterpenes in remote areas. AB - Studies have shown that biogenic compounds, long chain secondary compounds and long lifetime anthropogenic compounds are involved in the formation of organic aerosols in both polluted areas and remote places. This work aims at developing an active sampling method to monitor these compounds (i.e. 6 straight-chain saturated aldehydes from C6 to C11; 8 straight-chain alkanes from C9 to C16; 6 monoterpenes: alpha-pinene, beta-pinene, camphene, limonene, alpha-terpinene, & gamma-terpinene; and 5 aromatic compounds: toluene, ethylbenzene, meta-, para- and ortho-xylenes) in remote areas. Samples are collected onto multi-bed sorbent cartridges at 200 mL min(-1) flow rate, using the automatic sampler SyPAC (TERA Environnement, Crolles, France). No breakthrough was observed for sampling volumes up to 120 L (standard mixture at ambient temperature, with a relative humidity of 75%). As ozone has been shown to alter the samples (losses of 90% of aldehydes and up to 95% of terpenes were observed), the addition of a conditioned manganese dioxide (MnO(2)) scrubber to the system has been validated (full recovery of the affected compounds for a standard mixture at 50% relative humidity--RH). Samples are first thermodesorbed and then analysed by GC/FID/MS. This method allows suitable detection limits (from 2 ppt for camphene to 13 ppt for octanal--36 L sampled), and reproducibility (from 1% for toluene to 22% for heptanal). It has been successfully used to determine the diurnal variation of the target compounds (six 3 h samples a day) during winter and summer measurement campaigns at a remote site in the south of France. PMID- 21327232 TI - Biophysical characterization of the molecular orientation of an antibody immobilized layer using secondary ion mass spectrometry. AB - The molecular orientation of antibody layers formed on separate solid matrices (e.g., gold-coated glass substrate) was characterized by means of time-of-flight secondary ion mass spectrometry (ToF-SIMS) in static mode. For comparison, three different antibody species, IgG, F(ab')(2), and Fab, were prepared, biotinylated in random and site-directed fashions, and immobilized on distinct streptavidin coated surfaces. ToF-SIMS analyses of each antibody layer revealed that the secondary ion intensity peaks measured at the mass-to-charge (m/z) ratio 253, 325, and 647 were unique to the site-directly immobilized antibodies. The ions in the three peaks were detected neither from the streptavidin layer nor from the randomly prepared antibody, indicating that the insolubilized antibody layers constructed in the two different manners had distinct molecular arrangements. The antibody preparations were further tested for their binding characteristics in sandwich-type immunoassays, which showed that the site-directed antibodies consistently enhanced the detection capability comparing to those randomly prepared. Based on the analytical results of both the ToF-SIMS analysis and sandwich-type immunoassays, the site-directed antibody species were immobilized on the surfaces in a more orientated manner, with their antigen binding sites exposed to the bulk solution, than when random immobilization was used. PMID- 21327233 TI - Immobilization of chiral oxazaborolidine catalyst over highly ordered 3D mesoporous silica with Ia3d symmetry for enantioselective reduction of prochiral ketone. AB - Here we demonstrate for the first time the encapsulation of a chiral oxazaborolidine complex in the 3D mesoporous channels of an amine functionalized KIT-6 material via covalent bonding through a post-synthetic approach. The physico-chemical properties of the pure and immobilized KIT-6 catalysts were obtained by various techniques such as XRD, nitrogen adsorption, HRSEM, UV-Vis diffuse reflectance spectroscopy, and FT-IR spectroscopy. It has been found that the structural stability of the KIT-6 was not affected even after the immobilization of a significant amount of chiral ligand inside the mesoporous channels of the support. However, the values of structural parameters such as the specific surface area and the specific pore volume of the KIT-6 support was significantly lower than the pure KIT-6 support. The chemical interaction between the chiral ligand inside the mesochannels and the KIT-6 support was also confirmed by UV-Vis and FT-IR spectroscopy. The chiral catalytic performance of the immobilized catalysts for the enantioselective reduction of aromatic prochiral ketones was demonstrated and the results were compared with chiral catalyst immobilized supports with uni-dimensional porous structures, such as MCM 41 and SBA-15. Among the catalysts studied, chiral catalyst immobilized KIT-6 showed the highest performance with a high product yield and a high enantioselectivity due to its 3D porous structure with two continuous and interpenetrating systems of chiral channels and an interwoven 3D cylindrical type pores of Ia3d symmetry. The catalyst also exhibited much better recycling capability than other chiral catalyst supported mesoporous materials used in the study. PMID- 21327234 TI - Trigonal propeller-shaped [Mn(III)3M(II)Na] complexes (M = Mn, Ca): structural and functional models for the dioxygen evolving centre of PSII. AB - Two new polynuclear heterometallic cluster complexes with [Mn(III)(3)M(II)Na] (M = Mn, Ca) core were synthesized using two in situ formed Schiff bases. The compounds were structurally characterized by single crystal X-ray analysis. The compound with [Mn(III)Ca(II)Na] appeared to catalyse water oxidation which was followed by using Clark electrode and online mass spectrometry. PMID- 21327239 TI - Clarification of a misconception in the BINOL-based fluorescent sensors: synthesis and study of major-groove BINOL-amino alcohols. AB - The major-groove BINOL-amino alcohol (S)-6 shows greatly enhanced fluorescence over the minor-groove one (S)-3. The study of a series of the major-groove BINOL amino alcohol compounds demonstrates that the commonly accepted acid inhibition of the PET fluorescence quenching of aryl-amine compounds is not involved in the BINOL-amine sensors. PMID- 21327240 TI - Quantum chemical characterization of the generation of high-valent oxoruthenium species of Keggin type polyoxometalates: electronic structure and bonding features. AB - High-valent transition-metal-substituted Keggin-type polyoxometalates (POMs) are active and robust oxidation catalyst. The important oxidized intermediates of these POM complexes are very difficult to be characterized by using the experimental method, and thus no detail information is available on such species. In the present paper, density functional theory (DFT) calculations have been carried out to characterize the electronic structures of a series of mono ruthenium-substituted Keggin-type POMs. We find that the aquaruthenium(II/III/IV) species possess d(xy)(2)d(xz)(2)d(yz)(2), d(xy)(2)d(xz)(2)d(yz)(1), and d(xy)(2)d(xz)(1)d(yz)(1) electronic configuration, respectively, and hydroxyl/oxoruthenium(IV/V/VI) species possess d(xy)(2)d(xz)(1)pi*(yz)(1), d(xy)(2)pi*(xz)(1)pi*(yz)(1), d(xy)(1)pi*(xz)(1)pi*(yz)(1), and d(xy)(1)pi*(xz)(1)pi*(yz)(0) electronic configuration, respectively. Mulliken spin population shows that spin density is localized on the ruthenium center in aquaruthenium(II/III/IV) POM complexes, and the RuO(a) unit in hydroxyl/oxoruthenium(IV/V/VI) POM complexes. The O(a) atom has substantial radical character in oxoruthenium(IV/V) species, and the radical character of the O(a) atom are significantly weakened in the oxoruthenium(VI) species. The relevant energy of the important Ru-O(a)pi*-antibonding unoccupied orbitals with high RuO(a) compositions of oxoruthenium(IV/V/VI) POM complexes decrease in the order: oxoruthenium(IV) > oxoruthenium(V) > oxoruthenium(VI). The pH-independent multiple reduction energies for Ru(III/II), Ru(V/IV), and Ru(VI/V) couples are calculated, which is in agreement with the experimental data. PMID- 21327241 TI - Structural considerations and reactivity of peroxocomplexes of V(V), Mo(VI) and W(VI). AB - In this perspective we will discuss recent results on structural aspects of peroxocomplexes of transition metals having the d(0) configuration (V(V), Mo(VI), W(VI)), and show how these may be related to the reactivity of these species in both chemical and biological systems. In addition, we will consider the relevance of structural properties to their involvement as important intermediates in industrial and enzymatic catalysis. These will be related to the behaviour of peroxocomplexes of other diamagnetic transition metals, such as those with d(8) (Pd(II), Pt(II)) configurations. PMID- 21327242 TI - Theoretical characterization of a Ru N-heterocyclic carbene derivative of a polyoxometalate. Enhanced pi-interaction in oxide supported TM-organic linkages. AB - The electronic structure of the N-heterocyclic carbene (NHC) functionalized polyoxometalate [K(PW(9)O(34))(2)(cis-WO(2))(cis-RuLMe(2))](12-) (1) is studied computationally; and its Ru-NHC bonding situation is compared with other monometallic Ru-NHC complexes, as well as other representative carbene complexes. The DFT analysis further supports the low spin configuration, S = 1/2, as the ground state, as the unoccupied d ruthenium orbitals are high in energy and mixed with the d-type orbitals of W. We gauge the TM-carbene bonding nature by means of atoms in molecules (AIM) quantum theory and a modified version of energy decomposition analysis (EDA) based on orbital deletion. According to the calculations, the NCH ligand in POM derivative 1 is more tightly bonded than in its analogous neutral monometallic Ru-NHC complexes. This is manifested in a higher electron density rho(r) at the bond critical point (bcp) between Ru and the carbene carbon atoms. The energetic contribution of sigma-donation is similar for all Ru-NHC complexes, and significantly higher than for Fischer-type carbene complex, in agreement with the description of the N-heterocyclic carbene ligand as a strong sigma-donor. Among the studied Ru-NHC complexes, the POM derivative 1 shows the largest pi-back-donation ability, explaining the observed short Ru C(carbene) bond distance and the calculated high interaction energy. The POM framework acting as ligand makes the ruthenium d electrons more loose via orbital mixing and promotes the back-donation to the ligand. PMID- 21327243 TI - Structures and magnetism of {Ni2Na2}, {Ni4} and {Ni6(II)Ni(III)} 2-hydroxy-3 alkoxy-benzaldehyde clusters. AB - Three polynuclear complexes, [NiNa(MU(1,1,1)-N(3))(MU-hmb)(2)(DMF)](2), (1), [Ni(4)(MU(3)-OMe)(4)(heb)(4)(MeOH)(1.05)(H(2)O)(2.95)], (2) and [Ni(III)(OH)(6)(hmb)(6)Ni(II)(6)].(ClO(4))(3) (3) (Hhmb = 2-hydroxy-3-methoxy benzaldehyde; Hheb = 2-hydroxy-3-ethoxy-benzaldehyde), were prepared by reaction of the appropriate ligand with nickel(II) perchloride hexahydrate under solvothermal conditions. All compounds were characterized by elemental analysis, IR spectroscopy and X-ray single-crystal diffraction. Compound 1 exhibits a centrosymmetric heterotetranuclear cluster which represents the first nickel complex to possess two connected face-sharing cubes structure {Ni(2)Na(2)N(2)O(4)}. Compound 2 has a tetranuclear Ni cluster with a cubane topology in which the Ni(II) and the oxygen atoms from the methanol ligands occupying alternate vertices of the cube. Compound 3 consisits of a mixed-valence [Ni(III)(OH)(6)(hmb)(6)Ni(II)(6)](3+) subunits and it represents the first nickel {Ni(II)(6)Ni(III)} complex to possess a planar hexagonal disc-like structure. The results show that the minor ligand modifications or solvent change have a key role in the structural control of the self-assembly process. Magnetic properties of 1-3 in the 300-2 K have been discussed. The {Ni(2)Na(2)} (1) and {Ni(4)} (2) core display dominant ferromagnetic interactions from the nature of the binding modes through MU(3)-N(3)(-) or MU(3)-OCH(3)(-), while {Ni(II)(6)Ni(III)} core (3) displays dominant anti-ferromagnetic interactions from the nature of the binding modes through MU(3)-OH(-). PMID- 21327244 TI - Anion binding by metallo-receptors of 5,5'-dicarbamate-2,2'-bipyridine ligands. AB - Three 5,5'-dicarbamate-2,2'-bipyridine ligands (L = L(1)-L(3)) bearing ethyl, isopropyl or tert-butyl terminals, respectively, on the carbamate substituents were synthesized. Reaction of the ligands L with the transition metal ions M = Fe(2+), Cu(2+), Zn(2+) or Ru(2+) gave the complexes ML(n)X(2).xG (1-12, n = 1-3; X = Cl, NO(3), ClO(4), BF(4), PF(6), 1/2SO(4); G = Et(2)O, DMSO, CH(3)OH, H(2)O), of which [Fe(L(2))(3) ? SO(4)].8.5H(2)O (2), [Fe(L(1))(3) ? (BF(4))(2)].2CH(3)OH (7), [Fe(L(2))(3) ? (Et(2)O)(2)](BF(4))(2).2CH(3)OH (8), [ZnCl(2)(L(1))][ZnCl(2)(L(1))(DMSO)].2DMSO (9), [Zn(L(1))(3) ? (NO(3))(2)].2H(2)O (10), [Zn(L(2))(3) ? (ClO(4))(Et(2)O)]ClO(4).Et(2)O.2CH(3)OH.1.5H(2)O (11), and [Cu(L(1))(2)(DMSO)](ClO(4))(2).2DMSO (12) were elucidated by single-crystal X-ray crystallography. In the complexes ML(n)X(2).xG the metal ion is coordinated by n = 1, 2 or 3 chelating bipyridine moieties (with other anionic or solvent ligands for n = 1 and 2) depending on the transition metal and reaction conditions. Interestingly, the carbamate functionalities are involved in hydrogen bonding with various guests (anions or solvents), especially in the tris(chelate) complexes which feature the well-organized C(3)-clefts for effective guest inclusion. Moreover, the anion binding behavior of the pre-organized tris(chelate) complexes was investigated in solution by fluorescence titration using the emissive [RuL(3)](2+) moiety as a probe. The results show that fluorescent recognition of anion in solution can be achieved by the Ru(II) complexes which exhibit good selectivities for SO(4)(2-). PMID- 21327245 TI - Synthesis and catalytic activity of histidine-based NHC ruthenium complexes. AB - Main-chain C,N-protected histidine has been successfully alkylated at both side chain nitrogens. The corresponding histidinium salt was metallated with ruthenium(II) by a transmetalation procedure, thus providing histidine-derived NHC ruthenium complexes. These bio-inspired complexes show appreciable activity in the catalytic transfer hydrogenation of ketones. PMID- 21327246 TI - Distribution of mercury and organic matter in particle-size classes in sediments contaminated by a waste water treatment plant: Vidy Bay, Lake Geneva, Switzerland. AB - In Lake Geneva, Switzerland, the most Hg-contaminated sediments have been found in the Vidy Bay where high Hg contents largely exceeds the background levels of Lake Geneva sediments. This contamination has been attributed to the discharge of a waste water treatment plant (WWTP). Total Hg (THg) and monomethylmercury (MMHg) were determined in bulk sediment and in three different grain size fractions (i: clay and silt, ii: fine-coarse sand, iii: and very coarse sand and gravel) collected close to the outlet pipe of a WWTP in order to verify whether the standardized procedures of sediment treatment is adequate for this setting and, by extension, for similar contaminated sites. THg was homogeneously distributed in the different grain size fractions and was correlated to organic matter content (R(2) = 0.6). MMHg was homogeneously distributed in the two finer grain fractions (Phi < 0.063 mm; 0.063 mm < Phi <1 mm). The results of this study suggested that the analysis of the bulk sediment seems to be more appropriate for the assessment of the content and spatial distribution of Hg in freshwater sediments contaminated by WWTPs. PMID- 21327247 TI - Spatial analysis and land use regression of VOCs and NO2 in Dallas, Texas during two seasons. AB - Passive air sampling for nitrogen dioxide (NO(2)) and select volatile organic compounds (VOCs) was conducted at 24 fire stations and a compliance monitoring site in Dallas, Texas, USA during summer 2006 and winter 2008. This ambient air monitoring network was established to assess intra-urban gradients of air pollutants to evaluate the impact of traffic and urban emissions on air quality. Ambient air monitoring and GIS data from spatially representative fire station sites were collected to assess spatial variability. Pairwise comparisons were conducted on the ambient data from the selected sites based on city section. These weeklong samples yielded NO(2) and benzene levels that were generally higher during the winter than the summer. With respect to the location within the city, the central section of Dallas was generally higher for NO(2) and benzene than north and south. Land use regression (LUR) results revealed spatial gradients in NO(2) and selected VOCs in the central and some northern areas. The process used to select spatially representative sites for air sampling and the results of analyses of coarse- and fine-scale spatial variability of air pollutants on a seasonal basis provide insights to guide future ambient air exposure studies in assessing intra-urban gradients and traffic impacts. PMID- 21327248 TI - Multiplexed inkjet functionalization of silicon photonic biosensors. AB - The transformative potential of silicon photonics for chip-scale biosensing is limited primarily by the inability to selectively functionalize and exploit the extraordinary density of integrated optical devices on this platform. Silicon biosensors, such as the microring resonator, can be routinely fabricated to occupy a footprint of less than 50 * 50 um; however, chemically addressing individual devices has proven to be a significant challenge due to their small size and alignment requirements. Herein, we describe a non-contact piezoelectric (inkjet) method for the rapid and efficient printing of bioactive proteins, glycoproteins and neoglycoconjugates onto a high-density silicon microring resonator biosensor array. This approach demonstrates the scalable fabrication of multiplexed silicon photonic biosensors for lab-on-a-chip applications, and is further applicable to the functionalization of any semiconductor-based biosensor chip. PMID- 21327249 TI - Activated T lymphocytes migrate toward the cathode of DC electric fields in microfluidic devices. AB - Immune cell migration is a fundamental process that enables immunosurveillance and immune responses. Understanding the mechanism of immune cell migration is not only of importance to the biology of cells, but also has high relevance to cell trafficking mediated physiological processes and diseases such as embryogenesis, wound healing, autoimmune diseases and cancers. In addition to the well-known chemical concentration gradient based guiding mechanism (i.e. chemotaxis), recent studies have shown that lymphocytes can respond to applied physiologically relevant direct current (DC) electric fields by migrating toward the cathode of the fields (i.e. electrotaxis) in both in vitro and in vivo settings. In the present study, we employed two microfluidic devices allowing controlled application of electric fields inside the microfluidic channel for quantitative studies of lymphocyte electrotaxis in vitro at the single cell level. The first device is fabricated by soft-lithography and the second device is made in glass with integrated on-chip electrodes. Using both devices, we for the first time showed that anti-CD3/CD28 antibodies activated human blood T cells migrate to the cathode of the applied DC electric field. This finding is consistent with previous electrotaxis studies on other lymphocyte subsets suggesting electrotaxis is a novel guiding mechanism for immune cell migration. Furthermore, the characteristics of electrotaxis and chemotaxis of activated T cells in PDMS microfluidic devices are compared. PMID- 21327250 TI - Development of multistage distillation in a microfluidic chip. AB - Although there has been a lot of work on the development of microchemical processing systems such as micro-reactors and micro-sensors, little attention has been paid to micro-separation units, and in particular, microscale distillation. In this paper, various silicon-glass microscale distillation chips with different channel configurations were fabricated and tested. A temperature gradient was setup across the chip by heating and cooling the two ends. The feed was located at the middle of the microchannel. Arrays of micropillars were incorporated in order to guide the liquid flow. It was found that the separation performance was promoted by increasing the length of the microchannel. However, this created an imbalance of the liquid flows at the two sides of the microchannel and caused flooding. This hydrodynamic limitation was addressed by incorporating micropillars on both sides of the channel. The most efficient microdistillation chip consisted of a microchannel with 600 microns width and 40 cm length. Experimental results showed high efficiency for the separation of a 50 mol% acetone-water mixture when the heating and cooling temperature were 95 degrees C and 42 degrees C respectively. The concentrations of acetone were 3 mol% in the bottom stream and 95 mol% in the distillate, which was equivalent to at least 4 equilibrium stages at total reflux conditions. Furthermore, a 50 mol% methanol toluene mixture was separated into nearly pure toluene in the bottom stream and 75 mol% methanol in the distillate. The performance of the microdistillation unit was reproducible in repeated tests. PMID- 21327251 TI - On-demand microfluidic droplet manipulation using hydrophobic ferrofluid as a continuous-phase. AB - Multiple essential microdroplet operation units, including splitting, dispensing, oil-phase exchange, trapping, release and demulsification, were successfully implemented by combining hydrophobic ferrofluid with microfluidic chips. PMID- 21327252 TI - Studies on Parylene C-caulked PDMS (pcPDMS) for low permeability required microfluidics applications. AB - This note introduced a complete fabrication strategy of Parylene C-caulked PDMS (pcPDMS) for low permeability required microfluidics applications. The bonding issue enrolled in the pcPDMS fabrication was solved based on careful surface analyses of the Parylene C caulked status in the PDMS matrix. PMID- 21327253 TI - A simple and fast microfluidic approach of same-single-cell analysis (SASCA) for the study of multidrug resistance modulation in cancer cells. AB - Due to the cellular heterogeneity in multidrug resistance (MDR) cell populations, positive drug effects on the modulation of MDR can be obscured in conventional methods, especially when only a small number of cells are available. To address cellular variations among different MDR cells, we report a new microfluidic approach to study drug effect on MDR modulation, by investigating drug accumulation of daunorubicin in MDR leukemia cells. We have demonstrated that the new approach of same-single-cell analysis by accumulation (denoted as SASCA-A) is not only superior to different-single-cell analysis, but also has key advantages over our previous approach of same-single-cell analysis. First, SASCA-A is much simpler as it does not require multiple cycles of drug uptake and drug efflux. Second, it is faster, only taking about one fourth of the time used in the previous approach. Third, it provides a more 'identical' and reliable control because it compares the time points just before MDR modulator tests. To help understand the dynamics of drug accumulation in MDR cells, we also developed a mathematical model to describe the kinetics of drug accumulation conducted in individual cells. The SASCA-A method will benefit drug resistance research in minor cell subpopulations (e.g., cancer "stem" cells) because this method requires only a small number of cells in identifying the MDR reversal effect. PMID- 21327254 TI - Identification of O-GlcNAc sites within peptides of the Tau protein and their impact on phosphorylation. AB - Phosphorylation of the microtubule-associated Tau protein plays a major role in the regulation of its activity of tubulin polymerization and/or stabilization of microtubule assembly. A dysregulation of the phosphorylation/dephosphorylation balance leading to the hyperphosphorylation of Tau proteins in neurons is thought to favor their aggregation into insoluble filaments. This in turn might underlie neuronal death as encountered in many neurodegenerative disorders, including Alzheimer's disease. Another post-translational modification, the O-linked beta-N acetylglucosaminylation (O-GlcNAcylation), controls the phosphorylation state of Tau, although the precise mechanism is not known. Moreover, analytical difficulties have hampered the precise localization of the O-GlcNAc sites on Tau, except for the S400 site that was very recently identified on the basis of ETD-FT MS. Here, we identify three O-GlcNAc sites by screening a library of small peptides sampling the proline-rich, the microtubule-associated repeats and the carboxy-terminal domains of Tau as potential substrates for the O-beta-N acetylglucosaminyltransferase (OGT). The in vitro activity of the nucleocytoplasmic OGT was assessed by tandem mass spectrometry and NMR spectroscopy. Using phosphorylated peptides, we establish the relationship between phosphate and O-GlcNAc incorporation at these sites. Phosphorylation of neighboring residues S396 and S404 was found to decrease significantly S400 O GlcNAcylation. Reciprocally, S400 O-GlcNAcylation reduces S404 phosphorylation by the CDK2/cyclinA3 kinase and interrupts the GSK3beta-mediated sequential phosphorylation process. PMID- 21327255 TI - Mode of action and biosynthesis of the azabicycle-containing natural products azinomycin and ficellomycin. AB - Only a handful of aziridine-containing natural products have been identified out of the more than 100,000 natural products characterized to date. Among this class of compounds, only the azinomycins (azinomycin A and B) and ficellomycin contain an unusual 1-azabicyclo[3.1.0]hexane ring system, which has been reported to be the reason for theDNAcrosslinking abilities and cytotoxicity of these metabolites. Both families of natural products are produced by Streptomyces species, Streptomyces sahachiroi and Streptomyces ficellus, respectively. Up until recently, much of the work on these molecules has focused on the synthesis of these natural products or their corresponding analogs for in vitro investigations evaluating their DNA selectivity. While one of the most intriguing aspects of these natural products is their biosynthesis, progress made in this area was largely impeded by difficulties with obtaining a reliable culture method and securing a consistent source of these natural products. In this review, we will cover the discovery and biological activity of the azinomycins, their mode of action, related synthetic analogs and biosynthesis, and finish with a discussion on the less studied metabolite, ficellomycin. PMID- 21327256 TI - Architectural integration of the components necessary for electrical energy storage on the nanoscale and in 3D. AB - We describe fabrication of three-dimensional (3D) multifunctional nanoarchitectures in which the three critical components of a battery--cathode, separator/electrolyte, and anode--are internally assembled as tricontinuous nanoscopic phases. The architecture is initiated using sol-gel chemistry and processing to erect a 3D self-wired nanoparticulate scaffold of manganese oxide (>200 m(2) g(-1)) with a continuous, open, and mesoporous void volume. The integrated 3D system is generated by exhaustive coverage of the oxide network by an ultrathin, conformal layer of insulating polymer that forms via self-limiting electrodeposition of poly(phenylene oxide). The remaining interconnected void volume is then wired with RuO(2) nanowebs using subambient thermal decomposition of RuO(4). Transmission electron microscopy demonstrates that the three nanoscopic charge-transfer functional components--manganese oxide, polymer separator/cation conductor, and RuO(2)--exhibit the stratified, tricontinuous design of the phase-by-phase construction. This architecture contains all three components required for a solid-state energy storage device within a void volume sized at tens of nanometres such that nanometre-thick distances are established between the opposing electrodes. We have now demonstrated the ability to assemble multifunctional energy-storage nanoarchitectures on the nanoscale and in three dimensions. PMID- 21327257 TI - The story of making fullerenes. AB - Carbon is the most abundant condensable element in space. Our attempts to produce interstellar-like graphitic grains unexpectedly led to the discovery of a method for fullerene production in bulk amounts. These works opened the door for an entirely new branch of materials research and carbon chemistry. Here I present the various phases and steps of our work which, with interludes, lasted from 1983 to 1990. The starting point was the discovery of unexplained UV absorptions in the soot samples we had produced, while the endpoint was marked by the extraction of fullerenes in crystalline form from just these samples. PMID- 21327258 TI - Allosterically driven self-assemblies of interlocked calix[6]arene receptors. AB - The construction of self-assembled receptors based on flexible concave subunits is a challenging task and constitutes an interesting approach to mimic binding processes occurring in biological systems. The receptors studied herein are based on flexible calix[6]arene skeletons bearing three (or more) acid-base functionalities at their narrow rim. When complementary, they self-assemble in a tail-to-tail manner to give a diabolo-like complex, provided that each calixarene subunit hosts a guest. The allosterically-driven multi-recognition pattern is highly selective and leads to stable quaternary adducts. In order to evaluate the scope of this system, various polyamino and polyacidic calix[6]arenes have been studied. It is shown that modifications of the nature of the wide rim substituents do not alter the efficiency of the quaternary self-assembling process, even with the more flexible macrocycles that lack tBu substituents. On the contrary, the replacement of the latter by smaller groups led to receptors with broader scope, as larger guests such as tryptamine and dopamine derivatives were stabilized in the cavities. Implementation of extra-functionalities at the narrow rim were revealed also to be of high interest. Indeed, it is shown that secondary interactions take place between the two calix-subunits when they present additional and complementary functions such as carboxylate and ureido moieties. The ureido arms are also capable of binding the counter anion Cl(-) of the ammonium guest, thus leading to a quinternary neutral complex. Such remarkable behavior is due to the versatility of the calix[6]arene platform, which allows the implementation of a high number of functions, leading to multiple non-covalent attractive interactions, whereas the macrocycle remains flexible, thus allowing induced-fit processes to occur. PMID- 21327259 TI - Modulation of the photophysics of 2-(4'-N,N-dimethylaminophenyl)imidazo[4,5 b]pyridine by long chain N-alkylations. AB - The N-alkylated products of 2-(4'-N,N-dimethylaminophenyl)imidazo[4,5-b]pyridine (DMAPIP-b) were synthesized to study the effect of long alkyl chains on the photophysics of the fluorophore. Two different compounds were synthesized: in molecule 1, the alkyl chain was attached to the pyridine nitrogen of DMAPIP-b and in molecule 2 the alkyl chain was substituted on the imidazole nitrogen of DMAPIP b. Absorption, steady state and time-resolved fluorescence techniques were employed to investigate the spectral properties in different solvents. Density functional theory (DFT) and restricted configuration by singles (CIS) combined with time-dependent DFT (TDDFT) calculations were performed on the ground state and the excited state respectively to calculate the geometrical and the electronic properties of the molecules. Unlike DMAPIP-b, where dual emission was observed in protic solvents, which originates from both a locally excited state and an intramolecular charge transfer (ICT) state, the pyridine nitrogen alkylated product (1) emits a single emission from the ICT state and the imizadole nitrogen alkylated molecule (2) emits dual emission only in methanol and water. PMID- 21327260 TI - Recording force events of single quantum-dot endocytosis. AB - We applied force spectroscopy based on atomic force microscope (AFM) to demonstrate the possibility of measuring the interaction force between single quantum-dots (QDs) and living cells at single particle level under native conditions. In the force-distance cycle, we recorded the events of cellular uptake of single QDs and single QD detachment from the cell. PMID- 21327261 TI - Solvent denaturation of supramolecular capsules assembled via the hydrophobic effect. AB - The organic co-solvent induced denaturation of a series of capsular complexes formed between trioxolane guests and a water-soluble deep-cavity cavitand was examined. The results obtained demonstrate a wide range of denaturation properties, and suggest the important factors governing capsule stability. PMID- 21327262 TI - Introduction by the guest editors. A collection of papers presented at the 6th European Conference on Solar Chemistry & Photocatalysis: Environmental Applications (SPEA6). PMID- 21327263 TI - The complexity of mesoporous silica nanomaterials unravelled by single molecule microscopy. AB - Mesoporous silica nanomaterials are a novel class of materials that offer a highly complex porous network with nanometre-sized channels into which a wide amount of differently sized guests can be incorporated. This makes them an ideal host for various applications for example in catalysis, chromatography and nanomedicine. For these applications, analyzing the host properties and understanding the complicated host-guest interactions is of pivotal importance. In this perspective we review some of our recent work that demonstrates that single molecule microscopy techniques can be utilized to characterize the porous silica host with unprecedented detail. Furthermore, the single molecule studies reveal sample heterogeneities and are a highly efficient tool to gain direct mechanistic insights into the host-guest interactions. Single molecule microscopy thus contributes to a thorough understanding of these nanomaterials enabling the development of novel tailor-made materials and hence optimizing their applicability significantly. PMID- 21327264 TI - Continuous analysis of dye-loaded, single cells on a microfluidic chip. AB - Continuous analysis of two dyes loaded into single mammalian cells using laser based lysis combined with electrophoretic separation was developed and characterized on microfluidic chips. The devices employed hydrodynamic flow to transport cells to a junction where they were mechanically lysed by a laser generated cavitation bubble. An electric field then attracted the analyte into a separation channel while the membranous remnants passed through the intersection towards a waste reservoir. Phosphatidylcholine (PC)-supported bilayer membrane coatings (SBMs) provided a weakly negatively charged surface and prevented cell fouling from interfering with device performance. Cell lysis using a picosecond pulsed laser on-chip did not interfere with concurrent electrophoretic separations. The effect of device parameters on performance was evaluated. A ratio of 2 : 1 was found to be optimal for the focusing-channel : flow-channel width and 3 : 1 for the flow-channel : separation-channel width. Migration times decreased with increased electric field strengths up to 333 V cm(-1), at which point the field strength was sufficient to move unlysed cells and cellular debris into the electrophoretic channel. The migration time and full width half-maximum (FWHM) of the peaks were independent of cell velocity for velocities between 0.03 and 0.3 mm s(-1). Separation performance was independent of the exact lysis location when lysis was performed near the outlet of the focusing channel. The migration time for cell-derived fluorescein and fluorescein carboxylate was reproducible with <10% RSD. Automated cell detection and lysis were required to reduce peak FWHM variability to 30% RSD. A maximum throughput of 30 cells min(-1) was achieved. Device stability was demonstrated by analyzing 600 single cells over a 2 h time span. PMID- 21327265 TI - Tools for resolving complexity in the electron transfer networks of multiheme cytochromes c. AB - Examining electron transfer between two proteins with identical spectroscopic signatures is a challenging task. It is supposed that several multiheme cytochromes in Shewanella oneidensis form a molecular "wire" through which electrons are transported across the cellular space and a direct study of this transient protein-protein interaction has not yet been reported. In this study, we present variations on catalytic protein film voltammetry and an anaerobic affinity chromatography assay to demonstrate unidirectional electron transfer between proposed protein pairs. Through use of these techniques, we are able to confirm the transient interactions between these cytochromes, supporting the model of electron transfer that is present in the literature. PMID- 21327266 TI - Synthesis of octahedral Pt-Pd alloy nanoparticles for improved catalytic activity and stability in methanol electrooxidation. AB - We report Pt-Pd nanoparticles synthesized by means of a polyol process with glycerol as a reducing agent. The Pt-Pd nanoparticles exhibit dominantly exposed {111} facets in octahedral shape with complete alloy formation between Pt and Pd. Furthermore, the octahedral Pt-Pd alloy catalysts show improved catalytic activity and stability in methanol electrooxidation. PMID- 21327267 TI - Materials innovation through interfacial physics and chemistry. PMID- 21327272 TI - Evaluation of different fingerprinting strategies for differentiating marine oils by liquid chromatography ion-trap mass spectrometry and chemometrics. AB - Assessing the capabilities of instrumental techniques aiming at differentiating marine oils is a matter of great importance for both authorities and industries which has been highlighted over 120 years. In this study, different strategies were evaluated by means of principal component analysis (PCA) for their performance in differentiating various marine oils. Triacylglycerols (TAGs) composition and four different profiles including total ion current (TIC) and total mass spectral (TMS) profiles derived from liquid chromatography electrospray single and tandem mass spectrometry (LC-ESI-MS and LC-ESI-MS(2)) were used as the dataset for PCA study. Among these strategies, the tandem TMS profiles from LC-ESI-MS(2) experiments as the dataset demonstrated to be the most rapid and convenient approach for the differentiation of various marine and plant oils investigated and for the representation of the characteristics TAG patterns. This novel approach represents an alternative and promising tool for fingerprinting and differentiating marine oils. PMID- 21327273 TI - Mn12 single-molecule magnet aggregates as magnetic resonance imaging contrast agents. AB - Mn(12) single-molecule magnets have been dispersed in water through an emulsion assisted self-assembly method with an improved stability in water, in order to investigate the use of Mn(12) as MRI contrast agents. PMID- 21327274 TI - A luminescent cyclometalated platinum(II) complex and its green organic light emitting device with high device performance. AB - A luminescent cyclometalated platinum(II) complex has been demonstrated to show green electrophosphorescence in multilayer organic light-emitting devices (OLEDs) using a dual emissive layer with high current and external quantum efficiencies of 38.9 cd A(-1) and 11.5%, respectively. PMID- 21327275 TI - Effect of the N-terminal basic residue on facile Calpha-C bond cleavages of aromatic-containing peptide radical cations. AB - Fragmentation of radical cationic peptides [R(G)(n-2)X(G)(7-n)](+) and [R(G)(m 2)XG](+) (X = Phe or Tyr; m = 2-5; n = 2-7) leads selectively to a(n)(+) product ions through in situ C(alpha)-C peptide backbone cleavage at the aromatic amino acid residues. In contrast, substituting the arginine residue with a less-basic lysine residue, forming [K(G)(n-2)X(G)(7-n)](+) (X = Phe or Tyr; n = 2-7) analogs, generates abundant b-y product ions; no site-selective C(alpha)-C peptide bond cleavage was observed. Studying the prototypical radical cationic tripeptides [RFG](+) and [KFG](+) using low-energy collision-induced dissociation and density functional theory, we have examined the influence of the basicity of the N-terminal amino acid residue on the competition between the isomerization and dissociation channels, particularly the selective C(alpha)-C bond cleavage viabeta-hydrogen atom migration. The dissociation barriers for the formation of a(2)(+) ions from [RFG](+) and [KFG](+)via their beta-radical isomers are comparable (33.1 and 35.0 kcal mol(-1), respectively); the dissociation barrier for the charge-induced formation of the [b(2)- H](+) radical cation from [RFG](+)via its alpha-radical isomer (39.8 kcal mol(-1)) was considerably higher than that from [KFG](+) (27.2 kcal mol(-1)). Thus, the basic arginine residue sequesters the mobile proton to promote the charge-remote selective C(alpha)-C bond cleavage by energetically hindering the competing charge-induced pathways. PMID- 21327276 TI - Ionization dynamics of aminopyridine dimer: a direct ab initio molecular dynamics (MD) study. AB - The ionization dynamics of an aminopyridine dimer (AP)(2) has been investigated by means of the direct ab initio molecular dynamics (MD) method. It was found that the reaction process was composed of three steps after the vertical ionization of (AP)(2): dimer approach, proton transfer and energy relaxation. The timescales of these processes were 50-100, 10-20, and 200 fs, respectively. The timescale of the dimer approach was dependent on the initial separation between AP(+) and AP. After the ionization, AP approached gradually the ionized AP(+). The proton of AP(+) was transferred to AP at the nearest intermolecular distance, while the potential energy was quickly dropped according to the proton transfer. The energy relaxation of the dimer cation was significantly faster than that of the monomer cation. The mechanism of ionization dynamics of (AP)(2) was discussed on the basis of the theoretical results. PMID- 21327277 TI - Absorption of 10-hydroxycamptothecin on Fe3O4 magnetite nanoparticles with layer by-layer self-assembly and drug release response. AB - In this paper, the structural and zeta potential properties of 10 hydroxycamptothecin (HCPT) were investigated by FT-IR and zeta potential analyzer under different pH. The anticancer drug HCPT as a model drug was used to prepare a high-performance and relatively easy-to-fabricate system on Fe(3)O(4) magnetite nanoparticles by using a polystyrene sulfonate (PSS) and HCPT interlayer self assembly method. The results obtained from FT-IR and XRD confirmed that HCPT was molecularly dispersed into the nanoparticles. The method holds not only environment-friendly characteristics and the ability to mimic the self organization process in biological systems but also greatly decreases adjuvant polymers. In addition, the system has an ideal drug payload for the delivery of insoluble HCPTs. PMID- 21327278 TI - Rapid prototyping of microstructures in polydimethylsiloxane (PDMS) by direct UV lithography. AB - Microstructuring of polydimethylsiloxane (PDMS) is a key step for many lab-on-a chip (LOC) applications. In general, the structure is generated by casting the liquid prepolymer against a master. The production of the master in turn calls for special equipment and know how. Furthermore, a given master only allows the reproduction of the defined structure. We report on a simple, cheap and practical method to produce microstructures in already cured PDMS by direct UV-lithography followed by chemical development. Due to the available options during the lithographic process like multiple exposures, the method offers a high design flexibility granting easy access to complex and stepped structures. Furthermore, no master is needed and the use of pre-cured PDMS allows processing at ambient (light) conditions. Features down to approximately 5 um and a depth of 10 um can be realised. As a proof of principle, we demonstrate the feasibility of the process by applying the structures to various established soft lithography techniques. PMID- 21327279 TI - Rapid characterization and engineering of natural product biosynthetic pathways via DNA assembler. AB - We report a synthetic biology strategy for rapid genetic manipulation of natural product biosynthetic pathways. Based on DNA assembler, this method synthesizes the entire expression vector containing the target biosynthetic pathway and the genetic elements required for DNA maintenance and replication in various hosts in a single-step manner through yeast homologous recombination, offering unprecedented flexibility and versatility in pathway manipulations. PMID- 21327280 TI - Controlling side-chain density of electron donating polymers for improving their packing structure and photovoltaic performance. AB - A simple and efficient approach of controlling the side-chain density in the electron donating polymers has been demonstrated to tune their 3-D packing structure and HOMO level, which increases the hole mobility and V(oc) values, thus improving the solar cell performance. PMID- 21327281 TI - New insights into the mechanism of activation of atom transfer radical polymerization by Cu(I) complexes. AB - The kinetics of activation of RX by a Cu(I) complex has been investigated in MeCN both in the absence and presence of halide ions. The system Cu(I)/L/X(-) (L = Me(6)TREN) is mainly composed of Cu(I)L(+), XCu(I)L and Cu(I)X(2)(-), but only Cu(I)L(+) is found to be an active catalyst reacting with RX. PMID- 21327282 TI - Novel PEG functionalized graphene nanosheets: enhancement of dispersibility and thermal stability. AB - A series of polyethylene glycol (PEG) functionalized graphene sheet hybrid materials (FGHMs) have been successfully synthesized via ester linkages. Interestingly, our products can be dispersed in both polar/protic solvents and nonpolar/nonprotic ones, which differ significantly from previously reported systems and are of great value in the wide-spread application of these "carbon nanosheet" based materials by solution-phase processing. Furthermore, the addition of PEG-modified carbon nanosheets as nanofillers significantly improves the thermal stability of the bulk polymers. In our case, an increase of 35 K in thermal stability can be obtained for PEG4000 after filling with as low as 1 wt % of the PEG modified carbon sheets, suggesting their great potential as novel nanofillers in industry. PMID- 21327283 TI - Enhanced cycleability of LiMn2O4 cathodes by atomic layer deposition of nanosized thin Al2O3 coatings. AB - This report is the first effort to use atomic layer deposition method for deposition of nanosized-thin and highly conformal Al(2)O(3) coatings onto LiMn(2)O(4) cathodes with precise thickness-control at atomic scale. The coated cathodes exhibit significantly enhanced cycleability than bare cathodes, as the dense ALD coating protects the cathode material from severe dissolution. PMID- 21327284 TI - Sequential Birch reaction and asymmetric Ir-catalyzed hydrogenation as a route to chiral building blocks. AB - A range of 1,2,4-trisubstituted cyclohexadienes obtained from the Birch reaction were hydrogenated asymmetrically to produce synthetically valuable chiral compounds in high enantio- and diastereoselectivity. PMID- 21327285 TI - Electrogenerated chemiluminescence of bis[4-(dimethylamino)phenyl]squaraine. AB - For the first time, we reported the strong electrogenerated chemiluminescence of organic dye, bis[4-(dimethylamino)phenyl]squaraine (BDPSQ), a high quantum yield and light-stable species, which might find applications in ECL analysis and imaging. PMID- 21327286 TI - Conjugation of organic-metallic hybrid polymers and calf-thymus DNA. AB - Strong electrostatic interaction between metallo-supramolecular polymers and DNA was confirmed by UV-vis and CD spectral measurements during titration, and cyclic voltammetry. The stable conjugation structure based on groove binding was revealed by using QM/MM computational methodology and supported by AFM. PMID- 21327287 TI - Dual reactivity of N-heterocyclic carbenes towards copper(II) salts. AB - Complexes of N-heterocyclic carbenes (NHCs) with copper(II) halogenides are unstable. Upon formation, these complexes decompose to give haloamidinium salts. Contrastingly, O-substituted copper(II) NHC complexes are fairly stable. A series of new five-, six- and seven-membered ring NHC complexes of Cu(OAc)(2) have been synthesised and characterised in the solid state. PMID- 21327288 TI - Early kinematic outcome after treatment of cranial cruciate ligament rupture by tibial plateau levelling osteotomy in the dog. AB - OBJECTIVES: To establish the effect of tibial plateau levelling osteotomy (TPLO) on two selected pelvic limb kinematic variables in dogs treated for clinical cranial cruciate ligament rupture (CCLR). METHODS: Thirteen dogs that had incurred CCLR and were treated by TPLO walked on a treadmill whilst kinematic data on pelvic limb paw motion were acquired using motion capture equipment. Data were subject to secondary processing using matrix analysis software and statistical analysis. RESULTS: Pelvic limb stance duration significantly increased during the 12 week study period, recovering to near-normal values. Range of pelvic limb paw velocity also significantly increased but did not reach normal values by 12 weeks postoperatively. CLINICAL SIGNIFICANCE: The improvement in stance duration to near normality may aid in explaining the widely-held subjective impression that TPLO frequently provides an excellent outcome in the early stages after repair of the cruciate deficient canine stifle joint. Both stance length and range of paw velocity provide useful objective measures to compare outcome following surgery for CCLR. PMID- 21327289 TI - Preliminary experience of a modified Maquet technique for repair of cranial cruciate ligament rupture in dogs. AB - The modified Maquet technique (MMT) uses the same principle as the tibial tuberosity advancement (TTA) for stabilization of the cranial cruciate ligament deficient stifle in the dog. In the MMT, the tibial tuberosity is advanced in a similar manner to that used in the TTA, however the means by which the tibial crest is stabilized differs. The plate and fork originally described by Montavon et al. are not used (7). The MMT was first described by Maquet for use on humans; it leaves intact a distal bony attachment to the tibial shaft, and the tuberosity is either reinforced or not by a figure-of-eight wire. In this paper, we describe the MMT, and we report the results of our first 20 canine patients with cranial cruciate ligament rupture that were treated by the MMT. Mean clinical bone healing time was 6.8 weeks (range 4 to 12 weeks). The evidence provided by this clinical communication suggests that it is technically possible to achieve an advancement of the tibial tuberosity without the need for a plate. The MMT deserves consideration as a primary treatment option for cranial cruciate ligament rupture in dogs, and further evaluation in large clinical studies. Long term follow-up and force plate analysis would be necessary to compare the MMT to both the TTA and the tibial plateau levelling osteotomy. PMID- 21327290 TI - An investigation into risk factors for bilateral canine cruciate ligament rupture. AB - OBJECTIVES: To investigate the incidence of bilateral cranial cruciate ligament (CrCL) rupture and determine any associated risk factors. METHODS: The patient information system and surgical database at the Queen Mother Hospital for Animals, Royal Veterinary College, were searched from March 1998 to March 2007. Patient files were reviewed and data recorded. The risk factors considered included: gender, neuter status, breed, body mass, age and concurrent orthopaedic disease. RESULTS: In total, 511 dogs were identified as having cruciate rupture and included for analysis. Bilateral rupture of the CrCl was present in 38.7% (198/511) of the dogs. The mean (+/- SD) time that passed until the contralateral CrCL ruptured was 57.9 weeks (+/- 54.1; range 3 to 260 weeks). Dogs with bilateral cruciate rupture were younger (mean +/- SD; 4.3 +/- 2.7 years) than dogs with unilateral cruciate rupture (mean +/- SD; 5.3 +/- 2.8 years). In dogs with CrCL rupture, male dogs were more likely to have bilateral rupture than female dogs, overweight dogs were more likely to have bilateral rupture, Golden Retrievers were less likely to have bilateral rupture, and Rottweilers had the highest odds of bilateral rupture. CLINICAL SIGNIFICANCE: In dogs with CrCL rupture, this study suggests possible relationships towards the incidence of a bilateral rupture also occurring as more likely in male dogs, young dogs with a mean age of four years (4.3 +/- 2.7 years), Rottweiler dogs, and with an average elapsed time between ruptures of 57.9 weeks. PMID- 21327291 TI - Kinematic analysis of Labrador Retrievers and Rottweilers trotting on a treadmill. AB - OBJECTIVES: The purpose of the study was to evaluate kinematic patterns in clinically normal Labrador and Rottweiler dogs trotting on a treadmill at a constant velocity. METHODS: Ten Labrador Retrievers aged from 2.2 to 5.1 years, and 10 Rottweilers aged from two to 5.9 years were used. A three-dimensional capture system was used to perform analysis of joint kinematics. Kinematic data were collected by use of a triple-camera system. The kinematic study was performed first on the right side of the dog, and then on the left side. Data were analysed by use of a motion-analysis program. Flexion and extension joint angles, angular velocity and angular acceleration were determined for the shoulder, elbow, carpal, hip, stifle, and tarsal joints. RESULTS: Within each group, the differences between the right and left limbs in all variables were not significant. Significant differences occurred between Labradors and Rottweilers in the following categories: angular displacement and minimum angular acceleration of the stifle (Rottweiler >Labrador); angular displacement and maximum angular velocity of the tarsus (Rottweiler >Labrador); minimum angular velocity of the shoulder (Labrador >Rottweiler); angular displacement, maximum angular acceleration, maximum angular velocity, and minimum angular velocity of the elbow (Labrador>Rottweiler); and maximum angle and maximum angular velocity of the carpus (Labrador>Rottweiler). CLINICAL SIGNIFICANCE: Both breeds had similar kinematic patterns, but there were magnitude differences, especially of the elbow and stifle joints. Therefore, each breed should have a specific database. PMID- 21327292 TI - The intercondylar fossa indices of male and female dog femora. AB - The intercondylar fossa (ICF) indices can be used to evaluate fossa geometry, which may in turn affect the function, pathology and intracapsular surgical repair of the cranial cruciate ligament. The measurements of digital images of the distal femur of 44 dogs were used to calculate the fossa width, shape, height and area indices. The mean values of fossa width index were found to be 0.19, 0.28 and 0.37 at the cranial, central, and caudal levels of the fossa, respectively. The mean values for fossa shape, height and area indices were found to be 0.71, 0.33, and 0.16, respectively. The differences in ICF indices between male and female dog were not significant. Therefore, it is suggested that gender differences related to ICF geometry may not have any effect on incidence of cranial cruciate ligament injury in dogs. PMID- 21327293 TI - Carpal canal lipoma causing lameness in a dog. AB - Carpal canal syndrome, or carpal tunnel syndrome, is the most common entrapment neuropathy in humans and is caused by compression of the median nerve as it courses through the carpal canal. A similar condition has been reported in horses, however there have not been any reported cases of a dog showing lameness secondary to compression within the carpal canal. This report describes the case of a dog exhibiting lameness secondary to a lipoma within the carpal canal. Lameness improved after surgical removal of the mass. This case highlights the need to consider compression of the tendons and nerves in the carpal canal as a cause of forelimb lameness in dogs when pain is localised to the carpus. PMID- 21327294 TI - Use of a 1.5 mm butterfly locking plate for stabilization of atlantoaxial pathology in three toy breed dogs. AB - The objective of this study was to describe the use of a titanium 1.5 mm locking plate in the stabilization of atlantoaxial pathology in three toy breed dogs. Two dogs with atlantoaxial subluxation and another dog with an axial fracture, confirmed by diagnostic imaging, were stabilized via a ventral approach with a 1.5 mm titanium 5-hole locking butterfly-plate. Surgical reduction and stabilization were assessed by computed tomography and radiography after surgery. Follow-up evaluation for resolution of neurological signs and possible complications was performed in all three dogs. For long-term assessment, a telephone follow-up was performed. A considerable improvement of neurological signs occurred within two to four weeks after surgery. An excellent clinical outcome was identified in all three patients. Adequate stabilization and resolution of neurological signs in all three dogs was achieved. The stabilization of atlantoaxial surgical conditions in toy breeds with the 1.5 mm titanium 5-hole butterfly locking plate appears to be an effective means of surgical treatment. PMID- 21327295 TI - Use of the angularis oris cutaneous flap for repair of a rostral mandibular skin defect in a cat. AB - The angularis oris axial pattern flap is based on the blood supply of the angularis oris artery and vein. While the use of this flap for repair of canine facial wounds is well documented, this technique has not been reported in the cat. This case report presents the reconstruction of a large ventral chin and rostral lip wound with the use of this flap. Complete survival of this flap was observed in this patient. PMID- 21327296 TI - Chemokine expression by small sputum macrophages in COPD. AB - Small sputum macrophages represent highly active cells that increase in the airways of patients with inflammatory diseases such as chronic obstructive pulmonary disease (COPD). It has been reported often that levels of cytokines, chemokines and pro-teases are increased in sputum supernatants of these patients. In COPD, the small sputum macrophages may contribute to these supernatant proteins and recruit additional cells via specific chemokine expression patterns. We therefore investigated the expression profile of chemokines in sputum macrophages obtained from COPD patients in comparison to cells from healthy donors and cells isolated after inhalation of lipopolysaccharide (LPS). We used the minimally invasive procedure of sputum induction and have purified macrophages with the RosetteSep technology. Using macrophage purification and flow cytometry we show that in COPD small sputum macrophages account for 85.9% +/ 8.3% compared with 12.9% +/- 7.1% of total macrophages in control donors. When looking at chemokine expression we found, for the small macrophages in COPD, increased transcript and protein levels for CCL2, CCL7, CCL13 and CCL22 with a more than 100-fold increase for CCL13 mRNA (P < 0.001). Looking at active smokers without COPD, there is a substantial increase of small macrophages to 60% +/- 15% and, here, chemokine expression is increased as well. In a model of airway inflammation healthy volunteers inhaled 20 MUg of lipopolysaccharide (LPS), which resulted in an increase of small sputum macrophages from 18% +/- 19% to 64% +/- 25%. The pattern of chemokine expression was, however, different with an upregulation for CCL2 and CCL7, while CCL13 was downregulated three-fold in the LPS-induced small macrophages. These data demonstrate that sputum macrophages in COPD show induction of a specific set of CCL chemokines, which is distinct from what can be induced by LPS. PMID- 21327297 TI - Targeting S100P inhibits colon cancer growth and metastasis by Lentivirus mediated RNA interference and proteomic analysis. AB - S100P was recently found to be overexpressed in a variety of cancers and is considered a potential target for cancer therapy, but the functional role or mechanism of action of S100P in colon cancer is not fully understood. In the present study, we knocked down the gene expression of S100P in colon cancer cells using lentivirus-mediated RNA interference. This step resulted in significant inhibition of cancer cell growth, migration and invasion in vitro and tumor growth and liver metastasis in vivo. Moreover, S100P downstream target proteins were identified by proteomic analysis in colon cancer DLD-1 cells with deletion of S100P. Knockdown of S100P led to downregulation of thioredoxin 1 and beta tubulin and upregulation of Rho guanosine diphosphate (GDP) dissociation inhibitor alpha (RhoGDIA), all potential therapeutic targets in cancer. Taken together, these findings suggest that S100P plays an important role in colon tumorigenesis and metastasis, and the comprehensive and comparative analyses of proteins associated with S100P could contribute to understanding the downstream signal cascade of S100P, leading to tumorigenesis and metastasis. PMID- 21327298 TI - HDAC inhibition in lupus models. AB - Systemic lupus erythematosus (SLE) is a prototypic autoimmune inflammatory disease characterized by the production of autoantibodies directed against nuclear antigens such as nucleosomes, DNA and histone proteins found within the body's cells and plasma. Autoantibodies may induce disease by forming immune complexes that lodge in target organs or by crossreacting with targeted antigens and damaging tissue. In addition to autoantibody production, apoptotic defects and impaired removal of apoptotic cells contribute to an overload of autoantigens that initiate an autoimmune response. Besides the well-recognized genetic susceptibility to SLE, environmental and epigenetic factors play a crucial role in disease pathogenesis as evidenced by monozygotic twins typically being discordant for disease. Changes in DNA methylation and histone acetylation alter gene expression and are thought to contribute to the epigenetic deregulation in disease. In SLE, global and gene-specific DNA methylation changes have been demonstrated to occur. Additionally, aberrant histone acetylation is evident in individuals with SLE. Moreover, histone deacetylase inhibitors (HDACi) have been shown to reverse the skewed expression of multiple genes involved in SLE. In this review, we discuss the implications of epigenetic alterations in the development and progression of SLE, and how therapeutics designed to alter histone acetylation status may constitute a promising avenue to target disease. PMID- 21327299 TI - Inhibition of HDAC activity by ITF2357 ameliorates joint inflammation and prevents cartilage and bone destruction in experimental arthritis. AB - Inhibition of histone deacetylases (HDAC) has been shown to modulate gene expression and cytokine production after stimulation with several stimuli. In the present study, the antiinflammatory effect of a potent HDACi, ITF2357, was explored in different experimental models of arthritis. In addition, the bone protective effect of ITF2357 was investigated in vitro. Treatment of acute arthritis (Streptococcus pyogenes cell wall [SCW] arthritis) with ITF2357 showed that joint swelling and cell influx into the joint cavity were reduced. Furthermore, the chondrocyte metabolic function was improved by treatment of ITF2357. The production of proinflammatory cytokines by synovial tissue was reduced after ITF2357 treatment. To examine the effect of HDAC inhibition on joint destruction, ITF2357 was applied to both rat adjuvant arthritis and mouse collagen type II arthritis. ITF2357 treatment both ameliorates the severity scores in arthritis models and prevents bone destruction. In an in vitro bone destruction assay, ITF2357 was highly effective at a dose of 100 nmol/L. In conclusion, inhibition of HDAC prevents joint inflammation and cartilage and bone destruction in experimental arthritis. PMID- 21327300 TI - Altered methylation at microRNA-associated CpG islands in hereditary and sporadic carcinomas: a methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA)-based approach. AB - MicroRNAs (miRNAs) are small noncoding RNAs that contribute to tumorigenesis by acting as oncogenes or tumor suppressor genes and may be important in the diagnosis, prognosis and treatment of cancer. Many miRNA genes have associated CpG islands, suggesting epigenetic regulation of their expression. Compared with sporadic cancers, the role of miRNAs in hereditary or familial cancer is poorly understood. We investigated 96 colorectal carcinomas, 58 gastric carcinomas and 41 endometrial carcinomas, occurring as part of inherited DNA mismatch repair (MMR) deficiency (Lynch syndrome), familial colorectal carcinoma without MMR gene mutations or sporadically. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) assays were developed for 11 miRNA loci that were chosen because all could be epigenetically regulated through the associated CpG islands and some could additionally modulate the epigenome by putatively targeting the DNA methyltransferases or their antagonist retinoblastoma-like 2 (RBL2). Compared with the respective normal tissues, the predominant alteration in tumor tissues was increased methylation for the miRNAs 1-1, 124a-1, 124a-2, 124a-3, 148a, 152 and 18b; decreased methylation for 200a and 208a; and no major change for 373 and let-7a-3. The frequencies with which the individual miRNA loci were affected in tumors showed statistically significant differences relative to the tissue of origin (colorectal versus gastric versus endometrial), MMR proficiency versus deficiency and sporadic versus hereditary disease. In particular, hypermethylation at miR-148a and miR-152 was associated with microsatellite-unstable (as opposed to stable) tumors and hypermethylation at miR 18b with sporadic disease (as opposed to Lynch syndrome). Hypermethylation at miRNA loci correlated with hypermethylation at classic tumor suppressor promoters in the same tumors. Our results highlight the importance of epigenetic events in hereditary and sporadic cancers and suggest that MS-MLPA is an excellent choice for quantitative analysis of methylation in archival formalin-fixed, paraffin embedded samples, which pose challenges to many other techniques commonly used for methylation studies. PMID- 21327301 TI - Fibrinogen availability and coagulation function after hemorrhage and resuscitation in pigs. AB - Hemorrhagic coagulopathy (without neurological injuries) constitutes 40% of injury-related death in civilian hospitals and on the battlefield, and the underlying contributing mechanisms remain unclear. The purpose of this study is to investigate the effects of fibrinogen availability on coagulation function after hemorrhage in pigs. Sixteen crossbred commercial Yorkshire swine were randomized into the control group (group C) (n = 8) and hemorrhage group (group H) (n = 8). Hemorrhage was induced in group H by bleeding 35% of the estimated total blood volume, followed by resuscitation with lactated Ringer solution at three times the bled volume. Pigs in group C were not hemorrhaged or resuscitated. Blood samples were withdrawn at baseline, 15 min, 3 h, 6 h, and 24 h after hemorrhage and lactated Ringer (LR) resuscitation (H-LR). Coagulation was assessed by using thrombelastography. All baseline measurements were similar between groups C and H. Hemorrhage caused a decrease in mean arterial pressure and an increase in heart rate in group H, but LR resuscitation corrected these changes within 1 h. Compared to baseline values, fibrinogen concentrations in group H decreased at 15 min, 3 h and 6 h after H-LR, but increased to double that of the baseline value at 24 h; platelet counts decreased throughout the study; clot strength was decreased at 15 min, 3 h and 6 h, but returned to baseline value at 24 h after H-LR. Hemorrhage caused decreases in fibrinogen and platelets, and compromised clot strength. The rebound of fibrinogen at 24 h restored clot strength despite platelet deficit. These data suggest the potential compensatory role of fibrinogen in restoring coagulation function in vivo after hemorrhagic shock. PMID- 21327302 TI - Long-term home oxygen: a UK perspective. PMID- 21327303 TI - Analysis of invasive pneumonia-causing strains of Streptococcus pneumoniae: serotypes and antimicrobial susceptibility. AB - OBJECTIVES: To identify the most common pneumococcal serotypes in children hospitalized with invasive pneumonia, correlate isolated serotypes with those included in conjugate vaccines, and ascertain the sensitivity of the isolated pneumococcal strains to penicillin and other antibiotics. METHODS: From January 2003 to October 2008, a retrospective study of hospitalized children with a diagnosis of Streptococcus pneumoniae pneumonia was conducted at the university hospital of Universidade de Sao Paulo. Criteria for inclusion were: age greater than 29 days and less than 15 years, radiological and clinical diagnosis of pneumonia, and isolation of Streptococcus pneumoniae in blood cultures and/or pleural effusion. RESULTS: The study included 107 children. The most common serotypes were 14 (36.5%), 1 (16%), 5 (14.6%), 6B (6.3%) and 3 (4.2%). The proportion of identified serotypes contained in the heptavalent, 10-valent and 13 valent conjugate vaccines was 53.1, 86.5, and 96.9%, respectively. Pneumococcal strains were sensitive to penicillin (minimum inhibitory concentration, MIC <= 2 ug/mL) in 100 cases (93.5%) and displayed intermediate resistance (MIC = 4 ug/mL) in 7 cases (6.5%). No strains were penicillin-resistant (MIC >= 8 ug/mL) according to the Clinical and Laboratory Standards Institute 2008 standards. Tested isolates were highly sensitive to vancomycin, rifampicin, ceftriaxone, clindamycin, erythromycin, and chloramphenicol. CONCLUSIONS: Our results confirm a significant potential impact of conjugate vaccines, mainly 10-valent and 13 valent, on invasive pneumonia. Furthermore, susceptibility testing results show that penicillin is still the treatment of choice for invasive pneumonia in our setting. PMID- 21327305 TI - [Spiral computed tomography for lung cancer screening]. PMID- 21327306 TI - [The evolution of breast cancer mortality and the dissemination of mammography in Catalonia: an analysis by health region]. AB - BACKGROUND: The decrease of breast cancer (BC) mortality rates has been attributed to early detection programs and therapeutic advances. The objective is to compare BC mortality trend in health regions of Catalonia during the period 1993-2007. In parallel, dissemination of periodic mammography in the health regions has been analyzed. METHODS: Mortality and health surveys data were used. Poisson and "joinpoint" regression analyses were used to compare regional BC mortality rates and quantify their temporal evolution. Mixed effects models were used to compare the rates and their evolution by region. RESULTS: The BC mortality rate decreased 3% annually in Cataluna. Between 1993 and 2007, the standard mortality rate changed from 34.8 to 23.3 per 100,000 women. Barcelona ciutat showed higher mortality rates than the Centre (rate ratio (RR)=0.873), Costa de Ponent (RR=0.885), Tarragona (RR=0.9) and Lleida regions (RR=0.915), but these differences tend to disappear over time. There were no observed trend changes in the evolution of the regional mortality rates, except in the Centre region. The use of periodic mammography was similar across health regions. During the 90s, Barcelona ciutat had a 36.1% utilization of periodic mammography in women aged 40-74, in the 1994 survey, the Centre 23.7 and Costa de Ponent 25.2%. CONCLUSIONS: The progressive increase in the use of periodic mammography and the decrease of BC mortality were similar in the eight health regions of Catalonia. PMID- 21327307 TI - [Breast cancer survival after 10 years of follow up, in Granada and Almeria Spanish Provinces]. AB - BACKGROUND: To describe the overall and disease-free survival at five and ten years after breast cancer diagnosis in women from a previous case-control study, and establish related prognostic factors. METHODS: We followed up 202 patients diagnosed between 1996 and 1998 in three public hospitals in Granada and Almeria provinces in Spain. Survival rates were calculated using the Kaplan and Meier method, and the Cox proportional hazards model was applied to identify the most significant variables contributing to survival. RESULTS: Mean age at diagnosis was 54.27 +/- 10.4 years. Mean follow-up for overall survival was 119.91 months (95%CI 113.65-126.17); the five-year survival rate was 83.9% (95%CI: 78.13-89.66) and the ten-year rate was 71% (95% CI: 63.25-78.74). Mean follow-up for disease free survival was 118.75 months (95%CI 111.86-125.65); the five-year disease-free survival rate was 81% (95% CI: 74.52-87.47) and the ten-year rate was 71.3% (95% CI: 63.33-79.26). The mortality rate of the study population was 33.17%. CONCLUSIONS: Disease characteristics are similar in our population to those in other Spanish and European regions, while the overall survival is higher than the mean rate during the same period in Europe (5-yr rate of 79%) and similar to that in Spain (83%). PMID- 21327308 TI - [Satisfaction and expectations of the women participants and not participants in the breast cancer screening programme in Barcelona after 10 years of operation]. AB - BACKGROUND: In order to improve the strategies of communication and to increase the participation in the screening program, one considers to describe the sociodemographic characteristics of participants and nonparticipants of the Breast Cancer Screening Program (BCSP) in Barcelona (2007), to analyse the degree of satisfaction and knowledge with the programme, and to know the expectations of nonparticipants with respect to the programme. METHODS: Cross-sectional study in a sample of 600 women between 50 and 69 years of age registered in Barcelona. A telephone interview was carried out using a questionnaire composed of 35 questions, grouped in: knowledge of the disease and the programme, satisfaction with the programme, expectations (characteristics which might increase participation) and sociodemographic characteristics. The association between knowledge and satisfaction with the sociodemographic characteristics was analysed by means of bivariate and multivariate analysis (robust poisson models). A descriptive analysis of the expectations of nonparticipants was carried out. RESULTS: Among the 244 nonparticipants interviewed, 160 (65,6%) had middle or superior studies, and 163 (66,8%) were of a privileged social class. Of 356 women that indicated to be participants in the PDPCM 340 (95,5 %) were satisfied with the PDPCM in global. CONCLUSIONS: The degree of satisfaction and knowledge with the programme is very high. The expectations indicated suggest that women receive contradictory messages with regard to periodicity (annual respect biannual) and age range (40-69 respect 50-69). PMID- 21327309 TI - [Programme of screening for colorrectal cancer in the Valencia community, Spain: results of the first round (2005-2008)]. AB - BACKGROUND: Several studies evaluating colorectal cancer (CRC) screening with fecal occult blood testing (FOBT) have reported a significant reduction in mortality from this tumor. The study aims to describe the results of the first round of the CRC screening program in medium-risk population of Valencia and assessing their feasibility and acceptability. METHODS: Colorectal cancer screening pilot study using biennial FOBT. All residents (106,000 Inhabitants) between 50 and 69 years old (a subgroup of 70-74 years), from 3 selected health departments (04, 07 and 13) were invited by mail to participate. The individuals with FOBT positive were referred to hospital for colonoscopy. The following rates were calculated as indicators of program quality: the participation rate, positive FOBT rate, acceptance rate of colonoscopy, and detection rate of low and high-risk adenomas and invasive cancers, and positive predictive value of FOBT. RESULTS: The participation was 35,231 individuals (35.70%). The number of FOBT positive was 579 (1.64% of total analyzed test), 548 people agreed colonoscopy (acceptance rate: 94.69%). 61 CRC were detected, 61 and 153 High-Risk and Low Risk Adenomas (rates of 1.77, 1.77 and 4.46% per 1,000 participants). The positive predictive values for cancer, low-risk and high risk adenomas were 10.95%, 10.95%, and 27.46% respectively. CONCLUSION: The program indicators suggest that a population program of colorectal cancer is feasible in our community as the process indicators obtained are similar to those given in other programs in Spain and Europe. PMID- 21327310 TI - [Geographical inequalities in mortality and incidence in larynx cancer in men: socioeconomic and environmental factors]. AB - BACKGROUND: Several studies suggest the relationship between lower socioeconomic status and environmental factors with increased risk of cancer. Within the framework of the MEDEA project, this work aims to identify geographic inequalities in larynx cancer (LC) mortality and incidence in men and its association with deprivation and environmental factors. METHODS: Ecological study having as reference population men living in the city of Zaragoza. The study period was 1996-2003. The deaths were obtained from the Mortality Registry of Aragon, the incident cases from the Cancer Registry of Zaragoza and the socioeconomic data from the 2001 Census. We used the European Pollutant Emission Register database to locate possible polluting industries. For each census tract (CT) a deprivation index was obtained using principal components analysis. Smoothed Standardized Mortality and Incidence ratios were also calculated using Bayesian methods. RESULTS: We analysed 211 deaths and 569 incident cases with CT, corresponding to 95% of the total registered mortality cases and 97.8% incidence. The CTs in the highest quartile, highest deprivation index, had significantly higuer risk of mortality (2.74 times) as well as incidence (1.66 times) by LC. However, the environmental indicators have not been shown a statistically significance association. CONCLUSIONS: The CTs with the lowest socioeconomic status have higher risk of LC mortality and incidence. Nevertheless, the possible exposition to the polluting industrial focus does not explain the observed geographic variability. PMID- 21327311 TI - [Results of the screening program for colorectal cancer screening in Cantabria, Spain, during the period November 2008-March 2010]. AB - BACKGROUND: The colorectal cancer (CCR) is a Public Health problem because of its high incidence and mortality. Screening programs are important for early detection of CCR. An early detection of this illness could decrease its mortality. The objectives of our study are to present the colorectal cancer screening program in Cantabria and its main results. METHODS: Descriptive study of a two-year screening program for population in the 55 - 69 years age range, according to the Cantabria Health Service data base (92,605 people). The screening test used a qualitative immunochemical method in search of faecal occulted blood (FOB), complemented by optical colonoscopy confirmation. Eligible people were invited to participate in the screening program by means of personal letter and, in case of acceptance, they were dated in their primary Health Center. After application of exclusion criteria, selected people with a positive result test were submitted to optical colonoscopy. Those in which an invasive cancer was detected were directly addressed to the Digestive Service. RESULTS: The program was offered to 35,005 (37.8 %) of the eligible population of Cantabria at the end of study period. 2,384 persons participated (32.1%). The main colonoscopy findings were 1 "in situ" cancer, 2 invasive cancer and 43 high risk adenomas. CONCLUSION: Due to its integration into primary care, lack of apparatus, ease use and fast implementation, qualitative immunochemical test FOBT facilitates the extension of screening, with similar results to those of quantitative immunochemical test. PMID- 21327312 TI - [Unnecessary premature and avoidable mortality in Costa Rica]. AB - BACKGROUNDS: With the intention of establishing economic inequities, the article analyzes the variations of the Unnecessarily Premature and Sanitarily Avoidable Mortality (MIPSE) of each of the 81 cantons of Costa Rica during 2000-2005. It is important to identify those inequities, to establish policies and strategies trying to mitigate them. METHOD: It applies the MIPSE classification proposed by members of the Information and Studies Service, of the Catalunya's Sanitary Resources Headquarter, Spain. By an Indicator of Socioeconomic Development (IDSE) of a University of Costa Rica economist's team, it organised each canton in groups of quintiles (I for the richest, V for the poorest), previous people standardization. RESULTS: We found as a major causes of mortality MIPSE in the country: Heart Isquemic Disease (19,55% MIPSE causes), Traffic Accidents with Motor Vehicles (11,60%), Brain Vascular Disease (6,95%), Perinatal (6,92%) and Suicide (5,14%). CONCLUSION: The VIH infection - AIDS mortality, the Best Cancer in Women, Uterus Cancer, Skin Cancer and Hepatic Disease Secondary to Alcohol Consumption, affects more the cantons with better financial conditions and the Prostate Benign Hyperplasia mortality, Mothers mortality related with Pregnancy, Childbirth or Puerperal Stage and the Abdominal Hernia mortality, affects more to those with worst economic level. Two MIPSE groups were identified with similar inequality: Leukaemia and Congenital Cardiovascular Disease. PMID- 21327313 TI - [Socio-demographic and health factors associated with the institutionalization of dependent people]. AB - BACKGROUND: The analysis of the effect that different variables have in the probability that dependent people are institutionalized is a topic scantily studied in Spain. The aim of the work is to analyze as certain socio-demographic and health factors can influence probability of dependent person living in a residence. METHODS: A cross-section study has been conducted from a representative sample of the dependent population in Cuenca (Spain) in February, 2009. We have obtained information for people with level II and III of dependence. A binary logit regression model has been estimated to identify those factors related to the institutionalization of dependent people. RESULTS: People with ages between 65-74 years old are six times more likely to be institutionalized than younger people (< 65 years old); this probability increases sixteen times for those individuals with ages equal or higher than 95 years. The probability of institutionalization of people who live in an urban area is three times the probability of people who live in a rural area. People who need pharmacological, psychotherapy or rehabilitation treatments have between two and four times more probability of being institutionalized that those who do not need those. CONCLUSIONS: Age, marital status, place of residence, cardiovascular and musculoskeletal diseases and four times of medical treatment are the principal variables associated with the institutionalization of dependent people. PMID- 21327314 TI - [Exposure to carbon monoxide in wildland firefighters during wildfires suppression]. AB - BACKGROUND: Health and occupational performance in wildland firefighters are mainly impaired for the carbon monoxide inhalation. Therefore, the aim of this study was to analyze the personal exposure to carbon monoxide in wildland firefighters during wildfires suppression. METHODS: Carbon monoxide exposure was monitorized in 44 subjects during 58 real wildfires. Moreover, we analyzed the time weighted average exposure for an 8h shift (VA-ED). The wildfires were classified according to the work done (direct attack, indirect attack and mixed attack) and the current fuel (grass, bush, understory and mixed). RESULTS: The mean exposure to carbon monoxide was of 18,4 +/- 1,7 ppm, what supposed a VA-ED of 7,0 +/- 1,0 ppm. The highest exposures to carbon monoxide were found during the mixed attack (20,4 +/- 2,3 ppm) and direct attack (17,5 +/- 2,7 ppm). We only obtained significant differences (p < 0.05) between bush (19,8 +/- 2,2) and understory (17,2 +/- 3,9) and grass (12,0 +/- 5,6). CONCLUSIONS: Exposures to carbon monoxide were influenced for the work done during the wildfires suppression and the type of fuel involved. Mean values obtained in this study were within safety limits described by different Spanish (INSHT) and international (NIOSH, OSHA) occupational safety and health agencies. PMID- 21327315 TI - [Fulfilment of the criteria about scientific authorship in Spanish biomedical and health science journals included in Journal Citation Reports]. AB - BACKGROUND: Scientific journals have been recognized to have the authority to register both the ownership of ideas and the validity of published knowledge. This paper explores the extent to which the editorial policies of journals contribute to ensure the accuracy of scientific authorship. METHODS: Cross sectional study of scientific authorship criteria used by 23 Spanish medical journals included in Journal Citation Reports 2008 and evaluation of their fulfilment to the uniformity requirements URM of ICMJE. Criteria have been structured in observational items and six levels of fulfilment have been established in order to quantify its adjustment to URM. RESULTS: 52% of journals do not make a reference to URM, 39% only provides some information on the conditions to be respected by the signatories of an article and only 26% (6 magazines) comply with URM. 61% of the journals declare information regarding the responsibility contracted by authors. 35% of the journals give some type guidelines as to the number of authors but no one mentions signature order. As for acknowledgments and corresponding address instructions, 61% declare it but 30,4% only properly formulate their aims. CONCLUSIONS: Only 48% of the journals include one or some instructions related with scientific authorship. Results coincide with those of other studies. Despite the existence of an international standard such as URM, authorship criteria provided by journals are scarce and uneven. The assertion that URM is universally well-known by medical journals is questioned. PMID- 21327316 TI - [Construction and validation of a questionnaire to measure behavior, knowledge and attitudes on hand hygiene in health personnel training]. AB - BACKGROUND: Hand hygiene in the health context is a complex behaviour. There have been rarely given the role of the knowledge and attitudes as predictors of hand hygiene behaviour. The main objective of this work is the description of the development of a questionnaire on hand hygiene and the analysis of their measurement properties. METHOD: An instrument which was designed and validated a questionnaire. It was held in January 2009. It finally has had 50 items that assess risk behaviour intention before and after contact with the patient, declarative knowledge and attitudes about hand hygiene. It has been applied to 431 students of health sciences at the University of Granada. RESULTS: There were three factor analysis, ultimately obtaining a general convergence value that explains 46.01% of the total variance and high reliability (a = 0,843). There is correlation between knowledge and behavior intentions before and after patient contact (p < 0.01).In turn, the attitude correlates only with behavioral intention before (p < 0.05). The hand hygiene behavior refers to a higher mean after the completion of various health activities before the same (4.26 and 3.96 respectively). Both declarative knowledge and attitudes significantly predict behavioral intention, in particular the conduct before the contact with the patient (R2 = 0.100, standardized Beta 0.256 for knowledge and 0.145 for attitudes). CONCLUSIONS: The questionnaire shows high internal consistency. We have obtained a valid tool for assessing risk behavior, knowledge and attitudes about students' hand hygiene in health sciences. The tool detects deficiencies in basic skills in students. PMID- 21327317 TI - [Five years survival of women diagnosed with breast cancer during the period 1997 1999 in Toledo-Centro and Mancha Area, Spain]. AB - BACKGROUND: To determine 5-year relative survival (5 year-RS) of breast cancer cases in Toledo-Centro and Mancha area by age group and stage at diagnosis during the period 1997-1999. METHODS: Data of incident breast cancer was obtained from Toledo Cancer Registry. A total of 366 tumours were included, classified by stage and age group (according to their inclusion in the screening program for breast cancer, < 45, 45-64 and> 64). The 5 year-RS and its 95% confidence interval (CI) were calculated using the Hakulinen method through the web-based application WAERS. RESULTS: Global 5 year-RS was 78.4% (CI 73.6-83.6), being 93.3% (CI 87.0 99.4) in < 45 years, 87.6% (CI 81.5-94.1) for the 45-64 years age group and 75.4% (CI 65.3-86.9) in > 64 years. The 5 year-RS was 99.3% (CI: 94.4-104.5) for tumours with local stage, 81.9% (CI 74.0-90.8) for those tumours spread to lymph nodes and 20.1% (CI 9.7-41.6) for tumours with metastasis. At the time of diagnosis, 52.3% of tumours in women under age 45 had spread to lymph nodes, while 14.8% of women over 64 had distant metastasis. CONCLUSIONS: The 5 year-RS is similar to the European average of EUROCARE-4 study. These results are a first step to assess, through the monitoring of these indicators, the impact of screening activities and therapeutic improvements in the 5 year-RS of breast cancer in our area. PMID- 21327318 TI - [Frequency and factors associated with adverse reactions following the administration of influenza vaccine in personal health during the 2009-2010 Season]. AB - BACKGRAUND: Fear of adverse effects (AE) represents a frequent reason among healthcare workers (HCW) for not deciding to receive influenza vaccine. This investigation is carried out with the objectives of knowing the frequency of AE and the factors associated with them after the administration of influenza vaccines in the 2009-2010 season in HCW. METHODS: Cohort study that included the 969 HCW vaccinated against seasonal influenza and the 693 HCW vaccinated against new influenza A (H1N1) virus during the 2009-2010 season in a tertiary hospital. To detect adverse effects, HCW was telephoned one week after vaccination. RESULTS: Frequency of AE ranged between 24.5% of HCW who received only seasonal influenza vaccine and 82.6% of those who received vaccine against new influenza A (H1N1) virus. The most frequent AE were pain and general discomfort. None of the adverse effects was considered serious. Age and presence of an adjuvant in the vaccine were associated with appearance of AE after administration of vaccine against new influenza A (H1N1) virus. CONCLUSIONS: Vaccines against seasonal influenza and new influenza A (H1N1) are safe; frequency of AE related to this one was high, especially if it contained an adjuvant. Since none of the AE detected was serious, HCW can not justify his rejection of vaccination because of suffering the above-mentioned AE. PMID- 21327319 TI - Chacinero's lung - hypersensitivity pneumonitis due to dry sausage dust. AB - OBJECTIVE: Hypersensitivity pneumonitis (HP) comprises a large group of diseases that occur secondary to inhalation of a variety of antigens. This report describes a little-known cause of HP, previously unreported in the English literature. METHODS: Five patients (three women) with a mean age of 41 years who fulfilled the criteria for HP due to exposure to dry sausage dust were studied. The clinical findings, immunologic testing, results of the specific inhalation challenge, and follow-up are described. RESULTS: Three patients developed an acute form of disease and two patients a subacute form. A diffuse micronodular centrolobular pattern was seen on high-resolution computer tomography scanning of four patients. A restrictive pattern was identified on pulmonary function testing of four patients and decreased lung diffusion of carbon monoxide (DLCO) among three. In bronchoalveolar lavage specimens from three patients, lymphocytosis was 17%, 40%, and 40%, with a CD4/CD8 ratio of <0.6. Specific immunoglobin G (IgG) antibodies to Penicillium frequentans and Aspergillus fumigatus were positive for three patients. Performed on three patients, the specific inhalation challenge was positive for dry sausage dust extract in two cases and Penicillium frequentans in the third. Resolution of clinical, radiologic, spirometry, and DLCO alterations occurred among the three patients who avoided exposure following the diagnosis. CONCLUSIONS: A short patient series affected by a little-known cause of occupational HP is described. Penicillium frequentans may be the causative agent in some cases, but other fungi were found that could also be implicated in the etiology of this disease. PMID- 21327320 TI - Quality of life measurement and its relationship to disease severity in children with atopic dermatitis in general practice. AB - Atopic dermatitis (AD) has a big impact on quality of life. The usefulness of health-related quality of life questionnaires for children with AD in general practice, and the relationship of quality of life to disease severity, as assessed by parents and by investigators, however, is not known. This study used the Infants' Dermatitis Quality of Life Index (IDQoL) to assess quality of life in children with AD selected from general practice. Severity of AD was determined by investigators and parents using the objective SCORAD (SCORing Atopic Dermatitis), the TIS (three-item severity scale), or by an additional question on the IDQoL. A total of 66 patients (41% boys, mean age 31 months) were included. Correlations between disease severity assessed by parents and by investigators were low (Rs 0.29-0.51). Correlations between IDQoL and severity assessed by investigators were also low (Rs 0.08-0.36). However, correlations between IDQoL and severity according to parents were high (Rs 0.67-0.73). In conclusion, disease severity and disease-related quality of life are different aspects of AD and must be taken into consideration when evaluating treatment or investigating new dermatological therapies in trials. PMID- 21327321 TI - Successful photopatch testing with ketoprofen using one-hour occlusion. AB - The standard procedure for photopatch testing includes 24-h occlusion of the allergen, followed by irradiation at 5 J/cm2 ultraviolet A (UVA). Due to the timing, a separate visit to the clinic is needed for UV irradiation. The aim of this study was to determine whether a reduction in occlusion time from 24 h to 1 h, in order to simplify the testing procedure, influences test results when photopatch testing with ketoprofen. A total of 22 patients with a known or suspected photo-allergy to ketoprofen were simultaneously photopatch-tested with ketoprofen using both 1 h and 24 h occlusion. One side of the patient's back was irradiated with 5 J/cm2 UVA, and the other side was covered. Measurements were made after 3 days on both irradiated and non-irradiated sides. A total of 20 controls were photopatch-tested with ketoprofen using 1 h occlusion. All of the patients showed positive reactions on the irradiated side. No positive reactions were observed on the non-irradiated side. All controls were negative. In conclusion, 1 h occlusion time is sufficient to establish photo-contact allergy to ketoprofen. No adjustments in UVA or ketoprofen dose were needed. Limiting occlusion time to 1 h could simplify the photopatch test procedure by eliminating one visit to the clinic. These results apply only to ketoprofen; further studies are needed to determine whether a similar approach can be used with other components of photopatch test series. PMID- 21327322 TI - Level of activity and participation in adults with spastic diplegia 17-26 years after selective dorsal rhizotomy. AB - OBJECTIVE: To evaluate the activity and participation levels of adults with spastic diplegia 17-26 years after selective dorsal rhizotomy; to investigate relationships between subjects' functioning and age, socio-economic-status, level of satisfaction and their perceptions of the post-operative outcomes. DESIGN: Observational follow-up study. PATIENTS: Thirty-one subjects with spastic diplegia, age range 21-44 years, who underwent selective dorsal rhizotomy between 1981 and 1991. METHODS: A semi-structured interview was used to gather data on patients' characteristics and long-term experiences after the operation. The Functional Mobility Scale and Life-Habit questionnaire were completed. RESULTS: Based on the Functional Mobility Scale 84% of subjects were reported as independent for a distance of 5 m, and 61% for 50 and 500 m. Eighty percent were independent in accomplishing all life habits, with most problems found for Mobility and Recreation. This was in agreement with the subjects' perception, with strong correlations between Life-Habit questionnaire accomplishment and satisfaction levels. No significant associations were found between functioning and age at selective dorsal rhizotomy, current age and socio-economic status. CONCLUSION: More than 15 years after selective dorsal rhizotomy, adults with spastic diplegia showed high levels of functioning, and similar levels of satisfaction with life habits. The majority had positive feelings about the neurosurgical procedure, although there is a need for better follow-up after subjects leave school. PMID- 21327323 TI - Comment on "Restoration of walking function in an individual with chronic complete (AIS A) spinal cord injury". PMID- 21327324 TI - Basic helix-loop-helix transcription factors DEC1 and DEC2 regulate the paclitaxel-induced apoptotic pathway of MCF-7 human breast cancer cells. AB - Differentiated embryonic chondrocyte gene (DEC) 1 (BHLHE40/Stra13/Sharp2) and DEC2 (BHLHE41/Sharp1) are basic helix-loop-helix (bHLH) transcription factors that are associated with the regulation of apoptosis, cell proliferation and circadian rhythms, as well as malignancy in various cancers. However, the roles of DEC1 and DEC2 expression in breast cancer are poorly understood. In this study, we sought to examine the roles of DEC1 and DEC2 in MCF-7 human breast cancer cells that had been treated with paclitaxel. The expression of DEC1 and DEC2 was up-regulated in paclitaxel-treated MCF-7 cells. Knockdown of DEC1 by siRNA decreased the amount of cleaved poly (ADP-ribose) polymerase (PARP), after treatment with paclitaxel, whereas DEC2 knockdown increased the amount of cleaved PARP in both the presence and absence of paclitaxel. Immunofluorescent staining revealed that paclitaxel treatment increased the amount of DEC1 in the nucleus, and increased the amount of DEC2 in both the nucleus and cytoplasm. These results indicate that DEC1 has pro-apoptotic effects, whereas DEC2 has anti-apoptotic effects on the paclitaxel-induced apoptosis in human breast cancer MCF-7 cells. PMID- 21327325 TI - Cimetidine inhibits the adhesion of gastric cancer cells expressing high levels of sialyl Lewis x in human vascular endothelial cells by blocking E-selectin expression. AB - Cimetidine has been shown to have anti-metastatic activity and improves the survival of patients with colorectal cancer. One hypothesis is its modulation of the expression of the cell adhesion molecule by target organ endothelial cells. Because of the inconclusive results in clinical trials of gastric cancer, we investigated the effects of cimetidine on the adhesion of gastric cancer cells to activated endothelial cells and on the expression of some cell adhesion molecules. Human endothelial cells were pre-incubated with cimetidine for 6 h, incubated with the cytokine tumor necrosis factor for 4 h, and the endothelial surface expression of E-selectin was evaluated by flow cytometry, immunostaining and ELISA. Further, we investigated E-selectin mRNA expression by RT-PCR. Three gastric cancer cell lines (SGC-7901, MGC-803, BGC-823) and a normal gastric epithelial cell line, GES-1, were studied for the surface expression of sialyl Lewis x by flow cytometry and immunostaining. Adherence of CFSE-labeled gastric cancer cells and GES-1 cells to endothelial cell monolayers was determined. Cimetidine significantly reduced E-selectin expression of activated endothelial cells, but did not influence E-selectin expression at the mRNA level. Three gastric cancer cell lines expressed high levels of sialyl Lewis x, whereas GES-1 did not. Cimetidine also significantly decreased gastric cancer cell adherence to stimulated endothelial cells. The inhibition of E-selectin expression corresponded to the reduction of tumor cell adherence. The effects of cimetidine on tumor adhesion were almost nullified by pre-incubation with E-selectin and sialyl Lewis x antibody. Furthermore, there was no significant change of GES-1 adherence to endothelial cells by TNF-alpha, cimetidine, E-selectin and sialyl Lewis x antibody. The inhibiton of gastric cancer cell adherence to cytokine stimulated endothelial cells treated with cimetidine appears to result from blocking endothelial E-selectin expression. These data support the hypothesis that cimetidine may exert its anti-metastatic effects in gastric cancer, in part, by inhibiting E-selectin/sialyl Lewis x-mediated adherence of gastric cancer cells to endothelial cells in the metastasis target organs. PMID- 21327326 TI - Roles of exogenously regulated bFGF expression in angiogenesis and bone regeneration in rat calvarial defects. AB - Regulation of transgene expression and function is important for gene therapy because it allows complex biological processes to be controlled and monitored. Basic fibroblast growth factor (bFGF) is an effective angiogenic factor and bone regeneration factor; it can induce differentiation of mesenchymal stem cells (MSCs) in vitro and bone regeneration in vivo. Further, exogenous regulation of controllable bFGF expression in the bone regeneration area safely allows bone formation and regeneration. In our study, we constructed a recombinant adeno associated virus type 2 (rAAV2)-based bFGF gene delivery system, which is regulated by tetracycline or doxycycline (Dox, an analogue of tetracycline). We evaluated the regulatory effects of this system on bFGF transgenic expression in vitro and in vivo. We found that bFGF could increase the mRNA expression levels of osteoblast differentiation factor and the activity of alkaline phosphatase (ALP). Dox could effectively regulate bFGF expression, thus controlling MSC differentiation. After in vivo transplantation of genetically engineered MSCs, animals not treated with Dox showed significant bone formation and angiogenesis compared with the group treated with Dox. Dox may also effectively regulate angiogenesis and bone regeneration in vivo. Therefore, the inducible bFGF system is an effective way of regulating bone regeneration and formation. PMID- 21327327 TI - An active part of Artemisia sacrorum Ledeb. inhibits adipogenesis via the AMPK signaling pathway in 3T3-L1 adipocytes. AB - Artemisia sacrorum Ledeb. (Compositae) (ASL) has long been used in Oriental folk medicine to treat diverse hepatic diseases. In this study, we investigated the effect of ASL on adipocyte differentiation in 3T3-L1 cells. ASL significantly suppressed 3T3-L1 differentiation in a concentration-dependent manner. A significant increase of AMP-activated protein kinase (AMPK) was observed when the cells were treated with ASL. Activation of AMPK was also demonstrated by measuring the phosphorylation of acetyl-CoA carboxylase, a substrate of AMPK. These effects were abolished by pre-treatment with the AMPK inhibitor, compound C. In addition, ASL down-regulated the adipogenesis-related gene expression of the sterol regulatory element-binding protein 1c (SREBP1c) and its target genes, such as fatty acid synthase (FAS), stearoyl-CoA desaturase 1 (SCD1) and glycerol 3-phosphate acyltransferase (GPAT) in a concentration-dependent manner. These effects were abolished by pre-treatment with compound C. ASL significantly reduced the gene expression of the peroxisome proliferator-activated receptor gamma (PPARgamma) and of the CCAAT/enhancer binding protein-alpha (C/EBPalpha), two key transcription factors in adipogenesis. Meanwhile, adipocyte fatty acid binding protein (aP2) gene expression was also reduced in a concentration dependent manner. These findings indicated that ASL exerts anti-adipogenic activity via AMPK activation and may act to prevent obesity. PMID- 21327328 TI - Visfatin/PBEF/Nampt induces EMMPRIN and MMP-9 production in macrophages via the NAMPT-MAPK (p38, ERK1/2)-NF-kappaB signaling pathway. AB - The adipocytokine visfatin is closely associated with metabolic disorders. This study explored the effects of visfatin on macrophage-induced inflammation in atheroma. The ability of visfatin to enhance extracellular matrix metalloproteinase inducer (EMMPRIN) expression, matrix metalloproteinase-9 (MMP 9) production and enzymatic activity in THP-1 derived macrophages as well as the mechanisms involved were investigated. EMMPRIN and MMP-9 mRNA levels were investigated by RT-PCR. EMMPRIN and MMP-9 protein levels, nuclear factor (NF) kappaB -p65 protein levels, peroxisome proliferator-activated receptor gamma (PPARgamma) protein levels, and mitogen-activated protein kinase (MAPK) phosphorylation were determined by Western blotting. MMP-9 enzymatic activity was assayed by gelatin zymography. Visfatin (50-400 ng/ml) induced EMMPRIN and MMP-9 depending on the dosage used. Visfatin elicited the activation of NF-kappaB and MAPK (p38, ERK1/2). Exogenous nicotinamide mononucleotide (NMN), the product of nicotinamide phosphoribosyltransferase (NAMPT) activity, mimicked the effects of visfatin on MAPK (p38, ERK1/2)-NF-kappaB activation and EMMPRIN/MMP-9 induction. Using the p38 inhibitor, SB203580, the ERK1/2 inhibitor PD98059, the NF-kappaB inhibitor, pyrrolidine dithiocarbamate and the NAMPT inhibitor FK866, we demonstrated that the visfatin pro-inflammatory action was through the NAMPT-MAPK (p38, ERK1/2)-NF-kappaB pathway. Furthermore, the visfatin pro-inflammatory action was not prevented by insulin receptor blockade or by a PPARgamma agonist. Visfatin did not modulate PPARgamma expression. Retinoid X receptor (RXR) agonist suppressed the effects of visfatin on EMMPRIN/MMP-9, NF-kappaB, but not on MAPK activation. In conclusion, we have demonstrated that visfatin enhances atheroma inflammation through the NAMPT-MAPK (p38, ERK1/2)-NF-kappaB-EMMPRIN/MMP-9 pathway, a key feature of atherosclerotic diseases linked to metabolic disorders. PMID- 21327329 TI - Expression of xeroderma pigmentosum complementation group C protein predicts cisplatin resistance in lung adenocarcinoma patients. AB - DNA repair has been suggested to be a major cause of spontaneous drug resistance in patients with lung adenocarcinomas (LADC). Among the DNA repair-related proteins, excision repair cross-complementation group 1 (ERCC1) has been shown to be essential for repairing cisplatin-induced interstrand cross-linkage. However, the role of other DNA repair-related proteins in drug resistance has not been clearly elucidated. In this study, we used suppression subtractive hybridization and microarray analysis to identify the DNA repair-related genes associated with cisplatin resistance. We focused on the association of XPC protein expression, which plays a pivotal role in the earliest response to global genomic repair, with the survival of LADC patients. Using suppression subtractive hybridization and a microarray analysis to identify drug resistance-associated DNA repair related genes, we found that the mRNA levels of ERCC1, MSH-3, MSH-6 and XPC were significantly increased in LADC patients. Since the results of ERCC1 mRNA expression corresponded well with those in previous reports, in this study we focused on the clinical correlation between XPC expression and patient survival. The level of XPC protein was determined by immunohistochemical and immunoblotting analyses. We detected the XPC protein in 46 (43%) of 107 pathological LADC samples. XPC protein expression correlated with tumor stage, cigarette smoking and poor survival. In the in vitro experiments with LADC cell lines, increased XPC expression was associated with elevated drug resistance, and silencing of XPC expression reduced cisplatin resistance. Our results suggest that XPC expression predicts drug resistance in LADC. PMID- 21327330 TI - Vimentin expression is associated with decreased survival in gastric cancer. AB - Gastric cancer rich in stromal tissue, such as diffuse-type disease, carries a poor prognosis. In some cancers, expression of vimentin, a mesenchymal maker, is associated with poor survival. The expression of mesenchymal markers such as vimentin is observed after epithelial-mesenchymal transition (EMT), an important initial behavioral change related to the adhesion and migration properties of tumor cells that is required for local tumor invasion. A hallmark of EMT is the loss of E-cadherin. EMT-inducing regulators, including SIP1, Slug, and Twist, repress E-cadherin transcription by interacting with E-cadherin promoter. We investigated the expression of vimentin and EMT-related genes, including SIP1, Slug, and Twist, in frozen cancer tissues and normal tissues by real-time quantitative reverse-transcriptase polymerase chain reaction. Tumor samples were obtained from 106 patients with gastric adenocarcinomas who underwent a gastrectomy. The relation of the expression of these genes to clinicopathological factors and outcomes was studied. Vimentin mRNA was significantly higher in diffuse type compared to intestinal type according to Lauren's classification (p=0.048) and was significantly elevated in patients with recurrent or distant metastatic disease (p=0.049). Immunohistochemically, however, vimentin was detected only in cancer stroma. Twist mRNA expression significantly correlated with tumor depth (p=0.042) and advanced tumor stage (I-II vs. III-IV, p=0.030). E cadherin immunohistochemical expression was significantly associated with Lauren's histopathological type (p<0.001). Univariate analysis of relapse-free survival showed that tumor depth, lymph node metastasis, Lauren's histopathological type, and vimentin mRNA expression were significant prognostic factors (p<0.001, p=0.013, p=0.011, and p=0.019). On multivariate analysis, vimentin mRNA expression was an independent prognostic factor [hazard ratio (HR)=2.1; 95% confidence interval (CI), 1.0-4.4; p=0.036], coming after tumor depth (HR=9.7; 95%CI, 3.7-24; p<0.001). Vimentin mRNA expression is associated with recurrence or distant metastasis and decreased survival in gastric cancer. PMID- 21327331 TI - Development of a phylogenetic tree model to investigate the role of genetic mutations in endometrial tumors. AB - With the advancement of modern genome sequencing technology, thousands of genetic mutations have been identified in human tumors. However, analysis of the role of genetic mutations in tumor development is limited by the need for prevalence information among multiple tumors and by the lack of analytic capability to define the functional contribution of genetic mutations in patients, individually and collectively. To understand the genetic basis of human endometrial cancer, the fourth most common cancer in women, transcriptome sequencing was performed on an endometrial tumor paired with normal cervical tissue. Twenty-six non synonymous somatic mutations were validated in the tumor genome. A phylogenetic tree illustrating the mutational time-line was developed based upon the distribution of 26 mutations in 30 randomly-selected laser-captured single cells from the tumor sections. Five ubiquitous mutations were identified that are presumed to occur in the cancer founder cell of the tumor, and may collectively play critical roles in endometrial oncogenesis. However, further testing in 10 additional endometrial tumors failed to show overlapping mutations in the cancer founder cells, indicating the lack of a single common oncogenic pathway for these endometrial tumors. The effects of individual mutations in cancer cell proliferation were calculated based on descendant cell number and time span since acquiring each mutation. We have developed a phylogenetic approach to characterize individual genetic mutations in cancer cell proliferation in a single resected patient tumor. This approach provides the capability to study the tumor-specific role of genetic mutations, without relying on prevalence information from other patients. PMID- 21327332 TI - Basal cell adenoma arising in a minor salivary gland of the palate. AB - BACKGROUND: Basal cell adenoma is a benign neoplasm of the salivary glands. This tumor usually arises in the major glands, with the parotid being the most frequent site of occurrence, while it is rare in the minor salivary glands. We report a case of basal cell adenoma of a minor salivary gland on the palate. CASE: The patient was a 68-year-old man. Intraoral examination revealed a mass measuring 20 * 20 mm that was elastic-hard, dark violet, non-ulcerated, and covered the normal mucosa. Computed tomography scan and magnetic resonance imaging (MRI) both showed a mass situated in front of the soft palate. The T1 weighted MRI revealed tumor isointensity, and the T2-weighted image showed tumor hyperintensity. The clinical diagnosis was palate tumor, and excision was performed under general anesthesia. Histopathological examination revealed that an encapsulated mass had grown under the epithelium and indicated a diagnosis of basal cell adenoma. DISCUSSION: Although no recurrence has been detected in the 3 years and 6 months of follow up, there was a case of malignant transformation of a basal cell adenoma reported. Therefore, careful follow-up observation will continue to be important. PMID- 21327333 TI - Frequency alternation and an offbeat rhythm indicate foraging behavior in the echolocating bat, Saccopteryx bilineata. AB - The greater sac-winged bat, Saccopteryx bilineata (Emballonuridae), uses two distinct echolocation call sequences: a 'monotonous' sequence, where bats emit ~48 kHz calls at a relatively stable rate, and a frequency-alternating sequence, where bats emit calls at ~45 kHz (low-note call) and ~48 kHz (high-note call). The frequencies of these low-high-note pairs remain stable within sequences. In Panama, we recorded echolocation calls from S. bilineata with a multi-microphone array at two sites: one a known roosting site, the other a known foraging site. Our results indicate that this species (1) only produces monotonous sequences in non-foraging contexts and, at times, directly after emitting a feeding buzz and (2) produces frequency-alternating sequences when actively foraging. These latter sequences are also characterized by an unusual, offbeat emission rhythm. We found significant positive relationships between (1) call intensity and call duration and (2) call intensity and distance from clutter. However, these relationships were weaker than those reported for bats from other families. We speculate on how call frequency alternation and an offbeat emission rhythm might reflect a novel strategy for prey detection at the edge of complex habitat in this ancient family of bats. PMID- 21327334 TI - Circulating androgens are influenced by parental nest defense in a wild teleost fish. AB - While social interactions influence vertebrate endocrine regulation, the dynamics of regulation in relation to specific behaviors have not been clearly elucidated. In the current study, we investigated whether androgens (testosterone) or glucocorticoids (cortisol) play a functional role in aggressive offspring defense behavior in wild smallmouth bass (Micropterus dolomieu), a teleost fish with sole paternal care. We measured circulating testosterone and cortisol concentrations in plasma samples taken from parental males following a simulated nest intrusion by a common nest predator, the bluegill sunfish (Lepomis macrochirus). To understand whether endocrine regulation changes across the parental care period, we looked both at males guarding fresh eggs and at males guarding hatched embryos. Plasma testosterone levels increased in males subjected to a simulated nest intrusion when compared to sham controls. Testosterone concentrations in males guarding embryos were lower than in males guarding fresh eggs, but circulating testosterone was positively correlated with the level of aggression towards the nest predator at both offspring development stages. However, there was no increase in cortisol levels following a simulated nest intrusion, and no relationship between cortisol and any measured parameter. These results suggest that androgens play an important role in promoting aggressive nest defense behavior in teleost fish. PMID- 21327335 TI - Development of echolocation and communication vocalizations in the big brown bat, Eptesicus fuscus. AB - Big brown bats form large maternity colonies of up to 200 mothers and their pups. If pups are separated from their mothers, they can locate each other using vocalizations. The goal of this study was to systematically characterize the development of echolocation and communication calls from birth through adulthood to determine whether they develop from a common precursor at the same or different rates, or whether both types are present initially. Three females and their six pups were isolated from our captive breeding colony. We recorded vocal activity from postnatal day 1 to 35, both when the pups were isolated and when they were reunited with their mothers. At birth, pups exclusively emitted isolation calls, with a fundamental frequency range <20 kHz, and duration >30 ms. By the middle of week 1, different types of vocalizations began to emerge. Starting in week 2, pups in the presence of their mothers emitted sounds that resembled adult communication vocalizations, with a lower frequency range and longer durations than isolation calls or echolocation signals. During weeks 2 and 3, these vocalizations were extremely heterogeneous, suggesting that the pups went through a babbling stage before establishing a repertoire of stereotyped adult vocalizations around week 4. By week 4, vocalizations emitted when pups were alone were identical to adult echolocation signals. Echolocation and communication signals both appear to develop from the isolation call, diverging during week 2 and continuing to develop at different rates for several weeks until the adult vocal repertoire is established. PMID- 21327336 TI - Macroorchidism in an Indian boy with McCune-Albright syndrome. AB - McCune-Albright syndrome (MAS) is defined by the clinical triad of fibrous dysplasia of bone (FD), cafe-au-lait spots and precocious puberty (PP). It is a rare disease with estimated prevalence between 1/100,000 and 1/1,000,000. The authors report a case of MAS in an Indian boy who had history of unilateral macroorchidism (but no other signs of MAS) since birth, then presented with PP, FD and cafe-au-lait spots at 6 years of age. On examination he had asymmetry of the face, cafe-au-lait spots and signs of sexual precocity with a right testicular volume of 25 ml (left 8 ml). Investigations revealed suppressed gonadotropins with elevated testosterone levels. Skeletal survey showed dysplastic changes involving multiple bones and advanced bone age. Reports of MAS in a boy with unilateral macroorchidism are scarce. Thus, unilateral macroorchidism at birth in a baby may be a feature of MAS and should be followed up with care. PMID- 21327337 TI - Fanconi-Bickel syndrome. AB - We present the first mutation proven case of Fanconi-Bickel syndrome, a rare type of glycogen storage disease, from India. A four-year-old girl presented with severe growth retardation, genu varum and hepatomegaly. Investigations confirmed severe hypophosphatemic rickets and Fanconi syndrome. Molecular analysis confirmed a homozygous deletion insertion mutation in Glut 2 gene. PMID- 21327338 TI - Improving learning during pediatric lectures with multiple choice questions. AB - OBJECTIVE: To evaluate the role of multiple choice questions (MCQs) administered at the conclusion of the lecture in improving medical student learning. METHODS: This prospective interventional study was conducted in a Medical College. In ten randomly chosen pediatric lectures delivered to prefinal year medical students, MCQs were administered at the conclusion of the lecture and the answers were discussed with the students. After the series of lectures, students were evaluated by hundred 'single best response' MCQs with half from the lectures with MCQs self-assessment (MSA group) and the rest were from the other set of lectures (WMSA group). Scores from both groups were compared using paired 't' test. RESULTS: When the scores from MSA and WMSA groups were compared for the study population, no significant difference was noted. A significant difference (p = 0.003) was found between the groups, when the mean (+/- SD) scores of the men (25.2 +/- 4.8 in the MSA group and 28.6 +/- 7.3 in the WMSA group) were compared. No difference was seen among women, whose mean (+/- SD) scores in the MSA and the WMSA group were 26.6 +/- 6.9 and 26.3 +/- 6.9 respectively. When the scores of the first half of the session was analyzed, there was significant difference between the two groups among men (p = 0.0001) implying that lectures with MCQs self-assessment improved the long-term retention. CONCLUSIONS: MCQs' based self assessment at the conclusion of the lecture does not improve the learning among prefinal year medical students. However, this study has shown the usefulness of MCQs based self-assessment among male medical students. PMID- 21327339 TI - The effect of lexical predictability on distributions of eye fixation durations. AB - A word's predictability in context has a well-established effect on fixation durations in reading. To investigate how this effect is manifested in distributional terms, an experiment was carried out in which subjects read each of 50 target words twice, once in a high-predictability context and once in a low predictability context. The ex-Gaussian distribution was fit to each subject's first-fixation durations and single-fixation durations. For both measures, the MU parameter increased when a word was unpredictable, while the tau parameter was not significantly affected, indicating that a predictability manipulation shifts the distribution of fixation durations but does not affect the degree of skew. Vincentile plots showed that the mean ex-Gaussian parameters described the typical distribution shapes extremely well. These results suggest that the predictability and frequency effects are functionally distinct, since a frequency manipulation has been shown to influence both MU and tau. The results may also be seen as consistent with the finding from single-word recognition paradigms that semantic priming affects only MU. PMID- 21327340 TI - Time limits and gender differences on paper-and-pencil tests of mental rotation: a meta-analysis. AB - The purpose of this study was to summarize research relevant to the influence of time limits on gender differences in paper-and-pencil tasks of mental rotation by means of a meta-analysis. Thirty-six effect sizes from published and unpublished studies examining the influence of time constraints were retrieved. Results showed that gender differences in mental rotation are significantly larger when the task is administered with time constraints compared to when such constraints are absent. In addition, the magnitude of gender differences was linearly related to the amount of time available for test completion. These findings were not related to the age or the year of birth of participants in the retrieved studies. The results are discussed with regard to their implications for explanations of gender differences in mental rotation and cognitive abilities in general. PMID- 21327341 TI - Can expectancies produce placebo effects for implicit learning? AB - The placebo effect is an important phenomenon whereby real changes occur in response to an otherwise inert intervention. Despite increasing research attention, it remains unclear exactly which processes are amenable to placebo effects. The current study tested whether an instructional manipulation could produce placebo effects on a nonconscious cognitive task, namely implicit learning. Four hundred and sixty-four university students completed a visual search task while smelling an odor or no odor, in alternating blocks. Unknown to them, the task contained a contingency whereby on half the trials the target's location was cued by the pattern of distractors, which was achieved by repeating some configurations of targets and distractors. Prior to the task, participants received positive, negative, or no information about the odor's possible effects on performance. Those given positive information demonstrated faster reaction times on cued trials than other participants. Those given negative information showed slower reaction times on cued trials compared with participants given no information. Further, the cuing effect appeared to be nonconscious, with participants' ability to recognize the repeated configurations equivalent to chance and no evidence that performance on a recognition test was related to the magnitude of the cuing effect. This suggests that instructional manipulations can produce placebo effects on some nonconscious processes. PMID- 21327342 TI - When and why rare events are underweighted: a direct comparison of the sampling, partial feedback, full feedback and description choice paradigms. AB - Two paradigms are commonly used to examine risky choice based on experiential sampling. The feedback paradigm involves a large number of repeated, consequential choices with feedback about the chosen (partial feedback) or chosen and foregone (full feedback) payoffs. The sampling paradigm invites cost-free samples before a single consequential choice. Despite procedural differences, choices in both experience-based paradigms suggest underweighting of rare events relative to their objective probability. This contrasts with overweighting when choice options are described, thereby leading to a 'gap' between experience and description-based choice. Behavioural data and model-based analysis from an experiment comparing choices from description, sampling, and partial- and full feedback paradigms replicated the 'gap', but also indicated significant differences between feedback and sampling paradigms. Our results suggest that mere sequential experience of outcomes is insufficient to produce reliable underweighting. We discuss when and why underweighting occurs, and implicate repeated, consequential choice as the critical factor. PMID- 21327343 TI - Semantic priming is affected by real-time phonological competition: evidence for continuous cascading systems. AB - Lexical-semantic access is affected by the phonological structure of the lexicon. What is less clear is whether such effects are the result of continuous activation between lexical form and semantic processing or whether they arise from a more modular system in which the timing of accessing lexical form determines the timing of semantic activation. This study examined this issue using the visual world paradigm by investigating the time course of semantic priming as a function of the number of phonological competitors. Critical trials consisted of high or low density auditory targets (e.g., horse) and a visual display containing a target, a semantically related object (e.g., saddle), and two phonologically and semantically unrelated objects (e.g., chimney, bikini). Results showed greater magnitude of priming for semantically related objects of low than of high density words, and no differences for high and low density word targets in the time course of looks to the word semantically related to the target. This pattern of results is consistent with models of cascading activation, which predict that lexical activation has continuous effects on the level of semantic activation, with no delays in the onset of semantic activation for phonologically competing words. PMID- 21327344 TI - Selecting landmarks in novel environments. AB - People use salient landmarks when learning a route through a novel environment. However, it is not clear what makes a given landmark salient. In two experiments, subjects learned a route through a virtual museum, performed a recognition memory test for objects in the museum, and provided spatial descriptions and drew maps of the learned route. Objects with strong perceptual features occurred at decision points or at non-decision points along the route. Objects with both of these features were recognized faster and were included more often in the maps and written directions. When these features were separated, perceptual features maintained a strong influence on the recognition task, but had no influence on the spatial tasks, which were influenced only by spatial features. These findings challenge the idea that either a recognition task or descriptive task alone provides a complete account of landmark representation. PMID- 21327345 TI - Listener vs. speaker-oriented aspects of speech: studying the disfluencies of individuals with autism spectrum disorders. AB - This study investigates the role of disfluencies such as "um" or "uh" in conversation to discern whether these features of speech serve listener- or speaker-oriented functions by looking at their occurrence (or lack of occurrence) in the speech of participants with autism. Since the characteristic egocentricity of individuals with autism means they should engage in minimal listener-oriented behavior, they are a useful group to differentiate these functions. Transcription, analysis and categorization of 26 spontaneous language samples were derived from age-matched native English-speaking controls and high functioning individuals with Autism Spectrum Disorders (ASDs). Results showed that individuals with ASD produced fewer filled-pause words (ums and uhs) and revisions than controls, but more silent pauses and disfluent repetitions. Filled pause words therefore appear to be listener-oriented features of speech. PMID- 21327346 TI - The signature of inhibition in theory of mind: children's predictions of behavior based on avoidance desire. AB - Theory-of-mind reasoning may require inhibitory processing, a view for which we provide new, more direct, evidence. Our research capitalizes on the lingering property of inhibition: After a response is inhibited, it temporarily becomes more difficult to select than uninhibited responses. In two experiments, 3-year olds predicted to which of three buckets a girl would go, given a desire to avoid one (e.g., the red one). When next predicting where a boy would play, children were biased against the location the girl had avoided. However, predictions for the boy were unbiased when not preceded by predictions for the girl. These findings suggest that preschoolers predict behavior based on avoidance desires by inhibiting the target to be avoided, as well as that the inhibition lingers, reducing the target's accessibility for subsequent predictions. PMID- 21327347 TI - Young children reorient by computing layout geometry, not by matching images of the environment. AB - Disoriented animals from ants to humans reorient in accord with the shape of the surrounding surface layout: a behavioral pattern long taken as evidence for sensitivity to layout geometry. Recent computational models suggest, however, that the reorientation process may not depend on geometrical analyses but instead on the matching of brightness contours in 2D images of the environment. Here we test this suggestion by investigating young children's reorientation in enclosed environments. Children reoriented by extremely subtle geometric properties of the 3D layout: bumps and ridges that protruded only slightly off the floor, producing edges with low contrast. Moreover, children failed to reorient by prominent brightness contours in continuous layouts with no distinctive 3D structure. The findings provide evidence that geometric layout representations support children's reorientation. PMID- 21327348 TI - Does working memory training work? The promise and challenges of enhancing cognition by training working memory. AB - A growing body of literature shows that one's working memory (WM) capacity can be expanded through targeted training. Given the established relationship between WM and higher cognition, these successful training studies have led to speculation that WM training may yield broad cognitive benefits. This review considers the current state of the emerging WM training literature, and details both its successes and limitations. We identify two distinct approaches to WM training, strategy training and core training, and highlight both the theoretical and practical motivations that guide each approach. Training-related increases in WM capacity have been successfully demonstrated across a wide range of subject populations, but different training techniques seem to produce differential impacts upon the broader landscape of cognitive abilities. In particular, core WM training studies seem to produce more far-reaching transfer effects, likely because they target domain-general mechanisms of WM. The results of individual studies encourage optimism regarding the value of WM training as a tool for general cognitive enhancement. However, we discuss several limitations that should be addressed before the field endorses the value of this approach. PMID- 21327349 TI - Increased gaze following for fearful faces. It depends on what you're looking for! AB - An oculomotor visual search task was used to investigate how participants follow the gaze of a non-predictive and task irrelevant distractor gaze, and the way in which this gaze following is influenced by the emotional expression (fearful vs. happy) as well as participants' goal. Previous research has suggested that fearful emotions should result in stronger cueing effects than happy faces. Our results demonstrated that the degree to which the emotional expression influenced this gaze following varied as a function of the search target. When searching for a threatening target, participants were more likely to look in the direction of eye gaze on a fearful compared to a happy face. However, when searching for a pleasant target, this stronger cueing effect for fearful faces disappeared. Therefore, gaze following is influenced by contextual factors such as the emotional expression, as well as the participant's goal. PMID- 21327350 TI - Contrasting cue-density effects in causal and prediction judgments. AB - Many theories of contingency learning assume (either explicitly or implicitly) that predicting whether an outcome will occur should be easier than making a causal judgment. Previous research suggests that outcome predictions would depart from normative standards less often than causal judgments, which is consistent with the idea that the latter are based on more numerous and complex processes. However, only indirect evidence exists for this view. The experiment presented here specifically addresses this issue by allowing for a fair comparison of causal judgments and outcome predictions, both collected at the same stage with identical rating scales. Cue density, a parameter known to affect judgments, is manipulated in a contingency learning paradigm. The results show that, if anything, the cue-density bias is stronger in outcome predictions than in causal judgments. These results contradict key assumptions of many influential theories of contingency learning. PMID- 21327352 TI - Model discrimination through adaptive experimentation. AB - An ideal experiment is one in which data collection is efficient and the results are maximally informative. This standard can be difficult to achieve because of uncertainties about the consequences of design decisions. We demonstrate the success of a Bayesian adaptive method (adaptive design optimization, ADO) in optimizing design decisions when comparing models of the time course of forgetting. Across a series of testing stages, ADO intelligently adapts the retention interval in order to maximally discriminate power and exponential models. Compared with two different control (non-adaptive) methods, ADO distinguishes the models decisively, with the results unambiguously favoring the power model. Analyses suggest that ADO's success is due in part to its flexibility in adjusting to individual differences. This implementation of ADO serves as an important first step in assessing its applicability and usefulness to psychology. PMID- 21327351 TI - Sensori-motor spatial training of number magnitude representation. AB - An adequately developed spatial representation of number magnitude is associated with children's general arithmetic achievement. Therefore, a new spatial numerical training program for kindergarten children was developed in which presentation and response were associated with a congruent spatial numerical representation. In particular, children responded by a full-body spatial movement on a digital dance mat in a magnitude comparison task. This spatial-numerical training was more effective than a non-spatial control training in enhancing children's performance on a number line estimation task and a subtest of a standardized mathematical achievement battery (TEDI-MATH). A mediation analysis suggested that these improvements were driven by an improvement of children's mental number line representation and not only by unspecific factors such as attention or motivation. These results suggest a benefit of spatial numerical associations. Rather than being a merely associated covariate, they work as an independently manipulated variable which is functional for numerical development. PMID- 21327353 TI - The predictive mirror: interactions of mirror and affordance processes during action observation. AB - An important question for the study of social interactions is how the motor actions of others are represented. Research has demonstrated that simply watching someone perform an action activates a similar motor representation in oneself. Key issues include (1) the automaticity of such processes, and (2) the role object affordances play in establishing motor representations of others' actions. Participants were asked to move a lever to the left or right to respond to the grip width of a hand moving across a workspace. Stimulus-response compatibility effects were modulated by two task-irrelevant aspects of the visual stimulus: the observed reach direction and the match between hand-grasp and the affordance evoked by an incidentally presented visual object. These findings demonstrate that the observation of another person's actions automatically evokes sophisticated motor representations that reflect the relationship between actions and objects even when an action is not directed towards an object. PMID- 21327354 TI - Subsyllabic structure reflected in letter confusability effects in Korean word recognition. AB - Korean subsyllabic structure was investigated by observing the pattern of responses arising from letter transpositions within a syllable in the Hangul script. Experiment 1 revealed no confusions when the onset and coda of one syllable of a disyllabic word were transposed. This was also the case in Experiment 2, where the transposition took place within a syllable having a coda composed of two consonants. However, confusion with the baseword was observed when the two consonants within the complex coda were themselves transposed. These results are taken to support the view that Hangul (and possibly all concatenating orthographic scripts) is processed based on its onset, vowel, and coda structure. PMID- 21327355 TI - Perceptual congruency of audio-visual speech affects ventriloquism with bilateral visual stimuli. AB - Many studies on multisensory processes have focused on performance in simplified experimental situations, with a single stimulus in each sensory modality. However, these results cannot necessarily be applied to explain our perceptual behavior in natural scenes where various signals exist within one sensory modality. We investigated the role of audio-visual syllable congruency on participants' auditory localization bias or the ventriloquism effect using spoken utterances and two videos of a talking face. Salience of facial movements was also manipulated. Results indicated that more salient visual utterances attracted participants' auditory localization. Congruent pairing of audio-visual utterances elicited greater localization bias than incongruent pairing, while previous studies have reported little dependency on the reality of stimuli in ventriloquism. Moreover, audio-visual illusory congruency, owing to the McGurk effect, caused substantial visual interference on auditory localization. Multisensory performance appears more flexible and adaptive in this complex environment than in previous studies. PMID- 21327356 TI - The distractor frequency effect in a delayed picture-word interference task: further evidence for a late locus of distractor exclusion. AB - A picture-word interference experiment examined the origin of the distractor frequency effect, the effect that pictures are named slower in the context of low frequency than high-frequency words (Miozzo & Caramazza, Journal of Experimental Psychology, 132, 228-252, 2003). We compared two accounts of the effect: an early, input-related account and a late, response-related account. Participants named high and low-frequency pictures with low and high-frequency distractors in two conditions. In the immediate naming condition, picture and distractor were presented simultaneously. In the delayed naming condition, the distractor was presented 1,000 ms after the picture; pictures had to be named upon distractor presentation. There was a distractor frequency effect in both conditions, but an effect of picture frequency only in the immediate naming condition (showing that in the delayed naming condition, lexical selection had been completed). These results support a late origin of the distractor frequency effect. PMID- 21327357 TI - Scale and construal: how larger measurement units shrink length estimates and expand mental horizons. AB - Scale can vary by requiring a different number of units to measure the same target. But what are the consequences of using fewer, larger units? We draw on past psychophysical research that shows how using fewer units reduces clutter in measurement, translating to shorter length estimates. Additionally, we propose that larger scale is associated with targets further from a person's immediate experience (i.e., psychologically distant) and higher order mental representation. Evidence from Study 1 indicates that framing a target as further away causes it to be estimated as shorter because people use larger units to measure it compared to when the same target is framed as nearby. Two subsequent studies suggest that direct manipulation of larger (versus smaller) measurement scale produces not only shorter length estimates, but also more distal timing judgments (Study 2) and abstract mental representation (Study 3). Implications for scale and level of mental construal are discussed. PMID- 21327358 TI - Are things that are hard to physically move also hard to imagine moving? AB - Are objects that are more difficult to physically manipulate also more difficult to mentally manipulate? In our study, participants interacted with wooden objects modeled after the figures from Shepard and Metzler's (1971) classic mental rotation experiment. One pair of objects was easy to physically rotate while another pair was difficult. They then completed a standard mental rotation task on images of these objects. Participants were slower to mentally rotate objects that were harder to physically rotate when they engaged in motor imagery. Further, this cost accrued with increasing angles of rotation. We verified this was the result of motor imagery by showing that the costs can be eliminated by using a strictly visual imagery strategy (imagining the objects moving on their own). These results reveal a striking constraint imposed by our real-world motor experiences on mental imagery, and also demonstrate a way that we can overcome such constraints. PMID- 21327359 TI - Task preparation and task inhibition: a comment on Koch, Gade, Schuch, & Philipp (2010). AB - In their recent review article, Koch, Gade, Schuch, & Philipp, (Psychonomic Bulletin & Review, 17, 1-14, 2010) present compelling evidence for the role of inhibition in task switching, as measured by n-2 repetition costs. They promote the view that inhibition targets response-related processes of task performance rather than cue-based preparatory stages. In support of this distinction, they cite the finding in the literature that n-2 repetition costs are not reduced given longer preparation intervals. In this article, we advocate the analysis of whole reaction time distributions for investigating the influence of task preparation on task inhibition. We present such analyses from two of our published experiments that support the view that n-2 repetition costs can be reduced given sufficient preparation. The results suggest that cue-based processes do contribute to inhibition in task switching. PMID- 21327360 TI - Diffusion versus linear ballistic accumulation: different models but the same conclusions about psychological processes? AB - Quantitative models for response time and accuracy are increasingly used as tools to draw conclusions about psychological processes. Here we investigate the extent to which these substantive conclusions depend on whether researchers use the Ratcliff diffusion model or the Linear Ballistic Accumulator model. Simulations show that the models agree on the effects of changes in the rate of information accumulation and changes in non-decision time, but that they disagree on the effects of changes in response caution. In fits to empirical data, however, the models tend to agree closely on the effects of an experimental manipulation of response caution. We discuss the implications of these conflicting results, concluding that real manipulations of caution map closely, but not perfectly to response caution in either model. Importantly, we conclude that inferences about psychological processes made from real data are unlikely to depend on the model that is used. PMID- 21327361 TI - Who dunnit? Cross-linguistic differences in eye-witness memory. AB - Does eye-witness memory differ depending on the language one speaks? We examined English and Spanish speakers' descriptions of intentional and accidental events, and their memory for the agents of these events. English and Spanish speakers described intentional events similarly, using mostly agentive language (e.g., "She broke the vase"). However, when it came to accidental events English speakers used more agentive language than did Spanish speakers. Results from a non-linguistic memory task mirrored the patterns in language. English and Spanish speakers remembered the agents of intentional events equally well. However, English speakers remembered the agents of accidental events better than did Spanish speakers. Together these findings demonstrate that there are cross linguistic differences in event descriptions that have important consequences for eye-witness memory. PMID- 21327363 TI - Correct acceptance weighs more than correct rejection: a decision bias induced by question framing. AB - We propose that in attempting to detect whether an effect exists or not, people set their decision criterion so as to increase the number of hits and decrease the number of misses, at the cost of increasing false alarms and decreasing correct rejections. As a result, we argue, if one of two complementary events is framed as the positive response to a question and the other as the negative response, people will tend to predict the former more often than the latter. Performance in a prediction task with symmetric payoffs and equal base rates supported our proposal. Positive responses were indeed more prevalent than negative responses, irrespective of the phrasing of the question. The bias, slight but consistent and significant, was evident from early in a session and then remained unchanged to the end. A regression analysis revealed that, in addition, individuals' decision criteria reflected their learning experiences, with the weight of hits being greater than that of correct rejections. PMID- 21327362 TI - Modeling working memory: a computational implementation of the Time-Based Resource-Sharing theory. AB - Working memory is a core concept in cognition, predicting about 50% of the variance in IQ and reasoning tasks. A popular test of working memory is the complex span task, in which encoding of memoranda alternates with processing of distractors. A recent model of complex span performance, the Time-Based-Resource Sharing (TBRS) model of Barrouillet and colleagues, has seemingly accounted for several crucial findings, in particular the intricate trade-off between deterioration and restoration of memory in the complex span task. According to the TBRS, memory traces decay during processing of the distractors, and they are restored by attentional refreshing during brief pauses in between processing steps. However, to date, the theory has been formulated only at a verbal level, which renders it difficult to test and to be certain of its intuited predictions. We present a computational instantiation of the TBRS and show that it can handle most of the findings on which the verbal model was based. We also show that there are potential challenges to the model that await future resolution. This instantiated model, TBRS*, is the first comprehensive computational model of performance in the complex span paradigm. The Matlab model code is available as a supplementary material of this article. PMID- 21327364 TI - When bad stress goes good: increased threat reactivity predicts improved category learning performance. AB - The way in which we respond to everyday stressors can have a profound impact on cognitive functioning. Maladaptive stress responses in particular are generally associated with impaired cognitive performance. We argue, however, that the cognitive system mediating task performance is also a critical determinant of the stress-cognition relationship. Consistent with this prediction, we observed that stress reactivity consistent with a maladaptive, threat response differentially predicted performance on two categorization tasks. Increased threat reactivity predicted enhanced performance on an information-integration task (i.e., learning is thought to depend upon a procedural-based memory system), and a (nonsignificant) trend for impaired performance on a rule-based task (i.e., learning is thought to depend upon a hypothesis-testing system). These data suggest that it is critical to consider both variability in the stress response and variability in the cognitive system mediating task performance in order to fully understand the stress-cognition relationship. PMID- 21327365 TI - Indecision on decisional separability. AB - The theoretical framework of General Recognition Theory (GRT; Ashby & Townsend, Psychological Review, 93, 154-179, 1986) coupled with the empirical analysis tools of Multidimensional Signal Detection Analysis (MSDA; Kadlec & Townsend, Multidimensional models of perception and recognition, pp. 181-228, 1992) have become one important method for assessing dimensional interactions in perceptual decision-making. In this article, we critically examine MSDA and characterize cases where it is unable to discriminate two kinds of dimensional interactions: perceptual separability and decisional separability. We performed simulations with known instances of violations of perceptual or decisional separability, applied MSDA to the data generated by these simulations, and evaluated MSDA on its ability to accurately characterize the perceptual versus decisional source of these simulated dimensional interactions. Critical cases of violations of perceptual separability are often mischaracterized by MSDA as violations of decisional separability. PMID- 21327366 TI - Post-conflict slowing: cognitive adaptation after conflict processing. AB - The aftereffects of error and conflict (i.e., stimulus or response incongruency) have been extensively studied in the cognitive control literature. Each has been characterized by its own behavioral signature on the following trial. Conflict leads to a reduced congruency effect (Gratton effect), whereas an error leads to increased response time (post-error slowing). The reason for this dissociation has remained unclear. Here, we show that post-conflict slowing is not typically observed because it is masked by the processing of the irrelevant stimulus dimension. We demonstrate that post-conflict slowing does occur when tested in pure trials where helpful or detrimental impacts from irrelevant stimulus dimensions are removed (i.e., univalent stimuli). PMID- 21327367 TI - Neither backward masking of T2 nor task switching is necessary for the attentional blink. AB - Identification of the second of two targets (T1, T2, inserted in a stream of distractors) is impaired when presented within 500 ms after the first (attentional blink, AB). Barring a T1-T2 task-switch, it is thought that T2 must be backward-masked to obtain an AB (Giesbrecht & Di Lollo, Journal of Experimental Psychology: Human Perception and Performance, 24, 1454-1466, 1998). We tested the hypothesis that Giesbrecht & Di Lollo's findings were vitiated by ceiling constraints arising from either response scale (experiment 1) or data limitations (experiment 2). In experiment 1, digit-distractors were replaced with pseudoletters to increase task difficulty, bringing performance below ceiling. An AB occurred without backward masking of T2. In experiment 2, a ceiling-free procedure estimated the number of noise dots needed for 80% T2 identification. An AB was revealed: fewer noise dots were required during the AB period than outside it. Both outcomes confirm that an AB can be obtained without either masking of T2 or task switching. PMID- 21327368 TI - Visual noise disrupts conceptual integration in reading. AB - The Effortfulness Hypothesis suggests that sensory impairment (either simulated or age-related) may decrease capacity for semantic integration in language comprehension. We directly tested this hypothesis by measuring resource allocation to different levels of processing during reading (i.e., word vs. semantic analysis). College students read three sets of passages word-by-word, one at each of three levels of dynamic visual noise. There was a reliable interaction between processing level and noise, such that visual noise increased resources allocated to word-level processing, at the cost of attention paid to semantic analysis. Recall of the most important ideas also decreased with increasing visual noise. Results suggest that sensory challenge can impair higher level cognitive functions in learning from text, supporting the Effortfulness Hypothesis. PMID- 21327369 TI - Object-based representations govern both the storage of information in visual short-term memory and the retrieval of information from it. AB - Interest is growing in how information is retained in visual short-term memory (VSTM). We describe an experiment that assesses VSTM within the context of multidimensional signal detection theory. On every trial, participants were presented with a 250-ms display containing four colored shapes. They were then probed 900 ms later with a colored shape and made separate old/new judgments about the color and the shape. In any particular trial, one, both, or neither of the probed features had been presented. Performance differed according to whether both probed features belonged to a single object or to two different objects. When both probed features belonged to the same object, featural retrieval was better than would be predicted by independent feature storage. When both probed features belonged to two different objects, featural retrieval was worse than would be predicted by independent feature storage. We conclude that storage in and retrieval from VSTM operate on the basis of object-based representations. PMID- 21327370 TI - Surprise influences hindsight-foresight differences in temporal judgments of animated automobile accidents. AB - The hindsight bias occurs when people view an outcome as more foreseeable than it actually was. The role of an outcome's initial surprise in the hindsight bias was examined using animations of automobile accidents. Twenty-six participants rated the initial surprise of accidents' occurring in eight animations. An additional 84 participants viewed these animations in one of two conditions: Half stopped the animations when they were certain an accident would occur (i.e., in foresight), and the other half watched the entire animations first and then stopped the animations when they thought that a naive viewer would be certain that an accident would occur (i.e., in hindsight). When the accidents were low in initial surprise, there were no foresight-hindsight differences; when initial surprise was medium, there was a hindsight bias; and when initial surprise was high, there was a reversed hindsight bias. The results are consistent with a sense-making model of hindsight bias. PMID- 21327371 TI - Rapid changes in visual-spatial attention distort object shape. AB - Shifts of attention due to rapid cue onsets have been shown to distort the perceived location of objects, but are there also systematic distortions in the perceived shapes of the objects themselves from such shifts? The present study demonstrates that there are. In three experiments, oval contours were presented that varied in width and height. Two brief, bright white dots were presented as cues and were positioned horizontally or vertically either inside or outside the oval contour. Observers had to judge whether the oval was taller than wide. The results show that the perceived shape of an oval was changed by visual cues such that the oval contours were repelled by the cues (Exp. 1). This effect only occurred when the cues preceded the ovals, providing sufficient time between the presentations to attract involuntary attention (Exp. 2). Moreover, an explanation based on figural aftereffects was ruled out (Exp. 3). PMID- 21327372 TI - Are survival processing memory advantages based on ancestral priorities? AB - Recent research has suggested that our memory systems are especially tuned to process information according to its survival relevance, and that inducing problems of "ancestral priorities" faced by our ancestors should lead to optimal recall performance (Nairne & Pandeirada, Cognitive Psychology, 2010). The present study investigated the specificity of this idea by comparing an ancestor consistent scenario and a modern survival scenario that involved threats that were encountered by human ancestors (e.g., predators) or threats from fictitious creatures (i.e., zombies). Participants read one of four survival scenarios in which the environment and the explicit threat were either consistent or inconsistent with ancestrally based problems (i.e., grasslands-predators, grasslands-zombies, city-attackers, city-zombies), or they rated words for pleasantness. After rating words based on their survival relevance (or pleasantness), the participants performed a free recall task. All survival scenarios led to better recall than did pleasantness ratings, but recall was greater when zombies were the threat, as compared to predators or attackers. Recall did not differ for the modern (i.e., city) and ancestral (i.e., grasslands) scenarios. These recall differences persisted when valence and arousal ratings for the scenarios were statistically controlled as well. These data challenge the specificity of ancestral priorities in survival-processing advantages in memory. PMID- 21327373 TI - Numerical bias in bounded and unbounded number line tasks. AB - The number line task is often used to assess children's and adults' underlying representations of integers. Traditional bounded number line tasks, however, have limitations that can lead to misinterpretation. Here we present a new task, an unbounded number line task, that overcomes these limitations. In Experiment 1, we show that adults use a biased proportion estimation strategy to complete the traditional bounded number line task. In Experiment 2, we show that adults use a dead-reckoning integer estimation strategy in our unbounded number line task. Participants revealed a positively accelerating numerical bias in both tasks, but showed scalar variance only in the unbounded number line task. We conclude that the unbounded number line task is a more pure measure of integer representation than the bounded number line task, and using these results, we present a preliminary description of adults' underlying representation of integers. PMID- 21327374 TI - Categorizing entities by common role. AB - Many categories group together entities that play a common role across situations. For example, guest and host refer to complementary roles in visiting situations and, thus, are role-governed categories (A. B. Markman & Stilwell, Journal of Experiment & Theoretical Artificial Intelligence, 13, 329-358, 2001). However, categorizing an entity by role is one of many possible classification strategies. This article examines factors that promote role-governed categorization over thematic-relation-based categorization (Lin & Murphy, Journal of Experimental Psychology: General, 130, 3-28, 2001). In Experiments 1a and 1b, we demonstrate that the use of novel category labels facilitates role-governed categorization. In Experiments 2a and 2b, we demonstrate that analogical comparison facilitates role-governed categorization. In Experiments 1b and 2b, we show that these facilitatory factors induce a general sensitivity to role information, as opposed to only promoting role-governed categorization on an item by-item basis. PMID- 21327375 TI - When objects are close to me: affordances in the peripersonal space. AB - In the present study, we investigated, using language, which motor information is automatically activated by observing 3-D objects (i.e., manipulation vs. function) and whether this information is modulated by the objects' location in space. Participants were shown 3-D pictures of objects located in peripersonal versus extrapersonal space. Immediately after, they were presented with function, manipulation, or observation verbs (e.g., "to drink," "to grasp," "to look at") and were required to judge whether the verb was compatible with the presented object. We found that participants were slower with observation verbs than with manipulation and function verbs. With both function and manipulation verbs, participants were faster when objects were presented in reachable space. Interestingly, the fastest response times were recorded when participants read function verbs while objects were presented in the accessible space. Results suggest that artifacts are first conceived in terms of affordances linked to manipulation and use, and that affordances are differently activated, depending on context. PMID- 21327377 TI - Familiarity does not aid access to features. AB - Previous findings have suggested that a familiar pattern and the features within it are perceived better than an unfamiliar pattern. In Experiments 1 and 2, access to within-pattern colors in Stars and Stripes flags was equally efficient in the normal and the inverted orientations, thus suggesting that familiarity does not aid access to within-pattern features. However, in Experiment 3, which focused on the detection of the whole of a flag, rather than within-pattern colors, the selection of upright Stars and Stripes flags was significantly more efficient than that of inverted flags, thus confirming the greater familiarity of the former. I argue that familiarity aids the perception of a pattern only by allowing the whole pattern to be labeled as a single feature and does not directly aid access to features. PMID- 21327376 TI - Reaction time distribution analysis of spatial correspondence effects. AB - Since 1994, group reaction time (RT) distribution analyses of spatial correspondence effects have been used to evaluate the dynamics of the spatial Simon effect, a benefit of correspondence of stimulus location information with response location for tasks in which stimulus location is irrelevant. We review the history and justification for analyzing group RT distributions and clarify which conditions result in the Simon effect decreasing across the distribution and which lead to flat or increasing functions. Although the standard left-right Simon effect typically yields a function for which the effect decreases as RT increases, in most other task variations, the Simon effect remains stable or increases across the RT distribution. Studies that have used other means of evaluating the temporal dynamics of the Simon effect provide converging evidence that the changes in the Simon effect across the distribution are due mainly to temporal activation properties, an issue that has been a matter of some dispute. PMID- 21327378 TI - Does temporal integration of face parts reflect holistic processing? AB - We examined whether temporal integration of face parts reflects holistic processing or response interference. Participants learned to name two faces "Fred" and two "Bob." At test, the top and bottom halves of different faces formed composites and were presented briefly separated in time. Replicating prior findings (Singer & Sheinberg, Vision Research, 46, 1838-1847, 2006), naming of the target half for aligned composites was slowed when the irrelevant half was from a face with a different name rather than from the original face. However, no interference was observed when the irrelevant half had a name identical to the name of the target half but came from a different learned face, arguing against a true holistic effect. Instead, response interference was obtained when the target half briefly preceded the irrelevant half. Experiment 2 confirmed a double dissociation of holistic processing versus response interference for intact faces versus temporally separated face halves, suggesting that simultaneous presentation of facial information is critical for holistic processing. PMID- 21327379 TI - Automaticity without extensive training: the role of memory retrieval in implementation of task-defined rules. AB - Although the concept of automaticity is closely associated with extensive rote training, previous studies have shown that task-defined stimulus-response (S-R) mappings can be implemented in parallel and involuntarily, without much training, as if they are automatically processed. An irrelevant task context may trigger a task-defined rule because the rule is actively maintained in working memory, resulting in erroneous implementation of that rule. However, the present study demonstrated that active maintenance of task rules is not necessary for their automatic implementation. Instead, the results are consistent with the memory view of automaticity, according to which task-defined S-R rules are implemented via automatic retrieval of S-R episodes. PMID- 21327380 TI - Long-range correlation properties in motor timing are individual and task specific. AB - 1/f (beta) noise represents a specific form of (long-range) correlations in a time series that is pervasive across many sensorimotor variables. Recent studies have shown that the precise properties of the correlations demonstrated by a group of test participants may vary as a function of experimental conditions or factors characterizing the group. Our purpose in the present study was to clarify whether long-range correlations affect sensorimotor performance generally or in a task-specific manner and whether each individual produces characteristic long range correlations that are reliable across several runs of the same task. We analyzed the series of time intervals produced by 43 participants in two timing tasks: unimanual rhythmic tapping and circle drawing. We found that a participant's 1/f (beta) properties in tapping were not related to the 1/f (beta) properties in circle drawing. However, within each task, individual differences were reliable, and a Cronbach's alpha of .59 showed a high degree of within subjects reproducibility of the long-range correlations. Thus, long-range correlations represent a consistent and distinctive characteristic of individuals performing a particular task, rather than a ubiquitous generic property of sensorimotor time series. The implications of these results are discussed from both a theoretical and a methodological perspective. PMID- 21327381 TI - Different clues from different views: the role of image format in public perceptions of neuroimaging results. AB - We examined whether different types of brain images affect readers' evaluations of scientific reports. Five different brain images were selected from the neuroscience literature: a whole brain, an inflated brain, a cross-sectional brain slice, a glass brain, and a topographic map. First, the images were subjectively rated by 31 nonexperts for qualities associated with realism and perceived complexity. Each of the five images was later presented alongside one of five fictitious neuroscience articles (image-text pairings counterbalanced), and a different group of 122 novices rated the accompanying articles for scientific reasoning. They also separately reported their familiarity with each image type. Brain images previously rated as more three-dimensional produced more positive evaluations of the articles with which they were presented. Perceived image complexity also showed a marginal nonlinear relationship with article credibility ratings. Our findings suggest that choice of image format matters when disseminating neuroscience research to the general public. PMID- 21327382 TI - Pigeons' categorization may be exclusively nonanalytic. AB - Recent theoretical and empirical developments in human category learning have differentiated an analytic, rule-based system of category learning from a nonanalytic system that integrates information across stimulus dimensions. In the present study, the researchers applied this theoretical distinction to pigeons' category learning. Pigeons learned to categorize stimuli varying in the tilt and width of their internal striping. The matched category problems had either a unidimensional (rule-based) or multidimensional (information-integration) solution. Whereas humans and nonhuman primates strongly dimensionalize these stimuli and learn rule-based tasks far more quickly than information-integration tasks, pigeons learned the two tasks equally quickly to the same accuracy level. Pigeons may represent a cognitive system in which the commitment to dimensional analysis and category rules was not strongly made. Their performance could suggest the character of the ancestral vertebrate categorization system from which that of primates emerged. PMID- 21327383 TI - Does scene context always facilitate retrieval of visual object representations? AB - An object-to-scene binding hypothesis maintains that visual object representations are stored as part of a larger scene representation or scene context, and that scene context facilitates retrieval of object representations (see, e.g., Hollingworth, Journal of Experimental Psychology: Learning, Memory and Cognition, 32, 58-69, 2006). Support for this hypothesis comes from data using an intentional memory task. In the present study, we examined whether scene context always facilitates retrieval of visual object representations. In two experiments, we investigated whether the scene context facilitates retrieval of object representations, using a new paradigm in which a memory task is appended to a repeated-flicker change detection task. Results indicated that in normal scene viewing, in which many simultaneous objects appear, scene context facilitation of the retrieval of object representations-henceforth termed object to-scene binding-occurred only when the observer was required to retain much information for a task (i.e., an intentional memory task). PMID- 21327384 TI - When bicycle pump is harder to read than bicycle bell: effects of parsing cues in first and second language compound reading. AB - Reading and understanding morphologically complex words can sometimes be a particular challenge to nonnative speakers. For example, compound words consist of multiple free morphemes, oftentimes without explicit marking of the morpheme boundaries. In a lexical decision task, we investigated compound reading in native and nonnative speakers of Dutch. The compounds differed in that the letter bigram that formed the morpheme boundary could or could not occur within a Dutch morpheme, thus providing an orthotactic cue as to the position of the morpheme boundary. Native and nonnative speakers responded faster to compounds that contained such an orthotactic cue. Additional analyses showed that although native speakers used this cue for long, but not for short compounds, no such word length modulation was observed for nonnative speakers. It is suggested that orthotactic parsing cues are used during compound reading and possibly even more so in nonnative speakers. PMID- 21327385 TI - Categorical perception effects reflect differences in typicality on within category trials. AB - Many studies have shown better discrimination of two stimuli that cross a category boundary than of two stimuli belonging to the same category. This finding, known as categorical perception, is generally assumed to reflect consistently good performance on cross-category trials, relative to within category trials. However, Roberson, D., Damjanovic, L., and Pilling, M. (Memory & Cognition, 35, 1814-1829, 2007) revealed that performance on within-category pairs of morphed facial expressions matched performance on cross-category trials when the target was a good exemplar of its category. Here, we investigate the generality of that finding by conducting new analyses of data from a series of studies of categorical perception in facial identity and color domains with speakers of different languages. Consistent with Roberson et al. (2007), the new analyses demonstrate that performance for central targets on within-category trials is as good as performance on cross-category trials. Participants perform badly on within-category items only when the target is closer to the category boundary than is the distractor. These results provide no support for the view that categorical perception is associated with increased perceptual sensitivity at category boundaries. PMID- 21327386 TI - Robust expression and association of ZmCCA1 with circadian rhythms in maize. AB - In plants, the circadian clock is an endogenous mechanism that controls a wide range of biological processes. To date, as one of the key world crops, little is known about the molecular mechanism and components of the circadian clock in maize (Zea mays). In this study, we characterized the CIRCADIAN CLOCK ASSOCIATED1 gene of maize (ZmCCA1), an ortholog of CCA1 in Arabidopsis thaliana (AtCCA1). Quantitative real-time PCR analysis revealed that ZmCCA1 was expressed in leaves and stem apex meristems in a rhythmic pattern under long day and short day conditions, and its peak gene expression appeared during the morning. ZmCCA1 transcripts accumulated in all tissues evaluated, with higher levels in tassels and ears. Additionally, the expression of another photoperiod gene ZmTOC1 peaked 12 h after dawn on long days and at 10 h after dawn on short days. Subcellular localization analysis revealed that the ZmCCA1 protein is directed to the cell nucleus. Overexpression of ZmCCA1 in Arabidopsis reduced the expression levels of downstream genes, including GIGANTEA (AtGI), CONSTANS (AtCO), and FLOWERING LOCUST (AtFT), and resulted in longer hypocotyls and delayed flowering. Taken together, our data suggest that ZmCCA1 may be a core component of the circadian clock in maize. PMID- 21327387 TI - Transgene stacking and marker elimination in transgenic rice by sequential Agrobacterium-mediated co-transformation with the same selectable marker gene. AB - Rice chitinase (chi11) and tobacco osmotin (ap24) genes, which cause disruption of fungal cell wall and cell membrane, respectively, were stacked in transgenic rice to develop resistance against the sheath blight disease. The homozygous marker-free transgenic rice line CoT23 which harboured the rice chi11 transgene was sequentially re-transformed with a second transgene ap24 by co-transformation using an Agrobacterium tumefaciens strain harbouring a single-copy cointegrate vector pGV2260::pSSJ1 and a multi-copy binary vector pBin19?nptII-ap24 in the same cell. pGV2260::pSSJ1 T-DNA carried the hygromycin phosphotransferase (hph) and beta-glucuronidase (gus) genes. pBin19?nptII-ap24 T-DNA harboured the tobacco osmotin (ap24) gene. Co-transformation of the gene of interest (ap24) with the selectable marker gene (SMG, hph) occurred in 12 out of 18 T(0) plants (67%). Segregation of hph from ap24 was accomplished in the T(1) generation in one (line 11) of the four analysed co-transformed plants. The presence of ap24 and chi11 transgenes and the absence of the hph gene in the SMG-eliminated T(1) plants of the line 11 were confirmed by DNA blot analyses. The SMG-free transgenic plants of the line 11 harboured a single copy of the ap24 gene. Homozygous, SMG-free T(2) plants of the transgenic line 11 harboured stacked transgenes, chi11 and ap24. Northern blot analysis of the SMG-free plants revealed constitutive expression of chi11 and ap24. The transgenic plants with stacked transgenes displayed high levels of resistance against Rhizoctonia solani. Thus, we demonstrate the development of transgene-stacked and marker-free transgenic rice by sequential Agrobacterium-mediated co-transformation with the same SMG. PMID- 21327389 TI - MpAsr encodes an intrinsically unstructured protein and enhances osmotic tolerance in transgenic Arabidopsis. AB - Abscisic acid-, stress- and ripening (ASR) -induced proteins are plant-specific proteins whose expression is up-regulated under abiotic stresses or during fruit ripening. In this study, we characterized an ASR protein from plantain to explore its physiological roles under osmotic stress. The expression pattern of MpAsr gene shows that MpAsr gene changed little at the mRNA level, while the MpASR protein accumulates under osmotic treatment. Through bioinformatic-based predictions, circular dichroism spectrometry, and proteolysis and heat-stability assays, we determined that the MpASR protein is an intrinsically unstructured protein in solution. We demonstrated that the hydrophilic MpASR protein could protect L: -lactate dehydrogenase (L: -LDH) from cold-induced aggregation. Furthermore, heterologous expression of MpAsr in Escherichia coli and Arabidopsis enhanced the tolerance of transformants to osmotic stress. Transgenic 35S::MpAsr Arabidopsis seeds had a higher germination frequency than wild-type seeds under unfavorable conditions. At the physiological level, 35S::MpAsr Arabidopsis showed increased soluble sugars and decreased cell membrane damage under osmotic stress. Thus, our results suggest that the MpASR protein may act as an osmoprotectant and water-retaining molecule to help cell adjustment to water deficit caused by osmotic stress. PMID- 21327390 TI - Isolation and characterization of a chlorophyll degradation regulatory gene from tall fescue. AB - The non-yellowing gene (NYE1), initially identified from Arabidopsis, is a key regulatory gene responsible for chlorophyll degradation during senescence. Here, FaNYE1, an orthologue of AtNYE1, was further identified from a major type of cool season turf grass, tall fescue (Festuca arundinacea Schreb.), by RACE-PCR. It consists of 1,441 bp, with an open reading frame of 834 bp, encoding a predicted polypeptide of 278 amino acids. Sequence similarity as well as exon and intron characteristics clearly suggested that FaNYE1 encoded an AtNYE1-like chloroplast protein. FaNYE1 could be strongly induced by dark treatment and natural senescence. FaNYE1, driven by a 1.5 kb upstream fragment of AtNYE1, could rescue the stay-green phenotype of nye1-1. Constitutive overexpression of FaNYE1 in Arabidopsis resulted in the whole spectrum of leaf yellowing phenotypes, the severity of which correlates with its transcript level. These results collectively indicate that FaNYE1 might play an important regulatory role in chlorophyll degradation during senescence in tall fescue, and therefore is a valuable gene for improving the green period or lawn color of turf grasses by genetic engineering. PMID- 21327391 TI - The chromosome number, karyotype and genome size of the desert plant diploid Reaumuria soongorica (Pall.) Maxim. AB - Extreme drought and salt resistant plant Reaumuria soongorica is of great potential for revealing genetic bases unique to naturally stress-tolerant plants. A preliminary genome survey, including chromosome number, karyotype, chromosomal localization of 45S rDNA loci and genome size was conducted with R. soongorica collected from Lanzhou, China. Chromosome counting showed that R. soongorica is diploid with chromosome number of 22. Karyotypical analysis illustrated that the chromosomes size ranges from 3.38 to 5.51 MUm, and the chromosomal formula is 2n = 2x = 22 = 4 m + 14sm + 4st. Fluorescence in situ hybridization revealed that four pairs of 45SrDNA signals were detected at the end of R. soongorica chromosomes. The flow cytometry analysis indicated that the mean C value of R. soongorica is 0.806 pg with predicted genome size of about 778 Mb. The results indicate that the extreme drought and salt resistance of R. soongorica was not attributed to a big and complicate genome and also offer some clues in resolving the problems of taxonomy and evolution in Tamaricaceae. PMID- 21327392 TI - Phytochelatin synthase of Thlaspi caerulescens enhanced tolerance and accumulation of heavy metals when expressed in yeast and tobacco. AB - Phytochelatin synthase (PCS) is key enzyme for heavy metal detoxification and accumulation in plant. In this study, we isolated the PCS gene TcPCS1 from the hyperaccumulator Thlaspi caerulescens. Overexpression of TcPCS1 enhanced PC production in tobacco. Cd accumulation in the roots and shoots of TcPCS1 transgenic seedlings was increased compared to the wild type (WT), while Cd translocation from roots to shoots was not affected under Cd treatment. The root length of the TcPCS1 transgenic tobacco seedlings was significantly longer than that of the WT under Cd stress. These data indicate that TcPCS1 expression might increase Cd accumulation and tolerance in transgenic tobacco. In addition, the malondialdehyde content in TcPCS1 plants was below that of the wild type. However, the antioxidant enzyme activities of superoxide dismutase, peroxidase and catalase were found to be significantly higher than those of the WT when the transgenic plant was exposed to Cd stress. This suggests that the increase in PC production might enhance the Cd accumulation and thus increase the oxidative stress induced by the cadmium. The production of PCs could cause a transient decrease in the cytosolic glutathione (GSH) pool, and Cd and lower GSH concentration caused an increase in the oxidative response. We also determined TcPCS1 in Thlaspi caerulescens was regulated after exposure to various concentrations of CdCl(2) over different treatment times. Expression of TcPCS1 leading to increased Cd accumulation and enhanced metal tolerance, but the Cd contents were restrained by adding zinc in Saccharomyces cerevisiae transformants. PMID- 21327394 TI - Myeloperoxidase and elastase are only expressed by neutrophils in normal and in inflamed liver. AB - Myeloperoxidase (MPO) is involved in acute and chronic inflammatory diseases. The source of MPO in acute liver diseases is still a matter of debate. Therefore, we analysed MPO-gene expression on sections from normal and acutely damaged [carbon tetrachloride-(CCl(4)) or whole liver gamma-Irradiation] rat liver by immunohistochemistry, real time PCR and Western blot analysis of total RNA and protein. Also total RNA and protein from isolated Kupffer cells, hepatic stellate cells, Hepatocytes, endothelial cells and neutrophil granulocytes (NG) was analysed by real time PCR and Western blot, respectively. Sections of acutely injured human liver were prepared for MPO and CD68 immunofluorescence double staining. In normal rat liver MPO was detected immunohistochemically and by immunofluorescence double staining only in single NG. No MPO was detected in isolated parenchymal and non-parenchymal cell populations of the normal rat liver. In acutely damaged rat liver mRNA of MPO increased 2.8-fold at 24 h after administration of CCl(4) and 3.3-fold at 3 h after gamma-Irradiation and MPO was detected by immunofluorescence double staining only in elastase (NE) positive NGs but not in macrophages (ED1 or CD68 positive cells). Our results demonstrate that, increased expression of MPO in damaged rat and human liver is due to recruited elastase positive NGs. PMID- 21327395 TI - Telmisartan improves nonalcoholic steatohepatitis in medaka (Oryzias latipes) by reducing macrophage infiltration and fat accumulation. AB - We investigated the efficacy of the antihypertensive drug telmisartan (Tel) and the mechanisms underlying the progression from simple steatosis to nonalcoholic steatohepatitis (NASH) in a medaka (Oryzias latipes) NASH model. We used the NASH activity score (NAS) developed in humans to assess the histology of the medaka NASH model and found that NAS increased with time. Further, TUNEL-positive apoptosis hepatocytes were found in the medaka NASH model. Tel administration resulted in the increased expression of liver peroxisome proliferator-activated receptor-gamma, carnitine palmitoyltransferase 1 and acyl-CoA oxidase 1 and decreased the number of 8-hydroxydeoxyguanosine-positive hepatocytes and the migration of macrophages positive for diastase-periodic-acid-Schiff. Medaka NAS was improved by Tel administration but fatty acid content was not affected. Tel reduced the infiltration of macrophages into the liver and ameliorated NASH pathology. PMID- 21327396 TI - Progressive multifocal leukoencephalopathy following chemotherapy for lung cancer. AB - Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the JC virus infection and with a frequent lethal outcome. PML usually occurs in immunocompromised subjects, such as HIV positive individuals, as well as in other conditions characterized by depletion of cellular immunity, including hematological malignancies, autoimmune diseases, and immunomodulatory therapies. We describe the case of a 76-year-old man affected by advanced non-small cell lung cancer who developed PML after six cycles of carboplatin/gemcitabine therapy, during which a transitory leucopenia developed. The patient deceased a few months after the onset of the symptoms. Chemotherapy appears to be uncommon, but definite condition associated to PML. PMID- 21327397 TI - Cerebellar hematoma in a carrier of the A3243G MELAS mutation. PMID- 21327398 TI - Daptomycin in treatment of Methicillin-resistant Staphylococcus aureus diskitis. PMID- 21327399 TI - Alien hand syndrome in left posterior stroke. AB - Alien hand syndrome is a rare neurological disorder characterized by involuntary and uncontrollable motor behaviour, usually of an arm or hand. The patient perceives the affected limb as alien, and may personify it. The case of a 61-year old right-handed woman who developed right posterior AHS after ischaemic stroke in the left posterior cerebral artery territory is reported. Neuroimaging studies disclosed no frontal or parietal involvement, while a posterior thalamic lesion was detected. A possible role of the thalamus in the genesis of AHS is discussed. PMID- 21327400 TI - The Modified Five-Point Test: normative data for a sample of Italian healthy adults aged 16-60. AB - The Five-Point Test is one of the various measures of figural fluency functions that have been developed as nonverbal analogues to word fluency tasks, and used in neuropsychological assessment to evaluate the ability to initiate and sustain mental productivity, and to self-monitor and regulate responding in the visual spatial domain. The aim of the current study was to collect normative data for a version of the Five-Point Test (M-FPT) administered to a sample of Italian healthy adults aged 16-60 (n = 332). Performance on the M-FPT was scored by computing the cumulative number of unique designs (UDs) performed on a 3-min administration time. Two supplemental scores were also computed: (a) the cumulative strategies (CSs) consisting with the number of UDs incorporated into enumerative or rotational strategies; (b) the error index (ErrI), consisting with the percentage between the number of perseverative or rule-breaking errors and the number of designs overall. Multiple regression analyses revealed a significant effect of age and education, but not gender, for both UDs and CSs. Equivalent scores and cut-off scores were then determined for UDs and CSs. Descriptive statistical analyses and cut-off scores were reported for ErrI. The availability of normative data for the M-FPT will be valuable in clinical settings for assessing of executive dysfunctions on the visual-spatial subdomain of subjects with brain injury. However, in order to increase the usefulness of the test, the upper limits of the age range of the normative sample should be widened. Moreover, further analyses should be required for determining the inter rater and test-retest reliability for M-FPT performances, and providing evidence of the sensitivity of this measure to brain disturbances generally and to frontal lobe dysfunction specifically. PMID- 21327401 TI - Serum uric acid levels in multiple sclerosis patients inversely correlate with disability. AB - Uric acid (UA) is an endogenous antioxidant. Some studies have described that multiple sclerosis (MS) patients have lower serum UA levels than controls, although it has not been established whether UA is primarily deficient, or secondarily reduced due to its scavenging activity. UA has also been proposed as an indicator of disease activity. We, retrospectively, reviewed 478 serum UA levels obtained in 94 MS patients. Ninety samples were collected during a relapse. Correlation between UA levels obtained during a relapse or in a relapse free period, and comparison between UA and expanded disability status scale (EDSS) score was tested using a two-tailed Student's t test and Spearman correlation coefficients test. UA levels were significantly lower when measured during a relapse (n 90) than in a remission period (n 368) (r -0.16, p 0.003) UA levels measured outside a relapse inversely correlated with EDSS score (r -0.15, p 0.001). Lower uric acid levels in MS patients are associated with clinical relapse. This is the first description of an inverse correlation of serum UA levels with disability as assessed by EDSS score. PMID- 21327402 TI - The diagnosis of postencephalitic parkinsonism at the neurological unit of Boston City Hospital, 1930-1981. AB - The objective of the study is to ascertain the rationale for the diagnosis of postencephalitic parkinsonism (PEP) at Boston City Hospital's Neurological Unit (1930-1981). 5,270 discharge summaries were evaluated for the diagnoses of PEP. Sixteen cases of PEP were identified; the diagnosis of PEP was justified in approximately half of these cases based on the published criteria for distinguishing PEP from Parkinson's disease (PD). In conclusions, the absence of a clear justification for the diagnosis of PEP in many of the 16 cases suggests that the accepted relationship between encephalitis lethargica and PEP may be less definitive than currently believed. PMID- 21327403 TI - A European survey on the detection and management of iron overload in transfusion dependent patients with MDS. AB - To better understand the detection and management of iron overload in transfusion dependent patients with myelodysplastic syndromes (MDS), a 15-min web- or paper based survey was conducted among 338 European physicians from 27 countries. Respondents had a mean of 18 years of clinical experience. Forty-six percent and 27% of physicians noted that detecting and treating iron overload were either "very important" or "important," respectively. The main reason for not actively exploring iron overload was related to poor patient prognosis, while the main reasons for not initiating iron chelation therapy were poor patient prognosis and older patient age. Thirty-seven percent and 31% of physicians believed that treating iron overload in these patients was "very important" or "important," respectively. Ninety percent of physicians prescribed iron chelation therapy, and 38% of transfusion-dependent patients received iron chelation therapy. The key reasons for not initiating iron chelation therapy were related to poor patient prognosis (72%), patient age >=85 years (50%), and comorbidities (34%). The views of these experienced MDS physicians reflect available international MDS treatment guidelines. PMID- 21327404 TI - Increased requirement for platelet transfusions concurrent with enhanced bleeding during romiplostim treatment in a patient with thrombocytopenia due to bone marrow failure. PMID- 21327405 TI - Assessment of bone ingrowth potential of biomimetic hydroxyapatite and brushite coated porous E-beam structures. AB - The bone ingrowth potential of biomimetic hydroxyapatite and brushite coatings applied on porous E-beam structure was examined in goats and compared to a similar uncoated porous structure and a conventional titanium plasma spray coating. Specimens were implanted in the iliac crest of goats for a period of 3 (4 goats) or 15 weeks (8 goats). Mechanical implant fixation generated by bone ingrowth was analyzed by a push out test. Histomorphometry was performed to assess the bone ingrowth depth and bone implant contact. The uncoated and hydroxyapatite-coated cubic structure had significantly higher mechanical strength at the interface compared to the Ti plasma spray coating at 15 weeks of implantation. Bone ingrowth depth was significantly larger for the hydroxyapatite and brushite-coated structures compared to the uncoated structure. In conclusion, the porous E-beam surface structure showed higher bone ingrowth potential compared to a conventional implant surface after 15 weeks of implantation. Addition of a calcium phosphate coating to the E-beam structure enhanced bone ingrowth significantly. Furthermore, the calcium phosphate coating appears to work as an accelerator for bone ingrowth. PMID- 21327406 TI - Continuous pullulan fermentation in a biofilm reactor. AB - Biofilm is a natural form of cell immobilization in which microorganisms attach onto solid support. In this study, a pigment-reduced pullulan-producing strain, Aureobasidium pullulans (ATCC 201253), was used for continuous pullulan fermentation in a plastic composite support (PCS) biofilm reactor. Optimal conditions for the continuous pullulan production were determined by evaluating the effects of the feeding medium with various concentrations of ammonium sulfate and sucrose and dilution rate. Pullulan concentration and production rate reached maximum (8.3 g/l and 1.33 g/l/h) when 15 g/l of sucrose, 0.9 g/l of ammonium sulfate, and 0.4 g/l of yeast extract were applied in the medium, and the dilution rate was at 0.16 h(-1). The purity of produced pullulan was 93.0%. The ratio of hyphal cells of A. pullulans increased when it was grown on the PCS shaft. Overall, the increased pullulan productivity can be achieved through biomass retention by using PCS biofilm reactor. PMID- 21327407 TI - Isolation and characterisation of KP34--a novel phiKMV-like bacteriophage for Klebsiella pneumoniae. AB - Bacteriophage KP34 is a novel virus belonging to the subfamily Autographivirinae lytic for extended-spectrum beta-lactamase-producing Klebsiella pneumoniae strains. Its biological features, morphology, susceptibility to chemical and physical agents, burst size, host specificity and activity spectrum were determined. As a potential antibacterial agent used in therapy, KP34 molecular features including genome sequence and protein composition were examined. Phylogenetic analyses and clustering of KP34 phage genome sequences revealed its clear relationships with "phiKMV-like viruses". Simultaneously, whole-genome analyses permitted clustering and classification of all phages, with completely sequenced genomes, belonging to the Podoviridae. PMID- 21327408 TI - Diversity of metabolic shift in response to oxygen deprivation in Corynebacterium glutamicum and its close relatives. AB - Oxygen-deprived Corynebacterium glutamicum R cells remain metabolically active, producing considerable amounts of organic acids even when not actively growing. We compared the proficiencies of C. glutamicum and close relatives grown under aerobic conditions to metabolize glucose when deprived of oxygen. Eight strains that readily consumed glucose without cell growth subsequently produced organic acids. Among these, the glucose consumption rates of the two C. glutamicum strains (>40 mM/h) and Corynebacterium efficiens (>12 mM/h) were an order of magnitude higher than those of the other five strains. The resultant organic acid yields of these three strains (>86%) consequently exceeded those of the other five (<60%). This difference is probably rooted in the comparatively inferior activities of glyceraldehyde-3-phosphate dehydrogenase, lactate dehydrogenase, and malate dehydrogenase observed in the five strains. Moreover, under oxygen deprivation, phosphoenolpyruvate carboxylase (PEPC) activity of C. efficiens was elevated tenfold, but its lack of fumarase activity meant that no succinic acid could be produced. The metabolic shift occasioned by addition of the PEPC substrate sodium bicarbonate resulted in a doubling of the glucose consumption rate of the two C. glutamicum strains but not that of the other six close relatives. PMID- 21327410 TI - Analysis of denitrifier community in a bioaugmented sequencing batch reactor for the treatment of coking wastewater containing pyridine and quinoline. AB - The denitrifier community and associated nitrate and nitrite reduction in the bioaugmented and general sequencing batch reactors (SBRs) during the treatment of coking wastewater containing pyridine and quinoline were investigated. The efficiency and stability of nitrate and nitrite reduction in SBR was considerably improved after inoculation with four pyridine- or quinoline-degrading bacterial strains (including three denitrifying strains). Terminal restriction fragment length polymorphism (T-RFLP) based on the nosZ gene revealed that the structures of the denitrifier communities in bioaugmented and non-bioaugmented reactors were distinct and varied during the course of the experiment. Bioaugmentation protected indigenous denitrifiers from disruptions caused by pyridine and quinoline. Clone library analysis showed that one of the added denitrifiers comprised approximately 6% of the denitrifier population in the bioaugmented sludge. PMID- 21327409 TI - Engineering tubulin: microtubule functionalization approaches for nanoscale device applications. AB - With the emergences of engineered devices at microscale and nanoscale dimensions, there is a growing need for controlled actuation and transport at these length scales. The kinesin-microtubule system provides a highly evolved biological transport system well suited for these tasks. Accordingly, there is an ongoing effort to create hybrid nanodevices that integrate biological components with engineered materials for applications such as biological separations, nanoscale assembly, and sensing. Adopting microtubules for these applications generally requires covalent attachment of biotin, fluorophores, or other biomolecules to tubulin enable surface or cargo attachment, or visualization. This review summarizes different strategies for functionalizing microtubules for application focused as well as basic biological research. These functionalization strategies must maintain the integrity of microtubule proteins so that they do not depolymerize and can be transported by kinesin motors, while adding utility such as the ability to reversibly bind cargo. The relevant biochemical and electrical properties of microtubules are discussed, as well as strategies for microtubule stabilization and long-term storage. Next, attachment strategies, such as antibodies and DNA hybridization that have proven useful to date, are discussed in the context of ongoing hybrid nanodevice research. The review concludes with a discussion of less explored opportunities, such as harnessing the utility of tubulin posttranslational modifications and the use of recombinant tubulin that may enable future progress in nanodevice development. PMID- 21327411 TI - Biodegradation of deltamethrin and its hydrolysis product 3-phenoxybenzaldehyde by a newly isolated Streptomyces aureus strain HP-S-01. AB - A newly isolated actinomycete strain HP-S-01 from activated sludge could effectively degrade deltamethrin and its major hydrolysis product 3 phenoxybenzaldehyde. Based on the morphological, cultural, physio-biochemical characteristics, and 16S rDNA sequence analysis, strain HP-S-01 was identified as Streptomyces aureus. Strain HP-S-01 was also found highly efficient in degrading cyfluthrin, bifenthrin, fenvalerate, fenpropathrin, permethrin, and cypermethrin. Strain HP-S-01 rapidly degraded deltamethrin without a lag phase over a wide range of temperature (18~38 degrees C) and pH (5~10), and metabolized to produce alpha-hydroxy-3-phenoxy-benzeneacetonitrile and 3-phenoxybenzaldehyde by hydrolysis of the carboxylester linkage. The 3-phenoxybenzaldehyde was further oxidized to form 2-hydroxy-4-methoxy benzophenone resulting in its detoxification. No persistent accumulative product was detected by gas chromatography-mass spectrometry (GC/MS) analysis. Response surface methodology was used to optimize degradation conditions. Strain HP-S-01 completely removed 50~300 mg L(-1) deltamethrin within 7 days under the optimal degradation conditions. Furthermore, the biodegradation kinetics corresponded with the first order model. Therefore, strain HP-S-01 is suitable for the efficient and rapid bioremediation of pyrethroid-contaminated environment. PMID- 21327412 TI - Production and characterisation of AoSOX2 from Aspergillus oryzae, a novel flavin dependent sulfhydryl oxidase with good pH and temperature stability. AB - Sulfhydryl oxidases have found application in the improvement of both dairy and baking products due to their ability to oxidise thiol groups in small molecules and cysteine residues in proteins. A genome mining study of the available fungal genomes had previously been performed by our group in order to identify novel sulfhydryl oxidases suitable for industrial applications and a representative enzyme was produced, AoSOX1 from Aspergillus oryzae (Faccio et al. BMC Biochem 11:31, 2010). As a result of the study, a second gene coding for a potentially secreted sulfhydryl oxidase, AoSOX2, was identified in the genome of A. oryzae. The protein AoSOX2 was heterologously expressed in Trichoderma reesei and characterised with regard to both biochemical properties as well as preliminary structural analysis. AoSOX2 showed activity on dithiothreitol and glutathione, and to a lesser extent on D/L-cysteine and beta-mercaptoethanol. AoSOX2 was a homodimeric flavin-dependent protein of approximately 78 kDa (monomer 42412 Da) and its secondary structure presents alpha-helical elements. A. oryzae AoSOX2 showed a significant stability to pH and temperature. PMID- 21327413 TI - Direct ethanol production from cassava pulp using a surface-engineered yeast strain co-displaying two amylases, two cellulases, and beta-glucosidase. AB - In order to develop a method for producing fuel ethanol from cassava pulp using cell surface engineering (arming) technology, an arming yeast co-displaying alpha amylase (alpha-AM), glucoamylase, endoglucanase, cellobiohydrase, and beta glucosidase on the surface of the yeast cells was constructed. The novel yeast strain, possessing the activities of all enzymes, was able to produce ethanol directly from soluble starch, barley beta-glucan, and acid-treated Avicel. Cassava is a major crop in Southeast Asia and used mainly for starch production. In the starch manufacturing process, large amounts of solid wastes, called cassava pulp, are produced. The major components of cassava pulp are starch (approximately 60%) and cellulose fiber (approximately 30%). We attempted simultaneous saccharification and ethanol fermentation of cassava pulp with this arming yeast. During fermentation, ethanol concentration increased as the starch and cellulose fiber substrates contained in the cassava pulp decreased. The results clearly showed that the arming yeast was able to produce ethanol directly from cassava pulp without addition of any hydrolytic enzymes. PMID- 21327414 TI - A new phenol oxidase produced during melanogenesis and encystment stage in the nitrogen-fixing soil bacterium Azotobacter chroococcum. AB - Laccases are copper-containing phenol oxidases that are commonly found in many types of plant, insect, fungi and bacteria. Whilst phenol oxidases have been well characterized in fungal species, laccase-type enzymes originating from bacteria have been much less well defined. Bacteria belonging to the family Azotobacteraceae share many morphological characteristics with strains already known to exhibit polyphenol and phenol oxidase activity; and hence the aim of this work was to identify and characterize a novel laccase from the isolated strain Azotobacter chroococcum SBUG 1484 in an attempt to provide further understanding of the roles such enzymes play in physiological development. Laccase activity was clearly observed through oxidation of 2,6-dimethoxyphenol, other typical substrates including: methoxy-monophenols, ortho- and para diphenols, 4-hydroxyindole, and the non-phenolic compound para-phenylenediamine. A. chroococcum SBUG 1484 showed production of a cell-associated phenol oxidase when grown under nitrogen-fixing conditions, and was also observed when cells enter the melanogenic and encystment stages of growth. Catechol which is structurally related to melanin compounds was also released from Azotobacter cells into the surrounding culture medium during nitrogen-fixing growth. From our results we propose that a membrane-bound laccase plays an important role in the formation of melanin, which was monitored to correlate with progression of A. chroococcum SBUG 1484 cells into the encystment stage of growth. PMID- 21327415 TI - Early onset scoliosis: editorial comment. PMID- 21327416 TI - Frequency, risk factors, and prognosis of prolonged delirium in elderly patients after hip fracture surgery. AB - BACKGROUND: Delirium in elderly patients after hip fracture surgery is believed to be a transient event, although it frequently lasts for more than 4 weeks. QUESTIONS/PURPOSES: We determined the incidence, risk factors, morbidity, and mortality of prolonged delirium in elderly patients after hip fracture surgery. PATIENTS AND METHODS: We evaluated 232 elderly patients (older than 65 years) (232 hips) who underwent hip fracture surgery for the development and duration of delirium and categorized them into three groups; nondelirium group, transient (<= 4 weeks) delirium group, and prolonged (> 4 weeks) delirium group. Patients underwent a global geriatric evaluation, which included postoperative complications, mortality, and functional and mental status evaluations. The three groups were compared with respect to these variables. RESULTS: Seventy patients (30.2%) had delirium develop, and among these, 14 (20%) had prolonged delirium with a total incidence of 6%. Multivariate analysis showed preinjury dementia was a risk factor of prolonged delirium. At the final followup, five (62.5%) of the eight patients who were ambulatory outdoors in the prolonged delirium group became housebound, whereas only 18 (16.4%) of the 110 patients who were ambulatory outdoors in the nondelirium group became housebound. Survival at 40 months was 81.0% (95% confidence interval, 72.6%-89.3%) in the nondelirium group and 63.6% (95% confidence interval, 35.2%-92.1%) in the prolonged delirium group. CONCLUSIONS: Prolonged delirium was found to be associated with a poor functional outcome and increased mortality. LEVEL OF EVIDENCE: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 21327417 TI - Androgen receptor CAG repeat size is associated with stress fracture risk: a pilot study. AB - BACKGROUND: Stress fractures commonly affect military recruits during basic training. Several lines of evidence suggest genetic factors are involved in stress fracture predisposition. As gender steroid hormone levels and activity have been implicated in affecting bone strength, one of the candidate genes likely to be involved is the androgen receptor gene. QUESTIONS/PURPOSES: We assessed the possible involvement of the androgen receptor gene in stress fracture predisposition in Israeli soldiers. PATIENTS AND METHODS: Between January 2007 and December 2009, we collected clinical and imaging data from 454 Israeli soldiers referred for bone scans with clinical symptoms compatible with stress fractures: 171 soldiers (154 men, 17 women) (patients) with bone scan proven stress fractures and 283 soldiers (242 men, 41 women) with normal bone scans (control subjects). All participants were genotyped for the length of the CAG (cytosine-adenine-guanine) repeat in exon 1 of the androgen receptor gene using PCR and subsequent fragment analysis on sequence analyzer. RESULTS: The androgen receptor gene CAG repeat was ranged between six and 31 (mean +/- SD, 20.6 +/- 4.3) among patients and between 11 and 32 (mean +/- SD, 20.0 +/- 3.8) among control subjects. Smaller-sized (< 16) androgen receptor CAG repeats were more prevalent among control subjects (23%) than among patients (13%); the risk for having SFs was almost halved if the size of the repeat was shorter than 16 repeats. CONCLUSIONS: The androgen receptor gene CAG repeat has a different allele distribution among Israeli soldiers with stress fractures than in control subjects. While our finding must be validated, it could be used for screening individuals at risk for stress fractures. LEVEL OF EVIDENCE: Level II, prognostic study. See the Guidelines for Authors complete description of levels of evidence. PMID- 21327419 TI - Multiple coloured ornaments in male common kestrels: different mechanisms to convey quality. AB - The simultaneous exhibition of more than one secondary sexual trait is a widespread phenomenon in nature, though it has rarely been explored. It has been proposed that different ornaments may convey complementary or back-up information about a single aspect of individual quality (redundancy hypothesis) or that each ornament may convey unique information (multiple-messages hypothesis). During a 5 year period, we measured several carotenoid-based (eye ring, bill cere and tarsi skin) and melanin-based (head, back, rump and tail feathers) potential ornamental colours in male common kestrels. We analysed whether multiple ornaments can convey different or related information about individual quality. We explored whether different ornaments can express different information depending on the pigment (carotenoids or melanins), the time-scale over which the ornament can change (dynamic vs. static) and the season of the year when the ornament is formed. We found that both melanin- and carotenoid- based traits correlated with indexes of quality, including body condition, body condition of their partners and laying date. However, not all ornaments correlated with the same measures of quality. In addition, some ornaments were intercorrelated within the same individuals while others were not. These results suggest that different ornaments can convey information about different qualities, as predicted by the multiple messages hypothesis. In addition, this study suggests that the predominant pigment (e.g. carotenoid vs. melanin, eumelanin vs. pheomelanin), the time-scale over which the trait is developed (static feathers vs. dynamic skin) and the season of the year at which the ornament is produced can be potential mechanisms to convey different messages in male common kestrels. PMID- 21327421 TI - Retrospective study of the impact of pharmacogenetic variants on paclitaxel toxicity and survival in patients with ovarian cancer. AB - PURPOSE: Paclitaxel has a broad spectrum of anti-tumor activity and is useful in the treatment of ovarian, breast, and lung cancer. Paclitaxel is metabolized in the liver by CYP2C8 and CYP3A4 and transported by P-glycoprotein. The dose limiting toxicities are neuropathy and neutropenia, but the interindividual variability in toxicity and also survival is large. The main purpose of this study was to investigate the impact of genetic variants in CYP2C8 and ABCB1 on toxicity and survival. METHODS: The 182 patients previously treated for ovarian cancer with carboplatin and paclitaxel in either the AGO-OVAR-9 or the NSGO OC9804 trial in Denmark or Sweden were eligible for this study. Genotyping was carried out on formalin-fixed tissue. The patients' toxicity profiles and survival data were derived from retrospective data. CYP2C8*3, ABCB1 C1236T, G2677T/A, and C3435T were chosen a priori for primary analysis; a host of other variants were entered into an exploratory analysis. RESULTS: Clinical data and tissue were available from a total of 119 patients. Twenty-two single nucleotide polymorphisms (SNPs) in 10 genes were determined. Toxicity registration was available from 710 treatment cycles. In the primary analysis, no statistically significant correlation was found between CYP2C8*3, ABCB1 C1236T, G2677T/A, and C3435T and neutropenia, sensoric neuropathy, and overall survival. CONCLUSION: CYP2C8*3 and the ABCB1 SNPs C1236T, G2677T/A, and C3435T were not statistically significantly correlated to overall survival, sensoric neuropathy, and neutropenia in 119 patients treated for ovarian cancer with paclitaxel/carboplatin. PMID- 21327420 TI - Current and future treatment options in osteoporosis. AB - PURPOSE: The incidence of osteoporosis-related fractures will increase substantially over the coming decades as the population ages globally. This has important economic and public health implications, contributing substantially to morbidity and excess mortality in this population. METHODS: When prescribing for older patients the effectiveness profile of drugs needs to be balanced against their tolerability in individual patients. RESULTS: Currently we have good anti fracture data to support the use of many available anti-resorptive and anabolic drugs including bisphosphonates, strontium ranelate and recombinant human parathyroid hormone. We also have evidence to demonstrate the importance of calcium and vitamin D repletion in these patients. However, in recent years our understanding of normal bone physiology and the mechanisms underlying the development of osteoporosis has significantly advanced and this has led to the development of new therapies. Novel agents, particularly denosumab, but also inhibitors of cathepsin K and anabolic agents that act on Wnt signalling, will increase the therapeutic options for clinicians in the coming years. CONCLUSION: This review discusses the evidence supporting the use of currently available treatment options for osteoporosis and potential future advances in drug therapy. Particular consideration should be given when prescribing for certain older patients who have issues with compliance or tolerance and also in those with co morbidities or levels of frailty that may restrict the choice of therapy. Understanding the evidence for the benefit and possible harm of osteoporosis treatments is critical to appropriate management of this patient population. PMID- 21327422 TI - Gastrointestinal safety of triflusal solution in healthy volunteers: a proof of concept endoscopic study. AB - PURPOSE: Triflusal is an antiplatelet agent that irreversibly acetylates cyclooxygenase isoform 1 (COX-1) and therefore inhibits thromboxane biosynthesis. It was initially marketed as capsules containing 300 mg of active substance. In 2006 a new 600 mg (10 ml) oral solution form of triflusal was authorized in Spain. The primary aim of this study was to compare the gastrointestinal safety of the new triflusal oral solution with triflusal capsules in healthy volunteers. METHODS: Sixty healthy subjects were randomly assigned, in a 2.5:2.5: 1 ratio, into one of three groups, with 25 subjects receiving one bottle of triflusal oral solution (600 mg) daily, 25 subjects receiving two triflusal capsules (600 mg) once daily, and ten subjects receiving two placebo capsules once daily, respectively, during 7 consecutive days. Gastroscopy was performed at baseline before the administration of study drugs and after 4-8 h of the last dose of study drugs. Effects on the esophagus, stomach, and duodenum were measured in accordance with a modified Lanza scale. RESULTS: No differences between groups were detected at baseline. After treatment, median global scores in the placebo, triflusal solution, and triflusal capsules groups were, respectively, 0, 1, and 3 (p = 0.003 for comparison between placebo and triflusal capsules and p = 0.042 for comparison between triflusal solution and triflusal capsules). There were no significant differences between the scores on the triflusal solution and placebo groups. All treatments were well tolerated. CONCLUSION: In healthy subjects, triflusal solution induced less endoscopically apparent gastrointestinal mucosal damage than triflusal capsules and did not induce more damage than the placebo in healthy volunteers. PMID- 21327423 TI - Healthcare-associated infections in rheumatology in Japan. AB - Prospective observational study was performed to elucidate the incidence and characteristics of healthcare-associated infections in a university hospital for rheumatology care. In this study, a total of 1,226 patients were prospectively enrolled between March 2004 and February 2006 and between April 2008 and December 2008. Healthcare-associated infection was defined as an infection developing after the third day of admission to the rheumatology ward. We detected the following 54 healthcare-associated infections in 49 patients: respiratory tract infection, 14 cases; Clostridium difficile infection, 2 cases; urinary tract infection, 4 cases; bloodstream infection, 9 cases; skin infection, 2 cases; reactivation of latent cytomegalovirus infection, 6 cases; herpes zoster infection, 5 cases; Candida infection, 7 cases; others, 4 cases. The incidence rate of respiratory tract infection was the highest. Methicillin-resistant Staphylococcus aureus was the causative bacterium in 21% of respiratory tract infections cases. Bloodstream infection due to the insertion of a catheter and opportunistic infection by a latent virus were also occurred commonly. Respiratory tract infection, bloodstream infection and opportunistic infection by a latent virus were the most common causes of healthcare-associated infection in rheumatology. It is important to pay more attention to healthcare-associated infection. PMID- 21327424 TI - A case of primary Sjogren's syndrome presenting primarily with central nervous system vasculitic involvement. AB - Sjogren's syndrome is primarily a chronic systemic autoimmune disease that affects exocrine organs. Neurologic symptoms frequently present as peripheral neuropathy due to small vessel vasculitis. Type and prevalence of central nervous system involvement are still controversial. In this report, we present a 35-year old woman with primary Sjogren's syndrome with central nervous system vasculitic involvement. PMID- 21327425 TI - Extraarticular manifestations in Turkish patients with rheumatoid arthritis: impact of EAMs on the health-related quality of life in terms of disease activity, functional status, severity of pain, and social and emotional functioning. AB - The aim of our study was to investigate extraarticular manifestations (EAMs) in Turkish patients with rheumatoid arthritis (RA) and also assess the impact of EAMs on various health-related quality of life (HRQoL) domains, including physical, social, emotional, mental functioning, and bodily pain. A total of 150 patients were included in the study. EAMs were identified clinically. Pulmonary involvement was confirmed by using pulmonary function tests (PFT) and high resolution computed tomography (HRCT), atlantoaxial subluxation by cervical spine X-rays. Peripheral neuropathy, rheumatoid nodules, and Sicca symptoms were picked up on clinical examination. Peripheral neuropathy was also confirmed by electroneurophysiologic studies. Patients were evaluated by Rheumatoid Arthritis Quality of Life (RAQoL), and Short form-36 (SF36). The quadrivariate Disease Activity Score- 28 (DAS28) was used for measuring disease activity. Functional status was evaluated by using the Stanford Health Assessment Questionnaire (HAQ). The severity of pain was documented by using 10-cm Visual Analog Scale-Pain (VAS pain). EAMs were observed in 50 patients (33.3%). These were pulmonary involvement (28.7%), rheumatoid nodules (14.7%), Sicca Syndrome (8%), peripheral neuropathy (2.7%), and atlantoaxial subluxation (0.7%), respectively. It was not recorded any statistically significant difference in HAQ, DAS28, VAS-pain, and RAQoL scores between the patient groups with and without EAMs. Patients with EAMs scored significantly lower in physical functioning, role-physical, and role emotional subgroups of SF36 (P < 0.01). Presence of EAMs is not directly associated with disease activity and functional status, but influences negatively HRQoL including physical and emotional functioning. PMID- 21327426 TI - High frequency of osteoporosis and fractures in women with dermatomyositis/polymyositis. AB - Bone mass was only previously studied in juvenile dermatomyositis/polymyositis (DM/PM) patients. Therefore, the objective this study was to evaluate the prevalence of osteoporosis and fractures in adult DM/PM. Forty female DM/PM and 78 age-, gender-, and BMI-matched healthy controls were studied. Medical charts and clinical interviews of all patients were evaluated for demographic and clinical data, including disease activity, cumulative doses of glucocorticoid, menarche and menopause age, and fractures. Bone mineral density (BMD) using dual X-ray absorptiometry (DXA) were measured at lumbar spine (L1-L4) and hip. A decreased BMD in lumbar spine [0.902 (0.136) vs. 0.965 (0.141) g/cm(2), P = 0.022] and femoral neck [0.729 (0.12) vs. 0.784 (0.127) g/cm(2), P = 0.027] was observed in patients compared to controls. In addition, osteoporosis was more frequent in patients than in controls in both lumbar spine (20 vs. 3.8%, P = 0.007) and the femoral neck (27.5 vs. 10.3%, P = 0.016). Moreover, a high prevalence of fractures was found in patients in comparison to healthy subjects (17.9 vs. 5.1%, P = 0.040; OR = 3.92; CI 95%:1.07-14.33). Comparing DM/PM patients with (n = 17) and without (n = 23) osteoporosis/fractures, significant differences were observed regarding age [56.8 (11.9) vs. 48.3 (13.2) years, P = 0.042], weight [62.05 (13.56) vs. 71.51 (11.46) kg, P = 0.022] and frequency of post menopausal women (94.1 vs. 65.2%, P = 0.0002). No differences were observed concerning height, lean mass, total fat mass, disease activity, mean value of creatine kinase, cumulative glucocorticoid dose, or bisphosphonate use. Logistic regression analysis revealed a negative association between the presence of osteoporosis/fractures and weight (OR: 0.92, 95% CI: 0.85-0.98; P = 0.016). This is the first study that analyzed bone mass in adult DM/PM patients and it demonstrated that about one quarter of these patients have osteoporosis/fracture. PMID- 21327427 TI - Metastatic lymph node 51 and fibroblast-like synoviocyte hyperproliferation in rheumatoid arthritis pathogenesis. AB - One of the varied characteristic features of the pathogenesis of rheumatoid arthritis (RA) is synovial hyperplasia. Fibroblast-like synoviocytes (FLSs) play a key role in the development of sustained inflammation in arthritic joints. We have reported previously that metastatic lymph node 51 (MLN51) is involved in the proliferation of FLSs in the pathogenesis of RA. Interestingly, the overexpression of MLN51 was observed only in RA FLSs, but not in osteoarthritis FLSs, possibly expecting that MLN51 may be a RA-specific marker. Additionally, we found that granulocyte-macrophage colony-stimulating factor signaling activates mitogen-activated protein kinase, followed by the upregulation of MLN51 and FLICE inhibitory protein, resulting in FLS hyperplasia in RA. Based on these studies, we could be firm that MLN51 is a key factor in FLS hyperplasia of RA patients. PMID- 21327428 TI - Antigen-induced arthritis in rabbits: a comparative study between high-resolution ultrasound and contrast-enhanced ultrasound and pathologic findings. AB - The objective of this study was to explore the feasibility and value of high resolution ultrasound and contrast-enhanced ultrasound in evaluation of synovitis in rabbit knee joint in antigen-induced arthritis (AIA). Thirty-six rabbits were divided into three groups, each injected with different doses of ovalbumin (OVA) into the right knee joint. On week 1 and 4, 6 randomly selected in each group were killed. Each knee joint undergone the high-resolution ultrasound to measure capsule thickness and contrast-enhanced ultrasound to measure synovium thickness. The results from the ultrasound examinations were compared with those of pathologic examinations. Different OVA doses resulted in different modeling success rate, different pathological synovitis score, and different capsule and synovium thickness measured by ultrasound. The diagnostic accuracy of synovitis by ultrasound was high. The ultrasound measurement revealed that the capsule thickness on week 4 was lessened than that on week 1, while the synovial thickness on week 4 was greater than that on week 1. Both the joint capsule and synovium thickness measured by ultrasound were significantly and positively correlated to the pathologic synovitis score (P < 0.05). The synovial thickness on week 4 is more correlated to the synovitis score than the capsule thickness, rather than that on week 1. Injection of OVA of different doses results in different modeling success rate and synovitis severity. The high-resolution ultrasound and contrast-enhanced ultrasound can be used to determine whether the AIA was made successfully and evaluate the synovitis severity. In chronic inflammatory phase, the contrast-enhanced ultrasound has better effect. PMID- 21327429 TI - Pregnancy-associated spinal osteoporosis treated with bisphosphonates: long-term follow-up of maternal and infants outcome. AB - Pregnancy-associated spinal osteoporosis (PPSO) is a rare condition characterized by severe back pain occurring near the end of the first pregnancy or shortly afterward. The aim of this report is to present a 12-year follow-up of a patient with PPSO. Also, the outcomes of patient's two pregnancies and her infants after long-term treatment with bisphosphonates are assessed. A young woman was referred to our tertiary care hospital aged 30 years, due to intense pain in thoracic and lumbar region that started during the last month of her first pregnancy and got worse after delivery. Bone mineral density (BMD) measurement, clinical, and biochemical parameters were performed. Extremely low lumbar spine BMD, L2-L4: 0.627 g/cm(2), T-score -4.8, Z-score -4.3, 52% young adult indicated severe osteoporosis. Cyclical treatment with etidronate and then pamidronate was started, and a substantial increase in the BMD and the reduction in back pain intensity were observed. An increase in BMD of 44.8% over baseline was observed after 12 years of follow-up. Her two pregnancies were uneventful, and no neonatal adverse effects were observed. Control DXA scan in her girl child aged 6.8 years revealed low BMD at the lumbar spine. As PPSO seems to be an underdiagnosed severe disease, caution is recommended if back pain occurs in the last trimester or early post-partum period. Although pre-pregnancy use of bisphosponates does not pose a substantial fetal risk, their use in women of childbearing age might best be done only when strong clinical indications exist. PMID- 21327430 TI - Delayed diagnosis of Kawasaki syndrome and thrombosis of a medium-sized aneurysm of the anterior descending coronary artery: case report and literature review. AB - A 7-year-old child was first admitted for persistent fever of 15-day duration and suspected meningitis. Kawasaki syndrome was lately diagnosed upon the recognition of an extensive diffuse coronary artery damage characterized by medium-sized aneurysms of the epicardial vessels. An eccentric thrombus along the inferior wall of the left anterior descending artery suspected at transthoracic echocardiography was confirmed by coronary computed tomography angiography scan, without significant segmental stenosis. Strict cardiac surveillance and anticoagulant therapy were maintained, and no ischemic complications occurred at a short-term follow-up. This report emphasizes that thrombosis can be observed even in medium-sized aneurysms when the diagnosis of Kawasaki syndrome is delayed. PMID- 21327431 TI - Increased levels of rheumatoid factors after TNF inhibitor in rheumatoid arthritis. AB - Targeted inhibition of tumor necrosis factor-alpha (TNF-alpha) is an effective therapy in rheumatoid arthritis (RA). In some rare cases, autoimmune phenomena, including drug-induced lupus and vasculitis, is described. However, the immunological mechanisms underlying the development of autoimmunity are unknown. We report 3 patients that developed autoimmune phenomena while in use of TNF alpha inhibitor, showing concomitant increase in rheumatoid factor (RF). We hypothesize that the increase in RF several months prior to the occurrence of vasculitis may help identifying other patients at risk for the development of vasculitis secondary to these medications. PMID- 21327432 TI - Vaccination survey in patients with rheumatoid arthritis: a cross-sectional study. AB - The objective of this study is to evaluate the vaccination status in rheumatoid arthritis (RA) patients during routine clinical practice, data from a German non interventional cross-sectional study. In this prospective study, patients with rheumatoid arthritis were interviewed using a standardized questionnaire focusing on vaccination. Available vaccination documents were evaluated, and titers for common vaccination antigens (hepatitis B, rubella, mumps, measles, diphtheria, tetanus) were analyzed with special regard to the underlying treatment and age of patients. A total of 301 RA patients treated with conventional DMARDs alone (cohort I, n = 125), TNF-blocking agents (cohort II, n = 117), or B-cell depletion with rituximab (cohort III, n = 59) have been studied. Significantly more patients in the biologic cohorts II and III were aware of an increased risk of infections (I: 67.7%, II: 83.8%*, III: 89.9%*, P < 0.05). Pneumococcal vaccination rate was significantly higher (I: 20.2%, II 36.8%* and III: 39.0%*, P < 0.05) compared with cohort I. Differences were less evident for influenza. Significantly more patients >=60 years of age have been vaccinated against Streptococcus pneumoniae and influenza. An obvious discrepancy existed between vaccination awareness and actual vaccination rates for all cohorts. No significant differences in vaccination titers could be seen between the three cohorts. Awareness of infectious complications was more present in patients treated with biologicals, and also, the rate of patients vaccinated against Streptococcus pneumoniae increased significantly depending on the underlying treatment. Nevertheless, there was a discrepancy between vaccination awareness and actual vaccination rates for all cohorts. PMID- 21327433 TI - Predictive factors related to progression toward rheumatoid arthritis in Korean patients with undifferentiated arthritis. AB - Some patients with undifferentiated arthritis (UA) experience spontaneous remission; however, one-third of patients progress to rheumatoid arthritis (RA) in the final process of the disease. This study evaluated clinical variables in order to find a prediction model that could predict the development of RA in patients with UA. The medical records of 164 patients, who were initially diagnosed with undifferentiated arthritis in Yonsei University Medical Center from January 2004 to December 2007, were retrospectively reviewed. They were followed up for at least 6 months. The clinical variables related to the development of RA were identified by univariate analyses. Using logistic regression analysis, the prediction model was made and the diagnostic performance of the model was evaluated. Thirty-two patients of the 164 total patients progressed to RA during the follow-up period. The prediction model was composed of clinical factors including the duration of morning stiffness, the number of tender joints, the number of swollen joints, C-reactive protein level, rheumatoid factor, anti-cyclic citrullinated peptide antibody, and erosive change on baseline X-ray. The prediction score ranged from 0 to 10. All of the patients with a higher prediction score greater than five experienced RA progression. The area under the curve value for the prediction rule was 0.976. The prediction model could predict progression to RA in patients with UA. It especially helps the clinician to decide on a management plan for patients with a high prediction score. PMID- 21327434 TI - Atypical presentation of scleroderma in infancy. AB - We present a case of a female child who had developed progressive skin tightening of whole body, sclerodactyly, and severe contracture of all joints with restricted opening of mouth with disease onset at 6 weeks of life. The child also had anemia, failure to thrive, recurrent diarrhea, and ascites. Skin biopsy revealed characteristic histopathological features suggestive of scleroderma. Echocardiography revealed thrombus in the right atrium extending to inferior vena cava. Serological markers (antinuclear antibody, antiscl 70, anti-double-stranded DNA, anticentromere antibody) were negative. To our knowledge, this case of scleroderma with disease onset at 6 weeks of life could possibly be among youngest cases reported in the literature. Also, thrombosis in inferior vena cava in a child with scleroderma is being reported for the first time. PMID- 21327435 TI - Validity and reliability of the Turkish version of the Health Assessment Questionnaire for the Spondyloarthropathies. AB - The Health Assessment Questionnaire for Spondyloarthropathies (HAQ-S) was built by adding five new questions related with cervical and lumbar spine functions to HAQ by Daltroy et al. (in J Rheumatol 17(7):946-945, 1990). The aim of this study was to adapt the added five items into Turkish and then to test its reliability and validity. New questions were adapted to Turkish according to 'translation back translation' method. Seventy-nine patients with ankylosing spondylitis were asked with the Turkish version of HAQ-S (HAQ-S TV). To assess, construct validity patients were evaluated by HAQ, Bath AS Functional Index (BASFI), Bath AS Disease Activity Index (BASDAI), Bath AS Metrology Index (BASMI), Maastricht AS Enthesitis Score (MASES), Ankylosing Spondylitis Quality of Life (ASQoL), and laboratory variables (erythrocyte sedimentation rate, C-reactive protein). Construct validity was investigated with Spearmann's rank correlation coefficient. Reliability of HAQ-S TV was assessed by internal consistency. Inter- and intra-observer reliability were tested with Cronbach's alpha score. HAQ-S TV met set criteria of reliability and validity. Reliability of adapted version was found good with high internal consistency value. (Cronbach's alpha = 0.89). In addition to this intra-observer and inter-observer reliability were found adequate for total score of HAQ-S (Cronbach's alphas: 0.999 and 0.998 in order) and also for each added five questions (Cronbach's alphas >0.7). Positive correlations were found between HAQ-S TV and HAQ, BASFI, BASDAI, BASMI, MASES, ASQoL, ESR, and CRP (P < 0.05). The results of this study showed that HAQ-S TV was reliable and valid in patients with AS. PMID- 21327436 TI - Safety and effectiveness responses to etanercept for rheumatoid arthritis in Japan: a sub-analysis of a post-marketing surveillance study focusing on the duration of rheumatoid arthritis. AB - The aim is to investigate the relationship of duration of rheumatoid arthritis (RA) with safety and effectiveness of etanercept (ETN) in Japan. Post-marketing surveillance data for 7,099 patients treated with ETN were analyzed. Baseline characteristics, treatment effectiveness, incidence of adverse events (AEs), and serious AEs (SAEs) in relation to duration of RA were studied. At baseline, patients with RA for longer duration were older, weighed less, had more comorbidities, allergies, and corticosteroid use, but smoked less and had less morning stiffness. By 2-5 years with RA, more than half of the patients had advanced to Steinbrocker radiographic stage III or IV. Methotrexate (MTX) was the most commonly used pre-treatment disease-modifying antirheumatic drug; however, concomitant MTX use and its dose were lower among patients with longer duration of RA. Remission rates (26.6%) were greatest among patients having RA for <2 years. Less AEs and SAEs were observed among patients with shorter duration of RA. These results suggest that RA treatment in Japan in the era pre-biologics may not have been adequate to control disease activity and prevent joint destruction. Patients with shorter duration of RA may have better physical status which allows the opportunity to treat more intensively putting a higher percentage of patients in remission and possibly decreasing exposure to SAEs. PMID- 21327437 TI - Effects of pulsed electromagnetic fields on the mRNA expression of CAII and RANK in ovariectomized rats. AB - The present study was designed to determine the effects of pulsed electromagnetic fields (PEMFs) on the mRNA expression of the carbonic anhydrase II (CAII) and receptor activator of NF-kappaB (RANK) in ovariectomized rats. A total of 48 SD rats were randomly divided into four groups [Sham, OVX, PEMFs, and E(2) (premarin)], 12 rats in each group. Rats in the Sham group received sham ovariectomy, while rats in OVX, PEMFs, and E(2) groups received ovariectomy. Twelve weeks following the surgery, rats (whole body) in the PEMFs group were exposed to PEMFs for 30 days with 3.8 mT, 8 Hz, and 40 min per day; rats in the E(2) group were administered premarin (0.0625 mg/kg/d; intragastric administration 1-2 ml/100 g). Rats in the Sham and OVX groups housed in the same conditions. At the end of intervention, the level of serum estradiol of rats was measured. The gene expression of CAII and RANK in the left ilium of rats was determined with real-time fluorescent-nested quantitative polymerase chain reaction. Compared with the Sham group, the level of serum estradiol in the ovariectomized group was significantly decreased (P < 0.05); compared with the OVX group, CAIImRNA expression was significantly decreased in the PEMFs group and E group (P < 0.05, 0.01, respectively). Compared with the E group, RANKmRNA expression was significantly higher in the PEMFs group (P < 0.05); although RANKmRNA expression decreased in PEMFs group, no statistically significant difference was found between PEMF group and OVX group (P = 0.82). These data suggest that PEMFs could regulate the expression of CAIImRNA in ovariectomized rats. PMID- 21327438 TI - Effect of resveratrol on cartilage protection and apoptosis inhibition in experimental osteoarthritis of rabbit. AB - To observe the effect of resveratol on cartilage, chondrocyte apoptosis, and nitric oxide in experimental osteoarthritis (OA) of rabbit and to study the mechanism of resveratol in the treatment of osteoarthritis. Thirty New Zealand rabbits were randomly divided into 5 groups: group A (normal control group), group B (model control group), group C (resveratrol intervention high-dosage group), group D (resveratrol intervention middle dosage group), and group E (resveratrol intervention low-dosage group). The model of OA of the knee was established using Hulth technique in groups B, C, D, and E. After 4 weeks, group A and group B rabbits were administered daily a knees injection of dimethylsulfoxide (DMSO), whereas groups C, D, and E were administered daily a knees injection of resveratrol in DMSO in different dosages for 2 weeks. Daily dosage for rabbits of groups C, D, and E was fixed at 50, 20, and 10 MUmol/kg, respectively. Then, the rabbits were killed, and the lateral cartilage sections of right femoral medial condyle were evaluated using a histological scoring system (H&E and safranin-O staining) and analyzed by TUNEL for apoptosis. Nitric oxide (NO) in synovial fluid was measured by nitrate reduction method. Histological evaluation of cartilage tissue revealed a significantly reduced cartilage destruction; the evaluation also revealed the loss of matrix proteoglycan content in cartilage in resveratrol intervention groups compared to the model control. Resveratrol reduced the apoptosis rate of chondrocyte and level of NO in the synovial fluid. In the above experiments of OA rabbits, the protective effects of resveratrol were enhanced with increased resveratrol dosage. Resveratrol controls the progression of experimental OA. One of the mechanism(s) responsible for this effect would include lowering of the apoptosis rate of chondrocyte and reducing the production of NO in experimental OA. PMID- 21327439 TI - Epstein-Barr virus (EBV)-associated primary central nervous system lymphoma: is incidence of EBV expression associated with median survival time? AB - The frequency and clinical features of Epstein-Barr virus (EBV)-associated primary central nervous system lymphoma (PCNSL) in elderly patients were investigated in this study. Thirty-three PCNSL cases were enrolled in the retrospective study. Biopsies were performed, and tissue was embedded in paraffin and sectioned. In-situ hybridization of EBV-encoded small RNAs was then conducted. Specimens were scored as having one of three possible results: negative (no EBV-positive cells), slightly positive (<50% EBV-positive cells), and strongly positive (>50% EBV-positive cells). Fifteen cases were negative for EBV expression. Sixteen cases were slightly positive, and two cases (68 and 79 years of age) were strongly positive. The incidence of strongly positive EBV expression in PCNSL was 6.1%. The incidence of strongly positive EBV expression in PCNSL patients >=65 years of age was 13%. Median survival time differed significantly among PCNSL patients treated with high-dose methotrexate and radiotherapy. Importantly, the strongly EBV-positive PCNSL cases had the worst outcomes, and the EBV-negative PCNSL cases had the best outcomes. These results suggest that EBV infection may affect the treatment outcome of PCNSL. In the future, examination of EBV expression in PCNSL patients who receive individualized treatment may be useful. PMID- 21327440 TI - Management of adjuvant S-1 therapy after curative resection of gastric cancer: dose reduction and treatment schedule modification. AB - BACKGROUND: The aim of this study was to determine the optimal management of adjuvant S-1 therapy for stage II or III gastric cancer, encompassing the details of dose reduction and treatment schedule modification. METHODS: We retrospectively examined 97 patients with stage II or III gastric cancer who received S-1 chemotherapy following gastrectomy between January 2003 and December 2007. S-1 (80 mg/m2 per day) was orally administered twice daily for 4 weeks, followed by a 2-week rest. As a rule, treatment was continued for 1 year after gastrectomy. Dose reduction or treatment schedule modification was performed according to toxicity profiles. RESULTS: Among the 97 patients, 57 (59%) underwent dose reduction at least once and 39 (40%) received treatment schedule modification. Of the 57 patients who required dose reduction, 45 (79%) underwent reduction within 3 months of the beginning of treatment. The most common reasons for dose reduction were anorexia (47%), followed by diarrhea (32%), leukopenia (24%), and rash (16%), with the reasons overlapping. Although the difference in the requirement for dose reduction was not significant, patients with a low creatinine clearance level or those who underwent total gastrectomy had a greater tendency to require dose reduction. The duration of the S-1 treatment period was at least 3 months in 88% of the patients, at least 6 months in 82%, and the planned 1-year period in 73% of the patients. CONCLUSIONS: In most patients, the planned 1-year adjuvant S-1 therapy for stage II or III gastric cancer could be completed by modifying the dose reduction and treatment schedule. PMID- 21327441 TI - Neuroendocrine tumors of the stomach: chemotherapy with cisplatin plus irinotecan is effective for gastric poorly-differentiated neuroendocrine carcinoma. AB - BACKGROUND: Neuroendocrine tumors (NETs) occur in various primary sites, but rarely in the stomach. NETs are classified into three types, carcinoids, malignant carcinoids and poorly differentiated neuroendocrine carcinomas (PNECs), whose clinical behavior is different. Currently, clinical outcomes and standard chemotherapy for NETs of the stomach remain unclear. METHODS: We conducted a retrospective review of histopathologically confirmed NETs of the stomach at our hospital between January 2000 and August 2006. RESULTS: Thirty-seven NETs were identified. Fifteen patients had carcinoids while 22 had PNECs. Among the carcinoid patients, 7 underwent endoscopic mucosal resection and 5 had gastrectomy as first-line treatment. Three patients were observed without intervention. All patients were alive after an average follow-up period of 27 months. Among the 22 PNEC patients, 3 had no metastasis, 11 had regional lymph node metastasis, and 8 had distant metastasis. Eight of 14 patients relapsed at a median of 177 days (range 120-1459 days) after curative surgery. Twelve patients with metastatic or recurrent disease received palliative cisplatin plus irinotecan chemotherapy. The response rate was 75%, the median progression-free survival time was 212 days, and median survival time was 679 days. CONCLUSION: Gastric PNEC patients with distant metastasis had poor outcomes. Regimens containing cisplatin plus irinotecan produced a good response in gastric PNEC. PMID- 21327442 TI - Nutritional recovery after open and laparoscopic gastrectomies. AB - BACKGROUND: The aim of this study was to evaluate longitudinal changes in body composition after laparoscopic and open gastrectomies for gastric cancer. METHODS: Body mass, arm muscle mass, leg muscle mass, and fat mass were measured by performing a bioelectrical impedance analysis using a "Bodyscan" body composition analyzer (HXE19-JA; Konami, Tokyo, Japan) in 41 patients who had undergone gastrectomy: 14 patients underwent open distal gastrectomy, 8 patients underwent open total gastrectomy, and 19 patients underwent laparoscopy-assisted distal gastrectomy. All measurements were obtained preoperatively and at 1, 3, and 6 months after the operation. RESULTS: Fat mass decreased significantly throughout the 6-month period after distal gastrectomy and until 3 months after the laparoscopic surgery, while similar reductions in the total muscle mass and limb muscle mass were observed only in the first month after operation for all three groups. Patients with the laparoscopic approach had completely regained muscle mass at 6 months postoperatively. CONCLUSION: Both fat and muscle mass reductions were responsible for the body weight loss during the first postoperative month, whereas loss of fat mass contributed to further weight loss after that period. Enhanced recovery of muscle mass at 6 months after laparoscopic surgery suggests the benefit of this surgery, among other factors. PMID- 21327443 TI - Survival and prognosticators of gastric cancer that recurs after adjuvant chemotherapy with S-1. AB - BACKGROUND: Some patients experience a recurrence of cancer even after curative D2 gastrectomy followed by adjuvant S-1 chemotherapy. The objective of this retrospective study was to clarify the survival and prognosticators in these patients. METHODS: The study selected patients who underwent curative D2 surgery, were diagnosed with stage II, IIIA, or IIIB cancer, received adjuvant S-1 for more than 4 weeks, and experienced recurrence confirmed by an imaging study. RESULTS: A total of 34 patients were evaluated. The median overall survival (OS) was significantly longer in the 26 patients who received palliative chemotherapy than that in the 8 who did not (8.5 vs. 2.5 months, P = 0.002). Only 1 patient received S-1, 21 received taxane-containing regimens, and 4 received irinotecan plus cisplatin as the first-line chemotherapy. Univariate and multivariate analyses showed that the histological type was only independent significant prognosticator. CONCLUSIONS: These results suggested that the survival did not reach the level expected for first-line chemotherapy. The histological type was a significant prognosticator in patients who experienced recurrence after adjuvant S-1 therapy and thereafter received palliative chemotherapy. PMID- 21327444 TI - Influence of laser wavelength on the damage of comb's vasculature by photodynamic therapy--simulation and validation of mathematical models. AB - Lasers of different wavelengths have been used as a photodynamic therapy (PDT) light source in the treatment of port-wine stains. This study attempts to investigate the influence of wavelength on depth of vascular damage using a cock comb model and mathematical modeling/simulation. Monte Carlo simulation was used to calculate the distribution of laser light in skin tissue. A series of equations including the diffusion equation for modeling the distribution of photosensitizers and oxygen, and the photobleaching equation were established to calculate the singlet oxygen generation in PDT. The singlet oxygen generation in comb tissue model with vasculature was simulated with 532- and 627.8-nm laser, respectively. In the animal experiment, the comb was treated using hematoporphyrin monomethyl ether (HMME) (10 mg/kg dose) as a photosensitizer and lasers of two different wavelengths (532 and 627.8 nm) at an identical power density (100 mW/cm(2), fluence 120 J/cm(2)). The simulation results showed that the 627.8-nm laser was more effective in generating singlet oxygen in blood vessels at deep dermis. The animal experiments showed that the average depth of thrombosis was 1,012.5 +/- 647.06 MUm with the 532-nm laser, and 2,204.2 +/- 410.35 MUm with the 627.8-nm laser. The results showed that the laser wavelength had a strong effect on the depth of thrombosis in PDT treatment for the comb model. The simulation results were consistent with the animal experimental results. PMID- 21327445 TI - Use of daptomycin in complicated cases of infective endocarditis. AB - Infective endocarditis (IE) is a serious form of infection with a high mortality. Medical management can be a challenge because of organ dysfunction, lack of clinical response or allergy to the recommended antibiotics. Daptomycin is a lipopeptide antibiotic with a potent bactericidal activity against Gram-positive bacteria. There are limited data on the use of daptomycin in complicated cases of IE. We aim to report our experience of daptomycin use in complicated cases of IE through a prospective observational study (from 1 October 2008 to 30 September 2009). Daptomycin was prescribed for cases that were either unresponsive or allergic to the standard therapy. Clinical characteristics and outcomes were reviewed. Success was defined as clinical improvement accompanied with the resolution of laboratory markers of sepsis and continuation of the above findings for at least 8 weeks after the end of therapy. Eight cases were evaluable. Native and prosthetic valves were involved in equal proportions. The range of organisms was wide: Staphylococcus aureus, two cases; S. epidermidis, two cases; streptococci, two cases; and Enterococcus faecalis, two cases. The median duration of therapy was 42 days. All patients were successfully treated. Daptomycin was well tolerated. Daptomycin is useful in the management of complicated cases of IE. PMID- 21327446 TI - Complications of loco-regional therapy in the liver-spectrum of imaging findings by CT and MRI. AB - The aim of this study was to discuss the appearance of common complications from loco-regional therapy of primary and secondary malignant liver neoplasms on cross sectional imaging. Knowledge of common complications is important for the safe performance of loco-regional therapy (LRT) and for the interpretation of post-LRT follow-up imaging. With careful patient selection, LRT represents an effective and safe treatment of primary and secondary hepatic malignancies; however, complications related to LRT methods infrequently lead to additional morbidity. PMID- 21327447 TI - TaNF-YB3 is involved in the regulation of photosynthesis genes in Triticum aestivum. AB - Nuclear factor Y (NF-Y) transcription factor is a heterotrimer comprised of three subunits: NF-YA, NF-YB and NF-YC. Each of the three subunits in plants is encoded by multiple genes with differential expression profiles, implying the functional specialisation of NF-Y subunit members in plants. In this study, we investigated the roles of NF-YB members in the light-mediated regulation of photosynthesis genes. We identified two NF-YB members from Triticum aestivum (TaNF-YB3 & 7) which were markedly upregulated by light in the leaves and seedling shoots using quantitative RT-PCR. A genome-wide coexpression analysis of multiple Affymetrix Wheat Genome Array datasets revealed that TaNF-YB3-coexpressed transcripts were highly enriched with the Gene Ontology term photosynthesis. Transgenic wheat lines constitutively overexpressing TaNF-YB3 had a significant increase in the leaf chlorophyll content, photosynthesis rate and early growth rate. Quantitative RT-PCR analysis showed that the expression levels of a number of TaNF-YB3 coexpressed transcripts were elevated in the transgenic wheat lines. The mRNA level of TaGluTR encoding glutamyl-tRNA reductase, which catalyses the rate limiting step of the chlorophyll biosynthesis pathway, was significantly increased in the leaves of the transgenic wheat. Significant increases in the expression level in the transgenic plant leaves were also observed for four photosynthetic apparatus genes encoding chlorophyll a/b-binding proteins (Lhca4 and Lhcb4) and photosystem I reaction centre subunits (subunit K and subunit N), as well as for a gene coding for chloroplast ATP synthase gamma subunit. These results indicate that TaNF-YB3 is involved in the positive regulation of a number of photosynthesis genes in wheat. PMID- 21327448 TI - Synthesis of trimethylolpropane esters of oleic acid by Lipoprime 50T. AB - The ability of the commercial lipolytic enzyme Lipoprime 50T to catalyze the biotechnologically important synthesis of the biodegradable and environmentally acceptable trimethylolpropane (2-ethyl-2-(hydroxymethyl)-1,3-propanediol) ester of oleic acid was investigated. Simple and accurate thin-layer chromatography and computer analysis methods were used that enable one to follow changes of all reaction mixture components simultaneously. The processes of transesterification and esterification were compared. The effects of the molar ratio of the substrates, reaction temperature, time, and medium on the composition of the reaction mixture were analyzed. Esterification was determined to be more preferable than transesterification in both studied solvents. Under the optimal conditions identified (15% w/w water, temperature 60 degrees C, trimethylolpropane to oleic acid molar ratio 1:3.5, and reaction time 72 h), the highest trimethylolpropane trioleate yield of around 62% and trimethylolpropane mono-, di-, and trioleate overall yield of about 83% were obtained. Although the yields are not high enough for industrial application, the process shows the potential to be optimized for higher yields in the near future as the conversions were obtained at ambient pressure, whereas many other processes described in the literature are conducted under vacuum at a specific pressure. PMID- 21327450 TI - Objective response with lapatinib in patients with meningitis carcinomatosa derived from HER2/HER1-negative breast cancer. AB - A 45-year-old woman with HER2(-)/HER1(-) breast cancer underwent radical mastectomy, followed by radiation and chemotherapy. However, her symptoms progressed rapidly owing to meningitis carcinomatosa and she was fitted with a urethral catheter. She also had difficulty in walking. However, immediately after treatment with lapatinib, her symptoms almost completely disappeared. The catheter was removed and she no longer needed a wheelchair. Unfortunately, after treatment was stopped, the bilateral upper limb skin metastases reappeared, the brain metastases relapsed, and she again experienced symptoms of meningitis carcinomatosa. Lapatinib was restarted, resulting in an immediate improvement in the symptoms and a reduction in the skin and brain metastases. Immunohistochemical staining of the lapatinib-sensitive metastatic skin tumor showed it to be HER2(2+), FISH(-)/HER1(-). This result suggested that the lapatinib-sensitive lesions in the brain and meninges were also HER2-positive. Carcinomatosa meningitis has a very poor prognosis and no effective treatment has yet been developed. Here, we report the first case in which lapatinib has been used to effectively treat meningitis carcinomatosa in HER2(-)/HER1(-) relapsed breast cancer. PMID- 21327449 TI - Hydrolytic and phosphorolytic metabolism of cellobiose by the marine aerobic bacterium Saccharophagus degradans 2-40T. AB - Saccharophagus degradans 2-40 is a marine gamma proteobacterium that can produce polyhydroxyalkanoates from lignocellulosic biomass using a complex cellulolytic system. This bacterium has been annotated to express three surface-associated beta-glucosidases (Bgl3C, Ced3A, and Ced3B), two cytoplasmic beta-glucosidases (Bgl1A and Bgl1B), and unusual for an aerobic bacterium, two cytoplasmic cellobiose/cellodextrin phosphorylases (Cep94A and Cep94B). Expression of the genes for each of the above enzymes was induced when cells were transferred into a medium containing Avicel as the major carbon source except for Bgl1B. Both hydrolytic and phosphorolytic degradation of cellobiose by crude cell lysates obtained from cellulose-grown cells were demonstrated and all of these activities were cell-associated. With the exception of Cep94B, each purified enzyme exhibited their annotated activity upon cloning and expression in E. coli. The five beta-glucosidases hydrolyzed a variety of glucose derivatives containing beta-1, (2, 4, or 6) linkages but did not act on any alpha-linked glucose derivatives. All but one beta-glucosidases exhibited transglycosylation activity consistent with the formation of an enzyme-substrate intermediate. The biochemistry and expression of these cellobiases indicate that external hydrolysis by surface-associated beta-glucosidases coupled with internal hydrolysis and phosphorolysis are all involved in the metabolism of cellobiose by this bacterium. PMID- 21327451 TI - Significance of serum osteoprotegerin and receptor activator of nuclear factor kappaB ligand in Japanese prostate cancer patients with bone metastasis. AB - BACKGROUND: We aimed to assess the diagnostic accuracy of serum osteoclastogenesis markers for detection of bone metastasis in patients with prostate cancer (PCa) and to assess the usefulness of these markers as predictors of mortality from PCa. METHODS: Serum osteoprotegerin (OPG) and receptor activator of nuclear factor kappaB ligand (RANKL) levels were measured in 201 patients (51 with bone metastasis, 55 with T2M0 PCa, 46 with T3M0 PCa, and 49 without PCa). Multivariate stepwise logistic regression analysis was used to identify independent predictors of bone metastasis. Correlation of serum marker levels with bone metastasis was assessed using receiver operating characteristics (ROC) analysis. Multivariate Cox proportional hazards analysis was used to predict cause-specific survival in PCa patients with bone metastasis. RESULTS: Serum OPG and prostate-specific antigen levels were significantly elevated in patients with bone metastasis. Multivariate stepwise logistic regression analysis demonstrated that serum OPG levels were significant predictors of bone metastasis. ROC analyses showed that serum OPG levels were the most reliable predictor of bone metastasis (area under the curve = 0.68). Multivariate Cox proportional hazards analysis revealed that only serum OPG and extent of disease on bone scan (EOD) >3 were independent prognostic factors for PCa-related death. On the other hand, serum RANKL levels were not significant predictors of bone metastasis and could not predict survival probability in PCa patients with bone metastasis. CONCLUSIONS: Serum OPG was a more reliable marker than serum RANKL in detecting bone metastatic spread and in predicting survival probability in PCa patients with bone metastasis. PMID- 21327452 TI - Overexpression of Galectin-3 and its clinical significance in ovarian carcinoma. AB - BACKGROUND: Galectin-3 (Gal-3) is a beta-galactoside-binding lectin involved in regulating cell growth, angiogenesis, and tumor progression. We investigated the clinical significance of Gal-3 expression including its possible use as a prognostic marker or therapeutic target in epithelial ovarian carcinoma (EOC). METHODS: Gal-3 expression was evaluated by immunohistochemistry in 71 patients with 54 serous, 13 endometrioid, and 4 mucinous ovarian carcinomas. We assessed the correlation of Gal-3 expression with clinical characteristics including histology, optimal debulking, chemosensitivity, and survival. In vitro, Gal-3 was inhibited using siRNA to evaluate its role in cell growth and sensitivity to chemotherapeutic agents in ovarian carcinoma cell lines. RESULTS: Gal-3 protein, which was mainly cytoplasmic in location, was observed in a majority (63/71, 88.7%) of the EOCs but not in normal ovarian tissues (P < 0.001). High Gal-3 expression in EOCs correlated with shorter progression-free survival (PFS) of patients (P = 0.039; 43.1 and 49.5 months, respectively). Moreover, cotreatment with Gal-3 siRNA and paclitaxel showed an enhanced cytotoxic effect compared with control siRNA in SKOV3 cells. CONCLUSION: These findings suggest that Gal-3 expression can be a prognostic factor for PFS and may be involved in regulating the response to paclitaxel-based chemotherapy in the treatment of EOC. PMID- 21327453 TI - Onset of adult-onset Still's disease following influenza vaccination. AB - We describe that case of a 61-year-old woman who developed high spiking fever, sore throat, polyarthralgia, and salmon pink evanescent rash following influenza vaccination. A diagnosis of adult-onset Still's disease (AOSD) was made based on clinical and laboratory findings. Methylprednisolone pulse therapy followed by oral prednisolone resulted in a favorable outcome. This is the second published case in which a causal relationship between vaccination and onset of AOSD is suggested. Bystander activation would appear to play an important role in inducing the immune reaction. PMID- 21327454 TI - Central lymph node metastasis of unilateral papillary thyroid carcinoma: patterns and factors predictive of nodal metastasis, morbidity, and recurrence. AB - BACKGROUND: Although subclinical cervical lymph node (LN) metastases in papillary thyroid carcinoma (PTC) are common, the efficacy of prophylactic central LN dissection (CLND) is unclear. Few prospective studies have assessed the relationships between complete pathologic information regarding tumors and metastatic nodes in the central compartment. We therefore investigated the pattern and predictive indicators of central LN metastasis, morbidity, and recurrence in patients who underwent total thyroidectomy and prophylactic CLND for unilateral PTC and clinically node-negative neck (cN0) disease. METHODS: This prospective study involved 184 patients with previously untreated unilateral PTC and cN0 who underwent total thyroidectomy and bilateral CLND. Nodal samples were divided into the prelaryngeal/pretracheal and ipsilateral and contralateral paratracheal regions, with each assessed for clinicopathologic predictors of central metastases. Postoperative morbidity and recurrence were assessed. RESULTS: Rates of metastasis to ipsilateral and contralateral central compartments were 42.9 and 9.8%, respectively. Multivariate analysis showed that tumor size >1 cm and extrathyroidal extension were independent predictors of ipsilateral metastasis, and ipsilateral metastases independently predicted contralateral metastases (P < 0.05 each). Permanent hypoparathyroidism and incidental recurrent nerve paralysis were found in 1.6 and 0% of patients, respectively. After a mean follow-up of 46 months, none of these patients had recurrence in the central compartment. CONCLUSIONS: Subclinical metastases are highly prevalent in the ipsilateral central neck of patients with PTC >1 cm. Contralateral central metastases, although uncommon, are associated with ipsilateral central metastases. These findings may guide the necessity and extent of prophylactic bilateral or unilateral CLND. PMID- 21327455 TI - Multidisciplinary considerations in the implementation of the findings from the American College of Surgeons Oncology Group (ACOSOG) Z0011 study: a practice changing trial. PMID- 21327456 TI - Tumor size remains key for prediction of hepatocellular carcinoma recurrence after liver transplantation. PMID- 21327457 TI - Overexpression of long non-coding RNA HOTAIR predicts tumor recurrence in hepatocellular carcinoma patients following liver transplantation. AB - BACKGROUND: The long noncoding RNA HOTAIR has been reported as a poor prognostic biomarker in patients with breast cancer. The aim of the present study is to examine the expression pattern of HOTAIR in hepatocellular carcinoma (HCC) and its clinical significance as well as its biological role in tumor progression. MATERIALS AND METHODS: We examined the expression of HOTAIR in 110 HCC samples using real-time reverse transcription-polymerase chain reaction and analyzed its correlation with clinical parameters and prognosis in 60 HCC patients that have undergone liver transplantation (LT). Suppression of HOTAIR using siRNA was performed to explore its roles in tumor progression. RESULTS: The expression level of HOTAIR in cancer tissues was higher than in adjacent noncancerous tissues. High expression level of HOTAIR was an independent prognostic factor for predicting HCC recurrence in LT patients (P = .001, hazard ratio, 3.564). Furthermore, in patients exceeding the Milan criteria, those with a high expression level of HOTAIR revealed a significantly shorter recurrence-free survival. Moreover, siRNA suppression of HOTAIR in a liver cancer cell line reduced cell viability and cell invasion, sensitized TNF-alpha induced apoptosis, and increased the chemotherapeutic sensitivity of cancer cells to cisplatin and doxorubicin. CONCLUSIONS: The high expression level of HOTAIR in HCC could be a candidate biomarker for predicting tumor recurrence in HCC patients who have undergone liver transplant therapy and might be a potential therapeutic target. PMID- 21327458 TI - Anatomic sites at elevated risk of second primary cancer after an index head and neck cancer. AB - BACKGROUND: Patients with head and neck squamous cell carcinoma (HNSCC) are at significantly elevated risk of second primary malignancies (SPM), most commonly within the head and neck, lung, and esophagus (HNLE). Our objectives were to quantify the excess risk of SPM across all anatomic sites in which SPM risk is meaningfully elevated, including non-HNLE sites, in a large cohort of US patients. METHODS: Population-based analysis of 75,087 patients with HNSCC in the SEER program, quantifying excess SPM risk by integrating relative (standardized incidence ratio; SIR) and absolute (excess absolute risk per 10,000 person-years at risk; EAR) statistics. RESULTS: In HNSCC patients, the SIR of a second primary solid cancer was 2.2 (95% CI 2.1-2.2), corresponding to EAR of 167.7 additional cases per 10,000 person-years at risk. Over 1 year, 60 patients would need to be followed to observe one excess SPM. Lung cancer burden was most markedly elevated in absolute terms (EAR = 75.2), followed by HN (EAR = 59.8), esophageal (EAR = 14.2), and colorectal (EAR = 4.3) cancers. Lesser but significant excess risks were also observed for cancers of the bladder, liver, stomach, pancreas, kidney, salivary glands, nasopharynx, uterine cervix, and lymphoma. CONCLUSIONS: Data from a large population-based US cohort reveals that HNSCC patients experience markedly excess risk of SPM, predominantly in the HNLE sites. Furthermore, the risk of SPM is also meaningfully elevated, although to a lesser degree, in multiple other tobacco-associated sites. PMID- 21327459 TI - Abuse victimization and risk of breast cancer in the Black Women's Health Study [corrected]. AB - Few studies have examined the relation between abuse victimization and breast cancer, and results have been inconclusive. Using data from 35,728 participants in the Black Women's Health Study, we conducted multivariable Cox regression to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CI) for the association of abuse across the life span (childhood, adolescence, and adulthood) with breast cancer. Incident breast cancer diagnoses were reported during 1995 2009, and abuse histories were reported in 2005. No associations were found between abuse victimization in either childhood or adolescence and breast cancer. We found a weak positive association between abuse in adulthood and breast cancer (IRR = 1.18, 95% CI = 1.03-1.34). IRRs for physical abuse only, sexual abuse only, and both physical and sexual abuse in adulthood, relative to no abuse, were 1.28 (95% CI = 1.09-1.49), 0.96 (95% CI = 0.76-1.20), and 1.22 (95% CI = 1.00 1.49), respectively. IRRs for low, intermediate, and high frequencies of physical abuse in adulthood, relative to no abuse, were 1.28 (95% CI = 1.07-1.52), 1.37 (95% CI = 1.04-1.79), and 1.24 (95% CI = 0.95-1.62), respectively. Our data suggest an increased risk of breast cancer among African-American women who reported physical abuse in adulthood, but there was little evidence of a dose response relation. These results require confirmation in other studies. PMID- 21327460 TI - Birth characteristics and female sex hormone concentrations during adolescence: results from the Dietary Intervention Study in Children. AB - BACKGROUND: Birth characteristics and adult hormone concentrations influence breast cancer risk, but little is known about the influence of birth characteristics on hormone concentrations, particularly during adolescence. METHODS: We evaluated the association of birth characteristics (birth weight, birth length, and gestational age) with serum sex hormone concentrations during late childhood and adolescence in 278 female participants of the Dietary Intervention Study in Children. Repeated measures analysis of variance models were used to assess the relationships of birth characteristics and serum estrogens and androgens at five different time points over a mean period of 7 years. RESULTS: In analyses that did not take into account time from blood draw until menarche, birth weight was inversely associated with pre-menarche concentrations of estradiol, estrone sulfate, androstenedione, testosterone, and dehydroepiandrosterone sulfate (DHEAS). In the post-menarche analyses, birth weight was not significantly associated with concentration of any of the hormones under investigation. Birth length and gestational age were not associated with hormone concentrations before or after menarche. CONCLUSION: Birth weight is inversely associated with sex hormone concentrations before menarche in the model unadjusted for time from blood draw until menarche. IMPACT: The in utero environment has long-term influences on the hormonal milieu, which could potentially contribute to breast cancer risk. PMID- 21327461 TI - Weight loss and postmenopausal breast cancer in a prospective cohort of overweight and obese US women. AB - Overweight and obesity are associated with increased postmenopausal breast cancer risk; however, it is unclear whether losing excess weight will lower risk. Therefore, we examined the relationship between weight loss and postmenopausal breast cancer among 13,055 overweight and obese, cancer-free women who enrolled in the Cancer Prevention Study-II (CPS-II) Nutrition Cohort in 1992. During the 15 year follow-up, 816 postmenopausal breast cancer cases were diagnosed. Self reported weight was collected before diagnosis at baseline and 10 years prior to baseline. The median weight loss was 11 lbs, but only 58% of the women maintained this weight loss through the first 5 year follow-up interval (1992-1997). Using both restricted cubic splines and multivariate Cox proportional hazards modeling, we observed no association between weight loss and postmenopausal breast cancer. The hazard ratio for 30+ pounds of weight loss compared to stable weight was 0.95 (95%: CI 0.47-1.95). An inverse association was, however, suggested among women who maintained ten or more pounds of weight loss through the next interval. There was no evidence of effect modification by postmenopausal hormone use, initial BMI, or other factors examined. In summary, weight loss was not associated with postmenopausal breast cancer in this study. Future studies should focus on sustained weight loss and whether the timing of weight loss is important. PMID- 21327462 TI - Circulating free DNA: a new surrogate marker for minimal residual disease? PMID- 21327463 TI - The association between two polymorphisms in the TYMS gene and breast cancer risk: appraisal of a recent meta-analysis. PMID- 21327464 TI - Return to work after treatment for breast cancer. PMID- 21327465 TI - Tumor characteristics as predictors of local recurrence after treatment of ductal carcinoma in situ: a meta-analysis. AB - While ductal carcinoma in situ (DCIS) is seldom life threatening, the management of DCIS remains a dilemma for patients and their physicians. Aggressive treatment reduces the risk of ipsilateral breast tumor recurrence (IBTR), but has never been proven to improve survival. There is interest in identifying the prognostic factors for determining low-risk DCIS patients, but a comprehensive review of high-quality evidence on tumor characteristics in predicting local recurrence has never been carried out. We examined the following tumor characteristics: biomarkers, comedonecrosis, focality, surgical margin, method of detection, tumor grade, and tumor size. For this systematic review we restricted the analyses to the results of subgroup analyses from randomized controlled trials (RCTs) and multivariate analyses from RCTs and observational studies. We identified 44 eligible articles. The pooled random-effects risk estimates for IBTR are comedonecrosis 1.71(95% CI, 1.36-2.16), focality 1.95(95% CI, 1.59-2.40), margin 2.25(95% CI, 1.77-2.86), method of detection 1.35(95% CI, 1.12-1.62), tumor grade 1.81(95% CI, 1.53-2.13), and tumor size 1.63(95% CI, 1.30-2.06). Limited evidence indicated that women whose DCIS is ER-negative, PR-negative, or HER2/neu receptor positive have an IBTR higher than those whose DCIS is ER-positive, PR-positive, and HER2/neu receptor negative. A variety of tumor characteristics are significant predictors for IBTR. These results are important for both clinicians and patients to interpret the risk of local recurrence and to decide on a course of treatment. PMID- 21327466 TI - Are polymorphisms of the ataxia telangiectasia mutated gene associated with breast cancer risk? PMID- 21327467 TI - NBS1 8360G > C polymorphism is associated with breast cancer risk was not credible: appraisal of a recent meta-analysis. PMID- 21327469 TI - Genomic rearrangements of the BRCA1 gene in Chilean breast cancer families: an MLPA analysis. AB - Point mutations and small deletions and insertions in BRCA1 and BRCA2 genes are responsible of about 20% of hereditary breast cancer cases in Chilean population. Studies in other populations have identified the amplification and/or deletion of one or more exons in these genes as the cause of the disease. In this study the authors determined the presence of these types of alterations in BRCA1 and BRCA2, in 74 Chilean families with breast/ovarian cancer that were negative for germline mutations in these genes. Since these alterations are not detectable using the conventional PCR-based methods, the authors use MLPA (multiplex ligation dependent probe amplification) to detect amplifications and/or deletions in BRCA1 and BRCA2 genes. The authors identified two different alterations in BRCA1: exon 10 duplication in one family and amplification of exons 3, 5, and 6 in two families. Duplication of exon 10 contains intronic adjacent sequences suggesting gene duplication. The second rearrangement consist of a 4 times amplification of a fragment containing exons 3, 5, and 6 joined together with no introns, suggesting the presence of a processed pseudogene. No alterations were detected in BRCA2. In order to validate the MLPA results and characterize the genomic alterations the authors performed qPCR, long range PCR, and sequencing. PMID- 21327468 TI - Urinary cadmium and mammographic density in premenopausal women. AB - Mammographic density (MD), a strong marker of breast cancer risk, is influenced by genetic, environmental, and hormonal factors. Cadmium, a persistent and widespread environmental pollutant, has been associated with risk of breast cancer, and laboratory evidence suggests cadmium is a carcinogen in the breast. We investigated the hypothesis that cadmium exposure is associated with higher MD. In a cross-sectional study of MD and urinary cadmium concentration, percentage MD (MD%) and Breast Imaging-Reporting and Data Systems (BI-RADS(r)) density category were determined from screening mammograms of 190 premenopausal women ages 40-45 years. Women completed a health questionnaire, and the cadmium content of spot urine samples was measured with inductively coupled plasma mass spectrometry and corrected for urine creatinine. Urinary cadmium concentrations are thought to reflect exposure to cadmium during a period of 20-30 years. Multivariable linear regression and logistic regression were used to estimate the strength of association between urinary cadmium and mammographic breast density. Adjusted mean MD% among women in the upper tertile of creatinine-corrected urinary cadmium was 4.6% higher (95% CI: -2.3 to 11.6%) than in women in the lowest cadmium tertile. Each twofold increase in urinary cadmium was associated with higher odds of MD% in the upper tertile (OR: 1.29, 95% CI: 0.82-2.02) or a BI-RADS category rating of "extremely dense" (OR: 1.75, 95% CI: 1.14-2.70). Stronger associations were observed among nulliparous women, and current or former smokers. Exposure to cadmium may be associated with increased breast density in premenopausal women. PMID- 21327470 TI - EMSY and CCND1 amplification in familial breast cancer: from the Ontario site of the Breast Cancer Family Registry. AB - EMSY is a putative oncogene amplified in a minority of breast carcinomas, its protein product interacts with and transcriptionally silences BRCA2. We hypothesized that breast tumors from BRCA2 mutation carriers would be less likely than other familial breast cancers to exhibit EMSY amplification. As EMSY is located on 11q13 in proximity to CCND1, an established breast cancer oncogene, we also examined the amplification of CCND1 in the same tumor cohort. Amplification of EMSY and CCND1 were examined in 58 BRCA1-associated, 64 BRCA2-associated, and 242 familial non-BRCA1/BRCA2 breast cancers using fluorescent in situ hybridization (FISH). All tumors had a centralized pathology review and underwent molecular phenotyping by immunohistochemical profiling on tissue microarrays (TMAs). Tumors with amplification of EMSY and/or CCND1 were compared with non amplified tumors for morphological appearance, molecular subtype, and overall survival. EMSY amplification was detected in 8% of BRCA1-associated, 0% of BRCA2 associated, and 9% of familial non-BRCA1/BRCA2 breast tumors (P = 0.036). CCND1 was amplified in 4% of BRCA1-associated, 13% of BRCA2-associated and 21% of non BRCA1/BRCA2 breast tumors (P = 0.054). EMSY was amplified independently of CCND1 in 38% of cases. EMSY amplification was associated with increased tumor stage only; whereas CCND1 amplification was associated with high tumor grade, ER positivity, and inversely associated with the basal-like phenotype. There was a trend toward worse overall survival in ER-positive non-BRCA1/BRCA2 familial breast cancer patients whose tumors exhibited EMSY and CCND1 co-amplification. BRCA2-associated breast tumors are less likely than non-BRCA1/BRCA2 familial breast cancers to exhibit EMSY amplification. BRCA1-associated breast cancers are less likely than non-BRCA1/BRCA2 familial breast cancers to exhibit CCND1 amplification. EMSY amplification does occur independently of CCND1 amplification in a minority of familial breast cancers, supporting its role as a possible breast cancer oncogene. PMID- 21327471 TI - Improved web-based calculators for predicting breast carcinoma outcomes. AB - We describe a set of web-based calculators, available at http://www.CancerMath.net , which estimate the risk of breast carcinoma death, the reduction in life expectancy, and the impact of various adjuvant treatment choices. The published SNAP method of the binary biological model of cancer metastasis uses information on tumor size, nodal status, and other prognostic factors to accurately estimate of breast cancer lethality at 15 years after diagnosis. By combining these 15-year lethality estimates with data on the breast cancer hazard function, breast cancer lethality can be estimated at each of the 15 years after diagnosis. A web-based calculator was then created to visualize the estimated lethality with and without a range of adjuvant therapy options at any of the 15 years after diagnosis, and enable conditional survival calculations. NIH population data was used to estimate non-breast-cancer chance of death. The accuracy of the calculators was tested against two large breast carcinoma datasets: 7,907 patients seen at two academic hospitals and 362,491 patients from the SEER national dataset. The calculators were found to be highly accurate and specific, as seen by their capacity for stratifying patients into groups differing by as little as a 2% risk of death, and accurately accounting for nodal status, histology, grade, age, and hormone receptor status. Our breast carcinoma calculators provide accurate and useful estimates of the risk of death, which can aid in analysis of the various adjuvant therapy options available to each patient. PMID- 21327472 TI - Techniques of assessing hypoxia at the bench and bedside. AB - Tissues require an adequate supply of oxygen in order to maintain normal cell function. Low oxygen tension (hypoxia) is characteristic of a number of conditions, including cancer, atherosclerosis, rheumatoid arthritis, critical limb ischaemia, peripheral vascular disease, and ischaemic heart disease. Tissue hypoxia is found in tumours, atherosclerotic plaque, and ischaemic myocardium. There is a growing interest in methods to detect and assess hypoxia, given that hypoxia is important in the progression of these diseases. Hypoxia can be assessed at the level of the whole organ, tissue, or cell, using both invasive and non-invasive methods, and by a range of immunohistochemical, biochemical, or imaging techniques. This review describes and critiques current methods of assessing hypoxia that are used at the bench and in clinical practice. PMID- 21327473 TI - The natural compound n-butylidenephthalide derived from the volatile oil of Radix Angelica sinensis inhibits angiogenesis in vitro and in vivo. AB - Radix Angelica sinensis is a Chinese medicinal herb that has been used extensively in the East for the treatment of cardiovascular diseases (CVDs). Angiogenesis plays an important role in the pathogenesis of CVDs. We hypothesized that Radix A. sinensis may contain angiogenesis modulators. In the current study, we investigated the effects of a volatile oil of Radix A. sinensis (VOAS) and n butylidenephthalide (BP), one of the bioactive components in VOAS, on angiogenesis in vitro and in vivo. The results suggested that VOAS exerted anti angiogenic effects by inhibiting human umbilical vein endothelial cell proliferation, migration and capillary-like tube formation on Matrigel. BP was also shown to be anti-angiogenic and its mechanisms were through inhibition of cell cycle progression and induction of apoptosis. Western blotting analysis indicated that the anti-angiogenic actions of BP were associated with the activation of p38 and ERK 1/2 but not SAPK/JNK and Akt signaling pathways. Further investigations showed that BP inhibited endothelial sprouting in an ex vivo mouse aortic ring model and was a potent inhibitor of the development of zebrafish subintestinal vessels in vivo. Our data using the volatile oil contrast with previous findings, which showed an aqueous extract of Radix A. sinensis was pro-angiogenic. This highlights the importance of identifying pro- and anti angiogenic substances in Radix A. sinensis, not only for the development of novel angiogenesis modulators for the treatment of CVDs, but also to ensure the proper use of Radix A. sinensis as a nutraceutical. PMID- 21327474 TI - Issues in (inter)professionalism. PMID- 21327475 TI - Functionality of the S-layer protein from the probiotic strain Lactobacillus helveticus M92. AB - The objective of this study was the characterisation of the S-layer protein (SlpA) and its functional role in the probiotic activity of Lactobacillus helveticus M92. SlpA was isolated and identified by SDS-PAGE LC-MS/MS analysis. The slpA gene encoding the SlpA from L. helveticus M92 was sequenced and compared with other well characterised slpA genes. Sequence similarity searches revealed high homology with the SlpA of Lactobacillus strains. Purified SlpA showed significantly better immunomodulatory effects in orally immunised mice than L. helveticus M92 cells after SlpA removal. SlpA is involved in the autoaggregation of L. helveticus M92 cells and coaggregation of L. helveticus M92 with S. Typhimurium FP1 as these processes were negatively affected after SlpA removal from the cell surface. Therefore, the influence of oral treatment with L. helveticus M92 on an oral infection of mice by S. Typhimurium FP1 was investigated. Following the oral immunization of mice, with viable L. helveticus M92 and S. Typhimurium FP1 cells, the concentration in the luminal contents of total S-IgA and specific anti-Salmonella S-IgA antibodies, from all immunized mice was significantly higher compared to the control group or a group of mice infected only with S. Typhimurium FP1. These results demonstrate that the observed reduced infection by S. Typhimurium FP1 in mice with L. helveticus M92 is associated with competitive exclusion in the intestinal tract and enhanced immune protection conferred by the L. helveticus M92 and its SlpA. PMID- 21327476 TI - Rapid detection and identification of the free-living nitrogen fixing genus Azospirillum by 16S rRNA-gene-targeted genus-specific primers. AB - The modern agricultural practice utilizing plant growth promoting rhizobacteria (PGPR) has brought great benefits in the promotion of crop growth. Among PGPR, Azospirillum is considered as an important genus which is not only closely associated with plants but also shows potential in the degradation of organic contaminants. However, lack of media for selective isolation or techniques for specific detection or identification limit the exploration of these rhizobacteria. This motivated us to design a genus-specific oligonucleotide primer pair which could assist in rapid detection of species of the genus Azospirillum by means of PCR-specific amplification. The sensitivity and specificity of the newly designed primer pair Azo494-F/Azo756-R were tested against 12 Azospirillum type strains and other closely-related genera. The Azospirillum-specific 16S rRNA gene fragment (263 bp) was successfully amplified for all the reference Azospirillum species with the designed primer pair. No amplification was noted for closely-related species from other genera. The genus specificity was validated with 18 strains including environmental isolates. Interestingly, two strains assigned earlier as Azospirillum amazonense (DSM 2787(T)) and Azospirillum irakense (DSM 11586(T)) failed to produce an Azospirillum-specific fragment with this primer pair. Further phylogenetic analysis of these two isolates based on 16S rRNA gene sequences shows that these two strains might belong to other genera rather than Azospirillum. Preliminary screening of isolates and soil samples with the Azospirillum-specific primers was successful in terms of the rapid detection of Azospirillum isolates. By using real-time PCR analysis the minimum limit of Azospirillum detection was 10(2) CFU g(-1) in the seeded soil sample. The newly designed primers can be used to study the diversity of Azospirillum in ecosystems and aid in the exploration of novel species. PMID- 21327477 TI - Cylindrical glue container into bladder due to sexual practice. PMID- 21327478 TI - Lactoferrin: an iron-binding antimicrobial protein against Escherichia coli infection. AB - Escherichia coli (E. coli) are the most common aerobic gram-negative bacilli in a normal intestinal tract. They cause most of the intra-abdominal infections, wound infections associated with abdominal surgery, and septicemia. Most of these infections are of endogenous intestinal origin. Lactoferrin (LF) is an iron binding glycoprotein found in milk and various external secretions. This protein has been found to have a number of biological functions, including antimicrobial, anti-cancer, antioxidant, and immunomodulatory effects. Partial degradation of LF by pepsin can give rise to peptides termed lactoferricin (LFcin) with more potent antimicrobial activity. LF and LFcin have been shown to inhibit the growth of a number of pathogenic bacteria (including E. coli and antibiotic-resistant strains), fungi, and even viruses in both in vitro and in vivo studies. We previously demonstrated that both recombinant porcine LF (pLF) produced from yeast and a synthetic 20-residue porcine LFcin peptide exhibit antimicrobial activity in vitro. In one of our recent studies, we performed pathogen challenges, including pathogenic E. coli, Staphylococcus aureus and Candida albicans, of the digestive tract of a transgenic milk-fed animal model. The results showed that LF has broad spectrum antimicrobial activity in the digestive tract and protects the mucosa of the small intestine from injury. Our following study also revealed that pLF as a feedstuff additive enhances avian immunity, including antibody formation and cell-mediated immunity. All of these results suggest that LF could be a novel natural protein in the treatment and prevention of infections with E. coli or antibiotic-resistant bacteria strains. PMID- 21327479 TI - Treatment of mucopolysaccharidosis type II (Hunter syndrome) with idursulfase: the relevance of clinical trial end points. AB - The current treatment of mucopolysaccharidosis type II (MPS II, Hunter syndrome) is enzyme replacement therapy with recombinant idursulfase (Elaprase(r)). The efficacy of ERT was established based primarily on reduction in urine glycosaminoglycans:creatinine (GAG:Cr) ratio and improvement in a composite score of predicted forced vital capacity (FVC% predicted) and 6-min walk-test distance (6MWT). We retrospectively reviewed these parameters in 11 boys with MPS II treated with idursulfase between April 2007 (or the time of diagnosis) and February 2010. Some results were inconsistent with published trial data, and there was only a small number of analyzable results obtained for the FVC% predicted and 6MWT. A major drawback was the high prevalence of neurological involvement and young age of patients in the study cohort compared with the clinical trials. This study emphasizes the limitations of the current tools utilized to monitor ERT efficacy and MPS II disease burden in clinical practice. PMID- 21327480 TI - Exploiting a physiological regulator to improve the efficacy and safety of statins. PMID- 21327481 TI - Nitrous oxide fluxes from the littoral zone of a lake on the Qinghai-Tibetan Plateau. AB - Nitrous oxide (N(2)O) fluxes were measured in six littoral mirco-zones of Lake Huahu on Qinghai-Tibetan Plateau in the peak growing season of years of 2006 and 2007. The weighted mean N(2)O flux rate was 0.08 mg N m(-2) h(-1) (ranged from 0.07 to 0.35 mg N m(-2) h(-1)). The result was relatively high in the scope of N(2)O fluxes from boreal and temperate lakes. Emergent plant zones (Hippuris vulgaris and Glyceria maxima stands) recorded the highest N(2)O flux rate (0.11 +/- 0.24 and 0.08 +/- 0.17 mg N m(-2) h(-1), respectively). Non-vegetated lakeshore recorded the lowest N(2)O flux (0.03 +/- 0.11 mg N m(-2) h(-1)), lower than that from the floating mat zone of Carex muliensis (0.05 +/- 0.18 mg N m(-2) h(-1)), the floating-leaved plant zone of Polygonum amphibium (0.07 +/- 0.11 mg N m(-2) h(-1)), and the wet meadow (0.07 +/- 0.15 mg N m(-2) h(-1)). Standing water depths were important factors to explain such spatial variations in N(2)O fluxes. Significant temporal variations in N(2)O fluxes were also found. Such temporal variation in N(2)O flux in the littoral zone may be dependent on the interaction of water regime and thermal conditions, instead of the latter solely. These results showed the importance of the littoral zone of lake, especially the emergent plant zone, as a hotspot of N(2)O fluxes in such grazing meadows. PMID- 21327482 TI - Contribution of a municipal solid waste incinerator to the trace metals in the surrounding soil. AB - This study analyses the pedological environment of the area near a municipal waste incinerator that has been operating in the south-east district of Pisa for approximately 20 years. There are many other industrial activities in the area besides the incinerator, which represent possible sources of pollution, as well as heavy road traffic. The study area was defined by a 0-4-km zone around the site with a population of approximately 12,000 residents. The study included the physical and chemical characterisation of 100 samples of soil and an analysis of trace metals such as Cr, Ni, Pb, Zn, Hg, As and Cd. The samples were grouped into soil use categories. The results showed Zn, Pb and Hg correlated with their potentially mobile fractions, and suggested an anthropic contribution to their presence in the soil. Ni, Cr and As showed values attributable to a lithological origin. This was consistent with the PCA results. The aim was to define the environmental state of the soil of the area in order to create a reference for future research and to verify the possible presence of pollution from other sources (local industrial activities and traffic). PMID- 21327483 TI - Concentration of heavy metals in hair and skin of silver and red foxes (Vulpes vulpes). AB - The structure of hair and levels of main chemical elements (C, N, O, S, Cl, Ca, P, Al, Na) in the external layer of hair of silver and red foxes (Vulpes vulpes) in a non-industrialised, typically agricultural region of middle-west Poland was assessed using a scanning microscope. Additionally, analysis of the accumulation of certain heavy metals (Cr, Cu, Ni, Pb and Zn) in hair (washed) and skin (non tanned) of those foxes was conducted. Heavy metal levels were determined using a spectrophotometric method (ICP-OES), and correlations between these levels in hair and skin were calculated. The microscopic external (morphological) and internal structures (histological) of the hair of farm and wild foxes were not differentiated; however, the hair of farm foxes (external layer) contained higher amounts of C, Na, Al and P. A significantly higher Pb content was noted in non tanned skin of wild foxes in comparison to farm ones. In the case of farm foxes, a significantly higher Zn content in hair and Zn and Cu in skin was observed in comparison to wild ones. Positive significant correlations between Cr and Ni content (r = 0.622) and Zn and Cu (r = 0.721) in fox skin were noted. A similar relationship between Cr content in hair and Ni in skin (r = 0.643) and between Zn in hair and skin (r = 0.595) was also observed. PMID- 21327484 TI - Radiochemical characterization of mineral waters in the Eastern Black Sea Region, Turkey. AB - This study has evaluated the levels of natural radionuclides and chemical components of mineral waters in the Eastern Black Sea Region (Turkey). The mean activity concentrations of (226)Ra, (232)Th, (137)Cs, (40)K, gross alpha and gross beta were found as 129, 33, 28, 714, 125 and 170 mBq L(-1), respectively. Due to consumption of mineral waters, the radiological impact of them on the inhabitants was calculated by taking the annual intake into account through ingestion of aforementioned radionuclides. The estimated effective doses from mineral water were found to be 13.20 MUSv year(-1) ((226)Ra), 2.74 MUSv year(-1) ((232)Th), 0.13 MUSv year(-1) ((137)Cs) and 1.62 MUSv year(-1) ((40)K). The overall contribution of these radionuclides to the committed effective dose from a year's consumption of mineral water in the region is therefore estimated to be only 17.69%, which is in concordance with the recommended WHO value (100 MUSv year(-1)). The chemical analysis results showed that these waters contain Na, Al, P, Cl, K, Ca, V, Mn, Fe, Ni, Cu and Zn elements. These values were evaluated and compared with the internationally verified values. This study provides important information for consumers and authorities because of their internal radiochemical exposure risk from mineral water intake. PMID- 21327485 TI - Assessment of water quality in the Messolonghi-Etoliko and Neochorio region (West Greece) using hydrochemical and statistical analysis methods. AB - Assessment of the water quality can enhance understanding of the hydrochemical system and effective management of water resources. To this end, an assessment of water quality was conducted in the Messolonghi-Etoliko and Neochorio region. Surface water and groundwater samples have been collected, treated, and subjected to chemical analysis for the following parameters: Br-, Cl-, F-, NO2-, NO3-, PO43 , SO42-, Li+, Na+, NH4+, K+, Mg2+, Ca2+, HCO3-, Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, and Zn. A characterization has been carried out using the Piper trilinear diagram, the United States Salinity Laboratory diagram, and the Wilcox diagram. Assessment of water samples by comparing the recorded values of the water quality parameters with the parametric values established by European Community indicated that the 50% of the surface water samples and 67% of the groundwater samples in the study area are chemically suitable for drinking use. Assessment of water samples from calculation of chemical indexes like sodium adsorption ratio, sodium percentage, residual sodium carbonate, and by comparing the values of the water quality parameters with the water quality limits established by Canadian Council of Minister of the Environment indicated that 75% of the surface water and that all the groundwater samples are chemically suitable for irrigation use. PMID- 21327486 TI - Decrease in air pollution load in urban environment of Bratislava (Slovakia) inferred from accumulation of metal elements in lichens. AB - The study illustrates the response of epiphytic lichens to changing atmospheric conditions in Central Europe, where the emission of air pollutants has significantly decreased from 1990, in the area in and around Bratislava City. Variation in concentrations of seven metal elements (Cu, Cd, Cr, Mn, Ni, Pb and Zn) in the thalli of Evernia prunastri, Hypogymnia physodes and Parmelia sulcata is assessed. Samples of these species were exposed in lichen bags in 39 sites throughout the territory of the city (more than 300 km(2)) during the period December 2006-February 2007. The samples were analyzed by AAS for metal element contents prior to and after exposure. The decrease in air pollution (for all studied elements by more than 90%) corresponded to a decrease in the accumulation of elements in lichen thalli, e.g. the contents of Pb decreased by 69% and of Cd by 34% on average. The results show also variations in accumulation between with different lichen species. The background values of metal element contents in thalli of H. physodes growing in situ were measured in semi-natural sites in Slovakia. It is suggested that these can be used as a reference in large-scale monitoring studies in Central Europe. Analysis of compatible data from the current study, and the study performed at the end of 1990s shows a significant decrease of metal elements in the air pollution load. PMID- 21327487 TI - Assessment of lead exposure in Spanish imperial eagle (Aquila adalberti) from spent ammunition in central Spain. AB - The Spanish imperial eagle (Aquila adalberti) is found only in the Iberian Peninsula and is considered one of the most threatened birds of prey in Europe. Here we analyze lead concentrations in bones (n = 84), livers (n = 15), primary feathers (n = 69), secondary feathers (n = 71) and blood feathers (n = 14) of 85 individuals collected between 1997 and 2008 in central Spain. Three birds (3.6%) had bone lead concentration > 20 MUg/g and all livers were within background lead concentration. Bone lead concentrations increased with the age of the birds and were correlated with lead concentration in rachis of secondary feathers. Spatial aggregation of elevated bone lead concentration was found in some areas of Montes de Toledo. Lead concentrations in feathers were positively associated with the density of large game animals in the area where birds were found dead or injured. Discontinuous lead exposure in eagles was evidenced by differences in lead concentration in longitudinal portions of the rachis of feathers. PMID- 21327488 TI - Adverse effects of fipronil on avian reproduction and development: maternal transfer of fipronil to eggs in zebra finch Taeniopygia guttata and in ovo exposure in chickens Gallus domesticus. AB - Two studies were carried out to examine the impact of maternal fipronil exposure on embryonic and offspring development. In the first study, breeding female zebra finches were orally dosed with single sublethal levels of fipronil (1, 5, and 10 mg/kg body weight) to determine behavioural and developmental consequences on chicks following maternal pesticide exposure. Significant levels of fipronil and fipronil-sulfone residues were detected in eggs laid by females in all dosed groups, however, these were undetectable in eggs laid 13 days after treatment. The level of sulfone detected in eggs was consistently higher than that of the parent fipronil compound. Of the seven eggs laid in the treatment groups, only one (14%) chick hatched and this was from the lowest dose group. This chick was severely underdeveloped at 10 days of age in comparison to control chicks and fiproles were detected in brain, liver, and adipose tissues collected following euthanasia of this individual. In contrast, there was 100% hatchability of control group eggs and all chicks fledged nests on schedule. In the second study, domestic chicken eggs were injected with 5.5, 17.5, and 37.5 mg/kg egg weight of fipronil directly into the yolk sac on day 12 of incubation. Treatment did not affect hatching success, however, behavioural and developmental abnormalities were observed in hatchlings from the highest dose group. These chicks also demonstrated reduced feeding rates, as indicated by reduced body mass at 48 h period post hatch. Both fipronil and fipronil-sulfone residues were detected in brain and liver tissue of hatchlings at all pesticide dose levels tested. PMID- 21327489 TI - Durability of repaired pacemaker leads in the pediatric population. AB - PURPOSE: Lead failure is a common complication of pacemaker placement in the pediatric population and is often due to insulation breaks or lead fracture. Usually these leads are replaced with new leads. This study describes the surgical technique of lead repair and investigates the longevity of such repairs. METHODS: Retrospective review of lead repairs performed in the pediatric population (<21 years old) between December 1995 and December 2008. Operative records, pre-operative interrogation data, and most recent follow-up data were reviewed. RESULTS: Twenty-one lead repairs were performed on 17 patients. Sixteen were ventricular leads and five were atrial leads. There were 14 insulation defect repairs, six new lead tip splicings, and one lead extender splicing. The repaired leads were followed for a mean time of 3.6 +/- 3.0 years (range, 0.3 10.6 years). The freedom from repaired lead failure by Kaplan-Meier survival analysis was 89% at 5 years and 22% at 10 years. One atrial lead and two ventricular leads have been replaced since the repairs. One atrial lead has had a repeat insulation break repair since the initial repair. One of the five atrial leads had an elevated threshold at follow-up. Five of 16 ventricular leads had elevated thresholds at follow-up. All leads had normal impedance at follow-up. CONCLUSION: The option of pacemaker lead repair, if surgically feasible, offers an alternative to lead replacement in the pediatric population and may extend the longevity of pacemaker leads in this population. PMID- 21327490 TI - A His bundle extrasystole can both induce and reverse 2:1 atrioventricular block. AB - An 84 year-old man with history of recurrent dizziness presented with first degree atrio-ventricular block (1 degrees AVB) and periods of 2:1 AVB. An electrophysiological study revealed a predominant 1:1 AV conduction with markedly prolonged AH interval and frequent His bundle extrasystoles (H). A properly timed H could induce periods of 2:1 AV nodal block and 1:1 AV conduction could only resume following another properly timed H. Procainamide suppressed H. However, because of persistence of the patient symptoms, a permanent pacemaker was eventually inserted. The case illustrates a hitherto not described manifestation of H. PMID- 21327491 TI - High prevalence of right ventricular dysfunction in ICD patients with shocks: a potential new predictor in risk stratification. AB - BACKGROUND: Despite identifying several risk factors for sudden cardiac death, our ability to predict arrhythmic events in patients with an implantable cardioverter defibrillator (ICD) remains poor. The purpose of this study was to determine if patients who received appropriate ICD shocks had a higher degree of right ventricular (RV) dysfunction at baseline when compared to patients who did not receive ICD shocks. METHODS: We conducted a 1:2 case-control, retrospective study comparing RV end-diastolic and end-systolic areas (RV ED and RV ES areas, respectively), fractional RV area change, and RV wall thickness in 19 consecutive patients who received appropriate ICD shocks (shock group) with another group of 38 patients who did not receive ICD shocks (no-shock group). RESULTS: There was no significant difference in the RV end-diastolic areas between the groups. However, patients who experienced ICD shocks had a higher RV end-systolic area and a lower RV fractional area change when compared to patients without ICD shocks, 16.3 +/- 4.9 cm(2) and 27.7 +/- 9.0% in the shock group versus 14.2 +/- 4.4 cm(2) and 35.8 +/- 10.3% in the no-shock group; (p = 0.08 and 0.004, respectively). Furthermore, the RV wall thickness was greater in patients with ICD shocks when compared to patients without ICD shocks, 0.49 +/- 0.05 cm and 0.44 +/- 0.04 cm, respectively (p = 0.001). Utilizing a logistic regression analysis and after controlling for variables with univariate significance (p < 0.1), RV wall thickness independently predicted ICD shocks (OR 13.9 mm(-1) change of RV thickness, p = 0.004). CONCLUSION: Our findings suggest that some measurements of RV function might prove to be useful in predicting future arrhythmic events. Additional prospective studies are needed to test this hypothesis. PMID- 21327492 TI - Recombination-suppression: how many mechanisms for chromosomal speciation? AB - Over the past decade several theoretical and empirical studies have revived interest in the role of chromosomes in speciation. The resulting models do not suffer from the problems experienced by previously proposed mechanisms of chromosomal speciation, because they invoke suppression of recombination rather than a reduction in the fitness of heterokaryotypes as their core process. However, they are not free from difficulties. The evidence for recombination suppression models is discussed here. The general conclusion is that a consensus opinion on which models best describe the real-world situation is currently unlikely because of an inability of the available empirical evidence to fully distinguish between them, which may be due in part to a lack of exclusivity. I argue that future work should take this lack of exclusivity into account. Resolving the biogeography of speciation is also suggested in order to tell the various models apart. Further study is needed which focuses on confirming the operation of individual elements of the various models, rather than attempting to validate any single mechanism as a whole. PMID- 21327493 TI - Different types of plant chromatin associated with modified histones H3 and H4 and methylated DNA. AB - Eukaryotic chromosomes are organized into two large and distinct domains, euchromatin and heterochromatin, which are cytologically characterized by different degrees of chromatin compaction during interphase/prophase and by post synthesis modifications of histones and DNA methylation. Typically, heterochromatin remains condensed during the entire cell cycle whereas euchromatin is decondensed at interphase. However, a fraction of the euchromatin can also remain condensed during interphase and appears as early condensing prophase chromatin. 5S and 45S rDNA sites and telomere DNA were used to characterize these regions in metaphase and interphase nuclei. We investigated the chromosomal distribution of modified histones and methylated DNA in the early and late condensing prophase chromatin of two species with clear differentiation between these domains. Both species, Costus spiralis and Eleutherine bulbosa, additionally have a small amount of classical heterochromatin detected by CMA/DAPI staining. The distribution of H4 acetylated at lysine 5 (H4K5ac), H3 phosphorylated at serine 10 (H3S10ph), H3 dimethylated at lysine 4 or 9 (H3K4me2, H3K9me2), and 5-methylcytosine was compared in metaphase, prophase, and interphase cells by immunostaining with specific antibodies. In both species, the late condensing prophase chromatin was highly enriched in H4K5ac and H3K4me2 whereas the early condensing chromatin was very poor in these marks. H3K9me2 was apparently uniformly distributed along the chromosomes whereas the early condensing chromatin was slightly enriched in 5-methylcytosine. Signals of H3S10ph were restricted to the pericentromeric region of all chromosomes. Notably, none of these marks distinguished classical heterochromatin from the early condensing euchromatin. It is suggested that the early condensing chromatin is an intermediate type between classical heterochromatin and euchromatin. PMID- 21327494 TI - Arterial oxygenation during one-lung ventilation may not improve within 30 min. PMID- 21327496 TI - A NMR-based metabolomic approach for differentiation of hagfish dental and somatic skeletal muscles. AB - The hagfish dental muscle is a large and specialized element of the feeding apparatus that helps ingest food. This muscle has enzymatic activities and contractile properties different from the hagfish somatic skeletal muscle. To verify the functional relevance of protein alterations, we examined the metabolomic differentiation of hagfish dental and somatic skeletal muscles using 1H-nuclear magnetic resonance (NMR)-based metabolomics and multivariate analysis that separated hagfish dental and somatic muscles by principal component analysis and partial least squares for discriminant analysis. Our analysis of assigned metabolites showed that anserine and taurine levels were higher in dental muscle, but creatine, fructose, glucose, glycerate, pyruvate, and succinate levels were higher in somatic muscle. We concluded that the primary energy sources of dental and somatic muscles are related to the citric acid cycle and the anaerobic glycolysis and metabolism of creatine. Thus, 1H-NMR-based metabolomics can be integrated with the previous proteomic approach to derive biochemical and physiological information about hagfish muscles. PMID- 21327495 TI - Phase 1 study of the novel vascular disrupting agent plinabulin (NPI-2358) and docetaxel. AB - BACKGROUND: Plinabulin (NPI-2358) is a vascular disrupting agent (VDA) that destabilizes tumor vascular endothelial cell architecture resulting in selective collapse of established tumor vasculature producing anti-tumor activity alone or in combination with cytotoxic agents. The objective of this study was to assess the recommended Phase 2 dose (RP2D) of plinabulin combined with docetaxel. PATIENTS AND METHODS: Patients received 75 mg/m(2) docetaxel on day 1 and plinabulin on days 1 and 8 intravenously in 21 day cycles. Plinabulin was escalated from the biologically effective dose (BED) of 13.5 mg/m(2) to the standard single agent dose of 30 mg/m(2) using a "3+3" design. RESULTS: Thirteen patients were enrolled. Adverse events were consistent with those of both agents alone. Fatigue, pain, nausea, diarrhea and vomiting were the most common events. One dose limiting toxicity of nausea, vomiting, dehydration and neutropenia occurred. The RP2D was 30 mg/m(2) of plinabulin with 75 mg/m(2) docetaxel. Pharmacokinetics did not indicate drug-drug interactions. Of the 8 patients with NSCLC evaluable for response, 2 achieved a partial response and 4 demonstrated lesser decreases in tumor measurements. CONCLUSIONS: The combination of full doses of plinabulin and docetaxel is tolerable. With encouraging antitumor activity, this supported further development of this combination. PMID- 21327497 TI - Influence of increased environmental water salinity on gluconeogenesis in the air breathing walking catfish, Clarias batrachus. AB - The present study was aimed at determining the effect of hypertonicity due to increased environmental water salinity on gluconeogenesis in air-breathing walking catfish (Clarias batrachus). In situ exposure to hypertonic saline solution (150 mM NaCl) led to a significant stimulation of glucose efflux due to gluconeogenesis from the liver after 7 days with further elevation after 14 days in the presence of each of the three potential gluconeogenic substrates (lactate, pyruvate, and glutamate). This was accompanied by significant increase of activities of three key gluconeogenic enzymes, namely phosphoenolpyruvate carboxykinase (PEPCK), fructose 1,6-biphosphatase (FBPase), and glucose 6 phosphatase (G6Pase) in liver and kidney by about twofold to threefold. Environmental hypertonicity also led to a significant elevation in the levels of PEPCK, FBPase, and G6Pase enzyme proteins in both the tissues by about 2- to 2.75 fold, accompanied by a significant elevation in the level of PEPCK mRNA by about 2- to 2.5-fold after 7 days, and further enhancement to about 3.5- to 4-fold after 14 days. Thus, the upregulation of PEPCK, FBPase. and G6Pase activities appears to be a result of transcriptional regulation of these genes. The induction of gluconeogenesis under environmental hypertonicity, which this catfish faces regularly in its natural habitat, possibly occurs as a consequence of changes in hydration status/cell volume of different cell types. This would certainly assist in maintaining glucose homeostasis, and also for a proper energy supply to support metabolic demands for ion transport and other altered metabolic processes under various environmental hypertonic stress-related insults. PMID- 21327498 TI - Changes in digestive enzyme activity during initial ontogeny of bay snook Petenia splendida. AB - Several samples of P. splendida larvae were obtained from eggs until day 60 after hatching (dah) to determine acid and alkaline proteases, trypsin, chymotrypsin, leucine aminopeptidase, alpha-amylase, lipase, and acid and alkaline phosphatase activities using biochemical techniques. Additionally, SDS-PAGE alkaline protease zymogram and PAGE acid protease zymogram were carried out to identify active isoforms during larviculture. Alkaline protease and chymotrypsin were present at the moment of hatching, increased gradually reaching the maximum values at 35 dah. Trypsin and leucine aminopeptidase activities were low from hatching, increasing gradually as larvae grew. Alkaline protease zymogram showed four zymogens, which appears at different days, remaining present until the end of the larviculture (95.2 kDa at 11 dah, 26.4 kDa at 9 dah, 21.4 kDa at 3 dah, and 23.3 kDa at hatching). Pepsin activity was present at day 7 after hatching and increased progressively until the end of the larviculture. Acid protease zymogram only showed one zymogen (0.65 rf), which appear at 6 dah. Lipase was high at the time of hatching and increased until 15 dah, after which decreased gradually. Amylase was high from the beginning and until 15 dah and then decreased rapidly to almost nothing onward. Alkaline and acid phosphatases presented a high activity at the egg stage, fell slightly during the first feeding and increased again from 20 to 30 dah. Results obtained in this study show that larvae can be fed artificial diets starting on day 10 after hatching. PMID- 21327499 TI - Is sperm DNA damage associated with IVF embryo quality? A systematic review. AB - PURPOSE: Sperm DNA damage is common amongst infertile men and may adversely impact natural reproduction, IUI-assisted reproduction and to a lesser degree IVF pregnancy. The objective of this study was to examine the influence of sperm DNA damage on embryo quality and/or development at IVF and ICSI. METHODS: We conducted a systematic review of studies that evaluated sperm DNA damage and embryo development and/or quality after IVF and/or ICSI. RESULTS: We identified 28 studies (8 IVF, 12 ICSI and 8 mixed IVF-ICSI studies) that evaluated the relationship between sperm DNA damage and embryo quality. These 28 studies evaluated 3226 treatment cycles (1033 IVF and 873 ICSI, 1320 mixed IVF-ICSI cycles) and demonstrated highly variable characteristics. In 11 of the 28 studies (1/8 IVF, 5/12 ICSI and 5/8 mixed IVF-ICSI studies), sperm DNA damage was associated with poor embryo quality and/or development, whereas the remaining 17 studies showed no relationship between sperm DNA damage and embryo quality and/or development. CONCLUSIONS: This systematic review indicates that the evaluable studies are heterogeneous and that overall, there is no consistent relationship between sperm DNA damage and embryo quality and/or development. The data also suggest that the influence of sperm DNA damage on embryo quality/development may be more significant in ICSI compared to IVF cycles. PMID- 21327500 TI - The effect of intrafollicular IGF 1 and IGFBP 3 on IVF outcome in patients using different gonadotropins: a prospective study. AB - AIM: To investigate follicular fluid IGF 1, IGFBP 3 and their effects on IVF outcome in patients using different gonadotropins. MATERIALS AND METHODS: This prospective study was performed among 92 IVF patients who were categorized according to IVF pregnancy outcome. Two groups were formed as Group 1 : pregnant, Group 2: non pregnant. RESULTS: Follicular IGF 1 and IGFBP 3 levels were not different between the two groups. There were negative correlations between follicular IGF 1 and age, gonadotropin dose, embryo numbers in all patients and group 2, but there were no correlations between IGF1 and these parameters in group 1. Although IGFBP 3 levels were not different in patients using rec FSH or HMG, IGF 1 were higher in patients treated by rec FSH compared to patient using HMG. When the groups using rec FSH or HMG were analyzed according to pregnancy rate, there were no differences in IGF 1 levels. CONCLUSION: Follicular IGF 1, IGFBP 3 do not predict clinical IVF outcome regardless of the different gonadotropin preparations. PMID- 21327501 TI - Prevalence of vitamin D3 deficiency in orange county residents. AB - With the prevalence of sunlight exposure in Orange County, California, one would expect it to be rare and unusual to find high incidence of Vitamin D deficiencies among its residents. This study evaluated the concentration of Vitamin D3 as part of a larger study to evaluate bone health in Orange County residents. Our preliminary data shows that 19.2% of the 151 subjects evaluated had low Vitamin D3 (<30 pg/ml) and illuminates a growing problem in the United States. We speculate that the widespread sensitivity to skin cancer and sun exposure, the increased use of sun-screens and the filtering of UV waves in automobile glass has put the public at risk for low Vitamin D. PMID- 21327502 TI - Sodium recommendations for special populations and the resulting implications. AB - Based on the most recent Dietary Guidelines for Americans, sodium recommendations are set at 2,300 mg for the general population and 1,500 mg for special populations. However, sodium intake among adults has been shown to be much higher than this; on average 3,436 mg. The Centers for Disease Control and Prevention notes that special populations (those with hypertension, African Americans, and those 40 years of age and older) make up 70% of adults in the United States. Excess sodium in the diet has been shown to contribute to problems such as blood pressure abnormalities, kidney function problems, and congestive heart failure, which account for a large sum of health care costs in the United States. The purpose of this review and accompanying three case studies was to explore if adherence to the sodium recommendations for special populations is feasible. Current literature shows that while a food industry-wide sodium reduction would help reduce overall sodium intake, adherence to low-sodium diets is difficult for the majority of individuals. Three case studies were completed which looked at subjects with a sodium recommendation of 1,500 mg. None of the participants met the recommendation, were aware of their daily sodium intake or knew how much they should be consuming. The snapshot provided by these case studies suggests further research is warranted. Because of the current state of sodium in the American diet, a combination of personal interventions coupled with widespread industry sodium reduction would be the most beneficial way to reduce dietary sodium for most individuals. PMID- 21327504 TI - Update in bridging anticoagulation. AB - Patients treated with a vitamin K antagonist may require interruption of their anticoagulation prior to an invasive procedure or surgery, and as a result, may be placed at a higher risk for thromboembolic events during this time. Either low molecular-weight heparin (LMWH) or unfractionated heparin is frequently used to bridge the gap in anticoagulation treatment because of their relatively rapid onset and offset of action compared to warfarin. Despite the lack of randomized trials supporting the efficacy of this bridging therapy, guidelines have been developed to assist providers with this common clinical challenge. Key issues in bridging therapy include identifying patients who can safely undergo an invasive procedure while continuing their vitamin K antagonist, identifying those who will likely gain the most benefit from bridging anticoagulation, and determining the optimal dose and timing of parenteral anticoagulants in the perioperative period. PMID- 21327503 TI - Antithrombotic therapies in patients with prosthetic heart valves: guidelines translated for the clinician. AB - Patients with prosthetic heart valves require chronic oral anticoagulation. In this clinical scenario, physicians must be mindful of the thromboembolic and bleeding risks related to chronic anticoagulant therapy. Currently, only vitamin K antagonists are approved for this indication. This paper reviews the main heart valve guidelines focusing on the use of oral anticoagulation in these patients. PMID- 21327505 TI - Quality measures and benchmarking for warfarin therapy. AB - The ultimate goal of warfarin therapy, to prevent thromboembolism with the lowest possible risk of major bleeding complications, is most likely to be realized when therapeutic anticoagulation as measured by the international normalized ratio (INR) is quickly achieved and maintained in appropriate candidates. Realizing this goal requires optimal functioning of various anticoagulation management system components. The extent to which these components function smoothly together determines the quality of warfarin therapy management. A quality measure is used to ascertain the degree to which a given system is successfully coordinating care to accomplish a particular therapeutic goal. The quality of care can be evaluated at different levels such as outcomes (e.g. INR results, major bleeding, thromboembolism, death), processes (e.g. method used to adjust warfarin doses), and structures (e.g. clinic organization structure, workload statistics). There is great need for a structured program of quality measurement for warfarin therapy management. The arrival of new options for oral anticoagulation medications increases the need for credible information regarding the site-specific quality of warfarin therapy management because the potential advantages over warfarin therapy associated with some of these agents are in part dependent upon the quality of warfarin therapy management. PMID- 21327508 TI - Which patients with unprovoked VTE should receive extended anticoagulation? the minority. AB - Venous thromboembolism (VTE) is associated with a long term risk of recurrence. This risk is at least in part related to the presence of major identifiable risk factors at the time of the index event. It is generally low in the presence of removable risk factors, and very high in the presence of permanent risk factors such as active cancer. This categorization is important because it drives the duration of secondary prevention treatment with anticoagulant drugs. Unfortunately, up to 40-50% of VTE events remain classified as unprovoked. This large group of patients is obviously heterogeneous, with an unpredictable risk of recurrence. Evidences from clinical trials suggest that extending secondary prevention with vitamin K antagonists (VKAs) for 1 or 2 years after an initial course of treatment in patients with unprovoked VTE does not provide additional benefit in terms of reducing the long term risk of recurrence. Prolonging indefinitely the duration of treatment would likely be effective in reducing this risk, but at the cost of unnecessarily expose the majority of patients to several complications, there including major bleeding events, and inconveniences. A number of variables have been identified to predict the individual risk of recurrence in these patients and some clinical prediction rules have been proposed. Improved patients stratification, together with a better understanding of the mechanisms underlying unprovoked VTE, should allow physicians to individually tailor the optimal duration of secondary prevention and to identify those patients (likely the minority) for whom indefinite duration of treatment is warranted. PMID- 21327506 TI - Heparin-induced thrombocytopenia: present and future. AB - Heparin-induced thrombocytopenia (HIT) is a prothrombotic and potentially devastating complication of heparin therapy due to formation of platelet activating antibodies against complexes of platelet factor 4 and heparin. Over the last several decades, great advances in our understanding of HIT have elevated a once enigmatic syndrome, the mere existence of which was doubted by the medical community, to a well-characterized disorder. Nevertheless, critical questions remain unanswered. The objective of this review is to examine our current understanding of the epidemiology, pathophysiology, diagnosis, and management of HIT and to highlight areas of future inquiry. PMID- 21327509 TI - Transforming oral anticoagulation by combining international normalized ratio (INR) self testing and online automated management. AB - Because of the number and complexity of issues addressed, this manuscript is divided into two major sections. The first section focuses on how new technology can transform vitamin K antagonist therapy. Specifically, evidence suggest that combining INR self testing with online automated management (STOAM) can greatly reduce the time, expense, and hassle of managing VKA therapy; improve the quality of INR control to a degree that, in large studies, has been associated with a 50% or more reduction in major events (such as stroke, myocardial infarction, major hemorrhage, and death); reduce health care costs by an estimated $4 million per 1,000 patients per year; and improve quality of life and patient satisfaction. Such improved VKA therapy should be safer, more effective, and more cost effective than the new oral anticoagulants. The improved efficiency and outcomes also should prompt reconsideration of indications in which VKA therapy may not be the current standard of care. Although new reimbursement models are clearly needed for STOAM, the current Medicare reimbursement model for patient self testing can be utilized to make VKA management financially viable and sustainable. The second section of this article focuses on additional considerations that may be important in optimizing VKA therapy and/or selecting an online management system. A brief review is provided to examine why a recent meta analysis and a large randomized trial of self testing did not find the same degree of improvement as reported in the four STOAM trials described in the first section of this article. PMID- 21327510 TI - Challenges and benefits of an inpatient anticoagulation service: one hospital's experience. AB - While outpatient anticoagulation services (AMS) have existed extensively for a number of years, inpatient AMS have only recently begun to be implemented on a widespread basis. This is in direct response to anticoagulation regulations set forth by entities such as the Joint Commission (TJC) and the Centers for Medicare and Medicaid services (CMS). Hospitals not complying with these regulations are at risk for either financial or accreditation punition. Inpatient AMS have reported positive impacts on patient outcomes in the literature, which gives hospitals an additional impetus to provide this type of service. Inpatient AMS pose many challenges, including identification of resources for development and implementation of the service, means to make changes to the service as it evolves and effectively tracking performance of the service. Using a well-planned, methodical approach for implementation has helped our institution capitalize on the numerous potential benefits of an inpatient AMS, including improved inpatient anticoagulation therapy, improved transitions of care and enhanced interdisciplinary practices. PMID- 21327511 TI - New oral anticoagulants. AB - The new oral anticoagulants may prove to be one of the most significant innovations in clinical practice in the past 60 years. Apixaban and rivaroxaban are specific inhibitors of Factor Xa while dabigatran inhibits Factor IIa. The predictable pharmacological profile of these new agents will allow physicians to use these drugs without the need for routine coagulation monitoring which is the mainstay of warfarin therapy. In addition, these new agents have not been shown to have any food interactions and limited drug-drug interactions due to their minimal metabolism through the CYP450 system. This unique pharmacokinetic profile may usher in for clinicians a new era of managing thromboembolic disorders. In this paper, the pharmacology of these new oral anticoagulants are reviewed along with the major clinical trials in venous thromboembolism prevention in total hip and knee replacement orthopedic surgery, the treatment of venous thromboembolic disorders and stroke prevention in atrial fibrillation. PMID- 21327512 TI - Antiplatelet agents in cardiovascular disease. AB - Despite improvements in the treatment of acute coronary syndromes (ACS), cardiovascular disease remains the leading cause of death in the United States. Antiplatelet agents, such as aspirin and clopidogrel, play an important role in the treatment of patients with ACS, particularly those at high risk for whom treatment may yield the greatest benefits. The main challenge in preventing and managing ACS is to tailor treatment for each patient by taking into consideration patient characteristics, comorbidities, underlying short- and long-term risk factors, ischemic and bleeding risks, and expected individual responses to different medications. Several new alternatives providing more rapid and consistent platelet inhibition than aspirin and clopidogrel have been introduced for routine treatment of patients with ACS. These new treatments seem to provide additional benefits without a significant increase in the risk of bleeding, if used for the appropriate patients. In this article, we review the new antiplatelet agents being developed as well as their pharmacological characteristics, potential clinical indications, and key interactions with other antithrombotic drugs. PMID- 21327513 TI - Designer promoter: an artwork of cis engineering. AB - Advances in systematic computational biology and rapid elucidation of synergistic interplay between cis and trans factors governing transcriptional control have facilitated functional annotation of gene networks. The generation of data through deconstructive, reconstructive and database assisted promoter studies, and its integration to principles of synthetic engineering has started an era of designer promoters. Exploration of natural promoter architecture and the concept of cis engineering have not only enabled fine tuning of single or multiple transgene expression in response to perturbations in the chemical, physiological and environmental stimuli but also provided researchers with a unique answer to various problems in crop improvement in the form of bidirectional promoters. PMID- 21327514 TI - Citrus tristeza virus infection induces the accumulation of viral small RNAs (21 24-nt) mapping preferentially at the 3'-terminal region of the genomic RNA and affects the host small RNA profile. AB - To get an insight into the host RNA silencing defense induced by Citrus tristeza virus (CTV) and into the counter defensive reaction mediated by its three silencing suppressors (p25, p20 and p23), we have examined by deep sequencing (Solexa-Illumina) the small RNAs (sRNAs) in three virus-host combinations. Our data show that CTV sRNAs: (i) represent more than 50% of the total sRNAs in Mexican lime and sweet orange (where CTV reaches relatively high titers), but only 3.5% in sour orange (where the CTV titer is significantly lower), (ii) are predominantly of 21-22-nt, with a biased distribution of their 5' nucleotide and with those of (+) polarity accumulating in a moderate excess, and (iii) derive from essentially all the CTV genome (ca. 20 kb), as revealed by its complete reconstruction from viral sRNA contigs, but adopt an asymmetric distribution with a prominent hotspot covering approximately the 3'-terminal 2,500 nt. These results suggest that the citrus homologues of Dicer-like (DCL) 4 and 2 most likely mediate the genesis of the 21 and 22 nt CTV sRNAs, respectively, and show that both ribonucleases act not only on the genomic RNA but also on the 3' co terminal subgenomic RNAs and, particularly, on their double-stranded forms. The plant sRNA profile, very similar and dominated by the 24-nt sRNAs in the three mock-inoculated controls, was minimally affected by CTV infection in sour orange, but exhibited a significant reduction of the 24-nt sRNAs in Mexican lime and sweet orange. We have also identified novel citrus miRNAs and determined how CTV influences their accumulation. PMID- 21327516 TI - Genome-wide transcriptome and proteome analyses of tobacco psaA and psbA deletion mutants. AB - Photosynthesis in higher land plants is a complex process involving several proteins encoded by both nuclear and chloroplast genomes that require a highly coordinated gene expression. Significant changes in plastid differentiation and biochemical processes are associated with the deletion of chloroplast genes. In this study we report the genome-wide responses caused by the deletion of tobacco psaA and psbA genes coding core components of photosystem I (PSI) and photosystem II (PSII), respectively, generated through a chloroplast genetic engineering approach. Transcriptomic and quantitative proteomic analysis showed the down regulation of specific groups of nuclear and chloroplast genes involved in photosynthesis, energy metabolism and chloroplast biogenesis. Moreover, our data show simultaneous activation of several defense and stress responsive genes including those involved in reactive oxygen species (ROS) scavenging mechanisms. A major finding is the differential transcription of the plastome of deletion mutants: genes known to be transcribed by the plastid encoded polymerase (PEP) were generally down regulated while those transcribed by the nuclear encoded polymerase (NEP) were up regulated, indicating simultaneous activation of multiple signaling pathways in response to disruption of PSI and PSII complexes. The genome wide transcriptomic and proteomic analysis of the ?psaA and ?psbA deletion mutants revealed a simultaneous up and down regulation of the specific groups of genes located in nucleus and chloroplasts suggesting a complex circuitry involving both retrograde and anterograde signaling mechanisms responsible for the coordinated expression of nuclear and chloroplast genomes. PMID- 21327517 TI - Mutations in bone morphogenetic protein 15 and growth differentiation factor 9 genes are associated with increased litter size in fat-tailed sheep breeds. AB - The objective of this study was to investigate association between GDF9 and BMP15 gene polymorphism and litter size in fat-tailed sheep, a total of 97 mature ewes from four breeds (Afshari=19; Baluchi=18; Makui=30 and Mehraban=30) were genotyped for the BMP15 HinfI and GDF9 HhaI polymorphisms by PCR-RFLP technique. The highest and lowest mutant allele frequencies were found in Makui (0.27) and Afshari (0.10) sheep for the BMP15 gene and in Afshari (0.24) and Mehraban (0.18) sheep for the GDF9 gene, respectively. Litter size was significantly influenced by genotype of the ewe for two genes (P < 0.01). Heterozygous genotypes for both loci showed higher litter size than homozygous genotypes (P < 0.01). None of the individuals carried homozygous genotype for both of the GDF9 and BMP15 variants in these breeds. The individuals carrying the mutant allele for one of the investigated candidate gene still showed fertile phenotype. Thus, existence of homozygosity at one of the BMP15 and GDF9 variant is not probably able to block normal hormonal pathway of reproduction in fat-tailed sheep. PMID- 21327518 TI - Potential use of cholesterol lipoprotein profile to confirm obesity status in dogs. AB - A common sign of obesity, in dogs, is hyperlipidemia, which is characterized by hypercholesterolemia and/or hypertriglycemia. Hyperlipidemia can be caused by a quantitative increase in circulating lipoproteins (LP) or by a higher lipid concentration in the various LP classes. In this study, we sought to determine whether aberrations occur with cholesterol lipoprotein profile, especially with sub HDL-cholesterol fraction % in obese dogs. Using clinically healthy and disease free (no overt signs) body condition score classified obese dogs, of all ages, we attempted to determine the influence of age, gender and obesity status on cholesterol lipoprotein profiling. Overall, no aberration in pattern was observed in obese dogs <8 years of age. However, in older obese animals (>=8 years of age), the general aberration pattern to cholesterol lipoprotein observed was that a significant decrease in HDL2 and 3 fraction % occurs with a concomitant increase in either HDL1-Cho or VLDL and LDL -Cho fraction % depending on gender. Linear regression analysis indicated that obesity status appears to significantly affect total cholesterol, HDL2 and 3-Cho, VLDL and LDL-Cho levels (P=0.02, 0.046, and 0.045, respectively), whereas it is borderline with HDL1-Cho (P=0.062). On the other hand, age significantly influenced TG, Total cholesterol, and HDL1-Cho levels (P=0.009, 0.006, and 0.002, respectively), while gender influenced VLDL and LDL-Cho (P=0.024) level. Therefore, aberrations in cholesterol lipoprotein profile pattern might be of potential use to assess and diagnose obesity status, in conjunction with BCS, especially of older overweight animals which might be considered borderline obese. PMID- 21327519 TI - New phenolic compounds from Camellia sinensis L. leaves fermented with Aspergillus sp. AB - Two new phenolic compounds, teadenol A (1) and teadenol B (2), were isolated from tea (Camellia sinensis L.) leaves fermented with Aspergillus sp. (PK-1, FARM AP 21280). The chemical structures of 1 and 2 were elucidated based on the analyses of their spectroscopic data. The absolute configurations of the structures of 1 and 2 were also certified by their biosynthetic preparation in the treatment of tea catechins with Aspergillus sp. PMID- 21327520 TI - Ferrearin C induces apoptosis via heme oxygenase-1 (HO-1) induction in neuroblastoma. AB - We investigated the cytotoxicity of six neolignans (1-6), which are similar in structure to furanocyclohexenone with an angular allyl group, in human neuroblastoma cell lines (IMR-32, LA-N-1, NB-39, SK-N-SH) and normal cells [human umbilical vein endothelial cells (HUVEC) and human dermal fibroblasts (HDF)] using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Two neolignans, ferrearin C (1) and 2, showed significant cytotoxicity in neuroblastoma cells. Typical morphologic features of apoptosis were observed for the ferrearin-type neolignans using Hoechst 33342, and apoptotic cytoplasmic membrane inversion was also induced by ferrearin-type neolignans in IMR-32. Furthermore, a Proteome Profiler Array showed that the ferrearin-type neolignans induced the marked expression of heme oxygenase-1 (HO-1). In a western blot analysis, ferrearin C (1) increased the level of Bax and reduced the level of survivin, indicating the activation of the mitochondrial pathway of apoptosis. PMID- 21327521 TI - Honokiol enhances adipocyte differentiation by potentiating insulin signaling in 3T3-L1 preadipocytes. AB - Adipose tissue plays an essential role in energy homeostasis as a metabolic and endocrine organ. Accordingly, adipocytes are emerging as a major drug target for obesity and obesity-mediated metabolic syndrome. Dysfunction of enlarged adipocytes in obesity is involved in obesity-mediated metabolic syndrome. Adipocytokines, such as adiponectin released from small adipocytes, are able to prevent these disorders. In this study, we found that honokiol, an ingredient of Magnolia officinalis used in traditional Chinese and Japanese medicines, enhanced adipocyte differentiation in 3T3-L1 preadipocytes. Oil Red O staining showed that treatment with honokiol in the presence of insulin dose-dependently increased lipid accumulation in 3T3-L1 preadipoyctes although its activity was weak compared with rosiglitazone. During adipocyte differentiation, the expression of peroxisome proliferator-activated receptor gamma2 (PPARgamma2) mRNA and PPARgamma target genes such as adipocyte protein 2 (aP2), adiponectin, and GLUT4 was induced by treatment with 10 MUM honokiol. However, honokiol failed to show direct binding to the PPARgamma ligand-binding domain in vitro. In preadipocytes, treatment with honokiol in the presence of insulin increased the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 protein and Akt protein, early insulin signaling pathways related to adipocyte differentiation, compared with insulin-only treatment. Taken together, our results suggest that honokiol promotes adipocyte differentiation through increased expression of PPARgamma2 mRNA and potentiation of insulin signaling pathways such as the Ras/ERK1/2 and phosphoinositide-3-kinase (PI3K)/Akt signaling pathways. PMID- 21327522 TI - Psychopharmacological properties of an aqueous extract of Tetracarpidium conophorum Hutch. & Dalziel in mice. AB - The extract of the nut of Tetracarpidium conophorum (TC), commonly known as African walnut, is widely used to relieve pain, increase sperm count, enhance sexual performance in males and as a nerve tonic in ethnomedicine. This study describes the psychopharmacological properties of the aqueous extract of the nut of TC in mice. The spectrum of activities studied were the effects of TC on the duration of immobility in the forced swim test of the behavioural despair model of depression; prolongation of the duration of sleep produced by thiopentone; amphetamine-induced stereotyped behaviour; and on pain episodes produced by acetic acid and by formalin. Orally administered TC (50-200 mg/kg) produced a significant and dose-related decrease in the duration of immobility in the forced swim test in mice. TC also exhibited analgesic property, as shown by its ability to reduce the frequency of abdominal constrictions induced by acetic acid and to inhibit the nociceptive responses produced by formalin. However, at the tested oral doses of 50-200 mg/kg, TC did not prolong the duration of sleep produced by thiopentone nor alter the pattern of the stereotyped behaviour induced by amphetamine. This investigation provides evidence that may support the ethnomedicinal applications of the extract of the nut of TC in the treatment of pain. The study also revealed that TC seems to demonstrate antidepressant-like activity, as evidenced by its ability to shorten the period of immobility in the forced swim test; however, further studies are necessary to clearly define the role of TC in depression. PMID- 21327523 TI - Total, free, and protein-bound thiols in plasma of peritoneal dialysis and predialysis patients. AB - Thiol compounds such as glutathione, homocysteine, and cysteinyl-glycine are the natural reservoir of reductive capacity of the cells. Chronic renal failure is accompanied by disturbances in redox status of plasma thiols. The aim of the present study was to compare the changes in concentrations of different forms of thiols in plasma of terminal renal failure patients, nondialyzed and on peritoneal dialysis. Total concentrations of different redox forms of thiols were determined by high performance liquid chromatography. We observed that total concentration of glutathione in terminal renal failure patients decreased and total concentration of the remaining thiols in these patients significantly increased. Continuous ambulatory peritoneal dialysis had the following features in comparison with nondialyzed patients: (1) glutathione and cysteine concentration was restored and (2) free fraction of thiols rose, while protein bound fraction dropped (except for homocysteine). Continuous ambulatory peritoneal dialysis corrects total concentration of glutathione and cysteine, in comparison with nondialyzed patients. PMID- 21327524 TI - The epidemiology of end-stage renal disease in Nigeria: the way forward. AB - The incidence of CKD (Chronic kidney disease) in Nigeria has been shown by various studies to range between 1.6 and 12.4%. We have shown that the burden of renal disease in Nigeria is probably significantly higher than any previous study on end-stage renal disease (ESRD) has documented, as most studies are hospital based and fail to include the many patients who do not have access to hospital care. The increased prevalence of ESRD among blacks in the United States and South Africa compared with other races also suggests that ESRD may be more prevalent in Africa than in the United States and other developed nations. Common causes of CKD in Nigerian adults are glomerulonephritis and hypertension, while common causes in children are glomerulonephritis and posterior urethral valves. In the United States, diabetes and hypertension are the commonest causes of CKD and glomerulonephritis plays a less important role. Access to renal replacement therapy (RRT) in Nigeria is limited, and mortality rates are very high, ranging between 40 and 50%. Important steps towards improving the situation are the development of prevention programmes and increased funding to ensure increased availability of RRT. To achieve this, health policies concerning CKD must be formulated, and the lack of a renal registry makes it difficult for this to be done. There is need for the development of a functional organizational structure for the reporting of CKD in Nigeria, the Nigerian Renal Registry. PMID- 21327525 TI - Elevated serum parathyroid hormone is a cardiovascular risk factor in moderate chronic kidney disease. AB - INTRODUCTION: Over 8% of adults in the United States are estimated to have moderate (stages 3 and 4) chronic kidney disease (CKD), which is increasingly recognized as one of the independent predictors for cardiovascular (CV) disease and related mortality. Secondary hyperparathyroidism with elevated serum intact parathyroid hormone (iPTH) is associated with increased CV mortality in end-stage renal disease and this relationship is unclear in moderate CKD. METHODS: Medical records of 196 patients at Harry S. Truman Memorial Veterans Hospital with stages 3 and 4 CKD (glomerular filtration rate, GFR 16-59 ml/min/1.73 m(2)) who had iPTH levels determined from 4/2006 to 9/2007 were reviewed. CV event was defined as occurrence of any of the following during follow-up: myocardial infarction, stroke, coronary/carotid/peripheral artery revascularization, and death due to CV reasons. RESULTS: During median follow-up of 27.2 months, 48 patients had CV events, while 148 patients did not. iPTH was elevated (156.43 +/- 107.49) for patients who had CV events compared with those without (109.12 +/- 86.54, P = 0.003). Among the covariates studied in the multivariate analysis including history of vascular disease, 25-OH Vit D, corrected calcium, phosphorus levels, calcium-phosphorus product, and GFR, iPTH level was found to have a positive association with CV events during follow-up period (odds ratio = 1.3 for 50 pg/ml change in iPTH, 95% CI: 1.03-1.55, P = 0.02)). Cardiovascular disease history was the only other significant variable with estimated odds ratio of 5.9 (P = 0.002). CONCLUSION: iPTH level in patients with stages 3 and 4 CKD is associated with increased incidence of cardiovascular events independent of calcium-phosphorous level. PMID- 21327526 TI - Elephantiasis nostras verrucosa of the pannus. PMID- 21327527 TI - Groups' use of patient experience data. PMID- 21327528 TI - Filling the black hole of hospital discharge (editorial in response to article by Walz et al.,J Gen Intern Med 2011). PMID- 21327529 TI - Improving the follow-up of positive hemoccult screening tests: an electronic intervention. AB - BACKGROUND: Four population-based studies of screening for CRC with fecal occult blood testing (FOBT) have shown that mortality can be significantly reduced. However, nearly half of all positive screening tests are not appropriately evaluated. OBJECTIVES: We evaluated whether an electronic record intervention improved the follow-up of patients with a positive FOBT (FOBT+) result. DESIGN: We conducted a cluster randomized trial involving four Veteran's Affairs (VA) medical centers pair-matched by colonoscopy volume and randomized within the pair to receive the electronic intervention or usual care. PARTICIPANTS: All patients with FOBT+ results at participating facilities during a matched pre- and post intervention time period. INTERVENTIONS: In the two intervention sites, an electronic consult that imported relevant clinical information was automatically submitted to the gastroenterology (GI) clinic for all FOBT+ patients at the time the result was recorded in the laboratory. In both intervention and control sites (usual care), PCPs continued to be notified of FOBT+ results in the usual manner MEASURES: Pre- and post-intervention changes in the proportion of FOBT+ patients having: (1) a GI consult or (2) a GI consult plus complete diagnostic evaluation (CDE) of the colon within 30, 90 and 180 days were compared across intervention and control sites. Log rank tests were used to determine statistical significance. RESULTS: The 30-, 90- and 180-day GI consult rates improved 21-33 % (p < 0.001) among intervention sites, but did not change in the usual care sites. Thirty-, 90- and 180-day CDE rates improved 9-31% (p < 0.03) in intervention sites, but did not significantly change in the usual care sites. Time to GI consult and CDE decreased significantly over time in the intervention sites (p < 0.001), but remained unchanged in the usual care sites. CONCLUSIONS: The relatively simple electronic intervention evaluated can significantly improve the follow-up of FOBT+ results. Interventions such as this could improve patient care and may be applicable to other practice settings, as well as other types of tests. PMID- 21327530 TI - Engineering cotton (Gossypium hirsutum L.) for resistance to cotton leaf curl disease using viral truncated AC1 DNA sequences. AB - Several important biological processes are performed by distinct functional domains found on replication-associated protein (Rep) encoded by AC1 of geminiviruses. Two truncated forms of replicase (tAC1) gene, capable of expressing only the N-terminal 669 bp (5'AC1) and C-terminal 783 bp (3'AC1) nucleotides cloned under transcriptional control of the CaMV35S were introduced into cotton (Gossypium hirsutum L.) using LBA4404 strain of Agrobacterium tumefaciens to make use of an interference strategy for impairing cotton leaf curl virus (CLCuV) infection in transgenic cotton. Compared with nontransformed control, we observed that transgenic cotton plants overexpressing either N terminal (5'AC1) or C-terminal (3'AC1) sequences confer resistance to CLCuV by inhibiting replication of viral genomic and beta satellite DNA components. Molecular analysis by Northern blot hybridization revealed high transgene expression in early and late growth stages associated with inhibition of CLCuV replication. Of the eight T(1) transgenic lines tested, six had delayed and minor symptoms as compared to nontransformed control lines which developed disease symptoms after 2-3 weeks of whitefly-mediated viral delivery. Virus biological assay and growth of T(2) plants proved that transgenic cotton plants overexpressing 5'- and 3'AC1 displayed high resistance level up to 72, 81%, respectively, as compared to non-transformed control plants following inoculation with viruliferous whiteflies giving significantly high cotton seed yield. Progeny analysis of these plants by polymerase chain reaction (PCR), Southern blotting and virus biological assay showed stable transgene, integration, inheritance and cotton leaf curl disease (CLCuD) resistance in two of the eight transgenic lines having single or two transgene insertions. Transgenic cotton expressing partial AC1 gene of CLCuV can be used as virus resistance source in cotton breeding programs aiming to improve virus resistance in cotton crop. PMID- 21327531 TI - Prognostic factors for post-recurrence survival in esophageal squamous cell carcinoma patients with recurrence after resection. AB - OBJECTIVE: The survival of recurrent esophageal cancer is poor. But reports regarding prognostic factors for post-recurrence survival are limited. We analyzed the recurrence pattern and the prognostic factors for post-recurrence survival in esophageal squamous cell carcinoma with recurrence after resection. METHODS: Two hundred sixty-eight patients were included. Tumor recurrence occurred in 115 (42.9%) patients. Recurrence pattern was classified as locoregional, distant, and combined recurrence. The post-recurrence survival was defined as the interval between initial recurrence and either death or the last follow-up. RESULTS: Mediastinum lymphadenopathy was the most common site for locoregional recurrence, whereas lung, liver, and bone were the most common sites for distant recurrence. The overall 1- and 2-year post-recurrence survival rates were 32.6% and 12.6% with a median survival after recurrence of 6.0 months. The independent prognostic factors included liver recurrence (HR = 2.255, 95%CI = 1.073-4.741, p = 0.032), time to recurrence <=10 months (HR = 2.657, 95%CI = 1.438-4.911, p = 0.002), and no treatment for recurrences (HR = 2.745, 95%CI = 1.635-4.608, p < 0.001). CONCLUSIONS: We identify liver recurrence, early recurrence, and no treatment for recurrence as risk factors for dismal post recurrence survival. PMID- 21327532 TI - Analysis of factors associated with prognosis after colorectal cancer resection in 174 Chinese elderly patients. AB - PURPOSE: The purpose of the present study was to investigate risk factors associated with prognosis in elderly patients with colorectal cancer (CRC) and to determine treatment and follow-up strategies. MATERIALS AND METHODS: CRC patients (age >=70) who were treated with curative operation were studied. We compared 57 patients whose survival time was less than 2 years with 117 patients with survival time exceeding 5 years, based on the clinical, pathologic, and preoperative clinical laboratory analysis findings. A risk scoring system on basis of factors determined by multiple logistic regression analysis was explored and validated by both receiver operating characteristic and survival analysis. RESULTS: Neuroticism, rural residence, deep layer invasion, lymphovascular invasion, and high serum CEA levels were found to be associated with adverse prognosis in the multivariate logistic regression model. Risk scoring system based on these factors showed that the patients with total score exceeding 2.5 had a significantly poorer prognosis (P < 0.05), which was validated by survival analysis. CONCLUSIONS: Patients with neuroticism, rural residence, deep layer invasion, lymphovascular invasion, and high serum CEA level should be regarded as a high-risk group; a simple scoring system based on these factors could be used to evaluate the risk and facilitate treatment of CRC for elderly patients. PMID- 21327533 TI - Medically managed hypercholesterolemia and insulin-dependent diabetes mellitus preoperatively predicts poor survival after surgery for pancreatic cancer. AB - INTRODUCTION: Although patients with pancreatic ductal adenocarcinoma (PDAC) frequently require medications to treat pre-existing conditions, the impact of these treatments on outcomes post-resection is unknown. The purpose of this study was to determine the impact of preoperative medications on overall survival after pancreatic resection. METHODS: Multi-institutional data on preoperative medications and outcomes in patients undergoing resection for PDAC were analyzed. Univariate and multivariate analyses were performed to determine which medications were predictive of early mortality. RESULTS: Of the 518 patients resected for PDAC, 13.3% were being treated preoperatively with insulin, 14.8% were on a statin, 1.7% were on steroids, and 7.6% were on thyroxin. On univariate analysis, patients taking preoperative insulin had a higher 90-day mortality rate relative to those not on insulin (13.0% vs. 4.8%, p = 0.024), and those on a statin had a higher 90-day mortality than those who were not (10.8% vs. 4.6%, p = 0.035). Preoperative steroids and thyroxin were not associated with 90-day mortality (p = 0.409 and p = 0.474, respectively). Insulin and statin use was a stronger predictor of 90-day mortality than history of diabetes (p = 0.101), BMI >= 30 (p = 0.166), cardiac disease (p = 0.168), pulmonary disease (p = 1.000), or renal dysfunction (p = 1.000). Older patients also had a higher risk of early postoperative death (p = 0.011). On multivariate analysis, only preoperative insulin usage and statin treatment independently predicted early mortality (odds ratio (OR) = 3.043; 95% confidence interval (CI), 1.256-7.372; p = 0.014, and OR = 2.529; 95% CI, 1.048-6.104; p = 0.039, respectively). Based on the beta coefficients, a simple scoring system was devised to predict survival after resection from preoperative medication use. Zero points were assigned to patients who were on neither insulin nor a statin, one point to those who were on one or the other, and two points to those who were on both insulin and a statin. The score correlated with early postoperative survival (90-day mortality rates of 3.4%, 11.5%, and 13.3% for 0, 1, and 2 points, respectively, p = 0.004). Increasing score was also associated with poorer long-term outcomes, with a median overall survival of 19.6, 15.6, and 11.2 months for 0, 1, and 2 points, respectively (p = 0.002, median follow-up 14.4 months). CONCLUSIONS: Patients with PDAC being treated for pre-existing diabetes or hypercholesterolemia with either insulin or statin-based therapy have an increased risk of early postoperative mortality. A simple scoring system based on preoperative medications can be used to predict early and overall survival following resection. PMID- 21327534 TI - Electroacupuncture in reduction of discomfort associated with barostat-induced rectal distension--a randomized controlled study. AB - BACKGROUND: This pilot study aims to explore the effectiveness of electroacupuncture in reduction of colorectal discomfort caused by Barostat induced rectal distension. METHOD: Subjects scheduled for a colonoscopy screening procedure were recruited and randomized to receive either electroacupuncture (EA) or sham acupuncture (SA) (short stud instead of needle) for 45 min to acupuncture points Hegu (LI4), Neiguan (PC6), and Zusanli (ST36). A balloon catheter attached to the Dual Drive Barostat machine was then inserted into the subjects' rectal region. Colorectal discomfort after each incremental pressure (4 mmHg) rise was assessed by visual analog and a four-point subjective discomfort scale. Blood beta-endorphin level was measured before, immediately after acupuncture, at 24 mmHg, and at maximal tolerable inflation pressure. RESULTS: Forty subjects completed the study. Rectal discomfort was reported at a higher inflation pressure in the EA group compared to the SA group (p < 0.05). Twelve subjects in the EA group were able to tolerate the maximal inflation pressure (48 mmHg) compared to only four in the SA group. Beta-endorphin levels increased significantly in the EA group but not in the SA group. CONCLUSION: Electroacupuncture appeared to be effective in reduction of colorectal discomfort during Barostat-induced rectal distension. The role of electroacupuncture during colonoscopy warrants further investigation. PMID- 21327535 TI - Molecular dynamics of the diatom thylakoid membrane under different light conditions. AB - During the last years significant progress was achieved in unraveling molecular characteristics of the thylakoid membrane of different diatoms. With the present review it is intended to summarize the current knowledge about the structural and functional changes within the thylakoid membrane of diatoms acclimated to different light conditions. This aspect is addressed on the level of the organization and regulation of light-harvesting proteins, the dissipation of excessively absorbed light energy by the process of non-photochemical quenching, and the lipid composition of diatom thylakoid membranes. Finally, a working hypothesis of the domain formation of the diatom thylakoid membrane is presented to highlight the most prominent differences of heterokontic thylakoids in comparison to vascular plants and green algae during the acclimation to low and high light conditions. PMID- 21327537 TI - Stability-indicating spectrofluorimetric method for the assay of ziprasidone in capsules. AB - A simple, rapid and highly sensitive spectrofluorimetric method was developed for determination of ziprasidone hydrochloride (ZPS) in capsules. The method is based on measuring the native fluorescence of ZPS in acetate buffer of pH 4.5 at 398 nm after excitation at 315 nm. The fluorescence-concentration plot was rectilinear over the range of 0.05-0.80 MUg mL(-1) with a lower detection limit (LOD) of 6.0 ng mL(-1) and quantification limit (LOQ) of 20.0 ng mL(-1). The method was fully validated and successfully applied to the determination of ZPS in its capsules with average percentage recovery of 99.7 +/- 1.4. The method was extended to stability study of ZPS. The drug was exposed to acidic, alkaline, oxidative and photolytic degradation according to ICH guidelines. Moreover, the method was utilized to investigate the kinetics of the alkaline, acidic and oxidative degradation of the drug. A proposal for the degradation pathways was postulated. PMID- 21327536 TI - Algal and aquatic plant carbon concentrating mechanisms in relation to environmental change. AB - Carbon dioxide concentrating mechanisms (also known as inorganic carbon concentrating mechanisms; both abbreviated as CCMs) presumably evolved under conditions of low CO(2) availability. However, the timing of their origin is unclear since there are no sound estimates from molecular clocks, and even if there were, there are no proxies for the functioning of CCMs. Accordingly, we cannot use previous episodes of high CO(2) (e.g. the Palaeocene-Eocene Thermal Maximum) to indicate how organisms with CCMs responded. Present and predicted environmental change in terms of increased CO(2) and temperature are leading to increased CO(2) and HCO(3)(-) and decreased CO(3)(2-) and pH in surface seawater, as well as decreasing the depth of the upper mixed layer and increasing the degree of isolation of this layer with respect to nutrient flux from deeper waters. The outcome of these forcing factors is to increase the availability of inorganic carbon, photosynthetic active radiation (PAR) and ultraviolet B radiation (UVB) to aquatic photolithotrophs and to decrease the supply of the nutrients (combined) nitrogen and phosphorus and of any non-aeolian iron. The influence of these variations on CCM expression has been examined to varying degrees as acclimation by extant organisms. Increased PAR increases CCM expression in terms of CO(2) affinity, whilst increased UVB has a range of effects in the organisms examined; little relevant information is available on increased temperature. Decreased combined nitrogen supply generally increases CO(2) affinity, decreased iron availability increases CO(2) affinity, and decreased phosphorus supply has varying effects on the organisms examined. There are few data sets showing interactions amongst the observed changes, and even less information on genetic (adaptation) changes in response to the forcing factors. In freshwaters, changes in phytoplankton species composition may alter with environmental change with consequences for frequency of species with or without CCMs. The information available permits less predictive power as to the effect of the forcing factors on CCM expression than for their overall effects on growth. CCMs are currently not part of models as to how global environmental change has altered, and is likely to further alter, algal and aquatic plant primary productivity. PMID- 21327538 TI - Informative dropout modeling of longitudinal ordered categorical data and model validation: application to exposure-response modeling of physician's global assessment score for ustekinumab in patients with psoriasis. AB - The physician's global assessment (PGA) score is a 6-point measure of psoriasis severity that is widely used in clinical trials to assess response to psoriasis treatment. The objective of this study was to perform exposure-response modeling using the PGA score as a pharmacodynamic endpoint following treatment with ustekinumab in patients with moderate-to-severe psoriasis who participated in two Phase 3 studies (PHOENIX 1 and PHOENIX 2). Patients were randomly assigned to receive ustekinumab 45 or 90 mg or placebo, followed by active treatment or placebo crossover to ustekinumab, dose intensification or randomized withdrawal and long-term extension periods. A novel joint longitudinal-dropout model was developed from serum ustekinumab concentrations, PGA scores, and patient dropout information. The exposure-response component employed a semi-mechanistic drug model, integrated with disease progression and placebo effect under the mixed effect logistic regression framework. This allowed potential tolerance to be investigated with a mechanistic approach. The dropout component of the joint model allowed the examination of its potential influence on the exposure-response relationship. The flexible Weibull dropout hazard function was used. Visual predictive check of the joint longitudinal-dropout model required special handling, and a conditional approach was proposed. The conditional approach was extended to external model validation. Finally, appropriate interpretation of model validation is discussed. This longitudinal-dropout model can serve as a basis to support future alternative dosing regimens for ustekinumab in patients with moderate-to-severe plaque psoriasis. PMID- 21327539 TI - Ginsenoside-Rg1 enhances angiogenesis and ameliorates ventricular remodeling in a rat model of myocardial infarction. AB - Ginsenoside-Rg1 (Rg1) has been used in the traditional Chinese medicine for over 2,000 years. The present study was performed to test our hypothesis that Rg1 provides pro-angiogenic and anti-fibrotic benefits in the ischemic myocardium in a rat model of myocardial infarction. The expression of vascular endothelial growth factor (VEGF) and phosphorylation/activation of PI3K, Akt, and p38 MAPK signaling pathways were examined in human umbilical vein endothelial cells and in the myocardial samples of rats. In addition, the expression levels of TNF-alpha and collagen I level, the number of newly formed blood vessels, the extent of myocardial fibrosis, and left ventricular function were measured in vivo. Our results demonstrated that administration of Rg1 increased VEGF expression levels, activated PI3K/Akt, and inhibited p38 MAPK in vitro and in vivo. Furthermore, Rg1 increased the density of newly formed vessels, decreased TNF-alpha and collagen I expression levels and area of myocardial fibrosis, and improved left ventricle function in vivo. PI3K inhibitor LY294002 significantly attenuated Rg1-enhanced VEGF expression and capillary density. As well, inhibition of p38 MAPK slightly increased VEGF expression in vitro and in vivo, increased capillary density, and decreased TNF-alpha and collagen I expression levels and area of myocardial fibrosis in vivo. Rg1-induced activation of PI3K/Akt also contributed to the downregulation of p38 MAPK. Thus, Rg1 is effective in promoting angiogenesis and attenuating myocardial fibrosis, resulting in ameliorated left ventricular function. The possible mechanisms may involve activation of PI3K/Akt, inhibition of p38 MAPK, and cross talk between the two signaling pathways. PMID- 21327540 TI - Comparative docking and CoMFA analysis of curcumine derivatives as HIV-1 integrase inhibitors. AB - The docking studies and comparative molecular field analysis (CoMFA) were performed on highly active molecules of curcumine derivatives against 3' processing activity of HIV-1 integrase (IN) enzyme. The optimum CoMFA model was selected with statistically significant cross-validated r(2) value of 0.815 and non-cross validated r (2) value of 0.99. The common pharmacophore of highly active molecules was used for screening of HIV-1 IN inhibitors. The high contribution of polar interactions in pharmacophore mapping is well supported by docking and CoMFA results. The results of docking, CoMFA, and pharmacophore mapping give structural insights as well as important binding features of curcumine derivatives as HIV-1 IN inhibitors which can provide guidance for the rational design of novel HIV-1 IN inhibitors. PMID- 21327541 TI - Risk and protective predictors of trajectories of depressive symptoms among adolescents from immigrant backgrounds. AB - Although there has been an increasing number of studies that has examined depression among adolescents from immigrant backgrounds, findings have been mixed, with some studies reporting that immigrant status is associated with risk, while others report that immigration status is linked to adequate or positive outcomes. Thus, it is important to explore how underlying predictors contribute to trajectories of depressive symptoms among adolescents from immigrant backgrounds. Using data from a nationally representative Canadian sample (N = 1,060; aged 12 to 23; 48.9% female), this longitudinal study examined the effects of risk and protective factors on trajectories of depressive symptoms using multilevel modeling. Predictors of depressive symptoms tended to be protective and suggest a universal positive influence of self-esteem, positive peer relationships, and parent-child cohesion. Host language proficiency was predictive of greater increases in depressive symptoms over time. Findings highlight the value of promoting protective factors and aspects of one's heritage among immigrant adolescents. PMID- 21327542 TI - The use of chloroplast microsatellite markers for assessing cytoplasmic variation in a watermelon germplasm collection. AB - Fifteen chloroplast microsatellite (cpSSR) markers were tested to analyze cytoplasmic variation in a set of watermelon accessions containing 67 Chinese watermelon germplasms (CWGs) and 19 non-Chinese watermelon germplasms (NCGs), and 11 were polymorphic. These polymorphic cpSSR markers detected 2-4 alleles (mean = 2.8) in all the accessions, with diversity values ranging from 0.047 to 0.427 (mean = 0.252). Based on the polymorphic cpSSR loci, 17 distinct haplotypes were identified, of which six were from CWGs, seven were from NCGs, and four were shared by both of them. Most haplotypes from CWGs were nearly identical at the 11 cpSSR loci, but those from NCGs revealed higher variations. Of the haplotypes from CWGs, a predominant haplotype was found in 76.1% of CWGs, indicating that CWGs suffered a cytoplasmic bottleneck in domestication process and lost most of their cytoplasmic variability. To analyze the relationships among these 17 haplotypes, a dendrogram was constructed based on the cpSSR data using the unweighted pair-group method with arithmetic average (UPGMA). Three distinct groups were generated, revealing a genetic divergence between CWGs and NCGs. From this analysis, we obtained five rare haplotypes which had quite low genetic similarity to the others and would be useful for watermelon breeding in China. The results enriched the knowledge in genetic diversity of CWGs and could be informative for broadening the genetic base of watermelon. PMID- 21327543 TI - Utilization of natural chabazite and mordenite as a reactive barrier for immobilization of hazardous heavy metals. AB - INTRODUCTION: Understanding the sorption process in natural geomedia is necessary for effective utilization of these materials as low-cost adsorbents and consequently as controlled release hazardous elements. This research was oriented to investigate the affinity of two natural zeolite minerals towards cobalt, zinc, and nickel mixture as an important industrial and radioactive waste. METHOD: The uptake of metal ions as a function of different parameters has been studied using a batch equilibrium technique. RESULTS: The results revealed that the affinity and adsorption capacity of chabazite and mordenite follow the order: Zn(2+) > Co(2+) > Ni(2+), with good fits being obtained using Langmuir and Freundlich adsorption isotherms. The metal uptake was found to be concentration-dependent and independent of the pH over 3.0 to 8.0 range; this reveals that the adsorption mechanism is controlled mainly by a pure ion-exchange reaction at the experimental conditions used. Kinetic curves showed a rather fast exchange reaction for three cations, as equilibrium was mostly reached within 20 min. CONCLUSION: These materials especially chabazite are recommended to be used as a reactive barrier for hazardous heavy metals control. PMID- 21327544 TI - Polyfluorinated surfactants (PFS) in paper and board coatings for food packaging. AB - INTRODUCTION: In this study, we explore the identity of a range of polyfluorinated surfactants (PFS) used for food contact materials, primarily to impart oil and water repellency on paper and board. PFS are of interest, as they can be precursors of poly- and perfluorinated alkyl substances (PFAS), of which several are persistent and are found worldwide in human blood and in the environment. MATERIALS AND METHODS: To determine the elemental composition of PFS, we combined information from patents, chemical suppliers and analyses of industrial blends using ultra performance liquid chromatography-negative electrospray ionisation quadrupole time-of-flight mass spectrometry. RESULTS: At a high pH of 9.7, both non-ionic and anionic PFS were ionised and were recognised by negative mass defects of exact masses, and neutral fragment losses of n * 20 or n * 100 Da. More than 115 molecular structures were found in industrial blends from the EU, US and China, belonging to the groups of polyfluoroalkyl-mono- and di-ester phosphates (monoPAPS, diPAPS and S-diPAPS), -ethoxylates, -acrylates, amino acids, -sulfonamide phosphates and -thio acids, together with residuals and synthesis byproducts. In addition, a number of starting materials such as perfluorooctane sulfonamide N-alkyl esters were analysed. Di- and trialkylated PAPS and S-diPAPS were found in migrates from European food contact materials. CONCLUSION: This study highlights the need to monitor for more types of PFS in order to map the sources of PFAS in humans and the environment. PMID- 21327545 TI - Puerarin: a novel antagonist to inward rectifier potassium channel (IK1). AB - Puerarin, isolated from the root of pueraria, had been widely used to prevent and treat arrhythmia. We show that puerarin effectively prevents and reverses aconitine-induced arrhythmias in perfused heart in vitro and in rats in vivo. To study the mechanisms of antiarrhythmic action of puerarin, we investigated the electrophysiological actions of puerarin using whole-cell clamp in isolated rodent ventricular myocytes and two electrode voltage-clamp (TEV) in I(K1) expressing Xenopus oocytes. Puerarin had no prominent effect on action potentials of ventricular myocytes from guinea pig. However, puerarin (1.2 mM) significantly inhibited the I(K1) current in rat ventricular cells. Consistently, puerarin blocked I(K1) expressed in Xenopus oocytes in a dose-dependent manner. Puerarin competed with barium, an open-channel blocker of I(K1), to inhibit I(K1) currents. Thus, our data demonstrated that puerarin is a novel open-channel blocker of I(K1), which may underlie the antiarrhythmic action of puerarin. PMID- 21327546 TI - Neurological disorders associated with cassava diet: a review of putative etiological mechanisms. AB - Tropical ataxic neuropathy (TAN) and epidemic spastic paraparesis (konzo) are two neurological disorders associated with the consumption of cassava (Manihot esculenta) in several African countries. TAN is characterized by sensory polyneuropathy, sensory ataxia, bilateral optic atrophy and bilateral sensori neural deafness. It occurs in elderly individuals subsisting on a monotonous cassava diet with minimal protein supplementation. Konzo is a syndrome of symmetrical spastic paraparesis with a predilection for children and young women and invariably associated with consumption of inadequately processed bitter cassava roots with minimal protein supplementation. Despite numerous epidemiological, clinical and biochemical studies aimed at elucidating the etiological mechanisms of these disorders, their etiologies remain unknown, and there is no known treatment. The diseases continue to be prevalent in endemic areas, causing significant disability and increased mortality. A fresh appraisal of the putative etiologic mechanisms proposed for these intriguing and enigmatic syndromes is presented in this paper. Evidences against a causal role for cyanide intoxication are discussed, and evidences implicating thiamine deficiency as a unifying etiological mechanism for these neurological syndromes are presented. It is concluded that urgent research is needed to evaluate thiamine status and implement a therapeutic trial of thiamine in these debilitating neurological disorders. PMID- 21327547 TI - [Prophylaxis against infections after needle stick injuries]. AB - BACKGROUND: Needle stick injuries are associated with a risk of infection. The aim of this study was to collate the reasons for the failure to carry out prophylactic measures from the perspective of those affected. METHODS: An anonymous internet questionnaire was designed to record the experiences of health care workers at the University Hospital Rostock with secondary infection prophylaxis after needle stick injuries. RESULTS: During the investigation period 106 questionnaires were returned. There were deficiencies in the acceptance of prophylactic measures due to job-associated lack of time and social pressure. CONCLUSION: The study suggests reorganization of work-flows and additional educational measures about the necessity of prophylactic procedures after needle stick injuries. PMID- 21327548 TI - Correlates of current transactional sex among a sample of female exotic dancers in Baltimore, MD. AB - Transactional sex work, broadly defined as the exchange of money, drugs, or goods for sexual services, occurs in a wide range of environments. There is a large body of research characterizing the risks and harms associated with street- and venue-based sex work, but there is a dearth of research characterizing the risk associated with the environment of exotic dance clubs. The current study aimed to: (1) characterize the nature of female exotic dancers' sex- and drug-related risk behaviors, (2) to examine the role of the club environment in these behaviors, and (3) to examine correlates of currently exchanging sex. From June 2008 to February 2009, we conducted a cross-sectional study among women who were aged 18 years or older and reported exotic dancing within the past 3 months (n = 98). The survey ascertained socio-demographic characteristics, personal health, medical history, sexual practices, drug use, and employment at clubs on the block. Bivariate and multivariate Poisson regression with robust variance was used to identify correlates of current sex exchange. Participants were a median of 24 years old, and were 58% white; 43% had not completed high school. Seventy four percent reported ever having been arrested. Twenty-six percent reported having injected heroin and 29% reported having smoked crack in the past 3 months. Fifty-seven percent reported using drugs in the club in the past 3 months. Sixty one percent had ever engaged in transactional sex, and 67% of those did so for the first time after beginning to dance. Forty-three percent reported selling any sex in the club in the past 3 months. In multiple Poisson regression, factors associated with current sex exchange included: race, ever having been arrested, and using drugs in the club. High levels of both drug use and transactional sex among this sample of exotic dancers were reported. These findings indicate that there are a number of drug- and sex-related harms faced by exotic dancers in strip clubs, implicating the environment in the promotion of HIV/STI risk-taking behaviors. Prevention and intervention programs targeting this population are needed to reduce the harms faced by exotic dancers in this environment. PMID- 21327549 TI - Investigating environmental determinants of diet, physical activity, and overweight among adults in Sao Paulo, Brazil. AB - There is worldwide recognition that the burden of noncommunicable diseases (NCDs) and obesity-related health problems is rapidly increasing in low- and middle income countries. Environmental determinants of obesity are likely to differ between countries, particularly in those undergoing rapid socioeconomic and nutrition transitions such as Brazil. This study aims to describe some built environment and local food environment variables and to explore their association with the overweight rate and diet and physical activity area-level aggregated indicators of adults living in the city of Sao Paulo, the largest city in Brazil. This formative study includes an ecological analysis of environmental factors associated with overweight across 31 submunicipalities of the city of Sao Paulo using statistical and spatial analyses. Average prevalence of overweight was 41.69% (95% confidence interval 38.74, 44.64), ranging from 27.14% to 60.75% across the submunicipalities. There was a wide geographical variation of both individual diet and physical activity, and indicators of food and built environments, favoring wealthier areas. After controlling for area socioeconomic status, there was a positive correlation between regular fruits and vegetables (FV) intake and density of FV specialized food markets (r = 0.497; p < 0.001), but no relationship between fast-food restaurant density and overweight prevalence was found. A negative association between overweight prevalence and density of parks and public sport facilities was seen (r = -0.527; p < 0.05). Understanding the relationship between local neighborhood environments and increasing rates of poor diet, physical activity, and obesity is essential in countries undergoing rapid economic and urban development, such as Brazil, in order to provide insights for policies to reduce increasing rates of NCDs and food access and health inequalities. PMID- 21327550 TI - Can haemostatic factors predict atherothrombosis? AB - Thrombosis is "haemostasis in the wrong place", and there is increasing evidence that haemostatic factors are associated with increased risk of atherothrombotic events. Increasing plasma levels of fibrinogen are associated with increased risks of coronary heart disease, stroke and peripheral arterial disease, and with vascular and nonvascular mortality. However, as with other markers of haemostasis (and of inflammation), their additional predictive value to conventional risk factors is small. Ongoing studies of activation markers of coagulation (e.g. fibrin D-dimer), endothelium (e.g. von Willebrand factor, tissue plasminogen activator antigen) and platelets (mean platelet volume) may provide additional predictive value for atherothrombotic events. However, at present there is no sufficient evidence base for their routine measurement in prediction. PMID- 21327551 TI - Terlipressin infusion induces Tako-Tsubo syndrome in a cirrhotic man with hepato renal syndrome. PMID- 21327553 TI - Paediatric computer-assisted retroperitoneoscopic nephrectomy compared with open surgery. AB - PURPOSE: Computer-assisted laparoscopic surgery (CALS) in children is increasingly used and has proven to be feasible and safe. However, its full potential remains unclear and clinical comparative studies hardly exist. The aim of this study was to prospectively evaluate our experience with CALS for performing retroperitoneal nephrectomies in children when compared with controls undergoing open surgery in terms of safety, operative time, blood loss, opoid requirements, the duration of hospital stay and complications. CHILDREN AND METHODS: Computer-assisted retroperitoneoscopic nephrectomy was undertaken in ten consecutive children, mean age at the time of surgery 6.4 (SD +/- 4.5) years, and compared with a retrospectively collected control group of all other children, mean age 3.9 (SD +/- 4.6) years, who underwent the same procedure by conventional open surgery between the years 2005 and 2009. The endpoint of the study was 1 month postoperatively. RESULTS: Nephrectomies were performed in all the children and no child was excluded from the study. There was no per-operative complication in any of the groups. The median (range) operative time was 202 (128-325) and 72 (44-160) min for the CALS and open group, respectively. The blood loss was minimal (<20 ml) for all the patients. The postoperative opoid requirements did not differ. The median (range) postoperative hospital stay was 1 (1-4) and 2 (1 7) days for the CALS and the open group, respectively. One complication in the form of an urinoma appeared 5 days after surgery in the CALS group. CONCLUSION: Computer-assisted retroperitoneoscopic nephrectomy is a safe, feasible and effective procedure in children. Even though operative times are longer the patients benefit from the lower morbidity, improved cosmetics and shorter hospitalization associated with the minimally invasive approach. PMID- 21327552 TI - Bariatric surgery and renal function. AB - Obesity causes a significant healthcare burden and has been shown to be an important risk factor in the development of cardiovascular disease, type 2 diabetes, and increasingly chronic kidney disease. Bariatric surgery is the most effective treatment for obesity and has been shown to drastically improve both blood pressure and diabetic control. However, the interaction of bariatric surgery and renal function is less clear. This review focuses on the effect of bariatric surgery on renal function both in the acute situation, with respect to acute kidney injury, and also on changes in renal function parameters post bariatric surgery weight loss. The interaction of obesity, bariatric surgery, and nephrolithiasis as a precipitant of acute kidney injury will also be considered. The role of bariatric surgery in pre- and post-renal transplant recipients is discussed as well as possible mechanisms underlying the improvement in renal function. PMID- 21327554 TI - Histochemical staining for intestinal dysganglionosis: over 30 years experience with more than 1,500 biopsies. AB - PURPOSE: Intestinal dysganglionosis are a group of anomalies of the enteric nervous system that constitute infrequent but severe forms of constipation. Histochemical stainings are the gold standard diagnostic procedure for intestinal dysganglionosis. This study describes our experience with histochemistry in a large series of patients. METHODS: Between 1977 and 2010, 1,589 biopsies from children with persistent chronic constipation were studied. The specimens were snap frozen, sectioned and stained with acetylcholinesterase (AChE), acetylcholinesterase counterstained with hematoxilin and succinic dehydrogenase (SDH) histochemical stainings. RESULTS: Among the 1,589 biopsies, 946 (59.5%) were rectal biopsies, 242 (15.2%) were internal sphincter biopsies, 346 (21.8%) were intestinal mapping studies and 42 (2.7%) of them were colon specimens from surgical resections. From the rectal biopsy group, 544 (57.5%) patients were reported as normal. Hirschsprung disease was found in 163 (17.2%) patients with a median age at diagnosis of 8 months and a male to female ratio of 3:1. Intestinal neuronal dysplasia was found in 162 (17.2%) patients, hypoganglionosis in 3 (0.3%) of them and ganglioneuromatosis in 1 (0.1%). In 73 (7.7%) patients, the biopsy was not conclusive for different reasons. 34 out of the 42 resected colon specimens were Hirschsprung disease. Intestinal neuronal dysplasia was found in the proximal segment of the aganglionic bowel in 15 out of 34 (44%) patients. All the aganglionic resected colon specimens had a previous aganglionic rectal biopsy. There were no false positive results in this group. CONCLUSIONS: Histochemical stainings continue to be the gold standard in the diagnosis of intestinal dysganglionosis. The combination of two histochemical staining techniques provides a high level of accuracy in the diagnosis of intestinal dysganglionosis. PMID- 21327557 TI - Effect of abiotic stress on phosphate solubilization by biocontrol fungus Trichoderma sp. AB - This study was undertaken to explore the role of Trichoderma sp. in phosphate (P) solubilization and antagonism against fungal phytopathogens. All fungal isolates (SE(6), KT(6), KT(28), and BRT(11)) and a standard culture of T. harzianum (Th std) were able to antagonize two fungal phytopathogens (Sclerotium rolfsii and Rhizoctonia solani) of chickpea (Cicer arietinum L.) wilt complex. Transmission electron microscopic studies (TEM) further confirmed ultra-cytological changes in the sclerotia of S. rolfsii parasitized by Trichoderma sp. All fungal cultures exhibited production of NH(3) and siderophore, but only BRT(11), SE(6), and Th std could produce HCN. Among all the cultures tested, isolate KT(6) was found to be most effective for solubilization of ferric phosphate releasing 398.4 MUg ml( 1) phosphate while isolates BRT(11) and SE(6) showed more potential for tricalcium phosphate (TCP) solubilization releasing 449.05 and 412.64 MUg ml(-1) phosphate, respectively, in their culture filtrates. Part of this study focused on the influence of abiotic stress conditions such as pH, temperature, and heavy metal (cadmium) on phosphate (TCP) solubilizing efficiency. Two selected cultures KT(6) and T. harzianum retained their P solubilizing potential at varying concentrations of cadmium (0-1000 MUg ml(-1)). Isolate KT(6) and standard culture of T. harzianum released 278.4 and 287.6 MUg ml(-1) phosphate, respectively, at 1000 MUg ml(-1)cadmium. Maximum solubilization of TCP was obtained at alkaline pH and at 28 degrees C temperature. Isolate BRT(11) was found most alkalo-tolerant releasing 448.0 MUg ml(-1) phosphate at pH 9. PMID- 21327555 TI - Effect of dietary protein on heme iron uptake by Caco-2 cells. AB - OBJECTIVE: To study heme iron bioavailability and the role of dietary protein (animal and vegetable) on iron uptake using an in vitro model (Caco-2 cell line). METHODS: Caco-2 cells were seeded in bicameral chambers with different animal (beef, chicken or fish) or vegetable (peas, lentils, and soybeans) proteins or with pure animal (collagen and casein) or vegetable (gliadin, zein, and glutein) protein extracts. The effect of each protein over heme iron absorption was assessed. RESULTS: Intact heme uptake was higher than either heme plus albumin or digested heme plus albumin, but lower than digested heme. White meal exerted the highest inhibitory effect on hemin uptake. Heme iron uptake decreased in the presence of all legume extracts, but was not significantly different among them (one-way ANOVA, NS). Pure animal (collagen and casein) and vegetable (zein and glutelin) proteins increased heme iron uptake, except for gliadin. CONCLUSION: Animal and vegetable protein in general decreased heme iron uptake. However, purified animal and vegetable protein induce an increase in heme iron uptake. PMID- 21327556 TI - Evaluation antimicrobial and antiadhesive properties of the biosurfactant Lunasan produced by Candida sphaerica UCP 0995. AB - Different groups of biosurfactants exhibit diverse properties and display a variety of physiological functions in producer microorganisms; these include enhancing the solubility of hydrophobic/water-insoluble compound, heave metal binding, bacterial pathogenesis, cell adhesion and aggregation, quorum sensing and biofilm formation. Candida sphaerica was grown in a low cost medium, consisting of distilled water supplemented with 9% refinery residue of soybean oil and 9% corn steep liquor, for 144 h at 28 degrees C and 150 rpm. The cell free supernatant obtained at the end of the experiments was submitted to extraction, and afterward the biosurfactant was isolated using methanol with a yield of 9 g l(-1). The critical micelle concentration of the biosurfactant was found to be 0.25 mg ml(-1) with a surface tension of 25 mN m(-1). Several concentrations of the biosurfactant (0.625-10 mg ml(-1)) were used to evaluate its antimicrobial and antiadhesive activities against a variety of microorganisms. The biosurfactant showed antimicrobial activity against Streptococcus oralis (68%), Candida albicans (57%), and Staphylococcus epidermidis(57.6%) for the highest concentration tested. Furthermore, the biosurfactant at a concentration of 10 mg ml(-1) inhibited the adhesion between 80 and 92% of Pseudomonas aeruginosa, Streptococcus agalactiae, Streptococcus sanguis12. Inhibition of adhesion with percentages near 100% occurred for the higher concentrations of biosurfactant used. Results gathered in this study point to a potential use of the biosurfactant in biomedical applications. PMID- 21327558 TI - Diversity of endosymbionts in the potato psyllid, Bactericera cockerelli (Triozidae), vector of zebra chip disease of potato. AB - Zebra chip disease is an emerging, serious disease of solanaceous crops and the causal agent is a bacterium "Candidatus Liberibacter solanacearum" (CLs), also known as "Candidatus Liberibacter psyllaurous", which is transmitted by the potato psyllid, Bactericera cockerelli (Sulc). We performed bacterial tag-encoded FLX amplicon pyrosequencing (bTEFAP) of the 16S rDNA genes to determine the bacterial microbiota in adult insects from CLs-uninfected and CLs-infected strains of B. cockerelli and potato leaf samples. We obtained sequences from five bacterial species among the two psyllid strains, including "Candidatus Carsonella ruddii", Wolbachia, CLs, and two transient bacteria, Acinetobacter and Methylibium. We did not detect any common bacteria between psyllids and potato leaf samples using pyrosequencing. We performed PCR analysis using species specific 16S rDNA primers to confirm pyrosequencing results in individual psyllids including eggs, early-instars, late-instars, and adults of both sexes from both CLs-uninfected and CLs-infected psyllid strains. The primary endosymbiont, "Candidatus Carsonella ruddii" and Wolbachia were detected in all life-stages and sexes of both strains using PCR analyses. The percentage of CLs infected individuals increased from early-instar (0%), late-instar (40%) until adulthood (60%) in the CLs-infected strain. We believe that CLs levels in early instars are probably too low to be detected by standard PCR. Using PCR analyses, we confirmed the presence of Acinetobacter in CLs-uninfected and CLs-infected adults (75 and 25%, respectively) but not Methylibium. Further, we detected Acinetobacter in potato leaves using PCR indicating that the psyllids may have acquired this bacterium via feeding on the host plant. PMID- 21327559 TI - Identification and assessment of symbiotic effectiveness of phage-typed Rhizobium leguminosarum strains on lentil (Lens culinaris Medik) cultivars. AB - Symbiotic effectiveness of 19 indigenous and two exotic (USDA 2426 and USDA 2431) strains of lentil Rhizobium belonging to different phage-sensitive and phage resistant groups was compared under axenic condition. Four strains (USDA 2431, BHULR 104, BHULR 113, and BHULR 115) sensitive to different phages were found significantly superior over others in terms of nodule number, acetylene reduction activity, and total dry weight per plant. Inoculation response of these strains was then evaluated on six lentil cultivars under field condition. A significant symbiotic interaction between rhizobial strains and lentil cultivars was observed. Grain yield enhancement was noticed by the compatible interaction of lentil cultivars HUL-57, L-4147, K-75, and PL-4/DPL-15/DPL-62 with rhizobial strains USDA 2431, BHULR 104, BHULR 113, and BHULR 115, respectively. The authentication of rhizobial strains was accomplished through 16S rDNA sequence analysis. All rhizobial strains had close matching with R. leguminosarum bv. viciae strains. The results have shown that phages can trustfully help selecting out the symbiotically efficient most rhizobial strains for advantageous use with lentil cultivars, in order to strengthen the BNF-based future lentil breeding programs. PMID- 21327560 TI - Green space changes and planning in the capital region of China. AB - Green space plays an important role in complex urban ecosystems and provides significant ecosystem services with environmental, aesthetic, recreational and economic benefits. Beijing is the capital city of China and has a large population of about 15.81 million. Construction of green spaces is an important part of sustainable development in Beijing. To attain the sustainable development of Beijing as a capital city, an international city, a historical cultural city, and a living amenity city, this article attempts to develop a comprehensive plan of green space development both at the municipal and regional levels. At the municipal level of Beijing, based on the study of green space changes, and taking physical geographic conditions and historical context into account, we propose to establish green barriers in the mountainous area, and plan a comprehensive green space pattern composed of one city, two rings, three networks, eight water areas, nine fields, and several patches in the plain area. At the regional level of the Capital Circle Region, integrating the characteristics and causes of main environmental issues, we design a macroscopic pattern--"barriers by mountains in the northwest," "seaward open spaces in the southeast," "grassland-forest-field coast zones," and "green-blue symphony"--for ecological restoration and green space construction. Finally, we discuss the principles necessary to implement green space planning considering adaptation to local conditions, composite function exploitation, interregional equity and integrated planning. PMID- 21327561 TI - Current status and problems in certification of sustainable forest management in China. AB - Forest certification is a mechanism involving the regulation of trade of forest products in order to protect forest resources and improve forest management. Although China had a late start in adopting this process, the country has made good progress in recent years. As of July 31, 2009, 17 forest management enterprises and more than one million hectares of forests in China have been certified by the Forest Stewardship Council (FSC). Several major factors affect forest certification in China. The first set is institutional in nature. Forest management in China is based on centralized national plans and therefore lacks flexibility. A second factor is public awareness. The importance and value of forest certification are not widely understood and thus consumers do not make informed choices regarding certified forest products. The third major factor is the cost of certification. Together these factors have constrained the development of China's forest certification efforts. However, the process does have great potential. According to preliminary calculations, if 50% of China's commercial forests were certified, the economic cost of forest certification would range from US$0.66-86.63 million while the economic benefits for the forestry business sector could exceed US$150 million. With continuing progress in forest management practices and the development of international trade in forest products, it becomes important to improve the forest certification process in China. This can be achieved by improving the forest management system, constructing and perfecting market access mechanisms for certificated forest products, and increasing public awareness of environmental protection, forest certification, and their interrelationship. PMID- 21327562 TI - Managing for recreational experience opportunities: the case of hikers in protected areas in Catalonia, Spain. AB - Planning and management for recreational activities in protected areas involves an understanding of many complex factors. Segmentation of recreation demand and of the main physical or sporting activities can contribute to the design of more efficient management strategies, which may help to maintain or significantly enhance satisfaction with the recreation experience, and this in turn could improve the interest in and appreciation of the natural environment. The current study examined the motivations of hikers in three small Natura 2000 protected areas. It establishes a typology or categorization as a contribution to better management based on a survey conducted through on-site personal interviews with a representative sample of 569 hikers. Through an analysis of the principal intervening components by means of cluster analysis, we identified three groups of hikers based on three motivational dimensions: (1) nature-minded hikers, (2) sporting hikers and (3) general-purpose hikers. The most striking results were the significant differences among group variables related to visit behaviour (frequency and duration of visits and number of people per group), previous knowledge (protection status of the areas) and recreational frequentation (trail categories and protected areas visited). A positive correlation between the degree of sympathy for nature and the degree of satisfaction with the recreational experience (including positive evaluation of the public facilities, signposting and services offered) was also observed. The results are discussed in terms of their applicability and implications in hiking management in protected natural areas such as those of Natura 2000. PMID- 21327564 TI - Is subcutaneous bortezomib ready for prime time? PMID- 21327563 TI - New drugs for chronic myelogenous leukemia. AB - The introduction of tyrosine kinase inhibitors (TKIs) has changed the landscape of therapy for chronic myelogenous leukemia (CML). Once considered an incurable malignancy, CML now has become a manageable chronic condition. Despite the great advances that imatinib has brought to the treatment of CML, some patients still develop resistance to imatinib and other TKIs, such as dasatinib and nilotinib. Furthermore, none of the clinically available TKIs is capable of eradicating leukemia stem cells and therefore curing CML. Several new compounds have been developed in recent years in an attempt to manage TKI-resistant CML. These include third-generation TKIs (ponatinib, danusertib) and even old compounds such as omacetaxine, which were developed before imatinib and now find a possible niche in the treatment of imatinib-resistant CML. We review the current preclinical and clinical data on the most promising new compounds for the treatment of CML. PMID- 21327565 TI - New immunomodulatory drugs in myeloma. AB - Multiple myeloma (MM) is an incurable malignancy of plasma cells. The introduction of thalidomide was a milestone in the treatment of MM. Thalidomide analogues termed immunomodulatory drugs (IMiDs) have been developed that are more effective and have less toxicity than thalidomide. The role of lenalidomide in relapsed MM has been well defined. This review discusses the data regarding the upfront use of lenalidomide with dexamethasone or in multidrug combinations, as well as its potential role as maintenance therapy. It also reviews our experience with pomalidomide, a new IMid with remarkable activity in relapsed, refractory MM. PMID- 21327566 TI - Alcohol consumption, blood pressure, and the risk of stroke. AB - A synergistic effect of alcohol and hypertension has been suggested to increase the risk for stroke. However, the contribution of alcohol-induced hypertension to stroke morbidity and mortality may be greater than observed, because the effects of different drinking patterns have not been separately investigated. Alcohol induced transient peaks in systolic blood pressure may predispose to stroke. Recent studies have measured time trends of blood pressure elevations in relation to alcohol consumption. They found a significant morning surge in blood pressure, which was related to alcohol intake in a dose-dependent manner and was independent of smoking. Men with a severe form of hypertension showed a 12-fold increased risk for cardiovascular disease mortality associated with heavy binge drinking. Binge drinking is a significant risk factor for stroke. Hypertensive patients should be warned about the risks of alcohol and urged to avoid binge drinking because of an increased risk for all subtypes of stroke. PMID- 21327567 TI - Home blood pressure monitoring: how good a predictor of long-term risk? AB - Most management decisions for the diagnosis and treatment of hypertension are made using blood pressure (BP) measurements made in the clinic. However, home BP recordings may be of superior prognostic value. In this review, we show that home BP recordings are generally superior to clinic BP measurements in predicting long term prognosis. Home BP has been shown to significantly predict important end points including all-cause mortality, progression of chronic kidney disease, and functional decline in the elderly. In addition, home BP recordings significantly and strongly predict cardiovascular events. These findings are robust, as they concur despite having been studied in disparate populations, using heterogeneous methods of clinic and home BP measurement, and with varied methods of statistical analysis. The advantages of home BP recordings are not due solely to a larger number of measurements, and they extend to the elderly, patients with chronic kidney disease, and those on hemodialysis. Because home BP recordings combine improved accuracy with the advantages of low cost and easy implementation, most patients with known or suspected hypertension should have their BP assessed and managed by means of home BP recordings. PMID- 21327568 TI - Mannan-binding lectin and ficolin deposition in skin lesions of pemphigus. AB - Pemphigus is characterized by circulating autoantibodies directed against desmossomal antigens that, once bound to target antigens, induce disruption in the cell-cell adhesion of the epidermis and mucosal epithelium, leading to blister formation. Evidence has indicated a role for complement in the physiopathology of pemphigus, with complement deposition in intercellular spaces of skin and mucous membrane lesions. Mannan-binding lectin (MBL) and Ficolin-2 are recognition proteins of innate immunity, which by binding to specific molecular patterns on pathogens surfaces trigger the activation of complement, leading to phagocytosis and lyses of target cells and inflammation. In this study we report for the first time the deposition of MBL and ficolins in pemphigus lesions. Eight biopsies of skin lesions of pemphigus vulgaris were studied for in situ deposition of IgG and the complement components MBL, Ficolin 1, Ficolin-2, C1q, C3 and membrane attack complex C5b-9. All biopsies presented deposition of IgG and C3 in the intercellular spaces (ICS) of epidermis. MBL deposition was found in the ICS and basal membrane zone (BMZ) of all specimens, whereas C5b-9 showed deposition only in the ICS, with irregular distribution. Ficolin-2 were positive in 50% (4/8) of biopsies showing deposition in the BMZ. On the other hand, ficolin-1 and C1q were negative in all specimens. Our study suggest that MBL and to a lesser extend Ficolin-2 may bind to altered intercellular structures in the skin and lead to the activation of complement in situ, contributing to tissue damage in pemphigus. PMID- 21327569 TI - Growth factors and neuropathic pain. AB - A treatment for neuropathic pain is an important unmet medical need because this pain often is refractory to many medical interventions. An important element in the development of neuropathic pain is a dysfunction in the activity of peripheral nerves. Because neurotrophic factors affect nerve development and maintenance, modulating the activity of these factors can alter neuronal pathophysiology and produce a disease-modifying effect. Blocking the activity of nerve growth factor or enhancing the activity of either glial-derived neurotrophic factor or artemin has shown potential for normalizing neuronal activity and attenuating signs of neuropathic pain in animal models and clinical studies. This article discusses the role of these factors in neuropathic pain and the implications for the development of novel therapeutics. PMID- 21327570 TI - Blunt head trauma or extensive tension pneumothorax? PMID- 21327571 TI - Forensic and psychiatric aspects of joint suicide with carbon monoxide. AB - A case of joint suicide of a young woman and man who became acquainted in a suicide web forum and used this platform to make an appointment to commit suicide together is described. During their investigation, police were able to reconstruct the events by analysing the computer of the deceased women which was also found with the bodies. An indoor charcoal burning unit was used to release carbon monoxide as the method of suicide. PMID- 21327572 TI - Differentiated mesenchymal stem cells for sciatic nerve injury. AB - Sciatic nerve injury is common and may cause neurological deficits. Previous studies showed that administration of neurotrophic factors (NTFs), naturally occurring proteins that support the development and survival of neurons, preserved and protected damaged motor neuron in the injured sciatic nerve. We have been successful in converting bone marrow-derived mesenchymal stem cells into astrocyte-like cells that produce and secrete NTFs (NTF(+) cells). These cells demonstrate typical astrocyte morphology, express characteristic astrocyte markers and secrete high levels of NTFs. We have already shown that these cells and their conditioned media can protect neurons in culture and in animal models of neurodegenerative diseases. In the current study we examined whether NTF(+) cells are capable of rescuing motor neurons in a rat sciatic nerve injury model, where the right hind limb sciatic nerve was crushed. Rats were transplanted with NTF(+) cells, MSCs or PBS into the lesion site. In rats injected with the NTF(+) cells motor function was markedly preserved. Moreover, NTF(+) cells significantly inhibited the degeneration of the neuromuscular junctions and preserved the myelinated motor axons. Our findings suggest that autologous therapeutic approach can alleviate signs of sciatic nerve injury and probably other neurological disorders. PMID- 21327573 TI - Pathophysiology and treatment options for cardiac anorexia. AB - The anorexia-cachexia syndrome (ACS) occurs in many chronic illnesses, such as cancer, AIDS, and chronic obstructive pulmonary disease in addition to chronic congestive heart failure (CHF). Comparable to other chronic states, the ACS complicates CHF and impacts its prognosis; however, the available treatment options for this syndrome remain unsatisfactory. This review article focuses on the complex pathophysiology of cardiac anorexia. We focus on the recent data demonstrating the relationships between central appetite-regulating structures, inflammatory processes, and neurohormonal activation, and their respective roles in the development of anorexia. We then describe the different treatment options and discuss some future prospects for the management for cardiac anorexia. PMID- 21327574 TI - Isolation of RNA from field-grown jute (Corchorus capsularis) plant in different developmental stages for effective downstream molecular analysis. AB - Jute (Corchorus capsularis), as a natural fibre producing plant species, ranks next to cotton only. Today, biotechnological approach has been considered as most accepted means for any genetic improvement of plant species. However, genetic control of the fibre development in jute has not yet been explored sufficiently for desired genetic improvement. One of the major impediments in exploring the genetic architecture in this crop at molecular level is the availability of good quality RNA from field-grown plant tissues mostly due to the presence of high amount of mucilage and phenolics. Development of a suitable RNA isolation method is becoming essential for deciphering developmental stage-specific gene expression pattern related to fibre formation in this crop species. A combination of modified hot borate buffer followed by isopycnic centrifugation (termed as HBIC) was adopted and found to be the best isolation method yielding sufficient quantity (~350-500 MUg/gm fresh tissue) and good quality (A(260/280) ratio 1.88 to 1.91) RNA depending on the developmental stage of stem tissue from field-grown jute plant. The poly A(+) RNA purified from total RNA isolated by the present method was found amenable to efficient RT-PCR and cDNA library construction. The present development of RNA isolation was found to be appropriate for gene expression analysis related to fibre formation in this economically important jute plant in near future. PMID- 21327575 TI - The challenges with brain death determination in adult patients on extracorporeal membrane oxygenation. AB - BACKGROUND: To identify a reliable method of performing apnea testing as part of brain death determination in adult patients who develop loss of brainstem reflexes while receiving extracorporeal membrane oxygenation (ECMO). ECMO provides extracirculatory support to patients in cardiorespiratory failure who would otherwise be expected to die. Many studies have reported brain death as a potential complication of adult ECMO, but none have cited how apnea testing was performed in these patients. METHODS: This retrospective review identified adults 15 years or older treated with ECMO at our institution (2002-2010) and the method of determination of brain death when complete loss of brainstem reflexes occurred. RESULTS: Loss of all brainstem reflexes was identified in three cases (3/87, 3.4%). The apnea test was not performed since it was deemed "difficult," leading to withdrawal of ECMO and intensive care. Ancillary tests such as cerebral flow studies were not used because they may not document absent cerebral arterial flow due to the ischemic nature of the injury. We propose the use of an oxygenated apnea test on ECMO using continuous positive airway pressure (CPAP) through the ventilator or anesthesia bag, with an inline manometer and an end tidal CO(2) device. CONCLUSION: Apnea testing is essential in the determination of brain death, but may not be employed in ECMO-treated adult patients. Apnea testing using the above protocol may assist in better decision making for adult ECMO patients at risk of brain death. PMID- 21327576 TI - Posterior reversible encephalopathy syndrome associated with hemodynamic augmentation in aneurysmal subarachnoid hemorrhage. AB - BACKGROUND: Cerebral vasospasm has become the most concerning complication in patients with aneurysmal subarachnoid hemorrhage (aSAH) seen in the neurosciences intensive care unit (NSICU). Hemodynamic augmentation is frequently used to treat cerebral ischemia from vasospasm. In the last 5 years, posterior reversible encephalopathy syndrome (PRES) has been reported in three single case reports as a complication of hemodynamic augmentation. We describe an additional three patients seen in our institution. METHODS: Description of clinical course of three patients with a secured aneurysm treated with hemodynamic augmentation for cerebral vasospasm. RESULTS: We identified three patients (two female and one male), ranged in age from 62 to 70 years who developed PRES after treatment with induced or permissive arterial hypertension. During their NSICU stay, case 1 had worsening headache and confusion, case 2 and 3 had a decline in level of consciousness. Neuroimaging was compatible with vasogenic edema characteristic of PRES. Arterial blood pressure was reduced with a complete clinical and imaging resolution of PRES. CONCLUSIONS: PRES can be a cause of deterioration in patients with aSAH treated with hemodynamic augmentation. PRES should be differentiated from evolving infarctions due to cerebral vasospasm. Clinical manifestations and neuroimaging findings are reversible after gradual normalization of blood pressure. PMID- 21327577 TI - The influence of stress factors on the reactivation of latent herpes simplex virus type 1 in infected mice. AB - This study shows that the influence of different stress factors impacts the reactivation of latent herpes simplex virus type 1 (HSV-1) specifically in the trigeminal ganglion of infected mice. Different stress factors including hyperthermia, hypothermia, fatigue, and immunosuppression were exerted on mice infected with HSV-1. These viral antigens were then detected in the trigeminal ganglion region of infected mice under the influence of each stress factor, with hyperthermia having the most influence on reactivation. Interestingly, an increase in IL-6 was also detected in mice subjected to hyperthermia. These studies therefore suggest that stress can induce the reactivation of latent HSV 1, possibly through the induction of IL-6, in the trigeminal ganglion region of infected mice. This reveals a new insight on the pathogenesis of relapse infection of HSV-1. PMID- 21327578 TI - Aberrant expression of the p53-inducible antiproliferative gene BTG2 in hepatocellular carcinoma is associated with overexpression of the cell cycle related proteins. AB - We previously reported that the abnormal BTG2 expression was related to genesis/development of hepatocellular carcinoma (HCC). The aim of this study was to evaluate the BTG2 expression in HCC compared with p53, cyclin D1, and cyclin E. For this purpose, modified diethylnitrosamine (DEN)-induced primary HCC rat model was established. Target proteins and mRNAs were measured by western blot and RT-PCR/northern blot, respectively. In rat liver, expression of BTG2 and other proteins was determined by western blot, and BTG2 mRNA in HCC/normal tissues was detected by high-flux tissue microarray (TMA) and in situ hybridization (ISH). BTG2 mRNA/protein expression was increased in fetal liver, 7701, and LO2 cell lines but decreased in HepG2 cells. BTG2/p53 were expressed early after DEN treatment, peaked at 5 weeks and decreased gradually thereafter. Cyclin-D1/Cyclin-E expression increased significantly with the tumor progression. BTG2 mRNA was expressed in 71.19% HCC by ISH and correlated with differentiation. Expression of p53/cyclin D1/cyclin E was positive in 82.35/94.12/76.47% BTG2 mRNA negative tissues, respectively. BTG2 protein expression was lost in 32.2% (19/59) HCC tissues, and the mRNA/protein expression correlated significantly with the increasing tumor grade (P < 0.05). In conclusion, BTG2 expression is commonly impaired in HCC which may be a factor involved in deregulation of cyclin D1/cyclin-E expression during hepatocarcinogenesis. PMID- 21327579 TI - Expression of HIWI in human hepatocellular carcinoma. AB - In this study, the investigation of the expression of HIWI and its protein in hepatocellular carcinoma (HCC) was performed, and the relationships between HIWI expression and the location of HCC metastases were analyzed. Sets of fresh HCC and matched adjacent normal hepatic tissue and paraffin-embedded tissue slides were provided by the hospital hepatology and pathology departments. RT-PCR, Western blot, and immunohistochemistry were performed to detect HIWI mRNA and protein. Correlations between HIWI expression and patient's age, sex, type of tumor, and metastasis location were recorded. HIWI mRNA and protein levels were significantly higher in HCC tissues than in adjacent normal hepatic tissue (P < 0.05). Immunohistochemistry showed positive staining for HIWI in cell cytoplasm; however, the number of HIWI-positive cells in HCC tissue (65.2%; 60/92) was significantly higher than in adjacent normal hepatic tissue (27.2%; 25/92) (P < 0.05). HIWI expression was not correlated with patients' age, gender, tumors' size, and location but correlated with metastasis involving lymph nodes and other remote organs (P < 0.05). HIWI expression is significantly higher in HCC tissue than in adjacent normal hepatic tissue. The results of this study suggest that HIWI may have a crucial role in HCC carcinogenesis and could serve as a potential biomarker or treatment target for HCC. PMID- 21327580 TI - Phenotype switch of vascular smooth muscle cells after siRNA silencing of filamin. AB - Filamin (FLN) plays an important role in differentiation, migration, and signal transduction in vascular smooth muscle cells (VSMCs). We hypothesized that suppression of FLN expression would inhibit differentiation and migration of VSMCs, and interrupt the phenotype switch of these cells. We designed and tested different shRNA sequences to silence FLN expression. The degree of silencing was assessed at mRNA (qPCR) and protein (Western blot) levels. Two sequences, FL1 and FL2, lead to the most efficient FLN silencing. Subsequent experiments were conducted using the FL1 shRNA. Cells with silenced FLN were exposed to ox-LDL, and cell phenotypic changes (cell proliferation, cell cycle, apoptosis, and morphologic changes of cytoskeleton) were evaluated. When FLN was silenced, the phenotype switch of VSMCs exposed to ox-LDL was attenuated. Further, the injury to the cytoskeleton was less prominent in the FLN-silenced cells. To conclude, RNA silencing of FLN decreases the phenotype switch of VSMCs into a pathologic state. FLN silencing could be useful in treating atherosclerosis at genetic level. PMID- 21327581 TI - Aspirin attenuates pulmonary arterial hypertension in rats by reducing plasma 5 hydroxytryptamine levels. AB - Pulmonary arterial hypertension (PAH) is characterized by increasing pulmonary pressure, right ventricular failure, and death. The typical pathological changes include medial hypertrophy, intimal fibrosis and in situ thrombosis. Serotonin (5 HT) and other factors contribute to the development of pathologic lesions. Aspirin (ASA), a platelet aggregation inhibitor, inhibits 5-HT release from platelets. The aim of this study was to determine the efficacy of ASA in preventing or attenuating PAH. Sprague-Dawley rats injected with monocrotaline (MCT) developed severe PAH within 31 days. One hundred forty rats were randomized to receive either vehicle or ASA (0.5, 1, 2, or 4 mg/kg/day). The pre-ASA group was treated with ASA (1 mg/kg/day) for 30 days before the MCT injection. Thirty one days after the injection (day 61 for the pre-ASA group), pulmonary arterial pressure (PAP), right ventricular hypertrophy and pulmonary arteriole thickness were measured. Plasma 5-HT was measured by high-performance liquid chromatography. Aspirin suppressed PAH and increased the survival rate compared with the control group (84 vs. 60%, P < 0.05). Aspirin treatment also reduced right ventricular hypertrophy and pulmonary arteriole proliferation in ASA treated PAH model. In addition, plasma 5-HT was decreased in our ASA-treated PAH model. The degree of 5-HT reduction was associated with systolic PAP, right ventricular hypertrophy and wall thickness of pulmonary arterioles in rats. These results showed that ASA treatment effectively attenuated MCT-induced pulmonary hypertension, right ventricular hypertrophy, and occlusion of the pulmonary arteries. The effects of ASA was associated with a reduction of 5-HT. PMID- 21327582 TI - 17beta-estradiol protects dopaminergic neurons in organotypic slice of mesencephalon by MAPK-mediated activation of anti-apoptosis gene BCL2. AB - Both clinical and experimental studies provide growing evidences that marked sex differences in certain neurological disorders or disease models are largely attributed to the neuroprotective effects of estrogen. The purposes of this study were to assess the neuroprotective effect of 17beta-estradiol (E2) on dopaminergic neurons against 6-hydroxydopamine (6-OHDA) in organotypic mesencephalic slice culture and to elucidate the possible mechanism underlying neuroprotection. It was found that long-term exposure to E2 exerted marked effects on restoring the number of dopaminergic neurons, maintaining normal morphology of dopaminergic neurons, and preserving their ability to release dopamine at the presence of 6-OHDA. The neuroprotective effect of E2 could be dramatically blocked by an estrogen receptor antagonist ICI 182, 780 (ICI). The expression of GFAP, TLR4, and anti-apoptosis gene BCL2 were elevated at the presence of E2, whereas only BCL2 activation was blocked by ICI, dominantly responsible for E2-induced neuroprotection. Furthermore, activation of BCL2 was speculated to be mainly mediated through mitogen-activated protein kinase (MAPK) pathways, yet phosphatidylinositol-3-kinase signaling contributed largely to GFAP and TLR4 upregulation. Taken together, MAPK pathway-mediated BCL2 expression accounted for one of the key mechanisms involved in E2 neuroprotective effect on dopaminergic neurons against 6-OHDA insult. This finding provides new insight into controversial estrogen replacement therapy. PMID- 21327583 TI - Adipose tissue vascularization: its role in chronic inflammation. AB - In obesity, the vascular complication is a result of insulin resistance, such as decreased capillary recruitment in skeletal muscle from endothelial insulin resistance. Recent progress in the study of obesity-associated inflammation suggests that vasculature dysfunction occurs in adipose tissue before insulin resistance. In obesity, capillary density and function fail to meet the demand of adipose tissue growth. The failure leads to microcirculation dysfunction from an impaired blood perfusion, which results in a local hypoxia response in adipose tissue. The hypoxia response in adipocytes and macrophages is a new cellular basis for the chronic inflammation. The obesity-associated inflammation has both positive and negative effects in the body. At the early stage, it amplifies the hypoxia signal to stimulate vasculature remodeling locally, and promotes systemic energy expenditure against obesity. At the late stage, it causes adipose tissue dysfunction for insulin resistance. These points suggest that in obesity, adipose tissue vascularization controls chronic inflammation and influences systemic insulin sensitivity. PMID- 21327584 TI - Treatment of Aortoiliac Occlusive Disease: Medical versus Endovascular versus Surgical Therapy. AB - OPINION STATEMENT: Aortoiliac occlusive disease (AIOD) is an insidious, progressive atherosclerotic process that can lead to claudication, rest pain, tissue loss, and eventual lower extremity amputation. The patient with AIOD is also at risk for both fatal and nonfatal cardiovascular events. Treatment of the disease includes both risk factor modification and efforts to improve blood flow to the lower extremity. For mild to moderate intermittent claudication, medical therapy as well as a supervised exercise program is advised. For debilitating claudication or critical limb ischemia, a number of recent studies support an endovascular approach for patients with AIOD, citing patency rates that compare favorably to open surgery. Surgical revascularization, however, should still be considered in selected patients. PMID- 21327585 TI - Synovitis maps for the assessment of inflammatory diseases of the hand. AB - OBJECTIVES: To compare accuracy and review times of FLASH-MRI-derived synovitis maps (SM) with conventional MR images (cMRI) in the assessment of articular synovitis and tenosynovitis of the hand. METHODS: 80 hands in 40 patients (mean age, 48 years; range, 15-72 years) were assessed for synovitis on cMRI and SM by two readers independently. Reporting times and diagnostic confidence (scale: 1 = least, 5 = most confident) were measured. Results from an assessment of a panel of senior musculoskeletal radiologists served as the standard of reference. RESULTS: Sensitivity and specificity for the detection of articular synovitis were 0.91/1.00 (R1) and 1.00/0.67 (R2) on cMRI and 0.87/0.75 (R1) and 0.91/0.45 (R2) on SM and for the detection of tenosynovitis 0.95/0.63 (R1) and 0.67/0.79 (R2) on cMRI and 0.67/0.89 (R1) and 0.38/1.00 (R2) on SM. Mean review times (cMRI/SM, sec) were 142/37 (R1) and 167/25 (R2). Mean diagnostic confidence (cMRI/SM) was 3.7/3.4 (R1) and 3.2/3.5 (R2) for articular synovitis and 4.0/4.0 (R1), 3.3/3.7 (R2) for tenosynovitis. CONCLUSION: Synovitis maps provide a comparable diagnostic accuracy to conventional MR images in the assessment of articular synovitis and tenosynovitis of the hand. Because of short review times, synovitis maps provide a fast overview of locations with synovial enhancement. PMID- 21327586 TI - Assessment of thoracic aortic elasticity: a preliminary study using electrocardiographically gated dual-source CT. AB - OBJECTIVES: To gain a new insight into the elastic properties of the thoracic aorta in patients without aortic diseases using electrocardiographically (ECG) gated dual-source (DS) CT. METHODS: 56 subjects with no cardiovascular disease, selected from 2,700 people undergoing ECG-gated DSCT examination, were divided into three groups according to their age. CT data were reconstructed in 5% step throughout the RR interval. Diameter and area were measured at the curve of the ascending aorta (AA) and at the same level of the descending aorta (DA). The pulsation and elasticity of the aorta were evaluated. RESULTS: Aortic diameter changes were noted throughout the cardiac cycle. The maximum average diameter was seen at an RR interval of 24.02 +/- 4.99% for the AA and 25.63 +/- 4.77% for the DA. The minimum was at 93.5 +/- 4.04% for the AA and 96.6 +/- 4.58% for the DA. There was an age-dependent decrease in elasticity, while different correlation coefficients were found between various age groups and different elastic parameters. CONCLUSION: The properties of aortic pulsation and wall elasticity could be well shown by ECG-gated DSCT. The new findings regarding segment difference and age relevance were significant and should be taken into account in clinical trials and treatments for the elasticity related cardiovascular diseases. PMID- 21327587 TI - Calcifying epithelial odontogenic tumor (Pindborg tumor). AB - The calcifying epithelial odontogenic tumor is a benign epithelial tumor with characteristic clinical and histopathologic features. These features are discussed with a typical case presentation along with emphasis on newer variants and management strategies. PMID- 21327588 TI - Orofacial granulomatosis: a clinicopathologic correlation. AB - Orofacial granulomatosis is an uncommon disorder, but has been increasingly recognized in the past decade. It causes significant morbidity in the patient including oral ulcerations, enlargement of soft tissues which are often persistent and painful. This necessitates early medical intervention. We report one such case of a female patient who presented with a persistent upper lip enlargement. She had visited multiple general dental practitioners and general physicians but was undiagnosed. Ultrasonography proved an adjunctive tool in diagnosis. She was treated with a combination of topical and intra-lesional steroids. A 1-year follow-up did not show any evidence of recurrence. PMID- 21327589 TI - Myocbacterium-avium intracellulare associated inflammatory pseudotumor of the anterior nasal cavity. AB - In this case report, we describe an unusual case of mycobacterial associated inflammatory pseudotumor that occurred in a patient with a previous history of cocaine abuse. We discuss inflammatory pseudotumor (IPT) in general and emphasize the rare entity where an associated mycobacterial infection is seen. The histogenesis is not yet completely understood. The lesion can pose challenges for practicing pathologists and a misdiagnosis of malignancy can occur at multiple facets. A discussion about the differential diagnosis and clues to make the distinction is presented. In addition to spindle cell proliferation, the presence of a background of mixed inflammatory cell infiltrate and foamy macrophages are clues to make the diagnosis. In the case of mycobacteria associated IPT, Acid Fast Bacilli (AFB) stains will easily highlight the organisms confirming the diagnosis. PMID- 21327590 TI - Single burr hole endoscopic biopsy with third ventriculostomy-measurements and computer-assisted planning. AB - OBJECTIVE: In cases of non-communicating hydrocephalus, a combined endoscopic third ventriculostomy (ETV) and tumor biopsy might be necessary. We suggest a computer-assisted planning procedure to perform ETV and biopsy via a single burr hole. METHODS: In 15 patients with non-communicating hydrocephalus with a mass obstructing the Sylvian aqueduct, an ETV in parallel to targeting the lesion was planned to be performed via a single burr hole. Prior to surgery, a 3D MRI data set was planned to be acquired for computer-assisted planning. The lesion target points were located in the third ventricle or in the lateral ventricle. By defining the optimal entry point as single burr hole, the trajectory was calculated to cause the least amount of tissue shift at the foramen of Monro (FM) or within the hemispheric tissue. The burr hole localization was measured relative to nasion and to midline. The diagnostic yield and the success rate of ETV were evaluated. RESULTS: The optimal entry point for third ventricular lesions was 111 +/- 17 mm to the nasion and 16 +/- 11 mm to the midline. Tissue shift at the level of FM was 2.4 +/- 4 mm. For targeting the floor of the third ventricle in parallel to lesions of the lateral ventricle, the entry point was at 122 +/- 11 mm to the nasion and 17 +/- 9 mm to the midline. Rate of diagnostic yield was 86.7%. Success rate of ETV at follow-up of 34 +/- 19 months was 86.7%. CONCLUSIONS: Performing ETV in parallel to target paraventricular lesions causing a hydrocephalus is feasible via a single burr hole by using computer-assisted planning and performing a navigated endoscopic procedure. PMID- 21327591 TI - Fetal myelomeningocele surgery: preschool functional status using the Functional Independence Measure for children (WeeFIM). AB - OBJECTIVE: To study preschool functional status in children following fetal myelomeningocele (fMMC) surgery. MATERIAL AND METHODS: Prior to the NICHD-MOMS trial, 30 fMMC underwent standardized neurodevelopmental examination at 5 years of age. Functional status was determined with the Functional Independence Measure (WeeFIM), which assesses self-care, mobility, and cognitive independence. RESULTS: Evaluations were completed in 26 (87%). Mean cognitive (93.0 +/- 21.9), self-care (66.5 +/- 23.9), mobility (82.3 +/- 19.5), and total (77.9 +/- 20.3) functional quotient of fMMC children were significantly lower than age-matched population norms (P < 0.01). Complete caregiver independence was achieved by 22 (84%), 10 (38%), 16 (62%), and 15 (58%) fMMC children for cognition, self-care, mobility, and total functional outcome, respectively. Cognitive, mobility, and total independence were higher in non-shunted than shunted fMMC children (P = 0.02, P = 0.02, and P < 0.01, respectively) and in fMMC children with average neurodevelopmental scores (P < 0.001, P = 0.01, and P < 0.01, respectively). Self care independence tended to be higher in the non-shunted group and in fMMC children with normal neurodevelopmental outcome (P = 0.07 and P = 0.09, respectively). CONCLUSION: The majority of fMMC children achieved cognitive and mobility independence, but continue to require significant assistance in self care. Non-shunted and fMMC children with normal neurodevelopmental outcome were more likely to be independent in daily living activities. Better understanding of the extent of functional limitations following fMMC surgery will allow for more effective early interventions geared toward maximizing independence in everyday tasks in all environments. PMID- 21327592 TI - Acute respiratory distress and shock secondary to complicated diaphragmatic hernia. PMID- 21327593 TI - Improved survival in severe paraquat poisoning with repeated pulse therapy of cyclophosphamide and steroids. AB - PURPOSE: To clarify the efficacy of repeated methylprednisolone (MP) and cyclophosphamide (CP) pulse therapy and daily dexamethasone (DEX) therapy in patients with severe paraquat (PQ) poisoning. METHODS: A total of 111 patients with severe PQ poisoning and dark-blue color in urine tests within 24 h of intoxication were included prospectively. The control group consisted of 52 patients who were admitted between 1998 and 2001 and who received high doses of CP (2 mg/kg per day) and DEX (5 mg every 6 h) for 14 days. The study group consisted of 59 patients who were admitted from 2002 to 2007 and who received initial MP (1 g) for 3 days and CP (15 mg/kg per day) for 2 days, followed by DEX (5 mg every 6 h) until a PaO(2) of >80 mmHg had been achieved, or treated with repeated 1 g MP for 3 days and 1 g CP for 1 day if the PaO(2) was <60 mmHg. RESULTS: There were no differences between the two groups with regard to baseline data and plasma PQ levels. The study group patients had a lower mortality rate (39/59, 66%) than the control group patients (48/52, 92%; P=0.003, log-rank test). Multivariate Cox regression analysis revealed that the repeated pulse therapy was correlated with decreased hazard ratios (HR) for all-cause mortality (HR=0.50, 95% CI 0.31-0.80; P=0.004) and death from lung fibrosis-related hypoxemia (HR=0.10, 95% CI 0.04-0.25; P<0.001) in severely PQ-intoxicated patients. CONCLUSION: Repeated pulses of CP and MP, rather than high doses of CP and DEX, may result in a lower mortality rate in patients with severe PQ poisoning. PMID- 21327594 TI - Using fuzzy association rule mining in cancer classification. AB - The classification of the cancer tumors based on gene expression profiles has been extensively studied in numbers of studies. A wide variety of cancer datasets have been implemented by the various methods of gene selection and classification to identify the behavior of the genes in tumors and find the relationships between them and outcome of diseases. Interpretability of the model, which is developed by fuzzy rules and linguistic variables in this study, has been rarely considered. In addition, creating a fuzzy classifier with high performance in classification that uses a subset of significant genes which have been selected by different types of gene selection methods is another goal of this study. A new algorithm has been developed to identify the fuzzy rules and significant genes based on fuzzy association rule mining. At first, different subset of genes which have been selected by different methods, were used to generate primary fuzzy classifiers separately and then proposed algorithm was implemented to mix the genes which have been associated in the primary classifiers and generate a new classifier. The results show that fuzzy classifier can classify the tumors with high performance while presenting the relationships between the genes by linguistic variables. PMID- 21327595 TI - A novel porcine gene, LIPC, differentially expressed in the liver tissues from Meishan and Large White pigs. AB - The mRNA differential display technique was performed to investigate the differences in gene expression in the liver tissues from Meishan and Large White pigs. One novel gene that was differentially expressed was identified through semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and the cDNA complete sequence was then obtained using the rapid amplification of cDNA ends (RACE) method. The nucleotide sequence of the gene is not homologous to any of the known porcine genes. The sequence prediction analysis revealed that the open reading frame of this gene encoding a protein of 501 amino acids has high homology with the lipase, hepatic (LIPC) of seven species--cattle (82%), rhesus monkey (79%), chimpanzee (78%), rabbit (77%), human (78%), mouse (73%) and rat (72%)--so that it can be defined as the swine LIPC gene. Phylogenetic analysis revealed that the swine LIPC gene has a closer genetic relationship with the LIPC of cattle. Tissue expression profile analysis indicated that the swine LIPC gene is also differentially expressed in other detected tissues from Meishan and Large White pigs. Our experiment suggested that the swine LIPC gene might play an important role in the superabundant fat deposition of Chinese pigs. PMID- 21327596 TI - The significance of transient ischemic dilation in the setting of otherwise normal SPECT radionuclide myocardial perfusion images. AB - BACKGROUND: Transient ischemic dilation (TID) in the setting of an abnormal SPECT radionuclide myocardial perfusion imaging (MPI) study is considered a marker of severe and extensive coronary artery disease (CAD). However, the clinical significance of TID and its association with CAD in patients with an otherwise normal MPI study is unclear. METHODS: From a database of patients who underwent MPI over a 9-year period, 96 without known cardiac history who had normal image perfusion patterns, and who underwent coronary angiography within 6 months, were identified. TID quantitative values were derived. To adjust for varying stress and image protocols, a TID index based on published threshold values was derived for each patient, with >1 considered as TID. We examined the relationship of TID to the presence/extent of CAD, and to a CAD prognostic index. TID was also correlated with patient survival. To address referral bias, survival in a separate cohort of 3,691 patients with a normal perfusion MPI who did not undergo angiography in the 6-month interval was correlated with the presence and severity of TID. RESULTS: For 28 (29.2%) patients with normal MPI perfusion patterns but with TID, there was no increased incidence of CAD, multivessel or left main disease, or a higher prognostic index compared with no TID. In addition, there was no increased mortality associated with TID in both the angiography cohort and in the patients who did not undergo immediate angiography. CONCLUSIONS: TID in patients with an otherwise normal SPECT MPI study does not increase the likelihood of CAD, its extent or severity, and is not associated with worsened patient survival. PMID- 21327597 TI - Analyzing the cryptome: uncovering secret sequences. AB - The mammalian cryptome consists of bioactive peptides generated by the proteolysis of precursor proteins. It is speculated that the cryptide repertoire increases the complexity of the proteome by an order of magnitude. Cryptides have been found to function in a wide range of processes including neuronal signaling, antigen presentation, and the inflammatory response. Due to their potential as therapeutic agents, there has been an increasing interest in studying cryptides. In this review, we discuss different approaches for discovering these hidden peptides and how proteomic tools can be utilized to aid in their identification and characterization. PMID- 21327598 TI - Noninfectious wound complications in clean surgery: epidemiology, risk factors, and association with antibiotic use. AB - BACKGROUND: Noninfectious wound complications are frequent and often are confused with and treated as infection. METHODS: We assessed the epidemiology, impact, risk factors, and associations with antibiotic use of noninfectious wound complications in clean orthopedic and trauma surgery. We report a single-center, prospective, observational study in an orthopedic department. RESULTS: Among 1,073 adult patients, 630 (59%) revealed clinically relevant postoperative noninfectious wound complications, leading to a significant prolongation of hospital stay (14 vs. 12 days; Wilcoxon rank-sum test; p<0.02) compared with patients without complications. The most frequent and severe complications were discharge with dehiscence (n=437; 41%) and hematoma (n=379; 35%). Forty-seven patients (47/630; 7%) underwent reoperation for dehiscence (n=39) or hematoma (n=8). These patients made up 4.3% of the entire study population (47/1,073). In multivariate analysis, an ASA score>=2 points, age>=60 years, surgery duration for >=90 min, implant-related surgery, and poor compliance toward nurses' recommendations were pronounced risk factors for these complications, whereas antibiotic-related parameters had no influence. Staple use was significantly associated with wound discharge but not with hematoma. CONCLUSIONS: Wound complications, such as dehiscence with discharge or hematoma after clean orthopedic and trauma surgery, are frequent with an overall incidence of 60%. Although they lead to few surgical reinterventions, they prolong hospital stay by 2 days. Few clinical parameters show association with wound complications. Among them, improvements of patient compliance and avoidance of staples use for skin closure are the most promising actions to decrease complication risk. PMID- 21327599 TI - Promoting major pediatric surgical care in a low-income country: a 4-year experience in Eritrea. AB - BACKGROUND: Access to pediatric surgical care in many sub-Saharan African countries is strongly limited by lack of medical facilities, adequate transport system, and trained medical and nursing manpower. The mortality rate for major congenital abnormalities remains extremely elevated in this area of the world. Strong efforts have been spent during the past decades to elevate the level of pediatric surgery standards in these countries through cooperation programs acting through periodical medical missions or supporting local medical teaching institutions. This is a report of a partnership between an Italian Medical Institution and the Eritrean Ministry of Health with the goal to improve pediatric surgical standard of care in the country. METHODS: During the past 4 years, teams composed of two pediatric surgeons, a pediatric anesthetist, and a pediatric nurse regularly visited the Orotta Medical and Surgical Referral Hospital of Asmara (Eritrea) to offer modern surgical treatment to children with major congenital abnormalities and to offer academic training to local medical and nursing staff. The team worked in local health structures. A total of 714 patients have been visited and 430 surgical procedures have been performed during 35 weeks of clinical work. Among them were 32 anorectal malformations, 11 Hirschsprung's disease cases, 8 bladder extrophies, and many other major surgical problems, such as congenital intestinal obstructions, obstructive uropathies, and solid tumors. RESULTS: The standard of care has been based on the principle of researching sustainable solutions. Surgical options and timing of each procedure have been decided to reduce hospitalization and the recourse to temporary stomas, indwelling catheterization, and prolonged intravenous feeding. Posterior sagittal anorectoplasties (PSARP) and posterior vagino-anorectoplasty (PSVARP) were performed for anorectal malformations, introducing minimal technical variants to reduce the need for postoperative nursing. Endorectal pull-through of functional stoma was the treatment of choice for patients with Hirschsprung's disease because frozen sections were not possible. Eight late-referred bladder extrophy cases were all managed by internal diversion (Mainz II pouch). Solid abdominal tumors always came to observation weeks or months after the first symptoms appeared. No CT scan was available and indications of surgery were based on clinical symptoms only. Only 11 of 18 cases were resectable, and only 5 of them with favorable histology survived, 2 after adjuvant therapy abroad. A large number of hypospadias were observed at the mean age of 4.5 years. Failures of previous attempts at correction were frequently found. The postoperative complications rate progressively decreased with the use of dripping stents to avoid the risk of accidental catheter removal or kinking. CONCLUSIONS: On the basis of our experience, major pediatric surgery in many under-resourced areas of sub-Saharan Africa can be developed, taking care to adapt surgical options to local conditions. Late referral of many congenital abnormalities, the impact of local culture, difficulties to establish regular follow-up, and shortage of facilities and medical devices must always be kept in mind before transferring modern protocols of management. Strong efforts have been devoted to train local medical and nursing staff to establish pediatric surgical manpower to cope with a still largely unanswered demand of care in this area of Africa. PMID- 21327600 TI - Preoperative biliary MRSA infection in patients undergoing hepatobiliary resection with cholangiojejunostomy: incidence, antibiotic treatment, and surgical outcome. AB - BACKGROUND: There have been no reports on the impact of preoperative biliary MRSA infection on the outcome of major hepatectomy. The aim of this study was to review the surgical outcome of patients who underwent hepatobiliary resection after biliary drainage and to evaluate the impact of preoperative biliary MRSA infection. METHODS: Medical records from 350 patients who underwent hepatobiliary resection with cholangiojejunostomy after external biliary drainage were retrospectively reviewed. RESULTS: Of the 350 study patients, 14 (4.0%) had MRSA positive bile culture, 246 (70.3%) had positive bile culture without MRSA growth, and the remaining 90 (25.7%) had negative bile culture. In all of the patients with MRSA-positive bile culture, vancomycin was prophylactically administered after surgery. Of the 14 patients, 6 (42.9%) had surgical site infections, including wound infection in 5 patients and intra-abdominal abscess in 2 patients. The incidence of surgical site infection in the 14 MRSA-positive patients was higher but not statistically significant compared to the incidence in other patient groups. All 14 patients tolerated difficult hepatobiliary resection. Of the 350 study patients, 28 (8.0%) had postoperative MRSA infections. Multivariate analysis identified preoperative MRSA-positive bile culture as a significant independent risk factor for postoperative MRSA infection. CONCLUSIONS: Preoperative biliary MRSA infection is troublesome as it is an independent risk factor of postoperative MRSA infection. Even in such troublesome situations, however, difficult hepatobiliary resection can be performed with acceptable rates of morbidity and mortality using appropriate antibiotic prophylaxis, including vancomycin, based on bile culture. PMID- 21327601 TI - Changing incidence of acute appendicitis and nonspecific abdominal pain between 1987 and 2007 in Finland. AB - BACKGROUND: The incidence of acute appendicitis has declined in many countries. The aim of this study was to determine the trends in incidence of acute appendicitis (AA), appendectomies for AA, and nonspecific abdominal pain (NSAP) in Finland between 1987 and 2007. METHODS: We carried out a national register study. Demographic features were investigated. Diagnoses and procedures were classified according to the World Health Organization International Classification of Diseases. Data were analyzed for each of all five University Hospital districts (UHD) of Finland. RESULTS: During the observation period of 21 years, 186,558 appendectomies were performed in Finland, of which 137,528 (74%) cases were reported as AA. The incidence of acute appendicitis declined 32%. The diagnostic accuracy improved from 73 to 82% and was higher in men. The accuracy rate among the male patients was stable throughout the two decades; among the female patients it rose from 63 to 75%. The incidence of appendicitis was highest in patients aged 15-24 years. The average incidence of NSAP was 34/10,000/year, and it was higher in older age groups. There was a large geographical disparity in the incidence of NSAP. CONCLUSION: The incidence of acute appendicitis as well as the incidence of appendectomies is declining in Finland. The incidence of the NSAP has also been declining but we did not find any correlations between the incidences of the acute appendicitis and NSAP. There were clear geographical differences in the incidence of NSAP but not in the incidence of AA. PMID- 21327602 TI - Diffusion-weighted magnetic resonance imaging for detecting lymph node metastasis of rectal cancer. AB - BACKGROUND: Preoperative diagnosis of lymph node metastasis is important in determining the optimal therapy for rectal cancer. It has been shown that diffusion-weighted magnetic resonance imaging (DWI) is a useful tool for detecting malignant tumors. METHODS: One hundred twenty-nine consecutive patients with rectal cancer were examined with DWI + conventional (T1-weighted and T2 weighted) MRI and computed tomography (CT). All 129 patients underwent rectal resection with total mesorectal excision. Findings on DWI + conventional MRI and CT were compared with those from histopathologic examinations. RESULTS: Fifty nine (46%) patients had metastatic lymph nodes on histopathologic examinations. Two hundred twenty (18%) of 1,250 lymph nodes were pathologically positive for tumor metastasis. The overall patient-based sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of DWI + conventional MRI were 93, 81, 81, 93, and 87%, respectively. Corresponding values of CT were 73, 79, 74, 77, and 76%, respectively. The overall node-based sensitivity, specificity, PPV, NPV, and accuracy of DWI + conventional MRI were 97, 81, 52, 99, and 84%, respectively. Corresponding values of CT were 86, 80, 48, 96, and 81%, respectively. CONCLUSION: DWI + conventional MRI is effective for the detection of lymph node metastasis and useful for selection of the optimal therapy for rectal cancer. PMID- 21327603 TI - Surgical simulation tasks challenge visual working memory and visual-spatial ability differently. AB - BACKGROUND: New strategies for selection and training of physicians are emerging. Previous studies have demonstrated a correlation between visual-spatial ability and visual working memory with surgical simulator performance. The aim of this study was to perform a detailed analysis on how these abilities are associated with metrics in simulator performance with different task content. The hypothesis is that the importance of visual-spatial ability and visual working memory varies with different task contents. METHODS: Twenty-five medical students participated in the study that involved testing visual-spatial ability using the MRT-A test and visual working memory using the RoboMemo computer program. Subjects were also trained and tested for performance in three different surgical simulators. The scores from the psychometric tests and the performance metrics were then correlated using multivariate analysis. RESULTS: MRT-A score correlated significantly with the performance metrics Efficiency of screening (p = 0.006) and Total time (p = 0.01) in the GI Mentor II task and Total score (p = 0.02) in the MIST-VR simulator task. In the Uro Mentor task, both the MRT-A score and the visual working memory 3-D cube test score as presented in the RoboMemo program (p = 0.02) correlated with Total score (p = 0.004). CONCLUSIONS: In this study we have shown that some differences exist regarding the impact of visual abilities and task content on simulator performance. When designing future cognitive training programs and testing regimes, one might have to consider that the design must be adjusted in accordance with the specific surgical task to be trained in mind. PMID- 21327604 TI - "Clipless" cholecystectomy: evolution marches on, even for lap chole. PMID- 21327605 TI - Is there any benefit to incorporating a laparoscopic procedure into minimally invasive esophagectomy? The impact on perioperative results in patients with esophageal cancer. AB - BACKGROUND: The benefit of using the laparoscopic approach in minimally invasive esophagectomy (MIE) has not been established. We therefore compared the outcome of esophagectomy for patients with esophageal cancer performed with open surgery, video-assisted thoracic surgery (VATS)/laparotomy (hybrid MIE), and VATS/ laparoscopy (total MIE). METHODS: Patients with esophageal cancer undergoing tri incisional esophagectomy with three different approaches between 2005 and 2009 were analyzed from a prospective database. RESULTS: Three groups of patients underwent esophagectomy by open surgery (n = 64), hybrid MIE (n = 44), and total MIE (n = 30). The total MIE group had significantly longer operative times but had shorter postoperative ventilator usage times postoperative hospital stay, and they began jejunostomy feeding sooner (P < 0.05, compared with the other groups). There was a significant trend toward a decrease in postoperative pulmonary complications and anastomotic leakage in parallel to the proportion of minimally invasive procedures for esophagectomy (P < 0.05 for the trend test), with a significant difference between the open surgery and total MIE groups (30% vs. 6.7%, and 28% vs. 6.7%, respectively; P < 0.05). CONCLUSIONS: Use of a laparoscopic procedure in MIE for patients with esophageal cancer might provide benefit by facilitating postoperative recovery and reducing the rates of post esophagectomy pulmonary complications and anastomotic leakage. PMID- 21327606 TI - Characterization and locus-specific typing of MHC class I genes in the red-billed gull (Larus scopulinus) provides evidence for major, minor, and nonclassical loci. AB - A major challenge facing studies of major histocompatibility complex (MHC) evolution in birds is the difficulty in genotyping alleles at individual loci, and the consequent inability to investigate sequence variation and selection pressures for each gene. In this study, four MHC class I loci were isolated from the red-billed gull (Larus scopulinus), representing both the first characterized MHCI genes within Charadriiformes (shorebirds, gulls, and allies) and the first full-length MHCI sequences described outside Galloanserae (gamebirds + waterfowl). Complete multilocus genotypes were obtained for 470 individuals using a combination of reference-strand conformation analysis and direct sequencing of gene-specific amplification products, and variation of peptide-binding region (PBR) exons was surveyed for all loci. Each gene is transcribed and has conserved sequence features characteristic of antigen-presenting MHCI molecules. However, higher allelic variation, a more even allele frequency distribution, and evidence of positive selection acting on a larger number of PBR residues suggest that only one locus (Lasc-UAA) functions as a major classical MHCI gene. Lasc-UBA, with more limited variation and PBR motifs that encompass a subset of Lasc-UAA diversity, was assigned a putative minor classical function, whereas the divergent and largely invariant binding-groove motifs of Lasc-UCA and -UDA are suggestive of nonclassical loci with specialized ligand-binding roles. PMID- 21327608 TI - Pre-exposure enhances recovery of conditioned responding after extinction. AB - Four experiments used a within-subjects design with rats to study the effects of preexposure on the restoration of fear responses (freezing) to an extinguished conditioned stimulus (CS). In each experiment, rats were preexposed to one CS (A), but not to another (B), and then were exposed to pairings of each of these CSs with an aversive unconditioned stimulus (US). In each experiment, there was less freezing to A than to B across extinction, showing a latent inhibitory effect of preexposure. There was no differential recovery to A and B following either a US reexposure (Experiment 1) or a delay interval (Experiment 2). However, when a delay interval included US reexposure, there was greater recovery to the preexposed CS, A, than to the nonpreexposed CS, B (Experiments 1, 3, and 4). These results suggest that the effects of US reexposure and delay combine to affect recovery from the depressive effects of CS-alone exposure. The results are consistent with the view that US reexposure produces better mediated conditioning of CSs that are strongly associated with the context. The results may additionally reflect an effect of preexposure on the learning produced by extinction. PMID- 21327607 TI - Characterization and allelic polymorphisms of rhesus macaque (Macaca mulatta) IgG Fc receptor genes. AB - Macaque models are invaluable for AIDS research. Indeed, initial development of HIV-1 vaccines relies heavily on simian immunodeficiency virus-infected rhesus macaques. Neutralizing antibodies, a major component of anti-HIV protective responses, ultimately interact with Fc receptors on phagocytic and natural killer cells to eliminate the pathogen. Despite the major role that Fc receptors play in protective responses, there is very limited information available on these molecules in rhesus macaques. Therefore, in this study, rhesus macaque CD32 (FcgammaRII) and CD64 (FcgammaRI) homologues were genetically characterized. In addition, presence of CD16 (FcgammaRIII), CD32, and CD64 allelic polymorphisms were determined in a group of nine animals. Results from this study show that the predicted structures of macaque CD32 and CD64 are highly similar to their human counterparts. Macaque and human CD32 and CD64 extracellular domains are 88-90% and 94-95% homologous, respectively. Although all cysteines are conserved between the two species, macaque CD32 exhibits two additional N-linked glycosylation sites, whereas CD64 lacks three of them when compared to humans. Five CD32, three CD64, and three CD16 distinct allelic sequences were indentified in the nine animals examined, indicating a relatively high level of polymorphism in macaque Fcgamma receptors. Together, these results validate rhesus macaques as models for vaccine development and antibody responses, while at the same time, underscoring the need to take into account the high degree of genetic heterogeneity present in this species when designing experimental protocols. PMID- 21327609 TI - Comparison of cytotoxicity induced by 17alpha-ethynylestradiol and diethylstilbestrol in fish CCO and mammalian CHO-K1 cell lines. AB - The effects of synthetic estrogens 17alpha-ethynylestradiol (EE2) and diethylstilbestrol (DES) were compared on cell proliferation and morphology in Channel Catfish Ovary (CCO) and Chinese Hamster Ovary (CHO-K1) cells. EE2 exposure (0.1 and 0.5 MUg/mL) induced stimulatory effect on CCO and CHO-K1 cell proliferation, while higher concentrations (1-10 MUg/mL) showed cytotoxic effects. Increase in DES concentrations mainly resulted in dose-depended increase in cytotoxicity in both cell lines. Morphological changes induced by EE2 and DES exposure (5 MUg/mL) showed disrupted cell monolayer and increased number and size of lysosomes. Comparison of IC(50) values showed almost equal sensitivity towards cytotoxicity of tested compounds in CCO and CHO-K1 cells. PMID- 21327610 TI - Dissipation and residue of cyprodinil in strawberry and soil. AB - The dissipation of cyprodinil under field and greenhouse condition in China was investigated. The pesticide cyprodinil dissipation differed under different cultivate conditions, the half lives were 14.5 and 12.5 days in strawberry and soil, respectively, under the field condition, 5.5 and 6.5 days, respectively, under greenhouse. The results showed that the dissipation rate under greenhouse condition was much faster than under field condition either in strawberry or soil. The terminal residues in strawberries were below the EU maximum residue level (5 mg/kg) after 7 days of application. This study will give a suggestion for the reasonable use of cyprodinil under different cultivate conditions and can also provide reference to set MRL value in strawberry in China. PMID- 21327611 TI - Polycyclic aromatic hydrocarbons profile of kitchen dusts. AB - Concentrations and profiles of polycyclic aromatic hydrocarbons (PAHs) were determined in thirty dust samples collected from kitchens that use wood cook system (WCS), kerosene stove cook system (KSCS) and butane gas cook system (BGCS). The total PAHs concentrations ranged from 52 to 497, 39 to 96 and 37 to 155 MUg kg(-1) for WCS, KSCS and BGCS respectively. The results indicate predominance of lower molecular weight (2-3 rings) over higher molecular weight PAHs and users of wood cook system are more exposed to higher levels of PAHs than the users of either kerosene cook system or butane gas cook system. PMID- 21327612 TI - Determination of field-incurred chlorfluazuron residues in the peach. AB - Chlorfluazuron residues were determined in the peaches that were sprayed at dosage (a.i. 0.0167 kg 10a(-1)), using an analytical method that was validated as follows; r (2) = 0.9999, 0.02 mg kg(-1) (LOQ) and 87.8-93.6% (recovery). The residues from all samples were lower than the MRL (0.5 mg kg(-1), Korea). A maximum 0.27 mg kg(-1) of chlorfluazuron was detected in the samples applied at 6 days before harvest. The results signify that the 10% SC product would be used safely as an insecticide if it is applied two or three times onto peaches, with applications given until 6 days prior to harvest. PMID- 21327613 TI - [One-stage revision of knee endoprosthesis due to periprosthetic infection and Klippel-Trenaunay syndrome]. AB - We present the case of a patient with Klippel-Trenaunay syndrome (KTS) who underwent a one-stage revision of an infected total knee arthroplasty. A detailed orthopedic description of KT is presented as well as a discussion on the implementation of one-stage or multi-stage revision following infections of total knee arthroplasty. Due to vascular anomalies with severe coagulation problems, soft tissue swelling and increased risk of infection, surgical treatment of such patients presents a special challenge. PMID- 21327614 TI - Resolving semantic and proactive interference in memory over the short-term. AB - Interference is a major source of short-term errors of memory. The present investigation explores the relationship between two important forms of interference: proactive interference (PI), induced by the need to reject recently studied items no longer relevant to task performance, and semantic interference (SI), induced by the need to reject lures sharing a meaningful relationship with current memoranda. We explore the possibility that shared cognitive control processes are recruited to resolve both forms of interference. In Experiment 1, we find that the requirement to engage in articulatory suppression during the retention interval of tasks that induce either PI or SI increases both forms of interference similarly and selectively. In Experiment 2, we develop a task to examine PI and SI within the same experimental context. The results show interactive effects between factors that lead to the two forms of interference. Taken together, these findings support contextual-cuing models of short-term remembering (Nairne, Annual Review of Psychology, 53, 53-81 2002), where the context in which retrieval occurs can influence susceptibility to interference. Lastly, we discuss several theoretical hypotheses concerning the cognitive control processes that are recruited to resolve SI and PI in short-term remembering. PMID- 21327615 TI - Adipose tissue derived stem cells differentiate into carcinoma-associated fibroblast-like cells under the influence of tumor derived factors. AB - BACKGROUND: Carcinoma-associated fibroblasts (CAF) are considered to contribute to tumor growth, invasion and metastasis. However, the cell type of origin remains unknown. Since human adipose tissue derived stem cells (hASCs) are locally adjacent to breast cancer cells and might directly interact with tumor cells, we investigated whether CAFs may originate from hASCs. METHODS: hASCs cultured under different conditions were quantified for the expression of alpha smooth muscle actin. ELISA was performed using the human TGFbeta1, SDF-1alpha and CCL5 Quantikine Kit. The invasion potential of MDAMB231 cancer cells was evaluated using a Boyden chamber with filter inserts coated with Matrigel in 24 well dishes. RESULTS: We demonstrated that a significant percentage of hASCs differentiated into a CAF-like myofibroblastic phenotype (e.g. expression of alpha smooth muscle actin and tenascin-C) when exposed to conditioned medium from the human breast cancer lines MDAMB231 and MCF7. The conditioned medium from MDAMB231 and MCF7 contains significant amounts of transforming growth factor-beta 1 (TGFbeta1) and the differentiation of hASCs towards CAFs is dependent on TGFbeta1 signaling via Smad3 in hASCs. The induction of CAFs can be abolished using a neutralizing antibody to TGFbeta1 as well as by pretreatment of the hASCs with SB431542, a TGFbeta1 receptor kinase inhibitor. Additionally, we found that these hASC-derived CAF-like cells exhibit functional properties of CAFs, including the ability to promote tumor cell invasion in an in vitro invasion assay, as well as increased expression of stromal-cell derived factor 1 (SDF-1) and CCL5. CONCLUSION: Our data suggest that hASCs are a source of CAFs which play an important role in the tumor invasion. PMID- 21327616 TI - Our impasse in developing a malaria vaccine. AB - Malaria presents a challenge to world health that to date has been beyond the abilities of researchers to conquer. This critique presents some of the strategies employed by the parasite to overcome immunity and the immunological challenges that we face to develop vaccines. A conclusion is that a vaccine must identify novel antigens or epitopes that are not normally immunogenic and which are therefore not under immune pressure and most likely to be conserved between different strains. Such antigens are most likely to be targets of cellular immunity. The case for a whole parasite blood stage vaccine is presented based on these premises. PMID- 21327617 TI - The difference of glutathione antioxidant system in newly weaned and young mice liver and its involvement in isoline-induced hepatotoxicity. AB - Cellular glutathione antioxidant system plays important roles in counteracting hepatotoxins-induced oxidative stress injury. The present study was designed to observe the differences of this system in newly weaned and young mice liver and its involvement in the susceptibility to isoline-induced liver injury. Our results showed that liver reduced glutathione (GSH) amounts were higher in newly weaned mice than young mice. Glutamate-cysteine ligase (GCL) activity was higher in newly weaned mice due to the higher expression of catalytic subunit of GCL (GCLC) protein and mRNA. However, the activities of glutathione reductase (GR), glutathione peroxidase (GPx), and glutathione-S-transferase (GST) were higher in young mice liver, which might be due to the higher expression of GR, GPx-1, and GST-Pi proteins. Next, the results of AST analysis and histopathological evaluation showed that newly weaned mice demonstrated more severe liver injury induced by isoline. Furthermore, liver GSH amounts and the activities of GR, GPx, and GST were all lower in newly weaned mice than young mice after treated with isoline. Depletion of cellular GSH by D,L -buthionine-(S, R)-sulfoximine (BSO) aggravated isoline-induced cytotoxicity, while N-acetyl-l cysteine (NAC) ameliorated such cytotoxicity. Furthermore, the inhibitors of GR, GPx, and GST all aggravated isoline-induced cytotoxicity. In conclusion, our results demonstrated the differences of glutathione antioxidant system between newly weaned and young mice liver. Meanwhile, our results also revealed age-dependent liver injury induced by isoline for the first time, which might be due to the different responses of glutathione antioxidant system to isoline between newly weaned and young mice. PMID- 21327618 TI - Silencing of tissue factor by antisense deoxyoligonucleotide prevents monocrotaline/LPS renal injury in mice. AB - Tissue factor (TF) is involved in monocrotaline (MCT)/lipopolysaccharide (LPS) hepatotoxicity. It is not known whether MCT/LPS can cause renal toxicity and whether TF is involved in this toxicity. Thus, the present study was undertaken to investigate the potential renal toxicity after MCT/LPS co-treatment and the involvement of TF in this toxicity. MCT was delivered to ND4 male mice (200 mg/kg) per os followed 4 h later by treatment with LPS ip (6 mg/kg) to investigate its effect on kidney. We injected TF antisense oligonucleotide (TF AS) intravenously (i.v) in mice prior to LPS treatment, to block TF, and measured their blood urea nitrogen (BUN), creatinine (CRE), alkaline phosphatase (ALP), and potassium. In MCT/LPS co-treated group, fibrin was detected on the glomerular capillary lumina, distal tubules of renal cortex, and the necrotic tubules of renal medulla. An elevation of BUN, creatinine, and the BUN/creatinine ratio was seen in mice with MCT/LPS co-treatment, compared to animals receiving LPS or MCT alone. Simultaneously, an aggressive tubular necrosis was seen in the medullary tubules in the same group which may account for the oliguria observed in these animals. Fourfold inductions in the plasma TF level was detected at 10 h after MCT/LPS co-treatment which increased to 18-fold at 24 h. Increased blood level of leptin, interleukin-6 (IL-6) and downregulation of tubular chemokine (C-X-C motif) ligand 16 (CXCL16) are characteristic features in MCT/LPS co-treated animal. On the other hand, mice injected with TF-AS in the presence of MCT/LPS co treatment showed no elevation of the blood BUN, creatinine, potassium, and normal levels of the proinflammatory molecules. TF-AS injection significantly prevented glomerular and tubular fibrin deposition, tubular necrosis, and improvement of the animal survivability. Renal toxicity involving TF can be prevented successfully by the use of TF-AS. PMID- 21327619 TI - Sub-chronic effect of perfluorooctanesulfonate (PFOS) on the balance of type 1 and type 2 cytokine in adult C57BL6 mice. AB - As a ubiquitous and highly persistent environmental contaminant, the clear mechanisms to explain any perfluorooctanesulfonate (PFOS)-induced immunotoxicity are still unknown. This study here sought to examine the ability of PFOS to potentially perturb T-helper (T(H))-1 and T(H)-2 cell cytokine secreting activities, as well as to cause shifts in antibody isotype levels, and possible mechanisms involved in PFOS-induced immunotoxicity. Adult male C57BL/6 mice were exposed to PFOS daily via gavage for 60 days [0, 0.5, 1, 5, 25, or 50 mg/kg total administered dose (TAD)]. One day after the final exposure, the ex vivo production of the T(H)1-type cytokines (IL-2 and IFN-gamma), T(H)2-type (IL-4), and IL-10 cytokines by isolated splenocytes, serum levels of immunoglobulin (Ig) were assessed via ELISA or ELISPOT. The results showed that IL-4 secretion was increased at exposure >=5 mg PFOS/kg TAD in a dose-dependent manner. PFOS exposure increased IL-10 but decreased IL-2 and IFN-gamma formation markedly at 50 mg PFOS/kg TAD. Serum levels of sheep red blood cells (SRBC)-specific IgM synthesis decreased significantly with PFOS exposure in a dose-related manner; serum SRBC-specific IgG, IgG1, and IgE levels increased with 50 mg PFOS/kg TAD regimens. These results indicated that, after a long-term exposure to PFOS, a host's immune state is likely to be characterized by a shift toward a more T(H)2 like state that, in turn, may lead to enhancement of their humoral response and suppression of their cellular response at levels of upper range for occupationally exposed workers or approximately 150-fold for general human population. PMID- 21327620 TI - Absorption and metabolism of the food contaminant 3-chloro-1,2-propanediol (3 MCPD) and its fatty acid esters by human intestinal Caco-2 cells. AB - 3-Chloro-1,2-propanediol (3-MCPD) fatty acid esters are formed upon thermal processing of fat-containing foods in the presence of chloride ions. Upon hydrolytic cleavage, these substances could release free 3-MCPD. This compound is toxicologically well characterised and displayed cancerogenic potential in rodent models. Recently, serious contaminations of different food products with 3-MCPD fatty acid esters have been reported. In regard to a risk assessment, the key question is to which degree these 3-MCPD fatty acid esters are hydrolysed in the human gut. Therefore, the aim of the present project was to examine the hydrolysis of 3-MCPD fatty acid esters and the resulting release of free 3-MCPD by using differentiated Caco-2 cells, a cellular in vitro model for the human intestinal barrier. Here, we show that 3-MCPD fatty acid esters at a concentration of 100 MUM were neither absorbed by the cells nor the esters were transported via a Caco-2 monolayer. 3-MCPD-1-monoesters were hydrolysed in the presence of Caco-2 cells. In contrast, a 3-MCPD-1,2-diester used in this study was obviously absorbed and metabolised by the cells. Free 3-MCPD was not absorbed by the cells, but the substance migrated through a Caco-2 monolayer by paracellular diffusion. From these in vitro studies, we conclude that 3-MCPD-1 monoesters are likely to be hydrolysed in the human intestine, thereby increasing the burden with free 3-MCPD. In contrast, intestinal cells seem to have the capacity to metabolise 3-MCPD diesters, thereby detoxifying the 3-MCPD moiety. PMID- 21327621 TI - DNA damage in fetal liver cells of turkey and chicken eggs dosed with aflatoxin B1. AB - The present study was undertaken to investigate the potential of the potent hepatocarcinogen aflatoxin B(1) (AFB) to produce DNA damage in turkey and chicken fetal livers in ovo. Effects of a single injection of two different doses (0.062 and 6.2 MUg) of AFB were examined under both short-term (4 h) and longer-term (4 day) dosing of eggs from turkeys at 24 days and chickens at 18 days of development. Liver cells prepared from the fetuses were used to assess the extent of DNA damage by the alkaline single-cell gel electrophoresis (comet) assay. The results demonstrate that AFB produces dose-related DNA damage in the fetal livers of both turkeys and chicken at 4 h, which was reduced by 4 days. Turkey embryos appeared to be slightly more susceptible to AFB damage, although no difference in the survival between chicken and turkey fetuses was observed. PMID- 21327622 TI - Analytical and bioanalytical science in China. PMID- 21327623 TI - Semi-automated image analysis: detecting carbonylation in subcellular regions of skeletal muscle. AB - The level of carbonylation in skeletal muscle is a marker of oxidative damage associated with disease and aging. While immunofluorescence microscopy is an elegant method to identify carbonylation sites in muscle cross-sections, imaging analysis is manual, tedious, and time consuming, especially when the goal is to characterize carbonyl contents in subcellular regions. In this paper, we present a semi-automated method for the analysis of carbonylation in subcellular regions of skeletal muscle cross-sections visualized with dual fluorescent immunohistochemistry. Carbonyls were visualized by their reaction with 2,4 dinitrophenylhydrazine (DNPH) followed by immunolabeling with an Alexa488-tagged anti-DNP antibody. Mitochondria were probed with an anti-COXI primary antibody followed by the labeling with an Alexa568-tagged secondary antibody. After imaging, muscle fibers were individually analyzed using a custom-designed, lab written, computer-aided procedure to measure carbonylation levels in subsarcolemmal and interfibrillar mitochondrial regions, and in the cytoplasmic and extracellular regions. Using this procedure, we were able to decrease the time necessary for the analysis of a single muscle fiber from 45 min to about 1 min. The procedure was tested by four independent analysts and found to be independent on inter-person and intra-person variations. This procedure will help increase highly needed throughput in muscle studies related to ageing, disease, physical performance, and inactivity that use carbonyl levels as markers of oxidative damage. PMID- 21327624 TI - Hofmeister effect challenge. PMID- 21327625 TI - Kinetic analysis of the estrogen receptor alpha using RIfS. AB - The label-free time-resolved reflectometric interference spectroscopy has been used to study the interaction of the human estrogen receptor alpha (ERa) and different types of ligands. Different possible sensor surface coatings including various estrogen derivatives were evaluated for their suitability for detection of ERa. The determination of the kinetic and thermodynamic constants was carried out for the interaction in the heterogeneous phase as well as for the interaction in homogeneous phase. In addition, the affinity of 11 ligands ranging from natural hormones and pharmaceuticals to endocrine disrupting chemicals (EDCs) has been determined with this label-free assay format. PMID- 21327626 TI - Maria Sklodowska Curie--the precursor of radiation sterilization methods. PMID- 21327627 TI - Assessment of salsolinol N-methyltransferase activity in rat peripheral lymphocytes by liquid chromatography-electrospray time-of-flight mass spectrometry. AB - Salsolinol N-methyltranseferase (SNMT), which may play a crucial role in the pathogenesis of Parkinson's diseases (PD), is a key enzyme to metabolize salsolinol into N-methylsalsolinol that is a neurotoxin specific to dopaminergic neurons. A sensitive method for the quantitative determination of SNMT activity in rat peripheral lymphocytes was developed and validated using liquid chromatography-electrospray with time-of-flight mass spectrometry (LC-ESI-TOF). The calibration curve was linear over the range of 7.40-368.80 nM, with 7.40 nM of the lower limit of quantification. The inter-day and intra-day precisions and accuracy for all samples were acceptable. The validated method was successfully applied for the determination of SNMT activity in both the substantia nigra (SN) and peripheral lymphocytes of a unilateral 6-hydroxydopamine-lesion model of Parkinson's disease in rats. The SNMT activity in the peripheral lymphocytes treated with the 6-hydroxydopamine was significantly increased compared with the control and sham-operated groups, which was coincident with the alteration of SNMT activity in the SN. Our results might indicate that SNMT activity may become a potential clinical marker for PD. PMID- 21327628 TI - Molecular epidemiology of Enterococcus faecium isolates from an Italian hospital. AB - BACKGROUND: Outbreaks of vancomycin-resistant Enterococcus faecium (VRE) strains is an emerging problem worldwide. Even if still relatively uncommon in European hospitals, infections caused by VRE have also been increasing recently in this continent. METHODS: In this study, we characterized 50 consecutive VRE and 23 vancomycin-sensitive E. faecium (VSE) isolates collected in an Italian hospital. The presence of the esp gene and that of genes encoding resistance to glycopeptides was investigated by polymerase chain reaction (PCR). All of the isolates were typed by multi-locus sequence typing (MLST), and a selection of them also by pulsed-field gel electrophoresis (PFGE). RESULTS: We found that all of the VRE and 18 (78%) of the VSE strains belonged to the single clonal complex 17 (CC17). The most represented sequence type (ST) was ST78 (34% of the isolates). When further analyzed by PFGE, ST78 isolates were subdivided into five pulsotypes, four of them closely related. The strong association between the esp gene and CC17 was confirmed. Interestingly, such an association was higher among vancomycin-resistant isolates. Most of the esp-positive isolates (34/46, 74%) encoded Esp4, a rare variant of this protein characterized by the absence of A repeats. CONCLUSIONS: Our findings underscore the role of the CC17 lineage in the nosocomial spread of VRE and VSE, and its rapid local evolution, underscoring the need for programs designed to provide early detection in order to prevent its spreading among the nosocomial population. PMID- 21327629 TI - 2010 Riley Heart Center Symposium on Cardiac Development: cardiomyocyte injury and protection. PMID- 21327630 TI - Rho-kinase in development and heart failure: insights from genetic models. AB - Rho-kinase (ROCK) belongs to the AGC (protein kinase A/protein kinase G/protein kinase C, PKA/PKG/PKC) family of serine/threonine kinases and is a major downstream effector of small GTPase RhoA. Rho-kinase is involved in a wide range of fundamental cellular functions such as contraction, adhesion, migration, and proliferation. Two ROCK isoforms, ROCK1 and ROCK2, are assumed to be functionally redundant, based largely on the major common activators, the high degree of homology within the kinase domain, and studies from overexpression with kinase constructs and chemical inhibitors (e.g., Y27632 and fasudil), which inhibit both ROCK1 and ROCK2. Gene targeting and RNA interference approaches allow further dissection of distinct cellular, physiologic, and pathophysiologic functions of the two ROCK isoforms. This review focuses on the current understanding of ROCK isoform biology, with a particular emphasis on their functions in mouse development and the pathogenesis of heart failure. PMID- 21327632 TI - Increased cave dwelling reduces the ability of cave crickets to resist dehydration. AB - Differential strategies for maintaining water balance are reported for female adults of three cave crickets Hadenoecus cumberlandicus, H. opilionoides and H. jonesi, a species replacement series along the Cumberland Plateau in the southeastern United States. The distribution of H. cumberlandicus is much broader than the range of H. opilionoides, which is much smaller in body size, and that of H. jonesi, which possesses enhanced troglomorphic (cave dwelling) characteristics. Due to high net transpiration (water loss) rates and increased activation energies, H. jonesi and H. opilionoides are more susceptible to dehydration than H. cumberlandicus. To avoid dehydration, H. opilionoides and H. jonesi require more moisture than H. cumberlandicus to counter their higher rates of water loss. The heightened reliance on moisture likely indicates that the more troglomorphic H. jonesi and smaller H. opilionoides are required to spend more time in the moist cave region. Reliance on the cave for H. cumberlandicus is presumably less, allowing them to function in epigean habitats for longer periods and disperse to nearby caves, likely accounting for the more expansive distribution of this cricket. While in the cave habitat, cave crickets are exposed to water-saturated conditions, reducing the pressure of dehydration stress the longer a species remains in this wet environment. This reduced pressure leads to higher water loss rates as cave confinement increases. We conclude that increasing water loss rates associated with increasing troglomorphic adaptation in cave crickets is a side effect of extended residence in stable moist cave environments. PMID- 21327631 TI - The functions of endothelial progenitor cells were significantly improved after treatment with intravenous immunoglobulin and aspirin in children with Kawasaki disease. AB - We sought to determine the effects of treatment with intravenous immunoglobulin (IVIG) and aspirin on the functions of endothelial progenitor cells (EPCs) in patients with Kawasaki disease (KD) as well as its relationship with concentrations of tumor necrosis factor-alpha (TNF-alpha) and high-sensitivity C reactive protein (hs-CRP). Ten KD patients in the acute phase of their disease were recruited. We investigated EPC functions in children with KD before and after treatment with IVIG and aspirin. In vitro assays were used to measure the functions, including proliferation, adhesion, and migration activities, of EPCs. Plasma levels of TNF-alpha and hs-CRP were also assessed. All of the data were assessed before and at 7 days after treatment initiation. EPC functions after 7 days of treatment with IVIG and aspirin were significantly improved than they were before treatment with IVIG and aspirin. Treatment with IVIG and aspirin significantly decreased TNF-alpha and hs-CRP concentrations. There was a significant linear regression relationship between decreased plasma TNF-alpha levels, hs-CRP levels, and increased functions of circulating EPCs. The results of our study indicate that the functions of circulating EPCs improved after treatment with IVIG and aspirin, which may be related to decreased concentrations of TNF-alpha and hs-CRP. PMID- 21327633 TI - Modulatory action of alpha-tocopherol on erythrocyte membrane adenosine triphosphatase against radiation damage in oral cancer. AB - To investigate the possible effects of alpha-tocopherol on erythrocyte membrane adenosine triphosphatases against radiation damage in oral cancer patients. Adenosine triphosphatase activities were analysed in oral cancer patients before and after radiotherapy (at a dosage of 6000 cGY in five fractions per week for a period of six weeks) and after supplemented with alpha-tocopherol (400 IU per day for entire period of radiotherapy). The membrane bound enzymes such as Na(+)/K(+) ATPase, Ca(2+)-ATPase, Mg(2+)-ATPase and some trace elements were altered in oral cancer patients before and after radiotherapy. Supplemented with alpha-tocopherol modulates the erythrocyte membrane which is damaged by radiotherapy which suggests that alpha-tocopherol protects the erythrocyte membrane from radiation damage in oral cancer patients. PMID- 21327634 TI - PET/CT and 3-T whole-body MRI in the detection of malignancy in treated oropharyngeal and hypopharyngeal carcinoma. AB - PURPOSE: We performed a prospective comparison of the diagnostic capability of integrated fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) (PET/CT), 3-T whole-body magnetic resonance imaging (WB-MRI) and their combination in detecting malignancy in treated oropharyngeal or hypopharyngeal squamous cell carcinoma (OHSCC). METHODS: Seventy-nine OHSCC patients at a high risk of residual disease or suspected to have recurrence after the completion of chemoradiation were included in the study. All patients underwent PET/CT and WB-MRI within 10 days of each other. Histology and follow-up data were used as the reference standard. The McNemar test was used to compare sensitivity and specificity, while the area under the receiver-operating characteristic curve (AUC) was used for comparison of diagnostic capabilities. RESULTS: Twenty-nine patients (36.7%) had residual/recurrent tumours or second primary tumours. Overall, there was a trend towards increased sensitivity and diagnostic capability for PET/CT compared with WB-MRI (72.4 vs 55.2%, p = 0.13; 0.826 vs 0.753, p = 0.24, respectively). The diagnostic capability of combined interpretation of PET/CT and WB-MRI was similar to PET/CT alone (0.827 vs 0.826, p = 0.97) but was significantly higher than WB-MRI alone (0.827 vs 0.753, p = 0.04). CONCLUSION: PET/CT showed a trend towards higher diagnostic capability than 3-T WB-MRI in detecting residual/recurrent tumours or second primary tumours in OHSCC. The combined use of PET/CT and WB-MRI provided more added value to WB MRI alone than to PET/CT alone. Additional PET/CT can be useful in patients with questionable MRI findings of malignancy. PMID- 21327635 TI - Relationship between infarct size and severity measured by gated SPECT and long term left ventricular remodelling after acute myocardial infarction. AB - PURPOSE: After acute myocardial infarction (AMI), left ventricular (LV) remodelling may occur despite successful reperfusion. This study aimed to investigate by gated single photon emission computed tomography (SPECT) the long term evolution of myocardial perfusion and LV function after AMI and to identify the predictors of LV remodelling. METHODS: Sixty-eight AMI patients successfully treated by primary percutaneous coronary intervention underwent (99m)Tc-sestamibi gated SPECT at 1 month (baseline) and over 6-month follow-up after the acute event. LV remodelling was defined as 20% increase in LV end-diastolic volume at follow-up. RESULTS: At baseline, patients with remodelling (n = 14) showed larger (infarct size 29.3 +/- 7.8%) and more transmural (infarct severity 0.28 +/- 0.10) infarctions, and reduced LV ejection fraction (35.4 +/- 5.6%), but similar LV volume indexes, compared to patients without remodelling (n = 54) (infarct size 20.8 +/- 14.4%, p < 0.05, infarct severity 0.40 +/- 0.11, p < 0.001, ejection fraction 44.5 +/- 9.2, p < 0.001). At stepwise multivariate regression analysis, infarct severity showed the best predictive value for predicting LV remodelling (F = 5.54, p < 0.05). Using the thresholds identified by receiver-operating characteristic curve analysis, infarct size and severity detected patients with remodelling with 75% accuracy and 95% negative predictive value. Infarct resorption (defined as the defect size difference between follow-up and baseline) was comparable between patients with (-4.4 +/- 8.4%) and without remodelling ( 6.8 +/- 9.4%) (p = NS). CONCLUSION: Perfusion parameters assessed by gated SPECT in the subacute phase after successfully treated AMI correlate with changes in functional parameters at long-term follow-up. Infarct severity is more effective than infarct size, but both are helpful for predicting LV remodelling. PMID- 21327636 TI - Adoptive immunotherapy combined with intratumoral TLR agonist delivery eradicates established melanoma in mice. AB - Toll-like receptor (TLR) agonists can trigger broad inflammatory responses that elicit rapid innate immunity and promote the activities of lymphocytes, which can potentially enhance adoptive immunotherapy in the tumor-bearing setting. In the present study, we found that Polyinosinic:Polycytidylic Acid [Poly(I:C)] and CpG oligodeoxynucleotide 1826 [CpG], agonists for TLR 3 and 9, respectively, potently activated adoptively transferred T cells against a murine model of established melanoma. Intratumoral injection of Poly(I:C) and CpG, combined with systemic transfer of activated pmel-1 T cells, specific for gp100(25-33), led to enhanced survival and eradication of 9-day established subcutaneous B16F10 melanomas in a proportion of mice. A series of survival studies in knockout mice supported a key mechanistic pathway, whereby TLR agonists acted via host cells to enhance IFN gamma production by adoptively transferred T cells. IFN-gamma, in turn, enhanced the immunogenicity of the B16F10 melanoma line, leading to increased killing by adoptively transferred T cells. Thus, this combination approach counteracted tumor escape from immunotherapy via downregulation of immunogenicity. In conclusion, TLR agonists may represent advanced adjuvants within the setting of adoptive T-cell immunotherapy of cancer and hold promise as a safe means of enhancing this approach within the clinic. PMID- 21327637 TI - Molecular analysis of melanoma-induced sentinel lymph node immune dysfunction. AB - INTRODUCTION: Sentinel lymph nodes (SLNs) of melanoma patients show evidence of tumor-induced immune dysfunction. Our previous works have shown that IL-10 and IFNgamma co-regulate indoleamine-2,3-dioxygenase (IDO)-expressing immunosuppressive dendritic cells (DCs) in melanoma SLNs. The goal of this study is to examine the relationship between melanoma SLN tumor burden and the degree of SLN immune dysfunction as a model to study tumor-induced immune dysfunction. We hypothesize that SLN tumor burden correlates with the degree of SLN immune dysfunction. METHODS: Patients undergoing SLN biopsy for clinical stages I and II melanomas were enrolled in the study under an IRB-approved protocol. During the SLN biopsy, non-hot and non-blue portion of the SLN was harvested, flash-frozen in liquid nitrogen, and mRNA was extracted. By using quantitative real-time PCR, gene expressions of cytokines (IL-4, IL-10, IFNgamma, TGFbeta, GM-CSF) and the surrogates of immunosuppressive regulatory and effector cells (IDO-expressing DCs and Foxp3-expressing T-regs, respectively) were measured and correlated against the SLN tumor burden (MART1) and against each other. The data were log transformed for normalization. Statistical test used Student's t-test and stepwise multivariate regression analysis. Statistical significance was determined at P < 0.05. RESULTS: SLNs of 74 patients were analyzed in this analysis. Ten of seventy-four patients (13.5%) had tumor-positive SLNs. MART1 gene expression showed a significant difference between the SLN (+) and SLN (-) groups (P = 0.04). Among the various cytokines, multivariate analysis showed that only IFNgamma gene expression correlated independently with MART1 gene expression (P < 0.0001, r = 0.91). Similar multivariate analyses show that IFNgamma (P < 0.0001, r = 0.78), IL-10 (P = 0.0037, r = 0.60), and TGFbeta (P < 0.0001, r = 0.95) gene expressions correlated independently with IDO gene expression. IFNgamma (P < 0.0001, r = 0.87) and GM-CSF (P = 0.042, r = 0.76) gene expressions correlated independently with Foxp3 gene expression. MART1 gene expression showed independent correlation with IDO (P = 0.0002, r = 0.75) and Foxp3 (P = 0.0002, r = 0.75) gene expressions. CONCLUSION: SLN tumor burden correlates with immunosuppressive IDO and Foxp3 expressions within the SLNs of melanoma patients. Our data are consistent with our theory that melanoma induces expressions of specific cytokines, which in turn, stimulate immune suppressors within the SLN. This study also supports our previous finding that IL-10 and IFNgamma co-regulate IDO within the SLN. In our data, IFNgamma is the sole cytokine that correlates with the SLN tumor burden and seems to play a central role in tumor-induced immunological changes in the SLN immune microenvironment. PMID- 21327638 TI - TH1 predominance is associated with improved survival in pediatric medulloblastoma patients. AB - Medulloblastoma, a primitive neuro-ectodermal tumor that arises in the posterior fossa, is the most common malignant brain tumor occurring in childhood. Even though 60-70% of children with medulloblastoma will be cured with intensive multimodal therapy, including surgery, radiotherapy, and chemotherapy, a significant proportion of surviving patients may suffer from long-term treatment related sequelae. Therapeutic success is limited especially in younger children by radiotherapy-induced neurocognitive longterm deficits. In order to avoid or delay craniospinal radiotherapy, high-dose chemotherapy followed by autologous stem cell transplantation (HSCT) has become an established treatment modality. Data on the host immunologic environment in medulloblastoma patients are rare, notably data on cytokine expression and immune reconstitution in patients with medulloblastoma undergoing HSCT are lacking. In this present study, we therefore decided to prospectively assess immune function following 24 consecutive autologous HSCT in 17 children with medulloblastoma treated according to the German-Austrian-Swiss HIT-2000-protocol. TH1 predominance was found to be the most important factor for probability of survival. Already before HSCT, survivors showed higher IFNgamma levels in sera as well as higher numbers of IFNgamma positive T-cells. After transplantation, this effect was even more pronounced. Patients with higher numbers of IFNgamma- and TNFalpha-positive T-cells had a more favorable outcome at all analyzed time points. In addition, patients in complete remission (CR) before transplantation, known to have a better prognosis a priori, showed higher expression of IFNgamma in T-cells. Taken together, this is the first report to demonstrate that high expression of IFNgamma and TNFalpha in T-cells of medulloblastoma patients in the early post-transplant period correlates with a better prognosis. Our data point toward a potentially important influence of TH1-cytokine expression before and after transplantation on the survival of pediatric medulloblastoma patients. PMID- 21327639 TI - On the impact of the distance between two genes on their interaction curve. AB - We analyze a basic building block of gene regulatory networks using a stochastic/geometric model in search of a mathematical backing for the discrete modeling frameworks. We consider a network consisting only of two interacting genes: a source gene and a target gene. The target gene is activated by the proteins encoded by the source gene. The interaction is therefore mediated by activator proteins that travel, like a signal, from the source to the target. We calculate the production curve of the target proteins in response to a constant rate production of activator proteins. The latter has a sigmoidal shape (like a simple delay line) that is sharper and taller when the two genes are closer to each other. This provides further support for the use of discrete models in the analysis gene regulatory networks. Moreover, it suggests an evolutionary pressure towards making the interacting genes closer to each other to make their interactions more efficient and more reliable. PMID- 21327640 TI - [Kidney transplant pathology]. AB - Biopsy of the transplanted kidney plays an important role in the care and treatment of patients after kidney transplantation. Today the renal biopsy is a standard procedure which is performed early after renal transplantation in the case of a primary non-functioning graft or a significant rise in serum creatinine. On the other hand, a kidney biopsy is performed if an acute or creeping rise in serum creatinine or acute onset of proteinuria or erythrocyturia is observed during follow-up. Furthermore, zero biopsies or intraoperative biopsies of the graft are important in order to obtain information about the initial quality of the graft. This is particularly important in view of the shortage of donor organs and the resulting necessity to accept increasingly marginal organs, such as for example in the ESP program. In addition, an increasing number of transplant centres perform protocol biopsies, i.e. biopsies that are not based on clinical indication, but are performed at a certain time point after transplantation to detect subclinical rejections as well as histological alterations pointing to chronic allograft damage. Additionally, there is much scientific interest in protocol biopsies. PMID- 21327641 TI - delta-Aminolevulinic acid dehydratase single nucleotide polymorphism 2 and peptide transporter 2*2 haplotype may differentially mediate lead exposure in male children. AB - Child low-level lead (Pb) exposure is an unresolved public health problem and an unaddressed child health disparity. Particularly in cases of low-level exposure, source removal can be impossible to accomplish, and the only practical strategy for reducing risk may be primary prevention. Genetic biomarkers of increased neurotoxic risk could help to identify small subgroups of children for early intervention. Previous studies have suggested that, by way of a distinct mechanism, delta-aminolevulinic acid dehydratase single nucleotide polymorphism 2 (ALAD(2)) and/or peptide transporter 2*2 haplotype (hPEPT2*2) increase Pb blood burden in children. Studies have not yet examined whether sex mediates the effects of genotype on blood Pb burden. Also, previous studies have not included blood iron (Fe) level in their analyses. Blood and cheek cell samples were obtained from 306 minority children, ages 5.1 to 12.9 years. (208)Pb and (56)Fe levels were determined with inductively coupled plasma-mass spectrometry. General linear model analyses were used to examine differences in Pb blood burden by genotype and sex while controlling for blood Fe level. The sample geometric mean Pb level was 2.75 MUg/dl. Pb blood burden was differentially higher in ALAD(2) heterozygous boys and hPEPT2*2 homozygous boys. These results suggest that the effect of ALAD(2) and hPEPT2*2 on Pb blood burden may be sexually dimorphic. ALAD(2) and hPEPT2*2 may be novel biomarkers of health and mental health risks in male children exposed to low levels of Pb. PMID- 21327672 TI - MRI-guided percutaneous retrograde drilling of osteochondritis dissecans of the knee. AB - OBJECTIVE: The purpose of this study was to evaluate the feasibility of a new method for osteochondritis dissecans (OCD) treatment. MATERIALS AND METHODS: Ten OCD lesions of the knee unresponsive to conservative management were treated with MRI-guided percutaneous retrograde drilling to reduce symptoms and promote ossification of the lesion. All lesions were located in distal femoral condyles. Only stable OCD lesions were included (preprocedural MRI grade I or II). Five lesions were of juvenile type and five lesions were of adult type OCD. All the patients had severe limitation of activity due to the OCD-related pain. By using a 0.23 T open MRI scanner and spinal anesthesia, percutaneous retrograde drilling of the OCD lesions was performed (3 mm cylindrical drill, one to three channels). Optical tracking and MRI imaging were used to guide instruments during the procedure. Mean postprocedural clinical follow-up time was 3 years. Eight patients had a post-procedural follow-up MRI within 1 year. RESULTS: All the OCD lesions were located and drilled using the 0.23 T open MRI scanner without procedural complications. All the patients had pain relief, mean visual analog score (VAS) declined from 6 to 2. Follow-up MRI showed ossification in all lesions. Eight patients could return to normal physical activity with no or minor effect on function (Hughston score 3-4). Treatment failed in two cases where the continuation of symptoms led to arthroscopy and transchondral fixation. CONCLUSION: [corrected] MR-guided retrograde OCD lesion drilling is an accurate, feasible, and effective cartilage-sparing techique in OCD management. PMID- 21327673 TI - Efficacy of propiverine ER with or without alpha-blockers related to maximum urinary flow rate in adult men with OAB: results of a 12-week, multicenter, non interventional study. AB - PURPOSE: Comparison of efficacy of propiverine extended release (ER) 30 mg o.d. in the treatment of male OAB administered as monotherapy (MT) or add-on to alpha blockers (combination treatment, CT) in relation to maximum urinary flow (Q(max)) in a non-interventional study. METHODS: Men >=40 years with OAB symptoms, Q(max) >=10 ml/s, prostate volume <40 ml, post-void residuals (PVR) <100 ml, and IPSS <20 were included. OAB symptoms, IPSS, and PVR were recorded before and after 12 weeks of treatment. Participants were stratified by Q(max) (group A >=15 ml/s, group B <15 ml/s) and CT vs. MT. Safety parameters were monitored. RESULTS: A total of 2,219 men participated and were involved in safety analysis; 1,849 men (mean age 66 years) fulfilled the inclusion criteria and were involved in efficacy analysis. In group A, 291 men received MT and 479 CT; in group B, 184 men received MT and 895 CT. OAB symptoms improved significantly in all groups throughout the study without differences between MT and CT. IPSS improvement in group B was less with MT than with CT (-3.9 vs. -5.2; P < 0.001), whereas IPSS improvement was similar in group A (-4.6 vs. -5.1). Mean PVR change was not clinically relevant, but two men (0.1%) experienced urinary retention. CONCLUSIONS: Under real-life conditions, treatment of OAB symptoms with propiverine ER is equally effective in men with MT or CT regardless of baseline Q(max). In men with reduced Q(max), IPSS improvement is significantly smaller with MT. The incidence of urinary retention during propiverine ER treatment is low. PMID- 21327674 TI - Idiopathic retroperitoneal fibrosis with particular perirenal and intrarenal extension associated with left renal artery stenosis. The atheromatous periaortitis with retroperitoneal fibrosis suggests a pathogenic relationship between atherosclerosis and fibrosis? AB - We present a case of idiopathic retroperitoneal fibrosis (RPF) in a female patient of 45 years, obese (BMI = 39 kg/sqm), hypertensive since 2005, with diabetes mellitus treated with diet and diabetes insipidus in whom, during a routine control, the following has been found: serum creatinine 1.74 mg/dl, and an inflammatory syndrome associated with fever. Spiral-CT (Multi-slice-Sensation 64) scan shows retroperitoneal fibrosis in relation with periaortitis that affects the thoracic and abdominal aorta. RPF is extending perirenally and at the level of the renal hilum with subsequent calyceal dilations (hydrocalycosis) associated with left renal artery stenosis. The particularity of the case is represented by the perirenal and intrarenal evolution of fibrosis with left renal artery stenosis with moderate impairment of renal function reversible under treatment with Tamoxifen. This case, with chronic periaortitis subsequent to an extended aortic atherosclerosis with retroperitoneal fibrosis can be representative for the pathogenic relationship between atherosclerosis and fibrosis. PMID- 21327675 TI - The results of computed tomography guided tru-cut transthoracic biopsy: complications and related risk factors. AB - INTRODUCTION: Transthoracic biopsy (TTB) is a well-defined and effective method used for pathologic sampling in the diagnosis of the pulmonary lesions. It is less invasive in comparison to surgical procedures. In addition, diagnostic rate of tru-cut biopsy is higher than that of fine needle aspiration biopsy (FNAB) especially for benign lesions. In this study, we presented tru-cut transthoracic biopsy (TTB) procedure results and the frequency of TTB complications with related risk factors. MATERIAL AND METHODS: A total of 102 patients were evaluated by CT scan guided tru-cut TTB in the diagnosis of lung lesions between January 2003 and December 2007. The complications due to tru-cut TTB were recorded. The factors such as the lesion depth, the lesion size, and the emphysematous changes that accompany the lesion were evaluated through chi(2) test. RESULTS: Among the samples, 51% malignancy and 49% benign pathology were observed. Pneumothorax developed in 15.7% of the 102 procedures. It was found that the lesion's distance from the pleura, the size of the lesion, and emphysematous changes around the lesion significantly increased the risk of pneumothorax. DISCUSSION: The tru-cut biopsy complications are similar to those of FNAB. In the centers where cytologic examination is insufficient in the diagnosis of lung lesions, tru-cut biopsy should be routinely performed as it is a reliable biopsy technique compared to FNAB. PMID- 21327676 TI - Auricular electroacupuncture reduces frequency and severity of Raynaud attacks. AB - BACKGROUND: Acupuncture has been shown to influence skin perfusion and the subjective cold perception threshold. Therefore, we hypothesized that auricular electroacupuncture (EA) might reduce symptoms in primary Raynaud's phenomenon (PRP). METHODS: Twenty-six patients with PRP received 6 cycles of auricular EA. After 3, 6 and 24 weeks attack frequency and severity were reevaluated using standardized questionnaires and a visual analogue scale (VAS). Skin temperature was assessed by infrared thermography and laser Doppler perfusion imaging was used to determine skin perfusion. RESULTS: Compared to baseline we found a significant reduction of attack frequency after 3 (p = 0.001) and 6 weeks (p < 0.001) of auricular EA. This improvement sustained following cessation of EA, after 24 weeks (p < 0.001). Furthermore, attack associated pain was reduced after 3 (p = 0.003), 6 (p = 0.003) and 24 weeks (p = 0.001) of treatment, while skin temperature and skin perfusion did not change significantly throughout the study period. CONCLUSIONS: Auricular EA reduces symptoms by means of frequency and severity of attacks in PRP but has no influence on skin perfusion and skin temperature. PMID- 21327677 TI - Mitomycin C therapy for corneal intraepithelial neoplasia masquerading as limbal stem cell deficiency with recurrent epithelial defect. AB - Diagnosis of corneal intraepithelial neoplasia was missed in a patient who presented with recurrent large epithelial defects with pannus. The patient was eventually diagnosed and successfully treated with topical mitomycin C. Mitomycin C may be preferable to surgery in lesions with extensive corneal involvement. Impression cytology should be used for early diagnosis in suspicious lesions. PMID- 21327678 TI - A rare case of peripartum endogenous bacterial endophthalmitis. AB - We describe the case of a healthy, pregnant female who developed endogenous endophthalmitis at the time of delivery, and discuss the possible mechanism of infection and the management of this case. A 26-year-old Asian woman presented with a 3-week history of visual deterioration and pain in the right eye. There was no history of ocular trauma or surgery. The ocular symptoms developed one day after vaginal delivery of a healthy baby. The pregnancy had been uncomplicated until premature rupture of membranes one week prior to delivery. Right visual acuity was light perception. There was marked right anterior chamber activity with a hypopyon and fibrin. A B-scan ultrasound showed dense vitritis. Examination of the left eye was normal. Blood tests and a chest X-ray were normal. A vitreous tap was performed and bacterial culture grew Sphingomonas paucimobilis. Intravitreal antibiotics were injected (amikacin 0.4 mg/0.1 ml and vancomycin 2.0 mg/0.1 ml) and the patient was treated with oral moxifloxacin and corticosteroids. Right visual acuity improved to 6/9. This case highlights the need for clinicians to have a high level of awareness of endogenous bacterial endophthalmitis (a rare, potentially sight-threatening condition) in any patient with a painful eye or visual deterioration in the peripartum period, particularly if associated with complications such as premature rupture of membranes or perineal laceration. PMID- 21327679 TI - The contribution of SK3 polymorphisms to acute oxaliplatin-induced neurotoxicity: direct or indirect effects? PMID- 21327681 TI - In vivo comparative study of the cytotoxicity of a liposomal formulation of cisplatin (lipoplatinTM). AB - PURPOSE: Cisplatin is one of the most effective cytotoxic agents in the treatment of solid malignancies, but its use is limited by several side effects. Among them, peripheral neurotoxicity can be dose limiting. A liposomal formulation of cisplatin, LipoplatinTM, was developed to reduce the systemic toxicity of cisplatin but without preventing its efficacy. The aim of this study was to use an animal model to establish, through a multimodal approach, whether chronic treatment with two different schedules of LipoplatinTM, selected within the range of its anticancer effective dose, is less neurotoxic than cisplatin administration. METHODS: Female Wistar rats were treated intraperitoneally with cisplatin at a dose of 4 mg/kg or with LipoplatinTM at doses delivering 12 or 24 mg/kg of cisplatin once weekly for 4 weeks. General toxicity was assessed by daily observation, body weight change, hematological and blood chemistry analysis, and histopathology of liver and kidney. The onset of peripheral neurotoxicity was assessed by measuring tail nerve conduction velocity (NCV), morphological and morphometric analysis of dorsal root ganglia (DRG), and morphological analysis of the sciatic nerve. RESULTS: Cisplatin induced a statistically significant reduction in body weight, the development of renal failure, and impairment in NCV with pathological alterations in the DRG and sciatic nerve. By contrast, LipoplatinTM was markedly less nephrotoxic, and no significant weight gain reduction was observed in animals treated with both doses of the drug. Moreover, the lowest dose induced less severe damage to the peripheral nervous system with a moderate decrease in NCV and mild pathological alterations in DRG and the sciatic nerve. CONCLUSIONS: The results suggest that LipoplatinTM 12 mg/kg is less neurotoxic than cisplatin 4 mg/kg, thus opening up the possibility of using this new formulation in future studies where its anticancer activity and the peripheral neurotoxicity will be assessed in parallel. PMID- 21327683 TI - Bi-weekly docetaxel and gemcitabine regimen in her-2-negative and anthracycline pretreated metastatic breast cancer patients: a multicenter phase II trial. AB - PURPOSE: Bi-weekly gemcitabine (G) in combination with docetaxel (D) is an effective treatment for metastatic breast cancer (MBC) previously treated with adjuvant/neoadjuvant anthracyclines containing regimens with a good toxicity profile. In the present phase II study, we investigated the activity of the same regimen as first-line treatment. METHODS: Women with breast cancer pretreated in adjuvant/neoadjuvant setting with anthracyclines received bi-weekly G (1,250 mg/m2 days 1, 15) and D (50 mg/m2 days 1, 15) every 28 days with restaging after 3 and 6 cycles. RESULTS: Overall 42 patients were enrolled. Median age is 48 years (range, 31-71 years). Eight patients (19%) achieved complete responses, 18 (43%) partial responses for an overall response rate (ORR) of 62%; five patients (12%) obtained stable disease (SD), and 8 (19%) patients had progressive disease (PD). After a median 17-month follow-up, the median time to disease progression was 12 months (95% CI, 3-26 months) and the median survival time was 27 months (95% CI, 4-57 months). No grade 4 toxicity was seen except in one patient who developed a grade 4 neutropenia. Grade 3 toxicities were leukopenia (2%), neutropenia (14%), anemia (2%), nausea and vomiting (2%), diarrhea (2%), asthenia (2%), and skin toxicity (12%). CONCLUSION: The GD bi-weekly regimen is well tolerated and active as first line in anthracyclines-pretreated women with MBC. It appears as an interesting alternative compared to a 3-week schedule whenever hematological toxicity is the main clinical concern. PMID- 21327682 TI - Targeting granzyme B to tumor cells using a yoked human chorionic gonadotropin. AB - PURPOSE: Luteinizing hormone receptor (LHR) is found in abundance on human ovarian, breast, endometrial and prostate carcinomas but at only low levels on non-gonadal tissues. To selectively kill LHR-expressing tumors, granzyme B (GrB) was linked to a protein in which both chains of human chorionic gonadotropin were yoked together (YCG). METHODS: GrB-YCG was expressed and secreted from insect Sf9 cells. Its GrB enzymatic activity and binding affinity for hLHR were then characterized. The differential cytotoxicity of GrB-YCG versus GrB alone was tested in a panel of LHR-expressing tumor cells by SRB assay, and the mechanisms involved in the cell death were investigated by confocal fluorescence microscopy, flow cytometry, and western blot analysis. RESULTS: GrB-YCG was successfully expressed and secreted from Sf9 insect cells and purified from cell culture supernatants. The serine protease activity of GrB-YCG was equivalent to that of human recombinant GrB. An in vitro hormone binding assay revealed that the GrB YCG molecule also retained the ability to bind to the LHR receptor with an affinity similar to that of native hCG. Upon cell binding, GrB-YCG was rapidly internalized into LHR-expressing human ovarian cancer cells and produced selective and potent tumor cell killing by inducing apoptosis through activation of caspase-3. CONCLUSIONS: These results validate LHR as a therapeutic target and indicate that delivery of the human pro-apoptotic enzyme GrB to tumor cells by yoked hCG has substantial selectivity and therapeutic potential for human tumors that express high levels of LHR such as ovarian carcinomas. PMID- 21327684 TI - Salvage chemotherapy of biweekly irinotecan plus S-1 (biweekly IRIS) in previously treated patients with advanced gastric cancer. AB - PURPOSE: This phase II trial first describes the combination chemotherapy of biweekly irinotecan plus S-1 (biweekly IRIS) for pretreated advanced gastric cancer (AGC) patients. METHODS: Patients who had previously been treated with greater than or equal to one regimen were enrolled. They received S-1 35 mg/m(2) twice daily on days 1-14 and irinotecan 150 mg/m(2) on days 1 and 15, every 4 weeks. The primary endpoint was overall survival (OS). RESULTS: Among the 38 patients enrolled, 18 patients were treated as second line, and the remaining 20 patients were enrolled as third- or fourth line. A total of 208 cycles were administered with the median being four cycles (range 1-16). The median OS was 8.7 months [95% confidence interval (CI) 7.5-10.3], and the median progression free survival was 6.3 months (95% CI 5.3-7.3). Low serum albumin (<3.5 mg/dL) was an independent adverse prognosticator for survival. Overall response rate was 17% (95% CI 4-30%). The major grade 3/4 toxicities were neutropenia (26%) and diarrhea (18%). CONCLUSIONS: Biweekly IRIS showed the moderate activity as salvage treatment in AGC. Considering high neutropenia and gastrointestinal toxicity, patient selection should be warranted; serum albumin may be a predictive factor for treatment decision. PMID- 21327685 TI - Long-term functioning following whiplash injury: the role of social support and personality traits. AB - Transition from acute whiplash injury to either recovery or chronicity and the development of chronic whiplash-associated disorders (WAD) remains a challenging issue for researchers and clinicians. The roles of social support and personality traits in long-term functioning following whiplash have not been studied concomitantly. The present study aimed to examine whether social support and personality traits are related to long-term functioning following whiplash. One hundred forty-three subjects, who had experienced a whiplash injury in a traffic accident 10-26 months before the study took place, participated. The initial diagnoses were a 'sprain of the neck' (ICD-9 code 847.0); only the outcome of grades I-III acute WAD was studied. Long-term functioning was considered within the biopsychosocial model: it was expressed in terms of disability, functional status, quality of life and psychological well-being. Participants filled out a set of questionnaires to measure the long-term functioning parameters (i.e. the Neck Disability Index, Medical Outcome Study Short-Form General Health Survey, Anamnestic Comparative Self-Assessment measure of overall well-being and the Symptom Checklist-90) and potential determinants of long-term functioning (the Dutch Personality Questionnaire and the Social Support List). The results suggest that social support (especially the discrepancies dimension of social support) and personality traits (i.e. inadequacy, self-satisfaction and resentment) are related to long-term functioning following whiplash injury (Spearman rho varied between 0.32 and 0.57; p < 0.01). Within the discrepancy dimension, everyday emotional support, emotional support during problems, appreciative support and informative support were identified as important correlates of long-term functioning. Future prospective studies are required to confirm the role of social support and personality traits in relation to long-term functioning following whiplash. For such studies, a broad view of long-term functioning within the biopsychological model should be applied. PMID- 21327686 TI - Assessing joint involvement in haemophilia by clinical rheumatologic scores. A pilot study on similarities with subjects with psoriatic arthritis. AB - Because of joint haemorrhages, severe haemophilia subjects often have limitations in their daily activities. Current orthopaedic scores (OJS) in haemophilia miss mild joint impairments and only pick up severe alterations. Twelve young severe haemophiliacs (20.25 +/- 1.9 years of age), were evaluated for OJS as well as for indices employed in rheumatoid arthritis [28-joint Disease Activity Score (DAS 28), Ritchie index, Health Assessment Questionnaire (HAQ), visual analogue scale (VAS)], spondyloarthritis [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), HAQ, VAS] and osteoarthritis [Knee injury and Osteoarthritis Outcome Score (KOOS), VAS]. Twenty-four matched apparently healthy subjects and 29 subjects with psoriatic arthritis (PsA) with oligoarticular involvement (one to three swollen joints) served as controls. In addition to the impairment of target joints (elbow, in five of five in those on-demand treatment; three, elbows; four, knee in those on secondary prophylaxis), HAQ (mean 0.71 +/- 0.95) and VAS (3.12 +/- 2.36) documented a quality of life and a perception of pain in haemophiliacs similar to that of PsA subjects (p = 0.061 and p = 0.063, respectively). Their Ritchie index did not differ from that of subjects with psoriatic arthritis (5.75 +/- 8.1 vs 7.73 +/- 9.22; p = 0.408), nor did the BASDAI score with respect to psoriatic arthritis patients (p = 0.105). Six of 12 haemophiliacs (50%) had KOOS values from 70 to 50 (significant function joint impairment); 3 of 12 (25%) showed DAS-28 values >3.2 (moderate disease activity), 2 of 12 (16.6%) severe disease activity (>5.1). All these indices significantly correlated with VAS and HAQ in haemophilia subjects. A rheumatologic assessment may help identify early polyarticular disease and subclinical abnormalities involving joints not usually studied (not target joint) in haemophiliacs. These pilot data provide the rationale for testing a systemic involvement in haemophiliacs by means of high tech imaging and to start early-onset prophylaxis/treatment in this setting. PMID- 21327687 TI - Increasing levels of serum antioxidant status, total antioxidant power, in systemic sclerosis. AB - Oxidative stress is one of the important factors that contribute to tissue damage in systemic sclerosis (SSc). Since the physiological response to oxidative stress is regulated by multiple antioxidant systems, it is important to measure quantitatively the total antioxidant capacity in the biological specimens. To determine the clinical significance of total antioxidant power (TAP) in SSc, we investigated the prevalence and clinical correlation of serum TAP levels in SSc patients. Serum TAP levels were examined in 49 patients with SSc by colorimetric microplate assay. The assay measures the total abilities for reducing Cu++ into Cu+. Clinical evaluation including medical history, physical examination, and laboratory tests were conducted for all SSc patients. Serum TAP levels were significantly elevated in SSc patients compared to normal controls (p < 0.01). When values higher than the mean + 2SD of the control serum samples were considered to be elevated, TAP levels were elevated in 24% of total SSc patients, with 26% of diffuse cutaneous SSc patients and 23% of limited cutaneous SSc patients. Serum TAP levels were correlated positively with C-reacting protein (r = 0.35, p <= 0.05). However, no other significant correlation was observed between serum TAP levels and clinical features in SSc patients. These results suggested that oxidative stress is enhanced in SSc patients, and serum TAP levels increase as an indicator of the global response to oxidative stress. PMID- 21327688 TI - Infectious mononucleosis with atypical manifestations accompanied by transient IgM antibody response for cytomegalovirus. AB - Infectious mononucleosis (IM) is a clinical syndrome caused by primary infection with Epstein-Barr virus (EBV) that is common in adolescents. In adults, particularly in elderly people, the clinical picture of IM tends to be atypical, often leading to a diagnostic challenge. Diagnosis is also complicated because infection with EBV can induce the synthesis of cross-reacting immunoglobulin M antibodies for other herpesviruses. We report an unusual case of infectious mononucleosis in a 34-year-old immunocompetent adult. Epidemiological studies indicate that the average age of primary EBV infection in developed countries is increasing. IM with atypical presentation will be a diagnostic challenge in the future as the number of EBV-naive adults increases. PMID- 21327689 TI - Acute febrile hepato-renal dysfunction in the tropics: co-infection of malaria and leptospirosis. AB - Malaria and leptospirosis are both common in the tropics. Simultaneous infections are possible, although not frequently reported. We report two cases of malaria from India with compelling serologic evidence of coexistent acute leptospirosis. One was a case of infection with Plasmodium falciparum with acute and convalescent microscopic agglutination test titers for Leptospira serovar icterohaemorrhagiae of 1:200 and 1:1600, respectively. The other was a case of infection with Plasmodium vivax that seroconverted to a titer of 1:3200 for Leptospira serovar batavia. Both patients finally improved with cephalosporins and doxycycline after no significant clinical/biochemical improvement with antimalarials standalone. It is proposed that febrile patients with hepato-renal dysfunction should be considered possible co-infection of malaria and leptospirosis. PMID- 21327690 TI - A case of isoniazid-resistant miliary tuberculosis in which tuberculous meningitis paradoxically developed despite systemic improvement. AB - A 63-year-old man with chronic myelomonocytic leukemia was admitted to our hospital with miliary tuberculosis. He received anti-tuberculosis drugs: isoniazid (INH), rifampicin (RFP), ethambutol (EB), and pyrazinamide (PZA). His condition clearly and immediately improved after the therapy, but he experienced a high fever of about 38 degrees C every day from 1 month after the initiation of the therapy. Drug-induced fever and tumor fever were suspected as causes, but the etiology could not be determined. The tuberculosis was identified as an INH resistant strain, so INH was stopped and levofloxacin (LVFX) was introduced, with streptomycin (SM), in addition to RFP, EB, and PZA. At 2 months after the initiation of the therapy (about one week after the change in the anti tuberculosis drug regimen), his spinal fluid was examined, given his complaints of headache and vomiting. The spinal fluid analysis revealed invasion of lymphocytic inflammatory cells and high adenosine deaminase activity; the patient was thus diagnosed with tuberculous meningitis. His condition gradually improved after the changing of the anti-tuberculosis drugs. Thus, to summarize, the tuberculous meningitis had worsened paradoxically despite his systemic improvement, although it was successfully treated by the addition of LVFX and SM. We must keep in mind that a potential cause of fever during anti-tuberculosis therapy may be INH-resistant tuberculous meningitis. PMID- 21327691 TI - The usefulness of changing focus during examination using Gram staining as initial diagnostic clue for infective tuberculosis. AB - Gram staining is a useful technique for detecting bacteria but is highly questionable in detecting Mycobacterium tuberculosis. Its detection generally requires special staining, such as Ziehl-Neelsen staining. We experienced three cases in which tuberculosis was first suggested by Gram staining of sputum or pus, confirmed by Ziehl-Neelsen staining, and diagnosed by polymerase chain reaction or culture. To find colorless tubercle bacilli in clinical samples with various organisms, varying the focus to slightly longer and shorter during study of the slides is indispensable. We present criteria for detecting infective pulmonary tuberculosis in Gram staining. First, in the ordinary focus, weakly stained, thin, gram-positive bacilli are found; second, with a slightly longer focus distance, the thin, cord-like, conspicuous gram-positive bacilli can be observed; and third, with a shorter focus distance, the gram-positive bacilli have changed into the brightened, colorless, or ghost ones. Four laboratory technologists each evaluated 20 Gram-stained samples after being lectured on the criteria, with no prior information about the sample. They accurately evaluated the presence of the bacilli in Gram-stained preparations in more than 90% of samples containing 3+ bacilli on Ziehl-Neelsen staining. Gram staining is available as an easy and rapid initial clue to recognize highly infective tuberculosis. PMID- 21327692 TI - Combined effects between temporal heterogeneity of water supply, nutrient level, and population density on biomass of four broadly distributed herbaceous species. AB - Temporal heterogeneity of water supply affects grassland community productivity and it can interact with nutrient level and intraspecific competition. To understand community responses, the responses of individual species to water heterogeneity must be evaluated while considering the interactions of this heterogeneity with nutrient levels and population density. We compared responses of four herbaceous species grown in monocultures to various combinations of water heterogeneity, nutrient level, and population density: two grasses (Cynodon dactylon and Lolium perenne), a forb (Artemisia princeps), and a legume (Trifolium repens). Treatment effects on shoot and root biomass were analyzed. In all four species, shoot biomass was larger under homogeneous than under heterogeneous water supply. Shoot responses of L. perenne tended to be greater at high nutrient levels. Although root biomass was also larger under homogeneous water supply, effects of water heterogeneity on root biomass were not significant in the grasses. Trifolium repens showed marked root responses, particularly at high population density. Although greater shoot and root growth under homogeneous water supply appears to be a general trend among herbaceous species, our results suggested differences among species could be found in the degree of response to water heterogeneity and its interactions with nutrient level and intraspecific competition. PMID- 21327693 TI - More nitrogen partition in structural proteins and decreased photosynthetic nitrogen-use efficiency of Pinus massoniana under in situ polluted stress. AB - Masson pine (Pinus massoniana L.) trees in the Pearl River Delta have shown growth decline since late 1980s, particularly those around industrially polluted regions. As nitrogen is an important nutritional element composing functional proteins, structural proteins and photosynthetic machinery, investigation on nitrogen allocation is helpful to understand nutrient alteration and its regulation mechanism in response to pollution stress. Current year (C) and 1-year old needles (C + 1) of five mature trees were sampled in industrially polluted site and unpolluted natural reserve for bioassay. Needles of declining trees had significantly higher leaf nitrogen per unit area (N(L)) but lower photosynthetic capacity (P (max)), which resulted in lower photosynthetic nitrogen use efficiency (PNUE) than those of healthy trees. Nitrogen fraction to the photosynthetic apparatus in the C and C + 1 needles at polluted site was 27 and 22%, significantly lower than the corresponding healthy needles (48 and 32%). The content of structural proteins was positively correlated with N(L) in C and C + 1 needles. Moreover, the C and C + 1 needles of declining trees had about 1.8 times structural protein as those of healthy trees, suggesting that more nitrogen allocation to structural protein are needed for stronger structural defenses under polluted stress. Decreases in PNUE of declining pine trees could be partially explained by increases in structural protein nitrogen. PMID- 21327694 TI - Anatomical diversity of funicles in Leguminosae. AB - To clarify the diversity in funicular internal structures in Leguminosae, 59 legume species (classified into 46 genera, 20 tribes, and 3 subfamilies) were examined by a paraffin-sectioning method. The vascular bundles of legume funicles were clarified as collateral, amphicribral, or amphivasal. In species in which the funicular vascular bundle was collateral throughout the funicle, the xylem is positioned at the pericarpial side in the basal part of the funicle, and the xylem was always positioned at the micropylar side of the phloem in the apical end of the funicles. Whenever the seed direction (from hilum to the micropyle) faces the stylar side, the funicular vascular bundle appears to twist between the basal and the apical part of the funicle. This twist would involve a rotation of the seeds (ovules) during seed (ovule) development. This also may mean that the direction (from hilum to the micropyle) of legume seeds originally faces the pericarp. PMID- 21327695 TI - A novel zinc-finger-like gene from Tamarix hispida is involved in salt and osmotic tolerance. AB - In the present study, a zinc-finger-like cDNA (ThZFL) was cloned from the Tamarix hispida. Northern blot analysis showed that the expression of ThZFL can be induced by salt, osmotic stress and ABA treatment. Overexpression of the ThZFL confers salt and osmotic stress tolerance in both yeast Saccharomyces cerevisiae and tobacco. Furthermore, MDA levels in ThZFL transformed tobacco were significantly decreased compared with control plants under salt and osmotic stress, suggesting ThZFL may confer stress tolerance by decreasing membrane lipid peroxidation. Subcellular localization analysis showed the ThZFL protein is localized in the cell wall. Our results indicated the ThZFL gene is an excellent candidate for genetic engineering to improve salt and osmotic tolerance in agricultural plants. PMID- 21327696 TI - Levofloxacin-associated Achilles tendinitis in a patient with chronic kidney disease stage 5. PMID- 21327697 TI - A case report of retroaortic left renal vein with tumor thrombus of renal cell carcinoma. AB - A 75-year-old woman was referred to our department for evaluation of a left renal tumor. Computed tomography and other imaging studies demonstrated a left renal mass and tumor extension into the left renal vein passing caudally behind the aorta. We clinically diagnosed the tumor as renal cell carcinoma (RCC) associated with a retroaortic left renal vein thrombus, and performed a radical nephrectomy. Pathological examination of the surgical specimen showed a grade 2, clear cell carcinoma with a renal vein thrombus and negative surgical margin. Retroaortic left renal vein is a rare anomaly with a prevalence of 1.8-2.4%. RCC associated with a retroaortic left renal vein thrombus is rarer still. To our knowledge, this is only the third case report to describe an RCC associated with a tumor thrombus in the retroaortic left renal vein. PMID- 21327698 TI - Corticosteroid treatment of kidney disease in a patient with familial lecithin cholesterol acyltransferase deficiency. AB - Familial lecithin-cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare genetic disorder of lipid metabolism, characterised by low plasma HDL cholesterol, proteinuria, haemolytic anaemia and corneal opacities. Usually renal disease progresses during the third decade of life to renal failure; however the pathogenesis of renal disease is not well understood. In this study we describe treatment of renal disease in two siblings with FLD. The proband WX at the age of 31 years presented proteinuria and ankle oedema during her third pregnancy. Diagnosis of FLD was based on a renal biopsy with characteristic serpiginous fibrillar deposits under electron microscopy, markedly decreased HDL cholesterol, esterified cholesterol levels and LCAT activity, confirmed by molecular analysis. After 3 years her proteinuria increased and she received an ACE inhibitor to which she responded well. During further increases of proteinuria she additionally received methylprednisolone and her proteinuria decreased. This long term observation indicates the efficacy of corticosteroids and renin-angiotensin aldosterone system blockers in the treatment of proteinuria in patients with FLD. The results suggest the role of inflammatory processes as well as dyslipidemia in the pathogenesis of glomerular disorders in LCAT-deficient patients. PMID- 21327699 TI - Lead levels in long-tailed macaque (Macaca fascicularis) hair from Singapore. AB - Nonhuman primates are potentially good sentinels of environmental toxicants because they share a similar physiology and life history with humans. In this report we present the results of an analysis of lead concentrations in hair from long-tailed macaques in Singapore. We hypothesized that because Singapore is highly urbanized, its macaque population may be exposed to higher levels of lead. The results of our study indicated that Singapore's macaque population has not been exposed to high levels of environmental lead. Compared with previous studies of lead levels in human and nonhuman primate hair, the results of our analysis indicate a low level of exposure of monkeys to environmental lead (n = 27, arithmetic mean = 2.51 ppm, max = 6.45, min = 0.21 ppm). Hair lead concentrations varied both within social groups and by geographic location, with the highest concentrations observed in monkeys residing within an area containing a small arms firing range and a manufacturing facility. Although lead exposure in this area seems to be low, additional monitoring and possible remediation may be warranted. Our study is among the first to illustrate how primates can serve as potential sentinels of environmental toxicants such as lead. Future research examining the efficacy of primates as sentinels of lead exposure should include monitoring of environmental lead levels, and comparison of hair lead levels with levels measured in blood samples. PMID- 21327700 TI - Drastic population decline and conservation prospects of roadside dark-bellied bonnet macaques (Macaca radiata radiata) of southern India. AB - We carried out a survey on roadside dark-bellied bonnet macaques (Macaca radiata radiata) on the highways around the south Indian city of Mysore. The present survey was the fourth since 1989 on the same populations. We divided the habitats into intensive cultivation (IC), wet cultivation (WC), and scrub forests (SC). The number of groups has significantly reduced from 54 to 31 and the number of animals has declined from 1,207 to 697 from 1989 to 2009. This decline has been recorded only in the IC and WC areas, whereas the population in SC with places of Hindu worship has remained stable. Due to the loss of roadside Ficus trees over the years, the habitat of the monkeys has almost disappeared. Since bonnet macaque is not primarily a forest-dwelling species, the seemingly widespread primate may soon become 'threatened' if the non-forest populations continue to decline. Scrub forests in small hillocks housing Hindu temples remain the only prospective places for conservation of bonnet macaques. PMID- 21327701 TI - The quasi-linear viscoelastic properties of diabetic and non-diabetic plantar soft tissue. AB - The purpose of this study was to characterize the viscoelastic behavior of diabetic and non-diabetic plantar soft tissue at six ulcer-prone/load-bearing locations beneath the foot to determine any changes that may play a role in diabetic ulcer formation and subsequent amputation in this predisposed population. Four older diabetic and four control fresh frozen cadaveric feet were each dissected to isolate plantar tissue specimens from the hallux, first, third, and fifth metatarsals, lateral midfoot, and calcaneus. Stress relaxation experiments were used to quantify the viscoelastic tissue properties by fitting the data to the quasi-linear viscoelastic (QLV) theory using two methods, a traditional frequency-insensitive approach and an indirect frequency-sensitive approach, and by measuring several additional parameters from the raw data including the rate and amount of overall relaxation. The stress relaxation response of both diabetic and non-diabetic specimens was unexpectedly similar and accordingly few of the QLV parameters for either fit approach and none of raw data parameters differed. Likewise, no differences were found between plantar locations. The accuracy of both fit methods was comparable, however, neither approach predicted the ramp behavior. Further, fit coefficients varied considerably from one method to the other, making it hard to discern meaningful trends. Future testing using alternate loading modes and intact feet may provide more insight into the role that time-dependent properties play in diabetic foot ulceration. PMID- 21327702 TI - Expression and characterization of two new alkane-inducible cytochrome P450s from Trichoderma harzianum. AB - n-Dodecane and fatty acids were good inducers of cytochrome P450 (CYP) and the omega-hydroxylase of lauric acid, which is a marker for omega-hydroxylation of n alkanes, in Trichoderma harzianum. A cDNA, containing an ORF of 1520 bp, encoding a CYP52 of 520 amino acids, was isolated by RACE. Another n-alkane-inducible CYP was identified by LLC-MS/MS analysis of a microsomal protein band induced by n dodecane in a library of T. harzianum. This suggests that T. harzianum has a CYP dependent conversion of alkanes to fatty acids allowing their incorporation into lipids. PMID- 21327703 TI - Degradation of chloroform by immobilized cells of Bacillus sp. in calcium alginate beads. AB - A Bacillus sp., capable of degrading chloroform, was immobilized in calcium alginate. The beads in 20 g alginate l(-1) (about 2 * 10(8) cells/bead) could be re-used nine times for degradation of chloroform at 40 MUM. The immobilized cells had a higher range of tolerance (pH 6.5-9 and 20-41 degrees C) than free cells (pH 7-8.5 and 28-32 degrees C). At 5 g alginate l(-1), leakage of the cells from the beads was 0.51 mg dry wt ml(-1). This species is the first reported Bacillus that can degrade chloroform as the sole carbon source. PMID- 21327705 TI - Polyp recurrence after endoscopic mucosal resection of sessile and flat colonic adenomas. AB - BACKGROUND: Endoscopic mucosal resection (EMR) is used for treatment of sessile and flat colonic adenomas. There is limited data comparing polyp recurrence between piecemeal and en-bloc resections. AIM: The purpose of this study was to evaluate the incidence density and predictive factors for polyp recurrence after piecemeal and en-bloc resections. METHODS: Patients undergoing EMR of flat or sessile adenomas>=10 mm were included. Incidence density (ID) and incidence rate ratio (IRR) of polyp recurrence were calculated. Predictive factors for recurrence were assessed by multivariate analysis using logistic regression. RESULTS: A total of 105 patients (males 54, mean age 68) with 121 polyps were included. Sixty-seven polyps (mean size+/-SD, 23.3+/-9.2 mm) were resected piecemeal and 54 polyps (mean size 14.7+/-5.1 mm) were resected en-bloc. There were 12 recurrences in the piecemeal group and two in the en-bloc group. The ID of polyp recurrence in the piecemeal group was 13.1 (95% CI 7.43-23.03) and in the en-bloc group was 2.7 (95% CI 0.67-10.78) per 100 person-years of follow-up. Piecemeal resections were 5.5 (95% CI 1.1-30.48, P=0.045) times and flat polyps were 6.6 (95% CI 1.22-35.53, P=0.028) times more likely to result in recurrence compared to en-bloc resections and sessile polyps, respectively. In the piecemeal group, additional use of argon plasma coagulation (APC) did not affect the recurrence (OR 0.46, P=0.29). CONCLUSIONS: Piecemeal resections and flat polyps are associated with higher recurrence following EMR. Additional use of APC did not affect the recurrence rates after piecemeal resection. PMID- 21327706 TI - Mitochondrial dependent apoptosis: ameliorative effect of flunarizine on ischemia reperfusion of celiac artery-induced gastric lesions in the rat. AB - OBJECTIVES: Ischemia-reperfusion is a major event for induction of cellular apoptosis. Apoptosis is due to the activation of death receptor and/or mitochondrial pathways. Mitochondrial permeability transition pore opening is the cause of apoptosis. In our present study, we tried to evaluate the role of flunarizine in ischemia and reperfusion of celiac artery-induced gastric lesion in the rat. METHODS: The therapeutic potential of flunarizine was assessed by measuring the changes in gastric lesion index, biomarker (i.e., thiobarbituric acid reactive substance, reduced glutathione, superoxide dismutase, myeloperoxidase, and total calcium and protein content), and mitochondrial damage (i.e., adenosine triphosphate and deoxyribonucleic acid fragmentation content) in ischemia and reperfusion-induced gastric lesion model. RESULTS: Medium and higher doses of flunarizine produced a significant (P<0.05) ameliorative effect which was observed from the assessment of all the above-mentioned parameters (i.e., increase in reduced glutathione, superoxide dismutase and decrease in thiobarbituric acid reactive substance, myeloperoxidase, and total calcium content). Similar results were also obtained from omeprazole and cyclosporine. In the pre-treated group, deoxyribonucleic acid fragmentation pattern has also indicated that a mitochondria-associated anti-apoptotic effect of flunarizine was responsible to prevent the ischemia and reperfusion of celiac artery-induced gastric lesion. CONCLUSION: The gastroprotective effect of flunarizine may be produced due to its inactivation potential of mitochondrial permeability transition pore opening associated with anti-oxidative, calcium regulation along with its anti-apoptotic effect. PMID- 21327707 TI - Do we need multiple biopsies for assessing gastric cancer risk? PMID- 21327704 TI - Drug-induced autoimmune-like hepatitis. AB - The clinical phenotype of classical autoimmune hepatitis can be mimicked by idiosyncratic drug-induced liver injury, and differentiation can be difficult. The goals of this review are to enumerate the major agents of drug-induced autoimmune-like hepatitis, describe the clinical findings and risk factors associated with it, detail the clinical tools by which to assess causality, discuss putative pathogenic mechanisms, and describe treatment and outcome. The frequency of drug-induced autoimmune-like hepatitis among patients with classical features of autoimmune hepatitis is 9%. Minocycline and nitrofurantoin are implicated in 90% of cases. Female predominance, acute onset, and absence of cirrhosis at presentation are important clinical manifestations. Genetic factors affecting phase I and phase II transformations of the drug, polymorphisms that protect against cellular oxidative stress, and human leukocyte antigens that modulate the immune response may be important pathogenic components. Clinical judgment is the mainstay of diagnosis as structured diagnostic methods for drug induced liver injury are imperfect. The covalent binding of a reactive drug metabolite to a hepatocyte surface protein (commonly a phase I or phase II enzyme), formation of a neoantigen, activation of CD8 T lymphocytes with nonselective antigen receptors, and deficient immune regulatory mechanisms are the main bases for a transient loss of self-tolerance. Discontinuation of the offending drug is the essential treatment. Spontaneous improvement usually ensues within 1 month. Corticosteroid therapy is warranted for symptomatic severe disease, and it is almost invariably effective. Relapse after corticosteroid withdrawal probably does not occur, and its absence distinguishes drug-induced disease from classical autoimmune hepatitis. PMID- 21327708 TI - Serial pulse oximetry in hepatopulmonary syndrome. AB - BACKGROUND/AIM: The natural history of hepatopulmonary syndrome (HPS) is poorly characterized and how hypoxemia develops and progresses over time is unclear. We evaluated oxygenation over time in advanced liver disease patients with and without HPS using serial pulse oximetry. METHODS: Data from a prospective cohort of patients evaluated for liver transplantation were analyzed. All patients with significant cardiopulmonary disease were excluded and patients with and without HPS were compared. Arterial oxygen saturation measurements with pulse oximetry (SpO(2)) were recorded serially from initial evaluation until transplantation or last clinic visit on record. Patients with SpO(2) measurements at >= 2 visits were included. RESULTS: A total of 22 HPS patients were compared to 32 non-HPS patients (18 with intrapulmonary vasodilation on contrast echocardiography, CE) over a mean duration of 20 months and 4 SpO(2) measurements. HPS patients had lower SpO(2) at baseline (96.8 vs. 98.4%, P = 0.02) and at end of follow-up (95.8 vs. 98.2%, P = 0.02), and were more likely to have a >= 2% reduction (P = 0.04) and faster decline in SpO(2) as compared to non-HPS patients (F = 2.2, P = 0.04). HPS patients with lower SpO(2) and/or PO(2) at baseline appeared more likely to worsen over time. There was no difference in SpO(2) over time between the 2 non HPS subgroups (- or +CE). CONCLUSIONS: HPS patients have a significant decline in SpO(2) over time compared to non-HPS patients, and therefore, pulse oximetry may be useful for monitoring cirrhotics for development or worsening of HPS. Presence of intrapulmonary vasodilation in the absence of hypoxemia does not appear to affect SpO(2) over time. PMID- 21327709 TI - Sporadic primary malignant intracerebral nerve sheath tumors: case report and literature review. AB - We report the case of a seventy-five year old woman with a sporadic primary malignant intracerebral nerve sheath tumor (MINST). These tumors fall within the spectrum of malignant peripheral nerve sheath tumors (MPNST) but confirming the diagnosis of a MINST can be difficult due to its rarity and unusual intraparenchymal location. Radiographically, MINST's mimic malignant glioma and should be considered in the differential diagnosis of enhancing cerebral lesions. In this report, we present a comprehensive panel of histological, immunohistochemical, ultrastructural, and genetic considerations that may be used to diagnosis MINST based on their similarities to MPNSTs and brain parenchyma location. PMID- 21327710 TI - A radiotherapy technique to limit dose to neural progenitor cell niches without compromising tumor coverage. AB - Radiation therapy (RT) for brain tumors is associated with neurocognitive toxicity which may be a result of damage to neural progenitor cells (NPCs). We present a novel technique to limit the radiation dose to NPC without compromising tumor coverage. A study was performed in mice to examine the rationale and another was conducted in humans to determine its feasibility. C57BL/6 mice received localized radiation using a dedicated animal irradiation system with on board CT imaging with either: (1) Radiation which spared NPC containing regions; (2) Radiation which did not spare these niches; or (3) Sham irradiation. Mice were sacrificed 24 h later and the brains were processed for immunohistochemical Ki-67 staining. For the human component of the study, 33 patients with primary brain tumors were evaluated. Two intensity modulated radiotherapy (IMRT) plans were retrospectively compared: a standard clinical plan and a plan which spares NPC regions while maintaining the same dose coverage of the tumor. The change in radiation dose to the contralateral NPC-containing regions was recorded. In the mouse model, non-NPC-sparing radiation treatment resulted in a significant decrease in the number of Ki67(+) cells in dentate gyrus (DG) (P = 0.008) and subventricular zone (SVZ) (P = 0.005) compared to NPC-sparing radiation treatment. In NPC-sparing clinical plans, NPC regions received significantly lower radiation dose with no clinically relevant changes in tumor coverage. This novel radiation technique should significantly reduce radiation doses to NPC containing regions of the brain which may reduce neurocognitive deficits following RT for brain tumors. PMID- 21327711 TI - A multicenter phase I trial of combination therapy with interferon-beta and temozolomide for high-grade gliomas (INTEGRA study): the final report. AB - Our previous study demonstrated that interferon-beta markedly enhanced chemosensitivity to temozolomide; one of the major mechanisms is downregulation of O(6)-methylguanine DNA-methyltransferase transcription via p53 induction. This effect was also observed in an experimental animal model. The results of these studies suggest that compared to temozolomide-based chemotherapy performed concomitantly with radiotherapy, chemotherapy with interferon-beta and temozolomide and concomitant radiotherapy might further improve the clinical outcomes of patients with malignant gliomas. A multicenter phase I clinical trial the Integrated Japanese Multicenter Clinical Trial: a Phase I Study of Interferon beta and Temozolomide for Glioma in Combination with Radiotherapy (INTEGRA Study) was conducted in patients with high-grade gliomas in order to evaluate the safety, feasibility, and preliminary clinical effectiveness of combination therapy with interferon-beta and temozolomide. The primary endpoint was the incidence of adverse events. The exploratory endpoints were progression-free survival time and overall survival time. The study population comprised 16 patients with newly diagnosed and 7 patients with recurrent high-grade gliomas. Grades 3-4 leukocytopenia and neutropenia were observed in 6.7 and 13.3% of patients, respectively. Overall, 40% of patients showed an objective response to therapy. In patients with newly diagnosed glioblastoma, the median overall survival time was 17.1 months and the rate of 1-year progression-free survival was 50%. We conclude that this regimen is safe and well tolerated and may prolong survival of patients with glioblastoma. A phase II clinical study is essential to corroborate our findings. PMID- 21327712 TI - Mineral metabolism abnormalities and vitamin D receptor activation in cardiorenal syndromes. AB - Over the last decade, it has become increasingly clear that the cardiovascular and renal systems are interdependent. Primary disorders of either system have been shown to disturb the other system. As a result, a class of cardiorenal syndromes (CRS) has been identified wherein a vicious cycle is established as an acute/chronic dysfunction of either the kidney or the heart exacerbates the loss of function in the other organ. Progressive loss of kidney function observed in patients with CRS (mostly types 2 and 4) leads to reduced production of calcitriol (active vitamin D) and an imbalance in calcium and phosphorus levels, which are correlated with increased rates of cardiovascular events and mortality. In addition, hypocalcemia can lead to prolonged and excessive secretion of parathyroid hormone (PTH), eventually leading to development of secondary hyperparathyroidism. Therefore, based on this important mechanism of organ damage, one of the major goals of therapy for patients with CRS is to restore regulatory control of PTH. Although administration of calcitriol increases serum calcium levels and reduces PTH levels, it is also associated with elevated serum levels of calcium-phosphorus product. Therefore, compounds that selectively activate vitamin D receptors, potentially reducing calcium * phosphate toxicity, are likely to enhance cardiorenal protection and provide significant clinical benefit. PMID- 21327713 TI - Assessment on major factors that cause skin rejection at Modjo export tannery, Ethiopia. AB - A study was conducted from November 2009 to March 2010 with the objective of identifying the major causes of skin rejection on fresh, pickled, and wet blue skins at Modjo Mesaco Global tannery. A total of 401 fresh and 1,873 pickled and wet blue skins from the routine production system of the tannery were used. Overall, high prevalence of sheep ked (100%) followed by biting louse (64.4%), tick (50%), and sucking louse (45.8%) were observed on fresh sheep pelts, while, on fresh goat pelts, a high prevalence of sucking louse (54.5%), followed by tick (50%), and biting louse (35.5%) were observed. From the total of 90 rejected pickled and wet blue skins of sheep and goats, 98.8% were "ekek" and scratch, 85.6% sheep and goat pox, 74% poor substance, 73.3% heat, 72.2% scar, and 52.2% knife cut-in skins. Large number of skins rejections was recorded in large-sized skins (29.8%), and the lowest observed was in medium-sized skins (11.1%). There were highly statistically significant association (p < 0.05) between size and grades of shoat skins. Ekek and scratches together with sheep and goat pox were the common skin defects that hamper skin quality. However, there was no significant association (p > 0.05) between sheep and goat skins. Ekek and scratch caused high rejection of skin and entailed serious economic loss in terms of foreign exchange earning to Ethiopia. Therefore, the main causes of skin rejection and factors that cause downgrading of skin should be controlled. PMID- 21327714 TI - Seroprevalence of brucellosis and its associated risk factors in cattle from smallholder dairy farms in Zimbabwe. AB - A cross-sectional study was conducted to investigate seroprevalence of brucellosis and the associated risk factors in cattle from smallholder dairy farms in Gokwe, Marirangwe, Mushagashe, Nharira, Rusitu and Wedza areas of Zimbabwe. A total of 1,440 cattle from 203 herds were tested serially for Brucella antibodies using Rose Bengal test and the competitive ELISA. Weighted seroprevalence estimates were calculated and risk factors in individual cattle investigated using logistic regression analysis. The overall individual animal brucellosis seroprevalence was low, with mean of 5.6% (95% confidence interval (CI), 4.4%, 6.8%). Gokwe had the highest individual (12.6%; 95% CI, 3.9%, 21.4%) and herd-level (40.0%; 95% CI, 22.1%, 58.0%), while Wedza had the lowest individual (2.3%; 95% CI, 0%, 5.3%) and herd-level (8.0%; 95% CI, 0.0%, 18.9%) brucellosis seroprevalence, respectively. In individual cattle, the area of origin, age and history of abortion were independently associated with brucellosis seroprevalence. While the seroprevalence was independent of sex, it decreased with increasing age. Cattle 2-4 years old had higher odds (odds ratio (OR) = 3.2; 95% CI, 1.1%, 9.1%) of being seropositive compared to those >7 years. Cows with a history of abortion were more likely to be seropositive (OR = 7.9; 95% CI, 3.1, 20.1) than controls. In conclusion, the area-to-area variation of brucellosis may be linked to ecological factors and differences in management practices. The implementation of stamping out policy, bleeding and testing animals before movement and promoting the use self-contained units are likely to significantly reduce the public health risks associated with Brucella infections in cattle. PMID- 21327715 TI - Estimation of genetic and phenotypic relationships between age at first calving and productive performance in Iranian Holsteins. AB - Calving records from the Animal Breeding Center of Iran collected from January 1990 to December 2007 and comprising 207,106 first calving events of Holsteins from 2,506 herds were analysed using univariate and bivariate linear sire models to estimate heritabilities and genetic correlations between age at first calving (AFC) and productive performance. Average AFC was 26.48 months in this study. The peak in the frequency distribution of AFC clearly exists coinciding with cows calving for the first time at approximately 25 months of age. Heritability estimate for AFC was 0.34 which was greater than the corresponding values for productive traits. The heritability estimates were low to medium for productive traits which ranged from 0.17 to 0.26 for cows in their first calvings. Except for fat and protein percentages of milk, phenotypic and genetic correlations between AFC and productive performance traits were low to moderately negative. Range of genetic correlations between productive traits was -0.53 to 0.99. Reduction of age at first calving appeared to have a negative effect on first lactation protein and fat percentages; however, it had positive effects on milk yield, fat yield, protein yield and their mature equivalents. It seems that reducing age at first calving to 24-25 months is probably more profitable than reducing age at first calving to an earlier time in Iranian conditions. PMID- 21327716 TI - Effect of silage from ryegrass intercropped with winter or common vetch for grazing dairy cows in small-scale dairy systems in Mexico. AB - The objective was to determine the effect of including silages of annual ryegrass (Lolium multiflorum) intercropped with winter vetch (Vicia villosa) (ARG-VV) or with common vetch (Vicia sativa) (ARG-VS) compared with maize silage (MS) on milk yield and milk composition of dairy cows grazing cultivated perennial ryegrass white clover pastures with supplemented concentrate during the dry season. Six Holstein dairy cows with a mean yield of 19.0 kg/cow/day at the beginning of the experiment were randomly assigned to a 3 * 3 repeated Latin square. Treatments were: 8 h/day intensive grazing, 3.6 kg of dry matter (DM) per cow per day of concentrate plus MS, and ARG-VV or ARG-VS ad libitum at a stocking rate of 3.0 cows/ha for three experimental periods of 3 weeks each. Milk yield (MY) and milk composition, live weight and body condition score as well as silage and concentrate intakes were recorded during the third week of each experimental period, and pasture intake was estimated indirectly from utilised metabolisable energy. Economic analysis was obtained by preparing partial budgets. There were no statistical differences (P > 0.10) in MY, milk fat or protein content nor for live weight, but there was significant difference (P < 0.10) in body condition score. There were non-statistical differences in silage DM intake (P < 0.11); however, significant differences (P < 0.10) were obtained for estimated grazed herbage intake whilst no differences for total DM intake. Slightly higher economic returns (10%) were obtained with ARG-VS over MS, and this was 7% higher than ARG-VV. It is concluded that ARG-VS could be an option for complementing grazing for small-scale dairy production systems in the dry season as it is comparable to MS in animal performance and slightly better in economic terms. PMID- 21327718 TI - Expression of oxidative phosphorylation components in mitochondria of long-living Ames dwarf mice. AB - Reduced signaling of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) pathway is associated with extended life span in several species. Ames dwarf mice are GH-deficient and live >50% longer than wild-type littermates. Previously, we have shown that tissues from Ames mice exhibit elevated levels of antioxidative enzymes, less H(2)O(2) production, and lower oxidative damage suggesting that mitochondrial function may differ between genotypes. To explore the relationship between hormone deficiency and mitochondria in mice with extended longevity, we evaluated activity, protein, and gene expression of oxidative phosphorylation components in dwarf and wild-type mice at varying ages. Liver complex I + III activity was higher in dwarf mice compared to wild-type mice. The activity of I + III decreased between 3 and 20 months of age in both genotypes with greater declines in wild-type mice in liver and skeletal muscle. Complex IV activities in the kidney were elevated in 3- and 20-month-old dwarf mice relative to wild-type mice. In Ames mice, protein levels of the 39 kDa complex I subunit were elevated at 20 months of age when compared to wild-type mouse mitochondria for every tissue examined. Kidney and liver mitochondria from 20-month-old dwarf mice had elevated levels of both mitochondrially-encoded and nuclear-encoded complex IV proteins compared to wild-type mice (p < 0.05). Higher liver ANT1 and PGC-1alpha mRNA levels were also observed in dwarf mice. Overall, we found that several components of the oxidative phosphorylation (OXPHOS) system were elevated in Ames mice. Mitochondrial to nuclear DNA ratios were not different between genotypes despite the marked increase in PGC-1alpha levels in dwarf mice. The increased OXPHOS activities, along with lower ROS production in dwarf mice, predict enhanced mitochondrial function and efficiency, two factors likely contributing to long-life in Ames mice. PMID- 21327719 TI - The mitochondria mediate the induction of NOX1 gene expression by aldosterone in an ATF-1-dependent manner. AB - High aldosterone (Ald) levels can induce hypertrophy of vascular smooth muscle cells (VSMCs), which carries high risks of heart failure. A previous study showed that Ald induces hypertrophy of VSMCs by up-regulating NOX1, a catalytic subunit of NADPH oxidase that produces superoxides. However, the precise mechanism remains unknown. Diphenylene iodonium (DPI) is known as an inhibitor of complex I in the mitochondrial respiratory chain, and it was also found to almost completely suppress the induction of NOX1 mRNA and the phosphorylation of activating transcription factor (ATF-1) by PGF2alpha or PDGF in a rat VSMC cell line. In this study, we found that the Ald-induced phosphorylation of ATF-1 and NOX1 expression was significantly suppressed by DPI. Silencing of ATF-1 gene expression attenuated the induction of NOX1 mRNA expression, and over-expression of ATF-1 restored Ald-induced NOX1 expression. On the basis of this data, we show that the mitochondria mediate aldosterone-induced NOX1 gene expression in an ATF 1-dependent manner. PMID- 21327720 TI - Proteomic analysis of differentially expressed proteins between stenotic and normal colon segment tissues derived from patients with Hirschsprung's disease. AB - Hirschsprung's disease (HSCR) is the most common identifiable developmental disorder of the enteric nervous system. The present study was designed to analyze the differential proteomic patterns in stenotic colon segment tissues from patients with HSCR. We analyzed 20 paired stenotic and normal colon segment tissues from patients with HSCR, and identified 13 proteins from stenotic segment tissues peptide fingerprint mapping and SELDI MS that were separated using 2-DE. The protein levels of four selected proteins (alpha-actinin-4, ACTN4; myosin regulatory light chain interacting protein, MYLIP; fatty acid binding protein 7, FABP7; bone morphogenetic protein receptor type 1A, BMPR1A) were further validated by Western blot analysis. This study, investigating for the first time proteomic changes in stenotic colon segment tissues from patients with HSCR, provides potential markers or promising new candidate actors for the pathogenesis of HSCR. PMID- 21327721 TI - The happy genius of my household: phenomenological and poetic journeys into health and illness. AB - In recent years limitations in the biomedical conceptualisation of health and illness have been well documented and a variety of alternative explanations produced to replace or supplement it. One such is Fredrik Svenaeus's philosophy of medical practice, which is a development of Hans-Georg Gadamer and Martin Heideggers' phenomenological and hermeneutical writings. This paper explores two texts, a short story by H. G. Wells, The Country of the Blind, and a poem by William Carlos Williams, Danse Russe to add further insight into the ideas proposed by Svenaeus. Both texts were written before either Gadamer or Heidegger published their work. Analysis of the texts reveal examples of Heidegger's understanding of 'da-sein', human-being, as the fundamental of human existence how we relate to our 'life-world'-together with its conditions including the tools we use to engage with and the moods that interpret the world. Emerging from this core relationship of being are the phenomena of health and illness, which are conceptualised as home-like (Heimischkeit) and un-home-like (Unheimlichkeit) being-in-the-world. In the texts the sense of home-like (and un-home-like) being is an ontological 'web of significance', to use Heidegger's phrase, that creates, rather than results from a person's psychological state. One factor that is not fully explicated in the philosophical accounts is the role that behaviour (as the physical-relating of a person) plays as a pre-requisite for agency, the ability to act in taken-for-granted ways. A person's sense of authenticity, the extent to which someone makes their own choices rather than being led by what 'others' say, is linked with their ability to physically engage with and relate to their 'life world'. Finally, similarities between the ontological wholeness of poetry-the meaning structure of poetry-and of Dasein are noted. PMID- 21327723 TI - Those who have the gold make the evidence: how the pharmaceutical industry biases the outcomes of clinical trials of medications. AB - Pharmaceutical companies fund the bulk of clinical research that is carried out on medications. Poor outcomes from these studies can have negative effects on sales of medicines. Previous research has shown that company funded research is much more likely to yield positive outcomes than research with any other sponsorship. The aim of this article is to investigate the possible ways in which bias can be introduced into research outcomes by drawing on concrete examples from the published literature. Poorer methodology in industry-funded research is not likely to account for the biases seen. Biases are introduced through a variety of measures including the choice of comparator agents, multiple publication of positive trials and non-publication of negative trials, reinterpreting data submitted to regulatory agencies, discordance between results and conclusions, conflict-of-interest leading to more positive conclusions, ghostwriting and the use of "seeding" trials. Thus far, efforts to contain bias have largely focused on more stringent rules regarding conflict-of-interest (COI) and clinical trial registries. There is no evidence that any measures that have been taken so far have stopped the biasing of clinical research and it's not clear that they have even slowed down the process. Economic theory predicts that firms will try to bias the evidence base wherever its benefits exceed its costs. The examples given here confirm what theory predicts. What will be needed to curb and ultimately stop the bias that we have seen is a paradigm change in the way that we treat the relationship between pharmaceutical companies and the conduct and reporting of clinical trials. PMID- 21327724 TI - Recommendations for describing statistical studies and results in general readership science and engineering journals. AB - This paper recommends how authors of statistical studies can communicate to general audiences fully, clearly, and comfortably. The studies may use statistical methods to explore issues in science, engineering, and society or they may address issues in statistics specifically. In either case, readers without explicit statistical training should have no problem understanding the issues, the methods, or the results at a non-technical level. The arguments for those results should be clear, logical, and persuasive. This paper also provides advice for editors of general journals on selecting high quality statistical articles without the need for exceptional work or expense. Finally, readers are also advised to watch out for some common errors or misuses of statistics that can be detected without a technical statistical background. PMID- 21327725 TI - High doses of rosuvastatin are superior to low doses of rosuvastatin plus fenofibrate or n-3 fatty acids in mixed dyslipidemia. AB - The aim of the study was to compare the efficacy of high-dose rosuvastatin, low dose rosuvastatin plus fenofibrate and low-dose rosuvastatin plus omega-3 fatty acids with regard to the lipid profile in patients with mixed hyperlipidemia. The primary endpoint was changes in non-high density lipoprotein-cholesterol (non-HDL C) levels. Study participants were randomly allocated to receive rosuvastatin 40 mg (n = 30, R group), rosuvastatin 10 mg plus fenofibrate 200 mg (n = 30, RF group) or rosuvastatin 10 mg plus n-3 fatty acids 2 g (n = 30, RN group). Non-HDL C levels were reduced in all groups: in R group by 54%, in RF group by 42% and in RN group by 42%. Significant reductions in total cholesterol (TC), low density lipoprotein (LDL)-C and triglyceride levels were observed in all groups. The reductions in total and LDL-C were greatest in the R group while a more pronounced reduction of triglycerides in the RF group compared with that in the R and the RN group was observed. HDL-C levels were significantly increased only in the RF group. In conclusion, high doses of rosuvastatin and small doses of rosuvastatin plus either fenofibrate or n-3 fatty acids exhibit favorable effects on both LDL-C and non-HDL-C levels. However, rosuvastatin monotherapy more potently reduces these parameters. The combination of rosuvastatin plus fenofibrate leads to a greater decrease in triglyceride levels and a greater increase in HDL-C levels compared with the other two treatments. While awaiting the results of ongoing trials high doses of rosuvastatin may represent the treatment of choice in individuals with mixed dyslipidemia. PMID- 21327726 TI - Quantitative analysis of phospholipids using nanostructured laser desorption ionization targets. AB - Since its introduction as an ionization technique in mass spectrometry, matrix assisted laser desorption ionization (MALDI) has been applied to a wide range of applications. Quantitative small molecule analysis by MALDI, however, is limited due to the presence of intense signals from the matrix coupled with non homogeneous surfaces. The surface used in nano-structured laser desorption ionization (NALDI) eliminates the need for a matrix and the resulting interferences, and allows for quantitative analysis of small molecules. This study was designed to analyze and quantitate phospholipid components of liposomes. Here we have developed an assay to quantitate the DPPC and DC(8,9)PC in liposomes by NALDI following various treatments. To test our method we chose to analyze a liposome system composed of DPPC (1,2-dipalmitoyl-sn-glycero-3 phosphocholine) and DC(8,9)PC (1,2-bis(tricosa-10,12-diynoyl)-sn-glycero-3 phosphocholine), as DC(8,9)PC is known to undergo cross-linking upon treatment with UV (254 nm) and this reaction converts the monomer into a polymer. First, calibration curves for pure lipids (DPPC and DC(8,9)PC) were created using DMPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine) as an internal standard. The calibration curve for both DPPC and DC(8,9)PC showed an R(2) of 0.992, obtained using the intensity ratio of analyte and internal standard. Next, DPPC:DC(8,9)PC liposomes were treated with UV radiation (254 nm). Following this treatment, lipids were extracted from the liposomes and analyzed. The analysis of the lipids before and after UV exposure confirmed a decrease in the signal of DC(8,9)PC of about 90%. In contrast, there was no reduction in DPPC signal. PMID- 21327727 TI - Behavioral and psychophysiological responses to job demands and association with musculoskeletal symptoms in computer work. AB - INTRODUCTION: The purpose of this study was to identify and compare individual behavioral and psychophysiological responses to workload demands and stressors associated with the reporting of musculoskeletal symptoms with computer work. Evidence is growing that the prevalence of musculoskeletal symptoms increases with longer hours of computer work and exposure to psychosocial stressors such as high workloads and unrealistic deadlines. Workstyle, or how an individual worker behaves in response to such work demands, may also be an important factor associated with musculoskeletal symptoms in computer operators. METHOD: Approximately 8,000 employees of the Australian Public Service were invited to complete an on-line survey if they worked with a computer for 15 or more hours per week. The survey was a composite of three questionnaires: the ASSET to measure perceived organizational stressors, Nordic Musculoskeletal Questionnaire to measure reported prevalence of musculoskeletal symptoms and additional questions to measure individual work behaviors and responses. RESULTS: 934 completed surveys were accepted for analyses. Logistic regression was used to identify significant behavioral and work response predictors of musculoskeletal symptoms. Reporting of heightened muscle tension in response to workload pressure was more strongly associated, than other physical behavioral factors, with musculoskeletal symptoms for all body areas, particularly the neck (OR = 2.50, 95% CI: 2.09-2.99). CONCLUSIONS: Individual workstyles in response to workload demands and stressors, including working with heightened muscle tension and mental fatigue, were significantly associated with musculoskeletal symptoms. Future risk management strategies should have a greater focus on the identification and management of those organizational factors that are likely to encourage and exacerbate adverse workstyles. PMID- 21327728 TI - Treatment of sudden sensorineural hearing loss with transtympanic injection of steroids as single therapy: a randomized clinical study. AB - The aim of this study was to verify the efficacy and the safety of transtympanic dexamethasone to treat sudden sensorineural hearing loss as first and single drug method. Considering ethical implication of performing a mininvasive procedure on middle ear, we matched such proposed treatment with systemic prednisone administration that represents the widest adopted protocol. Randomized prospective study was conducted. The inclusion criterion was a sudden sensorineural hearing loss of at least 30 dB across three contiguous frequencies over a period of 24 h. Group A received transtympanic steroid injections; Group B received oral administration of steroids. 25 patients were treated with transtympanic therapy whereas 21 underwent systemic treatment. The mean of initial PTA was 59 dB for the whole series: 65 dB for group A and 51 dB for group B. The recovery better than 10 dB was obtained in 80% of patients of group A and in 17 81% of patients of group B, with a total of 80.5%. The mean relative gain in PTA was 41.16% in the group A and 44.7% in the group B. In the frequencies tested (0.5, 1, 2, and 4 kHz) PTA improvements after transtympanic treatment were higher than after systemic treatment, but these differences were not statistically significant (P = 0.61). Both transtympanic and systemic treatment had similar clinical recovery times. This prospective randomized clinical study showed good result in terms of hearing recovery, better than the expected results of the simple observation without treatment. We can consider transtympanic administration as a first line treatment, because of the statistical analysis confirmed similar results with systemic therapy, reducing possible side effects of systemic drug administration. The delay of treatment does not influence the outcome, allowing treating patients within 10 days of onset. PMID- 21327729 TI - Comparison of postoperative pain: piezoelectric device versus microdrill. AB - Piezosurgery(r) is a recently developed system for cutting bone with microvibrations. The objective of this study was to compare the severity of pain over the first 10 postoperative days in a group of 70 patients who underwent intact canal wall mastoidectomy, with the piezoelectric device, and to compare the results with traditional method by means of microdrill (70 patients). The subjective perception of pain was evaluated on a scale from 0 to 10, such that 0 represented no pain and 10 represented maximum pain; the severity was recorded as null when the score was 0; slight, when it was 1-4; moderate, when it was 5-7; or severe, when it was 8-10. Compared with microdrill, the patients that underwent surgery with the piezoelectric device showed a significant (P < 0.05) lower postoperative pain on day 1 (52 vs. 26 patients presented a slight pain, 12 vs. 37 presented a moderate pain, and 6 vs. 7 presented a severe pain) and day 3 (68 vs. 44 patients presented a slight pain, 2 vs. 23 presented a moderate pain, and 0 vs. 3 presented a severe pain). These results highlight as the piezoelectric device is a safe and minimally invasive tool. PMID- 21327730 TI - A new tool measuring oral malodor quality of life. AB - A valid measure of oral malodor (halitosis) and associated quality of life is required for the complete assessment of treatment effectiveness. The purpose of this study was to analyze the psychometric and clinimetric validity of the Halitosis Associated Life-quality Test (HALT) questionnaire, a specific 20-item quality-of-life measure for halitosis. The HALT is a de novo designed tool based on patient interviews and literature review. The University Hospital was the setting for the prospective random non-controlled study design. The comparison between the evaluator' scales on organoleptic testing and HALT scores was performed during the patient's initial visit. HALT was completed by 33 and 16 patients at the initial visit and at 3 months after treatment commencement, respectively. Two treatment arms comprising an experimental arm including Caphosol rinse for xerostomia-associated halitosis, and an established treatment arm with laser cryptolysis were compared. Cronbach's alpha was 0.93; coefficient alpha with deleted variables was between 0.92 and 0.94; equal length Spearman Brown coefficient is 0.95. The Cronbach's alphas of each split questionnaire were 0.85 and 0.88, respectively, and test-retest scores were highly correlated (r = 0.85). HALT scores were significantly associated with the scales of organoleptic test (F = 118, p < 0.001; r = 0.96, p < 0.001). HALT successfully measured each treatment arm and showed improvement (p < 0.002) in both arms. Although cryptolysis was more efficacious, the encouraging results of the Caphosol arm indicate that additional investigation is warranted. HALT proved a valid outcome measure for patients with halitosis, describes its burden and is sensitive to clinical change. PMID- 21327731 TI - Low flow vascular malformations of the head and neck: a study on brightness mode, color coded duplex and spectral Doppler sonography. AB - The clinical presentation of low flow vascular malformations of the head and neck (LFVM) can range from a birthmark to severe disfigurement, functional impairment or relevant hemorrhage. The values of Brightness mode (B-mode) ultrasound and Doppler sonography in the investigation, identifying and differentiating of these lesions has been sparingly documented in the literature. This study evaluates the sonografic features of different morphological subtypes of LFVM. This is a 2-year retrospective study of 51 patients who presented with LFVM based on routine ultrasound exam in the context of their clinical consultation. Diagnosis was based on the clinical and histological findings. B-mode, color coded duplex and spectral Doppler measurements were performed for venous, lymphatic, capillary, and mixed venous-lymphatic lesions of the head and neck. The echogenicity of the majority of venous malformations was heterogenic, of most lymphatic malformations hypoechoic, and of all capillary malformations isoechoic. Blood flow was detected in only 11 cases (36.7%) of venous malformations with a monophasic pattern. There was a statistical significant difference in the mean minimum and maximum Doppler shifts between venous and lymphatic malformation for cases when the blood flow was evident. No statistical significant difference in Doppler parameters existed between capillary and lymphatic, neither between venous and capillary nor mixed malformations. Phleboliths were present in eight cases (26.7%) of venous malformations and were not detectable in any other subtype of LFVM. The detection of flow in ultrasound was only possible in a small portion of LFVM. When considering differentiating among LFVM, features such as the echogenecity, spectral Doppler wave forms, and the evidence of phleboliths contribute to establish the correct diagnosis. PMID- 21327732 TI - Incidence of diffuse FDG uptake in the thyroid of patients with hypothyroidism. AB - Positron emission tomography (PET) positive lesions are common in the thyroid. The uptake can be focal or diffuse. Diffuse thyroid uptake is thought to be indicative of autoimmune thyroiditis and not for lesions of malignant potential. Hashimoto's thyroiditis as a cause for diffusely positive thyroid glands has been demonstrated. We determine the incidence of diffuse thyroid PET positivity in hypothyroid patients, presumed to have Hashimoto's thyroiditis. The study design was retrospective database and electronic medical record review. The study setting includes tertiary care and academic health sciences center. The subjects were patients at our medical center who underwent positron emission tomography. Hypothyroid patients were identified who had total body PET imaging performed for any reason. Patients were excluded if they were not taking levothyroxine, had a history of neck surgery, neck irradiation, Graves' disease, taking lithium, thalidomide, amiodarone or interleukin. Patients remaining after the application of these exclusion criteria were presumed to be hypothyroid from Hashimoto's thyroiditis. Only 9.5% of PET scans of hypothyroid patients display diffuse thyroid activity. Only a small minority of presumed Hashimoto's thyroiditis patients will display diffuse thyroid activity after PET imaging. The etiology of this effect is unknown. Diffuse thyroid activity rarely requires surgical intervention. PMID- 21327733 TI - Bisphosphonate-induced osteonecrosis of the external ear canal: a retrospective study. AB - In 2003, osteonecrosis of the jaw was described as an intraoral complication of bisphosphonate therapy. More recently, cases of avascular necrosis of the hip were reported in patients with long-lasting bisphosphonate therapy. Thus, it was the aim of the present study to analyze cases of benign osteonecrosis of the external ear canal and to retrospectively identify a possible relationship to long-lasting bisphosphonate therapy. 13 patients with osteonecrosis of the external ear canal operated on between 2005 and 2009 were included. Patient histories were reviewed for possible previous or current bisphosphonate therapy. Three patients with osteonecrosis of the external ear canal and long-term bisphosphonate therapy could be identified. They had been treated either for breast cancer or multiple myeloma. Certainly, the jaw is an area of increased risk for developing osteonecrosis with its high mechanical stress and intraoral bacterial flora. However, osteonecrosis of the hips and the external ear canal in patients receiving long-term bisphosphonate therapy necessitate further investigation of a possible systemic, bisphosphonate-related phenomenon. PMID- 21327734 TI - Adult primary intradural spinal cord tumors: a review. AB - Primary spinal cord tumors constitute 2% to 4% of all central nervous system neoplasms and are characterized based on their location as intramedullary, intradural extramedullary, and extradural. A contemporary literature review of primary intradural spinal cord tumors was performed. Among intramedullary tumors, ependymomas are more common and often can be surgically resected. However, astrocytomas infiltrate the spinal cord and complete resection is rare. Intradural extramedullary tumors include schwannomas, neurofibromas, and meningiomas and are usually amenable to surgical resection. Radiotherapy is reserved for malignant variants and recurrent gliomas, whereas chemotherapy is administered for recurrent primary spinal cord tumors without surgical or radiotherapy options. Early recognition of the signs and symptoms related to primary spinal cord tumors facilitates timely discovery, treatment, potentially minimizes neurologic morbidity, and may improve outcome. Treatment consists of surgical resection, and predictors of outcome include preoperative functional status, histologic grade of tumor, and extent of surgical resection. PMID- 21327737 TI - Pathogenesis of joint destruction in rheumatoid arthritis. AB - Synovial mesenchymal cells, matrix metalloproteinases (MMPs), and osteoclasts are the three major players directly responsible for the pathogenesis of rheumatoid joint destruction. First, synovial mesenchymal cells, internally driven by a transcription factor c-Fos/AP-1, not only directly invade cartilage and bone as a granulation tissue called "pannus" but also release inflammatory cytokine interleukin (IL)-1beta. IL-1beta induces MMPs and activates osteoclasts. Synovial cells can also present antigen to T cells to drive antigen-specific immune responses. Second, cartilaginous joint matrix can only be degraded after the first attack of collagen fibrils by MMPs, and importantly, most of the MMPs are under the control of c-Fos/AP-1 and IL-1beta as well. Third, differentiation of osteoclast is driven internally by NFATc1, where NFATc1 is under the control of TRAF6, c-Fos/AP-1 and osteoclastogenic signaling complex. IL-1beta has been shown to induce osteoclastogenesis directly and also indirectly via signaling through RANKL. Therefore, IL-1beta and c-Fos/AP-1 influence each other's gene expression and activity, resulting in an orchestrated cross-talk that is crucial to arthritic joint destruction, and thus, blockade of IL-1beta and/or c-Fos/AP-1 can be most promising as a therapeutic target, and in fact, a selective inhibition of c-Fos/AP-1 does resolve arthritic joint destruction. PMID- 21327735 TI - Neurosurgery for brain tumors: update on recent technical advances. AB - Advances in diagnostic imaging modalities and improved access to specialty care have led directly to an increased diagnosis of both metastatic and primary brain tumors. As technology has improved, so has the ability to treat this larger patient population. Diffusion tensor imaging (DTI) has recently shown the potential to aid in histologic diagnosis as well as to identify local brain invasion outside of that readily identifiable by conventional MRI. Similar to DTI, functional MRI provides a noninvasive means of delineating tumor margin from eloquent cortex and aids in preoperative surgical planning. As the literature shows increasing support for the advantages of extensive resection in glioma patients, modalities that aid in this regard are displaying increased importance. Surgeons have recently demonstrated the utility of intraoperative MRI in increasing extent of resection in both low- and high-grade glioma patients. Intraoperative tumor fluorescence provided by the chemical compound 5 aminolevulinic acid assists surgeons in identifying the true tumor margin during resection of glial neoplasms consequently increasing extent of resection. Finally, laser interstitial thermal therapy is an emerging treatment modality allowing surgeons to treat small intracranial lesions with potentially decreased morbidity via this minimally invasive approach. The following review analyzes the recent literature in an effort to describe how these modalities can and should be used in the treatment of patients with intracranial pathology. PMID- 21327736 TI - Recent advances in the genetics of hereditary axonal sensory-motor neuropathies type 2. AB - Hereditary axonal motor and sensory neuropathies or Charcot-Marie-Tooth disease type 2 (CMT2) are characterized clinically by distal muscle weakness and atrophy, sensory loss, and foot deformities. Conduction velocities are usually in the normal range or mildly slowed. The majority of CMT2 are autosomal-dominant but autosomal-recessive forms have been described. The number of genes associated with CMT2 have significantly increased in the past decade, with the gene causing CMT2C/SPSMA being the last one discovered. More than 10 genes are now associated with different subtypes of CMT2, which are classified from CMT2A to CMT2N. These genes have distinct functions, but some appear to be involved in common biological pathways, therefore, providing important clues for understanding the pathogenic mechanism of these heterogeneous disorders. PMID- 21327738 TI - Erlotinib in patients with advanced non-small-cell lung cancer: impact of dose reductions and a novel surrogate marker. AB - Erlotinib is a relatively well-tolerated treatment option for patients with advanced non-small-cell lung cancer (NSCLC). Some patients suffer from severe skin toxicity or diarrhea, making dose reductions or even treatment cessation necessary. Recent clinical trials usually defined a 100 mg daily dose as the lowest acceptable dose, whereas little is known about the efficacy with lower doses. We retrospectively reviewed the files of all patients with advanced non small-cell lung cancer (NSCLC) treated with erlotinib. We assessed demographic, disease- and treatment-related information. We tried to correlate tolerability with clinical efficacy. EGF receptor exon 18/19/21 mutations were analyzed in selected patients. Fifty-three patients with advanced non-small-cell lung cancer were treated with erlotinib. In nine patients (17%), the doses had to be reduced to 75 or 50 mg daily due to toxicity. We observed several sustained disease stabilizations in this subgroup. Patients suffering from paronychia with erlotinib had a significantly longer time to progression than did subjects without nail toxicity (P = 0.04). If patients were free from any toxicity, they were at high risk for early tumor progression (P = 0.001) and death. In patients with disease stabilization for 6 months or longer, we observed EGFR 18/19/21 wild type, exon 19 and exon 21 mutations. In conclusion, several patients required dose reductions during treatment with erlotinib. However, in tumors with sensitivity to erlotinib, even daily doses of 50-75 mg can result in sustained disease control. Paronychia represents a favorable surrogate marker for efficacy. PMID- 21327739 TI - The serum bone morphogenetic protein-2 level in non-small-cell lung cancer patients. AB - Bone morphogenetic proteins (BMPs) are members of the TGF-beta superfamily, and some studies demonstrated that BMPs enhance tumorigenesis and metastasis. The purpose of this study was to identify whether BMP-2 levels are elevated in the serum of non-small-cell lung cancer (NSCLC) patients and are associated with the stage and overall survival. Blood samples from 150 patients with NSCLC were analyzed. Also, 69 healthy volunteers were tested as control group. In NSCLC patients, whole blood was obtained before beginning any treatment modalities, and serum BMP-2 levels were quantified by commercially available ELISA kit. The NSCLC group demonstrated a significantly higher level of serum BMP-2 than the control group. (The median levels were 25.50 pg/ml for the control group and 72.23 pg/ml for the NSCLC group, P < 0.001). The median serum BMP-2 level in the advanced stage group (stage IIIb or IV) was significantly more elevated than that of the localized stage group (stage I, II, IIIa) (75.66 pg/ml and 44.36 pg/ml, P = 0.006). Patients with multiple metastatic sites (>=5) showed significantly higher level of serum BMP-2 than the patients with less than 5 metastatic sites. (79.39 pg/ml vs. 59.70 pg/ml, P = 0.013), and the median serum BMP-2 level from the patients with multiple metastatic organs (>=3) was significantly higher than that from the patients with single or two metastatic organs (<2) (89.39 pg/ml vs. 66.90 pg/ml, P = 0.001). Moreover, the patients with relatively lower BMP-2 level (<=70 pg/ml) had longer median overall survival than the patients with higher BMP 2 level (>70 pg/ml). (525 days vs. 260 days). One-year survival rate for the patients with lower BMP-2 level was also higher than that for the patients with higher BMP-2 level. (59.6% versus 40.2%, P = 0.034). The serum BMP-2 level is positively correlated with the stage and metastatic burden and maybe a probable predictor of survival in the NSCLC patients. PMID- 21327740 TI - Primary malignant melanoma of the penis: a case report. AB - We present the case of a patient with malignant melanoma of the glans penis and urethral meatus, which was found in a 60-year-old man with non-healing ulcerative penile lesion and bilateral clinically palpable inguinal lymphadenopathies at diagnosis. A diagnostic biopsy showed the characteristics of a malignant melanoma. Incisional biopsies from the cutaneous lesions on his glans penis and urethra were performed. Histopathological examination of both specimens showed generally ulceronecrotic surface and numerous atypical melanocytic cells. The diagnosis of giant cell melanoma was made. Two months later, bilateral inguinal lymph nodes dissection was performed. Histopathological examination of both specimens demonstrated malignant melanoma metastasis. Three months after the diagnosis, the patient underwent partial penectomy. High-dose interferon-alpha-2b treatment was started. Early diagnosis is of paramount importance, as the prognosis becomes very poor with an advanced tumor stage. PMID- 21327741 TI - Display of organophosphorus hydrolase on the cyanobacterial cell surface using synechococcus outer membrane protein a as an anchoring motif. AB - The display of proteins to cyanobacterial cell surface is made complex by combination of Gram-positive and Gram-negative features of cyanobacterial cell wall. Here, we showed that Synechococcus outer membrane protein A (SomA) can be used as an anchoring motif for the display of organophosphorus hydrolase (OPH) on cyanobacterial cell surface. The OPH, capable of degrading a wide range of organophosphate pesticides, was fused in frame to the carboxyl-terminus of different cell-surface exposed loops of SomA. Proteinase K accessibility assay and immunostaining visualized under confocal laser scanning microscopy demonstrated that a minor fraction of OPH with 12 histidines fused in frame with the third cell-surface exposed loop of SomA (SomAL3-OPH12H) was displayed onto the outermost cell surface with a substantial fraction buried in the cell wall, whereas OPH fused in frame with the fifth cell-surface exposed loop of SomA (SomAL5-OPH) was successfully translocated across the membrane and completely displayed onto the outermost surface of Synechococcus. The successful display of the functional heterologous protein on cell surface provides a useful model for variety of applications in cyanobacteria including screening of polypeptide libraries and whole-cell biocatalysts by immobilizing enzymes. PMID- 21327742 TI - Isolation and partial characterization of halotolerant lactic acid bacteria from two Mexican cheeses. AB - Isolated strains of halotolerant or halophilic lactic acid bacteria (HALAB) from Cotija and doble crema cheeses were identified and partially characterized by phenotypic and genotypic methods, and their technological abilities were studied in order to test their potential use as dairy starter components. Humidity, a(w), pH, and salt concentration of cheeses were determined. Genotypic diversity was evaluated by randomly amplified polymorphic DNA-polymerase chain reaction. Molecular identification and phylogenetic reconstructions based on 16S rRNA gene sequences were performed. Additional technological abilities such as salt tolerance, acidifying, and proteolytic and lipolytic activities were also investigated. The differences among strains reflected the biodiversity of HALAB in both types of cheeses. Lactobacillus acidipiscis, Tetragenococcus halophilus, Weissella thailandensis, and Lactobacillus pentosus from Cotija cheese, and L. acidipiscis, Enterococcus faecium, Lactobacillus plantarum, Lactobacillus farciminis, and Lactobacillus rhamnosus from doble crema cheese were identified based on 16S rRNA. Quantitative and qualitative assessments showed strains of T. halophilus and L. plantarum to be proteolytic, along with E. faecium, L. farciminis, and L. pentosus to a lesser extent. Lipolytic activity could be demonstrated in strains of E. faecium, L. pentosus, L. plantarum, and T. halophilus. Strains belonging to the species L. pentosus, L. plantarum, and E. faecium were able to acidify the milk media. This study evidences the presence of HALAB that may play a role in the ripening of cheeses. PMID- 21327744 TI - Consolidation of multifeature items in visual working memory: central capacity requirements for visual consolidation. AB - In the present study, we examined whether greater attentional resources are required for consolidating two features (e.g., color and orientation) than for consolidating one feature (e.g., color) in visual working memory (WM). We used a dual-task procedure: Subjects performed a WM task and a secondary probe task, sometimes concurrently. In the WM task, subjects decided whether two displays (containing one to four objects composed of one or two features) were the same or different. In the probe task, subjects made a speeded discrimination response to a tone. Performance in both tasks was impaired when they were performed concurrently; however, performance costs in the tone task were not greater for multi- than for single-feature conditions (when the orientation and conjunction conditions were considered). Results suggested that equivalent attentional resources were necessary for consolidation of single-orientation or multifeature items. PMID- 21327743 TI - Bone health issues in sarcoidosis. AB - Sarcoidosis affects the bone directly in only a minority of patients. Nonetheless, bone health should be considered in the management of all patients with sarcoidosis. Deficiency in vitamin D, an important contributor to bone health, has been linked to autoimmune disease incidence. Studies have shown that patients with sarcoidosis frequently have low levels of vitamin D-25 but may have normal or increased levels of vitamin D-1,25. In addition, granuloma formation has been linked to a failure of the innate immune system, which could be related to a deficiency in vitamin D, although this relationship has not been fully characterized. Furthermore, many patients with sarcoidosis are treated with corticosteroids, which are known to induce osteoporosis. Therefore, bone health may be impacted in several ways in sarcoidosis--by direct involvement with granulomas, vitamin D deficiency, or corticosteroid therapy. PMID- 21327745 TI - Apparent motion enhances visual rhythm discrimination in infancy. AB - Many studies have demonstrated that infants exhibit robust auditory rhythm discrimination, but research on infants' perception of visual rhythm is limited. In particular, the role of motion in infants' perception of visual rhythm remains unknown, despite the prevalence of motion cues in naturally occurring visual rhythms. In the present study, we examined the role of motion in 7-month-old infants' discrimination of visual rhythms by comparing experimental conditions with apparent motion in the stimuli versus stationary rhythmic stimuli. Infants succeeded at discriminating visual rhythms only when the visual rhythm occurred with an apparent motion component. These results support the view that motion plays a role in infants' perception of visual temporal information, consistent with the manner in which natural rhythms appear in the visual world. PMID- 21327746 TI - Manipulating informational constraints shapes movement reorganization in interceptive actions. AB - Movement organization of cricket batters' actions was analyzed under three distinct experimental task constraints: a representative condition of a practice context in which the batters batted against a "live" bowler, a ball projection machine, and a near life-size video simulation of a bowler. Results showed that each distinct set of task constraints led to significant variations in the patterns of movement control. Removal of advanced information sources from a bowler's actions when the batters faced the ball projection machine caused significant delays in movement initiation, resulting in reduced peak bat swing velocities and a reduction in the quality of bat-ball contact, when compared with batting against a "live" bowler. When responding to a two-dimensional video simulation, batters were able to use information from the bowlers' action, enabling fidelity of initial behavioral responses consistent with the task of batting against a "live" bowler. However, without interceptive task requirements or actual ball flight information, significant variations in downswing initiation timing and peak bat velocities were demonstrated. Findings stress the need for representative experimental and learning designs in fast ball sports for developing performers. PMID- 21327747 TI - Stimulus range and discontinuity effects on information-integration category learning and generalization. AB - Two studies are reported that support the hypothesis that categories that require a multiple-unit, as opposed to a single-unit, representation lead to worse initial acquisition but better generalization. On the basis of the constraints imposed by the procedural-based learning system thought to mediate information integration categorization, we argue that the need to train multiple units during initial category acquisition slows the procedural-based category learning process and adversely affects learning performance. However, we speculate that better generalization occurs because of the increased likelihood that a novel stimulus will activate at least one of the multiple units needed to represent the category. Relations to other findings in the literature and the implications of this work for training and clinical assessment are discussed. PMID- 21327748 TI - Spatial attention and conscious perception: the role of endogenous and exogenous orienting. AB - Attention has often been considered to be a gateway to consciousness (Posner, Proceedings of the National Academy of Sciences of the United States of America, 91(16), 7398-7403, 1994). However, its relationship with conscious perception (CP) remains highly controversial. While theoretical models and experimental data support the role of attention in CP (Chica, Lasaponara, Lupianez, Doricchi, & Bartolomeo, NeuroImage, 51, 1205-1212, 2010; Dehaene, Changeux, Naccache, Sackur, & Sergent, Trends in Cognitive Sciences, 10, 204-211, 2006; Mack & Rock, Inattentional blindness, 1998), recent studies have claimed that at least some forms of attention--endogenous or top-down spatial attention--are neither sufficient nor necessary for CP (Koch & Tsuchiya, Trends in Cognitive Sciences, 11, 16-22, 2007). In the present experiments, we demonstrate the importance of exogenously triggered attention for the modulation of CP. Weak or null effects were instead observed when attention was triggered endogenously. Our data are discussed in the framework of recent neuropsychological models (Dehaene et al., Trends in Cognitive Sciences, 10, 204-211, 2006), postulating that activity within reverberating frontoparietal networks, as colocalized with spatial orienting systems, is the brain correlate of consciously processed information. PMID- 21327753 TI - Trends in chronologic age and infant respiratory syncytial virus hospitalization: an 8-year cohort study. AB - INTRODUCTION: Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in infants and young children and the leading cause of hospitalization in infants aged <1 year. METHODS: We examined trends in RSV hospitalization (RSVH) among infants from 1998 to 2006, using the United States (US) National Hospital Discharge Survey (NHDS) database. RSVH was defined by the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes 079.6 (RSV), 466.11 (acute bronchiolitis due to RSV), and 480.1 (pneumonia due to RSV). Age at the time of hospitalization was determined using NHDS birth records; RSVH rates were analyzed for infants grouped into three age cohorts (<3 months, 3 to 6 months, and >6 to <24 months). Trends in hospitalization rates were evaluated using linear regression. Relative rates (RR) and 95% confidence intervals (CI) were computed to compare average RSVH rates for infants across age-specific groups. The annual proportion of RSVH by age group was also calculated. RESULTS: Approximately 1.1 million (90,000-147,000 per year) RSVHs in predominantly term children aged <24 months were analyzed. Compared with children aged >6 to <24 months, rates for RSVH were significantly higher among infants aged <3 months (RR, 7.38; 95% CI, 7.35-7.41) and infants aged 3 to 6 months (RR, 5.28; 95% CI, 5.26-5.29). The proportion of RSVH in the first year of life was lowest among infants aged <1 month (9%). [corrected] The greatest proportion of RSVH was observed in children aged 3 to 6 months (14%-23% RSVH per year; chi-square P<0.0001). When the definition of RSVH was expanded to include unspecified hospitalizations for acute bronchiolitis, similar results were observed. CONCLUSION: RRs were highest among the <3- month and 3- to 6-month age groups. The highest proportion of RSVH was among the 3- to 6-month age group. Analysis of the impact of RSV season, clinical practices, and other factors on these trends is warranted. PMID- 21327754 TI - Application of one-compartmental bio-metric blood loss calculations with transfused blood volume taken into account after aneurysmectomy. AB - Blood loss can be measured directly and indirectly. The latter reflects blood loss through the assessment of hemoglobin level. Thus aim of this study was to determine the applicability of the drop in hemoglobin levels blood loss calculation when transfused blood volume is taken into account on the patients who underwent aneurysmectomy and to estimate whether this model is applicable on geriatric population. In this study, 14 patients were included and their blood loss was calculated based on hemoglobin concentration. Linear correlation (y = 0.18467 + 1.19315.x) with high correlation coefficient (r = 0.90809) was found between calculated and collected blood loss only if transfused blood volume was taken into account. The coefficient of the regression slope for the blood volume measured during surgery and the calculated blood loss in eight patients <=65 years (y = 0.90866 + 0.86296.x) and six patients >65 years (y = 0.0299 + 1.32707.x) did not show any significant difference. The applicability of the indirect measurement of surgical blood loss, when transfused blood volume was taken into account, was demonstrated in both populations, in the age of 65 and less and in the age over 65 years after aneurysmectomy. PMID- 21327756 TI - Assessment of tumor hypoxia by 62Cu-ATSM PET/CT as a predictor of response in head and neck cancer: a pilot study. AB - OBJECTIVE: In radiotherapy and chemotherapy tumor hypoxia is recognized as a major obstacle to effective treatment. We undertook a pilot study in patients with locally advanced head and neck cancer to determine whether there is a relationship between tumor uptake of (62)Cu-ATSM and response to chemoradiotherapy. METHODS: Seventeen patients were studied using PET/CT with (62)Cu-ATSM and (18)F-FDG prior to the initiation of radiotherapy and chemotherapy. All patients had locally advanced head and neck cancer (stage III or IV). Tumor uptake in all patients was measured by region of interest analysis using the maximal standardized uptake value (SUVmax). A total dose of 50.4-70.2 Gy (median 70.2 Gy) was delivered in 29-39 fractions (median 39 fractions) to tumor. In patients with (non CR) and without (CR) residual/recurrent tumors at 2 year post irradiation, the statistical significance of the differences in tumor (62)Cu-ATSM SUVmax, T/M ratio, (18)F-FDG SUVmax and tumor volume were analyzed using Student's t test and Welch test. The relationship between clinical outcome and (62)Cu-ATSM/(18)F-FDG uptake patterns was analyzed using Kruskal-Wallis test. The correlation between SUVmax of (62)Cu-ATSM and (18)F-FDG was compared by Spearman's rank correlation test. RESULTS: Two of the 17 patients that were enrolled in our study were excluded from the final analysis. Of the 15 remaining patients, 9 patients were free of disease and 6 patients had residual/recurrent tumors. The SUVmax differed significantly (p < 0.05) between patients with or without residual/recurrent tumor on (62)Cu-ATSM PET/CT. Six of the 10 patients with tumors SUVmax >5.00 had residual/recurrent tumor, whereas all of the 5 patients with tumors SUVmax <5.00 were free of disease. There was no significant difference in FDG uptake between patients with and without residual/recurrent tumor. CONCLUSIONS: The results of this pilot study suggested that (62)Cu-ATSM uptake may be a predictive indicator of tumor response to chemoradiotherapy in patients with locally advanced head and neck cancer. PMID- 21327755 TI - Adult human adipose tissue contains several types of multipotent cells. AB - Multipotent mesenchymal stromal cells (MSCs) are a type of adult stem cells that can be easily isolated from various tissues and expanded in vitro. Many reports on their pluripotency and possible clinical applications have raised hopes and interest in MSCs. In an attempt to unify the terminology and the criteria to label a cell as MSC, in 2006 the International Society for Cellular Therapy (ISCT) proposed a standard set of rules to define the identity of these cells. However, MSCs are still extracted from different tissues, by diverse isolation protocols, are cultured and expanded in different media and conditions. All these variables may have profound effects on the selection of cell types and the composition of heterogeneous subpopulations, on the selective expansion of specific cell populations with totally different potentials and ergo, on the long term fate of the cells upon in vitro culture. Therefore, specific molecular and cellular markers that identify MSCs subsets as well as standardization of expansion protocols for these cells are urgently needed. Here, we briefly discuss new useful markers and recent data supporting the rapidly emerging concept that many different types of progenitor cells are found in close association with blood vessels. This knowledge may promote the necessary technical improvements required to reduce variability and promote higher efficacy and safety when isolating and expanding these cells for therapeutic use. In the light of the discussed data, particularly the identification of new markers, and advances in the understanding of fundamental MSC biology, we also suggest a revision of the 2006 ISCT criteria. PMID- 21327757 TI - Early life stress and psychopharmacology. PMID- 21327758 TI - Group II mGluR agonist LY354740 and NAAG peptidase inhibitor effects on prepulse inhibition in PCP and D-amphetamine models of schizophrenia. AB - RATIONALE: Group II metabotropic glutamate receptor (mGluR) agonists represent a novel approach to the treatment of schizophrenia. Inasmuch as the peptide neurotransmitter N-acetylaspartylglutamate (NAAG) activates these receptors, NAAG peptidase inhibitors conceptually represent a parallel path toward development of new antipsychotic drugs. While group II agonists are effective in several animal models of schizophrenia, they are reported to lack efficacy in moderating the effects of phencyclidine (PCP) on prepulse inhibition of acoustic startle in animal models of sensory processing deficits found in this disorder. OBJECTIVE: The objective of this study was to re-examine the efficacy of a group II metabotropic glutamate agonist and NAAG peptidase inhibitors in prepulse inhibition models of schizophrenia across two strains of mice. METHODS: The method used was an assay to determine the efficacy of these drugs in moderating the reduction in prepulse inhibition of acoustic startle in mice treated with PCP and D: -amphetamine. RESULTS: The group II agonist LY354740 (5 and 10 mg/kg) moderated the effects of PCP on prepulse inhibition of acoustic startle in DBA/2 but not C57BL/6 mice. In contrast, two NAAG peptidase inhibitors, ZJ43 (150 mg/kg) and 2-PMPA (50, 100, and 150 mg/kg), did not significantly affect the PCP induced reduction in prepulse inhibition in either strain. CONCLUSIONS: These data demonstrate that the efficacy of group II agonists in this model of sensory motor processing is strain-specific in mice. The difference between the effects of the group II agonist and the peptidase inhibitors in the DBA/2 mice may relate to the difference in efficacy of NAAG and the agonist at mGluR2. PMID- 21327759 TI - Effects of nicotine and alcohol on affective responses to emotionally toned film clips. AB - RATIONALE: Smoking abstinence can result in decreased affective reactions to positively valenced stimuli, and this can be reversed via smoking. Given their shared ability to trigger nucleus accumbens dopamine release, a priming dose of alcohol may likewise augment positive affective responses during abstinence. OBJECTIVES: The purpose of this study is to replicate our previous finding that compared to satiation, abstinence from smoking will be associated with decreased 'happiness' responses to positively valenced film clips (Study 1) and to explore whether a priming dose of alcohol can substitute for nicotine by concomitantly enhancing such responses (Study 2). In both studies, 'sadness' responses to negatively valenced clips were also included. METHODS: Thirty-two and 77 smokers, respectively, in Studies 1 and 2 were randomly allocated to abstain from smoking for 10 h (abstinent smokers) or smoke as usual (satiated smokers). Participants then rated the extent to which they felt a list of emotions in response to each of 16 film clips. In Study 2, participants were additionally allocated to an alcohol manipulation in which they received either alcohol or placebo. RESULTS: In Study 1, nicotine administration increased abstinent smokers' ratings of happiness and sadness to the corresponding film clips. In Study 2, nicotine and alcohol both enhanced positive reactivity to happy clips, and their effects were not additive. Alcohol but not nicotine likewise enhanced sadness responses to sad clips. CONCLUSIONS: Abstinence from smoking can result in blunting of affective responses to positively toned stimuli, an effect that can be ameliorated by both nicotine and alcohol. The impact of nicotine on negative reactivity appears to be less robust. PMID- 21327760 TI - Cigarette demand and delayed reward discounting in nicotine-dependent individuals with schizophrenia and controls: an initial study. AB - RATIONALE: The high prevalence of smoking and low cessation rates among individuals with schizophrenia and similar conditions are not well understood. Behavioral economics has been extensively applied to studying addictive behavior and may contribute to understanding smoking in this subpopulation. OBJECTIVES: This study compared smokers with schizophrenia or schizoaffective disorder (SS) and control smokers (CS) on indices of cigarette demand and delayed reward discounting, a behavioral economic index of impulsivity. MATERIALS AND METHODS: The SS (n=25) and CS (n=24) groups participated in two sessions approximately 1 week apart. During the first session, delay discounting was assessed using the Monetary Choice Questionnaire. During the second session, participants smoked their usual brand ad libitum through a smoking topography assessment device, after which cigarette demand was assessed using a cigarette purchase task. Primary comparisons were of the hyperbolic discounting function, k, and indices of cigarette demand. RESULTS: Compared to the CS group, the SS group exhibited significantly higher intensity of demand, and significantly greater consumption and expenditure across the inelastic portion of the demand curve, but no differences were evident on the other demand indices. No differences were evident for delay discounting. The SS group also exhibited heavier smoking topography and two indices of smoking topography were significantly correlated with demand. CONCLUSIONS: These results provide further evidence of higher incentive value of cigarettes among SS individuals, but not greater impulsivity, as measured by discounting. Considerations include potentially important methodological factors and the role of satiation/withdrawal. PMID- 21327764 TI - Enhancement of rotator cuff tendon-bone healing with injectable periosteum progenitor cells-BMP-2 hydrogel in vivo. AB - PURPOSE: The fixation and incorporation of ruptured rotator cuff tendon to bone is a major concern in rotator cuff repair surgery. Rotator cuff repair usually fails at the tendon-bone interface, especially in case of large or massive tears. To enhance tendon-bone healing, an injectable hydrogel made with periosteal progenitor cells(PPCs) and poly (ethylene glycol) diacrylate (PEGDA) tethered with bone morphogenic protein-2(BMP-2) was developed to encourage extracellular matrix synthesis for tendon-to-bone healing in rotator cuff repair. METHODS: The infraspinatus tendon was cut from the greater tuberosity and repaired through a transosseous tunnel with the injectable progenitor cell-BMP-2 hydrogel applied between the tendon-bone interface. The injectable hydrogel was prepared from 10% poly (ethylene glycol) diacrylate (PEGDA) containing 0.05% of the photoinitiator. BMP-2 tethered with poly(ethylene glycol) (PEG) was blended to the hydrogel. Rabbit periosteal progenitor cells (PPCs) isolated from periosteum were mixed with hydrogel and injected on the tendon-bone interface. Ultraviolet radiation (365 nm) was applied for 60 s to photopolymerize the injection and solidify the hydrogel. The rabbits were killed at 4 and 8 weeks. The morphological characteristics of the healing tendon-to-bone interface were evaluated by histological and immunohistochemical methods. The biomechanical test was done to determine healing attachment strength. RESULTS: At both the 4- and 8-week killing, histological analysis of the tendon-bone interface showed an increasing fibrocartilage and bone layer formed in the tendon-bone interface in PEGDA group. At 4 weeks, fibrocartilage-like tissue was observed in a focal area. At 8 weeks, further matrix deposition occurred with fibrocartilage formation in the tendon bone junction, and bone formation appeared near host bone. Immunohistochemistry revealed the presence of aggrecan and type II collagen. Biomechanical testing revealed a higher maximum pull-out load at all time points with a statistically significant difference at 4 and 8 weeks postoperatively. CONCLUSION: PEGDA hydrogel was approved as an adequate matrix for the encapsulation of cells and signal factor, and as an effective local delivery method to the tendon-bone interface through injection and photopolymerization. The PPCs-BMP2-hydrogel provides a powerful inductive ability between the tendon and the bone and enhances tendon-bone healing through the neoformation of fibrocartilage. PMID- 21327765 TI - Reduced osteoclastogenesis and RANKL expression in marrow from women taking alendronate. AB - Alendronate (AL) is commonly used for the prevention and treatment of osteoporotic fractures. Little is known about the effects of AL administration on osteoclast differentiation from human marrow progenitor cells. We used marrow discarded during orthopedic surgery to test the hypothesis that cultures of bone marrow-derived stem cells (BMCs) from subjects receiving AL (+AL) may differ from control subjects with respect to in vitro osteoclast differentiation and regulatory factors. The number of osteoclasts generated in BMC cultures from control subjects was 4.7-fold greater than that from +AL subjects (P = 0.015). RANKL expression in +AL BMCs was 57% of that in controls (P = 0.001), and OPG expression in +AL BMCs was greater than in controls (153%, P = 0.01). The mean RANKL/OPG ratio in BMCs was 0.65 +/- 0.35 for +AL specimens and 1.28 +/- 0.53 for controls (P = 0.031). In addition, we assessed the direct effect of AL on expression of RANKL and OPG in marrow stromal cells isolated from nine control women. Treatment with AL downregulated RANKL expression and upregulated OPG expression, with an average 50% decrease in RANKL/OPG ratio at 10(-7) M (P = 0.004). These results show that osteoclast differentiation is dysregulated in marrow isolated from +AL subjects. Furthermore, AL may inhibit human osteoclastogenesis by affecting the key regulatory genes in marrow cells. PMID- 21327766 TI - Effects of alfacalcidol on mechanical properties and collagen cross-links of the femoral diaphysis in glucocorticoid-treated rats. AB - Bone fragility is increased in glucocorticoid (GC)-induced osteopenia even though GC-treated patients have higher bone mineral density (BMD), suggesting that the impaired bone quality may affect bone strength. This study was conducted to clarify the effects of GC on bone strength and collagen cross-links of adult rats and the effect of coadministration of alfacalcidol (ALF), a prodrug of active vitamin D(3). Six-month-old male Wistar-Imamichi rats (n = 32) were divided into the following four groups with equal average body weight: (1) 4-week age-matched controls, (2) 4-week GC (prednisolone, 10 mg/kg daily, i.m.) with concomitant administration of vehicle, (3) 4-week GC with concomitant administration of ALF (0.05 MUg/kg daily, p.o.), and (4) 4-week GC with concomitant administration of ALF (0.1 MUg/kg daily, p.o.). At the end of treatment, BMD, collagen cross-links, mechanical properties of the femoral midshaft, bone metabolic markers, and biochemical parameters were analyzed. In the GC group, femoral bone strength decreased without any change of BMD. This was accompanied by a decrease in the content of enzymatic cross-links. ALF (0.1 MUg/kg) inhibited the GC-induced reduction in bone strength. The content of mature cross-links in the 0.1-MUg/kg ALF group was significantly higher than that in the GC group. GC treatment caused a decrease in bone metabolic markers and serum calcium levels, which was counteracted by ALF coadministration. Preventive treatment with ALF inhibited the deterioration of bone mechanical properties primarily in association with the restoration of enzymatic cross-link formation and amelioration of the adverse effects of GC treatment on calcium metabolism. PMID- 21327769 TI - Visual experience and blindsight: a methodological review. AB - Blindsight is classically defined as residual visual capacity, e.g., to detect and identify visual stimuli, in the total absence of perceptual awareness following lesions to V1. However, whereas most experiments have investigated what blindsight patients can and cannot do, the literature contains several, often contradictory, remarks about remaining visual experience. This review examines closer these remarks as well as experiments that directly approach the nature of possibly spared visual experiences in blindsight. PMID- 21327770 TI - When research is reconciled with care and ethics with science, reimbursement for clinical procedures can be linked to trial participation. PMID- 21327771 TI - Brain atrophy and lesion load are related to CSF lipid-specific IgM oligoclonal bands in clinically isolated syndromes. AB - INTRODUCTION: The objective of this work is to study the relationship between the presence of lipid-specific oligoclonal IgM bands (LS-OCMB) in CSF, with both T2 lesion volume (T2LV) accumulation and brain atrophy (percentage change of brain volume-PCBV-and brain parenchyma fraction-BPF) in patients with clinically isolated syndromes (CIS) suggestive of demyelination. METHODS: Twenty-four CIS patients were included in this prospective study. IgG oligoclonal bands (OCGB) and LS-OCMB were determined in paired serum and CSF samples within 3 months since clinical onset. Brain MRI studies were scheduled at baseline, 3 months, first and second years after CIS onset. Differences in T2LV, PCBV and BPF between CIS patients according to the type of OCB were studied. RESULTS: Nine patients had no OCB; 15 had only OCGB, and seven had OCGB + LS-OCMB present in the CSF. LS-OCMB were associated with greater T2LV in all scheduled MRI studies. At the end of follow-up (year 2), it was threefold higher in patients with these antibodies than in those without LS-OCMB (3.95 cm(3) vs. 1.36 cm(3), p = 0.001). At that point, brain atrophy was also higher in patients with LS-OCMB (BPF, 0.73 in LS OCMB+ patients vs. 0.76 in negative ones, p = 0.03). The rate in brain atrophy was higher in the first group of patients as well. Considering only patients with OCGB, the presence of LS-OCMB was also related to greater T2LV, T2LV increase and a trend towards higher atrophy rate. CONCLUSION: The presence of LS-OCMB in the first event suggestive of demyelination is related to an early increase in lesion load and brain atrophy. These data are in line with prospective studies showing the clinical prognostic value of LS-OCMB. PMID- 21327772 TI - Oncology protocols: how can we do better? AB - Diagnostic imaging provides information that is critical to the clinical care of pediatric oncology patients. Such information is also vital for assessing the effects of treatment on specific tumors during clinical trials. The design of such trials mandates standardization of imaging techniques, tumor measurements, data analysis, consistency of data collection and image interpretation in order to make scientific decisions about treatment regimens. In addition to these considerations, the optimal imaging modality to answer the scientific questions and simultaneously provide excellent patient care must be determined while minimizing patient exposure to ionizing radiation. This presentation will discuss these factors and potential means of improving upon inconsistencies, and consider factors that might influence the future. PMID- 21327773 TI - Clinical transplantation tolerance. AB - Transplantation is the treatment of choice for many if not most causes of end stage organ failure. Over 20,000 organ transplant procedures were performed in the USA in 2009 to treat patients with failed or failing kidneys, livers, hearts, lungs, and intestines, and there remain 85,000 individuals waiting on the transplant list. Currently, in the USA, there are over 170,000 individuals living with a transplanted organ. Virtually, all of these individuals receive maintenance immunosuppression in an attempt to maximize the function and survival of the transplanted organ. However, it is clear that the long-term use of immunosuppressive agents is associated with an extensive list of undesirable side effects that have the potential to limit the survival of the patient and transplanted organ as well as to compromise quality of life. Although the ability to induce reproducibly a state of robust, stable tolerance would address this problem, tolerance remains an infrequent event in clinical transplantation that is largely a consequence of chance. Factors limiting the broader investigation of clinical transplantation tolerance include the lack of therapeutic regimens known to favor tolerance in humans, the lack of validated assays or biomarkers predictive of tolerance, and concerns about the safety and ethics of complete withdrawal of immunosuppression given the very good results achievable with current immunosuppression. Despite these barriers, a number of investigators have continued to conduct well-designed and carefully supervised studies with the long term goal of making clinical transplantation tolerance more feasible. The aim of this review is to summarize the status of these studies. PMID- 21327775 TI - Steroid-resistant acute allograft rejection in renal transplantation. AB - Steroid-resistant rejection after pediatric renal transplantation forms a rare but severe complication with a guarded prognosis particularly if this occurs late after transplantation. There is a paucity of data on how to manage these challenging rejection episodes, particularly in the pediatric literature. Mohan Shenoy et al. published a case series of 15 patients who were treated with anti thymocyte globulin for steroid-resistant acute allograft rejection over a 15-year period in a single center in this issue of Pediatric Nephrology. While the results for the early rejection group were encouraging, the results in the eight patients with late rejection episodes after transplantation were unfavorable and afflicted with a high incidence of side-effects. Important diagnostic tools such as C4d staining of the renal transplant biopsy and the measurement of donor specific antibodies were underutilized. The editorial reviews the importance of the differentiation between humoral and cellular rejection and the challenges of treating late antibody-mediated acute rejection in these patients. A multi-center approach is required to establish a registry of these events and ideally prospective randomized interventions should be designed to provide some evidence base for the management of this challenging complication after pediatric renal transplantation. PMID- 21327777 TI - The definition of daytime and nighttime influences the interpretation of ABPM in children. AB - To test if an arbitrary definition of day and night periods that differs to patient-reported awake and sleep periods leads to inaccuracies in interpretation of ambulatory blood pressure monitoring (ABPM). A single-center, retrospective review was performed comparing three different methods to classify day and night periods following a single 24-h ABPM: method A: Patient's record during monitoring; method B: 7:00 am to 11:00 pm day and 11:00 pm to 7:00 am night; method C: 8:00 am to 8:00 pm day and midnight to 6:00 am night. We included 149 studies in 149 children with a mean +/- SD age of 13.0 +/- 3.4 years. Reported sleep duration was 9.2 +/- 1.3 h. Significant differences resulted between three methods for the means of several ambulatory BP parameters including indexed BP values during day, BP load, and nocturnal dipping status. During monitoring [median (range)], 7.5% (0.0-27.5%) readings were misclassified using method B and 0.0% (0.0-20.0%) using method C (p < 0.0001). This misclassification resulted in change of hypertension status for 11.4% (17/149) patients using method B and 9.4% (14/149) patients using method C (p = 0.70). Misclassification of measurements during ABPM can introduce significant errors in its interpretation. The clinical impact of these findings needs further evaluation in larger prospective studies. PMID- 21327776 TI - Current perspectives on congenital obstructive nephropathy. AB - Congenital obstructive nephropathy is the leading cause of chronic renal disease in children. As a result, it represents a tremendous societal burden in terms of morbidity and mortality, as well as in health care expenses of caring for children with chronic kidney disease and end-stage renal disease. The various diagnostic, prognostic, and therapeutic challenges associated with congenital obstructive nephropathy highlight the importance of developing effective experimental models for studying this disease process. In this review, we define the clinical entity that is congenital obstructive nephropathy, outline the current standards of diagnosis and care, and discuss the utilization of current experimental models designed to help clarify some of the clinical conundrums associated with this important disease. PMID- 21327778 TI - Glomerular basement membrane composition and the filtration barrier. AB - The glomerular basement membrane (GBM) is an especially thick basement membrane that contributes importantly to the kidney's filtration barrier. The GBM derives from the fusion of separate podocyte and endothelial cell basement membranes during glomerulogenesis and consists primarily of laminin-521 (alpha5beta2gamma1), collagen alpha3alpha4alpha5(IV), nidogens-1 and -2, and agrin. Of these nine proteins, mutations in the genes encoding four of them (LAMB2, COL4A3, COL4A4, and COL4A5) cause glomerular disease in humans as well as in mice. Furthermore, mutation of a fifth (Lama5) gene in podocytes in mice causes proteinuria, nephrotic syndrome, and progression to renal failure. These results highlight the importance of the GBM for establishing and maintaining a properly functioning glomerular filtration barrier. PMID- 21327779 TI - Self-reported quality of life in children and young people with chronic kidney disease. AB - Chronic kidney disease (CKD) would be expected to impact upon the quality of life (QoL) of children and young people; therefore, it is important that they are given the means to express their opinions about how they perceive their own QoL. We used the Generic Children's Quality of Life Measure (GCQ) in 225 paediatric renal patients (118 male, mean age 13.6 years, range 6.2-18.9 years) from seven UK centres. Of these, 47 were on dialysis (23 on haemodialysis), 128 were post transplant (47 pre-emptive) and 49 had advanced CKD. A comparison between the 124 renal patients (65 male, mean age 11.2 years) in the same age range as the general population (6-14 years) showed a higher GCQ QoL score for the renal patients (p = 0.02). Analysis of the whole group of renal patients (n = 225) revealed no significant difference between the mean GCQ scores of participants in various treatment modalities (p = 0.26) and no significant differences between gender (p = 0.90) and age group (p = 0.44). The results indicate that young people can perceive their QoL as good despite living with what others may perceive as severe limitations. This may seem counter-intuitive, but QoL is a subjective measure and thus may be difficult to predict from observable limitations (health status). The GCQ is an ideal measure for use in annual departmental audits of generic paediatric QoL and may help to individualise the work of psychosocial teams with each patient. PMID- 21327782 TI - Phylogeography of rabies virus isolated from dogs in Brazil between 1985 and 2006. AB - To establish the phylogeographic relationships in rabies viruses in Brazil, we studied a dataset retrieved from GenBank consisting of 71 genetic sequences from the coding region of the N gene of rabies viruses isolated in dogs over a period of 22 years. The Bayesian Markov chain Monte Carlo method available in the BEAST package was used with the GTR+G+G4 evolutionary model in conjunction with the relaxed uncorrelated lognormal molecular clock model and an exponential growth tree prior. A discrete phylogeographic diffusion model was also analyzed using a standard continuous-time Markov chain viewed with Google Earth to provide a spatial projection of the diffusion of genetic lineages based on their phylogeographic relationships. The topology of the time and substitution phylogenetic trees agreed with the spatial dispersal of the lineages. It was possible to infer that the lineages in the southeastern region of Brazil in the 1970s are the closest to the most common recent ancestor and that all the lineages in the midwestern, northern and northeastern regions are more distant. The importance of this study lies in the fact that it can help with the planning of rabies control measures, as dogs continue to be the main reservoir of rabies virus throughout the world. PMID- 21327783 TI - Complete nucleotide sequence of a Spanish isolate of alfalfa mosaic virus: evidence for additional genetic variability. AB - Alfalfa mosaic virus (AMV) is a plant virus that is distributed worldwide and can induce necrosis and/or yellow mosaic on a large variety of plant species, including commercially important crops. It is the only virus of the genus Alfamovirus in the family Bromoviridae. AMV isolates can be clustered into two genetic groups that correlate with their geographic origin. Here, we report for the first time the complete nucleotide sequence of a Spanish isolate of AMV found infecting Cape honeysuckle (Tecoma capensis) and named Tec-1. The tripartite genome of Tec-1 is composed of 3643 nucleotides (nt) for RNA1, 2594 nt for RNA2 and 2037 nt for RNA3. Comparative sequence analysis of the coat protein gene revealed that the isolate Tec-1 is distantly related to subgroup I of AMV and more closely related to subgroup II, although forming a distinct phylogenetic clade. Therefore, we propose to split subgroup II of AMV into two subgroups, namely IIA, comprising isolates previously included in subgroup II, and IIB, including the novel Spanish isolate Tec-1. PMID- 21327784 TI - The nonstructural protein pC6 of rice grassy stunt virus trans-complements the cell-to-cell spread of a movement-defective tomato mosaic virus. AB - The nonstructural protein pC6 encoded by rice grassy stunt virus is thought to correspond functionally to the nonstructural protein pC4 of rice stripe virus, which can support viral cell-to-cell movement. In a trans-complementation experiment with a movement-defective tomato mosaic virus, pC6 and pC4 facilitated intercellular transport of the virus. Transient expression of pC6, fused with green fluorescent protein, in epidermal cells was predominantly observed close to the cell wall as well as in a few punctate structures, presumably associated with plasmodesmata. These results suggest that pC6 has a role similar to that of pC4 in viral cell-to-cell movement. PMID- 21327781 TI - Mechanisms of cell polarity and aquaporin sorting in the nephron. AB - The kidneys participate in whole-body homeostasis, regulating acid-base balance, electrolyte concentrations, extracellular fluid volume, and regulation of blood pressure. Many of the kidney's functions are accomplished by relatively simple mechanisms of filtration, reabsorption, and secretion, which take place in the nephron. The kidneys generate 140-180 l of primary urine per day, while reabsorbing a large percentage, allowing for only the excretion of approximately 2 l of urine. Within the nephron, the majority of the filtered water and solutes are reabsorbed. This is mainly facilitated by specialized transporters and channels which are localized at different segments of the nephron and asymmetrically localized within the polarized epithelial cells. The asymmetric localization of these transporters and channels is essential for the physiological tasks of the renal tissues. One family of these proteins are the water-permeable aquaporins which are selectively expressed in cells along the nephron and localized at different compartments. Here, we discuss potential molecular links between mechanisms involved in the establishment of cell polarity and the members of the aquaporin family. In the first part of this review, we will focus on aspects of apical cell polarity. In the second part, we will review the motifs identified so far that are involved in aquaporin sorting and point out potential molecular links. PMID- 21327785 TI - Complete genome sequences of three tomato spotted wilt virus isolates from tomato and pepper plants in Korea and their phylogenetic relationship to other TSWV isolates. AB - Tomato spotted wilt virus (TSWV) infects numerous host plants and has three genome segments, called L, M and S. Here, we report the complete genome sequences of three Korean TSWV isolates (TSWV-1 to -3) infecting tomato and pepper plants. Although the nucleotide sequence of TSWV-1 genome isolated from tomato is very different from those of TSWV-2 and TSWV-3 isolated from pepper, the deduced amino acid sequences of the five TSWV genes are highly conserved among all three TSWV isolates. In phylogenetic analysis, deduced RdRp protein sequences of TSWV-2 and TSWV-3 were clustered together with two previously reported isolates from Japan and Korea, while TSWV-1 grouped together with a Hawaiian isolate. A phylogenetic tree based on N protein sequences, however, revealed four distinct groups of TSWV isolates, and all three Korean isolates belonged to group II, together with many other isolates, mostly from Europe and Asia. Interestingly, most American isolates grouped together as group I. Together, these results suggested that these newly identified TSWV isolates might have originated from an Asian ancestor and undergone divergence upon infecting different host plants. PMID- 21327786 TI - Rescue of Newcastle disease virus from cloned cDNA using an RNA polymerase II promoter. AB - A new system was developed to improve the efficiency and simplify the procedure of recovery of Newcastle disease virus (NDV) from cloned cDNA. A full-length cDNA clone of mesogenic NDV vaccine strain Mukteswar was assembled from five subgenomic cDNA fragments and cloned into a plasmid allowing transcription driven by cellular RNA polymerase II. The full-length viral cDNA was flanked by hammerhead ribozyme (HamRz) and hepatitis delta virus ribozyme (HdvRz) sequences, resulted in the synthesis of antigenomic RNA with exact termini. Without supplying T7 RNA polymerase, infectious NDV could be generated efficiently in some eukaryotic cell lines by simultaneous transcription of antigenomic RNA from the full-length plasmid and expression of NP, P and L proteins from helper plasmids introduced by cotransfection. The efficiency of recovery with the conventional T7 promoter system based on BRS-T7 cells and the cytomegalovirus (CMV) promoter system was compared, and the results demonstrate that the new system facilitates the generation of recombinant NDV and more efficient than the T7 rescue system using BRS-T7. PMID- 21327787 TI - Comparison of capsid gene sequences of turkey astrovirus-2 from poult-enteritis syndrome-affected and apparently healthy turkeys. AB - This study was conducted to determine genetic variations in the capsid gene of turkey astrovirus-2 (TAstV-2) detected in apparently healthy and poult enteritis syndrome (PES)-affected turkeys. Capsid genes of astroviruses obtained from 30 PES-affected and 45 apparently healthy turkey flocks had sequence homologies of 73.4-100% and 72.4-100% at the nucleotide levels, respectively. The analysis of deduced amino acid sequences revealed one amino acid deletion at position 552 in 28 (93.3%) of 30 PES-affected cases. However, there were two deletions (at positions 551 and 552) in 31 (68.9%) of 45 TAstV-2 from apparently healthy flocks. The TAstV-2 (6.7%) from two PES-affected cases had two amino acid insertions each between positions 552 and 553, while TAstV-2 from 14 (31.1%) of 45 healthy flocks had two insertions at the same position. Phylogenetic analysis based on nucleotide sequences revealed that the astroviruses in this study were closely related to most of the previously published TAstV-2 isolates. The sequence homology of TAstV-2 in this study ranged from 70.4% to 99.4% at the nucleotide level with those of previously published TAstV-2 isolates. The variations at the amino acid level in the capsid gene suggest the possibility of the existence of different serotypes of turkey astrovirus. The close relationship of turkey astroviruses from apparently healthy flocks to those from PES-affected cases in capsid gene phylogeny necessitates further studies to compare complete capsid gene sequences from both types of flocks from different geographic areas for better understanding of TAstV circulating in turkeys. PMID- 21327788 TI - Auricular chromoblastomycosis: a case report and review of published literature. AB - Subcutaneous chromoblastomycosis is an infection commonly seen in tropical and subtropical climates, usually caused by trauma with vegetables and often affects the host's lower limbs. We report a case of auricular chromoblastomycosis in a 67 year-old man and discuss the rarity of this clinical manifestation of chromoblastomycosis in the medical literature. In the present case, the etiologic agent was Fonsecaea pedrosoi, the most common agent found in Brazil. PMID- 21327789 TI - Gamma radiation effects on Sporothrix schenckii yeast cells. AB - Sporotrichosis is a subcutaneous mycosis caused by Sporothrix schenckii. Zoonotic transmission to man can occur after scratches or bites of animals, mainly cats. In this study, the gamma radiation effects on yeast of S. schenckii were analyzed with a view of developing a radioattenuated vaccine for veterinary use. The cultures were irradiated at doses ranging from 1.0 to 9.0 kGy. The reproductive capacity was measured by the ability of cells to form colonies. No colonies could be recovered above 8.0 kGy, using inocula up to 10(7) cells. Nevertheless, yeast cells irradiated with 7.0 kGy already were unable to produce infection in immunosuppressed mice. Evaluation by the FungaLightTM Kit (Invitrogen) indicated that yeast cells remained viable up to 9.0 kGy. At 7.0 kGy, protein synthesis, estimated by the incorporation of [L-(35)S] methionine, continues at levels slightly lower than the controls, but a significant decrease was observed at 9.0 kGy. The DNA of 7.0 kGy irradiated cells, analyzed by electrophoresis in agarose gel, was degraded. Cytoplasmic vacuolation was the main change verified in these cells by transmission electron microscopy. The dose of 7.0 kGy was considered satisfactory for yeast attenuation since irradiated cells were unable to produce infection but retained viability, metabolic activity, and morphology. PMID- 21327790 TI - Occurrence of ochratoxin A in grain and manufactured food products in China detected by HPLC with fluorescence detection and confirmed by LC-ESI-MS/MS. AB - A total of 110 commercially available samples of manufactured food products including bread, oat, barley, maize, corn, wheat, grape, soluble coffee, soya bean, red wine, and baby food were randomly collected in the northeast of China during the first six months of 2010. Samples were analyzed for the presence of ochratoxin A (OTA) using immunoaffinity column (IAC) clean-up and high performance liquid chromatography with fluorescence detection (HPLC-FD) and confirmed with LC-ESI-MS/MS. The range of average OTA recoveries was 78.3-103.3% at three spiked levels. The relative standard deviations (RSDs) of recoveries range of 2.1-4.3%. OTA were detected in 13 samples, which were below the maximum allowable limit established by the European Community. The results of this study suggest that those manufactured food products consumed in China present no risk by human exposure to OTA through their consumption. PMID- 21327791 TI - The -14010*C variant associated with lactase persistence is located between an Oct-1 and HNF1alpha binding site and increases lactase promoter activity. AB - In most people worldwide intestinal lactase expression declines in childhood. In many others, particularly in Europeans, lactase expression persists into adult life. The lactase persistence phenotype is in Europe associated with the -13910*T single nucleotide variant located 13,910 bp upstream the lactase gene in an enhancer region that affects lactase promoter activity. This variant falls in an Oct-1 binding site and shows greater Oct-1 binding than the ancestral variant and increases enhancer activity. Several other variants have been identified very close to the -13910 position, which are associated with lactase persistence in the Middle East and Africa. One of them, the -14010*C, is associated with lactase persistence in Africa. Here we show by deletion analysis that the -14010 position is located in a 144 bp region that reduces the enhancer activity. In transfections the -14010*C allele shows a stronger enhancer effect than the ancestral -4010*G allele. Binding sites for Oct-1 and HNF1alpha surrounding the 14010 position were identified by gel shift assays, which indicated that -14010*C has greater binding affinity to Oct-1 than -14010*G. PMID- 21327792 TI - Variability in pulmonary function following rapid altitude ascent to the Amundsen Scott South Pole station. AB - The impact of acute altitude exposure on pulmonary function is variable. A large inter-individual variability in the changes in forced expiratory flows (FEFs) is reported with acute exposure to altitude, which is suggested to represent an interaction between several factors influencing bronchial tone such as changes in gas density, catecholamine stimulation, and mild interstitial edema. This study examined the association between FEF variability, acute mountain sickness (AMS) and various blood markers affecting bronchial tone (endothelin-1, vascular endothelial growth factor (VEGF), catecholamines, angiotensin II) in 102 individuals rapidly transported to the South Pole (2835 m). The mean FEF between 25 and 75% (FEF(25-75)) and blood markers were recorded at sea level and after the second night at altitude. AMS was assessed using Lake Louise questionnaires. FEF(25-75) increased by an average of 12% with changes ranging from -26 to +59% from sea level to altitude. On the second day, AMS incidence was 36% and was higher in individuals with increases in FEF(25-75) (41 vs. 22%, P = 0.05). Ascent to altitude induced an increase in endothelin-1 levels, with greater levels observed in individuals with decreased FEF(25-75). Epinephrine levels increased with ascent to altitude and the response was six times larger in individuals with decreased FEF(25-75). Greater levels of endothelin-1 in individuals with decreased FEF(25-75) suggest a response consistent with pulmonary hypertension and/or mild interstitial edema, while epinephrine may be upregulated in these individuals to clear lung fluid through stimulation of beta(2)-adrenergic receptors. PMID- 21327793 TI - Hypothermia following exertional heat stroke treatment. AB - Exertional heat stroke (EHS) is a life-threatening condition, which deteriorates rapidly. Immediate cooling treatment can, therefore, be life saving. Over the past two winters, we witnessed three cases of hypothermia resulting from treatment of suspected EHS. Since no such cases were described in the literature before, we, therefore, in this study present one of those cases. In addition, recommended approaches for proper management of similar situations are discussed. We suggest that in order to avoid hypothermia following aggressive cooling, core temperature (T (core)) should be continuously monitored. Upon reaching 38 degrees C, cooling must be discontinued, and the patient should be dried and covered. PMID- 21327794 TI - Physiological elevation of endogenous hormones results in superior strength training adaptation. AB - The purpose of this study was to determine the influence of transiently elevated endogenous hormone concentrations during exercise on strength training adaptations. Nine subjects performed four unilateral strength training session per week on the elbow flexors for 11 weeks. During two of the weekly sessions, leg exercises were performed to acutely increase the systemic anabolic hormone concentration immediately before the exercises for one of the elbow flexors (L + A). On the two other weekly training sessions, the contralateral elbow flexors were trained without prior leg exercises (A). By randomizing one arm of the subjects to serve as a control and the other as experimental, both conditions have the same nutritional and genetic environment. Serum testosterone and growth hormone was significantly increased during the L - A training session, while no hormonal changes occurred in the A session. Both A and L + A increased 1RM in biceps curl, peak power in elbow flexors at 30 and 60% of 1RM, and muscle volume of the elbow flexors (p < 0.05). However, only L + A achieved increase in CSA at the part of the arm flexors with largest cross sectional area (p < 0.001), while no changes occurred in A. L + A had superior relative improvement in 1RM biceps curl and favorable muscle adaptations in elbow flexors compared to A (p < 0.05). In conclusion, performing leg exercises prior to arm exercises, and thereby increasing the levels of serum testosterone and growth hormone, induced superior strength training adaptations compared to arm training without acute elevation of hormones. PMID- 21327795 TI - NT-ProBNP levels, water and sodium homeostasis in healthy men: effects of 7 days of dry immersion. AB - Immersion is a useful tool for studying fluid-volume homeostasis. Natriuretic peptides play a vital role in renal, humoral, and cardiovascular regulation under changing environmental conditions. We hypothesized that dry immersion would rapidly induce a new steady state for water and sodium metabolism, and that serum NT-proBNP levels, a proxy measure for brain natriuretic peptide (BNP), would decrease during long-term dry immersion and increase during recovery. Eight healthy young men were studied before, during, and after 7 days of dry immersion. Body weight, water balance, and plasma volume changes were evaluated. Plasma and serum samples were analyzed for active renin, NT-proBNP, aldosterone, electrolytes, osmolality, total protein, and creatinine. Urine samples were analyzed to determine levels of electrolytes, osmolality, creatinine, and free cortisol. A stand test was performed before and after dry immersion to evaluate cardiovascular deconditioning. Long-term dry immersion induced acute changes in water and sodium homeostasis on day 1, followed by a new steady state. Plasma volume decreased significantly during dry immersion. The serum levels of NT proBNP increased significantly in recovery (10 +/- 3 ng/L before dry immersion vs. 26 +/- 5 ng/L on the fourth recovery day). Heart rate in the standing position was significantly greater after immersion. Results suggest that chronic dry immersion rapidly induced a new level of water-electrolyte homeostasis. The increase in NT-proBNP levels during the recovery period may be related to greater cardiac work and might reflect the degree of cardiovascular deconditioning. PMID- 21327796 TI - Effects of beta2-adrenergic stimulation on exercise capacity in normal subjects. AB - beta2-Adrenergic receptor agonists are believed to present with ergogenic properties. However, how combined respiratory, cardiovascular and muscular effects of these drugs might affect exercise capacity remain incompletely understood. The effects of salbutamol were investigated in 23 healthy subjects. The study was randomised, placebo-controlled in double-blind and followed a cross over design. Salbutamol was given at the dose of 10 MUg/min in 11 subjects and 20 MUg/min iv in the other 12 subjects. Measurements included muscle sympathetic nerve activity (MSNA), ventilatory responses to hyperoxic hypercapnia (7% CO(2) in O(2,) central chemoreflex), isocapnic hypoxia (10% O(2) in N(2), peripheral chemoreflex) and isometric muscle contraction followed by a local circulatory arrest (metaboreflex), cardiopulmonary exercise test (CPET) variables and isokinetic muscle strength. Salbutamol 10 MUg/min increased heart rate and blood pressure, while MSNA burst frequency remained unchanged. Peripheral chemosensitivity increased, as evidenced by an increased ventilatory response to hypoxia, but ventilatory responses to hypercapnia or muscle ischaemia remained unchanged. The effects of salbutamol 20 MUg/min were similar. Both doses of salbutamol did not affect CPET. Only the higher dose of salbutamol decreased the anaerobic threshold, but this was not associated with a change in VO(2) max. Salbutamol increased the slopes of ventilation as a function of VO(2) (P < 0.05) and VCO(2) (P < 0.001) during CPET. Maximal isokinetic muscle strength was not affected by salbutamol. In conclusion, the acute administration of either low or high dose salbutamol does not affect exercise capacity in normal subjects, in spite of an earlier anaerobic threshold and increased chemosensitivity. PMID- 21327797 TI - The effect of HMB supplementation on body composition, fitness, hormonal and inflammatory mediators in elite adolescent volleyball players: a prospective randomized, double-blind, placebo-controlled study. AB - The use of ergogenic nutritional supplements is becoming inseparable from competitive sports. beta-Hydroxy-beta-Methylbutyric acid (HMB) has recently been suggested to promote fat-free mass (FFM) and strength gains during resistance training in adults. In this prospective randomized, double-blind, placebo controlled study, we studied the effect of HMB (3 g/day) supplementation on body composition, muscle strength, anaerobic and aerobic capacity, anabolic/catabolic hormones and inflammatory mediators in elite, national team level adolescent volleyball players (13.5-18 years, 14 males, 14 females, Tanner stage 4-5) during the first 7 weeks of the training season. HMB led to a significant greater increase in FFM by skinfold thickness (56.4 +/- 10.2 to 56.3 +/- 8.6 vs. 59.3 +/- 11.3 to 61.6 +/- 11.3 kg in the control and HMB group, respectively, p < 0.001). HMB led to a significant greater increase in both dominant and non-dominant knee flexion isokinetic force/FFM, measured at fast (180 degrees /sec) and slow (60 degrees /sec) angle speeds, but had no significant effect on knee extension and elbow flexion and extension. HMB led to a significant greater increase in peak and mean anaerobic power determined by the Wingate anaerobic test (peak power: 15.5 +/- 1.6 to 16.2 +/- 1.2 vs. 15.4 +/- 1.6 to 17.2 +/- 1.2 watts/FFM, mean power: 10.6 +/- 0.9 to 10.8 +/- 1.1 vs. 10.7 +/- 0.8 to 11.8 +/- 1.0 watts/FFM in control and HMB group, respectively, p < 0.01), with no effect on fatigue index. HMB had no significant effect on aerobic fitness or on anabolic (growth hormone, IGF-I, testosterone), catabolic (cortisol) and inflammatory mediators (IL-6 and IL-1 receptor antagonist). HMB supplementation was associated with greater increases in muscle mass, muscle strength and anaerobic properties with no effect on aerobic capacity suggesting some advantage for its use in elite adolescent volleyball players during the initial phases of the training season. These effects were not accompanied by hormonal and inflammatory mediator changes. PMID- 21327798 TI - Effectiveness of low-frequency vibration recovery method on blood lactate removal, muscle contractile properties and on time to exhaustion during cycling at VO2max power output. AB - The aim of the study was to determine the effectiveness of low-frequency vibration recovery (LFV-rec) on blood lactate removal, muscle contractile properties, and on time to exhaustion during cycling at maximal oxygen uptake power output (pVO(2max)). Twelve active males carried out three experimental sessions. In session 1, participant's maximal oxygen uptake (VO(2max)) and pVO(2max) were determined, and in sessions 2 and 3, the participants performed a fatiguing exercise (2 min of cycling at pVO(2max)) and then a 15 min recovery period using one of two different methods: LFV-rec which consisted on sitting with feet on the vibratory platform (20 Hz; 4 mm) and passive recovery (P-rec), sitting without vibration stimulus. After that, participants performed an all-out exercise test on cycle ergometer at pVO(2max). In the recovery period, variables such as heart rate (HR), blood lactate concentration [Lac], and tensiomyographic parameters (D (m): maximal radial displacement; T (s): time of contraction maintenance, and T (r): relaxation time) were measured. In an all-out exercise test, mean time to exhaustion (TTE), total distance covered (TD), mean cycling velocity (V (m)), and maximal HR (HR(max)) were also assessed. The results showed no effect of recovery strategy on any of the assessed variables; nevertheless, higher values, although not significant, were observed in TTE, TD, and V (m) after LFV-rec intervention. In conclusion, LFV-rec strategy applied during 15 min after short and intense exercise does not seem to be effective on blood lactate removal, muscle contractile properties, and on time to exhaustion during cycling at pVO(2max). PMID- 21327799 TI - Analysis of marginal adaptation and sealing to enamel and dentin of four self adhesive resin cements. AB - This in vitro study compared the marginal adaptation of all-ceramic MOD-inlays luted to human molars with four self-adhesive resin cements. Thirty-two human third molars were randomly assigned to four test groups (n = 8 per group). MOD cavities were prepared with approximal finishing lines in dentin and enamel. All ceramic Empress 2 inlays were luted with four self-adhesive cements (Clearfil SA, iCEM, Bifix SE, seT). Oral stress was simulated by 90 day storage in water as well as by thermal and mechanical loading (TCML, 1.2 * 10(6) * 50 N, 6,000 * 5 degrees /55 degrees , 1.6 Hz). The marginal fit was evaluated by scanning electron microscopy (SEM) and dye penetration. Data were analyzed with the ANOVA/Tukey's test (alpha = 0.05). The SEM investigation of the gingival cement margins (cement-tooth interface) showed values of perfect margin [percent] (means +/- SD) after simulated aging between 84 +/- 9% and 95 +/- 5% for enamel and 80 +/- 9% and 92 +/- 3% for dentin. In enamel, seT showed significantly higher marginal integrity than iCEM after water storage and TCML (post hoc; p = 0.011). Furthermore, the marginal adaptation of iCEM in enamel deteriorated by simulated aging (p = 0.014, ANOVA). Mean values of dye penetration (percentage of dye entry into dentin) at the investigated restorations margins ranged between 3% and 8% for enamel and 12% and 22% for dentin. Clearfil SA, iCEM, and seT showed lower dye penetration in enamel than in dentin (Clearfil SA: p = 0.013, iCEM: p = 0.044, seT: p = 0.003). The results suggest that the four self-adhesive luting agents investigated seem to successfully bond to dentin-restricted as well as to enamel-restricted cavities, predicting good clinical performance. PMID- 21327800 TI - Clinical significance of progesterone receptor and HER2 status in estrogen receptor-positive, operable breast cancer with adjuvant tamoxifen. AB - PURPOSE: To evaluate prognostic factors in estrogen receptor (ER)-positive, operable breast cancer focusing on the progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). PATIENTS AND METHODS: A total of 819 patients with ER-positive, operable breast cancer were enrolled. All patients received upfront adjuvant tamoxifen, as stipulated by eligibility criteria. Prognostic values of the PR status and HER2 status were evaluated using Cox regression. RESULTS: Of all patients enrolled, 72% were PR positive and 20% were HER2 positive. PR and HER2 status were inversely correlated (P = 0.014). PR negative tumors were associated with older age over 50 years (P < 0.001) and higher histologic grade (P = 0.024). HER2 overexpression correlated with older age over 50 years (P = 0.007), higher T stage (P = 0.010), and higher histologic grade (P = 0.047). For recurrence, PR negativity was a poor prognostic factor before 5 years postsurgery (hazard ratio = 1.57; P = 0.049) and HER2 overexpression was a consistent poor prognostic factor over all time periods (hazard ratio = 1.93; P = 0.001) in the multivariate model adjusted by age, T/N stage, and histologic grade. CONCLUSIONS: In ER-positive, operable breast cancer, PR negativity may provide additional information on poor prognosis or tamoxifen resistance during adjuvant tamoxifen therapy within 5 years postsurgery. HER2 overexpression was a poor prognostic factor consistently throughout time. This suggests that an alternative adjuvant strategy, possibly incorporating prolonged HER2-targeted therapy, needs to be evaluated for HER2-overexpressing tumors. PMID- 21327801 TI - Rupture of intrapartum unscarred uterus at the fundus: a complication of passive cocaine abuse? AB - Uterine rupture is a potential obstetric catastrophe. We report a case of a gravida 2 para 1 with intrapartum unscarred uterine fundal rupture. Immediate resuscitation, laparotomy and hysterectomy, was done with maternal survival. History of passive cocaine smoke exposure elicited postoperatively was the possible etiology leading to complete fundal rupture. This case is an eye opener as regards to ill effects of drug abuse even though passive. A careful history of drug abuse must be elicited when the common causes of uterine rupture have been excluded or the rupture site is unusual. PMID- 21327802 TI - Obstetric outcome following cervical conization. AB - OBJECTIVE: The purpose of the present study was to examine obstetric outcome of patients following conization and specifically the risk for preterm delivery (PTD). METHODS: A population-based study was performed comparing pregnancies in women following conization with those who had not undergone the procedure. Stratified analysis, using a multiple logistic regression model was performed to control for confounders. RESULTS: Out of 104,670 deliveries, 53 women (0.05%) had undergone conization. Most conizations were performed using loop electrosurgical excision procedure (LEEP). Using multivariable analysis, the following conditions were significantly associated with conization: advanced maternal age, PTD before the 34th week, low birth weight, and cervical incompetence with cerclage. Higher rates of perinatal mortality were noted in pregnancies of women with conization, but after controlling for PTD, the association lost its significance. The risk of PTD <34 weeks was significantly higher than the comparison group (OR 7.73 95% CI 3.77-15.85, p < 0.001). This association remained significant after controlling for confounders, such as cervical incompetence, smoking, maternal age, birth order and year of delivery (OR 2.8 95% CI 1.3-6.1, p = 0.008). When comparing pregnancy outcomes of women with and without cerclage due to cervical incompetence, no significant differences were documented. CONCLUSIONS: A clear association exists between conization and PTD before the 34th week. This association persists after controlling for variables considered to coexist with PTD. Careful surveillance is required in pregnancies of women following conization for early detection of preterm contractions and PTD. PMID- 21327803 TI - Isolation and characterization of RDX-degrading Rhodococcus species from a contaminated aquifer. AB - Groundwater contamination by the explosive hexahydro-1,3,5-trinitro-1,3,5 triazine (RDX) is a global problem. Israel's coastal aquifer was contaminated with RDX. This aquifer is mostly aerobic and we therefore sought aerobic bacteria that might be involved in natural attenuation of the compound in the aquifer. RDX degrading bacteria were captured by passively sampling the indigenous bacteria onto sterile sediments placed within sampling boreholes. Aerobic RDX biodegradation potential was detected in the sediments sampled from different locations along the plume. RDX degradation with the native sampled consortium was accompanied by 4-nitro-2,4-diazabutanal formation. Two bacterial strains of the genus Rhodococcus were isolated from the sediments and identified as aerobic RDX degraders. The xplA gene encoding the cytochrome P450 enzyme was partially (~500 bp) sequenced from both isolates. The obtained DNA sequences had 99% identity with corresponding gene fragments of previously isolated RDX-degrading Rhodococcus strains. RDX degradation by both strains was prevented by 200 MUM of the cytochrome P450 inhibitor metyrapone, suggesting that cytochrome P450 indeed mediates the initial step in RDX degradation. RDX biodegradation activity by the T7 isolate was inhibited in the presence of nitrate or ammonium concentrations above 1.6 and 5.5 mM, respectively (100 mg l(-1)) while the T9N isolate's activity was retarded only by ammonium concentrations above 5.5 mM. This study shows that bacteria from the genus Rhodococcus, potentially degrade RDX in the saturated zone as well, following the same aerobic degradation pathway defined for other Rhodococcus species. RDX-degrading activity by the Rhodococcus species isolate T9N may have important implications for the bioremediation of nitrate rich RDX-contaminated aquifers. PMID- 21327804 TI - Characterisation of the initial degradation stage of Scots pine (Pinus sylvestris L.) sapwood after attack by brown-rot fungus Coniophora puteana. AB - In our study, early period degradation (10 days) of Scots pine (Pinus sylvestris L.) sapwood by the brown-rot fungus Coniophora puteana (Schum.: Fr.) Karst. (BAM Ebw.15) was followed at the wood chemical composition and ultrastructure-level, and highlighted the generation of reactive oxygen species (ROS). An advanced decay period of 50 days was chosen for comparison of the degradation dynamics. Scanning UV microspectrophotometry (UMSP) analyses of lignin distribution in wood cells revealed that the linkages of lignin and polysaccharides were already disrupted in the early period of fungal attack. An increase in the lignin absorption A(280) value from 0.24 (control) to 0.44 in decayed wood was attributed to its oxidative modification which has been proposed to be generated by Fenton reaction derived ROS. The wood weight loss in the initial degradation period was 2%, whilst cellulose and lignin content decreased by 6.7% and 1%, respectively. Lignin methoxyl (-OCH3) content decreased from 15.1% (control) to 14.2% in decayed wood. Diffuse reflectance Fourier-transform infrared (DRIFT) spectroscopy corroborated the moderate loss in the hemicellulose and lignin degradation accompanying degradation. Electron paramagnetic resonance spectra and spin trapping confirmed the generation of ROS, such as hydroxyl radicals (HO?), in the early wood degradation period. Our results showed that irreversible changes in wood structure started immediately after wood colonisation by fungal hyphae and the results generated here will assist in the understanding of the biochemical mechanisms of wood biodegradation by brown-rot fungi with the ultimate aim of developing novel wood protection methods. PMID- 21327805 TI - Oral melatonin, dexmedetomidine, and midazolam for prevention of postoperative agitation in children. AB - PURPOSE: Several studies have reported that sevoflurane was associated with a relatively high incidence of emergence agitation in children even in the absence of any surgical intervention. The aim of this study was to compare early agitation characteristics of oral melatonin, dexmedetomidine, and midazolam premedication in children who were given sevoflurane anesthesia for esophageal dilatation. METHODS: Following Internal Review Board approval and parental informed consent, 100 ASA physical status I-II children (3-9 years old) who were scheduled to undergo general anesthesia for esophageal dilatation procedures were enrolled. The patients were randomly assigned to four groups (n = 25 in each). The premedications in the groups were saline (group P), dexmedetomidine 2.5 MUg/kg (group D), 0.5 mg/kg midazolam (group MD), and melatonin 0.1 mg/kg (group ML), given orally. All premedication drugs were given with paracetamol 2-2.5 mg/kg to be easily drinkable 40-45 min before anesthesia induction. Anesthesia was maintained with sevoflurane 2-4%, N(2)O 50% in oxygen. No supplemental analgesic agent was given, and an emergence agitation scale (EAS) was measured on admission to the PACU, then every 5 min, and recorded during the postoperative period: 1, awake and calm, cooperative; 2, crying, requires consoling; 3, irritable/restless, screaming, inconsolable; 4, combative, disoriented, thrashing. Children with an agitation score of 3 or 4 were classified as agitated. RESULTS: There were no significant differences among the four groups demographically. The emergence agitation scale was higher in the placebo group than in the others at 5, 10, and 15 min postoperatively (P < 0.001). EA was similar among group D, group MD, and group ML. CONCLUSION: We found that oral melatonin, dexmedetomidine, and midazolam reduced the incidence of emergence agitation in children after sevoflurane anesthesia. PMID- 21327806 TI - The effect of ketamine on tracheal intubating conditions without neuromuscular blockade during sevoflurane induction in children. AB - PURPOSE: The purpose of this study was to investigate the effect of ketamine on intubating conditions for tracheal intubation during anesthesia induction with sevoflurane and alfentanil in pediatric patients. METHODS: After obtaining parental consents, 50 children, aged 3-10 years, were randomly allocated into two groups to receive either i.v. ketamine 0.5 mg/kg (ketamine group, n = 25) or i.v. saline 5 ml (control saline group, n = 25). One minute after injection of the study drug (ketamine or saline), anesthesia was induced with 5% sevoflurane, followed by injection of alfentanil 10 MUg/kg 1 min later. The trachea was intubated 4 min after inhalational induction of anesthesia. Acceptable intubation was defined as excellent or good intubating conditions. Mean arterial pressure (MAP) and heart rate (HR) were recorded during the induction period. RESULTS: The percentage of patients with acceptable intubating conditions was higher in the ketamine group (87%) than in the control group (52%) (P = 0.0129). MAP before intubation was significantly lower in the control group than in the ketamine group (P = 0.001). CONCLUSION: This study demonstrated that administration of ketamine 0.5 mg/kg could improve intubating conditions for tracheal intubation without neuromuscular blockade and preserve hemodynamic stability during sevoflurane inhalation induction with alfentanil in children. PMID- 21327807 TI - Effect of site-specific bronchial radon progeny deposition on the spatial and temporal distributions of cellular responses. AB - Inhaled short-lived radon progenies may deposit in bronchial airways and interact with the epithelium by the emission of alpha particles. Simulation of the related radiobiological effects requires the knowledge of space and time distributions of alpha particle hits and biological endpoints. Present modelling efforts include simulation of radioaerosol deposition patterns in a central bronchial airway bifurcation, modelling of human bronchial epithelium, generation of alpha particle tracks, and computation of spatio-temporal distributions of cell nucleus hits, cell killing and cell transformation events. Simulation results indicate that the preferential radionuclide deposition at carinal ridges plays an important role in the space and time evolution of the biological events. While multiple hits are generally rare for low cumulative exposures, their probability may be quite high at the carinal ridges of the airway bifurcations. Likewise, cell killing and transformation events also occur with higher probability in this area. In the case of uniform surface activities, successive hits as well as cell killing and transformation events within a restricted area (say 0.5 mm(2)) are well separated in time. However, in the case of realistic inhomogeneous deposition, they occur more frequently within the mean cycle time of cells located at the carinal ridge even at low cumulative doses. The site-specificity of radionuclide deposition impacts not only on direct, but also on non-targeted radiobiological effects due to intercellular communication. Incorporation of present results into mechanistic models of carcinogenesis may provide useful information concerning the dose-effect relationship in the low-dose range. PMID- 21327808 TI - Amendments to (63)Ni production calculation for Hiroshima by Takamiya et al. and DS02 fluence data by Egbert et al. AB - In a previous paper, Takamiya et al. calculated (63)Ni production in copper samples exposed to the Hiroshima atomic bomb. More specifically, they used their experimental cross-section values of the (63)Cu(n,p)(63)Ni reaction and compared the result with that of the corresponding calculation in the radiation dosimetry system DS02, which used another set of cross-section values. These results were different, and the following two reasons were found: typographical errors in several energy boundary values in the DS02 report that was also used in the calculation by Takamiya et al. and an inappropriate assumption on the cross section values of the low neutron energy region in the calculation by Takamiya et al. These two issues are described and amended in the present report. PMID- 21327809 TI - [Is polytrauma affordable these days? G-DRG system vs per diem charge based on 1,030 patients with multiple injuries]. AB - The introduction of diagnosis-related groups (DRG) in Germany comprises the risk of a non-cost-effective reimbursement in complex medical treatments. The aim of this study was to compare the reimbursement between the DRG system and the system of hospital per diem charge in effect until now. MATERIAL AND METHODS: The G-DRG (Version 2004) reimbursement was calculated for 1,030 polytrauma patients (average ISS 26.4) treated at the BGU Murnau from 2000 to 2004, using a base value of 2900 euros, and compared to the reimbursement of hospital per diem charge. RESULTS: Just half of all polytrauma patients are classified as a polytrauma according to the DRG (18.7%) or as requiring artificial respiration based on the DRG (29.1%). The average G-DRG reimbursement was 27,157 euros vs 36,387 euros (74.6%). Patients with minor trauma, increasing age, high GCS, ICU stay without artificial respiration, trauma of the upper extremity and patients who survived show the greatest discrepancy. CONCLUSION: A revision of the G-DRG definition of polytrauma is necessary to ensure adequate reimbursement for management of patients with multiple injuries. The severity of a trauma has to be considered in the DRG system. PMID- 21327810 TI - [Evaluation of a 2D fluoroscopy-based navigation system for insertion of femoral neck screws. An experimental study]. AB - INTRODUCTION: The aim of this study was the evaluation of a new computer-assisted planning and navigation system based on 2D-fluoroscopy for guidewire insertion in order to perform cannulated screw placement into the femoral neck. The image acquisition process was supported by a radiation-saving procedure called Zero dose C-arm navigation. MATERIAL AND METHODS: In the context of a sawbone study, we performed insertion of 3 cannulated screws positioned under navigation control as well as using the conventional technique in 12 sawbones. Both procedures were performed using open and closed techniques. RESULTS: The computer-assisted technique significantly reduced the amount of intraoperative fluoroscopic images (open technique: -14+/-3 images, closed technique: -29.4+/-6 images). Drilling attempts were reduced in the computer-assisted groups (open technique: -1.2+/-1 attempts, closed technique: -1.7+/-1.5 attempts) and the femoral neck area covered by the screws was greater in the navigation-assisted groups (open technique: +32.1+/-16.3 mm(2), closed technique: +32.6+/-14.9 mm(2)), There was no difference concerning parallelism of the screws or perforation of femoral neck or head. The operation time was significantly longer in the navigation-assisted groups (open technique: +24.2+/-2.1 min, closed technique: +22.8+/-5.8 min). CONCLUSION: The addition of computer-assisted planning and surgical guidance supported by Zero-dose C-arm navigation can be useful for the fixation of medial femoral neck fractures with cannulated screws. Further studies with the goal of reducing the operation time are indispensable before integrating this navigation system into the clinical workflow. PMID- 21327811 TI - [Endovascular treatment of traumatic ruptures of the thoracic aorta]. AB - Traumatic rupture of the descending aorta is an acute life-threatening event. The most common cause is deceleration trauma resulting in a sudden stretching of the aortic isthmus as for example in car and motorcycle accidents and falls from a great height. Exemplified by a case report of a multiply injured 57-year-old male the diagnostic pathways, therapy and postoperative complications are presented. PMID- 21327812 TI - Posterior arch defect in a dry atlas. PMID- 21327813 TI - Evaluation of tenoxicam on prevention of arachnoiditis in rat laminectomy model. AB - Post laminectomy arachnoiditis has been shown by experiments with rats and post operative radiological imaging in humans. The purpose of this experimental study was to determine the efficacy of tenoxicam in preventing arachnoiditis in rats. Twenty-four Wistar rats were divided into two groups, and L3 laminectomy was performed. In the tenoxicam group, 0.5 mg/kg tenoxicam was applied intraperitoneally. Normal saline was applied intraperitoneally in the control group. Later, the rats were killed at weeks 3 and 6, and the laminectomy sites were evaluated pathologically for arachnoiditis. The results showed that 6 weeks after surgery, the tenoxicam group showed lowest arachnoiditis grades. However, statistically significant difference was not found in arachnoiditis between the control group and the tenoxicam group. Based on these findings it is concluded that application of the tenoxicam after lumbar laminectomy did not effectively reduce arachnoiditis. Performing the most effective surgical technique without damage around tissue in a small surgical wound and having meticulous hemostasis in surgery seem to be the key for preventing arachnoiditis effectively. PMID- 21327814 TI - A fresh look at the nucleus-endplate region: new evidence for significant structural integration. AB - The disc nucleus is commonly thought of as a largely unstructured gel. However, exactly how the nucleus integrates structurally with the endplates remains somewhat ambiguous. The purpose of this study was to investigate whether a substantial level of structural/mechanical cohesion does, in fact, exist across the nucleus-endplate junction. Vertebra-nucleus-vertebra samples were obtained from mature ovine lumbar motion segments and subjected to a novel technique involving circumferential transverse severing (i.e. ring-severing) of the annulus fibrosus designed to eliminate its strain-limiting influence. These samples were loaded in tension and then chemically fixed in order to preserve the stretched nucleus material. Structural continuity across the nucleus-endplate junctions was sufficient for the samples to support, on average, 20 N before tensile failure occurred. Microscopic examination revealed nucleus fibres inserting into the endplates and the significant level of load carried by the nucleus material indicates that there is some form of structural continuity from vertebra to vertebra in the central nucleus region. PMID- 21327815 TI - A role for the anaphase promoting complex in hormone regulation. AB - To increase our knowledge of anaphase promoting complex (APC/C) function during plant development, we characterized an Arabidopsis thaliana T-DNA-insertion line where the T-DNA fell within the 5' regulatory region of the APC10 gene. The insert disrupted endogenous expression, resulting in overexpression of APC10 mRNA from the T-DNA- internal CaMV 35S promoter, and increased APC10 protein. Overexpression of APC10 produced phenotypes resembling those of known auxin and ethylene mutants, and increased expression of two tested auxin-regulated genes, small auxin up RNA (SAUR) 15 and SAUR24. Taken together, our data suggests that elevated APC10 likely mimics auxin and ethylene sensitive phenotypes, expanding our understanding of proteolytic processes in hormone regulation of plant development. PMID- 21327816 TI - Leaf proteomic analysis in cassava (Manihot esculenta, Crantz) during plant development, from planting of stem cutting to storage root formation. AB - Tuberization in cassava (Manihot esculenta Crantz) occurs simultaneously with plant development, suggesting competition of photoassimilate partitioning between the shoot and the root organs. In potato, which is the most widely studied tuber crop, there is ample evidence suggesting that metabolism and regulatory processes in leaf may have an impact on tuber formation. To search for leaf proteins putatively involved in regulating tuber generation and/or development in cassava, comparative proteomic approaches have been applied to monitor differentially expressed leaf proteins during root transition from fibrous to tuberous. Stringent cross comparison and statistical analysis between two groups with different plant ages using Student's t test with 95% significance level revealed a number of protein spots whose abundance were significantly altered (P < 0.05) during week 4 to week 8 of growth. Of these, 39 spots were successfully identified by ion trap LC-MS/MS. The proteins span various functional categories from antioxidant and defense, carbohydrate metabolism, cyanogenesis, energy metabolism, miscellaneous and unknown proteins. Results suggested possible metabolic switches in the leaf that may trigger/regulate storage root initiation and growth. This study provides a basis for further functional characterization of differentially expressed leaf proteins, which can help understand how biochemical processes in cassava leaves may be involved in storage root development. PMID- 21327817 TI - Within-plant distribution of induced resistance in apple seedlings: rapid acropetal and delayed basipetal responses. AB - Induction of plant resistance by herbivory is a complex process, which follows a temporal dynamic and varies spatially at the within-plant scale. This study aimed at improving the understanding of the induction process in terms of time scale and within-plant allocation, using apple tree seedlings (Malus * domestica) as plant model. Feeding preferences of a leaf-chewing insect (Spodoptera littoralis) for previously damaged and undamaged plants were assessed for six different time intervals with respect to the herbivore damage treatment and for three leaf positions. In addition, main secondary defense compounds were quantified and linked to herbivore feeding preferences. Significant herbivore preference for undamaged plants (induced resistance) was first observed 3 days after herbivore damage in the most apical leaf. Responses were delayed in the other leaf positions, and induced resistance decreased within 10 days after herbivore damage simultaneously in all tested leaf positions. Chemical analysis revealed higher concentrations of the flavonoid phloridzin in damaged plants as compared to undamaged plants. This indicates that herbivore preference for undamaged apple plants may be linked to phloridzin, which is the main secondary metabolite of apple leaves. The observed time course and distribution of resistance responses within plants contribute to the understanding of induction processes and patterns, and support the optimal defense theory stating young tissue to be prioritized. Moreover, induced resistance responses occurred also basipetally in leaves below the damage site, which suggests that signaling pathways involved in resistance responses are not unidirectional. PMID- 21327818 TI - Characterization of the glyoxalase 1 gene TcGLX1 in the metal hyperaccumulator plant Thlaspi caerulescens. AB - Stress tolerance is currently one of the major research topics in plant biology because of the challenges posed by changing climate and increasing demand to grow crop plants in marginal soils. Increased Zn tolerance and accumulation has been reported in tobacco expressing the glyoxalase 1-encoding gene from Brassica juncea. Previous studies in our laboratory showed some Zn tolerance-correlated differences in the levels of glyoxalase 1-like protein among accessions of Zn hyperaccumulator Thlaspi caerulescens. We have now isolated the corresponding gene (named here TcGLX1), including ca. 570 bp of core and proximal promoter region. The predicted protein contains three glyoxalase 1 motifs and several putative sites for post-translational modification. In silico analysis predicted a number of cis-acting elements related to stress. The expression of TcGLX1 was not responsive to Zn. There was no correlation between the levels of TcGLX1 expression and the degrees of Zn tolerance or accumulation among T. caerulescens accessions nor was there co-segregation of TcGLX1 expression with Zn tolerance or Zn accumulation among F3 lines derived from crosses between plants from accessions with contrasting phenotypes for these properties. No phenotype was observed in an A. thaliana T-DNA insertion line for the closest A. thaliana homolog of TcGLX1, ATGLX1. These results suggest that glyoxalase 1 or at least the particular isoform studied here is not a major determinant of Zn tolerance in the Zn hyperaccumulator plant T. caerulescens. In addition, ATGLX1 is not essential for normal Zn tolerance in the non-tolerant, non-accumulator plant A. thaliana. Possible explanations for the apparent discrepancy between this and previous studies are discussed. PMID- 21327819 TI - Heterologous expression of two FAD-dependent oxidases with (S) tetrahydroprotoberberine oxidase activity from Arge mone mexicana and Berberis wilsoniae in insect cells. AB - Berberine, palmatine and dehydrocoreximine are end products of protoberberine biosynthesis. These quaternary protoberberines are elicitor inducible and, like other phytoalexins, are highly oxidized. The oxidative potential of these compounds is derived from a diverse array of biosynthetic steps involving hydroxylation, intra-molecular C-C coupling, methylenedioxy bridge formation and a dehydrogenation reaction as the final step in the biosynthesis. For the berberine biosynthetic pathway, the identification of the dehydrogenase gene is the last remaining uncharacterized step in the elucidation of the biosynthesis at the gene level. An enzyme able to catalyze these reactions, (S) tetrahydroprotoberberine oxidase (STOX, EC 1.3.3.8), was originally purified in the 1980s from suspension cells of Berberis wilsoniae and identified as a flavoprotein (Amann et al. 1984). We report enzymatic activity from recombinant STOX expressed in Spodoptera frugiperda Sf9 insect cells. The coding sequence was derived successively from peptide sequences of purified STOX protein. Furthermore, a recombinant oxidase with protoberberine dehydrogenase activity was obtained from a cDNA library of Argemone mexicana, a traditional medicinal plant that contains protoberberine alkaloids. The relationship of the two enzymes is discussed regarding their enzymatic activity, phylogeny and the alkaloid occurrence in the plants. Potential substrate binding and STOX-specific amino acid residues were identified based on sequence analysis and homology modeling. PMID- 21327820 TI - Calbindin immunoreactivity in the enteric nervous system of larval and adult zebrafish (Danio rerio). AB - Calbindin is a calcium-binding protein, commonly found in certain subpopulations of the enteric nervous system in mammals. Recently, calbindin-immunoreactive enteric neurons have also been demonstrated in shorthorn sculpin (Myoxocephalus scorpius). In the present study, calbindin immunoreactivity has been investigated in the gut of adult and larval zebrafish (Danio rerio) and differences and similarities between the two species are discussed. Calbindin immunoreactivity is present in 40%-50% of all enteric neurons in adult zebrafish. It first appears at 3 days post-fertilisation (dpf) and is present in all regions of the gut by 13 dpf. Calbindin-immunoreactive nerve cell bodies do not differ in size from calbindin-negative cells. Zebrafish calbindin-immunoreactive neurons are serotonin-negative, with at least some being choline acetyltransferase (ChAT) positive, in contrast to the sculpin in which cells are generally smaller than the average enteric neuron and are serotonin-positive and ChAT-negative. These findings further emphasise the importance of comparative studies for understanding the diversity of chemical coding in the enteric nervous system of fish and other vertebrates. Improved knowledge of the role of the enteric nervous system is also essential for future studies of gut activity with regard to zebrafish being used as a model organism. PMID- 21327821 TI - Inadequate cytology of thyroid nodules. Repeat it or live with it. PMID- 21327822 TI - Recurrence pattern and prognosis of pancreatic cancer after pancreatic fistula. AB - BACKGROUND: The negative impact of anastomotic leakage on cancer-specific survival and recurrence patterns has been recognized in colorectal cancer. In pancreatic cancer, pancreatic fistula (PF) is a serious morbidity, but its negative effect on long-term outcome remains to be elucidated. The aim of this study was to determine the impact of PF on pancreatic cancer recurrence. METHODS: The medical records of 184 patients with curative pancreatectomy for pancreatic cancer were reviewed. PF was scored on the basis of the International Study Group of Pancreatic Fistula classification. Overall and disease-free survivals and recurrence patterns were analyzed. Grade A PF was excluded because the negative effects can be negligible. RESULTS: PF occurred in 51 of the 184 patients (27.7%). The mortality related to PF was 0.5% (1 of 184). PF was an independent risk factor for peritoneal recurrence (hazard ratio 3.974; 95% confidence interval 1.345-11.737; P = 0.013). According to the analysis of disease-free survival in patients with peritoneal recurrence, time to recurrence was shorter and the survival rate was worse in patients with PF than in those without PF (5.6 vs. 8.2 months; 6-month survival, 40 vs. 71%; 1-year survival, 7 vs. 19%; P = 0.053). PF was an independent prognostic factor after multivariate analysis (hazard ratio 3.257; 95% confidence interval 1.201-8.828; P = 0.020). CONCLUSIONS: PF was statistically significantly related to peritoneal recurrence, and patients with PF developed peritoneal recurrence earlier than those without PF. With regard to the development of peritoneal recurrence, PF may be considered to be a negative prognostic factor. PMID- 21327823 TI - Association of elevated HIF-2alpha levels with low Beclin 1 expression and poor prognosis in patients with chondrosarcoma. AB - BACKGROUND: Hypoxia inducible factor (HIF)-2alpha is an important transcription factor that contributes to tumor proliferation and progression. Beclin 1 is a key mediator of autophagy, and dysfunction of Beclin 1 is implicated in tumorigenicity. This study was designed to investigate the expression patterns of HIF-2alpha and Beclin 1 and to clarify their clinical significance in chondrosarcoma. METHODS: The mRNA and protein levels of HIF-2alpha and Beclin 1 in chondrosarcoma and the corresponding nontumor tissues were analyzed by real time polymerase chain reaction and Western blot, respectively. The protein expression of HIF-2alpha and Beclin 1 was investigated by immunohistochemistry, and their associations with clinicopathological factors and overall survival were evaluated. RESULTS: HIF-2alpha was remarkably elevated, whereas Beclin 1 was significantly reduced in chondrosarcoma compared with the corresponding nontumor tissues. High HIF-2alpha level and negative Beclin 1 expression were 52.9% and 58.8% in chondrosarcoma specimens, respectively. HIF-2alpha and Beclin 1 were associated with histological grade and Musculoskeletal Tumor Society stage. There was a significant inverse relationship between HIF-2alpha and Beclin 1. HIF 2alpha and Beclin 1 had significant impacts on the prognosis of chondrosarcoma patients. Multivariate analysis revealed that Beclin 1 was an independent prognostic factor for overall survival of patients with chondrosarcoma. CONCLUSIONS: Elevated HIF-2alpha levels associated with low Beclin 1 expression play a role in the development of chondrosarcoma. Beclin 1 can serve as a novel biomarker to predict survival of chondrosarcoma patients, and may represent a potential therapeutic target. PMID- 21327824 TI - Osteoarthritic tissues modulate functional properties of sensory neurons associated with symptomatic OA pain. AB - Osteoarthritis (OA) is an age-related degenerative disease of cartilaginous tissues that is accompanied by hyperalgesia. Molecular cause and effect relationships between OA and pain remain to be elucidated. In this study, we have developed an experimental ex vivo organ co-culture system with dorsal root ganglia (DRGs) and knee synovial tissues from OA patients or unaffected human subjects. Our results suggest that tissues may generate symptomatic pain by altering the functional properties of sensory neurons. Specifically, we find that the expression levels of genes associated with neuronal pathways (e.g., SP, NK1, NK2, NPYR1, NPYR2, alpha2delta1) or inflammation (COX2/PTGS2 and IL6/interferon beta2) are clearly elevated in DRG explants cultured in the presence of OA derived synovial tissues. These findings are consistent with a model in which cytokines and pain molecules produced by knee synovium sensitize nociceptive neurons in tissues peripheral to joint cartilage. PMID- 21327825 TI - BcMF20, a putative pollen-specific transcription factor from Brassica campestris ssp. chinensis. AB - The Arabidopsis transcription factor (At1g26610) was shown to be down-regulated in male sterile lines compared to their maintainer line in Chinese cabbage (Brassica campestris ssp. chinensis) in our previous study. The BcMF20 gene, homologue of the At1g26610 gene was isolated from Chinese cabbage. It encodes a putative C2H2 zinc finger protein. The spatial and temporal expression patterns examined by qRT-PCR and in situ hybridization, indicated BcMF20 is specifically expressed in the developing pollen grains and the tapetum from the uninucleate pollen stage to mature pollen stage. PMID- 21327827 TI - Modelling the isometric force response to multiple pulse stimuli in locust skeletal muscle. AB - An improved model of locust skeletal muscle will inform on the general behaviour of invertebrate and mammalian muscle with the eventual aim of improving biomedical models of human muscles, embracing prosthetic construction and muscle therapy. In this article, the isometric response of the locust hind leg extensor muscle to input pulse trains is investigated. Experimental data was collected by stimulating the muscle directly and measuring the force at the tibia. The responses to constant frequency stimulus trains of various frequencies and number of pulses were decomposed into the response to each individual stimulus. Each individual pulse response was then fitted to a model, it being assumed that the response to each pulse could be approximated as an impulse response and was linear, no assumption were made about the model order. When the interpulse frequency (IPF) was low and the number of pulses in the train small, a second order model provided a good fit to each pulse. For moderate IPF or for long pulse trains a linear third-order model provided a better fit to the response to each pulse. The fit using a second-order model deteriorated with increasing IPF. When the input comprised higher IPFs with a large number of pulses the assumptions that the response was linear could not be confirmed. A generalised model is also presented. This model is second-order, and contains two nonlinear terms. The model is able to capture the force response to a range of inputs. This includes cases where the input comprised of higher frequency pulse trains and the assumption of quasi-linear behaviour could not be confirmed. PMID- 21327826 TI - Action understanding and active inference. AB - We have suggested that the mirror-neuron system might be usefully understood as implementing Bayes-optimal perception of actions emitted by oneself or others. To substantiate this claim, we present neuronal simulations that show the same representations can prescribe motor behavior and encode motor intentions during action-observation. These simulations are based on the free-energy formulation of active inference, which is formally related to predictive coding. In this scheme, (generalised) states of the world are represented as trajectories. When these states include motor trajectories they implicitly entail intentions (future motor states). Optimizing the representation of these intentions enables predictive coding in a prospective sense. Crucially, the same generative models used to make predictions can be deployed to predict the actions of self or others by simply changing the bias or precision (i.e. attention) afforded to proprioceptive signals. We illustrate these points using simulations of handwriting to illustrate neuronally plausible generation and recognition of itinerant (wandering) motor trajectories. We then use the same simulations to produce synthetic electrophysiological responses to violations of intentional expectations. Our results affirm that a Bayes-optimal approach provides a principled framework, which accommodates current thinking about the mirror-neuron system. Furthermore, it endorses the general formulation of action as active inference. PMID- 21327828 TI - Deriving neural network controllers from neuro-biological data: implementation of a single-leg stick insect controller. AB - This article presents modular recurrent neural network controllers for single legs of a biomimetic six-legged robot equipped with standard DC motors. Following arguments of Ekeberg et al. (Arthropod Struct Dev 33:287-300, 2004), completely decentralized and sensori-driven neuro-controllers were derived from neuro biological data of stick-insects. Parameters of the controllers were either hand tuned or optimized by an evolutionary algorithm. Employing identical controller structures, qualitatively similar behaviors were achieved for robot and for stick insect simulations. For a wide range of perturbing conditions, as for instance changing ground height or up- and downhill walking, swing as well as stance control were shown to be robust. Behavioral adaptations, like varying locomotion speeds, could be achieved by changes in neural parameters as well as by a mechanical coupling to the environment. To a large extent the simulated walking behavior matched biological data. For example, this was the case for body support force profiles and swing trajectories under varying ground heights. The results suggest that the single-leg controllers are suitable as modules for hexapod controllers, and they might therefore bridge morphological- and behavioral-based approaches to stick insect locomotion control. PMID- 21327829 TI - Intermittent control: a computational theory of human control. AB - The paradigm of continuous control using internal models has advanced understanding of human motor control. However, this paradigm ignores some aspects of human control, including intermittent feedback, serial ballistic control, triggered responses and refractory periods. It is shown that event-driven intermittent control provides a framework to explain the behaviour of the human operator under a wider range of conditions than continuous control. Continuous control is included as a special case, but sampling, system matched hold, an intermittent predictor and an event trigger allow serial open-loop trajectories using intermittent feedback. The implementation here may be described as "continuous observation, intermittent action". Beyond explaining unimodal regulation distributions in common with continuous control, these features naturally explain refractoriness and bimodal stabilisation distributions observed in double stimulus tracking experiments and quiet standing, respectively. Moreover, given that human control systems contain significant time delays, a biological-cybernetic rationale favours intermittent over continuous control: intermittent predictive control is computationally less demanding than continuous predictive control. A standard continuous-time predictive control model of the human operator is used as the underlying design method for an event-driven intermittent controller. It is shown that when event thresholds are small and sampling is regular, the intermittent controller can masquerade as the underlying continuous-time controller and thus, under these conditions, the continuous-time and intermittent controller cannot be distinguished. This explains why the intermittent control hypothesis is consistent with the continuous control hypothesis for certain experimental conditions. PMID- 21327830 TI - Dynamic gene order on the Silene latifolia Y chromosome. AB - Dioecious Silene latifolia evolved heteromorphic sex chromosomes within the last ten million years, making it a species of choice for studies of the early stages of sex chromosome evolution in plants. About a dozen genes have been isolated from its sex chromosomes and basic genetic and deletion maps exist for the X and Y chromosomes. However, discrepancies between Y chromosome maps led to the proposal that individual Y chromosomes may differ in gene order. Here, we use an alternative approach, with fluorescence in situ hybridization (FISH), to locate individual genes on S. latifolia sex chromosomes. We demonstrate that gene order on the Y chromosome differs between plants from two populations. We suggest that dynamic gene order may be a general property of Y chromosomes in species with XY systems, in view of recent work demonstrating that the gene order on the Y chromosomes of humans and chimpanzees are dramatically different. PMID- 21327831 TI - Direct evidence that (-)-epicatechin increases nitric oxide levels in human endothelial cells. AB - BACKGROUND: The dietary flavanol (-)-epicatechin has been suggested to mediate its vasodilatory effect by increasing nitric oxide levels in endothelial cells. AIM OF THE STUDY: To directly prove the formation of nitric oxide (NO) in human endothelial cells (HUVEC) in vitro by trapping NO to yield a fluorescent nitrosamine. METHODS: HUVEC were treated with (-)-epicatechin; nitrite and NO formation were determined by reductive chemiluminescence detection and the NO sensitive fluorophore 5-methoxy-2-(1H-naphthol[2,3-d]imidazol-2-yl)-phenol copper complex (MNIP-Cu), respectively. MNIP was synthesized in a rapid and convenient one-step microwave reaction. Endothelial nitric oxide synthase (eNOS) mRNA levels and mRNA stability were measured. RESULTS: Incubation with (-)-epicatechin (0.3 10 MUM) led to elevated NO levels in HUVEC measured via reductive chemiluminescence detection and visualized as the fluorescent NO derivative of MNIP. Expression of eNOS mRNA and mRNA stability were not affected by (-) epicatechin treatment within the time frame studied. CONCLUSION: (-)-Epicatechin augments the level of NO in endothelial cells, a process suggested to be responsible for the vasodilatory properties of the compound. PMID- 21327832 TI - [Immunofluorescence]. AB - The existence of autoantibodies is characteristic of several rheumatic diseases and indicates impaired self-tolerance. The analysis and detection of these autoantibodies represent an important factor in the diagnosis of rheumatic diseases. Immunofluorescence is an important technique in basic science and also one of the most commonly used techniques for the characterization of autoantibodies in clinical medicine thus facilitating the diagnosis and evaluation of rheumatic diseases. Addition of serum samples from individual patients to an antigen substrate (present in fixed cells or tissue) results in a specific reaction between the autoantibodies and the respective antigens. Incubation with a second, fluorescence-linked, anti-human antibody which binds to the primary antigen-bound autoantibodies from patient serum results in fluorescence patterns which are characteristic of certain rheumatic diseases. PMID- 21327833 TI - The Swedish version of the Ritvo autism and asperger diagnostic scale: revised (RAADS-R). A validation study of a rating scale for adults. AB - There is a paucity of diagnostic instruments for adults with autism spectrum disorder (ASD). This study evaluates the psychometric properties of the Swedish version of the Ritvo Autism and Asperger Diagnostic Scale-Revised (RAADS-R), an 80-item self-rating scale designed to assist clinicians diagnosing ASD in adults. It was administered to 75 adults with ASD and 197 comparison cases. Also, a subset completed the Autism Spectrum Quotient (AQ). Three out of four subscales had high internal consistency. Sensitivity was 91% and specificity was 93%. The ASD subjects had significantly higher mean scores on all subscales. ASD females had higher scores than ASD males on the sensory motor subscale, a dimension not included in the AQ. RAADS-R showed promising test re-test reliability. PMID- 21327834 TI - Recent loss of plastid-encoded ndh genes within Erodium (Geraniaceae). AB - Plastid genomes in the flowering plant family Geraniaceae are known to be highly rearranged based on complete sequences representing the four major genera Erodium, Geranium, Monsonia, and Pelargonium. In this paper we report on the genome sequence of a second species of Erodium, E. carvifolium, representing the second major clade (clade II) in the phylogeny of this genus. Comparison of this genome sequence to the previously published sequence of E. texanum from clade I demonstrates that the plastid genomes of these two species encode the same number of proteins but differ greatly in their relative degree of rearrangement; 14 kb of additional sequence in E. texanum contains complex repeats associated with rearrangement endpoints, whereas the plastid genome of E. carvifolium is streamlined at 116 kb and displays no unique alterations in gene order. Furthermore, these species from both major clades of Erodium contain intact NADH dehydrogenase (ndh) genes, but the 11 ndh genes are represented as pseudogenes in a small clade of 13 species. It is unclear whether plastid-encoded ndh genes have been lost entirely or functionally transferred to the nucleus. This is the third report of the absence of functional ndh genes, and the current study describes the most recent loss of these genes among photosynthetic seed plants and the second such loss among angiosperms. The other ndh losses from Pinaceae/Gnetales and Orchidaceae are much more ancient. Comparative biochemistry between Erodium species with and without plastid-encoded ndh genes may elucidate changes in photosynthetic function and the role of the Ndh complex. PMID- 21327835 TI - Maize ABP9 enhances tolerance to multiple stresses in transgenic Arabidopsis by modulating ABA signaling and cellular levels of reactive oxygen species. AB - The phytohormone abscisic acid (ABA) and reactive oxygen species (ROS) play critical roles in mediating abiotic stress responses in plants. It is well known that ABA is involved in the modulation of ROS levels by regulating ROS-producing and ROS-scavenging genes, but the molecular mechanisms underlying this regulation are poorly understood. Here we show that the expression of maize ABP9 gene, which encodes a bZIP transcription factor capable of binding to the ABRE2 motif in the maize Cat1 promoter, is induced by ABA, H(2)O(2), drought and salt. Constitutive expression of ABP9 in transgenic Arabidopsis leads to remarkably enhanced tolerance to multiple stresses including drought, high salt, freezing temperature and oxidative stresses. ABP9 expressing Arabidopsis plants also exhibit increased sensitivity to exogenously applied ABA during seed germination, root growth and stomatal closure and improved water-conserving capacity. Moreover, constitutive expression of ABP9 causes reduced cellular levels of ROS, alleviated oxidative damage and reduced cell death, accompanied by elevated expression of many stress/ABA responsive genes including those for scavenging and regulating ROS. Taken together, these results suggest that ABP9 may play a pivotal role in plant tolerance to abiotic stresses by fine tuning ABA signaling and control of ROS accumulation. PMID- 21327836 TI - Aspergillus lung disease in patients with sarcoidosis: a case series and review of the literature. AB - Chronic cavitary pulmonary aspergillosis (CCPA) has been associated with advanced lung diseases. Pulmonary sarcoidosis, a granulomatous inflammatory disorder, is associated with CCPA. We identified CCPA in 2% of cases in a large cohort of sarcoidosis patients. We found a lack of response to medical treatment and poor outcome in this subgroup. PMID- 21327839 TI - ACMT position statement: interim guidance for the use of lipid resuscitation therapy. PMID- 21327837 TI - Risk factors for splenic injury during colectomy: a matched case-control study. AB - PURPOSE: We assessed risk factors for splenic injury during colectomy and associated outcomes for a 15-year period at a single institution. METHODS: All adult general surgery patients who sustained a splenic injury during colectomy at our institution from 1992 to 2007 were retrospectively identified and matched 1:1 to controls without splenic injury. Putative risk factors were assessed using paired univariate analysis and conditional logistic regression. Differences in short- and long-term mortality were assessed using the log-rank test. Results are reported as a proportion, median, or odds ratio [OR (95% confidence intervals)]. RESULTS: A total of 118 patients were included: 59 patients with splenic injury and 59 control patients. Statistically significant risk factors for splenic injury during colectomy found on univariate analysis included: splenic flexure mobilization, OR 21.00 (2.82-156.12); Charlson comorbidity index>=5, OR 3.17 (1.26-7.93); ASA class>=3, OR 5.33 (1.55-18.3); and nonelective surgery, OR 5.00 (1.1-22.82). On multivariate analysis, only splenic flexure mobilization was independently associated with increased risk of splenic injury (OR 18.4 (2.1 161); p=0.0085). Splenic injured patients trended toward decrease survival both at 30 days (98 vs. 88%; p=0.06) and at 5 years (58 vs. 55%), with a hazard ratio of 1.6 (1.0, 2.6; p=0.05). CONCLUSIONS: Splenic flexure mobilization is the primary risk factor for splenic injury during colectomy, independent of other factors, such as higher ASA class, Charlson score, and nonelective surgery. Splenic injury during colectomy has an increased risk of death in both the short- and long-term. PMID- 21327840 TI - ACMT position statement: recognition of medical direction and support of poison center activities. PMID- 21327841 TI - Spectral EEG frontal asymmetries correlate with the experienced pleasantness of TV commercial advertisements. AB - The aim of this research is to analyze the changes in the EEG frontal activity during the observation of commercial videoclips. In particular, we aimed to investigate the existence of EEG frontal asymmetries in the distribution of the signals' power spectra related to experienced pleasantness of the video, as explicitly rated by the eleven experimental subjects investigated. In the analyzed population, maps of Power spectral density (PSD) showed an asymmetrical increase of theta and alpha activity related to the observation of pleasant (unpleasant) advertisements in the left (right) hemisphere. A correlation analysis revealed that the increase of PSD at left frontal sites is negatively correlated with the degree of pleasantness perceived. Conversely, the de synchronization of left alpha frontal activity is positively correlated with judgments of high pleasantness. Moreover, our data presented an increase of PSD related to the observation of unpleasant commercials, which resulted higher with respect to the one elicited by pleasant advertisements. PMID- 21327842 TI - Sudden cardiac death in a patient with lamin A/C mutation in the absence of dilated cardiomyopathy or conduction disease. PMID- 21327843 TI - Biological variation of high sensitive Troponin T in stable heart failure patients with ischemic or dilated cardiomyopathy. AB - INTRODUCTION: High sensitive Troponin (hsTn) assays enable detection of minimal marker elevation in heart failure patients previously deemed Troponin negative. Biovariability, reference change values (RCV), and index of individuality (II) have not been previously described for hsTnT although serial testing is important in interpreting low concentrations. For these values, a difference between ischemic heart disease (IHD) and dilated cardiomyopathy (dCMP) appears conceivable. METHODS: Change in hsTnT was determined alongside with clinical variables in 41 patients with stable chronic systolic dysfunction at 2-week-, 1 month-, 2-month-, and 3-month-intervals (IHD n = 17; dCMP n = 24). RESULTS: HsTnT was detectable in all patients. Individual hsTnT-variations at 2-week, 1-month, 2 month, and 3-month follow-up were 7.2, 22.6, 28.9, and 15.7%, respectively, corresponding to RCVs of 20.1, 62.5, 80.0, and 43.3%, respectively, for crude values. For log-normalised values, individual variations were 3.2, 2.8, 2.7, and 3.5%, respectively, corresponding to RCVs of 8.8, 7.9, 7.6, and 9.7%, respectively. The II was 0.03 to 0.33 according to interval. Aetiology of heart failure was not a consistent determinant of variation (p = 0.28; p = 0.07; p = 0.98; p = 0.03 for 2-week, 1-month, 2-month, and 3-month follow-up, respectively). CONCLUSION: While short-term biological variation of hsTnT is low, it becomes relatively more important for intermediate follow-up. It is not related to aetiology of heart failure. The corresponding indices of individuality indicate high individuality of values. PMID- 21327844 TI - Prevalence and correlates of suicidal ideation during pregnancy. AB - Data are scarce regarding the prevalence and risk factors for antenatal suicidal ideation because systematic screening for suicidal ideation during pregnancy is rare. This study reports the prevalence and correlates of suicidal ideation during pregnancy. We performed cross-sectional analysis of data from an ongoing registry. Study participants were 2,159 women receiving prenatal care at a university obstetric clinic from January 2004 through March 2010. Multiple logistic regression identified factors associated with antenatal suicidal ideation as measured by the Patient Health Questionnaire. Overall, 2.7% of the sample reported antenatal suicidal ideation. Over 50% of women who reported antenatal suicidal ideation also reported major depression. In the fully adjusted model antenatal major depression (OR = 11.50; 95% CI 5.40, 24.48) and antenatal psychosocial stress (OR = 3.19; 95% CI 1.44, 7.05) were positively associated with an increased risk of antenatal suicidal ideation. We found that being non Hispanic White was associated with a decreased risk of antenatal suicidal ideation (OR = 0.51; 95% CI 0.26-0.99). The prevalence of antenatal suicidal ideation in the present study was similar to rates reported in nationally representative non-pregnant samples. In other words, pregnancy is not a protective factor against suicidal ideation. Given the high comorbidity of antenatal suicidal ideation with major depression, efforts should be made to identify those women at risk for antenatal suicidal ideation through universal screening. PMID- 21327845 TI - Defense/stress responses activated by chitosan in sycamore cultured cells. AB - Chitosan (CHT) is a natural, non-toxic, and inexpensive compound obtained by partial alkaline deacetylation of chitin, the main component of the exoskeleton of crustaceans and other arthropods. The unique physiological and biological properties of CHT make this polymer useful for a wide range of industries. In agriculture, CHT is used to control numerous pre- and postharvest diseases on various horticultural commodities. In recent years, much attention has been devoted to CHT as an elicitor of defense responses in plants, which include raising of cytosolic Ca(2+), activation of MAP kinases, callose apposition, oxidative burst, hypersensitive response, synthesis of abscisic acid, jasmonate, phytoalexins, and pathogenesis-related proteins. In this work, we investigated the effects of different CHT concentrations on some defense/stress responses of sycamore (Acer pseudoplatanus L.) cultured cells. CHT induced accumulation of dead cells, and of cells with fragmented DNA, production of H(2)O(2) and nitric oxide, release of cytochrome c from the mitochondrion, accumulation of regulative 14-3-3 proteins in the cytosol and of HSP70 molecular chaperone binding protein in the endoplasmic reticulum, accompanied by marked modifications in the architecture of this cell organelle. PMID- 21327846 TI - Parvovirus B19 infection antedating Guillain-Barre' syndrome variant with prominent facial diplegia. PMID- 21327847 TI - Postural function and subjective eye level in patients with idiopathic normal pressure hydrocephalus. AB - Disturbance of posture is a frequent indication of idiopathic normal pressure hydrocephalus (iNPH) and is characterised by an increased sway in the frontal and sagittal planes. Further, iNPH patients with increased backward sway are known to have a defective perception of the subjective visual vertical (SVV), with the upper portion of an articulated rod tilted towards themselves. The objective of the present study was to compare subjective eye level (SEL) with actual eye level (EL) and compare this data with SVV and postural function. Twenty iNPH patients and ten normal controls estimated SEL by placing an adjustable horizontal line at EL. Sway pattern and SVV were also examined as previously described. The patients presented larger errors on downward as compared to upward line adjustments; all patients also presented a SVV tilted towards them. The patients swayed more in the sagittal than in the frontal plane at a higher speed than the normal controls, and they were relatively less helped by their vision. This is in accordance with the tendency to fall backwards seen in many iNPH patients. iNPH patients have a tendency to place SEL higher than EL and this, together with examination of SVV and sway pattern, suggests defective internal processing of gravicentric information. PMID- 21327848 TI - Eyelid retraction in dementia with Lewy bodies and Parkinson's disease. PMID- 21327849 TI - Hyoid bone-related focal carotid vasculopathy. PMID- 21327850 TI - Temporal evolution of sporadic Creutzfeldt-Jakob disease monitored by 3-Tesla MR spectroscopy. PMID- 21327851 TI - Diabetic lumbosacral radiculoplexus neuropathy: a postmortem studied patient and review of the literature. PMID- 21327852 TI - Vascular risk factors are associated with faster decline of Alzheimer disease: a longitudinal SPECT study. AB - We investigated the effects of cardiovascular risk factors, such as hypertension, diabetes mellitus, and hypercholesterolemia, on longitudinal regional cerebral blood flow (rCBF) changes in Alzheimer's disease (AD). We followed 68 outpatients with probable AD for an average of 40 months. They were divided into three groups based on no (n = 24), single (n = 27), and multiple (n = 17) vascular risk factors. We assessed longitudinal changes on the Mini-Mental State Examination, Functional Assessment Staging scores, and in rCBF deficits using repeated single photon emission computed tomography (SPECT) using N-isopropyl-p-[(123)I] iodoamphetamine. During follow-up, the multiple vascular risk factor group showed faster cognitive and functional decline than the no and single vascular risk factor groups. When compared with the initial SPECT, the follow-up SPECT showed a significant rCBF reduction in widespread regions, including the parietotemporal, frontal, and limbic lobes, in the multiple and single vascular risk factor groups, while there was rCBF reduction in small scattered regions of the temporoparietal lobe in the no vascular risk factor group. Multiple vascular risk factors are associated with a greater rate of decline in cognition, function, and rCBF in patients with AD. Our results highlight the contribution of vascular risk factors on the progression of AD. PMID- 21327853 TI - Henri Parinaud (1844-1905). PMID- 21327854 TI - Decomposing income-related inequality in cervical screening in 67 countries. AB - OBJECTIVES: The development of successful policies to reduce income-related inequalities in cervical cancer screening rates requires an understanding of the reasons why low-income women are less likely to be screened. We sought to identify important determinants contributing to inequality in cervical screening rates. METHODS: We analyzed data from 92,541 women aged 25-64 years, who participated in the World Health Survey in 2002-2003. Income-related inequality in Pap screening was measured using the concentration index (CI). Using a decomposition method for the CI, we quantified the contribution to inequality of age, education level, marital status, urbanicity and recent health-care need. RESULTS: There was substantial heterogeneity in the contributions of different determinants to inequality among countries. Education generally made the largest contribution (median = 15%, interquartile range [IQR] = 23%), although this varied widely even within regions (e.g., 5% in Austria, 28% in Hungary). The contribution of rural residence was greatest in African countries (median = 10%, IQR = 13%); however, there was again substantial within-region variation (e.g., 26% in Zambia, 2% in Kenya). CONCLUSIONS: Considerable heterogeneity in the contributions of screening determinants among countries suggests interventions to reduce screening inequalities may require country-specific approaches. PMID- 21327855 TI - A quantile regression approach to re-investigate the relationship between sleep duration and body mass index in Taiwan. AB - OBJECTIVE: Previous studies on the relationship between sleep duration and body mass index (BMI) have shown inconsistent results by using estimation strategies within the framework of ordinary least squares (OLS). This study examined the relationship between sleep duration and BMI by using quantile regression to account for the potential heterogeneous effect of sleep duration on BMI in different BMI categories. METHODS: The data of 2,392 adults were from the 2005 Panel Study of Family Dynamics in Taiwan. The dependent variable was BMI of the respondents. Both OLS and quantile regression models were used for comparison. RESULTS: The OLS model does not show significant relationship, while the quantile regression model shows a U-shaped relationship between sleep duration and BMI beyond the 90th percentile in men (BMI = 28.69) and an inverse U-shaped relationship at the 30th percentile of BMI in women (BMI = 21.37). CONCLUSIONS: Quantile regression can provide information that may be masked by OLS in analyzing the relationship between sleep duration and BMI. Sleep modification with the aim to obtain the optimal sleep duration may help to reduce BMI in obese men. PMID- 21327856 TI - Development and validation of the stressful life event questionnaire. AB - OBJECTIVES: This study evaluates the development of the stressful life event (SLE) questionnaire and tests the validity and reliability of it. METHOD: In total, 3,951 adults aged over 18 years completed the SLE questionnaire. The General Health Questionnaire (GHQ-12) was used to further validate the SLE questionnaire. RESULTS: Eleven domains, including home life, financial problems, social relation, personal conflict, job conflict, educational concerns, job security, loss and separation, sexual life, daily life, and health concerns were obtained by factor analysis. Correlation coefficient was moderately significant among domains of the SLE questionnaire and moderately between the SLE questionnaire and GHQ-12 score, as well. The results of the discriminate validity analysis were promising. In addition, standardized Cronbach'-alpha was 92%. CONCLUSION: The resultant SLE questionnaire is, therefore, suggested to be potential for the stress measurement in both community and primary care setting. PMID- 21327857 TI - Multiple-labelling immunoEM using different sizes of colloidal gold: alternative approaches to test for differential distribution and colocalization in subcellular structures. AB - Various methods for quantifying cellular immunogold labelling on transmission electron microscope thin sections are currently available. All rely on sound random sampling principles and are applicable to single immunolabelling across compartments within a given cell type or between different experimental groups of cells. Although methods are also available to test for colocalization in double/triple immunogold labelling studies, so far, these have relied on making multiple measurements of gold particle densities in defined areas or of inter particle nearest neighbour distances. Here, we present alternative two-step approaches to codistribution and colocalization assessment that merely require raw counts of gold particles in distinct cellular compartments. For assessing codistribution over aggregate compartments, initial statistical evaluation involves combining contingency table and chi-squared analyses to provide predicted gold particle distributions. The observed and predicted distributions allow testing of the appropriate null hypothesis, namely, that there is no difference in the distribution patterns of proteins labelled by different sizes of gold particle. In short, the null hypothesis is that of colocalization. The approach for assessing colabelling recognises that, on thin sections, a compartment is made up of a set of sectional images (profiles) of cognate structures. The approach involves identifying two groups of compartmental profiles that are unlabelled and labelled for one gold marker size. The proportions in each group that are also labelled for the second gold marker size are then compared. Statistical analysis now uses a 2 * 2 contingency table combined with the Fisher exact probability test. Having identified double labelling, the profiles can be analysed further in order to identify characteristic features that might account for the double labelling. In each case, the approach is illustrated using synthetic and/or experimental datasets and can be refined to correct observed labelling patterns to specific labelling patterns. These simple and efficient approaches should be of more immediate utility to those interested in codistribution and colocalization in multiple immunogold labelling investigations. PMID- 21327858 TI - Nucleolar localization and identification of nuclear/nucleolar localization signals of the calmodulin-binding protein nucleomorphin during growth and mitosis in Dictyostelium. AB - The calmodulin-binding protein nucleomorphin isoform NumA1 is a nuclear number regulator in Dictyostelium that localizes to intra-nuclear patches adjacent to the nuclear envelope and to a lesser extent the nucleoplasm. Earlier studies have shown similar patches to be nucleoli but only three nucleolar proteins have been identified in Dictyostelium. Here, actinomycin-D treatment caused the loss of NumA1 localization, while calcium and calmodulin antagonists had no effect. In keeping with a nucleolar function, NumA1 moved out of the presumptive nucleoli during mitosis redistributing to areas within the nucleus, the spindle fibers, and centrosomal region before re-accumulating in the presumptive nucleoli at telophase. Together, these data verify NumA1 as a true nucleolar protein. Prior to this study, the dynamics of specific nucleolar proteins had not been determined during mitosis in Dictyostelium. FITC-conjugated peptides equivalent to presumptive nuclear localization signals within NumA1 localized to nucleoli indicating that they also act as nucleolar localization signals. To our knowledge, these represent the first precisely defined nucleolar localization signals as well as the first nuclear/nucleolar localization signals identified in Dictyostelium. Together, these results reveal that NumA1 is a true nucleolar protein and the only nucleolar calmodulin-binding protein identified in Dictyostelium. The possible use of nuclear/nucleolar localization signal-mediated drug targeting to nucleoli is discussed. PMID- 21327859 TI - Possibilities, intentions and threats: dual use in the life sciences reconsidered. AB - Due to the terrorist attacks of 9/11 and the anthrax letters of a few weeks later, the concept of dual use has spread widely in the life sciences during the past decade. This article is aimed at a clarification of the dual use concept and its scope of application for the life sciences. Such a clarification would greatly facilitate the work of policymakers seeking to ensure security while avoiding undesirable interventions of government in the conduct of science. The article starts with an overview of the main developments in life sciences in relation to dual use. This is illustrated by discussions on synthetic biology and dual use. The findings lead to a reconsideration of the dual use concept. An area in need of further attention is to what extent threats and intentions should have impact on the definition of dual use. Possible threats are analyzed against the background of the phenomenon of securitization of health care and life sciences: considering these sectors of society in security terms. Some caveats that should be taken into account in a dual use policy are described. An acceptable, adequate and applicable definition of the dual use concept could help researchers, universities, companies and policy makers. Such a definition should build upon, but go beyond, the view developed in the influential Fink-report, which concentrates on the so-called 'experiments of concern', e.g. experiments that enhance the virulence of pathogens (National Research Council of the National Academies 2004) It will be argued that-in addition to these more technical aspects-a definition of dual use should include the aspect of threats and intentions. PMID- 21327860 TI - Analysis of microbiological and chemical quality of poultry meat in the vicinity of the Mbeubeuss landfill in Malika (Senegal). AB - A total of 100 samples of poultry meat were collected in poultry farms in the vicinity of the Mbeubeuss landfill in the Niayes (Senegal) for microbiological and chemical analysis. Fifty-four (54) samples were collected in farms located less than 1 km from the landfill and 46 samples were collected in farms located a bit further (more than 1 km from the landfill). Microbiological quality was determined using techniques recommended by Association Francaise de Normalisation (AFNOR). Lead and cadmium concentration in poultry meat was measured by flame spectrometry while total mercury was determined by atomic absorption spectrometry. Three percent (3%) of the samples' quality were unsatisfactory for E. coli, 1% for Staphylococci and 7% for Salmonella spp. Poor meat quality was found either in farms located less than 1 km of the landfill or in farms located at more than 1 km of the landfill. Except for Salmonella, only meat samples from poultry receiving drinking water from well showed unsatisfactory microbiological quality. The samples were free of cadmium and lead but were contaminated by mercury. Sixty-eight percent (68%) of the samples contained mercury with a high contamination level (>0.011 mg/kg) in 20% of the samples. No significant difference was found between the farms that were nearest to and further away from the landfill while the source of drinking water seemed to be the main cause of contamination of poultry meat by mercury. PMID- 21327861 TI - Isolation of Histophilus somni from the nasal exudates of a clinically healthy adult goat. AB - METHODS: The nasal exudate from 42 goats of the Mixteca Region in the state of Puebla, Mexico, was evaluated. A strain was isolated after 4 days of incubation. This strain was identified according to its phenotypic characteristics and by means of a species-specific polymerase chain reaction (PCR), as well as by sequencing of the amplified product. RESULTS: The species-specific PCR amplified a 407-bp fragment of 16S RNAr subunit, and the product sequencing revealed 100% homology with Histophilus somni 129PT. The nucleotide sequence was deposited in the GenBank under accession number HM032735. CONCLUSION: This is the first worldwide isolation of H. somni from nasal exudates of a clinically healthy goat. PMID- 21327862 TI - Hypofractionated radiotherapy in the treatment of diffuse intrinsic pontine glioma in children: a single institution's experience. AB - We report herein our institutional experience in the treatment of diffuse intrinsic pontine glioma (DIPG) with a hypofractionated external-beam radiotherapy schedule. Between April 1996 and January 2004, 22 patients (age 2.9 12.5 years) with newly diagnosed DIPG were treated by hypofractionated radiation therapy delivering a total dose of 45 Gy in daily fractions of 3 Gy, given over 3 weeks. No other treatment was applied concomitantly. Fourteen of the 22 patients received the prescribed dose of 45 Gy in 15 fractions of 3 Gy, and 2 patients received a total dose of 60 and 45 Gy with a combination of two different beams (photons and neutrons). In five cases the daily fraction was modified to 2 Gy due to intolerance, and one patient died due to serious intracranial hypertension after two fractions of 3 Gy and one of 2 Gy. Among 22 children, 14 patients showed clinical improvement, usually starting in the second week of treatment. No grade 3 or 4 acute toxicity from radiotherapy was observed. No treatment interruption was needed. In six patients, steroids could be discontinued within 1 month after the end of radiotherapy. Median time to progression and median overall survival were 5.7 months and 7.6 months, respectively. External radiotherapy with a radical hypofractionated regimen is feasible and well tolerated in children with newly diagnosed DIPG. However, this regimen does not seem to change overall survival in this setting. It could represent a short duration alternative to more protracted regimens. PMID- 21327863 TI - Is the incidence of brain tumors really increasing? A population-based analysis from a cancer registry. AB - Recently, an increasing incidence of brain tumors has been reported from multiple studies. Brain tumors diagnosed in the period 1985-2005 were identified through the Tuscan Cancer Registry, a population-based registry active since 1985 in the area of Florence and Prato. Age-standardized incidence rates and average annual percent change (APC) was calculated for the entire period from 1985 to 2005 for sex and behavior. A total of 4,417 brain tumors was registered, 1,900 (43%) in male and 2,517 (57%) in female patients. Malignant and benign tumor incidence rates were 8.3 and 4.1, respectively, among males and 6.4 and 7.2, respectively, among females. The age-adjusted annual incidence rate of all brain tumors was 13.9, with a statistically significant increasing rate throughout the period (APC: +3.2, CI 2.2-4.2). The annual incidence rate remained stable for malignant brain tumors but increased significantly for benign brain tumors (APC: +6.2, CI 4.5-7.9). In our population-based study, the incidence of brain tumors increased from 1985 to 2005 overall and for benign tumors, but not for malignant tumors. Part of the temporal variations may be attributed to improvement in diagnostic imaging techniques and, particularly for benign tumors, in changes in registration practice. PMID- 21327864 TI - Inhibition of heme oxygenase-1 enhances anti-cancer effects of arsenic trioxide on glioma cells. AB - We have previously reported that arsenic trioxide (ATO) could inhibit glioma growth both in vitro and in vivo, and demonstrated its potent therapeutic effects on gliomas. In this study we showed that ATO induced cell damage and heme oxygenase-1 (HO-1) expression in glioma cells via ROS generation. HO-1 inducer clearly protected from ATO-induced cell death and ROS generation, and HO-1 inhibitor led to a significant increase in cell death and ROS generation induced by ATO. In addition, knockdown of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) strongly inhibited HO-1 expression induced by ATO, and significantly enhanced ATO-induced oxidative damage. Our results demonstrated, for the first time, that HO-1 inhibition or Nrf2 knockdown significantly potentiated ATO's effects on glioma cells. Considering that HO-1 is highly expressed in glioma tissues, administration of ATO in combination with either HO-1 inhibitor or Nrf2 knockdown may act as a new approach to the treatment of glioma. PMID- 21327865 TI - Mineral fibre toxicity: expression of retinoblastoma (Rb) and phospho retinoblastoma (pRb) protein in alveolar epithelial and mesothelial cell lines exposed to fluoro-edenite fibres. AB - Several asbestos-like mineral fibres, including fluoro-edenite, may cause lung cancer and/or other lung diseases. However, biological and molecular mechanisms linked to cancer development after mineral fibre exposure have not been fully investigated. In the present study, human non-malignant mesothelial (MeT-5A) and human bronchoalveolar alveolar epithelial (A549) cell lines were incubated with rising concentrations of fluoro-edenite to evaluate the expression of retinoblastoma (Rb) protein, which has been demonstrated to play an important role in cell cycle control and tumour progression. Intriguingly, these results show that Rb expression was unchanged, while the level of the phosphorylated protein increased significantly in a dose-dependent manner, suggesting an involvement of this regulator protein in the pathogenesis of the lung diseases induced by mineral fibres. In conclusion, fluoro-edenite regulates the expression of phospho-retinoblastoma to trigger a network of signals strictly connected with cell proliferation and neoplastic cell transformation. PMID- 21327866 TI - Per-arnt-sim (PAS) domain kinase (PASK) as a regulator of glucagon secretion. AB - The physiological and pathophysiological regulation of glucagon secretion from pancreatic alpha cells remains a hotly debated topic. The mechanism(s) contributing to the glucose sensitivity of glucagon release and its impaired regulation in diabetes remain unclear. A paper in the current issue of Diabetologia by da Silva Xavier and colleagues (doi: 10.1007/s00125-010-2010-7 ) provides intriguing new insight into a metabolic sensing pathway mediated by the per-arnt-sim (PAS) domain kinase (PASK) that may contribute to both the paracrine and the intrinsic glucose regulation of alpha cells. Importantly, the authors show that PASK is decreased in islets from patients with type 2 diabetes, providing a potential mechanism for impaired suppression of glucagon by hyperglycaemia in this disease. Much work remains to be done to determine the exact role and mechanism of PASK in alpha and beta cells. Nevertheless, the present work introduces a new player in the metabolic regulation of glucagon secretion. PMID- 21327867 TI - Effects of weight loss and exercise on insulin resistance, and intramyocellular triacylglycerol, diacylglycerol and ceramide. AB - AIMS/HYPOTHESIS: Intramyocellular lipids, including diacylglycerol (DAG) and ceramides, have been linked to insulin resistance. This randomised repeated measures study examined the effects of diet-induced weight loss (DIWL) and aerobic exercise (EX) on insulin sensitivity and intramyocellular triacylglycerol (IMTG), DAG and ceramide. METHODS: Sixteen overweight to obese adults (BMI 30.6 +/- 0.8; 67.2 +/- 4.0 years of age) with either impaired fasting glucose, or impaired glucose tolerance completed one of two lifestyle interventions: DIWL (n = 8) or EX (n = 8). Insulin sensitivity was determined using hyperinsulinaemic euglycaemic clamps. Intramyocellular lipids were measured in muscle biopsies using histochemistry and tandem mass spectrometry. RESULTS: Insulin sensitivity was improved with DIWL (20.6 +/- 4.7%) and EX (19.2 +/- 12.9%). Body weight and body fat were decreased by both interventions, with greater decreases in DIWL compared with EX. Muscle glycogen, IMTG content and oxidative capacity were all significantly (p < 0.05) decreased with DIWL and increased with EX. There were decreases in DAG with DIWL (-12.4 +/- 14.6%) and EX (-40.9 +/- 12.0%). Ceramide decreased with EX (-33.7 +/- 11.2%), but not with DIWL. Dihydroceramide was decreased with both interventions. Sphingosine was decreased only with EX. Changes in total DAG, total ceramides and other sphingolipids did not correlate with changes in glucose disposal. Stearoyl-coenzyme A desaturase 1 (SCD1) content was decreased with DIWL (-19.5 +/- 8.5%, p < 0.05), but increased with EX (19.6 +/- 7.4%, p < 0.05). Diacylglycerol acyltransferase 1 (DGAT1) was unchanged with the interventions. CONCLUSIONS/INTERPRETATION: Diet-induced weight loss and exercise training both improved insulin resistance and decreased DAG, while only exercise decreased ceramides, despite the interventions having different effects on IMTG. These alterations may be mediated through differential changes in skeletal muscle capacity for oxidation and triacylglycerol synthesis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00766298. PMID- 21327868 TI - Chronic insulin therapy reduces adipose tissue macrophage content in LDL-receptor deficient mice. AB - AIMS/HYPOTHESIS: Insulin has anti-inflammatory effects in short-term experiments. However, the effects of chronic insulin administration on inflammation are unknown. We hypothesised that chronic insulin administration would beneficially alter adipose tissue inflammation and several circulating inflammatory markers. METHODS: We administered two forms of long-acting insulin, insulin glargine (A21Gly,B31Arg,B32Arg human insulin) and insulin detemir (B29Lys[epsilon tetradecanoyl],desB30 human insulin), to LDL-receptor-deficient mice. After 8 weeks on a diet that causes obesity, hyperglycaemia, adipose tissue macrophage accumulation and atherosclerosis, the mice received subcutaneous glargine, detemir or NaCl (control) for 12 weeks. Serum amyloid A (SAA) and serum amyloid P (SAP), metabolic variables, adipose tissue macrophages and aortic atherosclerosis were evaluated. RESULTS: Weight gain was equivalent in all groups. The glycated haemoglobin level fell equivalently in both insulin-treated groups. Plasma cholesterol and triacylglycerol levels, and hepatic triacylglycerol level significantly improved in the glargine compared with the detemir or control groups. Levels of mRNA expression for monocyte chemotactic protein-1 and F4/80, a macrophage marker, in adipose tissue were decreased only in the glargine group (p < 0.05). Visceral adipose tissue macrophage content decreased in both insulin groups (p < 0.05), whereas atherosclerosis decreased only in the glargine group. Circulating SAA and SAP did not decrease in either insulin-treated group, but IL 6 levels fell in the glargine-treated mice. CONCLUSIONS/INTERPRETATION: While chronic insulin administration did not decrease SAA and SAP, administration of glargine but not detemir insulin improved dyslipidaemia, IL-6 levels and atherosclerosis, and both insulins reduced macrophage accumulation in visceral adipose tissue. Thus, chronic insulin therapy has beneficial tissue effects independent of circulating inflammatory markers in this murine model of diet induced obesity and diabetes. PMID- 21327869 TI - The expression of myogenic regulatory factors and muscle growth factors in the masticatory muscles of dystrophin-deficient (mdx) mice. AB - The activities of myogenic regulatory factors (MRF) and muscle growth factors increase in muscle that is undergoing regeneration, and may correspond to some specific changes. Little is known about the role of MRFs in masticatory muscles in mdx mice (the model of Duchenne muscular dystrophy) and particularly about their mRNA expression during the process of muscle regeneration. Using Taqman RT PCR, we examined the mRNA expression of the MRFs myogenin and MyoD1 (myogenic differentiation 1), and of the muscle growth factors myostatin, IGF1 (insulin like growth factor) and MGF (mechano-growth factor) in the masseter, temporal and tongue masticatory muscles of mdx mice (n = 6 to 10 per group). The myogenin mRNA expression in the mdx masseter and temporal muscle was found to have increased (P < 0.05), whereas the myostatin mRNA expressions in the mdx masseter (P < 0.005) and tongue (P < 0.05) were found to have diminished compared to those for the controls. The IGF and MGF mRNA amounts in the mdx mice remained unchanged. Inside the mdx animal group, gender-related differences in the mRNA expressions were also found. A higher mRNA expression of myogenin and MyoD1 in the mdx massterer and temporal muscles was found in females in comparison to males, and the level of myostatin was higher in the masseter and tongue muscle (P < 0.001 for all comparisons). Similar gender-related differences were also found within the control groups. This study reveals the intermuscular differences in the mRNA expression pattern of myogenin and myostatin in mdx mice. The existence of these differences implies that dystrophinopathy affects the skeletal muscles differentially. The finding of gender-related differences in the mRNA expression of the examined factors may indicate the importance of hormonal influences on muscle regeneration. PMID- 21327870 TI - Expression of human FUS/TLS in yeast leads to protein aggregation and cytotoxicity, recapitulating key features of FUS proteinopathy. AB - Mutations in the fused in sarcoma/translocated in liposarcoma (FUS/TLS) gene have been associated with amyotrophic lateral sclerosis (ALS). FUS-positive neuropathology is reported in a range of neurodegenerative diseases, including ALS and fronto-temporal lobar degeneration with ubiquitin-positive pathology (FTLDU). To examine protein aggregation and cytotoxicity, we expressed human FUS protein in yeast. Expression of either wild type or ALS-associated R524S or P525L mutant FUS in yeast cells led to formation of aggregates and cytotoxicity, with the two ALS mutants showing increased cytotoxicity. Therefore, yeast cells expressing human FUS protein recapitulate key features of FUS-positive neurodegenerative diseases. Interestingly, a significant fraction of FUS expressing yeast cells stained by propidium iodide were without detectable protein aggregates, suggesting that membrane impairment and cellular damage caused by FUS expression may occur before protein aggregates become microscopically detectable and that aggregate formation might protect cells from FUS-mediated cytotoxicity. The N-terminus of FUS, containing the QGSY and G rich regions, is sufficient for the formation of aggregates but not cytotoxicity. The C-terminal domain, which contains a cluster of mutations, did not show aggregation or cytotoxicity. Similar to TDP-43 when expressed in yeast, FUS protein has the intrinsic property of forming aggregates in the absence of other human proteins. On the other hand, the aggregates formed by FUS are thioflavin T positive and resistant to 0.5% sarkosyl, unlike TDP-43 when expressed in yeast cells. Furthermore, TDP-43 and FUS display distinct domain requirements in aggregate formation and cytotoxicity. PMID- 21327871 TI - SMART-T: a system for novel fully automated anticipatory eye-tracking paradigms. AB - Anticipatory eye movements (AEMs) are a natural and implicit measure of cognitive processing and have been successfully used to document such important cognitive capacities as learning, categorization, and generalization, especially in infancy (McMurray & Aslin, Infancy, 6, 203-229, 2004). Here, we describe an improved AEM paradigm to automatically assess online learning on a trial-by-trial basis, by analyzing eye gaze data in each intertrial interval of a training phase. Different measures of learning can be evaluated simultaneously. We describe the implementation of a system for designing and running a variety of such AEM paradigms. Additionally, this system is capable of a wider variety of gaze contingent paradigms, as well as implementations of standard noncontingent paradigms. Our system, Smart-T (System for Monitoring Anticipations in Real Time with the Tobii), is a set of MATLAB scripts with a graphical front end, written using the Psychophysics Toolbox. The system gathers eye gaze data using the commercially available Tobii eye-trackers via a MATLAB module, Talk2Tobii. We report a pilot study showing that Smart-T can detect 6-month-old infants' learning of simple predictive patterns involving the disappearance and reappearance of multimodal stimuli. PMID- 21327872 TI - Normal parenchymal enhancement patterns in women undergoing MR screening of the breast. AB - OBJECTIVES: To characterize the kinetic and morphological presentation of normal breast tissue on DCE-MRI in a large cohort of asymptomatic women, and to relate these characteristics to breast tissue density. METHODS: 335 consecutive breast MR examinations in 229 asymptomatic women undergoing high-risk screening evaluations based on recommendations from the American Cancer Society including strong family history and genetic predisposition were selected for IRB-approved review (average age 49.2 +/- 10.5 years). Breast tissue density was assessed on precontrast T2-weighted images. Parenchymal enhancement pattern (PEP) was qualitatively classified as minimal, homogeneous, heterogeneous or nodular. Quantitative analysis of parenchymal enhancement kinetics (PEK) was performed, including calculation of initial and peak enhancement percentages (E1, E(peak)), the time to peak enhancement (T ( peak )) and the signal enhancement ratio (SER). RESULTS: 41.8% of examinations were classified as minimal, 13.7% homogeneous, 23.9% heterogeneous and 21.2% nodular PEP. Women with heterogeneously or extremely dense breasts exhibited a higher proportion of nodular PEP (44.2% (27/61)) and significantly higher E1, and E(peak) (p < 0.003) compared with those with less dense breasts. CONCLUSIONS: Qualitative and quantitative parenchymal enhancement characteristics vary by breast tissue density. In future work, the association between image-derived MR features of the normal breast and breast cancer risk should be explored. PMID- 21327873 TI - Combination of acid labile detergent and C18 EmporeTM disks for improved identification and sequence coverage of in-gel digested proteins. AB - A protocol for improved extraction of peptides from in-gel protein digests, using a combination of the acid labile surfactant, sodium deoxycholate (SDC) and C18 EmporeTM membranes, is presented. This approach results in better mass spectrum quality, higher numbers of identified peptide peaks and improved identification scores compared to standard tryptic digestion protocols, or protocols using only SDC or only C18 EmporeTM disks. The advantages of the new protocol are demonstrated for two different types of samples: Merino wool intermediate filament proteins and Elaeis guineensis (oil palm) mesocarp proteins. PMID- 21327874 TI - Determination of cocaine on banknotes through an aptamer-based electrochemiluminescence biosensor. AB - A novel electrochemiluminescence (ECL) "sandwich" biosensor has been developed to detect cocaine. The sandwich biosensor was fabricated on the basis of the fact that a single aptamer could be split into two fragments and the two dissociated parts could form a folded, associated complex in the presence of targets. One of these (capture probe), which had hexane-thiol at its 5'-terminus, was immobilized on a gold electrode via thiol-gold binding. The other one (detection probe) was labeled with the ECL reagent tris(2,2'-bipyridyl)ruthenium(II)-doped silica nanoparticles (RuSiNPs) at its 3'-terminus. Owing to the weak interaction between the two fragments, the sensor exhibited a low ECL signal in the absence of cocaine. After the target cocaine had been added to the solution, it induced association of the two fragments and stabilized the associated complexes, leading to immobilization of RuSiNPs on the electrode surface, and the ECL detected on the electrode surface was enhanced. The enhanced ECL intensity was directly proportional to the logarithm of the cocaine concentration in the range from 1.0 * 10(-9) to 1.0 * 10(-11) mol/L, with a detection limit of 3.7 * 10(-12) mol/L. The biosensor was applied to detect trace amounts of cocaine on banknotes with satisfactory results. PMID- 21327875 TI - Simultaneous identification and validated quantification of 11 oral hypoglycaemic drugs in plasma by electrospray ionisation liquid chromatography-mass spectrometry. AB - The detection of diabetic metabolism disorders raises problems in forensic practice and sudden death with a subsequent negative autopsy finding is a common problem. In the case of an unclear hypoglycaemia, the detection of oral antidiabetics allows the differentiation of hypoglycaemia due to oral antidiabetics from that due to other reasons (insulin-induced, insulinoma). The development of an electrospray ionisation (ESI) liquid chromatography-tandem mass spectrometry (LC-MS/MS) procedure for the simultaneous identification and quantification of oral antidiabetics of the sulfonylurea, the glinide, the thiazolidinedione and the gliptin types in human plasma is desired. The following analytes were included: glimepiride, glibenclamide, gliquidone, glibornuride, glisoxepide, glipizide and gliclazide (sulfonylurea type), nateglinide and repaglinide (glinide type), rosiglitazone and pioglitazone (thiazolidinedione type) and the dipeptidyl peptidase inhibitors vildagliptin, sitagliptin and saxagliptin. After a liquid-liquid extraction with tert-butyl methyl ether at two pHs, the oral antidiabetics were separated with fast gradient elution over a C(8) column. Identification of the oral antidiabetics was achieved by two specific ion transitions of each analyte in multiple reaction monitoring mode. Quantification was performed by referring the most intense ion transition peak areas to peak areas of the ion transitions of deuterated oral antidiabetics (hydroxytolbutamide d(9) for the sulfonylureas, repaglinide-ethyl-d(5) for the glinides, pioglitazone d(4) for the thiazolidinediones and vildagliptin-d(3) for the gliptins). The assay was validated according to international guidelines. The LC-MS/MS assay allows the simultaneous identification of 14 oral antidiabetics and quantification of 11 oral antidiabetics in plasma in the ESI mode in a single run. Linearity is shown up to overdose concentrations. The limits of detection with a signal-noise-ratio greater than 3 were below 1 ng/ml for all analytes. Recoveries ranged from 78 to 105%; for vildagliptin and saxagliptin recoveries were worse (45%) owing to their hydrophilic character. Intraday and interday precision and accuracy were below 20% for 11 drugs at three concentrations. For the gliptins, several validation parameters were out of range and, therefore, quantitatively this method is inappropriate. PMID- 21327876 TI - Early graft thrombosis due to antithrombin III deficiency following CABG. AB - The serine protease inhibitor antithrombin III (AT-III), an alpha2-globulin synthesized in the liver and endothelial cells, is the principal in vivo inhibitor of blood coagulation inactivating mainly thrombin. AT-III deficiency presents a rare hereditary or acquired disorder that most often comes to light when a patient suffers recurrent venous thrombosis and pulmonary embolism. Triggers for the onset of the thrombosis include various mechanisms such as pregnancy, delivery, surgery, trauma, and contraceptive pill use. Decreased response to heparin may be the first sign of AT-III deficiency. Since heparin is a conditio sine qua non for cardiopulmonary bypass, rapid consumption of AT-III promoted by heparin may lead to systemic thrombosis. The effect of heparin on graft patency after CABG in patients with AT-III deficiency, particularly with respect to early graft thrombosis, has not been fully investigated. The early detection and timely treatment of this disorder may impact perioperative morbidity. We present a case of simultaneous thrombosis of three venous grafts after elective coronary artery bypass surgery in a patient with AT-III deficiency. PMID- 21327877 TI - Atrial lipomatous hypertrophy causing reduction in systemic venous return. AB - Lipomatous hypertrophy of the interatrial septum (LHIAS) is a benign condition characterized by an abnormal deposition of adipose tissue in the interatrial septum which appears as a pseudomass with a bilobed shape. We present the case of a 68-year-old obese female patient. LHIAS is an infrequent finding, but with recent improvements in imaging it is increasingly recognized. Cardiac MRI may prove useful in its diagnosis in terms of tissue characterization, as well as for the evaluation of disease extension and haemodynamic compromise. PMID- 21327878 TI - [Transcatheter aortic-valve implantation for aortic stenosis. An established procedure?]. AB - Western countries are facing a huge increase of hemodynamically relevant cases of aortic stenosis in an aging population. In the past, about 33% of patients with symptomatic aortic stenosis were not referred for aortic valve replacement although the three years survival rate is only 25 percent after conservative treatment. In Germany transcatheter aortic-valve implantations (TAVI) procedures are reimbursed according to a DRG number. Its usage its not only regulated in a position paper of the German Society of Cardiology giving detailed recommendations for its application and indication. In Germany, approximately 4.000 TAVI procedures were performed in 2009 and even more are expected in 2010. According to the frequency of its usage, DRG reimbursement, and position papers, TAVI procedures seem to be established. However, according to health regulations a new treatment modality is only established if its safety and efficiency is proven, if there is a demand, and if the procedure has economic advantages. According to this definition TAVI is not established since its safety and efficiency compared to the surgical treatment was not been proven in randomised trials yet. Its economic burden in this context is unclear, too. However, there is a need for an alternative to surgical aortic valve replacement to increase the acceptance of valve implantation in an aging population. PMID- 21327881 TI - Renewal-reward process formulation of motor protein dynamics. AB - Renewal-reward processes are used to provide a framework for the mathematical description of single-molecule bead-motor assays for processive motor proteins. The formulation provides a more powerful, general approach to the fluctuation analysis of bead-motor assays begun by Svoboda et al. (Proc. Natl. Acad. Sci. USA 91(25):11782, 1994). Fluctuation analysis allows one to gain insight into the mechanochemical cycle of motor proteins purely by measuring the statistics of the displacement of the cargo (e.g., bead) the protein transports. The statistical parameters of interest are shown to be the steady-state slopes (in time) of the cumulants of the bead (the cumulant rates). The first two cumulant rates are the steady-state velocity and slope of the variance. The cumulant rates are shown to be insensitive to experimental disturbances such as the initial state of the enzyme and from the viewpoint of modeling, unaffected by substeps. Two existing models--Elston (J. Math. Biol. 41(3):189-206, 2000) and Peskin and Oster (Biophys. J. 68(4):202S-211S, 1995)--are formulated as renewal-reward processes to demonstrate the insight that the formulation affords. A key contribution of the approach is the possibility of accounting for wasted hydrolyses and backward steps in the fluctuation analysis. For example, the randomness parameter defined in the first fluctuation analysis of optical trap based bead-motor assays (Svoboda et al. in Proc. Natl. Acad. Sci. USA 91(25):11782, 1994), loses its original purpose of estimating the number of rate-determining steps in the chemical cycle when backward steps and wasted hydrolyses are present. As a simple application of our formulation, we extend the randomness parameter's scope by showing how it can be used to infer the presence of wasted hydrolyses and backward steps with certainty. A more powerful fluctuation analysis using higher cumulant rate measurements is proposed: the method allows one to estimates the number of intermediate reactions, the average chemical rate, and the probability of stepping backward or forward. The stability of the method in the presence of measurement errors is demonstrated numerically to encourage its use in experiments. PMID- 21327879 TI - Prevention of cerebral ischemia-induced memory deficits by inhibition of phosphodiesterase-4 in rats. AB - Inhibition of phosphodiesterase-4 (PDE4) by rolipram, a prototypical PDE4 inhibitor, reverses memory impairment produced pharmacologically or genetically. Comparably, much less is known about the effect of rolipram on cerebral ischemia induced memory deficits. The objective of this study was to determine the effects of rolipram on ischemia-induced memory deficit, neuronal damage, and alteration of PDE4 activity in the hippocampus. Memory was examined using Morris water-maze and step-through passive avoidance tests in rats subjected to global cerebral ischemia with or without repeated treatment with rolipram (0.3 or 1 mg/kg, i.p.); neuronal damage in the hippocampus and PDE4 activity in hippocampal tissues were determined using Nissl staining and HPLC, respectively. In the water-maze test, cerebral ischemia significantly increased the escape latency to reach the platform during acquisition training and decreased the exploration time in the target quadrant in the probe trial test; these were blocked by rolipram in a dose dependent manner. Rolipram also reduced the distracted platform searches induced by cerebral ischemia. In the passive avoidance test, ischemia decreased the 24-h latency to the dark compartment, which was also blocked by rolipram treatment. In addition, Nissl staining revealed ischemia-induced neuron loss in hippocampal CA1; this was blocked by rolipram. Further, cerebral ischemia led to increases in activity of PDE, primarily PDE4, in the hippocampus, which also was antagonized by rolipram. These results suggest that rolipram prevents cerebral ischemia induced memory deficits via inhibition of increased PDE4 activity and attenuation of hippocampal, neuronal damages induced by ischemia. PDE4 may be a target for treatment of cognitive disorders associated with cerebral ischemia. PMID- 21327882 TI - Acid-induced formation of molten globule states in the wild type Escherichia coli 5-enolpyruvylshikimate 3-phosphate synthase and its three mutated forms: G96A, A183T and G96A/A183T. AB - Recent advances in protein chemistry have led to progress in the understanding of protein folding and properties of possible intermediates during the folding of proteins. The molten globule (MG) state, a major intermediate of protein folding, has a denatured state with native-like secondary structure. In the present work, the acid-induced unfolding of wild type Escherichia coli 5-enolpyruvylshikimate 3 phosphate synthase (EPSPS) and its three different variants (G96A, A183T and G96A/A183T) were studied by far- and near-UV circular dichroism (CD), intrinsic fluorescent emission spectroscopy and 1-anilino naphthalene-8-sulfonate (ANS) binding. At pH < 3.0, these EPSPS variants acquire partially folded state, which show the characteristics of the MG state, e.g., a drastic reduction of defined tertiary structure and almost no change in the secondary structure. ANS binding experiments show that hydrophobic surface of these variants is exposed to a greater extent in comparison to the native form, at acidic pH. Wild type, G96A, A183T and G96A/A183T acquire MG states at pH 2.0, 1.5, 3.0 and 3.0, respectively, which show that pH stability of MG state of G96A has increased in comparison to wild type; and pH stability of MG states of two other mutants is lower than that of the wild type. The results suggest that there is a direct relationship between stability of protein and pH stability of its folding intermediates. PMID- 21327883 TI - Diagnosing and understanding the mechanisms behind orthodeoxia syndrome. AB - Orthodeoxia is a rare clinical syndrome characterized by deoxygenation in the upright position and relieved by recumbency. Our rounds illustrate how cardiovascular imaging and echocardiography can be used to diagnose the etiology of this syndrome with respect to its association with patent foramen ovale (PFO) and ascending aortic aneurysms. The rounds also demonstrate the use of peri operative transesophageal echocardiography (TEE) in understanding the mechanisms contributing to the condition and aid in appropriately planning medical and surgical management. PMID- 21327884 TI - Accelerated osteoblast mineralization on a conductive substrate by multiple electrical stimulation. AB - One of the major benefits of a conductive PPy-based substrate is that the mediated electrical stimulation (ES) can be a stimulating factor to promote tissue regeneration. We cultured osteoblast-like Saos-2 cells on a conductive substrate made of biodegradable polylactide (95 wt%) and electrically conducting polypyrrole bioactivated with heparin (PPy/HE) (5 wt%). Using multi-well electrical cell culture plates, the effect of multiple ESs on osteoblast mineralization was investigated at various culture times. As ascertained by ARS, CPC and XPS analyses, the ES was able to promote osteoblast adhesion and growth, resulting in significantly higher calcium and phosphate content in the mineral deposition of the electrically stimulated membranes. Morphology, Ca/P ratio and crystalline structure demonstrated that the minerals on the conductive substrate surface were similar to those found on typical hydroxyapatite. ES also significantly upregulated the expression of the osteoblast-specific markers ALP, BMP2, Runx2 and OC. ES through a synthetic conductive polymer substrate therefore represents a vital option to promote bone regeneration. PMID- 21327886 TI - Aluminum bone toxicity in immature rats exposed to simulated high altitude. AB - Aluminum (Al) is an element to which humans are widely exposed. Chronic administration induces a negative effect on bone tissue, affecting collagen synthesis and matrix mineralization. Its toxic effects are cumulative. Hypobaric hypoxia induces stress erythropoiesis, leading to hypertrophy of the erythropoietic marrow affecting the bone. This study was designed to evaluate the risk of Al bone toxicity among immature rats maintained at simulated high altitude (SHA) by mechanical assessment of stiffness and strength, calculation of some indicators of bone material and geometrical properties, as well as blood determinations. Forty growing rats were divided into control and experimental groups whether injected with vehicle or Al, as Al(OH)(3), three times a week for 3 months. Half of each group was exposed to hypobaric conditions (HX) by placing the animals in a SHA chamber. Both treatments negatively affected structural properties of bones, decreasing the maximum capacity to withstand load, the limit elastic load and the capacity of absorbing energy in elastic conditions. Al administration significantly depressed mandible structural stiffness, although diaphyseal stiffness was not modified. Indicators of bone material intrinsic properties, elastic modulus and stress, were significantly reduced by Al or HX. Treatments increased the diaphyseal sectional bending moment of inertia, suggesting that femur, but not mandible, compensates for the decline in the material properties with an adaptation of its architecture to maintain structural properties. The different biomechanical behaviors between the two kinds of bone are probably due to their different embryological origin and specific functions, as mandible is a bone that adjusts its strength to biting forces, whereas femur is designed to support load. PMID- 21327885 TI - Lack of bone metabolism side effects after 3 years of nasal topical steroids in children with allergic rhinitis. AB - This study evaluated the effects on bone mineral status of long-term treatment with intranasal budesonide (INB) spray, using the recommended dose, in pediatric patients with allergic rhinitis (AR). This retrospective, case-control study of 230 prepubertal children with perennial AR, who had used nasal budesonide at a mean daily dose of 100 MUg (range, 89-132 MUg) for at least 3 years intermittently, was conducted from May 2007 through May 2010. The bone mineral density (BMD) of the lumbar spine was measured by dual-energy X-ray absorptiometry. Levels of serum calcium, phosphorus, alkaline phosphatase (ALP), parathyroid hormone, and osteocalcin were also assessed. The results were compared to sex- and age-matched controls (n = 140), who were newly diagnosed children with AR without any corticosteroid treatment. The 230 study patients (145 boys) were aged from 7 to 11 years. The average age (+/- SEM) was 8.7 +/- 0.7 years; the mean (+/- SEM) steroid dosage used was 73.5 +/- 7.0 MUg daily, with 65.2 +/- 5.2 g total steroid use during treatment. The 140 control patients (90 boys) were aged from 6 to 11 years. No significant differences were observed in BMD (P > 0.05) between the study and the control groups. Although mean serum ALP level was higher, and cortisol, phosphorus, and osteocalcin levels were lower, in the treatment group, these differences were not statistically significant. The findings suggest that long-term intermittent treatment for 3 years with INB spray, 50 MUg twice daily, for children with perennial rhinitis revealed no negative effect on BMD and associated parameters. PMID- 21327887 TI - Studies on removing sulfachloropyridazine from groundwater with microbial bioreactors. AB - Sulfachloropyridazine (SCP), an antibiotic used in aquaculture and in animal husbandry, is a common contaminant in surface and groundwaters. Two types of microbial reactors were evaluated as methods for removing SCP from flowing water. One type of reactor evaluated was a nitrogen-limiting biobarrier; the other a slow-sand-filter. Results showed that the soybean oil-fed, nitrogen-limiting biobarrier was not very effective at removing SCP from flowing water. When supplied with flowing water containing 2.4 mg l(-1) SCP the nitrogen-limiting biobarrier removed ~0.6 mg l(-1) SCP or about 28% of that present. SCP removal by the nitrogen-limiting biobarrier may not have been biological as abiotic removal was not ruled out. More efficient biological removal was obtained with the slow sand-filter which reduced the SCP levels from 2.35 to 0.048 mg l(-1), a removal efficiency of ~98%. High levels of nitrate nitrogen, 50 mg l(-1) N, did not interfere with the removal processes of either reactor suggesting that SCP was not being degraded as a microbial nitrogen source. PMID- 21327888 TI - Production of bioactive gamma-glutamyl transpeptidase in Escherichia coli using SUMO fusion partner and application of the recombinant enzyme to L-theanine synthesis. AB - The amino acid L-theanine (gamma-glutamylethylamide) has potential important applications in the food and pharmaceutical industries and increased demand for this compound is expected. It is the major "umami" (good taste) component of tea and its favorable physiological effects on mammals have been reported. An enzymatic method for the synthesis of L-theanine involving recombinant Escherichia coli gamma-glutamyltranspeptidase (GGT) has been developed. We report here the application of small ubiquitin-related modifier (SUMO) fusion technology to the expression and purification of recombinant Escherichia coli gamma-GGT. In order to obtain gamma-GGT with high theanine-forming activity, safety, and low cost for food and pharmaceutics industry, M9 (consisting of glycerol and inorganic salts) and 0.1% (w/v) lactose were selected as culture medium and inducer, respectively. The fusion protein was expressed in soluble form in E. coli, and expression was verified by SDS-PAGE and western blot analysis. The fusion protein was purified to 90% purity by nickel-nitrilotriacetic acid (Ni NTA) resin chromatography with a yield of 115 mg per liter fermentation culture. After the SUMO/gamma-GGT fusion protein was cleaved by the SUMO protease, the cleaved sample was reapplied to a Ni-NTA column. Finally, about 62 mg recombinant gamma-GGT was obtained from 1 l fermentation culture with no less than 95% purity. The recombinant gamma-GGT showed great transpeptidase activity, with 1500 U of purified recombinant gamma-GGT in a 1-l reaction system, a biosynthesis yield of 41 g of L-theanine was detected by paper chromatography or high pressure liquid chromatography (HPLC). Thus, the application of SUMO technology to the expression and purification of gamma-GGT potentially could be employed for the industrial production of L-theanine. PMID- 21327889 TI - Subtilase genes diversity in the biogas digester microbiota. AB - Biogas digesters contain microbial assemblages that process a mass of extracellular polymeric substances from animal manure and domestic wastewater; however, due to the limitation of available technology in cultivation of majority of the micro-organisms in biogas digesters, the enzymatic potential of these microbial communities remains largely unexplored. In this study, to evaluate subtilase gene diversity in a biogas digester, the partial sequences of the gene were directly amplified from the metagenomic DNA by using consensus-degenerate primers. The desired PCR products were cloned into pGEM-T Easy vector, and thirty positive clones were chose for Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis, from which thirteen distinguished patterns were obtained and then sequenced. Phylogenetic analysis showed that ten out of the thirteen sequences were related to the subtilase genes in GenBank and were grouped into three families of the subtilases superfamily. The nucleotide sequences analysis through BLAST search revealed that none of the partial genes the authors isolated showed significant similarity against the non-redundant Nucleotide database of NCBI. Meanwhile, the deduced amino acid sequences of ten partial subtilase genes showed moderate identities to the previously identified sequences in GenBank, with a range from 39 to 61%. Collectively, the data indicate that there is a great diversity of subtilase genes in the biogas digester; and may be a rich reservoir for novel subtilase genes. PMID- 21327890 TI - Future perspectives on neuroendocrine tumors. AB - In the last 30 years the incidence and prevalence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has increased substantially. This could be partly due to improvements in diagnostic imaging, which lead to the incidental diagnosis of asymptomatic cases. However, despite these improvements, patients typically experience long delays before they are diagnosed. In this review, we discuss both the limitations and advances in our understanding of the pathogenesis, molecular and cellular biology, diagnosis, classification, staging, and treatment of GEP-NETs in order to identify which factors could be contributing to the delay in diagnosis and timely treatment of these patients. Within this context, the results from the most relevant clinical trials the available targeted therapies for the treatment of GEP-NETs, such as the "RAD001 in Advanced Neuroendocrine Tumors," will be discussed. PMID- 21327891 TI - Multiple mirror-image peripheral arterial aneurysms in Kawasaki disease. AB - We present the case of a 5-year-old boy diagnosed with Kawasaki disease at 10 months of age who developed fusiform aneurysms of the coronary arteries as well as a previously undescribed pattern of mirror-image peripheral arterial aneurysms. These aneurysms were diagnosed on conventional angiography of the aortoiliac circulation and the bilateral upper extremity circulation. PMID- 21327892 TI - Congenital cardiac defects: a possible association of aminopterin syndrome and in utero methotrexate exposure? AB - Folate antagonist are chemotherapeutic agents used in many neoplastic, autoimmune, and inflammatory disorders. The first suggestions that folic acid antagonists were teratogenic in humans were based on reports of failed terminations in mothers given aminopterin in the first trimester. Newborns who survived after aminopterin exposure were noted for years to have defects of the neural tube, skull, or limbs. There is now a well-defined syndrome of congenital anomalies associated with the use of aminopterin. The aminopterin syndrome consists of cranial dysostosis, hypertelorism, anomalies of the external ears, micrognathia, limb anomalies, and cleft palate. The use of aminopterin has now fallen out of favor. Methotrexate is a folate antagonist that is now used more frequently. A similar pattern of malformations has been found in fetuses exposed to methotrexate. If used during pregnancy, it can cause congenital malformations or fetal death. A consistent association between methotrexate exposure and cardiac, renal, or gastrointestinal malformations has not been reported. We report two patients who presented with classic features of aminopterin syndrome combined with significant congenital cardiac malformations after first-trimester in utero methotrexate exposure. Both of these patients survived to undergo corrective cardiac surgery. PMID- 21327893 TI - Accuracy of cardiac auscultation in asymptomatic neonates with heart murmurs: comparison between pediatric trainees and neonatologists. AB - The aim of this study was to assess whether cardiac auscultation performed by pediatric trainees and neonatologists can reliably distinguish innocent from pathologic heart murmurs in asymptomatic neonates. From January 2008 to April 2009 the pediatric trainees of our institution were requested to refer all asymptomatic neonates with a murmur and classify the murmurs as "innocent," "pathologic," or "possibly pathologic." Prior to echocardiography, each neonate was evaluated by two experienced neonatologists. The echocardiographic studies of 169 neonates were analyzed. Abnormal cardiac anatomy was found in 55 neonates (32.6%). The overall ability of pediatric trainees in identifying congenital heart disease (CHD) was moderate [area under the curve (AUC) = 0.855] and significantly lower compared to neonatologists (AUC = 0.919, p = 0.007). However, at "lower" levels of clinical confidence (i.e., clinical diagnosis of possibly pathologic murmurs), pediatric trainees had good ability in excluding CHD (sensitivity 94.6%; negative likelihood ratio = 0.09). The ability of cardiac auscultation for diagnosing CHD in asymptomatic neonates is limited and dependent on the physician's experience and level of clinical confidence. Echocardiography should remain an option for all neonates with a possibly pathologic murmur. PMID- 21327894 TI - Noncoronary aortic cusp rupture in an adult patient with ventricular septal defect: echocardiographic diagnosis. AB - Aortic regurgitation is a common complication of ventricular septal defects. The most common mechanism is right or noncoronary cusp prolapse. Other mechanisms are right or noncoronary cusp fibrosis resulting in thickening and restricted motion of the leaflets or infective endocarditis leading to cusp perforation. We describe a case of subacute and severe aortic regurgitation due to noncoronary cusp prolapse resulting in the development of a large aneurysm and rupture of the noncoronary sinus of Valsalva into the right atrium. PMID- 21327895 TI - [The stiff elbow joint]. PMID- 21327896 TI - Host-specific genetic variation of highly pathogenic avian influenza viruses (H5N1). AB - The complete genome sequences of two isolates A/chicken/Egypt/CL6/07 (CL6/07) and A/duck/Egypt/D2br10/07 (D2br10/07) of highly pathogenic avian influenza virus (HPAI) H5N1 isolated at the beginning of 2007 outbreak in Egypt were determined and compared with all Egyptian HPAI H5N1 sequences available in the GenBank. Sequence analysis utilizing the RNA from the original tissue homogenate showed amino acid substitutions in seven of the viral segments in both samples. Interestingly, these changes were different between the CL6/07 and D2br10/07 when compared to other Egyptian isolates. Moreover, phylogenetic analysis showed independent sub-clustering of the two viruses within the Egyptian sequences signifying a possible differential adaptation in the two hosts. Further, pre amplification analysis of H5N1 might be necessary for accurate data interpretation and identification of distinct factor(s) influencing the evolution of the virus in different poultry species. PMID- 21327898 TI - Suture repair using loop technique in cases of acute complete acromioclavicular joint dislocation. AB - BACKGROUND: Acromioclavicular joint dissociation may not be a common injury, yet it may cause limitations in activity. Types IV, V, and VI dissociations need operative repair. In this study, a simple technique is advocated to reduce and maintain reduction of the acromioclavicular joint using no. 5 nonabsorbable suture material while the resutured coracoclavicular (CC) ligament heals. METHODS AND METHODS: Twenty-one patients (16 men and five women) with types IV and V acromioclavicular joint dissociation were studied. In all cases, acromioclavicular joint was reduced and reduction was maintained using no. 5 nonabsorbable suture material passed as a loop under the knuckle of the coracoid process and through a tunnel drilled through the lateral third of the clavicle. The CC ligament was then resutured. RESULTS: Patients were followed up over a period of 6-9 years. At the final follow-up, all patients had returned to their preinjury level of activity, with significant improvement in the University of California Los Angeles (UCLA), American Shoulder and Elbow Surgeons Shoulder (ASES), and the Constant scores. CONCLUSIONS: This technique provided good results with no loss of reduction, except in a single case, during the long follow-up period. We could not prove that the good results are due to the healing of the CC ligament. However, patients were able to return to their daily activities and even contact sports without any noticeable deformity, feeling of weakness, pain, or limitation of range of motion (compared with the contralateral side). This technique does not involve the use of metallic implants, which require another surgery to remove them, the use of expensive synthetic graft, or a graft harvested from a distant donor site. PMID- 21327897 TI - Biomarker-based prediction of inflammatory bowel disease-related colorectal cancer: a case-control study. AB - BACKGROUND: Regular colonoscopic surveillance for detection of dysplasia is recommended in longstanding inflammatory bowel disease (IBD), however, its sensitivity is disputed. Screening accuracy may increase by using a biomarker based surveillance strategy. METHODS: A case-control study was performed to determine the prognostic value of DNA ploidy and p53 in IBD-related neoplasia. Cases with IBD-related colorectal cancer (CRC), detected in our surveillance program between 1985-2008, were selected and matched with two controls, for age, gender, disease characteristics, interval of follow-up, PSC, and previous surgery. Biopsies were assessed for DNA ploidy, p53, grade of inflammation and neoplasia. Progression to neoplasia was analyzed with Cox regression analysis, adjusting for potentially confounding variables. RESULTS: Adjusting for age, we found statistically significant Hazard ratios (HR) between development of CRC, and low grade dysplasia (HR5.5; 95%CI 2.6-11.5), abnormal DNA ploidy (DNA index (DI) 1.06-1.34, HR4.7; 95%CI 2.9-7.8 and DI>1.34, HR6.6; 95%CI 3.7-11.7) and p53 immunopositivity (HR3.0; 95%CI 1.9-4.7) over time. When adjusting for all confounders, abnormal DNA ploidy (DI 1.06-1.34, HR4.7; 95%CI 2.7-7.9 and DI>1.34, HR5.0; 95%CI 2.5-10.0) and p53 immunopositivity (HR1.7; 95%CI 1.0-3.1) remained statistically significant predictive of neoplasia. CONCLUSION: In longstanding IBD, abnormal DNA ploidy and p53 immunopositivity are important risk factors of developing CRC. The yield of surveillance may potentially increase by adding these biomarkers to the routine assessment of biopsies. PMID- 21327899 TI - [AH-10/04 - international study on testicular cancer: randomized phase III study 1xBEP in comparison to 2xBEP for patients with non-seminomatous testicular cancer in clinical stage I (high risk)]. PMID- 21327900 TI - [Carcinoid tumor of the testis]. AB - A 69-year-old man presented with a 2.4 cm painless mass in his right testis. Inguinal orchiectomy was performed. Histologically a carcinoid tumor of the testis was diagnosed. These neuroendocrine, noninvasive tumors are very rare, representing 0.23% of all testicular neoplasms. In 10% these tumors are associated with carcinoid syndrome and in 20% with metastatic disease. PMID- 21327901 TI - [The role of tumour markers in diagnosis and management of testicular germ cell tumours]. AB - Alpha-fetoprotein (AFP), human choriogonadotropin (hCG) and lactate dehydrogenase (LDH) are established tumour markers of testicular germ cell tumours (TGCT) which are used according to the guidelines for primary diagnosis, staging, monitoring of therapeutic response and follow-up. Placental alkaline phosphatase and neurone specific enolase play no role at all in the diagnosis and management of TGCT.Metastasized TGCT are classified according to the IGCCCG classification system into tumours with good, intermediate and poor prognosis depending on their serum concentration. The risk classification has a direct impact on therapy and determines the intensity of chemotherapy. In rare cases AFP and hCG might be elevated due to non-testicular reasons which have to be taken into consideration for the differential diagnosis especially if marker concentration and clinical presentation do not match. Response to chemotherapy is monitored with AFP and hCG which are determined the day before initiation of the next treatment cycle. Marker increases during or shortly after discontinuation of chemotherapy indicate a poor prognosis and make the immediate initiation of salvage treatment regimes necessary. Only 40-50% and 30% of relapses in patients under active surveillance for clinical stage I disease and after systemic chemotherapy are associated with marker increases. The remainder will be diagnosed by imaging studies or clinical symptoms. Marker increases have to be validated by imaging studies. However, about 10% of all relapsing patients have marker increases only without any imaging evidence of metastatic disease. Residual masses of any size and location have to be treated by postchemotherapy resection once the marker concentration is normalized or once it has reached a stable plateau. So-called desperation surgery in the presence of rising tumour markers is only indicated if no curative chemotherapy is available, all residual masses are completely resectable and no hCG elevation are observed. For follow-up, AFP, hCG and LDH should be evaluated for advanced TGCT and clinical stage I nonseminomas, whereas clinical stage I seminomas should be monitored without any markers. PMID- 21327902 TI - A tipping point in drug dosing in late-life schizophrenia. AB - Minimally effective doses of antipsychotics are likely influenced by several clinical and demographic characteristics of patients, with age being one of the most important elements. In light of age-related physiologic changes as well as interindividual differences in pharmacokinetic and pharmacodynamic systems, individualized dosing with regard to age will be critically important for safer drug treatment for older patients with schizophrenia. In the present review, we propose the following cautious psychopharmacologic interventions for this population: 1) simple regimen (avoid polypharmacy), 2) be aware of the presence of patients who are very sensitive to drugs, 3) gradual dose titration, and 4) timely and thorough assessments of therapeutic and side effects. The age-related antipsychotic sensitivity highlights the importance of finding the lowest possible effective dose of antipsychotic drugs as patients with schizophrenia age to maximize therapeutic effects and minimize side effects. PMID- 21327903 TI - Identifying and assessing psychosis in deaf psychiatric patients. AB - This article reviews recent research in the area of psychotic disorders in deaf psychiatric patients. Comparisons of the rates of psychotic disorders in the deaf and hearing populations suggest that psychotic disorders occur equally as often or even somewhat less often in the deaf population as in the hearing population. Consideration is given to the limitations of this small body of research, and recommendations for future research are provided. The contradictory literature on hallucinations in the deaf is also reviewed, and current theory about the manner in which hallucinations are manifested and experienced based on audiological history is presented. The challenges encountered by clinicians in accurately assessing symptoms of thought disorganization in deaf people are reviewed. Specifically, the etiology of deafness, language dysfluency, and the skill and training of American Sign Language interpreters are considered as factors impacting accurate diagnosis. Recommendations from the current literature are also provided. PMID- 21327904 TI - Targeting criminal recidivism in mentally ill offenders: structured clinical approaches. AB - Decreasing criminal recidivism in justice-involved individuals with mental illness, is among the most consistently desired outcomes by programs, policy makers and funding agencies. Evidence-based practices with track records of effectiveness in treating mental illness and co-occurring substance abuse, while important clinically, do not necessarily address criminal recidivism. Addressing recidivism, therefore, may require a more targeted criminal justice focus. In this paper, we describe recent challenges to decriminalization approaches and review factors associated with recurrent criminal behavior. In particular, we focus on structured clinical interventions which were created or adapted to target the thoughts and behaviors associated with criminal justice contact. PMID- 21327905 TI - [Benign esophageal disorders. Gastroesophageal reflux disease, diffuse esophageal spasm, achalasia]. AB - Gastroesophageal reflux disease (GERD) is the most frequent benign disorder of the upper gastrointestinal (GI) tract and other defined disease entities, such as achalasia and diffuse esophageal spasm, also belong to this group. In addition to surgical therapy, medicinal therapy also has an important role in all 3 of these disorders. Therefore, it is very important to follow precise indication criteria based on diagnostic evaluation and patient selection as well as to use an optimal operative technique.The therapeutic spectrum for achalasia varies from Botox injections and endoscopic dilatation to laparoscopic myotomy which achieves a success rate up to 90%.Patients with diffuse spasm suffer from severe dysphagia, thoracic pain and burning sensations and even respiratory problems. Surgical therapy consists of thoracoscopic long myotomy and in selective cases with persisting pain even esophagectomy and gastric pull-up.Therapeutic options for GERD predominantly involve conservative medicinal therapy with proton pump inhibitors and selective laparoscopic antireflux procedures. Minimally invasive techniques have led to a higher acceptance of surgical therapy. The two major procedures most frequently used are total Nissen fundoplication and posterior partial Toupet fundoplication. PMID- 21327906 TI - [Management of mesh-related infections]. AB - Infections of an implanted hernia mesh are a major challenge. The incidence of mesh infections after incisional hernia repair is about 1% for endoscopic techniques and can be more than 15% in open techniques. Intraoperative mesh contamination is considered to be the primary cause. All woven or knitted hernia meshes have recesses where bacteria may adhere and establish colonies. The bacterial spectrum for mesh infection includes skin pathogens, such as Staphylococcus aureus (including MRSA), Streptococcus spp., as well as E. coli, Enterococcus and Mycobacteria. The therapy approach needs to be tailored to the morphological findings and the treatment for uncomplicated phlegmon is broad spectrum antibiotic therapy. If there is encapsulated fluid accumulation, CT controlled drainage and daily infusion of antiseptics via the drain is a good option. For dermal necrosis, mesh fistula, exposed mesh or enterocutaneous fistula, a precise CT evaluation is necessary to tailor the operation. Vacuum systems are gaining increased acceptance in conditioning the local findings. For most patients the therapeutic concept will be based on individual decisions. If parts of a formerly infected mesh remain in the patient, a lifelong follow-up is necessary. PMID- 21327907 TI - [Definition and management of wound infections]. AB - Surgical site infections (SSI) in the postoperative period represent the sword of Damocles in surgery. In spite of the medical progress in recent years these infections cannot always be avoided and occur in 25% of all nosocomial infections in Germany. They also generate up to 50% of the required costs in this context. The consequences vary from extended duration of hospitalization to elevated mortality. The degree of contamination of surgical wounds is of great importance as well as the patient's immune status and comorbidities. Prevention of infected surgical wounds is essential and important measures should begin even prior to the surgical procedure. In addition, during and following the surgical procedure several standards have to be followed. Rapid confirmation of diagnosis and correct management of surgical site infections are essential for the course of the disease. This study provides information on development, prevention and therapy of surgically infected wounds. PMID- 21327908 TI - Pathophysiological idiosyncrasies and pharmacokinetic realities may interfere with tacrolimus dose titration in liver transplantation. AB - PURPOSE: To explore the main factors that make it difficult to empirically monitor tacrolimus (TAC) in the early period post-liver transplantation (LTx), with a specific focus on those aspects related to patient idiosyncrasy and clinical status as well as to the pharmacokinetic (PK) assumptions on which drug individualization in clinical practice is based. METHODS: Retrospective monitoring data from 75 de novo liver transplant patients treated with twice daily with TAC and followed for up to 15 days were analyzed. An extensive battery of laboratory measurements were available. Dose adjustment was performed empirically using trough levels (C(min)). The population was separated into two major background groups according to low or high values of aspartate aminotransferase (AST) (Group 1 and 2, respectively) based on AST measurements made during the first 4 days post-LTx. Each of these two major groups was then further subdivided into two subgroups based on elevated (Groups 1A, 2A) or reduced (Groups 1B, 2B) combined albumin (cut-off 2.5 g/dl) and hematocrit (cut off 28%). RESULTS: The C(min)/Dose ratio [inversely proportional to systemic clearance (CL)] had a variability [coefficient of variation (CV) >80%) that was incongruently higher for the ratio than for C(min) and Dose separately. This was attributed to most patients not being at steady state or physiologically stable in the early post-LTx period. Group 1 patients were more predictable than Group 2 patients, who were responsible for the variability in the ratio. C(min) was lower in the reduced ALB and HCT patient groups when AST conditions were similar (1A vs. 1B and 2A vs. 2B), likely due to increased TAC metabolic clearance (reduced C(min)/Dose). This situation existed for two periods: 0-15 days post-LTx and 4-15 days post-LTx observations. Group 2A patients were the main source of the paradoxical variability in C(min)/Dose (higher ratio of 2.7; CV = 100%), suggesting a lower clearance and difficulty in the recovery of stability. In contrast, Group 2B patients had the lower ratio (1.4; 47%) but required the highest number of dose adjustments as the variability was hard to identify clinically. Group 1A patients were the most predictable empirically. When observations from 15 new patients who entered the clinic in 2007 and 2008 were used for the analysis, the same sub-groups existed in the same proportions in both years. CONCLUSION: The difficulty in empirical dose adjustment of TAC is associated to the inevitable non-fulfillment of PK assumptions early post-LTx and also to the inherent complexity of the clinical condition, leading to increased uncertainty for the clinician regarding dose selection. Identifying these sub categories provides a rational means of classifying patients akin to a phenotype. The complexity of the kinetics in LTx and TAC treatment does not invalidate C(min) as a biomarker, but a Bayes algorithm including a full PK structure and these covariates would be optimal. PMID- 21327909 TI - Effects of SLCO1B1 polymorphisms on the pharmacokinetics and pharmacodynamics of repaglinide in healthy Chinese volunteers. AB - PURPOSE: Repaglinide is commonly used in the treatment of patients with type 2 diabetes mellitus to reduce postprandial hyperglycemia. The objective of this research was to study the effects of SLCO1B1 polymorphisms on the pharmacokinetics and pharmacodynamics of repaglinide in healthy Chinese volunteers. METHODS: A total of 22 healthy young male participants were recruited from a pool of pharmacogenetically characterized participants genotyped for SLCO1B1, CYP3A4, and CYP2C8 SNPs by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Volunteers with CYP2C8*3 and CYP3A4*4 alleles were excluded from the clinical study. Then selected volunteers took part in the clinical pharmacokinetic study, receiving 2 mg repaglinide. RESULTS: Healthy participants with SLCO1B1*1A/*1B or *1A/*1A genotype and SLCO1B1 *15/*1A or *5/*1A genotype had significantly higher AUC(0-infinity) than participants with SLCO1B1*1B/*1B genotype, with the former showing an increase over the latter of 39.81 and 42.09%, respectively (P = 0.028, 0.032). The clearance in the former two genotype groups was significantly attenuated (by 27.39 and 28.55%, respectively) compared with individuals with SLCO1B1*1B/*1B genotype (P = 0.015, 0.019). No significant differences in blood glucose-lowering effect were observed among three genotype groups. CONCLUSIONS: SLCO1B1*1B/*1B genotype is associated with reduced pharmacokinetic exposure after a single dose oral administration of 2 mg repaglinide, including decreased AUC(0-infinity) and increased clearance of repaglinide. Moreover, this polymorphism of SLCO1B1 has significant influence on the pharmacokinetics of repaglinide, but no effects on its pharmacodynamics. PMID- 21327911 TI - Contribution of pH to systemic exposure of niflumic acid following oral administration of talniflumate. AB - PURPOSE: Systemic exposure to niflumic acid was significantly increased when talniflumate was given orally together with a meal. To clarify the underlying mechanism, an in vitro dissolution study of talniflumateonducted at different pH values, and magnesium hydroxide was co-administered in healthy volunteers. METHODS: In vitro dissolution tests of talniflumate tablets were performed in a USP Paddle apparatus at pH 1.2, 4.0, and 6.8, respectively, in the presence and absence of Tween 80 (2%). Serial samples of the talniflumate solution were taken and analyzed on a high-performance liquid chromatography (HPLC)/ultraviolet system. Healthy volunteers were divided randomly into two groups, and each volunteer received a single 740-mg dose of talniflumate, with or without 1 g of magnesium hydroxide, following an overnight fast. The plasma concentrations of niflumic acid were measured using HPLC coupled with tandem mass spectrometry. RESULTS: Talniflumate was completely insoluble at each of the tested pHs in the absence of Tween 80. The drug was slowly and steadily dissolved (54%) at pH 4 in the presence of the surfactant, but the extent of dissolution was only 15 and 0.5% at pH 1.2 and 6.0, respectively. Magnesium hydroxide co-administered with talniflumate significantly increased systemic exposure to niflumic acid: the mean maximum plasma concentration (C (max)) and area under the concentration-time curve (AUC (inf)) were augmented by 2.0- and 1.9-fold, respectively, compared with those in the absence of the antacid. Magnesium hydroxide significantly accelerated the appearance of niflumic acid in plasma by 2.8-fold. CONCLUSIONS: Magnesium hydroxide increases the rate and extent of systemic exposure to niflumic acid owing to the enhanced solubility of talniflumate and absorption of niflumic acid. The possible combination of talniflumate and an antacid should be considered in the development of pharmaceutical formulations. PMID- 21327910 TI - Arginine vasopressin (AVP) and treatment with arginine vasopressin receptor antagonists (vaptans) in congestive heart failure, liver cirrhosis and syndrome of inappropriate antidiuretic hormone secretion (SIADH). AB - Arginine vasopressin (AVP) is the major physiological regulator of renal water excretion and blood volume. The AVP pathways of V(1a)R-mediated vasoconstriction and V(2)R-induced water retention represent a potentially attractive target of therapy for edematous diseases. Experimental and clinical evidence suggests beneficial effects of AVP receptor antagonists by increasing free water excretion and serum sodium levels. This review provides an update on the therapeutic implication of newly developed AVP receptor antagonists in respective disorders, such as chronic heart failure, liver cirrhosis and syndrome of inappropriate antidiuretic hormone secretion. PMID- 21327912 TI - Intracoronary optical coherence tomography, basic theory and image acquisition techniques. AB - Optical coherence tomography (OCT) imaging is showing great potential as an alternative or complementary tool to intravascular ultrasound (IVUS) for aiding in stent procedures and future diagnosis/treatment of atherosclerosis. Here, we describe the basic theory behind OCT imaging and explain important parameters such as axial resolution, lateral resolution and sensitivity. Also, we describe several image acquisition techniques that have been adopted for OCT imaging. PMID- 21327913 TI - Dedicated bifurcation analysis: basic principles. AB - Over the last several years significant interest has arisen in bifurcation stenting, in particular stimulated by the European Bifurcation Club. Traditional straight vessel analysis by QCA does not satisfy the requirements for such complex morphologies anymore. To come up with practical solutions, we have developed two models, a Y-shape and a T-shape model, suitable for bifurcation QCA analysis depending on the specific anatomy of the coronary bifurcation. The principles of these models are described in this paper, as well as the results of validation studies carried out on clinical materials. It can be concluded that the accuracy, precision and applicability of these new bifurcation analyses are conform the general guidelines that have been set many years ago for conventional QCA-analyses. PMID- 21327914 TI - IVUS-based imaging modalities for tissue characterization: similarities and differences. AB - Gray-scale intravascular ultrasound (IVUS) is the modality that has been established as the golden standard for in vivo imaging of the vessel wall of the coronary arteries. The use of IVUS in clinical practice is an important diagnostic tool used for quantitative assessment of coronary artery disease. This has made IVUS the de-facto invasive imaging method to evaluate new interventional therapies such as new stent designs and for atherosclerosis progression regression studies. However, the gray-scale representation of the coronary vessel wall and plaque morphology in combination with the limited resolution of the current IVUS catheters makes it difficult, if not impossible, to identify qualitatively (e.g. visually) the plaque morphology similar as that of histopathology, the golden standard to characterize and quantify coronary plaque tissue components. Meanwhile, this limitation has been partially overcome by new innovative IVUS-based post-processing methods such as: virtual histology IVUS (VH IVUS, Volcano Therapeutics, Rancho Cordova, CA, USA), iMAP-IVUS (Bostoc Scientific, Santa Clara, CA, USA), Integrated Backscatter IVUS (IB-IVUS) and Automated Differential Echogenicity (ADE). PMID- 21327915 TI - What's the hype about CDK5RAP2? AB - Cyclin dependent kinase 5 regulatory subunit-associated protein 2 (CDK5RAP2) has gained attention in the last years following the discovery, in 2005, that recessive mutations cause primary autosomal recessive microcephaly. This disease is seen as an isolated developmental defect of the brain, particularly of the cerebral cortex, and was thus historically also referred to as microcephalia vera. Unraveling the pathomechanisms leading to this human disease is fascinating scientists because it can convey insight into basic mechanisms of physiologic brain development (particularly of cortex formation). It also finds itself in the spotlight because of its implication in trends in mammalian evolution with a massive increase in the size of the cerebral cortex in primates. Here, we provide a timely overview of the current knowledge on the function of CDK5RAP2 and mechanisms that might lead to disease in humans when the function of this protein is disturbed. PMID- 21327917 TI - Proximal and overall gastric emptying of solids in patients with reduced gastric volume accommodation compared to matched controls. AB - BACKGROUND: Interventions such as gastric surgery and erythromycin result in displacement of solids to the distal stomach and acceleration of overall and proximal gastric emptying. The effect of non-surgical impairment of gastric accommodation on gastric emptying is unclear. Non-surgical impairment of gastric accommodation is associated with accelerated gastric emptying. AIM: To compare measurements of proximal and overall gastric emptying in patients with reduced postprandial gastric volume accommodation with the emptying rates in age- and gender-matched controls with normal postprandial gastric volume accommodation. METHODS: We evaluated overall and proximal gastric emptying in nine patients with impaired gastric accommodation and age-equivalent and gender-matched controls. Gastric volumes and emptying were measured using validated SPECT and dual gamma camera scintigraphy, respectively. We compared group differences in overall and proximal gastric emptying t (1/2) by t test. RESULTS: Patients with impaired postprandial gastric volume accommodation had greater fasting gastric volume. The proportion of food emptied from the proximal stomach immediately after meal ingestion was lower and t (1/2) of proximal gastric emptying correspondingly longer in the group with reduced postprandial gastric accommodation. In contrast, differences were not detected in overall gastric emptying in the two groups, and the ratio of overall to proximal gastric emptying t (1/2) was greater in the group with impaired volume accommodation. CONCLUSIONS: Proximal stomach emptying is reduced in patients with impaired postprandial volume accommodation; this difference occurs predominantly during the time of meal ingestion. Compensatory mechanisms that result in normal overall gastric emptying require further elucidation. PMID- 21327916 TI - Novel therapy for myocardial infarction: can HGF/Met be beneficial? AB - Myocardial infarction (MI) is a leading cause of hospitalization worldwide. A recently developed strategy to improve the management of MI is based on the use of growth factors which are able to enhance the intrinsic capacity of the heart to repair itself or regenerate after damage. Among others, hepatocyte growth factor (HGF) has been proposed as a modulator of cardiac repair of damage due to the pleiotropic effects elicited by Met receptor stimulation. In this review we describe the mechanistic basis for autocrine and paracrine protection of HGF in the injured heart. We also analyse the role of HGF/Met in stem cell maintenance and in stem cell therapies for MI. Finally, we summarize the most significant results on the use of HGF in experimental models of heart injury and discuss the potential of the molecule for treating ischaemic heart disease in humans. PMID- 21327919 TI - A comparative study of endoscopic ultrasound guided fine needle aspiration with and without a stylet. AB - BACKGROUND: Despite lack of evidence, use of a stylet during endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is assumed to improve the quality and diagnostic yield of specimens. AIM: The purpose of this study was to compare EUS-FNA specimens obtained with stylet (S+) and without stylet (S-) for: (i) cellularity, contamination, adequacy, and amount of blood and (ii) diagnostic yield of malignancy. METHODS: Patients who underwent EUS-FNA of solid lesions by two experienced endosonographers at a tertiary referral center using a 22-gauge FNA needle with suction were included. Stylet was used for all EUS-FNA procedures performed between January 2006 and September 2007 and no stylet was used between October 2007 and April 2009 allowing comparison between the two techniques. Cytology slides were retrieved, de-identified and evaluated by two experienced cytopathologists blinded to FNA technique. Slides were evaluated for cellularity, degree of contamination, adequacy, amount of blood and cytologic diagnosis. Fisher's exact and unpaired t-test were used for comparative analysis. RESULTS: A total of 162 patients with 228 lesions were included. FNA of 106 and 122 lesions each was performed in the S+ and S- groups, respectively. FNA sites included pancreas [41 (18%)], lymph node [125 (55%)], liver [20 (9%)], adrenal [21 (9%)] and others [21 (9%)]. No significant differences in the cellularity (P=0.37), contamination (P=0.18), significant blood (P=0.42) and adequacy of specimen (P=0.45) were found between S+ and S- specimens. There was no statistically significant difference in the diagnostic yield of malignant lesions (P=0.48). CONCLUSIONS: The use of stylet during FNA does not appear to confer any advantage with regards to the adequacy of specimen or diagnostic yield of malignancy. PMID- 21327918 TI - Medication nonadherence with long-term management of patients with hepatitis B e antigen-negative chronic hepatitis B. AB - BACKGROUND AND AIMS: Antiviral treatment responses for patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) are well-defined by data from registration trials but may differ from patients seen in community settings where medical adherence is usually not as strictly monitored. The goal of this study was to examine the long-term outcomes of HBeAg-negative patients in a community clinical setting. METHODS: We performed a cohort study of 189 consecutive treatment-naive patients with CHB who were treated with either entecavir (ETV) 0.5 mg daily (n=107) or adefovir dipivoxil (ADV) 10 mg daily (n=82) from 2002 to 2009 at two community clinics. RESULTS: All patients were Asians. Both ETV and ADV cohorts had similar median baseline ALT and HBV DNA levels. By year 4, a similar proportion of ETV and ADV patients who remained on monotherapy achieved complete viral suppression (91-96%); however, more patients in the ADV cohort required alternative therapy (27 vs. 5%). No patients in the ETV cohort developed resistance while 18% of the ADV cohort did. Cumulative nonadherence rates were 10 and 12% in ADV and ETV cohorts, respectively. CONCLUSIONS: Failure to monotherapy in a community clinical setting is due to both antiviral resistance and patient nonadherence. Medication nonadherence is likely to be a more important contributor to treatment failure than antiviral resistance, especially with new anti-HBV agents such as ETV and tenofovir. PMID- 21327920 TI - Should a colonoscopy be recommended for healthy individuals with increased carcinoembryonic antigen levels? A case-control study. AB - BACKGROUND AND AIM: Despite the limitations of screening or early diagnosis of colorectal cancers (CRC), carcinoembryonic antigen (CEA) is frequently measured in practice and during health promotion programs. The aim of this study was to evaluate the role of colonoscopy in healthy individuals with elevated CEA levels. METHODS: From January 2003 to November 2008, 117,731 healthy persons underwent an opportunistic screening program in two health promotion centers; 1,497 subjects (1.3%) showed an elevated CEA level (>5 ng/ml). Among them, 174 patients were recruited to undergo a colonoscopy to determine if colorectal malignancies were present. A total of 372 age- and sex-matched persons were selected as controls from among the healthy subjects who had a normal level of CEA and had received surveillance colonoscopy. The primary outcome was the incidences of CRC in elevated CEA and normal CEA groups. The secondary outcome was the predictive factors of CRC in the elevated CEA group. RESULTS: The incidence of CRC was higher in the group with higher CEA-levels than in the group with normal CEA levels (4.6 vs. 1.3%; P=0.031). In the CEA-elevated group, patients with CRCs were diagnosed at more advanced stages than were those in the CEA-normal group. The incidence of colorectal polyps was not different between the two groups. In the CEA-elevated group, anemia was an independent predictive factor of CRCs by multivariate analysis (P=0.002). CONCLUSION: Anemia itself is not a predictive factor of CRC in the entire population, but is an independent predictive factor of CRC in healthy individuals with an elevated level of CEA. Therefore, colonoscopy should be recommended for healthy subjects with an elevated level of CEA accompanied with anemia in the absence of other adenocarcinomas to evaluate the presence of colorectal malignancy. PMID- 21327921 TI - Correlation analysis between gene expression profile of rat liver tissues and high-fat emulsion-induced nonalcoholic fatty liver. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is caused by fat metabolism disorders and thereby abnormal or excessive accumulation of fat in hepatocytes, and characterized by steatosis, inflammation, fibrosis, apoptosis or necrosis. AIM: This study was carried out to explore the correlation between gene expression profiles of rat livers and the occurrence and progression of NAFLD at the transcriptional level. METHODS: A rat model of nonalcoholic steatohepatitis (NASH) was established by feeding male rats with high-fat emulsion via gavage, and Rat Genome 230 2.0 Array was used to detect gene expression profiles of liver tissues obtained from male rats following 0, 2, 4, and 6 weeks of high-fat emulsion feeding. Methods of bioinformatics and systems biology were applied to analyze the correlation between gene expression changes and physiological activities involved in NAFLD. RESULTS: In total, 93 function-known genes, including 36 up-regulated and 57 down-regulated, differed significantly in expression compared to those of control rats, and 18 physiological activities were closely related to NAFLD. Especially, the activity of cell differentiation was decreased during the whole process of NAFLD, and the activities of inflammation response, stimulus response, cell migration and adhesion were attenuated in the second, fourth and sixth week, respectively. In the fourth and sixth weeks, lipid metabolism and cell apoptosis were augmented, and the former might be associated with the enhanced expression of plin, acsl6, scd2, elovl3, etc. CONCLUSION: These data provide useful information on the global gene expression changes due to high-fat emulsion feeding and bring important insights into the mechanisms of NAFLD. PMID- 21327922 TI - Molecular motions in drug design: the coming age of the metadynamics method. AB - Metadynamics is emerging as a useful free energy method in physics, chemistry and biology. Recently, it has been applied also to investigate ligand binding to biomolecules of pharmacological interest. Here, after introducing the basic idea of the method, we review applications to challenging targets for pharmaceutical intervention. We show that this methodology, especially when combined with a variety of other computational approaches such as molecular docking and/or molecular dynamics simulation, may be useful to predict structure and energetics of ligand/target complexes even when the targets lack a deep binding cavity, such as DNA and proteins undergoing fibrillation in neurodegenerative diseases. Furthermore, the method allows investigating the routes of molecular recognition and the associated binding energy profiles, providing a molecular interpretation to experimental data. PMID- 21327923 TI - Clinical impact of a strategy involving endoscopic submucosal dissection for early gastric cancer: determining the optimal pathway. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) is a technique developed to enable the endoscopic resection (ER) of large and ulcerative neoplastic lesions that were previously unresectable using conventional endoscopic mucosal resection (EMR). We investigated the clinical outcomes of ER of early gastric cancer (EGC) before and after the introduction of ESD, with particular attention to surgery and its potential consequences. METHODS: We reviewed 2,785 consecutive surgical patients with EGC and 2,469 consecutive lesions treated by ER with curative intent between 1990 and 2005. The study was divided into an EMR period (1990 1999) and an ESD period (2000-2005). We analyzed the clinical outcomes of endoscopic and surgical resections and defined 'potentially avoidable surgery' as cases of surgery performed for lesions curable by ER. RESULTS: The rate of potentially avoidable surgery was 3.8% (52/1,369) in the EMR period and 0.2% (3/1,416) in the ESD period (P < 0.001). For ER patients, the rate of overall non curative ER was 36.9% (154/417) in the EMR group and 17.0% (348/2,052) in the ESD group (P < 0.001). The rate of non-curative ER for lesions defined as having 'positive or difficult to estimate horizontal margins only' decreased significantly, from 26.1% (109/417) in the EMR group to 1.4% (29/2,052) in the ESD group (P < 0.001). Conversely, the rate of non-curative ER for lesions defined as having 'possible lymph node metastasis' significantly increased in the ESD group (15.5%; 319/2,052) compared to that in the EMR group (10.8%; 45/417) (P < 0.01). CONCLUSIONS: The application of a pathway involving ESD resulted in a significant decrease in the rate of potentially avoidable surgery, highlighting the advantages associated with performing ESD. PMID- 21327924 TI - Depth-predicting score for differentiated early gastric cancer. AB - BACKGROUND: Intramucosal and minute submucosal (M-SM1; < 500 MUm in depth) differentiated gastric cancers, which have a negligible risk of lymph node metastasis, are the targets for endoscopic resection. However, there have been few reports about the endoscopic distinction between these cancers and cancers with deeper submucosal invasion (SM2; >= 500 MUm in depth). The aim of this retrospective study was to analyze the differences in the endoscopic features between M-SM1 and SM2 cancers, and to develop a simple scoring model to predict the depth of these early gastric cancers. METHODS: We analyzed 853 differentiated early gastric cancers treated endoscopically or surgically as a derivation group. Endoscopic images were reviewed to determine the relationship between depth of invasion and the following endoscopic features: tumor location, macroscopic type, tumor size, and endoscopic findings (remarkable redness, uneven surface, margin elevation, ulceration, and enlarged folds). Secondly, we created a depth predicting model based on the obtained data and applied the model to 211 validation samples. RESULTS: On logistic regression analysis, tumor size more than 30 mm, remarkable redness, uneven surface, and margin elevation were significantly associated with deeper submucosal cancers. A depth-predicting score was created by assigning 2 points for margin elevation and tumor size more than 30 mm, and 1 point for each of the other endoscopic features. When validation lesions of 3 points or more were diagnosed as deeper submucosal cancers, the sensitivity, specificity, and accuracy as evaluated by three endoscopists were 29.7-45.9, 93.1-93.7, and 82.5-84.8%, respectively. CONCLUSIONS: The depth predicting score could be useful in the decisions on treatment strategy for differentiated M-SM1 early gastric cancers. PMID- 21327925 TI - Assessing clinical benefit response in the treatment of gastric malignant ascites with non-measurable lesions: a multicenter phase II trial of paclitaxel for malignant ascites secondary to advanced/recurrent gastric cancer. AB - BACKGROUND: Paclitaxel has shown promise against advanced gastric cancer and associated malignant ascites with non-measurable lesions. In order to evaluate the therapeutic effect of paclitaxel against malignant gastric ascites, a prospective phase II clinical trial was designed according to our previously proposed criteria represented by the clinical benefit response in gastric cancer (CBR-GC) criteria and the five-point method (5PM). METHODS: Patients with advanced gastric cancer with malignant ascites were treated with 1-h intravenous (i.v.) infusions of 80 mg/m2 of paclitaxel weekly over a 3-week cycle on days 1, 8, and 15, followed by 1 week of rest. Therapeutic responses were measured according to the CBR-GC criteria and the 5PM. RESULTS: The CBR-GC criteria showed improved ascites volume and functional status in 39.1% of patients. A positive CBR-GC response in abdominal girth was seen in 31.3% of patients, and this was significantly correlated with the 5PM-estimated change in ascites volume (p < 0.001). The median number of treatment cycles was 3 (range 1-12). The most common non-hematological toxicity was anorexia, in 22.2% of patients. CONCLUSION: Weekly i.v. paclitaxel is a safe and effective chemotherapeutic regimen based on validated CBR-CG criteria. PMID- 21327928 TI - From the editors' desk: decisions, decisions. PMID- 21327926 TI - Adjuvant chemoradiation for resected gastric cancer: a 10-year experience. AB - BACKGROUND: The Intergroup 0116 study demonstrated that concurrent chemoradiation improved overall survival (OS) in resected gastric cancer. However, there are few reports focusing on late toxicity and factors governing prognosis. This study aimed to determine these two important aspects for employing this regimen. METHODS: Patients with resected gastric cancer stage IB to IV (M0) disease, treated between July 1998 and December 2007, were analyzed. The majority of the patients were treated using 5 cycles of 5-fluorouracil (5FU)/leucovorin chemotherapy with 45 Gy/25 fractions radiotherapy concurrent with cycles 2 and 3, as per the Intergroup 0116 study. RESULTS: We treated 120 patients (107 standard protocol, 13 with concurrent 5FU alone), and 14% had a close or positive margin. Median age was 59 years (35-79 years). Acute toxicity >= grade 3 was seen in 66% of all patients (hematological 61%, stomatitis 3%, diarrhea 6%, vomiting 2%). Median follow-up was 33 months (range 6-125 months). Five-year OS and relapse free survival were 51 and 54%, respectively. On multivariate analysis, surgical margin status, stage of the disease, and radiotherapy with computed tomography (CT) planning were important prognostic factors. Anemia and gastritis were the two most frequently occurring late complications, though they were usually mild and asymptomatic. Clinically significant renal impairment was uncommon. Other rare complications included intestinal obstruction, malabsorption, hypertension, and secondary malignancy. CONCLUSIONS: Postoperative chemoradiation is safe and late toxicity is usually mild in extent. Results were comparable to the Intergroup 0116 study. R0 resection is of utmost importance and radiotherapy should best be delivered by conformal techniques. PMID- 21327929 TI - A case of slowly progressive scleroderma kidney. AB - A rapidly progressive renal deterioration accompanied by acute-onset/uncontrolled hypertension characterizes scleroderma renal crisis (SRC), a life-threatening complication that occurs in patients with systemic sclerosis (SSc). To date, however, SSc with advanced renal failure has only rarely been reported in the absence of SRC. We report here an atypical case of diffuse cutaneous SSc where renal insufficiency progressed slowly to end-stage renal failure over a 14-year follow-up period after the diagnosis of SSc. In the renal biopsy, which was obtained at a relatively early stage of renal impairment, we found histological findings consistent with those of scleroderma kidneys. Unlike typical SRC, however, the larger renal arteries seemed to be unaffected. These histological findings were probably responsible for the "slowly progressive" renal impairment over the years without causing typical SRC. PMID- 21327930 TI - Efficacy of infusional 5-fluorouracil, doxorubicin, and mitomycin-C (iFAM) in the treatment of patients with gemcitabine-pretreated pancreatic cancer and analysis of prognostic factors in a salvage setting. AB - PURPOSE: In gemcitabine-pretreated pancreatic cancer, salvage chemotherapy has not been established, and the prognostic factors are not completely known. The purpose of this study was to determine the efficacy and safety of infusional 5 fluorouracil (5-FU), doxorubicin, and mitomycin-C (iFAM) in patients with gemcitabine-pretreated pancreatic cancer and to elucidate the prognostic factors. METHODS: Study eligibility was as follows: (1) 18-75 years of age; (2) relapse within 6 months after adjuvant gemcitabine-based chemotherapy (GBC) or previously treated with palliative GBC; and (3) an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2. iFAM consisted of a 5-FU (800 mg/m(2)) infusion over 10 h on days 1-5, doxorubicin (30 mg/m(2)) on day 1, and mitomycin-C (8 mg/m(2)) on day 1 every 4 weeks. RESULTS: Sixty patients were enrolled. The responses to iFAM included a partial response in 6 patients (10.0%) and stable disease in 8 patients (13.3%). The median progression-free survival (PFS) and overall survival (OS) were 2.4 months (95% confidence interval [CI], 2.0-2.8 months) and 6.1 months (95% CI, 4.2-8.0 months), respectively. The 6- and 12 month survival rates were 50.4 and 26.4%, respectively. Grade 3/4 hematologic toxicities included neutropenia (3.3%) and thrombocytopenia (3.3%). The ECOG PS was a significant prognostic factor for PFS (P < 0.001) and OS (P = 0.022). An elevated CA 19-9 at the time of initiating iFAM (P = 0.011) was a poor prognostic factor for OS. CONCLUSIONS: iFAM is an effective and well-tolerated in patients with gemcitabine-pretreated pancreatic cancer, even patients with an ECOG PS of 2. ECOG PS and CA 19-9 were shown to be significant prognostic factors in this salvage setting. PMID- 21327931 TI - Statins are logical candidates for overcoming limitations of targeting therapies on malignancy: their potential application to gastrointestinal cancers. AB - PURPOSE: Molecular targeting approaches have been an intensive focus of treatment strategies against advanced gastric and colorectal cancers. Recent clinical trials have demonstrated promising survival prolongation of targeted human epidermal growth factor receptors; however, patients harboring mutations in the K Ras gene (human homolog of the Kirsten rat sarcoma-2 virus oncogene) do not derive benefit from the anti-epidermal growth factor receptor antibodies. K-Ras mutations cause a stimuli-independent activation of a large cohort of downstream effectors that permit cells to acquire a sustained growth. The perpetuated growth activation manifests resistance to molecular targeting therapies. METHODS: Literature review has been made to explore the possibilities that, given that K Ras or downstream effector proteins require farnesyl or geranylgeranyl moiety for their activity (e.g., prenylation), statins are logical candidates to overcome the limitations of or to potentiate the effect of molecular targeting therapies as statins suppress the mevalonate pathway leading to depletion of an end product of mevalonate such as farnesylpyrophosphate and geranylgeranylpyrophosphate, which are used as substrates by their respective transferase enzyme for protein prenylation, and ultimately impair functions of K-Ras and downstream effector proteins. RESULTS: In the last few years, statins have gained interest in therapeutic value for anticancer treatments extending beyond their lipid-lowering effects as single agents or in combined use with other chemotherapeutic agents. This review provides insights into possible anticancer mechanisms of statins and introduces current achievements or ongoing studies of statins in the field of cancer treatment in single or combined uses. This review also offers information to help establish optimal treatment schedules of statins that overcome current limitations of molecular targeting therapies. CONCLUSIONS: It is expected that therapeutic scope of statins will expand considerably in the future as anticancer agents in addition to their proven benefits of hyperlipidemia. PMID- 21327932 TI - Durable remission after treatment with very low doses of imatinib for FIP1L1 PDGFRalpha-positive chronic eosinophilic leukaemia. PMID- 21327933 TI - Phase II study of cisplatin/etoposide and endostar for extensive-stage small-cell lung cancer. AB - PURPOSE: To investigate the efficacy and safety of endostar, a novel recombinant human endostatin, plus cisplatin, and etoposide in patients with extensive-stage small-cell lung cancer (ED-SCLC). PATIENTS AND METHODS: Chemotherapy-naive patients with histologically confirmed, measurable ED-SCLC were enrolled. Treatment consisted of cisplatin (25 mg/m(2)) administered intravenously (IV) on days 1-3; etoposide (120 mg/m(2)) administered intravenously (IV) on days 1-3; endostar (15 mg) administered intravenously (IV) on days 1-14 every 21 days for up to four cycles. The primary objective was to assess the progression-free survival (FPS). Secondary objectives were to assess the objective response rate, median overall survival (OS), and treatment-related toxicity. RESULTS: Thirty three patients were enrolled, the median age of the patients was 53 years (range, 29-74), twenty-three patients (69.7%) were men and 10 patients were women. Eastern Cooperative Oncology Group performance status scores were 0, 1,and 2 in 30.3, 60.6, and 9.1% of the patients, respectively. The overall response rate was 69.7%, one patient (3%) had a complete response, and 22 patients (66.7%) had partial responses. Five patients (15.1%) had stable disease; the median PFS was 5.0 months (95% CI, 4.2-5.6 months), and the 6-month PFS was 33.3%. The median OS was 11.5 months (95% CI, 9.6-13.4 months), and the 1-year OS was 38.1% (95% CI, 26-50.1%). Sixteen patients (48.5%) had at least one grade 3/4 adverse events; the most common grade 3/4 hematologic toxicity included neutropenia in 57.6%, thrombocytopenia in 12.1% of patients. The most common grade 3/4 non-hematologic toxicities included fatigue in 15.2%, nausea/vomiting in 9.1%, diarrhea in 6.1%, anorexia in 6.1%, mucositis in 6.1% of patients. CONCLUSION: The addition of rh endostain to cisplatin and etoposide in patients with ED-SCLC results in slightly improved PFS and OS relative to historical controls who received this chemotherapy regimen alone. This regimen appears to be well tolerated; the promising results suggest the further randomized phase III trial to define endostar's impact on SCLC treatment. PMID- 21327934 TI - In vitro effectiveness of antifungal lock solutions on catheters infected with Candida species. AB - The antibiotic lock technique involves filling the catheter lumen with an antibiotic solution and allowing it to dwell for sufficient time to sterilize the infected device. However, antifungal therapy for treating catheter-related fungal infection in this setting is unknown. In this study, the effectiveness of the commercially available antifungal drugs, which are commonly used in candidemia, were assessed in an in vitro antibiotic lock model. Amphotericin B, caspofungin, fluconazole, itraconazole, and voriconazole were used as lock solutions against catheters infected with slime-forming Candida albicans and Candida parapsilosis. Infected catheters were exposed to each of the antifungal lock solution (300-, 500- and 1,000-fold MIC) for 1, 3, 5, and 7 days. The presence of the remaining Candida in the catheter was evaluated quantitatively. Among the antifungal agents, amphotericin B and caspofungin lock solutions decreased the yeast colony count significantly from baseline starting on the first day of treatment (P < 0.001). Significant decrease in the colony count continued, and the catheters were completely sterile at the fifth day. Fluconazole, itraconazole, and voriconazole lock solutions failed to sterilize the catheters, and the numbers of yeast colonies were >10(5) at the end of the study. In summary, amphotericin B and caspofungin appear to have unique activities against Candida-infected catheters. It seems that one of these drugs may permit the retention of an affected intravascular catheter by sterilizing it in a few days. PMID- 21327935 TI - Dissemination of multiple MRSA clones among community-associated methicillin resistant Staphylococcus aureus infections from Japanese children with impetigo. AB - The proportion of MRSA strains that cause skin and soft infections has recently increased. In 3 months we have characterized 17 MRSA strains isolated from children with impetigo at a Japanese hospital. Seventeen MRSA strains belonged to 7 clones defined by clonal complex (CC) in MLST genotype and type of SCCmec, which were rarely identified among healthcare-associated MRSA: CC 91-SCCmecIIb (4 strains); CC91-SCCmecIIn (2 strains); CC91-SCCmecIVa (2 strains); CC91-SCCmecV (4 strains); CC88-SCCmecIVg (3 strains); CC1-SCCmecIVc (1 strain); and CC5-SCCmecIVn (1 strain). Although one strain belonged to CC5, which has been commonly identified in healthcare-associated MRSA, it did not carry type II SCCmec, but carried type IV SCCmec. Fourteen of the 17 strains carried exfoliative toxin a or b gene, and none carried Panton-Valentine leukocidine gene. Furthermore, we determined the entire nucleotide sequences of two type V SCCmec elements carried by strains JCSC5952, a CC91 strain, and TSGH17, a Taiwanese CC59 strain. The structure of SCCmecJCSC5952 was more than 99% homologous in nucleotide identity with those of Taiwanese PVL-positive ST59 MRSA strains TSGH17 and PM1, which were designated as type V (5C2&5). Identification of multiple MRSA clones distinct from those disseminating at the hospital suggests that MRSA strains might be emerging in the community from MSSA strains by acquiring SCCmec elements on various occasions. Carriage of the similar type V(5C2&5) SCCmec element by strains of distinct genetic backgrounds, CC91 and CC59, suggested horizontal transfer of the SCCmec element. PMID- 21327936 TI - In vitro trans-differentiation of human umbilical cord derived hematopoietic stem cells into hepatocyte like cells using combination of growth factors for cell based therapy. AB - The aim of the study was to develop a new strategy for the differentiation of hematopoietic stem cell (HSC) derived from UCB into hepatocyte like cells and also to estimate the effects of combination of fibroblast growth factor 4 (FGF 4) and hepatocyte growth factor (HGF) on hematopoietic stem cell differentiation. HSCs were isolated and purified by magnetic activated cell sorting. HSCs were induced to hepatocyte like cells under a 2-step protocol with combination of growth factors. Reverse transcription polymerase chain reaction was performed to detect multiple genes related to hepatocyte like cells development and function. Hepatocyte like morphology was illustrated by inverted repeat microscope and the secretion of albumin and alpha- fetoprotein by these cells was confirmed by enzyme linked immunosorbent assay. Hepatocyte like cells was observed at the end of the protocol (days 14). These differentiated cells were observed to show high expression of genes related to hepatocytes (tryptophan 2, 3-dioxygenase [TO], glucose 6-phosphate [G6P], cytokeratin 18 [CK 18], albumin and alpha- fetoprotein [AFP]). The quantities of albumin and AFP at day 0 were low and upon differentiation the cells were able to produce albumin and AFP at high levels. Our results show a new strategy for differentiation in a short duration, using a combination of growth factors for the differentiation of umbilical cord blood derived HSC into hepatocyte like cells under certain in vitro conditions. After further studies this approach has the potency, for widespread cell replacement therapy for liver diseases. PMID- 21327937 TI - High-resolution genetic mapping and candidate gene identification of the SLP1 locus that controls glume development in rice. AB - Stunted lemma palea 1 (slp1) is a rice mutant that displays dwarfism, shortened inflorescence lengths, severely degenerated lemmas/paleas, and sterility. The SLP1 locus was mapped between markers RM447 and D275 in the distal region of the long arm of chromosome 8, using the F2 progeny derived from the cross between the Slp1/slp1 mutant (Oryza sativa subsp. japonica) and the variety Taichung Native 1 (TN1, O. sativa subsp. indica). The SLP1 locus was further delimited to a 46.4-kb genomic region containing three putative genes: OsSPL16, OsMADS45, and OsMADS37. Comparisons of the sequence variations and expression levels of the three candidate genes between wild-type plants and homozygous slp1 mutants suggested that a missense mutation in the sixth amino acid of the OsSPL16 protein was likely responsible for the slp1 mutant phenotypes. PMID- 21327938 TI - Reproductive and menstrual factors and mammographic density in African American, Caribbean, and white women. AB - OBJECTIVE: We investigated the associations between reproductive and menstrual risk factors for breast cancer and mammographic density, a strong risk factor for breast cancer, in a predominantly ethnic minority and immigrant sample. METHODS: We interviewed women (42% African American, 22% African Caribbean, 22% White, 9% Hispanic Caribbean, 5% other) without a history of breast cancer during their mammography appointment (n = 191, mean age = 50). We used a computer-assisted method to measure the area and percentage of dense breast tissue from cranio caudal mammograms. We used multivariable linear regression analyses to estimate the associations between reproductive and menstrual risk factors and mammographic density. RESULTS: Age was inversely associated with percent density and dense area, and body mass index (BMI) was inversely associated with percent density. Adjusting for age, BMI, ethnicity and menopausal status, later age at menarche (e.g., beta = -7.37, 95% CI: -12.29, -2.46 for age >= 13 years vs. <= 11 years), and any use of hormonal birth control (HBC) methods (beta = -5.10, 95% CI: -9.37, -0.84) were associated with reduced dense area. Ethnicity and nativity (foreign- vs. US-born) were not directly associated with density despite variations in the distribution of several risk factors across ethnic and nativity groups. CONCLUSIONS: The mean level of mammographic density did not differ across ethnic and nativity groups, but several risk factors for breast cancer were associated with density in ethnic minority and immigrant women. PMID- 21327939 TI - Formation of an adherent hematopoietic expansion culture using fucoidan. AB - Expansion of transplantable cord blood (CB) progenitors using a stroma requires provision of an exogenous cell source because of the low frequency of stromal precursor cells in CB. A simpler approach from a clinical regulatory perspective would be to provide synthetic extracellular matrix. The aim of this study was to characterize the effect on hematopoietic cell culture of fucoidan. The modulation of cytokine-driven hematopoietic cell expansion by fucoidan was investigated using two-level fractional and full factorial experimental designs. Mobilized peripheral blood (PB) CD34(+) cells were grown over 10 days in various combinations of FL, SCF, TPO, G-CSF, and SDF-1. Cultures were analyzed by immunophenotype. The effect of fucoidan on the divisional recruitment of CD34(+) cells was studied by CFDA-SE division tracking. Fucoidan was adsorbed by polystyrene to tissue culture plates and promoted formation of an adherent hematopoietic culture. Factorial design experiments with mobilized PB-CD34(+) cells showed that fucoidan reduced the production of CD34(+) cells and CD34(+)CXCR4(+) ratio but did not affect the production of monocytic, granulocytic, or megakaryocytic cells. The inhibitory effect of fucoidan on expansion of CB-CD34(+) cells was greater than mobilized PB. Division tracking analysis showed that CD34(+) cell generation times were lengthened by fucoidan. Fucoidan binds growth factors via their heparin-binding domain. The formation of an adherent hematopoietic culture system by fucoidan is most likely mediated by the binding of L-selectin and integrin-alphaMbeta2 on myeloids. Fucoidan deserves further investigation as glycan scaffold that is suitable for immobilization of other matrix molecules thought to comprise blood stem cell niche. PMID- 21327940 TI - Prevalence and clinical impact of autoimmune diseases and chronic infections in malignant lymphomas at diagnosis. AB - There is increasing evidence for the role of chronic antigenic stimulation (CS) in the development of cancer. Clinical data, however, are rare as is the information on outcome. In this study, the occurrence of chronic infections (CI) and autoimmune diseases (AI) in patients with malignant lymphoma at diagnosis was assessed. Of 367 patients [non-Hodgkin's lymphoma (NHL) N = 297, Hodgkin's lymphoma N = 70], 9.8% (N = 36) had a history of chronic antigenic stimulation (4.4% AI, 5.4% CI) at diagnosis. After a median observation time of 74.7 months, 118 patients have died. There were more male patients in this cohort. However, sex ratio among patients with chronic antigenic stimulation was skewed in favor of women (p = 0.018), in particular among lymphoma patients with AI (p = 0.001). NHL patients with autoimmune diseases showed a tendency to develop diffuse large B cell lymphoma [8 of 12 AI + NHL patients (66.7%) vs. 100 of 266 non-CS NHL (37.6%); p = 0.066]. No significant difference in overall survival (OS) between CS and non-CS patients could be observed (median OS after 48 months was: CS 77.7% vs. non-CS 71.8%). In conclusion, chronic antigenic stimulation at diagnosis appears to be associated with a higher prevalence in women, in particular among patients with autoimmune disease. However, no difference in overall survival was observed. This suggests that the presence of chronic inflammatory conditions does not decisively influence the outcome of lymphoma patients. PMID- 21327941 TI - Adult grade II diffuse astrocytomas are genetically distinct from and more aggressive than their paediatric counterparts. AB - Diffuse astrocytomas (WHO grade II) typically present as slow-growing tumours showing significant cellular differentiation, but possessing a tendency towards malignant progression. They account for ~10% of all astrocytic tumours, with a peak incidence between 30 and 40 years of age. Median survival is reported as around 6-8 years. Mutations of TP53 and IDH1 have been described as genetic hallmarks, while copy number alterations are also relatively common. However, there is some evidence to suggest that these characteristics may vary with age. Here, we present an integrated clinicopathologic, genomic and transcriptomic analysis suggesting that paediatric and adult tumours are associated with distinct genetic signatures. For example, no childhood tumour showed mutation of IDH1/2 or TP53, virtually no copy number changes were seen, and MGMT methylation was absent. In contrast, adult tumours showed IDH1/2 mutation in 94% and TP53 mutation in 69% of cases, with multiple copy number alterations per case and hypermethylation of MGMT in the majority of tumours. These differences were associated with a worse prognosis in the adult patients. The expression array data also revealed a significant difference in the expression of a number of genes putatively involved in neural stem cell maintenance and CNS development, including DLL3, HES5, BMP2, TIMP1 and BAMBI. Genes involved in DNA replication and the cell cycle were also enriched in the adult tumours, suggesting that their more aggressive behaviour may be due to derivation from a more rapidly dividing, less differentiated cell type. PMID- 21327943 TI - [Optimal point of time for initiation of dialysis. IDEAL Study (Initiating Dialysis EArly and Late)]. PMID- 21327942 TI - Optineurin is co-localized with FUS in basophilic inclusions of ALS with FUS mutation and in basophilic inclusion body disease. PMID- 21327944 TI - An improved isolation procedure for adult mouse cardiomyocytes. AB - Isolated adult mouse cardiomyocytes are an important tool in cardiovascular research, but are challenging to prepare. Because the energy supply determines cell function and viability, we compared total creatine ([Cr]) and [ATP] in isolated cardiomyocytes with the intact mouse heart. Isolated myocytes suffered severe losses of Cr (-70%) and ATP (-53%). Myocytes were not able to replete [Cr] during a 5 h incubation period in medium supplemented with 1 mM Cr. In contrast, adding 20 mM Cr to the digestion buffers was sufficient to maintain normal [Cr]. Supplementing buffers with 5 mM of inosine (Ino) and adenosine (Ado) to prevent loss of cellular nucleosides partially protected against loss of ATP. To test whether maintaining [ATP] and [Cr] improves contractile function, myocytes were challenged by varying pacing rate from 0.5 to 10 Hz and by adding isoproterenol (Iso) at 5 and 10 Hz. All groups performed well up to 5 Hz, showing a positive cell shortening-frequency relationship; however, only 16% of myocytes isolated under standard conditions were able to sustain pacing with Iso challenge at 10 Hz. In contrast, 30-50% of the myocytes with normal Cr levels were able to contract and maintain low diastolic [Ca(2+)]. Cell yield also improved in Cr and the Cr/Ino/Ado-treated groups (85-90% vs. 70-75% rod shaped in untreated myocytes). These data suggest that viability and performance of isolated myocytes are improved when they are protected from the severe loss of Cr and ATP during the isolation, making them an even better research tool. PMID- 21327945 TI - Quantitative analysis of quercetin in Euphorbia helioscopia L by RP-HPLC. AB - Euphorbia helioscopia L is widespread in China and has a large number of flavonoids. Quercetin glycosides, having useful biological activities, are abundant in this plant, and no validated analytical method has so far been developed for their determination. We, therefore, standardized a reversed-phase high-performance liquid chromatography (RP-HPLC) assay for quercetin detection. For this, the plant was locally procured and identification was confirmed based on its morpho-histological characteristics. Ethyl acetate extracts of leaves, stems, and roots were analyzed by RP-HPLC using Agilent 1120 HPLC TC-C(18) column (250 * 4.6 mm; 5 MUm) with UV-detector system. The mobile phase of methanol-0.2% phosphoric acid (65:35) solution was used with the flow rate of 1.0 ml min(-1) at 30 degrees C, and the detection was performed at 360 nm wavelength. Our data show that the linear range of quercetin was 0.025-0.150 mg.ml(-1) (r = 0.9995; n = 6) with the recovery rate of 97.50-103.30% (average 100.40%; RSD = 2.28%). The target component was baseline separated during only the period of 9 min. The repeatability of RP-HPLC analysis was demonstrated with an RSD of 1.77% (n = 6), and the highest quercetin content (average 1.42 mg g(-1)dry-weight) was present in leaves. It was, therefore, concluded that RP-HPLC is a simple, rapid, accurate, and sensitive method for the detection of quercetin from Euphorbia helioscopia L. PMID- 21327946 TI - Fluid dynamics of heart development. AB - The morphology, muscle mechanics, fluid dynamics, conduction properties, and molecular biology of the developing embryonic heart have received much attention in recent years due to the importance of both fluid and elastic forces in shaping the heart as well as the striking relationship between the heart's evolution and development. Although few studies have directly addressed the connection between fluid dynamics and heart development, a number of studies suggest that fluids may play a key role in morphogenic signaling. For example, fluid shear stress may trigger biochemical cascades within the endothelial cells of the developing heart that regulate chamber and valve morphogenesis. Myocardial activity generates forces on the intracardiac blood, creating pressure gradients across the cardiac wall. These pressures may also serve as epigenetic signals. In this article, the fluid dynamics of the early stages of heart development is reviewed. The relevant work in cardiac morphology, muscle mechanics, regulatory networks, and electrophysiology is also reviewed in the context of intracardial fluid dynamics. PMID- 21327947 TI - [Bilateral acute angle-closure glaucoma due to an infection with Hantavirus]. AB - A poor general condition of patients with hemorrhagic fever and elevated creatinine should raise suspicion of a systemic infection with Hantavirus. This can often also cause ocular changes. Above all, changes of intraocular pressure, in our case bilateral acute angle-closure glaucoma, due to edema and hemorrhage in the ciliary body result in anterolateral rotation of the iris-lens diaphragm with closure of the chamber angle. It can also cause a transient myopia, and intraretinal hemorrhages can also occur. Hantavirus infection is mostly transmitted through red-backed voles in Europe. The predominant type in Europe is the Puumala virus that can lead to an epidemic nephropathy with high fever, headache, gastrointestinal complaints, and an impaired renal function to the point of renal failure. No specific treatment is needed, but adequate symptomatic therapy is of utmost importance. When the infection has been overcome, complete recovery is possible. Measures for prophylaxis should be taken with respect to contact with mice and their excreta. PMID- 21327948 TI - Inhibitory effect of drug-free hybrid liposomes on metastasis of human neuroblastoma. AB - PURPOSE: Hybrid liposomes composed of vesicular and micellar molecules have been used as drug-delivery systems. It has become clear that hybrid liposomes alone have an inhibitory effect against the growth of various tumor cells. The present study was designed to determine whether a drug-free hybrid liposome composed of dimyristoylphosphatidylcholine (DMPC) and polyoxyethylenealkyl ether (EO) [90 mol% DMPC/10% C(12)(EO)(21) (HL21), 90 mol% DMPC/10% C(12)(EO)(23) (HL23), or 90 mol% DMPC/10% C(12)(EO)(25) (HL25)], inhibit the liver metastasis of human neuroblastoma cells and thus increases survival. METHODS: A human neuroblastoma cell, TNB9, and BALB/C-nu/nu athymic mice were used in this study. First, we determined the inhibitory effect of the hybrid liposomes on TNB9 cells in vitro. Next, to determine the inhibitory effect of the hybrid liposomes on metastasis of neuroblastoma cells to the liver, we made a murine hepatic metastasis model by implanting TNB9 cells (2 * 106) in the spleen of the mice and compared anatomic appearance, weights, and histological findings of the livers of treated mice and control mice 60 days after the beginning of a 7-day intraperitoneal injection of a hybrid liposome. We also compared survival rates using the Kaplan-Meier method. RESULTS: In mice implanted with TNB9 neuroblastoma cells and treated with HL21 or HL25, no histological evidence of metastasis was found, the weight of the liver was normal, and survival was a mean of 88 and 87.9 days, respectively. In contrast, mice treated with HL23 and control mice had countless tumor cell masses histologically, their liver weight was increased, and their survival was 73.0 and 68.6 days, respectively. CONCLUSIONS: Two kinds of hybrid liposomes, HL21 and HL25, inhibit metastasis of human neuroblastoma cells to the liver, and thus increase survival. PMID- 21327949 TI - Management of isolated and associated colonic atresia. AB - PURPOSE: Colonic atresia is a rare cause of congenital intestinal obstruction in the neonate. A review of the management and outcome of children with colonic atresia was performed. METHODS: A retrospective analysis of the complete records of children treated for colonic atresia during the 30-year period. RESULTS: A total of 14 newborns were treated. Seven infants suffered from an isolated colonic atresia (group 1). In the other seven infants (group 2), colonic atresia was either associated with additional intestinal atresias (n = 2), or gastroschisis (n = 5). Gestational age and birth weight were significantly lower in infants from group 2 compared to group 1 (40 +/- 0.5 vs. 37 +/- 1 weeks (P < 0.05); and 3,478 +/- 208 vs. 2,626 +/- 242 g (P < 0.01), respectively). The first surgical procedure was performed in all newborns within 24 h after birth. All but one infant from group 1 received primary colostomies at the level of colonic atresia, followed by end-to-side anastomoses. All but one infant from group 2 needed ileocoecal resection due to bowel necrosis. No child died in group 1, whereas three children died in group 2. CONCLUSIONS: Isolated colonic atresia is amenable with a short hospital stay and an excellent outcome. In contrast, infants with colonic atresia associated with gastroschisis present a serious clinical challenge. PMID- 21327950 TI - Body Area Networks for ubiquitous healthcare applications: opportunities and challenges. AB - Body Area Networks integrated into mHealth systems are becoming a mature technology with unprecedented opportunities for personalized health monitoring and management. Potential applications include early detection of abnormal conditions, supervised rehabilitation, and wellness management. Such integrated mHealth systems can provide patients with increased confidence and a better quality of life, and promote healthy behavior and health awareness. Automatic integration of collected information and user's inputs into research databases can provide medical community with opportunity to search for personalized trends and group patterns, allowing insights into disease evolution, the rehabilitation process, and the effects of drug therapy. A new generation of personalized monitoring systems will allow users to customize their systems and user interfaces and to interact with their social networks. With emergence of first commercial body area network systems, a number of system design issues are still to be resolved, such as seamless integration of information and ad-hoc interaction with ambient sensors and other networks, to enable their wider acceptance. In this paper we present state of technology, discuss promising new trends, opportunities and challenges of body area networks for ubiquitous health monitoring applications. PMID- 21327951 TI - Does continued treatment with methotrexate in juvenile idiopathic arthritis in remission prevent flare? PMID- 21327952 TI - Gestational diabetes and subsequent growth patterns of offspring: the National Collaborative Perinatal Project. AB - Our objective was to test the hypothesis that intrauterine exposure to gestational diabetes [GDM] predicts childhood growth independent of the effect on infant birthweight. We conducted a prospective analysis of 28,358 mother-infant pairs who enrolled in the National Collaborative Perinatal Project between 1959 and 1965. The offspring were followed until age 7. Four hundred and eighty-four mothers (1.7%) had GDM. The mean birthweight was 3.2 kg (range 1.1-5.6 kg). Maternal characteristics (age, education, race, family income, pre-pregnancy body mass index and pregnancy weight gain) and measures of childhood growth (birthweight, weight at ages 4, and 7) differed significantly by GDM status (all P < 0.05). As expected, compared to their non-diabetic counterparts, mothers with GDM gave birth to offspring that had higher weights at birth. The offspring of mothers with GDM were larger at age 7 as indicated by greater weight, BMI and BMI z-score compared to the offspring of mothers without GDM at that age (all P < 0.05). These differences at age 7 persisted even after adjustment for infant birthweight. Furthermore, the offspring of mothers with GDM had a 61% higher odds of being overweight at age 7 compared to the offspring of mothers without GDM after adjustment for maternal BMI, pregnancy weight gain, family income, race and birthweight [OR = 1.61 (95%CI:1.07, 1.28)]. Our results indicate that maternal GDM status is associated with offspring overweight status during childhood. This relationship is only partially mediated by effects on birthweight. PMID- 21327953 TI - [Replacement of the comminuted radial head fracture by a bipolar radial head prosthesis]. AB - OBJECTIVE: Radial head arthroplasty as a treatment of non-reconstructable, comminuted fractures of the radial head in order to achieve elbow stability and to prevent secondary complications, such as valgus elbow instability and radius proximalization. INDICATIONS: In acute trauma, a radial head fracture not suitable for internal fixation without (Mason grade III) and with (Mason grade IV) concomitant destabilizing injury, Essex-Lopresti injury, sequelae following radial head resection (e.g., elbow instability or wrist pain), failed reconstruction of the radial head, and tumor-associated radial head or neck resection. CONTRAINDICATIONS: General medical contraindications for surgical intervention, cobalt-chromium allergy, and osteoporosis of the proximal radius. SURGICAL TECHNIQUE: In supine position, a lateral or posterolateral approach at the elbow was used. The annular ligament was exposed and the radial neck identified just above the bicipital tuberosity. In pronation of the forearm in order to protect the radial nerve, the medullary canal was prepared using rasps. The size of the implant was determined using trial stems. A distance of 0.5 mm between the head of the prosthesis and the capitulum humeri was recommended. After using a small bone plug, the prosthesis was cemented with respect to the anatomical radial curvature. After reconstruction of the annular ligament, the stability of the elbow was verified. In case of instability, the medial collateral ligament was reconstructed and afterwards the wound closed. POSTOPERATIVE MANAGEMENT: Early mobilization begins the day after surgery. In case of additional injuries, the elbow was supported by an above-elbow cast for 3 4 weeks. To prevent heterotopic ossification, nonsteroidal antiinflammatory drugs were used for up to 4 weeks with gastric protection. RESULTS: A total of 13 patients with 15 radial head prosthesis were analyzed at a mean follow-up of 29.5+/-20.8 months. In all patients, the elbow was stable. Subjectively, good and excellent results were found with one exception. Compared to the pretrauma status, the subjective rate was 78+/-12%. Based on the Radin and Riseborough score, 6 of the results were good and 9 were fair. According to the Broberg and Morrey score, 1 result was very good, 8 were good, and 6 were fair. The mean DASH score was 9.9+/-9.7 points. Two temporary nerve lesions were observed. Five patients were diagnosed with heterotopic ossification stage I, while 2 patients were classified with stage II on the Brooker scale. PMID- 21327954 TI - [Operative treatment of the peripelvic Morel-Lavallee lesion]. AB - OBJECTIVE: Evacuation of hematoma, hemostasis, reduction of dead space by vacuum systems for minimization of secondary complications, such as full skin necrosis, deep infections, and secondary wound closure. INDICATIONS: Morel-Lavallee lesion (MLL), all larger epifascial hematomas. CONTRAINDICATIONS: None. SURGICAL TECHNIQUE: Central longitudinal incision, detection of the extent of the hematoma, transection of the full length of the lesion, hemostasis, debridement, application of vacuum systems, secondary wound closure, or splitskin coverage. POSTOPERATIVE MANAGEMENT: Vacuum therapy must be continued until secretions are less than 30 ml/24 hours. Negative bacterial culture before wound closure is imperative. Daily change of wound dressings, frequent control of inflammation parameters. Weight bearing until consolidation of soft tissue. RESULTS: Operative treatment of the MLL with vacuum systems is a relatively new concept, and results on larger collectives have not been published yet. A total of 8 patients in our hospital underwent vacuum therapy after sustaining a MLL, 5 of them with concomitant instability of the pelvic ring. Emergency stabilization and initiation of vacuum therapy were performed on the day of admission. Three patients had initially positive bacterial colonialization. Duration of vacuum therapy was 8.5 days (range 4-14 days). Dressings were changed every 2.6 days (range 1-4 days). While 6 wounds could be closed secondarily, 2 needed split skin coverage. Complications were not observed. Vacuum therapy facilitates wound management and helps reduce bacterial colonialization. It has also been proved to have a beneficial effect on qualitative and quantitative granulation. PMID- 21327955 TI - Primary fracture arthroplasty of the proximal humerus using a new and freely adjustable modular prosthesis combined with compression osteosynthesis of the tuberosities. AB - OBJECTIVE: Prosthetic joint replacement in case of non-reconstructable proximal humerus fracture in order to obtain a pain-free shoulder and an acceptable range of motion. INDICATIONS: The non-reconstructable proximal humerus fracture in aged, frail patients (over 70 years of age or ASA 3). CONTRAINDICATIONS: Patient inoperable or rehabilitation is inacceptable, pre-existing infection of the shoulder, coexisting bacteremia, or rotator cuff insufficiency. SURGICAL TECHNIQUE: Using a deltopectoral or deltoid split approach, the head fragment is removed. After reaming of the humeral canal, a stem is cemented in place. The Affinis Fracture prosthesis consists of three parts: the stem (3 sizes), a metaphyseal part (2 sizes), and a ceramic head (3 sizes). The retroversion of the metaphyseal part is freely adjustable (360 degrees ) after cementing the stem. The length can be adjusted over 1 cm. After reconstruction of the height and retroversion, the tuberosities are reattached anatomically. Finally, a compression osteosynthesis of the tuberosities is realized, using a metal cable, compressing the tuberosities directly upon the metaphyseal part. POSTOPERATIVE MANAGEMENT: As the stability of this construct is very high, early postoperative mobilization is allowed. In order to avoid adhesion, rehabilitation exercises are started the day after surgery. During the first few days, passive mobilization, within pain limits, is performed. As soon as possible, active assisted mobilization is started. No stretching is performed, especially in rotation, before the sixth postoperative week. The arm is supported in a sling, only for analgesic reasons. RESULTS: Using this technique, anatomical healed tuberosities were obtained in 84% of the 44 patients with a mean Constant score of 59 points. PMID- 21327956 TI - Open reconstruction of the anterior glenohumeral capsulolabral structures with tendon allograft in chronic shoulder instability. AB - OBJECTIVE: The presented technique aims at reconstruction of the anterior capsulolabral structures of the glenohumeral joint in the case of recurrent severe instability after multiple surgical attempts to achieve stabilization. INDICATIONS: The procedure is indicated for patients experiencing significant lifestyle-limiting recurrent shoulder instability with etiologic soft tissue deficiency. CONTRAINDICATIONS: Bony defects or abnormalities can not be addressed with the index technique. SURGICAL TECHNIQUE: A standard deltopectoral approach with lateral incision of the subscapularis tendon is used for exposure to prepare the anterior glenoid rim. Suture anchors placed at the glenoid rim are used for fixation of a tibialis anterior tendon allograft, which is tightened and fixed to the bone on the humerus with intereference screws. This recreates the anterior labrum and the middle glenohumeral ligament and the anterior band of the inferior glenohumeral ligament. Intraosseuos repair of the subscapularis tendon and reinforcement of the capsular structures by sewing the capsule into the allograft complete the procedure. POSTOPERATIVE MANAGEMENT: Postoperatively, the use of an arm sling is recommended for 6 weeks with limited physical exercises to avoid stretching the tightened and reconstructed soft tissue structures. RESULTS: The results of this salvage procedure in this highly challenging population have been satisfying. Twenty shoulders in 15 patients were operated (3 male, 12 female, average age 26 years) from July 2002 to April 2008. In 14 of the 20 (70%) shoulders, adequate stability was gained and no further surgery was required. The average ASES score increased by 37 points at a mean follow-up of 37 months (range 22-74 months). Mean satisfaction with surgical outcomes was 6.5 points (max. 10). In 5 patients, 6 shoulders were considered failures and required further surgical treatment after a mean of 9 months (range 3-24 months). PMID- 21327957 TI - Development of an RNA interference method in the cladoceran crustacean Daphnia magna. AB - Daphnids are small crustaceans ubiquitous in fresh water; they have been a subject of study in ecology, evolution, and environmental sciences for decades. To understand data accumulated in daphnid biology at the molecular level, expressed sequence tags and a genome sequence have been determined. However, these discoveries lead to the problem of how to understand the functions of newly discovered genes. Double-stranded RNA (dsRNA)-mediated RNA interference (RNAi) is a useful tool to achieve specific gene silencing in nontransformable species. Hence, we established a technique to inject exogenous materials into ovulated eggs and developed a dsRNA-based RNAi method for Daphnia magna. Eggs were collected just after ovulation and injected with dsRNA specific to the Distal less (Dll) gene, which functions in appendage development in invertebrates and vertebrates. We found that the dsRNA successfully triggered the degradation of Dll mRNAs, which induced the truncation of the second antenna in a dose-dependent manner. This effect was sequence specific in that: (1) an unrelated dsRNA did not induce any morphological abnormalities and (2) two non-overlapping Dll dsRNAs generated the same phenotype. This is the first report of an RNAi technique in D. magna and, together with the emerging genome sequences, will be useful for advancing knowledge of the molecular biology of daphnids. PMID- 21327959 TI - Improved and high throughput quantitative measurements of weak GFP expression in transgenic plant materials. AB - Green fluorescent proteins (GFPs) are widely used in tracing transgene expression and have been known as convenient and efficient markers for plant transformation. However, sometimes researchers are still puzzled by the weak fluorescence since it makes the observation of GFP signals and confirmation of transgenic plants difficult. In this investigation, we explored the possibility of enhancing the weak signals by changing the pH environment of detection and took microplate reader as a more effective instrument compared to traditional fluorescent microscope to detect the weak signals. It was found that the fluorescence intensity of enhanced GFP (EGFP) in transgenic plants can be increased 2-6 folds by altering the environmental pH, and the concentration of EGFP at a large scale (ranged from 20 ng/ml to 20 MUg/ml) can be detected and quantified. It can exclude the influence of degradation fragment and hence facilitate later analysis; these advantages were further verified by comparing with western blotting and confocal microscopy. It was reliable and effective for the qualitative and quantitative analysis of transgenic plants and was more suitable for the detection of very weak fluorescent signals. PMID- 21327960 TI - SA and ROS are involved in methyl salicylate-induced programmed cell death in Arabidopsis thaliana. AB - Programmed cell death (PCD) is a genetically encoded, active process that results in the death of individual cells, tissues, or whole organs, which plays an important role in the life cycles of plants and animals. Previous studies show that methyl salicylate (MeSA) is a defense signal molecular associated with systemic acquired resistance and hypersensitive reaction; however, whether MeSA can induce PCD in plant is still unknown. The morphological changes of Arabidopsis thaliana protoplasts exposed to MeSA were observed under fluorescence microscopy and transmission electron microscopy, and the induction of PCD was clearly distinguished by intense perinuclear chromatin margination, condensation of nuclear chromatin and DNA laddering after 3-h exposure of 100 MUM MeSA. Our results also showed that salicylic acid (SA) was involved in MeSA-induced PCD by using a transgenic nahG Arabidopsis thaliana line, and the process was mediated by reactive oxygen species, which functioned with SA by making an amplification loop. Our study showed that MeSA could induce PCD in plant cell for the first time. PMID- 21327958 TI - Dendritic cells in hepatitis C infection: can they (help) win the battle? AB - Infection with hepatitis C virus (HCV) is a public health problem; it establishes a chronic course in ~85% of infected patients and increases their risk for developing liver cirrhosis, hepatocellular carcinoma, and significant extrahepatic manifestations. The mechanisms of HCV persistence remain elusive and are largely related to inefficient clearance of the virus by the host immune system. Dendritic cells (DCs) are the most efficient inducers of immune responses; they are capable of triggering productive immunity and maintaining the state of tolerance to self- and non-self antigens. During the past decade, multiple research groups have focused on DCs, in hopes of unraveling an HCV specific DC signature or DC-dependent mechanisms of antiviral immunity which would lead to a successful HCV elimination strategy. This review incorporates the latest update in the current status of knowledge on the role of DCs in anti-HCV immunity as it relates to several challenging questions: (a) the phenotype and function of diverse DC subsets in HCV-infected patients; (b) the characteristics of non-human HCV infection models from the DCs' point of view; (c) how can in vitro systems, ranging from HCV protein- or peptide-exposed DC to HCV protein expressing DCs, and in vivo systems, ranging from HCV protein-expressing transgenic mice to HCV-infected non-human primates, be employed to dissect the role of DCs in triggering/maintaining a robust antiviral response; and (d) the prospect of DC-based strategy for managing and finding a cure for HCV infection. PMID- 21327961 TI - Expression and characterization of (R)-specific enoyl coenzyme A hydratases making a channeling route to polyhydroxyalkanoate biosynthesis in Pseudomonas putida. AB - We investigated the expression of (R)-specific enoyl coenzyme A hydratase (PhaJ) in Pseudomonas putida KT2440 accumulating polyhydroxyalkanoate (PHA) from sodium octanoate in order to identify biosynthesis pathways of PHAs from fatty acids in pseudomonads. From a database search through the P. putida KT2440 genome, an additional phaJ gene homologous to phaJ4(Pa) from Pseudomonas aeruginosa, termed phaJ4(Pp), was identified. The gene products of phaJ1(Pp), which was identified previously, and phaJ4(Pp) were confirmed to be functional in recombinant Escherichia coli on PHA synthesis from sodium dodecanoate. Cytosolic proteins from P. putida grown on sodium octanoate were subjected to anion exchange chromatography and one of the eluted fractions with hydratase activity included PhaJ4(Pp), as revealed by western blot analysis. These results strongly suggest that PhaJ4(Pp) forms a channeling route from beta-oxidation to PHA biosynthesis in P. putida. Moreover, the substrate specificity of PhaJ1(Pp) was suggested to be different from that of PhaJ1(Pa) from P. aeruginosa although these two proteins share 67% amino acid sequence identity. PMID- 21327962 TI - Extracellular polymeric substances enhanced mass transfer of polycyclic aromatic hydrocarbons in the two-liquid-phase system for biodegradation. AB - The objective was to elucidate the role of extracellular polymeric substances (EPS) in biodegradation of polycyclic aromatic hydrocarbons in two-liquid-phase system (TLPs). Therefore, biodegradation of phenanthrene (PHE) was conducted in a typical TLPs--silicone oil-water--with PHE-degrading bacteria capable of producing EPS, Sphingobium sp. PHE3 and Micrococcus sp. PHE9. The results showed that the presence of both strains enhanced mass transfer of PHE from silicone oil to water, and that biodegradation of PHE mainly occurred at the interfaces. The ratios of tightly bound (TB) proteins to TB polysaccharides kept almost constant, whereas the ratios of loosely bound (LB) proteins to LB polysaccharides increased during the biodegradation. Furthermore, polysaccharides led to increased PHE solubility in the bulk water, which resulted in an increased PHE mass transfer. Both LB-EPS and TB-EPS (proteins and polysaccharides) correlated with PHE mass transfer in silicone oil, indicating that both proteins and polysaccharides favored bacterial uptake of PHE at the interfaces. It could be concluded that EPS could facilitate microbial degradation of PHE in the TLPs. PMID- 21327963 TI - Membrane interaction and antibacterial properties of two mildly cationic peptide diastereomers, bombinins H2 and H4, isolated from Bombina skin. AB - Bombinins H are mildly cationic antimicrobial peptides isolated from the skin of the anuran genus Bombina, the fire-bellied toad. Some members of this peptide family coexist in skin secretions as diastereomers in which a single D: -amino acid (alloisoleucine or leucine) is incorporated as a result of the post translational modification of the respective gene-encoded L-amino acid. Here we report on the antimicrobial properties and membrane interactions of bombinins H2 and H4. The latter differs from H2 by the presence of a D-alloisoleucine at the second N-terminal position. Specifically, we have evaluated the antimicrobial activity of H2 and H4 against a large panel of reference and clinical isolates of Gram-negative and Gram-positive bacteria; performed membrane permeation assays on both intact cells and model membranes (lipid monolayers and liposomes) mimicking the composition of the plasma membrane of Gram-negative/positive bacteria; used biochemical tools, such as trypsin-encapsulated liposomes and capillary electrophoresis, to monitor the peptides' ability to translocate through the membrane of liposomes mimicking Escherichia coli inner membrane. The results revealed interesting relationships between the presence of a single D: -amino acid in the sequence of an antimicrobial peptide and its target microbial cell selectivity/membrane-perturbing activity. PMID- 21327964 TI - The presence of membranes or micelles induces structural changes of the myristoylated guanylate-cyclase activating protein-2. AB - Guanylate cyclase-activating proteins (GCAPs) are neuronal Ca(2+) sensors that play a central role in shaping the photoreceptor light response and in light adaptation through the Ca(2+)-dependent regulation of the transmembrane retinal guanylate cyclase. GCAPs are N-terminally myristoylated, and the role of the myristoyl moiety is not yet fully understood. While protein lipid chains typically represent membrane anchors, the crystal structure of GCAP-1 showed that the myristoyl chain of the protein is completely buried within a hydrophobic pocket of the protein, which stabilizes the protein structure. Therefore, we address the question of the localization of the myristoyl group of GCAP-2 in the absence and in the presence of lipid membranes as well as DPC detergents (as a membrane substitute amenable to solution state NMR). We investigate membrane binding of both myristoylated and nonmyristoylated GCAP-2 and study the structure and dynamics of the myristoyl moiety of GCAP-2 in the presence of POPC membranes. Further, we address structural alterations within the myristoylated N-terminus of GCAP-2 in the presence of membrane mimetics. Our results suggest that upon membrane binding the myristoyl group is released from the protein interior and inserts into the lipid bilayer. PMID- 21327965 TI - What differences exist in the appropriate treatment of congenital versus acquired adult Chiari type I malformation? AB - Chiari type I malformation is found in 1 out of 20 magnetic resonance imaging (MRI) studies. Isolated tonsillar herniation is of limited utility and should be considered within the clinical context because these patients can be asymptomatic. Cine MRI showing compression of the cerebrospinal fluid (CSF) spaces in the foramen magnum area is a crucial technique for making treatment decisions. Congenital malformation is thought to be due to a volumetric small posterior fossa. The most common symptom in these patients is cough headache. Posterior fossa reconstruction is mandatory in patients with progressive symptoms/signs, hydrocephalus, or syringomyelia, but not in patients who are asymptomatic or those with stable and tolerable symptoms. Acquired tonsillar descent can be secondary to a variety of disorders conditioning disproportion between the volume of the cranial cavity and that of the intracranial contents, or to CSF hypovolemia, which is the most common cause for acquired herniation. CSF hypovolemia can be spontaneous or secondary to CSF removal. Treatment of acquired tonsillar herniation depends on the responsible etiology. PMID- 21327966 TI - Foreign born status and HIV/AIDS: a comparative analysis of HIV/AIDS characteristics among foreign and U.S. born individuals. AB - The purpose of this study was to observe differences in HIV characteristics between the foreign and U.S. born HIV population. The study sample consisted of individuals, >=13 years of age, who have been diagnosed with HIV and are patients of the Lexington Bluegrass Care Clinic. For the comparison analysis, the sample was divided into two groups (n = 1070), foreign born and U.S. born. Compared to U.S. born patients, foreign born patients were younger at the time of their HIV diagnosis (31 years vs. 36 years, P = 0.005), of Hispanic origin (63.1% vs. 1.1%, P < 0.001), and reported heterosexual contact as their mode of transmission (67.7% vs. 33.9% P < 0.001). Foreign born patients enrolled into care at a much lower CD4+ count and compared to the U.S. born, they were more likely to be classified as late testers (53.9% vs. 32.8%, P = 0.006). There were many differences found between foreign born and U.S. born HIV patients. Upon enrolling into care, foreign born individuals were more likely to have multiple OI's and have an AIDS diagnosis. In regards to testing, foreign born individuals were more likely to have tested late for HIV compared to their U.S. born counterparts. PMID- 21327967 TI - Substance use and HIV risk in a sample of severely mentally Ill Puerto Rican women. AB - Latinos, and Puerto Ricans in particular, have been disproportionately impacted by HIV/AIDS. Severe mental illness (SMI) is associated with an increase in HIV risk. Relatively little research has focused on the role of SMI among Puerto Rican injection drug users (IDUs) and non-IDUs in susceptibility to and transmission of HIV and there are few published reports on HIV risk among Latina SMI. We conducted a longitudinal mixed methods study with 53 Puerto Rican women with schizophrenia, bipolar disorder, or major depression to examine the cultural context of HIV risk and HIV knowledge, beliefs, and behaviors among a larger study with Puerto Rican and Mexican women with serious mental illness (SMI). There was a high prevalence of past and current substance use and a high prevalence of substance use-associated HIV risk behaviors, such as unprotected sexual relations with an IDU. The violence associated with substance use frequently increased participants' HIV risk. Choice of substance of abuse depended on cost, availability, and use within the individual participant's network. Participants attributed their substance use to the need to relieve symptoms associated with their mental illness, ameliorate unpleasant feelings, and deaden emotional pain. HIV prevention interventions for poorer Puerto Rican women with SMI must target the individuals themselves and others within their networks if the women are to be supported in their efforts to reduce substance use-related risk. The content of any intervention must address past and current trauma and its relationship to substance use and HIV risk, as well as strategies to prevent HIV transmission. PMID- 21327968 TI - Phase II-inducing, polyphenols content and antioxidant capacity of corn (Zea mays L.) from phenotypes of white, blue, red and purple colors processed into masa and tortillas. AB - White, blue, red and purple corns (Zea mays L.) were lime-cooked to obtain masa for tortillas. The total phenolics and anthocyanins content, antioxidant activity expressed as total reducing power (TRP), peroxyl radical bleaching (PRAC), total antioxidant activity (TAA) and quinone reductase (QR) induction in the murine hepatoma (Hepa 1 c1c7 cell line) as a biological marker for phase II detoxification enzymes were investigated. Among the extracts prepared from raw corn varieties the highest concentration of total phenolics, anthocyanins, antioxidant index and induction of QR-inducing activity were found in the Veracruz 42 (Ver 42) genotype. The nixtamalization process (masa) reduced total phenolics, anthocyanins and antioxidant activities and the ability for QR induction when was compared to raw grain. Processing masa into tortillas also negatively affected total phenolics, anthocyanin concentration, antioxidant activities, and QR induction in the colored corn varieties. The blue variety and its corresponding masa and tortillas did not induce QR. Ver 42 genotype and their products (masa and tortilla) showed the greatest antioxidant activity and capacity to induce QR. PMID- 21327970 TI - Genotoxicity and carcinogenicity studies of antihistamines. AB - This review provides a compendium of the results of genotoxicity and carcinogenicity assays performed on marketed antihistamines. Of the 70 drugs examined, 29 (41.4%) have at least one genotoxicity and/or carcinogenicity test result: 12 tested positive in at least one genotoxicity assay, six in at least one carcinogenicity assay, and four gave a positive response in both at least one genotoxicity assay and at least one carcinogenicity assay. Of 19 drugs with both genotoxicity and carcinogenicity data, eight were neither genotoxic nor carcinogenic, two were carcinogenic in at least one sex of mice or rats but tested negative in genotoxicity assays, five tested positive in at least one genotoxicity assay but were non-carcinogenic, and four gave a positive response in at least one genotoxicity assay and in at least one carcinogenicity assay. Only 12 (17.1%) of the 70 drugs examined have all data required by present guidelines for testing of pharmaceuticals, but it should be considered that a large fraction of them were developed and marketed prior the present regulatory climate. PMID- 21327969 TI - Impact of fetal versus perinatal hypoxia on sex differences in childhood outcomes: developmental timing matters. AB - PURPOSE: To examine how the timing of hypoxic exposure results in specific childhood outcomes and whether there is a differential effect by sex. METHODS: A sample of 10,879 prospectively followed pregnancies was drawn from the Boston and Providence sites (New England, NE) of the National Collaborative Perinatal Project. Based on placental pathology, we developed and validated a measure of probable chronic placental hypoxia (CHP) and contrasted the effects of acute perinatal hypoxia on age 7 emotional, behavioral, and cognitive outcomes. RESULTS: Perinatal hypoxia had a significant impact on multiple behavioral and cognitive outcomes in boys and girls by age 7, in contrast to probable CHP which had a differential effect on girls and boys such that there was decreased verbal IQ and increased inhibition in females alone. CONCLUSIONS: Findings underscore the importance of considering the timing of obstetric complications and offspring sex in investigations of the impact of fetal and perinatal hypoxia on offspring's outcomes throughout the life course. PMID- 21327971 TI - A clinical case of serious "natural medicine" incompetence. PMID- 21327972 TI - Positron emission tomography of copper metabolism in the Atp7b-/- knock-out mouse model of Wilson's disease. AB - PURPOSE: This study aims to determine feasibility and utility of copper-64(II) chloride (64CuCl2) as a tracer for positron emission tomography (PET) of copper metabolism imbalance in human Wilson's disease (WD). PROCEDURES: Atp7b-/- mice, a mouse model of human WD, were injected with 64CuCl2 intravenously and subjected to PET scanning using a hybrid PET-CT (computerized tomography) scanner, with the wild-type C57BL mice as a normal control. Quantitative PET analysis was performed to determine biodistribution of 64Cu radioactivity and radiation dosimetry estimates of 64Cu were calculated for PET of copper metabolism in humans. RESULTS: Dynamic PET analysis revealed increased accumulation and markedly reduced clearance of 64Cu from the liver of the Atp7b-/- mice, compared to hepatic uptake and clearance of 64Cu in the wild-type C57BL mice. Kinetics of copper clearance and retention was also altered for kidneys, heart, and lungs in the Atp7b/- mice. Based on biodistribution of 64Cu in wild-type C57BL mice, radiation dosimetry estimates of 64Cu in normal human subjects were obtained, showing an effective dose (ED) of 32.2 MU (micro)Sv/MBq (weighted dose over 22 organs) and the small intestine as the critical organ for radiation dose (61 MUGy/MBq for males and 69 MUGy/MBq for females). Radiation dosimetry estimates for the patients with WD, based on biodistribution of 64Cu in the Atp7b-/- mice, showed a similar ED of 32.8 MU (micro)Sv/MBq (p = 0.53), with the liver as the critical organ for radiation dose (120 MUSv/MBq for male and 161 MUSv/MBq for female). CONCLUSIONS: Quantitative PET analysis demonstrates abnormal copper metabolism in the mouse model of WD with improved time-resolution. Human radiation dosimetry estimates obtained in this preclinical study encourage direct radiation dosimetry of 64CuCl2 in human subjects. The results suggest feasibility of utilizing 64CuCl2 as a tracer for noninvasive assessment of copper metabolism in WD with PET. PMID- 21327973 TI - Marker-controlled watershed for lesion segmentation in mammograms. AB - Lesion segmentation, which is a critical step in computer-aided diagnosis system, is a challenging task as lesion boundaries are usually obscured, irregular, and low contrast. In this paper, an accurate and robust algorithm for the automatic segmentation of breast lesions in mammograms is proposed. The traditional watershed transformation is applied to the smoothed (by the morphological reconstruction) morphological gradient image to obtain the lesion boundary in the belt between the internal and external markers. To automatically determine the internal and external markers, the rough region of the lesion is identified by a template matching and a thresholding method. Then, the internal marker is determined by performing a distance transform and the external marker by morphological dilation. The proposed algorithm is quantitatively compared to the dynamic programming boundary tracing method and the plane fitting and dynamic programming method on a set of 363 lesions (size range, 5-42 mm in diameter; mean, 15 mm), using the area overlap metric (AOM), Hausdorff distance (HD), and average minimum Euclidean distance (AMED). The mean +/- SD of the values of AOM, HD, and AMED for our method were respectively 0.72 +/- 0.13, 5.69 +/- 2.85 mm, and 1.76 +/- 1.04 mm, which is a better performance than two other proposed segmentation methods. The results also confirm the potential of the proposed algorithm to allow reliable segmentation and quantification of breast lesion in mammograms. PMID- 21327974 TI - Perceptions of prominent neighborhood individuals regarding neighborhood factors and intimate partner violence. AB - Research addressing the impact of neighborhood factors on intimate partner violence (IPV) often lacks discussion of how and why such factors impact IPV. In order to address this gap, 16 prominent neighborhood individuals (PNI) from 4 low income urban neighborhoods were asked to share through in-depth interviews their insights and perceptions of IPV as an issue in their neighborhoods, and the relationship between social and structural neighborhood-level factors and IPV. PNIs most often associated IPV with only physical violence. Several did not feel IPV was a significant issue in their neighborhood, confirming a lack of awareness and underreporting of IPV. However, other PNIs were able to speak of the relationship between IPV and neighborhood factors, including lack of opportunities for employment, vacant housing, trash management, lack of community awareness, and social capacity to act to address IPV. Results provide unique insights regarding the mechanisms linking neighborhood factors to IPV outcomes. These results contribute to a deeper understanding of contextual influences upon IPV, the development of tailored quantitative research and to the design of local multi-level public health IPV intervention and prevention efforts. PMID- 21327975 TI - Action-effect associations revealed by eye movements. AB - We move our eyes not only to get information, but also to supply information to our fellows. The latter eye movements can be considered as goal-directed actions to elicit changes in our counterparts. In two eye-tracking experiments, participants looked at neutral faces that changed facial expression 100 ms after the gaze fell upon them. We show that participants anticipate a change in facial expression and direct their first saccade more often to the mouth region of a neutral face about to change into a happy one and to the eyebrows region of a neutral face about to change into an angry expression. Moreover, saccades in response to facial expressions are initiated more quickly to the position where the expression was previously triggered. Saccade-effect associations are easily acquired and are used to guide the eyes if participants freely select where to look next (Experiment 1), but not if saccades are triggered by external stimuli (Experiment 2). PMID- 21327976 TI - Magnitude comparison revisited: an alternative approach to binary choice under uncertainty. AB - Two generations of psychologists have been interested in understanding binary choice under uncertainty. In the 1970s and 1980s, researchers assumed that people rely on a two-stage magnitude comparison process to make these decisions (Banks, 1977; Moyer & Dumais, 1978). More recently, the focus has shifted to approaches that rely on probabilistic cues and simple heuristics (Gigerenzer & Goldstein, Psychological Review 103, 650-669, 1996). Here, we test competing predictions derived from these two very different approaches and conclude that the magnitude comparison process plays a central role in this task. In support of this conclusion, we present an experiment in which participants were timed as they decided which of two vehicles was more expensive. Pairs composed of one luxury vehicle (e.g., BMW 323i) and one nonluxury vehicle (e.g., Toyota 4Runner) were critical because the magnitude comparison approach correctly predicted that reaction times would decrease with subjective distance, whereas the heuristics approach incorrectly predicted that there would be no relation. PMID- 21327977 TI - Urinary and sexual disorders after laparoscopic TME for rectal cancer in males. AB - BACKGROUND: Urinary and sexual dysfunctions are frequent after surgery for rectal cancer. Total mesorectal excision (TME) improves local recurrence and survival rates, and does not hamper recognition and sparing of hypogastric and pelvic splanchnic nerves. It is not known how laparoscopic rectal resection could change functional complication rates. MATERIALS AND METHODS: From a global series of 1,216 laparoscopic interventions for colorectal diseases, 35 cases of males less than 70 years old, undergoing rectal resection and TME for a T1-3M0 medium and low rectal cancer were selected. Urinary and sexual functions after the operations were retrospectively recorded by means of specific tools (International Prostate Symptom Score (IPSS) and IIEF questionnaires, respectively). RESULTS: None of the patients necessitated permanent or intermittent catheterization. More than half the patients had no complaints about urinary functions; about one third had nocturia; 72% of the patients had an IPSS less that 10, and no case of IPSS worse that 31 was recorded. Sexual desire was reduced and spontaneous erectile function was impaired in almost half the cases, while induced erections were possible in about 90% of cases; about 70% of patients still had the possibility of penetration and a normal ejaculation and orgasm after the intervention. DISCUSSION AND CONCLUSIONS: The present series confirms previous data and contribute to the creation of a benchmark specifically related to the laparoscopic approach to which surgeons should face when informing the patients before the operation. While severe urinary dysfunction is rare, sexual impairment remains a serious concern after rectal resection with TME. PMID- 21327978 TI - Direct application of MR images to computer-assisted bone tumor surgery. AB - BACKGROUND: We describe a method for the direct application of MR images to navigation-assisted bone tumor surgery as an alternative to CT-MRI fusion. METHOD: Six patients with an orthopedic malignancy were employed for this method during navigation-assisted tumor resection. Tumor types included osteosarcoma (4), high-grade chondrosarcoma (1), and adamantinoma (1). Mean patient age was 25.3 years (range 18-52 years). Mean duration of follow-up was 25.8 months (range 18-32 months). Resorbable pin placement and rapid 3-dimensional spoiled gradient echo sequences made the direct application of MR images to computer-assisted bone tumor surgery without CT-MR image fusion possible. A paired-point registration technique was employed for patient-image registration in all patients. RESULTS: It took 20 min on average to set up the navigation (range 15-25 min). The mean registration error was 0.98 mm (range 0.4-1.7 mm). On histologic examination, distances from tumors to resection margins were in accord with preoperative plans. No patient had a local recurrence or distant metastasis at the last follow up. CONCLUSION: Direct patient-to-MRI registration is a very useful method for bone tumor surgery, permitting the application of MR images to intraoperative visualization without any additional costs or exposure of the patient to radiation from the preoperative CT scan. PMID- 21327979 TI - Surgical treatment of developmental dysplasia of the hip presenting in children above 10 years. AB - BACKGROUND: Management of developmental dysplasia of the hip in older children remains controversial. The objective of this study was to evaluate the results of surgical treatment of developmental dysplasia of the hip in children older than 10 years. METHOD: Sixty-three patients (75 hips) whose mean age at the time of surgery was 11.5 years (range 10-19 years) were treated using Salter osteotomy, Pemberton acetabuloplasty, Dega osteotomy, or Westin osteotomy. Subtrochanter transverse femoral shortening and derotation osteotomy were performed for all patients. A long leg cast, rather than a spica cast, was applied postoperation, and progressive flexion and extension exercises of the hip joint were initiated 2 weeks after the surgery. RESULT: All 63 patients (75 hips) were followed for an average of 7.6 years (range 5-10 years) after surgery. According to the McKay criteria and Severin X-ray criteria, the fineness ratios were 82.7 and 82.6%, respectively. After surgery, there were 4 cases of semiluxation (6.3%); 4 of femoral head ischemia necrosis (6.3%), and 9 of hip joint stiffness (14.3%). CONCLUSION: We believe that preoperation overall evaluation and personalized operation plans, experience with the surgical procedure, and commencement of functional exercise soon after the operation are the main reasons for the satisfactory therapeutic effects achieved in this study after surgery for developmental dysplasia of the hip presenting in children older than 10 years. PMID- 21327980 TI - Extraskeletal Ewing's sarcoma in a 67-year-old man. PMID- 21327981 TI - Update of a cohort mortality study of workers exposed to methylene chloride employed at a plant producing cellulose triacetate film base. AB - PURPOSE: To update the mortality experience of employees of a factory that produced cellulose triacetate film base at Brantham in the United Kingdom and generate information on the effects of exposure to methylene chloride, in particular, mortality from cardiovascular disease and cancers of the lung, liver and biliary tract, pancreas and brain. METHODS: All 1,785 male employees with a record of employment at the film factory in 1946-1988 were followed through 2006, including 1,473 subjects exposed to methylene chloride on average for 9 years at a concentration of 19 ppm (8 h time-weighted average). RESULTS: A total of 559 deaths occurred during the follow-up period. In the subcohort of workers exposed to methylene chloride, substantially reduced mortalities compared with national and local rates were found for all causes, all cancers, and all the principal cancer sites of interest except for brain cancer. There was a small excess of brain cancer deaths (8 observed and 4.4 expected), but no evidence of an association with exposure to methylene chloride. Lung cancer mortality was significantly reduced in exposed workers, even compared to the low mortality rate in the local population (SMR 55). In contrast, mortality from ischaemic heart disease in exposed workers was slightly increased compared with local rates (SMR 102), but was lower in active employees (SMR 94; local rates), where a direct effect of exposure to methylene chloride should be concentrated. CONCLUSIONS: The study provided no indication that employment at the plant, or exposure to methylene chloride, had adversely affected the mortalities of workers. PMID- 21327982 TI - Advanced glycation end products induce moesin phosphorylation in murine retinal endothelium. AB - Increase in vascular permeability is the most important pathological event during the development of diabetic retinopathy. Deposition of advanced glycation end products (AGEs) plays a crucial role in the process of diabetes. This study was to investigate the role of moesin and its underlying signal transduction in retinal vascular hyper-permeability induced by AGE-modified mouse serum albumin (AGE-MSA). Female C57BL/6 mice were used to produce an AGE-treated model by intraperitoneal administration of AGE-MSA for seven consecutive days. The inner blood-retinal barrier was quantified by Evans blue leakage assay. Endothelial F actin cytoskeleton in retinal vasculature was visualized by fluorescence probe staining. The expression and phosphorylation of moesin in retinal vessels were detected by RT-PCR and western blotting. Further studies were performed to explore the effects of Rho kinase (ROCK) and p38 MAPK pathway on the involvement of moesin in AGE-induced retinal vascular hyper-permeability response. Treatment with AGE-MSA significantly increased the permeability of the retinal microvessels and induced the disorganization of F-actin in retinal vascular endothelial cells. The threonine (T558) phosphorylation of moesin in retinal vessels was enhanced remarkably after AGE administration. The phosphorylation of moesin was attenuated by inhibitions of ROCK and p38 MAPK, while this treatment also prevented the dysfunction of inner blood-retinal barrier and the reorganization of F-actin in retinal vascular endothelial cells. These results demonstrate that moesin is involved in AGE-induced retinal vascular endothelial dysfunction and the phosphorylation of moesin is triggered via ROCK and p38 MAPK activation. PMID- 21327983 TI - Leptin is an independent determinant of bone mineral density in men with type 2 diabetes mellitus. AB - To investigate the possible relationship of leptin to bone mineral density (BMD) in men with type 2 diabetes mellitus (T2DM), we screened 168 Belarusian men aged 45-65 years. Plasma total cholesterol (TC), high-density lipoprotein cholesterol, and triglyceride concentrations were assessed, and low-density lipoprotein cholesterol and very low-density lipoprotein cholesterol (LDL-C) were calculated. Hemoglobin A(1c), immune-reactive insulin (IRI), serum total testosterone, and sex hormone-binding globulin were also evaluated. BMD was evaluated using dual energy X-ray absorptiometry. By univariate linear regression analysis, BMD was significantly correlated with body mass index (r = 0.23, P = 0.002) and leptin (r = 0.21, P = 0.006). By multivariate regression analysis adjusting for confounding factors, log leptin was independently correlated with BMD (beta = 0.058, P = 0.001). Our study revealed that leptin is an independent determinant of BMD in patients with T2DM. Further research is necessary to confirm this association and to develop ways to correct abnormalities of bone metabolism in patients with T2DM. PMID- 21327984 TI - Enhanced syndecan-1 expression on neutrophils in patients with type 2 diabetes mellitus. AB - The peripheral neutrophils are one of the main inflammatory cells and significantly influence the damage of endothelium. Type 2 diabetes is a manifestation of an ongoing low-grade inflammation. In diabetes, impairment of neutrophil adhesion to the endothelium and migration to the site of inflammation were detected, which associated closely with adhesion molecules expressed on neutrophils and endothelial cells. To detect the expression of syndecan-1 on neutrophils in patients with type 2 diabetes mellitus, we recruited 29 patients with type 2 diabetes mellitus without any diabetic complication and 24 healthy subjects (controls). Expression of syndecan-1 was determined by flow cytometry, and potential correlations between syndecan-1 and clinical characteristics were analyzed. On neutrophils, percentage of positive syndecan-1 cells was significantly higher in subjects with diabetes (10.363 +/- 1.689%) than that of the controls (3.775 +/- 0.634%, P = 0.001). An association between body mass index (BMI) and percentage of positive syndecan-1 neutrophils was detected (r = 0.415, P = 0.025). When BMI was categorized into subgroups of <=25 kg/m(2) (n = 10) and >25 kg/m(2) (n = 19), the average percentages of positive syndecan-1 neutrophils in patients with diabetes were 5.733 +/- 1.842% and 12.642 +/- 2.251%, respectively (t = -2.137, P = 0.042). A multiple regression analysis showed that BMI (beta = 0.783, P < 0.000) was a significant predictor of positive syndecan-1 neutrophils in subjects with type 2 diabetes. PMID- 21327985 TI - Oxidative stress and antioxidant status in patients with late-onset gestational diabetes mellitus. AB - The relationship between late-onset gestational diabetes mellitus [GDM] and oxidative stress is not well known, and the importance of the oxidant/antioxidant equilibrium in the clinical evolution and its complications require elucidation. The aim of the study was to evaluate the relationships between maternal levels of markers of oxidative stress in women with late-onset GDM that, potentially, may have considerable clinical implications in the pathogenesis and/or the evolution of GDM. Pregnant women (n = 78; 53 with GDM, 25 controls), between the 24th and 29th week of gestation, were enrolled. Both groups were analysed for demographic data, perinatal and obstetrics outcomes together with the levels of the marker's oxidative stress and antioxidant status. Control versus patient results in the univariate analysis were the following: pre-gestational body mass index [BMI] 23.31 +/- 4.2 vs. 27.13 +/- 4.6 kg/m(2) (P = 0.001); weeks at delivery 39.2 +/- 3.05 vs. 38.9 +/- 1.8 (P = 0.09); Caesarean delivery 12.5 vs. 43% (P = 0.004); macrosomia 4 vs. 9.4% (P = 0.6); lipoperoxides [LPO] 2.06 +/- 1.00 vs. 3.14 +/- 1.55 MUmol/mg (P = 0.001); catalase 3.23 +/- 1.41 vs. 2.52 +/- 1.3 nmol/min/ml (P = 0.03); superoxide dismutase [SOD] 0.11 +/- 0.04 vs. 0.08 +/- 0.01 U/ml (P = 0.0003); glutathione peroxidase [GPX] 0.03 +/- 0.006 vs. 0.025 +/- 0.006 nmol/min/ml (P = 0.01); glutathione reductase [GSH] 0.004 +/- 0.002 vs. 0.004 +/- 0.004 nmol/min/ml (P = 0.9)]; and glutathione transferase [GST] 0.0025 +/- 0.0012 vs. 0.0027 +/- 0.00017 nmol/min/ml (P = 0.7). Multivariate analysis showed catalase might have a protective effect against GDM development and LPO seems to be a risk factor for the disease. These data suggest an increase in oxidative stress and a decrease in antioxidative defence in women with late-onset GDM and, as such, may have considerable clinical implications in the pathogenesis and/or the course of the pregnancy in these patients. PMID- 21327986 TI - Enzymatic synthesis of farnesyl laurate in organic solvent: initial water activity, kinetics mechanism, optimization of continuous operation using packed bed reactor and mass transfer studies. AB - The influence of water activity and water content was investigated with farnesyl laurate synthesis catalyzed by Lipozyme RM IM. Lipozyme RM IM activity depended strongly on initial water activity value. The best results were achieved for a reaction medium with an initial water activity of 0.11 since it gives the best conversion value of 96.80%. The rate constants obtained in the kinetics study using Ping-Pong-Bi-Bi and Ordered-Bi-Bi mechanisms with dead-end complex inhibition of lauric acid were compared. The corresponding parameters were found to obey the Ordered-Bi-Bi mechanism with dead-end complex inhibition of lauric acid. Kinetic parameters were calculated based on this model as follows: V (max) = 5.80 mmol l(-1) min(-1) g enzyme(-1), K (m,A) = 0.70 mmol l(-1) g enzyme(-1), K (m,B) = 115.48 mmol l(-1) g enzyme(-1), K (i) = 11.25 mmol l(-1) g enzyme(-1). The optimum conditions for the esterification of farnesol with lauric acid in a continuous packed bed reactor were found as the following: 18.18 cm packed bed height and 0.9 ml/min substrate flow rate. The optimum molar conversion of lauric acid to farnesyl laurate was 98.07 +/- 0.82%. The effect of mass transfer in the packed bed reactor has also been studied using two models for cases of reaction limited and mass transfer limited. A very good agreement between the mass transfer limited model and the experimental data obtained indicating that the esterification in a packed bed reactor was mass transfer limited. PMID- 21327987 TI - Identification and characterization of microRNAs in Trichinella spiralis by comparison with Brugia malayi and Caenorhabditis elegans. AB - Trichinella spiralis is an important zoonotic nematode causing trichinellosis which is associated with human diseases such as malaise, anorexia, nausea, vomiting, abdominal pain, fever, diarrhea, and constipation. microRNAs (miRNAs) are endogenous small non-coding RNAs that play important roles in the regulation of gene expression. The objective of the present study was to examine the miRNA expression profile of the larvae of T. spiralis by Solexa deep sequencing combined with stem-loop real-time polymerase chain reaction (PCR) analysis. T. spiralis larvae were collected from the skeletal muscle of naturally infected pigs in Henan province, China, by artificial digestion using pepsin. The specific identity of the T. spiralis larvae was confirmed by PCR amplification and subsequent sequence analysis of the internal transcribed spacer of ribosomal DNA. A total of 17,851,693 reads with 2,773,254 unique reads were obtained. Eleven conserved miRNAs from 115 unique xsmall RNAs (sRNAs) and 12 conserved miRNAs from 130 unique sRNAs were found by BLAST analysis against the known miRNAs of Caenorhabditis elegans ( ftp://ftp.ncbi.nih.gov/genomes/Caenorhabditis_elegans ) and Brugia malayi dataset ( http://www.ncbi.nlm.nih.gov/genomeprj?Db=genomeprj&cmd=ShowDetailView&TermToSearc =9549 ) in miRBase, respectively. One novel miRNA with 12 precursors were identified and certified using the reference genome of B. malayi, while no novel miRNA was found when using the reference genome of C. elegans. Nucleotide bias analysis showed that the uracil was the prominent nucleotide, particularly at the 1st, 6th, 18th, and 23th positions, which were almost at the beginning, middle, and the end of the conserved miRNAs. The identification and characterization of T. spiralis miRNAs provides a new resource to study regulation of genes and their networks in T. spiralis. PMID- 21327988 TI - Occurrence and genetic characterization of Giardia duodenalis from captive nonhuman primates by multi-locus sequence analysis. AB - Giardia is the most common enteric protozoan that can be pathogenic to both humans and animals. Transmission can be direct through the faecal-oral route, or through ingestion of contaminated water or food. Genetic characterization of Giardia duodenalis isolates has demonstrated the existence of seven groups (assemblages A to G) which differ in their host distribution. Assemblages A and B are present in humans and other primates, dogs, cats, rodents, and other species of wild mammals, but the role of the different host animals in the epidemiology of human infection remains unclear. With this preliminary data, we can infer that nonhuman primates (NHP) might be a potential reservoir for zoonotic transmission. This research paper discusses the presence of Giardia in nonhuman primates housed in two Spanish zoological gardens (located in Valencia and Madrid). Twenty faecal samples obtained from 16 different species of NHP were studied; 70% were positives to Giardia, and genetic analyses were performed by sequencing of four genes (SSrRNA, glutamate dehydrogenase, triose phosphate isomerase, and beta giardin). The assemblage A was the most frequent (63.4%) in the species studied. A sequence from a red ruffed lemur (corresponding to genotype AI) was obtained, and this is the first reported sequence of a gdh gene obtained from this species. The multi-locus sequence analysis was also performed on the samples positive to nested PCR belonging to assemblage B. After amplification using the GDHeF, GDHiF, and GDHiR gdh primers; AL3543, AL3546, AL3544, and AL3545 tpi primers; G7, G759, GBF, and GBR bg primers, amplicons of 432, 500, and 511 bp respectively were obtained. Amplification products were sequenced and the sequence and phylogenetic analyses showed that genotype IV like was the most frequent in the samples belonging to this assemblage. PMID- 21327989 TI - Induction of proinflammatory cytokines and nitric oxide by Trypanosoma cruzi in renal cells. AB - Chagas disease is typically associated with cardiac involvement. During the acute phase of murine infection with Trypanosoma cruzi, severe acute myocarditis can develop. Prior to cardiac alteration, however, infected mice present with renal inflammatory infiltration causing acute kidney injury due to an ischemia/reperfusion lesion. Thus, the present study was undertaken in order to evaluate whether the parasites or some of their components would directly affect renal cells. As such, this study employed kidney cell lines (mesangial, epithelial, and proximal tubular) that mimic different regions of the renal system. Mesangial cells are more resistant to infection, showing reduced parasite internalization relative to epithelial and proximal tubular cells. Upon infection, mesangial cells produced more nitric oxide, tumor factor necrosis alpha, and interferon-gamma and showed decreased viability when compared to the other cell lines. These results indicate that the resistance of mesangial cells to infection may be related to the increased expression of nitric oxide and proinflammatory cytokines. Conversely, the high levels of nitric oxide produced by these cells caused impairment of cell integrity and viability. Higher nitric oxide concentrations promote cellular injury and can be involved in the genesis of ischemia/reperfusion lesions in acute kidney injury. PMID- 21327990 TI - Trypanosoma cruzi: evaluation of (-)-cubebin derivatives activity in the messenger RNAs processing. AB - No fully effective treatment has been developed since the discovery of Chagas' disease. Since drug-resistant Trypanosoma cruzi strains are occurring and the current therapy is effective in the acute phase but with various adverse side effects, more studies are needed to characterize the susceptibility of T. cruzi to new drugs. Pre-mRNA maturation in trypanosomatids occurs through a process called trans-splicing, which is unusual RNA processing reaction, and it implies the processing of polycistronic transcription units into individual mRNAs; a short transcript spliced leader (SL RNA) is trans-spliced to the acceptor pre mRNA, giving origin to the mature mRNA. Cubebin derivatives seem to provide treatments with less collateral effects than benznidazole and showed similar or better trypanocidal activities than benznidazole. Therefore, the cubebin derivatives ((-)-6,6'-dinitrohinokinin (DNH) and (-)-hinokinin (HQ)) interference in the mRNA processing was evaluated using T. cruzi permeable cells (Y and BOL (Bolivia) strains) following by RNase protection reaction. These substances seem to intervene in any step of the RNA transcription, promoting alterations in the RNA synthesis, even though the RNA processing mechanism still occurs. Furthermore, HQ presented better activity against the parasites than DNH, meaning that BOL strain seems to be more resistant than Y. PMID- 21327991 TI - A real-time multiplex-nested PCR system for coprological diagnosis of Echinococcus multilocularis and host species. AB - A hybridization probe-based real-time multiplex-nested PCR system was developed for the simultaneous detection of Echinococcus multilocularis and host species directly from faecal samples. Species identification was determined by melting curve analysis. Specificity was assessed by using DNA extracted from various cestodes (E. multilocularis, Echinococcus granulosus (G1), Echinococcus ortleppi, Echinococcus canadensis (G6, G7), Taenia crassiceps, Taenia hydatigena, Taenia mustelae, Taenia pisiformis, Taenia serialis, Taenia taeniaeformis, Mesocestoides leptothylacus), carnivores (Vulpes vulpes, Vulpes corsac, Vulpes ferrilata, Canis familiaris, Felis catus, Martes foina), Microtus arvalis and Arvicola terrestris. The analytical sensitivity was 10 fg, evaluated with serially diluted DNA of E. multilocularis to 10 MUl total DNA solution from E. multilocularis-negative canid faeces. Based on a comparison of 47 dog samples from China, the proportion of the E. multilocularis-positive-tested samples by the real-time multiplex-nested PCR was moderately higher (38% vs. 30%) as when tested with a previously evaluated nested PCR with a sensitivity of 70-100%, depending on the number and gravidity status of worms present in the intestine (Dinkel et al., J Clin Microbiol 36:1871 1876, 1998). To assess the epidemiological applicability of this method, 227 canid faecal samples collected in the field were analysed. This newly developed real-time multiplex-nested PCR system is a specific, sensitive and reliable method for the detection of E. multilocularis and host species in faecal samples for epidemiological purposes. PMID- 21327992 TI - Antischistosomal activity of ginger (Zingiber officinale) against Schistosoma mansoni harbored in C57 mice. AB - The repeated chemotherapy of schistosomiasis has resulted in the emergence of drug-resistant schistosome strains. The development of such resistance has drawn the attention of many authors to alternative drugs. Many medicinal plants were studied to investigate their antischistosomal potency. The present work aimed to evaluate antischistosomal activity of crude aqueous extract of ginger against Schistosoma mansoni. Sixteen mice of C57 strain were exposed to 100 +/- 10 cercariae per mouse by the tail immersion method; the mice were divided into two groups: untreated group and ginger-treated one. All mice were sacrificed at the end of 10th week post-infection. Worm recovery and egg counting in the hepatic tissues and faeces were determined. Surface topography of the recovered worms was studied by scanning electron microscopy. Histopathological examination of liver and intestine was done using routine histological procedures. The worm burden and the egg density in liver and faeces of mice treated with ginger were fewer than in non-treated ones. Scanning electron microscopical examination revealed that male worms recovered from mice treated with ginger lost their normal surface architecture, since its surface showed partial loss of tubercles' spines, extensive erosion in inter-tubercle tegumental regions and numerous small blebs around tubercles. Histopathological data indicated a reduction in the number and size of granulomatous inflammatory infiltrations in the liver and intestine of treated mice compared to non-treated mice. The results of the present work suggested that ginger has antischistosomal activities and provided a basis for subsequent experimental and clinical trials. PMID- 21327994 TI - [Update on emergency surgery. Rotator cuff injuries]. PMID- 21327993 TI - Trichinella sp. in red foxes (Vulpes vulpes) from Catalonia, NE Spain. AB - European legislation allows the official recognition of Trichinella-free pig holdings, provided Trichinella sp. infection is absent from humans and prevalence of Trichinella sp. infection in red foxes (Vulpes vulpes) is below 0.1% in the area, region or country. Tibialis anterior muscle samples from 1,319 red foxes captured in Catalonia (NE Spain) between 1998 and 2007 were analyzed for Trichinella sp. using the digestion method. Four foxes resulted positive (one in 1999, one in 2002 and two in 2006), accounting for a low prevalence (0.3%). However, this prevalence was concentrated in mountain or rural areas with a low sample size, reaching high local prevalences. The two positive samples in 2006 were characterized as Trichinella britovi, and a sylvatic cycle of trichinellosis seems to occur, at least in the rural insufficiently sampled regions of Catalonia. Overall, the results obtained do not currently allow the establishment of Trichinella-free pig holdings in the study area, but further research is needed to better know the prevalence and cycle of Trichinella sp. in Catalonia. PMID- 21327995 TI - [Minimally invasive dorsal stabilization of the thoracolumbar spine]. AB - Thoracolumbar spine injuries represent the vast majority of unstable spine fractures. In common, patients are instrumented from a dorsal position while primary stabilization of those fractures using a ventral approach remains exceptional. Fracture morphology and concomitant injuries of the discoligamentous complex help to determine whether combined positions or second staged ventral positioned stabilization is indicated. While segmental stabilization and proper fracture reduction are the primary goals, the latter is of specific importance due to the angular point of the vertebral column in fractures of the thoracolumbar spine. The invasive surgical approach in open reduction and stabilization from a dorsal position seems to be replaced increasingly by less invasive angular stable internal spine fixator systems. This article describes the principle, suited indications and the limitations of one of the internal spine fixators available to achieve angular stable percutaneous dorsal stabilization. PMID- 21327996 TI - [Multisegmental and minimally invasive dorsal stabilization of thoracic and lumbar vertebral column. Operative technique]. AB - Dorsal stabilization of the thoracic and lumbar vertebral column is still the fundamental technique for acute treatment of unstable vertebral fractures and intervertebral ligament injuries as well as in tumor surgery and the treatment of degenerative and inflammatory diseases. The aim is to achieve the best possible anatomical and axis-correct stabilization of the physical lordosis and kyphosis. This article describes in detail the operational preparation (e.g. necessary imaging, possible positioning of the patient) and procedure (e.g. access, placement of screws and plates, wound closure and postoperative follow-up treatment) and possible complications due to misplaced pedicle screws, the rate of which can possibly be reduced by intraoperative 3D imaging. PMID- 21327998 TI - The impact of tracheostomy on the nose. AB - To establish the effect of tracheostomy on nasal function and quality of life. Teaching Hospital, Scotland, UK. Cross-sectional case-control study. Two groups of patients were selected; a group of ten patients who underwent surgical tracheostomy and a control group of ten patients with confirmed or suspected head and neck malignancy that did not require tracheostomy. Two questionnaires, the SNOT-22 quality of life instrument, and the Rhinogram nasal symptoms score were used to evaluate each group. For the Rhinogram questionnaire the median total score was 13.5 for the tracheostomy group and 2 for the control group (P = 0.02) whilst for the SNOT-22, the mean total scores were 39 and 29, respectively (P = 0.205). The tracheostomy group scored worse for all Rhinogram questions, and for the anosmia score this was independently statistically significant (5 vs. 0 units, P = 0.001). The tracheostomy group most commonly identified "loss of smell & taste" as their most important symptom, compared with only 2 subjects in the control group. Tracheostomy can give rise to nasal symptoms. This needs to be addressed in the routine follow up of these patients. PMID- 21327999 TI - Pharyngo-laryngeal examination with the narrow band imaging technology: early experience. AB - The prognosis of cancer patients is highly dependent on the time of diagnosis. Early, stage 1 disease is often curable whereas late stage diseases are usually beyond curable treatments. Therefore, new diagnostic tools for malignancies of the upper aerodigestive tract are developed all the time and narrow band imaging (NBI) is one of these new options for early diagnostics. In this paper, we describe the implementation of NBI technique in our institution. During the first 6 weeks we used NBI to examine 73 patients with different types of pharyngeal or laryngeal problems. Most of the patients (77%) were on follow-up visits after earlier malignant disease. In our series we had 11 NBI-positive patients and the histological diagnosis was carcinoma or dysplasia among 10 of these. Among the NBI negative patients we found four carcinomas. It is notable that NBI affected the decision of a biopsy procedure in three patients, with final diagnosis of dysplasia or carcinoma. In conclusion, we find NBI useful in the diagnostics of malignancies of the upper aerodigestive tract. This is a useful tool in improving the accuracy of the diagnostics. However, it still takes an experienced clinician and a learning curve can be expected. PMID- 21328000 TI - Prevalence and clinical features of human papillomavirus in head and neck squamous cell carcinoma in Okinawa, southern Japan. AB - Previous studies from Okinawa, a subtropical island in southern Japan, demonstrated a higher prevalence of human papillomavirus (HPV) in oral carcinoma and a higher incidence of oral and pharyngeal carcinoma than those for mainland Japan. The present study aims to investigate epidemiologic and clinical features of HPV in head and neck squamous cell carcinoma (HNSCC) in Okinawa. A total of 150 DNA samples from 150 Okinawan patients with head and neck squamous cell carcinoma (HNSCC) were screened for HPV sequences by PCR using three consensus primer sets, and HPV types were determined by direct sequencing. The samples were consisted of 46 cases from the hypopharynx, 44 from the oropharynx, 16 from the larynx, 25 from the oral cavity, 10 from the maxillary sinus, and 9 from the nasopharynx. HPV DNA was detected in 45 (30.0%) HNSCCs, and HPV-16 was identified in 86.7% of positive specimens. The highest prevalence of the HPV sequence was found in oropharyngeal carcinomas (50.0%), especially in tonsillar cancer (63.6%). Multivariate analysis showed that oropharyngeal carcinoma (P = 0.002; OR = 5.34; 95% CI = 1.83-15.58), oral cavity carcinoma (P = 0.012; OR = 4.94; 95% CI = 1.43-17.10), and histological poor differentiation (P = 0.011; OR = 4.25; 95% CI = 1.39-13.04) each independently increased the prevalence of HPV infection. The present study reveals that patients with HNSCC, e.g., oropharyngeal and oral cavity carcinomas, in Okinawa have relatively high HPV-16 positive rates and low HPV-18 positive rates comparing with mainland Japan. PMID- 21328001 TI - Surgery for plunging ranula: the lesson not yet learned? AB - Our objective is to review our experience with treatment of plunging ranula and examine the efficacy of transoral excision of sublingual gland as the principal treatment. This study comprises a case series with chart review. A secondary otolaryngology service was used as the setting. Retrospective analysis of patient records was performed for a series of 95 consecutive cases of plunging ranula, which presented to our department between January 2001 and February 2010. Clinical presentation, investigations, diagnosis, treatment, complications and outcome were recorded. Literature search was performed using MEDLINE and OLD MEDLINE. 81 cases of plunging ranula were treated surgically by transoral excision of sublingual gland and evacuation of ranula contents. Mean operating time was 75.3 min. Twelve patients had undergone previous surgery elsewhere. One patient in our series had a recurrence, needing excision of sublingual gland remnant. Two patients had trauma to submandibular duct requiring excision of submandibular gland. Other complications were minor and transient. Review of literature revealed many diverse methods of treating ranula, with varying results. Our series makes a substantial contribution to the number of plunging ranulas reported in the world, and supports the use of transoral sublingual gland excision as first-line treatment of plunging ranula. PMID- 21328002 TI - Safety and patient selection of totally implantable hearing aid surgery: Envoy system, Esteem. AB - Patient's low compliance of conventional hearing aids has lead to innovation of totally implantable hearing devices such as Esteem, Envoy system. This study was designed to evaluate safety of device implantation, patient's hearing gain, importance of anatomic landmarks, and to describe suitable criteria for patient selection. Via a non-randomized controlled clinical trial, ten patients with moderate-to-severe sensorineural hearing loss were implanted from 2007 to 2009. Mean follow-up period was 29.4 months. Correlation of pre-operative temporal bone CT scan anatomy with postoperative outcome was evaluated. Except one, all other implanted devices are active and patients' overall average hearing gain are similar to conventional hearing aids (10-22 dB), but patients reported relatively better subjective sound quality compared with their pre-operative conventional hearing aids. One implanted device was explanted in a patient due to facial weakness and low-hearing gain. Revision surgery was done successfully in another patient secondary to excessive bone growth. Totally implantable hearing device surgery seems to be relatively safe and correct patient selection could lead to good outcomes. Lateral location of facial nerve, sclerotic mastoid air cells and narrow facial recess space seems to be related to postoperative complications. PMID- 21328003 TI - The incidence of thyroid dysfunction following radiotherapy for early stage carcinoma of the larynx. AB - External beam radiotherapy is currently the commonest form of treatment for early laryngeal cancer (T1/2) and thyroid dysfunction is a well recognised complication of this treatment. Overt hypothyroidism is a specific clinical disorder which in most patients will be recognized and treated. The problems associated with subclinical hypothyroidism (elevated TSH with normal T4), however, are only now being recognized and their management is to some extent still controversial. The aims of our study are to determine the incidence of clinical and subclinical hypothyroidism in those who have been treated solely with curative radiotherapy for early laryngeal cancer. We performed a retrospective observational study encompassing all patients who underwent curative radiotherapy for T1/T2 laryngeal cancer between 1998 and 2002. 33 patients were identified (mean 66.85 years, range 48-93). 19 patients had T1 lesions (58%), 14 had T2 lesions (42%) and 27 were N0 (82%). 23 patients were euthyroid post treatment (70%), 2 became overtly hypothyroid (6%) and 8 developed subclinical hypothyroidism (24%). There was no association between tumour stage (p = 0.97), nodal stage (p = 0.46) and thyroid status, however, there was an association between increasing age and deteriorating thyroid function (p = 0.01). Our study showed that of patients with early laryngeal cancers treated solely with curative radiotherapy 24% developed subclinical hypothyroidism and 6% were overtly hypothyroid (Elevated TSH and reduced T4). We feel patients should receive regular thyroid function testing following completion of treatment and should be adequately counselled on the risk of thyroid dysfunction following radiotherapy at pre-treatment visits. PMID- 21328004 TI - Errors associated with the concentration of epinephrine in endonasal surgery. AB - This paper presents two cases of using erroneous concentrations of epinephrine during endonasal surgery. The two patients discussed were part of a larger study aimed at monitoring the absorption of epinephrine upon injection into the nasal mucosa. During this study, we observed major cardiovascular reactions in two consecutive patients--ventricular tachycardia with ventricular extrasystole and a significant rise in systolic and diastolic blood pressure and pulse rate. This state required pharmacological intervention. In hindsight, it was found that an erroneous application of ten times higher (1:10,000) concentration of epinephrine than the usual was injected. The applied solution was prepared in our institutional pharmacy and was labelled incorrectly (1:100,000 instead of 1:10,000). The authors have analysed the steps leading to the erroneous applications and recommend safety precautions for the prevention of errors in the concentration levels of epinephrine. Epinephrine injections in concentrations of 1:10,000, followed by analyses of epinephrine levels in venous blood, have not yet been described in available literature. PMID- 21328005 TI - Otolith function in patients with head trauma. AB - This study evaluates the otolith function of patients with head trauma, postulating that otolith dysfunction is a cause of nonspecific dizziness after head trauma. We prospectively enrolled 28 patients referred within 3 months after head trauma between March 2007 and December 2009. Pure tone audiometry, caloric testing and otolith function tests, including cervical vestibular evoked myogenic potential (cVEMP) and subjective visual vertical (SVV) tests, were performed on all patients. The relationship between otolith function and otologic symptoms was analyzed. Of the 28 patients with head trauma, 18 complained of dizziness and 12 experienced hearing loss, including 6 patients who complained of both. On defining otolith dysfunction as an abnormal cVEMP or abnormal SVV, a significant difference in otolith dysfunction existed between the groups with and without dizziness [72 (13/18) vs. 20% (2/10)]. In contrast, no significant difference in otolith dysfunction was detected between the abnormal and normal hearing groups. A significant number of the patients who complained of nonspecific dizziness after trauma had abnormal otolith function. After trauma, when patients complain of dizziness, vestibular function tests, including otolith function tests, should be considered. PMID- 21328006 TI - Professional oral health care reduces oral mucositis and febrile neutropenia in patients treated with allogeneic bone marrow transplantation. AB - GOAL OF WORK: Little is known about the effects of professional oral health care (POHC) on the outcome of hematopoietic stem cell transplantation (HSCT). We evaluated the effects of POHC given by dentists and dental hygienists on the development of oral mucositis and febrile neutropenia (FN) after allogeneic bone marrow transplantation (BMT). PATIENTS AND METHODS: We retrospectively studied 140 adult patients who had received allogeneic BMT, with or without POHC, in our hospital consecutively between February 2002 and December 2009. Oral mucositis was evaluated according to the World Health Organization scale. MAIN RESULTS: The incidence of oral mucositis was 66.7% (52/78) in the patients who had received POHC, compared to 93.5% (58/62) in the non-POHC group (P < 0.001). The incidence of FN and the maximal level of CRP were also significantly lower in the POHC group. Multivariate analysis revealed that the POHC was significantly associated with the incidence of oral mucositis (odds ratio, 7.58; 95%CI, 2.45-23.34; P < 0.001). CONCLUSIONS: We concluded that POHC reduced the incidences of oral mucositis and FN by upgrading the overall oral hygiene during HSCT. PMID- 21328007 TI - The effects of transported Asian dust on the composition and concentration of ambient fungi in Taiwan. AB - This study was conducted to evaluate the effects of transported Asian dust and other environmental parameters on the levels and compositions of ambient fungi in the atmosphere of northern Taiwan. We monitored Asian dust events in Taipei County, Taiwan from January 2003 to June 2004. We used duplicate Burkard portable air samplers to collect ambient fungi before, during, and after dust events. Six transported Asian dust events were monitored during the study period. Elevated concentrations of Aspergillus (A. niger, specifically), Coelomycetes, Rhinocladiella, Sporothrix and Verticillium were noted (p < 0.05) during Asian dust periods. Botryosporium and Trichothecium were only recovered during dust event days. Multiple regression analysis showed that fungal levels were positively associated with temperature, wind speed, rainfall, non-methane hydrocarbons and particulates with aerodynamic diameters <=10 MUm (PM(10)), and negatively correlated with relative humidity and ozone. Our results demonstrated that Asian dust events affected ambient fungal concentrations and compositions in northern Taiwan. Ambient fungi also had complex dynamics with air pollutants and meteorological factors. Future studies should explore the health impacts of ambient fungi during Asian dust events, adjusting for the synergistic/antagonistic effects of weather and air pollutants. PMID- 21328008 TI - Functional consequences of climate change-induced plant species loss in a tallgrass prairie. AB - Future climate change is likely to reduce the floristic diversity of grasslands. Yet the potential consequences of climate-induced plant species losses for the functioning of these ecosystems are poorly understood. We investigated how climate change might alter the functional composition of grasslands for Konza Prairie, a diverse tallgrass prairie in central North America. With species specific climate envelopes, we show that a reduction in mean annual precipitation would preferentially remove species that are more abundant in the more productive lowland positions at Konza. As such, decreases in precipitation could reduce productivity not only by reducing water availability but by also removing species that inhabit the most productive areas and respond the most to climate variability. In support of this prediction, data on species abundance at Konza over 16 years show that species that are more abundant in lowlands than uplands are preferentially reduced in years with low precipitation. Climate change is likely to also preferentially remove species from particular functional groups and clades. For example, warming is forecast to preferentially remove perennials over annuals as well as Cyperaceae species. Despite these predictions, climate change is unlikely to unilaterally alter the functional composition of the tallgrass prairie flora, as many functional traits such as physiological drought tolerance and maximum photosynthetic rates showed little relationship with climate envelope parameters. In all, although climatic drying would indirectly alter grassland productivity through species loss patterns, the insurance afforded by biodiversity to ecosystem function is likely to be sustained in the face of climate change. PMID- 21328009 TI - Direct and socially-mediated effects of food availability late in life on life history variation in a short-lived lizard. AB - Food availability is a major environmental factor that can influence life history within and across generations through direct effects on individual quality and indirect effects on the intensity of intra- and intercohort competition. Here, we investigated in yearling and adult common lizards (Zootoca vivipara) the immediate and delayed life-history effects of a prolonged food deprivation in the laboratory. We generated groups of fully fed or food-deprived yearlings and adults at the end of one breeding season. These lizards were released in 16 outdoor enclosures together with yearlings and adults from the same food treatment and with food-deprived or fully fed juveniles, creating four types of experimental populations. Experimental populations were then monitored during 2 years, which revealed complex effects of food on life-history trajectories. Food availability had immediate direct effects on morphology and delayed direct effects on immunocompetence and female body condition at winter emergence. Also, male annual survival rate and female growth rate and body size were affected by an interaction between direct effects of food availability and indirect effects on asymmetric competition with juveniles. Reproductive outputs were insensitive to past food availability, suggesting that female common lizards do not solely rely on stored energy to fuel reproduction. Finally, food conditions had socially mediated intergenerational effects on early growth and survival of offspring through their effects on the intensity of competition. This study highlights the importance of social interactions among cohorts for life-history trajectories and population dynamics in stage-structured populations. PMID- 21328010 TI - A phylogenetically controlled analysis of the roles of reproductive traits in plant invasions. AB - Reproductive traits are tightly linked to plant fitness and may therefore be mechanisms driving biological invasions, including the greater success of more phylogenetically novel introduced species in some systems. We present a phylogenetic comparative analysis of "Baker's law'', that introduced plants with the ability to reproduce autogamous or asexually may be better able to establish on introduction. We gathered data from both published and unpublished sources on pollen limitation of 141 species, including 26 introduced species and 115 native species. Our analysis compared differences in the proportion of autonomous autogamy, asexual reproduction, and pollen limitation among native, introduced noninvasive, and introduced invasive plant species, and included the phylogenetic novelty of the introduced species to the native species in that community. Introduced species were more likely to be autogamous than native species, consistent with Baker's law. On the other hand, introduced species were less likely to have the ability to reproduce asexually. Further, among species with no autonomous autogamy, pollen limitation was greater for introduced compared to native species. Such a result is consistent with the idea that plants entering a new continent receive lower quality or quantity of services from resident pollinators than species native to that continent. Finally, more phylogenetically novel invasive species had lower pollen limitation than less novel invasive species, potentially because they experience less competition for pollinators. This is the first evidence that enhanced pollination may be one mechanism driving the greater invasiveness of phylogenetically novel introduced species observed in some systems. PMID- 21328011 TI - High regeneration capacity helps tropical seeds to counter rodent predation. AB - Rapid germination of non-dormant seeds is one adaptation plants have evolved to counter seed predation by rodents. Some rodent species have evolved behaviors that prevent or slow the seed germination process through seed embryo removal or seed pruning; however, no plant species is known to have successfully escaped embryo removal or seed pruning by rodents. Here, we report that the non-dormant seeds of Pittosporopsis kerrii Craib in tropical rain forests in China have a high regeneration capacity to counter seed pruning by rodents. We found seed pruning, instead of embryo removal, was commonly used by rodents to increase food storage time by slowing down the seed germination process, but that P. kerrii seeds have a high regeneration capacity to escape seed predation by rodents: all pruned seeds, pruned roots and embryo-removed seeds by rodents or people retain the ability to develop into seedlings. Seeds of P. kerrii also have other capacities (i.e. rapid seed decomposition and indigestible dormant taproots) to escape predation by reducing the plant's attractiveness to rodents. The association between seed pruning behavior in rodents and high regeneration capacity of pruned seeds or roots in P. kerrii seeds are likely novel adaptation strategies adopted by seeds and rodents, respectively. PMID- 21328014 TI - Kidney histologic alterations in alpha-Galactosidase-deficient mice. AB - Fabry disease is a rare X-linked disorder caused by mutations in the alpha galactosidase gene (GLA), the resultant deficiency of lysosomal alpha galactosidase enzyme activity leading to systemic accumulation of globotriaosylceramide and other glycosphingolipids. GLA knockout mice ("Fabry mice") were generated as an animal model for Fabry disease but, as they do not manifest progressive chronic kidney disease (CKD), their relevance as a model for human Fabry nephropathy is uncertain. We evaluated the histological alterations in the kidneys of Fabry mice at different ages, as contrasted to those observed in wild-type mice. Furthermore, we compared the renal histological alterations of Fabry mice to the kidney pathology reported in patients with Fabry disease at comparable age ranges and across different CKD stages, using a scoring system that has been developed for Fabry nephropathy. Fabry mice are phenotypically different from wild-type mice, displaying progressive age-related accumulation of glycosphingolipids in all types of renal cells. There were no statistically significant differences between Fabry mice and Fabry patients in the prevalence of glycosphingolipid storage per renal cell type with the exceptions of mesangial (higher in humans) and proximal tubular cells (higher in mice). However, Fabry mice lack the nonspecific histological glomerulosclerotic and interstitial fibrotic renal lesions that best correlate with progressive CKD in Fabry patients, and do not develop large podocyte inclusions. We postulate that the elucidation of the mechanisms underlying these species differences, may contribute important clues to a better understanding of the pathogenesis of Fabry nephropathy. PMID- 21328015 TI - Protective effects of haloperidol and clozapine on energy-deprived OLN-93 oligodendrocytes. AB - Magnetic resonance imaging and postmortem studies on schizophrenia provided evidence for compromised myelin integrity and reduced numbers of oligodendrocytes, which may worsen during the disease course. However, it is not clear whether these findings result from disease-inherent oligodendrocyte degeneration or side effects of antipsychotic treatment. Therefore, effects of haloperidol and clozapine on the viability and apoptosis of immature oligodendrocytes (OLN-93 cells, immunopositive for NG2, Olig1, Olig2) have been evaluated in the present study by labeling with propidium iodide and a caspase 3 assay. Given the indications for impaired cerebral energy supply in schizophrenia, a serum and glucose deprivation (SGD) model was chosen in comparison with the basal condition (BC). SGD led to increased necrotic and apoptotic cell death. Haloperidol and clozapine were partially protective in this model and reduced the percentage of propidium iodide-positive cells, while caspase 3 activity was not altered. No significant drug effects were observed under BC. The observed protective effects of haloperidol and clozapine on energy deprived OLN-93 oligodendrocytes suggest that previously reported reductions in oligodendrocyte density in schizophrenia are rather disease related than a side effect of medication. A new mechanism of antipsychotic action is suggested, which may help to establish new oligodendrocyte-directed therapies of schizophrenia. PMID- 21328016 TI - The functional sequelae of schizophrenia: consequences of long-term pharmacotherapy and the neurobiology of addiction. PMID- 21328017 TI - Flow distribution during infusion of UW and HTK solution in anaesthetised rats. AB - PURPOSE: Organ transplantation necessitates the use of preservation solutions to maintain the integrity of the organs during retrieval. The aim of this study was to investigate the flow distribution in abdominal organs in rats during acute infusion of preservation solution. METHODS: Microspheres were used to estimate the distribution of flow in the pancreas, duodenum, ileum, colon, liver, kidneys and lungs in untreated Wistar-Furth rats and in animals with an opened abdominal cavity and catheterised aorta. Some animals were infused by free flow of 5 ml of UW, HTK or Ringer solution containing microspheres at a pressure of 100 cm H(2)O through an intra-aortic catheter. RESULTS: Opening of the abdominal cavity did not affect any of the organ blood flow values. However, the fraction of total pancreatic blood flow diverted through the islets increased. During infusion of microsphere-containing UW, HTK or Ringer solution, splanchnic and renal organ flow values, represented by microsphere contents, were similar. The fraction of microspheres found in the islets was lower in UW-infused rats. The number of microspheres present in the lungs or liver was very low, suggesting that shunting was negligible. CONCLUSIONS: Infusion of HTK and UW solution into anaesthetised rats results in a flow distribution which is similar to that in normal animals in most abdominal organs, but there is a reduction in islet blood perfusion by UW but not HTK solution. PMID- 21328018 TI - Splenectomy for non-haematological metastatic malignant disease. AB - PURPOSE: Multiple cases and small series of patients who have undergone splenectomy for metastatic malignant disease have been reported. This study examines the outcome of patients with metastatic malignant disease to the spleen treated by splenectomy at a tertiary oncology centre and a review of cases published in the last 10 years. METHODS: The hospital histopathology database was searched over a 25-year period up to 2004 for patients who had undergone splenectomy for non-haematological malignancy. Medical records of these patients were reviewed and clinical course was examined. The literature review was undertaken using a search of PubMed for the terms "splenectomy" and "metastasis" from 2000 to 2010. RESULTS: Twenty-one cases at our institution were identified. The most common primary site of malignancy was ovary (nine cases), followed by malignant melanoma (three) and pancreas (three). There were two cases of metastatic disease from colonic primary and one each from renal, breast, nasopharyngeal and unknown primary disease. There were two cases of long-term disease-free survival (both primary ovarian tumours) and four cases of patients who survived more than 4 years but had disease recurrence (ovarian and colonic primaries). The literature review provided a further 115 cases. CONCLUSIONS: More favorable outcomes were seen in patients with metachronous disease. There was a trend to improved outcome in ovarian and colorectal primaries over malignant melanoma. It is postulated that improved outcome may be seen in patients for whom there were effective adjuvant chemotherapeutic options, low probability of other metastatic disease and less aggressive tumour biology. However, frequently the presentation is indicative of aggressive widespread disease with a poor prognosis. PMID- 21328019 TI - Simultaneous nailing of skeletal metastases: is the mortality really that high? AB - INTRODUCTION: The risk of death during simultaneous nailing of pathologic and impending fractures in patients with metastatic disease is believed to be so high that some authors have advocated a staged approach, especially for impending fractures. However, there are limited data to either support or refute the appropriateness of staging of multiple impending or pathologic fractures. QUESTIONS/PURPOSES: We therefore determined the rate of pulmonary mortality and morbidity in patients who underwent simultaneous nailing for metastatic disease of the skeleton. METHODS: We retrospectively reviewed 16 patients who underwent simultaneous intramedullary nailing of impending or pathologic fractures between 1993 and 2009. There were 10 men and six women with a mean age of 60 years (range, 40-78 years). The intramedullary nailings included 15 femurs, 17 humeri, and one tibia. Thirty-one nails were reamed and two were unreamed. RESULTS: Three of 16 patients died before discharge; two of these deaths were presumed to be the direct result of acute pulmonary complications related to simultaneous nailing and one was intraoperative. For the 13 patients who survived after discharge, there were three pulmonary complications. There were no intraoperative or perioperative deaths in the prophylactic nailing group. CONCLUSIONS: Simultaneous nailing of impending and pathologic fractures can be performed with lower mortality rates than previously reported. Patients with impending fractures did not appear to be at higher risk than patients with pathologic fractures. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of level of evidence. PMID- 21328020 TI - Nonoperative treatment of an os peroneum fracture in a high-level athlete: a case report. AB - BACKGROUND: The os peroneum is a sesamoid bone in the peroneus longus tendon. Fractures of the os peroneum are rare. Some authors recommend surgery for active patients. CASE DESCRIPTION: A 41-year-old male professional tennis coach sustained a minimally displaced fracture of the os peroneum. He was treated with restricted weightbearing for 2 weeks, followed by physical therapy and gradual return to activities. He returned to tennis 8 weeks after injury. Followup 7 years after the injury showed he had full strength, full motion, and a radiographically healed os peroneum. The American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Scale score was 100 and Ankle Activity Score and Tegner Activity Level Scale were unchanged from those before injury. LITERATURE REVIEW: Fracture of the os peroneum is a rare injury and treatment recommendations are based largely on very small series and case reports. Proposed treatment strategies for fracture of the os peroneum include nonoperative treatment, fixation of the fracture, excision of the bone with direct repair of the tendon, and tenodesis of the peroneus longus to the peroneus brevis. PURPOSES AND CLINICAL RELEVANCE: Although some surgeons suggest fracture of the os peroneum should be treated operatively in active patients, this case shows nonoperative treatment allowed pain-free return to activities in a high-level athlete with a minimally-displaced fracture. PMID- 21328021 TI - A complication-based learning curve from 200 reverse shoulder arthroplasties. AB - BACKGROUND: Reported early complication rates in reverse total shoulder arthroplasty have widely varied from 0% to 75% in part due to a lack of standard inclusion criteria. In addition, it is unclear whether revision arthroplasty is associated with a higher rate of complications than primary arthroplasty. QUESTIONS/PURPOSE: We therefore (1) determined the types and rates of early complications in reverse total shoulder arthroplasty using defined criteria, (2) characterized an early complication-based learning curve for reverse total shoulder arthroplasty, and (3) determined whether revision arthroplasties result in a higher incidence of complications. PATIENTS AND METHODS: From October 2004 to May 2008, an initial series of 200 reverse total shoulder arthroplasties was performed in 191 patients by a single surgeon. Forty of the 200 arthroplasties were revision arthroplasties. Of these, 192 shoulders were available for minimum 6-month followup (mean, 19.4 months; range, 6-49.2 months). We determined local and systemic complications and distinguished major from minor complications. RESULTS: Nineteen shoulders involved local complications (9.9%), including seven major and 12 minor complications. Nine involved perioperative systemic complications (4.7%), including eight major complications and one minor complication. The local complication rate was higher in the first 40 shoulders (23.1%) versus the last 160 shoulders (6.5%). Seven of 40 (17.5%) revision arthroplasties involved local complications, including two major and five minor complications compared to 12 of 152 (7.9%) primary arthroplasties, including five major and seven minor complications. Nerve palsies occurred less frequently in primary arthroplasties (0.6%) compared to revisions (9.8%). CONCLUSIONS: The early complication-based learning curve for reverse total shoulder arthroplasty is approximately 40 cases. There was a trend toward more complications in revision versus primary reverse total shoulder arthroplasty and more neuropathies in revisions. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the guidelines online for a complete description of level of evidence. PMID- 21328022 TI - Breakout session: Gender disparities in knee osteoarthritis and TKA. AB - BACKGROUND: Biologically derived (sex-based) and behaviorally influenced (gender based) disparities exist in knee osteoarthritis and treatment with TKA. QUESTIONS/PURPOSES: We sought to highlight sex- and gender-based differences with respect to knee osteoarthritis and its treatment. Our purposes were to (1) define where we are now, (2) outline where we need to go, and (3) generate solutions to how we can get there. WHERE ARE WE NOW?: A growing body of evidence shows sex- and gender-based disparities contribute to differences in the incidence, treatment, and outcomes of patients with knee osteoarthritis. Moreover, the influence of unconscious provider bias in disparities in care is becoming recognized. WHERE DO WE NEED TO GO?: Sex- and gender-based differences need to be identified and translated into clinical practice to effect patient-centered sex- and gender-based medicine. Equitable and evidence-based care must be provided. HOW DO WE GET THERE?: Research must continue to focus on sex-based differences in cartilage degeneration and gender-related factors influencing the development and progression of knee osteoarthritis. Development of evidence-based guidelines for optimal timing of TKA would assist patients and clinicians with surgical decision making. Training of healthcare providers to mitigate again unconscious basis is essential. Care must be patient-focused, with patients empowered to be full partners with providers in healthcare outcomes. PMID- 21328023 TI - Comparing the detectability of hepatocellular carcinoma by C-arm dual-phase cone beam computed tomography during hepatic arteriography with conventional contrast enhanced magnetic resonance imaging. AB - PURPOSE: To evaluate the sensitivity of dual-phase cone-beam computed tomography during hepatic arteriography (CBCTHA) for the detection of hepatocellular carcinoma (HCC) by comparing it with the diagnostic imaging "gold standard": contrast-enhanced magnetic resonance imaging (CE-MRI) of the liver. MATERIALS AND METHODS: Eighty-eight HCC lesions (mean diameter 3.9 +/- 3.3 cm) in 20 patients (13 men, mean age 61.4 years [range 50 to 80]), who sequentially underwent baseline diagnostic liver CE-MRI and then underwent early arterial- and delayed portal venous-phase CBCTHA during drug eluting-bead transarterial chemoembolization, were evaluated. Dual-phase CBCTHA findings of each tumor in terms of conspicuity were compared with standard CE-MR images and classified into three grades: optimal, suboptimal, and nondiagnostic. RESULTS: Seventy-seven (mean diameter 4.2 +/- 3.4 cm [range 0.9 to 15.9]) (93.9%) of 82 tumors were detected. Sensitivity of arterial-phase (71.9%) was lower than that of venous phase CBCTHA (86.6%) for the detection of HCC lesions. Of the 82 tumors, 33 (40.2%) and 52 (63.4%), 26 (31.7%) and 19 (23.2%), and 23 (28%) and 11 (13.4%) nodules were classed as optimal, suboptimal, and nondiagnostic on arterial- and venous-phase CBCTHA images, respectively. Seventeen (73.9%) of the 23 tumors that were not visible on arterial phase were detected on venous phase. Six (54.5%) of the 11 tumors that were not visible on venous phase were detected on arterial phase. CONCLUSIONS: Dual-phase CBCTHA has sufficient image quality to detect the majority of HCC lesions compared with the imaging "gold standard": CE-MRI of the liver. Moreover, dual-phase CBCTHA is more useful and reliable than single-phasic imaging to depict HCC nodules. PMID- 21328024 TI - Emergency endovascular "bridge" treatment for iliac-enteric fistula. AB - Aortic aneurysm has been reported to be the dominant cause of primary iliac enteric fistula (IEF) in >70% of cases [1]; other less common causes of primary IEF include peptic ulcer, primary aortitis, pancreatic pseudocyst, or neoplastic erosion into an adjacent artery [2, 3]. We describe an unusual case of IEF managed with a staged approach using an endovascular stent-graft as a "bridge" in the emergency setting to optimize the next elective definitive excision of the lesion. PMID- 21328025 TI - Low-dose and long-term G-CSF treatment can improve severe myocardial ischemia in patients with severe coronary artery disease. AB - BACKGROUND: It has been reported that granulocyte colony-stimulating factor (G CSF) can promote angiogenesis by mobilizing bone marrow stem cells to blood vessels. The purpose of this study is to clarify whether low-dose and long-term G CSF treatment can improve severe myocardial ischemia. METHODS: We studied 40 patients (M/F = 29/11, age = 68 +/- 9 years) who had severe coronary artery disease (7 with and 5 without old myocardial infarction; 3VD/2VD/1VD = 17/17/6) and severe myocardial ischemia with no indication for revascularization. G-CSF (1.5 MUg/kg) was injected for 14 consecutive days. All patients were evaluated using stress myocardial scintigraphy, the Canadian Cardiovascular Society (CCVS) score, and cardiopulmonary exercise testing before and after 3 months of treatment. On 17 SPECT segments, the total defect score (TDS) and delta TDS (TDS (stress) minus TDS (resting)) were evaluated to assess the severity of myocardial ischemia. RESULTS: The changes in stress TDS, delta TDS, and regional wall motion score were significantly greater in the G-CSF group than the control group (P < .0001). The CCVS score improved significantly from baseline to the 3-month follow up assessment in the G-CSF group (P < .0001). The increase of peak VO2 was significantly larger in the G-CSF group than the control group (P = .015). CONCLUSION: Low-dose and long-term G-CSF treatment can improve severe ischemia in patients with severe coronary artery disease. PMID- 21328026 TI - Myocardial perfusion imaging in the acute care setting: does it still have a role? PMID- 21328027 TI - Diagnostic performance of computed tomography angiography for differentiating ischemic vs nonischemic cardiomyopathy. AB - BACKGROUND: Although the use of computed tomography angiography (CTA) is considered "appropriate" to distinguish ischemic vs nonischemic etiology in patients with cardiomyopathy under the current clinical practice guideline, the evidence to support this has not been evaluated in larger scale studies. Thus, we conducted a meta-analysis of available studies published by October 2010 to address this question. METHODS: Studies evaluating the diagnostic accuracy of CTA versus invasive coronary angiography (as the gold standard) for significant coronary artery disease (CAD) detection (ischemic cardiomyopathy) in patients with no known history of CAD with significantly depressed left ventricular function (ejection fraction; EF < 35%) were selected for the meta-analysis. Sensitivity, specificity, positive, and negative likelihood ratios were calculated on per patient and per segment basis using random effects model (DerSimonian-Laird Method) for computing summary estimates and receiver operator curve (ROC) analysis for evaluating overall diagnostic accuracy. RESULTS: Six studies comprising 452 patients met the selection criteria for the meta-analysis. The pooled patient population was 62 +/- 3 years old, with 29% females, 16% diabetics, and 43% with a history of hypertension. Mean EF was 32% +/- 1%. The pooled summary estimate of sensitivity of CTA for diagnosis of ischemic cardiomyopathy was 98% [95% confidence interval (CI); 94% to 99%] and specificity was 97% (CI 94% to 98%), yielding a negative likelihood ratio of 0.06 (CI 0.02 to 0.13) and positive likelihood ratio of 20.85 (CI 12 to 36). There was no significant heterogeneity between studies for these estimates. The receiver operator curve analysis showed a robust discriminate diagnostic accuracy of ischemic etiology with an area under curve of 0.99 (P < .00001). CONCLUSION: CTA appears as a clinically applicable accurate diagnostic modality to exclude ischemic etiology in patients with cardiomyopathy of undetermined cause and this further supports the appropriateness of the use of CTA to determine the cause of new onset cardiomyopathy of unknown etiology. PMID- 21328028 TI - Investigation of the mechanism of reverse redistribution in thallium-201 myocardial perfusion scintigraphy in patients with suspicion for coronary artery spasm. AB - BACKGROUND: Reverse redistribution (RR) is one of the features on myocardial perfusion scintigraphy (MPS) in patients with coronary artery spasm (CAS). This study was aimed to explore the mechanism of RR in patients with suspicion for CAS. METHODS AND RESULTS: Thirty patients with RR and suspicion for CAS but without coronary artery stenosis (RR group) and 32 control patients without RR (control group) underwent coronary angiography before and after a dipyridamole administration. Coronary blood flow velocity and myocardial perfusion, as determined by corrected thrombolysis in myocardial infarction (TIMI) frame count (CTFC) and TIMI myocardial perfusion grade (TMPG), were measured. Coronary angiography showed significantly slower blood flow velocity [CTFC (37 +/- 6) frame vs (29 +/- 7) frame, P < .01] and lower myocardial perfusion [TMPG (2.08 +/ 0.38) grade vs (2.55 +/- 0.33) grade, P < .05] in RR-related arteries than in RR unrelated arteries in the RR group. But, there was no significant difference among different coronary artery branches in the control group. After the injection of dipyridamole, CTFC decreased and TMPG increased in the RR group. The decline in CTFC and the increase in TMPG in RR-related arteries were more significant than those in RR-unrelated ones (28% vs 14% and 45% vs 16%, respectively; both P < .01). The endothelin-1/nitric oxide (NO) ratio was significantly higher in the RR group than in the control group before the injection of dipyridamole (2.79 +/- 0.37 vs 1.70 +/- 0.19, P < .01). After the injection of dipyridamole, the ratio went down in both groups, but the decline was statistically significant in the RR group (2.42 +/- 0.33, P < .05) but not in the control group (1.42 +/- 0.19, P < .05). Pearson correlation analysis showed that there was a positive correlation between summed rest scores on MPS and the endothelin-1/NO ratio (r = 0.853, P = .000) as well as CTFC (r = 0.808, P = .000) before the injection of dipyridamole in the RR group. CONCLUSION: Patients with suspicion for CAS may exhibit a mild spasm of RR-related arteries and corresponding microvasculature and a significant imbalance of coronary blood flow velocity and myocardial perfusion at rest between RR-related and RR-unrelated areas. This is overcome by stress-induced hyperemic flow increases and which may account for RR on MPS. PMID- 21328039 TI - The leverage of demographic dynamics on carbon dioxide emissions: does age structure matter? AB - This article provides a methodological contribution to the study of the effect of changes in population age structure on carbon dioxide (CO(2)) emissions. First, I propose a generalization of the IPAT equation to a multisector economy with an age-structured population and discuss the insights that can be obtained in the context of stable population theory. Second, I suggest a statistical model of household consumption as a function of household size and age structure to quantitatively evaluate the extent of economies of scale in consumption of energy intensive goods, and to estimate age-specific profiles of consumption of energy intensive goods and of CO(2) emissions. Third, I offer an illustration of the methodologies using data for the United States. The analysis shows that per capita CO(2) emissions increase with age until the individual is in his or her 60s, and then emissions tend to decrease. Holding everything else constant, the expected change in U.S. population age distribution during the next four decades is likely to have a small, but noticeable, positive impact on CO(2) emissions. PMID- 21328040 TI - Efficacy of the Survivor Health and Resilience Education (SHARE) program to improve bone health behaviors among adolescent survivors of childhood cancer. AB - PURPOSE: The purpose of this study is to test the efficacy of the Survivor Health and Resilience Education Program intervention--a manualized, behavioral intervention focusing on bone health behaviors among adolescent survivors of childhood cancer. METHODS: Participants were 75 teens aged 11-21 years, one or more years post-treatment, and currently cancer-free. Teens were randomized to a group-based intervention focusing on bone health or a wait-list control. Bone health behaviors were assessed at baseline and 1-month post-intervention. RESULTS: Controlling for baseline outcome measures and theoretical predictors, milk consumption frequency (p=0.03), past month calcium supplementation (p<0.001), days in the past month with calcium supplementation (p<0.001), and dietary calcium intake (p=0.04) were significantly greater at 1-month follow-up among intervention participants compared with control participants. CONCLUSIONS: The intervention had a significant short-term impact on self-reported bone health behaviors among adolescent survivors of childhood cancer. Research examining long term intervention effectiveness is warranted. PMID- 21328042 TI - Remote patient management using implantable devices. AB - Remote patient management utilizing the Internet is a milestone in the management of patients with an implantable cardiac device. Pacemakers and implantable cardioverter-defibrillators (ICDs) store diagnostic information about device and lead integrity, the occurrence of atrial and ventricular arrhythmias, and parameters that may reflect on a patient's heart failure status. Previously, these data could only be retrieved with a programmer at an in-person office visit. The introduction of remote follow-up and monitoring has changed the paradigm for the management of patients with implanted devices. Remote follow-up has been shown to be superior to traditional transtelephonic monitoring for the detection of clinically actionable events in pacemaker patients. Remote monitoring using ICDs with wireless technology has been demonstrated to result in detection of lead malfunction and atrial and ventricular arrhythmias while reducing the need for in-office evaluations without compromising patient safety. Studies are underway to evaluate the clinical utility of identification of atrial high-rate episodes and to identify patients at risk for exacerbation of heart failure. Remote monitoring technology has yet to be universally adopted by patients or physicians. Impediments to the implementation of remote monitoring including issues related to work flow and data management are explored. PMID- 21328041 TI - Verbal learning and memory in adolescent cannabis users, alcohol users and non users. AB - RATIONALE: Long-term heavy cannabis use can result in memory impairment. Adolescent users may be especially vulnerable to the adverse neurocognitive effects of cannabis. OBJECTIVES AND METHODS: In a cross-sectional and prospective neuropsychological study of 181 adolescents aged 16-20 (mean 18.3 years), we compared performance indices from one of the most widely used measures of learning and memory--the Rey Auditory Verbal Learning Test--between cannabis users (n=52; mean 2.4 years of use, 14 days/month, median abstinence 20.3 h), alcohol users (n=67) and non-user controls (n=62) matched for age, education and premorbid intellectual ability (assessed prospectively), and alcohol consumption for cannabis and alcohol users. RESULTS: Cannabis users performed significantly worse than alcohol users and non-users on all performance indices. They recalled significantly fewer words overall (p<0.001), demonstrating impaired learning (p<0.001), retention (p<0.001) and retrieval (p<0.05) (Cohen's d 0.43-0.84). The degree of impairment was associated with the duration, quantity, frequency and age of onset of cannabis use, but was unrelated to alcohol exposure or other drug use. No gender effects were detected and the findings remained after controlling for premorbid intellectual ability. An earlier age of onset of regular cannabis use was associated with worse memory performance after controlling for extent of exposure to cannabis. CONCLUSIONS: Despite relatively brief exposure, adolescent cannabis users relative to their age-matched counterparts demonstrated similar memory deficits to those reported in adult long-term heavy users. The results indicate that cannabis adversely affects the developing brain and reinforce concerns regarding the impact of early exposure. PMID- 21328043 TI - Left atrial lesion formation and volume overload by open irrigation ablation technology during pulmonary vein antrum isolation: acute effects on cardiac hemodynamics. AB - PURPOSE: Our goal was to evaluate acute effects of left atrial lesion formation and volume overload on hemodynamics during pulmonary vein antrum isolation (PVAI) as it might be a potential cause of acute pulmonary edema. METHODS: In consecutive patients presenting for PVAI, open irrigation ablation was performed (50 W, 48 degrees C, 15 s lesion duration, saline flow rate 30 mL/min). Blood samples were drawn from the left atrium and the pulmonary artery immediately before and 30 min after PVAI. The cardiac output (CO) and stroke volume (SV) were calculated by the method of Fick. RESULTS: We included 61 (27 female, 61 +/- 11 years) patients suffering from paroxysmal (px; 33) or persistent (per; 28) atrial fibrillation (AF) in this study. A total of 2,917 +/- 242 mL of volume was infused (2,651 +/- 223 mL pxAF vs. 3,184 +/- 255 mL perAF, (p < 0.01)). Total ablation time was 60 +/- 7 min (52 +/- 7 min in pxAF vs. 69 +/- 8 min in perAF; (p < 0.001)). CO increased from 5.2 +/- 1.3 to 6.2 +/- 1.5 L/min (p < 0.001) during PVAI (5.7 +/- 1.3 to 6.5 +/- 1.7 L/min in pxAF; (p < 0.002) and 4.8 +/- 1.1 to 5.9 +/- 1.2 L/min in perAF; (p < 0.001)). SV increased from 74 +/- 24 to 83 +/- 21 mL (p < 0.005) during PVAI, and subgroups showed an increase of 82 +/- 23 to 88 +/- 22 mL in pxAF (p < 0.009) and 62 +/- 21 to 76 +/- 16 mL in perAF (p < 0.009). CONCLUSIONS: From our preliminary experience, left atrial scarring and volume overload during PVAI do not seem to impact negatively hemodynamics. On the contrary, an improvement in cardiac output was documented acutely independent of type of AF. PMID- 21328044 TI - Visual evaluation and usefulness of medical high-resolution liquid-crystal displays with use of independent sub-pixel driving technology. AB - Liquid-crystal displays (LCDs) used for medical imaging, such as luminance characteristics and panel surface processing, have been developed as a medium substituting for film. There are various models of and specifications for display, but those compatible with high-resolution radiographic diagnostic images have been required with the recent progression of high-resolution modalities. Displays are necessary for faithful presentation of radiographic diagnostic images acquired by X-ray systems. In independent sub-pixel driving (ISD) technology, aiming at high-resolution display, three sub-pixels contained in one pixel of the LCD independently display images, which increases the threefold resolutions in direction of the sub-pixels, facilitating faithful image display with less curtailed pixels. This is a new display technology which may improve the diagnostic performance with regard to reading of medical images. We evaluated the characteristics of ISD technology and performed a visual evaluation of phantom images to investigate its usefulness. After confirming the physical properties of LCDs, we performed a visual evaluation of CDMAM phantom images employing the calculated image quality figure (IQF). The detectability of 15 mega sub-pixel (15 MsP) significantly improved despite the specification being 5 mega pixel (5 MP), and that of 9 MsP was higher than that of 5 MP despite the specification being 3 MP. The usefulness of ISD for 6 MsP was also confirmed. Therefore, ISD technology was useful for all LCDs. ISD technology markedly advanced the LCD display performance for medical use. PMID- 21328045 TI - [Incidental radiological findings]. PMID- 21328046 TI - [Transient splenial lesion in influenza A H1N1 2009 infection]. AB - Severe neurologic complications have been rarely reported during novel pandemic influenza A(H1N1) virus infections. We describe the case of an 10-year-old boy with new onset seizures and proven influenza A(H1N1) 2009 infection showing a reversible hyperintense lesion in the splenium of the corpus callosum on T2 weighted and FLAIR magnetic resonance images without contrast enhancement. Transient splenial lesions have been described in the context of virus encephalopathy and do not require specific treatment. PMID- 21328047 TI - [Whole-body diffusion-weighted imaging in oncology: technical aspects and practical relevance]. AB - This review illustrates the relevance of whole-body diffusion-weighted imaging (WB-DWI) in the field of oncological imaging. WB-DWI is an alternative method to positron-emission tomography/computed tomography (PET/CT) due to the lack of radiation and lower examination costs. Technical aspects of WB-DWI and the current role of the method in cancer imaging regarding practical requirements in oncology are presented. PMID- 21328048 TI - [Diffusion-weighted MRI of the prostate]. AB - Diffusion-weighted magnetic resonance imaging (DWI) can complement MRI of the prostate in the detection and localization of prostate cancer, particularly after previous negative biopsy. A total of 13 original reports and 2 reviews published in 2010 demonstrate that prostate cancer can be detected by DWI due to its increased cell density and decreased diffusiveness, either qualitatively in DWI images or quantitatively by means of the apparent diffusion coefficient (ADC). In the prostate, the ADC is influenced by the strength of diffusion weighting, localization (peripheral or transitional zone), presence of prostatitis or hemorrhage and density and differentiation of prostate cancer cells. Mean differences between healthy tissue of the peripheral zone and prostate cancer appear to be smaller for ADC than for the (choline + creatine)/citrate ratio in MR spectroscopy. Test quality parameters vary greatly between different studies but appear to be slightly better for combined MRI and DWI than for MRI of the prostate alone. Clinical validation of DWI of the prostate requires both increased technical conformity and increased numbers of patients in clinical studies. PMID- 21328049 TI - [Diffusion-weighted imaging in neuroradiology]. AB - Diffusion-weighted imaging is becoming increasingly more important in neuroradiology. Formerly this technique was mainly used in stroke diagnostics but the spectrum of applications is becoming increasingly larger. Diffusion-weighted imaging is a useful tool for differentiation between metastases and abscesses, for assessment of the depth of invasiveness of tumors and to differentiate inflammation from astrocytomas. It has now become a standard technique in multiple sclerosis imaging. A further advantage in addition to the diagnostic capabilities is the speed of the sequence which makes it insensitive to movement artefacts. PMID- 21328050 TI - [Interesting facts about the ligaments of the elbow joint]. PMID- 21328051 TI - [The challenge of subarachnoid hemorrhaging]. PMID- 21328052 TI - [Endovascular therapy options for aneurysmal subarachnoid hemorrhage]. AB - Aneurysmal subarachnoid hemorrhaging (ASH) is a severe condition with an acute symptomatic, often with a difficult course and accompanied by many complications. Aneurysms can be detected using computed tomography (CT), magnetic resonance angiography (MRA) and digital subtraction angiography (DSA). Possible therapy options for ASH are surgical clipping and endovascular treatment using platinum coils. The surgical approach is an effective and safe method for avoiding recurrent bleeding.So-called Guglielmi detachable coils, with which aneurysms can be successfully embolized, have been available since 1991. Initially only a few different sizes of platinum coils were available but now complex forms of platinum coils with different lengths and rigidness are available so that many forms of aneurysm can be treated. Broad-based aneurysms, which could previously only be treated by surgery, can now be treated by the so-called balloon remodeling technique or stent-assisted coiling, whereby a balloon or stent is placed in the parent vessel to act as a scaffold for the coil. The results of the ISAT study demonstrated that a better outcome for patients could be achieved by endovascular treatment of aneurysms than by neurosurgical clipping of ruptured aneurysms. For this reason the first option should be endovascular treatment when possible. Asymptomatic aneurysms are being observed increasingly more often and primary treatment should be endovascular when possible. The somewhat higher re bleeding rate for endovascular treatment could not diminish the better results of the ISAT study even during the 5-year follow-up. PMID- 21328053 TI - [Secondary complications of acute subarachnoid hemorrhage]. AB - Despite further improvement of diagnostic procedures and the management of patients with acute subarachnoid hemorrhage it is still a severe clinical condition often worsened by several secondary complications after the initial bleeding. The most important and most frequent are early rehemorraging, cerebral vasospasm and the development of hydrocephalus. In addition there are many other sequelae, such as disturbances of electrolytes, seizures and the general complications of intensive care medicine which can greatly influence clinical outcome. This report provides an overview of the possible mechanisms for the development of complications, the typical temporary course and the currently available therapeutic strategies, in particular focused on the role of diagnostic imaging in early detection of these pathological conditions. PMID- 21328055 TI - Receptor activator of nuclear factor kappa B ligand serum and synovial fluid level. A comparative study between rheumatoid arthritis and osteoarthritis. AB - To assess the levels of receptor activator of NF-kappaB ligand (RANKL) in serum and synovial fluid (SF) of patients with rheumatoid arthritis (RA) and osteoarthritis (OA) and to correlate its levels with disease activity and severity. Serum and SF levels of RANKL were measured in 24 patients with RA (Group I) and 20 patients with OA (Group II); patients were selected according to the ACR criteria, and serum RANKL was measured in 13 healthy controls. All patients were subjected to full rheumatological assessment. In RA group, serum level of RANKL was significantly higher than control group (P = 0.01), but not correlated with disease activity and severity parameters apart from number of tender joints (P = 0.03). SF level of RANKL was significantly correlated with disease duration (P = 0.02), number of tender (P = 0.002) and swollen joints (P = 003), ESR (P = 0.01), CRP (P = 0.000), DAS-28 (P = 0.004), and SENS (P = 0.03). In patients with OA, serum level of RANKL was significantly higher than the control group (P < 0.001), and it was statistically insignificant with clinical, laboratory, or radiological data, while SF level of RANKL was statistically significantly higher in patients with Heberden and Bouchard nodes (P = 0.007), Kellgren-Lawrence score (P = 0.002), and with the erosive changes of hands (P = 0.006). The mean serum RANKL in RA group was insignificant with that of total OA group. SF level of RANKL was significantly higher in RA than erosive OA patients and in erosive than non-erosive OA with (P = 0.001, in each one). The SF level of RANKL is an important marker of both disease activity and severity in RA patients; while in OA patients, it is an important marker of disease severity especially in erosive than non-erosive types. Serum level of RANKL may be of low benefit in disease activity and severity of both rheumatoid arthritis and osteoarthritis. PMID- 21328056 TI - Decreased levels of sCD21 and sCD23 in blood of patients with systemic-juvenile arthritis, polyarticular-juvenile arthritis, and pauciarticular-juvenile arthritis. AB - A soluble form of CD21 (sCD21) and CD23 (sCD23) is released from the surface of human white blood cells upon shedding of the extracellular domain. sCD21 circulates in a complex with cleavage fragments of C3 and sCD23, which were previously identified as ligands of membrane and soluble CD21. sCD21 seems to be a marker of chronic inflammatory disease. To assess the sCD21 and sCD23 status in patients with subsets of juvenile arthritis (JA), we determined plasma levels sCD21 and sCD23. Plasma sCD21 levels were significantly decreased in all JA subtypes (O-JA P < 0.0068; P- and S-JA P < 0.0001) compared to healthy controls. Plasma sCD23 levels were significantly decreased in P-JA and S-JA (both P < 0.0001), but not in O-JA (P < 0.3843) in comparison with healthy controls, and data statistically analyzed. Our results suggest that pathological mechanisms relevant to autoimmune disorders interfere with the regulation of both CD21 and CD23 shedding. PMID- 21328057 TI - Painful myositis in the anti-synthetase syndrome with anti-PL12 antibodies. PMID- 21328058 TI - Early spondyloarthritis in multiracial society: differences between gender, race, and disease subgroups with regard to first symptom at presentation, main problem that the disease is causing to patients, and employment status. AB - To determine whether the first presenting symptoms, the main problem that the disease is causing to patients, and the employment status at presentation of patients with early spondyloarthritis (SpA) in a multicultural/multiracial patient cohort are different between gender, race, and disease subgroups of the SpA spectrum (ankylosing spondylitis, enteropathic arthritis, psoriatic arthritis, or undifferentiated arthritis). All patients above the age of 16 years, with disease duration of less than 3 years since symptom onset, seen in clinic between 2004 and 2008 with spondyloarthritis (SpAs) were assessed regarding their first presenting symptom, the main problem caused by the disease, and their employment status. In addition, clinical parameters such as the degree of disease activity (measured by BASDAI, ESR, and CRP), functional ability (measured by BASFI), night pain, sleep disturbance, well-being over past week, and over past 6 months prior to assessment (measured by a 10 cm VAS; 0 = good health, 10 = worst possible) were obtained. Statistical analysis with Pearson's chi(2) test compared and correlated two groups, and one-way analysis of variance (ANOVA) was used when more than two groups were compared and correlated. A total of 96 patients [(male:female = 33:63; (34.4:65.6%), (mean age 43.8 +/- (SD) 13.9)] with early SpA were assessed. They were of multiethnic background representing Caucasians (n = 52; 54.2%), Asians (n = 33; 34.4%), and Africans (n = 10; 10.4%) mixed race (n = 1; 1%). The disease spectrum consisted of ankylosing spondylitis (AS) (n = 12; 12.7%), enteropathic arthritis or SpA associated with inflammatory bowel disease (IBD) (n = 9; 9.4%), psoriatic arthritis (PsA) (n = 47; 49%), undifferentiated spondyloarthritis (USpA) (n = 27; 28.2%), reactive arthritis (n = 1;1%), and juvenile SpA (n = 1;1%). Back pain stated as the first presenting symptom by 45 patients (46.8%) (followed by knee pain) and joint pains as the main problem by 49 patients (51.7%), while 47 patients of 93 who replied on the employment section (50.5%) were working. The total group had BASDAI score of 5.91 (+/-2.1), ESR of 19.65 (+/-19.4) mmHg/h, CRP of 8.10 (+/-9.2) mmol/L, BASFI score of 4.51 (+/-2.57), night pain of 5.26 (+/-3.2), sleep disturbance of 5.24 (+/-3.03) well-being over past week of 5.9 (+/-2.7), and well-being over past 6 months of 6.4 (+/-2.5). Most patients had PsA at presentation. Comparisons between genders showed significantly more women to have knee pain as first presenting symptom than men. No differences between races found in the first presenting symptom, main problem caused to patients by disease, and employment, but Africans have significantly more sleep disturbance than other races. Comparisons between disease subgroups showed patients with AS to have significantly more back pain and hip pain as first presenting symptom and patients with IBD to have more joint pain as main problem caused by the disease. PMID- 21328059 TI - Workstyle risk factors for work related musculoskeletal symptoms among computer professionals in India. AB - INTRODUCTION: Work-related musculoskeletal disorders are common in computer professionals. Workstyle may be one of the risk factors in the development of musculoskeletal discomfort. The objective of this retrospective study was to examine the prevalence of adverse workstyle in computer professionals from India and to evaluate if workstyle factors were predictors of pain and loss of productivity. METHODS: Office workers from various information technology (IT) companies in India responded to the short-form workstyle questionnaire and pain questionnaire. Correlation analyses were conducted to examine the associations between different variables followed by a multivariate logistic regression to understand the unique predictors of pain and loss of productivity. RESULTS: 4,500 participants responded to the workstyle and pain questionnaire. 22% of participants were reported to have a high risk of an adverse workstyle. 63% of participants reported pain symptoms. Social reactivity, lack of breaks, and deadlines/pressure subscales of workstyle questionnaire were significantly correlated with pain and loss of productivity. Regression analyses revealed that workstyle factors and duration of computer use per day were significant predictors of pain. CONCLUSION: Workstyle seems to be a mediating factor for musculoskeletal pain, discomfort, and loss of productivity. Based on the study findings, it is recommended that intervention efforts directed towards prevention of musculoskeletal disorders should focus on psychosocial work factors such adverse workstyle in addition to biomechanical risk factors. PMID- 21328060 TI - Influence of efforts of employer and employee on return-to-work process and outcomes. AB - BACKGROUND: Research on disability and RTW outcome has led to significant advances in understanding these outcomes, however, limited studies focus on measuring the RTW process. After a prolonged period of sickness absence, the assessment of the RTW process by investigating RTW Effort Sufficiency (RTW-ES) is essential. However, little is known about factors influencing RTW-ES. Also, the correspondence in factors determining RTW-ES and RTW is unknown. The purpose of this study was to investigate 1) the strength and relevance of factors related to RTW-ES and RTW (no/partial RTW), and 2) the comparability of factors associated with RTW-ES and with RTW. METHODS: During 4 months, all assessments of RTW-ES and RTW (no/partial RTW) among employees applying for disability benefits after 2 years of sickness absence, performed by labor experts at 3 Dutch Social Insurance Institute locations, were investigated by means of a questionnaire. RESULTS: Questionnaires concerning 415 cases were available. Using multiple logistic regression analysis, the only factor related to RTW-ES is a good employer employee relationship. Factors related to RTW (no/partial RTW) were found to be high education, no previous periods of complete disability and a good employer employee relationship. CONCLUSIONS: Different factors are relevant to RTW-ES and RTW, but the employer-employee relationship is relevant for both. Considering the importance of the assessment of RTW-ES after a prolonged period of sickness absence among employees who are not fully disabled, this knowledge is essential for the assessment of RTW-ES and the RTW process itself. PMID- 21328061 TI - A conceptual definition of vocational rehabilitation based on the ICF: building a shared global model. AB - BACKGROUND: The International Classification of Functioning, Disability and Health (ICF) is a conceptual framework and classification system by the World Health Organization (WHO) to understand functioning. The objective of this discussion paper is to offer a conceptual definition for vocational rehabilitation (VR) based on the ICF. METHOD: We presented the ICF as a model for application in VR and the rationale for the integration of the ICF. We also briefly reviewed other work disability models. RESULTS: Five essential elements of foci were found towards a conceptual definition of VR: an engagement or re engagement to work, along a work continuum, involved health conditions or events leading to work disability, patient-centered and evidence-based, and is multi professional or multidisciplinary. CONCLUSIONS: VR refers to a multi-professional approach that is provided to individuals of working age with health-related impairments, limitations, or restrictions with work functioning and whose primary aim is to optimize work participation. We propose that the ICF and VR interface be explored further using empirical and qualitative works and encouraging stakeholders' participation. PMID- 21328062 TI - A systematic review of functioning in vocational rehabilitation using the International Classification of Functioning, Disability and Health. AB - BACKGROUND: Vocational rehabilitation (VR) is aimed at engaging or re-engaging individuals with work participation and employment. The International Classification of Functioning, Disability and Health (ICF) by the World Health Organization can be operationalized in the context of VR. The objective of this study is to review the literature to identify outcomes or measures being used in VR using a systematic review methodology and link those measures to the ICF. METHODS: We applied a structured search strategy using multiple databases. Items or constructs of the measures or outcomes identified were linked to the ICF by two trained individuals. RESULTS: We have identified 648 measures which contained 10,582 concepts that were linked to the ICF which resulted in 87 second-level ICF categories. Out of the 87 categories, 31 (35.6%) were related to body functions, 43 (49.4%) were related to activities and participation, and 13 (14.9%) were related to environmental factors. No category was related to body structures. CONCLUSIONS: Our review found great diversity in the ICF contents of the measures used in different VR settings and study populations, which indicates the complexity of VR. This systematic review has provided a list of ICF categories which could be considered towards a successful VR. PMID- 21328063 TI - Occupational rehabilitation in Singapore and Malaysia. AB - INTRODUCTION: Asia is the new and favored magnet of economic attention and foreign investments after it made an almost uneventful rebound from the depths of financial crisis of 2008/2009. Not many Western observers fully understand the diversity that is Asia other than perhaps its 2 growing economic giants of China and India. Indeed many smaller countries like Singapore and Malaysia in South East Asia along with Australia and Hong Kong (a Special Administrative Region within China) look to symbiotic relationships with these two economic giants. The purpose of this discussion paper is to examine the current issues related to the development and provision of occupational rehabilitation services in Singapore and Malaysia with a forward-looking view of how Asia's different developing societies could potentially benefit from better alignment of occupational rehabilitation practices and sharing of expertise through international collaboration and dialogue platforms. METHODS: Seven therapists and one physician who are frequently involved in occupational rehabilitation services in their home countries critically reviewed the current issues in Singapore and Malaysia which included analysis of the prevalence and cost of occupational injury; overview of workers' compensation system; current practices, obstacles, and challenges in providing occupational rehabilitation and return to work practices. They also offered opinions about how to improve the occupational rehabilitation programs of their two home countries. CONCLUSION: Even though Malaysia and Singapore are two different countries, in many ways their current provision of occupational rehabilitation services and the problems they face with are very similar. There is a lot of room for systemic improvements that require government support and action. Most prominently, the training of more healthcare professionals in the assessment and rehabilitation of the injured worker should be encouraged. There could be better liaison between the many stakeholders and more funding made available to develop resources and to jump start strategic programs. As these two countries are witnessing rapid economic growth, more resources should be allocated to establish holistic care of the injured workers emphasizing early interventions and prevention of chronic disabilities. PMID- 21328064 TI - Challenges to remaining at work with common health problems: what helps and what influence do organisational policies have? AB - INTRODUCTION: Common health problems have a significant impact on work productivity (presenteeism), and sickness absence. The aim of this study was to examine the attitudes and beliefs of employees in the public sector about common health problems and work using the Flags system as a conceptual framework to identify problems and potential solutions. METHOD: 63 employees took part in 14 focus groups in two public sector organisations. Discussions were audio-recorded, transcribed, and analysed thematically using NVivo. RESULTS: The study confirmed the importance of heath-focused clinical factors (Yellow flags), perceptions of work (Blue flags), and more objective characteristics of work and organisational policies (Black flags), which emerged as major themes. The social and moral norms surrounding sickness absence and presenteeism were frequently discussed, including the impact of absence on colleagues, guilt, legitimising illness, and trust. There were interactions between the different Flags, often mediated by managers via their relationships with employees and their role in implementing organisational policy. CONCLUSIONS: The Flags system was useful as a conceptual framework in this context for identifying a number of obstacles to working with health problems, many of which were potentially modifiable on worker, workplace, or wider systems levels. PMID- 21328065 TI - Effects of season and reproductive state on lipid intake and fatty acid composition of gastrointestinal tract contents in the European hare. AB - We investigated lipid content and fatty acid (FA) composition of gastrointestinal tract contents in free-living, herbivorous European hares (Lepus europaeus). Mean crude fat content in hare stomachs and total gastrointestinal (GI) tracts was higher than expected for typical herbivore forages and peaked in late fall when hares massively deposited body fat reserves. Changes of FA proportions in different parts of the GI-tract indicated a highly preferential absorption of polyunsaturated fatty acids (PUFA). A further reduction of PUFA content in the caecum, along with the appearance of odd-chained FAs in caecum, caecotrophes, and colon content, pointed to a biohydrogenation of PUFA in the hare's hindgut. GI tract contents showed significant seasonal changes in their FA composition. Among PUFA, alpha-linolenic acid peaked in spring while linoleic acid was predominant in late summer and fall, which probably reflected changes in the plant composition of forage. However, independent of seasonal changes, GI-tracts of lactating females showed a significantly (+33%) higher content of linoleic acid, a FA that is known to increase reproductive performance in European hares. This finding suggests that lactating females actively selected dietary plants rich in linoleic acid, a PUFA that may represent a limited resource for European hares. PMID- 21328066 TI - Dietary fatty acid composition influences tissue lipid profiles and regulation of body temperature in Japanese quail. AB - Many avian species reduce their body temperature (T(b)) to conserve energy during periods of inactivity, and we recently characterized how ambient temperature (T(a)) and nutritional stress interact with one another to influence physiologically controlled hypothermic responses in Japanese quail (Coturnix japonica). In the present study, we examined how the fatty acid (FA) composition of the diet influences the FA composition of phospholipids in major organs and how these affect controlled hypothermic responses and metabolic rates in fasted birds. For 5 weeks prior to fasting, quail were fed a standard diet and gavaged each morning with 0.7 ml of water (control), or a vegetable oil comprising saturated fatty acids (SFA; coconut oil), or unsaturated fatty acids (UFA; canola oil). Birds were then fasted for 4 days at a T(a) of 15 degrees C. We found that, while fasting, both photophase and scotophase T(b) decreased significantly more in the SFA treatment group than in the control group; apparently the former down regulated their T(b) set point. This deeper hypothermic response was correlated with changes in the phospholipid composition of the skeletal muscle and liver, which contained significantly more oleic acid (18:1) and less arachidonic acid (20:4), respectively. Our data imply that these two FAs may be associated with thermoregulation. PMID- 21328068 TI - Reproductive failure, possible maternal infanticide, and cannibalism in wild moustached tamarins, Saguinus mystax. AB - Maternal infanticide in wild non-human primates has only been reported twice. In this paper, we report a possible new case of infanticide and cannibalism within a series of four successive reproductive failures in wild moustached tamarins, Saguinus mystax. Necropsy and genetic analyses of the corpses enabled us to rule out any pathology, and to determine paternity. The mother was seen biting and then eating the head of its own infant during a period when another female was pregnant and gave birth just 1 month later. Before that, the perpetrator had given birth to twins three times successfully when four to five adult and subadult males were present in the group. Although we do not know for certain that the infant was alive when the mother started biting it, our field observations preceding the event suggest it probably was. The possible infanticide case and the two cases of births and early death of the infants occurred while only two to three adult males were present in the group. This could be the second case of maternal infanticide reported in the genus Saguinus and the similar circumstances suggest a common pattern. We discuss these events in the light of the different functional explanations of infanticide and conclude that parental manipulation was the most likely: the mother could have terminated the investment in offspring that had low chances of survival in a group with low availability of helpers. PMID- 21328067 TI - Membrane-bound intestinal enzymes of passerine birds: dietary and phylogenetic correlates. AB - Bird species exhibit great diversity in digestive tract morphology and enzymatic activity that is partly correlated with the chemical composition of their natural diets. However, no studies have assessed whether the activities of digestive enzymes of the enterocytes correlate with dietary chemical composition data analyzed as a continuous variable at an evolutionary scale. We used a phylogenetically explicit approach to examine the effect of diet on the hydrolytic activity of three digestive enzymes (maltase, sucrase, and aminopeptidase-N) in 16 species of songbirds (Order Passeriformes) from Central Chile. The total activities (MUmol/min) of these enzymes were positively associated with body mass using both conventional least squares regressions and phylogenetically independent contrasts. After removing mass effects, we found a significant negative correlation between the ratio of aminopeptidase-N and maltase to the proportion of seeds found in the gizzard, but this relationship was no longer significant after controlling for phylogeny. When we analyzed the specific nutritional content of the diet, we found that the percentage of nitrogen in diet was negatively correlated with residual maltase activity and positively correlated with the ratio aminopeptidase-N/maltase. Given the large interspecific differences in biochemical capacity, we conclude that these differences reflect genetically determined evolutionary changes associated with the nutrient contents of each species' natural diet. PMID- 21328069 TI - Anatomic and isometric points on femoral attachment site of popliteus muscle tendon complex for the posterolateral corner reconstruction. AB - STUDY DESIGN: Descriptive laboratory study. PURPOSE: The femoral anatomic insertion site and the optimal isometric point of popliteus tendon for posterolateral reconstruction are not well known. Purpose of this study was to determine the relative relationship between the femoral anatomic insertion and isometric point of popliteus muscle-tendon complex with the lateral epicondyle of femur. METHODS: Thirty unpaired cadaveric knees were dissected to determine the anatomic femoral insertion of the popliteus tendon. The distance and the angle from the lateral epicondyle of femur to the center of the anatomic insertion of the popliteus tendon were measured using digital caliper and goniometer. Eight unpaired fresh cadaveric knees were examined to determine the optimal isometric point of femoral insertion of popliteus tendon using computer-controlled motion capture analysis system (Motion Analysis, CA, USA). Distances from targeted tibial tunnel for popliteus tendon reconstruction to the 35 points gained on the lateral surface of femur were recorded at 0, 30, 60, 90, and 120 degrees knee flexion. A point with the least excursion (<2.0 mm) was determined as the isometric point. RESULTS: The center of anatomic insertion points and the optimal isometric point for the main fibers of popliteus tendon were found to be posterior and distal to the lateral epicondyle of femur. The distance from the lateral epicondyle of femur to the center of anatomic femoral insertion of popliteus tendon was 11.3 +/- 1.2 mm (mean +/- SD). The angle between long axis of femur and the line from lateral epicondyle of femur to anatomic femoral insertion of popliteus tendon was 31.4 +/- 5.3 degrees . The isometric points for the femoral insertion of popliteus muscle-tendon complex were situated posterior and distal to the lateral epicondyle in all 8 knees. The distance between the least excursion point and the lateral epicondyle was calculated as 10.4 +/- 1.7 mm. The angle between the long axis of femur and the line from lateral epicondyle of femur to optimum isometric point of popliteus tendon was calculated as 41.3 +/ 14.9 degrees . CONCLUSION: The optimal isometric point for the femoral insertion of popliteus muscle-tendon complex is situated posterior and distal to the lateral epicondyle of femur. Femoral tunnel for "posterolateral corner sling procedure" should be placed at this point to achieve least amount of graft excursion during knee motion. PMID- 21328070 TI - Arthroscopic treatment for symptomatic discoid lateral meniscus during childhood. AB - PURPOSE: The purpose of this study was to review the operative long-term results of a large cohort of children treated arthroscopically for a symptomatic discoid lateral meniscus. METHODS: We retrospectively reviewed the arthroscopic procedures performed on 104 knees (97 patients) between 1990 and 2006 to treat symptomatic discoid lateral meniscus in children. The median age at the time of surgery was 8 years (range 2.5-13.9 years). RESULTS: The follow-up was 8.5 +/- 2.5 (mean +/- SD) years (median 9, range 2-18.5 years). In this series, young children (2-7 years) usually presented complete discoid menisci with deficit in extension and little pain. The meniscal tissue was almost degenerated, and subtotal meniscectomy was performed. Children aged from 8 to 14 years referred to our institute typically presented a symptomatic tear (pain and swelling joint with snap) of a complete or incomplete discoid lateral meniscus, usually pursuant to a trauma. The treatment performed in this group was a partial meniscectomy. Clinical results at long-term follow-up show better results for subtotal meniscectomies than for partial ones. CONCLUSION: The results showed the long term efficacy of arthroscopic treatment of a symptomatic discoid lateral meniscus. On the basis of this study, subtotal meniscectomies in younger patients are preferable when meniscal tissue is degenerated. In older children, we recommend to preserve meniscal tissue as much as possible. In younger patients submitted to subtotal meniscectomies, some adaptation of the knee to stress activity may occur. LEVEL OF EVIDENCE: Therapeutic case series, Level IV. PMID- 21328071 TI - Arthroscopic pullout repair of posterior root tear of the medial meniscus: the anterior approach using medial collateral ligament pie-crusting release. AB - Posterior root tears of the medial meniscus are frequently encountered and should be repaired if possible to prevent osteoarthritis of the medial compartment. Various surgical techniques have been proposed to repair posterior root tears. The anterior arthroscopic approach can cause an iatrogenic chondral injury due to the narrow medial joint space. The posterior approaches might be technically unfamiliar to many surgeons because they require the establishment of a posteromedial or trans-septal portal. This paper describes the medial collateral ligament pie-crusting release technique for arthroscopic double transosseous pullout repair of posterior root tears of the medial meniscus through the anterior approach to provide the good visualization of the footprint and sufficient working space. PMID- 21328072 TI - Bilateral consecutive rupture of the quadriceps tendon in a man with BstUI polymorphism of the COL5A1 gene. PMID- 21328073 TI - Chronic acquired hepatocerebral degeneration: effects of liver transplantation on neurological manifestations. AB - Three cirrhotic patients with chronic acquired hepatocerebral degeneration (CAHD) received neurologic, neuropsychologic and neuroimaging assessment before and after liver transplantation (LT). Before transplantation, neurologic dysfunction consisted in severe bradykinesia, dystonia, dyskinesia, ataxia and dysarthria. Cognitive impairment affected mainly attentional and executive domains. Brain MRI showed bilateral hyperintensities of the basal ganglia on T1-weighted images. After transplantation, motor manifestations promptly resolved. Cognitive testing showed a major improvement in two patients, whereas cognitive performances were slightly worsened in the third, reasonably due to the effects of a head injury before LT and a tacrolimus-related encephalopathy arising early after LT. MRI images 12 months later showed a slight reduction of the previously disclosed abnormalities in all three patients. None of them experienced recurrence of CAHD. Our observation reinforces the assumption that surgery is the best treatment option for CAHD and that severe neurological impairment in CAHD should not be considered a contraindication for LT. PMID- 21328074 TI - Analysis of experimental errors in bioprocesses. 1. Production of lactobionic acid and sorbitol using the GFOR (glucose-fructose oxidoreductase) enzyme from permeabilized cells of Zymomonas mobilis. AB - The proper determination of experimental errors in bioprocesses can be very important because experimental errors can exert a major impact on the analysis of experimental results. Despite this, the effect of experimental errors on the analysis of bioprocess data has been largely overlooked in the literature. For this reason, we performed detailed statistical analyses of experimental errors obtained during the production of lactobionic acid and sorbitol in a system utilizing as catalyst the GFOR (glucose-fructose oxidoreductase) enzyme from permeabilized cells of the bacteria Zymomonas mobilis. The magnitude of the experimental errors thus obtained were then correlated with the process operation conditions and with the composition of the culture media used for bacterial growth. It is shown that experimental errors can depend very significantly on the operation conditions and affect the interpretation of available experimental data. More specifically, in this study, experimental errors depended on the nutritional supplements added to the cultivation medium, the inoculation process, and the reaction time, which may be of fundamental importance for actual process development. The results obtained also indicate, for the first time, that GFOR activity can be affected by the composition of the medium in which cells are cultivated. PMID- 21328075 TI - Detailed 3D-morphometry of the anterior communicating artery: potential clinical and neurosurgical implications. AB - PURPOSE: Although a site common for pathology and of great importance to the neurosurgeon, the three-dimensional (3D) morphometry of the anterior communicating artery (ACoA) has had incomplete descriptions in the literature. METHODS: Using a novel 3D digital-image computer data analysis system, 115 patients underwent evaluation of their ACoA based on DICOM files derived from CT angiography. Measurements included the length, internal diameter, volume, deviation index (DI) and tortuosity index (TI). RESULTS: Of 115 samples, 85 were visualized clearly enough for morphometric analysis. The mean internal diameter was 1.86 mm and this tended to be greater in males (P < 0.05). The mean length of the ACoA was 3.99 mm and the mean volume was 11.61 mm(3). The mean TI for the ACoA was 0.84 and the mean DI was 0.62 mm. A significant relationship between DI and length, DI and volume, and DI and TI were found. The significant correlation of diameter to volume, and length related to volume, DI and TI, as well as TI related to length, volume and DI were noticed. There were no relationship between any parameter and age. CONCLUSIONS: A detailed knowledge of the 3D-morphometry of the ACoA demonstrates that in almost 50% of individuals the ACoA is straight in their course. Detailed data regarding arterial topography and trajectory as found in our study may be also of use in detecting early changes in this vessel due to pathology and may assist in the treatment of vascular lesions and planning of neurosurgical or interventional radiological procedures in the region including ACoA aneurysms. PMID- 21328076 TI - Iatrogenic femoral nerve injury: a systematic review. AB - PURPOSE: Iatrogenic femoral nerve injury is a recognized complication of abdominal and pelvic surgery. It causes distress and disability and may lead to permanent motor and/or sensory sequelae. The aim of this systematic review was to explore the contemporary spectrum of this injury reported in the literature. METHODS: A systematic review of iatrogenic femoral nerve injuries reported between 2000 and October 2010 was undertaken using the electronic databases Medline, PubMed, Cochrane Library, and Google Scholar. The context, frequency, mechanism of injury, and outcome were recorded. Relevant clinical and anatomical literature was reviewed to provide an overview of the surgical anatomy. RESULTS: Iatrogenic femoral nerve injury is not rare, occurring as a complication of common abdominal, pelvic, and orthopedic operations and after femoral nerve blocks and femoral artery puncture. Mechanisms of injury are diverse and include direct trauma and ischemia from retraction or stretching of the nerve. Variant anatomy is very rarely the source of the problem. Although the prognosis in most cases is good some affected patients require nerve repair or grafting and some are left with permanent residual neurologic deficits. CONCLUSIONS: A wider awareness of this complication, particularly the context in which it may occur, together with an appropriate understanding of the anatomy of the femoral nerve may help to reduce the frequency of this distressing and disabling iatrogenic complication. PMID- 21328077 TI - Pica: an uncommon cause of acute abdominal pain in children. PMID- 21328078 TI - Cardiopulmonary arrest caused by craniometaphyseal dysplasia. AB - Craniometaphyseal dysplasia is a rare congenital disorder that can cause craniofacial skeleton and tubular bone anomalies. A 7-month-old girl, with congenital facial palsy, mouth breathing, and nasal obstruction, was brought to the hospital because she suffered sudden cardiopulmonary arrest. Computed tomography showed bony narrowing of the choanae. The diagnosis was cardiopulmonary arrest triggered by asphyxia caused by severe choanal stenosis. She showed hypoxic encephalopathy and underwent a tracheotomy and an operation to enlarge choanae. When a neonate or young infant shows signs of nasal obstruction, physicians should aggressively search for and consider the possibility of choanal atresia or severe stenosis. PMID- 21328079 TI - Management of a vertically transmitted neonatal Chikungunya thrombocytopenia. AB - Chikungunya is an arthropod-borne acute viral disease caused by Chikungunya virus (CHIKV).In this report the vertical transmission of CHIKV is reported in a neonate. Molecular diagnostic technique plays an important role in patient management and disease control. Thrombocytopenia was found to be a major hematological parameter which should be treated at early stage to prevent hemorrhagic manifestations. PMID- 21328080 TI - Recombinant activated factor VII usage in life threatening hemorrhage: a pediatric experience. AB - OBJECTIVE: To determine the safety and efficacy of off label usage of Recombinant activated factor VII (rFVIIa) in children with severe bleeding in non-hemophiliac children with diverse etiologies like leukemia, post hematopoietic stem cell transplantation, dengue shock syndrome and Glanzmann thrombasthenia. METHOD: Medical records of 16 non-hemophiliac children with 20 bleeding episodes where rFVIIa was administered only after failure of standard measures to control bleeding were retrospectively reviewed and data collected regarding patient demographics, diagnosis and location of bleeding. Blood counts, coagulation and other lab parameters, both pre and post rFVIIa, were also noted. Severity of bleeding was assessed using a scoring system used previously by Nevo S et al. A record of usage of the amount of blood components (red blood cells, platelets, fresh frozen plasma, and cryoprecipitate) 24 h pre and post rFVIIa was also made. The dose of rFVIIa and any adverse side effects were recorded. RESULTS: Bleeding sites were gastrointestinal (13/20), pulmonary hemorrhage (6/20) and intracranial hemorrhage (1/20). Thrombocytopenia (platelet count <50,000/cumm) was present in 50% episodes and five had refractory low platelets. Usage of packed red cells and platelets was significantly less after usage of rFVIIa (p value 0.001 and 0.006, respectively). Mean dosage of rFVIIa was 77 MUgm/kg/dose (range 60 to 90 MUgm/kg/dose). The bleeding stopped completely in 11(55%), decreased to minimal in 2 (10%), reduced but transfusions needed in 4 (20%) and did not stop in 3 (15%) episodes. Five patients (31%) did not survive the bleeding episode. None of the patients developed thrombosis. CONCLUSIONS: rFVIIa appears to be safe and effective in controlling life-threatening bleed in non-hemophiliac children. PMID- 21328081 TI - Increased prevalence of restless legs syndrome in patients with acromegaly and effects on quality of life assessed by Acro-QoL. AB - Restless legs syndrome (RLS), a neurological sensory-motor disorder characterized by a compelling urge to move the limbs during the night, is a sleep disturbance that impairs quality of life. Prevalence of RLS and consequences on quality of life were investigated in acromegalic patients. Fifty-six patients (20 men, 55.0 +/- 1.6 years), 22 with active acromegaly (group 1) and 34 with controlled disease (group 2), and 95 controls (35 men, 52.9 +/- 1.1 years) were evaluated by a structured sleep interview concerning insomnia, circadian sleep disorders and excessive diurnal sleepiness (EDS). The Epworth Sleepiness Scale (ESS) questionnaire was administered to those reporting EDS. Patients were investigated by RLS diagnostic interview and International Restless Leg Syndrome-Rating Scale (IRLS-RS). Quality of life was investigated by AcroQoL questionnaire. RLS was diagnosed in 21% of acromegalics and in 4% of controls (P < 0.002). Prevalence of RLS and mean IRLS-RS was higher in group 1 than in group 2 (P < 0.05). Prevalence of insomnia (P < 0.0002) and of EDS (P < 0.05) and mean ESS score (P < 0.01) were higher in RLS-positive than in RLS-free acromegalics. Video-PSG showed that mean sleep latency (P < 0.01), micro-arousal index (P < 0.05) and wakefulness after sleep onset (P < 0.01) were higher, whereas sleep efficiency (P < 0.01) was lower, in RLS-positive than in RLS-free patients. Global and physical AcroQoL scores were significantly lower in RLS-positive than in RLS-free acromegalics (P < 0.01 and P < 0.001, respectively). Prevalence and severity of RLS is increased in patients with active acromegaly and impacts negatively on their physical performances, dramatically impairing quality of life. PMID- 21328082 TI - Vitamin D in chronic heart failure. AB - Recent evidence suggests a number of mechanisms whereby vitamin D may positively influence the pathophysiology of heart failure. These include actions on the renin-angiotensin system, calcium handling, reduction of proinflammatory cytokines, and improvements in endothelial function and blood pressure. Observational data suggest that low vitamin D levels are common in patients with heart failure and are associated with worse exercise capacity and natriuretic peptide levels. Little interventional data are currently available, but evidence to date does not support vitamin D supplementation, even in patients with low vitamin D levels. Further studies are needed to establish whether larger doses of vitamin D given over a longer period of time can reduce symptoms, hospitalization, and mortality in heart failure. PMID- 21328084 TI - Pseudolymphoma of the orbit. PMID- 21328083 TI - Entorhinal cortex volume is associated with episodic memory related brain activation in normal aging and amnesic mild cognitive impairment. AB - The present study examined the relationship between entorhinal cortex and hippocampal volume with fMRI activation during episodic memory function in elderly controls with no cognitive impairment and individuals with amnesic mild cognitive impairment (aMCI). Both groups displayed limited evidence for a relationship between hippocampal volume and fMRI activation. Smaller right entorhinal cortex volume was correlated with reduced activation in left and right medial frontal cortex (BA 8) during incidental encoding for both aMCI and elderly controls. However, during recognition, smaller left entorhinal cortex volume correlated with reduced activation in right BA 8 for the control group, but greater activation for the aMCI group. There was no significant relationship between entorhinal cortex volume and activation during intentional encoding in either group. The recognition-related dissociation in structure/function relationships in aMCI paralleled our behavioral findings, where individuals with aMCI displayed poorer performance relative to controls during recognition, but not encoding. Taken together, these results suggest that the relationship between entorhinal cortex volume and fMRI activation during episodic memory function is altered in individuals with aMCI. PMID- 21328085 TI - Is there an association between human immunodeficiency virus infection and breast cancer? PMID- 21328086 TI - Primary sarcomatoid malignant mesothelioma of the pericardium. PMID- 21328087 TI - Antigens from Leishmania amastigotes inducing clinical remission of psoriatic arthritis. AB - A first generation vaccine (AS100-1) was manufactured with protein from four cultured Leishmania species, which proved to be effective in the treatment of psoriasis. A single blind trial on 3,132 psoriasis patients revealed 508 (16.2%) subjects with psoriatic arthritis (PsA) that received AS100-1 antigens. The study group was distributed according to percent psoriasis area and severity index (PASI) reduction from PASI 10 to PASI 100. All groups decreased in arthritis score (AS), tender joints counts and nail changes after treatment; the highest decreased in the PASI 100 group. Relapses of psoriasis and PsA had PASI and AS lower than initial values before treatment. Clinical remissions were at lower doses and less time, after the second course of treatment. Peripheral blood mononuclear cells (PBMC) lymphocyte subsets (LS) varied with PASI range (1-10, 11 20 and 21-72). Pre-treatment, absolute values of gated LS: CD4+, CD8+HLA-, CD8+HLA+, CD8+CD3-, CD8+CD3+ decreased in PBMC as PASI increased, suggesting migration from the blood to the skin. In contrary to the previous finding, the following LS: CD8+CD4-, CD3+CD8-, HLA+CD8-, CD19, CD8+CD4+ and membrane surface immunoglobulin IgA+, IgD+, IgM+, IgE+, and IgG+ increased in PBMC as PASI increased suggesting activation and proliferation by unknown antigens creating a homeostatic cycle between skin/joints and peripheral blood. After nine doses of AS100-1, the following LS: CD8+CD3+, CD8+HLA+, CD3+CD8-, CD4+CD8-, CD8+HLA-, HLA+CD8-, CD8+CD3-, CD19+, CD8+CD4-, CD8+CD4+, IgA+, IgD+, IgM+, IgE+, and IgG+ decreased significantly as compared with values before treatment. The LS decreased stops the vicious cycle between skin/joints and blood explaining clinical remission of lesions. PMID- 21328088 TI - A stimulatory effect of Cassia occidentalis on melanoblast differentiation and migration. AB - In vitiligo, the active melanocytes in the epidermis are totally missing, whereas melanoblast cells in the outer root sheath of hair follicles are not affected. In an attempt to find potent repigmenting agents for vitiligo therapy, pod extracts of Cassia occidentalis was found to be effective in inducing differentiation and migration of mouse melanoblast cell line. Methanolic extract redissolved in DMSO at 12.5 MUg/ml was found to cause 3.5- to 3.8-fold melanin induction in melb-a melanoblast cells after 4 days in treatment medium. In addition it induced the tyrosinase activity and altered melb-a cell morphology. Transwell migration assay showed the potential of this herbal candidate to induce direct migration of treated cells. To the best of our knowledge, this is the first report investigating the effect of Cassia occidentalis on the differentiation and migration of melanoblast cells. The findings of present study are significant in designing preclinical and clinical studies on the efficacy of C. occidentalis as a stimulant for skin repigmentation in vitiligo. PMID- 21328089 TI - The IDEAL recommendations and urological innovation. AB - PURPOSE: Like other branches of surgery, Urology has encountered major challenges in aligning the research processes by which new interventions are assessed with the principles of Evidence-Based Medicine. This article explains the IDEAL framework and recommendations and illustrates how they might affect the evaluation of current controversial urological procedures. METHODS: From an inside perspective, we provide an overview of the efforts of the IDEAL Working Group to date with special emphasis on the field of Urology. RESULTS: There are clear differences between drugs and interventions in the natural history of innovations. Since the conventional framework for conducting trials of new treatments is largely based on the former, the evaluation of surgical innovations using the same template can encounter significant problems. Difficulties in performing randomized controlled trials of surgical techniques and the persistence of the case series as an important feature of the scientific literature have been the two most controversial aspects of this mismatch between the subject of research and the methodology used. The IDEAL framework provides a description of the process of innovation and development for surgical trials, and the associated recommendations provide a suggested alternative approach to developing study designs, which are appropriate for the specific problems of new techniques. CONCLUSIONS: IDEAL provides a new framework for surgical innovation that was developed with broad stakeholder input from the surgical community and is expected to have a transformative impact on the way that urologists perform clinical research. PMID- 21328090 TI - Clinical correlates of health-related quality of life among opioid-dependent patients. AB - PURPOSE: Previous work suggests that opioid users have lower health-related quality of life (HRQOL) than patients with more prevalent chronic illnesses such as hypertension or diabetes. Although comparisons with population norms are informative, studies of the correlates of HRQOL for opioid users are needed to plan clinical services. METHODS: We tested a conceptual model of the pathways between physiologic factors and symptoms in relation to HRQOL among 344 opioid users in a clinical trial. Physical and mental HRQOL were measured by the Short Form (SF)-36; withdrawal signs, symptoms, and functioning were also measured with validated instruments. Using structural equation modeling, we tested hypotheses that medical history directly predicts withdrawal signs and symptoms, and that medical history, withdrawal signs and symptoms, and functioning predict the physical and mental HRQOL latent variables of the SF-36. RESULTS: Most hypothesized relationships were significant, and model fit was good. The model explained 36% of the variance in mental HRQOL and 34% of the variance in physical HRQOL. CONCLUSIONS: The conceptual framework appears valid for explaining variation in the physical and mental HRQOL of opioid users undergoing medically managed withdrawal. Analysis of longitudinal data would help to evaluate more rigorously the adequacy of the model for explaining HRQOL in opioid withdrawal. PMID- 21328091 TI - Modulation of lipopolysaccharide-induced pro-inflammatory mediators by an extract of Glycyrrhiza glabra and its phytoconstituents. AB - OBJECTIVE: To evaluate the inhibitory property of de-glycyrrhizinated extract of Glycyrrhiza glabra root and its phytoconstituents (glabridin, isoliquiritigenin and glycyrrhizin) on LPS-induced production of pro-inflammatory mediators. MATERIALS AND METHODS: Inhibitory effect of G. glabra extract and its phytoconstituents were studied on lipopolysaccharide (LPS)-induced nitric oxide (NO), interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) levels in J774A.1 murine macrophages. RESULTS: G. glabra and isoliquiritigenin significantly inhibited LPS stimulated NO, IL-1 beta and IL-6 production. Glabridin showed significant inhibition of NO and IL-1 beta release, but failed to attenuate IL-6 levels at the tested concentrations. In addition, glycyrrhizin did not exhibit inhibitory response towards any of the LPS-induced pro-inflammatory mediators at the tested concentrations. CONCLUSION: From the results we speculate that the inhibitory effect of G. glabra extract on LPS-induced pro-inflammatory mediators is influenced by glabridin and isoliquiritigenin and is not contributed by glycyrrhizin. PMID- 21328097 TI - Parkinson's disease and the bones. AB - PRINCIPLES: Bone and joint problems in Parkinson's disease (PD) are manifold: decreased mobility, abnormal posture, as well as the risk of falling may cause both acute and chronic damage to the musculoskeletal system. In patients with Parkinson's disease, postural instability and falls are frequently observed. The aim of the study was to review the literature with respect to the bone health and risk of fractures in these patients. METHODS: We conducted a review on bone health in patients with Parkinson's disease. RESULTS: There is evidence that patients with PD have an increased risk of fractures, especially of the hip, due to the elevated risk of falling. While rigidity, bradykinesia and postural instability (but not tremor) predict falls, fractures also correlate with bone mineral density, which is generally lowered in this group of patients as compared to age- and sex-matched controls. Typically PD patients have "high turnover osteoporosis" due to several causes. CONCLUSIONS: Any newly diagnosed patient with PD should be evaluated for the risk of falling and osteoporosis and routinely be supplemented with vitamin D. In the case of osteoporosis, blood samples for detecting underlying and treatable conditions should be taken and bisphosphonates administered to the patient. It is unclear whether drugs typically used for PD provoke or worsen osteoporosis. Nevertheless, every long term medication should undergo safety studies to demonstrate lack of negative interference with bone metabolism. Drug admission authorities should demand these data when registering new substances or when renewing old admissions. PMID- 21328098 TI - Hypothermia for perinatal asphyxial encephalopathy. AB - BACKGROUND: Perinatal asphyxial encephalopathy occurs in 1 per 1000 live births and is associated with high mortality and morbidity. Therapeutic hypothermia increases intact survival and improves neurodevelopmental outcome in survivors. AIMS: To evaluate (i) the opinion and practice of therapeutic hypothermia as a therapy for moderate to severe perinatal asphyxial encephalopathy amongst Swiss neonatologists and paediatric intensive care specialists, (ii) the current clinical management of infants with perinatal asphyxial encephalopathy and (iii) the need for a national perinatal asphyxia and therapeutic hypothermia registry. METHODS: Two web-based questionnaires were sent to 18 senior staff physicians within the Swiss Neonatal Network. RESULTS: Therapeutic hypothermia was considered effective by all responders, however only 11 of 18 units provided therapeutic hypothermia. Cooling was initiated during transfer and performed passively in 82% of centres with a target rectal temperature of 33-34 degrees C. Most units ventilated infants with perinatal asphyxial encephalopathy if clinically indicated and 73% of responders gave analgesia routinely to cooled infants. Neuromonitoring included continuous amplitude integrated EEG (aEEG) and EEG. Neuroimaging included cranial ultrasound (cUS), magnetic resonance imaging (MRI) and computed tomography (CT). Sixty-seven percent of units treating infants with perinatal asphyxial encephalopathy performed MRI routinely. All heads of departments questioned indicated that a "Swiss National Asphyxia and Cooling Registry" is needed. CONCLUSIONS: In Switzerland, access to therapeutic hypothermia is widespread and Swiss neonatologists believe that therapeutic hypothermia for perinatal asphyxia is effective. National cooling protocols are needed for the management of infants with perinatal asphyxial encephalopathy in order to ensure safe cooling, appropriate monitoring, imaging and follow-up assessment. A national registry is needed to collect data on diagnosis, treatment, adverse events and outcome. PMID- 21328099 TI - Morbidity and mortality on chronic haemodialysis: a 10-year Swiss single centre analysis. AB - BACKGROUND: Patient survival on chronic haemodialysis varies considerably among different countries and healthcare systems. To date, the survival of Swiss dialysis patients has not been analysed separately. METHODS: We consecutively enrolled 266 patients entering the chronic haemodialysis program of the University Hospital Basel between 01.01.1995 and 30.06.2006 into a cohort study. Patient survival on chronic haemodialysis was the primary endpoint. Pre-specified sub-group analyses were performed for female and diabetic patients. RESULTS: Patient age ranged from 15 to 90 years. Seventy-two percent suffered either from coronary artery, peripheral artery or cerebrovascular disease and 34% from diabetes. Sixty-nine (26%) patients underwent kidney transplantation. Transplanted patients were significantly younger (p <0.01) and less likely to suffer from diabetes (p <0.01) and atherosclerotic diseases (coronary, peripheral, cerebrovascular p for all <=0.01). Median survival was 4.25 years (95%CI 3.66-5.50), with one, three and five year survival rates reaching 88%, 68% and 46%. Survival rates were equal in men and women (p = 0.34), among diabetic and non-diabetic patients (p = 0.41) and among men and women stratified for the presence of diabetes (p = 0.13). Overall, 34% (91/266) patients died during the observational period. Thirty three percent of all deaths were caused by cardiac events, followed by malignant diseases (8%) and infections (7%). In 9% (23/266) dialysis was withdrawn and withdrawal of dialysis contributed to death in 25% (23/91). CONCLUSION: Survival on chronic haemodialysis treatment in Switzerland compares favourably to international reference values. Dialysis withdrawal and the frequency of kidney transplantation impact long term patient outcome and should be adjusted for when comparing mortality analysis. PMID- 21328100 TI - Association between polymorphisms in the SLC27A1 gene and milk production traits in Chinese Holstein cattle. AB - We assessed SLC27A1, a candidate gene for milk production traits in Chinese Holstein cattle. DNA was extracted from the blood of 48 top Chinese Holstein Cattle selected according to phenotypic character and mixed into DNA pool for SNP detection. We tested blood samples of these cattle for SNPs in exon 3 and the 3' flanking region of the SLC27A1 gene by using polymerase chain reaction-single stranded conformation polymorphism (PCR-SSCP) and DNA sequencing. We found 2 polymorphic sites: 112T>C, a synonymous mutation, in exon 3 (SNP(1)), and 64G>A in the 3'-UTR (SNP(2)). We also determined the genotypes of 330 Chinese Holstein cattle by using PCR-restriction fragment length polymorphism (RFLP). We found 3 genotypes each at SNP(1) (TT, TC, and CC) and SNP(2) (GG, GA, and AA). The association among the different genotypes at these 2 sites and milk production traits was analyzed using a least-squares procedure. The results showed that cows with genotype CC had higher milk yields than those with genotype TC (0.01 < p < 0.05). No significant difference was detected among the 3 SNP(2) genotypes in terms of milk production traits. Our results provide evidence that the C allele have potential effects on milk yield trait. PMID- 21328101 TI - Identification of SNPs in interferon gamma, interleukin-22, and their receptors and associations with health and production-related traits in Canadian Holstein bulls. AB - Genetic variants in a number of immunoregulatory genes have been previously associated with health and production traits in dairy cattle. Therefore, in the following study, the genes coding interferon gamma (IFNG), IFNG receptor 1 and 2 domains, interleukin-22 (IL22), and IL22 receptor alpha 1, were investigated for single nucleotide polymorphisms (SNPs) in Holstein bulls. These SNPs, along with SNPs previously identified in IL10, IL10 receptor, and transforming growth factor beta 1 (TGFB1) genes, were evaluated for statistical associations to estimated breeding values for milk somatic cell score (SCS), a trait highly correlated to mastitis incidence, and various production-related traits, including milk yield, protein yield, fat yield, and lactation persistency. While no significant associations were found between these SNPs and SCS, SNPs in IL10 receptor beta subunit showed a significant effect on protein yield and lactation persistency. While there is evidence that IL10 plays an important role during lactation, it is also likely that the effects of SNPs in IL10 receptor beta subunit on protein yield and lactation persistency are due to linkage disequilibrium with a neighboring QTL. PMID- 21328102 TI - Microsatellite analysis of genetic population structure of zebu cattle (Bos indicus) breeds from north-western region of India. AB - The present study aims to understand the existing genetic diversity and structure of six native cattle breeds (Rathi, Tharparkar, Nagori, Mewati, Gir, and Kankrej) adapted to the north-western arid and semi-arid region of India based on microsatellite loci. Various diversity estimates, mean number of alleles (12.84); effective number of alleles (5.02); gene diversity (0.769), and observed heterozygosity (0.667) reflected the existence of substantial within-breed diversity in all the investigated cattle breeds. Mean estimates of F-statistics: F(IT) = 0.144 +/- 0.023, F(IS) = 0.071 +/- 0.021, and F(ST) = 0.078 +/- 0.014 were significantly different from zero (P < 0.05). The interbreed relationships indicated moderate level of breed differentiation between the six cattle breeds with least differentiation between Kankrej-Mewati pair. The phylogeny structuring further supported close grouping of Kankrej and Mewati breeds. Correspondence analysis plotted Rathi, Tharparkar, and Gir individuals into three separate areas of multivariate space; whereas, Kankrej, Mewati, and Nagori cattle showed low breed specific clustering. This reflected the existence of discrete genetic structure for Tharparkar, Rathi, and Gir, the prominent dairy breeds of the region; whereas, admixture was observed for Kankrej, Mewati, and Nagori individuals. PMID- 21328103 TI - Mapping, cDNA cloning and tissue expression of the porcine thyrotropin-releasing hormone receptor gene. AB - Thyrotropin-releasing hormone receptor (TRHR) is a G-protein-coupled receptor that plays a crucial role in regulating the hypothalamic-pituitary-thyroid axis by conveying the action of the hypothalamic tripeptide TRH, which is the primary central activator of this hormonal cascade. In the present study, the porcine TRHR (pTRHR) gene was localized to chromosome 4 by Radiation hybrid mapping. Quantitative trait loci affecting average backfat thickness, daily gain, and carcass and meat quality traits have been mapped to the region containing this gene. Further, the full-length cDNA of pTRHR was cloned and sequenced. pTRHR contains an open reading frame encoding 398 amino acids and shares 96.2% amino acid identity to human TRHR. Real-time quantitative RT-PCR showed that the mRNA of pTRHR is expressed in a variety of tissues, with high expression in the brain, hypothalamus, pituitary, testis, and fat tissue. The considerable expression level of TRHR mRNA found in fat tissue indicates potential direct action of TRH on lipocyte might exist. Additionally, two alternative spliced transcript variants of pTRHR were also isolated in this study. Our data provided basic molecular information which will be useful for further investigation on pTRHR gene. PMID- 21328104 TI - PCR-SSCP variation of GH and STAT5A genes and their association with estimated breeding values of growth traits in Baluchi sheep. AB - Growth hormone (GH) selected for its important role in economically relevant traits and signal transducers and activators of transcription 5A (STAT5A) is also known as a main mediator of growth hormone action on target genes. A total number of 190 lambs of Iranian purebred Baluchi sheep were genotyped at exon 5 of GH and exons 7 and 8 of STAT5A genes by using PCR-SSCP analysis. GH gene revealed three (G1, G2, and G3) conformational patterns; however, STAT5A loci were not polymorphic. Breeding values of growth traits including birth weight, weaning weight, 6 months weight, 9 months weight, and yearling weight were estimated by using the Best Linear Unbiased Prediction based on an animal model with a relationship matrix. Studied growth traits were examined for association analysis. Our findings suggest that animals with G2 genotype have highest breeding value for six month weight, while these animals have lowest breeding value for pre-weaning traits. Higher performance of G2 animals in adult ages may be related to the growth hormone role in puberty ages. The other traits showed no relationship to the genotypes examined. PMID- 21328105 TI - Decreased expression of matrix metalloproteinase-9 and increased expression of tissue inhibitors of matrix metalloproteinase-1 in paratuberculosis-infected cattle in the ELISA-negative subclinical stage. AB - We investigated the gene expression of matrix metalloproteinases-9 (MMP-9) and tissue inhibitors of matrix metalloproteinases-1 (TIMP-1) in peripheral blood cells from infected cattle with Mycobacterium avium subsp. paratuberculosis (Map) in the ELISA-negative subclinical stage compared with uninfected control cattle. Significant decreased MMP-9 expression and increased TIMP-1 expression were found in peripheral blood cells from Map-infected cattle after stimulation with Map lysate and Map purified protein derivative (PPD) than in control cattle by real time RT-PCR analysis. In contrast to the uninfected controls, the activity of MMP 9 was also decreased in peripheral blood cell culture supernatants from Map infected cattle at 24 hr after Map lysate and MapPPD stimulation by gelatin zymography analysis. As a result, the MMP-9 may play an important role in the development of Mycobacterium avium subsp. paratuberculosis disease. PMID- 21328106 TI - Athletes' inclination to play through pain: a coping perspective. AB - Previous studies have shown how social networks lead athletes to accept pain as a "part of the game," which generates pressure on athletes to continue competing despite being in pain. Little is known, however, about the potential coping strategies that are related to pain behavior in sport. This study of 205 combat athletes examined whether pain coping strategies, including distraction from pain, praying, reinterpreting pain sensations, ignoring pain, and pain catastrophizing, are related to athletes' inclination to play through pain. Results revealed that pain catastrophizing led athletes to reduce their physical involvement in their sport activity. Of particular interest was the moderating effect of ignoring pain such that ignoring pain significantly attenuated the negative effect of pain intensity on athletes' inclination to play through pain. Few studies have tested and supported the contribution of pain coping to the prediction of behavior in real sport situations. By identifying which coping strategies athletes could use to maintain their physical involvement despite being in (sometimes intense) pain, the current study makes an important contribution for tailoring pain management programs for this at-risk population. PMID- 21328107 TI - A review on the fate of pesticides during the processes within the food production Chain. AB - Only the intake of toxicologically-significant amounts can lead to adverse health effects even for a relatively toxic substance. In the case of residues in foods this is based on two major aspects--first, how to determine quantitatively the presence of a pollutant in individual foods and diets, including its fate during the processes within the food production chain; and second, how to determine the consumption patterns of the individual foods containing the relevant pollutants. The techniques used for the evaluation of the fate of pesticides during food processing have been critically reviewed in this paper to determine those areas where improvements are needed or desirable. Options for improvements are being suggested, including, for example, the development of a pan-European food composition database, activities to understand better effects of processing on individual food pesticides, and harmonization of food consumption survey methods with the option of a regular pan-European survey. The ultimate aim is to obtain appropriate estimations for the presence and quantity of a given chemical in a food and in the diet in general. Existing pragmatic approaches are a first crude step to model food pollutant intake. It is recommended to extend, refine, and validate this approach in the near future. This has to result in a cost-effective exposure-assessment system to be used for existing and potential categories of pollutants. This system of knowledge (with information on sensitivities, accuracy, etc.) will guide future data collection. PMID- 21328108 TI - Micro-oxygenation of red wine: techniques, applications, and outcomes. AB - Wine micro-oxygenation (MOX) is the controlled addition of oxygen to wine in a manner designed to ensure that complete mass transfer of molecular oxygen from gaseous to dissolved state occurs. MOX was initially developed to improve the body, structure, and fruitfulness in red wines with high concentrations of tannins and anthocyanins, by replicating the ingress of oxygen thought to arise from barrel maturation, but without the need for putting all wine to barrel. This review describes the operational parameters essential for the effective performance of the micro-oxidation process as well as the chemical and microbiological outcomes. The methodologies for introducing oxygen into the wine, the rates of oxygen addition, and their relationship to oxygen solubility in the wine matrix are examined. The review focuses on the techniques used for monitoring the MOX process, including sensory assessment, physicochemical properties, and the critical balance of the rate of oxygen addition in relation to maintaining the sulfur dioxide concentration. The chemistry of oxygen reactivity with wine components, the changes in wine composition that occur as a consequence of MOX, and the potential for wine spoilage if proper monitoring is not adopted are examined. Gaps in existing knowledge are addressed focusing on the limitations associated with the transfer of concepts from research trials in small volume tanks to commercial practice, and the dearth of kinetic data for the various chemical and physical processes that are claimed to occur during MOX. PMID- 21328109 TI - Microbial safety of tropical fruits. AB - There are approximately 140 million tons of over 3,000 types of tropical fruits produced annually worldwide. Tropical fruits, once unfamiliar and rare to the temperate market, are now gaining widespread acceptance. Tropical fruits are found in a variety of forms, including whole, fresh cut, dried, juice blends, frozen, pulp, and nectars in markets around the world. Documented outbreaks of foodborne disease associated with tropical fruits have occurred. Norovirus and Salmonella are the leading viral and bacterial pathogens, respectively, documented to have caused outbreaks of infections associated with consumption of tropical fruits. Sources of contamination of tropical fruit have been identified in the production environment and postharvest handling, primarily related to sanitation issues. Limited data exist on the specific route of transmission from these sources. Research on the microbial safety of tropical fruits is minimal; with the growing market for tropical fruit expected to increase by 33% in 2010 this research area needs to be addressed. The aim of this review is to discuss the foodborne pathogen outbreaks associated tropical fruit consumption, research previously completed on pathogen behavior on tropical fruits, preventive strategies for pathogen contamination, and research needs. PMID- 21328110 TI - Understanding critical factors for the quality and shelf-life of MAP fresh meat: a review. AB - Due to increased demands for greater stringency in relation to hygiene and safety issues associated with fresh food products, coupled with ever-increasing demands by retailers for cost-effective extensions to product shelf-lives and the requirement to meet consumer expectations in relation to convenience and quality, the food packaging industry has rapidly developed to meet and satisfy expectations. One of the areas of research that has shown promise, and had success, is modified atmosphere packaging (MAP). The success of MAP-fresh meat depends on many factors including good initial product quality, good hygiene from the source plants, correct packaging material selection, the appropriate gas mix for the product, reliable packaging equipment, and maintenance of controlled temperatures and humidity levels. Advances in plastic materials and equipment have propelled advances in MAP, but other technological and logistical considerations are needed for successful MAP systems for raw chilled meat. Although several parameters critical for the quality of MA packed meat have been studied and each found to be crucial, understanding of the interactions between the parameters is needed. This review was undertaken to present the most comprehensive and current overview of the widely available, scattered information about the various integrated critical factors responsible for the quality and shelf life of MA packed meat with an interest to stimulate further research to optimize different quality parameters. PMID- 21328111 TI - Prebiotic and other health-related effects of cereal-derived arabinoxylans, arabinoxylan-oligosaccharides, and xylooligosaccharides. AB - Arabinoxylans (AX) from cereals are cell wall components that constitute an important part of the dietary fiber intake in humans. Enzymatic hydrolysis of AX yields arabinoxylan-oligosaccharides (AXOS), consisting of arabinoxylooligosaccharides and xylooligosaccharides (XOS). This reaction takes place in the production of AXOS and of cereal-derived food products such as bread and beer, as well as in the colon upon ingestion of AX. This review mainly focuses on the available evidence that AXOS and XOS exert prebiotic effects in the colon of humans and animals through selective stimulation of beneficial intestinal microbiota. In addition, in vitro experiments and in vivo intervention studies on animals or humans are discussed that have investigated potential health-related effects resulting from the dietary intake of AX, AXOS, or XOS. PMID- 21328112 TI - Gender differences in affective suffering among racial/ethnically diverse, community-dwelling elders. AB - Objective. Copious research shows a female excess of unipolar depression. The generalizability of this finding is examined in a racial/ethnically diverse, community-residing, elder sample. Design. Depressive suffering was assessed both categorically and linearly with the Index of Affective Suffering (IAS), a hierarchal measure designed to examine intensity and extensity of suffering. In home interviews by specially trained raters also collected demographic, functional, and social health data. Prevalence rates of affective suffering were examined separately for Latinos (N=996, Females=46.8%), Blacks (N=717, Females=36.5%), and Whites (N=415, Females=18.6%). Results. Analyzed by gender alone these data support the typical wisdom that females report significantly more depressed affect than males. However, by racial/ethnic group categorical analysis indicates that among Whites and Latinos, women reported more symptoms of clinically significant affective suffering than males; whereas, among Blacks, women and men did not differ from each other. Moreover, risk factors commonly associated with excess female depression failed to explain observed differences. Conclusion. The absence of a between-gender difference in affective suffering observed among Black elders in this study raises questions about generalized assumptions of greater 'female' vulnerability for this age group. A need for research to appreciate the heterogeneity of elder individuals is highlighted as is the importance of using dimensional assessment techniques in psychiatric epidemiology. PMID- 21328113 TI - Muslim women's reflections on the acceptability of vaginal microbicidal products to prevent HIV infection. AB - This paper examines South African Muslim women's opinions of the acceptability of microbicidal products to prevent HIV infection if these were to become available in the future. In the context of the HIV pandemic, prophylactic methods such as male circumcision, vaccines and microbicidal preparations are increasingly thought of as ways to reduce the incidence of infection. We examine the extent to which participants' religious beliefs and the implications of religious norms and ideals might influence decision-making concerning hypothetical acceptability to use a microbicide. We conducted qualitative interviews with 29 Muslim women residing in South Africa, a country with one of the highest HIV prevalence rates in the world. Four themes emerged from the data, namely, (1) participants' questioning of the need for microbicides; (2) reasons they gave in favour of microbicide use; (3) the juxtaposition of microbicide use and religious ethics; and (4) the role of religious authorities in decision-making regarding microbicide use. The juxtaposition of microbicide use and religious ethics was further informed by three sub-themes, namely, the life-promoting nature of both Islam and microbicide use, the possibility that microbicide use could encourage sexual risk-taking among male partners, and that the use of these products contradicted womens' notions of ethical agency and ideals about marriage. These themes and sub-themes are analysed in the context of gender relations among South African Muslims. The study findings are significant in light of recent data showing the effectiveness of a microbicidal preparation in reducing the risk of HIV infection in South Africa. We also show that the acceptability of microbicidal products is to a certain extent linked to a variety of religious persuasions and ideals. When microbicides become available in the future, proponents of their use will need to consider religious reasoning of potential users, including that of Muslim women. PMID- 21328114 TI - My Mother's Bed. PMID- 21328116 TI - Information behaviors and problem chain recognition effect: applying situational theory of problem solving in organ donation issues. AB - Identification of active subpopulations who are motivated to talk about, seek out, and select information about organ donation-related issues can improve health communicators' efficacy in increasing awareness of the shortage of organ and health donors. Using the Situational Theory of Problem Solving (STOPS), we segmented the general population into more meaningful subgroups (e.g., active, aware publics about an organ donation issue) and examined whether segmented public profiles could predict their likelihood of active information giving, taking, and selecting about donor shortage. We also tested whether those publics that are more active about the organ donation issue would recognize and be interested in other organ donation issues (e.g., shortage of bone marrow donors). Findings based on two survey data sets (N = 316 and N = 347) suggested that perceptual and motivation variables could predict the likelihood of information behaviors and further donation-related behavioral intentions. In addition, we found some evidence on the problem chain recognition effect-if one becomes active about an organ donation issue, she or he is likely to perceive similar or related issues as problematic. Based on the findings, we discuss the segmentation method and its utility for more strategic planning and practice of health campaigns. PMID- 21328117 TI - Identifying comorbidities in home health care patients: does the Outcome and Assessment Information Set have incremental value to Medicare claims data? AB - We compare the proportion of patients presenting with comorbid conditions among fee-for-service Medicare beneficiaries with heart failure obtained by using (a) home health care claims data, (b) data from the Medicare Provider Analysis and Review (MedPAR), and (c) the Outcome and Assessment Information Set (OASIS), using a unique database developed by linking the records of Medicare administrative data and the OASIS. Data from the MedPAR yielded a higher proportion of patients with comorbid conditions compared to the OASIS or home health care claims data (77%, 51%, and 51%, respectively), leading us to conclude that non-home health care claims data must be used for risk adjustment in studies involving home health care patients. PMID- 21328118 TI - Preliminary assessment of appropriateness of emergency care service use: actions taken and consultations obtained before emergency care presentation. AB - Inappropriate use of emergency care services can increase hospital readmissions and related costs. This pilot, cross-sectional survey project determined whether home health care patients who receive emergency care services during a Medicare approved home care episode sought consultation from health care professionals before they made the emergency care visit. The two research questions were: (a) What actions were taken by the patient before making an emergency care visit?; (b) If prior consultation was obtained, what were the suggestions? Preliminary data were obtained from a Michigan-based, Medicare-certified, not-for-profit home health agency affiliated with a university health system. A two-page questionnaire recorded up to three emergency care visits. Volunteer participants were Medicare patients who had no cognitive deficits and were able to communicate with home health care providers (HHCPs) by themselves. Thirty-five emergency care visits were reported; 31 (88.6%) Medicare patients participated and 4 (11.4%) of them had two emergency care visits. Before the patients made an emergency care visit, they most often called their primary care physicians (PCPs; N = 20, 57.1%), followed by the HHCPs (N = 10, 28.6%). All 20 patients who contacted their PCPs and 7 patients who contacted their HHCPs were advised to seek emergency care services. In 20 emergency care visits the patient was admitted for an acute hospital stay; the other 15 patients went home. Most patients contacted their PCPs or HHCPs before they went to an emergency department or urgent care facility. These results implied that PCPs and HHCPs seemed to perceive that the need for emergency care should be determined at an emergency room or urgent care facility. This study was unable to differentiate the need for emergency care services or the appropriateness of the advice given by PCPs or HHCPs when the home care patients were under the care of a medical team. PMID- 21328119 TI - Using a measure of person-perception skills to identify outstanding home care workers. AB - This study involved university-community collaboration with an international home care company for the purpose of developing a tool to identify talented caregivers. Tested was the hypothesis that workers' ability to provide care in person-centered ways would be positively associated with their ability to describe others in complex ways--that is, their person-perception skills. Company coordinators functioning as supervisors used an innovative 10-item instrument to screen 554 home health aides for their person centeredness. The most and least person-centered workers were evaluated for their person-perception skills. Person centeredness was positively associated with the complexity of home care workers' descriptions of others. PMID- 21328121 TI - Removal of 2-chlorophenol from water using rice-straw derived ash. AB - Removal of 2-chlorophenol from water using rice-straw derived ash (RSDA) was evaluated in this study to compare with commercial activated carbon. RSDA was obtained by burning rice-straw at 400 degrees C and 700 degrees C for 1 h. This ash can provide a better adsorbent for 2-chlorophenol. The adsorption capacities of RSDA at 400 degrees C and 700 degrees C are 37 and 52 mg g-1 at pH 4, respectively, and decrease to 9.0 and 40 mg g-1 at pH 10. Adsorption of either neutral or anionic 2-cholorphenol by the RSDA are shown as L-shaped nonlinear isotherms, suggesting surface adsorption rather than partitioning is occurring. At higher-burning temperatures, the surface area, porosity, point of zero charge and aromaticity of the resultant RSDA increase, but the oxygen content and surface acidity decrease. The combined effects result in a higher 2-chlorophenol adsorption of RSDA at 700 degrees C, which shows a slight pH effect on the adsorption of 2-chlorophenol, due to the lower content of oxygen-containing functional groups. Oxygen-containing functional groups contribute to surface acidity and H-bonding sites for adsorbed water, which compromises the interaction between 2-chlorophenol and the adsorbents. Thus, it suggests that rice-straw derived carbon (RSDC) can be used as an effective low-cost substitute material for activated carbon for removal of chlorophenols from wastewater. PMID- 21328120 TI - Detection of Escherichia coli in a cattle manure composting process by selective cultivation and colony polymerase chain reaction. AB - Livestock manure is suitable for use as a composting material. However, various intestinal microbes, such as Escherichia coli, are significant components of such manures. Thus, it is desirable that the level of intestinal microbes, and particularly opportunistic pathogens, in compost is inspected and counted regularly. The sensitivity and specificity of detection of E. coli in compost have been improved by selective cultivation followed by colony polymerase chain reaction (PCR) using the ECO primer. Indeed, the sensitivity of this method is higher than that of DNA extraction from compost and PCR. In this study, changes in numbers of E. coli present in a field-scale composting process over time was assessed using selective cultivation and colony PCR. Numbers of ECO-positive colonies after 24 h decreased, with a concomitant rise in compost temperature. ECO-positive colonies were not detected from 33 to 48 h. However, ECO-positive colony numbers increased beginning on day 4 and continuing until day 42. Thus, it seems likely that the high temperatures reached during the composting process did not affect E. coli numbers in the final compost. Additionally, selective cultivation followed by colony PCR using specific primers is an appropriate method of determining levels of cultivable pathogens in composted materials. PMID- 21328122 TI - Characterization of non-extractable 14C- and 13C-sulfadiazine residues in soil including simultaneous amendment of pig manure. AB - Recently, we reported on soil fate of SDZ residues amended with pig manure treated with 14C-labeled sulfadiazine 14C-SDZ). The first objective of the present study was to determine whether this strategy can be substituted by application of 14C-SDZ to soil. The second objective was to characterize non extractable SDZ residues by fractionation, size exclusion chromatography (SEC) and solid state 13C-NMR. The fate of 14C-SDZ was examined for 28 d, using two soils with and without amendment of pig manure. Mineralization of 14C-SDZ was low; extractable residues decreased to 7-30%. Compared to the previous study, results were similar. 14C-SDZ derived bound radioactivity was found in HCl washings, fulvic, humic acids and humin. According to SEC, one bound 14C portion (70%) co-eluted with fulvic acids (above 910 g mol-1); the other consisted of adsorbed/entrapped 14C-SDZ. The 13C-SDZ study was performed for 30 d; humic acids were examined by 13C-NMR. A signal (100-150 ppm) was referred to 13C-SDZ. SEC and 13C-NMR demonstrated rapid integration of SDZ into humics. PMID- 21328123 TI - Validation and application of an analytical method for determining pesticides in the gas phase of ambient air. AB - A method for determining atmospheric concentrations of eight pesticides applied to corn and soybean crops in Mato Grosso state, Brazil is presented. The method involved a XAD-2 resin cartridge coupled to a low volume air pump at 2 L min-1 over 8 hours. Pesticides were recovered from the resin using sonication with n hexane:ethyl acetate and determined by GC-MS. Good accuracy (76-128%) and precision (CV < 20%) were obtained for atrazine, chlorpyrifos, alpha- and beta endosulfan, endosulfan sulfate, flutriafol, malathion, metolachlor and permethrin. Method detection ranged from 9.0 to 17.9 ng m-3. This method was applied to 61 gas phase samples collected between December 2008 and June 2009. Atrazine and endosulfan were detected both in urban and rural areas indicating the importance of atmospheric dispersion of pesticides in tropical areas. The simple and efficient extraction method and sampling system employed was considered suitable for identifying pesticides in areas of intense agricultural production. PMID- 21328124 TI - Urinary dialkyl phosphate levels before and after first season chlorpyrifos spraying amongst farm workers in the Western Cape, South Africa. AB - The study investigated urinary levels of dialkyl phosphates resulting from pesticide exposure amongst 40 farm workers. Workers were tested (urinary dialkyl phosphate levels, anthropometry, short exposure questionnaire) before and after the first day of seasonal chlorpyrifos spraying. Median baseline urinary dialkyl phosphates was high amongst both non-applicators (1587.5 MUg/g creatinine, n = 8) and applicators (365.6 MUg/g creatinine, n = 9). There was not much evidence of an increase in post-spray dialkyl phosphates levels from pre-spray levels amongst both applicators and non-applicators. Hours mixing, spraying, driving a tractor and hours worked by non-applicators were not significantly associated with an increase in post-spray dialkyl phosphate levels, adjusting for age, height, weight, gender, use of empty pesticide containers and self-reported kidney problems. Past applicator status was weakly positively associated with pre-spray dialkyl phosphate levels adjusting for age, height, weight, and gender, self reported kidney problems, smoking and alcohol (beta= 1019.5, p = 0.307, R2 = 0.28). The high dialkyl phosphate levels call for an epidemiological investigation into the health effects of organophosphorous pesticides. PMID- 21328125 TI - Isolation of a selected microbial consortium capable of degrading methyl parathion and p-nitrophenol from a contaminated soil site. AB - A bacterial consortium with the ability to degrade methyl parathion and p nitrophenol, using these compounds as the only carbon source, was obtained by selective enrichment in a medium with methyl parathion. Samples were taken from Moravia, Medellin; an area that is highly contaminated, owing to the fact that it was used as a garbage dump from 1974 to 1982. Acinetobacter sp, Pseudomonas putida, Bacillus sp, Pseudomonas aeruginosa Citrobacter freundii, Stenotrophomonas sp, Flavobacterium sp, Proteus vulgaris, Pseudomonas sp, Acinetobacter sp, Klebsiella sp and Proteus sp were the microorganisms identified within the consortium. In culture, the consortium was able to degrade 150 mg L-1 of methyl-parathion and p-nitrophenol in 120 h, but after adding glucose or peptone to the culture, the time of degradation decreased to 24 h. In soil, the consortium was also able to degrade 150 mg L-1 of methyl parathion in 120 h at different depths and also managed to decrease the toxicity. PMID- 21328126 TI - Characterization of microbial consortia that reductively dechlorinate 4 chlorophenol and transform phenol to benzoate enriched from estuarine sediment of Lake Shinji. AB - Monochlorophenols were degraded to benzoate via phenol by the initial dechlorination and the subsequent conversion of phenol to benzoate in anaerobic sediment samples of estuarine Lake Shinji under methanogenic conditions. To characterize bacteria that dechlorinate 4-chlorophenol and transform phenol to benzoate, we analyzed the microbial community structure of the enrichment culture with each 4-chlorophenol and phenol by the limiting dilution method with polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) of 16S rRNA gene. After serial dilution of the culture, the 4-chlorophenol dechlorinating culture consisted of two dominant bacteria, one of which was most homologous with Dehalobacter sp. In the enriched culture with phenol, minor band homologous with Cryptanaerobacter phenolicass corresponded to the transformation activity. PMID- 21328127 TI - Comparison of two sample preparation methods for analysis of organochlorine pesticides residues in fish muscle. AB - The aim of this study was to compare recoveries of organochlorine pesticides (heptachlor, alpha-HCH, beta-HCH, gamma-HCH, op'-DDD, pp'-DDD, pp'-DDE, op'-DDT, pp'-DDT) from fish muscle dried by two alternative methods: (i) grinding with anhydrous sodium sulphate and (ii) freeze drying. Pesticide residues content was determined by gas chromatography-mass spectrometry (GS-MS) method. For four pesticides (gamma-HCH, alpha-HCH, heptachlor and pp;-DDD) in four of five fish species, higher recoveries were obtained from the freeze-dried samples. For five remaining pesticides, correlations between fish species and drying method were not found. The results of this study do not clearly indicate which drying method caused lower losses of analytes. Recoveries from the freeze-dried samples ranged from 69.9 to 117.6 %, while recoveries from the samples ground with sodium sulphate varied from 64.4 to 126.7 %. Either of the methods gave satisfactory recoveries and they both can be used interchangeably. PMID- 21328129 TI - Antibacterial activity of 15-deoxygoyazensolide isolated from the stems of Minasia alpestris (Asteraceae) against oral pathogens. AB - This work reports the isolation of the sesquiterpene lactone 15 deoxygoyazensolide from the stems of Minasia alpestris and the evaluation of its antimicrobial activity against the following oral pathogens: Enterococcus faecalis, Streptococcus salivarius, Streptococcus sobrinus, Streptococcus mutans, Streptococcus mitis, Streptococcus sanguinis, and Lactobacillus casei. Despite the cytotoxicity and genotoxicity of other sesquiterpene lactones of the furanoheliangolide-type, our results revealed that this compound exhibits low antibacterial activity against the evaluated oral pathogens; however, an interesting selectivity against E. faecalis (minimum inhibitory concentration [MIC]=40 ug mL(-1)) and S. sobrinus (MIC=60 ug mL(-1)) was observed. PMID- 21328130 TI - Apoptosis and membrane permeabilisation induced by macranthoside B on HL-60 cells. AB - Triterpene saponins are throught to be potential anti-tumour agents in many cell types. This study aims to evaluate the cytotoxic activity and mechanism of a triterpene saponin, macranthoside B (MB), isolated from Lonicera macranthoides Hand.-Mazz. (Caprifoliaceae). A cell viability assay showed that MB inhibited cell growth of a panel of six cancer cell lines, especially in human acute promyelocytic leukaemia HL-60 cells, with an IC50 value of 3.8 umol. A hypodiploid cells assay and an annexin-V-FITC/PI double staining assay showed a significant increase of apoptosis in a dose-dependent manner on HL-60 cells both 24 and 48 h after MB treatment. MB-induced apoptosis was through the caspase mediated pathway, by activation of caspase-3. Furthermore, a lactate dehydrogenase (LDH) release test suggested that an MB-cholesterol interaction led to the rearrangement of the lipid bilayer and to subsequent cell membrane impairment. Taken together, these findings demonstrate that MB may exhibit cytotoxic activity against HL-60 cells by inducing apoptosis via caspase dependent pathways and also membrane permeabilisation. PMID- 21328131 TI - Modulation of pancreatic beta-cells in neonatally streptozotocin-induced type 2 diabetic rats by the ethanolic extract of Momordica charantia fruit pulp. AB - Effective doses of the Momordica charantia fruit pulp (MCF) ethanolic extract on pancreatic beta-cells modulation in neonatally streptozotocin-induced type 2 diabetic rats were studied. Diabetic rats (n=8) were treated with MCF extract (400 mg kg(-1) day(-1)) or glibenclamide (5 mg kg(-1)) for 28 days. Control rats (n=11) and untreated diabetic rats (n=8) received only water. Fasting glucose, serum insulin (by ELISA) and beta-cell function (HOMA %B by homeostasis model assessment) were measured. beta- and alpha-cells were identified by immunostaining, nuclei by DAPI, and beta-cell size and number by morphometry. Significant improvement of fasting blood glucose, serum insulin and beta-cell function was observed with the MCF extract for the diabetic rat model. The islet size, total beta-cell area and number of beta-cells were increased to almost double in the diabetic rats treated with MCF extract as compared to the untreated diabetic rats. The number of alpha-cells did not change significantly. Insulin granules in beta-cells were notably reduced in diabetic islets as compared to control islets. However, extract-treated diabetic rat beta-cells were abundant with insulin granules, which was comparable to non-diabetic control islets. The modulation of pancreatic beta-cells may be involved in the experimental observation of anti-diabetic effects of M. charantia extract. PMID- 21328132 TI - Anti-allergic effect of the flavonoid myricitrin from Myrica rubra leaf extracts in vitro and in vivo. AB - Flavonoids are ingested by the general population as anti-oxidant and anti inflammatory agents. In this study, we investigated the effects of myricitrin, a flavonoid rich in Myrica rubra leaf, upon anti-inflammatory action. Myrica rubra leaf extracts inhibited pro-inflammatory TNFalpha production in a macrophage cell line, Raw264.7 cells. We observed that the serum IgE levels in the leaf extract treated DO11.10, a mouse allergy model, were down-regulated. HPLC was performed to demonstrate that M. rubra leaf extracts contain a large amount of myricitrin. We observed an inhibitory effect of HPLC-purified myricitrin on TNFalpha production in Raw264.7 cells. Thus, myricitrin may be of potential interest in the management of inflammatory conditions. PMID- 21328133 TI - Isolation and identification of 2-isopropyl-5-methylphenol from Stellera chamaejasme and its insecticidal activity against Aphis craccivora and Pieris rapae. AB - In this study, the root powder of Stellera chamaejasme was extracted with chloroform. The crude extract thus obtained was chromatographed several times with silica gel columns and finally one pure natural product was obtained. This product was identified as 2-isopropyl-5-methylphenol (thymol), which was separated for the first time from S. chamaejasme root. The results of a laboratorial bioassay showed that it had good insecticidal activity against Aphis craccivora and Pieris rapae. Its median lethal concentrations (LC50) (24 h after treatment) were 14.81 and 47.68 mg L(-1), respectively. This is the first time that the insecticidal activity of thymol against A. craccivora and P. rapae has been reported. PMID- 21328134 TI - Management of Parthenium hysterophorus (Asteraceae) by Withania somnifera (Solanaceae). AB - This study was designed to evaluate the herbicidal activity of Withania somnifera (L.) Dunal against the noxious weed parthenium (Parthenium hysterophorus L.). In a laboratory bioassay, the effect of aqueous, methanol and n-hexane shoot and root extracts of 5%, 10%, 15% and 20% w/v concentrations (on a fresh weight basis) of W. somnifera were tested against the germination and seedling growth of parthenium. In general, aqueous and methanol extracts markedly suppressed the germination, root and shoot growth of parthenium. The shoot extracts were more inhibitory than the root extracts. In a foliar spray bioassay, the aqueous and methanol shoot extracts of 10% w/v (on a dry weight basis) concentration were sprayed on 1-week and 2-week-old pot-grown parthenium seedlings. Two subsequent sprays were carried out 5 and 10 days after the first spray. The aqueous and methanol extracts significantly reduced the length and biomass of parthenium shoots. In a soil amendment bioassay, the crushed shoots of W. somnifera were incorporated in the soil at 1-5% w/w. Parthenium seeds were sown one week after the residue incorporation and plants were harvested 40 days after sowing. All the soil amendment treatments significantly reduced seed germination by 43-89%. The highest dosages of 4% and 5% significantly suppressed the root and shoot biomasses of parthenium. This study concludes that foliar spray of aqueous and methanol extracts, and soil amendment with leaf residue of W. somnifera, can control the germination and growth of parthenium, one of the world's worst weeds. PMID- 21328135 TI - On the antibacterial activity of roots of Capparis spinosa L. AB - A decoction of Capparis spinosa L. roots, widely used in the traditional folk medicine of southern Italy, was prepared and submitted to antibacterial activity tests, which showed an interesting bacteriostatic activity on the growth of Deinococcus radiophilus. Heterocyclic compounds were also recovered from the chloroformic extract of the roots. PMID- 21328136 TI - Weight-reducing effect of Acer truncatum Bunge may be related to the inhibition of fatty acid synthase. AB - In order to study the anti-obesity ability and inhibition towards fatty acid synthase (FAS) of the extract, a 70% ethanol extract of Acer truncatum Bunge (AT) leaves was further extracted with ethyl acetate. FAS is a very significant lipogenic enzyme, participating in energy metabolism in vivo; it has also been observed that FAS inhibitors might be potent anti-obesity agents. Experimental results on animals showed that the extract significantly reduced food intake and adipose, and effectively controlled weight evolution. Lipogenesis inhibition might be regarded as one of the reasons for the weight control and adipose reduction by AT. The extract was further isolated using a series of column chromatography that yielded 10 known compounds. 1,2,3,4,6-Penta-O-galloyl-beta-D glucose was found to be one of the major active constituents in the extract of AT. PMID- 21328137 TI - Antimicrobial activities of the CH2Cl2-CH3OH (1:1) extracts and compounds from the roots and fruits of Pycnanthus angolensis (Myristicaceae). AB - This study was designed at evaluating the antimycobacterial, antibacterial and antifungal activities of the CH2Cl2-CH3OH (1:1) extracts and isolated compounds, namely 3,4-dimethoxy-3',4'-methylenedioxy-7,7'-epoxylignan (1), genkwainin (2), pycnanthulignene C (3), 4,5-dimethoxy-3',4'-methylenedioxy-2,7'-cycloligna-7,7' diene (4), pycnanthulignene A (5) from the roots, and calycosin (6), biochanin A (7) and prunetin (8), from the fruits of Pycnanthus angolensis. The microplate alamar blue assay and the broth microdilution method were used to determine the minimal inhibitory concentration (MIC) and minimal microbicidal concentration of the samples. The H+-ATPase-mediated proton pumping assay was used to evaluate one of the possible mechanisms of action of the extracts and isolated compounds. The results of MIC determinations showed that the extract from roots was able to prevent the growth of all the studied organisms, including mycobacteria, fungi, and Gram-positive and Gram-negative bacteria. All tested compounds showed antimicrobial activities to different extents, compound 1 and 8 exhibiting the best antimicrobial spectrum, with 92.3% of the tested organisms being sensitive. The results obtained in this study also showed that the extracts as well as most of the compounds were able to inhibit the H(+)-ATPase activity. The overall results provided evidence that P. angolensis and some of its components might be potential sources of antimicrobial drugs against tuberculosis, bacterial and fungal diseases. PMID- 21328138 TI - Antibacterial, antifungal, antispasmodic and Ca++ antagonist effects of Caesalpinia bonducella. AB - Caesalpinia bonducella F. (Leguminosae) has been used as a folk medicine for a variety of ailments. The crude extract of C. bonducella and its fractions were studied for antibacterial, antifungal, antispasmodic and Ca++ antagonistic properties. The strongest antibacterial effect was displayed by the n-butanol (72%) and ethyl acetate (80%) fractions, followed by the crude extract (46% and 42%), against Escherichia coli and Bacillus subtilis, respectively. The plant extract and its fractions showed mild to excellent activity in antifungal bioassays, with maximum antifungal activity against Candida glaberata (80%) and Aspergillus flavus (70%) by the n-butanol and chloroform fractions, followed by the crude extract (70% and 65%). Caesalpinia bonducella extract caused concentration-dependent inhibition of spontaneous and high K+ (80 mM)-induced contractions of isolated rabbit jejunum preparations, similar to that caused by Verapamil. These results indicate that C. bonducella exhibits antibacterial, antifungal, spasmolytic and Ca++ channel blocking actions. PMID- 21328139 TI - Antidepressant activity of Ceratonia siliqua L. fruit extract, a source of polyphenols. AB - A previous study from our laboratory has shown the facilitatory effect of Ceratonia siliqua L. (Fabaceae) on the dopaminergic function. This study investigates the involvement of monoamines in the antidepressant activity of the total polyphenol content of Ceratonia siliqua extract (CS) in mice using a tail suspension test (TST) and forced swim test (FST). The immobility time in the TST and FST were significantly reduced by CS (25 and 50 mg kg(-1), i.p.). The extract considerably attenuated the duration of immobility induced by prazosin (62.5 ug kg(-1), i.p., an alpha-adrenoceptor antagonist) and eticlopride (0.1 ug kg(-1), i.p., a classical D2-like dopamine receptor antagonist) in both TST and FST, whereas the extract could not modify the immobility in mice treated with p chlorophenylalanine (100 mg kg(-1), i.p., *3 days; an inhibitor of serotonin synthesis) and baclofen (10 mg kg(-1), i.p., GABAB agonist). This suggests that the antidepressant effect of CS is mediated by dopamine and noradrenaline. PMID- 21328140 TI - Microcalorimetric study of the effect of Benzoinum and Styrax on the growth of Escherichia coli. AB - In this study, the effects of Benzoinum and Styrax on Escherichia coli (E. coli) growth were investigated by microcalorimetry. Using a TAM Air Isothermal Calorimeter, ampoule method, the power-time curves of E. coli growth at 37 degrees C affected by Benzoinum and Styrax were measured. By analysing some quantitative thermokinetic parameters, such as growth rate constants k, the maximum heat-out power Pm, the time of the maximum heat-out power tm, the total heat production Qt and inhibitory ratio I, one could find that low concentrations (0-3.9 mg mL(-1)) of Benzoinum and Styrax had stimulation effects on E. coli growth, and high concentrations (7.8-125.0 mg mL(-1)) of these two drugs would inhibit the growth of the bacteria. The antibacterial effects of Benzoinum and Styrax can also be expressed as half inhibitory concentration IC50. The IC50 values for Benzoinum and Styrax are 78.5 and 88.0 mg mL(-1), respectively, which suggests that the antibacterial effect of Benzoinum on E. coli was much stronger than that of Styrax. This study provides a useful method to investigate the effects of herbal medicines on microbes. It also supplies some references for the application of Benzoinum and Styrax in clinical treatment. PMID- 21328141 TI - Modulation effect of Semen Ziziphi Spinosae extracts on IL-1beta, IL-4, IL-6, IL 10, TNF-alpha and IFN-gamma in mouse serum. AB - This study aims to explore and evaluate the effects of Semen Ziziphi Spinosae extracts on the serum levels of interleukin (IL)-6, IFN-gamma, IL-1beta, TNF alpha, IL-10 and IL-4 in mice, and the regulative effect of Semen Ziziphi Spinosae on the cytokine system. Using an ELISA assay, the serum levels of IL-6, IFN-gamma, IL-1beta, TNF-alpha, IL-10 and IL-4 were examined in mice after intraperitoneal injection (i.p.) with Semen Ziziphi Spinosae extracts. The results showed that the levels of IL-6 and IL-1beta were significantly increased compared with the control groups (p<0.01), while the level of tumour necrosis factor-alpha (TNF-alpha) was significantly decreased (p<0.01). Semen Ziziphi Spinosae possesses certain modulation effects on cytokines, and the immuno regulating function and hypnosis effects of Semen Ziziphi Spinosae may be relevant to these modulation effects on cytokines. PMID- 21328142 TI - Health locus of control and health behaviour: results from a nationally representative survey. AB - The present study aims to examine the association between sociodemographic variables and health locus of control (HLC) as well as HLC and health behaviour. Data from a representative sample of the German adult population, the Telephone Health Survey 2006 (GSTel06; N=5542), were used. A German version of the MHLC (multidimensional HLC) scales was used. Associations between sociodemographic variables and three dimensions of HLC (internal, powerful others and chance) and between HLC and health behaviour were calculated. In particular, higher age, low socioeconomic status and migration background were associated with higher HLC scores on the powerful others and chance dimension. Subjects scoring high on the chance dimension did less sports activity (OR: 0.8; CI: 0.7-0.9), had less medical teeth protection (0.7; 0.6-0.9), fewer health courses (0.8; 0.7-0.9) and conducted less systematic information-seeking (0.8; 0.6-0.9), while results regarding internal and powerful others HLC remained mainly insignificant. High chance HLC can be regarded as risk factor of adequate health behaviour. The associations between high chance HLC, low socioeconomic status and migration background emphasise the need for treatments and prevention programmes tailored to modify the high chance HLC of socially disadvantaged populations. PMID- 21328143 TI - Improving adolescent contraceptive use: evaluation of a theory-driven classroom based intervention. AB - The aim of the research was to evaluate the impact of intervention materials, designed to enhance self-efficacy and anticipated regret, on contraceptive behaviour and antecedents of contraceptive use in a sample of adolescents. It was hypothesised that materials designed to enhance self-efficacy and anticipated regret would lead to improvements in outcome measures compared with controls. A 4(intervention condition) * 3(time) mixed design was used to assess the impact of intervention materials. Participants (N = 414) were recruited from five secondary schools in the north of England. They were assigned to an active control group, an anticipated regret (AR) manipulation, a self-efficacy (SE) manipulation or both AR and SE manipulations. Outcome measures included psychological antecedents of contraceptive behaviour change, intentions and behaviour. Multivariate analysis of variance (MANOVA) revealed increases across several outcome measures over time (F[14,287] = 8.99, P < 0.001, eta(p)(2) = 0.305) including intentions, but these did not differ by condition (F[42,852] = 1.35, P = 0.07, eta(p)(2) = 0.062). There was evidence that the questionnaires may have caused reactivity in participants. Amongst sexually active participants with relatively low levels of intention to use contraception at the outset, increases in several outcome measures including intention and behaviour were observed (F[3,35] = 10.359, P < 0.001, eta(p)(2) = 0.47). Findings support the potential for effective delivery of behaviour change theory-driven interventions in classroom settings. The possibility that the questionnaires may have acted as a form of intervention contributes to recent discussion of this issue in the literature, and the findings also strengthen the case for post-decisional and behavioural skills interventions to enhance behaviour amongst those already motivated to use contraception. PMID- 21328144 TI - Feasibility of telephone-based cognitive behavioral therapy targeting major depression among urban dwelling African-American people with co-occurring HIV. AB - Given the burden of depression among those with HIV, and the impact of HIV on urban minority communities there is an urgent need to assess innovative treatment interventions that not only treat depression but do so in a way that allows for increased access to mental health care. This single site, uncontrolled, pilot study sought to determine the feasibility and depression outcomes of an 11 session telephone-based cognitive behavioral therapy intervention delivered over 14 weeks targeting low-income, urban-dwelling, HIV-infected African-American people with major depression. The diagnosis of major depression was made using the Mini International Neuropsychiatric Interview. The primary outcome was the Hamilton Depression Rating Scale (HAM-D) and the secondary outcome was the Quick Inventory of Depression Symptomatology-Self Report (QIDS-SR). Feasibility and satisfaction were also assessed. Assessments occurred at baseline, midpoint and at study conclusion (14 weeks). Fifteen people were screened for the study. Six HIV-infected, low-income, African-American people individuals (five females and one male) were eligible and participated in the study. All patients finished the study. On average, participants completed nine sessions. The sessions lasted for an average of 48 min (SD = 11.5). Compared to mean HAM-D score at baseline (HAM-D = 22.8 (SD = 3.1), the mean HAM-D score was significantly reduced at study conclusion (HAM-D = 9.8 (SD = 7.4); (t (5) = 4.6, p = 0.006); (Cohen d = 1.9)). Compared to the mean QIDS-SR score at baseline (QIDS-SR = 15.5 (SD = 4.2) the mean QIDS score was significantly reduced at study conclusion (QIDS = 7.0 (SD = 5.4);(t (5) = 3.2, p = 0.02); (Cohen d = 1.3)).The mean satisfaction scores across all participants at post-treatment was 5.7 (SD = 0.3) with of a maximum score of 6. Telephone-based CBT can be delivered to low-income, urban-dwelling ethnic minority HIV-infected people resulting in significant reductions in depression symptoms with high satisfaction. The efficacy of this intervention will be assessed in a planned randomized control trial. PMID- 21328145 TI - Influence of patients' self-respect on their experience of feeling respected in doctor-patient interactions. AB - The study aimed to investigate the effect of patients' self-respect on their experience of feeling respected in doctor-patient interactions. It also explored influences of different behaviours of doctors on patients' experience of feeling respected. Forty-five participants were invited to identify with either a respect worthy or non-respect worthy self-description in random order and subsequently, to watch a series of ten video clips of doctor-patient interactions, while imagining they were the patients depicted. The video clips were designed to illustrate five behaviours of doctors that varied in terms of respectfulness. After watching each one, participants indicated how respected they felt on a visual analogue scale. Results showed a significant main effect of self description on participants' feelings of being respected. Differences between the effects of doctors' behaviours on participants' feelings of being respected were also observed. The study thus showed that patients' self-respect is likely to have an impact on how respected they feel when interacting with their doctor. Implications of this for the quality of the doctor-patient relationship and patient health outcomes are raised. Implications of the respect shown by doctors are also discussed. PMID- 21328146 TI - Short-term effects of a multi-disciplinary cardiac rehabilitation programme on psychological well-being, exercise capacity and weight in a sample of obese in patients with coronary heart disease: a practice-level study. AB - Given that many patients referred to cardiac rehabilitation (CR) are obese, diet therapy, exercise training, nutritional and psychological counselling for both obesity and psychological distress should be included as important components in all CR programmes. In this practice-level, observational study we evaluated the short-term within-group effects of a four-week multi-factorial inpatient CR programme specifically addressed to weight loss, fitness improvement and psychological health increase on 176 obese in-patients with coronary heart disease (CHD). Outcome measures were exercise capacity measured with estimated metabolic equivalents (METs), body mass index (BMI) and psychological well-being (PGWBI). Results show statistically significant improvements in all the PGWBI sub scales and total score, except in general health (p = 0.393). No moderation effects were found for BMI class, age, diabetes and ejection fraction (EF). METs significantly increased by 30.3% (p < 0.001) and BMI decreased by 1.37 points (p < 0.001). Significant correlations were found between BMI and weight reductions with PGWBI anxiety and total score improvements. This multi-disciplinary CR programme including diet therapy, exercise training and psychological counselling provides indication for short-term within-group effectiveness on functional exercise capacity, BMI and PGWBI in a sample of obese in-patients with CHD. However, controlled studies are needed to corroborate the results we found. PMID- 21328147 TI - Food meanings in HIV and AIDS caregiving trajectories: ritual, optimism and anguish among caregivers in Lesotho. AB - The article describes the caregiving responsibility to provide food for chronically ill family members and the meanings attached to food and eating when ill created stress for family caregivers. The results come from a qualitative phenomenological study using in-depth interviews with 21 family caregivers of chronically ill HIV and AIDS patients in one district in Lesotho. Analysis of the interview data showed that the caregivers attached profound meanings to food and feeding care recipients. Their perceptions about food as part of family life and caring, the role of food and eating in curbing disease progression, the link between food and medical efficacy and the link between food and life led to ritualized behaviour around food, and moments of optimism and anguish in caregiving. Patients' behaviour in relation to food was in most instances inconsistent with the caregivers' goals, thus leading this aspect of caregiving to induce stress. Services intended to support home-based caregivers and patients could contribute to the reduction of stress associated with food through suitably tailored food assistance and professional support to caregivers to enhance their competences and understanding of the dynamics of food intake as AIDS progressed. PMID- 21328148 TI - Mothers continuing bonds and ambivalence to personal mortality after the death of their child--an interpretative phenomenological analysis. AB - The main objective of this study was to identify how bereaved mothers describe their coping strategies in their own words. The literature on parental bereavement is sparse, and the present study aims to add to existing knowledge by eliciting the mothers' experiences covering a wide range of child ages including infants, younger children and adults. Semi-structured interviews were held with 13 bereaved mothers in the UK. Causes of death include accident, illness and suicide. The methodological approach was interpretative phenomenological analysis (IPA). This article reports two inter-related recurrent themes: (1) Continuing the bond with the deceased child and (2) Ambivalence to personal mortality. Participants reported that the relationship with their child was continued in a variety of ways, from tending to the grave and the child's remains, through linking objects or by establishing a symbolic representation of the child within their daily lives. All mothers talked openly about their own mortality, either demonstrating ambivalence about their own death, or expressing clear suicidal ideation. Death was seen as a release from living with the pain of loss. The presence of surviving siblings appeared to moderate suicidal ideation, but mothers expressed concerns about their ability to care adequately for other family members during times of intense grief. PMID- 21328149 TI - Alexithymia in chronic urticaria patients. AB - Alexithymia has been described as an important dimension in several medical and psychiatric diseases. Chronic urticaria (CU) is a chronic condition, in which treatment is difficult. Our aim is to determine the prevalence of alexithymia traits in patients with CU, and to identify the relationships between alexithymia and psychological variables and quality-of-life dimensions. Fifty-five sequential CU patients in a faculty ambulatory specialized consultation, with an average age of 44.92, were compared with 31 healthy volunteers. Both groups were studied by means of validated scales for alexithymia (Toronto Alexithymia Scale [TAS-20]), attachment (Adult Attachment Scale-R [AAS-R]), psychopathology (Brief Symptom Inventory [BSI]), personality dimensions (The NEO Five-Factor inventory [NEO FFI]) and quality of life (Short Form-36 [SF-36]). The classification of CU reactions was obtained from the patient's history, physical examination, laboratory assessment and histopathologic findings. All the patients were under treatment with sedating H1-antihistamines, non-sedating H1-antihistamines combination of H1 and H2 blocker, 2 H1-antihistamines and 3 H1-antihistamines. High traits of alexithymia were found on CU patients (56.9%) as well as high symptom rates of anxiety. Alexithymia traits were significantly positively correlated with insecure attachment styles, with psychopathological symptoms, and with the defense mechanism turn against self. We also reported a significant negative correlation between alexithymia traits and the dimensions of quality of life. Insecure attachment styles were positively correlated with psychopathological symptoms and negatively correlated with quality of life. We did not find significant statistical correlations between alexithymia and clinical variables. CU patients present serious difficulty in dealing with emotion arousal. There is strong evidence of a psychosomatic specificity in CU, with marked alexithymic traits. PMID- 21328150 TI - Is social isolation/alienation confounded with, and non-independent of, emotional distress in its association with early onset of coronary artery disease? AB - Both emotional distress (ED) and social isolation/alienation (SI/A) have been found to prospectively predict adverse cardiac events, but few studies have tested the confounding/redundancy of these measures as correlates/predictors of outcomes. In this study, 163 patients with documented coronary artery disease (CAD) were interviewed for multiple indices of SI/A and administered the Symptom Checklist 90 - Revised (SCL90R). A spouse or friend provided an independent rating of ED using the spouse/friend version of the Ketterer Stress Symptom Frequency Checklist (KSSFC). The measures of ED and SI/A covaried. All three scales from the KSSFC (depression, anxiety, and "AIAI" - aggravation, irritation, anger, and impatience), and three scales from the SCL90R (anxiety, depression, and psychoticism), were associated with early Age at Initial Diagnosis (AAID) of CAD. Neither three scales derived from the SCL90R (shyness, feeling abused, and feeling lonely) nor the interview indices of SI/A (married, living alone, having a confidant, self description as a lone wolf, and self-description as lonely) were associated with early AAID. Thus, it is concluded that the present results indicate that ED and SI/A are confounded and that, even when tested head-to-head in a multivariate analysis, only ED is associated with AAID. PMID- 21328151 TI - Challenging the myth of the irrational dairy farmer; understanding decision making related to herd health. AB - Veterinarians working with dairy cows are suggested to refocus their efforts from being task-oriented providers of single-cow therapy and develop themselves into advice-oriented herd health management advisors. The practising cattle veterinarian's ability to translate knowledge into on-farm application requires a profound understanding of the dairy farm as an integrated system. Consequently, educating and motivating farmers are key issues. To achieve such insight the veterinarian needs to work with several scientific disciplines, especially epidemiology and (behavioural) economics. This trans-disciplinary approach offers new methodological possibilities and challenges to students of dairy herd health management. Advisors working with dairy herd health management may sometimes experience that farmers do not follow their advice. Potentially, this could lead to the interpretation that such farmers are behaving irrationally. However, farmers who are confronted with advice suggesting a change of behaviour are placed in a state of cognitive dissonance. To solve such dissonance they may either comply with the advice or reduce the dissonance by convincing themselves that the suggested change in management is impossible to implement. Consequently, herd health management advisors must understand the fundamental and instrumental relationships between individual farmers' values, behaviour and perception of risk, to stimulate and qualify the farmer's decision-making in a way that will increase the farmer's satisfaction and subjective well-being. Traditionally, studies on herd health economics have focussed on financial methods to measure the value of technical outcomes from suggested changes in management, following the basic assumption that farmers strive to maximise profit. Farmers, however, may be motivated by very different activities, e.g. animal health and welfare or other farmers' recognition, making it impossible to provide 'one-size-fts-all' consultancy because the best decision depends heavily on the internal logic and context-bound reality on each dairy farm. Relevant information may be available, but to be implemented at farm level it has to be communicated effectively. This requires a trustworthy communicator. Consequently, veterinarians are recommended to receive training in communication; keywords in this process are dialogue and reflection. An educational framework based on science and the authors' experience is presented. The aim is to guide practising cattle veterinarians into a personal learning process considered necessary for them to be recognised by farmers as trustworthy dairy herd health advisors. PMID- 21328152 TI - What veterinarians need to know about communication to optimise their role as advisors on udder health in dairy herds. AB - The veterinary practitioner is one of the most important advisors for farmers in the field of udder health. He or she has the tools to improve udder health if farmers are motivated to do so. Many farmers think that udder health is important, but this does not always mean that management of mastitis is up to standard. Many veterinarians are of the opinion that they are unable to convince their clients of the possible profits to be gained from investing in management of mastitis. Something is required to bridge this gap. This article, based on data and experiences from The Netherlands, describes the communication issues that can be considered in order to improve the role of the veterinarian as advisor, to achieve better udder health. The outcome is beneficial for both farmers and veterinarians, the former for reasons of economics, welfare and ease of work; the latter because it creates extra, challenging work. It is concluded that the veterinary practitioner is in an ideal situation to advise and motivate farmers to improve udder health but, to do this, the means of communication need to take account of the different learning styles of farmers. The most important aspects of such communication are found to be a pro-active approach, personalisation of messages, providing a realistic frame of reference for the farmer, and use of the farmer's social environment. Importantly, all persons and organisations in a farmer's social environment should articulate the same message. PMID- 21328153 TI - Economic aspects of mastitis: new developments. AB - Good udder health is not only important for the dairy farmer but, because of increasing interest of consumers in the way dairy products are produced, also for the dairy production chain as a whole. An important role of veterinarians is in advising on production diseases such as mastitis. A large part of this advice is given around the planning of management to maintain or improve the udder health status of a farm. Mastitis is a costly disease, due to losses (a reduction of output due to mastitis) and expenditure (additional inputs to reduce the level of mastitis). Worldwide, published estimates of the economic losses of clinical mastitis range from ?61 to ?97 per cow on a farm, with large differences between farms, e.g. in The Netherlands, losses due to clinical and subclinical mastitis varied between ?17 and ?198 per cow per year. Moreover, farmers tended to underestimate these costs. This indicates that for a large proportion of farms there are many avoidable losses. In order to provide good support to farmers' decision-making, it is important to describe the mastitis setting not only in terms of disease, e.g. incidence of clinical mastitis, but also in monetary terms; and to make good decisions, it is necessary to provide the dairy farmer with information on the additional expenditure and reduced losses associated with alternative decisions. Six out of 18 preventive measures were shown to have a positive nett benefit, viz blanket use of dry-cow therapy, keeping cows standing after milking, back-flushing of the milk cluster after milking a cow with clinical mastitis, application of a treatment protocol, washing dirty udders, and the use of milkers' gloves. For those measures that included a large amount of routine labour or investment, the reduced losses did not outweigh the additional expenditure. The advisor cannot expect that measures that are cost-effective are always implemented. Reasons for this are the objectives of the dairy farmer can be other than maximisation of profit, resources to improve the mastitis situation compete with other fields of management, risk involved with the decision, economic behaviour of the dairy farmer, and valuation of the cost factors by the dairy farmer. For all decision-makers this means that, although financial incentives do have an effect on the management of mastitis, it is not always sufficient to show the economic benefits of improved management to induce an improvement of management of mastitis. PMID- 21328154 TI - Developing new veterinary services in milk quality: a review of a recent mastitis risk management co-development in Australia. AB - A new veterinary service to promote ongoing, incremental improvements in the risk management of mastitis and milk quality was developed between 2005 and 2008. This was designed to enhance the relationship between the farmer and advisor, as an extension of the Countdown Downunder programme, Australia's national mastitis and milk quality programme. This service was co-developed between the Countdown Downunder programme team and a core development group of veterinarians involved with trialling the service, and farmers and social researchers. The service, known as Countdown MAX, involved advisory input at the planning stage, a written risk management plan, multiple engagements between the farm team and advisor for tracking and re-planning, and a service fee. Risk management resources (modules) were developed to be employed at the drying-off and calving periods, and during lactation. During the development and implementation phase eight veterinary practices conducted Countdown MAX consultations on 55 farms. Eighty-eight Countdown MAX modules were delivered in total, with 55% of farms completing more than one module but only 38% of modules reviewed successfully. A social research project examined the implementation of the Countdown MAX service in participating veterinary practices during the development phase. Findings of the project were that the successful uptake of a new mastitis service into a veterinary practice was enhanced through uptake by practice owners of the concept, the formation of a written practice plan, adequate communication and explanation of the new service to all staff, logistical support for the service within the practice, and transfer of mastitis expertise within the practice. PMID- 21328155 TI - Reproductive management of dairy herds in New Zealand: attitudes, priorities and constraints perceived by farmers managing seasonal-calving, pasture-based herds in four regions. AB - AIMS: To examine attitudes, priorities, and constraints pertaining to herd reproductive management perceived by farmers managing seasonal-calving, pasture based dairy herds in four regions of New Zealand, and to explore how these varied with demographic and biophysical factors. METHODS: Key decision makers (KDM) on 133 dairy herds in four dairy regions (Waikato, Taranaki, and north and south Canterbury) were interviewed between May and July 2009. They were asked to provide demographic and biophysical data about the farm, and to rate their attitude in relation to their own personality traits, management issues and priorities, and likely constraints affecting reproductive performance in their herds. Associations between demographic factors and attitudes, priorities and constraints were analysed using univariable and multivariable proportional-odds regression models. RESULTS: Farms in the regions studied in the South Island were larger, had larger herds and more staff than farms in the regions studied in the North Island. The farms in the South Island were more likely to be owned by a corporation, managed by younger people or people who had more education, and the herds were more likely to be fed a higher percentage of supplementary feed. The majority of KDM rated the current genetics, milksolids performance and reproductive performance of their herds as high or very high, and >70% believed that the reproductive performance had remained the same or improved over the preceding 3 years. Despite this, improving reproductive performance was the most highly rated priority for the next 3 years. The constraints considered most likely to have affected reproductive performance in the last 2 years were anoestrous cows, protracted calving periods, and low body condition scores; those considered least likely were artificial breeding and heat detection. Of the variables examined related to attitudes, priorities and likely constraints, there were significant differences between region for 10/40, and with age and occupation of the KDM for 24/40 and 5/40, respectively (p<0.05). CONCLUSIONS: The majority of KDM reported the current reproductive performance of their herds to be high or very high, yet rated improving reproductive performance as a very high priority for the next 3 years. Mismatch between perceived and actual performance may result in reduced uptake of extension programmes designed to improve performance, and accurate benchmarking may help increase uptake and engagement. Further work is needed to determine whether the attitudes and perceptions about performance of farmers affect the likelihood of changes in their management behaviour which translate to measurable change in the actual reproductive performance of their herds. The variation in attitude, priorities and perceived constraints among age groups and region indicates that design of extension programmes may need to vary with these demographics. PMID- 21328156 TI - Outbreaks of pleuritis and peritonitis in calves associated with Pasteurella multocida capsular type B strain. AB - CASE HISTORY: Three dairy calf-rearing properties experienced high mortality in calves during 2008 and 2009. Affected calves were aged 13-18 weeks (Farm I), 6 months (Farm II), and 2-11 weeks (Farm III), and the mortality rate was 22/175 (13%), 5/80 (6%), and 60/900 (7%), respectively. CLINICAL AND LABORATORY FINDINGS: Affected calves rapidly became moribund, were in respiratory distress, and had a fever (40-41 degrees C). Post-mortem examination of nine calves revealed fibrinopurulent pleuritis, pericarditis, and peritonitis. This was confirmed histopathologically on tissues from three calves, one from each farm; aggregates of small Gram-negative coccobacilli were evident on Gram stain. Pasteurella multocida was cultured from tissues from affected calves on the three farms, and PCR of DNA extracted from tissue samples amplified cap-sular type B specific DNA. Multi-locus sequence typing (MLST) demonstrated that all capsular type B isolates belonged to the same sequence type (ST), ST62, but did not belong to serotype B:2, the only B serotype classified as causing haemorrhagic septicaemia by the Office International des Epizooties (OIE). DIAGNOSIS: Pleuritis and peritonitis due to infection with P. multocida capsular type B strain. CLINICAL RELEVANCE: Haemorrhagic septicaemia was excluded as a cause of disease from the three farms, however P. multocida was the primary agent in the affected calves. It is possible the agent has been present in New Zealand for some time but not reported, as there had been no transfer of animals between affected farms. Emergence of the syndrome could potentially be a result of factors other than just the presence of the organism, such as changing management. The syndrome described may be of increasing importance in the future. PMID- 21328157 TI - Surgical treatment of osteomyelitis and formation of a sequestrum in the distal metaphysis of the humerus in an alpaca cria. AB - CASE HISTORY: An 8-week-old, 16-kg alpaca cria was presented with a 2-week history of acute onset of left forelimb lameness. CLINICAL FINDINGS: The cria was weight-bearing but lame at the walk in the left forelimb. There was swelling, heat and pain on palpation of the soft tissues, extending from the mid-shaft of the humerus to the elbow. There was no evidence of a traumatic injury. Radiologically, there was evidence of osteomyelitis and a sequestrum involving the distal metaphysis of the humerus. The sequestrum was removed surgically. No bacteria were cultured from samples taken during surgery. After an initial improvement, the cria became acutely lame, and developed an abscess at the surgical site, which was drained. A pure growth of a strictly anaerobic, Gram negative, non-spore-forming, pleomorphic, filamentous rod was cultured from fluid from the abscess. Further radiographs suggested a second sequestrum was present, and this was removed surgically. Apart from partial dehiscence of the wound, the cria recovered well, and was sound and without complications 18 months after surgery. DIAGNOSIS: Osteomyelitis and formation of sequestra in the distal metaphysic of the left humerus. CLINICAL RELEVANCE: There has only been one case of osteomyelitis and bone sequestration without evidence of trauma in alpaca crias reported in the literature. However, anecdotal reports by veterinary practitioners described similar cases of osteomyelitis and bone sequestration, usually affecting the long bones. Further investigation of osteomyelitis and bone sequestration in crias is needed, to define the incidence, determine the pathogenesis, and develop specific recommendations for prevention and treatment. PMID- 21328158 TI - Heterotopic ossification in combat amputees from Afghanistan and Iraq wars: five case histories and results from a small series of patients. AB - Heterotopic ossification (HO) is excess bone growth in soft tissues that frequently occurs in the residual limbs of combat amputees injured in Operation Iraqi Freedom and Operation Enduring Freedom, or Iraq and Afghanistan wars, respectively. HO can interfere with prosthetic use and walking and delay patient rehabilitation. This article describes symptomatic and/or radiographic evidence of HO in a patient series of combat amputees rehabilitating at a military amputee care clinic (27 patients/33 limbs). We conducted a retrospective review of patient records and physician interviews to document evidence of HO symptoms in these limbs (e.g., pain during prosthetic use, skin breakdown). Results showed HO related symptoms in 10 of the 33 residual limbs. Radiographs were available for 25 of the 33 limbs, and a physician identified at least moderate HO in 15 of the radiographs. However, 5 of the 15 patients who showed at least moderate radiographic HO did not report adverse symptoms. Five individual patient histories described HO onset, symptoms, treatments, and outcomes. These case histories illustrated how HO location relative to pressure-sensitive/pressure tolerant areas of the residual limb may determine whether patients experienced symptoms. These histories revealed the uncommon but novel finding of potential benefits of HO for prosthetic suspension. PMID- 21328159 TI - Falls requiring medical attention among veterans with multiple sclerosis: a cohort study. AB - The purpose of this study was to estimate the relative risk of an injurious fall requiring medical attention in veterans with multiple sclerosis (MS) compared with veterans without MS after controlling for sex, age, and healthcare use. The sample included 195,417 veterans treated at Veterans Health Administration (VHA) facilities in the Northwest United States in fiscal year 2008. We obtained information regarding MS diagnosis, injurious falls (operationalized as International Classifi cation of Diseases-9th Revision-Clinical Modification codes E880-E888), and demographic and healthcare use data from the VHA Consumer Health Information Performance Set database. Using logistic regression, we determined the adjusted odds ratio (OR) of an injurious fall to be three times higher in female veterans with MS than in female veterans without MS (OR = 3.0, 95% confidence interval [CI] = 1.6-5.5). The adjusted OR of an injurious fall for men with MS was also higher than for men without MS, but this difference was not statistically significant (OR = 1.2, 95% CI = 0.8-2.1). We recommend further studies evaluating the medical, social, and economic consequences of injurious falls, as well as interventions to prevent injurious falls, to improve the independence and quality of life of veterans and others living with MS. PMID- 21328160 TI - Validity of PTSD diagnoses in VA administrative data: comparison of VA administrative PTSD diagnoses to self-reported PTSD Checklist scores. AB - Little research has been done on the validity of posttraumatic stress disorder (PTSD) diagnoses that are found in Department of Veterans Affairs (VA) administrative data, even though they are often used in VA research. We compared PTSD diagnoses found in VA administrative data with PTSD Checklist (PCL) scores self-reported by 4,777 newly diagnosed participants in a national postal survey study. Using PCL scores of at least 50 as the gold standard, we compared positive predictive values (PPVs) for at least one versus at least two PTSD diagnoses (found within 4 months of the first) in VA administrative data overall and by subgroups of interest: age, sex, and clinic where first diagnosed. The overall PPV was 75% for at least one PTSD diagnosis and 82% for at least two PTSD diagnoses. Similarly, the PPV significantly increased for all subgroup analyses when at least two PTSD diagnoses were used. The increase in PPV was greatest for those first diagnosed in primary care and for those older than 65. To select a sample of veterans with more definitive PTSD from administrative data, researchers should select those veterans with at least two PTSD diagnoses as opposed to at least one. PMID- 21328161 TI - Dimensional accuracy of ankle-foot orthoses constructed by rapid customization and manufacturing framework. AB - Passive-dynamic ankle-foot orthoses (PD-AFOs) constitute a class of ankle braces that rely on material properties and physical features to establish functional characteristics such as bending or rotational stiffness. We have developed a novel framework that combines a fully parameterized PD-AFO computer-aided design (CAD) model and free-form fabrication to rapidly manufacture customized PD-AFOs. The three-dimensional locations of select anatomic landmarks serve to fit customize the PD-AFO CAD model. A virtual orthopedic alignment process and selection of discrete design parameter values further customize the orthosis, which is fabricated via selective laser sintering. CAD models were customized and full-scale orthoses were manufactured for two nondisabled subjects. The surface of one half-scale CAD model was marked with 3 mm hemispherical dimples, and four orthoses were manufactured in different build orientations and positions. Dimensional accuracy was determined by calculating discrepancies between corresponding CAD and fabricated orthoses interdimple distances. Subjective evaluations of the full-scale PD-AFOs following use in gait were positive. Dimension discrepancies were well under a 2 mm tolerance for the four half-scale orthoses. Mean foot plate, strut, and cuff component discrepancies were 0.31 +/- 0.28, 0.34 +/- 0.08, 0.52 +/- 0.39 mm, respectively, and 0.29 +/- 0.23 mm for the overall orthosis. Dimensional accuracy of the rapid customization and manufacturing framework was well within tolerances suggested in the literature. PMID- 21328162 TI - Pain neurophysiology education improves cognitions, pain thresholds, and movement performance in people with chronic whiplash: a pilot study. AB - Chronic whiplash is a debilitating condition characterized by increased sensitivity to painful stimuli, maladaptive illness beliefs, inappropriate attitudes, and movement dysfunctions. Previous work in people with chronic low back pain and chronic fatigue syndrome indicates that pain neurophysiology education is able to improve illness beliefs and attitudes as well as movement performance. This single-case study (A-B-C design) with six patients with chronic whiplash associated disorders (WAD) was aimed at examining whether education about the neurophysiology of pain is accompanied by changes in symptoms, daily functioning, pain beliefs, and behavior. Periods A and C represented assessment periods, while period B consisted of the intervention (pain neurophysiology education). Results showed a significant decrease in kinesiophobia (Tampa Scale for Kinesiophobia), the passive coping strategy of resting (Pain Coping Inventory), self-rated disability (Neck Disability Index), and photophobia (WAD Symptom List). At the same time, significantly increased pain pressure thresholds and improved pain-free movement performance (visual analog scale on Neck Extension Test and Brachial Plexus Provocation Test) were established. Although the current results need to be verified in a randomized, controlled trial, they suggest that education about the physiology of pain is able to increase pain thresholds and improve pain behavior and pain-free movement performance in patients with chronic WAD. PMID- 21328163 TI - Stability of handwriting performance following injury-induced hand-dominance transfer in adults: a pilot study. AB - The aim of this study was to quantify stability of nondominant handwriting kinematics and legibility in participants with functional loss of the previously dominant hand. Twelve adult volunteers provided two handwriting samples 6 weeks apart. Handwriting tasks (Compose a Sentence, Copy Alphabet, Copy Date, Copy Sentence, and Draw Circles) were performed in cursive writing on standard white, lined paper taped to a digitizer to record kinematic and kinetic variables of velocity, displacement, force, and on-paper time. Results showed minimal performance variability within subjects and marked variability between subjects, as well as variability between tasks for all participants. Stylistic stability of the handwriting samples was assessed by two independent evaluators. These evaluators matched all handwriting samples at test to retest times with 89%-100% accuracy, suggesting value in the "whole" handwriting sample and emphasizing the idiosyncratic nature of handwriting. Results suggest that handwriting skill stability in the previously nondominant hand varies across subjects and task demands. PMID- 21328164 TI - Development of finger-motion capturing device based on optical linear encoder. AB - This article presents the design and validation of a wearable glove-based multifinger-motion capture device (SmartGlove), specifically focusing on the development of a new optical linear encoder (OLE). The OLE specially designed for this project is compact and lightweight and has low-power consumption. The characterization tests showed that the OLE's digital out put has good linearity and is accurate. The first prototype of SmartGlove, which uses 10 OLEs to capture the flexion/extension motion of the 14 finger joints, was constructed based on the multipoint-sensing method. A user study evaluated the SmartGlove using a standard protocol and found high repeatability and reliability in both the gripped and flat-hand positions compared with four other evaluated data gloves using the same protocol. PMID- 21328165 TI - Measurement of lower-limb muscle spasticity: intrarater reliability of Modified Modified Ashworth Scale. AB - The Modified Modified Ashworth Scale (MMAS) is a clinical instrument for measuring spasticity. Few studies have been performed on the reliability of the MMAS. The aim of the present study was to investigate the intrarater reliability of the MMAS for the assessment of spasticity in the lower limb. We conducted a test-retest study on spasticity in the hip adductors, knee extensors, and ankle plantar flexors. Each patient was measured by a hospital-based clinical physiotherapist. Twenty-three patients with stroke or multiple sclerosis (fourteen women, nine men) and a mean +/- standard deviation age of 37.3 +/- 14.1 years participated. The weighted kappa was moderate for the hip adductors (weighted kappa = 0.45, standard error [SE] = 0.16, p = 0.007), good for the knee extensors (weighted kappa = 0.62, SE = 0.12, p < 0.001), and very good for the ankle plantar flexors (weighted kappa = 0.85, SE = 0.05, p < 0.001). The kappa value for overall agreement was very good (weighted kappa = 0.87, SE = 0.03, p < 0.001). The reliability for the ankle plantar flexors was significantly higher than that for the hip adductors. The intrarater reliability of the MMAS in patients with lower-limb muscle spasticity was very good, and it can be used as a measure of spasticity over time. PMID- 21328166 TI - [Quality management and documentation. First publication of the article in: General and Visceral Surgery update 2008; 2: 453-468]. PMID- 21328167 TI - [Relevance of intraocular pressure and tonometry in glaucoma]. PMID- 21328168 TI - [Biological and physical aspects of intraocular pressure]. AB - A thorough understanding of intraocular pressure homeostasis is the biological foundation for the development of new strategies to treat patients with elevated intraocular pressure or glaucoma. However, investigations on the physiology of intraocular pressure homeostasis are also important to gain more comprehensive insights into the pathogenesis of glaucoma and other diseases with associated alterations of intraocular pressure. The present review intends to give alternative insights into the biological and physical aspects of intraocular pressure regulation. The pressure-volume as well as the hydraulic model of intraocular pressure and also the relationship between ciliary blood flow and aqueous humor production, which has moved into the centre of interest because of its possible clinical relevance for glaucoma patients, will be explained. The authors Have attempted to interrelate the different aspects of intraocular pressure genesis and regulation in a comprehensive but understandable way. PMID- 21328169 TI - [Physiology of aqueous humor formation, diurnal fluctuation of intraocular pressure and its significance for glaucoma]. AB - In the human eye there is a balance between production of aqueous humor as well as its drainage. The intraocular pressure is held through different mechanisms in a stable balance. The aqueous humor is secreted by the ciliary epithelium lining the ciliary processes. Three physiological processes contribute to the formation and chemical composition of the aqueous humor: diffusion (5 %), ultrafiltration (15 %) and active secretion (80 %). The normal intraocular pressure amounts to 15 +/- 3 mmHg, the normal diurnal fluctuation 5 mmHg. Aqueous humor leaves the eye by passive bulk flow via two pathways: the trabecular route and the uveoscleral route. In glaucoma patients this balance is disturbed resulting in individual high intraocular pressure or, respectively, high diurnal fluctuations. This leads to loss of retinal ganglion cells and visual field loss. As a recommendation for glaucoma patients it is useful to construct diurnal intraocular pressure curves to evaluate the "type of pressure" and to determine the diurnal fluctuations or, respectively, the time of the pressure maxima. With this knowledge, treatment of glaucoma patients can be managed in a more individualised manner and it seems to slow down the progress of the disease better than by merely reducing the intraocular pressure. PMID- 21328170 TI - [Factors influencing applanation tonometry - a practical approach]. AB - Applanation tonometry has been the gold standard in clinical ophthalmology for more than fifty years. The most popular factor is central corneal thickness that is now routinely considered in glaucoma management. However, other individual features of the cornea can also play a key role for the interpretation of the applanation values. Other factors influencing applanation tonometry that have been well known for decades include tear film, fluorescein illumination etc., and should be kept in mind. According to the available literature the absence of a correct calibration cannot be neglected. PMID- 21328171 TI - [The effect of central corneal thickness on tonometry]. AB - Central corneal thickness (CCT) affects IOP measurements and is an independent risk factor for the development of glaucoma. IOP measurements of all common tonometers, such as the Goldmann applanation tonometer, non-contact tonometer and rebound tonometer, are affected by CCT. Nomograms to correct IOP measurements according to CCT have been established. These nomograms lead to a reduction of the measurement error caused by CCT in groups of patients. However, one has to be aware of the fact that, in individuals, the correction of IOP measurements can even increase the deviation of the IOP measurement from the actual IOP. The effect of CCT on dynamic contour tonometry and IOP (cc) measured by ORA is negligible. CCT is an important parameter in glaucoma management and needs to be considered when interpreting IOP measurements. This can be done by using nomograms or by implementing CCT in the calculation of the individual target pressure. PMID- 21328172 TI - [Techniques of intraocular pressure measurement]. AB - The correct interpretation of measured tonometric values has become more and more complex in recent years. Large clinical studies have shown that an average central corneal thickness (CCT) of 550 um can be assumed for the general population. Since the standard Glodmann applanation tonometry is based on a central corneal thickness of 520 um, mathematical correction formula have been discussed for calculation of the true intraocular pressure. Newer tonometry devices, e. g. the dynamic contour tonometry (DCT) which seems to be independent from CCT, or the Ocular Response Analyzer(r) (ORA), taking into account the biomechanical properties of the cornea, have been designed to measure intraocular pressure (IOP). In this article, several IOP measurement devices and their clinical relevance for a correct and feasible determination of the IOP are discussed. PMID- 21328173 TI - [Metrological controls for impression tonometers - ensuring quality standards in ophthalmology]. AB - BACKGROUND: Impression tonometers are not only used for fast measurements of intraocular pressure on supine patients but also during surgery on the human eye. These mechanically very delicate devices have to be checked by metrological controls according to the German Medical Devices Act ("Medizinproduktegeset") and the German Ordinance on Operators of Medical Devices ("Medizinprodukte Betreiberverordnung") every two years. These controls are carried out by independent testing agencies and are mandatory for all ophthalmologists in Germany using impression tonometers. For this purpose, special test devices have been developed by Physikalisch-Technische Bundesanstalt, Germany's national metrology institute. A large number of these test devices have been in use at private test agencies and verification offices since 1975. PROCEDURE AND METHOD: Eighteen test devices for impression tonometers from private test agencies, verification offices, or the Physikalisch-Technische Bundesanstalt were investigated. The instruments were checked for their measurement accuracy and their suitability to perform metrological controls. An impression tonometer of the Schiotz design served as reference instrument. The test devices were investigated with respect to parameters like tonometer mass, mass of the plunger lever-pointer system, plunger displacement, or correlation of the curvature between foot plate and plunger. The findings were analysed by statistic methods. RESULTS: The main outcome of the present work is the conclusion that the investigated test devices are generally suitable to perform metrological controls on impression tonometers. For certain parameters some instruments reached the error tolerances, but the majority was inside permissible limits. For one parameter (effective mass of plunger-lever-pointer system for scale value 10) the reference tonometer itself was not within permissible tolerances. This was correctly determined by all test devices. Failures of test devices due to damage or maladjustment were not observed. CONCLUSION: Test devices for impression tonometers are mechanically delicate instruments. They have to be recalibrated at fixed intervals in order to remain suitable for metrological controls. If regularly maintained and recalibrated at least every three years, even devices with an age of 20 years or more are still absolutely fit for this purpose. PMID- 21328174 TI - [New options in the therapy for neovascular age-related macular degeneration: critieria for repeat treatment in anti-VEGF therapy - current supplementary statement of the Retinological Society, The German Ophthalmological Society and the Professional Association of Ophthalmologists in Germany]. PMID- 21328175 TI - [Surgical treatment of a perforated scleral staphyloma in Wegener's granulomatosis]. PMID- 21328176 TI - [70th Birthday of Lord Univ. Prof. Dr. Herbert Kaufmann - Review and Announcement of a symposium in his honor.]. PMID- 21328177 TI - Patent literature on mosquito repellent inventions which contain plant essential oils--a review. AB - Bites Bites of mosquitoes belonging to the genera Anopheles Meigen, Aedes Meigen, Culex L. and Haemagogus L. are a general nuisance and are responsible for the transmission of important tropical diseases such as malaria, hemorrhagic dengue and yellow fevers and filariasis (elephantiasis). Plants are traditional sources of mosquito repelling essential oils (EOs), glyceridic oils and repellent and synergistic chemicals. A Chemical Abstracts search on mosquito repellent inventions containing plant-derived EOs revealed 144 active patents mostly from Asia. Chinese, Japanese and Korean language patents and those of India (in English) accounted for roughly 3/4 of all patents. Since 1998 patents on EO containing mosquito repellent inventions have almost doubled about every 4 years. In general, these patents describe repellent compositions for use in topical agents, cosmetic products, incense, fumigants, indoor and outdoor sprays, fibers, textiles among other applications. 67 EOs and 9 glyceridic oils were individually cited in at least 2 patents. Over 1/2 of all patents named just one EO. Citronella [Cymbopogon nardus (L.) Rendle, C.winterianus Jowitt ex Bor] and eucalyptus (Eucalyptus L'Her. spp.) EOs were each cited in approximately 1/3 of all patents. Camphor [Cinnamomum camphora (L.) J. Presl], cinnamon (Cinnamomum zeylanicum Blume), clove [Syzygium aromaticum (L.) Merr. & L.M. Perry], geranium (Pelargonium graveolens L'Her.), lavender (Lavandula angustifolia Mill.), lemon [Citrus * limon (L.) Osbeck], lemongrass [Cymbopogon citratus (DC.) Stapf] and peppermint (Mentha * piperita L.) EOs were each cited in > 10% of patents. Repellent chemicals present in EO compositions or added as pure "natural" ingredients such as geraniol, limonene, p-menthane-3,8-diol, nepetalactone and vanillin were described in approximately 40% of all patents. About 25% of EO containing inventions included or were made to be used with synthetic insect control agents having mosquito repellent properties such as pyrethroids, N,N diethyl-m-toluamide (DEET), (+/-)-p-menthane-3,8-diol (PMD) and dialkyl phthalates. Synergistic effects involving one or more EOs and synthetic and/or natural components were claimed in about 10% of all patents. Scientific literature sources provide evidence for the mosquito repellency of many of the EOs and individual chemical components found in EOs used in patented repellent inventions. PMID- 21328178 TI - Herbal medicines and infectious diseases: characterization by LC-SPE-NMR of some medicinal plant extracts used against malaria. AB - The extracts of two medicinal plants used in traditionalmedicine against malariawere characterized by means of an LC-SPE-NMR and LC-MS platform. The structure of a series of major constituents from Bafodeya benna, as well as minor constituents from Ormocarpum kirkii, was determined. Bafodeya benna was found to contain (2R,3R)-taxifolin-3-O-alpha-L-rhamnoside or astilbin, and its isomers neoastilbin, neoisoastilbin, and isoastilbin, as well as quercetin-3-O-alpha-L rhamnoside. From Ormocarpum kirkii, a series of known flavonoids and biflavonoids was obtained, as well as three new compounds, i.e., 7,7''-di-O-beta-D-glucosyl-( )-chamaejasmin, 7-O-beta-D-glucosyl-(I-3,II-3)-biliquiritigenin, and isovitexin (I-3,II-3)-naringenin. The isolated constituents may explain, at least in part, the traditional use against malaria. LC-SPE-NMR, in combination with LC-MS, is a powerful tool for the fast characterization of plant extracts, in order to define priorities at an early stage of a fractionation procedure. In addition, herbal medicinal products can completely be characterized, both with regard to their major as well as their minor constituents. PMID- 21328179 TI - (-)-Oleocanthal as a c-Met inhibitor for the control of metastatic breast and prostate cancers. AB - The proto-oncogene receptor tyrosine kinase c-Met encodes the high-affinity receptor for hepatocyte growth factor (HGF). Dysregulation of the HGF-c-Met pathway plays a significant oncogenic role in many tumors. Overexpression of c Met is a prognostic indicator for some transitional cell carcinomas. Extra-virgin olive oil (EVOO) provides a variety of minor phenolic compounds with beneficial properties. (-)-Oleocanthal (1) is a naturally occurring minor secoiridoid isolated from EVOO, which showed potent anti-inflammatory activity via its ability to inhibit COX-1 and COX-2. It altered the structure of neurotoxic proteins believed to contribute to the debilitating effects of Alzheimer's disease. Computer-Assisted Molecular Design (CAMD) identified 1 as a potential virtual c-Met inhibitor hit. Oleocanthal inhibited the proliferation, migration, and invasion of the epithelial human breast and prostate cancer cell lines MCF7, MDA-MB-231, and PC-3, respectively, with an IC (50) range of 10-20 uM, and demonstrated anti-angiogenic activity via downregulating the expression of the microvessel density marker CD31 in endothelial colony forming cells with an IC (50) of 4.4 uM. It inhibited the phosphorylation of c-Met kinase IN VITRO in the Z'-LYTETM assay, with an IC (50) value of 4.8 uM. (-)-Oleocanthal and EVOO can have potential therapeutic use for the control of c-Met-dependent malignancies. PMID- 21328181 TI - Epidemiology of pediatric brain tumors in Greece (1991-2008). Experience from the Agia Sofia Children's Hospital. AB - BACKGROUND: We set out to determine the epidemiology of pediatric brain tumors in a single Greek institute. METHODS: We reviewed all cases of brain tumors in children, under the age of 15 years, that were treated surgically in the Neurosurgical Department of Children's Hospital "Agia Sofia", between January 1991 and December 2008. RESULTS: From January 1991 through December 2008, we encountered 335 cases of pediatric brain tumors. The mean age was 7.2 years and there was a slight male predominance. Astrocytomas made up the largest component, with pilocytic astrocytomas accounting for 25.6% of all tumors. The second most common entity was medulloblastoma, accounting for 18% of all tumors, whereas ependymomas were the third most frequent tumor. There was an increase in the total number of brain tumors during the last decade. Furthermore, examining low grade astrocytoma, medulloblastoma and ependymoma trends over the last 2 decades, we found a trend for a decrease of low-grade astrocytomas and an increase of the more aggressive medulloblastomas and ependymomas. CONCLUSION: This study presents the first epidemiological data of pediatric brain tumors in Greece. Astrocytomas were the most common tumor followed by medulloblastomas and ependymomas. Furthermore, a trend for an increase of malignant tumors over the last decade has been observed. PMID- 21328182 TI - Comment to the article: Foramen magnum meningioma: successful surgical resection in a 76-year-old Nigerian. PMID- 21328183 TI - In memoriam. Dr. Hans-Gunther Niebeling. PMID- 21328184 TI - [Focus on basic and continuing education]. PMID- 21328185 TI - [Undergraduate education in orthopaedic and trauma surgery - a nationwide survey in Germany]. AB - AIM: Musculoskeletal conditions consume enormous resources and costs, and their incidence is increasing worldwide. Therefore, an appropriate education of medical students about these conditions is required. This study examines the extent of medical education in orthopaedic and trauma surgery in Germany. MATERIAL AND METHODS: A questionnaire comprising 7 topics (curriculum design, lecture, practical training, e-learning, examination, evaluation, resources) with a total of 44 items was sent to all assistant lecturers in orthopaedic and trauma surgery at the 37 medical schools in Germany. RESULTS: The survey attained a return rate of 76 % for orthopaedic surgery and 81 % for trauma surgery, respectively. Medical training in musculoskeletal conditions represents with an average of 38.4 hours of lectures and further 55.9 hours of practical training less than 6 % of the entire undergraduate medical education. This study demonstrates a high inhomogeneity regarding the curriculum design when comparing the different German medical schools not only in total training time but also regarding its contents. E-learning as additional teaching method is only offered in 39 % of orthopaedic training and in 47 % of the trauma surgery training. Practical examinations like the OSCE are offered at 8 medical schools for orthopaedic training and 15 schools for trauma surgical training, respectively. CONCLUSION: Medical training in musculoskeletal conditions is very inhomogeneous and requires further improvement and standardisation regarding quantity and implementation. PMID- 21328186 TI - [Comparison of the diagnostic value of X-ray versus MRI in paediatric spine injuries]. AB - AIM: The evaluation of paediatric thoracic or lumbar compression fractures can be challenging. The anatomy of the growing spine often makes a correct diagnosis by plain radiography difficult. The aim of our study was to compare the diagnostic reliability of X-Ray and that of magnetic resonance imaging in the evaluation of acute compression fractures of the paediatric spine. METHOD: From January to December 2008 20 patients (12 boys, 8 girls) who were treated because of clinically suspected compression fractures of the vertebra were included in our study. The average age was 8.3 years. In all cases a radiograph in two planes and an MRI of the lumbar and thoracic spine were obtained. Two orthopaedic surgeons and one radiologist retrospectively assessed the radiographs. The results were compared with the MRI findings. RESULTS: In six cases the MRI was normal, in one case there was only a bone bruise without compression of the vertebra. 13 children had two or more than two minor compression fractures (29 fractures altogether). The 5th and 6th thoracic vertebra predominated. In only two cases there was a corresponding result of all three physicians and the MRI. In 4 cases the observers agreed on the localisation of the fracture. There was no agreement about the number of fractured vertebrae. CONCLUSION: An exact evaluation of minor compression fractures of the pediatric spine with plain X-ray was not satisfactory. PMID- 21328188 TI - [Distal humeri fractures]. AB - Fractures of the distal humerus are rare and count only for a small number of all fractures in mature patients. Due to demographic changes surgeons will be faced with an increasing number of complex multifragmentary fractures with diminished bone quality. As conservative treatment frequently leads to limited and painful elbow function, open reduction and stable internal fixation with early range of motion exercises are considered the gold standard. Detailed knowledge of the complex articular anatomy, the biomechanics, operative approaches and available implants is needed for the proper management of these complex fractures. PMID- 21328187 TI - [Treatment of heterotopic ossification after spinal cord injury - clinical outcome after single-dose radiation therapy]. AB - INTRODUCTION: Heterotopic ossification (HO) is a common and serious complication after spinal cord injury, with an incidence of 5-50 %. Single-dose radiation therapy with 7 Gy is an established procedure for HO prophylaxis after total hip replacement. The aim of our study was to determine the clinical outcome after single-dose radiation therapy in the prophylaxis of HO in paraplegic patients. PATIENTS AND METHODS: Between January 2006 and July 2009, 75 paraplegic patients with heterotopic ossification were treated in our hospital. On the basis of the defined inclusion and exclusion criteria, 62 patients were included in our study, whereas 55 patients participated in our follow-up examination. All patients received a bi-weekly ultrasound of the hip for an attempt at early diagnosis of the condition. In case of an ultrasound suspicion of HO, a computed tomography (CT) or magnetic resonance imaging (MRI) of the hip was performed. After confirmation of HO, a single-dose radiation therapy with 7 Gy was performed. In group A, the patients were irradiated with an electrode voltage of 15 MeV (36 patients) and in group B with 6 MeV (26 patients). All patients were assessed with a standardised questionnaire with a mean follow-up of 30.6 months (range 6 78 months). RESULTS: The mean interval time between the initial spinal injury and HO development was 58,2 days (range 14-125). 69,4 % of all patients revealed a Brooker grade I, 27.4 % grade II and 3.2 % a grade III. No cases of Brooker grade IV (ankylosis) occurred. No patient showed side-effects after radiation therapy. However, in group A one patient (3,2 %) and in group B three patients (12.5 %) developed HO relapse. Those patients were treated again with a single-dose radiation therapy with 7 Gy and 15 MeV and, afterwards, they were free of complaints. Deep vein thrombosis was confirmed in 11 patients (32.3 %) in group A and in 8 patients (33.3 %) in group B. CONCLUSIONS: Single-dose radiation therapy with 7 Gy in the treatment of heterotopic ossification is an effective option. A higher electrode voltage improves the effectiveness of the irradiation and the clinical outcome. Essential for the outcome is the early detection and treatment of HO with single-dose radiation therapy. Randomised, prospective studies should be undertaken in order to confirm these findings. PMID- 21328190 TI - Factors associated with mortality in neonates with gastroschisis. AB - PURPOSE: The ongoing epidemic of gastroschisis has created multiple challenges and continues to raise questions concerning the optimal management of these high risk patients. Although the overall survival rate has increased over the past 3 decades, morbidity and mortality remain significant. The purpose of this study was to analyze the main factors associated with mortality in neonates admitted to an intensive care unit for the management of this abdominal wall defect. METHODS: This study is a retrospective review of a large de-identified neonatal intensive care dataset encompassing 284 institutions in 32 states and Puerto Rico, from 1/1/1997 to 1/1/2010. Of the 629 440 neonates in the dataset, a total of 3 456 newborns were diagnosed with gastroschisis (5.5/1 000 hospital discharges). Of these, 685 were transferred to other centers and data was missing on 22, leaving 2 749 infants available for analysis. RESULTS: Out of these 2 749 infants of whom we knew the outcome, 115 (4.2%) died. Multivariate logistic regression showed that the factors independently associated with an increased risk of death were male gender, immature gestational age, low birth weight, low 5 min Apgar Score, the need for vasopressors during the first week after birth and the need for high levels of oxygen support. The presence of associated anomalies, vaginal delivery, treatment with surfactant and the need for ventilator support on the day of birth were not independent risk factors associated with an increased mortality. CONCLUSION: Premature delivery and low birth weight are the most important factors associated with an increased risk of mortality. Cesarean section does not appear to reduce the risk. PMID- 21328191 TI - Late surgery for spinal deformities in children previously treated for neural tumors. AB - BACKGROUND/AIM: Surgery for neural tumors occasionally involves opening of the neural canal and/or costovertebral resection that may be followed by radiotherapy. Spinal deformities (SD) may occur in these cases. This study investigated the incidence, surgical indications and results of repair of late SD in a large series of patients with neural tumors. METHODS: A retrospective review of neural tumors treated between 1991 and 2009 at our institution identified children with SD who subsequently required spinal surgery. SD was meaA-sured using Cobb's angle. Instrumentation of the spine was indicated in patients with a Cobb's angle of more than 60 degrees or rapidly progressing SD. The operation was adapted to the location, type and degree of SD. Patients were followed up and the remaining deviations were measured annually. RESULTS: Out of a series of 188 patients with neural tumors, 5 of 173 patients with neuroblastomas/ganglioneuromas (NB/GN) and 3 of 15 patients with PNET/Askin tumors developed SD over time. NB/GN children had intraspinal tumors requiring laminotomy (n=3) or laminectomy (n=2). PNET/Askin tumor patients had undergone largescale rib and partial vertebral body resection and radiotherapy. Scoliosis or kyphosis were located in the thoracic spine in 4, in the thoracolumbar spine in 3 and in the cervicothoracic spine in 1. The median preoperative Cobb's angle was 65 degrees (50 degrees -90 degrees ) prior to spinal surgery performed 2.9 (0.4-11) years after tumor removal. 3 growth bars, 2 vertical expandable prosthetic titanium ribs, 1 pediatric ISOLA device and anterior instrumentation were used. Arthrodesis was necessary in 3 patients. Median post-instrumentation deformity after 3.1 (0.2-12.2) years was 40 degrees (20 degrees -50 degrees ), giving an improvement of 38.4%. CONCLUSIONS: With increasing numbers of children surviving cancer, attention must focus on sequelae. A sizeable number of survivors of NB/GN and PNET/Askin tumors develop serious SD requiring surgical correction. Pediatric surgeons, patients and relatives must be aware of these possible sequelae. PMID- 21328193 TI - The reconstruction of foot soft tissue defects by tangential debulking of the latissimus dorsi flap. AB - Reconstruction of foot soft tissue is challenging particularly in the presence of a large defect involving both dorsal and plantar surfaces. In large defects, use of a latissimus dorsi muscle (LDM) flap is the preferred coverage method, yet LDM flaps are bulky. Despite undergoing multiple debulking procedures, patients whose feet are repaired with LDM flaps must wear oversized custom-made shoes. We developed an approach to allow patients to wear regular shoes. In six patients, we used a debulking procedure that was based on tangential trimming of the flap to the level of thickness required for normal foot contour. All patients underwent debulking 3 months after initial LDM flap coverage. The mean duration of follow-up care was 21 months (range, 8 to 32 months). All flaps survived a secondary debulking procedure. One patient developed an ulcer at the weight bearing area of a sole. All six patients were able to wear regular shoes without difficulty. PMID- 21328194 TI - [Complications and management of complications in oesophageal surgery]. AB - BACKGROUND: Prevention, early recognition and an adequate management of perioperative complications in resectional oesophageal surgery are the keys to an increased safety of these complex procedures. RECOGNITION, DIAGNOSTICS, MANAGEMENT AND TREATMENT: Preoperative registration and - if required - pretreatment of specific risk factors can considerably decrease the complication rate. The precise implementation of significant preoperative score systems in patients with high operative risk can lead to a negative risk-benefit consideration concerning the indication for an operation. The patients will then be assigned to an alternative treatment process. Anastomotic leakage is the most frequent technical-surgical complication. A precise suturing technique with the prevention of tension and the avoidance of reduction of perfusion of the conduit (stomach, colon, small intestine) can reduce the rate of such insufficiencies. The most frequent non-surgical complication is postoperative pneumonia, which can be avoided or combated through effective pain-relieving therapy like peridural anaesthesia and specific techniques of postoperative ventilation. It is of vital importance to identify, at the earliest possible timepoint, complications that might emerge after the operation. The occurrence of postoperative tachyarrhythmia has proven to be a frequent and early indicator of such complications. The treatment of complications after oesophageal resections includes adequate conservative, interventional, e. g., endoscopic placement of a stent in cases of covered insufficiency of the suture line, and operative procedures like reoperation in cases of uncovered leakage with pleural connection. All the other surgical complications like haemorrhage, tracheobronchial leak-ages or chylothorax are rarely seen and demand specific therapeutic procedures. CONCLUSION: It is not only the surgery that determines a high or low complication rate in oesophageal resectional procedures. It has clearly been proved that interdisciplinary management of complications after oesophagectomy is much more effective in high-volume centres, leading to a lower mortality, than in surgical departments with a lower case rate and thus with less experience in such complex operations. PMID- 21328195 TI - Impact of duration of antidepressant treatment on the risk of occurrence of a new sequence of antidepressant treatment. AB - INTRODUCTION: Despite the recommendation that antidepressant treatment should be continued for several months to reduce the risk of relapse/recurrence of depression, early discontinuation is frequent in naturalistic conditions. The study was aimed at exploring the impact of early discontinuation of antidepressant treatment on the risk of antidepressant re-initiation. METHODS: A follow-up study of persons (n=35,053) starting antidepressant treatment was performed using a representative sample of the French Social Security Insurance national database. RESULTS: The risk of re-initiation of antidepressant treatment was higher if the duration of the index episode of antidepressant treatment was >= 6 months [hazard ratio (HR)=2.35; 95% CI 2.25-2.45) or 2-5 months (HR=1.65; 95% CI 1.59-1.71) compared to <= 1 month. The other characteristics independently associated with re-initiation of treatment were older age, female gender, low income, serious chronic illness, index prescription by a specialist and co prescription of other psychotropic drugs. CONCLUSIONS: The lower risk of re initiation of antidepressant treatment in persons with shorter-than-recommended duration of antidepressant treatment might be explained by overprescription of antidepressants in persons with sub-threshold symptoms. PMID- 21328196 TI - Treatment of pathological gambling with disulfiram: a report of 2 cases. PMID- 21328197 TI - Sclerosing adenosis of the breast: radiologic appearance and efficiency of core needle biopsy. AB - PURPOSE: To examine the mammography and ultrasonography findings of patients who have a final histopathological diagnosis of sclerosing adenosis after breast biopsy, and to evaluate the follow-up results of patients who underwent core needle biopsies. MATERIALS AND METHODS: Seventy-six of the 723 patients who underwent breast biopsy in our institution were diagnosed with sclerosing adenosis on histopathological examination. Mammography and ultrasonography findings from these 76 lesions were analyzed retrospectively. Thirty-seven of these lesions were sampled by image-guided core needle biopsy; the remaining lesions were excised surgically. Mammograms and ultrasound images of the lesions were re-evaluated, and the post-biopsy medical records of these patients were evaluated. RESULTS: Sclerosing adenosis was the main diagnosis in 41 patients and the complementary diagnosis in 35 patients. Among the first 41 lesions in which sclerosing adenosis was the main diagnosis, there were 18 (44%) mass lesions, 16 (39%) microcalcification clusters, two (5%) lesions with asymmetrical opacity, three (7%) lesions with architectural distortion, and two (5%) lesions with focal acoustical shadowing that was only detected by ultrasonography. No alterations suggesting malignancy were noted during the follow-up examinations of 35 patients who underwent core needle biopsy. CONCLUSION: Sclerosing adenosis is a benign proliferative disease of the breast that can be confused with malignancy on clinical, radiological, and even histopathological examination. There is no typical radiological criterion for diagnosis. Core needle biopsy or excisional biopsy can be used, depending on the lesion's characteristics. Core needle biopsy can be the first step in the diagnosis of sclerosing adenosis. PMID- 21328199 TI - [Paradigm shifting in community building and knowledge production: the Taiwan journey of Professor Byron Good]. AB - This review considers health professionalism in community practices within a Taiwan social-historical context. The author adopted a contrast-of-context approach to examine the community practices of Taiwan health professionals and intellectual transformation of Professor Byron Good. Focusing on the formation of an international collaborative platform for community mental health, this paper articulates the historical and social values of community health practices, identifies the essence of health practices, and highlights the significance of the Taiwan experience to advancing community mental practice worldwide. It furthermore underscores the strategic role of Taiwan in efforts to bridge Asian community health knowledge with that of the world. This essay first introduces the recent establishment of the international collaborative platform. Community psychiatric rehabilitation practices in Taiwan are then contrasted with the worldwide de-institutionalization intellectual movement. Paradigm shifts in the academic pursuits and intellectual journey of Professor Byron Good are then delineated, then community practices and social missions of Taiwan health professionals are contrasted. The implied connotations of health professionalism and bioethics in large-scale social change are explored next. This paper integrates relationships amongst community practice, health professionalism and civil society. Professor Byron Good and other friends, either domestic or international, will work together to highlight the new values embedded in recent Taiwan experience and the contributions such have made to global knowledge production. PMID- 21328198 TI - Correlation of dynamic multidetector CT findings with pathological grades of hepatocellular carcinoma. AB - PURPOSE: Our objective was to examine whether different vascularization patterns seen during three phases of dynamic multidetector computed tomography (MDCT) of the liver correlated with the histopathological differentiation findings of hepatocellular carcinoma (HCC) in chronic liver disease patients. MATERIALS AND METHODS: Dynamic MDCT images from 46 patients (38 males and 8 females; ages between 1 and 90 years; mean age, 53) pathologically diagnosed with HCC were retrospectively evaluated. Lesions were divided into three groups according to MDCT enhancement patterns. Pathologically determined differentiation degrees were compared with contrast enhancement patterns in the hepatic arterial, portal venous, and hepatic venous phases. RESULTS: Lesion characterization was as follows: Type 1 (6 patients), hypoattenuating in the hepatic arterial and hepatic venous phases and hyperattenuating in the portal venous phase; Type 2 (10 patients), hypoattenuating in all phases; and Type 3 (30 patients), hyperattenuating in the hepatic arterial and portal venous phases and hypoattenuating in the hepatic venous phase. Patients were pathologically classified as having either well-differentiated (n=32) or poorly differentiated HCC (n=14). All patients with poorly differentiated HCC had a Type 3 enhancement pattern. All patients with Type 1 and 2 enhancement patterns had well differentiated HCC. There was a significant correlation between pathological differentiation degrees and radiological enhancement (P = 0.003). CONCLUSION: Dynamic MDCT revealed that poorly differentiated HCC patients all had hypervascular enhancement patterns, and hypovascular- type enhancement was present in all patients with well-differentiated HCC. Imaging patterns of dynamic MDCT scanning in HCC patients may be helpful for follow-up examinations and for determining clinical prognosis. PMID- 21328200 TI - [Community health building: the safe community promotion experience]. AB - Safety and health promotion at the community level involves special concerns and approaches. A community may develop into a safe community or healthy city depending on the focus of relevant promotion efforts. Neither area nor population size should be factors affecting an initial decision to start safe community or healthy city programs. However, one should consider the diversity of issues that may have the potential impact on people with different gender and age or on different environments and situations, and whether a planned program is sustainable. While safe communities and healthy cities may be linked to international networks, the qualifications for joining such networks differ. The Healthy City Alliance emphasizes outcome measures and the International Safe Community Network emphasizes the appropriateness of sustainability mechanisms. While Taiwan communities are eligible for designation as international safe communities, they may are eligible for associate membership only in the Healthy City Alliance. The author has the following recommendations with regard to sustainability in community health building in Taiwan: 1) The relevant infrastructure must involve both public and private sectors; 2) The community should try to receive financial support from diverse sources; 3) involve significant numbers of active volunteers; and 4) charge local health centers with data collection and analysis responsibilities. PMID- 21328201 TI - [Empowering the family-center health model: the toy library as a health promotion platform]. AB - Facing the lowest birth rates in its history, Taiwan is increasingly recognizing the centrality of children's healthcare needs to effective family care. The World Health Organization's goal of health for all emphasizes health promotion. However, little research attention has been given to how families actively promote personal health in everyday life. This article considers 'family-centric' healthcare, with a particular emphasis on children's health and well-being and the mother health promotion model. Authors employ a 'toy library' as the health promotion platform to build community interaction and empower the health enhancement process. Results suggested the following: 1. The fixed-point type toy library may be an effective tool in a health promotion strategy; 2. A model may be developed for rural institution agencies; 3. Cooperation may be facilitated using a medical service vehicle; 4. The love bag program can serve extended purposes. The authors found that the empowerment and growth of tribal mothers is a key element to facilitate the successful development of their children. Based on findings, the implementation of a toy library as the platform to build community-based health promotion model is suggested. PMID- 21328202 TI - [Empowerment in the public health practice]. AB - Public health personnel are the first-line workers of preventive care and medical services. In the face of rapid social and demographic changes, empowerment and on job training have become important approaches to enhance the function of nurses. Health centers act like the "peripheral nerves" of the government healthcare system, as they must both reflect the needs of community residents and fully implement government mandated services. While widely distributed, health centers face manpower shortages and disorderly information collection and distribution systems. Empowerment and on-job training programs can enhance public heath staff knowledge in order to cope with heavy workloads and shift toward multi dimensional development. This paper examines the experience of the New Taipei City Public Health Bureau in conducting health center empowerment programs from four perspectives, including personal cultivation and organizational cultivation. It was found that public health staff self-recognition of professional values can also be further strengthened through alliances within the community, and that establishing personal relationships with patients by "treating patients as relatives" was effective in realizing health center objectives. This paper also reminds agency supervisors that staff training is a critical management task. Health authorities should thus introduce in a timely manner organizational management, on-job training, service reengineering, and other related corporate philosophies; facilitate staff empowerment; consolidate core professional knowledge; and construct intellectual and social capital that meets health unit needs in order to enhance health center competitiveness and public health staff knowledge. PMID- 21328203 TI - [Smoking and cigarette dependence among Taiwanese adolescent smokers: factors of influence]. AB - BACKGROUND: The current literature in Taiwan on adolescent smoking behavior focuses primarily on epidemiological surveys. The literature outside of Taiwan is consistent in indicating that the experience of an individual with his or her first cigarette predicts consequent smoking behavior during adolescence. Smoking behavior has been associated with cigarette dependence. However the concept of smoking behavior differs from cigarette dependence, and their predictors may vary considerably. PURPOSE: The aims of this study were to examine predictors of regular smoking, cigarette dependence and attempts to quit amongst adolescent smokers. METHODS: Researchers conducted a cross-sectional survey in twelve senior high schools in central and southern Taiwan between November 2007 and May 2009. Participants (N = 370), all of who had smoked at least once during the preceding one-year period, completed a questionnaire. Logistic analyses and multiple regression were used to explore predictors of smoking behavior, cigarette dependence and quit attempts. RESULT: The sample included 306 "regular" smokers. In a multivariate logistic regression analysis, having friends who smoked significantly influenced regular smoking behavior. Parental nagging about participant smoking behavior was a protective factor inhibiting regular smoking. Multiple regression analysis found smoking amongst siblings and friends to be a significant predictor of cigarette dependence. Cigarette dependence was found to significantly influence the success of attempts to quit. CONCLUSION / IMPLICATIONS FOR PRACTICE: Family and peer groups were the most important factors of influence on adolescent smoking behavior. This finding suggests that nursing professionals should leverage family and peer support when planning and implementing smoking cessation programs. PMID- 21328204 TI - [Critical care nurse learning of continuous renal replacement therapy: the efficacy of a self-learning manual]. AB - BACKGROUND: Many nurses have difficulty learning to use the complex, non traditional, and regularly-updated critical care equipment. Failure to use such equipment properly can seriously compromise treatment and endanger patient health and lives. New self-learning materials for novice nurses are necessary to provide essential and effective guidance as a part of formal nursing training. Such materials can enhance the capabilities of critical care nurses and, thus, improve the general quality of critical care. OBJECTIVES: The purpose of this research was to develop a continuous renal replacement therapy (CRRT)-themed self-learning manual that would provide easily absorbed and understood knowledge in an easy-to carry format for ICU nursing staff. This study also investigated CCRT skill learning efficacy. METHODS: This study adopted a quasi-experimental design with pretests and posttests. Purposive sampling generated a sample of 66 critical care nurses currently working at one hospital in Taipei City. Participants submitted a completed self-assessment survey that rated their command of continuous renal replacement therapy before and after the self-learning manual intervention. Survey data were analyzed using SPSS Version 17.0 for Windows. FINDINGS: The two major findings derived from the study included: (1) The mean response score from the self-assessment survey filled out after the intervention was 91.06 and 79.75 (SD = 9.49 and 11.65), respectively, for experimental and control groups. Such demonstrated significant difference. (2) The mean posttest score after the intervention for the experimental group was 91.06 +/- 9.49. This represents a significant increase of 10.35 +/- 10.35 over their mean pretest score (80.71 +/- 11.82). The experimental group showed other significant differences in terms of the CRRT self-assessment survey posttest. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: Self-learning manuals may be introduced in nursing education as useful aids and catalysts to achieve more effective and satisfying learning experiences. PMID- 21328205 TI - [The efficacy of multi-sensory environment therapy on psychological, behavioral symptoms among elderly patients with dementia]. AB - BACKGROUND: The treatment and care of demented elderly represents a major medical and social issue in Taiwan. Many empirical studies have demonstrated the efficacy of applying multi-sensory environment therapy to improve mood symptoms and reduce disturbed behavior frequencies among this population. While the technique has been widely applied in various clinical settings in the West, a study focusing on the treatment efficacy of multi-sensory environment therapy has yet to be conducted in Taiwan. PURPOSE: The purpose of the current study was to investigate the treatment efficacy of multi-sensory environment therapy on psychological and behavioral symptomatology among elderly patients with dementia. METHODS: This quasi-experimental study recruited 20 study participants from a nursing home in northern Taiwan. Treatment and control groups were arranged to contain 10 cases each. Participants were stratified by Mini-Mental State Examination (MMSE) score before random assignment to one of the two groups. The treatment group received a total of 24 sessions of multi-sensory environment therapy for 12 weeks. The control group received routine nursing home care. Researchers assessed treatment outcomes by comparing Neuropsychiatry Inventory (NPI) scores at baseline, week 6, and week 12, respectively. RESULTS: The experimental group showed a significant improvement over the control group on the NPI item "Motor Disturbance" at week 6. The experimental group scored significantly better than the control group on overall NPI score and on NPI items "Irritability or Liability" and "Motor Disturbance" after completion of the 12-week treatment regimen. CONCLUSIONS: Multi-sensory environment therapy helps improve behavioral and emotional symptoms in elderly patients with dementia. This technique may offer the potential to both improve the life quality of this population and reduce caretaker burdens. PMID- 21328206 TI - [Chronic pain and associated factors amongst institutionalized elderly with arthritis]. AB - BACKGROUND: The World Health Organization has predicted that arthritis will rise to become the fourth ranked global disability among the elderly. Arthritis is already a main cause of chronic pain, depression, and institutionalization in this group. Chronic pain resulting from arthritis is a serious threat to the elderly population. PURPOSE: Study purposes were to: (1) explore chronic pain in elderly residents with arthritis residing at long-term care facilities and to understand the relationship between associated chronic pain and associated factors, and (2) identify the predictive factors of chronic pain. METHODS: This study used a cross-sectional, descriptive correlational research design. A sample of 114 elderly residents, 65 years of age and older, were recruited from five long-term care facilities in Kaohsiung and Pingtung, Taiwan. RESULTS: Findings showed that the average pain intensity resulting from chronic arthritis during the three months of study was medium (4.51 +/- 1.75). There were positive relationships amongst average pain intensity, previous pain intensity, self perception of arthritis severity and depression status. Negative correlations were found amongst age, self-perception of arthritis severity, number of chronic illnesses experienced, function of daily activity and social support. Previous pain intensity, self-perception of arthritis severity, number of chronic illnesses experienced, function of daily activity and depression status were all found to predict chronic pain. Together, these factors explained 40.4% of total variance. CONCLUSION: Study results provide information for nurses to consider the physical, psychological, and social aspects of chronic pain when caring for the elderly. Healthcare providers should design individualized health care interventions for elderly people to promote their quality of life. PMID- 21328207 TI - [Historical changes in community concepts and the effect of such on community health nursing praxis]. AB - In the 21st century, many healthcare programs are delivered in community settings. As such, successfully recruiting target members of the community to participate in programs represents a key challenge for the nursing profession. Although the "community" is not a new concept, its meaning has changed over the past century or more of public healthcare, which has had a profound effect on community health nursing praxis. This article describes changes in community concepts through history in order to define the significance of community participation in today's community health nursing practice. PMID- 21328208 TI - [Using alternative therapies in treating sleep disturbance]. AB - Sleep disturbance is a common health problem among adults, and enhancing sleep quality is an issue of significant importance to healthcare providers. As sleep quality worsens into insomnia, individuals may seek assistance from medication. However, sedative hypnotic drugs pose potentially adverse effects. Also, most medical treatments (e.g., positive pressure assistant ventilators) represent invasive interventions that must be prescribed by physicians. Non-pharmacological alternative therapies are commonly recommended and adopted by community nurses. Alternative therapies for sleep disturbance included exercise, cognitive behavior therapy, multiple strategies, music, and acupressure. In general, moderately intensive walking exercise is the intervention most recommended by professionals to help patients deal with sleep disturbance. Therefore, it is suggested that future researchers devise sleep quality promotion strategies that are suitable for home practice in order to apply the findings and spirit of research already done in this area. PMID- 21328209 TI - [Information technology in nursing: using the decision-making support system in the OPD nursing instruction information system]. AB - In line with Department of Health promotion of electronic medical records, health care institutions have increased their information technology facilities in order to improve medical quality and patient safety, streamline healthcare procedures, reduce hospital management costs, and increase the use of statistical analysis in medical teaching, research and administration. However, applying information technology must consider many factors apart from system design and development. Such other factors include effectiveness in reducing user reliance on memory faculties, ability to streamline work processes, and capacity to recommend viable decisions. This paper provides an example of the nursing instruction information system deployment process. In addition to describing the development and implementation, applications of patient education and nursing decision-making are also presented. It is hoped that this experience may serve as reference to other healthcare institutions in the process of building nursing information systems. PMID- 21328210 TI - [Dementia patients: effective communication strategies]. AB - The importance of effective communication with dementia sufferers has grown with the increasing prevalence of this degenerative condition. Regardless of the presence of aphasia, the vocal tones and behaviors of dementia patients are meaningful, and may signal unmet needs. If caregivers ignore or fail to respond to these messages, more irritable or aggressive behaviors may result. Therefore, it is critical for caregivers to learn and apply appropriate communication strategies and skills with dementia patients. Based on a review of the literature, this paper provides guidelines for assessing dementia patients' residual communication ability and suggests strategies and skills for communicating with dementia patients. Evidence based guidelines are important for caregivers when communicating with dementia patients in order to achieve positive outcomes and high care quality. PMID- 21328211 TI - [Palliative care for persons with dementia]. AB - Dementia is irreversible. Although currently available drugs are typically able to ameliorate symptoms and slow down its progress, there is yet no known cure for this disease. The inevitable consequence of dementia is the gradual deterioration of the condition until final decline into the end of life stage. The priority care plan for patients with end stage dementia, therefore, must focus on palliative care that provides for a comfortable and high as possible quality of life. However, dementia is rarely looked upon as an end-stage disease. In 2009, the Taiwan National Health Insurance began reimbursing the costs of hospice care for patients with end stage dementia. This paper discusses end stage dementia cases in which patients received inappropriate interventions during their final days as well as the barriers faced in developing countries to providing palliative care. This paper also suggests strategies to promote quality of care and quality of life in people with end of life dementia. PMID- 21328212 TI - [Internationalized medical care services increase need of health care providers to improve English communication skills]. AB - English is the most important language used in international communication. Nurses today have significantly more opportunities to come into contact with clients of different nationalities. Therefore, English communication abilities are a critical to the effective care of foreign clients. Miscommunication due to language barriers can endanger the health and safety of foreign clients and hinder their access to healthcare resources. Basic English communicate skills allow nurses to better understand the feelings of foreign clients and to affect their satisfaction with healthcare services provided. The majority of clinical nurses in Taiwan are inadequately prepared to communicate with foreign clients or use English when delivering nursing care services. Although English is not an official language in Taiwan, strengthening English communication skills is necessary for Taiwan's healthcare service system. Faced with increasing numbers of foreign clients in their daily work, first-line nursing staffs need more training to improve English proficiency. In order to do so, support from the hospital director is the first priority. The second priority is to motivate nursing staffs to learn English; the third is to incorporate different English classes into the medical system and schedule class times to meet nurse scheduling needs; and the fourth is to establish international medical wards, with appropriate incentives in pay designed to attract and retain nursing staff proficient in English communication. PMID- 21328213 TI - [Unity of knowing and action- exploring moral courage in nursing practice]. AB - Ethics is a core value of nursing, and hospital nurses will try, as much as possible, to be "good" in terms of established nursing ethics and values. Nurses learn the value of providing "patient centered care" in school and try to establish relationships of trust with their patients in clinical settings. However, the realities of working in the hospital teaches nurses that actual situations are complex to the point of inducing "ethical dilemmas" and "moral distress" because of the many factors that affect medical decisions regarding individual patients. If nurses could follow their conscience in managing difficult ethical situations with moral courage, they would promote the value of "good nurse" which is innate in both nurses and society. This article defines the parameters of conscience and moral courage, the conditions such should exhibit, strategies nurses should consider, and appropriate nursing training methods. The authors hope to help foster the development of moral courage and create positive practice environments for nursing staff. PMID- 21328214 TI - Warfarin-induced sublingual hematoma mimicking Ludwig angina: Conservative management of a potentially life-threatening condition. AB - Sublingual hematoma secondary to excessive anticoagulation is a rare, life threatening condition. Reports in the literature have emphasized the importance of a prompt reversal of the causative coagulopathy by intravenous administration of vitamin K and fresh frozen plasma. In the event of an unstable airway, surgical intervention via tracheostomy or cricothyroidectomy is advocated. We report a case of sublingual hematoma that was treated conservatively, and we discuss the presentation and management of this entity. PMID- 21328215 TI - Bilateral asymmetrical mucoceles of the paranasal sinuses with unilateral orbital complications. AB - We report the rare occurrence of bilateral asymmetrical mucoceles of the paranasal sinuses that resulted in a unilateral orbital complication. The patient was a 47-year-old woman who presented with complaints of diplopia, blurred vision, and protrusion of her right eye that had progressed over a period of several months following an upper respiratory tract infection. Computed tomography detected the presence of two large, asymmetrical mucoceles. The lesion on the right involved the frontal and ethmoid sinuses, and the one on the left involved the ethmoid sinus. The mucoceles were locally expansile and had eroded the surrounding bony structures on the right. The expansile nature of the right sided mass had displaced the right orbit, which was the cause of the vision deterioration. Transnasal endoscopic surgery was performed to excise and marsupialize the mucoceles. This modality was preferred over conventional open surgery because it affords good visualization, it is safe, and it is a less morbid procedure. The patient's recovery was uneventful, and she was discharged home on the third postoperative day. On continuing follow-up, her vision had improved, her intraocular pressure had returned to normal, and her orbits were in their normal position. Based on our literature search, no case of bilateral frontal and ethmoid sinus mucoceles has been previously reported. PMID- 21328216 TI - Incomplete Horner syndrome: Report of a case and description of the sympathetic nervous system anatomy involved in Horner syndrome. AB - Horner syndrome, in which ptosis, miosis, and anhidrosis occur concomitantly, can arise from injury to the sympathetic nerve pathways anywhere from the brain to the end organs. Incomplete Horner syndrome lacks the sign of anhidrosis. We present a case of incomplete Horner syndrome caused by internal carotid artery dissection and provide a road map of the cervical sympathetic nerves involved in Horner syndrome to explain its etiology. We also discuss the imaging of and therapy for internal carotid artery dissections. PMID- 21328217 TI - An expansile mandibular mass as the initial manifestation of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most frequently encountered malignancies. Distant metastasis is a common sequela, occurring in approximately 50% of cases. Metastasis to the oral cavity is very rare. Careful immunohistochemical evaluation is critical in differentiating HCC from other metastatic malignancies. An understanding of the possibility that HCC may initially present as a mandibular metastasis is crucial to guide management. We describe the case of a 76-year-old man with a 3- to 4-month history of a painless, slowly enlarging, left-sided jaw mass. Biopsy findings were consistent with HCC. While the patient was a known hepatitis C carrier, the presence of HCC had been previously unknown. Additional workup revealed a large hepatic lesion. In view of his poor health, the patient elected to forgo chemotherapy, and he entered a hospice facility. This case provides an illustration that an isolated mandibular mass may represent the initial presentation of HCC. Subsequent identification of the primary tumor via radiographic and pathologic evaluations is important for the guidance of further management. PMID- 21328218 TI - Acute parotitis induced by trimethoprim/sulfamethoxazole. AB - Adverse drug reactions to the sulfonamide antibiotics are uncommon. When they do occur, they usually manifest as a rash or urticaria. Our review of the recent literature found that while sialadenitis is listed as a possible side effect of sulfonamide use, no actual case has ever been reported until now. We describe a case of acute bilateral parotitis that arose as a side effect of sulfonamide antibiotic treatment. We also examine the relevance of such pathology to the proposed mechanisms of sialadenitis, and we briefly discuss sulfonamide-induced pancreatitis. Lastly, we review the controversy over the possibility that some adverse drug reactions may be caused by cross-reactivity among different classes of sulfonamides. PMID- 21328219 TI - EHR/EMR: "Meaningful use," stimulus money, and the Serenity Prayer. PMID- 21328220 TI - Otoscopic view of an ossicular prosthesis. PMID- 21328221 TI - Dystonias of the head and neck: An overview. AB - Dystonias are a group of disorders characterized by muscle contractions that can produce twisting and repetitive movements or abnormal postures. Dystonias of the head and neck region, except for spasmodic dysphonia, are rarely described in the otolaryngology literature. Ironically, it is the otolaryngologic surgeon's knowledge of anatomy and physiology of the head and neck that can be of greatest benefit for patients suffering from these disorders. Medical and surgical treatment options are available in treating this disorder. This article is intended to serve as an introduction and overview of dystonias for the otolaryngologist-head and neck surgeon. PMID- 21328222 TI - Jaw-opening dystonia: Quality of life after botulinum toxin injections. AB - The objective of this study was to investigate quality-of-life outcomes in patients with jaw-opening oromandibular dystonia who had received treatment with botulinum neurotoxin injections. The Glasgow Benefit Inventory (GBI) was used as a post-intervention questionnaire to measure patient benefit. Twenty-five questionnaires were sent to patients. Of the 12 patients who returned the form (48% response rate), the mean scores for the general GBI subscore (p = 0.001), the social support GBI subscore (p = 0.031), and the physical health GBI subscore (p = 0.002) demonstrated statistically significant benefit from the injections. No scores demonstrated a negative impact. Botulinum neurotoxin injections were demonstrated to benefit the quality of life in patients suffering from jaw opening oromandibular dystonia. PMID- 21328223 TI - World Voice Day 2011. PMID- 21328224 TI - Endoscopic view of the drainage pathway of an agger nasi cell. PMID- 21328225 TI - Vocal fold varicosities. PMID- 21328226 TI - Isolated neurofibroma of the tongue presenting as a papilloangiomatous mass. PMID- 21328227 TI - MRSA otorrhea: A case series and review of the literature. AB - Methicillin-resistant Staphylococcus aureus (MRSA) has become an increasingly common cause of difficult-to-treat head and neck infections. We report a retrospective analysis of 3 cases of MRSA otorrhea treated in our clinic between 2007 and 2009. Culture analysis of otorrhea isolates revealed MRSA infections with identical drug sensitivities. Treatment success was achieved using combinations of linezolid with gentamicin ear drops for 3 to 4 weeks or trimethoprim/sulfamethoxazole (TMP/SMX) with gentamicin drops for 6 weeks. This study illustrates the importance of determining individual drug sensitivities for optimal treatment and maintaining current knowledge of the local MRSA strains. Empiric combination therapy of TMP/SMX with gentamicin is an effective first-line treatment for MRSA otorrhea. Regional differences in clindamycin sensitivities warrant clinical discretion. Fluoroquinolones should be avoided because of high rates of resistance unless culture sensitivity determines that they are appropriate. First-line agents for severe infections include combination therapy with vancomycin or linezolid. PMID- 21328228 TI - Characteristics of osteoma of the temporal bone in young adolescents. AB - The author conducted a retrospective review of the clinical presentation, management, and complications of temporal bone osteoma in young adolescents. The study population was made up of 9 patients-5 girls and 4 boys, aged 12 to 15 years at presentation (mean: 13.7)-who had been seen for radiologically and histopathologically proven temporal bone osteoma at the author's institution over a 9-year period. Of this group, 5 patients had extracanalicular osteoma (3 in the mastoid portion of the temporal bone, 1 in the squamous portion, and 1 in the mastoid antrum) and 4 patients had osteoma of the external auditory canal. Six of the 9 patients underwent surgical treatment; of the remainder, 1 refused surgery and 2 were managed conservatively with ongoing observation. All patients were followed for a minimum of 1 year, and no recurrences and no complications were observed during that time. PMID- 21328229 TI - [Complex regional pain syndrome type 1 (CRPS 1)]. PMID- 21328230 TI - [CME - ORL - 1]. PMID- 21328232 TI - [What is your diagnosis?]. PMID- 21328233 TI - [Mini-review BMJ "rational testing" Praxis 2011;100(2):99-103]. PMID- 21328234 TI - [Comments on rule of fist]. PMID- 21328235 TI - [Polypharmacy is an indicator for a poor prognosis, which is not altered by deprescribing in nursing home]. AB - AIM: To examine the influence of polypharmacy ordered by the pretreating site and deprescribing (i.e. the appropriate withdrawal of prescribed drugs) by the nursing home physician on survival time. METHODS: Retrospective Analysis of medical databasis from 1,249 patients, thereof 611 in a nursing home with practice of deprescribing. RESULTS: 70% of the patients with excessive polypharmacy (>9 drugs), 57% of those with polypharmacy (6 to 9 drugs) and 43% of the remaining patients (<6 drugs) deceased within 286 days after admission (chi squared 2 DF = 43.72; p <0.001). Deprescribing by the nursing home physician at admission revealed no influence on survival time. CONCLUSION: Polypharmacy is not the reason, but an indicator for a poor prognosis, which is not altered by deprescribing. PMID- 21328236 TI - [Diagnosis and treatment of interstitial cystitis]. AB - Interstitial Cystitis, first described in 1887 as an inflammatory disease of the bladder wall, is now regarded as a very common disease with an estimated number of unreported cases. Reasons for underdiagnosis is the widespread use of strict exclusion criteria. The disease can already be suspected by a careful medical history and physical examination in an early stage and then be treated with promising multimodal therapeutic approaches. In addition to a symptomatic oral therapy, local instillations with constituents of the protective glycosaminoglycan-layer are the most common therapeutic approach, because its defective integrity plays a key role in the pathogenesis of interstitial cystitis. PMID- 21328237 TI - [The lazy eye - contemporary strategies of amblyopia treatment]. AB - Amblyopia is a condition of decreased monocular or binocular visual acuity caused by form deprivation or abnormal binocular interaction. Amblyopia is the most common cause of monocular vision loss in children with a prevalence of 2 to 5%. During the last decade, several prospective randomized studies have influenced our clinical management. Based on these studies, optimum refractive correction should be prescribed first. However, most patients will need additional occlusion therapy which is still considered the "gold standard" of amblyopia management. Now much lower doses have been shown to be effective. In moderate amblyopia, penalization with atropine is as effective as patching. New treatment modalities including perceptual learning, pharmacotherapy with levodopa and citicholine or transcranial magnetic stimulation have not yet been widely accepted. PMID- 21328238 TI - [Pulmonary embolism]. PMID- 21328239 TI - [Mononeuritis multiplex under the TNF-alpha inhibitor infliximab]. AB - A 21-year-old patient with ankylosing spondylitis under treatment with the TNF alpha inhibitor infliximab developed a multifocal, demyelinating axonal neuropathy affecting several peripheral nerves simultaneously (mononeuritis multiplex). This represents an additional rare peripheral nervous system side effect of infliximab therapy. The underlying cause is unknown. Intravenous immunoglobulin therapy (0.4 g/kg per day for five days) led to a complete regression of muscle paresis and sensory defects in this case. PMID- 21328240 TI - [Not Available]. PMID- 21328241 TI - [Not Available]. PMID- 21328244 TI - [The physicians -- art column]. PMID- 21328245 TI - [Physicians -- literature riddle]. PMID- 21328246 TI - Vitamin E for neuroleptic-induced tardive dyskinesia. AB - BACKGROUND: Antipsychotic (neuroleptic) medication is used extensively to treat people with chronic mental illnesses. Its use, however, is associated with adverse effects, including movement disorders such as tardive dyskinesia (TD) - a problem often seen as repetitive involuntary movements around the mouth and face. Vitamin E has been proposed as a treatment to prevent or decrease TD. OBJECTIVES: To determine the effects of vitamin E for people with schizophrenia or other chronic mental illnesses who also developed neuroleptic-induced TD. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group Trials Register (March 2010), inspected references of all identified studies for further trials and contacted authors of trials for additional information. SELECTION CRITERIA: We included reports if they were controlled trials dealing with people with neuroleptic-induced TD and schizophrenia who had been randomly allocated to either vitamin E or to a placebo or no intervention. DATA COLLECTION AND ANALYSIS: We independently extracted data from these trials and we estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CI). We assumed that people who dropped out had no improvement. MAIN RESULTS: The review now includes 11 poorly reported randomised trials (total 427 people). There was no clear difference between vitamin E and placebo for the outcome of 'clinically relevant improvement in TD' (6 trials, 256 people, RR 0.95 CI 0.89 to 1.02). For the outcome of 'any improvement in TD symptoms', again, we found no clear difference between groups (7 trials, 311 people, RR 0.86 CI 0.75 to 1.00). However, people allocated to placebo showed more deterioration of their symptoms compared with those given vitamin E (5 trials, 98 people, RR 0.38 CI 0.16 to 0.9). There was no difference in the incidence of adverse effects (9 trials, 203 people, RR 1.29 CI 0.51 to 3.24) or leaving the study early (medium term 6 trials, 173 people, RR 1.29 CI 0.72 to 2.3). There is no trial-based information regarding the effect of vitamin E for those with early onset of TD. AUTHORS' CONCLUSIONS: Small trials of limited quality suggest that vitamin E may protect against deterioration of TD. There is no evidence that vitamin E improves symptoms of this problematic and disfiguring condition once established. New and better trials are indicated in this under-researched area, and, of the many adjunctive treatments that have been given for TD, vitamin E would be a good choice for further evaluation. PMID- 21328247 TI - WITHDRAWN: Vitamin D supplementation in pregnancy. AB - BACKGROUND: Vitamin D deficiency can occur in people whose diet is relatively low in the vitamin and those who are not exposed to much sunlight. OBJECTIVES: The objective of this review was to assess the effects of vitamin D supplementation on pregnancy outcome. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register (October 2001) and the Cochrane Controlled Trials Register (Issue 3, 2001). SELECTION CRITERIA: Acceptably controlled trials of vitamin D supplementation during pregnancy. DATA COLLECTION AND ANALYSIS: One reviewer assessed trial quality and extracted data. MAIN RESULTS: Two trials involving 232 women were included. In one trial the mothers had higher mean daily weight gain and lower number of low birthweight infants. In the other trial the supplemented group had lower birthweights. AUTHORS' CONCLUSIONS: There is not enough evidence to evaluate the effects of vitamin D supplementation during pregnancy. PMID- 21328248 TI - Long-chain polyunsaturated fatty acid supplementation in preterm infants. AB - BACKGROUND: Controversy exists over whether longchain polyunsaturated fatty acids (LCPUFA) are essential nutrients for preterm infants, who may not be able to synthesise sufficient amounts of LCPUFA to satisfy the needs of the developing brain and retina. OBJECTIVES: The aim of this review is to assess whether supplementation of formula with LCPUFA is safe and of benefit to preterm infants. SEARCH STRATEGY: Trials were identified by MEDLINE (1966 to December 2009), Oxford Database of Perinatal Trials, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2009) and by checking reference lists of articles and conference proceedings. SELECTION CRITERIA: All randomised trials of formula supplemented with LCPUFA and with clinical endpoints were reviewed. DATA COLLECTION AND ANALYSIS: All authors assessed eligibility and trial quality, two authors extracted data separately. Study authors were contacted for additional information. MAIN RESULTS: Of the 17 trials included in the review, 13 were classified as of high quality. Visual acuity Visual acuity over the first year was measured by Teller or Lea acuity cards in eight studies, by VEP in six studies and by ERG in two studies. Most studies found no significant differences in visual assessment between supplemented and control infants.Development Three out of seven studies reported some benefit of LCPUFA on neurodevelopment in different populations at different postnatal ages. Meta analysis of Bayley Scales of Infant Development of four studies at 12 months (N = 364) and three studies at 18 months (N = 494) post-term showed no significant effect of supplementation on neurodevelopment.Growth Four out of 15 studies reported benefits of LCPUFA on growth of supplemented infants at different postnatal ages. Two trials suggested that LCPUFA supplemented infants grow less well than controls. One trial reported mild reductions in length and weight z scores at 18 months. Meta-analysis of five studies showed increased weight and length at two months post-term in supplemented infants. Meta-analysis of four studies at 12 months (N = 271) and two studies at 18 months (N = 396) post-term showed no significant effect of supplementation on weight, length or head circumference. AUTHORS' CONCLUSIONS: Infants enrolled in the trials were relatively mature and healthy preterm infants. Assessment schedule and methodology, dose and source of supplementation and fatty acid composition of the control formula varied between trials. On pooling of results, no clear long-term benefits or harms were demonstrated for preterm infants receiving LCPUFA supplemented formula. PMID- 21328249 TI - Intra-venous fluids for the prevention of severe ovarian hyperstimulation syndrome. AB - BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is a serious and potentially fatal complication of ovarian stimulation, which affects 1% to 14% of all in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycles. A number of clinical studies with conflicting results have reported on the use of intravenous fluids such as albumin, hydroxyethyl starch, Haemaccel(r) and dextran as a possible way for preventing the severe form of OHSS. OBJECTIVES: To review the effectiveness and safety of administration of intravenous fluids such as albumin, hydroxyethyl starch, Haemaccel(r) and dextran in the prevention of severe ovarian hyperstimulation syndrome (OHSS) in IVF or ICSI treatment cycles. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register of controlled trials, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, to third quarter 2010), MEDLINE (1950 to November 2010), EMBASE (1980 to November 2010) and The National Research Register (to November 2010). The citation lists of relevant publications, review articles, abstracts of scientific meetings and included studies were also searched. The authors were contacted to provide or clarify data that were unclear from the trial reports. SELECTION CRITERIA: Randomised controlled trials (RCTs) which compared the effects of intravenous fluids with placebo or no treatment for the prevention of severe OHSS in high risk women undergoing IVF or ICSI treatment cycles. DATA COLLECTION AND ANALYSIS: Two review authors independently scanned the abstracts, identified relevant papers, assessed inclusion of trials and trial quality and extracted relevant data. Validity was assessed in terms of method of randomisation, allocation concealment and outcomes. Where possible, data were pooled for analysis. A separate analysis of studies was performed for human albumin and hydroxyethyl starch versus placebo or no treatment. Other potential intravenous fluids have been identified, such as Haemaccel and dextran, however no randomised controlled studies on their applicability could be found. MAIN RESULTS: Nine RCTs involving 1660 (human albumin vs placebo) and 487 (HES vs placebo) randomised women, have been included in this review. There was a borderline statistically significant decrease in the incidence of severe OHSS with administration of human albumin (8 RCTs, OR 0.67, 95% CI 0.45 to 0.99).There was a statistically significant decrease in severe OHSS incidence with administration of hydroxyethyl starch (3 RCTs, OR 0.12, 95% CI 0.04 to 0.40). There was no evidence of statistical difference in the pregnancy rate between both groups of treatment. AUTHORS' CONCLUSIONS: There is limited evidence of benefit from intra-venous albumin administration at the time of oocyte retrieval in the prevention or reduction of the incidence of severe OHSS in high risk women undergoing IVF or ICSI treatment cycles. Hydroxyethyl starch markedly decreases the incidence of severe OHSS. PMID- 21328250 TI - Oral naltrexone maintenance treatment for opioid dependence. AB - BACKGROUND: Research on the clinical application of oral naltrexone agrees on several things. From a pharmacological perspective, naltrexone works. From an applied perspective, however, the medication compliance and the retention rates are very poor. OBJECTIVES: To evaluate the effects of naltrexone maintenance treatment versus placebo or other treatments in preventing relapse in opioid addicts after detoxification. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL - The Cochrane Library issue 6 2010), PubMed (1973- June 2010), CINAHL (1982- June 2010). We inspected reference lists of relevant articles and we contacted pharmaceutical producers of naltrexone, authors and other Cochrane review groups. SELECTION CRITERIA: All randomised and controlled clinical trials which focus on the use of naltrexone maintenance treatment versus placebo, or other treatments to reach sustained abstinence from opiate drugs DATA COLLECTION AND ANALYSIS: Three reviewers independently assessed studies for inclusion and extracted data. One reviewer carried out the qualitative assessments of the methodology of eligible studies using validated checklists. MAIN RESULTS: Thirteen studies, 1158 participants, met the criteria for inclusion in this review.Comparing naltrexone versus placebo or no pharmacological treatments, no statistically significant difference were noted for all the primary outcomes considered. The only outcome statistically significant in favour of naltrexone is re incarceration, RR 0.47 (95%CI 0.26 0.84), but results come only from two studies.Comparing naltrexone versus psychotherapy, in the two considered outcomes, no statistically significant difference was found in the single study considered.Naltrexone was not superior to benzodiazepines and to buprenorphine for retention and abstinence and side effects. Results come from single studies. AUTHORS' CONCLUSIONS: The findings of this review suggest that oral naltrexone did not perform better than treatment with placebo or no pharmacological agent with respect to the number of participants re-incarcerated during the study period. If oral naltrexone is compared with other pharmacological treatments such as benzodiazepine and buprenorphine, no statistically significant difference was found. The percentage of people retained in treatment in the included studies is however low (28%). The conclusion of this review is that the studies conducted have not allowed an adequate evaluation of oral naltrexone treatment in the field of opioid dependence. Consequently, maintenance therapy with naltrexone cannot yet be considered a treatment which has been scientifically proved to be superior to other kinds of treatment. PMID- 21328251 TI - Zinc for the common cold. AB - BACKGROUND: The common cold is one of the most widespread illnesses and is a leading cause of visits to the doctor and absenteeism from school and work. Trials conducted since 1984 investigating the role of zinc for the common cold symptoms have had mixed results. Inadequate treatment masking and reduced bioavailability of zinc from some formulations have been cited as influencing results. OBJECTIVES: To assess the effect of zinc on common cold symptoms. SEARCH STRATEGY: We searched CENTRAL (2010, Issue 2) which contains the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to May week 3, 2010) and EMBASE (1974 to June 2010). SELECTION CRITERIA: Randomised, double blind, placebo-controlled trials using zinc for at least five consecutive days to treat, or for at least five months to prevent the common cold. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality. MAIN RESULTS: We included 13 therapeutic trials (966 participants) and two preventive trials (394 participants). Intake of zinc is associated with a significant reduction in the duration (standardized mean difference (SMD) -0.97; 95% confidence interval (CI) -1.56 to -0.38) (P = 0.001), and severity of common cold symptoms (SMD -0.39; 95% CI -0.77 to -0.02) (P = 0.04). There was a significant difference between the zinc and control group for the proportion of participants symptomatic after seven days of treatment (OR 0.45; 95% CI 0.2 to 1.00) (P = 0.05). The incidence rate ratio (IRR) of developing a cold (IRR 0.64; 95% CI 0.47 to 0.88) (P = 0.006), school absence (P = 0.0003) and prescription of antibiotics (P < 0.00001) was lower in the zinc group. Overall adverse events (OR 1.59; 95% CI 0.97 to 2.58) (P = 0.06), bad taste (OR 2.64; 95% CI 1.91 to 3.64) (P < 0.00001) and nausea (OR 2.15; 95% CI 1.44 to 3.23) (P = 0.002) were higher in the zinc group. AUTHORS' CONCLUSIONS: Zinc administered within 24 hours of onset of symptoms reduces the duration and severity of the common cold in healthy people. When supplemented for at least five months, it reduces cold incidence, school absenteeism and prescription of antibiotics in children. There is potential for zinc lozenges to produce side effects. In view of this and the differences in study populations, dosages, formulations and duration of treatment, it is difficult to make firm recommendations about the dose, formulation and duration that should be used. PMID- 21328252 TI - Intermittent pneumatic compression for treating venous leg ulcers. AB - BACKGROUND: Intermittent pneumatic compression (IPC) is a mechanical method of delivering compression to swollen limbs that can be used to treat venous leg ulcers and limb swelling due to lymphoedema. OBJECTIVES: To determine whether IPC increases the healing of venous leg ulcers. To determine the effects of IPC on health related quality of life of venous leg ulcer patients. SEARCH STRATEGY: For this update we searched the Cochrane Wounds Group Specialised Register (searched 10 December 2010); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 4); Ovid MEDLINE (2007 to November Week 3 2010); Ovid MEDLINE (In-Process & Other Non-Indexed Citations December 09, 2010); Ovid EMBASE (2007 to 2010 Week 48); and EBSCO CINAHL (2007 to 3 December 2010). SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared the effects of IPC with control (sham IPC or no IPC) or made comparisons between IPC treatment regimens, in venous ulcer management. DATA COLLECTION AND ANALYSIS: Both review authors reviewed titles and abstracts and agreed on full studies to be retrieved. One review author extracted data and assessed studies for risk of bias and this was checked by a second review author. MAIN RESULTS: We identified seven randomised controlled trials (including 367 people in total). Only one trial was at low risk of bias having reported adequate randomisation, allocation concealment and blinded outcome assessment. In one trial (80 people) more ulcers healed with IPC than with dressings (62% vs 28%; p=0.002). Four trials compared IPC plus compression with compression alone. The first of these trials (45 people) found increased ulcer healing with IPC plus compression than with compression alone (risk ratio for healing 11.4, 95% Confidence Interval 1.6 to 82). The remaining three trials (122 people) found no evidence of a benefit for IPC plus compression compared with compression alone.One small trial (16 people) found no difference between IPC (without additional compression) and compression bandages alone. One trial (104 people) compared different ways of delivering IPC and found that rapid IPC healed more ulcers than slow IPC (86% vs 61%). AUTHORS' CONCLUSIONS: IPC may increase healing compared with no compression, but it is not clear whether it increases healing when added to treatment with bandages, or if it can be used instead of compression bandages. Rapid IPC was better than slow IPC in one trial. Further trials are required to determine whether IPC increases the healing of venous leg ulcers when used in modern practice where compression therapy is widely used. PMID- 21328253 TI - WITHDRAWN: Pharmacological interventions for non-ulcer dyspepsia. AB - BACKGROUND: The commonest cause of upper gastrointestinal symptoms is non-ulcer dyspepsia (NUD) and yet the pathophysiology of this condition has been poorly characterised and the optimum treatment is uncertain. It is estimated that L450 million is spent on dyspepsia drugs in the UK each year. OBJECTIVES: This review aims to determine the effectiveness of six classes of drugs (antacids, histamine H2 antagonists, proton pump inhibitors, prokinetics, mucosal protecting agents and antimuscarinics) in the improvement of either the individual or global dyspepsia symptom scores and also quality of life scores patients with non-ulcer dyspepsia. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2005), MEDLINE (1966 to January 2006), EMBASE (1988 to January 2006), CINAHL (1982 to January 2006), SIGLE, and reference lists of articles. We also contacted experts in the field and pharmaceutical companies. Trials were located through electronic searches of the Cochrane Controlled Trials Register (CCTR), MEDLINE, EMBASE, CINAHL and SIGLE, using appropriate subject headings and text words, searching bibliographies of retrieved articles, and through contacts with experts in the fields of dyspepsia and pharmaceutical companies. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing drugs of any of the six groups with each other or with placebo for non-ulcer dyspepsia (NUD). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility, trial quality and extracted data. MAIN RESULTS: We included 73 trials: prokinetics (19 trials with dichotomous outcomes evaluating 3178 participants; relative risk reduction (RRR) 33%; 95% confidence intervals (CI) 18% to 45%), H(2)RAs (12 trials evaluating 2,183 participants; RRR 23%; 95% CI 8% to 35%) and PPIs (10 trials evaluating 3,347 participants; RRR 13%; 95% CI 4% to 20%) were significantly more effective than placebo. Bismuth salts (six trials evaluating 311 participants; RRR 40%; 95% CI -3 to 65%) were superior to placebo but this was of marginal statistical significance. Antacids (one trial evaluating 109 participants; RRR 2%; 95% CI -36% to 24%) and sucralfate (two trials evaluating 246 participants; RRR 29%; 95% CI -40% to 64%) were not statistically significantly superior to placebo. A funnel plot suggested that the prokinetic results could be due to publication bias or other small study effects. AUTHORS' CONCLUSIONS: There is evidence that anti-secretory therapy may be effective in NUD. The trials evaluating prokinetic therapy are difficult to interpret as the meta-analysis result could have been due to publication bias. The effect of these drugs is likely to be small and many patients will need to take them on a long-term basis so economic analyses would be helpful and ideally the therapies assessed need to be inexpensive and well tolerated. PMID- 21328254 TI - WITHDRAWN: Eradication of Helicobacter pylori for non-ulcer dyspepsia. AB - BACKGROUND: Helicobacter pylori (H pylori) is the main cause of peptic ulcer disease. The role of H pylori in non-ulcer dyspepsia is less clear. OBJECTIVES: To determine the effect of H pylori eradication on dyspepsia symptoms in patients with non-ulcer dyspepsia. SEARCH STRATEGY: Trials were identified through electronic searches of the Cochrane Controlled Trials Register (CCTR), MEDLINE, EMBASE, CINAHL and SIGLE, using appropriate subject headings and keywords, searching bibliographies of retrieved articles, and through contacts with experts in the fields of dyspepsia and with pharmaceutical companies. SELECTION CRITERIA: All parallel group randomised controlled trials (RCTs) comparing drugs to eradicate H pylori with placebo or other drugs known not to eradicate H pylori for patients with non-ulcer dyspepsia. DATA COLLECTION AND ANALYSIS: Data were collected on individual and global dyspeptic symptom scores, quality of life measures and adverse effects. Dyspepsia outcomes were dichotomised into minimal/resolved versus same/worse symptoms. MAIN RESULTS: Twenty one randomised controlled trials were included in the systematic review. Eighteen trials compared antisecretory dual or triple therapy with placebo antibiotics +/- antisecretory therapy, and evaluated dyspepsia at 3-12 months. Seventeen of these trials gave results as dichotomous outcomes evaluating 3566 patients and there was no significant heterogeneity between the studies. There was a 10% relative risk reduction in the H pylori eradication group (95% CI = 6% to 14%) compared to placebo. The number needed to treat to cure one case of dyspepsia = 14 (95% CI = 10 to 25). A further three trials compared Bismuth based H pylori eradication with an alternative pharmacological agent. These trials were smaller and had a shorter follow-up but suggested H pylori eradication was more effective than either H2 receptor antagonists or sucralfate in treating non-ulcer dyspepsia. AUTHORS' CONCLUSIONS: H pylori eradication therapy has a small but statistically significant effect in H pylori positive non-ulcer dyspepsia. An economic model suggests this modest benefit may still be cost-effective but more research is needed. PMID- 21328255 TI - WITHDRAWN: Psychological interventions for non-ulcer dyspepsia. AB - BACKGROUND: Studies have also shown that non-ulcer dyspepsia (NUD) patients have higher scores of anxiety, depression, neurotism, chronic tension, hostility, hypochondriasis and tendency to be more pessimistic when compared with the community controls. However, the role of psychological interventions in NUD remains uncertain. OBJECTIVES: This review aims to determine the effectiveness of psychological interventions including psychotherapy, psychodrama, cognitive behavioural therapy, relaxation therapy and hypnosis in the improvement of either individual or global dyspepsia symptom scores and quality of life scores in patients with NUD. SEARCH STRATEGY: Trials were identified by searching the Cochrane Controlled Trials Register (Issue 3-1999), MEDLINE (1966-99), EMBASE (1988-99), PsycLIT (1987-1999) and CINAHL (1982-99). Bibliographies of retrieved articles were also searched and experts in the field were contacted. Searches were updated on 10 December 2002 and 21 January 2004. The searches were re-run on 24 January 2005 and 9 January 2006 and no new trials were found SELECTION CRITERIA: All randomised controlled trials (RCTs) or quasi-randomised studies assessing the effectiveness of psychological interventions (including psychotherapy, psychodrama, cognitive behavioural therapy, relaxation therapy and hypnosis) for non-ulcer dyspepsia (NUD) were identified. DATA COLLECTION AND ANALYSIS: Data collected included both individual and global dyspepsia symptom scores and quality of life (QoL) scores. MAIN RESULTS: We identified only four trials each using different psychological interventions; three presented results in a manner that did not allow synthesis of the data to form a meta-analysis. All trials suggested that psychological interventions benefit dyspepsia symptoms and this effect persists for one year. However, all trials used statistical techniques that adjusted for baseline differences between groups. This should not be necessary for a randomised trial that is adequately powered suggesting that the sample size was too small. Unadjusted data was not statistically significant. The other problems of psychological intervention included low recruitment and high drop out rate, which has been shown to be greater in patients receiving group therapy. AUTHORS' CONCLUSIONS: There is insufficient evidence from this review to confirm the efficacy of psychological intervention in NUD. PMID- 21328256 TI - Coasting (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome. AB - BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic and potentially life threatening condition resulting from excessive ovarian stimulation. Reported incidence varies from 1% to 10% of in vitro fertilization (IVF) cycles. The factors contributing to OHSS have not been completely explained. The release of vasoactive substances secreted by the ovaries under human chorionic gonadotrophin (hCG) stimulation may play a key role in triggering this syndrome. This condition is characterised by a massive shift of fluid from the intra-vascular compartment to the third space resulting in profound intra vascular depletion and haemoconcentration. OBJECTIVES: To assess the effect of withholding gonadotrophins (coasting) on the prevention of ovarian hyperstimulation syndrome in assisted reproduction cycles. SEARCH STRATEGY: For the update of this review we searched the Cochrane Menstrual Disorders and Subfertility Review Group Trials Register (July 2010), CENTRAL (inception to July 2010), MEDLINE (PubMed) (inception to July 2010), and EMBASE (inception to July 2010) for randomised controlled trials (RCTs) in which coasting was used to prevent OHSS. SELECTION CRITERIA: Only randomised controlled trials (RCTs) in which coasting was used to prevent OHSS were included. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials and extracted data. Disagreements were resolved by discussion. Study authors were contacted to request additional information or missing data. The intervention comparisons were coasting versus early unilateral follicular aspiration (EUFA), no coasting or other interventions. Statistical analysis was performed in accordance with the Cochrane Menstrual Disorders and Subfertility Group guidelines. MAIN RESULTS: This updated review identified 16 studies of which four met the inclusion criteria. There was no evidence of a difference in the incidence of moderate and severe OHSS (odds ratio (OR) 0.53, 95% CI 0.23 to 1.23), live birth (OR 0.48, 95% CI 0.14 to 1.62; P = 0.24) or in the clinical pregnancy rate (OR 0.69, 95% CI 0.44 to 1.08) between the groups. Significantly fewer oocytes were retrieved in coasting groups compared with GnRHa (OR -2.44, 95% CI -4.30 to -0.58; P = 0.01) or no coasting (OR -3.92, 95% CI -4.47 to -3.37; P < 0.0001). Data for coasting versus EUFA were not pooled for number of oocytes retrieved due to heterogeneity (I(2) = 87%). AUTHORS' CONCLUSIONS: There was no evidence to suggest a benefit of using coasting to prevent OHSS compared with no coasting or other interventions. PMID- 21328257 TI - Herbal therapy for treating rheumatoid arthritis. AB - BACKGROUND: Herbal medicine interventions have been identified as having potential benefit in the treatment of rheumatoid arthritis (RA). OBJECTIVES: To update an existing systematic (Cochrane) review of herbal therapies in RA. SEARCH STRATEGY: We searched electronic databases Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, AMED, CINAHL, Web of Science, Dissertation Abstracts (1996 to 2009), unrestricted by language, and the WHO International Clinical Trials Registry Platform in October 2010. SELECTION CRITERIA: Randomised controlled trials of herbal interventions compared with placebo or active controls in RA. DATA COLLECTION AND ANALYSIS: Two authors selected trials for inclusion, assessed risk of bias and extracted data. MAIN RESULTS: Twelve new studies were added to the update, a total of 22 studies were included.Evidence from seven studies indicate potential benefits of gamma linolenic acid (GLA) from evening primrose oil, borage seed oil, or blackcurrent seed oil, in terms of reduced pain intensity (mean difference (MD) -32.83 points, 95% confidence interval (CI) -56.25 to -9.42,100 point pain scale); improved disability (MD -15.75% 95% CI -27.06 to -4.44%); and an increase in adverse events (GLA 20% versus placebo 3%), that was not statistically different (relative risk 4.24, 95% CI 0.78 to 22.99).Three studies compared Tripterygium wilfordii (thunder god vine) to placebo and one to sulfasalazine and indicated improvements in some outcomes, but data could not be pooled due to differing interventions, comparisons and outcomes. One study reported serious side effects with oral Tripterygium wilfordii Hook F. In the follow-up studies, all side effects were mild to moderate and resolved after the intervention ceased. Two studies compared Phytodolor((r)) N to placebo but poor reporting limited data extraction. The remaining studies each considered differing herbal interventions. AUTHORS' CONCLUSIONS: Several herbal interventions are inadequately justified by single studies or non-comparable studies in the treatment of rheumatoid arthritis. There is moderate evidence that oils containing GLA (evening primrose, borage, or blackcurrant seed oil) afford some benefit in relieving symptoms for RA, while evidence for Phytodolor(r) N is less convincing.Tripterygium wilfordii products may reduce some RA symptoms, however, oral use may be associated with several side effects. Many trials of herbal therapies are hampered by research design flaws and inadequate reporting. Further investigation of each herbal therapy is warranted, particularly via well designed, fully powered, confirmatory clinical trials that use American College of Rheumatology improvement criteria to measure outcomes and report results according to CONSORT guidelines. PMID- 21328258 TI - Techniques for the interruption of tubal patency for female sterilisation. AB - BACKGROUND: Female sterilisation is the most popular contraceptive method worldwide. Several techniques are described in the literature, however only few of them are commonly used and properly evaluated. OBJECTIVES: To compare the different tubal occlusion techniques in terms of major and minor morbidity, failure rates (pregnancies), technical failures and difficulties, and women's and surgeons' views. SEARCH STRATEGY: Originally MEDLINE and The Cochrane Controlled Trials Register were searched. For the 2010 update, searches of Popline, Lilacs, Pubmed and The Cochrane Controlled Trials Register were performed. Reference lists of identified trials were searched. SELECTION CRITERIA: All randomised controlled trials comparing different techniques for tubal sterilisation, regardless of the route of Fallopian tube access or the method of anaesthesia. DATA COLLECTION AND ANALYSIS: Trials under consideration were evaluated for methodological quality and appropriateness for inclusion. Nine relevant studies were included and the results were stratified in five groups: tubal ring versus clip, modified Pomeroy versus electrocoagulation, tubal ring versus electrocoagulation, modified Pomeroy versus Filshie clip and Hulka versus Filshie clip. Results are reported as odds ratio for dichotomous outcomes and weighted mean differences for continuous outcomes. MAIN RESULTS: Tubal ring versus clip: Minor morbidity was higher in the ring group (Peto OR 2.15; 95% CI 1.22, 3.78). Technical difficulties were found less frequent in the clip group ( Peto OR 3.87; 95% CI 1.90, 7.89). There was no difference in failure rates between the two groups (Peto OR 0.70; 95% CI 0.28, 1.76). Pomeroy versus electrocoagulation: Women undergoing modified Pomeroy technique had higher major morbidity than those with the electrocoagulation technique (Peto OR 2.87; 95% CI 1.13, 7.25). Postoperative pain was more frequent in the Pomeroy group (Peto OR 3.85; 95% CI 2.91, 5.10). Tubal ring versus electrocoagulation: Post operative pain was more frequently reported in the tubal ring group. No pregnancies were reported. Pomeroy versus Filshie clip: In the only trial comparing the two interventions only one pregnancy was reported in the Pomeroy group after follow-up for 24 months. No differences were found when comparing Hulka versus Filshie clip in the only study that compared these two devices. AUTHORS' CONCLUSIONS: Electrocoagulation was associated with less morbidity including post-operative pain when compared with the modified Pomeroy and tubal ring methods, despite the risk of burns to the small bowel. The small sample size and the relative short period of follow-up in these studies limited the power to show clinical or statistical differences for rare outcomes such as failure rates. Aspects such as training, costs and maintenance of the equipment may be important factors in deciding which method to choose. PMID- 21328259 TI - WITHDRAWN: Medical treatments in the short term management of reflux oesophagitis. AB - BACKGROUND: Oesophagitis arises when reflux of acid from the stomach into the oesophagus causes mucosal inflammation. It is a common problem and a systematic review on the optimum treatment would be useful. OBJECTIVES: To assess the effectiveness of proton pump inhibitors (PPIs), H2 receptor antagonists (H2RAs), prokinetic therapy, sucralfate and placebo in healing oesophagitis or curing reflux symptoms or both. To compare adverse effects with the different treatments. SEARCH STRATEGY: We searched MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials and the National Research Register until December 2004 and reference lists of articles. We also contacted manufacturers and researchers in the field. SELECTION CRITERIA: Randomised controlled trials assessing the healing of oesophagitis or reflux symptoms or both. Treatment involving PPIs, H2RAs, prokinetics, sucralfate and combinations either in comparison to another treatment regimen or to placebo for 2 and 12 weeks. DATA COLLECTION AND ANALYSIS: Two reviews independently assessed trial quality and extracted data. MAIN RESULTS: We included 134 trials involving 35,978 oesophagitis participants. Five RCTs evaluated standard dose of PPI versus placebo in 965 participants. There was a statistically significant benefit of taking standard dose PPI therapy compared to placebo in healing of oesophagitis (RR = 0.22; 95% CI 0.15 to 0.31). Ten RCTs reported on the outcome for H2RA versus placebo evaluating 1241 participants. There was statistically significant benefit of taking H2RA compared to placebo in healing of oesophagitis (RR 0.74,95% CI = 0.66 to 0.84). Three RCTs evaluated prokinetic therapy versus placebo in 198 participants. There was no statistically significant benefit of taking prokinetic therapy compared to placebo in healing of oesophagitis (RR 0.71, 95% CI 0.46 to 1.10). Twenty six RCTs reported the outcome for PPI versus H2RA or H2RA plus prokinetics, evaluating 4032 participants. There was statistically significant benefit of taking PPI therapy compared to H2RA or H2RA plus prokinetics in healing of oesophagitis (RR 0.51, 95% CI 0.44 to 0.59). AUTHORS' CONCLUSIONS: PPI therapy is the most effective therapy in oesophagitis but H2RA therapy is also superior to placebo. There is a paucity of evidence on prokinetic therapy but no evidence that it is superior to placebo. PMID- 21328260 TI - Treatment for Lambert-Eaton myasthenic syndrome. AB - BACKGROUND: Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder of neuromuscular transmission. Treatments attempt to overcome the harmful autoimmune process, or improve residual neuromuscular transmission OBJECTIVES: The objective was to examine the efficacy of treatment in Lambert-Eaton myasthenic syndrome. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Specialized Register (12 October 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (12 October 2010, Issue 4 2010 in the Cochrane Library), MEDLINE (January 1966 to September 2010) and EMBASE (January 1980 to September 2010). SELECTION CRITERIA: All randomised or quasi-randomised trials of adults and children with a diagnosis of Lambert-Eaton myasthenic syndrome, with or without small-cell lung cancer, receiving any form of pharmacological or physical treatment. DATA COLLECTION AND ANALYSIS: All authors independently assessed studies for inclusion and extracted data. Study authors were contacted for missing information when possible. MAIN RESULTS: Four controlled trials of 3,4 diaminopyridine compared with placebo in a total of 54 participants with Lambert Eaton myasthenic syndrome were eligible: three cross-over trials and one parallel group. Two were added at this update. One of these trials also assessed pyridostigmine in conjunction with 3,4-diaminopyridine. A further cross-over trial compared intravenous immunoglobulin (IVIg) to placebo in nine participants.Four trials of 3,4-diaminopyridine reported significant improvement in the primary outcome, muscle strength score, or myometric limb measurement for between hours and a week following treatment, and significant improvement in resting compound muscle action potential (CMAP) amplitude following 3,4 diaminopyridine, compared with placebo.A meta-analysis of the primary endpoint showed Quantitative Myasthenia Gravis (QMG) muscle score assessed between three and eight days was likely to improve by a mean of 2.44 points (95% confidence interval 3.6 to 1.22). Meta-analysis of the secondary endpoint CMAP amplitude also showed a mean improvement of 1.36 mV (95% confidence interval 0.99 to 1.72) over the same period. The risk of bias was determined to be low, and quality of evidence moderate to high.A single cross-over trial reported significant improvement in myometric limb strength and non-significant improvement in mean resting CMAP amplitude with IVIg compared to placebo. Clinical improvement lasted for up to eight weeks. AUTHORS' CONCLUSIONS: Limited but moderate to high quality evidence from randomised controlled trials showed that over days 3,4 diaminopyridine, or for up to 8 weeks IVIg, improved muscle strength scores and CMAP amplitudes in participants with Lambert-Eaton myasthenic syndrome. There are insufficient data at present to quantify this effect. Other possible treatments have not been tested in randomised controlled trials. PMID- 21328261 TI - Feeding interventions for growth and development in infants with cleft lip, cleft palate or cleft lip and palate. AB - BACKGROUND: Cleft lip and cleft palate are common birth defects, affecting about one baby of every 700 born. Feeding these babies is an immediate concern and there is evidence of delay in growth of children with a cleft as compared to those without clefting. In an effort to combat reduced weight for height, a variety of advice and devices are recommended to aid feeding of babies with clefts. OBJECTIVES: This review aims to assess the effects of these feeding interventions in babies with cleft lip and/or palate on growth, development and parental satisfaction. SEARCH STRATEGY: The following electronic databases were searched: the Cochrane Oral Health Group Trials Register (to 27 October 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 4), MEDLINE via OVID (1950 to 27 October 2010), EMBASE via OVID (1980 to 27 October 2010), PsycINFO via OVID (1950 to 27 October 2010) and CINAHL via EBSCO (1980 to 27 October 2010). Attempts were made to identify both unpublished and ongoing studies. There was no restriction with regard to language of publication. SELECTION CRITERIA: Studies were included if they were randomised controlled trials (RCTs) of feeding interventions for babies born with cleft lip, cleft palate or cleft lip and palate up to the age of 6 months (from term). DATA COLLECTION AND ANALYSIS: Studies were assessed for relevance independently and in duplicate. All studies meeting the inclusion criteria were data extracted and assessed for validity independently by each member of the review team. Authors were contacted for clarification or missing information whenever possible. MAIN RESULTS: Five RCTs with a total of 292 babies, were included in the review. Comparisons made within the RCTs were squeezable versus rigid feeding bottles (two studies), breastfeeding versus spoon-feeding (one study) and maxillary plate versus no plate (two studies). No statistically significant differences were shown for any of the primary outcomes when comparing bottle types, although squeezable bottles were less likely to require modification. No difference was shown for infants fitted with a maxillary plate compared to no plate. However, there was some evidence of an effect on weight at 6 weeks post-surgery in favour of breastfeeding when compared to spoon-feeding (mean difference 0.47; 95% confidence interval 0.20 to 0.74). AUTHORS' CONCLUSIONS: Squeezable bottles appear easier to use than rigid feeding bottles for babies born with clefts of the lip and/or palate, however, there is no evidence of a difference in growth outcomes between the bottle types. There is weak evidence that breastfeeding is better than spoon-feeding following surgery for cleft. There was no evidence to suggest that maxillary plates assist growth in babies with clefts of the palate. No evidence was found to assess the use of any types of maternal advice and/or support for these babies. PMID- 21328262 TI - Modification of the home environment for the reduction of injuries. AB - BACKGROUND: Injury in the home is common, accounting for approximately a third of all injuries. The majority of injuries to children under five and people aged 75 and older occur at home. Multifactorial injury prevention interventions have been shown to reduce injuries in the home. However, few studies have focused specifically on the impact of physical adaptations to the home environment and the effectiveness of such interventions needs to be ascertained. OBJECTIVES: To determine the effect of modifications to the home environment on the reduction of injuries due to environmental hazards. SEARCH STRATEGY: We searched The Cochrane Library, MEDLINE, EMBASE and other specialised databases. We also scanned conference proceedings and reference lists. We contacted the first author of all included randomised controlled trials. The searches were last updated to the end of December 2009, and were not restricted by language or publication status. SELECTION CRITERIA: Randomised controlled trials. DATA COLLECTION AND ANALYSIS: Two authors screened all abstracts for relevance, outcome and design. Two authors independently assessed methodological quality and extracted data from each eligible study. We performed meta-analysis to combine effect measures, using a random-effects model. We assessed heterogeneity using an I(2) statistic and a Chi(2) test. MAIN RESULTS: We found 28 published studies and one unpublished study. Only two studies were sufficiently similar to allow pooling of data for statistical analyses. Studies were divided into three groups; children, older people and the general population/mixed age group. None of the studies focusing on children or older people demonstrated a reduction in injuries that were a direct result of environmental modification in the home. One study in older people demonstrated a reduction in falls and one a reduction in falls and injurious falls that may have been due to hazard reduction. One meta-analysis was performed which examined the effects on falls of multifactorial interventions consisting of home hazard assessment and modification, medication review, health and bone assessment and exercise (RR 1.09, 95% CI 0.97 to 1.23). AUTHORS' CONCLUSIONS: There is insufficient evidence to determine whether interventions focused on modifying environmental home hazards reduce injuries. Further interventions to reduce hazards in the home should be evaluated by adequately designed randomised controlled trials measuring injury outcomes. Recruitment of large study samples to measure effect must be a major consideration for future trials. Researchers should also consider using factorial designs to allow the evaluation of individual components of multifactorial interventions. PMID- 21328263 TI - Continuous support for women during childbirth. AB - BACKGROUND: Historically, women have been attended and supported by other women during labour. However in hospitals worldwide, continuous support during labour has become the exception rather than the routine. OBJECTIVES: Primary: to assess the effects of continuous, one-to-one intrapartum support compared with usual care. Secondary: to determine whether the effects of continuous support are influenced by: (1) routine practices and policies; (2) the provider's relationship to the hospital and to the woman; and (3) timing of onset. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 December 2010). SELECTION CRITERIA: All published and unpublished randomized controlled trials comparing continuous support during labour with usual care. DATA COLLECTION AND ANALYSIS: We used standard methods of the Cochrane Collaboration Pregnancy and Childbirth Group. Two authors independently evaluated methodological quality and extracted the data. We sought additional information from the trial authors. We used random-effects analyses for comparisons in which high heterogeneity was present, and we reported results using the risk ratio for categorical data and mean difference for continuous data. MAIN RESULTS: Twenty-one trials involving 15061 women met inclusion criteria and provided usable outcome data. Results are of random-effects analyses, unless otherwise noted. Women allocated to continuous support were more likely to have a spontaneous vaginal birth (RR 1.08, 95% CI 1.04 to 1.12) and less likely to have intrapartum analgesia (RR 0.90, 95% CI 0.84 to 0.97) or to report dissatisfaction (RR 0.69, 95% CI 0.59 to 0.79). In addition their labours were shorter (mean difference -0.58 hours, 95% CI -0.86 to -0.30), they were less likely to have a caesarean (RR 0.79, 95% CI 0.67 to 0.92) or instrumental vaginal birth (fixed-effect, RR 0.90, 95% CI 0.84 to 0.96), regional analgesia (RR 0.93, 95% CI 0.88 to 0.99), or a baby with a low 5-minute Apgar score (fixed-effect, RR 0.70, 95% CI 0.50 to 0.96). There was no apparent impact on other intrapartum interventions, maternal or neonatal complications, or on breastfeeding. Subgroup analyses suggested that continuous support was most effective when provided by a woman who was neither part of the hospital staff nor the woman's social network, and in settings in which epidural analgesia was not routinely available. No conclusions could be drawn about the timing of onset of continuous support. AUTHORS' CONCLUSIONS: Continuous support during labour has clinically meaningful benefits for women and infants and no known harm. All women should have support throughout labour and birth. PMID- 21328264 TI - WITHDRAWN: Human menopausal gonadotropin versus recombinant follicle stimulation hormone for ovarian stimulation in assisted reproductive cycles. AB - BACKGROUND: hMG and recombinant FSH, have both been used successfully for controlled ovarian hyperstimulation in in vitro fertilization and embryo transfer (IVF-ET). OBJECTIVES: To compare the effectiveness of hMG with rFSH in ovarian stimulation protocols in IVF or ICSI treatment cycles. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Group trials register (searched 3rd Jan 2002), PubMed, MEDLINE, Web of Science (all searched 1985 to May 15 2002), and reference lists of articles. We also contacted manufacturers and researchers in the field. SELECTION CRITERIA: Randomised trials comparing hMG with rFSH for ovarian stimulation in IVF or ICSI treatment for treatment of infertility in normogonadotrophic women. DATA COLLECTION AND ANALYSIS: The main outcome measure was ongoing pregnancy/live birth per woman.Secondary outcomes included total gonadotrophin dose used, cancellation, number of oocytes retrieved, implantation, clinical pregnancy per woman, multiple pregnancy, spontaneous abortion and ovarian hyperstimulation syndrome. Peto odds ratios (OR) for hMG relative to rFSH were calculated after testing for homogeneity of treatment effect across all trials. Analyses were performed separately for the three different GnRHa protocols used: (1) without GnRHa down-regulation, (2) with GnRHa down-regulation using a short protocol and (3) with GnRHa down-regulation using a long protocol. MAIN RESULTS: Eight trials that met the inclusion criteria could be identified. One trial did not use down-regulation, one trial used a short protocol and six trials used a long down-regulation protocol. In the one trial with non-down-regulated women and in the one trial that used a short down regulation protocol there was no evidence of a difference between hMG and rFSH in any clinical outcome. Data of four truly randomised trials in women down regulated using a long protocol could be pooled. There was no evidence of a difference between hMG and rFSH in ongoing pregnancy/live birth per woman (OR 1.27; 95% CI 0.98 to 1.64). Furthermore there was no clear difference on any of the secondary outcomes, although the clinical pregnancy rate per woman was of borderline significance in favour of hMG (summary OR 1.28; 95% CI 1.00 to 1.64). The other secondary outcomes were comparable for both gonadotrophins. AUTHORS' CONCLUSIONS: For all three GnRHa protocols analysed there is insufficient evidence of a difference between hMG and rFSH on ongoing pregnancy or live birth. More large randomised trials are needed to estimate the difference between hMG and rFSH more precisely. Such trials should preferably (1) use a consistent long GnRHa protocol and (2) use a fixed dose of gonadotrophin such to prevent potentially subjective decisions of the clinician in dosing and (3) take live birth as primary endpoint. At this moment in time however, in prescribing gonadotrophins for ovarian hyperstimulation in IVF one should use the least expensive medication. PMID- 21328265 TI - Thymic peptides for treatment of cancer patients. AB - BACKGROUND: Purified thymus extracts (pTE) and synthetic thymic peptides (sTP) are thought to enhance the immune system of cancer patients in order to fight the growth of tumour cells and to resist infections due to immunosuppression induced by the disease and antineoplastic therapy. OBJECTIVES: To evaluate the effectiveness of pTE and sTP for the management of cancer. SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library 2010, Issue 3), MEDLINE, EMBASE, AMED, BIOETHICSLINE, BIOSIS, CATLINE, CISCOM, HEALTHSTAR, HTA, SOMED and LILACS (to February 2010). SELECTION CRITERIA: Randomised trials of pTE or sTP in addition to chemotherapy or radiotherapy, or both, compared to the same regimen with placebo or no additional treatment in adult cancer patients. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data from published trials. We derived odds ratios (OR) from overall survival (OS) and disease-free survival (DFS) rates, tumour response (TR) rates, and rates of adverse effects (AE) related to antineoplastic treatments. We used a random-effects model for meta analysis. MAIN RESULTS: We identified 26 trials (2736 patients). Twenty trials investigated pTE (thymostimulin or thymosin fraction 5) and six trials investigated sTP (thymopentin or thymosin alpha(1)). Twenty-one trials reported results for OS, six for DFS, 14 for TR, nine for AE and 10 for safety of pTE and sTP. Addition of pTE conferred no benefit on OS (RR 1.00, 95% CI 0.79 to 1.25); DFS (RR 0.97, 95% CI 0.82 to 1.16); or TR (RR 1.07, 95% CI 0.92 to 1.25). Heterogeneity was moderate to high for all these outcomes. For thymosin alpha(1) the pooled RR for OS was 1.21 (95% CI 0.94 to 1.56, P = 0.14), with low heterogeneity; and 3.37 (95% CI 0.66 to 17.30, P = 0.15) for DFS, with moderate heterogeneity. The pTE reduced the risk of severe infectious complications (RR 0.54, 95% CI 0.38 to 0.78, P = 0.0008; I2 = 0%). The RR for severe neutropenia in patients treated with thymostimulin was 0.55 (95% CI 0.25 to 1.23, P = 0.15). Tolerability of pTE and sTP was good. Most of the trials had at least a moderate risk of bias. AUTHORS' CONCLUSIONS: Overall, we found neither evidence that the addition of pTE to antineoplastic treatment reduced the risk of death or disease progression nor that it improved the rate of tumour responses to antineoplastic treatment. For thymosin alpha(1), there was a trend for a reduced risk of dying and of improved DFS. There was preliminary evidence that pTE lowered the risk of severe infectious complications in patients undergoing chemotherapy or radiotherapy. PMID- 21328266 TI - Interventions for smokeless tobacco use cessation. AB - BACKGROUND: Use of smokeless tobacco (ST) can lead to nicotine addiction and long term use can lead to health problems including periodontal disease, cancer, and cerebrovascular and cardiovascular disease. OBJECTIVES: To assess the effects of behavioural and pharmacologic interventions for the treatment of ST use. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, Web of Science, PsycINFO, Dissertation Abstracts Online, and Scopus. Date of last search: October 2010. SELECTION CRITERIA: Randomized trials of behavioural or pharmacological interventions to help users of ST to quit with follow up of at least six months. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data. We summarised as odds ratios. For subgroups of trials with similar types of intervention and without substantial statistical heterogeneity, we estimated pooled effects using a Mantel Haenszel fixed-effect method. MAIN RESULTS: Data from one study suggest that varenicline increases ST abstinence rates (Odds Ratio [OR] 1.6, 95% Confidence Interval (CI) 1.08 to 2.36) among Swedish snus users.Two trials of bupropion SR did not detect a benefit of treatment at six months or longer (OR 0.86, 95% CI 0.47 to 1.57). Nicotine replacement therapy (patch, gum, and lozenge) was not observed to increase tobacco abstinence rates (OR 1.14, 95% CI: 0.91 to 1.42). There was statistical heterogeneity among the 14 trials of behavioural interventions; seven of them reported statistically and clinically significant benefits, four suggested benefit but with wide CIs, whilst two had similar intervention and control quit rates and relatively narrow CIs. Heterogeneity was not explained by the design (individual or cluster randomization), whether participants were selected for interest in quitting, or specific intervention components. Most trials included either telephone counselling, an oral examination and feedback about any ST induced mucosal changes, or both. In a post hoc subgroup analysis there was some evidence that behavioural interventions which include telephone counselling might increase abstinence rates more than interventions with less contact. In one trial an interactive website increased abstinence more than a static website. AUTHORS' CONCLUSIONS: Varenicline and behavioural interventions may help ST users to quit. Behavioural interventions incorporating telephone counselling or an oral examination are likely to increase abstinence rates. PMID- 21328268 TI - Advising patients to increase fluid intake for treating acute respiratory infections. AB - BACKGROUND: Acute respiratory infection is a common reason for people to present for medical care. Advice to increase fluid intake is a frequent treatment recommendation. Attributed benefits of fluids include replacing increased insensible fluid losses, correcting dehydration from reduced intake and reducing the viscosity of mucus. However, there are theoretical reasons for increased fluid intake to cause harm. Anti-diuretic hormone secretion is increased in lower respiratory tract infections of various aetiologies. This systematic examination of the evidence sought to determine the benefit versus harm from increasing fluid intake. OBJECTIVES: To answer the following questions.1. Does recommending increased fluid intake as a treatment for acute respiratory infections improve duration and severity of symptoms? 2. Are there adverse effects from recommending increased fluids in people with acute respiratory infections? 3. Are any benefits or harms related to site of infection (upper or lower respiratory tract) or a different severity of illness? SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, issue 4), which contains the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to November Week 3, 2010), EMBASE (1974 to December 2010), Current Contents (2000 to December 2010) and CINAHL (1982 to December 2010). We searched reference lists of articles identified and contacted experts in the relevant disciplines. SELECTION CRITERIA: Randomised controlled trials (RCTs) that examined the effect of increasing fluid intake in people with acute respiratory infections. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the identified studies to determine eligibility for inclusion. MAIN RESULTS: No RCTs assessing the effect of increasing fluid intake in acute respiratory infections were found. AUTHORS' CONCLUSIONS: There is currently no evidence from RCTs for or against the recommendation to increase fluids in acute respiratory infections. The implications for fluid management of acute respiratory infections in the outpatient or primary care setting have not been studied in any RCTs to date. Some non-experimental (observational) studies report that increasing fluid intake in acute respiratory infections of the lower respiratory tract may cause harm. RCTs need to be done to determine the true effect of this very common medical advice. PMID- 21328267 TI - Compulsory community and involuntary outpatient treatment for people with severe mental disorders. AB - BACKGROUND: There is controversy as to whether compulsory community treatment for people with severe mental illnesses reduces health service use, or improves clinical outcome and social functioning. Given the widespread use of such powers it is important to assess the effects of this type of legislation. OBJECTIVES: To examine the clinical and cost effectiveness of compulsory community treatment for people with severe mental illness. SEARCH STRATEGY: We undertook searches of the Cochrane Schizophrenia Group Register 2003, 2008, and Science Citation Index. We obtained all references of identified studies and contacted authors of each included study. SELECTION CRITERIA: All relevant randomised controlled clinical trials of compulsory community treatment compared with standard care for people with severe mental illness. DATA COLLECTION AND ANALYSIS: We reliably selected and quality assessed studies and extracted data. For binary outcomes, we calculated a fixed effects risk ratio (RR), its 95% confidence interval (CI) and, where possible, the weighted number needed to treat/harm statistic (NNT/H). MAIN RESULTS: We identified two randomised clinical trials (total n = 416) of court ordered 'Outpatient Commitment' (OPC) from the USA. We found little evidence that compulsory community treatment was effective in any of the main outcome indices: health service use (2 RCTs, n = 416, RR for readmission to hospital by 11-12 months 0.98 CI 0.79 to 1.2); social functioning (2 RCTs, n = 416, RR for arrested at least once by 11-12 months 0.97 CI 0.62 to 1.52); mental state; quality of life (2 RCTs, n = 416, RR for homelessness 0.67 CI 0.39 to 1.15) or satisfaction with care (2 RCTs, n = 416, RR for perceived coercion 1.36 CI 0.97 to 1.89). However, risk of victimisation may decrease with OPC (1 RCT, n = 264, RR 0.5 CI 0.31 to 0.8). In terms of numbers needed to treat (NNT), it would take 85 OPC orders to prevent one readmission, 27 to prevent one episode of homelessness and 238 to prevent one arrest. The NNT for the reduction of victimisation was lower at six (CI 6 to 6.5). A new search for trials in 2008 did not find any new trials that were relevant to this review. AUTHORS' CONCLUSIONS: Compulsory community treatment results in no significant difference in service use, social functioning or quality of life compared with standard care. People receiving compulsory community treatment were, however, less likely to be victims of violent or non violent crime. It is unclear whether this benefit is due to the intensity of treatment or its compulsory nature. Evaluation of a wide range of outcomes should be considered when this type of legislation is introduced. PMID- 21328269 TI - Creatine for treating muscle disorders. AB - BACKGROUND: Progressive muscle weakness is a main symptom of most hereditary and acquired muscle diseases. Creatine improves muscle performance in healthy individuals. This is an update of our 2007 Cochrane review that evaluated creatine treatment in muscle disorders. OBJECTIVES: To evaluate the efficacy of creatine compared to placebo for the treatment of muscle weakness in muscle diseases. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Specialized Register (4 October 2010), the Cochrane Central Register of Controlled Trials (11 October 2010, Issue 4, 2010 in The Cochrane Library), MEDLINE (January 1966 to September 2010) and EMBASE (January 1980 to September 2010) for randomised controlled trials (RCT) of creatine used to treat muscle diseases. SELECTION CRITERIA: RCTs or quasi-RCTs of creatine treatment compared to placebo in hereditary muscle diseases or idiopathic inflammatory myopathies. DATA COLLECTION AND ANALYSIS: Two authors independently applied the selection criteria, assessed trial quality and extracted data. We obtained missing data from investigators. MAIN RESULTS: The updated searches identified two new studies. A total of 14 trials, including 364 randomised participants, met the selection criteria. Meta-analysis of six trials in muscular dystrophies including 192 participants revealed a significant increase in muscle strength in the creatine group compared to placebo, with a weighted mean difference of 8.47%; (95% confidence intervals (CI) 3.55 to 13.38). Pooled data of four trials including 115 participants showed that a significantly higher number of patients felt better during creatine treatment compared to placebo with a risk ratio of 4.51 (95% CI 2.33 to 8.74). One trial in 37 participants with idiopathic inflammatory myopathies also showed a significant improvement in functional performance. No trial reported any clinically relevant adverse event. In metabolic myopathies, meta-analyses of three cross-over trials including 33 participants revealed no significant difference in muscle strength. One trial reported a significant deterioration of ADL (mean difference 0.54 on a 1 to 10 scale; 95% CI 0.14 to 0.93) and an increase in muscle pain during high-dose creatine treatment in McArdle disease. AUTHORS' CONCLUSIONS: High quality evidence from RCTs shows that short- and medium-term creatine treatment increases muscle strength in muscular dystrophies. There is also evidence that creatine improves functional performance in muscular dystrophy and idiopathic inflammatory myopathy. Creatine is well tolerated in these people. High quality but limited evidence from RCTs does not show significant improvement in muscle strength in metabolic myopathies. High-dose creatine treatment impaired ADL and increased muscle pain in McArdle disease. PMID- 21328270 TI - Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia. AB - BACKGROUND: Recombinant factor VIIa (rFVIIa) is licensed for use in patients with haemophilia and inhibitory allo-antibodies. It is also increasingly being used for off-license indications to prevent bleeding in operations where blood loss is likely to be high, and/or to stop bleeding that is proving difficult to control by other means. OBJECTIVES: To assess the effectiveness of rFVIIa when used therapeutically to control active bleeding, or prophylactically to prevent (excessive) bleeding in patients without haemophilia. SEARCH STRATEGY: We searched the Cochrane Injuries Group Specialised Register, CENTRAL, MEDLINE, EMBASE and other specialised databases up to 25 February 2009. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing rFVIIa with placebo, or one dose of rFVIIa with another, in any patient population (except haemophilia). Outcomes were mortality, blood loss or control of bleeding, red cell transfusion requirements, number of patients transfused and thromboembolic adverse events. DATA COLLECTION AND ANALYSIS: Two authors independently assessed potentially relevant studies for inclusion, extracted data and examined risk of bias. We considered prophylactic and therapeutic rFVIIa studies separately. MAIN RESULTS: Twenty-five RCTs were included: 24 were placebo-controlled double-blind RCTs and one compared different doses of rFVIIa.Fourteen trials involving 1137 participants examined the prophylactic use of rFVIIa; 713 received rFVIIa. There was no evidence of mortality benefit (RR 1.06; 95% CI 0.50 to 2.24). There was decreased blood loss (WMD -272 mL; 95% CI -399 to -146) and decreased red cell transfusion requirements (WMD -243 mL; 95% CI -393 to -92) with rFVIIa treatment; however these values were likely overestimated due to the inability to incorporate data from trials showing no difference of rFVIIa treatment compared to placebo. There was a trend in favour of rFVIIa in the number of participants transfused (RR 0.91; 95% CI 0.82 to 1.02). But there was a trend against rFVIIa with respect to thromboembolic adverse events (RR 1.32; 95% CI 0.84 to 2.06).Eleven trials involving 2366 participants examined the therapeutic use of rFVIIa; 1507 received rFVIIa. There were no outcomes where any observed advantage, or disadvantage, of rFVIIa over placebo could not have been observed by chance alone. There was a trend in favour of rFVIIa for reducing mortality (RR 0.89; 95% CI 0.77 to 1.03). However, there was a trend against rFVIIa for increased thromboembolic adverse events (RR 1.21; 95% CI 0.93 to 1.58). AUTHORS' CONCLUSIONS: The effectiveness of rFVIIa as a more general haemostatic drug, either prophylactically or therapeutically, remains unproven. The use of rFVIIa outside its current licensed indications should be restricted to clinical trials. PMID- 21328271 TI - WITHDRAWN: Interventions for dysphagia in oesophageal cancer. AB - BACKGROUND: The majority of oesophageal and gastro-oesophageal cancers are diagnosed at an advanced stage and palliative treatment is the realistic management option for most patients. The optimal intervention for the palliation of dysphagia in these patients has not been established. OBJECTIVES: To systematically analyse and summarise the efficacy of different interventions used in the palliation of dysphagia in primary oesophageal carcinoma. SEARCH STRATEGY: We undertook a search according to the Cochrane Upper Gastrointestinal and Pancreatic Diseases model using the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE and CINAHL and major conference proceedings up to August 2005. The literature search was re-run in August 2006 and March 2007. SELECTION CRITERIA: Randomised controlled trials (RCTs) in patients with inoperable or unresectable primary oesophageal cancer who underwent palliative treatment. We included rigid plastic intubation, self expanding metallic stent (SEMS) insertion, brachytherapy, external beam radiotherapy, chemotherapy, oesophageal bypass surgery, chemical and thermal ablation therapy, either head-to-head or in combination. The primary outcome was dysphagia improvement. Secondary outcomes included recurrent dysphagia, technical success, procedure related mortality, 30-day mortality, adverse effects and quality of life. DATA COLLECTION AND ANALYSIS: One author assessed the eligibility criteria of each study and extracted data regarding outcomes and factors affecting risk of bias. MAIN RESULTS: We included 2542 patients from 40 studies. SEMS insertion is safer and more effective than plastic tube insertion. Thermal and chemical ablative therapy provide comparable dysphagia palliation but have an increased requirement for re-interventions and adverse effects. Anti reflux stents provide comparable dysphagia palliation to conventional metal stents. Some anti-reflux stents might reduce gastro-oesophageal reflux compared to conventional metal stents. Brachytherapy might be a suitable alternative to SEMS in providing a survival advantage and possibly a better quality of life. AUTHORS' CONCLUSIONS: Self-expanding metal stent insertion is safe, effective and quicker in palliating dysphagia compared to other modalities. However, high-dose intraluminal brachytherapy is a suitable alternative and might provide additional survival benefit with a better quality of life. Self-expanding metal stent insertion and brachytherapy provide comparable palliation to endoscopic ablative therapy but are preferable due to the reduced requirement for re-interventions. Rigid plastic tube insertion, dilatation alone or in combination with other modalities, chemotherapy alone, combination chemoradiotherapy and bypass surgery are not recommended for palliation of dysphagia due to a high incidence of delayed complications and recurrent dysphagia. PMID- 21328272 TI - Shengmai (a traditional Chinese herbal medicine) for heart failure. AB - BACKGROUND: Heart failure is a major public health problem worldwide. Shengmai (a traditional Chinese herbal medicine) has long been used as a complementary treatment for heart failure in China. OBJECTIVES: To determine the effects (both benefits and harms) of Shengmai plus usual treatment versus usual treatment alone for heart failure. SEARCH STRATEGY: We searched CENTRAL and DARE on The Cochrane Library (Issue 3, 2008), MEDLINE (1966 to August 2008), EMBASE (1984 to August 2008), AMED (1985 to August 2008) and BIOSIS (1997 to August 2008) and CBM (1978 to August 2008). We added two new Chinese databases for the update; VIP (1989 to September 2008) and CNKI (1979 to September 2008). We also handsearched Chinese journals. No language restrictions were applied. SELECTION CRITERIA: Randomized controlled trials (RCTs) of Shengmai plus usual treatment versus usual treatment alone or Shengmai versus placebo for heart failure, irrespective of blinding status, were included. More stringent inclusion criteria were applied in this update and only studies that have a clear description of randomisation methods are classed as true RCTs and hence included. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, assessed methodological quality and extracted data. Dichotomous and continuous data were calculated as relative risk (RR), and mean differences (MD) or standardized mean difference (SMD). Random effect model and fixed-effect model were used to perform meta-analysis for with and without heterogeneity respectively. MAIN RESULTS: Only six RCTs with a total of 440 patients were included in this updated review. Compared to usual treatment alone, Shengmai plus usual treatment in five trials indicated an improvement in NYHA classification (RR 0.37; 95% CI 0.25 to 0.54). Other benefits were observed, but were limited to low patient numbers and significant heterogeneity: ejection fraction, cardiac output, stroke volume, exercise test and ratio of peak early to late diastolic filling velocity. Only one RCT with 40 patients compared Shengmai to placebo, and improvements were seen in stroke volume, Heath and Cardic index and myocardial contractility. Two studies reported mild adverse effects, but no patients were withdrawn or needed medication due to these adverse effects. AUTHORS' CONCLUSIONS: Shengmai may be beneficial for heart failure compared to placebo or plus usual treatment compared to usual treatment alone. However, long term and more high quality studies are needed to provide clear evidence for the future use of Shengmai. PMID- 21328273 TI - Oximes for acute organophosphate pesticide poisoning. AB - BACKGROUND: Acute organophosphorus pesticide poisoning causes tens of thousands of deaths each year across the developing world. Standard treatment involves administration of intravenous atropine and oxime to reactivate inhibited acetylcholinesterase. The clinical usefulness of oximes, such as pralidoxime and obidoxime, has been challenged over the past 20 years by physicians in many parts of the world. OBJECTIVES: To quantify the effectiveness and safety of the administration of oximes in acute organophosphorus pesticide-poisoned patients. SEARCH STRATEGY: We searched both English and Chinese databases: Cochrane Injuries Group Specialised Register, Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE (Ovid SP), EMBASE (Ovid SP), ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED), ISI Web of Science: Conference Proceedings Citation Index-Science (CPCI-S) and the Chinese language databases CNKI and WANGFANG. All searches were run in September 2009. SELECTION CRITERIA: Articles that could possibly be RCTs were retrieved to determine if they were randomised. DATA COLLECTION AND ANALYSIS: The published methodology of three RCTs was not clear. We contacted the principal authors of these, but did not obtain further information. MAIN RESULTS: Seven pralidoxime RCTs were found. Three RCTs including 366 patients studied pralidoxime vs placebo and four RCTs including 479 patients compared two or more different doses. These trials found quite disparate results with treatment effects ranging from benefit to harm. However, many studies did not take into account several issues important for outcomes. In particular, baseline characteristics were not balanced, oxime doses varied widely, there were substantial delays to treatment, and the type of organophosphate was not taken into account. Only one RCT compared the World Health Organization (WHO) recommended doses with placebo. This trial showed no clinical benefits and a trend towards harm in all sub-groups, despite clear evidence that these doses reactivated acetylcholinesterase in the blood. AUTHORS' CONCLUSIONS: Current evidence is insufficient to indicate whether oximes are harmful or beneficial. The WHO recommended regimen (30 mg/kg pralidoxime chloride bolus followed by 8 mg/kg/hr infusion) is not supported. Further RCTs are required to examine other strategies and regimens. There are many theoretical and practical reasons why oximes may not be useful, particularly for late presentations of dimethyl OP and those with a large excess of OP that simply re inhibits reactivated enzymes. Future studies should screen for patient sub-groups that may benefit and may need flexible dosing strategies as clinical effectiveness and doses may depend on the type of OP. PMID- 21328274 TI - WITHDRAWN: Chinese herbal medicines for induction of remission in advanced or late gastric cancer. AB - BACKGROUND: Gastric cancer is difficult to cure once it progresses into an advanced or late stage. Although some chemotherapies or bio-therapies have made progress in the remission of this disease, mortality remains high. A variety of Chinese medicinal herbs have been used to treat gastric cancer. OBJECTIVES: To assess the effectiveness of Chinese medicinal herbs in the short term remission of advanced or late gastric cancer. SEARCH STRATEGY: We searched the Cochrane Library, MEDLINE, EMBASE, AHMED (Allied and Complementary Medicine Database) and CBM (Chinese Biomedical Database) from the first year of the databases to May, 2008. We handsearched a number of journals. SELECTION CRITERIA: All randomised clinical trials of Chinese herbs for advanced or late gastric cancer were included. DATA COLLECTION AND ANALYSIS: Two authors independently extracted the data, which were analysed by RevMan 5.0 software. For dichotomous data, we estimated the relative risk. For continuous data, we calculated the weighted mean difference. MAIN RESULTS: Fifty-five qualified trials with 5261 advanced or late gastric cancer patients were identified, most of which were of low quality and used TCMHs plus chemotherapy compared with the same chemotherapy alone (41 trials). Except for four trials of Huachansu, we could not pool the results because no more than two used the same intervention or outcomes. TCMHs combined with or without chemotherapy in the 51 trials showed statistically significant difference for the improvement of mortality in six trials, quality of life in 13 trials, rate of remission in ten trials, discontinuation from treatment in three trials, leukopenia in one trial, vomiting/nausea in one trial. The pooled results from the four trials of Huachansu showed statistically significant difference for the improvement of leukopenia, but no significant difference for the improvement of adverse events in the digestive system or rate of short-term remission. AUTHORS' CONCLUSIONS: This review did not provide assured evidence concerning the effectiveness of TCMHs in improving the quality of life or rate of remission, alleviating the toxic and side effects caused by the chemotherapy, or reducing short-term mortality. Limited and weak evidence showed that Huachansu, when used together with chemotherapy, improved leukopenia caused by chemotherapy, but did not improve rate of short-term remission. Large, well designed clinical trials are required urgently before any confident conclusions can be drawn about the value of TCMHs for advanced or late gastric cancer. PMID- 21328275 TI - Interventions for preventing neuropathy caused by cisplatin and related compounds. AB - BACKGROUND: Cisplatin and several related antineoplastic agents used to treat many types of solid tumors are neurotoxic, and most patients completing a full course of cisplatin chemotherapy develop a clinically detectable sensory neuropathy. Effective neuroprotective therapies have been sought. OBJECTIVES: To examine the efficacy of purported chemoprotective agents to prevent or limit the neurotoxicity of cisplatin and related agents. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Specialized Register (25 August 2010), the Cochrane Central Register of Controlled Trials (Issue 3, 2010 in The Cochrane Library), MEDLINE (January 1966 to August 2010), EMBASE (January 1980 to August 2010), LILACS (January 1982 to August 2010), CINAHL (January 1982 to August 2010) for randomized trials designed to evaluate neuroprotective agents used to prevent or limit neurotoxicity of cisplatin and related agents among human patients. SELECTION CRITERIA: Quasi-randomized or randomized controlled trials whose participants received cisplatin (or related compounds) chemotherapy with or without a potential chemoprotectant (acetylcysteine, amifostine, ACTH, BNP7787, calcium and magnesium, diethyldithiocarbamate, glutathione, Org 2766, oxcarbazepine, or vitamin E) and were evaluated zero to six months after completing chemotherapy using quantitative sensory testing (primary) or other measures including nerve conduction studies or neurological impairment rating using validated scales (secondary). DATA COLLECTION AND ANALYSIS: We identified 16 randomized trials involving five possible chemoprotective agents in the initial 2006 review. Each study was reviewed by two authors who extracted the data and reached consensus. The 2010 update identified 11 additional randomized trials consisting of nine possible chemoprotective agents, including three treatments (acetylcysteine, calcium and magnesium, and oxcarbazepine) not among those described in the 2006 review. The included trials in the updated review involved eight unrelated treatments and included many disparate measures of neuropathy, resulting in insufficient data for any one measure to combine the results in most instances. MAIN RESULTS: One of four eligible amifostine trials (541 total participants in all four trials) used quantitative sensory testing and demonstrated a favorable outcome in terms of amifostine neuroprotection, but the vibration perception threshold result was based on data from only 14 participants receiving amifostine who completed the post-treatment evaluation and should be regarded with caution. Of the six eligible glutathione trials (354 participants), one used quantitative sensory testing but reported only qualitative analyses. Four eligible Org 2766 trials (311 participants) employed quantitative sensory testing reported disparate results; meta-analyses of three trials using comparable measures showed no significant vibration perception threshold neuroprotection. The remaining trial reported only descriptive analyses. The single eligible trials involving acetylcysteine (14 participants), diethyldithiocarbamate (195 participants), calcium and magnesium (33 participants), and oxcarbazepine (32 participants) and the two eligible trials involving vitamin E (57 participants) did not perform quantitative sensory testing. In all, data from 1,537 participants were included. AUTHORS' CONCLUSIONS: At present, the data are insufficient to conclude that any of the purported chemoprotective agents (acetylcysteine, amifostine, calcium and magnesium, diethyldithiocarbamate, glutathione, Org 2766, oxycarbazepine, or Vitamin E) prevent or limit the neurotoxicity of platin drugs among human patients. PMID- 21328276 TI - Recombinant versus urinary gonadotrophin for ovarian stimulation in assisted reproductive technology cycles. AB - BACKGROUND: Several systematic reviews compared recombinant gonadotrophin with urinary gonadotrophins (HMG, purified FSH, highly purified FSH) for ovarian hyperstimulation in IVF and ICSI cycles and these reported conflicting results. Each of these reviews used different inclusion and exclusion criteria for trials. Our aim in producing this review is to bring together all randomised studies in this field under common inclusion criteria with consistent and valid statistical methods. OBJECTIVES: To compare the effectiveness of recombinant gonadotrophin (rFSH) with the three main types of urinary gonadotrophins (i.e. HMG, FSH-P and FSH-HP) for ovarian stimulation in women undergoing IVF or ICSI treatment cycles. SEARCH STRATEGY: An extended search was done according to Cochrane guidelines including the Menstrual Disorders & Subfertility Group's Specialised Register of controlled trials, The Cochrane Central Register of Controlled Trials, MEDLINE (1966 to May 2010), EMBASE (1980 to May 2010), CINAHL (1982 to May 2010), National Research Register, and Current Controlled Trials. SELECTION CRITERIA: All randomised controlled trials reporting data comparing clinical outcomes for women undergoing IVF/ICSI cycles and using recombinant FSH in comparison with HMG or highly purified HMG, purified urinary FSH (FSH-P), and highly purified urinary FSH (FSH-HP) for ovarian hyperstimulation in IVF or ICSI cycles were included. DATA COLLECTION AND ANALYSIS: Primary outcome measure was live birth rate and OHSS per randomised woman.Binary outcomes were analysed using odds ratios and also reported in absolute terms. Grouped analyses were carried out for all outcomes to explore whether relative effects differed due to key features of the trials. MAIN RESULTS: We included 42 trials with a total of 9606 couples. Comparing rFSH to any of the other gonadotrophins irrespective of the down regulation protocol used, did not result in any evidence of a statistically significant difference in live birth rate (28 trials, 7339 couples, odds ratio 0.97, 95% CI 0.87 to 1.08). This suggests that for a group with a 25% live birth rate using urinary gonadotrophins the rate would be between 22.5% and 26.5% using rFSH. There was also no evidence of a difference in the OHSS rate (32 trials, 7740 couples, OR 1.18, 95% CI 0.86 to 1.61). This means that for a group with 2% risk of OHSS using urinary gonadotrophins, the risk would be between 1.7% and 3.2% using rFSH. AUTHORS' CONCLUSIONS: Clinical choice of gonadotrophin should depend on availability, convenience and costs. Further research on these comparisons is unlikely to identify substantive differences in effectiveness or safety. PMID- 21328277 TI - Vestibular rehabilitation for unilateral peripheral vestibular dysfunction. AB - BACKGROUND: This is an update of a Cochrane Review first published in The Cochrane Library in Issue 4, 2007.Unilateral peripheral vestibular dysfunction (UPVD) can occur as a result of disease, trauma or postoperatively. The dysfunction is characterised by complaints of dizziness, visual or gaze disturbances and balance impairment. Current management includes medication, physical manoeuvres and exercise regimes, the latter known collectively as vestibular rehabilitation (VR). OBJECTIVES: To assess the effectiveness of vestibular rehabilitation in the adult, community-dwelling population of people with symptomatic unilateral peripheral vestibular dysfunction. SEARCH STRATEGY: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ISRCTN and additional sources for published and unpublished trials. The most recent search was 1 July 2010, following a previous search in March 2007. SELECTION CRITERIA: Randomised trials of adults living in the community, diagnosed with symptomatic unilateral peripheral vestibular dysfunction. We sought comparisons of VR versus control (placebo etc.), other treatment (non-VR, e.g. pharmacological) or another form of VR. We considered the outcome measures of frequency and severity of dizziness or visual disturbance; changes in balance impairment, function or quality of life; and measure/s of physiological status with known functional correlation. DATA COLLECTION AND ANALYSIS: Both authors independently extracted data and assessed trials for risk of bias. MAIN RESULTS: We included 27 trials, involving 1668 participants, in the review. Trials addressed the effectiveness of VR against control/sham interventions, medical interventions or other forms of VR. Individual and pooled data showed a statistically significant effect in favour of VR over control or no intervention. The exception to this was when movement-based VR was compared to physical manoeuvres for benign paroxysmal positional vertigo (BPPV), where the latter was shown to be superior in cure rate in the short term. There were no reported adverse effects. AUTHORS' CONCLUSIONS: There is moderate to strong evidence that VR is a safe, effective management for unilateral peripheral vestibular dysfunction, based on a number of high quality randomised controlled trials. There is moderate evidence that VR provides a resolution of symptoms and improvement in functioning in the medium term. However, there is evidence that for the specific diagnostic group of BPPV, physical (repositioning) manoeuvres are more effective in the short term than exercise-based vestibular rehabilitation; although a combination of the two is effective for longer-term functional recovery. There is insufficient evidence to discriminate between differing forms of VR. PMID- 21328278 TI - Levodopa for restless legs syndrome. AB - BACKGROUND: Levodopa plus dopamine decarboxylase inhibitor is a common treatment for restless legs syndrome (RLS). OBJECTIVES: To evaluate efficacy and safety of levodopa for RLS compared to placebo and other active agents. SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library 2008, Issue 4), MEDLINE, EMBASE, PsycINFO and CINAHL, from January 1985 to December 2008, reference lists of articles, and contacted pharmaceutical companies. SELECTION CRITERIA: We included double-blind randomised controlled trials (RCT) investigating levodopa treatment versus placebo or other treatment for at least seven days in patients with RLS (age >= 18 years). Outcomes included symptom severity, CGI-I, objective as well as self rated sleep parameters, quality of life, and safety parameters. DATA COLLECTION AND ANALYSIS: Two authors extracted data, assessed risk of bias, and contacted pharmaceutical companies and authors for additional information. We collected dropouts due to adverse events and patients experiencing adverse events. MAIN RESULTS: Six placebo controlled and three active controlled RCTs were included (521 participants). Symptom severity (11 point rating scale, 0 points indicating no symptoms, 10 points indicating maximally severe symptoms) was more reduced with levodopa than placebo in two studies (mean difference (MD) -1.34, 95% confidence interval (CI) -2.18 to -0.5, P = 0.002). Periodic limb movements in sleep per hour of sleep (PLMS-Index; PLMSI) improved by -26.28/h compared to placebo (95% CI -30.53 to -22.02, P < 0.00001).The CGI-I changed more with levodopa than placebo in two studies (MD -1.25, 95% CI -1.89 to -0.62, P = 0.0001). In two studies, sleep quality (sleep questionnaire, visual analogue scale) showed a large effect (standardised mean difference (SMD) 0.92, 95% CI 0.52 to 1.33, P < 0.00001) whereas quality of life (50 mm Visual Analogue Scales) improved by 3.23 compared to placebo (95% CI 1.64 to 4.82, P < 0.0001). Few patients dropped out of treatment (3 of 218 patients) but more levodopa treated patients experienced adverse events than with placebo (odds ratio 2.61, 95% CI 1.35 to 5.04, P = 0.004). Two dopamine agonist controlled studies showed smaller effects with levodopa than cabergoline and pramipexole on the IRLS (MD 5.25, 95% CI 2.10 to 8.40, P =0.001), CGI-I (MD 0.62, 95% CI 0.37 to 0.87, P < 0.00001), and quality of life (MD 5.54, 95% CI 2.65 to 8.43, P = 0.0002). AUTHORS' CONCLUSIONS: Levodopa is efficacious for the short-term treatment of RLS. Augmentation, the clinically most relevant adverse event, was not investigated sufficiently. PMID- 21328279 TI - Phosphate binders for preventing and treating bone disease in chronic kidney disease patients. AB - BACKGROUND: Phosphate binders are widely used to lower serum phosphorus levels in people with chronic kidney disease (CKD) but their impact in CKD remains controversial. OBJECTIVES: To review the effects of various phosphate binders on biochemical and patient-level end-points in CKD stages 3 to 5D. SEARCH STRATEGY: In March 2010 we searched MEDLINE, EMBASE, the Cochrane Renal Group's Specialised Register and CENTRAL for relevant studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs that assessed the effects of various phosphate binders in adults with CKD. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed search results and extracted data. Results were expressed as mean differences (MD) for continuous outcomes and risk ratios (RR) for dichotomous outcomes with 95% confidence intervals (CI) using a random-effects model. MAIN RESULTS: Sixty studies (7631 participants) were included. There was no significant reduction in all-cause mortality (10 studies, 3079 participants: RR 0.73, 95% CI 0.46 to 1.16), or serum calcium by phosphorus (Ca x P) product with sevelamer hydrochloride compared to calcium-based agents. There was a significant reduction in serum phosphorus (16 studies, 3126 participants: MD 0.23 mg/dL, 95% CI 0.04 to 0.42) and parathyroid hormone (PTH) (12 studies, 2551 participants; MD 56 pg/mL, 95% CI 26 to 84) but a significant increase in the risk of hypercalcaemia (12 studies, 1144 participants: RR 0.45, 95% CI 0.35 to 0.59) with calcium-based agents compared to sevelamer hydrochloride. There was a significant increase in the risk of adverse gastrointestinal events with sevelamer hydrochloride in comparison to calcium salts (5 studies, 498 participants: RR 1.58, 95% CI 1.11 to 2.25). Compared with calcium-based agents, lanthanum significantly reduced serum calcium (2 studies, 122 participants: MD 0.30 mg/dL, 95% CI -0.64 to -0.25) and the Ca x P product, but not serum phosphorus levels. The effects of calcium acetate on biochemical end-points were similar to those of calcium carbonate. The phosphorus lowering effects of novel agents such as ferric citrate, colestilan and niacinamide were only reported in a few studies. AUTHORS' CONCLUSIONS: Available phosphate-binding agents have been shown to reduce phosphorus levels in comparison to placebo. However, there are insufficient data to establish the comparative superiority of novel non-calcium binding agents over calcium-containing phosphate binders for patient-level outcomes such as all-cause mortality and cardiovascular end-points in CKD. PMID- 21328280 TI - Lamotrigine for acute and chronic pain. AB - BACKGROUND: This is an update of the original Cochrane review published in Issue 2, 2007. Some antiepileptic medicines have a place in the treatment of neuropathic pain (pain due to nerve damage). This updated review adds five new additional studies looking at evidence for Lamotrigine as an effective treatment for acute and chronic pain. OBJECTIVES: To assess analgesic efficacy and adverse effects of the antiepileptic drug lamotrigine in acute and chronic pain. SEARCH STRATEGY: Randomised controlled trials (RCTs) of lamotrigine in acute, and chronic pain (including cancer pain) were identified from MEDLINE, EMBASE and CENTRAL up to January 2011. Additional studies were sought from the reference list of the retrieved papers. SELECTION CRITERIA: RCTs investigating the use of lamotrigine (any dose, by any route, and for any study duration) for the treatment of acute or chronic pain. Assessment of pain intensity or pain relief, or both, using validated scales. Participants were adults aged 18 and over. Only full journal publication articles were included. DATA COLLECTION AND ANALYSIS: Dichotomous data (ideally for the outcome of at least 50% pain relief) were used to calculate relative risk with 95% confidence intervals. Meta-analysis was undertaken using a fixed-effect model. Numbers needed to treat to benefit (NNTs) were calculated as the reciprocal of the absolute risk reduction. For unwanted effects, the NNT becomes the number needed to harm (NNH) and was calculated. MAIN RESULTS: Twelve included studies in 11 publications (1511 participants), all with chronic neuropathic pain: central post stroke pain (1), chemotherapy induced neuropathic pain (1), diabetic neuropathy (4), HIV related neuropathy (2), mixed neuropathic pain (2), spinal cord injury related pain (1), and trigeminal neuralgia (1); none investigated lamotrigine in acute pain. The update had five additional studies (1111 additional participants). Participants were aged between 26 and 77 years. Study duration was 2 weeks in one study and at least 6 weeks in the remainder; eight were of eight week duration or longer. There is no convincing evidence that lamotrigine is effective in treating acute or chronic pain at doses of about 200-400 mg daily. Almost 10% of participants taking lamotrigine reported a skin rash. AUTHORS' CONCLUSIONS: The additional studies tripled participant numbers providing data for analysis, and new, more stringent criteria for outcomes and analysis were used; conclusions about lamotrigine's lack of efficacy in chronic pain did not change. Given availability of more effective treatments including antiepileptics and antidepressant medicines, lamotrigine does not have a significant place in therapy based on available evidence. PMID- 21328281 TI - WITHDRAWN: Pancreaticoduodenectomy (classic Whipple) versus pylorus-preserving pancreaticoduodenectomy (pp Whipple) for surgical treatment of periampullary and pancreatic carcinoma. AB - BACKGROUND: Pancreatic cancer is the fourth leading cause of cancer death for men and the fifth for women. The standard treatment for resectable tumours is either a classic Whipple operation or a pylorus-preserving pancreaticoduodenectomy. It is unclear which of the procedures is more favourable in terms of survival, mortality, complications and quality of life. OBJECTIVES: Several publications have highlighted advantages and disadvantages of the two techniques and the current basis of evidence remains unclear. The objective of this systematic review is to compare the effectiveness of each operation. SEARCH STRATEGY: We conducted a search on 28/03/2006 to identify all RCTs, applying no language restriction.We searched the following electronic databases: CENTRAL, CDSR and DARE from The Cochrane Library (2006, issue 2), MEDLINE (1966 to 2006) and EMBASE (1980 to 2006). We handsearched abstracts from 1995 to 2006 from the American Digestive Disease Week (DDW), published in Gastroenterology, and the United European Gastroenterology Week (UEGW), published in Gut. SELECTION CRITERIA: We considered randomised controlled trials comparing the classic Whipple operation with pylorus-preserving pancreaticoduodenectomy to be eligible if they included patients with periampullary or pancreatic carcinoma. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data from the included studies. We used a random-effects model for pooling data. We compared binary outcomes using odds ratios (OR), pooled continuous outcomes using weighted mean differences (WMD), and used hazard ratios (HR) for meta-analysis of survival. Two authors independently evaluated the methodological quality of included studies according to quality standards and by using a questionnaire. MAIN RESULTS: We retrieved 1235 abstracts and checked these for eligibility, including seven randomised controlled trials. Our critical appraisal revealed vast heterogeneity with respect to methodological quality and outcome parameters. Our comparisons of in hospital mortality (OR 0.49; 95% confidence interval (CI) 0.17 to 1.40; P = 0.18), overall survival (HR 0.84; 95% CI 0.61 to 1.16; P = 0.29) and morbidity showed no significant differences. However, we noted that operating time (WMD 68.26 minutes; 95% CI -105.70 to -30.83; P = 0.0004) and intra-operative blood loss (WMD -0.76 millilitres; 95% CI -0.96 to -0.56; P < 0.00001) were significantly reduced in the pylorus-preserving pancreaticoduodenectomy group. AUTHORS' CONCLUSIONS: There is no evidence of relevant differences in mortality, morbidity and survival between the two operations. Given obvious clinical and methodological heterogeneity, future research must be undertaken to perform high quality randomised controlled trials of complex surgical interventions on the basis of well-defined outcome parameters. PMID- 21328282 TI - Nicotine receptor partial agonists for smoking cessation. AB - BACKGROUND: Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist) and reducing smoking satisfaction (acting as an antagonist). Varenicline was developed as a nicotine receptor partial agonist from cytisine, a drug widely used in central and eastern Europe for smoking cessation. The first trial reports of varenicline were released in 2006, and further trials have now been published or are currently underway. OBJECTIVES: The primary objective of this review is to assess the efficacy and tolerability of nicotine receptor partial agonists, including varenicline and cytisine, for smoking cessation. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group's specialised register for trials, using the terms ('varenicline' or 'cytisine' or 'Tabex' or 'nicotine receptor partial agonist') and 'smoking' in the title or abstract, or as keywords. We also searched MEDLINE, EMBASE, PsycINFO and CINAHL using MeSH terms and free text, and we contacted authors of trial reports for additional information where necessary. The latest search was in September 2010. SELECTION CRITERIA: We included randomized controlled trials which compared the treatment drug with placebo. We also included comparisons with bupropion and nicotine patches where available. We excluded trials which did not report a minimum follow-up period of six months from start of treatment. DATA COLLECTION AND ANALYSIS: We extracted data on the type of participants, the dose and duration of treatment, the outcome measures, the randomization procedure, concealment of allocation, and completeness of follow up.The main outcome measured was abstinence from smoking after at least six months from the beginning of treatment. We used the most rigorous definition of abstinence, and preferred biochemically validated rates where they were reported. Where appropriate we performed meta-analysis to produce a risk ratio, using the Mantel-Haenszel fixed effect model. MAIN RESULTS: We found 11 trials of varenicline compared with placebo for smoking cessation; three of these included a bupropion experimental arm. We also found one relapse prevention trial, comparing varenicline with placebo, and two open-label trials comparing varenicline with nicotine replacement therapy (NRT). We also include one trial in which all the participants were given varenicline, but received behavioural support either online or by phone calls, or by both methods. This trial is not included in the analyses, but contributes to the data on safety and tolerability. The included studies covered >10,300 participants, 6892 of whom used varenicline. We identified one trial of cytisine (Tabex) for inclusion.The pooled risk ratio (RR) (10 trials, 4443 people, excluding one trial evaluating long term safety) for continuous abstinence at six months or longer for varenicline at standard dosage versus placebo was 2.31 (95% confidence interval [CI] 2.01 to 2.66). Varenicline at lower or variable doses was also shown to be effective, with an RR of 2.09 (95% CI 1.56 to 2.78; 4 trials, 1272 people). The pooled RR for varenicline versus bupropion at one year was 1.52 (95% CI 1.22 to 1.88; 3 trials, 1622 people). The RR for varenicline versus NRT for point prevalence abstinence at 24 weeks was 1.13 (95% CI 0.94 to 1.35; 2 trials, 778 people). The two trials which tested the use of varenicline beyond the 12-week standard regimen found the drug to be well-tolerated during long-term use. The main adverse effect of varenicline was nausea, which was mostly at mild to moderate levels and usually subsided over time. Post-marketing safety data raised questions about a possible association between varenicline and depressed mood, agitation, and suicidal behaviour or ideation. The labelling of varenicline was amended in 2008, and the manufacturers produced a Medication Guide. Thus far, surveillance reports and secondary analyses of trial data lend little support to a causal relationship.The one cytisine trial included in this review found that more participants taking cytisine stopped smoking compared with placebo at two-year follow up, with an RR of 1.61 (95% CI 1.24 to 2.08). AUTHORS' CONCLUSIONS: Varenicline at standard dose increased the chances of successful long-term smoking cessation between two- and threefold compared with pharmacologically unassisted quit attempts. Lower dose regimens also conferred benefits for cessation, while reducing the incidence of adverse events. More participants quit successfully with varenicline than with bupropion. Two open-label trials of varenicline versus NRT suggested a modest benefit of varenicline but confidence intervals did not rule out equivalence. Limited evidence suggests that varenicline may have a role to play in relapse prevention. The main adverse effect of varenicline is nausea, but mostly at mild to moderate levels and tending to subside over time. Possible links with serious adverse events, including depressed mood, agitation and suicidal thoughts, have been reported but are so far not substantiated.There is a need for further independent community-based trials of varenicline, to test its efficacy and safety in smokers with varying co-morbidities and risk patterns. There is a need for further trials of the efficacy of treatment extended beyond 12 weeks. Cytisine may also increase the chances of quitting, but the evidence at present is inconclusive. PMID- 21328283 TI - Anticoagulation for patients with cancer and central venous catheters. AB - BACKGROUND: Central venous catheter (CVC) placement increases the risk of thrombosis in cancer patients. Thrombosis often necessitates the removal of the CVC, resulting in treatment delays and thrombosis related morbidity and mortality. OBJECTIVES: To evaluate the efficacy and safety of anticoagulation in cancer patients with a CVC. SEARCH STRATEGY: We searched The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1 2010), MEDLINE (January 1966 to February 2010; accessed via OVID), EMBASE (January 1980 to February 2010; accessed via OVID) and ISI the Web of Science (1975 to February 2010). We handsearched conference proceedings, checked references of included studies and used the "related article" feature within PubMed. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing any dose of unfractionated heparin (UFH), low molecular weight heparin (LMWH), vitamin K antagonists (VKA), or fondaparinux to no intervention or placebo or comparing two different anticoagulants in cancer patients with a CVC. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data from each included study and resolved their disagreements by discussion. MAIN RESULTS: Of 8187 identified citations, we included 12 RCTs enrolling 3611 patients and assessing either prophylactic dose heparin or low dose VKAs. Prophylactic dose heparin was not associated with a statistically significant effect on death (relative risk (RR) = 0.85; 95% confidence interval (CI): 0.53 to 1.37), symptomatic deep venous thrombosis (DVT) (RR = 0.54; 95% CI: 0.28 to 1.05) asymptomatic DVT (RR = 0.81; 95% CI: 0.64 to 1.02), major bleeding (RR = 0.68; 95% CI: 0.10 to 4.78), thrombocytopenia (RR = 0.85; 95% CI: 0.49 to 1.46), or infection (RR = 0.91; 95% CI: 0.49 to 1.68). Similarly, low dose VKAs were not associated with a statistically significant effect on death (RR = 0.97; 95% CI: 0.82 to 1.15), symptomatic DVT (RR = 0.63; 95% CI: 0.35 to 1.11) or major bleeding (RR = 6.93; 95% CI: 0.86 to 56.08). However, they were associated with a statistically significant reduction in asymptomatic DVT (RR = 0.42; 95% CI: 0.28 to 0.61). Studies comparing heparin to VKA found no effects on any of the outcomes of interest. AUTHORS' CONCLUSIONS: We found no statistically significant effect of heparin or VKA on the outcomes of interest. However, the findings did not rule out clinically important benefits and harms. Patients with cancer with CVCs considering anticoagulation should balance the possible benefit of reduced thromboembolic complications with the possible harms and burden of anticoagulants. PMID- 21328284 TI - Nebulized epinephrine for croup in children. AB - BACKGROUND: Croup is a common childhood illness characterized by barky cough, stridor, hoarseness and respiratory distress. Children with severe croup are at risk for intubation. Nebulized epinephrine (NE) may prevent intubation. OBJECTIVES: To evaluate the efficacy and safety of NE in children presenting to emergency department (ED) or admitted to hospital with croup. SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library 2010, Issue 4), containing the Cochrane Acute Respiratory Infections Group's Specialized Register, MEDLINE (1966 to November Week 1, 2010), EMBASE (1980 to November 2010), Web of Science (1974 to November 2010), CINAHL (1982 to November 2010) and Scopus (1996 to November 2010). SELECTION CRITERIA: Randomized controlled trials (RCTs) or quasi-RCTs of children with croup evaluated in an ED or admitted to hospital. Comparisons were: NE versus placebo, racemic NE versus L-epinephrine (an isomer), and NE delivered by intermittent positive pressure breathing (IPPB) versus NE without IPPB. Primary outcome was change in croup score post-treatment. Secondary outcomes were rate and duration of intubation and hospitalization, croup return visit, parental anxiety and side effects. DATA COLLECTION AND ANALYSIS: Two authors independently identified potentially relevant studies by title and abstract (when available) and examined relevant studies using a priori inclusion criteria, followed by methodologic quality assessment. One author extracted data while the second checked accuracy. We performed standard statistical analyses. MAIN RESULTS: Eight studies (225 participants) were included. NE was associated with croup score improvement 30 minutes post-treatment (three RCTs, standardized mean difference (SMD) -0.94; 95% confidence interval (CI) -1.37 to -0.51; I(2) statistic = 0%). This effect was not significant two and six hours post-treatment. NE was associated with significantly shorter hospital stay than placebo (one RCT, mean difference -32.0 hours; 95% CI -59.1 to -4.9). Comparing racemic and L epinephrine, no difference in croup score was found after 30 minutes (SMD 0.33; 95% CI -0.42 to 1.08). After two hours, L-epinephrine showed significant reduction compared with racemic epinephrine (one RCT, SMD 0.87; 95% CI 0.09 to 1.65). There was no significant difference in croup score between administration of NE via IPPB versus nebulization alone at 30 minutes (one RCT, SMD -0.14; 95% CI -1.24 to 0.95) or two hours (SMD -0.72; 95% CI -1.86 to 0.42). AUTHORS' CONCLUSIONS: NE is associated with clinically and statistically significant transient reduction of symptoms of croup 30 minutes post-treatment. Evidence does not favor racemic epinephrine or LE, or IPPB over simple nebulization. PMID- 21328285 TI - Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer. AB - BACKGROUND: Compared to patients without cancer, patients with cancer who receive anticoagulant treatment for venous thromboembolism are more likely to develop recurrent venous thromboembolism (VTE). OBJECTIVES: To compare the efficacy and safety of three types of parenteral anticoagulants for the initial treatment of VTE in patients with cancer. SEARCH STRATEGY: A comprehensive search for studies of anticoagulation in cancer patients including a February 2010 electronic search of: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and ISI Web of Science. SELECTION CRITERIA: Randomized clinical trials (RCTs) comparing low molecular weight heparin (LMWH), unfractionated heparin (UFH), and fondaparinux in patients with cancer and objectively confirmed VTE. DATA COLLECTION AND ANALYSIS: Using a standardized data form, data was extracted in duplicate on methodological quality, participants, interventions, and outcomes of interest that included mortality, recurrent VTE, major bleeding, minor bleeding, postphlebitic syndrome, quality of life, and thrombocytopenia. MAIN RESULTS: Of 3986 identified citations, 16 RCTs were eligible: 13 compared LMWH to UFH, two compared fondaparinux to heparin, and one compared dalteparin to tinzaparin. Meta analysis of 11 studies showed a statistically significant reduction in mortality at three months of follow up with LMWH compared with UFH (relative risk (RR) 0.71; 95% confidence interval (CI) 0.52 to 0.98). There was little change in the effect estimate after excluding studies of lower methodological quality (RR 0.72; 95% CI 0.52 to 1.00). A meta-analysis of three studies comparing LMWH with UFH showed no statistically significant reduction in VTE recurrence (RR 0.78; 95% CI 0.29 to 2.08). The overall quality of evidence was low for LMWH versus UFH due to imprecision and likely publication bias. There were no statistically significant differences between heparin and fondaparinux for the outcomes of death (RR 1.27; 95% CI 0.88 to 1.84), recurrent VTE (RR 0.95; 95% CI 0.57 to 1.60), major bleeding (RR 0.79; 95% CI 0.39 to1.63) or minor bleeding (RR 1.50; 95% CI 0.87 to 2.59). The one study comparing dalteparin to tinzaparin did not find a statistically significant difference in mortality (RR 0.86; 95% CI 0.43 to 1.73). AUTHORS' CONCLUSIONS: LMWH is possibly superior to UFH in the initial treatment of VTE in patients with cancer. Additional trials focusing on patient important outcomes will further inform the questions addressed in this review. PMID- 21328286 TI - Azithromycin for treating uncomplicated malaria. AB - BACKGROUND: To prevent the development of drug resistance, the World Health Organization (WHO) recommends treating malaria with combination therapy. Azithromycin, an antibiotic with antimalarial properties, may be a useful additional option for antimalarial therapy. OBJECTIVES: To compare the use of azithromycin alone or in combination with other antimalarial drugs with the use of alternative antimalarial drugs for treating uncomplicated malaria caused by Plasmodium falciparum or Plasmodium vivax. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group Specialized Register (August 2010); CENTRAL (The Cochrane Library Issue 3, 2010); MEDLINE (1966 to August 2010); EMBASE (1974 to August 2010); LILACS (August 2010); the metaRegister of Controlled Trials (mRCT, August 2010); conference proceedings; and reference lists. We also contacted researchers and a pharmaceutical company. SELECTION CRITERIA: Randomized controlled trials comparing azithromycin, either alone or combined with another antimalarial drug, with another antimalarial drug used alone or combined with another antimalarial drug, or with azithromycin combined with another antimalarial drug if different combinations or doses of azithromycin were used. The primary outcome was treatment failure by day 28, defined as parasitological or clinical evidence of treatment failure between the start of treatment and day 28. Secondary outcomes included treatment failure by day 28 corrected for new infections confirmed by polymerase chain reaction (PCR), fever and parasite clearance time, and adverse events. DATA COLLECTION AND ANALYSIS: Two people independently applied the inclusion criteria, extracted data and assessed methodological quality. We used risk ratio (RR) and 95% confidence intervals (CI). MAIN RESULTS: Fifteen trials met the inclusion criteria (2284 participants, 69% males, 16% children). They were conducted in disparate malaria endemic areas, with the earlier studies conducted in Thailand (five) and India (two), and the more recent studies (eight) spread across three continents (South America, Africa, Asia). The 15 studies involved 41 treatment arms, 12 different drugs, and 28 different treatment regimens. Two studies examined P. vivax.Three day azithromycin (AZ) monotherapy did not perform well for P. vivax or P. falciparum (Thailand: P. vivax failure rate 0.5 g daily, 56%, 95% CI 31 to 78. India: P. vivax failure rate 1 g daily,12%, 95% CI 7 to 21; P. falciparum failure rate 1 g daily, 64%, 95% CI 36 to 86.) A 1 g azithromycin and 0.6 g chloroquine combination daily for three days for uncomplicated P. falciparum infections was associated with increased treatment failure in India and Indonesia compared with the combination of sulphadoxine-pyrimethamine and chloroquine (pooled RR 2.66, 95% CI 1.25 to 5.67), and compared with the combination atovaquone-proguanil in a multicentre trial in Columbia and Surinam (RR 24.72, 95% CI 6.16 to 99.20). No increased risk of treatment failure was seen in two studies in Africa with mefloquine as the comparator drug (pooled RR 2.02, 95% CI 0.51 to 7.96, P = 0.3); the pooled RR for PCR-corrected data for the combination versus mefloquine was 1.01, 95% CI 0.18 to 5.84 (P = 1.0). An increased treatment failure risk was seen when comparing azithromycin in a dose of 1.2 to 1.5 mg in combination with artesunate (200 mg per day for three days) with artemether-lumefantrine (pooled RR 3.08, 95% CI 2.09 to 4.55; PCR-corrected pooled RR 3.63, 95% CI 2.02 to 6.52).Serious adverse events and treatment discontinuation were similar across treatment arms. More adverse events were reported when comparing the 1 g azithromycin/ 0.6 g chloroquine combination with mefloquine (pooled RR 1.20, 95% CI 1.06 to 1.36) or atovaquone-proguanil (RR 1.41, 95% CI 1.09 to1.83). AUTHORS' CONCLUSIONS: Currently, there is no evidence for the superiority or equivalence of azithromycin monotherapy or combination therapy for the treatment of P. falciparum or P. vivax compared with other antimalarials or with the current first-line antimalarial combinations. The available evidence suggests that azithromycin is a weak antimalarial with some appealing safety characteristics. Unless the ongoing dose, formulation and product optimisation process results in a universally efficacious product, or a specific niche application is identified that is complementary to the current scala of more efficacious antimalarial combinations, azithromycin's future for the treatment of malaria does not look promising. PMID- 21328287 TI - Treatment for ulnar neuropathy at the elbow. AB - BACKGROUND: Ulnar neuropathy at the elbow is the second most common entrapment neuropathy after carpal tunnel syndrome. Treatment may be conservative or surgical but optimal management remains controversial. OBJECTIVES: The objectives of this systematic review were to determine the effectiveness and safety of conservative and surgical treatments in ulnar neuropathy at the elbow. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Specialized Register (16 February 2010), Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 1), MEDLINE (January 1966 to February 2010), EMBASE (January 1980 to February 2010), AMED (January 1985 to February 2010), CINAHL Plus (January 1937 to February 2010), LILACS (January 1982 to Feburary 2010), PEDro (January 1980 to February 2010), and the papers cited in relevant reviews. SELECTION CRITERIA: The review included only randomised controlled clinical trials. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed titles and abstracts of references retrieved from the searches and selected all potentially relevant studies. The authors extracted data from included trials and assessed trial quality independently. They contacted trial investigators for missing information. MAIN RESULTS: We identified 1461 papers and selected six randomised controlled clinical trials with moderate quality evidence. The sequence generation was not adequate in one study and not described in two studies. We performed two meta-analyses to evaluate the clinical and neurophysiological outcomes of simple decompression versus decompression with submuscular or subcutaneous transposition.We found no difference between simple decompression and transposition of the ulnar nerve for both clinical improvement (risk ratio (RR) 0.93, 95% CI 0.80 to 1.08) and neurophysiological improvement (RR 1.47, 95% CI -0.94 to 3.87). Transposition showed a higher number of wound infections (RR 3.10, 95% CI 1.18 to 8.15).In one trial the authors compared medial epicondylectomy with anterior transposition and found no difference in the clinical and neurophysiological outcomes.One trial assessed conservative treatment in clinically mild or moderate ulnar neuropathy at the elbow. The authors found that information on avoiding prolonged movements or positions was effective in improving subjective discomfort. Night splinting and nerve gliding exercises in addition to the information did not produce further improvement. AUTHORS' CONCLUSIONS: The available evidence is not sufficient to identify the best treatment for idiopathic ulnar neuropathy at the elbow on the basis of clinical, neurophysiological and imaging characteristics. We do not know when to treat a patient conservatively or surgically. However, the results of our meta analysis suggest that simple decompression and decompression with transposition are equally effective in idiopathic ulnar neuropathy at the elbow, including when the nerve impairment is severe. In mild cases, evidence from one small randomised controlled trial of conservative treatment showed that information on movements or positions to avoid may reduce subjective discomfort. PMID- 21328288 TI - Psychological interventions for treatment of inflammatory bowel disease. AB - BACKGROUND: The effect of psychological interventions in inflammatory bowel diseases (IBD) is controversial. OBJECTIVES: To assess the effects of psychological interventions (psychotherapy, patient education, relaxation techniques) on health related quality of life, coping, emotional state and disease activity in IBD. SEARCH STRATEGY: We searched the specialized register of the IBD/FBD Group, CENTRAL (Issue 5, 2010) and from inception to April 2010: Medline, Embase, LILACS, Psyndex, CINAHL, PsyInfo, CCMed, SOMED and Social SciSearch. Conference abstracts and reference lists were also checked. SELECTION CRITERIA: Randomized, quasi-randomized and non randomized controlled trials of psychological interventions in children or adults with IBD with a minimum follow up time of 2 months. DATA COLLECTION AND ANALYSIS: Data were extracted and study quality was independently assessed by two raters. Pooled standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated using a random effects model. MAIN RESULTS: Twenty-one studies were eligible for inclusion (1745 participants, 8 RCT, 4 QRCT, 8 NRCT; 19 in adults, 2 in adolescents). Most studies used multimodular approaches. The risk of bias was high for all studies.In adults, psychotherapy had no effect on quality of life at around 12 months (3 studies, 235 patients, SMD -0.07; 95% CI -0.33 to 0.19), emotional status (depression, 4 studies, 266 patients, SMD 0.03; 95% CI -0.22 to 0.27) or proportion of patients not in remission (5 studies, 287 patients, OR 0.85; 95% CI 0.48 to 1.48). Results were similar at 3 to 8 months. There was no evidence for statistical heterogeneity or subgroup effects based on type of disease or intensity of the therapy. In adolescents, there were positive short term effects of psychotherapy on most outcomes assessed including quality of life (2 studies, 71 patients, SMD 0.70; 95% CI 0.21 to 1.18) and depression (1 study, 41 patients, SMD -0.62; 95% CI -1.25 to 0.01).Educational interventions were ineffective with respect to quality of life at 12 months (5 studies, 947 patients, SMD 0.11; 95% CI -0.02 to 0.24), depression (3 studies, 378 patients, SMD -0.08; 95% CI -0.29 to 0.12) and proportion of patients not in remission (3 studies, 434 patients, OR 1.00; 95% CI 0.65 to 1.53). AUTHORS' CONCLUSIONS: There is no evidence for efficacy of psychological therapy in adult patients with IBD in general. In adolescents, psychological interventions may be beneficial, but the evidence is limited. Further evidence is needed to assess the efficacy of these therapies in subgroups identified as being in need of psychological interventions, and to identify what type of therapy maybe most useful. PMID- 21328289 TI - Strategies for the withdrawal of nasal continuous positive airway pressure (NCPAP) in preterm infants. AB - BACKGROUND: While indications for the use of nasal continuous positive airway pressure (NCPAP) and its associated risks and benefits are extensively investigated, the best strategy for the withdrawal of NCPAP remains unknown. In a survey of Australian and New Zealand Neonatologists, 56% stated that their approach to NCPAP weaning was "ad hoc" (Jardine 2008). At what point an infant is considered stable enough to attempt to start withdrawing their NCPAP is not clearly established. The criteria for a failed attempt at NCPAP withdrawal is also not clear. OBJECTIVES: To determine the risks and benefits of different strategies used for the withdrawal of NCPAP in preterm infants. SEARCH STRATEGY: Searches were made of the Cochrane Neonatal Review Group Specialised Register, MEDLINE from 1966 to June 2010, CINAHL from 1982 to June 2010, and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2010, Issue 2). Previous reviews (including cross references) were also searched. SELECTION CRITERIA: We included all randomised and quasi-randomised controlled trials in which either individual newborn infants or clusters of infants (such as separate neonatal units) were randomised to different NCPAP withdrawal strategies (from the first time they come off NCPAP and any subsequent weaning and/or withdrawal attempt). DATA COLLECTION AND ANALYSIS: We used standard methods of The Cochrane Collaboration and its Neonatal Review Group. MAIN RESULTS: We identified four potentially eligible studies. Three studies are included in this review. One study showed a significant decrease in the duration of oxygen therapy and a significantly decreased length of stay for babies randomised to a weaning strategy where NCPAP is simply stopped when infants met predefined stability criteria. AUTHORS' CONCLUSIONS: Infants who have their NCPAP pressure weaned to a predefined level and then stop NCPAP completely have less total time on NCPAP and shorter durations of oxygen therapy and hospital stay compared with those that have NCPAP removed for a predetermined number of hours each day. Future trials of withdrawing NCPAP should compare proposed strategies with weaning NCPAP pressure to a predefined level and then stopping NCPAP completely. Clear criteria need to be established for the definition of stability prior to attempting to withdraw NCPAP. PMID- 21328290 TI - Acetylcholinesterase inhibitor treatment for myasthenia gravis. AB - BACKGROUND: In myasthenia gravis, antibody-mediated blockade of acetylcholine receptors at the neuromuscular junction abolishes the naturally occurring 'safety factor' of synaptic transmission. Acetylcholinesterase inhibitors provide temporary symptomatic treatment of muscle weakness, but there is controversy about their long-term efficacy, dosage and side effects. OBJECTIVES: To evaluate the efficacy of acetylcholinesterase inhibitors in all forms of myasthenia gravis. SEARCH STRATEGY: We searched The Cochrane Neuromuscular Disease Group Specialized Register (5 October 2009), The Cochrane Central Register of Controlled Trials CENTRAL) (The Cochrane Library Issue 3, 2009), MEDLINE (January 1966 to September 2009), EMBASE (January 1980 to September 2009) for randomised controlled trials and quasi-randomised controlled trials regarding usage of acetylcholinesterase inhibitors in myasthenia gravis. Two authors scanned the articles for any study eligible for inclusion. We also contacted the authors and known experts in the field to identify additional published or unpublished data. SELECTION CRITERIA: Types of studies: all randomised or quasi-randomised trials. TYPES OF PARTICIPANTS: all myasthenia gravis patients diagnosed by an internationally accepted definition.Types of interventions: treatment with any form of acetylcholinesterase inhibitor.Types of outcome measuresPrimary outcome measureImprovement in the presenting symptoms within 1 to 14 days of the start of treatment.Secondary outcome measures(1) Improvement in the presenting symptoms more than 14 days after the start of treatment.(2) Change in impairment measured by a recognised and preferably validated scale, such as the quantitative myasthenia gravis score within 1 to 14 days and more than 14 days after the start of treatment.(3) Myasthenia Gravis Association of America post-intervention status more than 14 days after start of treatment.(4) Adverse events: muscarinic side effects. DATA COLLECTION AND ANALYSIS: One author (MMM) extracted the data, which were checked by a second author. We contacted study authors for extra information and collected data on adverse effects from the trials. MAIN RESULTS: We did not find any large randomised or quasi-randomised trials of acetylcholinesterase inhibitors in generalised myasthenia gravis. One cross-over randomised trial using intranasal neostigmine in a total of 10 subjects was only available as an abstract. AUTHORS' CONCLUSIONS: Except for one small and inconclusive trial of intranasal neostigmine, no randomised controlled trial has been conducted on the use of acetylcholinesterase inhibitors in myasthenia gravis. Response to acetylcholinesterase inhibitors in observational studies is so clear that a randomised controlled trial depriving participants in the placebo arm of treatment would be difficult to justify. PMID- 21328291 TI - Chemotherapy alone versus chemotherapy plus radiotherapy for early stage Hodgkin lymphoma. AB - BACKGROUND: Combined modality treatment (CMT) consisting of chemotherapy followed by localised radiotherapy is standard treatment for patients with early stage Hodgkin lymphoma (HL). However, due to long term adverse effects such as secondary malignancies, the role of radiotherapy has been questioned recently and some clinical study groups advocate chemotherapy only for this indication. OBJECTIVES: We performed a systematic review with meta-analysis of randomised controlled trials (RCTs) comparing chemotherapy alone with CMT in patients with early stage Hodgkin lymphoma with respect to response rate, progression-free survival (alternatively tumour control) and overall survival (OS). SEARCH STRATEGY: We searched MEDLINE, EMBASE and CENTRAL as well as conference proceedings from January 1980 to November 2010 for randomised controlled trials comparing chemotherapy alone to the same chemotherapy regimen plus radiotherapy. SELECTION CRITERIA: Randomised controlled trials comparing chemotherapy alone with CMT in patients with early stage HL. Trials in which the chemotherapy differed between treatment arms were excluded. Trials with more than 20% of patients in advanced stage were also excluded. DATA COLLECTION AND ANALYSIS: Effect measures used were hazard ratios (HR) for tumour control and OS as well as relative risks for response rates. Two review authors independently extracted data and assessed quality of trials. We contacted study authors to obtain missing information. Since none of the trials reported progression-free survival according to our definitions, all similar outcomes were evaluated as tumour control. MAIN RESULTS: Five RCTs involving 1245 patients were included. The HR was 0.41 (95% confidence interval (CI) 0.25 to 0.66) for tumour control and 0.40 (95% CI 0.27 to 0.61) for OS for patients receiving CMT compared to chemotherapy alone. Complete response rates were similar between treatment groups. In sensitivity analyses another six trials were included that did not fulfil the inclusion criteria of our protocol but were considered relevant to the topic. These trials underlined the results of the main analysis. AUTHORS' CONCLUSIONS: Adding radiotherapy to chemotherapy improves tumour control and overall survival in patients with early stage Hodgkin lymphoma. PMID- 21328292 TI - Pharmacologic treatment of depression in multiple sclerosis. AB - BACKGROUND: Depression is a common problem in patients with multiple sclerosis (MS). It is unclear which pharmacologic treatment is the most effective and the least harmful. OBJECTIVES: To investigate the efficacy and tolerability of pharmacologic treatments for depression in patients with MS. SEARCH STRATEGY: We searched the Cochrane Multiple Sclerosis Group's Trials Register (June 2010), reference lists of relevant articles and conference proceedings. Regulatory agencies were used as additional sources of information on adverse effects. SELECTION CRITERIA: Adequately and quasi-randomized controlled blinded or unblinded trials in children and adults with MS. EXPERIMENTAL INTERVENTION: pharmacologic treatments for depression without restrictions regarding dose, route of administration, frequency, or duration. Control intervention: placebo treatment or no treatment. DATA COLLECTION AND ANALYSIS: Two teams of reviewers independently assessed trial quality and extracted data. We contacted study authors for additional information. We collected adverse effects from the trials.Information about study population, type of intervention, outcome measures, and study design were extracted from the selected studies. Trial quality was evaluated with the criteria: randomization, allocation concealment, blinding, handling of incomplete outcome data, freedom from selective reporting and freedom from other bias.The impact of missing data on the study results was explored with sensitivity analyses comparing the results from the analyses of study completers with those from best- and worst-case scenarios. MAIN RESULTS: Two trials (70 participants) were included. One trial (28 participants) compared treatment with desipramine for five weeks to placebo. The other trial (42 participants) compared treatment with paroxetine for twelve weeks to placebo. Both trials had a significant number of patients lost to follow-up or with missing outcome measurements.There was a trend towards efficacy of both treatments compared to placebo, but this difference was not statistically significant except for one outcome. Confidence intervals were wide in all analyses and our sensitivity analysis showed that the missing data may have had an important effect in both trials, with large differences between best-case and worst-case scenarios for all assessed outcomes.Both treatments were associated with adverse effects, with significantly more patients treated with paroxetine suffering from nausea or headache. Given the difference in trial duration and type of drug, we decided not to perform a meta-analysis. AUTHORS' CONCLUSIONS: Both desipramine and paroxetine show a trend towards efficacy in depression in MS the short term, but both treatments were associated with adverse effects, with significantly more patients treated with paroxetine suffering from nausea or headache. Further clinical research on the treatment of depression in MS is clearly needed. Future trials should address the efficacy and tolerability in the long term and compare antidepressant treatments head-to-head. PMID- 21328293 TI - Surgical interventions for the early management of Bell's palsy. AB - BACKGROUND: Bell's palsy is an acute paralysis of one side of the face of unknown aetiology. Bell's palsy should only be used as a diagnosis in the absence of all other pathology. As the proposed pathophysiology is swelling and entrapment of the nerve, some surgeons suggest surgical decompression of the nerve as a possible management option. OBJECTIVES: The objective of this review was to assess the effectiveness of surgery in the management of Bell's palsy and to compare this to outcomes of medical management. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Specialized Register (23 November 2010). We also searched the Cochrane Central Register of Controlled Trials (CENTRAL) (23 November in The Cochrane Library, Issue 4 2010). We adapted this strategy to search MEDLINE (January 1966 to November 2010) and EMBASE (January 1980 to November 2010). SELECTION CRITERIA: We included all randomised or quasi randomised controlled trials involving any surgical intervention for Bell's palsy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed whether trials identified from the search strategy were eligible for inclusion. Two review authors assessed trial quality and extracted data independently. MAIN RESULTS: Two trials with a total of 69 participants met the inclusion criteria. The first study considered the treatment of 403 patients but only included 44 in their surgical study. These were randomised into a surgical and non surgical group. The second study had 25 participants which they randomly allocated into surgical or control groups.The nerves of all the surgical group participants in both studies were decompressed using a retroauricular approach. The primary outcome was recovery of facial palsy at 12 months. The first study showed that both the operated and non operated groups had comparable facial nerve recovery at nine months. This study did not statistically compare the groups but the scores and size of the groups suggested that statistically significant differences are unlikely. The second study reported no statistically significant differences between their operated and control groups. One operated patient in the first study had 20 dB sensorineural hearing loss and persistent vertigo. AUTHORS' CONCLUSIONS: There is only very low quality evidence from randomised controlled trials and this is insufficient to decide whether surgical intervention is beneficial or harmful in the management of Bell's palsy.Further research into the role of surgical intervention is unlikely to be performed because spontaneous recovery occurs in most cases. PMID- 21328294 TI - Lifestyle changes in women with polycystic ovary syndrome. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) affects 4% to 18% of reproductive aged women and is associated with reproductive, metabolic and psychological dysfunction. Obesity worsens the presentation of PCOS and weight management (weight loss, maintenance or prevention of excess weight gain) is proposed as an initial treatment strategy, best achieved through lifestyle changes incorporating diet, exercise and behavioural interventions. OBJECTIVES: To assess the effectiveness of lifestyle treatment in improving reproductive, anthropometric (weight and body composition), metabolic and quality of life factors in PCOS. SEARCH STRATEGY: Electronic databases (Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, PsycINFO, CINAHL, AMED), controlled trials register, conference abstracts, relevant journals, reference lists of relevant papers and reviews and grey literature databases, with no language restrictions applied. SELECTION CRITERIA: Randomised controlled trials comparing lifestyle treatment (diet, exercise, behavioural or combined treatments) to minimal or no treatment in women with PCOS. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, assessed methodological quality and risk of bias and extracted data. MAIN RESULTS: Six studies were included. Three studies compared physical activity to minimal dietary and behavioural advice or no advice. Three studies compared combined dietary, exercise and behavioural interventions to minimal intervention. There were no studies assessing fertility primary outcomes and no data for meta-analysis on ovulation or menstrual regularity. For secondary outcomes, lifestyle intervention provided benefits when compared to minimal treatment for endpoint values for total testosterone (mean difference (MD) -0.27 nmol/L, 95% confidence interval (CI) -0.46 to -0.09, P = 0.004), hirsutism by the Ferriman-Gallwey score (MD 1.19, 95% CI -2.35 to -0.03, P = 0.04), weight (MD -3.47 kg, 95% CI -4.94 to 2.00, P < 0.00001), waist circumference (MD -1.95 cm, 95% CI -3.34 to -0.57, P = 0.006), waist to hip ratio (MD -0.04, 95% CI -0.07 to -0.00, P = 0.02), fasting insulin (MD -2.02 uU/mL, 95% CI -3.28 to -0.77, P = 0.002) and oral glucose tolerance test insulin (standardised mean difference -1.32, 95% CI -1.73 to 0.92, P < 0.00001) and per cent weight change (MD -7.00%, 95% CI -10.1 to -3.90, P < 0.00001). There was no evidence of effect of lifestyle for body mass index, free androgen index, sex hormone binding globulin, glucose or lipids; and no data for quality of life, patient satisfaction or acne. AUTHORS' CONCLUSIONS: Lifestyle intervention improves body composition, hyperandrogenism (high male hormones and clinical effects) and insulin resistance in women with PCOS. There was no evidence of effect for lifestyle intervention on improving glucose tolerance or lipid profiles and no literature assessing clinical reproductive outcomes, quality of life and treatment satisfaction. PMID- 21328295 TI - Interventions for preventing and reducing the use of physical restraints in long term geriatric care. AB - BACKGROUND: Physical restraints (PR) are commonly used in geriatric long-term care. Restraint-free care should be the aim of high quality nursing care. OBJECTIVES: To evaluate the effectiveness of interventions to prevent and reduce the use of physical restraints in older people who require long-term nursing care (either in community nursing care or in residential care facilities). SEARCH STRATEGY: The Cochrane Dementia and Cognitive Improvement Group's Specialized Register, MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS, a number of trial registers and grey literature sources were searched on 7 September 2009. The following search terms were used: "physical restraint*", bedrail*, bedchair*, "containment measure*, elderly, "old people", geriatric*, aged, "nursing home*", "care home*", "geriatric care", "residential facilit*". SELECTION CRITERIA: Individual or cluster-randomised controlled trials comparing an intervention aimed at reducing the use of physical restraints with usual care in long-term geriatric care settings. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the retrieved articles for relevance and methodological quality and extracted data. Critical appraisal of studies addressed risk of bias through selection bias, performance bias, attrition bias, and detection bias, as well as critera related to cluster designa. We contacted study authors for additional information where necessary. PR were defined heterogeneously throughout the studies. Not all studies offered sufficient data for aggregated data meta-analysis, and therefore study results are presented in a narrative form. MAIN RESULTS: Five cluster randomised controlled studies met the inclusion criteria. All of them investigated educational approaches. Two studies offered consultation in addition and two other studies offered guidance for nursing staff in addition. Four studies examined nursing home residents and one study residents in group dwelling units. No studies in community settings were included. Three studies included only one or two nursing homes per study condition. Overall, methodological quality of studies was low.The studies revealed inconsistent results. One study in the nursing home setting documented an increase of PR use in both groups after eight months, while the other three studies found reduced use of PR in the intervention groups after seven and 12 months of follow up respectively. The single study examining residents in group dwelling units found no change in PR use in the intervention group after six months whereas PR use increased significantly in the control group. AUTHORS' CONCLUSIONS: There is insufficient evidence supporting the effectiveness of educational interventions targeting nursing staff for preventing or reducing the use of physical restraints in geriatric long-term care. PMID- 21328296 TI - Single dose oral fenoprofen for acute postoperative pain in adults. AB - BACKGROUND: Fenoprofen is a non-steroidal anti-inflammatory drug (NSAID), available in several different countries, but not widely used. OBJECTIVES: To assess the efficacy of single dose oral fenoprofen in acute postoperative pain, and associated adverse events. SEARCH STRATEGY: We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to December 2010. SELECTION CRITERIA: Single oral dose, randomised, double-blind, placebo controlled trials of fenoprofen for relief of established moderate to severe postoperative pain in adults. DATA COLLECTION AND ANALYSIS: Studies were assessed for methodological quality and data extracted by two review authors independently. Summed total pain relief (TOTPAR) or pain intensity difference (SPID) over 4 to 6 hours was used to calculate the number of participants achieving at least 50% pain relief. These derived results were used to calculate, with 95% confidence intervals, the relative benefit compared to placebo, and the number needed to treat (NNT) for one participant to experience at least 50% pain relief over 4 to 6 hours. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals was collected. MAIN RESULTS: Five studies (696 participants) met the inclusion criteria; 24 participants were treated with fenoprofen 12.5 mg, 23 with fenoprofen 25 mg, 79 with fenoprofen 50 mg, 78 with fenoprofen 100 mg, 146 with fenoprofen 200 mg, 55 with fenoprofen 300 mg, 43 with zomepirac 100 mg, 30 with morphine 8 mg, 77 with codeine 60 mg, and 141 with placebo. Participants had pain following third molar extraction, laparoscopy, minor day surgery and episiotomy. The NNT for at least 50% pain relief over 4 to 6 hours with a single dose of fenoprofen 200 mg compared to placebo was 2.3 (1.9 to 3.0). There were insufficient data to analyse other doses or active comparators, time to use of rescue medication, or numbers of participants needing rescue medication. There was no difference in numbers of participants experiencing any adverse events between fenoprofen 200 mg and placebo. No serious adverse events or adverse event withdrawals were reported in these studies. AUTHORS' CONCLUSIONS: Oral fenoprofen 200 mg is effective at treating moderate to severe acute postoperative pain, based on limited data for at least 50% pain relief over 4 to 6 hours. Efficacy of other doses, other efficacy outcomes, and safety and tolerability could not be assessed. PMID- 21328297 TI - Interventions to enhance return-to-work for cancer patients. AB - BACKGROUND: Cancer survivors are 1.4 times more likely to be unemployed than healthy people. It is therefore important to provide cancer patients with programmes to support the return-to-work process. OBJECTIVES: To evaluate the effectiveness of interventions aimed at enhancing return-to-work in cancer patients. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, in The Cochrane Library Issue 2, 2010), MEDLINE, EMBASE, CINAHL, OSH-ROM, PsycINFO, DARE, ClinicalTrials.gov, Trialregister.nl and Controlled-trials.com to February 2010, reference lists of included articles and selected reviews, and contacted authors of relevant articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) and controlled before-after studies (CBAs) of the effectiveness of psychological, vocational, physical, medical or multidisciplinary interventions enhancing return-to-work in cancer patients. The primary outcome was return-to-work measured as either return-to-work rate or sick leave duration. Secondary outcome was quality of life. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, assessed the risk of bias and extracted data. We pooled studies with sufficient data, judged to be clinically homogeneous in different comparisons. We assessed the overall quality of the evidence for each comparison using the GRADE approach. MAIN RESULTS: Fourteen articles reporting 14 RCTs and 4 CBAs were included. These studies involved a total of 1652 participants. Results indicated low quality evidence of similar return-to-work rates for psychological interventions compared to care as usual (odds ratio (OR) = 2.32, 95% confidence interval (CI) 0.94 to 5.71). No vocational interventions were retrieved. Very low evidence suggested that physical training was not more effective than care as usual on improving return to-work (OR = 1.20, 95% CI 0.32 to 4.54). Eight RCTs on medical interventions showed low quality evidence that functioning conserving approaches had similar return-to-work rates as more radical treatments (OR = 1.53, 95% CI 0.95 to 2.45). Moderate quality evidence showed multidisciplinary interventions involving physical, psychological and vocational components led to higher return-to-work rates than care as usual (OR = 1.87, 95% CI 1.07 to 3.27). No differences in the effect of psychological, physical, medical or multidisciplinary interventions compared to care as usual were found on quality of life outcomes. AUTHORS' CONCLUSIONS: Moderate quality evidence showed that employed patients with cancer experience return-to-work benefits from multidisciplinary interventions compared to care as usual. More high quality RCTs aimed at enhancing return-to-work in cancer patients are needed. PMID- 21328298 TI - Fast track surgery versus conventional recovery strategies for colorectal surgery. AB - BACKGROUND: In recent years the Enhanced Recovery after Surgery (ERAS) postoperative pathway in (ileo-)colorectal surgery, aiming at improving perioperative care and decreasing postoperative complications, has become more common. OBJECTIVES: We investigated the effectiveness and safety of the ERAS multimodal strategy, compared to conventional care after (ileo-)colorectal surgery. The primary research question was whether ERAS protocols lead to less morbidity and secondary whether length of stay was reduced. SEARCH STRATEGY: To answer the research question we entered search strings containing keywords like "fast track", "colorectal and surgery" and "enhanced recovery" into major databases. We also hand searched references in identified reviews concerning ERAS. SELECTION CRITERIA: We included published randomised clinical trials, in any language, comparing ERAS to conventional treatment in patients with (ileo-) colorectal disease requiring a resection. RCT's including at least 7 ERAS items in the ERAS group and no more than 2 in the conventional arm were included. DATA COLLECTION AND ANALYSIS: Data of included trials were independently extracted by the reviewers. Analyses were performed using "REVMAN 5.0.22". Data were pooled and rate differences as well as weighted mean differences with their 95% confidence intervals were calculated using either fixed or random effects models, depending on heterogeneity (I(2)). MAIN RESULTS: 4 RCTs were included and analysed. Methodological quality of included studies was considered low, when scored according to GRADE methodology. Total numbers of inclusion were limited. The trials included in primary analysis reported 237 patients, (119 ERAS vs 118 conventional). Baseline characteristics were comparable. The primary outcome measure, complications, showed a significant risk reduction for all complications (RR 0.50; 95% CI 0.35 to 0.72). This difference was not due to reduction in major complications. Length of hospital stay was significantly reduced in the ERAS group (MD -2.94 days; 95% CI -3.69 to -2.19), and readmission rates were equal in both groups. Other outcome parameters were unsuitable for meta-analysis, but seemed to favour ERAS. AUTHORS' CONCLUSIONS: The quantity and especially quality of data are low. Analysis shows a reduction in overall complications, but major complications were not reduced. Length of stay was reduced significantly. We state that ERAS seems safe, but the quality of trials and lack of sufficient other outcome parameters do not justify implementation of ERAS as the standard of care. Within ERAS protocols included, no answer regarding the role for minimally invasive surgery (i.e. laparoscopy) was found. Furthermore, protocol compliance within ERAS programs has not been investigated, while this seems a known problem in the field. Therefore, more specific and large RCT's are needed. PMID- 21328299 TI - Certolizumab pegol (CDP870) for rheumatoid arthritis in adults. AB - BACKGROUND: TNF-alpha inhibitors have been shown to reduce the risk of joint damage and improve physical function and quality of life in people with rheumatoid arthritis (RA). This is the first Cochrane review of certolizumab pegol, a new TNF-alpha inhibitor. OBJECTIVES: To assess the effectiveness and safety of certolizumab pegol (CDP870) in patients with RA who have not responded well to conventional disease modifying anti-rheumatic drugs (DMARDs). SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2009, Issue 3), MEDLINE (1966 to November 2009), EMBASE (1966 to November 2009), Scopus (January 2004 to November 2009), TOXLINE (until November 2009), Web of Knowledge (until November 2009); websites of the US Food and Drug Administration (FDA) and European Medicines Evaluation Agency (EMEA) (until November 2009), and reference lists of articles. SELECTION CRITERIA: Randomised controlled trials that compared certolizumab pegol with any other agent including placebo or methotrexate (MTX) in adult RA patients with active rheumatoid arthritis despite current or prior treatment with conventional DMARDs, such as methotrexate (MTX). DATA COLLECTION AND ANALYSIS: Two authors independently assessed search results, trial quality and extracted data. MAIN RESULTS: Five trials were included. We included in the analysis 2394 people for effectiveness and 2094 people for safety. The duration of follow-up was from 12 to 52 weeks, and the range of doses of certolizumab pegol were from 50 to 400 mg subcutaneously (sc). In three trials the control was placebo plus methotrexate (MTX) and in two trials it was just placebo. Significant improvements were observed at 24 weeks with the approved dose of 200 mg certolizumab pegol: American College of Rheumatology (ACR) 50% improvement: risk ratio (RR) 6.01 (95% CI 3.84 to 9.40) with an absolute benefit of 29% (95% CI 25% to 34%), number needed to treat to benefit (NNTB) of 4 (3 to 5) and the Health Assessment Questionnaire (HAQ) mean difference (MD) - 0.39 (95% CI -0.45 to -0.32) (scale 0 to 3). At 52 weeks the results were quite similar: ACR 50% improvement RR 5.27 (95% CI 3.19 to 8.71), HAQ mean difference (MD) - 0.42 (95% CI -0.52 to -0.32). Serious adverse events were more frequent for certolizumab pegol 200 mg, Peto OR 2.02 (95% CI 1.24 to 3.30). The most common adverse events with certolizumab pegol 200 mg were: upper respiratory tract infections, Peto OR 2.21 (95% CI 1.15 to 4.25); hypertension, Peto OR 2.81 (95% CI 1.38 to 5.75); and nasopharyngitis, Peto OR 2.71 (95% CI 1.30 to 5.66). AUTHORS' CONCLUSIONS: With an overall high grade of evidence this review revealed an improvement of clinical results (ACR50, 28 joint disease activity score (DAS-28) remission and HAQ scores) with certolizumab pegol. Adverse events were more frequent with certolizumab; there was a statistically significant increase in the number of serious adverse events, infections and hypertension. PMID- 21328300 TI - Edaravone for acute intracerebral haemorrhage. AB - BACKGROUND: Intracerebral haemorrhage (ICH) causes significant morbidity and mortality. Prognosis for ICH patients is poor. Edaravone may be safe and effective in reducing the risk of early death and improving long-term functional outcomes in survivors. OBJECTIVES: To assess the safety and efficacy of edaravone for acute ICH. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (March 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 2 2010), the Chinese Stroke Trials Register (August 2010), MEDLINE (1950 to August 2010), EMBASE (1980 to March 2010) and 12 Chinese databases (August 2010). We also searched ongoing trials registers, reference lists, relevant conference proceedings and contacted companies manufacturing edaravone. SELECTION CRITERIA: Randomised controlled trials (RCTs) in which edaravone was compared with placebo, or edaravone plus routine treatment was compared with routine treatment alone, in patients with acute ICH. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data, collected adverse events data and contacted trialists for missing information. MAIN RESULTS: We included 10 RCTs involving 768 participants; quality was generally poor. For all trials, the control group was usual care/routine therapy (not placebo), treatment allocation and outcome evaluations were not blinded or not described, and the primary outcome (death or dependency at the end of long-term follow-up) was not reported. Only one trial reported deaths, indicating that edaravone treatment did not decrease the number of deaths significantly either during the scheduled treatment (RR 0.62, 95% CI 0.11 to 3.50) or at three month follow-up (RR 0.93, 95% CI 0.20 to 4.32). Four studies assessed activities of daily living (ADL) but ADL score was not improved significantly (MD 21.65, 95% CI -6.98 to 50.28) at the end of long-term follow-up. Combining data from all studies, edaravone treatment did increase the rate of improvement of neurological impairment (RR 1.48, 95% CI 1.29 to 1.69) until the end of the scheduled treatment, but it is not clear that this translates to any longer-term benefit of clinical importance. Reported adverse events with edaravone were mild and were common (9%), but there was no significant difference in adverse effect between the two groups (RR 2.09, 95% CI 0.71 to 6.19). AUTHORS' CONCLUSIONS: All 10 studies were inconclusive in finding a beneficial or deleterious effect provided by edaravone for the treatment of ICH. Further high quality, large scale RCTs are required. PMID- 21328302 TI - Screening for testicular cancer. AB - BACKGROUND: Testicular cancer commonly affects men aged between 20 and 35 years. Screening for testicular cancer may reduce both morbidity and mortality, yet the effectiveness of any method is unknown. Equally, screening may also promote treatment procedures that are unwarranted or may adversely affect the health outcomes of the patient with no net benefit. Additionally, many organisations recommend against screening for testicular cancer due to the low incidence of testicular cancer and favourable outcomes in the absence of screening. OBJECTIVES: The primary objective of this review is to determine whether screening for testicular cancer (physician or patient self-examination) reduces testicular cancer-specific mortality. The secondary objective of this review is to determine impact of screening for testicular cancer on quality of life and adverse outcomes. SEARCH STRATEGY: Electronic searches were conducted across MEDLINE, CINAHL, the Cochrane Central Register of Controlled Trials (CENTRAL) and PsychINFO. SELECTION CRITERIA: All published randomised controlled trials (RCTs) of screening versus no screening for testicular cancer were eligible for inclusion in this review. DATA COLLECTION AND ANALYSIS: The search identified 19 potentially relevant articles, which were selected for full text review. None of the articles that were reviewed were evaluated as eligible for inclusion in this review. MAIN RESULTS: There are no published RCTs evaluating the effectiveness of screening for testicular cancer. AUTHORS' CONCLUSIONS: Patients with increased clinical risk factors for testicular cancer, including a family history of testicular cancer, undescended testis (cryptorchidism) or testicular atrophy should be informed by their physicians of their potential increased risk of testicular cancer, along with potential benefits and harms associated with screening. PMID- 21328301 TI - Treatment for postpolio syndrome. AB - BACKGROUND: Postpolio syndrome (PPS) may affect survivors of paralytic poliomyelitis and is characterised by a complex of neuromuscular symptoms leading to a decline in physical functioning. The effectiveness of pharmacological treatment and rehabilitation management in PPS is not yet established. OBJECTIVES: To review systematically the effects of any treatment for PPS compared to placebo, usual care or no treatment. SEARCH STRATEGY: We searched the following databases on 1 October 2010: Cochrane Neuromuscular Disease Group Specialized Register, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, PsycINFO and CINAHL Plus from inception to September 2010. SELECTION CRITERIA: Randomised and quasi-randomised trials of any form of pharmacological or non-pharmacological treatment for people with PPS. The primary outcome was self-perceived activity limitations and secondary outcomes were muscle strength, muscle endurance, fatigue, pain and adverse events. DATA COLLECTION AND ANALYSIS: Two authors independently selected eligible studies, assessed risk of bias and extracted data. MAIN RESULTS: Nine pharmacological (modafinil, intravenous immunoglobulin, pyridostigmine, lamotrigine, amantadine, prednisone) and three non-pharmacological (muscle strengthening, rehabilitation in a warm climate (i.e. temperature +/- 25 degrees C, dry and sunny) and a cold climate (i.e. temperature +/- 0 degrees C, rainy or snowy), static magnetic fields) studies were included in this review. None of the included studies was completely free from any risk of bias and the most prevalent risk of bias was lack of blinding.There is moderate quality evidence that intravenous immunoglobulin has no beneficial effect on activity limitations and there is inconsistency in the evidence for effectiveness on muscle strength and pain. Results of one trial provide very low quality evidence that lamotrigine might be effective in reducing pain and fatigue, resulting in fewer activity limitations. Data from two single trials suggest that muscle strengthening of thumb muscles (very low quality evidence) and static magnetic fields (moderate quality evidence) are beneficial for improving muscle strength and pain, respectively, with unknown effects on activity limitations. Finally, there is evidence varying from very low quality to high quality that modafinil, pyridostigmine, amantadine, prednisone and rehabilitation in a warm or cold climate are not beneficial in PPS. AUTHORS' CONCLUSIONS: Due to insufficient good quality data and lack of randomised studies it is impossible to draw definite conclusions on the effectiveness of interventions for PPS. Results indicate that IVIG, lamotrigine, muscle strengthening exercises and static magnetic fields may be beneficial but need further investigation. PMID- 21328303 TI - Low-fat diets for acquired hypercholesterolaemia. AB - BACKGROUND: Hypercholesterolaemia, characterised by raised blood cholesterol levels, is not a disease itself but a metabolic derangement that often contributes to many diseases, notably cardiovascular disease. In most cases, elevated cholesterol levels are associated with high-fat diet, especially saturated fat, coupled with an inactive lifestyle. Less commonly, raised cholesterol may be related to an inherited disorder, familial hypercholesterolaemia. This systematic review is only concerned with acquired hypercholesterolaemia. OBJECTIVES: To assess the effects of low-fat diets for acquired hypercholesterolaemia and to investigate the incidence of adverse effects from low-fat dietary interventions. We planned to compare the relative effectiveness of low-fat diets with calorie-restricted diets for acquired hypercholesterolaemia. We also wanted to look into the relative effectiveness of low-fat diets and pharmacological interventions for acquired hypercholesterolaemia. SEARCH STRATEGY: Studies were obtained from computerised searches of The Cochrane Library, MEDLINE, EMBASE and databases of ongoing trials. Date of last search was February 2010. SELECTION CRITERIA: Otherwise healthy adults (equal to or greater than 18 years) with acquired (not familial) hypercholesterolaemia. We defined hypercholesterolaemia as either total cholesterol greater than 5.2 mmol/L, LDL-cholesterol greater than 3.0 mmol/L, HDL cholesterol less than 1.0 mmol/L or a combination thereof, although investigators' definitions were also accepted. We wanted to include any low-fat dietary intervention, like low-fat and low-saturated fat diets, intended to lower serum total and LDL-cholesterol or to raise HDL-cholesterol. A low-fat diet was considered as a fat calorie intake less than 20% of the total calories. The minimum duration of the intervention had to be six months. We excluded studies in unhealthy people. DATA COLLECTION AND ANALYSIS: Two authors were planned to independently assess risk of bias and extract data. MAIN RESULTS: No study met our inclusion criteria. AUTHORS' CONCLUSIONS: Well designed, adequately powered randomised controlled trials investigating patient-relevant outcomes of low-fat diets for otherwise healthy people with hypercholesterolaemia are required. PMID- 21328304 TI - Spinal manipulative therapy for chronic low-back pain. AB - BACKGROUND: Many therapies exist for the treatment of low-back pain including spinal manipulative therapy (SMT), which is a worldwide, extensively practiced intervention. OBJECTIVES: To assess the effects of SMT for chronic low-back pain. SEARCH STRATEGY: An updated search was conducted by an experienced librarian to June 2009 for randomised controlled trials (RCTs) in CENTRAL (The Cochrane Library 2009, issue 2), MEDLINE, EMBASE, CINAHL, PEDro, and the Index to Chiropractic Literature. SELECTION CRITERIA: RCTs which examined the effectiveness of spinal manipulation or mobilisation in adults with chronic low back pain were included. No restrictions were placed on the setting or type of pain; studies which exclusively examined sciatica were excluded. The primary outcomes were pain, functional status and perceived recovery. Secondary outcomes were return-to-work and quality of life. DATA COLLECTION AND ANALYSIS: Two review authors independently conducted the study selection, risk of bias assessment and data extraction. GRADE was used to assess the quality of the evidence. Sensitivity analyses and investigation of heterogeneity were performed, where possible, for the meta-analyses. MAIN RESULTS: We included 26 RCTs (total participants = 6070), nine of which had a low risk of bias. Approximately two thirds of the included studies (N = 18) were not evaluated in the previous review. In general, there is high quality evidence that SMT has a small, statistically significant but not clinically relevant, short-term effect on pain relief (MD: -4.16, 95% CI -6.97 to -1.36) and functional status (SMD: -0.22, 95% CI -0.36 to -0.07) compared to other interventions. Sensitivity analyses confirmed the robustness of these findings. There is varying quality of evidence (ranging from low to high) that SMT has a statistically significant short-term effect on pain relief and functional status when added to another intervention. There is very low quality evidence that SMT is not statistically significantly more effective than inert interventions or sham SMT for short-term pain relief or functional status. Data were particularly sparse for recovery, return-to-work, quality of life, and costs of care. No serious complications were observed with SMT. AUTHORS' CONCLUSIONS: High quality evidence suggests that there is no clinically relevant difference between SMT and other interventions for reducing pain and improving function in patients with chronic low-back pain. Determining cost-effectiveness of care has high priority. Further research is likely to have an important impact on our confidence in the estimate of effect in relation to inert interventions and sham SMT, and data related to recovery. PMID- 21328305 TI - Antidepressants for agitation and psychosis in dementia. AB - BACKGROUND: Agitation and psychosis are common among older adults with dementia and are challenging to manage. At the present time, little is known about the efficacy and safety of antidepressant medications when used to treat these symptoms. OBJECTIVES: To assess the safety and efficacy of antidepressants in treating psychosis and agitation in older adults with Alzheimer's disease, vascular, or mixed dementia. SEARCH STRATEGY: We searched the Cochrane Dementia and Cognitive Improvement Group's Specialized Register which included Cochrane Central Register of Controlled Trials (The Cochrane Library 2009, Issue 3), MEDLINE (January 1950 to October 2009), EMBASE (1980 - October 2009), CINAHL (all dates - October 2009) and PsycINFO (1806 to October 2009). SELECTION CRITERIA: Randomized, controlled trials of antidepressants (selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, trazodone, and other antidepressants), compared to either placebo or comparator medications (typical or atypical antipsychotics, anticonvulsants, benzodiazepines, cholinesterase inhibitors, memantine or other medications) for treatment of agitation or psychosis in older adults with dementia. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted trial data. We collected information on efficacy as measured by dementia neuropsychiatric symptom rating scales and adverse effects. Study authors were contacted for additional information. MAIN RESULTS: Nine trials including a total of 692 individuals were included in the review. Five studies compared SSRIs to placebo and two studies were combined in a meta-analysis for the outcome of change in Cohen-Mansfield Agitation Inventory (CMAI) scores. There was a significant difference between antidepressants and placebo on measures of agitation as reported on the change in CMAI total score (mean difference (MD), -0.89, 95% CI, 1.22 to -0.57) although the results were heavily weighted by one large study. There were no significant differences in change in behavioral symptoms of dementia for SSRIs compared to placebo in the one study that reported on changes in the Neuropsychiatric Inventory and Behavioral Pathology in Dementia scales. One study comparing citalopram to placebo found a significant difference in NPS as measured on the Neurobehavioral Rating Scale (NBRS) after controlling for baseline severity NBRS score although the unadjusted mean difference was not statistically significant (MD - 7.70, 95% CI: -16.57 to 1.17). There was no difference in the rates of trial withdrawals due to adverse events for SSRIs compared to placebo for four studies reporting this outcome (relative risk (RR), 1.07, 95% CI: 0.55 to 2.11) or in the number of trial withdrawals due to any cause in the three studies reporting this outcome (RR, 0.91, 95% CI, 0.65 to 1.26). One study compared the SSRI citalopram to the atypical antipsychotic risperidone and found no difference in NBRS scores, trial withdrawals due to any cause or trial withdrawals due to adverse events although the rates of adverse events as measured on the UKU side effect scale total score were lower for citalopram (MD -2.82, 95% CI: -4.94 to -0.70). Three studies compared SSRIs to typical antipsychotics. In meta-analysis of two studies there was no statistically significant differences in changes in CMAI total scores (MD, 4.66, 95% CI: -3.58 to 12.90). There was also no difference in trial withdrawals due to any cause or due to adverse events for SSRIs compared to typical antipsychotics. One study of trazodone compared to placebo did not find any significant difference in change in CMAI total scores (MD, 5.18, 95% CI, -2.86 to 13.22) or trial withdrawals due to any cause (RR, 1.06, 95% CI, 0.54 to 2.09). Two studies comparing trazodone to haloperidol also failed to detect any difference in change in CMAI total scores (MD, 3.28, 95% CI, -3.28 to 9.85) or trial withdrawals due to any cause (RR, 0.79, 95% CI, 0.43 to 1.46). AUTHORS' CONCLUSIONS: Currently there are relatively few studies of antidepressants for the treatment of agitation and psychosis in dementia. The SSRIs sertraline and citalopram were associated with a reduction in symptoms of agitation when compared to placebo in two studies. Both SSRIs and trazodone appear to be tolerated reasonably well when compared to placebo, typical antipsychotics and atypical antipsychotics. Future studies involving more subjects are required to determine if SSRIs, trazodone, or other antidepressants are safe and effective treatments for agitation and psychosis in dementia. PMID- 21328306 TI - Transparent Cap Colonoscopy versus Standard Colonoscopy for Investigation of Gastrointestinal Tract Conditions. AB - BACKGROUND: Colonoscopy is considered the gold-standard investigation for screening and diagnosis of colorectal cancer. It is also becoming increasingly desirable for assessment, management, diagnosis and follow-up of other colorectal diseases, such as inflammatory bowel diseases and acute diverticulitis. Hence, due to the increasing demand for colonoscopy, devices to advance examination techniques are highly sought-after and the colonoscope with the transparent cap could be one of these. OBJECTIVES: To identify and review all relevant data in order to determine whether colonoscopy with a transparent cap is a more effective diagnostic tool than colonoscopy. SEARCH STRATEGY: We searched the MEDLINE, EMBASE and CINAHL databases, and the Cochrane Central Register of Controlled Trials for all randomised controlled trials (RCTs) comparing the use of colonoscopy with a transparent cap with standard colonoscopy. SELECTION CRITERIA: Studies were included if they were randomised controlled trials which compared the use of colonoscopy with a transparent cap with standard colonoscopy. DATA COLLECTION AND ANALYSIS: Data on study methods, participants, interventions used and outcomes measured was extracted from each study. Data was entered into the Cochrane Review Manager software (RevMan 5.0, 2008) and analysed using Cochrane MetaView. MAIN RESULTS: In the present meta-analysis, we considered for the first time all five randomised controlled trials so far performed. The findings of our work indicate that colonoscopy with transparent cap has a faster caecal intubation time when compared with standard colonoscopy. Reviewing studies individually would also seem to favour colonoscopy with transparent cap for polyp detection rate and pain during procedure but due to lack of comparable data meta analysis was not feasible. AUTHORS' CONCLUSIONS: This review suggests that a transparent cap on the end of the colonoscope may give a marginally faster caecal intubation time compared with standard colonoscopy. It also suggests that there is a better polyp detection rate and less pain with the cap. However, the authors feel that further randomised controlled trials in this area would provide more clinically significant information on this adjunct to colonoscopy. PMID- 21328307 TI - Autologous hematopoietic stem cell transplantation following high-dose chemotherapy for non-rhabdomyosarcoma soft tissue sarcomas. AB - BACKGROUND: Soft tissue sarcomas (STS) are a highly heterogeneous group of rare malignant solid tumors. Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) comprise all STS except rhabdomyosarcoma. In patients with advanced local or metastatic disease, autologous hematopoietic stem cell transplantation (HSCT) applied after high-dose chemotherapy (HDCT) is a planned rescue therapy for HDCT related severe hematologic toxicity. OBJECTIVES: To assess the effectiveness and safety of HDCT followed by autologous HSCT for all stages of soft tissue sarcomas in children and adults. SEARCH STRATEGY: We searched the electronic databases CENTRAL (The Cochrane Library 2010, Issue 2), MEDLINE and EMBASE (February 2010). Online trial registers, congress abstracts and reference lists of reviews were searched and expert panels and authors were contacted. SELECTION CRITERIA: Terms representing STS and autologous HSCT were required in the title, abstract or keywords. In studies with aggregated data, participants with NRSTS and autologous HSCT had to constitute at least 80% of the data. Comparative non-randomized studies were included because randomized controlled trials (RCTs) were not expected. Case series and case reports were considered for an additional descriptive analysis. DATA COLLECTION AND ANALYSIS: Study data were recorded by two review authors independently. For studies with no comparator group, we synthesised results for studies reporting aggregate data and conducted a pooled analysis of individual participant data using the Kaplan-Meyer method. The primary outcomes were overall survival (OS) and treatment-related mortality (TRM). MAIN RESULTS: We included 54 studies, from 467 full texts articles screened (11.5%), reporting on 177 participants that received HSCT and 69 participants that received standard care. Only one study reported comparative data. In the one comparative study, OS at two years after HSCT was estimated as statistically significantly higher (62.3%) compared with participants that received standard care (23.2%). In a single-arm study, the OS two years after HSCT was reported as 20%. In a pooled analysis of the individual data of 54 participants, OS at two years was estimated as 49% (95% CI 34% to 64%). Data on TRM, secondary neoplasia and severe toxicity grade 3 to 4 after transplantation were sparse. All 54 studies had a high risk of bias. AUTHORS' CONCLUSIONS: Due to a lack of comparative studies, it is unclear whether participants with NRSTS have improved survival from autologous HSCT following HDCT. Owing to this current gap in knowledge, at present HDCT and autologous HSCT for NRSTS should only be used within controlled trials. PMID- 21328308 TI - General physical health advice for people with serious mental illness. AB - BACKGROUND: There is currently much focus on provision of general physical health advice to people with serious mental illness and there has been increasing pressure for services to take responsibility for providing this. OBJECTIVES: To assess the effects of general physical health advice as a means of reducing morbidity, mortality and improving or maintaining quality of life in people with serious mental illness. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group Trials Register (November 2009) which is based on regular searches of CINAHL, EMBASE, MEDLINE and PsycINFO. SELECTION CRITERIA: All randomised clinical trials focusing on general physical health advice. DATA COLLECTION AND ANALYSIS: We extracted data independently. For binary outcomes we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data we estimated mean difference (MD) between groups and its 95% CI. We employed a random-effects model for analyses. MAIN RESULTS: For the comparison of physical healthcare advice versus standard care we identified five studies (total n = 884) of limited quality. For measures of quality of life one trial found no difference (n = 54, 1 RCT, MD Lehman scale 0.00 CI -0.67 to 0.67) but another did (n = 407, 1 RCT, MD Quality of Life Medical Outcomes Scale - mental component 3.7 CI 1.7 to 5.6). There was no difference between groups for the outcome of death (n = 407, 1 RCT, RR 1.3 CI 0.3 to 6.0), for the outcome of uptake of ill-health prevention services, one study found percentages significantly greater in the advice group (n = 363, 1 RCT, MD 36.9 CI 33.1 to 40.7). Economic data were equivocal. Attrition was large (> 30%) but similar for both groups (n = 884, 5 RCTs, RR 1.18 CI 0.97 to 1.43). Comparisons of one type of physical healthcare advice with another were grossly underpowered and equivocal. AUTHORS' CONCLUSIONS: General physical health could lead to people with serious mental illness accessing more health services which, in turn, could mean they see longer term benefits such as reduced mortality or morbidity. On the other hand it is possible clinicians are expending much effort, time and financial expenditure on giving ineffective advice. This is an important area for good research reporting outcome of interest to carers and people with serious illnesses as well as researchers and fundholders. PMID- 21328309 TI - Adverse effects of biologics: a network meta-analysis and Cochrane overview. AB - BACKGROUND: Biologics are used for the treatment of rheumatoid arthritis and many other conditions. While the efficacy of biologics has been established, there is uncertainty regarding the adverse effects of this treatment. Since serious risks such as tuberculosis (TB) reactivation, serious infections, and lymphomas may be common to the biologics but occur in small numbers across the various indications, we planned to combine the results from biologics used in many conditions to obtain the much needed risk estimates. OBJECTIVES: To compare the adverse effects of tumor necrosis factor blocker (etanercept, adalimumab, infliximab, golimumab, certolizumab), interleukin (IL)-1 antagonist (anakinra), IL-6 antagonist (tocilizumab), anti-CD28 (abatacept), and anti-B cell (rituximab) therapy in patients with any disease condition except human immunodeficiency disease (HIV/AIDS). METHODS: Randomized controlled trials (RCTs), controlled clinical trials (CCTs) and open-label extension (OLE) studies that studied one of the nine biologics for use in any indication (with the exception of HIV/AIDS) and that reported our pre-specified adverse outcomes were considered for inclusion. We searched The Cochrane Library, MEDLINE, and EMBASE (to January 2010). Identifying search results and data extraction were performed independently and in duplicate. For the network meta-analysis, we performed mixed-effects logistic regression using an arm-based, random-effects model within an empirical Bayes framework. MAIN RESULTS: We included 163 RCTs with 50,010 participants and 46 extension studies with 11,954 participants. The median duration of RCTs was six months and 13 months for OLEs. Data were limited for tuberculosis (TB) reactivation, lymphoma, and congestive heart failure. Adjusted for dose, biologics as a group were associated with a statistically significant higher rate of total adverse events (odds ratio (OR) 1.19, 95% CI 1.09 to 1.30; number needed to treat to harm (NNTH) = 30, 95% CI 21 to 60) and withdrawals due to adverse events (OR 1.32, 95% CI 1.06 to 1.64; NNTH = 37, 95% CI 19 to 190) and an increased risk of TB reactivation (OR 4.68, 95% CI 1.18 to 18.60; NNTH = 681, 95% CI 143 to 14706) compared to control.The rate of serious adverse events, serious infections, lymphoma, and congestive heart failure were not statistically significantly different between biologics and control treatment. Certolizumab pegol was associated with significantly higher risk of serious infections compared to control treatment (OR 3.51, 95% CI 1.59 to 7.79; NNTH = 17, 95% CI 7 to 68). Infliximab was associated with significantly higher risk of withdrawals due to adverse events compared to control (OR 2.04, 95% CI 1.43 to 2.91; NNTH = 12, 95% CI 8 to 28). Indirect comparisons revealed that abatacept and anakinra were associated with a significantly lower risk of serious adverse events compared to most other biologics. Although the overall numbers are relatively small, certolizumab pegol was associated with significantly higher odds of serious infections compared to etanercept, adalimumab, abatacept, anakinra, golimumab, infliximab, and rituximab; abatacept was significantly less likely than infliximab and tocilizumab to be associated with serious infections. Abatacept, adalimumab, etanercept and golimumab were significantly less likely than infliximab to result in withdrawals due to adverse events. AUTHORS' CONCLUSIONS: Overall, in the short term biologics were associated with significantly higher rates of total adverse events, withdrawals due to adverse events and TB reactivation. Some biologics had a statistically higher association with certain adverse outcomes compared to control, but there was no consistency across the outcomes so caution is needed in interpreting these results.There is an urgent need for more research regarding the long-term safety of biologics and the comparative safety of different biologics. National and international registries and other types of large databases are relevant sources for providing complementary evidence regarding the short- and longer-term safety of biologics. PMID- 21328310 TI - Prediction of the binding mode between GSK3beta and a peptide derived from GSKIP using molecular dynamics simulation. AB - GSK3beta plays an important role in many physiological functions; dysregulated GSK3beta is involved in human diseases such as diabetes, cancer, and Alzheimer's disease. This study uses MD simulations to determine the interaction between GSK3beta and a peptide derived from GSKIP, a novel GSK3beta interacting protein. Results show that GSKIPtide is inlaid in a binding pocket consisting of an alpha helix and an extended loop near the carboxy-terminal end. This binding pocket is hydrophobic, and is responsible for the protein-protein interaction of two other GSK3beta interacting proteins: FRAT and Axin. The GSKIPtide binding mode is closer to that of AxinGID (in the Axin-GSK3-interacting domain). The single-point mutations of V267G and Y288F in GSK3beta differentiate the binding modes between GSK3 and GSKIPtide, AxinGID, and FRATide. The V2677G mutation of GSK3beta reduces the GSKIPtide binding affinity by 70% and abolishes the binding affinity with AxinGID, but has no effect on FRATide. However, GSK3beta Y288F completely abolishes the FRATide binding without affecting GSKIPtide or AxinGID binding. An analysis of the GSK3beta-GSKIPtide complex structure and the X-ray crystal structures of GSK3beta-FRATide and GSK3beta-AxinGID complexes suggests that the hydroxyl group of Y288 is crucial to maintaining a hydrogen bond network in GSK3beta-FRATide. The hydrophobic side chain of V267 maintains the integrity of helix-helix ridge-groove hydrophobic interaction for GSK3beta-GSKIPtide and GSK3beta-AxinGID. This study simulates these two mutant systems to provide atomic level evidence of the aforementioned experimental results and validate the wild type complex structure prediction. PMID- 21328311 TI - Time resolved SAXS and RNA folding. AB - Small angle X-ray scattering provides low resolution structural information about macromolecules in solution. When coupled with rapid mixing methods, SAXS reports time-dependent conformational changes of RNA induced by the addition of Mg(2+) to trigger folding. Thus time-resolved SAXS provides unique information about the global or overall structures of transient intermediates populated during folding. Notably, SAXS provides information about the earliest folding events, which can evade detection by other methods. PMID- 21328313 TI - Study of robustness of filamentous bacteriophages for industrial applications. AB - The development of a whole new class of industrial agents, such as biologically based nanomaterials and viral vectors, has raised many challenges for their large scale manufacture, principally due to the lack of essential physical data and bioprocessing knowledge. A new example is the promise of filamentous bacteriophages and their derivatives. As a result, there is now an increasing need for the establishment of strong biochemical engineering foundations to serve as a guide for future manufacture. This article investigates the effect of high energy fluid flow on filamentous bacteriophage M13 to determine its robustness for large-scale processing. By the application of well-understood ultra scale down predictive techniques, the viability of bacteriophage M13 was studied as a measure of its robustness and as a function of energy dissipation rate and fluid conditions. These experiments suggested that despite being perceived as a relatively fragile molecule in the literature, bacteriophage M13 should tolerate processing conditions in existing large-scale equipment designs. No loss of viability was noted up to a maximum energy dissipation rate of 2.9 * 10(6) W kg( 1) . Furthermore, significant losses above this threshold only occurred over periods well in excess of the exposure times expected in a bioprocess environment. Filamentous bacteriophages may therefore be regarded as a viable process material for industrial applications. PMID- 21328314 TI - Predicting diafiltration solution compositions for final ultrafiltration/diafiltration steps of monoclonal antibodies. AB - Many liquid formulations for monoclonal antibodies (MAbs) require the final ultrafiltration/diafiltration step to operate at high protein concentrations, often at or above 100 g/L. When operating under these conditions, the excipient concentrations and pH of the final diafiltered retentate are frequently not equal to the corresponding excipient concentrations and pH of the diafiltration buffer. A model based on the Poisson-Boltzmann equation combined with volume exclusion was extended to predict both pH and excipient concentrations in the retentate for a given diafiltration buffer. This model was successfully applied to identify the diafiltration buffer composition required to achieve the desired pre-formulated bulk drug substance (retentate) conditions. Predictions were in good agreement with the experimental results, and reduced the number of experimental iterations needed to define the diafiltration buffer composition. Additionally, the predictive model was applied in a sensitivity analysis across ranges of protein charge, protein concentration, and diafiltration buffer pH and excipient concentration. This sensitivity analysis can facilitate the design of experiments for robustness testing, and allow for generalized predictions across classes of molecules such as MAbs. PMID- 21328315 TI - Ion channel electrophysiology via integrated planar patch-clamp chip with on demand drug exchange. AB - Planar patch clamp has revolutionized characterization of ion channel behavior in drug discovery primarily via advancement in high throughput. Lab use of planar technology, however, addresses different requirements and suffers from inflexibility to enable wide range of interrogation via a single cell. This work presents integration of planar patch clamp with microfluidics, achieving multiple solution exchanges for tailor-specific measurement and allowing rapid replacement of the cell-contacting aperture. Studies via endogenously expressed ion channels in HEK 293T cells were commenced to characterize the device. Results reveal the microfluidic concentration generator produces distinct solution/drug combination/concentrations on-demand. Volume-regulated chloride channel and voltage-gated potassium channels in HEK 293T cells immersed in generated solutions under various osmolarities or drug concentrations show unique channel signature under specific condition. Excitation and blockage of ion channels in a single cell was demonstrated via serial solution exchange. Robustness of the reversible bonding and ease of glass substrate replacement were proven via repeated usage of the integrated device. The present approach reveals the capability and flexibility of integrated microfluidic planar patch-clamp system for ion channel assays. PMID- 21328316 TI - Construction of an E. Coli genome-scale atom mapping model for MFA calculations. AB - Metabolic flux analysis (MFA) has so far been restricted to lumped networks lacking many important pathways, partly due to the difficulty in automatically generating isotope mapping matrices for genome-scale metabolic networks. Here we introduce a procedure that uses a compound matching algorithm based on the graph theoretical concept of pattern recognition along with relevant reaction information to automatically generate genome-scale atom mappings which trace the path of atoms from reactants to products for every reaction. The procedure is applied to the iAF1260 metabolic reconstruction of Escherichia coli yielding the genome-scale isotope mapping model imPR90068. This model maps 90,068 non-hydrogen atoms that span all 2,077 reactions present in iAF1260 (previous largest mapping model included 238 reactions). The expanded scope of the isotope mapping model allows the complete tracking of labeled atoms through pathways such as cofactor and prosthetic group biosynthesis and histidine metabolism. An EMU representation of imPR90068 is also constructed and made available. PMID- 21328317 TI - Development of a dichloroacetic acid-hemoglobin conjugate as a potential targeted anti-cancer therapeutic. AB - This work focuses on conjugating the anti-cancer drug dichloroacetic acid (DCA) to the monocyte/macrophage targeting protein hemoglobin (Hb). The DCA-Hb conjugate carries approximately 12 DCA molecules per Hb tetramer, and binds to haptoglobin (Hp) forming stable DCA-Hb-Hp complexes, in a similar manner to unmodified Hb. The results of this study show that DCA-Hb-Hp is taken up by the monocytic cancer cell line THP-1, where it depolarizes the mitochondrial membrane potential, thereby inhibiting cancerous cell growth at a comparable level to free DCA. Taken together, the results of this study show promise for the use of the DCA-Hb conjugate as a potential therapeutic to treat monocytic leukemia. PMID- 21328318 TI - High-end pH-controlled delivery of glucose effectively suppresses lactate accumulation in CHO fed-batch cultures. AB - A simple method for control of lactate accumulation in suspension cultures of Chinese hamster ovary (CHO) cells based on the culture's pH was developed. When glucose levels in culture reach a low level (generally below 1 mM) cells begin to take up lactic acid from the culture medium resulting in a rise in pH. A nutrient feeding method has been optimized which delivers a concentrated glucose solution triggered by rising pH. We have shown that this high-end pH-controlled delivery of glucose can dramatically reduce or eliminate the accumulation of lactate during the growth phase of a fed-batch CHO cell culture at both bench scale and large scale (2,500 L). This method has proven applicable to the majority of CHO cell lines producing monoclonal antibodies and other therapeutic proteins. Using this technology to enhance a 12-day fed-batch process that already incorporated very high initial cell densities and highly concentrated medium and feeds resulted in an approximate doubling of the final titers for eight cell lines. The increase in titer was due to additional cell growth and higher cell specific productivity. PMID- 21328319 TI - Targeted cell immobilization by ultrasound microbeam. AB - Various techniques exerting mechanical stress on cells have been developed to investigate cellular responses to externally controlled stimuli. Fundamental mechanotransduction processes about how applied physical forces are converted into biochemical signals have often been examined by transmitting such forces through cells and probing its pathway at cellular levels. In fact, many cellular biomechanics studies have been performed by trapping (or immobilizing) individual cells, either attached to solid substrates or suspended in liquid media. In that context, we demonstrated two-dimensional acoustic trapping, where a lipid droplet of 125 um in diameter was directed transversely toward the focus (or the trap center) similar to that of optical tweezers. Under the influence of restoring forces created by a 30 MHz focused ultrasound beam, the trapped droplet behaved as if tethered to the focus by a linear spring. In order to apply this method to cellular manipulation in the Mie regime (cell diameter > wavelength), the availability of sound beams with its beamwidth approaching cell size is crucial. This can only be achieved at a frequency higher than 100 MHz. We define ultrasound beams in the frequency range from 100 MHz to a few GHz as ultrasound microbeams because the lateral beamwidth at the focus would be in the micron range. Hence a zinc oxide (ZnO) transducer that was designed and fabricated to transmit a 200 MHz focused sound beam was employed to immobilize a 10 um human leukemia cell (K-562) within the trap. The cell was laterally displaced with respect to the trap center by mechanically translating the transducer over the focal plane. Both lateral displacement and position trajectory of the trapped cell were probed in a two-dimensional space, indicating that the retracting motion of these cells was similar to that of the lipid droplets at 30 MHz. The potential of this tool for studying cellular adhesion between white blood cells and endothelial cells was discussed, suggesting its capability as a single cell manipulator. PMID- 21328320 TI - A limited LCA of bio-adipic acid: manufacturing the nylon-6,6 precursor adipic acid using the benzoic acid degradation pathway from different feedstocks. AB - A limited life cycle assessment (LCA) was performed on a combined biological and chemical process for the production of adipic acid, which was compared to the traditional petrochemical process. The LCA comprises the biological conversion of the aromatic feedstocks benzoic acid, impure aromatics, toluene, or phenol from lignin to cis, cis-muconic acid, which is subsequently converted to adipic acid through hydrogenation. Apart from the impact of usage of petrochemical and biomass-based feedstocks, the environmental impact of the final concentration of cis, cis-muconic acid in the fermentation broth was studied using 1.85% and 4.26% cis, cis-muconic acid. The LCA focused on the cumulative energy demand (CED), cumulative exergy demand (CExD), and the CO(2) equivalent (CO(2) eq) emission, with CO(2) and N(2) O measured separately. The highest calculated reduction potential of CED and CExD were achieved using phenol, which reduced the CED by 29% and 57% with 1.85% and 4.26% cis, cis-muconic acid, respectively. A decrease in the CO(2) eq emission was especially achieved when the N(2) O emission in the combined biological and chemical process was restricted. At 4.26% cis, cis muconic acid, the different carbon backbone feedstocks contributed to an optimized reduction of CO(2) eq emissions ranging from 14.0 to 17.4 ton CO(2) eq/ton adipic acid. The bulk of the bioprocessing energy intensity is attributed to the hydrogenation reactor, which has a high environmental impact and a direct relationship with the product concentration in the broth. PMID- 21328321 TI - Modulation of antibody galactosylation through feeding of uridine, manganese chloride, and galactose. AB - Through process transfer and optimization for increased antibody production to 3 g/L for a GS-CHO cell line, an undesirable drop in antibody Fc galactosylation was observed. Uridine (U), manganese chloride (M), and galactose (G), constituents involved in the intracellular galactosylation process, were evaluated in 2-L bioreactors for their potential to specifically increase antibody galactosylation. These components were placed in the feed medium at proportionally increasing concentrations from 0 to 20 * UMG, where a 1* concentration of U was 1 mM, a 1* concentration of M was 0.002 mM, and a 1* concentration of G was 5 mM. Antibody galactosylation increased rapidly from 3% at 0* UMG up to 21% at 8* UMG and then more slowly to 23% at 20* UMG. The increase was primarily due to a shift from G0F to G1F, with minimal impact on other glycoforms or product quality attributes. Cell culture performance was largely not impacted by addition of up to 20* UMG except for suppression of glucose consumption and lactate production at 16 and 20* UMG and a slight drop in antibody concentration at 20* UMG. Higher accumulation of free galactose in the medium was observed at 8* UMG and above, coincident with achieving the plateau of maximal galactosylation. A concentration of 4* UMG resulted in achieving the target of 18% galactosylation at 2-L scale, a result that was reproduced in a 1,000-L run. Follow-up studies to evaluate the addition of each component individually up to 12* concentration revealed that the effect was synergistic; the combination of all three components gave a higher level of galactosylation than addition of the each effect independently. The approach was found generally useful since a second cell line responded similarly, with an increase in galactosylation from 5% to 29% from 0 to 8* UMG and no further increase or impact on culture performance up to 12* UMG. These results demonstrate a useful approach to provide exact and specific control of antibody galactosylation through manipulation of the concentrations of uridine, manganese chloride, and galactose in the cell culture medium. PMID- 21328322 TI - Induction of anthraquinone biosynthesis in Rubia cordifolia cells by heterologous expression of a calcium-dependent protein kinase gene. AB - Calcium-dependent protein kinases (CDPKs) play an important role in plant cell responses to stress and pathogenic attack. In this study, we investigated the effect of heterologous expression of the Arabidopsis CDPK gene, AtCPK1, on anthraquinone production in transgenic Rubia cordifolia cells. AtCPK1 variants (a constitutively active, Ca(2+) -independent form and a non-active form used as a negative control) were transferred to callus cells by agrobacterial transformation. Overexpression of the constitutively active, Ca(2+) -independent form in R. cordifolia cells caused a 10-fold increase in anthraquinone content compared with non-transformed control cells, while the non-active form of AtCPK1 had no effect on anthraquinone production. Real-time PCR measurements showed that the activation of anthraquinone biosynthesis in transgenic calli correlated with the activation of isochorismate synthase gene expression. The activator effect of AtCPK1 was stable during prolonged periods of transgenic cell cultivation (more than 3 years) and the transgenic cultures exhibited high growth. Our results provide the first evidence that a CDPK gene can be used for the engineering of secondary metabolism in plant cells. PMID- 21328323 TI - A highly efficient ADH-coupled NADH-recycling system for the asymmetric bioreduction of carbon-carbon double bonds using enoate reductases. AB - The asymmetric bioreduction of activated alkenes catalyzed by flavin-dependent enoate reductases from the OYE-family represents a powerful method for the production of optically active compounds. For its preparative-scale application, efficient and economic NADH-recycling is crucial. A novel enzyme-coupled NADH recycling system is proposed based on the concurrent oxidation of a sacrificial sec-alcohol catalyzed by an alcohol dehydrogenase (ADH-A). Due to the highly favorable position of the equilibrium of ene-reduction versus alcohol-oxidation, the cosubstrate is only required in slight excess. PMID- 21328324 TI - Stiffness of photocrosslinked RGD-alginate gels regulates adipose progenitor cell behavior. AB - Adipose progenitor cells (APCs) are widely investigated for soft tissue reconstruction following tumor resection; however, the long-term success of current approaches is still limited. In order to develop clinically relevant therapies, a better understanding of the role of cell-microenvironment interactions in adipose tissue regeneration is essential. In particular, the effect of extracellular matrix (ECM) mechanics on the regenerative capability of APCs remains to be clarified. We have used artificial ECMs based on photocrosslinkable RGD-alginate to investigate the adipogenic and pro-angiogenic potential of 3T3-L1 preadipocytes as a function of matrix stiffness. These hydrogels allowed us to decouple matrix stiffness from changes in adhesion peptide density or extracellular Ca(2+) concentration and provided a physiologically relevant 3D culture context. Our findings suggest that increased matrix rigidity promotes APC self-renewal and angiogenic capacity, whereas, it inhibits adipose differentiation. Collectively, this study advances our understanding of the role of ECM mechanics in adipose tissue formation and vascularization and will aid in the design of efficacious biomaterial scaffolds for adipose tissue engineering applications. PMID- 21328325 TI - Prospective study of growth and development in older girls and risk of benign breast disease in young women. AB - BACKGROUND: In adult women with retrospective data, childhood adiposity, pubertal growth and development were associated with benign breast disease (BBD) and/or breast cancer. The authors prospectively evaluated these childhood/adolescent characteristics and BBD risk. METHODS: The Growing Up Today Study (GUTS) included females, aged 9-15 years in 1996, who completed annual questionnaires through 2001, then 2003, 2005, and 2007. Participants annually/biennially provided information on menarche, height, and weight, from which the authors derived body mass index (BMI in kg/m(2) ). Peak height growth velocity (PHV in cm/year) was estimated from longitudinal data. On 2005-2007 surveys, 6899 females (18-27 years of age) reported whether a healthcare provider ever diagnosed BBD (n = 147), and whether it was confirmed by biopsy (n = 67). Logistic models investigated risk factors adjusted for age, alcohol, pregnancy, and maternal history. RESULTS: More childhood adiposity (odds ratio [OR], 0.91/[kg/m(2) ]; P = .04) and shorter adult height (OR, 0.93/inch shorter; P = .07) were associated with lower risk of biopsy confirmed BBD. Girls with most rapid height growth were at increased risk (OR, 2.12; P = .09) relative to those with the slowest growth. Age at menarche was not associated (OR, 1.11/year; P = .32) nor was adult BMI (adjusted for childhood BMI: OR, 1.01/[kg/m(2) ]; P = .98); larger BMI increases (childhood to adulthood) were not protective (OR + 1.04/[kg/m(2) ]; P = .37). Among girls with maternal breast cancer, those with more rapid growth had higher risk (OR, 1.47/[cm/year]; P = .02). All estimates were age-adjusted. CONCLUSIONS: Increased BBD risk (likely evolving to elevated breast cancer risk) was observed in thinner girls, girls with the most rapid growth, and taller women. Contrary to expectations, later menarche age was not protective against BBD, consistent with studies that found BBD patients are not protected against breast cancer by later menarche. PMID- 21328326 TI - Supplementation with fish oil increases first-line chemotherapy efficacy in patients with advanced nonsmall cell lung cancer. AB - BACKGROUND: Palliative chemotherapy is aimed at increasing survival and palliating symptoms. However, the response rate to first-line chemotherapy in patients with nonsmall cell lung cancer (NSCLC) is less than 30%. Experimental studies have shown that supplementation with fish oil (FO) can increase chemotherapy efficacy without negatively affecting nontarget tissue. This study evaluated whether the combination of FO and chemotherapy (carboplatin with vinorelbine or gemcitabine) provided a benefit over standard of care (SOC) on response rate and clinical benefit from chemotherapy in patients with advanced NSCLC. METHODS: Forty-six patients completed the study, n = 31 in the SOC group and n = 15 in the FO group (2.5 g EPA + DHA/day). Response to chemotherapy was determined by clinical examination and imaging. Response rate was defined as the sum of complete response plus partial response, and clinical benefit was defined as the sum of complete response, partial response, and stable disease divided by the number of patients. Toxicities were graded by a nurse before each chemotherapy cycle. Survival was calculated 1 year after study enrollment. RESULTS: Patients in the FO group had an increased response rate and greater clinical benefit compared with the SOC group (60.0% vs 25.8%, P = .008; 80.0% vs 41.9%, P = .02, respectively). The incidence of dose-limiting toxicity did not differ between groups (P = .46). One-year survival tended to be greater in the FO group (60.0% vs 38.7%; P = .15). CONCLUSIONS: Compared with SOC, supplementation with FO results in increased chemotherapy efficacy without affecting the toxicity profile and may contribute to increased survival. PMID- 21328327 TI - Rapid early monoclonal protein reduction after therapy with bortezomib or bortezomib and pegylated liposomal doxorubicin in relapsed/refractory myeloma is associated with a longer time to progression. AB - BACKGROUND: A rapid and early monoclonal (M) protein response during initial therapy in patients with multiple myeloma had been identified as a predictor of superior long-term outcome in some--but not all--studies. METHODS: To determine if the parameter of M protein reduction was of value in the relapsed and/or refractory setting, retrospective landmark analyses were performed at the end of cycles 2 and 4 of a phase 3 study, which randomized such patients to receive bortezomib alone or pegylated liposomal doxorubicin (PLD) with bortezomib. RESULTS: Compared with a <25% reduction in M protein at the landmark time point, patients with a 50% to <75% reduction after cycle 2 had a significantly lower hazard ratio (HR) for time to progression (HR = 0.41; 95% confidence interval [CI], 0.26-0.64; P <.001), as did those with a >=75% reduction (HR = 0.26; 95% CI, 0.15-0.45; P < .001). In all of these groups, PLD + bortezomib provided superior outcomes to bortezomib alone, and did so without an increase in the risk of adverse events overall and with a predictable toxicity profile. CONCLUSIONS: These analyses supported the possibility that a robust early M protein response is a good prognostic factor for long-term outcome of myeloma patients with relapsed and/or refractory disease receiving bortezomib or PLD + bortezomib. PMID- 21328328 TI - Randomized phase 3 trial comparing preoperative and postoperative chemoradiotherapy with capecitabine for locally advanced rectal cancer. AB - BACKGROUND: Although many trials have shown the efficacy of preoperative chemoradiotherapy (CRT) or postoperative CRT compared with surgery alone, the optimal sequence of radiotherapy and surgery is unclear. The authors reported the final results of this single institution prospective randomized phase 3 trial comparing preoperative CRT with postoperative CRT using capecitabine in survival, local control, sphincter preservation, and toxicity for the treatment of locally advanced rectal cancer. METHODS: Patients with locally advanced rectal cancer (cT3, potentially resectable cT4 or N+) were randomly assigned to receive preoperative or postoperative CRT. CRT consisted of 50 Gy/25 fractions and concurrent capecitabine (1,650 mg/m(2)/day). Total mesorectal excision was performed. RESULTS: From March 2004 to April 2006, 240 patients were enrolled. Clinical characteristics were well balanced between both arms, except for more low-lying (<5 cm from anal verge) tumors in the preoperative CRT arm (60% vs 46%, P = .041). After a median follow-up time of 52 months, the 3- and 5-year disease free survival, overall survival, and cumulative incidence of local recurrence were similar between both arms. However, for the patients with low-lying tumors, the preoperative CRT arm had a higher rate of sphincter preservation (68% vs 42%, P = .008). Acute and late complication rates were similar between both arms. CONCLUSIONS: Although significant benefit of preoperative CRT in local control and survival was not demonstrated, the data showed that increased rate of sphincter preservation was possible in low-lying tumors without jeopardizing local control and surgical complication by preoperative CRT. PMID- 21328329 TI - Number of lymph nodes examined and prognosis among pathologically lymph node negative patients after preoperative chemoradiation therapy for rectal adenocarcinoma. AB - BACKGROUND: Preoperative chemoradiation for rectal cancer can decrease the number of evaluable lymph nodes. Hence, the prognostic role of lymph node evaluation in patients with rectal cancer who receive preoperative chemoradiation is unclear. The authors of this report evaluated the prognostic impact of the number of lymph nodes examined in patients with rectal cancer who had negative lymph nodes based on the pathologic extent of disease (ypN0) after they received preoperative chemoradiation. METHODS: Between 1990 and 2004, 372 patients with nonmetastatic rectal adenocarcinoma received preoperative chemoradiation followed by mesorectal excision and had ypN0 disease. The median radiation dose was 45 gray, and 68% of patients received adjuvant chemotherapy. RESULTS: Patients had a median of 7 lymph nodes examined after preoperative chemoradiation. Compared with patients who had <=7 lymph nodes examined, patients who had >7 lymph nodes had higher 5 year rates of freedom from relapse (86% vs 72%; log-rank P = .005) and cancer specific survival (95% vs 86%; log-rank P = .0004), but no significant difference was observed in the overall survival rate (87% vs 81%; log-rank P = .07). Multivariate Cox proportional models demonstrated that patients who had >7 lymph nodes examined had a significantly lower risk of relapse (hazard ratio [HR], 0.39; P = .003) and death from rectal cancer (HR, 0.45; P = .04) but a similar risk of all-cause mortality (HR, 0.75; 95% CI, 0.46-1.20; P = .23) compared with patients who had <=7 lymph nodes examined. CONCLUSIONS: The number of lymph nodes examined was associated independently with disease relapse and cancer-specific survival in patients with rectal cancer who had ypN0 disease after receiving preoperative chemoradiation. Hence, the authors concluded that the number of negative lymph nodes examined may be a prognostic factor in patients with rectal cancer who receive preoperative chemoradiation. PMID- 21328335 TI - High expression of indoleamine 2,3-dioxygenase in the tumour is associated with medullary features and favourable outcome in basal-like breast carcinoma. AB - Medullary breast cancer (MBC) is a basal-like breast carcinoma (BLBC) with a favourable outcome, whereas nonmedullary BLBC has a poor prognosis. Tumour infiltrating lymphocytes (TILs) are present in both MBC and BLBC. We hypothesized that the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) could modulate the TILs effects among these tumours and explain their different outcomes. The amount of TILs and IDO expression were analysed using immunohistochemistry (IHC) in 155 BC cases including MBC (n = 17), atypical MBC (n = 13) and non-MBC (n = 125). Messenger RNA expression of the INDO gene, which encodes IDO, was measured in 262 cases from our institution. INDO mRNA expression and histoclinical data of 1,487 BC cases were collected from public databases. IDO immunostaining was present in both neoplastic and stromal cells in 100% of MBC and was associated with histological medullary features among non-MBC cases. There was a significant correlation between IDO positivity and TIL amounts. In our series including mostly grade-3 BC, IDO immunostaining was the most significant marker (p = 0.02) associated with better survival in multivariate analysis. Among our 262 analysed BC cases, INDO mRNA showed significant overexpression in BLBC as compared to luminal A tumours, and in MBC as compared to basal-like non-MBC. In the pooled series of 1,749 BC cases, INDO mRNA was overexpressed in BLBC and was the most significant predictor of better survival in this subtype using multivariate analysis (p = 0.0024). In conclusion, high IDO expression is associated with morphological medullary features and has an independent favourable prognostic value in BLBC. PMID- 21328336 TI - Osteoblast-secreted factors enhance the expression of dysadherin and CCL2 dependent migration of renal carcinoma cells. AB - Renal cell carcinoma (RCC) frequently metastasizes to the bone marrow. These metastases are characterized by extensive osteolytic lesions. The mechanism, however, by which RCC cells metastasize to bone marrow remains poorly understood. To unravel the role of bone marrow cells in this context, we performed cell adhesion and migration assays using human RCC cell lines to analyze the influence of resident bone marrow cells on renal tumor cells. The strongest adhesion of RCC cells was observed to osteoblasts. Moreover, conditioned medium of osteoblasts (OB-CM) significantly increased RCC cell migration. By gene expression analysis dysadherin was identified as a transcript whose expression could be elevated more than twofold in RCC cells when exposed to OB-CM. Suppression of dysadherin expression in RCC cells by siRNA reduced their ability to migrate in the presence of OB-CM. Furthermore, the RCC cells secreted high amounts of the chemokine CCL2 when tumor cells migrated under the influence of osteoblast-secreted factors. CCL2 neutralization strongly reduced the migratory ability of the RCC cells. Silencing the expression of dysadherin in RCC cells resulted in a twofold reduction of CCL2 protein expression indicating a dysadherin-dependent expression of the chemokine. Taken together, our data show that osteoblasts are the major cell type of the bone marrow that affect RCC cells by secreting factors that increase the expression of dysadherin and CCL2 in the tumor cells leading to enhanced cell migration. These data suggest an osteoblast-induced autocrine mechanism for a facilitated homing of RCC cells to the bone marrow. PMID- 21328337 TI - Expression of CD147 is associated with prostate cancer progression. AB - Novel molecular markers that are associated with prostate cancer (PCa) progression will provide valuable information in the diagnosis and treatment of the disease. Extracellular matrix metalloproteinase inducer (CD147) has been demonstrated to be involved in tumor invasion, metastasis, growth and survival. In our study, we examined whether the expression of CD147 can be used as a prognostic marker for predicting PCa progression. Tissue samples from 240 patients who received radical prostatectomy for PCa were obtained. CD147 expression in these samples was evaluated using immunohistochemical staining with a monoclonal antibody specifically against CD147. Increased expression of CD147 was correlated with higher Gleason scores (GS), positive surgical margin, prostate-specific antigen (PSA) failure, metastasis and reduced overall survival. Both univariate Cox regression analysis and multivariate analysis including competing biological variables demonstrated that increased CD147 expression was associated with increased risk for reduced PSA failure-free, metastasis-free and overall survival. Kaplan-Meier survival curves showed that the CD147 overexpression was a significant predictor for the PSA failure-free, metastasis free and the overall survival in both pT2 and pT3 PCa patients. More significantly, higher expression of CD147 can serve as an independent prognostic predictor for PSA failure-free survival in PCa patients when they are stratified by GS. Our study results demonstrate the involvement of CD147 in PCa progression and suggest its potential role as an independent predictor of biochemical recurrence, development of metastasis and reduced overall survival in PCa. PMID- 21328338 TI - Spectrin alphaII and betaII tetramers contribute to platinum anticancer drug resistance in ovarian serous adenocarcinoma. AB - To overcome drug resistance in ovarian carcinoma, novel resistance mechanisms must be elucidated for clinical application. We purified 2 proteins in the 300 kDa range from cisplatin-resistant cells (NOS2CR2) by affinity chromatography with cisplatin-exposed Glutathione Sepharose 4B. The purified proteins were identified as spectrin alphaII and betaII by peptide mass mapping analysis. Western blot analysis detected greater expression of spectrin alphaII and betaII in NOS2CR2 than in wild-type cells (NOS2). The same result was obtained for spectrin betaII expression by immunohistochemical staining. To determine whether spectrin alphaII and betaII contribute to resistance, a drug sensitivity test was performed on SKOV3 ovarian cancer cells transfected with small interfering RNA. Sensitivity to platinum drugs was increased in the expression reduced cells. In a clinical study of five ovarian serous adenocarcinoma cases, tumor specimens taken after treatment with carboplatin stained more strongly for spectrin betaII expression than untreated specimens. Fifty-two tumor specimens from 46 patients with ovarian serous adenocarcinoma were immunohistochemically stained for spectrin betaII and scored. Tumors previously treated by chemotherapy scored higher than those not treated. Of 27 cases with detectable residual tumors at the time of surgery, cases scoring 4-6 had shorter progression-free survival periods after platinum-based chemotherapy than cases scoring 0-3 (p = 0.012). The cytoskeleton proteins Spectrin alphaII and betaII contributed to drug resistance by anchoring the GS-Pt complex to the cell membrane, arresting cisplatin activity. Thus spectrin betaII may be a useful predictor of platinum sensitivity in ovarian serous adenocarcinoma. PMID- 21328339 TI - Lower sensitivity of screening mammography after previous benign breast surgery. AB - Few data are available on the effect of previous benign breast surgery on screening mammography accuracy. We determined whether sensitivity of screening mammography and tumor characteristics are different for women with and without previous benign breast surgery. We included a consecutive series of 317,398 screening mammograms of women screened between 1997 and 2008. During 2-year follow-up, clinical data, breast imaging, biopsy and surgery reports were collected from women with screen-detected or interval breast cancers. Screening sensitivity, tumor biology and tumor stages were compared between 168 women with breast cancer and prior ipsilateral benign breast surgery and 2,039 women with breast cancer but without previous ipsilateral, benign breast surgery. The sensitivity of screening mammography was significantly lower for women with prior surgery [64.3% (108/168) versus 73.4% (1,496/2,039), p = 0.01]. The concomitant increased interval cancer risk remained significant after logistic regression adjustment for age and breast density (OR = 1.5, 95% CI: 1.1-2.1). Comparing screen-detected cancers in women with and without prior breast surgery, no significant differences in estrogen receptor status (p = 0.56), mitotic activity (p = 0.17), proportions of large (T2+) tumors (p = 0.6) or lymph node positive tumors (p = 0.4) were found. Also for interval cancers, no differences were found in estrogen receptor status (p = 0.41), mitotic activity (p = 0.39), proportions of large tumors (p = 0.9) and lymph node positive tumors (p = 0.5) between women with and without prior breast surgery. We conclude that sensitivity of screening mammography is significantly lower in women with previous benign breast surgery than without, but tumor characteristics are comparable both for screen detected cancers and interval cancers. PMID- 21328340 TI - TMZ-induced PrPc/par-4 interaction promotes the survival of human glioma cells. AB - Malignant gliomas recur even after extensive surgery and chemo-radiotherapy. Although a relatively novel chemotherapeutic agent, temozolomide (TMZ), has demonstrated promising activity against gliomas, the effects last only a few months and drug resistance develops thereafter in many cases. It has been acknowledged that glioma cells respond to TMZ treatment by undergoing G2/M arrest, but not apoptosis. Here we demonstrate a phase-specific chemotherapy resistance due to cellular prion protein (PrPc) in human glioma cells upon TMZ treatment. TMZ-induced G2/M-arrested cultures show an upregulation of PrPc expression and are more resistant, whereas G1/S-phase cells that show decreased levels of PrPc are more sensitive to apoptosis. Furthermore, an investigation into the biological significance of PrPc association with par-4 provided the first evidence of a relationship between the endogenous levels of PrPc and the resistance of glioma cells to the apoptotic effects of TMZ. Upon TMZ treatment, PrPc exerts its antiapoptotic activity by inhibiting PKA-mediated par-4 phosphorylation that are important for par-4 activation, nuclear entry and initiation of apoptosis. In context with cell cycle-dependent responses to chemotherapy, the data from this study suggest the possibility of exploiting the PrPc-dependent pathway to improve the efficacy of TMZ-based regimen for patients with gliomas. PMID- 21328341 TI - Combining 33 genetic variants with prostate-specific antigen for prediction of prostate cancer: longitudinal study. AB - The aim of this study was to investigate if a genetic risk score including 33 common genetic variants improves prediction of prostate cancer when added to measures of prostate-specific antigen (PSA). We conducted a case-control study nested within the Northern Sweden Health and Disease Cohort (NSHDC), a prospective cohort in northern Sweden. A total of 520 cases and 988 controls matched for age, and date of blood draw were identified by linkage between the regional cancer register and the NSHDC. Receiver operating characteristic curves with area under curve (AUC) estimates were used as measures of prostate cancer prediction. The AUC for the genetic risk score was 64.3% [95% confidence interval (CI) = 61.4-67.2], and the AUC for total PSA and the ratio of free to total PSA was 86.2% (95% CI = 84.4-88.1). A model including the genetic risk score, total PSA and the ratio of free to total PSA increased the AUC to 87.2% (95% CI = 85.4 89.0, p difference = 0.002). The addition of a genetic risk score to PSA resulted in a marginal improvement in prostate cancer prediction that would not seem useful for clinical risk assessment. PMID- 21328342 TI - Inhibition of neutrophil infiltration into A549 lung tumors in vitro and in vivo using a CXCR2-specific antagonist is associated with reduced tumor growth. AB - Neutrophils are important innate immune cells that are involved in microbial clearance at sites of infection and in wound healing. The microenvironment of tumors often resembles that of chronic inflammation and increased numbers of neutrophils have been observed in several tumors and, in some cases, these positively correlate with poor prognosis. Neutrophil recruitment into tumors appears to be dependent on chemokines that bind to CXCR1 and CXCR2 expressed by neutrophils. In our study, we used lung adenocarcinoma A549 multicellular tumor spheroids and A549 tumor xenografts along with a CXCR2-specific small molecule inhibitor (AZ10397767) to investigate the recruitment and function of human neutrophils in tumors. We found that A549 spheroids constitutively secrete high levels of CXCL chemokines and that neutrophil recruitment into A549 tumors in vitro and in vivo is largely dependent on CXCR2 activation. AZ10397767 significantly reduced the numbers of infiltrating neutrophils into both in vitro and in vivo tumor models, which was associated with slower growing tumors. Neutrophil infiltration into A549 tumor spheroids increased their size compared to noninfiltrated spheroids and neutrophil-derived factors increased the proliferation of A549 tumor cells and induced endothelial cell tubule formation in vitro. In contrast, we saw no reduction in microvascular density in AZ10397767 treated A549 tumors or in tumors grown in CXCR2(-/-) mice, suggesting that angiogenesis in these tumors is CXCR2-independent. Our data show that neutrophils can contribute to lung tumor growth and that CXCR2 antagonists may be a useful therapeutic agent in the treatment of lung carcinomas. PMID- 21328343 TI - Selective and efficient retardation of cancers expressing cytoskeleton-associated protein 2 by targeted RNA replacement. AB - Human cytoskeleton-associated protein 2 (hCKAP2) is upregulated and highly expressed in various human malignances. hCKAP2 has microtubule-stabilizing characteristics and potentially regulates the dynamics and assembly of the mitotic spindle and chromosome segregation, indicating that hCKAP2 plays important functions during mitosis. In this study, we evaluated hCKAP2 as a plausible anticancer target through development and validation of a targeted cancer gene therapy strategy based on targeting and replacement of hCKAP2 RNA using a trans-splicing ribozyme. This targeted RNA replacement triggered transgene activity via accurate trans-splicing reaction selectively in human cancer cells expressing the hCKAP2 RNA and simultaneously reduced the expression level of the RNA in the cells. Adenoviral vector encoding the hCKAP2-specific trans-splicing ribozyme selectively induced cytotoxicity in tumor cells expressing hCKAP2. Moreover, intratumoral injection of the virus produced selective and efficient regression of tumor that had been subcutaneously inoculated with hCKAP2-positive colon cancer cells in mice with minimal liver toxicity. Furthermore, orthotopically multifocal hCKAP2-positive hepatocarcinoma established in mice were efficiently regressed by systemic delivery of adenoviral vector encoding the specific ribozyme under the control of a liver-selective phosphoenolpyruvate carboxykinase promoter with least hepatotoxicity. The results indicate that hCKAP2 RNA is a promising target for anticancer approach based on trans-splicing ribozyme-mediated RNA replacement. PMID- 21328344 TI - Intake of vegetables, fruits, carotenoids and vitamins C and E and pancreatic cancer risk in The Netherlands Cohort Study. AB - Epidemiological data investigating the relation between fruit and vegetable consumption and pancreatic cancer risk have shown inconsistent results so far. Most case-control studies observed an inverse association with total fruit and vegetable consumption, whereas results from most cohort studies have largely been null. We examined prospectively the relation between pancreatic cancer risk and intake of vegetables, fruits, carotenoids and vitamins C and E. The Netherlands Cohort Study consisted of 120,852 men and women who completed a questionnaire at baseline in 1986, including a validated 150-item food-frequency questionnaire. After 16.3 years of follow-up, 423 cases were available for analysis. Total vegetable and total fruit consumption were not associated with pancreatic cancer risk (highest vs. lowest quintile, multivariable-adjusted hazard rate ratio = 1.23, 95% confidence interval: 0.86-1.75 and multivariable-adjusted hazard rate ratio = 0.90, 95% confidence interval: 0.66-1.24, respectively). Also, for cooked vegetables, raw vegetables and vegetables and fruits classified into subgroups, no associations were observed. Dietary carotenoids, vitamin C and E intake and supplements containing vitamin C or E were not associated with pancreatic cancer risk. The results were not modified by sex, smoking status and body mass index. In conclusion, we observed no association between a high consumption of vegetables and fruits and pancreatic cancer risk in this large cohort study, which is in agreement with previous prospective studies. Furthermore, we observed no association between the intake of carotenoids, vitamins and vitamin supplements and pancreatic cancer risk. PMID- 21328345 TI - Sugars in diet and risk of cancer in the NIH-AARP Diet and Health Study. AB - Prospective epidemiologic data on the effects of different types of dietary sugars on cancer incidence have been limited. In this report, we investigated the association of total sugars, sucrose, fructose, added sugars, added sucrose and added fructose in the diet with risk of 24 malignancies. Participants (n = 435,674) aged 50-71 years from the NIH-AARP Diet and Health Study were followed for 7.2 years. The intake of individual sugars was assessed using a 124-item food frequency questionnaire (FFQ). Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) in multivariable models adjusted for confounding factors pertinent to individual cancers. We identified 29,099 cancer cases in men and 13,355 cases in women. In gender combined analyses, added sugars were positively associated with risk of esophageal adenocarcinoma (HR(Q5 vs. Q1) : 1.62, 95% CI: 1.07-2.45; p(trend) = 0.01), added fructose was associated with risk of small intestine cancer (HR(Q5 vs. Q1) : 2.20, 95% CI: 1.16-4.16; p(trend) = 0.009) and all investigated sugars were associated with increased risk of pleural cancer. In women, all investigated sugars were inversely associated with ovarian cancer. We found no association between dietary sugars and risk of colorectal or any other major cancer. Measurement error in FFQ-reported dietary sugars may have limited our ability to obtain more conclusive findings. Statistically significant associations observed for the rare cancers are of interest and warrant further investigation. PMID- 21328346 TI - Tumor-derived macrophage migration inhibitory factor modulates the biology of head and neck cancer cells via neutrophil activation. AB - Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that has been reported to enhance the aggressiveness and metastatic potential of tumor cells. However, the mechanisms through which MIF influences tumor development and progression are not understood. The objectives of our study were to assess the effects of tumor-derived MIF on neutrophils in head and neck cancer (HNC) and to identify possible feedback effects on tumor cells. To this end, we used an in vitro system to model the interaction between human HNC cells and neutrophils. In addition, we analyzed expression of MIF in tissues from HNC patients in relation to neutrophilic infiltration and clinical parameters. Our results show that human HNC is infiltrated by neutrophils proportional to the levels of tumoral MIF. Strong MIF expression by the tumor is associated with higher lymph node metastasis and reduced survival in HNC patients. In vitro, MIF modulated functions of human neutrophils by inducing chemokine CXC motif receptor 2(CXCR2) dependent chemotaxis, enhancing neutrophil survival and promoting release of chemokine C-C Motif Ligand 4 (CCL4) and matrix metalloprotease 9(MMP9). Further, neutrophils activated with tumor-derived MIF enhanced migratory properties of HNC cells. In conclusion, our data indicate that the effects of tumor-derived MIF on neutrophils represent an additional mechanism by which MIF might contribute to tumor progression. PMID- 21328347 TI - Inactivation of the vitamin D receptor in APC(min/+) mice reveals a critical role for the vitamin D receptor in intestinal tumor growth. AB - Emerging evidence supports an inhibitory role for vitamin D in colorectal carcinogenesis; however, the mechanism remains unclear. The adenomatous polyposis coli (APC)/beta-catenin pathway plays a critical role in colorectal carcinogenesis. The purpose of our study is to explore the interactions of vitamin D and APC/beta-catenin pathways in intestinal tumor development. APC(min/+) mice with genetic inactivation of the vitamin D receptor (VDR) were generated through breeding. Intestinal tumorigenesis was compared between APC(min/+) and APC(min/+) VDR(-/-) mice at different ages. No differences were seen in the number of small intestinal and colonic tumors between APC(min/+) and APC(min/+) VDR(-/-) mice aged 3, 4, 6 and 7 months. The size of the tumors, however, was significantly increased in APC(min/+) VDR(-/-) mice in all age groups. Immunostaining showed significant increases in beta-catenin, cyclin D1, phosphorylated Stat-3 and MSH-2 levels and decreases in Stat-1 in APC(min/+) VDR( /-) tumors compared to APC(min/+) tumors. These observations suggest that VDR signaling inhibits tumor growth rather than tumor initiation in the intestine. Thus, the increased tumor burden in APC(min/+) VDR(-/-) mice is likely due to the loss of the growth-inhibiting effect of VDR. This study provides strong evidence for the in vivo relevance of the interaction demonstrated in vitro between the vitamin D and beta-catenin signaling pathways in intestinal tumorigenesis. PMID- 21328348 TI - Galbanic acid decreases androgen receptor abundance and signaling and induces G1 arrest in prostate cancer cells. AB - Androgen receptor (AR) signaling is crucial for the genesis and progression of prostate cancer (PCa). We compared the growth responses of AR(+) LNCaP and LNCaP C4-2 vs. AR(-) DU145 and PC-3 PCa cell lines to galbanic acid (GBA) isolated from the resin of medicinal herb Ferula assafoetida and assessed their connection to AR signaling and cell cycle regulatory pathways. Our results showed that GBA preferentially suppressed AR(+) PCa cell growth than AR(-) PCa cells. GBA induced a caspase-mediated apoptosis that was attenuated by a general caspase inhibitor. Subapoptotic GBA downregulated AR protein in LNCaP cells primarily through promoting its proteasomal degradation, and inhibited AR-dependent transcription without affecting AR nuclear translocation. Whereas docking simulations predicted binding of GBA to the AR ligand binding domain with similarities and differences with the AR antagonist drug bicalutamide (Bic), LNCaP cell culture assays did not detect agonist activity of GBA. GBA and Bic exerted greater than additive inhibitory effect on cell growth when used together. Subapoptotic GBA induced G(1) arrest associated with an inhibition of cyclin/CDK4/6 pathway, especially cyclin D(1) without the causal involvement of cyclin-dependent kinase (CDK) inhibitory proteins P21(Cip1) and P27(Kip1) . In summary, the novelty of GBA as an anti-AR compound resides in the distinction between GBA and Bic with respect to AR protein turnover and a lack of agonist effect. Our observations of anti-AR and cell cycle arrest actions plus the anti-angiogenesis effect reported elsewhere suggest GBA as a multitargeting drug candidate for the prevention and therapy of PCa. PMID- 21328350 TI - Evaluation of the genotype, environment and their interaction on carotenoid and ascorbic acid accumulation in tomato germplasm. AB - BACKGROUND: Tomatoes are an important source of antioxidants (carotenoids, vitamin C, etc.) owing to their high level of consumption. There is great interest in developing cultivars with increased levels of lycopene, beta-carotene or L-ascorbic acid. There is necessary to survey new sources of variation. In this study, the potential of improvement for each character in tomato breeding programmes, in a single or joint approach, and the nature of genotype (G), environment (E) and G * E interaction effects in the expression of these characters were investigated. RESULTS: The content of lycopene, beta-carotene and ascorbic acid determined was very high in some phenotypes (up to 281, 35 and 346 mg kg(-1) respectively). The important differences in the three environments studied (with some stressing conditions in several situations) had a remarkable influence in the phenotypic expression of the functional characters evaluated. Nevertheless, the major contribution came from the genotypic effect along with a considerable G * E interaction. CONCLUSION: The joint accumulation of lycopene and beta-carotene has a high genetic component. It is possible to select elite genotypes with high content of both carotenoids in tomato breeding programmes but multi-environment trials are recommended. The improvement of ascorbic acid content is more difficult because the interference of uncontrolled factors mask the real genetic potential. Among the accessions evaluated, there are four accessions with an amazing genetic potential for functional properties that can be used as donor parents in tomato breeding programmes or for direct consumption in quality markets. PMID- 21328349 TI - The role of the membrane potential in chondrocyte volume regulation. AB - Many cell types have significant negative resting membrane potentials (RMPs) resulting from the activity of potassium-selective and chloride-selective ion channels. In excitable cells, such as neurones, rapid changes in membrane permeability underlie the generation of action potentials. Chondrocytes have less negative RMPs and the role of the RMP is not clear. Here we examine the basis of the chondrocyte RMP and possible physiological benefits. We demonstrate that maintenance of the chondrocyte RMP involves gadolinium-sensitive cation channels. Pharmacological inhibition of these channels causes the RMP to become more negative (100 uM gadolinium: DeltaV(m) = -30 +/- 4 mV). Analysis of the gadolinium-sensitive conductance reveals a high permeability to calcium ions (PCa/PNa ~80) with little selectivity between monovalent ions; similar to that reported elsewhere for TRPV5. Detection of TRPV5 by PCR and immunohistochemistry and the sensitivity of the RMP to the TRPV5 inhibitor econazole (DeltaV(m) = -18 +/- 3 mV) suggests that the RMP may be, in part, controlled by TRPV5. We investigated the physiological advantage of the relatively positive RMP using a mathematical model in which membrane stretch activates potassium channels allowing potassium efflux to oppose osmotic water uptake. At very negative RMP potassium efflux is negligible, but at more positive RMP it is sufficient to limit volume increase. In support of our model, cells clamped at -80 mV and challenged with a reduced osmotic potential swelled approximately twice as much as cells at +10 mV. The positive RMP may be a protective adaptation that allows chondrocytes to respond to the dramatic osmotic changes, with minimal changes in cell volume. PMID- 21328351 TI - Physicochemical, thermal and functional characterisation of protein isolates from Kabuli and Desi chickpea (Cicer arietinum L.): a comparative study with soy (Glycine max) and pea (Pisum sativum L.). AB - BACKGROUND: Chickpea (Cicer arietinum L.) seeds are a good source of protein that has potential applications in new product formulation and fortification. The main objectives of this study were to analyse the physicochemical, thermal and functional properties of chickpea protein isolates (CPIs) and compare them with those of soy (SPI) and pea (PPI) protein isolates. RESULTS: Extracted CPIs had mean protein contents of 728-853 g kg(-1) (dry weight basis). Analysis of their deconvoluted Fourier transform infrared spectra gave secondary structure estimates of 25.6-32.7% alpha-helices, 32.5-40.4% beta-sheets, 13.8-18.9% turns and 16.3-19.2% disordered structures. CPIs from CDC Xena, among Kabuli varieties, and Myles, among Desi varieties, as well as SPI had the highest water-holding and oil absorption capacities. The emulsifying properties of Kabuli CPIs were superior to those of PPI and Desi CPIs and as good as those of SPI. The heat induced gelation properties of CPIs showed a minimum protein concentration required to form a gel structure ranging from 100 to 140 g L(-1) . Denaturation temperatures and enthalpies of CPIs ranged from 89.0 to 92.0 degrees C and from 2.4 to 4.0 J g(-1) respectively. CONCLUSION: The results suggest that most physicochemical, thermal and functional properties of CPIs compare favourably with those of SPI and are better than those of PPI. Hence CPI may be suitable as a high-quality substitute for SPI in food applications. PMID- 21328352 TI - Antimicrobial activity of weak acids in liquid feed fermentations, and its effects on yeasts and lactic acid bacteria. AB - BACKGROUND: The efficacy of weak organic acids in the control of yeasts in pig liquid feed was studied taking into account the effects on lactic acid bacteria (LAB) responsible for beneficial fermentation. RESULTS: The yeast population in pig liquid feed was taxonomically identified. Kazachstania exigua, Debaryomyces hansenii and Pichia deserticola dominated the fermentation in liquid feed and whey. Pichia deserticola was found in whey and foaming liquid feed and dominated the fermentation after incubation. The sensitivity of the isolates against weak acids was measured in culture medium as well as in fermented and non-fermented liquid feed. Formic acid and potassium sorbate successfully reduced the growth of yeasts in all media without interfering with LAB development. Both of these organic acids showed an increased antifungal effect when used in liquid feed fermented by a Lactobacillus plantarum strain. CONCLUSION: The loss of energy, reduced palatability and other practical problems due to the high growth of yeasts in fermented liquid diets can be reduced by organic acids without affecting lactic acid fermentation. PMID- 21328353 TI - Changes in fatty acid content and composition in silage maize during grain filling. AB - BACKGROUND: The stage of maturity at harvest has a major effect on the fatty acid (FA) content and composition of forage plants consumed by dairy cows. The present study investigated the dynamics of FA content and composition in stover (leaves and stem) and ears (cob, shank and husks) of two maize genotypes (G2 and G6) grown on sandy and clay soils and harvested at 14, 42, 56, 70 and 84 days after flowering (DAF). In addition, the FA content and composition of six maize genotypes (G1-G6) grown on the two soil types were compared at the normal harvest time of early genotypes in the Netherlands (70 DAF). RESULTS: The contents of total FAs and major individual FAs in both stover and ears changed significantly (P < 0.001) during the grain-filling period (14-84 DAF). In stover the contents of C16:0, C18:2, C18:3 and total FAs declined (P < 0.001) while those of C18:0 and C18:1 increased (P < 0.001) with progressive grain filling. The rate of decline in C18:3 and total FA contents was slower during 14-56 DAF as compared with 56-84 DAF. In ears, the contents of C16:0, C18:1, C18:2 and total FAs increased up to 56 DAF and then remained more or less constant until 84 DAF. At 70 DAF the content of polyunsaturated fatty acids (PUFAs) in both stover and ears did not differ among the six genotypes. However, the average contents of C16:0, C18:3 and total FAs in stover were higher (P < 0.05) on clay soil, whereas those of C18:0 and C18:1 were higher on sandy soil. CONCLUSION: The results demonstrate that the maximum PUFA content in silage maize is harvested around 56 DAF, in the present study at a T(sum) of 927 degrees C.d or at an ear dry matter content of 440 g kg(-1) , which is before the onset of rapid senescence. Any further delay in harvesting will cause a rapid decline in C18:3 content in maize silages. PMID- 21328354 TI - Commercial quality, major bioactive compound content and antioxidant capacity of 12 cultivars of loquat (Eriobotrya japonica Lindl.) fruits. AB - BACKGROUND: Modern consumers are increasingly interested in their personal health and expect the food they purchase to be tasty and attractive while being safe and healthful. The aim of this study was to determine the commercial quality, characterise the antioxidant capacity and quantify the major bioactive compounds of 12 cultivars of loquat fruits in order to establish a database for utilising these germplasm resources. RESULTS: Of the 12 cultivars, 'Guanyu' produced the biggest fruits, while 'Tianzhong' and 'Bingtangzhong' had the highest soluble solids content but the lowest titratable acidity. 'Taipinghong' was reddest in colour. Sucrose, fructose, glucose and sorbitol were the major sugars in loquat fruits, with the highest total sugar content being observed in 'Bingtangzhong' and 'Tianzhong'. Phenolics and flavonoids were the main bioactive compounds and were abundant in 'Tianzhong' and 'Zhaozhong'. 'Taipinghong' had the highest total carotenoid content, while 'Qingzhong' had the highest vitamin C content. 'Tianzhong', 'Bingtangzhong' and 'Ninghaibai' showed higher antioxidant activity than the other cultivars, as measured by assays of 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2-azino-bis(3-ethylbenzthiozoline-6-sulfonic acid) (ABTS) scavenging and ferric-reducing/antioxidant power (FRAP). CONCLUSION: Commercial fruit quality, major bioactive compound content and antioxidant capacity varied greatly among the 12 cultivars. 'Bingtangzhong' and 'Tianzhong' were the highest-ranking cultivars based on their good commercial quality and high nutritional value. The loquat fruits with higher total phenolic and flavonoid contents also had clearly higher antioxidant capacities. PMID- 21328355 TI - Discrimination of seasonality in cheeses by near-infrared technology. AB - BACKGROUND: Owing to the importance of the season of collection of milk for cheese quality, a study was made of the usefulness of near-infrared spectroscopy (NIRS) for discriminating the seasonal origin (winter or summer) of milk and quantifying the fat content of cheeses, since fat is one of the components most affected by the season of collection of milk for the elaboration of cheeses. RESULTS: In the internal validation, 96% of samples from winter milk and 97% of samples from summer milk were correctly classified, while in the external validation the prediction rate of samples correctly classified was 92%. Moreover, quantitative models allowed the determination of fat in winter, summer and winter + summer cheeses. CONCLUSION: Rapid prediction of the fat content of cheeses and the seasonal origin (winter or summer) of milk was achieved using NIRS without previous destruction or treatment of samples. PMID- 21328356 TI - The effect of different atmospheric conditions on the changes in myoglobin and colour of refrigerated Eastern little tuna (Euthynnus affinis) muscle. AB - BACKGROUND: Oxidation of myoglobin is responsible for the undesirable appearance and loss in acceptability of fish and fish products. The retardation of such a change by a modification of the surrounding atmosphere would be a means to maintain the quality of fish during the refrigerated storage. RESULTS: The changes in oxymyoglobin and metmyoglobin from dark muscle of Eastern little tuna (Euthynnus affinis) as affected by different atmospheric systems (closed system, opened system and flushed oxygen system) were determined. A saturated oxygen atmosphere more likely weakened the haem-globin complex, especially as the exposure time increased. Autoxidation of the oxy form proceeded rapidly in the presence of oxygen with the concomitant formation of the met form. When the oxygen was excluded, oxidation of oxymyoglobin was retarded. With flushed oxygen and increasing exposure time, conformational changes of globin occurred, mainly associated with protein oxidation. Generally, oxymyoglobin was more susceptible to oxidation and conformational change than did metmyoglobin. After keeping the samples at 4 degrees C for 3 days, dark muscle of tuna fillet kept in vacuum packaging had a slight decrease in redness and it was still acceptable. The fillets stored in exposed air or packed in 100% O(2) atmosphere turned brown, most likely due to myoglobin oxidation. CONCLUSION: The oxygen level of the packaging atmosphere had a profound impact on myoglobin alteration, which was governed by the forms of myoglobin. PMID- 21328357 TI - Contribution of major lipophilic antioxidants to the antioxidant activity of basil extracts: an EPR study. AB - BACKGROUND: The present research analyses the contribution of some lipid antioxidants to the antioxidant activity of lipophilic extracts from basil by an electron paramagnetic resonance (EPR) study using the stable free radical 1,1 diphenyl-2-picrylhydrazyl (DPPH). DPPH assay is considered an easy and accurate method with regard to measuring the antioxidant activity of plant extracts and EPR has already been employed to determine antioxidant activities of lipophilic plant extracts. RESULTS: Lipid extracts were obtained from basil grown hydroponically for 20 or 35 days from sowing and in soil for 35 days from sowing. Fast and slow rate constants were distinguishable in the decay kinetics of DPPH mixture added with lipid extract. Antioxidants with kinetics characterized by a fast decay rate were tocopherols and chlorophylls, whereas those characterized by a slow decay rate were carotenoids, among which were beta-carotene, lutein, beta apo-8'-carotenal and zeaxanthin. The 20-day hydroponically grown sample, which showed higher contents of tocopherol, chlorophyll and carotenoid molecules, was the sample endowed with the higher content of fast lipophilic antioxidants (FLA) and slow lipophilic antioxidants (SLA). CONCLUSION: The three samples showed different compositions of FLA and SLA, giving rise to different decay kinetics. Despite the differences, in all samples tocopherol contributed about 0.3% to the bulk of FLA, whereas the figure for chlorophyll was about 40%, evidencing the relevant but little-studied role of chlorophyll as an antioxidant. PMID- 21328358 TI - Effect of distillation waste water and plant hormones on spearmint growth and composition. AB - BACKGROUND: Distillation waste water (DWW) is a by-product from steam distillation of essential-oil crops; and currently, it is discharged into streams and rivers. The effects of DWW from 13 essential-oil crops, extracts from two alkaloid-containing species, and three plant hormones (methyl jasmonate, MJ; gibberellic acid, GA3; and salicylic acid, SA) were evaluated on productivity, essential-oil content and composition of spearmint (Mentha spicata L.) cv. 'Native'. RESULTS: Spearmint plant height was increased by the application of GA3 and Melissa officinalis DWW but suppressed by the application of Rosmarinus officinalis and Tagetes lucida DWW. Generally, MJ, GA3 and M. officinalis and Mentha arvensis DWW increased dry yields. The concentration of L-carvone in the oil ranged from 550 g kg(-1) (with Monarda citriodora DWW) to 670 g kg(-1) (with T. lucida DWW). M. citriodora DWW reduced the concentration of L-carvone in the oil by 23% relative to the control. CONCLUSION: Results suggest that DWW from essential-oil crops may affect monoterpene synthesis in M. spicata and, hence, may have a direct effect on the essential oil composition. DWW from essential-oil crops may be used as a growth promoter and modifier of the essential oil composition of spearmint. PMID- 21328359 TI - Free iron in pale, dark and alcohol-free commercial lager beers. AB - BACKGROUND: A highly sensitive, selective, rapid, reliable and inexpensive method has been developed for the direct analysis of free iron in 40 samples of bottled lager beer. RESULTS: A differential pulse adsorptive stripping voltammetry technique at a hanging mercury drop electrode without any sample digestion was performed. The iron content in the analysed samples was in the range of 41 to 165 ppb. CONCLUSIONS: The results point out that dark beers keep the highest free iron concentrations, which may be related to the highest amounts of minor ingredients in dark beers. Meanwhile, alcohol-free beers present the lowest free iron concentrations. Some discussion is presented regarding the basis of the free and complexed iron in beer and its participation as an essential element in the human diet. PMID- 21328360 TI - Characterisation of selected hazelnut cultivars: phenology, growing and yielding capacity, market quality and nutraceutical value. AB - BACKGROUND: Sixteen hazelnut cultivars growing in the continental climate of Slovenia were analysed over 15 years for their phenology, growth habit, yield potential, susceptibility to hazelnut weevil and the pomological traits and phenolic content of their nuts in order to obtain a complex value of these cultivars for growers, the confectionary industry and consumers. RESULTS: Blooming occurred over an interval of 10-23 days for female (pistillate) flowers and 11-22 days for male (staminate) flowers. Nocchione, Romai, Pauetet, ID and Daria were the most productive cultivars, with a nine-year cumulative yield ranging from 31.8 to 44.7 kg per plant. Pauetet, F. Coutard, Nocchione and Segorbe were less susceptible to unfavourable weather conditions during blooming and fertilisation, in terms of maintaining acceptable yields with limited blank production. Under integrated pest management, less than 2% of the nuts of Romai, Daria, TGDL and Nocchione were affected by hazelnut weevil, compared with an average of 5.5% for the other cultivars. Daria, Pauetet and T. Giffoni performed best with regard to kernel percentage and blanching ratio. The results suggest that raw kernels are a good source of the natural antioxidants gallic acid and epicatechin. CONCLUSION: The results of this study provide direction when choosing hazelnut cultivars for planting, consuming or processing. They can be applied not only in Slovenia and nearby countries but also in other parts of central and northern European countries with similar climates and growing conditions. PMID- 21328361 TI - Adequacy of different wheat cultivars for low-hydration bread making. AB - BACKGROUND: There is considerable interest in recovering landraces as genetic resources and as raw materials in ecological production. Low-hydration bread, whose dough is submitted to a sheeting roll process, is commonly prepared in Spain and other countries. The aim of this study was to assess the adequacy of some landraces, compared with commercial cultivars and flours, for making this type of bread. Eight Spanish landraces, four wheat cultivars developed during the green revolution and three commercial flours were chosen, their alveographic and kneading behaviours were analysed and the characteristics of the resulting breads were determined. RESULTS: The best correlations were obtained in breads with improver. Flours with extreme alveographic behaviour differed markedly from the rest. When these flours were excluded from the analysis, the parameters best correlated with bread quality (when using improver) were strength, tenacity and development time. A significant correlation between flour colour, a genetic factor, and crumb colour was found. This correlation was higher in breads without improver. CONCLUSION When flours with extreme characteristics were removed, the protein quality characteristics of flours defined the quality characteristics of low-hydration breads. PMID- 21328362 TI - Wettability, surface microstructure and mechanical properties of films based on phosphorus oxychloride-treated zein. AB - BACKGROUND: Zein, the predominant protein in corn, has been extensively studied as an alternative packaging material in edible and biodegradable films. However, films made from 100% zein are brittle under normal conditions. The aim of this investigation was to improve the film-forming properties of zein by chemical phosphorylation. The surface hydrophobicity, surface microstructure and mechanical properties of films based on untreated and phosphorus oxychloride (POCl(3))-treated zein were evaluated and compared. The effect of POCl(3) treatment on the rheological properties of zein solutions was also studied. RESULTS: POCl(3) treatment, especially at pH 7 and 9, led to an increase in the apparent viscosity of zein solutions. Atomic force microscopy (AFM) analysis showed that the film based on POCl(3) -treated zein at pH 7 had a stone-like surface microstructure with a higher roughness (R(q)) than the untreated zein film. The AFM data may partially account for the phenomenon that this film exhibited high surface hydrophobicity (H(0) ). POCl(3) treatment diminished the tensile strength (TS) of zein films from 4.83-6.67 to 1.3-2.29 MPa. However, the elongation at break (EAB) of the films at pH 7 and 9 increased from 3.0-4.5% (control film) to 150.1-122.7% (POCl(3) -treated film), indicating the potential application of zein films in wrapping foods or in non-food industries such as sugar, fruit or troche that need good extension packing materials. CONCLUSION: The data presented suggest that the properties of zein films could be modulated by chemical phosphorylation treatment with POCl(3) at an appropriate pH value. PMID- 21328363 TI - Physical and stress-strain properties of wheat (Triticum aestivum) kernel. AB - BACKGROUND: Two hard wheat varieties and one soft variety grown under the same agroecological conditions were analyzed for their physical and uniaxial stress strain compression properties. RESULTS: The physical properties of wheat kernel were determined at a moisture content of 0.13 kg kg(-1) (wet basis), whereas the stress-strain compression test was conducted at a kernel moisture content from 0.082 to 0.433 kg kg(-1) . Mean kernel lengths were 5.46 (5.37 and 5.38) mm, widths were 2.56 (2.47 and 2.62) mm and thicknesses were 2.12 (2.18 and 2.43) mm for Simonida, Dragana and NS 40S cultivars, respectively. Bulk densities were 791.34 (Simonida), 788.51 (Dragana) and 731.77 kg m(-3) (NS 40S). The force at the yield point was 241.46 N for Dragana (moisture content 0.133 kg kg(-1) ), 244.30 N for Simonida (0.136 kg kg(-1) ) and 164.90 N for NS 40S (0.433 kg kg(-1) ). CONCLUSION: The width and thickness of the analyzed kernels were small compared with the length, and bulk densities were also moderate. The yield point force values of the two hard varieties were 2.2 times higher than the values of the soft variety, at a moisture content of 0.136 kg kg(-1) for Simonida, 0.133 kg kg(-1) for Dragana and 0.141 kg kg(-1) for NS 40S. PMID- 21328364 TI - Yield and fruit quality of four sweet corn hybrids (Zea mays) under conventional and integrated fertilization with vermicompost. AB - BACKGROUND: Vermicompost has been proposed as a valuable fertilizer for sustainable agriculture. The effects of vermicompost on yield and quality of sweet corn were evaluated in this study. In two field trials, sweet corn plants were grown under (i) a conventional fertilization regime with inorganic fertilizer, and integrated fertilization regimes in which 75% of the nutrients were supplied by the inorganic fertilizer and 25% of the nutrients were supplied by either (ii) rabbit manure, or (iii) vermicompost. All three types of fertilization regime were supplied at two doses. Two pairs of nearly isogenic sweet corn hybrids homozygous for sugary1 and shrunken2 mutants were included in the trials to explore fertilizer * genotype interactions. Growth, yield and ear quality of the plants were evaluated in relation to the three fertilization regimes. RESULTS: In general, the integrated regimes yielded the same productivity levels as the conventional treatment. Moreover, both vermicompost and manure produced significant increases in plant growth and marketable yield, and also affected the chemical composition and quality of the marketable ear. Nevertheless, most of the observed effects of the organic fertilizers were genotype-dependent. CONCLUSION: The results confirm that the use of organic fertilizers such as vermicompost has a positive effect on crop yield and quality. Nevertheless, these effects were not general, indicating the complexity of the organic amendment-plant interactions and the importance of controlling genetic variation when studying the effects of vermicompost on plant growth. PMID- 21328365 TI - Effect of amino acid level in the pig diet during growing and early finishing on growth response during the late finishing phase of lean meat type gilts. AB - BACKGROUND: This experiment examined the influence of different amino acid levels during the growing and early finishing diet and the late finishing diet on growth performance and carcass quality of a lean meat type gilt. In a two by two factorial trial, 96 gilts were divided over four treatments. The two factors were (1) amino acid level in growing and early finishing and (2) amino acid level in late finishing. For the low amino acid diets we lowered the lysine, methionine, threonine and tryptophan levels by 20% and 30% in the growing and two finishing phases, respectively. RESULTS: Restricting amino acid levels in growing and early finishing led to a decreased growth rate but improved efficiency of amino acid use, which lasted into the subsequent phase. Pigs on a high amino acid diet in late finishing pigs were able to compensate to a large extent for amino acid restriction in growing and early finishing. Amino acid content in late finishing determined carcass quality. CONCLUSION: In the lean meat type gilts used in this experiment, restricting amino acid concentrations by 20% in the growing and 30% in the early finishing phase increased the growth rate and efficiency of growth in the subsequent late finishing phase. In order to obtain good carcass quality, it is crucial to provide the animals with a balanced diet during the late finishing phase. PMID- 21328366 TI - Effects of feeding salt-tolerant forage cultivated in saline-alkaline land on rumen fermentation, feed digestibility and nitrogen balance in lamb. AB - BACKGROUND: Mixing salt-tolerant plants with other plants may affect rumen fermentation, which could result in an increase of feed conversion rate. The objective of this study was to evaluate the effects of partially or entirely replacing the corn stover with a mixture of salt-tolerant forage (Dahurian wildrye grass, weeping alkaligrass and erect milkvetch) in the diet of lambs on ruminal fermentation, feed digestibility and nitrogen (N) balance. Ratios of corn stover to the mixture of salt-tolerant forages in the four experimental diets were 100:0, 67:33, 33:67 and 0:100, respectively, for control, low (LF), medium (MF) and high (HF). RESULTS: Ruminal pH was lower (P = 0.048) with LF and MF than with control and HF diets. Total VFA concentration was consistently higher (P = 0.039) for LF and MF than for control and HF with increasing amount of salt tolerant forage. Ratio of acetate to propionate was linearly (P = 0.019) decreased due to the decrease in acetate production. Digestibilities of OM, NDF and CP in the whole tract linearly (P < 0.002) decreased with increasing amount of salt-tolerant forage. Similarly, retained N and ratio of retained N to digestible N also linearly (P < 0.005) decreased. CONCLUSION: Feeding salt tolerant forage cultivated in saline-alkaline land improved rumen fermentation with increased total VFA production, and changed the rumen fermentation pattern to increased butyrate production. However, the decreased feed digestibility in the whole digestive tract of lamb may reduce nutrient availability to animals and thus adversely affect animal productivity. Additionally, feeding salt-tolerant forages may require more protein supplement to meet animal requirements, because of the low protein content and low protein digestibility of the salt-tolerant forages. PMID- 21328367 TI - Nutrient composition of the marine snail (Hexaplex trunculus) from the Tunisian Mediterranean coasts. AB - BACKGROUND: Marine snail (Hexaplex trunculus) presents increasing nutritional, commercial and economical importance, being widely consumed in northern Africa, particularly in Mediterranean countries. From a nutritional point of view there is still limited information on the chemical composition of edible tissues (meat and hepatopancreas) of this species. Therefore, the aims of the present work were to study the proximate chemical composition, fatty acid and amino acid profiles of H. trunculus from the Tunisian Mediterranean coasts. RESULTS: Fatty acid profiles showed that the polyunsaturated fatty acids (PUFA) content is higher than the saturated fatty acids (SFA). The yields of PUFA and SFA present in the meat fat were 68.2% and 33.4% of the total fatty acids, respectively. Similar values were obtained in the hepatopancreatic lipidic fraction. Snail tissues contain valuable concentrations of PUFA, especially n-6 and n-3 with chain lengths of 20 and 22 carbons. All edible tissues were valuable sources of essential amino acids. Aspartic acid is the major amino acids present in the meat and hepatopancreas. The concentrations of nutrients were also determined in the hepatopancreas and meat of H. trunculus. Significantly high concentrations of minerals and trace elements were found in these tissues. CONCLUSION: This study suggests that H. trunculus is an important source of protein and essential amino acids. Furthermore, the snail lipidic fraction contains high proportions of polyunsaturated fatty acids benefical for human health. PMID- 21328368 TI - Monoclonal antibodies to the haemagglutinin HA1 subunit of the pandemic influenza A/H1N1 2009 virus and potential application to serodiagnosis. AB - In order to provide specific serological reagents for pandemic influenza A/H1N1 2009 virus, monoclonal antibodies (Mabs) to recombinant haemagglutinin component HA1 (rHA1) were generated after fusing spleen cells from a mouse immunized with rHA1 protein derived from influenza strain A/California/06/09 H1N1 with a mouse myeloma cell line. Five hybridoma clones secreting Mabs specific for the rHA1 protein derived from pandemic influenza A/H1N1 2009 and not for rHA1 from seasonal H1N1 influenza strains A/Brisbane/59/07 and A/Solomon Islands/03/06 were identified by EIA. Mabs 7H4, 9A4, and 9E12 were reactive in Western blots with full length rHA and/or rHA1 subunit derived from A/California/06/09 strain. Only Mab 1F5 inhibited haemagglutination of turkey red blood cells with recombinant NIBRG-121 virus derived from A/California/07/09, but did not react in Western blots. Immunostaining of MDCK cells infected with NIBRG-121 was localized to the membrane/cytoplasm for four of the reactive Mabs. The differing reactivity of the Mabs in Western blots, immunostaining, EIA, and haemagglutination inhibition assay suggest that at least four of the five Mabs recognize different epitopes on HA1 of the pandemic influenza A/H1N1 2009 virus. Ferret antisera to pandemic influenza A/H1N1 2009 (A/England/195/09 and A/California/07/09 strains) and sera from human subjects vaccinated with Influenza A (H1N1) 2009 Monovalent Vaccine (CELTURA(r), Novartis Vaccines, Germany), inhibit binding of 1F5-HRP to biotinylated rHA1 derived from A/California/06/09 in a competitive EIA, suggesting that the epitope recognized by this Mab also evokes an antibody response in infected ferrets and vaccinated humans. PMID- 21328369 TI - Mobile and accurate detection system for infection by the 2009 pandemic influenza A (H1N1) virus with a pocket-warmer reverse-transcriptase loop-mediated isothermal amplification. AB - The 2009 pandemic H1N1 influenza A virus spread quickly worldwide in 2009. Since most of the fatal cases were reported in developing countries, rapid and accurate diagnosis methods that are usable in poorly equipped laboratories are necessary. In this study, a mobile detection system for the 2009 H1N1 influenza A virus was developed using a reverse-transcriptase loop-mediated isothermal amplification (RT-LAMP) kit with a disposable pocket-warmer as a heating device (designated as pwRT-LAMP). The pwRT-LAMP can detect as few as 100 copies of the virus--which is nearly as sensitive as real-time reverse-transcription polymerase chain reaction (RT-PCR)--and does not cross-react with RNA of seasonal influenza viruses. To evaluate the usefulness of the pwRT-LAMP system, nasal swab samples were collected from 56 patients with flu-like symptoms and were tested. Real-time RT PCR confirmed that the 2009 H1N1 influenza A virus was present in 27 of the 56 samples. Of these 27 positive samples, QuickVue Influenza A+B immunochromatography detected the virus in only 11 samples (11/27; 40.7%), whereas the pwRT-LAMP system detected the virus in 26 of the 56 samples (26/27 of the positive samples; 96.3%). These findings indicate that the mobile pwRT-LAMP system is an accurate diagnostic system for the 2009 H1N1 influenza A virus, and has great potential utility in diagnosing future influenza pandemics. PMID- 21328370 TI - Benefits of random-priming: exhaustive survey of a cDNA library from lung tissue of a SARS patient. AB - The severe acute respiratory syndrome (SARS) leads to severe injury in the lungs with multiple factors, though the pathogenesis is still largely unclear. This paper describes the particular analyses of the transcriptome of human lung tissue that was infected by SARS-associated coronavirus (SARS-CoV). Random primers were used to produce ESTs from total RNA samples of the lung tissue. The result showed a high diversity of the transcripts, covering much of the human genome, including loci which do not contain protein coding sequences. 10,801 ESTs were generated and assembled into 267 contigs plus 7,659 singletons. Sequences matching to SARS CoV RNAs and other pneumonia-related microbes were found. The transcripts were well classified by functional annotation. Among the 7,872 assembled sequences that were identified as from human genome, 578 non-coding genes were revealed by BLAST search. The transcripts were mapped to the human genome with the restriction of identity=100%, which found a candidate pool of 448 novel transcriptional loci where EST transcriptional signal was never found before. Among these, 13 loci were never reported to be transcriptional by other detection methods such as gene chips, tiling arrays, and paired-end ditags (PETs). The result showed that random-priming cDNA library is valid for the investigation of transcript diversity in the virus-infected tissue. The EST data could be a useful supplemental source for SARS pathology researches. PMID- 21328371 TI - Host sphingolipid biosynthesis is a promising therapeutic target for the inhibition of hepatitis B virus replication. AB - Serine palmitoyltransferase (SPT) catalyzes the first step in the sphingolipid biosynthetic pathway. Myriocin inhibits SPT and was shown to suppress the replication of hepatitis C virus (HCV) in vitro and in vivo. However, its effect on hepatitis B virus (HBV) replication is unknown. In this study, the HBV DNA levels in HuH7 cell culture supernatants were lowered successfully by using myriocin and it was found that the 50% inhibitory concentration of myriocin is approximately 5 uM. Myriocin and/or pegylated interferon (PEG-IFN) were also administered to chimeric mice for 2 weeks and the effects of these compounds on HBV DNA levels were determined. Myriocin alone did not reduce effectively the HBV DNA levels, whereas PEG-IFN alone reduced the DNA levels to 1/10th of the control levels. The combination of myriocin with PEG-IFN reduced the HBV levels to about 1/1,000 th of the control levels and induced a 1.0 log reduction in the levels of the HBV surface antigen and core protein. This latter effect was not observed in the other treatment groups. In conclusion, the combination of myriocin with PEG IFN represses synergistically HBV replication in vivo without inducing hepatotoxicity. PMID- 21328372 TI - Combined use of wild-type HBV precore and high serum iron marker as a potential tool for the prediction of cirrhosis in chronic hepatitis B infection. AB - Hepatitis B virus (HBV) and high liver iron deposits have both been associated with the development of cirrhosis. Among HBV factors, genotype and mutations in the basal core promoter (BCP) and precore regions have been most frequently studied but the evidence for a positive association with cirrhosis has been inconsistent. In this study, sera from persons with chronic HBV infection with and without cirrhosis were used for whole HBV genome analysis and for the estimation of serum iron marker (serum iron or ferritin) levels. Single codon analysis showed that the precore wild-type, TGG (nt 1,895-1,897), gave the highest accuracy (77.5%) for the identification of cirrhosis compared to other codons. When TGG was analyzed together with the precore start codon wild-type, ATG (nt 1,814-1,816), the accuracy was improved to 80.0% (odds ratio=35.29; 95% confidence interval=3.87-321.93; Phi=0.629; P<0.001). When the serum iron marker was included for analysis, it was clear that a combination of a precore wild-type and high serum iron marker gave a better accuracy (90.0%) (odds ratio=107.67; 95% confidence interval=10.21-1,135.59; Phi=0.804; P<0.001) for the identification of cirrhosis than either biomarker alone. It appeared that a combined use of both these biomarkers might help to predict the development of cirrhosis in a person with chronic HBV infection, but longitudinal studies are required to test this hypothesis. PMID- 21328373 TI - Association of intrahepatic cccDNA reduction with the improvement of liver histology in chronic hepatitis B patients receiving oral antiviral agents. AB - Covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) is difficult to eradicate using current antiviral therapy. This study compares cccDNA reduction with relation to liver histology in nucleoside/nucleotide-naive chronic hepatitis B patients receiving oral antiviral monotherapy (n=35), including entecavir (ETV, n=13), adefovir dipivoxil (ADV, n=22) or placebo (n=14). Serum HBV DNA, intrahepatic total HBV DNA and cccDNA are quantified. Histological hepatic examination is performed at baseline and at 48 weeks of treatment. Treatment with ETV or ADV shows significant median reduction in serum HBV DNA ( 6.21 and -4.27 log(10) copies/mL) and intrahepatic total HBV DNA (-1.69 and -1.23 log(10) copies/cell). Intrahepatic cccDNA levels are reduced slightly in the ETV and the ADV groups, but do not differ statistically from the placebo group (-0.17 vs. -0.01 vs. 0.02 copies/cell). Only the level of intrahepatic cccDNA correlates with Knodell necroinflammation activity (r=0.527, P<0.001) and Ishak fibrosis severity (r=0.348, P=0.015) before treatment. Multivariate logistic regression analysis indicates that treatment-induced cccDNA reduction is associated with improved necroinflammation (P=0.041) and fibrosis (P=0.026). In conclusion, baseline intrahepatic cccDNA loads correlate with histologic activity. Although one-year ETV or ADV treatment is insufficient for cccDNA eradication, oral antiviral therapies may improve liver histology, probably by suppressing intrahepatic cccDNA. PMID- 21328375 TI - Prevalence of and risk factors for hepatitis C virus infection among blood donors in Chengdu, China. AB - The objectives of the study were to estimate the prevalence of anti-hepatitis C virus (HCV) positivity among blood donors from Chengdu, China, and to determine risk factors associated with infection. In this study, data were collected from volunteer blood donors between July 2006 and June 2007. Anti-HCV test was performed in 119,518 donors. To identify risk factors associated with HCV infections a case-control study was conducted in 305 unique HCV-seropositive blood donors and 610 seronegative donors matched for age and sex. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression. The population attributable risk (PAR) to risk factor was estimated according to the Bruzzi's formula. The prevalence of anti-HCV positivity was 0.53% (95% CI: 0.489-0.572%). The final multivariate model included the following independent HCV risk factors: razor sharing (OR=29.16; 95% CI: 12.89-66.00), blood transfusion (OR=20.84; 95% CI: 3.76-115.45), acupuncture (OR=8.01; 95% CI: 3.16-20.30), a history of hospitalization, injections >10 years earlier, a family history of hepatitis B, dental treatment, and ear piercing. The PAR of risk factors are 68.4%, 6.3%, 14.1%, 23.1%, 29.5%, 29.3%, 38.9%, and 27.8%, respectively, and the total PAR is 98.3%. Infection with HCV among blood donors in Chengdu is associated with iatrogenic risk factors and beauty treatment related risk. Razor sharing is an important risk factor for HCV infection. These results indicate that infection control measures in healthcare settings may reduce the burden of HCV infection and there is a need for development of effective educational programs to improve HCV knowledge among beauty culture professionals, barber cosmetologists, and the general public to avoid risk behaviors. PMID- 21328374 TI - Hepatitis C virus subtypes circulating among intravenous drug users in Lisbon, Portugal. AB - Hepatitis C virus (HCV) infects 2-3% of the world population and intravenous drug consumption is the leading cause of transmission in industrialized countries. The unavailability of data on the molecular epidemiology of HCV infection in Portugal prompted the study of HCV subtypes circulating among intravenous drug users residing in the Lisbon metropolitan area and sampled about 10 years apart (1998 2000 and 2008-2009). Partial coding sequences for E1 and/or NS5B were obtained from 124 individuals with HCV viremia, both mono-infected and co-infected with HIV. Phylogenetic analysis showed that, for both time periods, the most prevalent subtypes were 1a and 3a, found, altogether, in 64.9% and 71.6% of the individuals, respectively for the first and the second sampling periods. However, genotype 4 viruses (subtypes 4a and 4d), introduced later, as inferred by comparison of intra-subtype genetic distances, were also relatively frequent even one decade ago (24.6%). This HCV subtype profile for Portuguese intravenous drug users is in agreement with those described for other southern European countries when in association with drug consumption. With the exception of subtype 1b, phylogenetic trees did not show clustering of the Portuguese sequences, but rather phylogenetic mixing of HCV sequences from different geographic origins, as described previously in other Western countries and suggestive of a large international transmission network. Consistent with the low recombination rates reported for HCV, only one sample revealed discordant subtypes for the two regions analyzed (4d in E1 and 4a in NS5B), representing a potential new recombinant that deserves further analysis. PMID- 21328376 TI - Investigating an outbreak of acute viral hepatitis caused by hepatitis E virus variants in Karachi, South Pakistan. AB - Hepatitis E is a classic water-borne disease in developing countries. Detection of anti-HEV IgM and IgG antibodies, in addition to HEV RNA are useful epidemiological markers in diagnosis of hepatitis E. This study was conducted to investigate an outbreak of acute viral hepatitis in South-Pakistan. Anti-HEV IgM and IgG were assessed comparatively with serological kits manufactured by Abbott, Cosmic, TGH, and Wantai, selecting HEV RNA as reference assay. Molecular evolutionary analysis was performed by phylogeny and HEV spread time analysis by Bayesian Coalescent Theory approach. Of the 89 patients, 24 (26.9%) did not have acute hepatitis viral marker. Of the remaining 65 cases, 4 (6.1%) were positive for anti-HAV IgM, one (1.5%) for anti-HBc IgM, 2 (3%) for HCV, 53 (81.5%) for anti-HEV IgM, and 5 (7.7%) were hepatitis-negative. The Wantai test was 100% sensitive and specific followed by Cosmic (98.1% and 100%), TGH (98.1% and 97.2%) and Abbott (79.2% and 83.3%). Two HEV variant strains were detected by phylogeny responsible for this acute hepatitis outbreak. Estimates on demographic history of HEV showed that HEV in Pakistan has remained at a steady nonexpanding phase from around 1970 to the year 2005, in which it expanded explosively with the emergence of new HEV variants. In conclusion, the limited sensitivity of available assay (Abbott anti-HEV EIA) may be a concern in HEV diagnosis in Pakistan. This study cautions that the dissemination of the variant strains to other areas of Pakistan may lead to explosive HEV outbreaks. PMID- 21328377 TI - CASP8 promoter polymorphism is associated with high-risk HPV types and abnormal cytology but not with cervical cancer. AB - Only a small fraction of women infected with human papillomavirus (HPV) progress to cervical cancer pointing to additional risk factors including host genetics that might play a role in development of cervical cancer. Caspase-8 (encoded by CASP8 gene) is crucial in generating cell death signals to eliminate potentially malignant cells. Genetic variation in CASP8 might influence the susceptibility to cancer. CASP8 -652 6N ins/del polymorphism has been previously reported to influence the progression to several cancers including cervical cancer. This polymorphism was investigated in 445 women of black African and Mixed Ancestry origin with invasive cervical cancer and 1,221 controls matched (1:3) by age, ethnicity, and domicile status. Genotyping for CASP8 -652 6N ins/del was done by PCR-RFLP. In the control women cervical disease was detected by cervical cytology. The CASP8 -652 6N del/del genotype did not show any significant association (P=0.948) with cervical cancer. Further analysis within the controls showed a weak association (P=0.048) of this polymorphism with abnormal cytology in both ethnicities and high-risk HPV infection (P=0.030) only in the black Africans. This is the first study of the role of CASP8 -652 6N ins/del polymorphism in cervical cancer in an African population. These results show that CASP8 -652 6N del/del genotype increases the risk of abnormal cytology and high risk HPV infection but does not show an association with cervical cancer. This result points towards an important role of CASP8 in HPV infection and in the development of pre-cancers. PMID- 21328378 TI - Evaluation of type-specific HPV persistence and high-risk HPV viral load quantitation in HPV positive women under 30 with normal cervical cytology. AB - The persistence of high-risk HPV (HR-HPV) infection is necessary for the development of cervical intraepithelial neoplasia. The aim of this study was to evaluate if HR-HPV typing and HPV16, 18, 31, and 33 quantitation are predictive for type-specific infection persistence and/or the development of CIN in women under 30 with normal cervical cytology. Young women (under 30) attending a family planning clinic who were HPV positive with normal cervical cytology were included. HPV genotyping was assessed by MY09/MY11 PCR, sequencing, phylogenetic analysis, and cloning when necessary. HR-HPV viral load was quantified using duplex real-time PCR. Study patients were offered for a second smear and HR-HPV detection and quantitation after 12 months. HR-HPV was identified in 43 (21.9%) of the 199 included women. Of these, 39 patients had a second cervical sample taken within a mean interval of 11.7 months (8.8-18.3 months). The mean HR-HPV 16, 18, 31, and 33 initial viral load was 1.9 * 10(6) copies/million cells. The level of viral load did not reveal any significant association with type-specific HR-HPV persistence or the subsequent development of cervical intraepithelial neoplasia. Only HPV16 infection was significantly more likely to persist (91.7% vs. 33.1%, P=0.001) and to develop CIN (33.3% vs. 3.7%, P=0.025). In women under 30 with normal cytology, HR-HPV viral load is common and is not predictive of HPV persistence or the development of cervical intraepithelial neoplasia. HPV16 positive women are significantly more likely to have persistent infection and to develop cervical intraepithelial neoplasia. PMID- 21328379 TI - Conservation and mutation of viral interleukin-10 gene in gastric carcinomas and nasopharyngeal carcinomas. AB - The Epstein-Barr virus (EBV) BamHI-C fragment rightward reading frame 1 (BCRF1) coded viral interleukin-10 (vIL-10), exhibits high homology with human interleukin-10 (hIL-10) gene. The protein product vIL-10, which shares some functional properties with hIL-10, primarily mediates immunosuppressive functions. To characterize the variations of the vIL-10 gene and to explore the association between vIL-10 gene variations and EBV associated diseases, the vIL 10 gene was analyzed (using direct sequencing) in 41 cases of EBV-associated gastric carcinoma (EBVaGC), 83 nasopharyngeal carcinoma biopsies, and 40 throat washing samples from healthy donors in Northern China. One silent mutation (c9980a) was observed in the majority of EBVaGC, nasopharyngeal carcinoma and throat washing samples (134/164, 81.7%). Two consensus mutations (V6M and G23S) were identified in the signal peptide region in some nasopharyngeal carcinoma and throat washing isolates. These results indicate that the pattern B95-8 (identical sequence to B95-8) is the dominant type among the EBV isolates from Northern China, while the pattern SPM (mutation in the signal peptide present only in nasopharyngeal carcinoma and throat washing isolates) seems more relevant with the EBV-positive nasopharyngeal and laryngopharyngeal epithelial cells. The conservation of vIL-10, with a few variations, suggests the critical role of the vIL-10 gene for EBV in gaining an advantage over the host's immune system. PMID- 21328380 TI - HPV types and variants among cervical cancer tumors in three regions of Tunisia. AB - Cervical cancer is the second most common cancer among Tunisian women, and the incidence rates vary by region. Three Tunisian registries report age-standardized rates of 6.3/10(5) in the central region, 5.4/10(5) in the north, and 2.7/10(5) in the south. High-risk human papillomavirus (HPV) types and their variants differ in carcinogenic potential and geographic distribution. The HPV type and variant distribution could be a factor in the differing rates between regions of Tunisia. Tumor tissue was collected from 142 Tunisian cervical cancer patients. Demographic and reproductive characteristics of the patients were abstracted from cancer registry and hospital records. HPV type and variant analyses were performed using PCR-based Luminex and dot-blot hybridization assays. Eighty-three percent of tumors were infected with at least one HPV type. European variants of HPV16/18 were the most prevalent in tumors from all three regions, with all HPV18 infections and 64% of HPV16 infections being of European lineage. A higher frequency of HPV16 was present in Northern Tunisia (80%) than in Central (68%) or Southern Tunisia (50%) (P=0.02). HPV18/45 was significantly more common in adenocarcinomas (50%) than in squamous cell carcinomas (11%) (P=0.004). Frequent infection with European HPV variants most likely reflects the history of European migration to Tunisia. In addition to the importance of understanding the variants of HPV in Tunisia, behavioral and cultural attitudes towards screening and age specific infection rates should be investigated to aid the development of future vaccination and HPV screening programs and policies. PMID- 21328381 TI - Modulation of innate immunity in human pancreatic islets infected with enterovirus in vitro. AB - Present knowledge of innate immunity in infected cells relies on studies of cell lines and animal models. In this study, primary human pancreatic islets of Langerhans were used to study virus-host interactions in a model of the possible induction of type 1 diabetes by enterovirus (EV). Human islets were infected with a strain of EV isolated at onset of type 1 diabetes, or exposed to synthetic dsRNA (poly(I:C)), used commonly to mimic viral infection. Induction of innate immunity and the effect of the female sex hormone 17beta-estradiol, known to have cell-protective effects, on islet chemokine secretion were investigated. 17beta Estradiol reduced EV-but not poly(I:C)-induced IP-10/CXCL10 secretion from human islets, suggesting that separate signaling pathways of the innate immune response are triggered by EV and poly(I:C), respectively. Infection with EV increased the gene-expression of toll-like receptor 3, interferon-beta, and the intracellular helicase MDA5, involved in antiviral innate immunity, multi-fold over time, whereas poly(I:C) increased the expression of these genes transiently. The induced expression pattern was similar in all donors, but the expression levels varied greatly. Pre-exposure to poly(I:C) blocked viral replication in islets from 56% of the donors. These data provide insight on the innate immune responses induced by EV in human islets, and show that this can be modulated by 17beta estradiol, and suggest an important difference between virus- and poly(I:C) induced signaling. PMID- 21328382 TI - Humoral immune responses to Epstein-Barr virus encoded tumor associated proteins and their putative extracellular domains in nasopharyngeal carcinoma patients and regional controls. AB - Epstein-Barr virus (EBV) latency proteins EBNA1, LMP1, LMP2, and BARF1 are expressed in tumor cells of nasopharyngeal carcinoma (NPC). IgG and IgA antibody responses to these non-self tumor antigens were analyzed in NPC patients (n=125) and regional controls (n=100) by three approaches, focusing on the putative LMP1, LMP2 extracellular domains. Despite abundant IgG and IgA antibody responses to lytic antigens and EBNA1, patients had low titer (1:25-1:100) IgG to LMP1 (81.2%), LMP2 (95.6%), and BARF1 (84.8%), while immunoblot showed such reactivity in 24.2%, 12.5%, and 12.5% at 1:50 dilution, respectively. Few IgA responses were detected, except for EBNA1. Controls only showed IgG to EBNA1. ELISA using peptides from different domains of LMP1, LMP2, and BARF1 also yielded mostly negative results. When existing, low level IgG to intracellular C-terminus of LMP1 (62.9%) prevailed. Rabbit immunization with peptides representing extracellular (loop) domains yielded loop-specific antibodies serving as positive control. Importantly, these rabbit antibodies stained specifically extracellular domains of LMP1 and LMP2 on viable cells and mediated complement-driven cytolysis. Rabbit anti-LMP1 loop-1 and -3 killed 50.4% and 59.4% of X50/7 and 35.0% and 35.9% of RAJI cells, respectively, and 22% of both lines were lysed by anti-LMP2 loop-2 or -5 antibodies. This demonstrates that (extracellular domains of) EBV-encoded tumor antigens are marginally immunogenic for humoral immune responses. However, peptide-specific immunization may generate such antibodies, which can mediate cell killing via complement activation. This opens options for peptide-based tumor vaccination in patients carrying EBV latency type II tumors such as NPC. PMID- 21328383 TI - Viral detection in hydrops fetalis, spontaneous abortion, and unexplained fetal death in utero. AB - This study was undertaken to investigate the occurrence of viral infection in fetal death by examining tissues for the presence of DNA of several viral agents. Tissue specimens including heart, kidney, liver, lung, and placenta of 73 cases of fetal death were examined with 27 cases of elective termination of pregnancy as a control group. DNA extracted from these samples was tested for the presence of HSV, CMV, EBV, VZV, HHV-6, HHV-7, and PVB19. Viral DNA was found in one or more tissue samples from 25/73 cases (34%): CMV in 20, HSV in 5, parvovirus B19 in 5, HHV-7 in 3, and HHV-6 in 2. The presence of HHV-6 in fetal tissue has been reported rarely. No study so far has reported the detection of HHV-7 in fetal tissues with normal or adverse outcomes. Viral DNA was not found in any of the termination of pregnancy samples. Among the positive cases, eight had dual infection. One further case was positive for three viruses: HSV, CMV, and HHV-7. HHV-6 was the sole infectious agent in two cases, HHV-7 in one case, PVB19 in three, and CMV in ten cases. The finding of multiple viral DNA in 12% of the cases suggests the involvement of complex risk factors in cases of fetal loss. Although the cause of fetal death often includes other factors (e.g., chromosomal abnormalities) these data suggest the incidence of viral infective etiology may be higher than considered previously. However, larger studies are required to establish this link. PMID- 21328385 TI - Monitoring epidemic viral respiratory infections using one-step real-time triplex RT-PCR targeting influenza A and B viruses and respiratory syncytial virus. AB - Rapid and specific diagnosis of influenza A/B and respiratory syncytial virus (RSV) viruses is needed for optimal management of patients with acute respiratory infections. In this study, a one-step triplex real-time RT-PCR assay was developed for rapid diagnosis of influenza A/B and RSV infections to optimize diagnosis efficiency of acute respiratory infections. Cell-culture supernatants and clinical samples were used to evaluate specificity and sensitivity of the assay. The assay was used routinely during two winter epidemics for testing respiratory specimens from 2,417 patients. The limit of detection in cell-culture supernatant was 1-10 plaque forming units/input (influenza A/B) and 2 * 10(-2) 50% tissue culture infectious dose/input (RSV). In clinical samples, the assay was as sensitive as commercial molecular assays for the detection of each influenza A/B and RSV (Flu-A/B and RSV-A/B r-geneTM) individually, and far more sensitive than antigen detection. During the winter 2008-2009, the assay identified 145 RSV, 42 influenza A, and one mixed RSV-influenza A infections among 298 patients. The next winter, the assay was used in two independent hospital laboratory settings. 776 patients were tested in one hospital and 1,343 in the other, resulting in 184 and 501 RSV, 133 and 150 influenza A, and 1 and 11 mixed RSV-influenza A infections, respectively, being detected. This new user friendly assay allows rapid (within hours), effective molecular diagnosis of single or mixed infections involving influenza A (including seasonal A H1N1 and H3N2, and A(H1N1) 2009), influenza B, and RSV(A/B). The assay is very valuable for managing patients during winter epidemics when influenza and respiratory syncytial viruses co-circulate. PMID- 21328384 TI - Evidence for extensive genotypic diversity and recombination of GB virus C (GBV C) in Germany. AB - Multiple genotypes of GB virus C (GBV-C)-a non-pathogenic flavivirus-have been identified to date, although they are not uniformly distributed worldwide. It has also been suggested that GBV-C genotype may play a role in modulating HIV disease; however, the prevalence and genotype distribution of GBV-C has not been adequately studied in most countries. Among 408 HIV positive subjects in Germany, 97 (23.8%) had detectable GBV-C RNA. Based on sequencing of the 5' untranslated region (5'-UTR), the GBV-C genotypes were 1 (n=8; 8.2%), 2 (n=81; 83.5%), and 3 (n=2; 2.1%), as well as a unique genotype not previously reported (n=6; 6.2%). Among 17 samples also sequenced in the envelope 2 (E2) region, 14 had concordant genotype results when comparing the 5'-UTR and E2, while evidence of intergenotypic recombination was observed among E2 sequences from 3 individuals. These results suggest that genotypic diversity and viral recombination contribute to the overall genetic variability of GBV-C. PMID- 21328386 TI - High incidence of cytomegalovirus, human herpesvirus-6, and Epstein-Barr virus reactivation in patients receiving cytotoxic chemotherapy for adult T cell leukemia. AB - The etiology of cytomegalovirus (CMV), human herpesvirus-6 (HHV-6), and Epstein Barr virus (EBV) reactivation and the potential for complications following cytotoxic chemotherapy in the absence of allogeneic transplantation are not clearly understood. Patients with adult T cell leukemia (ATL) are susceptible to opportunistic infections. In this study, the incidence, kinetics and clinical significance of reactivation of CMV, HHV-6, and EBV in ATL patients were investigated. Viral DNA in a total of 468 plasma samples from 34 patients was quantified using real-time PCR. The probability of CMV, HHV-6, and EBV reactivation by 100 days after the start of chemotherapy was 50.6%, 52.3%, and 21.6%, respectively. Although most CMV reactivations were self-limited, plasma CMV DNA tended to persist or increase if the CMV DNA levels in plasma reached >= 10(4) copies/ml. CMV reactivation was negatively associated with survival, but the P-value for this association was near the borderline of statistical significance (P=0.052). One patient developed fatal interstitial pneumonia concomitant with peak CMV DNA accumulation (1.6 * 10(6) copies/ml plasma). Most HHV-6 and EBV reactivations were self-limited, and no disease resulting from HHV 6 or EBV was confirmed. HHV-6 and EBV reactivation were not associated with reduced survival (P=0.35 and 0.11, respectively). These findings demonstrated that subclinical reactivation of CMV, HHV-6, and EBV were common in ATL patients receiving chemotherapy. There were differences in the viral reactivation patterns among the three viruses. A CMV load >= 10(4) copies/ml plasma was indicative of subsequent exacerbation of CMV reactivation and developing serious clinical course. PMID- 21328387 TI - Prevalence and association of human parvovirus B19V with hepatitis B and C viruses in Nigeria. AB - Co-infection of parvovirus B19 with hepatitis B virus has been found in patients with acute and chronic hepatitis. The clinical significance of parvovirus B19 in hepatitis B co-infected patients is still controversial. In this study parvovirus B19 antibodies and DNA were investigated in serum samples from 76 patients with HBV infection, 17 with HBV/HCV co-infection and 44 healthy controls. In the sera from patients with HBV infection, anti-B19V IgM and IgG antibodies were detected in 24/76 (32%) and 25/76 (33%), in 6/17 (35%) and 8/17 (47%) of HBV/HCV co infected patients, and in 14/44 (32%) and 12/44 (12%) of a non-hepatitis healthy controls, respectively. B19V DNA was detected in 8/76 (11%) of patients with HBV infection and in 3/17 (18%) of patients with a HBV/HCV co-infection, and in 4/44 (9%) healthy controls. The occurrence of parvovirus B19 DNA was significantly higher in patients with symptomatic HBV 4/20 (20%) compared to asymptomatic HBV carrier 4/56 (7%) (P<0.05). Ten of the positive B19V DNA sequences belonged to B19V genotype 1 while two belonged to genotype 3. The results of this study showed a significant difference in the prevalence of parvovirus B19 DNA in symptomatic HBsAg positive as compared to asymptomatic HBsAg positive individuals; however, the conclusion that parvovirus B19 infection increased the frequency of liver disease was not supported. Long-term longitudinal studies are, however, required to determine the synergistic effect of parvovirus B19 infection in HBV or HBV and HCV co-infected persons. PMID- 21328388 TI - Parvovirus 4 in French in-patients: a study of hemodialysis and lung transplant cohorts. AB - The epidemiology and the clinical implication of human parvovirus 4 (PARV4) in human populations is still under evaluation. The distribution of PARV4 DNA was determined in cohorts of French hemodialysis and lung transplant patients. Plasma samples (n=289) were tested for PARV4 by real-time PCR assay (ORF2), and amplification products selected at random were sequenced. Analysis of available serological and biological markers was also undertaken. Fifty-seven samples out of 185 (30.8%) were positive for PARV4 DNA in the cohort of hemodialysis patients. A higher prevalence of the virus was identified in patients with markers of HBV infection. PARV4 was also identified in 14 out of 104 samples (13.5%) from lung transplant recipients, with no clear-cut association with available clinical markers. Point mutations located on the zone of real-time detection were identified for some amplification products. This study describes the detection of PARV4 in the blood of hemodialysis and lung transplanted patients with significant difference in prevalence in these two cohorts. Further studies will be needed in order to understand better both the potential implication in host health and the natural history of this virus. PMID- 21328389 TI - A molecular case-control study of the Merkel cell polyomavirus in colon cancer. AB - To explore the putative role of the Merkel cell polyomavirus in human colon cancer, a prospective molecular case-control study was undertaken in patients and their relatives enrolled during a screening program. Fresh tissue samples from 64 cases of colon cancer (mean age 69.9 +/- 11.0 years; 40 males) and fresh biopsies from 80 relatives (mean age 53.7 +/- 8.6 years; 43 male; 55 son/daughter, 23 brother/sister, 2 parents) were analyzed by PCR and sequencing. Pre-cancerous lesions, namely adenomas and polyps, were detected in 15 (18.8%) and 9 (11.2%) of the controls, respectively. In addition, 144 blood samples were examined. Merkel cell polyomavirus DNA was detected in 6.3% of cases and 8.8% of controls. This difference was not statistically significant in the logistic regression analysis, after adjustment for age. Whereas blood samples from both cases and controls tested negative, the DNA Merkel cell polyomavirus was identified in 12.5% of adenoma/polyp tissues. No statistically significant difference was found when prevalence rates of Merkel cell polyomavirus in normal, pre-cancerous and cancer tissues were compared. Sequence analysis of the viral LT3 and VP1 regions showed high homology (>99%) with those of strains circulating worldwide, especially with genotypes detected in France. The findings of this survey are consistent with the hypothesis that the Merkel cell polyomavirus, in addition to other human polyomaviruses, can be recovered frequently from the gastrointestinal tract, because it is transmitted throughout the fecal-oral route. Moreover, the study does not indicate a role for Merkel cell polyomavirus in the genesis of colon cancer. PMID- 21328390 TI - Distribution of BK polyomavirus genotypes in Tunisian renal transplant recipients. AB - BK polyomavirus (BKV) is a ubiquitous virus in humans that remains latent in the urogenital tract after a primary infection during childhood. The virus, which is reactivated frequently and excreted in urine, can cause nephropathy in renal transplant recipients. BKV sequences are classified into four subtypes (I-IV). Subtype I and IV are divided further into four and six subgroups, respectively. To characterize the subtypes of BKV prevalent in Tunisia, the presence of the virus was investigated by real-time PCR in urine samples from 77 renal transplant recipients. For subtype identification, a DNA fragment in the VP1 coding region, amplified by nested PCR from positive samples, was sequenced and a phylogenetic analysis was performed. In the studied population, subtype I (75.5%), II (14.5%), and IV (2.5%) were identified with a clear predominance of subtype Ib-2 (73%) as observed in European population. This study suggests that in North Africa, the BKV genotype distribution is similar to that of Europe and different from that of sub-Saharan Africa. PMID- 21328391 TI - High activity of indoleamine 2,3-dioxygenase is associated with renal insufficiency in Puumala hantavirus induced nephropathia epidemica. AB - Nephropathia epidemica (NE) is a hemorrhagic fever with renal syndrome caused by Puumala hantavirus. The severity of NE varies greatly. The aim of the present study was to evaluate whether serum indoleamine 2,3-dioxygenase (IDO) activity is associated with the severity of NE. A prospectively collected cohort of 102 consecutive patients with acute serologically confirmed NE was examined. Serum kynurenine, tryptophan, creatinine, CRP, and blood cell count were measured for up to 5 consecutive days after admission. The kynurenine to tryptophan (kyn/trp) ratio reflecting IDO activity was calculated. A maximum kyn/trp ratio >202 umol/mmol had a sensitivity of 85% and a specificity of 75% for detecting maximum serum creatinine values >250 umol/L by receiver operating characteristic (ROC) analysis. A maximum kyn/trp ratio >202 umol/mmol (high IDO level) was also associated with other parameters reflecting the severity of the disease and renal impairment. Patients with high IDO levels had higher maximum serum creatinine (379 vs. 102 umol/L, P<0.001), plasma C-reactive protein (104.1 vs. 72.1 mg/L, P=0.029), and blood leukocyte values (11.9 vs. 9.0 * 10(9) /L, P<0.001) compared to patients with kyn/trp ratio <= 202 umol/mmol. They also had lower minimum urinary output (1,100 vs. 1,900 ml/day, P<0.001) and longer hospital stays (8 vs. 5 days, P<0.001). In conclusion, high serum IDO activity was associated with increased disease severity and renal impairment in NE. PMID- 21328392 TI - Emergence of G9 as a predominant genotype of human rotaviruses in Cuba. AB - To study human rotaviruses in Cuban children up to 5 years old with acute diarrhea, a total of 64 faecal samples from two pediatric hospitals between 2006 and 2008 were analyzed. Thirty-nine samples (60.9%) were found positive for rotaviruses by enzyme-linked immunosorbent assay (ELISA) and polyacrylamide gel electrophoresis (PAGE), while four (6.2%) exhibited discordant results (ELISA positives/PAGE negatives). All the positive samples were genotyped by a reverse transcription-polymerase chain reaction (RT-PCR). The most prevalent G and P types were G1 (60.5%) and P[8] (90.6%), respectively. Among the rotaviruses detected, two long RNA patterns were identified by PAGE (L/A and L/B). The predominant genotype in 2006 and 2007 was G1/P[8] with detection rates 71.4% and 80%, respectively. In contrast, G9/P[8] was found at the highest rate (78.5%) in 2008. The phylogenetic analysis of VP7 genes of the ten representative strains indicated that Cuban G1/P[8] rotaviruses were close to those reported in the Americas, and G9/P[8] rotaviruses were located in the lineage of the emerging G9 strains spreading worldwide. This is the first molecular epidemiologic study of rotaviruses in Cuba, highlighting the current increase of the G9 rotavirus which has been recognized globally as an emerging genotype. The study reinforces the need for a systematic surveillance of the molecular epidemiology of rotaviruses. PMID- 21328393 TI - Prevalence of human T-cell lymphotropic virus type 1 and 2 among patients with malignant hematological diseases in south Chile. AB - Human T-cell lymphotropic virus type 1 and 2 (HTLV-1/2) are oncogenic retroviruses linked etiologically to human diseases. In Chile, these viruses have been studied in ethnic populations, or patients diagnosed clinically with HTLV-1 associated myelopathy/tropical spastic paraparesis, but have not been studied in patients with malignant hematological diseases. The aim of this study was to determine the seroprevalence and viral prevalence of HTLV-1/2 among patients with malignant hematological diseases. Eighty-eight patients with malignant hematological diseases were tested by enzyme-linked immunosorbent assay (ELISA) for IgG anti-HTLV-1/2 and nested-PCR for the tax gene. The seroprevalence by ELISA was 3.4% and the viral prevalence by nested-PCR tax was 18.2%. HTLV-1 was found in 17% and HTLV-2 in 1% of the patients tested. HTLV-1/2 was found in 17.4% of patients with non-Hodgkin's lymphomas, 28.6% of patients with Hodgkin's lymphomas, 80% of patients with chronic lymphocytic leukemia, 11.4% of patients with acute lymphoblastic leukemia, and 22.2% of patients with acute myeloid leukemia. A high prevalence of HTLV-1/2 was found in patients with malignant hematological diseases. A high proportion of patients were seronegative to HTLV 1/2 infection, similar to other HTLV-1/2 associated disorders. Because 50% of patients positive for HTLV-1/2 were below 30 years old, it is suggested that vertical transmission could have played an important role in these patients. PMID- 21328395 TI - Analysis of methylene blue and its metabolites in blood by capillary electrophoresis/electrospray ionization mass spectrometry. AB - A method for the determination of methylene blue (MB) and its metabolites (azure A, azure B and azure C) in rat blood by CE-electrospray ionization mass spectrometry (CE-ESI-MS) was developed in this paper. Different analytical parameters were investigated in detail such as pH and concentration of separation buffer, and ESI-MS instrumental parameters. Under the optimum conditions, MB and its metabolites were separated and detected in 27.3 min. LODs (defined as S/N=3) of this method were 0.22, 0.25, 0.10 and 0.30 MUg/mL for MB, azure A, azure B and azure C, respectively. To get a satisfactory extraction efficiency of MB and its metabolites in rat blood, different extraction solutions were studied. By using this method, MB and its metabolites (azure A, azure B and azure C) were successfully analyzed in rat blood samples. PMID- 21328394 TI - Two-photon fluorescence and second-harmonic generation imaging of collagen in human tissue based on multiphoton microscopy. AB - Multiphoton microscopic imaging of collagen plays an important role in noninvasive diagnoses of human tissue. In this study, two-photon fluorescence and second-harmonic generation (SHG) imaging of collagen in human skin dermis and submucosa of colon and stomach tissues were investigated based on multiphoton microscopy (MPM). Our results show that multiphoton microscopic image of collagen bundles exhibits apparently different pattern in human tissues. The collagen bundles can simultaneously reveal its SHG and two-photon excited fluorescence images in the submucosa of colon and stomach, whereas it solely emit SHG signal in skin dermis. The intensity spectral information from tissues further demonstrated the above results. This indicates that collagen bundles have completely different space arrangement in these tissues. Our experimental results bring more detailed information of collagen for the application of MPM in human noninvasive imaging. PMID- 21328396 TI - Chiral separation and quantitation of cetirizine and hydroxyzine by maltodextrin mediated CE in human plasma: effect of zwitterionic property of cetirizine on enantioseparation. AB - In the present study, a very simple CE method for chiral separation and quantitation of zwitterionic cetirizine (CTZ), as the main metabolite of hydroxyzine (HZ), and HZ has been developed. In addition, the effect of zwitterionic property of CTZ on enantioseparation was investigated. Maltodextrin, a linear polysaccharide, as a chiral selector was used and several parameters affecting the separation such as pH of BGE, concentration of chiral selector and applied voltage were studied. The best BGE conditions for CTZ and HZ enantiomers were optimized as 75 mM sodium phosphate solution at pH of 2.0, containing 5% w/v maltodextrin. Results showed that, compared to HZ, pH of BGE was an effective parameter in enantioseparation of CTZ due to the zwitterionic property of CTZ. The linear range of the method was over 30-1200 ng/mL for all enantiomers of CTZ and HZ. The quantification and detection limits (S/N=3) of all enantiomers were 30 and 10 ng/mL, respectively. The method was used to quantitative enantioseparation of CTZ and HZ in spiked human plasma. PMID- 21328397 TI - Testing the ONIOM G2R3 model against donor-acceptor dissociation energies of group 13-15 complexes: accuracy comparable to CCSD(T)/aug-CC-pVTZ at a fraction of the resource cost. AB - The ability of the composite three-layer ONIOM G2R3 (OG2R3) method to match experimental dissociation energies for group 13-15 donor-acceptor complexes was examined for a database of 34 complexes. The composite approach provides energies that agree reasonably with experiment, performing nearly as well as both the CCSD(T)/aug-CC-pVTZ and CCSD(T)/6-311+G(2df, 2p) models for small molecules and nearly as well as the latter for slightly larger ones. Broadly, all three models exhibit average absolute errors of ~3 kcal mol(-1) , and root mean square errors of ~4 kcal mol(-1) . The average signed error suggest that the OG2R3 approach systematically underbinds by ~2.3 kcal mol(-1) ; if this is used as a general correction, the approach performs as well or better than the pure CCSD(T) models. However, the OG2R3 model can be applied to molecules too large to be studied by the other CCSD(T) methods, as it requires only a fraction of the time and computer resources. PMID- 21328398 TI - A comparison of the behavior of functional/basis set combinations for hydrogen bonding in the water dimer with emphasis on basis set superposition error. AB - We evaluate the performance of ten functionals (B3LYP, M05, M05-2X, M06, M06-2X, B2PLYP, B2PLYPD, X3LYP, B97D, and MPWB1K) in combination with 16 basis sets ranging in complexity from 6-31G(d) to aug-cc-pV5Z for the calculation of the H bonded water dimer with the goal of defining which combinations of functionals and basis sets provide a combination of economy and accuracy for H-bonded systems. We have compared the results to the best non-density functional theory (non-DFT) molecular orbital (MO) calculations and to experimental results. Several of the smaller basis sets lead to qualitatively incorrect geometries when optimized on a normal potential energy surface (PES). This problem disappears when the optimization is performed on a counterpoise (CP) corrected PES. The calculated interaction energies (DeltaEs) with the largest basis sets vary from 4.42 (B97D) to -5.19 (B2PLYPD) kcal/mol for the different functionals. Small basis sets generally predict stronger interactions than the large ones. We found that, because of error compensation, the smaller basis sets gave the best results (in comparison to experimental and high-level non-DFT MO calculations) when combined with a functional that predicts a weak interaction with the largest basis set. As many applications are complex systems and require economical calculations, we suggest the following functional/basis set combinations in order of increasing complexity and cost: (1) D95(d,p) with B3LYP, B97D, M06, or MPWB1k; (2) 6-311G(d,p) with B3LYP; (3) D95++(d,p) with B3LYP, B97D, or MPWB1K; (4) 6 311++G(d,p) with B3LYP or B97D; and (5) aug-cc-pVDZ with M05-2X, M06-2X, or X3LYP. PMID- 21328399 TI - The shape of gaseous n-butylbenzene: assessment of computational methods and comparison with experiments. AB - Conformational landscape of neutral and ionized n-butylbenzene has been examined. Geometries have been optimized at the B3LYP/6-31G(d), B3LYP/6-31+G(d,p), B3LYP D/6-31+G(d,p), B2PLYP/6-31+G(d,p), B2PLYP-D/6-31+G(d,p), B97-D/6-31+G(d,p), and M06-2X/6-31+G(d,p) levels. This study is complemented by energy computations using 6-311++G(3df,2p) basis set and CBS-QB3 and G3MP2B3 composite methods to obtain accurate relative enthalpies. Five distinguishable conformers have been identified for both the neutral and ionized systems. Comparison with experimentally determined rotational constants shows that the best geometrical parameters are provided by B3LYP-D and M06-2X functionals, which include an explicit treatment of dispersion effects. Composite G3MP2B3 and CBS-QB3 methods, and B2PLYP-D, B3LYP-D, B97-D, and M06-2X functionals, provide comparable relative energies for the two sets of neutral and ionized conformers of butyl benzene. An exception is noted however for conformer V(+) the stability of which being overestimated by the B3LYP-D and B97-D functionals. The better stability of neutral conformers I, III, and IV, and of cation I(+) , demonstrated by our computations, is in perfect agreement with conclusions based on micro wave, fluorescence, and multiphoton ionization experiments. PMID- 21328400 TI - A self-consistent Hirshfeld method for the atom in the molecule based on minimization of information loss. AB - Based on the so-called Hirshfeld atom in the molecule scheme, a new AIM method is presented. The method is similar to the Hirshfeld-I scheme, with the AIM weight function being constructed by minimizing the information loss upon formation of the molecule, but now requiring explicitly that the promolecular densities integrate to the same number of electrons as the AIM densities. This new weight function leads to a new iterative AIM scheme, and the resulting operative scheme is examined and discussed. The final results indicate that the newly proposed method does not perform as well as the Hirshfeld-I method. PMID- 21328401 TI - Fast construction of assembly trees for molecular graphs. AB - A number of modeling and simulation algorithms using internal coordinates rely on hierarchical representations of molecular systems. Given the potentially complex topologies of molecular systems, though, automatically generating such hierarchical decompositions may be difficult. In this article, we present a fast general algorithm for the complete construction of a hierarchical representation of a molecular system. This two-step algorithm treats the input molecular system as a graph in which vertices represent atoms or pseudo-atoms, and edges represent covalent bonds. The first step contracts all cycles in the input graph. The second step builds an assembly tree from the reduced graph. We analyze the complexity of this algorithm and show that the first step is linear in the number of edges in the input graph, whereas the second one is linear in the number of edges in the graph without cycles, but dependent on the branching factor of the molecular graph. We demonstrate the performance of our algorithm on a set of specifically tailored difficult cases as well as on a large subset of molecular graphs extracted from the protein data bank. In particular, we experimentally show that both steps behave linearly in the number of edges in the input graph (the branching factor is fixed for the second step). Finally, we demonstrate an application of our hierarchy construction algorithm to adaptive torsion-angle molecular mechanics. PMID- 21328402 TI - Predicting protein folding rates using the concept of Chou's pseudo amino acid composition. AB - One of the most important challenges in computational and molecular biology is to understand the relationship between amino acid sequences and the folding rates of proteins. Recent works suggest that topological parameters, amino acid properties, chain length and the composition index relate well with protein folding rates, however, sequence order information has seldom been considered as a property for predicting protein folding rates. In this study, amino acid sequence order was used to derive an effective method, based on an extended version of the pseudo-amino acid composition, for predicting protein folding rates without any explicit structural information. Using the jackknife cross validation test, the method was demonstrated on the largest dataset (99 proteins) reported. The method was found to provide a good correlation between the predicted and experimental folding rates. The correlation coefficient is 0.81 (with a highly significant level) and the standard error is 2.46. The reported algorithm was found to perform better than several representative sequence-based approaches using the same dataset. The results indicate that sequence order information is an important determinant of protein folding rates. PMID- 21328403 TI - Pharmacophore alignment search tool: influence of scoring systems on text-based similarity searching. AB - The text-based similarity searching method Pharmacophore Alignment Search Tool is grounded on pairwise comparisons of potential pharmacophoric points between a query and screening compounds. The underlying scoring matrix is of critical importance for successful virtual screening and hit retrieval from large compound libraries. Here, we compare three conceptually different computational methods for systematic deduction of scoring matrices: assignment-based, alignment-based, and stochastic optimization. All three methods resulted in optimized pharmacophore scoring matrices with significantly superior retrospective performance in comparison with simplistic scoring schemes. Computer-generated similarity matrices of pharmacophoric features turned out to agree well with a manually constructed matrix. We introduce the concept of position-specific scoring to text-based similarity searching so that knowledge about specific ligand-receptor binding patterns can be included and demonstrate its benefit for hit retrieval. The approach was also used for automated pharmacophore elucidation in agonists of peroxisome proliferator activated receptor gamma, successfully identifying key interactions for receptor activation. PMID- 21328404 TI - Pharmacophore alignment search tool: influence of the third dimension on text based similarity searching. AB - Previously (Hahnke et al., J Comput Chem 2010, 31, 2810) we introduced the concept of nonlinear dimensionality reduction for canonization of two-dimensional layouts of molecular graphs as foundation for text-based similarity searching using our Pharmacophore Alignment Search Tool (PhAST), a ligand-based virtual screening method. Here we apply these methods to three-dimensional molecular conformations and investigate the impact of these additional degrees of freedom on virtual screening performance and assess differences in ranking behavior. Best performing variants of PhAST are compared with 16 state-of-the-art screening methods with respect to significance estimates for differences in screening performance. We show that PhAST sorts new chemotypes on early ranks without sacrificing overall screening performance. We succeeded in combining PhAST with other virtual screening techniques by rank-based data fusion, significantly improving screening capabilities. We also present a parameterization of double dynamic programming for the problem of small molecule comparison, which allows for the calculation of structural similarity between compounds based on one dimensional representations, opening the door to a holistic approach to molecule comparison based on textual representations. PMID- 21328405 TI - Franck-Condon simulation of the photoelectron spectrum of AsCl2 and the photodetachment spectrum of AsCl 2- employing UCCSD(T)-F12a potential energy functions: IE and EA of AsCl2. AB - The currently most reliable theoretical estimates of the adiabatic ionization energies (AIE(0)) from the X(2)B(1) state of AsCl(2) to the X(1)A(1) and a(3)B(1) states of AsCl 2+, and the electron affinity (EA(0)) of AsCl(2) , including DeltaZPE corrections, are calculated as 8.687(11), 11.320(23), and 1.845(12) eV, respectively (estimated uncertainties based on basis-set effects at the RCCSD(T) level). State-of-the-art ab initio calculations, which include RCCSD(T), CASSCF/MRCI, and explicitly correlated RHF/UCCSD(T)-F12x (x = a or b) calculations with basis sets of up to quintuple-zeta quality, have been carried out on the X(2)B(1) state of AsCl(2) , the X(1)A(1) , a(3)B(1) , and A(1)B(1) states of AsCl 2+, and the X(1)A(1) state of AsCl 2-. Relativistic, core correlation and complete basis-set (CBS) effects have been considered. In addition, computed UCCSD(T)-F12a potential energy functions of relevant electronic states of AsCl(2) , AsCl (2)(+), and AsCl( 2)(-) were used to calculate Franck-Condon factors, which were then used to simulate the valence photoelectron spectrum of AsCl(2) and the photodetachment spectrum of AsCl (2)( ), both yet to be recorded. Lastly, we have also computed the AIE and EA values for NCl(2) , PCl(2) , and AsCl(2) at the G4 level and for SbCl(2) at the RCCSD(T)/CBS level. The trends in the AIE and EA values of the group V pnictogen dichlorides, PnCl(2) , where Pn = N, P, As, and Sb, were examined. The AIE and EA of PCl(2) were found to be smaller than those of AsCl(2) , contrary to the order expected from the IE values of P and As. PMID- 21328406 TI - Specific interactions between lactose repressor protein and DNA affected by ligand binding: ab initio molecular orbital calculations. AB - Transcription mechanisms of gene information from DNA to mRNA are essentially controlled by regulatory proteins such as a lactose repressor (LacR) protein and ligand molecules. Biochemical experiments elucidated that a ligand binding to LacR drastically changes the mechanism controlled by LacR, although the effect of ligand binding has not been clarified at atomic and electronic levels. We here investigated the effect of ligand binding on the specific interactions between LacR and operator DNA by the molecular simulations combined with classical molecular mechanics and ab initio fragment molecular orbital methods. The results indicate that the binding of anti-inducer ligand strengthens the interaction between LacR and DNA, which is consistent with the fact that the binding of anti inducer enhances the repression of gene transcription by LacR. It was also elucidated that hydrating water molecules existing between LacR and DNA contribute to the specific interactions between LacR and DNA. PMID- 21328407 TI - Infinite Basis set extrapolation for Double Hybrid Density Functional Theory 1: effect of applying various extrapolation functions. AB - We applied the Infinite Basis (IB) set extrapolation and Double Hybrid Density Functional Theory (DHDF) to calculate the databases of atomization energies, ionization energies, electron affinities, reaction barrier heights, proton affinities, alkyl bond dissociation energies, and noncovalent interactions. The Complete Basis Set (CBS) limit is estimated by extrapolating the hybrid density functional theory and PT2 energies using extrapolation functions including exponential, inverse power, modified exponential, and the combination of the these functions. We found that the combination of B2KPLYP/cc-pV[D|T]Z (which is the extrapolation based on the energies calculated in cc-pVDZ and cc-pVTZ) gives results in quadruple-zeta quality. However, if we want to reach the ~2 kcal/mol chemical accuracy limit, the cc-pV[T|Q]Z is required. Similar results with various extrapolation functions obtained, because the IB parameters were determined by minimizing the averaged mean unsigned error of the calculated databases. We generalized the IB set extrapolation to include more than two basis sets, but we found that extrapolation with two basis sets is satisfactory to give reasonable results. The largest error occurred in the databases of the electron affinities and the weak interactions between the noble gas and the nonpolar molecules. We expect that performing the DHDF-IB scheme with the basis sets augmented by diffuse basis functions will further improve the results. PMID- 21328409 TI - Paths to which the nudged elastic band converges. AB - A recent letter to the editor (Quapp and Bofill, J Comput Chem 2010, 31, 2526) claims that the nudged elastic band (NEB) method can converge toward gradient extremal paths and not to steepest descent paths, as has been assumed. Here, we show that the NEB does in fact converge to steepest descent paths and that the observed tendency for the NEB to approach gradient extremal paths was a consequence of implementation errors. We also note that while the NEB finds steepest descent paths, these are not necessarily minimum energy paths in the sense of being a set of points which are minima in the potential energy surface perpendicular to the path. An example is given where segments of steepest descent paths follow potential energy ridges. PMID- 21328410 TI - Modeling the electron density kernels. AB - Existing approximation to the softness kernel, successfully explored in earlier work, has been extended; the normal Gauss distribution function has been used instead of the Dirac delta. The softness kernel becomes continuous functions in space and may be used to calculate the linear response function of the electron density. Three-dimensional visualization of the softness kernel and the linear response function are presented for a nitrogen atom as a working example. By using a single parameter of the spatial Gauss distribution, the novel softness kernel has been adjusted to be consistent with the standard form of the hardness kernel, representing the leading fraction of the electronic interactions in the system. PMID- 21328411 TI - Computational exposure assessment of electromagnetic fields generated by an RFID system for mother--newborn identity reconfirmation. AB - Radio frequency identification (RFID) is an innovative technology currently applied in a large number of industrial and consumer applications. The spread of RFID technology does not correspond to a parallel increase in studies on its possible impact on health in terms of electromagnetic field (EMF) exposure. The aim of this paper is to estimate, by computational techniques, the EMF generated by passive RFID systems for mother-newborn identity reconfirmation. The computation was performed on realistic models of newborn and mother for three different reader positions. The compliance with EMF exposure guidelines was investigated as a function of the change in reader-tag specifications (magnetic field threshold and maximum distance of the reader to awake the tag) and time of use of the reader close to the body. The results show that attention should be paid to the identification of the optimal reader-tag technical specifications to be used in this type of application. That should be done by an accurate exposure assessment investigation, in particular for newborn exposure. The need to reduce the exposure time as much as possible indicates the importance of specific training on the practical applications of the RFID (DATALOGIC J-series, Bologna, Italy) device. PMID- 21328412 TI - The effects of metallothionein 2A polymorphism on placental cadmium accumulation: Is metallothionein a modifiying factor in transfer of micronutrients to the fetus? AB - Metallothionein affects the metabolism, transport and storage of micronutrients such as zinc, copper and iron, and the detoxification of heavy metals, especially cadmium. Cd is a common, highly toxic environmental pollutant that accumulates in human placenta, elevated concentrations of which are associated with impaired zinc transfer to the fetus. This prospective study investigated the effects of metallothionein 2A (MT2A) -5 A/G single nucleotide polymorphism on the accumulation of Cd in human placenta and micronutrient transfer to the fetus in 95 pregnant women and their newborns. Venous blood from the mother was collected to investigate Cd, Zn, Cu, Fe levels and MT2A polymorphism. Cord blood from the neonate and placenta was collected for metal levels. MT2A polymorphism was determined by the standard PCR-restriction fragment length polymorphism technique. Metal levels were analyzed by Atomic Absorption Spectrometry (AAS). Maternal blood Cd levels were statistically higher for mothers with a heterozygote genotype compared with a homozygote genotype (P<0.05). In contrast, placental Cd levels were significantly higher in mothers with a homozygote rather than a heterozygote genotype (P<0.05). No difference existed in cord blood Cd, Zn and Cu levels. However, cord blood Fe levels of newborns with heterozygote genotype mothers were higher than in others. Placental Cd levels of heterozygote genotype mothers were negatively associated with Zn in cord blood. Cd exposure at environmental levels may be associated with alteration of the umbilical cord micronutrient levels for newborns with mothers of a heterozygote genotype. PMID- 21328413 TI - The proportional lack of archaeal pathogens: Do viruses/phages hold the key? AB - Although Archaea inhabit the human body and possess some characteristics of pathogens, there is a notable lack of pathogenic archaeal species identified to date. We hypothesize that the scarcity of disease-causing Archaea is due, in part, to mutually-exclusive phage and virus populations infecting Bacteria and Archaea, coupled with an association of bacterial virulence factors with phages or mobile elements. The ability of bacterial phages to infect Bacteria and then use them as a vehicle to infect eukaryotes may be difficult for archaeal viruses to evolve independently. Differences in extracellular structures between Bacteria and Archaea would make adsorption of bacterial phage particles onto Archaea (i.e. horizontal transfer of virulence) exceedingly hard. If phage and virus populations are indeed exclusive to their respective host Domains, this has important implications for both the evolution of pathogens and approaches to infectious disease control. PMID- 21328414 TI - Distinguishing the common components of oil- and water-based metalworking fluids for assessment of cancer incidence risk in autoworkers. AB - BACKGROUND: Metalworking fluids (MWF)--straight, soluble, and synthetic--have overlapping components. We derived constituent-based metrics of polycyclic aromatic hydrocarbons (PAHs), water-based MWF, biocides, and nitrosamines to account for this overlap and examined their relations with cancer incidence. METHODS: An autoworkers cohort of 30,000 was followed for cancer incidence. Hazard ratios were estimated for each cancer and cumulative exposure (lagged) to each new metric; soluble MWF contributed variably to several metrics with weight k = 0-1. RESULTS: For most cancer sites, the constituent-based metrics resulted in stronger exposure-disease associations than the MWF classes alone. Laryngeal and bladder cancer were most strongly associated with PAH (k = 0). Protective effects for stomach and lung cancer were observed with biocide, a component that may be a surrogate for endotoxin. CONCLUSIONS: Our findings provide support and clarification of possible etiologies for previous positive associations and provide support for distinguishing exposure from oil- and water-based MWF in epidemiologic studies. PMID- 21328415 TI - Using community-based methods and a social ecological framework to explore workplace health and safety of bloqueros on the Olympic Peninsula. AB - BACKGROUND: Occupational health and safety issues among Latino immigrants are increasingly important as increased immigration has led to a burgeoning workforce with limited English language skills or lack of documentation status. Foreign born Latino immigrants are consistently the ethnic group with the highest occupational mortality rates in the United States. We aimed to understand and document the occupational safety and health hazards faced by a particularly at risk Latino immigrant workforce--cedar block cutters, or bloqueros--on the Olympic Peninsula. METHODS: Key informant interviews were conducted using community-based participatory methods. Qualitative analysis was guided by grounded theory and a social ecological framework. RESULTS: Thirteen interviews were conducted lasting 1-2 hr each. Three prominent findings arose: (1) bloqueros face occupational risks similar to those found in other forestry occupations, (2) bloqueros face unexpected risks that are likely unique to block cutting, and (3) bloqueros face four overlapping marginalization forces (societal, economical, political, and occupational) that undermine workplace health and safety. CONCLUSIONS: Bloqueros work low-paying, high-risk jobs with little health and safety regulation, documentation, or coverage. Workers' precarious socio-economic position and various structural factors compound workplace risks and contribute to a lack of ability to advocate for safer and healthier working conditions. PMID- 21328416 TI - Ethnic differences in patterns of occupational exposure in New Zealand. AB - OBJECTIVES: To investigate the differences in occupational exposure between Maori (New Zealand's indigenous people) and non-Maori. METHODS: Participants were randomly selected from the Electoral Roll. Exposure to occupational risk factors was assessed through telephone interviews and exposure prevalences of Maori (n = 273) and non-Maori (n = 2,724) were compared. Subsequently, Maori were matched with non-Maori on current occupation (n = 482) to assess whether ethnic differences also exist within occupations. RESULTS: Maori were more likely to report exposure to physical strain (e.g., lifting, standing). Part of these differences remained when Maori were compared with non-Maori in the same job. In addition, Maori women were twice as likely to categorize their job as very or extremely stressful than non-Maori women in the same job, while Maori men were twice as likely to report exposure to dust. CONCLUSION: Marked ethnic differences exist in risk factors for occupational ill-health, due to both occupational distribution and the distribution of tasks within occupations. PMID- 21328417 TI - Work-related asthma in health care in Ontario. AB - BACKGROUND: The health of workers in health care has been neglected in the past. There are few reports regarding occupational asthma (OA) in this group, and work exacerbated asthma (WEA) has rarely been considered. METHODS: We examined the frequency of claims for OA and WEA allowed by the compensation board in Ontario, Canada for which industry was coded as "health care" between 1998 and 2002, to determine the frequency of OA and WEA, causative agents, and occupations. RESULTS: During this period, five claims were allowed for sensitizer OA, two for natural rubber latex (NRL), and three for glutaraldehyde/photographic chemicals. The two NRL cases occurred in nurses who had worked for >10 years prior to "date of accident." There were 115 allowed claims for WEA; health care was the most frequent industry for WEA. Compared to the rest of the province, claims in health care made up a significantly greater proportion of WEA claims (17.8%) than OA (5.1%) (odds ratio, 4.1, 95% CI 1.6-11.6; P = 0.002). The rate of WEA claims was 2.1 times greater than that in the rest of the workforce (P < 0.0001). WEA claims occurred in many jobs (e.g., clerk), other than "classic" health care jobs such as nurses, and were attributed to a variety of agents such as construction dust, secondhand smoke, and paint fumes. CONCLUSIONS: WEA occurs frequently in this industrial sector. Those affected and attributed agents include many not typically expected in health care. The incidence of OA claims in this sector in general was low; the continued low number of OA claims due to NRL is consistent with the successful interventions for prevention. PMID- 21328418 TI - Cancer incidence and mortality among workers exposed to benzidine. AB - BACKGROUND: A historical cohort study was conducted among 997 individuals employed at a chemical production facility to investigate whether occupational exposures to benzidine and other arylamines were associated with the increased risk of cancer. METHODS: Cancers were identified from cancer registries, death certificates, and medical records. Exposures were evaluated using a job-exposure matrix. Workers were categorized into exposure groups to calculate cancer specific standardized incidence ratios (SIRs) and perform survival analyses. RESULTS: SIRs for cancer of the bladder (SIR = 3.5; CI 1.7, 6.4), small intestine (SIR 18.4; CI 2.2, 66.4), and soft tissue including heart (SIR = 11.9; CI 1.4, 42.8) were elevated among workers with the highest exposures and risk increased with increasing exposures. SIRs for several additional cancers were also elevated. CONCLUSION: Our results support previous findings of increased risk of bladder cancer among individuals exposed to benzidine and other arylamines. Workers may also have been at increased risk for cancers other than cancer of the bladder. PMID- 21328419 TI - Assessing occupational health and safety of young workers who use youth employment centers. AB - BACKGROUND: Adolescents and young adults who are out of school are at elevated risk for a work injury. METHODS: To obtain more information on this "high risk" group of young workers, young people at youth employment centers across Ontario were asked through an online survey about training, unsafe work conditions, work injuries and safety knowledge. RESULTS: The 1,886 youth who completed the survey reported a medically attended work injury rate of 14.45 per 100 FTEs. Also, the most common unsafe work conditions were dust/particles, trip hazards and heavy lifting. In addition, many young workers reported using much of their income for living essentials (e.g., rent). CONCLUSIONS: Though not a representative sample, it appears that youth using employment centers experience many unsafe work conditions and work injuries. While many report safety training, the nature and effectiveness of this training remains to be determined. The large portion of young workers out of school and working for living essentials included in this sample suggest that youth employment centers should be considered in future prevention efforts targeting this vulnerable subgroup of workers. PMID- 21328421 TI - Impact of organization on occupational injury risk: evidence from high-speed railway construction. AB - BACKGROUND: The construction industry is at the top of the list of priorities for surveillance and research, although it is often difficult to perform detailed analysis of the risk factors. In mid-2002, construction work started on the Torino to Novara high-speed railway line. A Regional Epidemiological Observatory developed a standardized data collection system that provided a rare opportunity for researchers in Italy to analyze risk factors for occupational injury in a large cohort of workers involved in a single major construction project. The aim of this study is to describe the characteristics of a cohort of workers employed at construction sites of the high-speed Torino to Novara railway between 2003 and 2005, analyze the main determinants of occupational injury risk and estimate incidence rates. METHODS: Frequency rates of occupational injury were calculated by characteristics of workers and firms and relative risks were estimated using a Poisson model. RESULTS: Annual injury incidence decreased over the period and was higher than the Italian construction industry rate. The risk was highest among workers performing the least skilled jobs and with the shortest contracts. Moreover the risk was higher in large enterprises. CONCLUSIONS: Although calculated within a specific context, the results provide information applicable to all construction sites. The high risk of occupational injury associated with short-term contracts suggests, at such large and long-term construction sites, to engage workers on a permanent basis for the duration of the construction project. PMID- 21328422 TI - Regarding "absence of radiographic asbestosis and the risk of lung cancer among asbestos-cement workers: extended follow-up of a cohort", by Murray Finkelstein, American Journal of Industrial Medicine 2010. PMID- 21328423 TI - Why do capuchin monkeys urine wash? An experimental test of the sexual communication hypothesis using fMRI. AB - Urine washing (UW) consists of depositing urine on the hands and vigorously rubbing the body. As urine contains chemical and pheromonal cues, UW may convey socially relevant information. Although ritualized UW is observed in many New World primates, including capuchin monkeys, the functional significance of UW remains unclear. In this experiment, we investigated the social signaling hypothesis of UW. Specifically, we hypothesized that UW by males conveys socially relevant signals that females can detect. We used functional magnetic resonance imaging (fMRI) to test whether adult female capuchins show differential brain activation in response to adult male and juvenile male capuchin urine. We expected to see changes in activation of structures involved in olfactory processing, including the piriform cortex, medial preoptic and anterior hypothesis, orbitofrontal cortex, hippocampus, and cerebellum. Data were acquired from four adult female capuchin monkeys. Presentations of odor stimuli (obtained from unfamiliar males) were made during fMRI acquisition using a standard ON-OFF design. All fMRI data were spatially normalized to a template and analyzed using the FMRI Expert Analysis Tool Version 5.98, part of the FMRIB's Software Library (www.fmrib.ox.ac.uk/fsl). Whole brain analyses revealed significant activations in the inferior temporal cortex, parahippocampal gyrus, precuneus, hippocampus, pulvinar, and cerebellum when females were presented with the adult male urine. Notably, significantly greater signal activation was observed in several regions associated with olfactory processing, when subjects were presented with adult male urine as compared with urine from juvenile males. Our results indicate that UW serves a social communicative function in capuchins, providing support for the sexual signaling hypothesis. PMID- 21328424 TI - Understanding emotions in primates: in honor of Darwin's 200th birthday. AB - In the bicentenary year of Darwin's birth, the American Society of Primatologists honored his memory by convening a symposium entitled "Understanding emotions in primates: In honor of Darwin's 200th birthday." The four articles in this special section, excepting this introduction, derive from that symposium. The section confirms that the topic of emotion is once again, as in Darwin's lifetime, the subject of wide-ranging, theoretically exciting research, and that studies with nonhuman primates are at the leading edge of a rapidly changing field. PMID- 21328425 TI - Bone marrow aspirate and trephine biopsy findings in lymphoplasmacytic lymphoma. PMID- 21328426 TI - Donor cell leukemia following unrelated donor bone marrow transplantation for primary granulocytic sarcoma of the small intestine. PMID- 21328427 TI - Anti-CD20 monoclonal antibodies and their use in adult autoimmune hematological disorders. AB - Autoimmune hematological disorders encompass a broad group of hematological conditions characterized by the loss of self-tolerance to a variety of antigens. Despite good response to first-line therapy in the majority of patients, relapses are common, necessitating new and safe therapeutic options. The anti-CD20 monoclonal antibody rituximab has led to substantial improvement in the treatment of malignant and immune-mediated disorders involving B cells. Although experience with rituximab in immune-mediated hematological disorders is rarely supported by randomized trials, there is now substantial experience with rituximab suggesting that anti-CD20 therapy is an effective and well-tolerated alternative to immunosuppressive therapy in these disorders. However, caution is needed based on recent reports describing-sometimes severe-rituximab-related complications. PMID- 21328428 TI - My home is my castle. PMID- 21328429 TI - Imatinib as the first-line treatment of patients with chronic myeloid leukemia diagnosed in the chronic phase: can we compare real life data to the results from clinical trials? PMID- 21328430 TI - Prognostic factors in patients with HIV-associated peripheral T-cell lymphoma: a multicenter study. AB - HIV infection has been associated with an increased risk of developing several types of malignancies, including aggressive peripheral T-cell lymphomas (PTCL). However, this is a rare occurrence with no more than a hundred cases reported in the literature. The purpose of this multicenter study is to describe the characteristics and to identify prognostic factors in patients with HIV associated PTCL. Data from HIV-positive patients with a pathological diagnosis of non-primary cutaneous, non-leukemic PTCL were gathered retrospectively and are reported using descriptive statistics. Univariate and multivariate survival analyses were also performed. Fifty one patients were included in our analysis. Median age was 38 years with a 5:1 male-to-female ratio. Patients presented with a median CD4(+) count of 173 cells mm-3, and a median HIV viral load of 334,787 copies ml-1. The median time from HIV diagnosis to PTCL diagnosis was 4.5 years. About 75% of patients presented with advanced clinical stage and 66% with B symptoms. The most common subtypes were PTCLU (61%) and anaplastic large cell lymphoma (ALCL, 22%). None of the ALCL patients tested expressed ALK. The median overall survival (OS) for the group was 12 months. In the multivariate survival analysis, the use of HAART and patients' performance status were independently associated with OS. HIV-associated PTCL presents predominantly in young men with low CD4(+) counts and high HIV viral loads. Both HIV-related and lymphoma-related factors were associated with OS. PMID- 21328432 TI - Acquired hemophilia: we now see it with myeloproliferative neoplasms. PMID- 21328431 TI - Changes in serum-free light chain rather than intact monoclonal immunoglobulin levels predicts outcome following therapy in primary amyloidosis. AB - Current response criteria for light-chain amyloidosis (AL) relegate FLC response to a subsidiary status relative to serum M-protein response. Given that light chains form the substrate for amyloid fibril formation, we hypothesized that changes in FLC might better predict outcome compared to changes in intact immunoglobulin levels. Two patient cohorts were studied, 347 patients who underwent an autologous stem-cell transplant (SCT) and 96 patients treated with melphalan/dexamethasone. We identified the lowest value following therapy for intact serum M-protein and the difference between involved and uninvolved FLC (FLC-diff). We first examined the relative contribution of M-protein and FLC-diff on the overall survival (OS), and found that FLC reduction, rather than M-protein reduction, significantly impacted OS. The median OS was not reached among those with a 50% decrease in FLC-diff compared to 20 months for the remainder. On regression analysis, a 90% reduction in FLC-diff following SCT best predicted being alive at 3 or 5 years. The median OS among those with a 90% decrease was not reached compared to 37.4 months for the rest P < 0.001. The current study supports the notion that FLC response is a more useful measure of hematological response than M-protein response. It also highlights the importance of achieving at least a 90% reduction in the FLC-diff to improve the outcome of patients with light-chain AL. PMID- 21328433 TI - Duplex quantitative PCR for molecular monitoring of BCR-ABL1-associated hematological malignancies. PMID- 21328434 TI - Evaluation of empiric versus nomogram-based direct thrombin inhibitor management in patients with suspected heparin-induced thrombocytopenia. AB - The aim of this study was to evaluate a direct thrombin inhibitor (DTI) titration protocol in patients with suspected HIT. This observational study compared patients treated with argatroban or bivalirudin according to the University of Colorado Hospital DTI titration protocol versus a control group treated prior to protocol implementation. Protocol patients had DTI initial doses based on organ function and fixed dosage adjustments of 10, 25, or 50%. Initial doses and titrations in the control group were made per physician discretion. A total of 130 patients were enrolled: 47 in the protocol group and 83 in the control group (median age 54 years, 63% male, 78% critically ill, and 54% received argatroban). Goal aPTT was achieved with initial DTI dose in 64% of protocol patients and 46% of control patients (P = 0.07). Median (IQR) time to goal aPTT was reduced in the protocol group compared to the control group [5 hr (2-10 hr) vs. 13 hr (6-29 hr); P < 0.0001]. Median time to dose stabilization was 10 hr (6-27 hr) and 22 hr (13 40 hr) in the protocol and control groups, respectively; P < 0.0001. Median number of titrations to goal was 0 (0-1) versus 1 (0-4), respectively; P = 0.02. Median percentage of aPTT values in goal was 67% (41-100%) versus 53% (33-76%), respectively; P = 0.027. The DTI titration protocol shortened time to achieve goal aPTT, reduced time to dose stabilization, decreased the number of titrations required to achieve aPTT goal, and improved the percentage of aPTT values in goal range. PMID- 21328435 TI - Severe mental retardation and recessive congenital methemoglobinemia in three Indian patients: compound heterozygous for NADH-cytochrome b5 reductase gene mutations. PMID- 21328436 TI - G6PD deficiency and stroke in the CSSCD. PMID- 21328438 TI - Programmed death 1 is expressed in cutaneous infiltrates of mycosis fungoides and Sezary syndrome. PMID- 21328437 TI - Transfusion intensity, not the cumulative red blood cell transfusion burden, determines the prognosis of patients with myelodysplastic syndrome on chronic transfusion support. AB - Transfusion-dependency is associated with poor prognosis in patients with MDS although the causal link for such association is disputed. This study tests thee hypotheses on the association between transfusion burden and prognosis in the MDS: (1) the cumulative transfusion burden is a confounder merely reflecting the time elapsed from diagnosis; (2) it is a surrogate for higher transfusion intensity, which would reflect a more severe disease; and (3) it is the total amount of transfused RBC units that influences on prognosis. We studied 191 transfusion-dependent patients with MDS or chronic myelomonocytic leukemia. Transfusion intensity was calculated at the time of each transfusion as the yearly-equivalent number of RBC units. The main outcome was acute leukemia-free survival from first transfusion. Median transfusion burden was 30 (range: 4-330) RBC units and 112 patients received >= 25 units after a median of 9 months from first transfusion. In nested Cox models, having received >= 25 RBC units had a significant effect on survival (P < 0.001) that was not abrogated by including follow-up >= 9 months as a time-dependent covariate. Including transfusion intensity in the model had a significant effect on leukemia-free survival (P < 0.001) and cancelled the prognostic value of having received >= 25 RBC units. In conclusion, transfusion intensity, instead of the cumulative transfusion burden, is the transfusion-related variable really influencing on the prognosis of patients with transfusion-dependent MDS. PMID- 21328439 TI - Feasibility of the TNM-based staging system of ocular adnexal extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). AB - The American Joint Committee on Cancer has proposed the tumor, node, metastasis (TNM) staging system to overcome the limitations of the Ann Arbor staging system for ocular adnexal lymphoma. We performed this study to evaluate the feasibility of the TNM staging system for ocular adnexal extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (OAML). The data form 66 total eyes from 54 patients with biopsy-confirmed OAML according to World Health Organization classification were retrospectively analyzed. Using the TNM staging system, we reclassified all patients into two categories: (1) T1N0M0 stage group (n = 26), for patients with lymphoma involving only the conjunctiva; and (2) above T1N0M0 or bT1N0M0 stage group (n = 28), for patients with lymphoma extending to the orbit, eyelid, or adjacent structures, and/or bilateral OAML. After a 24-month median follow-up period for all patients, the T1N0M0 group revealed higher progression-free survival (PFS) than the above T1N0M0 or the bT1N0M0 group (P = 0.041). In a separate analysis of only 50 patients categorized as Ann Arbor stage IE, the T1N0M0 group demonstrated higher PFS (100%) than the above T1N0M0 or the bT1N0M0 group (84.7%; P = 0.067). Our data show that the poor prognostic group classified as Ann Arbor stage IE can be further distinguished by using the TNM staging system. Thus, further studies to develop treatment strategies for reducing relapse after treatment for OAML should use the TNM staging system. PMID- 21328440 TI - Successful management with clofarabine for refractory leukaemia in a young adult with chronic renal failure. PMID- 21328441 TI - Hydroxyurea adherence and associated outcomes among Medicaid enrollees with sickle cell disease. AB - While laboratory and clinical benefits of hydroxyurea for patients with sickle cell disease (SCD) are well-established, few data describe the extent and implications of non-adherence. We sought to assess adherence to hydroxyurea among patients with SCD and investigate associations between adherence and clinical and economic outcomes. Insurance claims of North Carolina Medicaid enrollees (6/2000 8/2008) with SCD were analyzed. Inclusion criteria included age < 65 years, continuous Medicaid enrollment >= 12 months before and following hydroxyurea initiation, and >= 2 hydroxyurea prescriptions. Three hundred twelve patients, mean age 21 (+/- 12.2) years, met inclusion criteria and 35% were adherent, defined as a medication possession ration (MPR) >= 0.80; mean MPR was 0.60. In the 12 months following hydroxyurea initiation, adherence was associated with reduced risk of SCD-related hospitalization (hazard ratio [HR] = 0.65, p = .0351), all-cause and SCD-related emergency department visit (HR = 0.72, p = .0388; HR = 0.58, p =.0079, respectively), and vaso-occlusive event (HR = 0.66, p = .0130). Adherence was associated with reductions in health care costs such as all-cause and SCD-related inpatient (-$5,286, p < .0001; -$4,403, p < .0001, respectively), ancillary care (-$1,336, p < .0001; -$836, p < .0001, respectively), vaso-occlusive event-related (-$5,793, p < .0001), and total costs (-$6,529, p < .0001; -$5,329, p <.0001, respectively). Adherence to hydroxyurea among SCD patients appears suboptimal and better adherence is associated with improved clinical and economic outcomes. PMID- 21328446 TI - Hypoxia-mediated biological control. AB - When oxygen demand is greater than oxygen supply, cells need to rapidly adjust their metabolism in order for the tissue to survive. Oxygen sensing by an organism influences a host of processes including growth, development, metabolism, pH homeostasis, and angiogenesis. Hypoxia also contributes to a wide number of human diseases including vascular disease, inflammatory conditions and cancer. Recently, major advances have been made in understanding the response of cells and tissues to hypoxia with the goal of providing mechanistic insight and novel therapeutic targets. In this article we review both the normal biological effects of hypoxia as well as the alterations that occur in specific disease conditions with an emphasis on the cell signaling and gene transcription mechanisms that underlie the changes associated with chronic hypoxia. Comparisons of studies in the fields of cardiac ischemia and tumor angiogenesis reveal the complexities within the microenvironment that control responses to hypoxia. It is clear that more interaction between researchers in these fields will improve the development of therapies that either promote or prevent hypoxic responses. PMID- 21328447 TI - Loss of runt-related transcription factor 3 causes development and progression of hepatocellular carcinoma. AB - Runt-related transcription factor 3 (RUNX3) is reported as a tumor suppressor gene for gastric cancer, and may be important in the development of hepatocellular carcinoma (HCC). RUNX3 expression is frequently lost or decreased by hemizygous deletion or hypermethylation of its promoter lesion in HCC. The significance of decreased expression of RUNX3 in HCC has not been fully elucidated, but is likely related to dysfunction of cell cycle regulation, decrement of apoptosis, enhancement of angiogenesis, and development of epithelial-mesenchymal transition. RUNX3 is a promising candidate as a tumor suppressor gene for HCC. PMID- 21328448 TI - Signaling networks in RUNX2-dependent bone development. AB - RUNX2 is an essential transcription factor for osteoblast differentiation and chondrocyte maturation. SP7, another transcription factor, is required for osteoblast differentiation. Major signaling pathways, including FGF, Wnt, and IHH, also play important roles in skeletal development. RUNX2 regulates Sp7 expression at an early stage of osteoblast differentiation. FGF2 upregulates Runx2 expression and activates RUNX2, and gain-of-function mutations of FGFRs cause craniosynostosis and limb defect with upregulation of Runx2 expression. Wnt signaling upregulates Runx2 expression and activates RUNX2, and RUNX2 induces Tcf7 expression. IHH is required for Runx2 expression in osteoprogenitor cells during endochondral bone development, and RUNX2 directly regulates Ihh expression in chondrocytes. Thus, RUNX2 regulates osteoblast differentiation and chondrocyte maturation through the network with SP7 and with FGF, Wnt, and IHH signaling pathways during skeletal development. PMID- 21328449 TI - Nuclear protein isoforms: implications for cancer diagnosis and therapy. AB - Post-translational modifications (PTMs) of nuclear proteins play essential roles in the regulation of gene transcription and signal transduction pathways. Numerous studies have demonstrated a correlation between specific nuclear protein isoforms and cellular malignant process. This communication reviews the impact of major PTM events such as phosphorylation, acetylation, methylation, ubiquitination, and sumoylation on several important nuclear proteins including p53, histones, proliferating cellular nuclear antigen (PCNA), and retinoblastoma protein (Rb) in the process. In addition, the implications of the PTMs as cancer biomarkers and therapeutic targets are considered. PMID- 21328450 TI - Roscovitine, a selective CDK inhibitor, reduces the basal and estrogen-induced phosphorylation of ER-alpha in human ER-positive breast cancer cells. AB - Roscovitine (ROSC), a selective cyclin-dependent kinase (CDK) inhibitor, arrests human estrogen receptor-alpha (ER-alpha) positive MCF-7 breast cancer cells in the G(2) phase of the cell cycle and concomitantly induces apoptosis via a p53 dependent pathway. The effect of ROSC is markedly diminished in MCF-7 cells maintained in the presence of estrogen-mimicking compounds. Therefore, we decided to examine whether ROSC has any effect on the functional status of the ER-alpha transcription factor. Exposure of MCF-7 cells to ROSC abolished the activating phosphorylation of CDK2 and CDK7 in a concentration and time-dependent manner. This inhibition of site-specific modification of CDK7 at Ser164/170 prevented phosphorylation of RNA polymerase II and reduced basal phosphorylation of ER alpha at Ser118 in non-stimulated MCF-7 cells (resulting in its down-regulation). In MCF-7 cells, estrogen induced strong phosphorylation of ER-alpha at Ser118 but not at Ser104/Ser106. ROSC prevented this estrogen-promoted activating modification of ER-alpha. Furthermore, we sought to determine whether the activity of ROSC could be enhanced by combining it with an anti-estrogen. Tamoxifen (TAM), a selective estrogen receptor modulator (SERM), affected breast cancer cell lines irrespective of their ER status. In combination with ROSC, however, it had a different impact, enhancing G(1) or G(2) arrest. Our results indicate that ROSC prevents the activating phosphorylation of ER-alpha and that its mode of action is strongly dependent on the cellular context. Furthermore, our data show that ROSC can be combined with anti-estrogen therapy. The inhibitory effect of TAM on ER-negative cancer cells indicates that SERMs crosstalk with other steroid hormone receptors. PMID- 21328451 TI - Insufficient peroxiredoxin-2 expression in uterine NK cells obtained from a murine model of abortion. AB - The CBA/J * DBA/2 mouse mating combination is prone to spontaneous embryo loss, in contrast to the MHC-identical CBA/J * BALB/c mating combination, which yields successful pregnancies. The underlying mechanisms for these observations are unclear. In this study, multi-vision immunohistochemical staining (IHC), flow cytometry and Western blot analysis were used to detect peroxiredoxin-2 (PRX-2) expression in the uterine natural killer (uNK) cells from CBA/J * DBA/2 and CBA/J * BALB/c mice. In IHC analysis, co-localization of PRX-2 and lectin from Dolichos biflorus agglutinin (DBA-lectin) was confirmed and the frequency of PRX-2(+) DBA lectin(+) cells was significantly lower in CBA/J * DBA/2 than CBA/J * BALB/c. In flow cytometry and Western blotting, PRX-2 was found expressed at a significantly lower level in CBA/J * DBA/2 mice. PRX-2 inhibition with a neutralizing antibody significantly decreased PRX-2 expression, increased the cytotoxicity of uNK cells, and increased the percentage of embryo loss in CBA/J * DBA/2J mice. Our data suggest that PRX-2 may be involved in the modulation of maternal-fetal tolerance and that insufficient expression of this protein may correlate with increased embryo loss in CBA/J * DBA/2J mice. PMID- 21328452 TI - Proteasome inhibition causes epithelial-mesenchymal transition upon TM4SF5 expression. AB - Transmembrane 4 L six family member 5 (TM4SF5) is highly expressed in hepatocarcinoma and causes epithelial-mesenchymal transition (EMT) of hepatocytes. We found that TM4SF5-expressing cells showed lower mRNA levels but maintained normal protein levels in certain gene cases, indicating that TM4SF5 mediates stabilization of proteins. In this study, we explored whether regulation of proteasome activity and TM4SF5 expression led to EMT. We observed that TM4SF5 expression caused inhibition of proteasome activity and proteasome subunit expression, causing morphological changes and loss of cell-cell contacts. shRNA against TM4SF5 recovered proteasome expression, with leading to blockade of proteasome inactivation and EMT. Altogether, TM4SF5 expression appeared to cause loss of cell-cell adhesions via proteasome suppression and thereby proteasome inhibition, leading to repression of cell-cell adhesion molecules, such as E cadherin. PMID- 21328453 TI - Bone morphogenetic protein 2 signaling in osteoclasts is negatively regulated by the BMP antagonist, twisted gastrulation. AB - Bone morphogenetic proteins (BMPs) have been shown to regulate both osteoblasts and osteoclasts. We previously reported that BMP2 could directly enhance RANKL mediated osteoclast differentiation by increasing the size and number of osteoclasts. Similarly, genetic deletion of the BMP antagonist Twisted gastrulation (TWSG1) in mice, resulted in an enhancement of osteoclast formation, activity and osteopenia. This was accompanied by increased levels of phosphorylated Smad (pSmad) 1/5/8 in Twsg1(-/-) osteoclasts in vitro. The purpose of this study was to develop an adenoviral vector overexpressing Twsg1 as a means of inhibiting osteoclast activity. We demonstrate that overexpressing TWSG1 in primary osteoclasts decreased the size and number of multinuclear TRAP-positive osteoclasts, expression of osteoclast genes, and resorption ability. Overexpression of TWSG1 did not affect osteoclast proliferation or apoptosis. However, overexpression of TWSG1 decreased the levels of pSmad 1/5/8 in osteoclasts. Addition of exogenous BMP2 to osteoclasts overexpressing TWSG1 rescued the size and levels of pSmad 1/5/8 compared to cultures infected with a control virus. Finally, TWSG1 overexpression in osteoclasts isolated from the Twsg1(-/-) mice rescued size of the osteoclasts while further addition of exogenous BMP2 reversed the effect of TWSG1 overexpression and increased the size of the osteoclasts similar to control virus infected cells. Taken together, we demonstrate that overexpressing TWSG1 in osteoclasts via an adenoviral vector results in inhibition of osteoclastogenesis and may provide a potential therapy for inhibiting osteoclast activity in a localized manner. PMID- 21328455 TI - Associations of saposin C, Src, and androgen receptor upregulate the expression and function of androgen receptor in human prostate cancer cells. AB - We previously demonstrated that ectopic expression of neurotrophic peptide (NP) derived from saposin C promotes androgen receptor (AR) expression and transactivation in human prostate cancer cells. This prompted us to investigate how NP or saposin C can function in cells. We constructed plasmids expressing saposin C or a chimeric peptide of a viral TAT transduction domain and saposin C (TAT-saposin C) with His-tag. Intracellular localization of saposin C and NP was predominantly shown in transfected cells, while TAT-saposin C was detected around membrane and in cytosol by immunofluorescence staining. Furthermore, induction of the AR expression and activation of the AR transcriptional function were observed in cells transfected with saposin C or TAT-saposin C, compared to control cells transfected with an empty plasmid. The effects of saposin C and TAT-saposin C on AR activity were examined in the presence of inhibitors of GPCR, MAPK1/2, and PI3K/Akt. Interestingly, we found that these inhibitors only affect AR activities in cells with TAT-saposin C expression but not with saposin C expression. Immunostaining images showed that co-localization of saposin C, Src, and the AR occurred in transfected cells. Physical interactions of saposin C/NP, Src, and the AR were then demonstrated by co-immunoprecipitation assays. Blockage of Src activity by specific inhibitor led to a decrease in the saposin C-mediated enhancement of AR transactivity, suggesting that intracellular expression of saposin C caused stimulation of AR expression and activity by associations with Src in LNCaP cells. This effect may not be mediated by GPCR. PMID- 21328456 TI - Essential roles of the nitric oxide (no)/cGMP/protein kinase G type-Ialpha (PKG Ialpha) signaling pathway and the atrial natriuretic peptide (ANP)/cGMP/PKG Ialpha autocrine loop in promoting proliferation and cell survival of OP9 bone marrow stromal cells. AB - Inappropriate signaling conditions within bone marrow stromal cells (BMSCs) can lead to loss of BMSC survival, contributing to the loss of a proper micro environmental niche for hematopoietic stem cells (HSCs), ultimately causing bone marrow failure. In the present study, we investigated the novel role of endogenous atrial natriuretic peptide (ANP) and the nitric oxide (NO)/cGMP/protein kinase G type-Ialpha (PKG-Ialpha) signaling pathway in regulating BMSC survival and proliferation, using the OP9 BMSC cell line commonly used for facilitating the differentiation of HSCs. Using an ANP-receptor blocker, endogenously produced ANP was found to promote cell proliferation and prevent apoptosis. NO donor SNAP (S-nitroso-N-acetylpenicillamine) at low concentrations (10 and 50 uM), which would moderately stimulate PKG activity, protected these BMSCs against spontaneous apoptosis. YC-1, a soluble guanylyl cyclase (sGC) activator, decreased the levels of apoptosis, similar to the cytoprotective effects of low-level NO. ODQ (1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one), which blocks endogenous NO-induced activation of sGC and thus lowers endogenous cGMP/PKG activity, significantly elevated apoptotic levels by 2.5- and three fold. Pre-incubation with 8-Bromo-cGMP or ANP, which bypass the ODQ block, almost completely prevented the ODQ-induced apoptosis. A highly-specific PKG inhibitor, DT-3, at 20, and 30 uM, caused 1.5- and two-fold increases in apoptosis, respectively. ODQ and DT-3 also decreased BMSCs proliferation and colony formation. Small Interfering RNA gene knockdown of PKG-Ialpha increased apoptosis and decreased proliferation in BMSCs. The data suggest that basal NO/cGMP/PKG Ialpha activity and autocrine ANP/cGMP/PKG-Ialpha are necessary for preserving OP9 cell survival and promoting cell proliferation and migration. PMID- 21328454 TI - Differential roles of hypoxia inducible factor subunits in multipotential stromal cells under hypoxic condition. AB - Cell therapy with bone marrow multipotential stromal cells (MSCs) represents a promising approach to promote wound healing and tissue regeneration. MSCs expanded in vitro lose early progenitors with differentiation and therapeutic potentials under normoxic condition, whereas hypoxic condition promotes MSC self renewal through preserving colony forming early progenitors and maintaining undifferentiated phenotypes. Hypoxia inducible factor (HIF) pathway is a crucial signaling pathway activated in hypoxic condition. We evaluated the roles of HIFs in MSC differentiation, colony formation, and paracrine activity under hypoxic condition. Hypoxic condition reversibly decreased osteogenic and adipogenic differentiation. Decrease of osteogenic differentiation depended on HIF pathway; whereas decrease of adipogenic differentiation depended on the activation of unfolded protein response (UPR), but not HIFs. Hypoxia-mediated increase of MSC colony formation was not HIF-dependent also. Hypoxic exposure increased secretion of VEGF, HGF, and basic FGF in a HIF-dependent manner. These findings suggest that HIF has a limited, but pivotal role in enhancing MSC self-renewal and growth factor secretions under hypoxic condition. PMID- 21328457 TI - Bioluminescence reporter gene imaging characterize human embryonic stem cell derived teratoma formation. AB - Human embryonic stem (hES) cells have a potential use for the repair and regeneration of injured tissues. However, teratoma formation can be a major obstacle for hES-mediated cell therapy. Therefore, tracking the fate and function of transplanted hES cells with noninvasive imaging could be valuable for a better understanding of the biology and physiology of teratoma formation. In this study, hES cells were stably transduced with a double fusion reporter gene consisting of firefly luciferase and enhanced green fluorescent protein. Following bioluminescence imaging and histology, we demonstrated that engraftment of hES cells was followed by dramatically increasing signaling and led to teratoma formation confirmed by histology. Studies of the angiogenic processes within teratomas revealed that their vasculatures were derived from both differentiated hES cells and host. Moreover, FACS analysis showed that teratoma cells derived from hES cells expressed high levels of CD56 and SSEA-4, and the subcultured SSEA 4(+) cells showed a similar cell surface marker expression pattern when compared to undifferentiated hES cells. We report here for the first time that SSEA-4(+) cells derived from teratoma exhibited multipotency, retained their differentiation ability in vivo as confirmed by their differentiation into representative three germ layers. PMID- 21328458 TI - Silybin and dehydrosilybin decrease glucose uptake by inhibiting GLUT proteins. AB - Silybin, the major flavonoid of Silybum marianum, is widely used to treat liver diseases such as hepatocellular carcinoma and cirrhosis-associated insulin resistance. Research so far has focused on its anti-oxidant properties. Here, we demonstrate that silybin and its derivative dehydrosilybin inhibit glucose uptake in several model systems. Both flavonoids dose-dependently reduce basal and insulin-dependent glucose uptake of 3T3-L1 adipocytes, with dehydrosilybin showing significantly stronger inhibition. However, insulin signaling was not impaired, and immunofluorescence and subcellular fractionation showed that insulin-induced translocation of GLUT4 to the plasma membrane is also unchanged. Likewise, hexokinase activity was not affected suggesting that silybin and dehydrosilybin interfere directly with glucose transport across the PM. Expression of GLUT4 in CHO cells counteracted the inhibition of glucose uptake by both flavonoids. Moreover, treatment of CHO cells with silybin and dehydrosilybin reduced cell viability which was partially rescued by GLUT4 expression. Kinetic analysis revealed that silybin and dehydrosilybin inhibit GLUT4-mediated glucose transport in a competitive manner with K(i)=60 and 116 uM, respectively. We conclude that silybin and dehydrosilybin inhibit cellular glucose uptake by directly interacting with GLUT transporters. Glucose starvation offers a novel explanation for the anti-cancer effects of silybin. PMID- 21328459 TI - Ganoderma atrum polysaccharide induces anti-tumor activity via the mitochondrial apoptotic pathway related to activation of host immune response. AB - Ganoderma atrum polysaccharide (PSG-1), the major active ingredient isolated from Ganoderma atrum, has been suggested as a candidate for cancer therapy. The aim of this study was to investigate the anti-tumor effect of PSG-1 using sarcoma 180 (S 180) transplanted mice and further to examine the molecular mechanisms of PSG-1 induced anti-tumor effect. Results showed that PSG-1 significantly inhibited tumor growth in S-180-bearing mice. PSG-1-induced tumor apoptosis was associated with the alteration of Bcl-2 family proteins, increase of reactive oxygen species generation, loss of mitochondrial membrane potential (Deltapsi(m) ), release of cytochrome c from the mitochondria into cytosol, and activation of caspase-3 and 9. Elevation of immune function was also shown during PSG-1-induced tumor apoptosis, as evidenced by increase of spleen and thymus indexes, lymphocyte proliferation, concentrations of tumor necrosis factor (TNF)-alpha, and interleukin-2 in serum. Furthermore, the combined treatment of PSG-1 and cyclophosphamide (CTX) results in an enhancement of the anti-tumor effect of CTX alone via increased host immune response. These results suggested that PSG-1 had a potent anti-tumor activity by induction of tumor apoptosis through mitochondrial pathways, and immunoenhancement effect of PSG-1 was related to its anti-tumor effect. In addition, PSG-1 enhanced CTX-induced anti-tumor activity in S-180-bearing mice. PMID- 21328460 TI - miR-21 downregulates the tumor suppressor P12 CDK2AP1 and stimulates cell proliferation and invasion. AB - The present study was undertaken to investigate the regulation of P12(CDK2AP1) by miRNAs. A conserved target site for miR-21 within the CDK2AP1-3'-UTR at nt 349 370 was predicted by bioinformatics software and an inverse correlation of miR-21 and CDK2AP1 protein was observed. Highly specific amplification and quantification of miR-21 was achieved using real-time RT-PCR. Transfection of HaCaT cells with pre-miR-21 significantly suppressed a luciferase reporter including the CDK2AP1-3'-UTR, whereas transfection of Tca8113 with anti-miR-21 increased activity of this reporter. This was abolished when a construct mutated at the miR-21/nt 349-370 target site was used instead. Anti-miR-21-transfected Tca8113 cells showed an increase of CDK2AP1 protein and reduced proliferation and invasion. Resected primary tumors and tumor-free surgical margins of 18 patients with head and neck squamous cell carcinomas demonstrated an inverse correlation between miR-21 and P12(CDK2AP1). This study shows that P12(CDK2AP1) is downregulated by miR-21 and that miR-21 promotes proliferation and invasion in cultured cells. PMID- 21328461 TI - ACSL3 and GSK-3beta are essential for lipid upregulation induced by endoplasmic reticulum stress in liver cells. AB - The endoplasmic reticulum (ER) is essential for lipid biosynthesis, and stress signals in this organelle are thought to alter lipid metabolism. Elucidating the mechanisms that underlie the dysregulation of lipid metabolism in hepatocytes may lead to novel therapeutic approaches for the treatment of lipid accumulation. We first tested the effects of several inhibitors on lipid dysregulation induced by tunicamycin, an ER stress inducer. Triacsin C, an inhibitor of long-chain acyl CoA synthetase (ACSL) 1, 3, and 4, was the most potent among these inhibitors. We then analyzed the expression of the ACSL family during ER stress. The expression of ACSL3 was induced by ER stress in HuH-7 cells and in mice livers. ACSL3 shRNA, but not ACSL1 shRNA, inhibited the induction of lipid accumulation. GSK-3beta inhibitors attenuated ACSL3 expression and the lipid accumulation induced by ER stress in HuH-7 cells. shRNA that target GSK-3beta also inhibited the upregulation of ACSL3 and lipid accumulation in HuH-7 and HepG2 cells. The hepatitis B virus mutant large surface protein, which is known to induce ER stress, increased the lipid content of cells. Similarly, Triacsin C, and GSK 3beta inhibitors abrogated the lipid dysregulation caused by the hepatitis B virus mutant large surface protein. Altogether, ACSL3 and GSK-3beta represent novel therapeutic targets for lipid dysregulation by ER stress. PMID- 21328462 TI - Vitamin C down-regulates VEGF production in B16F10 murine melanoma cells via the suppression of p42/44 MAPK activation. AB - It is known that vitamin C induces apoptosis in several kinds of tumor cells, but its effect on the regulation of the angiogenic process of tumors is not completely studied. Vascular endothelial growth factor (VEGF) is the most well known angiogenic factor, and it has a potent function as a stimulator of endothelial survival, migration, as well as vascular permeability. Therefore, we have investigated whether vitamin C can regulate the angiogenic process through the modulation of VEGF production from B16F10 melanoma cells. VEGF mRNA expression and VEGF production at protein levels were suppressed by vitamin C. In addition, we found that vitamin C suppressed the expression of cyclooxygenase (COX)-2 and that decreased VEGF production by vitamin C was also restored by the administration of prostaglandin E2 which is a product of COX-2. These results suggest that vitamin C suppresses VEGF expression via the regulation of COX-2 expression. Mitogen-activated protein kinases are generally known as key mediators in the signaling pathway for VEGF production. In the presence of vitamin C, the activation of p42/44 MAPK was completely inhibited. Taken together, our data suggest that vitamin C can down-regulate VEGF production via the modulation of COX-2 expression and that p42/44 MAPK acts as an important signaling mediator in this process. PMID- 21328463 TI - Activation of CFTR trafficking and gating by vasoactive intestinal peptide in human bronchial epithelial cells. AB - Cystic fibrosis transmembrane conductance regulator (CFTR) is an apical membrane chloride channel critical to the regulation of fluid, chloride, and bicarbonate transport in epithelia and other cell types. The most common cause of cystic fibrosis (CF) is the abnormal trafficking of CFTR mutants. Therefore, understanding the cellular machineries that transit CFTR from the endoplasmic reticulum to the cell surface is important. Vasoactive intestinal polypeptide (VIP) plays an important role in CFTR-dependent chloride transport. The present study was designed to observe the affection of VIP on the trafficking of CFTR, and channel gating in human bronchial epithelium cells (HBEC). Confocal microscopy revealed CFTR immunofluorescence extending from the apical membrane deeply into the cell cytoplasm. After VIP treatment, apical extension of CFTR immunofluorescence into the cell was reduced and the peak intensity of CFTR fluorescence shifted towards the apical membrane. Western blot showed VIP increased cell surface and total CFTR. Compared with the augmented level of total CFTR, the surface CFTR increased more markedly. Immunoprecipitation founded that the mature form of CFTR had a marked increase in HBEC treated with VIP. VIP led to a threefold increase in Cl(-) efflux in HBEC. Glibenclamide-sensitive and DIDS insensitive CFTR Cl(-) currents were consistently observed after stimulation with VIP (10(-8) mol/L). The augmentation of CFTR Cl(-) currents enhanced by VIP (10( 8) mol/L) was reversed, at least in part, by the protein kinase A (PKA) inhibitor, H-89 and the protein kinase C (PKC) inhibitor, H-7, suggesting PKA and PKC participate in the VIP-promoted CFTR Cl(-) currents. PMID- 21328464 TI - Delayed production of arachidonic acid contributes to the delay of proteinase activated receptor-1 (PAR1)-triggered prostaglandin E2 release in rat gastric epithelial RGM1 cells. AB - Proteinase-activated receptor-1 (PAR1), upon activation, exerts prostanoid dependent gastroprotection, and increases prostaglandin E(2) (PGE(2)) release through cyclooxygenase-2 (COX-2) upregulation in rat gastric mucosal epithelial RGM1 cells. However, there is a big time lag between the PAR1-triggered PGE(2) release and COX-2 upregulation in RGM1 cells; that is, the former event takes 18 h to occur, while the latter rapidly develops and reaches a plateau in 6 h. The present study thus aimed at clarifying mechanisms for the delay of PGE(2) release after PAR1 activation in RGM1 cells. Although a PAR1-activating peptide, TFLLR NH(2), alone caused PGE(2) release at 18 h, but not 6 h, TFLLR-NH(2) in combination with arachidonic acid dramatically enhanced PGE(2) release even for 1 6 h. TFLLR-NH(2) plus linoleic acid caused a similar rapid response. CP-24879, a Delta(5)/Delta(6)-desaturase inhibitor, abolished the PGE(2) release induced by TFLLR-NH(2) plus linoleic acid, but not by TFLLR-NH(2) alone. The TFLLR-NH(2) induced PGE(2) release was not affected by inhibitors of cytosolic phospholipase A(2) (cPLA(2)), Ca(2+)-independent PLA(2) (cPLA(2)) or secretory PLA(2) (sPLA(2)), but was abolished by their mixture or a pan-PLA(2) inhibitor. Among PLA(2) isozymes, mRNA of group IIA sPLA(2) (sPLA(2)-IIA) was upregulated following PAR1 stimulation for 6-18 h, whereas protein levels of PGE synthases were unchanged. These data suggest that the delay of PGE(2) release after COX-2 upregulation triggered by PAR1 is due to the poor supply of free arachidonic acid at the early stage in RGM1 cells, and that plural isozymes of PLA(2) including sPLA(2)-IIA may complementarily contribute to the liberation of free arachidonic acid. PMID- 21328465 TI - Icariin is more potent than genistein in promoting osteoblast differentiation and mineralization in vitro. AB - There has been a strong interest in searching for natural therapies for osteoporosis. Genistein, an isoflavone abundant in soy, and icariin, a prenylated flavonol glycoside isolated from Epimedium Herb, have both been identified to exert beneficial effects in preventing postmenopausal bone loss. However, the relative potency in osteogenesis between the individual phytoestrogen flavonoids remains unknown. The present study compared ability of genistein and icariin in enhancing differentiation and mineralization of cultured rat calvarial osteoblasts in vitro. Dose-dependent studies in osteoblast differentiation measuring alkaline phosphatase (ALP) activity revealed optimal concentrations of genistein and icarrin for stimulating osteogenesis to be both at 10(-5) M. Time course studies comparing the two compounds both at 10(-5) M demonstrated that icariin treatment always produced higher ALP activity, more and larger areas of CFU-F(ALP) colonies and mineralized nodules, more osteocalcin secretion, and calcium deposition, and a higher level of mRNA expression of osteogenesis-related genes COL1alpha2, BMP-2, OSX, and RUNX-2. However, they inhibited the proliferation of osteoblasts to a similar degree. In conclusion, although future in vivo studies are required to investigate whether icariin is more efficient in improving bone mass and/or preventing bone loss, our in vitro studies have demonstrated that icariin has a stronger osteogenic activity than genistein. In addition, while the prenyl group on C-8 of icariin could be the active group that takes part in osteoblastic differentiation and explains its greater potency in osteogenesis, mechanisms of action, and reasons for the relative potency of icariin versus genistein need to be further studied. PMID- 21328466 TI - The anandamide effect on NO/cGMP pathway in human platelets. AB - In this study the effect of the endocannabinoid anandamide on platelet nitric oxide (NO)/cGMP pathway was investigated. Data report that anandamide in a dose and time-dependent manner increased NO and cGMP levels and stimulated endothelial nitric oxide synthase (eNOS) activity. These parameters were significantly reduced by LY294002, selective inhibitor of PI3K and by MK2206, specific inhibitor of AKT. Moreover anandamide stimulated both eNOSser1177 and AKTser473 phosphorylation. Finally the anandamide effect on NO and cGMP levels, eNOS and AKT phosphorylation/activation were inhibited by SR141716, specific cannabinoid receptor 1 antagonist, supporting the involvement of anandamide binding to this receptor. Overall data of this report indicate that low concentrations of anandamide, through PI3K/AKT pathway activation, stimulates eNOS activity and increases NO levels in human platelets. In such way anandamide contributes to extend platelet survival. PMID- 21328467 TI - RANKL increases migration of human lung cancer cells through intercellular adhesion molecule-1 up-regulation. AB - Invasion of distant tissues by tumor cells is the primary cause of therapeutic failure in the treatment of malignant lung cancer cells. Receptor activator of nuclear factor-kappaB ligand (RANKL) and its receptor, RANK, play a key role in osteoclastogenesis and tumor metastasis. Intercellular adhesion molecule-1 (ICAM 1, also called CD54), a member of the immunoglobulin supergene family, is an inducible surface glycoprotein that mediates adhesion-dependent cell-to-cell interactions. The effects of RANKL on cell migration and ICAM-1 expression in human lung cancer cells are largely unknown. We found that RANKL directed the migration and increased ICAM-1 expression in human lung cancer (A549) cells. Pretreatment of A549 cells with the MAPK kinase (MEK) inhibitor PD98059 or U0126 inhibited RANKL-mediated migration and ICAM-1 expression. Stimulation of cells with RANKL increased the phosphorylation of MEK and extracellular signal regulating kinase (ERK). In addition, an NF-kappaB inhibitor (PDTC) and IkappaB protease inhibitor (TPCK) also inhibited RANKL-mediated cell migration and ICAM-1 up-regulation. Taken together, these results suggest that the RANKL and RANK interaction acts through MEK/ERK, which in turn activates NF-kappaB, resulting in the activation of ICAM-1 and contributing to the migration of human lung cancer cells. PMID- 21328468 TI - Cdk1 is required for the self-renewal of mouse embryonic stem cells. AB - Cyclin-dependent kinase 1 (Cdk1) is indispensible for the early development of the embryo. However, its role in maintaining the undifferentiated state of the embryonic stem (ES) cells remains unknown. In this study, we dissected the function of Cdk1 in mouse ES cells by RNA-interference and gene expression analyses. Cdk1 expression is tightly correlated with the undifferentiated state of the ES cells. Upon differentiation, Cdk1 expression reduced drastically. Cdk1 knock-down by RNA interference resulted in the loss of proliferation and colony formation potential of the ES cells. Consequentially, expression of self-renewal genes was reduced while differentiation markers such as Cdx2 were induced. Our results suggest a role for Cdk1 in maintaining the unique undifferentiated and self-renewing state of the mouse ES cells. PMID- 21328469 TI - Imaging the recruitment of cancer-associated fibroblasts by liver-metastatic colon cancer. AB - The tumor microenvironment (TME) is critical for tumor growth and progression. However, the formation of the TME is largely unknown. This report demonstrates a color-coded imaging model in which the development of the TME can be visualized. In order to image the TME, a green fluorescent protein (GFP)-expressing mouse was used as the host which expresses GFP in all organs but not the parenchymal cells of the liver. Non-colored HCT-116 human colon cancer cells were injected in the spleen of GFP nude mice which led to the formation of experimental liver metastasis. TME formation resulting from the liver metastasis was observed using the Olympus OV100 small animal fluorescence imaging system. HCT-116 cells formed tumor colonies in the liver 28 days after cell transplantation to the spleen. GFP expressing host cells were recruited by the metastatic tumors as visualized by fluorescence imaging. A desmin positive area increased around and within the liver metastasis over time, suggesting cancer-associated fibroblasts (CAFs) were recruited by the liver metastasis which have a role in tumor progression. The color-coded model of the TME enables its formation to be visualized at the cellular level in vivo, in real-time. This imaging model of the TME should lead to new visual targets in the TME. PMID- 21328470 TI - Cellular prion proteins in human platelets show a phenotype different to those in brain tissues. AB - Prion diseases are characterized by high accumulation of infectious prion proteins (PrP(Sc)) in brains. PrP(Sc) are propagated by the conversion of host encoded cellular prion proteins (PrP(C)) which are essential for developing the disease but are heterogeneously expressed in brains. The disease can be transmitted to humans and animals through blood and blood products, however, little attention has been given to molecular characterization of PrP(C) in blood cells. In this presented study, we characterized phenotypically PrP(C) of platelets (plt) and characterized the proteins regarding their glycobanding profiles by quantitative immunoblotting using a panel of monoclonal antibodies. The glycosylation patterns of plt and brain PrP(C) were compared using the ratios of di-, mono-, and non-glycosylated prions. The detergent solubility of plt and brain PrP(C) was also analyzed. The distinct banding patterns and detergent solubility of plt PrP(C) differed clearly from the glycosylation profiles and solubility characteristics of brain PrP(C). Plt PrP(C) exhibited single or only few prion protein types, whereas brain PrP(C) showed more extensive banding patterns and lower detergent solubility. Plt PrP(C) are post-translational modified differently from PrP(C) in brain. These findings suggest other or less physiological functions of plt PrP(C) than in brain. PMID- 21328471 TI - Uroflowmetry in asymptomatic and symptomatic women. PMID- 21328472 TI - Quality of life in complete spinal cord injury patients with a Brindley bladder stimulator compared to a matched control group. AB - AIMS: To determine the effects on Quality of Life (QoL) of a Brindley procedure, which combines a sacral dorsal root rhizotomy to treat neurogenic detrusor overactivity with sacral anterior root stimulation to enable micturition, defecation, and penile erections in complete spinal cord injury (SCI) patients compared to a matched Control Group. METHODS: Cross-sectional study. The Qualiveen questionnaire, SF-36 questionnaire, and multiple choice questions about urinary continence and urinary tract infections were sent to 93 patients who had a Brindley stimulator implanted in the Netherlands and a matched Control Group of 70 complete SCI patients with neurogenic detrusor overactivity. Primary study outcomes were Specific Impact of Urinary Problems score and general QoL index of the Qualiveen. RESULTS: Response rates were 78% and 40% for patients with a Brindley stimulator and controls, respectively. Stimulators were still used for micturition in 46 (63%). These patients had a significant better Specific Impact of Urinary Problems score, general QoL index (Qualiveen), and continence rate, and less urinary tract infections compared to the Control Group. Patients also benefited of the rhizotomy with regard to QoL and continence rate if the stimulator was not used anymore. The subscales of the SF-36 had better scores for the patients who used their stimulator as compared to those who did not use the stimulator and compared to the Control Group. CONCLUSIONS: The Brindley stimulator for complete spinal cord injury patients improves Quality of Life, continence, and urinary tract infection rate compared to a matched Control Group. PMID- 21328473 TI - Hand grip and pinch strength in patients with nocturnal enuresis: is there a role of muscle strength in pathogenesis of enuresis? AB - AIMS: To examine the association of muscle strength with nocturnal enuresis. SUBJECTS AND METHODS: One hundred sixty-three patients with monosymptomatic nocturnal enuresis (8-14 years old) were recruited from outpatient clinics. Two hundred eight healthy students served as the control group (8-14 years old) from two primary schools. Physical examinations and the age, gender, height, weight, dominant hand, and body mass of these children index were recorded. A calibrated, Jamar dynamometer was used to assess grip strength at the first two settings. A pinch gauge was used to assess the key pinch of the right and left hands of these children. Two measurements of each grip and pinch were obtained at 15 sec intervals and mean values were analyzed. RESULTS: The hand grip strength test and pinch was significantly lower in the enuretic group compared with the control group. These low results of the muscle strength in the enuretic group showed that whole body muscle weakness may contribute to the pathogenesis of enuresis as a possible etiological factor. CONCLUSIONS: In this first study on the association of muscle strength with nocturnal enuresis, it was found that neuromuscular function is abnormal in enuretic patients. In this neuromuscular abnormality, the motor activity is affected. PMID- 21328474 TI - Advances in stalking risk assessment. AB - Over the past 15 years, forensic mental health has become more concerned with the concepts of violence prevention, management, and treatment. The development of specialist tools to aid in the assessment of a range of risks reflects this concern. This article explores contemporary thinking on violence risk assessment and how this knowledge can be applied to the relatively newer field of stalking risk assessment. The role of risk state and risk status are discussed, in addition to the way that standard structured professional judgment procedures need to be adapted to reflect the variety of risks present in stalking situations. The authors go on to describe the development and format of the Stalking Risk Profile, a set of structured professional judgment guidelines for assessing risk in stalkers. Suggestions are made for future research to enhance knowledge and improve practice in the field of stalking risk assessment. PMID- 21328475 TI - Frequent walking, but not total physical activity, is associated with increased fracture incidence: a 5-year follow-up of an Australian population-based prospective study (AusDiab). AB - Current public health physical activity (PA) guidelines recommend that older adults accumulate >= 2.5 hours per week of moderate- to vigorous-intensity PA to optimize health. The aim of this study was to examine (1) whether adults who meet the current PA guidelines are at reduced risk of fracture, (2) whether fracture risk varies by PA type/intensity and frequency, and (3) whether prolonged TV viewing, as a marker of sedentary behavior, is associated with fracture risk. This national, population-based prospective study with a 5-year follow-up included 2780 postmenopausal women and 2129 men aged 50 years or older. Incident nontraumatic clinical fractures were self-reported. Overall, 307 (6.3%) participants sustained at least one incident low-trauma fracture (women 9.3%, men 2.3%). Multivariate logistic regression, adjusting for age, body mass index (BMI), physical function, previous fracture history, smoking, and dietary calcium and serum 25-hydroxyvitamin D levels, showed that women who walked more than 3 hours per week or completed at least 6 weekly bouts of walking had a 51% and 56% increased fracture risk, respectively, compared with women who did no walking [odds ratio (OR) time = 1.51, 95% confidence interval (CI) 1.01-2.24; OR frequency = 1.56, 95% CI 1.07-2.27]. However, total and moderate to vigorous PA time and the accumulation of 2.5 hours per week or more of PA and TV viewing time were not associated with incident fractures. In men, there also was an increased fracture risk for those who walked more than 3 hours per week (OR = 2.30, 95% CI 1.06-4.97) compared with those who reported no walking. In conclusion, older adults who adhered to the current PA guidelines were not protected against fragility fractures, but more frequent walking was associated with an increased fracture risk. PMID- 21328476 TI - Skeletal phenotype of the leptin receptor-deficient db/db mouse. AB - Leptin, a major hormonal product of the adipocyte, regulates appetite and reproductive function through its hypothalamic receptors. The leptin receptor is present in osteoblasts and chondrocytes, and previously we have shown leptin to be an anabolic bone factor in vitro, stimulating osteoblast proliferation and inhibiting osteoclastogenesis. Leptin increases bone mass and reduces bone fragility when administered peripherally but also can indirectly reduce bone mass when administered into the central nervous system. However, data from animal models deficient in either leptin (ob/ob) or its receptor (db/db) remain contradictory. We compared the bone phenotype of leptin receptor-deficient (db/db) and wild-type mice using micro-computed tomographic (uCT) analysis of the proximal tibias and vertebrae. In the tibia, db/db mice had reduced percent trabecular bone volume (13.0 +/- 1.62% in wild-type versus 6.01 +/- 0.601% in db/db mice, p = .002) and cortical bone volume (411 +/- 21.5 um(3) versus 316 +/- 3.53 um(3), p = .0014), trabecular thickness (48.4 +/- 001.07 um versus 45.1 +/- 0.929 um, p = .041) and trabecular number (2.68 +/- 0.319 mm(-1) versus 1.34 +/- 0.148 mm(-1), p = .0034). In the fifth lumbar vertebral body, the trabecular thickness and cortical thickness were decreased in the db/db versus wild-type mice (0.053 +/- 0.0011 mm versus 0.047 +/- 0.0013 mm, p = .0002 and 0.062 +/- 0.00054 mm versus 0.056 +/- 0.0009 mm, p = .0001), respectively, whereas the trabecular and cortical percent bone volume and trabecular number did not reach significance. The total (endosteal and periosteal) cortical perimeter (12.2 +/- 0.19 mm versus 13.2 +/- 0.30 mm, p = .01) was increased. The serum osteocalcin levels were reduced in the db/db mice, suggesting that bone formation rates are decreased. The material properties of db/db femurs were determined by three-point bending and nanoindentation, showing decreased bone strength (13.3 +/- 0.280 N versus 7.99 +/- 0.984 N, p = .0074) and material stiffness (28.5 +/- 0.280 GPa versus 25.8 +/- 0.281 GPa, p < .0001). These results demonstrate that bone mass and strength are reduced in the absence of leptin signaling, indicating that leptin acts in vivo as an anabolic bone factor. This concurs with results of in vitro studies and of peripheral leptin administration in vivo and suggests that leptin's direct effects on bone cells are likely to override its actions via the central nervous system. PMID- 21328478 TI - Bionanoelectronics. AB - Every cell in a living organisms performs a complex array of functions using a vast arsenal of proteins, ion channels, pumps, motors, signaling molecules, and cargo carriers. With all the progress that humankind has made to date in the development of sophisticated machinery and computing capabilities, understanding and communicating with living systems on that level of complexity lags behind. A breakthrough in these capabilities could only come if a way is found to integrate biological components into artificial devices. The central obstacle for this vision of bionanoelectronics is the absence of a versatile interface that facilitates two-way communication between biological and electronic structures. 1D nanomaterials, such as nanotubes and nanowires, open up the possibility of constructing tight interfaces that could enable such bidirectional flow of information. This report discusses the overall progress in building such interfaces on the level of individual proteins and whole cells and focuses on the latest efforts to create device platforms that integrate membrane proteins, channels, and pumps with nanowire bioelectronics. PMID- 21328479 TI - Metal-catalyzed growth of semiconductor nanostructures without solubility and diffusivity constraints. PMID- 21328480 TI - Conformable solid-index phase masks composed of high-aspect-ratio micropillar arrays and their application to 3D nanopatterning. PMID- 21328481 TI - The MEMOLED: active addressing with passive driving. PMID- 21328482 TI - Elastically tunable self-organized organic lasers. PMID- 21328483 TI - Compact hybrid cell based on a convoluted nanowire structure for harvesting solar and mechanical energy. PMID- 21328484 TI - Non-volatile photochemical gating of an epitaxial graphene/polymer heterostructure. PMID- 21328486 TI - Improvement of electroluminescence performance of organic light-emitting diodes with a liquid-emitting layer by introduction of electrolyte and a hole-blocking layer. PMID- 21328487 TI - Woven electrochemical transistors on silk fibers. PMID- 21328488 TI - Low-power high-performance non-volatile memory on a flexible substrate with excellent endurance. PMID- 21328489 TI - Carbon nanotube webs: a novel material for sensor applications. PMID- 21328490 TI - Photoenhancement of a quantum dot nanocomposite via UV annealing and its application to white LEDs. PMID- 21328491 TI - Palladium(II)-mediated assembly of biotinylated ion channels. AB - Simple synthetic methodology has been used to create biotinylated pyridyl cholate lipids that can undergo multiple self-assembly events when inserted into phospholipid vesicles; Pd(II) links cholates into transmembrane lipids, while avidin laterally clusters these complexes together and concomitantly assembles the vesicles into aggregates. The transmembrane assembly of cholates by Pd(II) "opened" the ion channels, whereas avidin addition produced vesicle aggregates, giving a system that mimicked both transmembrane transport and cellular adhesion. Complexation of these Pd(II)-linked cholates by avidin gave a measurable decrease in ion flow, suggesting some channels became blocked or were prevented from adopting the optimum geometry for ion conduction. This reflects the importance of spatially appropriate preorganisation when generating active supramolecular assemblies. PMID- 21328492 TI - C5-functionalized DNA, LNA, and alpha-L-LNA: positional control of polarity sensitive fluorophores leads to improved SNP-typing. AB - Single nucleotide polymorphisms (SNPs) are important markers in disease genetics and pharmacogenomic studies. Oligodeoxyribonucleotides (ONs) modified with 5-[3 (1-pyrenecarboxamido)propynyl]-2'-deoxyuridine monomer X enable detection of SNPs at non-stringent conditions due to differential fluorescence emission of matched versus mismatched nucleic acid duplexes. Herein, the thermal denaturation and optical spectroscopic characteristics of monomer X are compared to the corresponding locked nucleic acid (LNA) and alpha-L-LNA monomers Y and Z. ONs modified with monomers Y or Z result in a) larger increases in fluorescence intensity upon hybridization to complementary DNA, b) formation of more brightly fluorescent duplexes due to markedly larger fluorescence emission quantum yields (Phi(F)=0.44-0.80) and pyrene extinction coefficients, and c) improved optical discrimination of SNPs in DNA targets. Optical spectroscopy studies suggest that the nucleobase moieties of monomers X-Z adopt anti and syn conformations upon hybridization with matched and mismatched targets, respectively. The polarity sensitive 1-pyrenecarboxamido fluorophore is, thereby, either positioned in the polar major groove or in the hydrophobic duplex core close to quenching nucleobases. Calculations suggest that the bicyclic skeletons of LNA and alpha-L LNA monomers Y and Z influence the glycosidic torsional angle profile leading to altered positional control and photophysical properties of the C5-fluorophore. PMID- 21328493 TI - C--H activation on aluminum-vanadium bimetallic oxide cluster anions. AB - Aluminum-vanadium bimetallic oxide cluster anions (BMOCAs) have been prepared by laser ablation and reacted with ethane and n-butane in a fast-flow reactor. A time-of-flight mass spectrometer was used to detect the cluster distribution before and after the reactions. The observation of hydrogen-containing products AlVO(5)H(-) and Al(x)V(4-x)O(11-x)H(-) (x=1-3) strongly suggests that AlVO(5)(-) and Al(x)V(4-x)O(11-x)(-) (x=1-3) can react with ethane and n-butane by means of an oxidative dehydrogenation process at room temperature. Density functional theory studies have been carried out to investigate the structural, bonding, electronic, and reactive properties of these BMOCAs. Terminal-oxygen-centered radicals (O(t)(.)) were found in all of the reactive clusters, and the O(t)(.) atoms, which prefer to be bonded with Al rather than V atoms, are the active sites of these clusters. All the hydrogen-abstraction reactions are favorable both thermodynamically and kinetically. To the best of our knowledge, this is the first example of hydrogen-atom abstraction by BMOCAs and may shed light on understanding the mechanisms of C--H activation on the surface of alumina supported vanadia catalysts. PMID- 21328494 TI - Surface chemistry in the process of coating mesoporous SiO2 onto carbon nanotubes driven by the formation of Si-O-C bonds. AB - The deposition of mesoporous silica (SiO(2)) on carbon nanotubes (CNTs) has opened up a wide range of assembling possibilities by exploiting the sidewall of CNTs and organosilane chemistry. The resulting systems may be suitable for applications in catalysis, energy conversion, environmental chemistry, and nanomedicine. However, to promote the condensation of silicon monomers on the nanotube without producing segregated particles, (OR)(4-x)SiO(x)(x-) units must undergo nucleophilic substitution by groups localized on the CNT sidewall during the transesterification reaction. In order to achieve this preferential attachment, we have deposited silica on oxidized carbon nanotubes (single-walled and multiwalled) in a sol-gel process that also involved the use of a soft template (cetyltrimethylammonium bromide, CTAB). In contrast to the simple approach normally used to describe the attachment of inorganic compounds on CNTs, SiO(2) nucleation on the tube is a result of nucleophilic attack mainly by hydroxyl radicals, localized in a very complex surface chemical environment, where various oxygenated groups are covalently bonded to the sidewall and carboxylated carbonaceous fragments (CCFs) are adsorbed on the tubes. Si-O-C covalent bond formation in the SiO(2)-CNT hybrids was observed even after removal of the CCFs with sodium hydroxide. By adding CTAB, and increasing the temperature, time, and initial amount of the catalyst (NH(4)OH) in the synthesis, the SiO(2) coating morphology could be changed from one of nanoparticles to mesoporous shells. Concomitantly, pore ordering was achieved by increasing the amount of CTAB. Furthermore, preferential attachment on the sidewall results mostly in CNTs with uncapped ends, having sites (carboxylic acids) that can be used for further localized reactions. PMID- 21328495 TI - Exciton-coupled charge-transfer dynamics in a porphyrin J-aggregate/TiO(2) complex. AB - Exciton-coupled charge-transfer (CT) dynamics in TiO(2) nanoparticles (NP) sensitized with porphyrin J-aggregates has been studied by femtosecond time resolved transient absorption spectroscopy. J-aggregates of 5,10,15-triphenyl-20 (3,4-dihydroxyphenyl) porphyrin (TPPcat) form CT complexes on TiO(2) NP surfaces. Catechol-mediated strong CT coupling between J-aggregate and TiO(2) NP facilitates interfacial exciton dissociation for electron injection into the conduction band of the TiO(2) nanoparticle in pulse width limited time (<80 fs). Here, the electron-transfer (<80 fs) process dominates over the intrinsic exciton relaxation process (J-aggregates: ca. 200 fs) on account of exciton-coupled CT interaction. The parent hole on J-aggregates is delocalized through J-aggregate excitonic coherence. As a result, holes immobilized on J-aggregates are spatially less accessible to electrons injected into TiO(2) , and thus the back electron transfer (BET) process is slower than that of the monomer/TiO(2) system. The J aggregate/porphyrin system shows exciton spectral and temporal properties for better charge separation in strongly coupled composite systems. PMID- 21328496 TI - How does aromaticity rule the thermodynamic stability of hydroporphyrins? AB - Several measures of aromaticity including energetic, magnetic, and electron density criteria are employed to show how aromatic stabilization can explain the stability sequence of hydroporphyrins, ranging from porphin to octahydroporphin, and their preferred hydrogenation paths. The methods employed involve topological resonance energies and their circuit energy effects, bond resonance energies, multicenter delocalization indices, ring current maps, magnetic susceptibilities, and nuclear-independent chemical shifts. To compare the information obtained by the different methods, the results have been put in the same scale by using recently proposed approaches. It is found that all of them provide essentially the same information and lead to similar conclusions. Also, hydrogenation energies along different hydrogenation paths connecting porphin with octahydroporphin have been calculated with density functional theory. It is shown by using the methods mentioned above that the relative stability of different hydroporphyrin isomers and the observed inaccessibility of octahydroporphin both synthetically and in nature can be perfectly rationalized in terms of aromaticity. PMID- 21328497 TI - Reactivity of a silylsilylene bearing a functionalized diaminochlorosilyl substituent. AB - The reactivity of the silylsilylene [{PhC(NtBu)(2)}SiSi(Cl){(NtBu)(2)C(H)Ph}] (2) towards diphenylacetylene, azobenzene, 2,6-diisopropylphenyl azide, sulfur, and selenium is described. The reaction of 2 with one equivalent of azobenzene in toluene afforded compound 3, which is the first example of a 1,2-diaza-3,4 disilacyclobutane containing a pentacoordinate silicon center. The formation of 3 can be explained by a [1+2] cycloaddition of the divalent Si center in 2 with PhN=NPh to form a diazasilacyclopropane intermediate, which then undergoes a 1,2 chlorine shift to release the ring strain to form 3. Similarly, the reaction of 2 with one equivalent of diphenylacetylene in toluene afforded the 1,2 disilacyclobutene 4, which contains a pentacoordinate silicon center. The reaction of 2 with 1.6 equivalents of 2,6-diisopropylphenylazide in toluene afforded the silaimine [LSi(=NAr)N(Ar)L'] (5, L=PhC(NtBu)(2) , L'=Si(Cl){(NtBu)(2)C(H)Ph}, Ar=2,6-iPr(2)C(6)H(3)). The formation of 5 can be explained by an oxidative addition of the divalent Si center in 2 with ArN(3) to afford a silaimine intermediate, which then reacts with another molecule of ArN(3) to give compound 5. The reaction of 2 with elemental sulfur in toluene afforded the chlorosilanethione [LSi(S)Cl] (6) and dithiodisiletane [{Ph(H)C(NtBu)(2) }Si(MU-S)](2) (7). Treatment of 2 with elemental selenium in THF afforded the di(silaneselone) [LSi(Se)Si(Se)L] (8). Evidently, the divalent Si center in 2 undergoes oxidative addition with chalcogens to afford a silylsilanechalcogenone intermediate, which then displaces ":Si{(NtBu)(2)C(H)Ph}" and "ClSi{(NtBu)(2) C(H)Ph}" to form 6 and 8, respectively. Moreover, compound 8 was synthesized by the reaction of [{PhC(NtBu)(2)}Si:](2) (10) with elemental selenium in THF. The results show that the reactions of 2 are initiated by oxidative addition of the divalent silicon center, and then the intermediate formed undergoes a rearrangement involving the diaminochlorosilyl substituent to form compounds 3-8. These products have been characterized by NMR spectroscopy and X-ray crystallography. PMID- 21328498 TI - Greatly enhanced intermolecular pi-dimer formation of a porphyrin trimer radical trications through multiple pi bonds. AB - A trefoil-like porphyrin trimer linked by triphenylamine (TPA-TPZn(3)) was synthesized. A three-electron oxidation of TPA-TPZn(3) forms a radical trication (TPA-TPZn(3)(3+)), in which each porphyrin ring undergoes a one-electron oxidation. The radical trication TPA-TPZn(3)(3+) spontaneously dimerizes to afford (TPA-TPZn(3))(2)(6+) in CH(2)Cl(2) . The characteristic charge-resonance band due to the charge delocalization over the pi system of (TPA-TPZn(3))(2)(6+) was observed in the NIR region. The initial oxidation potential of TPA-TPZn(3) is negatively shifted relative to that of the corresponding monomer porphyrin, which results from the stabilization of the oxidized state of TPA-TPZn(3) associated with the dimerization. The thermodynamic parameters (i.e., DeltaH, DeltaS, and DeltaG) for the formation of (TPA-TPZn(3))(2)(6+) were determined by measuring Vis/NIR spectra at various temperatures. The formation constant of (TPA TPZn(3))(2)(6+) is significantly larger than that of the radical cation dimer of the corresponding monomer porphyrin (e.g., over 2000-fold at 233 K). The electronic states were investigated using EPR spectroscopic analysis. The greatly enhanced dimerization of TPA-TPZn(3)(3+) results from multiple pi-bond formation between the porphyrin radical cations. PMID- 21328499 TI - Sr(2)Ni(3)--a strontium subnickelide? PMID- 21328500 TI - Catalyst-free conjugation and in situ quantification of nanoparticle ligand surface density using fluorogenic Cu-free Click chemistry. PMID- 21328501 TI - Evolution from lyotropic liquid crystal to helical fibrous organogel of an achiral fluorescent twin-tapered bi-1,3,4-oxadiazole derivative. AB - We report an unprecedented hierarchical self-assembly of an achiral twin-tapered bi-1,3,4-oxadiazole derivative (2,2-bis(3,4,5-trioctanoxyphenyl)-bi-1,3,4 oxadiazole, BOXD-T8). This molecule can form a layer-structured lyotropic liquid crystal and further forms a helical fibrous organogel in DMF at concentrations above 0.6 wt %. The self-assembly process of BOXD-T8 in DMF is accompanied by a change in its fluorescence. The pitches of the helical fibers are non-uniform, and both left- and right-handed helical fibers are observed in equal quantities. Intermolecular pi-pi interactions between aromatic segments have been demonstrated to be the driving force for aggregate formation. This helical structure of BOXD-T8 is dependent on the solvent, concentration, and the layer structured intermediate liquid-crystalline state. PMID- 21328502 TI - Coupled crystallographic order-disorder and spin state in a bistable molecule: multiple transition dynamics. AB - A novel bispyrazolylpyridine ligand incorporating lateral phenol groups, H(4)L, has led to an Fe(II) spin-crossover (SCO) complex, [Fe(H(4)L)(2)][ClO(4)](2)?H(2)O?2 (CH(3))(2)CO (1), with an intricate network of intermolecular interactions. It exhibits a 40 K wide hysteresis of magnetization as a result of the spin transition (with T(0.5) of 133 and 173 K) and features an unsymmetrical and very rich structure. The latter is a consequence of the coupling between the SCO and the crystallographic transformations. The high-spin state may also be thermally trapped, exhibiting a very large T(TIESST) (~104 K). The structure of 1 has been determined at various temperatures after submitting the crystal to different processes to recreate the key points of the hysteresis cycle and thermal trapping; 200 K, cooled to 150 K and trapped at 100 K (high spin, HS), slowly cooled to 100 K and warmed to 150 K (low spin, LS). In the HS state, the system always exhibits disorder for some components (one ClO(4)(-) and two acetone molecules) whereas the LS phases show a relative ~9 % reduction in the Fe-N bond lengths and anisotropic contraction of the unit cell. Most importantly, in the LS state all the species are always found to be ordered. Therefore, the bistability of crystallographic order-disorder coupled to SCO is demonstrated here experimentally for the first time. The variation in the cell parameters in 1 also exhibits hysteresis. The structural and magnetic thermal variations in this compound are paralleled by changes in the heat capacity as measured by differential scanning calorimetry. Attempts to simulate the asymmetric SCO behaviour of 1 by using an Ising-like model underscore the paramount role of dynamics in the coupling between the SCO and the crystallographic transitions. PMID- 21328503 TI - Synthesis of dodecavalent fullerene-based glycoclusters and evaluation of their binding properties towards a bacterial lectin. AB - Multivalency is playing a major role in biological processes and particularly in lectin-carbohydrate interactions. The design of high-affinity ligands of lectins should provide molecules capable of interfering with these biological processes and potentially inhibit bacterial or viral infections. Azide-alkyne "click" chemistry was applied to the synthesis of dodecavalent fullerene-based glycoclusters. The conjugation could be efficiently performed from alkyne or azide functions on either partners (i.e. hexakis-fullerene adduct or glycoside). PA-IL is a bacterial lectin from the opportunistic pathogen Pseudomonas aeruginosa and is involved in the recognition of glycoconjugates on human tissues. The glycoclusters obtained were evaluated as ligands of PA-IL and for their potential for competing with its binding to glycosylated surfaces. The affinities measured by hemagglutination inhibition assay (HIA), enzyme-linked lectin assay (ELLA), and surface plasmon resonance (SPR) displayed a significant "glycoside cluster effect" with up to a 12,000-fold increase in binding when comparing a monovalent carbohydrate reference probe with a dodecavalent fullerene based glycocluster, albeit with some differences depending on the analytical technique. PMID- 21328504 TI - A general access to zaragozic acids: total synthesis and structure elucidation of zaragozic acid D and formal syntheses of zaragozic acids A and C. PMID- 21328505 TI - Bis(2,2'-biphenoxy)borates for electrochemical double-layer capacitor electrolytes. AB - Fluorine makes the difference! Bis(2,2'-biphenoxy)borates decorated with fluorine substituents have been synthesized and studied in supercapacitor test cells (see scheme). A clear trend towards higher electrochemical stability with the increase of the fluorine content has been observed. For a maximum performance, only two fluorine substituents per benzene moiety are required. PMID- 21328506 TI - A microwave-assisted domino rearrangement of propargyl vinyl ethers to multifunctionalized aromatic platforms. PMID- 21328507 TI - Enantioselective gold-catalyzed functionalization of unreactive sp3 C-H bonds through a redox-neutral domino reaction. AB - Selectivity is golden: The first asymmetric redox-neutral domino reaction catalyzed by gold that results in the direct functionalization of unreactive sp(3) C-H bonds has been reported. This method consists of a heterocyclization/1,5-hydride transfer/cyclization reaction and provides synthetically valuable azepines with high enantioselectivities and in high yields (Tf = triflate; see scheme). PMID- 21328508 TI - Molecular and functional characterizations of gastrula organizer cells derived from human embryonic stem cells. AB - The Spemann-Mangold organizer is the structure that provides the signals, which initiate pattern formation in the developing vertebrate embryo, affecting the main body axes. Very little is known about axial induction in the gastrulating human embryo, as research is hindered by obvious ethical restrictions. Human embryonic stem cells (hESCs) are pluripotent cells derived from the pregastrula embryo that can differentiate in culture following a program similar to normal embryonic development but without pattern formation. Here, we show that in hESC derived embryoid bodies, we can induce differentiation of cells that harbor markers and characteristics of the gastrula-organizer. Moreover, genetic labeling of these cells enabled their purification, and the discovery of a comprehensive set of their secreted proteins, cell surface receptors, and nuclear factors characteristic of the organizer. Remarkably, transplantation of cell populations enriched for the putative human organizer into frog embryos induced a secondary axis. Our research demonstrates that the human organizer can be induced in vitro and paves the way for the study of pattern formation and the initial regulation of body axis establishment in humans. PMID- 21328509 TI - Brief report: ectopic expression of NUP98-HOXA10 augments erythroid differentiation of human embryonic stem cells. AB - Hox genes encode highly conserved transcription factors that have been implicated in hematopoietic development and self-renewal of hematopoietic stem cells (HSCs) and hematopoietic development. The potency of NUP98-HOXA10hd (NA10) on adult murine bone marrow HSC self-renewal prompted us to examine its effect on specification and proliferation of hematopoietic cells derived from human embryonic stem cells (hESCs). Here, we demonstrate that expression of NA10 in hESCs influences the hematopoietic differentiation program. The specific effect of NA10 is dependent on the developmental stage of hematopoietic emergence from hESCs. Overexpression of NA10 in either undifferentiated hESCs or early hemogenic precursors augmented the frequency of CD45(-) GlycophorinA(+) cells and erythroid progenitors (blast-forming unit-erythrocyte). In contrast, targeted NA10 expression in primitive CD34+ cells committed to the hematopoietic lineage had no effect on erythropoietic capacity but instead increased hematopoietic progenitor proliferation. Our study reveals a novel neomorphic effect of NA10 in early human erythroid development from pluripotent stem cells. PMID- 21328510 TI - In-situ monitoring of the formation of crystalline solids. AB - The processes occurring during the early stages of the formation of crystalline solids are not well understood thus preventing the rational synthesis of new solids. The investigation of the structure-forming processes is an enormous challenge for both analytical and theoretical methods because very small particles or aggregates with different chemical composition and different sizes must be probed, both before and during nucleation. Furthermore, these precursors are present in a complex and dynamic equilibrium. This Review gives a survey of the in-situ methods available for the study of the early stages of crystallization of solids and how they can help in the synthesis of metastable polymorphs, of transient intermediates, and/or precursors displaying new or improved properties. Examples of actual research demonstrate the necessity and potentials but also the limitations of in-situ monitoring of the formation of crystalline solids. PMID- 21328511 TI - From conventional to unusual enzyme inhibitor scaffolds: the quest for target specificity. AB - The tremendous challenge presented by the specific molecular recognition of single biomacromolecular targets within complex biological systems demands novel and creative design strategies. This Minireview discusses some conventional and unusual approaches for the design of target-selective enzyme inhibitors with a focus on the underlying chemical scaffolds. These include complicated natural product-like organic molecules, stable octahedral metal complexes, fullerenes, carboranes, polymetallic clusters, and even polymers. Thus the whole repertoire of organic, inorganic, and macromolecular chemistry can be applied to tackle the problem of target-specific enzyme inhibition. PMID- 21328512 TI - A chiral N-phosphinyl phosphoramide: another offspring for the sage phosphoric acid progenitor. PMID- 21328513 TI - Synthesis and pro-apoptotic activity of novel glycyrrhetinic acid derivatives. AB - Triterpenoids are used for medicinal purposes in many countries. Some, such as oleanolic and glycyrrhetinic acids, are known to be anti-inflammatory and anticarcinogenic. However, the biological activities of these naturally occurring molecules against their particular targets are weak, so the synthesis of new synthetic analogues with enhanced potency is needed. By combining modifications to both the A and C rings of 18betaH-glycyrrhetinic acid, the novel synthetic derivative methyl 2-cyano-3,12-dioxo-18betaH-olean-9(11),1(2)-dien-30-oate was obtained. This derivative displays high antiproliferative activity in cancer cells, including a cell line with a multidrug-resistance phenotype. It causes cell death by inducing the intrinsic caspase-dependent apoptotic pathway. PMID- 21328514 TI - Spacer effects on in vivo properties of DOTA-conjugated dimeric [Tyr3]octreotate peptides synthesized by a "Cu(I)-click" and "sulfo-click" ligation method. AB - We report on the SSTR2-binding properties of a series of four dimeric [Tyr3]octreotate analogues with different spacer lengths (nine, 19, 41, and 57 atoms) between the peptides. Two analogues (9 and 57 atoms) were selected as precursors for the design, synthesis, and biological evaluation of DOTA conjugated dimeric [Tyr3]octreotate analogues for tumor targeting. These compounds were synthesized by using a two-stage click ligation procedure: a Cu(I) -catalyzed 1,3-dipolar cycloaddition ("copper-click" reaction) and a thio acid/sulfonyl azide amidation ("sulfo-click" reaction). The IC(50) values of these DOTA-conjugated [Tyr3]octreotate analogues were comparable, and internalization studies showed that the nine-atom (111) In-DOTA-labeled [Tyr3]octreotate dimer had rapid and high receptor binding. Biodistribution studies with BALB/c nude mice bearing subcutaneous AR42J tumors showed that the (111) In-labeled [Tyr3]octreotate dimer (nine atoms) had a high tumor uptake at 1 h p.i. (38.8 +/- 8.3 % ID g(-1) ), and excellent tumor retention at 4 h p.i. (40.9 +/- 2.5 % ID g(-1) ). However, the introduction of the extended hydrophilic 57 atoms spacer led to rapid clearance from the circulation; this limited tumor accumulation of the radiotracer (21.4 +/- 4.9 % ID g(-1) at 1 h p.i.). These findings provide important insight on dimerization and spacer effects on the in vivo properties of DOTA-conjugated [Tyr3]octreotate dimers. PMID- 21328515 TI - Fluorescence anisotropy of molecular rotors. AB - We present polarization-resolved fluorescence measurements of fluorescent molecular rotors 9-(2-carboxy-2-cyanovinyl)julolidine (CCVJ), 9-(2,2 dicyanovinyl)julolidine (DCVJ), and a meso-substituted boron dipyrromethene (BODIPY-C(12)). The photophysical properties of these molecules are highly dependent on the viscosity of the surrounding solvent. The relationship between their quantum yields and the viscosity of the surrounding medium is given by an equation first described and presented by Forster and Hoffmann and can be used to determine the microviscosity of the environment around a fluorophore. Herein we evaluate the applicability of molecular rotors as probes of apparent viscosity on a microscopic scale based on their viscosity dependent fluorescence depolarization. We develop a theoretical framework, combining the Forster Hoffmann equation with the Perrin equation and compare the dynamic ranges and usable working regimes for these dyes in terms of utilising fluorescence anisotropy as a measure of viscosity. We present polarization-resolved fluorescence spectra and steady-state fluorescence anisotropy imaging data for measurements of intracellular viscosity. We find that the dynamic range for fluorescence anisotropy for CCVJ and DCVJ is significantly lower than that of BODIPY-C(12) in the viscosity range 0.6= 99 in each group). The primary endpoint was the efficacy of balaglitazone 10 and 20 mg versus placebo on the absolute change in haemoglobin A(1c) . Secondary endpoints included levels of fasting serum glucose, and changes in body composition and bone mineral density as measured by dual energy X-ray absorptiometry, in comparison to pioglitazone 45 mg. This study is registered with Clinicaltrials.gov identifier: NCT00515632. RESULTS: In the 10- and 20-mg balaglitazone groups, and in the 45-mg pioglitazone group, significant reductions in haemoglobin A(1c) levels were observed (-0.99, -1.11, and -1.22%, respectively; p < 0.0001) versus placebo. Fasting serum glucose was similarly reduced in all treatment arms. Dual energy X-ray absorptiometry analyses showed that, while balaglitazone at 10 mg caused weight gain and fluid retention compared to placebo, the magnitude of these effects was significantly smaller than that of pioglitazone 45 mg and balaglitazone 20mg. Balaglitazone at either dose did not appear to reduce bone mineral density, while Pioglitazone showed a trend towards a reduction. CONCLUSION: Patients treated with balaglitazone at 10 mg and 20 mg and pioglitazone at 45 mg showed clinically meaningful improvements in glucose levels and HbA(1c) . With the 10 mg dose, the benefits (glucose & HgA(1c) lowering) and untoward effects (fluid and fat accumulation) were less, results that encourage further studies of this drug candidate. PMID- 21328518 TI - Direct examination of chromosomal clustering of organ-specific genes in the chordate Ciona intestinalis. AB - One of challenges in the field of developmental biology is to understand how spatially and/or temporally coordinated expression of genes is controlled at the chromosomal level. It remains controversial whether genes expressed in a given tissue are randomly distributed throughout a given animal genome, or instead resolve into clusters. Here we used microarray analysis to identify more than 1,700 genes that are expressed preferentially in each of 11 organs of the chordate Ciona intestinalis adult, and determined the location of these genes on the 14 pairs of Ciona chromosomes. In spite of extensive mapped gene analysis, we only confirmed small clusters containing two or three genes. Our result indicates that organ-specific genes are distributed rather evenly all over chromosomes, suggesting that the notion of clustering of organ-specific genes in animal genomes is not generally applicable to this chordate. PMID- 21328520 TI - Podosomal proteins as causes of human syndromes: a role in craniofacial development? AB - Podosomes and invadopodia are actin-rich protrusions of the plasma membrane important for matrix degradation and cell migration. Most of the information in this field has been obtained in cancer cells, where the presence of invadopodia has been related to increased invasiveness and metastatic potential. The importance of the related podosome structure in other pathological or physiological processes that require cell invasion is relatively unexplored. Recent evidence indicates that essential components of podosomes are responsible for several human syndromes, some of which are characterized by serious developmental defects involving the craniofacial area, skeleton and heart, and very poor prognosis. Here we will review them and discuss the possible role of podosomes as a player in correct embryo development. PMID- 21328519 TI - Taste bud cells of adult mice are responsive to Wnt/beta-catenin signaling: implications for the renewal of mature taste cells. AB - Wnt/beta-catenin signaling initiates taste papilla development in mouse embryos, however, its involvement in taste cell turnover in adult mice has not been explored. Here we used the BATGAL reporter mouse model, which carries an engineered allele in which the LacZ gene is expressed in the presence of activated beta-catenin, to determine the responsiveness of adult taste bud cells to canonical Wnt signaling. Double immunostaining with markers of differentiated taste cells revealed that a subset of Type I, II, and III taste cells express beta-galactosidase. Using in situ hybridization, we showed that beta-catenin activates the transcription of the LacZ gene mainly in intragemmal basal cells that are immature taste cells, identified by their expression of Sonic Hedgehog (Shh). Finally, we showed that beta-catenin activity is significantly reduced in taste buds of 25-week-old mice compared with 10-week-old animals. Our data suggest that Wnt/beta-catenin signaling may influence taste cell turnover by regulating cell differentiation. Reduced canonical Wnt signaling in older mice could explain in part the loss of taste sensitivity with aging, implicating a possible deficiency in the rate of taste cell renewal. More investigations are now necessary to understand if and how Wnt signaling regulates adult taste cell turnover. PMID- 21328521 TI - Generation and characterization of Col10a1-mcherry reporter mice. AB - We report here on the generation of a new fluorescent protein reporter transgenic mouse line, Col10a1-mCherry, which can be used as a tool to study chondrocyte biology and pathology. Collagen, Type X, alpha 1 (Col10a1) is highly expressed in hypertrophic chondrocytes and commonly used as a gene marker for this cell population. The Col10a1-mCherry reporter line was generated using a bacterial recombination strategy with the mouse BAC clone RP23-192A7. To aid in the characterization of this animal model, we intercrossed Col10a1-mCherry mice with Collagen, Type II, alpha 1 (Col2a1) enhanced cyan fluorescent protein (ECFP) reporter mice and characterized the expression of both chondrocyte reporters during embryonic skeletal development from days E10.5 to E17.5. Additionally, at postnatal day 0, Col10a1-mCherry reporter expression was compared to endogenous Col10a1 mRNA expression in long bones and revealed that mCherry fluorescence extended past the Col10a1 expression domain. However, in situ hybridization for mCherry was consistent with the zone of Col10a1 mRNA expression, indicating that the persistent detection of mCherry fluorescence was a result of the long protein half life of mCherry in conjunction with a very rapid phase of skeletal growth and not due to aberrant transcriptional regulation. Taking advantage of the continued fluorescence of hypertrophic chondrocytes at the chondro-osseus junction, we intercrossed Col10a1-mCherry mice with two different Collagen, Type 1, alpha 1, (Col1a1) osteoblast reporter mice, pOBCol3.6-Topaz and pOBCol2.3 Emerald to investigate the possibility that hypertrophic chondrocytes transdifferentiate into osteoblasts. Evaluation of long bones at birth suggests that residual hypertrophic chondrocytes and osteoblasts in the trabecular zone exist as two completely distinct cell populations. genesis 49:410-418, 2011. PMID- 21328522 TI - Comparison of 123I-metaiodobenzylguanidine (MIBG) and 131I-MIBG semi-quantitative scores in predicting survival in patients with stage 4 neuroblastoma: a report from the Children's Oncology Group. AB - BACKGROUND: 123I-metaiodobenzylguanidine (MIBG) scans are preferable to 131I-MIBG for neuroblastoma imaging as they deliver less patient radiation yet have greater sensitivity in disease detection. Both 123I-MIBG and 131I-MIBG scans were used for disease assessments of neuroblastoma patients enrolled on Children's Oncology Group (COG) high-risk study A3973. The hypothesis was that 123I-MIBG and 131I MIBG scans were sufficiently similar for clinical purposes in terms of ability to predict survival. PROCEDURE: Patients enrolled on COG A3973 with stage 4 disease who completed 123I-MIBG or 131I-MIBG scans at diagnosis, post-induction, post transplant, or post-biotherapy were analyzed. The performance of the Curie score for each MIBG scan type in predicting survival was evaluated. At each time point, survival curves for 123I-MIBG versus 131I-MIBG were compared using the log-rank test. RESULTS: Of the 413 patients on A3973 with at least one MIBG scan, 350 were stage 4. The 5-year event-free survival (EFS) and overall survival (OS) rates were 33.4 +/- 3.6% and 45.6 +/- 4.0% (N = 350). At post-induction, EFS (P = 0.3501) and OS (P = 0.5337) for 123I-MIBG versus 131I-MIBG were not significantly different. Similarly, comparisons at the three other time points were non significant. CONCLUSIONS: We found no evidence of a statistically significant difference in outcome by type of scan. For future survival analyses of MIBG Curie scores, 123I-MIBG and 131I-MIBG results may be combined and analyzed overall, without adjustment for scan type. PMID- 21328523 TI - Auditory complications in childhood cancer survivors: a report from the childhood cancer survivor study. AB - BACKGROUND: Studies have found associations between cancer therapies and auditory complications, but data are limited on long-term outcomes and risks associated with multiple exposures. PROCEDURE: The Childhood Cancer Survivor Study is a retrospective cohort investigating health outcomes of long-term survivors (5+ years) diagnosed and treated between 1970 and 1986 compared to a randomly selected sibling cohort. Questionnaires were completed by 14,358 survivors of childhood cancer and 4,023 sibling controls. Analysis determined the first occurrence of four auditory conditions in two time periods: diagnosis to 5 years post-diagnosis, and >= 5 years post-diagnosis. Multivariable analyses determined the relative risks (RR) and 95% confidence interval (CI) of auditory conditions by treatment exposure. RESULTS: Five or more years from cancer diagnosis, survivors were at increased risk of problems hearing sounds (RR = 2.3; 95% CI: 1.8-2.8), tinnitus (RR = 1.7; 95% CI: 1.4-2.1), hearing loss requiring an aid (RR = 4.4; 95% CI: 2.8-6.9), and hearing loss in 1 or both ears not corrected by a hearing aid (RR = 5.2; 95% CI: 2.8-9.5), when compared to siblings. Temporal lobe and posterior fossa radiation was associated with these outcomes in a dose dependent fashion. Exposure to platinum compounds was associated with an increased risk of problems hearing sounds (RR = 2.1; 95% CI: 1.3-3.2), tinnitus (RR = 2.8; 95% CI: 1.9-4.2), and hearing loss requiring an aid (RR = 4.1; 95% CI: 2.5-6.7). CONCLUSIONS: Childhood cancer survivors are at risk of developing auditory complications. Radiation and platinum compounds are determinants of this risk. Follow-up is needed to evaluate the impact of auditory conditions on quality of life. PMID- 21328524 TI - Perspectives on quality and content of information on the internet for adolescents with cancer. AB - OBJECTIVES: To assess the quality and content of Internet information about cancer from the perspectives of adolescents with cancer (AWC), their parents and healthcare professionals (HCP). METHODS: Key words relevant to pediatric cancer were searched across 6 search engines. Quality of information was appraised using the DISCERN tool. Website content completeness, accuracy, readability, cultural sensitivity, and desirability were assessed. RESULTS: Only 29 websites had DISCERN scores above 50 (indicating fair quality; mean 55.76 +/- 8.23, range 42.50-70.5). The majority of sites targeted parents and only four (14%) were specific to AWC. Overall completeness of the sites was rated 11.46 out of 20 (+/- 3.60; range 4-17.5) and accuracy was rated 4/4, indicating high accuracy with moderate completeness. The average SMOG score was 11.87 (+/- 2.51, range 7.7 18.67) and the Flesch Reading Ease score was 57.44 (+/- 16.94, range 9.1-92.4) indicating that the material was too difficult to read. The average cultural sensitivity scores for the Format, Written message and Visual material scales were 3.08/4 (+/- 0.53, range 2-4), 3.48/4 (+/- 0.41, range 2.6-4) and 2.84/4 (+/- 1.03, range 0-4) indicating the websites were adequately culturally sensitive. On Average, websites had 4/21 features from the desirability checklist, indicating the sites had low desirability. CONCLUSION: Given the paucity of high quality Internet health information at an appropriate reading level for AWC there is a critical need for HCP's to develop Internet programs to meet their unique needs. PMID- 21328527 TI - Evolution of developmental pattern for vertebrate dentitions: an oro-pharyngeal specific mechanism. AB - Classically the oral dentition with teeth regulated into a successional iterative order was thought to have evolved from the superficial skin denticles migrating into the mouth at the stage when jaws evolved. The canonical view is that the initiation of a pattern order for teeth at the mouth margin required development of a sub-epithelial, permanent dental lamina. This provided regulated tooth production in advance of functional need, as exemplified by the Chondrichthyes. It had been assumed that teeth in the Osteichthyes form in this way as in tetrapods. However, this has been shown not to be true for many osteichthyan fish where a dental lamina of this kind does not form, but teeth are regularly patterned and replaced. We question the evolutionary origin of pattern information for the dentition driven by new morphological data on spatial initiation of skin denticles in the catshark. We review recent gene expression data for spatio-temporal order of tooth initiation for Scyliorhinus canicula, selected teleosts in both oral and pharyngeal dentitions, and Neoceratodus forsteri. Although denticles in the chondrichthyan skin appear not to follow a strict pattern order in space and time, tooth replacement in a functional system occurs with precise timing and spatial order. We suggest that the patterning mechanism observed for the oral and pharyngeal dentition is unique to the vertebrate oro-pharynx and independent of the skin system. Therefore, co-option of a successional iterative pattern occurred in evolution not from the skin but from mechanisms existing in the oro-pharynx of now extinct agnathans. PMID- 21328525 TI - Disparities in cancer outcomes: lessons learned from children with cancer. AB - Disparities in cancer burden by race/ethnicity have been reported, primarily in adults with cancer. However, there appear to be gaps in the pediatric oncology literature with regards to a comprehensive overview on this topic. Extant literature is used to highlight the results of studies focusing on racial and ethnic disparities in outcome observed in selected childhood cancers. A comprehensive approach is utilized to understand possible underlying causes of disparities in cancer outcomes, and to highlight the gaps that currently exist. This review helps define areas of future research that could help develop targeted, disease-specific approaches to eliminate the disparities. PMID- 21328529 TI - Ontogeny of ENaC expression in the gills and the kidneys of the Japanese black salamander (Hynobius nigrescens Stejneger). AB - A full-length cDNA cloning and tissue distribution of epithelial sodium channel (ENaC) protein were studied during ontogeny by immunohistochemistry in the external gills, and the kidney, pronephros and mesonephros, of the Japanese black salamander, Hynobius nigrescens (Family Hynobiidae; a primitive caudate species). The amino acid sequence of Hynobius ENaCalpha is 64 and 63% identical to Bufo ENaCalpha and Rat ENaCalpha, respectively. In aquatic larva salamander at the digit differentiation stage, Hynobius ENaCalpha mRNA was expressed in the external gills and pronephros. In the adult, the mRNA was expressed in the skin and the mesonephros. In the larvae, juvenile, and adult specimens, Hynobius ENaCalpha immunoreactivity was observed at the apical cell membrane of the external gills, late parts of the distal tubules, and mesonephric duct in the kidney. Colocalization of the apical Hynobius ENaCalpha and the basolateral Na(+) ,K(+) -ATPase was observed in the tubular cells of pronephros and mesonephros. These results suggest that Hynobius ENaCalpha plays an important role in the regulation of sodium transport in the external gills and pronephros of aquatic larvae, and in the skin and mesonephros of terrestrial adult. This is the first study to indicate ENaC expression during ontogeny in amphibians. Since no orthologs or paralogs for ENaC have been found, so far, in databases of the genomes of teleosts, it is assumed that ENaC might have played a role in terrestriality during the evolution of early tetrapods, the origin of lissamphibians. PMID- 21328528 TI - Developmental transcriptome of Aplysia californica. AB - Genome-wide transcriptional changes in development provide important insight into mechanisms underlying growth, differentiation, and patterning. However, such large-scale developmental studies have been limited to a few representatives of Ecdysozoans and Chordates. Here, we characterize transcriptomes of embryonic, larval, and metamorphic development in the marine mollusc Aplysia californica and reveal novel molecular components associated with life history transitions. Specifically, we identify more than 20 signal peptides, putative hormones, and transcription factors in association with early development and metamorphic stages-many of which seem to be evolutionarily conserved elements of signal transduction pathways. We also characterize genes related to biomineralization-a critical process of molluscan development. In summary, our experiment provides the first large-scale survey of gene expression in mollusc development, and complements previous studies on the regulatory mechanisms underlying body plan patterning and the formation of larval and juvenile structures. This study serves as a resource for further functional annotation of transcripts and genes in Aplysia, specifically and molluscs in general. A comparison of the Aplysia developmental transcriptome with similar studies in the zebra fish Danio rerio, the fruit fly Drosophila melanogaster, the nematode Caenorhabditis elegans, and other studies on molluscs suggests an overall highly divergent pattern of gene regulatory mechanisms that are likely a consequence of the different developmental modes of these organisms. PMID- 21328531 TI - Testing evolutionary hypotheses about the phylotypic period of zebrafish. AB - Vertebrate embryos pass through a period of morphological similarity, the phylotypic period. Since Haeckel's biogenetic law of recapitulation, proximate and ultimate evolutionary causes of such similarity of embryos were discussed. We test predictions about changes in phenotypic and genetic variances that were derived from three hypotheses about the evolutionary origin of the phylotypic stage, i.e. random, epigenetic effects, and stabilizing selection. The random hypothesis predicts increasing values for phenotypic variances and stable or increasing values for genetic variances; the epigenetic effects hypothesis predicts declining values for phenotypic variances but stable or increasing values of genetic variances, and the stabilizing selection predicts stable phenotypic variances but decreasing genetic variances. We studied zebrafish as a model species, because it can be bred in large numbers as necessary for a quantitative genetics breeding design. A half-sib breeding scheme provided estimates of additive genetic variances from 11 embryonic characters from 12 through to 24 hr after fertilization, i.e. before, during (15-19 hr), and after the phylotypic period. Because additive genetic variances are size dependent, we calculated narrow-sense heritabilities as a size independent gauge of genetic contributions to the phenotype. The results show declining phenotypic variances and stable heritabilities. In conclusion, we reject the random and the stabilizing selection hypotheses and favor ideas about epigenetic effects that constrain the early embryonic development. Additive genetic variance during the phylotypic stage makes it accessible for evolution, thus explaining in a simple and straightforward way why the phylotypic period differs among vertebrates in timing, duration, and morphologies. PMID- 21328530 TI - Developmental and genetic origins of murine long bone length variation. AB - If we wish to understand whether development influences the rate or direction of morphological evolution, we must first understand the developmental bases of morphological variation within species. However, quantitative variation in adult morphology is the product of molecular and cellular processes unfolding from embryonic development through juvenile growth to maturity. The Atchley-Hall model provides a useful framework for dissecting complex morphologies into their component parts as a way of determining which developmental processes contribute to variation in adult form. We have examined differences in postnatal allometry and the patterns of genetic correlation between age-specific traits for ten recombinant inbred strains of mice generated from an intercross of LG/J and SM/J. Long bone length is closely tied to body size, but variation in adult morphology is more closely tied to differences in growth rate between 3 and 5 weeks of age. These analyses show that variation generated during early development is overridden by variation generated later in life. To more precisely determine the cellular processes generating this variation we then examined the cellular dynamics of long bone growth plates at the time of maximum elongation rate differences in the parent strains. Our analyses revealed that variation in long bone length is the result of faster elongation rates of the LG/J stain. The developmental bases for these differences in growth rate involve the rate of cell division and chondrocyte hypertrophy in the growth plate. PMID- 21328532 TI - Quantification of branched-chain amino acids in blood spots and plasma by liquid chromatography tandem mass spectrometry for the diagnosis of maple syrup urine disease. AB - Individuals with maple syrup urine disease (MSUD) have an inherited metabolic disorder resulting in a deficiency in the branched-chain keto-acid dehydrogenase complex. As a result, these individuals have elevated concentrations of the branched-chain amino acids valine, isoluecine, allo-isoleucine, and leucine. MSUD presents in the first few days of life and progression may lead to irreversible intellectual disability, coma, cerebral edema, and death. However, early diagnosis and intervention can mitigate or eliminate many of the potential adverse effects. Consequently, it is important to develop techniques to screen for MSUD. We have developed an LC-MS/MS assay for the diagnosis of MSUD. The method is amenable to high-throughput formats due to the minimal sample prep required. The assay was shown to be robust, precise, and accurate. Finally, we identified and addressed some of the problems associated with working with bloodspots and implemented satisfactory approaches to overcoming these problems. PMID- 21328533 TI - Ultrasonication extraction coupled with magnetic solid-phase clean-up for the determination of polycyclic aromatic hydrocarbons in soils by high-performance liquid chromatography. AB - C18-functionalized magnetic microspheres synthesized in a three-stage system and characterized by Fourier transform infrared (FTIR) spectroscopy and SEM were applied for clean-up and enrichment of polycyclic aromatic hydrocarbons (PAHs) in soil samples combined with ultrasonication extraction. Magnetic solid-phase extraction (MSPE) parameters, such as elution solvents, amounts of sorbents, enrichment time and organic modifier, were optimized together with ultrasonication time and extraction solvents. Under the optimal conditions, the developed method provided spiked recoveries of 63.2-92.8% with RSDs of less than 6.4% and limits of detection were 0.5-1.0 ng/g. This new method provides several advantages, such as high extraction efficiency, convenient extraction procedure and short analysis times. Finally, the method was successfully applied to the determination of polycyclic aromatic hydrocarbons in soil samples. PMID- 21328534 TI - Chromatographic fingerprint analysis and simultaneous determination of eight lignans in Justicia procumbens and its compound preparation by HPLC-DAD. AB - HPLC fingerprints were developed for the quality evaluation of Justicia procumbens and its compound preparation, Jian-er syrup, together with the simultaneous quantification of eight arylnaphthalide lignans (6'-hydroxy justicidin B, 6'-hydroxy justicidin A, 6'-hydroxy justicidin C, justicidin B, chinensinaphthol methyl ether, justicidin C, taiwanin C, and neojusticin A). Samples were separated with a Shiseido Capcell Pak C(18) reversed-phase column (250*4.6 mm id, 5 MUm) using acetonitrile and water as the mobile phase. The column temperature was maintained at 35 degrees C and the wavelength of detector was set at 256 nm. For fingerprint analysis, 17 peaks were selected as the characteristic peaks for the evaluation of the similarities among different J. procumbens samples collected in different places. The structures of lignans were confirmed by diagnostic fragments in the positive ESI-MS(n) . The new method was successfully applied for the chromatographic fingerprint analysis and simultaneous determination of eight lignans in its compound preparation, Jian-er syrup. All the results indicated that HPLC fingerprint assay in combination with multi-marker determination afforded a useful method for the quality control of J. procumbens and its compound preparation, Jian-er syrup. PMID- 21328535 TI - Functionalized polymeric stationary phases for ion chromatography. AB - Synthesis and properties of the multilayered stationary phases, which contain quaternary amine functional groups for the analysis of anions by ion chromatography, are described. The bonded phases were characterized by elemental analysis, solid-state (13)C NMR spectroscopy and chromatographic methods. The surface of 1,4-di(2-hydroxy-3-methacryloyloxypropoxy)phenol (solid support) was coated with polymeric layers formed by condensation polymerization of primary amine with diepoxide. Each layer of the anion exchange stationary phase consists of copolymer of methylamine (MA) and 1,4-butanedioldiglycidyl ether (BDDE). A series of stationary phases with different numbers of polymerized layers were tested. The separation of an inorganic anions sample (F(-), Cl(-), NO(2)(-), Br( ), NO(3)(-), additionally HPO(4)(2-) and SO(4)(2-)) was performed. In the measurement, a hydroxide, carbonate, bicarbonate and their mixture were used as mobile phases. PMID- 21328536 TI - Separation behavior of U(VI) and Th(IV) on a cation exchange column using 2,6 pyridine dicarboxylic acid as a complexing agent and its application for the rapid separation and determination of U and Th by ion chromatography. AB - The retention behavior of U and Th as their 2,6-pyridine dicarboxylic acid (PDCA) complexes on a cation exchange column was investigated under low pH conditions. Based on the observed retention characteristics, an ion chromatographic method for the rapid separation of uranium and thorium in isocratic elution mode using 0.08 mM PDCA and 0.24 M KNO(3) in 0.22 M HNO(3) as the eluent was developed. Both uranium and thorium were eluted as their PDCA complexes within 2 min, whereas the transition and lanthanide metal cations were eluted as an unresolved broad peak after thorium. Under the optimized conditions both U and Th have no interference either from alkali and alkaline earth elements up to a concentration ratio of 1:500 or from other elements up to 1:100. The detection limits (LOD) of U and Th were calculated as 0.04 and 0.06 ppm, respectively (S/N=3). The precision in the measurement of peak area of 0.5 ppm of both U and Th was better than 5% and a linear calibration in the concentration range of 0.25-25 ppm of U and Th was obtained. The method was successfully applied to determine U and Th in effluent water samples. PMID- 21328537 TI - Toward a standardized urine proteome analysis methodology. AB - Urine is an easily accessible bodily fluid particularly suited for the routine clinical analysis of disease biomarkers. Actually, the urinary proteome is more diverse than anticipated a decade ago. Hence, significant analytical and practical issues of urine proteomics such as sample collection and preparation have emerged, in particular for large-scale studies. We have undertaken a systematic study to define standardized and integrated analytical protocols for a biomarker development pipeline, employing two LC-MS analytical platforms, namely accurate mass and time tags and selected reaction monitoring, for the discovery and verification phase, respectively. Urine samples collected from hospital patients were processed using four different protocols, which were evaluated and compared on both analytical platforms. Addition of internal standards at various stages of sample processing allowed the estimation of protein extraction yields and the absolute quantification of selected urinary proteins. Reproducibility of the entire process and dynamic range of quantification were also evaluated. Organic solvent precipitation followed by in-solution digestion provided the best performances and was thus selected as the standard method common to the discovery and verification phases. Finally, we applied this protocol for platforms' cross validation and obtained excellent consistency between urinary protein concentration estimates by both analytical methods performed in parallel in two laboratories. PMID- 21328538 TI - Quality control of nano-LC-MS systems using stable isotope-coded peptides. AB - In analytical sciences, there is a general need for quality control to assess whether a product or a process meets defined requirements. Especially in proteomics, which implies analysis of ten thousands of analytes within a complex mixture, quality control to validate LC-MS performance and method setup is inevitable to achieve day-to-day-, inter-system-, as well as inter-user reproducibility. Thus, results deriving from LC-MS analyses can be benchmarked and the need for system maintenance can be revealed. In particular with the advent of label-free quantification of peptides and proteins, which above all depends on highly stable and reproducible LC separations, HPLC performance has to be appropriately monitored throughout the entire analytical procedure to assure quality and validity of the obtained data. Oftentimes, proteolytic digests of standard proteins are used in this context; however, this approach implies some limitations, such as inadequate batch-to-batch reproducibility, limited (if any) dynamic range and compositional inflexibility. Here, we present an alternative strategy of nano-LC-MS/MS quality control based on a mixture of synthetic peptides covering the entire LC-gradient as well as a dynamic range of more than two orders of magnitude. Thus, (i) reproducibility of LC separation, (ii) MS performance (including limit of detection, identification and quantification), as well as (iii) overall nano-LC-MS system performance and reproducibility can be routinely monitored even in highly complex samples. PMID- 21328539 TI - A global analysis of peptide fragmentation variability. AB - Understanding the fragmentation process in MS/MS experiments is vital when trying to validate the results of such experiments, and one way of improving our understanding is to analyze existing data. We here present our findings from an analysis of a large and diverse data set of MS/MS-based peptide identifications, in which each peptide has been identified from multiple spectra, recorded on two commonly used types of electrospray instruments. By analyzing these data we were able to study fragmentation variability on three levels: (i) variation in detection rates and intensities for fragment ions from the same peptide sequence measured multiple times on a single instrument; (ii) consistency of rank-based fragmentation patterns; and (iii) a set of general observations on fragment ion occurrence in MS/MS experiments, regardless of sequence. Our results confirm that substantial variation can be found at all levels, even when high-quality identifications are used and the experimental conditions as well as the peptide sequences are kept constant. Finally, we discuss the observed variability in light of ongoing efforts to create spectral libraries and predictive software for target selection in targeted proteomics. PMID- 21328540 TI - iTRAQ protein quantification: a quality-controlled workflow. AB - Reporter ion-based methods are among the major techniques to quantify peptides and proteins. Two main labels, tandem mass tag (TMT) and iTRAQ, are widely used by the proteomics community. They are, however, often applied as out-of-the-box methods, without thorough quality control. Thus, due to undiscovered limitations of the technique, irrelevant results might be trusted. To address this issue, we here propose a step-by-step quality control of the iTRAQ workflow. From sample preparation to final ratio calculation we provide metrics and techniques assessing the actual effectiveness of iTRAQ quantification as well as a novel method for more reliable protein ratio estimation. PMID- 21328541 TI - Disruption of the SapM locus in Mycobacterium bovis BCG improves its protective efficacy as a vaccine against M. tuberculosis. AB - Mycobacterium bovis bacille Calmette-Guerin (BCG) provides only limited protection against pulmonary tuberculosis. We tested the hypothesis that BCG might have retained immunomodulatory properties from its pathogenic parent that limit its protective immunogenicity. Mutation of the molecules involved in immunomodulation might then improve its vaccine potential. We studied the vaccine potential of BCG mutants deficient in the secreted acid phosphatase, SapM, or in the capping of the immunomodulatory ManLAM cell wall component with alpha-1,2 oligomannoside. Both systemic and intratracheal challenge of mice with Mycobacterium tuberculosis following vaccination showed that the SapM mutant, compared to the parental BCG vaccine, provided better protection: it led to longer-term survival. Persistence of the SapM-mutated BCG in vivo resembled that of the parental BCG indicating that this mutation will likely not compromise the safety of the BCG vaccine. The SapM mutant BCG vaccine was more effective than the parental vaccine in inducing recruitment and activation of CD11c(+) MHC II(int) CD40(int) dendritic cells (DCs) to the draining lymph nodes. Thus, SapM acts by inhibiting recruitment of DCs and their activation at the site of vaccination. PMID- 21328542 TI - ZNF703 gene amplification at 8p12 specifies luminal B breast cancer. AB - Luminal B breast cancers represent a fraction of oestrogen receptor (ER)-positive tumours associated with poor recurrence-free and disease-specific survival in all adjuvant systemic treatment categories including hormone therapy alone. Identification of specific signalling pathways driving luminal B biology is paramount to improve treatment. We have studied 100 luminal breast tumours by combined analysis of genome copy number aberrations and gene expression. We show that amplification of the ZNF703 gene, located in chromosomal region 8p12, preferentially occurs in luminal B tumours. We explored the functional role of ZNF703 in luminal B tumours by overexpressing ZNF703 in the MCF7 luminal cell line. Using mass spectrometry, we identified ZNF703 as a co-factor of a nuclear complex comprising DCAF7, PHB2 and NCOR2. ZNF703 expression results in the activation of stem cell-related gene expression leading to an increase in cancer stem cells. Moreover, we show that ZNF703 is implicated in the regulation of ER and E2F1 transcription factor. These findings point out the prominent role of ZNF703 in transcription modulation, stem cell regulation and luminal B oncogenesis. PMID- 21328544 TI - Prospects for microbial biodiesel production. AB - As the demand for biofuels for transportation is increasing, it is necessary to develop technologies that will allow for low-cost production of biodiesel. Conventional biodiesel is mainly produced from vegetable oil by chemical transesterification. This production, however, has relatively low land-yield and is competing for agricultural land that can be used for food production. Therefore, there is an increasing interest in developing microbial fermentation processes for production of biodiesel as this will allow for the use of a wide range of raw-materials, including sugar cane, corn, and biomass. Production of biodiesel by microbial fermentation can be divided into two different approaches, (1) indirect biodiesel production from oleaginous microbes by in vitro transesterification, and (2) direct biodiesel production from redesigned cell factories. This work reviews both microbial approaches for renewable biodiesel production and evaluates the existing challenges in these two strategies. PMID- 21328543 TI - Hyaline fibromatosis syndrome inducing mutations in the ectodomain of anthrax toxin receptor 2 can be rescued by proteasome inhibitors. AB - Hyaline Fibromatosis Syndrome (HFS) is a human genetic disease caused by mutations in the anthrax toxin receptor 2 (or cmg2) gene, which encodes a membrane protein thought to be involved in the homeostasis of the extracellular matrix. Little is known about the structure and function of the protein or the genotype-phenotype relationship of the disease. Through the analysis of four patients, we identify three novel mutants and determine their effects at the cellular level. Altogether, we show that missense mutations that map to the extracellular von Willebrand domain or the here characterized Ig-like domain of CMG2 lead to folding defects and thereby to retention of the mutated protein in the endoplasmic reticulum (ER). Mutations in the Ig-like domain prevent proper disulphide bond formation and are more efficiently targeted to ER-associated degradation. Finally, we show that mutant CMG2 can be rescued in fibroblasts of some patients by treatment with proteasome inhibitors and that CMG2 is then properly transported to the plasma membrane and signalling competent, identifying the ER folding and degradation pathway components as promising drug targets for HFS. PMID- 21328545 TI - Opportunities for yeast metabolic engineering: Lessons from synthetic biology. AB - Constant progress in genetic engineering has given rise to a number of promising areas of research that facilitated the expansion of industrial biotechnology. The field of metabolic engineering, which utilizes genetic tools to manipulate microbial metabolism to enhance the production of compounds of interest, has had a particularly strong impact by providing new platforms for chemical production. Recent developments in synthetic biology promise to expand the metabolic engineering toolbox further by creating novel biological components for pathway design. The present review addresses some of the recent advances in synthetic biology and how these have the potential to affect metabolic engineering in the yeast Saccharomyces cerevisiae. While S. cerevisiae for years has been a robust industrial organism and the target of multiple metabolic engineering trials, its potential for synthetic biology has remained relatively unexplored and further research in this field could strongly contribute to industrial biotechnology. This review also addresses are general considerations for pathway design, ranging from individual components to regulatory systems, overall pathway considerations and whole-organism engineering, with an emphasis on potential contributions of synthetic biology to these areas. Some examples of applications for yeast synthetic biology and metabolic engineering are also discussed. PMID- 21328546 TI - Mutation detection in plasmid-based biopharmaceuticals. AB - As the number of applications involving therapeutic plasmid DNA (pDNA) increases worldwide, there is a growing concern over maintaining rigorous quality control through a panel of high-quality assays. For this reason, efficient, cost effective and sensitive technologies enabling the identification of genetic variants and unwanted side products are needed to successfully establish the identity and stability of a plasmid-based biopharmaceutical. This review highlights several bioinformatic tools for ab initio detection of potentially unstable DNA regions, as well as techniques used for mutation detection in nucleic acids, with particular emphasis on pDNA. PMID- 21328547 TI - Editorial: A current perspective on photocatalysis. PMID- 21328549 TI - Remarkable improvement of the photocatalytic activity of Ga2O3 towards the overall splitting of H2O. PMID- 21328550 TI - Electrocatalytic carbon dioxide activation: the rate-determining step of pyridinium-catalyzed CO2 reduction. AB - The reactivity of reduced pyridinium with CO(2) was investigated as a function of catalyst concentration, temperature, and pressure at platinum electrodes. Concentration experiments show that the catalytic current measured by cyclic voltammetry increases linearly with pyridinium and CO(2) concentrations; this indicates that the rate-determining step is first order in both. The formation of a carbamate intermediate is supported by the data presented. Increased electron density at the pyridyl nitrogen upon reduction, as calculated by DFT, favors a Lewis acid/base interaction between the nitrogen and the CO(2). The rate of the known side reaction, pyridinium coupling to form hydrogen, does not vary over the temperature range investigated and had a rate constant of 2.5 M(-1) s(-1). CO(2) reduction followed Arrhenius behavior and the activation energy determined by electrochemical simulation was (69+/-10) kJ mol(-1). PMID- 21328551 TI - Effects of distortion of metal-oxygen octahedra on photocatalytic water-splitting performance of RuO2-loaded niobium and tantalum phosphate bronzes. AB - Sodium, niobium, and tantalum phosphate bronzes Na(4)M(8)P(4)O(32) (M=Nb, Ta) are employed as photocatalysts for water splitting to reveal the effects of the distortion of metal-oxygen octahedra on the photocatalytic performance. Addition of RuO(2) as a co-catalyst leads to high, stable activity in the stoichiometric production of H(2) and O(2) under UV irradiation. The combination of highly crystallized phosphates and a high dispersion of RuO(2) particles result in high photocatalytic activity. The sodium niobium phosphate bronze Na(2)Nb(8)P(4)O(32), consisting of a framework built up from slabs of corner-sharing NbO(6) octahedra connected through isolated PO(4) tetrahedra, provide heavily distorted NbO(6) octahedra with large internal dipole moments. The results support the existing view that the activity correlates with the magnitude of the dipole moment. The heavy distortion of NbO(6) octahedra is shown to play a significant role in photocatalytic water splitting. PMID- 21328552 TI - Interfacial electron transfer dynamics following laser flash photolysis of [Ru(bpy)2((4,4'-PO3H2)2bpy)]2+ in TiO2 nanoparticle films in aqueous environments. AB - Nanosecond laser flash photolysis has been used to investigate injection and back electron transfer from the complex [(Ru(bpy)(2)(4,4'-(PO(3)H(2))(2)bpy)](2+) surface-bound to TiO(2) (TiO(2)-Ru(II)). The measurements were conducted under conditions appropriate for water oxidation catalysis by known single-site water oxidation catalysts. Systematic variations in average lifetimes for back electron transfer, , were observed with changes in pH, surface coverage, incident excitation intensity, and applied bias. The results were qualitatively consistent with a model involving rate-limiting thermal activation of injected electrons from trap sites to the conduction band or shallow trap sites followed by site-to-site hopping and interfacial electron transfer, TiO(2)(e(-))-Ru(3+) -> TiO(2)-Ru(2+). The appearance of pH-dependent decreases in the efficiency of formation of TiO(2)-Ru(3+) and in incident-photon-to-current efficiencies with the added reductive scavenger hydroquinone point to pH-dependent back electron transfer processes on both the sub-nanosecond and millisecond-microsecond time scales, which could be significant in limiting long-term storage of multiple redox equivalents. PMID- 21328554 TI - A structurally diverse Ru(II),Pt(II) tetrametallic motif for photoinitiated electron collection and photocatalytic hydrogen production. AB - Coupling a reactive metal to light absorbers affords molecular devices for photoinitiated electron collection and photocatalytic conversion of substrates to fuels. A new Ru(II),Pt(II) tetrametallic supramolecule, [{(phen)(2)Ru(dpp)}(2)Ru(dpq)PtCl(2)](PF(6))(6), and the trimetallic precursors, [{(phen)(2)Ru(dpp)}(2)RuCl(2)](PF(6))(4) and [{(phen)(2)Ru(dpp)}(2)Ru(dpq)](PF(6))(6), have been synthesized, and their redox, spectroscopic, spectroelectrochemical, photophysical and photocatalytic properties studied. They efficiently absorb UV and visible light. The electrochemistry of [{(phen)(2)Ru(dpp)}(2)Ru(dpq)PtCl(2)](PF(6))(6) suggests a lowest-lying terminal Ru->dpq charge-separated state that quenches the emission of the parent complex with non-unity population of the emissive (3)MLCT excited state. Photolysis of [{(phen)(2)Ru(dpp)}(2)Ru(dpq)PtCl(2)](6+) at 470 nm with DMA gives multielectron reduction, storing electrons in a new manner on the central (dpp)(2)Ru(II)(dpq) moiety. Addition of H(2)O to the photolysis system produces 21 MUmol of H(2) in 5 h, with 115 turnovers of the tetrametallic photocatalyst. PMID- 21328553 TI - Ce(IV)- and light-driven water oxidation by [Ru(terpy)(pic)3]2+ analogues: catalytic and mechanistic studies. AB - A series of mononuclear ruthenium polypyridyl complexes [Ru(Mebimpy)(pic)(3)](PF(6))(2) (2; Mebimpy = 2,6-bis(1-methylbenzimidazol-2 yl)pyridine; pic = 4-picoline), Ru(bimpy)(pic)(3) (3; H(2)bimpy = 2,6 bis(benzimidazol-2-yl)pyridine), trans-[Ru(terpy)(pic)(2)Cl](PF(6)) (4; terpy = 2,2';6',2"-terpyridine), and trans-[Ru(terpy)(pic)(2)(OH(2))](ClO(4))(2) (5) are synthesized and characterized as analogues of the known Ru complex, [Ru(terpy)(pic)(3)](PF(6))(2) (1). The effect of the ligands on electronic and catalytic properties is studied and discussed. The negatively charged ligand, bimpy(2-), has a remarkable influence on the electrochemical events due to its strong electron-donating ability. The performance in light- and Ce(IV)-driven (Ce(IV) = Ce(NH(4))(2)(NO(3))(6)) water oxidation is successfully demonstrated. We propose that ligand exchange between pic and H(2)O occurs to form the real catalyst, a Ru-aqua complex. The synthesis and testing of trans [Ru(terpy)(pic)(2)(OH(2))](ClO(4))(2) (5) confirmed our proposal. In addition, complex 5 possesses the best catalytic activity among these five complexes. PMID- 21328555 TI - Photoreduction of water by using modified CuInS2 electrodes. AB - Polycrystalline CuInS(2) films were fabricated by sulfurization of electrodeposited Cu and In metallic precursor films. Structural analyses revealed that the CuInS(2) film formed compact agglomerates of crystallites with grain sizes of ca. 0.5-1.5 MUm. Photoelectrochemical characterization revealed that the film was p-type with a flat band potential of 0.3-0.4 V (vs Ag/AgCl at pH 4), which is suitable for water reduction but cannot be for water oxidation. Upon loading Pt deposits, the film worked as a hydrogen (H(2)) liberation electrode under cathodic polarization. Moreover, by introduction of n-type thin layers such as CdS and ZnS on the CuInS(2) surface before the Pt loading, appreciable improvements of H(2) liberation efficiency were achieved: for the CdS modified sample, spectral response data showed incident photon to current efficiency as high as 20 % at wavelengths ranging from ca. 500 to 750 nm. Appreciable H(2) evolution on this sample under potentials of power-producing regions was also confirmed. PMID- 21328558 TI - Seasonality and fasting effect in raccoon dog Nyctereutes procyonoides serum leptin levels determined by canine leptin-specific enzyme-linked immunosorbent assay. AB - Leptin is an adipocyte-derived peptide hormone that acts on the brain and regulates food intake and energy balance. Several previous reports have suggested that overwintering raccoon dogs Nyctereutes procyonoides are able to control their adiposity efficiently, but the contribution of leptin to weight regulation in these animals remains unclear. To study the seasonality of overwintering raccoon dogs as well as the effects of fasting on them, serum leptin levels were investigated using a newly established canine leptin-specific enzyme-linked immunosorbent assay (ELISA) kit. Of the nine animals studied, five were fed and four were fasted (deprived of food for 2 months in winter). Blood samples and body fat weights were monitored once a month throughout the experimental period (July 2007-March 2008). Leptin concentrations obtained by ELISA were significantly higher than and had a positive correlation with those obtained by previously used multispecies radioimmunoassay (RIA) kits. Moreover, ELISA showed a clearer correlation between the body fat weight and leptin levels compared with RIA, suggesting the efficacy of canine leptin-specific ELISA kit for leptin estimation in raccoon dogs. Autumnal fattening was observed in both groups of animals, but the wintertime loss of adipose tissue was more obvious in the fasted group. Serum leptin concentrations determined by ELISA showed seasonal changes without significant differences between the fed and fasted animals. Therefore, high levels of leptin may be responsible for the suppression of feeding behavior in raccoon dogs before winter. PMID- 21328559 TI - CiMT-1, an unusual chordate metallothionein gene in Ciona intestinalis genome: structure and expression studies. AB - The present article reports on the characterization of the urochordate metallothionein (MT) gene, CiMT-1, from the solitary ascidian Ciona intestinalis. The predicted protein is shorter than other known deuterostome MTs, having only 39 amino acids. The gene has the same tripartite structure as vertebrate MTs, with some features resembling those of echinoderm MTs. The promoter region shows the canonical cis-acting elements recognized by transcription factors that respond to metal, ROS, and cytokines. Unusual sequences, described in fish and echinoderms, are also present. In situ hybridization suggests that only a population of hemocytes involved in immune responses, i.e. granular amebocytes, express CiMT-1 mRNA. These observations support the idea that urochordates perform detoxification through hemocytes, and that MTs may play important roles in inflammatory humoral responses in tunicates. The reported data offer new clues for better understanding the evolution of these multivalent proteins from non vertebrate to vertebrate chordates and reinforce their functions in detoxification and immunity. PMID- 21328560 TI - Circulating carotenoid concentrations are positively correlated with later clutch initiation in Florida Scrub-Jays (Aphelocoma coerulescens). AB - Antioxidants play key roles in preventing free radical damage to various molecules, cells, and tissues, but it is not well understood how variation in antioxidant levels may relate to the reproductive success or health of wild animals. We explored the relationship between circulating antioxidant concentrations and both body condition and timing of reproduction in male and female Florida Scrub-Jays (Aphelocoma coerulescens), a cooperatively breeding passerine bird. We examined whether levels of uric acid, vitamin E, and carotenoids (all potentially important antioxidants) were linked to body condition and timing of reproduction, two measures that are directly related to reproductive success. Antioxidant concentrations were not correlated with body condition, but they were related to timing of first clutch initiation, though not always in the predicted direction. Elevated circulating levels of carotenoids were associated with delayed clutch initiation in female breeders. Relatively higher vitamin E levels in control birds were associated with earlier clutch initiation, whereas male breeders that received long-term food supplementation had elevated levels of vitamin E and delayed reproduction. Several potential explanations for the link between elevated levels of antioxidants and delayed clutch initiation are discussed. Separate explanations for each sex include, but are not limited to, oxidative stress as a result of territory defense efforts in males, different dietary regimes due to supplementation, and mobilized plasma antioxidants in females that were coping with a stressor. PMID- 21328562 TI - Reply to: The development of the human anorectum. PMID- 21328561 TI - A genome-wide linkage scan for quantitative trait loci influencing the craniofacial complex in humans (Homo sapiens sapiens). AB - The genetic architecture of the craniofacial complex has been the subject of intense scrutiny because of the high frequency of congenital malformations. Numerous animal models have been used to document the early development of the craniofacial complex, but few studies have focused directly on the genetic underpinnings of normal variation in the human craniofacial complex. This study examines 80 quantitative traits derived from lateral cephalographs of 981 participants in the Fels Longitudinal Study, Wright State University, Dayton, Ohio. Quantitative genetic analyses were conducted using the Sequential Oligogenic Linkage Analysis Routines analytic platform, a maximum-likelihood variance components method that incorporates all familial information for parameter estimation. Heritability estimates were significant and of moderate to high magnitude for all craniofacial traits. Additionally, significant quantitative trait loci (QTL) were identified for 10 traits from the three developmental components (basicranium, splanchnocranium, and neurocranium) of the craniofacial complex. These QTL were found on chromosomes 3, 6, 11, 12, and 14. This study of the genetic architecture of the craniofacial complex elucidates fundamental information of the genetic architecture of the craniofacial complex in humans. PMID- 21328563 TI - Cranial suture biology of the Aleutian Island inhabitants. AB - Research on cranial suture biology suggests there is biological and taxonomic information to be garnered from the heritable pattern of suture synostosis. Suture synostosis along with brain growth patterns, diet, and biomechanical forces influence phenotypic variability in cranial vault morphology. This study was designed to determine the pattern of ectocranial suture synostosis in skeletal populations from the Aleutian Islands. We address the hypothesis that ectocranial suture synostosis pattern will differ according to cranial vault shape. Ales Hrdlicka identified two phenotypes in remains excavated from the Aleutian Island. The Paleo-Aleutians, exhibiting a dolichocranic phenotype with little prognathism linked to artifacts distinguished from later inhabitants, Aleutians, who exhibited a brachycranic phenotype with a greater amount of prognathism. A total of 212 crania representing Paleo-Aleuts and Aleutian as defined by Hrdlicka were investigated for suture synostosis pattern following standard methodologies. Comparisons were performed using Guttmann analyses. Results revealed similar suture fusion patterns for the Paleo-Aleut and Aleutian, a strong anterior to posterior pattern of suture fusion for the lateral-anterior suture sites, and a pattern of early termination at the sagittal suture sites for the vault. These patterns were found to differ from that reported in the literature. Because these two populations with distinct cranial shapes exhibit similar patterns of suture synostosis it appears pattern is independent of cranial shape in these populations of Homo sapiens. These findings suggest that suture fusion patterns may be population dependent and that a standardized methodology, using suture fusion to determine age-at-death, may not be applicable to all populations. PMID- 21328564 TI - Exploring femoral diaphyseal shape variation in wild and captive chimpanzees by means of morphometric mapping: a test of Wolff's law. AB - Long bone shafts (diaphyses) serve as load-bearing structures during locomotion, implying a close relationship between diaphyseal form and its locomotor function. Diaphyseal form-function relationships, however, are complex, as they are mediated by various factors such as developmental programs, evolutionary adaptation, and functional adaptation through bone remodeling during an individual's lifetime. The effects of the latter process ("Wolff's Law") are best assessed by comparing diaphyseal morphologies of conspecific individuals under different locomotor regimes. Here we use morphometric mapping (MM) to analyze the morphology of entire femoral diaphyses in an ontogenetic series of wild and captive common chimpanzees (Pan troglodytes troglodytes). MM reveals patterns of variation of diaphyseal structural and functional properties, which cannot be recognized with conventional cross-sectional analysis and/or geometric morphometric methods. Our data show that diaphyseal shape, cortical bone distribution and inferred cross-sectional biomechanical properties vary both along ontogenetic trajectories and independent of ontogeny. Mean ontogenetic trajectories of wild and captive chimpanzees, however, were found to be statistically identical. This indicates that the basic developmental program of the diaphysis is not altered by different loading conditions. Significant differences in diaphyseal shape between groups could only be identified in the distal diaphysis, where wild chimpanzees exhibit higher mediolateral relative to anteroposterior cortical bone thickness. Overall, thus, the hypothesis that Wolff's Law predominantly governs long bone diaphyseal morphology is rejected. PMID- 21328565 TI - Different localization of ATP sensitive K+ channel subunits in rat testis. AB - ATP sensitive K(+) (K(ATP) ) channels are important linkage of cell membrane excitability to its cellular bioenergetic state. These channels are composed of pore-forming subunits and regulatory subunits. The present study focused on the cellular expressions and localizations of these subunits in rat testis. RT-PCR analysis showed that rat testis contained five K(ATP) channel subunits, Kir6.1, Kir6.2, SUR1, SUR2A and SUR2B. Immunoblot assay showed that proteins of Kir6.1, Kir6.2, SUR2A and SUR2B were expressed in rat testis. Immunohistochemistry revealed these K(ATP) channel subunits were positive in different localizations of spermatogenic cells, Sertoli cells and Leydig cells, which implies these subunits playing important roles in spermatogenesis. Co-localization of Kir6.2 with SUR2B was determined in acrosome or head cap of spermatids by double immunofluorescence analysis by indicating K(ATP) channel might be formed by Kir6.2 and SUR2B in acrosome of spermatids. Different localizations of the K(ATP) channel subunits in the cell membrane and membranous organelles of spermatogenic cells and Sertoli cells indicated the complex and multiple functions of K(ATP) channels in rat testis. PMID- 21328566 TI - PAX8 is expressed in pancreatic well-differentiated neuroendocrine tumors and in extrapancreatic poorly differentiated neuroendocrine carcinomas in fine-needle aspiration biopsy specimens. AB - BACKGROUND: PAX (paired box) genes encode a family of transcription factors important for organogenesis. Recently, PAX8 has been recognized as a potential immunohistochemical marker of pancreatic neuroendocrine tumors. The authors evaluated PAX8 expression in fine-needle aspiration biopsies of neuroendocrine tumors to establish whether PAX8 immunohistochemistry can be used as an ancillary marker of pancreatic origin for neuroendocrine tumors. METHODS: Fine-needle aspiration biopsies from 72 neuroendocrine tumors were evaluated for PAX8 expression: 32 primary and 23 metastatic well-differentiated neuroendocrine tumors (25 pancreatic, 13 pulmonary, 3 ileal, 2 duodenal, 1 rectal, 1 ovarian, and 10 primary site unknown) and 17 poorly differentiated neuroendocrine carcinomas (11 pulmonary, 1 pancreas, 1 breast, 1 thymus, and 3 primary site unknown). RESULTS: Among well-differentiated neuroendocrine tumors, only tumors from the pancreas were PAX8 positive (14 of 25, 56%) whereas no cases of pulmonary (0 of 13), ileal (0 of 3), duodenal (0 of 2), rectal (0 of 1), or ovarian (0 of 1) well-differentiated neuroendocrine tumors were positive for PAX8. One of 10 (10%) well-differentiated neuroendocrine tumors of unknown primary origin was PAX8 positive. Among poorly differentiated neuroendocrine carcinomas, PAX8 expression was identified in 1 of 1 (100%) pancreatic, 1 of 1 (100%) thymic, 4 of 11 (36%) pulmonary, and 0 of 1 (0%) breast carcinomas. One of 3 (33%) poorly differentiated neuroendocrine carcinomas of unknown primary origin was PAX8 positive. CONCLUSIONS: Pancreatic well-differentiated neuroendocrine tumors frequently express PAX8, which can help distinguish pancreatic primary tumors from tumors of other anatomic sites. In contrast, PAX8 expression in poorly differentiated neuroendocrine carcinomas is not specific for pancreatic origin and can be seen in extrapancreatic poorly differentiated neuroendocrine carcinomas. PMID- 21328567 TI - Commentary for special issue of Autism research on mouse models in ASD: a clinical perspective. PMID- 21328568 TI - Behavioral profiles of mouse models for autism spectrum disorders. AB - Autism spectrum disorders (ASD) are characterized by impairments in reciprocal social communication, and stereotyped verbal and nonverbal behaviors. In approximately 10-25% of the affected individuals, a genetic mutation associated with the condition can be identified. Recently, mutations altering synapse formation, cellular/synaptic growth rate and regulation of excitatory and inhibitory currents were identified in patients with intellectual disability, typical autism, Asperger syndrome or neurological syndromes associated with autistic traits. Following these genetic findings, mouse models carrying mutations similar to those identified in patients have been generated. These models offer the opportunity to investigate in vivo the physiological and behavioral consequences of the mutations. Here, we review the existing data on the phenotypes of mice carrying mutations in genes associated with ASD including neuroligin, neurexin and Shank mutant mice as well as the Fmr1, Mecp2, Ube3a, Nf1, Pten and Tsc1/Tsc2 mutant mice. The diversity and complexity of the phenotype of these mouse models reflect the broad range of phenotypes observed in patients with ASD. Remarkably, results from therapeutic approaches (e.g., modulation of gene expression, administration of pharmacological and nonpharmacological substances, enriched environment) are encouraging since some behavioral alterations could be reversed even when treatment was performed on adult mice. These ongoing studies should therefore increase our understanding of the biological alterations associated with ASD as well as the development of knowledge-based treatments. PMID- 21328569 TI - Haploinsufficiency of Gtf2i, a gene deleted in Williams Syndrome, leads to increases in social interactions. AB - Identifying genes involved in social behavior is important for autism research. Williams-Beuren syndrome (WBS) is a developmental syndrome with unique neurocognitive features, including low IQ, deficits in visuospatial and visual motor abilities, hypersensitivity to sounds, hypersociability, and increased general anxiety. The syndrome is caused by a recurrent hemizygous deletion of the 7q11.23 region, containing about 28 genes. One of genes in the region, GTF2I, has been implicated in the hypersociability and visuospatial deficits of WBS based on genotype-phenotype correlation studies of patients with atypical deletions. In order to clarify the involvement of GTF2I in neurocognitive function, especially social behavior, we have developed and characterized Gtf2i-deficient mice. We found that homozygous deletion of Gtf2i causes lethality during embryonic development with neural tube closure defects and exencephaly, consistent with other reports. Gtf2i heterozygous animals show no gross changes in brain structure or development. Furthermore, heterozygous animals show no alterations in learning and memory, including spatial memory as assessed by the Morris water maze, but show alterations in the recognition of novel objects. Interestingly, they show increased social interaction with unfamiliar mice and do not show typical social habituation processes, reminiscent of the hypersociability observed in WBS patients. The mice do not appear to show increased anxiety, supporting a specific effect of Gtf2i on defined domains of the WBS phenotype. These data indicate that Gtf2i is involved in several aspects of embryonic development and the development of social neurocircuitry and that GTF2I haploinsufficiency could be a contributor to the hypersociability in WBS patients. PMID- 21328570 TI - The autism risk genes MET and PLAUR differentially impact cortical development. AB - Candidate risk genes for autism spectrum disorder (ASD) have been identified, but the challenge of determining their contribution to pathogenesis remains. We previously identified two ASD risk genes encoding the receptor tyrosine kinase MET and the urokinase plasminogen activator receptor (PLAUR), which is thought to modulate availability of the MET ligand. We also reported a role for Met signaling in cortical interneuron development in vitro and a reduction of these neurons in uPAR (mouse ortholog of PLAUR) null mice, suggesting that disruption of either gene impacts cortical development similarly. Here, we modify this conclusion, reporting that interneuron numbers are unchanged in the neocortex of Met(fx/fx) / Dlx5/6(cre) mice, in which Met is ablated from cells arising from the ventral telencephalon (VTel). Consistent with this, Met transcript is not detected in the VTel during interneuron genesis and migration; furthermore, during the postnatal period of interneuron maturation, Met is co-expressed in glutamatergic projection neurons, but not interneurons. Low levels of Met protein are expressed in the VTel at E12.5 and E14.5, likely reflecting the arrival of Met containing corticofugal axons. Met expression, however, is induced in E12.5 VTel cells after 2 days in vitro, perhaps underlying discrepancies between observations in vitro and in Met(fx/fx) / Dlx5/6(cre) mice. We suggest that, in vivo, Met impacts the development of cortical projection neurons, whereas uPAR influences interneuron maturation. An altered balance between excitation and inhibition has been postulated as a biological mechanism for ASD; this imbalance could arise from different risk genes differentially affecting either or both elements. PMID- 21328574 TI - Socio-economic factors and outcomes in chronic lung disease of prematurity. AB - RATIONALE: Infants and children with chronic lung disease of prematurity (CLDP) are at increased risk for respiratory morbidities. We sought to determine (1) whether socio-economic status, race/ethnicity, and/or sex are risk factors for respiratory morbidities and (2) whether disparities in care existed for major therapy decisions such as home supplemental oxygen and gastrostomy tubes as well as initial length of stay in the neonatal intensive care unit. METHODS: Between January 2008 and February 2010 sociodemographic and respiratory morbidity data were collected on premature (<32 weeks gestation) infants and children (<3 years old) with CLDP. Associations between risk factors and respiratory morbidities and treatment parameters were examined using adjusted regression models. RESULTS: Data were collected on 135 subjects (gestational age: 26.2+/-2.0 weeks). Self reported non-Whites were more likely to report rescue medication use in the past 7 days [adjusted OR: 2.87 (1.28-6.45), P=0.011] and the use of systemic steroids for respiratory symptoms since the last clinic visit [adjusted OR: 2.12 (1.02 4.43), P=0.045]. Lower median household income was associated with increased activity limitations [adjusted OR: 2.79 (1.16-6.70), P=0.022] and public insurance coverage was associated with a decreased risk for hospitalizations [adjusted OR: 0.36 (0.13-0.98), P=0.045]. Major therapy decisions were not associated with disparities of care. CONCLUSIONS: A key finding was that non Whites were more likely to report rescue medication and systemic steroid use than Whites, but there was no difference in the frequency of respiratory symptoms or preventative inhaled corticosteroid use. Etiologies for these findings remain unclear and require further research. PMID- 21328575 TI - Impact of an evidence-based algorithm on quality of care in pediatric parapneumonic effusion and empyema. AB - OBJECTIVE: To determine whether implementation of a collaborative, evidence-based algorithm for care of pediatric parapneumonic effusion and empyema (PPE) can improve the quality of care delivered. STUDY DESIGN: Prospective cohort with retrospective control comparison of children aged 1 month to 18 years admitted with a clinical diagnosis of PPE. Quality improvement techniques were used to develop an algorithm, which was implemented September 2008. Primary outcome measures were decreased median and variability in length of stay (LOS), reduction in the use of chest computed tomography (CT), reduction in the total number of painful procedures, and increased initial use of effective drainage procedures when drainage was indicated. RESULTS: Compared with controls, algorithm implementation substantially reduced use of chest CT (0% vs. 41% of patients, P = 0.01) with no observed negative impact on LOS. Reductions in median LOS were not significant, but variability in LOS was reduced (P < 0.01 by F-test). Changes in number of procedures and use of effective drainage when indicated were in the predicted direction but not statistically significant. CONCLUSIONS: Quality improvement techniques are an effective means for incorporating evidence-based medicine into pediatric care. PPE can be managed safely without the use of chest CT. PMID- 21328576 TI - Chitosan molecular structure as a function of N-acetylation. AB - Molecular dynamics simulations have been carried out to characterize the structure and solubility of chitosan nanoparticle-like structures as a function of the deacetylation level (0, 40, 60, and 100%) and the spatial distribution of the N-acetyl groups in the particles. The polysaccharide chains of highly N deacetylated particles where the N-acetyl groups are uniformly distributed present a high flexibility and preference for the relaxed two-fold helix and five fold helix motifs. When these groups are confined to a given region of the particle, the chains adopt preferentially a two-fold helix with phi and psi values close to crystalline chitin. Nanoparticles with up to 40% acetylation are moderately soluble, forming stable aggregates when the N-acetyl groups are unevenly distributed. Systems with 60% or higher N-acetylation levels are insoluble and present similar degrees of swelling regardless the distribution of their N-acetyl groups. Overall particle solvation is highly affected by electrostatic forces resulting from the degree of acetylation. The water mobility and orientation around the polysaccharide chains affects the stability of the intramolecular O3-HO3((n)) ...O5((n +) (1)) hydrogen bond, which in turn controls particle aggregation. PMID- 21328577 TI - The effects of Cannabis sativa L. seed (hemp seed) on reproductive and neurobehavioral end points in rats. AB - This study determined the effects of maternal dietary intake of hemp seed on reproductive and neurobehavioral end points of Wistar rats. Time-mated rats were fed 100% hemp seed (n = 15), 50% hemp seed (n = 15) or basal diet (n = 15) once a day. The amount of food made available was based on control feed consumption records. All dams remained on their respective diets from premating (14 days) throughout gestation and lactation. After weaning, all pups were given their maternal diet until puberty. Mating and delivery weights of dams in all groups did not show significant changes. Number of pregnancies, number and post natal survival rate of total rat pups, litter size and milk yield were lower in the group that received 100% hemp seed. Offspring that received 50% hemp seed diet expressed reproductive and neurobehavioral end points from a modified Fox battery earlier than rats on 100% hemp seed or basal diet, except acoustic startle results where no differences appeared. In conclusion, this study shows that hemp seed supplementation does not improve the reproductive and neurobehavioral performances of rats. Pregnant women and nursing mothers should be cautious about the using of Cannabis sativa L. byproducts in their diets. PMID- 21328578 TI - Fetal ventriculomegaly secondary to isolated large choroid plexus cysts: prenatal findings and postnatal outcome. AB - OBJECTIVE: To report the prenatal findings and postnatal outcome of fetal ventriculomegaly associated with isolated large choroid plexus cysts (CPCs). METHOD: Cases of isolated fetal ventriculomegaly and large CPCs (>10 mm) were identified through a search of patient records from 2003 to 2006. Ultrasound (US) findings were reviewed: unilateral or bilateral ventriculomegaly, ventricular size, size of CPCs, and changes on serial scans. Correlation was made with fetal magnetic resonance imaging (MRI), pregnancy outcome, and long-term follow-up. RESULTS: Six cases of isolated large CPCs (12-30 mm) with ventriculomegaly (11-17 mm) were detected on US at 18 to 26 weeks of gestation. Serial prenatal US showed the CPCs resolved (one case) or decreased in size (five cases). Ventricular size became normal during pregnancy in five cases and decreased in size in one case. Fetal MRI performed in three cases showed no additional findings. Five patients had amniocentesis which showed normal karyotype. There was one termination of pregnancy (the fetus showed no abnormality on external examination). There were five healthy newborns, with follow-up to 4.5 years of age (one), 5.5 years (one), and 6 years (three). All had normal physical and developmental outcome. CONCLUSION: Large isolated CPCs may transiently dilate the fetal cerebral ventricles. Follow-up to 6 years has shown normal growth and development. PMID- 21328579 TI - Long-term clinical and immunological effects of p53-SLP(r) vaccine in patients with ovarian cancer. AB - Vaccine-induced p53-specific immune responses were previously reported to be associated with improved response to secondary chemotherapy in patients with small cell lung cancer. We investigated long-term clinical and immunological effects of the p53-synthetic long peptide (p53-SLP(r)) vaccine in patients with recurrent ovarian cancer. Twenty patients were immunized with the p53-SLP(r) vaccine between July 2006 and August 2007. Follow-up information on patients was obtained. Clinical responses to secondary chemotherapy after p53-SLP(r) immunizations were determined by computerized tomography and/or tumor marker levels (CA125). Disease-specific survival was compared to a matched historical control group. Immune responses were analyzed by flow cytometry, proliferation assay, interferon gamma (IFN-gamma) ELISPOT and/or cytokine bead array. Lymphocytes cultured from skin biopsy were analyzed by flow cytometry and proliferation assay. Of 20 patients treated with the p53-SLP(r) vaccine, 17 were subsequently treated with chemotherapy. Eight of these patients volunteered another blood sample. No differences in clinical response rates to secondary chemotherapy or disease-specific survival were observed between immunized patients and historical controls (p = 0.925, resp. p = 0.601). p53-specific proliferative responses were observed in 5/8 patients and IFN-gamma production in 2/7 patients. Lymphocytes cultured from a prior injection site showing inflammation during chemotherapy did not recognize p53-SLP(r). Thus, treatment with the p53-SLP(r) vaccine does not affect responses to secondary chemotherapy or survival, although p53-specific T-cells do survive chemotherapy. PMID- 21328580 TI - IGFBP7 downregulation is associated with tumor progression and clinical outcome in hepatocellular carcinoma. AB - Insulin-like growth factor-binding protein 7 (IGFBP7) functions in several cellular processes including proliferation, senescence and apoptosis. This study analyzed IGFBP7 function in hepatocellular carcinoma (HCC) cells by gene manipulation and investigated the prognostic significance of IGFBP7 expression in clinical HCC samples. In this study, we investigated changes in malignant potential such as cell growth and invasiveness in an HCC cell line, PLC/PRF/5, after transfection with shRNA against IGFBP7. The extent of apoptosis and cell cycle progression were examined after the transfection. The correlation between immunohistochemically determined IGFBP7 expression and long-term postoperative prognosis after curative resection was also investigated in clinical HCC specimens obtained from 104 patients. PLC/PRF/5 cells transfected with shRNA against IGFBP7 showed significantly more rapid growth and stronger invasiveness than control cells. Annexin V assays showed that the IGFBP7-depleted cells were significantly more resistant to apoptosis than the control cells, and showed decreased expression of cleaved caspase-3 and PARP. Cell cycle progression was more rapid in the IGFBP7-suppressed cells. In clinical HCC specimens, IGFBP7 expression was judged as positive in 67 patients (64.4%) and negative in the remaining 37 patients (35.6%). The IGFBP7 downregulation correlated significantly with poor postoperative prognosis, and IGFBP7 status was identified as an independent significant prognostic factor. Our results indicated that IGFBP7 expression correlated significantly with the malignant potential in HCC cells, suggesting that the expression could be a useful prognostic marker for HCC. PMID- 21328581 TI - Solution-mediated phase transformation of salts during dissolution: investigation using haloperidol as a model drug. AB - Soluble salts can undergo solution-mediated phase transformation to a lower solubility form due to pH gradients in the gastrointestinal tract. Therefore, dissolution rate rather than solubility may be the best predictor of bioavailability for such compounds. The purpose of this project was to examine the kinetics of the conversion of a basic compound, haloperidol, and its salt forms using a flow-through dissolution apparatus and rotating disk method in neutral conditions. The effects of buffer concentration, salt form, dissolution apparatus, and hydrodynamics were examined. Raman microscopy was used to characterize solids after dissolution. Haloperidol mesylate and haloperidol chloride showed a decrease in dissolution rate with time in the dissolution media. Haloperidol mesylate and haloperidol chloride dissolution rates also decreased with increasing buffer capacity. Raman microscopy confirmed phase conversion from the salt forms to the free base form in phosphate buffer. Hydrodynamics did not affect the time course of the solution-mediated phase transformation of salt forms. Dissolution and precipitation appear to be a function of pH close to the surface of the dissolving solid. In situations where equilibrium solubility of salts cannot be assessed experimentally, dissolution experiments are useful for examining the extent and duration of the dissolution rate enhancement. PMID- 21328582 TI - Complex dielectric properties of microcrystalline cellulose, anhydrous lactose, and alpha-lactose monohydrate powders using a microwave-based open-reflection resonator sensor. AB - The real (epsilon') and imaginary (epsilon") components of the complex permittivity of anhydrous lactose and microcrystalline cellulose (MCC) under different bulk densities, moisture contents (MCs), and times of hydration (for anhydrous lactose) were measured nondestructively using a microwave resonator sensor operating in the range of 700-800 MHz. Measurements of sensor resonant frequency and conductance allow, through calibration, determination of the complex dielectric properties epsilon' (relative permittivity) and epsilon" (relative dielectric loss) of the test material. Characteristic graphs of epsilon" versus epsilon' - 1 curve for each powder were generated as a function of bulk density and MC. Such data can be used to develop empirical models for the simultaneous in situ measurement of the bulk density and MC of the powders. Unlike MCC, anhydrous lactose is converted to its hydrate form in the presence of moisture, which causes a reduction in the amount of physisorbed and "free" water and a subsequent change in the dielectric properties. For powders such as anhydrous lactose that can form a crystal hydrate in the presence of moisture, a combination of techniques such as vibrational spectroscopy together with microwave resonator measurements are appropriate to characterize, in situ, the physical and chemical properties of the powder. PMID- 21328583 TI - Stabilization of liposomes in frozen solutions through control of osmotic flow and internal solution freezing by trehalose. AB - The purpose of this study was to elucidate the effect of trehalose distribution across the membrane on the freeze-related physical changes of liposome suspensions and their functional stability upon freeze-thawing. Cooling thermal analysis of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine liposome suspensions showed exotherm peaks of bulk (-15 degrees C to -25 degrees C) and intraliposomal (approx. -45 degrees C) solution freezing initiated by heterogeneous and homogeneous ice nucleation, respectively. The extent of the intraliposomal solution freezing exotherm depended on liposome size, lipid composition, cosolutes, and thermal history, suggesting that osmotic dehydration occurred due to the increasing difference in solute concentrations across the membrane. A freeze-thawing study of carboxyfluorescein-encapsulated liposomes suggested that controlling the osmotic properties to avoid the freeze-induced intraliposomal solution loss either by rapid cooling of suspensions containing trehalose in both sides of the membrane (retention of the intraliposomal supercooled solution) or by cooling of suspensions containing trehalose in the extraliposomal media prior to freezing (e.g., osmotic shrinkage) led to higher retention of the water-soluble marker. Evaluation and control of the osmotically mediated freezing behavior by optimizing the formulation and process factors should be relevant to the cryopreservation and freeze-drying of liposomes. PMID- 21328584 TI - High-precision absolute (true) density measurements on hygroscopic powders by gas pycnometry: application to determining effects of formulation and process on free volume of lyophilized products. AB - As density (free volume) of the amorphous solids should be related to mobility and stability, an attempt was made to develop a simple, sensitive, and reproducible method to evaluate free volume via high-precision gas pycnometry density measurements, and to apply this methodology to study the variation of free volume with formulation and thermal history (i.e., annealing). Annealed samples were prepared either by heating the product after freeze drying (postannealing) or drying at higher temperature in secondary drying than normal (in-process annealing). Density was measured using a gas pycnometer. We find that the key to high-precision density measurements is isolation of the instrument from atmospheric moisture; accordingly, all operations were carried out in a dry box. With suitable care, densities of amorphous freeze-dried products can be measured with a precision of better than 0.5% in a series of independent but nominally identical samples. Density decreased with increasing molecular weight of dextran, but density of proteins was independent of molecular weight. Small but significant increases in density upon annealing were observed for several formulations. Thus, we conclude that accurate density measurements may be made by carefully controlling residual moisture. Density may be a useful parameter to predict long-term stability. PMID- 21328585 TI - Improved facial nerve identification with novel fluorescently labeled probe. AB - OBJECTIVES/HYPOTHESIS: By phage display, we have developed a novel peptide (NP41) that binds selectively to nerves following systemic administration. We evaluated the pattern of facial nerve labeling with fluorescently-labeled NP41 (F-NP41). We also tested whether F-NP41 highlights facial nerves well enough to identify nerve stumps accurately several weeks after nerve transection. STUDY DESIGN: Forty seven wild-type mice were studied prospectively. One surgeon performed the nerve transection, reanastomosis, and monitoring of functional recovery. METHODS: Fluorescent labeling: F-NP41 was administered intravenously (20 mice). Nerve labeling was studied with fluorescence microscopy. Transection and reanastomosis: the right facial nerve was transected (25 mice). Three weeks after transection, F NP41 was administered intravenously and fluorescence microscopy was used to identify the nerve stumps and reanastomosis in one group. Nerve identification and reanastomosis was performed with white light in another group without F-NP41. The control group underwent sham surgery. Time to nerve identification was recorded. Functional recovery was monitored for at least 8 weeks. RESULTS: We found excellent labeling of intact and transected facial nerves following F-NP41 administration. Several weeks following nerve transection, F-NP41 provided accurate identification of the proximal and distal nerve stumps. Following reanastomosis, time to recovery and level of functional recovery was similar in the absence and presence of F-NP41. CONCLUSIONS: We show improved visualization of facial nerves with a novel systemically applied fluorescently labeled probe. Use of F-NP41 resulted in accurate identification of facial nerve stumps several weeks following transection. Functional recovery was similar with and without the use of F-NP41. PMID- 21328587 TI - A possible mechanism for hepatotoxicity induced by BIRB-796, an orally active p38 mitogen-activated protein kinase inhibitor. AB - BIRB-796, a selective inhibitor of p38 mitogen-activated protein kinase, has entered clinical trials for the treatment of autoimmune diseases. Levels of alanine transaminase, a biomarker of hepatic toxicity in clinical pathology, were found to be increased in Crohn's disease patients treated with BIRB-796. The purpose of the present study was to clarify the molecular mechanism(s) of this hepatotoxicity. A toxicogenomic analysis using a highly sensitive DNA chip, 3D GeneTM Mouse Oligo chip 24k, indicated that BIRB-796 treatment activated the nuclear factor (erythroid-derived 2)-like 2 signaling pathway, which plays a key role in the response to oxidative stress. A reactive intermediate of BIRB-796 was detected by the glutathione-trapping method using mouse and human liver microsomes. The production of this reactive metabolite in the liver may be one of the causes of BIRB-796's hepatotoxicity. PMID- 21328588 TI - Cardiotoxicity testing using pluripotent stem cell-derived human cardiomyocytes and state-of-the-art bioanalytics: a review. AB - In this article, recent progress in cardiotoxicity testing based on the use of immortalized cell lines or human embryonic stem cell (hESC) derived cardiomyocytes in combination with state-of-the-art bioanalytical methods and sensors is reviewed. The focus is on hESC-derived cells and their refinement into competent testing cells, but the access and utility of other relevant cell types are also discussed. Recent developments in sensor techniques and bioanalytical approaches for measuring critical cardiotoxicity parameters are highlighted, together with aspects of data evaluation and validation. Finally, recommendations for further research are given. PMID- 21328589 TI - How feeding competition determines female chimpanzee gregariousness and ranging in the Tai National Park, Cote d'Ivoire. AB - Socioecological theory suggests that feeding competition shapes female social relationships. Chimpanzees (Pan troglodytes) live in fission-fusion societies that allow them to react flexibly to increased feeding competition by forming smaller foraging parties when food is scarce. In chimpanzees at Gombe and Kibale, female dominance rank can crucially influence feeding competition and reproductive success as high-ranking females monopolize core areas of relatively high quality, are more gregarious, and have higher body mass and reproductive success than low-ranking females. Chimpanzee females in Tai National Park do not monopolize core areas; they use the entire territory as do the males of their community and are highly gregarious. Although female chimpanzees in Tai generally exhibit a linear dominance hierarchy benefits of high rank are currently not well understood. We used a multivariate analysis of long-term data from two Tai chimpanzee communities to test whether high-ranking females (1) increase gregariousness and (2) minimize their travel costs. We found that high-ranking females were more gregarious than low-rankers only when food was scarce. During periods of food scarcity, high rank allowed females to enjoy benefits of gregariousness, while low-ranking females strongly decreased their gregariousness. High-ranking females traveled more than low-ranking females, suggesting that low-rankers might follow a strategy to minimize energy expenditure. Our results suggest that, in contrast to other chimpanzee populations and depending on the prevailing ecological conditions, female chimpanzees at Tai respond differently to varying levels of feeding competition. Care needs to be taken before generalizing results found in any one chimpanzee population to the species level. PMID- 21328590 TI - Coevolutionary relationship between striatum size and social play in nonhuman primates. AB - The striatum is a region of the brain specifically tied to the experience and anticipation of pleasure, reward, appropriate behavioral sequencing, cognition, learning, and social modulation. Furthermore, the striatum is connected neurologically and functionally to other brain regions associated with the exhibition of social play, such as the neocortex, cerebellum, and limbic system. For these reasons, the striatum is especially interesting to researchers of play behavior. Moreover, the caudate-putamen area of the striatum has been specifically implicated in laboratory studies of social play behavior. This study uses the phylogenetic comparative method of independent contrasts to test for an evolutionary relationship between striatum volume and a measure of social play in nonhuman primates. Relative volume of the primate striatum correlates with rate of social, but not nonsocial, play behavior across species, suggesting a coevolution of traits. The pleasurable and procedural aspects of social play behavior may be mediated in part by the striatum and further to its connection to dopaminergic pathways in the primate brain. PMID- 21328591 TI - Great apes use weight as a cue to find hidden food. AB - Bonobos (Pan paniscus; n=5), orangutans (Pongo pygmaeus abelii; n=6), and a gorilla (Gorilla gorilla gorilla; n=1) were presented with two opaque cups, one empty and one baited (containing two bananas). Subjects had to independently gain weight information about the contents of the cups to find the hidden food. Six apes attained above chance level within a total of 16 trials. Successful subjects spontaneously adopted the method of successively lifting the cups and thus comparing their weight before making a choice. Prior to testing, these apes had participated in a weight discrimination task. To rule out that a subject's good performance was influenced by previous experience in weight experiments, we ran a second test in which the same task was presented to a group of chimpanzees (Pan troglodytes; n=9) who were naive to weight experiments. These subjects also participated in an additional test condition in which the same problem was presented based on learning to associate arbitrary visual stimuli. The results show that experience did not affect performance because the nine naive subjects were equally able to find the food when the task stimuli held a causal relation (i.e. weight indicates the hidden food). Interestingly, only one of the naive subjects solved the task when the task elements held an arbitrary relation (i.e. certain visual pattern indicates food). Our results confirm previous findings that apes perform better in problems grounded on causal compared to arbitrary relations. PMID- 21328592 TI - Resource partitioning in sympatric langurs and macaques in tropical rainforests of the central Western Ghats, south India. AB - In a competitive sympatric association, coexisting species may try to reduce interspecific interactions as well as competition for similar resources by several ecological and behavioral practices. We studied resource utilization of three sympatric primate species namely, lion-tailed macaques (Macaca silenus), bonnet macaques (M. radiata) and Hanuman langurs (Semnopithecus entellus) in a tropical rainforest of the central Western Ghats, south India. We studied resource use, tree-height use, foraging height, substrate use when consuming animal prey and interspecific interactions. The results revealed that across the year, there was very limited niche overlap in diet between each species-pair. Each primate species largely depended on different plant species or different plant parts and phenophases from shared plant species. Primate species used different heights for foraging, and the two macaque species searched different substrates when foraging on animal prey. We also recorded season-wise resource abundance for the resources shared by these three primate species. While there was low dietary overlap during the dry season (a period of relatively low resource abundance), there was high dietary overlap between the two macaque species during the wet season (a period of high resource abundance for the shared resources). We observed only a few interspecific interactions. None of these were agonistic, even during the period of high niche overlap. This suggests that the sympatric primate species in this region are characterized by little or no contest competition. Unlike in some other regions of the Western Ghats, the lack of interspecific feeding competition appears to allow these primates, especially the macaques, to remain sympatric year-round. PMID- 21328593 TI - Habitat selection of black-and-white snub-nosed monkeys (Rhinopithecus bieti) in Tibet: implications for species conservation. AB - As anthropogenic habitat changes are often considered a threat to natural ecosystems and wildlife, a sound understanding of the effects of habitat alteration on endangered species is crucial when designing management strategies or performing conservation activities. Black-and-white snub-nosed monkeys (Rhinopithecus bieti) are categorized as endangered on the IUCN Red List and are endemic to the trans-Himalayas in China. At present, there are only 15 groups and 2,500 individuals remaining in the wild, and they are facing intense habitat degradation with selective logging for house building and firewood. Habitat deterioration through wood extraction is occurring at Xiaochangdu, Tibet, where one stable group of R. bieti lives in a marginal habitat in the northernmost part of the species' distribution. To understand the species' response to selective logging in an extremely marginal habitat, data on habitat preference and diet composition of a group of R. bieti were collected at Xiaochangdu from 2003 to 2005. The monkeys used different habitats nonrandomly during the year. The selection index for secondary conifer forest (SC), where selective logging has occurred, was the highest of all habitat types (>1), suggesting that the groups strongly preferred SC. The monkeys fed more on buds/leaves, more on flowers/fruit/seeds, and less on lichen in SC than in primary conifer forest (PC). Dietary diversity was significantly higher in SC than in PC. These results indicate that over the short term, low-intensity disturbances may result in increased foliage diversity that enable groups of R. bieti to survive in this marginal habitat. PMID- 21328594 TI - Male-immature relationships in multi-male groups of mountain gorillas (Gorilla beringei beringei). AB - We examined the pattern and possible functions of social interactions between adult males and immatures in three free-ranging, multi-male groups of mountain gorillas (Gorilla beringei beringei). Previous studies conducted during the 1970s when groups contained one to three adult males concluded that male-immature relationships were likely to be a form of low-cost paternal investment [Stewart, Mountain gorillas: three decades of research at Karisoke. Cambridge, UK: Cambridge University Press, 2001]. We evaluated whether this hypothesis still held in groups containing six to nine adult males, or if male-immature relationships might serve other functions (e.g. mating effort, kin selection, or alliance building). Overall, we found that immatures spent the most time near, and interacted most with, the alpha silverback. These behaviors peaked during the period when infants were still quite vulnerable but increasing their independence from their mothers. Such findings suggest that parenting effort remains the primary function of male-immature relationships; however, there is some evidence for the mating effort hypothesis as well. PMID- 21328595 TI - Sexual interference in the Golden snub-nosed monkey (Rhinopithecus roxellana): a test of the sexual competition hypothesis in a polygynous species. AB - Sexual interference (SI), which is defined as any disturbance directed to a mating pair by other individuals, has been reported in several primate species. It is widely suggested that successful harassers experience improved mating success by increasing their access to reproductive partners as well as by reducing the mating success of rivals. Although theories of primate sexual conflict highlight male intra-sexual mating competition, females also are reported to actively disrupt copulations between mating partners. In this study, we investigated SI in a multilevel troop of Golden snub-nosed monkeys (Rhinopithecus roxellana) inhabiting the Qinling Mountains, China. Behavioral observations of 11 one-male units (OMU) that comprised the multilevel troop were conducted from September 2007 to May 2008. During this period 17.1% of 652 documented intra-OMU sexual encounters were characterized either by mild or aggressive forms of harassment. Sexual harassment was typically performed by a single individual (91.9%), and in 75.7% of cases the harasser was an adult or sub adult female. The frequency of female harassment was positively correlated with the number of adult and sub-adult females residing in an OMU, and resulted in a significant decrease in matings ending in ejaculation. We found that the amount of SI a female received was not a significant predictor of her reproductive success. However, females who conceived during the mating season directed higher levels of harassment at other females than females who did not conceive. We evaluate the strength of the sexual competition hypothesis and the hormonally modulated aggression hypothesis in explaining patterns of SI in female Golden snub-nosed monkeys. PMID- 21328596 TI - Social and developmental influences on urinary androgen levels in young male white-faced marmosets (Callithrix geoffroyi). AB - Callitrichine primates (marmosets and tamarins) often remain in their natal groups beyond the time of sexual maturity. Although studies have characterized the development of female reproductive function in callitrichine offspring, less is known about the male reproductive development. To document reproductive development in male marmosets, we monitored urinary androgen (uA) excretion in males housed in a captive colony of white-faced marmosets (Callithrix geoffroyi). Young male marmosets showed relatively low and stable rates of uA excretion early in life, with elevated production at the end of the juvenile period (9-10 months) and again at the onset of adulthood (16 months). uA levels of adult breeding males were also measured to compare to adult-aged sons. Although breeding males did have higher uA levels than their adult-aged sons, these differences did not reach conventional levels of significance. Evidence from some other reports has suggested that androgen levels of males in other species are influenced by social factors, such as the presence of a sexually receptive female or of dependent offspring. In this study, however, uA levels did not vary, based on their mothers' pregnancy status or the presence of younger siblings in the natal group. Patterns of androgen excretion in the white-faced marmoset roughly reflect those of other callitrichine species. Furthermore, unlike callitrichine daughters, gonadal activity in sons does not seem to be sensitive to within-group social cues. PMID- 21328597 TI - Patterns of mineral lick visitation by spider monkeys and howler monkeys in Amazonia: are licks perceived as risky areas? AB - Mineral licks--also known as "salados," "saladeros," or "collpas"--are specific sites in tropical and temperate ecosystems where a large diversity of mammals and birds come regularly to feed on soil. Although the reasons for vertebrate geophagy are not completely understood, animals are argued to obtain a variety of nutritional and health benefits from the ingestion of soil at mineral licks. We studied the temporal patterns of mineral lick use by white-bellied spider monkey (Ateles belzebuth) and red howler monkey (Alouatta seniculus) in a lowland rain forest in Amazonian Ecuador. Using camera and video traps at four different mineral licks, combined with behavioral follows of one group of spider monkeys, we documented rates of mineral lick visitation by both primate species and the relative frequency and intensity of mineral lick use by spider monkeys. On the basis of 1,612 days and 888 nights of mineral lick monitoring, we found that A. belzebuth and A. seniculus both visit mineral licks frequently throughout the year (on average ~14% of days for both species), and mineral lick visitation was influenced by short-term environmental conditions (e.g. sunny and dry weather). For spider monkeys, the area surrounding the lick was also the most frequently and most intensively used region within the group's home range. The fact that spider monkeys spent long periods at the lick area before coming to the ground to obtain soil, and the fact that both species visited the lick preferentially during dry sunny conditions (when predator detectability is presumed to be relatively high) and visited simultaneously more often than expected by chance, together suggest that licks are indeed perceived as risky areas by these primates. We suggest that howler and spider monkeys employ behavioral strategies aimed at minimizing the probability of predation while visiting the forest floor at risky mineral lick sites. PMID- 21328598 TI - Third-party postconflict affiliation of aggressors in chimpanzees. AB - Postconflict management strategies have been defined as any postconflict interaction that mitigates the negative consequences of the preceding agonistic conflict. Although most studies have investigated postconflict interactions between former opponents or between victims and uninvolved bystanders, interactions between aggressors and bystanders have received much less attention. In this study, we examined a database of 1,102 agonistic interactions and their corresponding postconflict periods in two outdoor-housed groups of captive chimpanzees in order to test the occurrence of postconflict third-party affiliation of aggressors. Our results confirmed the occurrence of appeasement, i.e. postconflict affiliation by a bystander toward an aggressor, but failed to detect the occurrence of postconflict affiliation directed from aggressors toward bystanders. Appeasement rates did not differ according to the sex of the involved individuals. In addition, appeasement occurred more often in the absence of reconciliation than after its occurrence suggesting that appeasement may act as an alternative to reconciliation when the latter fails to occur. Both study groups showed behavioral specificity for appeasement, i.e. context-specific use of certain behaviors, supporting the view that chimpanzees exhibit highly visible explicit postconflict affiliation. PMID- 21328599 TI - The application of mass spectrometry in molecular dosimetry: ethylene oxide as an example. AB - Mass spectrometry plays an increasingly important role in the search for and quantification of novel chemically specific biomarkers. The revolutionary advances in mass spectrometry instrumentation and technology empower scientists to specifically analyze DNA and protein adducts, considered as molecular dosimeters, derived from reactions of a carcinogen or its active metabolites with DNA or protein. Analysis of the adducted DNA bases and proteins can elucidate the chemically reactive species of carcinogens in humans and can serve as risk associated biomarkers for early prediction of cancer risk. In this article, we review and compare the specificity, sensitivity, resolution, and ease-of-use of mass spectrometry methods developed to analyze ethylene oxide (EO)-induced DNA and protein adducts, particularly N7-(2-hydroxyethyl)guanine (N7-HEG) and N-(2 hydroxyethyl)valine (HEV), in human samples and in animal tissues. GC/ECNCI-MS analysis after HPLC cleanup is the most sensitive method for quantification of N7 HEG, but limited by the tedious sample preparation procedures. Excellent sensitivity and specificity in analysis of N7-HEG can be achieved by LC/MS/MS analysis if the mobile phase, the inlet (split or splitless), and the collision energy are properly optimized. GC/ECNCI-HRMS and GC/ECNCI-MS/MS analysis of HEV achieves the best performance as compared with GC/ECNCI-MS and GC/EI-MS. In conclusion, future improvements in high-throughput capabilities, detection sensitivity, and resolution of mass spectrometry will attract more scientists to identify and/or quantify novel molecular dosimeters or profiles of these biomarkers in toxicological and/or epidemiological studies. PMID- 21328600 TI - Update of uremic toxin research by mass spectrometry. AB - Mass spectrometry (MS) has been successfully applied for the identification and quantification of uremic toxins and uremia-associated modified proteins. This review focuses on the recent progress in the MS analysis of uremic toxins. Uremic toxins include low-molecular weight solutes, protein-bound low-molecular weight solutes, and middle molecules (peptides and proteins). Based on MS analysis of these uremic toxins, the pathogenesis of the uremic symptoms will be elucidated to prevent and manage the symptoms. Notably, protein-bound uremic toxins such as indoxyl sulfate, p-cresyl sulfate, and 3-carboxy-4-methyl-5-propyl-2 furanpropionic acid have emerged as important targets of therapeutic removal. Hemodialysis even with a high-flux membrane cannot efficiently remove the protein bound uremic toxins because of their high albumin-binding property. The accumulation of these protein-bound uremic toxins in the blood of dialysis patients might play an important role in the development of uremic complications such as cardiovascular disease. Indoxyl sulfate is the most promising protein bound uremic toxin as a biomarker of progress in chronic kidney disease. Novel dialysis techniques or membranes should be developed to efficiently remove these protein-bound uremic toxins for the prevention and management of uremic complications. PMID- 21328601 TI - Informatics for mass spectrometry-based RNA analysis. AB - Mass spectrometry (MS) allows the sensitive and direct characterization of biological macromolecules and therefore has the potential to complement the more conventional genetic and biochemical methods used for RNA characterization. Although MS has been used much less frequently for RNA research than it has been for protein research, recent technical improvements in both instrumentation and software make MS a powerful tool for RNA analysis because it can now be used to sequence, quantify, and chemically analyze RNAs. Mass spectrometry is particularly well suited for the characterization of RNAs associated with ribonucleoprotein complexes. This review focuses on the software and databases that can be used for MS-based RNA studies. Software for the processing of raw mass spectra, the identification and characterization of RNAs by mass mapping, de novo sequencing, and tandem MS-based database searching are available. PMID- 21328602 TI - An overview of techniques for linking high-dimensional molecular data to time-to event endpoints by risk prediction models. AB - Analysis of molecular data promises identification of biomarkers for improving prognostic models, thus potentially enabling better patient management. For identifying such biomarkers, risk prediction models can be employed that link high-dimensional molecular covariate data to a clinical endpoint. In low dimensional settings, a multitude of statistical techniques already exists for building such models, e.g. allowing for variable selection or for quantifying the added value of a new biomarker. We provide an overview of techniques for regularized estimation that transfer this toward high-dimensional settings, with a focus on models for time-to-event endpoints. Techniques for incorporating specific covariate structure are discussed, as well as techniques for dealing with more complex endpoints. Employing gene expression data from patients with diffuse large B-cell lymphoma, some typical modeling issues from low-dimensional settings are illustrated in a high-dimensional application. First, the performance of classical stepwise regression is compared to stage-wise regression, as implemented by a component-wise likelihood-based boosting approach. A second issues arises, when artificially transforming the response into a binary variable. The effects of the resulting loss of efficiency and potential bias in a high-dimensional setting are illustrated, and a link to competing risks models is provided. Finally, we discuss conditions for adequately quantifying the added value of high-dimensional gene expression measurements, both at the stage of model fitting and when performing evaluation. PMID- 21328603 TI - Leveraging external knowledge on molecular interactions in classification methods for risk prediction of patients. AB - Classification of patients based on molecular markers, for example into different risk groups, is a modern field in medical research. The aim of this classification is often a better diagnosis or individualized therapy. The search for molecular markers often utilizes extremely high-dimensional data sets (e.g. gene-expression microarrays). However, in situations where the number of measured markers (genes) is intrinsically higher than the number of available patients, standard methods from statistical learning fail to deal correctly with this so called "curse of dimensionality". Also feature or dimension reduction techniques based on statistical models promise only limited success. Several recent methods explore ideas of how to quantify and incorporate biological prior knowledge of molecular interactions and known cellular processes into the feature selection process. This article aims to give an overview of such current methods as well as the databases, where this external knowledge can be obtained from. For illustration, two recent methods are compared in detail, a feature selection approach for support vector machines as well as a boosting approach for regression models. As a practical example, data on patients with acute lymphoblastic leukemia are considered, where the binary endpoint "relapse within first year" should be predicted. PMID- 21328604 TI - Confidence scores for prediction models. AB - In medical statistics, many alternative strategies are available for building a prediction model based on training data. Prediction models are routinely compared by means of their prediction performance in independent validation data. If only one data set is available for training and validation, then rival strategies can still be compared based on repeated bootstraps of the same data. Often, however, the overall performance of rival strategies is similar and it is thus difficult to decide for one model. Here, we investigate the variability of the prediction models that results when the same modelling strategy is applied to different training sets. For each modelling strategy we estimate a confidence score based on the same repeated bootstraps. A new decomposition of the expected Brier score is obtained, as well as the estimates of population average confidence scores. The latter can be used to distinguish rival prediction models with similar prediction performances. Furthermore, on the subject level a confidence score may provide useful supplementary information for new patients who want to base a medical decision on predicted risk. The ideas are illustrated and discussed using data from cancer studies, also with high-dimensional predictor space. PMID- 21328605 TI - Comparison of procedures to assess non-linear and time-varying effects in multivariable models for survival data. AB - The focus of many medical applications is to model the impact of several factors on time to an event. A standard approach for such analyses is the Cox proportional hazards model. It assumes that the factors act linearly on the log hazard function (linearity assumption) and that their effects are constant over time (proportional hazards (PH) assumption). Variable selection is often required to specify a more parsimonious model aiming to include only variables with an influence on the outcome. As follow-up increases the effect of a variable often gets weaker, which means that it varies in time. However, spurious time-varying effects may also be introduced by mismodelling other parts of the multivariable model, such as omission of an important covariate or an incorrect functional form of a continuous covariate. These issues interact. To check whether the effect of a variable varies in time several tests for non-PH have been proposed. However, they are not sufficient to derive a model, as appropriate modelling of the shape of time-varying effects is required. In three examples we will compare five recently published strategies to assess whether and how the effects of covariates from a multivariable model vary in time. For practical use we will give some recommendations. PMID- 21328606 TI - Primary central nervous system lymphoma in a patient treated with natalizumab. PMID- 21328609 TI - Modulatory effects of connexin-43 expression on gap junction intercellular communications with mast cells and fibroblasts. AB - The influence of mast cells upon aberrant wound repair and excessive fibrosis has supportive evidence, but the mechanism for these mast cell activities is unclear. It is proposed that heterocellular gap junction intercellular communication (GJIC) between fibroblasts and mast cells directs some fibroblast activities. An in vitro model was used employing a rodent derived peritoneal mast cell line (RMC 1) and human dermal derived fibroblasts. The influence of the expression of the gap junction channel structural protein, connexin 43 (Cx-43) on heterocellular GJIC, the expression of microtubule beta-tubulin and microfilament alpha smooth muscle actin (SMA) were investigated. The knockdown of Cx-43 by siRNA in RMC-1 cells completely blocked GJIC between RMC-1 cells. SiRNA knockdown of Cx-43 within fibroblasts only dampened GJIC between fibroblasts. It appears Cx-43 is the only expressed connexin (Cx) in RMC-1 cells. Fibroblasts express other Cxs that participate in GJIC between fibroblasts in the absence of Cx-43 expression. Heterocellular GJIC between RMC-1 cells and fibroblasts transformed fibroblasts into myofibroblasts, expressing alpha SMA within cytoplasmic stress fibers. The knockdown of Cx-43 in RMC-1 cells increased beta-tubulin expression, but its knockdown in fibroblasts reduced beta-tubulin expression. Knocking down the expression of Cx-43 in fibroblasts limited alphaSMA expression. Cx-43 participation is critical for heterocellular GJIC between mast cells and fibroblasts, which may herald a novel direction for controlling fibrosis. PMID- 21328610 TI - PI3K and ERK/Nrf2 pathways are involved in oleanolic acid-induced heme oxygenase 1 expression in rat vascular smooth muscle cells. AB - Oleanolic acid (OA), a widely used plant-derived triterpenoid, has been shown to possess potent antiatherosclerotic effects, which may be associated with the induction of heme oxygenase-1 (HO-1). However, the underlying mechanisms involved in the effect of OA on HO-1 expression are unclear. In the current study, primary rat vascular smooth muscle cells (VSMCs) were exposed to OA and we found that it enhanced HO-1 expression in a concentration- and time-dependent manner, accompanied by increased HO-1 activity. VSMCs treated with OA exhibited activation of Akt, p38 and extracellular-signal-regulated kinase (ERK). Wortmannin (a PI3K inhibitor) and PD98059 (an ERK inhibitor) attenuated OA induced HO-1 expression, whereas SB203580 (a p38 inhibitor) had no effect. The transcription factor NF-E2-related factor 2 (Nrf2) is a key regulator of HO-1 expression. OA treatment increased Nrf2 nuclear translocation, which was also inhibited by wortmannin and PD98059. Furthermore, transfection of VSMCs with the Nrf2 siRNA-expressing lentiviral vector decreased HO-1 expression induced by OA. Finally, pretreatment of VSMCs with OA remarkably reduced hydrogen peroxide induced cell apoptotic death, and this effect was greatly attenuated in the presence of ZnPP (a HO-1 inhibitor), wortmannin or PD98059. Taken together, these results suggest that activation of Akt and ERK is required for OA-induced activation of Nrf2 followed by upregulation of HO-1 expression in VSMCs, which may confer an adaptive survival response in atherosclerosis. PMID- 21328611 TI - Effects of osteopontin on functional activity of late endothelial progenitor cells. AB - The aim of this study is to investigate the effect of osteopontin (OPN) on functional activity of late endothelial progenitor cells (EPCs). Total mononuclear cells (MNCs) were isolated from human umbilical cord blood by Ficoll density gradient centrifugation, and then the cells were plated on fibronectin coated culture plates. Late EPCs were positive for both 1,1-dioctadecyl-3,3,3,3 tetramethylindocarbocyanine-labeled acetylated low-density lipoprotein (DiI acLDL) and fluorescein-isothiocyanate-conjugated Ulex europaeus agglutinin lectin (UEA-1). Expression of von Willbrand factor (vWF) and kinase insert domain receptor (KDR) were detected by indirect immunofluorescence staining. Late EPCs of 3-5 passages were treated for 24 h with OPN (to make a series of final concentration: 0.005 ug/ml, 0.01 ug/ml, 0.05 ug/ml, 0.5 ug/ml, 2.5 ug/ml), or vehicle control. The proliferation, migration, and in vitro vasculogenesis activity of late EPCs were assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay, modified Boyden chamber assay and an in vitro angiogenesis assay, respectively. Late EPCs adhesion assay was performed by replating cells on fibronectin-coated plates, and then adherent cells were counted. Incubation with OPN dose-dependently inhibited the proliferative, adhesive, and in vitro vasculogenesis capacity and increased migratory activity of late EPCs. PMID- 21328612 TI - Epigallocatechin-3-gallate induces cell apoptosis of human chondrosarcoma cells through apoptosis signal-regulating kinase 1 pathway. AB - Chondrosarcoma is a malignant primary bone tumor that responds poorly to both chemotherapy and radiation therapy. (-)-Epigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, has been shown to inhibit tumorigenesis and cancer cell growth in animal models. The aim of this study was to elucidate the mechanism of EGCG-induced apoptosis of human chondrosarcoma cells. EGCG induced cell apoptosis in human chondrosarcoma cell lines but not primary chondrocytes. EGCG induced upregulation of Bax and Bak, downregulation of Bcl-2 and Bcl-XL, and dysfunction of mitochondria in chondrosarcoma. We also found that the accumulation of reactive oxygen species (ROS) is a critical mediator in EGCG induced cell death. EGCG induced apoptosis signal-regulating kinase 1 (ASK1) dephosphorylation and its dissociation from 14-3-3. Treatment of chondrosarcoma cells with EGCG induced p38 and c-jun-NH2-kinase (JNK) phosphorylation. Transfection with ASK1 siRNA or p38 and JNK mutant antagonized the EGCG-induced cell apoptosis. Therefore, EGCG triggered ROS and activated the ASK1-p38/JNK pathway, resulting chondrosarcoma cell death. Importantly, animal studies revealed a dramatic reduction in tumor volume after 24 days of treatment. Thus, EGCG may be a novel anti-cancer agent for the treatment of chondrosarcoma. PMID- 21328613 TI - Molecular characterisation of a serum-responsive, DAF-12-like nuclear hormone receptor of the fox-tapeworm Echinococcus multilocularis. AB - As the primary mediators of lipophilic and steroid hormone signalling, the family of nuclear receptors (NRs) plays a central role in the regulation of metazoan development. Lipophilic hormones are also thought to be important players in the molecular interaction between larval cestodes and their hosts but no member of the NR family has yet been characterised in this group of parasites. In this work, we provide for the first time evidence for the presence of NRs in cestodes of the genus Echinococcus. By bioinformatic analyses, we identified a set of 17 NRs in the genomes of E. multilocularis and E. granulosus which broadly overlapped with the set of NRs that is expressed by schistosomes, but also contained several members that are unique to cestodes. One of these receptors, EmNHR1, displayed structural homologies to the DAF-12/HR-96 subfamily of NRs that regulates cholesterol homeostasis and longevity in metazoans. By RT-PCR analyses, we demonstrate that the EmNHR1 encoding gene is expressed in all Echinococcus larval stages that are involved in the infection of the intermediate host. By yeast two-hybrid analyses, we further demonstrate cross-communication between EmNHR1 and TGF-beta signalling pathways in Echinococcus and that mammalian serum contains a ligand that induces homodimerisation of the EmNHR1 ligand-binding domain. EmNHR1 could thus play an important role in hormonal host-parasite cross communication mechanisms during an infection. On the basis of our results, further investigations into the role of NR signalling in cestode development and host-parasite interaction will be greatly facilitated. PMID- 21328614 TI - Sampling GWAS subjects from risk populations. AB - Power, i.e. sample size, is a crucial issue in genome-wide association studies (GWAS) on disorders generated by a multitude of weak genetic effects. Here, we examine the influence of sampling cases and/or controls from populations that are subjected to an external risk factor (such as smoking or nutritional factors). We use an additive threshold model and derive the necessary sample size as function of the external risk factor's strength and of the sampling scheme. If both cases and controls are sampled from the risk population, a loss of power must be expected. The loss of power (i.e. the increase of the necessary sample size) is even larger if only the cases are sampled from the risk population, whereas the inverse scheme (nonrisk cases and risk controls) provides a gain of power since nonrisk cases are enriched for disease-favouring alleles while risk controls are enriched for protective alleles. For small effect sizes, we derive simple approximations in analytically closed form. A strategy of GWAS sample collection from risk populations minimizing the necessary sample sizes may thus be deduced that generally applies as long as strong gene-environment interactions can be excluded. PMID- 21328615 TI - Validity and power of association testing in family-based sampling designs: evidence for and against the common wisdom. AB - Current common wisdom posits that association analyses using family-based designs have inflated type 1 error rates (if relationships are ignored) and independent controls are more powerful than familial controls. We explore these suppositions. We show theoretically that family-based designs can have deflated type-error rates. Through simulation, we examine the validity and power of family designs for several scenarios: cases from randomly or selectively ascertained pedigrees; and familial or independent controls. Family structures considered are as follows: sibships, nuclear families, moderate-sized and extended pedigrees. Three methods were considered with the chi(2) test for trend: variance correction (VC), weighted (weights assigned to account for genetic similarity), and naive (ignoring relatedness) as well as the Modified Quasi-likelihood Score (MQLS) test. Selectively ascertained pedigrees had similar levels of disease enrichment; random ascertainment had no such restriction. Data for 1,000 cases and 1,000 controls were created under the null and alternate models. The VC and MQLS methods were always valid. The naive method was anti-conservative if independent controls were used and valid or conservative in designs with familial controls. The weighted association method was generally valid for independent controls, and was conservative for familial controls. With regard to power, independent controls were more powerful for small-to-moderate selectively ascertained pedigrees, but familial and independent controls were equivalent in the extended pedigrees and familial controls were consistently more powerful for all randomly ascertained pedigrees. These results suggest a more complex situation than previously assumed, which has important implications for study design and analysis. PMID- 21328616 TI - Confounded by sequencing depth in association studies of rare alleles. AB - Next-generation DNA sequencing technologies are facilitating large-scale association studies of rare genetic variants. The depth of the sequence read coverage is an important experimental variable in the next-generation technologies and it is a major determinant of the quality of genotype calls generated from sequence data. When case and control samples are sequenced separately or in different proportions across batches, they are unlikely to be matched on sequencing read depth and a differential misclassification of genotypes can result, causing confounding and an increased false-positive rate. Data from Pilot Study 3 of the 1000 Genomes project was used to demonstrate that a difference between the mean sequencing read depth of case and control samples can result in false-positive association for rare and uncommon variants, even when the mean coverage depth exceeds 30* in both groups. The degree of the confounding and inflation in the false-positive rate depended on the extent to which the mean depth was different in the case and control groups. A logistic regression model was used to test for association between case-control status and the cumulative number of alleles in a collapsed set of rare and uncommon variants. Including each individual's mean sequence read depth across the variant sites in the logistic regression model nearly eliminated the confounding effect and the inflated false-positive rate. Furthermore, accounting for the potential error by modeling the probability of the heterozygote genotype calls in the regression analysis had a relatively minor but beneficial effect on the statistical results. PMID- 21328618 TI - Triad stimulation frequency for cortical facilitation in cortical myoclonus. AB - BACKGROUND: Abnormally enhanced cortical rhythmic activities have been reported in patients with cortical myoclonus. We recently reported a new triad conditioning transcranial magnetic stimulation (TMS) method to detect the intrinsic rhythms of the primary motor cortex (M1). Triad-conditioning TMS revealed a 40-Hz intrinsic rhythm of M1 in normal subjects. In this investigation, we study the motor cortical facilitation induced by rhythmic triple TMS pulses (triad-conditioning TMS) in patients with cortical myoclonus. METHODS: Subjects were 7 patients with cortical myoclonus (28-74 years old) and 13 healthy volunteers (30-71 years old). Three conditioning stimuli over M1 at the intensity of 110% active motor threshold preceded the test TMS at various interstimulus intervals corresponding to 10-200 Hz. The resulting amplitudes of conditioned motor evoked potentials recorded from the contralateral hand muscle were compared with those evoked by the test stimulus alone. RESULTS: The facilitation at 25 ms (40 Hz) observed in normal subjects was absent in patients with cortical myoclonus. Instead, triad-conditioning TMS induced facilitation at a 40 ms interval (25 Hz) in cortical myoclonus. DISCUSSIONS: This change in the timing of facilitation may be explained by a shift of the most preferential intrinsic rhythm of M1, or by some dysfunction in the interneuronal network in cortical myoclonus. PMID- 21328619 TI - Protective effect of proteins derived from the latex of Calotropis procera against inflammatory hyperalgesia in monoarthritic rats. AB - Calotropis procera (family: Apocynaceae) is a plant growing in the wild and has been used in the traditional medicinal system for the treatment of various diseases. The plant produces milky latex that possesses potent antiinflammatory and analgesic properties. In present study the non-dialysable protein fraction isolated from the latex (LP) of this plant was evaluated for its efficacy against inflammation in rats where paw edema was induced by sub-plantar injection of carrageenin or monoarthritis was induced by intra-articular injection of Freund's complete adjuvant (FCA). The effect of LP was evaluated on edema volume in the paw model and on joint diameter, stair climbing ability, motility, dorsal flexion pain, levels of oxidative stress markers and joint histology in arthritis model. The protection afforded by LP was compared with that of standard antiinflammatory drug, diclofenac (5 mg/kg). LP exhibited a dose-dependent antiinflammatory effect and produced 32% and 60% inhibition of paw edema at 10 and 25 mg/kg doses and 12% and 36% inhibition of joint inflammation at 50 and 150 mg/kg doses. The protective effect of LP was associated with normalization of joint functions, histology and levels of oxidative stress markers in joint tissue. The findings of this study suggest that the protein fraction of latex of Calotropis procera has the potential to relieve inflammation and pain associated with various arthritic conditions. PMID- 21328617 TI - Hypothalamic leptin gene therapy prevents weight gain without long-term detrimental effects on bone in growing and skeletally mature female rats. AB - Hypothalamic leptin gene therapy normalizes the mosaic skeletal phenotype of leptin-deficient ob/ob mice. However, it is not clear whether increased hypothalamic leptin alters bone metabolism in animals already producing the hormone. The objective of this study was to evaluate the long duration effects of recombinant adeno-associated virus-rat leptin (rAAV-Lep) hypothalamic gene therapy on weight gain and bone metabolism in growing and skeletally mature leptin-replete female Sprague-Dawley rats. Rats were either unoperated or implanted with cannulas in the third ventricle of the hypothalamus and injected with either rAAV-Lep or rAAV-GFP (control vector encoding green fluorescent protein) and maintained on standard rat chow fed ad libitum for either 5 or 10 weeks (starting at 3 months of age) or 18 weeks (starting at 9 months of age). Tibias, femurs, or lumbar vertebrae were analyzed by micro-computed tomography and/or histomorphometry. In comparison with age-matched rAAV-GFP rats, rAAV-Lep rats maintained a lower body weight for the duration of studies. At 5 weeks after vector administration, rAAV-Lep rats had lower cancellous bone volume and bone marrow adiposity but higher osteoblast perimeter compared with nonoperated controls. However, these values did not differ between the two groups at 10 weeks after vector administration. Differences in cancellous bone volume and architecture were not detected between the rAAV-Lep and rAAV-GFP groups at either time point. Also, rAAV-Lep had no negative effects on bone in the 9-month-old skeletally mature rats at 18 weeks after vector administration. We hypothesize that the transient reductions in bone mass and bone marrow adiposity at 5 weeks after vector administration were due to hypothalamic surgery. We conclude that increased hypothalamic leptin, sufficient to prevent weight gain, has minimal specific effects (rAAV-Lep versus rAAV-GFP) on bone metabolism in normal female rats. PMID- 21328620 TI - In vivo immunomodulatory effect of Tilia x viridis extracts on normal lymphocyte proliferation: a direct and an indirect action. AB - The flowers of Tilia species have been used in Europe for many years to treat colds, bronchitis, fever, inflammations and influenza. It is well known that lymphocytes play a role in acquired immunity related to pathogens and tumor cells attachment. The aim of this study was to determine the effect of an aqueous (AE) and a dichloromethane extract (DM) from Tilia x viridis which is widely used and distributed in Argentina, on normal murine lymphocyte proliferation after being administered to mice. Both extracts presented a stimulatory effect on normal murine lymphocyte proliferation. The effect exerted by DM was principally related to macrophage activation, meanwhile AE exerted an important direct effect on lymphocytes related to the rutin presence. The stimulating effect, exerted on normal lymphocytes was due to a protective effect of apoptosis and also to cell IL2 production. PMID- 21328621 TI - Biosynthesis and degradation of the endocannabinoid 2-arachidonoylglycerol. AB - 2-Arachidonoylglycerol (2-AG) is a monoacylglycerol (MAG) molecule containing an esterified arachidonic acid chain at sn-2 position of the glycerol backbone. Together with structurally similar N-arachidonoylethanolamine (anandamide), 2-AG has been extensively studied as an endogenous ligand of cannabinoid receptors (an endocannabinoid) in brain and other mammalian tissues. Accumulating evidence demonstrates that the endocannabinoid system, including the central-type cannabinoid receptor CB1 and 2-AG, is responsible for synaptic retrograde signaling in the central nervous system. As 2-AG is rapidly formed from membrane phospholipids on cellular stimuli and degraded to arachidonic acid and glycerol, the enzymes catalyzing its biosynthesis and degradation are believed to play crucial roles in the regulation of its tissue levels. The major biosynthetic pathway appears to consist of sequential hydrolyses of inositol phospholipids via diacylglycerol (DAG) by beta-type phospholipase C and DAG lipase, while MAG lipase is a principal enzyme in the degradation. In this short review, we will briefly outline rapid advances in enzymological research on the biosynthetic and degradative pathways of 2-AG. PMID- 21328623 TI - The outcome of 5-ALA-mediated photodynamic treatment in melanoma cells is influenced by vitamin C and heme oxygenase-1. AB - Photodynamic therapy (PDT) is an important clinical approach for cancer treatment. It involves the administration of a photosensitizer, followed by its activation with light and induction of cell death. The underlying mechanism is an increased production of reactive oxygen species (ROS) leading to oxidative stress, which is followed by cell death. However, effectiveness of PDT is limited due to an initiation of endogenous rescue response systems like heme oxygenase-1 (HO-1) in tumor cells. In recent years, consuming of antioxidant supplements has become widespread, but the effect of exogenously applied antioxidants on cancer therapy outcome remains unclear. Thus, this study was aimed to investigate if exogenous antioxidants might decrease ROS-induced cytotoxicity in photodynamic treatment. Lycopene, beta-carotene, vitamin C, N-acetylcysteine, trolox, and N tert-butyl-alpha-phenylnitrone in different doses were administered to human melanoma cells prior exposure to photodynamic treatment. Supplementation with vitamin C resulted in a significant decrease of the cell death rate, whereas the other tested antioxidants had no effect on cell viability and oxidative stress markers. The simultaneous application of vitamin C with the HO-1 activity inhibitor zinc protoporphyrine IX (ZnPPIX) caused a considerable decrease of photodynamic treatment-induced cytotoxicity compared to ZnPPIX alone. It can be summarized that exogenously applied antioxidants do not have a leading role in the protective response against photodynamic treatment. However, further studies are necessary to investigate more antioxidants and other substances, which might affect the outcome of photodynamic treatment in cancer therapy. PMID- 21328622 TI - Fatty acids and the endoplasmic reticulum in nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) represents a burgeoning public health concern in westernized nations. The obesity-related disorder is associated with an increased risk of cardiovascular disease, type 2 diabetes and liver failure. Although the underlying pathogenesis of NAFLD is unclear, increasing evidence suggests that excess saturated fatty acids presented to or stored within the liver may play a role in both the development and progression of the disorder. A putative mechanism linking saturated fatty acids to NAFLD may be endoplasmic reticulum (ER) stress. Specifically, excess saturated fatty acids may induce an ER stress response that, if left unabated, can activate stress signaling pathways, cause hepatocyte cell death, and eventually lead to liver dysfunction. In the current review we discuss the involvement of saturated fatty acids in the pathogenesis of NAFLD with particular emphasis on the role of ER stress. PMID- 21328624 TI - The antianxiety-like effect of astaxanthin extracted from Paracoccus carotinifaciens. AB - Astaxanthin is a red carotenoid pigment and is widely found in living organisms. Astaxanthin has a potent antioxidative ability and has been reported as having various biological effects on the central nerve system, such as a protective effect against ischemia/reperfusion injury and improvement in cognitive function. In this study, to investigate the effects of astaxanthin on anxiety and depression, we performed some behavioral trials including the elevated plus maze test, hole-board test, forced swim test, and tail suspension test. Astaxanthin (100 and 300 mg/kg/day for 10 days, p.o.) significantly increased the time spent in open arms in the elevated plus maze test and increased the head-dipping count and duration in the hole-board test. On the other hand, astaxanthin (10, 100, 300, and 500 mg/kg/day for 10 days, p.o.) did not change the immobility time in the forced swim test or the tail suspension test. In conclusion, in mice, astaxanthin exerted anxiolytic-like effects, but not antidepressant-like effects. PMID- 21328625 TI - Biochemical investigation and gene expression analysis of the immunostimulatory functions of an edible Salacia extract in rat small intestine. AB - Roots and bark from plants belonging to genus Salacia of the family Hippocrateaceae (Salacia reticulata, Salacia oblonga, etc.) have been used for traditional Ayurvedic medicine, particularly for the treatment of diabetes. In our study, we evaluated the gene expression profiles in the small intestinal epithelium of rats that were given a Salacia plant extract to gain insight into its effects on the small intestine. In detail, DNA microarray analysis was performed to evaluate the gene expression profiles in the rat ileal epithelium. The intestinal bacterial flora was also studied using T-RFLP (Nagashima method) in these rats. Expressions of many immune-related genes, especially Th1-related genes associated with cell-mediated immunity, were found to increase in the small intestinal epithelium and the intestinal bacterial flora became similar to those in the case with Salacia plant extract administration. Our study thus revealed that Salacia plant extract exerts bioregulatory functions by boosting intestinal immunity. PMID- 21328626 TI - Thyroid hormones alter the adenine nucleotide hydrolysis in adult rat blood serum. AB - The effects of ATP, ADP, and adenosine in the processes of platelet aggregation, vasodilatation, and coronary flow have been known for many years. The sequential hydrolysis of ATP to adenosine by soluble nucleotidases constitutes the main system for rapid inactivation of circulating adenine nucleotides. Thyroid disorders affect a number of biological factors including adenosine levels in different fractions. Then, we intend to investigate if the soluble nucleotidases responsible for the ATP, ADP, and AMP hydrolysis are affected by variations in the thyroid hormone levels in blood serum from adult rats. Hyperthyroidism was induced by daily intraperitoneal injections of L-thyroxine (T4) (2.5 and 10.0 MUg/100 g body weight, respectively) for 7 or 14 days. Hypothyroidism was induced by thyroidectomy and methimazole (0.05%) added to their drinking water during 7 or 14 days. The treatments efficacy was confirmed by determination of hemodynamic parameters and cardiac hypertrophy evaluation. T4 treatment predominantly inhibited, and hypothyroidism (14 days after thyroidectomy) predominantly increased the ATP, ADP, and AMP hydrolysis in rat blood serum. These results suggest that both excess and deficiency of thyroid hormones can modulate the ATP diphosphohydrolase and 5'-nucleotidase activities in rat blood serum and consequently modulate the effects mediated by these enzymes and their products in vascular system. PMID- 21328627 TI - Ascorbic acid prevents oxidant-induced increases in endothelial permeability. AB - Oxidative stress acutely increases the permeability of the vascular endothelium to large molecules that would not otherwise cross the barrier. Ascorbic acid is an antioxidant that tightens the endothelial permeability barrier, so we tested whether it might also prevent the increase in endothelial permeability due to cellular oxidative stress. Treatment of EA.hy926 endothelial cells cultured on filter inserts with H(2) O(2) , menadione, and buthionine sulfoximine increased endothelial permeability to radiolabeled inulin. Short-term ascorbate loading of the cells to what are likely physiologic concentrations of the vitamin by treating them with dehydroascorbate prevented the increase in endothelial permeability due to these agents. The nonphysiologic antioxidants dithiothreitol and tempol also prevented increases in endothelial barrier permeability induced by the agents. These results suggest that oxidative stress induced directly by oxidants or indirectly by glutathione depletion impairs endothelial barrier function and that intracellular ascorbate may serve to prevent this effect. PMID- 21328628 TI - (-)Schisandrin B ameliorates paraquat-induced oxidative stress by suppressing glutathione depletion and enhancing glutathione recovery in differentiated PC12 cells. AB - Exposure to paraquat (PQ; N,N'-dimethyl-4-4'-bipyridium), a potent herbicide, can lead to neuronal cell death and increased risk of Parkinson's disease because of oxidative stress. In this study, we investigated the effect of (-)schisandrin B [(-)Sch B, a potent enantiomer of schisandrin B] on PQ-induced cell injury in differentiated pheochromocytoma cells (PC12). PQ treatment caused cell injury in PC12 cells, as indicated by the significant increase in lactate dehydrogenase (LDH) leakage. Pretreatment with (-)Sch B (5 MUM) protected against PQ-induced toxicity in PC12 cells, as evidenced by the significant decrease in LDH leakage. (-)Sch B induced the cytochrome P-450-mediated reactive oxygen species generation in differentiated PC12 cells. The cytoprotection afforded by (-)Sch B pretreatment was associated with an increase in cellular reduced glutathione (GSH) level as well as the enhancement of gamma-glutamylcysteine ligase (GCL) and glutathione reductase (GR) activity in PQ-challenged cells. Both GCL and GR inhibitors abrogated the cytoprotective effect of (-)Sch B in PQ-challenged cells. The biochemical mechanism underlying the GSH-enhancing effect of (-)Sch B was further investigated in PC12 cells subjected to an acute peroxide challenge. Although the initial GSH depletion induced by peroxide was reduced through GR catalyzed regeneration of GSH in (-)Sch B-pretreated cells, the later enhanced GSH recovery was mainly mediated by GCL-catalyzed GSH synthesis. The results suggest that (-)Sch B treatment may increase the resistance of dopaminergic cells against PQ-induced oxidative stress through reducing the extent of oxidant induced GSH depletion and enhancing the subsequent GSH recovery. PMID- 21328629 TI - Effect of supplementation of micronutrients and phytochemicals to fructooligosaccharides on growth response of probiotics and E. coli. AB - Probiotics and prebiotics, which can change the colonic microenvironment, are the areas of current interest. Unutilizable fractions of the foods and fortificants, which reach the colon can affect the profile of probiotics. Effects of eight such factors viz. zinc sulphate, zinc carbonate, ferrous sulphate, ferric citrate, quercetin, gallic acid, phytic acid, and oxalic acid were, therefore, investigated on 24 H growth of Lactobacillus acidophilus (L1) and Lactobacillus plantarum (L2), two isolates of bifidobacteria (longum (L3) and bifidum (L4)) and a marketed consortium (L5) of eight probiotic cultures. MRS medium with marketed fructooligosaccharide as the only source of carbon was used for study of dose response curves. Quercetin and zinc sulphate showed significant positive effect for L1 and L5 (P < 0.01), whereas there was slight positive effect or no effect on growth of other probiotics. Phytic acid showed a significant inhibitory effect for L2 and a slight inhibitory effect on L3 and L4 whereas L5 were able to tolerate phytic acid. Oxalic acid had slight positive effect for L1 (P < 0.05) and L5 and no effect on growth of other probiotics (P > 0.05). Further, zinc sulphate, ferrous sulphate, quercetin, and oxalic acid significantly inhibited growth of E. coli (P < 0.05) PMID- 21328630 TI - Binding of small molecules to cavity forming mutants of a de novo designed protein. AB - A central goal of protein design is to devise novel proteins for applications in biotechnology and medicine. Many applications, including those focused on sensing and catalysis will require proteins that recognize and bind to small molecules. Here, we show that stably folded alpha-helical proteins isolated from a binary patterned library of designed sequences can be mutated to produce binding sites capable of binding a range of small aromatic compounds. Specifically, we mutated two phenylalanine side chains to alanine in the known structure of de novo protein S-824 to create buried cavities in the core of this four-helix bundle. The parental protein and the Phe->Ala variants were exposed to mixtures of compounds, and selective binding was assessed by saturation transfer difference NMR. The affinities of benzene and a number of its derivatives were determined by pulse field gradient spin echo NMR, and several of the compounds were shown to bind the mutated protein with micromolar dissociation constants. These studies suggest that stably folded de novo proteins from binary patterned libraries are well-suited as scaffolds for the design of binding sites. PMID- 21328631 TI - Crystal structures of CmeR-bile acid complexes from Campylobacter jejuni. AB - The TetR family of transcription regulators are diverse proteins capable of sensing and responding to various structurally dissimilar antimicrobial agents. Upon detecting these agents, the regulators allow transcription of an appropriate array of resistance markers to counteract the deleterious compounds. Campylobacter jejuni CmeR is a pleiotropic regulator of multiple proteins, including the membrane-bound multidrug efflux transporter CmeABC. CmeR represses the expression of CmeABC and is induced by bile acids, which are substrates of the CmeABC tripartite pump. The multiligand-binding pocket of CmeR has been shown to be very extensive and consists of several positively charged and multiple aromatic amino acids. Here we describe the crystal structures of CmeR in complexes with the bile acids, taurocholate and cholate. Taurocholate and cholate are structurally related, differing by only the anionic charged group. However, these two ligands bind distinctly in the binding tunnel. Taurocholate spans the novel bile acid binding site adjacent to and without overlapping with the previously determined glycerol-binding site. The anionic aminoethanesulfonate group of taurocholate is neutralized by a charge-dipole interaction. Unlike taurocholate, cholate binds in an anti-parallel orientation but occupies the same bile acid-binding site. Its anionic pentanoate moiety makes a water-mediated hydrogen bond with a cationic residue to neutralize the formal negative charge. These structures underscore the promiscuity of the multifaceted binding pocket of CmeR. The capacity of CmeR to recognize bile acids was confirmed using isothermal titration calorimetry and fluorescence polarization. The results revealed that the regulator binds these acids with dissociation constants in the micromolar region. PMID- 21328632 TI - Thiazolidinedione use in elderly patients with type 2 diabetes: with and without heart failure. AB - PURPOSE: To compare the prescribing patterns of thiazolidinediones (TZDs) in elderly patients with type 2 diabetes with and without heart failure (HF). METHODS: The national health insurance claims database from the Health Insurance Review & Assessment Service (HIRA), Korea was used. Elderly patients with type 2 diabetes taking at least one hypoglycemic agent were studied between July 1, 2005 and June 30, 2006. Patients were grouped according to the presence of HF. The proportion of patients receiving TZDs were compared between the two groups, and stratified by their diabetes medication regimen (monotherapy and combination therapy). The difference in the patterns of TZD prescribed was studied across all health care levels including: primary, secondary, and tertiary care facilities. RESULTS: Among 357,855 elderly patients with type 2 diabetes, 24,746 patients had HF. TZDs were prescribed to 10.4% of the patients with HF and 8.8% of the patients without HF (p < 0.01). In the combination therapy group, the proportion of patients receiving TZDs was 17.9% and 14.4% in patients with and without HF, respectively (p < 0.01). In the primary care setting, the proportion of TZD prescriptions in patients with HF was 5.6% and it was 4.6% in patients without HF (p < 0.01). CONCLUSIONS: TZDs were frequently prescribed to patients with HF, even though the TZDs were contraindicated in patients with HF. Health care professionals should consider alternative therapies for patients with type 2 diabetes mellitus. In addition, they should carefully monitor the impact of TZD use in patients with HF. PMID- 21328633 TI - Safety of non-therapeutic levetiracetam ingestions--a poison center based study. AB - BACKGROUND: Very limited data is available regarding the safety of levetiracetam in cases of unintentional or intentional ingestions. METHODS: All cases of single agent ingestions of levetiracetam, excluding adverse drug reactions (ADRs), reported to 61 American poison control centers during 2000-2009 were identified. Demographics, dose, symptoms, and medical outcome were abstracted from each case record. RESULTS: A total of 222 cases of single agent levetiracetam ingestions were reported during the study period. Median age was 14.0 years (IQR: 2.0 years, 39.0 years) and 51.8% were female. In 207 of 222 cases (93.2%) medical outcome was known. No deaths were reported and only 1 (0.5%) case resulted in a major outcome and 3 (1.4%) cases resulted in moderate outcomes. Minor, minimal, or no effects were reported in 198 (89.2%) cases. In 27 (12.2%) cases, ingestion was intentional and in 192 (86.5%) unintentional. There were no major outcomes and only one case (1.4%) of moderate outcome in 74 children aged 6 years or less. All ingestions in these children were unintentional. CONCLUSIONS: In this study with a limited number of cases, intentional and unintentional ingestions of levetiracetam were safe in the majority of cases. PMID- 21328634 TI - Patient views and experiences of making adverse drug reaction reports to the Yellow Card Scheme in the UK. AB - PURPOSE: To describe the characteristics of patient reporters to the UK's Yellow Card Scheme (YCS) and the suspect drugs reported, and to determine patient views and experiences of making a Yellow Card report. METHODS: A questionnaire was developed for distribution by the Medicines and Healthcare products Regulatory Agency (MHRA) to all patients reporting through the YCS between March 2008 and January 2009. Associations between reporting method (online, postal and telephone) and questionnaire responses were examined using Pearson's Chi-squared test. RESULTS: Evaluable questionnaires were returned by 1362 out of 2008 reporters (68%). Respondents' median (IQR) age was 56.5 (43.0, 67.0) years, 910 (66.8%) were female, 1274 (93.5%) were white and 923 (67.8%) had at least a further education qualification. The most frequent reporting method was postal (59.8%), followed by online (32.8%) and telephone (6.3%). Online reporters were younger with a higher education level than those using other reporting methods. Most respondents, 1274 (93.6%), thought that the report was fairly or very easy to complete, although many identified the need for improvements to the system. One third (n = 448; 32.9%) expected feedback from the MHRA and 828 (60.8%) would have liked feedback. Almost all respondents (n = 1302; 95.6%) would report again. CONCLUSIONS: The majority of patients found the current methods of reporting suspected ADRs easy to use and would recommend them to others. Different methods of reporting were used by different demographic subgroups of reporters. Improvements to the system, including the provision of feedback to reporters, could be made. PMID- 21328635 TI - Mediating role of peritraumatic dissociation and depression on post-MVA distress: path analysis. AB - BACKGROUND: The aim of this study was to examine the role of pre-trauma, traumatic event, and peri-traumatic psychological characteristics on post-motor vehicle accident (MVA) Posttraumatic Stress Disorder (PTSD) and depression. METHODS: The sample comprised 333 (54% female) hospital accident and emergency attendees who completed a self-report postal screening survey approximately 1 month post-accident and 128 (62% female) participants who completed a follow-up survey at 3-months. RESULTS: Path analysis (Model 1) showed that dissociation partially mediated the relationship between past emotional problems and initial post-MVA distress, as well as between fear of dying and levels of distress. Level of alertness and perceived accident severity had no direct effects on post-MVA distress. However, higher levels of exposure contributed to distress predominantly in the presence of high levels of fear and subsequent dissociative experiences. When ongoing PTSD and depression symptoms were included (Model 2), feeling depressed/sad at 1-month was the strongest predictor of both PTSD and depression symptom severity at 3-months post-MVA, explaining 53% and 40% of the variance, respectively. Dissociation remained an important mediating variable at both time points. CONCLUSIONS: These models show the influence of previous emotional vulnerability factors and the important mediating role of peri traumatic experiences (in the presence of fear due to increased levels of accident severity) on post-MVA morbidity. Additionally, MVA survivors who report feeling depressed/sad 1-month after their accident are at greater risk of developing both PTSD and depression. PMID- 21328639 TI - Didier Astruc. PMID- 21328640 TI - Allosteric, chelate, and interannular cooperativity: a mise au point. PMID- 21328636 TI - Gender differences in the effect of early life trauma on hypothalamic-pituitary adrenal axis functioning. AB - BACKGROUND: The objective of this study was to examine the modifying effect of gender on the association between early life trauma and the hypothalamic pituitary-adrenal (HPA) axis response to a pharmacologic challenge and a social stress task in men and women. Participants (16 men, 23 women) were the control sample of a larger study examining HPA axis function. Individuals with major depressive disorder, posttraumatic stress disorder, bipolar disorder, or psychotic or eating disorders were excluded. METHODS: In two test sessions, subjects received 1 ug/kg of corticotropin-releasing hormone (CRH) intravenously and participated in the Trier Social Stress Test (TSST). Primary outcomes included plasma cortisol and corticotropin levels measured at baseline and more than five time points following the challenges. Predictors included gender and early life trauma, as measured by the Early Trauma Index. Using factor analysis, the domains general trauma, severe trauma, and the effects of trauma were established. Using regression, these constructs were used to predict differential HPA reactivity in men and women following the challenges. RESULTS: The three factors accounted for the majority of the variance in the ETI. Following the CRH challenge, women had higher overall corticotropin response as dictated by the area under the curve analysis. There were no significant associations between trauma and neuroendocrine response to the TSST. CONCLUSIONS: CRH challenge results indicate that gender differences in the impact of early trauma may help explain the differential gender susceptibility to psychopathology following adverse childhood events. This may help explain gender differences in some stress sensitive psychiatric disorders. PMID- 21328641 TI - Electric power and synthesis gas co-generation from methane with zero waste gas emission. PMID- 21328642 TI - Yb(III)-HPDO3A: a dual pH- and temperature-responsive CEST agent. PMID- 21328643 TI - MALDI-TOF mass spectrometric analysis of enzyme activity and lectin trapping on an array of N-glycans. PMID- 21328644 TI - Dual stimulus switching of a [2]catenane in water. PMID- 21328645 TI - MoS2 hybrid nanostructures: from octahedral to quasi-spherical shells within individual nanoparticles. PMID- 21328646 TI - Flexible, light-weight, ultrastrong, and semiconductive carbon nanotube fibers for a highly efficient solar cell. PMID- 21328647 TI - Triplet-triplet energy transfer in DNA: a process that occurs on the nanosecond timescale. PMID- 21328648 TI - Powerful protein binders from designed polypeptides and small organic molecules- a general concept for protein recognition. PMID- 21328649 TI - Periplasmic binding proteins as optical modulators of single-walled carbon nanotube fluorescence: amplifying a nanoscale actuator. PMID- 21328650 TI - Use of metadynamics in the design of isoDGR-based alphavbeta3 antagonists to fine tune the conformational ensemble. PMID- 21328651 TI - Sensitive and selective colorimetric visualization of cerebral dopamine based on double molecular recognition. PMID- 21328652 TI - Switching through coordination-coupled proton transfer. PMID- 21328653 TI - A bidentate halogen-bonding bromoimidazoliophane receptor for bromide ion recognition in aqueous media. PMID- 21328655 TI - Evidence for a "carbene-like" intermediate during the reaction of methoxy species with light alkenes on H-ZSM-5. PMID- 21328654 TI - Cooperative assembly of three-ring-based zeolite-type metal-organic frameworks and Johnson-type dodecahedra. PMID- 21328656 TI - Rare-earth polyhydride complexes bearing bis(phosphinophenyl)amido pincer ligands. PMID- 21328657 TI - The direct asymmetric vinylogous aldol reaction of furanones with alpha ketoesters: access to chiral gamma-butenolides and glycerol derivatives. PMID- 21328658 TI - A highly enantioselective zirconium catalyst for intramolecular alkene hydroamination: significant isotope effects on rate and stereoselectivity. PMID- 21328659 TI - Atom-economical synthesis of unsymmetrical ketones through photocatalyzed C-H activation of alkanes and coupling with CO and electrophilic alkenes. PMID- 21328660 TI - Preparation of a dihydrogen complex of cobalt. PMID- 21328661 TI - Identification of a valuable kinetic process in copper-catalyzed asymmetric allylic alkylation. PMID- 21328662 TI - Insertion of an alkene into an ester: intramolecular oxyacylation reaction of alkenes through acyl C-O bond activation. PMID- 21328663 TI - Inherent oxygen preference in enolate monofluoromethylation and a synthetic entry to monofluoromethyl ethers. PMID- 21328664 TI - Soft robotics for chemists. PMID- 21328665 TI - Copper-mediated trifluoromethylation of heteroaromatic compounds by trifluoromethyl sulfonium salts. PMID- 21328666 TI - Access to biomolecular assemblies through one-pot triple orthogonal chemoselective ligations. PMID- 21328667 TI - A dual-responsive supramolecular polymer gel formed by crown ether based molecular recognition. PMID- 21328668 TI - A highly regio- and stereoselective cascade annulation of enals and benzodi(enone)s catalyzed by N-heterocyclic carbenes. PMID- 21328669 TI - Selective magnesiation or zincation of highly functionalized alkenes and cycloalkenes using 2,2,6,6-tetramethylpiperidyl bases. PMID- 21328670 TI - Suzuki coupling reactions in three-phase microemulsions. PMID- 21328672 TI - Electron transfer in peptides: the influence of charged amino acids. PMID- 21328671 TI - Synthesis and in vivo imaging of a 18F-labeled PARP1 inhibitor using a chemically orthogonal scavenger-assisted high-performance method. PMID- 21328673 TI - Fluorescence imaging of influenza H1N1 mRNA in living infected cells using single chromophore FIT-PNA. PMID- 21328674 TI - A parallel screen for the discovery of novel DNA base pairs. PMID- 21328675 TI - Spectroscopic observation of matrix-isolated carbonic acid trapped from the gas phase. PMID- 21328677 TI - Totally robotic single-position 'flip' arm technique for splenic flexure mobilizations and low anterior resections. AB - BACKGROUND: Using the da Vinci robot in low anterior resection (LAR) has not been widely adopted due to limited range of motion of the robotic arms and the need to move the robot during operations. Our technique uses all three arms for both the splenic flexure and the pelvis, but with only one docking position. METHODS: The robot is placed to the left of the patient. The camera port is 3 cm to the right of the umbilicus. Arm 1 is placed in the RLQ. Arm 2 is placed midepigastric. Arm 3 is placed in the LLQ. Arm 3 starts off on the left side of the robot, on the same side as Arm 1 aimed cephalad. During mobilization of colon and splenic flexure, Arms 2 and 3 help retract the colon while Arm 1 dissects. Our pelvic dissection begins with Arm 3 "flipped" to the right side of the robot and redocked to the same left sided port aimed caudally. The robot does not need to be repositioned and the patient does not need to be moved. The pelvic dissection can now be done in the standard fashion. RESULTS: Our early experience includes four patients: two LARs and two left hemicolectomies. Mean operative time = 347 minutes, docking time = 20 minutes, and robotic surgical time = 195 minutes. Two complications occurred: post-operative ileus and high ostomy output. Mean LOS = 5. CONCLUSIONS: The robotic "flip" arm technique allows the surgeon to fully utilize all the robotic arms in LAR, which is unique versus other techniques. PMID- 21328678 TI - Drug eluting stents in CTOs: why not? PMID- 21328679 TI - Safety and efficacy of drug eluting stents compared with bare metal stents for saphenous vein graft interventions: a comprehensive meta-analysis of randomized trials and observational studies comprising 7,994 patients. AB - BACKGROUND: Saphenous vein graft (SVG) lesions remain amongst the most challenging lesions for percutaneous coronary intervention (PCI). It is unknown whether drug eluting stents (DES) are superior to bare metal stents (BMS) for such lesions. Our objective is to determine the safety and efficacy of DES compared with BMS for SVG lesions by performing a meta-analysis of clinical trials and observational studies. DATA SOURCES: PubMed, Cochrane Register of Controlled Trials, conference proceedings, and internet-based resources of clinical trials. STUDY SELECTION: Studies comparing DES vs. BMS for SVG lesions with at least>30 patients in each study reporting the outcomes of interest [death, myocardial infarction (MI), target vessel revascularization (TVR), stent thrombosis (ST), and the composite of death, TVR and MI (major adverse cardiac events; MACE)] with at least 6 months clinical follow-up. The primary outcome of interest was death. RESULTS: Two randomized trials, one subgroup analysis of a randomized trial and 26 observational studies comprising a total of 7,994 patients (4,187 patients in DES and 3,807 patients in BMS group) were included in the analysis. Mean follow-up duration was 21+/-11 months (6-48 months). In the overall population, MACE events were 19% in DES and 28% in BMS with a risk ratio (RR) of 0.7 (0.6, 0.8) P<0.00001. This effect of MACE was sustained in studies with >2 years follow-up with RR of 0.77 (0.65, 0.91) P=0.003. Death rate was 7.8% in DES and 9% in BMS with a RR of 0.82 (0.7, 0.97) P=0.02. MI rate was 5.7% in DES and 7.6% in BMS with RR of 0.72 (0.57, 0.91) P=0.007. TVR was 12% in DES and 17% in BMS with RR of 0.71 (0.59, 0.85) P=0.0002. ST was 1% in DES and 1.7 % in BMS RR of 0.61 (0.35, 1.06) P=0.08. Specifically in randomized controlled trials, DES were associated with no significant differences in overall mortality [RR=1.97; 95% confidence interval (CI), 0.17-23; P=0.58] or MI (RR=1.24; 95% CI, 0.3-5.5; P=0.78) compared with BMS. CONCLUSIONS: Based on the results of this meta-analysis, DES may be considered as a safe and efficacious option for the percutaneous intervention of SVG lesions. PMID- 21328680 TI - DES in SVGs: safe and at least short-term effective. PMID- 21328681 TI - A new dedicated ultrashort steerable balloon for side branch ostial dilatation. AB - A dedicated balloon with a short beveled tip and the ability to rotate it from the proximal hub was successfully used to dilate the origin of a side branch which became totally occluded after deployment of a stent in the main vessel. Although regular low profile balloons are mostly successful in crossing struts of previously deployed stents, this new device has the potential to offer a more predictable and rapid solution in routine practice. PMID- 21328682 TI - To catch a thief: opening a CTO and its effect on the contralateral donor artery FFR. PMID- 21328683 TI - Aortic valve regurgitation following percutaneous closure of patent ductus arteriosus. AB - OBJECTIVES: To determine the incidence and outcome of aortic valve regurgitation (AR) following the percutaneous closure of patent ductus arteriosus (PDA). BACKGROUND: Aortic valve regurgitation is an overlooked consequence of percutaneous PDA closure. METHODS: Between December 2000 and May 2009, 51 children underwent percutaneous closure of PDA using Amplatzer Duct Occluders. Their median age at the time of the procedure was 2.6 years (range: 0.6-18.0 years), and median weight was 14.0 kg (range: 7.6-75.0 kg). Follow-up echocardiograms were performed a day after the procedure and at 1, 3, 12 months, and yearly thereafter. RESULTS: A day after the procedure, AR was detected for the first time in 13 of 48 patients (27.0%). A group of patients with newly developed AR was significantly different from a group of patients with competent aortic valves with respect to their age, weight, and minimal PDA diameter indexed to the body weight. The follow-up period ranged from 0.2 to 8.5 years (median 3.3 years) and at the latest follow-up evaluation, AR persisted in a single patient (2.0%) 6 years after the procedure. CONCLUSIONS: The aortic valve regurgitation following percutaneous PDA closure is trivial to mild and transient. It develops in approximately a quarter of children after percutaneous closure of PDA with a minimal diameter>=1.5 mm and is more likely to develop in infants and small children having significant left-to-right shunts. PMID- 21328684 TI - Acute coronary occlusion following TAVI. AB - Transcatheter aortic valve implantation (TAVI) has nowadays replaced open heart surgery as an alternative therapeutic tool in selected patients. Thirty-five percent of patients with severe degenerative aortic valve stenosis (AS) remain untreated because of the existing comorbidities that increase their perioperative risk. TAVI is a relatively new technique that has "come to stay" in the everyday clinical practice considering, that is the only alternative to surgery and appears to have excellent long term results. Herein, we describe a vascular complication immediately after the implantation of the Edwards SAPIEN (Edwards Lifesciences, Irvine, CA) prosthesis, followed by ad hoc percutaneous coronary intervention. PMID- 21328685 TI - Coronary obstruction following transcatheter aortic valve-in-valve implantation for failed surgical bioprostheses. AB - Transcatheter aortic valve implantation (TAVI) for failed surgical bioprostheses, or "valve-in-valve" implantation, is a therapeutic option for high-risk patients. While coronary occlusion during TAVI for native aortic stenosis has been described, in the setting of valve-in-valve implantation the bioprosthetic posts may be protective against this complication. We describe the first two cases of coronary occlusion following valve-in-valve therapy, both occurring during treatment of degenerated Mitroflow bioprostheses. Aortic root anatomy, coronary ostial position, and the specifics of the bioprosthetic valve type need to be considered in assessing and preventing this rare complication. PMID- 21328686 TI - Coronary obstruction following transcatheter aortic valve-in-valve implantation for failed surgical bioprostheses. PMID- 21328687 TI - The catheterization laboratory and interventional vascular suite of the future: anticipating innovations in design and function. PMID- 21328688 TI - Regarding changing outcomes and treatment strategies for wire-induced coronary perforations in the era of bivalirudin use. A word of caution concerning the use of bivalirudin during coronary intervention for lesions at high risk for perforation. PMID- 21328690 TI - Percutaneous intervention of a thrombotic-occluded saphenous vein graft successfully treated using the undersized stent approach to prevent distal embolization. AB - Percutaneous intervention carries a higher risk of distal embolization and poorer outcome in saphenous vein grafts (SVG) than in native coronary vessels. Embolic protection devices (EPD) have demonstrated value in decreasing the risk of embolization and post-procedural enzymes elevation after SVG intervention. Although there is ample evidence to support the routine use of EPD for SVG interventions, frequently those devices are not utilized or cannot be used because of technical reasons. As we previously reported, the "undersized stenting" approach seems to be an attractive strategy when EPD cannot be used. We present a case with severe SVG degeneration that illustrates the feasibility of this strategy. PMID- 21328691 TI - Effects of chlorpyrifos exposure on kidney Notch2-Jagged1 pathway of early prenatal embryo. AB - AIMS: To evaluate the effects of this insecticide on the embryonic development of kidney and to assess the important role of Notch2-Jagged1 pathway in this duration. METHODS AND RESULTS: Chlorpyrifos (CPF) 5 mg/kg/d were administrated on gestation 7.5-11.5 day by subcutaneous injection. On gestation 16.5 day, the normal embryo kidney developed through S shape duration to the original kidney, which had the nephrons and could start to secret the urine. But for the CPF treated mice, the embryo kidney developed much more slowly, they did not show the S shape and the nephrons. The Notch2-Jagged1 pathway should be expressed stronger in the normal embryo kidney on gestation 16.5 day, but for the CPF-treated mice we found the obvious weak pathway staining. CONCLUSIONS: CPF broke the Notch2 Jagged1 pathway during the embryo kidney development, and the Notch2-Jagged1 pathway plays an important role in the S shape to original kidney formation duration. PMID- 21328692 TI - Variation in the level of protection afforded to birds and crustaceans exposed to different pesticides under standard risk assessment procedures. AB - First-tier risk assessment for pesticides is often based on the quotient of the toxicity divided by the predicted environmental concentration or dose. This ratio is compared to a fixed assessment factor (AF) to decide whether the pesticide is to be allowed on the market or whether further research is needed. Often, a high value (e.g., the 90th percentile) is assumed for the predicted environmental concentration, and the lowest available value is chosen to represent toxicity; yet, the real level of protection is not known. Therefore, it is also not known whether the first tier is conservative enough or too conservative. By using 2 large toxicity databases and assuming a log-logistic species sensitivity distribution for each pesticide, the percent of species not covered by the AF is estimated in the scenario, where exposure is at the maximum level allowable in the first tier. In the case of crustaceans, the median estimate of the fraction of species not covered by the AF of 100 in the first-tier scenario is 3.4%, on average, for 72 pesticides. In other words, on average, 3.4% of the crustacean species will be exposed above their median lethal concentration (LC50) and median lethal dose (LD50) value in 10% of receiving surface waters that receive the maximum allowable exposure to an individual pesticide. The estimated level of protection varies widely between pesticides. For 10% of the pesticides, the estimated fraction of species not covered is >=10% (maximum=41.4%). For 28% of the pesticides, 99.9% of the species will have the assumed level of protection. For birds, the median estimate of the fraction of species exposed above their median lethal dose for the first-tier scenario (AF=10) is 3.0% on average, when the AF is applied to the lower of the toxicity values for the 2 standard test species. For 11% of the pesticides, the median estimate is >=10% (maximum=15.7%). When the AF is applied instead to the geometric mean of the toxicity values for the 2 standard species, the median estimate of the fraction of species not covered by the AF is increased to 7.4% on average; for 31% of the pesticides, this fraction is >=10% (maximum=33.4%). This variation in the level of protection should be considered when defining the assumptions, assessment factors, and decision criteria in regulatory risk assessment. PMID- 21328693 TI - A soft-tissue coupling for wound closure. AB - Wounds often cannot be successfully closed by conventional means of closure such as sutures or staples. Our group developed the FiberSecureTM device to close soft tissue wounds reliably, surpassing native tissue strength. We closed cross-fiber muscle incisions, to evaluate (1) four different configurations of FiberSecureTM for 30 days, then (2) the resulting preferred configuration for 180 days. The four treatment groups each placed 21,504 polyester (PET) 12-MUm fibers (cross sectional area 1% of muscle) traversing the incision, in the form of (A) Four large (No.7 suture) non-textured bundles, (B) Eight small (No.2 suture) non textured, (C) Four large textured, or (D) Eight small textured. Four incisions were closed in the external oblique muscle of 16 Sinclair minipigs. At 30 days, specimens were removed for biomechanics, histology, and total collagen content. Group (B) was selected for 180-day evaluations in the same wound model in eight animals, four closures each (n = 32), again with biomechanics and histology. In strength testing, every specimen tore through muscle remotely, while the repair region remained intact. Maximum forces were (A) 37.8 +/- 3.9 N, (B) 37.1 +/- 4.7 N, (C) 39.0 +/- 5.3 N, and (D) 32.4 +/- 3.4 N at 30 days, and 37.2 +/- 11.3 N at 180 days (mean +/- SEM). No significant difference was observed among the groups or time points (p > 0.05). PMID- 21328694 TI - Recent developments in the HPLC separation of phenolic compounds. AB - Phenolic compounds represent a class of highly complex naturally occurring molecules that possess a range of beneficial health properties. As a result, considerable attention has been devoted to the analysis of phenolics in a variety of samples. HPLC is the workhorse method for phenolic separation. However, conventional HPLC methods provide insufficient resolving power when faced with the complexity of real-world phenolic fractions. This limitation has been traditionally circumvented by extensive sample fractionation, multiple analysis methods and/or selective detection strategies. On the other hand, there is an increasing demand for improved throughput and resolving power from the chromatographic methods used for phenolic analyses. Fortunately, during the last decade, a number of important technological advances in LC have demonstrated significant gains in terms of both speed and resolution. These include ultra high pressure liquid chromatography (UHPLC), high-temperature liquid chromatography (HTLC), multi-dimensional separations as well as various new stationary phase chemistries and morphologies. In recent years, these technologies have also found increasing application for phenolic analysis. This review seeks to provide an updated overview of the application of recent advances in HPLC to phenolic separation, with the emphasis on how these methodologies can contribute to improve performance in HPLC analysis of phenolics. PMID- 21328695 TI - Comparison of the performance of non-ionic and anionic surfactants as mobile phase additives in the RPLC analysis of basic drugs. AB - Surfactants added to the mobile phases in reversed-phase liquid chromatography (RPLC) give rise to a modified stationary phase, due to the adsorption of surfactant monomers. Depending on the surfactant nature (ionic or non-ionic), the coated stationary phase can exhibit a positive net charge, or just change its polarity remaining neutral. Also, micelles in the mobile phase introduce new sites for solute interaction. This affects the chromatographic behavior, especially in the case of basic compounds. Two surfactants of different nature, the non-ionic Brij-35 and the anionic sodium dodecyl sulfate (SDS) added to water or aqueous-organic mixtures, are here compared in the separation of basic compounds (beta-blockers and tricyclic antidepressants). The reversible/irreversible adsorption of the monomers of both surfactants on the stationary phase was examined. The changes in the nature of the chromatographic system using different columns and chromatographic conditions were followed based on the changes in retention and peak shape. The study revealed that Brij-35 is suitable for analyzing basic compounds of intermediate polarity, using "green chemistry", since the addition of an organic solvent is not needed and Brij-35 is a biodegradable surfactant. In contrast, RPLC with hydro-organic mixtures or mobile phases containing SDS required high concentrations of organic solvents. PMID- 21328696 TI - Determination of flavanones in Citrus juices by means of one- and two-dimensional liquid chromatography. AB - 1-D and 2-D comprehensive (LC*LC) liquid chromatography methods have been developed and compared for the separation and quantification of flavanones in various Citrus juices. 1-D analyses were carried out on a superficially porous C18 column, whereas the 2-D LC approach was composed of a polyethylene glycol silica narrow-bore column packed with totally porous particles in the first dimension (D1) and a superficially porous C18 column in the second dimension (D2). Low-selectivity correlations were ensured by the complementary separation mechanisms offered by the D1 and D2 columns. Quantification was carried out both manually and by means of a software capable of detecting and quantifying each peak from the 2-D plot. Limit of detection (LOD) values as low as 0.023 MUg/mL were obtained for hesperidin used as reference material for 1-D LC analyses, whereas values as high as 0.432 MUg/mL were obtained by comprehensive LC. This discrepancy can be traced back to the minor sensitivity experienced in comprehensive LC due to both sample dilution in D1 and the high flow rates employed in D2. On the other hand, the separation capabilities of the LC*LC approach allowed to reduce the interferences coming from the matrix and to achieve the separation of some critical pairs, e.g. hesperidin/naringin difficult to accomplish in 1-D LC. PMID- 21328697 TI - A specific LC/ESI-MS/MS method for determination of 25-hydroxyvitamin D3 in neonatal dried blood spots containing a potential interfering metabolite, 3-epi 25-hydroxyvitamin D3. AB - Vitamin D deficiency in an infant is associated with a wide range of adverse health outcomes in later life. A method for the quantification of 25 hydroxyvitamin D(3) [25(OH)D(3), the best-established indicator of vitamin D status] in neonatal dried blood spots (DBSs) using LC/ESI-MS/MS has been developed and validated. The method employed two steps of derivatization, a Diels Alder reaction with 4-phenyl-1,2,4-triazoline-3,5-dione followed by acetylation, to enhance the detectability of 25(OH)D(3) in ESI-MS/MS and to separate 25(OH)D(3) from 3-epi-25-hydroxyvitamin D(3) [3-epi-25(OH)D(3)], a potent interfering metabolite. 25(OH)D(3) was extracted from two DBS punches (3 mm in diameter, equivalent to 5.3 MUL of whole blood), purified using an Oasis HLB((r)) cartridge, and subjected to derivatization prior to analysis with LC/ESI MS/MS. 25-Hydroxyvitamin D(4) was used as the internal standard. This method was reproducible (intra- and inter-assay RSDs, <6.9%) and accurate (analytical recovery, 95.2-102.7%), and the LOQ was 3.0 ng/mL. The developed method enabled specific quantification of 25(OH)D(3) in neonatal DBSs and detection of vitamin D deficiency without interference from 3-epi-25(OH)D(3). PMID- 21328698 TI - Aerobic oxidations catalyzed by colloidal nanogold. AB - Recently, dispersions of gold nanoclusters in liquid media (colloidal nanogold) have been extensively used as quasi-homogeneous catalysts for various aerobic oxidation reactions. This review describes recent progress in such reactions, with a focus on our comprehensive studies on gold clusters (<2 nm) stabilized by poly(N-vinyl-2-pyrrolidone) and their participation in oxidation reactions of alcohols, alpha-hydroxylation reactions of benzylic ketones, and homocoupling reactions of organoboronates, as well as formal Lewis acidic reactions, such as intramolecular hydroalkoxylation and hydroamination reactions of nonactivated alkenes. Mechanistic studies have shown that a partial electron transfer from the gold clusters to O(2) generates superoxide- or peroxide-like species and Lewis acidic centers, both of which play essential roles in the catalytic reactions. PMID- 21328699 TI - Synthesis, photophysical, and two-photon absorption properties of elongated phosphane oxide and sulfide derivatives. AB - A series of rod-shaped and related three-branched push-pull derivatives containing phosphane oxide or phosphane sulfide (PO or PS)-as an electron withdrawing group conjugated to electron-donating groups, such as amino or ether groups, with a conjugated rod consisting of arylene-vinylene or arylene ethynylene building blocks-were prepared. These compounds were efficiently synthesized by a Grignard reaction followed by Sonogashira coupling. Their photophysical properties including absorption, emission, time-resolved fluorescence, and two-photon absorption (TPA) were investigated with special attention to structure-property relationships. These fluorophores show high fluorescence quantum yields and solvent-dependent experiments reveal that efficient intramolecular charge transfer occurs upon excitation, thereby leading to highly polar excited states, the polarity of which can be significantly enhanced by playing on the end groups and conjugated linker. Rod-shaped and related three-branched systems show similar fluorescence properties in agreement with excitation localization on one of the push-pull branches. By using stronger electron donors or replacing the arylene-ethynylene linkers with an arylene vinylene one induces significant redshifts of both the low-energy one-photon absorption and TPA bands. Interestingly, a major enhancement in TPA responses is observed, whereas OPA intensities are only weakly affected. Similarly, phosphane oxide derivatives show similar OPA responses than the corresponding sulfides but their TPA responses are significantly larger. Finally, the electronic coupling between dipolar branches promoted by common PO or PS acceptor moieties induces either slight enhancement of the TPA responses or broadening of the TPA band in the near infrared (NIR) region. Such behavior markedly contrasts with triphenylamine-core-mediated coupling, which gives evidence for the different types of interactions between branches. PMID- 21328700 TI - A practical synthesis of cephalostatin 1. PMID- 21328701 TI - Dynamic study of PLGA/CS nanoparticles delivery containing drug model into phantom tissue using CO2 laser for clinical applications. AB - In this study, cationic nanoparticles (NPs) were prepared by coating chitosan (CS) on the surface of PLGA NPs. To our knowledge most of the work in the field of drug delivery systems using lasers has been performed using short pulses with micron and submicron durations. We carried out an experiment using superlong PLS R (10 ms) and CW CO2 laser modes on simulated drug-biogelatin model where drug was encapsulated by PLGA/CS NPs. Maximum depth of drug containing cavitation was achieved faster at higher powers and shorter irradiation time in CWC mode. We believe that the main mechanism at work with superlong pulses is both photothermal due to vaporization and photomechanical due to photophoresis and cavitation collapse. In the case of CW, however, it is purely photothermal. Thus, drug molecules can be transported into tissue bulk by thermal waves which can be described by the Fick's law in 3-D model for a given cavity geometry and the mechanical waves, unlike only by pure photomechanical waves (i.e. photoacoustically) as with short pulses. Therefore, our studies could offer an alternative for currently existing method for drug delivery. PMID- 21328702 TI - Molecular cytogenetic characterization of telomere-specific repetitive DNA sequences in Rana rugosa. AB - We performed a molecular cloning of the glutamic oxaloacetic transaminase (GOT1) gene from R. rugosa, and determined its chromosomal location. This gene was reportedly localized near the sex-determining region of the ZW sex chromosomes in the frog Buergeria buergeri; however, the GOT1 gene was mapped to the distal end of chromosome 9 in R. rugosa using a GOT1 cDNA FISH probe. This was also the case when a 46.3 kb genomic clone containing exon 8 and 9 and the 3'-neighboring region of the GOT1 gene, designated clone B, was used as probe. However, weak signals were also detected at the telomeric ends of other autosomes and the Z sex chromosome, and near the centromeric region of the W sex chromosome. To intensify the signals, we used eight internal fragments in clone B and applied them to chromosome mapping. Consequently, only two fragments containing repeated sequence blocks produced hybridization signals; those signals were observed on autosomes and ZW sex chromosomes. The 3'-neighboring region contained two types of repeated sequence elements: a 41 bp element, designated 41-REL, localized to telomeric ends of autosomes and a 31 bp element, designated 31-REL, localized to telomeric ends of all autosomes and the ZW sex chromosomes, and also near the centromere on the W long arm. The results collectively suggest that the two repeated sequence elements were independently amplified around the chromosomal telomeres in R. rugosa, indicating that they will be useful cytogenetic markers for studying karyotypic evolution-especially the W chromosome differentiation-in this species. PMID- 21328703 TI - Effect of basic fibroblast growth factor on the cellular repopulation of decellularized anterior cruciate ligament allografts. AB - The use of decellularized anterior cruciate ligament (ACL) allografts in ACL replacement surgery may allow for the native structure of the ligament to be retained, thereby recapturing the function of the ligament post-injury. Our previous work has focused on repopulating decellularized allograft ACL tissue with ACL fibroblasts in order to prevent destructive remodelling of the implanted tissue by extrinsic host cells. In this study, the use of basic fibroblast growth factor (bFGF) to improve the cellular repopulation of decellularized ACL tissue was assessed. A concentration of 6 ng/ml bFGF was demonstrated to be effective in increasing cellular growth in the absence of tissue; however, this concentration, as well as reduced and increased levels of bFGF (0.1 and 60 ng/ml, respectively), failed to increase cellular repopulation of ACL fibroblast-seeded decellularized tissue after 28 days of culture. Mean repopulation levels of 11-19% of fresh tissue [3200-5300 cells/mg dry weight (dwt) tissue] were achieved after 28 days in culture. Qualitative observation of histological samples suggested that different repopulation characteristics exist at various concentrations of bFGF and, in particular, that bFGF may be stimulating a catabolic pathway resulting in matrix destruction. Significant differences in the effects of bFGF observed between cell-only and cell-and-tissue studies serve to reinforce the concept that cells respond to stimuli in a different manner, depending on the surrounding environment. As a result, caution should be used when information obtained from studies utilizing cells alone is applied to the development of tissue-engineered constructs. PMID- 21328704 TI - Predicting protein folding rate from amino acid sequence. AB - Predicting protein folding rate from amino acid sequence is an important challenge in computational and molecular biology. Over the past few years, many methods have been developed to reflect the correlation between the folding rates and protein structures and sequences. In this paper, we present an effective method, a combined neural network--genetic algorithm approach, to predict protein folding rates only from amino acid sequences, without any explicit structural information. The originality of this paper is that, for the first time, it tackles the effect of sequence order. The proposed method provides a good correlation between the predicted and experimental folding rates. The correlation coefficient is 0.80 and the standard error is 2.65 for 93 proteins, the largest such databases of proteins yet studied, when evaluated with leave-one-out jackknife test. The comparative results demonstrate that this correlation is better than most of other methods, and suggest the important contribution of sequence order information to the determination of protein folding rates. PMID- 21328705 TI - Error tolerant NMR backbone resonance assignment and automated structure generation. AB - Error tolerant backbone resonance assignment is the cornerstone of the NMR structure determination process. Although a variety of assignment approaches have been developed, none works sufficiently well on noisy fully automatically picked peaks to enable the subsequent automatic structure determination steps. We have designed an integer linear programming (ILP) based assignment system (IPASS) that has enabled fully automatic protein structure determination for four test proteins. IPASS employs probabilistic spin system typing based on chemical shifts and secondary structure predictions. Furthermore, IPASS extracts connectivity information from the inter-residue information and the (automatically picked) (15)N-edited NOESY peaks which are then used to fix reliable fragments. When applied to automatically picked peaks for real proteins, IPASS achieves an average precision and recall of 82% and 63%, respectively. In contrast, the next best method, MARS, achieves an average precision and recall of 77% and 36%, respectively. The assignments generated by IPASS are then fed into our protein structure calculation system, FALCON-NMR, to determine the 3D structures without human intervention. The final models have backbone RMSDs of 1.25A, 0.88A, 1.49A, and 0.67A to the reference native structures for proteins TM1112, CASKIN, VRAR, and HACS1, respectively. The web server is publicly available at http://monod.uwaterloo.ca/nmr/ipass. PMID- 21328706 TI - Prediction of the exposure status of transmembrane beta barrel residues from protein sequence. AB - We present BTMX (Beta barrel TransMembrane eXposure), a computational method to predict the exposure status (i.e. exposed to the bilayer or hidden in the protein structure) of transmembrane residues in transmembrane beta barrel proteins (TMBs). BTMX predicts the exposure status of known TM residues with an accuracy of 84.2% over 2,225 residues and provides a confidence score for all predictions. Predictions made are in concert with the fact that hydrophobic residues tend to be more exposed to the bilayer. The biological relevance of the input parameters is also discussed. The highest prediction accuracy is obtained when a sliding window comprising three residues with similar C(alpha)-C(beta) vector orientations is employed. The prediction accuracy of the BTMX method on a separate unseen non-redundant test dataset is 78.1%. By employing out-pointing residues that are exposed to the bilayer, we have identified various physico chemical properties that show statistically significant differences between the beta strands located at the oligomeric interfaces compared to the non-oligomeric strands. The BTMX web server generates colored, annotated snake-plots as part of the prediction results and is available under the BTMX tab at http://service.bioinformatik.uni-saarland.de/tmx-site/. Exposure status prediction of TMB residues may be useful in 3D structure prediction of TMBs. PMID- 21328707 TI - Improved sequence-based prediction of strand residues. AB - Accurate identification of strand residues aids prediction and analysis of numerous structural and functional aspects of proteins. We propose a sequence based predictor, BETArPRED, which improves prediction of strand residues and beta strand segments. BETArPRED uses a novel design that accepts strand residues predicted by SSpro and predicts the remaining positions utilizing a logistic regression classifier with nine custom-designed features. These are derived from the primary sequence, the secondary structure (SS) predicted by SSpro, PSIPRED and SPINE, and residue depth as predicted by RDpred. Our features utilize certain local (window-based) patterns in the predicted SS and combine information about the predicted SS and residue depth. BETArPRED is evaluated on 432 sequences that share low identity with the training chains, and on the CASP8 dataset. We compare BETArPRED with seven modern SS predictors, and the top-performing automated structure predictor in CASP8, the ZHANG-server. BETArPRED provides statistically significant improvements over each of the SS predictors; it improves prediction of strand residues and beta-strands, and it finds beta-strands that were missed by the other methods. When compared with the ZHANG-server, we improve predictions of strand segments and predict more actual strand residues, while the other predictor achieves higher rate of correct strand residue predictions when under predicting them. PMID- 21328708 TI - Simulation of cell movement and interaction. AB - A mechanical model of cell motion was developed that reproduced the behaviour of cells in 2-dimensional culture. Cell adhesion was modelled with inter-cellular cross-links that attached for different times giving a range of adhesion strength. Simulations revealed an adhesion threshold below which cell motion was almost unaffected and above which cells moved as if permanently linked. Comparing simulated cell clusters (with known connections) to calculated clusters (based only on distance) showed that the calculated clusters did not correspond well across the full size range from small to big clusters. The radial distribution function of the cells was found to be a better measure, giving a good correlation with the known cell linkage throughout the simulation run. This analysis showed that cells were best modelled with a degree of stickiness just under the critical threshold level. This allowed fluidlike motion while maintaining cohesiveness across the population. PMID- 21328709 TI - Enhancing biological relevance of a weighted gene co-expression network for functional module identification. AB - Relationships among gene expression levels may be associated with the mechanisms of the disease. While identifying a direct association such as a difference in expression levels between case and control groups links genes to disease mechanisms, uncovering an indirect association in the form of a network structure may help reveal the underlying functional module associated with the disease under scrutiny. This paper presents a method to improve the biological relevance in functional module identification from the gene expression microarray data by enhancing the structure of a weighted gene co-expression network using minimum spanning tree. The enhanced network, which is called a backbone network, contains only the essential structural information to represent the gene co-expression network. The entire backbone network is decoupled into a number of coherent sub networks, and then the functional modules are reconstructed from these sub networks to ensure minimum redundancy. The method was tested with a simulated gene expression dataset and case-control expression datasets of autism spectrum disorder and colorectal cancer studies. The results indicate that the proposed method can accurately identify clusters in the simulated dataset, and the functional modules of the backbone network are more biologically relevant than those obtained from the original approach. PMID- 21328710 TI - A novel approach to DNA copy number data segmentation. AB - DNA copy number (DCN) is the number of copies of DNA at a region of a genome. The alterations of DCN are highly associated with the development of different tumors. Recently, microarray technologies are being employed to detect DCN changes at many loci at the same time in tumor samples. The resulting DCN data are often very noisy, and the tumor sample is often contaminated by normal cells. The goal of computational analysis of array-based DCN data is to infer the underlying DCNs from raw DCN data. Previous methods for this task do not model the tumor/normal cell mixture ratio explicitly and they cannot output segments with DCN annotations. We developed a novel model-based method using the minimum description length (MDL) principle for DCN data segmentation. Our new method can output underlying DCN for each chromosomal segment, and at the same time, infer the underlying tumor proportion in the test samples. Empirical results show that our method achieves better accuracies on average as compared to three previous methods, namely Circular Binary Segmentation, Hidden Markov Model and Ultrasome. PMID- 21328711 TI - Bioinformatic approaches for predicting substrates of proteases. AB - Proteases have central roles in "life and death" processes due to their important ability to catalytically hydrolyze protein substrates, usually altering the function and/or activity of the target in the process. Knowledge of the substrate specificity of a protease should, in theory, dramatically improve the ability to predict target protein substrates. However, experimental identification and characterization of protease substrates is often difficult and time-consuming. Thus solving the "substrate identification" problem is fundamental to both understanding protease biology and the development of therapeutics that target specific protease-regulated pathways. In this context, bioinformatic prediction of protease substrates may provide useful and experimentally testable information about novel potential cleavage sites in candidate substrates. In this article, we provide an overview of recent advances in developing bioinformatic approaches for predicting protease substrate cleavage sites and identifying novel putative substrates. We discuss the advantages and drawbacks of the current methods and detail how more accurate models can be built by deriving multiple sequence and structural features of substrates. We also provide some suggestions about how future studies might further improve the accuracy of protease substrate specificity prediction. PMID- 21328712 TI - The Janus-faced E-values of HMMER2: extreme value distribution or logistic function? AB - E-value guided extrapolation of protein domain annotation from libraries such as Pfam with the HMMER suite is indispensable for hypothesizing about the function of experimentally uncharacterized protein sequences. Since the recent release of HMMER3 does not supersede all functions of HMMER2, the latter will remain relevant for ongoing research as well as for the evaluation of annotations that reside in databases and in the literature. In HMMER2, the E-value is computed from the score via a logistic function or via a domain model-specific extreme value distribution (EVD); the lower of the two is returned as E-value for the domain hit in the query sequence. We find that, for thousands of domain models, this treatment results in switching from the EVD to the statistical model with the logistic function when scores grow (for Pfam release 23, 99% in the global mode and 75% in the fragment mode). If the score corresponding to the breakpoint results in an E-value above a user-defined threshold (e.g. 0.1), a critical score region with conflicting E-values from the logistic function (below the threshold) and from EVD (above the threshold) does exist. Thus, this switch will affect E value guided annotation decisions in an automated mode. To emphasize, switching in the fragment mode is of no practical relevance since it occurs only at E values far below 0.1. Unfortunately, a critical score region does exist for 185 domain models in the hmmpfam and 1,748 domain models in the hmmsearch global search mode. For 145 out the respective 185 models, the critical score region is indeed populated by actual sequences. In total, 24.4% of their hits have a logistic function-derived E-value < 0.1 when the EVD provides an E-value > 0.1. We provide examples of false annotations and critically discuss the appropriateness of a logistic function as alternative to the EVD. PMID- 21328713 TI - On occasion of the centennial year of the two greatest Croatian soccer teams: brief review of the evidence base for team physicians. PMID- 21328714 TI - Good season ahead. PMID- 21328715 TI - Stress among Croatian physicians: comparison between physicians working in emergency medical service and health centers: pilot study. AB - AIM: To determine the sources of stress, its intensity, frequency, and psychophysical and behavioral reactions in physicians working in emergency medical service and those working in health centers. METHODS: To a convenience sample of primary care physicians employed in emergency medical service (n = 79) and health centers (n = 81), we administered the list of demographic questions, Scale of Sources of Stress, Scale of Intentions of Leaving the Job, and Scale of Psychosomatic Symptoms. RESULTS: Emergency medicine physicians experienced significantly more intense and more frequent uncontrollable working situations, conflict between work and family roles, and unfavorable relationships with coworkers than physicians working in health centers. They were also more likely to leave the job during the next few years and/or change jobs within the profession (scores 2.2 +/- 0.9 vs 1.7 +/- 0.9 out of maximum 5.0, F = 12.2, P = 0.001) and they had a poorer physical health status (scores 1.8 +/- 0.5 vs 1.7 +/ 0.5 out of maximum 4.0, F = 5.3, P = 0.023). CONCLUSION: Physicians working in emergency medical service experience more stress in almost all aspects of their work than physicians working in health centers. They also have a stronger intention of leaving the job, which decreases with years of experience. PMID- 21328716 TI - Psychotropic medication use among elderly nursing home residents in Slovenia: cross-sectional study. AB - AIM: To determine the prevalence of psychotropic medication prescribing in elderly nursing home residents in Slovenia and to explore the residents', physicians', and nursing home characteristics associated with prescribing. METHODS: In a cross-sectional study, we collected the data for 2040 nursing home residents aged 65 years and older in 12 nursing homes in Slovenia between September 25 and November 30, 2006. Prescribed medications lists were retrieved from patients' medical records. Psychotropic medications were coded according to Anatomical Therapeutic Chemical Classification 2005, which we adjusted for the purposes of the study. Multivariate logistic regression analysis was performed to determine the residents', physicians', and nursing home characteristics associated with prescribing. RESULTS: Residents were from 65 to 104 years old (median, 83 years) and 1606 (79%) of them were female. A total of 970 (48%) residents had dementia and 466 had depression (23%). In 1492 (73%) residents, at least one psychotropic medication was prescribed. Nine hundred sixty residents were prescribed hypnotics and sedatives (47%), 572 (28%) antipsychotics, 460 (23%) antidepressants, and 432 (21%) anxiolytics. Residents' characteristics associated with psychotropic medication use were female sex (odds ratio [OR], 1.36; 95% confidence interval [CI], 1.03-1.80), age (OR, 0.97; 95% CI, 0.95 0.98), permanent restlessness (OR, 2.54; 95% CI, 1.71-3.78), dementia (OR, 1.76; 95% CI, 1.33-2.34), depression (OR, 5.51; 95% CI, 3.50-7.58), and the number of prescribed medications (OR, 1.29; 95% CI, 1.23-1.35). Of physicians' characteristics (sex, age, specialization in general practice, years of working experiences as a general practitioner, and years of experiences working in a nursing home), male sex was associated with psychotropic medication prescribing (OR, 1.80; 95% CI, 1.17-2.76). CONCLUSION: Frequency of psychotropic medication prescribing in elderly nursing home residents in Slovenia is high and is comparable to Western European countries. Our next step should be optimizing the prescribing in patients with the highest prescription rate. PMID- 21328717 TI - Risk factors of child physical abuse by parents with mixed anxiety-depressive disorder or posttraumatic stress disorder. AB - AIM: To determine the risk that parents with mixed anxiety and depressive disorder (MADD) or posttraumatic stress disorder (PTSD) will physically abuse their child and evaluate the specific contribution of mental health, perceived social support, experience of childhood abuse, and attributes of family relations to the risk of child physical abuse. METHOD: The study conducted in 2007 included men (n = 25) and women (n = 25) with a diagnosis of MADD, men with a diagnosis of PTSD (n = 30), and a control sample of parents from the general population (n = 100, 45 men and 55 women) with children of elementary school age. General Information Questionnaire, Child Abuse Experience Inventory, Perceived Social Support Scale, and the Child Abuse Potential Inventory (CAPI) Clinical Abuse Scale were used. RESULTS: Total results on the Clinical Abuse Scale of the CAPI indicated higher risk of child physical abuse in parents with MADD (273.3 +/- 13.6) and in fathers with PTSD (333.21 +/- 17.98) than in parents from the general population (79.6 +/- 9.9) (F = 110.40, P < 0.001; tPTSD,MADD = 13.73, P < 0.001). A hierarchical regression analysis showed that the greatest predictors in the multivariate model were mental health difficulties, poorer economic status, poor social support, and physical and verbal aggression in partner conflicts. CONCLUSION: Parents with MADD and PTSD exhibit high risk of child abuse. Since parents with PTSD have significantly higher risk of child abuse than parents with MADD, further large-sample research is needed to clarify the relationship between PTSD intensity and the risk of child abuse. PMID- 21328718 TI - Treatment of chronic hepatitis C in Croatian war veterans: experiences from Croatian reference center for viral hepatitis. AB - AIM: To examine the risk factors, comorbidity, severity of liver disease, treatment course, and outcome in Croatian war veterans with chronic hepatitis C, especially those suffering from posttraumatic stress disorder (PTSD). METHODS: We collected medical records of 170 adult men diagnosed with chronic hepatitis C who started treatment with a combination of pegylated interferon-alpha and ribavirin between January 2003 and June 2009 at the Croatian Reference Centre for Viral Hepatitis. RESULTS: Participants' mean age was 43 +/- 9 years. Among 170 participants, there were 37 war veterans (22%). The main risk factor in veteran patients were operative procedures with transfusions (46% vs 5% in non-veterans; P < 0.001) and in non-veteran patients intravenous drug use (42.1% vs 13%; P < 0.001). The average duration of infection was longer in war veterans (14.5 +/- 3.4 vs 12.2 +/- 7.2 years; P = 0.020). The percentage of PTSD comorbidity in the whole group was 11% (18/170) and in the war veterans group 49% (18/37). The prevalence of sustained virological response in patients with PTSD was 50% and in patients without PTSD 56%. Treatment reduction in patients with PTSD (33%) was higher than in patients without PTSD (12%; P = 0.030). CONCLUSION: Croatian war veterans are a group with high risk of chronic hepatitis C infection because many of them were wounded during the Croatian War 1991-1995. Considerations about PTSD as a contraindication for interferon treatment are unjustified. If treated, patients with PTSD have an equal chance of achieving sustained virological response as patients without PTSD. PMID- 21328719 TI - Blood lactate levels in patients receiving first- or second- generation antipsychotics. AB - AIM: To compare the blood lactate levels between patients with psychotic disorder receiving first- and those receiving second-generation antipsychotics. METHODS: The study was conducted at the psychiatric inpatient and outpatient clinics of the Split Clinical Hospital from June 6, 2008 to October 10, 2009. Sixty patients with psychotic disorder who were assigned to 6-month treatment were divided in two groups: 30 received haloperidol (first generation antipsychotic) and 30 received olanzapine (second generation antipsychotic). Blood lactate levels, other metabolic parameters, and scores on the extrapyramidal symptom rating scale were assessed. RESULTS: Patients receiving haloperidol had significantly higher blood lactate levels than patients receiving olanzapine (P < 0.001). They also more frequently had parkinsonism, which was significantly correlated with both haloperidol treatment at 1 month (P < 0.001) and 6 months (P = 0.016) and olanzapine treatment at baseline (P = 0.016), 3 months (P = 0.019), and 6 months (P = 0.021). Also, patients receiving haloperidol had significant correlation between blood lactate and dystonia at 1 month (P < 0.001) and 6 months (P = 0.012) and tardive dyskinesia at 1 month (P = 0.032). There was a significant difference between the treatment groups in lactate levels at all points from baseline to month 6 (P < 0.001). CONCLUSION: It is important to be aware of the potential effect of haloperidol treatment on increase in blood lactate levels and occurrence of extrapyramidal side effects. Therefore, alternative antipsychotics should be prescribed with lower risk of adverse side effects. PMID- 21328720 TI - Parental administration of antipyretics to children with upper respiratory tract infections without consultation with a physician. AB - AIM: To evaluate the administration of antipyretics to children with upper respiratory tract infections (URTI) by their parents or guardians without consultation with physicians, and compare epidemiological and clinical characteristics of patients who received antipyretics and of untreated patients. METHODS: A prospective observational study was performed in three pediatric clinics in Zagreb, Croatia, from March to June 2002. A total of 171 children aged from 2 to 14 years with symptoms and signs of URTI lasting more than 2 days and fever above 38 degrees C lasting more than 2 days were included in the study. Data were collected on the usage of antipyretics, patients' demographic and epidemiological characteristics, and clinical signs and symptoms. RESULTS: Antipyretics, predominantly paracetamol, were used in 29.8% of patients. Their usage was less frequent in children attending day-care centers (49% of treated and 70% of untreated children, P = 0.014) and in children with reiterated URTIs (33.3% of treated and 55.8% of untreated children, P = 0.008). However, it was more frequent in children with recent URTIs in the family (33.3% of treated and 7.5% of untreated children, P < 0.001). Overall, most clinical signs and symptoms of URTI were notably less pronounced in patients treated with antipyretics. CONCLUSIONS: Antipyretics use correlated with less pronounced clinical signs and symptoms of infection, which indicates their anti-inflammatory activity, but also with negative effects such as lethargy. It is necessary to educate parents on the positive and negative aspects of antipyretics use and on the optimal choice of an antipyretic drug. PMID- 21328721 TI - Ureterorenoscopic treatment of ureteral stones--influence of operator's experience and skill on the procedure outcome. AB - AIM: To observe the influence of operating urologist's education and adopted skills on the outcome of ureterorenoscopy treatment of ureteral stones. METHODS: The study included 422 patients (234 men, 55.4%) who underwent ureterorenoscopy to treat ureteral stones at the Urology Department of Clinical Hospital Center Split, Croatia, between 2001 and 2009. All interventions were carried out with a semi-rigid Wolf ureteroscope and an electropneumatic generator used for lithotripsy. The operating specialists were divided into two groups. The first group included 4 urologists who had started learning and performing endoscopic procedures at the beginning of their specialization and the second group included 4 urologists who had started performing endoscopic procedures later in their careers, on average more than 5 years after specialization. RESULTS: Radiology tests confirmed that 87% (208/238) of stones were completely removed from the distal ureter, 54% (66/123) from the middle ureter, and 46% (28/61) from the proximal ureter. The first group of urologists completed significantly more procedures successfully, especially for the stones in the distal (95% vs 74%; P = 0.001) and middle ureter (66% vs 38%; P = 0.002), and their patients spent less time in the hospital postoperatively. CONCLUSION: Urologists who started learning and performing endoscopic procedures at the beginning of their specialization are more successful in performing ureteroscopy. It is important that young specialists receive timely and systematic education and cooperate with more experienced colleagues. PMID- 21328722 TI - Incidence and predictors of asymptomatic atrial fibrillation in patients older than 70 years with complete atrioventricular block and dual chamber pacemaker implantation. AB - AIM: To evaluate predictors of asymptomatic atrial fibrillation in patients older than 70 years with complete atrioventricular (AV) block, normal left ventricular systolic function, and implanted dual chamber (DDD) pacemaker. METHODS: Hundred and eighty six patients with complete AV block were admitted over one year to the Sisters of Mercy University Hospital. The study recruited patients older than 70 years, with no history of atrial fibrillation, heart failure, or reduced left ventricular systolic function. All the patients were implanted with the same pacemaker. Out of 103 patients who were eligible for the study, 81 (78%) were evaluated. Among those 81 (78%) were evaluated. Eighty one (78%) patients were evaluated. Follow-up time ranged from 12 to 33 months (average +/-standard deviation 23 +/- 5 months). Primary end-point was asymptomatic atrial fibrillation occurrence recorded by the pacemaker. Atrial fibrillation occurrence was defined as atrial high rate episodes (AHRE) lasting >5 minutes. Binary logistic regression was used to identify the predictors of development of asymptomatic atrial fibrillation. Results. The 81 patients were stratified into two groups depending on the presence of AHRE lasting >5 minutes (group 1 had AHRE>5 minutes and group 2 AHRE<5 minutes). AHRE lasting >5 minutes were detected in 49 (60%) patients after 3 months and in 53 (65%) patients after 18 moths. After 3 months, only hypertension (odds ratio [OR], 17.63; P = 0.020) was identified as a predictor of asymptomatic atrial fibrillation. After 18 months, hypertension (OR, 14.0; P = 0.036), P wave duration >100 ms in 12 lead ECG (OR, 16.5; P = 0.001), and intracardial atrial electrogram signal amplitude >4 mV (OR, 4.27; P = 0.045) were identified as predictors of atrial fibrillation. CONCLUSION: In our study population, hypertension was the most robust and constant predictor of asymptomatic atrial fibrillation after 3 months, while P wave duration >100 ms in 12-lead ECG and intracardial atrial signal amplitude were predictors after 18 months. PMID- 21328723 TI - Cotton textiles modified with citric acid as efficient anti-bacterial agent for prevention of nosocomial infections. AB - AIM: To study the antimicrobial activity of citric acid (CA) and sodium hypophosphite monohydrate (SHP) against gram-positive and gram-negative bacteria, and to determine the influence of conventional and microwave thermal treatments, on the effectiveness of antimicrobial treatment of cotton textiles. METHOD: Textile material was impregnated with CA and SHP solution and thermally treated by either conventional or microwave drying/curing treatment. Antibacterial effectiveness was tested according to ISO 20743:2009 standard, using absorption method. The surfaces were morphologically observed by scanning electron microscopy, while physical characteristics were determined by wrinkle recovery angles method (DIN 53 891), tensile strength (DIN 53 837), and whiteness degree method (AATCC 110-2000). RESULTS: Cotton fabric treated with CA and SHP showed significant antibacterial activity against MRSA (6.38 log10 treated by conventional drying and 6.46 log10 treated by microwave drying before washing, and 6.90 log10 and 7.86 log10, respectively, after 1 cycle of home domestic laundering washing [HDLW]). Antibacterial activity was also remarkable against S. aureus (4.25 log10 by conventional drying, 4.58 log10 by microwave drying) and against P. aeruginosa (1.93 log10 by conventional drying and 4.66 log10 by microwave drying). Antibacterial activity against P. aeruginosa was higher in samples subjected to microwave than in conventional drying. Antibacterial activity was reduced after 10 HDLW cycles but the compound was still effective. The surface of the untreated cotton polymer was smooth, while minor erosion stripes appeared on the surfaces treated with antimicrobial agent, and long and deep stripes were found on the surface of the washed sample. CONCLUSION: CA can be used both for the disposable (non-durable) materials (gowns, masks, and cuffs for blood pressure measurement) and the materials that require durability to laundering. The current protocols and initiatives in infection control could be improved by the use of antimicrobial agents applied on cotton carbohydrate polymer. PMID- 21328724 TI - Urban-rural differences in a population-based breast cancer screening program in Croatia. AB - AIM: To investigate urban-rural differences in the distribution of risk factors for breast cancer. METHODS: We analyzed the data from the first round of the "Mamma" population based-screening program conducted in Croatia between 2007 and 2009 and self-reported questionnaire results for 924 patients with histologically verified breast cancer. Reproductive and anthropometric characteristics, family history of breast cancer, history of breast disease, and prior breast screening history were compared between participants from the city of Zagreb (n = 270) and participants from 13 counties with more than 50% of rural inhabitants (n = 654). RESULTS: The screen-detected breast cancer rate was 4.5 per 1000 mammographies in rural counties and 4.6 in the city of Zagreb, while the participation rate was 61% in rural counties and 59% in Zagreb. Women from Zagreb had significantly more characteristics associated with an increased risk of breast cancer (P<0.001 in all cases): no pregnancies (15% vs 7%), late age of first pregnancy (>= 30 years) (10% vs 4%), and the most recent mammogram conducted 2-3 years ago (32% vs 14%). Women from rural counties were more often obese (41% vs 28%) and had early age of first live birth (<20 years) (20% vs 7%, P<0.001 for both). CONCLUSION: Identification of rural-urban differences in mammography use and their causes at the population level can be useful in designing and implementing interventions targeted at the reduction of inequalities and modifiable risk factors. PMID- 21328725 TI - The founding of the Centre for Palliative Medicine, Medical Ethics and Communication Skills: a new step toward the development of patient-oriented medicine in Croatia. PMID- 21328726 TI - Everything for her! PMID- 21328727 TI - Influenza influencing democracy. PMID- 21328786 TI - Ask the doctor. My daughter gave me a pedometer and told me to walk 10,000 steps a day. When I wore it for a while, I realized I was taking only about 3,000 steps a day. Is 10,000 a realistic number for someone my age (70 years)? PMID- 21328787 TI - Ask the doctor. I have had a leaking aortic valve for many years. I get an echocardiogram every six months. After the latest one, my doctor told me that my heart was enlarging and asked me repeatedly whether I was getting short of breath with exercise. I told him that sure, I get tired, but it isn't like I am breathing hard while sitting still. Now he wants me to have surgery to replace the valve. Should I do this at age 68? PMID- 21328788 TI - Exercise at rest--no longer an oxymoron? PMID- 21328789 TI - Nanoburrs seek, heal injury in artery. PMID- 21328790 TI - An ICD that works without wires. PMID- 21328791 TI - Removing fat makes HDL ("good cholesterol") even better. PMID- 21328792 TI - Systematic review and meta-analysis of immunosuppressant therapy clinical trials in membranous lupus nephritis. AB - PURPOSE: We performed a systematic review and meta-analysis to compare response rates (complete remission plus partial remission) for nonsteroid immunosuppressant therapy to steroid-only immunosuppressant therapy in patients with membranous lupus nephritis. METHODS: A literature review was conducted from June 25, 2010 by querying PubMed, MEDLINE, and EMBASE databases. Inclusion criteria were trials containing remission data on patients with confirmed pure class V (Va and Vb) membranous lupus nephritis. The primary analysis evaluates response rates for regimens that contain at least one nonsteroid immunosuppressant therapy and steroid-only immunosuppressant therapy. A proportion meta-analysis using a DerSimonian-Laird random-effects model was performed. Data are reported as pooled proportions in percentages with 95% confidence intervals. Significant heterogeneity and/or bias were compensated for by trial exclusion. RESULTS: Twenty-four studies met inclusion criteria for meta analysis, which yielded 34 groups of patients' data. Upon meta-analysis, the response rate for nonsteroid immunosuppressant therapy is higher than for steroids alone (81% [74%-87%] vs 60% [39%-79%]), even when compensating for significant heterogeneity and bias (76% [71%-81%] versus 60% [39%-79%]). CONCLUSION: Nonsteroid immunosuppressant therapies in combination with steroids seem to be more effective than steroids alone for inducing partial or complete remission in patients with membranous lupus nephritis who have nephrotic proteinuria at baseline. This trial was not able to analyze adverse events, flares, relapses, or patient survival because of underreporting. PMID- 21328793 TI - [Dysmenorrhea in adolescents: epidemio-clinical study at the referral health center, Bamako District. Report of 300 cases]. AB - This clinical epidemiological study has been conducted at the district hospital of Commune II in Bamako area.Dysmenorrhea has become a very common feature during out patients consultation. It affects almost one adolescent out of 3 examined during this study which represent 42, 8% of the studied population ranged from 10 to 19 years, with a men age of 16 years. Most of them were household women (50%),never pregnant (60%) and never delivery (64%). Most of them have been mainly claiming about contraction pain (33%) and discomfort (17,3%). The pain has been followed by asthenia (86,7%), and irritability (87,7%).Dysmenorrhea was a major cause of absenteism (48,3%). The factors influencing this type of dysmenorhea was the age and psychological stress. PMID- 21328794 TI - Abstracts of the 7th International Conference of the Hospital Infection Society, Liverpool, UK, 10-13 October 2010. PMID- 21328796 TI - Tumors of sigmoid colon following ureterosigmoidostomy. PMID- 21328795 TI - Social support modifies the relationship between personality and depressive symptoms in older adults. AB - OBJECTIVE: To explore the relationship between personality, social support, and depression in older adults, identify the personality trait and social support dimension most closely associated with depression, and determine whether the relationship between personality and depression varies by level of social support. DESIGN: Cross-sectional analysis within longitudinal study. PARTICIPANTS: Older patients originally diagnosed with major depression (n = 108) and never-depressed comparison group of older adults (n = 103). MEASUREMENTS: Patients sufficiently recovered from major depression and comparison participants were administered the NEO Personality Inventory. Social support was measured annually for both groups. Patients were administered the Montgomery-Asberg Depression Rating Scale (MADRS) every 3 months. RESULTS: Patients and comparison participants differed on four of the five NEO domains and all four social support dimensions, but personality did not significantly predict depression status (patient/comparison) in controlled analyses. Within the patient group, subjective social support was the only dimension correlated with MADRS score. In separate linear regression analyses among the patients, controlling for age, sex, and subjective social support, the domains of Neuroticism, Openness to Experience, Conscientiousness, and Extraversion were associated with MADRS score. For Neuroticism and Openness, the association varied by level of subjective social support. CONCLUSIONS: Our research confirmed that older patients differed from never-depressed older adults in dimensions of personality and social support, and the relationship between these variables differed by depression status. The relationship between personality, social support, and depressive symptoms in older adults recovering from depression is also complex, with subjective social support modifying the association between personality and depression. PMID- 21328797 TI - Hospital Peer Review. As measures, reporting grow, so does the need for QI. PMID- 21328798 TI - Acknowledge the NCT. PMID- 21328799 TI - Retracted: Hydrostatic pressure promotes Wnt10b and Wnt4 expression dependent and independent on ERK signaling in early-osteoinduced MSCs. PMID- 21328800 TI - Lack of association between the IL-10 gene polymorphisms and features of the metabolic syndrome. AB - BACKGROUNDS: Insulin resistance plays a major role in the pathogenesis of the metabolic syndrome. Inflammation is the leading cause of insulin resistance, and interleukin 10 (IL-10) is one of the anti-inflammatory cytokines. We conducted a case-control study to investigate the association between the IL-10 polymorphisms and the metabolic syndrome. METHODS: One thousand two hundred two unrelated subjects residing in southern Taiwan were retrospectively recruited from a community-based health screening program. Two hundred sixty subjects were defined as the metabolic syndrome (3-5 risk components) and 549 subjects as controls (0-1 risk component) on the basis of the Asian version of the Adult Treatment Panel III criteria. A functional IL-10 single nucleotide polymorphism (SNP; rs1800871) and 2 tagging SNPs (rs3790622, rs3021094) were genotyped by TaqMan method. RESULTS: We analyzed the association between the genotypes and the presence of the metabolic syndrome or metabolic traits by chi2 test and multivariant logistic regression. None of the IL-10 SNPs were found to be significantly related with the metabolic syndrome or its risk components. All the 3 SNPs were in single linkage disequilibrium block. Haplotype analysis did not yield significant association between IL-10 gene and the metabolic syndrome (global P = 0.88). CONCLUSIONS: Because we used tagging SNPs and a modest clinical cohort, we concluded that the IL-10 gene polymorphisms may be unlikely to play an important role for the metabolic syndrome. PMID- 21328803 TI - Poverty in Edwardian Britain. AB - This article introduces a newly discovered household budget data set for 1904. We use these data to estimate urban poverty among working families in the British Isles. Applying Bowley's poverty line, we estimate that at least 23 per cent of people in urban working households and 18 per cent of working households had income insufficient to meet minimum needs. This is well above Rowntree's estimate of primary poverty for York in 1899 and high in the range that Bowley found in northern towns in 1912-13. The skill gradient of poverty is steep; for instance, among labourers' households, the poverty rates are close to 50 per cent. Measures of the depth of poverty are relatively low in the data, suggesting that most poor male-headed working households were close to meeting Bowley's new standard. PMID- 21328801 TI - The vascular depression hypothesis: an update. PMID- 21328804 TI - New series for agricultural prices in London, 1770-1914. AB - New annual series for the prices of major agricultural commodities sold in London markets between 1770 and 1914 are presented. These series are based on bimonthly observations drawn from newspaper market reports. The products covered are wheat, barley (grinding and malting), oats, potatoes, hay, butter, beef, mutton, and pork. Annual prices are calculated for both calendar and production years. The new series are compared to existing series. PMID- 21328805 TI - "Children of the city": juvenile justice, property, and place in England and Scotland, 1945-60. AB - This article uses cases studies of Dundee and Manchester to explain juvenile property-offending in terms of young people's use of objects and spaces in the period 1945-60. A composite picture is assembled of objects stolen, which reflects growth of the specifically "teenage" consumer market as well as continued significance of young people's contribution to family economies. Concerns about youth, property, and space were reported in newspapers in terms of vandalism and hooliganism. "Play" and "nuisance" were overlapping and contested categories; re-education of young people in the correct use of place, space, and property was a key aim of the postwar juvenile justice system. PMID- 21328806 TI - Do changes in the labour market take families out of poverty? Determinants of exiting poverty in Brazilian metropolitan regions. AB - Using survival models, we test whether short-term changes in the labour market affect poverty duration. Data are from the Brazilian Monthly Employment Survey. Such a monthly dataset permits more accurate estimations of events than using annual data, but its panel follows households for a short period. Then methods that control for both right- and left-censoring should be used. The results are as follows: households with zero income are not those with the lowest chances of exiting; changes in aggregate unemployment do not affect poverty duration; and increasing wages in the informal sector has a negative effect on poverty duration. PMID- 21328807 TI - Understanding the complexities of private standards in global agri-food chains as they impact developing countries. AB - The increasing prevalence of private standards governing food safety, food quality and environmental and social impacts of agri-food systems has raised concerns about the effects on developing countries, as well as the governance of agri-food value chains more broadly. It is argued that current debates have been 'clouded' by a failure to recognise the diversity of private standards in terms of their institutional form, who develops and adopts these standards and why. In particular, there is a need to appreciate the close inter-relationships between public regulations and private standards and the continuing ways in which private standards evolve. PMID- 21328808 TI - Abortion in late Imperial China: routine birth control or crisis intervention? AB - In late imperial China, a number of purported methods of abortion were known; but who actually attempted abortion and under what circumstances? Some historians have suggested that abortion was used for routine birth control, which presupposes that known methods were safe, reliable, and readily available. This paper challenges the qualitative evidence on which those historians have relied, and presents new evidence from Qing legal sources and modern medical reports to argue that traditional methods of abortion (the most common being abortifacient drugs) were dangerous, unreliable, and often cost a great deal of money. Therefore, abortion in practice was an emergency intervention in a crisis: either a medical crisis, in which pregnancy threatened a woman's health, or a social crisis, in which pregnancy threatened to expose a woman's extramarital sexual relations. Moreover, abortion was not necessarily available even to women who wanted one. PMID- 21328809 TI - Can microbicides prevent medical transmission in MSM? Vaginal microbicides will be used rectally. PMID- 21328810 TI - Ongoing microbicide studies may lead to more options. Daily doses and a vaginal ring are being tried. PMID- 21328811 TI - HIV risks remain, as needle safety goal fades. National surveillance of injuries still lacking. PMID- 21328812 TI - Study sheds light on HIV ART-naive population. ART is underused, findings suggest. PMID- 21328813 TI - CDC funds expand HIV prevention effort. Hard hit areas, risk groups targeted. PMID- 21328814 TI - FDA notifications. Entecavir (Baraclude(r)) labeling changed. PMID- 21328815 TI - FDA notifications. FDA tentatively approves fixed-dose lamivudine/zidovudine. PMID- 21328816 TI - FDA notifications. New risk information added to label of antiviral saquinavir. PMID- 21328817 TI - Research. Study aims to promote healthy lifestyle changes for individuals with HIV. PMID- 21328818 TI - Research. Center to examine health impact of alcohol for HIV patients. PMID- 21328819 TI - Study leads to revision in WHO guidelines for HIV women. PMID- 21328820 TI - Workers' compensation. Hospital not required to provide data on HIV-infected children. PMID- 21328821 TI - SSI. ALJ considered all impairments before denying benefits. PMID- 21328822 TI - [Neuroimaging and neurobiology of social anxiety]. AB - AIM: Social Anxiety Disorder (SAD) represents one of the most frequent psychiatric disorders. The results of a systematic review of the literature published until January 2010 on the neurobiology of SAD are reported, giving prominence to functional neuroimaging (fNI) findings. METHODS: A literature search of neuroimaging and neurobiology studies of SAD was conducted on PubMed and Medline electronic archives and by canvassing English-language and other European languages publications. Eligible studies were restricted to those on adult population (age 16 to 65) and using DSM and ICD criteria. RESULTS: The 19 reviewed fNI studies on SAD agree in identifying a dysfunction of five main cerebral areas: the amygdala, the medial prefrontal cortex, the insula, the hippocampus and the dorsolateral prefrontal cortex. Those findings strongly suggest the presence, in this disorder, of functional alterations in the neural systems involved in the genesis of fear, in the processing of emotional stimuli, in the "self" perception and in the evaluation of others' intentions. DISCUSSION: Neurobiology research on SAD is still relatively young and, up to today, available findings are still not exhaustive. Nonetheless, a growing evidence from different lines of research seems to suggest that SAD patients may present a distinct biologic background compared to control subjects. Until now, however, no specific neurobiological aspect has been proposed for the SAD only. Per contra, results from fNI studies seem to indicate the presence of a common pattern of neural dysfunction in all the major anxiety disorders. PMID- 21328823 TI - [Violence in psychiatric inpatients]. AB - AIM: To evaluate knowledges about violence acted by psychiatric in-patients. METHODS: We selected inherent articles classified as useful to our purpose encoded in PubMed in the last 5 years, not neglecting previous but equally valid for a more precise and complete reasoning EBM Literature. RESULTS: Risk factors for violent acts are: previous acts history, male sex and young age, alcohol and drug abuse/dependence, lack of insight, anger management problems, impulsivity discontrol and ostility at admission. Most of the acts are classified as impulsive and so schizophrenic spectrum whether in presence of productive symptoms, personality disorders and manic episodes are the most involved psychiatric pathology. Clinical experience evaluating behaviour at risk as threatening or provoking acts towards patients or clinical staff and the identification of personal history features (in particular if detected at admission) should lead to the classification of patients into risk groups for acting violence during hospitalization. CONCLUSIONS: Good clinical practice aimed at violent acts reduction and possible prevention into clinical environment couldn't leave aside a precise known risk factors identification and the observation and constant monitorization of patients behaviour predictive of a possible act. PMID- 21328824 TI - [Drop-out risk factors in mood disorder: a clinical study]. AB - INTRODUCTION: The aims of this study are (i) to assess the drop-out rate in an outpatient sample with mood disorder diagnosis in a psychotherapy unit; (ii) to focus clinical and sociodemographic variables related with drop-out; (iii) to delineate a psychopathological profile of the dropping-out patient through the SCL-90-R and OPD scores. METHOD: The sample of this study includes 90 depressive patients, which came to our service for a psychotherapy. The outcome is classified as drop-out and non drop-out. Each patient is submitted to the multidimensional scale SCL-90-R in the course of the first interview. At the end of the first visit each patient has been evaluated through the first and the fourth OPD axis. A descriptive analysis of all the data collected was made and the principal links between clinical and sociodemographic variables and dropout, between SCL-90-R score and drop-out, and between OPD scores and drop-out were detected. RESULTS: About 42% of the patients were drop-out, of which 89% by the third session. The variables associated with drop-out are: pathological score in the paranoic and interpersonal sensibility scale of SCL-90-R, low compliance scores, low integration of defences, self perception, object's perception and link. DISCUSSION: The drop-out rate in depressive patients turned out to be frequent. The patient's resources in terms of relationship, self-perception and object's perception are strongly related to the drop-out risk. These results are suggestive for the idea that the evaluation of drop-out risk in psychiatric patients must considerate the subjective aspects of the patient besides the clinical features. PMID- 21328825 TI - [The aggression in SPDC: an observational study. Preliminary data]. AB - AIM: In the different psychiatric disorders the aggression often leads to uncontrolled events, taking aspects of impulsiveness and irrationality. Our research proposes the assessment of socio-demographic and clinical characteristics of patients with a psychiatric disorder, who presented an aggressive event. METHODS: The observational study was conducted on a sample of 50 patients (34 men and 16 women), hospitalized following the manifestation of an aggressive event. For each patient was provided an assessment of socio demographic and clinical variables and a psychometric investigation through: the OAS, for the analysis of aggressive episodes; the BDHI, for the hostile behavior and attitudes; the BIS-11, for the impulsiveness and the BPRS for the psychopathological aspects. RESULTS: Among the socio-demographic features investigated, the highest correlation with aggressive behavior was related to the concomitant substance abuse, type of admission to psychiatric hospital and the male gender. The OAS has shown a greater propensity to directed-aggression in males with schizophrenia, and self-directed in females with major depression. The BPRS has shown a positive correlation between hetero-directed aggressive behavior and positive symptomatology, and between the self-directed and depression, risk of suicide, feelings of guilt and somatic concerns. The BDHI has indicated greater suspicion in women's group. DISCUSSION: The hypothesis that aggression is otherwise related to specific socio-demographic and clinical characteristics was confirmed by our study. The data suggest that early identification and assessment of potential risk factors involved in the genesis of aggressive episodes would allow the clinician to implement a better strategy for prevention and intervention. PMID- 21328826 TI - [Victimization and mental disorders: results of a case-control study]. AB - AIMS: The study aimed to evaluate prevalence rates of victimization in a sample of outpatients affected by psychotic or anxiety disorder. METHODS: After informed consent 101 patients (50 affected by psychotic disorders and 51 affected by anxiety disorders according to DSM-IV TR) and a control group of non affected people matched according to gender, age, marital status and education were included in the study. Psychotic patients were submitted to evaluation by means of PANNS; control group was submitted to the MINI interview. All subjects (cases and controls) fulfilled a 14-item Victimization Questionnaire. RESULTS: Subjects affected by mental disorders reported more frequently physical aggressions (6% vs. 1% of controls, p = 0.054), contact with police for help (22.8% vs. 5% of controls, p < 0.0001), insults or offences (39.6% vs. 18.8% of controls, p = 0.001), disturbing phone-calls (19.8% vs 8.9% of controls, p = 0.027), stalking (5.9% vs. 1% of controls p = 0.054). during the last 12 months. Subjects with anxiety disorders reported victimization more frequently than psychotic patients. The comparison of the data collected in the present study with those from international literature show lower rates of victimization in our sample. CONCLUSIONS: People affected by mental illness, particularly non psychotic patients, seem to be more frequently submitted to some forms of violent and non violent victimization. PMID- 21328827 TI - [Categorical and dimensional diagnosis in schizoid and narcissistic personality disorders: critical interpretation of literature cases]. AB - In the general reflection inherent categorical and dimensional diagnosis and the opportunity to put neurotic and psychotic personality in the various chapters of the discipline, a never-ending discussion on the similarities and differences between clinical pictures classified in separate entries (think of the comings and goings from one cluster to another between schizoid and avoidant personality disorder). Other cogent discussion focused on the nosographical criteria, targeted to a modified classification that takes into account dimensional rather than descriptive criteria. About personality disorders think of the debate on their degree of severity, as assessed by criteria such dissimilar from various authors, as to be very different in this sense a ranking according to the variables considered (eg, classifications by Kernberg and Millon). As an established tradition that a contribution to psychological studies derives also from the literary and artistic forms in general, we propose, through the interpretation of literary cases, the dimensional affinity between schizoid and narcissistic disorders. The dimensions taken into account are those of affectivity and intersubjectivity, impaired in both disorders. PMID- 21328828 TI - [2011, year of paradoxes]. PMID- 21328829 TI - [Campaign against pain in pediatrics, nurses are mobilized]. PMID- 21328830 TI - [Trauma of the child and the adolescent]. PMID- 21328831 TI - [Psychological trauma in pre-school children]. AB - Overall clinical pictures of post-traumatic experiences in pre-school children depend on several factors: developmental, environmental and socio-cultural. Knowledge of these clinical pictures and the early management of these children are essential for their development and for building their personality. PMID- 21328832 TI - [Corporal approach to trauma in children]. AB - The impact of a traumatic event is specific in children, especially when the child is not yet able to speak. The body bears the symptomatic expression of trauma. Corporal management based on the Berg s method of therapeutic relaxation highlights the work need to rebuild links between feelings, affection and representation. PMID- 21328833 TI - [The sibling relationship in the event of death]. AB - The sibling relationship in the event of death. For adults and children, the death of a loved one is an unbearable loss. Although individual support is available for families, very little attention is paid to brothers and sisters. Yet, a grieving child is exposed not only on a personal level, but also, when brothers and sisters are involved, in terms of sibling dynamics. PMID- 21328834 TI - [Trauma among children and parents within the context of international adoption]. AB - Although the large majority of international adoptions are problem free, some of them involve a certain degree of suffering as much for the children as for the adoptive parents. These stumbling blocks in the relationship need to be studied taking into account the trauma experienced by each of the protagonists. PMID- 21328835 TI - [Does trauma help teenagers to "grow up"?]. AB - Traumatic events may give rise to invalidating and chronic situations of distress. The concept of post-traumatic growth suggests that trauma may help people who have experienced it to mature and make positive changes in their lives, especially teenagers. This concept and its limits deserve to be studied in greater depth. PMID- 21328836 TI - [Bibliography. Trauma of the child and adolescent]. PMID- 21328837 TI - [Pain assessment in children by triage emergency nurses]. AB - The assessment of pain in children in the paediatric emergency department is essential for high quality care. Recognizing pain is not enough: only the use of validated assessments tools enables staff to include pain on part of daily care. The objective analysis of care practices helps to improve the quality of care in children. PMID- 21328838 TI - [Hippotherapy in the paedopsychiatric care project]. AB - Hippotherapy uses relationships with horses as a mediation method. The care treatment aims to act on the psychological functioning of children affected by relational disorders, especially in order to help the development of communication and emotions. A partnership has been established between the paedopsychiatric university centre at the CHRU in Tours (37) and a horse-riding centre. PMID- 21328839 TI - [Participative ergonomics for adapting the working space to meet the needs of nursing staff]. AB - Presst-Next, the European study carried out between 2004 and 2006, highlighted the importance of teamwork in reducing the frequency of professional exhaustion and the early departure of care staff. On the basis of these results, the Armand Trousseau Hospital in Paris (AP-HP 75) has committed to a participative ergonomics approach at its paediatric emergency service. PMID- 21328840 TI - [Child injuries]. PMID- 21328841 TI - [A French delay]. PMID- 21328843 TI - [Kidney failure: peritoneal dialysis should be considered more often]. PMID- 21328844 TI - [Epidemiology and financial aspects of peritoneal dialysis in end-stage renal disease]. PMID- 21328845 TI - [Your images. Bone sarcoidosis]. PMID- 21328846 TI - [First medical assessment of foreign born adopted children]. AB - In France, every year, more than 3000 children are adopted from foreign countries. These children are potential carriers of tropical diseases which have not been detected in their home country, diseases which could jeopardize the child's development and could also affect their new family members and carers. These potential illnesses for the most part derive from the infant's geographical country of birth, which is not taken into account by the French health guidelines and recommendations (it must be noted, recommendations which can vary greatly depending upon the source of that information). Starting from an international review on the health status and epidemiological diseases which are encountered in infants adopted from countries outside of France, this summary proposes a set of recommendations and guidelines for initial medical assessment for each adopted infant according to their country of birth. PMID- 21328847 TI - [Your images. Post traumatic cervical epidural hematoma]. PMID- 21328848 TI - [Plastic, reconstructive and esthetic surgery]. PMID- 21328849 TI - [Repair of wounds: healing, sutures, grafts and flaps]. PMID- 21328850 TI - [Skin graft]. PMID- 21328851 TI - [Breast reconstruction after mastectomy]. AB - The breast reconstruction is a part of the treatment of the breast cancer today. Classically made by means of implants, the progress of plastic surgery allows henceforth to reconstruct breast with own tissues of the patients without morbidity on the donor zone, the DIEP. This technique allows to reconstruct definitively a greasy, natural and evolutionary breast in the time. It requires no reintervention. These autologues techniques are practised by plastic surgeons specialists in cancer and in mammary reconstruction. The object of this article is to inform the practitioners of the existence of these techniques so that they can inform their patients and send them to the adequate surgeon. PMID- 21328852 TI - [Plastic surgery and reimbursement]. PMID- 21328853 TI - [Complications of breast implants]. PMID- 21328854 TI - [Body contouring surgery]. AB - Body contouring after massive weight loss is an important step of the treatment for obese and overweight patients. As a member of the bariatric multidisciplinary team, the plastic surgeon helps to finish the reconstruction process by removing skin and fat excess. With the rise of bariatric surgery and extreme weight loss, this surgery is more in demand and has became more and more performed recently and well codified. Over the last decade, surgical techniques have dramatically changed allowing providing safe procedures and harmonious results. Lower body lift surgery (also known as a belt lipectomy) allows to treat safely contour deformities of the abdomen, the thigh and the buttocks resulting from massive weight loss. The result will be harmonious because the treatment is circumferential. PMID- 21328855 TI - [Surgical treatment of lipodystrophy]. AB - With the introduction of highly active antiretroviral therapy HIV has become a chronic but not necessarily a life-threatening disease. One drawback of the medication is the lipodystrophy syndrome that develops. Its precise mechanisms underlying are not well understood. The syndrome includes peripheral fat wasting (e.g. face, buttocks) and central fat accumulation. This condition can be very distressing to the patient who may be depressed and lose self-esteem which eventually leads to social withdrawal. The facial lipoatrophy is often experienced as the main problem as it is a social stigma telling other people that the patient is infected with HIV. The second zone bothering these patients is the buttocks. Buttocks lipoatrophy constitutes both an esthetic problem as well as a functional problem causing pain on sitting and even on walking. PMID- 21328856 TI - [Facial surgery]. AB - The patient who has to sustain facial surgery is doubly concerned by the functional issues of his case and his cosmetic appearance. Fortunately, in the recent period of time, huge advancements have been done permitting to offer a solution in more and more difficult situations. The aim of the present article is to give a panorama of facial plastic surgery for non-specialized physicians. The main aspects of the specialty are approached through the surgical techniques born from the progress of technology and biology. This paper treats issues of orthognatic surgery, endoscopic techniques, osteogenic distraction, different types of graft, cosmetic surgery, skin expander-balloons. PMID- 21328857 TI - [Face transplantation]. PMID- 21328858 TI - [Surgery: descriptor or subheading?]. PMID- 21328859 TI - [Anesthesia: principles, objectives and means]. AB - Anaesthetic techniques and procedures aim to perform surgery while preserving whole body integrity. Preoperative anaesthetic consultation, peroperative multiparametric monitoring, and immediate postoperative management aim to preserve patient's safety during and after anaesthesia. Mortality that is 1,000 fold higher for surgery than for anaesthesia will be reduced by preventive postoperative care management. PMID- 21328860 TI - [The pre-anesthetic consultation]. AB - The French law of December 4, 1994 has made the preanaesthetic consultation a mandatory part of the perioperative process. This consultation should be performed several days before surgery when the procedure is scheduled. This law has established that every patient undergoing surgery or an invasive procedure requiring anaesthesia should have a medical encounter with an anaesthetist to evaluate the risks associated with the procedure, inform the patient about the process and obtain his (her) agreement for the planned clinical pathway. During this encounter, the anaesthetist will also assess the perioperative risks related to an underlying disease (especially cardiac, respiratory and renal) while optimisation of a pre-existing condition is sometimes necessary before surgery. Patient's regular treatment might require some changes related to the effect of anaesthesia (antihypertensive drugs and risk of hypotension) or to the surgery (bleeding and anticoagulants/antiplatelet drugs). It is believed that the role of the general practitioner will increase significantly in the next years both in the preoperative period (drug adjustment, specific investigations) and in the postoperative period (especially after ambulatory surgery or in situations associated with a short hospital stay). PMID- 21328861 TI - [Anesthetic risk]. PMID- 21328862 TI - [New check list in the surgical unit]. PMID- 21328863 TI - [Treatments to be maintained/discontinued before anesthesia]. PMID- 21328864 TI - [Anesthetic consultation in patients with cardiac risk]. PMID- 21328865 TI - [Long-term effects of anesthesia]. PMID- 21328866 TI - [Contract commitment to public service]. PMID- 21328867 TI - [Critical review of a paper addressing the assessment of a diagnostic procedure]. PMID- 21328868 TI - [Cataract]. PMID- 21328869 TI - [Principal complications of pregnancy]. PMID- 21328870 TI - [Cardiovascular risk factors and prevention]. PMID- 21328871 TI - [Benign hypertrophy of the prostate]. PMID- 21328872 TI - [Bicetre hospital. From the castle to the CHU]. PMID- 21328873 TI - [Ecto-nucleotidases of ectonucleoside triphosphate diphosphohydrolase family: structure, localization and functional significance]. AB - Ecto-nucleotidases are enzymes of hydrolase class. They split extracellular nucleoside tri- and diphosphate. In this review a short history of these enzymes investigation, classification, structure, and functional significance of ecto nucleoside triphosphate diphosphohydrolases (E-NTPDase) has been presented. These enzymes are glycoproteins anchored in membranes. They do not form phosphorylated enzyme's form during catalytic circle, and (by analogy with membrane-bound ATPases) form homooligomeric ensembles. Activity of these enzymes depends on bivalent ions, in particular Ca2+ and Mg2+. E-NTPDases function in the composition of ecto-nucleotidase cascade that contains other nucleotide hydrolyzing enzymes. They regulate P2-receptors by hydrolyzing its ligand specifically ATP. Both modern information and results of our investigation about influence of different endo- and exogenous factors on activity of these enzymes has been presented. PMID- 21328874 TI - [The modelling of N-stearoylethanolamine effect of 17beta-estradiol in the organism of male rats]. AB - The influence of N-stearoylethanolamine (NSE) on total 11-hydroxycorticosteroids (11-HCS) and testosterone level in the blood of male rats in normal conditions and under the action of 17beta-estradiol (400 mkg/kg of body weight during 3 days) was studied. It was shown that NSE administration per os (50 mg/kg of body weight during 7 days) to intact animals did not change the level of 11-HCS and of testosterone. The administration of NSE to estrogenized male rats decreased the elevated level of 11-HCS and normalized the amount of testosterone in blood. The correction of alterated weight of adenohypophysis and testis of estrogenized male rats compared to control can be a direct evidence of NSE-mediated modelling of the effect on hypothalamic-pituitary hormone system. The effect of NSE in the testis of estrogenized male rats inhibited the process of lipid peroxidation, caused the decrease of the amount of thiobarbituric acid reactive substances and increased the activity of superoxide dismutase and catalase. The NSE showed more expressed antioxidative effect compared to vitamin E. Taking into consideration all above mentioned data we suggested that NSE administration to male rats protected Leydig cells from damage under the increase of estrogen level. PMID- 21328875 TI - [Thermal inactivation of alpha-galactosidase from Penicillium canescens]. AB - The kinetics and mechanism of thermal inactivation of Penicillium canescens alpha galactosidase in the temperature range of 55-65 degrees C have been studied. The kinetic scheme of alpha-galactosidase thermal inactivation was proposed which included the reversible dissociation of active hexamers into associating monomers and irreversible denaturation of monomers. The kinetic constants of thermal inactivation have been determined. The effect of enzyme concentration and purification efficiency has been investigated. A possibility of defence of protein molecule from thermal inactivation in the presence of BSA, glycerol, melibiose, raffinose and stachyose is shown. PMID- 21328876 TI - [The activity of pro- and antioxidant systems in the liver of freshwater fishes during different seasons]. AB - The content of lipid peroxidation products--diene conjugates, lipid hydroperoxides, thiobarbituric acid reactive substances (TBARS), vitamins A, E and carotenoids and the activity of antioxidant enzymes--superoxide dismutase, glutathione peroxidase and catalase in the liver of freshwater fishes of different species (silver carp, grass carp and common carp) in different seasons have been studied. It was established the activity of antioxidant defence system in the liver of fish depends significantly on the season and fish species. In particular, the content of lipid peroxidation products in the liver of freshwater fishes at the beginning of winter and spring was significantly higher compared to their content at the beginning of summer and autumn. The superoxide dismutase and glutathione peroxidase activities in the liver of these fish species at the beginning of winter and spring were significantly lower than at the beginning of summer and autumn while the seasonal changes of catalase activity in the liver of fish are expressed insignificantly. The content of vitamins E, A1, A2 and carotenoids in the liver of fishes of different species at the beginning of winter and spring was significantly lower than at the beginning of summer and autumn. The content of lipid peroxidation products and vitamins E, A1 and A2 in the liver of common carp is significantly lower than in the liver of silver carp and grass carp and species differences in antioxidant enzymes activity are insignificant. PMID- 21328878 TI - [Quantum-chemical investigation of tautomerization ways of Watson-Crick DNA base pair guanine-cytosine]. AB - A novel physico-chemical mechanism of the Watson-Crick DNA base pair Gua.Cyt tautomerization Gua.Cyt*<---->Gua.Cyt<---->Gua*.Cyt (mutagenic tautomers of bases are marked by asterisks) have been revealed and realized in a pathway of single proton transfer through two mutual isoenergetic transition states with Gibbs free energy of activation 30.4 and 30.6 kcal/mol and they are ion pairs stabilized by three (N2H...N3, N1H...N4- and O6+H...N4-) and five (N2H...O2, N1H...O2, N1H...N3, O6+H...N4- and 06+H...N4-) H-bonds accordingly. Stable base pairs Gua Cyt* and Gua*.Cyt which dissociate comparably easy into monomers have acceptable relative Gibbs energies--12.9 and 14.3 kcal/mol--for the explanation of the nature of the spontaneous transitions of DNA replication. Results are obtained at the MP2/6-311++G(2df,pd)//B3LYP/6-31 1++G(d,p) level of theory in vacuum approach. PMID- 21328877 TI - [Dependence of biological activity of N-acyl derivates of 6-alkoxy-2-methyl-4 mercaptoquinoline on the nature of substituents in the position 6 of the heterocycle]. AB - The influence of substituents in the sixth position of N-acyl derivatives of 2 methyl-4-mercaptoquinoline on hepatoprotective and antioxidant effect was investigated. It was also determined that alcoxy-derivatives show hepatoprotective, antiradical, antioxidant activity and can act as preventive antioxidants. Introduction of the ethoxy-group into the sixth position of azoheterocycle potentiates activity. Symbasis of intensities of hepatoprotective and antioxidant actions of the investigated compounds was proved. PMID- 21328879 TI - [Effect of beta-carotene and carotene producing yeast Phaffia rhodozyma on oxidative stress in rats treated with tetrachloromethane]. AB - Supplementation of rats' diet with beta-carotene or biomass of carotene producing yeast Phaffia rhodozyma caused a decrease of aminotransferases in the blood serum as well as a decrease of lipid peroxidation products and protein carbonil groups in the liver, brain and myocardium tissues of animals treated with tetrachloromethane. When compared to the control group the activity of superoxide dismutase, catalase and glutathione peroxidase in the liver of carotene fed rats were respectively 1.6, 2.2, and 1.5-fold higher. Thus, these supplements to standard diet slow down development of tetrachlorometane mediated oxidative stress in rats. PMID- 21328880 TI - [Relationship between the reaching of equilibrium and the accuracy of the affinity determination for antibody-antigen reaction]. AB - Theoretical investigation of the relationship between the reaching of equilibrium and the accuracy of the affinity determination for antibody-antigen reaction were carried out. It was shown that evaluation of the reagent concentrations before reaching the dynamic equilibrium leads to a decrease of estimation accuracy for the affinity constant of this reaction. We have established that for most of typical antibodies the dynamic equilibrium of their reaction with corresponding antigens comes 2-4 hours after the beginning. PMID- 21328881 TI - [Formation of O. V. Palladin's scientific school of functional neurochemistry (Kharkiv period--1925-1931)]. PMID- 21328882 TI - [Recurrent herpetic corneal erosion: diagnosis and treatment]. AB - Recurrent corneal erosion (CE) is a common anterior eye disease, which usually occurs after injury, substantially limits a patient's ability to work, and is intractable. The authors single out an individual form of CE herpetic CE (HCE) on the basis of immunofluorescence assay of a conjunctival scrape, which shows the high concentration of herpes simplex virus antigen in 53% of CE cases. Confocal microscopy revealed epithelocyte polymorphism and basement membrane defects. The treatment of patients with HCE involved 2 steps: 1) relief of acute signs of the disease via drug therapy, rapid local autocyte cinotherapy (RLACCT), or phototherapeutic keratectomy (PTK) and 2) prevention of recurrences. For this the authors developed a method based on the systemic use of a new composition of the intradermal herpes vaccine Vitaherpavac in combination with the subcutaneous interferon inducer Poludan. RLACCT was found to be the most effective medical treatment for CE and PTK was the most effective surgical one. Vaccination with the concurrent subcutaneous injection of Poludan is an effective method in preventing recurrent HCE. During a follow-up of 2 years or more, 81% of the patients achieved clinical resolution; there was a decrease in recurrence rates and severity in 15.1% and no effect in 3.8%. PMID- 21328883 TI - [Study of the three-dimensional structure and biointegrative characteristics of porous orbital implant materials]. AB - Plastic repair operations in ophthalmic surgery frequently require the use of various biological and artificial implants. The biointegrative properties of implants are provided by the physicochemical characteristics of the material that is used to make them, by the three-dimensional structure of an implant and its immunological characteristics. The authors comparatively studied the three dimensional structure of a Carbotexim-M carbonic felt, porous polyethylene, polytetrafluoroethylene, demineralized bone alloimplant, and marine coral hydroxyapatite, which are employed in orbital surgery and also examined the adhesion of fibroblasts to their surface. Comparative study using scanning electron microscopy could reveal the specific features of the relief and parameters of the threshold space of the study implant materials. A method was developed to estimate cell adhesion to the implant materials, by taking into account three-dimensional structure of their surface. PMID- 21328884 TI - [TLR9 and HBD-2 gene expression by conjunctival and corneal cells in children with dendriform herpetic keratitis]. AB - The current views of the role of innate immunity in protecting the organ of vision from viral infection offer scope for a search for new approaches to diagnosing and treating viral keratitis. TLR9 and HBD-2 gene expression in the conjunctiva and cornea was studied in children with dendriform herpetic keratitis. The latter showed a significant (more than 20-fold) increase in TLR9 gene expression as compared in healthy children. Conventional antiviral therapy for herpetic keratitis resulted in a significant decrease in the level of TLR9 gene expression (by more than two orders of magnitude). The use of the immunomodulator Superlymph in complex treatment normalized the level of TLR9 gene expression in the conjunctiva and cornea; moreover, there was a rapid relief of inflammation signs, an increase in visual acuity, and a reduction in the duration of treatment in patients with herpetic keratitis. PMID- 21328885 TI - [Biochemical parameters and prediction of the development of glaucoma in patients with progressive myopia]. AB - Examinations were made in 3 groups of patients aged 15 to 27 years: 1) patients with rapidly progressive high-grade myopia; 2) those with slowly progressive high grade myopia; 3) healthy individuals (controls). Groups 1 and 2 patients had elevated levels of lactic and pyruvic acids along with the decreased activity of the antioxidant system in the tear. Thus, a combination of indicators, such as a rise in hypoxia index by more than 1.0 and a decrease in the lacrimal fluid content of superoxide dismutase by more than 40%, may be a predictor of glaucoma in persons with rapidly progressive high-grade myopia. PMID- 21328886 TI - [Errors of classical and spectral optical coherence tomography in the measurement of retinal nerve fiber layer in healthy individuals]. AB - Two similar groups of healthy individuals were examined by optical coherence tomography (OCT) on a Stratus OCT 3000 (Carl Zeiss Meditec, Inc. USA) (n = 26) and by spectral OCT on a 3D OCT-1000 (Topcon, Japan) (n = 25). Each of two operators made two peripapillary retinal nerve fiber layer measurements during a session. The measurement error indicators (intraindividual standard deviation and repeatability rate) were determined for each of the operators and in the comparison of the latter. Spectral OCT ensured a reduction in the measurement error indicators as compared with classical OCT, which was significant when the measurement was made by a rather skilled operator. PMID- 21328887 TI - [Role of primary and stepwise prosthetic replacement in the rehabilitation of subjects with anophthalmos]. AB - The study covered 1980 patients with anophthalmos and a cosmetically poor blind eye, who were followed up in the ocular prosthesis room, Helmgoltz Institute of Eye Diseases. The optimal periods of primary and stepwise prosthetic replacement are defined and standard ocular prostheses of the most appropriate shape and size are recommended depending on the specific features of the conjunctival cavity and stump in this period. Recommendations are given on the application of ocular prostheses in congenital pathology and subatrophy. PMID- 21328889 TI - [Combined treatment in patients with unstabilized glaucoma]. AB - The efficacy of cortexine used to treat patients with unstabilized primary open angle glaucoma (OAG) was studied after penetrating through trophic sclerectomy with cyclodialysis. Thirty-nine patients (58 eyes) with developed OAG were examined. All the patients underwent penetrating trophic sclerectomy with cyclodialysis, followed by a course of subconjunctival injections of cortexine 10 mg. The positive effect persisted for 1.5 years and a stabilizing glaucomic process was observed in 78% of the patients. PMID- 21328888 TI - [Immunomodulatory role of perfluorane in the preoperative preparation of patients with rhegmatogenous retinal detachment]. AB - The paper presents the results of studying the effect of 10% perfluorane (PF) emulsion intravenously injected 1-2 days before surgical treatment for rhegmatogenous retinal detachment on the levels of the cytokines IL-1beta, TNF alpha, IL-6, and IL-4 in the serum and subretinal fluid of patients. PF infusion was found to exert an immunomodulatory effect that favored a short-term increase in the serum level of proinflammatory cytokines (IL- 1beta and IL-6) at week 1 and TNF-alpha on day 1) with their gradual normalization. The subretinal fluid showed recovery of the mechanisms for local immunological reactions; eye inflammation reduced due to the decreased production of proinflammatory cytokines and simultaneously the elevated level of the anti-inflammatory cytokine IL-4. PMID- 21328890 TI - [Effectiveness of infrared exposure to periorbital areas in partial optic nerve atrophy of varying degrees]. AB - The paper gives the comparative results of infrared exposure, drug and multimodality treatment in partial optic nerve atrophy of varying degrees, as evidenced by Doppler, electrophysiological, and morphometric studies. PMID- 21328891 TI - [Determination of the qualitative and quantitative composition of antocyan pigments as components of dietary supplements and drugs for vision]. AB - Bilberry has been long used in folk medicine and credited for an ability to improve vision, primarily night vision. The major active ingredients of bilberries are antocyans. Experimental and clinical studies confirmed the ability of bilberry antocyans to accelerate the regeneration of the photosensitive pigment rhodopsin, to improve nutrition of the retina, and to restore the tissue mechanisms of its protection. The authors studied the level of bilberry antocyans in 5 samples of dietary supplements and medicines for eyes, which had been bought in Moscow drugstores. The total content of antocyans was determined by pH differential spectrophotometry. All the test samples were shown to contain antocyan pigments; however, their concentration in different samples varied in a wide range of 0.01 to 4.2%. The maximum content was found in the drug "Focus". The qualitative composition of antocyan pigments was estimated by reverse-phase high performance liquid chromatography. All the test samples other than Vitrum vision forte turned out to contain just bilberry antocyans. The chromatographic profile of a Vitrum vision forte sample was inconsistent with bilberry antocyan pigments and the agent was likely to have another source. PMID- 21328892 TI - [Palinopsy as a manifestation of neuro-ophthalmological disorders]. AB - Palinopsy or perseveration of a pre-seen image is impaired visual perception as preservation or repeated occurrence of a visual image of an object after its disappearance from the field of vision. Patients with palinopsy are rather frequently encountered in neurological practice; however, they may first visit an ophthalmologist in some cases. The author describes a few cases in which palinopsy was the first manifestation of cerebral arteriovenous malformation, ischemic stroke, and multiple sclerosis, as well as a case of visual perseverations while using narcotic drugs. The correct evaluation of a patient's status and the determination of the scope of additional studies are of great importance in this situation. PMID- 21328893 TI - [Efficiency of laser coagulation in the treatment of rhegmatogenous retinal detachment]. AB - A hundred and seventeen (143 eyes) patients with different types of retinal detachment were examined. The patients were treated by laser coagulation on a LAHTA device (Milon). The clinical findings indicated the efficiency of retinal laser coagulation as an independent treatment for retinal rhegmatogenous detachment and indications for laser coagulation were defined in the following types of retinal detachment: subclinical local retinal detachment; fresh mobile retinal detachment (Stages A and B); non-mobile retinal detachment occupying not more than one quadrant, and partially self-circumscribed retinal detachment (Stages B and C1) taking up the lower quadrants. The benefits of this method are noninvasiveness and high functional results, which enables laser coagulation to be regarded as an independent effective treatment for the above types of retinal detachment. PMID- 21328894 TI - [Anterior stromal puncture in the treatment for corneal diseases]. AB - The paper presents an anterior stromal puncture method that is used to treat recurrent corneal erosion and painful bullous keratopathy. The mechanisms of action of anterior stromal puncture as a technique used alone and in combination with amniotic transplantation and indications for the application of this method are described. PMID- 21328895 TI - [Surgical treatment options for paralytic lagophthalmos]. AB - Facial nerve palsy may result from a broad spectrum of causes, which is largely due to its topographic complexity. Different types of cross plastic surgery and nerve autografting and muscle transplantation and transposition are used to recover nerve function. Lagophthalmos is a most severe sequel of facial nerve palsy. Blephorrhaphy and tarsorrhaphy, operations for removal of lower eyelid ectropion, and different types of palpebral fissure narrowing are used widely to correct lagophthalmos and to prevent corneal complications. Various weight implants and special springs are employed to modify upper eyelid mobility. The lengthening of the upper eyelid levator and the administration of hyaluronic acid gel and botulotoxin type A are proposed for additional upper eyelid descent. PMID- 21328896 TI - [Current methods for the early diagnosis and monitoring of vascular pathology of the eyeground]. AB - The paper analyzes the references given to papers in the Russian and foreign literature on the current methods of the early diagnosis and monitoring of vascular pathology of the eyeground. Their main merits and demerits are noted. Data on that adaptive optics and calibrometry may be used concurrently are given. This problem needs further investigation. PMID- 21328897 TI - [Changes in the organ of vision in pathological tortuosity and atherosclerotic stenosis of the carotid arteries]. AB - Pathological tortuosity of the carotid arteries is a cause of not only cerebral circulatory disorders, but also visual impairments. There are nonspecific and specific signs of circulatory disorders in the anterior ocular segment - bulbar conjunctiva. In pathological tortuosity of the carotid arteries visual impairments are divided into transient, acute, and chronic. Transient impairments include amaurosis fugax, ocular and orbital pains; acute impairments involve ischemic uveitis, acute retinal ischemia, acute ischemic oculopathy, anterior and posterior ischemic optic neuropathy; chronic visual impairments comprise ischemic uveal, chorioidal, retinal, and ocular neuropathy. Noninvasive ultrasound techniques involving carotid duplex scanning and color Doppler mapping of ocular and orbital vessels are the most objective studies of patients with visual impairments in pathological tortuosity of the carotid arteries. PMID- 21328898 TI - [The ultrastructure of adrenocortical cells after intake of drinking sulfate- and boron-containing mineral waters (experimental study)]. AB - The present experimental study with the use of electron microscopy has shown that intake of sulfate mineral water (sulfate concentration: 2.2 g/l, mineralization: 3.9 g/l) by rats enhanced structural and functional reserves of their adrenocorticocytes. In contrast, intake of highly mineralized water containing large amounts of boron (concentration: 250 mg/l, mineralization: 10.6 g/l) resulted in reduced structural and functional reserves of adrenocortical cells; accordingly, their adaptive capacity decreased. The authors attribute these changes to the development of local destructive processes in selected cellular ultrastructures. PMID- 21328899 TI - [Innovative technologies of physical therapy for rehabilitation of outpatients with degenerative and dystrophic spinal lesions]. AB - A differential approach to the uses of remedial gymnastics for rehabilitative treatment of patients with a variety of degenerative and dystrophic spinal lesions has been proposed. Comparative analysis of therapeutic outcomes of remedial gymnastics and modem mechanotherapy (based on the "David" training complex) is presented. Contraindications to the use of mechanotherapy based on the "David" training complex have been developed. PMID- 21328900 TI - [Magnetotherapy designed to affect cervical sympathetic ganglia for the treatment of patients with primary open-angle glaucoma]. AB - The traveling magnetic field was used to treat primary open-angle glaucoma. The field was applied to the projection of cervical sympathetic ganglia of the patients. Hemodynamic parameters of posterior short ciliary arteries and central retinal artery were analysed along with visual evoked potentials, visual field limits, and visual acuity. It was shown that magnetotherapy with the use of an AMO-ATOS apparatus produces better clinical results in patients with stage I and II primary open-angle glaucoma compared with medicamentous therapy (intake of trental tablets). PMID- 21328901 TI - [The influence of vibration training in combination with general magnetotherapy on dynamics of performance efficiency in athletes]. AB - The objective of this study was to evaluate effects of a combined treatment including vibrostimulation and magnetotherapy on the working capacity of athletes. Participants of the study were 8 male judo wrestlers. It was shown that implementation of a specialized training program comprising seances of vibration loading and general magnetotherapy 40 and 60 min in duration respectively during 3 consecutive days produced marked beneficial effect on the hormonal status of the athletes. Specifically, the three-day long treatment resulted in a significant increase of blood cortisol and testosterone levels considered to be an objective sign of improved performance parameters in athletes engaged in strength and speed sports. The optimal length of vibration training during 3 days of specialized training is estimated at 20 to 40 minutes supplemented by general magnetotherapy for 60 minutes. PMID- 21328902 TI - [Combined application of interference therapy and "dry" carbon dioxide baths for the treatment of hemodynamic disorders in patients with implantation failure due to inflammation]. AB - This work was designed to evaluate the influence of different physiotherapeutic modalities on the possibility of implantation, development and outcome of pregnancy in patients with chronic endometriosis and previous failures of implantation. The study confirmed initial sonographic changes and deficit of uterine blood supply as well as gradual improvement of these parameters under effect of adequate physiotherapy. Inclusion of dry carbon dioxide baths in the combined treatment of hemodynamic disorders made it possible to "prepare" endometrium for implantation and optimize blood circulation in the uterine vasculature in order to enhance the probability of implantation, development of pregnancy, and its success. PMID- 21328903 TI - [The use of biologically controlled ultrasound therapy for the combined treatment of primary open-angle glaucoma]. AB - The present study included 160 patients (206 eyes) presenting with the initial and advanced stages of primary open-angle glaucoma. 120 patients (157 eyes) were treated using biologically controlled ultrasound therapy besides traditional medicamentous therapy, the remaining 40 ones (49 eyes) were given only conventional medication. Results of the treatment were evaluated based on a set of commonly used hydrodynamic and electrophysiological characteristics of the quality of visual function. Biologically controlled massage of trabecular structures of the affected eyes made it possible to stabilize and improve major hydrodynamic characteristics of the eyeball drainage system, visual function, and electrophysiological parameters. Biologically controlled ultrasound therapy proved to produce a more pronounced beneficial effect on ocular hydrodynamics than the traditional ultrasonic treatment. The positive action of biologically controlled therapy persisted during 8 months; its repeated sessions prolonged this period up to 2 years. PMID- 21328904 TI - [A method for predicting the efficiency of rehabilitative treatment based on decision tree analysis]. AB - The necessity of the choice of means and methods to facilitate optimal correction of individual reserves of the organism accounts for the importance of the search for the most efficient preventive, therapeutic, and rehabilitative modalities. One way to address this problem is to simulate prognosis of the outcomes of rehabilitative treatment. It is proposed to use a two-step method to achieve this goal. Step 1 consists of construction of the decision tree to perform categorization of all objects of interest (patients) into the previously established classes; it provides a basis for step 2 or classification proper of new observations. The original software program ensures high accuracy of prognosis of the efficiency of two scenarios of combined sanatorium and spa treatment used in the present study. A special case of application of the decision tree analysis in clinical practice is considered. It is concluded that this approach can be recommended for the use in all specialized medical and health care facilities for the management of a variety of pathological conditions. PMID- 21328905 TI - [Radon- and nitrogen-containing thermal waters of the Altai region]. AB - Hydrological and hydrochemical features of the sources of radon- and nitrogen containing thermal waters of the Altai region are considered. Data on the chemical composition of mineral waters from different sources are presented. Methods for the use of radon- and nitrogen-containing thermal waters from their natural sources of the Altai region for the purpose of sanatorium and spa treatment are described. PMID- 21328906 TI - [Electrodiagnostics and electrostimulation for the combined treatment of concomitant squint in children]. AB - Methods for the electrodiagnostics and combined treatment of concomitant squint in children including pulsed electrostimulation of oculomotor muscles, pre- and ortoptical exercise therapy with the use of a synoptophor to correct concomitant strabismus. Indications and contraindications to these treatments are specified. High therapeutic effectiveness of oculomotor electrostimulation has been demonstrated in the study including 208 children with strabismus. PMID- 21328907 TI - [Aromatherapy in the combined treatment of patients presenting with dorsopathies. Medical technology]. PMID- 21328908 TI - [Nanobiotechnologies in medicine: nanodiagnostics and nanodrugs]. PMID- 21328909 TI - [Visualization and identification of hepatitis C viral particles by atomic force microscopy combined with MS/MS analysis]. AB - Possibility of detection and identification of hepatitis C viral particles with mass spectrometry (MS) in combination with atomic force microscopy (AFM) had been investigated. AFM/MS approach is based on two technologies: (1) AFM-biospecific fishing that allows to detect, concentrate from solution and to count protein complexes on a surface of AFM-nanochip; (2) mass spectrometric identification of these complexes. AFM-biospecific fishing of HCVcoreAg from solution was carried onto surface of AFM-nanochips with immobilized anti-HCVcoreAg. It was shown that HCVcoreAg/anti-HCVcore(im) complexes were formed onto AFM-nanochips in quantity sufficient for mass spectrometric identification. Thus, AFM/MS approach allows to identify fragments of hepatitis C virus fished onto a surface of AFM-nanochip from serum. PMID- 21328910 TI - [Mass-spectrometric identification of interaction sites between cytochrome P450 2B4 and NADPH cytochrome P450 reductase]. AB - We determined the interaction sites of the cytochrome P450's protein-partners: 2B4 (d-2B4) and NADPH-cytochrome P450 of reductase (d-Fp). While in operation, these proteins are forming the complexes. We used 4-4'-dithio(bisphenyl)azide linker for non-specific covalent coupling of d-2B4 complexes with d-Fp in Emulgen 913-monomerized system. Covalently-linked peptides in this complex were identified with ESI-MS/MS. Several sites of these proteins' binding with each other were revealed. Based on them, a model of intermolecular protein interactions was created. The model includes 5 cross-linker-stabilized contact sites of d-2B4 with d-Fp involving the following peptides of d-2B4 and d-Fp: (1) d-2B4423-433 and d-Fp 102-109; (2) d-2B4324-336 and d-Fp570-585; (3) d-2B4327-336 and d-Fp452-464; (4) d-2B4 192-197 and d-Fp456-464; (5) d-2B4 134-139 and d-Fp406 425. Herein, in the latter two cases, the peptides of d-Fp are located in their inter-domain slit and stabilize protein-protein complex via nanoprobe cross linker; therefore, the formation of d-2B4/d-Fp complexes in these sites may involve aminoacid residues d-Fp456-464 and d-Fp406-425 surrounding inter-domain slit. PMID- 21328911 TI - [Sensor systems for medical application based on hemoproteins and nanocomposite materials]. AB - Recent advances in nanotechnologies stimulate the development of sensor systems based on nanocomposite materials. This review discusses the prospects and challenges of sensors coupled with functionally important for medicine hemoproteins and nanoscale materials. Authors summarized their own experimental results and literature data on hemoprotein-based sensor systems. Mechanisms and the main function principles of electrochemical nanosensors are also discussed. PMID- 21328913 TI - [Knowledgebases in postgenomic molecular biology]. AB - Knowledgebases can become an effective tool essentially raising quality of information retrieval in molecular biology, promoting the development of new methods of education and forecasting of the biomedical R&D. Knowledge-based technologies should induce "paradigm shift" in the life science due to integrative focusing of research groups towards the challenges of postgenomic era. This paper debates concept of the knowledgebase, which exploits web usage mining to personalize the access of molecular biologist to the Internet resources. PMID- 21328912 TI - [Photoaptamer heterodimeric constructs as a new approach to enhance the efficiency of formation of photocrosslinking with a target protein]. AB - Using two DNA aptamers selectively recognizing anion-binding exosites 1 and 2 of thrombin as a model, it has been demonstrated that their conjugation by a poly (dT)-linker (ranging from 5 to 65 nt in length) to produce aptamer heterodimeric constructs results into affinity enhancement. The apparent dissociation constant (Kd(app)) measured at the optical biosensor Biacore-3000 for complexes of thrombin with the heterodimeric constructs reached minimum values (Kd(app) = 0.2 0.4 nM) which were approximately 30-fold less than for the complexes with the primary aptamers. A photoaptamer heterodimeric construct was designed connecting photoaptamer and aptamer sequences with the poly-(dT)-linker of 35 nt long. The photoaptamer used could form photo-induced cross-links with the exosite 2 of thrombin and the aptamer used could bind to the exosite 1. The measured value of Kd(app) for the photoaptamer construct was approximately 40-fold less than that for the primary photoaptamer (5.3 and 190 nM, respectively). Upon exposure to the UV radiation at 308 nm of the equimolar mixtures of thrombin with the photoaptamer construct, the equal yield of the crosslinked complexes was observed at concentrations which were lower by two orders of magnitude than in the case of the primary photoaptamer. It was found that concurrently with crosslinking to thrombin a photo-induced inactivation of the photoaptamer occurs presumably due to formation of the intermolecular crosslinking. PMID- 21328914 TI - [Computer-based substrate specifity prediction for cytochrome P450]. AB - Cytochrome P450 is important class of enzymes metabolizing numerous drugs. The composition and activity of these enzymes are determined the drug distribution in organism, its pharmacological and toxic effect. Thus the prediction of the behaviour of compounds in organism is essential for discovery and development of new drugs in the early stages of this process. The different isoforms of cytochrome P450 can oxidized wide range of chemical compounds and their substrate specifity do not correlate with their taxonomical classification. The main methods of cytochrome P450 substrate specifity prediction is reviewed. These methods divided based on primary informations that used: prediction based on amino acid sequences, ligand-based (pharmacophore and QSAR models) and structure based (molecular docking, affinity prediction) methods. The common problem of cytochrome P450 substrate prediction and advantage and disadvantages of these methods are discussed. PMID- 21328916 TI - [Zebrafish as a model organism for biomedical studies]. AB - Zebrafish (Danio rerio) are now firmly established as a powerful research model for many areas of biology and medicine. Here, we review some achievements of zebrafish-based assays for modeling human diseases and for drug discovery and development. For drug discovery, zebrafish are especially valuable in the earlier stages of research as they provide a model organism to demonstrate a new treatment's efficacy and toxicity before more costly mammalian models are used. This review provides examples of compounds known to be toxic to humans that have been demonstrated to functional similarly in zebrafish. Major advantages of zebrafish embryons are that they are readily permeable to small molecules added to their incubation medium and the transparent chorion enables the easy observation of development. Assay of acute toxicity (LC50 estimation) in embryos can also include the screening for developmental disorders as an indicator of teratogenic effects. We used zebrafish for toxicity testing of new drugs on the base of phospholipid nanoparticles. The organization of the genome and the pathways controlling signal transduction appear to be highly conserved between zebrafish and humans that allow using zebrafish for modeling of human diseases some examples of which are illustrated in this paper. PMID- 21328915 TI - [Bioavailability of oral drug formulations and methods for its improvement]. AB - The recent studies in nanotechnology resulted in the development of novel formulations with improved bioavailability. This is especially important for oral administered drugs as the most convenient formulations. The current review deals with the processes occurring at the gastro-intestinal (GI) tract and their influence on the drug form. The increase of bioavailability of the drug may be achieved through designing novel formulations according to the specific drug properties. They include capsules that release pharmaceutical agents at various parts of the GI tract, floating systems that prolong the presence of the drug in the GI tract, dispersed forms with surface-active soluble polymers, micelles that carry poor-soluble drugs inside their non-polar core, agents that facilitate tight junction opening, such as caprate and chitosan, and lipid-based formulations. The own data show the stimulating influence of phospholipid nanoparticles on peroral absorption of drug indomethacin in rats and on passage of transport marker and drugs through Caco-2 cell monolayer in vitro. The review summarizes current understanding of factors that influence the bioavailability of the oral drug forms, currently used models for pharmacokinetic studies, and various approaches to developing novel pharmaceutical forms that increase the bioavailability of the drugs. PMID- 21328917 TI - [Fluorescence-based determination of enzyme activity of recombinant CYPS1B1 (sterol 14alpha-demethylase) with coumarin derivatives]. AB - The current investigation was undertaken with the aim to carry out an in vitro evaluation of the ability of coumarin derivatives as probe substrates to predict the activity of CYP51b1. The results obtained indicate that 7-aminocoumarin-4 acetic acid (ACAC) can be used to determine the recombinant CYP51b1 activity. Determination of CYP51b1 activity with ACAC is based on the direct registration of fluorescence increasing at 30 degrees C. It was found also that BMR in a simple soluble model system can be used as an electron donor for CYP51B1. Fluorescence-based assay is highly sensitive and can be used for the screening of sterol 14alpha-demethylase inhibitors. PMID- 21328918 TI - [Interaction of human cytokeratins with isatin analogues]. AB - Using an optical biosensor Biacore 3000 the interaction of human recombinant cytokeratins (CK) with isatin analogues (5-aminocaproyl-isatin and 5-aminoisatin) immobilized on the CM-5 chip has been investigated. CK-14 effectively interacted with 5-aminocaproyl-isatin immobilized on the carboxymethyl dextran chip surface, but not with a "shorter" analogue (5-aminoisatin). In contrast to CK14 CK8 effectively interacted only with 5-aminoisatin. In both cases cytokeratin binding with the immobilized isatin analogues was characterized by rather high affinity (Kd of 0.7 microM for the pair CK14/immobilized 5-aminocaproylisatin and 1.7 microM for the pair CK8/immobilized 5-aminoisatin). CK20 did not interact with both immobilized isatin analogues. Taking into consideration non-specific binding of mouse CK14 and rat CK8 with 5-aminocaproyl-Sepharose we have performed comparative analysis of amino acid sequences of human, mouse, and rat CK8 and CK14. The data obtained suggest that in the case of human, mouse, and rat CK14 the N-terminal domain is the most variable among these species, whereas the major differences between amino acid sequences of human, mouse, and rat CK8 have been found both in N-terminal and C-terminal regions. PMID- 21328919 TI - [Records of the invisible: Visa reperta in 18th- and 19th-century forensic medicine and their role as promoters of pathological-anatomical knowledge]. AB - Case reports in medicine serve as a tool to collect and to transfer knowledge. A special kind of case report in forensic medicine during the 18th and 19th centuries was the so-called Visum repertum. This format of note-taking and of rendering an expert opinion without presuppositions has rarely investigated in the history of medicine. Analyzing Visa reperta the authors argue that due to their special structure and mode of representation Visa reperta not only shaped the practice of forensic medicine but also the standardized examination and documentation in pathological anatomy. Based on previous studies on medical case reports, medical expert witnesses in court and traditions in pathological anatomy the authors examine two examples from the 18th and 19th centuries in order to show how semiological, classifying methods of presenting forensic examinations were replaced by the material aspect of the observation of examination results itself. The examples are a forensic case report by Michael Alberti (1682-1757) from 1728 and a Visum repertum by Joseph Bernt (1770-1842) from 1827. The authors argue that Visa reperta transcended their original forensic purpose and served as a guideline for pathology leading to an understanding of the origin of diseases in organs. They served as a promoter of scientific medicine, and their persuasiveness was backed by factors such as (a) the extreme conditions of forensic practice, (b) the claim to act as a tool for the sound and precise recording of facts and c) the awareness that they documented objects that were destroyed during the process of documentation. PMID- 21328920 TI - [Formalizing observation: The emergence of the modern patient record exemplified by Berlin and Paris medicine, 1725-1830]. AB - The paper focuses on the material basis of the development of modern clinical documentation. With the examples of Berlin and Paris medicine, it analyzes the various ways of recording clinical data in the 18th century, from where they came, and how they were introduced into bedside observations. Particular interest is given to the interrelation between administrative techniques (registration, book-keeping etc.) and the practices of medical recording developed within the hospitals. Comparing Berlin and Paris makes it possible to work out the differences in writing cultures and to consider the local interdependencies. With this approach it can be demonstrated that the "patient record" was already established as a patient related recording system in the form of loose files in the early 19th century. PMID- 21328921 TI - [Dis/arranged medical histories a la Friedrichsberg. Explorations of foreign patients by multilingual fellow patients in a German asylum about 1900]. AB - This paper deals with two examples of a particular patient's activity at the Friedrichsberg Asylum in Hamburg in the beginning of the 20th century. Two multilingual patients assumed the function of interpreters in each case for a foreign fellow patient. They were involved to a great extent in the documentation of the medical histories. Conversations and interrogations carried out by them and recorded by their own hand are passed down in the medical files of their foreign-language fellow patients. After some preliminary remarks about the Friedrichsberg Asylum and its patients, the various activities of patients in the psychiatric institution and the importance of the patients' manner of speaking for the psychiatric diagnosis, the two cases are described in detail. The patient interpreters were perceived as border-crossers, as "Figures of the Third". PMID- 21328922 TI - ["Crisis"--oscillating between keyword and buzzword. On the discourse about a "crisis of medicine" in the Weimar Republic]. AB - The buzzword "crisis" has not only become omnipresent since the recent financial crisis. The term that originated in Ancient Greece underwent several different usages--quantitatively as well as qualitatively; especially in the Weimar Republic, the time period that has long been considered as the crisis era par excellence. Using the discourse about the "crisis of medicine" in the 1920s and the early 1930s as an example, the article attempts to provide a critical reflection on the concept of "crisis". The focus of this article is on the idea's construction, the different semantic usages of "crisis" and the motives of the different authors for their respective rhetorical applications of this term. The analysis of the examined publications on the "crisis of medicine", how they influenced other periods and the reconstruction of their origin show that the semantics of the word "crisis" went far beyond a simply negative connotation, and with regard to its rhetorical usage have oscillated between keyword and a meaningless but catchy buzzword. PMID- 21328923 TI - [Diagnostic and surgical approach to an hourglass-shaped nasopalatine glioma in an infant]. AB - The authors report a case of glioma nasopalatine Multifoil in wallet, location intra nasal and palatal left. The nasal glioma is a rare congenital malformation presenting as a nasal mass composed of neuroglial tissue heteropias resulting from an abnormality in embryonic development. It is a benign tumor that fits into the nosology of the masses of the midline. This abnormality arises primarily a diagnostic problem because often mistaken for a meningo-encephalocele or a nasal dermoid cyst. Localization nose and palate, an hourglass, is extremely rare if not exceptional; The computed tomography (CT) has enabled the accurate assessment of injury and has guided the choice of surgical technique. The resection was done successfully without recurrence. Histology examination of the surgical specimen confirmed the nature of astrocytic neuroglial tumor. The location of the tumor pedide palate to that of the left nostril is special and especially histological diagnosis of this congenital malformation. PMID- 21328924 TI - [Preferred zones of accumulation of prosthetic microbial plaque on removable complete dentures]. AB - INTRODUCTION: Denture plaque (DP) is not visible with naked eye when it is not mineralized or not fully fixed. Describing and studying its qualitative and quantitative aspects in Complete Dentures (CD) require precisely-located sampling but selection criteria have not yet been well defined. In order to improve our treatment and preventive strategies for patients with CD, it is necessary to explore the various DP accumulation zones on CD fitting surfaces. PURPOSE: The aim of this study is to assess the DP accumulation on fitting surfaces of CD. MATERIAL AND METHODS: Distribution of DP accumulation zones was assessed by naked eye observation of the fitting surfaces on 31 maxillary and 31 mandibular CD. The prostheses were to be carried regularly since at least one year. The data were collected at the Prosthodontics department of the Annaba University Medical Center in Algeria. Prostheses were immersed for 24 hours in a plaque disclosing solution containing erythrosin 2% (Dento-Plaque Inava). The maxillary fitting surface was divided into five sectors: the post damming zone (1MaxFS), the top of the palate zone (2MaxFS), the incisor zone (3MaxFS), the maxillary tuberosity zone (4MaxFS), and the end of the canine and 1st premolar zone (5MaxFS). For mandibular fitting surfaces: trigonal and retromolar zone (1ManFS), canine and 1st premolar zone (2ManFS), and incisor zone (3ManFS). RESULTS: DP distribution was found to be homogeneous on the fitting surface of mandibular CD, however it was distributed in unequal way on the maxillary fitting surfaces. We noted a highly significant difference (p < 0.001) in the staining frequencies of the targeted zones. The most colored zone was the post damming one (1MaxFS), with a rate of 96.7%, whereas the least colored zone was the top of palate one (2MaxFS), with 35.5%. On the mandibular fitting surfaces, the rate of staining was 93.5% for the trigonal and retromolar zone (1ManFS) versus 83.8% on canine, 1st premolar (2ManFS) and incisor (3ManFS) zones. There was no significant difference (p = 0.422). CONCLUSION: The accumulation of DP was found to be homogeneous on mandibular fitting surfaces and no homogeneous on maxillary fitting surfaces. These results require further investigations in order to understand the causes of this difference. This will allow us to improve our treatment and preventive strategies for edentulous patients. PMID- 21328925 TI - [Correlation between the position of the 1st molars and the 3-dimensional trajectory of anterior guidance]. AB - This study tries to demonstrate that there is a correlation between the anterior trajectories of the mandible, in the anterior-posterior and lateral directions, and the occlusal morphology of the first permanent molars. The clinical consequences are interesting for prosthetic treatments, in the rehabilitation of anterior and canine guidance, and for orthodontic treatments. PMID- 21328926 TI - [Cephalometric features of patients referred for orthodontic treatment at the Dentistry Department of Dakar University]. AB - INTRODUCTION: Each ethnic group has its own characteristics. The aim of this study was to determine the morphological characteristics of a Senegalese population. MATERIALS AND METHODS: Sixty two lateral cephalograms of Senegalese patients were assessed in a cross sectional study. All lateral cephalometric films were traced on a transparent cellulose acetate sheet by the same operator. Conventional cephalomebic analysis was performed with 17 measurements (6 linear and 11 angular) t test was used to assess differences in age and cephalometric variable between subjects grouped according to sex (male and female). A P value of < or = 0.05 was considered statistically significant. RESULTS: No statistically significant differences were found between Senegalese men and women. This study shows an increase in the maxillary protrusion and a decrease in the mandibular protrusion with his corollary of skeletal class II. The mean of the vertical dimension measurements suggest a hyperdivergence. Protrusive lips were associated with incisors protrusion. CONCLUSION: These results which show morphological differences between Senegalese subjects and other populations consolidate the idea that the racial and ethnic characteristics must be taken into account during orthodontic diagnosis and treatment planning. PMID- 21328927 TI - [Open bite and and therapeutic strategy]. AB - Anterior open bites can be divided into two categories: skeletal and dento alveolar. The etiology, basically affecting dento-alveolar structures, is functional or mechanical such as the rotation of the first higher molars, the exaggerated curve of Spee and the incisor supraclusion and the simple orthodontic treatment can bring a therapeutic success but functional rehabilitation remains the guaranty of such a stability of our treatment. The purpose of this work is to make a teaching article which puts the point on the interest of the elements of the diagnosis and the orthodontic treatment indicated in certain clinical situations of anterior open-bite; this by detailing biomechanics of correction of this anomaly requiring various therapeutic strategies. Functional rehabilitation remains always the guaranty of such a therapeutic stability. For the teaching aspect, we want to attach stereotypic forms and also to present clinical cases treated in the service of consultation and dental treatment in order to answer such a request. PMID- 21328928 TI - [Carbon exchange of Chinese boreal forest during its growth season and related regulation mechanisms]. AB - Based on the two-year continuous observation on the carbon exchange of Chinese boreal forest during its growth seasons in 2007 and 2008 by the method of open path eddy covariance, this paper analyzed the seasonal dynamics of the gross ecosystem productivity (GEP), ecosystem respiration (Re), and net ecosystem carbon exchange (NEE) of the forest, with related regulation mechanisms approached. The GEP, Re, and NEE of the forest reached to their maximum in the vigorous growth period from late June to mid August, but the dates of the maximum appeared differed. The mean daily GEP, Re, and NEE were 19.45, 15.15, and -1.45 g CO2 x m(-2) x d(-1) in 2007, and 17.67, 14.11, and -1.37 g CO2 x m(-2) x d(-1) in 2008, respectively. The intensity of the carbon exchange during growth season was obviously stronger in 2007 than in 2008, possibly due to the higher mean air temperature (12.46 degrees C in 2007 vs. 11.04 degrees C in 2008) and the higher mean photosynthetically active radiation (PAR) (697 micromol x m(-2) x s(-1) in 2007 vs. 639 micromol x m(-2) x s(-1) in 2008). The GEP had close linear relationships with air temperature and PAR, and the correlation coefficient of GEP and air temperature was around 0.55 (P<0.01). The Re was mainly controlled by air temperature, with the correlation coefficient being 0.66-0.72 (P<0.01), and the NEE was mainly controlled by PAR, with the correlation coefficient being 0.59 0.63 (P<0.01). PMID- 21328929 TI - [Effects of tree diameter at breast height and soil moisture on transpiration of Schima superba based on sap flow pattern and normalization]. AB - The eigenvalues of continuous sap flow pattern, i. e. , skewness and kurtosis, were used to investigate the water usage of Schima superba with different diameter at breast height (DBH), and the method of normalization was firstly applied to eliminate the effects of strong affecting factor (photosynthetic active radiation, PAR) to explore the possible relationship between weak affecting factor (soil moisture) and sap flow. Generally, the trees with larger DBH had smaller skewness of sap flux density and later-appeared but larger peak values, suggesting that much more water was transpired, and the larger trees showed smaller skewness and later-appeared larger peak values in wet season than in dry season, suggesting that more water was transpired in wet season. On the other hand, smaller trees had lesser differences in the skewness between dry and wet seasons, suggesting that there was no significant difference in the transpiration between the two seasons. The relationship between individual tree's transpiration and soil moisture was significant and positive after the two parameters being normalized with PAR peak values. When the soil moisture content was higher, the transpiration of the trees with larger DBH was steadily increasing with soil moisture, while that of the trees with moderate or smaller DBH had opposite trend, presumably due to their transpiration and water absorption were approached to the limit. PMID- 21328930 TI - [Seasonal variations of fine root production and mortality in Larix gmelinii plantation in 2004-2008]. AB - Minirhizotron approach was employed to investigate the seasonal variations of fine root production and mortality in Larix gmelinii plantation in 2004-2008. At the same time, air temperature, precipitation, and soil temperature and moisture at 10 cm depth were recorded. The overall aim of this study was to determine the seasonal patterns of fine root production and mortality in the plantation, and their relationships with the four environmental factors. On an annual basis, the fine root length production ranged from 0.20 to 0.78 mm x cm(-2), while the mortality varied from 0.26 to 0.72 mm x cm(-2). The mean fine root production and mortality in 2004-2006 were 0.67 mm x cm(-2) and 0.59 mm x cm(-2), respectively, being greater than the corresponding values (0.37 mm x cm(-2) and 0.39 mm x cm( 2)) in 2007-2008. During growth season (from May to October), the fine root production in late spring and early summer (June and July) occupied 51% -68% of total, while that in late autumn (October) only occupied 1% -4%. The root mortality in late summer (August) and autumn (September and October) ranged from 59% to 70%, but that in early spring (May) only ranged from 1% to 5%. Correlation analysis indicated that 66% of the variation in fine root production could be explained by air temperature, and only 24% and 27% could be explained by the soil temperature at 10 cm depth and precipitation, respectively. Fine root mortality only showed an exponential positive correlation with the soil temperature at 10 cm depth. PMID- 21328931 TI - [Effects of simulated nitrogen deposition on the fine root characteristics and soil respiration in a Pleioblastus amarus plantation in rainy area of West China]. AB - Fine root is critical in the belowground carbon (C) cycling in forest ecosystem. Aimed to understand the effects of nitrogen (N) deposition on the fine root characteristics and soil respiration in Pleioblastus amarus plantation, a two year field experiment was conducted in the Rainy Area of West China. Four treatments with different levels of N deposition were installed, i. e., CK (0 g N x m(-2) x a(-1)), low N (5 g N x m(-2) x a(-1)), medium N (15 g N x m(-2) x a( 1)), and high N (30 g N x m(-2) x a(-1)). There were great differences in the biomass and element contents of <1 mm and 1-2 mm fine roots among the treatments. Comparing with < 1 mm fine roots, 1-2 mm fine roots had higher contents of lignin, P, and Mg, but lower contents of cellulose and Ca. Nitrogen deposition increased the biomass of < 2mm fine roots significantly, with the values being (533 +/- 89) g x m(-2) in CK, and (630 +/- 140), (632 +/- 168), and (820 +/- 161) g x m(-2) in treatments low N, medium N, and high N, respectively. The N, K, and Mg contents of <2 mm fine roots also had an obvious increase under N deposition. The annual soil respiration rate in treatments CK, low N, medium N, and high N was (5.85 +/- 0.43), (6.48 +/- 0.71), (6.84 +/- 0.57), and (7.62 +/- 0.55) t C x hm(-2) x a(-1), respectively, indicating that N deposition had obvious promotion effects on soil respiration. There were significant linear relationships between the annual soil respiration rate and the biomass and N content of <2 mm fine roots. N deposition increased the fine root biomass and promoted the root metabolism, and stimulated the rhizospheric soil respiration rate via promoting microbial activities. PMID- 21328932 TI - [Soil physical and chemical characteristics under different vegetation restoration patterns in China south subtropical area]. AB - This paper studied the change of soil physical and chemical properties under eleven vegetation restoration patterns (1 kind of secondary forest, 2 kinds of pure coniferous plantations, 5 kinds of evergreen broad-leaved plantations, 2 kinds of conifer and broad-leaved mixed plantations, and 1 kind of shrub) typical in Daqingshan of Guangxi. Obvious differences were observed in the soil physical and chemical properties under different vegetation restoration patterns. The soil physical properties were better in secondary forest but poorer in pure conifer plantations. Conifer and broad-leaved mixed plantations had lower soil bulk density, and their soil total porosity and water-holding capacity were higher than those in pure plantations. There were no significant differences in the soil porosity among the 5 evergreen broad-leaved plantations. Except that of soil total K, the contents of soil nutrients in secondary forest were higher than those in plantations, and the soil C/N ratio and pH value were relatively lower. Comparing with shrub, the 9 plantations had an obvious change in their soil nutrient contents, e. g. , the increase of soil total N and available K. The 2 pure coniferous plantations had lower soil nutrient contents, but after mixed planted with evergreen broad-leaved trees, their soil nutrient contents increased markedly, and the soil C/N ratio decreased. PMID- 21328933 TI - [Canopy interception characteristics of main vegetation types in Liupan Mountains of China]. AB - Based on field observation and modeling analysis, this paper studied the canopy interception, interception capacity, and some parameters for interception modeling of main forest types in Liupan Mountains of China. For the test main forest types, the ratio of their canopy interception to precipitation ranged from 8.59% to 17.94%, throughfall was more than 80%, and stemflow ranged from 0.23% to 3.10%. The canopy interception capacity was 0.78-1.88 mm, among which, leaf interception capacity was 0.62-1.63 mm, and stem interception capacity was 0.13 0.29 mm. Conifer forest had a higher canopy interception capacity than broad leaved forest. The modified model considering the change of leaf area index, which was used in this paper, had a higher simulating precision than the interception model used before. The simulation results for Betula albo-sinensis forest, Pinus armandii forest, Prunus shrub, and Quercus liaotungensis-Tilia paucicostata forest were good, but those for Quercus liaotungensis forest, Pinus tabulaeformis forest, and Acer tetramerum and Euonymus sanguineus shrub were bad, which might be related to the differences in canopy structure, leaf area index, and precipitation characteristics. PMID- 21328934 TI - [Effects of forest gap on herbaceous plant diversity in mixed birch-fir forest of Taibai Mountain]. AB - To better understand the effects of forest gap on the herbaceous species community in a mixed birch-fir forest of Taibai Mountain in Qinling, CCA ordination and random permutation test were employed to analyze the distribution pattern of the species composition across a gradient of gap size, and the relationships between the distribution of 55 herbaceous species with > or = 5 individuals and the habitat variables (convexity, slope, and soil total N, total P, available N, available P, pH, and organic matter). In this forest, gap area occupied 19.8% of the total land area, gap density was 20.7 per hm2, and gap size varied from 25.6 to 279.1 m2, with a mean of 93.7 m2. The species richness in herbaceous layer in gaps was significantly positively correlated with gap size, but of the 69 herbaceous species identified in the gaps, most species were found across all gap sizes, and only eight species were found in larger gaps (>120 m2). No successional change was observed in the herbaceous species distribution with gap size. The CCA ordination and random permutation test also showed that 27.3% of the 55 species with abundance > or = 5 had significant association with the eight habitat variables. It was concluded that gap size contributed to the species richness, but determined the diversity constitution in random. PMID- 21328935 TI - [Larix gmelinii tree-ring width chronology and its responses to climate change in Kuduer, Great Xing' an Mountains]. AB - Based on the established tree-ring width chronology of Larix gmelinii in Kuduer, Great Xing' an Mountains, this paper analyzed the relationships between L. gmelinii tree-ring width chronology and related climatic variables, including air temperature, precipitation, and PDSI. In the study area, the L. gmelinii tree ring width chronology was significantly negatively correlated with the air temperature in May and July (P<0.01), had no significant correlation with precipitation, but significantly positively correlated with the PDSI in June August (P<0.05), suggesting that hydro-thermal variables had significant coupling effects to the radial growth of L. gmelinii in its growth season, particularly in May and July. The L. gmelinii tree-ring width chronology had significant correlations with large scale climatic regimes such as the Pacific Decadal Oscillation (PDO) in both low and high frequency variations, illustrating the significant effects of the remote oceanic climatic regimes to the local tree growth. PMID- 21328936 TI - [Selection of distance thresholds of urban forest landscape connectivity in Shenyang City]. AB - By using the QuickBird remote sensing image interpretation data of urban forests in Shenyang City in 2006, and with the help of geographical information system, this paper analyzed the landscape patches of the urban forests in the area inside the third ring-road of Shenyang. Based on the habitat availability and the dispersal potential of animal and plant species, 8 distance thresholds (50, 100, 200, 400, 600, 800, 1000, and 1200 m) were selected to compute the integral index of connectivity, probability of connectivity, and important value of the landscape patches, and the computed values were used for analyzing and screening the distance thresholds of urban forest landscape connectivity in the City. The results showed that the appropriate distance thresholds of the urban forest landscape connectivity in Shenyang City in 2006 ranged from 100 to 400 m, with 200 m being most appropriate. It was suggested that the distance thresholds should be increased or decreased according to the performability of urban forest landscape connectivity and the different demands for landscape levels. PMID- 21328937 TI - [Total flavonoids and icariin contents of Epimedium pubescens in different types of communities and their relationships with soil factors]. AB - Epimedium pubescens and soil samples were collected from the Betula albosinensis community (community I ), Cyclobalanopsis glauca var. gracilis community (community II), and Cinnamomum longepaniculatum community (community III) in Tangjiahe Nature Reserve in August 2009, with the total flavonoids and icariin contents in E. pubescens samples measured by high performance liquid chromatography and UV-spectrophotometer, and the relationships between these contents and soil parameters analyzed. Among the plant organs of E. pubescens, leaf had the highest contents of total flavonoids and icariin, while stem had the lowest one. The total flavonoids and icariin contents of E. pubescens were significantly higher in community I [(5.32 +/- 0.23)%, (0.47 +/- 0.05)%] than in communities II [(4.06 +/- 0.03)%, (0.32 +/- 0.01)%] and III [(4.15 +/- 0.07)%, (0.28 +/- 0.09)%] (P<0.05), and negatively correlated with soil total nitrogen and alkali-hydrolyzable nitrogen (P<0.05) but positively correlated with soil pH (P<0.01), suggesting that the soil with lower level of nitrogen and higher level of acidity in community I could enhance the total flavonoids and icariin contents of E. pubescens. PMID- 21328938 TI - [Effects of water stress on photosynthesis, biomass, and medicinal material quality of Tribulus terrestri]. AB - A pot experiment was conducted to study the effects of water stress on the photosynthetic characteristics, biomass accumulation, and principal medicinal compositions of Tribulus terrestri. Water stress changed the diurnal variation of T. terrestri photosynthesis, decreased the net photosynthetic rate and transpiration rate significantly, weakened the plant photosynthetic and assimilative capability, and accordingly, hindered the dry matter accumulation and decreased the biomass. However, water stress promoted the accumulation of gross saponins in T. terrestri. In the treatments with irrigation amounts 150 and 450 mm, the gross saponins content was 13.26 and 12.47 mg x g(-1), respectively, being significantly different from that in the treatments with irrigation amounts 250 and 350 mm. The dynamic accumulation of gross flavonoids and gross saponins had an opposite tendency with that of biomass, namely, the contents of these principal medicinal compositions were the lowest when the biomass was the maximal. Correlation analysis showed that the biomass accumulation of T. terrestri was significantly correlated with outside environmental factors, while the contents of secondary metabolism products were affected not only by the outside environmental factors, but also by the inside factors such as biomass accumulation. PMID- 21328939 TI - [Effects of exogenous nitric oxide on highbush blueberry PSII photochemical activity and antioxidant system under high temperature stress]. AB - Taking the test tube 'Duke' highbush blueberry (Vaccinium corymbosum) seedlings having been transplanted to the field for 6 months as test materials, this paper studied the effects of exogenous nitric oxide (NO) on their growth, PS II photochemical activity, and antioxidant system under high temperature stress. Applying 0.2, 0.5, and 1.0 mmol x L(-1) of exogenous sodium nitroprusside (SNP) could alleviate the decrease of maximum photochemical efficiency (Fv/Fm), actual photochemical efficiency under light (phi PS II), photochemical quench (q(P)), and nonphotochemical quench (NPQ) caused by high temperature, and prevented the damage of high temperature on photosynthetic apparatus. Comparing with the control, treatments NO decreased the leaf membrane permeability and MDA content, increased the SOD and CAT activities significantly, and promoted proline accumulation. Appropriate concentration SNP could significantly alleviate the damage of high temperature stress on highbush blueberry seedlings, and 0.5 mmol x L(-1) of SNP had the most satisfactory effect. PMID- 21328940 TI - [Sorbus pohuashanensis seed dispersal and germination and their relationships with population natural regeneration]. AB - Sorbus pohuashanensis is an important non-timber tree species in Northeast China, but poor in natural regeneration via seed dispersal. In this paper, a field observation was made on the seed dispersal of S. pohuashanensis, its seedling emergence, and soil seed bank, aimed to study the factors affecting the natural regeneration of this tree species. There were 96.1% of naturally dispersed S. pohuashanensis seeds distributed within the range of 2 m around the stock tree, and 97.0% of the seeds in soil seed bank distributed in litter layer and 0-2 cm surface soil. The seed quantity in soil seed bank differed greatly with seasons, being the maximum [(257.7 +/- 69.2) seeds per square meter] in early November in the year of seed dispersal, and the minimum [only (2.9 +/- 2.9) seeds per square meter] in next July. Temperature was not the limiting factor affecting the seedling emergence of S. pohuashanensis [at 0 degrees C-5 degrees C, the seedling emergence percentage could reach (67.5 +/- 6.6)%], but strongly affected the seedling emergence rate. The most proper soil moisture content for the seedling emergence was 50% , under which, the seedling emergence percentage could reach (74.7 +/- 4.2)%. When the soil moisture content was up to 60%, the seedling mortality was the lowest (32.6% +/- 0.6%). All the results suggested that the seed dispersal pattern of S. pohuashanensis and the spatiotemporal dynamics of soil seed bank could affect the seedling emergence of the tree species, and further, affect the population natural regeneration of S. pohuashanensis via seed dispersal. PMID- 21328941 TI - [Effects of combined application of nitrogen and phosphorus on diurnal variation of photosynthesis at grain-filling stage and grain yield of super high-yielding wheat]. AB - Taking super high-yielding wheat cultivar Jimai 22 as test material, a field experiment was conducted to study the effects of combined application of nitrogen (N) and phosphorus (P) on the diurnal variation of photosynthesis at grain filling stage and the grain yield of the cultivar. In treatments CK (without N and P application) and low N/P application (225 kg N x hm(-2) and 75 kg P x hm( 2)), the diurnal variation of net photosynthetic rate (Pn) was presented as double-peak curve, and there existed obvious midday depression of photosynthesis. Under reasonable application of N/P (300 kg N x hm(-2) and 150 kg P x hm(-2), treatment N2P2), the midday depression of photosynthesis weakened or even disappeared. Stomatal and non-stomatal limitations could be the causes of the midday depression. Increasing N and P supply increased the Pn, stomatal conductance (Gs), stomatal limitation value (Ls), and transpiration rate (Tr). Fertilizer P had less effects on the photosynthesis, compared with fertilizer N. When the P supply was over 150 kg x hm(-2), the increment of Pn was alleviated and even decreased. Among the fertilization treatments, treatment N2P2 had the highest Pn, Gs, and water use efficiency, being significantly different from CK. It appeared that fertilizer N had greater regulatory effect on the diurnal variation of photosynthesis, compared with fertilizer P, while the combined application of N and P had significant co-effect on the Pn, Gs, and Tr. A combined application of 300 kg N x hm(-2) and 150 kg P x hm(-2) benefited the enhancement of Pn and grain yield. PMID- 21328942 TI - [Effects of elevated ozone concentration on wheat grain protein components with FACE system]. AB - In 2006-2009, a Free-Air Controlled Enrichment (FACE) system was applied to study the effects of elevated ozone concentration ([O3]) on the grain protein components and their dynamics of four winter wheat varieties Yannong 19, Yangmai 16, Yangmai 15, and Yangfumai 2. Two levels of [O3] were installed, i. e., ambient level (CK-O3) and 50% higher than the ambient level (E-O3). With the increase of [O3], the grain protein content of the varieties increased, with the increment being 7.55% - 16.37% (2006 - 2007), 4.93% - 22.63% (2007 - 2008), and 2.29% - 17.65% (2008 - 2009) in the three years, respectively, and the differences between treatments, varieties, and years being all significant. Adversely, the grain protein yield was decreased significantly by 1.83% - 11.64% (2006 - 2007), - 0.41% - 24.22% (2007 - 2008), and -1.90% - 15.81% (2008 - 2009), respectively in the three years. The contents of four grain protein components (albumin, globulin, gliadin, and glutenin) were significantly higher under E-O3 than under CK-O3, and the differences between treatments, varieties, and years were significant, except the albumin and glutenin contents between treatments. PMID- 21328943 TI - [Effects of DA-6 on leaf photosynthetic carboxylase and protective enzyme activities and grain yield of high-yielding summer maize]. AB - A field plot experiment was conducted to study the effects of foliar spraying DA 6 at the rates of 10, 20, and 40 mg x L(-1) at jointing stage on the leaf photosynthetic carboxylase and protective enzyme activities and grain yield of high-yielding summer maize cultivar Denghai 661. Comparing with the control (foliar spraying surfactant and water), spraying 10, 20, and 40 mg x L(-1) of DA 6 increased the grain yield of Denghai 661 significantly, with the increment being 10.0%, 8.9%, and 9.4%, respectively, but no significant differences were observed among the DA-6 treatments. Different concentration DA-6 increased the leaf area index, net photosynthetic rate, and RuBPCase and PEPCase activities significantly, and the promotion effects on the net photosynthetic rate and RuBPCase and PEPCase activities increased with increasing concentration of DA-6. After treated with DA-6, the leaf superoxide dismutase, catalase, peroxidase, and glutathione S-transferase activities and the leaf soluble protein content at the stages of silking, grain-filling, milky, and wax maturity all increased significantly, and the leaf malondialdehyde decreased significantly, compared with the control. The catalase activity increased with increasing DA-6 concentration, but the other indices had no significant differences among the DA 6 treatments. PMID- 21328944 TI - [Effects of nitrogen fertilization rate and harvest time on summer maize grain yield and its quality]. AB - In order to approach the optimal nitrogen fertilization rate and suitable harvest time for the high grain yield and quality of summer maize in Huanghe-Haihe Area, a field experiment with five nitrogen fertilization rates (0, 113, 181, 249, and 375 kg N x hm(-2)) and two harvest time (S1: September 23, conventional harvest time for local farmers, and S2: September 29, 6 days delayed) was conducted. The results showed that the kernel number, grain yield, and 1000-grain mass increased with nitrogen fertilization rate, but the differences were not significant. With increasing nitrogen fertilization rate, the protein and lysine contents of the grains increased, while the starch content decreased. After 6 days delayed for harvest, the grain yield, 1000-grain mass, and the starch and lysine contents of the grains increased, but the protein and crude fat contents decreased. Based on the yield level, the optimal nitrogen fertilization rate for the summer maize in Huanghe-Haihe Area was 113-180 kg N x hm(-2), and the suitable harvest time was from September 29 to October 5. PMID- 21328945 TI - [Proteomics of rice leaf and grain at late growth stage under different nitrogen fertilization levels]. AB - Taking super-rice Liangyoupeijiu as test material, and by the method of two dimensional gel electrophoresis (2-DE), this paper studied the changes in the leaf and grain proteomics of the variety at its late growth stage under different levels of nitrogen fertilization (1/2 times of normal nitrogen level, 20 mg x L( 1); normal nitrogen level, 40 mg x L(-1); 2 times of normal nitrogen level, 80 mg x L(-1)), with the biological functions of 16 leaf proteins, 9 inferior grain proteins, and 4 superior grain proteins identified and analyzed. Nitrogen fertilization could affect and regulate the plant photosynthesis via affecting the activation of photosynthesis-related enzymes and of CO2, the light system unit, and the constitution of electron transfer chain at the late growth stage of the variety. It could also promote the expression of the enzymes related to the energy synthesis and growth in inferior grains. High nitrogen fertilization level was not beneficial to the synthesis of starch in superior grain, but sufficient nitrogen supply was still important for the substance accumulation and metabolism. Therefore, rational nitrogen fertilization could increase the photosynthesis rate of flag leaves, enhance the source function, delay the functional early ageing, and promote the grain-filling at late growth stage. PMID- 21328946 TI - [Effects of exogenous melatonin on ascorbate metabolism system in cucumber seedlings under high temperature stress]. AB - Taking cucumber cultivar 'Jinchun 4' as test material, and by the method of foliar spraying, this paper studied the effects of exogenous melatonin (MT) on the ascorbic acid (AsA) metabolism system in cucumber seedlings under high temperature stress. Under the stress of high temperature, the leaf hydrogen peroxide (H2O2) and malondialdehyde (MDA) contents of the cucumber seedlings increased obviously, ascorbic acid (AsA) and glutathione (GSH) contents had a persistent decrease while dehydroascorbate (DHA) and oxidized-glutathione (GSSG) contents had a gradual increase, and AsA/DHA and GSH/GSSG decreased greatly. The activities of ascorbate peroxidase (APx), monodehydroascorbate reductase (MDHAR), dehydroascorbate reductase (DHAR), and glutathione reductase (GR) in the seedling leaves under high temperature stress increased markedly, with the maximum after 12 h stress. Foliar spraying MT could effectively restrain the accumulation of H2O2 and MDA in seedling leaves, increase the leaf AsA and GSH contents and the activities of ascorbic acid metabolizing enzymes APx, MDHAR, GR and DHAR, and accordingly, enhance the H2O2-scavenging ability, inhibit the production of active O2, maintain the stability of cell membrane, reduce the damage of high temperature to the plants, and improve the ability of cucumber seedlings against high temperature stress. PMID- 21328947 TI - [Effects of bio-fertilizer on organically cultured cucumber growth and soil biological characteristics]. AB - Field trials of organic farming were conducted to examine the effects of different bio-fertilizers on the organically cultured cucumber growth, soil enzyme activities, and soil microbial biomass. Four treatments were installed, i. e., organic fertilizer only (CK), bio-fertilizer "Zhonghe" combined with organic fertilizer (ZHH), bio-fertilizer "NST" combined with organic fertilizer (NST), and bio-fertilizer "Bio" combined with organic fertilizer (BIO). Bio-fertilizers combined with organic fertilizer increased the cucumber yield significantly, and improved the root growth and leaf chlorophyll content. Comparing with that in CK, the cucumber yield in treatments ZHH, NST, and BIO was increased by 10.4%, 12.4%, and 29.2%, respectively. At the seedling stage, early flowering stage, and picking time of cucumber, the soil microbial biomass C and N in treatments ZHH, NST, and BIO were significantly higher than that in CK, and the activities of soil urease, acid phosphatase, and catalase were also higher. PMID- 21328948 TI - [Amino sugars mineralization and its responses to exogenous substances in black soil of Northeast China]. AB - By the method of intermittent leaching aerobic incubation, this paper studied the mineralization of three kinds of microbes-derived amino sugar (glucosamine, muramic acid, and galactosamine) in black soil of Northeast China, and the responses to glucose addition and glucose plus nitrogen amendment. The mineralization of the amino sugars was compound-specific. During incubation period, the content of muramic acid decreased by 25.4%, while that of glucosamine decreased by 7.1%, suggesting that bacteria-derived muramic acid was more inclined to be mineralized, compared with fungi-originated glucosamine. However, the mineralized amount of glucosamine (68.4 mg x kg(-1)) was greater than that of muramic acid (15.4 mg x kg(-1)). Both glucose addition and glucose plus nitrogen amendment improved the contents of glucosamine and muramic acid significantly, but the effect varied. The mineralization of galactosamine was much slower, and less affected by exogenous substances addition, indicating that galactosamine was more stable in test soil. PMID- 21328949 TI - [Ecological reasons for the difference in nicotine content of flue-cured tobacco planted in different regions of Hunan Province]. AB - Aimed to explore the ecological reasons for the difference in nicotine content of flue-cured tobacco planted in different regions of Hunan Province, field experiments were conducted in Sangzhi, Liuyang, and Yongzhou counties, the three typical tobacco regions of Hunan Province, taking tobacco variety K326 as the test object. Simultaneously, pot experiments with local soils and guest soils were carried out. The nicotine content of mid position tobacco leaves was analyzed at harvest time. Field experiments showed that the average nicotine content of tobacco leaves differed significantly among test sites, with that in Sangzhi being the highest, followed by Liuyang, and Yongzhou. Pot experiments showed that climate had significant effects on the average nicotine content of tobacco leaves, while soil and its interaction with climate had less effects. The contribution rate of climate, soil, and their interaction on the variance of the average nicotine content was 60.0%, 12.8% and 27.2%, respectively. The main sub ecological factors closely related to the average nicotine content of flue-cured tobacco planted in different regions of Hunan Province were in turn the cloud cover at maturing stage, the relative humidity, sunshine hours, diurnal temperature variance, and rainfall at root-extending stage, and the average air temperature at vigorous growth stage. Generally, climate was the main ecological factor that led to the nicotine content difference of flue-cured tobacco planted in different regions of Hunan Province. PMID- 21328950 TI - [Changes of China agricultural climate resources under the background of climate change. I. Spatiotemporal change characteristics of agricultural climate resources in South China]. AB - By using the 1961-2007 daily weather data from 66 meteorological stations all over South China, this paper studied the spatiotemporal change characteristics of agricultural climate resources, including heat, light, and precipitation, in this region on the scales of whole year and temperature-defined growth season. In 1961 2007, the mean annual air temperature in this region tended to be increased by 0.20 degrees C x (10 a)(-1), and the climatic trend of > or = 10 degrees C accumulated temperature in temperature-defined growth season increased gradually from north to south, with an average of 98 degrees C x d x (10 a)(-1). Comparied with those in 1961-1980, the areas of the accumulated temperature zone of 6200 7500 degrees C x d and 7500-8000 degrees C x d in 1981-2007 increased by 1.5 x 10(4) and 4.7 x 10(4) km2, respectively. In 1961-2007, the sunshine hours on the scales of whole year and temperature-defined growth season decreased by -57 h x (10 a)(-1) and -38 h x (10 a)(-1), respectively, and the areas with sunshine hour > or = 1800 h on the two scales tended to be decreased, compared with those in 1961-1980. The precipitation on the two scales increased slightly, and the increment varied obviously in different parts of the region. There were 62% and 52% of the stations where the reference crop evapotranspiration on the scales of whole year and temperature-defined growth season was in negative, respectively. In 1981-2007, the high-value area of reference crop evapotranspiration decreased, while the low-value area increased, compared with those in 1961-1980. The mean climatic trend of annual humidity index was 0.01 x (10 a)(-1), and 70% of the stations showed an increasing trend. Comparing with that in 1961-1980, the humidity index on the scale of temperature-defined growth season in 1981-2007 was increased by 0. 02, with 53% of the stations showed positive. On the whole, the change characteristics of climate in South China in 1961-2007 showed a tendency of warming and wetting, which would impact the cropping system, yield, and agricultural structure in the region. PMID- 21328951 TI - [Evaluation of sustainable development of Dalian Economic and Technological Development Zone based on MuSIASEM theory]. AB - Based on the theory of multiple-scale integrated assessment of societal and ecosystem metabolism (MuSIASEM), a comprehensive evaluation was made on the human activity time, exosomatic energy input, and added value of Dalian Economic and Technological Development Zone in 2000-2007. During the study period, the life quality of local citizens increased year after year, while the agricultural industry dwindled. Manufacturing industry was still the main pillar industry, but its energy consumption was greater. Service industry was at its early stage, falling behind manufacturing industry. The exosomatic metabolic level of the whole zone and its various industries had an obvious increase, and the energy intensity decreased continuously. With the fact that both the human activity time and the exosomatic energy input had a ceaseless decrease, the economic added value increased steadily, and the zone was under its way towards sustainable development. PMID- 21328952 TI - [Characteristics and changes of landscape pattern in Wuhan City based on Ripley's K function]. AB - By using Ripley's K function, an important method of point pattern analysis, and taking the TM remote sensing images of 1987, 1996 and 2007 as data source, this paper studied the characteristics and changes of landscape pattern in Wuhan City. The results showed that in 1987 - 2007, farmland was the landscape matrix in Wuhan, while water body, forestland, grassland, urban and rural built-up land, and unutilized land types were the patches or corridors, which spatially clumped significantly in all scales. The landscape aggregation of water bodies was inferior to that of forestland, grassland, and urban and rural built-up land. The farmland clumped spatially in fine scales, but became random or uniform in coarse scales. Meantime, the areas of forestland and urban and rural built-up land increased largely, while water body, grassland, and farmland decreased greatly. In addition, the landscape spatial characteristics of all landscape types changed variously. On the whole, the landscape aggregation of forestland and urban and rural built-up land decreased, and became more uniform. Meanwhile, the water body, grassland, and farmland took on a more uneven and clumped landscape pattern. To analyze the landscape pattern through sample points had the advantages of conciseness, accuracy, and easiness-to-use, in comparison with the methods of quadrat and sample line (or transect). Ripley's K function was proved to be an efficient means for analyzing landscape pattern in different scales, and fit for the supplement and support of landscape metrics. PMID- 21328953 TI - [Genetic heterogeneity of Beauveria bassiana population in pure Masson's pine plantation]. AB - By the method of ISSR, the genetic heterogeneity of 111 Beauveria bassiana isolates in a pure Masson' s pine plantation in Magu Mountains of Anhui Province was analyzed. A total of 58 loci were obtained with 7 ISSR primers, 54 of which (93.10%) were polymorphic. For the isolates sampled at different time, their Nei's gene diversity (He) was 0.2552, Shannon's diversity index (I) was 0.3825, coefficient of gene differentiation (Gst) was 0.2269, and gene flow Nm was 0.8518. The genetic distance between the isolates sampled in May and July was the shortest (0.0408). For the isolates grouped based on host orders, their He was 0.2623, I was 0.3884, Gst was 0.1964, and Nm was 1.0223. The genetic distance between the isolates from Coleopteran and Hymenoteran was the shortest (0.0163). All the results suggested that the genetic heterogeneity of B. bassiana population in the test plantation was rich, and the genetic variation between B. bassiana sub-populations was relatively low but that within the sub-populations was high, and none of the isolates were identical or highly similar with each other. PMID- 21328954 TI - [Ecological distribution of arbuscular mycorrhizal fungi in alpine grasslands of Tibet Plateau]. AB - Seventy soil samples with the roots of 37 dominant or common plant species on the grasslands in south and north Tibet Plateau were collected to study the ecological distribution of arbuscular mycorrhizal (AM) fungi in the investigation area. A total of 35 AM fungi species belonging to 5 genera were isolated, among which, 18 species belonged to Glomus, 9 species belonged to Acaulospora, 6 species belonged to Scutellospora, 1 species belonged to Entrophospora, and 1 species belonged to Paraglomus. There were 23 AM fungi species belonging to 4 genera isolated from south Tibet, and 22 species belonging to 4 genera from north Tibet. The Shannon diversity index of AM fungi in south and north Tibet Plateau was 2.31 and 2.75, respectively, and the spore density and species richness were significantly higher in north Tibet than in south Tibet. In different ecological zones, lesser AM fungi common species were found, species distribution was more site-specific, and different dominant species were observed. In alpine grassland, mountain meadow, and alpine meadow, the Shannon index of AM fungi was 1.91, 1.83, and 1.80, respectively; while in severely degraded temperate grassland, this index was only 1.64. The highest species richness of AM fungi occurred at the altitude of 4000-4600 m, but the highest Shannon index and species evenness occurred at the altitude of 4600-5220 m, with the values being 2.42 and 0.79, respectively. At all altitudes, Glomus was the dominant genus, and its relative abundance was higher when the altitude was below 4000 m. Acaulospora was mainly observed at the altitudes higher than 4000 m, Scutellospora was mainly distributed at the altitude 3500-5220 m, Paraglomus mainly occurred in the north alpine meadow with an altitude of 4000-5220 m and occasionally in the alpine steppe, whereas Entrophospora was only found in the south temperate grassland with an altitude of 3500-3700 m. PMID- 21328955 TI - [Evolvement of soil bacterial community in intensively managed Phyllostachys praecox stand and related affecting factors]. AB - By using PCR-DGGE and redundancy analysis (RDA), this paper studied the variations of soil bacterial community structure during the intensive management of Phyllostachys praecox stand, and analyzed the soil factors affecting the diversity of the bacterial community. The results showed that after the transformation of paddy field into P. praecox stand, the Shannon and richness indices of soil bacterial community increased significantly. Long-term intensive management of P. praecox stand altered the community structure of soil bacteria, reflecting in the changes of main bacterial populations and the great decrease after an initial increase of the diversity indices of soil bacterial community. Soil pH, soil total nitrogen, and soil available nitrogen and potassium could explain 76.1% of the total variation of soil bacterial community, and soil pH showed the greatest effect though it was not significant, indicating that the evolvement of soil bacterial community under the long-term intensive management of P. praecox stand was the result of the synergistic effects of several soil factors. PMID- 21328956 TI - [Screening, identification, and biocontrol effect of antagonistic bacteria against Phytophthora capsici]. AB - A total of 98 isolates with antagonistic activity against Phytophthora capsici were isolated from the rhizosphere soil of healthy pepper plants in the fields seriously infected by pepper Phytophthora capsicit, and two strains named as HL-3 and LZ-8 were screened, which had the characteristics of wide-spectrum antagonism and good growth under poor soil condition. The HL-3 and LZ-8 were identified as Paenibacillus polymyxa and Bacillus pumilus, respectively, based on their morphological and biochemical characteristics and 16S rDNA sequences. The two strains could inhibit the mycelium growth of P. capsici, and the inhibitory effect of HL-3 and LZ-8 was 72% and 68%, respectively. The two strains also had antifungal activities toward other plant pathogens such as Verticillium dahliae, Fusarium oxysporum f. sp. cucumerinum, F. oxysporum f. sp. vasinfectum, Rhizoctonia solani, Phtophthora parasitica var. nicotiana, and Ralstonia solanacearum. Pot experiment showed that the biocontrol effects of HL-3 and LZ-8 against P. capsici at the seedling stage of pepper were 72% and 83%, respectively, and both of the strains had significant growth-promoting effect on pepper plants. PMID- 21328957 TI - [Changes of heavy metals form during aerobic high temperature composting of pig manure and the effects of passivators]. AB - Sequential extraction method was employed to study the heavy metals concentration and form change during aerobic high temperature compositing of pig manure, and the effects of amendment with different proportion of passivators on the concentration and form change. During the composting process, the concentrations of total As, Cu, and Zn in the manure all increased to some extent. As for the form change of the heavy metals, the exchangeable As and Zn decreased while the residual As and Zn increased, indicating that the availability of As and Zn declined through the composting process. On the other hand, the exchangeable and residual Cu decreased while the carbonate-, Fe/Mn-, and organic bound Cu increased, suggesting the potential environmental risk of the future application of the compost. Among the passivators amended, 5.0% of sepiolite and 2.5% of bentonite had the best effect in reducing the availability of As and Zn, with the residual form of As and Zn after composting increased by 79.8% and 158.6%, respectively, and 7.5% of sepiolite induced the least decrement (39.3%) of residual Cu, compared with the control. Therefore, amendment with appropriate proportion of passivator during pig manure composting could decrease the availability of heavy metals in the manure, and reduce the environmental risk of applying the compost to farmland. PMID- 21328958 TI - [Endogenous NO and ROS generation in grape roots and leaves under CdCl2 stress]. AB - Taking the cutting seedlings of grape variety 'Ze-xiang' as test materials, a hydroponic experiment was conducted to study the generation patterns of endogenous nitric oxide (NO) and reactive oxygen species (ROS) in their roots and leaves, and the changes of root MDA content and root activity under the stress of cadmium chloride (CdCl2). In the treatments 0-1 mmol x L(-1) of CdCl2, the NO content and NOS activity in roots and leaves and the root activity all presented a tendency of increasing first and decreasing afterwards with increasing CdCl2. At 0.01 mmol L(-1) of CdCl2, the NO content and NOS activity in roots increased by 51% and 63%, respectively; but at >0.1 mmol L(-1) of CdCl2, they decreased significantly. At 0.01 and 0.05 mmol x L(-1) of CdCl2, the leaf NO content and NOS activity had the greatest increase; at 0.5 and 1.0 mmol x L(-1) of CdCl2, the root O2 generation rate and H2O2 and MDA contents increased significantly. At the same concentrations of CdCl2, the O2 generation rate in leaves was much lower while the H2O2 content was much higher, compared with those in roots. PMID- 21328959 TI - [Leaf cell damage and changes in photosynthetic pigment contents of three moss species under cadmium stress]. AB - A hydroponic experiment was conducted to study the leaf cell damage and the changes in photosynthetic pigment contents of three moss species under Cd stress, aimed to reveal the Cd sensibility and tolerance of the species. Even though the Cd stress was relatively low (1 mg Cd x L(-1)), the leaf cells of Dolichomitriopsis diversiformis and Plagiomnium acutum were damaged. With the increasing level of Cd stress, the leaf cell damage of the three moss species aggravated significantly, and the resulted damage under high level (100 mg x L( 1)) Cd stress was in the order Brachythecium procumbens > P. acutum > D. diversiformis. Relatively low (1 mg x L(-1)) Cd stress had no significant effects on the total chlorophyll content of the three species. However, with the increase of Cd stress (> or = 10 mg x L(-1)), the total chlorophyll content decreased significantly, with the order of B. procumbens > P. acutum > D. diversiformis. The Cd stress at 1 and 10 mg x L(-1) had no significant effects on the chlorophyll a/b, but the Cd stress at 100 mg x L(-1) led to a significant decrease of chlorophyll a/b in P. acutum and B. procumbens. The maximal decline of carotenoid content in B. procumbens was observed at 1 mg x L(-1) of Cd. The three moss species could significantly enrich Cd, and the Cd enrichment was D. diversiformis > P. acutum > B. procumbens. The leaf cell damage rate and the changes of chlorophyll and carotenoid contents could be used to indicate the differences in the sensitivity of D. diversiformis, P. acutum, and B. procumbens to Cd stress. D. diversiformis had the strongest tolerance to Cd stress, while P. acutum and B. procumbens had weaker tolerance. The tolerance of the three moss species to Cd stress was positively correlated to the capability of their Cd enrichment. PMID- 21328960 TI - [Animal predation and dispersal of Sorbus pohuashanensis fruits and seeds]. AB - Sorbus pohuashanensis is an important non-timber tree species in Northeast China. There are two approaches for its fruit- and seed dispersal, i. e. , natural dispersal and animal dispersal. In this paper, a field observation was conducted to study the characteristics of animal predation and dispersal of S. pohuashanensis fruits and seeds, and the effects of the predation and dispersal on the natural regeneration of the tree species. During the fruit-ripening stage of S. pohuashanensis in 2008 and 2009, there were 8 species of birds visiting S. pohuashanensis fruits, among which, three pulp-eating species Turdus naumanni, Cyanopica cyana, and Dendrocopos leucotos could disperse S. pohuashanensis seeds. The visiting frequency of the three species to S. pohuashanensis fruits was 54%, 12%, and 7%, respectively, and the first stop spot after predation was mainly within 5-10 m away from the visited trees (with a proportion of 68.2%), secondly within 5 m (27.3%), and only 4.5% was out of 10 m. The retention time of S. pohuashanensis fruits in the digestive tract of the bird dispersers was up to 20 min, implying a long potential dispersal distance. Fruit- and seed placement tests showed that the fruits artificially placed in different habitats were disappeared within 6-7 days, and the fruit predators on the ground were mainly rodents and ground-feeding birds, with the predation rates being 50% -70%, while the seed predators on the ground were rodents, ground-feeding birds, and ants, with the predation rates only 1% -5%. S. pohuashanensis could provide food for a variety of frugivorous animals, and in return, the animals could disperse S. pohuashanensis seeds, which might have profound effects on the natural regeneration of S. pohuashanensis. PMID- 21328961 TI - [Coexistence mechanism of ant community in lac plantation under habitat heterogeneity]. AB - In order to reveal the coexistence mechanism of ant community in lac plantation, an investigation was made on the ant community composition and the ability of ant species in discovering and holding food resources in a lac plantation in Yayi Town of Mojiang County, Yunnan Province, with the relationships between ant body size and its ability of finding food under habitat heterogeneity probed. There were six dominant ant species in the plantation, i. e., Tetraponera allaborans (Walker), Crematogaster macaoensis Wheeler, Crematogasterferrarii Emery, Dolichoderus thoracicus (Smith), Polyrhachis proxima Roger, and Camponotus parius Emery. The hind leg length (y) of the six ant species increased allometrically with their head width (x), and the regression equation was y = 0.56 + 1.02x + 5.97x2 - 10.85x3. Different ant species had significant differences in their actual and relative frequency in discovering food resources in different habitats, but habitat type had no significant effects on the actual frequency in holding food resources by the ant species. The ant species with bigger head width and bigger body size index could discover more food resources in simple habitat. In contrast, the ant species with smaller head width, shorter hind leg length, and smaller body size index could discover more food resources in complex habitat. The heterogeneity of habitat caused the coexistence of ants: the smaller ant species lived in complex habitat, while the larger ones lived in simple habitat. In addition, numerically dominant ant species were unable to possess all resources, and thereby, could provide the opportunity to other ant species for resources acquisition, making the species coexistence come true. PMID- 21328962 TI - [Spatial structure and distribution simulation of Aphis gossipii Glover population based on GIS]. AB - Based on geographic information system (GIS) and geostatistical analysis, this paper studied the spatial structure of Aphis gossipii Glover population in Xiangshan District of Zhongwei City, Ningxia Province, with the spatial distribution of the population simulated by ordinary Kriging interpretation. The spatial structure of A. gossipii population varied with its occurrence stage (initial, blossom, and final stage). The semivariograms of A. gossipii could be described by exponential or Gaussian model, indicating that A. gossipii had an aggregated spatial arrangement. The aggregation degrees at different occurrence stages were all beyond 45%, and the spatial correlation ranged from 10.37 km to 29.11 km. The spatial variance was greatly affected by spatial autocorrelation. The population dynamics of A. gossipii at its different occurrence stages could be easily analyzed and intuitively simulated from the two aspects of time and space by spatial distribution simulation, and thus, the occurrence position and degree of A. gossipii could be easily determined. PMID- 21328963 TI - [Impact of climatic change on soybean production: a review]. AB - Since the industrial revolution, the rapid increase of global atmospheric concentration of CO2 and other greenhouse gases has induced the global warming and the change of global precipitation pattern. The growth, development, yield, and quality of soybean are subject to all these changes of climatic conditions. Soybean is one of the major grain and oil crops in the world and in China, and any change in the soybean production under future climate scenario will affect the grain- and edible oil security nationally and internationally. This paper reviewed the effects of elevated atmospheric CO2, global warming, and water stress on soybean growth, and discussed the future research needs, which could provide scientific basis for realizing soybean production in the future and for implementing in advance proper policies in the context of climatic change impact on soybean production. PMID- 21328965 TI - [Effects of elevated ultraviolet-B radiation on the chemical composition of wheat straw and the N2O emission from soil amended with the straw]. AB - An outdoor experiment was carried out to investigate the effects of elevated ultraviolet-B radiation on the chemical composition of wheat straw, and an indoor incubation test was conducted to study the effects of the amendment of the straw on soil N2O emission. Outdoor experiment showed that the enhanced UV-B decreased the aboveground biomass of wheat, increased the lignin and total N contents of wheat straw by 94.2% and 12.3%, respectively, and decreased the C/N ratio of the straw. Incubation test showed that comparing with the amendment of conventional wheat straw, the amendment of wheat straw received enhanced UV-B radiation during plant growth increased soil N2O emission under the dry-land and flooded conditions significantly. When nitrate was applied, the soil N2O emission in the treatment with straw received enhanced UV-B radiation during plant growth was 3.2 times higher than that with the conventional straw under dry-land condition, but did not differ significantly under flooded condition. The amendment of wheat straw which received UV-B radiation during plant growth had no significant effects on soil respiration. PMID- 21328964 TI - [Persisters and their effects on microbial biofilm tolerance: a review]. AB - Persisters are a group of special subpopulation of bacteria, only occupying < 0.1% of the whole population but having the characteristics different from the ordinary bacteria and resistant mutants. They have complex formation mechanism, and are difficult to isolate and culture. The persisters can adapt to the adverse environment via "dormancy-growth-proliferation" to maintain their survival and cell structure stability, and play a vital role in the multi-drug and multi-metal tolerance of microbial biofilm, being of great significance in maintaining the stability of microbial community structure. This paper reviewed the research progress on the characteristics of persisters, their gene regulation mechanisms, and their effects on the multi-drug and multi-metal tolerance of microbial biofilm. The related research directions in the future were also prospected. PMID- 21328966 TI - [Climatope change and its relations with city development of Haikou City in 1961 2007]. AB - Based on the 1961-2007 meteorological data of Haikou City and its urbanization level in 1989-2007, this paper studied the climatope change and its relations with city development of the City. In 1995-2007, the mean annual air temperature in Haikou had an obvious increase, with an increment of 0.93 degrees C x a(-1), while the mean annual relative humidity decreased obviously, with a decrement of 3% per year, compared with those in 1961-1990. Both the mean annual air temperature and the mean annual relative humidity had significant correlations with the urbanization level of Haikou, suggesting that urbanization could better explain the recent 20 years variation of climate elements in Haikou. The city development of Haikou not only changed the climatope elements, but also affected the air quality, making the frequency of acid rain increased, and the mean annual acid rain pH value decreased. PMID- 21328967 TI - [Effect of triptolide on airway smooth muscle proliferation and the expression of nuclear factor-kappa B, Bcl-2 in asthmatic rats]. AB - OBJECTIVE: To explore the effect of triptolide on airway remodeling and the expression of nuclear factor-kappaB, Bcl-2 in asthmatic rats. METHODS: 40 rats were randomly divided into 5 groups (n = 8): (1) Control group; (2) Asthmatic 4 week group; (3) Asthmatic 6 week group; (4) Therapeutic 4 week group; (5) Therapeutic 6 week group. The airway resistance and eosinophilic inflammation of airway wall were observed. The airway wall thickness (WA/Pi), the bronchial smooth muscle thickness (smooth muscle area/Pi) and the number of bronchial smooth muscle nucleus (N/Pi) were measured by image analysis system. The expression of PCNA, nuclear factor-kappaB and Bcl-2 protein were determined by immunohistochemical staining and Western blot. The expression of Bcl-2 mRNA was determined by reverse transcription-polymerase chain reaction(RT-PCR). RESULTS: (1) The expression of NF-kappaB protein in asthmatic 4 week group and asthmatic 6 week group was significantly higher than that in control group, respectively (P < 0.01). The above-mentioned parameters of therapeutic 6 week group were significantly lower than those of asthmatic 4 week group, asthmatic 6 week group and therapeutic 4 week group, respectively (P < 0.01, P < 0.01 P < 0.05). (2) The expression of Bcl-2 protein and mRNA of asthmatic 4 week group and asthmatic 6 week group were significantly higher than those in control group respectively (P < 0.01). The expression of Bcl-2 protein of therapeutic 6 week group was significantly lower than those of asthmatic 4 week group, asthmatic 6 week group and therapeutic 4 week group respectively (P < 0.05, P < 0.01, P < 0.01), but the expression of Bcl-2 mRNA was significantly higher than the above-mentioned groups respectively (P < 0.01), the expression of Bcl-2 protein and mRNA of therapeutic 6 week group were higher than control group respectively (P < 0.05, P < 0.01). (3) The expression of PCNA protein of asthmatic 4 week group and asthmatic 6 week group were significantly higher than those of control group respectively (P < 0.01). (4) The WA/ Pi, the smooth muscle area/Pi and the N/Pi of asthmatic 4 week group and asthmatic 6 week group were significantly higher than those of control group, respectively (P < 0.01). The above-mentioned parameters of therapeutic 6 week group were significantly lower than those of asthmatic 4 week group, asthmatic 6 week group and therapeutic 4 week group, respectively (P < 0.01). (5) The airway resistance of asthmatic 4 week group and asthmatic 6 week group were significantly higher than those of the control group, respectively (P < 0.01). The above-mentioned parameters of therapeutic 6 week group were significantly lower than those of asthmatic 4 week group, asthmatic 6 week group and therapeutic 4 week group, respectively (P < 0.01, P < 0.01, P < 0.05). CONCLUSION: The proliferation of airway smooth muscle(ASM) is related with apoptosis of airway smooth muscle cells in asthma. NF-kappaB may be involved in the process. Triptolide may prevent apoptosis of ASMCs and decrease the proliferation of ASM by inhibiting the expression of NF-kappaB, Bcl-2. PMID- 21328968 TI - [Correlations of lymphatic and vascular pressure on response of norepinephrine in hemorrhagic shock rats]. PMID- 21328969 TI - [The effect of GLP-2 on small intestine mucous membrane and different organs distribution in mice]. PMID- 21328970 TI - [The oxidative stress enhanced adenoviral E1A-involved transactivation of nuclear factor-kappaB]. AB - OBJECTIVE: The relationship between latent adenovirus infection and airway inflammation have not been well documented. The aim of this study is to illustrate the roles of adenovirus E1A protein on the level of glutathione (GSH) in response to oxidative stress and the effect of the oxidant/antioxidant imbalance upon the transactivation of NF-kappaB triggered by E1A protein. METHODS: Rat alveolar epithelial cell stably expressing adenoviral E1A or control plasmid were developed. For isolation of nuclear extracts, 5 x 10(5) cells were plated and grown overnight in 60 mm dishes. Experiments were repeated three times. The cell model of stably expressing adenoviral E1A was stimulated by H2O2. The level of GSH were measured. E1A positive clone was stimulated by LPS or TNF alpha and treated with L-Buthionine-sulfoximine (BSO). The expression of NF kappaB was measured by Western blot. Differences between groups were assessed for significance by Student' t test; multiple comparisons by the one-way ANOVA. RESULTS: There is no difference of GSH level without stimulation between E1A positive clones and E1A-negative clones. For E1A-positive clones, the level of GSH did not increase in response to H2O2 as E1A-negative clones. The quantitation by densitometry of the NF-kappaB expression in E1A-positive clones were (79.3 +/- 4.6), (80.3 +/- 3.8) respectively without treatment and were (81.8 +/- 3.9) - (89.9 +/- 1.6) and (94.1 +/- 1.9) - (99.8 +/- 1.6) respectively under LPS or TNF alpha stimulation, which were significantly higher than that of the control group (68.3 +/- 3.8), (69.4 +/- 4.3) respectively without stimulation and (70.1 +/- 2.8) - (80.8 +/- 3.6), (73.4 +/- 4.9) - (83.2 +/- 6.7) respectively under stimulation. The quantitation by densitometry of the NF-kappaB expression in E1A negative clones were (1.25 +/- 0.18) and (1.69 +/- 0.19) respectively under LPS and TNF-alpha-stimulation and (1.22 +/- 0.16) and (1.75 +/- 0.13) respectively upon treatment for LPS and TNF-alpha with BSO preincubation. There did not show difference upon treatment with LPS or TNF-alpha with or without BSO in E1A negative cell clone. The quantitation by densitometry of the NF-kappaB expression in E1A-positive clone were (1.75 +/- 0.10) and (2.26 +/- 0.21) respectively upon treatment for LPS and TNF-alpha with BSO preincubation which were significantly higher than that of LPS or TNF-alpha-stimulation alone (1.35 +/- 0.12), (1.80 +/- 0.14) respectively. CONCLUSION: These results indicate that E1A protein decreased GSH levels in oxidant stress and upregulated NF-kappaB transcription activity. The oxidant/antioxidant imbalance in rat alveolar epithelial cells enhances E1A modulated transcriptional activation of NF-kappaB. The mechanism underlying transactivation of NF-kappaB involved by E1A may be related to oxidative stress. PMID- 21328971 TI - [The relationship between mTor/S6K1 signaling pathway and insulin resistance and the study of aerobic exercise on this pathway]. AB - OBJECTIVE: In order to provide theoretic evidence of exercise preventing insulin resistance, we studied the effects of high-fat diet and aerobic exercise on expression of mammalian target of rapamycin/ribosomal protein kinase (mTOR/S6K1) in skeletal muscle of insulin resistant mice. METHODS: 8-week old, C57BL/6 mice were divided into two groups: which are normal chow and high-fat diet groups, each group has 20 animals feeding by normal chow and high fat diet respectively. 8-weeks later, mice from high fat diet group were proved to have insulin resistance symptoms and after that time point the mice were regrouped. The normal chow group was randomly divided into normal chow diet control group (NC) and normal chow exercise group (NE), and the high fat diet group was randomly divided into high fat diet control group (HC) and high fat diet exercise group (HE). All exercise groups were required to running on treadmill for 6 weeks. Mice were acclimatized to the motorized treadmill by running 60 min per day at the intensity of 75% VO2max five days per week for 6 weeks. By the end of training, we observed the changes of glucose tolerance by oral glucose tolerance test and morphology of pancreatic islet under microscope. Insulin concentration was measured by ELISA. Northern blot and Western blot were performed to detect mTOR, S6K1 (and/or pS6K1-Thr389) mRNA and protein expression in skeletal muscle. RESULTS: By comparing with NC group, the effect of high-fat diet increased the body weight, fasting serum insulin level and the area of pancreatic islet of the mice in HC group significantly. Furthermore, glucose tolerance was impaired. After 6-week aerobic exercise, above value of descriptive index were significantly decreased in skeletal muscle in HE group. In addition, OGTT was also improved. The expression of mTOR, S6K1 (and/or pS6K1-Thr389) mRNA and protein were significantly decreased. CONCLUSION: mTOR/S6K1 signaling pathway plays an important role in the development of diet induced insulin resistance. Aerobic exercise attenuates insulin resistance by increasing skeletal muscle insulin sensitivity evidenced by increased energy metabolism decreased activity of mTOR/S6K1 signaling pathway. PMID- 21328972 TI - [Study of hypoxia-induced immune injury and its intervention measure]. AB - OBJECTIVE: To explore the characteristic of hypoxia-induced immune injury, its mechanisms and the intervention measure. METHODS: The change of immune organ index, T lymphocyte subsets of peripheral blood and immune organ in mice during hypoxia were detected. Lymphocyte apoptosis of immune organ, pathology of lung and kidney in mice were observed. Then by way of prophylaxis we studied the effect of Chinese Traditional Medicine on hypoxia-induced immune injury in mice. RESULTS: (1) Exposure to hypoxia at 8 000 m simulated altitude for 8 h resulted in marked decrease in CD4+ CD8+ thymocytes and marked increase in CD4+ CD8-, CD4- CD8+ thymocytes (P < 0.01). After 3 days of hypoxia, the mice had a much lower percentage of CD4+ T-cell (P < 0.05). The ratio of CD4+/CD8+ decreased significantly and aforesaid changes of thymocyte were further enlarged. Also mice had a pronounced increase in rates of late apoptosis or necrosis of spleen lymphocyte and thymocyte (P < 0.05). After 6 days of hypoxia, index of spleen was significantly increased (P < 0.05), index of thymus was significantly decreased (P < 0.05) and CD3+, CD4+, CD8+ lymphocyte percentage of spleen were significantly decreased (P < 0.01). Also late apoptosis or necrosis lymphocytes of spleen and thymus were further increased (P < 0.01), viable cell rates of spleen lymphocyte and thymocytes were markedly decreased (P < 0.01), early apoptosis rates of spleen lymphocyte were markedly increased (P < 0.01). There was no significant change in the percentage of CD8+ lymphocyte in peripheral blood during the whole hypoxia period. (2) New Compound Codonopsis Pilosula (NCCP), Xiang Qi Polysaccharide (XQP) and NCCP + XQP could significantly increase the number of peripheral blood CD3+, CD4+ and spleen CD4+, but had no significant influence on the number of spleen CD8+. XQP and XQP+ NCCP could significantly decrease the number of CD4+ CD8+ (P < 0.01), increase that of CD4+ CD8- (P < 0.01), and had no significant influence on CD4- CD8+ in thymus. However, NCCP didn't influence the component of thymocytes. CONCLUSION: After hypoxia at 8 000 m simulated altitude decrease of lymphocyte of periphery in mice may be related with increase of apoptosis and necrosis of lymphocyte, and with increase of distribution of lymphocyte to lung in early period of exposure. NCCP and XQP have hopeful prospect in intervention study of hypoxia-induced immune injury. PMID- 21328973 TI - [Effect of Astragalus membranaceus polysaccharide on the expression of inflammation cytokines in THP-1 cells]. PMID- 21328974 TI - [Effect of low glucose and/or hypoxia on the proliferation and metabolism of neural stem cells]. AB - OBJECTIVE: Recent study demonstrated that hypoxia could regulate the proliferation and differentiation of neural stem cells in vitro. In the present study, effects of low glucose and/or hypoxia on the proliferation and metabolism of neural stem cells were investigated in vitro. METHODS: The neural stem cells were isolated from the rat embryonic mesencephalon (E13.5), and exposed to different oxygen concentrations (low oxygen: 3% O2 or normoxia: 20% O2) and different glucose concentrations (high glucose concentration: 4.5 g/L and low glucose concentration: 1.4 g/L) for 3 days. The proliferation of neural stem cells were examined by CCK-8 assay. Furthermore, the content of glucose, lactate, and pyruvic acid in the medium were measured after cultured in different condition for 1, 3, 5 days. RESULTS: Low oxygen and low glucose could increase the proliferation of neural stem cells respectively; in addition, the number of neurospheres under both low oxygen and glucose was the most among the four groups. The content of glucose and pyruvic acid in the medium from low oxygen or low glucose condition decreased, while the lactate concentration increased compared with the control group. CONCLUSION: The results indicate the neural stem cells prefer grow under the low glucose and low oxygen condition, and that is mainly under going glycolysis to maintain its self-renew ability. This study may provide us a useful clue for application of neural stem cells transplantation. PMID- 21328975 TI - [Effect of curcumine on the nuclear pathway of JNK during hippocampal ischemia/reperfusion injury in SHR]. AB - OBJECTIVE: To investigate the diversify of the nuclear pathway of c-Jun NH2 terminal kinases (JNK) during transient brain ischemia/reperfusion injury in hippocampal neuron apoptosis in spontaneously hypertensive rats (SHR) and to test whether the neuroprotection of curcumine on transient brain ischemia/reperfusion injury in SHR is related to the nuclear pathway of JNK. METHODS: Male Wistar Kyoto (WKY) rats and SHR were randomly divided into five groups (n = 6): WKY sham group (W-Sham), WKY ischemia/reperfusion group (W-I/ R), SHR sham group (S-Sham), SHR ischemia/reperfusion group (S-I/R) and SHR curcumine (a chinese traditional medicine)100 mg/kg treatment group (S-Cur), which were sacrificed at 2 h, 6 h, 24 h, 3 d and 7 d after reperfusion. Global brain ischemic model was established by 4-VO method. The TdT-mediated dUTP nick end labeling (TUNEL) method was used to detect the neuron apoptosis in hippocampal CA1 region. The immunohistochemical method was applied to investigate the expressions of c-jun and c-fos in hippocampal CA1 region. RESULTS: The expressions of apoptosis and c-jun and c-fos in CA1 region in S-Sham group, W-I/R group and S-I/R group were more than those in W-Sham group (P < 0.05), were significantly increased in S-I/R group than those in W-I/R group (P < 0.05), and were significantly decreased in S-Cur group than those in S-I/R group (P < 0.05). CONCLUSION: Neuronal apoptosis and the expressions of c-jun and c-fos are more in SHR hippocampal. Global brain ischemia/reperfusion injury induces more expressions of apoptosis in hippocampal neuron in SHR, and the more expressions of c-jun and c-fos may participate in that process. The neuroprotection of curcumine in SHR is related to c-jun and c fos. PMID- 21328976 TI - [Changes of myogenic regulatory factor in rat gastrocnemius muscle after downhill running]. PMID- 21328977 TI - [Study of the effects of Auricularia auricular polysaccharide on local ischemia/reperfusion injury in rat]. AB - OBJECTIVE: To investigate the influence of Auricularia Auricular polysaccharide (APP) on acute cerebral injury induced by ischemia/reperfusion in rats and its underlying mechanism. METHODS: Adult male SD rats were intragastrically pretreated with AAP at a low (50 mg/kg) or high (100 mg/kg) dose once a day for 20 days before operation. Rats intraperitoneally injected with ginkgo biloba extract (EGb671) were taken as positive control. Focal ischemia was achieved by middle cerebral artery occlusion (MCAO) on the right side for 60 min. After 24 hrs of reperfusion, the nerve function defects were recorded by Longa's score and the brain infarct sizes were measured by 2,3,5-Triphenyl-tetrazolium-chlor (TTC) staining. Apoptotic neurons were detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining after 48 h of reperfusion. The levels of oxidative stress was determined via the mitochondria generated reactive oxygen species (ROS). RESULTS: AAP treatment decreased Longa's score, brain infarct size, apoptotic neurons and mitochondria-generated ROS in a dose-dependent manner. AAP at 100 mg/kg gave a better performance compared with EGb671 on all parameters examined. CONCLUSION: AAP treatment protected rat brain from focal ischemia/reperfusion injury by its anti-oxidative effect and worked better than EGb671. PMID- 21328978 TI - [Effects of Jia Wei Huang Lian A Jiao Tang on expression of TGF-beta1 in nephrotoxicity-rats induced by cisplatin]. PMID- 21328979 TI - [Effect of notch signaling on differentiation of rat marrow mesenchymal stem cells into neurons induced by fasudil hydrochloride]. AB - OBJECTIVE: To investigate the effect of notch signaling on differentiation of rat bone marrow mesenchymal stem cells (MSCs) into neurons induced by fasudil hydrochloride. METHODS: The experiments were divided into non-transfected group, transfected group (transfected with Rn-Notch1-siRNA), positive control group (transfected with Rn-MAPK-1 Control siRNA) and negative control group (transfected with negative control siRNA). Fasudil hydrochloride induced MSCs differentiating into neurons. The fluorescence expressed by transfected MSCs were observed under inverted fluorescence microscope. The expression of notch1 mRNA, Hes1 mRNA and MAPK1 mRNA in MSCs was detected by RT-PCR. The expression of Notch1 protein, NSE, neurofilament M (NF-M) and glial fibrillary acidic protein(GFAP)was detected by immunocytochemical method. The viability of MSCs was detected by MTT. RESULTS: (1) The fluorescence of MSCs was mostly displayed after transfection for 72 h and the efficiency of transfection was up to 91.3% +/- 4.2%. Meanwhile, the notch1 mRNA and Hes1 mRNA expressed by MSCs of transfected group were significantly decreased (P < 0.05) and MTT displayed that the viability of MSCs was also significantly reduced (P < 0.05). (2) Fasudil hydrochloride could induce MSCs differentiate into neurons and the best efficiency of induction was observed in the transfected group. There was higher expression of NSE and neurofilament-M (NF-M) than the other groups (P < 0.05). CONCLUSION: There may be notch1 signaling and Rho/Rho GTPase signaling synergy on differentiation of rat bone marrow stromal cell into neurons induced by fasudil hydrochloride and they jointly promote the differentiation of MSCs into neurons. PMID- 21328980 TI - [Effects of tanycytes transplantation on the motor function score and rubrospinal motor evoked potentials of adult rats after spinal cord completely transected]. AB - OBJECTIVE: To determine whether tanycytes be able to support the regeneration of completely transected spinal cord in adult rats. METHODS: Subcultured tanycytes was transplanted into completely T8 transected spinal cord using the untranslated completely transected rats as control. After transplantation the rubrospinal motor evoked potentials were recorded below the injury level at the end of 12th week, assistant by Basso-Beatie-Bresnahan locomotor rating scale and histology method. RESULTS: At the end of 12th week the total peak amplitude of rubrospinal motor evoked potentials (MD = 133.2 microV, P < 0.01) and BBB locomotor rating scale (MD = 5.0000, P < 0.01) were both significantly improved in cell transplanted group compared with that in the untranslated control group, while the latency of the first peak was shortened (MD = 0.061 ms, P = 0.040). HE staining showed more integrity in transected spinal cords in cells transplanted groups. CONCLUSION: Transplanted tanycytes can support the regeneration of transected spinal cords in rats. PMID- 21328981 TI - [Anti-cD20scFv/CD80/CD28/zeta specific T lymphocytes eradicate primary chronic lymphocytic leukemia cells in vitro]. AB - OBJECTIVE: To construct anti-CD20scFv/CD80/CD28/zeta recombinant gene modified T cells, test its effectiveness of eradicating CD20 positive primary chronic lymphocytic leukemia (CLL) cells and provide a promising tool for tumor adoptive immunotherapy. METHODS: The recombinant vectors were transduced into PA 317 cells and high titer retroviruses were obtained to infect human peripheral blood T lymphocytes. Resistant T cells were obtained by G418 selection for one week. Then transduced T lymphocytes and primary CLL cells were co-cultured. The status of primary chronic lymphocytic leukemia cells were observed by microscope. The level of IL-2 and IFN-gamma in the culture medium were measured. RESULTS: Primary T cells expressing anti-CD20scFv/IgGFc/CD80/CD28/zeta could be constructed successfully. These T cells were able to lyse CD20+ targets and secrete high levels of IL-2 (1301.00 pg/ml) and IFN-gamma (602.18 pg/ml) in vitro. CONCLUSION: (1) Recombinant gene modified T cells can be constructed successfully. (2) Recombinant gene modified T cells can specially kill CD20 positive primary CLL cells in vitro. PMID- 21328982 TI - [Rapid inhibitory effect of glucocorticoids on peak of [Ca2+]i and PLC in airway smooth muscle]. AB - OBJECTIVE: In this study, we pretreated the mice ASMCs by dexamethasone (Dex) within 10 min, to test the peak of [Ca2+]i and phospho-PLCbeta (ser1105) in the cells by treated with Ach. METHODS: The peak of [Ca2+]i was measured by Fura-2/AM methods and the phospho-PLCbeta-ser1105 was by Western blot, and compared with dexamethasone pretreated groups. Glucocorticoid receptor antagonist RU486 and the protein synthesis inhibitor cycloheximide groups were settled in our study. RESULTS: Glucocorticoids (GCs) significantly decreased the resting values and peak of [Ca2+]i elevation and elevated the intracellular levels of phospho PLCbeta (ser1105) in 10 min. Neither the RU486 nor cycloheximide could alter the inhibitory effects of glucocorticoids stated above. CONCLUSION: Our results demonstrate that glucocorticoids exert rapid inhibitory effects. The series of signal changes in this process that restrain the peak of [Ca2+]i may be responsible for the rapid nongenomic inhibitory effects of GCs by reducing the activity of PLC. PMID- 21328983 TI - [Effect of GBE50 on delayed rectifier potassium current of ventricular myocytes in ischemic guinea pig]. AB - OBJECTIVE: Ginkgo biloba extract 50 (GBE50) is a new multicomponent drug with a polyvalent action extracted from the leave of Ginkgo biloba. The aim of this experiment was to study the effects of GBE50 on delayed rectifier potassium current (I(K)) in ventricular myocytes under normal and simulated ischemia conditions in guinea pigs. METHODS: Single ventricular myocytes were isolated by an enzymatic dissociation method. I(K) were recorded by whole-cell patch clamp technique in voltage clamp mode. GBE50 was added to the perfusion chamber from low to high concentrations (25, 50,100 mg/L) in normal condition. Different concentrations of GBE50 (25, 50, 100 mg/L) were prepared with simulated ischemic fluid. RESULTS: (1) Under normal condition, 100 mg/L GBE50 decreased I(K) (n = 7, P < 0.05). (2) Under ischemia condition, it was observed that I(K) was inhibited (n = 8, P < 0.05). (3) Perfusion with ischemia solution containing 50 mg/L (n = 8, P > 0.05) and 100 mg/L GBE50 (n = 6, P > 0.05) could reverse the decrease of I(K). CONCLUSION: GBE50 significantly decreased I(K) in a concentration-dependent manner. GBE50 could alleviate the electrophysiological heterogeneity of myocardium to prevent ischemic myocardium from arrhythmia. PMID- 21328984 TI - [Effects of ischemic preconditioning on skeletal muscle, small intestinal and lung injury following ischemia/reperfusion of hind limbs of rats]. PMID- 21328985 TI - [Role of calcitonin gene-related peptide in postconditioning induced cardioprotection in rat hearts]. PMID- 21328987 TI - [The protective effect of heparin to mesenteric microcirculation of LI/R injury rats]. PMID- 21328986 TI - [The effect of Crocin against hypoxia damage of myocardial cell and its mechanism]. AB - OBJECTIVE: To investigate the protective effect of Crocin against hypoxia damage of cardiac myocytes of neonatal rats and the regulation of HIF-1 and prolyhydroxylase (PHDs). METHODS: A model of CoCl2 simulated hypoxia damage was established in primary cultural myocardial cell. Expression levels of HIF-1alpha, VEGF, iNOS, as well as PHD1, 2, 3 protein in myocardial cells were detected by Western blot. RESULTS: Compared with CoCl2 group, the viability of myocardial cell was significantly increased after treated 24 h at 10(-5)mol/L Crocin (P < 0.01), HIF-1alpha, VEGF and iNOS were expressed higher than those in Crocin + CoCl2 group (P < 0.01), the expression of PHD2 was significantly increased (P < 0.01), while the expression of PHD3 was remarkably reduced in Crocin + CoCl2 Group (P < 0.01). CONCLUSION: Crocin has better protective effect on hypoxic damage of myocardial cell. The mechanisms of protective effect of Crocin may be related to the activation of HIF-1-mediated pathway of the hypoxia response. PHDs may be involved in the pathophysiology regulated process of myocardial cells. PMID- 21328988 TI - [The role of mitochondrial K+ channels in the cardioprotection of puerarin against hypoxia/reoxygenation injury in rats]. AB - OBJECTIVE: To determine whether the cardioprotection of puerarin (Pue) against hypoxia/reoxygenation injury is mediated by mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) and/or mitochondria calcium-activated potassium channel(mitoK(Ca)). METHODS: Cardiomyocytes were isolated from male Sprague Dawley rats and hypoxia/reoxygenation injury was induced by myocyte pelleting model. Cell viability was assessed by trypan blue exclusion and mitochondrial membrane potential was measured by loading with TMRE. The opening of mitochondrial permeability transition pore was determined spectrophotometrically. RESULTS: Pretreatment with Pue at 0.24 mmol/L for 5 min increased the cell viability against hypoxia/reoxygenation injury, while mitochondrial ATP-sensitive potassium channel inhibitor 5-hydroxydecanoate (5-HD, 100 micromol/L, 20 min) or mitochondrial calcium-activated potassium channel blocker paxilline (Pax, 1 micromol/L, 5 min) attenuated the effect of puerarin. The pretreatment with Pue at 0.24 mmol/L for 5 min attenuated collapse of delta-psim induced by hypoxia/reoxygenation injury, 5-HD and Pax abrogated the effect of Pue. In mitochondria isolated from hearts pretreated with Pue, a significant inhibition of Ca(2+)-induced swelling was observed, and this inhibition was attenuated by 5 HD and Pax. CONCLUSION: These findings indicate that Pue protects cardiomyocytes against hypoxia/reoxygenation injury via activating mitoK(ATP) channel and mitoK(Ca) channel, and inhibiting mitochondrial permeability transition pore opening. PMID- 21328989 TI - [Effects of kappa-opioid receptor stimulation on high glucose induced myocardial hypertrophy of neonatal rats]. AB - OBJECTIVE: To observe the effects of kappa-opioid receptor stimulation on high glucose induced myocardial hypertrophy of neonatal rats. METHODS: Using cultured myocardial cells as a model, the protein content was assayed with Lowrys method. The cardiomyocytes volumes were measured by computer photograph analysis system. The level of p-ERK44/42 was determined by Western blot. RESULTS: Compared with the control, U50488H significantly inhibited the protein content and volumes of cultured hypertrophic myocardial cells induced by high glucose. Meanwhile the role of ERK was important. CONCLUSION: The stimulation of kappa-opioid can inhibit myocardial hypertrophy induced by high glucose, which is possibly via attenuating p-ERK. PMID- 21328990 TI - [Effects of different intraabdominal pressure of carbon dioxide pneumoperitoneum on hemorrheology and microcirculation in rabbits]. AB - OBJECTIVE: To study effects of different intraabdominal pressure of carbon dioxide (Cq2) pneumoperitoneum on hemorrheology and microcirculation in rabbits. METHODS: Eighteen female healthy rabbits weighing 2.2 kg to 3.5 kg were randomly divided into three groups equally based on pneumoperitoneum pressure: 0 mmHg group (group I),10 mmHg group (group II) and 15 mmHg (group III). Each group received 1 h pneumoperitoneum under different pressure. Blood samples were taken at 5 min before CO2 pneumoperitoneum, at 30 and 60 min after pneumoperitoneum for the measurements of indexes of hemorrheology. Hemodynamics including heart rate (HR), mean arterial pressure (MAP) and the volume and velocity of the microcirculation of auricle were continuously monitored, such indexes were recorded at the related time. RESULTS: Afer pneumoperitoneum at 30 and 60 min, compared with group I, HR, MAP, the whole blood viscosity, the aggregation and rigid indexes of RBC were significantly raised in group II (P < 0.05), the deformability indexes of RBC, the volume and velocity of the microcirculation were markedly decreased (P < 0.05). Even more significant changes were observed in group III (P < 0.01). The plasma viscosity and the hematocrit changed little. CONCLUSION: After CO2 pneumoperitoneum, hemorrheology is decreased; Although HR, MAP are raised, the volume and velocity of the microcirculation are decreased. PMID- 21328991 TI - [Effect of mesenteric lymph duct ligation on erythrocyte rheology in acute hemorrhagic rats]. AB - OBJECTIVE: To observe the effects of mesenteric lymph duct (MLD) ligation on erythrocyte rheology in acute hemorrhagic rats. METHODS: Twenty male Wistar rats were randomly divided into hemorrhage group and ligation group (n = 10). Blood (one fourth of body whole blood volume) was withdrawn through right common carotid arteries after rats were anesthetized. In ligation group, the MLD was ligated after hemorrhage, and only threading under the MLD in hemorrhage group. The survival situation at 24 h was recorded. After 24 h, survival rats were anesthetized again, blood sample was withdrawn through left common carotid artery rapidly. And the erythrocyte sedimentation rate (ESR), electrophoresis of erythrocytes, hematocrit (Hct) were determined in blood samples of before and after hemorrhage, the erythrocytes aggregation and deformability indices were calculated. RESULTS: It showed that the ligation group survival (9 rats alive) was slightly better than that in hemorrhage group (6 rats alive). The results of erythrocyte rheology indices showed that the ESR, K value of equation, K value of emendation and electrophoresis time in hemorrhage group and ligation group were higher or longer than those before hemorrhage, the erythrocyte deformability was reduced significantly, respectively. And the erythrocytes aggregation index in hemorrhage group was increased, the electrophoresis length and migration of erythrocyte in hemorrhage group were lower than those before hemorrhage, respectively. But compared with hemorrhage group, the ESR, K value of equation, K value of emendation, erythrocytes aggregation index and electrophoresis time in ligation group were lower, the electrophoresis lenght, migration and deformability of erythrocyte were increased significantly. CONCLUSION: The results indicate that the higher erythrocyte aggregation ability, lower electrophoresis function and deformability are caused by acute hemorrhage in rats, and the MLD ligation can improve the abnormal erythrocyte rheology. PMID- 21328992 TI - [Effects of taurine on hemorheology of rats with type 2 diabetes]. AB - OBJECTIVE: To observe the effects of taurine on hemorheology and oxidative stress of diabetic rats. METHODS: 40 rats were divided into control group, diabetes group and treatment group at random. Diabetic model was reproduced by intraperitoneal injection of streptozotocin. After having been treated with taurine for 8 weeks, glycosylated hemoglobin (HbA1c) and the serum contents of glucose, superoxide dismutase(SOD), malondialdehyde (MDA) were measured. The changes of hemorheology in different groups were detected respectively. RESULTS: Compared with control group, the content of glucose, MDA and HbA1c in diabetic rats was increased, the activity of SOD was decreased, the levels of whole blood viscosity and the aggregation index of red blood cells and hematocrit were increased and RBC deformability index was decreased in diabetic rats. Moreover, taurine was able to apparently reduce high blood glucose and HbA1c (P < 0.05), markedly elevated the activity of SOD, lowered the content of MDA (P < 0.01); and taurine also could significantly reduce the levels of whole blood viscosity and the aggregation index of red blood cells and hematocrit in the meanwhile, and increase RBC deformability index (P < 0.05 or P < 0.01). CONCLUSION: Taurine could enhance the ability of oxidation resistance, improve blood rheology property in diabetic rats, at the same time it could be beneficial to prevent and cure the development of diabetic blood vessel complication. PMID- 21328993 TI - [Effect of exogenous hydrogen sulfide on polymorphonuclear neutrophil accumulation in acute lung injury rat induced by lipopolysaccharides and its mechanism]. AB - OBJECTIVE: To study the effects of sodium hydrosulfide (NaHS), hydrogen sulfide (H2S) donor, on LPS-induced polymorphonuclear neutrophil (PMN) accumulation and its mechanism. METHODS: The animal model of acute lung injury (ALI) caused by intravenous injection of lipopolysaccharides (LPS). Adult male Spraguce-Dawley (SD) rats were randomly divided into four groups (n = 8 - 12 per group): Control group (0.5 ml/kg normal saline i.v.), LPS-treated group (1 mg/kg, i.v.), LPS plus NaHS (1 mg/kg i.v. and 28 micromol/kg i.p., respectively) and NaHS group (28 micromol/kg i.p.). Animals were sacrificed at 6 h after agent administration. Morphological changes of lung tissues were observed and polymorphonuclear neutrophil (PMN) number in alveolar septum was tested. The apoptosis of PMN in the bronchoalveolar lavage fluid (BALF) was examined with in situ TdT-mediated dUTP end labeling (TUNEL). Intercellular adhesion factor-1 (ICAM-1) and nuclear factor-kappaB (NF-kappaB) expressions in the lung tissue were analyzed by Western Blot. RESULTS: The results showed that bleeding, edema, PMN accumulation and other pathological signs in the lung tissue emerged after LPS injection. Compared to control rats, the LPS-treated rats had increased PMN number, decreased PMN apoptotic percentages, and increased expressions of ICAM-1 and NF-kappaB. Administration of NaHS into LPS-treated rats reduced the PMN number and expressions of ICAM-1 and NF-kappaB but increased PMN apoptotic percentages. In addition, NaHS alleviated the degree of ALI. There were no significant differences of the above indicators between NaHS-treated rats and control rats. CONCLUSION: NaHS can reduce the PMN accumulation in the lung, and its mechanism is related to down-regulation expression of ICAM-1 and promotion of PMN apoptosis induced by inhibition of NF-kappaB pathway. PMID- 21328994 TI - [Protective effects of melatonin in acute lung injury rats caused by LPS]. AB - OBJECTIVE: To observe the expression of p-p38 mitogen-activated protein kinase in lung tissues of acute lung injury rat model induced by lipopolysaccharide (LPS) and to explore the protective effects of melatonin (MT) in lung tissues in rats. METHODS: Seventy-two rats was randomly assigned to three groups, control group, LPS group and LPS + MT group. Rat model of ALI was established by instilling LPS intratracheally. We used immunohistochemical SP and Western blot method to detect the expression of p-p38 mitogen-activated protein kinase in lung tissues and used light microscope to observe morphological changes. RESULTS: There were rare p-p38 mitogen-activated protein kinase positive cells scattered in alveolar and airway epithelial cells in control group (P < 0.01). The positive p-p38 mitogen activated protein kinase cells in LPS group increased obviously than those in control group (P < 0.01), and were mainly distributed in infiltrative inflammatory cells, airway epithelial cells, alveolar epithelial cells and pleurames epithelial cells. In MT group, the p-p38 mitogen-activated protein kinase positive cells in airway and lung tissues were much less than those in the LPS group (P < 0.05). The Western blot results were consistent with those of immunohistochemical method. CONCLUSION: The expression of p-p38 mitogen-activated protein kinase increases in alveolar and airway epithelial cells in acute lung injury rat models induced by LPS. The activation of p-p38 mitogen-activated protein kinase is found in most lung tissues, suggesting that p-p38 mitogen activated protein kinase participates in the signal transduction in inflammatory and noninflammatory cells. MT is an effective antioxidant, which relieves the inflammation in acute lung injury rats, possibly through the inhibition of the pathway of p38 MAPK over activation. PMID- 21328995 TI - [Effect of HANS electroacupuncture on the expression of NPY in PAG of heroin addicted rats]. AB - OBJECTIVE: To examine the effects of Han's acupoint and nerve stimulator (HANS) electroacupuncture on the expression of NPY in periaqueductal grey (PAG) of heroin addicted rats. METHODS: Heroin was injected subcutaneously according to the principle of daily increasing dose in rats of experimented group. The ability of special learning and memory were tested by Morris water maze; The expression of NPY in PAG of rat were detected by immunohistochemistry. RESULTS: (1) Escape latency and searching distance in heroin-addiction group were significantly increased compared with those of normal group during the place navigation test (P < 0.05). However, in acupuncture group, escape latency and searching distance was obviously shortened compared with those of heroin-addiction group (P < 0.05). The exploring time and distance of original platform area in proportion to the total distance in heroin-addiction group significantly decreased compared with those of normal group during spatial probe test (P < 0.05). The exploring time and distance of original platform area in proportion to the total distance in acupuncture group was increased compared with those in heroin-addiction group (P < 0.01). (2) The expression of NPY of heroin-addiction group was lower than that in normal group in PAG, while those of acupuncture group was higher than that in the heroin-addiction group (P < 0.05). CONCLUSION: The learning and memory induced by heroin-addiction could be reversed and the expression of NPY in PAG was increased by HANS in rats. PMID- 21328996 TI - [Effects of flunarizine on penicillin-induced seizures and hippocampal neuron unit discharges in rats]. PMID- 21328997 TI - [Effect of sinoaortic-denervation mitochondrial oxidation phosphorylation of rats cranial cell]. PMID- 21328998 TI - [Effects of cyclosporine A on pneumocyte apoptosis with lung ischemia/reperfusion injury in rats]. AB - OBJECTIVE: To investigate the effects of cyclosporine A (CsA), a powerful inhibitor of mitochondrial permeability transition pore (MPTP), on pneumocyte apoptosis, the release of cytochrome C and the activity of caspase-3 after lung ischemia/reperfusion, and explore the mechanisms. METHODS: Single lung in situ ischemia/reperfusion animal model was used. 30 SD rats were randomly divided into three groups (n = 10): sham (S) group, ischemia/reperfusion (I/R) group and cyclosporine A (CsA) group. Apoptosis of pneumocyte was assessed by TUNEL method, cytochrome C (CytC) in cytoplasm was detected by immunohistochemistry techniques, and the activity of caspase-3 was measured with spectrophotometer. RESULTS: The content of CytC in cytoplasm, the activity of caspase-3, and the value of apoptosis index (AI) in ischemia/reperfusion group were evidently higher than that in S group (P < 0.01). CsA suppressed apoptosis as well as CytC release and caspase-3 activity (P < 0.01). CONCLUSION: CsA can prevent the release of cytochrome C, block the apoptosis of pneumocyte accordingly maybe by closing the MPTP. PMID- 21328999 TI - [Protective effects of acupuncture on acute hypoxic neuronal injury in rats]. PMID- 21329000 TI - [The role of angelica injection on P-selectin and anti-cardiolipin antibodies in acute pulmonary embolism rats]. AB - OBJECTIVE: To study the effect of Chinese medicine, Angelica, injection on the expression of P-, E-selectin and anti-cardiolipin antibody in acute pulmonary embolism rats. METHODS: SD rats were randomly divided into 3 groups: normal control group(Group N), thromboembolism group (Group T), and treatment group of thromboembolism with angelica injection (Group TA). There were three time points in every group: 1 h, 4 h and 8 h. Plasma was detected by P-, with 4% paraformaldehyde, and paraffin embedded sections were detected by immunohistochemistry for P-, E-selectin and anti-cardiolipin antibodies. RESULTS: With HE stain, the inflammatory cells in the lung of rats were relatively rare in every time point in normal control group. In group T and group TA, the inflammatory cells were increasing in every time point in comparison to group N (P < 0.05) and the inflammatory cells were increasing with time in group T. The data revealed that the plasmic level of P-, E-selectin was significantly higher than that in group T1, group T4, group T8 in comparison to the corresponding sub groups of group N (P < 0.05), while it was significantly lower than that in group TA1, group TA4, group TA8 in comparison to the corresponding sub groups of group T (P < 0.05); For the OD value of plasmic anti-cardiolipin antibodies (ACA), no significant difference was observed during was lower expressed by immunohistochemistry. CONCLUSION: Acute pulmonary embolism can lead to infiltration of inflammatory cell in rat lungs. The lung inflammation of acute pulmonary embolism rats can be enhanced probably by the increased release of P-, E-selectin and anti-cardiolipin antibodies, and the enhanced inflammation promotes the release of a series of inflammatory mediators, which exacerbate the injury of lung. Angelica injection relieves the lung inflammation of acute pulmonary embolism rats possibly by inhibiting the expression of P-, E-selectin and anti-cardiolipin antibody, thus playing a role in reducing thrombogenesis. PMID- 21329001 TI - [Protective effect of limb ischemic preconditioning against liver ischemia/reperfusion injury in the rat]. AB - OBJECTIVE: To study the protective effect of limb ischemic preconditioning against liver ischemia/reperfusion injury in the rat. METHODS: Rats were randomly divided into four groups (n = 8): (1) Sham group (S group), rats without ischemic preconditioning (IPC), (2) Ischemia/reperfusion (I/R) without IP (I/R group); (3) Rats with 5 min IPC (IPC group); (4) Rats with lower limbs IPC and repeated three times (remote ischemic preconditioning, RPC group); The rats were subjected to 60 min sustained liver ischemia followed by 180-min reperfusion except S group. All ischemia rats were only subjected to 70% liver ischemia. Finally, blood and liver samples were obtained to determine the activity of ALT and AST, liver wet/dry weight (W/D), PMN counts and pathology. RESULTS: All IPC group and RPC group had obviously lower levels of ALT, AST, W/D, PMN counts than that of the I/R group (P < 0.01). CONCLUSION: The limb ischemic preconditioning has a protective effects against liver ischemia/reperfusion injury in the rat, possibly are due to suppression of liver inflammatory reaction, improvement of liver microcirculation. PMID- 21329002 TI - [Effects of curcumin on apoptosis and caspase-3 expression in cortex tissue in rats with hypoxic ischemic brain damage]. PMID- 21329003 TI - [Effects of fastigial nucleus stimulation on crucial cardiovascular physiological parameters]. AB - OBJECTIVE: In order to study the effect of fastigial nucleus stimulation (FNS) on human cardiovascular system, the photo plethysmogram (PPG) affected by FNS were recorded and analyzed. METHODS: Thirty volunteers' pulse signals were recorded before, during and after the FNS, and 5 PPG characteristics, such as H, Slope, and K were extracted. Changes of each characteristic in three stages were analyzed contrastive and based on which physiological changes caused by FNS were described. RESULTS: The pulse wave showed sensitive on-going short-term changes during the FNS. CONCLUSION: Changes of characteristics indicates that FNS results in ongoing short-term changes of some physiological parameters such as peripheral blood flow and peripheral resistance. PMID- 21329004 TI - [Studies on polysomnogram of the post-stroke depression in rat]. AB - OBJECTIVE: To explore detection method on polysomnogram of post-stroke depression and changes in rats. METHODS: Male Sprague-Dawley rats were randomly assigned to control group, stroke group, and post-stroke depression (PSD) group. The establishment of PSD model generally adopted the combination of deligation bilateral common carotid artery permanently raising alone and stress exertion. And suturing electrode under the rat scalp for polysomnogram. RESULTS: The polysomnogram could record the rats movement, electroencephalogram, electromyogram, and eye movement. The rapid eye movement (REM) latency of PSD group, and control group, stroke group were (108.2 +/- 16.1)s, (152.5 +/- 20.5)s, (145.1 +/- 18.7)s respectively. Compared with control, and stroke group, REM latency in PSD group were shortened (P < 0.01). The percentage of REM in PSD group, control group and stroke group were 5.2% +/- 1.2%, 8.3% +/- 1.4%, 7.9% +/- 1.6% respectively. Compared with control, and stroke group, REM latency in PSD group was decreased (P < 0.01). CONCLUSION: The method of suturing electrode under the rat scalp is suitable for polysomnogram. The polysomnogram could be a successful sign for PSD model. PMID- 21329005 TI - A cyclooxygase-2 inhibitor NS-398-enhanced apoptosis of esophageal carcinoma cell EC9706 by adjusting expression of survivin and caspase-3. AB - The aim of this study is to examine the effect and mechanism of a selective cyclooxygenase-2 (COX-2) inhibitor NS-398 on inducing apoptosis of esophageal cancer cells. After the treatment with NS-398 on esophageal carcinoma EC9706 cell, MTT assay was used to observe the inhibition of EC9706 cell growth and apoptosis was determined by electronic microscopy and flow cytometry. The expression of survivin and caspase-3 was examined using immunocytochemical technique. The dose of 0.01-0.1 mM NS398 showed the inhibitory effect on growth of EC9706 cell lines and induce apoptosis in a dose- and time-effective manner; moreover, NS-398 also downregulated the level of expression of survivin and elevated the expression of capase-3. NS-398 can induce apoptosis of the esophageal carcinoma EC9706 cells by means of adjusting expression of survivin and caspase-3. PMID- 21329006 TI - Function and histopathology of a cell adhesion molecule TSLC1 in cancer. AB - Even less than a decade since the discovery of TSLC1, overwhelming evidence demonstrates that the loss of TSLC1 expression by methylation-mediated epigenetic silencing or LOH is crucially implicated in various processes during tumorigenesis. Here, we summarize TSLC1 function, highlighting the concept that TSLC1 mediates the formation of tumor suppressor network via its multidomain structure and bridges extracellular adhesive activity with intracellular signaling. Next, we focus on the histopathology of TSLC1 in various cancers and the association with clinicopathological characteristics. On the basis of these, we propose that TSLC1 represents a promising biomarker for cancer diagnosis and a potential target for cancer therapy. PMID- 21329007 TI - Advance care planning as an urgent public health concern. PMID- 21329008 TI - Implementing health care reform: a nursing perspective. PMID- 21329009 TI - [Cholera outbreak after natural disasters]. PMID- 21329010 TI - [Should a patient who is not competent to consent receive dialysis treatment against own will?]. PMID- 21329011 TI - Schizophrenia, reification and deadened life. AB - Recent debates concerning the abolition of the schizophrenia label in psychiatry have focused upon problems with the scientific status of the concept. In this article, I argue that rather than attacking schizophrenia for its lack of scientific validity, we should focus on the conceptual history of this label. I reconstruct a specific tradition when exploring the conceptual history of schizophrenia. This is the concern with the question of the sense of life itself, conducted through the confrontation with schizophrenia as a form of life that does not live, or as Robert Jay Lifton termed it "lifeless life" (1979: 222-39). I conclude by arguing that the contemporary attempt to deconstruct or abolish the schizophrenia concept involves a fundamental shift in concern. The attempt both to normalize psychotic experiences, and to conceive them purely in terms of cognitive processes that can be mapped onto brain function, results in a fundamental move away from the attempt to understand the experience of madness. PMID- 21329012 TI - [Modern conceptions on the status epilepticus and possibilities of treatment with injection form of valproate (convulex)]. PMID- 21329013 TI - [Compliance in patients with epilepsy]. PMID- 21329014 TI - [Blood dehydroepiandrosterone sulfate as a prognostic index of treatment efficacy in residual schizophrenia]. PMID- 21329015 TI - [An unusual combination of myasthenia with late-disease-onset and lateral amyotrophic sclerosis]. PMID- 21329016 TI - [Diabetic polyneuropathy: epidemiology, pathogenesis, clinical presentations, diagnosis, treatment]. PMID- 21329017 TI - [The relationship of posttraumatic stress and exogenous-organic disorders]. PMID- 21329018 TI - [Description of statistical analysis of data in original articles. Typical errors]. PMID- 21329019 TI - [New developments in conduct disorder]. PMID- 21329020 TI - Assessing astronaut injury potential from suit connectors using a human body finite element model. AB - BACKGROUND: The new Orion space capsule requires additional consideration of possible injury during landing due to the dynamic nature of the impact. The purpose of this parametric study was to determine changes in the injury response of a human body finite element model with a suit connector (SC). METHODS: The possibility of thoracic bony injury, thoracic soft tissue injury, and femur injury were assessed in 24 different model configurations. These simulations had two SC placements and two SC types, a 2.27-kg rectangular and a 3.17-kg circular SC. A baseline model was tested with the same acceleration pulses and no SC for comparison. Further simulations were conducted to determine the protective effect of SC location changes and adding small and large rigid chest plates. The possibilities of rib, chest soft tissue, and femur injury were evaluated using sternal deflection, chest deflection, viscous criterion, and strain values. RESULTS: The results indicated a higher likelihood of chest injury than femur injury. The mean first principal strain in the femur was 0.136 +/- 0.007%, which is well below the failure limit for cortical bone. The placement of chest plates had a protective effect and reduced the sternal deflection, chest deflection, and viscous criterion values. CONCLUSION: If possible, the SC should be placed on the thigh to minimize injury risk metrics. Chest plates appear to offer some protective value; therefore, a large rigid chest plate or similar countermeasure should be considered for chest SC placement. PMID- 21329021 TI - Extremity compartment syndrome in pigs during hypobaric simulation of aeromedical evacuation. AB - INTRODUCTION: Extremity compartment syndrome (ECS) is diagnosed when the pressure within a muscle compartment increases to within 45 mmHg of mean arterial pressure. Increased pressure limits perfusion and eventually produces tissue necrosis. This can result in disability or loss of the affected limb. Hypobaric pressure during aeromedical evacuation (AE) has been hypothesized to increase the incidence of ECS. This was tested in a threshold model of ECS in swine. METHODS: Injury was induced by placing an angioplasty balloon between the tibia and the anterior muscle compartment and inflating the balloon to produce an intracompartmental pressure (ICP) 30 mmHg greater than mean arterial pressure for either 5 h or 6 h. Afterwards, animals were maintained either at ground level pressure or at a pressure equivalent to a simulated altitude of 2135 m above sea level for 8 h. ICP was monitored for signs of ECS development. At the end of the period the muscle was collected and evaluated for pathological changes and expression of various molecules associated with inflammation and tissue injury. RESULTS: Simulated altitude did not increase incidence of ECS, peak intracompartmental pressures, or time to onset of ECS. However, muscle degeneration and formation of microvascular thrombi were reduced by exposure to altitude. TNF, IL-1 b, IL-6, IGFBP5, and TGFB2 were increased (P < 0.05) by exposure to altitude, whereas FGF, IGF1, IGFBP4, BMP4, nitrotyrosine, and nitrate were unchanged (P > 0.05). DISCUSSION: Simulated altitude did not increase incidence of ECS. Inflammatory protein expression was increased in muscle, but some aspects of pathology were less severe following altitude exposure. PMID- 21329022 TI - Guided imagery, anxiety, heart rate, and heart rate variability during centrifuge training. AB - BACKGROUND: Centrifuge training is an important method of improving the hypergravity tolerance of pilots, cosmonauts, and Chinese astronauts. However, the concomitants of tension or anxiety often impede training. Guided imagery (GI), a mind-body relaxation technique, provides a behavioral and cognitive means whereby individuals are able to exert control over the focus of attention. This study aims to investigate the immediate effects of GI for reducing stress in centrifuge training. METHODS: There were 12 healthy young men who were randomly assigned to a GI group or music group. We measured changes in heart rate during centrifuge training, in heart rate variability before and after centrifuge training, and also evaluated relaxation and anxiety in three phases: before intervention, after intervention, and following centrifuge training. RESULTS: The change in the pattern of anxiety was different in the two groups over the three phases. Anxiety (measured by State Anxiety Inventory) in the GI group changed from 31.7 +/- 5.9 to 26.8 +/- 2.6 and 27.8 +/- 4.1, whereas for the music group this changed from 32.2 +/- 7.6 to 31.2 +/- 8.3 and 26.8 +/- 6.8. During centrifuge training, the maximal HR for the GI group (101.2 +/- 8.8) was lower than that of the music group (123.0 +/- 19.1). In addition GI showed a decrease in low frequency (LF, 0.04-0.15 Hz) components and an increase in high frequency (HF, 0.15-0.4 Hz) components before and after centrifuge training. CONCLUSION: GI was capable of decreasing tension, anxiety, and sympathetic nervous system activity pre- or post-centrifugation. PMID- 21329023 TI - Physiological equivalence of normobaric and hypobaric exposures of humans to 25,000 feet (7620 m). AB - INTRODUCTION: Skepticism exists about whether normobaric and hypobaric hypoxic exposures are equivalent. We have evaluated if physiological differences between the two environments would translate into actual differences in hypoxia symptoms. METHODS: We exposed 20 subjects to 5-min 25,000-ft (7620-m) equivalent environments in an altitude chami ber and then in a ground-level portable reduced oxygen training enclosure (PROTE). Heart rate and hemoglobin oxygen saturation (SaO2) were continuously monitored. Alveolar gas samples were collected at 1, 3, and 4 min elapsed time. Subjects completed hypoxia symptom questionnaires at the same time points. RESULTS: Mean fourth minute alveolar oxygen tension (PaO2), alveolar carbon dioxide tension (PaCO2), and respiratory quotient (RQ) differed significantly between the chamber and PROTE. Declines in SaO2 appeared biphasic, with steepest declines seen in the first minute. Rates of SaO2 decline over the 5 min exposure were significantly different. Heart rate was not different, even when indexed to body surface area. Mean number of hypoxia symptoms between hypobaric and normobaric environments after 1 min were significant. However, the temporal pattern of symptom frequencies across subjects between the chamber and PROTE were similar. CONCLUSIONS: Alveolar gas composition and arterial hemoglobin oxygen desaturation patterns differed between a ground level and hypobaric exposure. Differences in mean number of hypoxia symptoms between hypobaric and normobaric environments after 1 min, but not at 3 and 4 min, coupled with similar patterns in symptom frequencies, suggest that ground-level hypoxia training may be a sufficiently faithful surrogate for altitude chamber training. PMID- 21329024 TI - Evaluation of a novel basic life support method in simulated microgravity. AB - BACKGROUND: If a cardiac arrest occurs in microgravity, current emergency protocols aim to treat patients via a medical restraint system within 2-4 min. It is vital that crewmembers have the ability to perform single-person cardiopulmonary resuscitation (CPR) during this period, allowing time for advanced life support to be deployed. The efficacy of the Evetts-Russomano (ER) method has been tested in 22 s of microgravity in a parabolic flight and has shown that external chest compressions (ECC) and mouth-to-mouth ventilation are possible. METHODS: There were 21 male subjects who performed both the ER method in simulated microgravity via full body suspension and at +1 Gz. The CPR mannequin was modified to provide accurate readings for ECC depth and a metronome to set the rate at 100 bpm. Heart rate, rate of perceived exertion, and angle of arm flexion were measured with an ECG, elbow electrogoniometers, and Borg scale, respectively. RESULTS: The mean (+/- SD) depth of ECC in simulated microgravity was lower in each of the 3 min compared to +1 G2. The ECC depth (45.7 +/- 2.7 mm, 42.3 +/- 5.5 mm, and 41.4 +/- 5.9 mm) and rate (104.5 +/- 5.2, 105.2 +/- 4.5, and 102.4 +/- 6.6 compressions/min), however, remained within CPR guidelines during simulated microgravity over the 3-min period. Heart rate, perceived exertion, and elbow flexion of both arms increased using the ER method. CONCLUSION: The ER method can provide adequate depth and rate of ECC in simulated microgravity for 3 min to allow time to deploy a medical restraint system. There is, however, a physiological cost associated with it and a need to use the flexion of the arms to compensate for the lack of weight. PMID- 21329025 TI - Pilot age and geographic region of commuter and air taxi crashes: a case-control study. AB - BACKGROUND: Previous studies of major airline and general aviation crashes have identified a host of risk factors. We examined risk factors related to crashes involving commuter air carrier and air taxi flights. METHODS: A matched case control design was applied to assess the association of pilot age, total flight time, and geographic region with commuter air carrier and air taxi crashes (14 CFR Part 135) from 1983-2002 in the United States. A total of 2033 commuter air carrier or air taxi crashes from the National Transportation Safety Board aviation crash database were identified as eligible cases. Controls were randomly selected incidents from the Federal Aviation Administration's (FAA) aviation incident database coded under Part 135 operation. RESULTS: Relative to controls, commuter air carrier and air taxi crashes were less likely to occur in pilots under 30 yr of age (adjusted odds ratio 0.68, 95% confidence interval 0.54-0.88) after adjusting for geographic region and total flight time. With adjustment for pilot age and total flight time, the commuter air carrier and air taxi crashes with pilot error were nearly 13 times as likely to be in Alaska as their matched controls (adjusted odds ratio 12.84, 95% confidence interval 5.24-31.45). CONCLUSIONS: These results suggest that pilot age may be associated with risk of crash involvement in Part 135 operations. The excess crash risk in Alaska with or without pilot error underscores the importance of environmental hazards in flight safety. PMID- 21329026 TI - In-flight urine collection device: efficacy, maintenance, and complications in U 2 pilots. AB - INTRODUCTION: Urine collection systems for in-flight use have gradually improved over the past 50 yr; however, current management of urine evacuation remains suboptimal. This is a cross-sectional survey-based study on the current urine collection device employed in the U.S. Air Force's U-2S airframe, examining efficacy, problems with wear, device maintenance, and complaint reporting. METHODS: An anonymous survey consisting of 18 questions was generated inquiring about problems with wear of the urine collection system, care of the device, and education. The survey was offered at Beale AFB and overseas U-2 locations to pilots with at least 180 h of flying experience with the airframe. RESULTS: There were 57 subjects who completed the survey with 62.5% reporting complications, including mechanical dysfunction, pain and poor fit, skin irritation, allergic reaction, embarrassment, and urethral issues. Variation was seen in the degree of problem reporting and care of the device. Discussion and literature review is provided on in-flight and space urine collection and evacuation systems, sheath catheters, urine and contact dermatitis, urethritis, external catheter sizing methods, and psychological aspects of catheter use. CONCLUSIONS: The majority of surveyed pilots experienced various problems associated with wear of their urine collection device. Also, variation in reporting and care of the device exists. Potential improvements include standardization of fitting procedures and device maintenance, increased catheter draining capacity, use of skin barriers to urine, enhanced privacy measures, and incorporation of less injurious structural materials such as silicone. PMID- 21329027 TI - Respiratory function in hoist rescue: comparing slings, stretcher, and rescue basket. AB - INTRODUCTION: Some types of equipment used in helicopter hoist rescue have the potential to cause respiratory embarrassment due to chest compression and/or body positioning. This study compared the respiratory effects of four commonly used devices. METHODS: A randomized crossover trial was undertaken in 27 healthy adults while suspended in single sling (SSling), double sling (DSling), supine in a rescue stretcher, and in a rescue basket (RB) of the type used by the U.S. Coast Guard. Primary variables measured were 1-s forced expiratory volume (FEVI), forced vital capacity (FVC), FEV1/FVC ratio, and inspiratory capacity (IC) in each modality versus control. Secondary measurements were peripheral oxygen saturation (SpO2), heart rate (HR), and respiratory rate (RR). RESULTS: Data meeting repeatability standards was obtained from at least 24 subjects in each position. The SSling was associated with significant mean decreases from control of 17% in FEV1, 19.8% in FVC, and 28.3% in IC, together with increases in HR and RR and a decrease in SpO2. The DSling and stretcher were associated with smaller decreases in expiratory spirometry; the DSling was associated with a >10% decrease in IC and the stretcher was associated with a >10% increase in IC. The values for RB did not vary from control for any outcome measure. There was no decrease in FEV1/FVC ratios in any modality. CONCLUSION: The RB was not associated with any change in measured outcomes. Other methods tested, especially SSling, have detrimental effects on respiratory function. PMID- 21329028 TI - Miniaturized sensors to monitor simulated lunar locomotion. AB - INTRODUCTION: Human activity monitoring is a useful tool in medical monitoring, military applications, athletic coaching, and home healthcare. We propose the use of an accelerometer-based system to track crewmember activity during space missions in reduced gravity environments. It is unclear how the partial gravity environment of the Moorn or Mars will affect human locomotion. Here we test a novel analogue of lunar gravity in combination with a custom wireless activity tracking system. METHODS: A noninvasive wireless accelerometer-based sensor system, the activity tracking device (ATD), was developed. The system has two sensor units; one footwear-mounted and the other waist-mounted near the midlower back. Subjects (N=16) were recruited to test the system in the enhanced Zero Gravity Locomotion Simulator (eZLS) at NASA Glenn Research Center. Data were used to develop an artificial neural network for activity recognition. RESULTS: The eZLS demonstrated the ability to replicate reduced gravity environments. There was a 98% agreement between the ATD and force plate-derived stride times during running (9.7 km x h(-1)) at both 1 g and 1/6 g. A neural network was designed and successfully trained to identify lunar walking, running, hopping, and loping from ATD measurements with 100% accuracy. DISCUSSION: The eZLS is a suitable tool for examining locomotor activity at simulated lunar gravity. The accelerometer-based ATD system is capable of monitoring human activity and may be suitable for use during remote, long-duration space missions. A neural network has been developed to use data from the ATD to aid in remote activity monitoring. PMID- 21329029 TI - International medical evacuation in children: a primary care pediatric clinic's 3 year experience. AB - BACKGROUND: The decision whether to immediately evacuate children who have become ill is a challenge for pediatricians working in countries with limited medical resources. The aim of this study is to describe the injuries and diseases that required evacuation of children from our clinics in Ho Chi Minh City and Hanoi to tertiary critical care hospitals over a 3-yr period. METHODS: A retrospective chart review was performed of all patients aged less than 17 yr who underwent an international medical evacuation between April 1, 2006, and February 28, 2009. Patients were allocated to one of two groups: those requiring immediate aeromedical evacuation by air ambulance and those whose condition allowed nonurgent evacuation by commercial flight. RESULTS: There were 19 international medical evacuations that were executed: 5 immediate aeromedical evacuations with air ambulance and 14 nonurgent evacuations using commercial flights. Immediate evacuations were undertaken to Thailand and Singapore to access pediatric cardiac surgery and intensive care facilities. Some evacuations were performed mainly at parental request. CONCLUSIONS: Aeromedical evacuation requires a multidisciplinary approach and patient age, local resources, availability, location of resources, and parental preference are important factors to be considered. Effective communication is paramount and choice of transportation should be governed by pre-established policies and procedures if possible. PMID- 21329030 TI - Medical waiver for flying after microvascular decompression for hemifacial spasm. AB - BACKGROUND: Microvascular decompression has become the treatment of choice for hemifacial spasm. Post-surgical symptoms of vestibular dysfunction may appear, but are mostly transient. The unique occupational demands of military aviators necessitate complete otoneurological evaluation after vestibular insults to allow safe return to flying duties. CASE REPORT: We present a case of a military jet fighter pilot who developed transient vertigo and disequilibrium after microvascular decompression for hemifacial spasm. Resolution of symptoms and complete recovery as documented by vestibular bedside and laboratory tests allowed us to grant the pilot full solo flying privileges. PMID- 21329031 TI - Reduced G tolerance associated with supplement use. AB - BACKGROUND: High G forces encountered in tactical military aviation and aerobatic flight produce a host of physiologic responses aimed at preserving cerebral perfusion. The military has instituted measures to augment the physiologic response in order to avoid G-induced loss of consciousness (G-LOC) because of its potential to cause a catastrophic mishap. CASE REPORT: The case presented here details a Naval Aviator who experienced reduced G tolerance over two successive flights with a temporal relationship of starting a new supplement. Two components of the supplement, coenzyme Q10 and niacin, are highlighted here for their hemodynamic effects. After stopping the supplement the aviator regained his normal G tolerance and had no further issues in flight. There are several factors that can reduce G tolerance and supplement use has to be considered here because of the potential for altering the normal physiological response to increased G force. Our discussion reviews the physiological effects of increased G force, the spectrum of signs of decompensation under the stress of G force, and the potential effects this supplement had on the normal physiological response to increased G force, thus reducing the aviator's G tolerance. PMID- 21329032 TI - Sub-orbital commercial human spaceflight and informed consent. AB - Commercial spaceflight is expected to rapidly develop in the near future. This will begin with sub-orbital missions and then progress to orbital flights. Technical informed consent of spaceflight participants is required by the commercial spaceflight operator for regulatory purposes. Additionally, though not required by regulation, the aerospace medicine professional involved in the medical screening of both spaceflight participants and crewmembers will be asked to assist operators in obtaining medical informed consent for liability purposes. The various federal and state regulations regarding informed consent for sub orbital commercial spaceflight are evolving and are unfamiliar to most aerospace medical professionals and are reviewed and discussed. PMID- 21329033 TI - You're the flight surgeon. Left bundle branch block. PMID- 21329034 TI - Classics in space medicine. Prolonged exposure in the Navy full pressure suit at "space equivalent" altitudes. PMID- 21329035 TI - This month in aerospace medicine history. PMID- 21329036 TI - Rethinking health in a changing environment: a global challenge. PMID- 21329037 TI - Single-agency earth and space missions less risky. PMID- 21329038 TI - A special issue on skin nanotechnology. PMID- 21329039 TI - Engineered inorganic nanoparticles and cosmetics: facts, issues, knowledge gaps and challenges. AB - The cosmetic industry is among the first adaptors of nanotechnology through the use of engineered nanoparticles (ENPs) to enhance the performance of their products and meet the customers' needs. Recently, there have been increasing concerns from different societal stakeholders (e.g., governments, environmental activist pressure groups, scientists, general public, etc.) concerning the safety and environmental impact of ENPs used in cosmetics. This review paper seeks to address the twin concerns of the safety of cosmetics and the potential environmental impacts due to the constituent chemicals-the ENPs. The safety aspect is addressed by examining recently published scientific data on the possibility of ENPs penetrating human skin. Data indicates that although particular types of ENPs can penetrate into the skin, until now no penetration has been detected beyond the stratum corneum of the ENPs used in cosmetics. Yet, important lessons can be learned from the more recent studies that identify the characteristics of ENPs penetrating into and permeating through human skin. On the part of the environmental impact, the scientific literature has very limited or none existent specific articles addressing the environmental impacts of ENPs owing to the cosmetic products. Therefore, general ecotoxicological data on risk assessment of ENPs has been applied to ascertain if there are potential environmental impacts from cosmetics. Results include some of the first studies on the qualitative and quantitative risk assessment of ENPs from cosmetics and suggest that further research is required as the knowledge is incomplete to make definitive conclusions as is the case with skin penetration. The authors conclude that the cosmetic industry should be more transparent in its use of nanotechnology in cosmetic products to facilitate realistic risk assessments as well as scientists and pressure groups being accurate in their conclusions on the general applicability of their findings. Transparency in cosmetics needs nanotechnology, but nanotechnology in cosmetics also needs transparency... PMID- 21329040 TI - Designing inorganic light-protective skin nanotechnology products. AB - In this review, we discuss the use of inorganic nanoparticles, mainly zinc oxide (ZnO) and titanium dioxide (TiO2), for sunscreen applications considering their intrinsic physical properties and the Mie theory. These properties cause, from one side, attenuation of the ultraviolet light by absorption and scattering (dependent on a particle size), which is the purpose sunscreens are designed for, and formation of free radicals (i.e., phototoxicity) during this process--from the other. Particle penetration into skin is also an important issue addressed in this review due to possible adverse effects associated with interaction between nanoparticles and skin living cells. PMID- 21329041 TI - Are commercially available nanoparticles safe when applied to the skin? AB - There are a growing number of commercial uses of nanoparticles which involve direct people contact with the potential for absorption through the skin. Nanoparticles are present in a range of consumer products including colloidal health drinks, carbon fibre sports equipment, sunscreens, cosmetics, electronic products and as antibacterial components of toys, cooking products and wound dressings. Environmental sources of ultra-fine nanoparticles have been present for millennia and anthropogenic sources of similar materials result from industrial processes. Recent technological advances have enabled improvements in both the manufacture of nanoparticles and in the study of their safety. With subcellular dimensions, the physical properties of a nanoparticle cannot be easily predicted from the properties of a microparticle with identical chemical composition. Recent studies in animals and humans have sought to document the safety of consumer nanomaterials. In this article, the safety of such materials is critically reviewed. PMID- 21329042 TI - Focus on skin as a possible port of entry for solid nanoparticles and the toxicological impact. AB - Today, various anthropogenic sources account for an increasing atmospheric nanoparticle (NP) concentration and thus increase of human exposure to NPs. The situation may become problematic since commercial applications of nanotechnology expand more rapidly than the scientific knowledge on NP exposure. This review focuses on skin as a route of exposure for NPs and the toxicological impact in skin with special attention to physicochemical properties of NPs and skin. We will review data published on NP skin penetration, toxicological issues and on physicochemical NP characterisation. NPs are reported to be localised mainly in hair follicle openings and on the stratum corneum surface. Some studies report the localisation of NPs in the deeper layers of the stratum corneum, the viable epidermis and deeper hair follicle parts. Sporadically, penetration into the dermis is reported for 4 to 5 nm sized quantum dots. NP interactions with epidermal and dermal cells may cause cytotoxicity and undesired immune responses, especially in damaged skin. NP characteristics promoting skin penetration are still unclear. For sunscreen NP substances there are indications for cytotoxicity (TiO2) and genotoxicity (ZnO). Significant data gaps comprise skin penetration and toxicological areas of (metal) particles smaller than 10 nm. The importance of skin barrier function in NP exposure is underlined by NP's skin cell damaging potential. Although NP skin studies display, increasingly, a multidisciplinary character (penetration, toxicity studies) the results are often contradicting. Standardisation of available test systems for NPs and focusing on the correlating physicochemical NP properties to penetration potential is recommended. PMID- 21329043 TI - Skin absorption and potential toxicity of nanoparticulate nanomaterials. AB - Nanotechnology is going to change our lives in many different ways since its applications span from electronics to medical treatments. However, great concerns about nanomaterials' hazardous effects on the environment and human health are increasing as nanotechnology flourishes. Besides the benefits promoted by intentional use, worries mainly concern misuse or, worse, non-intentional exposure. In this contribution we would like to briefly summarize findings on skin penetration of nanoparticulate nanomaterials, herein indicated as nanotechnological nanoparticles, and to brain-storm on their potential ability to generate toxic effects. PMID- 21329044 TI - Nanoengineering a biocompatible inorganic scaffold for skin wound healing. AB - Tissue engineering is a multidisciplinary field that can directly benefit from advancements in nanotechnology and nanoscience. This article reviews a representative selection of commercially available procedures and techniques used to treat different degrees of skin burns. It also explores the emerging novel biocompatible inorganic nano-engineered alumina membrane in terms of skin wound healing. PMID- 21329045 TI - New nanosized technologies for dermal and transdermal drug delivery. A review. AB - Nanocarriers are promising dermal and transdermal drug delivery systems. The review recapitulates the most prominent nanocarriers such as microemulsions, liposomes and micro- and nanoparticles for the dermal and transdermal application. Microemulsions have a high solubilization capacity even for poorly soluble drugs and combined with their permeation enhancing effect high flux rates can be obtained. Liposomal carrier systems exhibit a high flexibility and mobility, whereas the follicular penetration of micro- and nanoparticular systems show an increase in the penetration depth. However, it is necessary to understand the particular mechanism of each transport system in order to limit undesired effects. PMID- 21329047 TI - Biphasic vesicles: a novel topical drug delivery system. AB - Non-invasive drug delivery systems provide alternative routes of administration and improved delivery of drugs to localized target sites in the body. Topically applied dermal and transdermal delivery systems could replace needles required to administer many of the new biologics-based drugs and vaccines, in addition to other significant advantages such as avoiding first-pass hepatic metabolism, gastric degradation and frequent dosing. However, the limited dermal and transdermal delivery of many small and large molecules is a significant challenge because of the unyielding barrier properties of the skin. This paper reviews the application of a novel topical delivery system, biphasic vesicles built from nanoscale components, to the delivery of several therapeutic agents and vaccine antigens and discusses progress toward clinical use. PMID- 21329046 TI - Current view on nanosized solid lipid carriers for drug delivery to the skin. AB - Drug delivery into the skin is problematic because, as a natural barrier, it has a very low permeation rate. Several approaches have been made to increase the latter. Current advances in materials science and nanotechnology promise the development of new generations of drug carriers for therapeutic, diagnostic and protective purposes. We have reviewed various lipid drug delivery systems to the skin, with the main focus on solid lipid nanoparticles (SLNs). Further the article concerns possible variants in formulation of SLNs, the selection of lipid compounds and safe stabilizers, and the influence of the physicochemical properties of the drugs on distribution after loading into SLNs. In the last part the advantages of delivery into keratinocytes by SLNs over that of the free drug is addressed, focusing on decreased cytotoxicity of the incorporated drug in SLNs and controlled drug delivery to the subcellular compartments. This knowledge is important in the design and production of advanced solid lipid drug carriers. Additionally, the need for novel approaches or devices to improving permeation is also discussed in the context of moving the nanocarriers to targets deeper in the skin. PMID- 21329048 TI - Drug delivery applications with ethosomes. AB - Ethosomes are specially tailored vesicular carriers able to efficiently deliver various molecules with different physicochemical properties into deep skin layers and across the skin. This paper reviews the unique characteristics of the ethosomal carriers, focusing on work carried out with drug containing ethosomal systems in animal models and in clinical studies. The paper concludes with a discussion on the safety of the ethosomal system applications. PMID- 21329049 TI - Ibuprofen transdermal ethosomal gel: characterization and efficiency in animal models. AB - A new ibuprofen transdermal nanosystem, designed by using an ethosomal carrier, was characterized and tested for its pharmacokinetic profile and therapeutic effects in animal models. It was found that the ethosomal nanosystem contains unilamellar vesicles with a normal size distribution of about 200 nm. The drug applied transdermally from the ethosomal gel was present in plasma for a longer period of time as compared to the oral administration and showed a high relative bioavailability. Ibuprofen plasma concentration reached a Cmax of 74.11 +/- 18.52 microg/ml 2 hours post application on rat skin. The ibuprofen ethosomal gel had an efficient antipyretic effect in fevered rats. Animal body temperature decreased to normal value gradually with duration of action of at least 12 hours compared to only 7 hours after the oral treatment. The transdermal ibuprofen gel also induced an analgesic effect 30 minutes following its application lasting for at least 6 hours. Biochemical and clinical hematological analysis results of the blood taken from animals in all experimental groups and those of skin histological examination show that ibuprofen ethosomal gel is safe and does not irritate the skin. Data obtained in this work suggest that the designed ethosomal ibuprofen gel could be further investigated in humans for its antipyretic effect. PMID- 21329050 TI - Skin delivery of ferulic acid from different vesicular systems. AB - The aim of the present research is to evaluate the skin delivery capabilities of different vesicular systems, including conventional liposomes (CL), Tween 80 based deformable liposomes (DL), invasomes (INS) and ethosomes bearing ferulic acid (FA) being an antioxidant exhibiting a wide range of therapeutic effects against various diseases. All of the test formulations were characterized for particle size distribution, zeta-potential, vesicular shape and surface morphology, in vitro human skin permeation and skin deposition. Dynamic Light Scattering (DLS) and Transmission Electron Microscopy (TEM) defined that all of liposomal vesicles were almost spherical, displaying unilamellar structures with low polydispersity (PDI < 0.2) and nanometric size range (z-average no more than 150 nm). In addition, all the vesicular systems except conventional liposomes were negatively charged to a certain extent. In vitro skin permeation and skin deposition experiments demonstrated that the permeation profile of ferulic acid through human stratum corneum epidermis membrane (SCE) and the drug deposition in skin were both improved significantly using these vesicular liposomal systems. Permeation and skin deposition enhancing effect was highlighted by the ethosomal system containing 18.0 mg/ml of ferulic acid with an significantly (P < 0.01) enhanced skin flux (267.8 +/- 16.77 microg/cm2/h) and skin drug deposition (51.67 +/- 1.94 microg/cm2), which was 75 times and 7.3 times higher than those of ferulic acid from saturated PBS (pH 7.4) solution, respectively. This study demonstrated that ethosomes are promising vesicular carriers for delivering ferulic acid into or across the skin. PMID- 21329051 TI - Penetration of quantum dot particles through human skin. AB - The skin is a large and accessible area of the body, offering the possibility to be used as an alternative route for drug delivery. In the last few years strong progress has been made on the developing of nanoparticulate systems for specific applications. The interaction of such small particles with human skin and their possible penetration attracted some interest from toxicological as well as from drug delivery perspectives. As size is assumed to play a key role, the aim of the present work was to investigate the penetration profile of very small model particles (approximately 4 nm) into excised human skin under conditions chosen to mimic the in vivo situation. Possible application procedures such as massaging the formulation (5 to 10 minutes) were analyzed by non-invasive multiphoton- and confocal laser scanning microscopy (MPM, CLSM). Furthermore, the application on damaged skin was taken into account by deliberately removing parts of the stratum corneum. Although it was clearly observed that the mechanical actions affected the distribution pattern of the QDs on the skin surface, there was no evidence of penetration into the skin in all cases tested. QDs could be found in deeper layers only after massaging of damaged skin for 10 min. Taking these data into account, obtained on the gold standard human skin, the potential applications of nanoparticulate systems to act as carrier delivering drugs into intact skin might be limited and are only of interest for partly damaged skin. PMID- 21329052 TI - Progress and challenges in quantifying skin permeability to nanoparticles using a quantum dot model. AB - Increases in the research and consumer applications of nanoparticles means an increased opportunity for human skin contact. As researchers work to evaluate the most important factors in assessing nanoparticle skin penetration risk, there are common pitfalls or noise factors that can easily complicate interpretation of results and induce ambiguity. We first look at the impact of time course on skin barrier impairment, as different treatments have immediate or delayed responses. The next important factor is the skin model, as the ability to relate animal model or ex vivo tissue data to in vivo human skin susceptibility to nanoparticle skin penetration varies depending on the treatment used to induce a barrier defect. Upon consideration of skin barrier status, the characterization and stability of applied nanoparticles- in our case quantum dots- is the next most important factor. Once accounting for the experimental inputs, evaluation techniques for assessing skin penetration have an additional set of specific challenges that must be met or accounted for. With proper consideration, the challenge of determining nanoparticle and skin barrier effect on human skin penetration can be met. PMID- 21329054 TI - Transdermal delivery enhanced by antimicrobial peptides. AB - Magainin antimicrobial peptide has been shown to increase skin permeability by perturbing stratum corneum lipids in the skin. In this study, we hypothesized that skin permeation enhancement depends on peptide structure. We therefore measured skin permeability enhancement by modified magainin derivitives and 20 different antimicrobial peptides in a formulation containing ethanol and N lauroyl sarcosine (NLS). We found that modification of magainin structure did not improve skin permeability enhancement. Although all six magainin-based peptides had alpha-helical structure and fluidized stratum corneum lipids, only magainin and a Gly-Ala substituted magainin with NLS and ethanol significantly increased skin permeability. Among the 20 antimicrobial peptides, only magainin itself and a Lys-Leu analog peptide showed enhancement. Overall, this is the first study to survey skin permeability enhancement by antimicrobial peptides. We conclude that over the range of conditions studied here, most antimicrobial peptides did not enhance skin permeability and that magainin peptide provided the optimal structure. PMID- 21329053 TI - A novel class of compounds with cutaneous wound healing properties. AB - Impaired wound healing is a major complication underlying several disease processes (such as diabetes). Efficient wound healing is hampered by a wide variety of processes including hypoxia (oxygen deprivation), inflammation, infection, and oxidative stress through the generation of harmful reactive oxygen species (ROS). The inherent complexity of the healing wound has resulted in limited efficacy of most therapies that target single parameters involved in the slow healing processes. Fullerenes are carbon nanospheres previously shown to exhibit a wide range of biological activities. Given that these molecules have been shown to be potent anti-inflammatories and antioxidants we hypothesized that fullerenes could aid in wound healing based on these properties. We designed and synthesized a panel of fullerene derivatives and investigated their ability to accelerate wound healing using a modified scratch assay, an ex vivo human skin model, and a mouse model of skin irritation. Several derivatives supported cell migration, induced wound closure in human skin explants, and greatly accelerated the rate at which wound healing occurred in vivo. Therefore, fullerene derivatives represent a potential new class of wound healing therapies that may aid in wound healing treatment. PMID- 21329055 TI - Taking pride in speaking the language of nursing. PMID- 21329056 TI - An all too familiar scenario. PMID- 21329057 TI - How to class perioperative nursing. PMID- 21329058 TI - Embracing burnout. PMID- 21329059 TI - Diabetes on the increase yet services being cut. PMID- 21329060 TI - Nurses need education to prevent and treat stroke. PMID- 21329061 TI - Nursing in Fiji under pressure. PMID- 21329062 TI - Young man with cerebral palsy knows his own mind. PMID- 21329063 TI - Believing in the paradigm of recovery. PMID- 21329064 TI - Sourcing health information. PMID- 21329065 TI - Recovery nursing in Nepal--a fulfilling journey. PMID- 21329066 TI - Continuing health inequalities must be addressed. PMID- 21329067 TI - Introducing family-centred care in Binh Dinh Province. PMID- 21329068 TI - Teaching in Vietnam a two-way learning process. PMID- 21329069 TI - 'Complementary, not in competition'. PMID- 21329070 TI - Demystifying supervision. PMID- 21329071 TI - Enriching neonatal nursing practice. PMID- 21329072 TI - Caring for flight nuses. PMID- 21329073 TI - NZNO takes issue with major aged-care provider over breach of good faith. PMID- 21329074 TI - Trusts fail to use warning systems. PMID- 21329075 TI - Staff miss danger signs. PMID- 21329076 TI - "Nurse involvement in QIPP could make cuts less painful". PMID- 21329077 TI - "Nursing is now unattractive--a bit like David Cassidy". PMID- 21329078 TI - "Should we support calls to decriminalise drug use"? PMID- 21329079 TI - Can adapted EWS improve response to deterioration? AB - All nurses must ensure deteriorating patients are identified early, and a timely and effective response is implemented. This article discusses a new early warning system and training programme, which are intended to prevent avoidable cardiac arrests. PMID- 21329080 TI - Early warning scores: effective use. AB - In June 2008, North Tees and Hartlepool Trust signed up to Patient Safety First. Our objectives were to put patients first and to develop a culture of patient safety. We implemented the intervention discussed here with the aim of preventing harm and reducing in-hospital cardiac arrest and mortality through earlier recognition and treatment of deteriorating patients. Acute illness is exacerbated by "failure to act" on recognised changes (Hillman et al, 2001). Analysis of serious patient safety incidents revealed that 11% of deaths were related to "deterioration not recognised or not acted upon" (National Patient Safety Agency, 2007a). The process can fail by not taking observations, not recognising early signs of deterioration, not communicating observations causing concern and not responding to concerns appropriately (NPSA, 2007b). We focused on improving all these areas. PMID- 21329081 TI - Simulation: can it eliminate failure to rescue? AB - Evidence shows the management of deteriorating patients needs to be improved, particularly in midwifery care. In a series of three simulation-based studies in Australia we examined qualified nurses', student nurses' and midwives' ability to manage patient deterioration. Nurses' knowledge levels were acceptable but their skill performance was low and there was a gap between the theory and practice they had experienced. In these high-pressure situations, demographic factors (including educational level) had no impact on their performance, which suggests they need repetitive "high-stakes" simulation, improved feedback mechanisms and enhanced educational processes. PMID- 21329082 TI - How to look after patients on anticoagulant therapy. PMID- 21329083 TI - Reducing anxiety in elective surgical patients. AB - Effective communication is the cornerstone of good healthcare. Poor communication can have serious consequences for patients and damage the nurse-patient relationship. This article explores how nurses can use communication tools with surgical patients to help relieve anxiety. PMID- 21329084 TI - How to develop patient trust in anorexia treatment. AB - Anorexia nervosa is a serious and commonly fatal psychological condition. It is essential that nurses develop positive relationships with patients to enable successful treatment. However, these relationships are often difficult to form. This article discusses how the features of anorexia affect creating and sustaining effective nurse-patient relationships. PMID- 21329085 TI - It's good to talk. PMID- 21329087 TI - Do you truly support the advancement of the nursing profession? PMID- 21329086 TI - Charge nurses are vital to personal care on wards. PMID- 21329088 TI - Some information that you may want to know... PMID- 21329089 TI - Lateral and vertical violence education: bringing students into the equation. PMID- 21329090 TI - PAPIN... here to help, here to heal. Confidential care and support for nurses struggling with alcohol and drug addiction. The revitalization of the peer assistance program in nursing (PAPIN). PMID- 21329091 TI - Legal commentary society. PMID- 21329092 TI - Should we retire Derek Parfit? PMID- 21329093 TI - To "sleep until death". PMID- 21329094 TI - Rights vs. liberty. PMID- 21329095 TI - The ghost print. PMID- 21329096 TI - The sausage-making of insurance reform. PMID- 21329097 TI - Case study. Conjectural mixed motives. PMID- 21329098 TI - Case study. Conjectural mixed motives. Commentary. PMID- 21329099 TI - Fable hospital 2.0: the business case for building better health care facilities. PMID- 21329100 TI - Case study: Dublin Methodist Hospital. PMID- 21329101 TI - Case study: Sacred Heart Medical Center. PMID- 21329102 TI - Values engineering: the ethics of design in community health centers. PMID- 21329103 TI - A third seat at the table: an insider's perspective on patient representatives. PMID- 21329104 TI - A not-so-new eugenics. Harris and Savulescu on human enhancement. AB - John Harris and Julian Savulescu, leading figures in the "new' eugenics, argue that parents are morally obligated to use genetic and other technologies to enhance their children. But the argument they give leads to conclusions even more radical than they acknowledge. Ultimately, the world it would lead to is not all that different from that championed by eugenicists one hundred years ago. PMID- 21329105 TI - Reprogenetics and the "parents have always done it" argument. AB - A common argument in favor of using reprogenetic technologies to enhance children goes like this: parents have always aimed at enhancing their children through upbringing and education, so why not use new tools to accomplish the same goal? But reprogenetics differs significantly from good childrearing and education, in its means, if not its ends. PMID- 21329106 TI - The "real-life" death panel, reformed. PMID- 21329107 TI - Reminder: Accreditation requirement for hospitals issuing durable medical equipment to patients. PMID- 21329108 TI - Joint Commission announces changes to its Board of Commissioners. PMID- 21329109 TI - Happy returns: reflections on a further visit. PMID- 21329110 TI - The demands of family caregivers of elderly individuals with dementia. AB - The purpose of this cross-sectional observational study was to identify characteristics of caregivers of elderly people with dementia, types of care demands and to relate demands to the stage of dementia. The study was carried out in 2004 with 104 older adults and 90 caregivers in Ribeirao Preto, state of Sao Paulo. The OARS instrument was utilized and a questionnaire answered by caregivers. Among older adults, 66.3% were female, aged 75.5 years in average and 86.5% had caregivers. Eighty percent of the caregivers were women family members, aged 52.3 years in average. They spent 15.10 hours/day with care, without help. An important relationship was observed between caregiver's burden, physical and emotional effort and stage of dementia. Emotional overburden was higher at dementia early and late stages, this difference was statistically non significant. Results reveal the urgent need to plan formal and informal support strategies to caregivers of Brazilian elderly people with dementia. PMID- 21329111 TI - Sexuality in the puerperium: the experience of a group of women. AB - Puerperium is a period of great changes in women's lives, in physiological, psychological and socio-cultural terms. Female sexuality is a broad topic that should be explored vis-a-vis the singularity of woman's experiences which themselves vary at different moments in time. This article is part of the project: Sexuality in the Puerperium, the objective of which was to understand what women's experience of their sexuality is in the postpartum period. Observation and semi-structured interview were used. The research approach was qualitative and narrative was used as the conceptual and methodological method. Six primiparas who gave birth in a public hospital in Sao Paulo took part in the study. Observation took place in the in-patients unit in the immediate post partum period. The interviews were conducted in the women's homes. The results of the study have enabled an understanding to be formed of the meanings and changes in sexuality during the postpartum period as well as of the experiences every woman faces in her new roles, relationships and difficulties. PMID- 21329112 TI - Work and health conditions of sugar cane workers in Brazil. AB - This is an exploratory research, with a quantitative approach, developed with the objective of analyzing the work and of life situations that can offer risks to the workers' health involved in the manual and automated cut of the sugar cane. The sample was composed by 39 sugar cane cutters and 16 operators of harvesters. The data collection occurred during the months of July and August of 2006, by the technique of direct observation of work situations and workers' homes and through interviews semi-structured. The interviews were recorded and later transcribed. Data were analyzed according to Social Ecological Theory. It was observed that the workers deal with multiple health risk situations, predominantly to the risks of occurrence of respiratory, musculoskeletal and psychological problems and work related accidents due to the work activities. The interaction of individual, social and environmental factors can determine the workers' tendency to falling ill. PMID- 21329113 TI - Evaluation of bedbath in critically ill patients: impact of water temperature on the pulse oximetry variation. AB - This is a participant study, quasi-experimental, of a before and after type. A quantitative approach of biophysiological measures was used, represented by the saturation of oxygen measured by pulse oximeter (SpO2), and recorded on three occasions: before, during and after the bedbath in critically ill patients hospitalized at the ICU of a University Hospital in Brazil. OBJECTIVE: to compare the SpO2 in various stages of the bath, with and without control of water temperature. Data collection was performed between December 2007 and April 2008 on a convenience sample consisting of 30 patients aged over 18 who had classification in TISS-28 from level II. Results show that water temperature control means a lower variation of SpO2 (p < 0.05). No marked differences in variation of saturation between men and women or between age groups were established. In conclusion, heated and constant water temperature during the bedbath is able to minimize the fall of SpO2 that occurs while handling patients during procedures. PMID- 21329114 TI - Approved: Modifications to National Patient Safety Goal on reconciling medication information. PMID- 21329115 TI - Approved: Revised public information policy. PMID- 21329116 TI - Approved: New and revised laboratory accreditation requirements. PMID- 21329117 TI - A follow-up report on preventing suicide. PMID- 21329118 TI - Joint Commission releases innovative Leading Practice Library. PMID- 21329119 TI - New performance reports coming for Joint Commission-certified staffing organizations. PMID- 21329120 TI - A battle worth fighting. PMID- 21329121 TI - Be vigilant or trusts will change employment terms, unions warn. PMID- 21329122 TI - Nurses say reforms will sideline patients and fragment services. PMID- 21329123 TI - 'Nurses are the best placed staff to help patients who wish to die'. PMID- 21329124 TI - NHS director assures BME staff they will not bear brunt of cuts. PMID- 21329125 TI - Cost-cutting demands prompt trusts to 'explore all options'. PMID- 21329126 TI - Upsurge in fuel costs leaves many nurses out of pocket. PMID- 21329127 TI - Every child is born to live. AB - This week Save the Children launches a campaign to make the millennium development goals on child health become a reality. PMID- 21329128 TI - Head for bed. AB - Monitoring patients' sleep patterns and providing them with educational sessions has proved beneficial in one mental health unit. PMID- 21329129 TI - In support of choice. AB - Professionals for Assisted Dying is a new organisation that wants to clarify the legal rights of terminally ill people and their carers. PMID- 21329130 TI - Happy to be of service. AB - Many NHS nurses volunteer for the St John Ambulance service in their spare time. PMID- 21329131 TI - Chronic pain syndromes in cancer survivors. AB - Advances in medical knowledge and treatment have resulted in improved five-year survival rates for some forms of cancer. However, pain syndromes resulting from chemotherapy, radiotherapy, surgery or interventional procedures continue to have a significant effect on cancer survivors' quality of life. Nurses are uniquely placed to assess pain in cancer survivors and ensure pain management strategies are initiated. This article focuses on chronic pain syndromes that can occur following cancer treatment, examining the effect of pain on patients' quality of life. PMID- 21329132 TI - Adopting a psychological approach to obesity. AB - In response to the growing challenge of obesity, South Essex Partnership University NHS Foundation Trust and South West Essex Primary Care Trust established a joint initiative to provide a psychological service for adults who were obese and had not been able to manage their weight through traditional methods. This article describes a pilot project providing psychological support for adults with chronic or morbid obesity. It presents the rationale for this approach and describes the service and preliminary outcome data. The implications for nurses working in this field are considered. PMID- 21329133 TI - Understanding cachexia in patients with cancer. AB - Cancer cachexia is a progressive wasting syndrome characterised by loss of both adipose tissue and lean body mass. It is a complex metabolic process common in patients with cancer and responsible for death. Consideration of this syndrome is important because of its prevalence and its significant effect on morbidity, mortality and nutritional and psychological status. PMID- 21329134 TI - Anticoagulant therapy. PMID- 21329135 TI - Gainful employment. PMID- 21329136 TI - Crisis in specialist home care. PMID- 21329137 TI - Offering an alternative. PMID- 21329138 TI - HIV meds as HIV prevention. PMID- 21329139 TI - Let the sun shine in. PMID- 21329140 TI - ICAAC 2010: New, improved therapies move forward. PMID- 21329141 TI - IAS/Vienna. PMID- 21329142 TI - Historians and health care reform: avoiding the "ash heap". PMID- 21329143 TI - Hell in the family: married women and madness before institutionalization at the St-Jean-de-Dieu Asylum, 1890-1921. AB - Research in Montreal's St-Jean-de-Dieu Asylum archives has revealed a number of letters from family members and local physicians pleading for asylum care for married women between 1890 and 1921. When added to other admission documents in patients' medical files, these letters allow an intimate glimpse into private lives of families and highlight the pain and distress of dealing with mentally ill people in the home before the introduction of community mental health services. Far from easily abandoning a spouse or mother, close-knit French Canadian families struggled until they could no longer cope before seeking help. To comply with asylum regulations, family members (primarily husbands, who were often illiterate) and local physicians were required to justify their applications for admission, but they did so in different ways. PMID- 21329144 TI - Life and death in Philadelphia's black belt: a tale of an urban tuberculosis campaign, 1900-1930. AB - The poor health status of black Americans was a widely recognized fact during the first third of the twentieth century. Excess mortality in black communities was frequently linked to the infectious disease tuberculosis, which was particularly menacing in densely populated urban settings. As health authorities in large cities struggled to keep pace with the needs of citizens, private charities worked to launch community-oriented attacks against the deadly disease. In 1914 a novel experiment to address excess mortality among blacks was launched in Philadelphia. The success of the health promotion campaign initiated by the Henry Phipps Institute and the Whittier Centre, two private charitable associations, has been attributed primarily to the presence of black clinicians, in particular public health nurse Elizabeth Tyler. This study suggests that community health efforts also rest on partnerships between like-minded organizations and coalition building. PMID- 21329145 TI - Sickening nurses: fever nursing, nurses' illness, and the anatomy of blame, New Zealand 1903-1923. AB - In the early twentieth century, patients with infectious fevers represented a danger to the health of others including their nurses. This research describes the training New Zealand nurses received in fever nursing during the period 1903 1923, and considers how they applied hospital cross-infection principles in emergency tent fever camps in remote rural areas. It examines the reaction of nurses, hospital boards, and physicians to nurses who succumbed with their patients' fevers. It therefore reveals attitudes to nurses, prevailing ideas about responsibility for nurses' health, and elements in the emerging professional culture of nursing. Although some measures protected them against epidemic fevers, nurses were held responsible for their own health. A complex anatomy of blame is evident against those who sickened; the nature of the blame shifted, depending on the observer, disease, and practice setting. Physicians blamed nurses, especially when they sickened with typhoid fever. The country's chief nurse and other nurses blamed those who jeopardized their health through ill-spent leisure time. Sick nurses could be absolved from blame for the lax discipline evident through their failure to observe cross-infection principles if their practice setting was the fever camp. Willingness to work in difficult circumstances showed they embodied the ideal of sacrifice that, like discipline, was part of the emerging nursing culture. PMID- 21329146 TI - Nurses without borders: the history of nursing as U.S. international history. AB - During World War I and its aftermath, thousands of U.S. nurses put their domestic careers on hold to work overseas. Many volunteered in the wake of war and disaster. Others worked as instructors in nursing schools and as the staff of fledgling public health agencies. This article charts the international travels of four especially mobile nurses, whose globetrotting careers took them to Europe, Asia, and the Caribbean. These women aspired to tackle world health issues, motivated by the conviction that the spread of U.S. professional nursing ideas stood to modernize the world. This article tells these nurses' stories and analyzes their ideologies of development and progress. In so doing, it demonstrates that professional women, working outside state channels, played a principal role in expanding U.S. influence in the world. Moreover, it makes the case for the centrality of nursing history to the history of U.S. foreign relations. PMID- 21329147 TI - Gender, politics, and regionalism: factors in the evolution of registered psychiatric nursing in Manitoba, 1920-1960. AB - In Canada, psychiatric nursing care is provided by two kinds of nurses. East of Manitoba, it is provided by registered nurses who may or may not have specialized psychiatric nursing education. In the four western provinces, a distinct professional group, registered psychiatric nurses, also provide care. Saskatchewan was the first province to achieve distinct legislation, in 1948, followed by British Columbia in 1951, Alberta in 1955, and Manitoba in 1960. Several factors coalesced to sway Manitoba to adopt the distinct profession model. First, there was little interest by the general nursing body in mental hospital nursing. Second, the other three western provinces had formed a Canadian Council of Psychiatric Nursing that encouraged mental hospital attendants and nurses in Manitoba. Third, a group of male attendants took on leadership roles supported by the mental hospital superintendents. Finally, Manitoba was culturally and geographically more aligned with western than eastern Canada. PMID- 21329148 TI - Political dreams, practical boundaries: the case of the Nursing Minimum Data Set, 1983-1990. AB - The initial development of the Nursing Minimum Data Set (NMDS) was analyzed based on archival material from Harriet Werley and Norma Lang, two nurses involved with the project, and American Nurses Association materials. The process of identifying information to be included in the NMDS was contentious. Individual nurses argued on behalf of particular data because of a strong belief in how nursing practice (through information collection) should be structured. Little attention was paid to existing practice conditions that would ultimately determine whether the NMDS would be used. PMID- 21329149 TI - Report from the Nursing History Section at the 2009 International Council of Nurses, Durban, South Africa. PMID- 21329150 TI - The history of nursing in Ethiopia. PMID- 21329151 TI - The history of nursing in Tanzania. PMID- 21329152 TI - The history of nursing in the Republic of Mauritius. PMID- 21329153 TI - The history of nursing in the Togolese Republic. PMID- 21329154 TI - The history of nursing in the Islamic Republic of Iran. PMID- 21329155 TI - The history of nursing in Romania. PMID- 21329156 TI - The history of nursing in Turkey. PMID- 21329157 TI - Networks of identity: the potential of biographical studies for teaching nursing identity. AB - This article reviews the historiographical elements of the professional identity of nursing, focusing on what historians have denoted as the "history of the present." Professional identity interacts with elements of power, gender, politics, philosophy, and history, and its value is tied to the importance it assumes at any given time in any given society. The collective identity of the profession is elucidated by the construction of nursing history, linked to the history of women and gender relationships in professional care and educational, organizational, and class practice, and also by the biographies of individuals who have shaped this identity through their reputations and life stories. In this light, it is argued that biographies could help illuminate the elements of identity formation of interest to nursing scholars and further the development of the profession; they could also bring discussions of the past and present into the teaching-learning process for nursing students. The authority and significance of these identities will also be discussed. PMID- 21329158 TI - A cause for celebration. PMID- 21329159 TI - Employers threaten job cuts after unions stand firm on pay. PMID- 21329161 TI - GPs and managers agree nurses must have say in commissioning. PMID- 21329160 TI - Clinical specialists are essential if cancer strategy is to succeed. PMID- 21329162 TI - Bank staff could take calculation tests to curb medication errors. PMID- 21329163 TI - Cuts to health services leaves region's staff at breaking point. PMID- 21329164 TI - Where in England do older people feel most vulnerable?. PMID- 21329165 TI - Fast-track to efficiency. AB - Changing the way nurses work in one medical assessment unit has resulted in quicker and more efficient patient care. PMID- 21329166 TI - Brighter prospects. AB - One London hospital provides a nursing service dedicated to people who are homeless. PMID- 21329167 TI - Age-appropriate care. AB - Project groups are working to improve the move between paediatric and adult services for adolescents who receive kidney care. PMID- 21329168 TI - Super educators. AB - Five comic book heroes are on hand to explain health and medical conditions to young adolescents and their parents. PMID- 21329169 TI - Chronic pelvic pain: causes, mechanisms and effects. AB - This article outlines the causes, mechanisms and effects of chronic pelvic pain. It provides a basic overview of the biopsychosocial treatment options delivered by a multidisciplinary team. The focus is on actively listening to patients to validate their pain experience and provide information on their condition. A combination of pain management psychology and pain management physiotherapy, medical interventions and medication are used to improve the quality of life of patients with this distressing condition. PMID- 21329170 TI - Use of peer teaching to enhance student and patient education. AB - This article describes an evaluation of a peer-teaching project undertaken by second-year nursing students at a higher education institution in England. The initiative has enhanced the students' understanding of peer education. The importance of the nurse's role in patient education is emphasised. It is hoped that the experience of peer teaching will prepare nursing students for their future roles as nurse educators for patients, students and other staff. PMID- 21329171 TI - Promoting mental health in older people admitted to hospitals. AB - Mental health problems are common in older people admitted to general hospitals. With an increasing ageing population, admissions will rise and nurses will be expected to manage patients' co-existing mental health problems as well as physical problems. This article explores potential strategies for the management of patients with depression, delirium and dementia. The emphasis is on improving quality of care for this group of vulnerable patients. PMID- 21329172 TI - Diuretic therapy. PMID- 21329173 TI - The shelf life of libraries. PMID- 21329174 TI - Raising the standards of quality and safety. PMID- 21329175 TI - Make a note of this. PMID- 21329176 TI - Epidemiology, surveillance and control of Nipah virus infections in Malaysia. AB - The outbreak of Nipah virus, affecting pigs and pig-farm workers, was first noted in September 1998 in the north-western part of peninsular Malaysia. By March 1999, the outbreak had spread to other pig-farming areas of the country, inclusive of the neighbouring country, Singapore. A total of 283 human cases of viral encephalitis with 109 deaths were recorded in Malaysia from 29 September 1998 to December 1999. During the outbreak period, a number of surveillances under three broad groups; Surveillance in Human Health Sector, Surveillance in Animal Health Sector, and Surveillance for the Reservoir Hosts, were carried out to determine the prevalence, risk of virus infections and transmission in human and swine populations as well as the source and reservoir hosts of Nipah virus. Surveillance data showed that the virus spread rapidly among pigs within infected farms and transmission was attributed to direct contact with infective excretions and secretions. The spread of the virus among pig farms within and between states of peninsular Malaysia was due to movement of pigs. The transmission of the virus to humans was through close contact with infected pigs. Human to human transmission was considered a rare event though the Nipah virus could be isolated from saliva, urine, nasal and pharyngeal secretions of patients. Field investigations identified fruitbats of the Pteropid species as the natural reservoir hosts of the viruses. The outbreak was effectively brought under control following the discovery of the virus and institution of correct control measures through a combined effort of multi-ministerial and multidisciplinary teams working in close co-operation and collaboration with other international agencies. PMID- 21329177 TI - Risk factors, prevention and communication strategy during Nipah virus outbreak in Malaysia. AB - An outbreak of acute febrile encephalitis affecting pig-farm workers and owners was recognized in peninsular Malaysia as early as September 1998. The outbreak was initially thought to be due to Japanese encephalitis (JE) virus and thus very intensive prevention, control and communication strategies directed at JE virus were undertaken by the Ministry of Health and Ministry of Agriculture of Malaysia. There was an immediate change in the prevention, control and communication strategies with focus and strategies on infected pigs as the source of infections for humans and other animals following the discovery of Nipah virus. Information and understanding the risks of Nipah virus infections and modes of transmission strengthened the directions of prevention, control and communication strategies. A number of epidemiological surveillances and field investigations which were broadly divided into 3 groups covering human health sector, animal health sector and reservoir hosts were carried out as forms of risk assessment to determine and assess the factors and degree of risk of infections by the virus. Data showed that there was significant association between Nipah virus infection and performing activities involving close contact with pigs, such as processing of piglets, administering injection or medication to pigs, assisting in the birth of piglets, assisting in pig breeding, and handling of dead pigs in the affected farms. A complex process of anthropogenic driven deforestation, climatic changes brought on by El Nino-related drought, forest fire and severe haze, and ecological factors of mixed agro-pig farming practices and design of pig-sties led to the spillovers of the virus from its wildlife reservoir into pig population. PMID- 21329178 TI - Pattern of homicidal deaths autopsied at Penang Hospital, Malaysia, 2007-2009: a preliminary study. AB - This article describes the homicide pattern in Penang Island, Malaysia over a three-year period (2007-2009). 65 homicide autopsies were performed at the Department of Forensic Medicine, Penang Hospital over the study period. The homicide rates ranged from 0.01 to 0.09/1000 population, the highest being in the Indian ethnic group. The majority (37%) of victims were in the 20-39 years age group. The male: female ratio was 3:1. The majority of deaths were caused by blunt instruments (46%), followed by stab/slash wounds (25%) and asphyxiation (12%). 63% of homicides occurred in areas served by the police stations at Jalan Patani (23.1%), Sg. Nibong (16.9%), Central (12.3%) and Bayan Lepas (10.9%). 56 (86%) victims were brought in dead to the hospital, while 9 (14%) died after admission. Most (39%) incidences occurred in the morning. The methods of homicide were different from Kuala Lumpur, another highly urbanised area of Malaysia. PMID- 21329180 TI - Observation of dendritic cell morphology under light, phase-contrast or confocal laser scanning microscopy. AB - Dendritic cells (DCs) are professional antigen presenting cells of the immune system. They can be generated in vitro from peripheral blood monocytes supplemented with GM-CSF, IL-4 and TNF alpha. During induction, DCs will increase in size and acquire multiple cytoplasmic projections when compared to their precursor cells such as monocytes or haematopoietic stem cells which are usually round or spherical. Morphology of DCs can be visualized by conventional light microscopy after staining or phase-contrast inverted microscopy or confocal laser scanning microscopy. In this report, we described the morphological appearances of DCs captured using the above-mentioned techniques. We found that confocal laser scanning microscopy yielded DCs images with greater details but the operating cost for such a technique is high. On the other hand, the images obtained through light microscopy after appropriate staining or phase contrast microscopy were acceptable for identification purpose. Besides, these equipments are readily available in most laboratories and the cost of operation is affordable. Nevertheless, morphological identification is just one of the methods to characterise DCs. Other methods such as phenotypic expression markers and mixed leukocyte reactions are additional tools used in the characterisation of DCs. PMID- 21329179 TI - Argininosuccinic aciduria: clinical and biochemical phenotype findings in Malaysian children. AB - Argininosuccinic aciduria is an inborn error of the urea cycle caused by deficiency of argininosuccinate lyase (ASL). ASL-deficient patients present with progressive intoxication due to accumulation of ammonia in the body. Early diagnosis and treatment of hyperammonemia are necessary to improve survival and prevent long-term handicap. Two clinical phenotypes have been recognized- neonatal acute and milder late-onset form. We investigated patients with hyperammonemia by a stepwise approach in which quantitative amino acids analysis was the core diagnostic procedure. Here, we describe the clinical phenotypes and biochemical characteristics in diagnosing this group of patients. We have identified 13 patients with argininosuccinic aciduria from 2003 till 2009. Ten patients who presented with acute neonatal hyperammonemic encephalopathy had markedly elevated blood ammonia (> 430 micromol/L) within the first few days of life. Three patients with late-onset disease had more subtle clinical presentations and they developed hyperammonemia only during the acute catabolic state at two to twelve months of age. Their blood ammonia was mild to moderately elevated (> 75-265 micromol/L). The diagnosis was confirmed by detection of excessive levels of argininosuccinate in the urine and/or plasma. They also have moderately increased levels of citrulline and, low levels of arginine and ornithine in their plasma. Two patients succumbed to the disease. To date, eleven patients remained well on a dietary protein restriction, oral ammonia scavenging drugs and arginine supplementation. The majority of them have a reasonable good neurological outcome. PMID- 21329181 TI - Mutations in mitochondrial NADH dehydrogenase subunit 1 (mtND1) gene in colorectal carcinoma. AB - Mitochondrial Subunit ND1 (mtND1) gene is involved in the first step of the electron transport chain of oxidative phosphorylation (OXPHOS). Alteration of the electron transport components by mutations in mtDNA may compromise the normal electron flow. This could lead to an increase of bifurcation and generation of superoxidase radicals and increase oxidative stress in various types of cancer cells. Genomic DNA was extracted from thirty matched primary colorectal tumour tissues and matching non-tumour tissues. Blood samples were obtained from twenty five normal people. The mtNDI coding region was amplified by step-down PCR. The purified products were then subjected to direct sequencing and subsequently, the DNA sequences obtained were compared with the revised Cambridge Reference Sequence (rCRS) and MITOMAP. From the analysis, the mtND1 gene showed 11 (45.8%) different mutations and also 13 (54.2%) polymorphisms. The heteroplasmic mutation A4123A/G (I273I/V) might have a pathogenic significance as it fulfills various pathogenic criteria. Three mutations, T3394C (Y30H), A3434G (Y43C) and C3497T (A64V) which occur in a highly conserved region were likely to alter the structure and function of the ND1 protein. We suggest that these mutations, and in combination with the polymorphic variance in mtDNA, may cause slight changes that generate subtly higher levels of toxic reactive oxygen species (ROS). PMID- 21329182 TI - Histomorphology of aberrant crypt foci in colorectal carcinoma. AB - Colorectal carcinogenesis is a complex multistep process that includes changes in histomorphological appearance of the colonic mucosa and changes at molecular level. Aberrant crypt foci (ACF) was first described by Bird in 1987 on examination of methylene-blue-stained colonic mucosa of azoxymethane-treated mice under light microscopy. Since then ACF was considered as the earliest preneoplastic change that can be seen in the colonic mucosa. The aim of this study was to look at the histomorphology and distribution of ACF in colorectal carcinoma. 50 formalin-fixed archival colectomy specimens for colorectal carcinoma were examined under light microscopy after staining with 0.2% methylene blue. ACF was identified by larger and darker crypts with thickened epithelium, and often elevated from adjacent normal mucosa. ACF was found in 41 of 50 colectomy specimens examined. There were 328 ACF consisting of 36 (11.0%) ACF without hyperplasia or dysplasia, 263 (80.2%) ACF with hyperplasia and 29 (8.8%) ACF with dysplasia. Of these 29 ACF with dysplasia, 25 showed low grade dysplasia and four high grade dysplasia. The density of ACF was higher in the left colon, those older than 65 years of age and among males but these findings were statistically not significant. The crypt multiplicity of hyperplastic ACF (30.149, SD 28.395) was larger than dysplastic ACF (20.613, SD 40.128). The spectrum of histological changes observed probably represent the evolution of ACF in colorectal carcinogenesis. PMID- 21329183 TI - Expression and mutational analysis of GATA3 in Malaysian breast carcinomas. AB - The GATA3 gene is a potential tumour marker and putative tumour suppressor gene in breast cancer. Its expression is associated with better prognosis and disease free survival in breast cancer patients. We aimed to evaluate GATA3 transcriptome expression and mutation in breast carcinomas and correlate its expression with oestrogen receptor (ER), progesterone receptor (PR), lymph node (LN) status, tumour grade and c-erbB-2 expression. Twenty-two breast infiltrating ductal carcinomas and paired normal tissues were used in Branch DNA assay to detect GATA3 mRNA expression. Normalized data for GATA3 mRNA expression were grouped according to the ER, PR and LN status, tumour grade and c-erbB-2 expression of the tumours. Statistical significance was tested using t-test and ANOVA at 95% confidence interval level. Mutational analysis of GATA3 was performed by direct sequencing of the coding regions of GATA3 mRNA. Our findings showed that GATA3 gene were over-expressed and under-expressed by > 2 fold change in 12 and 4 tested samples, respectively. Eighty per cent of ER positive breast carcinomas were GATA3 positive. There was a statistically significant correlation between GATA3 expression and ER at 95% confidence interval level between the study groups. On the contrary, GATA3 expression was not statistically significant with PR, LN, tumour grade and c-erbB-2 expression in our study. In addition, we observed that there was no mutation in mRNA coding region in 16 breast carcinomas that showed GATA3 differential gene expression. Our preliminary results suggested that GATA3 is linked to the ER. This scenario suggests that GATA3 may play a crucial role in oestrogen receptor positive breast cancer patients. Whether GATA3 expression is involved in regulating tumour cell growth in oestrogen responsive breast cancer is a key question that remains to be answered. PMID- 21329184 TI - A "tumour trifecta:" myelolipomata arising within an adrenocortical adenoma ipsilateral to a synchronous clear cell renal cell carcinoma. AB - We present an intriguing case of adrenal myelolipomata occurring within an adrenocortical adenoma in concert with an ipsilateral clear cell renal cell carcinoma. A 50-year-old female presented with dull right flank pain and hematuria. Computed tomography indicated a 2.5 cm right renal mass as well as a 5 cm right adrenal mass. Both masses were surgically resected concurrently. Histology of the renal mass was consistent with conventional clear cell renal cell carcinoma, Fuhrman grade III. There was no extra-renal extension or lymphovascular invasion. The adrenal mass was a cortical adenoma with solid and nested patterns, with discrete zones consisting of erythroid, myeloid and megakaryocytic cells intermixed with mature adipocytes. Mitoses were inconspicuous. The solid tumour component was strongly positive for vimentin, inhibin and CD56, focally positive for low-molecular-weight cytokeratin (Cam 5.2), calretinin and CD10 (chiefly in the myelolipomatous zones), and negative for chromogranin, S100, HMB-45, melan-A (A103), Mart-1, synaptophysin, SMA, CK7, CK20, ER, PR, TTF-1, CD99 and GCDFP (BRST-2). Ki67 (MIB1) staining indicated a low tumour proliferation index. Although well-described individually, a search of the English language literature suggests that this is the first such documented case of synchrony of these three lesions. We also present a relevant review of the literature pertaining to adrenal lesions. In particular, we emphasize the epidemiological, histological and immunohistochemical features that are helpful in determining the origin and malignant potential of adrenal lesions. PMID- 21329185 TI - Late aortic dilatation and regurgitation after Ross operation. AB - The Ross operation, a procedure of replacement of the diseased aortic valve with an autologous pulmonary valve, has many advantages such as no need for anticoagulation therapy and similar valve function and growth potential as native valves. However secondary aortic disease has emerged as a significant complication and indication for reoperation. We report a 48-year-old woman who had Ross operation in 1997 for a damaged bicuspid aortic valve and severe aortic regurgitation due to subacute bacterial endocarditis complicated by aortic root abscess. In 2009, 12 years later, progressive severe aortic regurgitation with incomplete coaptation and mild dilatation of the aortic root was shown on echocardiography and contrasted CT, while the pulmonary homograft retained normal function. She subsequently underwent aortic valve replacement. Histopathological examination of the explanted neo-aortic valve and neo-arterial wall revealed pannus formation at the nodulus Arantii area of the three valve cusps, ventricularis, and arterialis. The amount of elastic fibres in the neo-aorta media was less than usual for an aorta of this patient's age but was similar to a pulmonary artery. The pathological findings were not different from other studies of specimens removed between 7 to 12 years after Ross operation. However, the pathophysiology and long-term implications of these findings remain debatable. Considering the anatomical and physiological changes induced by the procedure, separate mechanisms for aortic dilatation and regurgitation are worthy of consideration. PMID- 21329187 TI - DNA damage and mutagenesis: is it an issue for swine flu? PMID- 21329186 TI - A family study of HbS in a Malay family by molecular analysis. AB - Sickle cell disease (SCD) is an inherited red cell disorder, characterized by the tendency of haemoglobin S or sickle haemoglobin to polymerize and assume a characteristic sickle shape. Molecular analysis has been the mainstay of detection method when confirmation is required. Previously a polymerase chain reaction (PCR)-based restriction enzyme analysis was used for this purpose. A simple bidirectional allele-specific amplification, recently described by Waterfall in 2001 was used to detect the GAG --> GTG mutation on codon 6 of the beta globin gene. Two sets of primers for the mutant and the wild type alleles were used in a single PCR reaction to amplify the regions of interest. The resultant PCR products will produce two fragments at 517 and 267 base pair (bp) respectively. This report highlights the investigations for SCD in the family of a 16-year old girl with recurrent painful crisis affecting the lower limbs whereby the family members are asymptomatic for the disease. Her haemoglobin electrophoresis at an alkaline pH showed dense bands at the HbS and HbF regions, while her father and two sisters had bands at HbS, HbF and HbA. The PCR analysis showed that she was homozygous for the mutation by the presence of only one band at 267 bp fragment, while the father and her sisters were heterozygotes, with the presence of two bands at 267 as well as 517 bp fragments. DNA sequencing of the sample confirmed the mutation. In conclusion, this case report highlighted the simple and cheap yet practical method for molecular confirmation of the presence of HbS gene in subjects with homozygous or heterozygous state of the condition. PMID- 21329188 TI - Race, class, and the child welfare system. Introduction. PMID- 21329189 TI - Social service availability & proximity and the over-representation of minority children in child welfare. AB - The goal of this study was to assess whether child welfare services were available and proximal in identified, predominantly Black and Hispanic zip code areas of three southern cities. GIS mapping of services contained in a state 2-1 1 community services data base revealed that there were no treatment services and/or no public transportation and/or lengthy public (bus) transportation times in 50% of the identified areas of one city and in almost 25% of the three cities combined. The authors suggest service availability and proximity should increase the likelihood of parent enrollment, attendance and completion which should increase parent dependency court compliance rates. Further, they suggest that court compliance rates should increase the rate of return of Black children to their parents and thereby reduce child welfare caseloads. Given, the logic of their argument, the authors go on to recommend that child welfare administrators annually perform GIS analyses of State 2-1-1 community services data bases to keep abreast of child welfare service availability and proximity. Additionally, they offer a number of recommendations for how to increase service availability and proximity in predominantly Black and Hispanic urban areas. PMID- 21329190 TI - How legal communities can use research to drive improvement: a response to Dorch, et. al. PMID- 21329191 TI - Measuring change in disproportionality and disparities: three diagnostic tools. AB - At present there are few examples of sustained reductions in disproportionate minority contact with the juvenile justice and child welfare systems. This article describes the use of three instruments that have been used to measure levels of racial and ethnic disproportionality and disparities: The Disproportionality Diagnostic Tool, Ecomap and Racial Equity Scorecard. Using a combination of community and public agency data, these tools measure and track change over time on racial and ethnic disproportionality and disparities. Study results indicated a reduction in racial and ethnic disproportionality and disparities and demonstrated the utility of all three instruments for targeting efforts and assessing improvements in child welfare over time. PMID- 21329192 TI - A critique of measures that assess community efforts to reduce disproportionality and disparities in child welfare and juvenile justice agencies. PMID- 21329193 TI - Disproportionality at the "front end" of the child welfare services system: an analysis of rates of referrals, "hits", "misses", and "false alarms". AB - Data from NIS-4, NCANDS, and the State of California were used to analyze the front end of the child welfare services system--the referral and substantiation components--in terms of the system's ability to diagnose or detect instances of child maltreatment. The analyses show that Blacks are disproportionately represented in rates of referral into the system. Moreover, the analyses demonstrate that the system is less accurate for Blacks than for other racial or ethnic groups. There is a higher rate of false positives (or "false alarms") for Blacks than for other groups--that is, referrals leading to unsubstantiated findings. There is also a higher rate of false negatives (or "misses") for Blacks than for other groups--that is, children for whom no referral was made but who are in fact neglected or abused. The rate of true positives (or "hits")--children for whom a referral has been made and for whom that allegation has been substantiated--is generally higher for Blacks than for other groups, but this is attributable largely to the higher rate of referral for Blacks. In sum, the system demonstrates lower levels of accuracy for Blacks than for other groups. A model is proposed demonstrating that random error, as opposed to systematic bias, could produce a pattern of results much like that observed in the data. PMID- 21329194 TI - Who gets a second chance? An investigation of Ohio's blended juvenile sentence. AB - Factors differentiating blended sentencing cases (Serious Youthful Offenders or SYOs) from conventional juvenile cases and cases transferred to the adult criminal court in Ohio were investigated using a two-stage probit. Conventional juvenile cases differed from cases selected for non-conventional processing (i.e., SYO or transfer) according to offense seriousness, number of prior Ohio Department of Youth Services placements, age and gender. Controlling for probability of selection for nonconventional processing, transfers differed from SYOs according to age, gender, and race. Minorities were significantly more likely than Whites to be transfers rather than SYOs, suggesting possible bias in the decision-making process. Objective risk and needs assessments should be used to identify the most suitable candidates for blended sentences and adult transfer and enhanced services should be provided to juvenile offenders given blended sentences. PMID- 21329195 TI - New tools and analyses for reducing disproportionality in child welfare and juvenile justice. Afterword. AB - This special issue moves us forward in the discussion on disproportionality and disparate outcomes and in the identification and implementation of strategies and solutions. What is clear from this journal's articles is that addressing the disparities of children of color in foster care will require that we take an approach that is comprehensive and inclusive to allow us get to the root causes and create real sustainable change. This means we have to address the issue not only inside child welfare but across all systems and institutions that touch the lives of children and families; not only from the perspective of the child's well being but also from the perspective of the family's well being; and not only on the local level but also on the state and federal levels through policy change that aligns with our goals to keep all children safe by strengthening families. As the articles indicate, if we are to achieve any measure of success, we must build our efforts and strategies on a foundation that embraces and encourages an integrated response. Too often child welfare and other child-serving agencies address the needs of children on a very individual basis, outside the context of their families. That is the way the system is set up. However, to improve outcomes for all children, including children of color, we have to change our paradigm from that of child welfare to that of family well being, always seeing children in the context of their families; families in the context of their communities; and any intervention in the context of an integrated family and community support network. For example, addressing child neglect associated with poverty issues requires that we not only address the needs of that child or poor families, but we must also ultimately take actions to address the needs of the poor communities in which those children and families are trying to exist. Such an integrated response leads us to acknowledge the interconnectedness of children, families and their communities and to design strategies of intervention with an understanding that only when we address causative factors across each of these three spectrums (child, family, community) can we truly create the change we seek--improved outcomes for children of color--for all children--in or at risk of entering foster care. PMID- 21329196 TI - Events in the Gulf of Mexico focused attention on the role and resiliency of the oceans. Preface. PMID- 21329197 TI - Geologist at sea: aspects of ocean history. AB - Ocean history is largely read from deep-sea sediments, using microscopic fossils, notably foraminifers. Ice age fluctuations in the ocean's sediments provided for a new geologic understanding of climate change. The discovery of rapid decay of ice masses at the end of glacial periods was especially important, yielding rates of sea level rise reaching values of 1 to 2 m per century for millennia. Thanks to deep-ocean drilling, the overall planetary cooling trend in the Cenozoic was recognized as occurring in three large steps. The first step is at the Eocene Oligocene boundary and is marked by a great change in sedimentation patterns; the second is in the middle Miocene, associated with a major pulse in the buildup of Antarctic ice masses and the intensification of upwelling regimes; and the third is within the late Pliocene and led into the northern ice ages. Evolution in the sea is linked to these various steps. PMID- 21329198 TI - Submarine paleoseismology based on turbidite records. AB - Many of the largest earthquakes are generated at subduction zones or other plate boundary fault systems near enough to the coast that marine environments may record evidence of them. During and shortly after large earthquakes in the coastal and marine environments, a spectrum of evidence may be left behind, mirroring onshore paleoseismic evidence. Shaking or displacement of the seafloor can trigger processes such as turbidity currents, submarine landslides, tsunami (which may be recorded both onshore and offshore), and soft-sediment deformation. Marine sites may also share evidence of fault scarps, colluvial wedges, offset features, and liquefaction or fluid expulsion with their onshore counterparts. This article reviews the use of submarine turbidite deposits for paleoseismology, focuses on the dating and correlation techniques used to establish stratigraphic continuity of marine deposits, and outlines criteria for distinguishing earthquake deposits and the strategies used to acquire suitable samples and data for marine paleoseismology. PMID- 21329199 TI - Natural processes in delta restoration: application to the Mississippi Delta. AB - Restoration of river deltas involves diverting sediment and water from major channels into adjoining drowned areas, where the sediment can build new land and provide a platform for regenerating wetland ecosystems. Except for local engineered structures at the points of diversion, restoration mainly relies on natural delta-building processes. Present understanding of such processes is sufficient to provide a basis for determining the feasibility of restoration projects through quantitative estimates of land-building rates and sustainable wetland area under different scenarios of sediment supply, subsidence, and sea level rise. We are not yet to the point of being able to predict the evolution of a restored delta in detail. Predictions of delta evolution are based on field studies of active deltas, deltas in mine-tailings ponds, experimental deltas, and countless natural experiments contained in the stratigraphic record. These studies provide input for a variety of mechanistic delta models, ranging from radially averaged formulations to more detailed models that can resolve channels, topography, and ecosystem processes. Especially exciting areas for future research include understanding the mechanisms by which deltaic channel networks self-organize, grow, and distribute sediment and nutrients over the delta surface and coupling these to ecosystem processes, especially the interplay of topography, network geometry, and ecosystem dynamics. PMID- 21329200 TI - Modeling the dynamics of continental shelf carbon. AB - Continental margin systems are important contributors to global nutrient and carbon budgets. Effort is needed to quantify this contribution and how it will be modified under changing patterns of climate and land use. Coupled models will be used to provide projections of future states of continental margin systems. Thus, it is appropriate to consider the limitations that impede the development of realistic models. Here, we provide an overview of the current state of modeling carbon cycling on continental margins as well as the processes and issues that provide the next challenges to such models. Our overview is done within the context of a coupled circulation-biogeochemical model developed for the northeastern North American continental shelf region. Particular choices of forcing and initial fields and process parameterizations are used to illustrate the consequences for simulated distributions, as revealed by comparisons to observations using quantitative statistical metrics. PMID- 21329201 TI - Estuarine and coastal ocean carbon paradox: CO2 sinks or sites of terrestrial carbon incineration? AB - Estuaries are a major boundary in the land-ocean interaction zone where organic carbon (OC) and nutrients are being processed, resulting in a high water-to-air carbon dioxide (CO2) flux (approximately 0.25 Pg C y(-1)). The continental shelves, however, take up CO2 (approximately 0.25 Pg C y(-1)) from the atmosphere, accounting for approximately 17% of open ocean CO2 uptake (1.5 Pg Cy( 1)). It is demonstrated here that CO2 release in estuaries is largely supported by microbial decomposition of highly productive intertidal marsh biomass. It appears that riverine OC, however, would bypass the estuarine zone, because of short river-transit times, and contribute to carbon cycling in the ocean margins and interiors. Low-latitude ocean margins release CO2 because they receive two thirds of the terrestrial OC. Because of recent CO2 increase in the atmosphere, CO2 releases from low latitudes have become weaker and CO2 uptake by mid- and high-latitude shelves has become stronger, thus leading to more dissolved inorganic carbon export to the ocean. PMID- 21329202 TI - Emerging topics in marine methane biogeochemistry. AB - Our knowledge of physical, chemical, geological and biological processes affecting methane in the ocean and in underlying sediments is expanding at a rapid pace. On first inspection, marine methane biogeochemistry appears simple: Methane distribution in sediment is set by the deposition pattern of organic material, and the balance of sources and sinks keeps its concentration low in most waters. However, recent research reveals that methane is affected by complex biogeochemical processes whose interactions are understood only at a superficial level. Such processes span the deep-subsurface, near subsurface, and ocean waters, and relate primarily to the production, consumption, and transport of methane. The purpose of this synthesis is to examine select processes within the framework of methane biogeochemistry, to formulate hypotheses on how they might operate and interact with one another, and to consider their controls. PMID- 21329203 TI - Observations of CFCs and SF6 as ocean tracers. AB - An advantage of using chlorofluorocarbons (CFCs) and sulfur hexafluoride (SF6) as tracers of ocean circulation is that the time-dependent source functions permit calculation of rates for ocean processes. These compounds are also sensitive indicators highlighting interior ocean regions where surface-derived anomalies can be transported on timescales of decades. Significant applications for CFCs have been for the deep limb of the Atlantic meridional overturning circulation, upper ocean ventilation, and biogeochemical rates, including apparent oxygen utilization rates and anthropogenic CO2 inventories. Although CFCs have started to decrease in the atmosphere, SF6 continues to increase. There are benefits to measuring both CFCs and SF6: A large global CFC data set exists; CFCs are still increasing in older waters; SF6 expands estimates of age; and calculations of anthropogenic CO2 inventory are enhanced. Thus, the outlook for using CFCs as tracers for oceanic processes, and in particular in concert with SF6, remains very positive. PMID- 21329204 TI - Nitrogen cycle of the open ocean: from genes to ecosystems. AB - The marine nitrogen (N) cycle controls the productivity of the oceans. This cycle is driven by complex biogeochemical transformations, including nitrogen fixation, denitrification, and assimilation and anaerobic ammonia oxidation, mediated by microorganisms. New processes and organisms continue to be discovered, complicating the already complex picture of oceanic N cycling. Genomics research has uncovered the diversity of nitrogen metabolism strategies in phytoplankton and bacterioplankton. The elemental ratios of nutrients in biological material are more flexible than previously believed, with implications for vertical export of carbon and associated nutrients to the deep ocean. Estimates of nitrogen fixation and denitrification continue to be modified, and anaerobic ammonia oxidation has been identified as a new process involved in denitrification in oxygen minimum zones. The nitrogen cycle in the oceans is an integral feature of the function of ocean ecosystems and will be a central player in how oceans respond during global environmental change. PMID- 21329205 TI - Marine primary production in relation to climate variability and change. AB - Marine photosynthetic plankton are responsible for approximately 50 petagrams (10(15)) of carbon per year of net primary production, an amount equivalent to that on land. This primary production supports essentially all life in the oceans and profoundly affects global biogeochemical cycles and climate. This review discusses the general distribution of primary production in the sea, the processes that regulate this distribution, and how marine primary production is sensitive to climate variability and change. Statistical modes of ocean variability and their characteristic interannual to multi-decadal timescales over the last century are described. Recent in situ and satellite time-series of primary production can be clearly linked to interannual ocean variability. Global marine primary production appears to have increased over the past several decades in association with multi-decadal variations. A paleoclimate record extends discussion to the centennial scale, providing contrasting insights into how marine primary production might vary in the future. PMID- 21329206 TI - Beyond the Calvin cycle: autotrophic carbon fixation in the ocean. AB - Organisms capable of autotrophic metabolism assimilate inorganic carbon into organic carbon. They form an integral part of ecosystems by making an otherwise unavailable form of carbon available to other organisms, a central component of the global carbon cycle. For many years, the doctrine prevailed that the Calvin Benson-Bassham (CBB) cycle is the only biochemical autotrophic CO2 fixation pathway of significance in the ocean. However, ecological, biochemical, and genomic studies carried out over the last decade have not only elucidated new pathways but also shown that autotrophic carbon fixation via pathways other than the CBB cycle can be significant. This has ramifications for our understanding of the carbon cycle and energy flow in the ocean. Here, we review the recent discoveries in the field of autotrophic carbon fixation, including the biochemistry and evolution of the different pathways, as well as their ecological relevance in various oceanic ecosystems. PMID- 21329207 TI - Carbon concentrating mechanisms in eukaryotic marine phytoplankton. AB - The accumulation of inorganic carbon from seawater by eukaryotic marine phytoplankton is limited by the diffusion of carbon dioxide (CO2) in water and the dehydration kinetics of bicarbonate to CO2 and by ribulose-1,5-bisphosphate carboxylase/oxygenase's (RubisCO) low affinity for its inorganic carbon substrate, CO2. Nearly all marine phytoplankton have adapted to these limitations and evolved inorganic carbon (or CO2) concentrating mechanisms (CCMs) to support photosynthetic carbon fixation at the concentrations of CO2 present in ocean surface waters (< 10-30 microM). The biophysics and biochemistry of CCMs vary within and among the three dominant groups of eukaryotic marine phytoplankton and may involve the activity of external or intracellular carbonic anhydrase, HCO3- transport, and perhaps a C4 carbon pump. In general, coccolithophores have low efficiency CCMs, and diatoms and the haptophyte genus Phaeocystis have high efficiency CCMs. Dinoflagellates appear to possess moderately efficient CCMs, which may be necessitated by the very low CO2 affinity of their form II RubisCO. The energetic and nutrient costs of CCMs may modulate how variable CO2 affects primary production, element composition, and species composition of phytoplankton in the ocean. PMID- 21329208 TI - Microbial nitrogen cycling processes in oxygen minimum zones. AB - Oxygen minimum zones (OMZs) harbor unique microbial communities that rely on alternative electron acceptors for respiration. Conditions therein enable an almost complete nitrogen (N) cycle and substantial N-loss. N-loss in OMZs is attributable to anammox and heterotrophic denitrification, whereas nitrate reduction to nitrite along with dissimilatory nitrate reduction to ammonium are major remineralization pathways. Despite virtually anoxic conditions, nitrification also occurs in OMZs, converting remineralized ammonium to N-oxides. The concurrence of all these processes provides a direct channel from organic N to the ultimate N-loss, whereas most individual processes are likely controlled by organic matter. Many microorganisms inhabiting the OMZs are capable of multiple functions in the N- and other elemental cycles. Their versatile metabolic potentials versus actual activities present a challenge to ecophysiological and biogeochemical measurements. These challenges need to be tackled before we can realistically predict how N-cycling in OMZs, and thus oceanic N-balance, will respond to future global perturbations. PMID- 21329209 TI - Microbial metagenomics: beyond the genome. AB - Metagenomics literally means "beyond the genome." Marine microbial metagenomic databases presently comprise approximately 400 billion base pairs of DNA, only approximately 3% of that found in 1 ml of seawater. Very soon a trillion-base pair sequence run will be feasible, so it is time to reflect on what we have learned from metagenomics. We review the impact of metagenomics on our understanding of marine microbial communities. We consider the studies facilitated by data generated through the Global Ocean Sampling expedition, as well as the revolution wrought at the individual laboratory level through next generation sequencing technologies. We review recent studies and discoveries since 2008, provide a discussion of bioinformatic analyses, including conceptual pipelines and sequence annotation and predict the future of metagenomics, with suggestions of collaborative community studies tailored toward answering some of the fundamental questions in marine microbial ecology. PMID- 21329210 TI - Environmental proteomics: changes in the proteome of marine organisms in response to environmental stress, pollutants, infection, symbiosis, and development. AB - Environmental proteomics, the study of changes in the abundance of proteins and their post-translational modifications, has become a powerful tool for generating hypotheses regarding how the environment affects the biology of marine organisms. Proteomics discovers hitherto unknown cellular effects of environmental stressors such as changes in thermal, osmotic, and anaerobic conditions. Proteomic analyses have advanced the characterization of the biological effects of pollutants and identified comprehensive and pollutant-specific sets of biomarkers, especially those highlighting post-translational modifications. Proteomic analyses of infected organisms have highlighted the broader changes occurring during immune responses and how the same pathways are attenuated during the maintenance of symbiotic relationships. Finally, proteomic changes occurring during the early life stages of marine organisms emphasize the importance of signaling events during development in a rapidly changing environment. Changes in proteins functioning in energy metabolism, cytoskeleton, protein stabilization and turnover, oxidative stress, and signaling are common responses to environmental change. PMID- 21329211 TI - Microbial extracellular enzymes and the marine carbon cycle. AB - Extracellular enzymes initiate microbial remineralization of organic matter by hydrolyzing substrates to sizes sufficiently small to be transported across cell membranes. As much of marine primary productivity is processed by heterotrophic microbes, the substrate specificities of extracellular enzymes, the rates at which they function in seawater and sediments, and factors controlling their production, distribution, and active lifetimes, are central to carbon cycling in marine systems. In this review, these topics are considered from biochemical, microbial/molecular biological, and geochemical perspectives. Our understanding of the capabilities and limitations of heterotrophic microbial communities has been greatly advanced in recent years, in part through genetic and genomic approaches. New methods to measure enzyme activities in the field are needed to keep pace with these advances and to pursue intriguing evidence that patterns of enzyme activities in different environments are linked to differences in microbial community composition that may profoundly affect the marine carbon cycle. PMID- 21329212 TI - Modeling diverse communities of marine microbes. AB - Biogeochemical cycles in the ocean are mediated by complex and diverse microbial communities. Over the past decade, marine ecosystem and biogeochemistry models have begun to address some of this diversity by resolving several groups of (mostly autotrophic) plankton, differentiated by biogeochemical function. Here, we review recent model approaches that are rooted in the notion that an even richer diversity is fundamental to the organization of marine microbial communities. These models begin to resolve, and address the significance of, diversity within functional groups. Seeded with diverse populations spanning prescribed regions of trait space, these simulations self-select community structure according to relative fitness in the virtual environment. Such models are suited to considering ecological questions, such as the regulation of patterns of biodiversity, and to simulating the response to changing environments. A key issue for all such models is the constraint of viable trait space and trade-offs. Size-structuring and mechanistic descriptions of energy and resource allocation at the individual level can rationalize these constraints. PMID- 21329213 TI - Biofilms and marine invertebrate larvae: what bacteria produce that larvae use to choose settlement sites. AB - Communities of microorganisms form thin coats across solid surfaces in the sea. Larvae of many marine invertebrates use biofilm components as cues to appropriate settlement sites. Research on the tube-dwelling polychaete worm Hydroides elegans, a globally common member of biofouling communities, is described to exemplify approaches to understanding biofilm bacteria as a source of settlement cues and larvae as bearers of receptors for bacterial cues. The association of species of the bacterial genus Pseudoalteromonas with larval settlement in many phyla is described, and the question of whether cues are soluble or surface-bound is reviewed, concluding that most evidence points to surface-bound cues. Seemingly contradictory data for stimulation of barnacle settlement are discussed; possibly both explanations are true. Paleontological evidence reveals a relationship between metazoans and biofilms very early in metazoan evolution, and thus the receptors for bacterial cues of invertebrate larvae are very old and possibly unique. Finally, despite more than 60 years of intense investigation, we still know very little about either the bacterial ligands that stimulate larval settlement or the cellular basis of their detection by larvae. PMID- 21329214 TI - DNA barcoding of marine metazoa. AB - More than 230,000 known species representing 31 metazoan phyla populate the world's oceans. Perhaps another 1,000,000 or more species remain to be discovered. There is reason for concern that species extinctions may out-pace discovery, especially in diverse and endangered marine habitats such as coral reefs. DNA barcodes (i.e., short DNA sequences for species recognition and discrimination) are useful tools to accelerate species-level analysis of marine biodiversity and to facilitate conservation efforts. This review focuses on the usual barcode region for metazoans: a approximately 648 base-pair region of the mitochondrial cytochrome c oxidase subunit I (COI) gene. Barcodes have also been used for population genetic and phylogeographic analysis, identification of prey in gut contents, detection of invasive species, forensics, and seafood safety. More controversially, barcodes have been used to delimit species boundaries, reveal cryptic species, and discover new species. Emerging frontiers are the use of barcodes for rapid and increasingly automated biodiversity assessment by high throughput sequencing, including environmental barcoding and the use of barcodes to detect species for which formal identification or scientific naming may never be possible. PMID- 21329215 TI - Local adaptation in marine invertebrates. AB - Local adaptation in the sea was regarded historically as a rare phenomenon that was limited to a handful of species with exceptionally low dispersal potential. However, a growing body of experimental studies indicates that adaptive differentiation occurs in numerous marine invertebrates in response to selection imposed by strong gradients (and more complex mosaics) of abiotic and biotic conditions. Moreover, a surprisingly high proportion of the marine invertebrates known or suspected of exhibiting local adaptation are species with planktonic dispersal. Adaptive divergence among populations can occur over a range of spatial scales, including those that are fine-grained (i.e., meters to kilometers), reflecting a balance between scales of gene flow and selection. Addressing the causes and consequences of adaptive genetic differentiation among invertebrate populations promises to advance community ecology, climate change research, and the effective management of marine ecosystems. PMID- 21329216 TI - Use of flow cytometry to measure biogeochemical rates and processes in the ocean. AB - An important goal of marine biogeochemists is to quantify the rates at which elements cycle through the ocean's diverse microbial assemblage, as well as to determine how these rates vary in time and space. The traditional view that phytoplankton are producers and bacteria are consumers has been found to be overly simplistic, and environmental metagenomics is discovering new and important microbial metabolisms at an accelerating rate. Many nutritional strategies previously attributed to one microorganism or functional group are also or instead carried out by other groups. To tease apart which organism is doing what will require new analytical approaches. Flow cytometry, when combined with other techniques, has great potential for expanding our understanding of microbial interactions because groups can be distinguished optically, sorted, and then collected for subsequent analyses. Herein, we review the advances in our understanding of marine biogeochemistry that have arisen from the use of flow cytometry. PMID- 21329217 TI - The impact of microbial metabolism on marine dissolved organic matter. AB - Microbes mediate global biogeochemical cycles through their metabolism, and all metabolic processes begin with the interaction between the microbial cell wall or membrane and the external environment. For all heterotrophs and many autotrophs, critical growth substrates and factors are present within the dilute and heterogeneous mixture of compounds that constitutes dissolved organic matter (DOM). In short, the microbe-molecule interaction is one of the fundamental reactions within the global carbon cycle. Here, I summarize recent findings from studies that examine DOM-microbe interactions from either the DOM perspective (organic geochemistry) or the microbe perspective (microbial ecology). Gaps in our knowledge are highlighted and future integrative research directions are proposed. PMID- 21329218 TI - The needs of the many... PMID- 21329219 TI - Health care reform--DC style. PMID- 21329220 TI - Clinical excellence in STD and high risk behavior prevention. PMID- 21329221 TI - Tips for navigating the hornet's nest of conflicts in the workplace. PMID- 21329222 TI - Health literacy in older adults. PMID- 21329223 TI - The future of Florida's nursing shortage under healthcare reform. PMID- 21329224 TI - Staying inside the lines: convenient care in 2011. PMID- 21329225 TI - Need job, will travel: consider locum tenens. PMID- 21329227 TI - Patient handout. Hot in here? Coping with hot flashes in menopause. PMID- 21329226 TI - Ups and downs for NPs and PAs Down Under. PMID- 21329228 TI - A changing landscape. The job outlook for NPs & PAs. PMID- 21329229 TI - Renal protection in diabetes. PMID- 21329230 TI - Contraception update. PMID- 21329231 TI - Laying the groundwork. Preanesthesia clinics promote safety and cost savings. PMID- 21329232 TI - Vegetarian diets in children. PMID- 21329233 TI - Barriers to obesity treatment. Developing management strategies that work. PMID- 21329234 TI - Medicinal marijuana. An overview of California's Proposition 215. PMID- 21329235 TI - Oliver Wendell Holmes, Sr. throws down the gauntlet: The claims of dentistry. AB - It had been over 30 years since the founding of the American Journal of Dental Science, the organization of the American Society of Dental Surgeons, and the establishment of the Baltimore College of Dental Surgery. Yet the general acceptance and inclusion of dentistry into the family of learned professions, and the recognition of dentistry as a truly professional calling by the public and medical community, were both still beyond reach. In 1872, Harvard University, under the new leadership of President Charles Eliot, re-confirmed American dentistry's profession legitimacy, implementing standards and reforms in the Harvard Dental School similar to those mandated to Harvard Medical School the previous year. Dr. Oliver Wendell Holmes, Sr. was given the task to articulate the justification for this contentious decision. PMID- 21329236 TI - The claims of dentistry. PMID- 21329237 TI - Your tooth it ain't so purty but it's gen-u-ine: Cole Porter's comic song "Snagtooth Gertie". AB - Cole Porter (1891-1964), an American musical icon, has been internationally acknowledged as one of the most cosmopolitan, sophisticated, elegant and influential composer-lyricists of the 20th century. Born in Indiana and raised in wealth and privilege, he attended both Yale and Harvard universities where he honed his song-writing skills. In his 800 tunes, many of which became smash hits, he blended fresh, witty, urbane and colloquial lyrics with catchy, singable melodies. He composed musical scores for both Broadway stage and Hollywood movies, but focused on the former. While Porter enjoyed penning comic songs, he rarely had them published. In 1946, Cole wrote the music and lyrics for a Broadway show entitled Around the World in Eighty Days. Deemed a failure, it closed after only 75 performances. One light-hearted ditty, "Snagtooth Gertie", which he composed for the show, was never used. The lyrics are presented for the first time in this paper. PMID- 21329238 TI - Not just two million teeth: Giovanni Battista Orsenigo, monk dentist. AB - Brother Giovanni Battista Orsenigo, a monk of the "Ospitalieri di San Giovanni di Dio--Fatebenefratelli" holy order, was the most famous dental surgeon in Rome from 1870 to the start of the 20th century, but it was his nomination in 1972 by the Guinness Book of Records as the "most dedicated dentist", having kept more than 2 million extracted teeth, that brought him international reknown. Orsenigo was not merely a tooth-drawer, but a truly great dentist, and one who honored the code of his monastic order. It is important that this distinguished colleague, who is not mentioned in international dental literature, be restored to dental history and that his memory be preserved. PMID- 21329239 TI - "That was the beginning": The professionalization and Americanization of dentistry in pre-state Israel. AB - The history of dental practice in Israel dates back to 1953, with the establishment of the Faculty of Dentistry at the Hebrew University. This article will discuss the early roots of American involvement in Israeli dentistry: beginning with the late Ottoman period in Palestine, through the British Mandate, the establishment of the State of Israel in 1948, and the institution of the Faculty of Dentistry at the Hebrew University of Jerusalem. It will introduce the central characters who promoted the professionalization process of dentistry in Israel--a process made possible by the 'Americanization' of the field: importing American knowledge and practice. Moreover, this article will demonstrate that although the majority of dentists and dental practitioners arrived in Palestine from Russia and from Germany, the main professional influence was American. PMID- 21329240 TI - Differences in health-related behaviors and body mass index risk categories in African American women in college. AB - OBJECTIVE: To determine if differences in health-related behaviors (diet and physical activity) exist in African American college women based on body mass index (BMI) risk categories. METHODS: One hundred eighty-six African American women (age, 19.5 +/- 2.5 y) in college were surveyed using the modified National College Health Risk Behavior Survey. Data regarding demographics, weight loss history/methods, food choices, and physical activity frequency were compared for obese (BMI > or = 30, n = 30), overweight (25 < or = BMI < 30, n = 45), and normal-weight (BMI < 25, n = 111) groups. Data were analyzed using multiple 2-way analyses of variance. RESULTS: No differences in food choices were determined between the groups. The overweight and obese groups were more likely than the normal-weight group to have used healthy modalities such as diet and/or exercise to try to lose weight instead of unhealthy methods such as laxatives and diet pills. The overweight group reported more vigorous aerobic training and strength training workouts than the normal-weight group. CONCLUSIONS: Food selection and activity frequency are not enough to differentiate African American women in different BMI categories. Other factors may contribute to obesity such as food portion sizes, genetics, and/or intensity of physical activities. PMID- 21329241 TI - The impact of high body mass index on postoperative complications and resource utilization in minority patients. AB - BACKGROUND: Obesity is disproportionately prevalent among minority patients, yet very little has been written about its effect on surgical outcome in this group. OBJECTIVE: We investigated the association of body mass index (BMI) category with perioperative complications and resource utilization. METHODS: Data from the American College of Surgeons National Surgical Quality improvement Program Participant Use Data File was used to calculate the BMI (kg/m2) of all minority patients undergoing inpatient surgery from 2005 to 2008. Patients were stratified into 4 BMI classes, ranging from normal weight to severely obese. Postoperative length of stay (LOS) was used as the main proxy for resource utilization. Stepwise logistic regression was used to calculate odds ratios for prolonged LOS after controlling for clinically relevant cofactors. RESULTS: Among 73978 patients, 28% were in the normal BMI category, 28.9% were overweight, 28.2% were obese, and 14.9% were severely obese. Morbidity and mortality distribution varied significantly by BMI category, with the highest proportion of cases occurring in the normal-BMI group and the lowest in the severely obese patients. Postoperative LOS was longer for patients in the normal-BMI group than for severely obese patients. Other markers of resource utilization also followed the same pattern with progressive decrease from normal-BMI patients to the severely obese group. CONCLUSION: Postoperative morbidity and mortality and markers of hospital resource consumption were highest in the normal-BMI patients and decreased progressively to the severely obese group. This group appears to enjoy a paradoxical protection from perioperative complications and so utilize fewer hospital resources. PMID- 21329242 TI - Paradoxes in obesity with mid-life African American women. AB - PURPOSE: To examine the relationship among socioeconomic status, psychological factors (ie, health locus of control, health satisfaction), and health behaviors (ie, physical exercise, eating patterns) in a volunteer sample of mid-life African American women residing within Washington, DC. METHODS: The study's sample included 351 African American women who participated in the 12-week Prime Time Sister Circles (PTSC) intervention and completed the initial self-report survey. Of the women completing the baseline survey, clinical assessments were taken on 277 participants. RESULTS: The majority (64.4%) of the women were either obese or extremely obese based upon their body mass index (BMI). Fewer than one third of the women were satisfied with their weight. Despite these outcomes, most (61.8%) of the sample rated their health, in comparison to other African American women, as either good or very good. Further, more than one-half of the women were somewhat to very satisfied with their health knowledge, attitudes, behaviors, and their physical, emotional, and spiritual health. There was no significant relationship between obesity level and socioeconomic status, as measured by education, personal income, and total household income. Additionally, there were no significant differences in weight or eating behaviors by education, personal income, and total household income. The findings revealed a significant difference in the number of days the women reported engaging in physical exercise by personal income (p < .01) and total household income (p = .05), surprisingly, with the women in the lower-income categories reporting engaging in more days of physical exercise than women in the higher-income categories. CONCLUSIONS: This study documents the paradox of obesity in mid-life African American women related to socioeconomic status inasmuch as there were no differences observed in the prevalence of obesity by socioeconomic status indicators. The obese women of lower socioeconomic status reported exercising more than obese women of high socioeconomic status. Paradoxically, most of the obese women were dissatisfied with their body weight, shape, and physical health, but more than 50% were satisfied with their health attitudes and behaviors and 61.8% rated their health favorably. The paradoxes of obesity and African American women across various income levels are important to understand for interventions to success. PMID- 21329243 TI - Pediatric obesity: observed impact in the ambulatory surgery setting. AB - More obese children are presenting for surgery, reflecting an increase in comorbidities requiring surgery or an increased prevalence in the community. The objectives of this study were to determine the prevalence of obesity in our pediatric surgery patient population, detect ethnic disparities amongst this cohort of obese patients and also to determine any increase in pediatric obesity related comorbidities requiring surgery. Day surgery patients between ages 3 and 17 years were prospectively studied over a 3-month period. The proportion of obese children, demographics, and surgical procedures were determined. Of the 1559 patients analyzed, 312 (20%) were obese. Close to half of this subset of children were of Hispanic descent. Adenotonsillectomy was the most common surgery; however, the case distribution of this cohort was similar to our operating room database. Prevalence of pediatric obesity in our day surgery patients therefore reflects that of the community and has not resulted in an increase in related comorbidities requiring surgery. Longitudinal studies to assess the incidence of pediatric obesity related complications will be beneficial. PMID- 21329244 TI - Disparities in the utilization of high-volume hospitals for total hip replacement. AB - OBJECTIVE: Higher hospital surgical volumes have been associated with lower complication rates following total-hip replacement. The objective of this study was to identify the characteristics of patients who undergo total-hip replacement at high-volume hospitals and their differences from those who receive care at low volume hospitals. METHODS: Discharge data from patients undergoing total hip replacement in California from 1995 to 2005 were analyzed. Hospitals were classified into 3 tiers of low, intermediate, or high surgical volume. The relationships between race/ethnicity and income to utilization of low-volume and high-volume hospitals were examined by creating logistic regression models that include patient covariates such as age, gender, and comorbidity. RESULTS: This study analyzed 138399 cases of primary total-hip replacements during the study period. Patients of Hispanic ethnicity, or black or Asian race had higher relative risk ratios for being treated at a low-volume center compared to white patients. CONCLUSIONS: There are disparities in the characteristics of patients receiving care at hospitals performing a high volume or low volume of total-hip replacements. Hispanic ethnicity, and black and Asian race were statistically significant predictors of utilization of a low-volume hospital. PMID- 21329245 TI - The prevalence of self-reported lactose intolerance and the consumption of dairy foods among African American adults are less than expected. AB - OBJECTIVE: To determine the self-reported incidence of lactose intolerance and its influence on dairy choices among African American adults. DESIGN, SETTING, AND PARTICIPANTS: An online survey closely matched to the 2000 US Census was administered to a nationally representative sample of African Americans (2016 adults) and a comparison sample of the general population (1084 adults). Statistical analyses performed included pairwise t tests for proportion conducted on percent responses at the 95% confidence level. RESULTS: African Americans were more likely to eat fewer dairy foods, experience physical discomfort after consumption, and believe they were lactose intolerant. While 49% of African Americans had ever experienced "some type of physical discomfort" after eating dairy foods, 24% believed they were lactose intolerant. Within this group, 85% of African Americans would be willing to consume more dairy products if they could avoid lactose intolerance symptoms. CONCLUSIONS AND IMPLICATIONS: Dairy food, calcium, and vitamin D intake in African Americans and the general population are below US recommendations. Deficiencies of these nutrients are associated with chronic diseases that disproportionately affect African Americans. In the United States, dairy foods are the primary source of calcium and vitamin D, and lactose intolerance can be a significant barrier to dairy food intake. However, self described lactose intolerance is less than commonly reported in African American populations. Low dairy intake may reflect concerns about lactose intolerance, other factors such as learned food habits and cultural preferences. Nutrition recommendations for African Americans and the general population should focus on the health benefits of dairy foods, provide culturally sensitive dietary options, and strategies to increase tolerance. PMID- 21329246 TI - Early radiology and the National Medical Association. AB - Both the discovery of the x-ray and the founding of the National Medical Association (NMA) occurred in 1895. Radiologists have participated importantly in the NMA since the lecture of Dr Marcus F. Wheatland at the 1909 Annual Meeting in Boston, Massachusetts, which led to his election as president of the NMA for the following year. More recently, Dr Tracy M. Walton was president of the NMA in its centennial year. This article details early and continued participation in the NMA by radiologists, including the founding of the Section on Radiology in 1949, with its first chairman, Dr William E. Allen, Jr, longtime leader in radiology, the section, and the NMA. PMID- 21329247 TI - Early radiology and early African American physicians. PMID- 21329248 TI - A woman with acute dilated veins over the anterior chest wall. PMID- 21329249 TI - Don't tread on my specialty hospital. PMID- 21329250 TI - Strongyloides duodenitis: case report and review of literature. AB - Strongyloides stercoralis affects 30 to 100 million people worldwide and is a common cause of abdominal pain and diarrhea. Strongyloidiasis is a chronic and limited disease; however, in immunocompromised patients, hyperinfection syndrome can occur. Diagnosing strongyloidiasis early is important, as almost all deaths due to helminths in the United States are due to S stercoralis hyperinfection. Patients infected with human immunodeficiency virus (HIV) do not appear to be at an increased risk for S stercoralis hyperinfection. We report a case of an HIV infected Hispanic woman presenting with dyspepsia, emesis, abdominal pain, and diarrhea diagnosed with S stercoralis on an esophagogastroduodenoscopy biopsy of the duodenum. The diagnostic workup had been inconclusive and deciding to biopsy the small bowel based on the nonerythematous boggy appearance of the duodenal folds was the key step in making the correct diagnosis. Early diagnosis and treatment thwarted the developing hyperinfection syndrome and likely prevented further morbidity and probably saved her life. PMID- 21329251 TI - A case of successfully treated acute respiratory distress syndrome complicating Plasmodium falciparum malaria. AB - While endemic malaria has been eliminated in the United States, approximately 1200 mostly imported cases are reported annually in the country, with fewer than 20 recorded deaths. Because of the rarity of this disease in the United States, clinicians are often unfamiliar with its diagnosis and presentation. In a review of all malaria deaths in the United States from 1963 to 2001, failure to diagnose malaria on initial presentation, promptly initiate treatment, and/or prescribe appropriate antimalarial drugs were identified as contributing factors to death. Plasmodium falciparum can lead to a particularly severe type of malaria complicated by acute respiratory distress syndrome (ARDS), and physicians must be alert to the possibility of this diagnosis in immigrants and returning travelers. We report a case of successfully treated acute respiratory distress syndrome complicating imported P falciparum malaria at a large teaching hospital in Washington, DC. PMID- 21329252 TI - Presentation and minimally invasive treatment of a type IV giant paraesophageal hernia. AB - Paraesophageal hernias (PEHs) result from a defect of the diaphragmatic hiatus with a gradual enlargement of the hiatal opening, allowing abdominal contents to shift into the mediastinum. PEHs are often confused with sliding hiatal hernias; however, it is paramount that physicians understand the subtle presentation differences in the types of diaphragmatic incompetence, as treatment may vary greatly. The type IV giant PEH is a dangerous variant that, once recognized, usually requires surgical intervention. In recent years, the laparoscopic approach has been associated with decreases in morbidity, hospital stay, and time off work, as well as increased quality of life. This case involves the proper workup and minimally invasive treatment of a 56-year-old black female who presented with a symptomatic giant PEH with colon, stomach, and duodenum displacement into the chest. PMID- 21329253 TI - Tuberositas osteotomy for total knee arthroplasty: a review of the literature. AB - Tibial tubercle osteotomy (TTO) is a well-known technique for improving exposure in difficult total knee arthroplasty (TKA). We have performed a review of the literature concerning this procedure with the purpose of evaluation using the clinical results and complication rates in primary and revision TKA using TTO. We conducted a search limited to the following databases: PubMed/Medline, Cochrane Database of Systematic Reviews, Cochrane Clinical Trial Register, and Embase. These were searched from 1979 to May 2009 to identify studies relating to the primary and revisions of TKA using a tuberositas osteotomy. Eighteen studies met the inclusion criteria including 823 cases. In 762 cases, a medial TTO was performed. Most patients had an improved knee function after TKA. Proximal migration of the osteotomized site (n=18), TTO-related pain (n=17), and avulsion fractures of the tubercle (n=13) were the most reported complications of this technique. TTO is a relatively safe and reproducible procedure for the enhancement of surgical exposure in difficult primary or revision TKA. Serious complications related to TTO were reported in 8 to 9% of all cases. Future studies should compare different fixation methods in a prospective randomized controlled way. PMID- 21329254 TI - The pivot shift test is of limited clinical relevance in the arthritic anterior cruciate ligament-deficient knee. AB - The pivot shift test is used to assess the integrity of the anterior cruciate ligament (ACL). This test has been shown to be highly sensitive in detecting instability in knees with complete ACL rupture. However, in the presence of osteoarthritis, the rotation and subluxation required for the pivot shift to be effective can be limited and therefore is likely to impact upon the reliability of this test. We performed the pivot shift test on 50 patients, under general anesthesia, prior to total knee replacement and then recorded the integrity of the ACL intraoperatively. This allowed us to assess the accuracy of this test in the presence of significant osteoarthritis. Of the 50 knees tested, none had a positive pivot shift test preoperatively; however, 14% of the knees included in the study had a completely ruptured ACL. This gives a sensitivity of 0% and a specificity of 1% for the pivot shift test for ACL ruptures in the presence of established osteoarthritis. We conclude that the pivot shift test may not be a reliable test for ACL function in the presence of symptomatic arthritis of the knee. PMID- 21329255 TI - Patient-reported outcome measures for the knee. AB - In the past 20 years, there has been considerable growth in the number of knee instruments and rating scales designed to measure outcomes from the perspective of the patient. Only a few of these instruments have been evaluated for reliability, validity, and responsiveness. The purpose of this systematic review was to examine the psychometric evidence of patient-reported outcome measures for the knee and identify the best scores for specific knee conditions. A literature search was performed to retrieve references relating to the development and evaluation of knee-specific instruments. Twenty-four unique instruments were identified, and most have satisfactory evidence for internal (alpha > or = 0.82) and test-retest reliability (intraclass correlation coefficient > or = 0.80). Face/content validity was typically assessed during the item selection process, and construct validity was evaluated through strict hypothesis testing or correlations with other clinical measures. For many instruments, effect sizes and standardized response means measuring responsiveness were large (> or = 0.80) within disease-specific populations. Based on the psychometric data, recommendations include the Cincinnati Knee Rating System, Knee Injury and Osteoarthritis Outcome Score (KOOS), and Lysholm Knee Score for anterior cruciate ligament (ACL) injuries, the Kujala Anterior Knee Pain Scale for anterior knee pain, the International Knee Documentation Committee (IKDC) Subjective Knee Form, KOOS, and Lysholm Knee Score for focal chondral defects, the Western Ontario Meniscal Evaluation Tool (WOMET) for meniscal injuries, and the KOOS for osteoarthritis (OA). Although the IKDC can be used as a general knee measure, no instrument is currently universally applicable across the spectrum of knee disorders and patient groups. Clinicians and researchers looking to use a patient based score for measurement of outcomes must consider the specific patient population in which it has been evaluated. Using a diagnostic algorithm that measures the anatomic parts of the knee as separate constructs may solve this dilemma, allowing for measurement of treatment outcomes across patient groups and selection of the optimal clinical intervention. PMID- 21329256 TI - Tibial insert micromotion of various total knee arthroplasty devices. AB - The objective of this study was to develop a novel method to quantify rotational micromotion of modular tibial components that incorporates physiologic loading conditions, a physiologic test environment, and constraint characteristics of the articulating surface. The methodology is reviewed and data are presented on four total knee designs. Results showed the design with a rotational stabilizing island to demonstrate the most capability in resisting rotational micromotion for a given reacted torque, followed by a full peripheral capture device, then a partial peripheral capture device, and then a full peripheral capture device with a posterior lipped edge. Under walking and stair-climbing loads, the full peripheral capture device imparts more torque to the insert than the other designs due to the higher constraint of its articulating surface and thus experiences the most micromotion. The rotational stabilizing island device reveals the least amount of motion, due to a combination of its locking mechanism and a less constrained articular surface. PMID- 21329257 TI - Total knee arthroplasty closure with barbed sutures. AB - Bidirectional barbed sutures, which do not require the tying of knots, have the potential to reduce closure times of total knee arthroplasty (TKA) wounds without adverse effect to wound security, cosmesis, or infection risk. In this retrospective study, data were reviewed from TKAs performed between January 2007 and September 2008. For 88 of these procedures, conventional absorbable sutures were used for interrupted closure of the retinacular and subcutaneous layers and for running closure of the subcuticular layer. For 90 procedures, bidirectional barbed absorbable sutures were used for running closure of the retinacular and subcutaneous layers. Surgeries performed with barbed sutures were significantly faster than those performed with conventional sutures (mean times of 74.3 minutes and 85.8 minutes, respectively, p < 0.001) with no detrimental clinical effects. PMID- 21329258 TI - Candida infection in total knee arthroplasty with successful reimplantation. AB - Fungal infections associated with prosthetic joints are uncommon. The first case report describes a woman with insidious onset of a candidal infection of a revision total knee arthroplasty. After multiple joint debridements and prolonged antibacterial and antifungal therapy, she had a successful reimplantation of a knee prosthesis. The second case report concerns a man who had a primary cemented total knee arthroplasty that became infected with Candida albicans. He underwent resection arthroplasty with eventual replant without recurrence at 20 years. Although resection arthroplasty should be maintained as the gold standard in the surgical treatment of this problem, the first case shows a successful short-term outcome ofreimplantation of a patient with fungal infection of long-stemmed, revision total knee replacement. It also shows a treatment failure with fluconazole that was cured by voriconazole and caspofungin, two more recently developed antifungal agents. PMID- 21329259 TI - Failure of interpositional membrane to prevent recurrent arthrofibrosis. AB - Silicone has been used in numerous health care roles, from catheters to finger joint arthroplasties, with proven success. Its use as an interpositional membrane for the prevention of adhesions has been attempted in various anatomic sites with unpredictable results. We present a case report of a patient with recurrent arthrofibrosis requiring multiple operative procedures including manipulations under anesthesia, arthroscopies, and unicompartmental and eventual total knee replacement. After developing stiffness after total knee arthroplasty, the patient received placement of a silicone interpositional membrane with the goal of minimizing scar formation. Arthrofibrosis recurred, and only eventual removal of the membrane and correction of the underlying overstuffed patellofemoral compartment has allowed for maintained functional improvement in motion after 3 years. PMID- 21329260 TI - Communicating openly: SAJCD is now an open-access journal. PMID- 21329261 TI - Self-reported outcomes of aural rehabilitation for adult hearing aid users in a South African context. AB - Hearing impairment has far-reaching consequences for affected individuals, in terms of quality of life indicators. In the public health care sector of South Africa the hearing-impaired population is faced with limited aural rehabilitation services. This study evaluated self-reported outcomes of aural rehabilitation in a group of adults in the public health care sector with a standardised outcomes measurement tool (IOI-HA). Sixty-one participants were included (44% male; sample mean age 69.7 years) through face-to-face or telephonic interviews. Results revealed that the average perceived outcome of participants (5 = best outcome; 1 = poorest outcome) was positive across all domains of the inventory including daily use of hearing aids (4.3); benefits provided by hearing aids (4.3); residual activity limitation (3.9); satisfaction with hearing aids (4.5); residual participation restriction (4.0); impact of hearing difficulties on others (4.6); and changes in quality of life (4.5). Statistically significant relationships for daily use of hearing aids, degree of hearing loss, type of hearing aids fitted, and the perceived benefit from hearing aids in difficult listening environments (p<0.05) were evident. Adult aural rehabilitation for hearing loss in a public health care facility, even without optimal hearing aid fittings, was effective in providing positive perceived outcomes comparable to similar studies in developed countries. The findings advocate for the initiation of affordable and sustainable aural rehabilitation services in developing countries despite apparent resource limitations. PMID- 21329262 TI - Speech-language therapists supporting foundation-phase teachers with literacy and numeracy in a rural and township context. AB - Language is required for learning, but educators often find it difficult to facilitate listening and language skills while they have to adapt to a new national curriculum with an outcomes-based approach for which they have not necessarily been adequately trained. A multifaceted support programme was developed for foundation-phase educators to facilitate listening and language for literacy and numeracy, with a particular focus on language for numeracy. The aim of the research was to determine the value of this particular support programme for foundation-phase educators in two different contexts (a semi-rural and a township context). A mixed methods approach with a concurrent, equal status triangulation design was used, where qualitative data were transformed to quantitative data in order to be compared in a matrix. The results show that the participants benefited to varying degrees from the programme. The combination of workshops, practical and mentoring components proved to be an effective means of support. The results indicate a need for pre-training selection procedures as more effective support can be provided to homogeneous groups. PMID- 21329263 TI - Maximising health literacy and client recall of clinical information: an exploratory study of clients and speech-language pathologists. AB - Limited research has been carried out in the field of speech-language pathology with regard to ways of maximising health literacy and client recall. However, speech-language pathologists (SLPs) frequently provide vast amounts of information that clients need to understand, apply and review in order to manage their (or their child's) health. This exploratory study aimed to contribute information about ways in which SLPs can overcome low health literacy and poor client recall so that treatment effectiveness is improved. A case-study design was used with specific focus on four clients receiving treatment for dysphagia, voice disorders (including laryngectomies) and cleft lip and/or palate management in Cape Town. Strategies which may be able to maximise health literacy and client recall of clinical information were trialled and evaluated by clients and their SLPs, using semi-structured interviews. The researchers proposed a combination of high-tech strategies which assisted in all the cases. No single solution or universal tool was found that would be appropriate for all. There is a need to evaluate the long-term effectiveness of the combined strategies across a wider population, at different stages of rehabilitation and in diverse contexts. Implications and suggestions for future related research are presented. PMID- 21329264 TI - Young children with fetal alcohol spectrum disorder--communication profiles. AB - The aim of the article is to describe the communication profiles of five young children with fetal alcohol spectrum disorder (FASD) from 4 to 58 months of age. A collective case-study design following a quantitative and descriptive approach was used to describe the communication profiles of the participants. The results are described according to the participants' case histories and a four-level early communication assessment framework. The significant findings were that all participants were in foster care, and presented with incomplete case histories, general developmental delays and delays regarding all aspects of their communication abilities. An increase in the severity of the spectrum disorder across the participants' combined communication profiles was also identified. Participants presented with complex multiple neurodevelopmental needs that should be viewed within a developmental systems and ecological framework. The importance of early identification, diagnosis and assessment of infants and young children prenatally exposed to alcohol, the identification of precursors to communication impairment at a very early age, and the need for individualised early communication intervention to improve developmental outcomes within a family centred approach are discussed. Suggestions for future research to accumulate knowledge about FASD in the field of early communication intervention are made. PMID- 21329265 TI - Development of semantic processes for academic language in foundation phase EAL learners. AB - It is widely acknowledged that language competence is central to educational success, primarily because literacy is inherently a language-based activity. Vocabulary knowledge specifically plays an important role in the acquisition of reading comprehension skills. Language in education practice in South Africa is currently highly controversial, as the implementation of home language or bilingual instruction policies has not been achieved in many schools. The aim of this study was to investigate the development of language skills in foundation phase English Additional Language (EAL) learners attending schools where English is the language of learning and teaching. A 3-year longitudinal investigation of the acquisition of some of the processes underlying language for academic purposes was undertaken using the semantics subtests of the Developmental Evaluation of Language Variation Criterion Referenced Edition (Seymour, Roeper & De Villiers, 2003). The results indicated that the majority of EAL learners improved with increased exposure to English in the academic environment and by the time they were in grade 3, were performing at a higher level than English First Language learners in grade 2. However, the effects of this protracted period of development on literacy attainment should be investigated. The significant individual variation in the learners' performance has implications for assessment and instruction of EAL learners and for the collaborative role of teachers and speech language therapists in the education system. PMID- 21329266 TI - Configurations of self-identity formations of adults who stutter. AB - It is important for clinicians to understand how adults who stutter construct who they are, i.e. their self-identity, in order to offer personally meaningful interventions. Early research on stuttering and self-concept provided initial knowledge, but there has been a dearth of further research in this field. This article, the third in a series of papers emanating from a doctoral study, provides new insight into the configurations of self-identity formations of adults who stutter. Previous articles from the study described how 'Able' (positive self-identity) and 'DisOther' (negative self-identity) self-identity formations developed over time. This paper describes the configurations of self identities, Able and DisOther, evident across participants' stories. The study used a life-history methodology in which 7 adult participants (5 men and 2 women) shared their experiences of living with stuttering through open-ended interviews. The data from the interviews were analysed at two levels. The first level of analysis resulted in a description of the types of self-identity formations (positive and negative) and processes (personal, social and temporal) shaping the self-identity formations. This result was represented as a research story for each participant. The second level of analysis described the configurations of the self-identities, Able and DisOther, across the research stories. The main findings, illustrated through three research stories, were that the two types of self-identity formations, Able and DisOther, were present in singular and dual configurations. The dual presentation of self-identity formations occurred in co existing, competing and coalescing configurations at particular time periods, illuminating the complexity of the stuttering experience. The clinical implications are discussed. PMID- 21329267 TI - Literacy development of English language learners: the outcomes of an intervention programme in grade R. AB - This study aims to contribute to the knowledge base on the status and development of emergent literacy skills of learners receiving formal education in their second or additional language. The focus is on young English language learners (ELLs), i.e. learners whose home language is not English but who have English as their language of teaching and learning. This article reports on a study that investigated ELLs' emergent literacy skills prior to entering grade 1 and then evaluated the effectiveness of an evidence-based stimulation programme on early literacy skills in the South African context. Using a quasi-experimental design, ELLs' emergent literacy skills were assessed with an adapted version of 8 of the subtests of the Emergent Literacy Assessment battery (Willenberg, 2004) and were compared to those of English first language (L1) and of ELL control groups, both before and after the 8-week purpose-designed programme. While learners showed significant improvement on 6 of the 8 subtests, the programme did not significantly improve ELLs' skills in comparison to those of the control groups. Possible independent variables contributing to the dearth of intervention effect include socio-economic status, learners' L1, and teacher- and classroom-specific characteristics, all of which were considered in this study. Clinical implications for speech-language therapists with regard to assessment, intervention, service delivery and outcome measures are highlighted. PMID- 21329268 TI - Children with speech difficulties: an exploratory survey of clinical practice in the Western Cape. AB - This study investigated the methods of assessment and intervention used by speech language therapists (SLTs) in the Western Cape when working with children with speech difficulties. Children with speech difficulties are likely to form a considerable part of SLT caseloads in South Africa, but assessment choice may not be clear-cut given the linguistic diversity of the region and that few assessments have been developed specifically for the SA population. Selection of intervention approaches may also pose difficulties, linked to the lack of assessments and the limited evidence base in our context. A questionnaire was sent to SLTs working with pre- and/or primary-school-aged children. Twenty-nine clinicians responded (18.7% response rate). The majority (89%) use informal assessment in combination with formal assessment. When using formal assessments, more than 50% of SLTs surveyed make procedural or linguistic modifications. Participants used a variety of interventions such as auditory discrimination and phonological awareness, often in combination, and based on a child's profile of difficulties. Forty-six per cent of SLTs felt unsure about the selection of assessments and intervention for bi/multilingual children. Clinical implications arising from this preliminary investigation are discussed together with some suggestions for developing knowledge of children's speech difficulties in South Africa. PMID- 21329269 TI - Comparison of postmenopausal voice changes across professional and non professional users of the voice. AB - Menopause effects a permanent change in certain body functions, including voice. If the voice is used continually as part of one's occupation, this may further impact on postmenopausal voice changes. The present study investigated individual and combined effects of menopause and professional voice use on voice. Ninety-two women were classified into reproductive (52) and postmenopausal (40) groups. Each group was divided into level II (teachers) and level IV (clerks) of Koufman and Isaacson's (1991) classification. Voice samples were recorded and analysed using the VisiPitch III software. Aerodynamic parameters were manually calculated. The Voice Handicap Index (VHI) was included to improve face validity of the study. Results suggest that fundamental frequency (F(o)), speaking fundamental frequency (SF(o)) and maximum phonation time (MPT) decrease after menopause while noise-to harmonic ratio and voice turbulence index increase. Being a professional voice user seems to affect the nature of postmenopausal voice changes, since an interaction effect was observed for some voice parameters. VHI scores reflect that teachers are aware of voice problems caused by vocal abuse, though relatively unaware of postmenopausal voice changes. The study has implications for improving the working conditions of teachers in India, developing norms for menopausal changes and modifying allowable limits for voice recognition systems in future. PMID- 21329270 TI - Acute myocardial infarction in non-cardiac critically ill patients: a clinical pathological study. AB - BACKGROUND: In patients admitted to the Intensive Care Unit (ICU) for non cardiac disease, the diagnosis of acute coronary syndromes can be challenging. The aim of the study was to define the rate of discrepancies concerning the diagnosis of acute myocardial infarction and to evaluate the presence of risk factors that could be helpful in identifying patients at higher risk of missed diagnosis. METHODS: We compared clinical and autopsy records of 600 critically ill patients who died in our ICU in a 10-years period. We identified patients in whom acute myocardial infarction was reported as the cause of death on the clinical records or was discovered only at post-mortem examination. These subjects were subsequently divided into two Groups: patients in Group 1 underwent diagnostic evaluation for acute myocardial infarction whereas those in Group 2 were not investigated for. RESULTS: In Group 1, a definite clinical diagnosis was reached in 11 patients (14,7%) but remained undetermined in 37 patients (48%). The diagnosis was totally missed in 8 patients in Group 1 (10,6%) and in 20 patients of Group 2 (26,6%). The diagnostic discrepancy was higher in septic patients, in whom the correct diagnosis of acute myocardial infarction was established at a rate lower than 50% in respect to non-septic patients. CONCLUSIONS: Our experience strengthens the role of post-mortem examination as a source of feed back of the overall diagnostic and therapeutic approach especially in septic patients, where the diagnostic error is more frequent. PMID- 21329272 TI - An unusual case of apical hypertrophic cardiomyopathy in a transplanted heart. PMID- 21329273 TI - Non-professional providers. PMID- 21329271 TI - Type D personality impairs quality of life, coping and short-term psychological outcome in patients attending an outpatient intensive program of cardiac rehabilitation. AB - BACKGROUND: Type D personality represents a risk factor for adverse outcome and impaired Quality of Life (QoL) in CHD patients. Only few studies investigated Type D patients following cardiac rehabilitation (CR). No study investigated Type D personality in Italian patients attending a CR program of 4 weeks. The aims of the study were a) to verify the presence of Type D personality among patients attending an Italian CR program; b) to investigate psychological health status, QoL and coping style of CR patients and c) to test the influence of Type D personality on CR patients outcome. METHODS: Data from 59 patients attending an outpatient intensive program of 4 weeks of CR were collected at admission, and 1 month after discharge, using a set of self-report questionnaires. Variables were measured using CBA-H, DS-14, Q-LES-Q and Brief COPE Scale. RESULTS: The percentage of Type D personality found in the study sample was 39%. At admission Type D patients showed a significant lower level of psychological health status and QoL satisfaction compared to non Type D patients (p<0.05). After CR a significant percentage of Type D patients, despite an overall improvement, continued to show a clinically relevant psychological impairment in terms of anxiety (p=0.003), depressive mood (p=0.001), impairment in psychophysical well being (p=0.002), perceived psychophysical stress (p=0.002), interpersonal difficulties (p<0.001), and social anxiety (p=0.045). Type D personality was also found to be associated with a significant greater use of maladaptive coping strategies (p<0.05). CONCLUSIONS: Type D personality played a significant clinically relevant role on psychological health outcome in CR. Type D personality patients reported a significant higher level of psychological impairment, in terms of anxiety, depressive mood, impairment in psychophysical wellbeing, perceived psychophysical stress, interpersonal difficulties, social anxiety, and a significant lower QoL, prior and after CR. Type D personality seemed also to be associated with maladaptive coping strategies. Importance of assessment for Type D personality is warranted in CR setting, as additional interventions seem required to enhance the outcome of these patients defined in letterature at high-risk. PMID- 21329274 TI - Mid-level providers and the "Austin Group": when is the issue coming to Louisiana? PMID- 21329275 TI - What your patients think about workforce. PMID- 21329276 TI - Benefits byline. PMID- 21329277 TI - The times they are a changing. PMID- 21329278 TI - The big picture. PMID- 21329279 TI - Mental health parity, nursing and our patients. PMID- 21329280 TI - Effective management of the patient's emotional response to acute and chronic illness. PMID- 21329281 TI - Spectrum disorders: a new generation of complex patients. PMID- 21329282 TI - Autistic spectrum disorders in 3D. AB - The 3D model of ASD teaches us that: Atypicality of any degree can coexist with any degree of general intelligence; Atypicality fades over time in most children; The higher a child's IQ, the faster and more completely the atypical features fade; ASD is not just a "childhood disease". Nurses who deal primarily with adults need to be alert to the possibility that their adult patient with anxiety, depression, alcoholism or "odd behavior" may be a "grown-up who once had ASD", taking into account the lifelong history of social maladaptation that that implies, as well as the recurrence risk for ASD in their offspring. PMID- 21329283 TI - Are you SAD? Recognizing seasonal affective disorder. PMID- 21329284 TI - Human trafficking: the role of nurses in identifying and helping victims. PMID- 21329285 TI - Propensity matched analysis of bleeding and vascular complications associated with vascular closure devices vs standard manual compression following percutaneous coronary intervention. AB - BACKGROUND: In patients undergoing percutaneous coronary intervention (PCI), controversy exists regarding the effect of vascular closure device (VCD) use on bleeding and vascular complications with limited data available for comparison of the different devices. METHODS: We developed propensity score matched groups, manual compression (MC) (n = 1,407) and VCD (n = 2,814), who underwent PCI in an eight-year period and compared their bleeding and vascular complications. Vascular closure device subtype analysis was also done. RESULTS: Compared to MC, the VCD group had lower rates of hematoma > or = 10 cm (1.1% vs 2.1%, P < 0.01). Angioseal use was associated with the highest rate of surgical repair. Perclose had the lowest rates of bleeding and the lowest composite outcome of all vascular and bleeding complications at 5.6% vs 9.2% forAngiosealand 10.2% for Starclose (P < 0.001). CONCLUSION: In patients undergoing PCI, VCD use is a safe method for achieving femoral artery hemostasis. Perclose use is associated with the least complications. PMID- 21329286 TI - Survival of geriatric idiopathic pulmonary arterial hypertension patients. AB - BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is increasingly being diagnosed in patients of advanced years. We sought to investigate observed vs expected mortality among geriatric IPAH patients treated with specific pulmonary arterial hypertension (PAH) therapy. METHODS: From the University of Connecticut's Pulmonary Vascular Disease Program database, 20 IPAH patients over 65 years of age were identified. Patient demographics, cardiopulmonary hemodynamics, PAH therapy, and mortality were retrospectively analyzed. Based on observed follow-up time, the probability of death was calculated for each subject using a prediction formula for PAH patients developed by the National Institutes of Health (NIH). Byar's method for Poisson counts was used to compare observed and expected tallies of deaths within the study sample. A P value < or = 0.05 was considered statistically significant. RESULTS: The mean age of the 20 geriatric IPAH patients was 77 years (+/- 6.6) of which 70% were female. The mean cardiopulmonary hemodynamic values for the cohort were: right atrial pressure: 10 mmHg (+/- 4); mean pulmonary artery pressure: 45 mmHg (+/- 9); pulmonary artery occlusion pressure: 11 mmHg (+/- 3); cardiac output: 4.1 L/min (+/- 1.2); cardiac index: 2.3 L/min (+/- 0.5); and pulmonary vascular resistance: 712 dynes / sec / cm-5 (+/- 319). Fourteen subjects received PAH monotherapy with bosentan, sildenafil, or epoprostenol. Six subjects received PAH combination therapy with bosentan, sildenafil, iloprost, or treprostinil. Total follow-up across the 20 subjects was 58.7 years, with average follow-up of 2.9 yrs (+/- 1.7) per subject. Based upon the NIH formula, the expected number of deaths for this cohort was 9.4. During follow-up, three deaths actually occurred. Thus, observed mortality was only 31.9% of expected (P = 0.03, 95% C.I. = [6.4%, 93.2%]). CONCLUSION: Geriatric patients are increasingly being diagnosed with IPAH. Efficacy of PAH therapy in geriatric patients is unknown. In this cohort of subjects, the outcomes of older adults treated with specific PAH therapy demonstrates improved survival relative to that predicted by the NIH formula. PMID- 21329287 TI - Familial Mediterranean fever presenting with pulmonary embolism. AB - Familial Mediterranean fever (FMF) is the autoinflammatory disease and hereditary periodic fever syndrome that most commonly affects people of Eastern Mediterranean origin. It is characterized by recurrent self-limited attacks of fever and serositis, with an increase in acute-phase reactant markers, and is transmitted in an autosomal recessive pattern. Inflammation shifts the hemostatic mechanisms favoring thrombosis. There are few reports of an increased risk of hypercoagulability in patients with FMF in the absence of amyloidosis and nephrotic syndrome. In this case report, we describe a 43-year-old Turkish patient who presented with right-sided pleuritic chest pain and pulmonary embolism. The patient described having prior similar attacks of serositis, but had never been diagnosed with FMF. Further workup revealed an increase in acute phase reactants, negative hypercoagulability studies and heterozygosity for the M694V mutation in the pyrin (MEFV) gene. We identified untreated FMF and chronic inflammation as his only risk factor for pulmonary embolism. With this case report, we support recent studies that have demonstrated that inflammation may lead to prothrombotic states in patients with FMF. PMID- 21329288 TI - Better late than never: diagnosis and successful treatment in late adulthood of supravalvular aortic stenosis secondary to Williams-Beuren syndrome. AB - This is a case report of a patient diagnosed at age 50 with supravalvular aortic stenosis secondary to Williams-Beuren Syndrome and successfully treated with aortic valve replacement and excision of supravalvular tissue. PMID- 21329289 TI - Clinical and economic impact of intravenous to oral conversion therapy programs. PMID- 21329290 TI - Are international and American graduates equally ACGME competent? Results of a pilot study. AB - BACKGROUND: Despite a substantial proportion of international medical graduates (IMG) matching to U.S. programs in Internal Medicine, little is known about their readiness in the six medical competencies compared to graduates of U.S. schools (USMG). METHODS: A brief questionnaire with two questions designed to assess basic understanding of each of the six medical competencies (knowledge, patient care, communication, professionalism, systems based- and practice-based learning) was sent by electronic mail to all 1,737 applicants to a community teaching hospital Categorical Internal Medicine Residency Program. Correct responses of IMG were compared to USMG. RESULTS: Two hundred and eight IMGs were similar except for older age (29 vs 27 years; P = 0.02) compared to 39 USMGs who responded. USMG and IMG had similar percent correct answers (67% vs 62%; P = 0.22). USMG and IMG scored similarly across all but two of the six medical competencies. USMGs more often answered correctly questions on U.S. healthcare economics (39.5% vs 20.4% correct, P = 0.01) and the elements of practice-based learning (69.2% vs 47.5%; P = 0.01). CONCLUSIONS: While this study is limited by its small sample size, it supports a hypothesis that USMG and IMG may differ in their preparedness for systems-based and practice-based learning. This hypothesis deserves exploration in future studies. PMID- 21329291 TI - A recession's impact on pediatric emergency household spending and attitudes about health-care reform. AB - BACKGROUND: We assessed changes in household spending and opinions about health care insurance reform among parents in the pediatric emergency department (PED) during the current recession. METHODS: We conducted a survey of parents at a PED. Enrollment was in June and July 2009. We assessed demographics, employment and insurance status, and difficulty paying for household expenses. Open-ended questions addressed attitudes about health-care reform. RESULTS: Among 467 parents, job loss was associated with difficulty paying for food (OR 2.32, 95% CI 1.53-3.52), housing (3.21, 2.11-4.88), and utilities (2.19, 1.44-3.32). In total, 226 respondents cut household expenses. More respondents cut food expenses (20.8%) and utilities (15.8%) than child health care (12.0%). Of 154 respondents providing opinions about health-care reform, 66.9% endorsed reform, and 9.7% disagreed. CONCLUSION: Parents with job loss reported hardship paying for household expenses. One in eight families have cut child health-care expenses. A population of PED parents commonly favored health-care insurance reform. PMID- 21329292 TI - Primary-care case management: the medical home future in Medicaid. PMID- 21329294 TI - "Ill equipped for the experience...". PMID- 21329293 TI - The pediatrician's role in adoption. 1961. PMID- 21329295 TI - So much to say. PMID- 21329296 TI - Branding your practice--image & identity matter! PMID- 21329298 TI - Medical education: progress and retreat. PMID- 21329297 TI - Re: YAGP--DeLuca and Rosson. PMID- 21329299 TI - Malaria epidemiology along Indo-Bangladesh border in Tripura State, India. AB - Malaria epidemiological surveys were conducted in 16 villages along the Indo Bangladesh border in Tripura, northeastern India. Insecticide resistance among malaria vectors and chloroquine resistance in the parasite were also studied along with monitoring of vector density using light traps. The epidemiological data indicated that malaria incidence was highest during June-July and lowest during November. Examination of blood smears collected through door to door surveys indicated slide positivity rate (SPR) of 25.2% and that Plasmodium falciparum was the predominant parasite (slide falciparum rate of 22.3%). The incidence rates of falciparum malaria varied significantly among the age groups (p<0.001) and 2-4 year olds were the most affected. Major malaria vectors recorded in light trap collections were An. dirus, An. minimus and An. philippinensis/nivipes. Chloroquine resistance studies indicated that treatment failure occurred in 35% of the cases and hence the use of artesunate combination therapy (ACT) was recommended for treatment of malaria in the area. PMID- 21329300 TI - Effect of malaria infection and dexamethasone on spleen morphology and histology. AB - The purpose of this study was to determine the histopathological changes of the spleen caused by parasite infection and steroid use to investigate pathological effects due to infection in ICR mice. The mice were divided into 5 groups: non malaria infected mice served as controls, mice with parasite infection only, and the other three groups; mice that were injected with dexamethasone (Dex) only, mice injected with Dex prior to and mice injected with Dex after malaria inoculation. Differences in spleen color between the groups were found. Compared to controls, malaria infected mice, and those injected with Dex only were significantly different (p < 0.05) in spleen weights and sizes. Histological changes were also seen in these two groups. Fused white pulps were found in the spleens of mice infected with malaria only, clear zones of white and red pulp were observed in the spleens of mice treated only with Dex; fibrinoids were also found in this group. The histology of spleens appeared normal except for infiltration by numerous megakaryocytes in the spleens of mice given Dex before or after parasite inoculation. Infection with malaria and use of Dex leads to destruction of typical features of spleen morphology and histology. However, uptake of Dex after malaria infection seems to reverse the pathology of the spleen. PMID- 21329301 TI - Progress of partial integration of malaria control with other vector borne diseases control in northern Thailand. AB - Thailand partially integrated the malaria program into the provincial and local Public Health system starting in 2003 by adding it to the control of other vector borne diseases and by transferring some activities to the Public Health Department. This study evaluates the results of this transfer on 8 high malaria incidence districts of Mae Hong Son and Chiang Mai Provinces. Indicators were measured for all community hospitals, Vector Borne Disease Control Units, (VBDU), health centers (HC), malaria clinics, and malaria posts in 2003 and 2004 during the first two years of partial integration. The number of Vector Borne Disease Control staff decreased 1.8 - 3%, and their operational budgets decreased 25%. The VBDU staff did all the indoor residual spraying (IRS), insecticide treated net (ITN) work and entomology surveys, they took 80.6% of the blood films, and treated 72% of the patients, while Public Health system did the remainder. The Annual Parasite Incidence (API) (1 - 10/1,000) and IRS coverage (88 - 100%) remained adequate in most areas during the first years after partial integration, but the API increased (to 31.6 - 57.6/1,000) in some populations. The percentage of insecticide treated bed net coverage was adequate in Mae Hong Son (95.4%), but inadequate in Chiang Mai (52.2%). Early diagnosis and prompt treatment (4 - 23 days), hospitals reporting disruption of anti-malarial drugs (3 of 7), and health centers having all needed equipment, training, and drugs for malaria diagnosis (9%) remain inadequate. If the program is allowed to diminish, malaria could spread again among the population. Integration of antimalarial activities into the general Public Health system has only been partially successful. We recommend the integration process and results should be monitored and evaluated to find and mitigate problems as they occur, and modify the integration process if needed. PMID- 21329302 TI - Long term primaquine administration to reduce Plasmodium falciparum gametocyte transmission in hypoendemic areas. AB - Artemesinin-combination therapies (ACTs) for falciparum malaria reduce gametocyte carriage, and therefore reduce transmission. Artemisinin derivatives act only against young gametocytes, but primaquine acts against mature gametocytes (which are usually present in the circulation at the time the patient presents for treatment). Both artemisnin derivatives and primaquine have short half-lives (less than 1 hour and 8 hours, respectively). Therefore, asexual parasites and young gametocytes may remain after completing ACT. Single dose of primaquine (0.5 0.75 mg base/kg) at the end of ACT can kill only mature gametocytes (if present) but cannot kill young gametocytes (if present). Remaining asexual forms and sequestered young gametocytes remaining after completion of ACT may develop into mature gametocytes 7-15 days later. Some patients have the first appearance of gametocytemia 4-8/day after completion of ACT. Thus, additional doses of primaquine (0.5-0.75 mg base/kg) given 15-18 days after or concurrently with 3 day-ACT respectively or given 15-22 days after or concurrently with 7 day-ACT respectively may be beneficial in killing the remaining mature gametocytes and thus contribute to interruption of P. falciparum gametocyte transmission more affectively than giving only a single dose of primaquine just after completing ACT. PMID- 21329303 TI - Trichomoniasis in cosmopolitan Malaysia: is it under control or is it under diagnosed? AB - In a prospective, observational study, 380 women attending a family planning (LPPKN) clinic and Sexually Transmitted Diseases (STD) clinic in Kuala Lumpur between January 2008 and November 2008 were enrolled. Patient information was obtained from the medical records and patients voluntarily completed questionnaires. Three vaginal swabs from the posterior fornix were taken from each patient examined. Different staining methods and cultivation in Diamonds medium were performed on the collected samples. Study subjects recruited in this survey were mostly young, with a geometric mean ages of 37.31 years (LPPKN clinic) and 32.06 years (STD clinic). Malay, Chinese, Indians and others ethnic groups accounted for 91, 4, 2 and 3%, respectively, at the LPPKN clinic. At the STD clinic, almost all subjects were Chinese. The prevalence rate of trichomoniasis was 0.36% at the LPPKN clinic and 0.0% at the STD clinic. Our findings suggested no association between contraceptive methods used and trichomoniasis infection at the LPPKN clinic. At the STD clinic, it was found a high risk for STD acquisition was not associated with trichomoniasis positivity. The data demonstrated the prevalence of trichomoniasis was very low at LPPKN clinic and absent at STD clinic. The high prevalence rates of other STD among sex workers found in this survey suggest the need for more active interventions focused on this group. PMID- 21329304 TI - Predictive factors for Gnathostoma seropositivity in patients visiting the Gnathostomiasis Clinic at the Hospital for Tropical Diseases, Thailand during 2000-2005. AB - This was a retrospective study of patients having Gnathostoma antibody testing at the Hospital for Tropical Diseases, Bangkok during 2000-2005 to investigate predictive factors for Gnathostoma seropositivity in patients attending the Gnathostomiasis Clinic. Out of 849 patients tested, 531 (62.5%) were Gnathostoma seropositive. The median absolute eosinophil counts were 464 (0-16,796) and 326.5 (0-10,971) cells/mm3 in seropositive and seronegative patients, respectively (p<0.001). Differences in a history of cutaneous swelling, the habit of eating raw meat, eosinophilia (>500 cells/mm3), and the frequency of cutaneous swellings between seropositive and seronegative patients were all statistically significant. Patients with a history of eating raw meat and a history of cutaneous swelling were at 2.1 and 1.8 times more likely to be Gnathostoma seropositive, respectively. Logistic regression analysis showed eosinophilia was not a predictive factor for Gnathostoma seropositivity. PMID- 21329305 TI - Hypereosinophilia responding to empirical antihelminthic treatment. AB - We report a 20-year-old college student presents with bilateral ankle edema associated with hypereosinophilia following a history of traveling in a rural area. Physical examinations and investigations failed to diagnose any underlying cause. She was treated with antihelminth medication and the edema subsided within a week and the eosinophil counts normalized within two weeks. PMID- 21329306 TI - Occurrence of ectoparasites on rodents in Sukhothai Province, northern Thailand. AB - A survey of ectoparasites on rodents was carried out bimonthly from April 2008 to March 2009 in 3 districts of Sukhothai Province, northern Thailand. A total of 130 rodents comprising 8 species of hosts were captured and examined for ectoparasites. The hosts examined were Bandicota indica, Bandicota savilei, Rattus losea, Rattus rattus, Rattus exulans, Rattus norvegicus, Menetes berdmorei and Tamiops mcclellandii. Ninety-seven ectoparasites were collected: 1 species of tick (Hemaphysalis bandicota), 2 species of mites (Laelaps nuttali and Laelaps echidninus), and 1 species of flea (Xenopsylla cheopis) were identified. The infestation rates by ticks, mites and fleas on the rodents were 0.77, 5.38 and 6.15%, respectively. Monitoring the rodent population and their ectoparasites is important for future planning of prevention and control of zoonotic diseases in the area. PMID- 21329307 TI - Infestation with the cat flea, Ctenocephalides felis felis (Siphonaptera: Pulicidae) among students in Kuala Lumpur, Malaysia. AB - This paper reports six male undergraduate students living at a local university hostel who were infested with cat fleas (Siphonaptera: Pulicidae: Ctenocephalides felis felis) in February 2009. All of them suffered from maculopapular rashes and severe pruritus after the bites. Investigation revealed the presence of a stray cat in the hostel building; five of the students had a history of contact with the cat. Six cat fleas were collected at the hostel and identified as C. felis felis. Most of the students were not aware of this infestation and did not seek medical treatment. PMID- 21329308 TI - Effects of microwave radiation on house dust mites, Dermatophagoides pteronyssinus and Dermatophagoides farinae (Astigmata: Pyroglyphidae). AB - Dermatophagoides pteronyssinus and Dermatophagoides farinae mites are commonly found in house dust, and are important sources of allergens affecting humans. Various approaches to killing the mites have been examined. This study investigated the mortalities of adult mites exposed to 2,450 MHz microwave radiation produced by 3 ovens at various exposure times and power settings. The ovens all had 3 power settings. The average maximum water temperatures generated at high, medium and low power settings were 99.4 +/- 0.2, 84.1 +/- 0.4 and 44.8 +/- 0.9 degrees C, respectively. At high and medium settings, there was 100.0% mortality in both species when exposed for 300 seconds. The mean mortality rates at low power were 10.8 +/- 0.7% for D. pteronyssinus and 9.7 +/- 2.6% for D. farinae. When mites were exposed in the presence of culture media, the mortality rates decreased with increasing weight of media. The mean mortality with the largest amount of media tested at high power setting was 61.4%. PMID- 21329309 TI - Potential larvicidal and pupacidal activities of herbal essential oils against Culex quinquefasciatus say and Anopheles minimus (Theobald). AB - The larvicidal and pupacidal effects of eight herbal essential oils were tested against third instar (L3), fourth instar (L4), and pupal stages of Culex quinquefasciatus and Anopheles minimus. Probit analysis was used to analyze the data. The larval mortality was recorded at 1, 5, 10, 30, and 60 minutes, and 24 hours. Pupal mortality was also recorded at 24 hours intervals for 96 hours when completed mortality was achieved. Citronella grass oil #2 (Cymbopogon nardus) proved to have the greatest toxicity against 3rd instar Cx. quinquefasciatus and An. minimus with LT50 at 1.2 and <0.2 minute, respectively. It exhibited a high level of effectiveness against 4th instar Cx. quinquefasciatus (LT50 at 5.1 minutes) and An. minimus (LT50 at 0.9 minute). Regarding pupacidal activity, Cx. quinquefasciatus and An. minimus pupae were susceptible to Lemon grass oil (LT50 at 1.2 hours) and Citronella grass oil #1 (LT50 at 0.6 hour), respectively. These oils had larvicidal and pupacidal activities with 100% mortality against L3, L4 and pupal stage Cx. quinquefasciatus at 10 minutes, 30 minutes and 24 hours. They also caused 100% mortality of An. minimus at 5 minutes (L3, L4), and 24 hours (pupal stage). PMID- 21329310 TI - Flow cytometric analysis of dengue virus-infected cells in peripheral blood. AB - With the development of permeabilization techniques in flow cytometry and the availability of various monoclonal antibodies (MAbs) that specifically bind with cell surface and intracellular antigens, it is now possible to use flow cytometric assay to identify dengue virus (DEN) infected cells in peripheral blood. Blood samples were analyzed using phycoerythrin (PE) labeled anti-CD3, anti-CD14, anti-CD16, and anti-CD19 antibodies and Alexa Fluor 488 labeled anti flavivirus monoclonal antibody (MAb) 6B6C-1. The predominant DEN-infected cells were CD19+ in this study. There was dim partial to moderately bright partial expression of CD19 positive cells in the blood samples tested. Virus isolation and serotype-specific RT-PCR revealed the cells were infected with dengue serotype 3 (DEN3). Our results suggest B cells may play an important role in DEN1 and DEN3 replication, and dissemination in vivo. PMID- 21329311 TI - Cloning and expression of envelope protein of Thai genotype I strain KE-093 of Japanese encephalitis virus. AB - The purpose of this study was to clone and express envelope (E) gene of Japanese encephalitis virus (JEV) genotype I, Thai strain KE-093. The E gene was amplified by PCR and cloned using the expression vector, pET-15b. Analysis of the insert sequence revealed a point mutation, which was corrected by site directed mutagenesis. The envelope 53 kDa protein expression was generated by in vitro coupled transcription translation system. Heterologous expression in Escherichia coli Rosetta 2 strain, but not in E. coli BL21 (DE3) resulted in 2 immunoreactive bands (13 and 53 kDa) using anti-JEV E protein antibodies, and an additional band (35 kDa) using anti-His antibodies, suggesting that E protein antigenicity is located at the carboxy-terminal region. This is the first report of a successful cloning and heterologous expression of an E gene of JEV genotype I. This should prove useful in the application for diagnostics and vaccine development of JEV genotype I strains. PMID- 21329312 TI - Seasonal influenza virus strains circulating in Malaysia from 2005 to 2009. AB - From 2005 to 2009, the Institute for Medical Research (IMR), Kuala Lumpur received a total of 7,117 respiratory specimens from patients with influenza-like illness (ILI) for influenza screening. Seasonal influenza virus was isolated from 17.3% of patients with ILI in 2005, 31.6% in 2006, 12.8% in 2007, 10.2% in 2008 and 13.5% in 2009. There were one or more influenza A and B virus strains circulating in Malaysia throughout the year, with distinctly a peak in May to August. The predominant circulating strains of seasonal influenza A were A/California/7/2004-like (H3N2) in 2005, A/New Caledonia/20/99-like (H1N1) in 2006, A/ Brisbane/10/2007-like (H3N2) in 2007 and 2008, and A/Perth/16/2009-like (H3N2) virus in 2009. The predominant circulating strains of influenza B were B/Hong Kong/330/2001-like in 2005, B/Malaysia/2506/2004-like in 2006, B/Florida/4/2006-like in 2007 and 2008, and B/Brisbane/60/2008-like in 2009. PMID- 21329313 TI - Identification of Chikungunya virus strains circulating in Kelantan, Malaysia in 2009. AB - Malaysia experienced its first outbreak of chikungunya virus (CHIKV) infection in late 1998 in Klang District in Selangor; six years later the virus re-emerged in the state of Perak. All the CHIKV isolates in 1988 and 2006 shared high sequence similarities and belonged to the Asian genotype. In 2007 and 2008 CHIKV infection again reemerged but the genotype was the Central/East African genotype. This strain was found to be similar to the strains causing outbreaks in the India Ocean. In 2009, the strains circulating in Malaysia, including the state of Kelantan, based on the partial E1 gene, also belong to the Central/East African genotype. PMID- 21329314 TI - Comparison of HBV ribonuclease H domain in naive and drug resistant patients. AB - Nucleotide or nucleoside analog (NA) drug resistance has increasingly become a problem in HBV treatment. Due to the similarity between HBV polymerase and HIV-1 reverse transcriptase, knowledge obtained from HIV research might be applied to the treatment of HBV infection. A previous study has shown that HIV-1 ribonuclease H (RNase H) mutation may contribute to nucleoside reverse transcriptase inhibitor (NRTI) resistance. Therefore, we hypothesized that it might be possible to have a mutation in the HBV RNase H domain of HBV NA drug resistant patients. A one-year cross-sectional study was conducted at a single university hospital. Serum samples were collected from HBV infection treatment naive and suspected HBV NA drug resistant patients. To confirm HBV NA drug resistance, genotype specific resistance was examined. The HBV genotype and RNase H domain were sequenced and compared. In total, 37 HBV-infected patients were finally analyzed. Of these, 24 were considered sensitive to the drug and 13 resistant, as determined by the genotypic resistance method. Comparison between the two groups showed they had comparable baseline characteristics; no mutation in the HBV RNase H domain was detected. Possibly due to the small sample size, no significant mutations were found in the HBV RNase H domain of either group of HBV infected patients. Further research of a larger patient group is needed to confirm these initial findings. PMID- 21329315 TI - Use of latex agglutination test to determine rabies antibodies in production of rabies antisera in horses. AB - A therapeutic anti-rabies immunoglobulin for human use has been produced mainly in horses. The presently available seroneutralization test, the rapid fluorescent focus inhibition test (RFFIT), is laborious and rather difficult to carry out in horse farms. This study was undertaken to develop a simple latex agglutination test (LAT) for determining rabies antibodies in horse sera. LAT was validated by testing a total of 468 horse serum samples characterized by RFFIT. Of these, 253 of 260 samples with antibody titers of less than 100 IU/ml had agglutination score of 1+, whereas 174 of 208 samples with antibody titers equal to or greater than 100 IU/ml had agglutination scores of 2-4+. Results of LAT correlated with those of RFFIT (r = 0.87, p < 0.0001). LAT has the advantages of being rapid, simple to perform, easy to interpret, and applicable as an on-site testing tool for the estimation of rabies antibodies in horses. PMID- 21329316 TI - Phylogenetic analysis of human rotavirus in Myanmar: detection of Indian Bangladeshi G1/G2 lineages, Chinese G3 lineage and OP354-like P[8] lineage (P[8]b subtype). AB - As a first phylogenetic study of human rotavirus in Myanmar, VP7 and VP8* gene sequences of 5 group A human rotaviruses detected in children in Yangon City were determined and analyzed for their relatedness to rotavirus strains reported in other countries. VP7 genes of the two G1P[8] strains and the two G2P[4] strains clustered phylogenetically with those of Indian-Bangladeshi lineages with extremely high sequence identities. In contrast, a G3P[8] strain exhibited a close relatedness of VP7 gene to G3 rotaviruses currently prevailing in China, which had been referred to as a new variant G3 rotavirus. While VP8* genes of P[4] and P[8] strains clustered with those of Indian and Bangladeshi strains, only the G1 strain was grouped into a rare P[8] subtype, ie, P[8]b (OP354-like P[8]) with close relatedness to the P[8]b strains in eastern India and Thailand. The coexistence in Myanmar of G1/G2 and G3 rotaviruses, which are virtually identical to those predominating in India/Bangladesh and China, respectively, suggests the spread of these predominant rotaviruses from the two regions into Myanmar. PMID- 21329317 TI - Serotypes and antimicrobial resistance of Salmonella enterica ssp in central Thailand, 2001-2006. AB - This study was carried out to elucidate the epidemiological trends and antimicrobial susceptibilities against Salmonella serovars among Thai patients and asymptomatic carriers during 2001-2006 in central Thailand. A total of 1,401 human and 260 non-human isolates from various sources were included. The isolates were characterized using serotyping and antimicrobial susceptibility testing. The most common serovars in patients submitting stool samples were S. Weltevreden, S. Stanley, S. Anatum, and S. Rissen. Significantly higher odds ratios were observed in blood samples versus stool sample for S. Choleraesuis, S. Enteritidis, S. Typhimurium, and S. Typhi. Children under five years old suffered the most frequently from gastroenteritis. The patients most commonly infected with an invasive serovar were children and people from 26 to 55 years of age. Antimicrobial susceptibility data revealed that S. Schwarzengrund, S. Choleraesuis, S. Anatum, S. Stanley, S. Rissen, and S. Typhimurium were the most resistant serovars observed. The invasive serovar, S. Choleraesuis was resistant to cefotaxime and norfloxacin. Antimicrobial resistance to cefotaxime, was observed in S. Agona, S. Rissen, S. Typhimurium, S. Anatum, and S. Weltevreden. An alarmingly high frequency of resistance to third generation cephalosporins was observed. We recommend Thai authorities take action in order to prevent spread of resistant S. Choleraesuis and other serovars among animals and humans by enforcing a more strict policy on the use of antimicrobials in food animals. PMID- 21329318 TI - Emergence and properties of fluoroquinolone resistant Salmonella enterica serovar Typhi strains isolated from Nepal in 2002 and 2003. AB - A total of 171 Salmonella enterica serovar Typhi strains isolated from Nepal, mostly from patients with typhoid fever in 2002-2003, were tested for antimicrobial susceptibility by disk diffusion assay. Selected S. enterica serovar Typhi isolates were tested for MICs by E-test for ceftriaxone, ciprofloxacin and ofloxacin. Mutations of DNA gyrase gyrA and gyrB and topoisomerase IV parC and parE were identified by sequencing of PCR amplicons. By disk diffusion assay, 75/171 S. enterica serovar Typhi isolates were resistant to nalidixic acid, ampicillin, choramphenicol, streptomycin, tetracycline, sulfisoxazole, and trimethroprim/sulfamethoxazoles. Multiple drug resistance to the 7 antimicrobials was most predominant among S. enterica serovar Typhi isolates in this study. Resistance to nalidixic acid was detected in 76/111 and 56/60 of total isolates collected in 2002 and 2003, respectively. Nalidixic acid resistant isolates in 2002 and 2003 showed MIC range for ciprofloxacin of 0.125 0.250 mg/l. Nalidixic acid-resistant isolates contained point mutations in gyrA and parC but not gyrB and parE. The gyrA mutation of nalidixic acid-resistant isolates obtained in 2002 and 2003 had amino acid substitution at position 83 of Serine-->Tyrosine and Serine-->Phenylalanine, respectively. Two different mutations of gyrA were detected among nalidixic acid-resistant isolates. Thus it is necessary to monitor mutation in DNA topoisomerase associated with increases in quinolones resistance. PMID- 21329319 TI - Nested polymerase chain reaction for detection of Helicobacter pylori in gastric biopsy specimens. AB - Sensitivity and specificity are important for tests used to defect Helicobacter pylori infection from gastric biopsy specimens. Molecular methods, such as PCR and nested PCR, are sensitive methods for H. pylori detection. The objective of this study was to evaluate the performance of PCR and nested PCR compared to culture, the rapid urease test (RUT) and histology for the diagnosis of H. pylori in 130 gastric biopsy specimens from symptomatic dyspeptic patients. Sensitivity and specificity with PCR were 91 and 100% and with nested PCR were 95 and 97%, respectively. H. pylori was detected by PCR and nested PCR at levels as low as 125 fg (70 cells) and 25 fg (14 cells), respectively. These results suggest nested PCR is a highly sensitive direct method to detect H. pylori infection from biopsy specimens. PMID- 21329320 TI - Identifying non-tuberculous mycobacterium lung diseases in acid-fast bacilli positive patients. AB - We conducted a case-control study by comparing the clinical and radiographic features of acid-fast bacilli positive patients with pulmonary tuberculosis (PTB) to those with non-tuberculous mycobacterium (NTM) lung diseases diagnosed according to American Thoracic Society (ATS) criteria. The occurrence of NTM lung disease was associated with persistence in symptoms after the fifth month of treatment (p=0.018), middle lobe involvement (p<0.01), lower lobe involvement (p=0.004), multiple lobe involvement (p=0.001) and reticulo-nodular infiltration (p=0.041). On logistic regression analysis, persistence of symptoms after 5 months of treatment (p<0.001), middle lobe involvement (p<0.001) and lower lobe involvement (p<0.05) were significant predictors of NTM lung disease.These findings suggest physicians should consider NTM lung disease if there is involvement of the middle lobe or lower lobes on chest radiography or the persistence of symptoms at the fifth month of treatment. PMID- 21329321 TI - Clinical features of tuberculous septic arthritis in Khon Kaen, Thailand: a 10 year retrospective study. AB - Tuberculous septic arthritis is difficult to diagnose. A retrospective analysis was done on patients over 15 years of age who attended Srinagarind Hospital, Khon Kaen, Thailand, between January 1, 1997 and December 31, 2006, whose synovial fluid culture was positive for Mycobacterium tuberculosis. The medical records of 77 patients were reviewed; one-third were in their sixth decade. Comorbid disease was found in 33 cases (42.9%), with systemic sclerosis being the most common (9 cases) followed by diabetes mellitus (5 cases) and chronic kidney disease (5 cases). Chronic monoarthritis was the most common presentation (34 cases) followed by acute monoarthritis (20 cases). More than half of the polyarticular involvements were disseminated tuberculosis. The knee was the most commonly affected joint (36.4%). Sixty percent had delayed diagnosis due to an incorrect diagnosis. Abnormal chest radiography and blood eosinophilia were found in 40 and 57.3% of cases, respectively. Synovial fluid and synovial tissue staining for acid-fast bacteria were positive in 30 and 40% of cases, respectively. A caseous granuloma was present in 57.5% of cases and non-specific synovitis in 12%. Sixty three percent had bone erosions. Tuberculous septic arthritis should be considered in patients who present with acute or chronic monoarthritis, and who have an abnormal chest radiograph or eosinophilia. Polyarticular involvement was commonly related to having disseminated tuberculosis and may indicate systemic involvement of tuberculous infection. PMID- 21329322 TI - Development of multiplex polymerase chain reaction for detection of feline hemotropic mycoplasma in blood and tissue specimens. AB - A multiplex polymerase chain reaction (PCR) was developed for the detection of feline hemotropic mycoplasmas which simultaneously differentiates infections of Mycoplasma haemofelis (Mhf), Candidatus Mycoplasma haemominutum (CMhm) and Candidatus Mycoplasma turicensis (CMtc) in feline blood and spleen. These organisms are responsible for the cause of various pathogenicity of feline infectious anemia. These infections are difficult to be detected by microscopic examination, the most commonly used method for general laboratory diagnoses. Specific primers were designed by selected consensus 16S rDNA sequences of three distinct species. The multiplex PCR assay developed in this study was sensitive and specific with detection limit 100 copies/microl DNA of Mhf and CMhm and 10 copies/microl DNA of CMtc. No amplicons could be amplified for other blood parasites or bacterial pathogens. This multiplex PCR will allow studies of pathogenicity and the monitoring of clinical treatment. PMID- 21329323 TI - Incidence and presence of virulence factors of Streptococcus suis infection in slaughtered pigs from Chiang Mai, Thailand. AB - This study was designed to determine the incidence of Streptococcus suis infection in slaughtered pigs raised in industrial facility and backyard system in Chiang Mai City, Thailand. A total of 90 tonsils and submaxillary salivary gland/lymph node samples from slaughtered pigs raised in industrial facility and 122 samples from slaughtered pigs raised in backyard system were collected. Isolation and identification of S. suis were conducted using standard bacteriological methods. Farm management and risk factor data were collected by a questionnaire. Serotyping and presence of virulence factor genes, epf, mrp and sly, were determined by multiplex PCR assay. The overall incidence of S. suis in this study was 9% (n = 212) and the incidence is significantly higher in districts located at a greater distance south of Chiang Mai City. S. suis serotype 2 was present more in healthy pigs (43%) than ill pigs (10%). Every S. suis isolate carried mrp and sly and ill pigs carried epf (80%) more than healthy pigs (57%). However, the probability of S. suis serotype 2 with epf+ (0.245) detected in healthy pigs was higher than in ill pigs (0.08) indicating people may have a higher risk of being infected with S. suis from healthy than ill pigs. PMID- 21329324 TI - Effect of temperature on growth of the pathogenic oomycete Pythium insidiosum. AB - Pythium insidiosum causes a potentially life-threatening infectious disease called pythiosis. An early, accurate diagnosis is important, since prompt treatment leads to a better prognosis. Unsuccessful attempts to isolate the organism have been associated with specimens subjected to lower temperatures. We analyzed growth of P. insidiosum at various temperatures. Culture at low (8 degrees C) and high (42 degrees C) temperatures resulted in death or inhibited growth of the organism. Culture under optimal temperatures (28 and 32 degrees C) was important for successful isolation of P. insidiosum. PMID- 21329325 TI - Youth and alcoholic beverages: Drinking patterns among high school students in central Thailand. AB - The objective of this study was to determine the drinking patterns of high school students in central Thailand. Eleven thousand three hundred sixty high school students from central Thailand were divided into 2 groups (drinkers and nondrinkers) according to their alcohol consumption. Information was obtained by an anonymous self-reporting questionnaire which consisted of 2 parts: general characteristics, and characteristics of alcohol drinking behavior. Data were analyzed using descriptive and inferential statistics by a computerized statistical package. The socio-demographic factors related to the student's alcohol consumption during the previous 12 months were: age > 15 years old, male sex, grades 9 and 11 education level, living in a private dormitory, staying with a relative or a friend, having a grade point average <2.0 or >3.0, having a job earning money and having family members with alcohol/drug problems (p<0.05). Drinking patterns were classified into 5 categories: life time drinking, drinking during the previous year, drinking during the previous 30 days, binge drinking during the previous 30 days and drinking until intoxication during the previous 30 days. A higher proportion of drinking was reported by boys than girls. The prevalence of drinking increased in proportion to the educational level. The 3 main drinking places were parties (48.5%), at home or in the dormitory (37.5%) and in shops around the school (12.4%). Boys drank alcohol on average 1-2 times per month in 59.8% and 1-2 standard drinks per time in 38.6%. Eighty point one percent of girls drank alcohol 1-2 times per month and 1-2 standard drinks per time in 55.6%. Drinking alcohol among high school students should be controlled by limiting access to alcoholic beverages in order to reduce accidents, injuries, violence and alcohol-related health problems among young people. PMID- 21329326 TI - Intimate relationships among adolescents in different social groups in northern Thailand. AB - With the influence of modernization, there is evidence of increasing Thai adolescent sexual activity. The purpose of this study was to describe and compare the intimate relationships of adolescents in different social groups in northern Thailand, and to note the health implications of their behavior. Quantitative and qualitative data from more than 1,750 unmarried young people aged 17-20 years revealed that adolescents from different social and educational backgrounds had significantly different types of intimate relationships. In the Thai context, social class differences are mostly based on young people's educational backgrounds and their families' financial power. Perceptions of love and relationships were interpreted according to social strata and sex. Notably, less well-off young people were likely to engage in much riskier sexual relationships. The present study provides detailed and constructive information to help plan and improve sexual and reproductive health counselling, programs and services for young people in northern Thailand. PMID- 21329327 TI - The effect of high calcium milk and casein phosphopeptide-amorphous calcium phosphate on enamel erosion caused by cholinated water. AB - The aim of this study was to determine the effectiveness of high calcium milk and casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) on enamel erosion caused by chlorinated water. Thirty-six bovine enamel samples without wear or caries 3x4 mm in size were placed in acrylic blocks. All specimens were randomly allocated into 3 groups (n=12/group): CPP-ACP in the form of paste, Anlene concentrated milk and a control (no treatment). All specimens were soaked in chlorinated water (pH =5.0) at room temperature for 72 hours following by soaking in artificial saliva for 30 minutes. Then, microhardness was determined using a microhardness tester. Data were analyzed using a one-way ANOVA and paired t-test. The microhardness value change in the control group was significantly higher than the other groups. No significant differences were seen between the 2 study groups. High calcium milk and CPP-ACP enhanced remineralization of enamel erosion caused by chlorinated water. PMID- 21329328 TI - Development of an airborne lead analysis kit and its application. AB - We developed a method to analyze airborne lead concentrations in the field. It was a modification of the colorimetric method using the reaction between 4(2 pyridylazo)-resorcinol (PAR) and lead with cyanex302 in an acid medium to reduce interfering metals. The lead concentration was detected with a photometer made in Thailand. The developed method uses an impinger containing 1% nitric acid solution as an absorbing agent to collect airborne lead at a flow rate of less than or equal to one liter/minute. Cyanex302 solution in toluene was used to extract metals from the samples and 0.1M nitric acid was used to extract just lead. The lead solution was reacted in 0.5 ml of 0.03% PAR solution, with 1 ml ammonium chloride buffer; the absorption of this solution was measured by a photometer. The results show the limit of detection (LOD) was 0.01 mg/l. The limit of quantification (LOQ) was 0.03 mg/l. The percent recovery of the lead concentrations of 0.05 - 3.0 mg/l was 94.0 to 103.5%. The precision presented as %CV ranged from 0.65 to 10.27%. Lead concentration in a lead smelting factory detected by this method was not significantly different from that detected by the NIOSH method: 7,303 at a 95% confidence level. PMID- 21329329 TI - General and highly alpha-regioselective zinc-mediated prenylation of aldehydes and ketones. AB - A simple, efficient, and general alpha-prenylation approach for the synthesis of a variety of alpha-prenylated alcohols has been successfully developed. A wide range of alpha-prenylated alcohol derivatives could be obtained in good yields by highly alpha-regioselective zinc-mediated prenylation of various aldehydes and ketones with prenyl bromide at 120 degrees C in HMPA. By simply altering the reaciton solvent and temperature, the method allows the achievement of a highly notable opposite regiocontrol, providing the expected regiochemical product. The method provides a convenient route for the direct alpha-prenylation of carbonyl compounds in a highly alpha-regioselective manner using a cheap and convenient mediator. Two possible pathways are proposed to account for the formation of these synthetically difficult-to-obtain molecules. PMID- 21329330 TI - 13C NMR studies of hydrocarbon guests in synthetic structure H gas hydrates: experiment and computation. AB - (13)C NMR chemical shifts were measured for pure (neat) liquids and synthetic binary hydrate samples (with methane help gas) for 2-methylbutane, 2,2 dimethylbutane, 2,3-dimethylbutane, 2-methylpentane, 3-methylpentane, methylcyclopentane, and methylcyclohexane and ternary structure H (sH) clathrate hydrates of n-pentane and n-hexane with methane and 2,2-dimethylbutane, all of which form sH hydrates. The (13)C chemical shifts of the guest atoms in the hydrate are different from those in the free form, with some carbon atoms shifting specifically upfield. Such changes can be attributed to conformational changes upon fitting the large guest molecules in hydrate cages and/or interactions between the guests and the water molecules of the hydrate cages. In addition, powder X-ray diffraction measurements revealed that for the hexagonal unit cell, the lattice parameter along the a-axis changes with guest hydrate former molecule size and shape (in the range of 0.1 A) but a much smaller change in the c-axis (in the range of 0.01 A) is observed. The (13)C NMR chemical shifts for the pure hydrocarbons and all conformers were calculated using the gauge invariant atomic orbital method at the MP2/6-311+G(2d,p) level of theory to quantify the variation of the chemical shifts with the dihedral angles of the guest molecules. Calculated and measured chemical shifts are compared to determine the relative contribution of changes in the conformation and guest water interactions to the change in chemical shift of the guest upon clathrate hydrate formation. Understanding factors that affect experimental chemical shifts for the enclathrated hydrocarbons will help in assigning spectra for complex hydrates recovered from natural sites. PMID- 21329331 TI - Development and applications of fluorescent indicators for Mg2+ and Zn2+. AB - In a study of the spectroscopic behavior of two Schiff base derivatives, salicylaldehyde salicylhydrazone (1) and salicylaldehyde benzoylhydrazone (2), Schiff base 1 has high selectivity for Zn(2+) ion not only in abiotic systems but also in living cells. The ion selectivity of 1 for Zn(2+) can be switched for Mg(2+) by swapping the solvent from ethanol-water to DMF (N,N-dimethylformamide) water mixtures. Imine 2 is a good fluorescent probe for Zn(2+) in ethanol-water media. Many other ions tested, such as Li(+), Na(+), Al(3+), K(+), Ca(2+), Cr(3+), Mn(2+), Fe(3+), Co(2+), Ni(2+), Cu(2+), Ag(+), Cd(2+), Sn(2+), Ba(2+), Hg(2+), and Pb(2+), failed to induce any spectral change in various solvents. The selectivity mechanism of 1 and 2 for metal ions is based on a combinational effect of proton transfer (ESPT), C?N isomerization, and chelation-enhanced fluorescence (CHEF). The coordination modes of the complexes were investigated. PMID- 21329332 TI - Copper-catalyzed oxidative cross-coupling of N,N-dimethylanilines with heteroarenes under molecular oxygen. AB - Nitrogen-containing heterocyclic compounds are important motifs of pharmaceuticals and functional materials, and there has been a growing interest in new synthetic methods for their preparation. In this paper, we report a direct cross-coupling reaction of heteroarenes with N,N-dimethylanilines in the presence of copper catalyst. Oxygen and/or air are successfully used as the oxidant, which is of great importance to the industrialized economies. The reaction is compatible with a wide range of heterocycles, including indolizines, imidazoles, indoles, and aniline, to enable the formation of various alkylated heteroarenes under very mild reaction conditions. PMID- 21329333 TI - Probing amyloid-beta fibril stability by increasing ionic strengths. AB - Previous experimental studies have demonstrated changing the ionic strength of the solvent to have a great impact on the mechanism of aggregation of amyloid beta (Abeta) protein leading to distinct fibril morphology at high and low ionic strength. Here, we use molecular dynamics simulations to elucidate the ionic strength-dependent effects on the structure and dynamics of the model Abeta fibril. The change in ionic strength was brought forth by varying the NaCl concentration in the environment surrounding the Abeta fibril. Comparison of the calculated vibrational spectra of Abeta derived from 40 ns all-atom molecular dynamics simulations at different ionic strength reveals the fibril structure to be stiffer with increasing ionic strength. This finding is further corroborated by the calculation of the stretching force constants. Decomposition of binding and dynamical properties into contributions from different structural segments indicates the elongation of the fibril at low ionic strength is most likely promoted by hydrogen bonding between N-terminal parts of the fibril, whereas aggregation at higher ionic strength is suggested to be driven by the hydrophobic interaction. PMID- 21329334 TI - Signatures of disorder in the minimum conductivity of graphene. AB - Graphene has been proposed as a promising material for future nanoelectronics because of its unique electronic properties. Understanding the scaling behavior of this new nanomaterial under common experimental conditions is of critical importance for developing graphene-based nanoscale devices. We present a comprehensive experimental and theoretical study on the influence of edge disorder and bulk disorder on the minimum conductivity of graphene ribbons. For the first time, we discovered a strong nonmonotonic size scaling behavior featuring a peak and saturation minimum conductivity. Through extensive numerical simulations and analysis, we are able to attribute these features to the amount of edge and bulk disorder in graphene devices. This study elucidates the quantum transport mechanisms in realistic experimental graphene systems, which can be used as a guideline for designing graphene-based nanoscale devices with improved performance. PMID- 21329335 TI - Indium oxide nanospirals made of kinked nanowires. AB - Helical inorganic nanostructures have received great attention due to their unique structures that could be interesting for both fundamental research and nanodevice applications. Using a tube-in-tube laser ablation chemical vapor deposition (CVD) method with gold nanoparticles as the catalysts, we reported the synthesis of self-assembled kinked In2O3 nanospirals and multikinked nanowires. As-synthesized nanostructures showed ultrafast photoinduced reversible wettability switching behavior from hydrophobic (132.7 degrees ) to superhydrophilic (0 degrees ) within 14 min. Single kinked In2O3 nanostructure based field-effect transistors were fabricated, and mobilities higher than 200 cm2/(V.s) were obtained, revealing good opportunity in fabricating high performance electronic and optoelectronic devices. PMID- 21329336 TI - Combining laser ablation/liquid phase collection surface sampling and high performance liquid chromatography-electrospray ionization-mass spectrometry. AB - This letter describes the coupling of ambient pressure transmission geometry laser ablation with a liquid phase sample collection method for surface sampling and ionization with subsequent mass spectral analysis. A commercially available autosampler was adapted to produce a liquid droplet at the end of the syringe injection needle while in close proximity to the surface to collect the sample plume produced by laser ablation. The sample collection was followed by either flow injection or a high-performance liquid chromatography (HPLC) separation of the extracted components and detection with electrospray ionization mass spectrometry (ESI-MS). To illustrate the analytical utility of this coupling, thin films of a commercial ink sample containing rhodamine 6G and of mixed isobaric rhodamine B and 6G dyes on glass microscope slides were analyzed. The flow injection and HPLC-ESI-MS analysis revealed successful laser ablation, capture, and with HPLC, the separation of the two compounds. The ablated circular area was about 70 MUm in diameter for these experiments. The spatial sampling resolution afforded by the laser ablation, as well as the ability to use sample processing methods like HPLC between the sample collection and ionization steps, makes this combined surface sampling/ionization technique a highly versatile analytical tool. PMID- 21329337 TI - High-throughput characterization of Pt supported on thin film oxide material libraries applied in the oxygen reduction reaction. AB - Thin film metal oxide material libraries were prepared by sputter deposition of nanoscale Ti/Nb precursor multilayers followed by ex situ oxidation. The metal composition was varied from 6 at.% Nb to 27 at.% Nb. Additionally, thin wedge type layers of Pt with a nominal thickness gradient from 0 to 5 nm were sputter deposited on top of the oxides. The materials libraries were characterized with respect to metallic film composition, oxide thickness, phases, electrical conductivity, Pt thickness, and electrochemical activity for the oxygen reduction reaction (ORR). Electrochemical investigations were carried out by cyclic voltammetry using an automated scanning droplet cell. For a nominal Pt thickness >1 nm, no significant dependence of the ORR activity on the Pt thickness or the substrate composition was observed. However, below that critical thickness, a strong decrease of the surface-normalized activity in terms of reduction currents and potentials was observed. For such thin Pt layers, the conductivity of the substrate seems to have a substantial impact on the catalytic activity. Results from X-ray photoelectron spectroscopy (XPS) measurements suggest that the critical Pt thickness coincides with the transition from a continuous Pt film into isolated particles at decreasing nominal Pt thickness. In the case of isolated Pt particles, the activity of Pt decisively depends on its ability to exchange electrons with the oxide layer, and hence, a dependence on the substrate conductivity is rationalized. PMID- 21329338 TI - Cyclic AMP receptor protein-aequorin molecular switch for cyclic AMP. AB - Molecular switches are designer molecules that combine the functionality of two individual proteins into one, capable of manifesting an "on/off" signal in response to a stimulus. These switches have unique properties and functionalities and thus, can be employed as nanosensors in a variety of applications. To that end, we have developed a bioluminescent molecular switch for cyclic AMP. Bioluminescence offers many advantages over fluorescence and other detection methods including the fact that there is essentially zero background signal in physiological fluids, allowing for more sensitive detection and monitoring. The switch was created by combining the properties of the cyclic AMP receptor protein (CRP), a transcriptional regulatory protein from E. Coli that binds selectively to cAMP with those of aequorin, a bioluminescent photoprotein native of the jellyfish Aequorea victoria . Genetic manipulation to split the genetic coding sequence of aequorin in two and genetically attach the fragments to the N and C termini of CRP resulted in a hybrid protein molecular switch. The conformational change experienced by CRP upon the binding of cyclic AMP is suspected to result in the observed loss of the bioluminescent signal from aequorin. The "on/off" bioluminescence can be modulated by cyclic AMP over a range of several orders of magnitude in a linear fashion in addition to the capacity to detect changes in cellular cyclic AMP of intact cells exposed to different external stimuli without the need to lyse the cells. We envision that the molecular switch could find applications in vitro as well as In Vivo cyclic AMP detection and/or imaging. PMID- 21329339 TI - Kinetic and mechanistic study of the reactions of atomic chlorine with CH3CH2Br, CH3CH2CH2Br, and CH2BrCH2Br. AB - A laser flash photolysis-resonance fluorescence technique has been employed to investigate the reactions of atomic chlorine with three alkyl bromides (R-Br) that have been identified as short-lived atmospheric constituents with significant ozone depletion potentials (ODPs). Kinetic data are obtained through time-resolved observation of the appearance of atomic bromine that is formed by rapid unimolecular decomposition of radicals generated via abstraction of a beta hydrogen atom. The following Arrhenius expressions are excellent representations of the temperature dependence of rate coefficients measured for the reactions Cl + CH(3)CH(2)Br (eq 1 ) and Cl + CH(3)CH(2)CH(2)Br (eq 2 ) over the temperature range 221-436 K (units are 10(-11) cm(3) molecule(-1) s(-1)): k(1)(T) = 3.73 exp( 378/T) and k(2)(T) = 5.14 exp(+21/T). The accuracy (2sigma) of rate coefficients obtained from the above expressions is estimated to be +/-15% for k(2)(T) and +15/-25% for k(1)(T) independent of T. For the relatively slow reaction Cl + CH(2)BrCH(2)Br (eq 3 ), a nonlinear ln k(3) vs 1/T dependence is observed and contributions to observed kinetics from impurity reactions cannot be ruled out; the following modified Arrhenius expression represents the temperature dependence (244-569 K) of upper-limit rate coefficients that are consistent with the data: k(3)(T) <= 3.2 * 10(-17)T(2) exp(-184/T) cm(3) molecule(-1) s(-1). Comparison of Br fluorescence signal strengths obtained when Cl removal is dominated by reaction with R-Br with those obtained when Cl removal is dominated by reaction with Br(2) (unit yield calibration) allows branching ratios for beta-hydrogen abstraction (k(ia)/k(i), i = 1,2) to be evaluated. The following Arrhenius-type expressions are excellent representations of the observed temperature dependences: k(1a)/k(1) = 0.85 exp(-230/T) and k(2a)/k(2) = 0.40 exp(+181/T). The accuracy (2sigma) of branching ratios obtained from the above expressions is estimated to be +/-35% for reaction 1 and +/-25% for reaction 2 independent of T. It appears likely that reactions 1 and 2 play a significant role in limiting the tropospheric lifetime and, therefore, the ODP of CH(3)CH(2)Br and CH(3)CH(2)CH(2)Br, respectively. PMID- 21329340 TI - Degradation mechanism of methyl mercury selenoamino acid complexes: a computational study. AB - Density functional theory (DFT) calculations have been carried out on the possible degradation/demethylation mechanism of methyl mercury (CH(3)Hg(+)) complexes with free cysteine and seleonocysteine. The binding of CH(3)Hg(+) ions with one (seleno)amino acid is thermodynamically favorable. However, the binding with another acid molecule is a highly unfavorable process. The CH(3)Hg (seleno)cysteinate then degrades to bis(methylmercuric)sulphide (selenide for the Se-containing complex) which in turn forms dimethyl mercury and HgS/HgSe, the latter being precipitated out as nanoparticles. The dimethyl mercury interacts with water molecules and regenerates the CH(3)HgOH precursor. The calculated free energies of formation confirm the thermodynamic feasibility of every intermediate step of the degradation cycle and fully support earlier experimental results. In completing the cycle, one unit of mercury precipitates out from two units of sources, and thereby Se antagonizes the Hg toxicity. The degradation of CH(3)Hg-L cysteinate is thermodynamically more favorable than the formation of CH(3)Hg-L cysteinate. The preferred degradation of the CH(3)Hg-L-cysteinate suggests that another mechanism for CH(3)Hg to cross the blood-brain barrier should exist. PMID- 21329341 TI - Modeling CO2 mass transfer in amine mixtures: PZ-AMP and PZ-MDEA. AB - The most common method of carbon dioxide (CO(2)) capture is the absorption of CO(2) into a falling thin film of an aqueous amine solution. Modeling of mass transfer during CO(2) absorption is an important way to gain insight and understanding about the underlying processes that are occurring. In this work a new software tool has been used to model CO(2) absorption into aqueous piperazine (PZ) and binary mixtures of PZ with 2-amino-2-methyl-1-propanol (AMP) or methyldiethanolamine (MDEA). The tool solves partial differential and simultaneous equations describing diffusion and chemical reaction automatically derived from reactions written using chemical notation. It has been demonstrated that by using reactions that are chemically plausible the mass transfer in binary mixtures can be fully described by combining the chemical reactions and their associated parameters determined for single amines. The observed enhanced mass transfer in binary mixtures can be explained through chemical interactions occurring in the mixture without need to resort to using additional reactions or unusual transport phenomena such as the "shuttle mechanism". PMID- 21329342 TI - Detection of the spatiotemporal trends of mercury in Lake Erie fish communities: a Bayesian approach. AB - The temporal trends of total mercury (THg) in four fish species in Lake Erie were evaluated based on 35 years of fish contaminant data. Our Bayesian statistical approach consists of three steps aiming to address different questions. First, we used the exponential and mixed-order decay models to assess the declining rates in four intensively sampled fish species, i.e., walleye (Stizostedion vitreum), yellow perch (Perca flavescens), smallmouth bass (Micropterus dolomieui), and white bass (Morone chrysops). Because the two models postulate monotonic decrease of the THg levels, we included first- and second-order random walk terms in our statistical formulations to accommodate nonmonotonic patterns in the data time series. Our analysis identified a recent increase in the THg concentrations, particularly after the mid-1990s. In the second step, we used double exponential models to quantify the relative magnitude of the THg trends depending on the type of data used (skinless-boneless fillet versus whole fish data) and the fish species examined. The observed THg concentrations were significantly higher in skinless boneless fillet than in whole fish portions, while the whole fish portions of walleye exhibited faster decline rates and slower rates of increase relative to the skinless boneless fillet data. Our analysis also shows lower decline rates and higher rates of increase in walleye relative to the other three fish species examined. The food web structural shifts induced by the invasive species (dreissenid mussels and round goby) may be associated with the recent THg trends in Lake Erie fish. PMID- 21329343 TI - Water use at pulverized coal power plants with postcombustion carbon capture and storage. AB - Coal-fired power plants account for nearly 50% of U.S. electricity supply and about a third of U.S. emissions of CO(2), the major greenhouse gas (GHG) associated with global climate change. Thermal power plants also account for 39% of all freshwater withdrawals in the U.S. To reduce GHG emissions from coal-fired plants, postcombustion carbon capture and storage (CCS) systems are receiving considerable attention. Current commercial amine-based capture systems require water for cooling and other operations that add to power plant water requirements. This paper characterizes and quantifies water use at coal-burning power plants with and without CCS and investigates key parameters that influence water consumption. Analytical models are presented to quantify water use for major unit operations. Case study results show that, for power plants with conventional wet cooling towers, approximately 80% of total plant water withdrawals and 86% of plant water consumption is for cooling. The addition of an amine-based CCS system would approximately double the consumptive water use of the plant. Replacing wet towers with air-cooled condensers for dry cooling would reduce plant water use by about 80% (without CCS) to about 40% (with CCS). However, the cooling system capital cost would approximately triple, although costs are highly dependent on site-specific characteristics. The potential for water use reductions with CCS is explored via sensitivity analyses of plant efficiency and other key design parameters that affect water resource management for the electric power industry. PMID- 21329344 TI - Sooting tendencies of oxygenated hydrocarbons in laboratory-scale flames. AB - Sooting tendencies have been measured for 186 oxygenated and 89 regular hydrocarbons under controlled laboratory conditions. The test compounds include alcohols, ethers, aldehydes, ketones, esters, alkanes, alkenes, and cycloalkanes ranging in size from methanol to isododecane. Sooting tendency was characterized with a new method based on measuring particle concentrations in methane/air nonpremixed flames when 1000 ppm of each test compound was added to the fuel. This method offers high precision and high sensitivity to the direct chemical effects of the additive. The results provide a wide-ranging yet detailed quantitative picture of how fuel oxygen affects soot formation, which will be useful for optimizing the soot-reducing benefits of oxygenated renewable fuels. The measured sooting tendencies of 1-alcohols are similar to those of n-alkanes with the same number of carbon atoms, while those of secondary alcohols are slightly higher. Aldehydes and ketones soot the same as n-alkanes with one less carbon atom. The sooting tendencies of esters depend strongly on molecular structure and increase in this order: methyl and ethyl esters < carboxylic acids, propyl esters, and n-alkanes < butyl and pentyl esters. The high sooting tendencies of the secondary alcohols and higher esters suggest that four-center and six-center reaction pathways are important. PMID- 21329345 TI - Enantioselective biotransformation of chiral PCBs in whole poplar plants. AB - Chiral PCBs have been used as molecular probes of biological metabolic processes due to their special physical, chemical, and biological properties. Many animal studies showed the enantioselective biotransformation of chiral PCBs, but it is unclear whether plants can enantioselectively biotransform chiral PCBs. In order to explore the enantioselectivity of chiral PCBs in whole plants, poplars (Populus deltoides * nigra, DN34), a model plant with complete genomic sequence, were hydroponically exposed to 2,2',3,5',6-pentachlorobiphenyl (PCB95) and 2,2',3,3',6,6'-hexachlorobiphenyl (PCB136) for 20 days. PCB95 and PCB136 were shown to be absorbed, taken-up and translocated in whole poplars, and they were detected in various tissues of whole poplars. However, the enantioselectivity of poplar for PCB95 and PCB136 proved to be quite different. The first eluting enantiomer of PCB95 was enantioselectively removed in whole poplar, especially in the middle and bottom xylem. It was likely enantioselectively metabolized inside poplar tissues, in contrast to racemic mixtures of PCB95 remaining in hydroponic solutions in contact with plant roots of whole and dead poplars. Unlike PCB95, PCB136 remained nearly racemic in most parts of whole poplars after 20 days exposure. These results suggest that PCB136 is more difficult to be enantioslectively biotransformed than PCB95 in whole poplars. This is the first evidence of enantioselectivity of chiral PCBs in whole plants, and suggests that poplars can enantioselectively biotransform at least one chiral PCB. PMID- 21329346 TI - Characterization of microbial fuel cells at microbially and electrochemically meaningful time scales. AB - The variable biocatalyst density in a microbial fuel cell (MFC) anode biofilm is a unique feature of MFCs relative to other electrochemical systems, yet performance characterizations of MFCs typically involve analyses at electrochemically relevant time scales that are insufficient to account for these variable biocatalyst effects. This study investigated the electrochemical performance and the development of anode biofilm architecture under different external loadings, with duplicate acetate-fed single-chamber MFCs stabilized at each resistance for microbially relevant time scales. Power density curves from these steady-state reactors generally showed comparable profiles despite the fact that anode biofilm architectures and communities varied considerably, showing that steady-state biofilm differences had little influence on electrochemical performance until the steady-state external loading was much larger than the reactor internal resistance. Filamentous bacteria were dominant on the anodes under high external resistances (1000 and 5000 Omega), while more diverse rod shaped cells formed dense biofilms under lower resistances (10, 50, and 265 Omega). Anode charge transfer resistance decreased with decreasing fixed external resistances, but was consistently 2 orders of magnitude higher than the resistance at the cathode. Cell counting showed an inverse exponential correlation between cell numbers and external resistances. This direct link of MFC anode biofilm evolution with external resistance and electricity production offers several operational strategies for system optimization. PMID- 21329347 TI - Boric acid permeation in forward osmosis membrane processes: modeling, experiments, and implications. AB - Forward osmosis (FO) is attracting increasing interest for its potential applications in desalination. In FO, permeation of contaminants from feed solution into draw solution through the semipermeable membrane can take place simultaneously with water diffusion. Understanding the contaminants transport through and rejection by FO membrane has significant technical implications in the way to separate clean water from the diluted draw solution. In this study, a model was developed to predict boron flux in FO operation. A strong agreement between modeling results and experimental data indicates that the model developed in this study can accurately predict the boron transport through FO membranes. Furthermore, the model can guide the fabrication of improved FO membranes with decreased boron permeability and structural parameter to minimize boron flux. Both theoretical model and experimental results demonstrated that when membrane active layer was facing draw solution, boron flux was substantially greater compared to the other membrane orientation due to more severe internal concentration polarization. In this investigation, for the first time, rejection of contaminants was defined in FO processes. This is critical to compare the membrane performance between different membranes and experimental conditions. PMID- 21329348 TI - Intrinsic protein kinase activity in mitochondrial oxidative phosphorylation complexes. AB - Mitochondrial protein phosphorylation is a well-recognized metabolic control mechanism, with the classical example of pyruvate dehydrogenase (PDH) regulation by specific kinases and phosphatases of bacterial origin. However, despite the growing number of reported mitochondrial phosphoproteins, the identity of the protein kinases mediating these phosphorylation events remains largely unknown. The detection of mitochondrial protein kinases is complicated by the low concentration of kinase relative to that of the target protein, the lack of specific antibodies, and contamination from associated, but nonmatrix, proteins. In this study, we use blue native gel electrophoresis (BN-PAGE) to isolate rat and porcine heart mitochondrial complexes for screening of protein kinase activity. To detect kinase activity, one-dimensional BN-PAGE gels were exposed to [gamma-(32)P]ATP and then followed by sodium dodecyl sulfate gel electrophoresis. Dozens of mitochondrial proteins were labeled with (32)P in this setting, including all five complexes of oxidative phosphorylation and several citric acid cycle enzymes. The nearly ubiquitous (32)P protein labeling demonstrates protein kinase activity within each mitochondrial protein complex. The validity of this two-dimensional BN-PAGE method was demonstrated by detecting the known PDH kinases and phosphatases within the PDH complex band using Western blots and mass spectrometry. Surprisingly, these same approaches detected only a few additional conventional protein kinases, suggesting a major role for autophosphorylation in mitochondrial proteins. Studies on purified Complex V and creatine kinase confirmed that these proteins undergo autophosphorylation and, to a lesser degree, tenacious (32)P-metabolite association. In-gel Complex IV activity was shown to be inhibited by ATP, and partially reversed by phosphatase activity, consistent with an inhibitory role for protein phosphorylation in this complex. Collectively, this study proposes that many of the mitochondrial complexes contain an autophosphorylation mechanism, which may play a functional role in the regulation of these multiprotein units. PMID- 21329349 TI - Anthropogenic currents and shoreline water quality in Avalon Bay, California. AB - Shoreline concentrations of fecal indicator bacteria (FIB) and fecal indicator viruses (FIV) in Avalon Bay (Catalina Island, California) display a marked diurnal pattern (higher at night and lower during the day) previously attributed to the tidal flux of sewage-contaminated groundwater and the tidal washing of contaminated sediments, coupled with light and dark die-off of FIB and FIV (Boehm, et al., Environ. Sci. Technol. 2009, 43, 8046-8052). In this paper we document the existence of strong (peak velocities between 20 to 40 cm/s) transient currents in the nearshore waters of Avalon Bay that occur between 07:00 and 20:00 each day. These currents, which have a significant onshore component, are generated by anthropogenic activities in the Bay, including prop wash from local boat traffic and the docking practices of large passenger ferries. A budget analysis carried out on simultaneous measurements of FIB at two cross-shore locations indicates that anthropogenic currents contribute to the diurnal cycling of FIB concentrations along the shoreline, by transporting relatively unpolluted water from offshore toward the beach. The data and analysis presented in this paper support the idea that anthropogenic currents represent a significant, and previously overlooked, source of variability in shoreline water quality. PMID- 21329350 TI - Cinnamon polyphenol extract regulates tristetraprolin and related gene expression in mouse adipocytes. AB - Cinnamon (Cinnamomum verum) has been widely used in spices, flavoring agents, and preservatives. Cinnamon polyphenol extract (CPE) may be important in the alleviation of chronic diseases, but the molecular evidence is not substantial. Tristetraprolin (TTP) family proteins have anti-inflammatory effects through the destabilization of pro-inflammatory mRNAs. TTP expression is reduced in fats of obese people with metabolic syndrome and brains of suicide victims. This study used quantitative real-time PCR to explore the effects of CPE on the regulation of TTP, VEGF, and related gene expression in mouse 3T3-L1 adipocytes. CPE (100 MUg/mL) increased TTP mRNA levels by up to 10-fold, and this stimulation was sustained over 16 h. The levels of VEGF mRNA, a putative target of TTP, were decreased 40-50% by CPE. It also affected the expression of other genes coding for ZFP36L1 and ZFP36L3 (TTP homologues), GM-CSF, COX2, IL6, APP, G-CSF, and PAI1. This study demonstrated that CPE rapidly induces TTP mRNA and reduces VEGF mRNA and affects the expression of a number of other genes in the cultured adipocytes. PMID- 21329351 TI - Effects of ultrasound pretreatment on the enzymatic hydrolysis of soy protein isolates and on the emulsifying properties of hydrolysates. AB - Soy protein isolate (SPI) was modified by ultrasound pretreatment (200 W, 400 W, 600 W) and controlled papain hydrolysis, and the emulsifying properties of SPIH (SPI hydrolysates) and USPIH (ultrasound pretreated SPIH) were investigated. Analysis of mean droplet sizes and creaming indices of emulsions formed by SPIH and USPIH showed that some USPIH had markedly improved emulsifying capability and emulsion stabilization against creaming during quiescent storage. Compared with control SPI and SPIH-0.58% degree of hydrolysis (DH), USPIH-400W-1.25% (USPIH pretreated under 400W sonication and hydrolyzed to 1.25% DH) was capable of forming a stable fine emulsion (d43=1.79 MUm) at a lower concentration (3.0% w/v). A variety of physicochemical and interfacial properties of USPIH-400W products have been investigated in relation to DH and emulsifying properties. SDS PAGE showed that ultrasound pretreatment could significantly improve the accessibility of some subunits (alpha-7S and A-11S) in soy proteins to papain hydrolysis, resulting in changes in DH, protein solubility (PS), surface hydrophobicity (H0), and secondary structure for USPIH-400W. Compared with control SPI and SPIH-0.58%, USPIH-400W-1.25% had a higher protein adsorption fraction (Fads) and a lower saturation surface load (Gammasat), which is mainly due to its higher PS and random coil content, and may explain its markedly improved emulsifying capability. This study demonstrated that combined ultrasound pretreatment and controlled enzymatic hydrolysis could be an effective method for the functionality modification of globular proteins. PMID- 21329352 TI - Reliable enzyme-linked immunosorbent assay for the determination of coconut milk proteins in processed foods. AB - This study was designed to develop a novel sandwich enzyme-linked immunosorbent assay (ELISA) for the detection and quantification of coconut milk proteins in processed foods. The developed sandwich ELISA was able to detect coconut milk proteins from various coconut milk products and did not show any cross-reactivity with 41 of 42 kinds of popularly used food ingredients, thus reflecting great specificity for coconut milk proteins. In addition, the established ELISA is highly sensitive and allowed the detection of 0.31 MUg/g of coconut milk protein in complex food matrices. This proposed assay could serve as a useful tool for the detection of the presence of hidden coconut milk proteins in processed foods. PMID- 21329353 TI - High sensitive detection of Cry1Ab protein using a quantum dot-based fluorescence linked immunosorbent assay. AB - Protein-based detection methods, enzyme-linked immunosorbent assay (ELISA) and lateral flow strip, have been widely used for rapid, spot, and sensitive detection of genetically modified organisms (GMOs). Herein, one novel quantum dot based fluorescence-linked immunosorbent assay (QD-FLISA) was developed employing quantum dots (QDs) as the fluorescent marker for the detection of the Cry1Ab protein in MON810 maize. The end-point fluorescent detection system was carried out using QDs conjugated with goat anti-rabbit secondary antibody. The newly developed Cry1Ab QD-FLISA assay was highly specific to the Cry1Ab protein and had no cross-reactivity with other target proteins, such as Cry2Ab, Cry1F, and Cry3Bb. The quantified linearity was achieved in the value range of 0.05-5% (w/w). The limits of detection (LOD) and quantification (LOQ) of the QD-FLISA were 2.956 and 9.854 pg/mL, respectively, which were more sensitive than the conventional sandwich ELISA method. All of the results indicated that QD-FLISA was a highly specific and sensitive method for the monitoring of Cry1Ab in GMOs. PMID- 21329354 TI - Measurement of conjugated linoleic acid (CLA) in CLA-rich potato chips by ATR FTIR spectroscopy. AB - A conjugated linoleic acid (CLA)-rich soy oil has been produced by photoisomerization of soy oil linoleic acid. Nutritional studies have shown that CLA possesses health benefits in terms of reducing certain heart disease and diabetes risk factors. Potato chips are snacks that are readily produced in the CLA-rich soy oil containing CLA levels similar to those of the oil used for frying. The objective of this study was to develop an FTIR method to rapidly determine the CLA content of oil in potato chips. Photoirradiated soy oil samples with ~25% total CLA were mixed with control soy oil, and 100 soy oil samples with total CLA levels ranging from 0.89 to 24.4% were made. Potato chips were fried using each of these 300 g CLA rich soy oil mixtures at 175 degrees C for approximately 3 min. Duplicate GC-FID fatty acid analyses were conducted on oil extracted from each batch of potato chips. The chip samples were ground and then scanned using ATR-FTIR spectroscopy with the aid of a high-pressure clamp, and duplicate spectra of each sample were averaged to obtain an average spectrum. Calibration models were developed using PLS regression analysis. These correlated the CLA isomer concentrations of potato chips obtained by GC-FID fatty acid analysis with their corresponding FTIR spectral features. The calibration models were fully cross validated and tested using samples that were not used in the calibration sample set. Calibrations for total CLA, trans,trans CLA, trans-10,cis 12 CLA, trans-9,cis-11 CLA, cis-10,trans-12 CLA, and cis-9,trans-11 CLA had coefficients of determinations (R2v) between 0.91 and 0.96 and corresponding root mean-square error of prediction (RMSEP) ranging from 0.005 to 1.44. The ATR-FTIR technique showed potential as a method for the determination of the CLA levels in unknown potato chip samples. PMID- 21329355 TI - Mechanism of resistance of evolved glyphosate-resistant Palmer amaranth (Amaranthus palmeri). AB - Evolved glyphosate resistance in weedy species represents a challenge for the continued success and utility of glyphosate-resistant crops. Glyphosate functions by inhibiting the plant enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS). The resistance mechanism was determined in a population of glyphosate resistant Palmer amaranth from Georgia (U.S.). Within this population, glyphosate resistance correlates with increases in (a) genomic copy number of EPSPS, (b) expression of the EPSPS transcript, (c) EPSPS protein level, and (d) EPSPS enzymatic activity. Dose response results from the resistant and an F(2) population suggest that between 30 and 50 EPSPS genomic copies are necessary to survive glyphosate rates between 0.5 and 1.0 kg ha(-1). These results further confirm the role of EPSPS gene amplification in conferring glyphosate resistance in this population of Palmer amaranth. Questions remain related to how the EPSPS amplification initially occurred and the occurrence of this mechanism in other Palmer amaranth populations and other glyphosate-resistant species. PMID- 21329356 TI - Determination of roasted pistachio (Pistacia vera L.) key odorants by headspace solid-phase microextraction and gas chromatography-olfactometry. AB - Key odorants in roasted pistachio nuts have been determined for the first time. Two different pistachio varieties (Fandooghi and Kerman) have been analyzed by means of headspace solid-phase microextraction (HS-SPME) and gas chromatography olfactometry (GCO). The aroma extract dilution analyses (AEDA) applied have revealed 46 and 41 odor-active regions with a flavor dilution (FD) factor>=64 for the Fandooghi and the Kerman varieties, respectively, and 39 of them were related to precisely identified compounds. These included esters, pyrazines, aldehydes, acids, furans, and phenols. The results show that the Fandooghi variety presents, not only more odor-active regions but also higher FD factors than the Kerman variety that can lead to the conclusion that the first variety has a richer aromatic profile than the second one. The descriptive sensory analysis (DSA) showed that the roasted, chocolate/coffee, and nutty attributes were rated significantly higher in the Fandooghi variety, whereas the green attribute was significantly higher in the Kerman one. PMID- 21329357 TI - Finite size effect of proton-conductivity of amorphous silicate thin films based on mesoscopic fluctuation of glass network. AB - The finite size effect of proton conductivity of amorphous silicate thin films, a M(0.1)Si(0.9)O(x) (M = Al, Ga, Hf, Ti, Ta, and La), was investigated. The proton conductivity across films, sigma, was measured in dry air by changing the thickness in the range of 10-1000 nm. sigma of the films with M = Al, Ga, and Ta was elevated in a power law by decreasing thickness into less than a few hundred nanometers, and the increment was saturated at a thickness of several 10's of nanometers. On the other hand, sigma of the films with M = Hf, Ti, and La was not related to the decrease of the thickness in the range of >10 nm. Thickness dependent conductivity of the former could be numerically simulated by a percolative resistor network model that involves the randomly distributed array of two kinds of resistors R(1) and R(2) (R(1) > R(2)) in the form of a simple cubic-type lattice. High-resolution TEM clarified that a-M(0.1)Si(0.9)O(x) films involved heterogeneous microstructures made of the condensed domain and the surrounding uncondensed matrix due to the fluctuation of glass networks on the nanometer scale. The condensed domain had a wormlike shape with an average length of several 10's of nanometers and performed the role of the proton conduction pathway penetrating through the poorly conducting matrix. It was concluded that the thickness-dependent conductivity could be identical to finite-size scaling of the percolative network of the interconnected domains in the nanometer range. PMID- 21329358 TI - Berry polyphenols inhibit alpha-amylase in vitro: identifying active components in rowanberry and raspberry. AB - Polyphenol-rich extracts from a range of berries inhibited alpha-amylase in vitro, but the most effective were from raspberry and rowanberry (IC50 values of 21.0 and 4.5 MUg/mL, respectively). The inhibitory components were examined by different approaches. Extracts from yellow and red raspberries were equally able to inhibit alpha-amylase. Because the yellow raspberry extracts effectively lacked anthocyanins, this suggested that they were not crucial for amylase inhibition. Notably, however, higher levels of other phenolic components in yellow raspberries (particularly, ellagitannins) did not increase amylase inhibition. Amylase inhibition in rowanberry was recovered in a fraction enriched in proanthocyanidins (PACs). Inhibition was ameliorated by bovine serum albumin, suggesting that PACs acted by binding to amylase. Co-incubation of rowanberry PACs with acarbose reduced the concentration of acarbose required for effective amylase inhibition. Such synergistic interactions could have implications for the current clinical use of acarbose for postprandial glycaemic control in type-2 diabetics. PMID- 21329359 TI - Mechanism of ferripyoverdine uptake by Pseudomonas aeruginosa outer membrane transporter FpvA: no diffusion channel formed at any time during ferrisiderophore uptake. AB - To get access to iron, Pseudomonas aeruginosa produces the siderophore pyoverdine (PVD), composed of a fluorescent chromophore linked to an octapeptide, and its corresponding outer membrane transporter FpvA. This transporter is composed of three domains: a beta-barrel inserted into the membrane, a plug that closes the channel formed by the barrel, and a signaling domain in the periplasm. The plug and the signaling domain are separated by a sequence of five residues called the TonB box, which is necessary for the interaction of FpvA with the inner membrane TonB protein. Genetic deletion of the plug domain resulted in the presence of a beta-barrel in the outer membrane unable to bind and transport PVD-Fe. Expression of the soluble plug domain with the TonB box inhibited PVD-(55)Fe uptake most likely through interaction with TonB in the periplasm. A reconstituted FpvA in the bacterial outer membrane was obtained by the coexpression of separately encoded plug and beta-barrel domains, each endowed with a signal sequence and a signaling domain. This resulted in polypeptide complementation after secretion across the cytoplasmic membrane. The reconstituted FpvA bound PVD-Fe with the same affinity as wild-type FpvA, indicating that the resulting transporter is correctly folded and reconstituted in the outer membrane. PVD-Fe uptake was TonB dependent but 75% less efficient compared to wild-type FpvA. These data are consistent with a gated mechanism in which no open channel with a complete removal of the plug domain for PVD-Fe diffusion is formed in FpvA at any point during the uptake cycle. PMID- 21329360 TI - Synthesis and spectroscopic studies of the aminoglycoside (neomycin)--perylene conjugate binding to human telomeric DNA. AB - Synthesis of a novel perylene-neomycin conjugate (3) and the properties of its binding to human telomeric G-quadruplex DNA, 5'-d[AG3(T2AG3)3] (4), are reported. Various spectroscopic techniques were employed to characterize the binding of conjugate 3 to 4. A competition dialysis assay revealed that 3 preferentially binds to 4, in the presence of other nucleic acids, including DNA, RNA, DNA-RNA hybrids, and other higher-order structures (single strands, duplexes, triplexes, other G-quadruplexes, and the i-motif). UV thermal denaturation studies showed that thermal stabilization of 4 increases as a function of the increasing concentration of 3. The fluorescence intercalator displacement (FID) assay displayed a significantly tighter binding of 3 with 4 as compared to its parent constituents [220-fold stronger than neomycin (1) and 4.5-fold stronger than perylene diamine (2), respectively]. The binding of 3 with 4 resulted in pronounced changes in the molar ellipticity of the DNA absorption region as confirmed by circular dichroism. The UV-vis absorption studies of the binding of 3 to 4 resulted in a red shift in the spectrum of 3 as well as a marked hypochromic change in the perylene absorption region, suggesting that the ligand quadruplex interaction involves stacking of the perylene moiety. Docking studies suggest that the perylene moiety serves as a bridge that end stacks on 4, making contacts with two thymine bases in the loop, while the two neomycin moieties branch into the grooves of 4. PMID- 21329361 TI - A nanomolar-potency small molecule inhibitor of regulator of G-protein signaling proteins. AB - Regulators of G-protein signaling (RGS) proteins are potent negative modulators of signal transduction through G-protein-coupled receptors. They function by binding to activated (GTP-bound) Galpha subunits and accelerating the rate of GTP hydrolysis. Modulation of RGS activity by small molecules is an attractive mechanism for fine-tuning GPCR signaling for therapeutic and research purposes. Here we describe the pharmacologic properties and mechanism of action of CCG 50014, the most potent small molecule RGS inhibitor to date. It has an IC(50) for RGS4 of 30 nM and is >20-fold selective for RGS4 over other RGS proteins. CCG 50014 binds covalently to the RGS, forming an adduct on two cysteine residues located in an allosteric regulatory site. It is not a general cysteine alkylator as it does not inhibit activity of the cysteine protease papain at concentrations >3000-fold higher than those required to inhibit RGS4 function. It is also >1000 fold more potent as an RGS4 inhibitor than are the cysteine alkylators N ethylmaleimide and iodoacetamide. Analysis of the cysteine reactivity of the compound shows that compound binding to Cys(107) in RGS8 inhibits Galpha binding in a manner that can be reversed by cleavage of the compound-RGS disulfide bond. If the compound reacts with Cys(160) in RGS8, the adduct induces RGS denaturation, and activity cannot be restored by removal of the compound. The high potency and good selectivity of CCG-50014 make it a useful tool for studying the functional roles of RGS4. PMID- 21329362 TI - Inhibition of light-induced tautomerization of 7-azaindole by phenol: indications of proton-coupled electron/energy transfer quenching. AB - The photophysical behavior of a 1:1 complex between phenol and 7-azaindole (7AI) has been investigated in methylcyclohexane solutions at temperatures in the range of 27 to -50 degrees C. A linear Benesi-Hildebrand plot associated with changes in absorbance of the complex with phenol concentration in the solutions ensures 1:1 stoichiometry of the produced complex. Our estimate for the value of the association constant (K(a)) of the complex is ~120 M-1 at 27 degrees C, and it is nearly twice compared to that for 1:1 complex between 7AI and ethanol measured under the same condition. The complexation results in dramatic quenching of the normal fluorescence of 7AI and the process is accelerated upon lowering of temperature. The measured spectra show no indication that phenol promotes tautomerization of 7AI in the excited state. We have argued that the hydrogen bonding between pyridinic N and phenolic O-H (N...O-H) is a vital structural factor responsible for quenching of 7AI fluorescence, and this idea has been corroborated by showing that under same condition the fluorescence of 7AI is enhanced in the presence of anisole. As a plausible mechanism of quenching, we have invoked a proton-coupled electron transfer (PCET) process between phenol and excited 7AI, which outweighs the competing tautomerization process. An analysis in terms of Remm-Weller model reveals that the PCET process involving phenol and excited 7AI could be energetically favorable (DeltaG(ET)(0) < 0). An alternative mechanism, where quenching can occur via electronic energy transfer from the excited protonated 7AI to phenoxide ion, following a proton transfer along the N...O-H hydrogen bond, is also discussed. PMID- 21329363 TI - Rational approach to select small peptide molecular probes labeled with fluorescent cyanine dyes for in vivo optical imaging. AB - We demonstrate that the structure of carbocyanine dyes, which are commonly used to label small peptides for molecular imaging and not the bound peptide, controls the rate of extravasation from blood vessels to tissue. By examining several near infrared (NIR) carbocyanine fluorophores, we demonstrate a quantitative correlation between the binding of a dye to albumin, a model plasma protein, and the rate of extravasation of the probe into tissue. Binding of the dyes was measured by fluorescence quenching of the tryptophans in albumin and was found to be inversely proportional to the rate of extravasation. The rate of extravasation, determined by kurtosis from longitudinal imaging studies using rodent ear models, provided a basis for quantitative measurements. Structure activity studies aimed at evaluating a representative library of NIR fluorescent cyanine probes showed that hydrophilic dyes with binding constants several orders of magnitude lower than their hydrophobic counterparts have much faster extravasation rate, establishing a foundation for rational probe design. The correlation provides a guideline for dye selection in optical imaging and a method to verify if a certain dye is optimal for a specific molecular imaging application. PMID- 21329364 TI - Murine interleukin-3: structure, dynamics, and conformational heterogeneity in solution. AB - Interleukin-3 (IL-3), a cytokine produced primarily by activated T-cells during immune responses, is a crucial regulator of allergic inflammation. The three dimensional structure of murine IL-3 (mIL-3) has remained elusive owing to its poor solubility and strong tendency toward aggregation under solution conditions typically used for structural studies. Here we describe the solution properties and structure of mIL-3 determined by NMR using an engineered construct of mIL-3 (mIL-3(33-156)). mIL-3 adopts a four-helical bundle fold, typical of proteins belonging to the short-chain cytokine family, and features a core of highly conserved hydrophobic residues. While significant line broadening and peak disappearance were observed in NMR spectra at higher temperatures, there was no evidence for temperature-dependent changes of the oligomeric state of mIL-3(33 156). Further analysis of the temperature dependence of amide (1)H chemical shifts and backbone (15)N relaxation parameters, including (15)N relaxation dispersion, revealed the presence of significant conformational exchange and local conformational heterogeneity. Residues recently shown by mutagenesis to play key roles in beta(IL-3) receptor recognition and activation, which are located within the alpha(A) and alpha(C) helices and aligned on one face of the mIL-3(33-156) structure, are relatively rigid. In contrast, pronounced conformational heterogeneity was observed for a cluster of residues located on the opposite side of mIL-3, which corresponds spatially to sites in the related cytokines human IL-3, IL-5, and GM-CSF that are known to mediate interactions with their respective alpha-receptor subunits. Such conformational heterogeneity may facilitate the interaction of mIL-3 with each of two naturally occurring mIL 3Ralpha isoforms, leading to structurally distinct high-affinity complexes. PMID- 21329366 TI - Multinuclear olefin polymerization catalysts. PMID- 21329365 TI - Expanding coverage of the metabolome for global metabolite profiling. AB - Mass spectrometry-based metabolomics is the comprehensive study of naturally occurring small molecules collectively known as the metabolome. Given the vast structural diversity and chemical properties of endogenous metabolites, biological extraction and chromatography methods bias the number, property, and concentration of metabolites detected by mass spectrometry and creates a challenge for global untargeted studies. In this work, we used Escherichia coli bacterial cells to explore the influence of solvent polarity, temperature, and pH in extracting polar and nonpolar metabolites simultaneously. In addition, we explored chromatographic conditions involving different stationary and mobile phases that optimize the separation and ionization of endogenous metabolite extracts as well as a mixture of synthetic standards. Our results reveal that hot polar solvents are the most efficient in extracting both hydrophilic and hydrophobic metabolites simultaneously. In addition, ammonium fluoride in the mobile phase substantially improved ionization efficiency in negative electrospray ionization mode by an average increase in signal intensity of 5.7 and over a 2-fold increase in the total number of features detected. The improvement in sensitivity with ammonium fluoride resulted in 3.5 times as many metabolite hits in databases compared to ammonium acetate or formic acid enriched mobile phases and allowed for the identification of unique metabolites involved in fundamental cellular pathways. PMID- 21329367 TI - Study of the conformationally flexible, wide bite-angle diphosphine 4,6-bis(3 diisopropylphosphinophenyl)dibenzofuran in rhodium(I) and palladium(II) coordination complexes. AB - The diphosphine 4,6-bis(3-diisopropylphosphinophenyl)dibenzofuran (abbreviated as (iPr)DPDBFphos) was prepared and studied for its potential as a trans-chelating ligand in transition-metal coordination complexes. In the rhodium norbornadiene complex [((iPr)DPDBFphos)Rh(NBD)]BF(4), which has been characterized with multinuclear NMR spectroscopy, X-ray crystallography, and electrochemical studies, the ligand binds in cis fashion. In the bis(acetonitrile) complexes of rhodium and palladium [((iPr)DPDBFphos)M(CH(3)CN)(2)](BF(4))(n) (M = Rh, Pd; n = 1, 2), the ligand adopts a trans coordination geometry. Density functional theory (DFT, M06-L) calculations predict that the trans conformer is energetically more favorable than the cis by 3.5 kcal/mol. Cyclic voltammograms of the bis(acetonitrile) Pd(II) and Rh(I) complexes contain reversible and quasi reversible reduction events, respectively, which are preliminarily assigned as metal-based redox reactions. PMID- 21329369 TI - Conferment of folding ability to a naturally unfolded apocytochrome c through introduction of hydrophobic amino acid residues. AB - Hyperthermophilic Aquifex aeolicus cytochrome c(555) (AA c(555)) exceptionally folds even in the apo state, unlike general cytochromes c including mesophilic Pseudomonas aeruginosa cytochrome c(551) (PA c(551)), which is structurally homologous to AA c(555) in the holo state. Here we hypothesized that the exceptional apo AA c(555) folding can be attributed to nine hydrophobic amino acid residues and proved this using a PA c(551) variant (denoted as PA-nh) carrying the nine hydrophobic residues at structurally corresponding positions. Circular dichroism experiments showed that the apo PA-nh variant became folded, unlike the wild-type apo PA c(551), and exhibited much higher stability than the wild type. Another difference between the holo forms of AA c(555) and PA c(551) is the existence of an extra helix in the former. Introduction of the amino acid residues forming the extra helix of AA c(555) into the PA-nh variant did not significantly affect its folding ability in the apo state. Therefore, the nine hydrophobic residues introduced into the apo PA-nh variant were enough to confer the folding ability. PA c(551) represents the first example of the conversion of an intrinsically unfolded apocytochrome c into an autonomously folded one, which was revealed by means of a protein engineering method without heme. Although heme is generally considered to be a trigger of apocytochrome c folding, the present results demonstrate a new heme-independent folding mechanism. PMID- 21329368 TI - "Sticky" and "promiscuous", the yin and yang of apolipoprotein A-I termini in discoidal high-density lipoproteins: a combined computational-experimental approach. AB - Apolipoprotein (apo) A-I-containing lipoproteins in the form of high-density lipoproteins (HDL) are inversely correlated with atherosclerosis. Because HDL is a soft form of condensed matter easily deformable by thermal fluctuations, the molecular mechanisms for HDL remodeling are not well understood. A promising approach to understanding HDL structure and dynamics is molecular dynamics (MD). In the present study, two computational strategies, MD simulated annealing (MDSA) and MD temperature jump, were combined with experimental particle reconstitution to explore molecular mechanisms for phospholipid- (PL-) rich HDL particle remodeling. The N-terminal domains of full-length apoA-I were shown to be "sticky", acting as a molecular latch largely driven by salt bridges, until, at a critical threshold of particle size, the associated domains released to expose extensive hydrocarbon regions of the PL to solvent. The "sticky" N-termini also associate with other apoA-I domains, perhaps being involved in N-terminal loops suggested by other laboratories. Alternatively, the overlapping helix 10 C terminal domains of apoA-I were observed to be extremely mobile or "promiscuous", transiently exposing limited hydrocarbon regions of PL. Based upon these models and reconstitution studies, we propose that separation of the N-terminal domains, as particles exceed a critical size, triggers fusion between particles or between particles and membranes, while the C-terminal domains of apoA-I drive the exchange of polar lipids down concentration gradients between particles. This hypothesis has significant biological relevance since lipid exchange and particle remodeling are critically important processes during metabolism of HDL particles at every step in the antiatherogenic process of reverse cholesterol transport. PMID- 21329370 TI - High frequency vibrational modulations in two-dimensional electronic spectra and their resemblance to electronic coherence signatures. AB - In this work we analyze how nuclear coherences modulate diagonal and off-diagonal peaks in two-dimensional electronic spectroscopy. 2D electronic spectra of pinacyanol chloride are measured with 8 fs pulses, which allows coherent excitation of the 1300 cm(-1) vibrational mode. The 2D spectrum reveals both diagonal and off-diagonal peaks related to the vibrational mode. On early time scales, up to 30 fs, coherent dynamics give rise to oscillations in the amplitudes, positions, and shapes of the peaks in the 2D spectrum. We find an anticorrelation between the amplitude and the diagonal width of the two diagonal peaks. The measured data are reproduced with a model incorporating a high frequency mode coupled to an electronic two-level-system. Our results show that these anticorrelated oscillations occur for vibrational wavepackets and not exclusively for electronic coherences as has been assumed previously. PMID- 21329371 TI - Amino-functionalized SAPO-34 membranes for CO2/CH4 and CO2/N2 separation. AB - SAPO-34 seeds and membranes were functionalized with several organic amino cations, such as ethylenediamine, hexylamine, and octylamine. The successful incorporation of the amino groups in the SAPO-34 framework was confirmed by Fourier transform infrared (FTIR) and X-ray photoemission (XPS) spectroscopies. The resultant SAPO-34 membranes were evaluated for the separation of CO2/CH4 and CO2/N2 gas mixtures. CO2/CH4 selectivities as high as 245, with CO2 permeances of ~5 * 10(-7) mol m(-2) s(-1) Pa(-1) at 295K and 138 kPa, were observed for an optimum ethylenediamine-functionalized membrane, which corresponded to a ~40% increase in the separation index, as compared to the nonfunctionalized SAPO-34 membrane. Similarly, the CO2/N2 separation performance was highly improved with the incorporation of ethylenediamine. CO2/N2 selectivities as high as 39, with CO2 permeances of ~2.1 * 10(-7) mol m(-2) s(-1) Pa(-1) at 295K and 138 kPa, were observed for an optimum ethylenediamine-functionalized membrane, which corresponded to a ~167% increase in the separation index, as compared to the nonfunctionalized SAPO-34 membrane. PMID- 21329372 TI - Formation and transformation of the subgel phase in dioctadecyldimethylammonium bromide aqueous dispersions. AB - We have characterized the structure and phase behavior of dioctadecyldimethylammonium bromide (DODAB) aqueous dispersions by using conventional and high-sensitivity nano-differential scanning calorimetry, microscopy, cryogenic transmission electron microscopy, attenuated total reflection Fourier transform infrared spectroscopy, and electric conductivity measurements. Special attention has been paid to the formation and transformation of the subgel phase. An almost pure subgel can be obtained in the dilute region (below 7.5 mM), while an almost pure coagel phase can be obtained in the concentrated region (above 6.7 wt %). We found that unilamellar vesicles were spontaneously formed in the subgel phase of a 5 mM DODAB dispersion. Infrared spectroscopic data reveal that the only significant change during the gel to subgel phase transition is the ordering in the lipid alkyl chain packing. That is, the head and tail parts of the DODAB molecules change nonsynchronously upon the gel to subgel transition, and the subgel phase is triggered only by the change of the lipid tail part. We propose that the morphological change (from curled membranes in the gel phase to unilamellar vesicles with faceted surface in the subgel phase) is coupled to the change of alkyl chain packing state during the gel to subgel transition. Finally, a full picture of the phase transition sequences for the dilute and concentrated DODAB dispersions is given. PMID- 21329373 TI - Controlled templating of porphyrins by a molecular command layer. AB - The copper porphyrin (5,10,15,20-tetraundecylporphyrinato)copper(II) can be templated in a well-defined arrangement using p (hexadecyloxycarbonyl)phenylacetylene as a command layer on graphite. The bicomponent system was characterized at the submolecular level at a solid/liquid interface by scanning tunneling microscopy (STM). It is proposed that the layer of copper porphyrins is templated on top of the command layer in a hierarchical fashion, via a combination of intermolecular pi-pi stacking and van der Waals interactions. A very subtle effect, i.e., a superstructure in the alkyl chain region of the phenylacetylene monolayers, was identified as a decisive factor for the templating process. PMID- 21329374 TI - Ordered honeycomb microporous films from self-assembly of alkylated guanosine derivatives. AB - Ordered honeycomb microporous films have previously been fabricated from polymeric macromolecules. We report here the successful fabrication of them from the supramolecular self-assembly of small molecules, alkylated guanosine derivatives. The ribbonlike self-assembly of the guanosines in CHCl3 is found to be the intrinsic structure that forms regular microporous structure via Benard Maragoni convection. Factors such as substrate, solvents, guanosine concentration, and solvent evaporation temperature are revealed to be able to control the size of the formed micropores, which in turn allows for the wettability of the honeycomb film surface to be modulated. These microporous materials exhibit excellent ability of loading organic dyes that eventually leads to the fabrication of luminescent honeycomb films. As structures of both the small molecules that can assemble and their self-assemblies can be varied and controlled, extended applications of this supramolecular method are expected to lead to microporous films of interesting functions. PMID- 21329375 TI - Capping-ligand effect on the stability of CdSe quantum dot Langmuir monolayers. AB - The stability of Langmuir monolayers of CdSe Qdots capped with dodecan-ethiol (DDT), with dithiocarbamates having one, two, or three long alkyl chains (DTC-1, DTC-2 and DTC-3) or with tri-n-octylphosphine oxide (TOPO), was investigated and linked to the transport of Qdots into the subphase via a dissolution and diffusion mechanism. Langmuir films of Qdots were created by depositing droplets of purified Qdots in chloroform at the air-water interface. While holding the Qdot films at 13 mN/m for 1 h in a Langmuir trough, the average monolayer areas decreased by roughly 9% for TOPO-capped Qdots, ~15-18% for the three DTC-capped Qdot preparations, and ~21% for DDT-capped Qdots. Using the model of Ter Minassian-Saraga, the relative stabilities of the Qdot films studied were related to differences in equilibrium partitioning into the subphase and to apparent Qdot diffusivities within the subphase. An analysis of the Qdot preparations by Fourier-transform infrared spectroscopy (FTIR) revealed that the aliphatic tails of capping ligands were assembled on Qdot surfaces with similar packing densities for all ligand chemistries. A combined analysis of the film-area contraction and FTIR data suggested that, for the chemistries examined in this study, both the capping-ligand headgroup and the aliphatic tail groups impact Qdot Langmuir film stability through their joint influence on nanoparticle wettability and the tendency to aggregate upon partitioning into the subphase. PMID- 21329377 TI - We are still alone! PMID- 21329376 TI - Proteomic analysis of acetaminophen-induced changes in mitochondrial protein expression using spectral counting. AB - Comparative proteomic analysis following treatment with acetaminophen (APAP) was performed on two different models of APAP-mediated hepatocellular injury in order to both identify common targets for adduct formation and track drug-induced changes in protein expression. Male C57BL/6 mice were used as a model for APAP mediated liver injury in vivo, and TAMH cells were used as a model for APAP mediated cytotoxicity in vitro. SEQUEST was unable to identify the precise location of sites of adduction following treatment with APAP in either system. However, semiquantitative analysis of the proteomic data sets using spectral counting revealed a downregulation of P450 isoforms associated with APAP bioactivation and an upregulation of proteins related to the electron transport chain by APAP compared to the control. Both mechanisms are likely compensatory in nature as decreased P450 expression is likely to attenuate toxicity associated with N-acetyl-p-quinoneimine (NAPQI) formation, whereas APAP-induced electron transport chain component upregulation may be an attempt to promote cellular bioenergetics. PMID- 21329384 TI - Multiple reaction monitoring assay for pre-eclampsia related calcyclin peptides in formalin fixed paraffin embedded placenta. AB - Although the cause of pre-eclampsia during pregnancy has not been elucidated yet, it is evident that placental and maternal endothelial dysfunction is involved. We previously demonstrated that in early onset pre-eclampsia placental calcyclin (S100A6) expression is significantly higher compared to controls ( De Groot , C. J. ; Clin. Proteomics 2007 , 1 , 325 ). In the current study, the results were confirmed and relatively quantified by using multiple reaction monitoring (MRM) on two peptide fragments of calcyclin. Cells were obtained from control (n = 5) and pre-eclamptic placental (n = 5) tissue collected by laser capture microdissection from formalin-fixed paraffin-embedded (FFPE) material treated with a solution to reverse formalin fixation. Two calcyclin peptides with an extra glycine inserted in the middle of the amino acid sequence were synthesized and used as an internal reference. Data presented show that MRM on laser microdissected material from FFPE tissue material is possible. The developed MRM assay to study quantitative levels of proteins in FFPE laser microdissected cells using nonisotopic-labeled chemical analogs of mass tagged internal references showed that in pre-eclamptic patients elevated levels of calcyclin is observed in placental trophoblast cells compared to normal trophoblast cells. By immunohistochemistry, we were able to confirm this observation in a qualitative manner. PMID- 21329385 TI - The consequences of kesterite equilibria for efficient solar cells. AB - Copper-zinc-tin-chalcogenide kesterites, Cu(2)ZnSnS(4) and Cu(2)ZnSnSe(4) (CZTS(e)) are ideal candidates for the production of thin film solar cells on large scales due to the high natural abundance of all constituents, a tunable direct band gap ranging from 1.0 to 1.5 eV, a large absorption coefficient, and demonstrated power conversion efficiencies close to 10%. However, Sn losses through desorption of SnS(e) from CZTS(e) at elevated temperatures (above 400 degrees C) impede the thorough control of film composition and film homogeneity. No robust and feasible fabrication process is currently available. Here we show that understanding the formation reaction of the kesterite absorber is the key to control the growth process and to drastically improve the solar cell efficiency. Furthermore, we demonstrate that this knowledge can be used to simplify the four dimensional parameter space (spanned by the four different elements) to an easy and robust two-dimensional process. Sufficiently high partial pressures of SnS(e) and S(e) (a) prevent the decomposition reaction of the CZTS(e) at elevated temperatures and (b) introduce any missing Sn into a Sn-deficient film. This finding enables us to simplify the precursor to a film containing only Cu and Zn, whereas Sn and S(e) are introduced from the gas phase by a self-regulating process. PMID- 21329386 TI - Spectral diffusion at the water/lipid interface revealed by two-dimensional fourth-order optical spectroscopy: a classical simulation study. AB - Using a classical simulation protocol for nonlinear optical signals, we predict the two-dimensional (2D) spectra of water near a monolayer of [1,2-dimytristoyl sn-glycero-3-phosphatidylcholine] (DMPC) generated by three IR probe pulses followed by one visible probe pulse. Sum-frequency-generation 1D spectra show two peaks of the OH stretch representing two environments: near-bulk water nonadjacent to DMPC and top-layer water adjacent to DMPC. These peaks create a 2D pattern in the fourth-order signal. The asymmetric cross-peak pattern with respect to the diagonal line is a signature of coherence transfer from the higher to the lower-frequency modes. The nodal lines in the imaginary part of the 2D spectrum show that the near-bulk water has fast spectral diffusion resembling that of bulk water despite the orientation by the strong electrostatic field of DMPC. The top-layer water has slower spectral diffusion. PMID- 21329387 TI - Thermodynamically controlled synthesis of a chiral tetra-cavitand nanocapsule and mechanism of enantiomerization. AB - The dynamic covalent synthesis, structure and conformational dynamics of a chiral polyimine nanocapsule 1a are reported. Reaction of four tetraformyl cavitands and eight H(2)N(CH(2))(2)NH(2) yields quantitatively 1a, which has a compact, asymmetrically folded, pseudo-C(2)-symmetric structure, as determined by X-ray crystallography, and encapsulates four CHCl(3) and three CH(3)OH guests in the solid state. In solution, 1a enantiomerizes by passing over a barrier of DeltaG(298)(double dagger) = 21.5 +/- 0.7 kcal mol(-1) via a refolding process. PMID- 21329388 TI - Palladium(I)-bridging allyl dimers for the catalytic functionalization of CO2. AB - In general, the chemistry of both eta(1)-allyl and eta(3)-allyl Pd complexes is extremely well understood; eta(1)-allyls are nucleophilic and react with electrophiles, whereas eta(3)-allyls are electrophilic and react with nucleophiles. In contrast, relatively little is known about the chemistry of metal complexes with bridging allyl ligands. In this work, we describe a more efficient synthetic methodology for the preparation of Pd(I)-bridging allyl dimers and report the first studies of their stoichiometric reactivity. Furthermore, we show that these compounds can activate CO(2) and that an N heterocyclic carbene-supported dimer is one of the most active and stable catalysts reported to date for the carboxylation of allylstannanes and allylboranes with CO(2). PMID- 21329389 TI - Photocatalytic generation of a non-heme oxoiron(IV) complex with water as an oxygen source. AB - The photocatalytic formation of a non-heme oxoiron(IV) complex, [(N4Py)Fe(IV)(O)](2+) [N4Py = N,N-bis(2-pyridylmethyl)-N-bis(2 pyridyl)methylamine], efficiently proceeds via electron transfer from the excited state of a ruthenium complex, [Ru(II)(bpy)(3)](2+)* (bpy = 2,2'-bipyridine) to [Co(III)(NH(3))(5)Cl](2+) and stepwise electron-transfer oxidation of [(N4Py)Fe(II)](2+) with 2 equiv of [Ru(III)(bpy)(3)](3+) and H(2)O as an oxygen source. The oxoiron(IV) complex was independently generated by both chemical oxidation of [(N4Py)Fe(II)](2+) with [Ru(III)(bpy)(3)](3+) and electrochemical oxidation of [(N4Py)Fe(II)](2+). PMID- 21329390 TI - Evaluation of androgenic activity of nutraceutical-derived steroids using mammalian and yeast in vitro androgen bioassays. AB - Androgenic steroids marketed online as nutraceuticals are a growing concern in sport doping. The inability of conventional mass spectrometry (MS)-based techniques to detect structurally novel androgens has led to the development of in vitro androgen bioassays to identify such designer androgens by their bioactivity. The objective of this study was to determine the androgenic bioactivity of novel steroidal compounds isolated from nutraceuticals using both yeast and mammalian cell-based androgen bioassays. We developed two new in vitro androgen bioassays by stably transfecting HEK293 and HuH7 cells with the human androgen receptor (hAR) expression plasmid together with a novel reporter gene vector (enhancer/ARE/SEAP). The yeast beta-galactosidase androgen bioassay was used for comparison. Our new bioassay featuring the enhancer/ARE/SEAP construct ( S) displayed simpler assay format and higher specificity with lower sensitivity compared with the commonly used mouse mammary tumour virus (MMTV)-luciferase. The relative potencies (RP), defined as [EC(50)] of testosterone/[EC(50)] of steroid, of nutraceutical extracts in the yeast, HEK293-S, and HuH7-S, were 34, 333, and 80,000 for Hemapolin; 208, 250, and 80 for Furazadrol; 0.38, 10, and 106 for Oxyguno; 2.7, 0.28, and 15 for Trena; and 4.5, 0.1, and 0.4 for Formadrol, respectively. The wide discrepancies in rank RP of these compounds was reconciled into a consistent potency ranking when the cells were treated with meclofenamic acid, a nonselective inhibitor of steroid metabolizing enzymes. These findings indicate that steroids extracted from nutraceuticals can be converted in vitro into more or less potent androgens in mammalian but not in yeast cells. We conclude that the putative androgenic bioactivity of a new compound may depend on the bioassay cellular format and that mammalian cell bioassays may have an added benefit in screening for proandrogens but sacrifice specificity for sensitivity in quantitation. PMID- 21329391 TI - MicroRNA profiling by simultaneous selective isotachophoresis and hybridization with molecular beacons. AB - We present and demonstrate a novel assay for the detection and quantification of microRNA (miRNA) that leverages isotachophoresis (ITP) and molecular beacon (MB) hybridization. We use ITP to selectively preconcentrate miRNA from total RNA. We simultaneously focus MBs and use the ITP zone as a 10 pL reactor with active mixing where MBs fluoresce upon hybridization to target miRNA. To increase both sensitivity and selectivity, we leverage a multistage ITP strategy composed of three discrete regions of different concentrations of denaturant, sieving matrix, and magnesium chloride. We show that ITP hybridization is specific and selective to the miRNA target. We demonstrate ITP hybridization of miRNA in a biologically relevant case by detecting and quantifying miR-122 in human kidney and liver. ITP hybridization is a cheap, simple, high-speed, and amplification-free miRNA profiling method which requires small amounts (order 100 ng) of sample. The technique therefore represents an attractive alternative to PCR or Northern blot for miRNAs. PMID- 21329392 TI - Insertion, isomerization, and cascade reactivity of the tethered silylalkyl uranium metallocene (eta(5)-C5Me4SiMe2CH2-kappaC)2U. AB - Investigation of the insertion reactivity of the tethered silylalkyl complex (eta(5)-C(5)Me(4)SiMe(2)CH(2)-kappaC)(2)U (1) has led to a series of new reactions for U-C bonds. Elemental sulfur reacts with 1 by inserting two sulfur atoms into each of the U-C bonds to form the bis(tethered alkyl disulfide) complex (eta(5):eta(2)-C(5)Me(4)SiMe(2)CH(2)S(2))(2)U (2). The bulky substrate N,N'-diisopropylcarbodiimide, (i)PrN?C?N(i)Pr, inserts into only one of the U-C bonds of 1 to produce the mixed-tether complex (eta(5)-C(5)Me(4)SiMe(2)CH(2) kappaC)U[eta(5)-C(5)Me(4)SiMe(2)CH(2)C((i)PrN)(2)-kappa(2)N,N'] (3). Carbon monoxide did not exclusively undergo a simple insertion into the U-C bond of 3 but instead formed {MU-[eta(5)-C(5)Me(4)SiMe(2)CH(2)C(?N(i)Pr)O kappa(2)O,N]U[OC(C(5)Me(4)SiMe(2)CH(2))CN((i)Pr)-kappa(2)O,N](2) (4) in a cascade of reactions that formally includes U-C bond cleavage, C-N bond cleavage of the amidinate ligand, alkyl or silyl migration, U-O, C-C, and C-N bond formations, and CO insertion. The reaction of 3 with isoelectronic tert-butyl isocyanide led to insertion of the substrate into the U-C bond, but with a rearrangement of the amidinate ligand binding mode from kappa(2) to kappa(1) to form [eta(5):eta(2) C(5)Me(4)SiMe(2)CH(2)C(?N(t)Bu)]U[eta(5)-C(5)Me(4)SiMe(2)CH(2)C(?N(i)Pr)N((i)Pr) kappaN] (5). The product of double insertion of (t)BuN=C into the U-C bonds of 1, namely [eta(5):eta(2)-C(5)Me(4)SiMe(2)CH(2)C(?N(t)Bu)](2)U (6), was found to undergo an unusual thermal rearrangement that formally involves C-H bond activation, C-C bond cleavage, and C-C bond coupling to form the first formimidoyl actinide complex, [eta(5):eta(5):eta(3) (t)BuNC(CH(2)SiMe(2)C(5)Me(4))(CHSiMe(2)C(5)Me(4))]U(eta(2)-HC?N(t)Bu) (7). PMID- 21329393 TI - A new family of 1D exchange biased heterometal single-molecule magnets: observation of pronounced quantum tunneling steps in the hysteresis loops of quasi-linear {Mn2Ni3} clusters. AB - First members of a new family of heterometallic Mn/Ni complexes [Mn(2)Ni(3)X(2)L(4)(LH)(2)(H(2)O)(2)] (X = Cl: 1; X = Br: 2) with the new ligand 2-{3-(2-hydroxyphenyl)-1H-pyrazol-1-yl}ethanol (H(2)L) have been synthesized, and single crystals obtained from CH(2)Cl(2) solutions have been characterized crystallographically. The molecular structures feature a quasi-linear Mn(III) Ni(II)-Ni(II)-Ni(II)-Mn(III) core with six-coordinate metal ions, where elongated axes of all the distorted octahedral coordination polyhedra are aligned parallel and are fixed with respect to each other by intramolecular hydrogen bonds. 1 and 2 exhibit quite strong ferromagnetic exchange interactions throughout (J(Mn-Ni) ~ 40 K (1) or 42 K (2); J(Ni-Ni) ~ 22 K (1) or 18 K (2)) that lead to an S(tot) = 7 ground state, and a sizable uniaxial magnetoanisotropy with D(mol) values -0.55 K (1) and -0.45 K (2). These values are directly derived also from frequency- and temperature-dependent high-field EPR spectra. Slow relaxation of the magnetization at low temperatures and single-molecule magnet (SMM) behavior are evident from frequency-dependent peaks in the out-of-phase ac susceptibilities and magnetization versus dc field measurements, with significant energy barriers to spin reversal U(eff) = 27 K (1) and 22 K (2). Pronounced quantum tunnelling steps are observed in the hysteresis loops of the temperature- and scan rate dependent magnetization data, but with the first relaxation step shifted above (1) or below (2) the zero crossing of the magnetic field, despite the very similar molecular structures. The different behavior of 1 and 2 is interpreted in terms of antiferromagnetic (1) or ferromagnetic (2) intermolecular interactions, which are discussed in view of the subtle differences of intermolecular contacts within the crystal lattice. PMID- 21329394 TI - High-throughput assay of oleopentanedialdheydes in extra virgin olive oil by the UHPLC-ESI-MS/MS and isotope dilution methods. AB - The quality of extra virgin olive oil is associated with the presence of microcomponents whose healing effects have been proved in some special cases. The enzymatic hydrolysis of oleuropein and ligstroside, and of their demethylated analogues, affords four different pentanedialdehydes, and for one of which, 2-(4 hydroxyphenyl)ethyl (3S,4E)-4-formyl-3-(2-oxoethyl)hex-4-enoate, also known as oleocanthal, an anti-inflammatory effect was quite recently carefully assessed. Extra virgin olive oil is now worldwide considered as a functional food whose daily intake, as for the Mediterranean diet, helps consumers in keeping a constant level of nonsteroidal anti-inflammatory drug (NSAID) in the blood. The presence of these active principles provides, therefore, olive oil with an important added value. In the framework of the actions of the recently funded Agrifood Regional Center, which should coordinate the scientific research and production worlds, an absolute analytical method was developed for the mass spectrometric detection of the two most abundant NSAIDs, Tyr-OLPD and HTyr-OLPD (oleopentanedialdehydes (OLPDs) conjugated to p-hydroxyphenylethanol and 3,4 dihydroxyphenylethanol, respectively), by UHPLC-ESI-MS/MS. PMID- 21329395 TI - Reaction of aminodihydropentalenes with HB(C6F5)2: the crucial role of dihydrogen elimination. AB - The aminodihydropentalene derivative 1a reacts with the Lewis acidic RB(C(6)F(5))(2) boranes (2a-c) by C-C bond cleavage to yield the formal borylene insertion products 3. In contrast, 1a,b react with HB(C(6)F(5))(2) at 55 degrees C by elimination of dihydrogen to yield the iminium-stabilized zwitterionic heterofulvenes 10a,b. The reaction pathways were studied by preparation of the kinetically controlled intermediates 7a,b and the thermodynamically controlled products 9a,b, monitored by variable-temperature NMR experiments, and supported by DFT calculations. The trapping reactions of 9a with HCl and PhCHO, respectively, led to the addition products 13 and 14. Compounds 3c, 7a,b, 10a,b, 11, 13, and 14 were characterized by X-ray diffraction. PMID- 21329396 TI - Mechanistic model to understand in vivo salt release and perception during the consumption of dairy gels. AB - The objective of this study was to develop a model to simulate salt release during eating. Salt release kinetics during eating was measured for four model dairy products with different dynamic salty perceptions. A simple in vivo model of salt release was developed to differentiate between the contribution of the individual and of the product to salt release. The most difficult model parameter to determine or predict is the evolution of the contact area between the product and the saliva. Fitting the model to the experimental data showed that the subject's masticatory performance and fracture initiation energy of the product determined the contact area between the product and the saliva generated by mastication. Finally, the role of release dynamics on sensory time-intensity profiles is discussed. PMID- 21329397 TI - Particle-stabilizing effects of flavonoids at the oil-water interface. AB - It has been shown that some common food flavonoids can act as excellent stabilizers of oil-in-water emulsions through their adsorption as water-insoluble particles to the surface of the oil droplets, i.e., Pickering emulsions are formed. Flavonoids covering a wide range of octanol-water partition coefficients (P) were screened for emulsification behavior by low shear mixing of flavonoid+n tetradecane in a vortex mixer. Most flavonoids with very high or very low P values were not good emulsifiers, although there were exceptions, such as tiliroside, which is very insoluble in water. When a high shear jet homogenizer was used with 20 vol% oil in the presence of 1 mM tiliroside, rutin, or naringin, much finer emulsions were produced: the average droplet sizes (d32) were 16, 6, and 5 MUm, respectively. These results may be highly significant with respect to the delivery of such insoluble compounds to the gut, as well as their digestion and absorption. PMID- 21329398 TI - Application of FT-MIR spectroscopy for fast control of red grape phenolic ripening. AB - The content of phenolic compounds determines the state of phenolic ripening of red grapes and is a key criterion in setting the harvest date to produce quality red wines. In this study, the feasibility of Fourier transform mid-infrared (FT MIR) spectroscopy combined with partial least-squares (PLS) regression to quantify phenolic compounds is reported. The reference methods used for quantifying these compounds (which were evaluated as total phenolic compounds, total anthocyanins, and condensed tannins) were the usual ones used in cellars that employed UV-vis spectroscopy. To take into account the high natural variability of grapes when building the calibration models, fresh grapes from six varieties, at different phenolic ripening states were harvested during three vintages. Destemmed and crushed grapes were subjected to an accelerated extraction process and used as calibration standards. A total of 192 extracts (objects) were obtained, and these were divided into a training set (106 objects) and a test set (86 objects) to evaluate the predictive ability of the models. Among the different MIR regions of the extract raw spectra, those that provided the highest variability on the absorption were selected. The results showed that the best PLS regression model was the one obtained when working in the region of 1168-1457 cm(-1) because it gave the most accurate and robust prediction for total phenolic compounds (RMSEP%=4.3 and RPD=4.5), total anthocyanins (RMSEP%=5.9 and RPD=3.5), and condensed tannins (RMSEP%=5.8 and RPD=3.8). Therefore, it can be concluded that FT-MIR spectroscopy can be a fast and reliable technique for monitoring the phenolic ripening in red grapes during the harvest period. PMID- 21329399 TI - Optimal pharmacotherapeutic management of chronic lymphocytic leukaemia: considerations in the elderly. AB - Although the majority of patients with chronic lymphocytic leukaemia (CLL) are of advanced age, these patients have not been well represented in past clinical trials. This has resulted in a lack of evidence that has complicated treatment in this patient group. However, data from an increasing number of subgroup analyses of recent trials as well as from trials specifically designed for elderly patients with CLL have provided some insight into the feasibility of the available treatments, thus allowing development of the first evidence-based recommendations for the pharmacotherapeutic management of these patients. Physically fit patients without significant co-morbidity are likely to benefit from the standard treatment of fludarabine, cyclophosphamide and rituximab (FCR). However, whether treatment with purine analogues and/or CD20 antibodies is also beneficial in physically unfit patients suffering from additional health problems remains to be determined. Latest data suggest that the alkylating drug chlorambucil rather than fludarabine is a reasonable chemotherapeutic backbone for chemoimmunotherapy in these patients. Trials are now underway to investigate combinations of chlorambucil with rituximab or with novel CD20 antibodies (GA101 [afutuzumab], ofatumumab) in older CLL patients. In parallel, other regimens, including bendamustine or lenalidomide with or without the addition of rituximab, low-dose fludarabine and low-dose FCR, hold promise in elderly patients with previously untreated or relapsed CLL. PMID- 21329400 TI - Use of low-molecular-weight heparins and new anticoagulants in elderly patients with renal impairment. AB - Elderly people with renal impairment are at high risk for venous thromboembolism (VTE) and acute coronary syndromes (ACS); however, they are also at increased risk for bleeding complications. Evidence-based data for the management of anticoagulation in elderly patients with severe renal impairment, in particular, are limited. These patients are frequently excluded from randomized clinical trials evaluating anticoagulants, confounding clinical decision making. Low molecular-weight heparins (LMWHs), such as enoxaparin sodium and dalteparin sodium, provide a predictable anticoagulant effect across almost all patient populations; however, because they are primarily eliminated through the kidneys, elderly patients with moderate or severe renal impairment are potentially at risk for LMWH accumulation. Clinical evidence suggests that treatment with full-dose enoxaparin sodium could increase the risk for bleeding in elderly patients with severe renal impairment; however, this risk is ameliorated with approved dose adjustments. Dalteparin sodium has been evaluated in small studies within this population but no strategy for reduced dosing has been developed. There are limited clinical data on the use of fondaparinux sodium and, in particular, the new anticoagulants, such as dabigatran etexilate and rivaroxaban, in elderly patients with renal impairment. Evidence suggests that the clearance of fondaparinux sodium is mildly reduced in elderly patients, and more substantially reduced in patients with severe renal impairment; a dose reduction has recently been approved in Europe. Age and renal function appear to affect the exposure of dabigatran etexilate. A dose reduction is recommended in the elderly and in those with moderate renal function, but dabigatran etexilate is contraindicated in severe renal impairment. Rivaroxaban has been associated with increased exposure and pharmacodynamic effects in the elderly and those with renal impairment; at present there is no facility for dose reduction. Monitoring anticoagulant activity may help improve the safety profile of anticoagulants in elderly patients with renal impairment, particularly when approved dose reductions are unavailable. However, unlike the LMWHs, clinical surveillance of the new anticoagulants is challenging. In conclusion, extra care should be taken when anticoagulants are administered to elderly patients with renal impairment. Additional data are needed, particularly for the new anticoagulants, in order to guide the prevention and treatment of VTE and ACS, and to ensure the optimal safety profile in older patients with renal impairment. PMID- 21329401 TI - Effects of anticholinergic drugs on verbal episodic memory function in the elderly: a retrospective, cross-sectional study. AB - BACKGROUND: An increasing number of medications that are frequently prescribed to elderly patients have been identified as having weak but definite anticholinergic properties. Few epidemiological studies have evaluated the impact of these drugs on verbal episodic memory using sensitive and specific neuropsychological testing in an elderly population presenting with cognitive impairment. OBJECTIVES: The aim of this study was to assess the effect of drugs with anticholinergic properties on verbal episodic memory function in elderly patients presenting for memory evaluation. STUDY DESIGN: We performed a retrospective, cross-sectional study that included 134 consecutive elderly outpatients who attended the daycare memory unit of Centre Hospitalier Sud, Lyon, France. We searched the MEDLINE database (1973-2008) to identify drugs with anticholinergic properties. All drugs with well known anticholinergic activity, mild reported anticholinergic effects or in vitro anticholinergic activity were included in the study. MEASUREMENTS: We used the Free and Cued Selective Reminding (FCSR) test to evaluate verbal episodic memory. RESULTS: The mean +/- SD number of drugs with anticholinergic properties taken by the subjects was 0.64 +/- 0.82. Fifty percent of the subjects (n = 67) had a prescription for at least one drug with anticholinergic properties and 16% (n = 21) had a prescription for two or more. Drugs with anticholinergic properties most frequently prescribed in our cohort were cardiovascular (furosemide, hydrochlorothiazide, digoxin), antidepressant (paroxetine, sertraline, fluoxetine) and antispasmodic (oxybutynin chloride) drugs. The number of drugs with anticholinergic properties that subjects were taking was associated with reduced performance on tasks that assessed verbal memory (p < 0.05). Neuropsychological test batteries revealed a significant unfavourable effect of use of drugs with anticholinergic activity on episodic verbal memory. Tests evaluating other cognitive functions were not affected by use of drugs with anticholinergic activity. These associations remained following multivariate analysis adjusting for age, sex, education level, number of anticholinergic drugs, number of co-morbidities, diagnosis, behavioural symptoms and depressive symptoms. CONCLUSION: Clinicians should assess the current use of drugs with anticholinergic properties in the elderly, particularly in patients presenting for memory evaluation. In such cases, use of other therapeutic alternatives should be considered. PMID- 21329402 TI - Potentially inappropriate medication use among Finnish non-institutionalized people aged >=65 years: a register-based, cross-sectional, national study. AB - BACKGROUND: The Beers criteria and their modifications are the most frequently used tools for measuring potentially inappropriate medication (PIM) use among older people. The prevalence of such use in various settings has been high, but no data have been reported for an entire national non-institutionalized elderly population, nor is there information on the reimbursement costs for those medications. OBJECTIVE: To determine the prevalence of PIM use according to the Beers 2003 criteria, independent of diagnoses, among Finnish non institutionalized people aged >=65 years, and the reimbursement costs for these medications. METHODS: A register-based cross-sectional national study used drug reimbursement data from Finland's Social Insurance Institution (SII). These data cover the entire non-institutionalized population aged >=65 years in 2007. The number of persons who received reimbursements for each PIM according to the Beers 2003 criteria and the total annual reimbursement costs for PIMs were calculated. Indirect costs were excluded. RESULTS: Of the non-institutionalized population aged >=65 years in Finland (n = 841,509), 14.7% (n = 123,545) had received PIMs according to the Beers 2003 criteria. Temazepam >15 mg/day was clearly the most commonly reimbursed PIM (4.4% of the population aged >=65 years), followed by amitriptyline (2.0%) and diazepam (1.8%). The SII paid drug reimbursements of ?2.9 million for PIMs, which was 0.7% of the total drug reimbursements (?421 million) for people aged >=65 years in Finland in 2007. CONCLUSIONS: The use of PIMs among outpatients aged >=65 years in Finland (14.7%) was less than in several earlier large-scale studies in other countries (17-42%) and reimbursement costs were modest, mainly as a result of the limited availability in Finland of medicines identified as PIMs by the Beers 2003 criteria. However, benzodiazepines were commonly used and actions to improve medication safety should target reducing their use. PMID- 21329403 TI - Naproxen/esomeprazole fixed-dose combination: for the treatment of arthritic symptoms and to reduce the risk of gastric ulcers. AB - Naproxen/esomeprazole is a fixed-dose combination of the NSAID naproxen and the proton pump inhibitor esomeprazole. In two well designed, 12-week studies, naproxen/esomeprazole fixed-dose combination was noninferior to celecoxib in treating the signs and symptoms of disease in patients with osteoarthritis of the knee, as assessed by the mean change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index pain and function scores and Patient Global Assessment scores (coprimary endpoints). Two other studies showed that the cumulative incidence of gastric ulcers (primary efficacy measure) was significantly lower with naproxen/esomeprazole than with enteric-coated naproxen alone during up to 6 months' therapy in patients with osteoarthritis, rheumatoid arthritis, ankylosing spondylitis or any other condition requiring daily NSAID therapy. The fixed-dose combination was generally well tolerated in these studies, with an upper gastrointestinal tolerability profile generally better than that of naproxen and similar to that of celecoxib. PMID- 21329405 TI - Delivering for aphasia. AB - Providing a quality service for people with aphasia is a primary goal of speech language pathologists working with neurogenic communication disorders. This paper reviews what is known about the incidence and prevalence of aphasia and what services are provided for people with aphasia. On the basis of the stroke data, the incidence of aphasia in the developed world ranges between 0.02-0.06% with prevalence ranging between 0.1-0.4%. Average hours of treatment for aphasic people in the developed world ranges between 1-5 hours per week, with a great deal of variability, although recent research suggests that intense treatment of ~9 hours per week over a relatively short period is needed in order to be effective. It is concluded that there is a significant gap between what the research suggests is the appropriate amount of treatment and actual provision throughout the English-speaking world. PMID- 21329404 TI - What works? PMID- 21329406 TI - Rethinking aphasia therapy: a neuroscience perspective. AB - This article explores how consideration of acquired speech and language disorders from the perspective of neuroscience permits new insights into the content and design of therapy for people with aphasia. Key proposals are that aspects of current therapies often neglect the sensory-motor components of speech and language processing, and the interconnectivity of sensory-perceptual and motor systems. Furthermore, current therapy regimes are often administered at too low an intensity to stimulate neural reorganization. Neuroscientific perspectives on learning are explored and in particular the issues of associationist learning, learned misuse, mirror neurone systems, and procedural and errorless learning. The value of use of computer programs in administering high intensity therapy is outlined and it is proposed that aphasia therapies can be enhanced if clinicians adopt an explicit neuroscientific rationale for intervention. PMID- 21329407 TI - Aphasia rehabilitation and the role of computer technology: can we keep up with modern times? AB - Numerous computer applications have been developed specifically for aphasia rehabilitation. In this paper, the role of these computer programs is discussed in relation to three complementary treatment approaches in aphasia rehabilitation: disorder-oriented treatment, functional treatment, and participation-oriented treatment. Most of the programs available focus on disorder-oriented treatment and several studies have reported a beneficial effect on language skills. Nowadays, in the context of disorder-oriented treatment, these applications are indispensible to achieve an adequate treatment frequency of at least 2 hours per week. Computer applications aiming at functional and social participation goals are less well-developed. Several studies show that high-technology AAC can be used to support off-line communication. Moreover, it is reported that the AAC training has a positive effect on overall communicative functioning. In the near future, computer applications for interactive communicative training may become an important tool in aphasia rehabilitation. Theoretically, the internet offers excellent opportunities to improve social participation for people with aphasia, but reading and writing problems limit their access to the internet. So far, only a few initiatives have been reported to support and increase their access. PMID- 21329408 TI - Physiological investigation of dysarthria: recent advances. AB - Recent years have seen the development and introduction of a range of new physiological instruments for investigating various aspects of articulatory function in persons with dysarthria. Included among these techniques are electromagnetic articulography (EMA), electropalatography (EPG), and pressure sensing EPG. The aim of this paper is to describe and evaluate these techniques, highlighting their relative advantages, disadvantages, and specific applications in assessing articulation in speakers with dysarthria associated with a variety of neurological disorders. Emphasis will be given to those instruments that enable researchers and clinicians to examine articulatory functions in 3 dimensions, such as 3D-EMA (AG500) and 3D-EPG. In addition the application of pressure-sensing EPG and ultrasonography will be outlined. Each of these physiological techniques will be fully described in terms of their component hardware and underlying principles of operation. The use of each technique in the assessment of dysarthria will be illustrated wherever possible by reference to specific case examples, and especially cases drawn from various neuropathological groups. Research findings reported to date based on each of the above physiological instruments will be reviewed and the research summarized. PMID- 21329409 TI - Therapy outcome measures: where are we now? AB - Outcomes information contributes to the provision of quality services: sharing that information requires speech-language pathologists (SLPs) to use terminology readily understood by professions ranging from health and education to social and voluntary services. The Therapy Outcome Measure (TOM) provides a way of presenting outcome data in a digestible form, comprising part of a range of multiple measures used to collect information on the structures, processes, and outcomes of care. TOM was developed to provide a practical method of measuring outcomes in routine clinical practice. Furthermore, it has been used in a number of research studies as an outcome indicator. As an example of its utility in research, the article cites a benchmarking study, together with examples of internal and external benchmarking of outcomes intended to illustrate how the benchmarking of TOM data can inform practice. The TOM can therefore inform SLPs on their own outcomes, the outcomes for specific client groups, and, by benchmarking TOM data, can contribute to the delivery of better, more efficient services. PMID- 21329410 TI - Evidence, expertise, and patient preference in speech-language pathology. AB - A consideration of evidence-based practice has led many to debate the nature of evidence. Rejecting the idea that randomized controlled trials should be the only legitimate source of evidence, writers have argued that other types of research and knowledge should be considered legitimate sources of evidence. This paper suggests that one should draw on systematic research, including qualitative research, for evidence, and that other types of knowledge such as craft and practice knowledge are part of the profession's expertise. This paper argues that evidence and expertise are both required for evidence-based practice to occur. Finally, a consideration of patients' values and expectations is explored as a third component of evidence-based practice. The paper argues that all three components are necessary for evidence-based practice. PMID- 21329411 TI - Assessing methodological quality of randomized and quasi-experimental trials: a summary of stuttering treatment research. AB - The purpose of this study is to provide a detailed analysis of the methodological quality of experimental and quasi-experimental group designed studies in the area of stuttering intervention. A total of 23 randomized controlled trials (RCT) and quasi-experimental studies of treatment in the area of stuttering were identified and retrieved from an electronic search of nine databases and 13 individual journals. Using the Downs and Black Checklist each study was coded for reporting, external validity, internal validity, and internal validity confounding. Results of the coding indicated that while overall reporting was reasonably complete, the quality of the external and internal validity scores was found to be substantively incomplete. This lack of clarity and completeness of reporting issues related to the external and internal validity makes the interpretation of the findings of individual study results problematic and seriously effects the replicability of the individual study. Implications of these findings are suggested for both researchers and clinicians. PMID- 21329412 TI - Lost in translation? Issues of content validity in interpreter-mediated aphasia assessments. AB - In many parts of the world, speech-language pathologists (SLPs) are frequently called upon to assess aphasia in bilingual speakers, or in speakers of languages of which they have little or no knowledge. One of the strategies that SLPs employ in these situations is to involve an interpreter in the assessment process. Three authentic interpreter-mediated aphasia assessments were analysed for the present study, which aimed to determine the degree to which the content validity of the individual tests was compromised in the process of their administration through an interpreter. Findings reveal that content validity was frequently weakened either at the point of administration of the test or at the point at which responses were reported back by the interpreter to the SLP. Based on these findings, it is argued that the conduct of interpreter-mediated aphasia assessments needs to be fundamentally re-thought to take account of the limitations inherent in the interpreting process. To this end, this study presents a number of practical recommendations for the involvement of interpreters in aphasia assessments, with a view to making optimal use of existing assessment materials and enhancing the quality of diagnostic information to emerge from such clinical sessions. PMID- 21329413 TI - Interaction-focused intervention for acquired language disorders: facilitating mutual adaptation in couples where one partner has aphasia. AB - This paper discusses the implementation and evaluation of an interaction-focused intervention single case study for a couple where one partner has aphasia. Drawing on conversation analytic research, naturally occurring conversations of the couple at home pre- and post-intervention were collected and analysed. Analysis of the speaker with aphasia's topic initiating turns in the pre intervention conversation showed that in each case a feature of the attempt was that the speaker had difficulty in getting the topic initiation accepted and established. Drawing on conversation analytic work on topic initiations in normal conversation, intervention focused on training the couple to co-produce these topic initiating turns of the speaker with aphasia in a collaborative and step-by step manner. Post-intervention, there was evidence that the couple were now using this new method, albeit in a slightly different way to that worked on in the intervention sessions. Drawing on work into adaptation by speakers with aphasia and their conversation partners, these results are discussed in terms of a process of mutual adaptation by the couple. PMID- 21329415 TI - Compilation of cost-effectiveness evidence for different heart conditions and treatment strategies. AB - OBJECTIVES: Despite the continuing interest in health economic research, we could find no accessible data set on cost-effectiveness, useful as practical information to decision makers who must allocate scarce resources within the cardiovascular field. The aim of this paper was to present cost-effectiveness ratios, based on a systematic literature search for the treatment of heart diseases. DESIGN: A comprehensive literature search on cost-effectiveness analyses of intervention strategies for the treatment of heart diseases was conducted. We compiled available cost-effectiveness ratios for different heart conditions and treatment strategies, in a cost-effectiveness ranking table. The cost-effectiveness ratios were expressed as a cost per quality adjusted life year (QALY) or life year gained. RESULTS: Cost-effectiveness ratios, ranging from dominant to those costing more than 1,000,000 Euros per QALY gained, and bibliographic references are provided for. The table was categorized according to disease group, making the ranking table readily available. CONCLUSIONS: Cost effectiveness ranking tables provide a means of presenting cost-effectiveness evidence. They provide valid information within a limited space aiding decision makers on the allocation of health care resources. This paper represents an extensive compilation of health economic evidence for the treatment of heart diseases. PMID- 21329416 TI - A no-reflow prediction model in patients with ST-elevation acute myocardial infarction and primary drug-eluting stenting. AB - OBJECTIVES: This study was undertaken to assess independent no-reflow predictors in patients with ST-elevation acute myocardial infarction (STEMI) and primary drug-eluting stenting in the current interventional strategies. DESIGN: One thousand four hundred and thirteen patients with STEMI were successfully treated with primary drug-eluting stenting within 12 h after AMI. All clinical, angiographic and procedural data were collected. Univariate and multivariate logistic regression was used to identify independent no-reflow predictors. RESULTS: The no-reflow was found in 297 (21%) of 1413 patients. Univariate and multivariate logistic regression identified that age (>65 years, OR 1.47, 95% CI 1.46-1.49; p = 0.007), long time-to-reperfusion (>6 h, OR 1.27, 95% CI 1.16-1.40; p = 0.001), admission plasma glucose (>13.0 mmol/L, OR 1.27, 95% CI 1.16-1.40; p = 0.027), collateral circulation (0-1, OR 1.69, 95% CI 1.25-2.29; p = 0.001), pre PCI thrombus score (>=4, OR 1.36, 95% CI 1.16-1.79; p = 0.011), and IABP use before PCI (OR 2.89, 95% CI 1.65-5.05; p < 0.0001) were independent no-reflow predictors. The no-reflow rate significantly increased as the number of independent predictors increased (0%, 6%, 15%, 25%, 40%, 50% and 100% in patients with 0, 1, 2, 3, 4, 5, and 6 independent predictors, respectively; p < 0.0001). CONCLUSIONS: The prediction model consisted of six no-reflow predictors in patients with STEMI and primary drug-eluting stenting and should be confirmed in large-scale prospective studies. PMID- 21329418 TI - Smoking during pregnancy and postpartum among Tunisian women. AB - OBJECTIVE: The validity of self-reported smoking in population surveys remains an important question yet to be answered. This has been of particular concern in a situation where there is a strong social pressure against pregnant and postpartum women. An associated question is what would be the value of measuring urinary cotinine concentrations in such surveys to obtain validated smoking data. METHODS: Cross-sectional analysis of data on self-reported smoking and urinary cotinine among a sample of 398 pregnant women and recently pregnant, mothers of infants under the age of 2 months, who came to the Family Planning Clinic in Tunis urban area for either prenatal or newborn care. We used quantitative colorimetric urine test based on the konig reaction, in which pink-red chromophores formed from nicotine and its metabolites condensation with barbituric acid were extracted into acetate buffer. RESULTS: The smoking prevalence among Tunisian pregnant women or mothers of newborn infants was 4%. The validity of self-reported daily smoking was relatively low. Among women reporting no smoking at the interview 16% misreported active smoking. According to urinary cotinine values, the smoking prevalence was 18.8%. CONCLUSIONS: These results substantiate the unreliability of self-report on smoking status among women in prenatal and postnatal period and have implications in clinical and education practice. PMID- 21329419 TI - Effect of ethinylestradiol/cyproterone acetate on endothelial function in young non-obese women with polycystic ovary syndrome: a pilot study. AB - BACKGROUND: Combined oral contraceptives are used in polycystic ovary syndrome (PCOS) women for the treatment of hyperandrogenism and menstrual cycle disturbances. AIM: To assess the effect of ethinylestradiol and cyproterone acetate (EE/CA) on endothelial function in young, non-obese PCOS women in a pilot study. METHODS: Thirteen young, non-obese PCOS women (20.9 +/- 3.7 years, 23.0 +/ 4.0 kg/m(2)) received 35 mcg EE & 2 mg CA for 6 months. Fourteen age- and body mass index (BMI)-matched healthy women served as controls. Endothelial function assessed by brachial artery flow-mediated dilation (FMD), indices of hyperandrogenism, and insulin resistance were studied at baseline and 6-month follow-up. RESULTS: FMD was impaired in PCOS compared to control women (4.67 +/- 2.38% vs. 10.12 +/- 3.19%, p < 0.001), but increased significantly following EE/CA (9.99 +/- 2.11%, p < 0.001 vs. baseline), reaching normal values (p = NS vs. controls). EE/CA also significantly decreased hyperandrogenism indices and increased total and HDL cholesterol and triglycerides (p < 0.05 vs. baseline). The only independent predictor of treatment-induced FMD improvement in PCOS women was the decrease in free androgen index. CONCLUSIONS: Treatment with combination of estrogens and antiandrogens reverses endothelial dysfunction in young, non obese PCOS women mainly via improving hyperandrogenism. Further research is needed to investigate whether this treatment may also reduce cardiovascular risk in these women. PMID- 21329420 TI - Glycoprotein IIb-IIIa content and platelet aggregation in healthy volunteers and patients with acute coronary syndrome. AB - Glycoprotein (GP) IIb-IIIa (alphaIIbbeta3-integrin) is the central receptor of platelet aggregation. Activated GP IIb-IIIa binds fibrinogen or von Willebrand factor, which forms molecular bridges between aggregating platelets. This review summarizes data on the relationship between GP IIb-IIIa expression on the platelet surface and platelet aggregating activity. GP IIb-IIIa number, measured as maximal binding of complex-specific monoclonal antibody, varied by approximately two fold in both healthy volunteers (n = 35) and patients with acute coronary syndrome (ACS) (n = 65). In healthy volunteers positive associations were observed between GP IIb-IIIa number and the level of ADP induced aggregation when this relationship was analysed in untreated platelet rich plasma (PRP) as well as upon in vitro addition of aspirin or non-saturating concentrations of GP IIb-IIIa blockers. In the same group of volunteers almost no differences in aggregating activity were detected between donors carrying the GP IIIa Pro33 allele (n = 15) and those with the GP IIIa Leu33Leu33 genotype (n = 20). No significant relationships were revealed between platelet aggregability and variations of plasma fibrinogen concentration. Positive correlation of the level of ADP-induced aggregation and GP IIb-IIIa content was detected in patients with ACS within the first hour upon admission to the hospital when they had already received aspirin, but not clopidogrel. However, there were no correlations between these parameters at days 3-5 and days 8-12 (before discharge). At these time points patients were treated not only with aspirin but were saturated with clopidogrel as well. In ACS patients we also evaluated the expression of another platelet adhesive receptor, GP Ib, and found a significant positive correlation between GP IIb-IIIa and GP Ib content. A strong association was also revealed between the number of both receptors and mean platelet volume. The latter observation indicated that individual variations of the number of glycoprotein molecules are mainly affected by platelet size but not the density of their expression on the platelet membrane. Possible usefulness of measuring GP IIb-IIIa content as a marker of increased platelet reactivity is discussed. PMID- 21329421 TI - Clinical associations with a placental diagnosis of delayed villous maturation: a retrospective study. AB - Delayed villous maturation (DVM) is a spectrum of placental disease characterized by decreased tertiary villus formation, reduced vasculosyncytial membrane formation, and, in its more severe forms, increased large bullous villi. In some series it has been associated with an increased risk of stillbirth in the late third trimester, but overall there are few data on its significance. The aim of this study was to assess perinatal factors associated with, and the clinical significance of, the finding of DVM on placental histology. This was a retrospective study investigating all pregnancies with DVM diagnosed on placental histology in a tertiary level unit between December 2001 and August 2006. Over a 6-year period, 2915 placentas were triaged for histopathological assessment, representing 6.1% of all 48 054 deliveries in this time period. One hundred ninety (6.3%) of these selected cases showed DVM. Fifteen placentas from infants with less than 34 completed weeks of gestation were excluded, leaving 175 for further analysis. When compared with controls matched for gestation and delivering within the same time period (n = 175), DVM was significantly associated with pregestational diabetes (8% vs 2.8%, P < .05; relative risk 2.8 [95% confidence interval 1.03-7.6]), gestational diabetes (8.6% vs 3.4%, P < 0.05; relative risk 2.5 [95% confidence interval 0.99-6.3]), and prenatal or intrapartum intrauterine death (8.6% vs 0%, P < 0.05). Delayed villous maturation is associated with both gestational and pregestational diabetes mellitus and with perinatal death. PMID- 21329422 TI - Proteomics and translational medicine: molecular biomarkers for cancer diagnosis, prognosis and prediction of therapy outcome. PMID- 21329423 TI - Biological models of breast cancer: one size does not fit all. PMID- 21329425 TI - How and why does the proteome respond to microgravity? AB - For medical and biotechnological reasons, it is important to study mammalian cells, animals, bacteria and plants exposed to simulated and real microgravity. It is necessary to detect the cellular changes that cause the medical problems often observed in astronauts, cosmonauts or animals returning from prolonged space missions. In order for in vitro tissue engineering under microgravity conditions to succeed, the features of the cell that change need to be known. In this article, we summarize current knowledge about the effects of microgravity on the proteome in different cell types. Many studies suggest that the effects of microgravity on major cell functions depend on the responding cell type. Here, we discuss and speculate how and why the proteome responds to microgravity, focusing on proteomic discoveries and their future potential. PMID- 21329426 TI - Defining pluripotent stem cells through quantitative proteomic analysis. AB - Embryonic stem cells (ESCs) are at the center stage of intense research, inspired by their potential to give rise to all cell types of the adult individual. This property makes ESCs suitable candidates for generating specialized cells to replace damaged tissue lost after injury or disease. However, such clinical applications require a detailed insight of the molecular mechanisms underlying the self-renewal, expansion and differentiation of stem cells. This has gained further relevance since the introduction of induced pluripotent stem cells (iPSCs), which are functionally very similar to ESCs. The key property that iPSCs can be derived from somatic cells lifts some of the major ethical issues related to the need for embryos to generate ESCs. Yet, this has only increased the need to define the similarity of iPSCs and ESCs at the molecular level, both before and after they are induced to differentiate. In this article, we describe the proteomic approaches that have been used to characterize ESCs with regard to self renewal and differentiation, with an emphasis on signaling cascades and histone modifications. We take this as a lead to discuss how quantitative proteomics can be deployed to study reprogramming and iPSC identity. In addition, we discuss how emerging proteomic technologies can become a useful tool to monitor the (de)differentiation status of ESCs and iPSCs. PMID- 21329428 TI - Protein microarrays and novel detection platforms. AB - The field of proteomics has undergone rapid advancements over the last decade and protein microarrays have emerged as a promising technological platform for the challenging task of studying complex proteomes. This gel-free approach has found an increasing number of applications due to its ability to rapidly and efficiently study thousands of proteins simultaneously. Different protein microarrays, including capture arrays, reverse-phase arrays, tissue microarrays, lectin microarrays and cell-free expression microarrays, have emerged, which have demonstrated numerous applications for proteomics studies including biomarker discovery, protein interaction studies, enzyme-substrate profiling, immunological profiling and vaccine development, among many others. The need to detect extremely low-abundance proteins in complex mixtures has provided motivation for the development of sensitive, real-time and multiplexed detection platforms. Conventional label-based approaches like fluorescence, chemiluminescence and use of radioactive isotopes have witnessed substantial advancements, with techniques like quantum dots, gold nanoparticles, dye-doped nanoparticles and several bead based methods now being employed for protein microarray studies. In order to overcome the limitations posed by label-based technologies, several label-free approaches like surface plasmon resonance, carbon nanotubes and nanowires, and microcantilevers, among others, have also advanced in recent years, and these methods detect the query molecule itself. The scope of this article is to outline the protein microarray techniques that are currently being used for analytical and function-based proteomics and to provide a detailed analysis of the key technological advances and applications of various detection systems that are commonly used with microarrays. PMID- 21329427 TI - Differential hydrogen/deuterium exchange mass spectrometry analysis of protein ligand interactions. AB - Functional regulation of ligand-activated receptors is driven by alterations in the conformational dynamics of the protein upon ligand binding. Differential hydrogen/deuterium exchange (HDX) coupled with mass spectrometry has emerged as a rapid and sensitive approach for characterization of perturbations in conformational dynamics of proteins following ligand binding. While this technique is sensitive to detecting ligand interactions and alterations in receptor dynamics, it also can provide important mechanistic insights into ligand regulation. For example, HDX has been used to determine a novel mechanism of ligand activation of the nuclear receptor peroxisome proliferator activated receptor-gamma, perform detailed analyses of binding modes of ligands within the ligand-binding pocket of two estrogen receptor isoforms, providing insight into selectivity, and helped classify different types of estrogen receptor-alpha ligands by correlating their pharmacology with the way they interact with the receptor based solely on hierarchical clustering of receptor HDX signatures. Beyond small-molecule-receptor interactions, this technique has also been applied to study protein-protein complexes, such as mapping antibody-antigen interactions. In this article, we summarize the current state of the differential HDX approaches and the future outlook. We summarize how HDX analysis of protein ligand interactions has had an impact on biology and drug discovery. PMID- 21329429 TI - Quantitative phosphoproteomics strategies for understanding protein kinase mediated signal transduction pathways. AB - Protein phosphorylation is a central regulatory mechanism of cell signaling pathways. This highly controlled biochemical process is involved in most cellular functions, and defects in protein kinases and phosphatases have been implicated in many diseases, highlighting the importance of understanding phosphorylation mediated signaling networks. However, phosphorylation is a transient modification, and phosphorylated proteins are often less abundant. Therefore, the large-scale identification and quantification of phosphoproteins and their phosphorylation sites under different conditions are one of the most interesting and challenging tasks in the field of proteomics. Both 2D gel electrophoresis and liquid chromatography-tandem mass spectrometry serve as key phosphoproteomic technologies in combination with prefractionation, such as enrichment of phosphorylated proteins/peptides. Recently, new possibilities for quantitative phosphoproteomic analysis have been offered by technical advances in sample preparation, enrichment, separation, instrumentation, quantification and informatics. In this article, we present an overview of several strategies for quantitative phosphoproteomics and discuss how phosphoproteomic analysis can help to elucidate signaling pathways that regulate various cellular processes. PMID- 21329430 TI - Proteomic analysis in allergy and intolerance to wheat products. AB - Owing to its extensive use in the human diet, wheat is among the most common causes of food-related allergies and intolerances. Allergies to wheat are provoked by ingestion, inhalation or contact with either the soluble or the insoluble gluten proteins in wheat. Gluten proteins, and particularly the gliadin fraction, are also the main factor triggering celiac disease, a common enteropathy induced by ingestion of wheat gluten proteins and related prolamins from oat, rye and barley in genetically susceptible individuals. The role of gliadin and of its derived peptides in eliciting the adverse reactions in celiac disease are still far from being completely explained. Owing to its unique pathogenesis, celiac disease is widely investigated as a model immunogenetic disorder. The structural characterization of the injuring agents, the gluten proteins, assumes a particular significance in order to deepen the understanding of the events that trigger this and similar diseases at the molecular level. Recent developments in proteomics have provided an important contribution to the understanding of several basic aspects of wheat protein-related diseases. These include: the identification of gluten fractions and derived peptides involved in wheat allergy and intolerance, including celiac disease, and the elucidation of their mechanism of toxicity; the development and validation of sensitive and specific methods for detecting trace amounts of gluten proteins in gluten-free foods for intolerant patients; and the formulation of completely new substitute foods and ingredients to replace the gluten-based ones. In this article, the main aspects of current and prospective applications of mass spectrometry and proteomic technologies to the structural characterization of gluten proteins and derived peptides are critically presented, with a focus on issues related to their detection, identification and quantification, which are relevant to the biochemical, immunological and toxicological aspects of wheat intolerance. PMID- 21329431 TI - Proteomic approaches to understanding the role of the cytoskeleton in host defense mechanisms. AB - The cytoskeleton is a cellular scaffolding system whose functions include maintenance of cellular shape, enabling cellular migration, division, intracellular transport, signaling and membrane organization. In addition, in immune cells, the cytoskeleton is essential for phagocytosis. Following the advances in proteomics technology over the past two decades, cytoskeleton proteome analysis in resting and activated immune cells has emerged as a possible powerful approach to expand our understanding of cytoskeletal composition and function. However, so far there have only been a handful of studies of the cytoskeleton proteome in immune cells. This article considers promising proteomics strategies that could augment our understanding of the role of the cytoskeleton in host-defense mechanisms. PMID- 21329434 TI - The technology of gene therapy. PMID- 21329432 TI - Profiling for novel proteomics biomarkers in neurodevelopmental disorders. AB - Protein biomarker discovery from biological fluids, such as serum, has been widely applied to disorders such as cancer and has more recently also been utilized in neuro-psychiatric disorders with relatively clear biological causes, such as Alzheimer's disease and schizophrenia. The application of the associated technologies for the identification of protein biomarker signatures in neurodevelopmental disorders, such as autism spectrum disorder and attention deficit hyperactivity disorder, is comparatively less well established. The aim of this article is to provide an overview of the various protocols available for such analysis, discuss reports in which these techniques have been previously applied in biomarker discovery/validation in neurodevelopmental disorders, and consider the future development of this area of research. PMID- 21329436 TI - What are the true costs of regulation? PMID- 21329437 TI - A comparative study on the flow experience in web-based and text-based interaction environments. AB - The purpose of this study was to explore a substantial phenomenon related to flow experiences (immersion) in text-based interaction systems. Most previous research emphasizes the effects of challenge/skill, focused attention, telepresence, web characteristics, and systems' interface design on users' flow experiences in online environments. However, text-based interaction systems without telepresence features and web characteristics still seem to create opportunities for flow experience. To explore this phenomenon, this study incorporates subject involvement and interpersonal interaction as critical antecedents into the model of flow experience, as well as considers the existence of telepresence. Results reveal that subject involvement, interpersonal interaction, and interactivity speed are critical to focused attention, which enhances users' immersion. With regard to the effect of telepresence, the perceived attractiveness of the interface is a significant facilitator determining users' immersion in web-based, rather than in text-based, interaction environments. Interactivity speed is unrelated to immersion in both web-based and text-based interaction environments. The influence of interpersonal involvement is diminished in web-based interaction environments. The implications and limitations of this study are discussed. PMID- 21329438 TI - Motives for maintaining personal journal blogs. AB - Although much has been learned about political and news blogs, there has been a lack of research on personal journal blogs. They deserve further research attention because of the implications blogs have in many bloggers' immediate social networks, as well as the opportunities for scientific inquiry in a rich and evolving communication environment. This study explored bloggers' motives for maintaining personal journal blogs, or blogs that resemble diaries about one's personal life. Stemming from the uses and gratifications perspective, antecedents (age, sex, loneliness, disclosiveness) and blogging motives composed a model for predicting the amount of blog use. Seven motives emerged from online survey data: helping/informing, social connection, pass time, exhibitionism, archiving/organizing, professionalism, and get feedback. Age, sex, loneliness, and disclosiveness predicted different motives, and the total model (age, sex, loneliness, disclosiveness, and motives) was useful for explaining 13% of the variance in the amount of blog use. PMID- 21329439 TI - Virtual conversation partner for adults with autism. AB - Autistic Spectrum Disorder (ASD) is notable for severely impaired reciprocal social interaction skills relative to language and intellectual abilities, presenting a major barrier to social integration and vocational success. Evidence based interventions to address these needs are lacking. We report on the development of a small, prototype conversation simulation to teach conversational skills to adolescents and adults with ASD and average to superior intellectual abilities. We also report on a test of the feasibility and acceptability of the simulation approach with a sample of the target population. The simulation engages the user in a virtual conversation with an on-screen partner whose reactions provide naturalistic feedback geared to the appropriateness of the learner's response choices. The prototype simulation, which provides for up to 12 potentially unique multi-turn conversations, was used over a period of 2 weeks by 16 adolescents and adults who then rated statements about the system on a linear scale of 1 (disagreement) to 5 (high agreement). The participants highly endorsed the majority of positive statements about the quality and credibility of the interaction and the virtual conversation partner. In contrast, agreement with positive statements about instructional features external to the conversation was moderate. Unexpectedly, most participants strongly agreed that using the simulation had been helpful to them. Further development and testing in the context of a controlled study with randomized assignment to control and experimental groups are needed to determine whether this approach is effective in improving real-world pragmatic language behavior of high-functioning adults with ASD. PMID- 21329440 TI - Therapists' perception of benefits and costs of using virtual reality treatments. AB - Research indicates that virtual reality is effective in the treatment of many psychological difficulties and is being used more frequently. However, little is known about therapists' perception of the benefits and costs related to the use of virtual therapy in treatment delivery. In the present study, 271 therapists completed an online questionnaire that assessed their perceptions about the potential benefits and costs of using virtual reality in psychotherapy. Results indicated that therapists perceived the potential benefits as outweighing the potential costs. Therapists' self-reported knowledge of virtual reality, theoretical orientation, and interest in using virtual reality were found to be associated with perceptual measures. These findings contribute to the current knowledge of the perception of virtual reality amongst psychotherapists. PMID- 21329441 TI - Comparative loneliness of users versus nonusers of online chatting. AB - Online chatting is an important component of improving interpersonal relationships online, but it may reduce participants' communication time with family members. We conducted a study of the relationship between participants' intent to engage in online chatting and three dimensions of loneliness: social, familial, and romantic. This study was designed to show the effect of online chatting on each of these three dimensions of loneliness. The participants in the study were 709 students at two universities in Taiwan who were classified on the basis of whether or not they had ever engaged in online chatting. Of the participants, 651 (91.82%) fully completed the questionnaires that served as the study instruments and were included in data analysis. The study found that individuals who had participated in online chatting exhibited greater familial loneliness than those who had not because the time spent in online chatting reduced the time spent in familial relationships. Social loneliness was related to the quality of Internet relationships rather than to the time spent online. Individuals who participated in online chatting had less romantic loneliness because of a greater ease of maintaining romantic relationships online. We conclude that online chatting can reduce social loneliness through high-quality Internet relationships but may exacerbate familial loneliness. PMID- 21329442 TI - Contingencies of self-worth and social-networking-site behavior. AB - Social-networking sites like Facebook enable people to share a range of personal information with expansive groups of "friends." With the growing popularity of media sharing online, many questions remain regarding antecedent conditions for this behavior. Contingencies of self-worth afford a more nuanced approach to variable traits that affect self-esteem, and may help explain online behavior. A total of 311 participants completed an online survey measuring such contingencies and typical behaviors on Facebook. First, exploratory factor analyses revealed an underlying structure to the seven dimensions of self-worth. Public-based contingencies explained online photo sharing (beta = 0.158, p < 0.01), while private-based contingencies demonstrated a negative relationship with time online (beta = -0.186, p < 0.001). Finally, the appearance contingency for self-worth had the strongest relationship with the intensity of online photo sharing (beta = 0.242), although no relationship was evident for time spent managing profiles. PMID- 21329443 TI - Problematic Internet Use among Greek university students: an ordinal logistic regression with risk factors of negative psychological beliefs, pornographic sites, and online games. AB - The aim of this paper is to investigate the relationships between Problematic Internet Use (PIU) among university students in Greece and factors such as gender, age, family condition, academic performance in the last semester of their studies, enrollment in unemployment programs, amount of Internet use per week (in general and per application), additional personal habits or dependencies (number of coffees, alcoholic drinks drunk per day, taking substances, cigarettes smoked per day), and negative psychological beliefs. Data were gathered from 2,358 university students from across Greece. The prevalence of PIU was 34.7% in our sample, and PIU was significantly associated with gender, parental family status, grade of studies during the previous semester, staying or not with parents, enrollment of the student in an unemployment program, and whether the student paid a subscription to the Internet (p < 0.0001). On average, problematic Internet users use MSN, forums, YouTube, pornographic sites, chat rooms, advertisement sites, Google, Yahoo!, their e-mail, ftp, games, and blogs more than non-problematic Internet users. PIU was also associated with other potential addictive personal habits of smoking, drinking alcohol or coffee, and taking drugs. Significant risk factors for PIU were being male, enrolment in unemployment programs, presence of negative beliefs, visiting pornographic sites, and playing online games. Thus PIU is prevalent among Greek university students and attention should be given to it by health officials. PMID- 21329444 TI - The impact of online brand community type on consumer's community engagement behaviors: consumer-created vs. marketer-created online brand community in online social-networking web sites. AB - The current study proposed and tested a theoretical model of consumers' online brand community engagement behaviors, with particular attention given to online brand community type (consumer vs. marketer-created). By integrating attribution and social identity theories, this study investigated the causal linkages between intrinsic motives of altruism, social identification motivations, and online brand community engagement behaviors. The results showed that consumers' online brand community engagement intentions were indirectly influenced by the different types of communities through different levels of consumers' attributions to intrinsic motives of altruism. This study also found that, in the attribution processes, consumers' intrinsic motives of altruism motivated them to identify themselves socially with the online communities they join. Finally, this study demonstrated that the intrinsic motives of altruism and social identification motivations provided strong social incentives to motivate consumers to engage in subsequent online brand community behaviors. PMID- 21329445 TI - Exploring the creation of learner-centered e-training environments among retail workers: a model development perspective. AB - Current business leaders continue to adopt e-learning technology despite concerns regarding its value. Positing that the effectiveness of e-training depends on how its environment is managed, we argue that a learner-centric approach is necessary in order to achieve workplace training goals. We subsequently develop a theoretical model that is aimed at identifying the key components of learner centered e-training environments, which serve the function of providing a benchmarked approach for evaluating e-training success. The model was empirically tested using data from an Internet survey of retail industry employees and partial least squares techniques were used for analysis. Based on the findings, this study clarifies what is needed for successful e-training in terms of instructional design, system design, and organizational support. PMID- 21329446 TI - Facebook and MySpace: complement or substitute for face-to-face interaction? AB - Previous studies have claimed that social-networking sites are used as a substitute for face-to-face interaction, resulting in deteriorating relationship quality and decreased intimacy among its users. The present study hypothesized that this type of communication is not a substitute for face-to-face interaction; rather, that it is an extension of communication with face-to-face partners. A survey was administered to examine the use of Facebook and MySpace in this regard among 183 college students. The study confirmed that Facebook and MySpace do act as an extension of face-to-face interaction, but that some users do tend to rely on Facebook and MySpace for interpersonal communication more than face-to-face interaction. PMID- 21329447 TI - Mirror, mirror on my Facebook wall: effects of exposure to Facebook on self esteem. AB - Contrasting hypotheses were posed to test the effect of Facebook exposure on self esteem. Objective Self-Awareness (OSA) from social psychology and the Hyperpersonal Model from computer-mediated communication were used to argue that Facebook would either diminish or enhance self-esteem respectively. The results revealed that, in contrast to previous work on OSA, becoming self-aware by viewing one's own Facebook profile enhances self-esteem rather than diminishes it. Participants that updated their profiles and viewed their own profiles during the experiment also reported greater self-esteem, which lends additional support to the Hyperpersonal Model. These findings suggest that selective self presentation in digital media, which leads to intensified relationship formation, also influences impressions of the self. PMID- 21329450 TI - Partial rescue of the phenotype in 1alpha-hydroxylase gene knockout mice by vitamin D3 injection. AB - OBJECTIVE: To investigate whether 25-hydroxyvitamin D [25(OH)D] can mediate effects without being converted to 1alpha,25-dihydroxyvitamin D [1,25(OH)2D]. METHODS: Vitamin D3 (VD3) was injected intramuscularly to 25-hydroxyvitamin D 1alpha-hydroxylase [1alpha(OH)ase] gene knockout (KO) male mice with a dose of 10,000 IU per week for 4 weeks. Skeleton Parameters and Serum biochemistry in mice were assayed. RESULTS: Serum 25(OH)D3 levels increased from 41 to 212 ng/mL in KO mice injected with VD3. Our results show that VD3 injections significantly increased the body weight of KO mice and there were no significant differences in body weight at 7 weeks of age between VD3-treated KO mice and wildtype (WT) mice. After 1 month injection, serum calcium and phosphorus levels of the KO mice were found indistinguishable from those of their WT littermates. Serum parathyroid hormone level declined significantly, but remained higher in treated KO mice. The dry weight, percentage ash weight, and calcium content of femur were returned to normal levels in VD3-treated KO mice whereas the femoral length, although increased significantly, remained significantly smaller than that of WT mice. VD3 injections also normalized the growth plate of KO mice within normal width. CONCLUSIONS: Our results demonstrate that high-dose VD3 injections can partially rescue the phenotype in 1alpha-hydroxylase gene KO mice. 25-Hydroxyvitamin D can mediate effects in the absence of conversion to 1alpha,25-dihydroxyvitamin D was confirmed in this study. PMID- 21329451 TI - Premature deaths close to home. PMID- 21329452 TI - Interactive role of trauma cytokines and erythropoietin and their therapeutic potential for acute and chronic wounds. AB - If controllable, stem cell activation following injury has the therapeutic potential for supporting regeneration in acute or chronic wounds. Human dermally derived stem cells (FmSCs) were exposed to the cytokines interleukin-6 (IL-6), IL 1beta, and tumor necrosis factor-alpha (TNF-alpha) in the presence of erythropoietin (EPO). Cells were cultured under ischemic conditions and phenotypically characterized using flow cytometry. Topical EPO application was performed in three independent clinical wound healing attempts. The FmSCs expressed the receptor for EPO. EPO had a strong inhibitory effect on FmSC growth in the absence of IL-6 and TNF-alpha. With IL-6, the EPO effects were reversed to that of growth stimulation. TNF-alpha had the strongest stimulatory effect. In contrast, IL-1beta had an inhibitory effect. Topically applied EPO considerably enhanced wound healing and improved wound conditions of acute and chronic wounds. Site specificity of stem cell activation is mediated by IL-6 and TNF-alpha. In trauma, EPO ceases its inhibitory role and reverts to a clinically relevant boosting function. EPO may be an important therapeutic tool for the topical treatment of acute and chronic wounds. PMID- 21329454 TI - Personal profile: interview with Michael Rae. Interview by Vicki Glaser. PMID- 21329458 TI - Abstracts of ICON 2011, International Congress for Endovascular Specialists. February 13-17, 2011. Scottsdale, Arizona, USA. PMID- 21329455 TI - Validated worldwide supercentenarians, living and recently deceased. PMID- 21329459 TI - Quantification of circulating plasma DNA in Friedreich's ataxia and spinocerebellar ataxia types 2 and 12. AB - DNA triplet repeat expansion-associated ataxias, Friedreich's ataxia, and different types of spinocerebellar ataxias (SCAs) are progressive multisystem neurodegenerative disorders. The diagnosis of this wide group of inherited ataxias is essentially based on clinical findings. Cell-free circulating DNA in plasma has been considered as a powerful tool in clinical diagnosis and prognosis of several human diseases. In the present study, clinically suspected patients were assessed on the International Co-operative Ataxia Rating Scale and further confirmed by molecular analysis of DNA triplet repeats. Quantification of plasma DNA using a highly sensitive and DNA-specific PicoGreen fluorescent assay was done. We found significantly high levels (p < 0.001) of plasma DNA of 167 +/- 43 ng/mL in Friedreich's ataxia patients (n = 15), 148 +/- 29 ng/mL in SCA2 patients (n = 10), and 137 +/- 29 ng/mL in SCA12 patients (n = 25), whereas those of healthy controls (n = 20) was only 59 +/- 15 ng/mL. Therefore, we were able to distinguish between ataxia patients and healthy controls using plasma DNA. Although the precise mechanism by which plasma DNA enters into circulation is not known, significantly higher concentrations of plasma DNA appears to be due to neuronal and muscular degeneration in these patients. Identification of genes in plasma DNA, which are overexpressed or novel, can be a promising tool for the prognosis of these diseases. PMID- 21329460 TI - IL-6 -174G/C polymorphism and IL-6 serum levels in patients with liver cirrhosis and hepatocellular carcinoma. AB - Recently, a link between high levels of circulating IL-6 and hepatocellular carcinoma (HCC) has been proposed. In addition, single nucleotide polymorphisms (SNPs) in the promoter region of the IL-6 gene have been reported to be related to several inflammatory-related conditions, including cancer. The purpose of this article is: (1) to evaluate the frequencies of SNPs in the IL-6 promoter region at position -174 and IL-6 serum levels in a group of patients with HCC and underlying liver cirrhosis (LC), and compare them with a group of LC patients without HCC; (2) to determine whether a possible correlation exists between the allelic variations, IL-6 serum levels, and the risk of developing HCC. The study included 105 HCC and 95 LC patients. Genomic DNA was isolated using commercially available kits. DNA samples were typed for relevant SNPs of the IL-6 promoter region (-174 G>C, G allele being associated with higher levels of the cytokine). The Restriction Fragment Length Polymorphism (RFLP-PCR) method was used to type the SNPs. IL-6 serum levels were determined using an ultrasensitive commercially available ELISA kit. IL-6 serum levels were higher in G/G compared to C/C genotypes only in HCC (z=2; p=0.04) and G/G versus G/C (z=1.8; p<0.03). IL-6 serum levels in G carriers (G/G+G/C) were higher in HCC 4.8 (0.2-17.5) versus LC patients 2.2 (0.07-11.5) (z=2.8; p=0.004). There was no difference for genotype C/C. IL-6 serum levels in HCC correlated with G carriers (G/G+G/C) (rho=0.25, p=0.05). A positive correlation was also found between sIL-6 levels and some parameters of liver function both in LC and in HCC patients. PMID- 21329461 TI - Stable isotope-resolved metabolomics (SIRM) in cancer research with clinical application to nonsmall cell lung cancer. AB - Metabolomics provides a readout of the state of metabolism in cells or tissue and their responses to external perturbations. For this reason, the approach has great potential in clinical diagnostics. Clinical metabolomics using stable isotope resolved metabolomics (SIRM) for pathway tracing represents an important new approach to obtaining metabolic parameters in human cancer subjects in situ. Here we provide an overview of the technology development of labeling from cells in culture and mouse models. The high throughput analytical methods NMR and mass spectrometry, especially Fourier transform ion cyclotron resonance, for analyzing the resulting metabolite isotopomers and isotopologues are described with examples of applications in cancer biology. Special technical considerations for clinical applications of metabolomics using stable isotope tracers are described. The whole process from concept to analysis will be exemplified by our on-going study of nonsmall cell lung cancer (NSCLC) metabolomics. This powerful new approach has already provided important new insights into metabolic adaptations in lung cancer cells, including the upregulation of anaplerosis via pyruvate carboxylation in NSCLC. PMID- 21329462 TI - Huge splicing frequency in human Y chromosomal UTY gene. AB - Over 90% of human genes produce more than one mRNA by alternative splicing (AS). Human UTY (ubiquitously transcribed tetratricopeptide repeat protein on the chromosome Y) has six mRNA-transcripts. UTY is subject to interdisciplinary approaches such as Y chromosomal genetics or development of leukemia immunotherapy based on UTY-specific peptides. Investigating UTY expression in a normal and leukemic setting we discovered an exceptional splicing phenomenon fostering huge transcript diversity. Transcript sequencing identified 90 novel AS events being almost randomly combined in 284 new transcripts. We uncovered a novel system of transcript architecture and genomic organization in UTY. On a basis of a new UTY-splicing multigraph including a mathematical model we calculated the theoretical yield to exceed 1.3 billion distinct transcripts. To our knowledge, this is the greatest estimated transcript diversity by AS. On protein level we demonstrated interaction of AS-derived proteins with new interactors by yeast-two-hybrid assay. For translational research we predicted new UTY-peptide candidates for leukemia therapy development. Our study provides new insights into the complexity of human alternative splicing and its potential contribution to the transcript diversity of the transcriptome. PMID- 21329463 TI - New approaches in molecular diagnosis and population carrier screening for spinal muscular atrophy. AB - Autosomal recessive spinal muscular atrophy, the leading genetic cause of infant death, is due to loss of functional SMN1 genes, mainly as a result of homozygous deletions. Carrier frequency in the general population varies widely from 1/50 to 1/125 and has significant counseling implications. In a cohort of 210 patients with spinal muscular atrophy confirmed at the molecular level, 91.9% had a homozygous deletion and 14 were compound heterozygotes. Two novel point mutations were detected (c.524delC and c.734dupC) and the 11 bp duplication c.770_780dup was found at a high frequency. We describe the development of a simple and robust method for homozygous deletion detection, which enabled us to simplify the diagnostic workup. Further, carrier frequency in our population was established by direct quantification with the commercially available MLPA kit, following optimization for the use of dried blood spots as sample specimens. PMID- 21329464 TI - Polymorphism of xenobiotic-metabolizing genes and breast cancer susceptibility in North Indian women. AB - NAD(P)H:quinone oxidoreductase 1 (NQO1) and cytochrome P450 1A2 (CYP1A2) are involved in the metabolism of estrogens. Genetic polymorphisms in these genes may lead to interindividual variation in breast cancer susceptibility. This study was undertaken to investigate the association of NQO1 exon 6 proline187serine (C609T) and CYP1A2 exon 2 phenylalanine21leucine (C63G) polymorphisms with breast cancer susceptibility in North Indian women. Polymorphisms were analyzed by polymerase chain reaction amplification of the desired segment of NQO1 and CYP1A2 genes followed by restriction fragment length polymorphism. NQO1 mRNA expression was analyzed by semiquantitative reverse transcription-polymerase chain reaction and its enzyme activity was estimated spectrofluorophotometrically. Odds ratios for NQO1 C609T heterozygous and homozygous variants were 0.66 (95% confidence interval: 0.39-1.13; p-value: 0.141) and 1.07 (95% confidence interval: 0.46 2.46; p-value: 0.976). All cases and controls were monomorphic for the CYP1A2 exon 2 phenylalanine21leucine (C63G) genotype. NQO1 mRNA expression and its catalytic activity among wild-type genotype, homozygous variant, and heterozygous variant were not significantly altered, except for catalytic activity of the NQO1 homozygous variant, which was observed extremely low. The results of the study suggest that NQO1 exon 6 proline187serine (C609T) and CYP1A2 exon 2 phenylalanine21leucine (C63G) polymorphisms do not play a significant role in breast cancer susceptibility in North Indian women. PMID- 21329465 TI - A new method for FMR1 gene methylation screening by multiplex methylation specific real-time polymerase chain reaction. AB - Fragile X Syndrome (FXS) is the most common form of inherited mental retardation in men. It is caused by abnormalities in the FMR1 gene that are associated with CGG repeat expansion and the hypermethylation status of its promoter. Methylated alleles lead to transcriptional inhibition and consequent loss of Fragile X Mental Retardation Protein. Chemical modification of cytosine to uracil by bisulfite treatment has proved to be an attractive method for DNA methylation studies that precludes labor-intensive Southern blot analysis, which is the gold standard test for FXS. In this report, bisulfite-treated DNA samples were amplified using real-time multiplex methylation-specific polymerase chain reaction followed by melting curve analysis. Our results show that all control samples with known CGG repeat numbers and methylation statuses were correctly diagnosed. The samples from 43 male patients were also successfully diagnosed, which were in complete agreement with the results of Southern blotting. By such means, 39 patients were found to have an unmethylated allele; 3, a fully mutated allele; and 1, both methylated and unmethylated alleles, thus implying a diagnosis of mosaicism. In conclusion, we find our method to be convenient for screening a large number of male patients with FXS, because it is rapid and easy to perform, especially when there is a low quantity of DNA that must be sensitively and accurately assayed. PMID- 21329466 TI - Hypoxia-inducible factor-1 alpha C1772T gene polymorphism and glioma risk: a hospital-based case-control study from China. AB - BACKGROUND: The hypoxia-inducible factor 1 alpha (HIF-1alpha) plays a major role in cancer progression. AIM: The aim of this study was to investigate the potential association between HIF-1alpha C1772T gene polymorphism and glioma risk. METHODS: We conducted a hospital-based case-control study from China. A total of 300 subjects (150 glioma patients and 150 healthy controls) were recruited in this study. The peripheral blood samples were extracted. The polymerase chain reaction-restriction fragment length polymorphism method was used to test genotypes. RESULTS: Glioma patients had a significantly lower frequency of CC genotype (odds ratio [OR] = 0.46, 95% confidence interval [CI] = 0.24, 0.91; p = 0.03) and C allele (OR = 0.49, 95% CI = 0.26, 0.91; p = 0.03) than controls. Glioma patients had a significantly higher frequency of CT genotype (OR = 2.13, 95% CI = 1.07, 4.25; p = 0.03) and T allele (OR = 2.05, 95% CI = 1.09, 3.83; p = 0.03) than controls. There were no significant differences in the distributions of HIF-1alpha C1772T gene polymorphism among glioma patients at different tumor type and stage. CONCLUSION: This study suggested that CT genotype and the T allele of HIF-1alpha C1772T gene polymorphism were associated with a higher glioma risk in the Han population of China. PMID- 21329467 TI - Age-dependent changes in the proteolytic-antiproteolytic balance after alcohol and black tea consumption. AB - Aging is accompanied by changes in the redox balance that is additionally modified by alcohol. Ethanol metabolism is connected with generation of free radicals which can damage cell components especially when antioxidant mechanisms are not able to neutralize them. In connection with the necessity of prevention against oxidative consequences, natural antioxidants are looked for. A natural and commonly used component of the diets with antioxidant properties are teas, especially the black tea. This study provides evidence of the role of black tea in the protection of rat plasma proteins and lipids against oxidative stress caused by aging and ethanol intoxication. For 5 weeks, the rats (2-, 12-, and 24 months old) used for the experiment received a black tea beverage (3 g/l) without or with alcohol (given for 4 weeks). The decrease in antioxidant abilities determined as total antioxidant status during aging and ethanol intoxication resulted in enhanced lipid and protein oxidation (determined as malondialdehyde, carbonyl groups, dityrosine, tryptophan and sulfhydryl groups level). In consequence the decrease in anti-proteases (alpha-1-antitrypsin, alpha-2 macroglobulin) activity and the increase in proteases (elastase and cathepsin G) activity were observed. Black tea protected the plasma antioxidants and prevented oxidative modifications of lipid and protein observed during aging as well as ethanol intoxication. The results indicate that a shift into plasma proteolytic activity results from a decrease in antioxidant abilities, so the use of black tea appears to be beneficial in reducing oxidative stress caused by ethanol and/or aging. PMID- 21329468 TI - Effects of ozone oxidative preconditioning on different hepatic biomarkers of oxidative stress in endotoxic shock in mice. AB - In endotoxic shock, variations are known to occur in different biochemical parameters of oxidative stress. Ozone oxidative preconditioning (OOP) is a good candidate to restore the redox balance on different tissue. This investigation examined the effect of OOP on different biomarkers of oxidative stress in hepatic tissue of mice treated with lipopolysaccharide (LPS). LPS doses of 30 mg/kg were administered intraperitoneally (i.p.) and pretreatment with ozone/oxygen mixture (OOM) was applied i.p. at 0.2, 0.4, and 1.2 mg/kg once daily during 5 days before LPS injection. The mice were euthanized under ether atmosphere at different times, 1 and 24 h after LPS injection. Hepatic tissue from all animals was taken for biochemical determinations of oxidative stress parameters such as thiobarbituric acid reactive substances (TBARS) content and activity of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione S-transferase (GST). The results demonstrated that OOP reduces levels of TBARS content and increases the activity of GPx in hepatic tissue. In conclusion, OOP was able to recover the redox balance and in this way to protect the animals against the oxidative damage induced by endotoxemia. PMID- 21329469 TI - What is the role of assisted reproduction technology in the management of age related infertility? AB - Although in the UK the upper age limit for National Health Service (NHS) provision of in vitro fertilisation (IVF) is 39 years of age there has been an increase in number of women having fertility treatment in their 40s. However, the success rates of IVF and intra-uterine insemination (IUI) in this group remain low. Human Fertilisation and Embryology Authority (HFEA) data from 2006 showed that the live-birth rate from IVF in the UK was 11% in the age group 40-42, 4.6% in the age group 43-44 and less than 4% in women over 44. We performed a literature search for studies using terms and combinations of terms in online databases and published meta-analyses reporting the outcome of interventions in older women. This review showed that assisted reproduction technologies (ARTs) continue to have low live-birth rates in women over 40. Trials showed that assisted hatching may increase the chance of pregnancy in women with poor history. Blastocyst transfer is associated with better outcome, whereas application of pre-implantation genetic screening (PGS) in older women has not increased the success rates. It appears that, with the exception of egg-donation, ART has no answer yet to age-related decline of female fertility. PMID- 21329470 TI - The impact of long down regulation in vitro fertilisation cycles on patients' weight. AB - AIM: A common concern of prospective in vitro fertilization (IVF) patients is the effect of treatment on their weight. The aim of this study was to document weight change throughout a long down regulation (LDR) IVF cycle and to examine any relationship between weight change, treatment outcome ovarian responsiveness and bloating. METHODS: Following recruitment of women prior to na LDR IVF cycle, four timed weighings and a control-validated daily bloating questionnaire were completed through the cycle. RESULTS: Sixty-six weight profiles were used in analysis, 66% (n=43) of which completed the bloating questionnaire. There was no significant weight change at the conclusion of the cycle (p = 0.234) despite significant weight gain during stimulation. These changes had no relationship to treatment outcome, the statistically significant reported bloating or to the ovarian responsiveness of participants. CONCLUSIONS: Despite anecdotal views to the contrary, LDR IVF cycles do not appear to result in lasting weight gain. Interestingly, there was no statistical association between weight change and the perceived degree of bloating. PMID- 21329471 TI - Infertility treatment: when is it time to give up? An Internet-based survey. AB - INTRODUCTION: Many factors have been suggested that influence a couple's decision to stop infertility treatment despite not achieving their goal of having a baby. This Internet-based questionnaire study aims to shed light on these reasons by surveying patients who have received treatment from a variety of different centres. METHODS: Registered users of an independent infertility website were invited to participate in the survey by filling in a structured questionnaire. RESULTS: Eighty users completed the questionnaire. Fifty-eight percent of patients received treatment in just one centre. Seventy-eight percent of the patients paid for the treatment themselves. Forty-two percent of couples intended to have only one treatment cycle and 60% of couples reported undergoing more cycles than they had originally intended. Ten percent of patients regretted not stopping their treatment earlier. The most common reasons why patients opted against further treatment cycles were financial constraints (46%), emotional burden (35%), poor response to treatment (29%) and poor egg quality (19%). CONCLUSIONS: The decision to stop treatment despite poor outcomes is a difficult one and unique to the couple. The findings of this study are consistent with the widely held belief that in vitro fertilization is a stressful, expensive process, given that almost all women cited these as reasons to stop treatment. PMID- 21329472 TI - Will new injection devices for interferon beta-1a s.c. affect treatment adherence in patients with multiple sclerosis? An expert opinion in the Middle East. AB - Treatment adherence to disease modifying drugs (DMDs) in multiple sclerosis is sub-optimal. This, in turn, can affect patients' long-term responses to therapy. A key factor that influences treatment adherence is the need for self-injection of DMDs, which can be demanding and disruptive for patients, and difficult for those with cognitive difficulties or reduced manual dexterity. In addition, pain resulting from poor injection technique, and needle anxiety, may both compromise adherence. Changes to the formulation of interferon (IFN) beta-1a for subcutaneous injection that were designed to improve injection local tolerability, and changes in drug-delivery technology, designed to make injections simpler and more convenient for patients, were reviewed by a group of experts on MS in the Middle East. The group also considered the possible effects of these changes in drug delivery technology on patient adherence to IFN beta-1a s.c. PMID- 21329473 TI - Sominone improves memory impairments and increases axonal density in Alzheimer's disease model mice, 5XFAD. AB - Previously we showed that steroidal sapogenin, sominone improved memory after a single i.p. injection into normal mice. However, it had not been reported that sominone could recover memory deficits in a severe Alzheimer's disease (AD) model animal. Therefore, we aimed to investigate that sominone improved memory impairments in the 5XFAD mouse, model for AD. In the current study, we used sominone that we had synthesized. 5XFAD mice were given 10 MUmol/kg sominone intraperitoneally for 9 days. In addition to object recognition memory, axonal density, amyloid plaque number, and activated microglia in the brain were evaluated. Sominone treatment significantly improved object recognition memory compared with vehicle control treatment. Sominone treatment significantly enhanced axonal densities in the frontal cortex and parietal cortex but had no effects on amyloid plaque number and activated microglia. In cultured cortical neurons, the axonal length was significantly reduced by Abeta(1-42) treatment. However, that was markedly recovered 5 days after the treatment with 1 MUM sominone. Neuronal loss was not observed in the cortex and hippocampus of 5XFAD mice at 6-8 months of age. These results suggest that memory deficits in AD may be improved by sominone independently of reducing amyloid plaques and neuroinflammation. PMID- 21329474 TI - Clinical features and Cu/Zn superoxide dismutase gene mutations in two mainland Chinese families with amyotrophic lateral sclerosis. AB - Clinical information of two families with amyotrophic lateral sclerosis (ALS) was studied and a mutation analysis of the SOD1 gene was performed using direct DNA sequencing. Two previously reported mutations of the SOD1 gene, G20T (Cys6Phe substitution), and G255C (Leu84Phe substitution), were identified and cosegregated with the disease in the two families. Patients with a Cys6Phe mutation demonstrated rapid disease progression with severe clinical phenotypes, and the patients with a Leu84Phe mutation had a variety of different clinical phenotypes. This is the third report of SOD1 gene mutations in Mainland Chinese patients with different ALS phenotypes. This supports the hypothesis that the clinical course of ALS may vary depending on the specific genetic mutation. PMID- 21329475 TI - IgE and IgG(4) autoantibodies against DFS70/LEDGF in atopic dermatitis. AB - BACKGROUND: DFS70/LEDGF is a known survival factor, growth factor, and HIV-1 transporter. It is also an autoantigen recognized by IgG autoantibodies (aAbs) in patients with atopic dermatitis (AD). In the past few decades, various IgE aAbs against self-proteins have been identified in AD. Although DFS70 is considered to be one of these proteins, to date, there has not been a detailed analysis of the significance of this putative autoantigen. OBJECTIVE AND METHODS: Using recombinant protein that was generated using a baculovirus and insect cell system, we established an ELISA that can measure IgE-anti-DFS70 aAbs and IgG(4) anti-DFS70 aAbs. Sera obtained from 61 AD patients and 20 healthy donors were analyzed using the ELISA. RESULTS: Nine of 61 AD patients were determined to be IgE-anti-DFS70 aAb-positive. IgG(4)-anti-DFS70 aAbs were detected in nine of 61 patients. The serum thymus and activation-regulated chemokine concentrations were significantly higher in the group that was positive for both aAbs compared to the aAb-negative group, although the total serum IgE levels were not significantly different between these groups. CONCLUSION: We conclude that serum IgE-anti-DFS70 aAbs and IgG(4)-anti-DFS70 aAbs may be related to the severity of AD. PMID- 21329476 TI - Effects of tamoxifen on estrogen receptor-alpha level in immune cells and humoral specific response after immunization of C3H/He male mice with syngeneic testicular germ cells (TGC). AB - Estrogens and estrogen receptors (ERs) are potent regulators of the immune response. Disruption of ERalpha or modulation of its function by selective ligands during experimental autoimmune conditions changes the course of disease by influencing specific humoral and cellular responses. However, it is not known whether fluctuation in the ERalpha level and the variable accessibility to its ligands in immune cells influence the development of specific immune responses against auto-antigens. This study was designed to evaluate the expression level of ERalpha in splenic immune cells and the specific humoral immune response in male C3H/He/W mice immunized with syngeneic testicular germ cells (TGC) in the presence of tamoxifen. Levels of ERalpha protein in immune cell subpopulations of immunized mice (assessed by flow cytometry) increased in MHCII(+)CD86(+), MHCII(+)CD86(- ), F4/80(+)MHCII(+), immature macrophages (F4/80(+)/MHCII(- )), and CD3(+)CD4(+) T cells. Addition of tamoxifen decreased the level of ERalpha in MHCII(+)CD86(+), MHCII(+)CD86(- ), F4/80(+)MHCII(+), immature macrophages (F4/80(+)/MHCII(- )), and the CD19(+)CD3(- ) cell subpopulation of immunized mice. Therefore, immunization with syngeneic antigen and tamoxifen treatment evoked cell-type specific changes in the level of ERalpha. Irrespective of tamoxifen treatment the humoral response in immunized animals toward TGCs was similar, suggesting that modulation of the level of ERalpha in immune cells is not directly related to specific auto-antibody production. PMID- 21329477 TI - Y chromosome diversity among the Iranian religious groups: a reservoir of genetic variation. AB - BACKGROUND: Iran is ethnically, linguistically and religiously diverse. However, little is known about the population genetics of Iranian religious communities. AIM: This study was performed in order to define the different paternal components of the Iranian gene pool. SUBJECTS AND METHODS: Fourteen Y chromosome bi-allelic markers were analysed in 130 male subjects from Assyrian, Armenian and Zoroastrian groups in comparison with 208 male subjects from three Iranian Muslim groups. RESULTS: Among the three Iranian Muslim groups, the Uromian people possessed a particularly close genetic relationship to the Armenian, whereas the Zoroastrian group was different from the Uromian, but had a close genetic relationship to the two other Muslim groups (Kermanian and Shirazian). The genetic results indicate a relationship between Armenian and Assyrian groups in Iran and a clear distinction of the former from the Zoroastrian group. However, Assyrians had elevated frequency (40%) of R*(xR1a) and low frequency (11%) of J. CONCLUSION: The results of this study may suggest that the Assyrian population either experienced Eurasian gene flow (possibly from Armenia) or that enforced relocations and expulsion of conquered people with different origin led to the integration of descendants with R haplogroup. This could also be due to genetic drift due to small population size and endogamy resulting from religious barriers. PMID- 21329478 TI - Quantitative genetics of human morphology and obesity-related phenotypes in nuclear families from the Greater Bilbao (Spain): comparison with other populations. AB - BACKGROUND: It is well established that variation of soft-tissue traits is less influenced by the genetic component than skeletal traits. However, it is still unclear whether heritabilities (h(2)) of obesity-related phenotypes present a common pattern across populations. AIM: To estimate familial resemblance and heritability of body size, shape and composition phenotypes and to compare these results with those from other populations. SUBJECTS AND METHODS: The subject group consisted of 533 nuclear families living in Greater Bilbao and included 1702 individuals aged 2-61 years. Familial correlations and h(2) were estimated for 29 anthropometric phenotypes (19 simple measures, three derived factors, four obesity indices and the three Heath-Carter somatotype components) using MAN and SOLAR programmes. RESULTS: All phenotypes were influenced by additive genetic factors with narrow sense heritabilities ranging from 0.28-0.69. In general, skeletal traits exhibited the highest h(2), whereas phenotypes defining the amount of adipose tissue, particularly central fat, were less determined by genetic factors. CONCLUSIONS: Familial correlations and heritability estimates of body morphology and composition from the Greater Bilbao sample were within the range observed in other studies. The lower heritability detected for central fat has also been found in some other populations, but further investigations in different populations using the same anthropometric traits and estimation methods are needed in order to obtain more robust conclusions. PMID- 21329479 TI - First report of cystic fibrosis mutations in Libyan cystic fibrosis patients. AB - BACKGROUND: There are few data on the molecular basis of Cystic Fibrosis (CF) in North Africa, probably due to under-diagnosis. AIM: This is the first study of cystic fibrosis transmembrane conductance regulator (CFTR) mutations in the Libyan population. SUBJECTS AND METHODS: This study analysed the complete coding region and flanking intronic sequences of the CFTR gene in 10 unrelated Libyan CF patients. RESULTS: This study identified four mutations (F508del, c.1670delC, N1303K and E1104X), with a high frequency of the latter. CONCLUSION: Identification of CF mutations facilitates molecular investigation of cystic fibrosis in the Libyan population and helps to provide effective genetic counselling among CF families. PMID- 21329480 TI - Correlates of aerobic fitness in urban and rural Portuguese adolescents. AB - BACKGROUND: Improving physical fitness is often an objective of programmes aimed at preventing obesity among youth. AIM: To evaluate the association between cardiorespiratory fitness (CRF) and area of residence controlling for several correlates in adolescents. SUBJECTS AND METHODS: CRF was assessed with the progressive aerobic cardiovascular endurance run (PACER) test in a cross sectional sample of 362 Portuguese adolescents (165 males, 197 females) of 13-16 years of age. Youth were classified by area of residence as urban or rural. Gender, age, weight status, parental education, screen time (inactivity) and moderate-to-vigorous physical activity (MVPA) were statistically controlled. Logistic regression analysis was used. RESULTS: Adolescents of both sexes from rural settings were 76% more likely to be classified as aerobically fit compared to those from urban areas. The odds ratio for CRF in the final model was similar in boys (OR = 0.24, 95% CI 0.06-0.99, p < 0.05) and girls (OR = 0.24, 95% CI 0.07 0.76, p < 0.05). MVPA and weight status were important predictors of CRF in Portuguese adolescents of 13-16 years of age. Maternal education was an additional predictor in girls. CONCLUSION: CRF and rural/urban settings were significantly related in this sample of Portuguese adolescents of both sexes. PMID- 21329481 TI - Overexpression of fibroblast growth factor receptors FGFR1 and FGFR2 in renal cell carcinoma. AB - OBJECTIVE: Fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) has recently emerged as a critical event in the transformation and tumorigenicity of several murine and human tumors. This pathway could be a mechanism driving angiogenesis in patients with metastatic renal cell carcinoma (RCC). Membrane antigens such as FGFR expressed in RCC are attractive targets for new therapeutic and diagnostic applications. This study evaluated the expression of FGFR1 and FGFR2 in RCC. MATERIAL AND METHODS: Formalin-fixed, paraffin-embedded specimens of 100 primary tumors and 40 metastatic lymph nodes removed from 140 untreated RCC patients were evaluated by immunohistochemistry with FGFR1 and FGFR2 antibodies. The extent of FGFR expression was compared with 40 specimens of normal human kidney tissue (selected from the surgical diagnostic files). Significant differences in the immunoexpression of FGFR among these groups were assessed bychi-squared and Fisher's exact tests using a semi-quantitative scoring system on the extent of stained cells and intensity of corresponding immunostained cells (0 to 3+). RESULTS: Expression of FGFR1 was observed in 98% (98/100) of primary renal tumors and in 82.5% (33/40) of lymph-node metastases. Intensity was 3+ in allcases. Nuclear expression of FGFR1 was found in 68% (95/140). FGFR2 staining was seen in 4% (4/100) of primary tumors and in 5% (2/40) of lymph-node metastases. FGFR2 was expressed in RCC of non-clear cell histology. FGFR1 expression was significantly lower in the normal kidney tissue(p = 0.001) and was detected in 2.5% of cases (1/40); no FGFR2 expression was found. CONCLUSION: This study has shown for the first time that FGFR1 is highly expressed in RCC patients. PMID- 21329482 TI - Intravesical bacille Calmette-Guerin-induced multiorgan failure after treatment for transitional cell carcinoma. AB - Intravesical bacille Calmette-Guerin (BCG) has been safely used to treat stage Ta and T1 bladder carcinoma since 1976. This report presents the case of a 56-year old man who presented with multiorgan failure after bacille Calmette-Guerin (BCG) treatment for stage T1 transitional cell carcinoma of the bladder. On admission the patient was jaundiced, had inflammatory infiltrates on chest radiography and required dialysis for renal failure. He had a persisting fever of unknown origin and elevated cholestatic liver function tests, which prompted a liver biopsy.This demonstrated hypersensitivity hepatic granuloma but no organism was identified. He responded well to steroid and antimycobacterial treatment. A small percentage of BCG-treated patients suffer hypersensitivity side-effects (pneumonitis, hepatitis or interstitial nephritis). This complication most commonly follows a traumatic installation. Mycobacteriumbovis is rarely cultured or identified using polymerase chain reaction techniques, and the diagnosis is based on histological findings of granuloma. PMID- 21329483 TI - Management of diuretic treatment: a challenge in the obese patient. AB - The obesity epidemic is a major health concern. The diagnosis of acute illness and fluid imbalance in the obese patient is complicated by a wide range of comorbidities such as cardiovascular disease, obesity hypoventilation syndrome, non-alcoholic steatohepatitis and lymphoedema. Thus, obesity warrants particularly careful clinical and biochemical assessment owing to its resemblance to fluid retention. Dosing of diuretics is difficult in these patients. The blood urea:creatinine ratio should be widely used to detect emerging cardiovascular and renal complications. This report presents an obese patient with congestive heart failure due to a myocardial infarction, who subsequently was overdosed with diuretics. His prerenal acute renal failure resolved when diuretics were stopped and the high urea:creatinine ratio was diagnostic. PMID- 21329484 TI - Infrared thermal imaging of the inner canthus of the eye as an estimator of body core temperature. AB - Several studies suggest that the temperature of the inner canthus of the eye (T(ca)), determined with infrared thermal imaging, is an appropriate method for core temperature estimation in mass screening of fever. However, these studies used the error prone tympanic temperature as a reference. Therefore, we compared T(ca) to oesophageal temperature (T(es)) as gold standard in 10 subjects during four conditions: rest, exercise, recovery and passive heating. T(ca) and T(es) differed significantly during all conditions (mean DeltaT(es) - T(ca) 1.80 +/- 0.89 degrees C) and their relationship was inconsistent between conditions. Also within the rest condition alone, intersubject variability was too large for a reliable estimation of core temperature. This poses doubts on the use of T(ca) as a technique for core temperature estimation, although generalization of these results to fever detection should be verified experimentally using febrile patients. PMID- 21329485 TI - Internet-based treatment after pregnancy loss: concept and case study. AB - The loss of a child during pregnancy results in significant psychological stress for many women, and may lead to long-lasting grief and psychological illnesses. However, only a small percentage of those affected seek or receive traditional forms of psychological treatment, and therefore novel treatment approaches and methods are required. This article introduces an Internet-based psychotherapy programme for patients after pregnancy loss. The five-week intervention comprises two components: structured writing disclosure and cognitive-behavioural therapy. Communication between the therapist and patient is text-based and asynchronous. The writing protocol consists of three treatment phases: self-confrontation, cognitive reappraisal and social sharing. A case report is presented to illustrate the course of the treatment and clinical considerations associated with delivering Internet-based interventions to patients after pregnancy loss. PMID- 21329486 TI - Sulfur mustard toxicity: history, chemistry, pharmacokinetics, and pharmacodynamics. AB - Sulfur mustard (SM) and similar bifunctional agents have been used as chemical weapons for almost 100 years. Victims of high-dose exposure, both combatants and civilians, may die within hours or weeks, but low-dose exposure causes both acute injury to the eyes, skin, respiratory tract and other parts of the body, and chronic sequelae in these organs are often debilitating and have a serious impact on quality of life. Ever since they were first used in warfare in 1917, SM and other mustard agents have been the subjects of intensive research, and their chemistry, pharmacokinetics and mechanisms of toxic action are now fairly well understood. In the present article we review this knowledge and relate the molecular-biological basis of SM toxicity, as far as it has been elucidated, to the pathological effects on exposure victims. PMID- 21329487 TI - Cervical myelopathy due to degenerative spondylolisthesis. AB - OBJECTIVE: To investigate clinical-radiological features of cervical myelopathy due to degenerative spondylolisthesis (DSL). METHODS: A total of 448 patients were operated for cervical myelopathy at Nishitaga National Hospital between 2000 and 2003. Of these patients, DSL at the symptomatic disc level was observed in 22 (4.9%) patients. Clinical features were investigated by medical records, and radiological features were investigated by radiographs. RESULTS: Disc levels of DSL were C3/4 in 6 cases and C4/5 in 16 cases. Distance of anterior slippage was 2 to 5 mm (average 2.9 mm) in flexion position. Space available for the spinal cord (SAC) was 11 to 15 mm (average 12.8 mm) in flexion position and 11 to 18 mm (average 14.6 mm) in extension position; 11 cases were reducible and 11 cases were irreducible in extension position. Myelograms demonstrated compression of spinal cord by the ligamentum flavum in extension position. Compression of spinal cord was not demonstrated in flexion position. C5-7 lordosis angle was lower than control. C5-7 range of motion (ROM) was reduced compared to controls. These alterations were statistically significant. CONCLUSIONS: DSL occurs in the mid cervical spine. Lower cervical spine demonstrated restricted ROM and lower lordosis angle. Pathogenesis of cervical myelopathy due to DSL is compression of spinal cord by the ligamentum flavum in extension position and not by reduced SAC in flexion position. PMID- 21329488 TI - Therapeutic management of type 1 diabetes before and during pregnancy. AB - INTRODUCTION: Pregnancy increases the risks of adverse outcomes for mother and infant in women with type 1 diabetes. Obtaining and maintaining adequate glycemic control during pregnancy is crucial for optimizing outcomes. AREAS COVERED: The importance of prepregnancy planning and treatment during pregnancy is reviewed. The use of insulin analogues and antihypertensive drugs in diabetic pregnancy are in focus. The reader is presented with evidence discussing the importance of prepregnancy counseling and treatment during pregnancy in women with type 1 diabetes. EXPERT OPINION: Tight glycemic control before and during pregnancy is crucial and the prevalence of severe hypoglycemia during pregnancy needs to be reduced. Rapid-acting insulin analogues are regarded as safe to use in pregnancy and studies on long-acting insulin analogues are in the pipeline. Supplementation with folic acid may reduce the risk of malformations. Screening for diabetic retinopathy, diabetic nephropathy and thyroid dysfunction is important, and indications for antihypertensive treatment and treatment of thyroid dysfunction need to be in focus before and during pregnancy. PMID- 21329489 TI - Urinary p-cresol is elevated in small children with severe autism spectrum disorder. AB - Several studies have described in autistic patients an overgrowth of unusual gut bacterial strains, able to push the fermentation of tyrosine up to the formation of p-cresol. We compared levels of urinary p-cresol, measured by high-performance liquid chromatography-ultraviolet, in 59 matched case-control pairs. Urinary p cresol was significantly elevated in autistic children smaller than 8 years of age (p < 0.01), typically females (p < 0.05), and more severely affected regardless of sex (p < 0.05). Urinary cotinine measurements excluded smoking related hydrocarbon contaminations as contributors to these differences. Hence, elevated urinary p-cresol may serve as a biomarker of autism liability in small children, especially females and more severely affected males. PMID- 21329490 TI - Hypothalamic glucose sensing and glycaemic disease. AB - An adequate supply of nutrients is obligatory for life. Glucose is one of the main circulating substrates fuelling the mammalian body, particularly brain, and is normally maintained within a narrow range to ensure health. Given the challenge of maintaining glucose homeostasis, mammals have evolved specialized sensors for monitoring changes in glucose availability. Glucose sensors are distributed centrally and peripherally. Hypothalamic glucose sensors are arousing burgeoning research interest particularly as a result of increasing evidence that the hypothalamus plays an important role in the control of glucose homeostasis. During the last decade, knowledge of hypothalamic glucose sensors has greatly improved, especially as a result of transgenic mice technology and other advances in molecular genetic approaches. This review provides a broad overview of the relevance of hypothalamic glucose sensors in the physiological regulation of glucose homeostasis and putative pathophysiologic relevance to glycaemic diseases. The primary focus of this report has been to discuss recent data suggesting novel roles for hypothalamic glucose sensors in the control of hepatic glucose production, insulin secretion and hypoglycemia counterregulation. Finally, an improved understanding of hypothalamic glucose sensing pathways may be pertinent for an integral comprehension of the regulation of glucose homeostasis and associated disorders. PMID- 21329491 TI - Dengue protease activity: the structural integrity and interaction of NS2B with NS3 protease and its potential as a drug target. AB - Flaviviral NS3 serine proteases require the NS2B cofactor region (cNS2B) to be active. Recent crystal structures of WNV (West Nile virus) protease in complex with inhibitors revealed that cNS2B participates in the formation of the protease active site. No crystal structures of ternary complexes are currently available for DENV (dengue virus) to validate the role of cNS2B in active site formation. In the present study, a GST (glutathione transferase) fusion protein of DENV-2 cNS2B49-95 was used as a bait to pull down DENV-2 protease domain (NS3pro). The affinity of NS3pro for cNS2B was strong (equilibrium-binding constant <200 nM) and the heterodimeric complex displayed a catalytic efficiency similar to that of single-chain DENV-2 cNS2B/NS3pro. Various truncations and mutations in the cNS2B sequence showed that conformational integrity of the entire 47 amino acids is critical for protease activity. Furthermore, DENV-2 NS3 protease can be pulled down and transactivated by cNS2B cofactors from DENV-1, -3, -4 and WNV, suggesting that mechanisms for activation are conserved across the flavivirus genus. To validate NS2B as a potential target in allosteric inhibitor development, a cNS2B-specific human monoclonal antibody (3F10) was utilized. 3F10 disrupted the interaction between cNS2B and NS3 in vitro and reduced DENV viral replication in HEK (human embryonic kidney)-293 cells. This provides proof-of concept for developing assays to find inhibitors that block the interaction between NS2B and NS3 during viral translation. PMID- 21329492 TI - The role of acidification in the inhibition of Neisseria gonorrhoeae by vaginal lactobacilli during anaerobic growth. AB - BACKGROUND: Vaginal lactobacilli protect the female genital tract by producing lactic acid, bacteriocins, hydrogen peroxide or a local immune response. In bacterial vaginosis, normal lactobacilli are replaced by an anaerobic flora and this may increase susceptibility to Neisseria gonorrhoeae, a facultative anaerobe. Bacterial interference between vaginal lactobacilli and N. gonorrhoeae has not been studied in liquid medium under anaerobic conditions. By co cultivating N. gonorrhoeae in the presence of lactobacilli we sought to identify the relative contributions of acidification and hydrogen peroxide production to any growth inhibition of N. gonorrhoeae. METHODS: Three strains of N. gonorrhoeae distinguishable by auxotyping were grown in the presence of high concentrations (107-108 cfu/mL) of three vaginal lactobacilli (L. crispatus, L. gasseri and L. jensenii) in an anerobic liquid medium with and without 2-(N-morpholino) ethanesulfonic (MES) buffer. Fusobacterium nucleatum was used as an indicator of anaerobiosis. Bacterial counts were performed at 15, 20 and 25 h; at 25 h pH and hydrogen peroxide concentrations were measured. RESULTS: Growth of F. nucleatum to >108 cfu/mL at 25 h confirmed anaerobiosis. All bacteria grew in the anaerobic liquid medium and the addition of MES buffer had negligible effect on growth. L. crispatus and L. gasseri produced significant acidification and a corresponding reduction in growth of N. gonorrhoeae. This inhibition was abrogated by the addition of MES. L. jensenii produced less acidification and did not inhibit N. gonorrhoeae. Hydrogen peroxide was not detected in any experiment. CONCLUSIONS: During anaerobic growth, inhibition of N. gonorrhoeae by the vaginal lactobacilli tested was primarily due to acidification and abrogated by the presence of a buffer. There was no evidence of a specific mechanism of inhibition other than acid production under these conditions and, in particular, hydrogen peroxide was not produced. The acidification potential of vaginal lactobacilli under anaerobic conditions may be their most important characteristic conferring protection against N. gonorrhoeae infection. PMID- 21329493 TI - Modified Alvarado Scoring System as a diagnostic tool for acute appendicitis at Bugando Medical Centre, Mwanza, Tanzania. AB - BACKGROUND: Decision-making in patients with acute appendicitis poses a diagnostic challenge worldwide, despite much advancement in abdominal surgery. The Modified Alvarado Scoring System (MASS) has been reported to be a cheap and quick diagnostic tool in patients with acute appendicitis. However, differences in diagnostic accuracy have been observed if the scores were applied to various populations and clinical settings. The purpose of this study was to evaluate the diagnostic value of Modified Alvarado Scoring System in patients with acute appendicitis in our setting. METHODS: A cross-sectional study involving all patients suspected to have acute appendicitis at Bugando Medical Centre over a six-month period between November 2008 and April 2009 was conducted. All patients who met the inclusion criteria were consecutively enrolled in the study. They were evaluated on admission using the MASS to determine whether they had acute appendicitis or not. All patients underwent appendicectomy according to the hospital protocol. The decision to operate was the prerogative of the surgeon or surgical resident based on overall clinical judgment and not the MASS. The diagnosis was confirmed by histopathological examination. Data was collected using a pre-tested coded questionnaire and analyzed using SPSS statistical computer software. RESULTS: A total number of 127 patients were studied. Their ages ranged from eight to 76 years (mean 29.64 +/- 12.97). There were 37 (29.1%) males and 90 (70.9%) females (M: F = 1:2.4). All patients in this study underwent appendicectomy. The perforation rate was 9.4%. Histopathological examination confirmed appendicitis in 85 patients (66.9%) and the remaining 42 patients had normal appendix giving a negative appendicectomy rate of 33.1% (26.8% for males and 38.3% for females). The sensitivity and specificity of MASS in this study were 94.1% (males 95.8% and females 88.3%) and 90.4% (males 92.9% and females 89.7%) respectively. The Positive Predictive Value and Negative Predictive Value were 95.2% (males 95.5% and females 90.6%) and 88.4% (males 89.3% and females 80.1%) respectively. The accuracy of MASS was 92.9% (males 91.5% and females 87.6%). CONCLUSION: The study shows that use of MASS in patients suspected to have acute appendicitis provides a high degree of diagnostic accuracy and can be employed at Bugando Medical Centre to improve the diagnostic accuracy of acute appendicitis and subsequently reduces negative appendicectomy and complication rates. However, additional investigations may be required to confirm the diagnosis in case of atypical presentation. PMID- 21329494 TI - Identification of gliadin-binding peptides by phage display. AB - BACKGROUND: Coeliac disease (CD) is a common and complex disorder of the small intestine caused by intolerance to wheat gluten and related edible cereals like barley and rye. Peptides originating from incomplete gliadin digestion activate the lamina propria infiltrating T cells to release proinflammatory cytokines, which in turn cause profound tissue remodelling of the small intestinal wall. There is no cure for CD except refraining from consuming gluten-containing products. RESULTS: Phage from a random oligomer display library were enriched by repeated pannings against immobilised gliadin proteins. Phage from the final panning round were plated, individual plaques picked, incubated with host bacteria, amplified to a population size of 1011 to 1012 and purified. DNA was isolated from 1000 purified phage populations and the region covering the 36 bp oligonucleotide insert from which the displayed peptides were translated, was sequenced. Altogether more than 150 different peptide-encoding sequences were identified, many of which were repeatedly isolated under various experimental conditions. Amplified phage populations, each expressing a single peptide, were tested first in pools and then one by one for their ability to inhibit binding of human anti-gliadin antibodies in ELISA assays. These experiments showed that several of the different peptide-expressing phage tested inhibited the interaction between gliadin and anti-gliadin antibodies. Finally, four different peptide-encoding sequences were selected for further analysis, and the corresponding 12-mer peptides were synthesised in vitro. By ELISA assays it was demonstrated that several of the peptides inhibited the interaction between gliadin molecules and serum anti-gliadin antibodies. Moreover, ELISA competition experiments as well as dot-blot and western blot revealed that the different peptides interacted with different molecular sites of gliadin. CONCLUSIONS: We believe that several of the isolated and characterised gliadin-binding peptides described here could provide valuable tools for researchers in the field of CD by facilitating studies on localisation and uptake of various gliadin peptides in the small intestine. In future work, the potential of these peptides to detoxify gluten will be investigated. PMID- 21329495 TI - The impact of tailored diabetes registry report cards on measures of disease control: a nested randomized trial. AB - BACKGROUND: Most studies of diabetes self-management that show improved clinical outcome performance involve multiple, time-intensive educational sessions in a group format. Most provider performance feedback interventions do not improve intermediate outcomes, yet lack targeted, patient-level feedback. METHODS: 5,457 low-income adults with diabetes at eight federally-qualified community health centers participated in this nested randomized trial. Half of the patients received report card mailings quarterly; patients at 4 of 8 clinics received report cards at every clinic visit; and providers at 4 of 8 clinics received quarterly performance feedback with targeted patient-level data. Expert recommended glycemic, lipid, and blood pressure outcomes were assessed. Assessment of report card utility and patient and provider satisfaction was conducted through mailed patient surveys and mid- and post-intervention provider interviews. RESULTS: Many providers and the majority of patients perceived the patient report card as being an effective tool. However, patient report card mailings did not improve process outcomes, nor did point-of-care distribution improve intermediate outcomes. Clinics with patient-level provider performance feedback achieved a greater absolute increase in the percentage of patients at target for glycemic control compared to control clinics (6.4% vs 3.8% respectively, Generalized estimating equations Standard Error 0.014, p < 0.001, CI -0.131 - -0.077). Provider reaction to performance feedback was mixed, with some citing frustration with the lack of both time and ancillary resources. CONCLUSIONS: Patient performance report cards were generally well received by patients and providers, but were not associated with improved outcomes. Targeted, patient-level feedback to providers improved glycemic performance. Provider frustration highlights the need to supplement provider outreach efforts. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00827710. PMID- 21329496 TI - Inflammatory myofibroblastic tumor causing unexplained anemia in a toddler: a case report. AB - INTRODUCTION: Inflammatory myofibroblastic tumor is a very rare benign tumor in children that mimics malignant tumors in its aggressiveness locally and by the possibility of recurrence after surgical resection, and causing anemia of chronic disease, which is a decrease in hemoglobin 1 to 2 g/dL below normal level in a patient with chronic illness. CASE PRESENTATION: A 32-month-old boy from Libya presented with microcytic hypochromic anemia. He had been treated in three countries and five centers without response to medical therapy. He was investigated at our center and found to have a mass in the colon causing intermittent intussusception and bleeding. He was treated surgically, and his condition improved dramatically. The pathology report proved a diagnosis of inflammatory myofibroblastic tumor. CONCLUSION: We report a case of an unusual tumor of the gastrointestinal tract causing chronic anemia not responding to medical treatment, and discuss the characteristics of inflammatory myofibroblastic tumor. In our case, we stress the involvement of a multidisciplinary team in treating such a patient who presents with common symptoms and signs but in whom there has been no response to any of the measures and treatment protocols. PMID- 21329497 TI - Advancing the STMS genomic resources for defining new locations on the intraspecific genetic linkage map of chickpea (Cicer arietinum L.). AB - BACKGROUND: Chickpea (Cicer arietinum L.) is an economically important cool season grain legume crop that is valued for its nutritive seeds having high protein content. However, several biotic and abiotic stresses and the low genetic variability in the chickpea genome have continuously hindered the chickpea molecular breeding programs. STMS (Sequence Tagged Microsatellite Sites) markers which are preferred for the construction of saturated linkage maps in several crop species, have also emerged as the most efficient and reliable source for detecting allelic diversity in chickpea. However, the number of STMS markers reported in chickpea is still limited and moreover exhibit low rates of both inter and intraspecific polymorphism, thereby limiting the positions of the SSR markers especially on the intraspecific linkage maps of chickpea. Hence, this study was undertaken with the aim of developing additional STMS markers and utilizing them for advancing the genetic linkage map of chickpea which would have applications in QTL identification, MAS and for de novo assembly of high throughput whole genome sequence data. RESULTS: A microsatellite enriched library of chickpea (enriched for (GT/CA)n and (GA/CT)n repeats) was constructed from which 387 putative microsatellite containing clones were identified. From these, 254 STMS primers were designed of which 181 were developed as functional markers. An intraspecific mapping population of chickpea, [ICCV-2 (single podded) * JG-62 (double podded)] and comprising of 126 RILs, was genotyped for mapping. Of the 522 chickpea STMS markers (including the double-podding trait, screened for parental polymorphism, 226 (43.3%) were polymorphic in the parents and were used to genotype the RILs. At a LOD score of 3.5, eight linkage groups defining the position of 138 markers were obtained that spanned 630.9 cM with an average marker density of 4.57 cM. Further, based on the common loci present between the current map and the previously published chickpea intraspecific map, integration of maps was performed which revealed improvement of marker density and saturation of the region in the vicinity of sfl (double-podding) gene thereby bringing about an advancement of the current map. CONCLUSION: An arsenal of 181 new chickpea STMS markers was reported. The developed intraspecific linkage map defined map positions of 138 markers which included 101 new locations.Map integration with a previously published map was carried out which revealed an advanced map with improved density. This study is a major contribution towards providing advanced genomic resources which will facilitate chickpea geneticists and molecular breeders in developing superior genotypes with improved traits. PMID- 21329498 TI - Methodological issues associated with collecting sensitive information over the telephone--experience from an Australian non-suicidal self-injury (NSSI) prevalence study. AB - BACKGROUND: Collecting population data on sensitive issues such as non-suicidal self-injury (NSSI) is problematic. Case note audits or hospital/clinic based presentations only record severe cases and do not distinguish between suicidal and non-suicidal intent. Community surveys have largely been limited to school and university students, resulting in little much needed population-based data on NSSI. Collecting these data via a large scale population survey presents challenges to survey methodologists. This paper addresses the methodological issues associated with collecting this type of data via CATI. METHODS: An Australia-wide population survey was funded by the Australian Government to determine prevalence estimates of NSSI and associations, predictors, relationships to suicide attempts and suicide ideation, and outcomes. Computer assisted telephone interviewing (CATI) on a random sample of the Australian population aged 10+ years of age from randomly selected households, was undertaken. RESULTS: Overall, from 31,216 eligible households, 12,006 interviews were undertaken (response rate 38.5%). The 4-week prevalence of NSSI was 1.1% (95% ci 0.9-1.3%) and lifetime prevalence was 8.1% (95% ci 7.6 8.6).Methodological concerns and challenges in regard to collection of these data included extensive interviewer training and post interview counselling. Ethical considerations, especially with children as young as 10 years of age being asked sensitive questions, were addressed prior to data collection. The solution required a large amount of information to be sent to each selected household prior to the telephone interview which contributed to a lower than expected response rate. Non-coverage error caused by the population of interest being highly mobile, homeless or institutionalised was also a suspected issue in this low prevalence condition. In many circumstances the numbers missing from the sampling frame are small enough to not cause worry, especially when compared with the population as a whole, but within the population of interest to us, we believe that the most likely direction of bias is towards an underestimation of our prevalence estimates. CONCLUSION: Collecting valid and reliable data is a paramount concern of health researchers and survey research methodologists. The challenge is to design cost-effective studies especially those associated with low-prevalence issues, and to balance time and convenience against validity, reliability, sampling, coverage, non-response and measurement error issues. PMID- 21329499 TI - Environmental and molecular analysis of the floral transition in the lower eudicot Aquilegia formosa. AB - BACKGROUND: Flowering is a critical transition in plant development, the timing of which can have considerable fitness consequences. Until recently, research into the genetic control of flowering time and its associated developmental changes was focused on core eudicots (for example, Arabidopsis) or monocots (for example, Oryza). Here we examine the flowering response of Aquilegia formosa, a member of the eudicot order Ranunculales that is emerging as an important model for the investigation of plant ecology and evolution. RESULTS: We have determined that A. formosa has a strong vernalization requirement but little or no photoperiod response, making it a day neutral (DN) plant. Consistent with this, the Aquilegia homolog of FLOWERING LOCUS T (AqFT) is expressed in both long and short days but surprisingly, the locus is expressed before the transition to flowering. In situ hybridizations with homologs of several Arabidopsis Floral Pathway Integrators (FPIs) do not suggest conserved functions relative to Arabidopsis, the potential exceptions being AqLFY and AqAGL24.2. CONCLUSIONS: In Aquilegia, vernalization is critical to flowering but this signal is not strictly required for the transcriptional activation of AqFT. The expression patterns of AqLFY and AqAGL24.2 suggest a hypothesis for the development of Aquilegia's determinate inflorescence whereby their differential expression controls the progression of each meristem from inflorescence to floral identity. Interestingly, none of the Aquilegia expression patterns are consistent with a function in floral repression which, combined with the lack of a FLC homolog, means that new candidate genes must be identified for the control of vernalization response in Aquilegia. PMID- 21329500 TI - Development of Buffalo Hump in the course of antiretroviral therapy including raltegravir and unboosted atazanavir: a case report and review of the literature. AB - INTRODUCTION: The availability of raltegravir plus atazanavir provides an alternative antiretroviral strategy that may be equally efficacious and less toxic than those currently recommended in HIV treatment guidelines. In fact, this new combination antiretroviral therapy attracts the attention of the scientific community because both drugs have a good safety profile coupled with potent antiviral activity, and their combined use would avert nucleoside- and ritonavir related toxicities. CASE PRESENTATION: We describe the case of a 47-year-old, Caucasian woman treated for HIV-1 infection who developed Buffalo Hump during antiretroviral therapy, including raltegravir and unboosted atazanavir. Clinical evaluation and an ultrasonography scan of the cervical region showed a new progressive increase of lipohypertrophy and the results of DEXA confirmed these data. In our patient the worsening of the Buffalo Hump cannot be attributed to hypercortisolism; insulin-resistance, diabetes, dyslipidemia, hyperlactatemia and metabolic syndrome were not present. Moreover, she was not in therapy with antiretroviral drugs that are described as the cause of Buffalo Hump; on the other hand she developed this side effect three months after the switch of the antiretroviral therapy to raltegravir plus unboosted atazanavir. CONCLUSION: Current data indicate that the etiology of HIV-associated Buffalo Hump remains elusive but is likely multifactorial; a possible contributing cause, but not the main cause, could be exposure to antiretroviral drugs. To the best of our knowledge, this is the first report on development of Buffalo Hump in the course of antiretroviral therapy, including the use of these drugs. On the basis of our data we can formulate the hypothesis of a pharmacological pathogenesis that underlies the development of this case of Buffalo Hump in the absence of other risk factors. PMID- 21329501 TI - Cognitive activity for the treatment of older adults with mild Alzheimer's disease (AD)--PACE AD: study protocol for a randomised controlled trial. AB - BACKGROUND: Participation in cognitive stimulation therapy (CST) may reduce the rate of cognitive decline in people with Alzheimer's disease (AD), however it is unclear if the training of carers to deliver activities is sufficient to improve the clinical outcome of patients. The Promoting Healthy Ageing with Cognitive Exercise for Alzheimer's Disease (PACE-AD) study has been designed to determine if change in cognitive function over a six month period can be achieved with participation in cognitive stimulating activities when the intervention is delivered to carers only as opposed to carers and patients. METHODS/DESIGN: The study will aim to recruit 128 community-dwelling men and women with probable AD according to NINCDS-ADRDS criteria. Participants will be randomly allocated to one of two cognitive activity treatment groups: (1) Participants with mild AD and their companions together (2) Companions of participants with mild AD alone. The intervention will consist of a twelve-week program of cognitive stimulation. Seven weeks of the program will involve 90-minute group sessions delivered once per week while the remaining weeks of the program will involve structured home based activities with telephone support. The primary outcome measure of the study is the change from baseline in the total score on the Alzheimer Disease Assessment Scale-Cognitive (ADAS-COG). Secondary outcomes of interest include changes in health related quality of life, mood, memory, language, executive functions, independent living abilities and psychiatric symptoms for participants with mild AD. Changes in companion quality of life, mood, and general health will also be monitored. Primary endpoints will be collected 13 and 26 weeks after the baseline assessment. DISCUSSION: The proposed project will provide evidence as to whether CST for people with AD and their companions is more beneficial than when used for companions alone. Outcomes sought include a reduction of further cognitive decline and improved quality of life amongst older adults with mild AD. We anticipate that the results of this study will have implications for the development of cost-effective evidence-based best practice to treat people with mild AD. TRIAL REGISTRATION: ACTRN12610000653066. PMID- 21329502 TI - Myosin-cross-reactive antigen (MCRA) protein from Bifidobacterium breve is a FAD dependent fatty acid hydratase which has a function in stress protection. AB - BACKGROUND: The aim of this study was to determine the catalytic activity and physiological role of myosin-cross-reactive antigen (MCRA) from Bifidobacterium breve NCIMB 702258. MCRA from B. breve NCIMB 702258 was cloned, sequenced and expressed in heterologous hosts (Lactococcus and Corynebacterium) and the recombinant proteins assessed for enzymatic activity against fatty acid substrates. RESULTS: MCRA catalysed the conversion of palmitoleic, oleic and linoleic acids to the corresponding 10-hydroxy fatty acids, but shorter chain fatty acids were not used as substrates, while the presence of trans-double bonds and double bonds beyond the position C12 abolished hydratase activity. The hydroxy fatty acids produced were not metabolised further. We also found that heterologous Lactococcus and Corynebacterium expressing MCRA accumulated increasing amounts of 10-HOA and 10-HOE in the culture medium. Furthermore, the heterologous cultures exhibited less sensitivity to heat and solvent stresses compared to corresponding controls. CONCLUSIONS: MCRA protein in B. breve can be classified as a FAD-containing double bond hydratase, within the carbon-oxygen lyase family, which may be catalysing the first step in conjugated linoleic acid (CLA) production, and this protein has an additional function in bacterial stress protection. PMID- 21329503 TI - Upregulation of microRNA-451 increases cisplatin sensitivity of non-small cell lung cancer cell line (A549). AB - BACKGROUND: Recently, miR-451 as a tumor suppressor has been reported in other studies. However, whether miR-451 can affect the sensitivity of non-small cell lung cancer (NSCLC) cells to cisplatin (DDP) remains unclear. The aim of this study is to evaluate the roles of miR-451 in the sensitivity of NSCLC cells to DDP. METHODS: Quantitative RT-PCR assay was performed to detect the expression of miR-451 in 10 pairs of NSCLC and noncancerous tissue samples. pcDNA-GW/EmGFP-miR 451 was stably transfected into NSCLC cell line (A549). Then, the effects of miR 451 upregulation on growth, colony formation and apoptosis of A549 cells were investigated. Finally, the effects of miR-451 upregulation on in vitro and in vivo sensitivity of A549 cells of DDP were also determined. RESULTS: The level of miR-451 expression in NSCLC tissues was significantly higher than that in corresponding noncancerous tissues. Ectopic overexpression of miR-451 could significantly inhibit growth and induce apoptosis of A549 cells. Moreover, ectopic overexpression of miR-451 could sensitize A549 cells to DDP possibly by increasing DDP-induced apoptosis which might be associated with the inactivation of Akt signaling pathway. CONCLUSIONS: This study demonstrated for the first time that combination of DDP application with miR-451 upregulation might be a potential strategy for the treatment of human NSCLC. PMID- 21329504 TI - Anti-dsDNA-NcX ELISA: dsDNA-loaded nucleosomes improve diagnosis and monitoring of disease activity in systemic lupus erythematosus. AB - INTRODUCTION: The objective of this study was to compare the clinical usefulness of the new anti-double-stranded DNA nucleosome-complexed enzyme-linked immunosorbent assay (Anti-dsDNA-NcX ELISA), which is based on dsDNA-loaded nucleosomes as antigens, with established test systems based on dsDNA or nucleosomes alone for systemic lupus erythematosus (SLE) diagnostics and determination of disease activity. METHODS: Sera from a cohort of 964 individuals comprising 207 SLE patients, 357 disease controls and 400 healthy donors were investigated using the Anti-dsDNA-NcX ELISA, Farr assay, Anti-dsDNA ELISA, Anti nucleosome ELISA and Crithidia luciliae immunofluorescence (CLIF) assay, all of which are tests available from EUROIMMUN Medizinische Labordiagnostika AG (Lubeck, Germany). Receiver operating characteristic curve analyses were performed to compare the sensitivity and specificity of each assay. The test results yielded by these assays in a group of 165 fully characterized SLE patients were compared with the corresponding medical records. RESULTS: The Anti dsDNA-NcX ELISA was found to have a sensitivity of 60.9% and a specificity of 98.9% in all 964 individuals at the manufacturer's cutoff of 100 U/ml. At a comparable specificity of 99%, the sensitivity amounted to 59.9% for the Anti dsDNA-NcX ELISA, 54.1% for the Farr assay, 53.6% for the antinucleosome ELISA and 35.8% for the anti-dsDNA ELISA. The CLIF assay had a sensitivity of 28.0% and a specificity of 98.2%. The Anti-dsDNA-NcX ELISA correlated mostly with global disease activity in a cross-sectional analysis. In a longitudinal analysis of 20 patients with 69 patient visits, changes in Anti-dsDNA-NcX ELISA and antinucleosome ELISA results correlated highly with changes in disease activity over time. CONCLUSIONS: The use of dsDNA-complexed nucleosomes as antigens in ELISA leads to optimized determination of diagnosis and disease activity in SLE patients and is available for clinical practice. PMID- 21329505 TI - Leiomyosarcoma with partial rhabdomyoblastic differentiation: first case report of primary cardiac origin. AB - BACKGROUND: Leiomyosarcoma occurring as a primary cardiac tumor has been known as an extremely rare condition. Previous studies of leiomyosarcoma with rhabdomyoblastic differentiation have conducted to those arisen from another site, and they indicated a poorer prognosis of this tumor. CASE PRESENTATION: A 69-year-old woman was referred to our hospital for an operation concerning umbilical hernia. Subsequent imaging examinations before an operation indicated the presence of primary cardiac malignant tumor due to its atypical shape. And then, it was surgically removed. Histopathologically, tumor cells consisted of two different types: spindle and polyhedral cells. Immunohistochemically, it is interesting to note that 2.1% of spindle cells and 23.1% of polyhedral cells showed positive reactivity for myogenin. Furthermore, we performed double immunostaining for alpha-smooth muscle actin (SMA) and myogenin. The rates of alpha-SMA and myogenin double negative, alpha-SMA single positive, myogenin single positive, and alpha-SMA and myogenin double positive in spindle cells were estimated as 69.1%, 28.8%, 1.1% and 1.0%, respectively. In contrast, the rates in polyhedral cells were estimated as 76.9%, 0.0%, 23.1%, and 0.0%, respectively. CONCLUSION: Our immunohistochemical evaluation suggested that rhabdomyoblastic differentiation in leiomyosarcoma might be generated not only by de novo generation from mesenchymal cells. To the best of our knowledge, this is the first case of primary cardiac leiomyosarcoma with partial rhabdomyoblastic differentiation. PMID- 21329506 TI - Following the funding trail: financing, nurses and teamwork in Australian general practice. AB - BACKGROUND: Across the globe the emphasis on roles and responsibilities of primary care teams is under scrutiny. This paper begins with a review of general practice financing in Australia, and how nurses are currently funded. We then examine the influence on funding structures on the role of the nurse. We set out three dilemmas for policy-makers in this area: lack of an evidence base for incentives, possible untoward impacts on interdisciplinary functioning, and the substitution/enhancement debate. METHODS: This three year, multimethod study undertook rapid appraisal of 25 general practices and year-long studies in seven practices where a change was introduced to the role of the nurse. Data collected included interviews with nurses (n = 36), doctors (n = 24), and managers (n = 22), structured observation of the practice nurse (51 hours of observation), and detailed case studies of the change process in the seven year-long studies. RESULTS: Despite specific fee-for-service funding being available, only 6% of nurse activities generated such a fee. Yet the influence of the funding was to focus nurse activity on areas that they perceived were peripheral to their roles within the practice. CONCLUSIONS: Interprofessional relationships and organisational climate in general practices are highly influential in terms of nursing role and the ability of practices to respond to and utilise funding mechanisms. These factors need to be considered, and the development of optimal teamwork supported in the design and implementation of further initiatives that financially support nursing in general practice. PMID- 21329507 TI - New investments in primary care in Australia. AB - There is a crisis in primary care health workforce shortages in Australia. Its government has attempted to fix this by role-substitution (replacing medical work with nursing instead). This was not completely successful. Obstacles included entrenched social roles (leading to doctors 'checking' their nurse role substituted work) and structures (nurses subservient to doctors)--both exacerbated by primary care doctors' ageing demographic; doctors owning their own practices; doctors feeling themselves to have primary responsibility for the care delivered; and greater attraction towards independence that may have selected doctors into primary care in the first place.Yet there is much to be optimistic about this social experiment. It was conducted, if not ideally, at least in an environment that the Australian government has enriched with capacity for research and evaluation. PMID- 21329508 TI - Interventions to enhance adherence to dietary advice for preventing and managing chronic diseases in adults: a study protocol. AB - BACKGROUND: Adoption of a healthy diet has been identified as the cornerstone in the prevention and management of chronic diseases. However, non-adherence to lifestyle changes raises an important issue since adherence level to dietary advice is a key determinant of the effectiveness of dietary treatment. Therefore, based on the results of a Cochrane systematic review on interventions for enhancing adherence to dietary advice for preventing and managing chronic diseases in adults, the aim of this study is to assess the importance and applicability of interventions enhancing adherence to dietary advice in the Canadian context. METHODS/DESIGN: In phase 1, dietitians' opinion will be assessed through a Delphi study regarding the importance and the applicability in the Canadian context of the interventions found the most effective to enhance adherence to dietary advice through a Cochrane systematic review. In phase 2, findings of the Cochrane systematic review assessing the effects of interventions for enhancing adherence to dietary advice will be reported in a practical format on an online knowledge translation tool for dietitians and other health professionals. DISCUSSION: In recent years, there has been an increasing recognition of the failure to translate research findings into clinical practice. Therefore, knowledge translation efforts need to prioritize effective interventions that will be the most relevant for practice and end-users by adapting them to the local context. Our study will provide decision makers in the field of dietetic practice with essential knowledge on adherence for elaborating educational activities for academic or professional settings that will respond to dietitians' priorities in terms of importance and applicability to day-to-day practice. PMID- 21329509 TI - Kalrn promoter usage and isoform expression respond to chronic cocaine exposure. AB - BACKGROUND: The long-term effects of cocaine on behavior are accompanied by structural changes in excitatory glutamatergic synapses onto the medium spiny neurons of the striatum. The Kalrn gene encodes several functionally distinct isoforms; these multidomain guanine nucleotide exchange factors (GEFs) contain additional domains known to interact with phosphatidylinositides as well as with a number of different proteins. Through their activation of Rho proteins and their interactions with other proteins, the different Kalirin isoforms affect cytoskeletal organization. Chronic exposure of adult male rodents to cocaine increases levels of Kalirin 7 in the striatum. When exposed chronically to cocaine, mice lacking Kalirin 7, the major adult isoform, fail to show an increase in dendritic spine density in the nucleus accumbens, show diminished place preference for cocaine, and exhibit increased locomotor activity in response to cocaine. RESULTS: The use of alternate promoters and 3'-terminal exons of the mouse Kalrn gene were investigated using real-time quantitative polymerase chain reaction. While the two most distal full-length Kalrn promoters are used equally in the prefrontal cortex, the more proximal of these promoters accounts for most of the transcripts expressed in the nucleus accumbens. The 3' terminal exon unique to the Kalirin 7 isoform accounts for a greater percentage of the Kalrn transcripts in prefrontal cortex than in nucleus accumbens. Western blot analyses confirmed these differences. Chronic cocaine treatment increases usage of the promoter encoding the Delta-Kalirin isoforms but does not alter full length Kalirin promoter usage. Usage of the 3'-terminal exon unique to Kalirin 7 increases following chronic cocaine exposure. CONCLUSIONS: Kalrn promoter and 3' terminal exon utilization are region-specific. In the nucleus accumbens, cocaine mediated alterations in promoter usage and 3'-terminal exon usage favor expression of Kalirin 7 and Delta-Kalirin 7. The Delta-isoform, which lacks a Sec14p domain and four of the nine spectrin-like repeats found in full-length Kalirin isoforms, increases spine headsize without increasing dendritic spine numbers. Thus cocaine-mediated changes in alternative splicing of the Kalrn gene may contribute importantly to the behavioral, morphological and biochemical responses observed. PMID- 21329510 TI - Differential expression of THOC1 and ALY mRNP biogenesis/export factors in human cancers. AB - BACKGROUND: One key step in gene expression is the biogenesis of mRNA ribonucleoparticle complexes (mRNPs). Formation of the mRNP requires the participation of a number of conserved factors such as the THO complex. THO interacts physically and functionally with the Sub2/UAP56 RNA-dependent ATPase, and the Yra1/REF1/ALY RNA-binding protein linking transcription, mRNA export and genome integrity. Given the link between genome instability and cancer, we have performed a comparative analysis of the expression patterns of THOC1, a THO complex subunit, and ALY in tumor samples. METHODS: The mRNA levels were measured by quantitative real-time PCR and hybridization of a tumor tissue cDNA array; and the protein levels and distribution by immunostaining of a custom tissue array containing a set of paraffin-embedded samples of different tumor and normal tissues followed by statistical analysis. RESULTS: We show that the expression of two mRNP factors, THOC1 and ALY are altered in several tumor tissues. THOC1 mRNA and protein levels are up-regulated in ovarian and lung tumors and down-regulated in those of testis and skin, whereas ALY is altered in a wide variety of tumors. In contrast to THOC1, ALY protein is highly detected in normal proliferative cells, but poorly in high-grade cancers. CONCLUSIONS: These results suggest a differential connection between tumorogenesis and the expression levels of human THO and ALY. This study opens the possibility of defining mRNP biogenesis factors as putative players in cell proliferation that could contribute to tumor development. PMID- 21329511 TI - To test or not to test: a cross-sectional survey of the psychosocial determinants of self-testing for cholesterol, glucose, and HIV. AB - BACKGROUND: Although self-tests are increasingly available and widely used, it is not clear whether their use is beneficial to the users, and little is known concerning the determinants of self-test use. The aim of this study was to identify the determinants of self-test use for cholesterol, glucose, and HIV, and to examine whether these are similar across these tests. Self-testing was defined as using in-vitro tests on body materials, initiated by consumers with the aim of diagnosing a particular disorder, condition, or risk factor for disease. METHODS: A cross-sectional Internet survey was conducted among 513 self-testers and 600 non-testers, assessing possible determinants of self-test use. The structured questionnaire was based on the Health Belief Model, Theory of Planned Behavior, and Protection Motivation Theory. Data were analyzed by means of logistic regression. RESULTS: The results revealed that perceived benefits and self efficacy were significantly associated with self-testing for all three conditions. Other psychosocial determinants, e.g. gender, cues to action, perceived barriers, subjective norm, and moral obligation, seemed to be more test specific. CONCLUSIONS: Psychosocial determinants of self-testing are not identical for all tests and therefore information about self-testing needs to be tailored to a specific test. The general public should not only be informed about advantages of self-test use but also about the disadvantages. Designers of information about self-testing should address all aspects related to self-testing to stimulate informed decision making which, in turn, will result in more effective self-test use. PMID- 21329512 TI - Predictors of consistent condom use based on the Information-Motivation Behavioral Skills (IMB) model among female sex workers in Jinan, China. AB - BACKGROUND: Female commercial sex workers (FSWs) are at high risk of human immunodeficiency virus (HIV) transmission in China. This study was designed to examine the predictors of condom use with clients during vaginal intercourse among FSWs based on the Information-Motivation-Behavioral Skills (IMB) model and to describe the relationships between IMB model constructs. METHODS: A cross sectional study was conducted in Jinan of Shandong Province, from May to October, 2009. Participants (N = 432) were recruited using Respondent-Driven Sampling (RDS). A self-administered questionnaire was used to collect data. Structural equation modeling was used to assess the IMB model. RESULTS: A total of 427 (98.8%) participants completed their questionnaires. Condom use was significantly predicted by social referents support, experiences with and attitudes toward condoms, self-efficacy, and health behaviors and condom use skills. Significant indirect predictors of condom use mediated through behavioral skills included HIV knowledge, social referents support, and substance use. CONCLUSIONS: These results suggest that the IMB model could be used to predict condom use among Chinese FSWs. Further research is warranted to develop preventive interventions on the basis of the IMB model to promote condom use among FSWs in China. PMID- 21329513 TI - A telephone- and text-message based telemedical care concept for patients with mental health disorders--study protocol for a randomized, controlled study design. AB - BACKGROUND: As in other countries worldwide, the prevalence of mental disorders in Germany is high. Although numerically a dense network of in- and outpatient psychiatric health services exists, the availability in rural and remote regions is insufficient.In rural regions, telemedical concepts can be a chance to unburden and complement the existing healthcare system. Telemedical concepts consisting of video or telephone consulting show first positive results, but there are only a few studies with a randomized controlled design.To improve the treatment of patients with mental disorders in rural regions, we developed a telemedical care concept based on telephone contacts and text-messages. The primary objective of this study is to evaluate the effects of the telemedical interventions on psychopathological outcomes, e. g. anxiety, depressive symptoms, and somatisation. Secondary objective of the study is the analysis of intervention effects on the frequency of medical contacts with healthcare services. Furthermore, the frequency of patients' crises and the frequency and kind of interventions, initiated by the project nurses will be evaluated. We will also evaluate the acceptance of the telemedical care concept by the patients. METHODS/DESIGN: In this paper we describe a three-armed, randomized, controlled study. All participants are recruited from psychiatric day hospitals. The inclusion criteria are a specialist-diagnosed depression, anxiety disorder, adjustment disorder or a somatoform disorder and eligibility to participate in the study. Exclusion criteria are ongoing outpatient psychotherapy, planned interval treatment at the day clinic and expected recurrent suicidality and self injuring behaviour.The interventions consist of regular patient-individual telephone consultations or telephone consultations with complementing text messages on the patients' mobile phone. The interventions will be conducted during a time period of 6 months. TRIAL REGISTRATION: This study is registered in the German Clinical Trials Register (DRKS00000662). PMID- 21329514 TI - Association of the D repeat polymorphism in the ASPN gene with developmental dysplasia of the hip: a case-control study in Han Chinese. AB - INTRODUCTION: Developmental dysplasia of the hip (DDH) is a common skeletal disease, which is characterized by abnormal seating of the femoral head in the acetabulum. Genetic factors play a considerable role in the etiology of DDH. Asporin (ASPN) is an ECM protein which can bind to TGF-beta1 and sequentially inhibit TGF-beta/Smad signaling. A functional aspartic acid (D) repeat polymorphism of ASPN was first described as an osteoarthritis-associated polymorphism. As TGF-beta is well known as an important regulator in the development of skeletal components, ASPN may also be involved in the etiology of DDH. Our objective is to evaluate whether the D repeat polymorphism of ASPN is associated with DDH in Han Chinese. METHODS: The D repeat polymorphism was genotyped in 370 DDH patients and 445 control subjects, and the allelic association of the D repeat was examined. RESULTS: From D11 to D18, eight alleles were identified. D13 allele is the most common allele both in control and DDH groups, the frequencies are 67.3% and 58.1% respectively. In the DDH group, a significantly higher frequency of the D14 allele and significantly lower frequency of D13 was observed. The association of D14 and D13 was found in both females and males after stratification by gender. There was no significant difference in any other alleles we examined. CONCLUSIONS: Our results show an obvious association between the D repeat polymorphism of ASPN and DDH. It indicates that ASPN is an important regulator in the etiology of DDH. PMID- 21329516 TI - Tracking and monitoring the health workforce: a new human resources information system (HRIS) in Uganda. AB - BACKGROUND: Health workforce planning is important in ensuring that the recruitment, training and deployment of health workers are conducted in the most efficient way possible. However, in many developing countries, human resources for health data are limited, inconsistent, out-dated, or unavailable. Consequently, policy-makers are unable to use reliable data to make informed decisions about the health workforce. Computerized human resources information systems (HRIS) enable countries to collect, maintain, and analyze health workforce data. METHODS: The purpose of this article is twofold. First, we describe Uganda's transition from a paper filing system to an electronic HRIS capable of providing information about country-specific health workforce questions. We examine the ongoing five-step HRIS strengthening process used to implement an HRIS that tracks health worker data at the Uganda Nurses and Midwives Council (UNMC). Secondly, we describe how HRIS data can be used to address workforce planning questions via an initial analysis of the UNMC training, licensure and registration records from 1970 through May 2009. RESULTS: The data indicate that, for the 25 482 nurses and midwives who entered training before 2006, 72% graduated, 66% obtained a council registration, and 28% obtained a license to practice. Of the 17 405 nurses and midwives who obtained a council registration as of May 2009, 96% are of Ugandan nationality and just 3% received their training outside of the country. Thirteen per cent obtained a registration for more than one type of training. Most (34%) trainings with a council registration are for the enrolled nurse training, followed by enrolled midwife (25%), registered (more advanced) nurse (21%), registered midwife (11%), and more specialized trainings (9%). CONCLUSION: The UNMC database is valuable in monitoring and reviewing information about nurses and midwives. However, information obtained from this system is also important in improving strategic planning for the greater health care system in Uganda. We hope that the use of a real-world example of HRIS strengthening provides guidance for the implementation of similar projects in other countries or contexts. PMID- 21329515 TI - A phage-targeting strategy for the design of spatiotemporal drug delivery from grafted matrices. AB - BACKGROUND: The natural response to injury is dynamic and normally consists of complex temporal and spatial cellular changes in gene expression, which, when acting in synchrony, result in patent tissue repair and, in some instances, regeneration. However, current therapeutic regiments are static and most rely on matrices, gels and engineered skin tissue. Accordingly, there is a need to design next-generation grafting materials to enable biotherapeutic spatiotemporal targeting from clinically approved matrices. To this end, rather then focus on developing completely new grafting materials, we investigated whether phage display could be deployed onto clinically approved synthetic grafts to identify peptide motifs capable of linking pharmaceutical drugs with differential affinities and eventually, control drug delivery from matrices over both space and time. METHODS: To test this hypothesis, we biopanned combinatorial peptide libraries onto different formulations of a wound-healing matrix (Integra(r)) and eluted the bound peptides with 1) high salt, 2) collagen and glycosaminoglycan or 3) low pH. After three to six rounds of biopanning, phage recovery and phage amplification of the bound particles, any phage that had acquired a capacity to bind the matrix was sequenced. RESULTS: In this first report, we identify distinct classes of matrix-binding peptides which elute differently from the screened matrix and demonstrate that they can be applied in a spatially relevant manner. CONCLUSIONS: We suggest that further applications of these combinatorial techniques to wound-healing matrices may offer a new way to improve the performance of clinically approved matrices so as to introduce temporal and spatial control over drug delivery. PMID- 21329517 TI - Non-linear relationships of cerebrospinal fluid biomarker levels with cognitive function: an observational study. AB - INTRODUCTION: Levels of cerebrospinal fluid (CSF) beta-amyloid (Abeta) and Tau proteins change in Alzheimer's disease (AD). We tested if the relationships of these biomarkers with cognitive impairment are linear or non-linear. METHODS: We assessed cognitive function and assayed CSF Abeta and Tau biomarkers in 95 non demented volunteers and 97 AD patients. We then tested non-linearities in their inter-relations. RESULTS: CSF biomarkers related to cognitive function in the non demented range of cognition, but these relations were weak or absent in the patient range; Abeta1-40's relationship was biphasic. CONCLUSIONS: Major biomarker changes precede clinical AD and index cognitive impairment in AD poorly, if at all. PMID- 21329518 TI - Bioprotective properties of Dragon's blood resin: in vitro evaluation of antioxidant activity and antimicrobial activity. AB - BACKGROUND: Food preservation is basically done to preserve the natural characteristics and appearance of the food and to increase the shelf life of food. Food preservatives in use are natural, chemical and artificial. Keeping in mind the adverse effects of synthetic food preservatives, there is a need to identify natural food preservatives. The aims of this study were to evaluate in vitro antioxidant and antimicrobial activities of Dragon's blood resin obtained from Dracaena cinnabari Balf f., with a view to develop safer food preservatives. METHODS: In this study, three solvents of varying polarity were used to extract and separate the medium and high polarity compounds from the non-polar compounds of the Dragon's blood resin. The extracts were evaluated for their antimicrobial activity against the food borne pathogens. The antioxidant activities of the extracts were assessed using DPPH and ABTS radical scavenging, FRAP, metal chelating and reducing power assays. Total phenolics, flavonoids and flavonols of extracts were also estimated using the standard methods. RESULTS: Phytochemical analysis of extracts revealed high phenolic content in CH(2)Cl(2) extract of resin. Free radical scavenging of CH(2)Cl(2) extract was found to be highest which is in good correlation with its total phenolic content. All test microorganisms were also inhibited by CH(2)Cl(2) extract. CONCLUSIONS: Our result provide evidence that CH(2)Cl(2) extract is a potential source of natural antioxidant compounds and exhibited good inhibitory activity against various food borne pathogens. Thus, CH(2)Cl(2) extract of Dragon's blood resin could be considered as possible source of food preservative. PMID- 21329519 TI - A national survey of 'inactive' physicians in the United States of America: enticements to reentry. AB - BACKGROUND: Physicians leaving and reentering clinical practice can have significant medical workforce implications. We surveyed inactive physicians younger than typical retirement age to determine their reasons for clinical inactivity and what barriers, real or perceived, there were to reentry into the medical workforce. METHODS: A random sample of 4975 inactive physicians aged under 65 years was drawn from the Physician Masterfile of the American Medical Association in 2008. Physicians were mailed a survey about activity in medicine and perceived barriers to reentry. Chi-square statistics were used for significance tests of the association between categorical variables and t-tests were used to test differences between means. RESULTS: Our adjusted response rate was 36.1%. Respondents were fully retired (37.5%), not currently active in medicine (43.0%) or now active (reentered, 19.4%). Nearly half (49.5%) were in or had practiced primary care. Personal health was the top reason for leaving for fully retired physicians (37.8%) or those not currently active in medicine (37.8%) and the second highest reason for physicians who had reentered (28.8%). For reentered (47.8%) and inactive (51.5%) physicians, the primary reason for returning or considering returning to practice was the availability of part-time work or flexible scheduling. Retired and currently inactive physicians used similar strategies to explore reentry, and 83% of both groups thought it would be difficult; among those who had reentered practice, 35.9% reported it was difficult to reenter. Retraining was uncommon for this group (37.5%). CONCLUSION: Availability of part-time work and flexible scheduling have a strong influence on decisions to leave or reenter clinical practice. Lack of retraining before reentry raises questions about patient safety and the clinical competence of reentered physicians. PMID- 21329520 TI - Comparison of clinical knowledge management capabilities of commercially available and leading internally-developed electronic health records. AB - BACKGROUND: We have carried out an extensive qualitative research program focused on the barriers and facilitators to successful adoption and use of various features of advanced, state-of-the-art electronic health records (EHRs) within large, academic, teaching facilities with long-standing EHR research and development programs. We have recently begun investigating smaller, community hospitals and out-patient clinics that rely on commercially-available EHRs. We sought to assess whether the current generation of commercially-available EHRs are capable of providing the clinical knowledge management features, functions, tools, and techniques required to deliver and maintain the clinical decision support (CDS) interventions required to support the recently defined "meaningful use" criteria. METHODS: We developed and fielded a 17-question survey to representatives from nine commercially available EHR vendors and four leading internally developed EHRs. The first part of the survey asked basic questions about the vendor's EHR. The second part asked specifically about the CDS-related system tools and capabilities that each vendor provides. The final section asked about clinical content. RESULTS: All of the vendors and institutions have multiple modules capable of providing clinical decision support interventions to clinicians. The majority of the systems were capable of performing almost all of the key knowledge management functions we identified. CONCLUSION: If these well designed commercially-available systems are coupled with the other key socio technical concepts required for safe and effective EHR implementation and use, and organizations have access to implementable clinical knowledge, we expect that the transformation of the healthcare enterprise that so many have predicted, is achievable using commercially-available, state-of-the-art EHRs. PMID- 21329521 TI - Breastfeeding and the risk of rotavirus diarrhea in hospitalized infants in Uganda: a matched case control study. AB - BACKGROUND: Rotavirus is responsible for over 25 million outpatient visits, over 2 million hospitalizations and 527,000 deaths annually, worldwide. It is estimated that breastfeeding in accordance with the World Health Organization recommendations would save 1.45 million children's lives each year in the developing countries. The few studies that examined the effect of breastfeeding on rotavirus diarrhea produced conflicting results. This study aimed to determine the effect of breastfeeding on rotavirus diarrhea among admitted infants in Uganda. METHODS: The study was conducted in the Pediatrics medical emergency unit of a National Referral hospital during a peak incidence time for rotavirus from February to April 2008. It was an age matched case-control study with a ratio of 1:1. We consecutively enrolled infants presenting at the study site during this period whose caretakers consented to participate in the study. A minimum sample size of 90 pairs was adequate with power of 80% to detect a 30% decrease in breastfeeding rate among the cases assuming a breastfeeding rate of 80% in the controls. The infants with rotavirus positive results were the "cases". We used the commercial enzyme immunoassay kit (DAKO IDEIATM rotavirus EIA detection kit) to diagnose the cases. The "controls" were admitted children with no diarrhea. We compared the cases and controls for antecedent breastfeeding patterns. RESULTS: Ninety-one matched case-control age-matched pairs with an age caliper of one month were included in the analysis. Breastfeeding was not protective against rotavirus diarrhea (OR 1.08: 95% CI 0.52 - 2.25; p = 0.8) in the conditional logistic model. CONCLUSIONS: Our study findings did not reveal breastfeeding as protective against rotavirus diarrhea in infants. This suggests searching for other complementary preventive methods such as rotavirus vaccination and zinc supplementation to reduce the problem of rotavirus diarrhea in infants irrespective of their feeding practices. PMID- 21329522 TI - Genome-wide prediction of discrete traits using Bayesian regressions and machine learning. AB - BACKGROUND: Genomic selection has gained much attention and the main goal is to increase the predictive accuracy and the genetic gain in livestock using dense marker information. Most methods dealing with the large p (number of covariates) small n (number of observations) problem have dealt only with continuous traits, but there are many important traits in livestock that are recorded in a discrete fashion (e.g. pregnancy outcome, disease resistance). It is necessary to evaluate alternatives to analyze discrete traits in a genome-wide prediction context. METHODS: This study shows two threshold versions of Bayesian regressions (Bayes A and Bayesian LASSO) and two machine learning algorithms (boosting and random forest) to analyze discrete traits in a genome-wide prediction context. These methods were evaluated using simulated and field data to predict yet-to-be observed records. Performances were compared based on the models' predictive ability. RESULTS: The simulation showed that machine learning had some advantages over Bayesian regressions when a small number of QTL regulated the trait under pure additivity. However, differences were small and disappeared with a large number of QTL. Bayesian threshold LASSO and boosting achieved the highest accuracies, whereas Random Forest presented the highest classification performance. Random Forest was the most consistent method in detecting resistant and susceptible animals, phi correlation was up to 81% greater than Bayesian regressions. Random Forest outperformed other methods in correctly classifying resistant and susceptible animals in the two pure swine lines evaluated. Boosting and Bayes A were more accurate with crossbred data. CONCLUSIONS: The results of this study suggest that the best method for genome-wide prediction may depend on the genetic basis of the population analyzed. All methods were less accurate at correctly classifying intermediate animals than extreme animals. Among the different alternatives proposed to analyze discrete traits, machine-learning showed some advantages over Bayesian regressions. Boosting with a pseudo Huber loss function showed high accuracy, whereas Random Forest produced more consistent results and an interesting predictive ability. Nonetheless, the best method may be case-dependent and a initial evaluation of different methods is recommended to deal with a particular problem. PMID- 21329523 TI - Purification and biochemical characterization of pancreatic phospholipase A2 from the common stingray Dasyatis pastinaca. AB - BACKGROUND: Mammalian sPLA2-IB are well characterized. In contrast, much less is known about aquatic ones. The aquatic world contains a wide variety of living species and, hence represents a great potential for discovering new lipolytic enzymes. RESULTS: A marine stingray phospholipase A2 (SPLA2) was purified from delipidated pancreas. Purified SPLA2, which is not glycosylated protein, was found to be monomeric protein with a molecular mass of 14 kDa. A specific activity of 750 U/mg for purified SPLA2 was measured at optimal conditions (pH 8.5 and 40 degrees C) in the presence of 4 mM NaTDC and 8 mM CaCl2 using PC as substrate. The sequence of the first twenty first amino-acid residues at the N terminal extremity of SPLA2 was determined and shows a close similarity with known mammal and bird pancreatic secreted phospholipases A2. SPLA2 stability in the presence of organic solvents, as well as in acidic and alkaline pH and at high temperature makes it a good candidate for its application in food industry. CONCLUSIONS: SPLA2 has several advantageous features for industrial applications. Stability of SPLA2 in the presence of organic solvents, and its tolerance to high temperatures, basic and acidic pH, makes it a good candidate for application in food industry to treat phospholipid-rich industrial effluents, or to synthesize useful chemical compounds. PMID- 21329524 TI - Genetic educational needs and the role of genetics in primary care: a focus group study with multiple perspectives. AB - BACKGROUND: Available evidence suggests that improvements in genetics education are needed to prepare primary care providers for the impact of ongoing rapid advances in genomics. Postgraduate (physician training) and master (midwifery training) programmes in primary care and public health are failing to meet these perceived educational needs. The aim of this study was to explore the role of genetics in primary care (i.e. family medicine and midwifery care) and the need for education in this area as perceived by primary care providers, patient advocacy groups and clinical genetics professionals. METHODS: Forty-four participants took part in three types of focus groups: mono-disciplinary groups of general practitioners and midwives, respectively and multidisciplinary groups composed of a diverse set of experts. The focus group sessions were audio-taped, transcribed verbatim and analysed using content analysis. Recurrent themes were identified. RESULTS: Four themes emerged regarding the educational needs and the role of genetics in primary care: (1) genetics knowledge, (2) family history, (3) ethical dilemmas and psychosocial effects in relation to genetics and (4) insight into the organisation and role of clinical genetics services. These themes reflect a shift in the role of genetics in primary care with implications for education. Although all focus group participants acknowledged the importance of genetics education, general practitioners felt this need more urgently than midwives and more strongly emphasized their perceived knowledge deficiencies. CONCLUSION: The responsibilities of primary care providers with regard to genetics require further study. The results of this study will help to develop effective genetics education strategies to improve primary care providers' competencies in this area. More research into the educational priorities in genetics is needed to design courses that are suitable for postgraduate and master programmes for general practitioners and midwives. PMID- 21329525 TI - An interdisciplinary intervention to prevent falls in community-dwelling elderly persons: protocol of a cluster-randomized trial [PreFalls]. AB - BACKGROUND: Prevention of falls in the elderly is a public health target in many countries around the world. While a large number of trials have investigated the effectiveness of fall prevention programs, few focussed on interventions embedded in the general practice setting and its related network. In the Prevent Falls (PreFalls) trial we aim to investigate the effectiveness of a pre-tested multi modal intervention compared to usual care in this setting. METHODS/DESIGN: PreFalls is a controlled multicenter prospective study with cluster-randomized allocation of about 40 general practices to an experimental or a control group. We aim to include 382 community dwelling persons aged 65 and older with an increased risk of falling. All participating general practitioners are trained to systematically assess the risk of falls using a set of validated tests. Patients from intervention practices are invited to participate in a 16-weeks exercise program with focus on fall prevention delivered by specifically trained local physiotherapists. Patients from practices allocated to the control group receive usual care. Main outcome measure is the number of falls per individual in the first 12 months (analysis by negative binomial regression). Secondary outcomes include falls in the second year, the proportion of participants falling in the first and the second year, falls associated with injury, risk of falls, fear of falling, physical activity and quality of life. DISCUSSION: Reducing falls in the elderly remains a major challenge. We believe that with its strong focus on a both systematic and realistic fall prevention strategy adapted to primary care setting PreFalls will be a valuable addition to the scientific literature in the field. TRIAL REGISTRATION: NCT01032252. PMID- 21329526 TI - Evaluation of the antibacterial and anticancer activities of some South African medicinal plants. AB - BACKGROUND: Several herbs are traditionally used in the treatment of a variety of ailments particularly in the rural areas of South Africa where herbal medicine is mainly the source of health care system. Many of these herbs have not been assessed for safety or toxicity to tissue or organs of the mammalian recipients. METHODS: This study evaluated the cytotoxicity of some medicinal plants used, inter alia, in the treatment of diarrhoea, and stomach disorders. Six selected medicinal plants were assessed for their antibacterial activities against ampicillin-resistant and kanamycin-resistant strains of Escherichia coli by the broth micro-dilution methods. The cytotoxicities of methanol extracts and fractions of the six selected plants were determined using a modified tetrazolium based colorimetric assay (3-(4, 5-dimethylthiazol)-2, 5-diphenyl tetrazolium bromide (MTT) assay). RESULTS: The average minimum inhibitory concentration (MIC) values of the plants extracts ranged from 0.027 mg/ml to 2.5 mg/ml after 24 h of incubation. Eucomis autumnalis and Cyathula uncinulata had the most significant biological activity with the least MIC values. The in vitro cytotoxicity assay on human hepatocarcinoma cell line (Huh-7) revealed that the methanol extract of E. autumnalis had the strongest cytotoxicity with IC(50) of 7.8 MUg/ml. Ethyl acetate and butanol fractions of C. uncinulata, Hypoxis latifolia, E. autumnalis and Lantana camara had lower cytotoxic effects on the cancer cell lines tested with IC(50) values ranging from 24.8 to 44.1 MUg/ml; while all the fractions of Aloe arborescens and A. striatula had insignificant or no cytotoxic effects after 72 h of treatment. CONCLUSIONS: Our results indicate that the methanol fraction of E. autumnalis had a profound cytotoxic effect even though it possessed very significant antibacterial activity. This puts a query on its safety and hence a call for caution in its usage, thus a product being natural is not tantamount to being entirely safe. However, the antibacterial activities and non-cytotoxic effects of A. arborescens and A. striatula validates their continuous usage in ethnomedicine. PMID- 21329527 TI - The population-based Barcelona-Asymptomatic Intracranial Atherosclerosis Study (ASIA): rationale and design. AB - BACKGROUND: Large-artery intracranial atherosclerosis may be the most frequent cause of ischemic stroke worldwide. Traditional approaches have attempted to target the disease when it is already symptomatic. However, early detection of intracranial atherosclerosis may allow therapeutic intervention while the disease is still asymptomatic. The prevalence and natural history of asymptomatic intracranial atherosclerosis in Caucasians remain unclear. The aims of the Barcelona-ASymptomatic Intracranial Atherosclerosis (ASIA) study are (1) to determine the prevalence of ASIA in a moderate-high vascular risk population, (2) to study its prognostic impact on the risk of suffering future major ischemic events, and (3) to identify predictors of the development, progression and clinical expression of this condition. METHODS/DESIGN: Cross-over and cohort, population-based study. A randomly selected representative sample of 1,503 subjects with a mild-moderate-high vascular risk (as defined by a REGICOR score >= 5%) and with neither a history of cerebrovascular nor ischemic heart disease will be studied. At baseline, all individuals will undergo extracranial and transcranial Color-Coded Duplex (TCCD) ultrasound examinations to detect presence and severity of extra and intracranial atherosclerosis. Intracranial stenoses will be assessed by magnetic resonance angiography (MRA). Clinical and demographic variables will be recorded and blood samples will be drawn to investigate clinical, biological and genetic factors associated with the presence of ASIA. A long-term clinical and sonographic follow-up will be conducted thereafter to identify predictors of disease progression and of incident vascular events. DISCUSSION: The Barcelona-ASIA is a population-based study aiming to evaluate the prevalence and clinical importance of asymptomatic intracranial large-artery atherosclerosis in Caucasians. The ASIA project may provide a unique scientific resource to better understand the dynamics of intracranial atherosclerosis from its early stages and to identify new potential therapeutic targets for this condition. PMID- 21329528 TI - The effect of experimental warming on leaf functional traits, leaf structure and leaf biochemistry in Arabidopsis thaliana. AB - BACKGROUND: The leaf is an important plant organ, and how it will respond to future global warming is a question that remains unanswered. The effects of experimental warming on leaf photosynthesis and respiration acclimation has been well studied so far, but relatively little information exists on the structural and biochemical responses to warming. However, such information is very important to better understand the plant responses to global warming. Therefore, we grew Arabidopsis thaliana at the three day/night temperatures of 23/18 degrees C (ambient temperature), 25.5/20.5 degrees C (elevated by 2.5 degrees C) and 28/23 degrees C (elevated by 5 degrees C) to simulate the middle and the upper projected warming expected within the 21st century for this purpose. RESULTS: The 28/23 degrees C treatment significantly reduced the life span, total biomass and total weight of seeds compared with the other two temperatures. Among the three temperature regimes, the concentrations of starch, chlorophyll, and proline were the lowest at 28/23 degrees C, whereas the total weight of seeds, concentrations of chlorophyll and proline, stomatal density (SD), stomatal conductance (gs), net CO2 assimilation rate (A) and transpiration rate (E) were the highest at 25.5/20.5 degrees C. Furthermore, the number of chloroplasts per cell and mitochondrial size were highest at 25.5/20.5 degrees C and lowest at 28/23 degrees C. CONCLUSIONS: The conditions whereby the temperature was increased by 2.5 degrees C were advantageous for Arabidopsis. However, a rise of 5 degrees C produced negative effects, suggesting that lower levels of warming may benefit plants, especially those which belong to the same functional group as Arabidopsis, whereas higher levels of warming may produce negative affects. In addition, the increase in A under moderately warm conditions may be attributed to the increase in SD, chlorophyll content, and number of chloroplasts. Furthermore, starch accumulation in chloroplasts may be the main factor influencing chloroplast ultrastructure, and elevated temperature regulates plant respiration by probably affecting mitochondrial size. Finally, high SOD and CAT activities may enable plants grown at elevated temperatures to exhibit relatively high tolerance to temperature stress, thus alleviating the harmful effects of superoxide anion radicals and hydrogen peroxide. PMID- 21329529 TI - Microwave assisted solvent free synthesis of 1,3-diphenylpropenones. AB - BACKGROUND: 1,3-Diphenylpropenones (chalcones) are well known for their diverse array of bioactivities. Hydroxyl group substituted chalcones are the main precursor in the synthesis of flavonoids. Till date various methods have been developed for the synthesis of these very interesting molecules. Continuing our efforts for the development of simple, eco-friendly and cost-effective methodologies, we report here a solvent free condensation of aryl ketones and aldehydes using iodine impregnated alumina under microwave activation. This new protocol has been applied to a variety of substituted aryl carbonyls with excellent yield of substituted 1,3-diphenylpropenones. RESULTS: Differently substituted chalcones were synthesized using iodine impregnated neutral alumina as catalyst in 79-95% yield in less than 2 minutes time under microwave activation without using any solvent. The reaction was studied under different catalytic conditions and it was found that molecular iodine supported over neutral alumina gives the best yield. The otherwise difficult single step condensation of hydroxy substituted aryl carbonyls is an attractive feature of this protocol to obtain polyhydroxychalcones in excellent yields. In order to find out the general applicability of this new endeavor it was successfully applied for the synthesis of 15 different chalcones including highly bioactive prenylated hydroxychalcone xanthohumol. CONCLUSION: A new, simple and solvent free method was developed for the synthesis of substituted chalcones in environmentally benign way. The mild reaction conditions, easy work-up, clean reaction profiles render this approach as an interesting alternative to the existing methods. PMID- 21329531 TI - Ethnic disparity in 21-hydroxylase gene mutations identified in Pakistani congenital adrenal hyperplasia patients. AB - BACKGROUND: Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders caused by defects in the steroid 21 hydroxylase gene (CYP21A2). We studied the spectrum of mutations in CYP21A2 gene in a multi-ethnic population in Pakistan to explore the genetics of CAH. METHODS: A cross sectional study was conducted for the identification of mutations CYP21A2 and their phenotypic associations in CAH using ARMS-PCR assay. RESULTS: Overall, 29 patients were analyzed for nine different mutations. The group consisted of two major forms of CAH including 17 salt wasters and 12 simple virilizers. There were 14 phenotypic males and 15 females representing all the major ethnic groups of Pakistan. Parental consanguinity was reported in 65% cases and was equally distributed in the major ethnic groups. Among 58 chromosomes analyzed, mutations were identified in 45 (78.6%) chromosomes. The most frequent mutation was I2 splice (27%) followed by Ile173Asn (26%), Arg 357 Trp (19%), Gln319stop, 16% and Leu308InsT (12%), whereas Val282Leu was not observed in this study. Homozygosity was seen in 44% and heterozygosity in 34% cases. I2 splice mutation was found to be associated with SW in the homozygous. The Ile173Asn mutation was identified in both SW and SV forms. Moreover, Arg357Trp manifested SW in compound heterozygous state. CONCLUSION: Our study showed that CAH exists in our population with ethnic difference in the prevalence of mutations examined. PMID- 21329530 TI - A 10 year follow-up study after Roux-Elmslie-Trillat treatment for cases of patellar instability. AB - BACKGROUND: A retrospective study concerning patients presenting with patella instability, treated using a Roux-Elmslie-Trillat reconstruction operation and followed up for 10 years following surgery, is presented. METHODS: Pre-operative and follow-up radiographic evaluation included the weight-bearing anteroposterior and merchant views. Evaluation was carried out using the Insall-Salvati index, sulcus and congruence angle. The Roux-Elmslie-Trillat reconstruction operation was performed on 18 patients. The clinical evaluation at follow-up was performed using the Knee-Society-Score (KSS) and Tegner-Score. RESULTS: Subjective results of the operation were classed as excellent or good in 16 of the 18 patients ten years after surgery; persistent instability of the patella was recorded in only one of the 18 patients. The majority of patients returned to the same level of sporting activity after surgery as they had participated in before injury. CONCLUSIONS: The Roux-Elmslie-Trillat procedure could be recommended in cases presenting with an increased q-angle, trochlea dysplasia or failed soft tissue surgery. In the present study the majority of patients report a return to previous sporting activity ten years after surgery. PMID- 21329532 TI - Effectively incorporating selected multimedia content into medical publications. AB - Until fairly recently, medical publications have been handicapped by being restricted to non-electronic formats, effectively preventing the dissemination of complex audiovisual and three-dimensional data. However, authors and readers could significantly profit from advances in electronic publishing that permit the inclusion of multimedia content directly into an article. For the first time, the de facto gold standard for scientific publishing, the portable document format (PDF), is used here as a platform to embed a video and an audio sequence of patient data into a publication. Fully interactive three-dimensional models of a face and a schematic representation of a human brain are also part of this publication. We discuss the potential of this approach and its impact on the communication of scientific medical data, particularly with regard to electronic and open access publications. Finally, we emphasise how medical teaching can benefit from this new tool and comment on the future of medical publishing. PMID- 21329533 TI - [A woman with unusual calcified depositions]. AB - A 63-years-old woman was admitted to the intensive care department because of a perforated appendix and peritonitis. On the CT-scan two calcified depositions were seen at the cervix-vagina-area. The IUD was removed and two calcified depositions on the IUD were seen. PMID- 21329534 TI - [Diabetes mellitus and cirrhosis of the liver: a prognostically unfavourable combination]. AB - We conducted a literature search to determine the prognostic effect of diabetes in patients with cirrhosis of the liver. We also searched for evidence on diagnosis and treatment of diabetes in these patients. Insulin resistance occurs in obese patients with cirrhosis due to non-alcoholic steatohepatitis, but also develops in patients with alcoholic or viral cirrhosis. Eventually, 20-40% of patients with cirrhosis have manifest diabetes mellitus. Diabetes mellitus may accelerate progression of liver fibrosis to cirrhosis and may lead to higher mortality rates among cirrhosis patients, largely due to infections and liver failure. Treatment of diabetes in patients with chronic liver disease can theoretically improve survival. In treating such patients, doctors should take into account the reduced clearance of insulin and oral antidiabetic agents in the liver. PMID- 21329535 TI - [MRSA carriership in families of MRSA patients]. AB - OBJECTIVE: To determine how many family members of methicillin resistant Staphylococcus aureus (MRSA) patients were colonised with MRSA and how this colonisation developed over time. DESIGN: Descriptive, prospective. METHOD: Two laboratories notified the Public Health Services of newly-diagnosed MRSA patients in three provinces of the Netherlands. These persons and their family members were screened for MRSA colonisation at baseline, after 3 to 4 months and after 6 to 12 months. No advice on medical intervention was given. Relevant medical interventions by general practitioners were registered. RESULTS: Nineteen index patients and their families were included. A total of 41% of the family members (n = 44) proved MRSA positive on at least one of the three tests. At second follow-up the proportion of colonised family members had decreased slightly from 32% to 27%; by the end of the study only a third of the index patients were still MRSA positive. Colonisation of index patients was more persistent if family members were colonised as well. CONCLUSION: A large and changing number of family contacts of MRSA-positive patients were shown to be colonised over time, and sometimes in the longer term. PMID- 21329536 TI - [Alarm symptoms of meningitis in children with fever]. AB - A 15-year-old girl presented with fever and pain in her legs. A viral infection was suspected, but within 24 hours she became confused and developed meningeal signs, based on which she was diagnosed as having meningitis. Within a few hours a 6-month-old boy developed fever, a grey colour, bulging fontanel, cold hands and feet, and was groaning. He too appeared to have meningitis. It is important to recognize this serious infection in children with fever, since delay of diagnosis and treatment may result in serious complications. Recognition is difficult because of non-specific symptoms on presentation and a lack of alarm symptoms early in the course of the disease. Alarm symptoms of serious infection in children are cyanosis, rapid breathing, decreased capillary refill, petechial rash, meningeal signs, leg pain and decreased consciousness. If serious infection is uncertain in a child with fever, parents should be advised on the potential course of the disease, the alarm symptoms and the need to seek medical help in time. PMID- 21329537 TI - [Endarterectomy more favourable than stenting in symptomatic significant carotid stenosis: higher risk of ischaemic stroke or death following stenting]. AB - Carotid endarterectomy (CEA) has proven its value in the treatment of patients with recent significant carotid artery stenosis. Percutaneous transluminal angioplasty with carotid artery stenting ('stenting' in short) is an alternative to CEA. The results of stenting and CEA in patients with symptomatic significant carotid artery stenosis were evaluated in 9 prospective randomized controlled trials and 11 meta-analyses. Almost all of these trials failed to show superiority of stenting to CEA. According to the 4 largest and most recent studies in this field the risk of a stroke or death within 30 days after the intervention is considerably higher following stenting than following CEA. In the long run the results of stenting and CEA seem to be comparable. CEA remains the gold standard in treatment of significant carotid artery stenosis, in particular in patients older than 70. PMID- 21329538 TI - [Physical examination of the lungs in suspected pneumonia]. AB - Physical examination of the lungs is easy to perform, but the interobserver agreement is poor due to lack of standardisation in the findings. The use of an electronic stethoscope with computerised analysis of the lung sounds might improve diagnostic accuracy. General signs such as fever and an accelerated respiratory and pulse rate increase the probability of a pneumonia. Percussion dullness increases the probability of pneumonia, but its absence does not exclude a pneumonia. Bronchial or decreased breath sounds or crackles increase the probability of pneumonia, but their absence does not exclude a pneumonia. There are no physical diagnostic findings that have a very high predictive value for a pneumonia; all findings should therefore be combined. PMID- 21329539 TI - [Chronic Q fever during pregnancy]. AB - A 42-year-old woman visited the pulmonologist for follow-up after a pneumonia. In retrospect the pneumonia appeared to be a manifestation of an acute Q fever infection. A few weeks later the patient was found to be unexpectedly pregnant. At the normal serological follow-up six months after the primary infection chronic Q fever infection was diagnosed. Doxycycline and hydroxychloroquine are contraindicated in pregnancy and the patient was found to be allergic to co trimoxazole. Therefore treatment with erythromycin was chosen on empirical grounds. The patient had many symptoms during pregnancy. After 38 weeks and 2 days amenorrhea labour was induced on maternal indication. Finally a healthy boy of 3850 grams was born by caesarean section. In view of the increased risk of chronic Q fever infection during pregnancy we advise intensified serological monitoring of patients with acute Q fever who subsequently become pregnant. PMID- 21329540 TI - [Endarterectomy in asymptomatic carotid stenosis: not worth the risk]. AB - A recent trial revealed a reduction in ischaemic infarcts after carotid endarterectomy in patients with asymptomatic carotid stenosis. However, the number needed to treat (NNT) was 22 to prevent 1 stroke in 10 years (including perioperative death as a primary outcome measurement). This is a modest effect in comparison to the trials with symptomatic patients with a 70-99% stenosis (NNT: 6). Furthermore, the number of surgical complications outweighs the benefits of surgery during the first 2 years after treatment. Finally, current medical treatment is significantly more effective than the medical treatment used in the control arm of this trial. Therefore, in our opinion, endarterectomy should not be performed routinely in asymptomatic patients. PMID- 21329541 TI - [Von Willebrand and his factor]. AB - Erik Adolf von Willebrand (1870-1949) studied medicine in Helsinki, where he subsequently joined the staff at the Deaconess Hospital. Haematological disorders were his main interest. In 1924 he was consulted about 5-year-old Hjordis S. She suffered from a severe bleeding disorder, as did six of her ten siblings; three of her sisters had died. In a Finnish article in a Journal in 1926 (in the Swedish language) he plotted the family pedigree (bleeding disorder in three preceding generations, on the part of both parents). Von Willebrand also distinguished the disorder from haemophilia and thrombopathies with purpura. His conjecture that the disorder was a special form of thrombocyte dysfunction would eventually be borne out, though the key factor is severe deficiency of a specific plasma protein. In milder, autosomal dominant forms of the disease, the protein is partly deficient or abnormal. PMID- 21329542 TI - [A man in a coma after varices bleeding]. AB - We admitted a 43-year-old comatose man with known liver cirrhosis and hyperintense subarachnoid spaces on brain CT, suggestive of subarachnoid hemorrhage. He died shortly thereafter. Autopsy did not show signs of subarachnoid hemorrhage, but revealed extensive cerebral edema. Pseudo subarachnoid hemorrhage due to metabolic disturbances was diagnosed. PMID- 21329543 TI - [Vasculitis associated with Churg-Strauss syndrome]. AB - A 52-year-old man was admitted to hospital with abdominal pain, erythema and mild eosinophilia. Medical history revealed fatigue and dyspnoea on exertion after returning from the Gambia a year previously, and allergic rhinitis with nasal polyps that were surgically excised. Before a cause of the abdominal symptoms was determined he developed mononeuropathy, severe eosinophilia and arthralgia in combination with positive anti-neutrophil cytoplasmic antibodies (ANCA) against myeloperoxidase, which lead to the diagnosis of 'Churg-Strauss syndrome'. Despite treatment with high-dose corticosteroids (prednisone 1 mg/kg) his abdominal complaints intensified. A CT-scan of the abdomen showed a soft tissue mass around the caecum. Subsequent colonoscopy showed severe ulcerative lesions and signs of colonic ischemia. When PCR for cytomegalovirus appeared to be negative, treatment was intensified with cyclophosphamide 2 mg/kg, resulting in resolution of the abdominal complaints and healing of the ulcerative lesions in the colon. PMID- 21329544 TI - [Familial gastric cancer: diagnosis, treatment and periodic surveillance]. AB - The only known genetic causes of hereditary diffuse gastric cancer (HDGC) are germline mutations in the CDH1 gene.- CDH1 mutation carriers have a lifetime risk of 70-80% of developing diffuse gastric cancer. As periodic gastric surveillance is of limited value in detecting early stages of HDGC, prophylactic gastrectomy is advised for this patient group. This group is small and little is known about other types of familial gastric cancer. The Dutch Working Group on Hereditary Gastric Cancer has formulated criteria for various aspects of medical care for families and individuals at high risk of developing gastric cancer, including criteria for diagnostics and periodic gastric surveillance. In order to optimize the care and increase the knowledge on hereditary gastric cancer it is important to centralize medical care for these patients. PMID- 21329545 TI - [Waveboard-related injuries. Greater protection is advised]. AB - OBJECTIVE: Waveboarding, a type of skateboarding, is a new craze among children. The aim of this study is to describe how many children visit the emergency department as a consequence of waveboarding and the types of injury they have. DESIGN: Retrospective, descriptive. METHOD: All records of children aged 5 to 15 years who had visited the emergency department of the Medical Center Alkmaar in the period March to May 2010 were examined. If a case of waveboard-related injury was found then the type of injury was noted. For all of the injuries a phone call was made to try to find out if protective gear had been worn. RESULTS: A total of 1418 records from 2010 were investigated. In 132 cases, a waveboard-related injury was found. Contusion was found in 31% of cases and a fracture in 64% of cases. The 2 most frequently occurring sites of injury were the forearm and wrist (53%) and the elbow (14%). In 3% of the waveboard-related injuries the child concerned had worn any protective gear. CONCLUSION: Children who visited the emergency department due to waveboard-related injuries mainly had injuries to the wrists, forearm and elbow. Only 3% of the children wore protective gear when waveboarding. As effective protection against accident-related injuries exists for skaters, the wearing of protective gear during waveboarding can be expected to lead to a reduced number of injuries. PMID- 21329546 TI - [Difficult consultations rather than difficult patients]. AB - Here we describe two patients attending the internal medicine out-patient clinic. The first patient, a 43-year-old male, consulted a resident in internal medicine with irritable bowel syndrome and complications a year after surgery. The second patient, a 39-year-old female, was referred with medically unexplained symptoms. No treatable cause was found for either of these patients, and the encounters were unsatisfying for both the patient and the physician. According to the literature, 1 in 6 medical encounters is labelled as 'difficult' by the physician. Patients with medically unexplained or psychiatric disorders are frequently labelled as difficult, and young and inexperienced doctors more often report encounters as difficult. These difficult encounters have a negative influence on patients' satisfaction and physicians who experience many of their patients as difficult are more likely to experience burnout. More training in communication skills and psychosocial medicine may be helpful in reducing the number of difficult encounters. PMID- 21329547 TI - [Palliative sedation largely in accordance with Dutch national guideline]. AB - OBJECTIVE: To evaluate the practice of continuous palliative sedation after the introduction of a national guideline. DESIGN: Investigation by questionnaire. METHOD: In 2008, 1580 physicians were asked to fill out a questionnaire regarding the last patient for whom they had prescribed continuous sedation until death. RESULTS: The response was 38% (n = 606). Eighty-two percent of the respondents were aware of the national guideline. Dyspnoea, pain and physical exhaustion were most often mentioned as the decisive indications for continuous sedation. The decision to use sedation was discussed with all mentally competent patients; in 18% of these cases, the patients had only been informed of the decision. Life expectancy at the start of continuous sedation was estimated to be less than 2 weeks in 97% of the cases. In 14% of the cases, the physicians felt pressured to start the sedation, predominantly by patients and relatives. Physicians were present at the start of sedation in 81% of the cases. Midazolam was used to induce sedation in 92%, and 41% of the physicians estimated that continuous sedation had hastened death to some extent. Most physicians believed that their patients' symptoms had been adequately relieved by continuous sedation, that the relatives were satisfied and that the quality of dying had been good. CONCLUSION: Continuous sedation practice in the Netherlands largely reflects the recommendations of the national guideline. Issues needing further attention are the pressure felt by physicians to start continuous sedation, as well as the possible life-shortening effect of continuous sedation as perceived by some of the physicians. PMID- 21329548 TI - [Percutaneous aortic valve implantation]. AB - Surgical replacement of the aortic valve is an effective treatment modality in patients with degenerative and calcific aortic stenosis. In an aging population, however, increasing numbers of patients have comorbidities that make surgical intervention a high-risk procedure. Recent developments in catheter technology have made less invasive alternatives possible, allowing the delivery of a bioprosthesis to the aorta by the femoral artery or transapical route. Promising first results of a randomized trial have recently been published. Although this publication certainly heralds a new era in the invasive treatment of valvular heart disease, further randomized trials with long term follow-up of mortality, morbidity and cost-effectiveness will be mandatory. PMID- 21329549 TI - [Churg-Strauss syndrome: diagnosis and treatment]. AB - Few randomized clinical trials (RCTs) have been performed in patients with Churg Strauss syndrome. Therefore, it is recommended to treat patients with this syndrome in accordance with the current practice guidelines for therapy for patients with ANCA-associated vasculitis. Standard therapy is prednisolone in combination with cyclophosphamide. Cyclophosphamide is stopped 3-6 months after diagnosis and subsequently azathioprine is started. Recently, it was demonstrated in two RCTs that B cell depletion by rituximab can be used as therapy for moderate to severe ANCA-associated vasculitis. Remission rates and adverse events were comparable with those of treatment with cyclophosphamide. It is pivotal to start therapy in patients with Churg-Strauss syndrome as soon as possible after the diagnosis is made. PMID- 21329550 TI - Further insights into the strange role of bacterial endosymbionts in whitefly, Bemisia tabaci: comparison of secondary symbionts from biotypes B and Q in China. AB - The percentage infection of secondary symbionts (SS) (Wolbachia, Arsenophonus, Rickettsia, Hamiltonella, Fritschea and Cardinium) in the exotic Bemisia tabaci (Genn.) invaders, commonly known as biotypes B and Q from China, were determined by PCR. In total, 373 biotype B and 1830 biotype Q individuals were screened for the presence of SS. Biotype B was more abundant than biotype Q from 2005 to 2006, and biotype Q was more abundant from 2007 to 2009. Each of the SS, with the exception of Fritschea, was detected in both biotypes B and Q; Fritschea was found in none of the samples examined. For biotype B, the percentage infection of Hamiltonella was the highest (92.0%) followed by Rickettsia (70.2%). For biotype Q, the percentage infection of Hamiltonella was again the highest (73.3%). Arsenophonus was the least common of the SS observed in both biotypes B and Q. The percentage infection of Wolbachia, Rickettsia and Hamiltonella in biotype B was each significantly higher than in biotype Q, whereas the percentage infection of Cardinium in biotype B was significantly lower than in biotype Q. The percentage infection of SS in biotypes B and Q varied from year to year over the period 2005-2009. Furthermore, within biotype Q, two distinct subgroups were identified which differ from each other in terms of their SS complement. We discuss these results in the light of the potentially influential factors and roles of the SS. PMID- 21329551 TI - Transorbital approach to infratemporal fossa: novel technique. AB - OBJECTIVE: To present a conservative surgical approach, via the transorbital route, for selected cases of infratemporal fossa involvement or inferolateral orbital tumours extending to the infratemporal fossa. DESIGN: Case series report. SETTING: Department of ENT, CSM Medical University (King George Medical College), Lucknow, India. PARTICIPANTS: One patient. MAIN OUTCOME MEASURES: Operative feasibility, intra-operative access, post-operative morbidity and cosmesis. RESULTS: This novel and relatively conservative technique provides excellent exposure in selected cases of infratemporal fossa involvement and has minimal post-operative morbidity. Cosmesis is excellent, as osteotomy is not required and scarring is minimal. There is no risk of trismus, Vth or VIIth cranial nerve injury, or cerebrospinal fluid leakage, and haemostasis is easily achieved. CONCLUSION: Classical, open approaches to the infratemporal fossa involve considerable morbidity, while conservative approaches have their limitations. Diagnostic uncertainty over a small infratemporal fossa mass (perhaps an extension from an inferolateral orbital tumour) is an uncommon clinical challenge. The transorbital approach described is suited to benign and early malignant tumours, and has excellent results when combined with orbital exenteration (if needed). This paper discusses this approach's technical details and feasibility in different clinical situations, and compares it with other infratemporal fossa approaches. PMID- 21329552 TI - Differential behavioural and neurochemical outcomes from chronic paroxetine treatment in adolescent and adult rats: a model of adverse antidepressant effects in human adolescents? AB - Selective serotonin reuptake inhibitor use is associated with increased risk of suicidal ideation in adolescent humans, yet the neuropharmacological basis of this phenomenon is unknown. Consequently, we examined the behavioural and neurochemical effects of chronic paroxetine (PRX) treatment in adult and adolescent rats. Rats received PRX in their drinking water (target dose 10 mg/kg) for 22 d, during which time they were assessed for depression- and anxiety-like behaviours. Subsequent ex-vivo analyses examined serum PRX concentrations, striatal neurotransmitter content, and regional serotonin and dopamine transporter (SERT, DAT) binding density. After 11-12 d treatment, PRX-treated adolescent rats showed a significant inhibition of social interaction while adults were unaffected. After 19-20 d treatment, adolescents failed to show an antidepressant-like effect of PRX treatment on the forced swim test (FST), while PRX-treated adults showed a typical decrease in immobility and increase in swimming. Two PRX-treated adolescents died unexpectedly after the FST suggesting a compromised response to physical stress. Despite their greater apparent adverse reaction to the drug, adolescents had significantly lower plasma PRX than adults at day 22 of treatment. Chronic PRX treatment had similar effects in adults and adolescents on striatal 5-HT (unchanged relative to controls) and 5-HIAA levels (decreased), while markers of dopaminergic function (DOPAC, HVA, DA turnover) were increased in adults only. SERT density was up-regulated in the amygdala in PRX-treated adolescents only while DAT density in the nucleus accumbens was down regulated only in PRX-treated adults. These data suggest that the immature rat brain responds differently to PRX and that this might be of use in modelling the atypical response of human adolescents to antidepressants. The age-specific PRX induced changes in dopaminergic markers and SERT and DAT binding provide clues as to the neural mechanisms underlying adverse PRX effects in adolescent humans. PMID- 21329553 TI - The evidence-based pharmacological treatment of paediatric ADHD. AB - Attention deficit hyperactivity disorder (ADHD) is common in children, adolescents, and adults, with extensive research establishing it as a valid neurobiological disorder. Without intervention, ADHD can result in significant impairment throughout the lifespan for the individuals it afflicts. Fortunately, multiple evidence-based options are available for the treatment of ADHD, including several efficacious pharmacotherapies. The role of medication, including stimulants as well as non-stimulants, is well-documented by an extensive body of literature. Although there may be less enthusiasm for behavioural and other psychosocial interventions as stand-alone treatments for moderate to severe ADHD, they are recommended as first-line treatment for ADHD management in preschool-aged children, for those patients with mild symptoms, and as an adjunct to medication in patients with comorbid disorders or suboptimal responses to pharmacotherapy. When planning treatment for individuals with ADHD, the potential risks associated with the available interventions must be carefully balanced against the risks of not treating, or not treating adequately. The treatment plan must also include ongoing re-assessment of the effectiveness of and the need for continued therapy. Recent practice parameters provide further specific guidance for the evidence-based assessment and treatment of children and adolescents with ADHD. PMID- 21329554 TI - Disruption of prepulse inhibition by 3,4-methylenedioxymethamphetamine (MDMA): comparison between male and female wild-type and 5-HT(1A) receptor knockout mice. AB - The aim of this study was to investigate the involvement of serotonin-1A (5 HT(1A)) receptors in the effects of 3,4-methylenedioxymetamphetamine (MDMA) on prepulse inhibition of acoustic startle (PPI) by comparing male and female wild type (WT) mice and 5-HT(1A) receptor knockout (1AKO) mice. MDMA dose-dependently decreased PPI in male and female mice although female mice were more sensitive at the 100-ms inter-stimulus interval (ISI). In male mice, 10 mg/kg MDMA disrupted PPI in 1AKO but not in WT controls. There was no genotype difference at higher or lower doses of MDMA. In female mice, there was no difference between genotypes at any dose of MDMA. Average startle was reduced by 10 mg/kg and 20 mg/kg MDMA similarly in male and female mice and all genotypes. These results show an involvement of 5-HT(1A) receptors in the effect of MDMA on PPI in male, but not female mice. PMID- 21329555 TI - Increased NF-kappaB signalling up-regulates BACE1 expression and its therapeutic potential in Alzheimer's disease. AB - Elevated levels of beta-site APP cleaving enzyme 1 (BACE1) were found in the brain of some sporadic Alzheimer's disease (AD) patients; however, the underlying mechanism is unknown. BACE1 cleaves beta-amyloid precursor protein (APP) to generate amyloid beta protein (Abeta), a central component of neuritic plaques in AD brains. Nuclear factor-kappa B (NF-kappaB) signalling plays an important role in gene regulation and is implicated in inflammation, oxidative stress and apoptosis. In this report we found that both BACE1 and NF-kappaB p65 levels were significantly increased in the brains of AD patients. Two functional NF-kappaB binding elements were identified in the human BACE1 promoter region. We found that NF-kappaB p65 expression resulted in increased BACE1 promoter activity and BACE1 transcription, while disruption of NF-kappaB p65 decreased BACE1 gene expression in p65 knockout (RelA-knockout) cells. In addition, NF-kappaB p65 expression leads to up-regulated beta-secretase cleavage and Abeta production, while non-steroidal anti-inflammatory drugs (NSAIDs) inhibited BACE1 transcriptional activation induced by strong NF-kappaB activator tumour necrosis factor-alpha (TNF-alpha). Taken together, our results clearly demonstrate that NF kappaB signalling facilitates BACE1 gene expression and APP processing, and increased BACE1 expression mediated by NF-kappaB signalling in the brain could be one of the novel molecular mechanisms underlying the development of AD in some sporadic cases. Furthermore, NSAIDs could block the inflammation-induced BACE1 transcription and Abeta production. Our study suggests that inhibition of NF kappaB-mediated BACE1 expression may be a valuable drug target for AD therapy. PMID- 21329558 TI - Occupational and living environment and the immune system. PMID- 21329556 TI - Divergent activation of ventromedial and ventrolateral dopamine systems in animal models of amphetamine sensitization and schizophrenia. AB - Aberrant dopamine-mediated behaviours are a hallmark of a number of psychiatric disorders, including substance use disorders and schizophrenia. It has been demonstrated recently that rodent models of these diseases display enhanced dopamine neuron activity throughout the ventral tegmental area (VTA). It is known, however, that the VTA is not a homogeneous structure, and that the dopamine neuron population provides discrete, topographical innervation of nucleus accumbens subregions. In addition, these ventromedial and ventrolateral dopamine systems are known to subserve complementary but distinct aspects of goal directed behaviour. Using in-vivo extracellular recordings of identified dopamine neurons in chloral hydrate-anaesthetized rats, we examined the level of dopamine neuron population activity across the mediolateral extent of the VTA following amphetamine sensitization or gestational methylazoxymethanol acetate (MAM) treatment, a verified rodent model of schizophrenia. Here we demonstrate that both models display an augmented medial VTA-ventromedial striatal dopamine system function that correlates with the augmented locomotor response to amphetamine observed in both models. In contrast, only MAM-treated rats exhibit an increase in VTA-ventrolateral striatal dopamine system function. This latter finding is consistent with human imaging studies in schizophrenia patients. In summary, we demonstrate that, although a number of disorders involving a hyperdopaminergic state demonstrate an increase in dopamine neuron population activity, there is divergence in the exact populations of neurons affected. This distinction probably underlies the observed differences in disease symptomatology. PMID- 21329557 TI - Long working hours and symptoms of anxiety and depression: a 5-year follow-up of the Whitehall II study. AB - BACKGROUND: Although long working hours are common in working populations, little is known about the effect of long working hours on mental health. METHOD: We examined the association between long working hours and the onset of depressive and anxiety symptoms in middle-aged employees. Participants were 2960 full-time employees aged 44 to 66 years (2248 men, 712 women) from the prospective Whitehall II cohort study of British civil servants. Working hours, anxiety and depressive symptoms, and covariates were measured at baseline (1997-1999) followed by two subsequent measurements of depressive and anxiety symptoms (2001 and 2002-2004). RESULTS: In a prospective analysis of participants with no depressive (n=2549) or anxiety symptoms (n=2618) at baseline, Cox proportional hazard analysis adjusted for baseline covariates showed a 1.66-fold [95% confidence interval (CI) 1.06-2.61] risk of depressive symptoms and a 1.74-fold (95% CI 1.15-2.61) risk of anxiety symptoms among employees working more than 55 h/week compared with employees working 35-40 h/week. Sex-stratified analysis showed an excess risk of depression and anxiety associated with long working hours among women [hazard ratios (HRs) 2.67 (95% CI 1.07-6.68) and 2.84 (95% CI 1.27-6.34) respectively] but not men [1.30 (0.77-2.19) and 1.43 (0.89-2.30)]. CONCLUSIONS: Working long hours is a risk factor for the development of depressive and anxiety symptoms in women. PMID- 21329559 TI - Suppressive effect of asbestos on cytotoxicity of human NK cells. AB - Asbestos, a naturally occurring fibrous mineral, causes malignant mesothelioma (MM). However, it takes a very long time to develop MM, which suggests that effects other than tumorigenicity of asbestos might contribute to the development of MM, and one of the possible targets is anti-tumor immunity. Therefore, we examined the effect of asbestos exposure on human natural killer (NK) cells using the cell line of YT-A1, Peripheral blood mononuclear cells (PBMCs) cultures and specimens from patients with MM. In particular, we focused on expression of NK cell-activating receptors, including NKG2D, 2B4 and NKp46. Analysis of the YT-CB5 subline of YT-A1, cultured with CB for over 5 months, showed a decrease in cytotoxicity with low expressions of NKG2D and 2B4, although there were no decreases after about one month. YT-CB5 showed decreases in phosphorylation of extracellular signal-regulated kinase (ERK) and degranulation stimulated by antibodies to NKG2D. Peripheral blood (PB-) NK cells from MM patients also showed decreased cytotoxicity compared with healthy volunteers (HV), and was accompanied with low expression of NKp46 unlike YT-CB5. PBMCs cultured with CB resulted in decreased expression of NKp46 on NK cells, although this did not occur when using glass wool, an asbestos substitute. These results indicate that asbestos has the potential to suppress cytotoxicity of NK cells. In particular, it is noteworthy that both NK cells from MM patients and those from a culture of PBMCs derived from HVs with asbestos showed the same characteristic of decreased cytotoxicity with low expression of NKp46. PMID- 21329560 TI - Dysregulation of autoimmunity caused by silica exposure and alteration of Fas mediated apoptosis in T lymphocytes derived from silicosis patients. AB - Silicosis patients suffer from pulmonary fibrosis caused by silica inhalation, as well as autoimmune diseases known as the adjuvant effects of silica. Caplan syndrome complicated with rheumatoid arthritis (RA) is well known epidemiologically, and the incidence of complicated systemic sclerosis (SSc), systemic lupus erythematosus (SLE) and antineutrophilic cytoplasmic antibody (ANCA)-related nephritis have been reported frequently in silicosis patients. To explore the detailed mechanisms of silica-induced dysregulation of autoimmunity, we had focused on Fas/CD95 and Fas-mediated apoptosis because Fas is one of the most important molecules regarding apoptosis of lymphocytes and its alteration makes some T cells survive longer. Additionally, if the long-survived T cells include the self-recognizing T-cell clones, it is easily thought that autoimmune diseases will appear in this situation. Furthermore, regulatory T cells (Treg) showing CD4+25+ and forkhead box P3 (FoxP3)-positive have been a central player in regulating activation of self- and foreign-antigen recognizing T cells, and it has been reported that activation of Treg causes its higher expression of Fas/CD95. Thus, in this review, we introduce the alteration of Fas and related molecules as found in silicosis and also present the Treg function of the CD4+25+ fraction in peripheral blood mononuclear cells derived from silicosis patients. PMID- 21329561 TI - Validation study of the new criteria for sensitizer using German sensitizers of Deutschen forschungsgemeinschaft (DFG). AB - The globally harmonized system of classification and labeling of chemicals (GHS) was recommended by United Nations (UN) and became available in 2008 all over the world. The classification criteria for skin and airway sensitizers in GHS include evidences from animal studies, for example, OECD Guideline 406 (guinea pig maximization test, GPMT and Buhler guinea pig test) and Guideline 429 (local lymph node assay, LLNA). According to Deutschen Forschungsgemeinschaft (DFG) in Germany and European Chemical Bureau (ECB), the criteria for sensitizers also include evidences from validated animal studies. At present recognized and validated animal models for the testing of respiratory hypersensitivity are not available. In Japan, the criteria from the Japan Society for Occupational Health (JSOH) for sensitizers do not include evidences from animal studies. We revised the criteria for sensitizers of JSOH and adopted evidences of animal studies. We organized the research group for sensitizer in 2005 and reviewed the criteria of Germany, EU, GHS and so on (19 experts). The meetings were held twelve times and made the revised criteria for sensitizer which adopted animal studies. We tried to validate the criteria using 28 German sensitizers of DFG, which were not sensitizers in JSOH. We could correctly classify 24 sensitizers by our revised criteria, however, 4 sensitizers could not be classified at first. Therefore, we visited the secretariat of the committee of DFG in Freising, Germany to investigate the evidenced papers of these 4 sensitizers in October, 2008. We could find out the evidenced papers of 2, however, 2 sensitizers could not be classified at last. We could correctly classify 24 of 26 sensitizers. We concluded that our revised criteria were appropriate and that this validation study was successful. PMID- 21329562 TI - In vivo toxicity of nano-alumina on mice neurobehavioral profiles and the potential mechanisms. AB - The rapid development and expanding applications of nanotechnology have led to enhanced exposure of human body to nanoparticles. It is, therefore, necessary to address the safety issue via rigorous toxicological evaluation and to understand the underlying interaction mechanism. However, only a few studies to date have evaluated the safety of nano-sized materials and their potential adverse effects on biological systems. In this study, we sought to investigate the potential toxicity of aluminum oxide (alumina) nanoparticles in ICR strained mice, focusing on potential neurobehavioral defects and the possible mechanisms. The results demonstrated that nano-alumina impaired neurobehavioral functions, including lengthened escape latency, shorter time spent in the target quadrant and reductions in the number of platform crossing. In addition, it induced cell necrosis and apoptosis, which were likely mediated by the reduction of MMP and ROS, and the induction of the caspase-3 gene. Our results implicated that mitochondrial impairment plays a key role in neurotoxicity of nano-alumina, sequent oxidative damage and neural cell loss, especially necrosis, may be direct causes for the neurobehavioral defects. Collectively, nano-alumina presents a strong pro-cell death effect on ICR mice in vivo, suggesting that nano-alumina may serve as an inducer for neural toxicology. Findings in the present study indicating that surface chemical characteristics and nanoscale sizes of nano alumina could co-contribute significantly to neurotoxicity. The impaired neurobehavioral patterns indicate that nano-alumina particles are more toxic to the cerebrum than those of nano-carbon with the same nanoparticle size and micro alumina with the same surface chemical characteristics. PMID- 21329563 TI - Environmental pollution and asthma. AB - Clinical evidences and epidemiological studies show that allergic pathologies of the respiratory tract are increasing in the world areas with high pollution impact, demonstrating how many polluting substances favor both allergic sensitization and the bronchial inflammatory changes characteristic of asthma. It has been shown that asthma, as many other diseases, is a complex interaction between genetic predisposition and environmental stimuli that results in clinical expression of various phenotypes of asthma: allergic, intrinsic etc. Many pollutants have such a potential. Diesel exhaust particles (DEP) can favor allergic sensitization, induce acute asthma attacks and increase bronchial reactivity, acting both on allergen, on bronchial mucosa and on immune cells. In fact, DEP can favor B lymphocytes to shift to a production of IgE and T cells to produce Th2 cytokines. Asthma can be also induced by high exposure to many other substances as NO2 and first of all ozone (O3): strong oxidizing substance that is synthesized, in absence of ventilation, by photochemical reaction due to the combination of ultraviolet sun radiation on exhaust gases as NO2 and hydrocarbons. Ozone is abundant in cities with minimal concentration in the morning gradually increasing during the day until maximal levels in the afternoon and then decreasing during the night. Epidemiological studies show that the number of access to hospital for acute asthma and even the use of bronchodilator by asthmatics increase during the high level periods when Ozone constitute almost 90 percent of the total oxidants in the environment. Particulate matter of very small diameter have a crucial role in favoring asthma attacks, and smaller the substance deeper the penetration in the bronchial tree, with an inflammatory reaction in the peripheral bronchial mucosa characterized by increased vessel permeability, mucosal edema, inflammatory mediator production by damaged epithelium and inflammatory cells that determines acutely a high narrowing of the bronchial lumen and in a long period favor airways remodeling and a rapid decline of respiratory function. PMID- 21329564 TI - Effect of forest environments on human natural killer (NK) activity. AB - Humans have enjoyed forest environments for ages because of the quiet atmosphere, beautiful scenery, mild climate, and fresh, clean air. In the present study, we found that visiting forest parks, but not a city, enhanced human natural killer (NK) activity, increased anti-cancer proteins, such as perforin, granzymes A and B, and granulysin in NK cells, and reduced the level of stress hormones in both male and female subjects. Moreover, this effect lasted for more than 30 days after the trips, suggesting that visiting a forest park once a month would enable individuals to maintain a higher level of NK activity. Phytoncides released from trees and the decreased production of stress hormones may partially contribute to the increased NK activity. Because NK cells can kill tumor cells by releasing anti-cancer proteins, and visiting forest parks increases NK activity and the amount of anti-cancer proteins; therefore, the above findings suggest that visiting forest parks may have a preventive effect on cancer generation and progression. PMID- 21329565 TI - Biological effects of probiotics: what impact does Lactobacillus casei shirota have on us? AB - Probiotics have been defined as live bacteria beneficial to the host when administered in adequate amounts. To evaluate the effect of probiotics on the prevention of carcinogenesis, Lactobacillus casei Shirota (LcS) was given to the patients who had undergone the resection of superficial bladder cancer, and administration of LcS significantly reduced the recurrence rate of bladder cancer. When LcS was given to the patients whose colonic polyps were surgically removed, the recurrence of colorectal cancer with moderate or severe atypia was suppressed. To assess the putative actions of LcS on innate immune responses, we examined the effect of LcS on natural killer (NK) cell activity in humans. Daily ingestion of fermented milk containing LcS restored NK cell activity in healthy subjects with low NK cell activity as well as human T lymphotropic virus (HTLV)-1 associated myelopathy patients. When peripheral blood mononuclear cells from healthy humans were cultured in the presence of heat-killed LcS, NK cell activity was augmented, which were partly mediated by monocyte-derived interleukin (IL) 12. These findings suggest that LcS may help the reinforcement of our defense system against cancer by modulating innate immune functions. PMID- 21329566 TI - Work stress and innate immune response. AB - Several reports highlight the relationship between blood NK cytotoxic activity and life style. Easy life style, including physical activity, healthy dietary habits as well as good mental health are characterized by an efficient immune response. Life style is related to the type of occupational activity since work has a central part in life either as source of income or contributing to represent the social identity. Not only occupational stress, but also job loss or insecurity are thus considered serious stressful situations, inducing emotional disorders which may affect both neuroendocrine and immune systems; reduced reactivity to mitogens and/or decreased blood NK cytotoxic activity was reported in unemployed workers or in those with a high perception of job insecurity and/or job stress. Although genetic factors have a key role in the pathogenesis of autoimmune disorders, occupational stress (as in night shifts) was reported associated to an increased incidence of autoimmune disorders. Monitoring blood NK response may thus be included in the health programs as an indirect index of stressful job and/or poor lifestyle. PMID- 21329567 TI - T regulatory cells in allergy. AB - The progressive understanding of the nature and mechanisms of T regulatory (Treg) cells in the last decade has changed the concept of immune tolerance, that is no longer considered as a mere lack of immune reactivity but as a finely regulated process that requires specific activity of cells, adhesion and secreted molecules. Tregs play a key role in maintenance of self-tolerance and induction of tolerance against ubiquitous innocuous non-self antigens, so preventing the onset of autoimmune diseases and allergies. This review will focus on the Treg response in allergy that is characterized by a down-regulation of allergen specific T cell proliferation and inhibition of both Th1 and Th2 cytokines production. Hence, Treg cells suppress allergen-specific Th1 and Th2 cell responses playing an important role in the physiological immune response to allergens. Further, Treg cells are able to suppress IgE production by B lymphocytes and directly or indirectly inhibit the activity of allergic inflammation effector cells, namely eosinophils, basophils and mastcells. Finally, increasing evidence suggests that Treg cells are also implicated in chronicity development of inflammatory diseases. This appears to happen through a fine interaction they entertain with resident tissue cells and has been particularly highlighted in the study of airways remodeling in asthma. The understanding of the mechanisms underlying allergen tolerance has brought new interest in the development of new allergy treatment, able to target Treg cells, both in allergy prevention and in the therapy of established allergy. PMID- 21329568 TI - Immunotoxicity of nanoparticles. AB - The interaction between NPs and immune system has been demonstrated, however, the data available are limited. Among all traits, i.s. hydrophilicity, lipophilicity, catalytic activity, composition, electronic structure, capacity to bind or coat surface species and solubility, the dimension, and consequently the surface area, seems to be the main factor that contribute to the interactions of NPs with biological tissues and immune system in particular. Certain NPs accumulate to regional lymph nodes, where they can be taken up and processed by dendritic cells, interact with self-proteins and, hence, modify their antigenicity and elicit altered immune responses and even autoimmunity. Other NPs may induce allergic sensitization, i.e. allergic contact dermatitis to Pd. In vitro studies demonstrated that NPs can modulate cytokine production toward Th1 (Pl, Pd, Ni, Co) or Th2 (Ti, mw and sw Carbon) production patterns. Some NPs have been linked to allergic sensitization, however, It is unlikely that NPs can act as a hapten inducing a specific IgE production, likely they can act as adjuvant and induce a specific pattern of cytokines, antibody and cells that favor allergic sensitization to environmental allergens. Furthermore, NPs demonstrated pro inflammatory effects in the lung in experimental animal with increased expression on IL-1beta, MIP-1alpha, MCP-1, MIP-2, keratinocyte chemoattractant, TARC, GM CSF, MIP-1alpha and activation of the stress-activated MAPKs p38 and JNKs. All considered, the available data suggest that through the elicitation of an oxidative stress mechanism, engineered NPs may contribute to pro-inflammatory disease processes in the lung, particularly allergy. PMID- 21329569 TI - Genetic susceptibility to occupational contact dermatitis. AB - Contact dermatitis (CD) is one of the most prevalent work-related diseases, often resulting in an impaired quality of life and a loss of work ability. CD can be divided into allergic (ACD) and irritant contact dermatitis (ICD). Although skin exposure is a prerequisite for the development of CD, there is substantial evidence that under similar exposure conditions some individuals are more prone to acquiring CD than others. Recently, a number of studies have investigated the link between individual susceptibility to CD and variations in the genes that are involved in the maintenance of the skin barrier, inflammatory response and biotransformation. The most important development has been the discovery that loss-of-function mutations in the gene encoding the epidermal protein filaggrin increase the risk for ICD and for nickel sensitization and nickel ACD, emphasizing the importance of the skin barrier in the pathophysiology of CD. Among the inflammatory genes, a TNFA-308 G/A polymorphism has been shown to associate with susceptibility to both ICD and ACD. In studies specifically for ACD, polymorphisms in genes encoding N-acetyltransferases were shown to modify the risk for sensitization to p-phenylenediamine. Although recent studies have identified a number of biologically plausible susceptibility genes, the predictive value of these genetic markers is too low for the reasonable selection of susceptible individuals in occupational health practice. Additional studies in larger cohorts with well-defined disease phenotypes and appropriate control population are needed to confirm and extend our knowledge of the impact of genetic variations on the susceptibility to occupational CD. PMID- 21329570 TI - Establishment of a poisoned animal model of toxic encephalopathy induced by 1,2 dichloroethane. AB - 1,2-dichloroethane(1,2-DCE) is toxic, especially by inhalation due to its high vapour pressure. Inhalation of concentrated 1,2-DCE vapor can induce effects on the human nervous system, even encephalopathy. However, 1,2-DCE toxic encephalopathy has seldom been reported, and no adequate data were available to evaluate the encephalopathy of 1,2-DCE in experimental animals. The aim of the present study was to establish a toxic experimental animal model induced by 1,2 DCE. Dose effect and time effect of 1,2-DCE on the nervous system were detected. The rats were treated by 1,2-DCE at various concentrations of 0, 2.5, 5.0, 10.0 g/m3 for 6 h and treatment of rats at 10.0 g/m3 for 0, 3, 6, and 12 h. Morphology of brain tissue was observed by HE staining and TEM under light and electron microscope, besides water contents in the cortex and medulla of rats were analyzed. The results indicated that 1,2-DCE induced abnormal histopathology, and significantly higher water content were confirmed in the cerebral cortex of toxic animal model in a dose- and time-dependent manner. To declare that 1,2-DCE could induce toxic encephalopathy with a pathological feature of cerebral edema is very important for the medical rescue in urgent toxic accidents. PMID- 21329571 TI - Peritoneal mesothelioma: description of a case and review of literature. AB - It is universally recognized by the scientific community that asbestos, widely used in the past in many industrial sectors, is responsible for the onset of certain diseases of pleural and peritoneal serous membranes; in particular, Peritoneal Mesothelioma (PM) is an exceptional case, extremely rare malignancy of the abdominal cavity. In this work we describe a 62 years-old man, formerly exposed to asbestos, complains of dyspepsia associated with pain, abdominal swelling and mild difficulty during inspiration. After intraoperative biopsy of three masses found in abdomen, malignant peritoneal mesothelioma was diagnosed. The patient subsequently was subjected to cycles of chemotherapy and multiple palliative paracentesis, the patient died after about 12 months from diagnosis. PMID- 21329572 TI - Prevention of occupational dermatitis. AB - Occupational dermatitis is among the most frequent occupational diseases. Dermal exposure risk affects many professional categories such as healthcare workers, hairdressers, bakers, cleaning and kitchen employees. The economical burden of occupational dermatitis (OD) is huge (greater than 5 billion Euro per year in Europe), comprising direct costs (treatment, compensation), as well as indirect costs due to sick leave and lack of productivity. A scientifically based preventive program consisting of skin protection during work, cleaning and skin care after work has generally been recommended to prevent occupational contact dermatitis. However the rate of reported occupational skin diseases seems unchanged in the recent years. In cases of impaired skin condition the secondary prevention (i.e. therapeutic treatment by dermatologists and health-educational intervention seminars) is fundamental. For cases of occupational dermatoses in which these outpatient prevention measures are not successful, interdisciplinary inpatient rehabilitation measures have been developed (tertiary individual prevention). In the past years, various pilot-concepts to improve occupational dermatitis prevention have been successfully put into practice focussing on interdisciplinary (dermatological and educational) skin protection training programmes for high-risk professions. Currently a multi-step intervention approach is implemented which is aiming at offering quick preventive help at all levels of severity of occupational contact dermatitis. Recent data reveals that there are reliable evidence-based options for multidisciplinary prevention and patient management of occupational dermatitis using a combined approach by a network of clinics, practices and statutory social insurance bodies. At this stage, it seemed reasonable to form a European joint initiative for skin prevention. Recently a European network of preventive dermatology (European Initiative for the Prevention of Occupational Skin Diseases-EPOS) has been organized based on the German experience in the specific field. PMID- 21329573 TI - The physical, social and symbolic environment supporting the well-being of home dwelling elderly people. AB - OBJECTIVES: The purpose of this study was to construct a theory on an environment that would support the well-being of home-dwelling elderly people in northern Finland. STUDY DESIGN: The study was carried out according to the phases of theory formulation using both qualitative and quantitative methods. METHODS: The data of the first phase consisted of focused interviews (n=39) with home-dwelling elderly people over the age of 65 years. Judgement-based snowball sampling was used. By means of inductive concept synthesis, hypothetical models were constructed of a physical, social and symbolic environment that would support the well-being of the elderly. In order to verify the concepts of the hypothetical model, an instrument was constructed in the second phase of the study and its reliability was evaluated by a panel of experts consisting of nurses (n=15), through expert evaluations (n=3) and by postal questionnaire. The final phase of the study (n=328) also targeted home-dwelling elderly people living in northern Finland. The sampling method used was a stratified random sampling. The data of (n=328) were analysed by principal component analysis (PCA) and confirmatory factor analysis (CFA). RESULTS: The physical environment that supports the well being of the elderly includes a northern environment, an environment that enables safe activity and a pleasant physical environment. The social environment that supports well-being enables the elderly to receive help, allows them to keep in contact with family members and friends as providers of support to their well being and offers a pleasant living community. The symbolic environment that supports well-being consists of the ideal attributes of well-being, spirituality, the normative attribute of well-being and a sense of history. CONCLUSIONS: Even though the environment is artificially divided into separate areas in the theory, in putting the results into practice, it needs to be taken into account that observing separate areas of the environment does not provide a comprehensive view on the connection between environment and well-being. PMID- 21329574 TI - Childhood sexual abuse of women in Greenland and its developmental correlates among their children. AB - OBJECTIVES: The objective was to study the prevalence of childhood sexual abuse (CSA) among the mothers of children in Greenland and its association with the psychosocial adjustment of their children. STUDY DESIGN: The study was based on a 2007-2008 survey of a national sample of children in Greenland designed by researchers at SFI - The Danish National Centre for Social Research in collaboration with the Greenlandic Home Rule. The survey was conducted via telephone interviews with the children's mothers. METHODS: The relationship between the mothers' childhood sexual abuse and their children's psychosocial adjustment was examined using OLS regression. Each mother's CSA was measured by a direct question and the child's psychosocial adjustment was measured by the total difficulties score on the Strengths and Difficulties Questionnaire. RESULTS: Thirty-six percent of the mothers reported having been sexually abused as children. The psychosocial adjustment of the children in the sample overall was good, with few children scoring on the upper end of the scale, indicating maladjustment. A strong inverse relationship between the mothers' childhood sexual abuse and the children's adjustment was found after controlling for demographic and socio-economic factors. CONCLUSIONS: Overall, children of mothers who were victims of CSA suffer from greater psychosocial maladjustment than children whose mothers were not victims of CSA. PMID- 21329575 TI - Fish consumption and socio-economic factors among residents of Arkhangelsk city and the rural Nenets autonomous area. AB - OBJECTIVES: The urban Russian and the rural Indigenous populations in the Russian European North have different lifestyles, living conditions and food supplies. The objective of this study was to investigate and compare fish consumption in relation to the socio-economic characteristics of 2 communities in Arkhangelsk County. STUDY DESIGN: A cross-sectional study. METHODS: In total, 166 adults (83.1% women) from Arkhangelsk city and 134 adults (80.6% women) from the village of Nelmin-Nos (of which 88.9% are Indigenous people, Nenets), in the Nenets Autonomous Area (NAO), attended a health screening. The screening included a physical examination, blood sampling and a questionnaire. RESULTS: The populations studied had different socio-economic characteristics. In the rural NAO group, education levels were lower, the number of full-time employees was less, the percentage of persons with low monthly income was higher and the number of children per household was higher when compared to the Arkhangelsk group. The median total fish intake was 48.8 g/day for Arkhangelsk city and 27.1 g/day for Nelmin-Nos (p=0.009). Locally caught whitefish constituted a major part of the total fish consumption in Nelmin-Nos, while lean marine fish species were rarely eaten. Cod and cod-family fish species were often consumed by residents of Arkhangelsk city (p < 0.001). Fish consumption was positively related to monthly income. The frequency of fishing in the respondents from the Nelmin-Nos group predicted their fish consumption. CONCLUSIONS: Monthly income had a significant influence on fish intake in both study populations from Northern Russia. Fishing seems to be an important factor for predicting fish consumption in the residents of the rural NAO. PMID- 21329576 TI - The relationship between internalizing and externalizing symptoms and cultural resilience factors in Indigenous Sami youth from Arctic Norway. AB - OBJECTIVES: To examine whether enculturation factors, like cultural activities, ethnic pride and native language competence, are related to decreased internalizing and externalizing symptoms in Indigenous Sami youth from Arctic Norway. The impact of self-efficacy on the relationship between enculturation factors and mental health problems was also examined. STUDY DESIGN: Population based, cross-sectional questionnaire study. METHODS: The Norwegian Arctic Adolescent Health Study was conducted among 10th graders in junior high schools in north Norway during 2003-2005. The study sample consisted of 450 Indigenous Sami youth, aged 15-16 years. Internalizing symptoms were measured with the Hopkins Symptom Check List-10 (HSCL-10), while externalizing symptoms were measured by two subscales of the Strengths and Difficulties Questionnaire (SDQ). RESULTS: For boys, self-efficacy and participation in cultural activities were associated with decreased internalizing symptoms. Additionally, self-efficacy interacted with Sami language competence and cultural activities: when self efficacy increased, these enculturation factors were related to symptom reduction. For girls, self-efficacy had an independent effect on internalizing symptoms and also strengthened the relationship between participation in cultural activities and reduced externalizing symptoms. Sami language competence was related to the reduction of both internalizing and externalizing symptoms in girls. CONCLUSIONS: In the present study, several enculturation factors as well as self-efficacy were identified as potential protective factors against mental health problems. In order to develop theoretical models that explain the mechanisms between cultural resilience and mental health, there is a need for both qualitative studies and longitudinal studies. PMID- 21329577 TI - Quitting a weight loss program is associated with anhedonia: preliminary findings of the Lifestyle Intervention Treatment Evaluation Study in northern Finland. AB - OBJECTIVES: To examine whether a diagnosis for major depression, chronic depression or specific symptoms of depression is associated with the risk of quitting a weight loss program. STUDY DESIGN: The study involved 82 overweight adults participating in the Lifestyle Intervention Treatment Evaluation (LITE) follow-up study at Oulu University Hospital in northern Finland. METHODS: Psychiatric diagnostic assessments were based on the Structured Clinical Interview for DSMIV disorders (SCID-I) conducted by a clinical psychiatrist. Anhedonia (lack of pleasure) was assessed as one of the core symptoms of major depression and chronic depression (dysthymia). Anhedonia was defined to be present if the participants reported having suffered a major loss of interest during the previous month. RESULTS: Twenty participants (24.4%) quit during the 6 month intervention period. Anhedonia put individuals at risk of quitting the weight loss program (bivariate analysis OR 3.1, 95% CI 0.8-11.6, p=0.091, multivariate analysis OR 6.5, 95% CI 1.1-38.2, p=0.038). However, a diagnosis for major depression or chronic depression did not predict quitting. CONCLUSIONS: Individual assessments of obesity and overweight should also include an assessment for subthreshold depression, mainly anhedonia. PMID- 21329578 TI - Alcohol controls and violence in Nunavut: a comparison of wet and dry communities. AB - OBJECTIVES: The purpose of this study was to determine if communities in Nunavut that prohibit the importation of alcoholic beverages have less violence relative to communities that allow alcohol importation. STUDY DESIGN: A retrospective cross-sectional study based on community-level records of violent crimes known to the police. METHODS: Violence was measured using community-level records of homicide, assault and sexual assault as reported to the Royal Canadian Mounted Police in 23 communities in Nunavut for the years 1986 to 2006. Crude-rate comparisons were made between wet communities (which allow alcohol importation) and dry communities (which prohibit alcohol importation) and contrasted with national rates for context. RESULTS: Wet communities in Nunavut recorded rates of violent crime that were higher than the rates recorded by dry communities. Relative to dry communities, wet communities' overall sexual assault rate was 1.48 (95% CI = 1.38-1.60) times higher, the serious assault rate was 2.10 (95% CI = 1.88-2.35) times higher and the homicide rate was 2.88 (95% CI = 1.18-8.84) times higher. Although safer than wet communities, dry communities reported rates of violence that were higher than national rates including a serious assault rate that was double the national rate (3.25 per 1,000 vs. 1.44 per 1,000) and a sexual assault rate that was at least seven times as high as the national rate (7.58 per 1,000 vs. 0.88 per 1,000). CONCLUSIONS: As elsewhere in the Arctic, communities in Nunavut that prohibited alcohol were less violent than those that allowed alcohol importation. Even with prohibition, dry communities recorded rates of violence much greater than the national average. PMID- 21329579 TI - Influence of n-3 fatty acids on cardiac autonomic activity among Nunavik Inuit adults. AB - OBJECTIVES: Inuit from Nunavik (northern Quebec) consume large amounts of fish and marine mammals, which are important sources of n-3 polyunsaturated fatty acids (n-3 PUFAs). These substances have a beneficial impact on heart rate (HR) and heart rate variability (HRV). However, it is unknown if this beneficial impact remains significant in populations with high mercury exposure. The study assessed the impact of n-3 PUFAs (Docosahexaenoic [DHA] and Eicosapentaenoic acid [EPA]) on resting HR and HRV among Nunavik Inuit adults considering mercury and other potential confounders. STUDY DESIGN: Cross-sectional study employing clinical measurements. METHODS: Complete data were collected among 181 adults >= 40 years old (109 women and 72 men) living in the 14 coastal villages of Nunavik. Several indices of HRV were derived from a 2-hour Holter monitoring assessment. n 3 PUFAs levels were measured in membrane erythrocytes. Simple linear regression was used to analyse the relationship between n-3 PUFAs levels and resting HR and HRV parameters while multiple linear regressions were carried out to control for confounders. RESULTS: In the overall analyses, EPA was associated with SDANN (beta = 0.07, p = 0.04) and LF norm (beta = -1.84, p = 0.03) after adjusting for confounders. Among women, DHA was associated with resting HR (beta =-1.40, p = 0.03) while EPA was associated with SDNN (beta = 0.08, p = 0.03), SDANN (beta = 0.09, p = 0.02) and resting HR (beta = -2.61, p = 0.002). No significant association was observed in men. CONCLUSIONS: These results suggest a beneficial impact of n-3 PUFAs on resting HR and HRV among Nunavik Inuit women. PMID- 21329580 TI - [Current status and advances in lung cancer vaccine]. PMID- 21329581 TI - [Study on the effects of p53 deletion and mutation on malignant phenotype of human lung cancer cell line]. AB - BACKGROUND: To study the inhibition effects of both extraneous right sense and antisense p53 on malignant phenotype of human lung cancer cell line. METHODS: The named 801D cell line with p53 deletion and mutation at 248 code was selected as a model in vitro. The recombined plasmid pEGFP-p53(RS) and pEGFP-p53(AS) were constructed. The extraneous gene was detected by PCR. The p53 mutation protein was examined by immunohistochemical stain of p53 antibody. The inhibition effect of extraneous p53 on tumor growth in vitro were determined by clonogenic survival assay. FCM analysis was carried out in cells. The inhibition effect on malignant growth of extraneous p53 in vivo was observed by heteroplastic transplant on nude mouse. RESULTS: The transfected cell lines, pEGFP-p53(AS)-801D, pEGFP-p53(RS) 801D and pEGFP-801D were established. Presence of extraneous p53 and neo genes in pEGFP-p53(AS)-801D and pEGFP-p53(RS)-801D was proved by PCR and green fluorescence was found out in those cells under the microscope. Mutant protein in pEGFP-p53(AS)-801D was negative by immunohistochemical stain. The malignant growth of these transfected cell lines was inhibited comparing with parents in vivo and in vitro. Inhibition rate of colony formation was 62.0% for pEGFP p53(AS)-801D and 80.8% for pEGFP-p53(RS)-801D. The tumorigenicity in nude mice was suppressed. Inhibition effects of extraneous right sense p53 on malignant growth of 801D was more distinct. FCM analysis showed that pEGFP-p53(AS)-801D cells were arrested at G1 phase. CONCLUSIONS: The transfected cell lines with extraneous right sense and antisense p53 appear that malignant growth can be inhibited in vivo and in vitro. PMID- 21329582 TI - [Detection of methylation and deletion of p16 gene in non-small cell lung cancer]. AB - BACKGROUND: To investigate the methylation and deletion of p16 gene and its diagnostic value in non-small cell lung cancer. METHODS: A total of 50 lung cancer tissues and 54 normal lung tissues were examined for p16 gene methylation in exon 1 and deletion in exon 2 by PCR based methylation analysis and duplex PCR respectively. RESULTS: Out of 50 lung cancer tissues, 16 were positive for the p16 gene exon 1 methylation (32.0%), and 14 for the p16 gene exon 2 deletion (28.0%). However, in 54 cases of normal lung tissues, only 2 showed the p16 gene exon 1 methylation(3.7%), and none showed the p16 gene exon 2 deletion. There were significant differences in methylation rate (Fisher's exact= 0.000 ) and deletion rate (Fisher's exact= 0.000) between the two groups. CONCLUSIONS: The methylation and deletion may be important mechanisms for p16 gene inactivation in non-small cell lung cancer. The detection of p16 gene status may contribute to the diagnosis of lung cancer. PMID- 21329583 TI - [Cisplatin-induced apoptosis in human lung adenocarcinoma cell line A549]. AB - BACKGROUND: To elucidate the pattern and mechanism of cisplatin-induced apoptosis and its role in tumor chemotherapy. METHODS: Apoptosis induced by cisplatin in human lung adenocarcinoma cell line A549 was detected by cell morphology, agarose gel electrophoresis, DNA-end-labeling and flow cytometry analysis techniques. RESULTS: Cisplatin-induced apoptosis of A549 cells persisted and augmented gradually from 12 to 72 hours after treated with 3 mg/L cisplatin. All of A549 cells treated respectively with 1, 3, 5 and 7 mg/L cisplatin showed apoptosis. Apoptotic effects increased in a time-dependent pattern and a concentration dependent pattern. A549 cells were blocked in G1 phase after treated with cisplatin. CONCLUSIONS: Induction of cell apoptosis may be an important mechanism of anti-tumor efficacy of cisplatin. PMID- 21329584 TI - [Apoptosis-inducing effect of Tanshinone and its molecular mechanism on human lung cancer cells]. AB - BACKGROUND: To study the apoptosis-inducing effect of Tanshinone and its molecular mechanism on human lung cancer cells. METHODS: Human lung cancer cell line (SPC-A-1) was treated in vitro with 0.5 mg/L Tanshinone IIA for five days, and the cells treated with all trans retinoic acid (RA) or DDP as controls. Changes in cell morphology, apoptotic index and apoptosis related gene expression were detected by electron microscope, FCM and DNA-end-labeling. RESULTS: Many apoptotic cells were observed by light and electron microscopes. FCM examination showed that apoptotic index in Tanshinone group was much higher than that of DDP and control groups, but no difference was found statistically compared with RA group. The expression of p53, Fas and Bax genes in Tanshinone group was up regulated markedly, but Bcl-2 was obviously down-regulated. CONCLUSIONS: Tanshinone IIA can induce apoptosis in human lung cancer cell line (SPC-A-1) . Up regulating expression of p53, Bax, Fas and down-regulating Bcl-2 expression might be its molecular mechanisms. PMID- 21329585 TI - [Expression of E-cadherin in non-small cell lung cancer: correlation with lymphatic metastasis and prognosis]. AB - BACKGROUND: To explore the expression level of E-cadherin gene and its relationship with lymph node metastasis and prognosis in patients with primary non-small cell lung cancer (NSCLC). METHODS: The expression of E-cadherin protein was detected in 138 human NSCLC tissues by immunohistochemistry, and 23 normal lung tissues as control. RESULTS: The positive rate of E-cadherin expression (41.48%) in lung cancer tissues was significantly lower than that in normal lung tissues (73.12%) (P < 0.05). E-cadherin expression rate was closely related to lymph node metastasis (P < 0.05) and TNM stages of lung cancer (P < 0.05), but not to the size of the primary tumor (T), differentiation of cancer cell, histological classification and history of smoking (P > 0.05). The 5-year survival rate of the patients with high expression of E-cadherin ( > 40%) was significantly higher than those with low expression (<=40%) (P < 0.05 ). CONCLUSIONS: Detection of E cadherin expression may be helpful to predict the prognosis of patients with non-small cell lung cancer. PMID- 21329586 TI - [A study on the relationship between E-cadherin, beta-catenin expression and metastasis and prognosis in non-small cell lung cancer]. AB - BACKGROUND: To investigate the roles of E-cadherin and beta-catenin genes in metastasis and prognosis of non-small cell lung cancer. METHODS: The expression of E-cadherin and beta-catenin were detected in 112 non-small cell lung cancer tissues and 30 benign pulmonary lesion tissues by immunohistochemical method (LSAB method). RESULTS: The expression of E-cadherin and beta-catenin in lung cancer tissues was significantly lower than that in adjacent non-cancerous lung tissues and benign pulmonary tissues (P < 0.01); The expression of E-cadherin and beta-catenin in lung cancer tissues with lymph node and/or distant metastasis was significantly lower than that in those without lymph node and distant metastasis (P < 0.01); The 5-year survival rate in patients with low E-cadherin expression and low beta-catenin expression (6.78%) was remarkably lower than that in cases with high expression (6.78% vs 35.85% and 3.78% vs 37.29%) (P < 0.01). CONCLUSIONS: Underexpressions of E-cadherin and beta-catenin are very common in non-small cell lung cancer, and it may play an important role in the progression and metastasis of lung cancer. Detection of expression of E-cadherin and beta catenin in lung cancer might be helpful to predict prognosis. PMID- 21329587 TI - [Decline of dendritic cells in the peripheral blood of patients with non-small cell lung cancer and its relation to vascular endothelial growth factor]. AB - BACKGROUND: To detect dendritic cells (DC)in the peripheral blood and plasma concentration of vascular endothelial growth factor (VEGF) of patients with non small cell lung cancer (NSCLC) and to evaluate their relationship. METHODS: The quantitation of DC in the blood was performed in 55 patients with NSCLC, 13 patients with pulmonary benign diseases, and 12 healthy volunteers by a novel flow cytometric assay. The concentration of VEGF in the plasma was measured by ELISA kit. RESULTS: No significant difference was found in the levels of DC and VEGF between the patients with pulmonary benign diseases and healthy volunteers (P>0.05). In comparison with subjects of healthy volunteers and pulmonary benign diseases, the level of DC was significantly decreased, while that of VEGF was significantly increased in the patients with NSCLC(P < 0.05 to 0.01). The levels of DC and VEGF in the peripheral blood of NSCLC were closely associated with TNM stages and lymph node metastasis. However, no correlation was found among the levels of DC and VEGF and age, gender, cell differentiation and histologic classification. There was a negative correlation between the VEGF concentration and the DC counts. CONCLUSIONS: The decline of DC count in peripheral blood and the enhancement of plasma VEGF are remarkably related to the malignancy of NSCLC. And VEGF overexpression may be one of mechanisms of DC maturation and differentiation inhibition in patients with NSCLC. PMID- 21329588 TI - [The primary applications of 153Sm-EDTMP plus chemotherapy in the treatment of bone metastasis of lung cancer]. AB - BACKGROUND: To study the clinical effects of 153Sm-EDTMP plus chemotherapy in the treatment of bone metastasis of lung cancer. METHODS: One hundred and ten lung cancer patients with one metastasis [male 82 and female 28, aged from 32 to 76 yrs; squamous cell carcinoma 28, adenocarcinoma 27, small cell lung cancer (SCLC) 7, mix type 41, alveolar carcinoma 7] who did not undergo an operation were entered into this study. The patients were divided into 3 groups: 153Sm-EDTMP therapy only (37 cases), 153Sm-EDTMP plus chemotherapy after 3 days (42 cases), 30 days after chemotherapy plus 153Sm-EDTMP (31 cases). The dosages of 153Sm EDTMP ranged from 1 111 to 2 660 MBq. The patients with SCLC were adapted CCNU, MTX and CTX; those with non-small cell lung cancer (NSCLC) were adapted MMC, VCR and DDP. Statistic analysis of the data was performed by Chi-square test. RESULTS: Total pain relief rate for 153Sm-EDTMP only was 89.2% , for 153Sm-EDTMP plus chemotherapy was 92.8%, and for chemotherapy plus 153 Sm EDTMP was 90.3% . The foci disappeared in 9 cases with 153Sm-EDTMP only, in 12 cases with 153Sm EDTMP plus chemotherapy, and in 9 cases with chemotherapy plus 153Sm-EDTMP. The 1 year survival rate was 29.7%(11/37) by 153 Sm only, 40.5%(17/42) by 153 Sm plus chemotherapy, 38.7%(12/31) by chemotherapy plus 153Sm-EDTMP. CONCLUSIONS: 153Sm EDTMP plus chemotherapy is effective in the treatment of bone metastasis of lung cancer. PMID- 21329589 TI - [The clinical significance of detection of telomerase in bronchoalveolar lavage liquid in patients with lung cancer]. AB - BACKGROUND: To investigate the diagnostic significance of detection of telomerase activity of bronchoalveolar lavage liquid (BALF) in primary lung cancer. METHODS: BALF of 63 patients with lung cancer and 31 patients with non-cancerous pulmonary disease was collected, and telomerase activity was detected with silver-stained TRAP. Brush cytology and BALF cytology were carried out simultaneously. RESULTS: The positive rate of telomerase was 76.2% (48/63) in lung cancer group, which was higher than 6.5% (2/31) in control group (Chi-square=40.6, P < 0.01). The positive rate was also higher than that of brush cytology (58.7%, 37/63) (Chi square =3.6, P > 0.05), and higher than that of BALF cytology (14.3%, 9/63) (Chi square=46.3, P < 0.01). In central type lung cancer group, the positive rate of telomerase was 71.4% (35/49), and higher than that of BALF cytology (12.2%, 6/49) (Chi-square= 35.3 , P < 0.01), but had no significant difference compared to that of brush cytology (61.2%, 30/49) (Chi-square=1.1, P > 0.05). In peripheral-type lung cancer group, the positive rate of telomerase in BALF was 92.9% (13/14), and higher than that of brush cytology (50.0%, 7/14) and that of BALF cytology (21.4%, 3/14). CONCLUSIONS: The telomerase activity could be detected in the BALF of the primary lung cancer. Hence, detection of telomerase in the BALF of patients may be helpful to diagnose lung cancer. PMID- 21329590 TI - [Expression and clinical significance of nm23-H1 and CD44v6 in non-small cell lung cancer]. AB - BACKGROUND: To study the role of nm23-H1 and CD44v6 gene in non-small cell lung cancer (NSCLC). METHODS: Expressions of nm23-H1 and CD44v6 genes were analyzed in 147 cases of NSCLC by SP immunohistochemistry method. RESULTS: The overall positive rate of nm23-H1 staining was 62.6% (92/147). Significant differences in the positive rate of nm23-H1 were found between well and poor differentiated groups [68.6% (83/121) [WTBX]vs 34.6% (9/26)], and between adenocarcinoma and squamous cell carcinoma , and between adenocarcinoma and squamous cell carcinoma [78.8% (52/66) [WTBX]vs 50.8% (32/63) ] ( (P < 0.05), but not between stage I+II and stage III+IV [ 65.3% (62/95) [WTBX]vs 57.7% (30/52) ], and between N0 and N1 3 , and between N0 and N1 3 [64.7% (55/85) [WTBX]vs 59.7% (37/62) ]( ( P > 0.05). The positive rate of nm23-H1 of patients who survived for more than 3 years was 71.4% (55/77), which was significantly higher than 52.9% (37/70) of patients who survived for less than 3 years (Chi-square=5.4, P < 0.05). For CD44v6, the overall positive rate was 63.9% (94/147). Significant differences in the positive rate of CD44v6 were found between well and poor differentiated groups [68.6% (83/121) [WTBX]vs 42.3% (11/26)], and between adenocarcinoma and squamous cell carcinoma , and between adenocarcinoma and squamous cell carcinoma [53.0% (35/66) [WTBX]vs 77.8% (49/63) ] ( (P < 0.05), but not between stage I+II and stage III+IV [ 66.3% (63/95) [WTBX]vs 59.6% (31/52) ], and between N0 and N1-3 , and between N0 and N1 3 [63.5% (54/85) [WTBX]vs 64.5% (40/62) ]((P > 0.05). The positive rate of CD44v6 of patients who survived for more than 3 years was much lower than that of patients who survived for less than 3 years (43/74 vs 51/70, P < 0.01 ). The 3-year survival rate in patients with nm23-H1(+)CD4v6(-) was significantly higher than those with nm23-H1(-)CV44v6(+) (22/32 vs 11/34, P < 0.01). CONCLUSIONS: There are some relationships among expressions of nm23-H1 and CD44v6 in NSCLC and cell differentiation, histological classification and prognosis, and no relation in stage and lymph node metastasis. PMID- 21329591 TI - [Surgical treatment of lung cancer via intrapericardial vascular management: A report of 56 cases]. AB - BACKGROUND: To study the significance of pneumonectomy via intrapericardial vascular management in the surgical treatment of lung cancer. METHODS: A total of 56 patients with central-type lung cancer underwent pneumonectomy via intrapericardial vascular management. RESULTS: The incidence of postoperative complications was 8.93%(5/56). One patient died and the mortality rate was 1.97%. The postoperative follow up rate was 96.4%. The 1-, 3- and 5-year survival rates were 72.7%(40/55), 31.4%(11/35) and 17.4% (4/23) respectively. CONCLUSIONS: Pneumonectomy via intrapericardial vascular management is safe and can improve the resection rate. It might provide a basis for the further treatment of lung cancer and should be widely applied. PMID- 21329592 TI - [The role of transbronchial needle aspiration in the staging of bronchogenic carcinoma]. AB - BACKGROUND: To explore the role of transbronchial needle aspiration (TBNA) in the staging of bronchogenic carcinoma. METHODS: To 42 cases of primary bronchogenic carcinoma with suspected lymph node metastasis by X-ray and CT scan of chest, the TBNA was performed before operation. The cytological results and c-TNM by TBNA were compared with the pathological ones and p-TNM after operation. RESULTS: The diagnosis of 10 cases with N2 metastasis was completely corresponding by TBNA and pathological examination after operation. Nineteen out of 22 cases with N1 metastasis were confirmed by TBNA, and the false negative results ocurred in 3 cases. The results of TBNA in lymph nodes' size from 2 to 3 cm was completely accordant with pathological ones after operation. For 1 to 2 cm lymphnodes, the accurate rate of TBNA was 88.5% (23/26). The overall accurate rate of c-TNM by TBNA was 85.7% (36/42) compared with p-TNM. A small amount of hemoptysis ocurred in 3 cases, no pneumothorax and other serious complications were observed. CONCLUSIONS: The TBNA for staging of bronchogenic carcinoma is a simple and economic method with high correct rate and high clinical applicable value. PMID- 21329593 TI - [Surgical treatment of primary pulmonary low-grade malignant carcinoma]. AB - BACKGROUND: To arrive at a rational diagnosis and effective surgical treatment of primary pulmonary low-grade malignant carcinoma. METHODS: Eighty-nine patients with primary pulmonary low-grade malignant carcinoma received surgical treatment from 1956 to 2000. RESULTS: Out of the 89 patients, 54 were bronchial carcinoid, 18 were mucoepidermoid cancer, and 17 were adenoid cystic carcinoma. The operative procedures included resection of tracheal carcinoma in 3, lobectomy in 49, sleeve lobectomy in 14, total pneumonectomy in 14, and wedge pneumonectomy in 6. All patients were complaint free. The 5-year survival rates of bronchial carcinoid and adenoid cystic carcinoma were 91.3% and 70.6% respectively, and no patients with bronchial mucoepidermoid cancer died until now. CONCLUSIONS: Bronchial carcinoid, adenoid cystic carcinoma and mucoepidermoid cancer are a series of primary pulmonary carcinoma of low malignant potential, whose predilection sites are main or lobe bronchi, and clinical symptoms are repeated infection of the lung or intermittent hemoptysis. The diagnosis depends on radiography or CT scan of chest and bronchofiberscopy. The operation is most important, and whose procedure is lobectomy or sleeve lobectomy mainly. PMID- 21329594 TI - [The efficacy and toxicity of the FUDR-based regimen in the treatment of advanced non-small cell lung cancer]. AB - BACKGROUND: To evaluate the efficacy and toxicity of the FUDR-based regimen in the treatment of advanced non-small cell lung cancer. METHODS: Fifty patients in group A received the L/FUDR-EP regimen, while 42 patients in group B were given the L/FEP regimen. The response and toxicity were evaluated after three courses of treatment. RESULTS: The therapeutic response of group A and group B were 40.0% and 38.1% respectively (P > 0.05). The toxicities such as marrow inhibition, gastrointestinal symptoms, alopecia and local phlebitis were remarkably lower in group A than those of group B (P < 0.01). CONCLUSIONS: The FUDR based regimen is effective to the advanced NSCLC, and its toxicity is lower than 5-FU. PMID- 21329595 TI - [Clinical combination therapy for adrenal metastasis from lung cancer]. AB - BACKGROUND: To study the results of combination therapy for adrenal metastasis from lung cancer. METHODS: Thirty patients with adrenal metastasis were treated in our hospital from Feb. 1995 to Apr. 2001. Forteen patients were small cell lung cancer (SCLC) and 16 patients were non-small cell lung cancer (NSCLC). All patients were treated with chemotherapy and/or radiotherapy. Eighteen patients were treated with combination therapy of chemotherapy and radiotherapy, while twelve patients with chemotherapy alone. RESULTS: The median survival time was 8 months. The response rate of chemotherapy alone was 25.0% (partial relief 3 cases), while the response rate of combination therapy was 44.4% (complete relief 1 case and partial relief 7 cases). Pain was relieved quickly after radiotherapy for the patients with pain symptom. CONCLUSIONS: Combination of radiotherapy and chemotherapy is better than chemotherapy alone for the treatment of adrenal metastasis from lung cancer. PMID- 21329596 TI - [Expression profile of 60 lung cancer related genes in BEP2D cell and R15Hp35T-2 cell]. AB - BACKGROUND: To profile the expression patterns of 60 lung cancer related genes in human bronchial epithelial cell (BEP2D) and alpha-particle induced malignantly transformed cell (R15Hp35T-2). METHODS: Sixty lung cancer related cDNAs were micro-arrayed onto the microscope slides using Cartesian PixSys5500 cDNA Microarray machine. Total RNA from BEP2D cell and R15Hp35T-2 cell was extracted and labeled by fluorescent dye. The labeled probe was then hybridized with the cDNA. RESULTS: Compared with the BEP2D cell, 27 genes up-regulated and 7 down regulated in the R15Hp35T-2 cell. The expression abundance of most tumor suppressor genes were similar in the two kinds of cells, however, most oncogenes and growth factor genes were overexpressed in R15Hp35T-2 cell. CONCLUSIONS: In malignantly transformed human bronchial epithelial cell model induced by alpha particle, some oncogenes and growth factor genes may promote the malignant transformation together. PMID- 21329597 TI - [The effect of RAB5A gene over-expression on invasive and metastatic capabilities of human lung adenocarcinoma cell lines]. AB - BACKGROUND: Over-expression of RAB5A gene has been proved to be associated with neoplasia metastasis. This study is to explore the effect of RAB5A gene on invasion and metastasis of human lung adenocarcinoma cell lines. METHODS: Constituted basement membrane invasion technique, adhesion capability of tumor cell assay, the chemotactic migration of tumor cells assay, and gelatinases SDS PAGE analysis method were used to detect the changes of invasive and metastatic capability of Anip973 (with high metastatic capability) and its parent AGZY83-a cell lines (with low metastatic capability). RESULTS: After AGZY83-a cells were transfected by PcDNA3.1-RAB5A plasmid, its invasion was significantly increased (t=24.36, P < 0.000 5); adhesion capability of cell was promoted (P < 0.05); the chemotactic migration of cells was higher than that of the parent lines (t=14.18, P < 0.000 5); and the activity of gelatinases secreted from transfected AGZY83-a was enhanced. The invasion of the transfected Anip973 cells with PcDNA3-AntiRAB5A was lower (t= 16.510 4, P < 0.002 5); adhesion capability of cell was decreased (P < 0.05); the chemotactic migration of cells was lower than that of the parent lines (t=6.062, P < 0.005); and the activity of gelatinases was obviously decreased. CONCLUSIONS: This study in vitro indicates that over-expression of RAB5A genes plays an important role in tumor invasion and metastatic phenotype formation of human lung adenocarcinoma cells; and antisense RNA can interrupt the translation of RAB5A gene. PMID- 21329598 TI - [Expression of cancer-testis antigens in human lung cancer]. AB - BACKGROUND: To investigate the expression of cancer-testis antigens(CTA) in human lung cancer. METHODS: Reverse-transcription polymerase chain reaction (RT-PCR) was used to investigate the expression of the MAGE-1, -3, SSX-1, -2, -4, -5 and NY-ESO-1 genes in 35 lung cancer samples and corresponding non-tumorous lung tissues. Three samples selected randomly from each CTA PCR product were sequenced. RESULTS: In 35 tumor samples, the MAGE-1, -3, SSX-1, -2, -4, -5 and NY ESO-1 mRNA expression rates were 34.3%(12/35), 57.1%(20/35), 17.1%(6/35), 17.1%(6/35), 20.0%(7/35), 25.7%(9/35) and 37.1%(13/35), respectively. The positive rate was 74.3%(26/35) for at least one of these genes expression, and 65.7%(23/35) for two or more genes coexpression. No non-tumorous lung tissue was positive for these genes. The DNA sequence confirmed that the RT-PCR products were truly CTA cDNA. CONCLUSIONS: The cancer-testis antigens are potential targets for antigen-special immunotherapy of lung cancer. The coexpression pattern of these antigens provides a theoretic foundation for developing a polyvalent lung cancer vaccine. PMID- 21329599 TI - [Detection and quantitation of CK19 mRNA in the peripheral blood and regional lymph nodes of lung cancer patients]. AB - BACKGROUND: To detect the micrometastases status in peripheral blood and regional lymph nodes of lung cancer patients by reverse transcription-polymerase chain reaction (RT-PCR). METHODS: CK19 mRNA expression in peripheral blood and regional lymph nodes was detected in 78 patients with lung cancer, and 30 patients with pulmonary benign lesions and 10 healthy volunteers as controls by RT-PCR. Meanwhile, all lymph nodes were also examined by traditional pathological method. RESULTS: The positive rate of CK19 mRNA expression was 38.5% in peripheral blood of lung cancer patients, and 6.7% in patients with pulmonary benign lesions (6.7%) (Chi-square=10.505,P=0.001). No positive CK19 mRNA expression was found in peripheral blood of 10 healthy volunteers. The positive rates of CK19 mRNA of lymph nodes were 36.9% and 0 in lung cancer patients and pulmonary benign disease patients respectively (Fisher's exact=0.014). In lung cancer group, the metastatic rate of lymph nodes was 17.9% by traditional pathological examination, which was much lower than that by RT-PCR (Chi-square=7.664, P=0.006). CONCLUSIONS: RT-PCR amplification of CK19 mRNA is an sensitive method to detect early haematogenous and regional lymph nodes dissemination of cancer cells for patients with lung cancer. This method may lead to an earlier diagnosis and treatment of patients with subclinical metastasis in circulation and regional lymph nodes. PMID- 21329600 TI - [Detection of serum total MMP-9 and its clinical significance for lung neoplasms]. AB - BACKGROUND: To investigate the clinical value of serum total MMP-9 detection in lung malignancies. METHODS: Serum total MMP-9 levels were detected in 63 patients with lung malignancies by sandwich ELISA with monoclonal antibody against human total MMP-9. RESULTS: Serum total MMP-9 was (92.2+/- 74.39) MUg/L in lung malignancy group, which was significantly higher than that of healthy control [(9.5+/- 6.74) MUg/L](P < 0.05). In lung cancer group, there were significant differences in serum total MMP-9 level between patients with and without lymph node metastasis, and between progressive disease+death group and complete response+partial response group. Significantly negative correlation was observed between serum CA242 and serum total MMP-9 levels (P=0.021). CONCLUSIONS: Detection of serum total MMP-9 may be helpful to predict metastasis and treatment response of lung cancer. PMID- 21329601 TI - [Clinical study on the bone marrow micrometastases in patients with non-small cell lung cancer by immunohistochemical techniques]. AB - BACKGROUND: To investigate the immunohistochemical detected method and the clinical incidence of the bone marrow micrometastases (BMM) in patients with non small cell lung cancer (NSCLC) and to analyze the sensitivity and specificity and clinical application value. METHODS: Bone marrow samples were collected from the anterior superior iliac spines or posterior superior iliac spines of 53 patients with NSCLC in clinical stage I to III and 15 patients in stage IV, and the BMM was detected by immunohistochemical techniques (IHC) using monoclonal antibodies AE1/AE3 against cytokeratin. Chi-square test was used statistically. RESULTS: The IHC sensitivity could be 10-5. The BMM positive rate was 22.6% (12/53) in stage I to III and 53.3% (8/15) in stage IV, and there was a significant difference in the BMM positive rate between stage I to III and stage IV (P < 0.05). No correlation was observed between BMM and sex, age, KPS, pathology classification and cancer cell differentiation. CONCLUSIONS: The detection of BMM by IHC is convenient, sensitive, and specific. It might be helpful to diagnose bone marrow micrometastasis in patients with NSCLC. PMID- 21329602 TI - [Clinicopathological analysis of loss of fragile histidine triad expression in lung cancer]. AB - BACKGROUND: To investigate the relationship between expression of fragile histidine triad gene protein, Fhit, and clinicopathological characteristics of human lung cancer. METHODS: Fhit protein expression was detected in 92 cases of formalin-fixed, paraffin-embedded human lung cancer by citrate-microwave-SP immunohistochemical method, of which 52 were non-small cell cancer (NSCLC) and 40 small cell cancer (SCLC). Its relationship to histological grade, lymph node metastasis and histological classification were analysed. RESULTS: The loss of Fhit protein expression were found in 62.0% (57/92) and 4.3% (4/92) of cancer tissue and normal lung tissue, respectively and there was a significant difference in the expression of Fhit protein between cancer and normal tissue (P=0.000). 53.8% (28/52) of the cases of NSCLC showed a marked loss or absence of Fhit expression, 46.2% (24/52) of cases were negative, 7.7% (4/52) showed a higher expression and 38.5% (20/52) equal to the level of Fhit expression compared with the matched normal tissues. The loss of Fhit expression was closely related to histological grade (P=0.003), to lymph node metastasis (P=0.029), and to histological classification of the cases (P=0.003). There was a significant difference between grade I+II (38.2%; 13/34) and grade III cancer (83.3%; 15/18), between cancers with lymph node metastasis (70.8%; 17/24) and those without (39.3%; 11/28), and between squamous cell carcinoma ( 68.6%; 24/35) and adenocarcinoma (23.5%; 4/17). The loss of Fhit protein expression was found in 33 of 40 cases of SCLC (82.5%) and the remainder 7 cases (17.5%) showed the same quantity of expression of Fhit, compared with the normal bronchial mucosa. CONCLUSIONS: The expression of Fhit protein may be associated with the decreasing differentiation, lymph node metastasis and histological classification in NSCLC, and be corresponding to the occurrence and evolution of SCLC. These results suggest that the decreased Fhit expression plays an important role in the development and progression of the tumor, and thus may become a new prognostic marker in human lung cancer. PMID- 21329603 TI - [Study on the relationship between estrogen receptor expression and level of serum sexual hormones in male patients with lung cancer]. AB - BACKGROUND: To evaluate the relationship between estrogen receptor (ER) expression and level of serum sexual hormones in male patients with lung cancer. METHODS: The levels of serum estradiol (E 2), testosterone (T), follicle stimulating hormone (FSH) and lutenising hormone (LH) were measured in 25 patients with lung cancer and 30 healthy men by enzyme immunoassay magnetic solid phase (IEMA), the ER expression was detected in 25 cancer tissues, 25 paracancerous tissues, and 11 benign pulmonary tissues by immunocytochemistry (ICC). RESULTS: The level of plasma E2 in male patients with lung cancer was significantly higher than that in normal controls [(22.4+/-15.7) ng/L [WTBX]vs ( 12.6+/-4.8) ng/L, P=0.001 9] while the level of T was significantly lower while the level of T was significantly lower [(2.9+/-1.3) MUg/L [WTBX]vs (4.1+/-1.5) MUg/L, P= 0.003 0]. The ratio of E2/T of male patients with lung cancer was also remarkably higher than that of control . The ratio of E2/T of male patients with lung cancer was also remarkably higher than that of control [(9.7+/-10.0) *10 3[WTBX]vs ( 3.4+/-1.6)*10-3, P=0.004 6]. The expression rate of ER in lung cancer tissue samples was 60.0% (15/25), but no ER expression was found in the paracancerous tissues and benign pulmonary tissues. The level of E2 had positive correlation with the expression of ER in male patients with lung cancer (. The expression rate of ER in lung cancer tissue samples was 60.0% (15/25), but no ER expression was found in the paracancerous tissues and benign pulmonary tissues. The level of E2 had positive correlation with the expression of ER in male patients with lung cancer (r=0.916 7, P < 0.001). CONCLUSIONS: There are disorders and imbalances of sexual hormone metabolism in male patients with lung cancer, and these imbalances relate to the expression of ER. The elevation of E2 level in peripheral blood might be related to the overexpression of ER. PMID- 21329604 TI - [Combination of docetaxel and cisplatin in the treatment of advanced non-small cell lung cancer]. AB - BACKGROUND: To evaluate the efficacy and toxicity of the combination of docetaxel and cisplatin in the treatment of patients with advanced non-small cell lung cancer (NSCLC). METHODS: Forty patients with locally advanced (stage III) or metastatic (stage IV) NSCLC were enrolled into the study. The patients received docetaxel 75 mg/m2 on day 1, and cisplatin 75-80 mg/m2 on day 1 or days devided into 1-3 of a 21-day cycle. Each patient should complete two cycles. RESULTS: An objective response rate was obtained in 43.6% of 39 patients (one complete and 16 partial response), whereas 15 patients had stable disease and 7 patients were progressive. The response rate was 44.4% (8/18) in the initial patients, and 42.9% (9/21) in the retreated patients. No significant difference existed between the two groups (P > 0.05). The main toxicities were leukopenia (17.5% in grade III+IV) and thrombocytopenia (12.5% in grade III+IV). One patients died of intracranial hemorrhage. CONCLUSIONS: The combination of docetaxel and cisplatin is a feasible, well-tolerated and active scheme in the first-line or second-line treatment of advanced NSCLC. Great attention must be paid to the possible severe bone marrow depression of the regimen. PMID- 21329605 TI - [Evaluation of topotecan combined with cisplatin in the treatment of small cell lung cancer]. AB - BACKGROUND: To evaluate the effects and toxicities of topotecan combined with cisplatin in the treatment of small cell lung cancer (SCLC). METHODS: Twenty-six patients with SCLC diagnosed by pathologic or cytologic examination were treated with topotecan 1.25 mg/(m2*d) on days 1-5 and cisplatin 25 mg/(m2*d) on days 1-3. The chemotherapy was repeated every 21 days as a cycle. RESULTS: Out of 26 evaluable patients, 3 achieved complete response and 11 achieved partial response with an overall response rate of 53.8%. The response rates were 75.0% and 35.7% in 12 previously untreated patients and 14 patients with prior chemotherapy, respectively. In addition, one of eight refractory patients and two of five patients with brain metastasis got partial responses. The median survival period was 27 weeks and one-year survival rate was 38.5%. Myelosuppression was the major dose-limiting toxicity. CONCLUSIONS: Topotecan combined with cisplatin is effective for SCLC and it toxicity is tolerable. PMID- 21329606 TI - [89SrCl2 and/or Bonefos in the treatment of bone metastasis from pulmonary carcinoma]. AB - BACKGROUND: To evaluate the effect of 89SrCl2 and/or Bonefos in the treatment of bone metastasis from pulmonary carcinoma. METHODS: A total of sixty-seven lung cancer patients with bone metastasis were enrolled in this study, who were divided into three groups: nineteen cases were treated with 89SrCl2; twenty-eight cases with Bonefos; and twenty cases combined 89SrCl2 with Bonefos. RESULTS: The total relief rate of the bone pain: the 89SrCl2 group was 84.2%, and the Bonefos group was 80.4%, the combination group was 90.0%. There was no statistical difference among three groups (P > 0.05). The effective rate of the bone metastasis: the 89SrCl2 group was 15.7%, the Bonefos group was 10.7%, and the combination group was 45.0%. The combination group had significantly higher effective rate than that of the 89SrCl2 group or the Bonefos group alone (P < 0.05). The rate of improvement of quality of life: the 89SrCl2 group was 47.3%, the Bonefos group was 42.8%, and the combination group was 80.0%. The combination group had significantly higher effective rate than that of the 89SrCl2 group or the Bonefos group alone (P < 0.05). The side effects of three groups were minimal. CONCLUSIONS: 89SrCl2 and Bonefos are two effective and safe drugs on relief of pain. Combined 89SrCl2 and Bonefos might be a better therapy for bone metastasis and improvement of quality of life than the single one, and the side effect is slight and tolerable. PMID- 21329607 TI - [The efficacy of bronchial artery infusion chemotherapy combined with immunotherapy for lung cancer with malignant hydrothorax]. AB - BACKGROUND: To explore the therapeutic effect of bronchial artery infusion chemotherapy combined with immunotherapy for lung cancer with malignant hydrothorax. METHODS: Seventy-five lung cancer patients with malignant hydrothorax were randomly divided into the two groups: 38 patients were given intrathoracic chemotherapy and bronchial artery infusion chemotherapy combined with immunotherapy as observing group; 37cases only received intrathoracic chemotherapy as control group. Chi-square assay was performed to analyze the efficacy (responses for lung cancer and hydrothorax control) after the first course of treatment and the 1-, 2-year survival rates in the two groups. RESULTS: After the first course of treatment, the total responses for lung cancer were 31.58% (12/38) and 5.41% (2/37) in the observing group and control group (Chi square=8.46, P < 0.01) respectively ; and responses for hydrothorax control were 86.84% and 64.86% respectively (Chi-square= 4.96, P <0.05). The 1- and 2-year survival rates in the observing group were 65.79% (25/38) and 26.32% (10/38) respectively, which were significantly higher than those of the control group (40.54% and 5.41%) respectively (Chi-square=4.80, P <0.05; Chi-square=6.10, P <0.05). CONCLUSIONS: The intrathoracic chemotherapy combined with bronchial artery infusion chemotherapy and immunotherapy is quite effective in the treatment of lung cancer with malignant hydrothorax. PMID- 21329608 TI - [Monitoring of the renal function changes during chemotherapy based on high-dose cisplatin in patients with lung cancer]. AB - BACKGROUND: To study the methods for monitoring nephrotoxicity of cisplatin in lung cancer chemotherapy. METHODS: The serum urea nitrogen (BUN), creatine (Cr) and urine beta2-microglobulin ( beta2-MG),alpha1-microglobulin(alpha1-MG), albumin (Alb), transferrin (TRF), and retinol-binding-protein (RBP) were measured dynamically in 61 patients with lung cancer who received high-dose chemotherapy with DDP (80- 120 mg/m2) (totally 114 cycles), and some indexes of early nephrotxcity were screened. RESULTS: At the early stage of chemotherapy (d1-5), the abnormal rates of urine beta2-MG and alpha1-MG were much more predominant than those of other indexes (P < 0.001). The abnormal rates of serum BUN and Cr were increased significantly in the late period of chemotherapy (d10). There were abnormal elevation of urine beta2-MG and/or alpha1-MG at the early stage of chemotherapy for the patients whose serum BUN and creatine were all abnormal at the late stage. CONCLUSIONS: The urine beta2-MG and /or alpha1-MG might be the valuable indexes for early diagnosis of nephrotoxicity in lung cancer chemotherapy with cisplatin. PMID- 21329609 TI - [Heart function in patients with advanced lung cancer]. AB - BACKGROUND: To evaluate the incidence and effective factors of cardiac dysfunction in patients with advanced lung cancer. METHODS: Echocardiography were carried out in 60 patients with advanced lung cancer before treatment. According to heart function, patients were divided into treatment group and control group. RESULTS: The incidence of cardiac dysfunction in patients with advanced lung cancer was 60%. All patients with malignant pleural effusion and pericardial effusion had cardiac dysfunction. Cardiac dysfunction occurred much earlier when patients had previous history of coronary artery diseases, hypertension or diabetes. Treatment against cardiac dysfunction may improve symptoms and prolong survival time. The cardiac dysfunction in the patients with advanced lung cancer is not concerned in chemotherapy. CONCLUSIONS: The incidence of cardiac dysfunction is closely related to patients' general condition, especially massive malignant pleural effusion and pericardial effusion. Treatment against cardiac dysfunction can significantly improve the clinical symptoms, life quality and survival time. PMID- 21329610 TI - Skipping Metastasis to Mediastinal Lymph Nodes in Non-small Cell Lung Cancer: A Clinical Study on the Reasonable Extent of Dissection. AB - BACKGROUND: To elucidate the characteristics and metastastic pattern of skipping mediastinal lymph node metastasis (skipping N2) in non-small cell lung cancer (NSCLC), and investigate reasonable extent of lymph node dissection. METHODS: From 1990 to 1998, lobectomy combined with systematic mediastinal lymph node dissection was performed in 109 patients with NSCLC. A retrospective study was carried out to elucidate the characteristics of skipping N2 disease and to compare the difference between skipping N2 and non-skipping N2 diseases. RESULTS: Twenty-one patients (19%) had skipping N2 diseases. Of the skipping N2 group, 18 cases (86%) were adenocarcinoma. Skipping N2 disease was more common in T1 and T2 group than that in T3 and T4 group (P < 0.01). All skipping N2 diseases only involved one nodal station, and most of them were regional mediastinal nodal metastasis. Skipping N2 from upper lobe tumors mainly involved superior tracheobronchial or subaortic lymph nodes, and skipping N2 from lower lobe tumors involved subcarinal lymph nodes. CONCLUSIONS: Skipping N2 disease presents certain clinical characteristics and metastastic pattern, and mediastinal nodal dissection might be modified according to the pattern. PMID- 21329611 TI - An evidence synthesis of qualitative and quantitative research on component intervention techniques, effectiveness, cost-effectiveness, equity and acceptability of different versions of health-related lifestyle advisor role in improving health. AB - BACKGROUND: There is a need to identify and analyse the range of models developed to date for delivering health-related lifestyle advice (HRLA), or training, for effectiveness and cost-effectiveness in improving the health and well-being of individuals and communities in the UK, with particular reference to the reduction of inequalities. OBJECTIVES: To identify the component intervention techniques of lifestyle advisors (LAs) in the UK and similar contexts, and the outcomes of HRLA interventions. DATA SOURCES: Stakeholder views, secondary analysis of the National Survey of Health Trainer Activity, telephone survey of health trainer leads/coordinators. A search of a range of electronic databases was undertaken [including the Applied Social Sciences Index and Abstracts (ASSIA), EMBASE, NHS Economic Evaluation Database (NHS EED), MEDLINE, Psyc INFO, etc.], as well searching relevant journals and reference lists, conducted from inception to September 2008. REVIEW METHODS: Identified studies were scanned by two reviewers and those meeting the following criteria were included: studies carrying out an evaluation of HRLA; those taking place in developed countries similar to the UK context; those looking at adult groups; interventions with the explicit aim of health improvement; interventions that involved paid or voluntary work with an individual or group of peers acting in an advisory role; advice delivered by post, online or electronically; training, support or counselling delivered to patients, communities or members of the public. After quality assessment, studies were selected for inclusion in the review. Data were abstracted from each study according to an agreed procedure and narrative, and realist and economic approaches were used to synthesise the data. Cost-effectiveness analysis of interventions was undertaken. RESULTS: In total, 269 studies were identified but 243 were excluded. The 26 included studies addressing chronic care, mental health, breastfeeding, smoking, diet and physical activity, screening and human immunodeficiency virus (HIV) infection prevention. Overall, there was insufficient evidence to either support or refute the use of LAs to promote health and improve quality of life (QoL), and thus uncertainty about the interventions' cost-effectiveness. However, the economic analysis showed that LA interventions were cost-effective in chronic care and smoking cessation, inconclusive for breastfeeding and mental health and not cost-effective for screening uptake and diet/physical activity. LA interventions for HIV prevention were cost-effective, but not in a UK context. LIMITATIONS: The wide variety of LA models, delivery settings and target populations prevented the reviewers from establishing firm causal relationships between intervention mode and study outcomes. CONCLUSIONS: Evidence was variable, giving only limited support to LAs having a positive impact on health knowledge, behaviours and outcomes. Levels of acceptability appeared to be high. LAs acted as translational agents, sometimes removing barriers to prescribed behaviour or helping to create facilitative social environments. Reporting of processes of accessing or capitalising on indigenous knowledge was limited. Ambiguity was apparent with respect to the role and impact of lay and peer characteristics of the interventions. A future programme of research on HRLA could benefit from further emphasis on identification of needs, the broadening of population focus and intervention aims, the measurement of outcomes and the reviewing of evidence. FUNDING: This study was funded by the Health Technology Assessment programme of the National Institute for Health Research. PMID- 21329612 TI - Clinical neuropathology, vol. 30 - no. 2/2011. PMID- 21329613 TI - FISH-based detection of 1p 19q codeletion in oligodendroglial tumors: procedures and protocols for neuropathological practice - a publication under the auspices of the Research Committee of the European Confederation of Neuropathological Societies (Euro-CNS). AB - The codeletion of chromosomal arms 1p 19q is a characteristic and early genetic event in oligodendroglial tumors, that is associated with a better prognosis and enhanced response to therapy. Over the last years, the increasing clinical demand to determine the 1p 19q status has led to the implementation of its testing in many neuropathology laboratories. Several different methods for 1p 19q testing are available: PCR-based loss of heterozygosity analysis, multiplex ligation dependent probe amplification, array comparative genomic hybridization, and fluorescence in situ hybridization (FISH). Herein, we focus and critically discuss the latter method because a detailed description of procedures and protocols for FISH-based 1p 19q testing in practice is lacking. We present a practical approach to the FISH-based assessment of the 1p 19q status in oligodendroglial tumors, from commonly used locus-specific probes and technical protocols to the neuropathological interpretation of results. Thereby, we aim to facilitate the implementation of FISH-based 1p 19q testing for clinical purposes in standard neuropathology laboratories without special focus on brain tumor research. PMID- 21329614 TI - Comparison of four neuropathological scales for Alzheimer's disease. AB - OBJECTIVE: There are several neuropathological scales for staging of Alzheimer pathology. The system proposed by Braak and Braak is based on the topographic distribution of neurofibrillary tangles and neuropil threads, while that of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) is based on the quantity of neocortical neuritic plaques. A combination of the Braak and CERAD staging scales was recommended by the National Institute on Aging and Reagan Institute (NIA-RI). The Poly-Pathology Alzheimer's Disease assessment, nine areas (PPAD9) is a staging system based on the extent of neuronal degeneration, microvacuolization, cytoarchitectural disorder and gliosis, in addition to neurofibrillary tangles and neuritic plaques, in nine cerebral regions. The aim of the present study was to critically compare these four neuropathological staging scales. METHODS: We assessed the Alzheimer pathology, using the four scales, in 43 patients with various dementia disorders, with focus on concordance and differences between the staging systems. RESULTS: Comparing the staging systems, the Spearman's rho value for PPAD9 vs. Braak was 0.65, for PPAD9 vs. CERAD 0.72, for PPAD9 vs. NIA-RI 0.67, and for Braak vs. CERAD 0.46. CONCLUSION: The correlation between the neuropathological staging systems was suboptimal, and we conclude that the choice of staging system affects the evaluation of Alzheimer pathology, and hence the final diagnosis. PMID- 21329615 TI - Chordoid meningioma of the third ventricle: a case report and review of the literature. AB - Chordoid meningioma is a rare variant of meningioma with histologic features that mimic chordoma and other chordoid neoplasms. This tumor is important to recognize, as there is a well-documented propensity for local recurrence and aggressive behavior. Most cases occur around the cerebral convexities, in locations that are similar to classical forms of meningioma. Intraventricular forms of chordoid meningioma are rare, with most reported cases arising in the lateral ventricles. We present a case of a chordoid meningioma that presented in the third ventricle of a 63-year-old female. This represents only the second documented case of a third ventricular chordoid meningioma and the first case in an adult. The distinction from other chordoid neoplasms can be challenging, particularly chordoid gliomas, which classically occur in this location. Herein, we compare and contrast chordoid meningioma with chordoid glioma and provide a review of the relevant literature. PMID- 21329617 TI - Central liponeurocytoma: case report and review of literature. AB - The lipomatous differentiation occurring within neurocytoma has more frequently been reported in neurocytoma of cerebellar origin as case reports and short series. This case report describes the clinical, radiological, histopathological and ultrastructural findings of supratentorial central neurocytoma with lipomatous differentiation in a 45-year-old female. Magnetic resonance imaging (MRI) revealed an intraventricular lesion in the right trigone which was isointense on T1 and hyperintense on T2 weighted images. There were small cystic areas and it enhanced brilliantly and homogenously on contrast. The rare lipomatous differentiation occurring in neurocytoma in the supratentorial location lends it a distinct morphological profile and thus recommends its designation as "central liponeurocytoma". PMID- 21329616 TI - Primary intracerebral Hodgkin lymphoma with recurrence. AB - OBJECTIVE: To report a case of primary intracerebral Hodgkin lymphoma with disease recurrence. METHODS: Case report and review of the literature. RESULTS: A 58-year-old immunocompetent male presented with aphasia. Neuroimaging revealed a left temporal lobe lesion. A craniotomy and resection were performed, and the diagnosis of classical Hodgkin lymphoma was made. Systemic work-up for lymphoma was negative. Postoperatively, the patient was treated with whole brain irradiation. 14 months later, the patient developed an enhancing lesion in his pons and received combination chemotherapy and radiation therapy. Repeat imaging demonstrated leptomeningeal enhancement and multiple lesions throughout the cerebral hemispheres, cerebellum and brainstem. COMMENT: We report what appears to be the first case of a patient with aggressive primary intracerebral Hodgkin lymphoma with disease recurrence. PMID- 21329618 TI - Unusual balloon cell features in melanoma brain metastasis: a potential diagnostic pitfall in surgical neuropathology. PMID- 21329619 TI - Medication review of community-dwelling seniors using intensified home-care service. AB - Investigations on medication burden, falling, and inappropriate dosing in renal impairment have been obtained in patients living in nursing homes. Data from home dwelling patients in intensified ambulatory care, especially from Germany are scant. MATERIAL AND METHOD: We evaluated patients daily visited by an ambulatory care service (Cohort 1, n = 102, median age 80 y) or had care given by relatives only (cohort 2, n = 101, median age 76 y) at baseline (V1), 6 (V2) and 12 months (V3). RESULTS: At V1 patients in Cohort 1 had 5 (median, range 3 - 15) and at V3 6 (3 - 17) medications. No differences could be observed between cohorts regarding number and pattern of medications. At V1, 30/102 patients of Cohort 1 had creatinine measured within the last 6 months, 13/30 patients had an eGFR < 50 ml/min. 6/34 medications which need dose-adjustment were unadjusted. Low surveillance of renal function and unadjusted dosing were also observed at other visits and also in Cohort 2. Within 1 year, 29/75 mobile patients in cohort 1 had a fall, 18/29 patients had a benzodiazepine prescribed regularly, whereas a benzodiazepine was prescribed in 6/46 patients which did not fall (chi2 p = 0.004). In Cohort 2, the number of falling patients was lower (19/84 mobile patients, p = 0.028). 11/19 patients had a benzodiazepine prescribed, in contrast to 5/65 patients which did not fall (chi2 p = 0.001). CONCLUSIONS: It needs to be elucidated whether a care service can contribute to medication safety in patients e.g. by reviewing medication charts and organizing for controls of ancillary laboratory values. PMID- 21329620 TI - Predictability of serious adverse reaction alerts for monoclonal antibodies. AB - OBJECTIVE: We analyzed the predictability of the United States Food and Drug Administration's Medwatch safety alerts on monoclonal antibodies with the aim of assessing the adequacy of their pre-approval safety evaluation. METHODS: An alert was considered observed when increased frequency, severity, or other new properties were reported for previously identified suspected adverse reactions. RESULTS: Up until January 2010, 36 safety alerts to mAbs were issued containing 61 alert terms. Just above a half (32) of the alert terms were assessed as observed. DISCUSSION: In addition to the observed reactions, a large proportion of unobserved reactions could have been predicted based on the mechanism of action and antibody target. Although retrospective assessment necessarily implies an element of subjectivity, there appears to be room for improvement in predicting adverse reactions to mAbs. CONCLUSIONS: Adverse reaction risk management and pharmaceutical care must focus on the observed reactions, but all effort should be made to extrapolate from the observed reactions to predict further safety issues. This should be taken into account by marketing authorization holders, prescribers, clinical trial sponsors, investigators and regulators. PMID- 21329621 TI - Serum CRP in patients with gout and effects of benzbromarone. AB - OBJECTIVE: C-reactive protein (CRP) is associated with increased risk for myocardial infarction, atherosclerosis, and peripheral artery diseases, while increased serum uric acid level is suggested to be independently associated with an increased risk of cardiovascular mortality. Accordingly, to investigate whether hyperuricemia is associated with serum CRP, we compared serum CRP levels between healthy subjects and patients with gout. In addition, we also examined whether benzbromarone has effects on serum CRP levels in patients with gout and the expression of CRP messenger RNA of CRP in the hepatoma cell line HuH7. METHODS: In the first experiment, 40 healthy males and 43 male patients with gout were enrolled, then blood samples were drawn from each after an overnight fast. In the second experiment, 42 male patients with gout were given uric acid lowering therapy with benzbromarone. Blood samples were drawn after an overnight fast before and 1 year after beginning benzbromarone treatment. In the third experiment, the effects of benzbromarone on IL1beta-induced CRP expression were determined in HuH7 cells. RESULTS: Log serum CRP levels were not significantly different between the patients with gout and healthy subjects, while log serum CRP levels were decreased by 11% after benzbromarone treatment, as compared to the values before treatment (p < 0.01). In addition, log serum adiponectin levels were elevated by 2% after treatment (p < 0.01). Furthermore, our in vitro findings demonstrated that benzbromarone down-regulated IL1beta-stimulated CRP gene expression. CONCLUSIONS: These results suggest that hyperuricemia may not contribute to an increase in serum CRP level, while benzbromarone may have a favorable effect on CRP. PMID- 21329622 TI - Efficacy and tolerability of two oral hyoscine butylbromide formulations in Chinese patients with recurrent episodes of self-reported gastric or intestinal spasm-like pain. AB - AIM: To compare the efficacy and tolerability of oral hyoscine butylbromide tablets and capsules in Chinese patients with recurrent episodes of self-reported gastric or intestinal spasm-like pain and to show non-inferiority of both formulations. METHODS: 302 patients were entered into a randomized, double-blind, double-dummy, active-controlled 2-arm parallel group study. They were randomized to 3 days of treatment with hyoscine butylbromide tablets or capsules. In patient diaries the pain intensity was assessed on 10 cm visual analogue scales on Day 1 (0, 30, 60, 90, 120, and 180 minutes after first dose), Days 2, and 3 (maximum pain intensity once daily). Pain frequency, overall efficacy, and tolerability were assessed on verbal rating scales. RESULTS: In the per-protocol dataset 281 patients were analyzed. The change from baseline after 180 minutes was 59% in both treatment groups; the adjusted means of pain intensity on Day 1 were reduced by -2.36 cm (tablets) and -2.31 cm (capsules). Pain intensity decreased within 30 minutes by approximately 20%. The decrease of the peak pain intensity was approximately 55% after 3 days in both treatment groups; the adjusted means after 3 days were reduced by -2.48 cm (tablets) and by -2.45 cm (capsules). Abdominal pain frequency decreased by 50% (tablets) and 42% (capsules). Both treatments were well tolerated. Drug-related adverse events were infrequent (3.5%). No serious adverse event occurred. CONCLUSIONS: Hyoscine butylbromide is effective in the treatment of recurrent gastric or intestinal spasm-like pain and well tolerated. Non-inferiority of tablets and capsules was demonstrated. PMID- 21329623 TI - Cephalosporin and penicillin cross-reactivity in patients allergic to penicillins. AB - BACKGROUND: Bata-lactam antibiotics are the most commonly used antibiotics which usually cause serious IgE-mediated allergic reactions. Of all bata-lactam antibiotics, penicillins have so far been the best-studied, but the studies of cephalosporins and their cross-reactivity with penicillins are rare. We sought to evaluate the IgE response in vitro and estimate cross-reactivity between penicillins and cephalosporins in patients allergic to penicillins. METHODS: We studied 87 control subjects and 420 subjects allergic to penicillins. Radioallergosorbent test (RAST) was performed to detect eight types of specific penicillin IgE and eleven types of specific-cephalosporin IgE. The cross reactivity and different molecules recognition by IgE were studied with a radioallergosorbent inhibition test. RESULTS: Of 420 patients allergic to penicillins, 95 patients (22.62%) showed specific-cephalosporin IgE positive, 73 patients (17.38%) showed IgEs positive to both penicillins and cephalosporins. In specific-penicillin IgE positive group, the positive rate of specific cephalosporin IgE was significantly higher than in specific-penicillin IgE negative group (27.14% vs. 14.57%, p < 0.01). In urticaria group, the positive rate of specific-cephalosporin IgE was significantly higher than in other symptoms group (30.65% vs. 8.11%, p < 0.05). The analysis of drugs which have the same or similar side-chains showed that benzylpenicillanyl-IgE (BPA-IgE), ampicillanyl-IgE (APA-IgE), amoxicillanyl-IgE (AXA-IgE) were respectively related to cephalothanyl-IgE (CLA-IgE), cephalexanyl-IgE (CEXA-IgE), cephalexanyl-IgE (CEXA-IgE)in sera of penicillin-allergic patients we studied, and compared with patients who had negative amoxicillin-IgE, the positive rates of specific ampicillin IgE and specific-cephalexin IgE were significantly higher in patients who had positive amoxicillin-IgE (14.43% vs. 3.72%, 14.00% vs. 2.96%, p < 0.01). Radioallergosorbent test and radioallergosorbent inhibition test confirmed that both nuclear structure and R1 side-chain contribute to IgE recognition. CONCLUSIONS: There exists cross-reactivity between cephalosporins and penicillins; patients allergic to several penicillins are more likely to develop allergic reaction to cephalosporins; due to sensitization to the similar structural characteristics (nuclear and R1 side-chain), penicillin-allergic patients may develop cross-allergic reactions with not only first-generation but also third-generation cephalosporins. PMID- 21329624 TI - Cost-effectiveness of insulin glargine versus NPH insulin for the treatment of Type 2 diabetes mellitus, modeling the interaction between hypoglycemia and glycemic control in Switzerland. AB - OBJECTIVE: The objective of this study was to evaluate the short-term and long term clinical and economic outcomes associated with insulin glargine or NPH insulin in patients with Type 2 diabetes mellitus (T2DM) inadequately controlled with oral anti-diabetic drugs in Switzerland, modeling the interaction between hypoglycemia and glycemic control (HbA1c). METHODS: A validated discrete event simulation model for T2DM was used to predict incidence of short-term complications (symptomatic, nocturnal and severe hypoglycemic events) and long term complications (microvascular and macrovascular events), life expectancy, quality-adjusted life years (QALYs) and direct medical costs in patients treated with insulin glargine or NPH insulin. The model was populated with published Swiss patient characteristics with T2DM. Baseline risks of hypoglycemic events, utility decrements of diabetes-related long-term complications and the hypoglycemia fear score were derived from the literature. Relative risk reductions of hypoglycemia adjusted for HbA1c using insulin glargine compared with NPH insulin were based on a published negative binomial meta-regression analysis. Costs of severe hypoglycemia, micro- and macrovascular events were analyzed from literature whenever possible otherwise guideline-projected resource use estimations were valued with Swiss official prices or tariffs in 2006 CHF. Simulations were run with 1,000 patients per cohort over a time horizon of 40 years. Incremental cost effectiveness ratios (ICERs) were presented as cost per QALY and per life year gained (LYG). Future costs and clinical benefits were discounted at 3.5%. Wide-range one-way sensitivity analyses were performed. RESULTS: Insulin glargine was associated with an improvement in quality of life (0.098 QALYs per patient) and additional life expectancy (0.05 life years gained per patient) compared to NPH insulin. Incremental costs of CHF 2,578 resulted in an ICER of CHF 26,271 per QALY and CHF 51,100 per LYG. The cost per QALY was most sensitive to changes in costs, utility decrements and relative risk reductions of hypoglycemia. CONCLUSIONS: This study evaluated, for the first time, the cost effectiveness of insulin glargine versus NPH insulin for the treatment of T2DM considering the interaction between glycemic control and hypoglycemia in Switzerland. The base case and sensitivity analyses demonstrated that insulin glargine proved to be cost-effective with respect to accepted willingness to pay thresholds and therefore represents good value for money. PMID- 21329625 TI - Healthy volunteers for bioequivalence trials: predictive factors for enrollment failures--a case-control study. AB - OBJECTIVE: To identify social predictors for enrollment failures of healthy volunteers (hv) in bioequivalence trials. METHODS: Retrospective case-control study. Data was collected from clinical files of hv recruited in 13 bioequivalence trials approved by an independent IRB and local regulatory authority carried out between January and December 2009 at a Pharmacokinetic Unit in Buenos Aires, Argentina. All hv signed the Inform Consent Form. Only subjects who fulfilled all inclusion criteria required by the protocols were studied. Cases (enrollment failures): hv who fulfilled the protocols eligibility criteria but were not enrolled in the trials by their own decision. CONTROLS: hv who fulfilled all the protocols eligibility criteria and were enrolled. Cases and controls were matched by demographic/ physical data and compared in relation to database contact, unemployment, alcoholic/ drug family environment, history of alcohol/ drug abuse, and other social variables. Chi2-test and t-test were used to compare data; variables presenting statistical difference were included in a logistic regression model. RESULTS: A sample of 375 hv. was analyzed. cases: 81/375(21.60%). Controls: 294/375 (78.40%). Cases did not differ from controls in relation to nationality, educational level, length of study and history of alcohol abuse. Statistical differences between cases and controls were found in non-database contact, unemployment, alcoholic environment, drug abuse environment and personal history of drug abuse. In a multivariate analysis only unemployment, (OR: 4.20, p < 0.001), non-database contact, (OR: 2.35, p = 0.004) and alcoholic environment, (OR: 1.94, p = 0.045) remained as predictive factors. CONCLUSION: In bioequivalence trials, an unemployment condition, and an alcoholic family environment were identified as negative predictors for effective enrollment in new healthy volunteers. PMID- 21329626 TI - Pharmacokinetics and bioequivalence of single dose and multiple doses of immediate- and extended-release formulations of dexibuprofen in healthy Chinese subjects. AB - OBJECTIVE: To compare the pharmacokinetic (PK) profiles and bioequivalence of the extended-release (ER) and immediate-release (IR) formulations of dexibuprofen (DI) in healthy Chinese volunteers after single dose and multiple doses. MATERIALS: Zefen(r) (IR capsule, containing 150 mg DI, Suzhou No.4 Pharmaceutical Factory, Jiangsu, China) and ER capsule (containing 225 mg DI, Tianjin Zhongtian Pharmaceutical Co. Ltd., Tianjin, China). METHODS: This was an open, randomized, two-period crossover study. Eligible subjects were healthy male Chinese volunteers. 22 subjects were randomly assigned to receive a single 450 mg dose of the test or reference formulation on the first day. During the next 6 days, the test group received a multiple-dose of ER DI capsule (450 mg, b.i.d.) and the reference group took a multiple-dose of IR DI capsule (300 mg, t.i.d.), respectively. Multiple blood samples were collected, and plasma concentrations of DI were analyzed using high performance liquid chromatography (HPLC) system. After a 9-day washout period, the subjects were administered the alternate formulation. Bioequivalence was concluded if the 90% confidence interval (CI) for the ratio between test and reference was within accepted limits. Adverse events (AEs) were monitored and documented throughout the confinement in the clinic and washout phases of each study period. RESULTS: 21 subjects completed the single dose administration and 20 subjects were evaluable for the multiple doses PK parameters. Single-dose Mean AUC0-t and AUC0-inf for ER formulation were 116.14 +/- 21.54 mg.h/l and 117.60 +/- 22.27 mg.h/l, and for IR formulation, were 107.25 +/- 23.48 mg.h/l and 108.18 +/- 23.93 mg.h/l, with the 90% CI within the limits accepted for bioequivalence. Mean Cmax for ER and IR formulations were 22.30 +/- 5.17 mg/l and 30.26 +/- 13.54 mg/l, respectively. And median tmax for ER and IR formulations were 4.5 h and 2.0 h. The retard quotient (delta R) for ER product was 1.9 +/- 0.93, which indicated an intermediate extended release effect. Multiple-dose Mean AUC0-24 for ER formulation was 217.93 +/- 41.07 mg.h/l and for IR formulation was 199.33 +/- 37.32 mg.h/l. Other PK parameters of ER and IR formulations were as follows: median tmax were 4.8 h and 2.0 h, Css-max were 20.21 +/- 2.69 mg/l and 19.71 +/- 3.46 mg/l, Css-min were 2.47 +/- 0.99 mg/l and 2.48 +/- 0.99 mg/l, Cav were 9.08 +/- 1.71 mg/l and 8.31 +/- 1.56 mg/l, respectively. CONCLUSIONS: This study found that in these subjects, the absorption rates of the two DI formulations were not bioequivalent, but at steady state, the daily exposure provided by less frequent DI ER dosing was not significantly different from the same daily dose with DI IR capsules, administered more frequently. PMID- 21329627 TI - Cinacalcet may reduce arterial stiffness in patients with chronic renal disease and secondary hyperparathyroidism - results of a small-scale, prospective, observational study. AB - AIMS: This study evaluated the impact of cinacalcet on arterial stiffness, determined by pulse wave velocity (PWV), in patients with chronic renal disease and secondary hyperparathyroidism (SHPT). PATIENTS AND METHODS: This prospective, observational study included, SHPT patients with chronic renal disease on dialysis undergoing cinacalcet treatment with a follow-up of 12 months. RESULTS: 21 patients, 62% males, with a mean age of 51.3 years (+/- 18.0) were included. Cinacalcet was given for at least a year with a mean daily dose of 35 mg (range 30-60 mg). Aortic PWV significantly decreased after 12 months of cinacalcet treatment (9.35 +/- 1.83 m/sg vs. 8.66 +/- 1.86 m/sg; p = 0.030). Additionally, there was a notable reduction trend in the left ventricular mass index (166.6 +/- 39.4 g/m2 vs. 156.1 +/- 31.8 g/m2), although it did not achieve statistical significance (p = 0.063). Alkaline phosphatase and PTH were significantly decreased during the study. However, serum calcium, phosphorus and blood pressure remained stable. CONCLUSION: The results of this study support the possibility that cinacalcet reduces arterial stiffness of SHPT patients with chronic renal disease after 12 months of treatment. Prospective, randomized clinical trials are needed to confirm these preliminary findings. PMID- 21329628 TI - Effects of peritoneal dialysis and hemodialysis on arterial stiffness compared with predialysis patients. AB - OBJECTIVE: Arterial stiffness is one of the major complications in chronic kidney disease. In this study, we investigated the association between glomerular filtration rate (GFR) and arterial stiffness in chronic kidney disease (CKD), and studied the effect of dialysis on arterial stiffness. METHODS: A total of 62 stable continuous ambulatory peritoneal dialysis (CAPD) patients, 56 patients on maintenance hemodialysis, 128 predialysis CKD patients and 40 healthy controls were included into this study. These four groups were all nondiabetic and comparable in age and gender. The pulse wave velocity (PWV) and augmentation index (AIx) were evaluated by an applanation tonometry (SphygmoCor). Clinical data and lab tests were collected from inpatient case history and dialysis data base. RESULTS: Female patients had higher AIx than male patients in both predialysis and dialysis patients. Both PWV and AIx were positively correlated with age, and were significantly higher in patients requiring antihypertensive drugs (p < 0.05). PWV and AIx were negatively correlated with GFR in predialysis CKD patients (p < 0.05). Patients on peritoneal dialysis or hemodialysis had better PWV and AIx than predialysis CKD 5 patients (19.8 +/- 10.9%, 19.7 +/- 9.4% vs. 25.3 +/- 10.1%, p < 0.05), indicating that dialysis may improve arterial stiffness. No difference was found between peritoneal dialysis and hemodialysis patients. CONCLUSION: This study demonstrates that arterial stiffness progresses with deterioration of renal function in CKD patients, and both peritoneal dialysis and hemodialysis can improve arterial stiffness in patients with uremia. PMID- 21329629 TI - Association of adiponectin and leptin with serum lipids and erythrocyte omega-3 and omega-6 fatty acids in dialysis patients. AB - AIMS: Besides regulating energy metabolism, leptin promotes and adiponectin suppresses inflammation which is a common feature of end-stage renal disease (ESRD). Omega-3 fatty acids (n-3FA) exert anti-inflammatory actions by inhibiting pro-inflammatory signal transduction pathways whereas arachidonic acid (an n-6FA) facilitates inflammation by mediating inflammatory signals and serving as precursor of pro-inflammatory eicosanoids. Given the functional overlap between adipokines and n-3FA and n-6FA, we sought to explore their interrelationship in patients with ESRD. METHODS: 44 ESRD patients maintained on hemodialysis (HD), 29 patients receiving peritoneal dialysis (PD), and 10 healthy subjects were enrolled. Body mass index (BMI), plasma leptin, adiponectin, lipids and CRP and erythrocyte fatty acids were measured. RESULTS: Compared to controls adiponectin was elevated and leptin level was reduced in the ESRD group. Adiponectin levels were comparable among PD and HD patients, but leptin and BMI were higher in PD than in HD patients. Despite comparable BMIs, female patients had higher leptin than male patients. Leptin levels were positively associations with BMI, total and LDL cholesterol whereas adiponectin was inversely related with BMI, triglycerides and CRP and directly associated with HDL cholesterol in ESRD patients. Plasma adiponectin was directly associated with erythrocyte n-3 FA (r = 0.581, p = 0.023) and inversely associated with n-6FA (r = -0.640, p = 0.010) in the HD patients. CONCLUSION: A direct association was found between plasma levels of adiponectin and HDL and erythrocyte n-3FA in ESRD patients. Prospective trials are needed to explore the effect of n-3FA supplementation on plasma adipokines and markers of oxidative stress and inflammation in this population. PMID- 21329630 TI - Warfarin use in hemodialysis patients: what is the risk? AB - BACKGROUND: There is a paucity of data concerning the risks associated with warfarin in hemodialysis (HD) patients. We compared major bleeding episodes in this group with HD patients not receiving warfarin and with a cohort of non-HD patients receiving warfarin. METHODS: A retrospective review of 141 HD patients on warfarin (HDW), 704 HD patients not on warfarin (HDNW) and 3,266 non-dialysis warfarin patients (NDW) was performed. Hospital admissions for hemorrhagic events and ischemic strokes were examined as was hospital length of stay and blood product use. INR variability was also assessed. RESULTS: The incidence rates for major hemorrhage per 100 patient years was 10.8 in the HDW group as compared to 8.0 in the HDNW (p = 0.593) and 2.1 in the NDW (p < 0.001) groups. Mean units of red blood cell transfusions required was higher in patients on dialysis with no significant difference between HDW and HDNW groups. The risk of ischemic stroke per 100 patient years was 1.7 in the HDW group as compared to 0.7 in the HDNW groups (p = 0.636) and 0.4 in the NDW (p = 0.003). The HDW group had higher inter measurement INR variability compared to the NDW group (p = 0.034). In patients with atrial fibrillation, HDW group had a higher incidence of ischemic stroke than the NDW group (2.2 versus 0.4 events per 100 patient years; p = 0.024). CONCLUSIONS: This study confirms the higher bleeding risk associated with HD/ESRD but suggests that warfarin use in these patients may not add significantly to this risk. We also demonstrated high rates of ischemic stroke in HD patients despite warfarin use. SUMMARY: Our study compares the frequency of major hemorrhage and secondarily, ischemic stroke in HD patients receiving or not receiving warfarin, with non-HD patients receiving warfarin. The major finding was that frequency of hemorrhage was higher in HD patients receiving warfarin than in non-HD patients receiving warfarin, but not different in HD patients with or without warfarin. A secondary finding was that INR variability was significantly higher in HD patients than non-HD patients on warfarin. PMID- 21329631 TI - The effect of heparinized catheter lock solutions on systemic anticoagulation in hemodialysis patients. AB - BACKGROUND: Hemodialysis catheter thrombosis is associated with loss of catheter patency, catheter-related bacteremia and sepsis. To limit these risks, many renal units use heparin as a catheter-locking solution. In this study we investigate the effect of different concentrations of heparin catheter lock solution on systemic anticoagulation in an investigator-blinded randomized study of patients with non-tunneled (temporary) central venous catheters. METHODS: 28 consecutive patients requiring insertion of a temporary non-tunneled dual lumen central venous hemodialysis catheter were randomly allocated to receive either heparin 5,000 IU/ml or heparin 1,000 IU/ml as catheter lock solutions. The primary outcome measure was the difference in activated partial thromboplastin time (APTT) at 10 minutes following catheter locking with heparin 5,000 IU/ml and heparin 1,000 IU/ml. Secondary outcomes included intradialytic blood flow rates, catheter removal due to insufficient hemodialysis blood flow to maintain hemodialysis and catheter-related bacteremia. RESULTS: 13 patients were randomized to the heparin 1,000 IU/ml group with 15 patients randomized to the heparin 5,000 IU/ml group. There was a statistically significant increase in APTT at 10 minutes between groups with median +22.2% (range 0 - 210) rise in APTT in the heparin 1,000 IU/ml group compared with +373.7% (range 133 - 800) in the heparin 5,000 IU/ml group (p < 0.001). There was no statistically significant difference between groups with the secondary outcomes of intradialytic blood flow, catheter failure rates and catheter-related bacteremia rates. CONCLUSIONS: Heparin 1,000 IU/ml catheter lock solution confers a significantly lower risk of systemic heparinization than heparin 5,000 IU/ml without any overtly detrimental effect on intradialytic blood flow, catheter failure rates and catheter-related bacteremia rates. PMID- 21329632 TI - Assessment of habitual physical activity and energy expenditure in dialysis patients and relationships to nutritional parameters. AB - BACKGROUND AND AIM: Assessment of physical activity level and of energy expenditure is important in the clinical and nutritional care of dialysis patients, but it is not so easy to accomplish. The SenseWearTM Armband (SWA) is a novel multisensory device that is worn on the upper arm and collects a variety of physiologic data related to physical activity. Thus, duration and intensity of physical activity is recorded and expressed as METs (Metabolic Equivalent Task), and energy expenditure is estimated. The aim of our study was to assess interdialytic spontaneous physical activity in stable chronic hemodialysis (HD) patients and the relation to nutritional status and dietary nutrient intake. PATIENTS AND METHODS: In 50 stable patients on maintenance hemodialysis treatment and 33 normal subjects (control group), level of spontaneous physical activity and estimated daily energy expenditure was assessed by SWA and related to biochemistry and anthropometry data, bioelectric impedance vector analysis, and energy and nutrient intake information coming from a 3-day food recall. RESULTS: In respect to controls, HD patients showed lower mean daily METs value (1.3 +/- 0.3 vs. 1.5 +/- 0.2, p < 0.01), a lower time spent on activities > 3 METs (89 +/- 85 vs. 143 +/- 104 min/day, p < 0.05), lower number of steps per day (5,584 +/- 3,734 vs. 11,735 +/- 5,130, p < 0.001), resulting in a lower estimated energy expenditure (2,190 +/- 629 vs. 2,462 +/- 443 Kcal/day, p < 0.05). 31 out of the 50 HD patients (62%) had a mean daily value < 1.4 METs and hence were defined as sedentary. They differed from the active patients for higher age (63 +/- 12 vs. 54 +/- 12 y, p < 0.01), lower energy intake (26.1 +/- 6.4 vs. 32.4 +/- 11.3 Kcal/day, p < 0.05) and lower phase angle (5.5 +/- 1.0 vs. 6.3 +/- 0.9, p < 0.05). SWA-based estimation of daily energy expenditure was negatively related to age (r = -0.31, p < 0.05), whereas positive relations were observed with BMI (r = 0.51, p < 0.001), phase angle (r = 0.40, p < 0.01), serum phosphate (r = 0.49, p < 0.001) and albumin (r = 0.41, p < 0.01). The mean daily METs values were strongly related to normalized energy intake (r = 0.47, p < 0.001) and also to protein intake (r = 0.33, p < 0.05) and to phase angle (r = 0.38, p < 0.01). Multiple regression analysis showed that energy intake and dietary protein intake were independently related to the intensity of physical activity. CONCLUSION: Our findings indicate that poor physical activity is highly prevalent in stable dialysis patients even when free from physical or neurological disabilities or severe comorbid conditions. The level and intensity of physical activity is positively related to body composition and to dietary nutrient intake. This confirms the strong interrelationship between exercise and nutrition, which in turn are associated with survival, rehabilitation and quality of life in dialysis patients. PMID- 21329633 TI - Serum relaxin levels and kidney function in late pregnancy with or without preeclampsia. AB - OBJECTIVE: Relaxin, a potent pregnancy-related hormone, has been proposed to be a major mediator of renal physiology in normal pregnancy. We wished to test relaxin levels in pregnancy and preeclampsia. METHODS: We performed precise physiologic measurements of kidney function in 38 normal peripartum women and 58 women with preeclampsia. We measured serum relaxin levels prior to delivery and over the first 4 postpartum weeks utilizing a modern, validated ELISA. Results were compared to those of 18 normal women of childbearing age. RESULTS: Relaxin levels were substantially elevated in women prior to delivery (364 +/- 268 vs. 15 +/- 16 pg/ml) and fell rapidly over the first postpartum week reaching normal non pregnant levels by Week 2 (32 +/- 64 vs. 15 +/- 16 pg/ml). No differences were seen between relaxin levels in normal pregnancy as compared to preeclampsia (364 +/- 268 vs. 376 +/- 241 pg/ml) despite substantial and persistent abnormalities in GFR (149 +/- 33 vs. 89 +/- 25 ml/min), albuminuria (14 vs. 687 mg/g) and mean arterial pressure (80 +/- 8 vs. 111 +/- 18). Furthermore no correlation could be established between physiologic measures (GFR, MAP, RBF, RVR) and relaxin levels (p > 0.3), either in the overall population or any of the subgroups. CONCLUSION: Relaxin is indeed significantly elevated in the serum of women during late pregnancy and the early puerperium. However, serum relaxin does not appear to influence BP, renal vascular resistance, renal blood flow or GFR in late pregnancy or in women with preeclampsia. PMID- 21329634 TI - Geographical variation in the response of lupus nephritis to mycophenolate mofetil induction therapy. AB - OBJECTIVE: The induction therapy used in the management of Class III and IV lupus nephritis has been narrowed down to a choice between cyclophosphamide (CYC) and mycophenolate mofetil (MMF). However, there has been variability in the response to these agents, which may relate to demographic factors. In this study, we analyzed geographic factors affecting the response to CYC or MMF with a stratified meta-analysis. METHODS: We found and included 11 studies for our analyses--7 randomized controlled trials (RCTs) and 4 non-RCTs--that were stratified as being in Asia or elsewhere. RESULTS: Meta-analysis of Asian studies showed no difference between regimens (RR = 0.98, 95% CI 0.74-1.28, p = ns) and no heterogeneity. The 2 RCT's from outside Asia showed significant advantage of MMF as induction therapy (RR = 3.69, 95%CI 1.45-9.3, p < 0.01) without heterogeneity. Together there was significant heterogeneity (Q = 11.69, I2 = 57.2%, p < 0.05) suggesting that the overall heterogeneity results from a difference between these groups. We repeated this analysis with the multicenter ALMS trial with their reported ethnicity-specific data. Again, no significant heterogeneity was seen in either subgroup (Asian: Q = 2.08, I2 = 0%, p = ns; Others: Q = 4.49, I2 = 55.5%, p = ns). Studies from Asia did not show a significant improvement with the use of MMF (RR = 1.06, 95%CI 0.79-1.41, p = ns) while data from RCTs conducted outside Asia suggested a greater likelihood of complete remission with the use of MMF (RR = 1.85, 95%CI 1.03-3.29, p < 0.05). CONCLUSION: Our analysis demonstrates a higher likelihood of complete remission with MMF in patients outside Asia. PMID- 21329635 TI - An observational study of the effectiveness of darbepoetin alpha administered in dialysis patients once every 2 weeks for 12 months. AB - AIMS: Erythropoiesis-stimulating agents (ESAs) are recommended for managing renal anemia. ALTERNATE is an observational study in European and Australian dialysis patients evaluating darbepoetin a (DA) once every 2 weeks (Q2W) in clinical practice. METHODS: Adult dialysis patients initiating treatment with DA Q2W were eligible regardless of previous/current ESA use. Data were collected 6 months before and 12 months after Q2W initiation. The primary endpoint was hemoglobin (Hb) concentration 12 months after initiation. RESULTS: A total of 6,112 patients were enrolled; 6,104 were eligible (87% hemodialysis, 12% peritoneal dialysis). Before initiation, 77.3%, 8.8%, and 7.8% of patients were receiving DA, epoetin beta, and epoetin alpha, respectively; 6% were ESA naive. Mean (95% CI) Hb (g/dl) was 11.68 (11.63-11.72) 6 months before initiation, 12.00 (11.97-12.04) at initiation, and 11.62 (11.58-11.66) 12 months after initiation. Geometric mean (95% CI) weekly ESA dose (ug/wk) was 27.27 (26.62-27.93) immediately before initiation, 23.69 (23.28 - 24.10) at initiation, and 26.80 (26.12-27.49) 12 months after initiation. At month 12, 77.3% of patients were receiving DA Q2W. CONCLUSIONS: This large observational study demonstrates that Hb concentrations can be effectively maintained over 12 months in a general dialysis population with DA Q2W without an increase in ESA dose. PMID- 21329636 TI - Rapid deterioration of renal insufficiency after magnetic resonance imaging with gadolinium-based contrast agent. AB - Gadolinium (Gd)-based contrast media were introduced as alternatives to iodinated media for magnetic resonance imaging (MRI). Although originally thought to be non nephrotoxic, Gd-based contrast media have recently been reported to be associated with acute kidney injury. The underlying mechanism of Gd-induced renal injury is not completely understood. We report an 80-year-old patient with buccal mucosa cancer for whom MRI with Gd-based contrast agent was conducted 3 times within 3 weeks. The patient developed rapid deterioration of preexisting renal insufficiency, and developed uremic symptoms and pulmonary edema. The patient was hemodialyzed 3 times. This resulted in improvement of renal function and clinical symptoms. This case emphasizes the potential nephrotoxicity of Gd-based contrast media and suggests that renal insufficiency, diabetes mellitus, old age and high dose of Gd-based contrast medium are risk factors for acute kidney injury. PMID- 21329637 TI - A notable case report of May-Hegglin anomaly with immune complex-related nephropathy: a genetic and histological analysis. AB - May-Hegglin anomaly (MHA) is a rare autosomal dominant disease characterized by macrothrombocytopenia and leukocyte inclusions with microfilaments in the ribosomes. Mutations in the MYH9 gene, encoding non-muscle myosin heavy chain IIA (NMMHC-IIA) have been identified in patients with MHA and other MYH9-related diseases. Two young males (an older and younger brother) presented with macrothrombocytopenia and leukocyte inclusion bodies. Electron microscopy (EM) revealed parallel filaments in leukocyte inclusion bodies characteristic of MHA. Immunofluorescence microscopy (IF) showed NMMHC-IIA antibodies in 1 - 2 leukocyte inclusion bodies. These findings were consistent with MHA and they were identified to express the MYH9 mutation, D1424H. The older brother underwent a renal biopsy because of persistent proteinuria. Histology revealed mesangial proliferative glomerulonephritis with granular deposits of IgG and C1q. EM showed that the dense deposits were located in subendothelial cells, mesangial cells and Bowman's capsule. Immunocytochemistry revealed that NMMHC-IIA antibodies were localized in podocyte and endothelial cells in the glomerulus. Moreover, the expression of nephrin and podocin, slit diagram protein, was normal. An inflammatory mechanism may occur separately from MYH9-related disease. This report presents a case of MHA with immune complex-related nephropathy. PMID- 21329638 TI - Cinacalcet in the treatment of persistent hyperparathyroidism after kidney transplantation. AB - BACKGROUND: Secondary hyperparathyroidism persists in 30 - 50% of patients after a successful kidney transplant and it is the most frequent cause of hypercalcemia after transplant, contributing to graft loss and mortality. Several medical therapies have been studied for the treatment of this condition without clear benefit. Recently, interest has grown in the use of cinacalcet in kidney transplant recipients. METHODS: We describe the efficacy of cinacalcet in 18 kidney transplant patients with persistent hyperparathyroidism and progressive hypercalcemia treated for a period of 12-months. We analyzed serum calcium, phosphorus and parathyroid hormone levels every 6 months, and cinacalcet was titrated if necessary. Statistical analysis was performed using ANOVA. RESULTS: With therapy, all patients exhibited significant reduction in parathyroid hormone levels, from a mean value of 242.04 +/- 105.82 pg/ml to a mean value of 145.62 +/ 54.99 pg/ml (p < 0.001) 12 months later. In addition, serum calcium levels normalized during the study period, from 11.16 mg/d to 9.95 mg/dl (mean values) (p < 0.001). No significant change in serum creatinine was found in this group of patients. Cinacalcet was well tolerated, with no side effects documented. CONCLUSION: This preliminary experience suggests that cinacalcet may be useful in the treatment of persistent hyperparathyroidism after kidney transplant. In addition, cinacalcet controlled hypercalcemia, which has well known adverse effects after transplant. This was accomplished with no evidence of declining kidney function or limiting side effects. PMID- 21329639 TI - Insertion of the dialysis catheter into right atrium or superior vena cava? PMID- 21329643 TI - The second wave of 2009 pandemic influenza A(H1N1) in New Zealand, January October 2010. AB - This paper uses data from multiple surveillance systems to describe the experience in New Zealand with the second complete wave of pandemic influenza A(H1N1)2009 in 2010. Measures such as hospitalisation rates suggest the overall impact of influenza A(H1N1)2009 in 2010 was between half and two thirds that of the first wave in 2009. There was considerable regional and sub-regional variation with a tendency for higher activity in areas that experienced low rates in 2009. Demographic characteristics of the second wave were similar to those in 2009 with highest rates seen in children under the age of five years, and in indigenous Maori and Pacific peoples. Hospital services including intensive care units were not under as much pressure as in 2009. Immunisation appears to have contributed to the reduced impact of the pandemic in 2010, particularly for those aged 60 years and older. PMID- 21329644 TI - Effectiveness of seasonal 2010/11 and pandemic influenza A(H1N1)2009 vaccines in preventing influenza infection in the United Kingdom: mid-season analysis 2010/11. AB - This study provides mid-season estimates of the effectiveness of 2010/11 trivalent influenza vaccine and previous vaccination with monovalent influenza A(H1N1)2009 vaccine in preventing confirmed influenza A(H1N1)2009 infection in the United Kingdom in the 2010/11 season. The adjusted vaccine effectiveness was 34% (95% CI: -10 - 60%) if vaccinated only with monovalent vaccine in the 2009/10 season; 46% (95% CI: 7 - 69%) if vaccinated only with trivalent influenza vaccine in the 2010/11 season and 63% (95% CI: 37 - 78%) if vaccinated in both seasons. PMID- 21329645 TI - Ceftriaxone treatment failure of pharyngeal gonorrhoea verified by international recommendations, Sweden, July 2010. AB - This report describes one case of verified treatment failure of pharyngeal gonorrhoea using ceftriaxone in Sweden. Previous reports described verified treatment failure of urogenital gonorrhoea using the internationally recommended first-line drug cefixime, but not with ceftriaxone, the last remaining option for empirical treatment of gonorrhoea. Enhanced awareness of clinical failures, pharmacodynamic considerations, follow-up and test of cure, adherence to appropriate case management and treatment guidelines as well as verification/falsification of presumed clinical treatment failures should be emphasised worldwide. PMID- 21329646 TI - First case of meningococcal meningitis due to Neisseria meningitidis serogroup Z' in Slovenia, December 2010. AB - We report here on the identification of the first meningococcal meningitis case in Slovenia caused by Neisseria meningitidis serogroup Z' in December 2010. The 19-year-old patient had not left the country during the incubation period. The patient was hospitalised and given the antibiotic treatment with cefotaxime very early in the course of the disease. The patient did not develop any complications during hospitalisation and was discharged on 5 January 2011. PMID- 21329647 TI - Stabilities of cubane type [Fe4S4(SR)4](2-) clusters in partially aqueous media. AB - The stability of cubane-type [Fe4S4(SR)4](2-) clusters in mixed organic/aqueous solvents was examined as an initial step in the development of stable water soluble cluster compounds possibly suitable for reconstitution of scaffold proteins in protein biosynthesis. The research involves primarily spectrophotometric assessment of stability in 20-80% Me2SO/aqueous media (v/v), from which it was found that conventional clusters tend to be stable for up to 12h in 60% Me2SO but are much less stable at higher aqueous content. alpha Cyclodextrin mono- and dithioesters and thiols were prepared as ligand precursors for cluster binding, which was demonstrated by spectroscopic methods. A potentially bidentate cyclodextrin dithiolate was found to be relatively effective for cluster stabilization in 40% Me2SO, suggesting (together with earlier results) that other exceptionally large thiolate ligands may promote cluster stability in aqueous media. PMID- 21329648 TI - Energy-filtered transmission electron microscopy of biological samples on highly transparent carbon nanomembranes. AB - Ultrathin carbon nanomembranes (CNM) comprising crosslinked biphenyl precursors have been tested as support films for energy-filtered transmission electron microscopy (EFTEM) of biological specimens. Due to their high transparency CNM are ideal substrates for electron energy loss spectroscopy (EELS) and electron spectroscopic imaging (ESI) of stained and unstained biological samples. Virtually background-free elemental maps of tobacco mosaic virus (TMV) and ferritin have been obtained from samples supported by ~1nm thin CNM. Furthermore, we have tested conductive carbon nanomembranes (cCNM) comprising nanocrystalline graphene, obtained by thermal treatment of CNM, as supports for cryoEM of ice embedded biological samples. We imaged ice-embedded TMV on cCNM and compared the results with images of ice-embedded TMV on conventional carbon film (CC), thus analyzing the gain in contrast for TMV on cCNM in a quantitative manner. In addition we have developed a method for the preparation of vitrified specimens, suspended over the holes of a conventional holey carbon film, while backed by ultrathin cCNM. PMID- 21329649 TI - High accuracy FIONA-AFM hybrid imaging. AB - Multi-protein complexes are ubiquitous and play essential roles in many biological mechanisms. Single molecule imaging techniques such as electron microscopy (EM) and atomic force microscopy (AFM) are powerful methods for characterizing the structural properties of multi-protein and multi-protein-DNA complexes. However, a significant limitation to these techniques is the ability to distinguish different proteins from one another. Here, we combine high resolution fluorescence microscopy and AFM (FIONA-AFM) to allow the identification of different proteins in such complexes. Using quantum dots as fiducial markers in addition to fluorescently labeled proteins, we are able to align fluorescence and AFM information to >=8nm accuracy. This accuracy is sufficient to identify individual fluorescently labeled proteins in most multi protein complexes. We investigate the limitations of localization precision and accuracy in fluorescence and AFM images separately and their effects on the overall registration accuracy of FIONA-AFM hybrid images. This combination of the two orthogonal techniques (FIONA and AFM) opens a wide spectrum of possible applications to the study of protein interactions, because AFM can yield high resolution (5-10nm) information about the conformational properties of multi protein complexes and the fluorescence can indicate spatial relationships of the proteins in the complexes. PMID- 21329650 TI - In vitro studies of DNA mismatch repair proteins. AB - The ability to monitor and characterize DNA mismatch repair activity in various mammalian cells is important for understanding mechanisms involved in mutagenesis and tumorigenesis. Since mismatch repair proteins recognize mismatches containing both normal and chemically altered or damaged bases, in vitro assays must accommodate a variety of mismatches in different sequence contexts. Here we describe the construction of DNA mismatch substrates containing G:T or O(6)meG:T mismatches, the purification of recombinant native human MutSalpha (MSH2-MSH6) and MutLalpha (MLH1-PMS2) proteins, and in vitro mismatch repair and excision assays that can be adapted to study mismatch repair in nuclear extracts from mismatch repair proficient and deficient cells. PMID- 21329651 TI - 4-O-methylascochlorin, methylated derivative of ascochlorin, stabilizes HIF 1alpha via AMPK activation. AB - Chemopreventive or anticancer agents induce cancer cells to apoptosis through the activation of adenosine AMP-activated protein kinase (AMPK), which plays a major role as energy sensors under ATP-deprived condition or ROS generation. In this study, we compared the effects of ascochlorin (ASC), from the fungus Ascochyta viciae, and its derivatives on AMPK activity. We also examined a regulatory mechanism for hypoxia-inducible factor-1alpha (HIF-1alpha) stabilization in response to 4-O-methylascochlorin (MAC). We found that AMPK activation was mainly involved with MAC, but not ASC and 4-O-carboxymethylascochlorin (AS-6), indicating that the substitution of 4-O-methyl group from 4-O-hydroxyl group of ASC is important in the activation of AMPK and the expression of HIF-1alpha. MAC stabilized HIF-1alpha via AMPK activation triggered by lowering the intracellular ATP level, not by ROS generation, increases glucose uptake and the expression of vascular endothelial growth factor (VEGF) and glucose transporter 1 (GLUT-1), major target genes of HIF-1alpha. Moreover, MAC-induced AMPK activity suppressed survival factors, including mTOR and ERK1/2 or translational regulators, including p70S6K and 4E-BP1. Our data suggest that AMPK is a key determinant of MAC-induced HIF-1alpha expression in response to energy stress, further implying its involvement in MAC-induced apoptosis. PMID- 21329652 TI - A novel approach to overcome temozolomide resistance in glioma and melanoma: Inactivation of MGMT by gene therapy. AB - Malignant glioma is the most common primary brain tumor. Malignant melanoma is the most malignant of skin tumor. The two malignancies are poorly responsive to conventional treatment regimens such as chemotherapy. Temozolomide (TMZ) is a DNA alkylating agent used for the treatment of glioma, astrocytoma, and melanoma. Resistance to alkylating agents such as TMZ correlates with increased expression of DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Several studies in animal models have demonstrated that decreasing MGMT level with gene therapy could overcome TMZ resistance and enhance tumor cell death. In the present review, we provide an overview of recent advances in this field. PMID- 21329653 TI - HMGA1a is involved in specific splice site regulation of human immunodeficiency virus type 1. AB - Human immunodeficiency virus type 1 (HIV-1) utilizes a highly complex splice site regulation system, taking advantage of host proteins, to express its own viral protein in an orderly way. We show here that one of the host proteins, high mobility group A protein 1a (HMGA1a), is involved in splice site regulation of 3' splice site 2 (A2) and 5'splice site 3 (D3) of HIV-1 genomic RNA. shRNA knockdown of HMGA1 in HeLa cells resulting in a decrease of HMGA1 showed a significant decrease of Vpr mRNA. RNA electrophoretic mobility shift assays showed HMGA1a specifically binds to a sequence adjacently upstream D3. In vitro splicing using heterologous pre-mRNA with A2 and D3, showed HMGA1a induced a splicing intermediate which decreased when an RNA decoy of the HMGA1a binding site was added. RT-PCR of in vitro splicing products revealed that HMGA1a induced an incomplete splicing product resulting from usage of A2 but inhibition of D3, which is reminiscent of the splicing pattern necessary for Vpr mRNA formation. HMGA1a interacted with hnRNPA1 shown by coimmunoprecipitation and supershifted U1 snRNP in an RNA electrophoretic mobility shift assay. We conclude that HMGA1a anchors U1 snRNP to inhibit D3 function, and that HMGA1a inhibits hnRNPA1 function on exon splicing silencer of Vpr (ESSV) to activate A2 function. We show here for the first time that HMGA1a is involved in specific splice site regulation of HIV-1. PMID- 21329654 TI - A Tat-grafted anti-nucleic acid antibody acquires nuclear-localization property and a preference for TAR RNA. AB - The 3D8 single chain variable fragment (3D8 scFv) is an anti-nucleic acid antibody that can hydrolyze nucleic acids and enter the cytosol of cells without reaching the nucleus. The Tat peptide, derived from the basic region of the HIV-1 Tat protein, translocates to cell nuclei and has TAR RNA binding activity. In this study, we generated a Tat-grafted antibody ((H3)Tat-3D8) by replacing complementarity-determining region 3 (CDR3) within the VH domain of the 3D8 scFv with a Tat48-60 peptide (GRKKRRQRRRPPQ). (H3)Tat-3D8 retained the DNA-binding and DNA-hydrolyzing activity of the scFv, and translocated to the nuclei of HeLa cells and preferentially recognized TAR RNA. Thus, the properties associated with the Tat peptide were transferred to the antibody via Tat-grafting without loss of the intrinsic DNA-binding and hydrolyzing activities of the 3D8 scFv antibody. PMID- 21329655 TI - PPARgamma ligands induce growth inhibition and apoptosis through p63 and p73 in human ovarian cancer cells. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, including thiazolidinediones (TZDs), can induce anti-proliferation, differentiation, and apoptosis in various cancer cell types. This study investigated the mechanism of the anticancer effect of TZDs on human ovarian cancer. Six human ovarian cancer cell lines (NIH:OVCAR3, SKOV3, SNU-251, SNU-8, SNU-840, and 2774) were treated with the TZD, which induced dose-dependent inhibition of cell growth. Additionally, these cell lines exhibited various expression levels of PPARgamma protein as revealed by Western blotting. Flow cytometry showed that the cell cycle was arrested at the G1 phase, as demonstrated by the appearance of a sub-G1 peak. This observation was corroborated by the finding of increased levels of Bax, p21, PARP, and cleaved caspase 3 in TGZ-treated cells. Interestingly, when we determined the effect of p53-induced growth inhibition in these three human ovarian cancer cells, we found that they either lacked p53 or contained a mutant form of p53. Furthermore, TGZ induced the expression of endogenous or exogenous p63 and p73 proteins and p63- or p73-directed short hairpin (si) RNAs inhibited the ability of TGZ to regulate expression of p21 in these cells. Thus, our results suggest that PPARgamma ligands can induce growth suppression of ovarian cancer cells and mediate p63 and p73 expression, leading to enhanced growth inhibition and apoptosis. The tumor suppressive effects of PPARgamma ligands may have applications for the treatment of ovarian cancer. PMID- 21329656 TI - 2D-PAGE of ovarian cancer: analysis of soluble and insoluble fractions using medium-range immobilized pH gradients. AB - Ovarian cancer remains a leading cause of cancer death. A comparative proteomic study was performed on normal ovarian tissue (n=5) and grade 3 ovarian tumours (n=5) to search for differentially expressed proteins. In contrast to other studies, here we extracted proteins in soluble and insoluble protein fractions using commercial kits and also utilised three medium-range IPG strips that encompassed the broad pH range of 3-10 (pH 3-6, 5-8 and 7-10). Protein fractions were compared by 2D-PAGE and MALDI-TOF/TOF-MS. Nineteen differentially expressed proteins were identified: HSP60, Grp78, CK19, EF-Tu, MRLC2, prohibitin, Stress-70 protein, TPI and tubulin alpha6 were up-regulated in grade 3 tumours whereas annexin A2 and A5, antithrombin-III precursor, CBR1, GSTM2, GSTM3, RALDH1, serum albumin precursor, transthyretin precursor and vimentin were found to be down regulated in grade 3 ovarian tumours. These proteins are associated with cytoskeleton rearrangement, cell metabolism, tumour suppression function, apoptosis and induction of host response. PMID- 21329657 TI - Continuous stress-induced dopamine dysregulation augments PAP-I and PAP-II expression in melanotrophs of the pituitary gland. AB - Under continuous stress (CS) in rats, melanotrophs, the predominant cell-type in the intermediate lobe (IL) of the pituitary, are hyperactivated to secrete alpha melanocyte-stimulating hormone and thereafter degenerate. Although these phenomena are drastic, the molecular mechanisms underlying the cellular changes are mostly unknown. In this study, we focused on the pancreatitis-associated protein (PAP) family members of the secretory lectins and characterized their expression in the IL of CS model rats because we had identified two members of this family as up-regulated genes in our previous microarray analysis. RT-PCR and histological studies demonstrated that prominent PAP-I and PAP-II expression was induced in melanotrophs in the early stages of CS, while another family member, PAP-III, was not expressed. We further examined the regulatory mechanisms of PAP I and PAP-II expression and revealed that both were induced by the decreased dopamine levels in the IL under CS. Because the PAP family members are implicated in cell survival and proliferation, PAP-I and PAP-II secreted from melanotrophs may function to sustain homeostasis of the IL under CS conditions in an autocrine or a paracrine manner. PMID- 21329658 TI - Importin beta-type nuclear transport receptors have distinct binding affinities for Ran-GTP. AB - Cargos destined to enter or leave the cell nucleus are typically transported by receptors of the importin beta family to pass the nuclear pore complex. The yeast Saccharomyces cerevisiae comprises 14 members of this protein family, which can be divided in importins and exportins. The Ran GTPase regulates the association and dissociation of receptors and cargos as well as the transport direction through the nuclear pore. All receptors bind to Ran exclusively in its GTP-bound state and this event is restricted to the nuclear compartment. We determined the Ran-GTP binding properties of all yeast transport receptors by biosensor measurements and observed that the affinity of importins for Ran-GTP differs significantly. The dissociation constants range from 230 pM to 270 nM, which is mostly based on a variability of the off-rate constants. The divergent affinity of importins for Ran-GTP suggests the existence of a novel mode of nucleocytoplasmic transport regulation. Furthermore, the cellular concentration of beta-receptors and of other Ran-binding proteins was determined. We found that the number of beta-receptors altogether about equals the amounts of yeast Ran, but Ran-GTP is not limiting in the nucleus. The implications of our results for nucleocytoplasmic transport mechanisms are discussed. PMID- 21329659 TI - Acetylation of pregnane X receptor protein determines selective function independent of ligand activation. AB - Pregnane X receptor (PXR), like other members of its class of nuclear receptors, undergoes post-translational modification [PTM] (e.g., phosphorylation). However, it is unknown if acetylation (a major and common form of protein PTM) is observed on PXR and, if it is, whether it is of functional consequence. PXR has recently emerged as an important regulatory protein with multiple ligand-dependent functions. In the present work we show that PXR is indeed acetylated in vivo. SIRT1 (Sirtuin 1), a NAD-dependent class III histone deacetylase and a member of the sirtuin family of proteins, partially mediates deacetylation of PXR. Most importantly, the acetylation status of PXR regulates its selective function independent of ligand activation. PMID- 21329660 TI - Polygonatum cyrtonema lectin, a potential antineoplastic drug targeting programmed cell death pathways. AB - Polygonatum cyrtonema lectin (PCL), a mannose/sialic acid-binding plant lectin, has recently drawn a rising attention for cancer biologists because PCL bears remarkable anti-tumor activities and thus inducing programmed cell death (PCD) including apoptosis and autophagy in cancer cells. In this review, we focus on exploring the precise molecular mechanisms by which PCL induces cancer cell apoptotic death such as the caspase-dependent pathway, mitochondria-mediated ROS p38-p53 pathway, Ras-Raf and PI3K-Akt pathways. In addition, we further elucidate that PCL induces cancer cell autophagic death via activating mitochondrial ROS p38-p53 pathway, as well as via blocking Ras-Raf and PI3K-Akt pathways, suggesting an intricate relationship between autophagic and apoptotic death in PCL-induced cancer cells. In conclusion, these findings may provide a new perspective of Polygonatum cyrtonema lectin (PCL) as a potential anti-tumor drug targeting PCD pathways for future cancer therapeutics. PMID- 21329661 TI - Redox-active tyrosine residue in the microcin J25 molecule. AB - Microcin J25 (MccJ25) is a 21 amino acid lasso-peptide antibiotic produced by Escherichia coli and composed of an 8-residues ring and a terminal 'tail' passing through the ring. We have previously reported two cellular targets for this antibiotic, bacterial RNA polymerase and the membrane respiratory chain, and shown that Tyr9 is essential for the effect on the membrane respiratory chain which leads to superoxide overproduction. In the present paper we investigated the redox behavior of MccJ25 and the mutant MccJ25 (Y9F). Cyclic voltammetry measurements showed irreversible oxidation of both Tyr9 and Tyr20 in MccJ25, but infrared spectroscopy studies demonstrated that only Tyr9 could be deprotonated upon chemical oxidation in solution. Formation of a long-lived tyrosyl radical in the native MccJ25 oxidized by H2O2 was demonstrated by Electron Paramagnetic Resonance Spectroscopy; this radical was not detected when the reaction was carried out with the MccJ25 (Y9F) mutant. These results show that the essential Tyr9, but not Tyr20, can be easily oxidized and form a tyrosyl radical. PMID- 21329662 TI - Chronic exercise ameliorates the neuroinflammation in mice carrying NSE/htau23. AB - The objective of the present study was to investigate whether chronic endurance exercise attenuates the neuroinflammation in the brain of mice with NSE/htau23. In this study, the tau-transgenic (Tg) mouse, Tg-NSE/htau23, which over expresses human Tau23 in its brain, was subjected to chronic exercise for 3 months, from 16 months of age. The brains of Tg mice exhibited increased immunoreactivity and active morphological changes in GFAP (astrocyte marker) and MAC-1 (microglia marker) expression in an age-dependent manner. To identify the effects of chronic exercise on gliosis, the exercised Tg mice groups were treadmill run at a speed of 12 m/min (intermediate exercise group) or 19 m/min (high exercise group) for 1h/day and 5 days/week during the 3 month period. The neuroinflammatory response characterized by activated astroglia and microglia was significantly repressed in the exercised Tg mice in an exercise intensity-dependent manner. In parallel, chronic exercise in Tg mice reduced the increased expression of TNF-alpha, IL-6, IL-1beta, COX-2, and iNOS. Consistently with these changes, the levels of phospho p38 and phospho-ERK were markedly downregulated in the brain of Tg mice after exercise. In addition, nuclear NF-kappaB activity was profoundly reduced after chronic exercise in an exercise intensity-dependent manner. These findings suggest that chronic endurance exercise may alleviate neuroinflammation in the Tau pathology of Alzheimer's disease. PMID- 21329663 TI - Artificial microRNAs (amiRNAs) engineering - On how microRNA-based silencing methods have affected current plant silencing research. AB - In recent years, endogenous microRNAs have been described as important regulators of gene expression in eukaryotes. Artificial microRNAs (amiRNAs) represent a recently developed miRNA-based strategy to silence endogenous genes. amiRNAs can be created by exchanging the miRNA/miRNA(*) sequence within a miRNA precursor with a sequence designed to match the target gene, this is possible as long as the secondary RNA structure of the precursor is kept intact. In this review, we summarize the basic methodologies to design amiRNAs and detail their applications in plants genetic functional studies as well as their potential for crops genetic improvement. PMID- 21329664 TI - miR-132 and miR-212 are increased in pancreatic cancer and target the retinoblastoma tumor suppressor. AB - Numerous microRNAs (miRNAs) are reported as differentially expressed in cancer, however the consequence of miRNA deregulation in cancer is unknown for many miRNAs. We report that two miRNAs located on chromosome 17p13, miR-132 and miR 212, are over-expressed in pancreatic adenocarcinoma (PDAC) tissues. Both miRNAs are predicted to target the retinoblastoma tumor suppressor, Rb1. Validation of this interaction was confirmed by luciferase reporter assay and western blot in a pancreatic cancer cell line transfected with pre-miR-212 and pre-miR-132 oligos. Cell proliferation was enhanced in Panc-1 cells transfected with pre-miR-132/-212 oligos. Conversely, antisense oligos to miR-132/-212 reduced cell proliferation and caused a G(2)/M cell cycle arrest. The mRNA of a number of E2F transcriptional targets were increased in cells over expressing miR-132/-212. Exposing Panc-1 cells to the beta2 adrenergic receptor agonist, terbutaline, increased the miR-132 and miR-212 expression by 2- to 4-fold. We report that over expression of miR-132 and miR-212 result in reduced pRb protein in pancreatic cancer cells and that the increase in cell proliferation from over-expression of these miRNAs is likely due to increased expression of several E2F target genes. The beta2 adrenergic pathway may play an important role in this novel mechanism. PMID- 21329665 TI - New aspects of the interactions between the cardiovascular nitric oxide system and natriuretic peptides. AB - Arterial blood pressure is regulated by a variety of endocrine, autocrine and neuronal systems. Natriuretic peptides and nitric oxide are important factors that exert synergistic vascular and cardiac actions and their activities are closely linked. The existence of a novel signal transduction mechanism involved in activation of nitric oxide synthase via natriuretic peptides is currently being explored. Since several cardiovascular disorders are associated with dysfunction of natriuretic peptides activity, selective modulation of the natriuretic peptides pathway represents an important therapeutic target. This review article highlights the current findings on cross-talk between natriuretic peptides and the nitric oxide system. PMID- 21329666 TI - Formation of beta-sheets in glutamine and alanine tripeptides. AB - The misfolding and aggregation of proteins is associated with many different diseases including the trinucleotide repeat disorders and Prion diseases. We have studied three residue peptides comprising alanine and glutamine in order to understand the short range interactions affecting the formation of beta-rich aggregates. Using infrared spectroscopy, we have found that trialanine and triglutamine form significant amounts of beta-sheet, but that tripeptides containing alanine and glutamine are only able to form beta-sheet if the glutamine side-chains extend outward on both faces of the sheet. From our data, we conclude that different stabilizing interactions are responsible for beta sheet formation in trialanine and triglutamine. PMID- 21329667 TI - Cloning and characterization of the biosynthetic gene cluster of the bacterial RNA polymerase inhibitor tirandamycin from marine-derived Streptomyces sp. SCSIO1666. AB - Tirandamycins are bacterial RNA polymerase inhibitors holding great potential for antibacterial agent design. To elucidate the biosynthetic machinery and generate new derivatives, the tirandamycin biosynthetic gene cluster was cloned and sequenced from marine-derived Streptomyces sp. SCSIO1666. The biosynthetic gene cluster of tirandamycin spans a DNA region of ~56kb and consists of 15 open reading frames (ORFs) which encode three type I polyketide synthases (TrdAI, AII, AIII), one non-ribosomal peptide synthetase (TrdD), one phosphopantetheinyl transferase (TrdM), one Type II thioesterase (TrdB), one FAD-dependent oxidoreductase (TrdL), one cytochrome P450 monooxygenase (TrdI), three proteins related to resistance and regulations (TrdHJK), and four proteins with unknown function (TrdCEFG). To investigate the roles of the genes played in the biosynthetic machinery, seven genes (trdAI and trdBDFHIK) were inactivated via in frame replacement with an apramycin gene cassette using lambda-RED recombination technology. The DeltatrdAI and DeltatrdD mutants targeting the ketosynthase and adenylation domain of TrdAI and TrdD, respectively, abolished the production of tirandamycins, confirming their involvement in the tirandamycin biosynthesis. TrdH showed high homology to LuxR family transcriptional regulatory proteins, disruption of which abolished the production of tirandamycins, indicating that TrdH is a positive regulator for tirandamycin biosynthesis. On the other hand, TrdK showed high homology to TetR-family transcriptional regulatory proteins, disruption of which significantly increased the yields of tirandamycins almost one-fold, implicating that TrdK is a negative regulator for tirandamycin biosynthesis. Disruption of the gene trdI resulted in the accumulation of the intermediate tirandamycin C (3) and a trace amount of new product tirandamycin C2 (5). A model of tirandamycin biosynthesis was proposed based on bioinformatics analyses, gene inactivation experiments and intermediates isolated from the mutants. These findings set the stage for further study of the tirandamycin biosynthetic mechanism and rationally engineer new tirandamycin analogues. PMID- 21329668 TI - Binding of natural cytotoxicity receptor NKp46 to sulfate- and alpha2,3-NeuAc containing glycans and its mutagenesis. AB - Natural cytotoxicity receptor 1 (NCR1, NKp46) binds to heparin and heparan sulfate; however, other natural ligands for NKp46 have yet to be elucidated. Using the recombinant extracellular region (coding for AA 22-258) of NKp46 tagged with 6* His (NKp46-H6), and mutants K136Q, R139Q, H142Q, R145Q, and K149Q, we determined their binding affinities to sulfate- and NeuAc-containing glycans coated plates. NKp46-H6 directly bound to plates coated with heparin- and heparan sulfate-conjugated bovine serum albumin with K(d) values of 770 and 850 nM, respectively. The binding of NKp46-H6 to heparin-BSA was suppressed by soluble heparin, herparan sulfate, fucoidan, lambda-carrageenan, and dextran sulfate, but not by 2-O-, 6-O-, and N-desulfated heparin. NKp46-H6 also bound to multimeric sialyl Lewis X expressing transferrin secreted by human hepatoma HepG2 cells (HepTF) with a K(d) value of 530 nM, but not to desialylated HepTF, commercially available TF, or 1-acid glycoprotein. Moreover, mutants R139Q, R145Q, and K149Q had significantly reduced binding to these sulfate-containing glycans, and K136Q and K149Q to HepTF, indicating that NKp46 binds to sulfate- and 2,3-NeuAc containing glycans mainly via ionic interactions. However, the binding sites of NKp46 were different. PMID- 21329669 TI - Ceftriaxone crystallization and its potential role in kidney stone formation. AB - Drug-induced nephrolithiasis contributes to 1-2% of the incidence of renal calculi. We examined whether ceftriaxone at therapeutic doses could be crystallized in the urine and also explored its role in kidney stone formation. Crystallization was induced by mixing ceftriaxone sodium at therapeutic urinary excretion levels (0.5-4.0 mg/ml) to calcium chloride at physiologic urinary concentration (5mM) in deionized (dI) water or artificial urine (AU). The results showed that ceftriaxone was crystallized with free calcium in dose- and time dependent manner. These ceftriaxone/calcium crystals showed birefringence property under polarized microscope. Individual crystals had needle-shape (5-100 MUm in length), whereas the aggregated form had star-burst and irregular-plate shape (40-200 MUm in diameter) (note that the crystal sizes were much larger than renal tubular lumens). Calcium-depletion assay revealed that crystallization required free calcium as a substrate. In AU, crystallization remained although it was partially inhibited when compared to that in dI water. Finally, these crystals could tightly adhere onto renal tubular cell surface. Our data demonstrated that ceftriaxone at therapeutic levels could be crystallized with free calcium in the urine under physiologic condition. We hypothesize that tubular occlusion and crystal-cell adhesion may play important role in pathogenic mechanisms of ceftriaxone-induced nephrolithiasis. PMID- 21329670 TI - Gangliosides expressed on breast cancer cells are E-selectin ligands. AB - Cancer cell adhesion to vascular endothelium is a critical process in hematogenous metastasis. We hypothesized that breast cancer cells express ligands that bind under blood flow conditions to E-selectin expressed by endothelial cells. At a hemodynamic wall shear rate, BT-20 and MDA-MB-468 breast cancer cells adhered to cytokine-activated human umbilical cord vein endothelial cells (HUVECs) but not to anti-E-selectin monoclonal antibody treated HUVECs, demonstrating that adhesion was specifically mediated by E-selectin. Characterization of glycans expressed on breast cancer cells by a panel of antibodies revealed that BT-20 cells expressed sialyl Lewis X (sLe(x)) and sialyl Lewis A (sLe(a)) but MDA-MB-468 cells did not, suggesting that the former possess classical glycans involved in E-selectin mediated adhesion while the latter have novel binding epitopes. Protease treatment of the breast cancer cells failed to significantly alter the carbohydrate expression profiles, binding to soluble E selectin-Ig chimera, or the ability of the cells to tether and roll on E-selectin expressed by HUVECs, indicating that glycosphingolipids are functional E-selectin ligands on these cells. Furthermore, extracted breast cancer cell gangliosides supported binding of E-selectin-Ig chimera and adhesion of E-selectin transfected cells under physiological flow conditions. In summary, our results demonstrate that breast cancer cells express sialylated glycosphingolipids (gangliosides) as E-selectin ligands that may be targeted for prevention of metastasis. PMID- 21329671 TI - Arabidopsis HDA6 is required for freezing tolerance. AB - Many plants exhibit altered gene expression patterns in response to low nonfreezing temperatures and an increase in freezing tolerance in a phenomenon known as cold acclimation. Here we show, for the first time, that the histone deacetylase gene HDA6 is required for cold acclimation and freezing tolerance in Arabidopsis. HDA6 is transcriptionally upregulated during long-term cold treatment. Cold-treated hda6 mutants showed reduced freezing tolerance compared with the cold-treated wild-type plants. Freezing-caused electrolyte leakage increased in the cold-treated hda6 mutant. In contrast, the non-cold-treated hda6 mutants showed no significant difference in survivability and electrolyte leakage compared to wild-type plants. Transcriptome analysis identified the genes that showed aberrant expression in the hda6 mutant after cold acclimation. We conclude that HDA6 plays a critical role in regulating cold acclimation process that confers freezing resistance on Arabidopsis. PMID- 21329672 TI - Tight junction regulates epidermal calcium ion gradient and differentiation. AB - It is well known that calcium ions (Ca(2+)) induce keratinocyte differentiation. Ca(2+) distributes to form a vertical gradient that peaks at the stratum granulosum. It is thought that the stratum corneum (SC) forms the Ca(2+) gradient since it is considered the only permeability barrier in the skin. However, the epidermal tight junction (TJ) in the granulosum has recently been suggested to restrict molecular movement to assist the SC as a secondary barrier. The objective of this study was to clarify the contribution of the TJ to Ca(2+) gradient and epidermal differentiation in reconstructed human epidermis. When the epidermal TJ barrier was disrupted by sodium caprate treatment, Ca(2+) flux increased and the gradient changed in ion-capture cytochemistry images. Alterations of ultrastructures and proliferation/differentiation markers revealed that both hyperproliferation and precocious differentiation occurred regionally in the epidermis. These results suggest that the TJ plays a crucial role in maintaining epidermal homeostasis by controlling the Ca(2+) gradient. PMID- 21329673 TI - The cysteine-rich domain of human T1R3 is necessary for the interaction between human T1R2-T1R3 sweet receptors and a sweet-tasting protein, thaumatin. AB - Thaumatin is an intensely sweet-tasting protein perceived by humans but not rodents. Its threshold value of sweetness in humans is 50nM, the lowest of any sweet-tasting protein. In the present study, the sites where sweet receptors interact with thaumatin were investigated using human embryonic kidney 293 (HEK293) cells expressing the sweet receptors T1R2-T1R3. Chimeric human- mouse sweet receptors were constructed and their responses to sweeteners were investigated. The human (h) T1R2- mouse (m) T1R3 combination responded to sucralose but not to thaumatin, clearly indicating that a T1R3 subunit from humans is necessary for the interaction with thaumatin. Furthermore, results obtained from using chimeric T1R3s showed that the cysteine-rich domain (CRD) of human T1R3 is important for the interaction with thaumatin. The CRD of T1R3 would be a prominent target for designing new sweeteners. PMID- 21329674 TI - A novel missense mutation of the ATP2C1 gene in a Chinese patient with Hailey Hailey disease. AB - Benign familial chronic pemphigus (Hailey-Hailey disease, HHD; MIM 169600) is a rare autosomal dominant hereditary disorder characterized by pruritic vesicles, painful erosions and scaly erythematous plaques at the sites of friction and flexures. Mutations in ATP2C1, which encoding the human secretory pathway Ca2(+)/Mn2(+)-ATPase protein 1 (hSPCA1), have been identified as the pathogenic gene of HHD. We found a novel, distinct, heterozygous mutation during study of a Chinese patient with HHD. We identified a C->T transition at nucleotide 1235 (p.Thr352IIe), in exon 13 of ATP2C1. This observation would be useful for genetic counseling and prenatal diagnosis for affected families and in expanding the repertoire of ATP2C1 mutations underlying HHD. PMID- 21329675 TI - Ikaros is degraded by proteasome-dependent mechanism in the early phase of apoptosis induction. AB - Ikaros is an important transcription factor involved in the development and differentiation of hematopoietic cells. In this work, we found that chemotherapeutic drugs or ultraviolet radiation (UV) treatment could reduce the expression of full-length Ikaros (IK1) protein in less than 3h in leukemic NB4, Kasumi-1 and Jurkat cells, prior to the activation of caspase-3. Etoposide treatment could not alter the mRNA level of IK1 but it could shorten the half life of IK1. Co-treatment with the proteasome inhibitor MG132 or epoxomicin but not calpain inhibitor calpeptin inhibited etoposide-induced Ikaros downregulation. Overexpression of IK1 could accelerate etoposide-induced apoptosis in NB4 cells, as evidenced by the increase of Annexin V positive cells and the more early activation of caspase 3. To our knowledge, this is the first report to show that upon chemotherapy drugs or UV treatment, IK1 could be degraded via the proteasome system in the early phase of apoptosis induction. These data might shed new insight on the role of IK1 in apoptosis and the post translational regulation of IK1. PMID- 21329676 TI - The role of apparent size in building- and object-specific regions of ventral visual cortex. AB - Images of buildings and manipulable objects have been found to activate distinct regions in the ventral visual pathway. Yet, many non-categorical properties distinguish buildings from common everyday objects, and perhaps the most salient of these is size. In this fMRI study, we investigated whether or not changes in perceived scale can account for some of the differences in category-specific responses, independent of the influence of semantic or retinotopic image properties. We used independent scans to localize object-specific ROIs in lateral occipital cortex (LO) and scene-specific ROIs in the parahippocampal place area (PPA) and posterior collateral sulcus. We then contrasted the effects of stimulus category and perceived size/distance in these regions in a factorial design. Participants performed an oddball detection task while viewing images of objects, buildings, and planar rectangles both with and without a background that indicated stimulus size/distance via simple pictorial cues. The analyses of fMRI responses showed effects of perceived size/distance in addition to effects of category in LO and the PPA. Interestingly, when simple rectangles were presented in a control condition against the background that indicated size/distance, LO in the right hemisphere responded significantly more to the small/close rectangles than to the large/far ones, in spite of the fact that the rectangles themselves were identical. These findings suggest that ventral stream regions that show category specificity are modulated by the perceived size and distance of visual stimuli. PMID- 21329677 TI - Latencies in BOLD response during visual attention processes. AB - One well-investigated division of attentional processes focuses on alerting, orienting and executive control, which can be assessed applying the attentional network test (ANT). The goal of the present study was to add further knowledge about the temporal dynamics of relevant neural correlates. As a right hemispheric dominance for alerting and orienting has previously been reported for intrinsic but not for phasic alertness, we additionally addressed a potential impact of this lateralization of attention by employing a lateralized version of the ANT, capturing phasic alertness processes. Sixteen healthy subjects underwent event related functional magnetic resonance imaging (fMRI) while performing the ANT. Analyses of BOLD magnitude replicated the engagement of a fronto-parietal network in the attentional subsystems. The amplitudes of the attentional contrasts interacted with visual field presentation in the sense that the thalamus revealed a greater involvement for spatially cued items presented in the left visual field. Comparisons of BOLD latencies in visual cortices, first, verified faster BOLD responses following contra-lateral stimulus presentation. Second and more importantly, we identified attention-modulated activation in secondary visual and anterior cingulate cortices. Results are discussed in terms of bottom-up and lateralization processes. Although intrinsic and phasic alertness are distinct cognitive processes, we propose that neural substrates of intrinsic alertness may be accessed by phasic alertness provided that the attention-dominant (i.e., the right) hemisphere is activated directly by a warning stimulus. PMID- 21329678 TI - Hyaluronan tetrasaccharide promotes regeneration of peripheral nerve: in vivo analysis by film model method. AB - Hyaluronan (HA) is known to inhibit neurons from regenerating in the central nervous system. However, hyaluronan tetrasaccharide (HA4) was found in in vitro experiments to promote outgrowth of neurons. To investigate the promotion by HA4 of nerve regeneration in vivo, we analyzed outgrowth of regenerating axons treated with HA4, using a film model method. After the common peroneal nerve in mice was transected, the proximal end of cut nerve was placed on a sheet of thin plastic film, immersed in several drops of HA4 solution, covered with another sheet of film, and then kept in vivo. Six hours after the procedure, terminal sprouts had grown out from ending bulbs formed at the cut end of parent nerve administered with HA4 solution 100 or 1000 MUg/mL, while no sprouts were observed in groups treated with 10 MUg/mL of HA4 or in controls. On the 2nd day after axotomy (day 2), many regenerating axons in the group treated with 100 MUg/mL of HA4 extended onto the flat film for a longer distance than those treated with 1000 MUg/mL of HA4 and controls. With the optimal dose of HA4 (100 MUg/mL), axonal outgrowth was significantly (p<0.01) greater than that in controls at each time point. Schwann cells appeared migrating from parent nerve onto the film from day 3 as well as in controls. Thus, enhanced outgrowth of regenerating axons and normal behavior of migratory Schwann cells suggested that HA4 promoted regeneration of neurons without the mediation of Schwann cells. PMID- 21329679 TI - Crossmodal interaction of facial and vocal person identity information: an event related potential study. AB - Hearing a voice and seeing a face are essential parts of person identification and social interaction. It has been suggested that both types of information do not only interact at late processing stages but rather interact at the level of perceptual encoding (<200 ms). The present study analysed when visual and auditory representations of person identity modulate the processing of voices. In unimodal trials, two successive voices (S1-S2) of the same or of two different speakers were presented. In the crossmodal condition, the S1 consisted of the face of the same or a different person with respect to the following voice stimulus. Participants had to decide whether the voice probe (S2) was from an elderly or a young person. Reaction times to the S2 were shorter when these stimuli were person-congruent, both in the uni- and crossmodal conditions. ERPs recorded to the person-incongruent as compared to the person-congruent trials (S2) were enhanced at early (100-140 ms) and later processing stages (270-530 ms) in the crossmodal condition. A similar later negative ERP effect (270-530 ms) was found in the unimodal condition as well. These results suggest that identity information conveyed by a face is capable to modulate the sensory processing of voice stimuli. PMID- 21329681 TI - Natural alcohol exposure: is ethanol the main substrate for alcohol dehydrogenases in animals? AB - Alcohol dehydrogenase (ADH) activity is widely distributed in all phyla. In animals, three non-homologous NAD(P)(+)-dependent ADH protein families are reported. These arose independently throughout evolution and possess different structures and mechanisms of reaction: type I (medium-chain) ADHs are zinc containing enzymes and comprise the most studied group in vertebrates; type II (short-chain) ADHs lack metal cofactor and have been extensively studied in Drosophila; and type III ADHs are iron-dependent/-activated enzymes that were initially identified only in microorganisms. The presence of these different ADHs in animals has been assumed to be a consequence of chronic exposure to ethanol. By far the most common natural source of ethanol is fermentation of fruit sugars by yeast, and available data support that this fruit trait evolved in concert with the characteristics of their frugivorous seed dispersers. Therefore, if the presence of ADHs in animals evolved as an adaptive response to dietary ethanol exposure, then it can be expected that the enzymogenesis of these enzymes began after the appearance of angiosperms with fleshy fruits, because substrate availability must precede enzyme selection. In this work, available evidence supporting this possibility is discussed. Phylogenetic analyses reveal that type II ADHs suffered several duplications, all of these restricted to flies (order Diptera). Induction of type II Adh by ethanol exposure, a positive correlation between ADH activity and ethanol resistance, and the fact that flies and type II Adh diversification occurred in concert with angiosperm diversification, strongly suggest that type II ADHs were recruited to allow larval flies to exploit new restricted niches with high ethanol content. In contrast, phyletic distribution of types I and III ADHs in animals showed that these appeared before angiosperms and land plants, independently of ethanol availability. Because these enzymes are not induced by ethanol exposure and possess a high affinity and/or catalytic efficiency for non-ethanol endogenous substrates, it can be concluded that the participation of types I and III ADHs in ethanol metabolism can be considered as incidental, and not adaptive. PMID- 21329680 TI - Human and rodent aldo-keto reductases from the AKR1B subfamily and their specificity with retinaldehyde. AB - NADP(H)-dependent cytosolic aldo-keto reductases (AKR) are mostly monomeric enzymes which fold into a typical (alpha/beta)(8)-barrel structure. Substrate specificity and inhibitor selectivity are determined by interaction with residues located in three highly variable loops (A, B, and C). Based on sequence identity, AKR have been grouped into families, namely AKR1-AKR15, containing multiple subfamilies. Two human enzymes from the AKR1B subfamily (AKR1B1 and AKR1B10) are of special interest. AKR1B1 (aldose reductase) is related to secondary diabetic complications, while AKR1B10 is induced in cancer cells and is highly active with all-trans-retinaldehyde. Residues interacting with all-trans-retinaldehyde and differing between AKR1B1 and AKR1B10 are Leu125Lys and Val131Ala (loop A), Leu301Val, Ser303Gln, and Cys304Ser (loop C). Recently, we demonstrated the importance of Lys125 as a determinant of AKR1B10 specificity for retinoids. Residues 301 and 304 are also involved in interactions with substrates or inhibitors, and thus we checked their contribution to retinoid specificity. We also extended our study with retinoids to rodent members of the AKR1B subfamily: AKR1B3 (aldose reductase), AKR1B7 (mouse vas deferens protein), AKR1B8 (fibroblast-growth factor 1-regulated protein), and AKR1B9 (Chinese hamster ovary reductase), which were tested against all-trans isomers of retinaldehyde and retinol. All enzymes were active with retinaldehyde, but with k(cat) values (0.02 0.52 min(-1)) much lower than that of AKR1B10 (27 min(-1)). None of the enzymes showed oxidizing activity with retinol. Since these enzymes (except AKR1B3) have Lys125, other residues should account for retinaldehyde specificity. Here, by using site-directed mutagenesis and molecular modeling, we further delineate the contribution of residues 301 and 304. We demonstrate that besides Lys125, Ser304 is a major structural determinant for all-trans-retinaldehyde specificity of AKR1B10. PMID- 21329682 TI - Aldose reductase-mediated induction of epithelium-to-mesenchymal transition (EMT) in lens. AB - Cataract is a key factor in the morbidity associated with diabetes. While the pathogenesis of diabetic cataract formation is poorly understood, previous research has identified aldose reductase (ALR2) as a key player. To elucidate a potential role for this enzyme in diabetic cataract formation, we created a series of transgenic mice designed for expression of human ALR2 (AKR1B1) in epithelial and outer cortical fiber cells of the lens. One of the founder lines, designated PAR39, developed an early onset cataract that involved formation of a plaque of cells at the anterior aspect of the lens. These cells appear to separate from the anterior epithelium and undergo a dramatic change that is reminiscent of the epithelial to mesenchymal transition (EMT). We characterized this phenotype in the PAR39 strain by examining rates of cell proliferation and by immunostaining for markers of EMT. Incorporation of the thymidine analog bromodeoxyuridine (BrdU) was used to estimate cell proliferation in two functional areas of the lens epithelium: the mitotically active germinative zone (GZ) and the less proliferative center zone (CZ). Staining cell nuclei with diamido 4',6-diamidino-2-phenylindole (DAPI) was used to establish a total cell count in the demarcated areas. Lens epithelium in PAR39 transgenic mice demonstrated a decrease in the percentage of BrdU/DAPI staining within the GZ as compared to nontransgenic littermate controls (8.1% vs. 10.9%). A similar decrease in BrdU/DAPI was observed in the CZ (0.6% compared to 3.3%). However, cell density was greater within the GZ of PAR39 mice as compared with nontransgenic controls, while it was not significantly different in the CZ among the two groups. Furthermore, cells associated with the epithelial plaque did not stain positive for BrdU, but were strongly positive for alpha-smooth muscle actin, a classical marker for EMT. These findings suggest that ALR2 over expression is associated with an alteration in the balance between proliferation and apoptosis of epithelial cells in the mouse lens, and that cells associated with epithelial plaques in the PAR39 lens have features in common with cells undergoing EMT. PMID- 21329683 TI - Characterization of new medium-chain alcohol dehydrogenases adds resolution to duplications of the class I/III and the sub-class I genes. AB - Four additional variants of alcohol and aldehyde dehydrogenases have been purified and functionally characterized, and their primary structures have been determined. The results allow conclusions about the structural and evolutionary relationships within the large family of MDR alcohol dehydrogenases from characterizations of the pigeon (Columba livia) and dogfish (Scyliorhinus canicula) major liver alcohol dehydrogenases. The pigeon enzyme turns out to be of class I type and the dogfish enzyme of class III type. This result gives a third type of evidence, based on purifications and enzyme characterization in lower vertebrates, that the classical liver alcohol dehydrogenase originated by a gene duplication early in the evolution of vertebrates. It is discernable as the major liver form at about the level in-between cartilaginous and osseous fish. The results also show early divergence within the avian orders. Structures were determined by Edman degradations, making it appropriate to acknowledge the methodological contributions of Pehr Edman during the 65 years since his thesis at Karolinska Institutet, where also the present analyses were performed. PMID- 21329684 TI - Human aldo-keto reductases 1B1 and 1B10: a comparative study on their enzyme activity toward electrophilic carbonyl compounds. AB - Aldo-keto reductase family 1 member B1 (AKR1B1, 1B1 in brief) and aldo-keto reductase family 1 member B10 (AKR1B10, 1B10 in brief) are two proteins with high similarities in their amino acid sequences, stereo structures, and substrate specificity. However, these two proteins exhibit distinct tissue distributions; 1B10 is primarily expressed in the gastrointestinal tract and adrenal gland, whereas 1B1 is ubiquitously present in all tissues/organs, suggesting their difference in biological functions. This study evaluated in parallel the enzyme activity of 1B1 and 1B10 toward alpha, beta-unsaturated carbonyl compounds with cellular and dietary origins, including acrolein, crotonaldehyde, 4 hydroxynonenal, trans-2-hexenal, and trans-2,4-hexadienal. Our results showed that 1B10 had much better enzyme activity and turnover rates toward these chemicals than 1B1. By detecting the enzymatic products using high-performance liquid chromatography, we measured their activity to carbonyl compounds at low concentrations. Our data showed that 1B10 efficiently reduced the tested carbonyl compounds at physiological levels, but 1B1 was less effective. Ectopically expressed 1B10 in 293T cells effectively eliminated 4-hydroxynonenal at 5 MUM by reducing to 1,4-dihydroxynonene, whereas endogenously expressed 1B1 did not. The 1B1 and 1B10 both showed enzyme activity to glutathione-conjugated carbonyl compounds, but 1B1 appeared more active in general. Together our data suggests that 1B10 is more effectual in eliminating free electrophilic carbonyl compounds, but 1B1 seems more important in the further detoxification of glutathione conjugated carbonyl compounds. PMID- 21329685 TI - The toxic effect of fluoride on MG-63 osteoblast cells is also dependent on the production of nitric oxide. AB - Some soda-lime-phospho-silicate glasses, such as Hench's Bioglass((r)) 45S5, form bone-like apatite on their surface when bound to living bone. To improve their osteointegration for clinical purposes, the fluoride insertion in their structure has been proposed, but we recently showed that fluoride causes oxidative damage in human MG-63 osteoblasts, via inhibition of pentose phosphate oxidative pathway (PPP) and its key enzyme glucose 6-phosphate dehydrogenase (G6PD). In the same cells we have now investigated the role of nitric oxide (NO) in these effects. Fluoride-containing bioactive glasses and NaF caused, as expected, release of lactate dehydrogenase in the extracellular medium, accumulation of intracellular malonyldialdehyde, inhibition of PPP and G6PD: we have now observed that these effects were significantly reverted not only by superoxide dismutase (SOD) plus catalase (scavengers of reactive oxygen species), but also by N-monomethyl l arginine (l-NMMA, a NOS inhibitor) and 2-phenyl-4,4,5,5,-tetramethylimidazoline 1oxyl 3-oxide (PTIO, a NO scavenger). Moreover the two highest concentrations of both fluoride-containing bioglasses and NaF caused increase of nitrite (a stable derivative of NO) levels in the culture supernatant, which was inhibited by l NMMA, erythrocytes, PTIO and SOD/catalase, and increase of intracellular NO synthase (NOS) activity. The incubation with bioglasses or NaF increased also the phosphorylation of Ser(1177) in the endothelial NOS isoform. Furthermore, the NO donor spermine NONOate was able to inhibit G6PD activity in vitro, and this effect was partly reverted by PTIO. Therefore our results suggest that most cytotoxic effects of fluoride are mediated by the production of NO: reactive oxygen species are important, causing NOS phosphorylation. We also observed, for the first time, that Tempol, but not SOD/catalase, besides inhibiting the oxidative stress induced by fluoride, also scavenges fluoride ions. For this reason it is not a selective inhibitor of the oxidative effects of fluoride. PMID- 21329686 TI - Antibodies to glycoprotein 2 (GP2) in patients with inflammatory bowel diseases from UK. PMID- 21329687 TI - High levels of apolipoproteins found in the soluble fraction of avian cornea. AB - Water-soluble proteins in avian corneas were profiled by two-dimensional electrophoresis and identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Comparative protein profiling of avian and mammalian corneas revealed five major protein spots specifically detected in avian species. These proteins were identified as apolipoproteins A1 and D by tandem mass spectrometry sequencing. This is the first report of the presence of apolipoproteins in avian cornea. These results could provide insight into the role of lipid metabolism in the avian-specific function of cornea. PMID- 21329688 TI - Effect of glucose on the stress-strain behavior of ex-vivo rabbit cornea. AB - The biomechanical changes in rabbit cornea preserved in storage media with different glucose concentrations are experimentally assessed. Two groups of eight fresh rabbit corneas were preserved for 10 days in storage medium Optisol-GS with glucose concentrations of 14 and 28 mM, respectively. Eight additional corneas preserved, glucose-free, in the same medium served as the control group. All specimens were tested under inflation conditions up to 45 mmHg posterior pressure, and the pressure-deformation data obtained experimentally were analyzed using shell theory to derive the stress-strain behavior. Comparisons were held between the three specimen groups in order to determine the effect of glucose concentration on corneal biomechanical behavior and thickness. After storage, the mean central corneal thickness in the control, low-glucose and high-glucose groups underwent statistically significant increases of 38.7 +/- 11.3%, 45.4 +/- 7.6% and 50.6 +/- 8.6%, respectively. The corneas also demonstrated consistent stiffness increases with higher glucose concentrations. The tangent modulus values determined at different pressure levels between 10 and 40 mmHg underwent statistically significant increases with glucose level (P < 0.05). Compared to the control group, other specimens had higher tangent modulus by 17-20% on average with low glucose and 30-37% with high-glucose concentration. The results of the study indicate that the influence of the high-glucose level commonly experienced in diabetes on the biomechanical stiffness of the cornea should be considered in clinical management and in understanding corneal ectasia, glaucoma and the response to refractive surgery. PMID- 21329689 TI - MiR-146a inhibits oxidized low-density lipoprotein-induced lipid accumulation and inflammatory response via targeting toll-like receptor 4. AB - Atherosclerosis is an inflammatory process due to oxidized low-density lipoprotein (oxLDL) accumulation in macrophages. We investigated the involvement of microRNAs in oxLDL accumulation and inflammatory response in macrophages. The expression of miR-146a decreases under oxLDL stimulation. MiR-146a significantly reduces intracellular LDL cholesterol content and secretion of interleukin 6, interleukin 8, chemokine (C-C motif) ligand 2 and matrix metallopeptidase 9. Toll like receptor 4 (TLR4) is a relevant target of miR-146a, and miR-146a inhibits the activation of TLR4-dependent intracellular signaling pathways involved in cytoskeleton rearrangement, lipid uptake, and inflammatory cytokine secretion. These results indicate that miR-146a contributes to the regulation of both oxLDL accumulation and inflammatory response by negatively regulating TLR4 and thereby inhibiting the activation of TLR4-dependent signaling pathways. Over-expression of miR-146a may be useful in the prevention and treatment of atherosclerosis. PMID- 21329691 TI - Life cycle truncation in a trematode: does higher temperature indicate shorter host longevity? AB - The typical three-host life cycle of most trematodes creates transmission challenges for which a variety of adaptations have evolved to increase the probability of transmission. Some species can abbreviate their life cycle via progenesis, the precocious maturation of the parasite in the second intermediate host resulting in the production of eggs through self-fertilisation without requiring a definitive host. Adoption of the progenetic life cycle may be a conditional strategy in response to different environmental cues related to low probability of transmission to the definitive host. Using high water temperature and/or limited diet as experimental stressors, we tested the effect of body condition and life span of the fish second intermediate host on facultative truncation of the typical three-host life cycle by progenesis in Stegodexamene anguillae. The results suggest that environmental cues, such as temperature and encystment site, may signal transmission opportunities to the parasite so that it may adjust its developmental strategy accordingly. Indeed, a greater proportion of worms became progenetic at higher temperatures, and progenesis was more common among worms encysted in the gonads or body cavity of their fish hosts than among those in other host tissues. These findings highlight the often unrecognised plasticity in parasite developmental and transmission strategies. PMID- 21329692 TI - Functional activation of T cells by dendritic cells and macrophages exposed to the intracellular parasite Neospora caninum. AB - Neospora caninum is an intracellular protozoan pathogen that causes abortion in cattle. We studied how the interaction between murine conventional dendritic cells or macrophages and N. caninum influences the generation of cell-mediated immunity against the parasite. We first explored the invasion and survival ability of N. caninum in dendritic cells and macrophages. We observed that protozoa rapidly invaded and proliferated into these two cell populations. We then investigated how Neospora-exposed macrophages or dendritic cells distinguish between viable and non-viable (heat-killed tachyzoites and antigenic extract) parasites. Viable tachyzoites and antigenic extract, but not killed parasites, altered the phenotype of immature dendritic cells. Dendritic cells infected with viable parasites down-regulated the expression of MHC-II, CD40, CD80 and CD86 whereas dendritic cells exposed to N. caninum antigenic extract up-regulated the expression of MHC-II and CD40 and down-regulated CD80 and CD86 expression. Moreover, only viable tachyzoites and antigenic extract induced IL-12 synthesis by dendritic cells. MHC-II expression was up-regulated and CD86 expression was down-regulated at the surface of macrophages, regardless of the parasitic form was encountered. However, IL-12 secretion by macrophages was only observed under conditions using viable and heat-killed parasite. We then analysed how macrophages and dendritic cells were involved in inducing T-cell responses. T lymphocyte IFN-gamma-secretion in correlation with IL-12 production occurred after interactions between T cells and dendritic cells exposed to viable tachyzoites or antigenic extract. By contrast, for macrophages IFN-gamma production was IL-12-independent and only occurred after interactions between T cells and macrophages exposed to antigenic extract. Thus, N. caninum-induced activation of murine dendritic cells, but not that of macrophages, was associated with T cell IFN-gamma production after IL-12 secretion. PMID- 21329690 TI - TSC1/TSC2 signaling in the CNS. AB - Over the past several years, the study of a hereditary tumor syndrome, tuberous sclerosis complex (TSC), has shed light on the regulation of cellular proliferation and growth. TSC is an autosomal dominant disorder that is due to inactivating mutations in TSC1 or TSC2 and characterized by benign tumors (hamartomas) involving multiple organ systems. The TSC1/2 complex has been found to play a crucial role in an evolutionarily-conserved signaling pathway that regulates cell growth: the mTORC1 pathway. This pathway promotes anabolic processes and inhibits catabolic processes in response to extracellular and intracellular factors. Findings in cancer biology have reinforced the critical role for TSC1/2 in cell growth and proliferation. In contrast to cancer cells, in the CNS, the TSC1/2 complex not only regulates cell growth/proliferation, but also orchestrates an intricate and finely tuned system that has distinctive roles under different conditions, depending on cell type, stage of development, and subcellular localization. Overall, TSC1/2 signaling in the CNS, via its multi faceted roles, contributes to proper neural connectivity. Here, we will review the TSC signaling in the CNS. PMID- 21329693 TI - Toxoplasma gondii inhibits granzyme B-mediated apoptosis by the inhibition of granzyme B function in host cells. AB - Host defense to the apicomplexan parasite Toxoplasma gondii is critically dependent on CD8(+) T cells, whose effector functions include the induction of apoptosis in target cells following the secretion of granzyme proteases. Here we demonstrate that T. gondii induces resistance of host cells to apoptosis induced by recombinant granzyme B. Granzyme B induction of caspase-independent cytochrome c release was blocked in T. gondii-infected cells. Prevention of apoptosis could not be attributed to altered expression of the Bcl-2 family of apoptotic regulatory proteins, but was instead associated with reduced granzyme B-mediated, caspase-independent cleavage of procaspase 3 to the p20 form in T. gondii infected cells, as well as reduced granzyme B-mediated cleavage of the artificial granzyme B substrate, GranToxiLux. The reduction in granzyme B proteolytic function in T. gondii-infected cells could not be attributed to altered granzyme B uptake or reduced trafficking of granzyme B to the cytosol, implying a T. gondii-mediated inhibition of granzyme B activity. Apoptosis and GranToxiLux cleavage were similarly inhibited in T. gondii-infected cells exposed to the natural killer-like cell line YT-1. The endogenous granzyme B inhibitor PI-9 was not up-regulated in infected cells. We believe these findings represent the first demonstration of granzyme B inhibition by a cellular pathogen and indicate a new modality for host cell protection by T. gondii that may contribute to parasite immune evasion. PMID- 21329694 TI - Geographic distribution modelling for ruminant liver flukes (Fasciola hepatica) in south-eastern Europe. AB - Maximum entropy ecological niche modelling was utilised to predict the geographic range for fluke genotypes and haplotypes in south-eastern Europe, using the Maxent program. The lowest (0.832) and the highest (0.947) area under the curve values were observed in the models for the haplotypes CtCmt1 and CtCmt2.2, respectively. Precipitation and temperature contribute equally to model building of the genotypes based on the 28S rDNA gene. In regard to the mtDNA gene region, precipitation is the most important factor in modelling the CtCmt1 haplotype range, while temperature appears to be the most important factor in modelling the CtCmt2.1 and CtCmt2.2 haplotype ranges. The highest level of probability for the geographic distribution of Fasciola hepatica genotypes and haplotypes covered the regions of southern Bulgaria and central and northern Greece which contain a high concentration of potential ruminant hosts. PMID- 21329695 TI - An example of molecular co-evolution: reactive oxygen species (ROS) and ROS scavenger levels in Schistosoma mansoni/Biomphalaria glabrata interactions. AB - The co-evolution between hosts and parasites involves huge reciprocal selective pressures on both protagonists. However, relatively few reports have evaluated the impact of these reciprocal pressures on the molecular determinants at the core of the relevant interaction, such as the factors influencing parasitic virulence and host resistance. Here, we address this question in a host-parasite model that allows co-evolution to be monitored in the field: the interaction between the mollusc, Biomphalaria glabrata, and its trematode parasite, Schistosoma mansoni. Reactive oxygen species (ROS) produced by the haemocytes of B. glabrata are known to play a crucial role in killing S. mansoni. Therefore, the parasite must defend itself against oxidative damage caused by ROS using ROS scavengers in order to survive. In this context, ROS and ROS scavengers are involved in a co-evolutionary arms race, and their respective production levels by sympatric host and parasite could be expected to be closely related. Here, we test this hypothesis by comparing host oxidant and parasite antioxidant capabilities between two S. mansoni/B. glabrata populations that have co-evolved independently. As expected, our findings show a clear link between the oxidant and antioxidant levels, presumably resulting from sympatric co-evolution. We believe this work provides the first supporting evidence of the Red Queen Hypothesis of reciprocal evolution for functional traits at the field-level in a model involving a host and a eukaryotic parasite. PMID- 21329697 TI - New lessons from random X-chromosome inactivation in the mouse. AB - X-chromosome inactivation (XCI) ensures dosage compensation in mammals. Random XCI is a process where a single X chromosome is silenced in each cell of the epiblast of mouse female embryos. Operating at the level of an entire chromosome, XCI is a major paradigm for epigenetic processes. Here we review the most recent discoveries concerning the role of long noncoding RNAs, pluripotency factors, and chromosome structure in random XCI. PMID- 21329696 TI - Folding kinetics of the cooperatively folded subdomain of the IkappaBalpha ankyrin repeat domain. AB - The ankyrin repeat (AR) domain of IkappaBalpha consists of a cooperative folding unit of roughly four ARs (AR1-AR4) and of two weakly folded repeats (AR5 and AR6). The kinetic folding mechanism of the cooperative subdomain, IkappaBalpha(67 206), was analyzed using rapid mixing techniques. Despite its apparent architectural simplicity, IkappaBalpha(67-206) displays complex folding kinetics, with two sequential on-pathway high-energy intermediates. The effect of mutations to or away from the consensus sequences of ARs on folding behavior was analyzed, particularly the GXTPLHLA motif, which have not been examined in detail previously. Mutations toward the consensus generally resulted in an increase in folding stability, whereas mutations away from the consensus resulted in decreased overall stability. We determined the free energy change upon mutation for three sequential transition state ensembles along the folding route for 16 mutants. We show that folding initiates with the formation of the interface of the outer helices of AR3 and AR4, and then proceeds to consolidate structure in these repeats. Subsequently, AR1 and AR2 fold in a concerted way in a single kinetic step. We show that this mechanism is robust to the presence of AR5 and AR6 as they do not strongly affect the folding kinetics. Overall, the protein appears to fold on a rather smooth energy landscape, where the folding mechanism conforms a one-dimensional approximation. However, we note that the AR does not necessarily act as a single folding element. PMID- 21329698 TI - Crystal structure of R120G disease mutant of human alphaB-crystallin domain dimer shows closure of a groove. AB - Small heat shock proteins form large cytosolic assemblies from an "alpha crystallin domain" (ACD) flanked by sequence extensions. Mutation of a conserved arginine in the ACD of several human small heat shock protein family members causes many common inherited diseases of the lens and neuromuscular system. The mutation R120G in alphaB-crystallin causes myopathy, cardiomyopathy and cataract. We have solved the X-ray structure of the excised ACD dimer of human alphaB R120G close to physiological pH and compared it with several recently determined wild type vertebrate ACD dimer structures. Wild-type excised ACD dimers have a deep groove at the interface floored by a flat extended "bottom sheet." Solid-state NMR studies of large assemblies of full-length alphaB-crystallin have shown that the groove is blocked in the ACD dimer by curvature of the bottom sheet. The crystal structure of R120G ACD dimer also reveals a closed groove, but here the bottom sheet is flat. Loss of Arg120 results in rearrangement of an extensive array of charged interactions across this interface. His83 and Asp80 on movable arches on either side of the interface close the groove by forming two new salt bridges. The residues involved in this extended set of ionic interactions are conserved in Hsp27, Hsp20, alphaA- and alphaB-crystallin sequences. They are not conserved in Hsp22, where mutation of the equivalent of Arg120 causes neuropathy. We speculate that the alphaB R120G mutation disturbs oligomer dynamics, causing the growth of large soluble oligomers that are toxic to cells by blocking essential processes. PMID- 21329699 TI - Computational protein design and large-scale assessment by I-TASSER structure assembly simulations. AB - Protein design aims at designing new protein molecules of desired structure and functionality. One of the major obstacles to large-scale protein design are the extensive time and manpower requirements for experimental validation of designed sequences. Recent advances in protein structure prediction have provided potentials for an automated assessment of the designed sequences via folding simulations. We present a new protocol for protein design and validation. The sequence space is initially searched by Monte Carlo sampling guided by a public atomic potential, with candidate sequences selected by the clustering of sequence decoys. The designed sequences are then assessed by I-TASSER folding simulations, which generate full-length atomic structural models by the iterative assembly of threading fragments. The protocol is tested on 52 nonhomologous single-domain proteins, with an average sequence identity of 24% between the designed sequences and the native sequences. Despite this low sequence identity, three-dimensional models predicted for the first designed sequence have an RMSD of <2 A to the target structure in 62% of cases. This percentage increases to 77% if we consider the three-dimensional models from the top 10 designed sequences. Such a striking consistency between the target structure and the structural prediction from nonhomologous sequences, despite the fact that the design and folding algorithms adopt completely different force fields, indicates that the design algorithm captures the features essential to the global fold of the target. On average, the designed sequences have a free energy that is 0.39 kcal/(mol residue) lower than in the native sequences, potentially affording a greater stability to synthesized target folds. PMID- 21329700 TI - Two wrongs don't make a right: the initial viability of different assessment rules in the evolution of indirect reciprocity. AB - Indirect reciprocity models are meant to correspond to simple moral systems, in which individuals assess the interactions of third parties in order to condition their cooperative behavior. Despite the staggering number of possible assessment rules in even the simplest of these models, previous research suggests that only a handful are evolutionarily stable against invasion by free riders. These successful assessment rules fall into two categories, one which positively judges miscreants when they refuse to help other miscreants, the other which does not. Previous research has not, however, demonstrated that all of these rules can invade an asocial population--a requirement for a complete theory of social evolution. Here, I present a general analytical model of indirect reciprocity and show that the class of assessment rules which positively judges a refusal to help scofflaws cannot invade a population of defectors, whereas the other class can. When rare, assessment rules which positively judge a refusal to help bad people produce a poor correlation between reputation and behavior. It is this correlation that generates the assortment crucial in sustaining cooperation through indirect reciprocity. Only assessment rules that require good deeds to achieve a good reputation guarantee a strong correlation between behavior and reputation. PMID- 21329701 TI - To signal a conjunction of many inputs negative regulation is likely. AB - Cells make many transitions from an old to a new phase of activity - between inactive and active states of an enzyme, or between phases of the cell cycle. If a cell is to survive, molecular prerequisites for functioning in the new phase should be available before a transition occurs. The cell's survival is more likely if a regulatory network gates the transition, preventing its occurrence until the prerequisites are available. Suppose a specific conjunction of inputs is required for a network, from which a single output governs the transition. Then we suggest that cells are likely to use negative regulation - a gating network based on a logical disjunction of signals for the absence of prerequisites - rather than positive regulation - a logical conjunction of signals for their presence. That is, if a logical conjunction of n prerequisites A1 AND A2 AND ...AND An is needed in the new phase, a negative regulatory network is likely to enforce the corresponding logical disjunction, NOT (NOT A1 OR NOT A2 OR ...OR NOT An). Five examples illustrate this conclusion. Arguments based on performance criteria support the hypothesis: negative regulation is more economical than positive regulation, because networks for computing OR can use fewer and simpler parts than those for computing AND. Negative regulation can increase reliability, because a mechanism that uses fewer, simpler parts is less likely to fail. And, a negative regulatory network can be more robust - less susceptible to errors resulting from noisy input. PMID- 21329702 TI - Methods for and results from the study of design principles in molecular systems. AB - Most aspects of molecular biology can be understood in terms of biological design principles. These principles can be loosely defined as qualitative and quantitative features that emerge in evolution and recur more frequently than one would expect by chance alone in biological systems that perform a given type of process or function. Furthermore, such recurrence can be rationalized in terms of the functional advantage that the design provides to the system when compared with possible alternatives. This paper focuses on those design features that can be related to improved functional effectiveness of molecular and regulatory networks. We begin by reviewing assumptions and methods that underlie the study of such principles in molecular networks. We follow by discussing many of the design principles that have been found in genetic, metabolic, and signal transduction circuits. We concentrate mainly on results in the context of Biochemical Systems Theory, although we also briefly discuss other work. We conclude by discussing the importance of these principles for both, understanding the natural evolution of complex networks at the molecular level and for creating artificial biological systems with specific features. PMID- 21329703 TI - Structure-function relations are subtle in genetic regulatory networks. AB - Recent studies have yielded insights into structure-function relations in genetic regulatory networks. Models of feed-forward loops show that the input-output behavior depends critically on the input signal as well as transcription interactions. Models of induction of the lac operon in Escherichia coli reveal the importance of metabolism in determining genetic regulatory network behavior. Combined experimental and computational studies of activation by MarA in E. coli show how mechanisms of transcription regulation, hidden at the level of genetic regulatory networks, can influence behavior. Together these studies illustrate that gene regulation is critically influenced by factors beyond the topology of genetic regulatory interactions. Prediction of the specific information processing roles of gene circuits is more difficult than we would like, but it is still possible. Thinking about evolution of proteins and networks might make it easier. PMID- 21329704 TI - Feedback-mediated dynamics in a model of coupled nephrons with compliant thick ascending limbs. AB - The tubuloglomerular feedback (TGF) system in the kidney, a key regulator of glomerular filtration rate, has been shown in physiologic experiments in rats to mediate oscillations in thick ascending limb (TAL) tubular fluid pressure, flow, and NaCl concentration. In spontaneously hypertensive rats, TGF-mediated flow oscillations may be highly irregular. We conducted a bifurcation analysis of a mathematical model of nephrons that are coupled through their TGF systems; the TALs of these nephrons are assumed to have compliant tubular walls. A characteristic equation was derived for a model of two coupled nephrons. Analysis of that characteristic equation has revealed a number of parameter regions having the potential for differing stable dynamic states. Numerical solutions of the full equations for two model nephrons exhibit a variety of behaviors in these regions. Also, model results suggest that the stability of the TGF system is reduced by the compliance of TAL walls and by internephron coupling; as a result, the likelihood of the emergence of sustained oscillations in tubular fluid pressure and flow is increased. Based on information provided by the characteristic equation, we identified parameters with which the model predicts irregular tubular flow oscillations that exhibit a degree of complexity that may help explain the emergence of irregular oscillations in spontaneously hypertensive rats. PMID- 21329705 TI - Exploring anodal and cathodal make and break cardiac excitation mechanisms in a 3D anisotropic bidomain model. AB - Published studies have investigated the relevance of cardiac virtual electrode responses to unipolar cathodal and anodal stimulations for explaining the make and break excitation mechanisms. Most of these studies have considered 2D bidomain models or cylindrical domains that by symmetry reduce to the 2D case, so the triggering mechanisms and onset of excitation have not yet been fully elucidated in 3D anisotropic models. The goal of this work is to revisit these excitation mechanisms with 3D bidomain simulations considering two tissue types with unequal anisotropy ratio, including transmural fiber rotation and augmenting the Luo-Rudy I membrane model with the so-called funny and the electroporation currents. In addition to usual snapshots of transmembrane potential patterns, we compute from the action potential waveforms the activation time and associated isochrone sequences, yielding a detailed 3D description of the instant and location of excitation origin, shape and propagation of activation wavefronts. A specific aim of this work is to detect the location of the excitation onset and whether its trigger mechanism is (a) electrotonic, i.e. originating from discharge diffusion of currents flowing between virtual cathodes and anodes and/or (b) membrane-based, i.e. arising only from intrinsic depolarizing membrane currents. Our results show that the electrotonic mechanism is observed independently of the degree of unequal anisotropy in diastolic anode make and systolic cathode break. The membrane-based mechanism is observed in diastolic cathode make, diastolic anode break, only for a relative weak anisotropy, and systolic anode break. The excitation trigger mechanism, the location of the excitation origin and the pattern of the isochrone sequence are independent of the degree of anisotropy for diastolic cathode make, systolic cathode and anode break, while they might depend on the degree of anisotropy for diastolic anode make and break. Moreover, the tissue anisotropy has a strong influence on the threshold amplitude of the stimulation pulse triggering these mechanisms. PMID- 21329706 TI - Induction and repair of DNA double strand breaks: the increasing spectrum of non homologous end joining pathways. AB - A defining characteristic of damage induced in the DNA by ionizing radiation (IR) is its clustered character that leads to the formation of complex lesions challenging the cellular repair mechanisms. The most widely investigated such complex lesion is the DNA double strand break (DSB). DSBs undermine chromatin stability and challenge the repair machinery because an intact template strand is lacking to assist restoration of integrity and sequence in the DNA molecule. Therefore, cells have evolved a sophisticated machinery to detect DSBs and coordinate a response on the basis of inputs from various sources. A central function of cellular responses to DSBs is the coordination of DSB repair. Two conceptually different mechanisms can in principle remove DSBs from the genome of cells of higher eukaryotes. Homologous recombination repair (HRR) uses as template a homologous DNA molecule and is therefore error-free; it functions preferentially in the S and G2 phases. Non-homologous end joining (NHEJ), on the other hand, simply restores DNA integrity by joining the two ends, is error prone as sequence is only fortuitously preserved and active throughout the cell cycle. The basis of DSB repair pathway choice remains unknown, but cells of higher eukaryotes appear programmed to utilize preferentially NHEJ. Recent work suggests that when the canonical DNA-PK dependent pathway of NHEJ (D-NHEJ), becomes compromised an alternative NHEJ pathway and not HRR substitutes in a quasi-backup function (B-NHEJ). Here, we outline aspects of DSB induction by IR and review the mechanisms of their processing in cells of higher eukaryotes. We place particular emphasis on backup pathways of NHEJ and summarize their increasing significance in various cellular processes, as well as their potential contribution to carcinogenesis. PMID- 21329707 TI - Radiation damage to DNA in DNA-protein complexes. AB - The most aggressive product of water radiolysis, the hydroxyl (OH) radical, is responsible for the indirect effect of ionizing radiations on DNA in solution and aerobic conditions. According to radiolytic footprinting experiments, the resulting strand breaks and base modifications are inhomogeneously distributed along the DNA molecule irradiated free or bound to ligands (polyamines, thiols, proteins). A Monte-Carlo based model of simulation of the reaction of OH radicals with the macromolecules, called RADACK, allows calculating the relative probability of damage of each nucleotide of DNA irradiated alone or in complexes with proteins. RADACK calculations require the knowledge of the three dimensional structure of DNA and its complexes (determined by X-ray crystallography, NMR spectroscopy or molecular modeling). The confrontation of the calculated values with the results of the radiolytic footprinting experiments together with molecular modeling calculations show that: (1) the extent and location of the lesions are strongly dependent on the structure of DNA, which in turns is modulated by the base sequence and by the binding of proteins and (2) the regions in contact with the protein can be protected against the attack by the hydroxyl radicals via masking of the binding site and by scavenging of the radicals. PMID- 21329708 TI - MicroRNAs in inflammation and response to injuries induced by environmental pollution. AB - MicroRNAs (miRNAs) are small noncoding RNAs that regulate basic biological processes by posttranscriptional suppression of their target genes. Altered miRNA expression may lead to widespread gene expression changes and has been implicated in pathophysiological processes such as cancer and inflammation. In this review, we summarize the present knowledge about the role of miRNAs in inflammation and in the response to environmental agents and pollutants, such as cigarette smoke, ethanol, carcinogenic chemicals such as benzo(a)pyrene (BaP) and dioxin, and UV radiation. PMID- 21329709 TI - Measurement of oxidatively generated base damage in cellular DNA. AB - This survey focuses on the critical evaluation of the main methods that are currently available for monitoring single and complex oxidatively generated damage to cellular DNA. Among chromatographic methods, HPLC-ESI-MS/MS and to a lesser extent HPLC-ECD which is restricted to a few electroactive nucleobases and nucleosides are appropriate for measuring the formation of single and clustered DNA lesions. Such methods that require optimized protocols for DNA extraction and digestion are sensitive enough for measuring base lesions formed under conditions of severe oxidative stress including exposure to ionizing radiation, UVA light and high intensity UVC laser pulses. In contrast application of GC-MS and HPLC-MS methods that are subject to major drawbacks have been shown to lead to overestimated values of DNA damage. Enzymatic methods that are based on the use of DNA repair glycosylases in order to convert oxidized bases into strand breaks are suitable, even if they are far less specific than HPLC methods, to deal with low levels of single modifications. Several other methods including immunoassays and (32)P-postlabeling methods that are still used suffer from drawbacks and therefore are not recommended. Another difficult topic is the measurement of oxidatively generated clustered DNA lesions that is currently achieved using enzymatic approaches and that would necessitate further investigations. PMID- 21329710 TI - Increased serotonin axons (immunoreactive to 5-HT transporter) in postmortem brains from young autism donors. AB - Imaging studies of serotonin transporter binding or tryptophan retention in autistic patients suggest that the brain serotonin system is decreased. However, treatment with drugs which increase serotonin (5-HT) levels, specific serotonin reuptake inhibitors (SSRIs), commonly produce a worsening of the symptoms. In this study we examined 5-HT axons that were immunoreactive to a serotonin transporter (5-HTT) antibody in a number of postmortem brains from autistic patients and controls with no known diagnosis who ranged in age from 2 to 29 years. Fine, highly branched, and thick straight fibers were found in forebrain pathways (e.g. medial forebrain bundle, stria terminalis and ansa lenticularis). Many immunoreactive varicose fine fibers were seen in target areas (e.g. globus pallidus, amygdala and temporal cortex). Morphometric analysis of the stained axons at all ages studied indicated that the number of serotonin axons was increased in both pathways and terminal regions in cortex from autism donors. Our findings provide morphological evidence to warrant caution when using serotonin enhancing drugs (e.g. SSRIs and receptor agonist) to treat autistic children. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'. PMID- 21329711 TI - The 5-HT6 serotonin receptor antagonist SB-271046 attenuates the development and expression of nicotine-induced locomotor sensitisation in Wistar rats. AB - 5-HT(6) receptors are almost exclusively expressed in the central nervous system, particularly in areas relevant for addictive behaviour. Based on this, together with other data, this receptor may be a viable target for the control of drug abuse. The present study tested the ability of the 5-HT(6) receptor antagonist SB 271046 to attenuate the development and expression of nicotine-induced behavioural sensitisation. Rats were habituated to the test apparatus prior to experimentation (day 0) and locomotor activity recorded. On days 1 and 5, animals were placed in locomotor test apparatus and after 30 min injected with SB-271046 (1, 3, and 6 mg/kg, intraperitoneally IP) or vehicle. Thirty minutes later, nicotine (0.4 mg/kg, subcutaneously SC) or saline were administered and activity recorded for 60 min. On days 2, 3 and 4 treatments were performed in the home cage. After 17 days of withdrawal (day 23), a challenge test was performed with nicotine (0.4 mg/kg SC) or saline. In a separate experiment of similar design the effects of SB-271046 (1, 3, and 6 mg/kg IP) was tested for its ability to reduce the expression of behavioural sensitisation (day 23). SB-271046 dose dependently reduced the development and expression of nicotine sensitisation vs respective controls. In conclusion, the 5-HT(6) receptor antagonist SB-271046 reduced both the development and expression of nicotine sensitisation, suggesting that the 5 HT(6) receptor may be a viable target for the control of nicotine abuse. Further studies are warranted to substantiate this conclusion and further understand the role of 5-HT(6) receptors in addiction. PMID- 21329712 TI - Functional neuroimaging studies of prospective memory: what have we learnt so far? AB - The complexity of the behaviour described by the term "prospective memory" meant that it was not at all clear, when the earliest studies were conducted, that this would prove a fruitful area for neuroimaging study. However, a consistent relation rapidly emerged between activation in rostral prefrontal cortex (approximating Brodmann Area 10) and performance of prospective memory paradigms. This consistency has greatly increased the accumulation of findings, since each study has offered perspectives on the previous ones. Considerable help too has come from broad agreement between functional neuroimaging findings and those from other methods (e.g. human lesion studies, electrophysiology). The result has been a quite startling degree of advance given the relatively few studies that have been conducted. These findings are summarised, along with those from other brain regions, and new directions suggested. Key points are that there is a medial lateral dissociation within rostral PFC. Some (but not all) regions of medial rostral PFC are typically more active during performance of the ongoing task only, and lateral aspects are relatively more active during conditions involving delayed intentions. Some of these rostral PFC activations seem remarkably insensitive to the form of stimulus material presented, the nature of the ongoing task, the specifics of the intention, how easy or hard the PM cue is to detect, or the intended action is to recall. However there are other regions within rostral PFC where haemodynamic changes vary with alterations in these, and other, aspects of prospective memory paradigms. It is concluded that rostral PFC most likely plays a super-ordinate role during many stages of creating, maintaining and enacting delayed intentions, which in some cases may be linked to recent evidence showing that this brain region is involved in the control of stimulus oriented vs. stimulus-independent attending. Other key brain regions activated during prospective memory paradigms appear to be the parietal lobe, especially Brodmann Area (BA) 40 and precuneus (BA 7), and the anterior cingulate (BA 32). These regions are often co-activated with lateral rostral PFC across a wide range of tasks, not just those involving prospective memory. PMID- 21329714 TI - Esterification of okadaic acid in the mussel Mytilus galloprovincialis. AB - Okadaic acid and other toxins of the diarrheic shellfish poisoning (DSP) group are transformed mainly to their acyl-derivatives in bivalves. Some recent studies suggest that bacteria present in the bivalve gut could contribute substantially to the acylation of the toxins. By feeding microcapsules containing okadaic acid to mussels we have shown unequivocally that the ingested okadaic acid is nearly completely transformed to its fatty acid esters (acyl-derivatives). Treating mussels with antibiotics did not have any significant effect on the acylation of the supplied okadaic acid, suggesting that bacteria do not play any significant role in this process. The microsomal and mitochondrial subcellular fractions of the cells of the digestive gland have been shown to have contain enzymes that are able to transfer a fatty acid molecule from Coenzyme A to okadaic acid (so, that have Acyl-CoA:OA acyltransferase activity). This activity was related to that of the enzyme Cytochrome C reductase (NADPH), a marker of endoplasmic reticulum, suggesting that this organelle is the main responsible for the acylation process. Acylation of DSP toxins seems to be a key step in the depuration of these toxins from mussels, as these compounds are found in feces as acyl-derivatives. This is probably true for most bivalves. The proportion of acyl-derivatives accumulated can point to the key process of the depuration: acylation or excretion of acylated derivatives. In the mussels Mytilus galloprovincialis, Mytilus edulis and in Donax trunculus, the first process seems to be the most important, but in most bivalve species it seems to be the second one. Other aspects of the relationship between depuration and acylation are also discussed. PMID- 21329713 TI - The tale of a resting gland: transcriptome of a replete venom gland from the scorpion Hottentotta judaicus. AB - cDNA libraries are increasingly being used for high-throughput interrogation of animal venomes. Most previous studies have focused on discovery of new venom toxins, whereas the dynamics of toxin transcription and associated cellular processes have received much less attention. Here we provide, for the first time, an analysis of a transcriptome from the venom gland of a scorpion (Hottentotta judaicus) that is not actively engaged in regenerating its venom. We demonstrate a low abundance of toxin-encoding transcripts coupled with a previously unobserved proliferation of protease sequences. Additionally, we identified several low abundance, toxin-like sequences that may represent decommissioned toxins that are unlikely to be translated. These sequences are not evenly distributed across all toxin families, but rather appear more frequently in transcripts related to alpha-toxins and beta-toxins that are known to target voltage-gated sodium channels. The transcriptomic profile of the replete venom gland is very different to that obtained previously from scorpion venom glands actively engaged in venom regeneration, and it highlights our lack of knowledge as to how the dynamics of transcription changes as the gland progresses from venom regeneration to a "resting" state. This study therefore provides an important foundation for future studies into the dynamics of transcription in the venom glands of scorpions and other venomous animals. PMID- 21329715 TI - Isolation and molecular cloning of beta-neurotoxins from the venom of the scorpion Centruroides suffusus suffusus. AB - This communication reports the identification and characterization of two new toxins from the venom of the scorpion Centruroides suffusus suffusus, named: CssVIII and CssIX, according to the original nomenclature of toxins previously described for this scorpion. The isolation was obtained by means of two chromatographic steps, and a cDNA library was used to fully identify their precursors. CssVIII and CssIX contain signal peptides of 19 and 17 amino acid residues, and mature peptides of 66 and 65 residues, respectively. Intracranial injections into mice of both purified toxins showed toxicity results similar to those found for toxins CssII and CssIV. Additionally, they compete with the parent toxin CssIV, in binding and displacement experiments, conducted with brain synaptosomes showing nanomolar affinities. These results strongly support the conclusion that they are new beta-neurotoxins and certainly would be of the interest of researchers in the field of venomics for studying sodium channels. PMID- 21329717 TI - Distinguishing the cyanobacterial neurotoxin beta-N-methylamino-L-alanine (BMAA) from other diamino acids. AB - beta-N-methylamino-L-alanine (BMAA) is produced by diverse taxa of cyanobacteria, and has been detected by many investigators who have searched for it in cyanobacterial blooms, cultures and collections. Although BMAA is distinguishable from proteinogenic amino acids and its isomer 2,4-DAB using standard chromatographic and mass spectroscopy techniques routinely used for the analysis of amino acids, we studied whether BMAA could be reliably distinguished from other diamino acids, particularly 2,6-diaminopimelic acid which has been isolated from the cell walls of many bacterial species. We used HPLC-FD, UHPLC-UV, UHPLC MS, and triple quadrupole tandem mass spectrometry (UHPLC-MS/MS) to differentiate BMAA from the diamino acids 2,6-diaminopimelic acid, N-2(amino)ethylglycine, lysine, ornithine, 2,4-diaminosuccinic acid, homocystine, cystine, tryptophan, as well as other amino acids including asparagine, glutamine, and methionine methylsulfonium. PMID- 21329716 TI - Recombinant snake venom cystatin inhibits the growth, invasion and metastasis of B16F10 cells and MHCC97H cells in vitro and in vivo. AB - Studies have shown that expression of snake venom cystatin (sv-cystatin) in mouse melanoma cells and human gastric carcinoma cells can inhibit their invasion and metastasis. To advance the research into the biological features and pharmaceutical applications of sv-cystatin, we investigated the expression of recombinant sv-cystatin in an optimized Pichia pastoris system. Approximately 5 mg/L of bioactive sv-cystatin was obtained with a purity of 95.08%. Kinetic analyses of recombinant sv-cystatin revealed highly effective inhibitory efficiency against papain (Ki = 2.67 nM). We further investigated the effects of recombinant sv-cystatin on the invasion and metastasis of B16F10 cells and MHCC97H cells in vitro and in vivo. Matrigel invasion assays showed significant inhibition of recombinant sv-cystatin on the tumor cells in vitro. For experimental lung colonization assays, C57BL/6 mice inoculated in the lateral tail vein with B16F10 cells were treated with three i.v. injections of recombinant sv-cystatin (25 and 50 mg/kg) 24 h before cell inoculation, and 2 h and 24 h after cell inoculation. Administration of recombinant sv-cystatin significantly suppressed the formation of lung tumor colonies. For spontaneous metastasis assays, MHCC97H cells were inoculated s.c. into nude mice. After 24 h, recombinant sv-cystatin was administered by i.p. injections at 25, 50 or 100 mg/kg once daily for 5 days. Administration of recombinant sv-cystatin significantly decreased the formation of lung tumor colonies. Taken together, recombinant sv-cystatin inhibits the invasion and metastasis of tumor cells in vitro and in vivo. These results may facilitate the future evaluation of the pharmaceutical applications of sv-cystatin. PMID- 21329718 TI - Beyond multiple pattern analyzers modeled as linear filters (as classical V1 simple cells): useful additions of the last 25 years. AB - This review briefly discusses processes that have been suggested in the last 25 years as important to the intermediate stages of visual processing of patterns. Five categories of processes are presented: (1) Higher-order processes including FRF structures; (2) Divisive contrast nonlinearities including contrast normalization; (3) Subtractive contrast nonlinearities including contrast comparison; (4) Non-classical receptive fields (surround suppression, cross orientation inhibition); (5) Contour integration. PMID- 21329720 TI - Structural features and in vivo antitussive activity of the water extracted polymer from Glycyrrhiza glabra. AB - Antitussive drugs are amongst the most widely used medications worldwide; however no new class of drugs has been introduced into the market for many years. Herein, we have analyzed the water-extracted polymeric fraction (WE) of Glycyrrhiza glabra. This arabinogalactan protein enriched fraction, >= 85% of which gets precipitated with Yariv reagent, consisted mainly of 3- and 3,6-linked galactopyranosyl, and 5- and 3,5-linked arabinofuranosyl residues. Peroral administration of this polymer in a dose of 50mg/kg body weight decreases the number of citric acid induced cough efforts in guinea pigs more effectively than codeine. It does not induce significant change in the values of specific airway resistance or provoked any observable adverse effects. PMID- 21329719 TI - Visual cognition. AB - Visual cognition, high-level vision, mid-level vision and top-down processing all refer to decision-based scene analyses that combine prior knowledge with retinal input to generate representations. The label "visual cognition" is little used at present, but research and experiments on mid- and high-level, inference-based vision have flourished, becoming in the 21st century a significant, if often understated part, of current vision research. How does visual cognition work? What are its moving parts? This paper reviews the origins and architecture of visual cognition and briefly describes some work in the areas of routines, attention, surfaces, objects, and events (motion, causality, and agency). Most vision scientists avoid being too explicit when presenting concepts about visual cognition, having learned that explicit models invite easy criticism. What we see in the literature is ample evidence for visual cognition, but few or only cautious attempts to detail how it might work. This is the great unfinished business of vision research: at some point we will be done with characterizing how the visual system measures the world and we will have to return to the question of how vision constructs models of objects, surfaces, scenes, and events. PMID- 21329721 TI - Nucleus incertus--an emerging modulatory role in arousal, stress and memory. AB - A major challenge in systems neuroscience is to determine the underlying neural circuitry and associated neurotransmitters and receptors involved in psychiatric disorders, such as anxiety and depression. A focus of many of these studies has been specific brainstem nuclei that modulate levels of arousal via their ascending monoaminergic projections (e.g. the serotonergic dorsal raphe, noradrenergic locus ceruleus and cholinergic laterodorsal tegmental nucleus). After years of relative neglect, the subject of recent studies in this context has been the GABAergic nucleus incertus, which is located in the midline periventricular central gray in the 'prepontine' hindbrain, with broad projections throughout the forebrain. Nucleus incertus neurons express receptors for the stress hormone, corticotropin-releasing factor (CRF), are activated by psychological stressors, and project to key nuclei involved in stress responses and behavioral activation. The nucleus incertus is also a node in neural circuits capable of modulating hippocampal theta rhythm, which is related to control of spatial navigation and memory. A significant population of nucleus incertus neurons express the recently discovered, highly conserved neuropeptide, relaxin 3; and the recent availability of structurally-related, chimeric peptides that selectively activate or inhibit the relaxin-3 receptor, RXFP3, is facilitating studies of relaxin-3/RXFP3 networks and associated GABA and CRF systems. It is predicted that such targeted research will help elucidate the functions of ascending nucleus incertus pathways, including their possible involvement in arousal (sleep/wakefulness), stress reponses, and learning and memory; and in the pathology of related psychiatric diseases such as insomnia, anxiety and depression, and cognitive deficits. PMID- 21329723 TI - Exposure to iodomethane and dichloromethane associated with a confusional state. AB - Dichloromethane and iodomethane are colorless relatively volatile liquids, which are used as solvents in chemical manufacturing processes. The major route of exposure is via inhalation and to a lesser extent through the skin and digestive tract. Both substances are characterized by significant neurotoxic effects. A 37 year-old chemist subjected to long-term inhalation exposure to both substances had been experiencing headaches, dizziness and fatigue for about 5 years. After an exceptional acute exposure, the man developed ataxia, increasing inhibition and a confusional and delirious state. Magnetic resonance imaging (MRI) of his brain in the acute state demonstrated the presence of a T2-hyperintense lesion in the splenium of the corpus callosum, suggestive as myelinolysis. On MRI 16 days later, the MRI changes had completely resolved and the clinical picture had improved significantly. To the best of our knowledge, this is the first published report of a case of "reversible focal splenial lesion syndrome of the corpus callosum", which was likely caused by industrial toxic substances. PMID- 21329722 TI - Development of auditory cortical synaptic receptive fields. AB - The central nervous system is plastic throughout life, but is most sensitive to the statistics of the sensory environment during critical periods of early postnatal development. In the auditory cortex, various forms of acoustic experience have been found to shape the formation of receptive fields and influence the overall rate of cortical organization. The synaptic mechanisms that control cortical receptive field plasticity are beginning to be described, particularly for frequency tuning in rodent primary auditory cortex. Inhibitory circuitry plays a major role in critical period regulation, and new evidence suggests that the formation of excitatory-inhibitory balance determines the duration of critical period plasticity for auditory cortical frequency tuning. Cortical inhibition is poorly tuned in the infant brain, but becomes co-tuned with excitation in an experience-dependent manner over the first postnatal month. We discuss evidence suggesting that this may be a general feature of the developing cortex, and describe the functional implications of such transient excitatory-inhibitory imbalance. PMID- 21329724 TI - Neurological complications of HIV infection in critically ill patients: clinical features and outcomes. AB - OBJECTIVE: We aimed to investigate the prognosis of HIV-infected patients with acute neurological complications at the highly active antiretroviral therapy (HAART) era. METHODS: We performed a retrospective study in HIV-infected patients admitted to a medical ICU with neurological complications between 2001 and 2008. RESULTS: Among the 210 studied patients (median [interquartile range] CD4-cell count: 80 [18-254]/MUL; HIV viral load: 4.8 [2-5.3] log10/mL), 40 (19%) had unknown HIV status at admission. Neurological complications consisted in delirium (45%), coma (39%), seizures (32%) and/or intracranial hypertension (21%). Admission diagnoses were AIDS-defining CNS disease for 88 (42%) patients, non AIDS-defining CNS disease for 45 (21%), and systemic disease with neurological signs for 77 (37%). Seizures (p=0.003), focal deficit (p<0.001) and intracranial hypertension (p<0.001) were more frequently observed in patients with AIDS defining CNS disease. Factors independently associated with ICU mortality (29.5%) were intracranial hypertension [odds ratio (OR), 5.09; 95% confidence interval (95% CI), 2.17-11.91], vasopressor use [OR, 3.92; 95% CI, 1.78-8.60] and SAPS II score [per 10-point increment, OR, 1.59; 95% CI, 1.31-1.93]. CONCLUSIONS: Prognosis of HIV-infected patients with neurological complications depends rather on clinical presentation than on HIV-related parameters. Intracranial hypertension symptoms at admission have a major impact on outcome. PMID- 21329725 TI - Tenofovir discontinuation could predispose to urolithiasis in atazanavir-treated patients. PMID- 21329726 TI - Effects of serum response factor (SRF) deletion on conditioned reinforcement. AB - Serum response factor (SRF) is a ubiquitously expressed stimulus-dependent transcription factor that regulates gene expression by binding to serum response element in the promoter region of target genes. Recent studies in mice have shown that SRF is important for activity-dependent gene expression and synaptic plasticity in the adult brain but is dispensable for neuronal survival. Given these important functions of SRF in the CNS, it is expected to play a critical role in several aspects of learning and memory. Here we evaluated the role of SRF in conditioned reinforcement using two lines of conditional SRF mutant mice. These SRF mutant mice exhibited different spatial patterns of SRF deletion in the post-natal forebrain and notably within the hippocampus. SRF deletion was more widespread in SRF-CKCre mutants than in SRF-SynCre mutants, particularly in areas of the cortex and striatum. Mutant and wild-type mice were trained to associate one auditory cue (CS+) with reward, whereas a second cue remained relatively neutral (CS-). All mice readily acquired this discrimination, entering the food cup during CS+ but not during CS-. In a subsequent test of conditioned reinforcement, in the absence of food, wild-type control mice and SRF-SynCre mice learned to selectively perform an instrumental response that yielded CS+ presentation rather than another response that produced CS-. SRF-CKCre mutants failed to show this preferential responding for CS+. These results suggest a role for SRF in conditioned reinforcement, a manifestation of incentive learning that has been implicated in many aspects of adaptive and maladaptive behavior, such as substance abuse and eating disorders. PMID- 21329727 TI - Possible involvement of PACAP and PACAP type 1 receptor in GnRH-induced FSH beta subunit gene expression. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor, PACAP type 1 receptor (PAC1-R) play an important role in the induction of pituitary gonadotropins. In this present study, we examined whether the PAC1-R was involved in the action of gonadotropin-releasing hormone (GnRH) on gonadotropin FSHbeta subunit expression. In a static culture, GnRH stimulation significantly increased PAC1-R expression as well as PACAP gene expression in the gonadotroph cell line, LbetaT2. Stimulation with low frequency GnRH pulses, which preferentially increase FSHbeta, increased the expression of both the PAC1-R and the PACAP genes to a greater extent than did high frequency pulses. In the determination of transcriptional activity, the GnRH antagonist, cetrotide inhibited GnRH-induced FSHbeta promoter activity completely, but PACAP6-38, a PACAP antagonist, had no effect on GnRH-induced FSHbeta promoter activity. As expected, PACAP-induced FSHbeta promoter activity was significantly prevented by PACAP6-38, but was not affected by cetrotide. PACAP6-38, however, significantly prevented GnRH-increased FSHbeta mRNA expression. These observations suggest that GnRH-induced FSHbeta gene expression is stimulated partially through PAC1-R by gonadotrophs producing PACAP or PAC1-R. PMID- 21329728 TI - Cell cycle regulation and proliferation in lichen sclerosus. AB - INTRODUCTION: Genital lichen sclerosus (LS) is considered a potential precursor lesion of squamous cell carcinoma. We aimed to investigate the expression pattern of cell cycle regulators, tumour suppressor proteins and proliferation markers in genital LS as compared to extragenital LS (ELS) and healthy controls (HC). METHODS: In order to assess the expression of minichromosome maintenance protein 3 (MCM3), MCM7, Ki-67, cyclin D1, cyclin E, p16, p21, and p53, immunohistochemistry and immunofluorescence were performed on skin specimens obtained from the genital region of LS patients (short-standing LS, n=19; long standing LS, n=15), patients with ELS (n=10), and HC (n=8). RESULTS: Median protein expression of MCM3 and Ki-67 was significantly higher in LS when compared to ELS and HC. In patients with long-standing LS, the expression profiles of MCM3 and Ki-67 significantly correlated. Moreover, long-standing LS lesions showed significantly increased expression of p53 when compared to short-standing LS, ELS, and HS. Immunoreactivity of MCM7, p16, p21, cyclin D1 and cyclin E did not significantly differ between the groups. CONCLUSIONS: Tumour suppressor proteins such as p53 are significantly overexpressed in genital LS when compared to extragenital disease and healthy skin. The significant p53 overexpression, particularly in long-standing genital lesions, may reflect the increased risk of malignant transformation and/or oxidative stress associated with LS. Moreover, we have demonstrated that proliferation markers such as Ki-67 and MCM3 are significantly up-regulated in genital LS as compared to controls. With regard to cell cycle regulation and proliferation rates, ELS significantly differs from its genital counterpart. PMID- 21329729 TI - Increased arginine-vasopressin response to hypertonic stimulation and upright posture in idiopathic hyperprolactinemia. AB - To evaluate the possible influence of idiopathic hyperprolactinemia on the arginine-vasopressin (AVP) response to osmotic and pressure-volumetric stimuli, 14 idiopathic hyperprolactinemic women and 13 normoprolactinemic women were studied during a hypertonic saline infusion test (0.51M NaCl infusion for 2h) and an orthostatic test (standing upright and maintaining an orthostatic position for 20min). In both experimental conditions, the AVP response was significantly higher in women with idiopathic hyperprolactinemia than in normal normoprolactinemic women. These results indicate that in women hyperprolactinemia influences the AVP response to hyperosmotic and hypovolemic stimuli. PMID- 21329730 TI - TRPV1, NK1 receptor and substance P immunoreactivity and gene expression in the rat lumbosacral spinal cord and urinary bladder after systemic, low dose vanilloid administration. AB - Transient receptor potential vanilloid 1 (TRPV1), neurokinin 1 (NK1) receptor and substance P (SP) immunoreactivity (-ir) and mRNA in the rat lumbosacral spinal cord and urinary bladder were measured 24h after s.c. injection of the vanilloids, capsaicin (50mg/kg) and resiniferatoxin (RTX, 100MUg/kg), or vehicle (10% ethanol/10% Tween 80/saline). In the spinal cord, capsaicin significantly reduced TRPV1 and SP-ir (40-45%) in laminae I/II compared to controls, while RTX produced decreases of ~35%. NK1-ir in the spinal cord was unaffected by both vanilloid treatments. In the bladder, SP-ir was reduced in urothelial cells of some capsaicin- and RTX-treated rats, while SP-ir in the suburothelium and muscularis was significantly reduced by RTX. A significant increase in NK1-ir was observed in the urothelium and muscularis after capsaicin administration. Capsaicin significantly increased SP mRNA in the spinal cord, and TRPV1 and SP mRNA in the bladder, whereas RTX increased TRPV1, SP and NK1 mRNA in the spinal cord, and TRPV1 and SP mRNA in the bladder. These data suggest that stimulation of TRPV1 by low dose vanilloid administration can rapidly (within 24h) alter both transcription and translation of TRPV1 channels, SP and NK1 receptors in the rat urinary bladder and spinal cord. PMID- 21329731 TI - A 4-arm polyethylene glycol derivative conjugated with exendin-4 peptide and palmitylamine having dual-function of size-increase and albumin-binding for long hypoglycemic action. AB - PEGylation and albumin binding are viewed as the most effective ways of prolonging the lifespans of short-lived peptides by delaying renal filtration. Here, we describe a derivative of exendin-4 with pharmaceutical benefits produced using both techniques. This exendin-4 derivative is based on a 4-arm PEG(20k) conjugated with two exendin-4s and two palmitylamines on its arms. PEG and palmitylamine were chosen to increase molecular size and bind to albumin, respectively. This derivative (Ex4-PEG-C16) was found to have larger molecular size (169kDa) than actual (28.9kDa) by size-exclusion chromatography and acceptable binding capability (~90%) to immobilized-albumin. Although the receptor-binding of Ex4-PEG-C16 to RIN-m5F cells was significantly lower than that of exendin-4, its acute anti-hyperglycemic efficacy was equivalent to that of exendin-4 in type 2 diabetic db/db mice. Furthermore, Ex4-PEG-C16 displayed a >6-fold increase in AUC and circulating t(1/2)vs. exendin-4. Due to this improvement, its hypoglycemic duration was greatly increased to 18.6h at a dose 250nmol/kg as compared with exendin-4 (8.7h). Our results show that the combined technique of PEGylation and albumin binding was effective when applied to exendin 4. We believe that this exendin-4 derivative has considerable pharmaceutical potential as a novel type 2 anti-diabetic systemic treatment. PMID- 21329732 TI - Dendroaspis natriuretic peptide is the most potent natriuretic peptide to cause relaxation of lower esophageal sphincter. AB - Atrial natriuretic peptide (ANP) causes relaxation in the opossum lower esophageal sphincter. The effects of dendroaspis natriuretic peptide (DNP) and other natriuretic peptides in the lower esophageal sphincter were not known. We measured the relaxation of transverse strips from the guinea pig lower esophageal sphincter caused by DNP, ANP, brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and a natriuretic peptide receptor-C agonist des[Gln(18), Ser(19), Gly(20), Leu(21), Gly(22)]ANP(4-23) amide (cANF(4-23)) in vitro. In resting strips of the guinea pig lower esophageal sphincter DNP and BNP caused marked relaxations. Furthermore, in both sarafotoxin S6c and carbachol-contracted lower esophageal sphincter strips, DNP caused marked and BNP caused moderate, concentration-dependent relaxations. ANP as well as CNP caused mild relaxations. In contrast, cANF(4-23) did not cause relaxation. The relative potencies for natriuretic peptides to cause relaxation were DNP>BNP>ANP>=CNP in both sarafotoxin S6c and carbachol-contracted lower esophageal sphincter strips. The DNP and BNP-induced relaxations were not affected by tetrodotoxin or atropine, suggesting that the natriuretic peptide-induced response was not neutrally mediated. In conclusion, these results demonstrate that natriuretic peptides cause the relaxation of the guinea pig lower esophageal sphincter. DNP is the most potent natriuretic peptide to cause lower esophageal sphincter relaxation, which might be mediated by natriuretic peptide receptor-A or a novel DNP selective natriuretic peptide receptor. PMID- 21329733 TI - Oral delivery of octreotide acetate in Intravail(r) improves uptake, half-life, and bioavailability over subcutaneous administration in male Swiss webster mice. AB - The most effective option for the medical treatment of patients with acromegaly is the use of somatostatin analogs. Octreotide acetate is a synthetic analog of somatostatin, with similar effects but a prolonged duration of action. Octreotide acetate is routinely given by subcutaneous (s.c.) or intramuscular injection. In the present study, we examined the feasibility of oral delivery of octreotide acetate reconstituted with increasing concentrations (0.5%, 1.5% and 3.0%) of Intravail(r), a patented alkylsaccharide transmucosal absorption enhancing agent. The pharmacokinetics of orally delivered (by gavage) octreotide acetate in Intravail(r) were compared to those of octreotide acetate administered subcutaneously in sodium acetate buffer to male Swiss Webster mice. Oral delivery of octreotide acetate in 0.5% Intravail(r) significantly enhanced total uptake (1254.08ng/ml/min vs. 311.63ng/ml/min, respectively), serum half-life (52.1min vs. 1.3min, respectively), and relative bioavailability (4.0 vs. 1.0, respectively) when compared to delivery by s.c. injection. Higher concentrations of Intravail (r)did not further enhance uptake, serum half-life, or bioavailability. The results of this study indicate that oral delivery of octreotide acetate in Intravail(r)is feasible, and is an effective method of administration which significantly improves uptake, bioavailability and half-life when compared to s.c. injection. Thus, oral delivery of octreotide acetate in Intravail(r) may have significant potential as a novel, non-invasive approach to the treatment of acromegaly and octreotide-mediated symptoms of carcinoid and VIP secreting tumors. PMID- 21329735 TI - Quantification of viable Legionella pneumophila cells using propidium monoazide combined with quantitative PCR. AB - One of the greatest challenges of implementing fast molecular detection methods as part of Legionella surveillance systems is to limit detection to live cells. In this work, a protocol for sample treatment with propidium monoazide (PMA) in combination with quantitative PCR (qPCR) has been optimized and validated for L. pneumophila as an alternative of the currently used time-consuming culture method. Results from PMA-qPCR were compared with culture isolation and traditional qPCR. Under the conditions used, sample treatment with 50 MUM PMA followed by 5 min of light exposure were assumed optimal resulting in an average reduction of 4.45 log units of the qPCR signal from heat-killed cells. When applied to environmental samples (including water from cooling water towers, hospitals, spas, hot water systems in hotels, and tap water), different degrees of correlations between the three methods were obtained which might be explained by different matrix properties, but also varying degrees of non-culturable cells. It was furthermore shown that PMA displayed substantially lower cytotoxicity with Legionella than the alternative dye ethidium monoazide (EMA) when exposing live cells to the dye followed by plate counting. This result confirmed the findings with other species that PMA is less membrane-permeant and more selective for the intact cells. In conclusion, PMA-qPCR is a promising technique for limiting detection to intact cells and makes Legionella surveillance data substantially more relevant in comparison with qPCR alone. For future research it would be desirable to increase the method's capacity to exclude signals from dead cells in difficult matrices or samples containing high numbers of dead cells. PMID- 21329734 TI - Visfatin exerts angiogenic effects on human umbilical vein endothelial cells through the mTOR signaling pathway. AB - The biologically active factors known as adipocytokines are secreted primarily by adipose tissues and can act as modulators of angiogenesis. Visfatin, an adipocytokine that has recently been reported to have angiogenic properties, is upregulated in diabetes, cancer, and inflammatory diseases. Because maintenance of an angiogenic balance is critically important in the management of these diseases, understanding the molecular mechanism by which visfatin promotes angiogenesis is very important. In this report, we describe our findings demonstrating that visfatin stimulates the mammalian target of the rapamycin (mTOR) pathway, which plays important roles in angiogenesis. Visfatin induced the expression of hypoxia-inducible factor 1alpha (HIF1alpha) and vascular endothelial growth factor (VEGF) in human endothelial cells. Inhibition of the mTOR pathway by rapamycin eliminated the angiogenic and proliferative effects of visfatin. The visfatin-induced increase in VEGF expression was also eliminated by RNA interference-mediated knockdown of the 70-kDa ribosomal protein S6 kinase (p70S6K), a downstream target of mTOR. Visfatin inactivated glycogen synthase kinase 3beta (GSK3beta) by phosphorylating it at Ser-9, leading to the nuclear translocation of beta-catenin. Both rapamycin co-treatment and p70S6K knockdown inhibited visfatin-induced GSK3beta phosphorylation at Ser-9 and nuclear translocation of beta-catenin. Taken together, these results indicate that mTOR signaling is involved in visfatin-induced angiogenesis, and that this signaling leads to visfatin-induced VEGF expression and nuclear translocation of beta catenin. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. PMID- 21329736 TI - Interference by pigment in the estimation of microalgal biomass concentration by optical density. AB - Optical density is used as a convenient indirect measurement of biomass concentration in microbial cell suspensions. Absorbance of light by a suspension can be related directly to cell density using a suitable standard curve. However, inaccuracies can be introduced when the pigment content of the cells changes. Under the culture conditions used, pigment content of the microalga Chlorella vulgaris varied between 0.5 and 5.5% of dry weight with age and culture conditions. This led to significant errors in biomass quantification over the course of a growth cycle, due to the change in absorbance. Using a standard curve generated at a single time point in the growth cycle to calculate dry weight (dw) from optical density led to average relative errors across the growth cycle, relative to actual dw, of between 9 and 18% at 680 nm and 5 and 13% at 750 nm. When a standard curve generated under low pigment conditions was used to estimate biomass under normal pigment conditions, average relative errors in biomass estimation relative to actual dw across the growth cycle were 52% at 680 nm and 25% at 750 nm. Similar results were found with Scenedesmus, Spirulina and Nannochloropsis. Suggested strategies to minimise error include selection of a wavelength that minimises absorbance by the pigment, e.g. 750 nm where chlorophyll is the dominant pigment, and generation of a standard curve towards the middle, or across the entire, growth cycle. PMID- 21329737 TI - Rapid identification of Salmonella enterica serovars, Typhimurium, Choleraesuis, Infantis, Hadar, Enteritidis, Dublin and Gallinarum, by multiplex PCR. AB - Salmonella enterica subsp. enterica poses a threat to both human and animal health, with more than 2500 serovars having been reported to date. Salmonella serovars are identified by slide and tube agglutination tests using O and H antigen-specific anti-sera, although this procedure is both labor intensive and time consuming. Establishment of a method for rapid screening of the major Salmonella serovars is therefore required. We have established multiplex polymerase chain reaction (m-PCR) assays for identification of seven serovars of Salmonella, i.e., Typhimurium, Choleraesuis, Infantis, Hadar, Enteritidis, Dublin and Gallinarum. Three serovar-specific genomic regions (SSGRs) of each serovar were selected using an approach in comparative genomics. The Salmonella-specific invA gene was used to confirm the genetic background of the organisms. The isolates tested were identified as a target serovar when the three selected SSGRs and invA were all positive for amplification. The specificity of each m-PCR assay was investigated using 118 serovars of Salmonella and 12 species of non Salmonella strains. Although a small number of false-positive results were observed in the m-PCR assays used to identify Typhimurium, Choleraesuis, Enteritidis and Dublin for closely related serovars, false-negative results were not observed in any assays. These assays had sufficient specificity to identify the seven Salmonella serovars, and therefore, have the potential for use as rapid screening methods. PMID- 21329738 TI - Enumeration of Vibrio parahaemolyticus in the viable but nonculturable state using direct plate counts and recognition of individual gene fluorescence in situ hybridization. AB - Vibrio parahaemolyticus is a gram-negative, halophilic bacterium indigenous to marine and estuarine environments and it is capable of causing food and water borne illness in humans. It can also cause disease in marine animals, including cultured species. Currently, culture-based techniques are used for quantification of V. parahaemolyticus in environmental samples; however, these can be misleading as they fail to detect V. parahaemolyticus in a viable but nonculturable (VBNC) state which leads to an underestimation of the population density. In this study, we used a novel fluorescence visualization technique, called recognition of individual gene fluorescence in situ hybridization (RING-FISH), which targets chromosomal DNA for enumeration. A polynucleotide probe labeled with Cyanine 3 (Cy3) was created corresponding to the ubiquitous V. parahaemolyticus gene that codes for thermolabile hemolysin (tlh). When coupled with the Kogure method to distinguish viable from dead cells, RING-FISH probes reliably enumerated total, viable V. parahaemolyticus. The probe was tested for sensitivity and specificity against a pure culture of tlh(+), tdh(-), trh(-)V. parahaemolyticus, pure cultures of Vibrio vulnificus, Vibrio harveyi, Vibrio alginolyticus and Vibrio fischeri, and a mixed environmental sample. This research will provide additional tools for a better understanding of the risk these environmental organisms pose to human health. PMID- 21329739 TI - First genomic analysis of the broad-host-range Rhizobium sp. LPU83 strain, a member of the low-genetic diversity Oregon-like Rhizobium sp. group. AB - Alfalfa (Medicago sativa) is the most cultivated forage legume for cattle and animal feeding, occupying about 32 million hectares over the world. Management of the N2-fixing symbiosis of this plant to maximize crop production is therefore an important objective. A fundamental constraint to this aim emerges when a moderately low soil pH hampers the establishment of an effective symbiosis with indigenous and/or inoculated rhizobia. Besides the association of alfalfa with Ensifer (Sinorhizobium) meliloti, this legume is able to establish a symbiosis with Ensifer (Sinorhizobium) medicae and with less characterized types of rhizobia, such as the Oregon-like strains, Rhizobium sp. Or191 initially isolated in the USA, and the Rhizobium sp. LPU83 strain, from Argentina. These strains are acid-tolerant, highly competitive for acidic-soil-alfalfa nodulation, but inefficient for biological nitrogen fixation with alfalfa. These features position the Oregon-like rhizobia as strains of potential risk in agricultural soils compared with the efficient symbiont E. meliloti. Moreover, the collected genetic information has revealed that the genomic structure of these rhizobial isolates is complex in terms of sequence similarities shared with other rhizobia. Such a "patched" genetic composition has obviously imposed severe restrictions to the classical taxonomy of these rhizobia. In this work we summarize the accumulated knowledge about the Oregon-like rhizobia and present a phylogenetic analysis based on genome sequence data of Rhizobium sp. LPU83 obtained by a high throughput sequencing on the Genome Sequencer FLX Titanium platform. The accessibility of the complete genomic sequence will release up more experimental possibilities since this information will then enable biochemical studies as well as proteomics and transcriptomics approaches. PMID- 21329740 TI - Complete genome sequencing of Agrobacterium sp. H13-3, the former Rhizobium lupini H13-3, reveals a tripartite genome consisting of a circular and a linear chromosome and an accessory plasmid but lacking a tumor-inducing Ti-plasmid. AB - Agrobacterium sp. H13-3, formerly known as Rhizobium lupini H13-3, is a soil bacterium that was isolated from the rhizosphere of Lupinus luteus. The isolate has been established as a model system for studying novel features of flagellum structure, motility and chemotaxis within the family Rhizobiaceae. The complete genome sequence of Agrobacterium sp. H13-3 has been established and the genome structure and phylogenetic assignment of the organism was analysed. For de novo sequencing of the Agrobacterium sp. H13-3 genome, a combined strategy comprising 454-pyrosequencing on the Genome Sequencer FLX platform and PCR-based amplicon sequencing for gap closure was applied. The finished genome consists of three replicons and comprises 5,573,770 bases. Based on phylogenetic analyses, the isolate could be assigned to the genus Agrobacterium biovar I and represents a genomic species G1 strain within this biovariety. The highly conserved circular chromosome (2.82 Mb) of Agrobacterium sp. H13-3 mainly encodes housekeeping functions characteristic for an aerobic, heterotrophic bacterium. Agrobacterium sp. H13-3 is a motile bacterium driven by the rotation of several complex flagella. Its behaviour towards external stimuli is regulated by a large chemotaxis regulon and a total of 17 chemoreceptors. Comparable to the genome of Agrobacterium tumefaciens C58, Agrobacterium sp. H13-3 possesses a linear chromosome (2.15 Mb) that is related to its reference replicon and features chromosomal and plasmid-like properties. The accessory plasmid pAspH13-3a (0.6 Mb) is only distantly related to the plasmid pAtC58 of A. tumefaciens C58 and shows a mosaic structure. A tumor-inducing Ti-plasmid is missing in the sequenced strain H13-3 indicating that it is a non-virulent isolate. PMID- 21329741 TI - Potassium channel expression in adult murine neural progenitor cells. AB - Neural progenitor cells (NPCs) are a source of new neurons and glia in the adult brain. Most NPCs reside in the forebrain subventricular zone (SVZ) and in the subgranular zone of the dentate gyrus, where they contribute to plasticity in the adult brain. To use their potential for repair, it is essential to identify the molecules that regulate their growth, migration and differentiation. Potassium (K+) channels are promising molecule candidates for NPC regulation as they are important components of signal transduction and their diversity is ideal to cover the complex functions required for cell proliferation and differentiation. There is increasing evidence that K+ channels influence cell growth and neurogenesis, however, very little is known regarding K+ channel distribution in NPCs. We therefore explored the expression of a variety of voltage-gated (Kv), inwardly rectifying (Kir) and two-pore (K2P) K+ channels in the SVZ of adult mice and in neurosphere cultures of NPCs during growth and differentiation. Immunocytochemical analysis revealed a differential expression pattern of K+ channels in nestin+ SVZ precursor cells, early SVZ doublecortin+ neurons and (sub)ependymal cells. These findings were confirmed in neurosphere cultures at the protein and mRNA levels. The expression of some K+ channel proteins, such as Kir4.1, Kir6.1, TREK1 or TASK1, suggests a role of K+ channels in the complex regulation of NPC proliferation, maturation and differentiation. PMID- 21329742 TI - Fluid-percussion brain injury induces changes in aquaporin channel expression. AB - Edema, the accumulation of excess fluid, is a major pathological change in the brain that contributes significantly to pathology and mortality after moderate to severe brain injury. Edema is regulated by aquaporin (AQP) channels which transport water across cellular membranes. Six AQPs are found in the brain (1, 3, 4, 5, 8, and 9), and previous studies have found that AQP4 is regulated after traumatic brain injury (TBI). To further understand how AQPs contribute to brain edema, we investigated whether expression of AQP1, 3, and 9 are also regulated after TBI. Adult male Sprague Dawley rats received moderate parasagittal fluid percussion brain injury (FPI) or sham surgery. After induction of FPI, the injured, ipsilateral parietal cortex and hippocampus were dissected and analyzed by Western blotting. We observed a small decrease in AQP3 and 4 levels at 7 days after FPI in the ipsilateral, parietal cortex. Both AQP1 and 9 significantly increased within 30 min post-injury and remained elevated for up to 6 h in the ipsilateral, parietal cortex. Aqp1 and 9 mRNA levels were also significantly increased at 30 min post-FPI. Administration of an AQP1 and 4 antagonist, AqB013, non-significantly increased brain water content in sham, non-injured animals, and did not prevent edema formation 24 h after trauma in either the parietal cortex or hippocampus. These results indicate that Aqp1 and 9 mRNA and protein levels increase after moderate parasagittal FPI and that an inhibitor of AQP1 and 4 does not decrease edema after moderate parasagittal FPI. PMID- 21329743 TI - Preproglucagon neurons project widely to autonomic control areas in the mouse brain. AB - Glucagon-like peptide 1 (GLP-1) and its analogue exendin-4 inhibit food intake, reduce blood glucose levels and increase blood pressure and heart rate by acting on GLP-1 receptors in many brain regions. Within the CNS, GLP-1 is produced only by preproglucagon (PPG) neurons. We suggest that PPG neurons mediate the central effects of GLP-1 by modulating sympathetic and vagal outflow. We therefore analysed the projections of PPG neurons to brain sites involved in autonomic control. In transgenic mice expressing yellow fluorescent protein (YFP) under the control of the PPG promoter, we assessed YFP-immunoreactive innervation using an anti-GFP antiserum and avidin-biotin-peroxidase. PPG neurons were intensely YFP immunoreactive and axons could be easily discriminated from dendrites. YFP immunoreactive cell bodies occurred primarily within the caudal nucleus tractus solitarius (NTS) with additional somata ventral to the hypoglossal nucleus, in raphe obscurus and in the intermediate reticular nucleus. The caudal NTS contained a dense network of dendrites, some of which extended into the area postrema. Immunoreactive axons were widespread throughout NTS, dorsal vagal nucleus and reticular nucleus with few in the hypoglossal nucleus and pyramids. The dorsomedial and paraventricular hypothalamic nuclei, ventrolateral periaqueductal grey and thalamic paraventricular nucleus exhibited heavy innervation. The area postrema, rostral ventrolateral medulla, pontine central grey, locus coeruleus/Barrington's nucleus, arcuate nucleus and the vascular organ of the lamina terminalis were moderately innervated. Only a few axons occurred in the amygdala and subfornical organ. Our results demonstrate that PPG neurons innervate primarily brain regions involved in autonomic control. Thus, central PPG neurons are ideally situated to modulate sympathetic and parasympathetic outflow through input at a variety of central sites. Our data also highlight that immunohistochemistry improves detection of neurons expressing YFP. Hence, animals in which specific populations of neurons have been genetically-modified to express fluorescent proteins are likely to prove ideal for anatomical studies. PMID- 21329744 TI - Response preparation and cognitive control of highly intelligent children: a Go Nogo event-related potential study. AB - A cued Go-Nogo task was employed to explore the neural correlation among response preparation, cognitive control and intelligence in two groups of early adolescents with different intellectual levels using event-related potential (ERP) technique. Behavioral results indicated that the gifted children had better cognitive control performances with higher correct hit rate and lower commission error rate than the average children. Electrophysiological results further showed that the gifted children elicited efficient cue-P2 response for automatic cue detection and stronger cue-P3 activation for cue evaluation. Moreover, gifted children induced faster N2 and Nogo-P3 responses for conflict monitoring and inhibition processing and stronger P3 activation for attentional control. The current results supported the neural efficiency hypothesis of intelligence and further shed light on the close relationship among response preparation, cognitive control and human intelligence. PMID- 21329745 TI - Vesicular acetylcholine transporter knock-down mice show sexual dimorphism on memory. AB - The key neural substrates involved in memory and cognitive tasks have been reported to receive important modulation from ovarian hormones. In fact, neurochemical systems associated with cognitive functions, such as the cholinergic system, are, at least in part, under modulation of estrogens. Here we show that vesicular acetylcholine transporter (VAChT) mutant mice, which express lower levels of the VAChT (VAChT KD) and reduced acetylcholine release, present sexual dimorphism on memory. We evaluate short- and long-term object recognition memories (STM and LTM) in both sexes. We have showed previously, and confirm here, that VAChT KDHET male mice present deficits in both STM and LTM object recognition memories in comparison with WT. In contrast, VAChT KDHET female mice present deficit in LTM, but not in STM. To test if the female hormones levels could be a determinant factor on sexual dimorphism observed, we submitted female mice to ovariectomy (OVX) or sham-surgery. After 1 week (1 w), we evaluate STM. Female hormone deprivation promotes STM impairment in VAChT KDHET, but not in WT female mice. Our results strongly suggest that the sexual dimorphism observed in VAChT KDHET mice on STM is due to modulation of cholinergic system by ovarian hormones. PMID- 21329746 TI - A cognitive regulatory control model of schizophrenia. AB - A puzzling aspect of schizophrenia concerns the relationship between negative and positive symptoms. Perspectives suggesting that they arise from the same pathophysiological process are not consistent with the numerous differences such as treatment response, and the underlying neurochemistry relevant to treatment. Explanations viewing negative and positive symptoms as independent processes or diseases cannot readily account for the typical developmental course of schizophrenia, consisting of a lengthy prodromal phase of negative followed by positive symptoms. A model of schizophrenia is presented positing that negative and positive symptoms are distinct but interrelated processes, with the former bringing forth the latter due to damaged or impaired cognitive regulatory control processes. The extensive cognitive distortions, thought form variants, and sensory perceptual experiences comprising psychosis represent a natural propensity derived from the evolution of human intelligence. To facilitate reality congruency typically necessary for adaptive functioning, cognitive regulatory control processes normally prevent these extreme variants from entering the conscious and awake state. During sleep when there is no need for reality congruency the cognitive regulatory control processes are deactivated and psychotic equivalents are expressed. Psychological defensive functioning can also deactivate these processes and allow psychosis to manifest. The negative symptoms of schizophrenia are seen as arising from diverse neural deficits that impair to varying degrees the cognitive regulatory control processes, thus producing psychosis. The pattern of neural damage determines the negative symptom profile, and the impact on cognitive regulatory control processes influences whether negative or positive symptoms dominate or exist in relatively equal proportions. PMID- 21329747 TI - DNA adducts and oxidative DNA damage induced by organic extracts from PM2.5 in an acellular assay. AB - The genotoxic activities of complex mixtures of organic extracts from the urban air particles collected in various localities of the Czech Republic, which differed in the extent and sources of air pollution, were compared. For this purpose, PM2.5 particles were collected by high volume samplers in the most polluted area of the Czech Republic--Ostrava region (localities Bartovice, Poruba and Karvina) and in the locality exhibiting a low level of air pollution--Trebon- a small town in the non-industrial region of Southern Bohemia. To prepare extractable organic matter (EOM), PM2.5 particles were extracted by dichloromethane and c-PAHs contents in the EOMs were determined. As markers of genotoxic potential, DNA adduct levels and oxidative DNA damage (8-oxo-7,8 dihydro-2'-deoxyguanosine, 8-oxodG, levels) induced by EOMs in an acellular assay of calf thymus DNA coupled with 32P-postlabeling (DNA adducts) and ELISA (8 oxodG) in the presence and absence of microsomal S9 fraction were employed. Twofold higher DNA adduct levels (17.20 adducts/108 nucleotides/m3 vs. 8.49 adducts/108 nucleotides/m3) were induced by EOM from Ostrava-Bartovice (immediate proximity of heavy industry) compared with that from Ostrava-Poruba (mostly traffic emissions). Oxidative DNA damage induced by EOM from Ostrava-Bartovice was more than fourfold higher than damage induced by EOM from Trebon (8-oxodG/108 dG/m3: 0.131 vs. 0.030 for Ostrava-Bartovice vs. Trebon, respectively). Since PM2.5 particles collected in various localities differ with respect to their c PAHs content, and c-PAHs significantly contribute to genotoxicity (DNA adduct levels), we suggest that monitoring of PM2.5 levels is not a sufficient basis to assess genotoxicity of respirable aerosols. It seems likely that the industrial emissions prevailing in Ostrava-Bartovice represent a substantially higher genotoxic risk than mostly traffic-related emissions in Ostrava-Poruba. B[a]P and c-PAH contents in EOMs are the most important factors relating to their genotoxic potential. PMID- 21329748 TI - Recombinant paraoxonase 1 protects against sarin and soman toxicity following microinstillation inhalation exposure in guinea pigs. AB - To explore the efficacy of paraoxonase 1 (PON1) as a catalytic bioscavenger, we evaluated human recombinant PON1 (rePON1) expressed in Trichoplusia ni larvae against sarin and soman toxicity using microinstillation inhalation exposure in guinea pigs. Animals were pretreated intravenously with catalytically active rePON1, followed by exposure to 1.2 X LCt50 sarin or soman. Administration of 5 units of rePON1 showed mild increase in the blood activity of the enzyme after 30 min, but protected the animals with a significant increase in survival rate along with minimal signs of nerve agent toxicity. Recombinant PON1 pretreated animals exposed to sarin or soman prevented the reduction of blood O2 saturation and pulse rate observed after nerve agent exposure. In addition, rePON1 pretreated animals showed significantly higher blood PON1, acetylcholinesterase (AChE), and butyrylcholinesterase activity after nerve agent exposure compared to the respective controls without treatments. AChE activity in different brain regions of rePON1 pretreated animals exposed to sarin or soman were also significantly higher than respective controls. The remaining activity of blood PON1, cholinesterases and brain AChE in PON1 pretreated animals after nerve agent exposure correlated with the survival rate. In summary, these data suggest that human rePON1 protects against sarin and soman exposure in guinea pigs. PMID- 21329749 TI - Modulation of CYP1A1 activity by a Ginkgo biloba extract in the human intestinal Caco-2 cells. AB - Ginkgo biloba is a widely consumed dietary supplement. Some dietary active compounds modulate the activity of biotransformation enzymes inside the enterocytes and more interestingly of cytochrome P-450 1A1 (CYP1A1). This enzyme is of a particular interest because of its implication in the metabolism of some exogenous pro-carcinogens or endogenous molecules. In the present work, we have used Caco-2 cells to study the effect of a standard reference material of a Ginkgo biloba extract (GBE) (10-400 MUg/ml), as well as of its major individual active compounds (kaempferol, quercetin, isorhamnetin, ginkgolides and bilobalide), alone or in mixtures, at realistic intestinal concentrations, on the induction of CYP1A1 activity, in the presence or absence of benzo[a]pyrene (B[a]P) (0.1 MUg/ml), a well-known CYP1A1 inducer. 3-O-rutinosides of kaempferol, quercetin and isorhamnetin were also tested. We have demonstrated a strong induction (p < 0.005) of CYP1A1 activity and a slight, but significant (p < 0.005), decrease of this activity in the presence of B[a]P by the GBE at the realistic exposure level of 100 MUg/ml. The inductive effect was explained, in part, by quercetin and kaempferol after 24h exposure while unknown compounds seem to be responsible for the strong CYP1A1 induction observed after 6h exposure. The inhibitory potency of flavonols on CYP1A1 activity in presence of B[a]P was much stronger for the aglycones than for the 3-O-rutinosides, explaining the slight effect observed with the GBE, mainly composed of glycosylated flavonoids. These results indicate that GBEs may disturb intestinal CYP1A1 activity and, in turn, affect the metabolism of other compounds. The present paper thus highlights the necessity to take these side effects into account when administrating Ginkgo biloba herbal supplements. PMID- 21329750 TI - Ion flow in stria vascularis and the production and regulation of cochlear endolymph and the endolymphatic potential. AB - This paper reviews some of what is known about ion transport through the cells of the mammalian stria vascularis, and discusses how the endolymph and endocochlear potential in scala media are produced by the stria's main cell types. It discusses the role of each cells' ion transport proteins from an engineering perspective, and the advantages and disadvantages in using the different transport proteins in the different cells to perform their different roles. To aid this discussion, the use of spreadsheet analysis in the modelling of ion transport in single cells and homogenous epithelia is outlined, including the current-voltage (IV) characteristics of the three main categories of transport proteins (pores, ports and pumps), and the constraint equations that apply under various conditions (the voltage or ionic steady states in the open- and closed circuit conditions). Also discussed are the circulation of K(+) within the cochlea, and the chloride, salt and water balance of scala media and stria vascularis, and what transport processes may be required to maintain such a balance. PMID- 21329751 TI - Unbiased counting of neurons in the cochlea of developing gerbils. AB - Accurate counting of neurons in the cochlea has a significant impact on the interpretation of research and clinically relevant data. However, reports of numbers of neurons in the spiral ganglion are widely variable across studies, even within the same species. We suggest that the implementation of a more standardized, unbiased counting method will improve the consistency and accuracy of neuron counts and will impact scientific interpretations. To test this view, we compared, in different ways, the numbers of neurons in the spiral ganglia of developing gerbils, previously reported to decrease by 22-27% between birth and age 7 days. Cochleae from gerbils, aged newborn, 7 days, 20 days, 1.5 years and 2.5 years were embedded in Araldite and serially sectioned at 5 MUm. A computer based stereological method was used to unambiguously count every neuron in serial sections, either throughout the entire cochlea, or in a 100-MUm segment of the cochlea. No significant changes in neuron numbers during cochlear maturation were found. We demonstrate that in methods using sampling of sections, the identity of the starting section and the interval between sections impacts the variability of the estimate of neuron numbers. In addition, we show that packing density differs between the newborn and seven-day old animals. The data demonstrate that variability in counting methods and the comparison of non-uniform samples can lead to neuron number estimates that show differences where none exist. We propose that a standardized counting protocol be implemented across studies and suggest possible approaches to different types of comparisons between neurons of spiral ganglia from different sources. PMID- 21329752 TI - Development of repetitive behavior in a mouse model: roles of indirect and striosomal basal ganglia pathways. AB - Restricted repetitive behaviors (stereotypy, compulsions, rituals) are diagnostic for autism spectrum disorder and common in related neurodevelopmental disorders. Despite their prevalence in clinical populations, underlying mechanisms associated with the development of these behaviors remain poorly understood. We examined the role of the indirect basal ganglia pathway in the development of stereotypy using deer mice. We measured neuronal metabolic activity in the subthalamic nucleus (STN) and other relevant brain regions using cytochrome oxidase (CO) histochemistry at three developmental time-points. Although no differences were observed in STN across development, significant differences were found when mice were grouped by developmental trajectory. At 6 weeks post weaning, significantly lower CO activity in STN was found in those trajectory groups that developed high levels of repetitive behavior versus the trajectory group that did not, suggesting the development of stereotypy is associated with decreased indirect basal ganglia pathway activity. In addition, we tested the hypothesis that preferential activation of striatal striosomes relative to surrounding matrix would be associated with the development of stereotypy. No differences in the relative activation of these striatal compartments were observed across development or among trajectory groups. Our results point to dynamic changes in the indirect pathway associated with the development of repetitive behavior and extends our prior work linking reduced indirect pathway activation to stereotypy in adult deer mice. PMID- 21329754 TI - Activation of M3 muscarinic receptors inhibits T-type Ca(2+) channel currents via pertussis toxin-sensitive novel protein kinase C pathway in small dorsal root ganglion neurons. AB - Cobrotoxin (CbT), a short-chain postsynaptic alpha-neurotoxin, has been reported to play a role in analgesia. However, to date, the detailed mechanisms still remain unknown. In the present study, we identify a novel functional role of CbT in modulating T-type Ca(2+) channel currents (T-currents) in small dorsal root ganglia (DRG) neurons as well as pain behaviors in mice. We found that CbT inhibited T-currents in a dose-dependent manner. CbT at 1MUM reversibly inhibited T-currents by ~26.3%. This inhibitory effect was abolished by the non-selective muscarinic acetylcholine receptor (mAChR) antagonist atropine, or the selective M3 mAChR antagonist 4-DAMP, while naloxone, an opioid receptor antagonist had no effect. Intracellular infusion of GDP-beta-S or pretreatment of the cells with pertussis toxin (PTX) completely blocked the inhibitory effects of CbT. Using depolarizing prepulse, we found the absence of direct binding between G-protein betagamma subunits and T-type Ca(2+) channels in CbT-induced T-current inhibition. CbT responses were abolished by the phospholipase C inhibitor U73122 (but not the inactive analog U73343). The classical and novel protein kinase C (nPKC) antagonist chelerythrine chlorid or GF109203X abolished CbT responses, whereas the classical PKC antagonist Ro31-8820 or inhibition of PKA elicited no such effects. Intrathecal administration of CbT (5MUg/kg) produced antinociceptive effects in mechanical, thermal, and inflammatory pain models. Moreover, CbT-induced antinociception could be abrogated by 4-DAMP. Taken together, these results suggest that CbT acting through M3 mAChR inhibits T currents via a PTX-sensitive nPKC pathway in small DRG neurons, which could contribute to its analgesic effects in mice. PMID- 21329753 TI - Major depressive disorder and immunity to varicella-zoster virus in the elderly. AB - Major depressive disorder has been associated with activation of inflammatory processes as well as with reductions in innate, adaptive and non-specific immune responses. The objective of this study was to evaluate the association between major depression and a disease-relevant immunologic response, namely varicella zoster virus (VZV)-specific immunity, in elderly adults. A cross-sectional cohort study was conducted in 104 elderly community dwelling adults >= 60years of age who were enrolled in the depression substudy of the shingles prevention study, a double blind, placebo-controlled vaccine efficacy trial. Fifty-two subjects had a current major depressive disorder, and 52 age- and sex-matched controls had no history of depression or any mental illness. VZV-specific cell-mediated immunity (VZV-CMI) was measured by VZV responder cell frequency (VZV-RCF) and interferon gamma enzyme-linked immunospot (ELISPOT) assays, and antibody to VZV was measured by an enzyme-linked immunosorbent assay against affinity-purified VZV glycoproteins (gpELISA). VZV-CMI, measured by VZV-RCF, was significantly lower in the depressed group than in the controls (p<0.001), and VZV-RCF was inversely correlated with the severity of depressive symptoms in the depressed patients. In addition, an age-related reduction in VZV-RCF was observed in the depressed patients, but not in the controls. Furthermore, there was a trend for depressive symptom severity to be associated with lower ELISPOT counts. Finally, VZV-RCF was higher in depressed patients treated with antidepressant medications as compared to untreated depressed patients. Since lower levels of VZV-RCF appear to explain the increased risk and severity of herpes zoster observed in older adults, these findings suggest that, in addition to increasing age, depression may increase the risk and severity of herpes zoster. PMID- 21329755 TI - IL6 and TNF expression in vessels and surrounding tissues after embolization with ibuprofen-loaded beads confirms diffusion of ibuprofen. AB - PURPOSE: In the treatment of uterine fibroid embolization related pain, the use of embolics loaded with non-steroidal anti-inflammatory drugs (NSAID) relies on an efficient delivery and impregnation of the embolized tissue. Immuno-labelling and spectroscopic techniques have demonstrated the release of ibuprofen from drug eluting beads (Wassef et al., 2008; Namur et al., 2009) but failed to demonstrate diffusion of the drug beyond the vascular wall (VW). We investigated whether ibuprofen diffused beyond the VW in surrounding tissues (ST), by tracking its biological effects through the modulation of expression of two main inflammatory cytokines. MATERIALS AND METHODS: Uterine arteries of 6 sheep were embolized with ibuprofen loaded beads (IBU-BB) or non-loaded beads (BB) and sacrificed at one week. On frozen tissue slices, VWs of occluded arteries were isolated from ST using laser capture microdissection. RNA was extracted from VW and ST samples. Gene expression of IL6 and TNFalpha genes was measured by quantitative real-time PCR (qPCR). RESULTS: IL6 expression was significantly increased in IBU-BB compared to BB group both in VW (VW: fold-change (FC)=4.9, p=0.0009) and ST (ST: FC=8.7, p=0.0003). In IBU-BB, IL6 was significantly more expressed in VW than in ST (FC=4.4; p=0.0009). TNFalpha expression was not significantly different between IBU-BB and BB groups. CONCLUSION: Using qPCR+microdissection was useful to evaluate the spread of the biological effects of drug-loaded systems which attest of the tissular release. This approach can be considered when other drug detection techniques are unsuccessful or difficult to achieve. IL6 can be used as a marker of ibuprofen released by drug eluting beads in uterus. Gradient of expression of IL6 suggests diffusion of ibuprofen across the VW into the ST. PMID- 21329756 TI - Cimetidine: an anticancer drug? AB - Cimetidine, H(2) receptor antagonists, is commonly prescribed for gastric and duodenal ulcer disease. Additionally, cimetidine has been shown to have anticancer effects. This review describes the mechanism of antitumor action of cimetidine including its ability to interfere with tumor cell adhesion, angiogenesis and proliferation; its effect on the immune system; as well as inhibition of postoperative immunosuppression. Its anticancer effect is also compared to that of the other H(2) receptor antagonists as well as outcomes of cimetidine in clinical studies in cancer patients. PMID- 21329757 TI - Use of conventional surfactant media as surrogates for FaSSIF in simulating in vivo dissolution of BCS class II drugs. AB - The usefulness of selected conventional surfactant media to enhance dissolution of BCS class II drugs similarly to fasted state simulated intestinal fluid (FaSSIF) and to predict the absorption of drugs in vivo was evaluated. Dissolution behavior of danazol (Danol), spironolactone (Spiridon) and N74 (phase I compound) was compared between FaSSIF, containing physiological levels of sodium taurocholate (STC) and lecithin, and dissolution media containing various concentrations of anionic surfactant, sodium lauryl sulfate (SLS) or non-ionic surfactant, polysorbate (Tween) 80. Although these media differed largely in their solubilization ability, micelle size, diffusivity and surface tension, similar dissolution enhancing levels were achieved between FaSSIF and drug specific concentrations of conventional surfactants. The dissolution enhancement was shown, however, to be important only for danazol and N74, molecules that are characterized by high hydrophobicity. An in vivo pharmacokinetic dog study was carried out with N74. Comparison of observed plasma profiles with simulated profiles obtained using compartmental absorption and transit model (CAT) indicated that 0.1% SLS medium was the best to predict in vivo plasma profiles and pharmacokinetic parameters (C(max) and AUC). This study demonstrates the potential of substituting FaSSIF with more simple and cost-effective conventional surfactant media. Use of in vivo prognostic amounts of synthetic surfactants in dissolution testing could largely assist in industrial drug development as well as in quality control purposes. PMID- 21329758 TI - A data-driven framework for neural field modeling. AB - This paper presents a framework for creating neural field models from electrophysiological data. The Wilson and Cowan or Amari style neural field equations are used to form a parametric model, where the parameters are estimated from data. To illustrate the estimation framework, data is generated using the neural field equations incorporating modeled sensors enabling a comparison between the estimated and true parameters. To facilitate state and parameter estimation, we introduce a method to reduce the continuum neural field model using a basis function decomposition to form a finite-dimensional state-space model. Spatial frequency analysis methods are introduced that systematically specify the basis function configuration required to capture the dominant characteristics of the neural field. The estimation procedure consists of a two stage iterative algorithm incorporating the unscented Rauch-Tung-Striebel smoother for state estimation and a least squares algorithm for parameter estimation. The results show that it is theoretically possible to reconstruct the neural field and estimate intracortical connectivity structure and synaptic dynamics with the proposed framework. PMID- 21329759 TI - Test-retest reliability of Quantitative Sensory Testing in knee osteoarthritis and healthy participants. AB - Quantitative Sensory Testing (QST), which assesses somatosensory function by recording participant's responses to external stimuli of controlled intensity, is a useful tool to provide insight into the complex pathophysiology of osteoarthritis (OA) pain. However, QST is not commonly used in rheumatology because the test-retest reliability properties of QST in OA patients have not yet been established. This brief report presents the finding of a study which assessed the test-retest reliability of light touch thresholds, pressure pain thresholds, thermal sensation thresholds and thermal pain thresholds in 50 knee OA patients and 50 healthy participants. Pressure pain thresholds were found to be the least variable measurement, as median thresholds did not differ significantly over the 1 week period and the results were highly correlated. This provides support for the inclusion of pressure algometry in studies assessing pain perception abnormalities in OA. PMID- 21329760 TI - Natural history of cartilage damage and osteoarthritis progression on magnetic resonance imaging in a population-based cohort with knee pain. AB - OBJECTIVES: To determine the natural history of cartilage damage and of osteoarthritis (OA) progression using magnetic resonance imaging (MRI); to evaluate whether OA progression varies by stage of disease. METHODS: A population based cohort with knee pain was assessed clinically, with X-ray (Kellgren Lawrence [KL] grading) and MRI. Cartilage was graded 0-3 on six joint surfaces. Frequency of cartilage damage change was determined for each joint site. Progression of OA was defined as a worsening of MRI cartilage damage by >=1 grade in at least two joint sites or >=2 grades in at least one joint site. The association of KL grade with OA progression was evaluated using parametric lifetime regression analysis. RESULTS: 163 subjects were assessed at baseline and follow-up (mean 3.2 years). KL grade >=2 was present in 39.4% at baseline. An increase in cartilage damage by >=1 grade was seen in 8.0-14.1% of subjects at different joint sites. OA progression on MRI was present in 15.5%. Baseline KL grade was a significant predictor of OA progression with hazard ratio (HR) of 6.5 (95% confidence interval [CI] 1.4-30.7), 6.1 (95% CI 1.3-28.9), and 9.2 (95% CI 1.9-44.9) for KL grades 1, 2 and >=3, respectively. CONCLUSION: A low OA progression rate was seen over 3 years in this population-based symptomatic cohort. Radiographic severity, including KL grade 1, was a significant predictor of OA progression. Future interventions aimed at reducing progression will need to target not only radiographic OA, but also those with early abnormalities suggestive of pre-radiographic OA. PMID- 21329761 TI - Exploring the mechanism of dishabituation. AB - In this study we explored elicitation and habituation of the orienting reflex (OR) in the context of indifferent and significant stimuli, particularly aiming to clarify the mechanism driving dishabituation. An in-depth analysis of the mechanisms of electrodermal habituation and dishabituation was conducted, focusing on the role of state measures as determinants of the phasic response profile. Twenty-four young adult participants completed an auditory dishabituation task while electrodermal activity was recorded. Participants listened to a series of 10 innocuous tones of the same frequency (standards), followed by a deviant tone of a different frequency, and succeeded by 2-4 tones of the same frequency as the initial 10 stimuli. All stimuli had a random stimulus onset asynchrony of 5-7 s. Participants completed an indifferent condition in which there was no task in relation to the stimuli, and a significant condition where instruction was given to count the stimuli silently; order was counterbalanced between participants. As predicted, both skin conductance responses (SCRs) and skin conductance levels (SCLs) were larger for the significant than the indifferent condition. The initial phasic ORs were dependent on pre-stimulus arousal level, and there were significant decreases in both SCR and SCL over the first 10 standards in both conditions. Phasic response recovery was apparent to the deviant stimulus, and dishabituation to the following standard stimulus; both effects were enhanced in the significant condition. Sensitisation was apparent in SCL following the initial and deviant stimuli, but the extent of this was confounded with incomplete resolution of the preceding phasic OR in the significant condition. In the indifferent condition, dishabituation was independent of deviant-related sensitisation; this could not be tested in the significant condition. These findings suggest that dishabituation is not a process of sensitisation, but rather, a disruption of the habituation process. PMID- 21329762 TI - Purinergic mechanisms in gliovascular coupling. AB - Regional elevations in cerebral blood flow (CBF) often occur in response to localized increases in cerebral neuronal activity. An ever expanding literature has linked this neurovascular coupling process to specific signaling pathways involving neuronal synapses, astrocytes and cerebral arteries and arterioles. Collectively, these structures are termed the "neurovascular unit" (NVU). Astrocytes are thought to be the cornerstone of the NVU. Thus, not only do astrocytes "detect" increased synaptic activity, they can transmit that information to proximal and remote astrocytic sites often through a Ca(2+)- and ATP-related signaling process. At the vascular end of the NVU, a Ca(2+)-dependent formation and release of vasodilators, or substances linked to vasodilation, can occur. The latter category includes ATP, which upon its appearance in the extracellular compartment, can be rapidly converted to the potent vasodilator, adenosine, via the action of ecto-nucleotidases. In the present review, we give consideration to experimental model-specific variations in purinergic influences on gliovascular signaling mechanisms, focusing on the cerebral cortex. In that discussion, we compare findings obtained using in vitro (rodent brain slice) models and multiple in vivo models (2-photon imaging; somatosensory stimulation evoked cortical hyperemia; and sciatic nerve stimulation-evoked pial arteriolar dilation). Additional attention is given to the importance of upstream (remote) vasodilation; the key role played by extracellular ATP hydrolysis (via ecto nucleotidases) in gliovascular coupling; and interactions among multiple signaling pathways. PMID- 21329763 TI - Thalamocortical dynamics of sleep: roles of purinergic neuromodulation. AB - Thalamocortical dynamics, the millisecond to second changes in activity of thalamocortical circuits, are central to perception, action and cognition. Generated by local circuitry and sculpted by neuromodulatory systems, these dynamics reflect the expression of vigilance states. In sleep, thalamocortical dynamics are thought to mediate "offline" functions including memory consolidation and synaptic scaling. Here, I discuss thalamocortical sleep dynamics and their modulation by the ascending arousal system and locally released neurochemicals. I focus on modulation of these dynamics by electrically silent astrocytes, highlighting the role of purinergic signaling in this glial form of communication. Astrocytes modulate cortical slow oscillations, sleep behavior, and sleep-dependent cognitive function. The discovery that astrocytes can modulate sleep dynamics and sleep-related behaviors suggests a new way of thinking about the brain, in which integrated circuits of neurons and glia control information processing and behavioral output. PMID- 21329764 TI - Highly conserved gene arrangement of the mitochondrial genomes of 23 Plasmodium species. AB - Mitochondrial (mt) genomes from diverse phylogenetic groups vary considerably in size, structure and organization. The genus Plasmodium, the causative agent of malaria, has the smallest mt genome in the form of a tandemly repeated, linear element of 6 kb. The Plasmodium mt genome encodes only three protein genes (cox1, cox3 and cob) and large- and small-subunit ribosomal RNA (rRNA) genes, which are highly fragmented with 19 identified rRNA pieces. The complete mt genome sequences of 21 Plasmodium species have been published but a thorough investigation of the arrangement of rRNA gene fragments has been undertaken for only Plasmodium falciparum, the human malaria parasite. In this study, we determined the arrangement of mt rRNA gene fragments in 23 Plasmodium species, including two newly determined mt genome sequences from P. gallinaceum and P. vinckei vinckei, as well as Leucocytozoon caulleryi, an outgroup of Plasmodium. Comparative analysis reveals complete conservation of the arrangement of rRNA gene fragments in the mt genomes of all the 23 Plasmodium species and L. caulleryi. Surveys for a new rRNA gene fragment using hidden Markov models enriched with recent mt genome sequences led us to suggest the mtR-26 sequence as a novel candidate LSU rRNA fragment in the mt genomes of the 24 species. Additionally, we found 22-25 bp-inverted repeat sequences, which may be involved in the generation of lineage-specific mt genome arrangements after divergence from a common ancestor of the genera Eimeria and Plasmodium/Leucocytozoon. PMID- 21329765 TI - Nanomedicine and experimental tuberculosis: facts, flaws, and future. AB - Nanoparticle-based drug delivery systems form the crux of nanomedicine and are suitable for targeting chronic diseases such as tuberculosis. Extensive experimental data supports the possibility of intermittent chemotherapy with key first-line as well as second-line antituberculosis drugs by employing synthetic or natural carriers, chiefly polymers. Besides sustained release of drugs in plasma and organs, other potential advantages of the system include the possibility of selecting various routes of chemotherapy; reduction in drug dosage, adverse effects, and drug interactions; and targeting drug-resistant and latent bacteria. On the other hand, the choice of carrier, large-scale production, stability, and toxicity of the formulation are some of the major issues that merit immediate attention and resolution. Nevertheless, keeping in view the hurdles in new antituberculosis drug development, nanomedicine has provided a sound platform and a ray of hope for an onslaught against tuberculosis. FROM THE CLINICAL EDITOR: Tuberculosis remains a major public health concern worldwide. In this paper, the role and significance of nanoparticle-based drug delivery systems are discussed for targeting tuberculosis, including strains that are drug resistant with conventional methods. PMID- 21329766 TI - Ontological aspects of pluripotency and stemness gene expression pattern in the rhesus monkey. AB - Two essential aspects of mammalian development are the progressive specialization of cells toward different lineages, and the maintenance of progenitor cells that will give rise to the differentiated components of each tissue and also contribute new cells as older cells die or become injured. The transition from totipotentiality to pluripotentiality, to multipotentiality, to monopotentiality, and then to differentiation is a continuous process during development. The ontological relationship between these different stages is not well understood. We report for the first time an ontological survey of expression of 45 putative "stemness" and "pluripotency" genes in rhesus monkey oocytes and preimplantation stage embryos, and comparison to the expression in the inner cell mass, trophoblast stem cells, and a rhesus monkey (ORMES6) embryonic stem cell line. Our results reveal that some of these genes are not highly expressed in all totipotent or pluripotent cell types. Some are predominantly maternal mRNAs present in oocytes and embryos before transcriptional activation, and diminishing before the blastocyst stage. Others are well expressed in morulae or early blastocysts, but are poorly expressed in later blastocysts or ICMs. Also, some of the genes employed to induce pluripotent stem cells from somatic cells (iPS genes) appear unlikely to play major roles as stemness or pluripotency genes in normal embryos. PMID- 21329767 TI - Fatal heart failure associated with CoQ10 and multiple OXPHOS deficiency in a child with propionic acidemia. AB - The role of a secondary respiratory chain deficiency as an additional mechanism to intoxication, leading to development of long-term energy-dependent complications, has been recently suggested in patients with propionic acidemia (PA). We show for the first time a coenzyme Q(10) (CoQ(10)) functional defect accompanied by a multiple organ oxidative phosphorylation (OXPHOS) deficiency in a child who succumbed to acute heart failure in the absence of metabolic stress. Quinone-dependent activities in the liver (complex I+III, complex II+III) were reduced, suggesting a decrease in electron transfer related to the quinone pool. The restoration of complex II+III activity after addition of exogenous ubiquinone to the assay system suggests CoQ(10) deficiency. Nevertheless, we disposed of insufficient material to perform direct measurement of CoQ(10) content in the patient's liver. Death occurred before biochemical diagnosis of OXPHOS deficiency could be made. However, this case highlights the usefulness of rapidly identifying CoQ(10) defects secondary to PA since this OXPHOS disorder has a good treatment response which could improve heart complications or prevent their appearance. Nevertheless, further studies will be necessary to determine whether CoQ(10) treatment can be useful in PA complications linked to CoQ(10) deficiency. PMID- 21329768 TI - Rapid isothermal substrate microfabrication of a biocompatible thermoplastic elastomer for cellular contact guidance. AB - The use of microstructured substrates to study and influence cell orientation, which plays an important role in tissue functionality, has been of great interest lately. Silicon and poly(dimethylsiloxane) substrates have typically been used, but long processing times and exogenous protein surface coating, required to enhance cell viability, limit their use as large-scale platforms. There is thus a need for a non-biodegradable biocompatible substrate that allows rapid and low cost microfabrication. In this paper a styrene-(ethylene/butylene)-styrene block co-polymer (SEBS) microstructured by a rapid replication technique using low pressure an isothermal hot embossing approach has been demonstrated. SEBS substrates were treated with oxygen plasma to enhance cell adhesion and sterilized using ethylene oxide gas. While cell adhesion to and proliferation on these substrates was as good as on tissue culture polystyrene, cellular alignment on microstructured SEBS was also very high (97.7+/-0.5%) when calculated within a 10 degrees angle variation from the longitudinal axis. Furthermore, tissue sheets on microstructured SEBS have been produced and exhibited cellular alignment within the engineered tissue. In addition, these results were obtained without coating the material with exogenous proteins. Such substrates should be helpful in the culture of tissue engineered substitutes with an intrinsic orientation and to elucidate questions in cell biology. PMID- 21329769 TI - Analysis of the in vitro swelling behavior of poly(vinyl alcohol) hydrogels in osmotic pressure solution for soft tissue replacement. AB - An osmotic solution was used to evaluate poly(vinyl alcohol) (PVA) hydrogels as potential non-degradable soft tissue replacements in vitro. Osmotic solutions are necessary in order to mimic the swelling pressure observed in vivo for soft tissues present in load-bearing joints. In vitro studies indicated that PVA hydrogels experience minimal changes in swelling with a polymer concentration of 20 wt.% PVA in phosphate-buffered saline solution (0 atm) and between 30 and 35 wt.% PVA in osmotic solution with a pressure of 0.95 atm. Swelling in osmotic pressure solutions caused decreases in the equilibrium hydrogel hydration. An investigation of hydrogel compressive modulus indicated that PVA hydrogels are within the range of articular cartilage, meniscal tissue, and the temporomandibular joint disk. Furthermore, it is possible to tailor PVA hydrogels through careful modification of the polymer concentration and freeze-thaw cycles during hydrogel preparation to match both a desired swelling ratio and a desired compressive modulus or porosity. The microstructure of the PVA hydrogels was also evaluated as a function of freeze-thaw cycles and polymer concentration to give an insight into the processes occurring during synthesis and swelling in osmotic solutions. PMID- 21329770 TI - Flexural characterization of cell encapsulated PEGDA hydrogels with applications for tissue engineered heart valves. AB - The limitations of the current clinical options for valve replacements have inspired the development of enabling technologies to create a tissue engineered heart valve (TEHV). Poly(ethylene glycol) diacrylate (PEGDA) hydrogel scaffolds permit greater biological and biomechanical customization than do non-woven mesh scaffold technologies. However, the material characterization of PEGDA hydrogels has been predominantly limited to compression and tension, as opposed to bending. Since large flexural deformations result in points of maximum stress in native valves as well as TEHVs, it is crucial to evaluate any potential scaffold material in this mode. The effect of formulation parameters on the bending mechanics of cell-seeded PEGDA hydrogels were investigated with a custom designed bending tester. Three molecular weights (3.4, 6, and 8 kDa) and three weight fractions (5%, 10%, and 15%, w/v) were subjected to three-point bending tests and the flexural stiffness was calculated. Manipulating the composition of the hydrogels resulted in flexural stiffnesses comparable with native tissues (15-220 kPa) with varied mesh sizes and swelling ratios. Hydrogels containing encapsulated valve cells, methacrylated heparin (Hep-MA), or both were substantially less stiff than acellular hydrogels. In conclusion, PEGDA hydrogels are an attractive potential scaffold system for TEHVs because they are not only cytocompatible and modifiable but can also withstand bending deformations. These studies are the first to explore the encapsulation of valvular interstitial cells in pure PEGDA hydrogels as well as to investigate the bending properties of PEGDA gels. PMID- 21329771 TI - Analysis of site-specific N-homocysteinylation of human serum albumin in vitro and in vivo using MALDI-ToF and LC-MS/MS mass spectrometry. AB - Elevated levels of homocysteine (Hcy) are associated with cardiovascular and neurodegenerative diseases in humans. Hcy becomes a component of human proteins as a result of N-homocysteinylation of protein lysine residues by Hcy thiolactone, which affects the protein's structure and function, and contributes to Hcy-related pathology. Albumin is the major target for N-homocysteinylation in human blood in vivo. Previous work has identified Lys-525 as a predominant site of N-homocysteinylation in vitro and in vivo. Here we show that Lys-4, Lys-12, Lys-137, Lys-159, Lys-205, and Lys-212 of human albumin are susceptible to N homocysteinylation in vitro and provide evidence that two of those residues, Lys 137 and Lys-212, in addition to Lys-525, are N-homocysteinylated in vivo in human plasma. PMID- 21329772 TI - Plant proteome changes under abiotic stress--contribution of proteomics studies to understanding plant stress response. AB - Plant acclimation to stress is associated with profound changes in proteome composition. Since proteins are directly involved in plant stress response, proteomics studies can significantly contribute to unravel the possible relationships between protein abundance and plant stress acclimation. In this review, proteomics studies dealing with plant response to a broad range of abiotic stress factors--cold, heat, drought, waterlogging, salinity, ozone treatment, hypoxia and anoxia, herbicide treatments, inadequate or excessive light conditions, disbalances in mineral nutrition, enhanced concentrations of heavy metals, radioactivity and mechanical wounding are discussed. Most studies have been carried out on model plants Arabidopsis thaliana and rice due to large protein sequence databases available; however, the variety of plant species used for proteomics analyses is rapidly increasing. Protein response pathways shared by different plant species under various stress conditions (glycolytic pathway, enzymes of ascorbate-glutathione cycle, accumulation of LEA proteins) as well as pathways unique to a given stress are discussed. Results from proteomics studies are interpreted with respect to physiological factors determining plant stress response. In conclusion, examples of application of proteomics studies in search for protein markers underlying phenotypic variation in physiological parameters associated with plant stress tolerance are given. PMID- 21329773 TI - The effects of Dickkopf-1 antibody on metaphyseal bone and implant fixation under different loading conditions. AB - The secreted protein Dickkopf-1 (Dkk1) is an antagonist of canonical Wnt signaling, expressed during fracture healing. It is unclear how it is involved in the mechanical control of bone maintenance. We investigated the response to administration of a Dkk1 neutralizing antibody (Dkk1-ab) in metaphyseal bone under different loading conditions, with or without trauma. In this three part experiment, 120 rats had a screw or bone chamber inserted either unilaterally or bilaterally in the proximal tibia. Mechanical (pull-out) testing, MUCT and histology were used for evaluation. The animals were injected with either 10mg/kg Dkk1-ab or saline every 14days for 14, 28, or 42days. Antibody treatment increased bone formation around the screws and improved their fixation. After 28days, the pull-out force was increased by over 100%. In cancellous bone, the bone volume fraction was increased by 50%. In some animals, one hind limb was paralyzed with Botulinum toxin A (Botox) to create a mechanically unloaded environment. This did not increase the response to antibody treatment with regard to screw fixation, but in cancellous bone, the bone volume fraction increased by 233%. Thus, the response in unloaded, untraumatized bone was proportionally larger, suggesting that Dkk1 may be up-regulated in unloaded bone. There was also an increase in thickness of the metaphyseal cortex. In bone chambers, the antibody treatment increased the bone volume fraction. The results suggest that antibodies blocking Dkk1 might be used to stimulate bone formation especially during implant fixation, fracture repair, or bone disuse. It also seems that Dkk1 is up-regulated both after metaphyseal trauma and after unloading, and that Dkk1 is involved in mechano-transduction. PMID- 21329774 TI - Change in hepatitis A epidemiology after vaccinating high risk children in Taiwan, 1995-2008. AB - Taiwan started to immunize children in 30 indigenous townships against hepatitis A since June 1995. The program was further expanded to 19 non-indigenous townships with higher incidence or increased risk of epidemic in 1997-2002, covering 2% of total population. Annual incidence of hepatitis A decreased from 2.96 in 1995 (baseline period) to 0.90/100,000 in 2003-2008 (vaccination period). The incidence in vaccinated townships and unvaccinated townships declined 98.3% (49.66-0.86/100,000) and 52.6% (1.90-0.90/100,000). In 2003-2008, incidence doubled in people aged >=30 years, mostly in unvaccinated townships (0.42-0.92). During 2003-2008, travel to endemic countries was the most commonly reported risk factor (13.5%). First dose vaccine coverage was 78.8% in 1994-2005 birth cohort. Taiwan's experience demonstrates the great, long-term efficacy of hepatitis A vaccine in disease control in vaccinated townships, and out-of-cohort effect in unvaccinated townships. Further reduction can be achieved by improving vaccination coverage of adults at risk. PMID- 21329775 TI - Ebola virus glycoprotein Fc fusion protein confers protection against lethal challenge in vaccinated mice. AB - Ebola virus is a Filoviridae that causes hemorrhagic fever in humans and induces high morbidity and mortality rates. Filoviruses are classified as "Category A bioterrorism agents", and currently there are no licensed therapeutics or vaccines to treat and prevent infection. The Filovirus glycoprotein (GP) is sufficient to protect individuals against infection, and several vaccines based on GP are under development including recombinant adenovirus, parainfluenza virus, Venezuelan equine encephalitis virus, vesicular stomatitis virus (VSV) and virus-like particles. Here we describe the development of a GP Fc fusion protein as a vaccine candidate. We expressed the extracellular domain of the Zaire Ebola virus (ZEBOV) GP fused to the Fc fragment of human IgG1 (ZEBOVGP-Fc) in mammalian cells and showed that GP undergoes the complex furin cleavage and processing observed in the native membrane-bound GP. Mice immunized with ZEBOVGP-Fc developed T-cell immunity against ZEBOV GP and neutralizing antibodies against replication-competent VSV-G deleted recombinant VSV containing ZEBOV GP. The ZEBOVGP-Fc vaccinated mice were protected against challenge with a lethal dose of ZEBOV. These results show that vaccination with the ZEBOVGP-Fc fusion protein alone without the need of a viral vector or assembly into virus-like particles is sufficient to induce protective immunity against ZEBOV in mice. Our data suggested that Filovirus GP Fc fusion proteins could be developed as a simple, safe, efficacious, and cost effective vaccine against Filovirus infection for human use. PMID- 21329776 TI - Randomized study of intradermal compared to intramuscular hepatitis B vaccination in HIV-infected children without severe immunosuppression. AB - HIV infected individuals have poorer response to hepatitis B vaccine (HBV) compared to normal host. Intradermal administration (i.d.) facilitates the exposure of antigen to antigen-presenting cells compared to intramuscular administration (i.m.). HIV-infected children aged 1-18 years with CD4%>=15% or 200 cells/mm(3) who had negative HBs Ag, antiHBs, and antiHBc were randomized to receive 3-dose of HBV via i.d. (2 MUg/dose) or i.m. (10 MUg/dose) route at months 0, 2, and 6. AntiHBs titers were measured at months 2, 6 and 7 after first HBV. AntiHBs>=10 mIU/mL was considered protective and AntiHBs>100 mIU/mL was considered good response. Participants included 41 in i.d. and 39 in i.m. arms. 64% had completed 3-doses HBV during infancy. The mean (SD) of age, nadir CD4% and current CD4% were 12 (3.3) years, 10.6 (7.9)% and 28 (8.0)% respectively. 91% were on HAART and 84% had undetectable HIV-RNA. Proportion of children with protective antiHBs in i.d. vs. i.m. group were 19.5% vs. 25.6% at month 2, 56.1% vs. 76.9% at month 6, and 90.2% vs. 92.3% at month 7 (NS, all). The geometric mean (95% confidence interval) of antiHBs titer in i.d. vs. i.m. group were 112.5 (34.4-367.6) vs. 141.2 (49.4-404.1) mIU/mL at month 2 (p=0.74), 70.4 (39.8-124.4) vs. 132.1 (79.4-219.8) mIU/mL at month 6 (p=0.10), and 157.0 (103.0-239.3) vs. 458.9 (324.0-647.0) mIU/mL at month 7 (p<0.001). However, only 56.1% of the i.d. arm had good response to HBV compared to 82.1% in the i.m. arm (p=0.01). The predictors for being a good responder to HBV were i.m. administration [OR 4.0, 95%CI 1.4-11.8, p=0.012] and body weight <35 kg at baseline [OR 3.8, 95%CI 1.3 10.8, p=0.013]. No adverse events grade 3/4 occurred. In conclusion, HIV-infected children without severe immune suppression, both i.d. and i.m. routes of HBV resulted in similar rates of protective antibody titers. However, high antibody titers to HBV were more common with i.m.; therefore, i.m. administration is preferred. PMID- 21329777 TI - Fungal cell wall agents suppress the innate inflammatory cytokine responses of human peripheral blood mononuclear cells challenged with lipopolysaccharide in vitro. AB - Exposure to high levels of fungi might lead to diseases, such as airway inflammation, hypersensitivity pneumonitis and allergy. To comprehend the mechanisms behind the exposure to fungi and a disease, we examined the in vitro innate inflammatory cytokine response of human peripheral blood mononuclear cells (PBMC) challenged by fungal cell wall agents (FCWAs), i.e., soluble and particulate (1->3)-beta-D-glucan-curdlan (BGS and BGP), zymosan (ZYM) and chitosan (CHT) in the absence or presence of lipopolysaccharide (LPS). We also studied FCWA effects on the mRNA expression of dectin-1, TLR2, TLR4 and mannose receptor (MR) by real-time RT-PCR. Our results demonstrated that BGP strongly induced the secretion of TNF-alpha, IL-6, IL-10 and IL-12; BGS, ZYM and CHT were weaker, but still significant cytokine inducers. We showed that BGS significantly augmented the LPS-induced in vitro secretion of TNF-alpha. On the other hand, BGP, ZYM and CHT suppressed the LPS-induced production of all cytokines. At the mRNA level, the dectin-1, TLR2 and TLR4 expressions were significantly reduced by all FCWAs in the absence of LPS and even more in the presence of LPS. While we demonstrated that the innate inflammatory cytokine response of PBMC induced by CHT was mediated by MR, the MR mRNA expression was significantly reduced by CHT. On the contrary, BGS significantly enhanced the MR mRNA expression. In conclusion, a long-term and massive exposure to LPS and FCWA (e.g., organic dust) may cause an important disruption of normal immune response and allow development and/or persistence of various immunopathological events. PMID- 21329779 TI - Gastroparesis: approach, diagnostic evaluation, and management. AB - Gastroparesis is a chronic motility disorder of the stomach that involves delayed emptying of solids and liquids, without evidence of mechanical obstruction. Although no cause can be determined for the majority of cases, the disease often develops as a complication of abdominal surgeries or because of other underlying disorders, such as diabetes mellitus or scleroderma. The pathophysiology behind delayed gastric emptying is still not well-understood, but encompasses abnormalities at 3 levels--autonomic nervous system, smooth muscle cells, and enteric neurons. Patients will often cite nausea, vomiting, postprandial fullness, and early satiety as their most bothersome symptoms on history and physical examination. Those that present with severe disease may already have developed complications, such as the formation of bezoars or masses of undigested food. In patients suspected of gastroparesis, diagnostic evaluation requires an initial upper endoscopy to rule out mechanical causes, followed by a gastric emptying scintigraphy for diagnosis. Other diagnostic alternatives would be wireless capsule motility, antroduodenal manometry, and breath testing. Once gastroparesis is diagnosed, dietary modifications, such as the recommendation of more frequent and more liquid-based meals, are encouraged. Promotility medications like erythromycin and antiemetics like prochlorperazine are offered for symptomatic relief. These agents may be frequently changed, as the right combination of effective medications will vary with each individual. In patients who are refractory to pharmacologic treatment, more invasive options, such as intrapyloric botulinum toxin injections, placement of a jejunostomy tube, or implantation of a gastric stimulator, are considered. Future areas of research are based on current findings from clinical studies. New medications, such as hemin therapy, are emerging because of a better understanding of the pathophysiology behind gastroparesis, and present treatment options, such as gastric electric stimulation, are evolving to be more effective. Regenerative medicine and stem cell-based therapies also hold promise for gastroparesis in the near future. PMID- 21329781 TI - New uses for old tools. PMID- 21329782 TI - The central role of 5-HT6 receptors in modulating brain neurochemistry. PMID- 21329783 TI - 5-HT6 receptor memory and amnesia: behavioral pharmacology--learning and memory processes. AB - Growing evidence indicates that antagonists of the 5-hydroxytryptamine (serotonin) receptor6 (5-HT6) improve memory and reverse amnesia, although the mechanisms involved are poorly understood. Hence, in this paper an attempt was made to summarize recent findings. Available evidence indicates that diverse 5 HT6 receptor antagonists produce promnesic and/or antiamnesic effects in diverse conditions, including memory formation, age-related cognitive impairments, memory deficits in diseases such as schizophrenia, Parkinson, and Alzheimer's disease (AD). Notably, some 5-HT6 receptor agonists seem to have promnesic and/or antiamnesic effects. At the present, it is unclear why 5-HT6 receptor agonists and antagonists may facilitate memory or may reverse amnesia in some memory tasks. Certainly, 5-HT6 drugs modulate memory, which are accompanied with neural changes. Likewise, memory, aging, and AD modify 5-HT6 receptors and signaling cascades. Further investigation in different memory tasks, times, and amnesia models together with more complex control groups might provide further clues. Notably, human studies suggest a potential utility of 5-HT6 receptor antagonists in mild-to-moderate AD patients. Even individuals with mild cognitive impairment (MCI) offer a great opportunity to test them. PMID- 21329784 TI - Behavioral pharmacology: potential antidepressant and anxiolytic properties. PMID- 21329785 TI - The 5-HT6 receptor as a target for developing novel antiobesity drugs. PMID- 21329786 TI - Behavioral and neurochemical pharmacology of 5-HT6 receptors related to reward and reinforcement. PMID- 21329787 TI - 5-HT6 receptor ligands and their antipsychotic potential. PMID- 21329788 TI - 5-HT6 receptor ligands as antidementia drugs. PMID- 21329789 TI - Other 5-HT6 receptor-mediated effects. PMID- 21329790 TI - The unfolded protein response and cellular stress, Part C. Preface. PMID- 21329791 TI - CFTR expression regulation by the unfolded protein response. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel and key regulator of epithelial functions. Mutations in the CFTR gene lead to reduced or dysfunctional CFTR protein and cause cystic fibrosis (CF), a generalized exocrinopathy affecting multiple organs. In the airways, loss of CFTR function leads to thickened mucus, reduced mucociliary clearance, chronic infections, and respiratory failure. Common airway disorders such as bronchitis and chronic obstructive pulmonary disease (COPD) also present CF-like symptoms such as mucus congestion and chronic inflammation without mutations in CFTR. The primary risk factors for COPD and chronic bronchitis include environmental stress insults such as pollutants and infections that often result in hypoxic conditions. Furthermore, environmental factors such as cigarette smoke and reactive oxygen species have been implicated in reduced CFTR function. Activation of cellular stress responses by these factors promotes differential, stress associated gene expression regulation. During our investigations on the mechanisms of CFTR expression regulation, we have shown that the ER stress response, the unfolded protein response (UPR), decreases CFTR expression at the transcriptional, translational, and maturational levels. Here, we provide a detailed description of the methods we employ to study CFTR expression regulation by the UPR. Similar approaches are applicable in studies on other genes and how they are affected by the UPR. PMID- 21329792 TI - GRP78/BiP modulation of GRP78/BiP in altering sensitivity to chemotherapy. AB - The glucose-regulated protein 78 (GRP78) is a key regulator of the endoplasmic reticulum (ER) stress response. This chapter discusses how GRP78 may be measured in vitro and in vivo. Because of the authors' expertise and experience with brain tumors, most of our work on GRP78 has focused on malignant gliomas. Here, we present our methodology for determining GRP78 in vitro using glioma cell lines and primary cell cultures, and in measuring GRP78 expression in tissue sections from rodent glioma models and human brain tumors. After discussion of measurement of GRP78 levels, modulation of GRP78 in vitro is demonstrated using glioma cell lines. Lastly, in vivo modulation of GRP78 levels via chemotherapy is determined using intracranial rodent models. PMID- 21329793 TI - Targeting the unfolded protein response in cancer therapy. AB - Rapid growth of tumor cells coupled with inadequate vascularization leads to shortage of oxygen and nutrients. The unfolded protein response (UPR), a defense cellular mechanism activated during such stress conditions, is a complex process that includes upregulation of the endoplasmic reticulum chaperones, such as glucose-regulated protein 78 (GRP78). Due to its central role in UPR, GRP78 is overexpressed in many cancers; it is implicated in cancer cell survival through supporting of drug- and radioresistance as well as metastatic dissemination, and is generally associated with poor outcome. This is the reason why selective destruction of GRP78 could become a novel anticancer strategy. GRP78 is the only known substrate of the proteolytic A subunit (SubA) of a bacterial AB(5) toxin, and the selective SubA-induced cleavage of GRP78 leads to massive cell death. Targeted delivery of SubA into cancer cells via specific receptor-mediated endocytosis could be a suitable strategy for assaulting tumor cells. We fused SubA to epidermal growth factor (EGF), whose receptor (EGFR) is frequently overexpressed in tumor cells, and demonstrated that the resulting EGF-SubA immunotoxin is an effective killer of EGFR-positive tumor cells. Furthermore, because of its unique mechanism of action, EGF-SubA synergizes with UPR-inducing drugs, which opens a possibility for the development of mechanism-based combination regimens for effective anticancer therapy. In this chapter, we provide experimental protocols for the assessment of the effects of EGF-SubA on EGFR-positive cancer cells, either alone or in combination with UPR-inducing drugs. PMID- 21329794 TI - Large-scale analysis of UPR-mediated apoptosis in human cells. AB - The historic distinction between academic- and industry-driven drug discovery, whereby academicians worked to identify therapeutic targets and pharmaceutical companies advanced probe discovery, has been blurred by an academic high throughput chemical genomic revolution. It is now common for academic labs to use biochemical or cell-based high-throughput screening (HTS) to investigate the effects of thousands or even hundreds of thousands of chemical probes on one or more targets over a period of days or weeks. To support the efforts of individual investigators, many universities have established core facilities where screening can be performed collaboratively with large chemical libraries managed by highly trained HTS personnel and guided by the experience of computational, medicinal, and synthetic organic chemists. The identification of large numbers of promising hits from such screens has driven the need for independent labs to scale down secondary in vitro assays in the hit to lead identification process. In this chapter, we will describe the use of luminescent and quantitative reverse transcription real-time PCR (qRT-PCR) technologies that permit evaluation of the expression patterns of multiple unfolded protein response (UPR) and apoptosis related genes, and simultaneously evaluate proliferation and cell death in 96- or 384-well format. PMID- 21329795 TI - Quantitative analysis of amino Acid oxidation markers by tandem mass spectrometry. AB - Oxidative stress plays a central role in the pathogenesis of diverse chronic inflammatory disorders including diabetic complications, cardiovascular disease, aging, neurodegenerative disease, autoimmune disorders, and pulmonary fibrosis. Protein misfolding can lead to chronic endoplasmic reticulum (ER) stress which can exacerbate oxidative stress. This can trigger apoptotic cascades resulting in chronic inflammatory disorders. Despite intense interest in origins and magnitude of oxidative stress, ability to quantify oxidants has been limited because they are short lived. We have developed quantitative mass spectrometry (MS)-based analytical strategies to analyze stable end products of protein oxidation. These molecules provide quantitative and mechanistic assessment of degree of oxidative stress in cell cultures, tissues, and biofluids of animal models of disease and human samples. Our studies support the hypothesis that unique reactive intermediates generated in localized microenvironments of vulnerable tissues promote end-organ damage. The ability to quantify these changes and assess response to therapies will be pivotal in understanding disease mechanisms and monitoring efficacy of therapy. PMID- 21329796 TI - Animal models in the study of the unfolded protein response. AB - The endoplasmic reticulum, a highly dynamic and complex organelle, is the site for synthesis, folding, and modification of transmembrane and secretory proteins. Any disruptions to the endoplasmic reticulum such as an accumulation of misfolded or unfolded proteins results in activation of the unfolded protein response (UPR). The UPR is comprised of three distinct signal transduction pathways that work to restore homeostasis to the endoplasmic reticulum. This review summarizes select mouse models available to study the UPR and the information learned from the analyses of these models. PMID- 21329797 TI - Measurement of fluoride-induced endoplasmic reticulum stress using Gaussia luciferase. AB - Endoplasmic reticulum (ER) stress and its consequent activation of the unfolded protein response (UPR) signaling pathway have been implicated in several pathophysiologic disorders as well as in drug resistance to treatment of tumors. Several techniques have been devised that qualitatively and quantitatively demonstrate the presence of ER stress and the activation of the UPR; however, most of these methods cannot be used to measure ER stress in real time. Here we describe the use of cells stably transduced with a secreted reporter, Gaussia luciferase (Gluc), to measure fluoride-induced ER stress. Factors that affect ER homeostasis, such as high-dose fluoride, will cause decreased Gluc secretion that can be measured as a decrease in Gluc activity in the culture medium supernatant. Gluc catalyzes the oxidative decarboxylation of coelenterazine (CTZ) to coeleneteramide, resulting in blue bioluminescence (lambda(max) 485 nm). Therefore, Gluc activity can be easily quantified by mixing a small aliquot of the medium supernatant with CTZ and measuring the resulting bioluminescence in a luminometer. Among the various reporters used so far, Gluc is regarded as the most sensitive indicator of ER stress. A second advantage for using Gluc is its ability to function in a wide pH range. This is especially useful for studying fluoride-mediated toxicity as fluoride-induced stress is enhanced under acidic conditions. Since Gluc can be measured in a noninvasive manner, it has been used in several in vitro and in vivo applications. In this chapter, we detail our methodology for using Gluc to monitor fluoride-induced ER stress. PMID- 21329798 TI - Analysis of nelfinavir-induced endoplasmic reticulum stress. AB - Nelfinavir (Viracept(r)) is an HIV protease inhibitor that has been shown to induce the endoplasmic reticulum (ER) stress reaction in human cancer cells. Although the presumed drug doses needed for an efficient ER stress reaction and ensuing apoptosis in cancer cells is somewhat higher than those prescribed for HIV-infected persons, nelfinavir represents one of the few clinically applicable ER stress-inducing agents, and is currently being tested in clinical studies on cancer patients. Therefore, this chapter describes how to obtain and use nelfinavir for in vitro and in vivo studies. In addition, methods are described that might facilitate the analysis and monitoring of the nelfinavir-induced ER stress response either in cancer cells in cell culture or in cancer tissue biopsies. These methods include various fluorescence-based ER staining techniques and the expression analysis of primary and secondary ER stress markers by immunoblotting and RT-PCR analysis. Among the several methods presented, the analysis of an unconventional XBP1 splicing, caused by the ER stress sensor IRE1, is shown to present the most sensitive and most specific marker for nelfinavir induced ER stress. Primers and PCR conditions suitable for XBP1 PCR and splicing analysis are presented. Such a PCR-based XBP1 splicing analysis might not only be suitable to monitor nelfinavir-induced ER stress, but could also be applied in drug screening programs to test for other ER stress-inducing agents with similar activities or synergistic activities with nelfinavir. PMID- 21329800 TI - Glycoprotein maturation and the UPR. AB - Glycosylation is a complex form of protein modification occurring in the secretory pathway. The addition of N- and O-glycans affects intracellular processes like the folding and trafficking of most glycoproteins. To better understand the impact of glycosylation in protein folding and maturation, parameters like glycosylation site occupancy and oligosaccharide structure must be measured quantitatively. In this chapter, we describe current methods enabling the determination of N-glycosylation by assessment of cellular dolichol phosphate levels, dolichol-linked oligosaccharides, and the occupancy of N-glycosylation sites. We also provide detailed methods for the analysis of O-glycosylation, whose role in intracellular protein maturation is often overlooked. PMID- 21329799 TI - Using temporal genetic switches to synchronize the unfolded protein response in cell populations in vivo. AB - In recent years, recognition of the importance of protein aggregation in human diseases has increasingly come to the fore and it is clear that many degenerative disorders involve activation of a metabolic signaling cascade known as the unfolded protein response (UPR). The UPR encompasses conserved mechanisms in cells to monitor and react to changes in metabolic flux through the secretory pathway. Such changes reflect an imbalance in cell homeostasis and the UPR integrates several signaling cascades to restore homeostasis. As such, the UPR is simply interpreted as a protection mechanism for cells as they perform their normal functions. A number of groups have suggested that the UPR also can eliminate cells in which homeostasis is lost, for example, during disease. This notion has kindled the rather paradoxical concept that inhibiting the UPR will ameliorate degenerative disease. However, several in vivo studies in the nervous system indicate that curtailing UPR function either exacerbates disease or may reduce severity through unexpected or unidentified pathways. Perhaps the notion that the UPR protects cells or eliminates them stems from widespread use of suboptimal paradigms to characterize the UPR; thus, too little is currently known about this homeostatic pathway. Herein, I describe the development of genetic switch technology (GST) to generate a novel model for studying UPR diseases. The model is geared toward obtaining high resolution in vivo detail for oligodendrocytes of the central nervous system, but it can be adapted to study other cell types and other UPR diseases. PMID- 21329802 TI - A screen for mutants requiring activation of the unfolded protein response for viability. AB - The unfolded protein response (UPR) is an intracellular signal transduction pathway that monitors endoplasmic reticulum (ER) homeostasis. Activation of the UPR is required to alleviate the effects of ER stress. However, our understanding of what physiologically constitutes ER stress or disequilibrium is incomplete. The current view suggests that stress manifests as the functional capacity of the ER becomes limiting. To uncover the range of functions under the purview of the UPR, we previously devised a method to isolate mutants that (1) activate the UPR and (2) require UPR activation for viability. These mutants that represent functions, when compromised, cause specific forms of disequilibrium perceived by the UPR. Making UPR activation essential to these mutants ensures a stringent physiological link and avoids stimuli causing nonproductive UPR activation. Thus far, the screen has revealed that the range of functions monitored is surprisingly diverse. Beyond the importance of the screen to understand UPR physiology, it has proven to be useful in discovering new genes in many aspects of protein biosynthesis and quality control. PMID- 21329801 TI - Monitoring and manipulating mammalian unfolded protein response. AB - The unfolded protein response (UPR) is a conserved, intracellular signaling pathway activated by endoplasmic reticulum (ER) stress. In mammalian cells, the UPR is controlled by three ER-resident transmembrane proteins: inositol-requiring enyzme-1 (IRE1), PKR-like ER kinase (PERK), and activating transcription factor-6 (ATF6), by which cytoprotective mechanisms are initiated to restore ER functions. However, if cellular homeostasis is not restored by the UPR's initial events, UPR signaling triggers apoptotic cell death, which correlates with the pathogenesis of a wide range of human diseases. The intrinsic function of the UPR in regulating cell survival and death suggests its importance as a mechanistic link between ER stress and disease pathogenesis. Understanding UPR regulatory molecules or signaling pathways involved in disease pathogenesis is critical to establishing therapeutic strategies. For this purpose, several experimental tools have been developed to evaluate individual UPR components. In this chapter, we present methods to monitor and quantify activation of individual UPR signaling pathways in mammalian cells and tissues, and we review strategies to artificially and selectively activate individual UPR signaling pathways using chemical-genetic approaches. PMID- 21329803 TI - Signaling pathways of proteostasis network unraveled by proteomic approaches on the understanding of misfolded protein rescue. AB - Attempts to promote normal processing and function of F508del-CFTR, the most common mutant in cystic fibrosis (CF), have been described as potential therapeutic strategies in the management of this disease. Here we described the proteomic approaches, namely two-dimensional electrophoresis (2DE), mass spectrometry (MS), and bioinformatics tools used in our recent studies to gain insight into the proteins potentially involved in low-temperature or mutagenic treatment-induced rescue process of F508del-CFTR. The proteins identified are part of the proteostasis network, such as the unfolded protein response (UPR) signaling pathways that may regulate the processing of CF transmembrane conductance regulator (CFTR) through the folding and trafficking progression. The complete characterization of these signaling pathways and their regulators in CF will certainly contribute to the development of novel therapeutic strategies against CF. PMID- 21329805 TI - Measuring signaling by the unfolded protein response. AB - The unfolded protein response (UPR) is activated by accumulation of unfolded proteins in the endoplasmic reticulum (ER). The unfolded protein response is associated with many diseases, including cancer, metabolic diseases such as type II diabetes and fatty liver diseases, and neurodegenerative diseases, for example, Alzheimer's disease. The UPR is also activated by numerous toxic chemicals and modulates drug action. Therefore, the UPR becomes increasingly important in toxicological and pharmacological research. In mammals, the UPR is transduced through three parallel signaling pathways originating at the ER resident transmembrane protein kinase-endoribonucleases (RNase) IRE1, the protein kinase PERK, and a family of type II transmembrane transcription factors, whose most prominent member is ATF6alpha. We discuss methods to experimentally activate the UPR in the yeast Saccharomyces cerevisiae and in cultured mammalian cells. We summarize methods to monitor activation of the three arms of the UPR, while providing detailed protocols for select, reliable assays. To monitor activation of the IRE1 branch, a Northern blotting protocol to monitor splicing of HAC1 mRNA in yeast and a reverse transcriptase-PCR assay for processing of the IRE1 RNase substrate XBP1 in mammalian cells are presented. Activation of the IRE1 kinase activity can be assayed by immunoblotting for IRE1 autophosphorylation. Activation of the PERK branch is monitored via phosphorylation of the translation initiation factor eIF2alpha, induction of CHOP at the mRNA and protein level, and induction of ATF4 at the protein level. Activation of ATF6 is assayed in Western blots through the appearance of its processed 50 kDa soluble cytosolic fragment. We summarize reverse transcriptase-PCR protocols to measure activation of target genes selectively induced by the three branches of the UPR and histological assays for UPR activation in tissue sections. This repertoire of methods will enable the newcomer to the UPR field to comprehensively assess the activation status of the UPR. PMID- 21329804 TI - Decreased secretion and unfolded protein response upregulation. AB - Recombinant antibody fragments, for example, the classic monovalent single-chain antibody (scFv), are emerging as credible alternatives to monoclonal antibody (mAb) products. scFv fragments maintain a diverse range of potential applications in biotechnology and can be implemented as powerful therapeutic and diagnostic agents. As such, a variety of hosts have been used to produce antibody fragments resulting in varying degrees of success. Yeast, Saccharomyces cerevisiae, is an attractive host due to quality control mechanisms of the secretory pathway that ensure secreted proteins are properly folded. However, the expression of a recombinant protein in yeast is not trivial; neither are the quality control mechanisms the cell initiates to respond to overwhelming stress, such as an increased protein load, simplistic. The endoplasmic reticulum (ER) is a dynamic organelle, capable of sensing and adjusting its folding capacity in response to increased demand. When protein abundance or terminally misfolded proteins overwhelm the ER's capacity, the unfolded protein response (UPR) is activated. In the guidelines presented here, we discuss varying aspects of quality control, its modulation, and ways to design appropriate constructs for yeast recombinant protein expression. Furthermore, we have provided protocols and methods to monitor intracellular protein expression and trafficking as well as evaluation of the UPR, with essential controls. The latter part of this chapter will review considerations for the experimental design of microarray and quantitative polymerase chain reaction (q-PCR) techniques while suggesting appropriate means of data analysis. PMID- 21329806 TI - Quantitative measurement of events in the mammalian unfolded protein response. AB - When the homeostasis of endoplasmic reticulum (ER) is disturbed by the accumulation of unfolded or misfolded proteins, a series of signaling responses collectively called the unfolded protein response (UPR) is triggered. UPR transducers IRE1, PERK, ATF6, and UPR-responsive genes such as GRP78/BiP, ERAD genes such as EDEM, and synthesis of the protein N-linked glycosylation donor lipid-linked oligosaccharides (LLOs) are mobilized. This chapter provides methods used in our laboratory to quantitatively measure the accumulation of mRNAs encoding BiP and EDEM, splicing of XBP1, cleavage of ATF6, inhibition of protein synthesis by PERK, and extension of LLOs under control and stress conditions. PMID- 21329807 TI - Regulation of immunoglobulin synthesis, modification, and trafficking by the unfolded protein response a quantitative approach. AB - Plasma cells are professional secretory cells, which function as cellular factories for immunoglobulin synthesis and secretion. Being the sole cell type responsible for antibody secretion they play an essential role in the immune response against a broad spectrum of pathogens. Since plasma cells have a long life span and are able to secrete copious amounts of antibody, their number and repertoire should be tightly regulated. Disruption of their homeostasis may lead to severe diseases, such as immunodeficiency or multiple myeloma. Much of the complications of multiple myeloma are attributed to the antibodies themselves, which accumulate in the bloodstream and lead to kidney and pulmonary insufficiencies. Similar pathologies are common to other plasma cell-related diseases, such as AL amyloidosis and autoimmune diseases, in which Ig molecules accumulate to toxic levels without good means to curtail their production. The process of plasma cell differentiation and maintenance is poorly understood. The discovery that the IRE1/XBP-1 arm of the unfolded protein response (UPR) is necessary to yield full-fledged plasma cells in vivo was a breakthrough in the field. Over the years valuable biochemical information on plasma cell differentiation was obtained by exploring the downstream activities of XBP-1. The most pronounced phenotype of XBP-1 deficiency in plasma cells in vitro is the steep reduction in MU chain synthesis albeit similar levels of its mRNA. Remarkably, the defect is specific to Ig heavy chains as synthesis of other glycoproteins remains normal. Furthermore, when XBP-1 is absent or its mRNA splicing is inhibited the efficiency of protein translocation into the ER is severely impaired. Still, fundamental questions remain unanswered, such as what exactly generates the conditions of endoplasmic reticulum (ER) stress that activates the UPR in the developing plasma cells. Another enigma is how lipid biosynthesis and protein synthesis, both dramatically modulated during differentiation, are coordinated. In this chapter, we will provide detailed methodologies for measurements of Ig synthesis and misinsertion into the ER as readout of ER physiology in the course of plasma cell differentiation. PMID- 21329808 TI - Use of chemical genomics in assessment of the UPR. AB - Glucose deprivation, one of the major physiological conditions in solid tumor, leads to activation of the unfolded protein response (UPR) in cancer cells. The UPR occurs through the transcriptional and translational regulatory mechanisms that improve the capacity of the endoplasmic reticulum (ER) to fold and traffic proteins and allows the cell to survive under stress conditions. We previously reported that the macrocyclic compound versipelostatin and the antidiabetic biguanides metformin, buformin, and phenformin could inhibit the UPR during glucose deprivation as well as induce the UPR by treatment of cells with 2-deoxy d-glucose (2DG), a glycolysis inhibitor. Versipelostatin and biguanides show highly selective cytotoxicity to glucose-deprived tumor cells and exert in vivo antitumor activity; thus, these compounds would be interesting anticancer agent candidates. By microarray analysis, we demonstrated that cancer cells under glucose deprivation conditions caused activation of the UPR transcription program, which was suppressed broadly by versipelostatin and biguanides. We also identified the drug-driven gene signatures that can be used to discover pharmacologic UPR modulators. Indeed, we found several bioactive drugs, such as pyrvinium pamoate, valinomycin, and rottlerin, that selectively suppressed 2DG induced GRP78 promoter activity as versipelostatin and biguanide did. Together with growing bioinformatics databases and analytical tools, our approach could provide a chemical genomic basis for developing UPR-targeting drugs against solid tumors. PMID- 21329809 TI - Small GTPase signaling and the unfolded protein response. AB - The endoplasmic reticulum (ER), first compartment of the secretory pathway, is mainly involved in calcium sequestration and lipid biosynthesis and in the translation, folding, and transport of secretory proteins. Under some physiological and physiopathological situations, secretory proteins do not acquire their folded conformation and accumulate in the ER. An adaptive response named the UPR is then triggered from this compartment to restore its homeostasis. In the past few years, interconnections between the UPR and small GTPase signaling have been established. In an attempt to further investigate these novel signaling networks, we hereby provide a detailed description of experimental strategies available. We describe in detail methods to monitor both UPR and small GTPase signaling and the outcomes of such approaches in the identification of new links between those signaling pathways using pharmacological and genetic screens. In physiopathological contexts, the guidelines herein should enable researchers in the field to establish essential means for determination of functional interactions between those pathways. PMID- 21329810 TI - Inhibitors of advanced glycation and endoplasmic reticulum stress. AB - Advanced glycation is one of the major pathophysiological posttranslational modifications. Under hyperglycemic conditions or oxidative stress, proteins and DNA are nonenzymatically modified by oxidative glycation and converted to advanced glycation endproducts (AGEs), which induce the loss of protein functions or apoptosis. This conversion to AGEs leads to the disease progression of hyperglycemia- or oxidative stress-related diseases, such as diabetic mellitus and its complications, neurodegenerative disease, atherosclerosis, and kidney disease. Further, recent evidence indicates that advanced glycation is initiated not only by oxidative stress but also by hypoxia, suggesting its pathogenesis across a wide range of diseases associated with aberrant oxygen tension as well as glucose metabolism. In addition to their role in triggering advanced glycation, these disturbances are also well known as initiators of endoplasmic reticulum (ER) stress, and of the consequent unfolded protein response (UPR). These findings strongly indicate the presence of cross talk between advanced glycation and ER stress in disease progression. In this chapter, I focus on the link between advanced glycation and ER stress, and the potential use of inhibitors of AGE formation as modulators of ER stress. PMID- 21329811 TI - Effectiveness of laser in dentinal hypersensitivity treatment: a systematic review. AB - INTRODUCTION: The effectiveness of laser treatment in reducing dentinal hypersensitivity (DH) is controversial, with important concerns related to the high efficacy of placebo laser. The purpose of this systematic review was to identify and evaluate literature regarding the effectiveness of laser therapy compared with placebo laser therapy. The secondary aim was to survey the literature regarding laser treatment safety. METHODS: An exhaustive literature search with strict inclusion and exclusion criteria was performed with electronic databases and by hand. The goal was to identify all randomized, placebo controlled clinical trials that have assessed the effectiveness of DH reduction compared with placebo laser. RESULTS: Only 3 randomized clinical trials were retrieved. These studies supported that laser treatment could reduce DH, but the reduction was not significant compared with placebo laser treatment. No side effects, adverse reactions, or pulp damage were reported at the energy and power settings used. CONCLUSIONS: Laser therapy can reduce DH-related pain, but the evidence for its effectiveness is weak, and the possibility of a placebo effect must be considered. PMID- 21329812 TI - In vivo antimicrobial effects of endodontic treatment procedures as assessed by molecular microbiologic techniques. AB - INTRODUCTION: This culture-independent molecular microbiology study evaluated the antimicrobial effects of chemomechanical preparation supplemented by intracanal medication during treatment of teeth with apical periodontitis. METHODS: Samples were taken from 24 necrotic root canals at the baseline (S1), after chemomechanical preparation by using 2.5% NaOCl as the irrigant (S2), and after a 7-day interappointment medication with calcium hydroxide paste in either glycerin (CHG) or camphorated paramonochlorophenol/glycerin (CHPG) (S3). Bacterial, archaeal, and fungal presence was evaluated by polymerase chain reaction (PCR), and bacterial identifications were performed by a closed-ended reverse-capture checkerboard approach targeting 28 candidate endodontic pathogens. RESULTS: All S1 samples were positive for bacteria but negative for both archaea and fungi. Treatment procedures were highly effective in reducing the bacterial levels and number of taxa. Overall, 46% of S2 samples and 62.5% of S3 samples were PCR negative for bacteria. Specifically, S2 and S3 samples yielded negative PCR results in 50% and 58% of the canals in the CHG group and in 42% and 67% of the canals in the CHPG group, respectively. Except for comparisons with S1 samples, no other statistically significant differences were observed for intragroup and intergroup comparisons involving S2 and S3. Several taxa were still found in S2 and S3 samples, and the most prevalent were Propionibacterium acnes and Streptococcus species. CONCLUSIONS: Bacterial levels and number of taxa were substantially reduced after chemomechanical preparation and intracanal medication. However, presence of detectable levels of persisting bacteria in many cases indicates that the search for more effective antimicrobial treatment strategies should be stimulated. PMID- 21329813 TI - Proximity of the mandibular canal to the tooth apex. AB - INTRODUCTION: Knowledge of the inferior alveolar nerve (IAN) position is important in avoiding nerve damage during invasive dental procedures. Because the exact position of the nerve bundle can vary in patients, this study evaluated the distance from the apices of mandibular premolar and molar teeth to the superior border of the mandibular canal. METHODS: Cone-beam computed tomography (CBCT) scans from 139 patients were analyzed to evaluate the proximity of the mandibular canal to the root apices of 743 mandibular second premolar and first and second molar teeth. Subjects were subgrouped by age and sex. A random intercept model was used to account for multiple measurements within a patient. RESULTS: In all groups, root apices of the mandibular second molars were closer to the mandibular canal than other teeth. The mesial root of the second molar was closer to the nerve in female patients compared with male patients. Root apices in younger patients (<18 years) were generally closer to the mandibular canal than in older patients. CONCLUSIONS: The CBCT scan is an accurate, noninvasive method to evaluate the position of the mandibular canal. The variable position of this structure between patients suggests the need for CBCT to determine the proximity of the nerve bundle before attempting invasive treatment in this area. Dental practitioners should consider potential differences of mandibular canal position as a result of age and gender when performing these procedures in this area. PMID- 21329814 TI - Outcomes of endodontic micro-resurgery: a prospective clinical study. AB - INTRODUCTION: This study examined the outcomes of endodontic resurgery by using current microsurgery techniques on failed teeth with previous endodontic surgery. Another goal was to determine any significant outcome predictors of endodontic surgery by determining the causes of failure in the first endodontic surgery. METHODS: The data were collected from patients in the Department of Conservative Dentistry at the Dental College, Yonsei University in Seoul, Korea between March 2001 and May 2009. All 54 teeth that required surgical retreatment were included in this study. All surgical procedures were performed by using an operating microscope and biocompatible root-end filling materials such as mineral trioxide aggregate (MTA) or Super EBA. The patients were recalled every 6 months for 2 years and every year thereafter to assess the clinical and radiographic signs of healing. RESULTS: The recall rate was 77.8% (42 of 54 patients). Of the 42 cases recalled, 39 cases were included in the success category, giving an overall success rate of 92.9%. The most common possible causes of failure were no root end filling and incorrect root-end preparation. CONCLUSIONS: The use of microsurgical techniques and biocompatible materials such as MTA and Super-EBA resulted in a high clinical success rate, even in endodontic resurgery. PMID- 21329815 TI - Cost-effectiveness of endodontic molar retreatment compared with fixed partial dentures and single-tooth implant alternatives. AB - INTRODUCTION: One of the most challenging situations in dentistry is a failed root canal treatment case. Should a failed root canal-treated tooth be retreated nonsurgically or surgically, or should the tooth be extracted and replaced with an implant-supported restoration or fixed partial denture? These four treatment alternatives were compared from the perspective of cost-effectiveness on the basis of the current best available evidence. METHODS: The costs of the four major treatment modalities were calculated using the national fee averages from the 2009 American Dental Association survey of dental fees. The outcome data of all treatment modalities were retrieved from meta-analyses after electronic and manual searches were undertaken in the database from MEDLINE, Cochrane, ISI Web of Knowledge, and Scopus up to April 2010. The treatment strategy model was built and run with TreeAge decision analysis software (TreeAge Software, Inc, Williamstown, MA). RESULTS: Endodontic microsurgery was the most cost-effective approach followed by nonsurgical retreatment and crown, then extraction and fixed partial denture, and finally extraction and single implant-supported restoration. CONCLUSIONS: The cost-effectiveness analysis showed that endodontic microsurgery was the most cost-effective among all the treatment modalities for a failed endodontically treated first molar. A single implant-supported restoration, despite its high survival rate, was shown to be the least cost-effective treatment option based on current fees. PMID- 21329816 TI - Endodontic outcome predictors identified with periapical radiographs and cone beam computed tomography scans. AB - INTRODUCTION: The outcome predictors identified with data from periapical radiographs (PA) and cone-beam computed tomography (CBCT) scans might not be the same. This retrospective study evaluated various factors that might affect the outcome of root canal therapy. METHODS: In total, 115 teeth (143 roots) with vital pulps were endodontically treated and followed up 2 years after treatment. Multivariate logistic regression was performed on the data from PA or CBCT to analyze outcome predictors. RESULTS: At recall, PA detected periapical lesions in 18 roots (12.6%), as compared with 37 on CBCT images (25.9%). The length and density of root filling determined by PA and CBCT were often different (p < .001). Overall, 20 of the 25 short root fillings (80%) diagnosed by PA appeared as flush fillings on CBCT images. PA revealed 23 root fillings (16.1%) with voids, as compared with 66 on CBCT images (46.2%). When findings from PA were analyzed, density and apical extent of root filling were identified as predictors (p < .05). When findings from CBCT were analyzed, density of root filling and quality of coronal restoration influenced the outcome significantly (p <= .001), whereas gender, tooth type, root curvature, number of visits, CBCT-determined apical extent of root filling, and use as abutment did not (p > .1). CONCLUSIONS: Treatment outcome, length and density of root fillings, and outcome predictors as determined with CBCT scans might not be the same as corresponding values determined with PA. PMID- 21329817 TI - ADAM28 manipulates proliferation, differentiation, and apoptosis of human dental pulp stem cells. AB - INTRODUCTION: The purpose of this study was to investigate the influence of a disintegrin and metalloproteinase 28 (ADAM28) on the proliferation, differentiation, and apoptosis of human dental pulp stem cells (HDPSCs) and possible mechanism. METHODS: After ADAM28 eukaryotic plasmid and antisense oligodeoxynucleotides (AS-ODNs) were constructed and respectively transfected into HDPSCs by Lipofectamine 2000, the ADAM28 expression levels among diverse groups were estimated by reverse transcription polymerase chain reaction (RT-PCR) and western blotting. Methabenzthiazuron (MTT) and cell cycle assays were used to test the HDPSCs proliferation activity. Annexin V- fluorescein isothiocyanate (FITC)/propidium iodide and alkaline phosphatase analysis were performed respectively to measure apoptosis and the cytodifferentiation level. Immunocytochemistry and western blotting were performed to determine the effects of ADAM28 eukaryotic plasmid on HDPSCs expressing dentin sialophosphoprotein (DSPP), dentin matrix protein 1, and bone sialoprotein. RESULTS: ADAM28 could be correctly transcribed, translated, and expressed in HDPSCs. The ADAM28 AS-ODN group displayed the highest optical density value, whereas the eukaryotic plasmid group showed the lowest, which suggested that ADAM28 had a negative regulatory effect on the proliferation of HDPSCs. ADAM28 eukaryotic plasmid could significantly inhibit the HDPSC proliferation, promote specific differentiation of HDPSCs, induce apoptosis, and enhance the DSPP expression, whereas ADAM28 AS ODN produced the opposite effects. CONCLUSIONS: Our results proved that ADAM28 might actively participate in manipulating the proliferation, differentiation, and apoptosis of HDPSCs. PMID- 21329818 TI - Spatiotemporal expression of sclerostin in odontoblasts during embryonic mouse tooth morphogenesis. AB - INTRODUCTION: Sclerostin is the product of the SOST gene. Loss-of-function mutations in the SOST gene result in a high bone mass phenotype, thus confirming that sclerostin is a negative regulator of bone mass. SOST knockdown in humans also causes oral and dental malformations. However, the relationship between sclerostin and tooth development is unclear. METHODS: Using immunohistochemical techniques, we investigated sclerostin expression during fetal mouse tooth development and adult mouse tooth morphogenesis. RESULTS: Sclerostin was expressed in the secretory odontoblasts located along the ameloblasts of fetal mouse tooth germ and adult incisor. Sclerostin expression was also observed in the fetal and adult osteocytes in the jaw bone. CONCLUSION: These results suggest that sclerostin, one of the important regulatory factors of differentiated odontoblast function, may usable in vital pulp therapy. PMID- 21329819 TI - Role of polymorphonuclear neutrophils in the clearance of Enterococcus faecalis derived from saliva and infected root canals. AB - OBJECTIVES: The goal of this study was to measure (1) the ability of polymorphonuclear neutrophil leukocytes (PMNs) to kill oral Enterococcus faecalis strains, (2) up-regulation of inflammatory mediators by PMNs in interaction with E. faecalis, and (3) the ability of E. faecalis to cause inflammation in mouse muscle tissue. METHODS: Fifteen endodontic and nine saliva strains of E. faecalis were isolated and identified by specific 16S ribosomal RNA (16S rRNA) primers. The bacteria were grown in BHI broth and incubated with mouse PMN in appropriate media to determine the ability of the PMNs to kill the bacteria. In other experiments up-regulation of interleukin (IL)-1alpha, tumor necrosis factor alpha (TNF-alpha), matrix metalloproteinase-8 (MMP-8), and cyclooxygenase (COX)-2 messenger RNA in the PMNs was measured after exposure of the leukocytes to the bacteria using real-time polymerase chain reaction. Finally, the inflammatory potential of and PMN response to E. faecalis suspension in mouse muscle tissue was examined from histological sections using hematoxylin-eosin staining and immunostaining. RESULTS: Murine PMNs killed about 80% of the E. faecalis cells in 1 hour, irrespective of the source of isolation of the strains. Quantitative PCR results showed that IL-1alpha, TNF-alpha, MMP-8, and COX-2 messenger RNA were markedly up-regulated in E. faecalis-stimulated PMNs or in E. faecalis-invaded muscular tissues. MMP-8 messenger RNA level was positively related to COX-2 messenger RNA level. Histological evaluation and immunostaining disclosed that all E. faecalis strains could recruit PMNs to the local infectious sites and cause abscess formation. CONCLUSION: E. faecalis strains from saliva and infected root canals have the potential to recruit PMNs in the infectious sites leading to inflammation via up-regulation of PMN IL-1alpha, TNF-alpha, MMP-8, and COX-2. PMNs can play an important role in killing of E. faecalis. PMID- 21329820 TI - Vasodilatory effect of hydroxyethyl methacrylate and triethylene glycol dimethacrylate in rat aorta through calcium antagonistic action. AB - INTRODUCTION: Resin-based dental materials contain various diluent monomers that can interfere with vascular function by causing vasodilation. In this study, we evaluated the vasoactive potential of hydroxyethyl methacrylate (HEMA) and triethylene glycol dimethacrylate (TEGDMA) and the possible mechanism of their vascular action on isolated rat aorta. METHODS: Responses of thoracic aorta rings were recorded isometrically by using force displacement transducers. After precontracting aorta rings with phenylephrine, relaxations to HEMA and TEGDMA were recorded in the absence and presence of nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester, cyclooxygenase inhibitor indomethacin, and K(+) channel inhibitors tetraethylammonium, glibenclamide, and 4 aminopyridine. To investigate the Ca(2+)-channel antagonistic effect of HEMA and TEGDMA in different aorta rings, concentration-response curves to CaCl(2) were obtained in the absence and presence of the test monomers. RESULTS: Both HEMA and TEGDMA elicited concentration-dependent relaxations. The vasorelaxant effect of HEMA and TEGDMA was not mediated via endothelium-dependent nitric oxide and prostanoid-dependent mechanisms or by K(+) efflux through K(+) channels. Both monomers significantly inhibited the contractions induced by CaCl(2). CONCLUSIONS: Our results showed that HEMA and TEGDMA induce vasodilation via Ca(2+)-antagonistic action, whereas nitric oxide and cyclooxgenase pathway and K(+) channels were not responsible for this vasoactive effect.